PMID- 25493688 TI - Retrospective study of epidural blood patch use for spontaneous intracranial hypotension. AB - BACKGROUND AND OBJECTIVES: Spontaneous intracranial hypotension (SIH) is characterized by a severe and disabling headache that is usually orthostatic in nature. Cisternography is a useful diagnostic test for evaluating the presence and location of cerebrospinal fluid (CSF) leakage, and a targeted epidural blood patch (EBP) based on the cisternography findings is a very effective treatment modality for SIH. However, the effects of EBPs are not predictable, making repeat EBPs essential in some cases. The aim of the present study was to find the relationship between the EBP response and cisternographic findings, hypothesizing that the number of required EBPs would increase with an increased number of CSF leakage levels as determined by radionuclide cisternography. METHODS: All patients who underwent an EBP and had been discharged with significant improvements in symptoms of SIH during 2006 to 2011 were enrolled. Patients who had no radionuclide cisternographic results were excluded. The demographic variables, number of EBPs, cisternographic findings (location, bilaterality, and number of leakage sites), and preprocedural and postprocedural pain scores were reviewed. RESULTS: There was no correlation found between the cisternographic findings and the number of EBPs. Only the preprocedural pain scores showed a statistically significant correlation with the number of EBPs. CONCLUSIONS: Our study suggests that the response to the EBP is related to the severity of symptoms but not to the number and locations of cisternographic CSF leakages. PMID- 25493689 TI - Lumbar Neuraxial Ultrasound for Spinal and Epidural Anesthesia: A Systematic Review and Meta-Analysis. AB - BACKGROUND: This systematic review examines the evidence for preprocedural neuraxial ultrasound as an adjunct to lumbar spinal and epidural anesthesia in adults. METHODS: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases from inception to June 30, 2014, for randomized controlled trials (RCTs) and cohort studies that reported data answering one or more of the following 3 questions: (1) Does ultrasound accurately identify a given lumbar intervertebral space? (2) Does ultrasound accurately predict the needle insertion depth required to reach the epidural or intrathecal space? (3) Does ultrasound improve the efficacy and safety of spinal or lumbar epidural anesthesia? RESULTS: Thirty-one clinical trials and 1 meta-analysis were included in this review. Data from 8 studies indicate that neuraxial ultrasound can identify a given lumbar intervertebral space more accurately than by landmark palpation alone. Thirteen studies reported an excellent correlation between ultrasound-measured depth and needle insertion depth to the epidural or intrathecal space. The mean difference between the 2 measurements was within 3 mm in most studies. Thirteen RCTs, 5 cohort studies, and 1 meta-analysis reported data on efficacy and safety outcomes. Results consistently showed that ultrasound resulted in increased success and ease of performance. Ultrasound seemed to reduce the risk of traumatic procedures but there was otherwise insufficient evidence to conclude if it significantly improves safety. CONCLUSIONS: There is significant evidence supporting the role of neuraxial ultrasound in improving the precision and efficacy of neuraxial anesthetic techniques. WHAT'S NEW: We know that neuraxial ultrasound is a useful complement to clinical examination when performing lumbar central neuraxial blocks. It provides anatomical information including the depth of the epidural space, the identity of a given intervertebral level, and the location of the midline and interspinous/interlaminar spaces. This information can be used to successfully guide subsequent needle insertion.Since 2010, new data from RCTs and 1 meta-analysis suggest that neuraxial ultrasound increases the success and reduces the technical difficulty of lumbar central neuraxial blocks. Findings from the meta-analysis suggest that neuraxial ultrasound reduces the risk of traumatic procedures, and thus may possibly contribute to the safety of lumbar central neuraxial blocks. PMID- 25493690 TI - Oxygen therapy for lower respiratory tract infections in children between 3 months and 15 years of age. AB - BACKGROUND: Treatment for lower respiratory tract infections (LRTIs) includes administering complementary oxygen. The effectiveness of oxygen therapy and of different delivery methods remains uncertain. OBJECTIVES: To determine the effectiveness and safety of oxygen therapy and oxygen delivery methods in the treatment of LRTIs and to define the indications for oxygen therapy in children with LRTIs. SEARCH METHODS: For this update, we searched CENTRAL, MEDLINE, EMBASE and LILACS from March 2008 to October 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) or non-RCTs comparing oxygen versus no oxygen therapy or different methods of oxygen delivery in children with LRTI aged from three months to 15 years. To determine the indications for oxygen therapy, we included observational studies or diagnostic test accuracy studies. DATA COLLECTION AND ANALYSIS: Three review authors independently scanned the search results to identify studies for inclusion. Two authors independently performed the methodological assessment and the third author resolved any disagreements. We calculated risk ratios (RRs) and their 95% confidence intervals (CIs) for dichotomous outcomes and adverse events (AEs). We performed fixed-effect meta analyses for the estimation of pooled effects whenever there was no heterogeneity between included RCTs. We summarised the results reported in the included observational studies for the clinical indicators of hypoxaemia. MAIN RESULTS: In this review update, we included four studies (479 participants) assessing the efficacy of non-invasive delivery methods for the treatment of LRTI in children and 14 observational studies assessing the clinical sign indicators of hypoxaemia in children with LRTIs.Three RCTs (399 participants) compared the effectiveness of nasal prongs or nasal cannula with nasopharyngeal catheter; one non-RCT (80 participants) compared head box, face mask, nasopharyngeal catheter and nasal cannula. The nasopharyngeal catheter was the control group. Treatment failure was defined as number of children failing to achieve adequate arterial oxygen saturation. All included studies had a high risk of bias because of allocation methods and lack of blinded outcome assessment.For nasal prongs versus nasopharyngeal catheter, the pooled effect estimate for RCTs showed a worrying trend towards no difference between the groups (two RCTs; 239 participants; RR 0.93, 95% CI 0.36 to 2.38). Similar results were shown in the one non-RCT (RR 1.0, 95% CI 0.44 to 2.27). The overall quality of this evidence is very low. Nasal obstruction due to severe mucus production was different between treatment groups (three RCTs, 338 participants; RR 0.20, 95% CI 0.09 to 0.44; I(2) statistic = 0%). The quality of this evidence is low.The use of a face mask showed a statistically significant lower risk of failure to achieve arterial oxygen > 60 mmHg than the nasopharyngeal catheter (one non-RCT; 80 participants; odds ratio (OR) 0.20, 95% CI 0.05 to 0.88).The use of a head box showed a non statistically significant trend towards a reduced risk of treatment failure compared to the nasopharyngeal catheter (one non-RCT; OR 0.40, 95% CI 0.13 to 1.12). The quality of this evidence is very low.To determine the presence of hypoxaemia in children presenting with LRTI, we assessed the sensitivity and specificity of nine clinical signs reported by the included observational studies and used this information to calculate likelihood ratios. The results showed that there is no single clinical sign or symptom that accurately identifies hypoxaemia. AUTHORS' CONCLUSIONS: It appears that oxygen therapy given early in the course of pneumonia via nasal prongs at a flow rate of 1 to 2 L/min does not prevent children with severe pneumonia from developing hypoxaemia. However, the applicability of this evidence is limited as it comes from a small pilot trial.Nasal prongs and nasopharyngeal catheter are similar in effectiveness when used for children with LRTI. Nasal prongs are associated with fewer nasal obstruction problems. The use of a face mask and head box has been poorly studied and it is not superior to a nasopharyngeal catheter in terms of effectiveness or safety in children with LRTI.Studies assessing the effectiveness of oxygen therapy and oxygen delivery methods in children with different baseline risks are needed.There is no single clinical sign or symptom that accurately identifies hypoxaemia in children with LRTI. The summary of results presented here can help clinicians to identify children with more severe conditions.This review is limited by the small number of trials assessing oxygen therapy and oxygen delivery methods as part of LRTI treatment. There is insufficient evidence to determine which non-invasive delivery methods should be used in children with LRTI and low levels of oxygen in their blood. PMID- 25493691 TI - IL-17A expression in HIV-specific CD8 T cells is regulated by IL-4/IL-13 following HIV-1 prime-boost immunization. AB - Although Th1 and Th2 cytokines can inhibit interleukin (IL)-17-secreting T cells, how these cells are regulated under different infectious conditions is still debated. Our previous studies have shown that vaccination of IL-4 and IL-13 gene knockout (KO) mice can induce high-avidity HIV K(d)Gag197-205-specific CD8 T cells with better protective efficacy. In this study, when IL-13, IL-4, STAT6 KO, and wild-type BALB/c mice were prime-boost immunized with an HIV poxviral modality, elevated numbers of IL-17A(+) splenic K(d)Gag197-205-specific CD8 T cells were observed in all the KO mice compared with the wt BALB/c control. Similarly, when wt BALB/c mice were immunized with IL-13Ralpha2-adjuvanted HIV vaccines (that transiently inhibited IL-13 activity and induced high-avidity CD8 T cells with enhanced protective efficacy), elevated IL-17A(+) K(d)Gag197-205 specific CD8 T cells were detected both in the lung and the spleen. However, at the transcriptional level, elevated TGF-beta, IL-6, ROR-gammat, and IL-17A mRNA copy numbers were mainly detected in IL-4 KO, but not the IL-13 KO mice. These data suggested that TGF-beta, IL-6, ROR-gammat, but not IL-23a, played a role in IL-17A regulation in K(d)Gag197-205-specific CD8 T cells. Collectively, our findings suggest that IL-4 and IL-13 differentially regulate the expression of IL 17A in K(d)Gag197-205-specific CD8 T cells at the transcriptional and translational level, respectively, implicating IL-17A as an indirect modulator of CD8 T cell avidity and protective immunity. PMID- 25493696 TI - Speedy eye movements in multiple sclerosis: association with performance on visual and nonvisual cognitive tests. AB - OBJECTIVE: Eye movement difficulties in multiple sclerosis (MS) are common and may influence performance on cognitive tests. The following studies examined associations between a new measure of speedy eye movement speed and visual/nonvisual cognitive tests. METHOD: In Experiment 1, MS patients (N = 71) were administered cognitive tests and the Speedy Eyes Test (SET) as a measure of purposeful speedy eye movements under timed conditions. Experiment 2 was composed of MS patients (n = 60) and a neurologically healthy comparison group (n = 31) and examined group differences in an abbreviated version of the SET. RESULTS: In both studies, slower eye movements were significantly associated with poorer performance on cognitive tests with a large effect size in Experiment 1 and a medium effect size in Experiment 2. Analyses in Experiment 2 also revealed significant group differences in an abbreviated measure of the SET, where MS patients had slower eye movements than the comparison group. CONCLUSIONS: Pending further research, the SET, a brief, inexpensive, and nontechnical measure of speedy eye movement, may serve as a visual/oculomotor indicator of cognitive impairment in multiple sclerosis. PMID- 25493697 TI - Resampling-based similarity measures for high-dimensional data. AB - An important issue in classification is the assessment of sample similarity. This is nontrivial in high-dimensional or megavariate datasets--datasets that are comprised of simultaneous measurements on thousands of features, many of which carry little or no information regarding consistent sample differences. Conventional similarity measures do not work particularly well for such data. As an alternative, we propose a distance measure that is based on a refiltering process: at each step of the process a random subset of features is selected and a cluster analysis is performed using only this subset; the relative frequency with which a pair of samples clusters together across several such random subsets forms the similarity measure. The features chosen at any step may be completely random or enriched by awarding the more informative features a higher chance of selection; this enrichment turns out to be particularly effective. We use actual datasets from the burgeoning genomics literature to demonstrate the superior performance of this similarity measure, especially the enriched form of the similarity measure, compared to more conventional measures such as Euclidean distance or correlation, or, if the data are categorical, Hamming distance. PMID- 25493698 TI - Multidrug-resistant tuberculosis: Treatment and outcomes of 93 patients. AB - BACKGROUND: Tuberculosis (TB) remains a leading cause of death worldwide and the emergence of multidrug-resistant TB (MDR TB) poses a threat to its control. There is scanty evidence regarding optimal management of MDR TB. The majority of Canadian cases of MDR TB are diagnosed in Ontario; most are managed by the Tuberculosis Service at West Park Healthcare Centre in Toronto. The authors reviewed 93 cases of MDR TB admitted from January 1, 2000 to December 31, 2011. RESULTS: Eighty-nine patients were foreign born. Fifty-six percent had a previous diagnosis of TB and most (70%) had only pulmonary involvement. Symptoms included productive cough, weight loss, fever and malaise. The average length of inpatient stay was 126 days. All patients had a peripherally inserted central catheter for the intensive treatment phase because medications were given intravenously. Treatment lasted for 24 months after bacteriologic conversion, and included a mean (+/- SD) of 5 +/- 1 drugs. A successful outcome at the end of treatment was observed in 84% of patients. Bacteriological conversion was achieved in 98% of patients with initial positive sputum cultures; conversion occurred by four months in 91%. CONCLUSIONS: MDR TB can be controlled with the available anti-TB drugs. PMID- 25493699 TI - Pulmonary hemorrhage in cryoglobulinemia. AB - Pulmonary manifestations of cryoglobulinemia are uncommon and their clinical behaviour is unpredictable, ranging from mild dyspnea to life-threatening presentations. A patient with cryoglobulinemia who presented with hypoxic respiratory failure attributed to pulmonary hemorrhage is reported. PMID- 25493700 TI - Self-report vs. kinematic screening test: prevalence, demographics, and sports biography of yips-affected golfers. AB - The yips is considered a task-specific movement disorder. Its estimated prevalence, however, is high compared to similar neurological movement disorders, possibly resulting from previous studies' restriction of samples based on skill level, and self-report bias. Alternatively, this high prevalence might be an indication of additional aetiologies, for example the influence of previously played racket sports. We estimated the prevalence of the putting yips across the skill range, using self-reports in one study and a screening test in a second study. We explored if previously played sports matter for the development of the yips. In study 1, yips prevalence (N = 1,306) and golfers' sports biographies (n = 264) were examined via two online surveys, in which golfers indicated if they were yips-affected. In study 2, golfers (N = 186) putted in a standardised putting test while kinematic and performance measures were recorded. Prevalence was estimated via a kinematic threshold. Sports biographies (n = 119) were obtained via an online survey. Prevalence of currently yips-affected golfers was 22.4% in study 1 and 16.7% in study 2. In both studies, more yips-affected than unaffected golfers had experience in playing racket sports. Yips prevalence remained higher than previously estimated prevalence of other movement disorders but decreased when the whole skill range including professionals and novices was considered. Future studies should use the kinematic screening test instead of self-reports to detect the yips and further investigate the influence of previously played racket sports. PMID- 25493701 TI - Postencephalitic bilateral heterotopic ossification of the hip in a pediatric patient. AB - Heterotrophic ossification has been defined as abnormal formation of mature lamellar bone in soft tissues. Neurogenic heterotopic ossification has been well described in adults. However, it is uncommon in the pediatric population, where it has been noted to recede in some cases. There are very few reports of postmeningitis bilateral involvement of the hip. We describe a case of bilateral heterotopic ossification of hip in a 13-year-old female. The patient had a history of encephalitis, prolonged vegetative state, and intubation for 6 weeks. The patient had fixed deformities of both hips in 30 degrees of flexion and 30 degrees of external rotation. A diagnosis of Brooker stage 4 heterotopic ossification was made. The patient underwent a staged procedure for excision of the heterotopic mass. Postoperatively, the patient was administered radiotherapy and indomethacin for 6 weeks. At the 2-year follow-up, there was no recurrence and both the hips were mobile with full range of motion. The patient was satisfied with the result. The incidence of heterotopic ossification is less than that observed in the adult population and alkaline phosphatase levels are not significantly elevated unlike in adults. To our knowledge, there is no reported case of postencephalitic bilateral anterior heterotopic ossification of the hip in a pediatric patient treated with excision successfully. Postencephalitic heterotopic ossification in children is an uncommon condition. This condition can be treated successfully with surgical excision, combined postoperative protocol of radiotherapy, indomethacin, and immediate postoperative mobilization of the joint. PMID- 25493702 TI - Beals-Hecht syndrome (congenital contractural arachnodactyly) with additional craniospinal abnormality: a case report. AB - Beals syndrome is an autosomal-dominant connective tissue disorder, characterized by multiple flexion contractures, arachnodactyly, severe kyphoscoliosis, crumpled ear, and muscular hypoplasia. It has similarities to Marfan syndrome (MFS) in many respects. It has much fewer incidences of eye and heart anomalies compared with MFS. Beals syndrome is caused by a mutation in the fibrillin-2 gene (FBN2) in 5q23; MFS is caused by mutations in fibrillin-1. With time, there is spontaneous improvement in joint contractures, but kyphosis tends to be progressive. The neonatal form results from new mutations and tends to be severe. Prenatal molecular diagnosis is possible. Ultrasound could be used to demonstrate hypokinesia and joint contractures in presumptive cases. We present a case of a patient with Beals syndrome who presented to the emergency department with pneumonia and was found to have narrowing of the foramen magnum, with partial fusion of C2-C3 vertebral bodies. To our knowledge, this has not been documented in the literature and could be characteristic in relation to Beals syndrome. PMID- 25493703 TI - Flexor digitorum accessorius longus muscle in resistant clubfoot patients: introduction of a new sign predicting its presence. AB - Clubfoot, talipes equino varus (TEV), is a common congenital foot anomaly. Some cases are resistant to conservative treatment. Many causes of resistance have been reported, among these, the presence of anomalous muscles; however, the effect of the presence of anomalous muscles on the outcome of conservative management is not well studied. These aberrant muscles are discovered during the extensive surgical release as an abnormal finding. The aim of this work is to study the demographic characteristics of patients with resistant TEV that necessitated extensive soft tissue release at Sudan Clubfoot Clinic and to document the prevalence of flexor digitorum accessorius longus (FDAL) muscle in a large series of clubfoot patients treated by extensive surgery: posteromedial release. Also, we introduce a new observation as an indication by which the surgeon can predict the presence of FDAL. On the basis of an observation that there is a special posture of the big toe in extension in relation to other flexed toes associated with the presence of FDAL, records of patients of clubfoot treated by extensive surgery between 2007 and 2012 at the Sudan Clubfoot Project were reviewed. Demographic characteristics were studied. Only patients with idiopathic TEV were included. Resistant clubfeet necessitated extensive release in 261 patients, 197 males and 64 females. Their ages ranged between 1 day and 15 years at presentation. FDAL muscle was found in 48 patients (54 feet) out of 261 patients (411 feet, 13.14%). In 46 of the 48 patients (95.8%), the presence of the FDAL could be predicted by a sign. FDAL is prevalent in 13% of resistant TEV cases requiring extensive soft tissue release, and the surgeon can expect resistant clubfoot and predict the presence of the FDAL in over 95% before he operates by observing the Samir-Adam sign. PMID- 25493704 TI - Synovial chondromatosis of the spine in the skeletally immature: case report and updated review of the literature. AB - Synovial chondromatosis is a benign disorder characterized by the formation of multiple cartilaginous nodules in the synovium of large joints. Synovial chondromatosis of the spine is very rare; this is the first reported case in the skeletally immature pediatric spine. A 12-year-old female presented with a posteriolateral neck mass and discomfort. A two-stage surgical resection of the mass was performed. This case shows that synovial chondromatosis can occur in the immature pediatric spine. Synovial chondromatosis should be included in the differential diagnosis of a calcified paravertebral or lateral neck mass in children. PMID- 25493705 TI - Births resulting from assisted reproductive technology: comparing birth certificate and National ART Surveillance System Data, 2011. AB - OBJECTIVES: This report compares data on births resulting from assisted reproductive technology (ART) procedures from 2011 birth certificates with data from the 2011 National ART Surveillance System (NASS) among the subset of jurisdictions that adopted the 2003 revised birth certificate as of January 1, 2011, with information on ART. METHODS: Birth certificate data are based on 100% of births registered in 27 states and the District of Columbia. NASS data included all ART cycles initiated in 2010 or 2011 for which a live birth in 2011 was reported. The same reporting area was used for both data sources and represents 67% of all births in the United States in 2011. A ratio was computed by dividing the percentage of births resulting from ART procedures for NASS data by the percentage for birth certificate data. A ratio of 1.0 represents equivalent levels of reporting. Because this reporting area is not a random sample of births, the results are not generalizable to the United States as a whole. RESULTS: Overall, the percentage of births resulting from ART procedures was 2.06 times higher for NASS data (1.44%) compared with birth certificate data (0.70%). The ratio for each jurisdiction varied from 1.04 for Utah and Wisconsin to 7.50 for Florida. Higher-risk groups had more consistent reporting. between data sources [e.g., triplet or higher-order multiples (1.36) compared with singletons (2.11)]. CONCLUSIONS: Births resulting from ART procedures appear to be underreported on the birth certificate; however, the magnitude of underreporting varied by jurisdiction and maternal-infant health characteristics. PMID- 25493706 TI - The potential impact of climate change and ultraviolet radiation on vaccine preventable infectious diseases and immunization service delivery system. AB - Climate change and solar ultraviolet radiation may affect vaccine-preventable infectious diseases (VPID), the human immune response process and the immunization service delivery system. We systematically reviewed the scientific literature and identified 37 relevant publications. Our study shows that climate variability and ultraviolet radiation may potentially affect VPID and the immunization delivery system through modulating vector reproduction and vaccination effectiveness, possibly influencing human immune response systems to the vaccination, and disturbing immunization service delivery. Further research is needed to determine these affects on climate-sensitive VPID and on human immune response to common vaccines. Such research will facilitate the development and delivery of optimal vaccination programs for target populations, to meet the goal of disease control and elimination. PMID- 25493707 TI - Podoplanin is Positive Not Only on Follicular Dendritic Cells and Their Tumoral Counterparts, But Also on Reticular Fibroblasts and in Some Tumors of Reticular Fibroblasts. PMID- 25493708 TI - Inter-Annual Variability of Fledgling Sex Ratio in King Penguins. AB - As the number of breeding pairs depends on the adult sex ratio in a monogamous species with biparental care, investigating sex-ratio variability in natural populations is essential to understand population dynamics. Using 10 years of data (2000-2009) in a seasonally monogamous seabird, the king penguin (Aptenodytes patagonicus), we investigated the annual sex ratio at fledging, and the potential environmental causes for its variation. Over more than 4000 birds, the annual sex ratio at fledging was highly variable (ranging from 44.4% to 58.3% of males), and on average slightly biased towards males (51.6%). Yearly variation in sex-ratio bias was neither related to density within the colony, nor to global or local oceanographic conditions known to affect both the productivity and accessibility of penguin foraging areas. However, rising sea surface temperature coincided with an increase in fledging sex-ratio variability. Fledging sex ratio was also correlated with difference in body condition between male and female fledglings. When more males were produced in a given year, their body condition was higher (and reciprocally), suggesting that parents might adopt a sex-biased allocation strategy depending on yearly environmental conditions and/or that the effect of environmental parameters on chick condition and survival may be sex dependent. The initial bias in sex ratio observed at the juvenile stage tended to return to 1?1 equilibrium upon first breeding attempts, as would be expected from Fisher's classic theory of offspring sex-ratio variation. PMID- 25493709 TI - Formazanate ligands as structurally versatile, redox-active analogues of beta diketiminates in zinc chemistry. AB - A range of tetrahedral bis(formazanate)zinc complexes with different steric and electronic properties of the formazanate ligands were synthesized. The solid state structures for several of these were determined by X-ray crystallography, which showed that complexes with symmetrical, unhindered ligands prefer coordination to the zinc center via the terminal N atoms of the NNCNN ligand backbone. Steric or electronic modifications can override this preference and give rise to solid-state structures in which the formazanate ligand forms a 5 membered chelate by binding to the metal center via an internal N atom. In solution, these compounds show dynamic equilibria that involve both 5- and 6 membered chelates. All compounds are intensely colored, and the effect of the ligand substitution pattern on the UV-vis absorption spectra was evaluated. In addition, their cyclic voltammetry is reported, which shows that all compounds may be electrochemically reduced to radical anionic (L2Zn(-)) and dianionic (L2Zn(2-)) forms. While unhindered NAr substituents lie in the plane of the ligand backbone (Ar = Ph), the introduction of sterically demanding substituents (Ar = Mes) favors a perpendicular orientation in which the NMes group is no longer in conjugation with the backbone, resulting in hypsochromic shifts in the absorption spectra. The redox potentials in the series of L2Zn compounds may be altered in a straightforward manner over a relatively wide range (~700 mV) via the introduction of electron-donating or -withdrawing substituents on the formazanate framework. PMID- 25493711 TI - Efficient triarylamine-perylene dye-sensitized solar cells: influence of triple bond insertion on charge recombination. AB - We synthesize two new metal-free donor-acceptor organic dyes (C266 and C267) featuring a N-annulated perylene block. Owing to the improved coplanarity of conjugated units as well as the prolonged conjugation upon inserting a triple bond between the triarylamine and perylene segments, the C267 dye exhibits a slightly red-shifted absorption peak and an enhanced maximum molar absorption coefficient with respect to its reference dye C266, leading to an improved photocurrent output in dye-sensitized solar cells. However, the triple-bond introduction also brings forth an over 100 mV reduced open-circuit photovoltage owing to faster interfacial charge recombination, which presents a clear correlation with a reduced mean thickness of self-assembled dye layer on titania as revealed by X-ray reflectivity measurements. The C266 dye, albeit with a relatively weaker light-harvesting capacity, displays a higher power conversion efficiency of 9.0% under the 100 mW cm(-2), simulated AM1.5G sunlight. PMID- 25493712 TI - Quantitative sum-frequency generation vibrational spectroscopy of molecular surfaces and interfaces: lineshape, polarization, and orientation. AB - Sum-frequency generation vibrational spectroscopy (SFG-VS) can provide detailed information and understanding of the molecular composition, interactions, and orientational and conformational structure of surfaces and interfaces through quantitative measurement and analysis. In this review, we present the current status of and discuss important recent developments in the measurement of intrinsic SFG spectral lineshapes and formulations for polarization measurements and orientational analysis of SFG-VS spectra. The focus of this review is to present a coherent description of SFG-VS and discuss the main concepts and issues that can help advance this technique as a quantitative analytical research tool for revealing the chemistry and physics of complex molecular surfaces and interfaces. PMID- 25493710 TI - Epigenetic contributions to the developmental origins of adult lung disease. AB - Perinatal insults, including intrauterine growth restriction, preterm birth, maternal exposure to toxins, or dietary deficiencies produce deviations in the epigenome of lung cells. Occurrence of perinatal insults often coincides with the final stages of lung development. The result of epigenome disruptions in response to perinatal insults during lung development may be long-term structural and functional impairment of the lung and development of lung disease. Understanding the contribution of epigenetic mechanisms to life-long lung disease following perinatal insults is the focus of the developmental origins of adult lung disease field. DNA methylation, histone modifications, and microRNA changes are all observed in various forms of lung disease. However, the perinatal contribution to such epigenetic mechanisms is poorly understood. Here we discuss the developmental origins of adult lung disease, the interplay between perinatal events, lung development and disease, and the role that epigenetic mechanisms play in connecting these events. PMID- 25493713 TI - Reaction dynamics at liquid interfaces. AB - The liquid interface is a narrow, highly anisotropic region, characterized by rapidly varying density, polarity, and molecular structure. I review several aspects of interfacial solvation and show how these affect reactivity at liquid/liquid interfaces. I specifically consider ion transfer, electron transfer, and SN2 reactions, showing that solvent effects on these reactions can be understood by examining the unique structure and dynamics of the liquid interface region. PMID- 25493714 TI - The statistical mechanics of dynamic pathways to self-assembly. AB - This review describes some important physical characteristics of the pathways (i.e., dynamical processes) by which molecular, nanoscale, and micrometer-scale self-assembly occurs. We highlight the existence of features of self-assembly pathways that are common to a wide range of physical systems, even though those systems may differ with respect to their microscopic details. We summarize some existing theoretical descriptions of self-assembly pathways and highlight areas notably, the description of self-assembly pathways that occur far from equilibrium-that are likely to become increasingly important. PMID- 25493715 TI - Coherence in energy transfer and photosynthesis. AB - Ultrafast energy transfer is used to transmit electronic excitation among the many molecules in photosynthetic antenna complexes. Recent experiments and theories have highlighted the role of coherent transfer in femtosecond studies of these proteins, suggesting the need for accurate dynamical models to capture the subtle characteristics of energy transfer mechanisms. Here we discuss how to think about coherence in light harvesting and electronic energy transfer. We review the various fundamental concepts of coherence, spanning from classical phenomena to the quantum superposition, and define coherence in electronic energy transfer. We describe the current status of experimental studies on light harvesting complexes. Insights into the microscopic process are presented to highlight how and why this is a challenging problem to elucidate. We present an overview of the applicable dynamical theories to model energy transfer in the intermediate coupling regime. PMID- 25493716 TI - Ultrafast dynamics of electrons in ammonia. AB - Solvated electrons were first discovered in solutions of metals in liquid ammonia. The physical and chemical properties of these species have been studied extensively for many decades using an arsenal of electrochemical, spectroscopic, and theoretical techniques. Yet, in contrast to their hydrated counterpart, the ultrafast dynamics of ammoniated electrons remained completely unexplored until quite recently. Femtosecond pump-probe spectroscopy on metal-ammonia solutions and femtosecond multiphoton ionization spectroscopy on the neat ammonia solvent have provided new insights into the optical properties and the reactivities of this fascinating species. This article reviews the nature of the optical transition, which gives the metal-ammonia solutions their characteristic blue appearance, in terms of ultrafast relaxation processes involving bound and continuum excited states. The recombination processes following the injection of an electron via photoionization of the solvent are discussed in the context of the electronic structure of the liquid and the anionic defect associated with the solvated electron. PMID- 25493718 TI - Understanding the reaction mechanism and intermediate stabilization in mammalian serine racemase using multiscale quantum-classical simulations. AB - Serine racemase (SerR) is a pyridoxal-5'-phosphate (PLP)-dependent enzyme catalyzing the racemization of l-Ser to d-Ser. In mammals, d-Ser is an endogenous coagonist required for the activation of N-methyl-d-aspartate receptors (NMDARs), thus making SerR a promising pharmaceutical target. However, mechanistic studies of SerR are scarce, and the details of the enzymatic racemization reaction are not fully understood. In the current study we elucidate the catalytic mechanism in SerR by employing combined multiscale classical/quantum simulations. The free energy profile of a model SerR racemization reaction is first calculated in the gas phase and in aqueous solution. To obtain the free energy profile for the enzymatic reaction, hybrid quantum mechanics/molecular mechanics molecular dynamics simulations in conjunction with umbrella sampling are performed. The results suggest that in SerR, similarly to the related enzyme alanine racemase, the unprotonated PLP-substrate intermediate is stabilized mostly due to solvation effects contributed by water molecules and active-site residues, as well as long range electrostatic interactions with the enzyme environment. In addition to a deeper understanding of the racemization mechanism in SerR, based on our simulations we propose specific mutations, which might shift the SerR equilibrium in favor of either l-Ser or d-Ser. Finally, the current studies have produced catalytically competent forms of the rat and human enzymes, which may serve as targets for future docking studies and drug design. PMID- 25493717 TI - Prevalence of mutations in GJB2, SLC26A4, and mtDNA in children with severe or profound sensorineural hearing loss in southwestern China. AB - AIM: To study the distribution characteristics of common mutations in the GJB2, SLC26A4, and mtDNA genes in children with severe or profound sensorineural hearing loss (SNHL) in southwestern China. MATERIALS AND METHODS: A total of 1,164 individuals were recruited to screen for the common GJB2, SLC26A4, and mtDNA mutations by microarrays. Subsequencing for the coding region of the GJB2 gene in the samples without the GJB2 hotspot mutations as well as subsequencing for the exon 1 of the TRMU gene in those samples with the mtDNA hotspot mutations was performed by Sanger sequencing. All mutations were analyzed in association with medical imaging. RESULTS: In this study, 28.43% of all subjects carried mutations. The mutation frequencies in the GJB2, SLC26A4, and mtDNA genes were 17.27%, 7.04%, and 4.12%, respectively. No TRMU mutation was found in the study. The frequency of the mtDNA mutations in the multiethnic minorities was six times that in the Han (11.23% vs. 1.91%; p approaches 0.000) and in the urban group was one-third of that in the suburban group(1.49% vs. 4.47%; p=0.047). The frequency of the GJB2 mutations in urban and suburban groups was 23.38% and 15.99%, respectively (p=0.012). The enlarged vestibular aqueduct (EVA) was the most common inner ear malformation and ~79.10% of EVA cases were associated with the SLC26A4 mutations. CONCLUSIONS: More than one-fourth of children with severe or profound SNHL carried the common deafness mutations. The proportions of ethnic minorities and urban subjects could impact the frequency of the GJB2 and mtDNA mutations. The SLC26A4 hotspot mutations are prevalent and correlate strongly with EVA. PMID- 25493719 TI - Locality, entanglement, and thermalization of isolated quantum systems. AB - A way to understand thermalization in an isolated system is to interpret it as an increase in entanglement between subsystems. Here we test this idea through a combination of analytical and Krylov-subspace-based numerical methods applied to a quantum gas of bosons. We find that the entanglement entropy of a subsystem is rapidly generated at the initial state of the evolution, to quickly approach the thermal value. Our results also provide an accurate numerical test of the eigenstate thermalization hypothesis (ETH), according to which a single energy eigenstate of an isolated system behaves in certain respects as a thermal state. In the context of quantum black holes, we propose that the ETH is a quantum version of the classical no-hair theorem. PMID- 25493720 TI - Machta-Zwanzig regime of anomalous diffusion in infinite-horizon billiards. AB - We study diffusion on a periodic billiard table with an infinite horizon in the limit of narrow corridors. An effective trapping mechanism emerges according to which the process can be modeled by a Levy walk combining exponentially distributed trapping times with free propagation along paths whose precise probabilities we compute. This description yields an approximation of the mean squared displacement of infinite-horizon billiards in terms of two transport coefficients, which generalizes to this anomalous regime the Machta-Zwanzig approximation of normal diffusion in finite-horizon billiards [J. Machta and R. Zwanzig, Phys. Rev. Lett. 50, 1959 (1983)PRLTAO0031 900710.1103/PhysRevLett.50.1959]. PMID- 25493721 TI - Phase transitions in the condition-number distribution of Gaussian random matrices. AB - We study the statistics of the condition number kappa=lambda_{max}/lambda_{min} (the ratio between largest and smallest squared singular values) of N*M Gaussian random matrices. Using a Coulomb fluid technique, we derive analytically and for large N the cumulative P(kappax) distributions of kappa. We find that these distributions decay as P(kappax)~exp[-betaNPhi_{+}(x)], where beta is the Dyson index of the ensemble. The left and right rate functions Phi_{+/-}(x) are independent of beta and calculated exactly for any choice of the rectangularity parameter alpha=M/N 1>0. Interestingly, they show a weak nonanalytic behavior at their minimum (corresponding to the average condition number), a direct consequence of a phase transition in the associated Coulomb fluid problem. Matching the behavior of the rate functions around , we determine exactly the scale of typical fluctuations ~O(N^{-2/3}) and the tails of the limiting distribution of kappa. The analytical results are in excellent agreement with numerical simulations. PMID- 25493722 TI - Comparison of the physical aging behavior of a colloidal glass after shear melting and concentration jumps. AB - Colloidal systems are considered good models of molecular glasses and we further explore the range of validity of this paradigm using a thermosensitive core-shell particle dispersion to study the aging response of a colloidal glass subsequent to both shear-melting and temperature (concentration)-jump perturbations in the vicinity of the glass transition concentration or temperature. Sequential creep experiments were used to probe the different aging responses of the system. The colloidal glass displays aging behavior after both types of perturbation and our results indicate that this colloidal glass is similar to a molecular glass, in that shift rates are found to be below unity and to decrease towards zero as the glass temperature (or concentration) is approached as temperature increases. However, the kinetics of the aging in the two cases are different indicating that the structural changes induced by the mechanical perturbation are different from those induced by the temperature or concentration jump-similar to findings on mechanical rejuvenation of molecular glasses. We also find differences between the colloidal glass and molecular glasses: In the case of the colloidal glass the structural recovery or equilibration times do not diverge, while the mechanical relaxation times do. On the other hand, for the molecular glass, both times change very rapidly with decreasing temperature, apparently towards a distant point of divergence. PMID- 25493723 TI - Kinetic origin of grain boundary migration, grain coalescence, and defect reduction in the crystallization of quenched two-dimensional Yukawa liquids. AB - The kinetic origin of grain boundary migration, grain coalescence, and defect reduction in the crystallization of quenched two-dimensional Yukawa liquids are numerically investigated. It is found that, in grain coalescence, stick-slip cracking the region in front of the grain boundary into smaller subgrains corotating with small angle, followed by healing, is the key for aligning lattice misorientation and inducing grain boundary stick-slip advance. Cracking is initiated from the weakly interlocked dislocation along its Burgers vector, which in turn causes dislocation motion along the crack. The cascaded scattering and recombination of two dislocations with 60^{?} and 120^{?} Burgers vector angle difference into two and one dislocations are the major processes for dislocation motion and reduction, respectively, in grain boundary migration. A rough grain boundary with large curvature easily supports the above process and induces high grain boundary mobility. Along a straight smooth grain boundary, the parallel Burgers vectors of the string of dislocations hinder defect reduction and induce coalescence stagnation. PMID- 25493724 TI - Minimal model of transcriptional elongation processes with pauses. AB - Fundamental biological processes such as transcription and translation, where a genetic sequence is sequentially read by a macromolecule, have been well described by a classical model of nonequilibrium statistical physics, the totally asymmetric exclusion principle (TASEP). This model describes particles hopping between sites of a one-dimensional lattice, with the particle current determining the transcription or translation rate. An open problem is how to analyze a TASEP where particles can pause randomly, as has been observed during transcription. In this work, we report that surprisingly, a simple mean-field model predicts well the particle current for all values of the average pause duration, using a simple description of blocking behind paused particles. PMID- 25493725 TI - Path-integral calculation for the emergence of rapid evolution from demographic stochasticity. AB - Genetic variation in a population can sometimes arise so fast as to modify ecosystem dynamics. Such phenomena have been observed in natural predator-prey systems and characterized in the laboratory as showing unusual phase relationships in population dynamics, including a pi phase shift between predator and prey (evolutionary cycles) and even undetectable prey oscillations compared to those of the predator (cryptic cycles). Here we present a generic individual level stochastic model of interacting populations that includes a subpopulation of low nutritional value to the predator. Using a master equation formalism and by mapping to a coherent state path integral solved by a system-size expansion, we show that evolutionary and cryptic quasicycles can emerge generically from the combination of intrinsic demographic fluctuations and clonal mutations alone, without additional biological mechanisms. PMID- 25493726 TI - Underestimating extreme events in power-law behavior due to machine-dependent cutoffs. AB - Power-law distributions are typical macroscopic features occurring in almost all complex systems observable in nature. As a result, researchers in quantitative analyses must often generate random synthetic variates obeying power-law distributions. The task is usually performed through standard methods that map uniform random variates into the desired probability space. Whereas all these algorithms are theoretically solid, in this paper we show that they are subject to severe machine-dependent limitations. As a result, two dramatic consequences arise: (i) the sampling in the tail of the distribution is not random but deterministic; (ii) the moments of the sample distribution, which are theoretically expected to diverge as functions of the sample sizes, converge instead to finite values. We provide quantitative indications for the range of distribution parameters that can be safely handled by standard libraries used in computational analyses. Whereas our findings indicate possible reinterpretations of numerical results obtained through flawed sampling methodologies, they also pave the way for the search for a concrete solution to this central issue shared by all quantitative sciences dealing with complexity. PMID- 25493727 TI - Scaling and correlation of human movements in cyberspace and physical space. AB - Understanding the dynamics of human movements is key to issues of significant current interest such as behavioral prediction, recommendation, and control of epidemic spreading. We collect and analyze big data sets of human movements in both cyberspace (through browsing of websites) and physical space (through mobile towers) and find a superlinear scaling relation between the mean frequency of visit and its fluctuation sigma:sigma~^{beta} with beta~1.2. The probability distribution of the visiting frequency is found to be a stretched exponential function. We develop a model incorporating two essential ingredients, preferential return and exploration, and show that these are necessary for generating the scaling relation extracted from real data. A striking finding is that human movements in cyberspace and physical space are strongly correlated, indicating a distinctive behavioral identifying characteristic and implying that the behaviors in one space can be used to predict those in the other. PMID- 25493728 TI - Predicting the enhancement of mixing-driven reactions in nonuniform flows using measures of flow topology. AB - The ability for reactive constituents to mix is often the key limiting factor for the completion of reactions across a huge range of scales in a variety of media. In flowing systems, deformation and shear enhance mixing by bringing constituents into closer proximity, thus increasing reaction potential. Accurately quantifying this enhanced mixing is key to predicting reactions and typically is done by observing or simulating scalar transport. To eliminate this computationally expensive step, we use a Lagrangian stochastic framework to derive the enhancement to reaction potential by calculating the collocation probability of particle pairs in a heterogeneous flow field accounting for deformations. We relate the enhanced reaction potential to three well known flow topology metrics and demonstrate that it is best correlated to (and asymptotically linear with) one: the largest eigenvalue of the (right) Cauchy-Green tensor. PMID- 25493729 TI - Induced-charge electro-osmosis around metal and Janus spheres in water: Patterns of flow and breaking symmetries. AB - We establish experimentally the flow patterns of induced-charge electro-osmosis around immobilized metallic spheres in aqueous electrolyte. The ac field modifies local electrolyte concentration and causes quadrupolar flows with inward velocities being smaller than the outward ones. At high fields, the flow becomes irregular, with vortices smaller than the size of the sphere. Janus metallodielectric spheres create dipolar flows and pump the fluid from the dielectric toward the metallic part. The experimentally determined far-field flows decay with distance as r^{-3}. PMID- 25493730 TI - On the edge of an inverse cascade. AB - We demonstrate that systems with a parameter-controlled inverse cascade can exhibit critical behavior for which at the critical value of the control parameter the inverse cascade stops. In the vicinity of such a critical point, standard phenomenological estimates for the energy balance will fail since the energy flux towards large length scales becomes zero. We demonstrate this using the computationally tractable model of two-dimensional (2D) magnetohydrodynamics in a periodic box. In the absence of any external magnetic forcing, the system reduces to hydrodynamic fluid turbulence with an inverse energy cascade. In the presence of strong magnetic forcing, the system behaves as 2D magnetohydrodynamic turbulence with forward energy cascade. As the amplitude of the magnetic forcing is varied, a critical value is met for which the energy flux towards the large scales becomes zero. Close to this point, the energy flux scales as a power law with the departure from the critical point and the normalized amplitude of the fluctuations diverges. Similar behavior is observed for the flux of the square vector potential for which no inverse flux is observed for weak magnetic forcing, while a finite inverse flux is observed for magnetic forcing above the critical point. We conjecture that this behavior is generic for systems of variable inverse cascade. PMID- 25493731 TI - Elevation of the temperature of liquid films caused by rapid rupturing. AB - Although there have been several experimental and numerical works on rapidly rupturing films, measurement of the spatial-temporal temperature during rupturing processes is lacking. Using molecular dynamics simulations, we show that a rupturing film with nanometer thickness generates a non-negligible temperature increase. We demonstrate a correlation between the rupture velocity, the temperature increase, and the initial film thickness. Our findings show that the temperature increase causes changes to the physical properties, which affect the film-rupturing behavior. PMID- 25493732 TI - Mechanism of formation of subnanosecond current front in high-voltage pulse open discharge. AB - The mechanism of subnanosecond current front rise observed previously in the experiment in high-voltage pulse open discharge in helium is studied in kinetic particle-in-cell simulations. The Boltzmann equations for electrons, ions, and fast atoms are solved self-consistently with the Poisson equations for the electrical potential. The partial contributions to the secondary electron emission from the ions, fast atoms, photons, and electrons, bombarding the electrode, are calculated. In simulations, as in the experiment, the discharge glows between two symmetrical cathodes and the anode grid in the midplane at P=6 Torr and the applied voltage of 20 kV. The electron avalanche development is considered for two experimental situations during the last stage of breakdown: (i) with constant voltage and (ii) with decreasing voltage. For case (i), the subnanosecond current front rise is set by photons from the collisional excitation transfer reactions. For the case (ii), the energetic electrons swamp the cathode during voltage drop and provide the secondary electron emission for the subnanosecond current rise, observed in the experiment. PMID- 25493733 TI - Kinetic effects and nonlinear heating in intense x-ray-laser-produced carbon plasmas. AB - The x-ray laser-matter interaction for a low-Z material, carbon, is studied with a particle-in-cell code that solves the photoionization and x-ray transport self consistently. Photoionization is the dominant absorption mechanism and nonthermal photoelectrons are produced with energy near the x-ray photon energy. The photoelectrons ionize the target rapidly via collisional impact ionization and field ionization, producing a hot plasma column behind the laser pulse. The radial size of the heated region becomes larger than the laser spot size due to the kinetic nature of the photoelectrons. The plasma can have a temperature of more than 10 000 K (>1eV), an energy density greater than 10^{4} J/cm^{3}, an ion ion Coulomb coupling parameter Gamma>=1, and electron degeneracy Theta>=1, i.e., strongly coupled warm dense matter. By increasing the laser intensity, the plasma temperature rises nonlinearly from tens of eV to hundreds of eV, bringing it into the high energy density matter regime. The heating depth and temperature are also controllable by changing the photon energy of the incident laser light. PMID- 25493734 TI - Aging of orientation fluctuations in stripe phases. AB - Stripe patterns, observed in a large variety of physical systems, often exhibit a slow nonequilibrium dynamics because ordering is impeded by the presence of topological defects. Using computer simulations based on a well-established model for stripe formation, we show that a slow dynamics and aging occur also in stripe patterns free of topological defects. For a wide range of noise strengths, the two-time orientation correlation function follows a scaling form that is typical for systems exhibiting a growing length scale. In our case, the underlying mechanism is the coarsening of orientation fluctuations, ultimately leading to power-law spatial correlations perpendicular to the stripes. Our results show that even for the smallest amount of noise, stripe phases without topological defects do not reach equilibrium. This constitutes an important aspect of the dynamics of modulated phases. PMID- 25493735 TI - Quench echo and work statistics in integrable quantum field theories. AB - We propose a boundary thermodynamic Bethe ansatz calculation technique to obtain the Loschmidt echo and the statistics of the work done when a global quantum quench is performed on an integrable quantum field theory. We derive an analytic expression for the lowest edge of the probability density function and find that it exhibits universal features, in the sense that its scaling form depends only on the statistics of excitations. We perform numerical calculations on the sinh Gordon model, a deformation of the free boson theory, and we obtain that by turning on the interaction the density function develops fermionic properties. The calculations are facilitated by a previously unnoticed property of the thermodynamic Bethe ansatz construction. PMID- 25493736 TI - Mixed-state fidelity susceptibility through iterated commutator series expansion. AB - We present a perturbative approach to the problem of computation of mixed-state fidelity susceptibility (MFS) for thermal states. The mathematical techniques used provide an analytical expression for the MFS as a formal expansion in terms of the thermodynamic mean values of successively higher commutators of the Hamiltonian with the operator involved through the control parameter. That expression is naturally divided into two parts: the usual isothermal susceptibility and a constituent in the form of an infinite series of thermodynamic mean values which encodes the noncommutativity in the problem. If the symmetry properties of the Hamiltonian are given in terms of the generators of some (finite-dimensional) algebra, the obtained expansion may be evaluated in a closed form. This issue is tested on several popular models, for which it is shown that the calculations are much simpler if they are based on the properties from the representation theory of the Heisenberg or SU(1, 1) Lie algebra. PMID- 25493737 TI - Kosterlitz-Thouless transitions and phase diagrams of the interacting monomer dimer model on a checkerboard lattice. AB - Using the tensor network approach, we investigate the monomer-dimer models on a checkerboard lattice, in which there are interactions (with strength v) between the parallel dimers on half of the plaquettes. For the fully packed interacting dimer model, we observe a Kosterlitz-Thouless (KT) transition between the low temperature symmetry breaking and the high-temperature critical phases; for the doped monomer-dimer case with finite chemical potential MU, we also find an order disorder phase transition which is of second order instead. We use the boundary matrix product state approach to detect the KT and second-order phase transitions and obtain the phase diagrams v-T and MU-T. Moreover, for the noninteracting monomer-dimer model (setting MU=nu=0), we get an extraordinarily accurate determination of the free energy per site (negative of the monomer-dimer constant h_{2}) as f=-0.662798972833746 with the dimer density n=0.638123109228547, both of 15 correct digits. PMID- 25493738 TI - Testing whether all eigenstates obey the eigenstate thermalization hypothesis. AB - We ask whether the eigenstate thermalization hypothesis (ETH) is valid in a strong sense: in the limit of an infinite system, every eigenstate is thermal. We examine expectation values of few-body operators in highly excited many-body eigenstates and search for "outliers," the eigenstates that deviate the most from ETH. We use exact diagonalization of two one-dimensional nonintegrable models: a quantum Ising chain with transverse and longitudinal fields, and hard-core bosons at half-filling with nearest- and next-nearest-neighbor hopping and interaction. We show that even the most extreme outliers appear to obey ETH as the system size increases and thus provide numerical evidences that support ETH in this strong sense. Finally, periodically driving the Ising Hamiltonian, we show that the eigenstates of the corresponding Floquet operator obey ETH even more closely. We attribute this better thermalization to removing the constraint of conservation of the total energy. PMID- 25493739 TI - Entropy of finite random binary sequences with weak long-range correlations. AB - We study the N-step binary stationary ergodic Markov chain and analyze its differential entropy. Supposing that the correlations are weak we express the conditional probability function of the chain through the pair correlation function and represent the entropy as a functional of the pair correlator. Since the model uses the two-point correlators instead of the block probability, it makes it possible to calculate the entropy of strings at much longer distances than using standard methods. A fluctuation contribution to the entropy due to finiteness of random chains is examined. This contribution can be of the same order as its regular part even at the relatively short lengths of subsequences. A self-similar structure of entropy with respect to the decimation transformations is revealed for some specific forms of the pair correlation function. Application of the theory to the DNA sequence of the R3 chromosome of Drosophila melanogaster is presented. PMID- 25493740 TI - Matter, energy, and heat transfer in a classical ballistic atom pump. AB - A ballistic atom pump is a system containing two reservoirs of neutral atoms or molecules and a junction connecting them containing a localized time-varying potential. Atoms move through the pump as independent particles. Under certain conditions, these pumps can create net transport of atoms from one reservoir to the other. While such systems are sometimes called "quantum pumps," they are also models of classical chaotic transport, and their quantum behavior cannot be understood without study of the corresponding classical behavior. Here we examine classically such a pump's effect on energy and temperature in the reservoirs, in addition to net particle transport. We show that the changes in particle number, of energy in each reservoir, and of temperature in each reservoir vary in unexpected ways as the incident particle energy is varied. PMID- 25493741 TI - Generalized exclusion processes: Transport coefficients. AB - A class of generalized exclusion processes with symmetric nearest-neighbor hopping which are parametrized by the maximal occupancy, k>=1, is investigated. For these processes on hypercubic lattices we compute the diffusion coefficient in all spatial dimensions. In the extreme cases of k=1 (symmetric simple exclusion process) and k=infinity (noninteracting symmetric random walks) the diffusion coefficient is constant, while for 2<=kinfinity nodes. The finite-size fluctuations of the resolvent are given in terms of a weighted series over the contributions coming from loops of all possible lengths, from which we obtain the isolated eigenvalue as well as an analytical expression for the O(1/N) correction to the continuous part of the spectrum. The comparison between this analytical formula and direct diagonalization results exhibits an excellent agreement, confirming the correctness of our expression. PMID- 25493743 TI - Effective models of membranes from symmetry breaking. AB - We show how to obtain all the models of the continuous description of membranes by constructing the appropriate nonlinear realizations of the Euclidean symmetries of the embedding. The procedure has the advantage of giving a unified formalism with which the models are generated and highlights the relevant order parameters in each phase. We use our findings to investigate a fluid description of both tethered and hexatic membranes, showing that both the melting and the loss of local order induce long-range interactions in the high-temperature fluid phase. The results can be used to understand the appearance of intrinsic ripples in crystalline membranes in a thermal bath. PMID- 25493744 TI - Arrays of stochastic oscillators: Nonlocal coupling, clustering, and wave formation. AB - We consider an array of units each of which can be in one of three states. Unidirectional transitions between these states are governed by Markovian rate processes. The interactions between units occur through a dependence of the transition rates of a unit on the states of the units with which it interacts. This coupling is nonlocal, that is, it is neither an all-to-all interaction (referred to as global coupling), nor is it a nearest neighbor interaction (referred to as local coupling). The coupling is chosen so as to disfavor the crowding of interacting units in the same state. As a result, there is no global synchronization. Instead, the resultant spatiotemporal configuration is one of clusters that move at a constant speed and that can be interpreted as traveling waves. We develop a mean field theory to describe the cluster formation and analyze this model analytically. The predictions of the model are compared favorably with the results obtained by direct numerical simulations. PMID- 25493745 TI - Annealed Ising model with site dilution on self-similar structures. AB - We consider an Ising model on the triangular Apollonian network (AN), with a thermalized distribution of vacant sites. The statistical problem is formulated in a grand canonical ensemble, in terms of the temperature T and a chemical potential MU associated with the concentration of active magnetic sites. We use a well-known transfer-matrix method, with a number of adaptations, to write recursion relations between successive generations of this hierarchical structure. We also investigate the analogous model on the diamond hierarchical lattice (DHL). From the numerical analysis of the recursion relations, we obtain various thermodynamic quantities. In the MU->infinity limit, we reproduce the results for the uniform models: in the AN, the system is magnetically ordered at all temperatures, while in the DHL there is a ferromagnetic-paramagnetic transition at a finite value of T. Magnetic ordering, however, is shown to disappear for sufficiently large negative values of the chemical potential. PMID- 25493746 TI - Generic transport coefficients of a confined electrolyte solution. AB - Physical parameters characterizing electrokinetic transport in a confined electrolyte solution are reconstructed from the generic transport coefficients obtained within the classical nonequilibrium statistical thermodynamic framework. The electro-osmotic flow, the diffusio-osmotic flow, the osmotic current, as well as the pressure-driven Poiseuille-type flow, the electric conduction, and the ion diffusion are described by this set of transport coefficients. The reconstruction is demonstrated for an aqueous NaCl solution between two parallel charged surfaces with a nanoscale gap, by using the molecular dynamic (MD) simulations. A Green-Kubo approach is employed to evaluate the transport coefficients in the linear-response regime, and the fluxes induced by the pressure, electric, and chemical potential fields are compared with the results of nonequilibrium MD simulations. Using this numerical scheme, the influence of the salt concentration on the transport coefficients is investigated. Anomalous reversal of diffusio osmotic current, as well as that of electro-osmotic flow, is observed at high surface charge densities and high added-salt concentrations. PMID- 25493747 TI - Signatures of Levy flights with annealed disorder. AB - We present theoretical and experimental results of Levy flights of light originating from a random walk of photons in a hot atomic vapor. In contrast to systems with quenched disorder, this system does not present any correlations between the position and the step length of the random walk. In an analytical model based on microscopic first principles including Doppler broadening we find anomalous Levy-type superdiffusion corresponding to a single-step size distribution P(x)?x^{-(1+alpha)}, with alpha~1. We show that this step size distribution leads to a violation of Ohm's law [T_{diff}?L^{-alpha/2}?L^{-1}], as expected for a Levy walk of independent steps. Furthermore, the spatial profile of the transmitted light develops power-law tails [T_{diff}(r)?r^{-3-alpha}]. In an experiment using a slab geometry with hot Rb vapor, we measured the total diffuse transmission T_{diff} and the spatial profile of the transmitted light T_{diff}(r). We obtained the microscopic Levy parameter alpha under macroscopic multiple scattering conditions paving the way to investigation of Levy flights in different atomic physics and astrophysics systems. PMID- 25493748 TI - Critical decay exponent of the pair contact process with diffusion. AB - We investigate the one-dimensional pair contact process with diffusion (PCPD) by extensive Monte Carlo simulations, mainly focusing on the critical density decay exponent delta. To obtain an accurate estimate of delta, we first find the strength of corrections to scaling using the recently introduced method [S.-C. Park. J. Korean Phys. Soc. 62, 469 (2013)KPSJAS0374-488410.3938/jkps.62.469]. For small diffusion rate (d<=0.5), the leading corrections-to-scaling term is found to be ~t^{-0.15}, whereas for large diffusion rate (d=0.95) it is found to be ~t^{-0.5}. After finding the strength of corrections to scaling, effective exponents are systematically analyzed to conclude that the value of critical decay exponent delta is 0.173(3) irrespective of d. This value should be compared with the critical decay exponent of the directed percolation, 0.1595. In addition, we study two types of crossover. At d=0, the phase boundary is discontinuous and the crossover from the pair contact process to the PCPD is found to be described by the crossover exponent phi=2.6(1). We claim that the discontinuity of the phase boundary cannot be consistent with the theoretical argument supporting the hypothesis that the PCPD should belong to the DP. At d=1, the crossover from the mean field PCPD to the PCPD is described by phi=2 which is argued to be exact. PMID- 25493749 TI - Work fluctuations for a Brownian particle driven by a correlated external random force. AB - We have considered the underdamped motion of a Brownian particle in the presence of a correlated external random force. The force is modeled by an Ornstein Uhlenbeck process. We investigate the fluctuations of the work done by the external force on the Brownian particle in a given time interval in the steady state. We calculate the large deviation functions as well as the complete asymptotic form of the probability density function of the performed work. We also discuss the symmetry properties of the large deviation functions for this system. Finally we perform numerical simulations and they are in a very good agreement with the analytic results. PMID- 25493750 TI - Quantum Szilard engines with arbitrary spin. AB - The quantum Szilard engine (QSZE) is a conceptual quantum engine for understanding the fundamental physics of quantum thermodynamics and information physics. We generalize the QSZE to an arbitrary spin case, i.e., a spin QSZE (SQSZE), and we systematically study the basic physical properties of both fermion and boson SQSZEs in a low-temperature approximation. We give the analytic formulation of the total work. For the fermion SQSZE, the work might be absorbed from the environment, and the change rate of the work with temperature exhibits periodicity and even-odd oscillation, which is a generalization of a spinless QSZE. It is interesting that the average absorbed work oscillates regularly and periodically in a large-number limit, which implies that the average absorbed work in a fermion SQSZE is neither an intensive quantity nor an extensive quantity. The phase diagrams of both fermion and boson SQSZEs give the SQSZE doing positive or negative work in the parameter space of the temperature and the particle number of the system, but they have different behaviors because the spin degrees of the fermion and the boson play different roles in their configuration states and corresponding statistical properties. The critical temperature of phase transition depends sensitively on the particle number. By using Landauer's erasure principle, we give the erasure work in a thermodynamic cycle, and we define an efficiency (we refer to it as information-work efficiency) to measure the engine's ability of utilizing information to extract work. We also give the conditions under which the maximum extracted work and highest information-work efficiencies for fermion and boson SQSZEs can be achieved. PMID- 25493751 TI - Universality classes in Coulomb blockade conductance peak-height statistics. AB - We investigate, using exact diagonalization techniques, the distribution of conductance peak heights in Coulomb blockade regime of a quantum dot connected to two leads under generic dot conditions. The study reveals a three-parametric dependence of the distribution: (i) two dot-lead contact characteristics and (ii) the complexity parameter, mimicking the combined effect of all dot conditions. This also indicates the presence of an infinite range of universality classes of conductance statistics, dominantly characterized just by the complexity parameter and global symmetry constraints. PMID- 25493752 TI - From explosive to infinite-order transitions on a hyperbolic network. AB - We analyze the phase transitions that emerge from the recursive design of certain hyperbolic networks that includes, for instance, a discontinuous ("explosive") transition in ordinary percolation. To this end, we solve the q-state Potts model in the analytic continuation for noninteger q with the real-space renormalization group. We find exact expressions for this one-parameter family of models that describe the dramatic transformation of the transition. In particular, this variation in q shows that the discontinuous transition is generic in the regime q<2 that includes percolation. A continuous ferromagnetic transition is recovered in a singular manner only for the Ising model, q=2. For q>2 the transition immediately transforms into an infinitely smooth order parameter of the Berezinskii-Kosterlitz-Thouless type. PMID- 25493753 TI - Characterization of maximally random jammed sphere packings: Voronoi correlation functions. AB - We characterize the structure of maximally random jammed (MRJ) sphere packings by computing the Minkowski functionals (volume, surface area, and integrated mean curvature) of their associated Voronoi cells. The probability distribution functions of these functionals of Voronoi cells in MRJ sphere packings are qualitatively similar to those of an equilibrium hard-sphere liquid and partly even to the uncorrelated Poisson point process, implying that such local statistics are relatively structurally insensitive. This is not surprising because the Minkowski functionals of a single Voronoi cell incorporate only local information and are insensitive to global structural information. To improve upon this, we introduce descriptors that incorporate nonlocal information via the correlation functions of the Minkowski functionals of two cells at a given distance as well as certain cell-cell probability density functions. We evaluate these higher-order functions for our MRJ packings as well as equilibrium hard spheres and the Poisson point process. It is shown that these Minkowski correlation and density functions contain visibly more information than the corresponding standard pair-correlation functions. We find strong anticorrelations in the Voronoi volumes for the hyperuniform MRJ packings, consistent with previous findings for other pair correlations [A. Donev et al., Phys. Rev. Lett. 95, 090604 (2005)PRLTAO0031-900710.1103/PhysRevLett.95.090604], indicating that large-scale volume fluctuations are suppressed by accompanying large Voronoi cells with small cells, and vice versa. In contrast to the aforementioned local Voronoi statistics, the correlation functions of the Voronoi cells qualitatively distinguish the structure of MRJ sphere packings (prototypical glasses) from that of not only the Poisson point process but also the correlated equilibrium hard-sphere liquids. Moreover, while we did not find any perfect icosahedra (the locally densest possible structure in which a central sphere contacts 12 neighbors) in the MRJ packings, a preliminary Voronoi topology analysis indicates the presence of strongly distorted icosahedra. PMID- 25493754 TI - Controlling symmetry-breaking states by a hidden quantity in multiplicative noise. AB - The inhomogeneity of multiplicative white noise leads to various coupling modes between deterministic and stochastic forces. We investigate the phase transition induced by the variation of the coupling mode through manipulating its characteristic parameter continuously. Even when the noise strength is fixed, an increase of this parameter can enhance or inhibit the symmetry-breaking state. We also propose a scheme to implement these phase transitions experimentally. Our result demonstrates that the coupling mode previously considered to be a mathematical convention serves as an additional quantity leading to physically observable phase transitions. This observation provides a mechanism to control the effect of noise without regulating the noise strength. PMID- 25493755 TI - Ground-state structures in Ising magnets on the Shastry-Sutherland lattice with long-range interactions and fractional magnetization plateaus in TmB_{4} AB - A method for the study of the ground states of lattice-gas models or equivalent spin models with extended-range interactions is proposed. It is shown that effect of longer-range interactions can be studied in terms of the solution of the ground-state problem for a model with short-range interactions. The method is applied to explain the emergence of fractional magnetization plateaus in TmB_{4} regarded as a strong Ising magnet on the Shastry-Sutherland lattice with long range interactions. PMID- 25493756 TI - Noise-benefit forbidden-interval theorems for threshold signal detectors based on cross correlations. AB - We show that the main forbidden interval theorems of stochastic resonance hold for a correlation performance measure. Earlier theorems held only for performance measures based on mutual information or the probability of error detection. Forbidden interval theorems ensure that a threshold signal detector benefits from deliberately added noise if the average noise does not lie in an interval that depends on the threshold value. We first show that this result holds for correlation for all finite-variance noise and for all forms of infinite-variance stable noise. A second forbidden-interval theorem gives necessary and sufficient conditions for a local noise benefit in a bipolar signal system when the noise comes from a location-scale family. A third theorem gives a general condition for a local noise benefit for arbitrary signals with finite second moments and for location-scale noise. This result also extends forbidden intervals to forbidden bands of parameters. A fourth theorem gives necessary and sufficient conditions for a local noise benefit when both the independent signal and noise are normal. A final theorem derives necessary and sufficient conditions for forbidden bands when using arrays of threshold detectors for arbitrary signals and location-scale noise. PMID- 25493757 TI - General achievable bound of extractable work under feedback control. AB - A general achievable upper bound of extractable work under feedback control is given, where nonequilibrium equalities are generalized so as to be applicable to error-free measurements. The upper bound involves a term which arises from the part of the process whose information becomes unavailable and is related to the weight of the singular part of the reference probability measure. The obtained upper bound of extractable work is more stringent than the hitherto known one and sets a general achievable bound for a given feedback protocol. Guiding principles of designing the optimal protocol are also suggested. Examples are presented to illustrate our general results. PMID- 25493758 TI - Universal free-energy distribution in the critical point of a random Ising ferromagnet. AB - We discuss the non-self-averaging phenomena in the critical point of weakly disordered Ising ferromagnet. In terms of the renormalized replica Ginzburg Landau Hamiltonian in dimensions D<4, we derive an explicit expression for the probability distribution function (PDF) of the critical free-energy fluctuations. In particular, using known fixed-point values for the renormalized coupling parameters, we obtain the universal curve for such PDF in the dimension D=3. It is demonstrated that this function is strongly asymmetric: its left tail is much slower than the right one. PMID- 25493759 TI - Temperature gradients in equilibrium: Small microcanonical systems in an external field. AB - We consider the statistical mechanics of a small gaseous system subject to a constant external field. As is well known, in the canonical ensemble, that the system (i) obeys a barometric formula for the density profile, and (ii) the kinetic temperature is independent of height, even when the system is small. We show here that in the microcanonical ensemble the kinetic temperature of the particles affected by the field is not constant with height, but that rather, generally speaking, it decreases with a gradient of order 1/N. Even more, if we have a mixture of two species, one which is influenced by the field and the other which is not, we find that the two species' kinetic temperatures are generally different, even at the same height. These facts are shown in detail by studying a simple mechanical model: a Lorentz Gas where particles and spinning disks interact and the particles are subjected to a constant external force. In the microcanonical ensemble, the kinetic temperature of the particles is indeed found to vary with height; the disks' kinetic temperature, on the other hand, is height independent, and thus, differs from that of the particles with which they interact. PMID- 25493760 TI - Multiplicative jump processes and applications to leaching of salt and contaminants in the soil. AB - We consider simple systems driven multiplicatively by white shot noise, which appear in the modeling of the dynamics of soil nutrients and contaminants. The dynamics of these systems is analyzed in two ways: solving a hierarchy of linear ordinary differential equations for the moments, which gives a time scale of convergence of the stationary probability density function; and characterizing the crossing properties, such as the mean first-passage time and the mean frequency of level crossing. These results are readily applicable to the study of geophysical systems, such as the problem of accumulation of salt in the root zone, i.e., soil salinization. PMID- 25493761 TI - Stability of fixed points and generalized critical behavior in multifield models. AB - We study models with three coupled vector fields characterized by O(N_{1})?O(N_{2})?O(N_{3}) symmetry. Using the nonperturbative functional renormalization group, we derive beta functions for the couplings and anomalous dimensions in d dimensions. Specializing to the case of three dimensions, we explore interacting fixed points that generalize the O(N) Wilson-Fisher fixed point. We find a symmetry-enhanced isotropic fixed point, a large class of fixed points with partial symmetry enhancement, as well as partially and fully decoupled fixed-point solutions. We discuss their stability properties for all values of N_{1},N_{2}, and N_{3}, emphasizing important differences to the related two-field models. For small numbers of field components, we find no stable fixed-point solutions, and we argue that this can be attributed to the presence of a large class of possible (mixed) couplings in the three-field and multifield models. Furthermore, we contrast different mechanisms for stability interchange between fixed points in the case of the two- and three-field models, which generically proceed through fixed-point collisions. PMID- 25493762 TI - Dynamics of a homogeneous active dumbbell system. AB - We analyze the dynamics of a two-dimensional system of interacting active dumbbells. We characterize the mean-square displacement, linear response function, and deviation from the equilibrium fluctuation-dissipation theorem as a function of activity strength, packing fraction, and temperature for parameters such that the system is in its homogeneous phase. While the diffusion constant in the last diffusive regime naturally increases with activity and decreases with packing fraction, we exhibit an intriguing nonmonotonic dependence on the activity of the ratio between the finite-density and the single-particle diffusion constants. At fixed packing fraction, the time-integrated linear response function depends nonmonotonically on activity strength. The effective temperature extracted from the ratio between the integrated linear response and the mean-square displacement in the last diffusive regime is always higher than the ambient temperature, increases with increasing activity, and, for small active force, monotonically increases with density while for sufficiently high activity it first increases and next decreases with the packing fraction. We ascribe this peculiar effect to the existence of finite-size clusters for sufficiently high activity and density at the fixed (low) temperatures at which we worked. The crossover occurs at lower activity or density the lower the external temperature. The finite-density effective temperature is higher (lower) than the single dumbbell one below (above) a crossover value of the Peclet number. PMID- 25493763 TI - Role of interference in the photosynthetic heat engine. AB - The observation of quantum coherence in pigment-protein complexes has attracted considerable interest. One such endeavor entails applying a quantum heat engine to model the photosynthetic reaction center, but the definition of work used is inconsistent with that defined in quantum thermodynamics. Using the definition of work proposed in Weimer et al. [Europhys. Lett. 83, 30008 (2008)EULEEJ0295 507510.1209/0295-5075/83/30008], we investigated two proposals for enhancing the performance of the photosynthetic reaction center. In proposal A, which is similar to that in Dorfman et al. [Proc. Natl. Acad. Sci. USA 110, 2746 (2013)PNASA60027-842410.1073/pnas.1212666110], we found that the power and current-voltage characteristic of the heat engine can be increased by Fano interference but the efficiency cannot. In proposal B, which is similar to that in Creatore et al. [Phys. Rev. Lett. 111, 253601 (2013)PRLTAO0031 900710.1103/PhysRevLett.111.253601], we found that the mechanism of strengthening the performance of the heat engine is invalid; i.e., the dipole-dipole interaction between two electron donors could not increase the power, efficiency, or current-voltage characteristic. PMID- 25493764 TI - Suppression of work fluctuations by optimal control: An approach based on Jarzynski's equality. AB - Understanding and manipulating work fluctuations in microscale and nanoscale systems are of both fundamental and practical interest. For example, aspects of work fluctuations will be an important factor in designing nanoscale heat engines. In this work, an optimal control approach directly exploiting Jarzynski's equality is proposed to effectively suppress the fluctuations in the work statistics, for systems (initially at thermal equilibrium) subject to a work protocol but isolated from a bath during the protocol. The control strategy is to minimize the deviations of individual values of e^{-betaW} from their ensemble average given by e^{-betaDeltaF}, where W is the work, beta is the inverse temperature, and DeltaF is the free energy difference between two equilibrium states. It is further shown that even when the system Hamiltonian is not fully known, it is still possible to suppress work fluctuations through a feedback loop, by refining the control target function on the fly through Jarzynski's equality itself. Numerical experiments are based on linear and nonlinear parametric oscillators. Optimal control results for linear parametric oscillators are also benchmarked with early results based on shortcuts to adiabaticity. PMID- 25493765 TI - Eigenstate thermalization and representative states on subsystems. AB - We consider a quantum system A?B made up of degrees of freedom that can be partitioned into spatially disjoint regions A and B. When the full system is in a pure state in which regions A and B are entangled, the quantum mechanics of region A described without reference to its complement is traditionally assumed to require a reduced density matrix on A. While this is certainly true as an exact matter, we argue that under many interesting circumstances expectation values of typical operators anywhere inside A can be computed from a suitable pure state on A alone, with a controlled error. We use insights from quantum statistical mechanics-specifically the eigenstate thermalization hypothesis (ETH) to argue for the existence of such "representative states." PMID- 25493766 TI - Restoring the consistency with the contact density theorem of a classical density functional theory of ions at a planar electrical double layer. AB - Classical density functional theory (DFT) of fluids is a fast and efficient theory to compute the structure of the electrical double layer in the primitive model of ions where ions are modeled as charged, hard spheres in a background dielectric. While the hard-core repulsive component of this ion-ion interaction can be accurately computed using well-established DFTs, the electrostatic component is less accurate. Moreover, many electrostatic functionals fail to satisfy a basic theorem, the contact density theorem, that relates the bulk pressure, surface charge, and ion densities at their distances of closest approach for ions in equilibrium at a smooth, hard, planar wall. One popular electrostatic functional that fails to satisfy the contact density theorem is a perturbation approach developed by Kierlik and Rosinberg [Phys. Rev. A 44, 5025 (1991)PLRAAN1050-294710.1103/PhysRevA.44.5025] and Rosenfeld [J. Chem. Phys. 98, 8126 (1993)JCPSA60021-960610.1063/1.464569], where the full free-energy functional is Taylor-expanded around a bulk (homogeneous) reference fluid. Here, it is shown that this functional fails to satisfy the contact density theorem because it also fails to satisfy the known low-density limit. When the functional is corrected to satisfy this limit, a corrected bulk pressure is derived and it is shown that with this pressure both the contact density theorem and the Gibbs adsorption theorem are satisfied. PMID- 25493767 TI - Stochastic resonance in bistable spin-crossover compounds with light-induced transitions. AB - This article presents a theoretical prediction of stochastic resonance in spin crossover materials. The analysis of stochastic resonance phenomenon in a spin crossover system is performed in the framework of the phenomenological kinetic model with light-induced transition described by dynamical potential in terms of the Lyapunov functions. By using numerical simulation of stochastic trajectories with white- and colored-noise action, the evaluation of stochastic resonance is carried out by signal-to-noise ratio of the system output. The corresponding signal-to-noise ratio features a two-peak behavior which is related to the asymmetric shape of the dynamic potential. For the case of the Ornstein-Uhlenbeck process, the variations of resonance condition with respect to different autocorrelation times are additionally studied. PMID- 25493768 TI - Reexamination of pure qubit work extraction. AB - Many work extraction or information erasure processes in the literature involve the raising and lowering of energy levels via external fields. But even if the actual system is treated quantum mechanically, the field is assumed to be classical and of infinite strength, hence not developing any correlations with the system or experiencing back-actions. We extend these considerations to a fully quantum mechanical treatment by studying a spin-1/2 particle coupled to a finite-sized directional quantum reference frame, a spin-l system, which models an external field. With this concrete model together with a bosonic thermal bath, we analyze the back-action a finite-size field suffers during a quantum mechanical work extraction process and the effect this has on the extractable work and highlight a range of assumptions commonly made when considering such processes. The well-known semiclassical treatment of work extraction from a pure qubit predicts a maximum extractable work W=kTlog2 for a quasistatic process, which holds as a strict upper bound in the fully quantum mechanical case and is attained only in the classical limit. We also address the problem of emergent local time dependence in a joint system with a globally fixed Hamiltonian. PMID- 25493769 TI - Statistical properties of spectral fluctuations of N interacting bosons in a harmonic trap. AB - Spectral fluctuations of a system of N weakly interacting bosons in an isotropic harmonic trap are studied, with the focus on the deviations from Poisson spectral statistics, typical of a quantum integrable systems. We have utilized the ideas formulated by Makino et al. [Phys. Rev. E 67, 066205 (2003)1063 651X10.1103/PhysRevE.67.066205] who have extended the approach of Berry and Robnik [J. Phys. A 17, 2413 (1984)JPHAC50305-447010.1088/0305-4470/17/12/013]. Earlier investigations of the Berry conjecture [Proc. R. Soc. London, Ser. A 356, 375 (1977)1364-502110.1098/rspa.1977.0140] of Poisson spectral statistics mainly considered quantum systems whose classical counterparts are integrable. However, the system of N weakly interacting bosons in the external trap has no classical counterpart. Also, it is a realistic and experimentally achievable system with close relation to Bose-Einstein condensation. Thus, a stringent analysis of the applicability of the Berry conjecture to this kind of systems is indeed required. We observe that for small boson number, the system is close to integrability and the nearest-neighbor level spacing distribution and the level number variance exhibit deviations from Poisson statistics similar to those of rational rectangular billiards. PMID- 25493770 TI - Noncontractible loops in the dense O(n) loop model on the cylinder. AB - A lattice model of critical dense polymers O(n) is considered for finite cylinder geometry. Due to the presence of noncontractible loops with a fixed fugacity xi, the model at n=0 is a generalization of the critical dense polymers solved by Pearce, Rasmussen, and Villani. We found the free energy for any height N and circumference L of the cylinder. The density rho of noncontractible loops is obtained for N->infinity and large L. The results are compared with those found for the anisotropic quantum chain with twisted boundary conditions. Using the latter method, we derived rho for any O(n) model and an arbitrary fugacity. PMID- 25493771 TI - Diffusion of interacting particles in discrete geometries: Equilibrium and dynamical properties. AB - We expand on a recent study of a lattice model of interacting particles [Phys. Rev. Lett. 111, 110601 (2013)PRLTAO0031-900710.1103/PhysRevLett.111.110601]. The adsorption isotherm and equilibrium fluctuations in particle number are discussed as a function of the interaction. Their behavior is similar to that of interacting particles in porous materials. Different expressions for the particle jump rates are derived from transition-state theory. Which expression should be used depends on the strength of the interparticle interactions. Analytical expressions for the self- and transport diffusion are derived when correlations, caused by memory effects in the environment, are neglected. The diffusive behavior is studied numerically with kinetic Monte Carlo (kMC) simulations, which reproduces the diffusion including correlations. The effect of correlations is studied by comparing the analytical expressions with the kMC simulations. It is found that the Maxwell-Stefan diffusion can exceed the self-diffusion. To our knowledge, this is the first time this is observed. The diffusive behavior in one dimensional and higher-dimensional systems is qualitatively the same, with the effect of correlations decreasing for increasing dimension. The length dependence of both the self- and transport diffusion is studied for one-dimensional systems. For long lengths the self-diffusion shows a 1/L dependence. Finally, we discuss when agreement with experiments and simulations can be expected. The assumption that particles in different cavities do not interact is expected to hold quantitatively at low and medium particle concentrations if the particles are not strongly interacting. PMID- 25493772 TI - Ground-state energy of the q-state Potts model: The minimum modularity. AB - A wide range of interacting systems can be described by complex networks. A common feature of such networks is that they consist of several communities or modules, the degree of which may quantified as the modularity. However, even a random uncorrelated network, which has no obvious modular structure, has a finite modularity due to the quenched disorder. For this reason, the modularity of a given network is meaningful only when it is compared with that of a randomized network with the same degree distribution. In this context, it is important to calculate the modularity of a random uncorrelated network with an arbitrary degree distribution. The modularity of a random network has been calculated [Reichardt and Bornholdt, Phys. Rev. E 76, 015102 (2007)PLEEE81539 375510.1103/PhysRevE.76.015102]; however, this was limited to the case whereby the network was assumed to have only two communities, and it is evident that the modularity should be calculated in general with q(>=2) communities. Here we calculate the modularity for q communities by evaluating the ground-state energy of the q-state Potts Hamiltonian, based on replica symmetric solutions assuming that the mean degree is large. We found that the modularity is proportional to / regardless of q and that only the coefficient depends on q. In particular, when the degree distribution follows a power law, the modularity is proportional to ^{-1/2}. Our analytical results are confirmed by comparison with numerical simulations. Therefore, our results can be used as reference values for real-world networks. PMID- 25493773 TI - Fick-Jacobs equation for channels over three-dimensional curves. AB - The purpose of this paper is to provide a new formula for the effective diffusion coefficient of a generalized Fick-Jacobs equation for narrow three-dimensional channels. The generalized Fick-Jacobs equation is obtained by projecting the three-dimensional diffusion equation along the normal directions of a curve in three-dimensional space that roughly resembles the narrow channel. The projection (or dimensional reduction) is achieved by integrating the diffusion equation along the cross sections of the channel contained in the planes orthogonal to the curve. We show that the resulting formula for the associated effective diffusion coefficient can be expressed in terms of the geometric moments of the channel's cross sections and the curve's curvature. We show the effect that a rotating cross section with offset has on the effective diffusion coefficient. PMID- 25493774 TI - Re-examining the self-contained quantum refrigerator in the strong-coupling regime. AB - We revisit the self-contained quantum refrigerator in the strong-internal coupling regime by employing the quantum optical master equation. It is shown that strong internal coupling reduces the cooling ability of the refrigerator. In contrast to the weak-coupling case, strong internal coupling could lead to quite different and even converse thermodynamic behaviors. PMID- 25493775 TI - Weakly nonequilibrium properties of a symmetric inclusion process with open boundaries. AB - We study close-to-equilibrium properties of a one-dimensional symmetric inclusion process (SIP) with finite size by coupling it to two particle reservoirs at the two boundaries with slightly different chemical potentials. The boundaries introduce irreversibility and induce a weak particle current in the system. We calculate the McLennan ensemble for the SIP, which corresponds to the entropy production, and the first-order nonequilibrium correction for the stationary state. We find that the first-order correction is a product measure and is exactly consistent with the local equilibrium measure corresponding to the steady state density profile in the finite-size SIP, without the need to be in the thermodynamic limit. This provides a novel example for microscopic extensions of the McLennan formula and the interpretation of first-order nonequilibrium correction as entropy production. PMID- 25493776 TI - Dynamical theory of spin noise and relaxation: Prospects for real-time NMR measurements. AB - Recent developments in theoretical aspects of spin noise and relaxation and their interrelationship reveal a modified spin density, distinct from the density matrix, as the necessary object to describe fluctuations in spin systems. These fluctuations are to be viewed as an intrinsic quantum mechanical property of such systems immersed in random magnetic environments and are observed as "spin noise" in the absence of any radio frequency excitation. With the prospect of ultrafast digitization, the role of spin noise in real-time parameter extraction for (NMR) spin systems, and the advantage over standard techniques, is of essential importance, especially for systems containing a small number of spins. In this article we outline prospects for harnessing the recent dynamical theory in terms of spin-noise measurement, with attention to real-time properties. PMID- 25493777 TI - Universal theory of efficiency fluctuations. AB - Using the fluctuation theorem supplemented with geometric arguments, we derive universal features of the (long-time) efficiency fluctuations for thermal and isothermal machines operating under steady or periodic driving, close or far from equilibrium. In particular, the probabilities for observing the reversible efficiency and the least likely efficiency are identical to those of the same machine working under the time-reversed driving. For time-symmetric drivings, this reversible and the least probable efficiency coincide. PMID- 25493778 TI - Detection of weak signals in memory thermal baths. AB - The nonlinear relaxation time and the statistics of the first passage time distribution in connection with the quasideterministic approach are used to detect weak signals in the decay process of the unstable state of a Brownian particle embedded in memory thermal baths. The study is performed in the overdamped approximation of a generalized Langevin equation characterized by an exponential decay in the friction memory kernel. A detection criterion for each time scale is studied: The first one is referred to as the receiver output, which is given as a function of the nonlinear relaxation time, and the second one is related to the statistics of the first passage time distribution. PMID- 25493779 TI - Virial coefficients in the (MU[over ],q)-deformed Bose gas model related to compositeness of particles and their interaction: Temperature-dependence problem. AB - We establish the relation of the second virial coefficient of a recently proposed (MU[over ],q)-deformed Bose gas model [A. M. Gavrilik and Yu. A. Mishchenko, Ukr. J. Phys. 58, 1171 (2013)] to the interaction and compositeness parameters when either of these factors is taken into account separately. When the interaction is dealt with, the deformation parameter becomes linked directly to the scattering length and the effective radius of interaction (in general, to scattering phases). The additionally arising temperature dependence is a feature absent in the deformed Bose gas model within the adopted interpretation of the deformation parameters MU[over ] and q. Here the problem of the temperature dependence is analyzed in detail and its possible solution is proposed. PMID- 25493780 TI - Improving extreme value statistics. AB - The rate of convergence in extreme value statistics is nonuniversal and can be arbitrarily slow. Further, the relative error can be unbounded in the tail of the approximation, leading to difficulty in extrapolating the extreme value fit beyond the available data. We introduce the T method, and show that by using simple nonlinear transformations the extreme value approximation can be rendered rapidly convergent in the bulk, and asymptotic in the tail, thus fixing both issues. The transformations are often parametrized by just one parameter, which can be estimated numerically. The classical extreme value method is shown to be a special case of the proposed method. We demonstrate that vastly improved results can be obtained with almost no extra cost. PMID- 25493781 TI - Nonadditive entropy maximization is inconsistent with Bayesian updating. AB - The maximum entropy method-used to infer probabilistic models from data-is a special case of Bayes's model inference prescription which, in turn, is grounded in basic propositional logic. By contrast to the maximum entropy method, the compatibility of nonadditive entropy maximization with Bayes's model inference prescription has never been established. Here we demonstrate that nonadditive entropy maximization is incompatible with Bayesian updating and discuss the immediate implications of this finding. We focus our attention on special cases as illustrations. PMID- 25493782 TI - Unraveling the cause-effect relation between time series. AB - Given two time series, can one faithfully tell, in a rigorous and quantitative way, the cause and effect between them? Based on a recently rigorized physical notion, namely, information flow, we solve an inverse problem and give this important and challenging question, which is of interest in a wide variety of disciplines, a positive answer. Here causality is measured by the time rate of information flowing from one series to the other. The resulting formula is tight in form, involving only commonly used statistics, namely, sample covariances; an immediate corollary is that causation implies correlation, but correlation does not imply causation. It has been validated with touchstone linear and nonlinear series, purportedly generated with one-way causality that evades the traditional approaches. It has also been applied successfully to the investigation of real world problems; an example presented here is the cause-and-effect relation between the two climate modes, El Nino and the Indian Ocean Dipole (IOD), which have been linked to hazards in far-flung regions of the globe. In general, the two modes are mutually causal, but the causality is asymmetric: El Nino tends to stabilize IOD, while IOD functions to make El Nino more uncertain. To El Nino, the information flowing from IOD manifests itself as a propagation of uncertainty from the Indian Ocean. PMID- 25493783 TI - Coefficient of performance under maximum chi criterion in a two-level atomic system as a refrigerator. AB - A two-level atomic system as a working substance is used to set up a refrigerator consisting of two quantum adiabatic and two isochoric processes (two constant frequency processes omega_{a} and omega_{b} with omega_{a}0, in agreement with previous work. For larger k where a hard but detectable regime exists, we find that the easy/hard transition (the point at which efficient algorithms can do better than chance) becomes a line of transitions where the accuracy jumps discontinuously at a critical value of alpha. This line ends in a critical point with a second-order transition, beyond which the accuracy is a continuous function of alpha. We demonstrate qualitatively similar transitions in two real-world networks. PMID- 25493830 TI - Effective degree Markov-chain approach for discrete-time epidemic processes on uncorrelated networks. AB - Recently, Gomez et al. proposed a microscopic Markov-chain approach (MMCA) [S. Gomez, J. Gomez-Gardenes, Y. Moreno, and A. Arenas, Phys. Rev. E 84, 036105 (2011)PLEEE81539-375510.1103/PhysRevE.84.036105] to the discrete-time susceptible infected-susceptible (SIS) epidemic process and found that the epidemic prevalence obtained by this approach agrees well with that by simulations. However, we found that the approach cannot be straightforwardly extended to a susceptible-infected-recovered (SIR) epidemic process (due to its irreversible property), and the epidemic prevalences obtained by MMCA and Monte Carlo simulations do not match well when the infection probability is just slightly above the epidemic threshold. In this contribution we extend the effective degree Markov-chain approach, proposed for analyzing continuous-time epidemic processes [J. Lindquist, J. Ma, P. Driessche, and F. Willeboordse, J. Math. Biol. 62, 143 (2011)JMBLAJ0303-681210.1007/s00285-010-0331-2], to address discrete-time binary state (SIS) or three-state (SIR) epidemic processes on uncorrelated complex networks. It is shown that the final epidemic size as well as the time series of infected individuals obtained from this approach agree very well with those by Monte Carlo simulations. Our results are robust to the change of different parameters, including the total population size, the infection probability, the recovery probability, the average degree, and the degree distribution of the underlying networks. PMID- 25493831 TI - Simple model for multiple-choice collective decision making. AB - We describe a simple model of heterogeneous, interacting agents making decisions between n>=2 discrete choices. For a special class of interactions, our model is the mean field description of random field Potts-like models and is effectively solved by finding the extrema of the average energy E per agent. In these cases, by studying the propagation of decision changes via avalanches, we argue that macroscopic dynamics is well captured by a gradient flow along E. We focus on the permutation symmetric case, where all n choices are (on average) the same, and spontaneous symmetry breaking (SSB) arises purely from cooperative social interactions. As examples, we show that bimodal heterogeneity naturally provides a mechanism for the spontaneous formation of hierarchies between decisions and that SSB is a preferred instability to discontinuous phase transitions between two symmetric points. Beyond the mean field limit, exponentially many stable equilibria emerge when we place this model on a graph of finite mean degree. We conclude with speculation on decision making with persistent collective oscillations. Throughout the paper, we emphasize analogies between methods of solution to our model and common intuition from diverse areas of physics, including statistical physics and electromagnetism. PMID- 25493832 TI - Role of long cycles in excitable dynamics on graphs. AB - Topological cycles in excitable networks can play an important role in maintaining the network activity. When properly activated, cycles act as dynamic pacemakers, sustaining the activity of the whole network. Most previous research has focused on the contributions of short cycles to network dynamics. Here, we identify the specific cycles that are used during different runs of activation in sparse random graphs, as a basis of characterizing the contribution of cycles of any length. Both simulation and a refined mean-field approach evidence a decrease in the cycle usage when the cycle length increases, reflecting a trade-off between long time for recovery after excitation and low vulnerability to out-of phase external excitations. In spite of this statistical observation, we find that the successful usage of long cycles, though rare, has important functional consequences for sustaining network activity: The average cycle length is the main feature of the cycle length distribution that affects the average lifetime of activity in the network. Particularly, use of long, rather than short, cycles correlates with higher lifetime, and cutting shortcuts in long cycles tends to increase the average lifetime of the activity. Our findings, thus, emphasize the essential, previously underrated role of long cycles in sustaining network activity. On a more general level, the findings underline the importance of network topology, particularly cycle structure, for self-sustained network dynamics. PMID- 25493833 TI - Impact of constrained rewiring on network structure and node dynamics. AB - In this paper, we study an adaptive spatial network. We consider a susceptible infected-susceptible (SIS) epidemic on the network, with a link or contact rewiring process constrained by spatial proximity. In particular, we assume that susceptible nodes break links with infected nodes independently of distance and reconnect at random to susceptible nodes available within a given radius. By systematically manipulating this radius we investigate the impact of rewiring on the structure of the network and characteristics of the epidemic. We adopt a step by-step approach whereby we first study the impact of rewiring on the network structure in the absence of an epidemic, then with nodes assigned a disease status but without disease dynamics, and finally running network and epidemic dynamics simultaneously. In the case of no labeling and no epidemic dynamics, we provide both analytic and semianalytic formulas for the value of clustering achieved in the network. Our results also show that the rewiring radius and the network's initial structure have a pronounced effect on the endemic equilibrium, with increasingly large rewiring radiuses yielding smaller disease prevalence. PMID- 25493834 TI - Supramolecular x-ray signature of susceptibility amplification in hydrogen-bonded liquids. AB - Mixing two nonconducting hydrogen-bonded liquids, each exhibiting a low dielectric relaxation strength, can result in a highly electrically absorbing fluid. This susceptibility amplification effect is demonstrated for mixtures of monohydroxy alcohols. Whereas in the pure liquids a tendency to form ringlike low dipole moment clusters prevails, in the mixtures such supramolecular structures are disfavored leading to an up to tenfold enhancement of the dielectric loss. The compositional evolution of density and mean cluster-cluster separation is traced using x-ray scattering and indicates deviations from ideal mixing with decreased C-C but simultaneously increased O-O correlation lengths. Thus, the variation in the supramolecular absorption strength could be tracked using a static scattering technique. These observations are in harmony with volume exclusion and ring open effects that predict an optimized susceptibility amplification for mixtures in which the two components occupy equal volume fractions as experimentally observed. PMID- 25493835 TI - Localization and centrality in networks. AB - Eigenvector centrality is a common measure of the importance of nodes in a network. Here we show that under common conditions the eigenvector centrality displays a localization transition that causes most of the weight of the centrality to concentrate on a small number of nodes in the network. In this regime the measure is no longer useful for distinguishing among the remaining nodes and its efficacy as a network metric is impaired. As a remedy, we propose an alternative centrality measure based on the nonbacktracking matrix, which gives results closely similar to the standard eigenvector centrality in dense networks where the latter is well behaved but avoids localization and gives useful results in regimes where the standard centrality fails. PMID- 25493836 TI - Giant components in directed multiplex networks. AB - We describe the complex global structure of giant components in directed multiplex networks that generalizes the well-known bow-tie structure, generic for ordinary directed networks. By definition, a directed multiplex network contains vertices of one type and directed edges of m different types. In directed multiplex networks, we distinguish a set of different giant components based on the existence of directed paths of different types between their vertices such that for each type of edges, the paths run entirely through only edges of that type. If, in particular, m=2, we define a strongly viable component as a set of vertices in which for each type of edges each two vertices are interconnected by at least two directed paths in both directions, running through the edges of only this type. We show that in this case, a directed multiplex network contains in total nine different giant components including the strongly viable component. In general, the total number of giant components is 3^{m}. For uncorrelated directed multiplex networks, we obtain exactly the size and the emergence point of the strongly viable component and estimate the sizes of other giant components. PMID- 25493837 TI - Multilayer weighted social network model. AB - Recent empirical studies using large-scale data sets have validated the Granovetter hypothesis on the structure of the society in that there are strongly wired communities connected by weak ties. However, as interaction between individuals takes place in diverse contexts, these communities turn out to be overlapping. This implies that the society has a multilayered structure, where the layers represent the different contexts. To model this structure we begin with a single-layer weighted social network (WSN) model showing the Granovetterian structure. We find that when merging such WSN models, a sufficient amount of interlayer correlation is needed to maintain the relationship between topology and link weights, while these correlations destroy the enhancement in the community overlap due to multiple layers. To resolve this, we devise a geographic multilayer WSN model, where the indirect interlayer correlations due to the geographic constraints of individuals enhance the overlaps between the communities and, at the same time, the Granovetterian structure is preserved. PMID- 25493838 TI - Nonconsensus opinion model on directed networks. AB - Dynamic social opinion models have been widely studied on undirected networks, and most of them are based on spin interaction models that produce a consensus. In reality, however, many networks such as Twitter and the World Wide Web are directed and are composed of both unidirectional and bidirectional links. Moreover, from choosing a coffee brand to deciding who to vote for in an election, two or more competing opinions often coexist. In response to this ubiquity of directed networks and the coexistence of two or more opinions in decision-making situations, we study a nonconsensus opinion model introduced by Shao et al. [Phys. Rev. Lett. 103, 018701 (2009)PRLTAO0031 900710.1103/PhysRevLett.103.018701] on directed networks. We define directionality xi as the percentage of unidirectional links in a network, and we use the linear correlation coefficient rho between the in-degree and out-degree of a node to quantify the relation between the in-degree and out-degree. We introduce two degree-preserving rewiring approaches which allow us to construct directed networks that can have a broad range of possible combinations of directionality xi and linear correlation coefficient rho and to study how xi and rho impact opinion competitions. We find that, as the directionality xi or the in degree and out-degree correlation rho increases, the majority opinion becomes more dominant and the minority opinion's ability to survive is lowered. PMID- 25493839 TI - Growing networks with superjoiners. AB - We study the Krapivsky-Redner (KR) network growth model, but where new nodes can connect to any number of existing nodes, m, picked from a power-law distribution p(m)~m^{-alpha}. Each of the m new connections is still carried out as in the KR model with probability redirection r (corresponding to degree exponent gamma_{KR}=1+1/r in the original KR model). The possibility to connect to any number of nodes resembles a more realistic type of growth in several settings, such as social networks, routers networks, and networks of citations. Here we focus on the in-, out-, and total-degree distributions and on the potential tension between the degree exponent alpha, characterizing new connections (outgoing links), and the degree exponent gamma_{KR}(r) dictated by the redirection mechanism. PMID- 25493840 TI - Origin of the computational hardness for learning with binary synapses. AB - Through supervised learning in a binary perceptron one is able to classify an extensive number of random patterns by a proper assignment of binary synaptic weights. However, to find such assignments in practice is quite a nontrivial task. The relation between the weight space structure and the algorithmic hardness has not yet been fully understood. To this end, we analytically derive the Franz-Parisi potential for the binary perceptron problem by starting from an equilibrium solution of weights and exploring the weight space structure around it. Our result reveals the geometrical organization of the weight space; the weight space is composed of isolated solutions, rather than clusters of exponentially many close-by solutions. The pointlike clusters far apart from each other in the weight space explain the previously observed glassy behavior of stochastic local search heuristics. PMID- 25493841 TI - Blind and myopic ants in heterogeneous networks. AB - The diffusion processes on complex networks may be described by different Laplacian matrices due to heterogeneous connectivity. Here we investigate the random walks of blind ants and myopic ants on heterogeneous networks: While a myopic ant hops to a neighbor node every step, a blind ant may stay or hop with probabilities that depend on node connectivity. By analyzing the trajectories of blind ants, we show that the asymptotic behaviors of both random walks are related by rescaling time and probability with node connectivity. Using this result, we show how the small eigenvalues of the Laplacian matrices generating the two random walks are related. As an application, we show how the return-to origin probability of a myopic ant can be used to compute the scaling behaviors of the Edwards-Wilkinson model, a representative model of load balancing on networks. PMID- 25493842 TI - Imitation versus payoff: Duality of the decision-making process demonstrates criticality and consensus formation. AB - We consider a dual model of decision making, in which an individual forms its opinion based on contrasting mechanisms of imitation and rational calculation. The decision-making model (DMM) implements imitating behavior by means of a network of coupled two-state master equations that undergoes a phase transition at a critical value of a control parameter. The evolutionary spatial game, being a generalization of the prisoner's dilemma game, is used to determine in objective fashion the cooperative or anticooperative strategy adopted by individuals. Interactions between two sources of dynamics increases the domain of initial states attracted to phase transition dynamics beyond that of the DMM network in isolation. Additionally, on average the influence of the DMM on the game increases the final observed fraction of cooperators in the system. PMID- 25493843 TI - Properties of interaction networks underlying the minority game. AB - The minority game is a well-known agent-based model with no explicit interaction among its agents. However, it is known that they interact through the global magnitudes of the model and through their strategies. In this work we have attempted to formalize the implicit interactions among minority game agents as if they were links on a complex network. We have defined the link between two agents by quantifying the similarity between them. This link definition is based on the information of the instance of the game (the set of strategies assigned to each agent at the beginning) without any dynamic information on the game and brings about a static, unweighed and undirected network. We have analyzed the structure of the resulting network for different parameters, such as the number of agents (N) and the agent's capacity to process information (m), always taking into account games with two strategies per agent. In the region of crowd effects of the model, the resulting networks structure is a small-world network, whereas in the region where the behavior of the minority game is the same as in a game of random decisions, networks become a random network of Erdos-Renyi. The transition between these two types of networks is slow, without any peculiar feature of the network in the region of the coordination among agents. Finally, we have studied the resulting static networks for the full strategy minority game model, a maximal instance of the minority game in which all possible agents take part in the game. We have explicitly calculated the degree distribution of the full strategy minority game network and, on the basis of this analytical result, we have estimated the degree distribution of the minority game network, which is in accordance with computational results. PMID- 25493844 TI - Epidemic spreading and risk perception in multiplex networks: A self-organized percolation method. AB - In this paper we study the interplay between epidemic spreading and risk perception on multiplex networks. The basic idea is that the effective infection probability is affected by the perception of the risk of being infected, which we assume to be related to the fraction of infected neighbors, as introduced by Bagnoli et al. [Phys. Rev. E 76, 061904 (2007)PLEEE81539 375510.1103/PhysRevE.76.061904]. We rederive previous results using a self organized method that automatically gives the percolation threshold in just one simulation. We then extend the model to multiplex networks considering that people get infected by physical contacts in real life but often gather information from an information network, which may be quite different from the physical ones. The similarity between the physical and the information networks determines the possibility of stopping the infection for a sufficiently high precaution level: if the networks are too different, there is no means of avoiding the epidemics. PMID- 25493845 TI - Repeated-drive adaptive feedback identification of network topologies. AB - The identification of the topological structures of complex networks from dynamical information is a significant inverse problem. How to infer the information of network topology from short-time dynamical data is a challenging topic. The presence of synchronization among nodes makes the identification of network topology difficult. In this paper we present an efficient method called the repeated-drive adaptive feedback scheme to reveal the network connectivity from short-time dynamics. By applying the short asynchronous transient data as a repeated drive, the adjacency matrix can be successfully determined in terms of the modified adaptive feedback scheme. This improved scheme is valid for both synchronous and asynchronous cases of the network and is especially efficient in the presence of global or local synchronization, where the transient drive can be obtained by perturbing the system to get a very short asynchronous transient. The detection speed of our scheme exhibits the optimized effect by adjusting the time series segment length and the coupling strength among nodes in the network. PMID- 25493846 TI - Phase transitions in a coevolving snowdrift game with costly rewiring. AB - We propose and study a dissatisfied adaptive snowdrift game with a payoff parameter r that incorporates a cost for rewiring a connection. An agent, facing adverse local environment, may switch action without a cost or rewire an existing link with a cost a so as to attain a better competing environment. Detailed numerical simulations reveal nontrivial and nonmonotonic dependence of the frequency of cooperation and the densities of different types of links on a and r. A theory that treats the cooperative and noncooperative agents separately and accounts for spatial correlation up to neighboring agents is formulated. The theory gives results that are in good agreement with simulations. The frequency of cooperation f_{C} is enhanced (suppressed) at high rewiring cost relative to that at low rewiring cost when r is small (large). For a given value of r, there exists a critical value of the rewiring cost below which the system evolves into a phase of frozen dynamics with isolated noncooperative agents segregated from a cluster of cooperative agents, and above which the system evolves into a connected population of mixed actions with continual dynamics. The phase boundary on the a-r phase space that separates the two phases with distinct structural, population and dynamical properties is mapped out. The phase diagram reveals that, as a general feature, for small r (small a), the disconnected and segregated phase can survive over a wider range of a(r). PMID- 25493847 TI - Self-avoiding walk on fractal complex networks: Exactly solvable cases. AB - We study the self-avoiding walk on complex fractal networks called the (u,v) flower by mapping it to the N-vector model in a generating function formalism. First, we analytically calculate the critical exponent nu and the connective constant by a renormalization-group analysis in arbitrary fractal dimensions. We find that the exponent nu is equal to the displacement exponent, which describes the speed of diffusion in terms of the shortest distance. Second, by obtaining an exact solution for the (u,u)-flower, we provide an example which supports the conjecture that the universality class of the self-avoiding walk on graphs is not determined only by the fractal dimension. PMID- 25493848 TI - Evolution of regulatory networks towards adaptability and stability in a changing environment. AB - Diverse biological networks exhibit universal features distinguished from those of random networks, calling much attention to their origins and implications. Here we propose a minimal evolution model of Boolean regulatory networks, which evolve by selectively rewiring links towards enhancing adaptability to a changing environment and stability against dynamical perturbations. We find that sparse and heterogeneous connectivity patterns emerge, which show qualitative agreement with real transcriptional regulatory networks and metabolic networks. The characteristic scaling behavior of stability reflects the balance between robustness and flexibility. The scaling of fluctuation in the perturbation spread shows a dynamic crossover, which is analyzed by investigating separately the stochasticity of internal dynamics and the network structure differences depending on the evolution pathways. Our study delineates how the ambivalent pressure of evolution shapes biological networks, which can be helpful for studying general complex systems interacting with environments. PMID- 25493849 TI - Solving the collective-risk social dilemma with risky assets in well-mixed and structured populations. AB - In the collective-risk social dilemma, players lose their personal endowments if contributions to the common pool are too small. This fact alone, however, does not always deter selfish individuals from defecting. The temptations to free ride on the prosocial efforts of others are strong because we are hardwired to maximize our own fitness regardless of the consequences which might have for the public good. Here we show that the addition of risky assets to the personal endowments, both of which are lost if the collective target is not reached, can contribute to solving the collective-risk social dilemma. In infinite well-mixed populations, risky assets introduce new stable and unstable mixed steady states, whereby the stable mixed steady state converges to full cooperation as either the risk of collective failure or the amount of risky assets increases. Similarly, in finite well-mixed populations, the introduction of risky assets enforces configurations where cooperative behavior thrives. In structured populations cooperation is promoted as well, but the distribution of assets among the groups is crucial. Surprisingly, we find that the completely rational allocation of assets only to the most successful groups is not optimal, and this regardless of whether the risk of collective failure is high or low. Instead, in low-risk situations bounded rational allocation of assets works best, while in high-risk situations the simplest uniform distribution of assets among all the groups is optimal. These results indicate that prosocial behavior depends sensitively on the potential losses individuals are likely to endure if they fail to cooperate. PMID- 25493850 TI - Equitable random graphs. AB - Random graph models have played a dominant role in the theoretical study of networked systems. The Poisson random graph of Erdos and Renyi, in particular, as well as the so-called configuration model, have served as the starting point for numerous calculations. In this paper we describe another large class of random graph models, which we call equitable random graphs and which are flexible enough to represent networks with diverse degree distributions and many nontrivial types of structure, including community structure, bipartite structure, degree correlations, stratification, and others, yet are exactly solvable for a wide range of properties in the limit of large graph size, including percolation properties, complete spectral density, and the behavior of homogeneous dynamical systems, such as coupled oscillators or epidemic models. PMID- 25493851 TI - Evolutionary dynamics of time-resolved social interactions. AB - Cooperation among unrelated individuals is frequently observed in social groups when their members combine efforts and resources to obtain a shared benefit that is unachievable by an individual alone. However, understanding why cooperation arises despite the natural tendency of individuals toward selfish behavior is still an open problem and represents one of the most fascinating challenges in evolutionary dynamics. Recently, the structural characterization of the networks in which social interactions take place has shed some light on the mechanisms by which cooperative behavior emerges and eventually overcomes the natural temptation to defect. In particular, it has been found that the heterogeneity in the number of social ties and the presence of tightly knit communities lead to a significant increase in cooperation as compared with the unstructured and homogeneous connection patterns considered in classical evolutionary dynamics. Here, we investigate the role of social-ties dynamics for the emergence of cooperation in a family of social dilemmas. Social interactions are in fact intrinsically dynamic, fluctuating, and intermittent over time, and they can be represented by time-varying networks. By considering two experimental data sets of human interactions with detailed time information, we show that the temporal dynamics of social ties has a dramatic impact on the evolution of cooperation: the dynamics of pairwise interactions favors selfish behavior. PMID- 25493852 TI - Experimental observation of the generation of cutoff solitons in a discrete LC nonlinear electrical line. AB - We address the problem of supratransmission of waves in a discrete nonlinear system, driven at one end by a periodic excitation at a frequency lying above the phonon band edge. In an experimental electrical transmission line made of 200 inductance-capacitance LC cells, we establish the existence of a voltage threshold for a supratransmission enabling the generation and propagation of cut off solitons within the line. The decisive role of modulational instability in the onset and development of the process of generation of cut-off solitons is clearly highlighted. The phenomenon of dissipation is identified as being particularly harmful for the soliton generation, but we show that its impact can be managed by a proper choice of the amplitude of the voltage excitation of the system. PMID- 25493853 TI - Interaction of sine-Gordon kinks and breathers with a parity-time-symmetric defect. AB - The scattering of kinks and low-frequency breathers of the nonlinear sine-Gordon (SG) equation on a spatially localized parity-time-symmetric perturbation (defect) with a balanced gain and loss is investigated numerically. It is demonstrated that if a kink passes the defect, it always restores its initial momentum and energy, and the only effect of the interaction with the defect is a phase shift of the kink. A kink approaching the defect from the gain side always passes, while in the opposite case it must have sufficiently large initial momentum to pass through the defect instead of being trapped in the loss region. The kink phase shift and critical velocity are calculated by means of the collective variable method. Kink-kink (kink-antikink) collisions at the defect are also briefly considered, showing how their pairwise repulsive (respectively, attractive) interaction can modify the collisional outcome of a single kink within the pair with the defect. For the breather, the result of its interaction with the defect depends strongly on the breather parameters (velocity, frequency, and initial phase) and on the defect parameters. The breather can gain some energy from the defect and as a result potentially even split into a kink antikink pair, or it can lose a part of its energy. Interestingly, the breather translational mode is very weakly affected by the dissipative perturbation, so that a breather penetrates more easily through the defect when it comes from the lossy side, than a kink. In all studied soliton-defect interactions, the energy loss to radiation of small-amplitude extended waves is negligible. PMID- 25493854 TI - Homogeneous delays in the Kuramoto model with time-variable parameters. AB - The Kuramoto model with time-varying parameters has been extended to consider the effect of delay in couplings. A collective dynamics arises from the interplay between the time scales of the original system, the external forcing, and the delays. This complex low-dimensional dynamics is described, uncovering an echo effect near the synchronization threshold. Hence, the delayed couplings substantially alter the dynamics of what is an open system and should be taken into consideration, depending on the ensemble's evolution time scale. We also introduce a first-harmonic approximation for the evolution of the mean field under harmonic forcing, valid for any delays and forcing of a coherent population. PMID- 25493855 TI - Synchronization in a semiclassical Kuramoto model. AB - Synchronization is a ubiquitous phenomenon occurring in social, biological, and technological systems when the internal rythms of their constituents are adapted to be in unison as a result of their coupling. This natural tendency towards dynamical consensus has spurred a large body of theoretical and experimental research in recent decades. The Kuramoto model constitutes the most studied and paradigmatic framework in which to study synchronization. In particular, it shows how synchronization appears as a phase transition from a dynamically disordered state at some critical value for the coupling strength between the interacting units. The critical properties of the synchronization transition of this model have been widely studied and many variants of its formulations have been considered to address different physical realizations. However, the Kuramoto model has been studied only within the domain of classical dynamics, thus neglecting its applications for the study of quantum synchronization phenomena. Based on a system-bath approach and within the Feynman path-integral formalism, we derive equations for the Kuramoto model by taking into account the first quantum fluctuations. We also analyze its critical properties, the main result being the derivation of the value for the synchronization onset. This critical coupling increases its value as quantumness increases, as a consequence of the possibility of tunneling that quantum fluctuations provide. PMID- 25493856 TI - Effect of delay mismatch in Pyragas feedback control. AB - Pyragas time-delayed feedback is a control scheme designed to stabilize unstable periodic orbits, which occur naturally in many nonlinear dynamical systems. It has been successfully implemented in a number of applications, including lasers and chemical systems. The control scheme targets a specific unstable periodic orbit by adding a feedback term with a delay chosen as the period of the unstable periodic orbit. However, in an experimental or industrial environment, obtaining the exact period or setting the delay equal to the exact period of the target periodic orbit may be difficult. This could be due to a number of factors, such as incomplete information on the system or the delay being set by inaccurate equipment. In this paper, we evaluate the effect of Pyragas control on the prototypical generic subcritical Hopf normal form when the delay is close to but not equal to the period of the target periodic orbit. Specifically, we consider two cases: first, a constant, and second, a linear approximation of the period. We compare these two cases to the case where the delay is set exactly to the target period, which serves as the benchmark case. For this comparison, we construct bifurcation diagrams and determine any regions where a stable periodic orbit close to the target is stabilized by the control scheme. In this way, we find that at least a linear approximation of the period is required for successful stabilization by Pyragas control. PMID- 25493857 TI - Integrable approximation of regular regions with a nonlinear resonance chain. AB - Generic Hamiltonian systems have a mixed phase space where regions of regular and chaotic motion coexist. We present a method for constructing an integrable approximation to such regular phase-space regions including a nonlinear resonance chain. This approach generalizes the recently introduced iterative canonical transformation method. In the first step of the method a normal-form Hamiltonian with a resonance chain is adapted such that actions and frequencies match with those of the nonintegrable system. In the second step a sequence of canonical transformations is applied to the integrable approximation to match the shape of regular tori. We demonstrate the method for the generic standard map at various parameters. PMID- 25493858 TI - Backward and covariant Lyapunov vectors and exponents for hard-disk systems with a steady heat current. AB - The covariant Lyapunov analysis is generalized to systems attached to deterministic thermal reservoirs that create a heat current across the system and perturb it away from equilibrium. The change in the Lyapunov exponents as a function of heat current is described and explained. Both the nonequilibrium backward and covariant hydrodynamic Lyapunov modes are analyzed and compared. The movement of the converged angle between the hydrodynamic stable and unstable conjugate manifolds with the free flight time of the dynamics is accurately predicted for any nonequilibrium system simply as a function of their exponent. The nonequilibrium positive and negative LP mode frequencies are found to be asymmetrical, causing the negative mode to oscillate between the two functional forms of each mode in the positive conjugate mode pair. This in turn leads to the angular distributions between the conjugate modes to oscillate symmetrically about pi/2 at a rate given by the difference between the positive and negative mode frequencies. PMID- 25493859 TI - Delay-induced Turing instability in reaction-diffusion equations. AB - Time delays have been commonly used in modeling biological systems and can significantly change the dynamics of these systems. Quite a few works have been focused on analyzing the effect of small delays on the pattern formation of biological systems. In this paper, we investigate the effect of any delay on the formation of Turing patterns of reaction-diffusion equations. First, for a delay system in a general form, we propose a technique calculating the critical value of the time delay, above which a Turing instability occurs. Then we apply the technique to a predator-prey model and study the pattern formation of the model due to the delay. For the model in question, we find that when the time delay is small it has a uniform steady state or irregular patterns, which are not of Turing type; however, in the presence of a large delay we find spiral patterns of Turing type. For such a model, we also find that the critical delay is a decreasing function of the ratio of carrying capacity to half saturation of the prey density. PMID- 25493860 TI - Dielectric square resonator investigated with microwave experiments. AB - We present a detailed experimental study of the symmetry properties and the momentum space representation of the field distributions of a dielectric square resonator as well as the comparison with a semiclassical model. The experiments have been performed with a flat ceramic microwave resonator. Both the resonance spectra and the field distributions were measured. The momentum space representations of the latter evidenced that the resonant states are each related to a specific classical torus, leading to the regular structure of the spectrum. Furthermore, they allow for a precise determination of the refractive index. Measurements with different arrangements of the emitting and the receiving antennas were performed and their influence on the symmetry properties of the field distributions was investigated in detail, showing that resonances with specific symmetries can be selected purposefully. In addition, the length spectrum deduced from the measured resonance spectra and the trace formula for the dielectric square resonator are discussed in the framework of the semiclassical model. PMID- 25493861 TI - Model-free quantification of time-series predictability. AB - This paper provides insight into when, why, and how forecast strategies fail when they are applied to complicated time series. We conjecture that the inherent complexity of real-world time-series data, which results from the dimension, nonlinearity, and nonstationarity of the generating process, as well as from measurement issues such as noise, aggregation, and finite data length, is both empirically quantifiable and directly correlated with predictability. In particular, we argue that redundancy is an effective way to measure complexity and predictive structure in an experimental time series and that weighted permutation entropy is an effective way to estimate that redundancy. To validate these conjectures, we study 120 different time-series data sets. For each time series, we construct predictions using a wide variety of forecast models, then compare the accuracy of the predictions with the permutation entropy of that time series. We use the results to develop a model-free heuristic that can help practitioners recognize when a particular prediction method is not well matched to the task at hand: that is, when the time series has more predictive structure than that method can capture and exploit. PMID- 25493862 TI - Autocorrelation properties of chaotic delay dynamical systems: A study on semiconductor lasers. AB - We present a detailed experimental characterization of the autocorrelation properties of a delayed feedback semiconductor laser for different dynamical regimes. We show that in many cases the autocorrelation function of laser intensity dynamics can be approximated by the analytically derived autocorrelation function obtained from a linear stochastic model with delay. We extract a set of dynamic parameters from the fit with the analytic solutions and discuss the limits of validity of our approximation. The linear model captures multiple fundamental properties of delay systems, such as the shift and asymmetric broadening of the different delay echoes. Thus, our analysis provides significant additional insight into the relevant physical and dynamical properties of delayed feedback lasers. PMID- 25493863 TI - Multicomponent long-wave-short-wave resonance interaction system: Bright solitons, energy-sharing collisions, and resonant solitons. AB - We consider a general multicomponent (2+1)-dimensional long-wave-short-wave resonance interaction (LSRI) system with arbitrary nonlinearity coefficients, which describes the nonlinear resonance interaction of multiple short waves with a long wave in two spatial dimensions. The general multicomponent LSRI system is shown to be integrable by performing the Painleve analysis. Then we construct the exact bright multisoliton solutions by applying the Hirota's bilinearization method and study the propagation and collision dynamics of bright solitons in detail. Particularly, we investigate the head-on and overtaking collisions of bright solitons and explore two types of energy-sharing collisions as well as standard elastic collision. We have also corroborated the obtained analytical one soliton solution by direct numerical simulation. Also, we discuss the formation and dynamics of resonant solitons. Interestingly, we demonstrate the formation of resonant solitons admitting breather-like (localized periodic pulse train) structure and also large amplitude localized structures akin to rogue waves coexisting with solitons. For completeness, we have also obtained dark one- and two-soliton solutions and studied their dynamics briefly. PMID- 25493864 TI - Traveling waves and global oscillations triggered by attractive molecular interactions in an excitable system. AB - During pattern formation in spatially extended systems, different mechanisms with different characteristic length scales, e.g., reaction-diffusion processes or molecular interactions, can be active. Such multiscale effects may generate new phenomena, which are not observed in systems where pattern formation occurs on a single scale. Here, we derive and analyze a reaction-diffusion model of the FitzHugh-Nagumo type with short-range attractive molecular interactions of the activator species. The model exhibits a wave instability. Simulations in one and two dimensions show traveling waves with a wavelength set by the parameters of the molecular interaction in the model. In two dimensions, simulations reveal a labyrinthine arrangement of the waves in systems with isotropic diffusion, whereas parallel bands of counterpropagating waves are formed in simulations of a model with anisotropic diffusion. The latter findings are in good qualitative agreement with experimental observation in the catalytic NO+H_{2} reaction on an anisotropic Rh(110) surface. In addition we have identified a transition regime in the simulations, where a short scale instability triggers global oscillations in an excitable regime. PMID- 25493865 TI - Self-sustained pulsations in a quantum-dot laser. AB - We analyze a delay differential equation for the amplitude of the electrical field in order to understand recent experimental observations of low-frequency oscillations in a QD laser. The laser contains no saturable absorber section and exhibits no relaxation oscillations. We investigate the problem both analytically and numerically. We show that there exists a homoclinic bifurcation from a cavity mode that is responsible for the generation of low-frequency pulsating oscillations. We discuss the role of optothermal effects in the formation of the pulsed dynamics. PMID- 25493866 TI - Donor-acceptor electron transport mediated by solitons. AB - We study the long-range electron and energy transfer mediated by solitons in a quasi-one-dimensional molecular chain (conjugated polymer, alpha-helical macromolecule, etc.) weakly bound to a donor and an acceptor. We show that for certain sets of parameter values in such systems an electron, initially located at the donor molecule, can tunnel to the molecular chain, where it becomes self trapped in a soliton state, and propagates to the opposite end of the chain practically without energy dissipation. Upon reaching the end, the electron can either bounce back and move in the opposite direction or, for suitable parameter values of the system, tunnel to the acceptor. We estimate the energy efficiency of the donor-acceptor electron transport depending on the parameter values. Our calculations show that the soliton mechanism works for the parameter values of polypeptide macromolecules and conjugated polymers. We also investigate the donor acceptor electron transport in thermalized molecular chains. PMID- 25493867 TI - Efficiency of Monte Carlo sampling in chaotic systems. AB - In this paper we investigate how the complexity of chaotic phase spaces affect the efficiency of importance sampling Monte Carlo simulations. We focus on flat histogram simulations of the distribution of finite-time Lyapunov exponent in a simple chaotic system and obtain analytically that the computational effort: (i) scales polynomially with the finite time, a tremendous improvement over the exponential scaling obtained in uniform sampling simulations; and (ii) the polynomial scaling is suboptimal, a phenomenon known as critical slowing down. We show that critical slowing down appears because of the limited possibilities to issue a local proposal in the Monte Carlo procedure when it is applied to chaotic systems. These results show how generic properties of chaotic systems limit the efficiency of Monte Carlo simulations. PMID- 25493868 TI - Dynamics and statistics of wave-particle interactions in a confined geometry. AB - A walker is a droplet bouncing on a liquid surface and propelled by the waves that it generates. This macroscopic wave-particle association exhibits behaviors reminiscent of quantum particles. This article presents a toy model of the coupling between a particle and a confined standing wave. The resulting two dimensional iterated map captures many features of the walker dynamics observed in different configurations of confinement. These features include the time decomposition of the chaotic trajectory in quantized eigenstates and the particle statistics being shaped by the wave. It shows that deterministic wave-particle coupling expressed in its simplest form can account for some quantumlike behaviors. PMID- 25493869 TI - Stable radiating gap solitons and their resonant interactions with dispersive waves in systems with a parametric pump. AB - We study the formation of gap solitons in the presence of a parametric pump. It is shown that a parametric pump can stabilize stationary solitons continuously emitting dispersive waves. The resonant interactions of the radiation and the solitons are studied and it is shown that the solitons can be effectively controlled by the radiation. In particular it is shown that the solitons can collide or get pinned to inhomogeneities due to the interactions mediated by the resonant radiation. PMID- 25493870 TI - Influence of excitability on unpinning and termination of spiral waves. AB - Application of electrical forcing to release pinned spiral waves from unexcitable obstacles and to terminate the rotation of free spiral waves at the boundary of excitable media has been investigated in thin layers of the Belousov-Zhabotinsky (BZ) reaction, prepared with different initial concentrations of H_{2}SO_{4}. Increasing [H_{2}SO_{4}] raises the excitability of the reaction and reduces the core diameter of free spiral waves as well as the wave period. An electric current with density stronger than a critical value Junpin causes a pinned spiral wave to drift away from the obstacle. For a given obstacle size, Junpin increases with [H_{2}SO_{4}]. Under an applied electrical current, the rotation center of a free spiral wave drifts along a straight path to the boundary. When the current density is stronger than a critical value Jterm, the spiral tip is forced to hit the boundary, where the spiral wave is terminated. Similar to Junpin for releasing a pinned spiral wave, Jterm also increases with [H_{2}SO_{4}]. These experimental findings were confirmed by numerical simulations using the Oregonator model, in which the excitability was adjusted via the ratio of the excitation rate to the recovery rate of the BZ reaction. Therefore, our investigation shows that decreasing the excitability can facilitate elimination of spiral waves by electrical forcing, either in the presence of obstacles or not. PMID- 25493871 TI - Cyclic motifs as the governing topological factor in time-delayed oscillator networks. AB - We identify the relative amount of short cyclic motifs as an important topological factor in networks of time-delayed Kuramoto oscillators. The patterns emerging from the cyclic motifs are most clearly distinguishable in the average frequency and the momentary frequency dispersion as a function of the time delay. In particular, the common distinction between bidirectional and unidirectional couplings is shown to have a decisive effect on the network dynamics. We argue that the behavior peculiar to the sparsely connected unidirectional random network can be described essentially as the lack of distinguishable patterns originating from cyclic motifs of any specific length. PMID- 25493872 TI - Transverse compactlike pulse signals in a two-dimensional nonlinear electrical network. AB - We investigate the compactlike pulse signal propagation in a two-dimensional nonlinear electrical transmission network with the intersite circuit elements (both in the propagation and transverse directions) acting as nonlinear resistances. Model equations for the circuit are derived and can reduce from the continuum limit approximation to a two-dimensional nonlinear Burgers equation governing the propagation of the small amplitude signals in the network. This equation has only the mass as conserved quantity and can admit as solutions cusp and compactlike pulse solitary waves, with width independent of the amplitude, according to the sign of the product of its nonlinearity coefficients. In particular, we show that only the compactlike pulse signal may propagate depending on the choice of the realistic physical parameters of the network, and next we study the dissipative effects on the pulse dynamics. The exactness of the analytical analysis is confirmed by numerical simulations which show a good agreement with results predicted by the Rosenau and Hyman K(2,2) equation. PMID- 25493873 TI - Localized lasing modes of triangular organic microlasers. AB - We investigated experimentally the ray-wave correspondence in organic microlasers of various triangular shapes. Triangular billiards are of interest since they are the simplest cases of polygonal billiards and the existence and properties of periodic orbits in triangles are not yet fully understood. The microlasers with symmetric shapes that were investigated exhibited states localized on simple periodic orbits, and their lasing characteristics like spectra and far-field distributions could be well explained by the properties of the periodic orbits. Furthermore, asymmetric triangles that do not feature simple periodic orbits were studied. Their lasing properties were found to be more complicated and could not be explained by periodic orbits. PMID- 25493874 TI - Escape dynamics of many hard disks. AB - Many-particle effects in escapes of hard disks from a square box via a hole are discussed in a viewpoint of dynamical systems. Starting from N disks in the box at the initial time, we calculate the probability P_{n}(t) for at least n disks to remain inside the box at time t for n=1,2,...,N. At early times, the probabilities P_{n}(t),n=2,3,...,N-1, are described by superpositions of exponential decay functions. On the other hand, after a long time the probability P_{n}(t) shows a power-law decay ~t^{-2n} for n?1, in contrast to the fact that it decays with a different power law ~t^{-n} for cases without any disk-disk collision. Chaotic or nonchaotic properties of the escape systems are discussed by the dynamics of a finite-time largest Lyapunov exponent, whose decay properties are related with those of the probability P_{n}(t). PMID- 25493875 TI - Turbulent diffusion of chemically reacting gaseous admixtures. AB - We study turbulent diffusion of chemically reacting gaseous admixtures in a developed turbulence. In our previous study [Phys. Rev. Lett. 80, 69 (1998)PRLTAO0031-900710.1103/PhysRevLett.80.69] using a path-integral approach for a delta-correlated in a time random velocity field, we demonstrated a strong modification of turbulent transport in fluid flows with chemical reactions or phase transitions. In the present study we use the spectral tau approximation that is valid for large Reynolds and Peclet numbers and show that turbulent diffusion of the reacting species can be strongly depleted by a large factor that is the ratio of turbulent and chemical times (turbulent Damkohler number). We have demonstrated that the derived theoretical dependence of a turbulent diffusion coefficient versus the turbulent Damkohler number is in good agreement with that obtained previously in the numerical modeling of a reactive front propagating in a turbulent flow and described by the Kolmogorov-Petrovskii Piskunov-Fisher equation. We have found that turbulent cross-effects, e.g., turbulent mutual diffusion of gaseous admixtures and turbulent Dufour effect of the chemically reacting gaseous admixtures, are less sensitive to the values of stoichiometric coefficients. The mechanisms of the turbulent cross-effects differ from the molecular cross-effects known in irreversible thermodynamics. In a fully developed turbulence and at large Peclet numbers the turbulent cross-effects are much larger than the molecular ones. The obtained results are applicable also to heterogeneous phase transitions. PMID- 25493876 TI - Convective stability of turbulent Boussinesq flow in the dissipative range and flow around small particles. AB - We consider arbitrary, possibly turbulent, Boussinesq flow which is smooth below a dissipative scale l_{d}. It is demonstrated that the stability of the flow with respect to growth of fluctuations with scale smaller than l_{d} leads to a nontrivial constraint. That involves the dimensionless strength of fluctuations of the gradients of the scalar in the direction of gravity Fl and the Rayleigh scale L depending on the Rayleigh number Ra, the Nusselt number Nu, and l_{d}. The constraint implies that the stratified fluid at rest, which is linearly stable, develops instability in the limit of large Ra. This limits observability of solution for the flow around small swimmer in quiescent stratified fluid that has closed streamlines at scale L [A. M. Ardekani and R. Stocker, Phys. Rev. Lett. 105, 084502 (2010)PRLTAO0031-900710.1103/PhysRevLett.105.084502]. Correspondingly, to study the flow at scale L one has to take turbulence into account. We demonstrate that the resulting turbulent flow around small particles or swimmers can be described by a scalar integro-differential advection-diffusion equation. Describing the solutions, we show that closed streamlines persist with finite probability. Our results seem to be the necessary basis in understanding flows around small particles and swimmers in natural marine environments. PMID- 25493877 TI - Suppression of viscous fingering in nonflat Hele-Shaw cells. AB - Viscous fingering formation in flat Hele-Shaw cells is a classical and widely studied fluid mechanical problem. Recently, instead of focusing on the development of the fingering instability, researchers have devised different strategies aiming to suppress its appearance. In this work, we study a protocol that intends to inhibit the occurrence of fingering instabilities in nonflat (spherical and conical) Hele-Shaw cell geometries. By using a mode-coupling theory to describe interfacial evolution, plus a variational controlling technique, we show that viscous fingering phenomena can be minimized in such a confined, curved environment by properly manipulating a time-dependent injection flow rate Q(t). Explicit expressions for Q(t) are derived for the specific cases of spherical and conical cells. The suitability of the controlling method is verified for linear and weakly nonlinear stages of the flow. PMID- 25493878 TI - Chemical convection in the methylene-blue-glucose system: Optimal perturbations and three-dimensional simulations. AB - A case of convection driven by chemical reactions is studied by linear stability theory and direct numerical simulations. In a plane aqueous layer of glucose, the methylene-blue-enabled catalytic oxidation of glucose produces heavier gluconic acid. As the oxygen is supplied through the top surface, the production of gluconic acid leads to an overturning instability. Our results complement earlier experimental and numerical work by Pons et al. First, we extend the model by including the top air layer with diffusive transport and Henry's law for the oxygen concentration at the interface to provide a more realistic oxygen boundary condition. Second, a linear stability analysis of the diffusive basic state in the layers is performed using an optimal perturbation approach. This method is appropriate for the unsteady basic state and determines the onset time of convection and the associated wavelength. Third, the nonlinear evolution is studied by the use of three-dimensional numerical simulations. Three typical parameters sets are explored in detail showing significant differences in pattern formation. One parameter set for which the flow is dominated by viscous forces, displays persistently growing convection cells. The other set with increased reaction rate displays a different flow regime marked by local chaotic plume emission. The simulated patterns are then compared to experimental observations. PMID- 25493879 TI - Effective surface dilatational viscosity of highly concentrated particle-laden interfaces. AB - The effective surface dilatational viscosity is calculated of a flat interface separating two immiscible fluids laden with half-immersed monodisperse rigid spherical non-Brownian particles in the limit of high particle concentration. The derivation is based upon the facts that (i) highly concentrated particle arrays in a plane form a hexagonal structure and (ii) the dominant contribution to the viscous dissipation rate arises in the thin gaps between neighboring particles. PMID- 25493880 TI - Versatile low-Reynolds-number swimmer with three-dimensional maneuverability. AB - We design and simulate the motion of a swimmer, the Quadroar, with three dimensional translation and reorientation capabilities in low-Reynolds-number conditions. The Quadroar is composed of an I-shaped frame whose body link is a simple linear actuator and four disks that can rotate about the axes of flange links. The time symmetry is broken by a combination of disk rotations and the one dimensional expansion or contraction of the body link. The Quadroar propels on forward and transverse straight lines and performs full three-dimensional reorientation maneuvers, which enable it to swim along arbitrary trajectories. We find continuous operation modes that propel the swimmer on planar and three dimensional periodic and quasiperiodic orbits. Precessing quasiperiodic orbits consist of slow lingering phases with cardioid or multiloop turns followed by directional propulsive phases. Quasiperiodic orbits allow the swimmer to access large parts of its neighboring space without using complex control strategies. We also discuss the feasibility of fabricating a nanoscale Quadroar by photoactive molecular rotors. PMID- 25493881 TI - Analytical asymptotic velocities in linear Richtmyer-Meshkov-like flows. AB - An analytical model to study the perturbation flow that evolves between a rippled piston and a shock is presented. Two boundary conditions are considered: rigid and free surface. Any time a corrugated shock is launched inside a fluid, pressure, velocity, density, and vorticity perturbations are generated downstream. As the shock separates, the pressure field decays in time and a quiescent velocity field emerges in the space in front of the piston. Depending on the boundary conditions imposed at the driving piston, either tangential or normal velocity perturbations evolve asymptotically on its surface. The goal of this work is to present explicit analytical formulas to calculate the asymptotic velocities at the piston. This is done in the important physical limits of weak and strong shocks. An approximate formula for any shock strength is also discussed for both boundary conditions. PMID- 25493882 TI - Control of flow around a circular cylinder for minimizing energy dissipation. AB - Control of flow around a circular cylinder is studied numerically aiming at minimization of the energy dissipation. First, we derive a mathematical relationship (i.e., identity) between the energy dissipation in an infinitely large volume and the surface quantities, so that the cost function can be expressed by the surface quantities only. Subsequently a control law to minimize the energy dissipation is derived by using the suboptimal control procedure [J. Fluid Mech. 401, 123 (1999)JFLSA70022-112010.1017/S002211209900659X]. The performance of the present suboptimal control law is evaluated by a parametric study by varying the value of the arbitrary parameter contained. Two Reynolds numbers, Re=100 and 1000, are investigated by two-dimensional simulations. Although no improvement is obtained at Re=100, the present suboptimal control shows better results at Re=1000 than the suboptimal controls previously proposed. With the present suboptimal control, the dissipation and the drag are reduced by 58% and 44% as compared to the uncontrolled case, respectively. The suction around the front stagnation point and the blowing in the rear half are found to be weakened as compared to those in the previous suboptimal control targeting at pressure drag reduction. A predetermined control based on the control input profile obtained by the suboptimal control is also performed. The energy dissipation and the drag are found to be reduced as much as those in the present suboptimal control. It is also found that the present suboptimal and predetermined controls have better energy efficiencies than the suboptimal control previously proposed. Investigation at different control amplitudes reveals an advantage of the present control at higher amplitude. Toward its practical implementation, a localized version of the predetermined control is also examined, and it is found to work as effectively as the continuous case. Finally, the present predetermined control is confirmed to work well in a three dimensional flow too. PMID- 25493883 TI - Gravity-driven instability of a thin liquid film underneath a soft solid. AB - The gravity-driven instability of a thin liquid film located underneath a soft solid material is considered. The equations and boundary conditions governing the solid deformation are systematically converted from a Lagrangian representation to an Eulerian representation, which is the natural framework for describing the liquid motion. This systematic conversion reveals that the continuity-of-velocity boundary condition at the liquid-solid interface is more complicated than has previously been assumed, even in the small-strain limit. We then make clear the conditions under which the commonly used simplified version of this boundary condition is valid. The small-strain approximation, lubrication theory, and linear stability analysis are applied to derive an expression for the growth rate of small-amplitude perturbations. Asymptotic analysis reveals that the coupling between the liquid and solid manifests itself as a lower effective liquid-air interfacial tension that leads to larger instability growth rates. Although this suggests that it is more difficult to maintain a stable liquid coating underneath a soft solid, the effect is expected to be weak for cases of practical interest. PMID- 25493884 TI - Spectral analysis of structure functions and their scaling exponents in forced isotropic turbulence. AB - The pseudospectral method, in conjunction with a technique for obtaining scaling exponents zeta_{n} from the structure functions S_{n}(r), is presented as an alternative to the extended self-similarity (ESS) method and the use of generalized structure functions. We propose plotting the ratio |S_{n}(r)/S_{3}(r)| against the separation r in accordance with a standard technique for analyzing experimental data. This method differs from the ESS technique, which plots S_{n}(r) against S_{3}(r), with the assumption S_{3}(r)~r. Using our method for the particular case of S_{2}(r) we obtain the result that the exponent zeta_{2} decreases as the Taylor-Reynolds number increases, with zeta_{2}->0.679+/-0.013 as R_{lambda}->infinity. This supports the idea of finite viscosity corrections to the K41 prediction for S_{2}, and is the opposite of the result obtained by ESS. The pseudospectral method also permits the forcing to be taken into account exactly through the calculation of the energy input in real space from the work spectrum of the stirring forces. PMID- 25493885 TI - Leidenfrost effect: Accurate drop shape modeling and refined scaling laws. AB - We here present a simple fitting-parameter-free theory of the Leidenfrost effect (droplet levitation above a superheated plate) covering the full range of stable shapes, i.e., from small quasispherical droplets to larger puddles floating on a pocketlike vapor film. The geometry of this film is found to be in excellent quantitative agreement with the interferometric measurements of Burton et al. [Phys. Rev. Lett. 109, 074301 (2012)PRLTAO0031 900710.1103/PhysRevLett.109.074301]. We also obtain new scalings generalizing classical ones derived by Biance et al. [Phys. Fluids 15, 1632 (2003)PHFLE61070 663110.1063/1.1572161] as far as the effect of plate superheat is concerned and highlight the relative role of evaporation, gravity, and capillarity in the vapor film. To further substantiate these findings, a treatment of the problem by matched asymptotic expansions is also presented. PMID- 25493886 TI - Effect of ambient pressure on Leidenfrost temperature. AB - The accurate prediction and control of the interaction of liquids with hot surfaces is paramount in numerous areas, including cooling applications. We present results illustrating the effect of ambient pressure on the temperature required for a droplet to levitate over a hot surface, i.e., the Leidenfrost temperature. In the present study the dependence of wetting and levitating temperatures on ambient pressure in a range of subatmospheric pressures is reported. Experimental data indicate that the Leidenfrost temperature decreases with decreasing pressure at subatmospheric pressures. A physical approach for the dependence of Leidenfrost temperature on ambient pressure, based on an analogy with saturation pressure dependence, is proposed. Furthermore, previous literature data for pressures above atmospheric are also included in the analysis to support and validate the proposed approach. In addition, the effect of substrate material, substrate roughness, and type of fluid on the Leidenfrost temperature is discussed. PMID- 25493887 TI - Collinear swimmer propelling a cargo sphere at low Reynolds number. AB - The swimming velocity and rate of dissipation of a linear chain consisting of two or three little spheres and a big sphere is studied on the basis of low Reynolds number hydrodynamics. The big sphere is treated as a passive cargo, driven by the tail of little spheres via hydrodynamic and direct elastic interaction. The fundamental solution of Stokes equations in the presence of a sphere with a no slip boundary condition, as derived by Oseen, is used to model the hydrodynamic interactions between the big sphere and the little spheres. PMID- 25493888 TI - Two-dimensional simulation of red blood cell motion near a wall under a lateral force. AB - The motion of a red blood cell suspended in a linear shear flow adjacent to a fixed boundary subject to an applied lateral force directed toward the boundary is simulated. A two-dimensional model is used that represents the viscous and elastic properties of normal red blood cells. Shear rates in the range of 100 to 600 s^{-1} are considered, and the suspending medium viscosity is 1 cP. In the absence of a lateral force, the cell executes a tumbling motion. With increasing lateral force, a transition from tumbling to tank-treading is predicted. The minimum force required to ensure tank-treading increases nonlinearly with the shear rate. Transient swinging motions occur when the force is slightly larger than the transition value. The applied lateral force is balanced by a hydrodynamic lift force resulting from the positive orientation of the long axis of the cell with respect to the wall. In the case of cyclic tumbling motions, the orientation angle takes positive values through most of the cycle, resulting in lift generation. These results are used to predict the motion of a cell close to the outer edge of the cell-rich core region that is generated when blood flows in a narrow tube. In this case, the lateral force is generated by shear-induced dispersion, resulting from cell-cell interactions in a region with a concentration gradient. This force is estimated using previous data on shear induced dispersion. The cell is predicted to execute tank-treading motions at normal physiological hematocrit levels, with the possibility of tumbling at lower hematocrit levels. PMID- 25493889 TI - Exploring the Klinkenberg effect at different scales. AB - Simulations of microflows usually require sophisticated numerical tools. Nevertheless in the slip regime, the hydrodynamic equation with slip boundary condition may be sufficient to account for the so-called Klinkenberg effect. We propose to visit this effect using a basic network of microchannels in which the Knudsen number is multiplied by two or four by introducing successive derivations to the channel. We derived an equivalent hydraulic conductivity up to second order. Theoretical results are compared both with the results of the Navier Stokes equations with slip condition and with those obtained using a Bhatnagar Gross-Krook-Hermite model developed especially for flows with a large spectrum of Knudsen numbers (typically 10^{-4}2.5*10^{-3}. PMID- 25493891 TI - Soft mean spherical approximation for dusty plasma liquids: One-component Yukawa systems with plasma shielding. AB - The structure and thermodynamics of strongly coupled dusty plasmas are investigated with the soft mean spherical approximation. This integral theory approach is analytically solvable for Yukawa pair interactions yielding a closed form solution for the direct correlation function. The pair correlation function, the structure factor, and basic thermodynamic quantities are calculated for a wide range of parameters. Exact consistency between the "energy"-"virial" thermodynamic routes and approximate consistency between the "energy" "compressibility" paths is demonstrated. Comparison with extensive molecular dynamics results is carried out and a remarkable agreement from the Coulomb limit to the strongly screened limit is revealed. The soft mean spherical approximation is concluded to be particularly well suited for the study of dusty plasma liquids, uniquely combining simplicity and accuracy. PMID- 25493892 TI - Dielectric function of dense plasmas, their stopping power, and sum rules. AB - Mathematical, particularly, asymptotic properties of the random-phase approximation, Mermin approximation, and extended Mermin-type approximation of the coupled plasma dielectric function are analyzed within the method of moments. These models are generalized for two-component plasmas. Some drawbacks and advantages of the above models are pointed out. The two-component plasma stopping power is shown to be enhanced with respect to that of the electron fluid. PMID- 25493893 TI - Connecting the wakefield instabilities in dusty plasmas. AB - The wakefield, or ion focus, formed by ions streaming past dust particles trapped in the plasma sheath leads to two types of instabilities: the Schweigert instability in multilayer systems and the mode-coupling instability that already appears in single-layer dust systems. Here, a model is presented that treats both types of instability in a common description. The parameter space for the onset of the instabilities is determined. A new variant of the mode-coupling instability is found to arise from the interaction among the layers. For weak confinement, all instabilities continuously merge into each other. For stronger confinement of the dust mainly the Schweigert type of instability is observed. PMID- 25493894 TI - Wave transmission in time- and space-variant helicoidal phononic crystals. AB - We present a dynamically tunable mechanism of wave transmission in one dimensional helicoidal phononic crystals in a shape similar to DNA structures. These helicoidal architectures allow slanted nonlinear contact among cylindrical constituents, and the relative torsional movements can dynamically tune the contact stiffness between neighboring cylinders. This results in cross-talking between in-plane torsional and out-of-plane longitudinal waves. We numerically demonstrate their versatile wave mixing and controllable dispersion behavior in both wavenumber and frequency domains. Based on this principle, a suggestion toward an acoustic configuration bearing parallels to a transistor is further proposed, in which longitudinal waves can be switched on and off through torsional waves. PMID- 25493895 TI - Resonances and circuit theory for the interaction of metallic disks and annuli with an electromagnetic field. AB - To understand the nature of the electromagnetic resonances of finite metallic surfaces, we formulate a rigorous and rapidly convergent circuit theory for the interaction of a metallic disk and a metallic annulus with an electromagnetic field. Expressions for the current induced and the resonance condition are derived. A new understanding of the nature of the resonances is obtained. For half of the resonances we find a divergent electric field at the edge of the disk, even though it is smooth in shape. For the disk, we compare with previous results using vector spheroidal wave functions and found good agreement for the resonance condition. Our approach can be generalized to other finite surfaces. PMID- 25493896 TI - State-transition-matrix method for inverse scattering in one-dimensional inhomogeneous media. AB - This study presents an analytical approach for the electromagnetic characterization of one-dimensional inhomogeneous media. The proposed approach provides the permittivity profile of the medium in terms of the reflection and transmission coefficients. The inverse solution of the permittivity profile is obtained with the help of the state-transition matrix (STM) and its properties, which are presented and proved. The advantage of using this analytic reconstruction technique is its ability to remove complexity and nonlinearity of the inverse problem. Several examples have been considered for validation of the proposed technique and, in each case, quite good agreement has been found between the original and reconstructed profiles. It has been established from the obtained results that when the scattering parameters are combined with the properties of STM, a robust and reliable technique is provided for the electromagnetic characterization of one-dimensional inhomogeneous media. PMID- 25493897 TI - Generalization of the extended optical theorem for scalar arbitrary-shape acoustical beams in spherical coordinates. AB - The extended optical theorem is generalized for scalar acoustical beams of arbitrary character with any angle of incidence interacting with an object of arbitrary geometric shape and size, and placed randomly in the beam's path with any scattering angle. Analytical expressions for the extinction, absorption, and scattering cross sections are derived, and the connections with the axial (i.e., along the direction of wave propagation) torque and radiation force calculations are discussed. As examples to illustrate the analysis for a viscoelastic object, the extinction, absorption, and scattering cross sections are provided for an infinite plane progressive wave, infinite nondiffracting Bessel beams, a zero order spherical quasi-Gaussian beam, and a Bessel-Gauss vortex beam emanating from a finite circular aperture, which reduces to a finite high-order Bessel beam, a finite zero-order Bessel beam, and a finite piston radiator vibrating uniformly with appropriate selection of beam parameters. The similarity with the asymptotic quantum inelastic cross sections is also mentioned. PMID- 25493898 TI - Contact angles in the pseudopotential lattice Boltzmann modeling of wetting. AB - In this paper we investigate the implementation of contact angles in the pseudopotential lattice Boltzmann modeling of wetting at a large density ratio rho_{L}/rho_{V}=500. The pseudopotential lattice Boltzmann model [X. Shan and H. Chen, Phys. Rev. E 49, 2941 (1994)10.1103/PhysRevE.49.2941] is a popular mesoscopic model for simulating multiphase flows and interfacial dynamics. In this model the contact angle is usually realized by a fluid-solid interaction. Two widely used fluid-solid interactions, the density-based interaction and the pseudopotential-based interaction, as well as a modified pseudopotential-based interaction formulated in the present paper are numerically investigated and compared in terms of the achievable contact angles, the maximum and the minimum densities, and the spurious currents. It is found that the pseudopotential-based interaction works well for simulating small static (liquid) contact angles theta<90^{?}, however, it is unable to reproduce static contact angles close to 180^{?}. Meanwhile, it is found that the proposed modified pseudopotential-based interaction performs better in light of the maximum and the minimum densities and is overall more suitable for simulating large contact angles theta>90^{?} as compared with the two other types of fluid-solid interactions. Furthermore, the spurious currents are found to be enlarged when the fluid-solid interaction force is introduced. Increasing the kinematic viscosity ratio between the vapor and liquid phases is shown to be capable of reducing the spurious currents caused by the fluid-solid interactions. PMID- 25493899 TI - Integral method for the calculation of Hawking radiation in dispersive media. I. Symmetric asymptotics. AB - Hawking radiation has become experimentally testable thanks to the many analog systems which mimic the effects of the event horizon on wave propagation. These systems are typically dominated by dispersion and give rise to a numerically soluble and stable ordinary differential equation only if the rest-frame dispersion relation Omega^{2}(k) is a polynomial of relatively low degree. Here we present a new method for the calculation of wave scattering in a one dimensional medium of arbitrary dispersion. It views the wave equation as an integral equation in Fourier space, which can be solved using standard and efficient numerical techniques. PMID- 25493900 TI - Integral method for the calculation of Hawking radiation in dispersive media. II. Asymmetric asymptotics. AB - Analog gravity experiments make feasible the realization of black hole space times in a laboratory setting and the observational verification of Hawking radiation. Since such analog systems are typically dominated by dispersion, efficient techniques for calculating the predicted Hawking spectrum in the presence of strong dispersion are required. In the preceding paper, an integral method in Fourier space is proposed for stationary 1+1-dimensional backgrounds which are asymptotically symmetric. Here, this method is generalized to backgrounds which are different in the asymptotic regions to the left and right of the scattering region. PMID- 25493901 TI - Sign problem of the fermionic shadow wave function. AB - We present a whole series of methods to alleviate the sign problem of the fermionic shadow wave function in the context of variational Monte Carlo. The effectiveness of our techniques is demonstrated on liquid ^{3}He. We found that although the variance is reduced, the gain in efficiency is restricted by the increased computational cost. Yet, this development not only extends the scope of the fermionic shadow wave function, but also facilitates highly accurate quantum Monte Carlo simulations previously thought not feasible. PMID- 25493902 TI - Iterative method for generating correlated binary sequences. AB - We propose an efficient iterative method for generating random correlated binary sequences with a prescribed correlation function. The method is based on consecutive linear modulations of an initially uncorrelated sequence into a correlated one. Each step of modulation increases the correlations until the desired level has been reached. The robustness and efficiency of the proposed algorithm are tested by generating sequences with inverse power-law correlations. The substantial increase in the strength of correlation in the iterative method with respect to single-step filtering generation is shown for all studied correlation functions. Our results can be used for design of disordered superlattices, waveguides, and surfaces with selective transport properties. PMID- 25493903 TI - Changes in pore geometry and relative permeability caused by carbonate precipitation in porous media. AB - The CO_{2} behavior within the reservoirs of carbon capture and storage projects is usually predicted from large-scale simulations of the reservoir. A key parameter in reservoir simulation is relative permeability. However, mineral precipitation alters the pore structure over time, and leads correspondingly to permeability changing with time. In this study, we numerically investigate the influence of carbonate precipitation on relative permeability during CO_{2} storage. The pore spaces in rock samples were extracted by high-resolution microcomputed tomography (CT) scanned images. The fluid velocity field within the three-dimensional pore spaces was calculated by the lattice Boltzmann method, while reactive transport with calcite deposition was modeled by an advection reaction formulation solved by the finite volume method. To increase the computational efficiency and reduce the processing time, we adopted a graphics processing unit parallel computing technique. The relative permeability of the sample rock was then calculated by a highly optimized two-phase lattice Boltzmann model. We also proposed two pore clogging models. In the first model, the clogging processes are modeled by transforming fluid nodes to solid nodes based on their precipitated mass level. In the second model, the porosity is artificially reduced by adjusting the gray scale threshold of the CT images. The developed method accurately simulates the mineralization process observed in laboratory experiment. Precipitation-induced evolution of pore structure significantly influenced the absolute permeability. The relative permeability, however, was much more influenced by pore reduction in the nonwetting phase than in the wetting phase. The output of the structural changes in pore geometry by this model could be input to CO_{2} reservoir simulators to investigate the outcome of sequestered CO_{2}. PMID- 25493904 TI - Variational solution of Poisson's equation using plane waves in adaptive coordinates. AB - A procedure for solving Poisson's equation using plane waves in adaptive coordinates (u) is described. The method, based on Gygi's work, writes a trial potential xi as the product of a preselected Coulomb weight MU times a plane-wave expansion depending on u. Then, the Coulomb potential generated by a given density rho is obtained by variationally optimizing xi, so that the error in the Coulomb energy is second-order with respect to the error in xi. The Coulomb weight MU is chosen to provide to each xi the typical long-range tail of a Coulomb potential, so that calculations on atoms and molecules are made possible without having to resort to the supercell approximation. As a proof of concept, the method is tested on the helium atom and the H_{2} and H_{3}^{+} molecules, where Hartree-Fock energies with better than milli-Hartree accuracy require only a moderate number of plane waves. PMID- 25493905 TI - Dean instability in double-curved channels. AB - We study the Dean instability in curved channels using the lattice Boltzmann model for generalized metrics. For this purpose, we first improve and validate the method by measuring the critical Dean number at the transition from laminar to vortex flow for a streamwise curved rectangular channel, obtaining very good agreement with the literature values. Taking advantage of the easy implementation of arbitrary metrics within our model, we study the fluid flow through a double curved channel, using ellipsoidal coordinates, and study the transition to vortex flow in dependence of the two perpendicular curvature radii of the channel. We observe transitions not only to two-cell vortex flow but also to four-cell and even six-cell vortex flow, and we find that the critical Dean number at the transition to two-cell vortex flow exhibits a minimum when the two curvature radii are approximately equal. PMID- 25493906 TI - Systematic bias in the calculation of spectral density from a three-dimensional spatial grid. AB - The energy spectral density E(k), where k is the spatial wave number, is a well known diagnostic of homogeneous turbulence and magnetohydrodynamic turbulence. However, in most of the curves plotted by different authors, some systematic kinks can be observed at k=9, 15, and 19. We claim that these kinks have no physical meaning and are in fact the signature of the method that is used to estimate E(k) from a three-dimensional spatial grid. In this paper we give another method in order to get rid of the spurious kinks and to estimate E(k) much more accurately. PMID- 25493907 TI - Consistent lattice Boltzmann equations for phase transitions. AB - Unlike conventional computational fluid dynamics methods, the lattice Boltzmann method (LBM) describes the dynamic behavior of fluids in a mesoscopic scale based on discrete forms of kinetic equations. In this scale, complex macroscopic phenomena like the formation and collapse of interfaces can be naturally described as related to source terms incorporated into the kinetic equations. In this context, a novel athermal lattice Boltzmann scheme for the simulation of phase transition is proposed. The continuous kinetic model obtained from the Liouville equation using the mean-field interaction force approach is shown to be consistent with diffuse interface model using the Helmholtz free energy. Density profiles, interface thickness, and surface tension are analytically derived for a plane liquid-vapor interface. A discrete form of the kinetic equation is then obtained by applying the quadrature method based on prescribed abscissas together with a third-order scheme for the discretization of the streaming or advection term in the Boltzmann equation. Spatial derivatives in the source terms are approximated with high-order schemes. The numerical validation of the method is performed by measuring the speed of sound as well as by retrieving the coexistence curve and the interface density profiles. The appearance of spurious currents near the interface is investigated. The simulations are performed with the equations of state of Van der Waals, Redlich-Kwong, Redlich-Kwong-Soave, Peng Robinson, and Carnahan-Starling. PMID- 25493908 TI - Detection of two isomeric binding configurations in a protein-aptamer complex with a biological nanopore. AB - Protein-DNA interactions play critical roles in biological systems, and they often involve complex mechanisms and dynamics that are not easily measured by ensemble experiments. Recently, we showed that folded proteins can be internalized inside ClyA nanopores and studied by ionic current recordings at the single-molecule level. Here, we use ClyA nanopores to sample the interaction between the G-quadruplex fold of the thrombin binding aptamer (TBA) and human thrombin (HT). Surprisingly, the internalization of the HT:TBA complex inside the nanopore induced two types of current blockades with distinguished residual current and lifetime. Using single nucleobase substitutions to TBA we showed that these two types of blockades originate from TBA binding to thrombin with two isomeric orientations. Voltage dependencies and the use of ClyA nanopores with two different diameters allowed assessing the effect of the applied potential and confinement and revealed that the two binding configurations of TBA to HT display different lifetimes. These results show that the ClyA nanopores can be used to probe conformational heterogeneity in protein:DNA interactions. PMID- 25493909 TI - A conjugate vaccine using enantiopure hapten imparts superior nicotine-binding capacity. AB - A leading nicotine conjugate vaccine was only efficacious for one-third of clinical trial participants, likely due in part to its use of racemic nicotine hapten, (+/-)-3'-AmNic. Immunization of male Wistar rats with (+)-, (-)-, or (+/ )-3'-AmNicSucTT and subsequent antibody immunoassays suggest that a vaccine using enantiopure (-)-3'-AmNic hapten imparts superior capacity to bind (-)-nicotine. Future nicotine vaccine clinical candidates must incorporate this design consideration (i.e., hapten enantiopurity) in order to maximize efficacy. PMID- 25493910 TI - A simple protocol for the management of deep sternal surgical site infection: a retrospective study of twenty-five cases. AB - BACKGROUND: Deep sternal incisional surgical site infection is a serious and potentially life-threatening complication after open heart surgery. Although a rare post-operative complication, the rates of post-operative morbidity and mortality are greater in patients who develop a deep sternal incisional surgical site infection than in those who do not. METHODS: We evaluated retrospectively the results of patients who developed a deep sternal incisional surgical site infection who were treated with either a pectoralis major flap or delayed primary closure after previous negative-pressure wound therapy (NWPT). From July 2007 to July 2012, 25 patients had a deep sternal incisional surgical site infection after open heart surgery in the Departments of Plastic Surgery and Cardiac Surgery of the Tri-Service General Hospital Medical Center. Sternal refixation was not performed in our patients. RESULTS: In 15 patients, a unilateral or bilateral pectoralis major advancement flap with a myocutaneous or muscle flap was used. In seven patients, delayed primary closure was performed after NPWT. One patient received a rectus abdominis myocutaneous flap and another received a free anterior lateral thigh flap. One patient died after developing nosocomial pneumonia with severe sepsis after debridement. CONCLUSIONS: In our series, no patient required sternal re-fixation. Our findings suggest that delayed primary closure and use of a unilateral or bilateral pectoralis major flap following NPWT for a deep sternal incisional surgical site infection are simple and quick methods for managing such difficult surgical incisions even if the deep sternal surgical site infection is located in the lower one-third of the sternum. PMID- 25493911 TI - Nanoscale charge localization induced by random orientations of organic molecules in hybrid perovskite CH3NH3PbI3. AB - Perovskite-based solar cells have achieved high solar-energy conversion efficiencies and attracted wide attentions nowadays. Despite the rapid progress in solar-cell devices, many fundamental issues of the hybrid perovskites have not been fully understood. Experimentally, it is well-known that in CH3NH3PbI3 the organic molecules CH3NH3 are randomly orientated at the room temperature, but the impact of the random molecular orientation has not been investigated. Because of the dipole moment of the organic molecule, the random orientation creates a novel system with long-range potential fluctuations unlike alloys or other conventional disordered systems. Using linear scaling ab initio methods, we find that the charge densities of the conduction band minimum and the valence band maximum are localized in nanoscales due to the potential fluctuations. The charge localization causes electron-hole separation and reduces carrier recombination rates, which may contribute to the long carrier lifetime observed in experiments. PMID- 25493912 TI - First-in-man radial access renal denervation with the ReCor RadianceTM catheter. AB - AIMS: Renal denervation is a potential new treatment therapy for resistant hypertension. However, anatomic vascular variations might complicate the procedure and increase complications. A radial approach offers easier renal artery access and is associated with a decreased risk of vascular access complications. METHODS AND RESULTS: We describe the first-in-man use of a radial access ultrasound-based renal denervation device (RadianceTM; ReCor, Palo Alto, CA, USA) in two patients with therapy-resistant hypertension. Both procedures were uneventful and resulted in significant blood pressure reductions at three month follow-up (mean office blood pressure drop [-40/-29 mmHg]; mean ambulatory blood pressure drop [-11/-8 mmHg]). CONCLUSIONS: Radial access renal artery denervation using the Radiance catheter appears to be safe and effective and should be considered an alternative option in patients referred for renal denervation. PMID- 25493913 TI - First-in-man report of residual "intra-clip" regurgitation between two MitraClips treated by AMPLATZER Vascular Plug II. AB - AIMS: We present here the first-in-man case report of a patient with a significant residual "intra-clip" jet treated by the implantation of an AMPLATZER Vascular Plug II. METHODS AND RESULTS: A 64-year-old gentleman came to our attention for mitral regurgitation (MR) recurrence four years after transcatheter mitral repair with MitraClip. After the implantation of two further MitraClips, residual intra-clip MR was present, without room for a further clip. An AMPLATZER Vascular Plug II was successfully deployed between the two clips. Final echocardiography showed residual mild MR, without any sign of mitral stenosis. CONCLUSIONS: This case demonstrates the feasibility of the implantation of an AMPLATZER Vascular Plug between two MitraClips to treat significant residual "intra-clip" MR, when the implantation of an adjunctive clip is not feasible. This approach may represent an effective therapeutic solution in case of a significant residual intra-clip jet. PMID- 25493914 TI - Equity in primary health care delivery: an examination of the cohesiveness of strategies relating to the primary healthcare system, the health workforce and hepatitis C. AB - OBJECTIVE: To suggest ways of increasing the cohesiveness of national primary healthcare strategies and hepatitis C strategies, with the aim of ensuring that all these strategies include ways to address barriers and facilitators to access to primary healthcare and equity for people with hepatitis C. METHODS: A critical review was conducted of the first national Primary Healthcare System Strategy and Health Workforce Strategy with the concurrent Hepatitis C Strategy. Content relating to provision of healthcare in private general practice was examined, focussing on issues around access and equity. RESULTS: In all strategies, achieving access to care and equity was framed around providing sufficient medical practitioners for particular locations. Equity statements were present in all policies but only the Hepatitis C Strategy identified discrimination as a barrier to equity. Approaches detailed in the Primary Healthcare System Strategy and Health Workforce Strategy regarding current resource allocation, needs assessment and general practitioner incentives were limited to groups defined within these documents and may not identify or meet the needs of people with hepatitis C. CONCLUSIONS: Actions in the primary healthcare system and health workforce strategies should be extended to additional groups beyond those listed as priority groups within the strategies. Future hepatitis C strategies should outline appropriate, detailed needs assessment methodologies and specify how actions in the broad strategies can be applied to benefit the primary healthcare needs of people with hepatitis C. PMID- 25493915 TI - Bicomponent H-bonded porous molecular networks at the liquid-solid interface: what is the influence of preorganization in solution? AB - Tailoring the architecture of porous two-dimensional networks formed by molecules is essential for developing functional materials with low dimensionality. Here we present bicomponent porous networks with tunable pore-sizes that were formed by self-assembly of hydrogen-bonding molecules at the liquid/graphite interface. Scanning tunneling microscopy investigations demonstrate the formation and coexistence of three polymorphs. It is found that the occurrence of these polymorphs depends critically on the surface coverage. Further on, atomic force microscopy measurements, spectroscopic studies, and dynamic light scattering investigations show the propensity of one of the two molecular components to form aggregates beyond the monolayer. We discuss how these preorganized aggregates in solution may affect the self-assembly at the interface. PMID- 25493916 TI - GB Virus C (GBV-C) Infection in Hepatitis C Virus (HCV) Seropositive Women with or at Risk for HIV Infection. AB - BACKGROUND: GB virus C (GBV-C) may have a beneficial impact on HIV disease progression; however, the epidemiologic characteristics of this virus are not well characterized. Behavioral factors and gender may lead to differential rates of GBV-C infection; yet, studies have rarely addressed GBV-C infections in women or racial/ethnic minorities. Therefore, we evaluated GBV-C RNA prevalence and genotype distribution in a large prospective study of high-risk women in the US. RESULTS: 438 hepatitis C virus (HCV) seropositive women, including 306 HIV infected and 132 HIV-uninfected women, from the HIV Epidemiologic Research Study were evaluated for GBV-C RNA. 347 (79.2%) women were GBV-C RNA negative, while 91 (20.8%) were GBV-C RNA positive. GBV-C positive women were younger than GBV-C negative women. Among 306 HIV-infected women, 70 (22.9%) women were HIV/GBV-C co infected. Among HIV-infected women, the only significant difference between GBV negative and GBV-positive women was age (mean 38.4 vs. 35.1 years; p<0.001). Median baseline CD4 cell counts and plasma HIV RNA levels were similar. The GBV-C genotypes were 1 (n = 31; 44.3%), 2 (n = 36; 51.4%), and 3 (n = 3; 4.3%). The distribution of GBV-C genotypes in co-infected women differed significantly by race/ethnicity. However, median CD4 cell counts and log10 HIV RNA levels did not differ by GBV-C genotype. GBV-C incidence was 2.7% over a median follow-up of 2.9 (IQR: 1.5, 4.9) years, while GBV-C clearance was 35.7% over a median follow-up of 2.44 (1.4, 3.5) years. 4 women switched genotypes. CONCLUSIONS: Age, injection drug use, a history of sex for money or drugs, and number of recent male sex partners were associated with GBV-C infection among all women in this analysis. However, CD4 cell count and HIV viral load of HIV/HCV/GBV-C co-infected women were not different although race was associated with GBV-C genotype. PMID- 25493917 TI - Proton-transfer mediated enhancement of nonlocal electronic relaxation processes in X-ray irradiated liquid water. AB - We have simulated the oxygen 1s Auger-electron spectra of normal and heavy liquid water using ab initio and quantum dynamical methods. The computed spectra are analyzed and compared to recently reported experimental data. The electronic relaxation in liquid water exposed to ionizing X-ray radiation is shown to be far more diverse and complex than anticipated and extremely different than for an isolated water molecule. A core-level ionized water molecule in the liquid phase, in addition to a local Auger process, relaxes through nonlocal energy and charge transfer, such as intermolecular Coulombic decay and electron-transfer mediated decay (ETMD). We evaluate the relative efficiencies for these three classes of relaxation processes. The quantitative estimates for the relative efficiencies of different electronic decay modes help determine yields of various reactive species produced by ionizing X-rays. The ETMD processes which are considered here for the first time in the core-level regime are found to have a surprisingly high efficiency. Importantly, we find that all nonlocal electronic relaxation processes are significantly enhanced by ultrafast proton transfer between the core-ionized water and neighboring molecules. PMID- 25493918 TI - Statistical Reporting Errors and Collaboration on Statistical Analyses in Psychological Science. AB - Statistical analysis is error prone. A best practice for researchers using statistics would therefore be to share data among co-authors, allowing double checking of executed tasks just as co-pilots do in aviation. To document the extent to which this 'co-piloting' currently occurs in psychology, we surveyed the authors of 697 articles published in six top psychology journals and asked them whether they had collaborated on four aspects of analyzing data and reporting results, and whether the described data had been shared between the authors. We acquired responses for 49.6% of the articles and found that co piloting on statistical analysis and reporting results is quite uncommon among psychologists, while data sharing among co-authors seems reasonably but not completely standard. We then used an automated procedure to study the prevalence of statistical reporting errors in the articles in our sample and examined the relationship between reporting errors and co-piloting. Overall, 63% of the articles contained at least one p-value that was inconsistent with the reported test statistic and the accompanying degrees of freedom, and 20% of the articles contained at least one p-value that was inconsistent to such a degree that it may have affected decisions about statistical significance. Overall, the probability that a given p-value was inconsistent was over 10%. Co-piloting was not found to be associated with reporting errors. PMID- 25493919 TI - Is sitting worse than static standing? How a gender analysis can move us toward understanding determinants and effects of occupational standing and walking. AB - The Yant Award was established in 1964 to honor the contributions of William P. Yant, the first president of the American Industrial Hygiene Association. It is presented annually for outstanding contributions in industrial hygiene or allied fields to an individual residing outside the United States. The 2014 award recipient is Dr. Karen Messing, Professor emeritus, Department of Biological Sciences, Universite du Quebec a Montreal and Researcher, CINBIOSE Research Centre. Gender (socially determined) differences in occupations, employment, and working conditions, task assignments, and work methods that affect exposure to health risks are increasingly documented. Interactions of (biologically influenced) sex differences with workplace parameters may also influence exposure levels. During field studies, ergonomists learn a lot about gender and sex that can be important when generating and testing hypotheses about the mechanisms that link workplace exposures to health outcomes. Prolonged standing is common in North America; almost half (45%) of Quebec workers spend more than three-quarters of their working time on their feet and 40% of these cannot sit at will. This posture has been linked to chronic back pain and musculoskeletal disorders (MSDs) in the lower limbs, but many health professionals suggest workers should stand rather than sit at work. We ask: (1) Given the fact that roughly the same proportion of men and women stand at work, what does a gender-sensitive analysis add to our ability to detect and thus prevent work-related MSDs?; (2) How does ergonomics research inform gender-sensitive analysis of occupational health data?; and (3) What do researchers need to know to orient interventions to improve general working postures? We have sought answers to these questions through collaborative research with specialists in epidemiology, occupational medicine, biomechanics, and physiology, carried out in partnership with public health organisations, community groups, and unions. We conclude that failure to characterize prolonged static standing and to apply gender-sensitive analysis can confuse assessment of musculoskeletal and circulatory effects of working postures. We suggest that prolonged static sitting and standing postures can and should be avoided by changes to workplace organization and environments. Research is needed to define optimal walking speeds and arrive at optimal ratios of sitting, standing, and walking in the workplace. PMID- 25493920 TI - Effects of sodium dodecyl sulfate on structures of poly(N-isopropylacrylamide) at the particle surface. AB - The effect of sodium dodecyl sulfate (SDS) on the poly(N-isopropylacrylamide) (PNIPAM) tethered to nanoparticles was experimentally investigated using dynamic light scattering below the lower critical solution temperature. A mean-field analytical model was used to calculate the parameters of interfacial PNIPAM-SDS complexes. Particularly, the magnitude of SDS adsorption energy obtained decreases with decreasing excluded volume parameter, implying that the partially collapsed PNIPAM brush virtually favors the adsorption of SDS onto the PNIPAM chains. A self-consistent field theory (SCFT) model was used to get a detailed quantitative description of monomer density distribution. By lowering the solvent quality, a number of phenomena related to the noncontinuity of monomer density are revealed. These phenomena are either referred to as the vertical phase separation or as its precursor, which can be delayed and eventually eliminated as the SDS coverage is increased. The distribution of free chain ends was calculated using the SCFT model. Increasing the SDS coverage gives rise to a broader and more asymmetric distribution of free chain ends, accompanied by a considerable expansion of the dead zone (below which the free chain ends do not exist), but lowering the solvent quality has opposite influences. The relative thickness of the dead zone can be scaled to a master curve, regardless of SDS coverage. PMID- 25493921 TI - Nanopore single-molecule analysis of DNA-doxorubicin interactions. AB - Anticancer activity and toxicity of doxorubicin (Dox) are associated with its DNA intercalation. To understand the role in gene regulation and the drug mechanism, it is a challenge to detect the DNA-Dox interaction at the single-molecule level without the use of laborious, time-consuming labeling assays and an error-prone amplification method. Here, we utilized the simplest and cheapest, yet highly sensitive, single-molecule nanopore technology to investigate the DNA-Dox interaction and explore in situ the intercalative reaction kinetics. Distinctive electronic signal patterns between DNA and the DNA-Dox complex allow protein nanopore to readily detect the changes in structure and function of DNA. After Dox insertion, nanopore unzipping time of DNA was elevated 10-fold while the blocking current decreased, demonstrating the higher affinity of the DNA-Dox complex (formation constant K(f) = 3.09 * 10(5) M(-1)). Continuous rapid nanopore detection in real time displayed that Dox intercalation in DNA is a two-state dynamic process: fast binding and slow conformational adaption. The nanopore platform provides a powerful tool for studying small molecule-biomacromolecule interactions and paves the way for novel applications aimed at drug screening and functional analysis. PMID- 25493922 TI - The role of parental cognitive, behavioral, and motor profiles in clinical variability in individuals with chromosome 16p11.2 deletions. AB - IMPORTANCE: Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood. OBJECTIVES: To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs. DESIGN, SETTING, AND PARTICIPANTS: Family based study design with a volunteer sample of 56 individuals with de novo 16p11.2 deletions and their noncarrier parents and siblings from the Simons Variation in Individuals Project. MAIN OUTCOMES AND MEASURES: We used linear mixed-model analysis to measure effect size and intraclass correlation to determine the influence of family background for a de novo CNV on quantitative traits representing the following 3 neurodevelopmental domains: cognitive ability (Full Scale IQ), social behavior (Social Responsiveness Scale), and neuromotor performance (Purdue Pegboard Test). We included an anthropometric trait, body mass index, for comparison. RESULTS: A significant deleterious effect of the 16p11.2 deletion was demonstrated across all domains. Relative to the biparental mean, the effect sizes were -1.7 SD for cognitive ability, 2.2 SD for social behavior, and -1.3 SD for neuromotor performance (P < .001). Despite large deleterious effects, significant positive correlations between parents and probands were preserved for the Full-Scale IQ (0.42 [P = .03]), the verbal IQ (0.53 [P = .004]), and the Social Responsiveness Scale (0.52 [P = .009]) scores. We also observed a 1-SD increase in the body mass index of probands compared with siblings, with an intraclass correlation of 0.40 (P = .07). CONCLUSIONS AND RELEVANCE: Analysis of families with de novo CNVs provides the least confounded estimate of the effect size of the 16p11.2 deletion on heritable, quantitative traits and demonstrates a 1- to 2-SD effect across all neurodevelopmental dimensions. Significant parent-proband correlations indicate that family background contributes to the phenotypic variability seen in this and perhaps other CNV disorders and may have implications for counseling families regarding their children's developmental and psychiatric prognoses. Use of biparental mean scores rather than general population mean scores may be more relevant to examine the effect of a mutation or any other cause of trait variation on a neurodevelopmental outcome and possibly on systems of diagnosis and trait ascertainment for developmental disorders. PMID- 25493923 TI - A fluorescent probe for detection of an intracellular prognostic indicator in early-stage cancer. AB - Cyclin A2 is a promising cancer prognostic indicator, but its intracellular in situ imaging is still a challenging task. This work designs an "off-on" fluorescent probe, which can fluorescently detect intracellular cyclin A2 and distinguish cancer cells. In addition, this work sheds light on the development of future protein biosensors. PMID- 25493924 TI - Suppression of the Leidenfrost effect via low frequency vibrations. AB - The ability to suppress the Leidenfrost effect is of significant importance in applications that require rapid and efficient cooling of surfaces with temperature higher than the Leidenfrost point TSL. The Leidenfrost effect will result in substantial reduction in cooling efficiency and hence there have been a few different approaches to suppress the Leidenfrost effect. The majority of these approaches relies on fabricating micro/nano-structures on heated surfaces, others rely on inducing an electric field between the droplets and the heated surfaces. In this paper, we present an approach that induces low frequency vibrations (f~10(2) Hz) on a heated surface to suppress the effect. By mapping the different magnitudes of surface acceleration [greek xi with two dots above]sversus different initial surface temperatures Ts of the substrate, three regimes that represent three distinct impact dynamics are analyzed. Regime-I represents gentle film boiling ([greek xi with two dots above]s~10(2) m s(-2) and Ts~TSL), which is associated with the formation of thin spreading lamella around the periphery of the impinged droplet; Regime-II ([greek xi with two dots above]s~10(2) m s(-2) and Ts>TSL) represents film boiling, which is associated with the rebound of the impinged droplet due to the presence of a thick vapor layer; Regime-III ([greek xi with two dots above]s~10(3) m s(-2) and Ts~TSL) represents contact boiling, which is associated with the ejection of tiny droplets due to the direct contact between the droplet and the heated surface. The estimated cooling enhancement for Regime-I is between 10% and 95%, Regime-II is between 5% and 15%, and Regime-III is between 95% and 105%. The improvement in cooling enhancement between Regime-I (strong Leidenfrost effect) and Regime-III (suppressed Leidenfrost effect) is more than 80%, demonstrating the effectiveness of using low frequency vibrations to suppress the Leidenfrost effect. PMID- 25493925 TI - Arylation of diorganochalcogen compounds with diaryliodonium triflates: metal catalysts are unnecessary. AB - Diaryliodonium triflates transfer an aryl group to the chalcogen atom of organic sulfides, selenides, and tellurides (but not ethers), in the absence of transition-metal catalyst, simply upon heating in chloroform or dichloroethane solution. PMID- 25493926 TI - Efficacy and Safety of a Lidocaine and Ropivacaine Mixture for Scalp Nerve Block and Local Infiltration Anesthesia in Patients Undergoing Awake Craniotomy. AB - BACKGROUND: Mixtures of various local anesthetics, such as lidocaine and ropivacaine, have been widely used. However, their efficacy and safety for scalp nerve blocks and local infiltration during awake craniotomy have not been fully elucidated. METHODS: We prospectively investigated 53 patients who underwent awake craniotomy. Scalp block was performed for the blockade of the supraorbital, supratrochlear, zygomaticotemporal, auriculotemporal, greater occipital, and lesser occipital nerves with a mixture containing equal volumes of 2% lidocaine and 0.75% ropivacaine, including 5 MUg/mL of epinephrine. Infiltration anesthesia was applied at the site of skin incision using the same mixture. The study outcomes included changes in heart rate and blood pressure after head pinning and skin incision, and incidence of severe pain on emergence from anesthesia. Total doses and plasma concentrations of lidocaine and ropivacaine were measured at different time points after performing the block. RESULTS: The heart rate and blood pressure after head pinning were marginally, but significantly, increased when compared with baseline values. There were no significant differences in heart rate and blood pressure before and after the skin incision. Nineteen percent of the patients (10/53) complained of incisional pain at emergence from anesthesia. The highest observed blood concentrations of lidocaine and ropivacaine were 1.9+/-0.9 and 1.1+/-0.4 MUg/mL, respectively. No acute anesthetic toxicity symptom was observed. CONCLUSIONS: Scalp block with a mixture of lidocaine and ropivacaine seems to provide effective and safe anesthetic management in patients undergoing awake craniotomy. PMID- 25493927 TI - Dexmedetomidine as an Anesthetic Adjuvant in Patients Undergoing Transsphenoidal Resection of Pituitary Tumor. AB - BACKGROUND: Transnasal transsphenoidal (TNTS) resection of pituitary tumors involves wide fluctuation in hemodynamic parameter and causes hypertension and tachycardia due to intense noxious stimuli during various stages of surgery. None of routinely used anesthetic agents effectively blunts the undesirable hemodynamic responses, and therefore usually there is a need to use increased doses of anesthetic agents. Dexmedetomidine (DEX) an alpha-2 adrenergic receptor agonist, because its sympatholytic and antinociceptive properties may ensure optimal intraoperative hemodynamic stability during critical moments of surgical manipulation. In addition, DEX reduced the anesthetic requirement with rapid recovery at the end of surgery. The main aim of our study was to evaluate the effect of DEX on perioperative hemodynamics, anesthetic requirements, and recovery characteristics in patients undergoing TNTS resection of pituitary tumors. MATERIALS AND METHODS: Forty-six patients scheduled for elective TNTS resection of pituitary tumor were randomized to receive a continuous infusion of DEX (group D) or 0.9% saline (group C). Patients in both the groups were subjected to a standardized anesthesia comprising of induction with propofol, fentanyl, vecuronium, and positive pressure ventilation with O2/air (1:1)/isoflurane. The response entropy target range during maintenance of anesthesia was 40 to 60. The hemodynamic variables at various stages of surgery, intraoperative anesthetic, and analgesic and recovery characteristics were recorded. RESULTS: Total fentanyl consumption during the study period was significantly lower in group D compared with group C (4.7 and 7.7 ug/kg, respectively; P<0.01). End-tidal isoflurane concentration requirement was found to be significantly reduced in group D compared with group C throughout the surgical period. Fentanyl and end-tidal isoflurane concentration requirement was reduced in group D compared with group C by 40% and 33.3%, respectively. Heart rate and mean arterial pressure were significantly higher in the group C compared with group D after intubation, during various stages of surgery and immediately after extubation. The group D had excellent surgical conditions and lesser bleeding in comparison to group C. Emergence time and extubation time were significantly shorter in group D compared with group C. CONCLUSIONS: DEX as an anesthetic adjuvant improved hemodynamic stability and decreased anesthetic requirements in patients undergoing TNTS resection of pituitary tumor. In addition, DEX provided better surgical field exposure conditions and early recovery from anesthesia. PMID- 25493928 TI - The Monitoring and Management of Severe Traumatic Brain Injury in the United Kingdom: Is there a Consensus?: A National Survey. AB - BACKGROUND: To survey the current practice of monitoring and management of severe traumatic brain injury (TBI) patients in the critical care units across the United Kingdom. METHODS: A structured telephone interview was conducted with senior medical or nursing staff of all the adult neurocritical care units. Thirty one neurocritical care units that managed adult patients with severe TBI were identified from the Risk Adjustment in Neurocritical Care (RAIN) study and the Society of British Neurological Surgeons. RESULTS: Intracranial pressure (ICP) monitoring was used in all the 31 institutions. Cerebral perfusion pressure was used in 30 of the 31 units and a Cerebral perfusion pressure target of 60 to 70 mm Hg was the most widely used target (25 of 31 units). Transcranial Doppler was used in 12 units (39%); brain tissue oxygen (PbtO(2)) was used in 8 (26%); cerebral microdialysis was used in 4 (13%); jugular bulb oximetry in 1 unit; and near-infrared spectrometry was not used in any unit. Continuous capnometry was used in 28 (91%) units for mechanically ventilated patients. Mannitol was the most commonly used agent for osmotherapy to treat intracranial hypertension. CONCLUSIONS: We identified that there was no clear consensus and considerable variation in practice in the management of TBI patients in UK neurocritical care units. A protocol-based management has been shown to improve outcome in sepsis patients. Given the magnitude of the problem, we conclude that there is an urgent need for international consensus guidelines for management of TBI patients in critical care units. PMID- 25493929 TI - Transesophageal Echocardiography as a Guide to Central Venous Catheter Placement in a Patient With Functional Ventriculo-atrial CSF Shunt. PMID- 25493930 TI - 2014 SNACC annual meeting report. PMID- 25493931 TI - Nuclease-containing media for resettable operation of DNA logic gates. AB - We designed and tested a system that allows DNA logic gates to respond multiple times to the addition of oligonucleotide inputs. After producing an output signal, the system spontaneously resets to the background state. This system does not require any operator action to achieve reset of a DNA logic gate, and may become useful for construction of reusable DNA-based computational devices. PMID- 25493932 TI - Giant Lysosomes as a Chemotherapy Resistance Mechanism in Hepatocellular Carcinoma Cells. AB - Despite continuous improvements in therapeutic protocols, cancer-related mortality is still one of the main problems facing public health. The main cause of treatment failure is multi-drug resistance (MDR: simultaneous insensitivity to different anti-cancer agents), the underlying molecular and biological mechanisms of which include the activity of ATP binding cassette (ABC) proteins and drug compartmentalisation in cell organelles. We investigated the expression of the main ABC proteins and the role of cytoplasmic vacuoles in the MDR of six hepatocellular carcinoma (HCC) cell lines, and confirmed the accumulation of the yellow anti-cancer drug sunitinib in giant (four lines) and small cytoplasmic vacuoles of lysosomal origin (two lines). ABC expression analyses showed that the main ABC protein harboured by all of the cell lines was PGP, whose expression was not limited to the cell membrane but was also found on lysosomes. MTT assays showed that the cell lines with giant lysosomes were more resistant to sorafenib treatment than those with small lysosomes (p<0.01), and that verapamil incubation can revert this resistance, especially if it is administered after drug pre incubation. The findings of this study demonstrate the involvement of PGP positive lysosomes in drug sequestration and MDR in HCC cell lines. The possibility of modulating this mechanism using PGP inhibitors could lead to the development of new targeted strategies to enhance HCC treatment. PMID- 25493933 TI - Natural Variation in Fish Transcriptomes: Comparative Analysis of the Fathead Minnow (Pimephales promelas) and Zebrafish (Danio rerio). AB - Fathead minnow and zebrafish are among the most intensively studied fish species in environmental toxicogenomics. To aid the assessment and interpretation of subtle transcriptomic effects from treatment conditions of interest, better characterization and understanding are needed for natural variation in gene expression among fish individuals from lab cultures. Leveraging the transcriptomics data from a number of our toxicogenomics studies conducted over the years, we conducted a meta-analysis of nearly 600 microarrays generated from the ovary tissue of untreated, reproductively mature fathead minnow and zebrafish samples. As expected, there was considerable batch-to-batch transcriptomic variation; this "batch-effect" appeared to differentially impact subsets of fish transcriptomes in a nonsystematic way. Temporally more closely spaced batches tended to share a greater transcriptomic similarity among one another. The overall level of within-batch variation was quite low in fish ovary tissue, making it a suitable system for studying chemical stressors with subtle biological effects. The observed differences in the within-batch variability of gene expression, at the levels of both individual genes and pathways, were probably both technical and biological. This suggests that biological interpretation and prioritization of genes and pathways targeted by experimental conditions should take into account both their intrinsic variability and the size of induced transcriptional changes. There was significant conservation of both the genomes and transcriptomes between fathead minnow and zebrafish. The high degree of conservation offers promising opportunities in not only studying fish molecular responses to environmental stressors by a comparative biology approach, but also effective sharing of a large amount of existing public transcriptomics data for developing toxicogenomics applications. PMID- 25493934 TI - Measuring Evolutionary Isolation for Conservation. AB - Conservation planning needs to account for limited resources when choosing those species on which to focus attention and resources. Currently, funding is biased to small sections of the tree of life, such as raptors and carnivores. One new approach for increasing the diversity of species under consideration considers how many close relatives a species has in its evolutionary tree. At least eleven different ways to measure this characteristic on phylogenies for the purposes of setting species-specific priorities for conservation have been proposed. We find that there is much redundancy within the current set, with three pairs of metrics being essentially identical. Non-redundant metrics represent different trade-offs between the unique evolutionary history represented by a species verses its average distance to all other species. Depending on which metric is used, species priority lists can differ as much as 85% for the top 100 species. We call for some consensus on the theory behind these metrics and suggest that all future developments are compared to the current published set, and offer scripts to aid such comparisons. PMID- 25493936 TI - Independent Transitions between Monsoonal and Arid Biomes Revealed by Systematic Revison of a Complex of Australian Geckos (Diplodactylus; Diplodactylidae). AB - How the widespread expansion and intensification of aridity through the Neogene has shaped the Austral biota is a major question in Antipodean biogeography. Lineages distributed across wide aridity gradients provide opportunities to examine the timing, frequency, and direction of transitions between arid and mesic regions. Here, we use molecular genetics and morphological data to investigate the systematics and biogeography of a nominal Australian gecko species (Diplodactylus conspicillatus sensu lato) with a wide distribution spanning most of the Australian Arid Zone (AAZ) and Monsoonal Tropics (AMT). Our data support a minimum of seven genetically distinct and morphologically diagnosable taxa; we thus redefine the type species, ressurrect three names from synonymy, and describe three new species. Our inferred phylogeny suggests the history and diversification of lineages in the AAZ and AMT are intimately linked, with evidence of multiple independent interchanges since the late Miocene. However, despite this shared history, related lineages in these two regions also show evidence of broadly contrasting intra-regional responses to aridification; vicarance and speciation in older and increasingly attenuated mesic regions, versus a more dynamic history including independent colonisations and recent range expansions in the younger AAZ. PMID- 25493937 TI - The Hidden Snake in the Grass: Superior Detection of Snakes in Challenging Attentional Conditions. AB - Snakes have provided a serious threat to primates throughout evolution. Furthermore, bites by venomous snakes still cause significant morbidity and mortality in tropical regions of the world. According to the Snake Detection Theory (SDT Isbell, 2006; 2009), the vital need to detect camouflaged snakes provided strong evolutionary pressure to develop astute perceptual capacity in animals that were potential targets for snake attacks. We performed a series of behavioral tests that assessed snake detection under conditions that may have been critical for survival. We used spiders as the control stimulus because they are also a common object of phobias and rated negatively by the general population, thus commonly lumped together with snakes as "evolutionary fear relevant". Across four experiments (N = 205) we demonstrate an advantage in snake detection, which was particularly obvious under visual conditions known to impede detection of a wide array of common stimuli, for example brief stimulus exposures, stimuli presentation in the visual periphery, and stimuli camouflaged in a cluttered environment. Our results demonstrate a striking independence of snake detection from ecological factors that impede the detection of other stimuli, which suggests that, consistent with the SDT, they reflect a specific biological adaptation. Nonetheless, the empirical tests we report are limited to only one aspect of this rich theory, which integrates findings across a wide array of scientific disciplines. PMID- 25493938 TI - Moderate Thermal Stress Causes Active and Immediate Expulsion of Photosynthetically Damaged Zooxanthellae (Symbiodinium) from Corals. AB - The foundation of coral reef biology is the symbiosis between corals and zooxanthellae (dinoflagellate genus Symbiodinium). Recently, coral bleaching, which often results in mass mortality of corals and the collapse of coral reef ecosystems, has become an important issue around the world as coral reefs decrease in number year after year. To understand the mechanisms underlying coral bleaching, we maintained two species of scleractinian corals (Acroporidae) in aquaria under non-thermal stress (27 degrees C) and moderate thermal stress conditions (30 degrees C), and we compared the numbers and conditions of the expelled Symbiodinium from these corals. Under non-thermal stress conditions corals actively expel a degraded form of Symbiodinium, which are thought to be digested by their host coral. This response was also observed at 30 degrees C. However, while the expulsion rates of Symbiodinium cells remained constant, the proportion of degraded cells significantly increased at 30 degrees C. This result indicates that corals more actively digest and expel damaged Symbiodinium under thermal stress conditions, likely as a mechanism for coping with environmental change. However, the increase in digested Symbiodinium expulsion under thermal stress may not fully keep up with accumulation of the damaged cells. There are more photosynthetically damaged Symbiodinium upon prolonged exposure to thermal stress, and corals release them without digestion to prevent their accumulation. This response may be an adaptive strategy to moderate stress to ensure survival, but the accumulation of damaged Symbiodinium, which causes subsequent coral deterioration, may occur when the response cannot cope with the magnitude or duration of environmental stress, and this might be a possible mechanism underlying coral bleaching during prolonged moderate thermal stress. PMID- 25493939 TI - Contraceptive Use and the Risk of Ectopic Pregnancy: A Multi-Center Case-Control Study. AB - OBJECTIVE: To evaluate the association between the risk of ectopic pregnancy (EP) and the use of common contraceptives during the previous and current conception/menstrual cycle. METHODS: A multi-center case-control study was conducted in Shanghai. Women diagnosed with EP were recruited as the case group (n = 2,411). Women with intrauterine pregnancy (IUP) (n = 2,416) and non-pregnant women (n = 2,419) were matched as controls at a ratio of 1?1. Information regarding the previous and current use of contraceptives was collected. Multivariate logistic regression analyses were performed to calculate odds ratios (ORs) and the corresponding 95% confidential intervals (CIs). RESULTS: Previous use of intrauterine devices (IUDs) was associated with a slight risk of ectopic pregnancy (AOR1 = 1.87 [95% CI: 1.48-2.37]; AOR2 = 1.84 [1.49-2.27]), and the risk increased with the duration of previous use (P1 for trend <10-4, P2 for trend <10-4). The current use of most contraceptives reduced the risk of both unwanted IUP (condom: AOR = 0.04 [0.03-0.05]; withdrawal method: AOR = 0.10 [0.07 0.13]; calendar rhythm method: AOR = 0.54 [0.40-0.73]; oral contraceptive pills [OCPs]: AOR = 0.03 [0.02-0.08]; levonorgestrel emergency contraception [LNG-EC]: AOR = 0.22 [0.16-0.30]; IUDs: AOR = 0.01 [0.005-0.012]; tubal sterilization: AOR = 0.01 [0.001-0.022]) and unwanted EP (condom: AOR1 = 0.05 [0.04-0.06]; withdrawal method: AOR1 = 0.13 [0.09-0.19]; calendar rhythm method: AOR1 = 0.66 [0.48-0.91]; OCPs: AOR1 = 0.14 [0.07-0.26]; IUDs: AOR1 = 0.17 [0.13-0.22]; tubal sterilization: AOR1 = 0.04 [0.02-0.08]). However, when contraception failed and pregnancy occurred, current use of OCPs (AOR2 = 4.06 [1.64-10.07]), LNG-EC (AOR2 = 4.87 [3.88-6.10]), IUDs (AOR2 = 21.08 [13.44-33.07]), and tubal sterilization (AOR2 = 7.68 [1.69-34.80]) increased the risk of EP compared with the non-use of contraceptives. CONCLUSION: Current use of most contraceptives reduce the risk of both IUP and EP. However, if the contraceptive method fails, the proportions of EP may be higher than those of non-users. In the case of contraceptive failure in the current cycle, EP cases should be differentiated according to current use of OCPs, LNG-EC, IUDs, and tubal sterilization. In addition, attention should be paid to women with previous long-term use of IUDs. PMID- 25493940 TI - Triacylglycerol Storage in Lipid Droplets in Procyclic Trypanosoma brucei. AB - Carbon storage is likely to enable adaptation of trypanosomes to nutritional challenges or bottlenecks during their stage development and migration in the tsetse. Lipid droplets are candidates for this function. This report shows that feeding of T. brucei with oleate results in a 4-5 fold increase in the number of lipid droplets, as quantified by confocal fluorescence microscopy and by flow cytometry of BODIPY 493/503-stained cells. The triacylglycerol (TAG) content also increased 4-5 fold, and labeled oleate is incorporated into TAG. Fatty acid carbon can thus be stored as TAG in lipid droplets under physiological growth conditions in procyclic T. brucei. beta-oxidation has been suggested as a possible catabolic pathway for lipids in T. brucei. A single candidate gene, TFEalpha1 with coding capacity for a subunit of the trifunctional enzyme complex was identified. TFEalpha1 is expressed in procyclic T. brucei and present in glycosomal proteomes, Unexpectedly, a TFEalpha1 gene knock-out mutant still expressed wild-type levels of previously reported NADP-dependent 3-hydroxyacyl CoA dehydrogenase activity, and therefore, another gene encodes this enzymatic activity. Homozygous Deltatfealpha1/Deltatfealpha1 null mutant cells show a normal growth rate and an unchanged glycosomal proteome in procyclic T. brucei. The decay kinetics of accumulated lipid droplets upon oleate withdrawal can be fully accounted for by the dilution effect of cell division in wild-type and Deltatfealpha1/Deltatfealpha1 cells. The absence of net catabolism of stored TAG in procyclic T. brucei, even under strictly glucose-free conditions, does not formally exclude a flux through TAG, in which biosynthesis equals catabolism. Also, the possibility remains that TAG catabolism is completely repressed by other carbon sources in culture media or developmentally activated in post procyclic stages in the tsetse. PMID- 25493941 TI - PCR Duplication: A One-Step Cloning-Free Method to Generate Duplicated Chromosomal Loci and Interference-Free Expression Reporters in Yeast. AB - Here, we report on a novel PCR targeting-based strategy called 'PCR duplication' that enables targeted duplications of genomic regions in the yeast genome using a simple PCR-based approach. To demonstrate its application we first duplicated the promoter of the FAR1 gene in yeast and simultaneously inserted a GFP downstream of it. This created a reporter for promoter activity while leaving the FAR1 gene fully intact. In another experiment, we used PCR duplication to increase the dosage of a gene in a discrete manner, from 1* to 2x. Using TUB4, the gene encoding for the yeast gamma-tubulin, we validated that this led to corresponding increases in the levels of mRNA and protein. PCR duplication is an easy one-step procedure that can be adapted in different ways to permit rapid, disturbance-free investigation of various genomic regulatory elements without the need for ex vivo cloning. PMID- 25493942 TI - Zinc absorption from micronutrient powder is low but is not affected by iron in Kenyan infants. AB - Interference with zinc absorption is a proposed explanation for adverse effects of supplemental iron in iron-replete children in malaria endemic settings. We examined the effects of iron in micronutrient powder (MNP) on zinc absorption after three months of home fortification with MNP in maize-based diets in rural Kenyan infants. In a double blind design, six-month-old, non-anemic infants were randomized to MNP containing 5 mg zinc, with or without 12.5 mg of iron (MNP + Fe and MNP - Fe, respectively); a control (C) group received placebo powder. After three months, duplicate diet collections and zinc stable isotopes were used to measure intake from MNP + non-breast milk foods and fractional absorption of zinc (FAZ) by dual isotope ratio method; total absorbed zinc (TAZ, mg/day) was calculated from intake * FAZ. Mean (SEM) TAZ was not different between MNP + Fe (n = 10) and MNP - Fe (n = 9) groups: 0.85 (0.22) and 0.72 (0.19), respectively, but both were higher than C (n = 9): 0.24 (0.03) (p = 0.04). Iron in MNP did not significantly alter zinc absorption, but despite intakes over double estimated dietary requirement, both MNP groups' mean TAZ barely approximated the physiologic requirement for age. Impaired zinc absorption may dictate need for higher zinc doses in vulnerable populations. PMID- 25493943 TI - A novel hemp seed meal protein hydrolysate reduces oxidative stress factors in spontaneously hypertensive rats. AB - This report shows the antioxidant effects of a hemp seed meal protein hydrolysate (HMH) in spontaneously hypertensive rats (SHR). Defatted hemp seed meal was hydrolyzed consecutively with pepsin and pancreatin to yield HMH, which was incorporated into rat feed as a source of antioxidant peptides. Young (8-week old) SHRs were divided into three groups (8 rats/group) and fed diets that contained 0.0%, 0.5% or 1.0% (w/w) HMH for eight weeks; half of the rats were sacrificed for blood collection. After a 4-week washout period, the remaining 20 week old SHRs were fed for an additional four weeks and sacrificed for blood collection. Plasma total antioxidant capacity (TAC) and superoxide dismutase (SOD), catalase (CAT) and total peroxides (TPx) levels were determined. Results showed that plasma TAC, CAT and SOD levels decreased in the older 20-week old SHRs when compared to the young SHRs. The presence of HMH in the diets led to significant (p < 0.05) increases in plasma SOD and CAT levels in both young and adult SHR groups; these increases were accompanied by decreases in TPx levels. The results suggest that HMH contained antioxidant peptides that reduced the rate of lipid peroxidation in SHRs with enhanced antioxidant enzyme levels and total antioxidant capacity. PMID- 25493944 TI - Nrf2-mediated HO-1 induction contributes to antioxidant capacity of a Schisandrae Fructus ethanol extract in C2C12 myoblasts. AB - This study was designed to confirm the protective effect of Schisandrae Fructus, which are the dried fruits of Schisandra chinensis (Turcz.) Baill, against oxidative stress-induced cellular damage and to elucidate the underlying mechanisms in C2C12 myoblasts. Preincubating C2C12 cells with a Schisandrae Fructus ethanol extract (SFEE) significantly attenuated hydrogen peroxide (H2O2) induced inhibition of growth and induced scavenging activity against intracellular reactive oxygen species (ROS) induced by H2O2. SFEE also inhibited comet tail formation and phospho-histone gammaH2A.X expression, suggesting that it prevents H2O2-induced cellular DNA damage. Furthermore, treating C2C12 cells with SFEE significantly induced heme oxygenase-1 (HO-1) and phosphorylation of nuclear factor-erythroid 2 related factor 2 (Nrf2). However, zinc protoporphyrin IX, a potent inhibitor of HO-1 activity, significantly reversed the protective effects of SFEE against H2O2-induced growth inhibition and ROS generation in C2C12 cells. Additional experiments revealed that the potential of the SFEE to induce HO-1 expression and protect against H2O2-mediated cellular damage was abrogated by transient transfection with Nrf2-specific small interfering RNA, suggesting that the SFEE protected C2C12 cells against oxidative stress-induced injury through the Nrf2/HO-1 pathway. PMID- 25493945 TI - Dictator Game Giving: The Importance of Descriptive versus Injunctive Norms. AB - Human behaviour is influenced by social norms but norms can entail two types of information. Descriptive norms refer to what others do in this context, while injunctive norms refer to what ought to be done to ensure social approval. In many real-world situations these norms are often presented concurrently meaning that their independent effects on behaviour are difficult to establish. Here we used an online Dictator Game to test how descriptive and injunctive norms would influence dictator donations when presented independently of one another. In addition, we varied the cost of complying with the norm: By stating that $0.20 or $0.50 cent donations from a $1 stake were normal or suggested, respectively. Specifying a higher target amount was associated with increased mean donation size. In contrast to previous studies, descriptive norms did not seem to influence giving behaviour in this context, whereas injunctive norms were associated with increased likelihood to give at least the target amount to the partner. This raises the question of whether injunctive norms might be more effective than descriptive norms at promoting prosocial behaviour in other settings. PMID- 25493947 TI - Vasopressin receptor antagonists, heart failure, and polycystic kidney disease. AB - The synthesis of nonpeptide orally bioavailable vasopressin antagonists devoid of agonistic activity (vaptans) has made possible the selective blockade of vasopressin receptor subtypes for therapeutic purposes. Vaptans acting on the vasopressin V2 receptors (aquaretics) have attracted attention as a possible therapy for heart failure and polycystic kidney disease. Despite a solid rationale and encouraging preclinical testing, aquaretics have not improved clinical outcomes in randomized clinical trials for heart failure. Additional clinical trials with select population targets, more flexible dosing schedules, and possibly a different drug type or combination (balanced V1a/V2 receptor antagonism) may be warranted. Aquaretics are promising for the treatment of autosomal dominant polycystic kidney disease and have been approved in Japan for this indication. More studies are needed to better define their long-term safety and efficacy and optimize their utilization. PMID- 25493946 TI - Computational Identification and Systematic Classification of Novel Cytochrome P450 Genes in Salvia miltiorrhiza. AB - Salvia miltiorrhiza is one of the most economically important medicinal plants. Cytochrome P450 (CYP450) genes have been implicated in the biosynthesis of its active components. However, only a dozen full-length CYP450 genes have been described, and there is no systematic classification of CYP450 genes in S. miltiorrhiza. We obtained 77,549 unigenes from three tissue types of S. miltiorrhiza using RNA-Seq technology. Combining our data with previously identified CYP450 sequences and scanning with the CYP450 model from Pfam resulted in the identification of 116 full-length and 135 partial-length CYP450 genes. The 116 genes were classified into 9 clans and 38 families using standard criteria. The RNA-Seq results showed that 35 CYP450 genes were co-expressed with CYP76AH1, a marker gene for tanshinone biosynthesis, using r>=0.9 as a cutoff. The expression profiles for 16 of 19 randomly selected CYP450 obtained from RNA-Seq were validated by qRT-PCR. Comparing against the KEGG database, 10 CYP450 genes were found to be associated with diterpenoid biosynthesis. Considering all the evidence, 3 CYP450 genes were identified to be potentially involved in terpenoid biosynthesis. Moreover, we found that 15 CYP450 genes were possibly regulated by antisense transcripts (r>=0.9 or r<=-0.9). Lastly, a web resource (SMCYP450, http://www.herbalgenomics.org/samicyp450) was set up, which allows users to browse, search, retrieve and compare CYP450 genes and can serve as a centralized resource. PMID- 25493948 TI - Exercise Increases Markers of Spermatogenesis in Rats Selectively Bred for Low Running Capacity. AB - The oxidative stress effect of exercise training on testis function is under debate. In the present study we used a unique rat model system developed by artificial selection for low and high intrinsic running capacity (LCR and HCR, respectively) to evaluate the effects of exercise training on apoptosis and spermatogenesis in testis. Twenty-four 13-month-old male rats were assigned to four groups: control LCR (LCR-C), trained LCR (LCR-T), control HCR (HCR-C), and trained HCR (HCR-T). Ten key proteins connecting aerobic exercise capacity and general testes function were assessed, including those that are vital for mitochondrial biogenesis. The VO2 max of LCR-C group was about 30% lower than that of HCR-C rats, and the SIRT1 levels were also significantly lower than HCR C. Twelve weeks of training significantly increased maximal oxygen consumption in LCR by nearly 40% whereas HCR remained unchanged. LCR-T had significantly higher levels of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC 1alpha), decreased levels of reactive oxygen species and increased acetylated p53 compared to LCR-C, while training produced no significant changes for these measures in HCR rats. BAX and Blc-2 were not different among all four groups. The levels of outer dense fibers -1 (Odf-1), a marker of spermatogenesis, increased in LCR-T rats, but decreased in HCR-TR rats. Moreover, exercise training increased the levels of lactate dehydrogenase C (LDHC) only in LCR rats. These data suggest that rats with low inborn exercise capacity can increase whole body oxygen consumption and running exercise capacity with endurance training and, in turn, increase spermatogenesis function via reduction in ROS and heightened activity of p53 in testes. PMID- 25493949 TI - Correlation between imaging characteristics and microbiology in patients with deep neck infections: a retrospective review of one hundred sixty-one cases. AB - BACKGROUND: This study reviews our recent experience with deep neck infections in order to propose recommendations in selecting presumptive antibiotics according to imaging characteristics and identifying predisposing factors of life threatening complications. METHODS: The records of 161 patients treated for deep neck infections at the Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital from 2002 to 2012 were reviewed retrospectively. The demographic data, comorbidities, source of infections, complications, duration of hospital stay, imaging characteristics, and bacteriologic studies were evaluated. The involved neck space was determined by computed tomography (CT) scan with contrast. Complications included mortality and life-threatening conditions. RESULTS: The most common cause of deep neck infections in our study was odontogenic infection (20.5%), followed by pharyngo-tonsillitis (18.6%), and lymphadenitis (10.5%). The most commonly involved neck space was the submandibular space (40.9%), followed by the carotid space (37.2%), and the para pharyngeal space (33.5%). Gas formation was detected in 31 (19.3%) cases. Infections of the different neck spaces and patients with gas formation noted on CT scan showed a specific distribution of common microorganisms. Streptococcus spp. was the most common pathogen in submandibular/sublingual space infections. Klebsiella pneumoniae infection accounted for 53.1% of peri-tonsillar/para pharyngeal space infections, and 40% of carotid space infections. When gas formation was noted on CT imaging, anaerobic infection was the most common pathogen. Chronic kidney disease, diabetes mellitus (DM), multiple space infection, and gas formation present on CT scan were independent predictors of complications (p<0.05). CONCLUSION: The imaging characteristics and microbiology of patients with deep neck infections are correlated and can facilitate the optimal selection of antibiotics. We can administer more precise presumptive antibiotics according to the identified involved neck space on CT scan. Patients with predisposing factors of life-threatening complications require early aggressive multi-disciplinary management to prevent severe sequelae. PMID- 25493950 TI - Shear displacement controlled periodic wrinkles in hexagonal boron nitride sheet. AB - The initiation and geometry pattern of wrinkles in a single-layer hexagonal boron nitride sheet induced by in-plane shear displacement are studied. The periodic wrinkles in the central region are parallel to each other with an angle of approximate 50 degrees to the fix edges, and the longitudinal shape of the wrinkle matches the sinusoidal mode shape well. The wrinkle wavelength decreases with an increase in shear loading, while the amplitude is found to initially increase and then become stable. The dependence of the wrinkle geometry on chirality and shear direction is further elucidated. This study theoretically provides a powerful way to produce uniform wrinkles in two-dimensional membranes and to tune their properties in devices. PMID- 25493951 TI - Peritoneal dialysis per se is a risk factor for sclerostin-associated adynamic bone disease. AB - Chronic kidney disease--mineral bone disorder (CKD-MBD) is a complex syndrome influenced by various factors, such as age, CKD etiology, uremic toxins, and dialysis modality. Although extensively studied in hemodialysis (HD) patients, only a few studies exist for peritoneal dialysis (PD) patients. Since most of these older studies contain no bone biopsy data, we studied the pattern of renal osteodystrophy in 41 prevalent PD patients. The most common presentation was adynamic bone disease (49%). There was a significant inverse association between serum sclerostin (a Wnt/beta-catenin pathway inhibitor that decreases osteoblast action and bone formation) and the bone formation rate. Bone alkaline phosphatase had the best sensitivity and specificity to detect both high- and low-turnover diseases. The comparison between nondiabetic PD and HD patients, matched by age, gender, parathyroid hormone level, and length of dialysis, revealed low 25 hydroxyvitamin D levels, worse bone mineralization, and low bone turnover in the nondiabetic PD group. Thus, adynamic bone disease was the most frequent type of renal osteodystrophy in PD patients. Sclerostin seems to participate in the pathophysiology of adynamic bone disease and bone alkaline phosphatase was the best serum marker of bone turnover in these patients. PMID- 25493952 TI - Association between strict blood pressure control during chronic kidney disease and lower mortality after onset of end-stage renal disease. AB - There is controversy regarding whether strict blood pressure control is indicated in chronic kidney disease (CKD) since the primary results of randomized controlled trials failed to show any impact on progression of kidney disease with this strategy. However, strict blood pressure control may have other beneficial effects beyond reducing the risk of end-stage renal disease (ESRD), such as lowering mortality after ESRD onset. The Modification of Diet in Renal Disease (MDRD) trial randomized 840 patients with CKD to strict (mean arterial pressure under 92 mm Hg) versus usual (mean arterial pressure under 107 mm Hg) blood pressure control between 1989 and 1993. Here we extended follow-up of study enrollees by linkage with United States Renal Data System and National Death Index to ascertain ESRD and vital status through 2010. Overall, 627 patients developed ESRD through 2010 with a median follow-up of 19.3 years. After ESRD onset, there were 142 deaths in the strict blood pressure arm and 182 deaths in the usual blood pressure arm (significant unadjusted hazard ratio for death was 0.72 (95% CI 0.58-0.89)). Overall, there were 212 deaths in the strict blood pressure control arm and 233 deaths in the usual arm (significant unadjusted hazard ratio for death 0.82 (95% CI 0.68-0.98)). Thus, although strict blood pressure control did not delay progression of CKD to ESRD, this strategy was associated with a lower risk of death after ESRD. Hence, long-term post-ESRD outcomes should be considered when formulating blood pressure targets for CKD. PMID- 25493953 TI - Modifiable lifestyle and social factors affect chronic kidney disease in high risk individuals with type 2 diabetes mellitus. AB - This observational study examined the association between modifiable lifestyle and social factors on the incidence and progression of early chronic kidney disease (CKD) among those with type 2 diabetes. All 6972 people from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) with diabetes but without macroalbuminuria were studied. CKD progression was defined as decline in GFR of more than 5% per year, progression to end-stage renal disease, microalbuminuria, or macroalbuminuria at 5.5 years. Lifestyle/social factors included tobacco and alcohol use, physical activity, stress, financial worries, the size of the social network and education. Adjustments were made for known risks such as age, diabetes duration, GFR, albuminuria, gender, body mass index, blood pressure, fasting plasma glucose, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers use. Competing risk of death was considered. At study end, 31% developed CKD and 15% had died. The social network score (SNS) was a significant independent risk factor of CKD and death, reducing the risk by 11 and 22% when comparing the third to the first tertile of the SNS (odds ratios of CKD 0.89 and death 0.78). Education showed a significant association with CKD but stress and financial worries did not. Those with moderate alcohol consumption had a significantly decreased CKD risk compared with nonusers. Regular physical activity significantly decreased the risk of CKD. Thus, lifestyle is a determinant of kidney health in people at high cardiovascular risk with diabetes. PMID- 25493954 TI - Janus kinase 3 regulates renal 25-hydroxyvitamin D 1alpha-hydroxylase expression, calcitriol formation, and phosphate metabolism. AB - Calcitriol, a powerful regulator of phosphate metabolism and immune response, is generated by 25-hydroxyvitamin D 1alpha-hydroxylase in the kidney and macrophages. Renal 1alpha-hydroxylase expression is suppressed by Klotho and FGF23, the expression of which is stimulated by calcitriol. Interferon gamma (INFgamma) regulates 1alpha-hydroxylase expression in macrophages through transcription factor interferon regulatory factor-1. INFgamma-signaling includes Janus kinase 3 (JAK3) but a role of JAK3 in the regulation of 1alpha-hydroxylase expression and mineral metabolism has not been shown. Thus, the impact of JAK3 deficiency on calcitriol formation and phosphate metabolism was measured. Renal interferon regulatory factor-1 and 1alpha-hydroxylase transcript levels, serum calcitriol and FGF23 levels, intestinal phosphate absorption as well as absolute and fractional renal phosphate excretion were significantly higher in jak3 knockout than in wild-type mice. Coexpression of JAK3 increased the phosphate induced current in renal sodium-phosphate cotransporter-expressing Xenopus oocytes. Thus, JAK3 is a powerful regulator of 1alpha-hydroxylase expression and phosphate transport. Its deficiency leads to marked derangement of phosphate metabolism. PMID- 25493956 TI - Regional variation in phasic dopamine release during alcohol and sucrose self administration in rats. AB - While dopamine input to the dorsal striatum is well-known to be critical for action selection, including alcohol-motivated behaviors, it is unknown whether changes in phasic dopamine accompany these behaviors. Long-term alcohol abuse is believed to promote alterations in the neurocircuitry of reward learning in both ventral and dorsal striatum, potentially through increasing dopamine release. Using fast-scan cyclic voltammetry, we measured phasic dopamine release in the dorsal and ventral striatum during alcoholic and nonalcoholic reward-seeking behavior and reward-related cues in rats trained on a variable-interval schedule of reinforcement. We observed robust phasic dopamine release in the dorsolateral striatum after reinforced lever presses and inconsistent dopamine release in the dorsomedial striatum. Contrary to our expectations, alcohol did not enhance dopamine release in rats drinking alcoholic rewards. Cue-induced dopamine release was also observed in the nucleus accumbens core of rats drinking the reward solutions. These data demonstrate that alcoholic and nonalcoholic reward self administration on a variable-interval schedule of reinforcement in rats is accompanied by phasic dopamine release time-locked to reinforcement in the dorsolateral striatum and the nucleus accumbens, but not the dorsomedial striatum. PMID- 25493957 TI - Muon spin relaxation study on itinerant ferromagnet CeCrGe3 and the effect of Ti substitution on magnetism of CeCrGe3. AB - A Muon spin relaxation (uSR) study has been performed on the Kondo lattice heavy fermion itinerant ferromagnet CeCrGe3. Recent investigations of bulk properties have revealed a long-range ordering of Cr moments at Tc = 70 K in this compound. Our uSR investigation between 1.2 K and 125 K confirm the bulk magnetic order which is marked by a loss in initial asymmetry below 70 K accompanied with a sharp increase in the muon depolarization rate. Field dependent uSR spectra show that the internal field at the muon site is higher than 0.25 T apparently due to the ferromagnetic nature of ordering. The effect of Ti substitution on the magnetism in CeCrGe3 is presented. A systematic study has been made on polycrystalline CeCr(1-x)Ti(x)Ge3 (0 ? x ? 1) using magnetic susceptibility chi(T), isothermal magnetization M(H), specific heat C(T) and electrical resistivity rho(T) measurements which clearly reveal that the substitution of Ti for Cr in CeCrGe3 strongly influences the exchange interaction and ferromagnetic ordering of Cr moments. The Cr moment ordering temperature is suppressed gradually with increasing Ti concentration up to x = 0.50 showing Tc = 7 K beyond which Ce moment ordering starts to dominate and a crossover between Cr and Ce moment ordering is observed with a Ce moment ordering Tc = 14 K for x = 1.0. The Kondo lattice behavior is evident from temperature dependence of rho(T) in all CeCr(1-x)Ti(x)Ge3 samples. PMID- 25493958 TI - Introduction: Lessons Learnt from the Use of Cytokines and Cytokine Antagonists. PMID- 25493955 TI - Genome-wide association study of kidney function decline in individuals of European descent. AB - Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline. PMID- 25493959 TI - Mechanisms Underlying the Immunogenicity of Therapeutic Proteins: Risk Assessment and Management Strategies. AB - Antibodies to therapeutic proteins have caused serious adverse events and loss of efficacy in patients. Therefore, it is critical to manage the risk of antitherapeutic antibodies (ATA) during drug development and in the postmarketing environment. Risk assessments are an important tool for managing immunogenicity risk because they provide a format for considering the consequences and likelihood of ATA development. Because many factors influence both the severity of the consequences and likelihood of ATA development, successful risk assessments require input from all relevant disciplines, including product quality, manufacturing, nonclinical, pharmacology, and clinical. The results of risk assessments are used to develop appropriate risk reduction strategies, which may include product quality and manufacturing controls and elements of clinical trial design. This article discusses considerations for immunogenicity risk assessments and management. PMID- 25493960 TI - Pharmacogenetics and the Immunogenicity of Protein Therapeutics. AB - The recognition that genetic factors influence the heterogeneity of individual responses to medications with respect to both toxicity and efficacy is not new. However, only following dramatic advances in functional genomics during the last decade did the development of so-called personalized medicine become a realistic possibility. Although drug development approaches that integrate pharmacogenetic information about both the protein drug and its protein target appear logical, given the complexity of biological systems, the selection of appropriate biomarkers and the study design remain daunting tasks. Here we present potential applications of pharmacogenetics in the development of recombinant coagulation factors. In addition, we highlight the potential utility of a personalized approach to predicting and eventually circumventing immunogenicity using the recombinant Factor VIII in the treatment of hemophilia A as a model system. The immunogenicity of protein therapeutics is of increasing concern during the development and licensure of biologics and clearly calls for a pharmacogenetic approach. This is because, with immunogenicity, the predicament is not that all patients develop inhibitory antibodies but that some individuals, ethnicities, or other subpopulations have a stronger immunogenic reaction than others do. PMID- 25493961 TI - Interferon-Beta: Neutralizing Antibodies, Binding Antibodies, Pharmacokinetics and Pharmacodynamics, and Clinical Outcomes. AB - Antibodies to interferon-beta (IFNb) may occur during treatment with this drug and can be measured at several levels, the totality of antibodies referred to as antidrug antibodies (ADA) or binding antibodies, and in case of interference with the drug activity referred to as neutralizing antibodies (NAB). Antibodies can also interfere with the biological activity of IFNb as measured by pharmacodynamic markers. To get a complete picture of the interference between IFNb as a drug and the ADA, all the 3 above levels need to be considered. Furthermore, the interaction of these biomarkers changes over time with a shift of antibody properties with respect to immunoglobulin subtypes, affinity, and titers of antibodies. In case of persistent NAB, the clinical benefit of IFNb in the treatment of multiple sclerosis is abolished. In this report, the current knowledge on these issues will be reviewed. The data have been presented at a meeting in Coral Gables, Florida on April 18-21, 2012. PMID- 25493962 TI - Manifestations of Antidrug Antibodies Response: Hypersensitivity and Infusion Reactions. AB - Immunogenicity of biological agents leads to the development of antidrug antibodies (ADA) and it may be associated to hypersensitivity reactions. Immediate infusion reactions occur during or within 1 h after infusion, and their clinical manifestations vary considerably, ranging from mild to severe and life threatening. Recent studies show that different mechanisms sustain hypersensitivity reactions toward biologics, and the application of novel methods for detecting ADA has demonstrated the involvement of specific IgE isotypes. Considering the severity of the reactions, it is important for clinicians to recognize their symptoms, to know their pathophysiological mechanisms, and to take risk assessment and prophylactic procedures. This review summarizes the clinical manifestations of antibody and nonantibody-mediated reactions as well as the humoral and cellular mechanisms of antidrug responses. Last, the management of patients at risk is discussed. The definition of diagnostic and prophylactic strategies represents an unavoidable need in the management of potentially reactive patients to improve the safety profile of biologics. PMID- 25493963 TI - Clinical Manifestations of an Anti-Drug Antibody Response: Autoimmune Reactions. AB - Antibodies can be generated against a therapeutic protein upon administration to human subjects. When the therapeutic protein closely mimics one of the subject's endogenous proteins, those antibodies might bind to the endogenous protein in addition to the therapeutic protein. This scenario results when tolerance to the endogenous protein is broken. The consequences of breaking tolerance include an autoimmune response where antibodies are generated against the endogenous protein. These autoantibodies could have significant clinical relevance depending on several factors, including the redundancy of action of the endogenous protein as well as the concentration, binding affinity, and neutralizing potential of the antibodies. The consequences of a therapeutic-protein-induced autoimmune reaction can be challenging to manage as the stimulus for further perpetuation of the immune response can shift from the therapeutic protein to the endogenous protein. The potential for inducing an autoimmune response is one of the reasons that the immune response to a therapeutic protein should be monitored if it persists through the end of the study. PMID- 25493964 TI - The Potential Role of Nucleic Acids in Mediating Autoimmune Recognition Events: The Alpha-Omega of Innate Immunity. AB - The hypothesis proposed in this article suggests that in the innate immune response involving IgM moieties, nucleic acids and probably miRNAs play roles as mediators and regulators. After a discussion on how such a mechanism may operate, various diagnostic and therapeutic possibilities will be suggested. PMID- 25493966 TI - Grey zones in the diagnosis of adult migraine without aura based on the International Classification of Headache Disorders-III beta: exploring the covariates of possible migraine without aura. AB - BACKGROUND: Exploring clinical characteristics and migraine covariates may be useful in the diagnosis of migraine without aura. OBJECTIVE: To evaluate the diagnostic value of the International Classification of Headache Disorders (ICHD) III beta-based diagnosis of migraine without aura; to explore the covariates of possible migraine without aura using an analysis of grey zones in this area; and, finally, to make suggestions for the final version of the ICHD-III. METHODS: A total of 1365 patients (mean [+/- SD] age 38.5+/-10.4 years, 82.8% female) diagnosed with migraine without aura according to the criteria of the ICHD-III beta were included in the present tertiary care-based retrospective study. Patients meeting all of the criteria of the ICHD-III beta were classified as having full migraine without aura, while those who did not meet one, two or >=3 of the diagnostic criteria were classified as zones I, II and III, respectively. The diagnostic value of the clinical characteristics and covariates of migraine were determined. RESULTS: Full migraine without aura was evident in 25.7% of the migraineurs. A higher likelihood of zone I classification was shown for an attack lasting 4 h to 72 h (OR 1.560; P=0.002), with pulsating quality (OR 4.096; P<0.001), concomitant nausea/vomiting (OR 2.300; P<0.001) and photophobia/phonophobia (OR 4.865; P<0.001). The first-rank determinants for full migraine without aura were sleep irregularities (OR 1.596; P=0.005) and periodic vomiting (OR 1.464; P=0.026). However, even if not mentioned in ICHD-III beta, the authors determined that motion sickness, abdominal pain or infantile colic attacks in childhood, associated dizziness and osmophobia have important diagnostic value. CONCLUSIONS: In cases that do not fulfill all of the diagnostic criteria although they are largely consistent with the characteristics of migraine in clinical terms, the authors believe that a history of infantile colic; periodic vomiting (but not periodic vomiting syndrome); recurrent abdominal pain; the presence of motion sickness or vertigo, dizziness or osmophobia accompanying the pain; and comorbid atopic disorder are characteristics that should to be discussed and considered as additional diagnostic criteria (covariates) in the preparation of the final version of ICHD III. PMID- 25493967 TI - Simulation Methods and Validation Criteria for Modeling Cardiac Ventricular Electrophysiology. AB - We describe a sequence of methods to produce a partial differential equation model of the electrical activation of the ventricles. In our framework, we incorporate the anatomy and cardiac microstructure obtained from magnetic resonance imaging and diffusion tensor imaging of a New Zealand White rabbit, the Purkinje structure and the Purkinje-muscle junctions, and an electrophysiologically accurate model of the ventricular myocytes and tissue, which includes transmural and apex-to-base gradients of action potential characteristics. We solve the electrophysiology governing equations using the finite element method and compute both a 6-lead precordial electrocardiogram (ECG) and the activation wavefronts over time. We are particularly concerned with the validation of the various methods used in our model and, in this regard, propose a series of validation criteria that we consider essential. These include producing a physiologically accurate ECG, a correct ventricular activation sequence, and the inducibility of ventricular fibrillation. Among other components, we conclude that a Purkinje geometry with a high density of Purkinje muscle junctions covering the right and left ventricular endocardial surfaces as well as transmural and apex-to-base gradients in action potential characteristics are necessary to produce ECGs and time activation plots that agree with physiological observations. PMID- 25493969 TI - The role of systemic antibiotics in acquiring respiratory tract colonization with gram-negative bacteria in intensive care patients: a nested cohort study. AB - OBJECTIVE: Colonization of the respiratory tract with Gram-negative bacteria in intensive care patients increases the risk of subsequent infections. Application of systemic antibiotics may prevent colonization with Gram-negative bacteria, but this effect has never been quantified. The objective of this study was to determine associations between systemic antibiotic use and acquisition of respiratory tract colonization with Gram-negative bacteria in ICUs. DESIGN: A nested cohort study. SETTING: A university hospital and a teaching hospital. PATIENTS: Patients with ICU stay of more than 48 hours and absence of respiratory tract colonization with Gram-negative bacteria on ICU admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Acquisition was determined through protocolized surveillance. Associations were investigated with Cox regression models with antibiotics as a time-dependent covariate. In all, 250 of 481 patients (52%) acquired respiratory tract colonization with Gram-negative bacteria after a median of 5 days (interquartile range, 3-8 d) (acquisition rate, 77.1/1,000 patient-days at risk). Antibiotic exposure during ICU admission was present in 78% and 72% of the patients with and without acquired Gram-negative bacteria colonization, respectively. In Kaplan-Meier curve analysis, the median times to acquisition of Gram-negative bacteria were 9 days (95% CI, 7.9-10.1) and 6 days (95% CI, 4.8-7.2) in patients receiving and not receiving antibiotics, respectively. In time varying Cox regression analysis, however, the association between acquired colonization and systemic antibiotics was not statistically significant (hazard ratio, 0.90; 95% CI, 0.70-1.16). CONCLUSIONS: Among patients not colonized with Gram-negative bacteria in the respiratory tract at admission to ICU, systemic antibiotics during ICU stay were not associated with a reduction in acquisition of Gram-negative bacteria carriage in the respiratory tract during the ICU stay. PMID- 25493968 TI - Prevalence, risk factors, and outcomes of delirium in mechanically ventilated adults. AB - OBJECTIVE: Delirium is common during critical illness and associated with adverse outcomes. We compared characteristics and outcomes of delirious and nondelirious patients enrolled in a multicenter trial comparing protocolized sedation with protocolized sedation plus daily sedation interruption. DESIGN: Randomized trial. SETTING: Sixteen North American medical and surgical ICUs. PATIENTS: Four hundred thirty critically ill, mechanically ventilated adults. INTERVENTIONS: All patients had hourly titration of opioid and benzodiazepine infusions using a validated sedation scale. For patients in the interruption group, infusions were resumed, if indicated, at half of previous doses. Delirium screening occurred daily; positive screening was defined as an Intensive Care Delirium Screening Checklist score of 4 or more at any time. MEASUREMENTS AND MAIN RESULTS: Delirium was diagnosed in 226 of 420 assessed patients (53.8%). Coma was identified in 32.7% of delirious compared with 22.7% of nondelirious patients (p = 0.03). The median time to onset of delirium was 3.5 days (interquartile range, 2-7), and the median duration of delirium was 2 days (interquartile range, 1-4). Delirious patients were more likely to be male (61.1% vs 46.6%; p = 0.005), have a surgical/trauma diagnosis (21.2% vs 11.0%; p = 0.030), and history of tobacco (31.5% vs 16.2%; p = 0.002) or alcohol use (34.6% vs 20.9%; p = 0.009). Patients with positive delirium screening had longer duration of ventilation (13 vs 7 d; p < 0.001), ICU stay (12 vs 8 d; p < 0.0001), and hospital stay (24 vs 15 d; p < 0.0001). Delirious patients were more likely to be physically restrained (86.3% vs 76.7%; p = 0.014) and undergo tracheostomy (34.6% vs 15.5%; p < 0.0001). Antecedent factors independently associated with delirium onset were restraint use (hazard ratio, 1.87; 95% CI, 1.33-2.63; p = 0.0003), antipsychotic administration (hazard ratio, 1.67; 95% CI, 1.005-2.767; p = 0.047), and midazolam dose (hazard ratio, 0.998; 95% CI, 0.997-1.0; p = 0.049). There was no difference in delirium prevalence or duration between the interruption and control groups. CONCLUSION: In mechanically ventilated adults, delirium was common and associated with longer duration of ventilation and hospitalization. Physical restraint was most strongly associated with delirium. PMID- 25493971 TI - The role of aerosolized colistin in the treatment of ventilator-associated pneumonia: a systematic review and metaanalysis. AB - OBJECTIVES: The present meta-analysis and systematic review evaluated the efficacy and safety of aerosolized colistin as adjunctive therapy to i.v. antimicrobials or as monotherapy in the treatment of ventilator-associated pneumonia. DESIGN: The databases of MEDLINE and Cochrane Library up to June 2013 and all reference lists of the included studies and relevant reviews were searched. Studies were eligible if the efficacy and safety of aerosolized colistin in the treatment of ventilator-associated pneumonia was evaluated. An overall effect estimate for all dichotomous data as an odds ratio with 95% CI was calculated by the Mantel-Haenszel or the DerSimonian and Laird method depending on the statistical heterogeneity. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to interpret the findings. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixteen studies fulfilled the inclusion criteria: eight were comparing adjunctive aerosolized versus i.v. colistin (seven observational cohort or case-control studies and one randomized trial) and were meta-analyzed, and eight were single arm and were only systematically reviewed. The Grading of Recommendations Assessment, Development, and Evaluation approach showed limitations of the study design and presence of inconsistency in most of the outcomes, but no obvious indirectness or imprecision of results reporting. Based on the above assessments, the quality of evidence presented for each outcome ranged from "very low" to "low." A significant improvement in clinical response (odds ratio, 1.57; 95% CI, 1.14-2.15; p = 0.006; I2 = 37%), microbiological eradication (odds ratio, 1.61; 95% CI, 1.11-2.35; p = 0.01; I2 = 0%), and infection-related mortality (odds ratio, 0.58; 95% CI, 0.34 0.96; p = 0.04; I2 = 46%) was observed with the addition of aerosolized colistin to i.v. treatment, whereas the addition of aerosolized colistin did not affect overall mortality (odds ratio, 0.74; 95% CI, 0.54-1.01; p = 0.06; I2 = 25%) or nephrotoxicity (odds ratio, 1.18; 95% CI, 0.76-1.83; p = 0.45; I2 = 0%). CONCLUSION: Based on the present results and awaiting further evidence from randomized trials, aerosolized colistin is associated with improved outcome in the treatment of ventilator-associated pneumonia although the level of evidence was low. PMID- 25493972 TI - The efficacy and safety of heparin in patients with sepsis: a systematic review and metaanalysis. AB - OBJECTIVE: To evaluate the efficacy and safety of heparin in patients with sepsis, septic shock, or disseminated intravascular coagulation associated with infection. DESIGN: Systematic review and metaanalysis. DATA SOURCES: Randomized controlled trials from MEDLINE, EMBASE, CENTRAL, Global Health, Scopus, Web of Science, the International Clinical Trials Registry Platform (inception to April 2014), conference proceedings, and reference lists of relevant articles. STUDY SELECTION AND DATA EXTRACTION: Two reviewers independently identified and extracted trial-level data from randomized trials investigating unfractionated or low molecular heparin administered to patients with sepsis, severe sepsis, septic shock, or disseminated intravascular coagulation associated with infection. Internal validity was assessed in duplicate using the Risk of Bias tool. The strength of evidence was assessed in duplicate using Grading of Recommendations Assessment, Development, and Evaluation methodology. Our primary outcome was mortality. Safety outcomes included hemorrhage, transfusion, and thrombocytopenia. MEASUREMENTS AND MAIN RESULTS: We included nine trials enrolling 2,637 patients. Eight trials were of unclear risk of bias and one was classified as having low risk of bias. In trials comparing heparin to placebo or usual care, the risk ratio for death associated with heparin was 0.88 (95% CI, 0.77-1.00; I2 = 0%; 2,477 patients; six trials; moderate strength of evidence). In trials comparing heparin to other anticoagulants, the risk ratio for death was 1.30 (95% CI, 0.78-2.18; I2 = 0%; 160 patients; three trials; low strength of evidence). In trials comparing heparin to placebo or usual care, major hemorrhage was not statistically significantly increased (risk ratio, 0.79; 95% CI, 0.53 1.17; I2 = 0%; 2,392 patients; three trials). In one small trial of heparin compared with other anticoagulants, the risk of major hemorrhage was significantly increased (2.14; 95% CI, 1.07-4.30; 48 patients). Important secondary and safety outcomes, including minor bleeding, were sparsely reported. CONCLUSIONS: Heparin in patients with sepsis, septic shock, and disseminated intravascular coagulation associated with infection may be associated with decreased mortality; however, the overall impact remains uncertain. Safety outcomes have been underreported and require further study. Increased major bleeding with heparin administration cannot be excluded. Large rigorous randomized trials are needed to evaluate more carefully the efficacy and safety of heparin in patients with sepsis, severe sepsis, and septic shock. PMID- 25493970 TI - Invasive Candida infections and the harm from antibacterial drugs in critically ill patients: data from a randomized, controlled trial to determine the role of ciprofloxacin, piperacillin-tazobactam, meropenem, and cefuroxime. AB - OBJECTIVE: Use of antibiotics in critically ill patients may increase the risk of invasive Candida infection. The objective of this study was to determine whether increased exposure to antibiotics is associated with increased prevalence of invasive Candida infection. DESIGN: Substudy using data from a randomized controlled trial, the Procalcitonin And Survival Study 2006-2010. SETTING: Nine multidisciplinary ICUs across Denmark. PATIENTS: A total of 1,200 critically ill patients. INTERVENTION: Patients were randomly allocated to either a "high exposure" antibiotic therapy (intervention arm, n = 604) or a "standard exposure" guided by current guidelines (n = 596). MEASUREMENTS AND MAIN RESULTS: Seventy four patients met the endpoint, "invasive Candida infection," 40 in the high exposure arm and 34 in standard exposure arm (relative risk = 1.2; 95% CI, 0.7 1.8; p = 0.52). Among medical patients in the high exposure arm, the use of ciprofloxacin and piperacillin/tazobactam was 51% and 75% higher than in the standard exposure arm; no difference in antibiotic exposure was observed between the randomized arms in surgical patients. Among medical intensive care patients, invasive Candida infection was more frequent in the high exposure arm (6.2%; 27/437) than in standard exposure arm (3.3%; 14/424) (hazard ratio = 1.9; 95% CI, 1.0-3.6; p = 0.05). Ciprofloxacin used at study entry independently predicted invasive Candida infection (adjusted hazard ratio = 2.1 [1.1-4.1]); the risk gradually increased with duration of ciprofloxacin therapy: six of 384 in patients not exposed (1.6%), eight of 212 (3.8%) when used for 1-2 days (hazard ratio = 2.5; 95% CI, 0.9-7.3), and 31 of 493 (6.3%) when used for 3 days (hazard ratio = 3.8; 95% CI, 1.6-9.3; p = 0.002). Patients with any ciprofloxacin containing antibiotic regimen the first 3 days in the trial had a higher risk of invasive Candida infection than did patients on any antibiotic regimen not containing ciprofloxacin (unadjusted hazard ratio = 3.7; 95% CI, 1.6-8.7; p = 0.003; adjusted hazard ratio, 3.4; 95% CI, 1.4-8.0; p = 0.006). CONCLUSIONS: High exposure to antibiotics is associated to increased risk of invasive Candida infection in medical intensive care patients. Patients with ciprofloxacin containing regimens had higher risk of invasive Candida infection. Other antibiotics, such as meropenem, piperacillin/tazobactam, and cefuroxime, were not associated with such a risk. PMID- 25493973 TI - Recommendations for the role of extracorporeal treatments in the management of acute methanol poisoning: a systematic review and consensus statement. AB - OBJECTIVE: Methanol poisoning can induce death and disability. Treatment includes the administration of antidotes (ethanol or fomepizole and folic/folinic acid) and consideration of extracorporeal treatment for correction of acidemia and/or enhanced elimination. The Extracorporeal Treatments in Poisoning workgroup aimed to develop evidence-based consensus recommendations for extracorporeal treatment in methanol poisoning. DESIGN AND METHODS: Utilizing predetermined methods, we conducted a systematic review of the literature. Two hundred seventy-two relevant publications were identified but publication and selection biases were noted. Data on clinical outcomes and dialyzability were collated and a two-round modified Delphi process was used to reach a consensus. RESULTS: Recommended indications for extracorporeal treatment: Severe methanol poisoning including any of the following being attributed to methanol: coma, seizures, new vision deficits, metabolic acidosis with blood pH <= 7.15, persistent metabolic acidosis despite adequate supportive measures and antidotes, serum anion gap higher than 24 mmol/L; or, serum methanol concentration 1) greater than 700 mg/L (21.8 mmol/L) in the context of fomepizole therapy, 2) greater than 600 mg/L or 18.7 mmol/L in the context of ethanol treatment, 3) greater than 500 mg/L or 15.6 mmol/L in the absence of an alcohol dehydrogenase blocker; in the absence of a methanol concentration, the osmolal/osmolar gap may be informative; or, in the context of impaired kidney function. Intermittent hemodialysis is the modality of choice and continuous modalities are acceptable alternatives. Extracorporeal treatment can be terminated when the methanol concentration is <200 mg/L or 6.2 mmol/L and a clinical improvement is observed. Extracorporeal Treatments in Poisoning inhibitors and folic/folinic acid should be continued during extracorporeal treatment. General considerations: Antidotes and extracorporeal treatment should be initiated urgently in the context of severe poisoning. The duration of extracorporeal treatment extracorporeal treatment depends on the type of extracorporeal treatment used and the methanol exposure. Indications for extracorporeal treatment are based on risk factors for poor outcomes. The relative importance of individual indications for the triaging of patients for extracorporeal treatment, in the context of an epidemic when need exceeds resources, is unknown. In the absence of severe poisoning but if the methanol concentration is elevated and there is adequate alcohol dehydrogenase blockade, extracorporeal treatment is not immediately required. Systemic anticoagulation should be avoided during extracorporeal treatment because it may increase the development or severity of intracerebral hemorrhage. CONCLUSION: Extracorporeal treatment has a valuable role in the treatment of patients with methanol poisoning. A range of clinical indications for extracorporeal treatment is provided and duration of therapy can be guided through the careful monitoring of biomarkers of exposure and toxicity. In the absence of severe poisoning, the decision to use extracorporeal treatment is determined by balancing the cost and complications of extracorporeal treatment to that of fomepizole or ethanol. Given regional differences in cost and availability of fomepizole and extracorporeal treatment, these decisions must be made at a local level. PMID- 25493975 TI - Progesterone for traumatic brain injury--resisting the sirens' song. PMID- 25493976 TI - Predicting the fallout from King v. Burwell--exchanges and the ACA. PMID- 25493977 TI - Unraveling Obamacare--can Congress and the Supreme Court undo health care reform? PMID- 25493979 TI - [The importance of continuity in European national health systems for health policies in Latin America.] PMID- 25493980 TI - Ethical issues in the management of patients with Ebola virus disease. PMID- 25493981 TI - The use of modified mosquitoes in Brazil for the control of Aedes aegypti: methodological and ethical constraints. PMID- 25493982 TI - The financial crisis and health care systems in Europe: universal care under threat? Trends in health sector reforms in Germany, the United Kingdom, and Spain. AB - The paper analyzes trends in contemporary health sector reforms in three European countries with Bismarckian and Beveridgean models of national health systems within the context of strong financial pressure resulting from the economic crisis (2008-date), and proceeds to discuss the implications for universal care. The authors examine recent health system reforms in Spain, Germany, and the United Kingdom. Health systems are described using a matrix to compare state intervention in financing, regulation, organization, and services delivery. The reforms' impacts on universal care are examined in three dimensions: breadth of population coverage, depth of the services package, and height of coverage by public financing. Models of health protection, institutionality, stakeholder constellations, and differing positions in the European economy are factors that condition the repercussions of restrictive policies that have undermined universality to different degrees in the three dimensions specified above and have extended policies for regulated competition as well as commercialization in health care systems. PMID- 25493974 TI - Very early administration of progesterone for acute traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. METHODS: We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score. RESULTS: A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. CONCLUSIONS: This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.). PMID- 25493983 TI - [Coordination of care for people living with HIV/AIDS in a city in Sao Paulo State, Brazil.] AB - The aim of this study was to analyze the coordination of health activities and services for persons living with AIDS. This was a cross-sectional study of 301 persons living with AIDS. The analysis used descriptive techniques, analysis of variance, and multiple comparisons of means. Coordination of care was found to be satisfactory (mean = 3.69 and SD = 1.74). Persons living with AIDS used other health services in addition to the Services for Specialized HIV/AIDS Care (67.0% emergency departments, 43.2% primary care, 23.6% other specialized services, 15% private services). The five specialized HIV/AIDS clinics showed different performance levels as well as distinct contexts and healthcare configurations, but adequate clinical management (comparatively better than management of social issues). Provision of the referral guide was considered satisfactory, but the counter-referral guide was found to be unsatisfactory. Strategies are needed to promote the development of shared and cooperative actions within the healthcare teams in the specialized HIV/AIDS clinics and between the different services in order to strengthen the provision of care with case-resolution capacity. PMID- 25493984 TI - [Social Sciences and Humanities in Health in ABRASCO: the construction of social theory in health.] AB - The development of recent social thinking in health in Brazil is associated with the establishment of the Public Health field and the Brazilian Association of Graduate Studies in Public Health (ABRASCO). The area of Social Sciences in Health was created together with the founding of ABRASCO. This article presents the main aspects related to the establishment and institutionalization of Social Sciences in Health in ABRASCO, based on interviews with its presidents and the coordinators of the Social Sciences Committees from 1995 to 2011. The interviews allowed capturing and analyzing the context in which this field was established and its relevance and history in Public Health as a whole, grouped in five analytical categories: (1) the development of Social Sciences and the Humanities in Health; (2) interdisciplinarity in Public Health; (3) the contribution of Social Sciences to Public Health; (4) Social Sciences in Health and the "traditional" Social Sciences; and (5) challenges for Social Sciences and the Humanities in Health. PMID- 25493978 TI - A clinical trial of progesterone for severe traumatic brain injury. AB - BACKGROUND: Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 randomized, controlled trials. We investigated the efficacy and safety of progesterone in a large, prospective, phase 3 randomized clinical trial. METHODS: We conducted a multinational placebo-controlled trial, in which 1195 patients, 16 to 70 years of age, with severe TBI (Glasgow Coma Scale score, <=8 [on a scale of 3 to 15, with lower scores indicating a reduced level of consciousness] and at least one reactive pupil) were randomly assigned to receive progesterone or placebo. Dosing began within 8 hours after injury and continued for 120 hours. The primary efficacy end point was the Glasgow Outcome Scale score at 6 months after the injury. RESULTS: Proportional-odds analysis with covariate adjustment showed no treatment effect of progesterone as compared with placebo (odds ratio, 0.96; confidence interval, 0.77 to 1.18). The proportion of patients with a favorable outcome on the Glasgow Outcome Scale (good recovery or moderate disability) was 50.4% with progesterone, as compared with 50.5% with placebo. Mortality was similar in the two groups. No relevant safety differences were noted between progesterone and placebo. CONCLUSIONS: Primary and secondary efficacy analyses showed no clinical benefit of progesterone in patients with severe TBI. These data stand in contrast to the robust preclinical data and results of early single-center trials that provided the impetus to initiate phase 3 trials. (Funded by BHR Pharma; SYNAPSE ClinicalTrials.gov number, NCT01143064.). PMID- 25493985 TI - Self-efficacy as a mediator of the relationship between subjective well-being and general health of military cadets. AB - The objective of this study is to investigate the role of self-efficacy beliefs as a mediator of the relationship between the subjective well-being and general health of military cadets (police and firefighters). For this study, 228 cadets participated, the majority being Military Police officer candidates (65%), male (79%), between 17 and 34 years of age (99%), and unmarried (74%). They responded to questionnaires on general health (GHQ-12), perceived general self-efficacy, to the multiple scales that cover subjective well-being, and demographic questions. Initial regression analyses indicate the predictive power of subject well-being regarding general health. Subsequently, the mediation analyses provide satisfactory evidence for the role of perceived self-efficacy as a mediator of the relationship between the subjective well-being variables and the overall health of military cadets. The implications of these results for the professional training of the cadets are discussed. PMID- 25493986 TI - Associations between time spent traveling in motor vehicles and physical activity in Colombian adults from urban areas. AB - Sedentary behaviors are associated with less physical activity. Little evidence exists about this association and its relation with commuting time in Latin America. This study examined the association between time spent traveling in motor vehicles and physical activity levels in the domains of leisure time physical activity and transportation, among Colombian adults in urban areas. A secondary data analysis of the 2010 National Nutrition Survey was conducted. Time spent traveling in motor vehicles and physical activity were assessed using the International Physical Activity Questionnaire. Binary logistic regressions were conducted. Time spent traveling in motor vehicles for 120 minutes or more was reported among 27.6% of the sample. The prevalence of walking and bicycling as a means of transportation for at least 150 minutes per week was 34% and 4.4%, respectively. Achieving at least 150 minutes of leisure time physical activity a week was reported by 18.4% of the sample. This study suggests negative associations between time spent traveling in motor vehicles and active transport, with significant trend associations in stratified analyses. No significant associations were found between time spent traveling in motor vehicles and leisure time physical activity. PMID- 25493987 TI - [Avoidable infant deaths in the 1993 and 2004 Pelotas birth cohorts, Rio Grande do Sul State, Brazil.] AB - Infant mortality classified as avoidable (through immunization, adequate prenatal, childbirth, and neonatal care, adequate diagnostic and therapeutic measures, and adequate health promotion associated with appropriate health care) was compared in the 1993 and 2004 Pelotas Birth Cohorts, Rio Grande do Sul State, Brazil. Deaths were monitored by visits to hospitals, notary public offices, cemeteries, and the Regional Health Division and by a search in the Mortality Information System database. There were 5,249 live births and 111 infant deaths in the 1993 cohort and 4,231 live births and 82 infant deaths in 2004. The avoidable infant mortality rate was 15.2:1,000 live births in 1993 and 15.4 in 2004. Avoidable neonatal and post-neonatal mortality rates were 11.2 and 4.0, respectively, in 1993, and 10.9 and 4.5 in 2004. Preterm births were the main variable associated with avoidable mortality in both cohorts. Strategies to prevent preterm birth may help reduce infant mortality in this context. PMID- 25493988 TI - [Selection of essential medicines and the burden of disease in Brazil.] AB - The World Health Organization (WHO) defines essential medicines as those that meet the population's priority healthcare needs. Their selection aims to reflect collective needs, thus recommending the use of studies on global burden of disease. An exploratory study was performed to link the medicines from the RENAME lists to Global Burden of Disease in Brazil (1998 and 2008) and the scientific evidence. The study thus sought to verify whether the RENAME (2002 to 2012) met WHO guidelines for drug selection. Although RENAME 2010 and 2012 both adhere to Global Burden of Disease in Brazil 2008, the 2012 version includes a longer list of medicines and appears to be pressured by the growing market for new technologies. Thus, RENAME is no longer a list of essential medicines, but has become a list of financing for pharmaceutical care. PMID- 25493989 TI - Incidence of metabolic syndrome and related diseases in the Khisedje indigenous people of the Xingu, Central Brazil, from 1999-2000 to 2010-2011. AB - The aim of this study was to identify the incidence of metabolic syndrome and related diseases in the Khisedje population living in the Xingu Indigenous Park, Mato Grosso State, Brazil, from 1999-2000 to 2010-2011. The study included 78 individuals aged >=20 years. Data were analyzed using Student t test, linear regression, and Poisson regression. In 10 years of follow-up, cumulative incidence rates were 37.5% for metabolic syndrome, 47.4% for hypetriglyceridemia, 38.9% for arterial hypertension, 32% for central obesity, 30.4% for excess weight, 29.1% for hypercholesterolemia, 25% for low HDLc, 10.4% for high LDLc, and 2.9% for diabetes mellitus. Age proved to be a risk factor for incidence of hypertension, diabetes, and elevated LDLc, regardless of gender; male gender was a protective factor against incidence of central obesity, independently of age. The study showed deterioration of most target health indicators and exposure of the Khisedje to high cardiometabolic risk. These results may be related to changes in traditional lifestyle. PMID- 25493990 TI - Evidence-based medicine and prejudice-based medicine: the case of homeopathy. AB - In recent decades an important social movement related to Complementary and Alternative Medicine has been identified worldwide. In Brazil, although homeopathy was recognized as a specialist medical area in 1980, few medical schools offer courses related to it. In a previous study, 176 resident doctors at the University of Campinas Medical School were interviewed and 86 (49%) rejected homeopathy as a subject in the core medical curriculum. Thus, this qualitative study was conducted to understand their reasons for refusing. 20 residents from 15 different specialist areas were interviewed. Very few of them admitted to a lack of knowledge for making a judgment about homeopathy; none of them made a conscientious objection to it; and the majority demonstrated prejudice, affirming that there is not enough scientific evidence to support homeopathy, defending their position based on personal opinion, limited clinical practice and on information circulated in the mass media. Finally, resident doctors' prejudices against homeopathy can be extended to practices other than allopathic medicine. PMID- 25493991 TI - [Screening for posttraumatic stress disorder in people affected by the 2010 earthquake in Chile.] AB - The authors conducted an assessment of post-traumatic stress disorder screening in the Chilean population following the February 2010 earthquake, based on the Post Earthquake Survey with a multistage sample of 24,982 individuals over 18 years of age, applying the Davidson Trauma Scale. Multivariate analysis was performed with significance set at p<0.05. Prevalence of positive screening for post-traumatic stress disorder was 11% for the country as a whole, but reached 30% at lower-level disaggregation. The logistic regression model for post traumatic stress disorder identified the following risk factors: belonging to a low-income family, having suffered damage to the household, a history of health problems in the previous month, and female gender (p<0.05). Family coping with the earthquake proved to be a protective factor as compared to other social or neighborhood groups, and more years of schooling were also protective (p<0.05). Positive screening for posttraumatic stress disorders revealed clear social inequalities. PMID- 25493992 TI - Individual and social determinants of self-rated health and well-being in the elderly population of Portugal. AB - This article aims to identify the main determinants of self-rated health and well being in the elderly Portuguese population, using a set of dimensions including demographic and socioeconomic indicators, characteristics of interpersonal networks and social activities, health, sexual activity, representations of aging, and feeling of happiness. Taking socioeconomic, behavioral, and attitudinal predictors into account to analyze the explanatory value of the interrelated dimensions and weights for each factor, the author argues that social capital, activities associated with active aging, and greater optimism towards aging can contribute greatly to better self-rated health and wellbeing among the elderly, partially offsetting the effect of socioeconomic factors and illness associated with age. PMID- 25493993 TI - [Management, operations, and menus in Kaingang indigenous schools participating in the National School Nutrition Program in Rio Grande do Sul State, Brazil.] AB - Few studies have focused on the National School Nutrition Program (PNAE) in indigenous schools in Brazil. The current study describes the program's operations, management, and menus in 35 Kaingang indigenous schools in Rio Grande do Sul State, Brazil. A cross-sectional study design was used to obtain information on the program through questionnaires submitted to the Regional Educational Offices (CRE) and to the schools. The menus suggested to the schools by the regional offices were obtained. There were no Centers for Indigenous Education in the regional offices. All the assistant principals were indigenous, 26 schools (74.6%) practiced local management of the meal program, and 34 (97.1%) reported purchasing food from local markets. Most cooks (63.9%) had temporary work contracts with the schools and 65.7% were indigenous. Low offerings of veges, milk and dairy products were observed in around 60% of the menus, and legumes and fruits low in around 80%. It points out the need for more studies about the indigenous PNAE and intends to support public policies in health, food and nutrition for the national indigenous school . PMID- 25493994 TI - Prevalence of comorbidities between mood and anxiety disorders: associated factors in a population sample of young adults in southern Brazil. AB - This research aims to evaluate factors associated with the presence of comorbidities between mood and anxiety disorders in young adults aged 18 to 24 years, from Pelotas, Rio Grande do Sul State, Brazil. This was a cross-sectional, population-based study with a probabilistic sample by conglomerates. The Mini International Neuropsychiatric Interview (MINI) was used to assess mood and anxiety disorders. The prevalence of mental disorders in the sample (n = 1,561) was of 26.8% of which 9.7% had comorbidities between mood and anxiety disorders. The prevalence of comorbidities on mood and anxiety disorders is almost three times higher among women than men (p < 0.001). Lower education levels, socioeconomic status (p < 0.001) and a history of divorced parents (p < 0.050) was associated with comorbidities between mood and anxiety disorders. The main conclusion is that social factors are highly associated with comorbidities between mood and anxiety disorders. Prevention strategies on mental health should focus particularly on women in vulnerable social conditions. PMID- 25493995 TI - HIV knowledge and related sexual practices among Portuguese men who have sex with men. AB - Qualitative studies of the sexual risk practices of Portuguese men who have sex with men (MSM) are scarce, as have been campaigns to target this group despite high HIV infection rates. This study investigates the concepts and practices of safer sex of a group of 36 Portuguese self-identified gay men (age: x = 34.4, SD = 9.1) who have met sexual partners online; two identified as HIV positive. Thematic analysis of interviews showed that our participants were aware of HIV transmission risks and tended to protect themselves in most sexual practices. Oral sex and steady relationships, however, did not always include safer practices. Participants tended to rely on indirect sources of information when assessing their partners' HIV status, such as their physical characteristics or the information available in online profiles. Contrasting HIV positive and negative men's sexual expectations and practices indicated that communication shortcomings might be putting some at risk. Findings suggest that safe sex is a relational practice which can only be understood and addressed within the context in which it occurs. PMID- 25493996 TI - [Psychosocial aspects of work and commonmental disorders among civil aviation pilots.] AB - This study aimed to investigate associations between psychosocial aspects of work and prevalence of common mental disorders (CMD) among Brazilian civil aviation pilots. This was a quantitative cross-sectional study using the self-administered Job Content Questionnaire (JCQ) and Self-Reporting Questionnaire (SRQ-20). A total of 778 pilots answered the questionnaires. Multiple logistic regression showed a strong association with highly demanding work and prevalence of CMD, compared to pilots with less demanding work as the reference group (adjusted OR = 29.0). In the final adjusted model, only variables related to workload and physical activity maintained statistically significant associations. The expected CMD prevalence in pilots with highly demanding work, heavy workload, and no regular physical exercise was 39.7%, compared to the subgroup with less demanding work, regular physical exercise, and light workload, which showed an expected prevalence of 0.4%. Working conditions can be considered potential contributing factors to CMD, with probable impact on flight safety. PMID- 25493997 TI - Risk behaviors for eating disorders and depressive symptoms: a study of female adolescents in Juiz de Fora, Minas Gerais State, Brazil. AB - The objective of this study was to analyze the relationship between depressive symptoms and eating disorders in female adolescents. The sample included 371 girls ranging from 12 to 16 years of age in Juiz de Fora, Minas Gerais State, Brazil. The study used the Eating Attitudes Test (EAT-26) and Major Depression Inventory (MDI) to evaluate eating disorders and depressive symptoms, respectively. The linear regression model showed that 18% of the EAT-26 scores were influenced by MDI (F(1, 370) = 14.18; p = 0.001). Moreover, the findings indicated a statistically significant association between depressive symptoms and eating disorders (chi2 = 14.71; Wald = 12.90; p = 0.001). The authors concluded that depressive symptoms were related to eating disorders in female adolescents. Thus, girls with some level of depression showed a greater tendency to adopt disordered eating as a daily habit. PMID- 25493998 TI - Future burden of prostate cancer mortality in Brazil: a population-based study. AB - Prostate cancer mortality projections at the nationwide and regional levels to the year 2025 are carried out in this ecological study that is based on an analysis of Brazilian trends between 1996 and 2010. The predictions were made for the period 2011-2025 utilizing the Nordpred program based on the period of 1996 2010, using the age-period-cohort model. A significant increase was observed in the Brazilian rates between 1996 and 2006, followed by a non-significant decrease. The projections indicate a decrease in rates at a national level as well as for the Central, South and Southeast regions. Increases are expected for the North and Northeast regions. In conclusion, a reduction in the mortality rates for prostate cancer in Brazil is expected to the year 2025, as well as for the Central, South and Southeast regions. However, an increase in the absolute number of deaths in all regions is expected due to the anticipated aging of the population. PMID- 25493999 TI - [Improved quality of tuberculosis data using record linkage.] AB - The aim of this study was to improve data quality on tuberculosis (TB) after record linkage and outcome correction through probabilistic linkage between the Information System for Notifiable Diseases (SINAN) and the Mortality Information System (SIM). Record linkage was conducted between SINAN records for Brazil in 2008 and 2009 in order to exclude notifications not removed by routine SINAN procedures performed by States and Municipalities. The databases were constructed according to the case outcomes. Linkage between SINAN and SIM used the database resulting from record linkage and SIM data that mentioned TB as the underlying or associated cause from 2008 to 2010 in Brazil. Record linkage decreased the percentage of new cases closed with patient transfer as the outcome, ranging from 34.8% in 2008 to 35.5% in 2009. After linkage between SINAN and SIM, the percentage of TB deaths among new cases increased, varying around 15%. The results highlight the need for attention to data quality for TB treatment outcomes in SINAN. PMID- 25494000 TI - Time spent by Brazilian students in different modes of transport going to school: changes over a decade (2001-2011). AB - To examine changes in the time spent in each mode of transportation used for going to school by gender and age among adolescents from Santa Catarina State, Brazil. Two school-based surveys were performed in 2001 (N = 5,028) and 2011 (N = 6,529) in high school students (15-19 years old). The mode of transportation (on foot; by bicycle; by bus; car/motorcycle) and the time spent for commuting to school were assessed. Active commuting increased for short trips in both genders (male: 25.1% to 36.7%; female: 18.8% to 29.2%) and in all ages (15-16 years: 21% to 32.7%; 17-19 years: 21.9% to 32.4%), and declined for longer trips in males (30.5% to 21.9%) and in 15-16 years old students (25.7% to 34.7%). Car/motorcycle use has doubled for short trips in males (38.1% to 65.9%) and in 17-19 years old students (37.7% to 62.7%), while the use of buses remained stable in both genders. Our findings contribute to discussions on public policy focusing on the design of safe environments to promote active commuting to schools, particularly to decrease the use of motorized transport for short trips. PMID- 25494001 TI - ? PMID- 25494002 TI - ? PMID- 25494003 TI - Simultaneous spectral and temporal analyses of kinetic energies in nonequilibrium systems: theory and application to vibrational relaxation of O-D stretch mode of HOD in water. AB - A time series of kinetic energies (KE) from classical molecular dynamics (MD) simulation contains fundamental information on system dynamics. It can also be analyzed in the frequency domain through Fourier transformation (FT) of velocity correlation functions, providing energy content of different spectral regions. By limiting the FT time span, we have previously shown that spectral resolution of KE evolution is possible in the nonequilibrium situations [Jeon and Cho, J. Chem. Phys. 2011, 135, 214504]. In this paper, we refine the method by employing the concept of instantaneous power spectra, extending it to reflect an instantaneous time-correlation of velocities with those in the future as well as with those in the past, and present a new method to obtain the instantaneous spectral density of KE (iKESD). This approach enables the simultaneous spectral and temporal resolution of KE with unlimited time precision. We discuss the formal and novel properties of the new iKESD approaches and how to optimize computational methods and determine parameters for practical applications. The method is specifically applied to the nonequilibrium MD simulation of vibrational relaxation of the OD stretch mode in a hydrated HOD molecule by employing a hybrid quantum mechanical/molecular mechanical (QM/MM) potential. We directly compare the computational results with the OD band population relaxation time profiles extracted from the IR pump-probe measurements for 5% HOD in water. The calculated iKESD yields the OD bond relaxation time scale ~30% larger than the experimental value, and this decay is largely frequency-independent if the classical anharmonicity is accounted for. From the integrated iKESD over intra- and intermolecular bands, the major energy transfer pathways were found to involve the HOD bending mode in the subps range, then the internal modes of the solvent until 5 ps after excitation, and eventually the solvent intermolecular modes. Also, strong hydrogen-bonding of HOD is found to significantly hinder the initial intramolecular energy transfer process. PMID- 25494004 TI - Microfluidic static droplet array for analyzing microbial communication on a population gradient. AB - Quorum sensing (QS) is a type of cell-cell communication using signal molecules that are released and detected by cells, which respond to changes in their population density. A few studies explain that QS may operate in a density dependent manner; however, due to experimental challenges, this fundamental hypothesis has never been investigated. Here, we present a microfluidic static droplet array (SDA) that combines a droplet generator with hydrodynamic traps to independently generate a bacterial population gradient into a parallel series of droplets under complete chemical and physical isolation. The SDA independently manipulates both a chemical concentration gradient and a bacterial population density. In addition, the bacterial population gradient in the SDA can be tuned by a simple change in the number of sample plug loading. Finally, the method allows the direct analysis of complicated biological events in an addressable droplet to enable the characterization of bacterial communication in response to the ratio of two microbial populations, including two genetically engineered QS circuits, such as the signal sender for acyl-homoserine lactone (AHL) production and the signal receiver bacteria for green fluorescent protein (GFP) expression induced by AHL. For the first time, we found that the population ratio of the signal sender and receiver indicates a significant and potentially interesting partnership between microbial communities. Therefore, we envision that this simple SDA could be a useful platform in various research fields, including analytical chemistry, combinatorial chemistry, synthetic biology, microbiology, and molecular biology. PMID- 25494005 TI - Atomic-scale structure and properties of highly stable antiphase boundary defects in Fe3O4. AB - The complex and intriguing properties of the ferrimagnetic half metal magnetite (Fe3O4) are of continuing fundamental interest as well as being important for practical applications in spintronics, magnetism, catalysis and medicine. There is considerable speculation concerning the role of the ubiquitous antiphase boundary (APB) defects in magnetite, however, direct information on their structure and properties has remained challenging to obtain. Here we combine predictive first principles modelling with high-resolution transmission electron microscopy to unambiguously determine the three-dimensional structure of APBs in magnetite. We demonstrate that APB defects on the {110} planes are unusually stable and induce antiferromagnetic coupling between adjacent domains providing an explanation for the magnetoresistance and reduced spin polarization often observed. We also demonstrate how the high stability of the {110} APB defects is connected to the existence of a metastable bulk phase of Fe3O4, which could be stabilized by strain in films or nanostructures. PMID- 25494006 TI - Uptake and costs of hypofractionated vs conventional whole breast irradiation after breast conserving surgery in the United States, 2008-2013. AB - IMPORTANCE: Based on randomized evidence, expert guidelines in 2011 endorsed shorter, hypofractionated whole breast irradiation (WBI) for selected patients with early-stage breast cancer and permitted hypofractionated WBI for other patients. OBJECTIVES: To examine the uptake and costs of hypofractionated WBI among commercially insured patients in the United States. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, observational cohort study, using administrative claims data from 14 commercial health care plans covering 7.4% of US adult women in 2013, we classified patients with incident early-stage breast cancer treated with lumpectomy and WBI from 2008 and 2013 into 2 cohorts: (1) the hypofractionation-endorsed cohort (n = 8924) included patients aged 50 years or older without prior chemotherapy or axillary lymph node involvement and (2) the hypofractionation-permitted cohort (n = 6719) included patients younger than 50 years or those with prior chemotherapy or axillary lymph node involvement. EXPOSURES: Hypofractionated WBI (3-5 weeks of treatment) vs conventional WBI (5-7 weeks of treatment). MAIN OUTCOMES AND MEASURES: Use of hypofractionated and conventional WBI, total and radiotherapy-related health care expenditures, and patient out-of-pocket expenses. Patient and clinical characteristics included year of treatment, age, comorbid disease, prior chemotherapy, axillary lymph node involvement, intensity-modulated radiotherapy, practice setting, and other contextual variables. RESULTS: Hypofractionated WBI increased from 10.6% (95% CI, 8.8%-12.5%) in 2008 to 34.5% (95% CI, 32.2%-36.8%) in 2013 in the hypofractionation-endorsed cohort and from 8.1% (95% CI, 6.0%-10.2%) in 2008 to 21.2% (95% CI, 18.9%-23.6%) in 2013 in the hypofractionation-permitted cohort. Adjusted mean total health care expenditures in the 1 year after diagnosis were $28,747 for hypofractionated and $31,641 for conventional WBI in the hypofractionation-endorsed cohort (difference, $2894; 95% CI, $1610-$4234; P < .001) and $64,273 for hypofractionated and $72,860 for conventional WBI in the hypofractionation-permitted cohort (difference, $8587; 95% CI, $5316-$12,017; P < .001). Adjusted mean total 1-year patient out-of-pocket expenses were not significantly different between hypofractionated vs conventional WBI in either cohort. CONCLUSIONS AND RELEVANCE: Hypofractionated WBI after breast conserving surgery increased among women with early-stage breast cancer in 14 US commercial health care plans between 2008 and 2013. However, only 34.5% of patients with hypofractionation-endorsed and 21.2% with hypofractionation-permitted early-stage breast cancer received hypofractionated WBI in 2013. PMID- 25494007 TI - Baclofen and gamma-hydroxybutyrate (GHB), a dangerous combination. AB - Baclofen is a gamma-aminobutyric acid (GABA)-beta receptor agonist with a muscle relaxant effect. It increases GABA activity and reduces the production of glutamate and dopamine. The GABA precursor gamma-hydroxybutyrate (GHB) has gained popularity as a drug of abuse. For the first time, we report a case of a GHB dependent patient, who ingested several days' doses of baclofen (80 mg) simultaneously with 0.3 L (215 g) of illicit GHB. Baclofen (40 mg/d) was prescribed to prevent relapse after a successful detoxification. The patient developed a rapid coma (E2M5V1 with oxygen support), bradypnea, and hypotonia. Physicians should be alert to the danger of this combination because of the hazards of coma and respiratory distress. PMID- 25494008 TI - Possible addiction transference from cocaine insufflation to oral bupropion in bipolar patient. AB - OBJECTIVE: Alert for the risk of oral bupropion addiction in patients with cocaine dependence. METHODS: Single-case study. RESULTS: After a period of cocaine and alcohol abstinence, a 42-year-old patient started taking oral bupropion to relieve the symptoms of cocaine craving. He increased the bupropion dose up to 2250 mg/d without seizures. CONCLUSION: This case highlights the possibility of oral bupropion addiction after cocaine dependence. To our knowledge, it is the first case in the literature and emphasizes the risk of bupropion's misuse. Therefore, physicians should carefully examine the patient's profile before prescribing it, as well as follow appropriate measures. PMID- 25494009 TI - Survival in patients with metachronous second primary lung cancer. AB - RATIONALE: Four to 10% of patients with non-small cell lung cancer subsequently develop a metachronous second primary lung cancer. The decision to perform surveillance or screening imaging for patients with potentially cured lung cancer must take into account the outcomes expected when detecting metachronous second primaries. OBJECTIVES: To assess potential survival differences between patients with metachronous second primary lung cancer compared to matched patients with first primary lung cancer. METHODS: We retrospectively reviewed patients diagnosed with lung cancer at the Cleveland Clinic (2006-2010). Metachronous second primary lung cancer was defined as lung cancer diagnosed after a 4-year, disease-free interval from the first lung cancer, or if there were two different histologic subtypes diagnosed at different times. Patients with first primary lung cancer diagnosed in the same time period served as control subjects. Propensity score matching was performed using age, sex, smoking history, histologic subtype, and collaborative stage, with a 1:3 case-control ratio. Survival analyses were performed by Cox proportional hazards modeling and Kaplan Meier estimates. MEASUREMENTS AND MAIN RESULTS: Forty-four patients met criteria for having a metachronous second primary lung cancer. There were no statistically significant differences between case subjects and control subjects in prognostic variables. The median survival time and 2-year overall survival rate for the metachronous second primary group, compared with control subjects, were as follows: 11.8 versus 18.4 months (P = 0.18) and 31.0 versus 40.9% (P = 0.28). The survival difference was largest in those with stage I metachronous second primaries (median survival time, 26.8 vs. 60.4 mo, P = 0.09; 2-year overall survival, 56.3 vs. 71.2%, P = 0.28). CONCLUSIONS: Patients with stage I metachronous second primary lung cancer may have worse survival than those who present with a first primary lung cancer. This could influence the benefit-risk balance of screening the high-risk cohort with a previously treated lung cancer. PMID- 25494010 TI - Identification of Genetic Alterations, as Causative Genetic Defects in Long QT Syndrome, Using Next Generation Sequencing Technology. AB - BACKGROUND: Long QT Syndrome is an inherited channelopathy leading to sudden cardiac death due to ventricular arrhythmias. Despite that several genes have been associated with the disease, nearly 20% of cases remain without an identified genetic cause. Other genetic alterations such as copy number variations have been recently related to Long QT Syndrome. Our aim was to take advantage of current genetic technologies in a family affected by Long QT Syndrome in order to identify the cause of the disease. METHODS: Complete clinical evaluation was performed in all family members. In the index case, a Next Generation Sequencing custom-built panel, including 55 sudden cardiac death related genes, was used both for detection of sequence and copy number variants. Next Generation Sequencing variants were confirmed by Sanger method. Copy number variations variants were confirmed by Multiplex Ligation dependent Probe Amplification method and at the mRNA level. Confirmed variants and copy number variations identified in the index case were also analyzed in relatives. RESULTS: In the index case, Next Generation Sequencing revealed a novel variant in TTN and a large deletion in KCNQ1, involving exons 7 and 8. Both variants were confirmed by alternative techniques. The mother and the brother of the index case were also affected by Long QT Syndrome, and family cosegregation was observed for the KCNQ1 deletion, but not for the TTN variant. CONCLUSIONS: Next Generation Sequencing technology allows a comprehensive genetic analysis of arrhythmogenic diseases. We report a copy number variation identified using Next Generation Sequencing analysis in Long QT Syndrome. Clinical and familiar correlation is crucial to elucidate the role of genetic variants identified to distinguish the pathogenic ones from genetic noise. PMID- 25494011 TI - Identifying and assessing the substance-exposed infant. AB - As the rate of opioid prescription grows, so does fetal exposure to opioids during pregnancy. With increasing fetal exposure to both prescription and nonprescription drugs, there has been a concurrent increase in identification of Neonatal Withdrawal Syndrome (NWS) and adaptation difficulties after birth. In addition, extended use of opioids, barbiturates, and benzodiazepines in neonatal intensive care has resulted in iatrogenic withdrawal syndromes. There is a lack of evidence to support the use of any one specific evaluation strategy to identify NWS. Clinicians caring for infants must use a multimethod approach to diagnosis, including interview and toxicology screening. Signs of NWS are widely variable, and reflect dysfunction in autonomic regulation, state control, and sensory and motor functioning. Several assessment tools have been developed for assessing severity of withdrawal in term neonates. These tools assist in determining need and duration of pharmacologic therapy and help in titration of these therapies. Considerable variability exists in the pharmacologic and nonpharmacologic approaches to affected babies across settings. An evidence-based protocol for identification, evaluation, and management of NWS should be in place in every nursery. This article provides an overview of identification and assessment considerations for providers who care for babies at risk for or who are experiencing alterations in state, behavior, and responses after prenatal or iatrogenic exposure to agents associated with the spectrum of withdrawal. PMID- 25494012 TI - Concussion evaluation and management in pediatrics. AB - Concussions are among the most complex injuries to assess and manage in sports medicine and primary care. Sports concussion in youth has received much attention in recent years because research shows that improperly managed concussion can lead to long-term cognitive deficits and mental health problems. There are several notable risk factors affecting the incidence and severity of concussion in school-age children and adolescents, including a history of a previous concussion. A more conservative approach for return to activities following concussion has been proposed for children and adolescents. Programs of individualized, stepwise increases in physical activity have largely replaced use of algorithms for assigning a grade and activity expectations to concussions. Although validity and reliability testing is ongoing to support use of concussion assessment instruments in pediatric patients, it is practical and appropriate that clinicians incorporate symptom checklists, sideline and balance assessment tools, and neurocognitive assessment instruments into their practice in accordance with evidence-based guidelines. PMID- 25494013 TI - Oral feeding readiness assessment in premature infants. AB - Oral feeding readiness is a complex concept. More evidence is needed on how to approach beginning oral feedings in premature hospitalized infants. This article provides a review of literature related to oral feeding readiness in the premature infant and strategies for promoting safe and efficient progression to full oral intake. Oral feeding readiness assessment tools, clinical pathways, and feeding advancement protocols have been developed to assist with oral feeding initiation and progression. Recognition and support of oral feeding readiness may decrease length of hospital stay and have a positive impact on reducing healthcare costs. Supporting effective cue-based oral feeding through use of rigorous assessment or evidence-based care guidelines can also optimize the hospital experience for infants and caregivers, which, in turn, can promote attachment and parent satisfaction. PMID- 25494014 TI - Correlation between C-reactive protein in peripheral vein and coronary sinus in stable and unstable angina. AB - BACKGROUND: High sensitivity C-reactive protein (hs-CRP) is commonly used in clinical practice to assess cardiovascular risk. However, a correlation has not yet been established between the absolute levels of peripheral and central hs CRP. OBJECTIVE: To assess the correlation between serum hs-CRP levels (mg/L) in a peripheral vein in the left forearm (LFPV) with those in the coronary sinus (CS) of patients with coronary artery disease (CAD) and a diagnosis of stable angina (SA) or unstable angina (UA). METHODS: This observational, descriptive, and cross sectional study was conducted at the Instituto do Coracao, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, and at the Hospital Beneficencia Portuguesa de Sao Paulo, where CAD patients referred to the hospital for coronary angiography were evaluated. RESULTS: Forty patients with CAD (20 with SA and 20 with UA) were included in the study. Blood samples from LFPV and CS were collected before coronary angiography. Furthermore, analysis of the correlation between serum levels of hs-CRP in LFPV versus CS showed a strong linear correlation for both SA (r = 0.993, p < 0.001) and UA (r = 0.976, p < 0.001) and for the entire sample (r = 0.985, p < 0.001). CONCLUSION: Our data suggest a strong linear correlation between hs-CRP levels in LFPV versus CS in patients with SA and UA. PMID- 25494016 TI - Vascular response of ruthenium tetraamines in aortic ring from normotensive rats. AB - BACKGROUND: Ruthenium (Ru) tetraamines are being increasingly used as nitric oxide (NO) carriers. In this context, pharmacological studies have become highly relevant to better understand the mechanism of action involved. OBJECTIVE: To evaluate the vascular response of the tetraamines trans [Ru(II)(NH3)4(Py)(NO)](3+), trans-[Ru(II)(Cl)(NO) (cyclan)](PF6)2, and trans [Ru(II)(NH3)4(4-acPy)(NO)](3+). METHODS: Aortic rings were contracted with noradrenaline (10(-6) M). After voltage stabilization, a single concentration (10(-6) M) of the compounds was added to the assay medium. The responses were recorded during 120 min. Vascular integrity was assessed functionally using acetylcholine at 10(-6) M and sodium nitroprusside at 10(-6) M as well as by histological examination. RESULTS: Histological analysis confirmed the presence or absence of endothelial cells in those tissues. All tetraamine complexes altered the contractile response induced by norepinephrine, resulting in increased tone followed by relaxation. In rings with endothelium, the inhibition of endothelial NO caused a reduction of the contractile effect caused by pyridine NO. No significant responses were observed in rings with endothelium after treatment with cyclan NO. In contrast, in rings without endothelium, the inhibition of guanylate cyclase significantly reduced the contractile response caused by the pyridine NO and cyclan NO complexes, and both complexes caused a relaxing effect. CONCLUSION: The results indicate that the vascular effect of the evaluated complexes involved a decrease in the vascular tone induced by norepinephrine (10(-6) M) at the end of the incubation period in aortic rings with and without endothelium, indicating the slow release of NO from these complexes and suggesting that the ligands promoted chemical stability to the molecule. Moreover, we demonstrated that the association of Ru with NO is more stable when the ligands pyridine and cyclan are used in the formulation of the compound. PMID- 25494017 TI - Neural mechanisms and delayed gastric emptying of liquid induced through acute myocardial infarction in rats. AB - BACKGROUND: In pathological situations, such as acute myocardial infarction, disorders of motility of the proximal gut can trigger symptoms like nausea and vomiting. Acute myocardial infarction delays gastric emptying (GE) of liquid in rats. OBJECTIVE: Investigate the involvement of the vagus nerve, alpha 1 adrenoceptors, central nervous system GABAB receptors and also participation of paraventricular nucleus (PVN) of the hypothalamus in GE and gastric compliance (GC) in infarcted rats. METHODS: Wistar rats, N = 8-15 in each group, were divided as INF group and sham (SH) group and subdivided. The infarction was performed through ligation of the left anterior descending coronary artery. GC was estimated with pressure-volume curves. Vagotomy was performed by sectioning the dorsal and ventral branches. To verify the action of GABAB receptors, baclofen was injected via icv (intracerebroventricular). Intravenous prazosin was used to produce chemical sympathectomy. The lesion in the PVN of the hypothalamus was performed using a 1 mA/10 s electrical current and GE was determined by measuring the percentage of gastric retention (% GR) of a saline meal. RESULTS: No significant differences were observed regarding GC between groups; vagotomy significantly reduced % GR in INF group; icv treatment with baclofen significantly reduced %GR. GABAB receptors were not conclusively involved in delaying GE; intravenous treatment with prazosin significantly reduced GR% in INF group. PVN lesion abolished the effect of myocardial infarction on GE. CONCLUSION: Gastric emptying of liquids induced through acute myocardial infarction in rats showed the involvement of the vagus nerve, alpha1- adrenergic receptors and PVN. PMID- 25494018 TI - Differential expression of vascular endothelial growth factor-a isoforms in neovascular age-related macular degeneration. AB - PURPOSE: To investigate the role of vascular endothelial growth factor-A (VEGF-A) isoforms in neovascular age-related macular degeneration. METHODS: Choroidal neovascular membranes (CNV) were excised in 24 patients, 8 of them underwent previous photodynamic therapy. All procedures were performed before anti-VEGF therapies were implemented in Germany. Normal human donor eyes served as controls. Messenger RNA expression of total VEGF-A and VEGF-A isoforms was measured. RESULTS: Vascular endothelial growth factor-A121 is the most abundant isoform in CNV and control tissues. In controls, VEGF-A121 is lowest in neural retina and highest in choroids. For total VEGF-A and VEGF-A165, this is vice versa. VEGF-A165 and VEGF-A189 are significantly higher in CNV than in control choroids, the opposite is found for VEGF-A121. After photodynamic therapy, total VEGF-A and VEGF-A121 are increased, VEGF-A165 and VEGF-A189 are decreased. Age dependently, there is an increase in VEGF-A165 and a decrease in VEGF-A121. CONCLUSION: Vascular endothelial growth factor-A isoforms are differentially distributed, suggesting that tissue-specific regulation of various isoforms is physiologically important. The disruption of this homeostasis in CNV membranes may be significant in the onset and progression of neovascular age-related macular degeneration. Our findings support the dominant role of VEGF-A121 in neovascular age-related macular degeneration but hint that VEGF-A165 may have an equivalent role in other neovascular retinal pathology. PMID- 25494019 TI - Correspondence. PMID- 25494020 TI - Surgical Outcomes of Developmental Dysplasia of the Hip With or Without Prior Failed Closed Reduction. AB - BACKGROUND: Osteonecrosis of the femoral head is a major complication in the treatment of developmental dysplasia of the hip (DDH). Redislocation and secondary surgeries were regarded as risk factors of osteonecrosis. This study aims to clarify whether prior failed closed reduction is a risk factor of osteonecrosis in subsequent surgery. METHODS: We retrospectively studied 124 patients treated by open reduction and pelvic osteotomy for unilateral DDH before 3 years old. Twenty-five patients had failed closed reduction before the surgery (secondary surgery group), and the other 99 patients had the same surgery as the first treatment (primary surgery group). Osteonecrosis was defined by broadening of femoral neck and fragmentation of epiphysis in the first 3 years after operation. The background data and rate of osteonecrosis were compared between the 2 groups using t test and chi2 test. RESULTS: Age at surgery and Tonnis grade were not significantly different between the 2 groups. Broadening of the femoral neck was observed in 63 of the 99 hips (63.6%) in the primary surgery group and 7 of the 25 hips (28.0%) in the secondary surgery group (P=0.001). Rate of epiphyseal fragmentation was 34% in primary surgery group and 24% in secondary surgery group (P=0.323). CONCLUSIONS: Soft tissue tension could be reduced by previous closed reduction, and redislocation would not carry a greater risk of osteonecrosis in the subsequent open reduction. PMID- 25494021 TI - Current Practice in the Management of Type I Open Fractures in Children: A Survey of POSNA Membership. AB - BACKGROUND: Treatment of pediatric type I open fractures is controversial. Centers have reported good success with emergency room (ER) treatment of low energy (type I) open pediatric fractures. The purpose of this study was to ascertain the treatment preferences of pediatric orthopaedic surgeons for type I open fractures. We hypothesize that surgeons will have different treatment protocols and preferred location for these injuries. METHODS: A questionnaire was given to Pediatric Orthopaedic Society of North America (POSNA) members at the 2012 annual meeting. Demographic questions inquired about surgeon's practice environment and experience, whereas clinical questions queried opinions regarding the typical treatments and past experiences with open fractures. Clinical scenarios questioned preferred management of open fractures. RESULTS: A total of 181 surveys were collected from the 503 POSNA members in attendance (36%). Years in practice were well represented with 34%: <10 years, 37%: 10 to 19 years, and 29%: >20 years. Most respondents' practices comprised over 80% pediatric patients (86%), were academic (68%), and worked with residents (77%). After initial treatment of an open fracture, 86% of respondents admitted patients for intravenous antibiotics and 57% gave oral antibiotics. There was no consensus regarding the amount or type of irrigation preferred, use of antibiotics in the irrigation, or whether the bone ends are delivered during irrigation and debridement. Soft-tissue infections and delayed union were noted by 13% and 8%, respectively, of respondents in type I open fractures treated in the ER and in 16% and 30% treated in the operating room (OR). ER treatment was preferred in 19% to 31% of respondents for type I open fractures. When queried if level 1 evidence existed that demonstrated equivalent results between ER and OR management, 92% of respondents would change their practice. CONCLUSIONS: Treatment methods of type I open fractures are variable. Many surgeons prefer to treat type I open fractures in the ER as opposed to the traditional OR irrigation and debridement. On the basis of this survey, either children are going to the OR when ER treatment would be adequate or they may be receiving inadequate care when they avoid OR management. This survey establishes the equipoise necessary for a randomized, prospective trial comparing ER and OR management in the treatment of pediatric type I open fractures. PMID- 25494022 TI - The Quality of Randomized Controlled Trials in Pediatric Orthopaedics: Are We Improving? AB - PURPOSE: The quality of randomized controlled trials (RCTs) in orthopaedics is a topic of considerable importance, as RCTs play a major role in guiding clinical practice. The quality of RCTs published between 1995 and 2005 has previously been documented. The purpose of the current study was to assess and describe the quality of pediatric orthopaedic RCTs published from 2005 to 2012, by identifying study characteristics associated with higher quality and outlining areas for improvement. METHODS: A standardized literature search was used to identify pediatric orthopaedic RCTs published in 7 well-recognized journals between September 2005 and July 2012 inclusive. The Detsky Quality Assessment Scale and the CONSORT checklist for Non-Pharmacologic Trials were used to assess the quality of the RCTs. Scores for the Detsky and CONSORT were calculated by 2 independent blinded orthopaedic surgeon reviewers with epidemiologic training. RESULTS: Forty RCTs were included in this analysis. The mean percentage score on the Detsky quality scale was 67%. Sixteen (40%) of the articles satisfied the threshold for a satisfactory level of methodological quality (Detsky >75%). Twenty-five (63%) of these studies were negative studies, concluding no difference between treatment arms. In 52% of the negative studies, an a priori sample size analysis was absent, and 28% were self-described as underpowered. In multiple variable regression analysis, only working with a statistician was significantly associated with higher Detsky percentage scores (P=0.01). CONCLUSIONS: There is a trend for improving quality in pediatric orthopaedic RCTs. Compared with past reports, the mean Detsky score improved from 53% to 67%, and the proportion meeting an acceptable level of quality improved from 19% to 40%. One of the most concerning findings of this study was the lack of attention to sample size and power analysis, and the potential for underpowered studies. Ongoing efforts are necessary to improve the conduct and reporting of clinical trials in pediatric orthopaedics. SIGNIFICANCE: Pediatric orthopaedic surgeons, JPO, and POSNA are working toward improving levels of quality in pediatric orthopaedic research. This paper highlights progress that has been made, and addresses some high-yield areas for future improvement. PMID- 25494023 TI - How Critical is Patient Positioning in Radiographic Assessment of the Hip in Cerebral Palsy When Measuring Migration Percentage? AB - BACKGROUND: Migration percentage (MP) is an accepted method of assessing lateral displacement of the femoral head in children with cerebral palsy (CP). Difficulty in positioning of patients for pelvic radiography remains a concern for the reliability of the MP. METHODS: This 2-part quantitative study examined 100 anteroposterior pelvic radiographs for children with CP. Fifty were from a region that had a positioning protocol for hip surveillance of children with CP and 50 images were from a region without. Images were assessed for acceptability of position in relation to hip abduction/adduction and/or pelvic rotation.Ten images deemed Acceptable or Borderline from the region with no protocol were then randomly selected. MP was measured on 2 separate occasions by 5 children's orthopaedic surgeons and statistically analyzed for intrarater and interrater reliability. RESULTS: There was no statistically significant difference in the acceptability of images between the 2 regions with 60% to 66% of the images meeting the criteria outright. When allowances were made for slight variation of abduction/adduction within 5 degrees, 74% to 80% of the images were acceptable.Reliability was variable with limits of agreement between 4.96% and 15.15%. Observers more familiar with the software measuring package had higher reliability within and between occasions. Variability within and between observers decreased as MP increased. CONCLUSIONS: Poor positioning did not appear to be the main reason for the variation in reliability of MP. Repeat measurements were reliable although standardized technique, training, and familiarity with software measuring programmes did influence outcomes. PMID- 25494024 TI - Screw Fixation of Lateral Condyle Fractures: Results of Treatment. AB - BACKGROUND: Fixation of lateral condyle distal humeral fractures has traditionally been achieved with K-wires. Screw fixation provides the advantage of compression across the fracture site, but the results of screw fixation and risk of iatrogenic physeal damage are not well defined. This study was designed to evaluate the efficacy of screw fixation for lateral condyle fractures. METHODS: A retrospective study of patients with lateral condyle elbow fractures treated using screw fixation at a single institution was undertaken. Patients 12 years and younger with isolated fractures were included. Clinical notes were examined for residual symptoms, alignment, range of motion, and complications. Radiographs were reviewed for healing and growth arrest. RESULTS: Ninety-six patients who were treated over a 7-year period met inclusion criteria. Mean patient age was 5.8 years (range, 2 to 12 y). Fifty-four patients required open reduction; 42 patients underwent a closed reduction. Mean follow-up was 28.1 weeks (range, 4.9 to 417 wk). The overall complication rate was 19% and was 5% when lateral overgrowth was excluded as a complication. Initial fracture union was achieved in 99% of patients. One patient required revision fixation with a bone graft. Hardware was symptomatic with prominence or loss of flexion in 4% of patients. There were no cases of growth arrest or alterations of the carrying angle. For patients with final follow-up >12 months, the mean extension loss was 2 degrees (range, 0 to 25 degrees) and the mean loss of flexion was 8 degrees (range, 0 to 25 degrees). CONCLUSION: Screw fixation of lateral condyle fractures results in satisfactory union with a low risk of complications at early follow up. PMID- 25494025 TI - Closed Reduction and Percutaneous Pinning of Displaced Pediatric Lateral Condyle Fractures of the Humerus: A Cohort Study. AB - BACKGROUND: In treating pediatric lateral condyle fractures (LCFs) of the humerus, closed reduction and percutaneous pinning (CRPP) is an attractive alternative to open reduction and internal fixation (ORIF) because of the potential decrease in tissue injury, shorter surgical times, and faster functional recovery. However, there is limited information available regarding its outcome. METHODS: The data on 191 pediatric LCFs [163 fractures (85%) treated with ORIF (group 1) and 28 fractures (15%) treated with CRPP (group 2)], who were followed for over 12 weeks, was included in the present analysis. We compared several aspects related to the outcome of CRPP (as compared with ORIF), including issues related to surgical time, recovery of range of motion, lateral spur formation, complications, and overall outcome. RESULTS: The surgical time was significantly shorter for patients in group 2 (mean: 25.4 min; range: 18 to 50 min), as compared with group 1 (mean: 52.6 min; range: 24 to 121 min). A nearly anatomic reduction (<2 mm of residual displacement) was obtained in all fractures. No intraoperative or immediate postoperative complications were observed. The recovery of range of motion was similar in both groups: during the latest follow-up appointment, elbows in group 1 and 2 had achieved a mean relative arc of motion of 99.2% and 99.7%, respectively (P=0.3). Lateral spur formation was seen in 75% of fractures in group 1 and in 68% of fractures in group 2 (P=0.2). The overall rate of complications was 6.3% and 3.6% for fractures is groups 1 and 2, respectively (P=0.5). A satisfactory outcome was observed in 88.3% of fractures in group 1 and in 89.3% of fractures in group 2 (P=0.6) (Table 1). CONCLUSIONS: CRPP is a viable alternative for the treatment of pediatric LCFs with limited initial displacement (between 2 and 4 mm). In addition to the obvious cosmetic advantage of avoiding an unsightly scar, it is associated with decreased surgical times and does not significantly increase the incidence of complications. PMID- 25494026 TI - Normal Parameters of the Skeletally Immature Knee: Developmental Changes on Magnetic Resonance Imaging. AB - BACKGROUND: A child's knee undergoes significant morphologic changes during development. Age-specific normal parameters have not been previously described. The purpose of this study was to delineate knee morphology changes that occur with maturation utilizing magnetic resonance imaging (MRI). METHODS: A retrospective review of knee MRIs, ages 4 to 18 years, was performed using "normal" diagnosis codes, including: knee pain, plicae, septic arthritis, jumper's knee, growing pains, benign neoplasm, and osteomyelitis. Seventeen osseous parameters were measured, plus their cartilaginous counterparts, if different. Spearman rho correlations were calculated between age and MRI measures. RESULTS: A total of 132 MR images were reviewed. Significant correlation with age was observed in all osseous measurements, except medial patellofemoral ligament (MPFL) insertion (P<0.05). Similarly, the cartilage measures demonstrated significant correlation with age, except the notch width index, MPFL insertion, and trochlear morphology. The magnitude of correlation was significantly different between the osseous and cartilage measures for all but 4 of the variables: anterior cruciate ligament (ACL) length and width, intercondylar width and tibial tubercle-trochlear groove (TT-TG) interval. Sex seems to affect ACL length, Insall-Salvati ratio, intercondylar width, and sulcus angle.The MPFL origin starts distal to the physis and moves proximal with age (rho=0.33, P<0.001), when at age 7 years, it is located at or above the femoral physis. The mean ACL diameter grows from 6.5 to 9.8 mm. Cartilage sulcus angle remains consistently 150 degrees, and the TT-TG interval shifts from 6 to 12 mm with maturity. CONCLUSIONS: The normative data presented here demonstrates that maturity correlates well with the morphologic changes seen in most of the studied parameters. These data not only aid in the identification of the abnormal findings by sex and age, but also provides normal sizes of the ACL and location of insertion for the MPFL which can benefit surgical planning. PMID- 25494027 TI - Functional Loss With Displacement of Medial Epicondyle Humerus Fractures: A Computer Simulation Study. AB - BACKGROUND: Assessment and management of the medial humeral epicondyle fracture remains controversial, with conflicting reports of displacement direction and consequent functional deficits unclear. The purpose of this study was to define biomechanically likely directions of medial epicondyle fracture displacement and to determine possible changes in muscle function related to that displacement. METHODS: A 3-dimensional computer model of the upper extremity was used to simulate the consequences of medial epicondyle fracture displacements from 1 to 20 mm in the anterior, medial, and inferior directions relative to the humerus with the elbow at 90-degree flexion and neutral forearm rotation (a replication of accepted positions for clinical strength testing). Muscle length and force were calculated following displacement. Maximum isometric wrist flexion moments were calculated over the full range of wrist motion based on known force generating properties of the muscles. RESULTS: Anterior displacement resulted in shortened muscles and reduced wrist flexion moment, with a decrease in strength averaging 2% for every 1 mm of anterior fragment displacement at neutral wrist position (maximum decrease of 39% with 20 mm displacement). In contrast, displacement in the medial and inferior directions resulted in stretched muscles and increased wrist flexion moments and therefore are not biomechanically likely. CONCLUSIONS: Computer simulation of a medial epicondyle fracture suggests that anterior displacement could result in a dramatic loss of initial muscle strength and function. Medial displacement is unlikely to occur in vivo due to consequential muscle lengthening, suggesting that alternatives to the historical use of AP radiographs to assess displacement of this fracture are needed. CLINICAL RELEVANCE: Our work provides a biomechanical explanation for anterior displacement of medial epicondyle fractures observed radiographically and motivates alternative methods of fracture assessment. A functional basis for determining acceptable displacement of medial epicondyle fractures is suggested; however, all individual clinical factors should be considered. PMID- 25494028 TI - Scoliosis in Children With Aicardi Syndrome. AB - BACKGROUND: Aicardi syndrome (ACS) is a rare neurodevelopmental disorder that was classically characterized by the triad of agenesis of corpus callosum, infantile spasms, and chorioretinal lacunae. As new cases emerge and new common phenotypic features are being described in subsequent reports, new modified diagnostic criteria have been proposed that now classify the observed costovertebral abnormalities as supporting diagnostic features. To our knowledge there are no previous studies focusing and describing the scoliosis observed in children with ACS. METHODS: We screened billing lists to identify patients seen in the Division of Orthopaedic Surgery at our institution with a diagnosis of ACS that were treated for scoliosis after 2001. A total of 5 patients were identified. Medical records and radiographs were retrospectively reviewed in all cases. In all of the patients the diagnosis of ACS had been confirmed through complete genetic evaluation and advanced imaging. RESULTS: The mean age when scoliosis was first noticed was 3.9+/-4.2 years (range, 0.5 to 10.5 y) with a mean Cobb angle of 22.5+/-6.7 degrees (range, 10 to 27 degrees). The mean age at the first orthopedic visit was 5.8+/-5.0 years (range, 1.5 to 13 y) with a progressed mean Cobb angle of 39.5+/-17.3 degrees (range, 15 to 57 degrees). Congenital vertebral anomalies were observed in 1 patient. Three patients were treated surgically; 1 of the 3 patients had a surgical complication with loss of intraoperative neuromonitoring signals. Two patients had not undergone surgery at the last visit with a mean Cobb angle of 75.5 degrees. The mean postoperative follow-up for the surgical group (cases 1 to 3) was 3+/-3.6 years (range, 0.6 to 7.2 y) and the mean total follow-up for both groups was 6.6+/-2.5 years (range, 2.6 to 8.6 y). CONCLUSIONS: Scoliosis in ACS can represent a clinically significant problem that is underdiagnosed and overshadowed by the other severe medical complications associated with the syndrome. Our data suggest that scoliosis in patients with ACS is rapidly progressive and bracing is ineffective; early screening, close observation, and low threshold for referral to an orthopedic surgeon are crucial. LEVEL OF EVIDENCE: Level IV-case series. PMID- 25494029 TI - Valgus Osteotomy of the Proximal Humerus to Treat Humerus Varus in Children. AB - PURPOSE: Humerus varus is a rare disease in children that can cause limited active abduction and forward flexion of the shoulder as well as upper limb length discrepancies. Valgus osteotomy of the proximal humerus is an effective method to treat this disease, although internal fixation with a plate and screws is rarely reported. The purpose of this article is to investigate the clinical outcome and radiographic changes of valgus osteotomy of the proximal humerus through internal fixation with a plate and screws. METHODS: From April 2005 to August 2011, our group treated 5 patients including 1 girl and 4 boys. The left side was the affected side in all cases. The mean operation age was 13 years. We performed valgus osteotomy of the proximal humerus with internal fixation provided by a plate and screws to treat these patients. Follow-ups were performed with an average of 35.6 months (range, 24 to 74 mo). The changes in postoperative shoulder function and radiographic images were analyzed. RESULTS: The actual cause of the humerus varus was not clear. Abduction and forward flexion of the shoulder were significantly increased in all patients. However, there was no obvious improvement in upper limb length. The postoperative humeral neck-shaft angle improved notably as well. We used a paired t test for statistical treatment. The P value was 0.001. No bony nonunion or delayed union was observed. The time required for union was 3 to 6 months. No obvious complications occurred. CONCLUSIONS: Valgus osteotomy of the proximal humerus using a plate-screw fixation method can correct the deformity and provide strong fixation in children. The postoperative improvement of shoulder motion and radiologic changes were satisfactory. However, we need to do second operation to remove the plate. Meanwhile, the patients would require a second operation to elongate the affected limb. PMID- 25494030 TI - Outcomes of Tibial Derotational Osteotomies Performed in Patients With Myelodysplasia. AB - BACKGROUND: Rotational deformities of the tibia are common in patients with myelodysplasia. The current recommended treatment is tibial derotational osteotomy to improve gait biomechanics. Previously reported complication rates are widely variable. The purpose of this study is to review the outcomes of derotational osteotomies as a function of complication and revision surgery rates as compared with previous studies. METHODS: A retrospective chart review was performed on all tibial derotational osteotomies performed in patients with myelodysplasia from 1985 to 2010 in patients older than 5 years with > 2 years of follow-up. Charts were reviewed for demographics, amount of derotation at index surgery, incidence of complications, and the need for repeat derotational surgery. Descriptive statistics were used to determine the incidence of complications as well as need for reoperation. Further analysis was performed using Fisher Exact Test and the Student t test to identify independent risk factors for complication and rerotation. RESULTS: Eighty-two patients (129 limbs) had sufficient data for inclusion. The average follow-up was 7.15 years. Surgery was indicated for symptomatic torsion measuring > 20 degrees. The average amount of derotation was 28 +/- 12 degrees. The incidence of complications was 10.85%, with a 3.10% incidence of major complications including fracture, deep infection, and hardware failure. The repeat derotation rate was 16.28%, all in patients initially treated for external tibial torsion. Age at initial surgery had no effect on complication rate or need for reoperation. Level of spinal involvement was not associated with complication risk; however, lumbar-level involvement was an independent risk factor for rerotation. CONCLUSIONS: With meticulous operative technique, derotational osteotomy of the tibia in patients with myelomeningocele remains a safe and effective method to treat tibial torsion, with an acceptable overall complication rate of 10.85% and a major complication rate of 3.10%. The data presented will aid providers in appropriate counseling of patients considering tibial derotational osteotomy. PMID- 25494031 TI - Complications Associated With High-dose Corticosteroid Administration in Children With Spinal Cord Injury. AB - BACKGROUND: Complications with high-dose steroid administration for spinal cord injury are documented in adult patients. Our purpose was to determine the incidence of early complications of this therapy in pediatric patients with spinal cord injuries. METHODS: An IRB-approved retrospective review was performed for patients treated for spinal cord injury at a level 1 pediatric trauma center between 2003 and 2011. Demographic data, injury characteristics, and surgical interventions were documented. Complications were divided into 4 categories: infectious, gastrointestinal (GI), hyperglycemia/endocrine, and wound healing problems. Complication rates were compared using a Student's t test and Fischer's exact test. RESULTS: Thirty-four spinal cord injury patients were identified. Twenty-three patients (mean age 6.6 y) in the treatment group received high-dose steroid treatment and 11 patients (mean age 8.4 y) did not and comprised the control group. No statistical difference was detected between the 2 groups regarding age, mechanism of injury, rate of surgical intervention, level of injury, and injury severity. Hyperglycemia was the most common complication and was present in all patients in both the treatment and control groups. The overall infection rate was 64% in the control group compared with 26% in the treatment (P<0.05). The control group demonstrated a significantly increased rate of respiratory tract infections [45% control vs. 9% treatment (P<0.05)]. No surgical patients developed a wound infection. One treatment group patient experienced a GI bleed. CONCLUSIONS: This is the largest study evaluating the complications associated with high-dose steroid administration for spinal trauma in a pediatric population. Hyperglycemia was found in all spinal cord injury patients, regardless of steroid treatment. Paradoxically, infection rates were noted to be higher in the control group. GI and wound problems were not significantly different. Larger, multicenter prospective studies are needed to better understand the risks in pediatric SCI patients. PMID- 25494032 TI - Effect of sodium phosphate supplementation on repeated high-intensity cycling efforts. AB - Limited research has investigated how sodium phosphate supplementation affects exercise performance typical of athletic competition and whether any effects linger in the short term. This study examined the effect of sodium phosphate supplementation on a cycling protocol consisting of repeated-sprint (4 sets of 6 * 15 s) and time-trial (2 * 5 min) efforts on day 1 and 4 post-loading. Trained male cyclists (VO(2peak) 5.3 L . min-1) were randomised to 6 days of sodium phosphate supplementation (50 mg . kg.fat-free-mass-1 . day-1; n = 7) or placebo (n = 10). Performance was assessed at baseline and 1 and 4 days post supplementation on an air-braked cycle ergometer. Compared with baseline, the sodium phosphate group recorded significantly improved (P < 0.05) work and mean power output values in both the sprint (baseline, 259 kJ/719 W; day 1, 271 kJ/754 W; day 4, 271 kJ/753 W) and time-trial (baseline, 225 kJ/374 W; day 1, 235 kJ/398 W; day 4, 236 kJ/393 W) aspects of the performance test post-loading. In the placebo group, no differences (P > 0.05) in total work or power output were noted in response to supplementation. In summary, sodium phosphate supplementation improved repeated-sprint and time-trial cycling efforts both 1 and 4 days post loading in trained cyclists. PMID- 25494033 TI - Local liquid phase deposition of silicon dioxide on hexagonally close-packed silica beads. AB - Liquid phase deposition (LPD) is a useful method for the production of oxide film with low reaction temperature and production cost. With the report that the LPD of oxide films is conformally processed with uniform thickness and composition, there has been significant attention given to investigating its kinetic controls and growth mechanism on the flat surface. In this work, we explored the LPD of silicon dioxide on the hexagonally close-packed silica beads array as a nanostructured surface. The deposition and etching reactions of SiO2 occurred locally and simultaneously on silica beads, and were distinguished from the amount of fumed silica added in LPD solution. From locally competitive reactions, we obtained the anisotropic morphology of close-packed silica beads, and proposed a mechanism for the local LPD of SiO2 driven by nanostructured surfaces. This work contributes highly to improve metal oxide-based engineering, and also provide greater insight into the topography-driven LPD. PMID- 25494034 TI - Discharge communication from inpatient care: an audit of written medical discharge summary procedure against the new National Health Service Standard for clinical handover. AB - OBJECTIVE: To audit written medical discharge summary procedure and practice against Standard Six (clinical handover) of the Australian National Safety and Quality Health Service Standards at a major regional Victorian health service. METHODS: Department heads were invited to complete a questionnaire about departmental discharge summary practices. RESULTS: Twenty-seven (82%) department heads completed the questionnaire. Seven (26%) departments had a documented discharge summary procedure. Fourteen (52%) departments monitored discharge summary completion and 13 (48%) departments monitored the timeliness of completion. Seven (26%) departments informed the patient of the content of the discharge summary and six (22%) departments provided the patient with a copy. Seven (26%) departments provided training for staff members on how to complete discharge summaries. Completing discharge summaries was usually delegated to the medical intern. CONCLUSIONS: The introduction of the National Service Standards prompted an organisation-wide audit of discharge summary practices against the external criterion. There was substantial variation in the organisation's practices. The Standards and the current audit results highlight an opportunity for the organisation to enhance and standardise discharge summary practices and improve communication with general practice. PMID- 25494035 TI - Toward Prospective Prediction of Pharmacokinetics in OATP1B1 Genetic Variant Populations. AB - Physiologically based pharmacokinetic (PBPK) models are increasingly being used to provide human pharmacokinetic (PK) predictions for organic anion-transporting polypeptide (OATP) substrates based on in vitro assay data. As a natural extension in the application of these models, in this study, we incorporated in vitro information of three major OATP1B1 genetic variants into a previously reported PBPK model to predict the impact of OATP1B1 polymorphisms on human PK. Using pravastatin and rosuvastatin as examples, we showed that the predicted plasma concentration-time profiles in groups carrying different OATP1B1 genetic variants reasonably matched the clinical observations from multiple studies. This modeling and simulation approach may aid decision making in early pharmaceutical research and development as well as patient-specific dose adjustment in clinical practice. PMID- 25494036 TI - Evidence of rapid coaggregation of globular proteins during amyloid formation. AB - The question of how an aggregating protein can influence aggregation of other proteins located in its vicinity is particularly significant because many proteins coexist in cells. We demonstrate in vitro coaggregation and cross seeding of lysozyme, bovine serum albumin, insulin, and cytochrome c during their amyloid formation. The coaggregation process seems to be more dependent on the temperature-induced intermediate species of these proteins and less dependent on their sequence identities. Because amyloid-linked inclusions and plaques are recognized as multicomponent entities originating from aggregation of the associated protein, these findings may add new insights into the mechanistic understanding of amyloid-related pathologies. PMID- 25494037 TI - Monofunctionalization and dimerization of nanoparticles using coordination chemistry. AB - This paper describes a strategy for controlled nanoparticle dimerization by using a solid support approach. Two types of nanoparticles have been linked by using a 5-([2,2':6',2"-terpyridine]-4'-yloxy)pentan-1-amine (terpy-amine) iron complex. The strategy includes two major steps: first, the monofunctionalization of individual nanoparticles with terpy-amine ligand molecules on a solid support, followed by release of monofunctionalized particles and subsequent dimerization. The versatility of the approach was demonstrated by dimerizing two different types of nanoparticles: spherical gold and cube-shaped iron oxide nanoparticles. PMID- 25494038 TI - Profiling of oxidized phospholipids in lipoproteins from patients with coronary artery disease by hollow fiber flow field-flow fractionation and nanoflow liquid chromatography-tandem mass spectrometry. AB - Oxidized phospholipids (Ox-PLs) are oxidatively modified PLs that are produced during the oxidation of lipoproteins; oxidation of low density lipoproteins especially is known to be associated with the development of coronary artery disease (CAD). In this study, different lipoprotein classes (high density, low density, and very low density lipoproteins) from pooled plasma of CAD patients and pooled plasma from healthy controls were size-sorted on a semipreparative scale by multiplexed hollow fiber flow field-flow fractionation (MxHF5), and Ox PLs that were extracted from each lipoprotein fraction were quantified by nanoflow liquid chromatography-tandem mass spectrometry (nLC-ESI-MS/MS). The present study showed that oxidation of lipoproteins occurred throughout all classes of lipoproteins with more Ox-PLs identified from CAD patient lipoproteins: molecular structures of 283 unique PL species (including 123 Ox PLs) from controls and 315 (including 169 Ox-PLs) from patients were identified by data-dependent collision-induced dissociation experiments. It was shown that oxidation of PLs occurred primarily with hydroxylation of PL; in particular, a saturated acyl chain such as 16:0, 18:0, or even 18:1 at the sn-1 location of the glycerol backbone along with sn-2 acyl chains with at least two double bonds were identified. The acyl chain combinations commonly found for hydroxylated Ox-PLs in the lipoproteins of CAD patients were 16:0/18:2, 16:0/20:4, 18:0/18:2, and 18:0/20:4. PMID- 25494039 TI - Functionalized silicon nanoparticles from reactive cavitation erosion of silicon wafers. AB - A new sonochemical process for the top-down production of silicon nanoparticles (<1 nm) with surface functional groups is described. The procedure involves a combination of acoustic cavitation erosion of a single-crystalline silicon surface coupled with simultaneous reaction with a reactive organic compound such as 1-hexyne. The sonochemical formation of the photoluminescent silicon nanoparticles by reactive cavitation erosion can be easily up-scaled. PMID- 25494040 TI - New compstatin peptides containing N-terminal extensions and non-natural amino acids exhibit potent complement inhibition and improved solubility characteristics. AB - Compstatin peptides are complement inhibitors that bind and inhibit cleavage of complement C3. Peptide binding is enhanced by hydrophobic interactions; however, poor solubility promotes aggregation in aqueous environments. We have designed new compstatin peptides derived from the W4A9 sequence (Ac-ICVWQDWGAHRCT-NH2, cyclized between C2 and C12), based on structural, computational, and experimental studies. Furthermore, we developed and utilized a computational framework for the design of peptides containing non-natural amino acids. These new compstatin peptides contain polar N-terminal extensions and non-natural amino acid substitutions at positions 4 and 9. Peptides with alpha-modified non-natural alanine analogs at position 9, as well as peptides containing only N-terminal polar extensions, exhibited similar activity compared to W4A9, as quantified via ELISA, hemolytic, and cell-based assays, and showed improved solubility, as measured by UV absorbance and reverse-phase HPLC experiments. Because of their potency and solubility, these peptides are promising candidates for therapeutic development in numerous complement-mediated diseases. PMID- 25494041 TI - Plastic Pollution in the World's Oceans: More than 5 Trillion Plastic Pieces Weighing over 250,000 Tons Afloat at Sea. AB - Plastic pollution is ubiquitous throughout the marine environment, yet estimates of the global abundance and weight of floating plastics have lacked data, particularly from the Southern Hemisphere and remote regions. Here we report an estimate of the total number of plastic particles and their weight floating in the world's oceans from 24 expeditions (2007-2013) across all five sub-tropical gyres, costal Australia, Bay of Bengal and the Mediterranean Sea conducting surface net tows (N = 680) and visual survey transects of large plastic debris (N = 891). Using an oceanographic model of floating debris dispersal calibrated by our data, and correcting for wind-driven vertical mixing, we estimate a minimum of 5.25 trillion particles weighing 268,940 tons. When comparing between four size classes, two microplastic <4.75 mm and meso- and macroplastic >4.75 mm, a tremendous loss of microplastics is observed from the sea surface compared to expected rates of fragmentation, suggesting there are mechanisms at play that remove <4.75 mm plastic particles from the ocean surface. PMID- 25494042 TI - Does Forest Continuity Enhance the Resilience of Trees to Environmental Change? AB - There is ample evidence that continuously existing forests and afforestations on previously agricultural land differ with regard to ecosystem functions and services such as carbon sequestration, nutrient cycling and biodiversity. However, no studies have so far been conducted on possible long-term (>100 years) impacts on tree growth caused by differences in the ecological continuity of forest stands. In the present study we analysed the variation in tree-ring width of sessile oak (Quercus petraea (Matt.) Liebl.) trees (mean age 115-136 years) due to different land-use histories (continuously existing forests, afforestations both on arable land and on heathland). We also analysed the relation of growth patterns to soil nutrient stores and to climatic parameters (temperature, precipitation). Tree rings formed between 1896 and 2005 were widest in trees afforested on arable land. This can be attributed to higher nitrogen and phosphorous availability and indicates that former fertilisation may continue to affect the nutritional status of forest soils for more than one century after those activities have ceased. Moreover, these trees responded more strongly to environmental changes - as shown by a higher mean sensitivity of the tree-ring widths - than trees of continuously existing forests. However, the impact of climatic parameters on the variability in tree-ring width was generally small, but trees on former arable land showed the highest susceptibility to annually changing climatic conditions. We assume that incompletely developed humus horizons as well as differences in the edaphon are responsible for the more sensitive response of oak trees of recent forests (former arable land and former heathland) to variation in environmental conditions. We conclude that forests characterised by a long ecological continuity may be better adapted to global change than recent forest ecosystems. PMID- 25494043 TI - Retroperitoneal mass. PMID- 25494044 TI - Novel Anti-Nicotine Vaccine Using a Trimeric Coiled-Coil Hapten Carrier. AB - Tobacco addiction represents one of the largest public health problems in the world and is the leading cause of cancer and heart disease, resulting in millions of deaths a year. Vaccines for smoking cessation have shown considerable promise in preclinical models, although functional antibody responses induced in humans are only modestly effective in preventing nicotine entry into the brain. The challenge in generating serum antibodies with a large nicotine binding capacity is made difficult by the fact that this drug is non-immunogenic and must be conjugated as a hapten to a protein carrier. To circumvent the limitations of traditional carriers like keyhole limpet hemocyanin (KLH), we have synthesized a short trimeric coiled-coil peptide (TCC) that creates a series of B and T cell epitopes with uniform stoichiometry and high density. Here we compared the relative activities of a TCC-nic vaccine and two control KLH-nic vaccines using Alum as an adjuvant or GLA-SE, which contains a synthetic TLR4 agonist formulated in a stable oil-in-water emulsion. The results showed that the TCC's high hapten density correlated with a better immune response in mice as measured by anti nicotine Ab titer, affinity, and specificity, and was responsible for a reduction in anti-carrier immunogenicity. The Ab responses achieved with this synthetic vaccine resulted in a nicotine binding capacity in serum that could prevent >90% of a nicotine dose equivalent to three smoked cigarettes (0.05 mg/kg) from reaching the brain. PMID- 25494045 TI - Determining the Depth of Injury in Bioengineered Tissue Models of Cornea and Conjunctiva for the Prediction of All Three Ocular GHS Categories. AB - The depth of injury (DOI) is a mechanistic correlate to the ocular irritation response. Attempts to quantitatively determine the DOI in alternative tests have been limited to ex vivo animal eyes by fluorescent staining for biomarkers of cell death and viability in histological cross sections. It was the purpose of this study to assess whether DOI could also be measured by means of cell viability detected by the MTT assay using 3-dimensional (3D) reconstructed models of cornea and conjunctiva. The formazan-free area of metabolically inactive cells in the tissue after topical substance application is used as the visible correlate of the DOI. Areas of metabolically active or inactive cells are quantitatively analyzed on cryosection images with ImageJ software analysis tools. By incorporating the total tissue thickness, the relative MTT-DOI (rMTT DOI) was calculated. Using the rMTT-DOI and human reconstructed cornea equivalents, we developed a prediction model based on suitable viability cut-off values. We tested 25 chemicals that cover the whole range of eye irritation potential based on the globally harmonized system of classification and labelling of chemicals (GHS). Principally, the MTT-DOI test method allows distinguishing between the cytotoxic effects of the different chemicals in accordance with all 3 GHS categories for eye irritation. Although the prediction model is slightly over predictive with respect to non-irritants, it promises to be highly valuable to discriminate between severe irritants (Cat. 1), and mild to moderate irritants (Cat. 2). We also tested 3D conjunctiva models with the aim to specifically address conjunctiva-damaging substances. Using the MTT-DOI method in this model delivers comparable results as the cornea model, but does not add additional information. However, the MTT-DOI method using reconstructed cornea models already provided good predictability that was superior to the already existing established in vitro/ex vivo methods. PMID- 25494046 TI - Quantitative Genetic Analyses of Male Color Pattern and Female Mate Choice in a Pair of Cichlid Fishes of Lake Malawi, East Africa. AB - The traits involved in sexual selection, such as male secondary sexual characteristics and female mate choice, often co-evolve which can promote population differentiation. However, the genetic architecture of these phenotypes can influence their evolvability and thereby affect the divergence of species. The extraordinary diversity of East African cichlid fishes is often attributed to strong sexual selection and thus this system provides an excellent model to test predictions regarding the genetic architecture of sexually selected traits that contribute to reproductive isolation. In particular, theory predicts that rapid speciation is facilitated when male sexual traits and female mating preferences are controlled by a limited number of linked genes. However, few studies have examined the genetic basis of male secondary sexual traits and female mating preferences in cichlids and none have investigated the genetic architecture of both jointly. In this study, we artificially hybridized a pair of behaviorally isolated cichlid fishes from Lake Malawi and quantified both melanistic color pattern and female mate choice. We investigated the genetic architecture of both phenotypes using quantitative genetic analyses. Our results suggest that 1) many non-additively acting genetic factors influence melanistic color patterns, 2) female mate choice may be controlled by a minimum of 1-2 non-additive genetic factors, and 3) F2 female mate choice is not influenced by male courting effort. Furthermore, a joint analysis of color pattern and female mate choice indicates that the genes underlying these two traits are unlikely to be physically linked. These results suggest that reproductive isolation may evolve rapidly owing to the few genetic factors underlying female mate choice. Hence, female mate choice likely played an important role in the unparalleled speciation of East African cichlid fish. PMID- 25494047 TI - Combining Methods to Describe Important Marine Habitats for Top Predators: Application to Identify Biological Hotspots in Tropical Waters. AB - In tropical waters resources are usually scarce and patchy, and predatory species generally show specific adaptations for foraging. Tropical seabirds often forage in association with sub-surface predators that create feeding opportunities by bringing prey close to the surface, and the birds often aggregate in large multispecific flocks. Here we hypothesize that frigatebirds, a tropical seabird adapted to foraging with low energetic costs, could be a good predictor of the distribution of their associated predatory species, including other seabirds (e.g. boobies, terns) and subsurface predators (e.g., dolphins, tunas). To test this hypothesis, we compared distribution patterns of marine predators in the Mozambique Channel based on a long-term dataset of both vessel- and aerial surveys, as well as tracking data of frigatebirds. By developing species distribution models (SDMs), we identified key marine areas for tropical predators in relation to contemporaneous oceanographic features to investigate multi species spatial overlap areas and identify predator hotspots in the Mozambique Channel. SDMs reasonably matched observed patterns and both static (e.g. bathymetry) and dynamic (e.g. Chlorophyll a concentration and sea surface temperature) factors were important explaining predator distribution patterns. We found that the distribution of frigatebirds included the distributions of the associated species. The central part of the channel appeared to be the best habitat for the four groups of species considered in this study (frigatebirds, brown terns, boobies and sub-surface predators). PMID- 25494048 TI - Accuracy and user performance evaluation of a blood glucose monitoring system. AB - BACKGROUND: The accuracy of the Contour((r)) Plus (Bayer HealthCare LLC, Diabetes Care, Whippany, NJ) blood glucose monitoring system (BGMS) was evaluated in two separate studies. MATERIALS AND METHODS: In the laboratory study, fingerstick samples from 100 subjects were tested in duplicate using three test strip lots and assessed per International Organization for Standardization (ISO) 15197:2003, Section 7 (>=95% of results within +/-15 mg/dL or +/-20% of the reference result for samples with glucose concentrations <75 and >=75 mg/dL, respectively) and ISO 15197:2013, Section 6.3 (>=95% of results within +/-15 mg/dL or +/-15% of the reference result for samples with glucose concentrations <100 and >=100 mg/dL, respectively) accuracy criteria. In the clinical trial, 220 subjects with diabetes, naive to the BGMS, tested capillary glucose from fingertip and palm blood samples and completed an ease-of-use questionnaire. BGMS and YSI glucose analyzer results were compared. RESULTS: In the laboratory study, 100% of results met ISO 15197:2003 and ISO 15197:2013 accuracy criteria. In the clinical trial, 100% and 99.1% of subject fingerstick results and 98.1% and 96.7% of subject palm results met ISO 15197:2003 and ISO 15197:2013 accuracy criteria, respectively. By Parkes Consensus Error Grid analysis, 100% of subject fingerstick results and 98.1% of subject palm results were within Zone A (remainder within Zone B). Questionnaire results showed most subjects found the BGMS easy to use. CONCLUSIONS: The Contour Plus BGMS meets ISO 15197:2003 and ISO 15197:2013 accuracy criteria in the laboratory and when used by untrained individuals. PMID- 25494049 TI - New structural anomaly induced by nanoconfinement. AB - We explore the structural properties of anomalous fluids confined in a nanopore using molecular dynamics simulations. The fluid is modeled by core-softened (CS) potentials that have a repulsive shoulder and an attractive well at a further distance. Changing the attractive well depth of the fluid-fluid interaction potential, we studied the behavior of the anomalies in the translational order parameter t and excess entropy s(2) for the particles near to the nanopore wall (contact layer) for systems with two or three layers of particles. When the attractive well of the CS potential is shallow, the systems present a three to two layers transition and, additionally to the usual structural anomaly, a new anomalous region in t and s(2). For attractive well deep enough, the systems change from three layers to a bulk-like profile and just one region of anomaly in t and s(2) is observed. Our results are discussed on the basis of the fluid-fluid and fluid-surface interactions. PMID- 25494050 TI - Deciphering the imperative: translating public health quality improvement into organizational performance management gains. AB - With the launching of the national public health accreditation program under the auspices of the Public Health Accreditation Board (PHAB), health department momentum around quality improvement adoption has accelerated. Domain 9 of the PHAB standards (one of 12 domains) focuses on evaluation and improvement of performance and is acting as a strong driver for quality improvement and performance management implementation within health departments. Widespread adoption of quality improvement activities in public health trails that in other US sectors. Several performance management models have received broad acceptance, including models among government and nonprofits. A model specifically for public health has been developed and is presented herein. All models in current use reinforce customer focus; streamlined, value-added processes; and strategic alignment. All are structured to steer quality improvement efforts toward organizational priorities, ensuring that quality improvement complements performance management. High-performing health departments harness the synergy of quality improvement and performance management, providing powerful tools to achieve public health strategic imperatives. PMID- 25494051 TI - Focused deterrence and the prevention of violent gun injuries: practice, theoretical principles, and scientific evidence. AB - Focused deterrence strategies are a relatively new addition to a growing portfolio of evidence-based violent gun injury prevention practices available to policy makers and practitioners. These strategies seek to change offender behavior by understanding the underlying violence-producing dynamics and conditions that sustain recurring violent gun injury problems and by implementing a blended strategy of law enforcement, community mobilization, and social service actions. Consistent with documented public health practice, the focused deterrence approach identifies underlying risk factors and causes of recurring violent gun injury problems, develops tailored responses to these underlying conditions, and measures the impact of implemented interventions. This article reviews the practice, theoretical principles, and evaluation evidence on focused deterrence strategies. Although more rigorous randomized studies are needed, the available empirical evidence suggests that these strategies generate noteworthy gun violence reduction impacts and should be part of a broader portfolio of violence prevention strategies available to policy makers and practitioners. PMID- 25494052 TI - Trade policy and public health. AB - Twenty-first-century trade policy is complex and affects society and population health in direct and indirect ways. Without doubt, trade policy influences the distribution of power, money, and resources between and within countries, which in turn affects the natural environment; people's daily living conditions; and the local availability, quality, affordability, and desirability of products (e.g., food, tobacco, alcohol, and health care); it also affects individuals' enjoyment of the highest attainable standard of health. In this article, we provide an overview of the modern global trade environment, illustrate the pathways between trade and health, and explore the emerging twenty-first-century trade policy landscape and its implications for health and health equity. We conclude with a call for more interdisciplinary research that embraces complexity theory and systems science as well as the political economy of health and that includes monitoring and evaluation of the impact of trade agreements on health. PMID- 25494053 TI - Immigration as a social determinant of health. AB - Although immigration and immigrant populations have become increasingly important foci in public health research and practice, a social determinants of health approach has seldom been applied in this area. Global patterns of morbidity and mortality follow inequities rooted in societal, political, and economic conditions produced and reproduced by social structures, policies, and institutions. The lack of dialogue between these two profoundly related phenomena social determinants of health and immigration-has resulted in missed opportunities for public health research, practice, and policy work. In this article, we discuss primary frameworks used in recent public health literature on the health of immigrant populations, note gaps in this literature, and argue for a broader examination of immigration as both socially determined and a social determinant of health. We discuss priorities for future research and policy to understand more fully and respond appropriately to the health of the populations affected by this global phenomenon. PMID- 25494054 TI - Effects of Sodium Bicarbonate on High-Intensity Endurance Performance in Cyclists: A Double-Blind, Randomized Cross-Over Trial. AB - BACKGROUND: While the ergogenic effect of sodium bicarbonate (BICA) on short term, sprint-type performance has been repeatedly demonstrated, little is known about its effectiveness during prolonged high-intensity exercise in well-trained athletes. Therefore, this study aims to examine the influence of BICA on performance during exhaustive, high-intensity endurance cycling. METHODS: This was a single-center, double-blind, randomized, placebo-controlled cross-over study. Twenty-one well-trained cyclists (mean +/- SD: age 24+/-8 y, BMI 21.3+/ 1.7, VO2peak 67.3+/-9.8 ml.kg-1.min-1) were randomly allocated to sequences of following interventions: oral ingestion of 0.3 g.kg-1 BICA or 4 g of sodium chloride (placebo), respectively. One h after ingestion subjects exercised for 30 min at 95% of the individual anaerobic threshold (IAT) followed by 110% IAT until exhaustion. Prior to these constant load tests stepwise incremental exercise tests were conducted under both conditions to determine IAT and VO2peak. Analysis of blood gas parameters, blood lactate (BLa) and gas exchange measurements were conducted before, during and after the tests. The main outcome measure was the time to exhaustion in the constant load test. RESULTS: Cycling time to exhaustion was improved (p<0.05) under BICA (49.5+/-11.5 min) compared with placebo (45.0+/ 9.5 min). No differences in maximal or sub-maximal measures of performance were observed during stepwise incremental tests. BICA ingestion resulted in an increased pH, bicarbonate concentration and BLa before, throughout and after both exercise testing modes. CONCLUSION: The results suggest that ingestion of BICA may improve prolonged, high-intensity cycling performance. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) DRKS00006198. PMID- 25494055 TI - A Tank Bromeliad Favors Spider Presence in a Neotropical Inundated Forest. AB - Tank bromeliads are good models for understanding how climate change may affect biotic associations. We studied the relationships between spiders, the epiphytic tank bromeliad, Aechmea bracteata, and its associated ants in an inundated forest in Quintana Roo, Mexico, during a drought period while, exceptionally, this forest was dry and then during the flooding that followed. We compared spider abundance and diversity between 'Aechmea-areas' and 'control-areas' of the same surface area. We recorded six spider families: the Dipluridae, Ctenidae, Salticidae, Araneidae, Tetragnathidae and Linyphiidae among which the funnel-web tarantula, Ischnothele caudata, the only Dipluridae noted, was the most abundant. During the drought period, the spiders were more numerous in the Aechmea-areas than in the control-areas, but they were not obligatorily associated with the Aechmea. During the subsequent flooding, the spiders were concentrated in the A. bracteata patches, particularly those sheltering an ant colony. Also, a kind of specificity existed between certain spider taxa and ant species, but varied between the drought period and subsequent flooding. We conclude that climatic events modulate the relationship between A. bracteata patches and their associated fauna. Tank bromeliads, previously considered only for their ecological importance in supplying food and water during drought, may also be considered refuges for spiders during flooding. More generally, tank bromeliads have an important role in preserving non-specialized fauna in inundated forests. PMID- 25494056 TI - Group 1 Allergen Genes in Two Species of House Dust Mites, Dermatophagoides farinae and D. pteronyssinus (Acari: Pyroglyphidae): Direct Sequencing, Characterization and Polymorphism. AB - Group 1 allergens of Dermatophagoides farinae (Der f 1) and D. pteronyssinus (Der p 1) dominate overall allergic responses in house dust mite allergy patients. The need for accurate identification and characterization of representative variants of group 1 allergens in any given geographic locality has been emphasized for development of appropriate allergen extracts. Regional amino acid sequence polymorphism has been described but the extent of this polymorphism is not well understood. Such data are completely absent for the USA and many other countries. Most previous studies used cDNA libraries generated by reverse transcriptase (RT PCR) and/or primers amplifying shorter fragments of this gene. Using novel species-specific primers and direct PCR, we document group 1 allergen gene sequence polymorphism in populations of D. farinae and D. pteronyssinus from the USA and Pakistan. We report two novel introns (nt pos 87 and 291) in both species, and the absence of intron 3 in Der p 1. Thirteen silent and one novel non-synonymous mutation (Tryptophan W197 to Arginine R197) were detected in D. farinae. The potential medical significance of the latter mutation is discussed. Two haplotypes of the Der f 1 gene were identified, haplotype 1 (63%) was more frequent than haplotype 2 (18%). Polymorphism in Der f 1 displayed geographical localization, since both haplotypes were present in mite populations from Pakistan whereas haplotype 1 was observed only in the USA. In Der p 1, a silent mutation at nt (aa) position 1011(149) and four non-synonymous mutations at positions 589(50), 935(124), 971(136), 1268(215) were observed. These mutations were reported from many other geographic regions, suggesting that polymorphism in the Der p 1 gene is panmictic. The extent of polymorphism in both genes is substantially lower than that reported previously (0.10-0.16% vs 0.31-0.49%), indicating the need for careful evaluation of potential polymerase errors in studies utilizing RT-PCR. PMID- 25494057 TI - Modeling Wood Encroachment in Abandoned Grasslands in the Eifel National Park - Model Description and Testing. AB - The degradation of natural and semi-natural landscapes has become a matter of global concern. In Germany, semi-natural grasslands belong to the most species rich habitat types but have suffered heavily from changes in land use. After abandonment, the course of succession at a specific site is often difficult to predict because many processes interact. In order to support decision making when managing semi-natural grasslands in the Eifel National Park, we built the WoodS Model (Woodland Succession Model). A multimodeling approach was used to integrate vegetation dynamics in both the herbaceous and shrub/tree layer. The cover of grasses and herbs was simulated in a compartment model, whereas bushes and trees were modelled in an individual-based manner. Both models worked and interacted in a spatially explicit, raster-based landscape. We present here the model description, parameterization and testing. We show highly detailed projections of the succession of a semi-natural grassland including the influence of initial vegetation composition, neighborhood interactions and ungulate browsing. We carefully weighted the single processes against each other and their relevance for landscape development under different scenarios, while explicitly considering specific site conditions. Model evaluation revealed that the model is able to emulate successional patterns as observed in the field as well as plausible results for different population densities of red deer. Important neighborhood interactions such as seed dispersal, the protection of seedlings from browsing ungulates by thorny bushes, and the inhibition of wood encroachment by the herbaceous layer, have been successfully reproduced. Therefore, not only a detailed model but also detailed initialization turned out to be important for spatially explicit projections of a given site. The advantage of the WoodS-Model is that it integrates these many mutually interacting processes of succession. PMID- 25494059 TI - Universal Postquench Prethermalization at a Quantum Critical Point. AB - We consider an open system near a quantum critical point that is suddenly moved towards the critical point. The bath-dominated diffusive nonequilibrium dynamics after the quench is shown to follow scaling behavior, governed by a critical exponent that emerges in addition to the known equilibrium critical exponents. We determine this exponent and show that it describes universal prethermalized coarsening dynamics of the order parameter in an intermediate time regime. Implications of this quantum critical prethermalization are: (i) a power law rise of order and correlations after an initial collapse of the equilibrium state and (ii) a crossover to thermalization that occurs arbitrarily late for sufficiently shallow quenches. PMID- 25494060 TI - High-Fidelity Preparation, Gates, Memory, and Readout of a Trapped-Ion Quantum Bit. AB - We implement all single-qubit operations with fidelities significantly above the minimum threshold required for fault-tolerant quantum computing, using a trapped ion qubit stored in hyperfine "atomic clock" states of ^{43}Ca^{+}. We measure a combined qubit state preparation and single-shot readout fidelity of 99.93%, a memory coherence time of T_{2}^{*}=50 sec, and an average single-qubit gate fidelity of 99.9999%. These results are achieved in a room-temperature microfabricated surface trap, without the use of magnetic field shielding or dynamic decoupling techniques to overcome technical noise. PMID- 25494058 TI - Development of Chiral Bis-hydrazone Ligands for the Enantioselective Cross Coupling Reactions of Aryldimethylsilanolates. AB - A palladium-catalyzed, enantioselective, aryl-aryl cross-coupling reaction using 1-naphthyldimethylsilanolates and chiral bis-hydrazone ligands has been developed. A family of glyoxal bis-hydrazone ligands containing various 2,5 diarylpyrrolidine groups was prepared to evaluate the influence of ligand structure on the rate and enantioselectivity of the cross-coupling. New synthetic routes to the 1-amino-2,5-diarylpyrrolidines were developed to enable the structure/reactivity-selectivity studies. Role reversal experiments of aryldimethylsilanolates and aryl bromides result in biaryl products with the same configuration and similar enantioselectivities implying that reductive elimination is the stereodetermining step. The origin of stereoselectivity is rationalized through computational modeling of diarylpalldium(II) complex which occurs through a conrotatory motion for the two aryl groups undergoing C-C bond formation. PMID- 25494061 TI - Qubit Architecture with High Coherence and Fast Tunable Coupling. AB - We introduce a superconducting qubit architecture that combines high-coherence qubits and tunable qubit-qubit coupling. With the ability to set the coupling to zero, we demonstrate that this architecture is protected from the frequency crowding problems that arise from fixed coupling. More importantly, the coupling can be tuned dynamically with nanosecond resolution, making this architecture a versatile platform with applications ranging from quantum logic gates to quantum simulation. We illustrate the advantages of dynamical coupling by implementing a novel adiabatic controlled-z gate, with a speed approaching that of single-qubit gates. Integrating coherence and scalable control, the introduced qubit architecture provides a promising path towards large-scale quantum computation and simulation. PMID- 25494062 TI - Momentum Distribution of a Dilute Unitary Bose Gas with Three-Body Losses. AB - Using a combination of Boltzmann's equation and virial expansion, we study the effect of three-body losses and interactions on the momentum distribution of a homogeneous unitary Bose gas in the dilute limit where quantum correlations are negligible. The comparison of our results to the recent measurement made at JILA on a unitary gas of ^{85}Rb allows us to determine an experimental fugacity z=0.5(1). PMID- 25494063 TI - First Order Transition for the Optimal Search Time of Levy Flights with Resetting. AB - We study analytically an intermittent search process in one dimension. There is an immobile target at the origin and a searcher undergoes a discrete time jump process starting at x_{0}>=0, where successive jumps are drawn independently from an arbitrary jump distribution f(eta). In addition, with a probability 0<=r<1, the position of the searcher is reset to its initial position x_{0}. The efficiency of the search strategy is characterized by the mean time to find the target, i.e., the mean first passage time (MFPT) to the origin. For arbitrary jump distribution f(eta), initial position x_{0} and resetting probability r, we compute analytically the MFPT. For the heavy-tailed Levy stable jump distribution characterized by the Levy index 0=10^{17} eV. PMID- 25494066 TI - Constraints on Primordial Non-Gaussianity from 800 000 Photometric Quasars. AB - We derive robust constraints on primordial non-Gaussianity (PNG) using the clustering of 800 000 photometric quasars from the Sloan Digital Sky Survey in the redshift range 0.51.8*10^{20} photons s^{-1} mm^{-2} mrad^{-2} 0.1% BW) gamma-ray beam from the scattering of an ultrarelativistic laser-wakefield accelerated electron beam in the field of a relativistically intense laser (dimensionless amplitude a_{0}~2). The spectrum of the generated gamma-ray beam is measured, with MeV resolution, seamlessly from 6 to 18 MeV, giving clear evidence of the onset of nonlinear relativistic Thomson scattering. To the best of our knowledge, this photon source has the highest peak brilliance in the multi-MeV regime ever reported in the literature. PMID- 25494076 TI - Role of Structure and Entropy in Determining Differences in Dynamics for Glass Formers with Different Interaction Potentials. AB - We present a study of two model liquids with different interaction potentials, exhibiting similar structure but significantly different dynamics at low temperatures. By evaluating the configurational entropy, we show that the differences in the dynamics of these systems can be understood in terms of their thermodynamic differences. Analyzing their structure, we demonstrate that differences in pair correlation functions between the two systems, through their contribution to the entropy, dominate the differences in their dynamics, and indeed overestimate the differences. Including the contribution of higher order structural correlations to the entropy leads to smaller estimates for the relaxation times, as well as smaller differences between the two studied systems. PMID- 25494077 TI - Surface segregation driven by molecular architecture asymmetry in polymer blends. AB - The contributions of chain ends and branch points to surface segregation of long branched chains in blends with linear chains have been studied using neutron reflectometry and surface-enhanced Raman spectroscopy for a series of novel, well defined polystyrenes. A linear response theory accounting for the number and type of branch points and chain ends is consistent with surface excesses and composition profile decay lengths, and allows the first determination of branch point potentials. Surface excess is determined primarily by chain ends with branch points playing a secondary role. PMID- 25494065 TI - Precision Measurement of the (e^{+}+e^{-}) Flux in Primary Cosmic Rays from 0.5 GeV to 1 TeV with the Alpha Magnetic Spectrometer on the International Space Station. AB - We present a measurement of the cosmic ray (e^{+}+e^{-}) flux in the range 0.5 GeV to 1 TeV based on the analysis of 10.6 million (e^{+}+e^{-}) events collected by AMS. The statistics and the resolution of AMS provide a precision measurement of the flux. The flux is smooth and reveals new and distinct information. Above 30.2 GeV, the flux can be described by a single power law with a spectral index gamma=-3.170+/-0.008(stat+syst)+/-0.008(energy scale). PMID- 25494078 TI - Origin of High-Resolution IETS-STM Images of Organic Molecules with Functionalized Tips. AB - Recently, the family of high-resolution scanning probe imaging techniques using decorated tips has been complemented by a method based on inelastic electron tunneling spectroscopy (IETS). The new technique resolves the inner structure of organic molecules by mapping the vibrational energy of a single carbon monoxide (CO) molecule positioned at the apex of a scanning tunneling microscope (STM) tip. Here, we explain high-resolution IETS imaging by extending a model developed earlier for STM and atomic force microscopy (AFM) imaging with decorated tips. In particular, we show that the tip decorated with CO acts as a nanoscale sensor that changes the energy of its frustrated translation mode in response to changes of the local curvature of the surface potential. In addition, we show that high resolution AFM, STM, and IETS-STM images can deliver information about the charge distribution within molecules deposited on a surface. To demonstrate this, we extend our mechanical model by taking into account electrostatic forces acting on the decorated tip in the surface Hartree potential. PMID- 25494079 TI - Ultrafast Control and Rabi Oscillations of Polaritons. AB - We report the experimental observation and control of space and time-resolved light-matter Rabi oscillations in a microcavity. Our setup precision and the system coherence are so high that coherent control can be implemented with amplification or switching off of the oscillations and even erasing of the polariton density by optical pulses. The data are reproduced by a quantum optical model with excellent accuracy, providing new insights on the key components that rule the polariton dynamics. PMID- 25494080 TI - High Stability of Faceted Nanotubes and Fullerenes of Multiphase Layered Phosphorus: A Computational Study. AB - We present a paradigm in constructing very stable, faceted nanotube and fullerene structures by laterally joining nanoribbons or patches of different planar phosphorene phases. Our ab initio density functional calculations indicate that these phases may form very stable, nonplanar joints. Unlike fullerenes and nanotubes obtained by deforming a single-phase planar monolayer at substantial energy penalty, we find faceted fullerenes and nanotubes to be nearly as stable as the planar single-phase monolayers. The resulting rich variety of polymorphs allows us to tune the electronic properties of phosphorene nanotubes and fullerenes not only by the chiral index but also by the combination of different phosphorene phases. In selected phosphorene nanotubes, a metal-insulator transition may be induced by strain or by changing the number of walls. PMID- 25494081 TI - Persistent Detwinning of Iron-Pnictide EuFe_{2}As_{2} Crystals by Small External Magnetic Fields. AB - Our comprehensive study on EuFe_{2}As_{2} reveals a dramatic reduction of magnetic detwinning fields compared to other AFe_{2}As_{2} (A=Ba, Sr, Ca) iron pnictides by indirect magnetoelastic coupling of the Eu^{2+} ions. We find that only ~0.1 T are sufficient for persistent detwinning below the local Eu^{2+} ordering; above T_{Eu}=19 K, higher fields are necessary. Even after the field is switched off, a significant imbalance of twin domains remains constant up to the structural and electronic phase transition (190 K). This persistent detwinning provides the unique possibility to study the low temperature electronic in-plane anisotropy of iron pnictides without applying any symmetry breaking external force. PMID- 25494082 TI - Long-Range Spin-Triplet Helix in Proximity Induced Superconductivity in Spin Orbit-Coupled Systems. AB - We study proximity induced triplet superconductivity in a spin-orbit-coupled system, and show that the d vector of the induced triplet superconductivity undergoes precession that can be controlled by varying the relative strengths of Rashba and Dresselhaus spin-orbit couplings. In particular, a long-range spin triplet helix is predicted when these two spin-orbit couplings have equal strengths. We also study the Josephson junction geometry and show that a transition between 0 and pi junctions can be induced by controlling the spin orbit coupling with a gate voltage. An experimental setup is proposed to verify these effects. Conversely, the observation of these effects can serve as a direct confirmation of triplet superconductivity. PMID- 25494083 TI - Evidence of Surface Loss as Ubiquitous Limiting Damping Mechanism in SiN Micro- and Nanomechanical Resonators. AB - Silicon nitride (SiN) micro- and nanomechanical resonators have attracted a lot of attention in various research fields due to their exceptionally high quality factors (Qs). Despite their popularity, the origin of the limiting loss mechanisms in these structures has remained controversial. In this Letter we propose an analytical model combining acoustic radiation loss with intrinsic loss. The model accurately predicts the resulting mode-dependent Qs of low-stress silicon-rich and high-stress stoichiometric SiN membranes. The large acoustic mismatch of the low-stress membrane to the substrate seems to minimize radiation loss and Qs of higher modes (n?m>=3) are limited by intrinsic losses. The study of these intrinsic losses in low-stress membranes reveals a linear dependence with the membrane thickness. This finding was confirmed by comparing the intrinsic dissipation of arbitrary (membranes, strings, and cantilevers) SiN resonators extracted from literature, suggesting surface loss as ubiquitous damping mechanism in thin SiN resonators with Q_{surf}=betah and beta=6*10^{10}+/ 4*10^{10} m^{-1}. Based on the intrinsic loss the maximal achievable Qs and Qf products for SiN membranes and strings are outlined. PMID- 25494084 TI - Coherent Precession of an Individual 5/2 Spin. AB - We present direct observation of a coherent spin precession of an individual Mn^{2+} ion, having both electronic and nuclear spins equal to 5/2, embedded in a CdTe quantum dot and placed in a magnetic field. The spin state evolution is probed in a time-resolved pump-probe measurement of absorption of the single dot. The experiment reveals subtle details of the large-spin coherent dynamics, such as nonsinusoidal evolution of states occupation, and beatings caused by the strain-induced differences in energy levels separation. Sensitivity of the large spin impurity on the crystal strain opens the possibility of using it as a local strain probe. PMID- 25494085 TI - Barlowite: A Spin-1/2 Antiferromagnet with a Geometrically Perfect Kagome Motif. AB - We present thermodynamic studies of a new spin-1/2 antiferromagnet containing undistorted kagome lattices-barlowite Cu_{4}(OH)_{6}FBr. Magnetic susceptibility gives theta_{CW}=-136 K, while long-range order does not happen until T_{N}=15 K with a weak ferromagnetic moment MU<0.1MU_{B}/Cu. A 60 T magnetic field induces a moment less than 0.5MU_{B}/Cu at T=0.6 K. Specific-heat measurements have observed multiple phase transitions at T??theta_{CW}?. The magnetic entropy of these transitions is merely 18% of k_{B}ln2 per Cu spin. These observations suggest that nontrivial spin textures are realized in barlowite with magnetic frustration. Comparing with the leading spin-liquid candidate herbertsmithite, the superior interkagome environment of barlowite sheds light on new spin-liquid compounds with minimum disorder. The robust perfect geometry of the kagome lattice makes charge doping promising. PMID- 25494086 TI - Novel Phase Transitions in the Breathing Pyrochlore Lattice: ^{7}Li-NMR on LiInCr_{4}O_{8} and LiGaCr_{4}O_{8} AB - We report ^{7}Li-NMR studies on LiInCr_{4}O_{8} and LiGaCr_{4}O_{8}, in which Cr^{3+} ions with spin 3/2 form a breathing pyrochlore lattice, a network of tetrahedra with alternating sizes. In LiInCr_{4}O_{8} with large alternation, the nuclear relaxation rate 1/T_{1} shows an activated temperature (T) dependence down to 18 K, indicating a singlet ground state with a spin gap. This behavior, however, is disrupted by an antiferromagnetic transition at 13 K, which is preceded by another, most likely structural, transition at 16 K. In contrast, LiGaCr_{4}O_{8} with a small alternation shows no spin gap but exhibits a first order antiferromagnetic transition over a distributed T range 13-20 K. Nevertheless, 1/T_{1} of the paramagnetic phase diverges toward 13 K, indicating proximity to a second-order transition. The results indicate that LiGaCr_{4}O_{8} is located in the vicinity of a tricritical point in the phase diagram. PMID- 25494087 TI - Strongly Anisotropic Ballistic Magnetoresistance in Compact Three-Dimensional Semiconducting Nanoarchitectures. AB - We establish theoretically that in nonmagnetic semiconducting bilayer or multilayer thin film systems rolled up into compact quasi-one-dimensional nanoarchitectures, the ballistic magnetoresistance is very anisotropic: conductances depend strongly on the direction of an externally applied magnetic field. This phenomenon originates from the curved open geometry of rolled-up nanotubes, which leads to a tunability of the number of quasi-one-dimensional magnetic subbands crossing the Fermi energy. The experimental significance of this phenomenon is illustrated by a sizable anisotropy that scales with the inverse of the winding number, and persists up to a critical temperature that can be strongly enhanced by increasing the strength of the external magnetic field or the characteristic radius of curvature, and can reach room temperature. PMID- 25494088 TI - Tunable Charge and Spin Order in PrNiO_{3} Thin Films and Superlattices. AB - We use polarized Raman scattering to probe lattice vibrations and charge ordering in 12 nm thick, epitaxially strained PrNiO_{3} films, and in superlattices of PrNiO_{3} with the band insulator PrAlO_{3}. A carefully adjusted confocal geometry is used to eliminate the substrate contribution to the Raman spectra. In films and superlattices under tensile strain which undergo a metal-insulator transition upon cooling, the Raman spectra reveal phonon modes characteristic of charge ordering. These anomalous phonons do not appear in compressively strained films, which remain metallic at all temperatures. For superlattices under compressive strain, the Raman spectra show no evidence of anomalous phonons indicative of charge ordering, while complementary resonant x-ray scattering experiments reveal antiferromagnetic order associated with a modest increase in resistivity upon cooling. This confirms theoretical predictions of a spin density wave phase driven by spatial confinement of the conduction electrons. PMID- 25494089 TI - Extremely Nonperturbative Nonlinearities in GaAs Driven by Atomically Strong Terahertz Fields in Gold Metamaterials. AB - Terahertz near fields of gold metamaterials resonant at a frequency of 0.88 THz allow us to enter an extreme limit of nonperturbative ultrafast terahertz electronics: Fields reaching a ponderomotive energy in the keV range are exploited to drive nondestructive, quasistatic interband tunneling and impact ionization in undoped bulk GaAs, injecting electron-hole plasmas with densities in excess of 10^{19} cm^{-3}. This process causes bright luminescence at energies up to 0.5 eV above the band gap and induces a complete switch-off of the metamaterial resonance accompanied by self-amplitude-modulation of transmitted few-cycle terahertz transients. Our results pave the way towards highly nonlinear terahertz optics and optoelectronic nanocircuitry with subpicosecond switching times. PMID- 25494090 TI - Sequential Activation of Molecular Breathing and Bending during Spin-Crossover Photoswitching Revealed by Femtosecond Optical and X-Ray Absorption Spectroscopy. AB - We study the basic mechanisms allowing light to photoswitch at the molecular scale a spin-crossover material from a low- to a high-spin state. Combined femtosecond x-ray absorption performed at LCLS X-FEL and optical spectroscopy reveal that the structural stabilization of the photoinduced high-spin state results from a two step structural trapping. Molecular breathing vibrations are first activated and rapidly damped as part of the energy is sequentially transferred to molecular bending vibrations. During the photoswitching, the system follows a curved trajectory on the potential energy surface. PMID- 25494091 TI - Non-Gilbert-damping Mechanism in a Ferromagnetic Heusler Compound Probed by Nonlinear Spin Dynamics. AB - The nonlinear decay of propagating spin waves in the low-Gilbert-damping Heusler film Co_{2}Mn_{0.6}Fe_{0.4}Si is reported. Here, two initial magnons with frequency f_{0} scatter into two secondary magnons with frequencies f_{1} and f_{2}. The most remarkable observation is that f_{1} stays fixed if f_{0} is changed. This indicates, that the f_{1} magnon mode has the lowest instability threshold, which, however, cannot be understood if only Gilbert damping is present. We show that the observed behavior is caused by interaction of the magnon modes f_{1} and f_{2} with the thermal magnon bath. This evidences a significant contribution of the intrinsic magnon-magnon scattering mechanisms to the magnetic damping in high-quality Heusler compounds. PMID- 25494092 TI - Structure of Cholesterol in Lipid Rafts. AB - Rafts, or functional domains, are transient nano-or mesoscopic structures in the plasma membrane and are thought to be essential for many cellular processes such as signal transduction, adhesion, trafficking, and lipid or protein sorting. Observations of these membrane heterogeneities have proven challenging, as they are thought to be both small and short lived. With a combination of coarse grained molecular dynamics simulations and neutron diffraction using deuterium labeled cholesterol molecules, we observe raftlike structures and determine the ordering of the cholesterol molecules in binary cholesterol-containing lipid membranes. From coarse-grained computer simulations, heterogenous membranes structures were observed and characterized as small, ordered domains. Neutron diffraction was used to study the lateral structure of the cholesterol molecules. We find pairs of strongly bound cholesterol molecules in the liquid-disordered phase, in accordance with the umbrella model. Bragg peaks corresponding to ordering of the cholesterol molecules in the raftlike structures were observed and indexed by two different structures: a monoclinic structure of ordered cholesterol pairs of alternating direction in equilibrium with cholesterol plaques, i.e., triclinic cholesterol bilayers. PMID- 25494093 TI - Comment on "Fitting the Annual Modulation in DAMA with Neutrons from Muons and Neutrinos" AB - A Comment on the Letter by J. H. Davis, Phys. Rev. Lett. 113, 081302 (2014)PRLTAO0031-900710.1103/PhysRevLett.113.081302. PMID- 25494094 TI - Correction: Running the Gauntlet: Regional Movement Patterns of Manta alfredi through a Complex of Parks and Fisheries. AB - [This corrects the article DOI: 10.1371/journal.pone.0110071.]. PMID- 25494095 TI - A Description of Biremis panamae sp. nov., a New Diatom Species from the Marine Littoral, with an Account of the Phylogenetic Position of Biremis D.G. Mann et E.J. Cox (Bacillariophyceae). AB - Here we present a formal description of Biremis panamae Barka, Witkowski et Weisenborn sp. nov., which was isolated from the marine littoral environment of the Pacific Ocean coast of Panama. The description is based on morphology (light and electron microscopy) and the rbcL, psbC and SSU sequences of one clone of this species. The new species is included in Biremis due to its morphological features; i.e. two marginal rows of foramina, chambered striae, and girdle composed of numerous punctate copulae. The new species also possesses a striated valve face which is not seen in most known representatives of marine littoral Biremis species. In this study we also present the relationship of Biremis to other taxa using morphology, DNA sequence data and observations of auxosporulation. Our results based on these three sources point to an evolutionary relationship between Biremis, Neidium and Scoliopleura. The unusual silicified incunabular caps present in them are known otherwise only in Muelleria, which is probably related to the Neidiaceae and Scoliotropidaceae. We also discuss the relationship between Biremis and the recently described Labellicula and Olifantiella. PMID- 25494096 TI - Photochromism-induced amplification of critical current density in superconducting boron-doped diamond with an azobenzene molecular layer. AB - A key issue in molecular electronics is the control of electronic states by optical stimuli, which enables fast and high-density data storage and temporal spatial control over molecular processes. In this article, we report preparation of a photoswitchable superconductor using a heavily boron-doped diamond (BDD) with a photochromic azobenzene (AZ) molecular layer. BDDs electrode properties allow for electrochemical immobilization, followed by copper(I)-catalyzed alkyne azide cycloaddition (a "click" reaction). Superconducting properties were examined with magnetic and electrical transport measurements, such as field dependent isothermal magnetization, temperature-dependent resistance, and the low temperature voltage-current response. These measurements revealed reversible amplification of the critical current density by 55% upon photoisomerization. This effect is explained as the reversible photoisomerization of AZ inducing an inhomogeneous electron distribution along the BDD surface that renormalizes the surface pinning contribution to the critical current. PMID- 25494097 TI - Clustering of Physical Inactivity in Leisure, Work, Commuting, and Household Domains: Data From 47,477 Industrial Workers in Brazil. AB - BACKGROUND: Physical inactivity in each domain (leisure, work, commuting, and household) is not completely independent. This study aimed to describe the clustering of physical inactivity in different domains and its association with sociodemographic factors among Brazilian industrial workers. METHODS: This was a cross-sectional, population-based study using data from 23 Brazilian states and the Federal District collected via questionnaires between 2006 and 2008. Physical inactivity in each domain was defined as nonparticipation in specific physical activities. Clustering of physical inactivity was identified using the ratio of the observed (O) and expected (E) percentages of each combination. Multinomial logistic regression was used to identify sociodemographic factors with the outcome. RESULTS: Among the 44,477 interviewees, most combinations exceeded expectations, particularly the clustering of physical inactivity in all domains among men (O/E = 1.37; 95% CI: 1.30; 1.44) and women (O/E = 1.47; 95% CI: 1.36; 1.60). Physical inactivity in 2 or more domains was observed more frequently in women, older age groups, individuals living without a partner, and those with higher education and income levels. CONCLUSIONS: Physical inactivity tends to be observed in clusters regardless of gender. Women and workers with higher income levels were the main factors associated with to be physically inactive in 2 or more domains. PMID- 25494098 TI - Analysis of computational models for an accurate study of electronic excitations in GFP. AB - Using the chromophore of the green fluorescent protein (GFP), the performance of a hybrid RI-CC2/polarizable embedding (PE) model is tested against a quantum chemical cluster approach. Moreover, the effect of the rest of the protein environment is studied by systematically increasing the size of the cluster and analyzing the convergence of the excitation energies. It is found that the influence of the environment of the chromophore can accurately be described using a polarizable embedding model with only a minor error compared to a full quantum chemical description. It is also shown that the treatment of only a small region around the chromophore is only by coincidence a good approximation. Therefore, such cluster approaches should be used with care. Based on our results, we suggest that polarizable embedding models, including a large part of the environment to describe its effect on biochromophores on top of an accurate way of describing the central subsystem, are both accurate and computationally favourable in many cases. PMID- 25494099 TI - Do Size and Insecticide Treatment Matter? Evaluation of Different Nets against Phlebotomus argentipes, the Vector of Visceral Leishmaniasis in Nepal. AB - In the Indian subcontinent, Leishmania donovani, the parasite causing visceral leishmaniasis (VL) is transmitted by the sand fly vector Phlebotomus argentipes. Long lasting insecticide treated nets (LN) have been postulated as alternative or complement to Indoor Residual Spraying but there are few field studies evaluating the entomological efficacy of different nets against this vector. We conducted two crossover trials in a VL endemic area in Nepal to compare the barrier effect of (1) LN with different mesh sizes (156 holes/inch2 vs 625 holes/inch2) and (2) alpha-cypermethrin treated LN and untreated nets having the same mesh size (156 holes/inch2). Each crossover trial had two arms consisting of a sequence of two different nets for 8 nights. We used 10 cattle sheds per trial. A cow placed under the net was used as bait. CDC light traps placed inside the nets were used to evaluate the number of P. argentipes crossing the net barrier. Negative binomial generalized estimating equation (GEE) population-averaged models adjusted by night and sequence were used to estimate the barrier effect of the different nets. The crossover trials conducted in a rural village in Morang district (South-eastern Nepal) demonstrated that reducing the size of the holes in treated nets (625 holes/inch2) increased the barrier effect of LN by 77% (95% confidence interval (CI): 56%-88%) compared with treated nets with larger holes (156 holes/inch2). Treating nets with alpha-cypermethrin reduced the number of P. argentipes captured inside the nets by 77% (95% CI: 27%-93%) compared with untreated nets. The effectiveness and acceptability of finer mesh pyrethroid treated LN should be tested for VL prevention in a randomized controlled trial. PMID- 25494100 TI - A Mec17-Myosin II Effector Axis Coordinates Microtubule Acetylation and Actin Dynamics to Control Primary Cilium Biogenesis. AB - Primary cilia are specialized, acetylated microtubule-based signaling processes. Cilium assembly is activated by cellular quiescence and requires reconfiguration of microtubules, the actin cytoskeleton, and vesicular trafficking machinery. How these components are coordinated to activate ciliogenesis remains unknown. Here we identify the microtubule acetyltransferase Mec-17 and myosin II motors as the key effectors in primary cilium biogenesis. We found that myosin IIB (Myh10) is required for cilium formation; however, myosin IIA (Myh9) suppresses it. Myh10 binds and antagonizes Myh9 to increase actin dynamics, which facilitates the assembly of the pericentrosomal preciliary complex (PPC) that supplies materials for cilium growth. Importantly, Myh10 expression is upregulated by serum starvation and this induction requires Mec-17, which is itself accumulated upon cellular quiescence. Pharmacological stimulation of microtubule acetylation also induces Myh10 expression and cilium formation. Thus cellular quiescence induces Mec17 to couple the production of acetylated microtubules and Myh10, whose accumulation overcomes the inhibitory role of Myh9 and initiates ciliogenesis. PMID- 25494101 TI - Correlation of ECR1 A3650G polymorphism with neonatal respiratory distress syndrome. AB - OBJECTIVE: This study aims to determine the correlation of erythrocyte complement receptor 1 (ECR1) A3650G (His1208Arg, rs2274567) polymorphism with the pathogenesis and development of neonatal respiratory distress syndrome (NRDS). MATERIALS AND METHODS: This case-control study was conducted at the Huaihe Hospital of Henan University. Sixty-six infants who met the diagnostic criteria of NRDS were placed into the case group. There were 60 healthy infants without respiratory symptoms in the control group. Genetic analyses were conducted using peripheral blood-extracted genomic DNA. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied to detect SNP. RESULTS: No apparent differences in gender, weight, and gestational age were observed between NRDS and healthy infants (all p>0.05). However, the NRDS group had more premature infants than the control group (59.1% vs. 38.3%, p=0.019). In the NRDS group, the premature infants had shorter gestational ages than the full-term infants, while the duration of mechanical ventilation and oxygen inhalation for premature infants was longer than those of full-term infants (all p<0.05). Genotype frequencies were in Hardy-Weinberg equilibrium in both the NRDS and control groups (both p>0.05). The results showed that the A carrier (AG/GG) and the A allele of the ECR1 A3650G polymorphism were associated with risk for NRDS (both p<0.05). Furthermore, premature infants with NRDS had higher frequencies of the A carrier (AG/GG) of ECR1 A3650G polymorphism than full-term infants (p=0.002). CONCLUSION: Our findings provide evidence that the A carrier (AG/GG) and the A allele of the ECR1 A3650G polymorphism may be correlated to the pathogenesis of NRDS and, hence, might be involved in the susceptibility to NRDS. PMID- 25494102 TI - Relationship between organisational safety culture dimensions and crashes. AB - Knowing about organisational safety culture in public transportation system can provide an appropriate guide to establish effective safety measures and interventions to improve safety at work. The aim of this study was investigation of association between safety culture dimensions (leadership styles and company values, usage of crashes information and prevention programmes, management commitment and safety policy, participation and control) with involved self reported crashes. The associations were considered through Spearman correlation, Pearson chi-square test and logistic regression. The results showed an association among self-reported crashes (occurrence or non-occurrence) and factors including leadership styles and company values; management commitment and safety policy; and control. Moreover, it was found a negative correlation and an odds ratio less than one between control and self-reported crashes. PMID- 25494103 TI - Crystal structure and bonding in BaAu5Ga2 and AeAu4+xGa3-x (Ae = Ba and Eu): hexagonal diamond-type Au frameworks and remarkable cation/anion partitioning in the Ae-Au-Ga systems. AB - Five new polar intermetallic compounds in the Ae-Ga-Au system (Ae = Ba, Eu), BaAu(5)Ga(2) (I), BaAu(4.3)Ga(2.7) (II), Ba(1.0)Au(4.5)Ga(2.4 )(III), EuAu(4.8)Ga(2.2) (IV), and Eu(1.1)Au(4.4)Ga(2.2) (V), have been synthesized and their crystal structures determined by single-crystal X-ray diffraction. I crystallizes in the orthorhombic crystal system with a large unit cell [Pearson symbol oP64; Pnma, Z = 8, a = 8.8350(5) A, b = 7.1888(3)A, c = 20.3880(7) A], whereas all other compounds are hexagonal [hP24; P62m, Z = 3, a = 8.54-8.77(1) A, c = 7.19-7.24(1) A]. Both structures contain mutually orthogonal layers of Au(6) hexagons in chair and boat conformations, resulting in a hexagonal diamond-like network. Ae atoms and additional (Au/Ga)(3) groups are formally encapsulated by (Au(6))(2) distorted hexagonal prisms formed of three edge-sharing hexagons in the boat conformation or, alternatively, lie between two Au(6) hexagons in the chair conformation. The (Au/Ga)(3) groups can be substituted by Ae atoms in some of the hexagonal structures with no change to the structural symmetry. Tight binding electronic structure calculations using linear-muffin-tin-orbital methods on idealized models "BaAu(5)Ga(2)" and "BaAu(4)Ga(3)" show both compounds to be metallic with evident pseudogaps near the corresponding Fermi levels. The integrated crystal orbital Hamilton populations are dominated by Au-Au and Au-Ga orbital interactions, although Ba-Au and Ba-Ga contributions are significant. Furthermore, Au-Au interactions vary considerably along different directions in the unit cells, with the largest values for the hexagons in the boat conformation and the lowest values for those in the chair conformation. II revealed that partial substitution of Au atoms in the hexagonal diamond net by a post transition element (Ga) may occur in this family, whereas the sizes of the (Au/Ga)(3) groups and strong Ba-Au covalent interactions allow for their mutual replacement in the voids. PMID- 25494104 TI - Evaluation of ultrasound application in diagnosis and clinical staging of thyroid cancers. AB - Objectives: The usage of Ultrasonography (US) in the diagnosis and management of patients with thyroid nodules and thyroid cancer is increasing. This method is also advocated for the pre-operative and post-operative diagnosis of cervical lymph node (LN) metastases. This article is trying to figure out the correlation between ultrasound features and pathological classification of thyroid carcinoma (TC). Materials and Methods: A total of 407 cases of patients with TC were selected from records between 2000 and 2006, which were used to analyze and compare the ultrasound features in different pathologic classification of TC. We grouped the US typing of TC according to the ultrasound features. Then, we implemented pre-surgery evaluation of TC by ultrasound assessment. Results: We classified these patients into six groups by ultrasound: (1) classical, (2) non typical, (3) microminiaturize, (4) diffuse sclerosing, (5) medullary, and (6) undifferentiated. Ultrasonographic types of papillary TC: (1) classical, (2) microminiaturize, (3) diffuse, (4) cystic, (5) peripheral, (6) multi-nodules, (7) invasive, and (8) complicated Hashimoto. Grouping of the ultrasonic type of cervical LN metastasis: (1) cystic, (2) micro calcification, (3) macro-lymph, (4) microminiaturize, and (5) invasive. The ultrasound assessment of clinical staging had a higher sensitivity rate and specificity, and the accuracy rate of T stage was 93.9%. Conclusion: Ultrasound is a useful tool in the evaluation, characterization, quantification, and location of TC and cervical LN metastasis. PMID- 25494105 TI - A review of Indian literature for association of smokeless tobacco with malignant and premalignant diseases of head and neck region. AB - In India, about 60% of tobacco users use smokeless tobacco (ST) alone. Head and neck squamous cell carcinoma is one of the most common cancers in India. International Agency for Research on Cancer (IARC) monograph (Vol 89) found a significant association between ST use and oral cancer. However, only a few articles from India were included in this monograph. To overcome this lacuna, we have reviewed the articles published from India investigating the association between ST use and malignant and premalignant diseases of head and neck region. Data collection has been performed by computer-aided search of the MedLine and PubMed databases using different combinations of the key words. For malignant lesions, only cohort and case control studies were considered for review. For premalignant lesions and dental diseases other than case control studies, some cross-sectional studies have also been reviewed. Studies found a significant association between ST use and cancer of the oral cavity. The association was stronger for the buccal mucosa compared to tongue and for females compared to males. Significant association noted between cancer of the hypopharynx and oropharynx with ST use but no definitive association noted for cancer of the larynx and nasopharynx. Some dental disease and oral premalignant conditions were also associated with ST use. Indian studies suggest ST use is strongly associated with cancer of the oral cavity, oropharynx and hypopharynx. PMID- 25494106 TI - Tissue electrical properties in head and neck tumors before and after surgery: Preliminary observations. AB - : Context: Bioelectrical impedance analysis (BIA) detects changes in tissue electrical properties and has been seen as a prognostic tool in several chronic conditions, including cancer. AIMS: The study was conducted to investigate whether there are any tissue electrical differences in patients with head and neck cancer (H and NC) before and after surgery treatment. Settings and Design: The observational study was performed at the Otolaryngology Department, Head and Neck Oncology. Materials and Methods : Tissue electrical properties were assessed in 31 patients with H and NC before and 2 weeks after surgery treatment. Direct bioimpedance measures [resistance, reactance, phase angle (PA)] were determined by BIA. Statistical Analysis Used: The Shapiro-Wilk test was used to assess the distribution conformity of examined parameters with a normal distribution; the Fisher (F) test was used to assess variance homogeneity. For group comparisons of metric data we used the Mann-Whitney U test. P value < 0.05 was considered as statistically significant. The statistical analysis for this study was performed using the computer software STATISTICA v. 8.0 (StatSoft). Results: PA at 50 kHz was found to be significantly (P = 0.000009) lower after surgery in patients with H and NC than before treatment (4.69 degrees +/-0.71 vs. 4.22 +/- 0.83, respectively). Resistance was significantly (P = 0.0005) greater after surgery in patients with H and NC than before (596.24 +/- 96.31 ohm vs 647.64 +/- 276.11 ohm, respectively). Conclusions: There are tissue electrical differences before and after surgery in patients diagnosed with H and NC. Further observations would be useful to feedback in support therapy planning of individual patients. PMID- 25494107 TI - Serum and salivary sialic acid as a biomarker in oral potentially malignant disorders and oral cancer. AB - Background: Aberrant glycosylation is the universal feature of cancer and components of various glycoconjugates, such as sialic acid is found to rise in various malignancies. The objective of this study was to evaluate the serum and salivary sialic acid in oral potentially malignant disorders (OPMD) and oral cancer (OC) to investigate the possibility of using this as a diagnostic marker. Materials and Methods: The study included 85 subjects, who were grouped as control (30), OPMD patients (25), and oral cancer patients (30). Serum and unstimulated whole saliva was collected from subjects of all groups and sialic acid estimation was done using spectrophotometry. The results were tabulated and analyzed statistically. Results: The mean serum sialic acid levels in normal, OPMD, and oral cancer group were 7.515, 19.620, and 55.235 mg/dL, respectively, whereas the levels of salivary sialic acid were 1.5113, 2.3302, and 9.0304 mg/dL, respectively. A very highly significant rise (P < 0.005) in serum and salivary sialic acid was observed in the study subjects compared with that of the control. Conclusions: The present study showed a significant and gradual increase in serum and salivary sialic acid from control to oral potentially malignant disorders to oral cancer. From this study we can suggest that sialic acid can be used as a reliable biomarker. As this monosaccharide is observed in saliva in detectable quantity, saliva can be used as a diagnostic medium for screening and early detection of oral cancer. PMID- 25494108 TI - ABO blood groups and oral premalignancies: A clinical study in selected Indian population. AB - Background: The ABO blood group antigens are present on the surface of red blood cells and various epithelial cells. As the majority of human cancers are derived from epithelial cells, changes in blood group antigens constitute an important aspect of human cancers. The aim of the study was to establish clinical usefulness of ABO blood group as a predisposing factor in early diagnosis and management of patients with oral precancerous lesions/conditions. Materials and Methods: The study sample consisted of 50 control and 50 oral precancer (25 leukoplakia and 25 Oral Submucous Fibrosis) confirmed by histopathologic examination. All samples were subjected to blood group testing and their prevalence was compared by Z-test using STATA version 8. Results: The "A" blood group was prevalent among the precancerous group. Significant differences on prevalences of blood groups were found (P < 0.05) between control versus leukoplakia and OSMF. Interestingly, 24% gutka chewers who had higher number of grades of dysplasia were falling in "A" blood group. Conclusion: Blood group type should be considered along with other risk factors to understand the individual patient's risk and further studies in larger samples with inclusion of Rh factor is needed to elucidate the relationship with ABO blood group types. PMID- 25494109 TI - Oral submucous fibrosis in India: Are we progressing?? AB - Oral submucous fibrosis (OSMF) a condition first described in the 1950s in the modern literature still remains elusive of a cure. For many years this condition had been confined to countries like India, Pakistan, Bangladesh, etc., but now this condition is being reported from Western countries as well. Inspite of intensive research over the years into the etiologic factors of OSMF, a single etiologic factor cannot be pointed out with certainty rather several causative factors have been proposed. Patients suffering with OSMF initially present with a blanched or marble-like pale mucosa, vesiculations, and also intolerance to hot and spicy food. Gradually, the patient may develop fibrous bands in the buccal and labial mucosa which causes a restriction in opening the mouth. The evidence for the various treatment modalities for OSMF is weak hence better documentation of the studies performed with standardized criteria is required. The current review aims to refresh our knowledge regarding OSMF from an Indian perspective and make a few suggestions to fill the lacunae in this field. PMID- 25494110 TI - Serum levels of interleukin-7 and interleukin-8 in head and neck squamous cell carcinoma. AB - Background: The aim of this study was to investigate the association of head and neck squamous cell carcinoma (HNSCC) with serum levels of interleukin-7 (IL-7) and IL-8, the two cytokines whose associations with HNSCC need more clarifications. Materials and Methods: Commercial enzyme-linked immunosorbent assay kits were used for the quantification of the cytokines. Sera were collected from 48 untreated patients (36 men and 12 women; mean age: 52.7 +/- 9.8 years) and 34 healthy donors (26 men and 8 women; mean age: 53.1 +/- 9.0 years). Results: Serum IL-8 level was neither significantly different between HNSCC patients and control individuals nor associated with smoking status, gender, age, tumor location, tumor grade, and stage of the patients (P > 0.05). Regarding IL 7, all control individuals had serum levels below the sensitivity of the kit (3 pg/ml), but nine patients had detectable levels, and that the mean serum IL-7 was significantly higher in the patients compared to the controls (P = 0.008). Conclusions: Serum IL-8 level is not significantly associated with HNSCC. With the sensitivity of the kit we employed, it seems that serum IL-7 levels are specifically elevated in HNSCC patients compared to healthy individuals. Data from other independent studies are required to clarify the possible employment of IL-7 as an HNSCC biomarker. PMID- 25494111 TI - Factors predicting 'time to distant metastasis' in radically treated head and neck cancer. AB - Context: Various studies have shown the important risk factors for distant metastasis in head and neck cancer (HNC) which are present in most of the patients in developing countries. Identification of factors on the basis of time to distant metastasis (TDM) can help in future trials targeting smaller subgroups. Aims and Objectives: To identify the factors that predict TDM in radically treated HNC patients. Settings and Design: Retrospective audit. Materials and Methods: Retrospective audit of the prospectively maintained electronic database of a single HNC radiotherapy clinic from 1990 to 2010 was done to identify radically treated patients of HNC who developed distant metastasis. Univariate and multivariate analysis were done to identify baseline (demographic, clinical, pathological, and treatment) factors which could predict TDM, early time to metastasis (ETM; <12 months), intermediate time to metastasis (ITM; 12-24 months), and late time to metastasis (LTM; >2 years) using Kaplan Meier and Cox regression analysis, respectively. Results: One hundred patients with distant metastasis were identified with a median TDM of 7.4 months; 66 had ETM, 17 had ITM, and 17 had LTM. On multivariate analysis, the nodal stage 2-3 (N2/3) was the only baseline factor independently predicting TDM, ETM, and ITM, whereas none of the baseline factors predicted LTM. Conclusions: Higher nodal burden (N2/3) is associated with both ETM and ITM, and calls for aggressive screening, systemic therapy options, and surveillance. It is difficult to predict patients who are at a risk of developing LTM with baseline factors alone and evaluation of biological data is needed. PMID- 25494112 TI - Evaluation of focal thyroid lesions incidentally detected in fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography images. AB - Background and Purpose: Increased uptake in the thyroid gland (TG) is often identified as an incidental finding on the whole body fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in non-thyroid cancer patients. Currently, there is no consensus on the appropriate approach for the management of these cases. Thyroid ultrasound, scintigraphy and fine-needle aspiration biopsy (FNAB) are suggested to exclude malignant thyroid lesions. Our aim is to determine the importance of increased F 18-FDG uptake in the TG on positron emission tomography/computed tomography (PET/CT) scans in patients who are being screened for various forms of non thyroid cancer. Materials and Methods: We evaluated 2000 cases undergoing whole body PET/CT scanning between April 2011 and October 2012. The age, sex, type of primary cancer, maximum standardized uptake value (SUV max ), size of the thyroid nodules and cervical lymph nodes (CLNs) on 18 F-FDG PET/CT images and if available, the biopsy results were evaluated. Results: In total, 57 patients (23 men, 34 women, mean age +/- standard deviation (SD), 60.89 +/- 14 years) showed an increased fluorine-18-fluorodeoxyglucose ( 18 F-FDG) uptake by the TG (average SUV max : 4.07 +/- 3.7). The CLNs were detected in 19/57 patients (33%). Only 20 cases (35%) received FNAB. The final histopathological diagnosis was papillary thyroid carcinoma in seven patients (mean SUV max +/- SD: 6.0 +/- 5.43) and benign thyroid disease in seven patients (mean SUV max +/- SD: 2.36 +/- 0.63). The FNAB results were undetermined for six patients. Conclusion: Focal high 18 F FDG uptake in the TG may be associated with an increased risk of malignancy, but the clinical significance is unclear. More data are needed to elucidate the role of the SUV in the differentiation of benign and malign thyroid lesions. If a focal increase in 18 F-FDG uptake in the TG on PET/CT is present, a prompt histopathological evaluation should be suggested to clinicians for definitive diagnosis. PMID- 25494113 TI - Modern chemoradiation practices for malignant tumors of the trachea: An institutional experience. AB - Background: Malignant tumors of the trachea are rare. A multimodality treatment approach is often necessary. Outcomes of radical non-surgical approaches are sparse. Radiation combined with sequential or concurrent chemotherapy is an important treatment option. Materials and Methods: We present an analysis of outcomes using modern radiotherapy and chemotherapy for tracheal tumors. Results: Radiation dose escalation using modern techniques is of benefit for these tumors. The results with chemotherapy are encouraging. Conclusions: Radiation plays a distinct role and should be a part of treatment for these tumors. The role of chemotherapy needs to be studied further. PMID- 25494114 TI - Solar elastosis in conjunctival squamous cell neoplasm. AB - Aim: To study the role of solar elastosis in the patient's with Conjunctival Squamous Cell Neoplasia (CSCN). Materials and Methods: Paraffin embedded 30 Conjunctival Squamous Cell Neoplasia tissues were studied for the presence of solar elastosis by Verhoeff's stain. Nineteen Squamous Cell Carcinoma (SCC), 6 Carcinoma In Situ (CIS) and 5 Conjunctival Intraepithelial Neoplasia (CIN) specimens were included in the study. Disease free conjunctiva and pterygium tissues were used as negative and positive control respectively. Results: Solar elastosis was found to be present in 19 of 30 (63.3%) Conjunctival Squamous Cell neoplasia specimens. Conclusion: Our study showed the presence of solar elastosis in conjunctival squamous cell neoplasia. Poor socioeconomic condition is an important factor as most of the elastosis positive patients were farmers. PMID- 25494115 TI - CD44: A key player in breast cancer. AB - CD44 is a principal transmembrane hyluronate receptor, which acts as a hook between Extracellular Matrix and the cytoskeleton. CD44 is up regulated in breast cancer, which in turn helps in tumor progression and metastasis. There has been a lot of attention given to CD44 in recent years because of the discovery, CD44+/CD24- lineage marks breast cancer stem cells. Recent clinical and experimental findings show that CD44 is involved in the tumor associated proliferation, invasion, migration, and in many pathways involved in maintaining cancer cells which inturn are correlated with patient's survival. All these findings make CD44 as a potential target for breast cancer treatment. The methods of literature search for this article include Pubmed, BMC cancer and other printed journal article. PMID- 25494116 TI - Reproductive risk factors associated with breast carcinoma in a tertiary care hospital of north India: A case-control study. AB - Context: Worldwide, breast cancer is the most common cancer among women. In India and other developing countries, breast carcinoma ranks second only to cervical carcinoma among women. But the incidence of breast cancer is on the rise and may become number one cancer in females in near future. Aims: (1) To find out the magnitude of reproductive risk factors of carcinoma breast among the study subjects; and (2) to find out the association of reproductive risk factors with breast carcinoma. Materials and Methods: The study was done in the wards of General Surgery and Oncosurgery from August 2009-July 2010 in a tertiary care institute. A total of 128 histopathologically confirmed cases of breast cancer those came in this duration were considered. Equal controls were selected by simple random sampling by lottery method. The controls were matched for age with a range of +/- 2 years. The subjects were interviewed using a pre-tested questionnaire. Written informed consent was taken from study subjects before starting the interview. Statistical Analysis Used: Chi-square test, odds ratio with 95% confidence interval, and t test. Results: The age group of the cases was 25-78 years, whereas that of the controls was 24-79 years. The difference among cases and controls regarding age at marriage, age at menarche, age at menopause, age at first pregnancy, and number of children was statistically significant. Continuous variables of the study population were analyzed by independent t tests, in which age at menarche and age at first pregnancy were found statistically significant. Conclusions: Information, education, and communication activities regarding risk factors and breast self-examination should be imparted to the women to create awareness about this fatal disease. PMID- 25494117 TI - Primary synchronous bilateral breast cancer. AB - Background: Primary synchronous bilateral breast cancer (PSBBC) is a rare clinical entity. The reported incidence ranges between 0.3% and 12%. There are several controversial issues regarding PSBBC pertaining to the diagnostic criteria, nomenclature, and management policies. Materials and Methods: Fourteen cases of PSBBC treated between 2001 to 2010 at our institute were retrospectively analysed in regards to demographic data, management and follow up. Results: PSBBC constituted 0.19% of total breast cancer patients at our institute. Age ranged from 28 to 78 years. PSBBC were detected by clinical examination in eight cases and by mammography in six cases. Twelve patients underwent bilateral modified radical mastectomy, one had unilateral mastectomy on one side and breast conservation on the other side and one patient has bilateral breast conservation. Majority of patients belonged to stage 2 and stage 3. All patients were found to have invasive ductal carcinoma. Five cases were ER/PR positive and 8 patients were triple hormone receptor negative. Eight patients received unilateral and six received bilateral adjuvant radiotherapy. Nine patients received adjuvant chemotherapy. 5 patients received adjuvant hormonal therapy. Median follow up of patients was 15.4 months. Conclusion: PSBBC is a rare event warranting awareness and screening of the contralateral breast in patients with unilateral breast cancer. These patients require individualized treatment planning based on the tumor factors of the index lesion. Further multi institutional prospective studies are needed for adequate understanding of management of PSBBC. PMID- 25494118 TI - Pattern of childhood malignant tumors at a teaching hospital in Kano, Northern Nigeria: A prospective study. AB - Background: Childhood cancers represent an important global public health problem. Survival is still dismal in most low income countries. Materials and Methods: A prospective study of childhood cancers diagnosed at AKTH, Kano was undertaken from January 2003 to December 2009 to determine the pattern, socio economic and geographical features. Results: Malignant lymphomas constituted 46.5% of all cases, of which 30.1% were Burkitt's lymphoma, 9.8% were Non-Hodgkin (non Burkitt's) lymphoma and 6.6% were Hodgkin lymphoma. Retinoblastoma was the second most common malignancy constituting 15.2% of all cases, followed by Nephroblastoma 12.5% and acute leukemia's accounted for 14.1% of all cases. Others were Neuroblastoma 5.5%, Rhabdomyosarcoma 1.9% and CNS and Hepatissc tumors 4.3%. About 80% of parents of these children are very poor and could not afford the cost of treatment. Fifty one percent of the patients were alive at 12 months and the mortality was 24%. Conclusion: Childhood cancer is common in Kano. Free treatment is what is required since majority of the parents could not afford the cost of treatment. PMID- 25494119 TI - Information and rehabilitation needs of Indian breast cancer patients: Report of a cross-sectional study. AB - Background: Breast cancer causes significant disruption to the quality of life (QOL) of its patients, which is compounded further by lack of information and adequate facilities for rehabilitation. Materials and Methods: This descriptive cross-sectional study was conducted in women who had completed their Primary treatment of breast cancer. The QOL was assessed by Functional assessment of cancer therapy-breast (FACT-B) version 4, and information and rehabilitation needs were enquired about in a semi-structured interview. Results: A total of 154 patients were enrolled and divided into three groups according to the time elapsed after initial treatment; Group I: 1-2 years, Group II: 2-5 years, Group III: >5 years The FACT-B mean scores were; Group I (n = 64): 79.06 +/- 14.60; Group II (n = 48): 85.75 +/- 20.15; and Group III (n = 42): 89.83 +/- 12.80. Patients in Group I scored lowest on physical well-being subscale, Group II on breast specific subscale and Group III on Social well-being subscale. Pain, lack of energy, inability to meet the needs of the family, fear that the condition will get worse and loss of body image were significant factors contributing to poor QOL. Analysis of interviewshowed many unmet information needs. Main rehabilitation needs were effective treatment of physical symptoms and counselling about body image issues and sexual dysfunctions. Easy availability of clinical and social support services were major felt needs in the long-term follow-up. Conclusions: Targeted Interventions are needed to address issues relating to QOL and rehabilitation needs of breast cancer patients. PMID- 25494120 TI - Immunohistochemical detection of axillary lymph node micrometastases in breast cancer patients: Increasing the accuracy of detection and decreasing labor intensive serial sectioning. AB - Background: The histological detection of axillary lymph node tumor metastases in cases of breast carcinoma is of major prognostic significance, but may be difficult when metastases are of microscopic size. The micrometastases can be detected either by immunohistochemistry (IHC) or serial sectioning. Aims: We investigated whether immunohistochemical techniques and serial sectioning can increase the accuracy of metastatic detection and compared the efficacy of both. Materials and Methods: Thirty cases of breast carcinoma were studied in all of whom the axillary lymph nodes had been reported as free of metastases. Blocks from these cases were serially sectioned and stained with hematoxylin and eosin and a single section was stained with monoclonal antibody to cytokeratin AE1/AE3 and epithelial membrane antigen. The positivity for micrometastases was correlated with size, number, grade and histological type of primary tumor, lymph node size and number. Results and Conclusion: In 5/30 previously unsuspected cases, micrometastases were revealed by IHC and in 1/30 by serial sectioning. These findings suggested that serial sectioning is a labor intensive, time consuming and impractical procedure. Micrometastases were more frequently detected with age of patient >50 years, Grade 2/3 tumor, tumor size >5 cm and more than one primary tumor. Immunohistochemical analysis can be recommended as a routine procedure or an adjunct to routine histological procedures for the correct staging of breast carcinoma and use of adjuvant chemotherapy, especially in the high risk group. PMID- 25494121 TI - Efficacy and safety of bevacizumab in the treatment of human epidermal growth factor receptor type 2 negative metastatic breast cancer: About a large series in moroccan population. AB - Context: Randomized studies have shown different magnitude of bevacizumab (BV) benefit in the treatment of advanced breast cancer. Aims: The aim of the study is to evaluate the efficacy and safety of BV for the treatment of human epidermal growth factor receptor type 2 (HER2) negative metastatic disease. Settings and Design: A large observational institutional study in Moroccan population. Materials and Methods: From January 2009 to December 2011, 42 patients with HER2 negative metastatic breast cancer were analyzed. Results: The median age was 51 years. Approximately two-third of patients analyzed were treated at the first line with BV in association with (paclitaxel, docetaxel or capecitabine) in (40.7%; 40.7% and 18.5%) and the other third at second-line therapy with a combination of the same drugs in (46.6%, 26.6% and 266% respectively); the median number of cycles was 15. In terms of the clinical benefit rate there was a trend in favor of the combination with taxanes and among responders, median duration of objective response was longer with paclitaxel. In addition, analyses of progression-free survival (PFS) across subgroups in both first and second line therapy showed consistent improvements in PFS with the combination of BV and paclitaxel the difference was statistically significant. Concerning safety, the BV was generally well-tolerated. Conclusions: BV in HER2 negative metastatic diseases potentially improved objective response rate and PFS especially in combination with Paclitaxel, which confirm and expand on the results from published literature, with tolerable toxicity. PMID- 25494122 TI - Rural urban differences in breast cancer in India. AB - Context: Breast cancer incidence rates are high in developed countries and much lower in less developed countries including India. Aims: The aim of the following study is to compare breast cancer incidence rates in rural, urban and metro regions of India and to estimate risk of developing breast cancer associated with residence in a rural area. Settings and Design: Descriptive and analytical study design. Materials and Methods: We extracted age adjusted incidence rate from 26 population-based cancer registries and data from hospital-based case-control study to estimate rate and risk ratio for developing breast cancer in an urban region compared with a rural residence. Statistical Analysis: The rate ratios and 95% confidence interval (CI) for developing breast cancer in the urban and metro region compared with rural registry of Barshi were estimated. The odds ratio (OR) and 95% CI for developing breast cancer in women residing in a rural region was estimated by fitting unconditional logistic regression using hospital-based case control study data. Average annual percentage change in most recent 15 years (1996-2010) for Barshi (rural), Aurangabad (urban), and Mumbai (metro) cancer registry was obtained by fitting a log-linear model using joint point regression. Results: Living first 20 years of life in a rural area reduces the risk of breast cancer (OR = 0.65, 95% CI: 0.56-0.76). Conclusions: The current study demonstrates that lifestyle operative in a rural area is protective against risk of developing breast cancer. PMID- 25494123 TI - Cancer stem cell: A rogue responsible for tumor development and metastasis. AB - Cancer stem cells are a small population of cells in a tumor. They have the ability to self-renew and maintain the tumor. The most apt and accepted hypothesis for tumor development is Cancer Stem Cells. This review focuses on this concept of cancer stem cells, serving their purpose and leading to the development of tumor. There are many cell biomarkers which have been described for the identification and characterization of cancer stem cells. The most prominent of the cellular markers for the detection of cancer stem cells; CD133, CD44, ALDH-1 along with some others have been discussed in detail in this review. PMID- 25494124 TI - Primary gastrointestinal lymphomas - A study of 81 Cases from a Tertiary Healthcare Centre. AB - Purpose: Retrospective analysis of 81 routinely diagnosed gastrointestinal (GI) lymphoma to illustrate clinicopathological and immunohistochemical characteristics with predisposing condition. Materials and Methods: Age, sex, site, tumour stage, associated pathological features like lympho-epithelial lesion (LEL), atrophic gastritis (AG), intestinal metaplasia (IM) and enteropathy changes were analysed. Requisite immunohistochemical panel was applied wherever needed. Results: There were 55 male and 26 female patients with median age of 54.5 years. Site wise distributions were stomach 40, small intestine 22, colon 4, cecum 2, ileocecum 3, esophagus 1 and multiple sites 9. Histological subtypes were mucosa associated lymphoid tissue lymphoma (MALTOMA) 48, diffuse large B cell lymphoma (DLBL) 21, T cell lymphoma 9 [5 anaplastic large cell lymphoma (ALCL) and 4 enteropathy associated T cell lymphoma (EATL)], immunoproliferative small intestinal disease (IPSID) 2 and follicular lymphoma 1. LEL was present in 31 cases. Of the 19 AG, 8 had associated IM, and 1 case each had associated H Pylori infection and neuroendocrine tumor. Enteropathy was observed in 4 EATL, and one case each of DLBL and high grade MALTOMA. Giardia infection was present in 1 low grade duodenal MALTOMA. Of the 24 resected specimens, 16 were stage IE, 7 stage IIE and 1 stage IV (Mushoff's staging). Conclusion: Primary GI lymphoma was frequently observed in 6 th decade of life with male preponderance. Stomach was the commonest site and high grade MALTOMA being the commonest histological variant. Isolated colonic involvement and intestinal perforations were not infrequent. Rare variants like ALCL and follicular lymphomas were also observed. PMID- 25494125 TI - Cutaneous T-cell lymphomas and their management strategies. AB - Cutaneous T-cell lymphomas (CTCLs) comprise a heterogeneous group of lymphoproliferative disorders characterized by the proliferation of skin-homing post-thymic T-cells. It is the second most common extranodal non-Hodgekin's lymphoma. Many variants of mycosis fungoides and CTCLs are known to date, differing in clinical, histological, and immunophenotypic characteristics. Oral involvement has also been reported rarely in CTCLs. Treatment depends on the disease stage or the type of variant. New insights into the disease and the number of emerging novel therapeutic options have made it an interesting area for dermatologists and medical oncologists. PMID- 25494126 TI - Pulmonary embolism and hematologic outcome in cancer patients initiating chemotherapy. AB - Purpose: The aim of this study was to determine the relationship between chemotherapy use and the frequency of pulmonary embolism (PE) and associated mortality, clinical, and biochemical parameters. An additional aim was to analyze computed tomography pulmonary angiography findings. Materials and Methods: The study population comprised 65 of 368 consecutive patients diagnosed with PE who underwent chemotherapy in the Medical Oncology Department. The study population had cancer of various origins, including breast, colorectal, lung, gynecological, gastric and pancreatic, lymphatic, and other sites. The patients' clinical records were reviewed for leukocyte and platelet count, mean platelet volume (MPV), neutrophil to lymphocyte ratio, and level of mortality. As the parameters were normally distributed, the correlation coefficients and their significance were calculated using Pearson's test. One-way analysis of variance was used to compare the leukocyte counts among the cancer groups. A t-test was used to compare the means of the platelet and leukocyte counts between the patients. A Chi-square test was used to compare binary outcomes for categorical variables. Patients who died in the 1 st year and others (survivors and patients who died after the 1 st year) were compared using multinomial logistic regression analysis. Results: When the patients who died in the 1 st year and the survivors were compared, there was a statistically significant difference in the platelet count between the two groups. The platelet count, MPV, and leukocyte count of the patients with PE were significantly high. The leukocyte count was also significantly high in patients with breast, colorectal, lung, and gynecological cancers. Conclusion: Our results indicate that in cancer patients with PE who undergo chemotherapy, the platelet count, MPV, and leukocyte count are significantly high. PMID- 25494127 TI - Primary Intestinal Lymphoma: A Clinicopathological Study. AB - Introduction: Primary intestinal lymphoma (PIL) is defined as an extranodal lymphoma arising in the intestine. This study includes 11 PILs. Objectives: The objective of this study was to evaluate the clinicopathological characteristics of primary non-Hodgkin's lymphoma (NHL) in the small and large intestine. All cases were reclassified according to the World Health Organization classification of lymphoma in 2001. Immunohistochemistry (IHC) was used to confirm the histopathological diagnosis. Materials and Methods: Eleven cases of primary non Hodgkin in the small and large intestine were studied retrospectively in a 5 year period. There were seven cases of resected intestinal specimens and four biopsy specimens. Five cases from ileum and two cases each from caecum and duodenum and one case each from jejunum and duodenum. Hematoxylin and eosin stained sections were studied with light microscopy and IHC for CD5, 20, 21 and cyclin D1 were done. Results: It is a retrospective study of 11 cases of intestinal lymphomas. Abdominal pain and abdominal lump were two main common presenting symptoms. NHLs were more common in the small intestine. PILs are common in adults (75% above 46 years) with male preponderance. All were NHLs and B-cell type. Five cases were diffuse large B-cell lymphoma and four cases each were mucosa-associated lymphatic tissue lymphoma and follicular lymphoma. One case was lymphomatoid polyposis or mantle cell lymphoma. Conclusion: PILs is rare and differs significantly from their gastric counterpart, not only in pathology but also with regard to clinical features, management and prognosis. Due to the lack of characteristic symptoms and a low incidence rate, PIL is misdiagnosed until serious complications occur, such as perforation and bleeding and hence needs to be accurately diagnosed. PMID- 25494128 TI - Treatment outcome and prognostic factors in intermediate risk stage I endometrial carcinoma. AB - Introducton: The aim of this study was to evaluate the clinical characteristics, post-surgery adjuvant treatment approach and posttreatment disease course in patients with intermediate risk stage I endometrium cancer and also to assess the effects of known prognostic factors on this group of patients. Patients and Methods: A total of 148 patients followed up postoperatively or after adjuvant treatment between 1996 and 2007 were evaluated retrospectively. Median follow-up duration was 67 months (range: 7-166). Among the study population 14.9% had Ib and 83.1% had stage Ic disease. 72 were treated by external beam radiotherapy (EBRT), 7 by intracavitary radiotherapy (ICRT), 65 by external + intracavitary radiotherapy (EBRT + ICRT), and one by chemoradiotherapy (CRT). Results: Vaginal vault is found to be the most common site of recurrences. Five and 10-year local control (LC) rates were 96.6% and 95.9%, respectively, while 5 and 10-year distant control (DC) rates were 94.6% and 91.9%, respectively. One, 5 and 10-year overall survival rates (OS) were 99.3%, 87.6% and 71.2%, respectively, while 1, 5 and 10-year progression-free survival rates (PFS) were 97.3%, 87.6% and 71.2%, respectively. Univariate analysis has revealed that prognostic factors as age (P = 0.0001), menopausal status (P = 0.049) and EBRT duration (P = 0.003) statistically significantly affected OS; while age (P = 0.0001) and EBRT duration (P = 0.006) affected PFS. Multivariate analysis has revealed that only age (P = 0.001) (P = 0.0001) and ERT duration (P = 0.021) (P = 0.027) affected both OS and PFS. Conclusion: LC and OS rates are high in the intermediate risk group. Age over 60 years and EBRT duration of 35 days and over both have negative effects on outcome in this group. PMID- 25494129 TI - Elevated chromogranin A serum levels in ovarian carcinoma patients. AB - Background: The observation of neuroendocrine activity during clinical course of ovarian cancer, suggested the use of neuroendocrine serum markers to detect this tumor. Aim: To evaluate the usefulness of serum measurements of chromogranin A (CgA) in the various stages of ovarian cancer. Materials and Methods: We measured serum concentrations of CgA and cancer antigen 125 (CA125) in 79 women at different clinical stages of ovarian cancer, enrolled between 2000 and 2007, and in a control group of 50 female volunteers. Results: CgA showed increased levels in patients with ovarian cancer as compared with healthy subjects, as it has been seen for CA125 serum levels. We also observed significant increase in CgA and CA125 serum levels when comparing patients with ovarian cancer in stage I versus stage II (P < 0.001); stage I versus stage III (P < 0.001); stage I versus stage IV (P < 0.001); stage II versus stage III (P < 0.001); stage II versus stage IV (P < 0.001). In patients with ovarian carcinoma in stage IV we observed a correlation between CgA and CA125 with a difference of 0.718 (P < 0.001). Conclusions: CgA serum levels were elevated in ovarian cancer and increased with the stage. Further studies are needed to elucidate the role of CgA as a prognostic indicator during treatment for ovarian cancer. PMID- 25494130 TI - Knowledge, attitude and practice of cervical cancer screening in women visiting a tertiary care hospital of Delhi. AB - Background: Cervical cancer being a major cause of morbidity and mortality in women in developing countries, its awareness is essential. Aim: The aim of this study is to assess the knowledge, attitude and practices of women regarding the basic screening test for detection of cancer cervix. Settings and Design: Population based cross-sectional study. Materials and Methods: Cross-sectional prospective study was conducted. Information from consenting participants (450) was collected using structured questionnaire. Answers were described in terms of knowledge, attitude and practice and their respective adequacy with respect to Papanicolaou (Pap) test, the most common test used for early detection of cervical cancer. Adequacy was compared between the categories of socio demographic and clinical variables. Statistical Analysis: The data collected was analyzed using statistical package (SPSS version 18.0). Adequacy was compared between the categories of the control variables by chi2 test with a 5% significance level. Results: Knowledge, attitude and practices regarding Pap test were adequate in 32.7%, 18.2% and 7.3% of women respectively. Major impediment to adequate practice was lack of request by physician. Knowledge, attitudes and practices were found to increase significantly with increasing age and education. Conclusion: Effective information, education and communication strategies are required to improve the level of awareness of public. Health-care professional should be proactive in imparting knowledge at every opportunity. PMID- 25494131 TI - The effect of small-molecular-weight heparin added to chemotherapy on survival in small-cell lung cancer - A retrospective analysis. AB - Aims and Background: Small cell lung cancer (SCLC) is a chemotherapy-responsive tumor and associated with alterations in the coagulation system. Addition of low molecular-weight heparin (LMWH) to combination chemotherapy (CT) had resulted in increase in survival. The present retrospective trial was designed to determine whether the duration of dalteparin usage has an effect on progression and survival. Materials and Methods: The medical records of 67 patients with SCLC who were given cisplatin-etoposide and concomitant LMWH (dalteparin) was evaluated retrospectively. Results: Median follow-up of patients was 11.3 months. Outcome: 10.6% complete response, 3.0% good partial response, 36.4% partial response, 10.6% stable disease, and 39.4% progressive disease. Side-effects were seen in 40.3% of the patients. Median dalteparin duration was 6,1 months. According the duration of dalteparin patients were grouped in three: who took dalteparin less than 4 months (Group A), 4-6 months (Group B) and more than 6 months (Group C). Mean overall survival (OS) in Group A was 6.5 months, in Group B 11.8 months, and Group C 14.6 months. Mean OS in Group B and C were statistically significantly (P < 0.001) longer than Group A, between Group B and C there was not any significant difference (P = 0.037). Mean progression free survival (PFS) was 9 months. Conclusions: The CT plus LMWH minimum 4 months long is well-tolerable, and may improve PFS and OS in patients with SCLC. For treatment of patients with SCLC CT plus LMWH may be considered as effective future-therapy, and further multi-centre randomised prospective clinical trials must be done to determine the new standard treatment approach for SCLC. PMID- 25494132 TI - Public opinion about smoking and smoke free legislation in a district of North India. AB - Context: A growing number of cities, districts, counties and states across the globe are going smoke-free. While an Indian national law namely Cigarettes and Other Tobacco Products Act (COTPA) exists since 2003 and aims at protecting all the people in our country; people still smoke in public places. Aim: This study assessed knowledge and perceptions about smoking, SHS and their support for Smoke free laws among people residing in Mohali district, Punjab. Materials and Methods: This cross-sectional study was conducted in Mohali district of Punjab, India. A sample size of 1600 people was obtained. Probability Proportional to Size technique was used for selecting the number of individuals to be interviewed from each block and also from urban and rural population. Statistical Analysis Used: We estimated proportions and tested for significant differences by residence, smoking status, literacy level and employment level by means of the chi-square statistics. Statistical software SPSS for Windows version 20 was used for analysing data . Results: The overall prevalence of current smoking among study participants was 25%. Around 96% were aware of the fact that smoking is harmful to health, 45% viewed second-hand smoke to be equally harmful as active smoking, 84.2% knew that smoking is prohibited in public places and 88.3% wanted the government to take strict actions to control the menace of public smoking. Multivariate logistic regression analysis showed that people aged 20 years and above, unemployed, urban, literate and non-smokers had significantly better perception towards harms of smoking. The knowledge about smoke free provisions of COTPA was significantly better among males, employed individuals, urban residents, and literate people. Conclusions: There was high knowledge about deleterious multi-dimensional effects of smoking among residents and a high support for implementation of COTPA. Efforts should be taken to make Mohali a "smoke-free district". PMID- 25494133 TI - Low free to total PSA ratio is not a good discriminator of chronic prostatitis and prostate cancer: An Indian experience. AB - Aims: To find out the utility of free to total PSA ratio in discriminating chronic prostatitis and prostate cancer. Setting and design: The patients visited urology clinics at Batra Hospital and Medical Research Center, New Delhi. Background: The use of serum free to total PSA as a diagnostic tool for prostate cancer has led to early detection of prostate cancer; however, the effect of inflammation on f/t PSA ratio restricts its use in early detection of cancer. Materials and Methods: The study was conducted in age related 101 patients which include 27 carcinoma patients (group I), 34 BPH patients (group II) and 40 chronic prostatitis patients (group III). Serum total PSA (tPSA) and free PSA (fPSA) were analyzed on Elecsys 2010. These were compared with histological reports of biopsy specimen. Other biochemistry tests were done on Randox Imola. P Value was calculated using one way ANOVA with posthoc Bonferroni analysis. Results: Serum total PSA levels were comparable in group I and III and were higher than group II (P < 0.049). Serum fPSA in group I was not significantly different from group II and III, However, group II has higher levels than group III (P < 0.035). Difference was significant for f/t PSA ratio in group I and II (P < 0.00) and group II and III (P < 0.000).Group I and III were with comparable levels (P < 0.807). Conclusions: f/t PSA ratio is not a good discriminator for malignancy and chronic prostatitis. This limitation of f/t PSA ratio must be taken into consideration while interpreting the results clinically. PMID- 25494134 TI - Dendritic cell vaccine treatment of advanced de novo colorectal cancer in renal transplant patients. AB - Objective: The clinical outcome, especial the immunologic responses to cancer and graft, of dendritic cell (DC) vaccine in the treatment of advanced de novo colorectal cancer (CRC) in renal transplant patients was investigated in this study. Materials and Methods: 7 patients were received 1 cycle tumor lysate pulsed autologous DC vaccine. The positive cell-mediated cytotoxicity responses to DC vaccine against CRC cell in two out of 7 patients were seen by delayed type hypersensitivity (DTH) test. The positive cell-mediated cytotoxicity responses to DC vaccine against normal kidney cell in all 7 patients were not seen by DTH tests and no notable change of renal function during and after vaccination. Conclusions: DC vaccine has emerged as a promising new strategy in the treatment of advanced de novo CRC in renal transplant patients and DC vaccines have become an attractive therapeutic option, developing immune responses specific against CRC cell, achieving clinical efficacy without graft failure. PMID- 25494135 TI - Prognostic role of serum interleukin-18 in Egyptian patients with hepatitis c virus-related hepatocellular carcinoma treated by radiofrequency ablation. AB - Aim: The aim of this study is to identify the prognostic value of serum interleukin (IL)-18 level in hepatitis C virus (HCV) -related hepatocellular carcinoma (HCC) patients. Materials and Methods: This study was conducted in Tropical Medicine department and HCC unit in Ain Shams University Hospitals. It included 35 patients with HCV associated HCC fit for radio frequency ablation and 20 healthy control subjects. Serum IL-18 level was measured for all participants at the beginning of the study. Patients were followed-up for 1 year then serum IL 18 re-measured at the end of the follow-up period. Results: Pre-intervention serum IL-18 level was significantly higher in patients than healthy control subjects and was associated with bad clinical, laboratory or radiological prognosis. Post follow-up mean value of IL-18 level was significantly lower than pre-intervention level. Conclusion: Higher pre-intervention serum IL-18 level in HCV -related HCC patients level was associated with bad prognosis either clinically, laboratory or radiologically. PMID- 25494136 TI - Quality of life after oesophagectomy in patients with carcinoma of oesophagus: A prospective study. AB - Background: The present study was done to see if quality of life improves following oesophagectomy for carcinoma of oesophagus. Materials and Methods: This was a prospective study done from June 2007 to July 2009. All patients undergoing oesophagectomy and cervical anastomoses for squamous cell carcinoma and adenocarcinoma of oesophagus were included in the study. Quality of life assessment was done using EORTC QLQ C-30 and its oesophagus specific module (OES 18) before surgery and at 3, 6, 9 and 12 months. Results: There were 55 patients who underwent oesophagectomy for carcinoma of oesophagus. On the EORTC functional scale it was noted that patients undergoing transhiatal oesophagectomy showed significant improvement of emotional function only. Patients undergoing transthoracic oesophagectomy showed a decrease in functional scores in the first three months which improved later but this change was not significant. On the EORTC symptom scale, patients undergoing transhiatal oesophagectomy showed significant improvement of constipation but not in other symptoms. Patients undergoing transthoracic oesophagectomy showed an increase in symptoms for the first three months followed by a decrease which was significant with respect to scores for constipation and pain. On the EORTC oesophagus specific symptom scores, patients in both groups showed significant improvement of dysphagia and eating. Conclusion: Patients with carcinoma of oesophagus undergoing transhiatal oesophagectomy may not show significant improvement in quality of life. However there will be significant improvement in dysphagia and eating. Patients undergoing transthoracic oesophagectomy may show an initial decrease in the quality of life. PMID- 25494137 TI - Adenomatous polyposis coli gene large deletions in Iranian patients with familial adenomatous polyposis. AB - Context: Familial adenomatous polyposis (FAP) is one type of hereditary colon cancer with a large number of precancerous polyps that initiation to growth in childhood and adolescent. Mutation in adenomatous polyposis coli (APC) gene is the cause of FAP. Aims: The aim of the current study was to standardize multiplex ligation probe amplification (MLPA) method in screening of APC large deletions for the first time in Iranian patients with FAP. Subjects and Methods: Deoxyribonucleic acid was extracted from 34 FAP patients by saluting out method. All patients were screened for APC large deletions whit MLPA and for the positive results, respective region was investigated by polymerase chain reaction sequencing. All genetic alterations were doubled checked in two separated rounds of MLPA. Results: The detection rate of large fragment deletions in APC was 5.8% (2/34). Both of the Iranian patients had deletion in the middle and the end of exon 15, however, comparing of clinical features between patient with the large deletion and patients without deletion did not show any significant difference in each variable including, age at diagnosis, signs of disease and poly type. Conclusions: It seems that exon 15 of APC gene is probably the hotspot region in Iranian FAP patients. Association of genotype/phenotype is well known in FAP patients, but in this study statistical analyses did not show a significant difference in each considerable factor between patients with and without large deletions. It seems better to consider MLPA as an initial step to screening APC mutations. PMID- 25494138 TI - Epidermal growth factor receptor gene expression evaluation in colorectal cancer patients. AB - Background: Colorectal cancer is one of the most common causes of death in the world and third and fourth most common cancer among men and women in Iran respectively. Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor that shows over expression in epithelial tumors and regulates important processes in tumorigenesis. Incidence and characteristics of colorectal cancer are based on the geographic region and race. Aim: In this research work, the over expression of EGFR in formalin fixed paraffin-embedded (FFPE) colorectal cancer tumor tissue of patients was studied. Materials and Methods: Fifteen FFPE colorectal cancer tumor tissues (10 women and 5 men; 25-65 years old and stage IV) and 15 non-patients (nine women and six men; 25-65 years old) that were collected during 2006-2012. EGFR gene expression level was analyzed by real-time quantitative reverse transcriptase polymerase chain reaction (PCR). All PCR reactions were performed in triplicate for both target gene and internal control (18s ribosomal ribonucleic acid) with the 2-DeltaDeltaCT method. Gene expression differences in patients and controls were evaluated with t-test. Results: The results were showed EGFR gene over expression in 12 (80%) of 15 patients. There was a statistically significant difference in the prevalence of EGFR expression between patients and control (P < 0.05). Conclusion: Our results demonstrated EGFR gene over expression in colorectal cancer tumor tissue compared with controls. PMID- 25494139 TI - Beyond ten cycles of cabazitaxel for castrate-resistant prostate cancer. AB - Background: There are limited data regarding cabazitaxel use beyond 10 cycles. Patients and Methods: Retrospective analysis of prospectively collected data of patients with metastatic castrate-resistant prostate cancer who received over 10 cycles of cabazitaxel after docetaxel failure. Results: Four patients received between 14 and 27 cycles. Reasons for stopping cabazitaxel were toxicity (2), progression (1) and logistics (1). Two of the three patients with measurable disease attained a partial remission (PR). Three patients continued to have a PSA response after 10 cycles; PSA nadir occurred between 17 and 23 cycles. Other than peripheral neuropathy (PN), all the cabazitaxel-related toxicities occurred after the initial cycles and did not increase cumulatively. Clinically significant neuropathy occurred after 15-17 cycles. The cabazitaxel-induced PN was partially reversible, with improvement from grade 3 to grade 2 after a 3-5-month long drug holiday. Conclusion: Cautiously continuing cabazitaxel until progression or intolerable toxicity may maximize efficacy. PMID- 25494140 TI - Toward better quality of anticancer generics in India. AB - Treatment of cancer is limited by affordability of patients in the many developing countries including India. Generic drug manufacturers have responded to this scenario by making drugs available at affordable costs, often at less than 10% the cost of the original brand. In our practice, it is found that there is a three-fold higher prescription of generic brands compared to innovator, accompanied by cost savings of up to 80% per prescription. Unfortunately, the regulatory environment prevailing in India is not geared to ensure satisfactory quality of generic products. The standards set by the regulatory agencies for establishing equivalence of generics vis-upsilon-vis the innovator product allow anticancer generics to enter markets without undergoing clinical evaluation. Many drug manufacturing units in India flout good manufacturing practice norms, which was evident during the center for drug evaluation and research classifications inspection in the year 2006. Inferior drugs have therefore, made their way into the Indian markets, compromising the quality of care. The system of drug manufacturing and marketing approval needs a major overhaul, including regular inspection of manufacturing facilities. Bioequivalence should be made mandatory for all oral formulations. Unless these measures are rigidly implemented, the benefits of generic substitution would be seriously undermined. PMID- 25494141 TI - An unusual presentation of pancreatic cancer: Muscular metastasis. PMID- 25494143 TI - Restricted diffusion in chemotherapy-induced posterior reversible encephalopathy syndrome: Not necessarily a bad omen? PMID- 25494142 TI - Primary renal lymphoma: An unusual presentation of non-Hodgkin's lymphoma. PMID- 25494144 TI - Solitary parotid plexiform neurofibroma - diagnostic difficulty in a clinically unsuspected case. PMID- 25494145 TI - Ovarian undifferentiated carcinoma resembling giant cell carcinoma of lung. PMID- 25494146 TI - One more common tumor in an uncommon location: Squamous cell carcinoma on nipple areola complex. PMID- 25494147 TI - Multiple head and neck carcinomas are of independent or common clonal origin? PMID- 25494148 TI - Immature ovarian teratoma with peritoneal gliomatosis. PMID- 25494149 TI - Orbital melanoma: Recurrence versus primary: A diagnostic dilemma. PMID- 25494150 TI - Bendamustine induced tumor lysis syndrome with acute renal failure in chronic lymphocytic leukemia. PMID- 25494151 TI - Metaplastic carcinoma of the breast: A case report with review of literature. PMID- 25494152 TI - Isodicentric Philadelphia [idic(Ph)] chromosome in a case of CML at chronic phase. PMID- 25494153 TI - Small-cell lung cancer with epidermal growth factor receptor mutation: Case report and review of literature. PMID- 25494154 TI - Lymphoma of bone masquerading as osteomyelitis and causing compartment syndrome of the leg. PMID- 25494155 TI - FNAC diagnosis of granulocytic sarcoma of the neck. PMID- 25494156 TI - Synchronous primary double malignancy involving stomach and hepatic flexure of colon: A case report. PMID- 25494157 TI - Importance of under graduate oncology training. PMID- 25494158 TI - Response assessment to Sunitinib by F-18 Fluorodeoxyglucose PET/CT in a case of venous tumor thrombosis from renal cell carcinoma. PMID- 25494159 TI - Detection and response evaluation of penile metastasis from urinary bladder carcinoma demonstrated by F-18 FDG PET/CT. PMID- 25494160 TI - Detection of a case of cervical dysplasia with co-existent cervical tuberculosis by pap smear examination. PMID- 25494161 TI - Respiratory symptoms as first manifestation in an occult alveolar soft part sarcoma. PMID- 25494162 TI - Long term survival after whole brain radiotherapy for brain metastasis in follicular dendritic cell sarcoma. PMID- 25494163 TI - Psuedo Chediak Higashi anomaly in case of hypogranular variant of acute promyelocytic leukemia (AML-M3v): A morphologic enigma. PMID- 25494164 TI - Chronic myeloid leukemia in acute lymphoblastic leukemia survivor: A case report. PMID- 25494165 TI - Recurrent sinonasal teratocarcinosarcoma with intracranial extension: Case report. PMID- 25494166 TI - Response to oral metronomic chemotherapy in carcinoma of the Buccal Mucosa: A case report. PMID- 25494167 TI - Oral cutaneous leishmaniasis mimicking carcinoma of tongue: A case report. PMID- 25494168 TI - Evolving meningococcal immunization strategies. AB - Meningococcal disease is a major public health problem and immunization is considered the best strategy for prevention. The introduction of meningococcal C conjugate immunization schedules that targeted adolescents, with catch-up programs in several European countries, Australia and Canada proved to be highly effective, with dramatic reduction in the incidence of serogroup C disease, not only in vaccinated, but also in unvaccinated individuals. Meningococcal quadrivalent (A, C, W, Y) conjugate vaccines are now licensed and are being used in adolescent programs in North America and to control serogroup W disease in South America. In the African meningitis belt, a mass immunization campaign against serogroup A disease using a meningococcal A conjugate vaccine is now controlling the devastating epidemics of meningococcal disease. After introducing new immunization programs, it is of importance to maintain enhanced surveillance for a better understanding of the changing nature of disease epidemiology. This information is crucial for identifying optimal immunization policies. PMID- 25494169 TI - Nanooptics of molecular-shunted plasmonic nanojunctions. AB - Gold nanoparticles are separated above a planar gold film by 1.1 nm thick self assembled molecular monolayers of different conductivities. Incremental replacement of the nonconductive molecules with a chemically equivalent conductive version differing by only one atom produces a strong 50 nm blue-shift of the coupled plasmon. With modeling this gives a conductance of 0.17G(0) per biphenyl-4,4'-dithiol molecule and a total conductance across the plasmonic junction of 30G(0). Our approach provides a reliable tool quantifying the number of molecules in each plasmonic hotspot, here <200. PMID- 25494170 TI - Describing Art - An Interdisciplinary Approach to the Effects of Speaking on Gaze Movements during the Beholding of Paintings. AB - Ever since the Renaissance speaking about paintings has been a fundamental approach for beholders, especially experts. However, it is unclear whether and how speaking about art modifies the way we look at it and this was not yet empirically tested. The present study investigated to the best of our knowledge for the first time in what way speaking modifies the patterns of fixations and gaze movements while looking at paintings. Ninety nine university students looked at four paintings selected to cover different art historical typologies for periods of 15 minutes each while gaze movement data were recorded. After 10 minutes, the participants of the experimental group were asked open questions about the painting. Speaking dramatically reduced the duration of fixations and painting area covered by fixations while at the same time increasing the frequencies of fixations, gaze length and the amount of repeated transitions between fixation clusters. These results suggest that the production of texts as well-organised sequences of information, structures the gazes of art beholders by making them quicker, more focused and better connected. PMID- 25494171 TI - Asymmetric synthesis of 3,3'-spirooxindoles fused with cyclobutanes through organocatalytic formal [2 + 2] cycloadditions under H-bond-directing dienamine activation. AB - The first organocatalytic asymmetric synthesis of a spirooxindole skeleton incorporated with a cyclobutane moiety has been successfully developed on the basis of H-bond-directing dienamine activation. Structurally complex spirocyclobutyl oxindoles, which possess four contiguous stereocenters, including one spiro quaternary center, were obtained in good yields (up to 83%) with excellent beta,gamma-regioselectivity (>19:1) and stereocontrol (up to >19:1 dr and 97% ee). PMID- 25494173 TI - Dual stimuli-responsive multi-drug delivery system for the individually controlled release of anti-cancer drugs. AB - A dual stimuli-responsive multi-drug delivery system was developed for "cancer cocktail therapy". Upon UV irradiation, microcapsules could rapidly release the small-molecule drugs, and thereafter the macromolecular drugs would be released in the presence of MMP in the tumor cells. This system will find great potential as a novel chemotherapeutic combination for cancer treatment. PMID- 25494172 TI - Squaraine-based polymer dots with narrow, bright near-infrared fluorescence for biological applications. AB - This article describes the design and development of squaraine-based semiconducting polymer dots (Pdots) that show large Stokes shifts and narrow-band emissions in the near-infrared (NIR) region. Fluorescent copolymers containing fluorene and squaraine units were synthesized and used as precursors for preparing the Pdots, where exciton diffusion and likely through-bond energy transfer led to highly bright and narrow-band NIR emissions. The resulting Pdots exhibit the emission full width at half-maximum of ~36 nm, which is ~2 times narrower than those of inorganic quantum dots in the same wavelength region (~66 nm for Qdot705). The squaraine-based Pdots show a high fluorescence quantum yield (QY) of 0.30 and a large Stokes shift of ~340 nm. Single-particle analysis indicates that the average per-particle brightness of the Pdots is ~6 times higher than that of Qdot705. We demonstrate bioconjugation of the squaraine Pdots and employ the Pdot bioconjugates in flow cytometry and cellular imaging applications. Our results suggest that the narrow bandwidth, high QY, and large Stokes shift are promising for multiplexed biological detections. PMID- 25494174 TI - Obesity Associated Cerebral Gray and White Matter Alterations Are Interrelated in the Female Brain. AB - Obesity is known to affect the brain's gray matter (GM) and white matter (WM) structure but the interrelationship of such changes remains unclear. Here we used T1-weighted magnetic resonance imaging (MRI) in combination with voxel-based morphometry (VBM) and diffusion-tensor imaging (DTI) with tract-based spatial statistics (TBSS) to assess the relationship between obesity-associated alterations of gray matter density (GMD) and anisotropic water diffusion in WM, respectively. In a small cohort of lean to obese women, we confirmed previous reports of obesity-associated alterations of GMD in brain regions involved in executive control (i.e., dorsolateral prefrontal cortex, DLPFC) and habit learning (i.e., dorsal striatum). Gray matter density alterations of the DLPFC were negatively correlated with radial diffusivity in the entire corpus callosum. Within the genu of the corpus callosum we found a positive correlation with axial diffusivity. In posterior region and inferior areas of the body of the corpus callosum, axial diffusivity correlated negatively with altered GMD in the dorsal striatum. These findings suggest that, in women, obesity-related alterations of GMD in brain regions involved in executive control and habit learning might relate to alterations of associated WM fiber bundles within the corpus callosum. PMID- 25494175 TI - Effects of the Workplace Health Promotion Activities Soccer and Zumba on Muscle Pain, Work Ability and Perceived Physical Exertion among Female Hospital Employees. AB - OBJECTIVES: This 40-week workplace physical training RCT investigated the effect of soccer and Zumba, respectively, on muscle pain intensity and duration, work ability, and rating of perceived exertion (RPE) during work among female hospital employees. METHODS: 107 hospital employees were cluster-randomized into two training groups, and a control group. The training was conducted outside working hours as two-three 1-h sessions per week for the first 12 weeks, and continued as one-two 1-h sessions per week for the last 28 weeks. Muscle pain intensity and duration, work ability, and RPE during work were measured at baseline and after 12 and 40 weeks. RESULTS: After 12 weeks, both the soccer (-1.9, 95% CI, -3.0, 0.8, P = 0.001) and the Zumba group (-1.3, 95% CI, -2.3, -0.3, P = 0.01) reduced the pain intensity (on a scale from 0 to 10) in the neck-shoulder region (eta squared = 0.109), whereas only the soccer group (-1.9, 95% CI, -3.2, -0.7, P = 0.002, eta squared = 0.092) showed a reduction after 40 weeks referencing the control group. After 40 weeks, both the soccer (-16.4 days, 95% CI, -29.6, -3.2, P<0.02) and the Zumba group (-16.6 days, 95% CI, -28.9, -4.2, P<0.01) reduced the pain duration during the past 3 months in the neck-shoulder region (eta squared = 0.077). No significant effects on intensity or duration of pain in the lower back, RPE during work or work ability were found. CONCLUSIONS: The present study indicates that workplace initiated soccer and Zumba training improve neck shoulder pain intensity as well as duration among female hospital employees. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number Register ISRCTN 61986892. PMID- 25494177 TI - Suture Closure versus Non-Closure of Subcutaneous Fat and Cosmetic Outcome after Cesarean Section: A Randomized Controlled Trial. AB - INTRODUCTION: To investigate the effect of subcutaneous fat suture closure versus non-closure at cesarean section (CS) on long-term cosmetic outcome. MATERIAL AND METHODS: Women undergoing planned or unplanned CS were randomized to either subcutaneous fat suture closure or non-closure using a 1?1 allocation algorithm. Participants and outcome assessors were blinded to group allocation. Scar evaluation was performed after two and six months. Primary outcome measures were Patient and Observer Scar Assessment Scale (POSAS) summary scores six months after surgery. Secondary outcome measures were Vancouver Scar Scale (VSS) summary scores, retraction of the scar below the level of the surrounding skin, duration of surgery, and development of hematoma, seroma, surgical site infection (SSI) or wound disruption. Data were analyzed according to the intention to treat principle. RESULTS: A total of 116 women were randomized and 91 participants, 47 in the closure and 44 in the non-closure group, completed the trial and were analyzed. There were no differences in patient morphometrics or surgery indications between groups. At two and six months no significant differences were found with respect to POSAS or VSS scores between groups. After two months significantly more women in the non-closure group described their scar as being retracted below the level of the skin (36% vs. 15%, p = 0.02) whereas no difference was observed at six months. There were significantly more hematomas in the non-closure (25%) compared to the closure group (4%) (p = 0.005). There was no difference in duration of surgery, SSI, seroma formation or wound disruption between groups. CONCLUSIONS: Suture closure of the subcutaneous fat at CS does not affect long-term cosmetic outcome. (Level I evidence). TRIAL REGISTRATION: ClinicalTrials.gov NCT01542346. PMID- 25494176 TI - Risk Assessment of Adverse Birth Outcomes in Relation to Maternal Age. AB - BACKGROUND: Although a number of studies have investigated correlations of maternal age with birth outcomes, an extensive assessment using age as a continuous variable is lacking. In the current study, we estimated age-specific risks of adverse birth outcomes in childbearing women. METHOD: National population-based data containing maternal and neonatal information were derived from the Health Promotion Administration, Taiwan. A composite adverse birth outcome was defined as at least anyone of stillbirth, preterm birth, low birth weight, macrosomia, neonatal death, congenital anomaly, and small for gestational age (SGA). Singletons were further analyzed for outcomes of live birth in relation to each year of maternal age. A log-binomial model was used to adjust for possible confounders of maternal and neonatal factors. RESULTS: In total, 2,123,751 births between 2001 and 2010 were utilized in the analysis. The risk of a composite adverse birth outcome was significantly higher at extreme maternal ages. In specific, risks of stillbirth, neonatal death, preterm birth, congenital anomaly, and low birth weight were higher at the extremes of maternal age. Furthermore, risk of macrosomia rose proportionally with an increasing maternal age. In contrast, risk of SGA declined proportionally with an increasing maternal age. The log-binomial model showed greater risks at the maternal ages of <26 and > 30 years for a composite adverse birth outcome. CONCLUSIONS: Infants born to teenagers and women at advanced age possess greater risks for stillbirth, preterm birth, neonatal death, congenital anomaly, and low birth weight. Pregnancies at advanced age carry an additional risk for macrosomia, while teenage pregnancies carry an additional risk for SGA. The data suggest that the optimal maternal ages to minimize adverse birth outcomes are 26~30 years. PMID- 25494178 TI - IL-17 Enhances Chemotaxis of Primary Human B Cells during Asthma. AB - IL-17 is a pro-inflammatory mediator that is believed to play a critical role in regulating tissue inflammation during asthma, COPD, as well as other inflammatory disorders. The level of expression of IL-17 has been shown to be upregulated in lung bronchial tissue of asthmatic patients. Several reports have provided further evidence that this cytokine could play a key role in enhancing the migration of inflammatory as well as structural cells of the bronchial lung tissue during asthma and COPD. B cell infiltration to sites of inflammation during inflammatory disorders such as bowel disease, asthma and COPD has been reported. Accordingly, in this study we hypothesized that IL-17 may exert a chemotactic effect on primary B cells during asthma. We observed that B cells from asthmatic patients expressed significantly higher levels of IL-17RA and IL 17RC, compared to those of healthy subjects. Using an in-vitro migration assay, B cells were shown to migrate towards both IL-17A and IL-17F. Interestingly, blocking IL-17A and IL-17F signaling using either anti-IL-17R antibodies or MAP kinase inhibitors prevented in vitro migration of B cell towards IL-17. These observations indicate a direct chemotactic effect of IL-17 cytokines on primary peripheral blood B cells with higher effect being on asthmatic B cells. These findings revealed a key role for IL-17 in enhancing the migration of B cells to the lung tissue during asthma or COPD. PMID- 25494179 TI - Behavioral and Transcriptomic Fingerprints of an Enriched Environment in Horses (Equus caballus). AB - The use of environmental enrichment (EE) has grown in popularity over decades, particularly because EE is known to promote cognitive functions and well-being. Nonetheless, little is known about how EE may affect personality and gene expression. To address this question in a domestic animal, 10-month-old horses were maintained in a controlled environment or EE for 12 weeks. The control horses (n = 9) lived in individual stalls on wood shaving bedding. They were turned out to individual paddocks three times a week and were fed three times a day with pellets or hay. EE-treated horses (n = 10) were housed in large individual stalls on straw bedding 7 hours per day and spent the remainder of the time together at pasture. They were fed three times a day with flavored pellets, hay, or fruits and were exposed daily to various objects, odors, and music. The EE modified three dimensions of personality: fearfulness, reactivity to humans, and sensory sensitivity. Some of these changes persisted >3 months after treatment. These changes are suggestive of a more positive perception of the environment and a higher level of curiosity in EE-treated horses, explaining partly why these horses showed better learning performance in a Go/No-Go task. Reduced expression of stress indicators indicated that the EE also improved well being. Finally, whole-blood transcriptomic analysis showed that in addition to an effect on the cortisol level, the EE induced the expression of genes involved in cell growth and proliferation, while the control treatment activated genes related to apoptosis. Changes in both behavior and gene expression may constitute a psychobiological signature of the effects of enrichment and result in improved well-being. This study illustrates how the environment interacts with genetic information in shaping the individual at both the behavioral and molecular levels. PMID- 25494181 TI - Dental and Mandibular Morphologies of Arboroharamiya (Haramiyida, Mammalia): A Comparison with Other Haramiyidans and Megaconus and Implications for Mammalian Evolution. AB - BACKGROUND: Two recent studies published in the same issue of Nature reached conflicting conclusions regarding the phylogeny of early mammals: One places the clade containing haramiyidans and multituberculates within the Mammalia and the other separates haramiyidans from multituberculates and places the former outside of the Mammalia. These two contrasting results require that the minimally oldest divergence time of the Mammalia was within the Late Triassic or the Middle Jurassic, respectively. Morphological descriptions of the species named in the two papers were brief, and no comparisons between the newly named species were possible. PRINCIPAL FINDINGS: Here we present a detailed description of the dentary bone, teeth, occlusal and wear patterns of the haramiyidan Arboroharamiya and compare it with other haramiyidans and Megaconus. Using this new information, we suggest that tooth identifications and orientations of several previously described haramiyidan species are incorrect, and that previous interpretations of haramiyidan occlusal pattern are problematic. We propose that the published upper tooth orientation of Megaconus was problematic and question the number of upper molars, the length of dentition and mandible, and presence of the mandibular middle ear in Megaconus. CONCLUSIONS: The additional morphological descriptions and comparisons presented here further support the view that Arboroharamiya, as a derived haramiyidan, shows similarity to multituberculates in tooth and mandible morphologies. Our comparison also suggests that Megaconus lacks many diagnostic features for the family Eleutherodontidae and that its close affinity with multituberculates cannot be ruled out. The detailed morphological data demonstrate that haramiyidans are more similar to multituberculates than to any other mammaliaforms. PMID- 25494180 TI - The Possible Impact of Vaccination for Seasonal Influenza on Emergence of Pandemic Influenza via Reassortment. AB - BACKGROUND: One pathway through which pandemic influenza strains might emerge is reassortment from coinfection of different influenza A viruses. Seasonal influenza vaccines are designed to target the circulating strains, which intuitively decreases the prevalence of coinfection and the chance of pandemic emergence due to reassortment. However, individual-based analyses on 2009 pandemic influenza show that the previous seasonal vaccination may increase the risk of pandemic A(H1N1) pdm09 infection. In view of pandemic influenza preparedness, it is essential to understand the overall effect of seasonal vaccination on pandemic emergence via reassortment. METHODS AND FINDINGS: In a previous study we applied a population dynamics approach to investigate the effect of infection-induced cross-immunity on reducing such a pandemic risk. Here the model was extended by incorporating vaccination for seasonal influenza to assess its potential role on the pandemic emergence via reassortment and its effect in protecting humans if a pandemic does emerge. The vaccination is assumed to protect against the target strains but only partially against other strains. We find that a universal seasonal vaccine that provides full-spectrum cross immunity substantially reduces the opportunity of pandemic emergence. However, our results show that such effectiveness depends on the strength of infection induced cross-immunity against any novel reassortant strain. If it is weak, the vaccine that induces cross-immunity strongly against non-target resident strains but weakly against novel reassortant strains, can further depress the pandemic emergence; if it is very strong, the same kind of vaccine increases the probability of pandemic emergence. CONCLUSIONS: Two types of vaccines are available: inactivated and live attenuated, only live attenuated vaccines can induce heterosubtypic immunity. Current vaccines are effective in controlling circulating strains; they cannot always help restrain pandemic emergence because of the uncertainty of the oncoming reassortant strains, however. This urges the development of universal vaccines for prevention of pandemic influenza. PMID- 25494182 TI - A Ceratopsian Dinosaur from the Lower Cretaceous of Western North America, and the Biogeography of Neoceratopsia. AB - The fossil record for neoceratopsian (horned) dinosaurs in the Lower Cretaceous of North America primarily comprises isolated teeth and postcrania of limited taxonomic resolution, hampering previous efforts to reconstruct the early evolution of this group in North America. An associated cranium and lower jaw from the Cloverly Formation (?middle-late Albian, between 104 and 109 million years old) of southern Montana is designated as the holotype for Aquilops americanus gen. et sp. nov. Aquilops americanus is distinguished by several autapomorphies, including a strongly hooked rostral bone with a midline boss and an elongate and sharply pointed antorbital fossa. The skull in the only known specimen is comparatively small, measuring 84 mm between the tips of the rostral and jugal. The taxon is interpreted as a basal neoceratopsian closely related to Early Cretaceous Asian taxa, such as Liaoceratops and Auroraceratops. Biogeographically, A. americanus probably originated via a dispersal from Asia into North America; the exact route of this dispersal is ambiguous, although a Beringian rather than European route seems more likely in light of the absence of ceratopsians in the Early Cretaceous of Europe. Other amniote clades show similar biogeographic patterns, supporting an intercontinental migratory event between Asia and North America during the late Early Cretaceous. The temporal and geographic distribution of Upper Cretaceous neoceratopsians (leptoceratopsids and ceratopsoids) suggests at least intermittent connections between North America and Asia through the early Late Cretaceous, likely followed by an interval of isolation and finally reconnection during the latest Cretaceous. PMID- 25494183 TI - Reconsidering the Avian Nature of the Oviraptorosaur Brain (Dinosauria: Theropoda). AB - The high degree of encephalization characterizing modern birds is the product of a long evolutionary history, our understanding of which is still largely in its infancy. Here we provide a redescription of the endocranial space of the oviraptorosaurian dinosaur Conchoraptor gracilis with the goal of assessing the hypothesis that it shares uniquely derived endocranial characters with crown group avians. The existence of such features has implications for the transformational history of avian neuroanatomy and suggests that the oviraptorosaur radiation is a product of the immediate stem lineage of birds after the divergence of Archaeopteryx lithographica. Results derived from an expanded comparative sample indicate that the strong endocranial similarity between Conchoraptor and modern birds largely reflects shared conservation of plesiomorphic features. The few characters that are maintained as being uniquely expressed in these two taxa are more likely products of convergence than homology but still indicate that the oviraptorosaur endocranial cavity has much to teach us about the complex history of avian brain evolution. PMID- 25494184 TI - [Clear Way for a Primary Training in Psychotherapy?] PMID- 25494185 TI - ['How Much Sex do Medical Studies Need?' - A Survey of the Knowledge and Interest in Sexual Medicine of Medical Students.] AB - Background: Because of the increasing need for medical care of problems concerning human sexuality, the International Society for Sexual Medicine (ISSM) in 2010 suggested to include sexual medicine in the current curricula of medical studies. Based on the ISSM's suggestions sexual medicine should be taught on a multidisciplinary basis throughout the whole study process. Furthermore, health care providers have repeatedly indicated that they have lacking knowledge concerning sexual medicine and patients have criticized that their health care providers only infrequently address their sexuality. Methods: 404 medical students from 2 German university medical centers answered an online questionnaire assessing the quality of sexual medicine education. The students were asked about their interest in and their knowledge about different issues concerning human sexuality in the following 4 domains: Sexual development, Sexual behavior, Sexual physiology and psychology, Sexual medicine and therapy of sexual disorders. Results: The great majority of students were interested in education about sexual medicine within medical studies, whereby most students were of the opinion that sexual medicine should be included in the already existing subjects. Furthermore, students mostly evaluated the current quality of sexual medicine education as insufficient and more than half of the students thought that they do not have enough knowledge about human sexuality for their future profession as medical health care providers. On average the students correctly answered 50% of the knowledge questions, however they showed some knowledge gaps especially in the domains of sexual development and sexual physiology and psychology. Discussion: The results of the present study suggest that medical students have lacking knowledge concerning important parts of human sexuality but at the same time express great interest in the field. Therefore, in Germany more structured educational programs in sexual medicine should be developed taking the suggestion of the ISSM into account. Conclusion: Besides medical education about pathological sexuality future educational efforts should also address healthy sexuality and its sociocultural meaning more frequently. Thereby, the students' wishes would be met and moreover, health care providers of all fields would be enabled to provide an unbiased, holistic and sensitive treatment of sexual problems. PMID- 25494186 TI - [Extradyadic Sex and its Predictors in Homo- and Heterosexuals.] AB - Infidelity appears to be a common phenomenon. Although there are initially positive consequences for the unfaithful partner, it has negative impacts on individuals, the relationship and health in the long-term. How often are extradyadic sexual contacts indicated within a German sample? Which factors predict infidelity? Via Internet (n=1 899) socio-demographic, individual (attitudes towards infidelity, religiosity), relationship (global and emotional relationship satisfaction, length of primary relationship, sexual agreements), and contextual factors (opportunities) were surveyed. The results of the regression analysis on an 80% subsample (n=1 533) were cross-validated with the remaining 20% of the data (n=366). The analysis showed that 4% of lesbian women, 34% of gay men, 29% of heterosexual women and 49% of heterosexual men reported extra-dyadic sexual contacts. Sexual orientation and restrictive attitudes towards monogamy and infidelity were found to be significant predictors. Low global relationship satisfaction, longer duration of primary relationship, non monogamous relationships, availability of alternative sexual partners and ways to conceal infidelity increased the likelihood of extradyadic involvement. Cross validation with 20% of the data (n=366) confirmed the stability of the regression model. Future research should examine identified predictors using representative population-based data. Predictors should be considered in therapy. PMID- 25494187 TI - [Factoranalytic Structure of a Short Version of the Eating Attitudes Test (EAT 13) and Prevalences of Disordered Eating in a Representative German Sample.] AB - Early detection of disordered eating behavior is a first hint to prevent clinically relevant eating disorders. Screening instruments are aimed at detecting disordered eating behavior at an early stage, to identify risk groups and as necessary initiate treatment. The EAT-13 is an economic screening instrument (13 items), that allows identification of risk groups in big unselected samples with help of determination of sum score. Factorial validity of the EAT-13 and the suitability for different ages were determined in a representative sample of the German population (N=2 508). Furthermore prevalence of disordered eating behavior was assessed in the sample. Results show that the EAT-13 is a reliable and economic screening instrument that is eligible to select risk groups. An inspection of criterion validity shall be conducted in further studies. PMID- 25494188 TI - [Depression in late-Life - Substantial Public Health Impact.] AB - Depression in late-life is common and psychosocial and biological factors are proposed. Searching for modifiable risk factors is of utmost importance. However, depression in late life is under-recognized and undertreated. Much room for improvement is determined, especially in utilizing psychotherapeutic interventions and taking advantage of internationally excellent evaluated collaborative care approaches. Late-life depression does have a major public health impact. It is an important field for health service research in Germany to optimize care. PMID- 25494189 TI - [How to Calculate Statistical Power.] PMID- 25494190 TI - [Social Anxiety Disorders.] PMID- 25494191 TI - Transferring learning from faculty development to the classroom. AB - This study's purpose was to better understand the transfer of learning by uncovering how various factors supported the integration of health information technology knowledge and skills gleaned from the Health Resources and Services Administration-funded faculty development programs into nursing education curricula. Through interviews with 20 participants from four programs, this study confirmed the importance of findings related to faculty, program, and work environment characteristics for supporting successful transfer of learning and substantiates a variety of other transfer-of-learning research. New or seldom discussed supportive individual characteristics were found, including leadership abilities, lifelong learning, ability to recognize limitations, persistence, creativity, and risk taking. The importance of networking, diversity of perspectives, postconference support, and teams in program designs were found to positively influence transfer. The variety of supportive factors and barriers in the participants' work environments strengthens the assertions that transfer may be context dependent. Findings provided insight for recommendations to improve learning transfer. PMID- 25494192 TI - Developing a global curriculum in a school of nursing. AB - Nurses care for an increasingly diverse ethnic population, but nursing education may not always include the necessary global learning components necessary for students to provide the most culturally appropriate and patient-centered care. Although much of the literature already attends to the importance of international experiences, this article focuses on an initiative to develop an on campus global curriculum in a school of nursing. Through a global framework informed by a literature review and surveys of faculty and courses, a task force delivered two faculty workshops. The first focused on cultural self-awareness and cultural competence development in both faculty and students. The second workshop focused on how to incorporate a global learning objective into course syllabi. This article discusses the goals, format, and outcomes of each workshop, highlighting the importance of faculty development and the implications for other institutions to pursue this type of initiative. PMID- 25494193 TI - Interprofessional teaching project with nursing and physical therapy students to promote caregiver and patient safety. AB - Nurse educators must adjust curricula to meet the dynamic and critical changes in the health care environment, and to recognize the risk of injury our educational approach has on safety, team effectiveness, and culture change. Interprofessional collaboration and simulation are key components in the preparation of our students. Utilizing the interprofessional alliance model, an experience to promote collaborative relationships among nursing and physical therapy (PT) students to improve patient and caregiver safety was developed. Through this model, PT students taught safe patient-handling skills in a simulated setting to undergraduate nursing students. The majority of nursing students (N=351) from 2009-2014 strongly agreed or agreed that they were confident in the skills taught by the PT students and provided an overall course rating of outstanding or above average. This educational model, which includes simulation and safe patient handling, was a valuable addition to the curriculum, reinforcing the significance of developing collaborative relationships. PMID- 25494194 TI - An innovative approach to enhance dermatology competencies for advanced practice nurses: service-learning with a migrant farm worker health clinic. AB - The purpose of this article is to describe a novel service-learning opportunity for graduate nursing students that promotes competency in dermatology. A hybrid service-learning course with online didactic content is described, along with tools for evaluation of dermatology competencies. Student evaluation of the course is discussed, and selected research articles are reviewed. Advanced practice nursing and medical education frequently does not adequately prepare primary care providers to be competent in the assessment and management of dermatologic conditions. Embedding dermatology content in a service-learning program can optimize the provision of care, strengthen competencies in dermatology and inter-professional care, and allow students to gain a deeper understanding of the population with which they work. The innovative service learning program presented is a model for advanced practice nursing education. Tools for evaluating clinical competency and courses often need validation. PMID- 25494196 TI - Visual Saliency Models for Text Detection in Real World. AB - This paper evaluates the degree of saliency of texts in natural scenes using visual saliency models. A large scale scene image database with pixel level ground truth is created for this purpose. Using this scene image database and five state-of-the-art models, visual saliency maps that represent the degree of saliency of the objects are calculated. The receiver operating characteristic curve is employed in order to evaluate the saliency of scene texts, which is calculated by visual saliency models. A visualization of the distribution of scene texts and non-texts in the space constructed by three kinds of saliency maps, which are calculated using Itti's visual saliency model with intensity, color and orientation features, is given. This visualization of distribution indicates that text characters are more salient than their non-text neighbors, and can be captured from the background. Therefore, scene texts can be extracted from the scene images. With this in mind, a new visual saliency architecture, named hierarchical visual saliency model, is proposed. Hierarchical visual saliency model is based on Itti's model and consists of two stages. In the first stage, Itti's model is used to calculate the saliency map, and Otsu's global thresholding algorithm is applied to extract the salient region that we are interested in. In the second stage, Itti's model is applied to the salient region to calculate the final saliency map. An experimental evaluation demonstrates that the proposed model outperforms Itti's model in terms of captured scene texts. PMID- 25494197 TI - Asymmetric papilledema in idiopathic intracranial hypertension. AB - BACKGROUND: Very asymmetric papilledema in idiopathic intracranial hypertension (IIH) is rare, and few studies have dealt with this atypical presentation of IIH. Our aim was to describe the clinical and radiologic features of patients with IIH and very asymmetric papilledema. METHODS: We identified all adult patients from our IIH database with very asymmetric papilledema defined as a >=2 modified Frisen grade difference between the 2 eyes. Demographic data and initial symptoms were collected, and all brain imaging studies performed at our institution were reviewed. RESULTS: Of the 559 adult patients with definite IIH, 20 (3.6%; 95% confidence interval [CI], 2.3-5.6) had very asymmetric papilledema at initial evaluation. They were older (39 vs 30 years; P < 0.001), had lower cerebrospinal opening pressure (35.5 vs 36 cm of water; P = 0.03), and were more likely to be asymptomatic compared with patients with symmetric papilledema (27% vs 3%; P < 0.001). Visual fields were worse on the side of the highest-grade papilledema (P = 0.02). The bony optic canal was smaller on the side of the lowest-grade edema in all 8 patients (100%) in whom the imaging was sufficient for reliable measurements (P = 0.008). CONCLUSIONS: IIH with very asymmetric papilledema is uncommon. Very asymmetric papilledema may result from differences in size of the bony optic canals, supporting the concept of compartmentation of the perioptic subarachnoid spaces. PMID- 25494198 TI - Complaints of Poor Sleep and Risk of Traffic Accidents: A Population-Based Case Control Study. AB - INTRODUCTION: This study aimed to determine the sleepiness-related factors associated with road traffic accidents. METHODS: A population based case-control study was conducted in 2 French agglomerations. 272 road accident cases hospitalized in emergency units and 272 control drivers matched by time of day and randomly stopped by police forces were included in the study. Odds ratios were calculated for the risk of road traffic accidents. RESULTS: As expected, the main predictive factor for road traffic accidents was having a sleep episode at the wheel just before the accident (OR 9.97, CI 95%: 1.57-63.50, p<0.05). The increased risk of traffic accidents was 3.35 times higher in subjects who reported very poor quality sleep during the last 3 months (CI 95%: 1.30-8.63, p<0.05), 1.69 times higher in subjects reporting sleeping 6 hours or fewer per night during the last 3 months (CI 95%: 1.00-2.85, p<0.05), 2.02 times higher in subjects reporting symptoms of anxiety or nervousness in the previous day (CI 95%: 1.03-3.97, p<0.05), and 3.29 times higher in subjects reporting taking more than 2 medications in the last 24 h (CI 95%: 1.14-9.44, p<0.05). Chronic daytime sleepiness measured by the Epworth Sleepiness Scale, expressed heavy snoring and nocturnal leg movements did not explain traffic accidents. CONCLUSION: Physicians should be attentive to complaints of poor sleep quality and quantity, symptoms of anxiety-nervousness and/or drug consumption in regular car drivers. PMID- 25494199 TI - Acridine based (S,N,S) pincer ligand: designing silver(I) complexes for the efficient activation of A3 (aldehyde, alkyne and amine) coupling. AB - Complexes [AgL(NO3)CH3CN](1) and [AgLNO3] (2) were formed on reacting AgNO3 with L in acetonitrile for 12 h (at room temperature) and 24 h (at 90 degrees C), respectively, where L is a (S,N,S) pincer ligand, 4,5 bis(phenylthiomethyl)acridine, synthesized by the reaction of in situ generated PhS(-) with 4,5-bis(bromomethyl)acridine under N2 atmosphere. (1)H and (13)C{(1)H} NMR and the mass spectra of L and its two Ag-complexes were characterized. The structures of complexes 1 and 2 were established with single crystal X-ray crystallography. The Ag-S bond distances of complexes 1 and 2 are 2.5682 (11)/2.5017 (11) A and 2.4894 (15)/2.4834 (15) A, respectively. The ligand L in complex 2 is coordinated with the metal in a pincer mode and the complex has a pseudo-pyramidal geometry of donor atoms around the Ag. In 1, the metal is encapsulated by a ten-membered chelate ring. The two Ag(I) complexes were explored for the coupling of aldehyde, alkyne and amine (A(3) reaction) and were found to be efficient as a 2.0 mol% loading of 1 and 0.5 mol% of 2 for good conversion. Complex 2 is a rare example of a catalyst that can efficiently activate A(3) coupling at a 0.5 mol% loading of Ag. PMID- 25494200 TI - Preparation of Spray-Dried Soy Isoflavone-Loaded Gelatin Microspheres for Enhancement of Dissolution: Formulation, Characterization and in Vitro Evaluation. AB - The most bioactive soy isoflavones (SI), daidzein (DAI) and genistein (GEN) have poor water solubility, which reduces their bioavailability and health benefits and limits their use in industry. The goal of this study was to develop and characterize a new gelatin matrix to microencapsulate DAI and GEN from soy extract (SE) by spray drying, in order to obtain solid dispersions to overcome solubility problems and to allow controlled release. The influences of 1:2 (MP2) and 1:3 (MP3) SE/polymer ratios on the solid state, yield, morphology, encapsulation efficiency, particle size distribution, release kinetics and cumulative release were evaluated. Analyses showed integral microparticles and high drug content. MP3 and MP2 yield were 43.6% and 55.9%, respectively, with similar mean size (p > 0.05), respectively. X-ray diffraction revealed the amorphous solid state of SE. In vitro release tests showed that dissolution was drastically increased. The results indicated that SE microencapsulation might offer a good system to control SI release, as an alternative to improve bioavailability and industrial applications. PMID- 25494201 TI - Evaluation of Rapidly Disintegrating Vaginal Tablets of Tenofovir, Emtricitabine and Their Combination for HIV-1 Prevention. AB - Vaginal tablets are being developed as an alternative to gels as an inexpensive, discreet dosage form for the administration of microbicides. This work describes the pharmacokinetic (PK) evaluation of rapidly disintegrating vaginal tablets containing tenofovir (TFV, 10 mg), emtricitabine (FTC, 10 mg), and the combination of TFV and FTC (10 mg each) under in vitro and in vivo conditions, and in direct comparison to the clinical TFV 1% gel, a microbicide product in Phase III clinical testing. The PK of TFV and FTC from tablets were also evaluated in female rabbits following intravaginal administration. Direct comparison of a single dose of TFV tablets (intact or predissolved at 10 mg/mL) and TFV 1% gel showed no differences in the vaginal PK of TFV between groups; however systemic bioavailability of TFV was significantly higher from the gel. When rabbits were dosed either once or daily for seven days with intact tablets of TFV, FTC, or the combination of TFV/FTC, vaginal and systemic concentrations of TFV and FTC were unaffected by co-formulation. Moreover, plasma PK parameters were similar following a single dose or seven once-daily doses. Tissue concentrations of TFV and FTC in the cranial vagina 4 h after administration ranged between 104 and 105 ng/g. Concentrations of TFV-diphospate (TFV-DP, the active metabolite) were also high (over 103 ng/g or about 3000 to 6000 fmol/mg) in the cranial vagina 4 h after administration and similar to those measured following administration of TFV 1% gel. These data demonstrate that rapidly disintegrating vaginal tablets may be a suitable topical microbicide dosage form providing similar vaginal TFV PK to that of TFV 1% gel. The data also support co administration of FTC with TFV in a single vaginal tablet to create a combination microbicide in a simple and inexpensive dosage form. PMID- 25494203 TI - Global protected area expansion is compromised by projected land-use and parochialism. AB - Protected areas are one of the main tools for halting the continuing global biodiversity crisis caused by habitat loss, fragmentation and other anthropogenic pressures. According to the Aichi Biodiversity Target 11 adopted by the Convention on Biological Diversity, the protected area network should be expanded to at least 17% of the terrestrial world by 2020 (http://www.cbd.int/sp/targets). To maximize conservation outcomes, it is crucial to identify the best expansion areas. Here we show that there is a very high potential to increase protection of ecoregions and vertebrate species by expanding the protected area network, but also identify considerable risk of ineffective outcomes due to land-use change and uncoordinated actions between countries. We use distribution data for 24,757 terrestrial vertebrates assessed under the International Union for the Conservation of Nature (IUCN) 'red list of threatened species', and terrestrial ecoregions (827), modified by land-use models for the present and 2040, and introduce techniques for global and balanced spatial conservation prioritization. First, we show that with a coordinated global protected area network expansion to 17% of terrestrial land, average protection of species ranges and ecoregions could triple. Second, if projected land-use change by 2040 (ref. 11) takes place, it becomes infeasible to reach the currently possible protection levels, and over 1,000 threatened species would lose more than 50% of their present effective ranges worldwide. Third, we demonstrate a major efficiency gap between national and global conservation priorities. Strong evidence is shown that further biodiversity loss is unavoidable unless international action is quickly taken to balance land-use and biodiversity conservation. The approach used here can serve as a framework for repeatable and quantitative assessment of efficiency, gaps and expansion of the global protected area network globally, regionally and nationally, considering current and projected land-use pressures. PMID- 25494202 TI - Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. AB - Systematic interrogation of gene function requires the ability to perturb gene expression in a robust and generalizable manner. Here we describe structure guided engineering of a CRISPR-Cas9 complex to mediate efficient transcriptional activation at endogenous genomic loci. We used these engineered Cas9 activation complexes to investigate single-guide RNA (sgRNA) targeting rules for effective transcriptional activation, to demonstrate multiplexed activation of ten genes simultaneously, and to upregulate long intergenic non-coding RNA (lincRNA) transcripts. We also synthesized a library consisting of 70,290 guides targeting all human RefSeq coding isoforms to screen for genes that, upon activation, confer resistance to a BRAF inhibitor. The top hits included genes previously shown to be able to confer resistance, and novel candidates were validated using individual sgRNA and complementary DNA overexpression. A gene expression signature based on the top screening hits correlated with markers of BRAF inhibitor resistance in cell lines and patient-derived samples. These results collectively demonstrate the potential of Cas9-based activators as a powerful genetic perturbation technology. PMID- 25494204 TI - Zinc oxide nanowire-poly(methyl methacrylate) dielectric layers for polymer capacitive pressure sensors. AB - Polymer capacitive pressure sensors based on a dielectric composite layer of zinc oxide nanowire and poly(methyl methacrylate) show pressure sensitivity in the range of 2.63 * 10(-3) to 9.95 * 10(-3) cm(2) gf(-1). This represents an increase of capacitance change by as much as a factor of 23 over pristine polymer devices. An ultralight load of only 10 mg (corresponding to an applied pressure of ~0.01 gf cm(-2)) can be clearly recognized, demonstrating remarkable characteristics of these nanowire-polymer capacitive pressure sensors. In addition, optical transmittance of the dielectric composite layer is approximately 90% in the visible wavelength region. Their low processing temperature, transparency, and flexible dielectric film makes them a highly promising means for flexible touching and pressure-sensing applications. PMID- 25494205 TI - Effects of rye bread enriched with green tea extract on weight maintenance and the characteristics of metabolic syndrome following weight loss: a pilot study. AB - We examined whether the incorporation of green tea extract enriched rye bread (GTRB) into the diet can improve weight loss (WL) maintenance and control of abnormalities linked to metabolic syndrome (MS). A total of 55 obese men and women (mean age: 53.0+/-7.0 years, body mass index: 35.0+/-5.5 kg m(-2)) were recruited. The study had a single-blind randomized study design and consisted of an 8-week WL phase with low-energy calorie diet, followed by a 12-week weight maintenance (WM) phase. During the WM phase, the subjects were randomized into two groups, receiving either the control rye bread (control group) or the GTRB (intervention group). The ingestion of 280 and 360 g GTRB provided daily totals of 123.2 and 158.4 mg caffeine, and 188.3 and 242.1 mg of epigallocatechin gallate, for women and men, respectively. After the WL phase, subjects lost 7.3+/ 3.1 kg of their baseline body weight. GTRB intake did not significantly influence the maintenance of WL, high-density lipoprotein-cholesterol, triglycerides, and glucose concentrations. Although, it resulted in significant differences (mean difference [95% confidence interval]) between the treatment groups in the maintenance of waist circumference (-1.22 cm [-2.4, -0.02; P=.04]), the results were not clinically meaningful. Nevertheless, the ingestion of GTRB led to the maintenance of lower blood pressure (BP), also the proportion of subjects fulfilling the criteria of MS after the WM phase was lower in the intervention group than in the control group. Although GTRB consumption did not improve significantly the WL maintenance, it resulted in a better control of BP. PMID- 25494206 TI - Oral Health Across the Life Course. PMID- 25494208 TI - The Economic Depression and Public Health Memorandum Prepared by the Health Section. PMID- 25494207 TI - No Exceptions: Documenting the Abortion Experiences of US Peace Corps Volunteers. AB - Since 1979, US federal appropriations bills have prohibited the use of federal funds from covering abortion care for Peace Corps volunteers. There are no exceptions; unlike other groups that receive health care through US federal funding streams, including Medicaid recipients, federal employees, and women in federal prisons, abortion care is not covered for volunteers even in cases of life endangerment, rape, or incest. We interviewed 433 returned Peace Corps volunteers to document opinions of, perceptions about, and experiences with obtaining abortion care. Our results regarding the abortion experiences of Peace Corps volunteers, especially those who were raped, bear witness to a profound inequity and show that the time has come to lift the "no exceptions" funding ban on abortion coverage. PMID- 25494209 TI - Media Use, Sports Participation, and Well-Being in Adolescence: Cross-Sectional Findings From the UK Household Longitudinal Study. AB - Objectives. We investigated the relationship between selected types of screen based media (SBM) use, total SBM use, sports participation, and markers of well being. Methods. Data came from the youth panel (n = 4899) of Understanding Society, the UK Household Longitudinal Study, conducted in 2009. Well-being was measured by the Strengths and Difficulties Questionnaire and markers of happiness in different life domains. Results. The majority of young people used multiple types of SBM for at least 1 hour per day; only 30% participated in sports every day. Overall, young people with heavy SBM use were less happy than moderate users and more likely to have socioemotional difficulties. Chatting on social networking Web sites and game console use were associated with higher odds of socioemotional problems. Higher total SBM use was associated with lower odds of happiness and higher odds of socioemotional difficulties. Greater participation in sports was associated with higher odds of happiness and lower odds of socioemotional difficulties. Conclusions. Further longitudinal research could inform future interventions to reduce sedentary behavior and encourage healthy lifestyles among young people. PMID- 25494212 TI - Autologous islet transplantation with remote islet isolation after pancreas resection for chronic pancreatitis. AB - IMPORTANCE: Autologous islet transplantation is an elegant and effective method for preserving euglycemia in patients undergoing near-total or total pancreatectomy for severe chronic pancreatitis. However, few centers worldwide perform this complex procedure, which requires interdisciplinary coordination and access to a sophisticated Food and Drug Administration-licensed islet-isolating facility. OBJECTIVE: To investigate outcomes from a single institutional case series of near-total or total pancreatectomy and autologous islet transplantation using remote islet isolation. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study between March 1, 2007, and December 31, 2013, at tertiary academic referral centers among 9 patients (age range, 13-47 years) with chronic pancreatitis and reduced quality of life after failed medical management. INTERVENTIONS: Pancreas resection, followed by transport to a remote facility for islet isolation using a modified Ricordi technique, with immediate transplantation via portal vein infusion. MAIN OUTCOMES AND MEASURES: Islet yield, pain assessment, insulin requirement, costs, and transport time. RESULTS: Eight of nine patients had successful islet isolation after near-total or total pancreatectomy. Four of six patients with total pancreatectomy had islet yields exceeding 5000 islet equivalents per kilogram of body weight. At 2 months after surgery, all 9 patients had significantly reduced pain or were pain free. Of these patients, 2 did not require insulin, and 1 required low doses. The mean transport cost was $16,527, and the mean transport time was 31/2 hours. CONCLUSIONS AND RELEVANCE: Pancreatic resection with autologous islet transplantation for severe chronic pancreatitis is a safe and effective final alternative to ameliorate debilitating pain and to help prevent the development of surgical diabetes. Because many centers lack access to an islet-isolating facility, we describe our experience using a regional 2-center collaboration as a successful model to remotely isolate cells, with outcomes similar to those of larger case series. PMID- 25494213 TI - Fetal Bovine Collagen Matrix in the Treatment of a Full Thickness Burn Wound: A Case Report With Long-Term Follow-Up. AB - The treatment of full thickness skin wounds commonly associated with large burns continues to represent a challenging clinical entity. The current treatment for large TBSA burns is split thickness autologous skin grafting; however, this treatment often results in poor textural durability, hypertrophic scarring, and fibrotic contractures. In this case report, we describe our experience and long term follow-up results after the application of fetal bovine collagen (FBC) matrix (PriMatrix, TEI Biosciences, Boston, MA) to burn wounds clinically assessed as full thickness that healed without the need for subsequent skin grafting. The patient presented with 25% TBSA burns and was debrided and covered with FBC on postburn day 7. By postoperative day 12, the patient had large areas of reepithelialization distributed throughout the wound bed. By postoperative day 26, the patient had significantly more areas of wound closure and was discharged. Reepithelialization and repigmentation continued, and long-term follow-up after 26 months demonstrated complete reepithelialization and nearly complete repigmentation, without the appearance of contractures or hypertrophic scarring. This case report highlights the use of FBC as a scaffold capable of dermal regeneration and spontaneous reepithelialization with an excellent long-term functional and cosmetic outcome. PMID- 25494217 TI - Early initiation of continuous renal replacement therapy improves clinical outcomes in patients with acute respiratory distress syndrome. AB - BACKGROUND: The acute respiratory distress syndrome (ARDS) is a common devastating syndrome in intensive care unit in critically ill patients. Continuous renal replacement therapy (CRRT) has been shown beneficial effects on oxygenation and survival in patients with ARDS. However, it is still controversial about the timing of initiation of CRRT. METHODS: Fifty-three patients with ARDS admitted to intensive care unit in Zhejiang Provincial People's Hospital, China from 2009 to 2013 were enrolled in the study. The authors compared ventilation parameter, including PaO2/FIO2, A-a gradient, positive end-expiratory pressure, plateau pressure, dynamic compliance and hemodynamic parameters, including central venous pressure, mean arterial pressure, cardiac index, extravascular lung water index, fluid balance between early initiation (within 12 hours after ARDS onset) and late initiation of CRRT (48 hours after ARDS onset) groups. The authors further investigated transforming growth factor (TGF)-beta1 level changes in serum and bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assay during 7 days of follow-up. RESULTS: Significant improvement of oxygenation and shorter duration of mechanical ventilation were observed in early CRRT group during 7-day follow-up. In addition, TGF-beta1 concentrations in serum and BALF were significantly decreased in patients with early initiation of CRRT compared to those with late initiation of CRRT on day 2 and day 7. Furthermore, patients who died of ARDS had higher levels of TGF-beta1 in BALF than survivors. CONCLUSIONS: Our findings showed that early initiation of CRRT is associated with favorable clinical outcomes in ARDS patients, which might be due to the reduced serum and BALF TGF-beta1 levels through CRRT. However, large multi-center studies are needed to make further recommendations as to the optimal use of CRRT in ARDS patient populations. PMID- 25494218 TI - Incorrigible hypokalemia caused by barium chloride ingestion. PMID- 25494214 TI - Induction of Covalently Crosslinked p62 Oligomers with Reduced Binding to Polyubiquitinated Proteins by the Autophagy Inhibitor Verteporfin. AB - Autophagy is a cellular catabolic process responsible for the degradation of cytoplasmic constituents, including organelles and long-lived proteins, that helps maintain cellular homeostasis and protect against various cellular stresses. Verteporfin is a benzoporphyrin derivative used clinically in photodynamic therapy to treat macular degeneration. Verteporfin was recently found to inhibit autophagosome formation by an unknown mechanism that does not require exposure to light. We report that verteporfin directly targets and modifies p62, a scaffold and adaptor protein that binds both polyubiquitinated proteins destined for degradation and LC3 on autophagosomal membranes. Western blotting experiments revealed that exposure of cells or purified p62 to verteporfin causes the formation of covalently crosslinked p62 oligomers by a mechanism involving low-level singlet oxygen production. Rose bengal, a singlet oxygen producer structurally unrelated to verteporfin, also produced crosslinked p62 oligomers and inhibited autophagosome formation. Co-immunoprecipitation experiments demonstrated that crosslinked p62 oligomers retain their ability to bind to LC3 but show defective binding to polyubiquitinated proteins. Mutations in the p62 PB1 domain that abolish self-oligomerization also abolished crosslinked oligomer formation. Interestingly, small amounts of crosslinked p62 oligomers were detected in untreated cells, and other groups noted the accumulation of p62 forms with reduced SDS-PAGE mobility in cellular and animal models of oxidative stress and aging. These data indicate that p62 is particularly susceptible to oxidative crosslinking and lead us to propose a model whereby oxidized crosslinked p62 oligomers generated rapidly by drugs like verteporfin or over time during the aging process interfere with autophagy. PMID- 25494219 TI - Bacteremia due to vancomycin-resistant Leuconostoc lactis in a patient with pneumonia and abdominal infection. PMID- 25494220 TI - All-organic optoelectronic sensor for pulse oximetry. AB - Pulse oximetry is a ubiquitous non-invasive medical sensing method for measuring pulse rate and arterial blood oxygenation. Conventional pulse oximeters use expensive optoelectronic components that restrict sensing locations to finger tips or ear lobes due to their rigid form and area-scaling complexity. In this work, we report a pulse oximeter sensor based on organic materials, which are compatible with flexible substrates. Green (532 nm) and red (626 nm) organic light-emitting diodes (OLEDs) are used with an organic photodiode (OPD) sensitive at the aforementioned wavelengths. The sensor's active layers are deposited from solution-processed materials via spin-coating and printing techniques. The all organic optoelectronic oximeter sensor is interfaced with conventional electronics at 1 kHz and the acquired pulse rate and oxygenation are calibrated and compared with a commercially available oximeter. The organic sensor accurately measures pulse rate and oxygenation with errors of 1% and 2%, respectively. PMID- 25494221 TI - Orofacial granulomatosis responding to weekly azithromycin pulse therapy. PMID- 25494224 TI - Edition of March 2014, vol. 102 (3), Supl. 1, pg. 1-61. PMID- 25494223 TI - ACE I/D Gene Polymorphism in Children with Family History of Premature Coronary Disease. PMID- 25494222 TI - Cardiovascular Computed Tomography and Magnetic Resonance: History and Growing Impact in Brazil and in the World. PMID- 25494225 TI - Case 5/2014 - 41-Year-Old Woman with Rheumatic Disease and Previous Mitral Valve Repair with Pulmonary Embolism and Cardiogenic and Septic Shock. PMID- 25494226 TI - Multiple Benefits of Rehabilitation in a Patient with Heart and Renal Failure. PMID- 25494227 TI - Left Internal Mammary Artery Graft-to-Pulmonary Artery Fistula. PMID- 25494228 TI - Dengue vaccine development: strategies and challenges. AB - Infection with dengue virus may result in dengue fever or a more severe outcome, such as dengue hemorrhagic syndrome/shock. Dengue virus infection poses a threat to endemic regions for four reasons: the presence of four serotypes, each with the ability to cause a similar disease outcome, including fatality; difficulties related to vector control; the lack of specific treatment; and the nonavailability of a suitable vaccine. Vaccine development is considered challenging due to the severity of the disease observed in individuals who have acquired dengue-specific immunity, either passively or actively. Therefore, the presence of vaccine-induced immunity against a particular serotype may prime an individual to severe disease on exposure to dengue virus. Vaccine development strategies include live attenuated vaccines, chimeric, DNA-based, subunit, and inactivated vaccines. Each of the candidates is in various stages of preclinical and clinical development. Issues pertaining to selection pressures, viral interaction, and safety still need to be evaluated in order to induce a complete protective immune response against all four serotypes. This review highlights the various strategies that have been employed in vaccine development, and identifies the obstacles to producing a safe and effective vaccine. PMID- 25494229 TI - Temperature evolution of magnetic and transport behavior in 5d Mott insulator Sr2IrO4: significance of magneto-structural coupling. AB - We have investigated the temperature evolution of magnetism and its interrelation with structural parameters in the perovskite-based layered compound Sr2IrO4, which is believed to be a J(eff) = 1/2 Mott insulator. The structural distortion plays an important role in this material and induces a weak ferromagnetism in an otherwise antiferromagnetically ordered magnetic state with a transition temperature around 240 K. Interestingly, at low temperatures, below around 100 K, a change in the magnetic moment has been observed. Temperature dependent x-ray diffraction measurements show that sudden changes in structural parameters around 100 K are responsible for this. Resistivity measurements show insulating behavior throughout the temperature range across the magnetic phase transition. The electronic transport can be described with Mott's two-dimensional variable range hopping (VRH) mechanism, however, three different temperature ranges are found for VRH, which is a result of varying the localization length with temperature. A negative magnetoresistance (MR) has been observed at all temperatures in contrast to positive behavior generally observed in strongly spin-orbit coupled materials. The quadratic field dependence of MR implies the relevance of a quantum interference effect. PMID- 25494230 TI - Purpura fulminans managed with multi-limb amputation: substituted judgment and surrogate decision-making in the surgical management of necrotizing soft tissue infections. AB - BACKGROUND: Purpura fulminans (PF) is a rare but lethal complication of severe infection. Aggressive surgical debridement of irreversibly devitalized tissue improves survival frequently at the cost of disfigurement. The ethical dilemma of surrogate decision-making for these often incapacitated patients presents a unique challenge for acute care surgeons managing necrotizing soft tissue infections (NSTI). METHODS: Case presentation and scholarly discussion of substituted judgment. RESULTS: A previously healthy 72-y-old fisherman developed PF as a consequence of Neisseria meningiditis severe sepsis requiring bilateral partial finger amputations and bilateral below-knee amputations of the affected gangrenous extremities. Skin biopsy confirmed the clinical impression of disseminated intra-vascular coagulation (DIC). During his 55-d hospitalization, medical decisions were made by a surrogate because the patient's mental status failed to recover to his pre-morbid baseline. A literature review revealed a paucity of data on the accuracy of a health care agent's ability to represent a patient's preferences accurately in elective as well as emergency surgery. CONCLUSIONS: Patients with NSTI and the surgeons who care for them are often confronted with the need to make prompt decisions of radical debridement or amputation. These patients are frequently incapable of making these decisions because of the severity of systemic illness. In such cases, physicians must help patient surrogates or health care agents (when identified) navigate a complex process of acute interventions balancing known or inferred patient's wishes. We urge surgeons to become familiar with the concept of substituted judgment and the challenges of surrogate decision-making. PMID- 25494232 TI - Patient-Focused Drug Development: A New Direction for Collaboration. AB - CONTEXT: Patient-Focused Drug Development (PFDD) is a new initiative from the Food and Drug Administration (FDA) intended to bring patient perspectives into an earlier stage of product development. The goal is that patients will be able to provide context for benefit-risk assessments and input to review divisions, and also aid in the development of new assessment tools, study endpoints, and risk communications. This paper provides a summary on what is known to date about FDA's PFDD initiative and describes implications for patients, researchers, payers, and the biopharmaceutical industry. It also provides a roadmap for stakeholders to consider in defining their role in and in shaping PFDD's direction, and for expanding PFDD principles to conditions beyond the current 20 under FDA consideration. METHODS: A search was conducted of the peer-reviewed and gray literature using PubMed and Google. This included laws, FDA guidance documents, the peer-reviewed literature, and FDA presentations for content relevant to the search term "patient-focused drug development." FINDINGS: Currently, FDA activities within PFDD are limited to gaining patient insights through 20 disease-specific meetings. However, many stakeholders see the initiative much more generally as representing a broad shift toward patient centeredness in biopharmaceutical product development. CONCLUSIONS: Depending upon the trajectory taken and whether or not all PFDD aims are eventually addressed, the initiative has the potential to change product development in fundamental ways. Further research should explore how patient input on disease manifestation and treatment options is best ascertained from patients and documented before initiating and during drug development. PMID- 25494233 TI - Self-reported Usual Care for Self-directed Violence During the 6 Months Before Emergency Department Admission. AB - BACKGROUND: The literature describing the health services individuals receive before and following self-directed violence (SDV) is limited. OBJECTIVES: This study examines services received for the 6 months preceding admission to an urban county medical center emergency department (ED) for SDV. We predicted that individuals with at least 1 prior act of SDV in the past 6 months would have received more services than those for whom the index admission was their only recent act. METHODS: Participants were recruited from ED admissions during shifts selected to maximize representativeness. Participants (n=202) were interviewed using the Suicide Attempt Self-Injury Interview, Suicide Attempt Self-Injury Count, Treatment History Interview, Mini International Neuropsychiatric Interview, Brief Symptom Index, and SF-12. RESULTS: The majority of index acts of SDV (79%) were suicide attempts. The participants were characterized by low socioeconomic status, substantial symptomatology, low physical and mental health functioning, and multiple psychiatric diagnoses. In the preceding 6 months, 34% were admitted to a hospital and 56% received crisis services (including 44% in the ED). Although three quarters (76%) had seen an outpatient medical provider and most (70%) received psychotropic medications, less than half of the sample received psychiatric services (40%) or outpatient psychosocial treatment (48%). As predicted, utilization for most types of usual care was higher for those engaging in SDV in the 6 months preceding the index admission. CONCLUSION: Individuals admitted to this ED for SDV received inadequate outpatient psychosocial and psychiatric services despite severe illness and disability. PMID- 25494234 TI - The Effect of the Diffusion of the Surgical Robot on the Hospital-level Utilization of Partial Nephrectomy. AB - INTRODUCTION: The rapid diffusion of the surgical robot has been controversial because of the technology's high costs and its disputed marginal benefit. Some, however, have suggested that adoption of the robot may have improved care for patients with renal malignancy by facilitating partial nephrectomy, an underutilized, technically challenging procedure believed to be less morbid than radical nephrectomy. We sought to determine whether institutional acquisition of the robot was associated with increased utilization of partial nephrectomy. METHODS: We used all payer data from 7 states to identify 21,569 nephrectomies. These patient-level records were aggregated to the hospital-level then merged with the American Hospital Association Annual Survey and publicly available data on timing of robot acquisition. We used a multivariable difference-in-difference model to assess at the hospital-level whether robot acquisition was associated with an increase in the proportion of partial nephrectomy, adjusting for hospital nephrectomy volume, year of surgery, and several additional hospital-level factors. RESULTS: In the multivariable-adjusted differences-in-differences model, hospitals acquiring a robot between 2001 and 2004 performed a greater proportion of partial nephrectomy in both 2005 (29.9% increase) and 2008 (34.9% increase). Hospitals acquiring a robot between 2005 and 2008 also demonstrated a greater proportion of partial nephrectomy in 2008 (15.5% increase). In addition, hospital nephrectomy volume and urban location were also significantly associated with increased proportion of partial nephrectomy. CONCLUSIONS: Hospital acquisition of the surgical robot is associated with greater proportion of partial nephrectomy, an underutilized, guideline-encouraged procedure. This is one of the few studies to suggest robot acquisition is associated with improvement in quality of patient care. PMID- 25494236 TI - The goals of medicine: health? Joy? And lessons along the way. PMID- 25494235 TI - Methylation-dependent acyl transfer between polyketide synthase and nonribosomal peptide synthetase modules in fungal natural product biosynthesis. AB - Biochemical studies of purified and dissected fungal polyketide synthase and nonribosomal peptide synthetase (PKS-NRPS) hybrid enzymes involved in biosynthesis of pseurotin and aspyridone indicate that one alpha-methylation step during polyketide synthesis is a prerequisite and a key checkpoint for chain transfer between PKS and NRPS modules. In the absence of the resulting gamma methyl feature, the completed polyketide intermediate is offloaded as an alpha pyrone instead of being aminoacylated by the NRPS domain. These examples illustrate that precisely timed tailoring domain activities play critical roles in the overall programming of the iterative PKS (and NRPS) functions. PMID- 25494237 TI - Phytochemical profiles and antioxidant activity of different varieties of Adinandra Tea (Adinandra Jack). AB - Consumption of plant foods has been negatively associated with the risk of developing chronic diseases, which is partly attributed to their rich and diverse phytochemicals. To promote the rational and effective application of Adinandra tea (Adinandra Jack), a traditional Chinese tea (Shiyacha) widely consumed as a health beverage, the complete phytochemical profile and antioxidant activity of four varieties of Adinandra tea were analyzed. They were rich in phenolics and flavonoids, ranging from 71.29 to 140.54 mg of gallic acid equivalent/g and from 19.13 to 88.72 mg of catechin equivalent/g, respectively. Their antioxidant capacities were high, as revealed by oxygen radical absorbance capacity, peroxyl radical scavenging capacity, and cellular antioxidant activity (CAA) assays. An obvious antiproliferation effect was observed in HepG2 and MCF-7 cells, with EC50 ranging from 1.05 to 6.44 mg/mL and from 2.26 to 8.02 mg/mL, respectively. Among the four varieties compared, Nitida and Millettii had a higher CAA value and antiproliferation activity, while Latifolia contained considerable bound phenolics. PMID- 25494238 TI - Isolation and stereospecific synthesis of janolusimide B from a New Zealand collection of the bryozoan Bugula flabellata. AB - NMR-directed screening of New Zealand marine organisms has led to the isolation of the modified tripeptide janolusimide B from the common invasive bryozoan Bugula flabellata. The structure was established by NMR and MS analysis, degradative hydrolysis and derivatization, and stereoselective fragment synthesis. The bryozoan natural product is an N-methyl analogue of janolusimide, previously reported from the Mediterranean nudibranch Janolus cristatus, a species known to prey upon bryozoa. PMID- 25494240 TI - Erratum. PMID- 25494239 TI - Understanding the conformation transition in the activation pathway of beta2 adrenergic receptor via a targeted molecular dynamics simulation. AB - G protein coupled receptors (GPCRs) play a crucial role in regulating signal recognition and transduction through their activation. The conformation transition in the activation pathway is of particular importance for their function. However, it has been poorly elucidated due to experimental difficulties in determining the conformations and the time limitation of conventional molecular dynamics (CMD) simulation. Thus, in this work, we employed a targeted molecular dynamic (TMD) simulation to study the activation process from an inactive structure to a fully active one for beta2 adrenergic receptor (beta2AR). As a reference, 110 ns CMD simulations on wild beta2AR and its D130N mutant were also carried out. TMD results show that there is at least an intermediate conformation cluster in the activation process, evidenced by the principal component analysis and the structural and dynamic differences of some important motifs. It is noteworthy that the activation of the ligand binding site lags the G-protein binding site, displaying uncoupled correlation. Comparisons between the CMD and TMD results show that the D130N mutation significantly speeds up ICL2 and key ionic lock to enter into the intermediate state, which to some extent facilitates the activation involved in the NPxxY, DRY region and the separation between TM3 and TM6. However, the contribution from the D130N mutation to the activation of the ligand binding site could not be observed within the scale of 110 ns time. These observations could provide novel insights into previous studies for better understanding of the activation mechanism for beta2AR. PMID- 25494241 TI - Hydrogen bonds and ionic forms versus polymerization of imidazole at high pressures. AB - Imidazole (C3H4N2) is an important biomaterial for material research and applications. Our high-pressure Raman spectroscopic investigations combined with ab initio calculations on crystalline imidazole suggest that C-H---X (X = N, pi) and N-H---N intermolecular hydrogen bonding interactions largely influence the nature of its structural and polymeric transformations under pressure. At pressures around ~10 GPa, the reduction in the N---N distances close to the symmetrization limit and the emergence of the spectral features of the cationic form indicate the onset of proton disorder. The pressure-induced strengthening of the "blue-shifting hydrogen bonds" C-H---X (X = N, pi) in this compound is revealed by the Raman spectra and the ab initio calculations. No polymer phase was retrieved on release from the highest pressure of 20 GPa in this study. PMID- 25494242 TI - Validation of an Activity Monitor in Older Inpatients Undergoing Slow Stream Rehabilitation. AB - BACKGROUND: Older adults undergoing rehabilitation may have limited mobility, slow gait speeds and low levels of physical activity. Devices used to quantify activity levels in older adults must be able to detect these characteristics. OBJECTIVE: To investigate the validity of the Positional Activity Logger (PAL2) for monitoring position and measuring physical activity in older inpatients (slow stream rehabilitation). METHODS: Twelve older inpatients (>=65 years) underwent a 1-hour protocol (set times in supine, sitting, standing; stationary and moving). Participants were video-recorded while wearing the PAL2. Time spent in positions and walking (comfortable and fast speeds) were ascertained through video recording analysis and compared with PAL2 data. RESULTS: There was no difference between the PAL2 and video recording for time spent in any position (P-values 0.055 to 0.646). Walking speed and PAL2 count were strongly correlated (Pearson's r = .913, P < .01). The PAL2 was responsive to within-person changes in gait speed: activity count increased by an average of 52.47 units (95% CI 3.31, 101.63). There was 100% agreement for transitions between lying to sitting and < 1 transition difference between siting to standing. CONCLUSION: The PAL2 is a valid tool for quantifying activity levels, position transitions, and within person changes in gait speed in older inpatients. PMID- 25494243 TI - Innovative ophthalmology. PMID- 25494245 TI - Augmented surgical amounts for intermittent exotropia to prevent recurrence. AB - Purpose: The purpose was to evaluate the results of bilateral lateral rectus (BLR) recession which is based on augmented surgical amounts of classical surgical table of Parks' for basic and pseudo-divergence excess type intermittent exotropia [X(T)]. Materials and Methods: Patients with X(T) operated by the same surgeon and followed-up for at least 6 months were included. Patients with prior surgery, neurobehavioral and musculoskeletal conditions, strabismus different from that mentioned above X(T) were excluded. All the patients received BLR only. The amount of the recession was increased by the amount needed to correct 5 prism diopters (PD) more X(T) than what was measured. After the operation, 1 st week, 2 nd and 6 months measurements were recorded. The patients were grouped according to their 1 st week (3-7 days) postoperative examination as: >10 PD esotropia (Group 1), <=10 PD esotropia (Group 2), exotropia (Group 3), and orthotropic (Group 4), respectively. Final surgical outcomes were classified as "good" (<=10 PD exotropia and <=5 PD esotropia), "recurrence" (>10 PD exotropia) and "overcorrected" (>5 esotropia). Results: Thirty-seven patients were included. The mean age was 6.78 +/- 2.87 years (range: 2-12 years). Mean preoperative deviation was 29.72 +/- 8.07 PD (range: 15-45 PD) at distance and 20.94 +/- 11.65 PD (range: 10-45 PD) at near (P < 0.0001). There were 21 (56.8%) patients in Group 1, 9 (24.3%) patients in Group 2, 1 (2.7%) patient in Group 3 and 6 (16.2%) patients in Group 4. Initial esotropia was achieved in 30 (30/37) of the patients. Twenty-eight of them had good results at the end of the 6 months. Overall "motor surgical" success rate was found to be 89.2% (33/37 patients), with 1 (2.7%) overcorrection and 3 (8.1%) recurrences at the end of the 6 months. Conclusion: This study demonstrated that early overcorrection of 10-20 PD after X(T) surgery can achieve acceptable motor outcomes in the first 6 months postoperative period. PMID- 25494244 TI - Scanning laser polarimetry in glaucoma. AB - Glaucoma is an acquired progressive optic neuropathy which is characterized by changes in the optic nerve head and retinal nerve fiber layer (RNFL). White-on white perimetry is the gold standard for the diagnosis of glaucoma. However, it can detect defects in the visual field only after the loss of as many as 40% of the ganglion cells. Hence, the measurement of RNFL thickness has come up. Optical coherence tomography and scanning laser polarimetry (SLP) are the techniques that utilize the evaluation of RNFL for the evaluation of glaucoma. SLP provides RNFL thickness measurements based upon the birefringence of the retinal ganglion cell axons. We have reviewed the published literature on the use of SLP in glaucoma. This review elucidates the technological principles, recent developments and the role of SLP in the diagnosis and monitoring of glaucomatous optic neuropathy, in the light of scientific evidence so far. PMID- 25494246 TI - Choroidal thickness profi le in healthy Indian subjects. AB - Purpose: The aim was to study choroidal thickness (CT) and its profile based on location in healthy Indian subjects using Cirrus high definition (HD) optical coherence tomography. Materials and Methods: A total of 211 eyes of 115 healthy subjects with no retinal or choroidal disease were consecutively scanned using Cirrus HD 1 line raster scan mode without pupillary dilation. Eyes with any ocular disease or axial length (AXL) >24 mm or <20 mm were excluded. Experienced technician measured CT from the lower border of the retinal pigment epithelium (RPE) to the lower border of choroid. CT was measured from the posterior edge of the RPE to the choroid/sclera junction at 500-MUm intervals up to 3000 MUm temporal and nasal to the fovea. Generalized estimating equations were used to evaluate the correlation between CT at various locations and age, AXL, spherical equivalent, and macular thickness. Results: Mean age was 42.8 +/- 13.6 years. Mean AXL was 22.84 +/- 0.78 mm. Median spherical equivalent was 0.16 +/- 0.64 D. Mean central macular thickness was 216.4 +/- 30.03 MUm. Choroidal was thinnest nasally and thickest subfoveally. On multivariate regression, age was the most significant factor affecting subfoveal CT (P = 0.000). Regression analysis showed an approximate decrease in CT of 1.18 MUm every year. Conclusions: Our study provides CT profile in Indian healthy subjects in various age groups. CT depends on its location, subfoveal being the thickest and nasal being the thinnest. Age is a critical factor, which is negatively correlated with CT. PMID- 25494247 TI - Effect of the color of the intraocular lens on optical and visual quality. AB - Purpose: To analyze the optical quality of intraocular lenses (IOL) with an orange (PC440Y) and a yellow (SN60AT) filter, and correlate these results with the visual quality of patients with these implants. Setting: Fisabio Oftalmolognua Miotadica, Valencia, Spain. Design: Randomized prospective study. Materials and Methods: The IOL optical quality was determined using the modulation transfer function (MTF) and the spectral transmission. The visual quality of 87 eyes with cataract (51 with orange filter and 36 with yellow filter) was determined by best corrected visual acuity (BCVA) and contrast sensitivity function (CSF) under photopic and mesopic conditions. To analyze the results, we use a Student's t-test. Results: Orange lens filtered more of the blue spectrum (cut-off wavelength of 370 nm) than the yellow lens (390 nm). The MTF of the yellow lens was better than the orange lens (average modulation of 0.676 for natural and 0.672 for orange). The patients' BCVA was 0.02 + 0.10 logMAR for both lenses. The CSF obtained with the yellow lens was slightly better, although without statistically significant differences (P > 0.05). Conclusions: Both lenses are of good optical quality. The patients' visual quality was similar with both lenses, and optical quality was also similar. The color of the lens does not affect the visual quality of the patient. PMID- 25494248 TI - High-risk histomorphological features in retinoblastoma and their association with p53 expression: An Indian experience. AB - Introduction: Histopathological features in retinoblastoma are considered high risk factors (HRF) for tumor progression and metastasis, thus their presence becomes an indication for adjuvant chemotherapy. Present study was undertaken to evaluate the incidence of HRF in retinoblastoma and to correlate them with p53 expression. Materials and Methods: This was a retrospective study where 17 diagnosed cases of retinoblastoma were included. Cases were re-evaluated for various histomorphological parameters. Immuno-histochemical analysis was done with p53 antibody by Streptavidin biotin method. Results: The patients were in the age range of 1.5-50 years. Common histological features included necrosis (70.5%), calcification (64.7%), and retinal detachment (58.8%). Incidence of various morphological parameters was anterior chamber seeding (47.2%), ciliary body involvement (29.4%), iris involvement (29.4%), choroid involvement (58.8%), scleral invasion (29.4%), extrascleral invasion (11.8%), and optic nerve infiltration (23.5%). p53 expression was present in four cases out of 13 cases (30.7%) and showed a significant association with choroid invasion (P = 0.02). Discussion: The presence of HRF should alert the physician for a possible metastasis, and such patients should be kept on regular follow-up to detect an early recurrence. p53 expression, a known poor prognostic indicator, showed significant association with choroid invasion, however, no association was seen with other HRF. Conclusion: Histopathological HRF have significant therapeutic and prognostic implications. The incidence of HRF is higher in developing countries as patients present with a more advanced stage of disease. p53 expression is significantly associated with choroid invasion out of all HRF. PMID- 25494249 TI - Diurnal variation in central corneal thickness and intraocular pressure in eyes with pseudoexfoliation syndrome without glaucoma. AB - Aim: The aim was to ascertain if any differences exist in diurnal central corneal thickness (CCT) and intra-ocular pressure (IOP) between eyes with pseudoexfoliation (PXF) syndrome without glaucoma and eyes with no ocular pathology. A secondary aim was to determine whether there was a significant relationship between CCT and IOP. Settings and Design: This study was a prospective design conducted within a hospital setting. Materials and Methods: The experimental group consisted of seven participants with bilateral PXF (14 eyes) and the control group comprised of 15 participants (30 eyes). Testing included CCT and IOP measured at four different times on one given day (8.00 a.m.; 11 a.m.; 2 p.m. and 5 p.m.). Statistical Analysis: The data were analyzed with the generalized linear latent mixed model. Results: PXF eyes displayed a significantly thinner overall mean CCT (520 MUm) compared to controls (530 MUm). Furthermore, a significant reduction in CCT and IOP occurred in the PXF group from 8 a.m. to 5 p.m. The mean overall IOP in PXF eyes was significantly lower than the control group. A significant association between IOP and CCT was also found in PXF eyes. Conclusions: Displaying a significantly thinner mean CCT highlights the importance of measuring CCT in an ophthalmic clinical setting as to avoid falsely underestimated IOP measurements in such a high-risk glaucoma population. Furthermore, a statistically significant correlation between IOP and CCT in PXF eyes suggests that the reduction in CCT that occurred in PXF eyes between 8 a.m. and 5 p.m. may be partly responsible for the reduction in IOP measurements. PMID- 25494250 TI - Maximizing the visual outcome in traumatic cataract cases: The value of a primary posterior capsulotomy and anterior vitrectomy. AB - Objective: The objective was to provide evidence-based care for patients with traumatic cataracts, we assessed whether a posterior capsulotomy and anterior vitrectomy, as part of the primary surgical procedure, could be a positive predictor of final visual outcome. Materials and Methods: This is a prospective randomized control trial. Patients presenting at our hospital between January 2010 and December 2012 having ocular trauma and traumatic cataracts were enrolled, according to the inclusion criteria. We enrolled two groups: Those with and without primary posterior capsulotomy and vitrectomy. Information regarding demographic and ocular trauma were collected using the World Eye Trauma Registry form at the first visit and follow-up, and specific information was collected for both the group who underwent posterior capsulectomies and vitrectomies as a part of the primary procedure, and the control group. Data were analyzed to evaluate the predictive value of primary posterior capsulectomy and anterior vitrectomy. Results: We enrolled 120 cases, 60 in each group, comprising 31 females and 89 males. When all other variables were controlled for, the visual outcome (best corrected visual acuity) differed significantly (P < 0.001) between the groups. Conclusion: Performance of posterior capsulectomy and anterior vitrectomy as part of the primary procedure improves the final visual outcome. PMID- 25494251 TI - Rectifying calibration error of Goldmann applanation tonometer is easy! AB - Purpose: Goldmann applanation tonometer (GAT) is the current Gold standard tonometer. However, its calibration error is common and can go unnoticed in clinics. Its company repair has limitations. The purpose of this report is to describe a self-taught technique of rectifying calibration error of GAT. Materials and Methods: Twenty-nine slit-lamp-mounted Haag-Streit Goldmann tonometers (Model AT 900 C/M; Haag-Streit, Switzerland) were included in this cross-sectional interventional pilot study. The technique of rectification of calibration error of the tonometer involved cleaning and lubrication of the instrument followed by alignment of weights when lubrication alone didn't suffice. We followed the South East Asia Glaucoma Interest Group's definition of calibration error tolerance (acceptable GAT calibration error within +/-2, +/-3 and +/-4 mm Hg at the 0, 20 and 60-mm Hg testing levels, respectively). Results: Twelve out of 29 (41.3%) GATs were out of calibration. The range of positive and negative calibration error at the clinically most important 20-mm Hg testing level was 0.5 to 20 mm Hg and -0.5 to -18 mm Hg, respectively. Cleaning and lubrication alone sufficed to rectify calibration error of 11 (91.6%) faulty instruments. Only one (8.3%) faulty GAT required alignment of the counter-weight. Conclusions: Rectification of calibration error of GAT is possible in-house. Cleaning and lubrication of GAT can be carried out even by eye care professionals and may suffice to rectify calibration error in the majority of faulty instruments. Such an exercise may drastically reduce the downtime of the Gold standard tonometer. PMID- 25494252 TI - Anterior migration of dexamethasone implant in a pseudophakic patient with intact posterior capsule. AB - Intravitreal application of Ozurdex (r) (Allergan, Inc., Irvine, CA, USA) which is a biodegradable, sustained-release dexamethasone implant has been reported to be effective in the treatment of macular edema. Migration of such implant into the anterior chamber has been recently described in cases without perfect zonular or the posterior capsular integrity. Herein, we report the first case with anterior migration of Ozurdex (r) implant that mislocated just behind the intraocular lens (IOL) in an intact capsular bag. It is thought that such implant migrated anteriorly towards into the posterior chamber through weak zonules as the present case had a medical history of uneventful phacoemulsification surgery with the implantation of posterior chamber IOL. However, the migrated implant was well tolerated since there was no sign of the corneal complication, rise in intraocular pressure, and anterior chamber reaction. Close follow-up was scheduled to find out any signs of anterior segment pathology. Meanwhile dexamethasone implant completely degraded at the 4 th month of postoperative follow-up. PMID- 25494253 TI - Publish or perish: The art of scientific writing. AB - Publishing manuscripts is the only way by which scientists communicate with each other. In recent times, there is an increasing desire to publish manuscripts from the developing world for a variety of reasons. Though, performing a research study is challenging in itself, writing it for publication is the final frontier that can be daunting, especially for the novice. Work that remains unpublished in one form or the other is essentially incomplete or undone. Hence, it is critically important for one to publish one's findings in a reputed journal. The purpose of this paper is to alleviate the mystique involved in manuscript writing and provide a blueprint where the subheadings given under each of the sections of introduction, methods, results and discussion can be expanded as per the particular study and the manuscript can be constructed in a stepwise manner. We hope that by following this approach, potential researchers and practicing ophthalmologists will develop the skill and aptitude for medical writing, and that the developing world shall do justice to its tremendous intellectual capital by making meaningful contributions to global scientific literature. PMID- 25494254 TI - Preoperative corneal astigmatism among adult patients with cataract in Northern Nigeria. AB - The prevalence and nature of corneal astigmatism among patients with cataract has not been well-documented in the resident African population. This retrospective study was undertaken to investigate preexisting corneal astigmatism in adult patients with cataract. We analyzed keratometric readings acquired by manual Javal-Schiotz keratometry before surgery between January 1, 2011 and December 31, 2011. There were 3,169 patients (3286 eyes) aged between 16 and 110 years involved with a Male to female ratio of 1.4:1. Mean keratometry in diopters was K1 = 43.99 and K2 = 43.80. Mean corneal astigmatism was 1.16 diopter and a majority (45.92%) of eyes had astigmatism between 1.00 and 1.99 diopters. Two thirds of the eyes (66.9%) in this study had preoperative corneal astigmatism equal to or above 1.00 diopter. Findings will help local cataract surgeons to estimate the potential demand for toric intraocular lenses. PMID- 25494255 TI - Novel surgical technique for the management of partial cryptophthalmos. AB - We report a case of a 2-month-old baby with bilateral nonsyndromic partial cryptophthalmos presenting with upper eyelid incomplete development and fusion to the cornea with resultant inability to close the eyes. He was managed successfully with bilateral upper lid reconstruction with composite graft using maternal skin and oral mucous membrane, amniotic membrane, and donor scleral graft. After this one stage surgery, lids were well-formed, and the patient was able to close both eyes, thus achieving good anatomical, functional, and cosmetic outcome. PMID- 25494256 TI - An intraorbital metallic foreign body. PMID- 25494257 TI - 0.5% Proparacain hydrochloride for clear corneal phacoemulsification in patients with co-morbid conditions. PMID- 25494258 TI - Improving the outcome of prosthetic rehabilitation following orbital exenteration. PMID- 25494259 TI - Multimedia interventions on the informed consent process for cataract surgery. PMID- 25494260 TI - Posttraumatic horseshoe-shaped macular tear. PMID- 25494261 TI - Repeat fluid- gas exchange for failed primary macular hole surgery. PMID- 25494262 TI - Glaucoma caused by isolated microspherophakia: A long story. PMID- 25494263 TI - Choroidal thickness in high-altitude sickness. PMID- 25494264 TI - Macular hemorrhage as a cause of acute angle closure - Photodynamic therapy and polypoidal choroidal vasculopathy. PMID- 25494265 TI - Antitrust enforcement in health care--controlling costs, improving quality. PMID- 25494266 TI - Integrating oral and general health care. PMID- 25494267 TI - The disease of the little paper. PMID- 25494268 TI - Racial and ethnic disparities among enrollees in Medicare Advantage plans. AB - BACKGROUND: Differences in the control of blood pressure, cholesterol, and glucose among the various racial and ethnic groups of Medicare enrollees may contribute to persistent disparities in health outcomes. METHODS: Among elderly enrollees in Medicare Advantage health plans in 2011 who had hypertension (94,171 persons), cardiovascular disease (112,039), or diabetes (105,848), we compared the respective age-and-sex-adjusted proportions with blood pressure lower than 140/90 mm Hg, low-density lipoprotein cholesterol levels below 100 mg per deciliter (2.6 mmol per liter), and a glycated hemoglobin value of 9.0% or lower, according to race or ethnic group. Comparisons were made nationally and within regions and health plans, and changes since 2006 were assessed. RESULTS: Black enrollees in 2006 and 2011 were substantially less likely than white enrollees to have adequate control of blood pressure (adjusted absolute differences in proportions of enrollees in the 2 years, 7.9 percentage points and 10.3 percentage points, respectively), cholesterol (11.4 percentage points and 10.2 percentage points, respectively), and glycated hemoglobin (10.1 percentage points and 9.4 percentage points, respectively) (P<0.001 for all comparisons). Differing distributions of enrollees among health plans accounted for 39 to 59% of observed disparities in 2011. These differences persisted in 2011 in the Northeast, Midwest, and South (6.9 to 14.1 percentage points, P<0.001 for all comparisons) but were eliminated in the West for all three measures (<1.5 percentage points, P>=0.15). Hispanic enrollees were less likely than whites in 2011 to have adequate control of blood pressure (adjusted difference, 1.6 percentage points), cholesterol (adjusted difference, 1.0 percentage points), and glycated hemoglobin (adjusted difference, 3.4 percentage points) (P<=0.02 for all comparisons). Asians and Pacific Islanders were more likely than whites to have adequate control of blood pressure (difference, 4.4 percentage points; P<0.001) and cholesterol (5.5 percentage points, P<0.001) and had similar control of glycated hemoglobin (0.3 percentage points, P=0.63). CONCLUSIONS: Disparities in control of blood pressure, cholesterol, and glucose have not improved nationally for blacks in Medicare Advantage plans, but these disparities were eliminated in the West in 2011. (Funded by the National Institute on Aging.). PMID- 25494269 TI - Quality and equity of care in U.S. hospitals. AB - BACKGROUND: Nearly every U.S. hospital publicly reports its performance on quality measures for patients who are hospitalized for acute myocardial infarction, heart failure, or pneumonia. Because performance rates are not reported according to race or ethnic group, it is unclear whether improvements in equity of care have accompanied aggregate improvements in health care quality over time. METHODS: We assessed performance rates for quality measures covering three conditions (six measures for acute myocardial infarction, four for heart failure, and seven for pneumonia). These rates, adjusted for patient- and hospital-level covariates, were compared among non-Hispanic white, non-Hispanic black, and Hispanic patients who received care between 2005 and 2010 in acute care hospitals throughout the United States. RESULTS: Adjusted performance rates for the 17 quality measures improved by 3.4 to 57.6 percentage points between 2005 and 2010 for white, black, and Hispanic adults (P<0.001 for all comparisons). In 2005, as compared with adjusted performance rates for white patients, adjusted performance rates were more than 5 percentage points lower for black patients on 3 measures (range of differences, 12.3 to 14.2) and for Hispanic patients on 6 measures (5.6 to 14.5). Gaps decreased significantly on all 9 of these measures between 2005 and 2010, with adjusted changes for differences between white patients and black patients ranging from -8.5 to -11.8 percentage points and from -6.2 to -15.1 percentage points for differences between white patients and Hispanic patients. Decreasing differences according to race or ethnic group were attributable to more equitable care for white patients and minority patients treated in the same hospital, as well as to greater performance improvements among hospitals that disproportionately serve minority patients. CONCLUSIONS: Improved performance on quality measures for white, black, and Hispanic adults hospitalized for acute myocardial infarction, heart failure, or pneumonia was accompanied by increased racial and ethnic equity in performance rates both within and among U.S. hospitals. (Funded by the Centers for Medicare and Medicaid Services and the Veterans Affairs Health Services Research and Development Career Development Program.). PMID- 25494270 TI - Lactic acidosis. PMID- 25494271 TI - Images in clinical medicine. Palpitations after dinner. PMID- 25494272 TI - Case records of the Massachusetts General Hospital. Case 38-2014. An 87-year-old man with sore throat, hoarseness, fatigue, and dyspnea. PMID- 25494273 TI - How to achieve health equity. PMID- 25494274 TI - Muscling in on depression. PMID- 25494275 TI - Neprilysin inhibition for heart failure. PMID- 25494276 TI - Neprilysin inhibition for heart failure. PMID- 25494277 TI - Neprilysin inhibition for heart failure. PMID- 25494278 TI - Neprilysin inhibition for heart failure. PMID- 25494279 TI - Prehospital ticagrelor in ST-segment elevation myocardial infarction. PMID- 25494280 TI - Prehospital ticagrelor in ST-segment elevation myocardial infarction. PMID- 25494281 TI - Prehospital ticagrelor in ST-segment elevation myocardial infarction. PMID- 25494282 TI - Prehospital ticagrelor in ST-segment elevation myocardial infarction. PMID- 25494283 TI - Influenza vaccination of pregnant women and protection of their infants. PMID- 25494284 TI - Influenza vaccination of pregnant women and protection of their infants. PMID- 25494285 TI - Dependent coverage and use of preventive care under the Affordable Care Act. PMID- 25494286 TI - Images in clinical medicine. Esophageal duplication cyst. PMID- 25494288 TI - Kaposi sarcoma incidence in Mozambique: national and regional estimates. AB - Kaposi sarcoma is expressed in four clinical variants, all associated with human herpes virus type 8 infection, namely, classic, endemic, immunosuppression related and AIDS-related. The latter currently accounts for most of the burden of Kaposi sarcoma in sub-Saharan Africa, reflecting the frequency of HIV infection and its management. We aimed to estimate the incidence of Kaposi sarcoma in Mozambique and in its provinces. We estimated the number of incident cases of Kaposi sarcoma by adding up the expected number of endemic and AIDS-related cases. The former were estimated from the rates observed in Kyandondo, Uganda (1960-1971). The latter were computed from the number of AIDS-related deaths in each region, assuming that the ratio between the AIDS-related Kaposi sarcoma incident cases and the number of AIDS-related deaths observed in the city of Beira applies to all regions. A total of 3862 Kaposi sarcoma cases were estimated to have occurred in Mozambique in 2007, mostly AIDS-related, in the age group 25 49 years, and in provinces from South/Centre. The age-standardized incidence rates were 36.1/100 000 in men and 11.5/100 000 in women, with a more than three fold variation across provinces. We estimated a high incidence of Kaposi sarcoma in Mozambique, along with large regional differences. These results can be used to improve disease management and to sustain political decisions on health policies. PMID- 25494287 TI - Enhanced MyoD-induced transdifferentiation to a myogenic lineage by fusion to a potent transactivation domain. AB - Genetic reprogramming holds great potential for disease modeling, drug screening, and regenerative medicine. Genetic reprogramming of mammalian cells is typically achieved by forced expression of natural transcription factors that control master gene networks and cell lineage specification. However, in many instances, the natural transcription factors do not induce a sufficiently robust response to completely reprogram cell phenotype. In this study, we demonstrate that protein engineering of the master transcription factor MyoD can enhance the conversion of human dermal fibroblasts and adult stem cells to a skeletal myocyte phenotype. Fusion of potent transcriptional activation domains to MyoD led to increased myogenic gene expression, myofiber formation, cell fusion, and global reprogramming of the myogenic gene network. This work supports a general strategy for synthetically enhancing the direct conversion between cell types that can be applied in both synthetic biology and regenerative medicine. PMID- 25494289 TI - Abolishing mammography screening programs? PMID- 25494290 TI - Association of molecular subtypes with breast cancer risk factors: a case-only analysis. AB - As breast cancer (BC) screening identifies many BCs with a good prognosis, which might be overdiagnosed and therefore overtreated, the identification of subgroups with a high risk for aggressive subtypes might be helpful. The aim of this case case analysis was to investigate the association between epidemiological risk factors and molecular subtypes in a cohort of BC patients. Epidemiological risk factors for 2587 BC patients were obtained using a structured questionnaire and from the patients' charts. The histopathological information (estrogen and progesterone receptor, HER2 and Ki-67) used in the analysis was retrieved from the original pathology reports. Analyses using conditional inference regression trees were carried out on these data. The strongest influence factor on the distribution of the molecular subtypes was age at first diagnosis of BC. An influence of BMI was also identified in patients aged either more than 42 years or 49.6 years or less. Older patients aged more than 49.6 years and perimenopausal women with a BMI of 32.4 kg/m or less were most likely to develop luminal A-like BC. Young patients aged 42 years or less and perimenopausal patients with a BMI more than 32.4 kg/m more often developed triple-negative BC. The study confirmed that age at diagnosis is an important factor influencing the distribution of molecular subtypes. In the perimenopausal group, it may be postulated that BMI plays a critical role in the pathogenesis of BC, defining a subgroup that is more likely to develop triple-negative BC or luminal B-like disease and another group in which there is a more postmenopausal distribution pattern. PMID- 25494291 TI - Visceral adipose tissue and the risk of colorectal adenomas: a meta-analysis of observational studies. AB - Visceral adipose tissue (VAT)-related metabolic syndromes are hypothesized to promote colorectal neoplasia; however, the results from studies investigating whether VAT directly measured by computed tomography is a risk factor for colorectal adenomas (CRA) have been inconsistent. We carried out a meta-analysis of epidemiological studies to quantitatively assess this association and dose response relationship between VAT and the risk of CRA. We searched PubMed for relevant studies that were published in any language, from January, 1950 to June, 2010. Three case-control studies and eight cross-sectional studies involving 11 111 participants contributed toward this meta-analysis. We pooled the odds ratio (OR) from individual studies and carried out dose-response, heterogeneity, and publication bias analyses. In a pooled analysis of all studies, the amount of VAT (in a comparison of the highest and lowest categories) was associated with an increased risk of CRA (OR=1.67, 95% confidence interval: 1.29-2.16). Subgroup meta-analyses by both sexes, VAT measurements, study designs, and Asian ethnicity yielded similar results. An increase of 500 cm of VAT volume was related to an increased risk of CRA from the dose-response meta-analysis (OR=1.06; 95% confidence interval: 1.03-1.11). These results suggest that a large amount of VAT measured by computed tomography significantly increases the risk of CRA both in men and in women. PMID- 25494292 TI - Analysis of clinical indexes and RUNX3, TBKBP1, PPARGC1B polymorphisms in Chinese Han patients with ankylosing spondylitis. AB - BACKGROUND: Ankylosing spondylitis (AS) is a genetically determined disease. Runt related transcription factor 3 (RUNX3), tumor necrosis factor family member associated NF-kappaB activator binding kinase 1 binding protein (TBKBP1), and peroxisome proliferator-activated receptor-gamma coactivator 1 beta (PPARGC1B) have recently been found to be associated with susceptibility to AS in patients of Western European descent. We hypothesize that these three genes may be related to clinical outcomes of Chinese Han AS patients. METHODS: Blood samples were drawn from 396 HLA-B27-positive Chinese Han AS patients. Clinical indexes were scored for each patient, including the Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), which measure patients' function of daily life and severity of AS. Twelve tagSNPs were selected from these three genes and genotyped. We analyzed the clinical indexes in different genotyped patients to investigate the relationship between severity of AS and different genotypes. RESULTS: The rs11249215 SNP in RUNX3 and the rs7379457 and rs32579 SNPs in PPARGC1B significantly affect the BASFI score in patients. The rs11249215, rs7551188, and rs1395621 SNPs in RUNX3 significantly affect the BASDAI scores. The two selected single nucleotide polymorphisms (SNPs) in TBKBP1 show no relationship with the clinical outcomes. None of the 12 SNPs is related to mSASSS. In conclusion, RUNX3 is related to both the severity of AS and the function of daily life. PPARGC1B is related to the function of daily life. PMID- 25494293 TI - Implantation and atomic-scale investigation of self-interstitials in graphene. AB - Crystallographic defects play a key role in determining the properties of crystalline materials. The new class of two-dimensional materials, foremost graphene, have enabled atomically resolved studies of defects, such as vacancies,1-4 grain boundaries,(5-7) dislocations,(8,9) and foreign atom substitutions.(10-14) However, atomic resolution imaging of implanted self interstitials has so far been reported neither in any three-dimensional nor in any two-dimensional material. Here, we deposit extra carbon into single-layer graphene at soft landing energies of ~ 1 eV using a standard carbon coater. We identify all the self-interstitial dimer structures theoretically predicted earlier,(15-17) employing 80 kV aberration-corrected high-resolution transmission electron microscopy. We demonstrate accumulation of the interstitials into larger aggregates and dislocation dipoles, which we predict to have strong local curvature by atomistic modeling, and to be energetically favorable configurations as compared to isolated interstitial dimers. Our results contribute to the basic knowledge on crystallographic defects and lay out a pathway into engineering the properties of graphene by pushing the crystal into a state of metastable supersaturation. PMID- 25494294 TI - Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges. AB - Protein kinases are important mediators of cellular communication and attractive drug targets for many diseases. Although success has been achieved with developing ATP-competitive kinase inhibitors, the disadvantages of ATP competitive inhibitors have led to increased interest in targeting sites outside of the ATP binding pocket. Kinase inhibitors with substrate-competitive, ATP noncompetitive binding modes are promising due to the possibility of increased selectivity and better agreement between biochemical and in vitro potency. However, the difficulty of identifying these types of inhibitors has resulted in significantly fewer small molecule substrate phosphorylation site inhibitors being reported compared to ATP-competitive inhibitors. This review surveys reported substrate phosphorylation site inhibitors and methods that can be applied to the discovery of such inhibitors, including a discussion of the challenges inherent to these screening methods. PMID- 25494295 TI - Noninvasive approaches for detecting and monitoring bladder cancer. AB - Bladder cancer is the second most common cancer of the urinary tract. Despite existing multiapproach treatment strategies, including radical cystectomy, bladder-sparing therapy with transurethral resection, chemotherapy and radiotherapy, patients with deeply invasive bladder cancers display poor prognosis, with a survival rate of only 30-50%. This can be avoided through proper surveillance and monitoring. Several genetic factors contribute to the progression of bladder cancer, and these molecules serve as cancer biomarkers. Blood, plasma, serum and urine are commonly analyzed for the presence of biomarkers, which can be both nuclear as well as mitochondrial in nature. This review discusses the efficacy of such biomarkers as well as highlights some potential prognostic markers in the field of noninvasive bladder cancer detection. PMID- 25494297 TI - Low-Iodine-Load and Low-Tube-Voltage CT Angiographic Imaging of the Kidney by Using Bolus Tracking with Saline Flushing. AB - PURPOSE: To prospectively determine the feasibility of low-iodine-load and low tube-voltage computed tomographic (CT) angiographic imaging of the kidney and to evaluate the opacification and image quality compared with moderate-iodine-load and high-iodine-load techniques. MATERIALS AND METHODS: Institutional review board approval and written informed consent was obtained. One hundred thirteen consecutive patients randomly underwent three protocols for dual-phase renal CT angiographic imaging: high-iodine-load (600 mg iodine per kilogram of body weight at 120 kVp); moderate-iodine-load (400 mg iodine per kilogram of body weight at 80 kVp); and low-iodine-load (contrast agent injection initially prepared at 400 mg iodine per kilogram of body weight but stopped immediately after bolus tracking trigger at 80 kVp) scanning. CT numbers of vessels and kidneys were measured. CT numbers and signal-to-noise ratio (SNR) were compared with one-way analysis of variance and posthoc Tukey-Kramer test and depiction of vessels and image noise, with Kruskal-Wallis test and pair-wise Mann-Whitney test with Bonferroni correction. RESULTS: Mean iodine weight administered was significantly reduced in order of low- (16.4 g), moderate- (23.5 g), and high-iodine-load (33.7 g) protocols (P < .001). Mean CT numbers of abdominal aorta, renal artery, and renal cortex in first phase were significantly lower with high-iodine-load protocol (308, 274, and 132 HU, respectively) than with moderate- (347, 334, and 156 HU, respectively; P = .001-.006) or low-iodine-load (362, 316, and 161 HU, respectively; P = .001-.003) protocol. Mean CT number of renal vein in second phase was significantly lower with low-iodine-load protocol (223 HU) than with moderate- (299 HU; P < .001) or high-iodine-load (258 HU; P = .020). Mean SNR of renal medulla in second phase was significantly lower (P = .019) with moderate iodine-load protocol (mean SNR, 7.2) than with high-iodine-load protocol (mean SNR, 10.0). No significant difference in image quality grades was found between high-iodine-load (mean grade, 2.6-2.9), moderate-iodine-load (mean grade, 2.6 3.0), and low-iodine-load (mean grade, 2.6-2.9) protocols (P = .018-.31). CONCLUSION: Combined application of low-iodine-load, bolus tracking with saline flushing, and low-tube-voltage scanning is feasible and resulted in substantial reduction of iodine dose for renal CT angiographic imaging without compromising image quality. PMID- 25494296 TI - Cobalt(III)-catalyzed synthesis of indazoles and furans by C-H bond functionalization/addition/cyclization cascades. AB - The development of operationally straightforward and cost-effective routes for the assembly of heterocycles from simple inputs is important for many scientific endeavors, including pharmaceutical, agrochemical, and materials research. In this article we describe the development of a new air-stable cationic Co(III) catalyst for convergent, one-step benchtop syntheses of N-aryl-2H-indazoles and furans by C-H bond additions to aldehydes followed by in situ cyclization and aromatization. Only a substoichiometric amount of AcOH is required as an additive that is both low-cost and convenient to handle. The syntheses of these heterocycles are the first examples of Co(III)-catalyzed additions to aldehydes, and reactions are demonstrated for a variety of aromatic, heteroaromatic, and aliphatic derivatives. The syntheses of both N-aryl-2H-indazoles and furans have been performed on 20 mmol scales and should be readily applicable to larger scales. The reported heterocycle syntheses also demonstrate the use of directing groups that have not previously been applied to Co(III)-catalyzed C-H bond functionalizations. Additionally, the synthesis of furans demonstrates the first example of Co(III)-catalyzed functionalization of alkenyl C-H bonds. PMID- 25494298 TI - Multiple sclerosis: myeloperoxidase immunoradiology improves detection of acute and chronic disease in experimental model. AB - PURPOSE: To test if MPO-Gd, a gadolinium-based magnetic resonance (MR) imaging probe that is sensitive and specific for the proinflammatory and oxidative enzyme myeloperoxidase (MPO), which is secreted by certain inflammatory cells, is more sensitive than diethylenetriaminepentaacetic acid (DTPA)-Gd in revealing early subclinical and chronic disease activity in the brain in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. MATERIALS AND METHODS: The protocol for animal experiments was approved by the institutional animal care committee. A total of 61 female SJL mice were induced with EAE. Mice underwent MPO-Gd- or DTPA-Gd-enhanced MR imaging on days 6, 8, and 10 after induction, before clinical disease develops, and during chronic disease at remission and the first relapse. Brains were harvested at these time points for flow cytometric evaluation of immune cell subtypes and immunohistochemistry. Statistical analysis was performed, and P < .05 was considered to indicate a significant difference. RESULTS: MPO-Gd helps detect earlier (5.2 vs 2.3 days before symptom onset, P = .004) and more (3.1 vs 0.3, P = .008) subclinical inflammatory lesions compared with DTPA-Gd, including in cases in which there was no evidence of overt blood-brain barrier (BBB) breakdown detected with DTPA-Gd enhancement. The number of MPO-Gd-enhancing lesions correlated with early infiltration of MPO-secreting monocytes and neutrophils into the brain (r = 0.91). MPO-Gd also helped detect more lesions during subclinical disease at remission (5.5 vs 1.3, P = .006) and at the first relapse (9.0 vs 2.7, P = .03) than DTPA-Gd, which also correlated well with the presence and accumulation of MPO-secreting inflammatory cells in the brain (r = 0.93). CONCLUSION: MPO-Gd specifically reveals lesions with inflammatory monocytes and neutrophils, which actively secrete MPO. These results demonstrate the feasibility of detection of subclinical inflammatory disease activity in vivo, which is different from overt BBB breakdown. PMID- 25494299 TI - Biochemical Properties and Biological Functions of FET Proteins. AB - Members of the FET protein family, consisting of FUS, EWSR1, and TAF15, bind to RNA and contribute to the control of transcription, RNA processing, and the cytoplasmic fates of messenger RNAs in metazoa. FET proteins can also bind DNA, which may be important in transcription and DNA damage responses. FET proteins are of medical interest because chromosomal rearrangements of their genes promote various sarcomas and because point mutations in FUS or TAF15 can cause neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. Recent results suggest that both the normal and pathological effects of FET proteins are modulated by low-complexity or prion like domains, which can form higher-order assemblies with novel interaction properties. Herein, we review FET proteins with an emphasis on how the biochemical properties of FET proteins may relate to their biological functions and to pathogenesis. PMID- 25494300 TI - Structure, dynamics, assembly, and evolution of protein complexes. AB - The assembly of individual proteins into functional complexes is fundamental to nearly all biological processes. In recent decades, many thousands of homomeric and heteromeric protein complex structures have been determined, greatly improving our understanding of the fundamental principles that control symmetric and asymmetric quaternary structure organization. Furthermore, our conception of protein complexes has moved beyond static representations to include dynamic aspects of quaternary structure, including conformational changes upon binding, multistep ordered assembly pathways, and structural fluctuations occurring within fully assembled complexes. Finally, major advances have been made in our understanding of protein complex evolution, both in reconstructing evolutionary histories of specific complexes and in elucidating general mechanisms that explain how quaternary structure tends to evolve. The evolution of quaternary structure occurs via changes in self-assembly state or through the gain or loss of protein subunits, and these processes can be driven by both adaptive and nonadaptive influences. PMID- 25494301 TI - The twin-arginine protein translocation pathway. AB - The twin-arginine translocation (Tat) system, found in prokaryotes, chloroplasts, and some mitochondria, allows folded proteins to be moved across membranes. How this transport is achieved without significant ion leakage is an intriguing mechanistic question. Tat transport is mediated by complexes formed from small integral membrane proteins from just two protein families. Atomic-resolution structures have recently been determined for representatives of both these protein families, providing the first molecular-level glimpse of the Tat machinery. I review our current understanding of the mechanism of Tat transport in light of these new structural data. PMID- 25494302 TI - Veritas per structuram. AB - When I entered graduate school in 1963, the golden age of molecular biology had just begun, and myoglobin was the only protein with a known high-resolution structure. The romance of working out the structure of a virus by X-ray crystallography nonetheless captured both my imagination and the ensuing 15 years of my scientific life, during which "protein crystallography" began to morph into "structural biology." The course of the research recounted here follows the broader, 50-year trajectory of structural biology, as I could rarely resist opportunities to capitalize on new technologies when they opened some interesting part of biology to three-dimensional rigor. That fascination shows no sign of subsiding. PMID- 25494303 TI - Progesterone receptor gene (PROGINS) polymorphism correlates with late onset of migraine. AB - Progesterone influences central neuronal excitability, a key event in migraine pathophysiology. Progesterone receptor gene (PGR) rs1042838 (G/T - Val660Leu) variant is indicative of PROGINS haplotype and associated to a reduced PGR activity. With the aim of investigating whether any type of association existed between this genetic variant and migraine pathophysiology, genotyping was performed in 380 consecutive migraine patients and 185 age-, sex-, and race ethnicity-matched healthy controls from Interinstitutional Multidisciplinary BioBank (BioBIM) of IRCCS San Raffaele Pisana, Rome, Italy. rs1042838 genotypes did not correlate with demographics or clinical migraine features. However, TT (Leu) genotype was significantly associated with a later age of migraine onset: Patients affected by migraine with aura showed a linear relationship between copy number of the T allele carried by the individual and the age of migraine onset. Our data suggest that the PROGINS PGR polymorphism does not directly predispose to migraine but significantly delays migraine onset probably via a reduction in brain neuronal excitability. PMID- 25494304 TI - On-chip cavity-enhanced absorption spectroscopy using a white light-emitting diode and polymer mirrors. AB - We have developed a disposable microfluidic chip with integrated cavity mirrors comprised of two pieces of 3M VikuitiTM enhanced specular reflector II (ESRII) film, for performing cavity-enhanced absorption spectroscopy with a white light emitting diode (LED). Compared to measurements made with a chip without cavity mirrors, the absorption path length is enhanced by a maximum factor of 28 at 544 nm, and the sensitivity is enhanced by approximately 5 times, enabling micromolar range detection limits to be achieved in an optical path length of only 50 MUm. PMID- 25494305 TI - Synthesis and reactivity of NHC-based rhodium macrocycles. AB - Using a general synthetic procedure employing readily accessed terminal alkene functionalized pro-ligands and macrocyclization by ring-closing olefin metathesis, rhodium carbonyl complexes have been prepared that contain lutidine (1a; n = 1) and pyridine (1b; n = 0) derived tridentate CNC macrocycles with dodecamethylene spacers. In solution, 1a shows temperature-invariant time averaged C2 symmetry by (1)H NMR spectroscopy (CD2Cl2, 500 MHz), whereas in the solid-state, two polymorphs can be obtained showing different conformations of the alkyl spacer about the metal-carbonyl bond (asymmetric and symmetric). In contrast, time-averaged motion of alkyl spacer in 1b can be halted by cooling below 225 K (CD2Cl2, 500 MHz), and the complex crystallizes as a dimer with an interesting unsupported Rh...Rh bonding interaction (3.2758(6) A). Oxidative addition reactions of 1a and 1b, using MeI and PhICl2, have been studied in situ by (1)H NMR spectroscopy, although pure Rh(III) adducts can be ultimately isolated only with the pyridine-based macrocyclic ligand. The lutidine backbone of 1a can be deprotonated by addition of K[N(SiMe3)2], and the resulting neutral dearomatized complex (5) has been fully characterized in solution, by variable temperature (1)H NMR spectroscopy, and in the solid state, by X-ray diffraction. PMID- 25494306 TI - To Crowdfund Research, Scientists Must Build an Audience for Their Work. AB - As rates of traditional sources of scientific funding decline, scientists have become increasingly interested in crowdfunding as a means of bringing in new money for research. In fields where crowdfunding has become a major venue for fundraising such as the arts and technology, building an audience for one's work is key for successful crowdfunding. For science, to what extent does audience building, via engagement and outreach, increase a scientist's abilities to bring in money via crowdfunding? Here we report on an analysis of the #SciFund Challenge, a crowdfunding experiment in which 159 scientists attempted to crowdfund their research. Using data gathered from a survey of participants, internet metrics, and logs of project donations, we find that public engagement is the key to crowdfunding success. Building an audience or "fanbase" and actively engaging with that audience as well as seeking to broaden the reach of one's audience indirectly increases levels of funding. Audience size and effort interact to bring in more people to view a scientist's project proposal, leading to funding. We discuss how projects capable of raising levels of funds commensurate with traditional funding agencies will need to incorporate direct involvement of the public with science. We suggest that if scientists and research institutions wish to tap this new source of funds, they will need to encourage and reward activities that allow scientists to engage with the public. PMID- 25494307 TI - A sensitive electrochemical aptasensor based on the co-catalysis of hemin/G quadruplex, platinum nanoparticles and flower-like MnO2 nanosphere functionalized multi-walled carbon nanotubes. AB - In this work, a sensitive electrochemical aptasensor for the detection of thrombin (TB) is developed and demonstrated based on the co-catalysis of hemin/G quadruplex, platinum nanoparticles (PtNPs) and flower-like MnO2 nanosphere functionalized multi-walled carbon nanotubes (MWCNT-MnO2). PMID- 25494308 TI - Re: Janssen MM, Kouwenhoven JW, Schlosser TP, et al. Analysis of pre-existent vertebral rotation in the normal infantile, juvenile, and adolescent spine. Spine 2011;36:E486-91. doi: 10.1097/BRS.0b013e3181f468cc. PMID- 25494309 TI - The association between insurance status and complications, length of stay, and costs for pediatric idiopathic scoliosis. AB - STUDY DESIGN: Observational cross-sectional population study using national sample of pediatric hospital discharges from 2000 to 2009. OBJECTIVE: To determine whether there is an association between insurance status and in hospital surgical outcome for pediatric patients with idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Association between health insurance status and in hospital surgical outcome after spinal fusion for pediatric idiopathic scoliosis is unknown. METHODS: An analysis of the Healthcare Cost and Utilization Project Kids' Inpatient Database 2000, 2003, 2006, and 2009 was performed. Patients aged 0 to younger than 18 years with idiopathic scoliosis and no underlying neurological disorders who underwent fusion were included. National trends, patient, hospital and surgical characteristics, postoperative in-hospital complications, and associated factors were studied. Univariate analysis and multivariable logistic regressions were used. RESULTS: An estimated 19,439 surgical procedures (Medicaid 4766 vs. private 14,673) were performed for pediatric idiopathic scoliosis from 2000 to 2009 in the United States. Spinal fusions for pediatric idiopathic scoliosis steadily increased from 2000 to 2009 by 18.0%. Patients with private insurance were more likely to undergo surgery than patients with Medicaid insurance (7.7 vs. 5.9 per 100,000 capita; P = 0.003). Patients with private insurance were slightly older than patients with Medicaid insurance at the time of surgery (mean age = 13.9 yr vs. 13.4 yr; P < 0.001). Patients with Medicaid insurance had a higher prevalence of asthma (10.8% vs. 7.4%; P < 0.001), hypertension (1.4% vs. 0.4%; P < 0.001), hyperlipidemia (0.3% vs. 0.1%; P = 0.01), diabetes (0.8% vs. 0.3%; P < 0.001), and obesity (2.6% vs. 1.5%; P < 0.001). Patients with Medicaid insurance underwent more fusions involving 9 or more vertebrae than private patients (43.0% vs. 33.9%; P < 0.001). Postoperative in-hospital complications, including neurological (Medicaid 1.8% vs. private 1.7%; P = 0.64) and infectious (Medicaid 0.3% vs. private 0.2%; P = 0.44), were similar. Length of stay was longer (6.1 d vs. 5.6 d; P < 0.001) and hospital costs were higher ($45,443 vs. $41,635; P < 0.001) for patients with Medicaid insurance. Surgery performed in the South and Midwest regions, older age, and female sex were associated with lower rates of in-hospital neurological complications, whereas the presence of cardiac disease, obesity, and refusion were associated with higher rates of in-hospital neurological complications. CONCLUSION: Patients with Medicaid insurance were younger, underwent longer fusions, and had more medical comorbidities than patients with private insurance. However, insurance status was not associated with an increased rate of postoperative in-hospital complications. LEVEL OF EVIDENCE: 4. PMID- 25494310 TI - Spinal osteotomy techniques in management of severe pediatric spinal deformity and analysis of postoperative complications. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To compare radiographical analysis and clinical outcomes of spinal osteotomy techniques, including Smith Petersen osteotomy (SPO), pedicle subtraction osteotomy (PSO), and vertebral column resection (VCR), and analyze the relationship between preoperative evaluation and postoperative complication incidence. SUMMARY OF BACKGROUND DATA: These 3 techniques have been extensively reported previously, whereas, few literatures are available on comparing these 3 techniques in management of severe pediatric spinal deformity. METHODS: In all the 34 pediatric patients, 14 were treated with SPO, 12 were treated with PSO, and 8 were treated with VCR. All operations were performed by the senior author (L. X.) between 2005 and 2009 in the Institute of Spinal Deformity, The First Affiliated Hospital of Zhengzhou University. Preoperative Halo-gravity traction was applied for 2 weeks in all patients; patients were evaluated by using standing radiographs taken before and after traction and after operation and a prospectively collected database with outcomes questionnaires. The postoperative complications and its relationship to preoperative assessment were also analyzed in this study. RESULTS: All the 34 patients' severe pediatric spinal deformity (22 females and 12 males) was diagnosed, with an average age of 11.97 years (range, 6-17 yr) and an average follow-up of 66.38 months (range, 48-97 mo). The mean preoperative major curve for each group was 103.43o in the SPO group, 108.08o in the PSO group, and 117.00o in the VCR group, and was corrected to 15.21o, 16.83o, and 25.88o, respectively. The apical vertebral translation was corrected by 73.29% by SPO, 73.35% by PSO, and 59.71% by VCR. The coronal balance was improved from 16.57 mm to 1.50 mm in the SPO group, 17.33 mm to 3.83 mm in the PSO group, and 29.38 mm to 3.63 mm in the VCR group. The mean correction of the kyphotic angle for single SPO was 19.00o, for those with 2 and 3 SPOs, the average correction was 34.40o and 47.5o, and 33.83o for the PSO group, 47.38o for the VCR group. There were significant improvements in the overall clinical outcomes. The overall complication rate was 35.3%. The complication rate was high in patients with respiratory insufficiency and rigid spine. CONCLUSION: There was no significant difference in coronal correction among these 3 techniques, whereas, the average corrections in the sagittal plane were progressively higher from single SPO to 2 SPOs or PSO to 3 SPOs or VCR. Preoperative respiratory insufficiency and rigidity of the spinal deformity are associated with a high complication rate. LEVEL OF EVIDENCE: 3. PMID- 25494311 TI - Oxidative/Nitrosative Stress in Patients With Modic Changes: Preliminary Controlled Study. AB - STUDY DESIGN: Oxidative/nitrosative stress in vertebral endplates of patients with low back pain and Modic changes (MCs) (types I, II, and III) endplate changes on magnetic resonance imaging. OBJECTIVE: The aim of this study was to assess the levels of oxidative/nitrosative stress biomarkers in patients with MCs. SUMMARY OF BACKGROUND DATA: Degenerated discs and endplate abnormalities is postulated as a possible source of low back pain. Oxidative/nitrosative stress plays an important the role in various human diseases. However, the presence of oxidative/nitrosative stress has not been studied in patients with low back pain and endplate changes on magnetic resonance imaging. METHODS: Patients with MCI, II, and III (n = 32) and age- and sex-matched controls subjects (n = 15) were enrolled in this study. Also, 3-nitrotyrosine (3-NT) and nitric oxide levels as nitrosative stress biomarkers were measured with enzyme-linked immunosorbent assay. Also, the activities of catalase (CAT) and superoxide dismutase (SOD), and the levels of malondialdehyde (MDA) as oxidative stress biomarkers were determined on spectrophotometer. RESULTS: Oxidative/nitrosative stress was confirmed by the significant elevation in nitric oxide, 3-NT, MDA and decreased of CAT and SOD activities in MCI compared with other MCs and the control group (P < 0.05). The highest CAT and SOD activities were found in patients with MCII compared with the other MCs and the control group. However, the levels of nitric oxide, 3-NT, and MDA showed moderate increase in this group (P < 0.05). In addition, the levels of nitrosative stress biomarkers in patients with MCIII were approximated to the control values (P > 0.05). However, the levels of oxidative stress biomarkers in patients with MCIII were slightly higher than that of the control group (P < 0.05). CONCLUSION: Our findings indicated that oxidative/nitrosative stress in patients with MCI may be aggravated as a result of oxidant/antioxidant imbalance and it may cause formation of the lesion in these patients. However, the increased antioxidant activities and MDA, 3-NT levels in patients with MCII and MCIII may be an adaptative response to against oxidative/nitrosative stress. LEVEL OF EVIDENCE: 4. PMID- 25494312 TI - Re: Could biomechanics studies make no distinction between different segmental levels? PMID- 25494313 TI - The impact of the depression and anxiety on prognosis of cervical total disc replacement. AB - STUDY DESIGN: Prospective clinical study. OBJECTIVE: To identify changes in depression and anxiety after cervical total disc replacement (CTDR) among patients with cervical spondylosis, and to investigate their effects on the prognosis. SUMMARY OF BACKGROUND DATA: Previous researches have reported relationships between mood disorders and lumbar surgery. There have been no previous studies on the effects of depressive and anxiety on the CTDR outcome at the 2-year postoperative phase. METHODS: Eighty-five patients with cervical spondylosis who underwent CTDR were included. Patients were evaluated preoperatively and at 6 postoperative time points, including 1 week, 1 month, 3 months, 6 months, 1 year, and 2 years. Depression and anxiety were evaluated by using the Zung Self-Rating Depression Scale and the Zung Self-Rating Anxiety Scale. Neurological function was evaluated by using the visual analogue scale and the Japanese Orthopaedic Association. The quality of life was assessed by a 36 item Short-Form Health Survey. A Spearman rank correlation analysis was used. RESULTS: All patients had improvements in clinical symptoms and neurological function. Twelve (14.12%) patients had symptoms of depression and 21 (24.71%) patients had symptoms of anxiety. There was a significant difference between the preoperative and the postoperative Zung Self-Rating Anxiety Scale scores, whereas the Zung Self-Rating Depression Scale scores were not significantly different over time. For all patients, the visual analogue scale scores and the 36-item Short-Form Health Survey scores were associated with the postoperative level of depression and anxiety but not age or the Japanese Orthopaedic Association score. CONCLUSION: Some patients with cervical spondylosis have preoperative depression and/or anxiety. CTDR may provide some improvements in these psychological symptoms. The presence of depression and/or anxiety may have a negative influence on the patient's prognosis. LEVEL OF EVIDENCE: 3. PMID- 25494314 TI - Injectable gelatin used as hemostatic agent to stop pedicle bleeding in long deformity surgical procedures: does it embolize? AB - STUDY DESIGN: Prospective porcine animal model. OBJECTIVE: Determine if injecting FloSeal into pedicles for hemostasis causes emboli. SUMMARY OF BACKGROUND DATA: Bleeding from spinal deformity cases can be substantial, especially when surgical procedures involve bilateral fixation at multiple segments. It is not unusual to observe hemorrhage from vascular pedicles during each step of pedicle screw tract preparation. When multiple fixation points are required, blood loss can be excessive. To minimize estimated blood loss and associated morbidity, surgeons have injected liquefied gelatin into pedicles after drilling, palpating, and/or tapping. FloSeal is one of the most popular commercially available injectable agents and we sought to investigate the potential for embolization when used as an intrapedicular hemostatic agent. METHODS: Two adult minipigs were anesthetized and underwent sequential bilateral pedicle cannulation from T-spine to sacrum. At every level, tracts were cannulated, palpated, and tapped. In every tract, FloSeal was injected into each pedicle until back pressure was detected on the syringe or to a maximum volume of 2 mL, then pedicle screws were inserted. The right ventricular outflow tract was visualized real time using transesophageal echocardiography. Postmortem evaluation of heart and lungs was performed. RESULTS: FloSeal injected into pedicles caused a consistent large showering of the right ventricular outflow tract in both pigs as visualized on intraoperative transesophageal echocardiography. A second large showering occurred during screw insertion after FloSeal was injected. Microscopic examination of lungs clearly identified amphophilic amorphous material in many small vessels consistent with FloSeal. CONCLUSION: This study suggests caution when injecting gelatin hemostatic agents into pedicles to stop bleeding during spinal surgery as we saw clear evidence of fat and gelatin emboli when used in this animal model. Further investigation into how to minimize this embolic showering may help the cardiopulmonary at risk patient who requires spinal surgery, especially when multiple points of pedicle screw fixation are used. LEVEL OF EVIDENCE: N/A. PMID- 25494315 TI - Risk of traumatic injury associated with chiropractic spinal manipulation in Medicare Part B beneficiaries aged 66 to 99 years. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: In older adults with a neuromusculoskeletal complaint, to evaluate risk of injury to the head, neck, or trunk after an office visit for chiropractic spinal manipulation compared with office visit for evaluation by primary care physician. SUMMARY OF BACKGROUND DATA: The risk of physical injury due to spinal manipulation has not been rigorously evaluated for older adults, a population particularly vulnerable to traumatic injury in general. METHODS: We analyzed Medicare administrative data on Medicare B beneficiaries aged 66 to 99 years with an office visit in 2007 for a neuromusculoskeletal complaint. Using a Cox proportional hazards model, we evaluated for adjusted risk of injury within 7 days, comparing 2 cohorts: those treated by chiropractic spinal manipulation versus those evaluated by a primary care physician. We used direct adjusted survival curves to estimate the cumulative probability of injury. In the chiropractic cohort only, we used logistic regression to evaluate the effect of specific chronic conditions on likelihood of injury. RESULTS: The adjusted risk of injury in the chiropractic cohort was lower than that of the primary care cohort (hazard ratio, 0.24; 95% confidence interval, 0.23-0.25). The cumulative probability of injury in the chiropractic cohort was 40 injury incidents per 100,000 subjects compared with 153 incidents per 100,000 subjects in the primary care cohort. Among subjects who saw a chiropractic physician, the likelihood of injury was increased in those with a chronic coagulation defect, inflammatory spondylopathy, osteoporosis, aortic aneurysm and dissection, or long-term use of anticoagulant therapy. CONCLUSION: Among Medicare beneficiaries aged 66 to 99 years with an office visit risk for a neuromusculoskeletal problem, risk of injury to the head, neck, or trunk within 7 days was 76% lower among subjects with a chiropractic office visit than among those who saw a primary care physician. LEVEL OF EVIDENCE: 3. PMID- 25494316 TI - Re: Two-year follow-up evaluation of surgical treatment for thoracolumbar fracture dislocation. PMID- 25494317 TI - Effects of nuclear factor kappa B signaling pathway in human intervertebral disc degeneration. AB - STUDY DESIGN: IL-1beta (interleukin-1beta) can activate human nucleus pulposus cells with or without nuclear factor kappa B (NF-kappaB) inhibition. We undertook a descriptive and mechanistic investigation of catabolic effects of NF-kappaB signaling pathway in intervertebral disc degenerative changes. OBJECTIVE: To clarify the mediatory role of NF-kappaB signaling pathway in human intervertebral disc degeneration (IDD). SUMMARY OF BACKGROUND DATA: IDD is a major cause of lower back pain, but the molecular mechanism behind this process is poorly understood. NF-kappaB is a family of transcription factors that play a central role in mediating cellular response to damage, stress, and inflammation. Growing evidence implicates chronic activation of NF-kappaB in many degenerative diseases, but its role in IDD has not been adequately explored. METHODS: Human nucleus pulposus cells in monolayer culture were exposed to IL-1beta, which increases matrix-degrading enzyme activity in the nucleus pulposus, with or without NF-kappaB inhibition by BAY11-7082; ribonucleic acid was isolated for real-time polymerase chain reaction analysis of gene expression, Western blot analysis was performed to detect the changes of protein expression. RESULTS: NF kappaB specific inhibitor BAY11-7082 significantly inhibited IL-1beta-induced NF kappaB activation. IL-1beta-dependent gene upregulation of matrix metalloproteinase (MMP)-3, MMP-9, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, and ADAMTS-5 was significantly reduced by NF-kappaB inhibition. The decreased gene expression of aggrecan and type II collagen, induced by IL-1beta was also reversed by BAY11-7082. NF-kappaB inhibition reversed the IL-1beta-induced changes of protein expression of MMP-3, MMP-9, MMP-13, ADAMTS-4, ADAMTS-5, aggrecan, and type II collagen. CONCLUSION: These findings demonstrate that the NF-kappaB signaling pathway is a key mediator of IDD and represents a therapeutic target for mitigating disc degenerative diseases. LEVEL OF EVIDENCE: N/A. PMID- 25494318 TI - Effect of disc degeneration on lumbar segmental mobility analyzed by kinetic magnetic resonance imaging. AB - STUDY DESIGN: Retrospective radiographical study. OBJECTIVE: To define the relationship between the grade of disc degeneration and the motion of the lumbar spine by using kinetic magnetic resonance imaging. SUMMARY OF BACKGROUND DATA: Disc degeneration is common after middle age. Lumbar instability has generally been recognized as a potential risk factor of low back pain. However, correlations between the grade of disc degeneration and the motion of the lumbar spine need more investigation. METHODS: Kinetic magnetic resonance imaging was performed in 162 patients with symptomatic low back pain without prior history of surgery. The lumbar intervertebral discs were graded by spine surgeons according to the degenerative grading system (grades I-V). Translational motion and angular variation were measured at each segment from L1-L2 through L5-S1. The relationship between the degree of lumbar disc degeneration and extent of lumbar spine mobility was analyzed. RESULTS: The translational motion in discs with grade I through IV increased gradually, but decreased with grade V. Compared with other less degenerative grades, grade V discs had significantly decreased total intervertebral translational motion (P < 0.05). The angular variation in discs with grade I through IV was fairly constant, but decreased with grade V. Compared with other degenerative grades (I-IV), grade V discs had significantly decreased total intervertebral translational motion (P < 0.05). For less degenerative grades I and II discs, the L2-L3 and L3-L4 segmental units contributed the majority of total angular mobility of the spine. However, for the severely degenerated segments, grade V discs, the contributions of the L2-L3 and L3-L4 significantly decreased (P < 0.01). CONCLUSION: As disc degeneration developed from the normal to an increasingly severe stage, the motion of lumbar spine progressed from the normal stage to an unstable phase with higher mobility and finally to an ankylosed stage where stability was increased. LEVEL OF EVIDENCE: 3. PMID- 25494319 TI - The reliability of sagittal pelvic parameters: the effect of lumbosacral instrumentation and measurement experience. AB - STUDY DESIGN: Sagittal pelvic parameters (SPPs) of a representative patient sample drawn from a consecutive adult spinal deformity database were measured using Surgimap Spine. Estimated coefficient of reliability intraclass coefficient (95% confidence interval), standard error of measurement, and mean absolute deviation were used for the analysis. OBJECTIVE: The primary objective of this study was to assess the reliability of SPP measurements using Surgimap Spine. The secondary objective was to evaluate the impact of pelvic instrumentation as well as the impact of user expertise. SUMMARY OF BACKGROUND DATA: The radiographical measurement of SPP is increasingly recognized as playing a critical role in establishing the surgical goals and surgical strategy of many spinal disorders. Although instrumented flatback is a common cause of sagittal malalignment, to our knowledge, SPP measurement reliability has never been assessed in instrumented spines. METHODS: Sixty-three adult full-spine standing lateral radiographs (31 with lumbosacral instrumentation) were measured twice by 13 observers using Surgimap Spine. Observers were stratified into 3 levels of experience: high (research coordinators, 4), mid (senior surgeons, 5), and low (junior surgeons, 4). Research coordinators trained all surgeons for less than 30 minutes. Parameters measured were pelvic incidence, pelvic tilt, and sacral slope. RESULTS: Thirteen observers and 63 radiographs generated 817 observations (2 misses). Overall inter- and intraobserver reliability of SPP measurement was excellent (intraclass coefficient > 0.85). Lumbosacral instrumentation did not modify intraobserver reliability but reduced significantly interobserver reliability of pelvic tilt (P = 0.006) and sacral slope (P = 0.007). Experience did not affect intraobserver reliability but interobserver reliability of highly experienced observers was significantly lower (P < 0.05) than among less experienced observers. CONCLUSION: Measurement of SPP using Surgimap Spine equals or improves previously reported reliability data. Lumbosacral instrumentation reduces interobserver reliability taking it from excellent to moderate in the sacral slope measurement. Inexperienced observers can measure SPP reliably after a short tutorial. LEVEL OF EVIDENCE: 4. PMID- 25494320 TI - Prevalence and risk factors for development of venous thromboembolism after degenerative spinal surgery. AB - STUDY DESIGN: Prospective clinical study. OBJECTIVE: To identify the incidence and risk factors for venous thromboembolism (VTE) associated with degenerative spinal surgery procedures at the different spinal levels for various pathologies. SUMMARY OF BACKGROUND DATA: Spinal surgery includes procedures for treatment of various pathologies at different spinal levels. There have been no studies on VTE after degenerative spinal surgery with respect to screening patients for both deep venous thrombosis and pulmonary thromboembolism (PE). METHODS: We prospectively investigated the occurrence of VTE after degenerative spinal surgery in 459 patients who were divided into 5 groups: group 1, patients with cervical degenerative disease treated with posterior decompression; group 2, patients with cervical degenerative disease treated with instrumentation for spinal fusion; group 3, patients with thoracolumbar degenerative disease treated with instrumentation for spinal fusion; group 4, patients with lumbar spinal stenosis treated with posterior decompression; and group 5, patients with lumbar spondylolisthesis treated with 1-level posterior lumbar interbody fusion. A deep venous thrombosis and PE screening was performed for all patients. Binomial logistic regression analysis was used to assess the association of risk factors. RESULTS: The incidence of VTE was 2.8%, 3.4%, 10.8%, 12.5%, and 10.1% in groups 1, 2, 3, 4, and 5, respectively. Female sex, advanced age, spinal level, and neurological deficits, were all risk factors. Cervical spinal surgery in particular had an associated low risk. In patients with PE, 3 of the 4 had no deep venous thrombosis, indicating that screening for PE is also needed in high risk patients. CONCLUSION: The prevalence of VTE after elective spinal surgery was different in each group. LEVEL OF EVIDENCE: 3. PMID- 25494321 TI - Single-level lumbar fusion for degenerative disc disease is associated with worse outcomes compared with fusion for spondylolisthesis in a workers' compensation setting. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: Compare lumbar fusion outcomes, return-to-work (RTW) status in particular, between workers' compensation (WC) subjects undergoing single-level posterolateral fusion for either spondylolisthesis or degenerative disc disease (DDD). SUMMARY OF BACKGROUND DATA: Lumbar fusion for spondylolisthesis tends to yield more consistent outcomes than fusion for DDD and discogenic low back pain. Within the clinically distinct WC population, relatively few studies exist that evaluate lumbar fusion outcomes. METHODS: A total of 889 Ohio WC subjects were identified that underwent single-level posterolateral lumbar fusion with or without posterior interbody fusion between 1993 and 2010 using Current Procedural Terminology procedural and International Classification of Diseases, Ninth Revision diagnostic codes. Of the total subjects, 269 underwent fusion for spondylolisthesis, and 620 underwent fusion for DDD. Subjects were considered to have returned-to-work (RTW) status within a reasonable timeline if they made a stable RTW within 2 years of fusion and remained working for greater than 6 months of the following year. To determine predictors of RTW status, we performed a multivariate logistic regression analysis. We measured a number of secondary outcomes. RESULTS: Fusion for spondylolisthesis was positively associated with RTW status (P = 0.050; odds ratio [OR], 1.42; 95% confidence interval [95% CI], 1.00-2.00). A total of 36.4% of the spondylolisthesis cohort and 24.4% of the DDD cohort returned to work in a reasonable timeline postoperatively. Other negative predictors included age more than 50 years at fusion (OR, 0.66; 95% CI, 0.45 0.95), time more than 2 years between injury and index fusion (OR, 0.59; 95% CI, 0.41-0.84), permanent disability (OR, 0.61; 95% CI, 0.43-0.86), legal representation (OR, 0.67; 95% CI, 0.46-0.97), and psychological comorbidity before fusion (OR, 0.30; 95% CI, 0.14-0.62). Subjects in the DDD cohort were prescribed opioid analgesics for an average of 294 of additional days postoperatively (P < 0.001), which equated to 24,759 additional milligrams of morphine equivalents (P < 0.001). CONCLUSION: Our study is supportive of the conclusion that DDD is a questionable indication for spinal fusion. Given the generally poor outcomes of this study, future studies should determine if lumbar fusion surgery is an effective treatment modality in similar patients with WC. LEVEL OF EVIDENCE: 3. PMID- 25494322 TI - Complications and survival after long posterior instrumentation of cervical and cervicothoracic fractures related to ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: This study investigates the results of long posterior instrumentation with regard to complications and survival. SUMMARY OF BACKGROUND DATA: Fractures of the cervical spine and the cervicothoracic junction related to ankylosing spinal disease (ASD) endanger both sagittal profile and spinal cord. Both anterior and posterior stabilization methods are well established, and clear treatment guidelines are missing. METHODS: Forty-one consecutive patients with fractures of the cervicothoracic junction related to ASD were treated by posterior instrumentation. All patients were followed prospectively for 2 years using a standardized protocol. RESULTS: Five patients experienced postoperative infections, 3 patients experienced postoperative pneumonia, 2 patients required postoperative tracheostomy, and 1 patient had postoperative cerebrospinal fluid leakage due to accidental durotomy. No patient required reoperation due to implant failure or nonunion. Mean survival was 52 months (95% confidence interval: 42-62 mo). Survival was affected by patient age, sex, smoking, and spinal cord injury. CONCLUSION: Patients with ASD experiencing a fracture of the cervicothoracic region are at high risk of developing complications. The posterior instrumentation of cervical spinal fractures related to ASD is recommended due to biomechanical superiority. LEVEL OF EVIDENCE: 4. PMID- 25494323 TI - Superion interspinous process spacer for intermittent neurogenic claudication secondary to moderate lumbar spinal stenosis: two-year results from a randomized controlled FDA-IDE pivotal trial. AB - STUDY DESIGN: Prospective, multicenter, randomized, controlled, investigational device exemption noninferiority trial. OBJECTIVE: To determine 2-year outcomes in patients with intermittent neurogenic claudication secondary to moderate lumbar spinal stenosis (LSS) who were treated with the Superion interspinous process spacer. SUMMARY OF BACKGROUND DATA: Interspinous spacers are a less-invasive treatment alternative compared with surgical decompression for patients with LSS unresponsive to conservative care. High-quality comparative data with these devices are lacking. METHODS: Patients presenting with intermittent neurogenic claudication secondary to moderate LSS who failed at least 6 months of nonsurgical management were randomly allocated to treatment with the Superion spacer or a control spacer (X-Stop) and followed for 2 years. RESULTS: A total of 391 randomized patients were implanted with Superion (n = 190) or control (n = 201) spacers at 29 sites in the United States between August 2008 and December 2011. Implants were successfully implanted in 99.5% of patients with Superion and 99.0% of control patients. The primary composite endpoint of this study was met, which demonstrated that the Superion spacer was noninferior to the X-Stop spacer. Leg pain, the predominant patient complaint, decreased in severity by 70% during 2 years in each group. Most (77%) patients achieved leg pain clinical success (improvement >=20 mm) at 2 years. Back pain clinical success (improvement >=20 mm) was 68%, with no differences between groups. Oswestry Disability Index clinical success (>=15% point improvement) was achieved in 65% of patients. The rates of complications and reoperations were similar between groups. CONCLUSION: The Superion interspinous process spacer relieves symptoms of intermittent neurogenic claudication secondary to moderate LSS in the majority of patients through 2 years. LEVEL OF EVIDENCE: 2. PMID- 25494325 TI - Point of View. PMID- 25494324 TI - Evidence-based medicine in spine surgery: a cross-sectional outcome analysis. PMID- 25494326 TI - Second harmonic super-resolution microscopy for quantification of mRNA at single copy sensitivity. AB - Cell-specific information on the quantity and localization of key mRNAs at single copy sensitivity in single cells is critical for evaluating basic cellular process, disease risk, and efficacy of therapy. Quantification of overexpressed mRNAs beyond the diffraction limit is constrained by the optical property of the probes and microscopy techniques. In this report, nanosized barium titanium oxide (BaTiO3, BTO) crystals were utilized as probes for mRNA quantification by a second harmonic super-resolution microscopy (SHaSM). The SHaSM was able to detect a single copy of the human epidermal growth factor receptor 2 (Her2) mRNA at a resolution of 55.6 nm with the ability to resolve multiple mRNA copies in a diffraction-limited spot. Her2 mRNA per cell was counted in SK-BR-3, MCF-7, and HeLa cell lines as 595+/-79.1, 38.9+/-8.26, and 1.5+/-2.8, respectively. Our single-cell quantification results were validated with the fluorescence in situ hybridization studies and quantitative PCR, showing better specificity and selectivity over current single-molecule approaches for transcript detection. The SHaSM is expected to have an upper limit of resolving ~10(4) transcripts in a single cell with the ability to monitor intracellular transcriptional dynamics at video rate. The developed approach has strong potential in clinical research and in the early diagnosis of life-threatening diseases such as cancer. PMID- 25494327 TI - I just want my research credit: frequency of suboptimal effort in a non-clinical healthy undergraduate sample. AB - Although performance validity testing is becoming fairly routine in clinical settings, research protocols involving neuropsychological tests infrequently include assessments of performance validity. The current study utilized an embedded measure of effort over two administrations of CNS Vital Signs to determine the frequency of poor effort in non-clinical healthy undergraduate students participating in a research study for course credit. Results indicate that more than 1 in 10 college students participating in a cognitive test battery for research showed test scores consistent with inadequate effort, which was associated with poor performance on testing across many domains. This conclusion was supported by poor performance on many other subtests. Healthy college students with suboptimal effort (n = 11) had an overall score in the 15th percentile on average compared to the 48th percentile in the rest of the students (n = 66). Those who failed validity indicators on the baseline administration were more likely to fail validity indicators on the repeat administration. Those who were tested in the morning were also more likely to fail validity indicators. The current study provides evidence for the potential limitations of conducting research using neuropsychological tests with healthy college student volunteers in the absence of performance validity testing. Revised college-level cutoffs are proposed. PMID- 25494328 TI - Identification of Dipeptidyl-Peptidase (DPP)5 and DPP7 in Porphyromonas endodontalis, Distinct from Those in Porphyromonas gingivalis. AB - Dipeptidyl peptidases (DPPs) that liberate dipeptides from the N-terminal end of oligopeptides are crucial for the growth of Porphyromonas species, anaerobic asaccharolytic gram negative rods that utilize amino acids as energy sources. Porphyromonas endodontalis is a causative agent of periapical lesions with acute symptoms and Asp/Glu-specific DPP11 has been solely characterized in this organism. In this study, we identified and characterized two P. endodontalis DPPs, DPP5 and DPP7. Cell-associated DPP activity toward Lys-Ala-4-methylcoumaryl 7-amide (MCA) was prominent in P. endodontalis ATCC 35406 as compared with the Porphyromonas gingivalis strains ATCC 33277, 16-1, HW24D1, ATCC 49417, W83, W50, and HNA99. The level of hydrolysis of Leu-Asp-MCA by DPP11, Gly-Pro-MCA by DPP4, and Met-Leu-MCA was also higher than in the P. gingivalis strains. MER236725 and MER278904 are P. endodontalis proteins belong to the S9- and S46-family peptidases, respectively. Recombinant MER236725 exhibited enzymatic properties including substrate specificity, and salt- and pH-dependence similar to P. gingivalis DPP5 belonging to the S9 family. However, the kcat/Km figure (194 uM 1.sec-1) for the most potent substrate (Lys-Ala-MCA) was 18.4-fold higher as compared to the P. gingivalis entity (10.5 uM-1.sec-1). In addition, P. endodontalis DPP5 mRNA and protein contents were increased several fold as compared with those in P. gingivalis. Recombinant MER278904 preferentially hydrolyzed Met-Leu-MCA and exhibited a substrate specificity similar to P. gingivalis DPP7 belonging to the S46 family. In accord with the deduced molecular mass of 818 amino acids, a 105-kDa band was immunologically detected, indicating that P. endodontalis DPP7 is an exceptionally large molecule in the DPP7/DPP11/S46 peptidase family. The enhancement of four DPP activities was conclusively demonstrated in P. endodontalis, and remarkable Lys-Ala-MCA hydrolysis was achieved by qualitative and quantitative potentiation of the DPP5 molecule. PMID- 25494329 TI - Spiders on a Hot Volcanic Roof: Colonisation Pathways and Phylogeography of the Canary Islands Endemic Trap-Door Spider Titanidiops canariensis (Araneae, Idiopidae). AB - Studies conducted on volcanic islands have greatly contributed to our current understanding of how organisms diversify. The Canary Islands archipelago, located northwest of the coast of northern Africa, harbours a large number of endemic taxa. Because of their low vagility, mygalomorph spiders are usually absent from oceanic islands. The spider Titanidiops canariensis, which inhabits the easternmost islands of the archipelago, constitutes an exception to this rule. Here, we use a multi-locus approach that combines three mitochondrial and four nuclear genes to investigate the origins and phylogeography of this remarkable trap-door spider. We provide a timeframe for the colonisation of the Canary Islands using two alternative approaches: concatenation and species tree inference in a Bayesian relaxed clock framework. Additionally, we investigate the existence of cryptic species on the islands by means of a Bayesian multi-locus species delimitation method. Our results indicate that T. canariensis colonised the Canary Islands once, most likely during the Miocene, although discrepancies between the timeframes from different approaches make the exact timing uncertain. A complex evolutionary history for the species in the archipelago is revealed, which involves two independent colonisations of Fuerteventura from the ancestral range of T. canariensis in northern Lanzarote and a possible back colonisation of southern Lanzarote. The data further corroborate a previously proposed volcanic refugium, highlighting the impact of the dynamic volcanic history of the island on the phylogeographic patterns of the endemic taxa. T. canariensis includes at least two different species, one inhabiting the Jandia peninsula and central Fuerteventura and one spanning from central Fuerteventura to Lanzarote. Our data suggest that the extant northern African Titanidiops lineages may have expanded to the region after the islands were colonised and, hence, are not the source of colonisation. In addition, T. maroccanus may harbour several cryptic species. PMID- 25494330 TI - Systematic Classification of Disease Severity for Evaluation of Expanded Carrier Screening Panels. AB - Professional guidelines dictate that disease severity is a key criterion for carrier screening. Expanded carrier screening, which tests for hundreds to thousands of mutations simultaneously, requires an objective, systematic means of describing a given disease's severity to build screening panels. We hypothesized that diseases with characteristics deemed to be of highest impact would likewise be rated as most severe, and diseases with characteristics of lower impact would be rated as less severe. We describe a pilot test of this hypothesis in which we surveyed 192 health care professionals to determine the impact of specific disease phenotypic characteristics on perceived severity, and asked the same group to rate the severity of selected inherited diseases. The results support the hypothesis: we identified four "Tiers" of disease characteristics (1-4). Based on these responses, we developed an algorithm that, based on the combination of characteristics normally seen in an affected individual, classifies the disease as Profound, Severe, Moderate, or Mild. This algorithm allows simple classification of disease severity that is replicable and not labor intensive. PMID- 25494331 TI - Complex Social Structure of an Endangered Population of Bottlenose Dolphins (Tursiops truncatus) in the Aeolian Archipelago (Italy). AB - We investigated social structure and association patterns for a small population of Mediterranean bottlenose dolphins, Tursiops truncatus, inhabiting the Aeolian Archipelago (southern Italy). Specifically we evaluate the role of sex and age composition, residency patterns and interaction with trammel nets on this social organization. Association data for 23 regularly sighted individuals were obtained from summer photoidentification surveys collected from 2005-2012. Using a combined cluster and social network analysis approach, we found associations between dolphins were hierarchically structured, where two mixed-sex social units were subdivided into smaller temporarily dynamic groups. We found non-random and long-term preferred associations in the population; however, the degree of social cohesion, residence pattern and interaction with trammel nets differed considerably between the two social units. Six of eight females occurred in the more resident social unit-1; in addition, social unit-1 individuals had significantly stronger associations, higher preferred associates, lived in larger groups and occurred less frequently with trammel nets. Nine of eleven males were clustered in social unit-2 and five of these males, interacting with trammel nets, formed small groups and preferred associations. We propose that female and male groups associate in the study area during the breeding season and that some males choose to interact with reproductive females forming a distinct but interrelated social unit. Other males may be associating in a larger fission fusion network, which consists of dolphins that appear to temporarily join the network from the coastal population. We cannot exclude that some males specialized in trammel net foraging, suggesting that this foraging technique may favor a solitary lifestyle. Large group sizes and high degree of social cohesion for females could be an indication of greater protection and more efficiency in detecting, deterring or repelling anthropogenic pressures. Most likely dolphins' social organization depends on a combination of socio-ecological, demographic and anthropogenic factors. PMID- 25494332 TI - Importance of Tryptophan in Transforming an Amphipathic Peptide into a Pseudomonas aeruginosa-Targeted Antimicrobial Peptide. AB - Here, we found that simple substitution of amino acids in the middle position of the hydrophobic face of an amphipathic peptide RI16 with tryptophan (T9W) considerably transformed into an antimicrobial peptide specifically targeting Pseudomonas aeruginosa. Minimal inhibitory concentration (MIC) results demonstrated that T9W had a strong and specifically antimicrobial activity against P. aeruginosa, including antibiotic-resistant strains, but was not active against Escherichia coli, Salmonella typhimurium, Staphylococcus aureus and Staphyfococcus epidermidis. Fluorescent spectroscopic assays indicated that T9W interacted with the membrane of P. aeruginosa, depolarizing the outer and the inner membrane of bacterial cells. Salt susceptibility assay showed that T9W still maintained its strong anti-pseudomonas activity in the presence of salts at physiological concentrations, and in hemolytic and MTT assays T9W also showed no toxicity against human blood cells and macrophages. In vivo assay demonstrated that T9W also displayed no toxicity to Chinese Kun Ming (KM) mice. Furthermore, the strong antibiofilm activity was also observed with the peptide T9W, which decreased the percentage of biomass formation in a dose-dependent manner. Overall, these findings indicated that design of single-pathogen antimicrobial agents can be achieved by simple amino acid mutation in naturally occurring peptide sequences and this study suggested a model of optimization/design of anti pseudomonas drugs in which the tryptophan residue was a conserved element. PMID- 25494333 TI - Complexity-Based Measures Inform Effects of Tai Chi Training on Standing Postural Control: Cross-Sectional and Randomized Trial Studies. AB - BACKGROUND: Diminished control of standing balance, traditionally indicated by greater postural sway magnitude and speed, is associated with falls in older adults. Tai Chi (TC) is a multisystem intervention that reduces fall risk, yet its impact on sway measures vary considerably. We hypothesized that TC improves the integrated function of multiple control systems influencing balance, quantifiable by the multi-scale "complexity" of postural sway fluctuations. OBJECTIVES: To evaluate both traditional and complexity-based measures of sway to characterize the short- and potential long-term effects of TC training on postural control and the relationships between sway measures and physical function in healthy older adults. METHODS: A cross-sectional comparison of standing postural sway in healthy TC-naive and TC-expert (24.5+/-12 yrs experience) adults. TC-naive participants then completed a 6-month, two-arm, wait list randomized clinical trial of TC training. Postural sway was assessed before and after the training during standing on a force-plate with eyes-open (EO) and eyes-closed (EC). Anterior-posterior (AP) and medio-lateral (ML) sway speed, magnitude, and complexity (quantified by multiscale entropy) were calculated. Single-legged standing time and Timed-Up-and-Go tests characterized physical function. RESULTS: At baseline, compared to TC-naive adults (n = 60, age 64.5+/ 7.5 yrs), TC-experts (n = 27, age 62.8+/-7.5 yrs) exhibited greater complexity of sway in the AP EC (P = 0.023), ML EO (P<0.001), and ML EC (P<0.001) conditions. Traditional measures of sway speed and magnitude were not significantly lower among TC-experts. Intention-to-treat analyses indicated no significant effects of short-term TC training; however, increases in AP EC and ML EC complexity amongst those randomized to TC were positively correlated with practice hours (P = 0.044, P = 0.018). Long- and short-term TC training were positively associated with physical function. CONCLUSION: Multiscale entropy offers a complementary approach to traditional COP measures for characterizing sway during quiet standing, and may be more sensitive to the effects of TC in healthy adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT01340365. PMID- 25494334 TI - Mineral Metabolism Markers Are Associated with Myocardial Infarction and Hemorrhagic Stroke but Not Ischemic Stroke in Hemodialysis Patients: A Longitudinal Study. AB - BACKGROUND/AIMS: The associations between phosphate, calcium, and intact parathyroid hormone (PTH) levels and composite cardiovascular end points have been studied. This study examined the associations of these markers with myocardial infarction (MI) and stroke separately. METHODS: This is a longitudinal study on 65,849 hemodialysis patients from the Japan Renal Data Registry. Patients with prior events at baseline were excluded. Predictors were phosphate, albumin-corrected calcium, intact PTH, and calcium times phosphate product levels. Outcome was the first episode of MI or stroke during a 1-year observation period. Data were analyzed using multiple logistic regression analyses, adjusted for potential confounders. RESULTS: There were 1,048, 651, and 2,089 events of incident MI, hemorrhagic, and ischemic stroke, respectively. Incident MI was associated with phosphate levels >=6.5 mg/dL (odds ratio 1.49; confidence interval 1.23-1.80) compared with phosphate levels of 4.7-5.4 mg/dL and intact PTH levels>500 pg/mL (1.35; 1.03-1.79) compared with intact PTH levels of 151-300 pg/mL. Higher albumin-corrected calcium level was positively associated with MI (p = 0.04 by trend analysis). Hemorrhagic stroke was associated only with intact PTH levels>500 pg/mL (1.54; 1.10-2.17). Incident ischemic stroke had no association with phosphate, calcium, or intact PTH levels. The association of calcium times phosphate product with outcomes was essentially the same pattern as that of phosphate and outcomes. CONCLUSIONS: MI was associated with phosphate, calcium, and intact PTH levels, whereas hemorrhagic stroke was associated only with intact PTH. Ischemic stroke was not associated with any of them. The potential distinct beneficial effect on MI and stroke by managing bone and mineral disease should be investigated in future studies. PMID- 25494335 TI - Comorbid bipolar disorder and borderline personality disorder and substance use disorder. AB - Bipolar disorder (BD) and borderline personality disorder (BPD) are disabling and life-threatening conditions. Both disorders share relevant comorbidities, particularly the risk of having a lifetime substance use disorder (SUD). We tested the hypothesis that patients with both BD type I (BDI) or II (BDII) and BPD would have a higher rate of SUD than would patients with either disorder alone. A total of 3651 psychiatric patients were evaluated with semistructured diagnostic interviews for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, axis I and II disorders. A total of 63 patients were diagnosed with both BD and BPD, and these patients were significantly more likely to have a SUD compared with BDII patients without BPD (76% vs. 50%, chi = 9.69, p < 0.01). There were no differences when comparing the comorbid group with BPD patients without BD (76% vs. 71%, chi = 0.519, p = 0.4). The present study shows the importance of taking both BPD and BD into consideration insofar as the co occurrence of the disorders increased the risk of having a SUD especially when compared with BDII alone. PMID- 25494336 TI - Associations between metabolic and aerobic fitness parameters in patients with schizophrenia. AB - The primary aim was to determine whether the presence of metabolic syndrome (MetS) limits aerobic fitness in patients with schizophrenia. A secondary aim was to investigate the associations between aerobic fitness and MetS parameters. Aerobic fitness (expressed as predicted maximal oxygen uptake) was assessed using the Astrand-Rhyming test. Those with MetS (n = 19) were similar in age, sex, antipsychotic medication use, symptoms, and smoking behavior than those without (n = 31). Estimated maximal oxygen uptake was 21.4% lower (p = 0.001) in patients with MetS than in patients without MetS (29.5 +/- 7.4 ml of O2/min/kg vs. 37.5 +/ 8.2 ml of O2/min/kg, respectively). The estimated maximal oxygen uptake of the entire sample was correlated with waist circumference, the level of high-density lipoproteins, and fasting glucose. The current study demonstrates that the additive burden of MetS might place people with schizophrenia at increased risk for functional limitations in daily life activities. PMID- 25494337 TI - Patulin and its dietary intake by fruit juice consumption in Iran. AB - A survey was conducted to determine levels and dietary intake of patulin (PAT) from fruit juices consumed in Iran. PAT content was determined using high performance liquid chromatography-diode array detection in 161 samples of fruit juices including apple, pineapple, pear, peach, pomegranate and white and red grape juices. Results revealed the presence of PAT in 16.1% of the samples examined, ranging from 5 to 190.7 ug/kg. Average and median PAT content in positive samples was 34.5 and 18.5 ug/kg, respectively. PAT concentration in 2.5% of the samples was higher than the maximum limit as set by European regulations for PAT in fruit products (50 ug/kg). Estimated daily intake of PAT by fruit juice was 16.4, 45.9 and 74.6 ng/kg bw/day for Iranian adults, children and babies, respectively. The results of this study showed that PAT does not seem to be a problem in fruit-based drinks commercialised in Iran, except for apple juice. PMID- 25494338 TI - Valence tautomeric dinuclear adducts of Co(II) diketonates with redox-active diquinones for the design of spin qubits: computational modeling. AB - The possibility of employing the mechanism of intramolecular electron transfer between metal and ligand centers in the valence tautomeric complexes formed as electrically neutral 2 : 1 adducts of Co(II) diketonates and redox-active tetradentate di-o-quinones, for quantum information processing, has been computationally studied using the DFT B3LYP*/6-311++G(d,p) method. It has been shown that by the proper choice of a linker group bridging the quinone rings and substituents in the diketonate fragments, complexes with the properties required in 2-qubit quantum gates (sufficiently narrow energy gaps between the spin states and weakly coupled paramagnetic centers) can be designed, in order to realize the mechanism of thermally driven migration of paramagnetic centers between the o quinone fragments and metal atoms. These are exemplified by the adduct of bis (hexafluoroacetylacetonate)Co(ii) with a diquinone containing dimethylene linker. Valence tautomerism is considered as a new, promising mechanistic paradigm for the molecular design of 2-qubit molecular systems. PMID- 25494339 TI - Development of therapeutic Au-methylene blue nanoparticles for targeted photodynamic therapy of cervical cancer cells. AB - Photodynamic therapy (PDT) involves the cellular uptake of a photosensitizer (PS) combined with oxygen molecules and light at a specific wavelength to be able to trigger cancer cell death via the apoptosis pathway, which is less harmful and has less inflammatory side effect than necrosis. However, the traditional PDT treatment has two main deficiencies: the dark toxicity of the PS and the poor selectivity of the cellular uptake of PS between the target cells and normal tissues. In this work, methylene blue (MB), a known effective PS, combined with Au nanoparticles (NPs) was prepared using an intermolecular interaction between a polystyrene-alt-maleic acid (PSMA) layer on the Au NPs and MB. The Au@polymer/MB NPs produced a high quantum yield of singlet oxygen molecules, over 50% as much as that of free MB, when they were excited by a dark red light source at 660 nm, but without significant dark toxicity. Furthermore, transferrin (Tf) was conjugated on the Au@polymer/MB NPs via an EDC/NHS reaction to enhance the selectivity to HeLa cells compared to 3T3 fibroblasts. With a hand-held single laser treatment (32 mW/cm) for 4 min, the new Au@polymer/MB-Tf NPs showed a 2 fold enhancement of PDT efficiency toward HeLa cells over the use of free MB at 4 times dosage. Cellular staining examinations showed that the HeLa cells reacted with Au@polymer/MB-Tf NPs and the 660 nm light excitation triggered PDT, which caused the cells to undergo apoptosis ("programmed" cell death). We propose that applying this therapeutic Au@polymer/MB-Tf nanoagent is facile and safe for delivery and cancer cell targeting to simultaneously minimize side effects and accomplish a significant enhancement in photodynamic therapeutic efficiency toward next-generation nanomedicine development. PMID- 25494340 TI - Small RNA changes en route to distinct cellular states of induced pluripotency. AB - MicroRNAs (miRNAs) are critical to somatic cell reprogramming into induced pluripotent stem cells (iPSCs), however, exactly how miRNA expression changes support the transition to pluripotency requires further investigation. Here we use a murine secondary reprogramming system to sample cellular trajectories towards iPSCs or a novel pluripotent 'F-class' state and perform small RNA sequencing. We detect sweeping changes in an early and a late wave, revealing that distinct miRNA milieus characterize alternate states of pluripotency. miRNA isoform expression is common but surprisingly varies little between cell states. Referencing other omic data sets generated in parallel, we find that miRNA expression is changed through transcriptional and post-transcriptional mechanisms. miRNA transcription is commonly regulated by dynamic histone modification, while DNA methylation/demethylation consolidates these changes at multiple loci. Importantly, our results suggest that a novel subset of distinctly expressed miRNAs supports pluripotency in the F-class state, substituting for miRNAs that serve such roles in iPSCs. PMID- 25494341 TI - A multinuclear solid state NMR spectroscopic study of the structural evolution of disordered calcium silicate sol-gel biomaterials. AB - Disordered sol-gel prepared calcium silicate biomaterials show significant, composition dependent ability to bond with bone. Bone bonding is attributed to rapid hydroxycarbonate apatite (HCA) formation on the glass surface after immersion in body fluid (or implantation). Atomic scale details of the development of the structure of (CaO)x(SiO2)1-x (x = 0.2, 0.3 and 0.5) under heat treatment and subsequent dissolution in simulated body fluid (SBF) are revealed through a multinuclear solid state NMR approach using one-dimensional (17)O, (29)Si, (31)P and (1)H. Central to this study is the combination of conventional static and magic angle spinning (MAS) and two-dimensional (2D) triple quantum (3Q) (17)O NMR experiments that can readily distinguish and quantify the bridging (BOs) and non-bridging (NBOs) oxygens in the silicate network. Although soluble calcium is present in the sol, the (17)O NMR results reveal that the sol-gel produced network structure is initially dominated by BOs after gelation, aging and drying (e.g. at 120 degrees C), indicating a nanoscale mixture of the calcium salt and a predominantly silicate network. Only once the calcium salt is decomposed at elevated temperatures do the Ca(2+) ions become available to break BO. Apatite forming ability in SBF depends strongly on the surface OH and calcium content. The presence of calcium aids HCA formation via promotion of surface hydration and the ready availability of Ca(2+) ions. (17)O NMR shows the rapid loss of NBOs charge balanced by calcium as it is leached into the SBF. The formation of nanocrystalline, partially ordered HCA can be detected via(31)P NMR. This data indicates the importance of achieving the right balance of BO/NBO for optimal biochemical response and network properties. PMID- 25494342 TI - [Restrictions of work ability]. PMID- 25494343 TI - [Vocational inpatient and post-treatment proposals in cardiac rehabilitation patients (BERUNA): results of a randomized controlled trial]. AB - BACKGROUND: The "Verband Deutscher Rentenversicherungstrager (VDR)" required the intense focus on vocational rehabilitation of medical problems since the early 1990s. By integrating elements of the working environment in the structures and processes of medical rehabilitation, vocational problems can be identified early in order to take appropriate countermeasures. Posttreatment proposals off er a way to provide a reliable long-term success. OBJECTIVE: The intention of this study is the implementation and the investigation of effectiveness of an intensified vocational program that integrates besides the in-patient rehabilitation post-treatment proposals as well. METHODS: Cardiac rehabilitation patient occurring special vocational problems participe. The recruited patients were randomized to either the vocational program or the common cardiac rehabilitation.Primary outcome was the vocational reintegration 12 months after the end of rehabilitation.The database was collected through a query of the pension insurance accounts and questionnaires. RESULTS: 306 people were included to the study at the beginning of rehabilitation. Rates of response:95 % of the survey to the end of rehabilitation,77 % of the survey 6 months and 73 % of the survey 12 months after the end of rehabilitation.The sample was characterized by great interferences of their professional involvement and a high demand for vocational treatments. At the beginning of the rehabilitation 50 % of study participants intended to make an application for reduction-pension. Nevertheless, one year after the end of rehabilitation a surprisingly high rate of vocational reintegration by over 70 % in both groups (IG: 72 %, KG: 75 %, p < 0.929) was indicated.The majority of the unemployed patients at the beginning of rehabilitation remained in the unemployment (IG: 69 %, KG: 65 %, p < 0.757). The participation rate at the post-treatment proposals was 42%. CONCLUSION: The results show that vocational programs in rehabilitation need to be revised, including with regard to the question, whether and in what way post-treatment proposals must be changed. PMID- 25494344 TI - [Concerning the impact of psychological comorbidity for chronic back pain: frequency, reduced earning capacity pension and rehabilitation aftercare in the course of the rehabilitation cohorts 2002-2009]. AB - BACKGROUND AND OBJECTIVE: Psychological comorbidities play a key role in the chronification process of back pain. The aim of this longitudinal study is to analyze the diagnostics of psychological comorbidities, their influence on back pain patients and the recommendations of aftercare over the course of time. METHODS: A descriptive analysis of diagnosed psychological comorbidities for the rehabilitation cohorts from 2002 to 2009 was conducted as well as a modelling of Poisson regressions to calculate relative risks and incidence rates. RESULTS: The frequency of at least one psychological comorbidity ranges from 17.6 to 17.9% in the years 2002-2004 and from 18.9 to 20.9% in the years 2005-2009. The risk of reduced earning capacity pension for persons with a comorbid psychological disorder is increasing significantly in almost all rehabilitation cohorts regardless of gender and adjusted for other risk factors compared to persons without comorbid psychological disorders. The number of recommended aftercare procedures is increasing over all cohorts:starting in 2005 with less than 5% of patients to every fourth patient with an aftercare recommendation in 2009. CONCLUSION: The frequencies of psychological comorbidities as reported in the discharge letters for the cohorts of patients in rehabilitation are below the reported frequencies of epidemiological studies. Psychological comorbidities have a considerable impact on pension for reduced earnings capacity. This finding could be useful for recommending aftercare programs. PMID- 25494345 TI - [The validity of the "Working Group on Nursing in Early Rehabilitation" (AGnFP) catalogue]. AB - INTRODUCTION: Nursing is most important in neurological early rehabilitation to achieve a good outcome. In the present study, the validity of the catalogue of the "Working Group on Nursing in Early Rehabilitation" (AGnFP) has been examined. METHODS: 54 neurological early rehabilitation patients (mean age 68.3 (14.7) years) have been enrolled. All nursing processes (basic and medical care) have been documented through timekeeping. RESULTS: A nursing total of 205.9 (122.6) min/d per patient was found. In the AGnFP-catalogue, 177.5 (130.9) min/d have been documented (86.2% of all nursing processes). Barthel-index correlated negatively with basic nursing care (r = - 0.42, p < 0.01). The early rehabilitation index showed a negative correlation with medical nursing processes (r = - 0.46, p < 0.01). The AGnFP catalogue correlated with basic nursing processes (r = 0.69, p < 0.001). DISCUSSION: The AGnFP-catalogue is a tool to document nursing in early neurological rehabilitation. Further studies are strongly encouraged. PMID- 25494346 TI - ? PMID- 25494348 TI - Penetration Characteristics of Air, Carbon Dioxide and Helium Transverse Sonic Jets in Mach 5 Cross Flow. AB - An experimental investigation of sonic air, CO2 and Helium transverse jets in Mach 5 cross flow was carried out over a flat plate. The jet to freestream momentum flux ratio, J, was kept the same for all gases. The unsteady flow topology was examined using high speed schlieren visualisation and PIV. Schlieren visualisation provided information regarding oscillating jet shear layer structures and bow shock, Mach disc and barrel shocks. Two-component PIV measurements at the centreline, provided information regarding jet penetration trajectories. Barrel shocks and Mach disc forming the jet boundary were visualised/quantified also jet penetration boundaries were determined. Even though J is kept the same for all gases, the penetration patterns were found to be remarkably different both at the nearfield and the farfield. Air and CO2 jet resulted similar nearfield and farfield penetration pattern whereas Helium jet spread minimal in the nearfield. PMID- 25494347 TI - Current Trends in Nanomaterial-Based Amperometric Biosensors. AB - The last decade has witnessed an intensive research effort in the field of electrochemical sensors, with a particular focus on the design of amperometric biosensors for diverse analytical applications. In this context, nanomaterial integration in the construction of amperometric biosensors may constitute one of the most exciting approaches. The attractive properties of nanomaterials have paved the way for the design of a wide variety of biosensors based on various electrochemical detection methods to enhance the analytical characteristics. However, most of these nanostructured materials are not explored in the design of amperometric biosensors. This review aims to provide insight into the diverse properties of nanomaterials that can be possibly explored in the construction of amperometric biosensors. PMID- 25494349 TI - Comparison of Global Navigation Satellite System Devices on Speed Tracking in Road (Tran)SPORT Applications. AB - Global Navigation Satellite Systems (GNSS) are, in addition to being most widely used vehicle navigation method, becoming popular in sport-related tests. There is a lack of knowledge regarding tracking speed using GNSS, therefore the aims of this study were to examine under dynamic conditions: (1) how accurate technologically different GNSS measure speed and (2) how large is latency in speed measurements in real time applications. Five GNSSs were tested. They were fixed to a car's roof-rack: a smart phone, a wrist watch, a handheld device, a professional system for testing vehicles and a high-end Real Time Kinematics (RTK) GNSS. The speed data were recorded and analyzed during rapid acceleration and deceleration as well as at steady speed. The study produced four main findings. Higher frequency and high quality GNSS receivers track speed at least at comparable accuracy to a vehicle speedometer. All GNSS systems measured maximum speed and movement at a constant speed well. Acceleration and deceleration have different level of error at different speeds. Low cost GNSS receivers operating at 1 Hz sampling rate had high latency (up to 2.16 s) and are not appropriate for tracking speed in real time, especially during dynamic movements. PMID- 25494350 TI - Generic Learning-Based Ensemble Framework for Small Sample Size Face Recognition in Multi-Camera Networks. AB - Multi-camera networks have gained great interest in video-based surveillance systems for security monitoring, access control, etc. Person re-identification is an essential and challenging task in multi-camera networks, which aims to determine if a given individual has already appeared over the camera network. Individual recognition often uses faces as a trial and requires a large number of samples during the training phrase. This is difficult to fulfill due to the limitation of the camera hardware system and the unconstrained image capturing conditions. Conventional face recognition algorithms often encounter the "small sample size" (SSS) problem arising from the small number of training samples compared to the high dimensionality of the sample space. To overcome this problem, interest in the combination of multiple base classifiers has sparked research efforts in ensemble methods. However, existing ensemble methods still open two questions: (1) how to define diverse base classifiers from the small data; (2) how to avoid the diversity/accuracy dilemma occurring during ensemble. To address these problems, this paper proposes a novel generic learning-based ensemble framework, which augments the small data by generating new samples based on a generic distribution and introduces a tailored 0-1 knapsack algorithm to alleviate the diversity/accuracy dilemma. More diverse base classifiers can be generated from the expanded face space, and more appropriate base classifiers are selected for ensemble. Extensive experimental results on four benchmarks demonstrate the higher ability of our system to cope with the SSS problem compared to the state-of-the-art system. PMID- 25494351 TI - Design Concepts, Fabrication and Advanced Characterization Methods of Innovative Piezoelectric Sensors Based on ZnO Nanowires. AB - Micro- and nano-scale materials and systems based on zinc oxide are expected to explode in their applications in the electronics and photonics, including nano arrays of addressable optoelectronic devices and sensors, due to their outstanding properties, including semiconductivity and the presence of a direct bandgap, piezoelectricity, pyroelectricity and biocompatibility. Most applications are based on the cooperative and average response of a large number of ZnO micro/nanostructures. However, in order to assess the quality of the materials and their performance, it is fundamental to characterize and then accurately model the specific electrical and piezoelectric properties of single ZnO structures. In this paper, we report on focused ion beam machined high aspect ratio nanowires and their mechanical and electrical (by means of conductive atomic force microscopy) characterization. Then, we investigate the suitability of new power-law design concepts to accurately model the relevant electrical and mechanical size-effects, whose existence has been emphasized in recent reviews. PMID- 25494352 TI - Precise Temperature Measurement for Increasing the Survival of Newborn Babies in Incubator Environments. AB - Precise temperature measurement is essential in a wide range of applications in the medical environment, however the regarding the problem of temperature measurement inside a simple incubator, neither a simple nor a low cost solution have been proposed yet. Given that standard temperature sensors don't satisfy the necessary expectations, the problem is not measuring temperature, but rather achieving the desired sensitivity. In response, this paper introduces a novel hardware design as well as the implementation that increases measurement sensitivity in defined temperature intervals at low cost. PMID- 25494354 TI - MPMI Acknowledgment of Reviewers 2014. PMID- 25494353 TI - Definition of an Ontology Matching Algorithm for Context Integration in Smart Cities. AB - In this paper we describe a novel proposal in the field of smart cities: using an ontology matching algorithm to guarantee the automatic information exchange between the agents and the smart city. A smart city is composed by different types of agents that behave as producers and/or consumers of the information in the smart city. In our proposal, the data from the context is obtained by sensor and device agents while users interact with the smart city by means of user or system agents. The knowledge of each agent, as well as the smart city's knowledge, is semantically represented using different ontologies. To have an open city, that is fully accessible to any agent and therefore to provide enhanced services to the users, there is the need to ensure a seamless communication between agents and the city, regardless of their inner knowledge representations, i.e., ontologies. To meet this goal we use ontology matching techniques, specifically we have defined a new ontology matching algorithm called OntoPhil to be deployed within a smart city, which has never been done before. OntoPhil was tested on the benchmarks provided by the well known evaluation initiative, Ontology Alignment Evaluation Initiative, and also compared to other matching algorithms, although these algorithms were not specifically designed for smart cities. Additionally, specific tests involving a smart city's ontology and different types of agents were conducted to validate the usefulness of OntoPhil in the smart city environment. PMID- 25494355 TI - Plant-Influenced Gene Expression in the Rice Endophyte Burkholderia kururiensis M130. AB - Burkholderia kururiensis M130 is one of the few rice endophytic diazotrophic bacteria identified thus far which is able to enhance growth of rice. To date, very little is known of how strain M130 and other endophytes enter and colonize plants. Here, we identified genes of strain M130 that are differentially regulated in the presence of rice plant extract. A genetic screening of a promoter probe transposon mutant genome bank and RNAseq analysis were performed. The screening of 10,100 insertions of the genomic transposon reporter library resulted in the isolation of 61 insertions displaying differential expression in response to rice macerate. The RNAseq results validated this screen and indicated that this endophytic bacterium undergoes major changes in the presence of plant extract regulating 27.7% of its open reading frames. A large number of differentially expressed genes encode membrane transporters and secretion systems, indicating that the exchange of molecules is an important aspect of bacterial endophytic growth. Genes related to motility, chemotaxis, and adhesion were also overrepresented, further suggesting plant-bacteria interaction. This work highlights the potential close signaling taking place between plants and bacteria and helps us to begin to understand the adaptation of an endophyte in planta. PMID- 25494356 TI - The Importance of the KR-Rich Region of the Coat Protein of Ourmia melon virus for Host Specificity, Tissue Tropism, and Interference With Antiviral Defense. AB - The N-terminal region of the Ourmia melon virus (OuMV) coat protein (CP) contains a short lysine/arginine-rich (KR) region. By alanine scanning mutagenesis, we showed that the KR region influences pathogenicity and virulence of OuMV without altering viral particle assembly. A mutant, called OuMV6710, with three basic residue substitutions in the KR region, was impaired in the ability to maintain the initial systemic infection in Nicotiana benthamiana and to infect both cucumber and melon plants systemically. The integrity of this protein region was also crucial for encapsidation of viral genomic RNA; in fact, certain mutations within the KR region partially compromised the RNA encapsidation efficiency of the CP. In Arabidopsis thaliana Col-0, OuMV6710 was impaired in particle accumulation; however, this phenotype was abolished in dcl2/dcl4 and dcl2/dcl3/dcl4 Arabidopsis mutants defective for antiviral silencing. Moreover, in contrast to CPwt, in situ immunolocalization experiments indicated that CP6710 accumulates efficiently in the spongy mesophyll tissue of infected N. benthamiana and A. thaliana leaves but only occasionally infects palisade tissues. These results provided strong evidence of a crucial role for OuMV CP during viral infection and highlighted the relevance of the KR region in determining tissue tropism, host range, pathogenicity, and RNA affinity, which may be all correlated with a possible CP silencing-suppression activity. PMID- 25494357 TI - A Septin-Dependent Diffusion Barrier at Dendritic Spine Necks. AB - Excitatory glutamatergic synapses at dendritic spines exchange and modulate their receptor content via lateral membrane diffusion. Several studies have shown that the thin spine neck impedes the access of membrane and solute molecules to the spine head. However, it is unclear whether the spine neck geometry alone restricts access to dendritic spines or if a physical barrier to the diffusion of molecules exists. Here, we investigated whether a complex of septin cytoskeletal GTPases localized at the base of the spine neck regulates diffusion across the spine neck. We found that, during development, a marker of the septin complex, Septin7 (Sept7), becomes localized to the spine neck where it forms a stable structure underneath the plasma membrane. We show that diffusion of receptors and bulk membrane, but not cytoplasmic proteins, is slower in spines bearing Sept7 at their neck. Finally, when Sept7 expression was suppressed by RNA interference, membrane molecules explored larger membrane areas. Our findings indicate that Sept7 regulates membrane protein access to spines. PMID- 25494358 TI - The impact of the organization of high-dependency care on acute hospital mortality and patient flow for critically ill patients. AB - RATIONALE: Little is known about the utility of provision of high-dependency care (HDC) that is in a geographically separate location from a primary intensive care unit (ICU). OBJECTIVES: To determine whether the availability of HDC in a geographically separate unit affects patient flow or mortality for critically ill patients. METHODS: Admissions to ICUs in the United Kingdom, from 2009 to 2011, who received Level 3 intensive care in the first 24 hours after admission and subsequently Level 2 HDC. We compared differences in patient flow and outcomes for patients treated in hospitals providing some HDC in a geographically separate unit (dual HDC) with patients treated in hospitals providing all HDC in the same unit as intensive care (integrated HDC) using multilevel mixed effects models. MEASUREMENTS AND MAIN RESULTS: In 192 adult general ICUs, 21.4% provided dual HDC. Acute hospital mortality was no different for patients cared for in ICUs with dual HDC versus those with integrated HDC (adjusted odds ratio, 0.94 [0.86 1.03]; P = 0.16). Dual HDC was associated with a decreased likelihood of a delayed discharge from the primary unit. However, total duration of critical care and the likelihood of discharge from the primary unit at night were increased with dual HDC. CONCLUSIONS: Availability of HDC in a geographically separate unit does not impact acute hospital mortality. The potential benefit of decreasing delays in discharge should be weighed against the increased total duration of critical care and greater likelihood of a transfer out of the primary unit at night. PMID- 25494359 TI - Time required for institutional review board review at one Veterans Affairs medical center. AB - IMPORTANCE: Despite growing concern that institutional review boards (IRBs) impose burdensome delays on research, little is known about the time required for IRB review across different types of research. OBJECTIVE: To measure the overall and incremental process times for IRB review as a process of quality improvement. DESIGN, SETTING, AND PARTICIPANTS: After developing a detailed process flowchart of the IRB review process, 2 analysts abstracted temporal data from the records pertaining to all 103 protocols newly submitted to the IRB at a large urban Veterans Affairs medical center from June 1, 2009, through May 31, 2011. Disagreements were reviewed with the principal investigator to reach consensus. We then compared the review times across review types using analysis of variance and post hoc Scheffe tests after achieving normally distributed data through logarithmic transformation. MAIN OUTCOMES AND MEASURES: Calendar days from initial submission to final approval of research protocols. RESULTS: Initial IRB review took 2 to 4 months, with expedited and exempt reviews requiring less time (median [range], 85 [23-631] and 82 [16-437] days, respectively) than full board reviews (median [range], 131 [64-296] days; P = .008). The median time required for credentialing of investigators was 1 day (range, 0-74 days), and review by the research and development committee took a median of 15 days (range, 0-184 days). There were no significant differences in credentialing or research and development times across review types (exempt, expedited, or full board). Of the extreme delays in IRB review, 80.0% were due to investigators' slow responses to requested changes. There were no systematic delays attributable to the information security officer, privacy officer, or IRB chair. CONCLUSIONS AND RELEVANCE: Measuring and analyzing review times is a critical first step in establishing a culture and process of continuous quality improvement among IRBs that govern research programs. The review times observed at this IRB are substantially longer than the 60-day target recommended by expert panels. The method described here could be applied to other IRBs to begin identifying and improving inefficiencies. PMID- 25494360 TI - Insight to the Epidemiology and Risk Factors of Extrapulmonary Tuberculosis in Tianjin, China during 2006-2011. AB - BACKGROUND: The proportion of extrapulmonary tuberculosis (EPTB) among all the reported tuberculosis (TB) cases has increased in different populations. Despite the large burden of TB in China, the epidemiology of EPTB in China remains largely understudied and the risk factors for having EPTB diagnosis in China have not been identified. METHODS: To gain insight to EPTB epidemiology in China, we analyzed TB surveillance data collected in Tianjin, China, during 2006 to 2011. The frequency of EPTB among all TB cases and within different socio-demographic groups of the study patients aged 15 years and older was determined for EPTB in general and by specific types. The distribution of socio-demographic characteristics was compared between pulmonary TB (PTB) group and EPTB group by chi-square test. Crude and multiple logistic regression-derived adjusted odds ratios (aOR) and 95% confidence intervals (CI) were determined to assess the associations between having EPTB diagnosis and each individual explanatory variable in question. RESULTS: About one-tenth (1,512/14,561) of the patients investigated in this study had EPTB. Of these 1,512 EPTB cases, about two thirds were pleural TB. Significant difference in age, occupation, and urbanity of residence were found between PTB and EPTB groups (p<0.05). Patients with EPTB diagnosis were more likely to be 65 years or older (aOR = 1.22, 95% CI: 1.02, 1.46), to be retired (aOR = 1.37, 95% CI: 1.08, 1.75), and to live in urban areas (aOR = 1 38, 95% CI: 1.22, 1.55). CONCLUSIONS: The findings of this study extends the knowledgebase of EPTB epidemiology in developing countries and highlight the need for improved EPTB detection in China, especially in subpopulations with high risk for EPTB or having limited access to medical facilities with adequate capacity for EPTB diagnosis. PMID- 25494361 TI - Analgesic and Anti-Inflammatory Activities of Rosa taiwanensis Nakai in Mice. AB - In this study, we evaluated the analgesic and anti-inflammatory activities of a 70% ethanol extract from Rosa taiwanensis Nakai (RTEtOH). The analgesic effect was determined using acetic acid-induced writhing response and formalin test. The anti-inflammatory activity was evaluated by lambda-carrageenan-induced paw edema in mice. The anti-inflammatory mechanism of RTEtOH was examined by measuring the levels of cyclooxygenase-2 (COX-2), nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and malondialdehyde (MDA) in the paw edema tissue and the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GRd) in the liver tissue. The betulinic acid and oleanolic acid contents of RTEtOH were assayed by HPLC. The results showed that RTEtOH decreased the acetic acid-induced writhing responses (1.0 g/kg) and the late phase of the formalin-induced licking time (0.5 and 1.0 g/kg). In the anti-inflammatory models, RTEtOH (0.5 and 1.0 g/kg) reduced the paw edema at 3, 4, and 5 h after lambda-carrageenan administration. Moreover, the anti-inflammatory mechanisms might be due to the decreased levels of COX-2, TNF alpha, IL-1beta, and IL-6, as well as the inhibition of NO and MDA levels through increasing the activities of SOD, GPx, and GRd. The contents of two active compounds, betulinic acid and oleanolic acid, were quantitatively determined. This study demonstrated the analgesic and anti-inflammatory activities of RTEtOH and provided evidence to support its therapeutic use in inflammatory diseases. PMID- 25494362 TI - Adenoma detection in excellent versus good bowel preparation for colonoscopy. AB - GOAL: To determine whether Excellent bowel cleansing is superior to Good for the detection of adenomas. BACKGROUND: High quality colonoscopy requires Adequate bowel preparation. However, it is unknown whether adenoma detection differs between subcategories of Adequate cleansing. STUDY: We utilized a retrospective, cross-sectional study design to obtain data about patients undergoing colonoscopy at a single university center between August 31, 2011 and September 1, 2012. Primary outcome was adenoma detection rate (ADR), the percentage of patients with >=1 adenoma. Secondary outcomes included adenomas per colonoscopy, adenoma distribution (proximal vs. distal), and detection of advanced adenomas, sessile serrated polyps (SSP), and cancer. RESULTS: The electronic medical record of 5113 consecutive colonoscopies with Good or Excellent preparation was queried for preparation quality, colonoscopy indication, demographics, medical history, and history of adenoma and colon cancer. Exclusion criteria were age below 18 years, inflammatory bowel disease, or familial polyposis. Adenoma detection was not superior with Excellent cleansing as compared with Good for ADR [respectively, 26% vs. 29%, odds ratio 0.97 (0.85, 1.11), P=0.618] or adenomas per colonoscopy [respectively, 0.437 vs. 0.499, incidence rate ratio (IRR) 0.98 (0.90, 1.07), P=0.705]. Excellent cleansing demonstrated superior detection of SSPs [IRR 1.66 (1.14, 2.40), P=0.008] and advanced adenomas [IRR 1.37 (1.09, 1.72), P=0.007] but not colon cancer [odds ratio 0.286 (0.083, 0.985), P=0.0474]. CONCLUSIONS: ADR is not significantly different between the Adequate subcategories of Excellent and Good. However, Excellent cleansing is associated with superior detection of advanced adenomas and SSPs. If confirmed, achieving an Excellent preparation may improve colonoscopy performance in the proximal colon where SSPs primarily occur. PMID- 25494363 TI - Combined fibrosis indices: more than 1 way to skin a cat. PMID- 25494364 TI - Cattle Manure Enhances Methanogens Diversity and Methane Emissions Compared to Swine Manure under Rice Paddy. AB - Livestock manures are broadly used in agriculture to improve soil quality. However, manure application can increase the availability of organic carbon, thereby facilitating methane (CH4) production. Cattle and swine manures are expected to have different CH4 emission characteristics in rice paddy soil due to the inherent differences in composition as a result of contrasting diets and digestive physiology between the two livestock types. To compare the effect of ruminant and non-ruminant animal manure applications on CH4 emissions and methanogenic archaeal diversity during rice cultivation (June to September, 2009), fresh cattle and swine manures were applied into experimental pots at 0, 20 and 40 Mg fresh weight (FW) ha-1 in a greenhouse. Applications of manures significantly enhanced total CH4 emissions as compared to chemical fertilization, with cattle manure leading to higher emissions than swine manure. Total organic C contents in cattle (466 g kg-1) and swine (460 g kg-1) manures were of comparable results. Soil organic C (SOC) contents were also similar between the two manure treatments, but dissolved organic C (DOC) was significantly higher in cattle than swine manure. The mcrA gene copy numbers were significantly higher in cattle than swine manure. Diverse groups of methanogens which belong to Methanomicrobiaceae were detected only in cattle-manured but not in swine-manured soil. Methanogens were transferred from cattle manure to rice paddy soils through fresh excrement. In conclusion, cattle manure application can significantly increase CH4 emissions in rice paddy soil during cultivation, and its pretreatment to suppress methanogenic activity without decreasing rice productivity should be considered. PMID- 25494365 TI - Spectral and Temporal Acoustic Features Modulate Response Irregularities within Primary Auditory Cortex Columns. AB - Assemblies of vertically connected neurons in the cerebral cortex form information processing units (columns) that participate in the distribution and segregation of sensory signals. Despite well-accepted models of columnar architecture, functional mechanisms of inter-laminar communication remain poorly understood. Hence, the purpose of the present investigation was to examine the effects of sensory information features on columnar response properties. Using acute recording techniques, extracellular response activity was collected from the right hemisphere of eight mature cats (felis catus). Recordings were conducted with multichannel electrodes that permitted the simultaneous acquisition of neuronal activity within primary auditory cortex columns. Neuronal responses to simple (pure tones), complex (noise burst and frequency modulated sweeps), and ecologically relevant (con-specific vocalizations) acoustic signals were measured. Collectively, the present investigation demonstrates that despite consistencies in neuronal tuning (characteristic frequency), irregularities in discharge activity between neurons of individual A1 columns increase as a function of spectral (signal complexity) and temporal (duration) acoustic variations. PMID- 25494366 TI - Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. AB - Recent studies of genomic variation associated with autism have suggested the existence of extreme heterogeneity. Large-scale transcriptomics should complement these results to identify core molecular pathways underlying autism. Here we report results from a large-scale RNA sequencing effort, utilizing region-matched autism and control brains to identify neuronal and microglial genes robustly dysregulated in autism cortical brain. Remarkably, we note that a gene expression module corresponding to M2-activation states in microglia is negatively correlated with a differentially expressed neuronal module, implicating dysregulated microglial responses in concert with altered neuronal activity dependent genes in autism brains. These observations provide pathways and candidate genes that highlight the interplay between innate immunity and neuronal activity in the aetiology of autism. PMID- 25494367 TI - Is Mild Dementia Related to Unsafe Street-Crossing Decisions? AB - The overrepresentation of very old people (75 or older) in pedestrian crash statistics raises the issue of the effects of normal and pathologic ageing on gap selection difficulties during street crossing. The present study focused on Alzheimer disease, a condition commonly associated with cognitive declines detrimental to daily life activities such as crossing the street. Twenty-five participants with mild dementia and 33 controls carried out a street-crossing task in a simulated environment. They also took a battery of cognitive tests. The mild-dementia group was more likely than the control group to make decisions that led to collisions with approaching cars, especially when the traffic was coming from 2 directions and they were in the far lane. Regression analyses demonstrated that the increased likelihood of collisions in the dementia group was associated with impairments in processing-speed and visual-attention abilities assessed on the Useful Field of View test. This test has already proven useful for predicting driving outcomes, falls, and street-crossing difficulties in healthy old adults, and among drivers with Alzheimer disease. Clinicians are encouraged to use it to help estimate whether a patient can drive, walk, and cross a street safely. PMID- 25494368 TI - Biopsies of nevi in children and adolescents in the United States, 2009 through 2013. PMID- 25494369 TI - Levels of interleukin-35 and its relationship with regulatory T-cells in chronic hepatitis B patients. AB - Interleukin-35 is a novel inhibition cytokine secreted by CD4+CD25+ regulatory T cells (Treg) in murine. However, it is disputed whether IL-35 could be secreted by Treg cells in humans. In this study, the levels of IL-35 were detected, and its relationship with regulatory T-cells in chronic hepatitis B (CHB) patients was investigated. It was shown that the levels of IL-35 in CHB patients were higher than those in normal controls, and the levels increased gradually, accompanied with the severe liver inflammation and necrosis and poor synthesis function. Treg cells may secrete IL-35, whose levels would become higher, accompanied by a longer activated time. Thus, IL-35 as a cytokine secreted by Treg cells may accelerate liver inflammation and necrosis, and inhibit the synthesis function. PMID- 25494370 TI - A new unity for angular measurements in strabismus. AB - The practical advantages of quantifying an angle by a ratio of linear lengths instead of arcs of circles has led to the definition of the prism-diopter, a conventional unity for numbering prisms and measuring strabismic deviations. However, a major inconvenience of using prism-diopter unities to express angular measurements is the non-linearity of the scale, which reaches an infinite value for the angle of 90o, then becomes negative, with decreasing magnitudes for increasing angles between 90o and 180o. As a consequence, arithmetical operations and comparisons of angles measured by such unities present errors of very great magnitudes. In order to retain the advantages of defining an angle by straight line dimensions but to diminish the severe inconveniences of this method, a new definition of the prism-diopter is proposed. Here, instead of defining the prism diopter by the asymmetrical condition, the conception of this new unity is based on a geometrically symmetrical condition; that of the relationship of an isosceles triangle (where the leg is perpendicular to the bisector of the angle and the bisector itself ). The condition of symmetry for the definition of the new unity represents a conceptual advance because it reproduces the already well accepted, conventional criteria for quantifying the value of a prism, that of its minimum deviation. Furthermore, it corresponds to the most commonly observed clinical conditions of binocular balance. The absolute differences between the unitary values of the prism-diopter and that of the new unity are negligible (0.0025%), but the scale of values expressed by the new unity is closer to the ideal scale of angular measurements. (With the new unity, the infinite value is only reached for an angle of 180o and the errors due to arithmetical operations are much smaller.) Numerical examples showing the advantages of using the new unity of angular measurements instead of the prism-diopter are presented. A mathematical generalization of the modifying concept (partition of an angle) with which the new unity is based is also provided. PMID- 25494371 TI - Evaluation of choroidal thickness in patients with obstructive sleep apnea/hypopnea syndrome. AB - Purpose: To compare the subfoveal choroidal thickness (SFCT) of patients with different severities of obstructive sleep apnea/hypopnea syndrome (OSAHS) and normal controls via enhanced depth imaging optical coherence tomography (EDI OCT). Methods: In this retrospective, case-control study, 49 eyes from 49 patients that had undergone polysomnography were included. SFCT of the horizontal and vertical line scans were manually measured for all eyes based on EDI-OCT images. Two separate analyses were performed according to different apnea/hypopnea index (AHI) groupings. Initial testing was conducted using non OSAHS, mild OSAHS (5<=AHI<15), moderate OSAHS (15<=AHI<30), and severe OSAHS (AHI>=30) patient groupings, while secondary testing used non-OSAHS, mild OSAHS (5<=AHI<15), and moderate/severe OSAHS (AHI>=15) patient groupings. Results: The mean SFCT was 314.5 MUm in the non-OSAHS patients (n=14), 324.5 MUm in the mild OSAHS patients (n=15), 269.3 MUm in the moderate OSAHS patients (n=11), and 264.3 MUm in the severe OSAHS patients (n=9). SFCT between the four groups revealed no significant differences despite a trend towards slight thinning in the severe group (P=0.08). When the moderate and severe groups were merged and compared with the mild OASHS and non-OSAHS groups, SFCT of the moderate/severe group was found to be significantly thinner than that of the mild group (P=0.016). A negative significant correlation was found between SFCT and AHI in OSAHS patients (r=0.368, P=0.033). Conclusions: In patients with moderate/severe OSAHS, EDI-OCT revealed a thinned SFCT. Other accompanying systemic or ocular diseases may induce perfusion and oxygenation deficiency in eyes of OSAHS patients. Further studies are required in order to determine the exact relationships between ocular pathologies and clinical grades of OSAHS. PMID- 25494372 TI - The role of mast cells in vascularized recurrent pterygium. AB - Objective: To determine and compare the mast cell count in primary and recurrent vascularized pterygium, and in normal bulbar conjunctiva. Methods: The study included 22 patients with primary pterygium (PP group) and 28 patients with vascularized recurrent pterygium (VRP group) that underwent excision via the limbal conjunctival autograft technique. Normal conjunctiva samples were collected from the superotemporal bulbar conjunctival region, just temporal to the site from which the autograft conjunctival tissue was harvested. The total number of mast cells in the pterygium (primary and recurrent) and control tissue samples was calculated microscopically using 1% toluidine blue stain under 400* magnification. Results: The mean mast cell count in primary and vascularized recurrent pterygium tissue was 7.45 +/- 2.06 mm-2 and 16.11 +/- 4.33 mm-2, respectively, and the difference was significant (independent samples t-test, P<0.001). The mean mast cell count in pterygium tissue was significantly higher than that in normal conjunctiva tissue in both groups (Student's t-test, P<0.001). Conclusion: An increase in the number of mast cells might play a role in the pathogenesis of recurrent pterygium. Determination of a mast cell count cut-off value could be of diagnostic significance for recurrent pterygium. PMID- 25494373 TI - Intraocular pressure fluctuation in healthy and glaucomatous eyes: a comparative analysis between diurnal curves in supine and sitting positions and the water drinking test. AB - Purpose: To compare intraocular pressure (IOP) using the simplified daily tensional curve (SDTC) between supine and sitting positions in terms of peak levels and amount of fluctuation in both, glaucomatous and healthy subjects. The secondary endpoint was the comparison of these measures with those derived from the water drinking test (WDT). Methods: Thirty patients with primary open-angle glaucoma (POAG) that were undergoing medical therapy and 30 healthy subjects were enrolled in this study. Each patient underwent a diurnal curve between 8 am and 4 pm. After lying down for 5 minutes, the IOP was measured with the Perkins tonometer. Patients were instructed to sit in the upright position for 5 minutes and the tonometry was repeated. At 4:15 pm, the WDT test was performed. Fluctuation was defined as the difference between the highest and the lowest IOP readings (range). The Student's t test was used to assess differences and a P value <0.05 was considered to be statistically significant. Results: The diurnal curve in the supine position demonstrated higher IOP average values (on average 3 4 mmHg higher) compared to the sitting position (p<0.0001) for both groups. IOP peaks were higher in the supine position; however, the IOP range was essentially the same between the three methods. Treated glaucomatous patients had higher IOP levels in all measurements, but the fluctuation for all tests performed appeared to be similar to that of healthy patients. Conclusion: The data suggested that WDT can be used to estimate the diurnal IOP peak and fluctuation observed in the SDTC of the supine position for treated glaucomatous patients. Further studies can compare the possible correlation between the WDT results and those obtained from nocturnal supine measurements. PMID- 25494374 TI - Managment of orbital complications of sinusitis. AB - Purpose: We reported on the clinical approaches of ophthalmology and otorhinolaryngology departments in the treatment of the orbital complications of sinusitis. We also included an in-depth literature review. Methods: We retrospectively reviewed the medical files of 51 patients from January 2008 to January 2014. The records were evaluated for age, gender, type of orbital complications, symptoms, predisposing factors, imaging studies, medical and surgical management, culture results, and follow-up information. SPSS version 15.0 software (Statistical Analysis, The Statistical Package for Social Sciences Inc, Chicago, IL) was used for the statistical analysis. Results: Fifty-one patients met the criteria, with available medical records, for the study (29 male, 22 female). Thirty-two (62.7%) were diagnosed with preseptal cellulitis and 19 (37.3%) with postseptal cellulitis. After a detailed evaluation, 15 were diagnosed with a subperiosteal abscess (SPA), and 4 were diagnosed with orbital cellulitis. The age and gender was similar for the two groups. Five patients with medial SPA were treated with endoscopic sinus surgery, one patient with inferior SPA was treated with external surgery, and six patients with other localizations were treated with a combination of endoscopic sinus surgery and external surgery. All patients presented with periorbital erythema and edema. The length of hospitalization and duration of symptoms were similar in both groups. Visual acuity was between 1/10 to 10/10 (mean 7/10) and statistically significant for preseptal and postseptal cellulitis groups (p<0.001). All patients received intravenous antibiotics upon the first day of admission. Conclusion: Orbital complications of acute sinusitis required intensive follow-up and a multidisciplinary approach. A contrast-enhanced paranasal sinus computerized tomography (CT) scan can detect the extent of the infection. An initial trial of intravenosus (IV) antibiotics may be appropriate when close monitoring is possible. Surgery may be indicated when there has been no improvement within 48 hours of intravenous treatment, loss of visual acuity (under 8/10), and a non medial abscess. PMID- 25494375 TI - Late diagnosis and surgical treatment of patients diagnosed with unilateral congenital cataract at Fundacion Vision, in Asuncion, Paraguay. AB - Purpose: Providing data on the late diagnosis and surgical treatment of patients who underwent surgery for total unilateral congenital cataract. Methods: Systematic retrospective review of the medical record of all patients between 0 and 16 years old with total unilateral congenital cataract who underwent surgery at Fundacion Vision between January 2010 and July 2012. Results: Medical records of 37 patients (51 % females) were studied, age was 7.4 (+/- 4.9) years (average +/- SD) and 62% lived on Departamento Central (the most populated region from Paraguay). A total of 97.3% patients underwent late surgical treatment and 86.5% received a late diagnosis. The average time elapsed between the diagnosis and the surgical treatment was one month, and 62.2% of the patients underwent surgery within six months from the diagnosis. Conclusion: This study evidences that most of the patients in our series had a late treatment as a result of a late diagnosis. Based on these results we recommend establishing strategies to improve the early detection and surgical treatment of the newborns. PMID- 25494376 TI - Teratogen exposure and congenital ocular abnormalities in Brazilian patients with Mobius sequence. AB - Purpose: To assess the sociodemographic profiles, teratogen exposures, and ocular congenital abnormalities in Brazilian patients with Mobius sequence. Method: Forty-four patients were recruited from the Brazilian Mobius Sequence Society. This cross-section comprised 41 patients (age, mean +/- standard deviation, 9.0 +/- 5.5 years) who fulfilled the inclusion criteria. The parent or caregiver answered a questionnaire regarding sociodemographic data and pregnancy history. Patients underwent ophthalmological assessments. They were subdivided into groups according to misoprostol exposure during pregnancy, and the two groups were compared. Results: Mothers/caregivers reported unplanned pregnancies in 36 (88%) cases. Of these, 19 (53%) used misoprostol during their first trimesters. A stable marital status tended to be more frequent in the unexposed group (P=0.051). Incomplete elementary school education was reported by two (11%) mothers in the exposed group and by three (14%) mothers in the unexposed group (P=0.538). The mothers' gestational exposures to cocaine, marijuana, alcohol, and cigarettes were similar in both groups (P=0.297, P=0.297, P=0.428, and P=0.444, respectively). One (5%) case of Rubella infection during pregnancy was found in the unexposed group. The main malformations in the exposed and unexposed groups were the following: strabismus (72% and 77%, respectively), lack of emotional tearing (47% and 36%, respectively), and lagophthalmos (32% and 41%, respectively). Conclusion: Stable marital statuses tended to be more frequent among mothers that did not take misoprostol during pregnancy. Exposures to other teratogens and the main ocular abnormalities were similar in both groups. PMID- 25494377 TI - Use of impression cytology for the detection of unsuspected ocular surface squamous neoplasia cells in pterygia. AB - Purpose: To evaluate the agreement between the methodologies of impression cytology (IC) and histopathology regarding epithelial lesions clinically diagnosed as pterygium and also regarding the detection of unsuspected and associated ocular surface squamous neoplasia (OSSN). Methods: Thirty-two Brazilian patients were included and IC was performed on all pterygia before excision. Histopathogical examination was considered the gold standard and was performed by two experienced ocular pathologists in which consensus existed regarding pterygia diagnosis. IC accuracy was assessed by sensitivity and specificity with a 95% confidence interval. Results: From the 32 primary lesions studied, histopathological examination confirmed the diagnosis of pterygium without atypical cells in 19 cases (60%) and showed unsuspected and associated OSSN cells in 13 cases (40%). IC demonstrated one false-negative and one false positive result for atypia. Statistical analysis showed an estimated sensitivity of 92%, specificity of 94%, positive predictive value of 92%, and negative predictive value of 94%. Conclusion: IC demonstrated high agreement with histopathological analysis in the detection of atypical epithelial cells in unsuspected OSSN in Brazilian pterygia patients. PMID- 25494378 TI - Induction of corneal collagen cross-linking in experimental corneal alkali burns in rabbits. AB - Objective: To evaluate the effect of riboflavin-ultraviolet-A-induced cross linking (CXL) following corneal alkali burns in rabbits. Methods: The right corneas and limbi of ten rabbits were burned using a 1N solution of NaOH and the animals were then divided into two groups: a control group submitted to clinical treatment alone and an experimental group that was treated 1 h after injury with CXL, followed by the same clinical treatment as administered to the controls. Clinical parameters were evaluated post-injury at 1, 7, 15, and 30 days by two independent observers. Following this evaluation, the corneas were excised and examined histologically. Results: There were no statistically significant differences in clinical parameters, such as hyperemia, corneal edema, ciliary injection, limbal ischemia, secretion, corneal neovascularization, symblepharon, or blepharospasm, at any of the time-points evaluated. However, the size of the epithelial defect was significantly smaller in the CXL group (p<0.05) (day 15: p=0.008 and day 30: p=0.008) and the extent of the corneal injury (opacity lesion) was also smaller (day 30: p=0.021). Histopathology showed the presence of collagen bridges linking the collagen fibers in only the CXL group. Conclusions: These results suggest that the use of CXL may improve the prognosis of acute corneal alkali burns. PMID- 25494379 TI - Grid laser photocoagulation in the treatment of serous avascular pigment epithelial detachment in age-related macular degeneration. AB - Purpose: Describe the outcomes of thermal laser photocoagulation in three cases of retinal pigment epithelium detachment associated to age-related macular degeneration. Methods: Three patients with avascular retinal pigment epithelium detachment were treated with green diode laser photocoagulation. Mild macular grid laser application, similar to the treatment of diabetic macular edema was performed after an unsuccessful intravitreal anti-angiogenic treatment. Results: After one year of the laser treatment, two cases reached anatomic resolution, with complete absorption of sub-epithelium serum fluid and improvement of the visual acuity. There was stability of the visual acuity and sub-epithelium fluid reduction, which, however, was partial in the third case. No complications related to the treatment occurred until the conclusion of this study. Conclusions: Macular photocoagulation in grid pattern produced regression of avascular serous pigment epithelium detachment associated with age-related macular degeneration in a short follow-up period. Although long term prospective studies with an increased sample are necessary, it is a method that can be applied in selected patients, with absence of sub-retinal neovascularization or sub-epithelium fibrovascular component. PMID- 25494380 TI - Interferon-associated retinopathy in a patient with metastatic melanoma. AB - We present the unusual case of a 35 year-old woman with stage IV melanoma and widespread metastases, who was undergoing treatment with interferon alpha-2b and who presented with interferon-associated retinopathy. The patient, who had been taking interferon treatment for three months, complained of a sudden loss of visual acuity in the left eye. An ocular examination revealed multiple cotton wool spots along the retina and macular involvement. Interferon treatment was suspended. Although rare, retinopathy represents a potentially serious adverse effect of interferon treatment. Although normally patients are asymptomatic, complications derived of its use may arise, which can lead to significant visual impairment. We therefore suggest that before initiating treatment with this drug, patients should be informed of its potential ocular risks, and that regular eye examinations are conducted along with the treatment. PMID- 25494381 TI - Yellowish dots in the retina: a finding of ocular syphilis? AB - Here we report the occurrence of pale yellowish perivascular preretinal dots in 12 patients with ocular syphilis. A case series of these patients was examined between March and October 2012 at the Uveitis Sector of Universidade Federal de Sao Paulo. After diagnostic confirmation of syphilis, fundus photographs and optical coherence tomography (OCT) were performed to verify the localization of the dots, and patients were treated with IV crystalline penicillin for 14 days. The study comprised 11 men (91.6%), 19 eyes, median presentation age of 38.1 years, and panuveitis as the main clinical manifestation (seven patients, 58.3%), being bilateral in four. Ten patients were taking oral prednisone (83.3%). Serum panels performed by the Venereal Disease Research Laboratory (VDRL) showed positive results in eight patients (66.7%), whereas VDRL cerebrospinal fluid (CSF) tests were negative in seven of nine collected (77.8%). However, serum FTA Abs was positive in 100% of patients, and eight patients (66.7%) had HIV infection. The best corrected visual acuity (BCVA) presented after treatment improved in 10 eyes (55.6%), did not change in seven eyes (38.9%), and worsened in one eye (5.6%). Although not yet acknowledged in the literature as a typical manifestation of ocular syphilis, these are very common findings in clinical practice. We believe that preretinal dots are due to perivasculitis secondary to treponema infection. It is important recognize them and remember that syphilis can present in several forms, including the one presented in this study. PMID- 25494382 TI - An association between subclinical familial exudative vitreoretinopathy and rod cone dystrophy. AB - A 21-year-old Caucasian man presented with a complaint of nyctalopia. Visual acuity in both eyes was 20/20 and anterior segment biomicroscopy results were unremarkable. Fundoscopy revealed peripheral avascular zones, minimal peripheral retinal exudation from the retinal vessels, peripheral retinal telangiectasias and anastomosis in both eyes, and retinal vascular dragging toward the temporal periphery in both eyes. Full field electroretinography showed that rod responses were almost absent and that cone responses were reduced. Macular optical coherence tomography showed normal structure in both eyes. Vascular changes were attributed to a subclinical form of familial exudative vitreoretinopathy. This was an interesting case due to the association of familial exudative vitreoretinopathy with rod-cone dystrophy. PMID- 25494383 TI - Bilateral acute visual loss from Rathke's cleft cyst apoplexy in a patient with dengue fever. AB - Hemorrhagic complications of optic pathway diseases are extremely rare causes of acute visual loss associated with dengue fever. In this paper we report a patient presenting with dengue fever and bilateral acute visual loss caused by chiasmal compression due to Rathke's cleft cyst apoplexy. Considering the importance of early diagnosis and treatment to visual recovery, apoplexy of sellar and suprasellar tumors should be considered in the differential diagnosis of patients with acute visual loss and dengue fever. PMID- 25494384 TI - Simulation models applied to practical learning and skill enhancement in direct and indirect ophthalmoscopy: a review. AB - The purpose of this review was to analyze and describe simulation methods for practical learning and training of the ophthalmoscopy exam and to organize them into specific topics relative to each principle of operation, while evaluating their preliminary results. A critical review of articles that described and evaluated simulated models for ophthalmoscopy published in the last ten years (2004-2014) was performed. One hundred articles about ophthalmology and simulation were found in national and international periodicals, but only a few discussed the examination of the posterior pole of the eye. For this study, 25 articles were considered; those articles described simulation methods, general concepts, and its actual use in ophthalmoscopy. There were many different simulation methods described, but only few articles proved their efficacy or performed a comparison between models. Review of this topic may give information for the critical analysis of the simulation devices and ideas for the development of new ones. PMID- 25494385 TI - Graves ophthalmopathy: low-dose glucocorticoid increases peroxisome proliferator activated receptor-gamma gene expression. PMID- 25494386 TI - The power of observation. PMID- 25494388 TI - Fracture Healing:"An Appraisal of the Effects of Frequently Prescribed Medications" AB - BACKGROUND: Recognizing the existence of adverse drug effects of frequently prescribed drugs can empower a clinician with knowledge to avoid dangerous adverse effects that may result in hazardous, negative patient outcomes on either fracture healing or bone health. Pharmacovigilance reports have described the influence of medications, allowing for bone health to be quite unpredictable. METHODS: First, mechanisms found in the medical literature of potential drug adverse effects regarding fracture healing are presented. Second, the 100 most frequently prescribed medications in 2010 are reviewed regarding adverse effects on fracture healing. These reported adverse effects are evaluated for medical causation. Last, a data table describing the 100 reviewed medications and their reported effects on fracture healing is provided. RESULTS: The actual number of different medications in the review was 72. Reported drug adverse effects on bone and fracture healing occurred with 59 of the 72 drugs (81.9%). These adverse effects are either described as a definitive statement or represented by postmarketing case reports. Thirteen of the 72 review drugs (18.1%) did not have any description of the possible effects on bone health. A total of 301 cases reports describing delayed union, malunion, and nonunion of fractures represent 31 of the 72 medications reviewed (43.1%). CONCLUSIONS: This review offers the health-care provider information regarding potential adverse drug effects on bone health. Empowered with this information, clinicians may assist their patients to maximize pharmacologic outcomes by avoiding these reported harmful adverse effects. PMID- 25494387 TI - A New Fossil of Necrotauliidae (Insecta: Trichoptera) from the Jiulongshan Formation of China and Its Taxonomic Significance. AB - BACKGROUND: Acisarcuatus variradius gen. et sp. nov., an extinct new species representing a new genus, is described from the Middle Jurassic Jiulongshan Formation in Daohugou Village, Inner Mongolia, China. METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we revised the diagnosis of Necrotauliidae Handlirsch, 1906. One new genus and species of Necrotauliidae is described. An analysis based on the fossil morphological characters clarified the taxonomic status of the new taxa. CONCLUSIONS/SIGNIFICANCE: New fossil evidence supports the viewpoint that the family Necrotauliidae belongs to the Integripalpia. PMID- 25494389 TI - Mental Fatigue Impairs Intermittent Running Performance. AB - PURPOSE: The purpose of the study was to investigate the effects of mental fatigue on intermittent running performance. METHODS: Ten male intermittent team sports players performed two identical self-paced, intermittent running protocols. The two trials were separated by 7 d and preceded, in a randomized counterbalanced order, by 90 min of either emotionally neutral documentaries (control) or the AX-continuous performance test (AX-CPT; mental fatigue). Subjective ratings of fatigue and vigor were measured before and after these treatments, and motivation was recorded before the intermittent running protocol. Velocity, heart rate, oxygen consumption, blood glucose and lactate concentrations, and ratings of perceived exertion (RPE) were measured throughout the 45-min intermittent running protocol. Session RPE was recorded 30 min after the intermittent running protocol. RESULTS: Subjective ratings of fatigue were higher after the AX-CPT (P = 0.005). This mental fatigue significantly reduced velocity at low intensities (1.28 +/- 0.18 m.s vs 1.31 +/- 0.17 m.s; P = 0.037), whereas high-intensity running and peak velocities were not significantly affected. Running velocity at all intensities significantly declined over time in both conditions (P < 0.001). Oxygen consumption was significantly lower in the mental fatigue condition (P = 0.007). Other physiological variables, vigor and motivation, were not significantly affected. Ratings of perceived exertion during the intermittent running protocol were not significantly different between conditions despite lower overall velocity in the mental fatigue condition. Session RPE was significantly higher in the mental fatigue condition (P = 0.013). CONCLUSION: Mental fatigue impairs intermittent running performance. This negative effect of mental fatigue seems to be mediated by higher perception of effort. PMID- 25494390 TI - Trunk Dynamics Are Impaired in Ballet Dancers with Back Pain but Improve with Imagery. AB - PURPOSE: Trunk control is essential in ballet and may be compromised in dancers with a history of low back pain (LBP) by associated changes in motor control. This study aimed to compare trunk mechanical properties between professional ballet dancers with and without a history of LBP. As a secondary aim, we assessed whether asking dancers to use motor imagery to respond in a "fluid" manner could change the mechanical properties of the trunk and whether this was possible for both groups. METHODS: Trunk mechanical properties of stiffness and damping were estimated with a linear second-order system, from trunk movement in response to perturbations, in professional ballet dancers with (n = 22) and without (n = 8) a history of LBP. The second-order model adequately described trunk movement in response to the perturbations. Trials were performed with and without motor imagery to respond in a fluid manner to the perturbation. RESULTS: Dancers with a history of LBP had lower damping than dancers without LBP during the standard condition (P = 0.002) but had greater damping during the "fluid" condition (P < 0.001), with values similar to dancers without LBP (P = 0.226). Damping in the dancers without LBP was similar between the conditions (P > 0.99). Stiffness was not different between the dancers with and those without a history of LBP (P = 0.252) but was less during the fluid condition than the standard condition (P < 0.001). CONCLUSION: Although dancers with a history of LBP have less trunk damping than those without LBP, they have the capacity to modulate the trunk's mechanical properties to match that of pain-free dancers by increasing damping with motor imagery. These observations have potential relevance for LBP recurrence and rehabilitation. PMID- 25494391 TI - Recent Advances in Iron Metabolism: Relevance for Health, Exercise, and Performance. AB - Iron is necessary for physiological processes essential for athletic performance, such as oxygen transport, energy production, and cell division. However, an excess of "free" iron is toxic because it produces reactive hydroxyl radicals that damage biological molecules, thus leading to cell and tissue injury. Therefore, iron homeostasis is strictly regulated; and in recent years, there have been important advancements in our knowledge of the underlying processes. Hepcidin is the central regulator of systemic iron homeostasis and exerts its function by controlling the presence of the iron exporter ferroportin on the cell membrane. Hepcidin binding induces ferroportin degradation, thus leading to cellular iron retention and decreased levels of circulating iron. As iron is required for hemoglobin synthesis, the tight link between erythropoiesis and iron metabolism is particularly relevant to sports physiology. The iron needed for hemoglobin synthesis is ensured by inhibiting hepcidin to increase ferroportin activity and iron availability and hence to make certain that efficient blood oxygen transport occurs for aerobic exercise. However, hepcidin expression is also affected by exercise-associated conditions, such as iron deficiency, anemia or hypoxia, and, particularly, inflammation, which can play a role in the pathogenesis of sports anemia. Here, we review recent advances showing the relevance of iron for physical exercise and athletic performance. Low body iron levels can cause anemia and thus limit the delivery of oxygen to exercising muscle, but tissue iron deficiency may also affect performance by, for example, hampering muscle oxidative metabolism. Accordingly, a hemoglobin-independent effect of iron on exercise capacity has been demonstrated in animal models and humans. Here, we review recent advances showing the relevance of iron for physical exercise and athletic performance. PMID- 25494392 TI - Energy Expenditure Prediction Using Raw Accelerometer Data in Simulated Free Living. AB - PURPOSE: The purpose of this study was to develop, validate, and compare energy expenditure (EE) prediction models for accelerometers placed on the hip, thigh, and wrists using simple accelerometer features as input variables in EE prediction models. METHODS: Forty-four healthy adults participated in a 90-min, semistructured, simulated free-living activity protocol. During the protocol, participants engaged in 14 different sedentary, ambulatory, lifestyle, and exercise activities for 3-10 min each. Participants chose the order, duration, and intensity of activities. Four accelerometers were worn (right hip, right thigh, as well as right and left wrists) to predict EE compared with that measured by the criterion measure (portable metabolic analyzer). Artificial neural networks (ANNs) were created to predict EE from each accelerometer using a leave-one-out cross-validation approach. Accuracy of the ANN was evaluated using Pearson correlations, root mean square error, and bias. Several ANNs were developed using different input features to determine those most relevant for use in the models. RESULTS: The ANNs for all four accelerometers achieved high measurement accuracy, with correlations of r > 0.80 for predicting EE. The thigh accelerometer provided the highest overall accuracy (r = 0.90) and lowest root mean square error (1.04 METs), and the differences between the thigh and the other monitors were more pronounced when fewer input variables were used in the predictive models. None of the predictive models had an overall bias for prediction of EE. CONCLUSIONS: A single accelerometer placed on the thigh provided the highest accuracy for EE prediction, although monitors worn on the wrists or hip can also be used with high measurement accuracy. PMID- 25494393 TI - Execution of Activities of Daily Living in Persons with Parkinson Disease. AB - INTRODUCTION: Muscular weakness and the motor difficulties associated with Parkinson disease (PD) often impair the performance of activities of daily living (ADL). However, little is known about the magnitude and distribution of relative muscular effort of persons with PD during ADL. The purpose of this investigation was to determine the relative magnitude of lower extremity moment production that persons with PD use to perform common ADL. METHODS: Fifteen participants with mild-to-moderate PD and 14 age/sex-matched controls volunteered. Participants performed a series of ADL tasks, as follows: gait initiation (GI), gait, and stair ascending tasks. Participants were then asked to perform maximal-effort isokinetic tests of hip and knee extension and ankle plantarflexion at speeds of 90 degrees per second and 120 degrees per second. Relative effort was quantified as a percentage of the maximal isokinetic value produced by a joint during performance of the ADL. Relative effort and peak isokinetic joint moments were analyzed using a mixed-model ANOVA with repeated measures. All other comparisons were evaluated using independent t-tests. RESULTS: Persons with PD produced smaller ankle plantarflexion moment at both 90 degrees per second and 120 degrees per second (P < 0.05). Relative effort during GI (271% vs 189%, P < 0.05) and gait (270% vs 161%, P < 0.05) was significantly greater at the ankle in persons with PD. Contribution of the ankle to the support moment was lower in PD during stair ascending (24% vs 34%) and GI (63% vs 57%) compared with that in controls. CONCLUSIONS: The reduced ankle moments during ADL are indicative of deficits in muscular capabilities in those with PD. Moreover, PD caused a redistribution of joint torques, such that PD participants used their hip extensors more and ankle plantarflexors less. PMID- 25494394 TI - The spirit of a Jasmine. PMID- 25494396 TI - Evolution of football match analysis research. PMID- 25494395 TI - The geriatric cytokine response to trauma: time to consider a new threshold. AB - BACKGROUND: Inflammatory responses to trauma, especially if exaggerated, drive mortality and morbidities including infectious complications. Geriatric patients are particularly susceptible to profound inflammation. Age-related declines in inflammatory and immune systems are known to occur. Geriatric patients display dampened inflammatory responses to non-critical disease processes. Specific inflammatory responses in critically ill geriatric trauma patients, and how the inflammatory profile associated with subsequent infections or mortality, remain unknown. METHODS: Geriatric (>=65 y) and young (18-50 y old) critically ill blunt trauma intensive care unit (ICU) patients were enrolled prospectively. Blood was drawn within 36 h of presentation to measure circulating cytokines including interleukin (IL)-6 (pg/mL), IL-10 (pg/mL), and tumor necrosis factor (TNF)-alpha (pg/mL) levels. Age, gender, Acute Physiology and Chronic Health Evaluation (APACHE II) score and outcomes were reviewed. RESULTS: Twenty-one young and 29 geriatric critically ill patients were recruited. Groups were comparable in male gender and age-adjusted APACHE II score, but geriatric patients had higher mortality (38% versus 9.5%; p=0.04). Within geriatric trauma patients, the development of a secondary infection was associated with significantly lower presenting IL-6 and IL-10 levels and no difference in TNF-alpha levels. Furthermore, geriatric patients who died had elevated IL-6 and IL-10 and decreased TNF-alpha levels compared with geriatric patients who lived. Compared with the young cohort, IL-6 and IL-10 levels were similar between geriatric patients who died and young patients who lived. However, geriatric patients who lived, compared with young patients who lived, had significantly lower IL-6 and IL-10. There was no such relation noted with TNF-alpha. CONCLUSIONS: A lowered inflammatory response in geriatric patients is associated with the development of a subsequent infection. However, geriatric patients exhibiting inflammatory responses as robust as their younger counterparts have increased mortality. Redefining our understanding of an appropriate geriatric inflammatory response to trauma will help future therapy, thereby improving morbidity and mortality. PMID- 25494398 TI - Charge-induced patchy attractions between proteins. AB - Static light scattering (SLS) combined with structure-based Monte Carlo (MC) simulations provide new insights into mechanisms behind anisotropic, attractive protein interactions. A nonmonotonic behavior of the osmotic second virial coefficient as a function of ionic strength is here shown to originate from a few charged amino acids forming an electrostatic attractive patch, highly directional and complementary. Together with Coulombic repulsion, this attractive patch results in two counteracting electrostatic contributions to the interaction free energy which, by operating over different length scales, is manifested in a subtle, salt-induced minimum in the second virial coefficient as observed in both experiment and simulations. PMID- 25494400 TI - Rhodium-catalyzed dehydrogenative germylation of C-H bonds: new entry to unsymmetrically functionalized 9-germafluorenes. AB - Rhodium-catalyzed dehydrogenative germylation leading to unsymmetrically functionalized 9-germafluorenes via Ge-H and C-H bond activation is described. Despite the significant achievements made in dehydrogenative functionalization of C-H bonds, only a limited number of examples with the fourth-row atom-H bonds have been reported. The current method enabled the synthesis of various 9 germafluorene derivatives, including tetracyclic as well as donor-acceptor substituted germoles, which may be useful for electronic device applications. PMID- 25494399 TI - Toward a Better Understanding of the Link Between Parent and Child Physical Activity Levels: The Moderating Role of Parental Encouragement. AB - BACKGROUND: Research on adolescent physical activity is mixed regarding the role of parent activity. This study tested parent encouragement, direct modeling, and perceived influence as moderators of objectively-measured (accelerometer) parent and child moderate-to-vigorous physical activity (MVPA) associations. METHODS: Parent-child dyads (n = 423; mean child age = 11.33 yrs.) wore accelerometers for 7 days; parents completed surveys. Hierarchical linear regression models tested moderation using a product of constituent terms interaction. RESULTS: Parent reported encouragement moderated the association between parent and child MVPA (beta = -.15, P = .01, DeltaR2 = .02, P < .01). Among parents with lower MVPA, child MVPA was higher for children receiving high encouragement (mean = 3.06, SE = .17) vs. low (mean = 3.03, SE = .15, P = .02) and moderate encouragement (mean = 3.40, SE = .09) vs. low (P = .04). CONCLUSIONS: Physical activity promotion programs may use parent encouragement as a tool to boost child activity, but must consider other child and parent characteristics that could attenuate effects. PMID- 25494401 TI - Varieties of integrative scholarship: why rules of evidence, criteria, and standards matter. AB - Integrative scholarship involves the aggregation of data and evidence in a way that allows the research community to comprehend and value the connections and perspectives that unite isolated facts and research studies. Integrative scholarship summarizes data, enlightens and informs readers broadly, and sets the stage for subsequent research. This article describes five approaches to integrative scholarship--narrative, systematic, scoping, critical-realist, open peer commentary--and argues that each approach uses different methods and rules of evidence to combine data and report their meaning. Different forms of integrative scholarship use methods, criteria, and standards that are matched to the integrative approach and data being evaluated. There is no one best strategy to conduct or judge integrative scholarship. Researchers who perform integrative scholarship should openly express the values that underlie their work. PMID- 25494402 TI - AM last page. Improving health care quality: a polarity management perspective. PMID- 25494404 TI - 4-Acetylantroquinonol B suppresses tumor growth and metastasis of hepatoma cells via blockade of translation-dependent signaling pathway and VEGF production. AB - Hepatocellular carcinoma (HCC) has become one of most common malignancies and a leading cause of cancer mortality worldwide. Previous study has shown that 4 acetylantroquinonol B (4AAQB) isolated from Antrodia cinnamomea (or niu-chang chih) was observed to inhibit HepG2 cell proliferation via affecting cell cycle. However, the in vivo effects and antimetastatic activity of 4AAQB have not yet been addressed. This study found that 4AAQB inhibited HepG2 and HuH-7 hepatoma cell growth in both in vitro and in vivo models and exhibited pronounced inhibitory effects on HuH-7 tumor growth in xenograft and orthotopic models. 4AAQB efficiently inhibited the phosphorylation of mTOR and its upstream kinases and the downstream effectors and decreased the production of VEGF and activity of Rho GTPases in HuH-7 cells. Furthermore, 4AAQB inhibited in vitro HuH-7 cell migration and in vivo pulmonary metastasis. The results suggested that 4AAQB is a potential candidate for HCC therapy. PMID- 25494405 TI - Angiotensin II type 1 receptor (AT1) gene A1166C is associated with the risk of hypertension. AB - AIM: This study was performed on primary hypertension patients in a Turkish population to determine the frequency of the A1166C polymorphism in the angiotensin II type 1 receptor (AT1) gene and to examine the role of this polymorphism in hypertension development. MATERIALS AND METHODS: In this study, 250 genomic DNA samples were collected (from 142 hypertension patients and 108 healthy subjects), randomized, and analyzed. Genomic DNA was prepared from peripheral blood using the salt extraction method. The presence of the A1166C polymorphism in the AT1 gene was determined using the polymerase chain reaction (PCR)-restriction fragment length polymorphism method. PCR products were separated by 2% agarose gel electrophoresis and visualized by a charge-coupled device camera. RESULTS: Genotype distribution and allele frequency A1166C genotype frequency was determined as AA 96.3% and AC 3.7% for controls and as AA 86.6% and AC 13.4% for patients. A statistically significant difference was found between the control group and patients in terms of genotype and allele frequency. CONCLUSION: Our results suggest that an interaction exists between the AT1 gene polymorphism and hypertension in the Turkish population. PMID- 25494406 TI - Chemical vapor deposition of thin crystals of layered semiconductor SnS2 for fast photodetection application. AB - Layered two-dimensional (2D) semiconductors, such as MoS(2) and SnS(2), have been receiving intensive attention due to their technological importance for the next generation electronic/photonic applications. We report a novel approach to the controlled synthesis of thin crystal arrays of SnS(2) at predefined locations on chip by chemical vapor deposition with seed engineering and have demonstrated their application as fast photodetectors with photocurrent response time ~ 5 MUs. This opens a pathway for the large-scale production of layered 2D semiconductor devices, important for applications in integrated nanoelectronic/photonic systems. PMID- 25494407 TI - Ironing out their differences: dissecting the structural determinants of a phenylalanine aminomutase and ammonia lyase. AB - Deciphering the structural features that functionally separate ammonia lyases from aminomutases is of interest because it may allow for the engineering of more efficient aminomutases for the synthesis of unnatural amino acids (e.g., beta amino acids). However, this has proved to be a major challenge that involves understanding the factors that influence their activity and regioselectivity differences. Herein, we report evidence of a structural determinant that dictates the activity differences between a phenylalanine ammonia lyase (PAL) and aminomutase (PAM). An inner loop region that closes the active sites of both PAM and PAL was mutated within PAM (PAM residues 77-97) in a stepwise approach to study the effects when the equivalent residue(s) found in the PAL loop were introduced into the PAM loop. Almost all of the single loop mutations triggered a lyase phenotype in PAM. Experimental and computational evidence suggest that the induced lyase features result from inner loop mobility enhancements, which are possibly caused by a 310-helix cluster, flanking alpha-helices, and hydrophobic interactions. These findings pinpoint the inner loop as a structural determinant of the lyase and mutase activities of PAM. PMID- 25494408 TI - The significant impact of polydopamine on the catalytic performance of the carried Au nanoparticles. AB - Mussel-inspired polydopamine catalyst carriers dramatically enhance the catalytic performance (~450%) of Au nanoparticles in methylene blue reduction, which is attributed to the local enrichment mechanism caused by the favourable attractive interaction between the polydopamine and reactants. PMID- 25494410 TI - MEGA (Multiple Essential Genes Assembling) deletion and replacement method for genome reduction in Escherichia coli. AB - Top-down reduction of the bacterial genome to construct desired chassis cells is important for synthetic biology. However, the current progress in the field of genome reduction is greatly hindered by indispensable life-essential genes that are interspersed throughout the chromosomal loci. Here, we described a new method designated as "MEGA (Multiple Essential Genes Assembling) deletion and replacement" that functions by assembling multiple essential genes in an E. coli S. cerevisiae shuttle vector, removing targeted chromosomal regions containing essential and nonessential genes using a one-round deletion, and then integrating the cloned essential genes into the in situ chromosomal loci via I-SceI endonuclease cleavage. As a proof of concept, we separately generated three large deletions (80-205 kbp) in the E. coli MDS42 chromosome. We believe that the MEGA deletion and replacement method has potential to become widely used in large scale genome reductions in other sequenced organisms in addition to E. coli. PMID- 25494409 TI - Hiding and recovering electrons in a dimetallic endohedral fullerene: air-stable products from radical additions. AB - Fullerenyl radicals can be generated by addition of a free radical to a fullerene surface, by nucleophilic addition followed by one-electron oxidation, or by thermal dissociation of singly bonded fullerene dimers. However, fullerenyl radicals are usually very reactive and generally cannot be isolated. On the contrary, we have found that the reactions of the dimetallic endofullerenes, La2@Ih-C80 and La2@D5h-C80, with 3-chloro-5,6-diphenyltriazine resulted in mono addition of the triazinyl radical to the fullerene cages to yield isolable fullerenyl radicals. The unusual stability of these fullerenyl radicals arises from the confinement of the unpaired electron to an internal, metal-metal bonding orbital. Accordingly, the fullerene cage protects the radical center from other reactive species. Furthermore, we demonstrate that the fullerenyl radical adduct of La2@Ih-C80 reacts with toluene to afford additional benzylation. Interestingly, the benzylated derivative is diamagnetic in solution, while it forms a paramagnetic dimer when crystallized. PMID- 25494413 TI - For the Care of the Underserved. PMID- 25494411 TI - New insights into protamine-like component organization in Mytilus galloprovincialis' sperm chromatin. AB - We have analyzed Mytilus galloprovincialis' sperm chromatin, which consists of three protamine-like proteins, PL-II, PL-III, and PL-IV, in addition to a residual amount of the four core histones. We have probed the structure of this sperm chromatin through digestion with micrococcal nuclease (MNase) in combination with salt fractionation. Furthermore, we used the electrophoretic mobility shift assay to define DNA-binding mode of PL-II and PL-III and turbidimetric assays to determine their self-association ability in the presence of sodium phosphate. Although in literature it is reported that M. galloprovincialis' sperm chromatin lacks nucleosomal organization, our results obtained by MNase digestion suggest the existence of a likely unusual organization, in which there would be a more accessible location of PL-II/PL-IV when compared with PL-III and core histones. So, we hypothesize that in M. galloprovincialis' sperm chromatin organization DNA is wrapped around a PL-III protein core and core histones and PL-II and PL-IV are bound to the flanking DNA regions (similarly to somatic histone H1). Furthermore, we propose that PL's K/R ratio affects their DNA-binding mode and self-association ability as reported previously for somatic and sperm H1 histones. PMID- 25494412 TI - Correlation between gamma index passing rate and clinical dosimetric difference for pre-treatment 2D and 3D volumetric modulated arc therapy dosimetric verification. AB - OBJECTIVE: To investigate comparatively the percentage gamma passing rate (%GP) of two-dimensional (2D) and three-dimensional (3D) pre-treatment volumetric modulated arc therapy (VMAT) dosimetric verification and their correlation and sensitivity with percentage dosimetric errors (%DE). METHODS: %GP of 2D and 3D pre-treatment VMAT quality assurance (QA) with different acceptance criteria was obtained by ArcCHECK(r) (Sun Nuclear Corporation, Melbourne, FL) for 20 patients with nasopharyngeal cancer (NPC) and 20 patients with oesophageal cancer. %DE were calculated from planned dose-volume histogram (DVH) and patients' predicted DVH calculated by 3DVH(r) software (Sun Nuclear Corporation). Correlation and sensitivity between %GP and %DE were investigated using Pearson's correlation coefficient (r) and receiver operating characteristics (ROCs). RESULTS: Relatively higher %DE on some DVH-based metrics were observed for both patients with NPC and oesophageal cancer. Except for 2%/2 mm criterion, the average %GPs for all patients undergoing VMAT were acceptable with average rates of 97.11% +/- 1.54% and 97.39% +/- 1.37% for 2D and 3D 3%/3 mm criteria, respectively. The number of correlations for 3D was higher than that for 2D (21 vs 8). However, the general correlation was still poor for all the analysed metrics (9 out of 26 for 3D 3%/3 mm criterion). The average area under the curve (AUC) of ROCs was 0.66 +/ 0.12 and 0.71 +/- 0.21 for 2D and 3D evaluations, respectively. CONCLUSIONS: There is a lack of correlation between %GP and %DE for both 2D and 3D pre treatment VMAT dosimetric evaluation. DVH-based dose metrics evaluation obtained from 3DVH will provide more useful analysis. ADVANCES IN KNOWLEDGE: Correlation and sensitivity of %GP with %DE for VMAT QA were studied for the first time. PMID- 25494414 TI - Damage-control thoracic surgery: Management and outcomes. AB - BACKGROUND: Damage-control surgery is successfully used for severe abdominal trauma. Although the damage-control surgery principles are applicable to thoracic trauma, there is a dearth of data on damage-control thoracic surgery. METHODS: This is an institutional review board-approved, retrospective trauma registry study, from January 2002 to December 2012, for thoracic injuries requiring emergency thoracotomy or sternotomy, with temporary closure. Demographics, physiologic and laboratory data, operative procedures, and outcomes were abstracted. Data are presented as mean and SD; Student's t test was used with p < 0.05 conferring statistically significance. RESULTS: Forty-four patients were identified, with a median age of 34 years and 86% males. Mean (SD) Injury Severity Score (ISS) was 33.2 (14.7), with 93% having a chest Abbreviated Injury Scale (AIS) score of 3 or greater, 61% having a chest AIS score of 4 or greater, and 32% having a chest AIS score of 5 or greater. Of the patients, 48% had gunshot wounds and 21% had stab wounds. Admission temperature, pH, base deficit, and international normalized ratio were 36 degrees C (1 degrees C), 7.07 (0.13), 11.1 (6.5), and 1.7, respectively. Incisions included anterolateral thoracotomy in 69% and sternotomy in 25%; 73% required pulmonary resection, 20% required cardiorraphy, and 9% had major vascular injuries; multiple procedures were common. Mean intraoperative transfusion was 13 U of packed red blood cells. Forty two patients (95%) had thoracic packing with vacuum-assisted closure. The thorax was closed when physiology normalized, on a mean (SD) of 3 (1) days. When comparing physiologic parameters at initial operation and chest closure, temperature was 34.4 degrees C (1.3 degrees C) versus 37.4 degrees C (0.8 degrees C), pH was 7.13 (0.14) versus 7.38 (0.6), and international normalized ratio was 1.8 (0.9) versus 1.2 (0.3), respectively, all statistically significantly (p < 0.001). Complications included sepsis (36%), renal failure requiring continuous renal replacement therapy (30%), adult respiratory distress syndrome (25%), and empyema (23%). Six required salvage extracorporeal membrane oxygenation with one survivor. Mortality was 23%. Predictors included higher ISS, renal failure, continuous renal replacement therapy, and extracorporeal membrane oxygenation. All survivors were neurologically intact and dialysis free. CONCLUSION: Patients with severe chest trauma and marked physiologic derangement can benefit from damage-control thoracic surgery. Thoracic packing and temporary vacuum closure avoids thoracic compartment syndrome. Timing of thoracic closure is based on physiology. While complications were common, mortality is acceptable in this group of severely injured, metabolically depleted, challenging patients. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 25494415 TI - Trauma center angiography use in high-grade blunt splenic injuries: Timing is everything. AB - BACKGROUND: The use of angiography (ANGIO) in the management of high-grade (Abbreviated Injury Scale [AIS] score > 2) blunt splenic injury (BSI) remains controversial. We aimed to compare patient characteristics of those treated at high and low ANGIO centers, to compare the characteristics of the patients undergoing ANGIO at high and low ANGIO centers, and to determine the relationship among hospital ANGIO use, the timing of angiography, and splenectomy after angiography. METHODS: The National Trauma Data Bank was used to identify patients 18 years and older with BSI (AIS score > 2) treated at Level I or II trauma centers that admitted at least 10 patients with high-grade BSI from 2007 to 2010. Timing of ANGIO and splenectomy was determined. Hospitals were stratified based on ANGIO use rates into three groups: 0% (no ANGIO); 1% to 19.9% (low ANGIO); and more than 20% (high ANGIO). Hierarchical logistic regression was used to control for patient clustering at the hospital level and to determine factors associated with splenectomy. Cox regression with ANGIO as a time-varying covariate was also used. RESULTS: A total of 10,405 met inclusion criteria. After adjusting for hospital case mix, low ANGIO (odds ratio, 1.02; 95% confidence interval [CI], 0.70-1.48) and no ANGIO (odds ratio, 0.88; 95% CI, 0.59-1.31) centers showed no difference with regard to splenectomy compared with high ANGIO centers. ANGIO (Hazard Ratio = 0.52; 95% CI, 0.41-0.65) was protective of splenectomy on Cox regression analysis, taking into account ANGIO timing relative to splenectomy. CONCLUSION: There were no differences in splenectomy rates after adjusting for case mix at high and low ANGIO centers. Early ANGIO, irrespective of hospital ANGIO use, is associated with splenic salvage. LEVEL OF EVIDENCE: Therapeutic study, level III. PMID- 25494417 TI - Barriers to implementing the World Health Organization's Trauma Care Checklist: A Canadian single-center experience. AB - BACKGROUND: Management of trauma patients is difficult because of their complexity and acuity. In an effort to improve patient care and reduce morbidity and mortality, the World Health Organization developed a trauma care checklist. Local stakeholder input led to a modified 16-item version that was subsequently piloted. Our study highlights the barriers and challenges associated with implementing this checklist at our hospital. METHODS: The checklist was piloted over a 6-month period at St. Michael's Hospital, a Level 1 trauma center in Toronto, Canada. At the end of the pilot phase, individual, semistructured interviews were held with trauma team leaders and nursing staff regarding their experiences with the checklist. Axial coding was used to create a typology of attitudes and barriers toward the checklist, and then, vertical coding was used to further explore each identified barrier. Checklist compliance was assessed for the first 7 months. RESULTS: Checklist compliance throughout the pilot phase was 78%. Eight key barriers to implementing the checklist were identified as follows: perceived lack of time for the use of the checklist in critically ill patients, unclear roles, no memory trigger, no one to enforce completion, not understanding its importance or purpose, difficulty finding physicians at the end of resuscitation, staff/trainee changes, and professional hierarchy. CONCLUSION: The World Health Organization Trauma Care Checklist was a well-received tool; however, consideration of barriers to the implementation and staff adoption must be done for successful integration, with special attention to its use in critically ill patients. LEVEL OF EVIDENCE: Therapeutic/care management, level V. PMID- 25494416 TI - Transfusion of stored red blood cells in trauma patients is not associated with increased procoagulant microparticles. AB - BACKGROUND: We set out to determine the effects of transfusing stored red blood cells (RBCs) on the levels of procoagulant microparticles (MPs) in the blood of trauma patients. METHODS: Blood was drawn and processed to platelet poor plasma for MP analysis for 409 injured patients seen in the trauma bay from February 2011 to January 2013. Blood from 27 noninjured volunteers was also analyzed. Quantification of total procoagulant MP (per microliter plasma) using a direct plasma analysis via flow cytometry was performed. Demographic data, Injury Severity Score (ISS), overall mortality, and units of transfused packed RBCs were collected. Data are presented as median (interquartile range [IQR]). Transfusion groups were assessed using t test or Wilcoxon rank-sum test as appropriate. The alpha level was set as 0.05 for statistical significance. RESULTS: Median ISS was 12 (IQR, 5-19), 12% were transfused, median age was 48 years (IQR, 29-62 years), 68% were male, and overall mortality was 3%. Median units transfused were 3 (IQR, 2-5). The median number of all procoagulant MP was greater in trauma patients (median 758; IQR, 405-1,627) when compared with our control subjects (median, 232; IQR, 125-372; p < 0.0001). This difference remained significant after adjusting for age and sex (p < 0.0001). In 39 patients who had MP levels measured before transfusion with RBC, the procoagulant MP levels did not change after transfusion (p = 0.07). Patients transfused with RBCs that were 14 days or older did not have increased procoagulant MP levels when compared with those that received RBCs that were younger than 14 days (p = 0.5).This was also true for those who received RBCs that were 28 days or older when compared with those that received RBCs that were younger than 28 days (p = 0.84). CONCLUSION: Procoagulant MP is significantly greater in trauma patients as compared with volunteers, even after adjusting for age and sex. We did not observe any change in the levels of procoagulant MPs after transfusion of stored RBCs. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III. PMID- 25494418 TI - The peril of thoracoabdominal firearm trauma: 984 civilian injuries reviewed. AB - BACKGROUND: Thoracoabdominal firearm injuries present major diagnostic and therapeutic challenges because of the risk for potential injury in multiple anatomic cavities and the attendant dilemma of determining the need for and correct sequencing of cavitary intervention. Injury patterns, management strategies, and outcomes of thoracoabdominal firearm trauma remain undescribed across a large population. METHODS: All patients with thoracoabdominal firearm injury admitted to a major Level I trauma center during a 16-year period were reviewed. RESULTS: The 984 study patients experienced severe injury burden; 25% (243 of 984) presented in cardiac arrest, and 75% (741 of 984) had an Abbreviated Injury Scale (AIS) score of 3 or greater in both the chest and the abdomen. Operative management occurred in 86% (638 of 741). Of the patients arriving alive, 68% (507 of 741) underwent laparotomy alone, 4% (27 of 741) underwent thoracotomy alone, and 14% (104 of 741) underwent dual-cavitary intervention. Negative laparotomy occurred in 3%. Diaphragmatic injury (DI) occurred in 63%. Seventy-five percent had either DI or hollow viscus injury. Cardiac injury was present in 33 patients arriving alive. Despite the use of trauma bay ultrasound, 44% of the patients with cardiac injury underwent initial laparotomy. In half of this group, ultrasound did not detect pericardial blood. The need for thoracotomy, either alone or as part of dual-cavitary intervention, was the strongest independent risk factor for mortality in those arriving alive. CONCLUSION: Greater kinetic destructive potential drives the peril of thoracoabdominal firearm trauma, producing clinical challenges qualitatively and quantitatively different from nonfirearm injuries. Severe injury, on both sides of the diaphragm, generates high operative need with low rates of negative exploration. The need for emergent intervention and a high incidence of DI or hollow viscus injury limit opportunity for nonoperative management. Even with ultrasound, emergent preoperative diagnosis remains challenging, as the complex combination of intra-abdominal, thoracic, and diaphragmatic injuries can provoke misinterpretation of both radiologic and clinical data. Successful emergent management requires thorough assessment of all anatomic spaces, integrating ultrasonographic, radiologic, and clinical findings. LEVEL OF EVIDENCE: Epidemiologic study, level III. PMID- 25494419 TI - Low level of procoagulant platelet microparticles is associated with impaired coagulation and transfusion requirements in trauma patients. AB - BACKGROUND: Following activation, platelets release small vesicles called platelet-derived microparticles (PMPs). PMPs accelerate thrombin generation and thus clot formation at sites of injury by exposing the procoagulant membrane phospholipid phosphatidylserine (PS). The role of PMPs in coagulopathy and hemorrhage following trauma remains elusive. We hypothesized that low levels of PS-positive PMPs (PS + PMPs) would be associated with impaired clot formation. METHODS: This is a prospective observational study of 210 trauma patients admitted directly to a Level 1 trauma center. Plasma levels of PS + PMPs were determined by flow cytometry. Coagulation status was assessed by rotational thrombelastometry, and impaired clot formation was defined by an alpha angle less than 63 degrees using the tissue factor-based EXTEM reagent. Transfusion requirement was assessed by number of units of red blood cells (RBCs) transfused within 24 hours of admission; platelet aggregation capacity was evaluated by the Multiplate assay; and injury severity was determined by the Injury Severity Score (ISS). RESULTS: The median ISS was 17, and blood samples were obtained after a median of 65 minutes following injury. Significantly lower levels of PS + PMPs were found in patients with impaired clot formation (p < 0.001). A low level of PS + PMPs was associated with a higher number of RBCs transfused during the initial 24 hours after admission (p < 0.03) when corrected for risk factors, for example, platelet count, hemoglobin level, and ISS. Platelet aggregation and PS + PMPs did not correlate significantly. CONCLUSION: Low levels of PMPs were associated with impaired clot formation in trauma patients at admission and also with the number of RBC transfusions. This suggests that PMPs may play an important and not previously investigated role in trauma-induced coagulopathy. LEVEL OF EVIDENCE: Prognostic study, level III. PMID- 25494420 TI - Blunt traumatic abdominal wall hernias: Associated injuries and optimal timing and method of repair. AB - BACKGROUND: Traumatic abdominal wall hernias resulting from blunt trauma can be difficult to identify and manage. Few reported series exist in the literature. This study aimed to identify strategies for traumatic hernia management, characterize associated injuries, and determine outcomes of this patient population. METHODS: Patients who sustained a traumatic abdominal wall hernia secondary to blunt trauma were reviewed during a 5-year period. Demographic data, Injury Severity Score (ISS), associated injuries, type of repair, and durability of repair were examined, and descriptive statistics were calculated. p < 0.05 was considered significant. RESULTS: Thirty-eight patients were identified. ISS ranged from 1 to 66, with a mean of 19.8. Of these patients, 34 had associated injuries; the most common organs injured were the small bowel followed by the colon. The average number of concomitant abdominal and pelvic injuries per patient was 2.4. Mortality rate was 5.3% (2 of 38). Twenty-seven patients (71%) underwent immediate repair, three (7.9%) underwent delayed repair, and eight did not have their hernias repaired. Of the patients who underwent repair, two developed a recurrence (6.7%); both were flank hernias. One of these patients had a biologic mesh placed, and one was repaired primarily. Mesh repair was performed in 11 patients. Four had a synthetic mesh placed, with three (75%) performed in a delayed fashion after discharge from their initial hospitalization. Nineteen (50%) underwent primary repair at the time of initial presentation. CONCLUSION: Associated abdominal and pelvic injuries are extremely common, and physicians should be diligent in searching for these injuries. Our data support the use of a synthetic mesh in delayed fashion when feasible. However, because of the low number of patients in this study, a definitive recommendation cannot be made. LEVEL OF EVIDENCE: Epidemiologic study, level III. Therapeutic study, level IV. PMID- 25494421 TI - Application of a uniform anatomic grading system to measure disease severity in eight emergency general surgical illnesses. AB - BACKGROUND: Emergent general surgical diseases encompass a broad spectrum of anatomy and pathophysiology, creating challenges for outcomes assessment, research, and surgical training. The goal of this study was to measure anatomic disease severity for eight emergent general surgical diseases using the uniform grading system of the American Association for the Surgery of Trauma (AAST). METHODS: The Committee on Patient Assessment and Outcomes of AAST applied the previously developed uniform grading system to eight emergent general surgical diseases using a consensus of experts. It was then reviewed and approved by the Board of Managers of AAST. RESULTS: Severity grades for eight commonly encountered emergent general surgical conditions were created: breast abscess, esophageal perforation, infectious colitis, pelvic inflammatory disease, perirectal abscess, pleural space infections, soft tissue infections, and surgical site infections. The range of grades from I through V, reflect progression from mild disease, limited to within the organ itself, to widespread severe disease. CONCLUSION: This article provides a uniform grading system for measuring anatomic severity of eight emergent general surgical diseases. Consistent adoption of these grades could improve standardization for quality assurance, outcomes research, and surgical training. PMID- 25494422 TI - Altering leukocyte recruitment following traumatic brain injury with ghrelin therapy. AB - BACKGROUND: Traumatic brain injury (TBI)-induced cerebral inflammation involves several mediators including activation of resident microglia, infiltration of leukocytes, and release of proinflammatory cytokines and chemokines at the site of injury. Invading leukocytes, mainly neutrophil and inflammatory monocytes, contribute to ongoing post-TBI cerebral edema and neuronal injury. Based on the beneficial effect of ghrelin hormone treatment following TBI, we hypothesized that ghrelin may alter the infiltrating inflammatory cell profile. METHODS: A weight drop model was used to create severe TBI. C57 mice were divided into three groups: sham, no TBI or ghrelin treatment; TBI, TBI only; TBI/ghrelin, animals were treated with ghrelin 20 MUg (intraperitoneally) immediately following TBI and again 1 hour later. Seven days after injury, brain sections were immunostained with Iba-1 and CD11b to assess the recruitment and activation of resident microglia and infiltrated leukocytes. Alternatively, brain dissociates were isolated, and flow cytometry was used to gate for microglia (CD11b, CD45 cells), monocytes (CD11b, CD45, F4/80 cells), and neutrophils (CD11b, CD45, F4/80 cells) to measure their recruitment to injury site. RESULTS: TBI resulted in a rapid invasion (16-fold) of inflammatory leukocytes to the site of injury, which persisted for at least 1 week. Ghrelin treatment significantly reduced infiltration of peripheral leukocytes (2.8-fold). In particular, recruitment of CD11bCD45 inflammatory monocytes (2.4-fold) and CD11bCD45F4/80 neutrophils (1.7 fold) was reduced following ghrelin treatment. There were no observed ghrelin mediated changes in either the number of CD11bCD45 resident microglia or its activation state. CONCLUSION: Together, our data demonstrate that ghrelin attenuated leukocyte recruitment, which correlates with improved histologic outcome following TBI. PMID- 25494423 TI - Systemic and microvascular effects of resuscitation with blood products after severe hemorrhage in rats. AB - BACKGROUND: Severe hemorrhage is associated with the disruption of the endothelial glycocalyx (EG), a key component of the endothelium. The effects of blood components on the EG are unknown. The present study furthers our investigations into the effects of resuscitation with blood products on the skeletal muscle microcirculation of hemorrhaged rats, focusing on packed red blood cells (PRBCs) or fresh whole blood (FWB). METHODS: Rats were bled 40% of total blood volume and resuscitated with 1:1 PRBC/lactated Ringer's solution (LR), 1:1 washed PRBC (wPRBC)/LR, FWB or LR only. Sham animals were subjected to all procedures except hemorrhage and resuscitation. EG thickness, blood flow, and microvascular permeability were studied using intravital microscopy. Hemodynamics and coagulation tests (rotational thromboelastometry) were performed. RESULTS: After severe hemorrhage, EG and permeability were restored to sham levels in the PRBC/LR and FWB groups, but not in the wPRBC/LR or LR groups. Clotting time was longer and clot elasticity and firmness were reduced in wPRBC/LR and LR, but not in FWB or PRBC/LR groups when compared with sham. CONCLUSION: Resuscitation with FWB or PRBC/LR was superior in reversing coagulopathy, restoring EG and permeability changes following hemorrhage, compared with wPRBC/LR or LR alone. As wPRBC/LR did not improve EG and permeability, these data suggest that the removal of residual plasma protein from wPRBC or resuscitation with a protein-free solution (LR) is not able to improve microcirculation and coagulation functions in this severe hemorrhage model. PMID- 25494424 TI - Aeromedical evacuation of combat patients by military critical care air transport teams with a lower hemoglobin threshold approach is safe. AB - BACKGROUND: Military critical care air transport teams (CCATT) evacuate critically ill and injured patients out of theater for tertiary treatment. Teams are led by a physician, nurse, and respiratory technician. Current aeromedical guidelines require a hemoglobin (Hgb) of 9 g/dL or greater to evacuate; however, civilians report that an Hgb of 8 g/dL or less is safe in critically ill patients. This study aimed to compare postflight short-term and 30-day patient outcomes for CCATT patients evacuated out of theater with an Hgb of 8 g/dL or less with those with an Hgb of greater than 8 g/dL. METHODS: We conducted a retrospective record review of all traumatically injured patients evacuated from theater by CCATT between March 2007 and December 2011. We recorded demographics, injury descriptions, vital signs, laboratory values, adverse events, and disposition at 30 days. Patients were separated into those with a preflight Hgb of 8 g/dL or less versus those with greater than 8 g/dL. Continuous data were analyzed using Student's t tests or Wilcoxon tests and reported as mean +/- SD. chi or Fisher's exact tests were performed. Stepwise, multifactorial logistic regression models were used. Statistical significance was considered with p < 0.05. RESULTS: Of 1,252 patients, 1,033 had a preflight Hgb of greater than 8 and 219 had an Hgb of 8 or less. Age, sex proportions, vitals, laboratory values, and Injury Severity Score (ISS; 24+/-13) were similar. The group with 8 or less had more blast injuries (68% vs. 76%, p = 0.01). No associations were identified between preflight Hgb levels and adverse outcomes. Disposition at 30 days was similar. We also compared preflight Hgb greater than 7 versus 7 or less (n = 1,212 vs. 45). Those with an Hgb greater than 7 had a greater incidence of hospitalization at 30 days (77% vs. 67%, p = 0.04). The group with an Hgb of 7 or less had more subjects discharged home or returning to duty (10% vs. 21%, p = 0.04). CONCLUSION: Evacuating CCATT patients with an Hgb of 8 or less had similar adverse outcomes and mortality at 30 days compared with those with an Hgb greater than 8. Patients with an Hgb of 7 or less had higher rates of hospital discharge and decreased incidence of hospitalization at 30 days. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 25494425 TI - Cleared for takeoff: The effects of hypobaric conditions on traumatic pneumothoraces. AB - BACKGROUND: Current guidelines suggest that traumatic pneumothorax (tPTX) is a contraindication to commercial airline travel, and patients should wait at least 2 weeks after radiographic resolution of tPTX to fly. This recommendation is not based on prospective, physiologic study. We hypothesized that despite having a radiographic increase in pneumothorax size while at simulated altitude, patients with a recently treated tPTX would not exhibit any adverse physiologic changes and would not report any symptoms of cardiorespiratory compromise. METHODS: This is a prospective, observational study of 20 patients (10 in Phase 1, 10 in Phase 2) with tPTX that has been treated by chest tube (CT) or high flow oxygen therapy. CT must have been removed within 48 hours of entering the study. Subjects were exposed to 2 hours of hypobaria (554 mm Hg in Phase 1, 471 mm Hg in Phase 2) in a chamber in Salt Lake City, Utah. Vital signs and subjective symptoms were recorded during the "flight." After 2 hours, while still at simulated altitude, a portable chest radiograph (CXR) was obtained. tPTX sizes on preflight, inflight, and postflight CXR were compared. RESULTS: Sixteen subjects (80%) were male. Mean (SD) age and ISS were 49 (5) years and 10.5 (4.6), respectively. Fourteen (70%) had a CT to treat tPTX, which had been removed 19 hours (range, 4-43 hours) before the study. No subject complained of any cardiorespiratory symptoms while at altitude. Radiographic increase in tPTX size at altitude was 5.6 (0.61) mm from preflight CXR. No subject developed a tension tPTX. No subject required procedural intervention during the flight. Four hours after the study, all tPTX had returned to baseline size. CONCLUSION: Patients with recently treated tPTX have a small increase in the size of tPTX when subjected to simulated altitude. This is clinically well tolerated. Current prohibitions regarding air travel following traumatic tPTX should be reconsidered and further studied. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 25494426 TI - What do the people who transport trauma patients know about tourniquets? AB - BACKGROUND: The primary study objectives were to gather information concerning the tourniquet knowledge, experience, training, protocols, preferences, and equipment of civilian prehospital providers. METHODS: This is a survey of 151 prehospital care providers. RESULTS: Survey respondents included 27 basic, 1 intermediate, and 75 paramedic emergency medical technicians; 1 registered nurse; 4 firefighters without medical certifications; 2 respondents not yet certified; and 1 respondent not listing certifications. Respondents had 2 months to 40 years of experience and came from emergency medical services in communities of 101 to 206,688 residents located 10 minutes to 103 minutes from a Level 1 or 2 trauma center. Twenty-five had used tourniquets: 5 in military and 22 in civilian settings. Civilian tourniquets were most frequently used for motor vehicle- then farm- and manufacturing-related injuries with severe bleeding. Tourniquet knowledge was poor for all groupings (with or without tourniquet experience, military experience, all certifications, all years of experience): 91% did not understand that wider tourniquets require less pressure for arterial occlusion, 69% did not know that stopping venous flow without arterial is harmful, and 37% did not know the correct tourniquet locations for distal limb injuries. Of the 81 on a service and without military experience, 44 had received any tourniquet training; 14 of the 44 had commercial emergency tourniquet access, and 27 indicated their service had a tourniquet protocol. Of the 37 on a service with no tourniquet training, 5 had access to a commercial emergency tourniquet, and 5 indicated their service had a tourniquet protocol. CONCLUSION: Civilian prehospital providers encounter situations for tourniquet use, but many do not know information important for optimal tourniquet use. Therefore, if surgeons want civilian prehospital care to include the use of effective, arterial flow occluding tourniquets at appropriate limb locations, they need to communicate with their emergency medical service providers concerning tourniquet knowledge, training, protocols, and appropriate equipment. PMID- 25494427 TI - Helmet use among motorcycle and moped riders injured in Hawaii: Final medical dispositions from a linked database. AB - BACKGROUND: Reports regarding helmets in motorcycle crashes have been limited by the lack of data across the spectrum of injury outcomes, generally excluding low severity injuries that do not require further medical treatment. We hypothesized that the protective effect of helmets may be underestimated in studies that focused only on patients who arrive at a trauma center and that it may differ depending on whether the crash involved a motorcycle or moped. METHODS: The emergency medical service reports of 2,553 crash patients treated from 2007 to 2009 were linked to police crash reports, hospital billing data, death certificates, and the Fatal Analysis Reporting System for a more complete description of the crashes throughout the state. RESULTS: The number of unhelmeted riders (n = 1,674) was nearly double those who were helmeted (n = 879). Multivariate logistic regression models estimated 45% greater odds of a hospital admission (vs. no hospital treatment or a discharge from the emergency department setting) among unhelmeted riders, compared with helmeted riders. Unhelmeted riders also had an adjusted odds of a fatal injury that was more than double that of helmeted riders (odds ratio, 2.71; 95% confidence interval, 1.68 4.46). Stratified analyses showed that these protective associations between helmet use and medical disposition were apparent only among motorcyclists. CONCLUSION: The magnitude of the protective associations between helmets and medical outcomes was generally greater than that reported by other studies. Motorcyclists seem to benefit from helmet use more than moped riders. This data could be used to promote helmet use through education and public policy. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level III. PMID- 25494428 TI - Establishing components of high-quality injury care: Focus groups with patients and patient families. AB - BACKGROUND: Each year, injuries affect 700 million people worldwide, more than 5 million people die of injuries, and 68,000 survivors remain permanently impaired. Half of all critically injured patients do not receive recommended care, and medical errors are common. Little is known about the aspects of injury care that are important to patients and their families. The purpose of this study was to explore the views of patients and families affected by injury on desired components of injury care in the hospital setting. METHODS: With the use of a grounded theory approach, this qualitative study involved focus groups with injured patients, family members of survivors, and bereaved family members from four Canadian trauma (injury care) centers. RESULTS: Thirty-eight participants included injured patients (n = 16), family members of survivors (n = 13), and bereaved family members (n = 9) across four trauma (injury care) centers in different jurisdictions. Participants articulated numerous themes reflecting important components of injury care organized across three domains as follows: clinical care (staff availability, professionalism, physical comfort, adverse events), holistic care (patient wellness, respect for patient and family, family access to patient, family wellness, hospital facilities, supportive care), and communication and information (among staff, with or from staff, content, delivery, and timing). Bereaved family members commented on decision making and end-of-life processes. Subthemes were revealed in most of these themes. Trends by site or type of participant were not identified. CONCLUSION: The framework of patient- and family-derived components of quality injury care could be used by health care managers and policy makers to guide quality improvement efforts. Further research is needed to extend and validate these components among injured patients and families elsewhere. Translating these components into quality indicators and blending those with measures that reflect a provider perspective may offer a comprehensive means of assessing injury care. PMID- 25494429 TI - Validation and reclassification of MGAP and GAP in hospital settings using data from the Trauma Audit and Research Network. AB - BACKGROUND: Recently, two simple clinical scores were published to predict survival in trauma patients. Both scores may successfully guide major trauma triage, but neither has been independently validated in a hospital setting. METHODS: This is a cohort study with 30-day mortality as the primary outcome to validate two new trauma scores-Mechanism, Glasgow Coma Scale (GCS), Age, and Pressure (MGAP) score and GCS, Age and Pressure (GAP) score-using data from the UK Trauma Audit and Research Network. First, an assessment of discrimination, using the area under the receiver operating characteristic (ROC) curve, and calibration, comparing mortality rates with those originally published, were performed. Second, we calculated sensitivity, specificity, predictive values, and likelihood ratios for prognostic score performance. Third, we propose new cutoffs for the risk categories. RESULTS: A total of 79,807 adult (>=16 years) major trauma patients (2000-2010) were included; 5,474 (6.9%) died. Mean (SD) age was 51.5 (22.4) years, median GCS score was 15 (interquartile range, 15-15), and median Injury Severity Score (ISS) was 9 (interquartile range, 9-16). More than 50% of the patients had a low-risk GAP or MGAP score (1% mortality). With regard to discrimination, areas under the ROC curve were 87.2% for GAP score (95% confidence interval, 86.7-87.7) and 86.8% for MGAP score (95% confidence interval, 86.2-87.3). With regard to calibration, 2,390 (3.3%), 1,900 (28.5%), and 1,184 (72.2%) patients died in the low, medium, and high GAP risk categories, respectively. In the low- and medium-risk groups, these were almost double the previously published rates. For MGAP, 1,861 (2.8%), 1,455 (15.2%), and 2,158 (58.6%) patients died in the low-, medium-, and high-risk categories, consonant with results originally published. Reclassifying score point cutoffs improved likelihood ratios, sensitivity and specificity, as well as areas under the ROC curve. CONCLUSION: We found both scores to be valid triage tools to stratify emergency department patients, according to their risk of death. MGAP calibrated better, but GAP slightly improved discrimination. The newly proposed cutoffs better differentiate risk classification and may therefore facilitate hospital resource allocation. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 25494430 TI - Impact of adding Level II and III trauma centers on volume and disease severity at a nearby Level I trauma center. AB - BACKGROUND: As emergency care becomes increasingly regionalized, systems planners must determine how system expansion impacts existing system assets. We hypothesized that accrediting new Level II and III trauma centers impacted the trauma patient census and severity at a nearby Level I trauma center and estimated the magnitude of the impact. METHODS: We conducted an interrupted time series analysis using monthly patient counts during the past 10 years for five trauma centers located near one another in Pennsylvania. The Level I center (TC A) operated for the entire period. A Level II center 39 miles away was accredited after 70 months (TC-B), one Level III center 46 miles away was accredited after 95 months but lost accreditation after 11 months (TC-C), and two other Level III centers 40 miles and 45 miles away were accredited after 107 months (TC-D and TC E). RESULTS: Monthly patient volume at the Level I center, which increased gradually over the study and summed to 25,120 patients, decreased by 10.8% (p < 0.05) when TC-B was accredited and decreased by an additional 12.9% (p < 0.05) when TC-D and TC-E were accredited simultaneously. No change stemmed from temporarily accrediting TC-C. Ultimately, the Level I center treated 1,903 fewer patients than expected over 51 months, an 11.9% volume reduction, and patient severity remained consistent but mortality decreased. CONCLUSION: Accrediting Level II and Level III trauma centers reduced patient volume and reduced overall mortality at a nearby Level I center. Strategic planning of statewide trauma systems can help balance rapid access to care with maintenance of adequate annual patient volumes of critically injured patients. LEVEL OF EVIDENCE: Epidemiologic study, Level IV. PMID- 25494432 TI - Erythropoietin for critically ill trauma patients: A missed opportunity? PMID- 25494431 TI - Clinical relevance of mold culture positivity with and without recurrent wound necrosis following combat-related injuries. AB - BACKGROUND: Invasive fungal wound infections (IFIs) are a recognized threat for personnel who sustain combat-related blast trauma in Afghanistan. Blast trauma, particularly when dismounted, has wounds contaminated with organic debris and potential for mold infection. Trauma-associated IFI is characterized by recurrent wound necrosis on serial debridement with histologic evidence of invasive molds and/or fungal culture growth. Wounds with mold growth but lacking corresponding recurrent necrosis present a clinical dilemma of whether to initiate antifungal treatment. Our objective was to assess the clinical significance of fungal culture growth without recurrent wound necrosis. METHODS: US military personnel wounded during combat in Afghanistan (June 2009 to August 2011) were assessed for growth of mold from wound cultures and/or histopathologic evidence of IFI. Identified patients were stratified based on clinical wound appearance (with/without recurrent necrosis), and the resultant groups were compared for injury characteristics, clinical management, and outcomes. RESULTS: A total of 96 patients were identified: 77 with fungal elements on histopathology and/or fungal growth plus recurrent wound necrosis and 19 with fungal growth on culture but no wound necrosis after initial debridements. Injury patterns and severity were similar between the groups. Patients with recurrent necrosis had more frequent fevers and leukocytosis during the first 2 weeks after injury, and the majority received antifungal therapy compared with only three patients (16%) without recurrently necrotic wounds. Overall, patients without recurrent wound necrosis had significantly less operative procedures (p = 0.02), shorter stay in the intensive care unit (p < 0.01), and lower rates of high-level amputations (5% vs. 20%) and deaths (none vs. 8%) despite no or infrequent antifungal use. CONCLUSION: The finding of molds on wound culture among patients with blast trauma in the absence of recurrently necrotic wounds on serial debridement does not require systemic antifungal chemotherapy. LEVEL OF EVIDENCE: Therapeutic study, level IV. Prognosti/epidemiologic study, level III. PMID- 25494433 TI - The definition of polytrauma revisited: An international consensus process and proposal of the new 'Berlin definition' AB - BACKGROUND: The nomenclature for patients with multiple injuries with high mortality rates is highly variable, and there is a lack of a uniform definition of the term polytrauma. A consensus process was therefore initiated by a panel of international experts with the goal of assessing an improved, database-supported definition for the polytraumatized patient. METHODS: The consensus process involved the following: RESULTS: A total of 28,211 patients in the trauma registry met the inclusion criteria. The mean (SD) age of the study cohort was 42.9 (20.2) years (72% males, 28% females). The mean (SD) ISS was 30.5 (12.2), with an overall mortality rate of 18.7% (n = 5,277) and an incidence of 3% of penetrating injuries (n = 886). Five independent physiologic variables were identified, and their individual cutoff values were calculated based on a set mortality rate of 30%: hypotension (systolic blood pressure <= 90 mm Hg), level of consciousness (Glasgow Coma Scale [GCS] score <= 8), acidosis (base excess <= 6.0), coagulopathy (international normalized ratio >= 1.4/partial thromboplastin time >= 40 seconds), and age (>=70 years). CONCLUSION: Based on several consensus meetings and a database analysis, the expert panel proposes the following parameters for a definition of "polytrauma": significant injuries of three or more points in two or more different anatomic AIS regions in conjunction with one or more additional variables from the five physiologic parameters. Further validation of this proposal should occur, favorably by mutivariate analyses of these parameters in a separate data set. PMID- 25494434 TI - Optimal timing of femur fracture stabilization in polytrauma patients: A practice management guideline from the Eastern Association for the Surgery of Trauma. AB - BACKGROUND: Femur fractures are common among trauma patients and are typically seen in patients with multiple injuries resulting from high-energy mechanisms. Internal fixation with intramedullary nailing is the ideal method of treatment; however, there is no consensus regarding the optimal timing for internal fixation. We critically evaluated the literature regarding the benefit of early (<24 hours) versus late (>24 hours) open reduction and internal fixation of open or closed femur fractures on mortality, infection, and venous thromboembolism (VTE) in trauma patients. METHODS: A subcommittee of the Practice Management Guideline Committee of the Eastern Association for the Surgery of Trauma conducted a systematic review and meta-analysis for the earlier question. RevMan software was used to generate forest plots. Grading of Recommendations, Assessment, Development, and Evaluations methodology was used to rate the quality of the evidence, using GRADEpro software to create evidence tables. RESULTS: No significant reduction in mortality was associated with early stabilization, with a risk ratio (RR) of 0.74 (95% confidence interval [CI], 0.50-1.08). The quality of evidence was rated as "low." No significant reduction in infection (RR, 0.4; 95% CI, 0.10-1.6) or VTE (RR, 0.63; 95% CI, 0.37-1.07) was associated with early stabilization. The quality of evidence was rated "low." CONCLUSION: In trauma patients with open or closed femur fractures, we suggest early (<24 hours) open reduction and internal fracture fixation. This recommendation is conditional because the strength of the evidence is low. Early stabilization of femur fractures shows a trend (statistically insignificant) toward lower risk of infection, mortality, and VTE. Therefore, the panel concludes the desirable effects of early femur fracture stabilization probably outweigh the undesirable effects in most patients. PMID- 25494435 TI - Delayed duodenal injury following abdominal gunshot wound. PMID- 25494436 TI - Traumatic brain injury is not associated with coagulopathy out of proportion to injury in other body regions. PMID- 25494437 TI - Problems in analyzing helicopter emergency medical service accidents. PMID- 25494439 TI - Re: Delayed hemorrhagic complications in the nonoperative management of blunt splenic trauma. PMID- 25494438 TI - Delayed hemorrhagic complications in the nonoperative management of blunt splenic trauma. PMID- 25494440 TI - Featured Articles for CME Credit November 2014. PMID- 25494442 TI - Imaging and sizing of single DNA molecules on a mobile phone. AB - DNA imaging techniques using optical microscopy have found numerous applications in biology, chemistry and physics and are based on relatively expensive, bulky and complicated set-ups that limit their use to advanced laboratory settings. Here we demonstrate imaging and length quantification of single molecule DNA strands using a compact, lightweight and cost-effective fluorescence microscope installed on a mobile phone. In addition to an optomechanical attachment that creates a high contrast dark-field imaging setup using an external lens, thin film interference filters, a miniature dovetail stage and a laser-diode for oblique-angle excitation, we also created a computational framework and a mobile phone application connected to a server back-end for measurement of the lengths of individual DNA molecules that are labeled and stretched using disposable chips. Using this mobile phone platform, we imaged single DNA molecules of various lengths to demonstrate a sizing accuracy of <1 kilobase-pairs (kbp) for 10 kbp and longer DNA samples imaged over a field-of-view of ~2 mm2. PMID- 25494443 TI - Translation of the assembling trajectory by preorganisation: a study of the magnetic properties of 1D polymeric unpaired electrons immobilised on a discrete nanoscopic scaffold. AB - A nitronyl nitroxide (NN)-appended hexabenzocoronene (HBC(NN)), when allowed to coassemble with bis(hexafluoroacetylacetonato)cobalt(II), forms a coaxial nanotubular architecture featuring NN-Co(II) coordinated copolymer chains immobilised on the outer and inner nanotube surfaces. Upon lowering the temperature, this nanotube has enhanced magnetic susceptibility below 10 K. PMID- 25494444 TI - The Structured Inventory of Malingered Symptomatology (SIMS): a systematic review and meta-analysis. AB - We meta-analytically reviewed studies that used the Structured Inventory of Malingered Symptomatology (SIMS) to detect feigned psychopathology. We present weighted mean diagnostic accuracy and predictive power indices in various populations, based on 31 studies, including 61 subsamples and 4009 SIMS protocols. In addition, we provide normative data of patients, claimants, defendants, nonclinical adults, and various experimental feigners, based on 41 studies, including 125 subsamples and 4810 SIMS protocols. We conclude that the SIMS (1) is able to differentiate well between instructed feigners and honest responders; (2) generates heightened scores in groups that are known to have a raised prevalence of feigning (e.g., offenders who claim crime-related amnesia); (3) may overestimate feigning in patients who suffer from schizophrenia, intellectual disability, or psychogenic non-epileptic seizures; and (4) is fairly robust against coaching. The diagnostic power of the traditional cut scores of the SIMS (i.e., > 14 and > 16) is not so much limited by their sensitivity-which is satisfactory-but rather by their substandard specificity. This, however, can be worked around by combining the SIMS with other symptom validity measures and by raising the cut score, although the latter solution sacrifices sensitivity for specificity. PMID- 25494445 TI - A theoretical study of the aromaticity in neutral and anionic borole compounds. AB - In this contribution, we have evaluated the (anti)aromatic character of thirty four different borole compounds in their neutral and reduced states based on two aromaticity indices, namely nucleus-independent chemical shift (NICS) and multicenter indices (MCI), calculated at the PBE0/6-31+G(d,p) level of theory. Both indices corroborate the notion that neutral borole compounds are antiaromatic and become increasingly aromatic upon addition of electrons. Effects of the ring substituents on the degree of (anti)aromaticity are discussed together with differences in the two theoretical methods, which are on the one hand based on magnetic (NICS) and on the other hand based on electronic criteria (MCI). PMID- 25494446 TI - Monosodium glutamate in chicken and beef stock cubes using high-performance liquid chromatography. AB - In this survey monosodium glutamate (MSG) levels in chicken and beef stock cube samples were determined. A total number of 122 stock cube samples (from brands A, B, C, D) were collected from local markets in Ankara, Turkey. High-performance liquid chromatography with diode array detection (HPLC-DAD) was used for quantitative MSG determination. Mean MSG levels (+/-SE) in samples of A, B, C and D brands were 14.6 +/- 0.2 g kg-1, 11.9 +/- 0.3 g kg-1, 9.7 +/- 0.1 g kg-1 and 7.2 +/- 0.1 g kg-1, respectively. Differences between mean levels of brands were significant. Also, mean levels of chicken stock cube samples were lower than in beef stock cubes. Maximum limits for MSG in stock cubes are not specified in the Turkish Food Codex (TFC). Generally the limit for MSG in foods (except some foods) is established as 10 g kg-1 (individually or in combination). PMID- 25494447 TI - Fabrication and optical characterization of silica optical fibers containing gold nanoparticles. AB - Gold nanoparticles have been used since antiquity for the production of red colored glasses. More recently, it was determined that this color is caused by plasmon resonance, which additionally increases the material's nonlinear optical response, allowing for the improvement of numerous optical devices. Interest in silica fibers containing gold nanoparticles has increased recently, aiming at the integration of nonlinear devices with conventional optical fibers. However, fabrication is challenging due to the high temperatures required for silica processing and fibers with gold nanoparticles were solely demonstrated using sol gel techniques. We show a new fabrication technique based on standard preform/fiber fabrication methods, where nanoparticles are nucleated by heat in a furnace or by laser exposure with unprecedented control over particle size, concentration, and distribution. Plasmon absorption peaks exceeding 800 dB m(-1) at 514-536 nm wavelengths were observed, indicating higher achievable nanoparticle concentrations than previously reported. The measured resonant nonlinear refractive index, (6.75 +/- 0.55) * 10(-15) m(2) W(-1), represents an improvement of >50*. PMID- 25494449 TI - One-staged aptamer-based isolation and application of endothelial progenitor cells in a porcine myocardial infarction model. AB - A multitude of stem cell types has been extensively studied and used for myocardial regenerative therapy. Amongst these endothelial progenitor cells form a promising source. In our present study, we investigated a one-staged approach for isolation and application of autologous endothelial progenitor cells in a pig model of myocardial infarction. Endothelial progenitor cell isolation was performed by immediately preprocedural bone marrow aspiration and consecutive positive selection by aptamer-based magnetic cell sorting. Animals were divided in three groups receiving endothelial progenitor cells, saline, or no intramyocardial injection respectively. Postprocedural follow-up consisted of weekly echocardiographic evaluations. Postmortem histological analysis after four weeks focused on detection of transplanted PKH26-positive endothelial progenitor cells and neovascularization within the infarcted myocardium. A significant difference in left ventricular ejection fraction could not be shown between the three groups. PKH26-stained endothelial progenitor cells could be found in the endothelial progenitor cells transplanted group, although detection was scarce. Large-sized capillaries were found to be significantly more in endothelial progenitor cells treated myocardium. The one-stage approach of endothelial progenitor cells isolation and application presented herein offers a new therapeutic concept. Even though a beneficial impact on myocardial function could not be assessed, increased neovascularization may indicate positive effects on remodeling processes. Being able to harvest endothelial progenitor cells right before application provides a wider scope of action in urgent cases. PMID- 25494450 TI - Investigation of the electromagnetic absorption properties of Ni@TiO2 and Ni@SiO2 composite microspheres with core-shell structure. AB - In this work, amorphous TiO2 and SiO2-coated Ni composite microspheres were successfully prepared by a two-step method. The phase purity, morphology, and structure of composite microspheres are characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), energy dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), and transmission electron microscopy (TEM). Due to the presence of the insulator SiO2 shell, the core-shell Ni-SiO2 composite microspheres exhibit better antioxidation capability than that of pure Ni microspheres. The core-shell Ni-SiO2 composite microspheres show the best microwave absorption properties than those of pure Ni microspheres and Ni TiO2 composites. For Ni-SiO2 composite microspheres, an optimal reflection loss (RL) as low as -40.0 dB (99.99% absorption) was observed at 12.6 GHz with an absorber thickness of only 1.5 mm. The effective absorption (below -10 dB, 90% microwave absorption) bandwidth can be adjusted between 3.1 GHz and 14.4 GHz by tuning the absorber thickness in the range of 1.5-4.5 mm. The excellent microwave absorption abilities of Ni-SiO2 composite microspheres are attributed to a higher attenuation constant, Debye relaxation, interface polarization of the core-shell structure and synergistic effects between high dielectric loss and high magnetic loss. PMID- 25494448 TI - Immunology of bats and their viruses: challenges and opportunities. AB - Bats are reservoir hosts of several high-impact viruses that cause significant human diseases, including Nipah virus, Marburg virus and rabies virus. They also harbor many other viruses that are thought to have caused disease in humans after spillover into intermediate hosts, including SARS and MERS coronaviruses. As is usual with reservoir hosts, these viruses apparently cause little or no pathology in bats. Despite the importance of bats as reservoir hosts of zoonotic and potentially zoonotic agents, virtually nothing is known about the host/virus relationships; principally because few colonies of bats are available for experimental infections, a lack of reagents, methods and expertise for studying bat antiviral responses and immunology, and the difficulty of conducting meaningful field work. These challenges can be addressed, in part, with new technologies that are species-independent that can provide insight into the interactions of bats and viruses, which should clarify how the viruses persist in nature, and what risk factors might facilitate transmission to humans and livestock. PMID- 25494451 TI - Proteome adaptation in cell reprogramming proceeds via distinct transcriptional networks. AB - The ectopic expression of Oct4, Klf4, c-Myc and Sox2 (OKMS) transcription factors allows reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). The reprogramming process, which involves a complex network of molecular events, is not yet fully characterized. Here we perform a quantitative mass spectrometry-based analysis to probe in-depth dynamic proteome changes during somatic cell reprogramming. Our data reveal defined waves of proteome resetting, with the first wave occurring 48 h after the activation of the reprogramming transgenes and involving specific biological processes linked to the c-Myc transcriptional network. A second wave of proteome reorganization occurs in a later stage of reprogramming, where we characterize the proteome of two distinct pluripotent cellular populations. In addition, the overlay of our proteome resource with parallel generated -omics data is explored to identify post transcriptionally regulated proteins involved in key steps during reprogramming. PMID- 25494453 TI - Injury severity and comorbidities alone do not predict futility of care after geriatric trauma. AB - BACKGROUND: When counseling surrogates of massively injured elderly trauma patients, the prognostic information they desire is rarely evidence based. OBJECTIVE: We sought to objectively predict futility of care in the massively injured elderly trauma patient using easily available parameters: age, Injury Severity Score (ISS), and preinjury comorbidities. METHODS: Two cohorts (70-79 years and >=80 years) were constructed from The National Trauma Data Bank (NTDB) for years 2007-2011. Comorbidities were tabulated for each patient. Mortality rates at every ISS score were tabulated for subjects with 0, 1, or >=2 comorbidities. Futility was defined a priori as an in-hospital mortality rate of >=95% in a cell with >=5 subjects. RESULTS: A total of 570,442 subjects were identified (age 70-79 years, n=217,384; age >=80 years, n=352,608). Overall mortality was 5.3% for ages 70-79 and 6.6% for >=80 years. No individual ISS score was found to have a mortality rate of >=95% for any number of comorbidities in either age cohort. The highest mortality rate seen in any cell was for an ISS of 66 in the >=80 year-old cohort with no listed comorbidities (93.3%). When upper extremes of ISS were aggregated into deciles, mortality for both cohorts across all number of comorbidities was 45.5%-60.9% for ISS 40-49, 56.6%-81.4% for ISS 50-59, and 73.9%-93.3% for ISS >=60. CONCLUSIONS: ISS and preinjury comorbidities alone cannot be used to predict futility in massively injured elderly trauma patients. Future attempts to predict futility in these age groups may benefit from incorporating measures of physiologic distress. PMID- 25494452 TI - Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes. AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) occurs in a minority of smokers and is characterized by intermittent exacerbations and clinical subphenotypes such as emphysema and chronic bronchitis. Although sphingolipids as a class are implicated in the pathogenesis of COPD, the particular sphingolipid species associated with COPD subphenotypes remain unknown. OBJECTIVES: To use mass spectrometry to determine which plasma sphingolipids are associated with subphenotypes of COPD. METHODS: One hundred twenty-nine current and former smokers from the COPDGene cohort had 69 distinct sphingolipid species detected in plasma by targeted mass spectrometry. Of these, 23 were also measured in 131 plasma samples (117 independent subjects) using an untargeted platform in an independent laboratory. Regression analysis with adjustment for clinical covariates, correction for false discovery rate, and metaanalysis were used to test associations between COPD subphenotypes and sphingolipids. Peripheral blood mononuclear cells were used to test associations between sphingolipid gene expression and plasma sphingolipids. MEASUREMENTS AND MAIN RESULTS: Of the measured plasma sphingolipids, five sphingomyelins were associated with emphysema; four trihexosylceramides and three dihexosylceramides were associated with COPD exacerbations. Three sphingolipids were strongly associated with sphingolipid gene expression, and 15 sphingolipid gene/metabolite pairs were differentially regulated between COPD cases and control subjects. CONCLUSIONS: There is evidence of systemic dysregulation of sphingolipid metabolism in patients with COPD. Subphenotyping suggests that sphingomyelins are strongly associated with emphysema and glycosphingolipids are associated with COPD exacerbations. PMID- 25494455 TI - Cell dipole behaviour revealed by ECM sub-cellular geometry. AB - Cells sense and respond to their mechanical environment by exerting forces on their surroundings. The way forces are modulated by extra-cellular matrix (ECM) properties plays a key role in tissue homoeostasis. Using highly resolved micropatterns that constrain cells into the same square envelope but vary the adhesive geometry, here we investigate how the adhesive micro-environment affects the architecture of actin cytoskeleton and the orientation of traction forces. Our data demonstrate that local adhesive changes can trigger orientational ordering of stress fibres throughout the cell, suggesting that cells are capable of integrating information on ECM geometry at the whole-cell level. Finally, we show that cells tend to generate highly polarized force pattern, that is, unidirectional pinching, in response to adequate adhesive conditions. Hence, the geometry of adhesive environment can induce cellular orientation, a process which may have significant implications for the formation and mechanical properties of tissues. PMID- 25494454 TI - Ion-specific control of the self-assembly dynamics of a nanostructured protein lattice. AB - Self-assembling proteins offer a potential means of creating nanostructures with complex structure and function. However, using self-assembly to create nanostructures with long-range order whose size is tunable is challenging, because the kinetics and thermodynamics of protein interactions depend sensitively on solution conditions. Here we systematically investigate the impact of varying solution conditions on the self-assembly of SbpA, a surface-layer protein from Lysinibacillus sphaericus that forms two-dimensional nanosheets. Using high-throughput light scattering measurements, we mapped out diagrams that reveal the relative yield of self-assembly of nanosheets over a wide range of concentrations of SbpA and Ca(2+). These diagrams revealed a localized region of optimum yield of nanosheets at intermediate Ca(2+) concentration. Replacement of Mg(2+) or Ba(2+) for Ca(2+) indicates that Ca(2+) acts both as a specific ion that is required to induce self-assembly and as a general divalent cation. In addition, we use competitive titration experiments to find that 5 Ca(2+) bind to SbpA with an affinity of 67.1 +/- 0.3 MUM. Finally, we show via modeling that nanosheet assembly occurs by growth from a negligibly small critical nucleus. We also chart the dynamics of nanosheet size over a variety of conditions. Our results demonstrate control of the dynamics and size of the self-assembly of a nanostructured lattice, the constituents of which are one of a class of building blocks able to form novel hybrid nanomaterials. PMID- 25494456 TI - Up-regulation of CX3CL1 via Nuclear Factor-kappaB-dependent Histone Acetylation Is Involved in Paclitaxel-induced Peripheral Neuropathy. AB - BACKGROUND: Up-regulation of CX3CL1 has been revealed to be involved in the neuropathic pain induced by nerve injury. However, whether CX3CL1 participates in the paclitaxel-induced painful peripheral neuropathy remains unknown. The aim of the current study was to elucidate the involvement of transcriptional factors nuclear factor-kappaB (NF-kappaB) and its causal interaction with CX3CL1 signaling in the paclitaxel-induced painful peripheral neuropathy. METHODS: Painful peripheral neuropathy induced by paclitaxel treatment was established in adult male Sprague-Dawley rats. The von Frey test were performed to evaluate neuropathic pain behavior, and real-time quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, Western blot, immunohistochemistry, and small interfering RNA were performed to understand the molecular mechanisms. RESULTS: The application of paclitaxel induced an up regulation of CX3CL1 expression in the spinal neurons, which is reduced significantly by NF-kappaB inhibitor ammonium pyrrolidinedithiocarbamate or p65 small interfering RNA. Blockade of either CX3CL1 (n = 12 each) or NF-kappaB (n = 12 each) signaling pathway attenuated mechanical allodynia induced by paclitaxel. Chromatin immunoprecipitation further found that paclitaxel induced an increased recruitment of nuclear factor-kappaB (NF-kappaB)p65 to the Cx3cl1 promoter region. Furthermore, an increased acetylation level of H4, but not H3, in Cx3cl1 promoter region in spinal neurons was detected after paclitaxel treatment, which was reversed by inhibition of NF-kappaB with ammonium pyrrolidinedithiocarbamate or p65 small interfering RNA. CONCLUSIONS: These findings suggest that up regulation of CX3CL1 via NF-kappaB-dependent H4 acetylation might be critical for paclitaxel-induced mechanical allodynia. PMID- 25494457 TI - VSVDeltaG/EBOV GP-induced innate protection enhances natural killer cell activity to increase survival in a lethal mouse adapted Ebola virus infection. AB - Members of the species Zaire ebolavirus cause severe hemorrhagic fever with up to a 90% mortality rate in humans. The VSVDeltaG/EBOV GP vaccine has provided 100% protection in the mouse, guinea pig, and nonhuman primate (NHP) models, and has also been utilized as a post-exposure therapeutic to protect mice, guinea pigs, and NHPs from a lethal challenge of Ebola virus (EBOV). EBOV infection causes rapid mortality in human and animal models, with death occurring as early as 6 days after infection, suggesting a vital role for the innate immune system to control the infection before cells of the adaptive immune system can assume control. Natural killer (NK) cells are the predominant cell of the innate immune response, which has been shown to expand with VSVDeltaG/EBOV GP treatment. In the current study, an in vivo mouse model of the VSVDeltaG/EBOV GP post-exposure treatment was used for a mouse adapted (MA)-EBOV infection, to determine the putative VSVDeltaG/EBOV GP-induced protective mechanism of NK cells. NK depletion studies demonstrated that mice with NK cells survive longer in a MA-EBOV infection, which is further enhanced with VSVDeltaG/EBOV GP treatment. NK cell mediated cytotoxicity and IFN-gamma secretion was significantly higher with VSVDeltaG/EBOV GP treatment. Cell mediated cytotoxicity assays and perforin knockout mice experiments suggest that there are perforin-dependent and independent mechanisms involved. Together, these data suggest that NK cells play an important role in VSVDeltaG/EBOV GP-induced protection of EBOV by increasing NK cytotoxicity, and IFN-gamma secretion. PMID- 25494458 TI - Fanconi syndrome induced by vemurafenib: a new renal adverse event. PMID- 25494459 TI - THE WORK BEHIND THE SCENES. PMID- 25494460 TI - RNA-Directed DNA Methylation: The Evolution of a Complex Epigenetic Pathway in Flowering Plants. AB - RNA-directed DNA methylation (RdDM) is an epigenetic process in plants that involves both short and long noncoding RNAs. The generation of these RNAs and the induction of RdDM rely on complex transcriptional machineries comprising two plant-specific, RNA polymerase II (Pol II)-related RNA polymerases known as Pol IV and Pol V, as well as a host of auxiliary factors that include both novel and refashioned proteins. We present current views on the mechanism of RdDM with a focus on evolutionary innovations that occurred during the transition from a Pol II transcriptional pathway, which produces mRNA precursors and numerous noncoding RNAs, to the Pol IV and Pol V pathways, which are specialized for RdDM and gene silencing. We describe recently recognized deviations from the canonical RdDM pathway, discuss unresolved issues, and speculate on the biological significance of RdDM for flowering plants, which have a highly developed Pol V pathway. PMID- 25494461 TI - Effector-triggered immunity: from pathogen perception to robust defense. AB - In plant innate immunity, individual cells have the capacity to sense and respond to pathogen attack. Intracellular recognition mechanisms have evolved to intercept perturbations by pathogen virulence factors (effectors) early in host infection and convert it to rapid defense. One key to resistance success is a polymorphic family of intracellular nucleotide-binding/leucine-rich-repeat (NLR) receptors that detect effector interference in different parts of the cell. Effector-activated NLRs connect, in various ways, to a conserved basal resistance network in order to transcriptionally boost defense programs. Effector-triggered immunity displays remarkable robustness against pathogen disturbance, in part by employing compensatory mechanisms within the defense network. Also, the mobility of some NLRs and coordination of resistance pathways across cell compartments provides flexibility to fine-tune immune outputs. Furthermore, a number of NLRs function close to the nuclear chromatin by balancing actions of defense repressing and defense-activating transcription factors to program cells dynamically for effective disease resistance. PMID- 25494463 TI - Genome evolution in maize: from genomes back to genes. AB - Maize occupies dual roles as both (a) one of the big-three grain species (along with rice and wheat) responsible for providing more than half of the calories consumed around the world, and (b) a model system for plant genetics and cytogenetics dating back to the origin of the field of genetics in the early twentieth century. The long history of genetic investigation in this species combined with modern genomic and quantitative genetic data has provided particular insight into the characteristics of genes linked to phenotypes and how these genes differ from many other sequences in plant genomes that are not easily distinguishable based on molecular data alone. These recent results suggest that the number of genes in plants that make significant contributions to phenotype may be lower than the number of genes defined by current molecular criteria, and also indicate that syntenic conservation has been underemphasized as a marker for gene function. PMID- 25494464 TI - The molecular biology of meiosis in plants. AB - Meiosis is the cell division that reshuffles genetic information between generations. Recently, much progress has been made in understanding this process; in particular, the identification and functional analysis of more than 80 plant genes involved in meiosis have dramatically deepened our knowledge of this peculiar cell division. In this review, we provide an overview of advancements in the understanding of all aspects of plant meiosis, including recombination, chromosome synapsis, cell cycle control, chromosome distribution, and the challenge of polyploidy. PMID- 25494462 TI - United in diversity: mechanosensitive ion channels in plants. AB - Mechanosensitive (MS) ion channels are a common mechanism for perceiving and responding to mechanical force. This class of mechanoreceptors is capable of transducing membrane tension directly into ion flux. In plant systems, MS ion channels have been proposed to play a wide array of roles, from the perception of touch and gravity to the osmotic homeostasis of intracellular organelles. Three families of plant MS ion channels have been identified: the MscS-like (MSL), Mid1 complementing activity (MCA), and two-pore potassium (TPK) families. Channels from these families vary widely in structure and function, localize to multiple cellular compartments, and conduct chloride, calcium, and/or potassium ions. However, they are still likely to represent only a fraction of the MS ion channel diversity in plant systems. PMID- 25494465 TI - Engineering plastid genomes: methods, tools, and applications in basic research and biotechnology. AB - The small bacterial-type genome of the plastid (chloroplast) can be engineered by genetic transformation, generating cells and plants with transgenic plastid genomes, also referred to as transplastomic plants. The transformation process relies on homologous recombination, thereby facilitating the site-specific alteration of endogenous plastid genes as well as the precisely targeted insertion of foreign genes into the plastid DNA. The technology has been used extensively to analyze chloroplast gene functions and study plastid gene expression at all levels in vivo. Over the years, a large toolbox has been assembled that is now nearly comparable to the techniques available for plant nuclear transformation and that has enabled new applications of transplastomic technology in basic and applied research. This review describes the state of the art in engineering the plastid genomes of algae and land plants (Embryophyta). It provides an overview of the existing tools for plastid genome engineering, discusses current technological limitations, and highlights selected applications that demonstrate the immense potential of chloroplast transformation in several key areas of plant biotechnology. PMID- 25494466 TI - Malaria in pregnant women living in areas of low transmission on the southeast Brazilian Coast: molecular diagnosis and humoural immunity profile. AB - Studies on autochthonous malaria in low-transmission areas in Brazil have acquired epidemiological relevance because they suggest continued transmission in what remains of the Atlantic Forest. In the southeastern portion of the state of Sao Paulo, outbreaks in the municipality of Juquitiba have been the focus of studies on the prevalence of Plasmodium, including asymptomatic cases. Data on the occurrence of the disease or the presence of antiplasmodial antibodies in pregnant women from this region have not previously been described. Although Plasmodium falciparum in pregnant women has been widely addressed in the literature, the interaction of Plasmodium vivax and Plasmodium malariae with this cohort has been poorly explored to date. We monitored the circulation of Plasmodium in pregnant women in health facilities located in Juquitiba using thick blood film and molecular protocols, as well as immunological assays, to evaluate humoural immune parameters. Through real-time and nested polymerase chain reaction, P. vivax and P. malariae were detected for the first time in pregnant women, with a positivity of 5.6%. Immunoassays revealed the presence of IgG antibodies: 44% for ELISA-Pv, 38.4% for SD-Bioline-Pv and 18.4% for indirect immunofluorescence assay-Pm. The high prevalence of antibodies showed significant exposure of this population to Plasmodium. In regions with similar profiles, testing for a malaria diagnosis might be indicated in prenatal care. PMID- 25494467 TI - Using a top predator as a sentinel for environmental contamination with pathogenic bacteria: the Iberian wolf and leptospires. AB - The Iberian wolf (Canis lupus) is the top predator in the Iberian environments in which it lives, feeding on a wide range of species, thus encountering a wide range of disease agents. Therefore, the wolf can serve as sentinel of environmental contamination with pathogens. We investigated the exposure of free living wolves to 14 serovars of Leptospira interrogans sensu lato. Kidney samples from 49 wolves collected from 2010-2013 in northwestern Spain were analysed by culture, direct immunofluorescence and polymerase chain reaction. Tissue fluids were analysed for antibodies by a microscopic agglutination test. Ten wolves (observed prevalence: 20%, 95% confidence interval = 11-33%) showed evidence of contact with leptospires, eight through direct detection and nine through serology (7 wolves were positive according to both techniques). Titres below the cut-off level were also detected in seven cases. Serovars confirmed were Canicola (n = 4), Icterohaemorrhagiae (n = 3) and Sejroe, Ballum and Grippotyphosa (n = 1 each), indicating that wolves were infected with serovars for which dogs, rodents and ungulates, are the natural hosts and supporting the utility of the wolf and other large predators as environmental sentinels for pathogens. PMID- 25494468 TI - CagA phosphorylation EPIYA-C motifs and the vacA i genotype in Helicobacter pylori strains of asymptomatic children from a high-risk gastric cancer area in northeastern Brazil. AB - Helicobacter pylori infection is one of the most common infections worldwide and is associated with gastric diseases. Virulence factors such as VacA and CagA have been shown to increase the risk of these diseases. Studies have suggested a causal role of CagA EPIYA-C in gastric carcinogenesis and this factor has been shown to be geographically diverse. We investigated the number of CagA EPIYA motifs and the vacA i genotypes in H. pylori strains from asymptomatic children. We included samples from 40 infected children (18 females and 22 males), extracted DNA directly from the gastric mucus/juice (obtained using the string procedure) and analysed the DNA using polymerase chain reaction and DNA sequencing. The vacA i1 genotype was present in 30 (75%) samples, the i2 allele was present in nine (22.5%) samples and both alleles were present in one (2.5%) sample. The cagA-positive samples showed distinct patterns in the 3’ variable region of cagA and 18 of the 30 (60%) strains contained 1 EPIYA-C motif, whereas 12 (40%) strains contained two EPIYA-C motifs. We confirmed that the studied population was colonised early by the most virulent H. pylori strains, as demonstrated by the high frequency of the vacA i1 allele and the high number of EPIYA-C motifs. Therefore, asymptomatic children from an urban community in Fortaleza in northeastern Brazil are frequently colonised with the most virulent H. pylori strains. PMID- 25494469 TI - Mycobacterium tuberculosis epitope-specific interferon-g production in healthy Brazilians reactive and non-reactive to tuberculin skin test. AB - The interferon (IFN)-gamma response to peptides can be a useful diagnostic marker of Mycobacterium tuberculosis (MTB) latent infection. We identified promiscuous and potentially protective CD4+ T-cell epitopes from the most conserved regions of MTB antigenic proteins by scanning the MTB antigenic proteins GroEL2, phosphate-binding protein 1 precursor and 19 kDa antigen with the TEPITOPE algorithm. Seven peptide sequences predicted to bind to multiple human leukocyte antigen (HLA)-DR molecules were synthesised and tested with IFN-gamma enzyme linked immunospot (ELISPOT) assays using peripheral blood mononuclear cells (PBMCs) from 16 Mantoux tuberculin skin test (TST)-positive and 16 TST-negative healthy donors. Eighty-eight percent of TST-positive donors responded to at least one of the peptides, compared to 25% of TST-negative donors. Each individual peptide induced IFN-gamma production by PBMCs from at least 31% of the TST positive donors. The magnitude of the response against all peptides was 182 +/- 230 x 106 IFN-gamma spot forming cells (SFC) among TST-positive donors and 36 +/- 62 x 106 SFC among TST-negative donors (p = 0.007). The response to GroEL2 (463 477) was only observed in the TST-positive group. This combination of novel MTB CD4 T-cell epitopes should be tested in a larger cohort of individuals with latent tuberculosis (TB) to evaluate its potential to diagnose latent TB and it may be included in ELISPOT-based IFN-gamma assays to identify individuals with this condition. PMID- 25494471 TI - Feedback-related negativity is enhanced in adolescence during a gambling task with and without probabilistic reinforcement learning. AB - Feedback-related negativity (FRN) is a negative deflection that appears around 250 ms after the gain or loss of feedback to chosen alternatives in a gambling task in frontocentral regions following outcomes. Few studies have reported FRN enhancement in adolescents compared with adults in a gambling task without probabilistic reinforcement learning, despite the fact that learning from positive or negative consequences is crucial for decision-making during adolescence. Therefore, the aim of the present research was to identify differences in FRN amplitude and latency between adolescents and adults on a gambling task with favorable and unfavorable probabilistic reinforcement learning conditions, in addition to a nonlearning condition with monetary gains and losses. Higher rate scores of high-magnitude choices during the final 30 trials compared with the first 30 trials were observed during the favorable condition, whereas lower rates were observed during the unfavorable condition in both groups. Higher FRN amplitude in all conditions and longer latency in the nonlearning condition were observed in adolescents compared with adults and in relation to losses. Results indicate that both the adolescents and the adults improved their performance in relation to positive and negative feedback. However, the FRN findings suggest an increased sensitivity to external feedback to losses in adolescents compared with adults, irrespective of the presence or absence of probabilistic reinforcement learning. These results reflect processing differences on the neural monitoring system and provide new perspectives on the dynamic development of an adolescent's brain. PMID- 25494470 TI - Temporal abundance of Aedes aegypti in Manaus, Brazil, measured by two trap types for adult mosquitoes. AB - A longitudinal study was conducted in Manaus, Brazil, to monitor changes of adult Aedes aegypti (L.) abundance. The objectives were to compare mosquito collections of two trap types, to characterise temporal changes of the mosquito population, to investigate the influence of meteorological variables on mosquito collections and to analyse the association between mosquito collections and dengue incidence. Mosquito monitoring was performed fortnightly using MosquiTRAPs (MQT) and BG Sentinel (BGS) traps between December 2008-June 2010. The two traps revealed opposing temporal infestation patterns, with highest mosquito collections of MQTs during the dry season and highest collections of BGS during the rainy seasons. Several meteorological variables were significant predictors of mosquito collections in the BGS. The best predictor was the relative humidity, lagged two weeks (in a positive relationship). For MQT, only the number of rainy days in the previous week was significant (in a negative relationship). The correlation between monthly dengue incidence and mosquito abundance in BGS and MQT was moderately positive and negative, respectively. Catches of BGS traps reflected better the dynamic of dengue incidence. The findings help to understand the effects of meteorological variables on mosquito infestation indices of two different traps for adult dengue vectors in Manaus. PMID- 25494472 TI - State-dependent and trait-related gray matter changes in nonrefractory depression. AB - Behavioral evidence suggests functional remission or recovery in nonrefractory depressive disorder after successful antidepressant therapy, but the effect of treatment on brain structures remains unclear. It is possible that some specific structural changes are trait-related, in addition to some state-dependent anatomical regions that could be normalized by medications. In the current study, 32 treatment-naive nonrefractory depressive disorder patients and 34 matched healthy controls underwent structural MRI scans and a subgroup including 16 patients underwent the second scans after clinical recovery with antidepressant treatment. The statistical analysis of gray matter images showed that the state dependent regions mainly comprised the key regions within the lateral default, dorsal attention, and frontoparietal networks, whereas the trait-related regions included the medial prefrontal cortex, right anterior insula, thalamus, right parahippocampal gyrus, and right middle occipital gyrus. Moreover, the gray matter changes in the left orbitofrontal cortex, right middle frontal gyrus, left inferior parietal lobule, thalamus, left precentral gyrus, left precuneus, and right middle occipital gyrus were significantly positively correlated with the durations of the current depressive episode. The current findings may not only shed new light on the neuronal effect of antidepressant on depression but also provide potential evidence of the relapse risks for the clinically recovered patients after antidepressant treatment. PMID- 25494473 TI - Tumor suppressor miR-181c attenuates proliferation, invasion, and self-renewal abilities in glioblastoma. AB - Glioblastoma multiforme (GBM) is well known for its aggressiveness, but the underlying mechanisms are unclear, limiting the treatment. In the present study, we showed that miR-181c, a commonly downregulated miRNA in GBM reported by several miRNA profiles, was associated with the mesenchymal subtype of GBM and predicted the outcome for patients from a GBM cohort (n=518) obtained from The Cancer Genome Atlas database. A multivariate analysis showed that miR-181c was an independent prognostic indicator for GBM patients. Quantitative reverse transcription PCR showed that miR-181c was expressed poorly in neurospheres of glioma cells that resemble glioma stem cells. Proliferation and invasion assays showed that miR-181c also blocked the proliferation and invasion abilities of glioma cells. Limiting dilution and colony formation assays showed that miR-181c attenuated the self-renewal ability of glioma cells. Finally, investigation of the mechanism defined Notch2, a key molecular of Notch signaling, as the functional downstream target of miR-181c. An inverse correlation was found between miR-181c and Notch2 in glioma cells and verified in fresh glioma samples. Taken together, the present study showed that miR-181c can be considered a valuable indicator for the outcome of GBM patients. miR-181c acts as a tumor suppressor that attenuates proliferation, invasion, and self-renewal capacities by downregulation of Notch2 in glioma cells. PMID- 25494474 TI - Uniform GaN thin films grown on (100) silicon by remote plasma atomic layer deposition. AB - The growth of uniform gallium nitride (GaN) thin films was reported on (100) Si substrate by remote plasma atomic layer deposition (RP-ALD) using triethylgallium (TEG) and NH3 as the precursors. The self-limiting growth of GaN was manifested by the saturation of the deposition rate with the doses of TEG and NH3. The increase in the growth temperature leads to the rise of nitrogen content and improved crystallinity of GaN thin films, from amorphous at a low deposition temperature of 200 degrees C to polycrystalline hexagonal structures at a high growth temperature of 500 degrees C. No melting-back etching was observed at the GaN/Si interface. The excellent uniformity and almost atomic flat surface of the GaN thin films also infer the surface control mode of the GaN thin films grown by the RP-ALD technique. The GaN thin films grown by RP-ALD will be further applied in the light-emitting diodes and high electron mobility transistors on (100) Si substrate. PMID- 25494475 TI - The use of very-low-dose methadone and haloperidol for pain control in the hospital setting: a preliminary report. AB - OBJECTIVE: Our aim was to evaluate the use of very-low-dose methadone with haloperidol in the acute-care setting. METHODS: We reviewed the records of 735 hospitalized patients receiving a palliative care consultation between 2011 and 2014. All patients with pain on opiates were offered conversion to methadone, 2.5 mg/day to 15 mg/day, in conjunction with scheduled haloperidol. Additional doses of haloperidol or short-acting opiates were given as needed for pain. Patients receiving an opiate at a morphine-equivalent daily dose (MEDD) of >=40 mg had pain scores assessed daily, before and after conversion. Descriptive statistics were used to summarize the results. RESULTS: Forty-three patients underwent conversion from another opiate (median MEDD, 78.5 mg) to methadone (median daily dose, 5 mg) and haloperidol (median daily dose, 1.5 mg). The median pain score was 5 in the week prior to conversion, 1 in week 1 after conversion (p<0.001 for difference), and zero in week 2. Similar results were seen for patients with cancer and noncancer diagnoses and for those with the highest and lowest initial opiate doses. CONCLUSION: The use of very-low-dose methadone in conjunction with haloperidol in the acute-care setting resulted in improved pain control after conversion from typical opiates. PMID- 25494476 TI - Spermatic cord abscess after coronary angiography via femoral artery mimicking incarcerated inguinal hernia. PMID- 25494478 TI - Comparison of direct dynamics simulations with different electronic structure methods. F(-) + CH3I with MP2 and DFT/B97-1. AB - In previous work, ion imaging experiments and direct chemical dynamics simulations with DFT/B97-1 were performed to study the atomic-level dynamics of the F(-) + CH3I -> FCH3 + I(-) SN2 nucleophilic substitution reaction at different collision energies. Overall, the simulations are in quite good agreement with experiment at the low collision energy of 0.32 eV, however there are differences between experiment and simulation at the high collision energy of 1.53 eV. A recent CCSD(T) study of the potential energy surface for the F(-) + CH3I -> FCH3 + I(-) SN2 reaction shows that it has both a traditional C3v and a hydrogen-bond entrance channel. They are represented by MP2 but not by B97-1, which has only the latter channel. On the other hand, B97-1 gives a reaction exothermicity in excellent agreement with experiment, while MP2 is in error by 24.3 kJ mol(-1). In the work presented here, direct dynamics simulations using MP2/aug-cc-pvdz/ECP/d were performed for the F(-) + CH3I -> FCH3 + I(-) reaction at a 1.53 eV collision energy. The same direct rebound and stripping and indirect atomistic reaction mechanisms are found in the B97-1 and MP2 simulations. Both the B97-1 and MP2 simulations agree with the experimental fraction of the available product energy partitioned to CH3F internal energy, i.e. fint = 0.59 +/ 0.08. However, the MP2 fint distribution is broader and in better agreement with experiment than B97-1. The two simulations methods give the same product energy partitioning for the stripping mechanism, but different partitionings for the rebound and indirect mechanisms. Compared to experiment, the principal difference between the B97-1 and MP2 results is the differential cross section which is nearly isotropic for B97-1. For MP2 backward scattering is more important than forward, as found in the experiments. Though there is no overall barrier for the reaction, B97-1 gives a reaction cross section appreciably larger than that for MP2, i.e. 8.6 +/- 2.2 A(2)versus 1.8 +/- 0.3 A(2). For B97-1 59% of the reaction consists of indirect mechanisms, while for MP2 the indirect mechanisms only comprise 11% of the reaction. The experimental differential cross section is more consistent with the atomistic mechanisms for MP2 than for B97-1. PMID- 25494477 TI - alpha-Hexylcinnamaldehyde inhibits the genotoxicity of environmental pollutants in the bacterial reverse mutation assay. AB - The antimutagenicity of alpha-hexylcinnamaldehyde (1), a semisynthetic and more stable derivative of cinnamaldehyde, was evaluated against common environmental pollutants in the bacterial reverse mutation assay. The pre-, co-, and post treatment protocols were applied to assess the involvement of desmutagenic and/or bioantimutagenic mechanisms. Compound 1 (9-900 MUM) produced a strong antimutagenicity (>40% inhibition) in the Salmonella typhimurium TA98 strain against the nitroarenes 2-nitrofluorene and 1-nitropyrene in almost all experimental conditions. A strong inhibition was also reached against the nitroarene 1,8-dinitropyrene and the arylamine 2-aminoanthracene in the cotreatment at the highest concentrations tested. In order to evaluate if an inhibition of bacterial nitroreductase (NR) and O-acetyltransferase (OAT) could be involved in the antimutagenicity of 1 against nitroarenes, the substance was further tested against 1-nitropyrene (activated by both NR and OAT) in TA98NR and TA98 1,8-DNP strains (lacking the NR and OAT enzymes, respectively). Although both desmutagenic and bioantimutagenic mechanisms appear mostly involved in the antimutagenicity of 1, based on data obtained in the TA98NR strain, applying the pretreatment protocol, compound 1 seems to act as an inhibitor of the OAT mediated mutagen bioactivation. These results provide justification for further studies on 1 as a possible chemopreventive agent. PMID- 25494479 TI - Total synthesis of elastin peptide using high pressure-liquid phase synthesis assisted by a soluble tag strategy. AB - A highly aggregating elastin peptide was prepared efficiently using a high pressure-liquid phase synthesis approach assisted by a soluble tag strategy. Two standard syringes were connected to each other to construct a reactor. This simple reactor was used to apply high pressure to the highly viscous reaction mixture thereby maintaining its fluidity. The reactions were completely inhibited due to aggregation when conducted in a standard flask reactor, whereas our high pressure approach accelerated the couplings to realize complete conversion within 5-7 min. All steps were conducted at 0.10 M concentration, affording grams of the desired product. PMID- 25494480 TI - Molecular characterization of a thermophilic endo-polygalacturonase from Thielavia arenaria XZ7 with high catalytic efficiency and application potential in the food and feed industries. AB - Thermophilic endo-polygalacturonases with high catalytic efficiency are of great interest in the food and feed industries. This study identified an endo polygalacturonase gene (pg7fn) of glycoside hydrolase family 28 in the thermophilic fungus Thielavia arenaria XZ7. Recombinant PG7fn produced in Pichia pastoris is distinguished from other enzyme counterparts by its high functional temperature (60 degrees C) and specific activity (34382 +/- 351 U/mg toward polygalacturonic acid). The enzyme exhibited good pH stability (pH 3.0-8.0) and resistance to pepsin and trypsin digestion and had a significant effect on disaggregation of soybean meal. Addition of 1 U/g PG7fn increased the pectin bioavailability by 19.33%. The excellent properties described above make PG7fn valuable for applications in the food and feed industries. Furthermore, a comparative study showed that N-glycosylation improved the thermostability and catalytic efficiency of PG7fn. PMID- 25494481 TI - High-Speed Planar GaAs Nanowire Arrays with fmax > 75 GHz by Wafer-Scale Bottom up Growth. AB - Wafer-scale defect-free planar III-V nanowire (NW) arrays with ~100% yield and precisely defined positions are realized via a patterned vapor-liquid-solid (VLS) growth method. Long and uniform planar GaAs NWs were assembled in perfectly parallel arrays to form double-channel T-gated NW array-based high electron mobility transistors (HEMTs) with DC and RF performance surpassing those for all field-effect transistors (FETs) with VLS NWs, carbon nanotubes (CNTs), or graphene channels in-plane with the substrate. For a planar GaAs NW array-based HEMT with 150 nm gate length and 2 V drain bias, the on/off ratio (ION/IOFF), cutoff frequency (fT), and maximum oscillation frequency (fmax) are 10(4), 33, and 75 GHz, respectively. By characterizing more than 100 devices on a 1.5 * 1.5 cm(2) chip, we prove chip-level electrical uniformity of the planar NW array based HEMTs and verify the feasibility of using this bottom-up planar NW technology for post-Si large-scale nanoelectronics. PMID- 25494482 TI - Might there be a link between intron 3 VNTR polymorphism in the XRCC4 DNA repair gene and the etiopathogenesis of rheumatoid arthritis? AB - DNA repair genes are involved in several diseases such as cancers and autoimmune diseases. Previous studies indicated that a DNA repair system was involved in the development of rheumatoid arthritis (RA). In this study, we aimed to examine whether four polymorphisms in the DNA repair genes (xeroderma pigmentosum complementation group D [XPD], X-ray repair cross-complementing group 1 [XRCC1], and X-ray repair cross-complementing group 4 [XRCC4]) were associated with RA. Sixty-five patients with RA and 70 healthy controls (HCs) were examined for XPD (A-751G), XRCC1 (A399G), and XRCC4 (intron 3 VNTR and G-1394T) polymorphisms. All polymorphisms were genotyped by PCR and/or PCR-RFLP. The association between the polymorphisms and RA was analyzed using the chi-square test and de Finetti program. The intron 3 VNTR polymorphism in the XRCC4 gene showed an association with RA patients. The DI genotype was found lower in RA patients (chi(2)=8.227; p=0.0021), while the II genotype was higher in RA patients (chi(2)=5.285; p=0.010). There were deviations from the Hardy-Weinberg Equilibrium (HWE) in both intron 3 VNTR and G-1394T polymorphisms in the XRCC4 gene and in the polymorphism in the XRCC1 gene, and the observed genotype counts deviated from those expected according to the HWE (p=0.027, 0.004, and 0.002, respectively); however, there was no deviation in the other gene polymorphisms. There is no statistical difference between the RA patients and HCs for XPD (A-751G), XRCC1 (A399G), and XRCC4 (G-1394T) gene polymorphisms (p>0.05). Although XPD (A-751G), XRCC1 (A399G), and XRCC4 (G-1394T) gene polymorphisms have been extensively investigated in different clinical pictures, this is the first study to evaluate the role of these polymorphisms in the genetic etiopathogenesis of RA in Turkish patients. In conclusion, we suggested that the intron 3 VNTR polymorphism in the XRCC4 gene may be associated with the etiopathogenesis of RA as a marker of immune aging. PMID- 25494484 TI - Rational design of humanized dual-agonist antibodies. AB - The ultralong heavy chain complementarity determining region 3 (CDR3H) of bovine antibody BLV1H12 folds into a novel "stalk-knob" structural motif and has been exploited to generate novel agonist antibodies through replacement of the "knob" domain with cytokines and growth factors. By translating this unique "stalk-knob" architecture to the humanized antibody trastuzumab (referred to hereafter by its trade name, Herceptin, Genentech USA), we have developed a versatile approach to the generation of human antibody agonists. Human erythropoietin (hEPO) or granulocyte colony-stimulating factor (hGCSF) was independently fused into CDR3H, CDR2H, or CDR3L of Herceptin using an engineered "stalk" motif. The fusion proteins express in mammalian cells in good yields and have similar in vitro biological activities compared to hEPO and hGCSF. On the basis of these results we then generated a bi-functional Herceptin-CDR fusion protein in which both hEPO and hGCSF were grafted into the heavy- and light-chain CDR3 loops, respectively. This bi-functional antibody fusion exhibited potent EPO and GCSF agonist activities. This work demonstrates the versatility of the CDR-fusion strategy for generating functional human antibody chimeras and provides a novel approach to the development of multi-functional antibody-based therapeutics. PMID- 25494483 TI - Gliotoxin suppresses NF-kappaB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC). AB - A linear ubiquitin chain, which consists of ubiquitin molecules linked via their N- and C-termini, is formed by a linear ubiquitin chain assembly complex (LUBAC) composed of HOIP, HOIL-1L, and SHARPIN, and conjugation of a linear ubiquitin chain on the NF-kappaB essential modulator (NEMO) is deeply involved in NF-kappaB activation induced by various signals. Since abnormal activation of NF-kappaB is associated with inflammatory disease and malignancy, we searched for an inhibitor of LUBAC by high-throughput screening (HTS) with a Tb(3+)-fluorescein FRET system. As a result, we found that the fungal metabolite gliotoxin inhibits LUBAC selectively by binding to the RING-IBR-RING domain of HOIP, the catalytic center of LUBAC. Gliotoxin has been well-known as an inhibitor of NF-kappaB activation, though its action mechanism has remained elusive. Here, we show that gliotoxin inhibits signal-induced NF-kappaB activation by selectively inhibiting LUBAC mediated linear ubiquitin chain formation. PMID- 25494486 TI - Quantitative microbial risk assessment of Cryptosporidium and Giardia in well water from a native community of Mexico. AB - Cryptosporidium and Giardia are gastrointestinal disease-causing organisms transmitted by the fecal-oral route, zoonotic and prevalent in all socioeconomic segments with greater emphasis in rural communities. The goal of this study was to assess the risk of cryptosporidiosis and giardiasis of Potam dwellers consuming drinking water from communal well water. To achieve the goal, quantitative microbial risk assessment (QMRA) was carried out as follows: (a) identification of Cryptosporidium oocysts and Giardia cysts in well water samples by information collection rule method, (b) assessment of exposure to healthy Potam residents, (c) dose-response modelling, and (d) risk characterization using an exponential model. All well water samples tested were positive for Cryptosporidium and Giardia. The QMRA results indicate a mean of annual risks of 99:100 (0.99) for cryptosporidiosis and 1:1 (1.0) for giardiasis. The outcome of the present study may drive decision-makers to establish an educational and treatment program to reduce the incidence of parasite-borne intestinal infection in the Potam community, and to conduct risk analysis programs in other similar rural communities in Mexico. PMID- 25494485 TI - Cardiac risks associated with antibiotics: azithromycin and levofloxacin. AB - INTRODUCTION: Azithromycin and levofloxacin have been shown to be efficacious in treating infections. The adverse drug events associated with azithromycin and levofloxacin were considered rare. However, the US FDA released warnings regarding the possible risk of QT prolongation with azithromycin and levofloxacin. AREAS COVERED: Case reports/case series, observational studies and clinical trials assessing cardiovascular risks associated with azithromycin and levofloxacin were critically reviewed, including 15 case reports/series, 5 observational studies and 5 clinical trials that investigated the cardiac risks associated azithromycin and levofloxacin. EXPERT OPINION: Results are discordant. Two retrospective studies utilizing large databases demonstrated an increased risk of cardiovascular death with azithromycin, when azithromycin was compared with amoxicillin. Two other retrospective studies found no difference in cardiovascular death associated with azithromycin and other antibiotics. For levofloxacin, the increased risk of cardiovascular death was only found in one retrospective study. Therefore, the risks and benefits of antibacterial therapies should be considered when making prescription decisions. This study should not preclude clinicians from avoiding azithromycin and levofloxacin. If a patient has an indication to receive an antibiotic and if azithromycin or levofloxacin is needed, it may be used, but the potential risks must be understood. PMID- 25494487 TI - Polyacrylonitrile/noble metal/SiO2 nanofibers as substrates for the amplified detection of picomolar amounts of metal ions through plasmon-enhanced fluorescence. AB - Electrospun polymer/noble metal hybrid nanofibers have developed rapidly as surface-enhanced Raman scattering (SERS)-active substrates over the last few years. However, polymer/noble metal nanofibers with plasmon-enhanced fluorescence (PEF) activity have received no attention to date. Herein, we show a general and facile approach for the preparation of polyacrylonitrile (PAN)/noble metal/SiO2 nanofibrous mats with PEF activity for the first time by combining electrospinning and controlled silica coatings. These PEF-active nanofibrous mats can selectively improve the fluorescence intensity of conjugated polyelectrolytes (CPEs). Importantly, the CPE solution in the presence of a PAN/noble metal/SiO2 nanofibrous mat showed dramatic fluorescence quenching towards picomolar (pM) amounts of heavy metal ions, while the fluorescence of the CPE solution without the nanofibrous mat had no apparent quenching towards micromolar (MUM) amounts of metal ions. The combination of the distance-dependent fluorescence enhancement performance of metal NPs and the ionic characteristics of the CPE solution makes the polymer/noble metal nanofibers promising substrates for greatly improving the detection sensitivity towards metal ions. We believe that this work provides a general strategy for preparing plasmon band-tuned PEF-active substrates with advantages including good selectivity, remarkable sensitivity and recyclability, which make them a preferable choice for practical sensing applications. PMID- 25494489 TI - Controlling surface reactions with nanopatterned surface elastic strain. AB - The application of elastic lattice strain is a promising approach for tuning material properties, but the attainment of a systematic approach for introducing a high level of strain in materials so as to study its effects has been a major challenge. Here we create an array of intense locally varying strain fields on a TiO2 (110) surface by introducing highly pressurized argon nanoclusters at 6-20 monolayers under the surface. By combining scanning tunneling microscopy imaging and the continuum mechanics model, we show that strain causes the surface bridge bonded oxygen vacancies (BBOv), which are typically present on this surface, to be absent from the strained area and generates defect-free regions. In addition, we find that the adsorption energy of hydrogen binding to oxygen (BBO) is significantly altered by local lattice strain. In particular, the adsorption energy of hydrogen on BBO rows is reduced by ~ 35 meV when the local crystal lattice is compressed by ~ 1.3%. Our results provide direct evidence of the influence of strain on atomic-scale surface chemical properties, and such effects may help guide future research in catalysis materials design. PMID- 25494488 TI - Assessing Treatment-Resistant Posttraumatic Stress Disorder: The Emory Treatment Resistance Interview for PTSD (E-TRIP). AB - Patients with posttraumatic stress disorder (PTSD) who fail to respond to established treatments are at risk for chronic disability and distress. Although treatment-resistant PTSD (TR-PTSD) is a common clinical problem, there is currently no standard method for evaluating previous treatment outcomes. Development of a tool that could quantify the degree of resistance to previously provided treatments would inform research in patients with PTSD. We conducted a systematic review of PTSD treatment trials to identify medication and psychotherapy interventions proven to be efficacious for PTSD. We then developed a semi-structured clinician interview called the Emory Treatment Resistance Interview for PTSD (E-TRIP). The E-TRIP includes clinician-administered questions to assess the adequacy and benefit derived from past treatment trials. For each adequately delivered treatment to which the patient failed to respond, a score is assigned depending on the strength of evidence supporting the treatment's efficacy. The E-TRIP provides a comprehensive assessment of prior PTSD treatments that should prove valuable for researchers studying TR-PTSD and evaluating the efficacy of new treatments for patients with PTSD. The E-TRIP is not intended to guide treatment; rather, the tool quantifies the level of treatment resistance in patients with PTSD in order to standardize TR-PTSD in the research domain. PMID- 25494490 TI - Evaporation kinetics of laboratory-generated secondary organic aerosols at elevated relative humidity. AB - Secondary organic aerosols (SOA) dominate atmospheric organic aerosols that affect climate, air quality, and health. Recent studies indicate that, contrary to previously held assumptions, at low relative humidity (RH) these particles are semisolid and evaporate orders of magnitude slower than expected. Elevated relative humidity has the potential to affect significantly formation, properties, and atmospheric evolution of SOA particles. Here we present a study of the effect of RH on the room-temperature evaporation kinetics of SOA particles formed by ozonolysis of alpha-pinene and limonene. Experiments were carried out on alpha-pinene SOA particles generated, evaporated, and aged at <5%, 50 and 90% RH, and on limonene SOA particles at <5% and 90% RH. We find that in all cases evaporation begins with a relatively fast phase, during which 30-70% of the particle mass evaporates in 2 h, followed by a much slower evaporation rate. Evaporation kinetics at <5% and 50% RH are nearly the same, while at 90% RH a slightly larger fraction evaporates. In all cases, aging the particles prior to inducing evaporation reduces the evaporative losses; with aging at elevated RH leading to a more significant effect. In all cases, the observed SOA evaporation is nearly size-independent. PMID- 25494491 TI - Rhabdoid tumor predisposition syndrome. AB - Rhabdoid tumors (RT), or malignant rhabdoid tumors, are among the most aggressive and lethal forms of human cancer. They can arise in any location in the body but are most commonly observed in the brain, where they are called atypical teratoid/rhabdoid tumors (AT/RT), and in the kidneys, where they are called rhabdoid tumors of the kidney. The vast majority of rhabdoid tumors present with a loss of function in the SMARCB1 gene, also known as INI1, BAF47, and hSNF5, a core member of the SWI/SNF chromatin-remodeling complex. Recently, mutations in a 2nd locus of the SWI/SNF complex, the SMARCA4 gene, also known as BRG1, were found in rhabdoid tumors with retention of SMARCB1 expression. Familial cases may occur in a condition known as rhabdoid tumor predisposition syndrome (RTPS). In RTPS, germline inactivation of 1 allele of a gene occurs. When the mutation occurs in the SMARCB1 gene, the syndrome is called RTPS1, and when the mutation occurs in the SMARCA4 gene it is called RTPS2. Children presenting with RTPS tend to develop tumors at a younger age, but the impact that germline mutation has on survival remains unclear. Adults who carry the mutation tend to develop multiple schwannomas. The diagnosis of RTPS should be considered in patients with RT, especially if they have multiple primary tumors, and/or in individuals with a family history of RT. Because germline mutations result in an increased risk of carriers developing RT, genetic counseling for families with this condition is recommended. PMID- 25494493 TI - Solution-processed highly efficient Cu2ZnSnSe4 thin film solar cells by dissolution of elemental Cu, Zn, Sn, and Se powders. AB - Solution deposition approaches play an important role in reducing the manufacturing cost of Cu2ZnSnSe4 (CZTSe) thin film solar cells. Here, we present a novel precursor-based solution approach to fabricate highly efficient CZTSe solar cells. In this approach, low-cost elemental Cu, Zn, Sn, and Se powders were simultaneously dissolved in the solution of thioglycolic acid and ethanolamine, forming a homogeneous CZTSe precursor solution to deposit CZTSe nanocrystal thin films. Based on high-quality CZTSe absorber layer, pure selenide CZTSe solar cell with a photoelectric conversion efficiency of 8.02% has been achieved without antireflection coating. PMID- 25494492 TI - Bioinspired nanocomplex for spatiotemporal imaging of sequential mRNA expression in differentiating neural stem cells. AB - Messenger RNA plays a pivotal role in regulating cellular activities. The expression dynamics of specific mRNA contains substantial information on the intracellular milieu. Unlike the imaging of stationary mRNAs, real-time intracellular imaging of the dynamics of mRNA expression is of great value for investigating mRNA biology and exploring specific cellular cascades. In addition to advanced imaging methods, timely extracellular stimulation is another key factor in regulating the mRNA expression repertoire. The integration of effective stimulation and imaging into a single robust system would significantly improve stimulation efficiency and imaging accuracy, producing fewer unwanted artifacts. In this study, we developed a multifunctional nanocomplex to enable self activating and spatiotemporal imaging of the dynamics of mRNA sequential expression during the neural stem cell differentiation process. This nanocomplex showed improved enzymatic stability, fast recognition kinetics, and high specificity. With a mechanism regulated by endogenous cell machinery, this nanocomplex realized the successive stimulating motif release and the dynamic imaging of chronological mRNA expression during neural stem cell differentiation without the use of transgenetic manipulation. The dynamic imaging montage of mRNA expression ultimately facilitated genetic heterogeneity analysis. In vivo lateral ventricle injection of this nanocomplex enabled endogenous neural stem cell activation and labeling at their specific differentiation stages. This nanocomplex is highly amenable as an alternative tool to explore the dynamics of intricate mRNA activities in various physiological and pathological conditions. PMID- 25494495 TI - Using a noninvasive decoding method to classify rhythmic movement imaginations of the arm in two planes. AB - A brain-computer interface (BCI) can help to overcome movement deficits in persons with spinal-cord injury. Ideally, such a BCI detects detailed movement imaginations, i.e., trajectories, and transforms them into a control signal for a neuroprosthesis or a robotic arm restoring movement. Robotic arms have already been controlled successfully by means of invasive recording techniques, and executed movements have been reconstructed using noninvasive decoding techniques. However, it is unclear if detailed imagined movements can be decoded noninvasively using electroencephalography (EEG). We made progress toward imagined movement decoding and successfully classified horizontal and vertical imagined rhythmic movements of the right arm in healthy subjects using EEG. Notably, we used an experimental design which avoided muscle and eye movements to prevent classification results being affected. To classify imagined movements of the same limb, we decoded the movement trajectories and correlated them with assumed movement trajectories (horizontal and vertical). We then assigned the decoded movements to the assumed movements with the higher correlation. To train the decoder, we applied partial least squares, which allowed us to interpret the classifier weights although channels were highly correlated. To conclude, we showed the classification of imagined movements of one limb in two different movement planes in seven out of nine subjects. Furthermore, we found a strong involvement of the supplementary motor area. Finally, as our classifier was based on the decoding approach, we indirectly showed the decoding of imagined movements. PMID- 25494494 TI - Sparse representation of electrodermal activity with knowledge-driven dictionaries. AB - Biometric sensors and portable devices are being increasingly embedded into our everyday life, creating the need for robust physiological models that efficiently represent, analyze, and interpret the acquired signals. We propose a knowledge driven method to represent electrodermal activity (EDA), a psychophysiological signal linked to stress, affect, and cognitive processing. We build EDA-specific dictionaries that accurately model both the slow varying tonic part and the signal fluctuations, called skin conductance responses (SCR), and use greedy sparse representation techniques to decompose the signal into a small number of atoms from the dictionary. Quantitative evaluation of our method considers signal reconstruction, compression rate, and information retrieval measures, that capture the ability of the model to incorporate the main signal characteristics, such as SCR occurrences. Compared to previous studies fitting a predetermined structure to the signal, results indicate that our approach provides benefits across all aforementioned criteria. This paper demonstrates the ability of appropriate dictionaries along with sparse decomposition methods to reliably represent EDA signals and provides a foundation for automatic measurement of SCR characteristics and the extraction of meaningful EDA features. PMID- 25494496 TI - A miniaturized, eye-conformable, and long-term reliable retinal prosthesis using monolithic fabrication of liquid crystal polymer (LCP). AB - A novel retinal prosthetic device was developed using biocompatible liquid crystal polymer (LCP) to address the problems associated with conventional metal- and polymer-based devices: the hermetic metal package is bulky, heavy, and labor intensive, whereas a thin, flexible, and MEMS-compatible polymer-based system is not durable enough for chronic implantation. Exploiting the advantageous properties of LCP such as a low moisture absorption rate, thermobonding, and thermoforming, we fabricate a small, light-weight, long-term reliable retinal prosthesis that can be conformally attached on the eye-surface. A LCP fabrication process using monolithic integration and conformal deformation was established enabling miniaturization and a batch manufacturing process as well as eliminating the need for feed-through technology. The functionality of the fabricated device was tested through wireless operation in saline solution. Its efficacy and implantation stability were verified through in vivo animal tests by measuring the cortical potential and monitoring implanted dummy devices for more than a year, respectively. PMID- 25494497 TI - A Kalman filtering framework for physiological detection of anxiety-related arousal in children with autism spectrum disorder. AB - OBJECTIVE: Anxiety is associated with physiological changes that can be noninvasively measured using inexpensive and wearable sensors. These changes provide an objective and language-free measure of arousal associated with anxiety, which can complement treatment programs for clinical populations who have difficulty with introspection, communication, and emotion recognition. This motivates the development of automatic methods for detection of anxiety-related arousal using physiology signals. While several supervised learning methods have been proposed for this purpose, these methods require regular collection and updating of training data and are, therefore, not suitable for clinical populations, where obtaining labelled data may be challenging due to impairments in communication and introspection. In this context, the objective of this paper is to develop an unsupervised and real-time arousal detection algorithm. METHODS: We propose a learning framework based on the Kalman filtering theory for detection of physiological arousal based on cardiac activity. The performance of the system was evaluated on data obtained from a sample of children with autism spectrum disorder. RESULTS: The results indicate that the system can detect anxiety-related arousal in these children with sensitivity and specificity of 99% and 92%, respectively. CONCLUSION AND SIGNIFICANCE: Our results show that the proposed method can detect physiological arousal associated with anxiety with high accuracy, providing support for technical feasibility of augmenting anxiety treatments with automatic detection techniques. This approach can ultimately lead to more effective anxiety treatment for a larger and more diverse population. PMID- 25494498 TI - Human experts' and a fuzzy model's predictions of outcomes of scoliosis treatment: a comparative analysis. AB - Brace treatment is the most commonly used nonsurgical treatment for adolescents with idiopathic scoliosis. However, brace treatment is not always successful and the factors influencing its success are not completely clear. This makes treatment outcome difficult to predict. A computer model which can accurately predict treatment outcomes could potentially provide valuable treatment recommendations. This paper describes a fuzzy system that includes a prediction model and a decision support engine. The model was constructed using conditional fuzzy c-means clustering to discover patterns in retrospective patient data. The model's ability to predict treatment outcome was compared to the ability of eight Scoliosis experts. The model and experts each predicted treatment outcome retrospectively for 28 braced patients, and these predictions were compared to the actual outcomes. The model outperformed all but one expert individually and performed similarly to the experts as a group. These results suggest that the fuzzy model is capable of providing meaningful treatment recommendations. This study offers the first model for this application whose performance has been shown to be at or above the human expert level. PMID- 25494499 TI - Monitoring cardiac stress using features extracted from S1 heart sounds. AB - It is known that acoustic heart sounds carry significant information about the mechanical activity of the heart. In this paper, we present a novel type of cardiac monitoring based on heart sound analysis. Specifically, we study two morphological features and their associations with physiological changes from the baseline state. The framework is demonstrated on recordings during laparoscopic surgeries of 15 patients. Insufflation, which is performed during laparoscopic surgery, provides a controlled, externally induced cardiac stress, enabling an analysis of each patient with respect to their own baseline. We demonstrate that the proposed features change during cardiac stress, and the change is more significant for patients with cardiac problems. Furthermore, we show that other well-known ECG morphology features are less sensitive in this specific cardiac stress experiment. PMID- 25494500 TI - Prediction of the biomechanical effects of compression therapy by finite element modeling and ultrasound elastography. AB - GOAL: In the present study, the biomechanical response of soft tissues from the fascia cruris to the skin is studied in the human leg under elastic compression. METHODS: The distribution of elastic moduli in these tissues is measured for a volunteer at inactive and active muscle states using transient ultrasound elastography (TUSE). After registering the elasticity maps against magnetic resonance imaging scans of the same volunteer, patient-specific finite element (FE) models are developed for the leg cross section at inactive and active muscle states. Elastic properties obtained with TUSE are assigned at each Gauss point of the models. The response to 20 mmHg elastic compression is eventually predicted with the models. RESULTS: Results show significantly higher elastic moduli in the fascia cruris tissue and also a significant increase of elastic moduli at active muscle state. CONCLUSION: This seems to have a marginal impact on pressure maps in the soft tissues of the leg predicted by the FE models. There is still an effect on the reduction of vein diameter induced by elastic compression, which is decreased at active muscle state. SIGNIFICANCE: The discussion of this paper highlights the benefits of using elastography to reconstruct patient-specific FE models of soft tissues. PMID- 25494502 TI - Analysis of the noise correlation in MRI coil arrays loaded with metamaterial magnetoinductive lenses. AB - A numerical method is shown for calculating the noise correlation coefficient in arrays of magnetic resonance imaging (MRI) coils loaded with capacitively-loaded ring metamaterial lenses, and in the presence of a conducting half-space resembling a sample. This numerical method is validated by comparison with experimental results obtained in two different experimental procedures for double check: noise resistance measurements with a network analyzer and noise correlation measurements in an MRI system. It is found that, for practical array configurations such as overlapping coils or capacitively-decoupled coils, the noise correlation coefficient turns negative for coils loaded with metamaterial lenses. In particular, the analysis is carried out with metamaterial structures known as magnetoinductive lenses, which have been demonstrated in previous works to improve the signal-to-noise ratio of MRI coils. Results are also shown to demonstrate that negative noise correlations have as an effect the improvement of the g-factor in coil arrays for parallel MRI. PMID- 25494503 TI - Random forest construction with robust semisupervised node splitting. AB - Random forest (RF) is a very important classifier with applications in various machine learning tasks, but its promising performance heavily relies on the size of labeled training data. In this paper, we investigate constructing of RFs with a small size of labeled data and find that the performance bottleneck is located in the node splitting procedures; hence, existing solutions fail to properly partition the feature space if there are insufficient training data. To achieve robust node splitting with insufficient data, we present semisupervised splitting to overcome this limitation by splitting nodes with the guidance of both labeled and abundant unlabeled data. In particular, an accurate quality measure of node splitting is obtained by carrying out the kernel-based density estimation, whereby a multiclass version of asymptotic mean integrated squared error criterion is proposed to adaptively select the optimal bandwidth of the kernel. To avoid the curse of dimensionality, we project the data points from the original high-dimensional feature space onto a low-dimensional subspace before estimation. A unified optimization framework is proposed to select a coupled pair of subspace and separating hyperplane such that the smoothness of the subspace and the quality of the splitting are guaranteed simultaneously. Our algorithm efficiently avoids overfitting caused by bad initialization and local maxima when compared with conventional margin maximization-based semisupervised methods. We demonstrate the effectiveness of the proposed algorithm by comparing it with state-of-the-art supervised and semisupervised algorithms for typical computer vision applications, such as object categorization, face recognition, and image segmentation, on publicly available data sets. PMID- 25494504 TI - Geodesic invariant feature: a local descriptor in depth. AB - Different from the photometric images, depth images resolve the distance ambiguity of the scene, while the properties, such as weak texture, high noise, and low resolution, may limit the representation ability of the well-developed descriptors, which are elaborately designed for the photometric images. In this paper, a novel depth descriptor, geodesic invariant feature (GIF), is presented for representing the parts of the articulate objects in depth images. GIF is a multilevel feature representation framework, which is proposed based on the nature of depth images. Low-level, geodesic gradient is introduced to obtain the invariance to the articulate motion, such as scale and rotation variation. Midlevel, superpixel clustering is applied to reduce depth image redundancy, resulting in faster processing speed and better robustness to noise. High-level, deep network is used to exploit the nonlinearity of the data, which further improves the classification accuracy. The proposed descriptor is capable of encoding the local structures in the depth data effectively and efficiently. Comparisons with the state-of-the-art methods reveal the superiority of the proposed method. PMID- 25494505 TI - Detection of dynamic background due to swaying movements from motion features. AB - Dynamically changing background (dynamic background) still presents a great challenge to many motion-based video surveillance systems. In the context of event detection, it is a major source of false alarms. There is a strong need from the security industry either to detect and suppress these false alarms, or dampen the effects of background changes, so as to increase the sensitivity to meaningful events of interest. In this paper, we restrict our focus to one of the most common causes of dynamic background changes: 1) that of swaying tree branches and 2) their shadows under windy conditions. Considering the ultimate goal in a video analytics pipeline, we formulate a new dynamic background detection problem as a signal processing alternative to the previously described but unreliable computer vision-based approaches. Within this new framework, we directly reduce the number of false alarms by testing if the detected events are due to characteristic background motions. In addition, we introduce a new data set suitable for the evaluation of dynamic background detection. It consists of real-world events detected by a commercial surveillance system from two static surveillance cameras. The research question we address is whether dynamic background can be detected reliably and efficiently using simple motion features and in the presence of similar but meaningful events, such as loitering. Inspired by the tree aerodynamics theory, we propose a novel method named local variation persistence (LVP), that captures the key characteristics of swaying motions. The method is posed as a convex optimization problem, whose variable is the local variation. We derive a computationally efficient algorithm for solving the optimization problem, the solution of which is then used to form a powerful detection statistic. On our newly collected data set, we demonstrate that the proposed LVP achieves excellent detection results and outperforms the best alternative adapted from existing art in the dynamic background literature. PMID- 25494501 TI - The Multimodal Brain Tumor Image Segmentation Benchmark (BRATS). AB - In this paper we report the set-up and results of the Multimodal Brain Tumor Image Segmentation Benchmark (BRATS) organized in conjunction with the MICCAI 2012 and 2013 conferences. Twenty state-of-the-art tumor segmentation algorithms were applied to a set of 65 multi-contrast MR scans of low- and high-grade glioma patients-manually annotated by up to four raters-and to 65 comparable scans generated using tumor image simulation software. Quantitative evaluations revealed considerable disagreement between the human raters in segmenting various tumor sub-regions (Dice scores in the range 74%-85%), illustrating the difficulty of this task. We found that different algorithms worked best for different sub regions (reaching performance comparable to human inter-rater variability), but that no single algorithm ranked in the top for all sub-regions simultaneously. Fusing several good algorithms using a hierarchical majority vote yielded segmentations that consistently ranked above all individual algorithms, indicating remaining opportunities for further methodological improvements. The BRATS image data and manual annotations continue to be publicly available through an online evaluation system as an ongoing benchmarking resource. PMID- 25494506 TI - Tubularity flow field--a technique for automatic neuron segmentation. AB - A segmentation framework is proposed to trace neurons from confocal microscopy images. With an increasing demand for high throughput neuronal image analysis, we propose an automated scheme to perform segmentation in a variational framework. Our segmentation technique, called tubularity flow field (TuFF) performs directional regional growing guided by the direction of tubularity of the neurites. We further address the problem of sporadic signal variation in confocal microscopy by designing a local attraction force field, which is able to bridge the gaps between local neurite fragments, even in the case of complete signal loss. Segmentation is performed in an integrated fashion by incorporating the directional region growing and the attraction force-based motion in a single framework using level sets. This segmentation is accomplished without manual seed point selection; it is automated. The performance of TuFF is demonstrated over a set of 2D and 3D confocal microscopy images where we report an improvement of >75% in terms of mean absolute error over three extensively used neuron segmentation algorithms. Two novel features of the variational solution, the evolution force and the attraction force, hold promise as contributions that can be employed in a number of image analysis applications. PMID- 25494507 TI - SuBSENSE: a universal change detection method with local adaptive sensitivity. AB - Foreground/background segmentation via change detection in video sequences is often used as a stepping stone in high-level analytics and applications. Despite the wide variety of methods that have been proposed for this problem, none has been able to fully address the complex nature of dynamic scenes in real surveillance tasks. In this paper, we present a universal pixel-level segmentation method that relies on spatiotemporal binary features as well as color information to detect changes. This allows camouflaged foreground objects to be detected more easily while most illumination variations are ignored. Besides, instead of using manually set, frame-wide constants to dictate model sensitivity and adaptation speed, we use pixel-level feedback loops to dynamically adjust our method's internal parameters without user intervention. These adjustments are based on the continuous monitoring of model fidelity and local segmentation noise levels. This new approach enables us to outperform all 32 previously tested state-of-the-art methods on the 2012 and 2014 versions of the ChangeDetection.net dataset in terms of overall F-Measure. The use of local binary image descriptors for pixel-level modeling also facilitates high-speed parallel implementations: our own version, which used no low-level or architecture-specific instruction, reached real-time processing speed on a midlevel desktop CPU. A complete C++ implementation based on OpenCV is available online. PMID- 25494508 TI - Multiresolution graph Fourier transform for compression of piecewise smooth images. AB - Piecewise smooth (PWS) images (e.g., depth maps or animation images) contain unique signal characteristics such as sharp object boundaries and slowly varying interior surfaces. Leveraging on recent advances in graph signal processing, in this paper, we propose to compress the PWS images using suitable graph Fourier transforms (GFTs) to minimize the total signal representation cost of each pixel block, considering both the sparsity of the signal's transform coefficients and the compactness of transform description. Unlike fixed transforms, such as the discrete cosine transform, we can adapt GFT to a particular class of pixel blocks. In particular, we select one among a defined search space of GFTs to minimize total representation cost via our proposed algorithms, leveraging on graph optimization techniques, such as spectral clustering and minimum graph cuts. Furthermore, for practical implementation of GFT, we introduce two techniques to reduce computation complexity. First, at the encoder, we low-pass filter and downsample a high-resolution (HR) pixel block to obtain a low resolution (LR) one, so that a LR-GFT can be employed. At the decoder, upsampling and interpolation are performed adaptively along HR boundaries coded using arithmetic edge coding, so that sharp object boundaries can be well preserved. Second, instead of computing GFT from a graph in real-time via eigen decomposition, the most popular LR-GFTs are pre-computed and stored in a table for lookup during encoding and decoding. Using depth maps and computer-graphics images as examples of the PWS images, experimental results show that our proposed multiresolution-GFT scheme outperforms H.264 intra by 6.8 dB on average in peak signal-to-noise ratio at the same bit rate. PMID- 25494509 TI - Pareto-depth for multiple-query image retrieval. AB - Most content-based image retrieval systems consider either one single query, or multiple queries that include the same object or represent the same semantic information. In this paper, we consider the content-based image retrieval problem for multiple query images corresponding to different image semantics. We propose a novel multiple-query information retrieval algorithm that combines the Pareto front method with efficient manifold ranking. We show that our proposed algorithm outperforms state of the art multiple-query retrieval algorithms on real-world image databases. We attribute this performance improvement to concavity properties of the Pareto fronts, and prove a theoretical result that characterizes the asymptotic concavity of the fronts. PMID- 25494510 TI - JF-cut: a parallel graph cut approach for large-scale image and video. AB - Graph cut has proven to be an effective scheme to solve a wide variety of segmentation problems in vision and graphics community. The main limitation of conventional graph-cut implementations is that they can hardly handle large images or videos because of high computational complexity. Even though there are some parallelization solutions, they commonly suffer from the problems of low parallelism (on CPU) or low convergence speed (on GPU). In this paper, we present a novel graph-cut algorithm that leverages a parallelized jump flooding technique and an heuristic push-relabel scheme to enhance the graph-cut process, namely, back-and-forth relabel, convergence detection, and block-wise push-relabel. The entire process is parallelizable on GPU, and outperforms the existing GPU-based implementations in terms of global convergence, information propagation, and performance. We design an intuitive user interface for specifying interested regions in cases of occlusions when handling video sequences. Experiments on a variety of data sets, including images (up to 15 K * 10 K), videos (up to 2.5 K * 1.5 K * 50), and volumetric data, achieve high-quality results and a maximum 40 fold (139-fold) speedup over conventional GPU (CPU-)-based approaches. PMID- 25494511 TI - CID2013: a database for evaluating no-reference image quality assessment algorithms. AB - This paper presents a new database, CID2013, to address the issue of using no reference (NR) image quality assessment algorithms on images with multiple distortions. Current NR algorithms struggle to handle images with many concurrent distortion types, such as real photographic images captured by different digital cameras. The database consists of six image sets; on average, 30 subjects have evaluated 12-14 devices depicting eight different scenes for a total of 79 different cameras, 480 images, and 188 subjects (67% female). The subjective evaluation method was a hybrid absolute category rating-pair comparison developed for the study and presented in this paper. This method utilizes a slideshow of all images within a scene to allow the test images to work as references to each other. In addition to mean opinion score value, the images are also rated using sharpness, graininess, lightness, and color saturation scales. The CID2013 database contains images used in the experiments with the full subjective data plus extensive background information from the subjects. The database is made freely available for the research community. PMID- 25494512 TI - Sensing and Force-Feedback Exoskeleton (SAFE) Robotic Glove. AB - This paper presents the design, implementation and experimental validation of a novel robotic haptic exoskeleton device to measure the user's hand motion and assist hand motion while remaining portable and lightweight. The device consists of a five-finger mechanism actuated with miniature DC motors through antagonistically routed cables at each finger, which act as both active and passive force actuators. The SAFE Glove is a wireless and self-contained mechatronic system that mounts over the dorsum of a bare hand and provides haptic force feedback to each finger. The glove is adaptable to a wide variety of finger sizes without constraining the range of motion. This makes it possible to accurately and comfortably track the complex motion of the finger and thumb joints associated with common movements of hand functions, including grip and release patterns. The glove can be wirelessly linked to a computer for displaying and recording the hand status through 3D Graphical User Interface (GUI) in real time. The experimental results demonstrate that the SAFE Glove is capable of reliably modeling hand kinematics, measuring finger motion and assisting hand grasping motion. Simulation and experimental results show the potential of the proposed system in rehabilitation therapy and virtual reality applications. PMID- 25494513 TI - Quantum algorithms and mathematical formulations of biomolecular solutions of the vertex cover problem in the finite-dimensional hilbert space. AB - In this paper, it is shown that the proposed quantum algorithm for implementing Boolean circuits generated from the DNA-based algorithm solving the vertex-cover problem of any graph G with m edges and n vertices is the optimal quantum algorithm. Next, it is also demonstrated that mathematical solutions of the same biomolecular solutions are represented in terms of a unit vector in the finite dimensional Hilbert space. Furthermore, for testing our theory, a nuclear magnetic resonance (NMR) experiment of three quantum bits to solve the simplest vertex-cover problem is completed. PMID- 25494514 TI - Region-Based Object Recognition by Color Segmentation Using a Simplified PCNN. AB - In this paper, we propose a region-based object recognition (RBOR) method to identify objects from complex real-world scenes. First, the proposed method performs color image segmentation by a simplified pulse-coupled neural network (SPCNN) for the object model image and test image, and then conducts a region based matching between them. Hence, we name it as RBOR with SPCNN (SPCNN-RBOR). Hereinto, the values of SPCNN parameters are automatically set by our previously proposed method in terms of each object model. In order to reduce various light intensity effects and take advantage of SPCNN high resolution on low intensities for achieving optimized color segmentation, a transformation integrating normalized Red Green Blue (RGB) with opponent color spaces is introduced. A novel image segmentation strategy is suggested to group the pixels firing synchronously throughout all the transformed channels of an image. Based on the segmentation results, a series of adaptive thresholds, which is adjustable according to the specific object model is employed to remove outlier region blobs, form potential clusters, and refine the clusters in test images. The proposed SPCNN-RBOR method overcomes the drawback of feature-based methods that inevitably includes background information into local invariant feature descriptors when keypoints locate near object boundaries. A large number of experiments have proved that the proposed SPCNN-RBOR method is robust for diverse complex variations, even under partial occlusion and highly cluttered environments. In addition, the SPCNN-RBOR method works well in not only identifying textured objects, but also in less textured ones, which significantly outperforms the current feature-based methods. PMID- 25494515 TI - Dynamic Surface Control Using Neural Networks for a Class of Uncertain Nonlinear Systems With Input Saturation. AB - In this paper, a dynamic surface control (DSC) scheme is proposed for a class of uncertain strict-feedback nonlinear systems in the presence of input saturation and unknown external disturbance. The radial basis function neural network (RBFNN) is employed to approximate the unknown system function. To efficiently tackle the unknown external disturbance, a nonlinear disturbance observer (NDO) is developed. The developed NDO can relax the known boundary requirement of the unknown disturbance and can guarantee the disturbance estimation error converge to a bounded compact set. Using NDO and RBFNN, the DSC scheme is developed for uncertain nonlinear systems based on a backstepping method. Using a DSC technique, the problem of explosion of complexity inherent in the conventional backstepping method is avoided, which is specially important for designs using neural network approximations. Under the proposed DSC scheme, the ultimately bounded convergence of all closed-loop signals is guaranteed via Lyapunov analysis. Simulation results are given to show the effectiveness of the proposed DSC design using NDO and RBFNN. PMID- 25494516 TI - A Predictive Model for Personalized Therapeutic Interventions in Non-small Cell Lung Cancer. AB - Non-small cell lung cancer (NSCLC) constitutes the most common type of lung cancer and is frequently diagnosed at advanced stages. Clinical studies have shown that molecular targeted therapies increase survival and improve quality of life in patients. Nevertheless, the realization of personalized therapies for NSCLC faces a number of challenges including the integration of clinical and genetic data and a lack of clinical decision support tools to assist physicians with patient selection. To address this problem, we used frequent pattern mining to establish the relationships of patient characteristics and tumor response in advanced NSCLC. Univariate analysis determined that smoking status, histology, epidermal growth factor receptor (EGFR) mutation, and targeted drug were significantly associated with response to targeted therapy. We applied four classifiers to predict treatment outcome from EGFR tyrosine kinase inhibitors. Overall, the highest classification accuracy was 76.56% and the area under the curve was 0.76. The decision tree used a combination of EGFR mutations, histology, and smoking status to predict tumor response and the output was both easily understandable and in keeping with current knowledge. Our findings suggest that support vector machines and decision trees are a promising approach for clinical decision support in the patient selection for targeted therapy in advanced NSCLC. PMID- 25494517 TI - A Novel Approach for Toe Off Estimation During Locomotion and Transitions on Ramps and Level Ground. AB - Identification of the toe off event is critical in many gait applications. Accelerometer threshold-based algorithms lack adaptability and have not been tested for transitions between locomotion states. We describe a new approach for toe off identification using one accelerometer in over ground and ramp walking, including transitions. The method uses invariant foot acceleration features in the segment of gait, where toe off is probable. Wavelet analysis of foot acceleration is used to derive a unique feature in a particular frequency band, yielding estimated toe off occurrence. We tested the new method for five conditions: over ground walking (W), ramp ascending (RA), ramp descending (RD); transitions between states (W-RA, W-RD). Mean absolute estimation error was 17.4 +/- 12.5, 13.8 +/- 8.5, and 22.0 +/- 16.4 ms for steady states W, RA, and RD, 20.1 +/- 15.5, and 17.1 +/- 13.7 ms for transitions W-RA and W-RD, respectively. Algorithm performance was equivalent across all pairs of transition and locomotion state except between RA and RD ( p = 0.03), demonstrating adaptability. The db1 wavelet outperformed db2 across states and transitions (p < 0.01). The presented algorithm is a simple, robust approach for toe off detection. PMID- 25494518 TI - Interrelationship-Based Selection for Decomposition Multiobjective Optimization. AB - Multiobjective evolutionary algorithm based on decomposition (MOEA/D), which bridges the traditional optimization techniques and population-based methods, has become an increasingly popular framework for evolutionary multiobjective optimization. It decomposes a multiobjective optimization problem (MOP) into a number of optimization subproblems. Each subproblem is handled by an agent in a collaborative manner. The selection of MOEA/D is a process of choosing solutions by agents. In particular, each agent has two requirements on its selected solution: one is the convergence toward the efficient front, the other is the distinction with the other agents' choices. This paper suggests addressing these two requirements by defining mutual-preferences between subproblems and solutions. Afterwards, a simple yet effective method is proposed to build an interrelationship between subproblems and solutions, based on their mutual preferences. At each generation, this interrelationship is used as a guideline to select the elite solutions to survive as the next parents. By considering the mutual-preferences between subproblems and solutions (i.e., the two requirements of each agent), the selection operator is able to balance the convergence and diversity of the search process. Comprehensive experiments are conducted on several MOP test instances with complicated Pareto sets. Empirical results demonstrate the effectiveness and competitiveness of our proposed algorithm. PMID- 25494519 TI - Decentralized Estimation and Control for Preserving the Strong Connectivity of Directed Graphs. AB - In order to accomplish cooperative tasks, decentralized systems are required to communicate among each other. Thus, maintaining the connectivity of the communication graph is a fundamental issue. Connectivity maintenance has been extensively studied in the last few years, but generally considering undirected communication graphs. In this paper, we introduce a decentralized control and estimation strategy to maintain the strong connectivity property of directed communication graphs. In particular, we introduce a hierarchical estimation procedure that implements power iteration in a decentralized manner, exploiting an algorithm for balancing strongly connected directed graphs. The output of the estimation system is then utilized for guaranteeing preservation of the strong connectivity property. The control strategy is validated by means of analytical proofs and simulation results. PMID- 25494520 TI - Biclustering Learning of Trading Rules. AB - Technical analysis with numerous indicators and patterns has been regarded as important evidence for making trading decisions in financial markets. However, it is extremely difficult for investors to find useful trading rules based on numerous technical indicators. This paper innovatively proposes the use of biclustering mining to discover effective technical trading patterns that contain a combination of indicators from historical financial data series. This is the first attempt to use biclustering algorithm on trading data. The mined patterns are regarded as trading rules and can be classified as three trading actions (i.e., the buy, the sell, and no-action signals) with respect to the maximum support. A modified K nearest neighborhood ( K -NN) method is applied to classification of trading days in the testing period. The proposed method [called biclustering algorithm and the K nearest neighbor (BIC- K -NN)] was implemented on four historical datasets and the average performance was compared with the conventional buy-and-hold strategy and three previously reported intelligent trading systems. Experimental results demonstrate that the proposed trading system outperforms its counterparts and will be useful for investment in various financial markets. PMID- 25494521 TI - Colored Traveling Salesman Problem. AB - The multiple traveling salesman problem (MTSP) is an important combinatorial optimization problem. It has been widely and successfully applied to the practical cases in which multiple traveling individuals (salesmen) share the common workspace (city set). However, it cannot represent some application problems where multiple traveling individuals not only have their own exclusive tasks but also share a group of tasks with each other. This work proposes a new MTSP called colored traveling salesman problem (CTSP) for handling such cases. Two types of city groups are defined, i.e., each group of exclusive cities of a single color for a salesman to visit and a group of shared cities of multiple colors allowing all salesmen to visit. Evidences show that CTSP is NP-hard and a multidepot MTSP and multiple single traveling salesman problems are its special cases. We present a genetic algorithm (GA) with dual-chromosome coding for CTSP and analyze the corresponding solution space. Then, GA is improved by incorporating greedy, hill-climbing (HC), and simulated annealing (SA) operations to achieve better performance. By experiments, the limitation of the exact solution method is revealed and the performance of the presented GAs is compared. The results suggest that SAGA can achieve the best quality of solutions and HCGA should be the choice making good tradeoff between the solution quality and computing time. PMID- 25494522 TI - Mining Top K Spread Sources for a Specific Topic and a Given Node. AB - In social networks, nodes (or users) interested in specific topics are often influenced by others. The influence is usually associated with a set of nodes rather than a single one. An interesting but challenging task for any given topic and node is to find the set of nodes that represents the source or trigger for the topic and thus identify those nodes that have the greatest influence on the given node as the topic spreads. We find that it is an NP-hard problem. This paper proposes an effective framework to deal with this problem. First, the topic propagation is represented as the Bayesian network. We then construct the propagation model by a variant of the voter model. The probability transition matrix (PTM) algorithm is presented to conduct the probability inference with the complexity O(theta(3)log2theta), while theta is the number nodes in the given graph. To evaluate the PTM algorithm, we conduct extensive experiments on real datasets. The experimental results show that the PTM algorithm is both effective and efficient. PMID- 25494524 TI - Prevention of mid-trimester loss following full dilatation caesarean section: a potential role for transabdominal cervical cerclage. PMID- 25494523 TI - Exposure to free and conjugated forms of bisphenol A and triclosan among pregnant women in the MIREC cohort. AB - BACKGROUND: Bisphenol A (BPA) and triclosan (TCS) are two nonpersistent chemicals that have been frequently measured in spot urine samples from the general population but less so in pregnant women; however, data are limited on the free (bioactive) and conjugated forms of these phenols. OBJECTIVES: The Maternal Infant Research on Environmental Chemicals (MIREC) Study addressed these data gaps by utilizing stored maternal urine samples from a large multicenter cohort study of Canadian pregnant women. METHODS: Concentrations of free and conjugated forms of BPA and TCS were measured in about 1,890 first-trimester urine samples by ultra performance liquid chromatography-tandem mass spectrometry using isotope dilution. RESULTS: The glucuronides of BPA and TCS were the predominant forms of these chemicals measured (detected in 95% and 99% of samples, respectively), whereas the free forms were detected in 43% and 80% of samples, respectively. The geometric mean urinary concentrations for glucuronides of BPA and TCS were 0.80 MUg/L (95% CI: 0.75, 0.85) and 12.30 MUg/L (95% CI: 11.08, 13.65), respectively. Significant predictors of BPA included maternal age < 25 vs. >= 35 years, current smoking, low vs. high household income, and low vs. high education. For TCS, urinary concentrations were significantly higher in women >= 25 years of age, never vs. current smokers, and women with high household income and high education. CONCLUSIONS: The results from this study represent the largest national-level data on urinary concentrations of free and conjugated forms of BPA and TCS in pregnant women and suggest that maternal characteristics predicting elevated urinary concentrations of these phenols largely act in opposite directions. PMID- 25494525 TI - Differential peptide labeling (iTRAQ) in LC-MS/MS based proteomics in Daphnia reveal mechanisms of an antipredator response. AB - Daphnia, an important model organism for studies on ecology and evolution, has become a textbook example for inducible defenses against predators. Inducible defenses are widespread in nature, and the underlying molecular mechanisms for this plasticity in general and in particular in Daphnia are not fully understood. Here, we provide for the first time a combination of established life-history changes (LHC), which are induced by chemical cues of a predator (fish kairomones), in Daphnia with differential peptide labeling (iTRAQ) in LC-MS/MS based proteomics. The aim of the present study is the elucidation of proteins involved in specific antipredator responses in a predator-prey system of ecological relevance by high-throughput proteomics. To obtain a highly specific antifish response of Daphnia, highly purified fish kairomones were applied in the presence or absence of light. We were able to identify a set of functional proteins, which are likely to explain the kairomone-mediated and light-dependent LHC in Daphnia. PMID- 25494526 TI - Agreement between objective and subjective assessment of image quality in ultrasound abdominal aortic aneurism screening. AB - OBJECTIVE: To investigate agreement between objective and subjective assessment of image quality of ultrasound scanners used for abdominal aortic aneurysm (AAA) screening. METHODS: Nine ultrasound scanners were used to acquire longitudinal and transverse images of the abdominal aorta. 100 images were acquired per scanner from which 5 longitudinal and 5 transverse images were randomly selected. 33 practitioners scored 90 images blinded to the scanner type and subject characteristics and were required to state whether or not the images were of adequate diagnostic quality. Odds ratios were used to rank the subjective image quality of the scanners. For objective testing, three standard test objects were used to assess penetration and resolution and used to rank the scanners. RESULTS: The subjective diagnostic image quality was ten times greater for the highest ranked scanner than for the lowest ranked scanner. It was greater at depths of <5.0 cm (odds ratio, 6.69; 95% confidence interval, 3.56, 12.57) than at depths of 15.1-20.0 cm. There was a larger range of odds ratios for transverse images than for longitudinal images. No relationship was seen between subjective scanner rankings and test object scores. CONCLUSION: Large variation was seen in the image quality when evaluated both subjectively and objectively. OBJECTIVE scores did not predict subjective scanner rankings. Further work is needed to investigate the utility of both subjective and objective image quality measurements. ADVANCES IN KNOWLEDGE: Ratings of clinical image quality and image quality measured using test objects did not agree, even in the limited scenario of AAA screening. PMID- 25494527 TI - Using natural abundance radiocarbon to trace the flux of petrocarbon to the seafloor following the Deepwater Horizon oil spill. AB - In 2010, the Deepwater Horizon accident released 4.6-6.0 * 10(11) grams or 4.1 to 4.6 million barrels of fossil petroleum derived carbon (petrocarbon) as oil into the Gulf of Mexico. Natural abundance radiocarbon measurements on surface sediment organic matter in a 2.4 * 10(10) m(2) deep-water region surrounding the spill site indicate the deposition of a fossil-carbon containing layer that included 1.6 to 2.6 * 10(10) grams of oil-derived carbon. This quantity represents between 0.5 to 9.1% of the released petrocarbon, with a best estimate of 3.0-4.9%. These values may be lower limit estimates of the fraction of the oil that was deposited on the seafloor because they focus on a limited mostly deep water area of the Gulf, include a conservative estimate of thickness of the depositional layer, and use an average background or prespill radiocarbon value for sedimentary organic carbon that produces a conservative value. A similar approach using hopane tracer estimated that 4-31% of 2 million barrels of oil that stayed in the deep sea settled on the bottom. Converting that to a percentage of the total oil that entered into the environment (to which we normalized our estimate) converts this range to 1.8 to 14.4%. Although extrapolated over a larger area, our independent estimate produced similar values. PMID- 25494528 TI - Wearable Triboelectric Generator for Powering the Portable Electronic Devices. AB - A cloth-base wearable triboelectric nanogenerator made of nylon and Dacron fabric was fabricated for harvesting body motion energy. Through the friction between forearm and human body, the generator can turn the mechanical energy of an arm swing into electric energy and power an electroluminescent tubelike lamp easily. The maximum output current and voltage of the generator reach up to 0.2 mA and 2 kV. Furthermore, this generator can be easily folded, kneaded, and cleaned like a common garment. PMID- 25494529 TI - Electrophilic alkylation of pseudotetrahedral nickel(II) arylthiolate complexes. AB - A kinetic study is reported for reactions of pseudotetrahedral nickel(II) arylthiolate complexes [(Tp(R,Me))Ni-SAr] (Tp(R,Me) = hydrotris{3-R-5-methyl-1 pyrazolyl}borate, R = Me, Ph, and Ar = C6H5, C6H4-4-Cl, C6H4-4-Me, C6H4-4-OMe, 2,4,6-Me3C6H2, 2,4,6-(i)Pr3C6H2) with organic electrophiles R'X (i.e., MeI, EtI, BzBr) in low-polarity organic solvents (toluene, THF, chloroform, dichloromethane, or 1,2-dichloroethane), yielding a pseudotetrahedral halide complex [(Tp(R,Me))Ni-X] (X = Cl, Br, I) and the corresponding organosulfide R'SAr. Competitive reactions with halogenated solvents and adventitious air were also examined. Akin to reactions of analogous and biomimetic zinc complexes, a pertinent mechanistic question is the nature of the reactive nucleophile, either an intact thiolate complex or a free arylthiolate resulting from a dissociative pre-equilibrium. The observed kinetics conformed to a second-order rate law, first order with respect to the complex and electrophile, and no intermediate complexes were observed. In the absence of a mechanistically diagnostic rate law, a variety of mechanistic probes were examined, including kinetic effects of varying the metal, solvent, electrophile, and temperature, as well as the 3 pyrazolyl and arylthiolate substituents. Compared to zinc analogues, the effect of Ni-SAr covalency is also of interest herein. The results are broadly interpreted with respect to the disparate mechanistic pathways. PMID- 25494530 TI - Compound pendant drop tensiometry for interfacial tension measurement at zero bond number. AB - A widely used method to determine the interfacial tension between fluids is to quantify the pendant drop shape that is determined by gravity and interfacial tension forces. Failure of this method for small drops or small fluid density differences is a critical limitation in microfluidic applications and when only small fluid samples are available. By adding a small spherical particle to the interface to apply an axisymmetric deformation, both the particle density and the interfacial tension can be simultaneously and precisely determined, providing an accurate and elegant solution to a long-standing problem. PMID- 25494531 TI - Bis-BN cyclohexane: a remarkably kinetically stable chemical hydrogen storage material. AB - A critical component for the successful development of fuel cell applications is hydrogen storage. For back-up power applications, where long storage periods under extreme temperatures are expected, the thermal stability of the storage material is particularly important. Here, we describe the development of an unusually kinetically stable chemical hydrogen storage material with a H2 storage capacity of 4.7 wt%. The compound, which is the first reported parental BN isostere of cyclohexane featuring two BN units, is thermally stable up to 150 degrees C both in solution and as a neat material. Yet, it can be activated to rapidly desorb H2 at room temperature in the presence of a catalyst without releasing other detectable volatile contaminants. We also disclose the isolation and characterization of two cage compounds with S4 symmetry from the H2 desorption reactions. PMID- 25494532 TI - Chromogenic chemodosimeter for highly selective detection of cyanide in water and blood plasma based on Si-O cleavage in the micellar system. AB - A novel silylated imine was designed to act efficiently in a chemodosimeter approach for the selective detection of cyanide in an aqueous micellar CTABr solution. This simple system allows the detection of cyanide, with high sensitivity and specific selectivity, in water and in human blood plasma. PMID- 25494533 TI - Determination of conformational entropy of fully and partially folded conformations of holo- and apomyoglobin. AB - Holo- and apomyoglobin can be stabilized in native folded, partially folded molten globules (MGs) and denatured states depending on the solvent composition. Although the protein has been studied as a model system in the field of protein folding, little is known about the internal dynamics of the different structural conformations on the picosecond time scale. In a comparative experimental study we investigated the correlation between protein folding and dynamics on the picosecond time scale using incoherent quasielastic neutron scattering (QENS). The measured mean square displacements (MSDs) of conformational motions depend significantly on the secondary structure content of the protein, whereas the correlation times of the observed internal dynamics were found to be similar irrespective of the degree of folding. The conformational entropy difference DeltaSconf between the folded conformations and the acid denatured state could be determined from the measured MSDs and was compared to the entropy difference DeltaS obtained from thermodynamic parameters reported in the literature. The observed difference between DeltaS and DeltaSconf was attributed to the entropy difference DeltaShydr of dynamically disordered water molecules of the hydration shell. The entropy content of the hydration water is significantly larger in the native folded proteins than in the partially folded MGs. We demonstrate the potential of incoherent neutron scattering for the investigation of the role of conformational dynamics in protein folding. PMID- 25494534 TI - Direct regioselective oxidative cross-coupling of indoles with methyl ketones: a novel route to C3-dicarbonylation of indoles. AB - The first C3-dicarbonylation of indoles was realized through direct oxidative cross-coupling of indoles with methyl ketones in the presence of molecular iodine and pyrrolidine. This reaction constructed a highly efficient indolyl diketones scaffold, which might be regarded as a useful biological and pharmacological tool in the exploration of therapeutic A2BAR modulators. The use of inexpensive molecular iodine and pyrrolidine and a broad substrate scope make this protocol very practical. Preliminary mechanistic studies indicate that two paths are involved in this process. PMID- 25494535 TI - Prediction of in vivo drug performance using in vitro dissolution coupled with STELLA: a study with selected drug products. AB - Prediction of the in vivo performance of the drug product from the in vitro studies is the major challenging job for the pharmaceutical industries. From the current regulatory perspective, biorelevant dissolution media should now be considered as quality control media in order to avoid the risk associated. Physiological based pharmacokinetic models (PBPK) coupled with biorelevant dissolution medium is widely used in simulation and prediction of the plasma drug concentration and in vivo drug performance. The present investigation deals with the evaluation of biorelevant dissolution media as well as in vivo drug performance by PBPK modelling using STELLA(r) simulation software. The PBPK model was developed using STELLA(r) using dissolution kinetics, solubility, standard gastrointestinal parameters and post-absorptive disposition parameters. The drug product selected for the present study includes Linezolid film-coated immediate release tablets (Zyvox), Tacrolimus prolonged-release capsules (Advagraf), Valganciclovir tablets (Valcyte) and Mesalamine controlled-release capsules (Pentasa) each belonging to different biopharmaceutics classification system (BCS). The simulated plasma drug concentration was analyzed and pharmacokinetic parameters were calculated and compared with the reported values. The result from the present investigation indicates that STELLA(r) when coupled with biorelevant dissolution media can predict the in vivo performance of the drug product with prediction error less than 20% irrespective of the dosage form (immediate release versus modified release) and BCS Classification. Thus, STELLA(r) can be used for in vivo drug prediction which will be helpful in generic drug development. PMID- 25494536 TI - Analysis of bacterial communities associated with the benthic amphipod Diporeia in the Laurentian Great Lakes Basin. AB - Bacterial communities play important roles in the biological functioning of crustaceans, yet little is known about their diversity, structure, and dynamics. This study was conducted to investigate the bacterial communities associated with the benthic amphipod Diporeia, an important component in the Great Lakes foodweb that has been declining over the past 3 decades. In this study, the combination of 16S rRNA gene sequencing and terminal restriction fragment length polymorphism revealed a total of 175 and 138 terminal restriction fragments (T-RFs) in Diporeia samples following treatment with the endonucleases HhaI and MspI, respectively. Relatively abundant and prevalent T-RFs were affiliated with the genera Flavobacterium and Pseudomonas and the class Betaproteobacteria. T-RFs affiliated with the order Rickettsiales were also detected. A significant difference in T-RF presence and abundance (P = 0.035) was detected among profiles generated for Diporeia collected from 4 sites in Lake Michigan. Comparison of profiles generated for Diporeia samples collected in 2 years from lakes Superior and Michigan showed a significant change in diversity for Lake Superior Diporeia but not Lake Michigan Diporeia. Profiles from one Lake Michigan site contained multiple unique T-RFs compared with other Lake Michigan Diporeia profiles, most notably one that represents the genus Methylotenera. This study generated the most extensive list of bacteria associated with Diporeia and sheds useful insights on the microbiome of Great Lakes Diporeia that may help to reveal potential causes of the decline of Diporeia populations. PMID- 25494537 TI - Flavor chemistry of lemon-lime carbonated beverages. AB - The most potent aroma-active components of Sprite (SP), Sierra Mist (SM), and 7UP (7UP) were identified. Aroma extracts were prepared by liquid-liquid continuous extraction/solvent-assisted flavor evaporation (LLCE/SAFE). Twenty-eight compounds were detected by gas chromatography-olfactometry (GC-O) with linalool (floral, lavender), octanal (pungent orange), and 2,3-dehydro-1,8-cineole (minty) determined to be predominant aroma compounds based on their high flavor dilution (FD) factors by aroma extract dilution analysis (AEDA). The data indicate that lemon-lime flavor is composed of a small number of compounds (22 at the most in SM), and only a subset of these may be important because many compounds were detected only at low FD factors. Predominant aroma compounds (23) were quantified using static headspace solid phase microextraction (SPME) combined with stable isotope dilution assays (SIDA). In contrast to FD factors, the calculated odor activity values (OAVs) indicate that octanal and limonene make the greatest contribution to the overall aroma of lemon-lime carbonated beverages, followed by nonanal, decanal, linalool, 1,8-cineole, and geranyl acetate. The results demonstrate that lemon-lime carbonated beverages share many of the same compounds but the relative abundance of these compounds varies by brand. PMID- 25494538 TI - Aza-acyclic nucleoside phosphonates containing a second phosphonate group as inhibitors of the human, Plasmodium falciparum and vivax 6-oxopurine phosphoribosyltransferases and their prodrugs as antimalarial agents. AB - Hypoxanthine-guanine-[xanthine] phosphoribosyltransferase (HG[X]PRT) is considered an important target for antimalarial chemotherapy as it is the only pathway for the synthesis of the purine nucleoside monophosphates required for DNA/RNA production. Thus, inhibition of this enzyme should result in cessation of replication. The aza-acyclic nucleoside phosphonates (aza-ANPs) are good inhibitors of Plasmodium falciparum HGXPRT (PfHGXPRT), with Ki values as low as 0.08 and 0.01 MUM for Plasmodium vivax HGPRT (PvHGPRT). Prodrugs of these aza ANPs exhibit antimalarial activity against Pf lines with IC50 values (0.8-6.0 MUM) and have low cytotoxicity against human cells. Crystal structures of six of these compounds in complex with human HGPRT have been determined. These suggest that the different affinities of these aza-ANPs could be due to the flexibility of the loops surrounding the active site as well as the flexibility of the inhibitors, allowing them to adapt to fit into three binding pockets of the enzyme(s). PMID- 25494539 TI - Electrochemical control of single-molecule conductance by Fermi-level tuning and conjugation switching. AB - Controlling charge transport through a single molecule connected to metallic electrodes remains one of the most fundamental challenges of nanoelectronics. Here we use electrochemical gating to reversibly tune the conductance of two different organic molecules, both containing anthraquinone (AQ) centers, over >1 order of magnitude. For electrode potentials outside the redox-active region, the effect of the gate is simply to shift the molecular energy levels relative to the metal Fermi level. At the redox potential, the conductance changes abruptly as the AQ unit is oxidized/reduced with an accompanying change in the conjugation pattern between linear and cross conjugation. The most significant change in conductance is observed when the electron pathway connecting the two electrodes is via the AQ unit. This is consistent with the expected occurrence of destructive quantum interference in that case. The experimental results are supported by an excellent agreement with ab initio transport calculations. PMID- 25494540 TI - Degree of abnormality is associated with rate of change in measures of beta amyloid, glucose metabolism and cognition in an autopsy-verified Alzheimer's disease case. AB - The degree of abnormality and rate of change in cognitive functions, positron emission tomography Pittsburg compound B (PET PIB), and fluorodeoxyglucose (FDG) measures were studied for 8 years in an autopsy-confirmed Alzheimer's disease (AD) patient, who died 61 years old (Mini-Mental State Examination (MMSE) score 7). At first encounter with medical care, the patient was very mildly demented (MMSE score 27). She had four cognitive assessments and two examinations with PET PIB and FDG in 23 bilateral brain regions. The onset of cognitive decline was retrospectively estimated to have started in the early forties. The degree of impairment was inversely related to the rate of decline. A similar relationship was seen between the rate of change and the level of abnormality in both PIB and FDG. To conclude, rate of change in cognition, PIB, and FDG was associated with the degree of abnormality. PMID- 25494541 TI - Generation and characterization of a single-chain anti-EphA2 antibody. AB - Recombinant antibody phage library technology provides multiple advantages, including that human antibodies can be generated against proteins that are highly conserved between species. We used this technology to isolate and characterize an anti-EphA2 single-chain antibody. We show that the antibody binds the antigen with 1:1 stoichiometry and has high specificity for EphA2. The crystal structure of the complex reveals that the antibody targets the same receptor surface cavity as the ephrin ligand. Specifically, a lengthy CDR-H3 loop protrudes deep into the ligand-binding cavity, with several hydrophobic residues at its tip forming an anchor-like structure buried within the hydrophobic Eph pocket, in a way similar to the ephrin receptor-binding loop in the Eph/ephrin structures. Consequently, the antibody blocks ephrin binding to EphA2. Furthermore, it induces apoptosis and reduces cell proliferation in lymphoma cells lines. Since Ephs are important mediators of tumorigenesis, such antibodies could have applications both in research and therapy. PMID- 25494543 TI - Application of a new oxidation-reduction potential assessment method in strenuous exercise-induced oxidative stress. AB - OBJECTIVES: The aim of the study was to test a novel method for assessing oxidative stress, the RedoxSYSTM diagnostic system, a holistic, fast, minimally invasive, and requiring small sample volume method, that measures two parameters, the static (sORP) and the capacity (cORP) oxidation-reduction potential. METHODS: The redox status of 14 athletes participating in a mountain marathon race was assessed. Redox status in blood obtained 1 day before the race and immediately after the race was assessed using the RedoxSYS diagnostic system as well as conventional oxidative stress markers such as glutathione levels (GSH), catalase activity (CAT), thiobarbituric acid reactive substances (TBARS), protein carbonyls (CARB), and total antioxidant activity. RESULTS: The results showed that after the race, the sORP was increased significantly by 7% indicating oxidative stress induction, while cORP was decreased by 14.6% but not significantly. Moreover, the conventional oxidative stress markers GSH and CAT were decreased significantly by 13.1 and 23.4%, respectively, while TBARS and CARB were increased significantly by 26.1 and 15.6%, respectively, after the race indicating oxidative stress induction. DISCUSSION: The present study demonstrated for the first time that the RedoxSYS diagnostic system can be used for evaluating the exercise-induced oxidative stress in athletes. PMID- 25494542 TI - ARHGEF3 controls HDACi-induced differentiation via RhoA-dependent pathways in acute myeloid leukemias. AB - Altered expression and activity of histone deacetylases (HDACs) have been correlated with tumorigenesis. Inhibitors of HDACs (HDACi) induce acetylation of histone and non-histone proteins affecting gene expression, cell cycle progression, cell migration, terminal differentiation and cell death. Here, we analyzed the regulation of ARHGEF3, a RhoA-specific guanine nucleotide exchange factor, by the HDACi MS275 (entinostat). MS275 is a well-known benzamide-based HDACi, which induces differentiation of the monoblastic-like human histiocytic lymphoma cell line U937 to monocytes/macrophages. Incubation of U937 cells with MS275 resulted in an up regulation of ARHGEF3, followed by a significant enhancement of the marker of macrophage differentiation CD68. ARHGEF3 protein is primarily nuclear, but MS275 treatment rapidly induced its translocation into the cytoplasm. ARHGEF3 cytoplasmic localization is associated with activation of the RhoA/Rho-associated Kinase (ROCK) pathway. In addition to cytoskeletal rearrangements orchestrated by RhoA, we showed that ARHGEF3/RhoA-dependent signals involve activation of SAPK/JNK and then Elk1 transcription factor. Importantly, MS275-induced CD68 expression was blocked by exposure of U937 cells to exoenzyme C3 transferase and Y27632, inhibitors of Rho and ROCK respectively. Moreover, ARHGEF3 silencing prevented RhoA activation leading to a reduction in SAPK/JNK phosphorylation, Elk1 activation and CD68 expression, suggesting a crucial role for ARHGEF3 in myeloid differentiation. Taken together, our results demonstrate that ARHGEF3 modulates acute myeloid leukemia differentiation through activation of RhoA and pathways directly controlled by small GTPase family proteins. The finding that GEF protein modulation by HDAC inhibition impacts on cell differentiation may be important for understanding the antitumor mechanism(s) by which HDACi treatment stimulates differentiation in cancer. PMID- 25494545 TI - Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria. AB - BACKGROUND: In erythropoietic protoporphyria (EPP), an inherited disease of porphyrin-biosynthesis, the accumulation of protoporphyrin in the skin causes severely painful phototoxic reactions. Symptom prevention was impossible until recently when afamelanotide became available. Afamelanotide-induced skin pigmentation has statistically significantly improved light-tolerance, although the clinical significance of the statistical effect was unknown. OBJECTIVES: To assess clinical effectiveness by recording compliance and safety during prolonged use. METHODS: We report longitudinal observations of 115 ambulatory patients with EPP, who were treated with a total of 1023 afamelanotide implants over a period of up to 8 years at two porphyria centres; one in Rome, Italy, and the other in Zurich, Switzerland. RESULTS: Since the treatment first became available in 2006, the number of patients treated with 16 mg afamelanotide implants rose continuously until June 2014, when 66% of all patients with EPP known to the porphyria centres were treated. Only three patients considered afamelanotide did not meet their expectations for symptom improvement; 23% discontinued the treatment for other, mostly compelling, reasons such as pregnancy or financial restrictions. The quality of life (QoL) scores, measured by an EPP-specific questionnaire, were 31 +/- 24% of maximum prior to afamelanotide treatment, rose to 74% after starting afamelanotide and remained at this level during the entire observation period. Only minor adverse events attributable to afamelanotide, predominantly nausea, were recorded. CONCLUSION: Based on the improved QoL scores, high compliance and low discontinuation rates, we conclude that afamelanotide exhibits good clinical effectiveness and good safety in EPP under long-term routine conditions. PMID- 25494546 TI - Annual research review: Rare genotypes and childhood psychopathology--uncovering diverse developmental mechanisms of ADHD risk. AB - BACKGROUND: Through the increased availability and sophistication of genetic testing, it is now possible to identify causal diagnoses in a growing proportion of children with neurodevelopmental disorders. In addition to developmental delay and intellectual disability, many genetic disorders are associated with high risks of psychopathology, which curtail the wellbeing of affected individuals and their families. Beyond the identification of significant clinical needs, understanding the diverse pathways from rare genetic mutations to cognitive dysfunction and emotional-behavioural disturbance has theoretical and practical utility. METHODS: We overview (based on a strategic search of the literature) the state-of-the-art on causal mechanisms leading to one of the most common childhood behavioural diagnoses - attention deficit hyperactivity disorder (ADHD) - in the context of specific genetic disorders. We focus on new insights emerging from the mapping of causal pathways from identified genetic differences to neuronal biology, brain abnormalities, cognitive processing differences and ultimately behavioural symptoms of ADHD. FINDINGS: First, ADHD research in the context of rare genotypes highlights the complexity of multilevel mechanisms contributing to psychopathology risk. Second, comparisons between genetic disorders associated with similar psychopathology risks can elucidate convergent or distinct mechanisms at each level of analysis, which may inform therapeutic interventions and prognosis. Third, genetic disorders provide an unparalleled opportunity to observe dynamic developmental interactions between neurocognitive risk and behavioural symptoms. Fourth, variation in expression of psychopathology risk within each genetic disorder points to putative moderating and protective factors within the genome and the environment. CONCLUSION: A common imperative emerging within psychopathology research is the need to investigate mechanistically how developmental trajectories converge or diverge between and within genotype defined groups. Crucially, as genetic predispositions modify interaction dynamics from the outset, longitudinal research is required to understand the multi-level developmental processes that mediate symptom evolution. PMID- 25494547 TI - Adults are intuitive mind-body dualists. AB - In the present research, we tested the hypotheses that (a) adults are intuitive mind-body dualists, (b) that this belief can be considered a default, and (c) that it is partially explained by essentialistic reasoning about the nature of the mind. Over 8 studies, using various thought experiment paradigms, participants reliably ascribed to a physically duplicated being a greater retention of physical than of mental properties. This difference was unrelated to whether or not this being was given a proper name (Study 1b) and was only found for entities that were considered to actually possess a mind (Study 1c). Further, we found that an intuitive belief in mind-body dualism may in fact be considered a default: Taxing participants' cognitive resources (Study 2) or priming them with an intuitive (vs. analytical) thinking style (Studies 3a and 3b) both increased dualistic beliefs. In a last set of studies, we found that beliefs in mind-body dualism are indeed related to essentialistic reasoning about the mind. When a living being was reassembled from its original molecules rather than recreated from new molecules, dualistic beliefs were significantly reduced (Studies 4a and 4b). Thus, results of the present research indicate that, despite any acquired scientific knowledge about the neurological origins of mental life, most adults remain "essentialistic mind-body dualists" at heart. PMID- 25494544 TI - Chromatin modification by the RNA Polymerase II elongation complex. AB - Transcription elongation by RNA polymerase II (RNAP II) involves the coordinated action of numerous regulatory factors. Among these are chromatin-modifying enzymes, which generate a stereotypic and conserved pattern of histone modifications along transcribed genes. This pattern implies a precise coordination between regulators of histone modification and the RNAP II elongation complex. Here I review the pathways and molecular events that regulate co-transcriptional histone modifications. Insight into these events will illuminate the assembly of functional RNAP II elongation complexes and how the chromatin landscape influences their composition and function. PMID- 25494548 TI - The perceptual homunculus: the perception of the relative proportions of the human body. AB - Given that observing one's body is ubiquitous in experience, it is natural to assume that people accurately perceive the relative sizes of their body parts. This assumption is mistaken. In a series of studies, we show that there are dramatic systematic distortions in the perception of bodily proportions, as assessed by visual estimation tasks, where participants were asked to compare the lengths of two body parts. These distortions are not evident when participants estimate the extent of a body part relative to a noncorporeal object or when asked to estimate noncorporal objects that are the same length as their body parts. Our results reveal a radical asymmetry in the perception of corporeal and noncorporeal relative size estimates. Our findings also suggest that people visually perceive the relative size of their body parts as a function of each part's relative tactile sensitivity and physical size. PMID- 25494549 TI - Positive consequences of conflict on decision making: when a conflict mindset facilitates choice. AB - Much research has shown that conflict is aversive and leads to increased choice deferral. In contrast, we have proposed that conflict can be beneficial. Specifically, exposure to nonconscious goal conflict can activate a mindset (a set of cognitive procedures) that facilitates the systematic processing of information without triggering the associated costs, such as negative affect and stress. In a conflict mindset, people should be better able to make tradeoffs and resolve choice conflict. We tested this proposition in 4 experiments, and demonstrated that priming conflicting goals before a decision increases choice in domains unrelated to the primed conflict. We further demonstrated that increased choice occurs because people in a conflict mindset process choice information more systematically, and we rule out several alternative explanations for the results. PMID- 25494550 TI - Time perception: the surprising effects of surprising stimuli. AB - The effects of stimulus repetition often increase when repetitions are more common (i.e., when repeats become more predictable), consistent with the idea that repetition effects reflect expectations about the recurrence of recent items. In contrast, the present experiments found a surprising pattern in which the compressed subjective duration of repeated items was reduced, eliminated, and even reversed when the frequency of repetitions was increased. Experiments 1-4b found that this pattern generalized across tasks, durations, and stimulus types; Experiments 5-9 investigated the mechanisms underlying these effects and suggest that recent exposure produces a short-lived contraction of subjective time consistent with a low-level process, such as neural fatigue, whereas elevating the predictability of a repeat produces a subjective time expansion that may result from more efficient perceptual processing. These findings (a) establish the important point that first-order repetition and second-order repetition expectations can have opposing functional effects, a possibility that has received little attention in general treatments of repetition effects, (b) run contrary to existing accounts of repetition effects in time perception, and suggest that there may be no simple mapping between apparent duration and the overall magnitude of the neural response, and (c) suggest a framework in which subjective time depends on the interplay between bottom-up signal strength and top-down gain control. PMID- 25494551 TI - Thiopurine-induced pancreatitis in inflammatory bowel diseases. AB - Crohn's disease and ulcerative colitis are chronic inflammatory conditions affecting the gut and can present at any age with increased numbers of diagnoses seen in many countries in recent years. The thiopurine drugs, azathioprine and 6 mercaptopurine, are commonly used to maintain remission in Crohn's disease and ulcerative colitis; however, the use of these drugs may be limited by the development of pancreatitis in some individuals. Recent data indicate a genetic risk factor and provides a potential immune-mediated mechanism for thiopurine induced pancreatitis. Management of thiopurine-induced pancreatitis requires exclusion of the triggering drug, which leads to prompt resolution of symptoms. This thiopurine side-effect may limit therapeutic options for future management of patients. PMID- 25494552 TI - Asthma control and health-related quality of life one year after inpatient pulmonary rehabilitation: the ProKAR Study. AB - OBJECTIVES: Although pulmonary rehabilitation (PR) is commonly used for asthmatics in many countries, so far there are no studies addressing the question of whether and for how long an improvement in asthma control (AC) is seen after rehabilitation. The ProKAR study (Prospektive Katamnesestudie Asthma Rehabilitation) was performed to provide data concerning the short- and long-term impact of PR on AC. METHODS: Two-hundred one adult patients with mild to severe persistent asthma were prospectively followed one year after completion of a 3 week PR program. AC, the primary outcome parameter, and health-related quality of life (HRQoL) were monitored using the Asthma Control Test (ACT) and St. George's Respiratory Questionnaire (SGRQ) at initiation (T0) and end of the PR (T1) and 3, 6 and 12 months thereafter. Pulmonary function, physical fitness (6MWD) and asthmatic inflammation (FENO) were measured at T0 and T1. RESULTS: The proportion of patients with well-controlled asthma (ACT score >=20) increased from 33.2% to 67.3% after PR and was still at 51% after 12 months. Slight but statistically significant improvements in pulmonary functions and an increase in 6MWD of nearly 60 m were reported at T1. One year after discharge 55.8% of the patients still showed a clinically relevant improvement of at least 4 points in the total SGRQ score. CONCLUSIONS: The multidisciplinary inpatient PR program resulted in significant short and long-term improvement in AC and HRQoL in adult asthmatic patients. PMID- 25494553 TI - Mobile-based asthma action plans for adolescents. AB - PURPOSE: To examine feasibility and utilization of a mobile asthma action plan (AAP) among adolescents. METHODS: Adolescents (aged 12-17 years) with persistent asthma had their personalized AAP downloaded to a smartphone application. Teens were prompted by the mobile application to record either daily symptoms or peak flow measurements and to record medications. Once data were entered, the application provided immediate feedback based on the teen's AAP instructions. Asthma Control Test (ACT((r))) and child asthma self-efficacy scores were examined pre- and post-intervention. RESULTS: Adolescents utilized the mobile AAP a median 4.3 days/week. Participant satisfaction was high with 93% stating that they were better able to control asthma by utilizing the mobile AAP. For participants with uncontrolled asthma at baseline, median (interquartile range) ACT scores improved significantly from 16 (5) to 18 (8) [p = 0.03]. Median asthma attack prevention self-efficacy scores improved from 34 (3.5) to 36 (5.3) [p = 0.04]. CONCLUSIONS: Results suggest that personalized mobile-based AAPs are a feasible method to communicate AAP instructions to teens. PMID- 25494555 TI - Sentinel lymph node biopsy for cutaneous head and neck malignancies. AB - Sentinel lymph node biopsy (SLNB) is a procedure that can provide critical information regarding pathologic lymph node status and accurate regional staging. This is very important for developing treatment plans and providing prognostic guidance for cutaneous malignancies. The head and neck (HN) region is unique from other body sites due to its complex lymphatic drainage pathways, multiple lymph node basins, proximity of important cranial nerves and potential for contralateral or bilateral drainage. These unique aspects of the HN previously created some uncertainty about the use of SLNB in the HN. This review will discuss the current reliable status of HN SLNB and provide a guide for its current application in cutaneous malignancy of the HN. PMID- 25494554 TI - Perennial aeroallergens sensitisation and risk of asthma in African children and adolescents: a case-control study. AB - OBJECTIVES: The distribution and impact of various aeroallergens on asthma occurrence vary across regions. We investigated the association between sensitisation to perennial aeroallergens and asthma risk in children and adolescents in Yaounde, Cameroon. METHODS: This was a case-control study involving children and adolescents with asthma (cases) vs. non-allergic counterparts (controls). Children/adolescents with doctor-diagnosed asthma were included over a period of 30 months, and controls were selected from the community through random sampling. Logistic regression models were used to relate perennial aeroallergens sensitisation with asthma. RESULTS: The asthma and control groups included, respectively, 151 and 372 participants, with no sex ratio difference. The mean age (standard deviation) was 11.9 (4.4) years in cases and 11.3 (3.7) years in controls. The prevalence of sensitisation to any aeroallergen (cases vs. controls) was 76.8% (116/151) and 32.3% (120/372), p < 0.001. Sensitisation to mites was found in 104 (68.9%) cases vs. 56 (15.1%) controls, p < 0.001. In multivariable analysis, sensitisation to Alternaria alternata, Blattella germanica and dander (cat and dog) was not associated with asthma. However, sensitisation to mites was significantly associated with asthma. Odds ratios (95% CI) for sensitisation to Dermatophagoides pteronyssinus, Dermatophagoides farinae and Blomia tropicalis in relation with asthma were 7.28 (3.75-14.15), 2.65 (1.27-5.45) and 3.23 (1.68-6.21), respectively. CONCLUSIONS: Sensitisation to mites was the main perennial allergenic factor associated with asthma in children and adolescents in this setting. This has application for the selection of patients with asthma who could benefit from the control of exposure to mites and specific immunotherapy. PMID- 25494556 TI - Shared toilet users' collective cleaning and determinant factors in Kampala slums, Uganda. AB - BACKGROUND: Dirty shared toilets are a health risk to users in urban slum settlements. For health and non-health benefits among users of shared toilets to be guaranteed, their cleanliness is important. The objective of this study was to investigate the cleanliness situation of shared toilets in Kampala's slums and the psychological and social dilemma factors influencing users' cleaning behaviour and commitment by using the risks, attitudes, norms, ability and self regulation (RANAS) model and factors derived from the social dilemma theory. METHODS: We conducted a cross-sectional study in three slums of Kampala between December 2012 and January 2013. Data were collected from 424 household respondents that were primarily using shared toilets. Semi-structured questionnaires administered through face-to-face interviews were used in data collection. Linear regression was done for the multivariate analysis to test for the association between respondent cleaning behaviour and a combination of RANAS and social dilemma predictors. RESULTS: Out of 424 respondents interviewed, 44.3% reported cleaning the shared toilet daily, 34.4% cleaned once or several times a week, 1.4% cleaned every second week, 5.4% cleaned once or several times a month and 14.4% did not participate in cleaning. The main RANAS factors significantly associated with respondents' cleaning behaviour were: attitudinal affective belief associated with cleaning a shared toilet (beta = -0.13, P = 0.00) and self regulating factors, such as coping planning (beta = 0.42, P = 0.00), commitment (beta = 0.24, P = 0.00), and remembering (beta = 0.10, P = 0.01). For social dilemma factors, only the social motive factor was statistically significant (beta = 0.15, P = 0.00). The R square for the linear model on factors influencing cleaning behaviour was 0.77 and R square for factors influencing cleaning commitment was 0.70. CONCLUSION: The RANAS factors provide a more robust understanding of shared toilet users' cleaning behaviour than social dilemma factors. Self-regulating factors and changing the negative affective cleaning feelings are shown to be very important for interventions to increase shared toilet users' collective participation in their cleaning. In addition to RANAS, social dilemma factors have an important influence on slum residents' commitment to clean their shared toilets. PMID- 25494557 TI - In situ TEM characterization of shear-stress-induced interlayer sliding in the cross section view of molybdenum disulfide. AB - The experimental study of interlayer sliding at the nanoscale in layered solids has been limited thus far by the incapability of mechanical and imaging probes to simultaneously access sliding interfaces and overcome through mechanical stimulus the van der Waals and Coulombic interactions holding the layers in place. For this purpose, straightforward methods were developed to achieve interlayer sliding in molybdenum disulfide (MoS2) while under observation within a transmission electron microscope. A method to manipulate, tear, and slide free standing atomic layers of MoS2 is demonstrated by electrostatically coupling it to an oxidized tungsten probe attached to a micromanipulator at a bias above +/-7 V. A first-principles model of a MoS2 bilayer polarized by a normal electric field of 5 V/nm, emanating from the tip, demonstrates the appearance of a periodic negative sliding potential energy barrier when the layers slide into the out-of-registry stacking configuration, hinting at electrostatic gating as a means of modifying the interlayer tribology to facilitate shear exfoliation. A method to shear focused ion beam prepared MoS2 cross section samples using a nanoindenter force sensor is also demonstrated, allowing both the observation and force measurement of its interlayer dynamics during shear-induced sliding. From this experiment, the zero normal load shear strength of MoS2 can be directly obtained: 25.3 +/- 0.6 MPa. These capabilities enable the site-specific mechanical testing of dry lubricant-based nanoelectromechanical devices and can lead to a better understanding of the atomic mechanisms from which the interlayer tribology of layered materials originates. PMID- 25494558 TI - The American Reinvestment and Recovery Act investment in comparative effectiveness research: lessons learned and implications for future investments. PMID- 25494559 TI - What does US$1.1 billion buy? An investment in the future. PMID- 25494560 TI - How a unique provision in the American Recovery and Reinvestment Act set a foundation for the Patient-Centered Outcomes Research Institute. PMID- 25494561 TI - Building electronic data infrastructure for comparative effectiveness research: accomplishments, lessons learned and future steps. AB - There are large gaps in our knowledge on the potential impact of diagnostics and therapeutics on outcomes of patients treated in the real world. Comparative effectiveness research aims to fill these gaps to maximize effectiveness of these interventions. Health information technology has the potential to dramatically improve the practice of medicine and of research. This is an overview of about US$100 million of American Recovery and Reinvestment Act investment in 12 projects managed by the Agency for Healthcare Research and Quality to build an electronic clinical data infrastructure that connects research with healthcare delivery. The achievements and lessons learned from these projects provided a foundation for the National Patient-Centered Clinical Research Network (PCORnet)and will help to guide future infrastructure development needed to build an efficient, scalable and sustainable learning health system. PMID- 25494562 TI - Patients and clinicians as stakeholders in comparative effectiveness research: multiple perspectives and evolving roles. PMID- 25494563 TI - The importance of collaboration in comparative effectiveness research. PMID- 25494564 TI - The ARRA investment in CER: a description of the midstream evaluation and how the funds were allocated and CER priorities addressed. AB - AIM: To describe the evaluation design of the American Recovery and Reinvestment Act of 2009 comparative effectiveness research (CER) investment, how funds were allocated and how CER priorities were addressed. MATERIALS & METHODS: Primary and secondary data included information from redacted project proposals, an investigator survey and federal project officers, investigators and expert panel discussions. RESULTS: More than 420 projects (US$1.1 billion) were awarded. Those generating new or synthesizing existing CER made up the plurality (194, or US$524 million). Data infrastructure projects were the second-largest area (28%, US$302 million). More than three-fourths addressed at least one priority population, condition category or intervention category. CONCLUSION: These investments expanded the nation's CER activities and its future capacity to conduct CER. PMID- 25494565 TI - American Recovery and Reinvestment Act investments in data infrastructure. AB - AIM: This article describes American Reinvestment and Recovery Act comparative effectiveness research data infrastructure (DI) investments and identifies facilitators and barriers to implementation. MATERIALS & METHODS: We reviewed original project proposals, conducted an investigator survey and interviewed project officers and principal investigators. RESULTS: DI projects assembled or enhanced existing clinical datasets, established linkages between public and private data sources and built infrastructure. Facilitators included building on existing relationships across organizations and making collection as seamless as possible for clinicians. CONCLUSION: To sustain DI, investigators should reduce the burden of comparative effectiveness research data collection on practices, adequately address data privacy and security issues, resolve or lessen the impact of data-linking issues and build research capacity for other investigators and clinicians. PMID- 25494566 TI - Lessons from comparative effectiveness research methods development projects funded under the Recovery Act. AB - BACKGROUND: The American Recovery and Reinvestment Act of 2009 (ARRA) directed nearly US$29.2 million to comparative effectiveness research (CER) methods development. AIM: To help inform future CER methods investments, we describe the ARRA CER methods projects, identify barriers to this research and discuss the alignment of topics with published methods development priorities. METHODS: We used several existing resources and held discussions with ARRA CER methods investigators. RESULTS & CONCLUSION: Although funded projects explored many identified priority topics, investigators noted that much work remains. For example, given the considerable investments in CER data infrastructure, the methods development field can benefit from additional efforts to educate researchers about the availability of new data sources and about how best to apply methods to match their research questions and data. PMID- 25494567 TI - Workforce development for comparative effectiveness research: training programs funded by the American Recovery and Reinvestment Act. AB - AIM: We conducted a midstream assessment of the comparative effectiveness research (CER) training programs funded by the American Recovery and Reinvestment Act (ARRA) by examining program characteristics, planned curriculum development activities and core competencies. MATERIALS & METHODS: We examined all 43 training projects funded by the US$46 million ARRA CER investment, collecting data from key informant discussions and a technical expert panel. RESULTS: The majority of projects leveraged institutional resources to provide an individualized combination of didactic and experiential learning supported by strong mentorship. Core competencies included skills in statistical modeling, evidence synthesis (systematic reviews and meta-analysis) and general research design skills. CONCLUSION: ARRA-supported CER training programs enhanced workforce capacity by developing curricula and preparing CER researchers to apply emerging methods and utilize new CER infrastructure. PMID- 25494568 TI - Differences among consumer segments with regard to perceptions of comparative effectiveness research. AB - AIM: To examine differences among health-related decision-making consumer segments with regard to knowledge, skills, attitudes, and behaviors pertinent to comparative effectiveness research. METHODS: Data were collected via an online survey from 603 adults with chronic conditions. Consumer segment was determined using a two-item tool. RESULTS: Active consumers (high skills and motivation) reported the highest levels of engagement in various behaviors. Passive consumers (low skills and motivation) reported the lowest levels of engagement in various behaviors. High-effort consumers (low skills, high motivation) reported more positive attitudes and opinions and more engagement in various behaviors than did complacent consumers (high skills, low motivation). CONCLUSION: Effective translation and dissemination of comparative effectiveness research will require the development of approaches tailored to consumers with varying levels of skills and motivation. PMID- 25494569 TI - Public perceptions of comparative effectiveness research and use of evidence in healthcare decision-making. AB - AIMS: This study elaborates on the public's understanding of comparative effectiveness research (CER) or patient-centered outcomes research (PCOR), attitudes toward CER/PCOR and use of evidence in healthcare decision-making. MATERIALS & METHODS: We conducted six focus groups with the general public - three with individuals actively engaged in healthcare decision-making and three with individuals more passive in their approach. RESULTS: The general public has little knowledge of CER/PCOR, and its perceptions of certain CER/PCOR concepts are inconsistent with those of researchers and policy-makers. Active healthcare consumers value information more than passive consumers and are likely to use evidence in decision-making. CONCLUSION: Providers are an important source for disseminating and communicating CER/PCOR evidence to active and passive consumers. PMID- 25494570 TI - Infrastructure to support learning health systems: are we there yet? Innovative solutions and lessons learned from American Recovery and Reinvestment Act CER investments. AB - The 11 big health data networks participating in the AcademyHealth Electronic Data Methods Forum represent cutting-edge efforts to harness the power of big health data for research and quality improvement. This paper is a comparative case study based on site visits conducted with a subset of these large infrastructure grants funded through the Recovery Act, in which four key issues emerge that can inform the evolution of learning health systems, including the importance of acknowledging the challenges of scaling specialized expertise needed to manage and run CER networks; the delicate balance between privacy protections and the utility of distributed networks; emerging community engagement strategies; and the complexities of developing a robust business model for multi-use networks. PMID- 25494571 TI - American Recovery and Reinvestment Act-comparative effectiveness research infrastructure investments: emerging data resources, tools and publications. AB - The Recovery Act provided a substantial, one-time investment in data infrastructure for comparative effectiveness research (CER). A review of the publications, data, and tools developed as a result of this support has informed understanding of the level of effort undertaken by these projects. Structured search queries, as well as outreach efforts, were conducted to identify and review resources from American Recovery and Reinvestment Act of 2009 CER projects building electronic clinical data infrastructure. The findings from this study provide a spectrum of productivity across a range of topics and settings. A total of 451 manuscripts published in 192 journals, and 141 data resources and tools were identified and address gaps in evidence on priority populations, conditions, and the infrastructure needed to support CER. PMID- 25494572 TI - Assessing the long-term impact of public investments in comparative effectiveness research: conceptual framework and lessons learned. AB - The American Recovery and Reinvestment Act (ARRA) of 2009 directed US$1.1 billion to the US Department of Health and Human Services for support of comparative effectiveness research (CER). As part of this investment, US Department of Health and Human Services commissioned a midstream evaluation of the ARRA CER portfolio. One goal of the evaluation was to identify issues to consider for a future evaluation of the long-term impact of this portfolio and other CER investments. In planning the ARRA CER evaluation, we developed and revised a conceptual framework and related policy research questions that may be useful to future efforts to assess the impact of CER or patient-centered outcomes research investments. In addition, we explored methodological challenges related to designing an evaluation to assess investments in CER that may be informative to any future plans to evaluate the long-term impact of ARRA CER as well subsequent investments made from the Patient-Centered Outcomes Research Trust Fund. PMID- 25494573 TI - Evaluating collaborations in comparative effectiveness research: opportunities and challenges for social network analysis. AB - Multidisciplinary, multi-institutional collaboration has become a key feature of comparative effectiveness research (CER), and CER funders have made promotion of these types of collaboration an implicit, and sometimes explicit, goal of funding. An important challenge in evaluating CER programs is understanding if and how different forms of collaboration are associated with successful CER projects. This article explores the potential use of social network analysis to address research questions about the associations between collaboration and the success of CER projects. PMID- 25494574 TI - Carbon monoxide and nitric oxide interactions in magnocellular neurosecretory neurones during water deprivation. AB - Nitric oxide (NO) and carbon monoxide (CO) are diffusible gas messengers in the brain. Previously, we have shown their independent involvement in central fluid/electrolyte homeostasis control. In the present study, we investigated a possible functional interaction between NO/CO in the regulation of vasopressin (VP) and oxytocin (OT) magnocellular neurosecretory cells (MNCs) activity in euhydrated (EU) and dehydrated [48-h water-deprived (48WD)] rats. Using brain slices from EU and 48WD rats, we measured, by immunohistochemistry, the expression of neuronal NO synthase (nNOS, which synthesises NO) and haeme oxygenase (HO-1, which synthesises CO) in the hypothalamic supraoptic nucleus (SON). In addition, we used patch-clamp electrophysiology to investigate whether regulation of SON MNC firing activity by endogenous CO was dependent on NO bioavailability and GABAergic inhibitory synaptic function. We found a proportion of OT and VP SON MNCs in EU rats to co-express both of HO-1 and nNOS (33.2 +/- 2.9% and 15.3 +/- 1.4%, respectively), which was increased in 48WD rats (55.5 +/- 0.9% and 21.0 +/- 1.7%, respectively, P < 0.05 for both). Inhibition of endogenous HO activity [chromium mesoporphyrin IX chloride (CrMP) 20 MUm] induced MNC membrane hyperpolarisation and decreased firing activity, and these effects were blunted by previous blockade of endogenous NOS activity (l-NAME, 2 mm) or blockade of inhibitory GABA function [Picrotoxin (Sigma-Aldrich, St Louis, MO, USA), 50 MUm]. No significant changes in SON NO bioavailability (4,5 diaminofluorescein diacetate fluorescence) were observed after CrMP treatment. Taken together, our results support a state-dependent functional inter relationship between NO and CO in MNCs, in which CO acts as an excitatory gas molecule, whose effects are largely dependent on interactions with the inhibitory SON signals NO and GABA. PMID- 25494575 TI - Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis targeting tyrosine kinase inhibitor-based therapy. AB - INTRODUCTION: Angiogenesis is fundamental for tumor development and progression. Hence, anti-angiogenic drugs have been developed to target VEGF and its receptors (VEGFRs). Several tyrosine kinase inhibitors (TKIs) have been developed over the years and others are still under investigation, each anti-VEGFR TKI showing a different cardiotoxic profile. Knowledge of the cardiac side-effects of each drug and the magnitude of their expression and frequency can lead to a specific approach. AREAS COVERED: This work reviews the mechanism of action of anti-VEGFR TKIs and the pathophysiological mechanisms leading to cardiotoxicity, followed by close examination of the most important drugs individually. A literature search was conducted on PubMed selecting review articles, original studies and clinical trials, with a focus on Phase III studies. EXPERT OPINION: Side-effects on the cardiovascular system could lead both to the worsening of general health status of cancer patients and to the discontinuation of the cancer treatment affecting its efficacy. Cardiologists often have to face new triggers of heart disease in these patients. They need a specific approach, which must be carried out in cooperation with oncologists. It must start before cancer treatment, continue during it and extend after its completion. PMID- 25494576 TI - Negative urodynamic testing in women with stress incontinence. AB - INTRODUCTION: A minority of women with a subjective complaint of stress urinary incontinence will have negative urodynamic stress incontinence (USI) findings. AIM: To test clinical and ultrasound measures as predictors of an unexpected absence of USI. We hypothesised that unexpectedly negative USI would be more common in young women with good pelvic floor and urethral function. METHODS: A retrospective study analysing 398 data sets from women attending a urogynaecology clinic for evaluation of lower urinary tract and pelvic floor dysfunction. Clinical, urodynamic and translabial ultrasound data were tested as possible predictors of negative USI findings. RESULTS: Women with unexpectedly negative USI findings were younger, had less anterior compartment prolapse and had a higher maximum urethral pressure. Measures of pelvic floor muscle function were not predictive. CONCLUSIONS: Women with unexpectedly negative USI are younger and have better urethral function, but voluntary pelvic floor muscle function seems unrelated to this phenomenon. PMID- 25494578 TI - Patterns and causes of observed pinon pine mortality in the southwestern United States. AB - Recently, widespread pinon pine die-off occurred in the southwestern United States. Here we synthesize observational studies of this event and compare findings to expected relationships with biotic and abiotic factors. Agreement exists on the occurrence of drought, presence of bark beetles and increased mortality of larger trees. However, studies disagree about the influences of stem density, elevation and other factors, perhaps related to study design, location and impact of extreme drought. Detailed information about bark beetles is seldom reported and their role is poorly understood. Our analysis reveals substantial limits to our knowledge regarding the processes that produce mortality patterns across space and time, indicating a poor ability to forecast mortality in response to expected increases in future droughts. PMID- 25494577 TI - Assessing the affective load in the narratives of women suffering from fibromyalgia: the clinicians' appraisal. AB - OBJECTIVE: Fibromyalgia is characterized by chronic widespread pain and various associated symptoms, including psychological distress. This study presents a secondary analysis of the interviews of patients with fibromyalgia to appraise the affective load of the patient narratives as assessed by independent clinicians. SETTING AND PARTICIPANTS: Three clinicians, an internist, a psychiatrist and a psychologist, who were experienced in chronic pain reviewed the interview transcripts of 56 women eliciting their views regarding fibromyalgia onset. A Clinical Global Impression (CGI) scale was used (0 = no affective load to 5 = maximum affective load) to provide a subjective appraisal of the intensity of the affective impact, as suggested in the transcripts and from the clinician perspectives. RESULTS: The mean affective load was 3.6 (SD = +/-1), indicating the perception of a high affective load in the clinicians. Values indicating a high or very high affective load (>=4 points on the CGI scale) were more frequent than those in the lower range [23 narratives (41%) vs. 3 (5%)]. The inter-rater agreement of the affective load of the narratives was high (K > 0.85). These results of the clinician perspectives parallel those of the patient narratives, emphasizing disruptive circumstances, psychological distress and hopelessness surrounding symptom onset. CONCLUSION: The affective load in the narratives of these patients with fibromyalgia was high and had a negative undertone when considered from the clinicians' perspective. This study highlights the importance of considering the affective resonance in the context of therapeutic relationships that are often emotionally laden and highly challenging for the clinician. PMID- 25494580 TI - What hath freud wrought? Current confusion and controversies about the clinical practice of psychoanalysis and psychodynamic psychotherapy. AB - This article discusses the current state of psychoanalysis and the challenges to the fundamental premises of Freud's psychoanalysis by those who have shifted to relationship or so-called two-person psychologies in our field. The author begins by briefly describing a parallel to the recent history of psychoanalysis in the sudden rise and fall of scholastic philosophy in the 14th century. He then focuses on contemporary attacks on Freud's psychoanalysis as a science, based on the contention by two-person psychologists that free association by the patient and evenly hovering attention by the analyst are actually impossible. He reviews Freud's idea of psychoanalysis, discusses psychodynamic psychotherapy, both conceived as scientific treatment procedures, and describes the current assault on their metapsychological and epistemological foundations. Returning to the parallel between what happened to medieval scholasticism and what has happened to psychoanalysis, he examines why this happened, and the resulting fragmentation of psychoanalytic practice. The article concludes with suggestions for the integration of various schools of psychoanalysis, reminding us of Benjamin Franklin's warning: "We must, indeed, all hang together or, most assuredly, we shall all hang separately." PMID- 25494581 TI - Editorial: contemporary psychodynamic psychiatry. PMID- 25494579 TI - Effect of applying lactic acid bacteria and propionic acid on fermentation quality and aerobic stability of oats-common vetch mixed silage on the Tibetan plateau. AB - The objective of this study was to evaluate effects of lactic acid bacteria and propionic acid on the fermentation quality and aerobic stability of oats-common vetch mixed silage by using a small-scale fermentation system on the Tibetan plateau. (i) An inoculant (Lactobacillus plantarum) (L) or (ii) propionic acid (P) or (iii) inoculant + propionic acid (PL) were used as additives. After fermenting for 60 days, silos were opened and the aerobic stability was tested for the following 15 days. The results showed that all silages were well preserved with low pH and NH3 -N, and high lactic acid content and V-scores. L and PL silages showed higher (P < 0.05) lactic acid and crude protein content than the control silage. P silage inhibited lactic acid production. Under aerobic conditions, L silage had similar yeast counts as the control silage (> 10(5) cfu/g fresh matter (FM)); however, it numerically reduced aerobic stability for 6 h. P and PL silages showed fewer yeasts (< 10(5) cfu/g FM) (P < 0.05) and markedly improved the aerobic stability (> 360 h). The result suggested that PL is the best additive as it could not only improved fermentation quality, but also aerobic stability of oats-common vetch mixed silage on the Tibetan plateau. PMID- 25494582 TI - A psychodynamic perspective on treatment of patients with conversion and other somatoform disorders. AB - Conversion disorder, the development of symptoms of neurological disease with no organic basis, is a challenge for mental health professionals to diagnose and treat effectively. There are well-established predisposing factors, such as female sex, childhood trauma, and alexithymia, but less clear is how to approach the subjective suffering that is symbolized with the symptom rather than consciously recognized. While there are overlapping comorbidities such as depression and anxiety that may be treated with medication, psychotherapy is the primary effective treatment for patients with adequate capacity to engage in the process. This article addresses means of identifying patients who might benefit from psychotherapy (along with medication in some instances) as well as some guidelines for conducting psychotherapy, with case examples. PMID- 25494583 TI - Psychodynamic therapies with infants and parents: a review of RCTs on mother infant psychoanalytic treatment and other techniques. AB - This article critically examines the existent evidence base for Psychodynamic Therapy with Infants and Parents (PTIP), specifically focusing on the available RCTs (Randomized Controlled Trials) in the literature. The author also discusses how these studies influenced the design of an RCT of a related novel treatment method, Mother-Infant Psychoanalytic treatment (MIP). He found that certain types of mothers and infants may be more likely to benefit from MIP. In addition to providing guidance on therapeutic techniques, this article also effectively outlines ways in which PTIP, as well as psychotherapy for emotional issues during pregnancy, can be better integrated into the comprehensive health care system. Local health care units comprised of a nurse group and one therapist may be a better way of handling mother-infant interactional difficulties than centralized, specialized perinatal psychiatry centers. PMID- 25494584 TI - Psychodynamic psychotherapy and global health. AB - This study surveys and examines the literature about psychodynamic psychotherapy in low and middle income countries. Although much has been written on this topic, the literature remains disjointed, unsystematic, and lacks randomized controlled trials. This trend is in stark contrast with a growing body of systematic literature and randomized controlled trials that exist in other types of psychotherapy used in low and middle income countries. While there is evidence that other types of psychotherapy are useful in these countries, questions remain regarding the implementation of psychodynamic psychotherapy. Is psychodynamic psychotherapy relevant to non-Western cultures? Are changes necessary to make it relevant? Is psychodynamic psychotherapy economically feasible in low and middle income countries? Although definitive answers to these questions do not yet exist, as psychodynamic psychotherapy is open-ended and client-centered, it is likely to be flexible across a wide range of cultures. PMID- 25494585 TI - Manifest dream content as a possible predictor of suicidality. AB - The prediction of suicidal intent remains a clinical problem. This presentation illustrates that a distinction may be made between the manifest dream reports of patients who are potentially or acutely suicidal and those who are not. A review of the literature reveals that the manifest dream reports of clinically depressed, non-suicidal individuals differ from those who are depressed and acutely suicidal. The former contain themes of loss, disappointment, rejection, helplessness, hopelessness, failure, and death. The latter contain themes of dying, death, destruction, and violence directed toward the dreamer or others, as well as hopelessness and helplessness. The author collected manifest dream reports from three clinically depressed, non-suicidal patients and three clinically depressed, potentially or acutely suicidal patients. There are apparent differences between the themes of manifest dream reports in the clinically depressed, non-suicidal patients and the clinically depressed, potentially or acutely suicidal patients. The former contain themes of death, loss, rejection, vulnerability, hopelessness, and helplessness. The latter contain themes of active harm or violence (specifically toward the dreamer), dying or being dead, aloneness, vulnerability, hopelessness, and helplessness. Clinical cases and corresponding manifest dream reports are presented. Although this is a preliminary study, it is possible that manifest dream content may be used as one of the predictors of suicidality, in conjunction with latent dream content, diagnosis, life circumstance, and clinical status. PMID- 25494586 TI - Clarifying values in psychotherapy. AB - This article addresses the complex issue of how to clarify conflicts involving value judgments. The author reviews his experiences as therapist, supervisor, and consultant in offering second opinions on in-progress therapies. He summarizes six major obstacles to effective value clarifications and interpretations. Therapists can help patients to explicitly verbalize otherwise only implicit values. Distress from guilt and shame can be reduced by helping a patient reprioritize values and gain self-reflective awareness skills for resolving moral dilemmas. PMID- 25494587 TI - Memoirs of a founding analyst. AB - My memoirs start with a description of the different spiritual climates in the early psychoanalytic centers of Vienna and Berlin. Whereas Berlin was enthusiastic and ready for new explorations, Vienna was bound tightly to Freud's vision. In the United States, tensions between orthodoxy and new ventures soon led to many organizational splits and finally to the creation of the American Academy of Psychoanalysis, a forum for new ideas, free of ideological restrictions. PMID- 25494588 TI - Sandberg and Busch respond to Robbins discussion. PMID- 25494589 TI - Response to Sandberg and Busch. PMID- 25494592 TI - Biomass-based targets and the management of multispecies coral reef fisheries. AB - The failure of fisheries management among multispecies coral reef fisheries is well documented and has dire implications for the 100 million people engaged in these small-scale operations. Weak or missing management institutions, a lack of research capacity, and the complex nature of these ecosystems have heralded a call for ecosystem-based management approaches. However, ecosystem-based management of coral reef fisheries has proved challenging due to the multispecies nature of catches and the diversity of fish functional roles. We used data on fish communities collected from 233 individual sites in 9 western Indian Ocean countries to evaluate changes in the site's functional composition and associated life-history characteristics along a large range of fish biomass. As biomass increased along this range, fish were larger and grew and matured more slowly while the abundance of scraping and predatory species increased. The greatest changes in functional composition occurred below relatively low standing stock biomass (<600 kg/ha); abundances of piscivores, apex predators, and scraping herbivores were low at very light levels of fishing. This suggests potential trade-offs in ecosystem function and estimated yields for different management systems. Current fishing gear and area restrictions are not achieving conservation targets (proposed here as standing stock biomass of 1150 kg/ha) and result in losses of life history and ecological functions. Fish in reefs where destructive gears were restricted typically had very similar biomass and functions to young and low compliance closures. This indicates the potentially important role of fisheries restrictions in providing some gains in biomass and associated ecological functions when fully protected area enforcement potential is limited and likely to fail. Our results indicate that biomass alone can provide broad ecosystem-based fisheries management targets that can be easily applied even where research capacity and information is limited. Of particular value, is our finding that current management tools may be used to reach key ecosystem-based management targets, enabling ecosystem-based management in many socioeconomic contexts. PMID- 25494593 TI - Maternal Asian ethnicity and the risk of anal sphincter injury. AB - OBJECTIVE: To examine associations between maternal Asian ethnicity (South Asian and South East/East Asian) and anal sphincter injury. DESIGN: Retrospective cross sectional study, comparing outcomes for Asian women with those of Australian and New Zealand women. SETTING: A large metropolitan maternity service in Victoria, Australia. POPULATION: Australian/New Zealand, South Asian and South East/East Asian women who had a singleton vaginal birth from 2006 to 2012. METHODS: The relation between maternal ethnicity and anal sphincter injury was assessed by logistic regression, adjusting for potential confounders. MAIN OUTCOME MEASURES: Anal sphincter injury was defined as a third or fourth degree tear (with or without episiotomy). RESULTS: Among 32,653 vaginal births there was a significant difference in the rate of anal sphincter injury by maternal region of birth (p < 0.001). After adjustment for confounders, nulliparous women born in South Asian and South East/East Asia were 2.6 (95% confidence interval 2.2-3.3; p < 0.001) and 2.1 (95% confidence interval 1.7-2.5; p < 0.001) times more likely to sustain an anal sphincter injury than Australian/New Zealand women, respectively. Parous women born in South Asian and South East/East Asia were 2.4 (95% confidence interval 1.8-3.2; p < 0.001) and 2.0 (95% confidence interval 1.5-2.7; p < 0.001) times more likely to sustain an anal sphincter injury than Australian/New Zealand women, respectively. CONCLUSION: There are ethnic differences in the rates of anal sphincter injury not fully explained by known risk factors for such trauma. This may have implications for care provision. PMID- 25494594 TI - Protective effect of corn peptides against alcoholic liver injury in men with chronic alcohol consumption: a randomized double-blind placebo-controlled study. AB - BACKGROUND: Corn peptides (CPs) are a novel food prepared from corn gluten meal, which is a main by-product of the corn starch industry. Recently, significant beneficial effects of CPs on early alcoholic liver injury in rats and on acute alcoholic injury in mice were observed. To our knowledge, the present study is the first report showing that CPs supplementation has beneficial effects on lipid profile, oxidative stress and alcoholic liver injury in men with chronic alcohol consumption. METHODS: A 9-week, randomized, double-blind, placebo-controlled study was conducted between September 2011 and August 2012 to assess the hepatoprotective effect of CPs. A total of 161 men were randomized to receive CPs (n=53), whey protein (n=54), or corn starch placebo (n=54) at the same dose of 2 g twice daily. 146 participants completed the study. Serum lipid profile, serum markers of liver injury, oxidative stress and inflammation, and fatty liver based on the results of abdominal ultrasonography were assessed at the beginning and end of the intervention. RESULTS: CPs supplementation (4 g/d) for 9 weeks significantly lowered serum levels or activities of total cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase, malondialdehyde and tumor necrosis factor-alpha, and significantly increased serum activities of superoxide dismutase and glutathione peroxidase, but the same dose of whey protein and corn starch (placebo) did not demonstrate these effects. CONCLUSIONS: Our results indicate that CPs may have protective effects on alcohol induced liver damage via modulation of lipid metabolism and oxidative stress. CPs may potentially be used as a functional food for the management of alcoholic liver disease in subjects with chronic alcohol consumption. PMID- 25494595 TI - A Latin American perspective of periodontology. AB - Periodontal diseases occur worldwide, and Latin American populations are significantly affected by different manifestations of periodontal disease. The interest in periodontics and periodontal therapy first developed in the early 1930s in the southernmost countries of Latin America, and spread, as the years went by, throughout the region. Today, periodontal research is vibrant in Latin America. The aim of this volume of Periodontology 2000 was to present an overview of the periodontal research currently being performed in different countries of Latin America. The epidemiology of periodontal diseases in adults, children and adolescents, and the pathogenesis of such diseases (including microbiological characteristics and risk factors), are discussed. The role of systemic antibiotic therapy and the effect of smoking are discussed in relation to the progression and the treatment of periodontitis. In addition, the benefit of lasers in periodontal therapy is evaluated. Latin American research groups have been active in exploring new venues of regenerative periodontal treatment, addressing the role of cementum proteins, growth factors and oral mesenchymal stem cells in tissue engineering. Finally, basic research to study cancerization is reported. PMID- 25494596 TI - Epidemiology of periodontal diseases in adults from Latin America. AB - A decade has passed since we first reviewed the epidemiology of periodontal diseases in Latin America. At that time, lack of population-based studies was the norm and our conclusions were based on very limited evidence. The aim of the present comprehensive review was to update and expand our previous work by providing a broad overview of Latin America and its current social, economic and demographic status and by focusing on the epidemiology of periodontal diseases in Latin American adults published in the last 15 years. The amount of periodontal epidemiological data available has increased but is still restricted to a few countries only. The scope of the literature available has also broadened to include oral health-related quality of life and systemic interactions; however, most studies had methodological limitations that might have biased their results. In general, periodontitis was very prevalent, but severe periodontal destruction was localized. Besides being associated with well-established risk factors, periodontitis was associated with demographics and socio-economic factors in Latin American populations. To advance epidemiological knowledge, population based cross-sectional and longitudinal studies, using appropriate methodologies, should be the future focus of the research agenda of researchers and public health planners in Latin American countries. PMID- 25494597 TI - Periodontal disease in children and adolescents of Latin America. AB - Periodontal diseases are a group of infectious diseases that mainly include gingivitis and periodontitis. Gingivitis is the most prevalent form of periodontal disease in subjects of all ages, including children and adolescents. Less frequent types of periodontal disease include aggressive periodontitis, acute necrotizing ulcerative gingivitis and various diseases of herpesviral and fungal origin. This review aimed to retrieve relevant information from Latin America on the prevalence of periodontal diseases among children and adolescents of the region. Gingivitis was detected in 35% of young Latin American subjects and showed the highest frequencies in Colombia (77%) and Bolivia (73%) and the lowest frequency in Mexico (23%). The frequency of gingivitis in subjects from other Latin American countries was between 31% and 56%. Periodontitis may affect <10% of the young population in Latin America, but the data are based on only a few studies. A more precise assessment of the distribution and severity of periodontal disease in children and adolescents of Latin America may help policy makers and dentists to institute more effective public health measures to prevent and treat the disease at an early age to avoid major damage to the permanent dentition. PMID- 25494598 TI - Periodontal microbiology in Latin America. AB - This review article describes the microbiota associated with periodontal disease in Latin America. This vast territory includes 22 nations, which show great ethnic diversity, with large groups of White people, Black people, Mestizo people and Native people. Widespread poverty and limited access to education and health care services, including periodontal care, are prominent predisposing factors for destructive periodontal disease in Latin America. Black people and Mestizo people seem to have particularly severe periodontal disease and are frequently colonized by the major periodontal pathogens Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. The 'red complex' bacterial pathogens and A. actinomycetemcomitans predominate in chronic and aggressive periodontitis, but gram-negative enteric rods and herpesviruses can also play important periodontopathic roles in Latin America. The key to minimizing the risk of periodontal disease is control of the pathogens, and new low-cost periodontal treatments deserve serious consideration in Latin America. PMID- 25494599 TI - Effect of periodontal treatment on preterm birth rate: a systematic review of meta-analyses. AB - Preterm birth is a major cause of neonatal morbidity and mortality in both developed and developing countries. Preterm birth is a highly complex syndrome that includes distinct clinical subtypes in which many different causes may be involved. The results of epidemiological, molecular, microbiological and animal model studies support a positive association between maternal periodontal disease and preterm birth. However, the results of intervention studies carried out to determine the effect of periodontal treatment on reducing the risk of preterm birth are controversial. This systematic review critically analyzes the methodological issues of meta-analyses of the studies to determine the effect of periodontal treatment to reduce preterm birth. The quality of the individual randomized clinical trials selected is of highest relevance for a systematic review. This article describes the methodological features that should be identified a priori and assessed individually to determine the quality of a randomized controlled trial performed to evaluate the effect of periodontal treatment on pregnancy outcomes. The AMSTAR and the PRISMA checklist tools were used to assess the quality of the six meta-analyses selected, and the bias domain of the Cochrane Collaboration's Tool was applied to evaluate each of the trials included in the meta-analyses. In addition, the methodological characteristics of each clinical trial were assessed. The majority of the trials included in the meta-analyses have significant methodological flaws that threaten their internal validity. The lack of effect of periodontal treatment on preterm birth rate concluded by four meta-analyses, and the positive effect of treatment for reducing preterm birth risk concluded by the remaining two meta-analyses are not based on consistent scientific evidence. Well-conducted randomized controlled trials using rigorous methodology, including appropriate definition of the exposure, adequate control of confounders for preterm birth and application of effective periodontal interventions to eliminate periodontal infection, are needed to confirm the positive association between periodontal disease and preterm birth. PMID- 25494600 TI - Systemic antibiotics in the treatment of periodontitis. AB - Despite the fact that several clinical studies have shown additional benefits when certain systemic antibiotics are used as adjuncts to periodontal treatment, clear guidelines for the use of these agents in the clinical practice are not yet available. Basic questions concerning the use of systemic antibiotics to treat periodontitis remain unanswered, such as: which drug(s) should be used; which patients would most benefit from treatment; which are the most effective protocols (i.e. doses and durations); and in which phase of the mechanical therapy should the drug(s) be administered? Although not all of those questions have been directly addressed by controlled randomized clinical trials, recent concepts related to the ecology of periodontal diseases, as well as the major advances in laboratory and clinical research methods that have occurred in the past decade, have significantly broadened our knowledge in this field. This article endeavored to provide a 'state of the art' overview on the use of systemic antibiotics in the treatment of periodontitis, based on the most recent literature on the topic as well as on a compilation of data from studies conducted at the Center of Clinical Trials at Guarulhos University (Sao Paulo, Brazil) from 2002 to 2012. PMID- 25494601 TI - Current perspective of the impact of smoking on the progression and treatment of periodontitis. AB - This literature review provides an overview of the current scenario regarding the impact of smoking on the progression and treatment of periodontitis; clinical, microbiological and immunological data from studies from our and other groups are presented. In general, preclinical and clinical data are unanimous in demonstrating that smokers present increased susceptibility, greater severity and faster progression of periodontal disease compared with nonsmokers. The evidence further demonstrates that smokers lose more teeth and have a less favorable response to therapy than do nonsmokers. Although it is well established that smoking significantly impacts on the onset, progression and outcome of periodontal disease, the mechanisms involved remain unclear. More importantly, some of the reported deleterious effects of smoking on periodontal tissues have been reported to be reversible upon participation in smoking-cessation programs. Therefore, clinicians should strongly advise smokers to enroll in cessation strategies, even temporarily, in order to improve the overall outcome. PMID- 25494602 TI - Cementum proteins: role in cementogenesis, biomineralization, periodontium formation and regeneration. AB - Destruction of the periodontium is normally associated with periodontal disease, although many other factors, such as trauma, aging, infections, orthodontic tooth movement and systemic and genetic diseases, can contribute to this process. Strategies (such as guided tissue regeneration) have been developed to guide and control regeneration using bioresorbable membranes and bone grafts. Although effective to a certain point, these strategies have the problem that they are not predictable and do not completely restore the architecture of the original periodontium. To achieve complete repair and regeneration it is necessary to recapitulate the developmental process with complete formation of cementum, bone and periodontal ligament fibers. Detailed knowledge of the biology of cementum is key for understanding how the periodontium functions, identifying pathological issues and for developing successful therapies for repair and regeneration of damaged periodontal tissue. It is the purpose of this review to focus on the role of cementum and its specific components in the formation, repair and regeneration of the periodontium. As cementum is a matrix rich in growth factors that could influence the activities of various periodontal cell types, this review will examine the characteristics of cementum, its composition and the role of cementum components, especially the cementum protein-1, during the process of cementogenesis, and their potential usefulness for regeneration of the periodontal structures in a predictable therapeutic manner. PMID- 25494603 TI - Research on growth factors in periodontology. AB - Growth factors play critical roles in periodontal repair through the regulation of cell behavior. Many of the cell responses regulated by these proteins include cell adhesion, migration, proliferation and differentiation. Periodontal regeneration involves an organized response of different cells, tissues and growth factors implicated in the coordination of these events. However, periodontal tissue reconstruction is an extremely difficult task. Multiple studies have been performed to understand the specific role of growth factors in periodontal wound healing. In the present review we analyze the evidence that supports the roles of growth factors in periodontal wound healing and regeneration. PMID- 25494604 TI - Mesenchymal stem cells from the oral cavity and their potential value in tissue engineering. AB - Periodontal disease is one of the most common conditions affecting humans, and current treatment strategies, which focus on the removal and long-term control of dental plaque, are generally successful in eliminating active disease and promoting tissue repair. However, regeneration of the supporting structures of the tooth remains an elusive goal and a challenge. The formation of new bone and cementum with supportive periodontal ligament is the ultimate objective, but current regeneration therapies are incapable of achieving this in a predictable way. The regeneration of periodontal tissue requires a combination of fundamental events, such as appropriate level and sequencing of regulatory signals, the presence of progenitor cells, an extracellular matrix or carrier and an adequate blood supply. Based on tissue-engineering concepts, the regeneration process may be modulated by manipulating the signaling pathways of regulatory molecules, the extracellular matrix or scaffold, or the cellular components. The identification of mesenchymal stem cells from bone marrow started a new era in regenerative medicine. Tissue engineering using mesenchymal stem cells became a therapeutic option with several advantages, including high-quality regeneration of damaged tissues without the formation of fibrous tissue, minimal donor-site morbidity compared with autografts and a low risk of autoimmune rejection and disease transmission. The aim of this review was to describe the main sources of mesenchymal stem cells from tissues in the oral cavity and the potential of these cells in regenerative therapy. Special attention is paid to gingival tissue derived mesenchymal stem cells because they represent the most accessible source of stem cells in the human mouth. PMID- 25494605 TI - Lasers in periodontal therapy. AB - About 50 years ago, lasers started to be used in periodontal treatment following evidence that wounds produced in animals healed more quickly after being irradiated with low-intensity lasers. Increased production of growth factors, stimulated mainly by red and infrared lasers, may participate in this process by influencing the behavior of various types of cells. High-intensity lasers have been used as an alternative to nonsurgical periodontal therapy in root biomodification and to reduce dentin hypersensivity; low-intensity lasers are frequently employed to improve tissue repair in regenerative procedures and in antimicrobial photodynamic therapy. Despite the abundance of promising data on the advantages of their use, there is still controversy regarding the real benefits of lasers and antimicrobial photodynamic therapy in periodontal and peri implant treatment. A huge variation in the parameters of laser application among studies makes comparisons very difficult. An overview of the current concepts and findings on lasers in periodontal therapy is presented with emphasis on data collected from Latin-American researchers. PMID- 25494606 TI - The hamster cheek pouch model for field cancerization studies. AB - External carcinogens, such as tobacco and alcohol, induce molecular changes in large areas of oral mucosa, which increase the risk of malignant transformation. This condition, known as 'field cancerization', can be detected in biopsy specimens using histochemical techniques, even before histological alterations are identified. The efficacy of these histochemical techniques as biomarkers of early cancerization must be demonstrated in appropriate models. The hamster cheek pouch oral cancer model, universally employed in biological studies and in studies for the prevention and treatment of oral cancer, is also an excellent model of field cancerization. The carcinogen is applied in solution to the surface of the mucosa and induces alterations that recapitulate the stages of cancerization in human oral mucosa. We have demonstrated that the following can be used for the early detection of cancerized tissue: silver staining of nucleolar organizer regions; the Feulgen reaction to stain DNA followed by ploidy analysis; immunohistochemical analysis of fibroblast growth factor-2, immunohistochemical labeling of proliferating cells to demonstrate an increase of epithelial cell proliferation in the absence of inflammation; and changes in markers of angiogenesis (i.e. those indicating vascular endothelial growth factor activity, endothelial cell proliferation and vascular density). The hamster cheek pouch model of oral cancer was also proposed and validated by our group for boron neutron capture therapy studies for the treatment of oral cancer. Clinical trials of this novel treatment modality have been performed and are underway for certain tumor types and localizations. Having demonstrated the efficacy of boron neutron capture therapy to control tumors in the hamster cheek pouch oral cancer model, we adapted the model for the long-term study of field cancerized tissue. We demonstrated the inhibitory effect of boron neutron capture therapy on tumor development in field cancerized tissue with acceptable levels of mucositis, a dose-limiting side-effect. PMID- 25494607 TI - How older black women perceive the effects of stigma and social support on engagement in HIV care. AB - As black women over age 50 represent a growing share of women living with HIV, understanding what helps them persist and engage in ongoing HIV care will become increasingly important. Delineating the specific roles of social support and stigma on HIV care experiences among this population remains unclear. We qualitatively examined how experiences with stigma and social support either facilitated or inhibited engagement in HIV care, from the perspective of older black women. Semi-structured interviews were conducted with 20 older black women currently receiving HIV care at primary care clinics in the Metropolitan Boston area. Women expressed that experiences with stigma and seeking support played an important role in evaluating the risks and benefits of engaging in care. Social support facilitated their ability to engage in care, while stigma interfered with their ability to engage in care throughout the course of their illness. Providers in particular, can facilitate engagement by understanding the changes in these women's lives as they struggle with stigma and disclosure while engaging in HIV care. The patient's experiences with social support and stigma and their perceptions about engagement are important considerations for medical teams to tailor efforts to engage older black women in regular HIV care. PMID- 25494608 TI - A new low-frequency alloantigen (Kha(b) ) located on platelet glycoprotein IIIa as a cause of maternal sensitization leading to neonatal alloimmune thrombocytopenia. PMID- 25494609 TI - Lack of Protection following Re-Exposure of Chinook Salmon to Ceratonova shasta (Myxozoa). AB - The recent identification of multiple genotypes of the salmonid parasite Ceratonova shasta with different virulence levels in Chinook Salmon Oncorhynchus tshawytscha suggests that it is possible to immunize fish against subsequent infection and disease. We hypothesized that exposure of Chinook Salmon to the less-virulent parasite genotype (II) prior to the more virulent parasite genotype (I) would decrease disease and/or result in fewer mature parasites compared with fish only infected with the more virulent genotype. To test this hypothesis, fish were challenged in a combination of field and laboratory exposures, and we measured infection prevalence, percent morbidity, and mature parasite production. Neither mortality nor mature parasite production were reduced when fish were exposed to genotype II prior to genotype I compared with fish exposed only to genotype I, suggesting that protection against C. shasta using a less-virulent genotype of the parasite does not occur. PMID- 25494610 TI - A population-based study of breast cancer prevalence in Australia: predicting the future health care needs of women living with breast cancer. AB - BACKGROUND: Breast cancer places a heavy burden on the Australian healthcare system, but information about the actual number of women living with breast cancer and their current or future health service needs is limited. We used existing population-based data and innovative statistical methods to address this critical research question in a well-defined geographic region. METHODS: Breast cancer data from the New South Wales (NSW) Central Cancer Registry and PIAMOD (Prevalence and Incidence Analysis MODel) software were used to project future breast cancer prevalence in NSW. Parametric models were fitted to incidence and survival data, and the modelled incidence and survival estimates were then used to estimate current and future prevalence. To estimate future healthcare requirements the projected prevalence was then divided into phases of care according to the different stages of the survivorship trajectory. RESULTS: The number of women in NSW living with a breast cancer diagnosis had increased from 19,305 in 1990 to 48,754 in 2007. This number is projected to increase further to 68,620 by 2017. The majority of these breast cancer survivors will require continued monitoring (31,974) or will be long-term survivors (29,785). About 9% will require active treatment (either initial therapy, or treatment for subsequent metastases or second cancer) and 1% will need end of life care due to breast cancer. CONCLUSIONS: Extrapolating these projections to the national Australian population would equate to 209,200 women living with breast cancer in Australia in 2017, many of whom will require active treatment or post-treatment monitoring. Thus, careful planning and development of a healthcare system able to respond to this increased demand is required. PMID- 25494611 TI - An improved genome of the model marine alga Ostreococcus tauri unfolds by assessing Illumina de novo assemblies. AB - BACKGROUND: Cost effective next generation sequencing technologies now enable the production of genomic datasets for many novel planktonic eukaryotes, representing an understudied reservoir of genetic diversity. O. tauri is the smallest free living photosynthetic eukaryote known to date, a coccoid green alga that was first isolated in 1995 in a lagoon by the Mediterranean sea. Its simple features, ease of culture and the sequencing of its 13 Mb haploid nuclear genome have promoted this microalga as a new model organism for cell biology. Here, we investigated the quality of genome assemblies of Illumina GAIIx 75 bp paired-end reads from Ostreococcus tauri, thereby also improving the existing assembly and showing the genome to be stably maintained in culture. RESULTS: The 3 assemblers used, ABySS, CLCBio and Velvet, produced 95% complete genomes in 1402 to 2080 scaffolds with a very low rate of misassembly. Reciprocally, these assemblies improved the original genome assembly by filling in 930 gaps. Combined with additional analysis of raw reads and PCR sequencing effort, 1194 gaps have been solved in total adding up to 460 kb of sequence. Mapping of RNAseq Illumina data on this updated genome led to a twofold reduction in the proportion of multi-exon protein coding genes, representing 19% of the total 7699 protein coding genes. The comparison of the DNA extracted in 2001 and 2009 revealed the fixation of 8 single nucleotide substitutions and 2 deletions during the approximately 6000 generations in the lab. The deletions either knocked out or truncated two predicted transmembrane proteins, including a glutamate-receptor like gene. CONCLUSION: High coverage (>80 fold) paired-end Illumina sequencing enables a high quality 95% complete genome assembly of a compact ~13 Mb haploid eukaryote. This genome sequence has remained stable for 6000 generations of lab culture. PMID- 25494612 TI - Autophagy regulates the stability of sialin, a lysosomal sialic acid transporter. AB - Macroautophagy plays a critical role in catabolizing cytosolic components via lysosomal degradation. Recent findings from our studies indicate that basal autophagy is required for the efficient lysosomal catabolism of sialyloligosaccharides, and that the downregulation of sialin, a lysosomal transporter of sialic acids can cause a significant delay in the cytosolic accumulation of such glycans. The findings reported herein show that the sialin protein level was increased when the autophagy process was inhibited. This effect appears to be specific to sialin, since the amount of LAMP1, another lysosomal membrane protein, remains constant under the same conditions. Our results suggest that autophagy may regulate the stability of sialin, and it could lead to the cytosolic accumulation of sialyloligosaccharides in autophagy-defective cells. PMID- 25494613 TI - Modular color evolution facilitated by a complex nanostructure in birds. AB - The way in which a complex trait varies, and thus evolves, is critically affected by the independence, or modularity, of its subunits. How modular designs facilitate phenotypic diversification is well studied in nonornamental (e.g., cichlid jaws), but not ornamental traits. Diverse feather colors in birds are produced by light absorption by pigments and/or light scattering by nanostructures. Such structural colors are deterministically related to the nanostructures that produce them and are therefore excellent systems to study modularity and diversity of ornamental traits. Elucidating if and how these nanostructures facilitate color diversity relies on understanding how nanostructural traits covary, and how these traits map to color. Both of these remain unknown in an evolutionary context. Most dabbling ducks (Anatidae) have a conspicuous wing patch with iridescent color caused by a two-dimensional photonic crystal of small (100-200 nm) melanosomes. Here, we ask how this complex nanostructure affects modularity of color attributes. Using a combination of electron microscopy, spectrophotometry, and comparative methods, we show that nanostructural complexity causes functional decoupling and enables independent evolution of different color traits. These results demonstrate that color diversity is facilitated by how nanostructures function and may explain why some birds are more color-diverse than others. PMID- 25494614 TI - Synthesis of lateral heterostructures of semiconducting atomic layers. AB - Atomically thin heterostructures of transition-metal dichalcogenides (TMDs) with various geometrical and energy band alignments are the key materials for next generation flexible nanoelectronics. The individual TMD monolayers can be adjoined laterally to construct in-plane heterostructures, which are difficult to reach with the laborious pick-up-and-transfer method of the exfoliated flakes. The ability to produce copious amounts of high quality layered heterostructures on diverse surfaces is highly desirable but it has remained a challenging issue. Here, we have achieved a direct synthesis of lateral heterostructures of monolayer TMDs: MoS(2)-WS(2) and MoSe(2)-WSe(2). The synthesis was performed using ambient-pressure chemical vapor deposition (CVD) with aromatic molecules as seeding promoters. We discuss possible growth behaviors, and we examine the symmetry and the interface of these heterostructures using second-harmonic generation and atomic-resolution scanning TEM. We found that the one-dimensinal (1D) interface of the lateral heterostructures picks the zigzag direction of the lattice instead of the armchair direction. Our method offers a controllable synthesis to obtain high-quality in-plane heterostructures of TMD atomic layers with 1D interface geometry. PMID- 25494615 TI - Associations of dietary intake and plasma concentrations of eicosapentaenoic and docosahexaenoic acid with prenatal depressive symptoms in Japan. AB - The association between depression and omega-3 polyunsaturated fatty acids, including eicosapentaenoic and docosahexaenoic acid, continues to gain focus. In this study, we examined whether dietary intakes and plasma concentrations of eicosapentaenoic and docosahexaenoic acid were associated with depressive symptoms during pregnancy. Healthy Japanese women with singleton pregnancies were recruited at a university hospital in Tokyo between 2010 and 2012. The depressive symptom group included participants with Edinburgh Postnatal Depression Scale scores greater than eight. Of the 329 participants, 19 (5.8%) had depressive symptoms. Lower plasma docosahexaenoic acid concentration was significantly associated with prenatal depressive symptoms. Women with depressive symptoms had a higher rate of pregnancy-associated nausea than those with non-depressive symptoms (52.6% vs 28.7%, respectively). Although we adjusted for the presence of pregnancy-associated nausea, dietary fatty acid intake was not associated with depressive symptoms in the multiple logistic regression analyses. Further large studies would be required to examine any preventive effect of dietary fatty acid intake on depressive symptoms among pregnant women. PMID- 25494616 TI - Distinguishing between the success and precision of recollection. AB - Recollection reflects the retrieval of complex qualitative information about prior events. Recently, Harlow and Donaldson developed a method for separating the probability of recollection success from the precision of the mnemonic information retrieved. In the current study, we ask if these properties are separable on the basis of subjective reports-are participants aware of these two aspects of recollection and can they reliably report on them? Participants studied words paired with a location on a circle outline, and at test recalled the location for a given word as accurately as possible. Additionally, participants provided separate subjective ratings of recollection confidence and recollection precision. The results indicated that participants either recollected the target location with considerable (but variable) precision or retrieved no accurate location information at all. Importantly, recollection confidence reliably predicted whether locations were recollected, while precision ratings instead reflected the precision of the locations retrieved. The results demonstrate the experimental separability of recollection success and precision, and highlight the importance of disentangling these two different aspects of recollection when examining episodic memory. PMID- 25494617 TI - Erratum. PMID- 25494618 TI - Motor asymmetry in elite fencers. AB - The authors previously reported that asymmetrical patterns of hand preference are updated and modified by present sensorimotor conditions. They examined whether participation in long-term training in the upper extremity sport fencing might modify arm selection and performance asymmetries. Eight fencers and eight nonfencers performed reaching movements under 3 experimental conditions: (a) nonchoice right, (b) nonchoice left, and (c) choice, either right or left arm as selected by subject. The nonchoice conditions allowed assessment of potential interlimb differences in movement performance, while the choice condition allowed assessment of the frequency and pattern of arm selection across subject groups. Our findings showed that the athlete group showed substantially greater symmetry in the performance and selection measures. These findings suggest that arm selection and performance asymmetries can be altered by intense long-term practice. PMID- 25494619 TI - Parallel multifunctionalization of nanoparticles: a one-step modular approach for in vivo imaging. AB - Multifunctional nanoparticles are usually produced by sequential synthesis, with long multistep protocols. Our study reports a generic modular strategy for the parallel one-step multifunctionalization of different hydrophobic nanoparticles. The method was designed and developed by taking advantage of the natural noncovalent interactions between the fatty acid binding sites of the bovine serum albumin (BSA) and the aliphatic surfactants on different inorganic nanomaterials. As a general example of the approach, three different nanoparticles-iron oxide, upconverting nanophosphors, and gold nanospheres-were nanoemulsified in water with BSA. To support specific applications, multifunctional capability was incorporated with a variety of previously modified BSA modules. These modules include different conjugated groups, such as chelating agents for (68)Ga or (89)Zr and ligand molecules for enhanced in vivo targeting. A large library of 13 multimodal contrast agents was developed with this convergent strategy. This platform allows a highly versatile and easy tailoring option for efficient incorporation of functional groups. Finally, as demonstration of this versatility, a bimodal (PET/MRI) probe including a maleimide-conjugated BSA was selectively synthesized with an RGD peptide for in vivo imaging detection of tumor angiogenesis. PMID- 25494620 TI - Antimicrobial activity of hop extracts against foodborne pathogens for meat applications. AB - AIMS: The objective of this study was the fundamental investigation of the antimicrobial efficiency of various hop extracts against selected foodborne pathogens in vitro, as well as their activity against Listeria monocytogenes in a model meat marinade and on marinated pork tenderloins. METHODS AND RESULTS: In a first step, the minimum inhibitory concentrations (MIC) of three hop extracts containing either alpha- or beta-acids or xanthohumol were determined against test bacteria including L. monocytogenes, Staphylococcus aureus, Salmonella enterica and Escherichia coli by a colorimetric method based on the measurement of bacterial metabolic activity. Moreover, the influence of either lactic or citric acid on the antimicrobial activity of the hop extracts was evaluated. The efficiency of hop extracts as a natural food preservative was then tested in a model meat marinade at 2 and 8 degrees C, respectively, and finally on marinated pork. The experiments showed that Gram-positive bacteria were strongly inhibited by hop extracts containing beta-acids and xanthohumol (MIC values of 6.3 and 12.5 ppm, respectively), whereas the antimicrobial activity of the investigated alpha acid extract was significantly lower (MIC values of 200 ppm). Gram-negative bacteria were highly resistant against all tested hop extracts. Acidification of the test media led to a decrease of the MIC values. The inhibitory activity of the hop extracts against L. monocytogenes was strongly reduced in a fat containing model meat marinade, but the efficiency of beta-acids in this matrix could be increased by lowering pH and storage temperatures. By applying 0.5 % beta-acids at pH = 5 in a model marinade, the total aerobic count of pork tenderloins was reduced up to 0.9 log10 compared with marinated pork without hop extract after 2 weeks of storage at 5 degrees C. CONCLUSIONS: beta-acid containing hop extracts have proven to possess a high antimicrobial activity against Gram-positive bacteria in vitro and in a practice-related application for food preservation. SIGNIFICANCE AND IMPACT OF THE STUDY: Antimicrobial hop extracts could be used as natural preservatives in food applications to extend the shelf life and to increase the safety of fresh products. PMID- 25494621 TI - A scoping review to understand the effectiveness of linking schemes from healthcare providers to community resources to improve the health and well-being of people with long-term conditions. AB - The prevalence of people living with long-term conditions is increasing, accompanied by an increased expectation that patients will become more involved in self-management. Long-term conditions are associated with increased social isolation and poor physical and mental health. But there remains a gap in health provision between providing medical treatment and effectively addressing psychosocial well-being. One potential way of addressing this gap is by utilising social interventions which link patients from health services to community-based sources of support. However, the mechanisms involved in the delivery of interventions providing that link and their effectiveness remain unclear. This review adopted the methodological framework for conducting scoping studies, searching for both academic and grey literature on social interventions which link people from healthcare settings to a range of community and voluntary sector organisations. A literature search between May and June 2013, involving five electronic databases, hand searching of two journals and the use of Google search engine, identified seven studies relevant to the review question. In terms of key characteristics and mechanisms of the interventions, mental health conditions and social isolation were the most common reasons for referral to the interventions, and referrals were usually made through general practices. Almost all the interventions were facilitator-led, whereby the facilitator worked to identify and link participants to appropriate community-based resources. In regard to health and social outcomes and their cost-effectiveness, studies reported improvement to participants' psychological and social well-being as well as their decreased use of health services, although there were limited measures of participants' physical health outcomes. Interventions for linking patients from healthcare setting to community-based resources target and address psychosocial needs of participants. The review identified involvement of health professionals in aiding the referral of patients to the intervention and the role of the intervention facilitators as key components of the interventions. PMID- 25494622 TI - Supporting physical activity engagement in people with Huntington's disease (ENGAGE-HD): study protocol for a randomized controlled feasibility trial. AB - BACKGROUND: Huntington's disease (HD) is a complex, single-gene inherited neurodegenerative condition resulting in symptoms that occur across a wide range of neurological domains, including cognitive, behavioral and motor. The benefits of regular physical activity for people with HD are widely recognized. However, a number of factors can prohibit sustained exercise and activity. The purpose of this trial is to explore the feasibility, acceptability and effectiveness of a physical activity intervention program targeted for people with early- to mid stage HD. METHODS/DESIGN: The proposed trial is a single blind, multisite, exploratory, randomized controlled feasibility trial of a physical activity intervention. A total of 62 participants with genetically confirmed HD will be recruited. Each participant will be involved in the trial for 26 weeks. Participants will be randomized immediately following the baseline assessment into either a physical activity intervention or a social contact control intervention. The physical activity intervention is framed around self determination theory placed within a broader behaviour change wheel framework. An HD-specific workbook and individual goal setting will be utilized over six 1:1 sessions, with interim telephone calls. All participants will be reassessed at 16 weeks following the baseline assessment, and then again at a final follow-up assessment 26 weeks later. At the end of the study, all participants will be offered a brief version of the alternative intervention, with one home visit and one follow-up telephone call. DISCUSSION: Engaging and supporting people with HD in a regular physical activity program raises a number of challenges. The physical activity intervention and the comparator social interaction intervention have been developed following consultation with people with HD and their families. Each are individually tailored and determined on individual needs and goals. The results from this trial will provide guidance for the development of definitive trials. TRIAL REGISTRATION: The trial was registered with ISRCTN ( http://www.isrctn.com/ISRCTN65378754) on 13 March 2014. PMID- 25494623 TI - Identification of gain- and loss-framed cancer screening messages that appeared in municipal newsletters in Japan. AB - BACKGROUND: Research suggests that cancer screening messages are more persuasive when framed in terms of the costs of not obtaining screening (i.e., loss-framed) than when framed in terms of the benefits of obtaining screening (i.e., gain framed). However, to what extent these findings have been integrated into public health practice is unknown. To analyze message framing of cancer screening information, the present study examined message framing of cancer screening announcement articles that appeared in municipal newsletters published from 23 wards in central Tokyo, Japan. Two independent raters coded the articles. Gain- and loss-framed sentences in each article were identified, and based on what the sentences conveyed, articles were classified into gain-framed, loss-framed, mixed framed, and non-framed. RESULT: Inter-rater reliability was acceptable (intraclass correlation coefficient = 0.88). Of the 129 articles evaluated, the total number of gain-framed sentences was 87, while that of loss-framed sentences was six. The total number of gain-framed articles was 32 (24.8%) while that of loss-framed articles was zero (0%). Five (3.9%) articles were mixed-framed. Ninety-two (71.3%) articles were non-framed. CONCLUSIONS: Cancer screening announcement articles of municipal newsletters were mostly non-framed or gain framed in 23 Tokyo wards in Japan. The absence of loss-framed articles and only a small number of loss-framed messages indicate a missed opportunity to persuade readers to obtain cancer screenings. Loss-framed messages and articles need to be increased to enhance the persuasiveness of cancer screening information in municipal newsletters. PMID- 25494624 TI - Antispasmodic and antidiarrhoeal activity of the fruit of Rosa moschata (J). AB - BACKGROUND: The fruit of Rosa moschata has traditionally been used for the treatment of abdominal spasm and diarrhoea. Therefore, the aim of this study was to investigate mechanism(s) responsible for its medicinal use in gut spasm and diarrhea. METHODS: Hydro-methanolic extract of Rosa moschata (Rm.Cr) was studied in isolated rabbit's jejunal preparations for possible antispasmodic activity. Based upon in vitro relaxant activity in isolated gut preparations, in vivo antidiarrheal activity was carried out in mice to confirm its antidiarrheal effect. Acute toxicity study was performed to determine safe dose range before in vivo experiments. RESULTS: In isolated rabbits' jejunal preparations, Rm.Cr inhibited the spontaneous and high K+-induced contractions with respective EC50 values of 0.66 (0.44-0.97; n = 5) and 2.28 mg/mL (1.43-3.62; n = 5), like that of verapamil. This suggests the presence of calcium channel blocking (CCB) activity as a possible mode of action. The Ca++ channel blocking activity was further confirmed when pre-treatment of isolated jejunums with Rm.Cr (1-5 mg/mL) caused a rightward shift in the Ca++ concentration-response curves (CRCs), similar to verapamil. Rm.Cr was safe up to 2000 mg/kg for in vivo acute toxicity. Rm.Cr provided 55% and 80% protection from diarrhoea in respective doses of 100 mg/kg and 1000 mg/kg. These data indicates that the crude extract of Rosa moschata possesses Ca++ antagonist-like constituent(s), which explains its inhibitory effect on gut motility; a mechanism that underlies its antidiarrheal and antispasmodic activities. CONCLUSION: The study shows that the crude extract of fruits of Rosa moschata possesses antispasmodic effects mediated possibly through voltage gated Ca++ channel blockade, which provides sound pharmacological base to its medicinal use in gut spasms and diarrhoea, though additional mechanism(s) cannot be ruled out. PMID- 25494625 TI - Pharmacokinetic profiles of the analgesic flupirtine in dogs after the administration of four pharmaceutical formulations. AB - OBJECTIVE: Flupirtine (FLU) is a non-opioid analgesic with no antipyretic or anti inflammatory effects which is used in the treatment of pain in humans. There is a substantial body of evidence on the efficacy of FLU in humans but this is inadequate for the recommendation of its off-label use in veterinary clinical practice. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after intravenous (IV), oral immediate release (POIR), oral prolonged release (POPR) and rectal (RC) administrations in healthy dogs. STUDY DESIGN: Four treatment, single-dose, four-phase, unpaired, cross-over design (4*4 Latin square). ANIMALS: Six adult Labrador dogs. METHODS: Animals in groups 1, 2 and 4 received a single dose of 5 mg kg(-1) FLU administered by IV, POIR and RC routes. Group 3 received a single dose of 200 mg subject(-1) via the POPR route. The wash out periods were 1 week. Blood samples (1 mL) were collected at assigned times for 48 hours and plasma FLU concentrations were analysed by a validated HPLC method. RESULTS: Adverse effects including salivation, tremors and vomiting were noted in the IV group and resolved spontaneously within 10 minutes. These effects did not occur in the other groups. The FLU plasma concentrations were detectable in all of the treatment groups for 36 hours following administration. The pharmacokinetic profiles after extravascular administrations showed similar trends. The bioavailability values after POIR, POPR and RC were 41.93%, 36.78% and 29.43%, respectively. There were no significant differences in pharmacokinetic profiles between the POIR and POPR formulations. A 5 mg kg(-1) POIR dose or a 200 mg subject(-1) POPR dose gave plasma concentrations similar to those reported in humans after clinical dosing. CONCLUSION AND CLINICAL RELEVANCE: This study provides pharmacokinetic data that can be used to design further studies to investigate FLU in dogs. PMID- 25494626 TI - Functional-thermoregulatory model for the differential diagnosis of psoriatic arthritis. AB - INTRODUCTION: Psoriasis arthritis (PsA) is a chronic inflammatory arthritis of joints of uncertain pathogenesis. PsA may lead to severe disabilities even in the absence of any clinical symptom. Therefore, PsA diagnosis in its early stages is critical. MATERIAL AND METHODS: This study uses Control System theory to model finger skin thermoregulatory processes overlying the hand joint in response to an isometric exercise. The proposed model is based on a homeostatic negative feedback loop characterized by four distinct parameters that describe how the control mechanisms are activated and maintained. Thermal infrared imaging was used to record a total of 280 temperature curves of 14 finger joints for each of 11 PsA patients and 9 healthy controls. RESULT AND CONCLUSION: PsA patients presented delayed and prolonged re-warming processes characterized by the undershoot onset after the end of the isometric exercise followed by a faster temperature increase. Region classification on the basis of the model parameters demonstrated that the interphalageal joint region of thumb better discriminates between patients and controls, providing 100% true-positive discrimination for PsA affected regions and 88.89% of correct classification of healthy regions. Even proved over a limited number of subjects, the proposed method may provide useful hints for early differential diagnosis in the IR assessment of PsA disease. PMID- 25494628 TI - Upward organelle motility. PMID- 25494627 TI - Comparative genomics reveals molecular features unique to the songbird lineage. AB - BACKGROUND: Songbirds (oscine Passeriformes) are among the most diverse and successful vertebrate groups, comprising almost half of all known bird species. Identifying the genomic innovations that might be associated with this success, as well as with characteristic songbird traits such as vocal learning and the brain circuits that underlie this behavior, has proven difficult, in part due to the small number of avian genomes available until recently. Here we performed a comparative analysis of 48 avian genomes to identify genomic features that are unique to songbirds, as well as an initial assessment of function by investigating their tissue distribution and predicted protein domain structure. RESULTS: Using BLAT alignments and gene synteny analysis, we curated a large set of Ensembl gene models that were annotated as novel or duplicated in the most commonly studied songbird, the Zebra finch (Taeniopygia guttata), and then extended this analysis to 47 additional avian and 4 non-avian genomes. We identified 10 novel genes uniquely present in songbird genomes. A refined map of chromosomal synteny disruptions in the Zebra finch genome revealed that the majority of these novel genes localized to regions of genomic instability associated with apparent chromosomal breakpoints. Analyses of in situ hybridization and RNA-seq data revealed that a subset of songbird-unique genes is expressed in the brain and/or other tissues, and that 2 of these (YTHDC2L1 and TMRA) are highly differentially expressed in vocal learning-associated nuclei relative to the rest of the brain. CONCLUSIONS: Our study reveals novel genes unique to songbirds, including some that may subserve their unique vocal control system, substantially improves the quality of Zebra finch genome annotations, and contributes to a better understanding of how genomic features may have evolved in conjunction with the emergence of the songbird lineage. PMID- 25494629 TI - The promoter of cell growth- and RNA protection-associated SND1 gene is activated by endoplasmic reticulum stress in human hepatoma cells. AB - BACKGROUND: Staphyloccocal nuclease domain-containing protein 1 (SND1) is involved in the regulation of gene expression and RNA protection. While numerous studies have established that SND1 protein expression is modulated by cellular stresses associated with tumor growth, hypoxia, inflammation, heat-shock and oxidative conditions, little is known about the factors responsible for SND1 expression. Here, we have approached this question by analyzing the transcriptional response of human SND1 gene to pharmacological endoplasmic reticulum (ER) stress in liver cancer cells. RESULTS: We provide first evidence that SND1 promoter activity is increased in human liver cancer cells upon exposure to thapsigargin or tunicamycin or by ectopic expression of ATF6, a crucial transcription factor in the unfolded protein response triggered by ER stress. Deletion analysis of the 5'-flanking region of SND1 promoter identified maximal activation in fragment (-934, +221), which contains most of the predicted ER stress response elements in proximal promoter. Quantitative real-time PCR revealed a near 3 fold increase in SND1 mRNA expression by either of the stress inducers; whereas SND1 protein was maximally upregulated (3.4-fold) in cells exposed to tunicamycin, a protein glycosylation inhibitor. CONCLUSION: Promoter activity of the cell growth- and RNA-protection associated SND1 gene is up regulated by ER stress in human hepatoma cells. PMID- 25494630 TI - Evidence-informed person-centred health care (part II): are 'cognitive biases plus' underlying the EBM paradigm responsible for undermining the quality of evidence? AB - INTRODUCTION: Recently, some leaders of the evidence-based medicine (EBM) movement drew attention to the "unintended" negative consequences associated with EBM. The term 'cognitive biases plus' was introduced in part I to encompass cognitive biases, conflicts of interests, fallacies and certain behaviours. HYPOTHESIS: 'Cognitive biases plus' in those closely involved in creating and promoting the EBM paradigm are responsible for their (1) inability to anticipate and then recognize flaws in the tenets of EBM; (2) discounting alternative views; and (3) delaying reform. METHODS: A narrative review style was used, with methods as in part I. APPRAISAL OF LITERATURE: Over the past two decades there has been mounting qualitative and quantitative methodological evidence to suggest that the faith placed in (1) the EBM hierarchy with randomized controlled trials and systematic reviews at the summit; (2) the reliability of biostatistical methods to quantitate data; and (3) the primacy of sources of pre-appraised evidence, is seriously misplaced. Consequently, the evidence that informs person-centred care is compromised. DISCUSSION: Arguments focusing on 'cognitive biases plus' are offered to support our hypothesis. To the best of our knowledge, EBM proponents have not provided an explanation. CONCLUSIONS: Reform is urgently needed to minimize continuing risks to patients. If our hypothesis is correct, then in addition to the suggestions made in part I, deficiencies in the paradigm must be corrected. Meaningful solutions are only possible if the biases of scientific inbreeding and groupthink are minimized by collaboration between EBM leaders and those who have been sounding warning bells. PMID- 25494631 TI - The Thriving of Older People Assessment Scale: validity and reliability assessments. AB - AIM: To explore construct validity and reliability of the Thriving of Older People Assessment Scale. BACKGROUND: The concept of thriving emphasizes person environment interaction in relation to well-being. The Thriving of Older People Assessment Scale has been developed and evaluated as a self-report and proxy scale based on the theory of thriving. DESIGN: Cross-sectional survey design. METHOD: The Thriving of Older People Assessment Scale was completed by a sample of 259 residents, 146 family members and 52 staff from 13 long-term care facilities in Norway and Sweden. Data were collected between April 2010-December 2011. Exploratory factor analysis was applied to explore construct validity in terms of factor structure and dimensionality of the 32-item scale in relation to the thriving theory. Reliability was explored through internal consistency estimation using Cronbach's alpha and through homogeneity evaluation using corrected item-total correlations. RESULTS: Exploratory factor analysis resulted in five factors (subscales) that corresponded meaningfully with the thriving theory and were labelled 1: Resident' attitudes towards being in long-term care; 2: Quality of care and caregivers; 3: Resident engagement and peer relationships; 4: Keeping in touch with people and places; and 5: Quality of the physical environment. The scale had satisfactory internal consistency and homogeneity estimates. CONCLUSION: The 32-item Thriving of Older People Assessment Scale can be regarded as construct valid and reliable. Its factor structure corresponded logically to the thriving theory and its factors showed satisfactory internal consistency and homogeneity. Nevertheless, the TOPAS would benefit from further testing in other populations and contexts. PMID- 25494632 TI - Lower irisin level in patients with type 2 diabetes mellitus: A case-control study and meta-analysis. AB - BACKGROUND: Irisin is a newly identified myokine in mice and humans. Many studies have reported irisin concentrations in patients with type 2 diabetes mellitus (T2DM). The large variations in irisin concentrations in different studies may be attributable to differences in sample size or populations. The aim of the present study was to establish an accurate confidence interval of irisin levels in T2DM patients using a case-control study and large-scale meta-analysis. METHODS: Serum irisin concentrations were determined in newly diagnosed T2DM patients (n = 50) and age- and body mass index-matched controls (n = 50) in a case-control study. Further, a meta-analysis was conducted to verify whether circulating irisin concentrations are lower in patients with T2DM. All publications regarding the association between irisin and T2DM in Medline, PubMed and EMBase were retrieved using the keywords "irisin" and "myokine". Review Manager 5.0 (Cochrane Collaboration, Oxford, UK) was used to pool the data. RESULTS: In the case control study, irisin concentrations were lower in newly diagnosed T2DM patients compared with healthy controls. In the meta-analysis, the pooled data indicated that irisin concentrations were 24.46 ng/mL (95% confidence interval [CI] 9.31, 39.60; P = 0.002) lower in T2DM patients than healthy controls. CONCLUSIONS: This study confirmed that circulating irisin concentrations were significantly lower in patients with T2DM. PMID- 25494633 TI - The influences of task repetition, napping, time of day, and instruction on the Sustained Attention to Response Task. AB - INTRODUCTION: The Sustained Attention to Response Task (SART) helps to quantify vigilance impairments.Previous studies, in which five SART sessions on one day were administered, demonstrated worse performance during the first session than during the others. The present study comprises two experiments to identify a cause of this phenomenon. METHOD: Experiment 1, counting eighty healthy participants, assessed effects of repetition,napping, and time of day on SART performance through a between-groups design. The SART was performed twice in the morning or twice in the afternoon; half of the participants took a 20-minute nap before the second SART. A strong correlation between error count and reaction time (RT) suggested effects of test instruction. Participants gave equal weight to speed and accuracy in Experiment 1; therefore, results of 20 participants were compared to those of 20 additional participants who were told to prefer accuracy (Experiment 2). RESULTS: The average SART error count in Experiment 1 was 10.1; the median RT was 280 ms. Neither repetition nor napping influenced error count or RT. Time of day did not influence error count, but RT was significantly longer for morning than for afternoon SARTs. The additional participants in Experiment 2 had a 49% lower error count and a 14% higher RT than the participants in Experiment 1. Error counts reduced by 50% from the first to the second session of Experiment 2, irrespective of napping or time of day. CONCLUSIONS: Preferring accuracy over speed was associated with a significantly lower error count. The data suggest that a worse performance in the first SART session only occurs when instructing participants to prefer accuracy, which is caused by repetition, not by napping or time of day. NOTE: We advise that participants are instructed to prefer accuracy over speed when performing the SART and that a full practice session is included. PMID- 25494634 TI - Association between joint hypermobility, scoliosis, and cranial base anomalies in paediatric Osteogenesis imperfecta patients: a retrospective cross-sectional study. AB - BACKGROUND: Joint hypermobility is a common clinical characteristic of patients with Osteogenesis imperfecta (OI), a disorder with serious comorbidities of scoliosis and cranial base anomalies. This study aimed at evaluating how prevalent joint hypermobility is in paediatric OI patients, and to find out whether it serves as a potential predictive marker of the different spinal complications; scoliosis and craniovertebral anomalies (basilar impression and basilar invagination). METHODS: In this cross-sectional one-center study we analysed retrospectively clinical patient records and radiographs of 47 OI patients, aged 1-19 years, some of whom were treated with bisphosphonates. Presence of joint hypermobility, scoliosis, and craniovertebral anomalies was recorded and possible connections between the phenomena were explored with correlation analysis. RESULTS: Joint hypermobility was found in 70% of the patients. Scoliosis and cranial base anomalies had developed in 26%. The presence of spinal complications was independent of the bisphosphonate treatment status and joint hypermobility. CONCLUSIONS: Scoliosis and craniovertebral anomalies are strongly associated in paediatric OI patients. Joint hypermobility that is much more common appears, however, to be a poor predictor. PMID- 25494635 TI - Sequencing bilateral and unilateral task-oriented training versus task oriented training alone to improve arm function in individuals with chronic stroke. AB - BACKGROUND: Recovering useful hand function after stroke is a major scientific challenge for patients with limited motor recovery. We hypothesized that sequential training beginning with proximal bilateral followed by unilateral task oriented training is superior to time-matched unilateral training alone. Proximal bilateral training could optimally prepare the motor system to respond to the more challenging task-oriented training. METHODS: PARTICIPANTS: Twenty-six participants with moderate severity hemiparesis Intervention: PARTICIPANTS received either 6-weeks of bilateral proximal training followed sequentially by 6 weeks unilateral task-oriented training (COMBO) or 12-weeks of unilateral task oriented training alone (SAEBO). A subset of 8 COMB0 and 9 SAEBO participants underwent three functional magnetic resonance imaging (fMRI) scans of hand and elbow movement every 6 weeks. MAIN OUTCOME MEASURES: Fugl-Meyer Upper extremity scale, Modified Wolf Motor Function Test, University of Maryland Arm Questionnaire for Stroke, Motor cortex activation (fMRI). RESULTS: The COMBO group demonstrated significantly greater gains between baseline and 12-weeks over all outcome measures (p = .018 based on a MANOVA test) and specifically in the Modified Wolf Motor Function test (time). Both groups demonstrated within-group gains on the Fugl-Meyer Upper Extremity test (impairment) and University of Maryland Arm Questionnaire for Stroke (functional use). fMRI subset analyses showed motor cortex (primary and premotor) activation during hand movement was significantly increased by sequential combination training but not by task oriented training alone. CONCLUSIONS: Sequentially combining a proximal bilateral before a unilateral task-oriented training may be an effective way to facilitate gains in arm and hand function in those with moderate to severe paresis post stroke compared to unilateral task oriented training alone. PMID- 25494636 TI - Development of bio-based fine chemical production through synthetic bioengineering. AB - Fine chemicals that are physiologically active, such as pharmaceuticals, cosmetics, nutritional supplements, flavoring agents as well as additives for foods, feed, and fertilizer are produced by enzymatically or through microbial fermentation. The identification of enzymes that catalyze the target reaction makes possible the enzymatic synthesis of the desired fine chemical. The genes encoding these enzymes are then introduced into suitable microbial hosts that are cultured with inexpensive, naturally abundant carbon sources, and other nutrients. Metabolic engineering create efficient microbial cell factories for producing chemicals at higher yields. Molecular genetic techniques are then used to optimize metabolic pathways of genetically and metabolically well characterized hosts. Synthetic bioengineering represents a novel approach to employ a combination of computer simulation and metabolic analysis to design artificial metabolic pathways suitable for mass production of target chemicals in host strains. In the present review, we summarize recent studies on bio-based fine chemical production and assess the potential of synthetic bioengineering for further improving their productivity. PMID- 25494639 TI - Is Pica under-reported in children with sickle cell disease? A pilot study in a Belgian cohort. AB - BACKGROUND: For centuries, writers have recorded their observations on pica. Nevertheless the association of pica with sickle cell disease (SCD) was poorly documented. METHODS: Cross-sectional evaluation performed on SCD children and caregivers attending the outpatient clinic who were invited to complete questionnaires assessing behavior of pica. RESULTS: Out of 55 sickle cell children, 31(56.4%) reported practicing pica regularly. Substances ingested by patients covered a broad spectrum. Compared with the non-pica group, subjects who reported pica were younger and had lower hemoglobin (8.3 g/dl (7.6-9.7) vs. 9.1 g/dl (7.9-10.5): P < 0.01). The level of ferritin, zinc, copper, and lead was similar between the pica and non-pica groups (P > 0.05). Discussion In this series, there are many substances consumed by SCD children and adolescents, and we did not find an occurrence of similar substances among this select group. Pica children were younger and more anemic than non-pica patients. CONCLUSION: This study suggests that pica remains an unknown and under-reported clinical problem in children with SCD and seems to be related to the severity of anemia. The next step of this project aims to clarify causal mechanisms for pica and its association with SCD in a larger population. PMID- 25494638 TI - In vitro histone lysine methylation by NSD1, NSD2/MMSET/WHSC1 and NSD3/WHSC1L. AB - BACKGROUND: Histone lysine methylation has a pivotal role in regulating the chromatin. Histone modifiers, including histone methyl transferases (HMTases), have clear roles in human carcinogenesis but the extent of their functions and regulation are not well understood. The NSD family of HMTases comprised of three members (NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L) are oncogenes aberrantly expressed in several cancers, suggesting their potential to serve as novel therapeutic targets. However, the substrate specificity of the NSDs and the molecular mechanism of histones H3 and H4 recognition and methylation have not yet been established. RESULTS: Herein, we investigated the in vitro mechanisms of histones H3 and H4 recognition and modifications by the catalytic domain of NSD family members. In this study, we quantified in vitro mono-, di- and tri- methylations on H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20 by the carboxyl terminal domain (CTD) of NSD1, NSD2 and NSD3, using histone as substrate. Next, we used a molecular modelling approach and docked 6-mer peptides H3K4 a.a. 1-7; H3K9 a.a. 5-11; H3K27 a.a. 23-29; H3K36 a.a. 32-38; H3K79 a.a. 75-81; H4K20 a.a. 16-22 with the catalytic domain of the NSDs to provide insight into lysine-marks recognition and methylation on histones H3 and H4. CONCLUSIONS: Our data highlight the versatility of NSD1, NSD2, and NSD3 for recognizing and methylating several histone lysine marks on histones H3 and H4. Our work provides a basis to design selective and specific NSDs inhibitors. We discuss the relevance of our findings for the development of NSD inhibitors amenable for novel chemotherapies. PMID- 25494637 TI - Genetics and timing of sex determination in the East African cichlid fish Astatotilapia burtoni. AB - BACKGROUND: The factors determining sex are diverse in vertebrates and especially so in teleost fishes. Only a handful of master sex-determining genes have been identified, however great efforts have been undertaken to characterize the subsequent genetic network of sex differentiation in various organisms. East African cichlids offer an ideal model system to study the complexity of sexual development, since many different sex-determining mechanisms occur in closely related species of this fish family. Here, we investigated the sex-determining system and gene expression profiles during male development of Astatotilapia burtoni, a member of the rapidly radiating and exceptionally species-rich haplochromine lineage. RESULTS: Crossing experiments with hormonally sex-reversed fish provided evidence for an XX-XY sex determination system in A. burtoni. Resultant all-male broods were used to assess gene expression patterns throughout development of a set of candidate genes, previously characterized in adult cichlids only. CONCLUSIONS: We could identify the onset of gonad sexual differentiation at 11-12 dpf. The expression profiles identified wnt4B and wt1A as the earliest gonad markers in A. burtoni. Furthermore we identified late testis genes (cyp19a1A, gsdf, dmrt1 and gata4), and brain markers (ctnnb1A, ctnnb1B, dax1A, foxl2, foxl3, nanos1A, nanos1B, rspo1, sf-1, sox9A and sox9B). PMID- 25494640 TI - Clinical and microbiological characteristics of bloodstream infections due to AmpC beta-lactamase producing Enterobacteriaceae: an active surveillance cohort in a large centralized Canadian region. AB - BACKGROUND: The objective of this study was to describe the clinical and microbiological characteristics of bloodstream infections (BSIs) due to AmpC producing Enterobacteriaceae (AE) in a large centralized Canadian region over a 9 year period. METHODS: An active surveillance cohort design in Calgary, Canada. RESULTS: A cohort of 458 episodes of BSIs caused by AE was assembled for analysis. The majority of infections were of nosocomial origin with unknown sources. Enterobacter spp. was the most common species while BSIs due to Serratia spp. had a significant higher mortality when compared to other AE. Delays in empiric or definitive antibiotic therapy were not associated with a difference in outcome. However, patients that did not receive any empiric antimicrobial therapy had increased mortality (3/5; 60% vs. 57/453; 13%; p = 0.018) as did those that did not receive definitive therapy (6/17; 35% vs. 54/441; 12%; p = 0.015). CONCLUSIONS: Delays in therapy were not associated with adverse outcomes although lack of active therapy was associated with increased mortality. A strategy for BSIs due to AE where beta-lactam antibiotics (including oxyimino-cephalosporins) are used initially followed by a switch to non-beta-lactam antibiotics once susceptibility results are available is effective. PMID- 25494642 TI - Photoactive PDI-cobalt complex immobilized on reduced graphene oxide for photoelectrochemical water splitting. AB - We report the synthesis of a perylene derivative (perylene tetracarboxylic di(propyl imidazole), abbreviated as PDI) that is coordinated with Co(II) ions to form a coordination polymer [PDI-Co(Cl)2(H2O)2]n (abbreviated as PDI-Co). The PDI Co complex combines the photoactivity of the perylene dye with the electrocatalytic activity of the "Co(II)" center for photoelectrochemical hydrogen evolution reaction (HER). To improve charge transfer interactions, the PDI-Co complex is immobilized on reduced graphene oxide (rGO) via noncovalent interactions to form the rGO-PDI-Co complex. The composite shows good performance in multiple cycle testing and the turnover number (TON vs Co(II)) of this hybrid material for hydrogen evolution reaction (754 after 5 h) is considerably higher than previously reported dye-sensitized cobalt-based catalysts. PMID- 25494641 TI - Hospital bed occupancy for rotavirus and all cause acute gastroenteritis in two Finnish hospitals before and after the implementation of the national rotavirus vaccination program with RotaTeq(r). AB - BACKGROUND: Vaccination-impact studies of the live-attenuated pentavalent oral vaccine Rotateq(r) have demonstrated that the burden of rotavirus gastroenteritis has been reduced significantly after the introduction of RotaTeq(r) vaccination, but less is known about the benefit of this vaccination on hospital overcrowding. METHODS: As part of an observational surveillance conducted during the RV seasons 2000/2001 to 2011/2012, we analysed hospital discharge data collected retrospectively from two Finnish hospitals (Oulu and Tampere), concerning ICD 10 codes A00-09 (acute gastroenteritis, AGE) and A08.0 (rotaviral acute gastroenteritis RV AGE). We estimated the reduction in the number of beds occupied and analysed the bed occupancy rate, for RV AGE and all cause AGE, among 0-16 year-old children, before and after the implementation of the RV immunisation program. RESULTS: The rate of bed days occupied for RV AGE was reduced by 86% (95% CI 66%-94%) in Tampere and 79% (95% CI 47%-92%) in Oulu after RV vaccination implementation. For all cause AGE, reduction was 50% (95% CI 29% to 65%) in Tampere and 70% (95% CI 58% to 79%) in Oulu. Results were similar among 0-2 year-old children. This effect was also observed on overcrowding in both hospitals, with a bed occupancy rate for all cause AGE >25% in only 1% of the time in Tampere and 9% in Oulu after the implementation of the immunisation program, compared to 13% and 48% in the pre-vaccination period respectively. After extrapolation to the whole country, the annual number of prevented hospitalizations for all cause AGE in the post-vaccination period in Finland was estimated at 1,646 and 2,303 admissions for 0-2 and 0-16 year-old children respectively. CONCLUSIONS: This study demonstrated that universal RV vaccination is associated with a clear decrease in the number of bed days and occupancy rates for RV AGE and all cause AGE. Positive consequences include increase in quality of care and a better healthcare management during winter epidemics. PMID- 25494643 TI - Prokaryotic arsenate reductase enhances arsenate resistance in Mammalian cells. AB - Arsenic is a well-known heavy metal toxicant in the environment. Bioremediation of heavy metals has been proposed as a low-cost and eco-friendly method. This article described some of recent patents on transgenic plants with enhanced heavy metal resistance. Further, to test whether genetic modification of mammalian cells could render higher arsenic resistance, a prokaryotic arsenic reductase gene arsC was transfected into human liver cancer cell HepG2. In the stably transfected cells, the expression level of arsC gene was determined by quantitative real-time PCR. Results showed that arsC was expressed in HepG2 cells and the expression was upregulated by 3 folds upon arsenate induction. To further test whether arsC has function in HepG2 cells, the viability of HepG2-pCI-ArsC cells exposed to arsenite or arsenate was compared to that of HepG2-pCI cells without arsC gene. The results indicated that arsC increased the viability of HepG2 cells by 25% in arsenate, but not in arsenite. And the test of reducing ability of stably transfected cells revealed that the concentration of accumulated trivalent arsenic increased by 25% in HepG2-pCI-ArsC cells. To determine the intracellular localization of ArsC, a fusion vector with fluorescent marker pEGFP-N1-ArsC was constructed and transfected into.HepG2. Laser confocal microscopy showed that EGFP-ArsC fusion protein was distributed throughout the cells. Taken together, these results demonstrated that prokaryotic arsenic resistant gene arsC integrated successfully into HepG2 genome and enhanced arsenate resistance of HepG2, which brought new insights of arsenic detoxification in mammalian cells. PMID- 25494644 TI - Molecular mechanism of the inhibition and remodeling of human islet amyloid polypeptide (hIAPP(1-37)) oligomer by resveratrol from molecular dynamics simulation. AB - Natural polyphenols are one of the most actively investigated categories of amyloid inhibitors, and resveratrol has recently been reported to inhibit and remodel the human islet amyloid polypeptide (hIAPP) oligomers and fibrils. However, the exact mechanism of its action is still unknown, especially for the full-length hIAPP1-37. To this end, we performed all-atom molecular dynamics simulations for hIAPP1-37 pentamer with and without resveratrol. The obtained results show that the binding of resveratrol is able to cause remarkable conformational changes of hIAPP1-37 pentamer, in terms of secondary structures, order degree, and morphology. By clustering analysis, two possible binding sites of resveratrol on the hIAPP1-37 pentamer were found, located at the grooves of the top and bottom surfaces of beta-sheet layer, respectively. After the binding free energy calculation and residue energy decomposition, it can be concluded that the bottom site is the more possible one, and that the nonpolar interactions act as the driving force for the binding of hIAPP1-37 to resveratrol. In addition, Arg11 is the most important residue for the binding of resveratrol. The full understanding of inhibitory mechanism of resveratrol on the hIAPP1-37 oligomer, and the identification of its binding sites on this protein are helpful for the future design and discovery of new amyloid inhibitors. PMID- 25494648 TI - Polyaniline-assisted synthesis of Si@C/RGO as anode material for rechargeable lithium-ion batteries. AB - A novel approach to fabricate Si@carbon/reduced graphene oxides composite (Si@C/RGO) assisted by polyaniline (PANI) is developed. Here, PANI not only serves as "glue" to combine Si nanoparticles with graphene oxides through electrostatic attraction but also can be pyrolyzed as carbon layer coated on Si particles during subsequent annealing treatment. The assembled composite delivers high reversible capacity of 1121 mAh g(-1) at a current density of 0.9 A g(-1) over 230 cycles with improved initial Coulombic efficiency of 81.1%, while the bare Si and Si@carbon only retain specific capacity of 50 and 495 mAh g(-1) at 0.3 A g(-1) after 50 cycles, respectively. The enhanced electrochemical performance of Si@C/RGO can be attributed to the dual protection of carbon layer and graphene sheets, which are synergistically capable of overcoming the drawbacks of inner Si particles such as huge volume change and low conductivity and providing protective and conductive matrix to buffer the volume variation, prevent the Si particles from aggregating, enhance the conductivity, and stabilize the solid-electrolyte interface membrane during cycling. Importantly, this method opens a novel, universal graphene coating strategy, which can be extended to other fascinating anode and cathode materials. PMID- 25494647 TI - Biotransformation on the triterpenoid saponin of Ardisia gigantifolia by Aspergillus avenaceus AS 3.4454. AB - Compound 1, a triterpenoid saponin from Ardisia gigantifolia Stapf. showing potential anti-tumor activity, was transformed into three derivatives (2-4) by Aspergillus avenaceus 3.4454. Among them, compounds 2 and 3 are new compounds. Their structures were elucidated on the basis of 1D NMR, 2D NMR, HR-ESI-MS, and optical rotation data. Compounds 1-3 were evaluated for their cytotoxicity against human hepatocellular carcinoma and normal liver cells by cell counting kit 8 colorimetric assay. Compound 3 displayed better cytotoxicity against Bel 7402 and HepG2 cell lines and much weaker cytotoxicity against normal liver L02 cell than that of positive control (epirubicin hydrochloride). PMID- 25494645 TI - VDR regulation of microRNA differs across prostate cell models suggesting extremely flexible control of transcription. AB - The Vitamin D Receptor (VDR) is a member of the nuclear receptor superfamily and is of therapeutic interest in cancer and other settings. Regulation of microRNA (miRNA) by the VDR appears to be important to mediate its actions, for example, to control cell growth. To identify if and to what extent VDR-regulated miRNA patterns change in prostate cancer progression, we undertook miRNA microarray analyses in 7 cell models representing non-malignant and malignant prostate cells (RWPE-1, RWPE-2, HPr1, HPr1AR, LNCaP, LNCaP-C4-2, and PC-3). To focus on primary VDR regulatory events, we undertook expression analyses after 30 minutes treatment with 1alpha,25(OH)2D3. Across all models, 111 miRNAs were significantly modulated by 1alpha,25(OH)2D3 treatment. Of these, only 5 miRNAs were modulated in more than one cell model, and of these, only 3 miRNAs were modulated in the same direction. The patterns of miRNA regulation, and the networks they targeted, significantly distinguished the different cell types. Integration of 1alpha,25(OH)2D3-regulated miRNAs with published VDR ChIP-seq data showed significant enrichment of VDR peaks in flanking regions of miRNAs. Furthermore, mRNA and miRNA expression analyses in non-malignant RWPE-1 cells revealed patterns of miRNA and mRNA co-regulation; specifically, 13 significant reciprocal patterns were identified and these patterns were also observed in TCGA prostate cancer data. Lastly, motif search analysis revealed differential motif enrichment within VDR peaks flanking mRNA compared to miRNA genes. Together, this study revealed that miRNAs are rapidly regulated in a highly cell-type specific manner, and are significantly co-integrated with mRNA regulation. PMID- 25494649 TI - Surface adsorption and electrochemical reduction of 2,4,6-trinitrotoluene on vanadium dioxide. AB - The electrochemical reduction of 2,4,6-trinitrotoluene (TNT) was investigated using films of vanadium dioxide. Three distinct reduction peaks were observed in the potential range of -0.50 to -0.90 V (vs an Ag/AgCl reference electrode), corresponding to the electrochemical reduction of the three nitro-groups on the TNT molecule. Adsorptive stripping voltammetry was performed to achieve detection down to 1 MUg/L (4.4 nM), revealing a linear response to TNT concentration. These results are the first describing the use of VO2 films as an electrochemical sensor and open new avenues for further electrochemical research using this unique material. PMID- 25494650 TI - CNS drug design: balancing physicochemical properties for optimal brain exposure. AB - The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochemical properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most critical physicochemical and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chemistry strategies toward molecules with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided. PMID- 25494651 TI - Ameliorative potential of ferulic acid in vincristine-induced painful neuropathy in rats: An evidence of behavioral and biochemical examination. AB - The present study was designed to investigate the effect of ferulic acid (FA) in vincristine-induced neuropathic pain in rats. Vincristine (50 ug/kg, i.p. for 10 consecutive days) was administered to induce painful neuropathy in rats. Various pain sensitive tests, viz., pinprick, hot plate, paint-brush, and acetone test were performed on different days (1, 6, 14, and 21) to assess the degree of mechanical hyperalgesia, heat hyperalgesia, mechanical dynamic allodynia, and cold allodynia, respectively. The electrophysiological and histopathological evaluations were also investigated. The tissue thiobarbituric acid reactive species (TBARS), reduced glutathione (GSH), myeloperoxidase (MPO), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), and total calcium were measured as the markers of inflammation and oxidative stress. FA (50 and 100 mg/kg, i.p.) and gabapentin (10 mg/kg, p.o.) were administered for 11 days. Administration of FA attenuated the vincristine-induced behavioral alteration along with electrophysiological and histopathological changes significantly (P < 0.05). FA also attenuated the vincristine-induced oxidative stress (TBARS, GSH, and total calcium levels) and inflammation (MPO, TNF-alpha, IL-6, and IL-10). It may be concluded that FA has ameliorative potential in mitigation of the painful states associated with vincristine-induced painful neuropathy that may further be attributed to anti-inflammatory actions with subsequent reduction in oxidative stress. PMID- 25494652 TI - Use of a Novel Abdominal Aortic and Junctional Tourniquet to Reduce or Eliminate Flow in the Brachial and Popliteal Arteries in Human Subjects. AB - BACKGROUND: Penetrating injuries of the proximal large arteries are a common cause of death on the battlefield due to rapid exsanguination. Applying an effective tourniquet to stop bleeding at the axillary and proximal femoral arteries (junctional sites) is difficult. Prior studies have shown that the Abdominal Aortic and Junctional Tourniquet (AAJT) effectively reduced blood flow in the common femoral artery with application of the device around the lower abdomen. Our objective was to determine the effectiveness of the AAJT to stop blood flow in the proximal femoral artery (PFA), and the axillary artery (AA). METHOD: This was a prospective observational trial using human volunteers. The AAJT consists of a wedge-shaped bladder and integrated strap. The bladder has an integrated manometer, which is used to measure the pressure in the bladder. For the AA, the AAJT was placed over the axillary junction at the anterior axillary line with the strap placed across the contralateral shoulder. For the PFA, the AAJT bladder was placed over the right groin with the strap positioned across both femoral trochanters. Spectral Doppler measurements were taken of the PFA and AA at baseline and as the bladder was inflated. Collected data included pressure of the AAJT. PMID- 25494653 TI - Revisiting peptide identification by high-accuracy mass spectrometry: problems associated with the use of narrow mass precursor windows. AB - Peptide identification is increasingly achieved through database searches in which mass precursor tolerance is set in the ppm range. This trend is driven by the high resolution and accuracy of modern mass spectrometers and the belief that the quality of peptide identification is fully controlled by estimating the false discovery rate (FDR) using the decoy-target approach. However, narrowing mass tolerance decreases the number of sequence candidates, and several authors have raised concerns that these search conditions can introduce inaccuracies. Here, we demonstrate that when scores that only depend on one sequence candidate are used, decoy-based estimates of the number of false positive identifications are accurate even with an average number of candidates of just 200, to the point that remarkably accurate FDR predictions can be made in completely different search conditions. However, when scores that are constructed taking information from additional sequence candidates are used together with low precursor mass tolerances, the proportion of peptides incorrectly identified may become significantly higher than the FDR estimated by the target-decoy approach. Our results suggest that with this kind of score the high mass accuracy of modern mass spectrometers should be exploited by using wide mass windows followed by postscoring mass filtering algorithms. PMID- 25494654 TI - Can we hear morphological complexity before words are complex? AB - Previous research has shown that listeners can tell the difference between phonemically identical onsets of monomorphemic words (e.g., cap and captain) using acoustic cues (Davis, Marslen-Wilson, & Gaskell, 2002). This study investigates whether this finding extends to multimorphemic words, asking whether listeners can use phonetic information to distinguish unsuffixed from suffixed words before they differ phonemically (e.g., clue vs. clueless). We report 4 experiments investigating this issue using forced-choice identification and mouse tracking tasks. We find that listeners are in fact able to distinguish mono- and multimorphemic words using only subphonemic information. Our experiments reveal that duration information alone is sufficient to make this discrimination and that listeners make use of an abstract rule that relates duration to morphological structure. The implications of these results for theories of morphological processing are discussed. PMID- 25494655 TI - A combination of genistein and magnesium enhances the vasodilatory effect via an eNOS pathway and BK(Ca) current amplification. AB - The phytoestrogen genistein (GST) and magnesium have been independently shown to regulate vascular tone; however, their individual vasodilatory effects are limited. The aim of this study was to examine the combined effects of GST plus magnesium on vascular tone in mesenteric arteries. The effects of pretreatment with GST (0-200 MUmol/L), MgCl2 (0-4.8 mmol/L) and GST plus MgCl2 on 10 MUmol/L phenylephrine (PE) precontracted mesenteric arteries in rats were assessed by measuring isometric force. BK(Ca) currents were detected by the patch clamp method. GST caused concentration- and partial endothelium-dependent relaxation. Magnesium resulted in dual adjustment of vascular tone. Magnesium-free solution eliminated the vasodilatation of GST in both endothelium-intact and denuded rings. GST (50 MUmol/L) plus magnesium (4.8 mmol/L) caused stronger relaxation in both endothelium-intact and denuded rings. Pretreatment with the nitric oxide synthase (NOS) inhibitor L-N-nitroarginine methyl ester (L-NAME, 100 MUmol/L) significantly inhibited the effects of GST, high magnesium, and the combination of GST and magnesium. BK(Ca) currents were amplified to a greater extent when GST (50 MUmol/L) was combined with 4.8 versus 1.2 mmol/L Mg(2+). Our data suggest that GST plus magnesium provides enhanced vasodilatory effects in rat mesenteric arteries compared with that observed when either is used separately, which was related to an eNOS pathway and BK(Ca) current amplification. PMID- 25494656 TI - Specific ion binding to carboxylic surface groups and the pH dependence of the Hofmeister series. AB - Ion binding to acidic groups is a central mechanism for ion-specificity of macromolecules and surfaces. Depending on pH, acidic groups are either protonated or deprotonated and thus change not only charge but also chemical structure with crucial implications for their interaction with ions. In a two-step modeling approach, we first determine single-ion surface interaction potentials for a few selected halide and alkali ions at uncharged carboxyl (COOH) and charged carboxylate (COO(-)) surface groups from atomistic MD simulations with explicit water. Care is taken to subtract the bare Coulomb contribution due to the net charge of the carboxylate group and thereby to extract the nonelectrostatic ion surface potential. Even at this stage, pronounced ion-specific effects are observed and the ion surface affinity strongly depends on whether the carboxyl group is protonated or not. In the second step, the ion surface interaction potentials are used in a Poisson-Boltzmann model to calculate the surface charge and the potential distribution in the solution depending on salt type, salt concentration, and solution pH in a self-consistent manner. Hofmeister phase diagrams are derived on the basis of the long-ranged forces between two carboxyl functionalized surfaces. For cations we predict direct, reversed, and altered Hofmeister series as a function of the pH, qualitatively similar to recent experimental results for silica surfaces. The Hofmeister series reversal for cations is rationalized by a reversal of the single-cation affinity to the carboxyl group depending on its protonation state: the deprotonated carboxylate (COO(-)) surface group interacts most favorably with small cations such as Li(+) and Na(+), whereas the protonated carboxyl (COOH) surface group interacts most favorably with large cations such as Cs(+) and thus acts similarly to a hydrophobic surface group. Our results provide a general mechanism for the pH dependent reversal of the Hofmeister series due to the different specific ion binding to protonated and deprotonated surface groups. PMID- 25494658 TI - Clinical, microbial, and immune responses observed in patients with diabetes after treatment for gingivitis: a three-month randomized clinical trial. AB - BACKGROUND: Although patients with diabetes are frequently affected by periodontitis, only a few investigations have focused on gingivitis in this at risk population. This randomized placebo-controlled clinical trial compared the response to a gingivitis treatment protocol that combined mechanical procedures and daily use of an essential oil (EO) mouthrinse between patients with and without diabetes. METHODS: The whole-mouth periodontal probing depth (PD), gingival index (GI), and plaque index (PI) were monitored in gingivitis cases among systemically healthy patients (n = 60) or those with diabetes (n = 60) at baseline and 3 months after treatment. Levels of Porphyromonas gingivalis, Tannerella forsythia, Aggregatibacter actinomycetemcomitans, and total bacterial load were determined by a real-time polymerase chain reaction in intrasulci plaque samples. The volume of gingival crevicular fluid (GCF) was quantified, and interleukin-1beta (IL-1beta) levels were determined in GCF samples. After a full mouth ultrasonic debridement, patients were randomly assigned to an EO or a placebo rinse for 90 days (40 mL/day). The data were analyzed through repeated measures analysis of variance and multiple comparisons Tukey tests (P <0.05). RESULTS: GI was more severe in the diabetes group. Diabetes impaired GI and reduced GCF volume. PD, bacterial levels, and IL-1beta improved similarly in both systemic conditions. The adjunctive use of EO provided greater reductions of PI, GI, total bacterial load, T. forsythia, A. actinomycetemcomitans, and GCF volume. CONCLUSIONS: Response to gingivitis treatment in patients with diabetes can slightly differ from that in patients without diabetes. Daily use of an EO mouthrinse after ultrasonic debridement benefited patients with and without diabetes. PMID- 25494657 TI - PET/CT-guided treatment planning for paediatric cancer patients: a simulation study of proton and conventional photon therapy. AB - OBJECTIVE: To investigate the impact of including fluorine-18 fludeoxyglucose ((18)F-FDG) positron emission tomography (PET) scanning in the planning of paediatric radiotherapy (RT). METHODS: Target volumes were first delineated without and subsequently re-delineated with access to (18)F-FDG PET scan information, on duplicate CT sets. RT plans were generated for three-dimensional conformal photon RT (3DCRT) and intensity-modulated proton therapy (IMPT). The results were evaluated by comparison of target volumes, target dose coverage parameters, normal tissue complication probability (NTCP) and estimated risk of secondary cancer (SC). RESULTS: Considerable deviations between CT- and PET/CT guided target volumes were seen in 3 out of the 11 patients studied. However, averaging over the whole cohort, CT or PET/CT guidance introduced no significant difference in the shape or size of the target volumes, target dose coverage, irradiated volumes, estimated NTCP or SC risk, neither for IMPT nor 3DCRT. CONCLUSION: Our results imply that the inclusion of PET/CT scans in the RT planning process could have considerable impact for individual patients. There were no general trends of increasing or decreasing irradiated volumes, suggesting that the long-term morbidity of RT in childhood would on average remain largely unaffected. ADVANCES IN KNOWLEDGE: (18)F-FDG PET-based RT planning does not systematically change NTCP or SC risk for paediatric cancer patients compared with CT only. 3 out of 11 patients had a distinct change of target volumes when PET-guided planning was introduced. Dice and mismatch metrics are not sufficient to assess the consequences of target volume differences in the context of RT. PMID- 25494659 TI - Evaluation of biochemical parameters and local and systemic levels of osteoactive and B-cell stimulatory factors in gestational diabetes in the presence or absence of gingivitis. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is defined as varying glucose intolerance, with first onset or recognition in pregnancy. This study evaluates clinical and biochemical parameters in a possible association between GDM and gingivitis. METHODS: A total of 167 pregnant females was included in the study. There were 101 females with GDM and 66 females without GDM. Subgroups were created according to the presence or absence of gingival inflammation. Plaque index, bleeding on probing, and probing depth were recorded at four sites per tooth. Serum, saliva, and gingival crevicular fluid (GCF) levels of interleukin (IL)-6, IL-8, soluble receptor activator of nuclear factor-kappa B ligand (sRANKL), osteoprotegerin (OPG), B-cell activating factor (BAFF), and a proliferation-inducing ligand (APRIL) were determined by enzyme-linked immunosorbent assay. Data were analyzed by Kruskal-Wallis and Mann-Whitney U tests and Spearman correlation analysis. RESULTS: Age and anthropometric indices were higher in the GDM than non-GDM group (P <0.0001). Clinical periodontal recordings, serum BAFF, IL-8, and saliva sRANKL levels were higher in the GDM group (P <0.05). Saliva IL-6 level was higher in the GDM with gingivitis group than non-GDM with gingivitis group (P = 0.044). Serum and GCF BAFF (P <0.0001), serum, saliva, and GCF APRIL (P <0.0001; P <0.0001; P = 0.032, respectively), GCF OPG (P = 0.036), and serum and saliva sRANKL (P <0.0001) were higher in the GDM with gingivitis group than GDM without gingivitis group. CONCLUSIONS: The inflammatory response seems to be more pronounced in females with GDM. The observed increase in both local and systemic levels of inflammatory cytokines may suggest an interaction between gingivitis and GDM. PMID- 25494660 TI - Effect of Porphyromonas gingivalis lipopolysaccharide on bone marrow mesenchymal stem cell osteogenesis on a titanium nanosurface. AB - BACKGROUND: Titanium (Ti) dental implants have been widely used for prosthetic reconstruction of dentition. Unfortunately, peri-implantitis can result in failure of dental implant osseointegration. Lipopolysaccharide (LPS) acts as a chronic inflammatory stimulus and maintains peri-implant inflammation, worsening the prognosis for implant osseointegration. The purpose of this study is to determine the effects of 10 M NaOH-modified Ti surface with nanonetwork structure on the proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMMSCs) in the context of Porphyromonas gingivalis LPS exposure. METHODS: Titanium disks treated with 10 M NaOH solution and control were incubated with BMMSCs and exposed to P. gingivalis LPS (0, 0.1, or 1 MUg/mL). The effects of the modified nanonetwork structure on osteogenic differentiation of rat BMMSCs were evaluated in the context of different concentrations of P. gingivalis LPS exposure. RESULTS: Rat BMMSCs on the 10 M NaOH-modified Ti surface with nanonetwork structure had higher levels of osteogenesis-related gene expression and significantly greater cell proliferation, alkaline phosphatase activity, and extracellular matrix deposition and mineralization than cells on the untreated Ti surfaces, in all the groups with different doses of P. gingivalis LPS exposure. CONCLUSION: The 10 M NaOH modified Ti surface with nanonetwork structure has better endotoxin tolerance under P. gingivalis LPS exposure than the non-modified surface. PMID- 25494662 TI - A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia. AB - CONTEXT: Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm. OBJECTIVES: The primary objective was to characterize the pharmacokinetic profile of Chronocort, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort with dose titration. DESIGN, SETTING, AND PATIENTS: Sixteen adults (eight females) with classic CAH participated in an open-label, nonrandomized, Phase 2 study at the National Institutes of Health Clinical Center. Twenty-four hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort. Chronocort was initiated at 10 mg (0700 h) and 20 mg (2300 h). Dose titration was performed based on androstenedione and 17 hydroxyprogresterone (17-OHP) levels and clinical symptomatology. MAIN OUTCOME MEASURES: The primary outcome was cortisol pharmacokinetics of Chronocort and secondary outcomes included biomarkers of CAH control (androstenedione and 17 OHP). RESULTS: In patients with CAH, Chronocort cortisol profiles were similar to physiologic cortisol secretion. Compared with conventional therapy, 6 months of Chronocort resulted in a decrease in hydrocortisone dose equivalent (28 +/- 11.8 vs 25.9 +/- 7.1 mg/d), with lower 24-hour (P = .004), morning (0700-1500 h; P = .002), and afternoon (1500-2300 h; P = .011) androstenedione area under the curve (AUC) and lower 24-hour (P = .023) and morning (0700-1500 h; P = .02) 17-OHP AUC. CONCLUSIONS: Twice-daily Chronocort approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH. PMID- 25494663 TI - Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer. AB - Overexpression of HER2 - found in approximately 15-20% of all breast cancers - is a negative prognostic factor. Although trastuzumab significantly improves the prognosis of HER2-positive breast cancer, half of the patients with metastatic breast cancer experience disease progression within 1 year. Pertuzumab is a novel HER2-targeted humanized monoclonal antibody that binds to the dimerization domain of HER2 and acts synergically with trastuzumab in inhibiting tumor progression. The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression-free survival and overall survival without increasing severe adverse events. Conclusively, pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer. Furthermore, various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present. Thus, pertuzumab has been becoming important for the treatment of patients with HER2 positive metastatic breast cancer. PMID- 25494661 TI - The choice of normative pediatric reference database changes spine bone mineral density Z-scores but not the relationship between bone mineral density and prevalent vertebral fractures. AB - OBJECTIVES: Our objectives were to assess the magnitude of the disparity in lumbar spine bone mineral density (LSBMD) Z-scores generated by different reference databases and to evaluate whether the relationship between LSBMD Z scores and vertebral fractures (VF) varies by choice of database. PATIENTS AND DESIGN: Children with leukemia underwent LSBMD by cross-calibrated dual-energy x ray absorptiometry, with Z-scores generated according to Hologic and Lunar databases. VF were assessed by the Genant method on spine radiographs. Logistic regression was used to assess the association between fractures and LSBMD Z scores. Net reclassification improvement and area under the receiver operating characteristic curve were calculated to assess the predictive accuracy of LSBMD Z scores for VF. RESULTS: For the 186 children from 0 to 18 years of age, 6 different age ranges were studied. The Z-scores generated for the 0 to 18 group were highly correlated (r >= 0.90), but the proportion of children with LSBMD Z scores <=-2.0 among those with VF varied substantially (from 38-66%). Odds ratios (OR) for the association between LSBMD Z-score and VF were similar regardless of database (OR = 1.92, 95% confidence interval 1.44, 2.56 to OR = 2.70, 95% confidence interval 1.70, 4.28). Area under the receiver operating characteristic curve and net reclassification improvement ranged from 0.71 to 0.75 and -0.15 to 0.07, respectively. CONCLUSIONS: Although the use of a LSBMD Z-score threshold as part of the definition of osteoporosis in a child with VF does not appear valid, the study of relationships between BMD and VF is valid regardless of the BMD database that is used. PMID- 25494664 TI - Transparent exopolymer particles: from aquatic environments and engineered systems to membrane biofouling. AB - Transparent exopolymer particles (TEP) are ubiquitous in marine and freshwater environments. For the past two decades, the distribution and ecological roles of these polysaccharide microgels in aquatic systems were extensively investigated. More recent studies have implicated TEP as an active agent in biofilm formation and membrane fouling. Since biofouling is one of the main hurdles for efficient operation of membrane-based technologies, there is a heightened interest in understanding the role of TEP in engineered water systems. In this review, we describe relevant TEP terminologies while critically discussing TEP biological origin, biochemical and physical characteristics, and occurrence and distributions in aquatic systems. Moreover, we examine the contribution of TEP to biofouling of various membrane technologies used in the desalination and water/wastewater treatment industry. Emphasis is given to the link between TEP physicochemical and biological properties and the underlying biofouling mechanisms. We highlight that thorough understanding of TEP dynamics in feedwater sources, pretreatment challenges, and biofouling mechanisms will lead to better management of fouling/biofouling in membrane technologies. PMID- 25494665 TI - Is ethnic density associated with risk of child pedestrian injury? A comparison of inter-census changes in ethnic populations and injury rates. AB - OBJECTIVES: Research on inequalities in child pedestrian injury risk has identified some puzzling trends: although, in general, living in more affluent areas protects children from injury, this is not true for those in some minority ethnic groups. This study aimed to identify whether 'group density' effects are associated with injury risk, and whether taking these into account alters the relationship between area deprivation and injury risk. 'Group density' effects exist when ethnic minorities living in an area with a higher proportion of people from a similar ethnic group enjoy better health than those who live in areas with a lower proportion, even though areas with dense minority ethnic populations can be relatively more materially disadvantaged. DESIGN: This study utilised variation in minority ethnic densities in London between two census periods to identify any associations between group density and injury risk. Using police data on road traffic injury and population census data from 2001 to 2011, the numbers of 'White,' 'Asian' and 'Black' child pedestrian injuries in an area were modelled as a function of the percentage of the population in that area that are 'White,' 'Asian' and 'Black,' controlling for socio-economic disadvantage and characteristics of the road environment. RESULTS: There was strong evidence (p < 0.001) of a negative association between 'Black' population density and 'Black' child pedestrian injury risk [incidence (of injury) rate ratios (IRR) 0.575, 95% CI 0.515-0.642]. There was weak evidence (p = 0.083) of a negative association between 'Asian' density and 'Asian' child pedestrian injury risk (IRR 0.901, 95% CI 0.801-1.014) and no evidence (p = 0.412) of an association between 'White' density and 'White' child pedestrian injury risk (IRR 1.075, 95% CI 0.904-1.279). When group density effects are taken into account, area deprivation is associated with injury risk of all ethnic groups. CONCLUSIONS: Group density appears to protect 'Black' children living in London against pedestrian injury risk. These findings suggest that future research should focus on structural properties of societies to explain the relationships between minority ethnicity and risk. PMID- 25494666 TI - Predicting outcomes in acute severe ulcerative colitis. AB - Response to corticosteroid treatment in acute severe ulcerative colitis (ASUC) has changed very little in the past 50 years. Predicting those at risk at an early stage helps stratify patients into those who may require second line therapy or early surgical treatment. Traditionally, risk scores have used a combination of clinical, radiological and biochemical parameters; established indices include the 'Travis' and 'Ho' scores. Recently, inflammatory bowel disease genetic risk alleles have been built into models to predict outcome in ASUC. Given the multifactorial nature of inflammatory bowel disease pathogenesis, in the future, composite scores integrating clinical, biochemical, serological, genetic and other '-omic' data will be increasingly investigated. Although these new genetic prediction models are promising, they have yet to supplant traditional scores, which remain the best practice. In this modern era of rescue therapies in ASUC, robust scoring systems to predict failure of ciclosporine and infliximab must be devised. PMID- 25494667 TI - Adatoms underneath single porphyrin molecules on Au(111). AB - The adsorption of porphyrin derivatives on a Au(111) surface was studied by scanning tunneling microscopy and spectroscopy at low temperatures in combination with density functional theory calculations. Different molecular appearances were found and could be assigned to the presence of single gold adatoms bonded by a coordination bond underneath the molecular monolayer, causing a characteristic change of the electronic structure of the molecules. Moreover, this interpretation could be confirmed by manipulation experiments of individual molecules on and off a single gold atom. This study provides a detailed understanding of the role of metal adatoms in surface-molecule bonding and anchoring and of the appearance of single molecules, and it should prove relevant for the imaging of related molecule-metal systems. PMID- 25494669 TI - Motor imagery: effects of age, task complexity, and task setting. AB - BACKGROUND/STUDY CONTEXT: Mental training may potentially enhance motor performance and self-efficacy in older adults. However, several studies revealed an age-related decay of motor imagery (MI), which suggests that mental training might be too challenging for older adults. Recognizing that laboratory results are often not transferable to real-life situations, the purpose of the present study was to evaluate imagery performance in the elderly with a more real-life like approach. METHODS: MI performance of 21 older (70.28 +/- 4.65 years) and 19 younger adults (24.89 +/- 3.16 years) was estimated by mental chronometry from the first-person perspective. Subjects were asked to walk in a supermarket scenario straight ahead (A), or with two changes of direction (B), or with two changes of direction while retrieving products (C). The three tasks were completed first in the subjects' imagination and then in reality, with time required as the dependent measure. MI ability was also assessed by the Controllability of Motor Imagery (CMI) test, in which subjects are required to mentally assume a sequence of body postures. RESULTS: Age-related alterations of MI were observed for walking only in Tasks B and C, and only in terms of intersubject variability, not in terms of across-subject means. This is in contrast to earlier studies that used a less realistic walking scenario and found an age-related decay even for MI means. Age-related alterations of CMI were observed as well, but they correlated little with those of walking. CONCLUSION: These findings suggest that MI is not a global phenomenon, as it decays in old age independently in the temporal and in the spatial domain, decays less with simple than with complex tasks, and less in an everyday-like than in a typical laboratory setting. These characteristics of MI should be taken into account when assessing its decay in old age, and when designing mental training for the elderly. PMID- 25494668 TI - The association between discrimination and depressive symptoms among older African Americans: the role of psychological and social factors. AB - BACKGROUND/STUDY CONTEXT: Several studies have demonstrated a link between perceived discrimination and depression in ethnic minority groups, yet most have focused on younger or middle-aged African Americans and little is known about factors that may moderate the relationship. METHODS: Participants were 487 older African Americans (60-98 years old) enrolled in the Minority Aging Research Study. Discrimination, depressive symptoms, and psychological and social resources were assessed via interview using validated measures. Ordinal logistic regression models were used to assess (1) the main relationship between discrimination and depression and (2) resilience, purpose in life, social isolation, and social networks as potential moderators of this relationship. RESULTS: In models adjusted for age, sex, education, and income, perceived discrimination was positively associated with depressive symptoms (odds ratio [OR]: 1.20, 95% confidence interval [CI]: 1.10-1.31; p < .001). However, there was no evidence of effect modification by resilience, purpose in life, social isolation, or social networks (all ps <= .05). CONCLUSION: Findings provide support for accumulating evidence on the adverse mental health effects of discrimination among older African Americans. Because the association was not modified by psychological or social factors, these findings do not support a role for a buffering effect of resources on discrimination and depressive symptoms. Further studies are needed to examine a wider range of coping resources among older adults. PMID- 25494670 TI - Face naming and retrieval inhibition in old and very old age. AB - BACKGROUND/STUDY CONTEXT: Aging has traditionally been related to impairments in proper name retrieval. This study analyzed the possible role of the Inhibitory Deficit Hypothesis in explaining face naming impairments during aging. The dynamics of inhibition have been thoroughly studied by the retrieval-practice paradigm (Anderson, Bjork, & Bjork, 1994, Journal of Experimental Psychology: Learning, Memory, and Cognition, 20, 1063-1087) and its aftereffect, the retrieval-induced forgetting effect. METHODS: A version of the retrieval-practice paradigm was employed: younger-old (YO; mean age = 66.40, SD = 3.94) and older old (OO; mean age = 80.94, SD = 4.53) adults were asked to repeatedly name faces of categorically related famous people. RESULTS: Retrieval-induced forgetting for names was observed in the YO group but not in the OO group. CONCLUSION: These findings indicate that whereas the YO adults had enough resources to inhibit intrusive names, OO adults were not able to suppress competing names, supporting the proposal of the Inhibitory Deficit Hypothesis at older ages. PMID- 25494671 TI - Does initial performance variability predict dual-task optimization with practice in younger and older adults? AB - BACKGROUND/STUDY CONTEXT: The variability associated with reaction time (RT) is sometimes considered as a proxy for inefficient neural processing, particularly in old age and complex situations relying upon executive control functions. Here, it is examined whether the amount of variability exhibited early in practice can predict the amount of improvement with later practice in dual-task performance, and whether the predictive power of variability varies between younger and older adults. METHODS: To investigate the relationship between variability and practice related improvement, RT mean and variability data are used, obtained from an experiment in which younger and older adults performed two tasks in single-task and dual-task conditions across seven practice sessions. These RT and variability data were related to the single-task and dual-task practice benefits. These benefits were computed as follows: dual-task/single-task RTs at the beginning of practice minus dual-task/single-task RTs at the end of practice. RESULTS: In both age groups, dual-task processing was speeded up with practice and variability associated with the means was reduced. Most important, independent of mean RTs, variability allowed predicting dual-task practice benefit in both age groups under specific conditions. CONCLUSION: These findings suggest that the relationship between performance variability and executive control functions under some specific conditions. Implications of these results for models of practiced dual tasks are discussed. PMID- 25494672 TI - Clinical functional tests help identify elderly women highly concerned about falls. AB - BACKGROUND/STUDY CONTEXT: Limited research exists on functional tests in the discrimination of elderly individuals with high concern about falls from individuals with low concern about falls. The purpose of this study was to determine which functional test best discriminates between elderly women with low and high concern about falls. METHODS: One hundred thirty-five elderly women (72.6 +/- 4.8 years) were divided into two groups based on their Falls Efficacy Scale-International score: low concern (n = 56) and high concern (n = 79) about falls. Five functional tests were applied: Timed Up and Go test (TUG), unipodal stance test, five-repetition sit-to-stand test (5-STS), gait velocity, and grip strength. Factorial analysis and discriminant analysis were used. RESULTS: Factorial analysis resulted in three factors that explained 83.8% of the total variance. Factor 1, with 49.5% of total variance explanation, was represented by the TUG, 5-STS, and gait velocity tests and was the only factor to discriminate between the groups, classifying correctly 68.9% of the observations. Among the original variables of Factor 1, the Fisher linear coefficient showed that the TUG was the most discriminant of the tests. CONCLUSION: The TUG test best discriminates elderly women with low and high concern about falls; therefore, it is an important test that should be performed during the assessment of elderly individuals afraid of falling. PMID- 25494673 TI - Trajectories of frailty and related factors of the older people in Taiwan. AB - BACKGROUND/STUDY CONTEXT: This study aimed to identify the different trajectories of frailty and factors related to frailty among older adults over time. METHODS: Data were obtained from a five-wave panel composed of older Taiwanese adults from 1993 to 2007 (N = 2306). Frailty was defined as the presence of three or more of the following criteria: shrinking, weakness, exhaustion, slowness, and low physical activity. A group-based model of trajectory analysis was applied with time-dependent and time-independent variables. RESULTS: Three trajectory groups were identified: maintaining nonfrailty, developing frailty, and high risk of frailty. Being female, older, and having a lower level of education were risk factors for being in the developing frailty group or high risk of frailty group. Physical risk factors and psychological factors were associated with frailty within each group. Higher financial satisfaction and social participation were protective factors from frailty for the developing frailty group and high risk of frailty group, respectively. CONCLUSION: Older adults should promote their health physically, psychologically, and socially. PMID- 25494674 TI - Nematicidal activities of 4-quinolone alkaloids isolated from the aerial part of Triumfetta grandidens against Meloidogyne incognita. AB - The methanol extract of the aerial part of Triumfetta grandidens (Tiliaceae) was highly active against Meloidogyne incognita, with second-stage juveniles (J2s) mortality of 100% at 500 MUg/mL at 48 h post-exposure. Two 4-quinolone alkaloids, waltherione E (1), a new alkaloid, and waltherione A (2), were isolated and identified as nematicidal compounds through bioassay-guided fractionation and instrumental analysis. The nematicidal activities of the isolated compounds against M. incognita were evaluated on the basis of mortality and effect on egg hatching. Compounds 1 and 2 exhibited high mortalities against J2s of M. incognita, with EC50 values of 0.09 and 0.27 MUg/mL at 48 h, respectively. Compounds 1 and 2 also exhibited a considerable inhibitory effect on egg hatching, which inhibited 91.9 and 87.4% of egg hatching, respectively, after 7 days of exposure at a concentration of 1.25 MUg/mL. The biological activities of the two 4-quinolone alkaloids were comparable to those of abamectin. In addition, pot experiments using the crude extract of the aerial part of T. grandidens showed that it completely suppressed the formation of gall on roots of plants at a concentration of 1000 MUg/mL. These results suggest that T. grandidens and its bioactive 4-quinolone alkaloids can be used as a potent botanical nematicide in organic agriculture. PMID- 25494676 TI - Channel partition into nanoscale polyhedral cages of a triple-self interpenetrated metal-organic framework with high CO2 uptake. AB - Reported herein is a novel porous metal-organic framework (MOF) exhibiting unique nanoscale cages derived from the 3-fold self-interpenetration of chiral eta networks based on trifurcate {Zn2(CO2)3} building blocks and 1,3,5-tris(4 carboxyphenyl)benzene ligands. The attractive self-interpenetrated structural features contribute to the highest CO2 uptake capacity and CO2 binding ability among the interpenetrated MOFs. PMID- 25494675 TI - Association of altered hemorheology with oxidative stress and inflammation in metabolic syndrome. AB - OBJECTIVE: We have shown increased whole blood viscosity (WBV), decreased erythrocyte deformability, and increased erythrocyte aggregation in metabolic syndrome (MetS) in our previous study. The objective of the study was to find out if the altered hemorheology shown in MetS in our previous study is associated with chronic inflammation and oxidative stress in the same subjects. METHODS: One hundred recruited participants were classified into three groups based on the number of the MetS components present following National Cholesterol Education Program, Adult Treatment Panel III definitions. WBV, erythrocyte aggregation, erythrocyte deformability, oxidative stress markers (erythrocyte reduced glutathione (GSH), superoxide dismutase (SOD), and urinary isoprostanes), inflammatory markers high-sensitivity C-reactive protein (hsCRP), and thrombotic marker D-dimer were measured. Data were analyzed by IBM SPSS 20 software. RESULTS: We found a significant association of altered hemorheology with chronic inflammation and oxidative stress in MetS. There was a linear increase in the level of hsCRP and a linear decrease in the level of SOD and GSH across the quartiles of erythrocyte aggregation. Similarly, the thrombotic marker D-dimer showed a linear increase and oxidative stress marker GSH showed a linear decrease trend across the quartiles of WBV. DISCUSSION: Alterations of hemorheology in MetS are probably due to the effect of chronic inflammation and oxidative stress. The negative effects of chronic inflammation and oxidative stress on the cardiovascular system could be due to the resulting altered hemorheology. PMID- 25494677 TI - Potential toxicity of graphene to cell functions via disrupting protein-protein interactions. AB - While carbon-based nanomaterials such as graphene and carbon nanotubes (CNTs) have become popular in state-of-the-art nanotechnology, their biological safety and underlying molecular mechanism is still largely unknown. Experimental studies have been focused at the cellular level and revealed good correlations between cell's death and the application of CNTs or graphene. Using large-scale all-atom molecular dynamics simulations, we theoretically investigate the potential toxicity of graphene to a biological cell at molecular level. Simulation results show that the hydrophobic protein-protein interaction (or recognition) that is essential to biological functions can be interrupted by a graphene nanosheet. Due to the hydrophobic nature of graphene, it is energetically favorable for a graphene nanosheet to enter the hydrophobic interface of two contacting proteins, such as a dimer. The forced separation of two functional proteins can disrupt the cell's metabolism and even lead to the cell's mortality. PMID- 25494679 TI - Nivolumab for the treatment of cancer. AB - INTRODUCTION: One mechanism by which tumor cells are thought to evade the host's immune system is by inducing negative signals that cause T-cell suppression. An important interaction that results in this phenomenon is the one between programmed death-1 (PD-1) on the T cell and its ligand PD ligand-1 (PD-L1) on the tumor cell. PD-1 pathway blocking agents, such as nivolumab , are therefore capable of reversing T-cell suppression and ultimately induce antitumor responses. AREAS COVERED: In this review, the authors summarize investigations related to the safety and efficacy of nivolumab in a variety of malignancies thus far, including advanced melanoma, renal cell carcinoma (RCC) and NSCLC. EXPERT OPINION: The results have been promising with a large number of objective responses and favorable safety profiles inspiring several Phase III trials in these settings. More recent studies are exploring the role of this drug in the treatment of various other cancers. Combination therapies involving nivolumab are also being studied and are yielding interesting results. Finally, the role of tumor PD-L1 expression as a predictive biomarker remains to be ascertained. Thus, with rational refinement through biomarker and combination clinical trials, nivolumab and other PD-1 blocking agents will likely lead to significant improvements in cancer therapeutics. PMID- 25494678 TI - Optimizing the measurement of mitochondrial protein synthesis in human skeletal muscle. AB - The measurement of mitochondrial protein synthesis after food ingestion, contractile activity, and/or disease is often used to provide insight into skeletal muscle adaptations that occur in the longer term. Studies have shown that protein ingestion stimulates mitochondrial protein synthesis in human skeletal muscle. Minor differences in the stimulation of mitochondrial protein synthesis occur after a single bout of resistance or endurance exercise. There appear to be no measurable differences in mitochondrial protein synthesis between critically ill patients and aged-matched controls. However, the mitochondrial protein synthetic response is reduced at a more advanced age. In this paper, we discuss the challenges involved in the measurement of human skeletal muscle mitochondrial protein synthesis rates based on stable isotope amino acid tracer methods. Practical guidelines are discussed to improve the reliability of the measurement of mitochondrial protein synthesis rates. The value of the measurement of mitochondrial protein synthesis after a single meal or exercise bout on the prediction of the longer term skeletal muscle mass and performance outcomes in both the healthy and disease populations requires more work, but we emphasize that the measurements need to be reliable to be of any value to the field. PMID- 25494680 TI - Ramalin inhibits VCAM-1 expression and adhesion of monocyte to vascular smooth muscle cells through MAPK and PADI4-dependent NF-kB and AP-1 pathways. AB - Cell adhesion molecules play a critical role in inflammatory processes and atherosclerosis. In this study, we investigated the effect of ramalin, a chemical compound from the Antarctic lichen Ramalina terebrata, on vascular cell adhesion molecule-1 (VCAM-1) expression induced by TNF-alpha in vascular smooth muscular cells (VSMCs). Pretreatment of VSMCs with ramalin (0.1-10 MUg/mL) concentration dependently inhibited TNF-alpha-induced VCAM-1 expression. Additionally, ramalin inhibited THP-1 (human acute monocytic leukemia cell line) cell adhesion to TNF alpha-stimulated VSMCs. Ramalin suppressed TNF-alpha-induced production of reactive oxygen species (ROS), PADI4 expression, and phosphorylation of p38, ERK, and JNK. Moreover, ramalin inhibited TNF-alpha-induced translocation of NF-kappaB and AP-1. Inhibition of PADI4 expression by small interfering RNA or the PADI4 specific inhibitor markedly attenuated TNF-alpha-induced activation of NF-kappaB and AP-1 and VCAM-1 expression in VSMCs. Our study provides insight into the mechanisms underlying ramalin activity and suggests that ramalin may be a potential therapeutic agent to modulate inflammation within atherosclerosis. PMID- 25494681 TI - Acrylamide levels in selected Colombian foods. AB - Acrylamide (AA) levels in conventional (n = 112) and traditional (n = 43) Colombian foods were analysed by gas chromatography with mass spectrometry (GC/MS) detection. Samples included: infant powdered formula, coffee and chocolate powders, corn snacks, bakery products and tuber-, meat- and vegetable based foods. There was a wide variability in AA levels among different foods and within different brands of the same food, especially for coffee powder, breakfast cereals biscuits and French fries samples. Among the conventional foods tested, the highest mean AA value was found in bakery products, such as biscuit (1104 ug kg(-1)) and wafer (1449 ug kg(-1)), followed by potato chips (916 ug kg(-1)). On the other hand, among the traditional foods, higher AA amounts were detected in fried platano (2813 ug kg(-1)) and yuca (3755 ug kg(-1)) compared to other products. Interestingly, the arepa, a traditional Colombian bakery product made with corn flour, showed a lower AA content (< 75 ug kg(-1)) when compared with similar bakery products tested, such as soft bread (102-594 ug kg(-1)), which is a made with wheat flour. PMID- 25494682 TI - Phosphorus limitation, soil-borne pathogens and the coexistence of plant species in hyperdiverse forests and shrublands. AB - Hyperdiverse forests occur in the lowland tropics, whereas the most species-rich shrublands are found in regions such as south-western Australia (kwongan) and South Africa (fynbos). Despite large differences, these ecosystems share an important characteristic: their soils are strongly weathered and phosphorus (P) is a key growth-limiting nutrient. Soil-borne pathogens are increasingly being recognized as drivers of plant diversity in lowland tropical rainforests, but have received little attention in species-rich shrublands. We suggest a trade-off in which the species most proficient at acquiring P have ephemeral roots that are particularly susceptible to soil-borne pathogens. This could equalize out the differences in competitive ability among co-occurring species in these ecosystems, thus contributing to coexistence. Moreover, effective protection against soil-borne pathogens by ectomycorrhizal (ECM) fungi might explain the occurrence of monodominant stands of ECM trees and shrubs amongst otherwise species-rich communities. We identify gaps in our knowledge which need to be filled in order to evaluate a possible link between P limitation, fine root traits, soil-borne pathogens and local plant species diversity. Such a link may help to explain how numerous plant species can coexist in hyperdiverse rainforests and shrublands, and, conversely, how monodominant stands can develop in these ecosystems. PMID- 25494683 TI - Room temperature observation of quantum confinement in single InAs nanowires. AB - Quantized conductance in nanowires can be observed at low temperature in transport measurements; however, the observation of sub-bands at room temperature is challenging due to temperature broadening. So far, conduction band splitting at room temperature has not been observed in III-V nanowires mainly due to the small energetic separations between the sub-bands. We report on the measurement of conduction sub-bands at room temperature, in single InAs nanowires, using Kelvin probe force microscopy. This method does not rely on charge transport but rather on measurement of the nanowire Fermi level position as carriers are injected into a single nanowire transistor. As there is no charge transport, electron scattering is no longer an issue, allowing the observation of the sub bands at room temperature. We measure the energy of the sub-bands in nanowires with two different diameters, and obtain excellent agreement with theoretical calculations based on an empirical tight-binding model. PMID- 25494684 TI - Validation of daily microincrement deposition in otoliths of juvenile and adult Peruvian anchovy Engraulis ringens. AB - Wild adult specimens of the Peruvian anchovy Engraulis ringens were captured and reared to validate the daily periodicity of otolith microincrement formation. The postcapture stress generated spontaneous spawning, making it possible to conduct a rearing trial on larvae first in an artificial nutrient-enriched system (ANES) for 52 days followed by an artificial feeding regime in a culture tank until day 115 post-hatch. Microincrements of the sagittal otoliths of sacrificed juveniles [mean +/- S.D. total length (LT ) = 5.13 +/- 0.37 cm, range 5-6 cm; c.v. = 7.5%] showed very distinct light and dark zones. The slope of the relationship between the total number of increments after the hatch check and days elapsed after hatching was not significantly different from 1. The transfer from ANES to the artificial feeding regime induced a mark in the sagittal otoliths. The number of microincrements after this induced mark coincided with the number of days elapsed after the transfer date. In parallel experiments, adult E. ringens (mean +/- S.D. LT = 14.92 +/- 0.55 cm, range 13-16 cm) were exposed to one of two fluorescent marking immersion treatments with either alizarin red S (ARS; 25 mg l(-1) per 6 h) or oxytetracycline hydrochloride (OTC; 200 mg l(-1) per 10 h). The microincrements between fluorescent bands were distinct, ranging from 0.89 to 2.75 um (mean +/- S.D. =1.43 +/- 0.28 um; c.v. = 32%) and from 0.71 to 2.89 um (1.53 +/- 0.27 um; c.v. = 35%) for ARS and OTC, respectively. The relationship between the number of microincrements between marks and the number of elapsed days for ARS and OCT treatments indicated that there was a significant correspondence between the number of increases observed and the number of days. Hence, daily microincrements of otoliths of E. ringens are likely to be formed in juveniles and adults under natural conditions. PMID- 25494685 TI - The yield of universal antibody to hepatitis B core antigen donor screening in the Netherlands, a hepatitis B virus low-endemic country. AB - BACKGROUND: In the Netherlands, universal antibody to hepatitis B core antigen (anti-HBc) donor screening was introduced in July 2011 to intercept potentially infectious donations slipping through hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA minipool screening (HBV DNA MP6). STUDY DESIGN AND METHODS: The yield and donor loss were evaluated after the first 2 years of universal anti-HBc donor screening. A total of 382,173 donors were tested for anti-HBc and, if positive, for antibody to HBsAg (anti-HBs). Anti-HBc-reactive donors with anti-HBs of less than 200 IU/L were deferred, but repeat donors were allowed retesting after 6 months if anti-HBs was less than 10 IU/mL. Anti-HBc false positivity was estimated using the crude anti-HBc signal, family name-based ethnicity scoring, and donor follow-up. RESULTS: Anti-HBc screening identified 13 confirmed or potential HBsAg- and HBV DNA MP6-negative recent HBV infections. In addition, 820 anti-HBc-reactive donors with low anti-HBs titers (<200 IU/mL), potentially harboring occult HBV infection (OBI), were identified and deferred. Overall, 1583 (0.41%) donors were deferred: 1178 (0.31%) during first-time anti HBc screening, 361 (0.09%) anti-HBc seroconverters, and 44 (0.01%) donors with waning anti-HBs titers. Only 188 of 1583 (12%) deferred donors could be reentered upon retesting. Estimated anti-HBc false positivity was 16%, but varied greatly among anti-HBc-reactive donors with and without anti-HBs (8% vs. 62%). CONCLUSION: Anti-HBc testing has improved the safety of the Dutch blood supply but its exact yield remains difficult to determine, due to the complexity of confirming anti-HBc reactivity and OBI. In a low-endemic country, donor loss associated with anti-HBc screening is sustainable, but adds to the already considerable list of donor exclusions. PMID- 25494686 TI - Evidence-based HIV pilot program for Chinese college students: Differences by gender. AB - This study explored gender differences in the effectiveness of the translated VOICES (Video Opportunities for Condom Education and Safer Sex) intervention on the condom use intention, perceived benefits and barriers to condom use, condom use self-efficacy, and HIV/AIDS knowledge among Chinese students in a US university. We utilized a pretest/post-test quasi-experimental design and recruited 67 Chinese students at the local university. Participants viewed a 20 min video with Chinese subtitles, attended one 25-min small group discussion and condom interactive educational activity. Female participants showed significantly greater mean scores of perceived benefits and condom use self-efficacy, in comparison with male participants. Female participants also reported significantly higher scores than male participants in five of the perceived benefits items and one self-efficacy item. These study results provide important information for developing more differentiated intervention strategies specific to gender for HIV and STI education programs. PMID- 25494687 TI - Age-related changes in distance from center of mass to center of pressure during one-leg standing. AB - The purpose of this study was to clarify the age-related effects of distances from the center of pressure (COP) to the center of mass (COM) (COP-COM distances) during one-leg standing (OLS) task. Healthy old and young adults (n = 11 each) participated in this study. The authors divided the task into 3 phases (accelerated, decelerated, and steady) based on the relationship between COM and COP. COP-COM distances in the older group were significantly reduced during the accelerated phase, then significantly increased during the decelerated and steady phases. Furthermore, distances during these phases correlated inversely with OLS time. The authors conclude that OLS time is shortened by the larger braking response to COM shifts just after leg-lifting, and the production of larger inertial forces to maintain COM position during the OLS in older individuals. PMID- 25494688 TI - Botulinum neurotoxin A for chronic migraine headaches: does it work and how? PMID- 25494689 TI - Genetic predisposition to chronic pain: from evolutionary advantage to a debilitating disease spectrum? PMID- 25494690 TI - Should health promotion be on the pain agenda? PMID- 25494691 TI - Choice of nonpharmacological pain therapies by ethnically diverse older adults. AB - AIM: This study compared nonpharmacological pain therapies used by ethnically diverse older adults with recommendations of family physicians and identified factors associated with nonpharmacological pain therapies use. METHODS: Using a descriptive cross-sectional design, 281 participants in four ethnic groups (European Americans, Hispanics, African-Americans, Afro-Caribbeans) with chronic pain were surveyed. Binary logistic regression analyses were employed to determine associated factors. RESULTS & CONCLUSION: Nonaquatic exercise and physical therapy were most frequently recommended by physicians, and nonaquatic exercise was most commonly used by participants. Lower pain levels predicted use of nonaquatic exercise, and ethnicity predicted use of prayer to manage chronic pain. Future research should examine barriers to use of psychological treatments and assess the value of combined physical and psychological treatments. PMID- 25494692 TI - Developmental and cultural perspectives on children's postoperative pain management at home. AB - Outpatient surgery is extremely common in children, and approximately 4 million children experience significant pain after surgery in the USA each year. Management of children's postoperative pain in the home setting is suboptimal and is impacted by characteristics of children and parents, as well as the larger family and cultural context. In particular, developmental status of the child, parental beliefs regarding pain expression and analgesic use in children, cultural values and language barriers can affect management of children's postoperative pain. Targeting the myriad barriers to children's pain management by capitalizing upon the use of tailored interventions may help bridge the gap between the translation of pain management guidelines to the home setting. PMID- 25494693 TI - A practical approach to ocular pain for the non-ophthalmologist. AB - Pain involving the eye has numerous etiologies and is a feared challenge of many clinicians. Between a fear of the patient losing vision and a lack of familiarity with the ophthalmic equipment necessary to diagnose the problem, working up eye pain can be a daunting task. While the ophthalmologist can be indispensable in challenging cases of eye pain, this article will help clarify the unique clinical features of each etiology that can help clinicians narrow down the differential and arrive at a diagnosis. PMID- 25494694 TI - A background for the management of osteoarthritic knee pain. AB - Knee osteoarthritis (KOA) is the most common degenerative arthritis and is treated by a wide range of practitioners. Treatment planning requires knowledge of the knee joint components and the influence of systemic and environmental factors. The treatment of KOA has changed little in 50 years. We are entering a new stage where KOA is now being viewed as an organ in failure. Neurotransmission of pain is both peripheral and central. Medical treatment can influence both pathways. Current guidelines for treatment have more rigid criteria based on the literature. In the future, the use of genetic-based biomarkers, clinical patterns of response and imaging characteristics will likely create subgroups of individuals who could benefit from improved designer therapies. PMID- 25494695 TI - The importance of medical education in the changing field of pain medicine. AB - Suffering chronic pain is a global epidemic that requires a closer look on how we are educating trainees to become more effective in pain management. The vast majority of medical professionals will encounter treatment of pain throughout their career. Our current system for educating these medical professionals is flawed in a number of ways. Improving pain education will narrow the gap between over and under treatment of acute and chronic pain. Reviews have demonstrated dissatisfaction among practitioners throughout the world on how pain education is currently conducted. Changing the educational process will require support from several areas: medical educators, clinicians, policymakers, administrators and several other organizations. PMID- 25494696 TI - Predicting, preventing and managing persistent pain after breast cancer surgery: the importance of psychosocial factors. AB - Persistent pain after breast cancer surgery (PPBCS) is increasingly recognized as a potential problem facing a sizeable subset of the millions of women who undergo surgery as part of their treatment of breast cancer. Importantly, an increasing number of studies suggest that individual variation in psychosocial factors such as catastrophizing, anxiety, depression, somatization and sleep quality play an important role in shaping an individual's risk of developing PPBCS. This review presents evidence for the importance of these factors and puts them within the context of other surgical, medical, psychophysical and demographic factors, which may also influence PPBCS risk, as well as discusses potential perioperative therapies to prevent PPBCS. PMID- 25494697 TI - Incorporating evolutionary processes into population viability models. AB - We examined how ecological and evolutionary (eco-evo) processes in population dynamics could be better integrated into population viability analysis (PVA). Complementary advances in computation and population genomics can be combined into an eco-evo PVA to offer powerful new approaches to understand the influence of evolutionary processes on population persistence. We developed the mechanistic basis of an eco-evo PVA using individual-based models with individual-level genotype tracking and dynamic genotype-phenotype mapping to model emergent population-level effects, such as local adaptation and genetic rescue. We then outline how genomics can allow or improve parameter estimation for PVA models by providing genotypic information at large numbers of loci for neutral and functional genome regions. As climate change and other threatening processes increase in rate and scale, eco-evo PVAs will become essential research tools to evaluate the effects of adaptive potential, evolutionary rescue, and locally adapted traits on persistence. PMID- 25494699 TI - Plasma concentrations and analgesic efficacy of lidocaine and prilocaine in leg ulcer-related pain during daily application of lidocaine-prilocaine cream (EMLATM) for 10 days. PMID- 25494700 TI - Effects of different rearing systems on meat production traits and meat fiber microstructure of Beijing-you chicken. AB - Beijing-you is a Chinese local chicken which is raised for both meat and eggs. In the present study, we detected the effects of different rearing systems on growth, slaughtering performances and meat quality of Beijing-you chickens at 26 40 weeks of age. Six hundred Beijing-you hens were randomly allocated into two groups at 16 weeks of age and raised in free range or battery cage systems. The body weight, slaughtering performance and meat quality were measured for each group at the ages of 26, 30, 35 and 40 weeks. Some of the traits were dramatically influenced by the two systems, although most of them did not show significant changes. For the meat fiber microstructure, we found that the diameter of thigh and breast muscle fiber in the free range group were significantly increased than in the cage group (P < 0.05) at 26 weeks of age. The ratio of fast muscle fiber in thigh muscle samples of the free range group was significantly reduced compared to that of cage group at both 35 (P < 0.01) and 40 (P < 0.01) weeks of age, indicating that the free range system could promote the transforming of fast muscle fiber to slow muscle fiber. PMID- 25494698 TI - Unbiased chromatin accessibility profiling by RED-seq uncovers unique features of nucleosome variants in vivo. AB - BACKGROUND: Differential accessibility of DNA to nuclear proteins underlies the regulation of numerous cellular processes. Although DNA accessibility is primarily determined by the presence or absence of nucleosomes, differences in nucleosome composition or dynamics may also regulate accessibility. Methods for mapping nucleosome positions and occupancies genome-wide (MNase-seq) have uncovered the nucleosome landscapes of many different cell types and organisms. Conversely, methods specialized for the detection of large nucleosome-free regions of chromatin (DNase-seq, FAIRE-seq) have uncovered numerous gene regulatory elements. However, these methods are less successful in measuring the accessibility of DNA sequences within nucelosome arrays. RESULTS: Here we probe the genome-wide accessibility of multiple cell types in an unbiased manner using restriction endonuclease digestion of chromatin coupled to deep sequencing (RED seq). Using this method, we identified differences in chromatin accessibility between populations of cells, not only in nucleosome-depleted regions of the genome (e.g., enhancers and promoters), but also within the majority of the genome that is packaged into nucleosome arrays. Furthermore, we identified both large differences in chromatin accessibility in distinct cell lineages and subtle but significant changes during differentiation of mouse embryonic stem cells (ESCs). Most significantly, using RED-seq, we identified differences in accessibility among nucleosomes harboring well-studied histone variants, and show that these differences depend on factors required for their deposition. CONCLUSIONS: Using an unbiased method to probe chromatin accessibility genome wide, we uncover unique features of chromatin structure that are not observed using more widely-utilized methods. We demonstrate that different types of nucleosomes within mammalian cells exhibit different degrees of accessibility. These findings provide significant insight into the regulation of DNA accessibility. PMID- 25494701 TI - A multicenter, non-randomized, phase II study of docetaxel and carboplatin administered every 3 weeks as second line chemotherapy in patients with first relapse of platinum sensitive epithelial ovarian, peritoneal or fallopian tube cancer. AB - BACKGROUND: In patients with ovarian cancer relapsing at least 6 months after end of primary treatment, the addition of paclitaxel to platinum treatment has been shown to improve survival but at the cost of significant neuropathy. In the first line setting, the carboplatin-docetaxel combination was as effective as the combination of carboplatin and paclitaxel but with less neurotoxicity. This study was initiated to evaluate the feasibility of carboplatin with docetaxel as second line treatment in patients with ovarian, peritoneal or fallopian tube cancer. METHODS: Patients with stage IC-IV epithelial ovarian, peritoneal or fallopian tube cancer were enrolled at the first relapse after at least 6 months since completion of the first line treatment. Docetaxel 75 mg/m2 was given as an one hour IV infusion followed immediately by carboplatin (AUC=5) given as a 30-60 min. IV infusion on day 1 and repeated every 3 weeks for 6-9 courses. Primary endpoint was toxicity; secondary endpoints were response rate and the time to progression. RESULTS: A total of 74 patients were included. Of these, 50 patients received 6 or more cycles, 13 received 3-5 courses and 11 received less than 3 courses. A total of 398 cycles were given. Grade 3/4 neutropenia was seen in 80% (59 of 74) patients with an incidence of febrile neutropenia of 16%. Grade 2/3 sensory peripheral neuropathy occurred in 7% of patients, but no grade 4 sensory peripheral neuropathy was observed. Sixty patients were evaluable for response. The overall response rate was 70% with 28% complete responses in the response evaluable patient population. Median progression-free survival was 12.4 months (95% CI 10.4-14.4). CONCLUSIONS: The three-weekly regimen of docetaxel in combination with carboplatin was feasible and active as second-line treatment of platinum-sensitive ovarian, peritoneal and Fallopian tube cancer. The major toxicity was neutropenia, while the frequency of peripheral neuropathy was low. PMID- 25494703 TI - Intrapartum management of twin pregnancies: are uncomplicated monochorionic pregnancies more at risk of complications than dichorionic pregnancies? AB - OBJECTIVE: To analyze mode of delivery and neonatal morbidity according to chorionicity in a hospital birth center with a policy of vaginal delivery for twins. STUDY DESIGN: Retrospective analysis over a 13-year period. SETTING: Department of Obstetrics, University Hospital, Lille, France. POPULATION: In all, 1009 twin pregnancies were included, divided into 171 uncomplicated monochorionic pregnancies (17%) and 838 dichorionic pregnancies (83%). METHODS: We compared the monochorionic and the dichorionic populations. MAIN OUTCOME MEASURES: Rate of cesarean section and neonatal outcome (umbilical artery pH, Apgar score and neonatal complications). RESULTS: The rate of cesarean sections was 45.7% with no difference found based on chorionicity. The reasons for elective cesarean section were mainly noncephalic presentation, which was more frequent in dichorionic than in monochorionic (48.8% vs. 37.2%, p = 0.025) pregnancies. Birthweight was lower in monochorionic twins (2249 +/- 469 g vs. 2329 +/- 478 g, p = 0.045). The rate of umbilical artery cord blood values with a pH < 7.10 was similar in monochorionic and dichorionic pregnancies. There was no difference in neonatal complications between the two groups. CONCLUSION: Monochorionic and dichorionic twin pregnancies had similar delivery outcomes. The neonatal outcome for twin 2 was not different between monochorionic and dichorionic pregnancies. Vaginal birth could be offered to women with twin pregnancies regardless of chorionicity. PMID- 25494702 TI - Empowering pharmacists in asthma management through interactive SMS (EmPhAsIS): study protocol for a randomized controlled trial. AB - BACKGROUND: Medication regimens for asthma are particularly vulnerable to adherence problems because of the requirement for long-term use and periods of symptom remission experienced by patients. Pharmacists are suited to impact medication adherence given their training, skills, and frequent contact with patients. The Empowering pharmacists in asthma management through interactive SMS (EmPhAsIS) trial involves an intervention leveraging mobile health (mHealth) technology to support community pharmacy practice with the hypothesis of improved medication adherence in asthma. METHODS/DESIGN: This study is a pragmatic pharmacy-based, cluster, randomized controlled trial with 12 months of intervention delivery and follow-up. Pharmacies (the clusters) will be randomized at a 1:1 ratio to provide intervention or usual care. The EmPhAsIS intervention consists of patient asthma education, short message service (SMS)-based monthly assessment of adherence, and follow-up of non-adherent individuals by community pharmacists. There are no inclusion or exclusion criteria for pharmacies. Patients are eligible if they: are 14 years of age or older, fill a prescription for inhaled corticosteroid (either monotherapy or in a combination inhaler with long-acting beta-agonists), have been diagnosed with asthma, possess a mobile phone with SMS capabilities, and have no communication difficulties such as inability to communicate in English, or significant impairment in vision, hearing, or speech. The primary outcome is adherence to inhaled corticosteroids ascertained by the medication possession ratio, the ratio of the days of medication supplied to days in a given time interval. This study will also evaluate secondary outcomes including: asthma control, asthma-related quality of life, asthma-related hospital admissions, and use of reliever medications during the follow-up period. A nested economic evaluation using a probabilistic decision analytic model will be used to perform a cost-effectiveness analysis from the societal perspective of the intervention compared with usual care over a 10-year time horizon. DISCUSSION: Considering the prevalence of asthma, the extent of the non-adherence problem in this disease, and the availability of effective treatments, there is a tremendous potential to reduce the burden of asthma through improving adherence. This is the first study of an intervention based on mobile communication technology involving community pharmacists in asthma management. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02170883; date of registration: 19 June 2014. PMID- 25494704 TI - Multiple intracranial and spinal metastases from a nonfunctioning pituitary adenoma following multiple surgeries: an illustrative case with 16 years of follow-up. AB - Pituitary adenomas are the third most common primary intracranial tumor; however, those with postoperative metastases are very rare and are classically considered as pituitary carcinomas. The field of neurosurgery has struggled with diagnosing and treating these unusual lesions. In this report, we retrospectively analyze the clinical features, imaging findings, pathological characteristics and prognosis of one patient with non-hormone-secreting pituitary adenoma who had multiple intracranial and spinal metastases and underwent four surgeries in a 16 year follow-up period. In addition, on the basis of the existing literature, we explore the underlying mechanisms of, as well as the preventive and therapeutic strategies used to treat, pituitary carcinomas and postoperative metastasis of pituitary tumors. PMID- 25494705 TI - Wings versus legs in the avian bauplan: development and evolution of alternative locomotor strategies. AB - Wings have long been regarded as a hallmark of evolutionary innovation, allowing insects, birds, and bats to radiate into aerial environments. For many groups, our intuitive and colloquial perspective is that wings function for aerial activities, and legs for terrestrial, in a relatively independent manner. However, insects and birds often engage their wings and legs cooperatively. In addition, the degree of autonomy between wings and legs may be constrained by tradeoffs, between allocating resources to wings versus legs during development, or between wing versus leg investment and performance (because legs must be carried as baggage by wings during flight and vice versa). Such tradeoffs would profoundly affect the development and evolution of locomotor strategies, and many related aspects of animal ecology. Here, we provide the first evaluation of wing versus leg investment, performance and relative use, in birds-both across species, and during ontogeny in three precocial species with different ecologies. Our results suggest that tradeoffs between wing and leg modules help shape ontogenetic and evolutionary trajectories, but can be offset by recruiting modules cooperatively. These findings offer a new paradigm for exploring locomotor strategies of flying organisms and their extinct precursors, and thereby elucidating some of the most spectacular diversity in animal history. PMID- 25494706 TI - Ductal carcinoma in situ: recent history and areas of controversy. AB - The authors provide a perspective on the rapidly evolving field of prognostic analyses designed to quantify the risk of local recurrence in conservatively treated ductal carcinoma in situ (DCIS). These include morphologic features variously defined, nomograms, algorithms and multi-gene expression assays-all of which have completed against the perceived conclusions of the randomized trials of irradiation and Tamoxifen for DCIS: "all subsets benefit". At present the majority of newly diagnosed DCIS can be adequately treated with surgery alone. A number will require irradiation to achieve acceptable local control, and a minority will require mastectomy regardless of adjuvant treatments. Differences in the definition of prognostic factors and in the methods used to establish them is a major reason for the lack of consensus in treatment recommendation. PMID- 25494707 TI - Understanding the role of patient organizations in health technology assessment. AB - BACKGROUND: The involvement of patient representatives in health technology assessment is increasingly seen by policy makers and researchers as key for the deployment of patient-centred health care, but there is uncertainty and a lack of theoretical understanding regarding the knowledge and expertise brought by patient representatives and organisations to HTA processes. OBJECTIVE: To propose a conceptually-robust typological model of the knowledge and expertise held by patient organisations. DESIGN, DATA COLLECTION AND ANALYSIS: The study followed a case-study design. Data were collected within an international research project on patient organisations' engagement with knowledge, and included archival and documentary data, in-depth interviews with key members of the organisation and participant observation. Data analysis followed standard procedure of qualitative analysis anchored in an analytic induction approach. RESULTS: Analysis identified three stages in the history of the patient organisation under analysis - Alzheimer's Society. In a first period, the focus is on 'caring knowledge' and an emphasis on its volunteer membership. In a transition stage, a combination of experiential, clinical and scientific knowledge is proposed in an attempt to expand its field of activism into HTA. In the most recent phase, there is a deepening of its network of associations to secure its role in the production of evidence. CONCLUSIONS: Analysis identified an important relationship between the forms of knowledge deployed by patient organisations and the networks of expertise and policy they mobilise to pursue their activities. A model of this relationship is outlined, for the use of further research and practice on patient involvement. PMID- 25494708 TI - How parents can affect excessive spending of time on screen-based activities. AB - BACKGROUND: The aim of this study is to explore the association between family related factors and excessive time spent on screen-based activities among school aged children. METHODS: A cross-sectional survey using the methodology of the Health Behaviour in School-aged Children study was performed in 2013, with data collected from Slovak (n = 258) and Czech (n = 406) 11- and 15-year-old children. The effects of age, gender, availability of a TV or computer in the bedroom, parental rules on time spent watching TV or working on a computer, parental rules on the content of TV programmes and computer work and watching TV together with parents on excessive time spent with screen-based activities were explored using logistic regression models. RESULTS: Two-thirds of respondents watch TV or play computer games at least two hours a day. Older children have a 1.80-times higher chance of excessive TV watching (CI: 1.30-2.51) and a 3.91-times higher chance of excessive computer use (CI: 2.82-5.43) in comparison with younger children. More than half of children have a TV (53%) and a computer (73%) available in their bedroom, which increases the chance of excessive TV watching by 1.59 times (CI: 1.17-2.16) and of computer use by 2.25 times (CI: 1.59-3.20). More than half of parents rarely or never apply rules on the length of TV watching (64%) or time spent on computer work (56%), and their children have a 1.76-times higher chance of excessive TV watching (CI: 1.26-2.46) and a 1.50-times greater chance of excessive computer use (CI: 1.07-2.08). A quarter of children reported that they are used to watching TV together with their parents every day, and these have a 1.84-times higher chance of excessive TV watching (1.25-2.70). CONCLUSIONS: Reducing time spent watching TV by applying parental rules or a parental role model might help prevent excessive time spent on screen-based activities. PMID- 25494709 TI - Identification of Novel Proteasome Inhibitors from an Enaminone Library. AB - A library of structurally distinct enaminones was synthesized using sonication or Ru(II) catalysis to couple primary, secondary, and tertiary thioamides with alpha halocarbonyls or alpha-diazocarbonyls. Screening the library for proteasome inhibition using a luciferase-based assay identified seven structurally diverse compounds. Two of these molecules targeted luciferase, while the remaining five exhibited varying potency and specificity for the trypsin-like, chymotrypsin like, or caspase-like protease activities of the proteasome. Physiological relevance was confirmed by showing these molecules inhibited proteasomal degradation of the full-length protein substrate p21cip1 expressed in tissue culture cells. A cell viability analysis revealed that the proteasome inhibitors differentially affected cell survival. Results indicate a subset of enaminones and precursor molecules identified in this study are good candidates for further development into novel proteasome inhibitors with potential therapeutic value. PMID- 25494710 TI - The effectiveness of integrative medicine interventions on pain and anxiety in cardiovascular inpatients: a practice-based research evaluation. AB - BACKGROUND: Pain and anxiety occurring from cardiovascular disease are associated with long-term health risks. Integrative medicine (IM) therapies reduce pain and anxiety in small samples of hospitalized cardiovascular patients within randomized controlled trials; however, practice-based effectiveness research has been limited. The goal of the study is to evaluate the effectiveness of IM interventions (i.e., bodywork, mind-body and energy therapies, and traditional Chinese medicine) on pain and anxiety measures across a cardiovascular population. METHODS: Retrospective data obtained from medical records identified patients with a cardiovascular ICD-9 code admitted to a large Midwestern hospital between 7/1/2009 and 12/31/2012. Outcomes were changes in patient-reported pain and anxiety, rated before and after IM treatments based on a numeric scale (0 10). RESULTS: Of 57,295 hospital cardiovascular admissions, 6,589 (11.5%) included IM. After receiving IM therapy, patients averaged a 46.5% (p-value < 0.001) decrease in pain and a 54.8% (p-value < 0.001) decrease in anxiety. There was no difference between treatment modalities on pain reduction; however, mind body and energy therapies (p-value < 0.01), traditional Chinese medicine (p-value < 0.05), and combination therapies (p-value < 0.01) were more effective at reducing anxiety than bodywork therapies. Each additional year of age reduced the odds of receiving any IM therapy by two percent (OR: 0.98, p-value < 0.01) and females had 96% (OR: 1.96, p-value < 0.01) higher odds of receiving any IM therapy compared to males. CONCLUSIONS: Cardiovascular inpatients reported statistically significant decreases in pain and anxiety following care with adjunctive IM interventions. This study underscores the potential for future practice-based research to investigate the best approach for incorporating these therapies into an acute care setting such that IM therapies are most appropriately provided to patient populations. PMID- 25494711 TI - Invariant heart beat span versus variant heart beat intervals and its application to fetal ECG extraction. AB - BACKGROUND: The fundamental assumptions for various kinds of fetal electrocardiogram (fECG) extraction methods are not consistent with each other, which is a very important problem needed to be ascertained. METHODS: Based on two public databases, the regularity on ECG wave durations for normal sinus rhythm is investigated statistically. Taking the ascertained regularity as an assumption, a new fECG extraction algorithm is proposed, called Partial R-R interval Resampling (PRR). RESULTS: Both synthetic and real abdominal ECG signals are used to test the algorithm. The results indicate that the PRR algorithm has better performance over the whole R-R interval resampling based comb filtering method (RR) and linear template method (LP), which takes advantages of both LP and RR. CONCLUSIONS: The final drawn conclusion is: (1) the proposition should be true that the individual's heart beat span is invariable for normal sinus rhythm; (2) the proposed PRR fetal ECG extraction algorithm can estimate the maternal ECG (mECG) more accurately and stably even in the condition of large HRV, finally resulting in better fetal ECG extraction. PMID- 25494713 TI - The cross-cultural process of adapting observational tools for pediatric pain assessment: the case of the Dental Discomfort Questionnaire. AB - BACKGROUND: A rigorous cross-cultural adaptation process of an existing instrument could be the best option for measuring health in different cultures, instead of developing a new tool, and prior to psychometric and validation testing. The Dental Discomfort Questionnaire (DDQ), a validated instrument for assessing toothache in young children, has not been cross-culturally adapted so far. This study aimed to explore the detailed phases of the cross-cultural adaptation process of a pain assessment tool, presenting the example of the DDQ Brazilian-Portuguese adapted version. METHODS: The study design was based on the universalist approach, which consists of a sequential analysis to assess the relevant phases of a cross-cultural process before testing the measures of the instrument: conceptual, item, semantic, and operational equivalences. Systematic information was gathered from the literature, expert discussions, translations, and pre-testing through cognitive interviews with Brazilian population. RESULTS: Detailed description of the three major phases for a cross-cultural adaptation process was given. Notes of the changes done in the structure of the presented instrument (DDQ) were specifically pointed out at each phase. Conceptual and item analyses showed that there are similarities in the DDQ construct between the original and Brazilian cultures that require minor modifications. Translations and back-translations allowed the development of the preliminary Brazilian Portuguese version of the DDQ, which was tested and underwent other minor changes to improve its comprehensibility. CONCLUSIONS: Describing the phases was important to show how changes are made in a cross-cultural adaptation process of an instrument. This also could help researchers in adapting similar pediatric pain assessment tools to different cultures. A Brazilian-Portuguese version of the DDQ was presented. PMID- 25494712 TI - Effectiveness of weight loss interventions--is there a difference between men and women: a systematic review. AB - Effective strategies are required to reduce the prevalence of overweight and obesity; however, the effectiveness of current weight loss programmes is variable. One contributing factor may be the difference in weight loss success between men and women. A systematic review was conducted to determine whether the effectiveness of weight loss interventions differs between men and women. Randomized controlled trials published up until March 2014 were included. Effect sizes (Hedges' g) were used to examine the difference in weight outcomes between men and women. A total of 58 studies met the eligibility criteria with 49 studies of higher quality included in the final data synthesis. Eleven studies that directly compared weight loss in men and women reported a significant sex difference. Ten of these reported that men lost more weight than women; however, women also lost a significant amount of weight. Analysis of effect sizes found small differences in weight loss favouring men for both diet (g = 0.489) and diet plus exercise (g = 0.240) interventions. There is little evidence from this review to indicate that men and women should adopt different weight loss strategies. Current evidence supports moderate energy restriction in combination with exercise for weight loss in both men and women. PMID- 25494714 TI - In vitro assessment of the gastrointestinal tolerance and immunomodulatory function of Bacillus methylotrophicus isolated from a traditional Korean fermented soybean food. AB - AIMS: This study aimed to investigate the potential of Bacillus methylotrophicus as a probiotic. METHODS AND RESULTS: A Bacillus isolate designated strain C14 was isolated from Korean traditional fermented soybean paste (doenjang). The strain was identified, and its physiological and biochemical properties were characterized. The gastrointestinal tolerance and immunomodulatory function of strain C14 were also investigated. Strain C14 was identified as B. methylotrophicus by analysis of its biochemical properties using the API 50CHB system and by phylogenetic analysis of the 16S rDNA sequence. Strain C14 showed >80% and >75% of survival for artificial gastric juices (pH 2.5 and 1% pepsin) and 0.5% (w/v) bile salt, respectively. Heat-killed B. methylotrophicus C14 inhibited the adhesion of various pathogens and enhanced the adhesion of probiotic bacteria to Caco-2 cells. The heat-killed cells also induced high levels of immune cell proliferation compared with the control and stimulated interleukin-6 and tumour necrosis factor-alpha production in mouse macrophages. CONCLUSIONS: Bacillus methylotrophicus C14 could be used as a probiotic. SIGNIFICANCE AND IMPACT OF THE STUDY: Recently identified B. methylotrophicus is a new potential probiotic with high gastrointestinal tolerance. PMID- 25494715 TI - Incidence of dementia in relation to genetic variants at PITX2, ZFHX3, and ApoE epsilon4 in atrial fibrillation patients. AB - INTRODUCTION: Mechanisms underlying atrial fibrillation (AF) and dementia are unknown. Some genetic risk factors convey risk for AF and cerebral ischemic events. These markers may identify AF patients at risk for dementia either directly or through a gene-gene interaction with the ApoE epsilon4 variant, a known marker of dementia risk. METHODS: Caucasian patients with AF and a subsequent dementia diagnosis (n = 112) were matched 1:2 on sex, AF onset age, and follow-up period to AF patients without dementia. AF patients with dementia and AF patients without dementia were matched 1:1 on sex and age at dementia diagnosis (n = 112). Genotyping employed Taqman real-time polymerase chain reaction. Multivariable conditional logistic regression was used to examine associations between AF/dementia groups and single nucleotide polymorphism (SNP), as well as gene-gene interactions. RESULTS: In dementia patients, there was an association between the PITX2 loci and AF (rs2634073: odds ratio [OR] = 2.11; P = 0.025 and rs2200733: OR = 2.27; P = 0.029). In patients with AF, there was an association between PITX2 loci, rs2200733, and dementia (OR = 2.15, P = 0.008). There was no association between ApoE epsilon4 allele and AF in patients with dementia, although confirmation of the association between the carriage of ApoE epsilon4 allele and dementia was found (OR = 1.79; P = 0.026) in patients with AF. There were no significant interactions between ApoE epsilon4 allele and both the PITX2 loci and ZFHX3. CONCLUSIONS: These findings support prior studies of ApoE risk of noncerebral vascular accident-related dementia/Alzheimer's risk in the Caucasians and provide support to suggest an association between PITX2 related SNPs and dementia, which may in part be attributed to silent cerebral ischemic events, a hypothesis deserving further testing. PMID- 25494717 TI - ADP-Ribosylargininyl reaction of cholix toxin is mediated through diffusible intermediates. AB - BACKGROUND: Cholix toxin is an ADP-ribosyltransferase found in non-O1/non-O139 strains of Vibrio cholera. The catalytic fragment of cholix toxin was characterized as a diphthamide dependent ADP-ribosyltransferase. RESULTS: Our studies on the enzymatic activity of cholix toxin catalytic fragment show that the transfer of ADP-ribose to toxin takes place by a predominantly intramolecular mechanism and results in the preferential alkylation of arginine residues proximal to the NAD+ binding pocket. Multiple arginine residues, located near the catalytic site and at distal sites, can be the ADP-ribose acceptor in the auto reaction. Kinetic studies of a model enzyme, M8, showed that a diffusible intermediate preferentially reacted with arginine residues in proximity to the NAD+ binding pocket. ADP-ribosylarginine activity of cholix toxin catalytic fragment could also modify exogenous substrates. Auto-ADP-ribosylation of cholix toxin appears to have negatively regulatory effect on ADP-ribosylation of exogenous substrate. However, at the presence of both endogenous and exogenous substrates, ADP-ribosylation of exogenous substrates occurred more efficiently than that of endogenous substrates. CONCLUSIONS: We discovered an ADP ribosylargininyl activity of cholix toxin catalytic fragment from our studies in auto-ADP-ribosylation, which is mediated through diffusible intermediates. The lifetime of the hypothetical intermediate exceeds recorded and predicted lifetimes for the cognate oxocarbenium ion. Therefore, a diffusible strained form of NAD+ intermediate was proposed to react with arginine residues in a proximity dependent manner. PMID- 25494716 TI - RNA-seq analysis of broiler liver transcriptome reveals novel responses to high ambient temperature. AB - BACKGROUND: In broilers, high ambient temperature can result in reduced feed consumption, digestive inefficiency, impaired metabolism, and even death. The broiler sector of the U.S. poultry industry incurs approximately $52 million in heat-related losses annually. The objective of this study is to characterize the effects of cyclic high ambient temperature on the transcriptome of a metabolically active organ, the liver. This study provides novel insight into the effects of high ambient temperature on metabolism in broilers, because it is the first reported RNA-seq study to characterize the effect of heat on the transcriptome of a metabolic-related tissue. This information provides a platform for future investigations to further elucidate physiologic responses to high ambient temperature and seek methods to ameliorate the negative impacts of heat. RESULTS: Transcriptome sequencing of the livers of 8 broiler males using Illumina HiSeq 2000 technology resulted in 138 million, 100-base pair single end reads, yielding a total of 13.8 gigabases of sequence. Forty genes were differentially expressed at a significance level of P-value < 0.05 and a fold-change >= 2 in response to a week of cyclic high ambient temperature with 27 down-regulated and 13 up-regulated genes. Two gene networks were created from the function-based Ingenuity Pathway Analysis (IPA) of the differentially expressed genes: "Cell Signaling" and "Endocrine System Development and Function". The gene expression differences in the liver transcriptome of the heat-exposed broilers reflected physiological responses to decrease internal temperature, reduce hyperthermia induced apoptosis, and promote tissue repair. Additionally, the differential gene expression revealed a physiological response to regulate the perturbed cellular calcium levels that can result from high ambient temperature exposure. CONCLUSIONS: Exposure to cyclic high ambient temperature results in changes at the metabolic, physiologic, and cellular level that can be characterized through RNA-seq analysis of the liver transcriptome of broilers. The findings highlight specific physiologic mechanisms by which broilers reduce the effects of exposure to high ambient temperature. This information provides a foundation for future investigations into the gene networks involved in the broiler stress response and for development of strategies to ameliorate the negative impacts of heat on animal production and welfare. PMID- 25494718 TI - A conceptual framework for evaluating the conceptualization, implementation and performance of transitional care programmes. AB - Developed health systems want to avoid unnecessary hospital admissions by addressing the needs of chronically ill older adults throughout acute episodes of illness. Transitional care (TC) is a set of actions designed to ensure the coordination and continuity of health care as patients transfer between different locations or different levels of care within the same location, of which the main outcome of interest is avoiding hospital readmission. Implementation of TC is complex because it entails different actions to put multiple care components into practice, with various degrees of flexibility of adapting the intervention. Furthermore, the outcome involves behaviour change required by those delivering or receiving the intervention. Although there are examples of promising interventions, the possible variations in conceptualization and implementation present a real challenge for the adaptation of efficacious TC interventions from trial to 'real-world' settings. There is a lack of a theoretical basis or explicit logic model for why adapted interventions should work. This study provides conceptual approaches for the implementation and evaluation of TC programmes. It describes a framework of (1) conceptualization - with respect to the components in an intervention and the population of interest; (2) manner and context of implementation; and (3) evaluation - how these processes of implementation impact health outcomes. PMID- 25494719 TI - A randomized controlled trial examining the effectiveness of a STOMA psychosocial intervention programme on the outcomes of colorectal patients with a stoma: study protocol. AB - AIMS: To report a study protocol that evaluates the effects of a psychosocial intervention on patients with a newly formed stoma. BACKGROUND: With the loss of a significant body function and distorted body image, stoma patients experience physical, psychological and social challenges. Nurses have an important role in helping patients' make a smooth transition to living with their stoma. Limited studies have examined the effects of psychosocial interventions on improving stoma-related health outcomes. DESIGN: A randomized controlled trial is planned. METHODS: Eighty-four patients with newly formed stoma in a tertiary hospital in Singapore (Research Ethics Committee approval obtained in January 2013) will be recruited. Participants will be randomly assigned to either a control group who receive routine care or an intervention group who receive STOMA psychosocial intervention besides routine care. Outcome variables include stoma care self efficacy, days to stoma proficiency, length of hospital stay, acceptance of stoma, anxiety and depression and quality of life. Data will be collected at four time points: before randomization and intervention (baseline), on the day of discharge (mid-intervention), at 4 weeks after discharge (postintervention 1) and at 4 months after discharge (postintervention 2). DISCUSSION: This study will develop a psychosocial intervention programme, which may improve patients' stoma related outcomes. The findings will provide direction to health professionals about education and the type of support that could be offered to patients concerning stoma care in the hospital setting, which will eventually improve their quality of life. PMID- 25494720 TI - "It's a horrible sin. If they find out, I will not be able to stay": Orthodox Jewish gay men's experiences living in secrecy. AB - This qualitative study examined the intersection of sexual orientation and religion in the Jewish Orthodox community by exploring 22 Orthodox Jewish gay men's experiences living in secrecy. Analysis of in-depth interviews conducted with these men revealed four primary themes: emotional turmoil, ways of coping, impact on family relationships, and importance of the context. Findings from this study describe the daily struggles these men experienced keeping their homosexuality a secret. The findings suggest that in order to design effective interventions with this population, it is crucial to consider the larger community and religious context. PMID- 25494721 TI - Arabidopsis ROOT HAIR DEFECTIVE3 is involved in nitrogen starvation-induced anthocyanin accumulation. AB - Anthocyanin accumulation is a common phenomenon seen in plants under environmental stress. In this study, we identified a new allele of ROOT HAIR DEFECTIVE3 (RHD3) showing an anthocyanin overaccumulation phenotype under nitrogen starvation conditions. It is known that ethylene negatively regulates light- and sucrose-induced anthocyanin biosynthesis. We hypothesized that RHD3 achieves its negative effect on anthocyanin biosynthesis via an ethylene regulating pathway. In support of this, similar to rhd3 mutants, the Arabidopsis ethylene signaling mutants etr1, ein2, and ein3/eil1 showed an anthocyanin overaccumulation phenotype under nitrogen starvation conditions. The ethylene precursor ACC strongly suppressed anthocyanin accumulation, dependent on ETR1, EIN2, EIN3/EIL1, and, partially, RHD3. In addition, inactivating RHD3 partially reversed the suppressive effect of ETO1 inactivation-evoked endogenous ethylene production on anthocyanin accumulation. The expression of nitrogen starvation induced anthocyanin biosynthesis genes was negatively regulated by RHD3, but ethylene response genes were positively regulated by RHD3. Wild-type seedlings overexpressing RHD3 showed similar phenotypes to rhd3 mutants, indicating the existence of a fine-tuned relationship between gene expression and function. RHD3 was initially identified as a gene involved in root hair development. This study uncovered a new physiological function of RHD3 in nitrogen starvation-induced anthocyanin accumulation and ethylene homeostasis. [Correction added on 6 August 2015, after first online publication: "RND3" corrected to "RHD3".]. PMID- 25494722 TI - Accelerated endochondral growth in adolescents with idiopathic scoliosis: a preliminary histomorphometric study. AB - BACKGROUND: Abnormal longitudinal growth has been identified in the early pubertal stage of idiopathic scoliosis (IS) and is thought to contribute to the development of scoliosis. This phenotype may be caused by abnormal endochondral ossification, but histological evidence is lacking. The aim of this study was to investigate whether there is abnormal endochondral ossification in IS patients at early stage of puberty by histomorphometric analysis of their iliac cartilage. METHODS: Fifty-two patients with IS and 19 controls were recruited and grouped according to their Risser grade (Group A: Risser grade 0 with Oxford stage 2-3; Group B: Risser grade 2). Group A consisted of 20 IS patients (mean age: 12.3 years) and 9 controls (mean age: 12.0 years), while Group B included 32 IS patients (mean age: 13.8 years) and 10 controls (mean age: 13.7 years). Biopsies of the iliac cartilage were harvested intra-operatively and prepared using routine histological methods. Histomorphometric analysis was performed to quantify the thickness of the hypertrophic zone, the area and number of chondrocytes in the cell-nest, and the number of chondrocytes in the proliferative zone using Image-Pro Plus software. RESULTS: In Group A, a significantly thicker hypertrophic zone and larger cell-nest area and number of cells within the cell-nest, and in the proliferative zone, were found in iliac cartilages from IS patients compared with those of controls (all P < 0.05). In group B however, there were no significant differences in histomorphometric parameters between IS patients and the controls. CONCLUSIONS: The differences in the histomorphometric results between IS patients and their controls for patients with Risser grade 0 and Oxford grades 2 & 3, but not in those with Risser grade 2, indicated a pattern of accelerated endochondral growth in IS at the early stage of puberty, but not at the late stage. TRIAL REGISTRATION: Current Controlled Trials: ChiCTR-CCC-13003988. Registered 17 December 2013. http://www.chictr.org/usercenter/project/edit.aspx?proj=6233. PMID- 25494724 TI - Design and fabrication of zwitter-wettable nanostructured films. AB - Manipulating surface properties using chemistry and roughness has led to the development of advanced multifunctional surfaces. Here, in a nanostructured polymer film consisting of a hydrophilic reservoir of chitosan/carboxymethyl cellulose capped with various hydrophobic layers, we demonstrate the role of a third design factor, water permeation rate. We use this additional design criterion to produce antifogging coatings that readily absorb water vapor while simultaneously exhibiting hydrophobic character to liquid water. These zwitter wettable films, produced via aqueous layer-by-layer assembly, consist of a nanoscale thin hydrophobic capping layer (chitosan/Nafion) that enables water vapor to diffuse rapidly into the underlying hydrophilic reservoir rather than nucleating drops of liquid water on the surface. We characterize these novel films using a quartz crystal microbalance with dissipation monitoring (QCM-D) and via depth-profiling X-ray photoelectron spectroscopy (XPS) in addition to extensive testing for fogging/antifogging performance. PMID- 25494723 TI - Mononeuritis multiplex as the first presentation of refractory sarcoidosis responsive to etanercept. AB - BACKGROUND: Several disorders may present with mononeuritis multiplex and the etiological diagnosis can be challenging. CASE PRESENTATION: We report a 42 year old female who presented with severe lower limb neuropathic pain, asymmetric weakness and sensory impairment and was diagnosed with mononeuritis multiplex. Biopsy showed a granulomatous vasculitic process with eosinophils, scarce granulomata and axonal neuropathy and granulomatosis with poliangiitis was assumed. Steroids, cyclophosphamide, alemtuzumab, azathioprine, mycophenolate mofetil and rituximab were used, all with transient and insufficient response. Skin biopsy performed in a further exacerbation allowed sarcoidosis diagnosis. Infliximab and, later, adalimumab induced good clinical and laboratorial response, but neutralizing antibodies developed to both drugs, so etanercept was tried with good clinical response. CONCLUSIONS: To the best of our knowledge, this is the first report of sarcoidosis successfully treated with etanercept. This drug may be considered in refractory sarcoidosis after other TNF-alpha inhibitors failure, having the advantage of not being associated with neutralizing antibodies development. PMID- 25494725 TI - Communication: time- and space-sliced velocity map electron imaging. AB - We develop a new method to achieve slice electron imaging using a conventional velocity map imaging apparatus with two additional components: a fast frame complementary metal-oxide semiconductor camera and a high-speed digitizer. The setup was previously shown to be capable of 3D detection and coincidence measurements of ions. Here, we show that when this method is applied to electron imaging, a time slice of 32 ps and a spatial slice of less than 1 mm thick can be achieved. Each slice directly extracts 3D velocity distributions of electrons and provides electron velocity distributions that are impossible or difficult to obtain with a standard 2D imaging electron detector. PMID- 25494726 TI - Fluctuating magnetic field induced resonant activation. AB - In this paper, we have studied the properties of a Brownian particle at stationary state in the presence of a fluctuating magnetic field. Time dependence of the field makes the system thermodynamically open. As a signature of that the steady state distribution function becomes function of damping strength, intensity of fluctuations and constant parts of the applied magnetic field. It also depends on the correlation time of the fluctuating magnetic field. Our another observation is that the random magnetic field can induce the resonant activation phenomenon. Here correlation time is increased under the fixed variance of the fluctuating field. But if the correlation time (tau) increases under the fixed field strength then the mean first passage time rapidly grows at low tau and it almost converges at other limit. This is sharp contrast to the usual colored noise driven open system case where the mean first passage time diverges exponentially. We have also observed that a giant enhancement of barrier crossing rate occurs particularly at large strength of constant parts of the applied magnetic field even for very weak fluctuating magnetic field. Finally, break down of the Arrhenius result and disappearance of the Kramers' turn over phenomenon may occur in the presence of a fluctuating magnetic field. PMID- 25494727 TI - Nonequilibrium thermodynamics of nucleation. AB - We present a novel approach to nucleation processes based on the GENERIC framework (general equation for the nonequilibrium reversible-irreversible coupling). Solely based on the GENERIC structure of time-evolution equations and thermodynamic consistency arguments of exchange processes between a metastable phase and a nucleating phase, we derive the fundamental dynamics for this phenomenon, based on continuous Fokker-Planck equations. We are readily able to treat non-isothermal nucleation even when the nucleating cores cannot be attributed intensive thermodynamic properties. In addition, we capture the dynamics of the time-dependent metastable phase being continuously expelled from the nucleating phase, and keep rigorous track of the volume corrections to the dynamics. Within our framework the definition of a thermodynamic nuclei temperature is manifest. For the special case of nucleation of a gas phase towards its vapor-liquid coexistence, we illustrate that our approach is capable of reproducing recent literature results obtained by more microscopic considerations for the suppression of the nucleation rate due to nonisothermal effects. PMID- 25494728 TI - Accurate adiabatic correction in the hydrogen molecule. AB - A new formalism for the accurate treatment of adiabatic effects in the hydrogen molecule is presented, in which the electronic wave function is expanded in the James-Coolidge basis functions. Systematic increase in the size of the basis set permits estimation of the accuracy. Numerical results for the adiabatic correction to the Born-Oppenheimer interaction energy reveal a relative precision of 10(-12) at an arbitrary internuclear distance. Such calculations have been performed for 88 internuclear distances in the range of 0 < R ? 12 bohrs to construct the adiabatic correction potential and to solve the nuclear Schrodinger equation. Finally, the adiabatic correction to the dissociation energies of all rovibrational levels in H2, HD, HT, D2, DT, and T2 has been determined. For the ground state of H2 the estimated precision is 3 * 10(-7) cm(-1), which is almost three orders of magnitude higher than that of the best previous result. The achieved accuracy removes the adiabatic contribution from the overall error budget of the present day theoretical predictions for the rovibrational levels. PMID- 25494729 TI - Modeling light-induced charge transfer dynamics across a metal-molecule-metal junction: bridging classical electrodynamics and quantum dynamics. AB - We develop a numerical approach for simulating light-induced charge transport dynamics across a metal-molecule-metal conductance junction. The finite difference time-domain method is used to simulate the plasmonic response of the metal structures. The Huygens subgridding technique, as adapted to Lorentz media, is used to bridge the vastly disparate length scales of the plasmonic metal electrodes and the molecular system, maintaining accuracy. The charge and current densities calculated with classical electrodynamics are transformed to an electronic wavefunction, which is then propagated through the molecular linker via the Heisenberg equations of motion. We focus mainly on development of the theory and exemplify our approach by a numerical illustration of a simple system consisting of two silver cylinders bridged by a three-site molecular linker. The electronic subsystem exhibits fascinating light driven dynamics, wherein the charge density oscillates at the driving optical frequency, exhibiting also the natural system timescales, and a resonance phenomenon leads to strong conductance enhancement. PMID- 25494730 TI - Multi-level coupled cluster theory. AB - We present a general formalism where different levels of coupled cluster theory can be applied to different parts of the molecular system. The system is partitioned into subsystems by Cholesky decomposition of the one-electron Hartree Fock density matrix. In this way the system can be divided across chemical bonds without discontinuities arising. The coupled cluster wave function is defined in terms of cluster operators for each part and these are determined from a set of coupled equations. The total wave function fulfills the Pauli-principle across all borders and levels of electron correlation. We develop the associated response theory for this multi-level coupled cluster theory and present proof of principle applications. The formalism is an essential tool in order to obtain size-intensive complexity in the calculation of local molecular properties. PMID- 25494731 TI - Many-body exchange-overlap interactions in rare gases and water. AB - Generalized-gradient approximations (GGAs) of density-functional theory can suffer from substantial many-body errors in molecular systems interacting through weak non-covalent forces. Here, the errors of a range of GGAs for the 3-body energies of trimers of rare gases and water are investigated. The patterns of 3 body errors are similar for all the systems, and are related to the form of the exchange-enhancement factor FX(x) at large reduced gradient x, which also governs 2-body exchange-overlap errors. However, it is shown that the 3-body and 2-body errors depend in opposite ways on FX(x), so that they tend to cancel in molecular aggregates. Embedding arguments are used to achieve a partial separation of contributions to 3-body error from polarization, non-local correlation, and exchange, and it emerges that exchange is a major contributor. The practical importance of beyond-2-body errors is illustrated by the energetics of the water hexamer. An analysis of exchange-energy distributions is used to elucidate why 2 body and 3-body errors of GGAs depend in opposite ways on FX(x). The relevance of the present analysis to a range of other molecular systems is noted. PMID- 25494732 TI - Derivative discontinuity and exchange-correlation potential of meta-GGAs in density-functional theory. AB - We investigate fundamental properties of meta-generalized-gradient approximations (meta-GGAs) to the exchange-correlation energy functional, which have an implicit density dependence via the Kohn-Sham kinetic-energy density. To this purpose, we construct the most simple meta-GGA by expressing the local exchange-correlation energy per particle as a function of a fictitious density, which is obtained by inverting the Thomas-Fermi kinetic-energy functional. This simple functional considerably improves the total energy of atoms as compared to the standard local density approximation. The corresponding exchange-correlation potentials are then determined exactly through a solution of the optimized effective potential equation. These potentials support an additional bound state and exhibit a derivative discontinuity at integer particle numbers. We further demonstrate that through the kinetic-energy density any meta-GGA incorporates a derivative discontinuity. However, we also find that for commonly used meta-GGAs the discontinuity is largely underestimated and in some cases even negative. PMID- 25494733 TI - Transitionless driving on adiabatic search algorithm. AB - We study quantum dynamics of the adiabatic search algorithm with the equivalent two-level system. Its adiabatic and non-adiabatic evolution is studied and visualized as trajectories of Bloch vectors on a Bloch sphere. We find the change in the non-adiabatic transition probability from exponential decay for the short running time to inverse-square decay in asymptotic running time. The scaling of the critical running time is expressed in terms of the Lambert W function. We derive the transitionless driving Hamiltonian for the adiabatic search algorithm, which makes a quantum state follow the adiabatic path. We demonstrate that a uniform transitionless driving Hamiltonian, approximate to the exact time dependent driving Hamiltonian, can alter the non-adiabatic transition probability from the inverse square decay to the inverse fourth power decay with the running time. This may open up a new but simple way of speeding up adiabatic quantum dynamics. PMID- 25494734 TI - Bottom-up derivation of conservative and dissipative interactions for coarse grained molecular liquids with the conditional reversible work method. AB - Molecular simulations of soft matter systems have been performed in recent years using a variety of systematically coarse-grained models. With these models, structural or thermodynamic properties can be quite accurately represented while the prediction of dynamic properties remains difficult, especially for multi component systems. In this work, we use constraint molecular dynamics simulations for calculating dissipative pair forces which are used together with conditional reversible work (CRW) conservative forces in dissipative particle dynamics (DPD) simulations. The combined CRW-DPD approach aims to extend the representability of CRW models to dynamic properties and uses a bottom-up approach. Dissipative pair forces are derived from fluctuations of the direct atomistic forces between mapped groups. The conservative CRW potential is obtained from a similar series of constraint dynamics simulations and represents the reversible work performed to couple the direct atomistic interactions between the mapped atom groups. Neopentane, tetrachloromethane, cyclohexane, and n-hexane have been considered as model systems. These molecular liquids are simulated with atomistic molecular dynamics, coarse-grained molecular dynamics, and DPD. We find that the CRW-DPD models reproduce the liquid structure and diffusive dynamics of the liquid systems in reasonable agreement with the atomistic models when using single-site mapping schemes with beads containing five or six heavy atoms. For a two-site representation of n-hexane (3 carbons per bead), time scale separation can no longer be assumed and the DPD approach consequently fails to reproduce the atomistic dynamics. PMID- 25494735 TI - Dissipation-induced transition of a simple harmonic oscillator. AB - We investigate the dissipation-induced transition probabilities between any two eigenstates of a simple harmonic oscillator. Using the method developed by Yu and Sun [Phys. Rev. A 49, 592 (1994)], the general analytical expressions for the transition probabilities are obtained. The special cases: transition probabilities from the ground state to the first few excited states are then discussed in detail. Different from the previous studies in the literature where only the effect of damping was considered, it is found that the Brownian motion makes the transitions between states of different parity possible. The limitations of the applicability of our results are also discussed. PMID- 25494736 TI - Relations between environmental noise and electronic coupling for optimal exciton transfer in one- and two-dimensional homogeneous and inhomogeneous quantum systems. AB - Recent studies have indicated that environmental noise may increase energy transfer efficiency in quantum systems. For homogeneous networks of chromophores previous studies have primarily considered excitonic transport in one-dimensional (linear) networks. In our study, we expand previous research to a two-dimensional fully coupled topology of chromophore molecules. We demonstrate that not only does an optimal dephasing rate exist in both one- and two-dimensional networks but also that it increases in magnitude with increasing coupling strength between chromophores. Optimal transport occurs when the noise quenches the entanglement between local modes that prevent the exciton from moving efficiently to the target site. We find that these results are insensitive to minor site defects such as those found in realistic systems. We contrast these findings to systems with a high degree of inhomogeneity, in which the optimal dephasing rate is largely set by the system topology and does not vary significantly with respect to coupling strength. Our findings have potential applications to systems such as quantum dot arrays and carbon nanotube structures. PMID- 25494737 TI - Smoothed particle hydrodynamics model for Landau-Lifshitz-Navier-Stokes and advection-diffusion equations. AB - We propose a novel smoothed particle hydrodynamics (SPH) discretization of the fully coupled Landau-Lifshitz-Navier-Stokes (LLNS) and stochastic advection diffusion equations. The accuracy of the SPH solution of the LLNS equations is demonstrated by comparing the scaling of velocity variance and the self-diffusion coefficient with kinetic temperature and particle mass obtained from the SPH simulations and analytical solutions. The spatial covariance of pressure and velocity fluctuations is found to be in a good agreement with theoretical models. To validate the accuracy of the SPH method for coupled LLNS and advection diffusion equations, we simulate the interface between two miscible fluids. We study formation of the so-called "giant fluctuations" of the front between light and heavy fluids with and without gravity, where the light fluid lies on the top of the heavy fluid. We find that the power spectra of the simulated concentration field are in good agreement with the experiments and analytical solutions. In the absence of gravity, the power spectra decay as the power -4 of the wavenumber except for small wavenumbers that diverge from this power law behavior due to the effect of finite domain size. Gravity suppresses the fluctuations, resulting in much weaker dependence of the power spectra on the wavenumber. Finally, the model is used to study the effect of thermal fluctuation on the Rayleigh-Taylor instability, an unstable dynamics of the front between a heavy fluid overlaying a light fluid. The front dynamics is shown to agree well with the analytical solutions. PMID- 25494738 TI - Narrowing the error in electron correlation calculations by basis set re hierarchization and use of the unified singlet and triplet electron-pair extrapolation scheme: application to a test set of 106 systems. AB - A method previously suggested to calculate the correlation energy at the complete one-electron basis set limit by reassignment of the basis hierarchical numbers and use of the unified singlet- and triplet-pair extrapolation scheme is applied to a test set of 106 systems, some with up to 48 electrons. The approach is utilized to obtain extrapolated correlation energies from raw values calculated with second-order Moller-Plesset perturbation theory and the coupled-cluster singles and doubles excitations method, some of the latter also with the perturbative triples corrections. The calculated correlation energies have also been used to predict atomization energies within an additive scheme. Good agreement is obtained with the best available estimates even when the (d, t) pair of hierarchical numbers is utilized to perform the extrapolations. This conceivably justifies that there is no strong reason to exclude double-zeta energies in extrapolations, especially if the basis is calibrated to comply with the theoretical model. PMID- 25494739 TI - A benchmark study of electronic excitation energies, transition moments, and excited-state energy gradients on the nicotine molecule. AB - In this work, we report a comparative study of computed excitation energies, oscillator strengths, and excited-state energy gradients of (S)-nicotine, chosen as a test case, using multireference methods, coupled cluster singles and doubles, and methods based on time-dependent density functional theory. This system was chosen because its apparent simplicity hides a complex electronic structure, as several different types of valence excitations are possible, including n-pi(*), pi-pi(*), and charge-transfer states, and in order to simulate its spectrum it is necessary to describe all of them consistently well by the chosen method. PMID- 25494740 TI - Efficient field-theoretic simulation of polymer solutions. AB - We present several developments that facilitate the efficient field-theoretic simulation of polymers by complex Langevin sampling. A regularization scheme using finite Gaussian excluded volume interactions is used to derive a polymer solution model that appears free of ultraviolet divergences and hence is well suited for lattice-discretized field theoretic simulation. We show that such models can exhibit ultraviolet sensitivity, a numerical pathology that dramatically increases sampling error in the continuum lattice limit, and further show that this pathology can be eliminated by appropriate model reformulation by variable transformation. We present an exponential time differencing algorithm for integrating complex Langevin equations for field theoretic simulation, and show that the algorithm exhibits excellent accuracy and stability properties for our regularized polymer model. These developments collectively enable substantially more efficient field-theoretic simulation of polymers, and illustrate the importance of simultaneously addressing analytical and numerical pathologies when implementing such computations. PMID- 25494741 TI - Understanding generalized inversions of nuclear magnetic resonance transverse relaxation time in porous media. AB - The nuclear magnetic resonance transverse relaxation time T2, measured using the Carr-Purcell-Meiboom-Gill (CPMG) experiment, is a powerful method for obtaining unique information on liquids confined in porous media. Furthermore, T2 provides structural information on the porous material itself and has many applications in petrophysics, biophysics, and chemical engineering. Robust interpretation of T2 distributions demands appropriate processing of the measured data since T2 is influenced by diffusion through magnetic field inhomogeneities occurring at the pore scale, caused by the liquid/solid susceptibility contrast. Previously, we introduced a generic model for the diffusion exponent of the form -ante(k) (where n is the number and te the temporal separation of spin echoes, and a is a composite diffusion parameter) in order to distinguish the influence of relaxation and diffusion in CPMG data. Here, we improve the analysis by introducing an automatic search for the optimum power k that best describes the diffusion behavior. This automated method is more efficient than the manual trial and-error grid search adopted previously, and avoids variability through subjective judgments of experimentalists. Although our method does not avoid the inherent assumption that the diffusion exponent depends on a single k value, we show through simulation and experiment that it is robust in measurements of heterogeneous systems that violate this assumption. In this way, we obtain quantitative T2 distributions from complicated porous structures and demonstrate the analysis with examples of ceramics used for filtration and catalysis, and limestone of relevance to the construction and petroleum industries. PMID- 25494742 TI - Proton decoupling and recoupling under double-nutation irradiation in solid-state NMR. AB - The effect of (1)H decoupling in magic-angle spinning solid-state NMR is studied under radiofrequency irradiation causing simultaneous nutations around a pair of orthogonal axes. Double-nutation with an arbitrary pair of nutation frequencies is implemented through modulation of the amplitude, phase, and frequency of the transmitting pulses. Similarity and difference of double-nutation decoupling and two-pulse phase-modulation decoupling schemes [A. E. Bennett, C. M. Rienstra, M. Auger, K. V. Lakshmi, and R. G. Griffin, J. Chem. Phys. 103, 6951-6958 (1995) and I. Scholz, P. Hodgkinson, B. H. Meier, and M. Ernst, J. Chem. Phys. 130, 114510 (2009)] are discussed. The structure of recoupling bands caused by interference of the (1)H spin nutation with sample spinning is studied by both experiments and numerical simulations. PMID- 25494743 TI - Intermolecular potential energy surface and thermophysical properties of the CH4 N2 system. AB - A five-dimensional potential energy surface (PES) for the interaction of a rigid methane molecule with a rigid nitrogen molecule was determined from quantum chemical ab initio calculations. The counterpoise-corrected supermolecular approach at the CCSD(T) level of theory was utilized to compute a total of 743 points on the PES. The interaction energies were calculated using basis sets of up to quadruple-zeta quality with bond functions and were extrapolated to the complete basis set limit. An analytical site-site potential function with nine sites for methane and five sites for nitrogen was fitted to the interaction energies. The PES was validated by calculating the cross second virial coefficient as well as the shear viscosity and binary diffusion coefficient in the dilute-gas limit for CH4-N2 mixtures. An improved PES was obtained by adjusting a single parameter of the analytical potential function in such a way that quantitative agreement with the most accurate experimental values of the cross second virial coefficient was achieved. The transport property values obtained with the adjusted PES are in good agreement with the best experimental data. PMID- 25494744 TI - Phosphorescence lifetimes of organic light-emitting diodes from two-component time-dependent density functional theory. AB - "Spin-forbidden" transitions are calculated for an eight-membered set of iridium containing candidate molecules for organic light-emitting diodes (OLEDs) using two-component time-dependent density functional theory. Phosphorescence lifetimes (obtained from averaging over relevant excitations) are compared to experimental data. Assessment of parameters like non-distorted and distorted geometric structures, density functionals, relativistic Hamiltonians, and basis sets was done by a thorough study for Ir(ppy)3 focussing not only on averaged phosphorescence lifetimes, but also on the agreement of the triplet substate structure with experimental data. The most favorable methods were applied to an eight-membered test set of OLED candidate molecules; Boltzmann-averaged phosphorescence lifetimes were investigated concerning the convergence with the number of excited states and the changes when including solvent effects. Finally, a simple model for sorting out molecules with long averaged phosphorescence lifetimes is developed by visual inspection of computationally easily achievable one-component frontier orbitals. PMID- 25494745 TI - Potential energy surface and bound states of the NH3-Ar and ND3-Ar complexes. AB - A new, four-dimensional potential energy surface for the interaction of NH3 and ND3 with Ar is computed using the coupled-cluster method with single, double, and perturbative triple excitations and large basis sets. The umbrella motion of the ammonia molecule is explicitly taken into account. The bound states of both NH3 Ar and ND3-Ar are calculated on this potential for total angular momentum values from J = 0 to 10, with the inclusion of Coriolis interactions. The energies and splittings of the rovibrational levels are in excellent agreement with the extensive high-resolution spectroscopic data accumulated over the years in the infrared and microwave regions for both complexes, which demonstrates the quality of the potential energy surface. PMID- 25494746 TI - The B11244 story: rovibrational calculations for C3H(+) and C3H(-) revisited. AB - New theoretical values for the rovibrational parameters of C3H(+) and C3H(-) in the ground vibrational states are reported for the quartic internal coordinate force fields constructed by Huang et al. [Astrophys. J., Lett. 768, L25 (2013)] and Fortenberry et al. [Astrophys. J. 772, 39 (2014)]. Effective spectroscopic parameters are derived from the rovibrational energies, calculated up to J = 20 for C3H(+) and J = 12 for C3H(-) by means of a computational strategy for numerically exact rovibrational computations. Our results help to resolve a disharmony between the experimental observations and previous theoretical predictions in the case of C3H(+): we show that the previously used perturbational approach is not sufficient to reliably predict relevant spectroscopic properties of C3H(+) and that the force field of Huang et al. in combination with the numerically exact rovibrational treatment in fact supports the experimental identification of C3H(+), in contrast to the original conclusion of Huang et al. and Fortenberry et al. that the astronomical assignment of the B11244 carrier to C3H(+) is incorrect. PMID- 25494747 TI - Suppression of the molecular ultra-fast dissociation in bromomethane clusters. AB - We address the influence of clustering on the ultra-fast dissociation of bromomethane. Valence and core photo-electron spectroscopy, partial electron yield absorption, and resonant Auger spectroscopy have been used together with ab initio calculations to investigate the properties of the ultra-fast dissociation. The ratio of ultra-fast dissociation of molecules in clusters as compared to free molecules is determined to be significantly reduced. We propose partial delocalization of the excited electronic state as being responsible for this behavior. PMID- 25494748 TI - On readout of vibrational qubits using quantum beats. AB - Readout of the final states of qubits is a crucial step towards implementing quantum computation in experiment. Although not scalable to large numbers of qubits per molecule, computational studies show that molecular vibrations could provide a significant (factor 2-5 in the literature) increase in the number of qubits compared to two-level systems. In this theoretical work, we explore the process of readout from vibrational qubits in thiophosgene molecule, SCCl2, using quantum beat oscillations. The quantum beats are measured by first exciting the superposition of the qubit-encoding vibrational states to the electronically excited readout state with variable time-delay pulses. The resulting oscillation of population of the readout state is then detected as a function of time delay. In principle, fitting the quantum beat signal by an analytical expression should allow extracting the values of probability amplitudes and the relative phases of the vibrational qubit states. However, we found that if this procedure is implemented using the standard analytic expression for quantum beats, a non negligible phase error is obtained. We discuss the origin and properties of this phase error, and propose a new analytical expression to correct the phase error. The corrected expression fits the quantum beat signal very accurately, which may permit reading out the final state of vibrational qubits in experiments by combining the analytic fitting expression with numerical modelling of the readout process. The new expression is also useful as a simple model for fitting any quantum beat experiments where more accurate phase information is desired. PMID- 25494749 TI - Comparative modelling of chemical ordering in palladium-iridium nanoalloys. AB - Chemical ordering in "magic-number" palladium-iridium nanoalloys has been studied by means of density functional theory (DFT) computations, and compared to those obtained by the Free Energy Concentration Expansion Method (FCEM) using derived coordination dependent bond energy variations (CBEV), and by the Birmingham Cluster Genetic Algorithm using the Gupta potential. Several compositions have been studied for 38- and 79-atom particles as well as the site preference for a single Ir dopant atom in the 201-atom truncated octahedron (TO). The 79- and 38 atom nanoalloy homotops predicted for the TO by the FCEM/CBEV are shown to be, respectively, the global minima and competitive low energy minima. Significant reordering of minima predicted by the Gupta potential is seen after reoptimisation at the DFT level. PMID- 25494750 TI - Unveiling the mechanism of photoinduced isomerization of the photoactive yellow protein (PYP) chromophore. AB - A detailed theoretical analysis, based on extensive ab initio second-order approximate coupled cluster calculations, has been performed for the S1 potential energy surface (PES) of four photoactive yellow protein (PYP) chromophore derivatives that are hydrogen bonded with two water molecules and differ merely in the carbonyl substituent. The main focus is put on contrasting the isomerization properties of these four species in the S1 excited state, related to torsion around the chromophore's single and double carbon-carbon bonds. The analysis provides evidence of the different isomerization behavior of these four chromophore complexes, which relates to the difference in their carbonyl substituents. While a stable double-bond torsion pathway exists on the S1 PES of the chromophores bearing the -O-CH3 and -NH2 substituents, this is not the case for the -S-CH3 and -CH3 substituted species. The presence of the -S-CH3 group leads to a strong instability of the chromophore with respect to the single-bond twist, whereas in the case of the -CH3 substituent a crossing of the S1 and S2 PESs occurs, which perturbs the pathway. Based on this analysis, the key factors that support the double-bond torsion have been identified. These are (i) the hydrogen bonds at the phenolic oxygen of the chromophore, (ii) the weak electron acceptor character of the carbonyl group, and (iii) the ethylene-like pattern of the torsion in the beginning of the process. Our results suggest that the interplay between these factors determines the chromophore's isomerization in the solvent environment and in the native PYP environment. PMID- 25494751 TI - Probing the electronic and vibrational structure of Au2Al2(-) and Au2Al2 using photoelectron spectroscopy and high resolution photoelectron imaging. AB - The electronic and vibrational structures of Au2Al2(-) and Au2Al2 have been investigated using photoelectron spectroscopy (PES), high-resolution photoelectron imaging, and theoretical calculations. Photoelectron spectra taken at high photon energies with a magnetic-bottle apparatus reveal numerous detachment transitions and a large energy gap for the neutral Au2Al2. Vibrationally resolved PE spectra are obtained using high-resolution photoelectron imaging for the ground state detachment transition of Au2Al2(-) at various photon energies (670.55-843.03 nm). An accurate electron affinity of 1.4438(8) eV is obtained for the Au2Al2 neutral cluster, as well as two vibrational frequencies at 57 +/- 8 and 305 +/- 13 cm(-1). Hot bands transitions yield two vibrational frequencies for Au2Al2(-) at 57 +/- 10 and 144 +/- 12 cm( 1). The obtained vibrational and electronic structure information is compared with density functional calculations, unequivocally confirming that both Au2Al2( ) and Au2Al2 possess C2v tetrahedral structures. PMID- 25494752 TI - Time-resolved radiation chemistry: dynamics of electron attachment to uracil following UV excitation of iodide-uracil complexes. AB - Electron attachment to uracil was investigated by applying time-resolved photoelectron imaging to iodide-uracil (I(-)U) complexes. In these studies, an ultraviolet pump pulse initiated charge transfer from the iodide to the uracil, and the resulting dynamics of the uracil temporary negative ion were probed. Five different excitation energies were used, 4.00 eV, 4.07 eV, 4.14 eV, 4.21 eV, and 4.66 eV. At the four lowest excitation energies, which lie near the vertical detachment energy of the I(-)U complex (4.11 eV), signatures of both the dipole bound (DB) as well as the valence bound (VB) anion of uracil were observed. In contrast, only the VB anion was observed at 4.66 eV, in agreement with previous experiments in this higher energy range. The early-time dynamics of both states were highly excitation energy dependent. The rise time of the DB anion signal was ~250 fs at 4.00 eV and 4.07 eV, ~120 fs at 4.14 eV and cross-correlation limited at 4.21 eV. The VB anion rise time also changed with excitation energy, ranging from 200 to 300 fs for excitation energies 4.00-4.21 eV, to a cross-correlation limited time at 4.66 eV. The results suggest that the DB state acts as a "doorway" state to the VB anion at 4.00-4.21 eV, while direct attachment to the VB anion occurs at 4.66 eV. PMID- 25494753 TI - Quantum interference in polyenes. AB - The explicit form of the zeroth Green's function in the Huckel model, approximated by the negative of the inverse of the Huckel matrix, has direct quantum interference consequences for molecular conductance. We derive a set of rules for transmission between two electrodes attached to a polyene, when the molecule is extended by an even number of carbons at either end (transmission unchanged) or by an odd number of carbons at both ends (transmission turned on or annihilated). These prescriptions for the occurrence of quantum interference lead to an unexpected consequence for switches which realize such extension through electrocyclic reactions: for some specific attachment modes the chemically closed ring will be the ON position of the switch. Normally the signs of the entries of the Green's function matrix are assumed to have no physical significance; however, we show that the signs may have observable consequences. In particular, in the case of multiple probe attachments - if coherence in probe connections can be arranged - in some cases new destructive interference results, while in others one may have constructive interference. One such case may already exist in the literature. PMID- 25494754 TI - Ba2phenanthrene is the main component in the Ba-doped phenanthrene superconductor. AB - We have systematically investigated the crystal structure of Ba-doped phenanthrene with various Ba doping levels by the first-principles calculations combined with the X-ray diffraction (XRD) spectra simulations. Although the experimental stoichiometry ratio of Ba atom and phenanthrene molecule is 1.5:1, the simulated XRD spectra, space group symmetry and optimized lattice parameters of Ba1.5phenanthrene are not consistent with the experimental ones, while the results for Ba2phenanthrene are in good agreement with the measurements. The strength difference of a few XRD peaks can be explained by the existence of pristine phenanthrene. Our findings suggest that instead of uniform Ba1.5phenanthrene, there coexist Ba2phenanthrene and undoped phenanthrene in the superconducting sample. The electronic calculations indicate that Ba2phenanthrene is a semiconductor with a small energy gap less than 0.05 eV. PMID- 25494755 TI - Glassy dynamics of convex polyhedra. AB - Self-assembly of polyhedral-shaped particles has attracted huge interest with the advent of new synthesis methods that realize these faceted particles in the lab. Recent studies have shown that polyhedral-shaped particles exhibit a rich phase behavior by excluded volume interactions alone; some of these particles are even alleged to show a transition to a glass phase by quenching the liquid sufficiently fast beyond the glass transition (supercooling), such that the formation of structures with long-range order is suppressed. Despite the recent progress, no study has been made on the glass formation of polyhedral-shaped particles. Here, we study the glass behavior of polyhedral particles using advanced Monte Carlo methods. We investigate the formation of a glass of monodisperse hard polyhedral-shaped particles, namely, octahedra, tetrahedra, and triangular cupola, using simulations. Finally, the fragility of these particles is determined and compared to that of a polydisperse hard-sphere system. PMID- 25494756 TI - Equilibrium ultrastable glasses produced by random pinning. AB - Ultrastable glasses have risen to prominence due to their potentially useful material properties and the tantalizing possibility of a general method of preparation via vapor deposition. Despite the importance of this novel class of amorphous materials, numerical studies have been scarce because achieving ultrastability in atomistic simulations is an enormous challenge. Here, we bypass this difficulty and establish that randomly pinning the position of a small fraction of particles inside an equilibrated supercooled liquid generates ultrastable configurations at essentially no numerical cost, while avoiding undesired structural changes due to the preparation protocol. Building on the analogy with vapor-deposited ultrastable glasses, we study the melting kinetics of these configurations following a sudden temperature jump into the liquid phase. In homogeneous geometries, we find that enhanced kinetic stability is accompanied by large scale dynamic heterogeneity, while a competition between homogeneous and heterogeneous melting is observed when a liquid boundary invades the glass at constant velocity. Our work demonstrates the feasibility of large scale, atomistically resolved, and experimentally relevant simulations of the kinetics of ultrastable glasses. PMID- 25494757 TI - Structural and physicochemical properties of liquid Al-Zn alloys: a combined study based on molecular dynamics simulations and the quasi-lattice theory. AB - Ordering phenomena have been investigated in liquid Al-Zn alloys performing molecular dynamics (MD) simulations using "empirical oscillating pair potentials." The local structural order is studied by computing two microscopic functions, namely, the concentration fluctuation function and the Warren-Cowley short-range order parameter. We also study the influence of ordering phenomena on transport properties like diffusivity and viscosity. The MD results are confronted to those determined from measurements and in the framework of the quasi-lattice theory. PMID- 25494758 TI - How does a thermal binary crystal break under shear? AB - When exposed to strong shearing, the particles in a crystal will rearrange and ultimately, the crystal will break by forming large nonaffine defects. Even for the initial stage of this process, only little effort has been devoted to the understanding of the breaking process on the scale of the individual particle size for thermalized mixed crystals. Here, we explore the shear-induced breaking for an equimolar two-dimensional binary model crystal with a high interaction asymmetry between the two different species such that the initial crystal has an intersecting square sublattice of the two constituents. Using Brownian dynamics computer simulations, we show that the combination of shear and thermal fluctuations leads to a characteristic hierarchical breaking scenario where initially, the more strongly coupled particles are thermally distorted, paving the way for the weakly coupled particles to escape from their cage. This in turn leads to mobile defects which may finally merge, proliferating a cascade of defects, which triggers the final breakage of the crystal. This scenario is in marked contrast to the breakage of one-component crystals close to melting. Moreover, we explore the orientational dependence of the initial shear direction relative to the crystal orientation and compare this to the usual melting scenario without shear. Our results are verifiable in real-space experiments of superparamagnetic colloidal mixtures at a pending air-water interface in an external magnetic field where the shear can be induced by an external laser field. PMID- 25494759 TI - Long-range orientation correlation in water. AB - Strong short-range intermolecular interactions result in position and orientation correlations between nearest neighbour molecules in isotropic liquids, but it is generally assumed that such correlations extend at most a few molecular diameters. Results from second-harmonic light scattering experiments presented here reveal long-range molecular orientation correlations in liquid water, where the molecular dipole orientation distribution has the form of a nearly pure transverse vector field. Spatial scales in the range 200-2000 nm are probed by the angle-dependent measurements and the observed correlations are thought to result from rotation-translation coupling in acoustic phonons in the liquid. PMID- 25494760 TI - Thermal behavior in Se-Te chalcogenide system: interplay of thermodynamics and kinetics. AB - Heat capacity measurements were performed for Se, Se90Te10, Se80Te20, and Se70Te30 materials in the 230-630 K temperature range. Both glassy and crystalline Cp dependences were found to be identical within the experimental error. The compositional dependence of the N-type undercooled liquid Cp evolution was explained on the basis of free-volume theory; vibrational and chemical contributions to heat capacity were found to be roughly similar for all Se-Te compositions. The thermal behavior in the Se-Te chalcogenide system was thoroughly studied: glass transition, cold crystallization, and melting were investigated in dependence on composition and various experimental conditions (heating rate, particle size, and pre-nucleation period). The kinetics of the structural relaxation and crystallization processes are described in terms of the Tool-Narayanaswamy-Moynihan and Johnson-Mehl-Avrami models. The complexity of these processes is thoroughly discussed with regard to the compositionally determined changes of molecular structures. The discussion is conducted in terms of the mutual interplay between the thermodynamics and kinetics in this system. PMID- 25494761 TI - Effects of configurational changes on electrical resistivity during glass-liquid transition of two bulk metal-alloy glasses. AB - Consequences of increase in structural fluctuations on heating Pd40Ni10Cu30P20 and Zr46.75Ti8.25Cu7.5Ni10Be27.5 through their glass to liquid transition range were investigated by measuring the electrical resistivity, rho, an electron scattering property. The temperature coefficient of resistivity (TCR = (1/rho) drho/dT) of the liquid and glassy states is negative. The plots of their rho against T in the Tg (glass to liquid transition) range show a gradual change in the slope similar to the change observed generally for the plots of the density, elastic modulus, and refractive index. As fluctuations in the melt structure involve fewer configurations on cooling, rho increases. In the energy landscape description, the melt's structure explores fewer minima with decrease in T, vibrational frequencies increase, and electron scattering and rho increase. Plots of (-drho/dT) against T resemble the plot of the specific heat of other glasses and show a sub-Tg feature and a rapid rise at T near Tg. Analysis shows that the magnitude of negative TCR is dominated by change in the phonon characteristics, and configurational fluctuations make it more negative. The TCR of the liquid and glassy states seems qualitatively consistent with the variation in the structure factor in Ziman's model for pure liquid metals as extended by Nagel to metal alloys and used to explain the negative TCR of a two-component metal glass. PMID- 25494762 TI - Partitioning and structural role of Mn and Fe ions in ionic sulfophosphate glasses. AB - Ionic sulfophosphate liquids of the type ZnO-Na2O-Na2SO4-P2O5 exhibit surprising glass forming ability, even at slow or moderate cooling rate. As a concept, they also provide high solubility of transition metal ions which could act as cross linking sites between the sulfate and phosphate entities. It is therefore investigated how the replacement of ZnO by MnO and/or FeO affects the glass structure and the glass properties. Increasing manganese levels are found to result in a monotonic increase of the transition temperature Tg and most of the mechanical properties. This trend is attributed to the change of metal-ion coordination from four-fold around Zn(2+) to six-fold around Mn(2+) ions. The higher coordination facilitates cross-linking of the ionic structural entities and subsequently increases Tg. Raman and infrared spectroscopy show that the structure of these glasses involves only SO4(2-) and PO4 (3-) monomers as well as P2O7(4-) dimers. Replacement of ZnO by MnO is found to favour PO4(3-) over P2O7(4 ) species, a trend which is enhanced by co-doping with FeO. Both transition metal ions show, like Zn(2+), a preference to selectively coordinate to phosphate anionic species, as opposed to sodium ions which coordinate mainly to sulfate anions. EPR spectroscopy finally shows that divalent Mn(2+) ions are present primarily in MnO6-clusters, which, in the studied sulfophosphate glasses, convert upon increasing MnO content from corner-sharing to edge-sharing entities. PMID- 25494763 TI - Interplay of anisotropy in shape and interactions in charged platelet suspensions. AB - Motivated by the intriguing phase behavior of charged colloidal platelets, we investigate the structure and dynamics of charged repulsive disks by means of Monte Carlo simulations. The electrostatic interactions are taken into account through an effective two-body potential, obtained within the nonlinear Poisson Boltzmann formalism, which has the form of anisotropic screened Coulomb potential. Recently, we showed that the original intrinsic anisotropy of the electrostatic potential in competition with excluded volume effects leads to a rich phase behavior that not only includes various liquid-crystalline phases but also predicts the existence of novel structures composed of alternating nematic antinematic sheets. Here, we examine the structural and dynamical signatures of each of the observed structures for both translational and rotational degrees of freedom. Finally, we discuss the influence of effective charge value and our results in relation to experimental findings on charged platelet suspensions. PMID- 25494764 TI - Site-specific intermolecular valence-band dispersion in alpha-phase crystalline films of cobalt phthalocyanine studied by angle-resolved photoemission spectroscopy. AB - The valence band structure of alpha-phase crystalline films of cobalt phthalocyanine (CoPc) grown on Au(111) is investigated by using angle-resolved photoemission spectroscopy (ARPES) with synchrotron radiation. The photo-induced change in the ARPES peaks is noticed in shape and energy of the highest occupied molecular orbital (HOMO, C 2p) and HOMO-1 (Co 3d) of CoPc, and is misleading the interpretation of the electronic properties of CoPc films. From the damage-free normal-emission ARPES measurement, the clear valence-band dispersion has been first observed, showing that orbital-specific behaviors are attributable to the interplay of the intermolecular pi-pi and pi-d interactions. The HOMO band dispersion of 0.1 eV gives the lower limit of the hole mobility for alpha-CoPc of 28.9 cm(2) V(-1) s(-1) at 15 K. The non-dispersive character of the split HOMO-1 bands indicates that the localization of the spin state is a possible origin of the antiferromagnetism. PMID- 25494765 TI - A first-principles polarized Raman method for determining whether a uniform region of a sample is crystalline or isotropic. AB - Previous methods for determining whether a uniform region of a sample is crystalline or isotropic-what we call the "state of internal orientation" S require a priori knowledge of properties of the purely crystalline and purely isotropic states. In addition, these methods can be ambiguous in their determination of state S for particular materials and, for a given material, the spectral methods can be ambiguous when using particular peaks. Using first principles Raman theory, we have discovered a simple, non-resonance, polarized Raman method for determining the state S that requires no information a priori and will work unambiguously for any material using any vibrational mode. Similar to the concept behind "magic angle spinning" in NMR, we have found that for a special set of incident/analyzed polarizations and scattering angle, the dependence of the Raman modulation depth M on the sample composition-and, for crystalline regions, the unit cell orientation-falls out completely, leaving dependence on only whether the region is crystalline (M = 1) or isotropic (M = 0). Further, upon scanning between homogeneous regions or domains within a heterogeneous sample, our signal M is a clear detector of the region boundaries, so that when combined with methods for determining the orientations of the crystalline domains, our method can be used to completely characterize the molecular structure of an entire heterogeneous sample to a very high certainty. Interestingly, our method can also be used to determine when a given mode is vibrationally degenerate. While simulations on realistic terthiophene systems are included to illustrate our findings, our method should apply to any type of material, including thin films, molecular crystals, and semiconductors. Finally, our discovery of these relationships required derivations of Raman intensity formulas that are at least as general as any we have found, and herein we present our comprehensive formulas for both the crystalline and isotropic states. PMID- 25494766 TI - Adaptive cluster expansion approach for predicting the structure evolution of graphene oxide. AB - An adaptive cluster expansion (CE) method is used to explore surface adsorption and growth processes. Unlike the traditional CE method, suitable effective cluster interaction (ECI) parameters are determined, and then the selected fixed number of ECIs is continually optimized to predict the stable configurations with gradual increase of adatom coverage. Comparing with traditional CE method, the efficiency of the adaptive CE method could be greatly enhanced. As an application, the adsorption and growth of oxygen atoms on one side of pristine graphene was carefully investigated using this method in combination with first principles calculations. The calculated results successfully uncover the structural evolution of graphene oxide for the different numbers of oxygen adatoms on graphene. The aggregation behavior of the stable configurations for different oxygen adatom coverages is revealed for increasing coverages of oxygen atoms. As a targeted method, adaptive CE can also be applied to understand the evolution of other surface adsorption and growth processes. PMID- 25494767 TI - Role of the potential landscape on the single-file diffusion through channels. AB - Transport of colloid particles through narrow channels is ubiquitous in cell biology as well as becoming increasingly important for microfluidic applications or targeted drug delivery. Membrane channels in cells are useful models for artificial designs because of their high efficiency, selectivity, and robustness to external fluctuations. Here, we model the passive channels that let cargo simply diffuse through them, affected by a potential profile along the way. Passive transporters achieve high levels of efficiency and specificity from binding interactions with the cargo inside the channel. This however leads to a paradox: why should channels which are so narrow that they are blocked by their cargo evolve to have binding regions for their cargo if that will effectively block them? Using Brownian dynamics simulations, we show that different potentials, notably symmetric, increase the flux through narrow passive channels and investigate how shape and depth of potentials influence the flux. We find that there exist optimal depths for certain potential shapes and that it is most efficient to apply a small force over an extended region of the channel. On the other hand, having several spatially discrete binding pockets will not alter the flux significantly. We also explore the role of many-particle effects arising from pairwise particle interactions with their neighbours and demonstrate that the relative changes in flux can be accounted for by the kinetics of the absorption reaction at the end of the channel. PMID- 25494768 TI - Scaling and alpha-helix regulation of protein relaxation in a lipid bilayer. AB - Protein conformation and orientation in the lipid membrane plays a key role in many cellular processes. Here we use molecular dynamics simulation to investigate the relaxation and C-terminus diffusion of a model helical peptide: beta-amyloid (Abeta) in a lipid membrane. We observed that after the helical peptide was initially half-embedded in the extracelluar leaflet of phosphatidylcholine (PC) or PC/cholesterol (PC/CHOL) membrane, the C-terminus diffused across the membrane and anchored to PC headgroups of the cytofacial lipid leaflet. In some cases, the membrane insertion domain of the Abeta was observed to partially unfold. Applying a sigmoidal fit to the process, we found that the characteristic velocity of the C-terminus, as it moved to its anchor site, scaled with thetau (-4/3), where thetau is the fraction of the original helix that was lost during a helix to coil transition. Comparing this scaling with that of bead-spring models of polymer relaxation suggests that the C-terminus velocity is highly regulated by the peptide helical content, but that it is independent of the amino acid type. The Abeta was stabilized by the attachment of the positive Lys28 side chain to the negative phosphate of PC or 3beta oxygen of CHOL in the extracellular lipid leaflet and of the C-terminus to its anchor site in the cytofacial lipid leaflet. PMID- 25494769 TI - Molecular crowding effect on dynamics of DNA-binding proteins search for their targets. AB - DNA-binding proteins locate and bind their target sequences positioned on DNA in crowded environments, but the molecular crowding effect on this search process is not clear. Using analytical techniques and Langevin dynamics simulations in two dimensions (2D), we find that the essential physics for facilitated diffusion in 2D search and 3D search is the same. We observe that the average search times have minima at the same optimal nonspecific binding energy for the cases with and without the crowding particle. Moreover, the molecular crowding increases the search time by increasing the average search rounds and the one-dimensional (1D) sliding time of a round, but almost not changing the average 2D diffusion time of a round. In addition, the fraction of 1D sliding time out of the total search time increases with increasing the concentration of crowders. For 2D diffusion, the molecular crowding decreases the jumping length and narrows its distribution due to the cage effect from crowders. These results shed light on the role of facilitated diffusion in DNA targeting kinetics in living cells. PMID- 25494771 TI - Preface: special topic on biological water. AB - This special issue presents a series of papers that highlight a new and evolving view of water's molecular role in biological structure and dynamics. Increasingly water is appreciated for playing an active role in biological function rather than just serving as a spectator. The areas represented include molecular interfaces with water, biological self-assembly, conformational changes by macromolecules, and chemical reactivity. PMID- 25494770 TI - Excluded volume and ion-ion correlation effects on the ionic atmosphere around B DNA: theory, simulations, and experiments. AB - The ionic atmosphere around a nucleic acid regulates its stability in aqueous salt solutions. One major source of complexity in biological activities involving nucleic acids arises from the strong influence of the surrounding ions and water molecules on their structural and thermodynamic properties. Here, we implement a classical density functional theory for cylindrical polyelectrolytes embedded in aqueous electrolytes containing explicit (neutral hard sphere) water molecules at experimental solvent concentrations. Our approach allows us to include ion correlations as well as solvent and ion excluded volume effects for studying the structural and thermodynamic properties of highly charged cylindrical polyelectrolytes. Several models of size and charge asymmetric mixtures of aqueous electrolytes at physiological concentrations are studied. Our results are in good agreement with Monte Carlo simulations. Our numerical calculations display significant differences in the ion density profiles for the different aqueous electrolyte models studied. However, similar results regarding the excess number of ions adsorbed to the B-DNA molecule are predicted by our theoretical approach for different aqueous electrolyte models. These findings suggest that ion counting experimental data should not be used alone to validate the performance of aqueous DNA-electrolyte models. PMID- 25494772 TI - Hydration shells of proteins probed by depolarized light scattering and dielectric spectroscopy: orientational structure is significant, positional structure is not. AB - Water interfacing hydrated proteins carry properties distinct from those of the bulk and is often described as a separate entity, a "biological water." We address here the question of which dynamical and structural properties of hydration water deserve this distinction. The study focuses on different aspects of the density and orientational fluctuations of hydration water and the ability to separate them experimentally by combining depolarized light scattering with dielectric spectroscopy. We show that the dynamics of the density fluctuations of the hydration shells reflect the coupled dynamics of the solute and solvent and do not require a special distinction as "biological water." The orientations of shell water molecules carry dramatically different physics and do require a separation into a sub-ensemble. Depending on the property considered, the perturbation of water's orientational structure induced by the protein propagates 3-5 hydration shells into the bulk at normal temperature. PMID- 25494773 TI - In silico studies of the properties of water hydrating a small protein. AB - Atomistic molecular dynamics simulation of an aqueous solution of the small protein HP-36 has been carried out with explicit solvent at room temperature. Efforts have been made to explore the influence of the protein on the relative packing and ordering of water molecules around its secondary structures, namely, three alpha-helices. The calculations reveal that the inhomogeneous water ordering and density distributions around the helices are correlated with their relative hydrophobicity. Importantly, we have identified the existence of a narrow relatively dehydrated region containing randomly organized "quasi-free" water molecules beyond the first layer of "bound" waters at the protein surface. These water molecules with relatively weaker binding energies form the transition state separating the "bound" and "free" water molecules at the interface. Further, increased contribution of solid-like caging motions of water molecules around the protein is found to be responsible for reduced fluidity of the hydration layer. Interestingly, we notice that the hydration layer of helix-3 is more fluidic with relatively higher entropy as compared to the hydration layers of the other two helical segments. Such characteristics of helix-3 hydration layer correlate well with the activity of HP-36, as helix-3 contains the active site of the protein. PMID- 25494774 TI - Ionic strength independence of charge distributions in solvation of biomolecules. AB - Electrostatic forces enormously impact the structure, interactions, and function of biomolecules. We perform all-atom molecular dynamics simulations for 5 proteins and 5 RNAs to determine the dependence on ionic strength of the ion and water charge distributions surrounding the biomolecules, as well as the contributions of ions to the electrostatic free energy of interaction between the biomolecule and the surrounding salt solution (for a total of 40 different biomolecule/solvent combinations). Although water provides the dominant contribution to the charge density distribution and to the electrostatic potential even in 1M NaCl solutions, the contributions of water molecules and of ions to the total electrostatic interaction free energy with the solvated biomolecule are comparable. The electrostatic biomolecule/solvent interaction energies and the total charge distribution exhibit a remarkable insensitivity to salt concentrations over a huge range of salt concentrations (20 mM to 1M NaCl). The electrostatic potentials near the biomolecule's surface obtained from the MD simulations differ markedly, as expected, from the potentials predicted by continuum dielectric models, even though the total electrostatic interaction free energies are within 11% of each other. PMID- 25494775 TI - Effect of cosolvent on protein stability: a theoretical investigation. AB - We developed a statistical thermodynamic algorithm for analyzing solvent-induced folding/unfolding transitions of proteins. The energetics of protein transitions is governed by the interplay between the cavity formation contribution and the term reflecting direct solute-cosolvent interactions. The latter is viewed as an exchange reaction in which the binding of a cosolvent to a solute is accompanied by release of waters of hydration to the bulk. Our model clearly differentiates between the stoichiometric and non-stoichiometric interactions of solvent or co solvent molecules with a solute. We analyzed the urea- and glycine betaine (GB) induced conformational transitions of model proteins of varying size which are geometrically approximated by a sphere in their native state and a spherocylinder in their unfolded state. The free energy of cavity formation and its changes accompanying protein transitions were computed based on the concepts of scaled particle theory. The free energy of direct solute-cosolvent interactions were analyzed using empirical parameters previously determined for urea and GB interactions with low molecular weight model compounds. Our computations correctly capture the mode of action of urea and GB and yield realistic numbers for (?DeltaG degrees /?a3)T,P which are related to the m-values of protein denaturation. Urea is characterized by negative values of (?DeltaG degrees /?a3)T,P within the entire range of urea concentrations analyzed. At concentrations below ~1 M, GB exhibits positive values of (?DeltaG degrees /?a3)T,P which turn positive at higher GB concentrations. The balance between the thermodynamic contributions of cavity formation and direct solute-cosolvent interactions that, ultimately, defines the mode of cosolvent action is extremely subtle. A 20% increase or decrease in the equilibrium constant for solute cosolvent binding may change the sign of (?DeltaG degrees /?a3)T,P thereby altering the mode of cosolvent action (stabilizing to destabilizing or vice versa). PMID- 25494776 TI - Theoretical vibrational sum-frequency generation spectroscopy of water near lipid and surfactant monolayer interfaces. II. Two-dimensional spectra. AB - The structural stability and function of biomolecules is strongly influenced by the dynamics and hydrogen bonding of interfacial water. Understanding and characterizing the dynamics of these water molecules require a surface-sensitive technique such as two-dimensional vibrational sum-frequency generation (2DSFG) spectroscopy. We have combined theoretical 2DSFG calculations with molecular dynamics simulations in order to investigate the dynamics of water near different lipid and surfactant monolayer surfaces. We show that 2DSFG can distinguish the dynamics of interfacial water as a function of the lipid charge and headgroup chemistry. The dynamics of water is slow compared to the bulk near water zwitterionic and water-anionic interfaces due to conformational constraints on interfacial water imposed by strong phosphate-water hydrogen bonding. The dynamics of water is somewhat faster near water-cationic lipid interfaces as no such constraint is present. Using hydrogen bonding and rotational correlation functions, we characterize the dynamics of water as a function of the distance from the interface between water and zwitterionic lipids. We find that there is a transition from bulk-like to interface-like dynamics approximately 7 A away from a zwitterionic phosphatidylcholine monolayer surface. PMID- 25494777 TI - Intermolecular interactions in highly concentrated protein solutions upon compression and the role of the solvent. AB - The influence of high hydrostatic pressure on the structure and protein-protein interaction potential of highly concentrated lysozyme solutions up to about 370 mg ml(-1) was studied and analyzed using small-angle X-ray scattering in combination with a liquid-state theoretical approach. In the concentration region below 200 mg ml(-1), the interaction parameters of lysozyme solutions are affected by pressure in a nonlinear way, which is probably due to significant changes in the structural properties of bulk water, i.e., due to a solvent mediated effect. Conversely, for higher concentrated protein solutions, where hydration layers below ~4 water molecules are reached, the interaction potential turns rather insensitive to compression. The onset of transient (dynamic) clustering is envisaged in this concentration range. Our results also show that pressure suppresses protein nucleation, aggregation and finally crystallization in supersaturated condensed protein solutions. These findings are of importance for controlling and fine-tuning protein crystallization. Moreover, these results are also important for understanding the high stability of highly concentrated protein solutions (as they occur intracellularly) in organisms thriving under hydrostatic pressure conditions such as in the deep sea, where pressures up to the kbar-level are reached. PMID- 25494778 TI - Changes in the hydrogen-bonding strength of internal water molecules and cysteine residues in the conductive state of channelrhodopsin-1. AB - Water plays an essential role in the structure and function of proteins, particularly in the less understood class of membrane proteins. As the first of its kind, channelrhodopsin is a light-gated cation channel and paved the way for the new and vibrant field of optogenetics, where nerve cells are activated by light. Still, the molecular mechanism of channelrhodopsin is not understood. Here, we applied time-resolved FT-IR difference spectroscopy to channelrhodopsin 1 from Chlamydomonas augustae. It is shown that the (conductive) P2(380) intermediate decays with tau ~ 40 ms and 200 ms after pulsed excitation. The vibrational changes between the closed and the conductive states were analyzed in the X-H stretching region (X = O, S, N), comprising vibrational changes of water molecules, sulfhydryl groups of cysteine side chains and changes of the amide A of the protein backbone. The O-H stretching vibrations of "dangling" water molecules were detected in two different states of the protein using H2 (18)O exchange. Uncoupling experiments with a 1:1 mixture of H2O:D2O provided the natural uncoupled frequencies of the four O-H (and O-D) stretches of these water molecules, each with a very weakly hydrogen-bonded O-H group (3639 and 3628 cm( 1)) and with the other O-H group medium (3440 cm(-1)) to moderately strongly (3300 cm(-1)) hydrogen-bonded. Changes in amide A and thiol vibrations report on global and local changes, respectively, associated with the formation of the conductive state. Future studies will aim at assigning the respective cysteine group(s) and at localizing the "dangling" water molecules within the protein, providing a better understanding of their functional relevance in CaChR1. PMID- 25494780 TI - Resolving anisotropic distributions of correlated vibrational motion in protein hydration water. AB - In this study, we analyze correlations of vibrational motion on the surface of a small globular protein and in its hydration shell. In contrast to single particle hydration water dynamics, which are perturbed by interactions with the protein solute only in the first few hydration layers, we find that correlated, collective motions extend into the surrounding solvent on a 10 A length scale, specifically at far-infrared frequencies below 100 cm(-1). As a function of frequency, we analyze the distribution of correlated longitudinal motions in the three-dimensional environment of the protein solute, as well as in the vicinity of different protein-water interfaces. An anisotropic distribution of these correlations is observed, which is related to specific protein-water vibrations and interactions at the interfaces, as well as flexibilities of solvent exposed sites. Our results show that coupling of protein and water dynamics leaves a three-dimensional imprint in the collective dynamics of its hydration shell, and we discuss potential implications for biomolecular function, e.g., molecular recognition and binding, and the dynamical coupling of proteins to their native solvation environment. PMID- 25494779 TI - Accurate small and wide angle x-ray scattering profiles from atomic models of proteins and nucleic acids. AB - A new method is introduced to compute X-ray solution scattering profiles from atomic models of macromolecules. The three-dimensional version of the Reference Interaction Site Model (RISM) from liquid-state statistical mechanics is employed to compute the solvent distribution around the solute, including both water and ions. X-ray scattering profiles are computed from this distribution together with the solute geometry. We describe an efficient procedure for performing this calculation employing a Lebedev grid for the angular averaging. The intensity profiles (which involve no adjustable parameters) match experiment and molecular dynamics simulations up to wide angle for two proteins (lysozyme and myoglobin) in water, as well as the small-angle profiles for a dozen biomolecules taken from the BioIsis.net database. The RISM model is especially well-suited for studies of nucleic acids in salt solution. Use of fiber-diffraction models for the structure of duplex DNA in solution yields close agreement with the observed scattering profiles in both the small and wide angle scattering (SAXS and WAXS) regimes. In addition, computed profiles of anomalous SAXS signals (for Rb(+) and Sr(2+)) emphasize the ionic contribution to scattering and are in reasonable agreement with experiment. In cases where an absolute calibration of the experimental data at q = 0 is available, one can extract a count of the excess number of waters and ions; computed values depend on the closure that is assumed in the solution of the Ornstein-Zernike equations, with results from the Kovalenko-Hirata closure being closest to experiment for the cases studied here. PMID- 25494781 TI - The remarkable hydration of the antifreeze protein Maxi: a computational study. AB - The long four-helix bundle antifreeze protein Maxi contains an unusual core for a globular protein. More than 400 ordered waters between the helices form a nano pore of internal water about 150 A long. Molecular dynamics simulations of hydrated Maxi were carried out using the CHARMM27 protein forcefield and the TIP3P water model. Solvation in the core and non-core first hydration shell was analyzed in terms of water-water H-bond distance-angle distributions. The core had an increased population of low-angle H-bonds between water pairs relative to bulk water. Enhancement of low angle H-bonds was particularly pronounced for water pairs at the interfaces between apolar and polar regions inside the protein core, characteristic of the anchored clathrate solvation structure seen previously in the ice-nuclei binding surfaces of type I, type III, and beta helical antifreeze proteins. Anchored clathrate type solvation structure was not seen in the exterior solvation shell except around residues implicated in ice binding. Analysis of solvation dynamics using water residence times and diffusion constants showed that exterior solvation shell waters exchanged rapidly with bulk water, with no difference between ice-binding and non-binding residues. Core waters had about ten-fold slower diffusion than bulk water. Water residence times around core residues averaged about 8 ps, similar to those on the exterior surface, but they tended to exchange primarily with other core water, resulting in longer, >40 ps residence times within the core. Preferential exchange or diffusion of the water along the long axis of the water core of Maxi was not detected. PMID- 25494782 TI - How water layers on graphene affect folding and adsorption of TrpZip2. AB - We present a computational study of the folding of the Trp-rich beta-hairpin TrpZip2 near graphene, a surface of interest as a platform for biosensors. The protein adsorbs to the surface, populating a new bound, folded state, coexisting with extended, adsorbed conformations. Adsorption and folding are modulated by direct interactions between the indole rings of TrpZip2 and the rings on the graphene surface, as well as by indirect water-mediated interactions. In particular, we observe strong layering of water near graphene, ice-like water configurations, and the formation of short lived hydrogen-bonds between water and protein. In order to study the effect of this layering in more detail, we modified the interactions between graphene and water to obtain two extreme cases: (1) enhanced layering of water that prevents the peptide from penetrating the water layer thereby enabling it to fold to a bulk-like structure, and (2) disruption of the water layer leading to adsorption and unfolding of the protein on the surface. These studies illuminate the roles of direct and solvent mediated interactions in modulating adsorption and folding of proteins on surfaces. PMID- 25494783 TI - Hydration properties of natural and synthetic DNA sequences with methylated adenine or cytosine bases in the R.DpnI target and BDNF promoter studied by molecular dynamics simulations. AB - Adenine and cytosine methylation are two important epigenetic modifications of DNA sequences at the levels of the genome and transcriptome. To characterize the differential roles of methylating adenine or cytosine with respect to their hydration properties, we performed conventional MD simulations and free energy perturbation calculations for two particular DNA sequences, namely the brain derived neurotrophic factor (BDNF) promoter and the R.DpnI-bound DNA that are known to undergo methylation of C5-methyl cytosine and N6-methyl adenine, respectively. We found that a single methylated cytosine has a clearly favorable hydration free energy over cytosine since the attached methyl group has a slightly polar character. In contrast, capping the strongly polar N6 of adenine with a methyl group gives a slightly unfavorable contribution to its free energy of solvation. Performing the same demethylation in the context of a DNA double strand gave quite similar results for the more solvent-accessible cytosine but much more unfavorable results for the rather buried adenine. Interestingly, the same demethylation reactions are far more unfavorable when performed in the context of the opposite (BDNF or R.DpnI target) sequence. This suggests a natural preference for methylation in a specific sequence context. In addition, free energy calculations for demethylating adenine or cytosine in the context of B-DNA vs. Z-DNA suggest that the conformational B-Z transition of DNA transition is rather a property of cytosine methylated sequences but is not preferable for the adenine-methylated sequences investigated here. PMID- 25494785 TI - Effect of viscogens on the kinetic response of a photoperturbed allosteric protein. AB - By covalently binding a photoswitchable linker across the binding groove of the PDZ2 domain, a small conformational change can be photo-initiated that mimics the allosteric transition of the protein. The response of its binding groove is investigated with the help of ultrafast pump-probe IR spectroscopy from picoseconds to tens of microseconds. The temperature dependence of that response is compatible with diffusive dynamics on a rugged energy landscape without any prominent energy barrier. Furthermore, the dependence of the kinetics on the concentration of certain viscogens, sucrose, and glycerol, has been investigated. A pronounced viscosity dependence is observed that can be best fit by a power law, i.e., a fractional viscosity dependence. The change of kinetics when comparing sucrose with glycerol as viscogen, however, provides strong evidence that direct interactions of the viscogen molecule with the protein do play a role as well. This conclusion is supported by accompanying molecular dynamics simulations. PMID- 25494786 TI - An improved simple polarisable water model for use in biomolecular simulation. AB - The accuracy of biomolecular simulations depends to some degree on the accuracy of the water model used to solvate the biomolecules. Because many biomolecules such as proteins are electrostatically rather inhomogeneous, containing apolar, polar, and charged moieties or side chains, a water model should be able to represent the polarisation response to a local electrostatic field, while being compatible with the force field used to model the biomolecules or protein. The two polarisable water models, COS/G2 and COS/D, that are compatible with the GROMOS biomolecular force fields leave room for improvement. The COS/G2 model has a slightly too large dielectric permittivity and the COS/D model displays a much too slow dynamics. The proposed COS/D2 model has four interaction sites: only one Lennard-Jones interaction site, the oxygen atom, and three permanent charge sites, the two hydrogens, and one massless off-atom site that also serves as charge-on-spring (COS) polarisable site with a damped or sub-linear dependence of the induced dipole on the electric field strength for large values of the latter. These properties make it a cheap and yet realistic water model for biomolecular solvation. PMID- 25494784 TI - Cholesterol enhances surface water diffusion of phospholipid bilayers. AB - Elucidating the physical effect of cholesterol (Chol) on biological membranes is necessary towards rationalizing their structural and functional role in cell membranes. One of the debated questions is the role of hydration water in Chol embedding lipid membranes, for which only little direct experimental data are available. Here, we study the hydration dynamics in a series of Chol-rich and depleted bilayer systems using an approach termed (1)H Overhauser dynamic nuclear polarization (ODNP) NMR relaxometry that enables the sensitive and selective determination of water diffusion within 5-10 A of a nitroxide-based spin label, positioned off the surface of the polar headgroups or within the nonpolar core of lipid membranes. The Chol-rich membrane systems were prepared from mixtures of Chol, dipalmitoyl phosphatidylcholine and/or dioctadecyl phosphatidylcholine lipid that are known to form liquid-ordered, raft-like, domains. Our data reveal that the translational diffusion of local water on the surface and within the hydrocarbon volume of the bilayer is significantly altered, but in opposite directions: accelerated on the membrane surface and dramatically slowed in the bilayer interior with increasing Chol content. Electron paramagnetic resonance (EPR) lineshape analysis shows looser packing of lipid headgroups and concurrently tighter packing in the bilayer core with increasing Chol content, with the effects peaking at lipid compositions reported to form lipid rafts. The complementary capability of ODNP and EPR to site-specifically probe the hydration dynamics and lipid ordering in lipid membrane systems extends the current understanding of how Chol may regulate biological processes. One possible role of Chol is the facilitation of interactions between biological constituents and the lipid membrane through the weakening or disruption of strong hydrogen-bond networks of the surface hydration layers that otherwise exert stronger repulsive forces, as reflected in faster surface water diffusivity. Another is the concurrent tightening of lipid packing that reduces passive, possibly unwanted, diffusion of ions and water across the bilayer. PMID- 25494787 TI - Does fluoride disrupt hydrogen bond network in cationic lipid bilayer? Time dependent fluorescence shift of Laurdan and molecular dynamics simulations. AB - Time-dependent fluorescence shift (TDFS) of Laurdan embedded in phospholipid bilayers reports on hydration and mobility of the phospholipid acylgroups. Exchange of H2O with D2O prolongs the lifetime of lipid-water and lipid-water lipid interactions, which is reflected in a significantly slower TDFS kinetics. Combining TDFS measurements in H2O and D2O hydrated bilayers with atomistic molecular dynamics (MD) simulations provides a unique tool for characterization of the hydrogen bonding at the acylgroup level of lipid bilayers. In this work, we use this approach to study the influence of fluoride anions on the properties of cationic bilayers composed of trimethylammonium-propane (DOTAP). The results obtained for DOTAP are confronted with those for neutral phosphatidylcholine (DOPC) bilayers. Both in DOTAP and DOPC H2O/D2O exchange prolongs hydrogen bonding lifetime and does not disturb bilayer structure. These results are confirmed by MD simulations. TDFS experiments show, however, that for DOTAP this effect is cancelled in the presence of fluoride ions. We interpret these results as evidence that strongly hydrated fluoride is able to steal water molecules that bridge lipid carbonyls. Consequently, when attracted to DOTAP bilayer, fluoride disrupts the local hydrogen-bonding network, and the differences in TDFS kinetics between H2O and D2O hydrated bilayers are no longer observed. A distinct behavior of fluoride is also evidenced by MD simulations, which show different lipid-ion binding for Cl(-) and F(-). PMID- 25494788 TI - Sticky water surfaces: helix-coil transitions suppressed in a cell-penetrating peptide at the air-water interface. AB - GALA is a 30 amino acid synthetic peptide consisting of a Glu-Ala-Leu-Ala repeat and is known to undergo a reversible structural transition from a disordered to an alpha-helical structure when changing the pH from basic to acidic values. In its helical state GALA can insert into and disintegrate lipid membranes. This effect has generated much interest in GALA as a candidate for pH triggered, targeted drug delivery. GALA also serves as a well-defined model system to understand cell penetration mechanisms and protein folding triggered by external stimuli. Structural transitions of GALA in solution have been studied extensively. However, cell penetration is an interfacial effect and potential biomedical applications of GALA would involve a variety of surfaces, e.g., nanoparticles, lipid membranes, tubing, and liquid-gas interfaces. Despite the apparent importance of interfaces in the functioning of GALA, the effect of surfaces on the reversible folding of GALA has not yet been studied. Here, we use sum frequency generation vibrational spectroscopy (SFG) to probe the structural response of GALA at the air-water interface and IR spectroscopy to follow GALA folding in bulk solution. We combine the SFG data with molecular dynamics simulations to obtain a molecular-level picture of the interaction of GALA with the air-water interface. Surprisingly, while the fully reversible structural transition was observed in solution, at the water-air interface, a large fraction of the GALA population remained helical at high pH. This "stickiness" of the air water interface can be explained by the stabilizing interactions of hydrophobic leucine and alanine side chains with the water surface. PMID- 25494790 TI - Combining molecular dynamics and an electrodiffusion model to calculate ion channel conductance. AB - Establishing the relation between the structures and functions of protein ion channels, which are protein assemblies that facilitate transmembrane ion transport through water-filled pores, is at the forefront of biological and medical sciences. A reliable way to determine whether our understanding of this relation is satisfactory is to reproduce the measured ionic conductance over a broad range of applied voltages. This can be done in molecular dynamics simulations by way of applying an external electric field to the system and counting the number of ions that traverse the channel per unit time. Since this approach is computationally very expensive we develop a markedly more efficient alternative in which molecular dynamics is combined with an electrodiffusion equation. This alternative approach applies if steady-state ion transport through channels can be described with sufficient accuracy by the one-dimensional diffusion equation in the potential given by the free energy profile and applied voltage. The theory refers only to line densities of ions in the channel and, therefore, avoids ambiguities related to determining the surface area of the channel near its endpoints or other procedures connecting the line and bulk ion densities. We apply the theory to a simple, model system based on the trichotoxin channel. We test the assumptions of the electrodiffusion equation, and determine the precision and consistency of the calculated conductance. We demonstrate that it is possible to calculate current/voltage dependence and accurately reconstruct the underlying (equilibrium) free energy profile, all from molecular dynamics simulations at a single voltage. The approach developed here applies to other channels that satisfy the conditions of the electrodiffusion equation. PMID- 25494789 TI - Small molecule solvation changes due to the presence of salt are governed by the cost of solvent cavity formation and dispersion. AB - We are interested in the free energies of transferring nonpolar solutes into aqueous NaCl solutions with salt concentrations upwards of 2 M, the Hofmeister regime. We use the semi-explicit assembly (SEA) computational model to represent these electrolyte solutions. We find good agreement with experiments (Setschenow coefficients) on 43 nonpolar and polar solutes and with TIP3P explicit-solvent simulations. Besides being much faster than explicit solvent calculations, SEA is more accurate than the PB models we tested, successfully capturing even subtle salt effects in both the polar and nonpolar components of solvation. We find that the salt effects are mainly due to changes in the cost of forming nonpolar cavities in aqueous NaCl solutions, and not mainly due to solute-ion electrostatic interactions. PMID- 25494791 TI - Dewetting transition assisted clearance of (NFGAILS) amyloid fibrils from cell membranes by graphene. AB - Clearance of partially ordered oligomers and monomers deposited on cell membrane surfaces is believed to be an effective route to alleviate many potential protein conformational diseases (PCDs). With large-scale all-atom molecular dynamics simulations, here we show that graphene nanosheets can easily and quickly win a competitive adsorption of human islet amyloid polypeptides (hIAPP22-28) NFGAILS and associated fibrils against cell membrane, due to graphene's unique two dimensional, highly hydrophobic surface with its all-sp(2) hybrid structure. A nanoscale dewetting transition was observed at the interfacial region between the fibril (originally deposited on the membrane) and the graphene nanosheet, which significantly assisted the adsorption of fibrils onto graphene from the membrane. The pi-pi stacking interaction between Phe23 and graphene played a crucial role, providing the driving force for the adsorption at the graphene surface. This study renders new insight towards the importance of water during the interactions between amyloid peptides, the phospholipidic membrane, and graphene, which might shed some light on future developments of graphene-based nanomedicine for preventing/curing PCDs like type II diabetes mellitus. PMID- 25494792 TI - Hydration of chloride anions in the NanC Porin from Escherichia coli: a comparative study by QM/MM and MD simulations. AB - Chloride anions permeate the bacterial NanC porin in physiological processes. Here we present a DFT-based QM/MM study of this porin in the presence of these anions. Comparison is made with classical MD simulations on the same system. In both QM/MM and classical approaches, the anions are almost entirely solvated by water molecules. However, the average water-Cl(-) distance is significantly larger in the first approach. Polarization effects of protein groups close to Cl( ) anion are sizeable. These effects might modulate the anion-protein electrostatic interactions, which in turn play a central role for selectivity mechanisms of the channel. PMID- 25494793 TI - Role of solvation in pressure-induced helix stabilization. AB - In contrast to the well-known destabilization of globular proteins by high pressure, recent work has shown that pressure stabilizes the formation of isolated alpha-helices. However, all simulations to date have obtained a qualitatively opposite result within the experimental pressure range. We show that using a protein force field (Amber03w) parametrized in conjunction with an accurate water model (TIP4P/2005) recovers the correct pressure-dependence and an overall stability diagram for helix formation similar to that from experiment; on the other hand, we confirm that using TIP3P water results in a very weak pressure destabilization of helices. By carefully analyzing the contributing factors, we show that this is not merely a consequence of different peptide conformations sampled using TIP3P. Rather, there is a critical role for the solvent itself in determining the dependence of total system volume (peptide and solvent) on helix content. Helical peptide structures exclude a smaller volume to water, relative to non-helical structures with both the water models, but the total system volume for helical conformations is higher than non-helical conformations with TIP3P water at low to intermediate pressures, in contrast to TIP4P/2005 water. Our results further emphasize the importance of using an accurate water model to study protein folding under conditions away from standard temperature and pressure. PMID- 25494794 TI - Entropy and enthalpy of interaction between amino acid side chains in nanopores. AB - Understanding the stabilities of proteins in nanopores requires a quantitative description of confinement induced interactions between amino acid side chains. We use molecular dynamics simulations to study the nature of interactions between the side chain pairs ALA-PHE, SER-ASN, and LYS-GLU in bulk water and in water filled nanopores. The temperature dependence of the bulk solvent potentials of mean force and the interaction free energies in cylindrical and spherical nanopores is used to identify the corresponding entropic and enthalpic components. The entropically stabilized hydrophobic interaction between ALA and PHE in bulk water is enthalpically dominated upon confinement depending on the relative orientations between the side chains. In the case of SER-ASN, hydrogen bonded configurations that are similar in bulk water are thermodynamically distinct in a cylindrical pore, thus making rotamer distributions different from those in the bulk. Remarkably, salt bridge formation between LYS-GLU is stabilized by entropy in contrast to the bulk. Implications of our findings for confinement-induced alterations in protein stability are briefly outlined. PMID- 25494795 TI - Infrared spectral marker bands characterizing a transient water wire inside a hydrophobic membrane protein. AB - Proton conduction along protein-bound "water wires" is an essential feature in membrane proteins. Here, we analyze in detail a transient water wire, which conducts protons via a hydrophobic barrier within a membrane protein to create a proton gradient. It is formed only for a millisecond out of three water molecules distributed at inactive positions in a polar environment in the ground state. The movement into a hydrophobic environment causes characteristic shifts of the water bands reflecting their different chemical properties. These band shifts are identified by time-resolved Fourier Transform Infrared difference spectroscopy and analyzed by biomolecular Quantum Mechanical/Molecular Mechanical simulations. A non-hydrogen bonded ("dangling") O-H stretching vibration band and a broad continuum absorbance caused by a combined vibration along the water wire are identified as characteristic marker bands of such water wires in a hydrophobic environment. The results provide a basic understanding of water wires in hydrophobic environments. PMID- 25494797 TI - Dehydration of multilamellar fatty acid membranes: towards a computational model of the stratum corneum. AB - The level of hydration controls the cohesion between apposed lamellae of saturated free fatty acids found in the lipid matrix of stratum corneum, the outermost layer of mammalian skin. This multilamellar lipid matrix is highly impermeable to water and ions, so that the local hydration shell of its fatty acids may not always be in equilibrium with the acidity and relative humidity, which significantly change over a course of days during skin growth. The homeostasis of the stratum corneum at each moment of its growth likely requires a balance between two factors, which affect in opposite ways the diffusion of hydrophilic species through the stratum corneum: (i) an increase in water order as the lipid lamellae come in closer contact, and (ii) a decrease in water order as the fraction of charged fatty acids is lowered by pH. Herein molecular dynamics simulations are employed to estimate the impact of both effects on water molecules confined between lamellae of fatty acids. Under conditions where membrane undulations are energetically favorable, the charged fatty acids are able to sequester cations around points of contact between lamellae that are fully dehydrated, while essentially maintaining a multilamellar structure for the entire system. This observation suggests that the undulations of the fatty acid lamellae control the diffusion of hydrophilic species through the water phase by altering the positional and rotational order of water molecules in the embedded/occluded "droplets." PMID- 25494798 TI - Electron transfer activation of a second water channel for proton transport in [FeFe]-hydrogenase. AB - Hydrogenase enzymes are important because they can reversibly catalyze the production of molecular hydrogen. Proton transport mechanisms have been previously studied in residue pathways that lead to the active site of the enzyme via residues Cys299 and Ser319. The importance of this pathway and these residues has been previously exhibited through site-specific mutations, which were shown to interrupt the enzyme activity. It has been shown recently that a separate water channel (WC2) is coupled with electron transport to the active site of the [FeFe]-hydrogenase. The water-mediated proton transport mechanisms of the enzyme in different electronic states have been studied using the multistate empirical valence bond reactive molecular dynamics method, in order to understand any role WC2 may have in facilitating the residue pathway in bringing an additional proton to the enzyme active site. In a single electronic state A(2-), a water wire was formed through which protons can be transported with a low free energy barrier. The remaining electronic states were shown, however, to be highly unfavorable to proton transport in WC2. A double amino acid substitution is predicted to obstruct proton transport in electronic state A(2-) by closing a cavity that could otherwise fill with water near the proximal Fe of the active site. PMID- 25494799 TI - On the role of interfacial hydrogen bonds in "on-water" catalysis. AB - Numerous experiments have demonstrated that many classes of organic reactions exhibit increased reaction rates when performed in heterogeneous water emulsions. Despite enormous practical importance of the observed "on-water" catalytic effect and several mechanistic studies, its microscopic origins remains unclear. In this work, the second generation Car-Parrinello molecular dynamics method is extended to self-consistent charge density-functional based tight-binding in order to study "on-water" catalysis of the Diels-Alder reaction between dimethyl azodicarboxylate and quadricyclane. We find that the stabilization of the transition state by dangling hydrogen bonds exposed at the aqueous interfaces plays a significantly smaller role in "on-water" catalysis than has been suggested previously. PMID- 25494796 TI - Multibody correlations in the hydrophobic solvation of glycine peptides. AB - Protein collapse during folding is often assumed to be driven by a hydrophobic solvation energy (DeltaGvdw) that scales linearly with solvent-accessible surface area (A). In a previous study, we argued that DeltaGvdw, as well as its attractive (DeltaGatt) and repulsive (DeltaGrep) components, was not simply a linear function of A. We found that the surface tensions, gammarep, gammaatt, and gammavdw, gotten from DeltaGrep, DeltaGatt, and DeltaGvdw against A for four configurations of deca-alanine differed from those obtained for a set of alkanes. In the present study, we extend our analysis to fifty decaglycine structures and atomic decompositions. We find that different configurations of decaglycine generate different estimates of gammarep. Additionally, we considered the reconstruction of the solvation free energy from scaling the free energy of solvation of each atom type, free in solution. The free energy of the isolated atoms, scaled by the inverse surface area the atom would expose in the molecule does not reproduce the gammarep for the intact decaglycines. Finally, gammaatt for the decaglycine conformations is much larger in magnitude than those for deca alanine or the alkanes, leading to large negative values of gammavdw (-74 and -56 cal/mol/A(2) for CHARMM27 and AMBER ff12sb force fields, respectively). These findings imply that DeltaGvdw favors extended rather than compact structures for decaglycine. We find that DeltaGrep and DeltaGvdw have complicated dependencies on multibody correlations between solute atoms, on the geometry of the molecular surface, and on the chemical identities of the atoms. PMID- 25494800 TI - Comparative study of hydration shell dynamics around a hyperactive antifreeze protein and around ubiquitin. AB - The hydration layer surrounding a protein plays an essential role in its biochemical function and consists of a heterogeneous ensemble of water molecules with different local environments and different dynamics. What determines the degree of dynamical heterogeneity within the hydration shell and how this changes with temperature remains unclear. Here, we combine molecular dynamics simulations and analytic modeling to study the hydration shell structure and dynamics of a typical globular protein, ubiquitin, and of the spruce budworm hyperactive antifreeze protein over the 230-300 K temperature range. Our results show that the average perturbation induced by both proteins on the reorientation dynamics of water remains moderate and changes weakly with temperature. The dynamical heterogeneity arises mostly from the distribution of protein surface topographies and is little affected by temperature. The ice-binding face of the antifreeze protein induces a short-ranged enhancement of water structure and a greater slowdown of water reorientation dynamics than the non-ice-binding faces whose effect is similar to that of ubiquitin. However, the hydration shell of the ice binding face remains less tetrahedral than the bulk and is not "ice-like". We finally show that the hydrogen bonds between water and the ice-binding threonine residues are particularly strong due to a steric confinement effect, thereby contributing to the strong binding of the antifreeze protein on ice crystals. PMID- 25494802 TI - Sensitivity of polarization fluctuations to the nature of protein-water interactions: study of biological water in four different protein-water systems. AB - Since the time of Kirkwood, observed deviations in magnitude of the dielectric constant of aqueous protein solution from that of neat water (~80) and slower decay of polarization have been subjects of enormous interest, controversy, and debate. Most of the common proteins have large permanent dipole moments (often more than 100 D) that can influence structure and dynamics of even distant water molecules, thereby affecting collective polarization fluctuation of the solution, which in turn can significantly alter solution's dielectric constant. Therefore, distance dependence of polarization fluctuation can provide important insight into the nature of biological water. We explore these aspects by studying aqueous solutions of four different proteins of different characteristics and varying sizes, chicken villin headpiece subdomain (HP-36), immunoglobulin binding domain protein G (GB1), hen-egg white lysozyme (LYS), and Myoglobin (MYO). We simulate fairly large systems consisting of single protein molecule and 20000-30000 water molecules (varied according to the protein size), providing a concentration in the range of ~2-3 mM. We find that the calculated dielectric constant of the system shows a noticeable increment in all the cases compared to that of neat water. Total dipole moment auto time correlation function of water ?deltaMW(0)deltaMW(t)? is found to be sensitive to the nature of the protein. Surprisingly, dipole moment of the protein and total dipole moment of the water molecules are found to be only weakly coupled. Shellwise decomposition of water molecules around protein reveals higher density of first layer compared to the succeeding ones. We also calculate heuristic effective dielectric constant of successive layers and find that the layer adjacent to protein has much lower value (~50). However, progressive layers exhibit successive increment of dielectric constant, finally reaching a value close to that of bulk 4-5 layers away. We also calculate shellwise orientational correlation function and tetrahedral order parameter to understand the local dynamics and structural re arrangement of water. Theoretical analysis providing simple method for calculation of shellwise local dielectric constant and implication of these findings are elaborately discussed in the present work. PMID- 25494803 TI - Poisson-Nernst-Planck-Fermi theory for modeling biological ion channels. AB - A Poisson-Nernst-Planck-Fermi (PNPF) theory is developed for studying ionic transport through biological ion channels. Our goal is to deal with the finite size of particle using a Fermi like distribution without calculating the forces between the particles, because they are both expensive and tricky to compute. We include the steric effect of ions and water molecules with nonuniform sizes and interstitial voids, the correlation effect of crowded ions with different valences, and the screening effect of water molecules in an inhomogeneous aqueous electrolyte. Including the finite volume of water and the voids between particles is an important new part of the theory presented here. Fermi like distributions of all particle species are derived from the volume exclusion of classical particles. Volume exclusion and the resulting saturation phenomena are especially important to describe the binding and permeation mechanisms of ions in a narrow channel pore. The Gibbs free energy of the Fermi distribution reduces to that of a Boltzmann distribution when these effects are not considered. The classical Gibbs entropy is extended to a new entropy form - called Gibbs-Fermi entropy - that describes mixing configurations of all finite size particles and voids in a thermodynamic system where microstates do not have equal probabilities. The PNPF model describes the dynamic flow of ions, water molecules, as well as voids with electric fields and protein charges. The model also provides a quantitative mean field description of the charge/space competition mechanism of particles within the highly charged and crowded channel pore. The PNPF results are in good accord with experimental currents recorded in a 10(8)-fold range of Ca(2+) concentrations. The results illustrate the anomalous mole fraction effect, a signature of L-type calcium channels. Moreover, numerical results concerning water density, dielectric permittivity, void volume, and steric energy provide useful details to study a variety of physical mechanisms ranging from binding, to permeation, blocking, flexibility, and charge/space competition of the channel. PMID- 25494804 TI - Pf1 bacteriophage hydration by magic angle spinning solid-state NMR. AB - High resolution two- and three-dimensional heteronuclear correlation spectroscopy ((1)H-(13)C, (1)H-(15)N, and (1)H-(13)C-(13)C HETCOR) has provided a detailed characterization of the internal and external hydration water of the Pf1 virion. This long and slender virion (2000 nm * 7 nm) contains highly stretched DNA within a capsid of small protein subunits, each only 46 amino acid residues. HETCOR cross-peaks have been unambiguously assigned to 25 amino acids, including most external residues 1-21 as well as residues 39-40 and 43-46 deep inside the virion. In addition, the deoxyribose rings of the DNA near the virion axis are in contact with water. The sets of cross-peaks to the DNA and to all 25 amino acid residues were from the same hydration water (1)H resonance; some of the assigned residues do not have exchangeable side-chain protons. A mapping of the contacts onto structural models indicates the presence of water "tunnels" through a highly hydrophobic region of the capsid. The present results significantly extend and modify results from a lower resolution study, and yield a comprehensive hydration surface map of Pf1. In addition, the internal water could be distinguished from external hydration water by means of paramagnetic relaxation enhancement. The internal water population may serve as a conveniently localized magnetization reservoir for structural studies. PMID- 25494801 TI - Exploring the role of hydration and confinement in the aggregation of amyloidogenic peptides Abeta(16-22) and Sup35(7-13) in AOT reverse micelles. AB - Knowledge of how intermolecular interactions of amyloid-forming proteins cause protein aggregation and how those interactions are affected by sequence and solution conditions is essential to our understanding of the onset of many degenerative diseases. Of particular interest is the aggregation of the amyloid beta (Abeta) peptide, linked to Alzheimer's disease, and the aggregation of the Sup35 yeast prion peptide, which resembles the mammalian prion protein linked to spongiform encephalopathies. To facilitate the study of these important peptides, experimentalists have identified small peptide congeners of the full-length proteins that exhibit amyloidogenic behavior, including the KLVFFAE sub-sequence, Abeta16-22, and the GNNQQNY subsequence, Sup357-13. In this study, molecular dynamics simulations were used to examine these peptide fragments encapsulated in reverse micelles (RMs) in order to identify the fundamental principles that govern how sequence and solution environment influence peptide aggregation. Abeta16-22 and Sup357-13 are observed to organize into anti-parallel and parallel beta-sheet arrangements. Confinement in the sodium bis(2-ethylhexyl) sulfosuccinate (AOT) reverse micelles is shown to stabilize extended peptide conformations and enhance peptide aggregation. Substantial fluctuations in the reverse micelle shape are observed, in agreement with earlier studies. Shape fluctuations are found to facilitate peptide solvation through interactions between the peptide and AOT surfactant, including direct interaction between non polar peptide residues and the aliphatic surfactant tails. Computed amide I IR spectra are compared with experimental spectra and found to reflect changes in the peptide structures induced by confinement in the RM environment. Furthermore, examination of the rotational anisotropy decay of water in the RM demonstrates that the water dynamics are sensitive to the presence of peptide as well as the peptide sequence. Overall, our results demonstrate that the RM is a complex confining environment where substantial direct interaction between the surfactant and peptides plays an important role in determining the resulting ensemble of peptide conformations. By extension the results suggest that similarly complex sequence-dependent interactions may determine conformational ensembles of amyloid forming peptides in a cellular environment. PMID- 25494806 TI - Influence of ultrasonic frequency on Swan band sonoluminescence and sonochemical activity in aqueous tert-butyl alcohol solutions. AB - The multibubble sonoluminescence (MBSL) spectra of t-BuOH aqueous solutions submitted to power ultrasound at 20, 204, 362, and 613 kHz show emissions for the Deltaupsilon = -1 to Deltaupsilon = +2 vibrational sequences of C2* Swan system (d(3)Pig -> a(3)Piu). The Deltaupsilon=+2 emission overlaps with the CH(A-X) emission band. The maximal Swan band emission is observed when the MBSL of water itself is almost completely quenched. In general, MBSL is more intense at high frequency compared to 20 kHz ultrasound. However, in the presence of Xe, the MBSL of C2* at 20 kHz is so bright that it can be seen by the unaided eye as a blue glow in the close vicinity of the ultrasonic tip. The intensity of the C2* band emission exhibits a maximum vs t-BuOH concentration: 0.1-0.2 M at 20 kHz and (1 8) * 10(-3) M at high-frequency ultrasound. Such a huge difference is attributed to a much smaller bubble size at high ultrasonic frequency or, in other words, to a much higher bubble surface/volume ratio providing more efficient saturation of the bubble interior with t-BuOH vapors and to the fact that high frequency bubbles remain active for many more cycles than 20 kHz ones, thus accumulating more hydrocarbon decomposition products. Simulation of the emission spectra using Specair software demonstrated the absence of thermal equilibrium for C2* radicals (Tv > Tr), where Tv and Tr are the vibrational and the rotational temperature, respectively. In Ar, Tv decreases with increasing t-BuOH concentration reaching a steady value in the concentration domain that corresponds to C2* emission maximum intensity. In the presence of Xe an extremely high Tv is obtained, which is explained by the relatively low ionization potential of Xe providing a higher electron temperature of nonequilibrium plasma generated during bubble collapse. Analysis of the gaseous products of t-BuOH sonolysis reveals a significant sonochemical activity even at high t-BuOH concentration when MBSL is totally quenched, indicating that drastic conditions could be produced also within nonsonoluminescing cavitation bubbles. PMID- 25494805 TI - THz absorption spectroscopy of solvated beta-lactoglobulin. AB - The influence of beta-lactoglobulin (betaLG) on the fast sub-picosecond collective hydration dynamics in the solvent was investigated by THz absorption spectroscopy as a function of pH. It is well-known that a change in pH from pH 6 to pH 8 reversibly opens or closes the binding cavity by a transition of the E-F loop. Furthermore, the aggregation of the protein into dimers is affected, which is thought to be triggered by changes in the enzyme's electrostatic potential. Our data reveal that pH has a clear influence on the THz absorption of betaLG. We discuss this influence in light of the changes observed in the sub-psec solute/solvent dynamics when probed by THz spectroscopy, which are, in turn, seen to correlate with changes in the pH value. PMID- 25494807 TI - Anti-Cancer Activity of 2,4-Disubstituted Thiophene Derivatives: Dual Inhibitors of Lipoxygenase and Cyclooxygenase. AB - 2,4-Disubstituted thiophene derivatives were synthesized and assessed for antiinflammatory and anti-cancer activities by targeting two important enzymes of the arachidonic acid metabolism. Both lipoxygenase and cyclooxygenase enzymes play vital role in chronic inflammation and carcinogenesis. Previous studies have proved that COX-2 and 5-LOX are highly activated in various types of cancers; hence inhibition of these clinically important enzymes constitutes the essential criterion for the suppression of tumor progression and metastasis. Among the tested derivatives, 2d and 2g compounds emerged as potent inhibitors of lipoxygenase and cyclooxygenase enzymes. The potent inhibitor of cyclooxygenase was further tested for in vitro cytotoxicity on cervical cancer (HeLa) cells and in vivo tumor model studies using EAT bearing mice where 2-(3,4,5- trimethoxyphenyl)-4-(N-methylindol-3-yl) thiophene (2g) showed eloquent activity. Further, in silico modeling results confirmed the active catalytic ligand binding pockets, which is evident from higher atomic contact energy values of 2d and 2g than compared to standard drug. Thus, 2g may find better application in management of inflammation and in proapoptotic therapeutic engineering. PMID- 25494808 TI - Synthesis and Biological Evaluation of Pyrazolo[3,4-b]pyridin-4-ones as a New Class of Topoisomerase II Inhibitors. AB - A series of 1,3,6-triphenylpyrazolo[3,4-b]pyridin-4-one derivatives was designed, synthesized and evaluated for cytotoxic activity in A375 human melanoma and human erythroleukemia (HEL) cells. The new pyrazolopyridones displayed comparable activities to the antitumor compound etoposide. The inhibitory effect of compounds 17, 18, 27 and 32 against topoisomerase II-mediated cleavage activities was measured finding good correlation with the results obtained from MTS assay. Docking studies into bacterial topoisomerase II (DNA Gyrase), topoisomerase IIalpha and topoisomerase IIbeta binding sites in the DNA binding interface were performed. PMID- 25494809 TI - Efficacy and safety of bortezomib-based retreatment at the first relapse in multiple myeloma patients: A retrospective study. AB - OBJECTIVE: Multiple myeloma remains incurable and retreatment with available therapies is of substantial interest. METHODS: This retrospective observational study included data from 35 patients treated initially and at the first relapse with bortezomib-containing regimens. RESULTS: Bortezomib retreatment provided a similar depth and time to response as first-line therapy; however, as could be expected, the duration of response was shorter with retreatment. The tolerability profile was similar with bortezomib as the first- and second-line therapy, with no evidence of cumulative toxicity. CONCLUSION: These findings support bortezomib retreatment after a treatment-free interval of >=6 months in patients who achieved at least a partial response to the first-line bortezomib-based therapy. PMID- 25494810 TI - pH-induced vesicle-to-micelle transition in amphiphilic diblock copolymer: investigation by energy transfer between in situ formed polymer embedded gold nanoparticles and fluorescent dye. AB - The ability to regulate the formation of nanostructures through self-assembly of amphiphilic block copolymers is of immense significance in the field of biology and medicine. In this work, a new block copolymer synthesized by using reversible addition-fragmentation chain transfer (RAFT) polymerization technique from poly(ethylene glycol) monomethyl ether acrylate (PEGMA) and Boc-l-tryptophan acryloyloxyethyl ester (Boc-l-trp-HEA) was found to spontaneously form pH responsive water-soluble nanostructures after removal of the Boc group. While polymer vesicles or polymerosomes were formed at physiological pH, the micelles were formed at acidic pH (< 5.2), and this facilitated a pH-induced reversible vesicle-to-micelle transition. Formation of these nanostructures was confirmed by different characterization techniques, viz. transmission electron microscopy, dynamic light scattering, and steady-state fluorescence measurements. Further, these vesicles were successfully utilized to reduce HAuCl4 and stabilize the resulting gold nanoparticles (AuNPs). These AuNPs, confined within the hydrophobic shell of the vesicles, could participate in energy transfer process with fluorescent dye molecules encapsulated in the core of the vesicles, thus forming a nanometal surface energy transfer (NSET) pair. Subsequently, following the efficiency of energy transfer between this pair, it was possible to monitor the process of transition from vesicles to micelles. Thus, in this work, we have successfully demonstrated that NSET can be used to follow the transition between nanostructures formed by amphiphilic block copolymers. PMID- 25494811 TI - Nocebo effects and psychotropic drug action. AB - The role of psychosocial context around patient and therapy can be studied through randomized clinical trials. The analysis of the results of clinical trials, and considering the adverse events (AEs) in the placebo groups, provides an important perspective of study for this phenomenon. In double-blind, randomized clinical trials, the side effects reported in placebo-treated groups are not associated with pharmacological treatment, but other factors should be taken into account to explain these symptoms. This phenomenon may be conceptualized as 'nocebo effects' relating to negative expectations for treatment outcome, even though a role of prior learning in the form of conditioning with active treatments cannot be excluded. This approach makes it possible to observe how associating the placebo groups with a particular drug can cause specific AEs that are consistent with those observed in the active group. This phenomenon was described in a systematic review that examined placebo AEs in tricyclic antidepressant randomized clinical trials. The authors depicted nocebo effects in antidepressant placebos similar to the AE profiles of the real drugs, which they were matched with. These key findings contrast with the belief that nocebo effects were simply nonspecific. Moreover, they emphasize the need to develop standardized procedures for collecting information about AEs in randomized, double-blind, placebo-controlled trials determining drug efficacy. PMID- 25494812 TI - Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers. AB - BACKGROUND: Women with BRCA1 and BRCA2 mutation carriers are at substantially elevated risk of developing ovarian cancer. The aim of the meta-analysis is to clarify the role of risk-reducing salpingo-oophorectomy (RRSO) to reduce ovarian cancer risk and mortality in women with BRCA 1 and BRCA 2 mutation carriers. METHODS: Pubmed, Medline and Scopus were searched to select English-language articles. Two investigators independently extracted characteristics and results of selected studies. Articles were included only if prospective and if absolute numbers of ovarian cancer and death events were available or derivable from the test. Pooled hazard ratio (HR) with 95% confidence interval (CI) was calculated using fixed effects model. RESULTS: Meta-analysis of 3 prospective studies demonstrated a significant risk reduction of ovarian cancer with RRSO in BRCA 1 and BRCA 2 mutation carriers, as well as benefit in all-causes mortality incidence. CONCLUSIONS: It may be justified to recommend RRSO to reduce ovarian cancer risk and all-causes mortality in women with a mutation in BRCA 1 and BRCA 2. PMID- 25494813 TI - An evolutionary scenario for gonadotrophin-inhibitory hormone in chordates. AB - In 2000, we discovered a novel hypothalamic neuropeptide that actively inhibits gonadotrophin release in quail and termed it gonadotrophin-inhibitory hormone (GnIH). GnIH peptides have subsequently been identified in most representative species of gnathostomes. They all share a C-terminal LPXRFamide (X = L or Q) motif. GnIH can inhibit gonadotrophin synthesis and release by decreasing the activity of GnRH neuroes, as well as by directly inhibiting pituitary gonadotrophin secretion in birds and mammals. To investigate the evolutionary origin of GnIH and its ancestral function, we identified a GnIH precursor gene encoding GnIHs from the brain of sea lamprey, the most ancient lineage of vertebrates. Lamprey GnIHs possess a C-terminal PQRFamide motif. In vivo administration of one of lamprey GnIHs stimulated the expression of lamprey GnRH in the hypothalamus and gonadotophin beta mRNA in the pituitary. Thus, GnIH may have emerged in agnathans as a stimulatory neuropeptide that subsequently diverged to an inhibitory neuropeptide during the course of evolution from basal vertebrates to later-evolved vertebrates, such as birds and mammals. From a structural point of view, pain modulatory neuropeptides, such as neuropeptide FF (NPFF) and neuropeptide AF, share a C-terminal PQRFamide motif. Because agnathans possess both GnIH and NPFF genes, the origin of GnIH and NPFF genes may date back before the emergence of agnathans. More recently, we identified a novel gene encoding RFamide peptides in the amphioxus. Molecular phylogenetic analysis and synteny analysis indicated that this gene is closely related to the genes of GnIH and NPFF of vertebrates. The results suggest that the identified protochordate gene is similar to the common ancestor of GnIH and NPFF genes, indicating that the origin of GnIH and NPFF may date back to the time of the emergence of early chordates. The GnIH and NPFF genes may have diverged by whole-genome duplication during the course of vertebrate evolution. PMID- 25494815 TI - Sensitive surface-enhanced Raman spectroscopy (SERS) detection of organochlorine pesticides by alkyl dithiol-functionalized metal nanoparticles-induced plasmonic hot spots. AB - In this work, we report the detection of the organochlorine pesticides aldrin, dieldrin, lindane, and alpha-endosulfan by using surface-enhanced Raman spectroscopy (SERS) and optimization of the SERS-sensing substrate. In order to overcome the inherent problem of the low affinity of the above pesticides, we have developed a strategy consisting of functionalization of the metal surface with alkyl dithiols in order to achieve two different goals: (i) to induce the nanoparticle linkage and create interparticle junctions where sensitive hot spots needed for SERS enhancement are present, and (ii) to create a specific environment in the nanogaps between silver and gold nanoparticles, making them suitable for the assembly and SERS detection of the analyzed pesticides. Afterward, an optimization of the sensing substrate was performed by varying the experimental conditions: type of metal nanoparticles, molecular linker (aromatic versus aliphatic dithiols and the length of the intermediate chain), surface coverage, laser excitation wavelength. From the adsorption isotherms, it was possible to deduce the corresponding adsorption constant and the limit of detection. The present results confirm the high sensitivity of SERS for the detection of the organochlorine pesticides with a limit of detection reaching 10( 8) M, thus providing a solid basis for the construction of suitable nanosensors for the identification and quantitative analysis of this type of chemical. PMID- 25494814 TI - Comparative population genetics and evolutionary history of two commonly misidentified billfishes of management and conservation concern. AB - BACKGROUND: Misidentifications between exploited species may lead to inaccuracies in population assessments, with potentially irreversible conservation ramifications if overexploitation of either species is occurring. A notable showcase is provided by the realization that the roundscale spearfish (Tetrapturus georgii), a recently validated species, has been historically misidentified as the morphologically very similar and severely overfished white marlin (Kajikia albida) (IUCN listing: Vulnerable). In effect, no information exists on the population status and evolutionary history of the enigmatic roundscale spearfish, a large, highly vagile and broadly distributed pelagic species. We provide the first population genetic evaluation of the roundscale spearfish, utilizing nuclear microsatellite and mitochondrial DNA sequence markers. Furthermore, we re-evaluated existing white marlin mitochondrial genetic data and present our findings in a comparative context to the roundscale spearfish. RESULTS: Microsatellite and mitochondrial (control region) DNA markers provided mixed evidence for roundscale spearfish population differentiation between the western north and south Atlantic regions, depending on marker statistical analysis combination used. Mitochondrial DNA analyses provided strong signals of historical population growth for both white marlin and roundscale spearfish, but higher genetic diversity and effective female population size (1.5 1.9X) for white marlin. CONCLUSIONS: The equivocal indications of roundscale spearfish population structure, combined with a smaller effective female population size compared to the white marlin, already a species of concern, suggests that a species-specific and precautionary management strategy recognizing two management units is prudent for this newly validated billfish. PMID- 25494816 TI - Is Ghana's pro-poor health insurance scheme really for the poor? Evidence from Northern Ghana. AB - BACKGROUND: Protecting the poor and vulnerable against the cost of unforeseen ill health has become a global concern culminating in the 2005 World Health Assembly resolution urging member states to ensure financial protection to all citizens, especially children and women of reproductive age. Ghana provides financial protection to its citizens through the National Health Insurance Scheme (NHIS). Launched in 2004, its proponents claim that the NHIS is a pro-poor financial commitment that implements the World Health Assembly resolution. METHODS: Using 2011 survey data collected in seven districts in northern Ghana from 5469 women aged 15 to 49 the paper explores the extent to which poor child-bearing age mothers are covered by the NHIS in Ghana's poorest and most remote region. Factors associated with enrolment into the NHIS are estimated with logistic regression models employing covariates for household relative socio-economic status (SES), location of residence and maternal educational attainment, marital status, age, religion and financial autonomy. RESULTS: Results from the analysis showed that 33.9 percent of women in the lowest SES quintile compared to 58.3 percent for those in the highest quintile were insured. About 60 percent of respondents were registered. However, only 40 percent had valid insurance cards indicating that over 20 percent of the registered respondents did not have insurance cards. Thus, a fifth of the respondents were women who were registered but unprotected from the burden of health care payments. Results show that the relatively well educated, prosperous, married and Christian respondents were more likely to be insured than other women. Conversely, women living in remote households that were relatively poor or where traditional religion was practised had lower odds of insurance coverage. CONCLUSION: The results suggest that the NHIS is yet to achieve its goal of addressing the need of the poor for insurance against health related financial risks. To ultimately attain adequate equitable financial protection for its citizens, achieve universal health coverage in health care financing, and fully implement the World Health Assembly resolution, Ghana must reform enrolment policies in ways that guarantee pre-payment for the most poor and vulnerable households. PMID- 25494817 TI - Ameliorative effect of kaempferol, a flavonoid, on oxidative stress in streptozotocin-induced diabetic rats. AB - OBJECTIVE: The aim of the present study was to evaluate the protective effect of kaempferol against oxidative stress in streptozotocin (STZ)-induced diabetic rats. METHODS: Diabetes was induced in male, adult albino rats of the Wistar strain, by intraperitoneal administration of STZ (40 mg/kg body weight (BW)). Kaempferol (100 mg/kg BW) or glibenclamide (600 ug/kg BW) was administered orally once daily for 45 days to normal and STZ-induced diabetic rats. RESULTS: The STZ induced diabetic rats showed significantly increased levels of plasma glucose, thiobarbituric acid reactive substances, lipid hydroperoxides, and conjugated dienes in plasma, liver, kidney, and heart whereas they showed significantly decreased level of plasma insulin. The levels of non-enzymic antioxidants (vitamin C, vitamin E, reduced glutathione) in plasma, liver, kidney, and heart and the activities of enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase) in liver, kidney, and heart were significantly decreased in diabetic rats. Administration of kaempferol to diabetic rats was showed brought back in plasma glucose, insulin, lipid peroxidation products, enzymatic, and non-enzymatic antioxidants to near normal. CONCLUSION: The present study indicates that kaempferol has a good antioxidant property, as evidenced by its increase of antioxidant status and decrease of lipid peroxidation markers, thus providing protection from the risks of diabetic complications. PMID- 25494819 TI - Utilisation of a direct access echocardiography service by general practitioners in a remote and rural area--distance and rurality are not barriers to referral. AB - INTRODUCTION: This study aimed to examine whether general practitioner (GP) practice locations in remote and rural areas affected the pattern of direct access echocardiography referral and to assess any variations in echocardiographic findings. METHODS: All referrals made by all GP practices in the Scottish Highlands over a 36-month period were analysed. Referral patterns were examined according to distance and rurality based on the Scottish Government's Urban-Rural Classification. Reasons for referral and cardiac abnormality detection rates were also examined. RESULTS: In total, 1188 referrals were made from 49 different GP practices; range of referral rates was 0.3-20.1 per 1000 population with a mean of 6.5 referrals per 1000 population. Referral rates were not significantly different between urban and rural practices after correction for population size. There was no correlation between the referral rates and the distance from the centre (r2=0.004, p=0.65). The most common reason for referral was the presence of new murmur (46%). The most common presenting symptom was breathlessness (44%). Overall, 28% of studies had significant abnormal findings requiring direct input from a cardiologist. There was no clear relationship between referral rates and cardiac abnormality detection rates (r2=0.07, p=0.37). The average cardiac abnormality detection rate was 56%, (range 52-60%), with no variation based on rurality (p=0.891). CONCLUSIONS: In this cohort, rurality and distance were not barriers to an equitable direct access echocardiography service. Cardiac abnormality detection rates are consistent with that of other studies. PMID- 25494818 TI - Use of cardiac CT and calcium scoring for detecting coronary plaque: implications on prognosis and patient management. AB - Clinicians often use risk factor-based calculators to estimate an individual's risk of developing cardiovascular disease. Non-invasive cardiovascular imaging, particularly coronary artery calcium (CAC) scoring and coronary CT angiography (CTA), allows for direct visualization of coronary atherosclerosis. Among patients without prior coronary artery disease, studies examining CAC and coronary CTA have consistently shown that the presence, extent and severity of coronary atherosclerosis provide additional prognostic information for patients beyond risk factor-based scores alone. This review will highlight the basics of CAC scoring and coronary CTA and discuss their role in impacting patient prognosis and management. PMID- 25494820 TI - The potential role of PD0332991 (Palbociclib) in the treatment of multiple myeloma. AB - INTRODUCTION: Multiple myeloma (MM) remains an incurable malignancy indicating a need for continued investigation of novel therapies. Recent studies have highlighted the role of cyclin-dependent kinases (CDK) in the pathogenesis of MM. PD0332991 (Palbociclib) is an orally bioavailable, highly selective inhibitor of the CDK4/6-cyclin complex and downstream retinoblastoma protein (Rb) activation pathway that induces cell cycle arrest in the G1 phase. AREAS COVERED: In this review, the authors summarize the role of the CDK4/6 signaling pathway in MM. They also summarize the development of PD0332991 as a specific inhibitor of CDK4/6, and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM. EXPERT OPINION: While PD0332991 is essentially cytostatic, inducing prolonged G1 arrest, it enhances the cytotoxic effect of other agents effective in MM, including bortezomib and lenalidomide, as confirmed in early phase clinical trials. However, with a plethora of other drugs of different classes being tested in MM, further development of PD0332991 will depend on defining the most efficacious combination with least toxicity. An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM. The next few years are likely to better define the place of PD0332991 in the treatment of MM. PMID- 25494821 TI - Long-term stabilization of maleimide-thiol conjugates. AB - Michael-addition of a thiol to a maleimide is commonly used for bioconjugation of drugs to macromolecules. Indeed, both current FDA-approved antibody-drug conjugates-Brentuximab vedotin and Trastuzumab emtansine-and one approved PEGylated conjugate-Cimzia-contain a thiol-maleimide adduct. However, the ultimate in vivo fate of such adducts is to undergo disruptive cleavage by thiol exchange or stabilizing ring opening. Therapeutic efficacy of a conjugate can be compromised by thiol exchange and the released drug may show toxicities. However, if the succinimide moiety of a maleimide-thiol conjugate is hydrolyzed, the ring opened product is stabilized toward cleavage. We determined rates of ring-opening hydrolysis and thiol exchange of a series of N-substituted succinimide thioethers formed by maleimide-thiol conjugation. Ring-opening of conjugates prepared with commonly used maleimides were too slow to serve as prevention against thiol exchange. However, ring-opening rates are greatly accelerated by electron withdrawing N-substituents, and ring-opened products have half-lives of over two years. Thus, conjugates made with electron-withdrawing maleimides may be purposefully hydrolyzed to their ring-opened counterparts in vitro to ensure in vivo stability. PMID- 25494822 TI - Toxicity of extracts from disposable chopsticks, toothpicks, and paper cups on L 929 cells. AB - OBJECTIVE: To evaluate the toxicity of extracts from disposable chopsticks, toothpicks, and paper cups on L-929 cells. METHODS: We followed national standards to prepare the extracts from disposable chopsticks, toothpicks, and paper cups used for the cell culture media, and the morphology of L-929 cells was observed with an optical microscope. The loss rate for adherent cells was evaluated with the trypan blue exclusion method, and cell proliferation was determined using the WST-1 assay. RESULTS: Compared with the control group, the cells cultured in media containing the extracts showed signs of apoptosis and necrosis after culturing for 4 or 7 days, and the loss rate for adherent cells was significantly increased (P < 0.05). An obvious decrease in cell viability was also observed (P < 0.05). CONCLUSION: The extracts from disposable chopsticks, toothpicks, and paper cups can affect the growth and proliferation of L-929 cells and are potentially toxic to humans. PMID- 25494824 TI - Stability of latanoprost in generic formulations using controlled degradation and patient usage simulation studies. AB - PURPOSE: To evaluate the stability of latanoprost in generic formulations by using controlled degradation and patient usage simulation studies METHODS: Standard latanoprost was subjected to controlled degradation studies. Latanoprost content was assessed by using MRM, and generated Degradation Products (DP) were analysed by using the Information Dependent Acquisition (IDA) protocol of positive ESI-LC-MS/MS. Latanoprost content and formation of DP were assessed in generic formulations and were compared with Xalatan((r)) in a controlled patient usage simulation studies. The last few drops of latanoprost, present in containers used by patients were also evaluated. RESULTS: Extreme pH conditions, oxidation, light and heat were found to be the significant factors for high degree of latanoprost degradation. Systematic analysis of 7 selected generics revealed that the latanoprost content varied from 90-330%. Concentration of the latanoprost in Xalatan was found to be 97% of the label claim. Degradation studies showed the formation of 3 novel and 3 already known impurities. Upon simulated patient usage, 2 of the generic formulations showed significant degradation of latanoprost. Generic formulations having thermally sealed gas tight packing showed good stability during patient usage. Overage of latanoprost was observed in generics with other than thermal sealing. Latanoprost bottles used by patients showed concentrations ranging from 20 to 250% of label claim (144% median). CONCLUSION: This study revealed the presence of overage of latanoprost in some generic formulations and formation of degradation products. Packaging with gas tight containers may be one of the important factors for latanoprost stability, along with its storage at low temperature during patient usage. PMID- 25494823 TI - The Calcineurin Inhibitor-Sparing (CIS) Trial - individualised calcineurin inhibitor treatment by immunomonitoring in renal allograft recipients: protocol for a randomised controlled trial. AB - BACKGROUND: Adequate monitoring tools are required to optimise the immunosuppressive therapy of an individual patient. Particularly, in calcineurin inhibitors, as critical dose drugs with a narrow therapeutic range, the optimal monitoring strategies are discussed in terms of safety and efficacy. Nevertheless, no pharmacokinetic monitoring markers reflect the biological activity of the drug. A new quantitative analysis of gene expression was employed to directly measure the functional effects of calcineurin inhibition: the transcriptional activities of the nuclear factor of activated T-cell (NFAT) regulated genes in the peripheral blood. METHODS/DESIGN: The CIS study is a randomised prospective controlled trial, comparing a ciclosporin A (CsA)-based immunosuppressive regimen monitored by CsA trough levels to a CsA-based immunosuppressive regimen monitored by residual NFAT-regulated gene expression. Pulse wave velocity as an accepted surrogate marker of the cardiovascular risk is assessed in both study groups. Our hypothesis is that an individualised CsA therapy monitored by residual NFAT-regulated gene expression results in a significantly lower cardiovascular risk compared to CsA therapy monitored by CsA trough levels. DISCUSSION: There is a lack of evidence in individualising standard immunosuppression in renal allograft recipients. The CIS study will consider the feasibility of individualised ciclosporin A immunosuppression by pharmacodynamic monitoring and evaluate the opportunity to reduce cardiovascular risk while maintaining sufficient immunosuppression. TRIAL REGISTRATION: EudraCT identifier 2011-003547-21, registration date 18 July 2011https://www.clinicaltrialsregister.eu. PMID- 25494825 TI - Performance of Junctional Tourniquets in Normal Human Volunteers. AB - BACKGROUND: Inguinal bleeding is a common and preventable cause of death on the battlefield. Four FDA-cleared junctional tourniquets (Combat Ready Clamp [CRoC], Abdominal Aortic and Junctional Tourniquet [AAJT], Junctional Emergency Treatment Tool [JETT], and SAM Junctional Tourniquet [SJT]) were assessed in a laboratory on volunteers in order to describe differential performance of models. OBJECTIVE: To examine safety and effectiveness of junctional tourniquets in order to inform the discussions of device selection for possible fielding to military units. METHODS: The experiment measured safety and effectiveness parameters over timed, repeated applications. Lower extremity pulses were measured in 10 volunteers before and after junctional tourniquet application aimed at stopping the distal pulse assessed by Doppler auscultation. Safety was determined as the absence of adverse events during the time of application. RESULTS: The CRoC, SJT, and JETT were most effective; their effectiveness did not differ (p > 0.05). All tourniquets were applied safely and successfully in at least one instance each, but pain varied by model. Subjects assessed the CRoC as most tolerable. The CRoC and SJT were the fastest to apply. Users ranked CRoC and SJT equally as performing best. CONCLUSION: The CRoC and SJT were the best-performing junctional tourniquets using this model. PMID- 25494826 TI - Decreased umbilical orexin-A level is associated with idiopathic polyhydramnios. AB - OBJECTIVE: To evaluate the association between orexin-A level and idiopathic polyhydramnios. DESIGN: Case-control study. SETTING: Tertiary-level university hospital. POPULATION: Ten term pregnant women with idiopathic polyhydramnios and, as the control group, 20 pregnant women with normal amniotic fluid levels. METHODS: Amniotic fluid level was measured at admission for delivery using enzyme linked immunosorbent assay. Maternal blood was obtained from a cannulated vein immediately before delivery, and umbilical blood was collected at the time of delivery, before the separation of the placenta. MAIN OUTCOME MEASURES: Maternal and umbilical levels of orexin-A. RESULTS: Mean umbilical serum orexin-A level was significantly lower than maternal serum orexin-A level. Umbilical serum orexin-A level was positively correlated with maternal serum orexin-A level, but negatively correlated with amniotic fluid index and birthweight. Umbilical serum orexin-A level was lower in the idiopathic polyhydramnios group than in the control group. However, no difference in maternal serum orexin-A level was observed between the two groups. CONCLUSIONS: Idiopathic polyhydramnios was associated with decreased umbilical serum orexin-A levels. Our results provide evidence that orexin-A expression may be involved in amniotic fluid regulation, causing polyhydramnios by downregulation. PMID- 25494827 TI - Direct observation of molybdenum disulfide, MoS2, domains by using a liquid crystalline texture method. AB - Because the properties of molybdenum disulfide (MoS2) are strongly influenced by the sizes and boundaries of its domains, the direct visualization of large-area MoS2 domains is one of the most important challenges in MoS2 research. In the current study, we developed a simple and rapid method to observe and determine the boundaries of MoS2 domains. The technique, which depends on observations of nematic liquid crystal textures on the MoS2 surface, does not damage the sample and is not limited by domain size. Thus, this approach should significantly aid not only efforts aimed at gaining an understanding of the relationships between grain boundaries and properties of MoS2 but also those focusing on how domain sizes are controlled during large-area synthesis. PMID- 25494828 TI - Growth of wrinkle-free graphene on texture-controlled platinum films and thermal assisted transfer of large-scale patterned graphene. AB - Growth of large-scale patterned, wrinkle-free graphene and the gentle transfer technique without further damage are most important requirements for the practical use of graphene. Here we report the growth of wrinkle-free, strictly uniform monolayer graphene films by chemical vapor deposition on a platinum (Pt) substrate with texture-controlled giant grains and the thermal-assisted transfer of large-scale patterned graphene onto arbitrary substrates. The designed Pt surfaces with limited numbers of grain boundaries and improved surface perfectness as well as small thermal expansion coefficient difference to graphene provide a venue for uniform growth of monolayer graphene with wrinkle-free characteristic. The thermal-assisted transfer technique allows the complete transfer of large-scale patterned graphene films onto arbitrary substrates without any ripples, tears, or folds. The transferred graphene shows high crystalline quality with an average carrier mobility of ~ 5500 cm(2) V(-1) s(-1) at room temperature. Furthermore, this transfer technique shows a high tolerance to variations in types and morphologies of underlying substrates. PMID- 25494829 TI - Self-assembly of fiber-forming collagen mimetic peptides controlled by triple helical nucleation. AB - Mimicking the multistep self-assembly of the fibrillar protein collagen is an important design challenge in biomimetic supramolecular chemistry. Utilizing the complementarity of oppositely charged domains in short collagen-like peptides, we have devised a strategy for the self-assembly of these peptides into fibers. The strategy depends on the formation of a staggered triple helical species facilitated by interchain charged pairs, and is inspired by similar sticky-ended fibrillation designs applied in DNA and coiled coil fibers. We compare two classes of collagen mimetic peptides with the same composition but different domain arrangements, and show that differences in their proposed nucleation events differentiates their fibrillation capabilities. Larger nucleation domains result in rapid fiber formation and eventual precipitation or gelation while short nucleation domains leave the peptide soluble for long periods of time. For one of the fiber-forming peptides, we elucidate the packing parameters by X-ray diffraction. PMID- 25494830 TI - Introduction of a mixture of beta-tricalcium phosphate into a complex of bone marrow mesenchymal stem cells and type I collagen can augment the volume of alveolar bone without impairing cementum regeneration. AB - BACKGROUND: The purpose of this study is to evaluate whether beta-tricalcium phosphate (beta-TCP) could be a promising modality to help augment alveolar bone in periodontal tissue regeneration by bone marrow mesenchymal stem cells (BMMSCs). METHODS: Expanded BMMSCs and atelocollagen (Col) were mixed together (MSC/Col). A combination of beta-TCP with MSC/Col was also prepared (MSC/Col/TCP). MSC/Col/TCP or MSC/Col was transplanted into experimental periodontal Class III furcation defects that had been exposed to inflammation in beagle dogs. Periodontal tissue regeneration was evaluated by histologic and morphometric analyses at 4 and 8 weeks after transplantation. RESULTS: MSC/Col and MSC/Col/TCP enhanced periodontal tissue regeneration compared to Col and TCP/Col according to hematoxylin and eosin staining. The percentage of new cementum length in the MSC/Col/TCP group was not significantly different from that in the MSC/Col group at 4 and 8 weeks. On the other hand, the percentage of new bone area in the MSC/Col/TCP group was much higher than that in the MSC/TCP group at 4 weeks. However, at 8 weeks, no significant difference in new bone area was found between the two groups. In the MSC/Col/TCP group, beta-TCP was surrounded by newly formed bone. Multinucleated cells, which were positive for osteopontin and tartrate-resistant acid phosphatase, were present in the interconnected macropores of beta-TCP. CONCLUSION: These findings suggest that beta-TCP is applicable as a scaffold for BMMSCs transplantation and helps augment alveolar bone without impairing regeneration of cementum. PMID- 25494832 TI - The impact of brief messages on HSV-2 screening uptake among female defendants in a court setting: a randomized controlled trial utilizing prospect theory. AB - Epidemiologic data demonstrate that women involved with the criminal justice system in the United States are at high risk for sexually transmitted infections, including herpes simplex virus type 2 (HSV-2). Female defendants were recruited from a misdemeanor court to assess whether brief framed messages utilizing prospect theory could encourage testing for HSV-2. Participants were randomly assigned to a message condition (gain, loss, or control), completed an interviewer-administered survey assessing factors associated with antibody test uptake/refusal and were offered free point-of-care HSV-2 serologic testing. Although individuals in the loss-frame group accepted testing at the highest rate, an overall statistical difference in HSV-2 testing behavior by group (p <= .43) was not detected. The majority of the sample (74.6%) characterized receiving a serological test for HSV-2 as health affirming. However, this did not moderate the effect of the intervention nor was it significantly associated with test acceptance (p <= .82). Although the effects of message framing are subtle, the findings have important theoretical implications given the participants' characterization of HSV-2 screening as health affirming despite being a detection behavior. Implications of study results for health care providers interested in brief, low cost interventions are also explored. PMID- 25494833 TI - Quantifying protein measurands by peptide measurements: where do errors arise? AB - Clinically actionable quantification of protein biomarkers by mass spectrometry (MS) requires analytical performance in concordance with quality specifications for diagnostic tests. Laboratory-developed tests should, therefore, be validated in accordance with EN ISO 15189:2012 guidelines for medical laboratories to demonstrate competence and traceability along the entire workflow, including the selected standardization strategy and the phases before, during, and after proteolysis. In this study, bias and imprecision of a previously developed MS method for quantification of serum apolipoproteins A-I (Apo A-I) and B (Apo B) were thoroughly validated according to Clinical and Laboratory Standards Institute (CLSI) guidelines EP15-A2 and EP09-A3, using 100 patient sera and either stable-isotope labeled (SIL) peptides or SIL-Apo A-I as internal standard. The systematic overview of error components assigned sample preparation before the first 4 h of proteolysis as major source (~85%) of within-sample imprecision without external calibration. No improvement in imprecision was observed with the use of SIL-Apo A-I instead of SIL-peptides. On the contrary, when the use of SIL Apo A-I was combined with external calibration, imprecision improved significantly (from ~9% to ~6%) as a result of the normalization for matrix effects on linearity. A between-sample validation of bias in 100 patient sera further supported the presence of matrix effects on digestion completeness and additionally demonstrated specimen-specific biases associated with modified peptide sequences or alterations in protease activity. In conclusion, the presented overview of bias and imprecision components contributes to a better understanding of the sources of errors in MS-based protein quantification and provides valuable recommendations to assess and control analytical quality in concordance with the requirements for clinical use. PMID- 25494831 TI - Vitamin D and tuberculosis: a multicenter study in children. AB - BACKGROUND: The aim of this study is to evaluate vitamin D levels in children with latent and active TB compared to healthy controls of the same age and ethnical background. METHODS: A multicenter observational study has been conducted in three tertiary care paediatric centres: Anna Meyer Children's University Hospital, Florence, Italy; Evelina London Children's Hospital, London, United Kingdom and Great Ormond Street Hospital, London, United Kingdom. Vitamin D was considered deficient if the serum level was <25 nmol/L, insufficient between 25 and 50 nmol/L and sufficient for a level >50 nmol/L. RESULTS: The study population included 996 children screened for TB, which have been tested for vitamin D. Forty-four children (4.4%) had active TB, 138 (13.9%) latent TB and 814 (81.7%) were controls. Our study confirmed a high prevalence of hypovitaminosis D in the study population. A multivariate analysis confirmed an increased risk of hypovitaminosis D in children with latent and active TB compared to controls [(P = 0.018; RR = 1.61; 95% CI: 1.086-2.388), (P < 0.0001; RR = 4.587; 95% CI:1.190-9.608)]. CONCLUSIONS: Hypovitaminosis D was significantly associated with TB infection in our study. Further studies are needed to evaluate a possible role of vitamin D in the treatment and prevention of tuberculosis in children. PMID- 25494834 TI - Copper(I)-catalyzed enantioselective nucleophilic borylation of aldehydes: an efficient route to enantiomerically enriched alpha-alkoxyorganoboronate esters. AB - The first catalytic enantioselective nucleophilic borylation of a C?O double bond has been achieved. A series of aldehydes reacted with a diboron reagent in the presence of a copper(I)/DTBM-SEGPHOS complex catalyst using MeOH as a proton source to give the corresponding optically active alpha-alkoxyorganoboronate esters with excellent enantioselectivities. Furthermore, the products could be readily converted to the corresponding functionalized chiral alcohol derivatives through stereospecific C-C bond forming reactions involving the stereogenic C-B bond. PMID- 25494835 TI - Deciphering regulatory variation of THI genes in alcoholic fermentation indicate an impact of Thi3p on PDC1 expression. AB - BACKGROUND: Thiamine availability is involved in glycolytic flux and fermentation efficiency. A deficiency of this vitamin may be responsible for sluggish fermentations in wine making. Therefore, both thiamine uptake and de novo synthesis could have key roles in fermentation processes. Thiamine biosynthesis is regulated in response to thiamine availability and is coordinated by the thiamine sensor Thi3p, which activates Pdc2p and Thi2p. We used a genetic approach to identify quantitative trait loci (QTLs) in wine yeast and we discovered that a set of thiamine genes displayed expression-QTL on a common locus, which contains the thiamine regulator THI3. RESULTS: We deciphered here the source of these regulatory variations of the THI and PDC genes. We showed that alteration of THI3 results in reduced expression of the genes involved in thiamine biosynthesis (THI11/12/13 and THI74) and increased expression of the pyruvate decarboxylase gene PDC1. Functional analysis of the allelic effect of THI3 confirmed the control of the THI and PDC1 genes. We observed, however, only a small effect of the THI3 on fermentation kinetics. We demonstrated that the expression levels of several THI genes are correlated with fermentation rate, suggesting that decarboxylation activity could drive gene expression through a modulation of thiamine content. Our data also reveals a new role of Thi3p in the regulation of the main pyruvate decarboxylase gene, PDC1. CONCLUSIONS: This highlights a switch from PDC1 to PDC5 gene expression during thiamine deficiency, which may improve the thiamine affinity or conservation during the enzymatic reaction. In addition, we observed that the lab allele of THI3 and of the thiamin transporter THI7 have diverged from the original alleles, consistent with an adaptation of lab strains to rich media containing an excess of thiamine. PMID- 25494839 TI - Clinical presentations of Behcet's disease among Nigerians: a 4-year prospective study. AB - BACKGROUND: Behcet's disease (BD) is a chronic, multisystem, inflammatory pan vasculitis of unknown etiology, with heterogeneous presentations in different parts of the world. It commonly involves the mucosae, skin, joints, eyes, and central nervous system. Behcet's disease is considered to represent an autoimmune reaction triggered by a yet to be identified infectious agent in a genetically predisposed person. It most commonly affects persons of Mediterranean or Far Eastern origin and is considered rare among Black Africans. OBJECTIVES: This study was conducted to document clinical presentations of BD in Nigerians. METHODS: A prospective study of the clinical and laboratory parameters of patients who attended dermatology and rheumatology clinics between 2007 and 2011 was carried out. RESULTS: Fifteen patients (nine males, six females) were diagnosed with BD at a mean age of 33 years. The mean age of onset of disease was 27 years. Oral ulceration was present in 100% of subjects and was the most frequent onset lesion, followed by genital ulceration in 93%. Skin, joint, vascular, gastrointestinal, and central nervous system (CNS) lesions occurred in 87, 80, 33, 20, and 13% of patients, respectively. Pathergy tests were positive in 38% of patients. Psychomorbidity was present in 60%. Remission was achieved with corticosteroids, nonsteroidal anti-inflammatory drugs, and disease-modifying anti-rheumatic drugs. Mortality was zero, but 27% of patients were disabled by blindness and 7% by CNS involvement. CONCLUSIONS: This is the first report on BD in a sample of Nigerians. The clinical phenotype of BD follows the Middle Eastern pattern. The small number of patients may reflect the rarity of BD in Nigerians or the poor ascertainment of BD by relevant clinicians. PMID- 25494838 TI - Effect of production phase on bottle-fermented sparkling wine quality. AB - This review analyzes bottle-fermented sparkling wine research at each stage of production by evaluating existing knowledge to identify areas that require future investigation. With the growing importance of enological investigation being focused on the needs of the wine production industry, this review examines current research at each stage of bottle-fermented sparkling wine production. Production phases analyzed in this review include pressing, juice adjustments, malolactic fermentation (MLF), stabilization, clarification, tirage, lees aging, disgorging, and dosage. The aim of this review is to identify enological factors that affect bottle-fermented sparkling wine quality, predominantly aroma, flavor, and foaming quality. Future research topics identified include regional specific varieties, plant-based products from vines, grapes, and yeast that can be used in sparkling wine production, gushing at disgorging, and methods to increase the rate of yeast autolysis. An internationally accepted sensory analysis method specifically designed for sparkling wine is required. PMID- 25494841 TI - Extensive feeding on sockeye salmon Oncorhynchus nerka smolts by bull trout Salvelinus confluentus during initial outmigration into a small, unregulated and inland British Columbia river. AB - Stomach contents were collected and analysed from 22 bull trout Salvelinus confluentus at the edge of the Chilko Lake and Chilko River in British Columbia, Canada, during spring outmigration of sockeye salmon Oncorhynchus nerka smolts. Twenty of the 22 (>90%) stomachs contained prey items, virtually all identifiable prey items were outmigrant O. nerka smolts and stomach contents represented a large portion (0.0-12.6%) of estimated S. confluentus mass. The results demonstrate nearly exclusive and intense feeding by S. confluentus on outmigrant smolts, and support recent telemetry observations of high disappearance rates of O. nerka smolts leaving large natural lake systems prior to entering high-order unregulated river systems. PMID- 25494842 TI - Preactivated oxazaphosphorines designed for isophosphoramide mustard delivery as bulk form or nanoassemblies: synthesis and proof of concept. AB - Oxazaphosphorines are alkylating agents used in routine clinical practices for treatment of cancer for many years. They are antitumor prodrugs that require cytochrome P450 bioactivation leading to 4-hydroxy derivatives. In the case of ifosfamide (IFO), the bioactivation produces two toxic metabolites: acrolein, a urotoxic compound, concomitantly generated with the isophosphoramide mustard; and chloroacetaldehyde, a neurotoxic and nephrotoxic compound, arising from the oxidation of the side chains. To improve the therapeutic index of IFO, we have designed preactivated IFO derivatives with the covalent binding of several O- and S-alkyl moieties including polyisoprenoid groups at the C-4 position of the oxazaphosphorine ring to avoid cytochrome bioactivation favoring the release of the active entity and limiting the chloroacetaldehyde release. Thanks to the grafted terpene moieties, some of these new conjugates demonstrated spontaneous self-assembling properties into nanoassemblies when dispersed in water. The cytotoxic activities on a panel of human tumor cell lines of these novel oxazaphosphorines, in bulk form or as nanoassemblies, and the release of 4 hydroxy-IFO from these preactivated IFO analogues in plasma are reported. PMID- 25494843 TI - Specific antidotes in development for reversal of novel anticoagulants: a review. AB - In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban, edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals) is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and the description of ongoing clinical trials with the new compounds. PMID- 25494844 TI - Identifying aggressive forms of endometrioid-type endometrial cancer: new insights into molecular subtyping. AB - Clinical heterogeneity represents a great challenge for cancer therapeutics. Molecular classification of patients into different subtypes based on genetic or epigenetic characteristics has the potential to revolutionize the clinical care and mechanistic understanding of a wide spectrum of cancers, including endometrial carcinoma, the most common gynecological cancer affecting women. PMID- 25494845 TI - Service utilisation in a public post-acute rehabilitation unit following traumatic brain injury. AB - Traumatic brain injury (TBI) causes disability in a proportion of survivors across the spectrum of injury severity. Previous research suggests physical changes are the primary focus of rehabilitation, although cognitive, emotional and behavioural difficulties cause greater concern in the long-term. There is little information about services accessed by those with mild injuries, who often have no physical disabilities. This study investigated factors determining service utilisation in a population-based sample which included 52% mild injuries (PTA <= 24 hours). Chi-squares and t-tests were used to examine the impact of demographic, clinical, psychological and physical variables on referral of 175 TBI patients to clinical disciplines in a public, community-based rehabilitation facility in Hobart, Tasmania. Increased service intensity (total disciplines referred to), was associated with greater injury severity (p = .006) and previous TBI (p = .041). Less traditional rehabilitation services (nursing, psychology) received more referrals than traditional disciplines (physiotherapy, occupational therapy, social work). Referral to physiotherapy and occupational therapy was associated with greater injury severity, functional dependence, hospitalisation and older age. Referral to nursing, psychology and social work was associated with more post-concussion symptoms, younger age, anxiety, depression and assault related injury. The large number of referrals to psychology strengthens the case for including it as a core rehabilitation discipline. PMID- 25494846 TI - Transfusion-related acute lung injury not a two-hit, but a multicausal model. AB - BACKGROUND: The etiology of transfusion-related acute lung injury (TRALI) is often referred to as a "two-hit model," the first hit being patient predisposition and the second being a transfusion. This model lumps all patient related risk factors together and thereby may hamper identification of individual, potentially preventable or modifiable risk factors. STUDY DESIGN AND METHODS: Like any disease, TRALI is multicausal in nature. To be able to effectively scrutinize all contributing causes, we need to clearly describe this multicausality as completely as possible. Several models are already commonly used to describe the multicausality of other diseases, including threshold models and the sufficient cause model. RESULTS: Here we describe the application of two different multicausal models to TRALI. These models can readily describe any potential scenario for the etiology of TRALI. First we will introduce the intuitively appealing threshold model, which shows some similarities with the Bux and Sachs threshold model for TRALI. Second we discuss the more abstract sufficient cause model. CONCLUSIONS: Both models have their strengths and limitations. Both are, however, better equipped than the two-hit model to describe the multicausal nature of TRALI. Further identification of all involved risk factors and the complex interplay between them is facilitated by these models. PMID- 25494847 TI - Preparation of a cross-linked porous protein crystal containing Ru carbonyl complexes as a CO-releasing extracellular scaffold. AB - Protein crystals generally are stable solid protein assemblies. Certain protein crystals are suitable for use as nanovessels for immobilizing metal complexes. Here we report the preparation of ruthenium carbonyl-incorporated cross-linked hen egg white lysozyme crystals (Ru.CL-HEWL). Ru.CL-HEWL retains a Ru carbonyl moiety that can release CO, although a composite of Ru carbonyl-HEWL dissolved in buffer solution (Ru.HEWL) does not release CO. We found that treatment of cells with Ru.CL-HEWL significantly increased nuclear factor kappa B (NF-kappaB) activity as a cellular response to CO. These results demonstrate that Ru.CL-HEWL has potential for use as an artificial extracellular scaffold suitable for transport and release of a gas molecule. PMID- 25494849 TI - Measurement of NO(x) fluxes from a tall tower in Central London, UK and comparison with emissions inventories. AB - Direct measurements of NOx concentration and flux were made from a tall tower in central London, UK as part of the Clean Air for London (ClearfLo) project. Fast time resolution (10 Hz) NO and NO2 concentrations were measured and combined with fast vertical wind measurements to provide top-down flux estimates using the eddy covariance technique. Measured NOx fluxes were usually positive and ranged from close to zero at night to 2000-8000 ng m(-2) s(-1) during the day. Peak fluxes were usually observed in the morning, coincident with the maximum traffic flow. Measurements of the NOx flux have been scaled and compared to the UK National Atmospheric Emissions Inventory (NAEI) estimate of NOx emission for the measurement footprint. The measurements are on average 80% higher than the NAEI emission inventory for all of London. Observations made in westerly airflow (from parts of London where traffic is a smaller fraction of the NOx source) showed a better agreement on average with the inventory. The observations suggest that the emissions inventory is poorest at estimating NOx when traffic is the dominant source, in this case from an easterly direction from the BT Tower. Agreement between the measurements and the London Atmospheric Emissions Inventory (LAEI) are better, due to the more explicit treatment of traffic flow by this more detailed inventory. The flux observations support previous tailpipe observations of higher NOx emitted from the London vehicle diesel fleet than is represented in the NAEI or predicted for several EURO emission control technologies. Higher-than anticipated vehicle NOx is likely responsible for the significant discrepancies that exist in London between observed NOx and long-term NOx projections. PMID- 25494848 TI - The induction of activating transcription factor 3 (ATF3) contributes to anti cancer activity of Abeliophyllum distichum Nakai in human colorectal cancer cells. AB - BACKGROUND: Recently, Abeliophyllum distichum Nakai (A. distichum) has been reported to exert the inhibitory effect on angiotensin converting enzyme. However, no specific pharmacological effects from A. distichum have been described. We performed in vitro study to evaluate anti-cancer properties of A. distichum and then elucidate the potential mechanisms. METHODS: Cell viability was measured by MTT assay. ATF3 expression level was evaluated by Western blot or RT-PCR and ATF3 transcriptional activity was determined using a dual-luciferase assay kit after the transfection of ATF3 promoter constructs. In addition, ATF3 dependent apoptosis was evaluated by Western blot after ATF3 knockdown using ATF3 siRNA. RESULTS: Exposure of ethyl acetate fraction from the parts of A. distichum including flower, leaf and branch to human colorectal cancer cells, breast cancer cells and hepatocellular carcinoma reduced the cell viability. The branch extracts from A. distichum (EAFAD-B) increased the expression of activating transcription factor 3 (ATF3) and promoter activity, indicating transcriptional activation of ATF3 gene by EAFAD-B. In addition, our data showed that EAFAD-B responsible sites might be between -147 and -85 region of the ATF3 promoter. EAFAD-B-induced ATF3 promoter activity was significantly decreased when the CREB site was deleted. However, the deletion of Ftz sites did not affect ATF3 promoter activity by EAFAD-B. We also observed that inhibition of p38MAPK and GSK3beta attenuated EAFAD-B-mediated ATF3 promoter activation. Also, EAFAD-B contributes at least in part to increase of ATF3 accumulation. CONCLUSION: These findings suggest that the anti-cancer activity of EAFAD-B may be a result of ATF3 promoter activation and subsequent increase of ATF3 expression. PMID- 25494850 TI - A rare case of tuberculosis with motor neuron disease. AB - Motor neuron disease (MND) is occasionally aggravated by chronic infection. A misdiagnosed case of tuberculosis with MND is illustrated in a 45-year-old woman who underwent successful VATS wedge excision, which is presented herein. MND in an adult is a rare clinical entity. In order to facilitate the preoperative diagnosis and avoid the misdiagnosis of this disease, more etiological factors need to be considered. PMID- 25494851 TI - Second generation of cryoballoons can improve efficiency of cryoablation for atrial fibrillation. AB - BACKGROUND: We investigated whether the new second generation of cryoballoons can improve the efficiency and safety of cryoablation for atrial fibrillation (AF) during ablation and in terms of outcome. METHODS: Data of AF patients consecutively treated with a single 28-mm cryoballoon were analyzed. Patients were divided into two groups: the G1 group was treated with the first-generation cryoballoons (ArcticFront) and G2 with the second generation (ArcticFront Advance). Failure of cryoablation treatment was defined as detection of an episode of AF, atrial flutter, or atrial tachycardia lasting >= 30 seconds during 3-month follow-up. Left atrial diameter (LAD) was measured by transthoracic echocardiography before cryoablation. RESULTS: One hundred twenty-five patients (group G1/G2: 57/68) were enrolled. Mean total time of the whole procedure, cryomapping, and cryoablation was shorter with G2 than with G1 (P < 0.05). No complication occurred with G1 whereas with G2 the complication rate was 8.8%. During mean 12 +/- 4 months follow-up, the overall success rate of cryoablation was 76.0% (95/125); it was higher with G2 (89.7% [61/68] vs 59.7% [34/57], P < 0.001). Patients in whom treatment failed had larger LAD (48 +/- 8 mm vs 44 +/- 6 mm, P = 0.002) than those in whom it succeeded. Type of cryoballoon (relative risk [RR] = 5.75 [2.16, 15.27], P < 0.0001) and LAD (RR = 0.90 [0.83, 0.97], P = 0.0043) were shown in multivariable analysis to be individually related to the difference in success rate. CONCLUSION: Ablation for AF with the new generation of cryoballoons is associated with higher success rate of pulmonary vein isolation and better outcome. However, more complications occurred during the early stage of application of the G2 cryoballoon. PMID- 25494852 TI - Structure and visible light luminescence of 3D flower-like Co3O4 hierarchical microstructures assembled by hexagonal porous nanoplates. AB - A two-step strategy has been developed to fabricate 3D flower-like Co3O4 hierarchical microstructures assembled by hexagonal porous nanoplates. The synthetic procedure was described as (1) 3D flower-like alpha-Co(OH)2 microstructures were prepared by a facile surfactant-free low-temperature hydrothermal process; (2) 3D flower-like Co3O4 hierarchical microstructures were fabricated by annealing the obtained 3D flower-like alpha-Co(OH)2 microstructures. X-ray diffraction and Raman spectrum analyses demonstrate that the hierarchical microstructures formed from 3D flower-like alpha-Co(OH)2 microstructures are composed of pure cubic phase Co3O4. Scanning electronic microscopy demonstrates that the as-prepared Co3O4 microstructures exhibit 3D flower-like hierarchical structures assembled by hexagonal porous nanoplates. Photoluminescence demonstrates that these novel 3D flower-like Co3O4 hierarchical microstructures display a broad strong emission in the visible range of 650 to 800 nm with a peak at around 710 nm (1.75 eV), which is very close to the indirect optical band gap of 1.60 eV for Co3O4 thin film. The result indicates that the photoluminescence emission likely originates from the indirect optical band gap emission. The broad photoluminescence emission may be resulted from a wide size distribution of porous nanoplates in 3D hierarchical microstructures. These 3D flower-like Co3O4 hierarchical microstructures with unique optical properties may find new potential applications in visible light emitting materials. PMID- 25494853 TI - Rate of resistance evolution and polymorphism in long- and short-lived hosts. AB - Recent theoretical work has shown that long-lived hosts are expected to evolve higher equilibrium levels of disease resistance than shorter-lived hosts, but questions of how longevity affects the rate of resistance evolution and the maintenance of polymorphism remain unanswered. Conventional wisdom suggests that adaptive evolution should occur more slowly in long-lived organisms than in short lived organisms. However, the opposite may be true for the evolution of disease resistance traits where exposure to disease, and therefore the strength of selection for resistance increases with longevity. In a single locus model of innate resistance to a frequency-dependent, sterilizing disease, longer lived hosts evolved resistance more rapidly than short-lived hosts. Moreover, resistance in long-lived hosts could only be polymorphic for more costly and more extreme resistance levels than short-lived hosts. The increased rate of evolution occurred in spite of longer generation times because longer-lived hosts had both a longer period of exposure to disease as well as higher disease prevalence. Qualitatively similar results were found when the model was extended to mortality inducing diseases, or to density-dependent transmission modes. Our study shows that the evolutionary dynamics of host resistance is determined by more than just levels of resistance and cost, but is highly sensitive to the life-history traits of the host. PMID- 25494854 TI - Clinical use of conventional reference intervals in the frail elderly. AB - RATIONALE, AIMS AND OBJECTIVES: Reference intervals provided by the laboratory are commonly established by measuring samples from apparently healthy subjects in the ages 18-65 years, excluding elderly individuals with chronic diseases and medication. The aim of our study was to establish whether current reference intervals for immune parameters and chemical biomarkers are valid for older individuals including those with chronic diseases, so-called frail elderly. METHODS: Data from our cohort of 138 non-infected nursing home residents (NHR), mean age 86.8 years, range 80-98, were compared with raw data, as basis for the development of reference intervals, obtained from reference populations, like blood donors (IgA, IgG, IgM, C3 and C4) and from the Nordic Reference Interval Project (NORIP) (alanine aminotransferase, albumin, aspartate aminotransferase, creatinine, gamma-glutamyl transferase, lactate dehydrogenase, phosphate, sodium and urea). Immune parameters were measured by nephelometry and in NORIP the measurements were performed by means of different routine methods, in more than 100 laboratories. RESULTS: Only nine individuals (7%) of NHR were found to be free from chronic disease. C3, C4 (P < 0.001) and IgG levels (P < 0.05) were higher, while IgM levels (P < 0.001) were lower in NHR compared with reference blood donors. Levels of alanine aminotransferase, phosphate (P < 0.001), albumin (P < 0.05) and sodium (P < 0.01) were lower while creatinine and urea levels were higher (P < 0.001) in NHR compared with NORIP subjects. CONCLUSION: Comparing laboratory results from elderly people with conventional reference intervals can be misleading or even dangerous, as normal conditions may appear pathological, or vice versa and thus lead to unnecessary or even harmful treatment. PMID- 25494855 TI - The association of the MTHFR c.1625A>C genetic variant with the risk of congenital heart diseases in the Chinese. AB - The purpose of this study is to investigate the association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms with the risk of congenital heart diseases (CHD). The genotypes of the MTHFR genetic variant were determined by the polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing methods. Our data suggested that the allelic and genotypic frequencies of CHD patients were significantly different from non-CHD controls. The MTHFR c.1625A>C genetic variant was significantly associated with the increased risk of CHD (CC vs. AA: odds ratio [OR]=2.29, 95% confidence interval [CI] 1.15-4.53, p=0.016; C vs. A: OR=1.47, 95% CI 1.11-1.96, p=0.008). Results from this study indicate that the MTHFR c.1625A>C genetic variant influences the risk of CHD in the studied population. PMID- 25494857 TI - Editorial JOR version 2.0. PMID- 25494858 TI - Marriage Matters But How Much? Marital Centrality Among Young Adults. AB - Marriage, once a gateway to adulthood, is no longer as widely considered a requirement for achieving adult status. With declining marriage rates and delayed marital transitions, some have wondered whether current young adults have rejected the traditional notion of marriage. Utilizing a sample of 571 young adults, the present study explored how marital centrality (the expected importance to be placed on the marital role relative to other adult roles) functioned as a unique and previously unexplored marital belief among young adults. Results suggested that marriage remains an important role for many young adults. On average, young adults expected that marriage would be more important to their life than parenting, careers, or leisure activities. Marital centrality profiles were found to significantly differ based on both gender and religiosity. Marital centrality was also associated with various outcomes including binge drinking and sexual activity. Specifically, the more central marriage was expected to be, the less young adults engaged in risk-taking or sexual behaviors. PMID- 25494856 TI - Thermal control of virulence factors in bacteria: a hot topic. AB - Pathogenic bacteria sense environmental cues, including the local temperature, to control the production of key virulence factors. Thermal regulation can be achieved at the level of DNA, RNA or protein and although many virulence factors are subject to thermal regulation, the exact mechanisms of control are yet to be elucidated in many instances. Understanding how virulence factors are regulated by temperature presents a significant challenge, as gene expression and protein production are often influenced by complex regulatory networks involving multiple transcription factors in bacteria. Here we highlight some recent insights into thermal regulation of virulence in pathogenic bacteria. We focus on bacteria which cause disease in mammalian hosts, which are at a significantly higher temperature than the outside environment. We outline the mechanisms of thermal regulation and how understanding this fundamental aspect of the biology of bacteria has implications for pathogenesis and human health. PMID- 25494859 TI - Adolescent non-adherence reveals a genetic cause for diabetes. AB - BACKGROUND: Glucokinase related maturity-onset diabetes of the young (GCK-MODY) is a form of monogenic diabetes characterized by mildly elevated fasting blood sugars and HbA(1c) typically ranging from 38 to 60 mmol/mol (5.6-7.6%). It is frequently unrecognized or misdiagnosed as Type 1 or Type 2 diabetes, resulting in unnecessary pharmacologic therapy. CASE REPORT: Two brothers were initially diagnosed with Type 1 diabetes mellitus. The brothers were maintained on a total daily insulin dose of 0.3-0.5 units/kg/day and had HbA(1c) values of 40-51 mmol/mol (5.8-6.8%) throughout childhood. After over 10 years of insulin treatment, the younger brother chose to discontinue his insulin therapy without informing his family or his clinician. Following cessation of insulin treatment, he did not experience any change in overall glycaemic control. Subsequent research-based genetic testing revealed a deleterious mutation in GCK in both brothers (p.Val182Met). The older brother subsequently discontinued insulin therapy and both have remained off all pharmacological therapy with good glycaemic control (HbA(1c) < 53 mmol/mol, < 7%) and no adverse complications. The family was advised to seek confirmatory genetic testing in the father and other relatives with hyperglycaemia. CONCLUSION: The family described above exemplifies the rationale behind considering a genetic cause when evaluating every person with new-onset hyperglycaemia or those with atypical diabetes. The cost of genetic testing for the most common MODY causing genes may be offset by savings made in therapeutic costs. It is important that all clinicians supervising diabetes care recognize the cardinal features that distinguish GCK-MODY from other forms of diabetes. PMID- 25494860 TI - Changes in leptin and peptide YY do not explain the greater-than-predicted decreases in resting energy expenditure after weight loss. AB - CONTEXT: It is unknown whether leptin and peptide YY (PYY) influence changes in resting energy expenditure (REE), independently of fat mass (FM) and fat-free mass (FFM) in addition to changes in other energy expenditure (EE) components during weight loss. OBJECTIVE: The objective of the study was to examine the relationships between leptin, PYY, and body composition with different EE components before and after weight loss and whether changes in leptin and PYY were associated with differences in predicted vs measured REE after the intervention. DESIGN: This was a randomized controlled design. SETTING: The study was conducted in a laboratory. PARTICIPANTS: Participants were ninety-three overweight/obese postmenopausal women (aged 58.1 +/- 4.8 y; body mass index 32.1 +/- 4.3 kg/m(2)). INTERVENTION: Interventions included a 6-month caloric restriction diet alone or caloric restriction diet+resistance training. MAIN OUTCOME MEASURES: Body composition (dual energy x-ray absorptiometry), REE (indirect calorimetry), total EE (TEE; doubly labeled water), and fasting leptin and total PYY before and after weight loss were measured. RESULTS: Both interventions yielded significant decreases in weight, FFM, REE, and leptin, whereas a significant time * group interaction was noted for FM (greater decrease in FM in the diet+resistance training group) (P < .05 for all outcomes). No significant differences in TEE, physical activity EE, and PYY were noted between baseline and after the intervention. Age, FFM, leptin, and PYY were the best predictors of baseline REE (R(2) = 0.77; P = .0001), whereas age, FFM, and FM were associated with REE after the intervention (R(2) = 0.88; P = .0001). The same predictors, except for leptin, were significantly related to TEE at baseline (R(2) = 0.70; P = .0001) and after the intervention (R(2) = 0.29; P = .0001), whereas only PYY was a significant predictor of physical activity EE at baseline and after the intervention. Changes in FM and leptin accounted for 27% of the variance in DeltaREE (P = .0001). Greater predicted vs measured REE was noted after the intervention (P = .02). However, Delta leptin and DeltaPYY were not significant predictors of the differences between postintervention measurement and predicted REE. CONCLUSIONS: Delta Leptin and DeltaFM were strong contributors to changes in REE. However, Delta leptin and DeltaPYY were not significant predictors of the differences between predicted and measured REE after the intervention. PMID- 25494861 TI - Somatostatin receptors in bronchopulmonary neuroendocrine neoplasms: new diagnostic, prognostic, and therapeutic markers. AB - CONTEXT AND OBJECTIVES: Gastroenteropancreatic neuroendocrine neoplasms are known for their overexpression of somatostatin receptors (SSTRs), which provide the molecular basis for diagnostic and therapeutic interventions. In contrast, few data on the SSTR expression profile exist for bronchopulmonary neuroendocrine neoplasms (BP-NEN). DESIGN AND SETTINGS: A total of 240 formalin-fixed, paraffin embedded specimens from 26 typical carcinoid (TC), 30 atypical carcinoid (AC), and 34 small cell lung cancer (SCLC) patients were examined retrospectively by immunohistochemistry (IHC) using specific rabbit monoclonal antibodies and evaluated by the immunoreactive score. Adjacent slides from 20 samples of each tumor type were subjected to additional RT-quantitative PCR mRNA analysis. RESULTS: With different expression patterns, SSTRs were present in most of the tumor sections, at both the protein and mRNA levels. The RT-quantitative PCR data correlated with the IHC scores. SSTR1 was detected in approximately 65% of the TC and AC, but hardly in the SCLC, whereas both SSTR2A and SSTR5 were present in approximately 45% of each entity. Furthermore, the SSTR1 expression level was positively correlated with patient survival. CONCLUSIONS: Our results suggest that SSTRs can be used as novel diagnostic, prognostic, and therapeutic markers of BP-NEN. The differences in the SSTR expression profile between the three types of BP-NEN may help to set a diagnostic cutoff and predict patient prognosis. Similar to TC and AC, our results also revealed a previously unappreciated high level of SSTR2A expression in SCLC within a subgroup of patients. However, in most cases, pan-somatostatin analogs may represent an additional therapeutic option. PMID- 25494862 TI - Newborn screening for congenital adrenal hyperplasia in New Zealand, 1994-2013. AB - OBJECTIVE: The objective of the study was to evaluate the efficacy of national newborn screening for severe congenital adrenal hyperplasia (CAH) in New Zealand over the past 20 years. METHODS: Newborn screening for CAH is performed through the estimation of 17-hydroxyprogesterone by a Delfia immunoassay. CAH cases diagnosed in the newborn period from 1994 to 2013 were identified from Newborn Metabolic Screening Programme records. RESULTS: Between 1994 and 2013, 44 neonates (28 females, 16 males) were diagnosed with CAH, giving an incidence of 1:26 727. Almost half (n = 21) of the newborns with CAH were detected solely via screening (not clinically suspected), including 21% of all affected females. Among the group solely ascertained by screening, 17-hydroxyprogesterone sampling occurred at a mean age of 3.3 days (range 2-8 d), the duration from sampling to notification was 5.2 days (0-12 d), and treatment was initiated at 12.0 days (6 122 d). Vomiting was present in 14% of those ascertained by screening, but none had hypotension or collapse at diagnosis. Increasing age at treatment was correlated with a progressive decrease in serum sodium (r = -0.56; P < .0001) and an increase in serum potassium concentrations (r = 0.38; P = .017). Compared with newborns diagnosed by screening alone, those clinically diagnosed were predominantly female (96% vs 29%; P < .0001), notification occurred earlier (4.8 vs 8.5 d; P = .002), and had higher serum sodium (136.8 vs 130.8 mmol/L; P < .0001) and lower serum potassium (5.3 vs 6.0 mmol/L; P = .011) concentrations. CONCLUSIONS: Screening alone accounted for nearly 50% cases of CAH detected in the newborn period, including a fifth of affected females, indicating that clinical diagnosis is unreliable in both genders. Symptoms were mild at diagnosis and there were no adrenal crises. This study confirms the benefits of newborn CAH screening. PMID- 25494864 TI - Genetic markers of insulin sensitivity and insulin secretion are associated with spontaneous postnatal growth and response to growth hormone treatment in short SGA children: the North European SGA Study (NESGAS). AB - PURPOSE: The wide heterogeneity in the early growth and metabolism of children born small for gestational age (SGA), both before and during GH therapy, may reflect common genetic variations related to insulin secretion or sensitivity. METHOD: Combined multiallele single nucleotide polymorphism scores with known associations with insulin sensitivity or insulin secretion were analyzed for their relationships with spontaneous postnatal growth and first-year responses to GH therapy in 96 short SGA children. RESULTS: The insulin sensitivity allele score (GS-InSens) was positively associated with spontaneous postnatal weight gain (regression coefficient [B]: 0.12 SD scores per allele; 95% confidence interval [CI], 0.01-0.23; P = .03) and also in response to GH therapy with first year height velocity (B: 0.18 cm/y per allele; 95% CI, 0.02-0.35; P = .03) and change in IGF-1 (B: 0.17 SD scores per allele; 95% CI, 0.00-0.32; P = .03). The association with first-year height velocity was independent of reported predictors of response to GH therapy (adjusted P = .04). The insulin secretion allele score (GS-InSec) was positively associated with spontaneous postnatal height gain (B: 0.15; 95% CI, 0.01-0.30; P = .03) and disposition index both before (B: 0.02; 95% CI, 0.00-0.04; P = .04) and after 1 year of GH therapy (B: 0.03; 95% CI, 0.01-0.05; P = .002), but not with growth and IGF-1 responses to GH therapy. Neither of the allele scores was associated with size at birth. CONCLUSION: Genetic allele scores indicative of insulin sensitivity and insulin secretion were associated with spontaneous postnatal growth and responses to GH therapy in short SGA children. Further pharmacogenetic studies may support the rationale for adjuvant therapies by informing the mechanisms of treatment response. PMID- 25494865 TI - A case of panniculitis caused by Mycobacterium massiliense mimicking erythema induratum. AB - Among nontuberculosis mycobacteria (NTM), rapidly growing mycobacteria (RGM) are the most common causative agents of soft tissue infection. Mycobacterium massiliense, a new species of NTM, was isolated in 2004. Due to the lower virulence of RGM, M. massiliense infection is rare in the general population. Here, we report a case of multiple infective panniculitis, due to M. massiliense, mimicking erythema induratum in a patient with Cushing syndrome. The organism was identified using traditional mycobacterial culturing and staining methods as well as molecular approaches, including erythromycin ribosome transferase gene polymerase chain reaction. The patient was treated with clarithromycin for 9 months, based on antibiotic susceptibility testing. PMID- 25494863 TI - Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort. AB - CONTEXT: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. OBJECTIVE: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. DESIGN: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. SETTING: The study was conducted at university hospitals. PATIENTS: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. OUTCOME: Outcomes included genetic screening and clinical characteristics. RESULTS: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. CONCLUSIONS: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma. PMID- 25494866 TI - Association between sensory function and medio-lateral knee position during functional tasks in patients with anterior cruciate ligament injury. AB - BACKGROUND: Patients with anterior cruciate ligament (ACL) injury often exhibit reduced movement quality during functional tasks in the form of a knee-medial-to foot position (KMFP). This movement pattern is suggested to be more common in women than in men, but the possible contributing sensorimotor factors for this altered knee position are poorly studied in these patients. The aim of this study was to evaluate the association between sensory function and medio-lateral knee position during functional tasks in men and women with ACL injury. METHODS: Fifty one patients (23 women) aged 18-40 years with ACL injury were included in this cross-sectional study. Measures of sensory function were assessed by the threshold to detection of passive motion (TDPM) for knee kinesthesia and by the vibration perception threshold (VPT) for vibration sense. Movement quality was assessed by visual observation of the position of the knee relative to the foot during the following four functional tasks with different degrees of difficulty: the single-limb mini-squat, stair descending, the forward lunge, and the drop jump. Spearman's rank correlation coefficient was used to determine the relationship between the sensory measures and the medio-lateral knee position during the functional tasks. Differences in TDPM and/or VPT between subjects with good and poor movement quality were evaluated using the independent t-test. Separate gender analyses were performed. RESULTS: Worse TDPM was associated with a KMFP during the drop jump in men. Worse VPT at the toe and ankle was associated with a KMFP during stair descending and the forward lunge in women, but no associations were found in men. CONCLUSION: Worse kinesthesia, measured by TDPM, might be associated with KMFP during the drop jump in men with ACL injury while worse vibration sense, measured by the VPT, at the foot and ankle might be related to KMFP in women. Further studies are needed to confirm these results. PMID- 25494869 TI - Effects of endurance training only versus same-session combined endurance and strength training on physical performance and serum hormone concentrations in recreational endurance runners. AB - This study investigated the effects of endurance training only (E, n = 14) and same-session combined training, when strength training is repeatedly preceded by endurance loading (endurance and strength training (E+S), n = 13) on endurance (1000-m running time during incremental field test) and strength performance (1 repetition maximum (1RM) in dynamic leg press), basal serum hormone concentrations, and endurance loading-induced force and hormone responses in recreationally endurance-trained men. E was identical in the 2 groups and consisted of steady-state and interval running, 4-6 times per week for 24 weeks. E+S performed additional mixed-maximal and explosive-strength training (2 times per week) immediately following an incremental running session (35-45 min, 65% 85% maximal heart rate). E and E+S decreased running time at week 12 (-8% +/- 5%, p = 0.001 and -7% +/- 3%, p < 0.001) and 24 (-13% +/- 5%, p < 0.001 and -9% +/- 5%, p = 0.001). Strength performance decreased in E at week 24 (-5% +/- 5%, p = 0.014) but was maintained in E+S (between-groups at week 12 and 24, p = 0.014 and 0.011, respectively). Basal serum testosterone and cortisol concentrations remained unaltered in E and E+S but testosterone/sex hormone binding globulin ratio decreased in E+S at week 12 (-19% +/- 26%, p = 0.006). At week 0 and 24, endurance loading-induced acute force (-5% to -9%, p = 0.032 to 0.001) and testosterone and cortisol responses (18%-47%, p = 0.013 to p < 0.001) were similar between E and E+S. This study showed no endurance performance benefits when strength training was performed repeatedly after endurance training compared with endurance training only. This was supported by similar acute responses in force and hormonal measures immediately post-endurance loading after the training with sustained 1RM strength in E+S. PMID- 25494870 TI - Skeletal muscle architectural adaptations to marathon run training. AB - We assessed lateral gastrocnemius (LG) and vastus lateralis (VL) architecture in 16 recreational runners before and after 12 weeks of marathon training. LG fascicle length decreased 10% while pennation angle increased 17% (p < 0.05). There was a significant correlation between diminished blood lactate levels and LG pennation angle change (r = 0.90). No changes were observed in VL. This is the first evidence that run training can modify skeletal muscle architectural features. PMID- 25494867 TI - The importance of biological oscillators for hypothalamic-pituitary-adrenal activity and tissue glucocorticoid response: coordinating stress and neurobehavioural adaptation. AB - The hypothalamic-pituitary-adrenal (HPA) axis is critical for life. It has a circadian rhythm that anticipates the metabolic, immunoregulatory and cognitive needs of the active portion of the day, and retains an ability to react rapidly to perceived stressful stimuli. The circadian variation in glucocorticoids is very 'noisy' because it is made up from an underlying approximately hourly ultradian rhythm of glucocorticoid pulses, which increase in amplitude at the peak of circadian secretion. We have shown that these pulses emerge as a consequence of the feedforward-feedback relationship between the actions of corticotrophin hormone (ACTH) on the adrenal cortex and of endogenous glucocorticoids on pituitary corticotrophs. The adrenal gland itself has adapted to respond preferentially to a digital signal of ACTH and has its own feedforward feedback system that effectively amplifies the pulsatile characteristics of the incoming signal. Glucocorticoid receptor signalling in the body is also adapted to respond in a tissue-specific manner to oscillating signals of glucocorticoids, and gene transcriptional and behavioural responses depend on the pattern (i.e. constant or pulsatile) of glucocorticoid presentation. During major stressful activation of the HPA, there is a marked remodelling of the pituitary-adrenal interaction. The link between ACTH and glucocorticoid pulses is maintained, although there is a massive increase in the adrenal responsiveness to the ACTH signals. PMID- 25494868 TI - Combination of anxiety and depression is associated with an increased headache frequency in migraineurs: a population-based study. AB - BACKGROUND: Although anxiety and depression have been classified as distinct traits of affective disorders, previous studies have reported their co-occurrence in subjects with migraine. However, few reports are available on the clinical implications of this comorbidity. This study is to assess the comorbidity of anxiety and depression in subjects with migraine and its clinical implications in a population-based sample from Korea. METHODS: We selected Korean subjects aged 19-69 years by the stratified random sampling method, and evaluated them using a semi-structured interview, designed to identify headache type, anxiety, and depression. We used Goldberg Anxiety Scale questions and Patient Health Questionnnaire-9 for the diagnosis of anxiety and depression, respectively. RESULTS: Of the 2,762 participants who completed the interview, 147 subjects (5.4%) were classified as having a migraine during the previous year. Among these 147 subjects, 17 (11.6%) had anxiety and depression, 28 (19.0%) had anxiety alone, 9 (6.1%) had depression alone, and 93 (63.3%) had neither anxiety nor depression. Headache frequency per month was remarkably higher in subjects having migraine with anxiety and depression (median [25-75 percentile values], 8.0 [2.5 21.0]) than in those having migraine with anxiety alone (2.0 [1.0-5.0], p = 0.003), migraine with depression alone (1.0 [0.3-4.0], p = 0.001), and migraine without anxiety or depression (1.0 [0.3-3.0], p < 0.001). The migraine with anxiety alone (7.0 [6.0-8.0], p = 0.011) group and migraine with anxiety and depression (7.0 [5.0-9.0], p = 0.018) group showed higher Visual Analogue Scale scores for pain intensity compare to migraine without anxiety or depression (6.0 [5.0-7.0]) group. CONCLUSIONS: Approximately 1/3 of migraineurs with anxiety had depression and 2/3 of migraineurs with depression had anxiety. Combination of anxiety and depression was associated with an increased headache frequency. Anxiety was associated with exacerbation of headache intensity. PMID- 25494871 TI - Fasting and exercise differentially regulate BDNF mRNA expression in human skeletal muscle. AB - Brain-derived neurotrophic factor (BDNF) gene expression was measured in human skeletal muscle following 3 intensities of exercise and a 48-h fast. No change in BDNF mRNA was observed following exercise, while fasting upregulated BDNF by ~ 3.5-fold. These changes were dissociated from changes in peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1alpha) following exercise (+2- to 15-fold) and fasting (~-25%). These results challenge our understanding of the response of BDNF to energetic stress and highlight the importance of future work in this area. PMID- 25494873 TI - Dimensions of nurse work time: Progress in instrumentation. AB - Because the work of health care is embedded in time, understanding nursing time allocation practices is essential for identifying nurse staffing and workflow patterns that optimize healthcare cost and quality outcomes. The interdependent nature of nursing care requires that nurses share time with other members of their work group. Shared time, also known as social or organizational time, requires careful negotiation of workflows within healthcare teams. Evaluation of negotiated workflows is contingent upon valid and reliable measures of sociological nursing time. In this study, we evaluated the psychometric properties of a newly adapted instrument for measuring sociological nursing time and describe the experience of sociological time among hospital-employed nurses. Using a cross-sectional survey design with a convenience sample of nurses (n = 359), we identified nine reliable components of sociological nursing time: insufficient time allocation; strict adherence to schedules; increased time awareness; value of quality over speed; fast and unpredictable pace changes; predictable job duties punctuated with unpredictable job demands; expectations for a fast work pace; inconsistent work-hour expectations across departments; and high expectations for punctuality. PMID- 25494874 TI - A conservation planning approach to mitigate the impacts of leakage from protected area networks. AB - Protected area networks are designed to restrict anthropogenic pressures in areas of high biodiversity. Resource users respond by seeking to replace some or all of the lost resources from locations elsewhere in the landscape. Protected area networks thereby perturb the pattern of human pressures by displacing extractive effort from within protected areas into the broader landscape, a process known as leakage. The negative effects of leakage on conservation outcomes have been empirically documented and modeled using homogeneous descriptions of conservation landscapes. Human resource use and biodiversity vary greatly in space, however, and a theory of leakage must describe how this heterogeneity affects the magnitude, pattern, and biodiversity impacts of leakage. We combined models of household utility, adaptive human foraging, and biodiversity conservation to provide a bioeconomic model of leakage that accounts for spatial heterogeneity. Leakage had strong and divergent impacts on the performance of protected area networks, undermining biodiversity benefits but mitigating the negative impacts on local resource users. When leakage was present, our model showed that poorly designed protected area networks resulted in a substantial net loss of biodiversity. However, the effects of leakage can be mitigated if they are incorporated ex-ante into the conservation planning process. If protected areas are coupled with nonreserve policy instruments such as market subsidies, our model shows that the trade-offs between biodiversity and human well-being can be further and more directly reduced. PMID- 25494875 TI - Extraction of absorption and scattering contribution of metallic nanoparticles toward rational synthesis and application. AB - Noble metal nanoparticles have unique localized surface plasmon resonance (LSPR), leading to their strong absorption and scattering in the visible light range. Up to date, the common practice in the selection of nanoparticles for a specific application is still based on the measured extinction spectra. This practice may be erroneous, because the extinction spectra contain both absorption and scattering contribution that may play different roles in different applications. It would be highly desirable to develop an efficient way to obtain the absorption and scattering spectra simultaneously. Herein, we develop a method to use the experimentally measured extinction and scattering signals to extract the absorption and scattering spectra that is in excellent agreement with that simulated by discrete dipole approximation (DDA). The heating curve measurement on the three types of gold nanorods, with almost the same extinction spectra but different absorption and scattering contribution, convincingly reveals an excellent correlation between the heating effect and the absorption strength rather than the extinction strength. The result demonstrates the importance to obtain the scattering and absorption spectra to predict the potential application for different types of nanoparticles, which in turn will screen efficiently nanoparticles for a specific application. PMID- 25494872 TI - The effect of neurospecific knockdown of candidate genes for locomotor behavior and sound production in Drosophila melanogaster. AB - Molecular mechanisms underlying the functioning of central pattern generators (CPGs) are poorly understood. Investigations using genetic approaches in the model organism Drosophila may help to identify unknown molecular players participating in the formation or control of motor patterns. Here we report Drosophila genes as candidates for involvement in the neural mechanisms responsible for motor functions, such as locomotion and courtship song. Twenty two Drosophila lines, used for gene identification, were isolated from a previously created collection of 1064 lines, each carrying a P element insertion in one of the autosomes. The lines displayed extreme deviations in locomotor and/or courtship song parameters compared with the whole collection. The behavioral consequences of CNS-specific RNAi-mediated knockdowns for 10 identified genes were estimated. The most prominent changes in the courtship song interpulse interval (IPI) were seen in flies with Sps2 or CG15630 knockdown. Glia specific knockdown of these genes produced no effect on the IPI. Estrogen-induced knockdown of CG15630 in adults reduced the IPI. The product of the CNS-specific gene, CG15630 (a predicted cell surface receptor), is likely to be directly involved in the functioning of the CPG generating the pulse song pattern. Future studies should ascertain its functional role in the neurons that constitute the song CPG. Other genes (Sps2, CG34460), whose CNS-specific knockdown resulted in IPI reduction, are also worthy of detailed examination. PMID- 25494876 TI - Management of atrial fibrillation in patients with congenital heart defects. AB - Due to improved surgical technologies and post-operative care, long-term survival has improved in patients with congenital heart disease. Atrial fibrillation (AF) is increasingly observed in this aging population and is associated with morbidity and mortality; however, reports about the pathophysiology and the outcome of different treatment modalities of AF are still scarce in patients with congenital heart disease. In this review, the authors describe the epidemiology, pathophysiology and outcome of the different therapies of AF in this specific patient population. PMID- 25494877 TI - Post-crisis Zimbabwe's innovative financing mechanisms in the social sectors: a practical approach to implementing the new deal for engagement in fragile states. AB - BACKGROUND: Donor engagement in transitional settings, complex emergencies and fragile states is increasing. Neither short-term humanitarian aid nor traditional development financing are well adapted for such environments. Multi-donor trust funds, in their current form, can be unwieldy and subject to long delays in initiation and work best when national governments are already strong. We reviewed the aid modalities used in Zimbabwe through the period of crisis, 2008 2012 and their results and implications. Literature review and case experience was utilised. DISCUSSION: By focusing on working with line ministries in non contested sectors to determine local priorities rather than following global prescriptions, pooling funds to achieve scale rather than delivering through fragmented projects, and building on national systems and capacities rather than setting up parallel mechanisms, the Transition Fund Model employed in Zimbabwe by UNICEF and partners in partnership with the Inclusive Government was able to achieve important results in health, education, social support and water services in a challenging setting. In addition, forums for collaboration were developed that provided a platform for further action. The initial emphasis on service delivery diffused much of the political delicateness that impeded progress in other sectors. The Zimbabwean experience may provide a model of innovative financing for countries facing similar circumstances. Such models may represent a new practical application of the Paris Principles, consistent with the major tenets of the 2011 New Deal for Engagement in Fragile States agreed in Busan. As we approach the Millennium Development Goal deadline, an over-arching, mutli sectoral and independent evaluation of this approach is recommended in order to validate findings and assess broader replicability of this approach. PMID- 25494878 TI - Female house mice avoid fertilization by t haplotype incompatible males in a mate choice experiment. AB - The t haplotype in house mice is a well-known selfish genetic element with detrimental, nonadditive fitness consequences to its carriers: recessive lethal mutations cause t/t homozygotes to perish in utero. Given the severe genetic incompatibility imposed by the t haplotype, we predict females to avoid fertilization by t haplotype incompatible males. Indeed, some of the strongest evidence for compatibility mate choice is related to the t haplotype in house mice. However, all previous evidence for compatibility mate choice in this system is based on olfactory preference. It is so far unknown how general these preferences are and whether they are relevant in an actual mating context. Here, we assess female compatibility mate choice related to t haplotypes in a setting that--for the first time--allowed females to directly interact and mate with males. This approach enabled us to analyse female behaviour during the testing period, and the resulting paternity success and fitness consequences of a given choice. We show that genetic incompatibilities arising from the t haplotype had severe indirect fitness consequences and t females avoided fertilization by t incompatible males. The results are inconclusive whether this avoidance of t fertilization by t females was caused by pre- or post-copulatory processes. PMID- 25494880 TI - Carbon sequestration is related to mycorrhizal fungal community shifts during long-term succession in boreal forests. AB - Boreal forest soils store a major proportion of the global terrestrial carbon (C) and below-ground inputs contribute as much as above-ground plant litter to the total C stored in the soil. A better understanding of the dynamics and drivers of root-associated fungal communities is essential to predict long-term soil C storage and climate feedbacks in northern ecosystems. We used 454-pyrosequencing to identify fungal communities across fine-scaled soil profiles in a 5000 yr fire driven boreal forest chronosequence, with the aim of pinpointing shifts in fungal community composition that may underlie variation in below-ground C sequestration. In early successional-stage forests, higher abundance of cord forming ectomycorrhizal fungi (such as Cortinarius and Suillus species) was linked to rapid turnover of mycelial biomass and necromass, efficient nitrogen (N) mobilization and low C sequestration. In late successional-stage forests, cord formers declined, while ericoid mycorrhizal ascomycetes continued to dominate, potentially facilitating long-term humus build-up through production of melanized hyphae that resist decomposition. Our results suggest that cord-forming ectomycorrhizal fungi and ericoid mycorrhizal fungi play opposing roles in below ground C storage. We postulate that, by affecting turnover and decomposition of fungal tissues, mycorrhizal fungal identity and growth form are critical determinants of C and N sequestration in boreal forests. PMID- 25494879 TI - Fibulin-5 inhibits hepatocellular carcinoma cell migration and invasion by down regulating matrix metalloproteinase-7 expression. AB - BACKGROUND: Fibulin-5 has been considered as a tumor suppressor through inhibiting tumor growth and invasion. Reduced expression of Fibulin-5 is frequently observed in various human cancers. In this study, we investigate the clinical significance of Fibulin-5 and its role in hepatocellular carcinoma (HCC) cell migration and invasion. METHODS: The expression of Fibulin-5 was evaluated by qRT-PCR and immunoblotting in HCC and matched noncancerous tissues. Fibulin-5 was over-expressed or knocked down by a retrovirus-mediated expression plasmid or a specific siRNA in HCC cells. Boyden chamber and Transwell assays were used to test HCC cell migration and invasion. Immunostaining was performed to determine matrix metalloproteinase-7 (MMP-7) expression in HCC specimens. MMP-7 retroviruses and siRNA were used to alter MMP-7 expression in HCC cells. RESULTS: In our study, the expression levels of Fibulin-5 protein and mRNA were down regulated in HCC tissues as compared with those in matched noncancerous tissues. Reduced expression of Fibulin-5 was observed in all HCC cell lines (HepG2, SMMC 7721, MHCC97L, Hep3B, MHCC97H and HCC-LM3) as compare with that in a non transformed hepatic cell line (LO2). Low expression of Fibulin-5 was significantly correlated with poor prognostic features including multiple tumor nodes, venous infiltration, high Edmondson-Steiner grading and advanced tumor node-metastasis (TNM) tumor stage. Furthermore, we demonstrated that Fibulin-5 was a novel independent prognostic marker for predicting 5-year survival of HCC patients. Our in vitro studies showed that Fibulin-5 overexpression inhibited HCC cell migration and invasion. While Fibulin-5 knockdown increased the number of migrated and invaded HCC cells. Fibulin-5 negatively regulated MMP-7 abundance in HCC cells. Moreover, the inverse correlation between Fibulin-5 and MMP-7 expressions was observed in HCC tissues. Mechanistically, we disclosed that MMP-7 knockdown reduced the number of migrated and invaded HCC cells. Restoring MMP-7 expression abrogated the suppressive effect of Fibulin-5 on HCC cell migration and invasion in vitro, suggesting that Fibulin-5 exerted its anti-metastatic function, at least in part, by down-regulating the expression of MMP-7 in HCC cells. CONCLUSIONS: These results indicate that Fibulin-5 may serve as a prognostic biomarker and inhibits HCC invasion and metastasis by suppressing MMP 7 expression. PMID- 25494881 TI - Genetic evaluation using random regression models with different covariance functions for test-day milk yield in an admixture population of Thailand goats. AB - The objectives of this study were to compare covariance functions (CF) and estimate the heritability of milk yield from test-day records among exotic (Saanen, Anglo-Nubian, Toggenburg and Alpine) and crossbred goats (Thai native and exotic breed), using a random regression model. A total of 1472 records of test-day milk yield were used, collected from 112 does between 2003 and 2006. CF of the study were Wilmink function, second- and third-order Legendre polynomials, and linear splines 4 knots located at 5, 25, 90 and 155 days in milk (SP25-90) and 5, 35, 95 and 155 of days in milk (SP35-95). Variance components were estimated by restricted maximum likelihood method (REML). Goodness of fit, Akaike information criterion (AIC), percentage of squared bias (PSB), mean square error (MSE), and empirical correlation (RHO) between the observed and predicted values were used to compare models. The results showed that CF had an impact on (co)variance estimation in random regression models (RRM). The RRM with splines 4 knots located at 5, 25, 90 and 155 of days in milk had the lowest AIC, PSB and MSE, and the highest RHO. The heritability estimated throughout lactation obtained with this model ranged from 0.13 to 0.23. PMID- 25494882 TI - Bacillus spp. from rainforest soil promote plant growth under limited nitrogen conditions. AB - AIMS: The aim of this study was to evaluate effects of PGPR (plant growth promoting rhizobacteria) isolated from rainforest soil on different plants under limited nitrogen conditions. METHODS AND RESULTS: Bacterial isolates from a Peruvian rainforest soil were screened for plant growth-promoting effects on Arabidopsis (Col-0). Four selected isolates including one Bacillus subtilis, two B. atrophaeus and one B. pumilus significantly promoted growth of Zea mays L. and Solanum lycopersicum under greenhouse conditions. Moreover, the PGPRs significantly promoted growth of S. lycopersicum in both low and nitrogen-amended soil conditions. These PGPR strains were further studied to obtain insights into possible mechanisms of plant growth promotion. Volatile chemicals from those isolates promoted Arabidopsis growth, and the expression of genes related to IAA production was induced in the Arabidopsis plants treated with PGPRs. Further, selected PGPR strains triggered induced systemic resistance (ISR) against Pseudomonas syringae pv tomato DC3000 in Arabidopsis. CONCLUSIONS: PGPR strains isolated from the rainforest soil promoted the plant growth of Arabidopsis, corn and tomato. SIGNIFICANCE AND IMPACT OF THE STUDY: New PGPR that have wider adaptability to different crops, soils and environmental conditions are needed to decrease our reliance on agricultural amendments derived from fossil-based fuels. The PGPRs isolated from a nonagricultural site constitute new plant growth promoting strains that could be developed for agricultural uses. PMID- 25494883 TI - Origin of circular dichroism of xanthorhodopsin. A study with artificial pigments. AB - Xanthorhodopsin (xR) is a retinal protein that contains, in addition to the retinal moiety, a salinixanthin chromophore absorbing at 456, 486, and 520 nm [Balashov, S. P.; Science 2005, 309, 2061]. The CD spectrum of xR is very unique with a "conservative" character, containing negative and positive lobes and resembling the first derivative of the absorption spectrum [Balashov, S. P.; Biochemistry 2006, 45, 10998]. It was suggested that the CD spectrum is likely to be composed of several components and that the salinixanthin interacts closely with the retinal chromophore [Balashov, S. P.; Biochemistry 2006, 45, 10998; Imasheva, E. S.; Photochem. Photobiol. 2008, 84, 977; Lanyi, J. K.; Acta Bioenerg. 2008, 1777, 684; Smolensky, E.; Biochemistry 2009, 48, 8179; Smolensky Koganov, E.; Biochemistry 2013, 52, 1290]. In this work, we aim to further explore the nature and origin of the unique CD spectrum of xR. We follow the absorption and CD spectra at different pHs of wild-type (wt) xR and of artificial xR pigments, characterized by a shifted absorption maximum of the retinal chromophore, as well as their corresponding reduced retinal protonated Schiff base pigments. Our results revealed a protein residue (other than the protonated Schiff base counterion), for which protonation affects the CD spectrum by decreasing the negative lobe at ~530 nm and the positive lobes at 478 and 455 nm, which might be due to elimination of excitonic coupling between the salinixanthin chromophores, although other possibilities cannot be completely excluded. This spectrum change occurs by the pH decreasing, even in artificial pigment where the absorption of the retinal pigment is significantly shifted from 570 to about 450 nm. The possible excitonic coupling between the salinixanthin chromophores and its contribution to the CD spectrum of xR were supported by a good fitting of the CD spectrum to conservative (excitonic) bands [Zsila, F.; Tetrahedron: Asymmetry 2001, 12, 3125; Zsila, F.; Tetrahedron: Asymmetry 2002, 13, 273]. We propose that the CD spectrum of xR consists of contributions from an excitonic coupling interaction between the salinixanthins chromophores located in different subunits of the 3D structure of xR, the chiral conformation of the salinixanthin within its binding site, and the contribution of the retinal chromophore to the negative lobe at around 550 nm. PMID- 25494885 TI - Improving target dose coverage and organ-at-risk sparing in intensity-modulated radiotherapy of advanced laryngeal cancer by a simple optimization technique. AB - OBJECTIVE: To evaluate a simple optimization technique intended to improve planning target volume (PTV) dose coverage and organ-at-risk (OAR) sparing in intensity-modulated radiotherapy (IMRT) of advanced laryngeal cancer. METHODS: Generally acceptable initial IMRT plans were generated for 12 patients and were improved individually by the following two techniques: (1) base dose function based (BDF) technique, in which the treatment plans were reoptimized based on the initial IMRT plans; (2) dose-controlling structure-based (DCS) technique, in which the initial IMRT plans were reoptimized by adding constraints for hot and cold spots. The initial, BDF and DCS IMRT plans and additionally generated volumetric modulated arc therapy (VMAT) plans were compared concerning homogeneity index (HI) and conformity index (CI) of PTVs prescribed at 70 Gy/60 Gy (PTV70/PTV60), OAR sparing, monitor units (MUs) per fraction and total planning time. RESULTS: Compared with the initial IMRT and DCS IMRT plans, the BDF technique provided superior HI/CI, by approximately 19-37%/4-11%, and lower doses to most OARs, by approximately 1-7%, except for the comparable HI of PTV60 to DCS IMRT plans. Compared with VMAT plans, the BDF technique provided comparable HI, CI and most-OAR sparing, except for the superior HI of PTV70, by approximately 13%. The BDF technique produced more MUs and reduced the planning time. CONCLUSION: The BDF optimization technique for IMRT of advanced laryngeal cancer can improve target dose homogeneity and conformity, spare most OARs and is efficient. ADVANCES IN KNOWLEDGE: A novel optimization technique for improving IMRT was assessed and found to be effective and efficient. PMID- 25494886 TI - [Objective need for cancer prevention in the Czech Republic and Europe, and the state thereof]. AB - There is no doubt today of the need for cancer prevention. The growing incidence of cancer itself provides a sufficient justification for prevention programmes. A review of literature presented in this paper also documents the strong background of evidence-based cancer prevention programmes. The article also provides a critical analysis of the current status of primary cancer prevention and cancer screening in the Czech Republic in contrast with available international comparisons. Relevant international data have been obtained from the regularly repeated "Health at a Glance" studies (published by the OECD). Although the Czech Republic is one of the countries with the highest cancer burden in Europe, it has failed to develop and support a cancer prevention policy on a central level, and this also applies to smoking prevention. The Czech population needs an effective national strategy for the support of cancer prevention, as well as a strategy which would ensure equitable cancer care in terms of both quality and correct indication; a strategy which would be sustainable for at least 10 to 15 years to come.Key words: oncology - screening - risk factor - prevention - population burden This study was supported by the project 36/14//NAP "Development and implementation of methodology for the evaluation of effectiveness of personalised invitations of citizens to cancer screening programmes" as part of the pro-gram me of the Czech Ministry of Health "National action plans and conceptions". The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE "uniform requirements" for biomedical papers. PMID- 25494884 TI - Site-specific antibody-drug conjugates: the nexus of bioorthogonal chemistry, protein engineering, and drug development. AB - Antibody-drug conjugates (ADCs) combine the specificity of antibodies with the potency of small molecules to create targeted drugs. Despite the simplicity of this concept, generation of clinically successful ADCs has been very difficult. Over the past several decades, scientists have learned a great deal about the constraints on antibodies, linkers, and drugs as they relate to successful construction of ADCs. Once these components are in hand, most ADCs are prepared by nonspecific modification of antibody lysine or cysteine residues with drug linker reagents, which results in heterogeneous product mixtures that cannot be further purified. With advances in the fields of bioorthogonal chemistry and protein engineering, there is growing interest in producing ADCs by site-specific conjugation to the antibody, yielding more homogeneous products that have demonstrated benefits over their heterogeneous counterparts in vivo. Here, we chronicle the development of a multitude of site-specific conjugation strategies for assembly of ADCs and provide a comprehensive account of key advances and their roots in the fields of bioorthogonal chemistry and protein engineering. PMID- 25494887 TI - [Epidemiology of screening-targeted cancers according to new data of the Czech National Cancer Registry]. AB - The Czech Society for Oncology has developed an information system which combines the population-based Czech National Cancer Registry with clinical databases in order to cover the main areas of health care assessment - monitoring of the population burden, prediction of the number of cancer patients, diagnostic and treatment results. The presented data demonstrate a high cancer burden within the Czech population - each year there are approximately 8,000 new cases of colorectal cancer, 6,500 new cases of breast cancer, and 1,000 new cases of cervical cancer. And each year, about 4,000 people die from colorectal cancer, around 2,000 women die from breast cancer, and approximately 400 women die from cervical cancer in the Czech Republic. Population-based screening programmes focus on all of the above-mentioned groups of malignant tumours; therefore, it is essential to monitor epidemiological trends in order to assess the screening impact. Despite the high incidence rates of all three cancer types, the trend in mortality rates has been stable or has even decreased in the long term, which has inevitably led to a significant increase in the total prevalence of cancer patients. In 2011, the prevalence of colorectal cancer, breast cancer and cervical cancer amounted to 51,064 people, 67,261 women and 17,398 women, respectively. When compared with the year 2001, there was a 59%, 69% and 25% increase in the prevalence of colorectal cancer, breast cancer, and cervical cancer, respectively. Undoubtedly, taking care of high numbers of cancer patients will continue to require significant financial resources in the near future. As the epidemiological burden is still on the increase, preventive programmes need to be further promoted, including secondary prevention, which is provided through organised screening programmes. Although effective methods exist for timely diagnosis of all three of the above-mentioned cancer types, the epidemiological situation in the Czech Republic is being steadily worsened by a relatively high proportion of primary cancers being diagnosed too late. Each year, more than 50% of new colorectal cancer cases are diagnosed in clinical stage III or higher; in cervical cancer, this proportion is nearly 35%. By contrast, the well-promoted breast cancer screening programme has led to more than 75% of new cases of breast cancer being diagnosed in stages I or II, when the chance of successful treatment is significantly higher. PMID- 25494888 TI - [Epidemiology of cancers with implemented screening programmes in an international comparison]. AB - International data document that the Czech Republic ranks among the countries with the highest cancer burden in Europe and worldwide. Preventable cancer diseases, i.e. colorectal, breast, and cervical cancer, are among the most frequent types. These international studies also bring some positive information, e.g., stabilised or slightly decreasing mortality, better treatment outcomes and patient survival rates. However, it should be noted that, with regard to the high population burden, these results are achieved at the very high price of costly modern cancer treatment. PMID- 25494889 TI - [State and development of background information for the evaluation of Czech cancer screening programmes]. AB - Czech cancer screening programmes feature a comprehensive multimodal information system which covers all the levels of assessment needed - population-based monitoring (Czech National Cancer Registry), monitoring of results in the diagnostic databases of centres, as well as the quantification of coverage and outputs of primary care according to the administrative data of health care payers. A system of personalised invitations to cancer screening programmes was launched in 2014, based on a stand-alone component of the information system which makes it possible to identify eligible clients in health care payers databases. The system was fully standardised and uniformly implemented in all health insurance companies; its functionalities also involve both continuous and retrospective assessment of the results of personalised invitation. The legislative framework in force will have to be applied and implemented for a more comprehensive and integrated employment of all involved data sources, i.e. cancer registries, screening registries, and administrative data. The system must be able to analyse de-identified individual records on clients participation in screening programmes, and thus to ensure an adequate analysis of performance indicators in compliance with international recommendations. PMID- 25494890 TI - [Approach to population-based screening in the Czech Republic, methodology and first results of the personalised invitation of citizens to cancer screening programmes]. AB - In January 2014, a programme of personalised invitations was launched in the Czech Republic, with the objective of inviting insured persons to cancer screening programmes; namely breast cancer screening and cervical cancer screening in women, and colorectal cancer screening both in women and men. This programme aims at strengthening the current cancer prevention programmes, and to increase the currently inadequate participation of the target population in these programmes; therefore, personalised invitations are sent to citizens who have not participated in these programmes for several years and therefore at risk of developing a serious disease. The project is coordinated by the Czech Ministry of Health in cooperation with the expert medical societies involved (gynaecology, gastroenterology, gastrointestinal oncology, diagnostic radiology, general practice), representatives of health care payers, and other experts nominated by the Minister of Health. All health care payers invite their clients (insured persons) to preventive check-ups, covering all examinations needed. The project has been realised with the assistance of financial resources from EU funds. This article describes the methodology of personalised invitations which has been implemented nationwide, its data background, and the first results of the project in the first half of 2014, when almost 1.3 million Czech citizens were invited. PMID- 25494891 TI - [Results of the Czech National Breast Cancer screening programme]. AB - INTRODUCTION: Breast cancer screening based on mammography is an effective tool for lowering mortality rates from this disease. The organised and nationwide Breast Cancer Screening Programme has been underway in the Czech Republic since 2002. MATERIAL AND METHODS: Monitoring of the programme is based on data from the Czech National Cancer Registry (CNCR), Breast Cancer Screening Registry, and the Czech National Reference Centre (CNRC). These data sources make it possible to evaluate early performance indicators according to international standards, and to monitor the cancer burden in the Czech population. The CNRC data allow us to document the high validity of the available data as well as to map non-organised mammography examinations (so-called opportunistic screening). RESULTS: Until the mid-1990s, breast cancer incidence and mortality rates saw a slight but continuous increase. In the last 15 years, however, incidence rates have grown more substantially; by contrast, mortality rates have stalled and even started to decline since the 2000s. In the mid-1990s, the proportion of cancers diagnosed at stage I was below 20%; this situation has dramatically improved since then, as more than 40% cases of breast cancer were diagnosed at stage I in 2011. Breast cancer screening coverage currently amounts to 50%; this value reached a plateau in the period 2007-2008, and unfortunately has not shown any further significant increase. CONCLUSION: Over the last few decades, the breast cancer burden among the Czech population has been significantly reduced - despite the growing incidence rates, mortality rates have decreased, which can be largely attributed to earlier detection of breast cancer based on the screening programme. Further improvements in the programmes effectiveness can only be achieved if the population coverage becomes higher; the programme of personalised invitations to mammography examinations, which was introduced in early 2014, should contribute to the accomplishment of this goal. PMID- 25494892 TI - [Results of the Czech National Cervical Cancer screening programme]. AB - INTRODUCTION: The nationwide Cervical Cancer Screening Programme in the Czech Republic was introduced in 2009. The aim of this article is to describe the results of this programme in the first few years after its transformation into a fully-fledged, organised programme. MATERIAL AND METHODS: During the first few years, a network of 37 accredited laboratories was stabilised, ensuring that examinations would be readily available across the Czech Republic. Although all women aged between 25 and 70 years fall within the target group of the current personalised invitation programme, women not in this age group are reimbursed for preventive screening examinations as well. The programme is equipped with an information support provided by the Institute of Biostatistics and Analyses of the Masaryk University, which runs the Cervical Cancer Screening Registry. RESULTS: Cervical cancer incidence and mortality rates in the Czech Republic have seen a significant decrease over the last decade. By the end of 2013, more than 11 million examinations were reported to the registry by the accredited laboratories, and more than 15,000 serious cervical lesions were detected. Analysis of the data from the registry makes it possible to monitor the quality of individual laboratories and the effectiveness of the entire programme. CONCLUSION: The promising start of the programme provides a strong argument for its continuation. The program--me has the potential to decrease cervical cancer incidence rates in the Czech Republic to values comparable with those reported by countries with advanced health care systems. PMID- 25494893 TI - [Results of the Czech National Colorectal Cancer screening programme - faecal occult blood tests]. AB - INTRODUCTION: The nationwide Colorectal Cancer Screening Programme was introduced in the Czech Republic in 2000. The aim of this article is to describe the employment of faecal occult blood tests (FOBTs) by the Czech population within the screening programme, and to provide information on the latest results of the programme. MATERIAL AND METHODS: Data on the development of the colorectal cancer (CRC) burden in the Czech population is obtained from the Czech National Cancer Registry, a database required by the Czech law that has been collecting comprehensive data on cancer patients since 1977. Data on FOBT employment can be obtained from health care payers, and was provided by the Czech National Reference Centre. RESULTS: Around 8,000 patients are diagnosed with colorectal cancer in the Czech Republic each year, and the number of CRC deaths is about 4,000. Despite the ongoing screening programme, significant improvements in the proportional representation of cancer stages (i.e., improvements in early detection of CRC cases) have yet to be seen. Although the number of FOBTs performed in the Czech Republic has significantly grown in the long term (which is accompanied by an increase in coverage by this screening test), the total coverage of the Czech population aged over 50 was only 25.5% in 2012. The Olomouc Region, the Zlin region, and the Usti nad Labem region had the highest coverage rates by CRC screening based on FOBT (over 28%), while the Capital of Prague had the lowest coverage rate (18%). Since 2008, FOBT positivity rates have seen a continuous and significant increase, reaching 6.9% in 2012. Between 13 to 14% of FOBTs in women are performed by practical gynaecologists. CONCLUSION: Despite a significant increase in the participation rate in recent years, which was partially improved by the involvement of practical gynaecologists, the programme unfortunately still covers only a quarter of the eligible population. Implementation of effective measures aimed at getting people interested in preventive examinations (including the recently introduced programme of personalized invitations) is therefore essential; otherwise, the screening programme will not be successful on the population level. PMID- 25494894 TI - [Results of the Czech National Colorectal Cancer Screening Programme - colonoscopy examinations]. AB - INTRODUCTION: Colorectal cancer (CRC) is one of the most common cancers, and the Central European countries have the highest CRC burden worldwide. CRC screening has repeatedly been proven capable of decreasing CRC mortality and incidence rates. The nationwide Colorectal Cancer Screening Programme in the Czech Republic involves the colonoscopic examination as a diagnostic method (for patients with a positive FOBT result - screening colonoscopy - SC), or as a screening method (primary screening colonoscopy - PSC). The aim of this article is to present the results of colonoscopic examinations performed as part of the Czech screening programme. MATERIAL AND METHODS: For the purpose of quality assurance, the Czech programme has been equipped since 2006 with an information system called the Colorectal Cancer Screening Registry, which collects and evaluates data on preventive colonoscopies performed in the colonoscopy screening centres. Performance indicators, as specified in the European Guidelines (and adapted for the Czech programme), are employed to assess preventive colonoscopies performed in the Czech Republic. RESULTS: Since 2006, more than 110,000 SCs and almost 20,000 PSCs were recorded. Approximately 95% of SCs and almost 98% of PSC were classified as total, i.e. examining the entire colonic mucosa up to the caecum. The positive predictive value of FOBT for adenomas has increased slightly and continuously over time, and was 39.7% in 2013. In PSC, the adenoma detection rate (ADR) has recently increased compared to previous years, and was 27.3% in 2013. CRC was detected in 3.7% of individuals undergoing an SC examination and in 1.0% of individuals undergoing a PSC examination. The programme safety is controlled based on the monitoring of complications during colonoscopies; these can occur either during diagnostic colonoscopy (perforation in 0.03% of cases since 2006) or during endoscopic polypectomy (perforation in 0.12% of cases, bleeding in 0.73% of cases since 2006). CONCLUSION: Our results confirm that the quality of colonoscopic examinations corresponds to the international standards and that this is not an obstacle to a positive impact of CRC screening on the Czech population, which has a high colorectal cancer burden. PMID- 25494895 TI - [Performance indicators in screening programmes]. AB - Breast, colorectal and cervical cancer screening programmes make it possible to decrease the population mortality rates of these diseases. How-ever, complex standards of the quality of care must be introduced and followed in order to maintain a favourable ratio between the benefits and risks arising from population-wide screening programmes. Such programmes should be organized and population-based, ensuring that quality control is performed at all levels. This review introduces the system of quality control in the Czech cancer screening programmes, and provides specific examples of performance indicators that are usable and/ or being used in these programmes. Cancer screening programmes in the Czech Republic are equipped with a comprehensive information background which involves monitoring of the cancer burden in the population, monitoring of the screening process based on clinical data, and monitoring of the screening process based on administrative data. In particular, the specific performance indicators describe the success rate of take up of the target population, ability of the screening test to reveal (sensitivity) or to exclude (specificity) the screened condition, correct employment of subsequent diagnostic methods or treatment of detected cancers or precancerous lesions where applicable. In the Czech breast cancer screening programme, these indicators are routinely used in order to monitor the individual centres; in both colorectal and cervical cancer screening programmes, these indicators are used to monitor the entire programme, whereas the system of quality control for individual centres is under continuous development. A project of personalized invitations was launched in 2014, and its results are regularly evaluated in cooperation with the Czech National Reference Centre and the Ministry of Health of the Czech Republic. PMID- 25494896 TI - [Implementation of performance indicators in the Czech Breast Cancer Screening Programme - results of the regular monitoring]. AB - The Czech organised breast cancer screening programme was initiated in 2002. Collection of data on screening mammography examinations, subsequent diagnostic procedures, and final dia-gnosis is an indispensable part of the programme. Data collection is obligatory for all accredited centres, in accordance with regulations issued by the Czech Ministry of Health. This contribution aims to demonstrate the recent results of quality monitoring of the accredited centres. Quality indicators, whose definition complies with international standards, involve the women's participation, the volume of performed examinations, the accuracy of screening mammography, the use of preoperative diagnostics, and the proportion of early detected tumours. Our evaluation documents a continuous improvement in quality of the Czech mammography screening programme, which is thereby in full agreement with international recommendations on quality assurance. PMID- 25494897 TI - [National web portals as an official communication platform of cancer screening programmes]. AB - Official web portals are an important component of the background information of the cancer screening programmes. They provide up-to-date and relevant information for health care professionals, the general public and those interested in preventive examinations. They also serve as an official medium for publication of individual programme outcomes. The Czech national screening programmes are presented at the following websites: www.mamo.cz (breast cancer screening), www.kolorektum.cz (colorectal cancer screening), and www.cervix.cz (cervical cancer screening). PMID- 25494898 TI - [Role and importance of civil society organisations in the support of cancer screening]. AB - Promotion of cancer screening programmes and provision of correct and comprehensive information to the general public are essential for achieving sufficient attendance at the program-mes and fulfilling their longterm function. Various NGOs and CSOs play a very important role in this field. The article provides an overview of the most visible activities and campaigns that spread information about cancer prevention and preventive examinations in the Czech Republic. PMID- 25494899 TI - [New European Information and Communication Platform Striving for Improved Care for Colorectal Cancer Patients - www.crcprevention.eu]. AB - The article introduces a new information and communication platform that focuses on the promotion of colorectal cancer prevention and on the improvement of care for colorectal cancer patients. In addition to the platforms objectives, the article also presents the conclusions of the first year of the "European Colorectal Cancer Days" international conference held annually in Brno since 2012. Further information and news are available at www.crcprevention.eu. PMID- 25494900 TI - COMBINE archive and OMEX format: one file to share all information to reproduce a modeling project. AB - BACKGROUND: With the ever increasing use of computational models in the biosciences, the need to share models and reproduce the results of published studies efficiently and easily is becoming more important. To this end, various standards have been proposed that can be used to describe models, simulations, data or other essential information in a consistent fashion. These constitute various separate components required to reproduce a given published scientific result. RESULTS: We describe the Open Modeling EXchange format (OMEX). Together with the use of other standard formats from the Computational Modeling in Biology Network (COMBINE), OMEX is the basis of the COMBINE Archive, a single file that supports the exchange of all the information necessary for a modeling and simulation experiment in biology. An OMEX file is a ZIP container that includes a manifest file, listing the content of the archive, an optional metadata file adding information about the archive and its content, and the files describing the model. The content of a COMBINE Archive consists of files encoded in COMBINE standards whenever possible, but may include additional files defined by an Internet Media Type. Several tools that support the COMBINE Archive are available, either as independent libraries or embedded in modeling software. CONCLUSIONS: The COMBINE Archive facilitates the reproduction of modeling and simulation experiments in biology by embedding all the relevant information in one file. Having all the information stored and exchanged at once also helps in building activity logs and audit trails. We anticipate that the COMBINE Archive will become a significant help for modellers, as the domain moves to larger, more complex experiments such as multi-scale models of organs, digital organisms, and bioengineering. PMID- 25494903 TI - Milestones in breast cancer treatment. AB - Modern treatment started in the 1880s with Halsted's mastectomy. The next milestone-a century later-was breast-conserving surgery, with equivalent survival but better esthetic outcomes than mastectomy. Sentinel node biopsy, introduced in the 1990s, was a milestone that permitted avoidance of axillary dissection if the sentinel node was disease-free. Chemotherapy was established for early breast cancer in the 1980s and its efficacy continues to improve; however side effects remain a concern, particularly since chemotherapy does not benefit most patients. External whole breast irradiation was introduced with conservative surgery, as it reduces recurrences. By the 2000s, 3-week regimens had been shown equivalent to standard 6-week regimens-easing pressure on patients and radiation centers. Intraoperative partial breast irradiation is potentially more beneficial as it permits complete local treatment in a single session; however, trials show that patients must be very carefully selected. From the 1990s irradiation technology was combined with imaging and computer technologies to produce equipment that directs radiation to more precisely defined target volumes, allowing increased dose to the target and markedly reduced dose to nearby tissues. Irradiation systems are evolving rapidly but are being implemented without data on long-term morbidity or efficacy, while costs rise steeply. The first targeted treatment was tamoxifen, a selective estrogen receptor inhibitor. Since its widespread use starting in the 1980s, tamoxifen has saved the lives or prolonged the survival of millions with estrogen-positive disease; it is cheap and has limited (but not negligible) side effects. The same cannot be said of newer targeted treatments like trastuzumab and pertuzumab, which, although effective against human epidermal growth factor receptor 2-positive cancer, come with important side effects and huge costs. Breast cancer mortality is declining in rich countries, but treatments have become more demanding and more expensive, so the outlook for the increasing numbers of women worldwide who develop the disease is uncertain. PMID- 25494902 TI - Novel RP1 mutations and a recurrent BBS1 variant explain the co-existence of two distinct retinal phenotypes in the same pedigree. AB - BACKGROUND: Molecular diagnosis of Inherited Retinal Dystrophies (IRD) has long been challenging due to the extensive clinical and genetic heterogeneity present in this group of disorders. Here, we describe the clinical application of an integrated next-generation sequencing approach to determine the underlying genetic defects in a Spanish family with a provisional clinical diagnosis of autosomal recessive Retinitis Pigmentosa (arRP). RESULTS: Exome sequencing of the index patient resulted in the identification of the homozygous BBS1 p.M390R mutation. Sanger sequencing of additional members of the family showed lack of co segregation of the p.M390R variant in some individuals. Clinical reanalysis indicated co-ocurrence of two different phenotypes in the same family: Bardet Biedl syndrome in the individual harboring the BBS1 mutation and non-syndromic arRP in extended family members. To identify possible causative mutations underlying arRP, we conducted disease-targeted gene sequencing using a panel of 26 IRD genes. The in-house custom panel was validated using 18 DNA samples known to harbor mutations in relevant genes. All variants were redetected, indicating a high mutation detection rate. This approach allowed the identification of two novel heterozygous null mutations in RP1 (c.4582_4585delATCA; p.I1528Vfs*10 and c.5962dupA; p.I1988Nfs*3) which co-segregated with the disease in arRP patients. Additionally, a mutational screening in 96 patients of our cohort with genetically unresolved IRD revealed the presence of the c.5962dupA mutation in one unrelated family. CONCLUSIONS: The combination of molecular findings for RP1 and BBS1 genes through exome and gene panel sequencing enabled us to explain the co-existence of two different retinal phenotypes in a family. The identification of two novel variants in RP1 suggests that the use of panels containing the prevalent genes of a particular population, together with an optimized data analysis pipeline, is an efficient and cost-effective approach that can be reliably implemented into the routine diagnostic process of diverse inherited retinal disorders. Moreover, the identification of these novel variants in two unrelated families supports the relatively high prevalence of RP1 mutations in Spanish population and the role of private mutations for commonly mutated genes, while extending the mutational spectrum of RP1. PMID- 25494904 TI - Molecular dynamics investigation on adsorption layer of alcohols at the air/brine interface. AB - Alcohols are a significant group of surfactants which have been employed extensively in industry to improve the interfacial effects. Recently, the change in surface potential (DeltaV) of two isomeric hexanols, methyl isobutyl carbinol (MIBC) and 1-hexanol, was investigated by using an ionizing (241)Am electrode. It clearly showed the opposite effects between MIBC and 1-hexanol in the interfacial zone: one enhanced the presence of cations, whereas the other enhanced the presence of anions. This study employs molecular dynamics simulation to provide new insights into the interactions between alcohol molecules and ions as well as water at the molecular level. The results qualitatively agreed with the experimental data and verified the significance of MIBC branching structure on the molecular arrangement within the interfacial zone. The results also highlighted the role of the second water layer on the interfacial properties. PMID- 25494905 TI - Are there differences between rural and urban populations in long-term outcome after systemic cerebral thrombolysis in a hospital located in an agricultural region? AB - INTRODUCTION: It is generally considered that rural hospitals have a much lower capacity to adequately care for patients with acute ischemic stroke (AIS). Analysis of the demographic and logistic factors affecting the outcome of intravenous (IV) thrombolysis in patients with AIS in a rural hospital are presented. METHODS: The observational study included 300 patients with AIS who were consecutively treated with IV thrombolysis. Long-term outcome and hemorrhagic complication rate in patients from rural and urban populations were compared. RESULTS: A total of 60.7% of patients were transported from rural areas. In the rural patients thrombolytic therapy at night was performed less frequently compared to that for urban patients (p=0.01). There were no differences in frequency of treatment between rural and urban patients treated with IV thrombolysis on weekends and on working days (p=0.47). In rural patients mortality was higher (p=0.04). The presence of hemorrhagic transformation (HT) (p=0.87) and of symptomatic intra-cerebral hemorrhage (SICH) (p=0.61) were similar in both groups. A multivariate analysis showed no impact of place of onset on favorable outcome after 3 months (p=0.9), on the presence of (SICH) (p=0.43) or on mortality rate (p=0.69). CONCLUSIONS: Patients from rural areas are less likely to be treated with IV thrombolysis during the night. Rural and urban patients treated in the hospital located in the agricultural region had a similar efficacy and safety profile of thrombolytic treatment. PMID- 25494906 TI - Lesbians' attitudes and practices of cervical cancer screening: a qualitative study. AB - BACKGROUND: Cervical cancer is the third most prevalent cancer in women, and since the introduction of the Papanicolaou test (Pap test or Pap smear), the incidence of cervical cancer and mortality rates worldwide have declined substantially. However significant disparities have been identified between the cervical screening rates of heterosexual and lesbian women. This study explores the attitudes and practices that lesbians have towards cervical cancer screening and aims to identify why such disparities occur. METHODS: A qualitative methodology based on feminist perspectives was used to collect narrative data from lesbians about their attitudes and practices of cervical screening through the use of semi structured interviews. Nine women who self-identified as lesbian that were living in New South Wales were recruited for the study. Interviews were digitally recorded and transcribed verbatim. Data were analysed using a thematic analysis approach. RESULTS: Four main themes emerged from the data namely: Encountering cervical cancer: "my friends had some early cancer cells detected", Misconceptions related to risk: "I am a lesbian I don't need one", Imposed screening: "It's a requirement of IVF treatment" and, Promoting cervical screening: "I think it should be spoken about in schools". CONCLUSIONS: Consistent with the literature, the findings show that the majority of these women do not undertake cervical screening at the recommended rate. This study highlights the multiple and complex issues related to cervical cancer screening for lesbians, mainly through misconceptions and underestimation of risk. Specific and targeted educational and promotional strategies are required for both lesbians and health professionals to enhance cervical cancer screening rates for lesbians in Australia. PMID- 25494907 TI - Dysphonia as a sign of HPV laryngeal infection: a case report. AB - BACKGROUND: Voice dysfunction or dysphonia may be associated with several clinical conditions. Among these, laryngeal human papillomavirus (HPV)-induced lesions should be considered as a possible causative factor. We report a case of dysphonia in a patient presenting with an HPV laryngeal lesion. We also discuss the clinical features of the disease, its histopathological findings, and treatment and rigorous follow-up. CASE PRESENTATION: We report a case of laryngeal papilloma in a 29-year-old, Afro-descendant, male patient with dysphonia. He was a non-smoker and was not a drug user. Videolaryngostroboscopy revealed signs suggestive of pharyngolaryngeal reflux. The right vocal fold presented with a papillomatous aspect in the posterior third, which underwent excision. Histopathological examination showed a nodular lesion of the right vocal fold, conclusive of squamous papilloma with absence of malignancy. CONCLUSION: Patients presenting with persistent voice dysfunction or dysphonia should be investigated for possible laryngeal HPV infection. Diagnostic confirmation by HPV genotyping is important for follow-up of potential recurrence. PMID- 25494908 TI - Emerging drugs for celiac disease. AB - INTRODUCTION: Celiac disease is an immune-mediated gluten-dependent disorder, primarily affecting the small intestine in genetically predisposed individuals. The disorder has a very heterogeneous clinical and histopathological spectrum. Current treatment with a gluten-free diet is very effective, but the diet is difficult to maintain and remains costly. AREAS COVERED: Alternatives to the gluten-free diet have been proposed to either replace this current treatment, or at least, to supplement use of the gluten-free diet. Studies in the published English language literature relevant to this review were examined for this report. EXPERT OPINION: Most recent published double-blind, placebo-controlled clinical trials have focused on an orally administered recombinant glutenase (ALV003) showing significant but limited benefit to celiac disease patients already compliant with a gluten-free diet. Other studies have addressed other immune mechanisms that may play a role in its pathogenesis and have not been so positive. Added investigations, particularly over the long-term, in other larger and more heterogeneous populations are needed. PMID- 25494909 TI - Ultrasensitive silicon nanowire for real-world gas sensing: noninvasive diagnosis of cancer from breath volatolome. AB - We report on an ultrasensitive, molecularly modified silicon nanowire field effect transistor that brings together the lock-and-key and cross-reactive sensing worlds for the diagnosis of (gastric) cancer from exhaled volatolome. The sensor is able to selectively detect volatile organic compounds (VOCs) that are linked with gastric cancer conditions in exhaled breath and to discriminate them from environmental VOCs that exist in exhaled breath samples but do not relate to the gastric cancer per se. Using breath samples collected from actual patients with gastric cancer and from volunteers who do not have cancer, blind analysis validated the ability of the reported sensor to discriminate between gastric cancer and control conditions with >85% accuracy, irrespective of important confounding factors such as tobacco consumption and gender. The reported sensing approach paves the way to use the power of silicon nanowires for simple, inexpensive, portable, and noninvasive diagnosis of cancer and other disease conditions. PMID- 25494910 TI - Current Practice and Utility of Chromosome Microarray Analysis in Infants Undergoing Cardiac Surgery. AB - OBJECTIVE: Traditionally, karyotype and fluorescence in situ hybridization (FISH) were used for cytogenetic testing of infants with congenital heart disease (CHD) who underwent cardiac surgery at our institution. Recently, chromosome microarray analysis (CMA) has been performed in lieu of the traditional tests. A standardized approach to cytogenetic testing does not exist in this population. The purpose of this study was to assess the utility of CMA based on our current ordering practice. DESIGN: We reviewed the records of all infants (<1 year old) who underwent cardiac surgery at our institution from January 2010 to June 2013. Data included results of all cytogenetic testing performed. Diagnostic yield was calculated as the percentage of significant abnormal results obtained by each test modality. Patients were grouped by classification of CHD. RESULTS: Two hundred seventy-five (51%) of 535 infants who underwent cardiac surgery had cytogenetic testing. Of those tested, 154 (56%) had multiple tests performed and at least 18% were redundant or overlapping. The utilization of CMA has increased each year since its implementation. The diagnostic yield for karyotype, FISH and CMA was 10%, 12%, and 14%, respectively. CMA yield was significantly higher in patients with septal defects (33%, P = .01) compared with all other CHD classes. CMA detected abnormalities of unknown clinical significance in 13% of infants tested. CONCLUSIONS: In our center, redundant cytogenetic testing is frequently performed in infants undergoing cardiac surgery. The utilization of CMA has increased over time and abnormalities of unknown clinical significance are detected in an important subset of patients. A screening algorithm that risk stratifies based on classification of CHD and clinical suspicion may provide a practical, data-driven approach to genetic testing in this population and limit unnecessary resource utilization. PMID- 25494911 TI - Peer education is a feasible method of disseminating information related to child nutrition and feeding between new mothers. AB - BACKGROUND: This study examined whether peer education based on the Theory of Planned Behaviour is a feasible method to share and disseminate nutrition and feeding information between mothers of babies and toddlers. METHODS: The Peer Educator Nutrition Training (PeerENT) study was a feasibility study. Participants were recruited from an existing cohort of mothers of six month to two year olds. An online survey tool was used to collect and collate data, which was then analysed using STATA statistical software. RESULTS: Thirty four mothers (35%) responded to the survey with 76% (n = 26) either very interested (n = 13) or interested (n = 13) in receiving child nutrition information from a trained peer educator, preferably in a structured group session. Sixty five per cent (n = 22) were "interested" or "very interested" in becoming a peer nutrition educator. The preferred methods of communicating information to other parents were online (n = 17), informally in a social group (n = 16) and via a face-to-face group program (n = 14). Participants predicted they would share child nutrition information with an average of fifteen people, a total reach of 510 individuals. CONCLUSIONS: High levels of interest in peer educator training and the capacity for mothers to share resources widely and easily via social media offers a potential opportunity to disseminate evidence-based nutrition information. A pilot study investigating the impact of a well-designed, theory-based peer nutrition education program on the child feeding practices of mothers with children aged between six months to two years is warranted. PMID- 25494912 TI - Computer modeling and ex vivo experiments with a (saline-linked) irrigated electrode for RF-assisted heating. AB - BACKGROUND: Externally irrigated radiofrequency (RF) electrodes have been widely used to thermally ablate tumors in surface tissue and to thermally coagulate the transection plane during a surgical resection. As far as we know, no mathematical model has yet been developed to study the electrical and thermal performance of these electrodes, especially the role of the saline layer that forms around the electrode. METHODS: Numerical models of a TissueLink device model DS3.0 (Salient Surgical Technologies, Portsmouth, NH, USA) were developed. Irrigation was modeled including a saline layer and a heat convection term in the governing equation. Ex vivo experiments based on fragments of bovine hepatic tissue were conducted to obtain information which was used in building the numerical model. We compared the 60 degrees C isotherm of the computer results with the whitening contour in the heated samples. RESULTS: Computer and experimental results were in fine agreement in terms of lesion depth (2.4 mm in the simulations and 2.4 +/- 0.6 mm in the experiments). In contrast, the lesion width was greater in the simulation (9.6 mm vs. 7.8 +/- 1.8 mm). The computer simulations allowed us to explain the role of the saline layer in creating the thermal lesion. Impedance gradually decreased as heating proceeded. The saline was not observed to boil. In the proximity of the electrode (around 1 mm) the thermal lesion was mainly created by the RF power in this zone, while at a further distance the thermal lesion was created by the hot saline on the tissue surface by simple thermal conduction. Including the heat convection term associated with the saline velocity in the governing equation was crucial to verifying that the saline layer had not reached boiling temperature. CONCLUSIONS: The model reproduced thermal performance during heating in terms of lesion depth, and provided an explanation for: 1) the relationship between impedance, electrode insertion depth, and saline layer, and 2) the process of creating thermal lesions in the tissue with this type of electrode. PMID- 25494913 TI - Prehospital Trauma Care in Singapore. AB - Prehospital emergency care in Singapore has taken shape over almost a century. What began as a hospital-based ambulance service intended to ferry medical cases was later complemented by an ambulance service under the Singapore Fire Brigade to transport trauma cases. The two ambulance services would later combine and come under the Singapore Civil Defence Force. The development of prehospital care systems in island city-state Singapore faces unique challenges as a result of its land area and population density. This article defines aspects of prehospital trauma care in Singapore. It outlines key historical milestones and current initiatives in service, training, and research. It makes propositions for the future direction of trauma care in Singapore. The progress Singapore has made given her circumstances may serve as lessons for the future development of prehospital trauma systems in similar environments. Key words: Singapore; trauma; prehospital emergency care; emergency medical services. PMID- 25494914 TI - The importance of complete tissue homogenization for accurate stoichiometric measurement of myosin light chain phosphorylation in airway smooth muscle. AB - The standard method for measuring the phosphorylation of the regulatory myosin light chain (MLC20) in smooth muscle is extraction of the light chain using a urea extraction buffer, urea-glycerol gel electrophoresis of the soluble portion of the extract (supernatant) and Western blot analysis. The undissolved portion of the tissue during extraction (the pellet) is usually discarded. Because the pellet contains a finite amount of MLC20, omission of the pellet could result in inaccurate measurement of MLC20 phosphorylation. In this study we compared the level of tracheal smooth muscle MLC20 phosphorylation in the supernatant alone, with that in the complete tissue homogenate (supernatant and pellet) using the standard method. The supernatant fraction showed the well-known double bands representing phosphorylated and un-phosphorylated MLC20. The dissolved pellet fraction showed varying amounts of un-phosphorylated and phosphorylated MLC20. There was a small but statistically significant overestimation of the percent MLC20 phosphorylation if the pellet was not taken into consideration. The overestimation was 7% +/- 2% (mean +/- SEM) (p < 0.05) in unstimulated muscle and 2% +/- 1% (p < 0.05) in acetylcholine (10(-6) mol/L) stimulated muscle. This finding suggests that for accurate estimation of the stoichiometry of MLC20 phosphorylation it is necessary to consider the contribution from the pellet portion of the muscle tissue homogenate. PMID- 25494915 TI - Robot-assisted surgery in cervical cancer patients reduces the time to normal activities of daily living. AB - OBJECTIVE: To evaluate current surgical cervical cancer treatment in Sweden 2008 12. DESIGN AND SETTING: Analysis of data in the Swedish National Quality Register for Gynecological Surgery (GynOP). SAMPLE: A total of 249 cervical cancer patients undergoing surgery. METHODS: Analysis of prospectively gathered preoperative and postoperative data including patient-reported information. MAIN OUTCOME MEASURES: Mean operating time, blood loss/transfusion, length of hospital stay, return to activities of daily living. RESULTS: The patients undergoing laparoscopic robot-assisted surgery (n = 64) or laparotomy (n = 185) did not differ in age, body mass index, American Society of Anesthesiologists score, International Federation of Gynecology and Obstetrics (FIGO) stage or mean operating time. Blood loss was higher in the laparotomy group (p < 0.001). Thirteen patients in the laparotomy group (7%) received a blood transfusion, but none in the robot group. Intraoperative complications were more common in the laparotomy group (p = 0.03). Re-admission or operations did not differ between the groups. The number of pelvic lymph nodes removed was significantly higher in the laparotomy group (median 31 vs. 24, p < 0.001). There was no difference regarding the number of patients with lymph node metastases in the two groups. The postoperative length of hospital stay was longer in the laparotomy group compared with the robot group (6.1 days vs. 2.1 days, p = 0.01). The patient reported time to resume normal activities of daily living was longer in the laparotomy than the robot group (13.4 days vs. 9.7 days, p = 0.04). CONCLUSIONS: Laparoscopic robotic-assisted surgery is preferable to laparotomy for cervical cancer patients because it entails a significantly shorter hospital stay, less blood loss, fewer intraoperative complications and shorter time to normal daily activities. PMID- 25494916 TI - Plasmid transfection in mammalian cells spatiotemporally tracked by a gold nanoparticle. AB - Recent advances in cell transfection have suggested that delivery of a gene on a gold nanoparticle (AuNP) can enhance transfection efficiency. The mechanism of transfection is poorly understood, particularly when the gene is appended to a AuNP, as expression of the desired exogenous protein is dependent not only on the efficiency of the gene being taken into the cell but also on efficient endosomal escape and cellular processing of the nucleic acid. Design of a multicolor surface energy transfer (McSET) molecular beacon by independently dye labeling a linearized plasmid and short duplex DNA (sdDNA) appended to a AuNP allows spatiotemporal profiling of the transfection events, providing insight into package uptake, disassembly, and final plasmid expression. Delivery of the AuNP construct encapsulated in Lipofectamine2000 is monitored in Chinese hamster ovary cells using live-cell confocal microscopy. The McSET beacon signals the location and timing of the AuNP release and endosomal escape events for the plasmid and the sdDNA discretely, which are correlated with plasmid transcription by fluorescent protein expression within the cell. It is observed that delivery of the construct leads to endosomal release of the plasmid and sdDNA from the AuNP surface at different rates, prior to endosomal escape. Slow cytosolic diffusion of the nucleic acids is believed to be the limiting step for transfection, impacting the time-dependent expression of protein. The overall protein expression yield is enhanced when delivered on a AuNP, possibly due to better endosomal escape or lower degradation prior to endosomal escape. PMID- 25494917 TI - Rosmarinic Acid Suppresses Subconjunctival Neovascularization in Experimental Glaucoma Surgery. AB - PURPOSE: Excessive subconjunctival scarring is associated with increased angiogenesis and leads to filtration failure in glaucoma surgery. In this study, we describe that rosmarinic acid (RA) has anti-angiogenic activity during wound healing in a rabbit model of glaucoma surgery. METHODS: Forty New Zealand rabbits underwent an experimental trabeculectomy and were randomly allocated into two treatment groups: RA group - treated with subconjunctival injections of 0.1 ml RA (15 mg/ml; n = 20) - and control group - treated with subconjunctival injections of 0.1 ml balanced salt solution (n = 20). The in vivo effect of RA was investigated after 5 and 15 d by measuring the intraocular pressure (IOP; with Tonopen) and bleb area and vascularity (using the Moorfields Bleb Grading System). Vascularization was also studied by counting histological blood vessels and by immunohistochemistry of vascular endothelial growth factor (VEGF) at the surgical site and by quantification of vessels in chicken's chorioallantoic membrane (CAM), treated with AR 500 MUg/ml for 48 h. RESULTS: On the fifth day, eyes of RA group displayed higher bleb area (3.6 +/- 0.2 versus 1.8 +/- 0.2; p = 0.004) and lower vascularity (3.0 +/- 0.5 versus 4.0 +/- 0.4; p = 0.009) than controls; however, difference in IOP reduction was not significant (-1.4 +/- 0.3 versus -0.8 +/- 0.3 mmHg; p = 0.226). Proportion of vessels/field (4.6 +/- 0.5 versus 10.4 +/- 0.9; p = 0.008) and VEGF immunostaining (15,347 +/- 3788 versus 31,043 +/- 3230; p = 0.019) also declined with RA treatment. However, at the 15th day, none of the parameters were different between the groups, except for vessels/field proportion (5.4 +/- 1.0 versus 10.6 +/- 1.6; p = 0.035). CAM exposed to AR inhibited vascularization (-45.67 +/- 4.74%; p < 0.001). CONCLUSION: These data indicate RA has a short-term anti-angiogenic effect and could be a potential modulator of neovascularization during subconjunctival healing at glaucoma filtration surgical sites. PMID- 25494919 TI - Framing life and death on YouTube: the strategic communication of organ donation messages by organ procurement organizations. AB - Using a sample of YouTube videos posted on the YouTube channels of organ procurement organizations, a content analysis was conducted to identify the frames used to strategically communicate prodonation messages. A total of 377 videos were coded for general characteristics, format, speaker characteristics, organs discussed, structure, problem definition, and treatment. Principal components analysis identified message frames, and k-means cluster analysis established distinct groupings of videos on the basis of the strength of their relationship to message frames. Analysis of these frames and clusters found that organ procurement organizations present multiple, and sometimes competing, video types and message frames on YouTube. This study serves as important formative research that will inform future studies to measure the effectiveness of the distinct message frames and clusters identified. PMID- 25494918 TI - Respiratory syncytial virus infection-associated hospitalization in adults: a retrospective cohort study. AB - BACKGROUND: Once considered primarily a pediatric concern, respiratory syncytial virus (RSV) infection is gaining recognition as a cause of significant morbidity and mortality in adults. A better understanding of RSV epidemiology and disease in adults is needed to guide patient management and to assess the need for prophylaxis, vaccines, and treatments. METHODS: We conducted a retrospective cohort study of adults admitted to four hospitals in Toronto, Canada, between September 2012 and June 2013 with RSV identified by a qualitative real-time reverse-transcriptase polymerase chain reaction assay in nasopharyngeal swab or bronchoscopy specimens. Main outcomes were hospital length of stay, need for intensive care unit (ICU) or mechanical ventilation, and all-cause mortality. RESULTS: Eighty-six patients were identified as requiring hospitalization for RSV infection (56% female). Median age was 74 (range 19-102) years; 29 (34%) were < 65 years. Eighty-three (97%) had underlying chronic medical conditions; 27 (31%) were immunosuppressed, and 10 (12%) known smokers. The most common symptoms and signs were cough in 73 (85%), shortness of breath in 68 (79%), sputum production in 54 (63%), weakness in 43 (50%), fever in 41 (48%), and wheezing in 33 (38%). Lower respiratory tract complications occurred in 45 (52%), cardiovascular complications occurred in 19 (22%), and possible co-pathogens were identified in 11 (13%). Sixty-seven (78%) were treated with antibiotics and 31 (36%) with anti influenza therapy. Thirteen (15%) required ICU care and 8 (9%) required mechanical ventilation. Five (6%) died during hospitalization. Need for ICU and mechanical ventilation were associated with mortality (P <= 0.02). Median hospital length of stay was 6 days (mean 10.8 days). CONCLUSIONS: RSV infection is associated with the need for extended hospital stay, ICU care and mortality in adults of all ages with chronic underlying conditions. Presenting signs and symptoms are nonspecific, co-infections occur, and patients often receive antibiotics and anti-influenza therapy. There is need for ongoing research and development of RSV prophylaxis, vaccines and treatments for adults. PMID- 25494920 TI - Francisella tularensis LVS surface and membrane proteins as targets of effective post-exposure immunization for tularemia. AB - Francisella tularensis causes disease (tularemia) in a large number of mammals, including man. We previously demonstrated enhanced efficacy of conventional antibiotic therapy for tularemia by postexposure passive transfer of immune sera developed against a F. tularensis LVS membrane protein fraction (MPF). However, the protein composition of this immunogenic fraction was not defined. Proteomic approaches were applied to define the protein composition and identify the immunogens of MPF. MPF consisted of at least 299 proteins and 2-D Western blot analyses using sera from MPF-immunized and F. tularensis LVS-vaccinated mice coupled to liquid chromatography-tandem mass spectrometry identified 24 immunoreactive protein spots containing 45 proteins. A reverse vaccinology approach that applied labeling of F. tularensis LVS surface proteins and bioinformatics was used to reduce the complexity of potential target immunogens. Bioinformatics analyses of the immunoreactive proteins reduced the number of immunogen targets to 32. Direct surface labeling of F. tularensis LVS resulted in the identification of 31 surface proteins. However, only 13 of these were reactive with MPF and/or F. tularensis LVS immune sera. Collectively, this use of orthogonal proteomic approaches reduced the complexity of potential immunogens in MPF by 96% and allowed for prioritization of target immunogens for antibody-based immunotherapies against tularemia. PMID- 25494921 TI - Endo-selective Pd-catalyzed silyl methyl Heck reaction. AB - A palladium (Pd)-catalyzed endo-selective Heck reaction of iodomethylsilyl ethers of phenols and aliphatic alkenols has been developed. Mechanistic studies reveal that this silyl methyl Heck reaction operates via a hybrid Pd-radical process and that the silicon atom is crucial for the observed endo selectivity. The obtained allylic silyloxycycles were further oxidized into (Z)-alkenyldiols. PMID- 25494923 TI - Structural characterization of two water-soluble polysaccharides from black soybean (Glycine max (L.) Merr.). AB - Black soybeans (Glycine max (L.) Merr.) have been widely used as a health food and medicinal herb in oriental medicine. In the present study, the chemical structures of two water-soluble polysaccharides (black soybean polysaccharide 1 (BSPS-1) and black soybean polysaccharide 3 (BSPS-3)) isolated from black soybeans were characterized by high performance size-exclusion chromatography (HPSEC), methylation analysis, and 1D (1H, 13C) and 2D (COSY, TOCSY, HSQC, NOESY, and HMBC) NMR spectra. The molecular weights of BSPS-1 and BSPS-3 were 1.95 * 105 and 1.88 * 105 Da, respectively. Methylation analysis and NMR spectra indicate that BSPS-1 is composed of 1,6-alpha-d-glucopyranosyl residues. By contrast, BSPS 3 is mainly composed of a 1,3-beta-d-galactopyranosyl residue backbone with side chains substituted at the O-6 position consisting of large content of T-alpha-l Araf-(1-> residues, and small contents of ->5)-alpha-l-Araf-(1->, ->2)-alpha-l Rhap-(1->, and 4-O-Me-beta-d-GlcAp-(1-> residues. Our results suggest that BSPS-1 is a linear (1->6)-alpha-d-glucan, whereas BSPS-3 is a type II arabinogalactan. The unique structures of BSPS-1 and BSPS-3 indicate that they might have wide applications in food and pharmaceutical industries. PMID- 25494922 TI - Construction of a high-density genetic map based on large-scale markers developed by specific length amplified fragment sequencing (SLAF-seq) and its application to QTL analysis for isoflavone content in Glycine max. AB - BACKGROUND: Quantitative trait locus (QTL) mapping is an efficient approach to discover the genetic architecture underlying complex quantitative traits. However, the low density of molecular markers in genetic maps has limited the efficiency and accuracy of QTL mapping. In this study, specific length amplified fragment sequencing (SLAF-seq), a new high-throughput strategy for large-scale SNP discovery and genotyping based on next generation sequencing (NGS), was employed to construct a high-density soybean genetic map using recombinant inbred lines (RILs, Luheidou2*Nanhuizao, F5:8). With this map, the consistent QTLs for isoflavone content across various environments were identified. RESULTS: In total, 23 Gb of data containing 87,604,858 pair-end reads were obtained. The average coverage for each SLAF marker was 11.20-fold for the female parent, 12.51 fold for the male parent, and an average of 3.98-fold for individual RILs. Among the 116,216 high-quality SLAFs obtained, 9,948 were polymorphic. The final map consisted of 5,785 SLAFs on 20 linkage groups (LGs) and spanned 2,255.18 cM in genome size with an average distance of 0.43 cM between adjacent markers. Comparative genomic analysis revealed a relatively high collinearity of 20 LGs with the soybean reference genome. Based on this map, 41 QTLs were identified that contributed to the isoflavone content. The high efficiency and accuracy of this map were evidenced by the discovery of genes encoding isoflavone biosynthetic enzymes within these loci. Moreover, 11 of these 41 QTLs (including six novel loci) were associated with isoflavone content across multiple environments. One of them, qIF20-2, contributed to a majority of isoflavone components across various environments and explained a high amount of phenotypic variance (8.7%-35.3%). This represents a novel major QTL underlying isoflavone content across various environments in soybean. CONCLUSIONS: Herein, we reported a high-density genetic map for soybean. This map exhibited high resolution and accuracy. It will facilitate the identification of genes and QTLs underlying essential agronomic traits in soybean. The novel major QTL for isoflavone content is useful not only for further study on the genetic basis of isoflavone accumulation, but also for marker-assisted selection (MAS) in soybean breeding in the future. PMID- 25494925 TI - Editor's Introduction. PMID- 25494924 TI - Development of the thalamo-dorsal ventricular ridge tract in the Chinese soft shelled turtle, Pelodiscus sinensis. AB - With the exception of that from the olfactory system, the vertebrate sensory information is relayed by the dorsal thalamus (dTh) to be carried to the telencephalon via the thalamo-telencephalic tract. Although the trajectory of the tract from the dTh to the basal telencephalon seems to be highly conserved among amniotes, the axonal terminals vary in each group. In mammals, thalamic axons project onto the neocortex, whereas they project onto the dorsal pallium and the dorsal ventricular ridge (DVR) in reptiles and birds. To ascertain the evolutionary development of the thalamo-telencephalic connection in amniotes, we focused on reptiles. Using the Chinese soft-shelled turtle (Pelodiscus sinensis), we studied the developmental course of the thalamic axons projecting onto the DVR. We found, during the developmental period when the thalamo-DVR connection forms, that transcripts of axon guidance molecules, including EphA4 and Slit2, were expressed in the diencephalon, similar to the mouse embryo. These results suggest that the basic mechanisms responsible for the formation of the thalamo telencephalic tract are shared across amniote lineages. Conversely, there was a characteristic difference in the expression patterns of Slit2, Netrin1, and EphrinA5 in the telencephalon between synapsid (mammalian) and diapsid (reptilian and avian) lineages. This indicates that changes in the expression domains of axon guidance molecules may modify the thalamic axon projection and lead to the diversity of neuronal circuits in amniotes. PMID- 25494926 TI - Amid the darkness and the light. PMID- 25494927 TI - Lessons learned from conducting research with participants receiving dialysis for end-stage renal disease. PMID- 25494928 TI - Enhancing collaborative leadership in palliative social work in oncology. AB - The Institute of Medicine (IOM) Report-Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs-provided recommendations for meeting the palliative care needs of our growing population of older Americans. The IOM report highlights the demand for social work leadership across all aspects of the health care delivery system. Social workers are core interdisciplinary members of the health care team and it is important for them to be well prepared for collaborative leadership roles across health care settings. The ExCEL in Social Work: Excellence in Cancer Education & Leadership education project was created as a direct response to the 2008 IOM Report. This article highlights a sampling of palliative care projects initiated by outstanding oncology social work participants in the ExCEL program. These projects demonstrate the leadership of social workers in palliative care oncology. PMID- 25494929 TI - Barriers associated with the implementation of an advance care planning program in a prison setting. AB - Advance care planning is considered a best practice within health care. However, the extent to which planning occurs within prison settings is unknown. Through the course of implementing an advance care planning (ACP) program for aging and dying offenders at a medical classification center, multiple barriers were identified that need to be addressed systemically to ensure the medical wishes of offenders were known and honored. This article will outline the barriers and the steps that were taken to create systems change to promote and sustain advance care planning. PMID- 25494930 TI - Values important to terminally ill African American older adults in receiving hospice care. AB - While racial disparity in the use of hospice care by older African Americans is widely acknowledged, little is known about the values that they consider as important in receiving health care services along with direct experiences with having these values respected by hospice care providers. Using individual, face to-face interviews, data were collected directly from 28 African American hospice patients about their experiences in hospice care. Content analysis was used to identify and categorize themes from multiple readings of the qualitative data. Resulting themes included: dying at home, open communications, independent decision-making, autonomy in daily life, unwillingness to be a burden, and relationships. Through the initial assessment, value preferences can be explored and then shared with hospice team members to ensure that services are provided in such a way that their values and preferences are respected. PMID- 25494931 TI - Enhancing palliative care for low-income elders with chronic disease: feasibility of a hospice consultation model. AB - Challenges exist in assimilating palliative care within community-based services for nursing home eligible low-income elders with complex chronic illness as they approach the end of life (EOL). This study assessed the feasibility of a consultation model, with hospice clinicians working with three Care Wisconsin Partnership Program teams. Consults occurred primarily during team meetings and also informally and on joint patient visits and were primarily with the palliative care nurse addressing physical issues. Fifty-seven percent of consultant recommendations were implemented. Benefits of consultation were identified with focus groups of clinical staff as were opportunities and barriers to the implementation. Models of integration are proposed. PMID- 25494933 TI - Thermal regime, predation danger and the early marine exit of sockeye salmon Oncorhynchus nerka. AB - Marine exit timing of sockeye salmon Oncorhynchus nerka populations on the Haida Gwaii Archipelago, British Columbia, Canada, is described, with specific focus on Copper Creek. Marine exit in Copper Creek occurs > 130 days prior to spawning, one of the longest adult freshwater residence periods recorded for any O. nerka population. Copper Creek presents an easy upstream migration, with mild water temperatures (7 to 14 degrees C), short distance (13.1 km) and low elevation gain (41 m) to the lake where fish hold prior to spawning. An energetic model estimates that <1% of the initial energy reserve is required for upstream migration, compared with 62% for lake holding and 38% for reproductive development. Historical records suggest that it is unlikely that water temperature in any of the O.nerka streams in Haida Gwaii has ever exceeded the presumed temperature threshold (19 degrees C) for early marine exit. Although it is not impossible that the thermal tolerance of Copper Creek O.nerka is very low, the data presented here appear inconsistent with thermal avoidance as an explanation for the early marine exit timing in Copper Creek and in three other populations on the archipelago with early marine exit. PMID- 25494935 TI - Selective biotemplated synthesis of TiO2 inside a protein cage. AB - Biological organisms have evolved tremendous control over the synthesis of inorganic materials in aqueous solutions at standard conditions. Such control over material properties is difficult to achieve with current synthesis strategies. Biotemplated synthesis of materials has been demonstrated to be efficient at facilitating the formation of various inorganic species. In this study, we employ a protein cage-based system to synthesize photoactive TiO2 nanoparticles less than 10 nm in diameter. We also demonstrate phase control over the material, with the ability to synthesize both anatase and rutile TiO2 using distinct biomineralization peptides within the protein cage. Finally, using analytical ultracentrifugation, we are able to resolve distinct reaction products and approximate their loading. We find that two distinct species comprise the reaction products, likely representing procapsid-like particles with early, precursor metal oxide clusters, and shells nearly full with crystalline TiO2 nanoparticles, respectively. PMID- 25494934 TI - Novel tetrahydropyran-based bacterial topoisomerase inhibitors with potent anti gram positive activity and improved safety profile. AB - Novel antibacterial drugs that are effective against infections caused by multidrug resistant pathogens are urgently needed. In a previous report, we have shown that tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. During the course of our optimization program, lead compound 5 was deprioritized due to adverse findings in cardiovascular safety studies. In the effort of mitigating these findings and optimizing further the pharmacological profile of this class of compounds, we have identified a subseries of tetrahydropyran-based molecules that are potent DNA gyrase and topoisomerase IV inhibitors and display excellent antibacterial activity against Gram positive pathogens, including clinically relevant resistant isolates. One representative of this class, compound 32d, elicited only weak inhibition of hERG K(+) channels and hNaV1.5 Na(+) channels, and no effects were observed on cardiovascular parameters in anesthetized guinea pigs. In vivo efficacy in animal infection models has been demonstrated against Staphylococcus aureus and Streptococcus pneumoniae strains. PMID- 25494936 TI - THB1, a truncated hemoglobin, modulates nitric oxide levels and nitrate reductase activity. AB - Hemoglobins are ubiquitous proteins that sense, store and transport oxygen, but the physiological processes in which they are implicated is currently expanding. Recent examples of previously unknown hemoglobin functions, which include scavenging of the signaling molecule nitric oxide (NO), illustrate how the implication of hemoglobins in different cell signaling processes is only starting to be unraveled. The extent and diversity of the hemoglobin protein family suggest that hemoglobins have diverged and have potentially evolved specialized functions in certain organisms. A unique model organism to study this functional diversity at the cellular level is the green alga Chlamydomonas reinhardtii because, among other reasons, it contains an unusually high number of a particular type of hemoglobins known as truncated hemoglobins (THB1-THB12). Here, we reveal a cell signaling function for a truncated hemoglobin of Chlamydomonas that affects the nitrogen assimilation pathway by simultaneously modulating NO levels and nitrate reductase (NR) activity. First, we found that THB1 and THB2 expression is modulated by the nitrogen source and depends on NIT2, a transcription factor required for nitrate assimilation genes expression. Furthermore, THB1 is highly expressed in the presence of NO and is able to convert NO into nitrate in vitro. Finally, THB1 is maintained on its active and reduced form by NR, and in vivo lower expression of THB1 results in increased NR activity. Thus, THB1 plays a dual role in NO detoxification and in the modulation of NR activity. This mechanism can partly explain how NO inhibits NR post translationally. PMID- 25494937 TI - The regulatory role of Streptomyces coelicolor TamR in central metabolism. AB - Trans-aconitate methyltransferase regulator (TamR) is a member of the ligand responsive multiple antibiotic resistance regulator (MarR) family of transcription factors. In Streptomyces coelicolor, TamR regulates transcription of tamR (encoding TamR), tam (encoding trans-aconitate methyltransferase) and sacA (encoding aconitase); up-regulation of these genes promotes metabolic flux through the citric acid cycle. DNA binding by TamR is attenuated and transcriptional derepression is achieved on binding of ligands such as citrate and trans-aconitate to TamR. In the present study, we show that three additional genes are regulated by S. coelicolor TamR. Genes encoding malate synthase (aceB1; SCO6243), malate dehydrogenase (mdh; SCO4827) and isocitrate dehydrogenase (idh; SCO7000) are up-regulated in vivo when citrate and trans-aconitate accumulate, and TamR binds the corresponding gene promoters in vitro, a DNA binding that is attenuated by cognate ligands. Mutations to the TamR binding site attenuate DNA binding in vitro and result in constitutive promoter activity in vivo. The predicted TamR binding sites are highly conserved in the promoters of these genes in Streptomyces species that encode divergent tam-tamR gene pairs, suggesting evolutionary conservation. Like aconitase and trans-aconitate methyltransferase, malate dehydrogenase, isocitrate dehydrogenase and malate synthase are closely related to the citric acid cycle, either catalysing individual reaction steps or, in the case of malate synthase, participating in the glyoxylate cycle to produce malate that enters the citric acid cycle to replenish the intermediate pool. Taken together, our data suggest that TamR plays an important and conserved role in promoting metabolic flux through the citric acid cycle. PMID- 25494938 TI - De novo assembly of the transcriptome of Acanthaster planci testes. AB - A key strategy to reduce coral loss is the development of effective control method for the corallivorous crown-of-thorns sea star (Acanthaster planci), an omnipresent scourge and threat to the biodiversity of reefs in the Indo-Pacific region. Limited genetic resources are available for this highly fecund species. In this study, we explored one aspect at the heart of A. planci outbreaks, the male reproductive system. Using high-throughput sequencing technology, we report for first time the production of a comprehensive transcriptomic data set for the testes of A. placni that can aid in understanding the molecular mechanisms involved in A. planci spermatogenesis and fertilization. Through de novo transcriptome sequencing, we produced 52 965 998 raw reads corresponding to 4.76 Gb clean read data. From this, 243 870 contigs were assembled with Trinity and used to construct 92 792 unigenes. Distinct genes were then annotated with blastx yielding 30 810 unigenes above the cut-off E-value set at 10(-5) , with ESTScan database query analyses yielding up to 5366 unigenes to known hits. The identification of genes directly involved in sperm development (DEAD-box family proteins), motility, fertilization and signalling (Bindin/Speract receptor) are also discussed. PMID- 25494939 TI - Ochratoxin A reduction in meat sausages using processing methods practiced in households. AB - The aim of this study was to investigate the possibilities of ochratoxin A (OTA) reduction in home-made meat products. Meat sausages (n = 50) produced from raw materials coming from pigs exposed to OTA-contaminated feed, were subject to common heat processes practiced in households (cooking, frying and baking). Concentrations of OTA in pre- and post-processed products were quantified using a validated immunoassay method, enzyme-linked immunosorbent assay, and confirmed using a high-performance liquid chromatography with fluorescence detection. In line with the differences in recipes used and the degree of OTA accumulation in raw materials, OTA concentrations established in Mediterranean and roast sausages were lower than those found in liver and blood sausages. Baking of contaminated sausages at the temperatures of 190-220 degrees C (for 60 min) resulted in significant reduction of OTA levels (75.8%), while 30-min cooking (at 100 degrees C) and frying (at 170 degrees C) proved to be significantly less effective (e.g. yielding OTA reductions of 7.4% and 12.6%, respectively). The results pointed out that despite high OTA stability, heat processes are capable of reducing its concentration in home-made meat products, depending on the processing modality used. PMID- 25494940 TI - A survey of the use of soy in processed Turkish meat products and detection of genetic modification. AB - To screen for possible illegal use of soybeans in meat products, the performance characteristics of a commercial polymer chain reaction (PCR) kit for detection of soybean DNA in raw and cooked meat products were established. Minced chicken and beef products containing soybean at levels from 0.1% to 10.0% were analysed by real-time PCR to amplify the soybean lectin gene. The PCR method could reliably detect the addition of soybean at a level of 0.1%. A survey of 38 Turkish processed meat products found only six samples to be negative for the presence of soybean. In 32 (84%) positive samples, 13 (34%) contained levels of soy above 0.1%. Of soybean positive samples, further DNA analysis was conducted by real time PCR to detect whether genetically modified (GM) soybean had been used. Of 32 meat samples containing soybean, two samples were positive for GM modification. PMID- 25494942 TI - Adjusting to living with multiple sclerosis: The role of social groups. AB - Multiple sclerosis (MS) is typically associated with life-long adjustment to wide ranging, changeable symptoms and psychosocial disruption as all relationships are changed or lost. Despite accumulating evidence, the therapeutic impact of harnessing social group factors in MS management and rehabilitation remains largely unexplored. We investigated their role specific to adjusting to MS. A qualitative approach was used with thematic analysis to induce a rich and developing account of the impact of social groups on adjustment for 15 individuals with MS. An adjustment questionnaire was used to provide a framework for its organisation and discussion. The analysis revealed three themes associated with loss, change and social processes that influenced adjustment. These features distinguished between those who were more or less able to adjust, and resonated well with processes previously identified as central to identity loss and change. Social factors enhanced adjustment through easing transition between pre- and post-MS diagnosis lives. Notably, maintenance of pre-existing social roles and relationships was critical in providing a meaningful basis for integrating the old with new senses of self. The capacity to join new social groups was as key in adjustment as was awareness of having access to multiple social groups to avoid being solely defined by MS. These concepts provided a more stable grounding upon which to nurture value systems and employ collective support to counter the negative consequences of living with MS. PMID- 25494943 TI - Odontogenic facial swelling of unknown origin. AB - BACKGROUND: Current radiography techniques have limitations in detecting subtle odontogenic anomalies or defects that can lead to dentoalveolar and facial infections. This report examines the application of micro-CT imaging on two extracted teeth to enable detailed visualization of subtle odontogenic defects that had given rise to facial swelling. METHODS: Two extracted non-carious mandibular left primary canine teeth (73) associated with odontogenic infections were selected from two patients, and an intact contralateral tooth (83) from one of the patients was used as a control. All three teeth were subjected to three dimensional micro-CT imaging at a resolution of 20 MUm. RESULTS: Tooth 73 from the first case displayed dentine pores (channels) that established communication between the pulp chamber and the exposed dentine surface. In comparison, tooth 73 from the second case had a major vertical crack extending from the external enamel surface into the pulp chamber. The control tooth did not display any anomalies or major cracks. CONCLUSIONS: The scope of micro-CT imaging can be extended from current in vitro applications to establish post-extraction diagnosis of subtle odontogenic defects, in a manner similar to deriving histopathological diagnoses in extracted teeth. Ongoing technological advancements hold the promise for more widespread translatory applications. PMID- 25494945 TI - Synergistic bifunctional catalyst design based on perovskite oxide nanoparticles and intertwined carbon nanotubes for rechargeable zinc-air battery applications. AB - Advanced morphology of intertwined core-corona structured bifunctional catalyst (IT-CCBC) is introduced where perovskite lanthanum nickel oxide nanoparticles (LaNiO3 NP) are encapsulated by high surface area network of nitrogen-doped carbon nanotubes (NCNT) to produce highly active and durable bifunctional catalyst for rechargeable metal-air battery applications. The unique composite morphology of IT-CCBC not only enhances the charge transport property by providing rapid electron-conduction pathway but also facilitates in diffusion of hydroxyl and oxygen reactants through the highly porous framework. Confirmed by electrochemical half-cell testing, IT-CCBC in fact exhibits very strong synergy between LaNiO3 NP and NCNT demonstrating bifunctionality with significantly improved catalytic activities of oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). Furthermore, when compared to the state-of-art catalysts, IT-CCBC outperforms Pt/C and Ir/C in terms of ORR and OER, respectively, and shows improved electrochemical stability compared to them after cycle degradation testing. The practicality of the catalyst is corroborated by testing in a realistic rechargeable zinc-air battery utilizing atmospheric air in ambient conditions, where IT-CCBC demonstrates superior charge and discharge voltages and long-term cycle stability with virtually no battery voltage fading. These improved electrochemical properties of the catalyst are attributed to the nanosized dimensions of LaNiO3 NP controlled by simple hydrothermal technique, which enables prolific growth of and encapsulation by highly porous NCNT network. The excellent electrochemical results presented in this study highlight IT-CCBC as highly efficient and commercially viable bifunctional catalyst for rechargeable metal-air battery applications. PMID- 25494944 TI - Jasmonic acid-isoleucine formation in grapevine (Vitis vinifera L.) by two enzymes with distinct transcription profiles. AB - The plant hormone jasmonic acid (JA) is essential for stress responses and the formation of reproductive organs, but its role in fruit development and ripening is unclear. Conjugation of JA to isoleucine is a crucial step in the JA signaling pathway since only JA-Ile is recognized by the jasmonate receptor. The conjugation reaction is catalyzed by JA-amido synthetases, belonging to the family of Gretchen Hagen3 (GH3) proteins. Here, in vitro studies of two grapevine (Vitis vinifera L. cv Shiraz) GH3 enzymes, VvGH3-7 and VvGH3-9, demonstrated JA conjugating activities with an overlapping range of amino acid substrates, including isoleucine. Expression studies of the corresponding genes in grape berries combined with JA and JA-Ile measurements suggested a primary role for JA signaling in fruit set and cell division and did not support an involvement of JA in the ripening process. In response to methyl JA (MeJA) treatment, and in wounded and unwounded (distal) leaves, VvGH3-9 transcripts accumulated, indicating a participation in the JA response. In contrast, VvGH3-7 was unresponsive to MeJA and local wounding, demonstrating a differential transcriptional regulation of VvGH3-7 and VvGH3-9. The transient induction of VvGH3-7 in unwounded, distal leaves was suggestive of the involvement of an unknown mobile wound signal. PMID- 25494946 TI - Impact of Joule Heating and pH on Biosolids Electro-Dewatering. AB - Electro-dewatering (ED) is a novel technology to reduce the overall costs of residual biosolids processing, transport, and disposal. In this study, we investigated Joule heating and pH as parameters controlling the dewaterability limit, dewatering rate, and energy efficiency. Temperature-controlled electrodes revealed that Joule heating enhances water removal by increasing evaporation and electro-osmotic flow. High temperatures increased the dewatering rate, but had little impact on the dewaterability limit and energy efficiency. Analysis of horizontal layers after 15-min ED suggests electro-osmotic flow reversal, as evidenced by a shifting of the point of minimum moisture content from the anode toward the cathode. This flow reversal was also confirmed by the pH at the anode being below the isoelectric point, as ascertained by pH titration. The important role of pH on ED was further studied by adding acid/base solutions to biosolids prior to ED. An acidic pH reduced the biosolids charge while simultaneously increasing the dewatering efficiency. Thus, process optimization depends on trade offs between speed and efficiency, according to physicochemical properties of the biosolids microstructure. PMID- 25494947 TI - Domination of second-sphere shrinkage effect to improve photoluminescence of red nitride phosphors. AB - Red Ca0.99Al(1-4delta/3-x)Si(1+delta+x)N(3-x)C(x):Eu(2+)0.01 (delta = 0.345; x = 0-0.2) nitride phosphors exhibit a blue-shifted emission with increased eye sensitivity function and excellent thermal stability. The variations in the photoluminescence in the Ca0.99Al(1-4delta/3-x)Si(1+delta+x)N(3-x)C(x):Eu(2+)0.01 (delta = 0.345; x = 0-0.2) system are thoroughly investigated. The enhanced emission energy and the improved thermal stability with increasing x are dominated by the second-sphere shrinkage effect via the substitution of small Si(4+) for large Al(3+) with simultaneous charge compensation. Related proofs of the second-sphere shrinkage effect control for photoluminescence are confirmed via high-resolution neutron powder diffraction, EXAFS, and (29)Si solid-state NMR techniques. PMID- 25494948 TI - Supramolecular control over molecular magnetic materials: gamma-cyclodextrin templated grid of cobalt(II) single-ion magnets. AB - Single-ion magnets (SIMs) are potential building blocks of novel quantum computing devices. Unique magnetic properties of SIMs require effective separation of magnetic ions and can be tuned by even slight changes in their coordination sphere geometry. We show that an additional level of tailorability in the design of SIMs can be achieved by organizing magnetic ions into supramolecular architectures, resulting in gaining control over magnetic ion packing. Here, gamma-cyclodextrin was used to template magnetic Co(II) and nonmagnetic auxiliary Li(+) ions to form a heterometallic {Co, Li, Li}4 ring. In the sandwich-type complex [(gamma-CD)2Co4Li8(H2O)12] spatially separated Co(II) ions are prevented from superexchange magnetic coupling. Ac/dc magnetic and EPR studies demonstrated that individual Co(II) ions with positive zero-field splitting exhibit field-induced slow magnetic relaxation consistent with the SIMs' behavior, which is exceptional in complexes with easy-plane magnetic anisotropy. PMID- 25494949 TI - Synthesis, structure, and magnetism of a family of heterometallic {Cu2Ln7} and {Cu4Ln12} (Ln = Gd, Tb, and Dy) complexes: the Gd analogues exhibiting a large magnetocaloric effect. AB - The syntheses, structures, and magnetic properties of two heterometallic Cu(II) Ln(III) (Ln(III) = Gd, Tb, and Dy) families, utilizing triethanolamine and carboxylate ligands, are reported. The first structural motif displays a nonanuclear {Cu(II)2Ln(III)7} metallic core, while the second reveals a hexadecanuclear {Cu(II)4Ln(III)12} core. The differing nuclearities of the two families stem from the choice of carboxylic acid used in the synthesis. Magnetic studies show that the most impressive features are displayed by the {Cu(II)2Gd(III)7} and {Cu(II)4Gd(III)12} complexes, which display a large magnetocaloric effect, with entropy changes -DeltaSm = 34.6 and 33.0 J kg(-1) K( 1) at T = 2.7 and 2.9 K, respectively, for a 9 T applied field change. It is also found that the {Cu(II)4Dy(III)12} complex displays single-molecule magnet behavior, with an anisotropy barrier to magnetization reversal of 10.1 K. PMID- 25494950 TI - High-level expression of tamavidin 2 in human cells by codon-usage optimization. AB - Tamavidin 2 is a fungal protein that binds to biotin with an extremely high affinity. Tamavidin 2 is superior to avidin or streptavidin in terms of its low level non-specific binding and high-level thermal stability. However, the gene for tamavidin 2 is highly expressed in Escherichia coli but not in mammalian cells, restricting its application as an affinity tag in mammalian cells. Here, we optimized the codon usage of tamavidin 2 for human cells and found that the resultant mutant expressed tamavidin 2 at approximately 30-fold higher level compared with the native gene. The protein thus produced in human cells could be purified by iminobiotin affinity chromatography, bound tightly to biotin, and was stable at high temperature (82 degrees C). This powerful technology for high level expression of tamavidin 2 in mammalian cells will be of value in evaluating various fusion proteins produced in mammalian cells for numerous applications. PMID- 25494951 TI - Three synchronous, sporadic and separate periampullary and pancreatic tumors: more than a coincidence? AB - Three sporadic, synchronous, and separate lesions in the ampulla of Vater and the head of the pancreas presented in an 81-year-old male. One was symptomatic and two were incidental. One was detected preoperatively (the ampullary lesion) and two by examination of the resected specimen (the neuroendocrine and pancreatic carcinomas). The case is summarized and the literature and the issue of commonality are reviewed. PMID- 25494952 TI - Virtual reality lead extraction as a method for training new physicians: a pilot study. AB - BACKGROUND: It is estimated that the demand for transvenous lead extraction (TLE) has reached an annual extraction rate of nearly 24,000 patients worldwide. Despite technologic advances, TLE still has the potential for significant morbidity and mortality. Complication rates with TLE directly parallel operator experience. However, obtaining adequate training during and postfellowship can be difficult. Given the potential for catastrophic complications and the steep learning curve (up to 300 cases) associated with this procedure, we sought to validate a virtual reality (VR) lead extraction simulator as an innovative training and evaluation tool for physicians new to TLE. METHODS: We randomized eight electrophysiology fellows to VR simulator versus conventional training. We compared procedural skill competency between the groups using simulator competency, tactile measurements, markers of proficiency and attitudes, and cognitive abilities battery. RESULTS: Practical skills and simulator complications differed significantly between the VR simulator and conventional training groups. The VR simulator group executed patient preparation and procedure performance better than the conventional group (P < 0.01). All four fellows randomized to conventional training experienced a simulator complication (two superior vena cava [SVC] tears, three right ventricle [RV] avulsions) versus one fellow in the VR simulator group (one SVC tear) (P = 0.02). Tactile measurements revealed a trend toward excess pushing versus pulling forces among the conventionally trained group. The time for lead removal was also significantly higher in the conventional training group (12.46 minutes vs 5.54 minutes, P = 0.02). There was no significant difference in baseline or posttraining cognitive ability. CONCLUSIONS: We contend that the implementation of alternative training tools such as a VR simulation model will improve physician training and allow for an innovative pathway to assess the achievement of competency. PMID- 25494953 TI - Significantly improved luminescence properties of nitrogen-polar (0001) InGaN multiple quantum wells grown by pulsed metalorganic chemical vapor deposition. AB - We have demonstrated nitrogen-polar (0001) (N-polar) InGaN multiple quantum wells (MQWs) with significantly improved luminescence properties prepared by pulsed metalorganic chemical vapor deposition. During the growth of InGaN quantum wells, Ga and N sources are alternately injected into the reactor to alter the surface stoichiometry. The influence of flow duration in pulsed growth mode on the luminescence properties has been studied. We find that use of pulsed-mode creates a high density of hexagonal mounds with an increased InGaN growth rate and enhanced In composition around screw-type dislocations, resulting in remarkably improved luminescence properties. The mechanism of enhanced luminescence caused by the hexagonal mounds is discussed. Luminescence properties of N-polar InGaN MQWs grown with short pulse durations have been significantly improved in comparison with a sample grown by a conventional continuous growth method. PMID- 25494954 TI - Positioning resilience for 2015: the role of resistance, incremental adjustment and transformation in disaster risk management policy. AB - Resilience is a ubiquitous term in disaster risk management and is an increasingly prominent concept in early discussions focused on elaborating the post-2015 international policy landscape. Riddled with competing meanings and diverse policy implications, however, it is a concept caught between the abstract and operational. This paper provides a review of the rise to prominence of the concept of resilience and advances an elaboration of the related concepts of resistance, incremental adjustment and transformation. We argue that these concepts can contribute to decision-making by offering three distinct options for risk management policy. In order to deliberately and effectively choose among these options, we suggest that critical reflexivity is a prerequisite, necessitating improved decision-making capacity if varied perspectives (including those of the most vulnerable) are to be involved in the selection of the best approach to risk management. PMID- 25494955 TI - A climate-compatible approach to development practice by international humanitarian NGOs. AB - If current climate-change predictions prove accurate, non-linear change, including potentially catastrophic change, is possible and the environments in which international humanitarian NGOs operate will change figuratively and literally. This paper proposes that a new approach to development is required that takes changing climate into account. This 'climate-compatible approach' to development is a bleak shift from some of the current orthodox positions and will be a major challenge to international humanitarian NGOs working with the most vulnerable. However, it is necessary to address the challenges and context such NGOs face, and the need to be resilient and adaptive to these changes. PMID- 25494956 TI - Dealing with uncertainty: integrating local and scientific knowledge of the climate and weather. AB - While climate science has made great progress in the projection of weather and climate information, its uptake by local communities remains largely elusive. This paper describes two innovative approaches that strengthen understanding between the providers and users of weather and climate information and support appropriate application: (1) knowledge timelines, which compare different sources and levels of certainty in community and scientific weather and climate information; and (2) participatory downscaling, which supports users to translate national and regional information into a range of outcomes at the local level. Results from piloting these approaches among flood-prone communities in Senegal and drought-prone farmers in Kenya highlight the importance of co-producing 'user useful' climate information. Recognising that disaster risk management actions draw on a wide range of knowledge sources, climate information that can effectively support community-based decision-making needs to be integrated with local knowledge systems and based on an appreciation of the inherent uncertainty of weather and climate information. PMID- 25494957 TI - Engendering development and disasters. AB - Over the last two decades the different impacts of disasters on women and men have been acknowledged, leading to calls to integrate gender into disaster risk reduction and response. This paper explores how evolving understandings of ways of integrating gender into development have influenced this process, critically analysing contemporary initiatives to 'engender' development that see the inclusion of women for both efficiency and equality gains. It has been argued that this has resulted in a 'feminisation of responsibility' that can reinforce rather than challenge gender relations. The construction of women affected by disasters as both an at-risk group and as a means to reduce risk suggests similar processes of feminisation. The paper argues that if disaster risk reduction initiatives are to reduce women's vulnerability, they need to focus explicitly on the root causes of this vulnerability and design programmes that specifically focus on reducing gender inequalities by challenging unequal gendered power relations. PMID- 25494958 TI - A systems approach to resilience in the built environment: the case of Cuba. AB - Through its capacity to evoke systemic adaptation before and after disasters, resilience has become a seductive theory in disaster management. Several studies have linked the concept with systems theory; however, they have been mostly based on theoretical models with limited empirical support. The study of the Cuban model of resilience sheds light on the variables that create systemic resilience in the built environment and its relations with the social and natural environments. Cuba is vulnerable to many types of hazard, yet the country's disaster management benefits from institutional, health and education systems that develop social capital, knowledge and other assets that support construction industry and housing development, systematic urban and regional planning, effective alerts, and evacuation plans. The Cuban political context is specific, but the study can nonetheless contribute to systemic improvements to the resilience of built environments in other contexts. PMID- 25494959 TI - Linking disaster resilience and urban sustainability: a glocal approach for future cities. AB - Resilience and sustainability will be two primary objectives of future cities. The violent consequences of extreme natural events and the environmental, social and economic burden of contemporary cities make the concepts of resilience and sustainability extremely relevant. In this paper we analyse the various definitions of resilience and sustainability applied to urban systems and propose a synthesis, based on similarities between the two concepts. According to the proposed approach, catastrophic events and the subsequent transformations occurring in urban systems represent a moment in the city life cycle to be seen in terms of the complex sustainability framework. Hence, resilience is seen as a requirement for urban system sustainability. In addition, resilience should be evaluated not only for single cities, with their physical and social systems, but also on a global scale, taking into account the complex and dynamic relationships connecting contemporary cities. PMID- 25494960 TI - Character displacement and the evolution of niche complementarity in a model biofilm community. AB - Colonization of vacant environments may catalyze adaptive diversification and be followed by competition within the nascent community. How these interactions ultimately stabilize and affect productivity are central problems in evolutionary ecology. Diversity can emerge by character displacement, in which selection favors phenotypes that exploit an alternative resource and reduce competition, or by facilitation, in which organisms change the environment and enable different genotypes or species to become established. We previously developed a model of long-term experimental evolution in which bacteria attach to a plastic bead, form a biofilm, and disperse to a new bead. Here, we focus on the evolution of coexisting mutants within a population of Burkholderia cenocepacia and how their interactions affected productivity. Adaptive mutants initially competed for space, but later competition declined, consistent with character displacement and the predicted effects of the evolved mutations. The community reached a stable equilibrium as each ecotype evolved to inhabit distinct, complementary regions of the biofilm. Interactions among ecotypes ultimately became facilitative and enhanced mixed productivity. Observing the succession of genotypes within niches illuminated changing selective forces within the community, including a fundamental role for genotypes producing small colony variants that underpin chronic infections caused by B. cenocepacia. PMID- 25494961 TI - Views of pharmacy graduates and pharmacist tutors on evidence-based practice in relation to over-the-counter consultations: a qualitative study. AB - RATIONALE, AIMS AND OBJECTIVES: Health care services offered to the public should be based on the best available evidence. We aimed to explore pharmacy tutors' and trainees' views on the importance of evidence when making decisions about over the-counter (OTC) medicines and also to investigate whether the tutor influenced the trainee in practice. METHODS: Following ethical approval and piloting, semi structured interviews were conducted with pharmacy graduates (trainees) and pharmacist tutors. Transcribed interview data were entered into the NVivo software package (version 10), coded and analysed via thematic analysis. RESULTS: Twelve trainees (five males, seven females) and 11 tutors (five males, six females) participated. Main themes that emerged were (in)consistency and contradiction, confidence, acculturation, and continuation and perpetuation. Despite having an awareness of the importance and potential benefits, an evidence based approach did not seem to be routinely or consistently implemented in practice. Confidence in products was largely derived from personal use and patient feedback. A lack of discussion about evidence was justified on the basis of not wanting to lessen patient confidence in requested product(s) or possibly negating the placebo effect. Trainees became acculturated to 'real-life' practice; university teaching and evidence was deemed less relevant than meeting customer expectations. The tutor's actions were mirrored by their trainee resulting in continuation and perpetuation of the same professional attitudes and behaviours. CONCLUSIONS: Evidence appeared to have limited influence on OTC decision making. The tutor played a key role in the trainee's professional development. More work could be performed to investigate how evidence can be regarded as relevant and something that is consistently implemented in practice. PMID- 25494962 TI - miR-26a promoted by interferon-alpha inhibits hepatocellular carcinoma proliferation and migration by blocking EZH2. AB - BACKGROUNDS: Interferon (IFN)-alpha has been used to treat hepatocellular carcinoma (HCC). Here, we report that the IFN-alpha-induced microRNA-26a (miR 26a) can inhibit HCC proliferation and invasion by suppressing enhancer of zeste homologue 2 (EZH2) expression in tumor cells. MATERIALS AND METHODS: First, the miR-26a transcription level was quantified by real-time quantitative PCR in the HCC specimens from IFN-alpha-treated HCC patients. Next, we transfected HepG2 cells with miR-26a mimics and miR control, and then we investigated the influence of miR-26a mimic transfection on HepG2 cell proliferation and invasion. RESULTS: It was shown that there was increased miR-26a accompanied with downregulated EZH2 expression in the HCC specimens, and EZH2 mRNA levels were inversely correlated with miR-26a expression. There was a dose-response correlation between the IFN alpha dosage and EZH2 expression. In addition, the miR-26a mimic transfection decreased the EZH2 expression level significantly in the transfected HepG2 cells and inhibited HepG2 cell proliferation and invasion effectively. CONCLUSION: Our results indicate that miR-26a exerts growth inhibition in HCC and that its inhibitory effect is mediated briefly by blocking EZH2 expression. PMID- 25494964 TI - Online colour training system for dental students: a comprehensive assessment of different training protocols. AB - The purpose of this study was to evaluate the training effect and to determine the optimal training protocol for a recently developed online colour training system. Seventy students participated in the evaluation. They first completed a baseline test with shade guides (SGT) and the training system (TST), and then trained with one of the three system training methods (Basic colour training for group E1, Vitapan Classical for E2, and Vitapan 3D-Master for E3) or shade guides (group C1) for 4 days. The control group (C2) received no training. The same test was performed after training and they finally completed a questionnaire. The correct matches after training increased in three experimental groups and group C1. Among experimental groups, the greatest improvement of correct matching number was achieved by group E3 (4.00 +/- 1.88 in SGT, 4.29 +/- 2.73 in TST), followed by E2 (2.29 +/- 2.73 in SGT, 3.50 +/- 3.03 in TST) and E1 (2.00 +/- 2.60 in SGT, 1.93 +/- 2.96 in TST). The difference between E3 and E1 was statistically significant (P = 0.036 in SGT, 0.026 in TST). The total average training time was shorter in group E2 (15.39 +/- 4.22 min) and E3 (17.63 +/- 5.22 min), with no significant difference between them. Subjective evaluations revealed that self confidence in colour matching were improved greater in group C1 and E3. In conclusion, all tested sections of the system effectively improved students' colour-matching ability. Among system training methods, Vitapan 3D-Master showed the best performance; it enabled greater shade-matching improvement, it saved time and was superior in subjective evaluations. PMID- 25494965 TI - Role of Mental Simulations in the Weight Loss Process. AB - Two experiments were conducted to verify the influence of various mental simulations on the effectiveness and persistence of weight loss processes. In study one, 40 female students (aged 19-27, M = 23) who were eager to lose weight were randomly assigned to one of four groups: positive outcome simulation, process simulations, mixed simulations (process followed by negative outcome), and control (no simulations). Students from the mixed and process simulation groups lost significantly more weight after five weeks than participants from the outcome simulation and control groups. A total of 106 females (aged 19-45, M = 29) participated in study two, in which five types of mental simulations were tested. Besides the images used in study one, process followed by positive outcome simulations and negative outcome simulations were implemented. Results showed that process followed by positive outcome simulations lead to the highest persistence in the weight loss process, while process followed by negative outcome simulations induced the greatest reduction in weight. Both studies revealed self-regulatory benefits from mental simulations in difficult and long term personal goal attainment. PMID- 25494963 TI - Aggregatibacter actinomycetemcomitans: virulence of its leukotoxin and association with aggressive periodontitis. AB - Periodontitis is an infection-induced inflammatory disease that causes loss of the tooth supporting tissues. Much focus has been put on comparison of the microbial biofilm in the healthy periodontium with the diseased one. The information arising from such studies is limited due to difficulties to compare the microbial composition in these two completely different ecological niches. A few longitudinal studies have contributed with information that makes it possible to predict which individuals who might have an increased risk of developing aggressive forms of periodontitis, and the predictors are either microbial or/and host-derived factors. The most conspicuous condition that is associated with disease risk is the presence of Aggregatibacter actinomycetemcomitans at the individual level. This Gram-negative bacterium has a great genetic variation with a number of virulence factors. In this review we focus in particular on the leukotoxin that, based on resent knowledge, might be one of the most important virulence factors of A. actinomycetemcomitans. PMID- 25494966 TI - Congenital hyperinsulinism, neonatal diabetes and the risk of malignancies: an international collaborative study. Preliminary communication. PMID- 25494967 TI - Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves' orbitopathy: a randomized controlled study. AB - BACKGROUND: Preliminary studies have shown that rituximab (RTX) is effective in the treatment of active Graves' orbitopathy (GO). METHODS: We conducted a double blind, randomized trial (European Clinical Trials Database [EudraCT] 2007-003910 33) to compare RTX with iv methylprednisolone (ivMP) in patients with active moderate to severe GO. Thirty-two patients were randomized to receive either ivMP (7.5 g) or RTX (2000 or 500 mg). The primary end point was the decrease of the clinical activity score of 2 points or to less than 3 at week 24. Changes of proptosis, lid fissure, diplopia and eye muscle motility, and quality of life score were secondary end points. The number of therapeutic responses, disease reactivation, and surgical procedures required during follow-up and the patients' quality of life were also assessed. RESULTS: The clinical activity score decreased with both treatments but more after RTX at 16, 20, and 24 weeks (P < .04, P < .02, P < .006, respectively), whether 1000 mg RTX twice or 500 mg RTX once was used (P = NS). At 24 weeks 100% of RTX patients improved compared with 69% after ivMP (P < .001). Disease reactivation was never observed in RTX patients but was observed in five after ivMP. Patients treated with RTX scored better motility at 52 weeks in both the right (P = .014) and the left eye (P = .026). Overall rehabilitative surgical procedures carried out during follow-up (at 76 wk) were 12 in 16 ivMP patients and 5 in 15 RTX patients (P = .049). CONCLUSIONS: The results of this trial confirm preliminary reports on a better therapeutic outcome of RTX in active moderate to severe GO, when compared with ivMP, even after a lower RTX dose. The better eye motility outcome, visual functioning of the quality of life assessment, and the reduced number of surgical procedures in patients after RTX seem to suggest a disease-modifying effect of the drug. PMID- 25494968 TI - Mobile teledermatology for a prompter and more efficient dermatological care in rural Mongolia. PMID- 25494969 TI - Transumbilical single-incision laparoscopic distal pancreatectomy: preliminary experience and comparison to conventional multi-port laparoscopic surgery. AB - BACKGROUND: Single-incision laparoscopic surgery (SILS), which has been demonstrated to be safely applied on kinds of surgeries, may represent an improvement over conventional multi-port laparoscopic surgery. However, there are still few clinical experiences of SILS in pancreatic surgery until now. In this study, we will summarize our experience of transumbilical single-incision laparoscopic distal pancreatectomy (TUSI-LDP), and compare its related parameters with conventional multi-port laparoscopic distal pancreatectomy (C-LDP). METHODS: A retrospective analysis was conducted for the patients who underwent C-LDP or TUSI-LDP in our department. The demographic data, operative parameters, and postoperative complications in the two groups were summarized and compared. RESULTS: Laparoscopic distal pancreatectomy was performed in a total of 21 cases, among which TUSI-LDP was performed in 14 cases. As far as the demographical results concerned, there were no significant differences between the two groups. The conversion to open surgery was conducted in one case in the TUSI-LDP group because of severe adhesion between pancreatic cyst and surrounding tissues, while in the C-LDP group the only one conversion was for the difficult detection of small lesion. The mean operating time and intraoperative blood loss in TUSI-LDP group was a little shorter (166.4 +/- 57.4 versus 202.1 +/- 122.5 minutes, p > 0.05, and 157.1 +/- 162.4 versus 168.6 +/- 157.4 ml, p > 0.05). The postoperative pain and post-operation lengths of hospital stay in the TUSI-LDP group were also less, though there was no significant statistical difference between the two groups. For the post-operation complications, in TUSI-LDP group the pancreatic leakage occurred in only one case, and ceased spontaneously with only a drain for 61 days. There were no other complications including postoperative hemorrhage, venous thrombosis, infections and so on in both groups. CONCLUSION: For the experienced laparoscopic surgeons, in selected patients, TUSI-LDP is a feasible technique, with excellent cosmetic effect, less postoperative pain and post operation lengths of hospital stay. With the experience accumulated, the operating time and intraoperative blood loss of TUSI-LDP could also gradually reduce. PMID- 25494971 TI - Internet addiction and physical and psychosocial behavior problems among rural secondary school students. AB - The aim of this study was to determine secondary school students' levels of Internet addiction and the physical and psychosocial behavior problems they face while using the Internet. This descriptive study was conducted in three state secondary schools in a rural area in the western part of Turkey. This study's sample consisted of 549 students who agreed to participate, with the consent of their families, and who had an Internet connection at home. The data were evaluated using t-tests and variance analyses. In this study the students' score of Internet addiction was at medium level (mean addiction score 44.51 +/- 17.90). There were significant differences between the students' Internet addiction scores and the presence of physical behavior problems (going to bed late, skipping meals, eating meals in front of the computer) and psychosocial behavior problems (suffering from conditions such as restlessness, anger, heart palpitations, or tremors when they could not connect to the Internet, decreased relationships with family and friends, feelings of anger, arguing with parents, and finding life boring and empty without an Internet connection). PMID- 25494970 TI - Patterns of social inequalities across pregnancy and birth outcomes: a comparison of individual and neighborhood socioeconomic measures. AB - BACKGROUND: This paper identifies patterns of health inequalities (consistency and magnitude) of socioeconomic disparities for multiple maternal and child health (MCH) outcomes that represent different health care needs of mothers and infants. METHODS: Using cross-sectional national data (unweighted sample = 6,421, weighted =76,508) from the Canadian Maternity Experiences Survey linked with 2006 Canadian census data, we categorized 25 health indicators of mothers of singletons into five groups of MCH outcomes (A. maternal and infant health status indicators; B. prenatal care; C. maternal experience of labor and delivery; D. neonatal medical care; and E. postpartum infant care and maternal perceptions of health care services). We then examined the association of these health indicators with individual socioeconomic position (SEP) (education and income), neighborhood SEP and combined SEP (a four-level measure of low and high individual and neighborhood SEP), and compared the magnitude (odds ratios and 95% confidence intervals) and direction of the associations within and between MCH outcome groups. RESULTS: We observed consistent positive gradients of socioeconomic inequalities within most groups and for 23/25 MCH outcomes. However, more significant associations and stronger gradients were observed for the MCH outcomes in the maternal and infant health status group as opposed to other groups. The neonatal medical care outcomes were weakly associated with SEP. The direction of associations was negative between some SEP measures and HIV testing, timing of the first ultrasound, caesarean section, epidural for vaginal births, infant needing non-routine neonatal care after discharge and any breastfeeding at 3 or 6 months. Gradients were steep for individual SEP but moderate for neighborhood SEP. Combined SEP had no consistent gradients but the subcategory of low individual-high neighborhood SEP often showed the poorest health outcomes compared to the categories within this SEP grouping. CONCLUSION: By examining SEP gradients in multiple MCH outcomes categorized into groups of health care needs, we identified large and consistent inequalities both within and between these groups. Our results suggest differences in pathways and mechanisms contributing to SEP inequalities across groups of MCH outcomes that can be examined in future research and inform prioritization of policies for reducing these inequalities. PMID- 25494972 TI - Sodium-induced hyperhydration decreases urine output and improves fluid balance compared with glycerol- and water-induced hyperhydration. AB - Before 2010, which is the year the World Anti-Doping Agency banned its use, glycerol was commonly used by athletes for hyperhydration purposes. Through its effect on osmoreceptors, we believe that sodium could prove a viable alternative to glycerol as a hyperhydrating agent. Therefore, this study compared the effects of sodium-induced hyperhydration (SIH), glycerol-induced hyperhydration (GIH) and water-induced hyperhydration (WIH) on fluid balance responses. Using a randomized, double-blind and counterbalanced protocol, 17 men (21 +/- 3 years, 64 +/- 6 kg fat-free mass (FFM)) underwent three 3-h hyperhydration protocols during which they ingested, over the first 60-min period, 30 mL/kg FFM of water with (i) an artificial sweetener (WIH); (ii) an artificial sweetener + 7.45 g/L of table salt (SIH); or (iii) an artificial sweetener + 1.4 g glycerol/kg FFM (GIH). Changes in body weight (BW), urine production, fluid retention, hemoglobin, hematocrit, plasma volume, and perceptual variables were monitored throughout the 3-h trials. After 3 h, SIH was associated with significantly (p < 0.05) lower hemoglobin, hematocrit (SIH: 43.1% +/- 2.8%; GIH: 44.9% +/- 2.4%), and urine production, as well as greater BW, fluid retention (SIH: 1144 +/- 294 mL; GIH: 795 +/- 337 mL), and plasma volume (SIH: 11.9% +/- 12.0%; GIH: 4.0% +/- 6.0%) gains, compared with GIH and WIH. No significant differences in heart rate or abdominal discomfort were observed between treatments. In conclusion, our results indicate that SIH is a superior hyperhydrating technique than, and proves to be a worthwhile alternative to, GIH. PMID- 25494973 TI - Muscle-tendon unit stiffness does not independently affect voluntary explosive force production or muscle intrinsic contractile properties. AB - This study examined the relationship of muscle-tendon unit (MTU) stiffness and explosive force production during voluntary and evoked contractions of the knee extensors. Thirty-four untrained participants performed a series of explosive voluntary and electrically evoked (octets (8 pulses, 300 Hz) via femoral nerve stimulation) isometric contractions. Maximum voluntary force (MVF) was assessed during maximum voluntary contractions. Explosive force production was assessed as the time taken, from force onset (0 N), to achieve specific levels of absolute (25-300 N) and relative force (5%-75% MVF) during the explosive contractions. Ultrasonic images of the vastus lateralis were recorded during 10-s ramp contractions to assess MTU stiffness, which was expressed in absolute (N . mm( 1)) and relative (to MVF and resting tendon-aponeurosis length) terms. Bivariate correlations suggested that absolute MTU stiffness was associated with voluntary explosive force (time to achieve 150-300 N: r = -0.35 to -0.54, P < 0.05). However, no relationships between stiffness and voluntary explosive force were observed when the influence of MVF was removed, either via partial correlations of absolute values (P >= 0.49) or considering relative values (P >= 0.14). Similarly, absolute MTU stiffness was related to explosive force during evoked octet contractions (r = -0.41 to -0.64, P < 0.05), but these correlations were no longer present when accounting for the influence of MVF (P >= 0.15). Therefore, once maximum strength was considered, MTU stiffness had no independent relationship with voluntary explosive force production or the evoked capacity for explosive force. PMID- 25494975 TI - Molecular Mechanism of Lead-Induced Superoxide Dismutase Inactivation in Zebrafish Livers. AB - Lead toxicity has been proved to be related with inducing oxidative stress of organisms and causing inactivation of antioxidant enzymes, the mechanism of which remains unknown. This study investigated and compared superoxide dismutase (Cu/Zn SOD) activity inhibited in lead-treated zebrafish livers and explored the mechanism of SOD inactivation by lead at the molecular level using multiple spectroscopic techniques, isothermal titration calorimetric (ITC) measurement, molecular docking study and ICP-AES detection. Results showed lead exposure decreased SOD activities in zebrafish livers due to direct interactions between lead and SOD, resulting in conformational and functional changes of the enzyme. To be specific, Studies at the molecular level indicated that lead bound into the active site channel of SOD, hindered the path of the catalytic substrate (O(2)( *)), damaged its skeleton conformation and secondary structure, and interacted with the enzymatically related residue (Arg 141) through electrostatic forces (DeltaH < 0, DeltaS > 0), and caused the release of Cu(2+) and Zn(2+) from the catalytic pocket of SOD. This work shows a correlation between results on organismal and molecular levels, and obtains a possible model hypothesizing mechanisms of lead toxicity using in vitro experiments instead of in vivo ones. PMID- 25494974 TI - Energy intake over 2 days is unaffected by acute sprint interval exercise despite increased appetite and energy expenditure. AB - A cumulative effect of reduced energy intake, increased oxygen consumption, and/or increased lipid oxidation could explain the fat loss associated with sprint interval exercise training (SIT). This study assessed the effects of acute sprint interval exercise (SIE) on energy intake, subjective appetite, appetite related peptides, oxygen consumption, and respiratory exchange ratio over 2 days. Eight men (25 +/- 3 years, 79.6 +/- 9.7 kg, body fat 13% +/- 6%; mean +/- SD) completed 2 experimental treatments: SIE and recovery (SIEx) and nonexercise control. Each 34-h treatment consisted of 2 consecutive 10-h test days. Between 0800-1800 h, participants remained in the laboratory for 8 breath-by-breath gas collections, 3 buffet-type meals, 14 appetite ratings, and 4 blood samples for appetite-related peptides. Treatment comparisons were made using 2-way repeated measures ANOVA or t tests. An immediate, albeit short-lived (<1 h), postexercise suppression of appetite and increase in peptide YY (PYY) were observed (P < 0.001). However, overall hunger and motivation to eat were greater during SIEx (P < 0.02) without affecting energy intake. Total 34-h oxygen consumption was greater during SIEx (P = 0.04), elicited by the 1491-kJ (22%) greater energy expenditure over the first 24 h (P = 0.01). Despite its effects on oxygen consumption, appetite, and PYY, acute SIE did not affect energy intake. Consequently, if these dietary responses to SIE are sustained with regular SIT, augmentations in oxygen consumption and/or a substrate shift toward increased fat use postexercise are most likely responsible for the observed body fat loss with this type of exercise training. PMID- 25494976 TI - Rural Affordable Care Act outreach and enrollment: what we learned during the first marketplace open enrollment period. AB - As part of the Patient Protection and Affordable Care Act (Affordable Care Act) of 2010, 2 new opportunities for health care coverage were established for many uninsured individuals beginning on January 1, 2014. The first opportunity was through Medicaid expansion where states had the opportunity to expand Medicaid coverage to individuals with household incomes up to 133% of the federal poverty level. The second opportunity was through the establishment of Health Insurance Marketplaces where individuals could purchase private health plans and potentially qualify for financial assistance in paying for their plans. The Office of Rural Health Policy (ORHP) provided supplemental grant awards to help stimulate Affordable Care Act outreach and education efforts in rural communities that were being served by the Rural Health Care Services Outreach (Outreach) Grant Program. As a result, Outreach grantees enrolled 9,300 rural Americans during the initial Open Enrollment period. Valuable outreach and enrollment lessons were learned from rural communities based on discussions with the Outreach grantees who received the supplemental funding. These lessons will help rural communities prepare for the next Open Enrollment period. PMID- 25494977 TI - Target-triggering multiple-cycle amplification strategy for ultrasensitive detection of adenosine based on surface plasma resonance techniques. AB - An ultrasensitive protocol for surface plasma resonance (SPR) detection of adenosine is designed with the aptamer-based target-triggering cascade multiple cycle amplification, and streptavidin-coated Au-NPs (Au NPs-SA) enhancement to enhance the SPR signals. The cascade amplification process consists of the aptamer-based target-triggering nicking enzyme signaling amplification (T-NESA), the nicking enzyme signaling amplification (NESA) and the hybridization chain reaction (HCR), the entire circle amplification process is triggered by the target recognition of adenosine. Upon recognition of the aptamer to target adenosine, DNA s1 is released from the aptamer and then hybridizes with hairpin DNA (HP1). The DNA s1 can be dissociated from HP1 under the reaction of nicking endonuclease to initiate the next hybridization and cleavage process. Moreover, the products of the upstream cycle (T-NESA) (DNA s2 and s3) could act as the "DNA trigger" of the downstream cycle (NESA and HCR) to generate further signal amplification, resulting in the immobilization of abundant Au NPs-SA on the gold substrate, and thus significant SPR enhancement is achieved due to the electronic coupling interaction between the localized surface plasma of Au NPs and the surface plasma wave. This detection method exhibits excellent specificity and sensitivity toward adenosine with a detection limit of 4 fM. The high sensitivity and specificity make this method a great potential for detecting biomolecules with trace amounts in bioanalysis and clinical biomedicine. PMID- 25494978 TI - Immunoadsorption therapy in dilated cardiomyopathy. AB - Dilated cardiomyopathy is a common myocardial disease characterized by ventricular chamber enlargement and systolic dysfunction that result in heart failure. In addition to genetic predisposition, viral infection and myocardial inflammation play a causal role in the disease process of dilated cardiomyopathy. Experimental and clinical studies suggest that activation of the humoral immune system, with production of circulating cardiac autoantibodies, plays an important functional role in the development and progression of cardiac dysfunction in patients with dilated cardiomyopathy. Small open-controlled studies showed that removal of circulating antibodies by immunoadsorption results in improvement of cardiac function and decrease in myocardial inflammation. At present, immunoadsorption is an experimental treatment option for improvement of cardiac function - therapy that calls for confirmation by a placebo-controlled multicenter study. PMID- 25494979 TI - From international health to global health: how to foster a better dialogue between empirical and normative disciplines. AB - BACKGROUND: Public health recommendations are usually based on a mixture of empirical evidence and normative arguments: to argue that authorities ought to implement an intervention that has proven effective in improving people's health requires a normative position confirming that the authorities are responsible for improving people's health. While public health (at the national level) is based on a widely accepted normative starting point - namely, that it is the responsibility of the state to improve people's health - there is no widely accepted normative starting point for international health or global health. As global health recommendations may vary depending on the normative starting point one uses, global health research requires a better dialogue between researchers who are trained in empirical disciplines and researchers who are trained in normative disciplines. DISCUSSION: Global health researchers with a background in empirical disciplines seem reluctant to clarify the normative starting point they use, perhaps because normative statements cannot be derived directly from empirical evidence, or because there is a wide gap between present policies and the normative starting point they personally support. Global health researchers with a background in normative disciplines usually do not present their work in ways that help their colleagues with a background in empirical disciplines to distinguish between what is merely personal opinion and professional opinion based on rigorous normative research. If global health researchers with a background in empirical disciplines clarified their normative starting point, their recommendations would become more useful for their colleagues with a background in normative disciplines. If global health researchers who focus on normative issues used adapted qualitative research guidelines to present their results, their findings would be more useful for their colleagues with a background in empirical disciplines. Although a single common paradigm for all scientific disciplines that contribute to global health research may not be possible or desirable, global health researchers with a background in empirical disciplines and global health researchers with a background in normative disciplines could present their 'truths' in ways that would improve dialogue. This paper calls for an exchange of views between global health researchers and editors of medical journals. PMID- 25494981 TI - Protein domain evolution is associated with reproductive diversification and adaptive radiation in the genus Eucalyptus. AB - Eucalyptus is a pivotal genus within the rosid order Myrtales with distinct geographic history and adaptations. Comparative analysis of protein domain evolution in the newly sequenced Eucalyptus grandis genome and other rosid lineages sheds light on the adaptive mechanisms integral to the success of this genus of woody perennials. We reconstructed the ancestral domain content to elucidate the gain, loss and expansion of protein domains and domain arrangements in Eucalyptus in the context of rosid phylogeny. We used functional gene ontology (GO) annotation of genes to investigate the possible biological and evolutionary consequences of protein domain expansion. We found that protein modulation within the angiosperms occurred primarily on the level of expansion of certain domains and arrangements. Using RNA-Seq data from E. grandis, we showed that domain expansions have contributed to tissue-specific expression of tandemly duplicated genes. Our results indicate that tandem duplication of genes, a key feature of the Eucalyptus genome, has played an important role in the expansion of domains, particularly in proteins related to the specialization of reproduction and biotic and abiotic interactions affecting root and floral biology, and that tissue specific expression of proteins with expanded domains has facilitated subfunctionalization in domain families. PMID- 25494980 TI - Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib. AB - BACKGROUND: Prostate cancer is the second leading cause of male cancer death in developed countries. Although the role of angiogenesis in its progression is well established, the efficacy of anti-angiogenic therapy is not clearly proved. Whether this could depend on differential responses between tumor and normal endothelial cells has not been tested. METHODS: We isolated and characterized three lines of endothelial cells from prostate cancer and we tested the effect of Sunitinib and Sorafenib, and the combined treatment with the anti-androgen Casodex, on their angiogenic functions. RESULTS: Endothelial cells isolated from prostate tumors showed angiogenic properties and expression of androgen and vascular endothelial cell growth factor receptors. Sunitinib affected their proliferation, survival and motility while Sorafenib only showed a minor effect. At variance, Sunitinib and Sorafenib showed similar cytotoxic and anti-angiogenic effects on normal endothelial cells. Sorafenib and Sunitinib inhibited vascular endothelial cell growth factor receptor2 phosphorylation of prostate cancer endothelial cells, while they differentially modulated Akt phosphorylation as no inhibitory effect of Sorafenib was observed on Akt activation. The combined treatment of Casodex reverted the observed resistance to Sorafenib both on cell viability and on Akt activation, whereas it did not modify the response to Sunitinib. CONCLUSIONS: Our study demonstrates a resistant behavior of endothelial cells isolated from prostate cancer to Sorafenib, but not Sunitinib. Moreover, it shows the benefit of a multi-target therapy combining anti angiogenic and anti-hormonal drugs to overcome resistance. PMID- 25494982 TI - Jerusalem artichoke as low-cost fructose-rich feedstock for fossil fuels desulphurization by a fructophilic bacterium. AB - AIMS: Through biodesulphurization (BDS) is possible to remove the sulphur present in fossil fuels to carry out the very strict legislation. However, this biological process is limited by the cost of the culture medium, and thus, it is important to explore cheaper alternative carbon sources, such as Jerusalem artichoke (JA). These carbon sources usually contain sulphates which interfere with the BDS process. The goal of this work was to remove the sulphates from Jerusalem artichoke juice (JAJ) through BaCl2 precipitation viewing the optimization of dibenzothiophene (DBT) desulphurization by Gordonia alkanivorans strain 1B. METHODS AND RESULTS: Using a statistical design (Doehlert distribution), the effect of BaCl2 concentration (0.125-0.625%) and pH (5-9) was studied on sulphate concentration in hydrolysed JAJ. A validated surface response derived from data indicated that zero sulphates can be achieved with 0.5-0.55% (w/v) BaCl2 at pH 7; however, parallel BDS assays showed that the highest desulphurization was obtained with the juice treated with 0.5% (w/v) BaCl2 at pH 8.73. Further assays demonstrated that enhanced DBT desulphurization was achieved using hydrolysed JAJ treated in these optimal conditions. A total conversion of 400 MUmol l(-1) DBT into 2-hydroxybiphenyl (2-HBP) in <90 h was observed, attaining a 2-HBP maximum production rate of 28.2 MUmol l(-1) h(-1) and a specific production rate of 5.06 MUmol(-1) g(-1) (DCW) h(-1) . CONCLUSIONS: These results highlight the efficacy of the treatment applied to JAJ in making this agromaterial a promising low-cost renewable feedstock for improved BDS by the fructophilic strain 1B. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is a fundamental step viewing BDS application at the industrial level as it accounts a cost-effective production of the biocatalysts, one of the main drawbacks for BDS scale-up. PMID- 25494984 TI - Relationships between immunoglobulin and fat-soluble vitamins in colostrum of Japanese Black multiparous cows. AB - Data from 19 Japanese Black multiparous cows were collected to clarify the relationships among immunoglobulin (Ig) G, IgA, beta-carotene, vitamin A and alpha-tocopherol contents in colostrum of cows in order to evaluate the role of fat-soluble vitamins on colostral IgG and IgA production. Mean colostral IgG was 141 mg/mL, ranging from 65 to 208 mg/mL, whereas mean colostral IgA was 8.7 mg/mL, ranging from 1.0 to 34.6 mg/mL. Colostral IgG increased with aging in multiparous cows. There were positive correlations between colostral IgG and colostral vitamin A or colostral alpha-tocopherol in cows, and the higher adjusted R(2) was obtained in the prediction model of colostral IgG from age and colostral vitamin A. Colostral vitamin A was positively correlated with colostral beta-carotene or colostral alpha-tocopherol in cows, but there were no relationships between colostral IgA and colostral IgG or colostral fat-soluble vitamins. These results indicate that fat-soluble vitamin contents in colostrum of cows may change in similar patterns and high colostral vitamin A is related with high colostral IgG. PMID- 25494985 TI - Electron-Transfer Reactions of Electronically Excited Zinc Tetraphenylporphyrin with Multinuclear Ruthenium Complexes. AB - Transient absorption decay rate constants (kobs) for reactions of electronically excited zinc tetraphenylporphyrin ((3)ZnTPP*) with triruthenium oxo-centered acetate-bridged clusters [Ru3(MU3-O)(MU-CH3CO2)6(CO)(L)]2(MU-pz), where pz = pyrazine and L = 4-cyanopyridine (cpy) (1), pyridine (py) (2), or 4 dimethylaminopyridine (dmap) (3), were obtained from nanosecond flash-quench spectroscopic data (quenching constants, kq, for (3)ZnTPP*/1-3 are 3.0 * 10(9), 1.5 * 10 (9), and 1.1 * 10(9) M(-1) s(-1), respectively). Values of kq for reactions of (3)ZnTPP* with 1-3 and Ru3(MU3-O)(MU-CH3CO2)6(CO)(L)2 [L = cpy (4), py (5), dmap (6)] monomeric analogues suggest that photoinduced electron transfer is the main pathway of excited-state decay; this mechanistic proposal is consistent with results from a photolysis control experiment, where growth of characteristic near-IR absorption bands attributable to reduced (mixed-valence) Ru3O-cluster products were observed. PMID- 25494986 TI - 2014 reports of the Regional Associations. AB - Includes the 2014 reports of the following Regional Associations: Eastern Psychological Association; Midwestern Psychological Association; New England Psychological Association; Rocky Mountain Psychological Association; Southeastern Psychological Association; Southwestern Psychological Association; Western Psychological Association; and the Southern Society for Philosophy and Psychology. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25494991 TI - Harrison Gough (1921-2014). AB - This article memorializes Harrison Gough (1921-2014), a major leader in the field of personality assessment. Gough's most important contribution to psychology was the development of the California Psychological Inventory (CPI), which continues to have immense influence on applied psychology. Further highlights of Gough's career and professional contributions are noted. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25494992 TI - Alvin R. Mahrer (1927-2014). AB - This article memorializes Alvin R. Mahrer (1927-2014), a founder of experiential psychotherapy. Highlights of Mahrer's career and professional contributions are noted. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25494993 TI - E. Mark Stern (1929-2014). AB - This article memorializes E. Mark Stern (1929 -2014), a clinical psychologist who found his ideological home in humanistic and existential psychology. Highlights of Stern's career and professional contributions are noted. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25494994 TI - The White House BRAIN Initiative has the potential to further strengthen multidisciplinary research and training in psychology. AB - Comments on the original article by Robiner et al. (see record 2014-07939-001) regarding psychologists in medical schools and academic medical center settings. The current authors also discuss how to advance training in psychology using the Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25494995 TI - Psychology departments in medical schools: there's one in Canada, eh? AB - Comments on the original article by Robiner et al. (see record 2014-07939-001) regarding psychologists in medical schools and academic medical center settings. Robiner et al. reported that their extensive review "revealed no independent departments of psychology in U.S. medical schools." The current authors note north of the border in Canada there is one department of psychology in a medical school. The Department of Clinical Health Psychology has been a department within the Faculty of Medicine of the University of Manitoba since 1995. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 25494997 TI - Masking as an effective quality control method for next-generation sequencing data analysis. AB - BACKGROUND: Next generation sequencing produces base calls with low quality scores that can affect the accuracy of identifying simple nucleotide variation calls, including single nucleotide polymorphisms and small insertions and deletions. Here we compare the effectiveness of two data preprocessing methods, masking and trimming, and the accuracy of simple nucleotide variation calls on whole-genome sequence data from Caenorhabditis elegans. Masking substitutes low quality base calls with 'N's (undetermined bases), whereas trimming removes low quality bases that results in a shorter read lengths. RESULTS: We demonstrate that masking is more effective than trimming in reducing the false-positive rate in single nucleotide polymorphism (SNP) calling. However, both of the preprocessing methods did not affect the false-negative rate in SNP calling with statistical significance compared to the data analysis without preprocessing. False-positive rate and false-negative rate for small insertions and deletions did not show differences between masking and trimming. CONCLUSIONS: We recommend masking over trimming as a more effective preprocessing method for next generation sequencing data analysis since masking reduces the false-positive rate in SNP calling without sacrificing the false-negative rate although trimming is more commonly used currently in the field. The perl script for masking is available at http://code.google.com/p/subn/. The sequencing data used in the study were deposited in the Sequence Read Archive (SRX450968 and SRX451773). PMID- 25495000 TI - Host-guest interactions derived multilayer perylene diimide thin film constructed on a scaffolding porphyrin monolayer. AB - The development of methods to grow well-ordered chromophore thin films on solid substrates is of importance because such surface-associated arrays have potential applications in the generation of functional electronic and optical materials and devices. In this article, we demonstrate a straightforward layer-by-layer (LBL) supramolecular deposition strategy to prepare numerous layers (up to 19) of functionalized perylene diimide (PDI) chromophores built upon a covalent scaffolding multivalent porphyrin monolayer. Our thin film formation strategy employs water as the immersion solvent and exploits the beta-cyclodextrin adamantane host-guest couple in addition to PDI based aromatic stacking. Within the resultant film the porphyrin scaffold is oriented close to parallel to the glass substrate while the PDI chromophores are aligned closer to the surface normal. Together, the porphyrin monolayer and the multi-PDI layers exhibit a large absorption bandwidth in the visible spectrum. Importantly, because a self assembly strategy was utilized, when a single monolayer of PDI is deposited on the porphyrin scaffolding layer, this PDI monolayer can be readily disassembled by washing with DMF leading to the regeneration of the porphyrin monolayer. The PDI thin film can subsequently be regrown from the regenerated porphyrin surface. The reported LBL strategy will be of broad interest for researchers developing well-organized chromophoric films and materials due to its simplicity as well as the added advantage of being performed in sustainable and cost-effective aqueous media. PMID- 25494999 TI - Lipid raft-based membrane order is important for antigen-specific clonal expansion of CD4(+) T lymphocytes. AB - BACKGROUND: Lipid rafts are cholesterol and saturated lipid-rich, nanometer sized membrane domains that are hypothesized to play an important role in compartmentalization and spatiotemporal regulation of cellular signaling. Lipid rafts contribute to the plasma membrane order and to its spatial asymmetry, as well. The raft nanodomains on the surface of CD4(+) T lymphocytes coalesce during their interaction with antigen presenting cells (APCs). Sensing of foreign antigen by the antigen receptor on CD4(+) T cells occurs during these cell-cell interactions. In response to foreign antigen the CD4(+) T cells proliferate, allowing the expansion of few antigen-specific primary CD4(+) T cell clones. Proliferating CD4(+) T cells specialize in their function by undergoing differentiation into appropriate effectors tailored to mount an effective adaptive immune response against the invading pathogen. RESULTS: To investigate the role of lipid raft-based membrane order in the clonal expansion phase of primary CD4(+) T cells, we have disrupted membrane order by incorporating an oxysterol, 7-ketocholesterol (7-KC), into the plasma membrane of primary CD4(+) T cells expressing a T cell receptor specific to chicken ovalbumin323-339 peptide sequence and tested their antigen-specific response. We report that 7-KC, at concentrations that disrupt lipid rafts, significantly diminish the c Ovalbumin323-339 peptide-specific clonal expansion of primary CD4(+) T cells. CONCLUSIONS: Our findings suggest that lipid raft-based membrane order is important for clonal expansion of CD4(+) T cells in response to a model peptide. PMID- 25495002 TI - Cost efficiency of canagliflozin versus sitagliptin for type 2 diabetes mellitus. AB - OBJECTIVES: To compare 1-year clinical outcomes and cost efficiency of treating adults with type 2 diabetes mellitus (T2DM) with canagliflozin (300 mg/day) or sitagliptin (100 mg/day), both added on a background of metformin and sulfonylurea. STUDY DESIGN: An economic model integrated data from an active controlled, randomized trial, claims database analyses, and published literature. METHODS: The model adopted a US managed care payer perspective and included the clinical and economic impact of achieving specific clinical quality goals. The model was run separately for 2 single clinical quality metrics, glycated hemoglobin (A1C) < 7% (used as base case) or < 8%, and 4 composite metrics (A1C < 7% or < 8% combined with body mass index < 30 kg/m2 and blood pressure < 140/90 mm Hg or low-density lipoprotein cholesterol < 100 mg/dL). Cost savings of achieving versus not achieving metrics were derived from a claims database analysis. Drug and adverse event costs were included. RESULTS: In the base case, compared with sitagliptin 100 mg, treatment with canagliflozin 300 mg resulted in $215 in annual cost savings and 12.3 absolute percentage points more patients achieving goal. Similar findings were found across all other quality metrics (difference in proportion achieving goal ranging from 6.7% to 19.0% and annual savings ranging from $1 to $669). Canagliflozin remained cost saving versus sitagliptin in sensitivity analyses. CONCLUSIONS: Canagliflozin 300 mg may represent a cost-efficient T2DM treatment option versus sitagliptin 100 mg for patients on metformin plus sulfonylurea due to lower overall costs and better achievement of A1C and quality composite goals. PMID- 25495001 TI - Helicobacter pylori-induced Sonic Hedgehog expression is regulated by NFkappaB pathway activation: the use of a novel in vitro model to study epithelial response to infection. AB - BACKGROUND: Helicobacter pylori (H. pylori) infection leads to acute induction of Sonic Hedgehog (Shh) in the stomach that is associated with the initiation of gastritis. The mechanism by which H. pylori induces Shh is unknown. Shh is a target gene of transcription factor Nuclear Factor-kappaB (NFkappaB). We hypothesize that NFkappaB mediates H. pylori-induced Shh. MATERIALS AND METHODS: To visualize Shh ligand expression in response to H. pylori infection in vivo, we used a mouse model that expresses Shh fused to green fluorescent protein (Shh::GFP mice) in place of wild-type Shh. In vitro, changes in Shh expression were measured in response to H. pylori infection using 3-dimensional epithelial cell cultures grown from whole dissociated gastric glands (organoids). Organoids were generated from stomachs collected from the fundic region of control and mice expressing a parietal cell-specific deletion of Shh (PC-Shh(KO) mice). RESULTS: Within 2 days of infection, H. pylori induced Shh expression within parietal cells of Shh::GFP mice. Organoids expressed all major gastric cell markers, including parietal cell marker H(+) ,K(+) -ATPase and Shh. H. pylori infection of gastric organoids induced Shh expression; a response that was blocked by inhibiting NFkappaB signaling and correlated with IkappaB degradation. H. pylori infection of PC-Shh(KO) mouse-derived organoids did not result in the induction of Shh expression. CONCLUSION: Gastric organoids allow for the study of the interaction between H. pylori and the differentiated gastric epithelium independent of the host immune response. H. pylori induces Shh expression from the parietal cells, a response mediated via activation of NFkappaB signaling. PMID- 25495003 TI - Ethnic disparity in prevalence of diabetic kidney disease in an Asian primary healthcare cluster. AB - AIMS: Diabetic kidney disease (DKD) incidence is rising in Singapore. While measures to prevent onset and early detection of diabetes as well as optimal diabetes and blood pressure control are important, early detection and treatment of DKD at primary care are crucial to ameliorate its course. This study aimed to evaluate the prevalence of DKD in a primary care cluster in Singapore and identify its risk factors in a multi-ethnic Asian population. METHODS: A total of 57,594 patients with type 2 diabetes mellitus (T2DM) followed-up at the National Healthcare Group Polyclinics with estimated glomerular filtration rate and at least two urine albumin/creatinine ratio (UACR) were stratified into DKD stages: normoalbuminuria (UACR <30 mg/g), microalbuminuria (MI, UACR 30-299 mg/g), macroalbuminuria (MA, >=300 mg/g) and renal impairment (RI, estimated glomerular filtration rate eGFR <60 mL/min per 1.73 m(2)). Factors associated with DKD stages were evaluated. RESULTS: Overall DKD prevalence (T2DM with MI, MA or RI) was high at 52.5%; 32.1% had MI, 5.3% had MA and 15.1% had RI. DKD prevalence within ethnic subpopulations was different: 52.2% of Chinese, 60.4% of Malays and 45.3% of Indians had DKD, respectively. Malays had a 1.42-fold higher DKD prevalence, while Indians had a 0.86-fold lower. Other independent risk factors were age, female gender, duration of diabetes and hypertension, HbA1c and body mass index. CONCLUSION: The high prevalence of DKD and its interethnic differences suggest need for additional measures to optimize the care of T2DM at primary care to mitigate its progression. PMID- 25495004 TI - Relationship satisfaction in lesbian and heterosexual couples before and after assisted reproduction: a longitudinal follow-up study. AB - BACKGROUND: More and more lesbian couples are planning parenthood through donor insemination and IVF and the number of planned lesbian families is growing in Sweden and other western countries. Research has shown that lesbian couples report as much overall satisfaction in their relationships as do heterosexual couples. However, although parenthood is highly desired, many parents are unaware of the demands of parenthood and the strain on their relationship that the arrival of the baby might bring. The aim of this study was to compare lesbian and heterosexual couples' perceptions of relationship satisfaction at a three-year follow up after assisted reproduction. METHODS: The present study is a part of the Swedish study on gamete donation, a prospective longitudinal cohort study. The present study constitutes a three-year follow up assessment of lesbian and heterosexual couples after assisted reproduction. Participants requesting assisted reproduction at all fertility clinics performing gamete donation in Sweden, were recruited consecutively during 2005-2008. A total of 114 lesbian women (57 treated women and 57 partners) and 126 heterosexual women and men (63 women and 63 men) participated. Participants responded to the ENRICH inventory at two time points during 2005-2011; at the commencement of treatment (time point 1) and about three years after treatment termination (time point 3). To evaluate the bivariate relationships between the groups (heterosexual and lesbian) and socio demographic factors Pearson's Chi- square test was used. Kolmogorov-Smirnov test was used for testing of normality, Mann-Whitney U- test to examine differences in ENRICH between the groups and paired samples t-test to examine scores over time. RESULTS: Lesbian couples reported higher relationship satisfaction than heterosexual couples, however the heterosexual couples satisfaction with relationship quality was not low. Both lesbian and heterosexual couples would be classified accordingly to ENRICH-typology as vitalized or harmonious couples. CONCLUSIONS: At a follow-up after assisted reproduction with donated sperm, lesbian couples reported stable relationships and a high satisfaction with their relationships, even when treatment was unsuccessful. PMID- 25495005 TI - A survey of population-based utility scores for cervical cancer prevention. AB - BACKGROUND: With human papillomavirus (HPV) vaccination introduced in a number of countries, there is considerable interest in evaluating the cost-effectiveness of HPV testing as the primary cervical screening test in these settings. However, the availability of utility scores for these newer interventions is limited. Our aim in this paper is to present utility scores for HPV vaccination, HPV testing and cytology based screening states among women targeted for cervical screening. METHODS: We invited a random sample of women targeted for cervical screening (aged 20-69 years) living in Sydney, Australia, to participate in a face-to-face interview. Participants were asked to indicate preferences (rank and utility scores) for 10 hypothetical health states relating to HPV vaccination, cytology and primary HPV screening, cervical precursor disease and early stage cervical cancer. Preferences for hypothetical health states were measured through ranking then a two-stage standard gamble. Each participant's own health state was measured as a utility score using the EQ5D. Potential differences by age were assessed using the Wilcox Rank Sum test. RESULTS: A maximum of 276 women were contacted, of which 43 (mean age 49 years) agreed to be interviewed (15.6%). The overall health state of women as measured by the EQ5D was 0.86 (95% CI: 0.83 0.89). Of the 10 health states, the highest ranked were 'normal cytology' and 'HPV vaccination' (equal 1st). States involving an HPV positive result with a subsequent normal cytology or colposcopy were ranked below those for low grade cytological abnormalities with or without a subsequent colposcopic normal result (ranks 3-4 vs. 4-5). However, mean utility scores were broadly similar for all health states, except cervical cancer. No significant differences in scores were identified between age groups. CONCLUSION: Our survey suggests health states relating to HPV testing are ranked below 'low grade cytology' disease abnormalities. However, this difference was minimal on the utility scale, as most values for health states were largely clustered. These results provide a preliminary set of non-clinic population-based utilities that may be used with other values to explore the economic implications of introducing HPV testing as a primary screening tool in the context of HPV vaccination. PMID- 25495006 TI - Experimental characterization of the nanoparticle size effect on the mechanical stability of nanoparticle-based coatings. AB - We present an experimental investigation of the mechanical stability of silica nanoparticle-based coatings as a function of the size of the nanoparticles. The coatings are built following a layer-by-layer procedure, alternating positive and negative surface charges. The mechanical stability of the multilayers is studied in water, on the basis of an ultrasonic cavitation test. The resistance of the coating to cavitation is found to remarkably increase with decreasing the size of the nanoparticles, indicating an increase of the cohesive energy density. The relative contribution of van der Waals and electrical double-layer interactions to the stability of the multilayer is discussed toward their size dependence. PMID- 25495007 TI - Genotype-Phenotype Correlations in Apical Variant Hypertrophic Cardiomyopathy. AB - OBJECTIVE: Hypertrophic cardiomyopathy is underscored by profound phenotypic and genotypic heterogeneity. Echocardiographically, hypertrophic cardiomyopathy can be categorized into four morphological subtypes: reverse curve, sigmoidal, neutral contour, and apical variant. Previous studies indicate that reverse curve hypertrophic cardiomyopathy is the strongest predictor of a positive genetic test. Little is known about the spectrum and prevalence of mutations and genotype phenotype correlations in apical hypertrophic cardiomyopathy. DESIGN: Between 1999 and 2007, 1053 patients with the diagnosis of hypertrophic cardiomyopathy (60% male, age at diagnosis 44.4 +/- 19 years) underwent sarcomeric genetic testing. Blinded to the genetic test results, each echocardiogram was scored for septal morphology and phenotyping was performed using the patient's medical record. Subset analysis was performed to elucidate the genotype, phenotype, and outcome of apical hypertrophic cardiomyopathy. RESULTS: Overall, 71 patients (7%) had apical hypertrophic cardiomyopathy on echocardiography (63% male, mean age 47.8 +/- 15 years, mean left ventricular wall thickness 19.8 +/- 6 mm). Left ventricular outflow tract obstruction was uncommon (seven patients; 10%). Eighteen patients (25%) had a positive genetic test, with the majority of mutations found in MYBPC3 (six; 35%) and MYH7 (six; 35%). Follow-up was available on 68 patients (96%) with a median age of 57.3 years (range 19.3-82 years). Mean follow-up was 5.5 years (range 0.1-18.2 years). There was no statistical difference between the occurrence rates of adverse events between genotype positive and genotype-negative groups. CONCLUSIONS: In this largest cohort of patients with genetic testing for hypertrophic cardiomyopathy, <10% exhibited apical disease. This least common subtype was associated with a negative genetic test result 75% of the time. In contrast to prior publications suggesting a predilection for ACTC1/TPM1 mutations in patients with apical hypertrophic cardiomyopathy, the two most common genotypes (MYBPC3-HCM and MYH7-HCM) remained most common among patients who had a positive genetic test. PMID- 25495008 TI - The quantity, quality and characteristics of Aboriginal and Torres Strait Islander Australian mentoring literature: a systematic review. AB - BACKGROUND: Mentoring is a key predictor of empowerment and prospectively a game changer in the quest to improve health inequities. This systematic review reports on the state of evidence on mentoring for Indigenous Australians by identifying the quantity, nature, quality and characteristics of mentoring publications. METHODS: Thirteen databases were searched using specific search strings from 1983 - 2012. Grey literature was also canvassed. The resultant publications were mined to identify their outputs, nature, and quality. These were then conceptually mined for their characteristics to develop a model of mentoring that included the initiating environments, facilitating environments, operational strategies and outcomes. RESULTS: 771 citations were identified; 37 full text publications met inclusion criteria and were assessed. Fifteen were eligible for review. Four of five original research publications used strong qualitative research designs. No publications were found before 1999; the largest proportion concentrated in 2011 (n = 4). Facilitating environments included: mapping participants' socio-cultural and economic context; formal mentoring practices with internal flexibility; voluntary participation; integrated models with wrap-around services; mentor/staff competencies; and sustained funding. Mentoring strategies comprised: holistic scaffolding approaches; respectful, trusting, one-on-one mentoring relationships; knowledgeable mentors; regular contact; longer-term relationships and exit strategies; culturally-tailored programs; personal and social development opportunities; and specialised skills and learning opportunities. Outcomes varied in accordance to program aims and included improvements in aspects of education and employment, offending behaviours, relationships, and personal, social and professional development. CONCLUSION: Little research explored the effectiveness of mentoring, captured its impact qualitatively or quantitatively, developed appropriate measures or assessed its cost effectiveness. There is a real need to evaluate programs particularly in terms of outcomes and, given there were no economic evaluations, costs. Commitments to improving Indigenous Australian mentoring rely on changes to funding structures and attitudes toward research. There was insufficient evidence to confidently prescribe a best practice model. Sufficient frequency of qualitative reporting between publications concluded that mentoring is a valuable empowerment strategy in the areas of health and wellbeing, education and employment and as a remedial and preventative measure in reducing offending behaviours. An evidence-informed mentoring model would take into account the key findings of the review. PMID- 25495009 TI - Granzyme B mediates both direct and indirect cleavage of extracellular matrix in skin after chronic low-dose ultraviolet light irradiation. AB - Extracellular matrix (ECM) degradation is a hallmark of many chronic inflammatory diseases that can lead to a loss of function, aging, and disease progression. Ultraviolet light (UV) irradiation from the sun is widely considered as the major cause of visible human skin aging, causing increased inflammation and enhanced ECM degradation. Granzyme B (GzmB), a serine protease that is expressed by a variety of cells, accumulates in the extracellular milieu during chronic inflammation and cleaves a number of ECM proteins. We hypothesized that GzmB contributes to ECM degradation in the skin after UV irradiation through both direct cleavage of ECM proteins and indirectly through the induction of other proteinases. Wild-type and GzmB-knockout mice were repeatedly exposed to minimal erythemal doses of solar-simulated UV irradiation for 20 weeks. GzmB expression was significantly increased in wild-type treated skin compared to nonirradiated controls, colocalizing to keratinocytes and to an increased mast cell population. GzmB deficiency significantly protected against the formation of wrinkles and the loss of dermal collagen density, which was related to the cleavage of decorin, an abundant proteoglycan involved in collagen fibrillogenesis and integrity. GzmB also cleaved fibronectin, and GzmB-mediated fibronectin fragments increased the expression of collagen-degrading matrix metalloproteinase-1 (MMP-1) in fibroblasts. Collectively, these findings indicate a significant role for GzmB in ECM degradation that may have implications in many age-related chronic inflammatory diseases. PMID- 25495010 TI - Examination of ceramic restoration adhesive coverage in cusp-replacement premolar using acoustic emission under fatigue testing. AB - BACKGROUND: This study investigates CAD/CAM ceramic cusp-replacing restoration resistance with and without buccal cusp replacement under static and dynamic cyclic loads, monitored using the acoustic emission (AE) technique. METHOD: The cavity was designed in a typical MODP (mesial-occlusal-distal-palatal) restoration failure shape when the palatal cusp has been lost. Two ceramic restorations [without coverage (WOC) and with (WC) buccal cuspal coverage with 2.0 mm reduction in cuspal height] were prepared to perform the fracture and fatigue tests with normal (200 N) and high (600 N) occlusal forces. The load versus AE signals in the fracture and fatigue tests were recorded to evaluate the restored tooth failure resistance. RESULTS: The results showed that non significant differences in load value in the fracture test and the accumulated number of AE signals under normal occlusal force (200 N) in the fatigue test were found between with and without buccal cuspal coverage restorations. The first AE activity occurring for the WOC restoration was lower than that for the WC restoration in the fracture test. The number of AE signals increased with the cyclic load number. The accumulated number of AE signals for the WOC restoration was 187, higher than that (85) for the WC restoration under 600 N in the fatigue test. CONCLUSION: The AE technique and fatigue tests employed in this study were used as an assessment tool to evaluate the resistances in large CAD/CAM ceramic restorations. Non-significant differences in the tested fracture loads and accumulated number of AE signals under normal occlusal force (200 N) between different restorations indicated that aggressive treatment (with coverage preparation) in palatal cusp-replacing ceramic premolars require more attention for preserving and protecting the remaining tooth. PMID- 25495011 TI - Fat Intravasation from Intraosseous Flush and Infusion Procedures. AB - STUDY HYPOTHESIS: The primary study objective was to delineate the procedural aspects of intraosseous (IO) infusions responsible for fat intravasation by testing the hypothesis that the fat content of effluent blood increases during IO infusions. METHODS: IO cannulas were inserted into the proximal tibiae of 35 anesthetized swine (Sus scrofa, 50.1 +/- 3.5 kg) and intravasated fat was assessed using a lipophilic fluoroprobe (Nile red) and by vascular ultrasound imaging. Effluent blood bone marrow fat was assessed at baseline, during flush, and with regimens of controlled infusion pressures (73-300 mmHg) and infusion flow rates (0.3-3.0 mL per second). Fat intravasation was also assessed with IO infusions at different tibial cannulation sites and in the distal femur. In 7 animals, the lipid uptake of alveolar macrophages and lung tissue assessed for fat embolic burden using oil red O stain 24 hours post infusion. Additionally, bone marrow shear-strain was assessed radiographically with IO infusions. RESULTS: Fat intravasation was observed during all IO infusion regimens, with subclinical pulmonary fat emboli persisting 24 hours post infusion. It was noted that initial flush was a significant factor in fat intravasation, low levels of intravasation occurred with infusions <=300 mmHg, fat intravasation and bone marrow shear-strain increased with IO infusion rates, and intravasation was influenced by cannula insertion site. Ultrasound findings suggest that echogenic particles consistent with fat emboli are carried in fast and slow venous blood flow fields. Echo reflective densities were observed to rise to the nondependent endovascular margins and coalesce in accordance with Stoke's law. In addition, ultrasound findings suggested that intravasated bone marrow fat was thrombogenic. CONCLUSION: Results suggest that in swine the intravasation of bone marrow fat is a common consequence of IO infusion procedures and that its magnitude is influenced by the site of cannulation and infusion forces. Although the efficacy and benefits of IO infusions for emergent care are well established, emergency care providers also should be cognizant that infusion procedures affect bone marrow fat intravasation. PMID- 25495013 TI - Lateral bracing of the tongue during the onset phase of alveolar stops: an EPG study. AB - Although raising the sides of the tongue to form a seal with the palate and upper teeth--lateral bracing--plays a key role in controlling airflow direction, providing overall tongue stability and building up oral pressure during alveolar consonant production, details of this articulatory gesture remain poorly understood. This study examined the dynamics of lateral bracing during the onset of alveolar stops /t/, /d/, /n/ produced by 15 typical English-speaking adults using electropalatography. Percent tongue palate contact in the lateral regions over a 150-ms period from the preceding schwa to stop closure was measured. Rapid rising of the sides of the tongue from the back towards the front during the 50 ms period before closure was observed, with oral stops showing significantly more contact than nasal stops. This feature corresponds to well-documented formant transitions detectable from acoustic analysis. Possible explanations for increased contact for oral stops and clinical implications are discussed. PMID- 25495012 TI - Effectiveness of school-based preventive interventions on adolescent alcohol use: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Preventive interventions for adolescents are an important priority within school systems. Several interventions have been developed, but the effectiveness of such interventions varies considerably between studies. The purpose of this study was to assess the effectiveness of universal school-based prevention programs on alcohol use among adolescents by using meta-analytic techniques. METHOD: A systematic literature search in the databases, PubMed (Medline), PsycINFO (Ovid), EMBASE (Ovid) and WEB of Science (ISI) was conducted to search for empirical articles published in the period January 1990 to August 2014. RESULTS: In total, 28 randomized controlled studies with 39,289 participants at baseline were included. Of these 28 articles, 12 studies (N = 16279) reported continuous outcomes (frequency of alcohol use and quantity of alcohol use), and 16 studies (N = 23010) reported categorical data (proportion of students who drank alcohol). The results of the random effects analyses showed that the overall effect size among studies reporting continuous outcomes was small and demonstrated a favorable effect from the preventive interventions (Hedges' g = 0.22, p < .01). The effect size among studies reporting categorical outcomes was not significant (OR = 0.94, p = .25). The level of heterogeneity between studies was found to be significant in most analyses. Moderator analyses conducted to explore the heterogeneity showed neither significant difference between the different school levels (junior high schools and high schools), nor between the varied program intensities (low, medium and high intensity programs). The meta-regression analyses examining continuous moderators showed no significant effects for age or gender. CONCLUSIONS: The findings from this meta analysis showed that, overall, the effects of school-based preventive alcohol interventions on adolescent alcohol use were small but positive among studies reporting the continuous measures, whereas no effect was found among studies reporting the categorical outcomes. Possible population health outcomes, with recommendations for policy and practice, are discussed further in this paper. PMID- 25495014 TI - Acta Psychiatrica Scandinavica--this issue. PMID- 25495015 TI - Psychiatry generating comparative respect: Happy New Year 2015. PMID- 25495016 TI - To be or not to be a psychiatrist--what is the question? PMID- 25495017 TI - Overcoming stigmatizing attitudes towards psychiatrists and psychiatry. PMID- 25495018 TI - Wet minds, dry minds, and the future of psychiatry as a science. PMID- 25495019 TI - Future perspectives on psychiatry. PMID- 25495020 TI - 'The past is a foreign country; they do things differently there'. PMID- 25495021 TI - Saving psychiatry from itself: will young psychiatrists choose authoritarian power or authoritative respect? PMID- 25495022 TI - Some thoughts how to improve the image of the psychiatry. PMID- 25495025 TI - Solution-processed pH-neutral conjugated polyelectrolyte improves interfacial contact in organic solar cells. AB - The intrinsic acidic nature of poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) hole-transporting layer (HTL) induces interfacial protonation and limits the device performance in organic solar cells based on basic pyridylthiadiazole units. By utilizing a pH neutral, water/alcohol soluble conjugated polyelectrolyte CPE-K as the HTL in p DTS(PTTh2)2:PC71BM solar cells, a 60% enhancement in PCE has been obtained with an increased V(bi), reduced R(s), and improved charge extraction. These effects originate from the elimination of interfacial protonation and energy barrier compared with the PEDOT:PSS HTL. PMID- 25495023 TI - Images of psychiatry and psychiatrists. AB - OBJECTIVE: This study surveyed medical teaching faculty to determine their attitudes toward psychiatry and psychiatrists. METHOD: We conducted a multisite survey of a probability sample of 1057 teaching medical faculty members from 15 academic teaching centers in the United Kingdom, Europe, and Asia stratified by early, middle, and late career stage. The average response rate across countries was 65%. RESULTS: The outstanding findings were that 90% of respondents considered that psychiatrists were not good role models for medical students, 84% thought psychiatric patients were unsuitable to be treated outside of specialized facilities, and 73% thought psychiatric patients were emotionally draining. We noted statistically significant differences by country, gender, career stage, and specialty. CONCLUSION: These results highlight why recruitment into psychiatry is problematic in many countries and suggest that greater attention should be given to improving the perception of psychiatrists as good role models and the efficacy of psychiatric treatments. PMID- 25495026 TI - High-Mobility Group Box-1 Modulates the Expression of Inflammatory and Angiogenic Signaling Pathways in Diabetic Retina. AB - PURPOSE: The expression of high-mobility group box-1 (HMGB1) is upregulated in epiretinal membranes and vitreous fluid from patients with proliferative diabetic retinopathy and in the diabetic retina. HMGB1 mediates inflammation, breakdown of the blood-retinal barrier and apoptosis in the diabetic retina. Here, we investigated inflammatory and angiogenic signaling pathways activated by HMGB1 in diabetic retina. METHODS: Human retinal microvascular endothelial cells (HRMEC) and retinas from 1-month diabetic rats and normal rats intravitreally injected with HMGB1 were studied using RT-PCR, Western blot analysis and co immunoprecipitation. We also studied the effect of the HMGB1 inhibitor glycyrrhizin on diabetes-induced biochemical changes in the retina. RESULTS: Diabetes and intravitreal injection of HMGB1 in normal rats induced significant upregulation of the mRNA levels of the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) receptor CXCR4 and protein levels of hypoxia-inducible factor 1alpha, early growth response-1, tyrosine kinase 2 and the CXCL12/CXCR4 chemokine axis. Constant glycyrrhizin intake from onset of diabetes did not affect the metabolic status of the diabetic rats, but it restored these increased mediators to control values. Stimulation of HRMEC with HMGB1 and intraviteral injection of HMGB1 significantly increased the expression of vascular endothelial growth factor (VEGF) and VEGF receptor-2. Co-immunoprecipitation studies showed that diabetes increased the interaction between CXCL12 and CXCR4 and between HMGB1 and receptor for advanced glycation end products (RAGE), but not between HMGB1 and the CXCL12/CXCR4 chemokine axis. CONCLUSIONS: Our findings suggest that HMGB1 activates inflammatory and angiogenic signaling pathways in diabetic retina mediated by RAGE. PMID- 25495027 TI - Socioeconomic and sociodemographic predictors of cancer-related information sources used by cancer survivors. AB - With 14 million cancer survivors in the United States, identifying and categorizing their use of sources of cancer-related information is vital for targeting effective communications to this growing population. In addition, recognizing socioeconomic and sociodemographic differences in the use of cancer related information sources is a potential mechanism for reducing health disparities in survivorship. Fourteen sources of information survivors (N = 519) used for cancer-related information were factor-analyzed to create a taxonomy of source use. The association between social determinants and use of these source types was analyzed in regression models. Factor analysis revealed 5 categories of information source use (mass media; Internet and print; support organizations; family and friends; health care providers), and use varied based on sociodemographic and socioeconomic characteristics. Higher education predicted increased use of all source categories except mass media. African American cancer survivors turned to health care providers as a source for cancer-related information less often than did White survivors. Social determinants predicted differences in the type of cancer-related information sources used. Providers and health communicators should target communication platforms based on the demographic profile of specific survivor audiences. PMID- 25495028 TI - Risk of cancer in the rectal remnant after ileorectal anastomosis in patients with familial adenomatous polyposis: single center experience. AB - BACKGROUND AND AIM: We aimed to evaluate the long-term risk of cancer in the rectal remnant in patients with familial adenomatous polyposis after ileorectal anastomosis. METHODS: Cumulative incidence and clinicopathological characteristics of cancer in the rectal remnant were retrospectively investigated in 27 patients with familial adenomatous polyposis who had undergone ileorectal anastomosis. RESULTS: During the follow-up period ranging from 3.0 to 35.0 years (median, 21.1 years), cancer in the rectal remnant developed in 10 patients. Cumulative risk of cancer in the rectal remnant 30 years after surgery was 57%. Five patients had metastases and three patients died of cancer in the rectal remnant after proctectomy. There was a trend towards a higher incidence of cancer in the rectal remnant in patients with small-intestinal adenoma and congenital hypertrophy of the retinal pigment epithelium. Multivariate analysis revealed that the ocular lesion was an independent risk factor associated with cancer in the rectal remnant. CONCLUSION: Subtotal colectomy with ileorectal anastomosis does not seem to be an appropriate prophylactic surgery in patients with familial adenomatous polyposis. PMID- 25495029 TI - Prevalence and molecular characterisation of human adenovirus in diarrhoeic children in Tanzania; a case control study. AB - BACKGROUND: Human adenovirus (HAdV) causes acute diarrhoea sporadically, as well as in outbreaks. Understanding the prevalence and types of HAdV in diarrhoea is important for control and preventive measures, especially in the African region where there is a high burden of diarrhoeal disease. The present study assessed the prevalence, molecular characteristics, seasonality and associated clinical features of HAdV infection Tanzanian children below two years of age with and without diarrhoea between 2010-2011. METHODS: Stool specimens, demographic and clinical information were collected in 690 cases and 545 controls. All stool samples were screened for HAdV-antigen using ELISA. Positive samples subsequently underwent real-time PCR and sequencing for molecular typing. RESULTS: HAdV was detected in 37 children, corresponding to a prevalence of 3.5% (24/690) in diarrhoeic and 2.4% (13/545) in non-diarrhoeic children (P > 0.05). Among HAdV infected children, the median age was significantly lower in diarrhoeic than in non-diarrhoeic children (10 vs. 14 months, P?0.001). More than half of HAdV infected (54.2%) were dehydrated as compared to diarrhoeic children without HAdV (45.8%, P = 0.01). The proportion of the enteric HAdV type 40/41 in diarrhoeic and non-diarrhoeic children was (50.0%, 12/24) and (46.2%, 6/13) respectively. Other HAdV types detected were; 1, 2, 7, 18, 19 and 31. The prevalence of adenovirus was not significantly different between rainy and dry seasons. HAdV was not detected in the 33 known HIV positive children. There was no significant association between HAdV infection and gender, nutritional status of the child and parent educational level. CONCLUSION: The present study provides further evidence of the contribution of adenovirus in causing gastroenteritis in young children, with symptomatic infection being significantly more prevalent in children below one year. We found similar prevalence of adenovirus in non diarrhoeic children and in diarrhoeic children. This first report on molecular epidemiology of human adenovirus in Tanzania observed diversity of HAdV types that circulate the study setting. The study findings suggest that HAdV is not an important cause of diarrhoea in young HIV-positive children. PMID- 25495030 TI - Outcome evaluation of the Palliative care Emphasis program on symptom management and Assessment for Continuous Medical Education: nationwide physician education project for primary palliative care in Japan. AB - OBJECTIVE: Palliative care is an essential part of medicine, but most physicians have had no formal opportunity to acquire basic skills in palliative care. In Japan, the Palliative care Emphasis program on symptom management and Assessment for Continuous Medical Education (PEACE) was launched to provide formal primary palliative care education for all physicians engaged in cancer care. This study sought to determine whether PEACE could improve physicians' knowledge of, practices in, and difficulties with palliative care. METHODS: In 2011, we conducted questionnaire-based surveys before, just after, and 2 months after completion of the PEACE program in physicians participating in the program at each of 15 designated cancer hospitals in Japan. Knowledge was measured using the palliative care knowledge questionnaire for PEACE (PEACE-Q). Practices and difficulties were evaluated using the Palliative Care self-reported Practice Scale (PCPS) and the Palliative Care Difficulties Scale (PCDS), respectively. RESULTS: Among 223 physicians participating in the program, 85 (38%) answered the follow-up survey. Significant improvements were noted on the PEACE-Q compared with baseline immediately after completion of the program, and this progress was maintained at 2 months (21.7 +/- 5.56 versus 29.5 +/- 2.10 versus 28.7 +/- 3.28, respectively; p < 0.0001). Similarly, significant improvements were noted for total scores on both the PCPS and the PCDS at 2 months after completion of the program (62.1 +/- 13.9 versus 69.6 +/- 9.94 [p < 0.0001] for the PCPS; 44.4 +/- 9.96 versus 39.4 +/- 10.7 [p < 0.0001] for the PCDS). CONCLUSIONS: The PEACE education program improved physicians' knowledge of, practices in, and difficulties with palliative care. PMID- 25495031 TI - Combining protein ratio p-values as a pragmatic approach to the analysis of multirun iTRAQ experiments. AB - iTRAQ labeling of peptides is widely used for quantitative comparison of biological samples using mass spectrometry. However, iTRAQ determined protein ratios have varying credibility depending on the number and quality of the peptide ratios used to generate them, and accounting for this becomes problematic particularly in the multirun scenario needed for larger scale biological studies. One approach to this problem relies on the use of sophisticated statistical global models using peptide ratios rather than working directly with the protein ratios, but these yield complex models whose solution relies on computational approaches such as stage-wise regression, which are nontrivial to run and verify. Here we evaluate an alternative pragmatic approach to finding differentially expressed proteins based on combining protein ratio p-values across experiments in a fashion similar to running a meta-analysis across different iTRAQ runs. Our approach uses the well-established Stouffer's Z-transform for combining p-values, alongside a ratio trend consistency measure, which we introduce. We evaluate this method with data from two iTRAQ experiments using plant and animal models. We show that in the specific context of iTRAQ data analysis this method has advantages of simplicity, high tolerance of run variability, low false discovery rate, and emphasis on proteins identified with high confidence. PMID- 25495032 TI - Catalytic spectrum of the penicillin-binding protein 4 of Pseudomonas aeruginosa, a nexus for the induction of beta-lactam antibiotic resistance. AB - Pseudomonas aeruginosa is an opportunistic Gram-negative bacterial pathogen. A primary contributor to its ability to resist beta-lactam antibiotics is the expression, following detection of the beta-lactam, of the AmpC beta-lactamase. As AmpC expression is directly linked to the recycling of the peptidoglycan of the bacterial cell wall, an important question is the identity of the signaling molecule(s) in this relationship. One mechanism used by clinical strains to elevate AmpC expression is loss of function of penicillin-binding protein 4 (PBP4). As the mechanism of the beta-lactams is PBP inactivation, this result implies that the loss of the catalytic function of PBP4 ultimately leads to induction of antibiotic resistance. PBP4 is a bifunctional enzyme having both dd carboxypeptidase and endopeptidase activities. Substrates for both the dd carboxypeptidase and the 4,3-endopeptidase activities were prepared by multistep synthesis, and their turnover competence with respect to PBP4 was evaluated. The endopeptidase activity is specific to hydrolysis of 4,3-cross-linked peptidoglycan. PBP4 catalyzes both reactions equally well. When P. aeruginosa is grown in the presence of a strong inducer of AmpC, the quantities of both the stem pentapeptide (the substrate for the dd-carboxypeptidase activity) and the 4,3-cross-linked peptidoglycan (the substrate for the 4,3-endopeptidase activity) increase. In the presence of beta-lactam antibiotics these altered cell-wall segments enter into the muropeptide recycling pathway, the conduit connecting the sensing event in the periplasm and the unleashing of resistance mechanisms in the cytoplasm. PMID- 25495033 TI - Decoding Ci: from partial degradation to inhibition. AB - Hedgehog is a morphogen, which is widely involved in the regulation of cell proliferation, differentiation and tissue patterning during development in both vertebrate and invertebrate, such as in coordination of eye, brain, gonad, gut and tracheal development. In invertebrate, Cubitus interruptus (Ci) modification process is the last identified step before transcriptional activation in the Hh signaling pathway. Ci can form a truncated repressor (Ci(R) /Ci75) or act as an activator (Ci(A) /Ci155) based on Hh gradient to regulate the expressions of target genes. The activity of Ci is mediated by different mechanisms, including processing, trafficking and degradation. While in vertebrate, Glioblastomas (Glis), homologs of Ci, play similar but more complex roles in the regulation of mammals Hh pathway. Hh signaling is responsible for a wide variety of processes during embryonic development and adult tissue homeostasis. Malfunction of Hh signaling could cause various diseases including birth defects and cancers. Enormous efforts were made in the past decades to explore the Hh pathway regulation and the results have provided us important insights into disease diagnosis and therapeutic treatment. In this review, we focus on a small branch of Hh pathway regulation based on studies in the Drosophila system, mainly about Ci degradation, aiming to explain how Ci is modified by different ubiquitin ligases due to the strong or moderate Hh signals and then been subjected to complete or partial degradation by proteasomes. Overall, we intend to offer an overview on how Ci responds to and relays Hh signals in a precise manner to control target genes expressions and ensures proper Hh signal transduction. PMID- 25495034 TI - Processes, contexts, and rationale for disinvestment: a protocol for a critical interpretive synthesis. AB - BACKGROUND: Practical solutions are needed to support the appropriate use of available health system resources as countries are continually pressured to 'do more with less' in health care. Increasingly, health systems and organizations are exploring the reassessment of possibly obsolete, inefficient, or ineffective health system resources and potentially redirecting funds to those that are more effective and efficient. Such processes are often referred to as 'disinvestment'. Our objective is to gain further understanding about: 1) whether how and under what conditions health systems decide to pursue disinvestment; 2) how health systems have chosen to undertake disinvestment; and 3) how health systems have implemented their disinvestment approach. METHODS/DESIGN: We will use a critical interpretive synthesis (CIS) approach, to develop a theoretical framework based on insights drawn from a range of relevant sources. We will conduct systematic searches of databases as well as purposive searches to identify literature to fill conceptual gaps that may emerge during our inductive process of synthesis and analysis. Two independent reviewers will assess search results for relevance and conceptually map included references. We will include all empirical and non empirical articles that focus on disinvestment at a system level. We will then extract key findings from a purposive sample of articles using frameworks related to government agendas, policy development and implementation, and health system contextual factors and then synthesize and integrate the findings to develop a framework about our core areas of interest. Lastly, we will convene a stakeholder dialogue with Canadian and international policymakers and other stakeholders to solicit targeted feedback about the framework (e.g., by identifying any gaps in the literature that we may want to revisit before finalizing it) and deliberating about barriers for developing and implementing approaches to disinvestment, strategies to address these barriers and about next steps that could be taken by different constituencies. DISCUSSION: Disinvestment is an emerging field and there is a need for evidence to inform the prioritization, development, and implementation of strategies in different contexts. Our CIS and the framework developed through it will support the actions of those involved in the prioritization, development, and implementation of disinvestment initiatives. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014013204. PMID- 25495035 TI - Combination of UV-C treatment and Metschnikowia pulcherrimas for controlling Alternaria rot in postharvest winter jujube fruit. AB - The potential of using antagonistic yeast Metschnikowia pulcherrimas alone or in combination with ultraviolet-C (UV-C) treatment for controlling Alternaria rot of winter jujube, and its effects on postharvest quality of fruit was investigated. The results showed that spore germination of Alternaria alternata was significantly inhibited by each of the 3 doses (1, 5, and 10 kJ m(-2) ) in vitro. In vivo, UV-C treatment (5 kJ m(-2) ) or antagonist yeast was capable of reducing the percentage of infected wounds and lesion diameter in artificially inoculated jujube fruits, however, in fruit treated with combination of UV-C treatment and M. pulcherrima, the percentage of infected wounds and lesion diameter was only 16.0% and 0.60 cm, respectively. The decay incidence on winter jujube fruits treated with the combination of UV-C treatment and M. pulcherrima was 23% after storage at 0 +/- 1 degrees C for 45 d followed by 22 degrees C for 7 d. None of the treatments impaired quality parameters of jujube fruit. Thus, the combination of UV-C radiation and M. pulcherrima could be an alternative to synthetic fungicides for controlling postharvest Alternaria rot of winter jujube. PMID- 25495037 TI - Cancer and the microbiome: potential applications as new tumor biomarker. AB - Microbial communities that colonize in humans are collectively described as microbiome. According to conservative estimates, about 15% of all types of neoplasms are related to different infective agents. However, current knowledge is not sufficient to explain how the microbiome contributes to the growth and development of cancers. Large and thorough studies involving colonized, diverse and complex microbiome entities are required to identify microbiome as a potential cancer marker and to understand how the immune system is involved in response to pathogens. This article reviews the existing evidence supporting the enigmatic association of transformed microbiome with the development of cancer through the immunological modification. Ascertaining the connection between microbiome and immunological responses with risk of cancer may direct to explaining significant advances in the etiology of cancer, potentially disclosing a novel paradigm of research for the management and prevention of cancer. PMID- 25495036 TI - Ectopic differentiation of melanocyte stem cells is influenced by genetic background. AB - Hair graying in mouse is attributed to the loss of melanocyte stem cell function and the progressive depletion of the follicular melanocyte population. Single gene, hair graying mouse models have pointed to a number of critical pathways involved in melanocyte stem cell biology; however, the broad range of phenotypic variation observed in human hair graying suggests that additional genetic variants involved in this process may yet be discovered. Using a sensitized approach, we ask here whether natural genetic variation influences a predominant cellular mechanism of hair graying in mouse, melanocyte stem cell differentiation. We developed an innovative method to quantify melanocyte stem cell differentiation by measuring ectopically pigmented melanocyte stem cells in response to the melanocyte-specific transgene Tg(Dct-Sox10). We make the novel observation that the production of ectopically pigmented melanocyte stem cells varies considerably across strains. The success of sensitizing for melanocyte stem cell differentiation by Tg(Dct-Sox10) sets the stage for future investigations into the genetic basis of strain-specific contributions to melanocyte stem cell biology. PMID- 25495038 TI - Fluorinated Fe(III) salophene complexes: optimization of tumor cell specific activity and utilization of fluorine labeling for in vitro analysis. AB - Fluorine-substituted iron(III) salophene complexes (salophene = N,N' bis(salicylidene)-1,2-phenylenediamine) were synthesized and evaluated for biological activity. All complexes showed growth inhibitory effects with IC50 values ranging from 0.05 to 2.45 MUM against HT-29 colon carcinoma as well as MCF 7 and MDA-MB-231 mammary carcinoma cells (cisplatin: 5.75, 12.72, 5.81 MUM, respectively). HR-CS MAS investigations revealed that the complexes were highly protein-bound already after an incubation period of 10 min and accumulated more effectively in tumor cells than cisplatin. Interestingly, the ligands were enriched in the cells too, indicating that the salophene moiety acts as a carrier ligand and mediates the uptake of the complexes. Furthermore, induction of apoptosis proved to be dependent on the substitution pattern as well as on the tumor cell line, as evidenced from the annexin V-FITC/PI assay. Most of the complexes, especially the highly active 5-Fe, showed tumor cell specific effects and no/less influence on the proliferation of T-cells generated from the peripheral blood of healthy individuals. PMID- 25495039 TI - Effects of Guanxinning injection on rat cytochrome P450 isoforms activities in vivo and in vitro. AB - 1. We aimed to investigate the regulatory effects of Guanxinning injection (GXNI) on activities of cytochrome P1A2 (CYP1A2), CYP2C11, CYP2D1 and CYP3A1/2 by probe drugs in rats in vivo and in vitro. 2. GXNI-treated and blank control groups were administered GXNI and physiological saline by caudal vein for 14 days consecutively, then they were given the probe drugs of caffeine (10 mg/kg), tolbutamide (10 mg/kg), metoprolol (20 mg/kg) and dapsone (10 mg/kg) by intraperitoneal injection. The blood samples were collected at different times for ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis. Changes of the pharmacokinetics parameters between the GXNI-treated and the blank control groups were used to evaluate the effects of GXNI on the four CYP450 isoforms in rats in vivo. After blood collection, the livers of rats were taken and made microsomes for in vitro tests. The relevant metabolites of phenacetin, tolbutamide, dextromethorphan and testosterone were analyzed quantitatively by high-performance liquid chromatography (HPLC) after microsome incubation. The statistical differences between the two groups were observed to detect the effects of GXNI on the four CYP450 isoforms in rats in vitro. 3. The in vivo and in vitro results demonstrated that GXNI could induce CYP1A2 activity in rats, but had no significant effects on CYP2C11, CYP2D1 and CYP3A1/2. PMID- 25495040 TI - Effect of Plum pox virus on chemical composition and fruit quality of plum. AB - The quality of fruit from PPV (Plum pox virus)-infected plum (Prunus domestica L.) trees was investigated during the last 3 weeks of ripening using healthy tree (T3), tree with short-term infection (T2), and tree with long-term infection (T1). The pomological variables (presence of necrosis on fruit, color of fruit, color of flesh, firmness, soluble solids content, and fruit weight) and composition of nutritive compounds (sugars and organic acids) and bioactive compounds (phenolics: anthocyanins, flavonols, and hydroxycinnamic acids) were evaluated. The results indicated that the PPV infection modified the ripening process (the most in T1) and the composition of nutritive and bioactive compounds in the healthy-looking part of the fruit. Long-term infected tree (T1) yielded fruit with the poorest pomological traits and with the most modified composition of nutritive and phenolic compounds. The short-term PPV infected tree also produced fruit with significantly altered phytochemicals composition, although the pomological traits had not changed significantly. PMID- 25495042 TI - TARP gamma-8 glycosylation regulates the surface expression of AMPA receptors. AB - TARP [transmembrane AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor regulatory protein] gamma-8 is an auxiliary subunit of AMPA receptors that is widely distributed in the hippocampus. It has been shown that TARP gamma-8 promotes surface expression of AMPA receptors; however, how TARP gamma-8 regulates the expression of AMPA receptors remains unclear. In the present study, we examined the effect of TARP glycosylation on AMPA receptor trafficking. We first showed that TARP gamma-8 is an N-glycosylated protein, which contains two glycosylation sites, Asn53 and Asn56, and compared this with the glycosylation of TARP gamma-2 and the AMPA receptor auxiliary protein CNIH-2 (cornichon homologue 2). We next examine the effect of TARP glycosylation on TARP trafficking and also on AMPA receptor surface expression. We find that TARP gamma 8 glycosylation is critical for surface expression of both TARP gamma-8 and GluA1 in heterologous cells and neurons. Specifically, knockdown of TARP gamma-8 causes a decrease in both total and surface AMPA receptors. We find that the expression of unglycosylated TARP gamma-8 in cultured neurons is unable to restore GluA1 expression fully. Furthermore, when the maturation of TARP gamma-8 is impaired, a large pool of immature GluA1 is retained intracellularly. Taken together, our data reveal an important role for the maturation of TARP gamma-8 in the trafficking and function of the AMPA receptor complex. PMID- 25495041 TI - Whole-Transcriptome profiling of formalin-fixed, paraffin-embedded renal cell carcinoma by RNA-seq. AB - BACKGROUND: Formalin-fixed paraffin-embedded (FFPE) tissue samples are routinely archived in the course of patient care and can be linked to clinical outcomes with long-term follow-up. However, FFPE tissues have degraded RNA which poses challenges for analyzing gene expression. Next-generation sequencing (NGS) is rapidly becoming accepted as an effective tool for measuring gene expressions for research and clinical use. However, the feasibility of NGS has not been firmly established when using FFPE tissue. RESULTS: We optimized strategies for whole transcriptome sequencing (RNA-seq) using FFPE tissue. Ribosomal RNA (rRNA) was successfully depleted by competitive hybridization using the Ribo-zeroTM Kit (Epicentre Biotechnologies), and rRNA sequence content was less than one percent for each library. Gene expression measured by FFPE RNA-seq was compared to two different standards: RNA-seq from fresh frozen (FF) tissue and quantitative PCR (qPCR). Both FF and FFPE tumors were sequenced on an Illumina Genome Analyzer IIX with an average of 10 million reads. The distribution of FPKMs (fragments per kilobase of exon per million fragments mapped) and number of detected genes were similar between FFPE and FF. RNA-seq expressions from FF and FFPE samples from the same renal cell carcinoma (RCC) correlated highly (r = 0.919 for tumor 1 and r = 0.954 for tumor 2). On hierarchical cluster analysis, samples clustered by patient identity rather than method of preservation. TaqMan qPCR of 424 RCC related genes correlated highly with FFPE RNA-seq expressions (r = 0.775 for FFPE tumor 1, r = 0.803 for FFPE tumor 2). Expression fold changes were considered, to assess biologic relevance of gene expressions. Expression fold changes between FFPE tumors (tumor 1/tumor 2) correlated well when comparing qPCR and RNA-seq (r = 0.890). Expression fold changes between tumors from different risk groups (our high risk RCC/The Cancer Genome Atlas, TCGA, low risk RCC) also correlated well when comparing RNA-seq from FF and FFPE tumors (r = 0.887). CONCLUSIONS: FFPE RNA seq provides reliable genes expression data, comparable to that obtained from fresh frozen tissue. It represents a useful tool for discovery and validation of biomarkers. PMID- 25495044 TI - Electronic absorption spectra of H2C6O+ isomers: produced by ion-molecule reactions. AB - Three absorption systems with origins at 354, 497, and 528 nm were detected after mass-selected deposition of H2C6O(+) in a 6 K neon matrix. The ions were formed by the reaction of C2O with HC4H(+) in a mixture of C3O2 and diacetylene in a hot cathode source, or by dissociative ionization of tetrabromocyclohexadienone. The 497 and 354 nm systems are assigned to the 1(2)A" <- X(2)A" and 2(2)A" <- X(2)A" electronic transitions of B(+), (2-ethynylcycloallyl)methanone cation, and the 528 nm absorption to the 1(2)A2 <- X(2)B1 transition of F(+), 2-ethynylbut-3-yn-1 enone-1-ylide, on the basis of calculated excitation energies with CASPT2. PMID- 25495043 TI - Effect of nitro-functionalization on the cross-linking and bioadhesion of biomimetic adhesive moiety. AB - Dopamine mimics the exceptional moisture-resistant adhesive properties of the amino acid, DOPA, found in adhesive proteins secreted by marine mussels. The catechol side chain of dopamine was functionalized with a nitro-group, and the effect of the electron withdrawing group modification on the cross-linking chemistry and bioadhesive properties of the adhesive moiety was evaluated. Both nitrodopamine and dopamine were covalently attached as a terminal group onto an inert, 4-armed poly(ethylene glygol) (PEG-ND and PEG-D, respectively). PEG-ND and PEG-D exhibited different dependence on the concentration of NaIO4 and pH, which affected the curing rate, mechanical properties, and adhesive performance of these biomimetic adhesives differently. PEG-ND cured instantly and its bioadhesive properties were minimally affected by the change in pH (5.7-8) within the physiological range. Under mildly acidic conditions (pH 5.7 and 6.7), PEG-ND outperformed PEG-D in lap shear adhesion testing using wetted pericardium tissues. However, nitrodopamine only formed dimers, which resulted in the formation of loosely cross-linked network and adhesive with reduced cohesive properties. UV-vis spectroscopy further confirmed nitrodopamine's ability for rapid dimer formation. The ability for nitrodopamine to rapidly cure and adhere to biological substrates in an acidic pH make it suitable for designing adhesive biomaterials targeted at tissues that are more acidic (i.e., subcutaneous, dysoxic, or tumor tissues). PMID- 25495045 TI - Achievements and developments. PMID- 25495046 TI - Doing, being and becoming what? PMID- 25495047 TI - Significant improvements in weight, body mass index and waist circumference for participants at the end of a 10-week health promotion intervention for people with mental disorders were not maintained at the six-month follow-up. PMID- 25495048 TI - Universally delivered workplace interventions made a small but significant contribution to reduced depressive symptoms in employees. PMID- 25495049 TI - 'Doing with not doing for': a paradigm shift in home care services and what it means for occupational therapy. PMID- 25495050 TI - Estimation of aerosol mass scattering efficiencies under high mass loading: case study for the megacity of Shanghai, China. AB - Aerosol mass scattering efficiency (MSE), used for the scattering coefficient apportionment of aerosol species, is often studied under the condition of low aerosol mass loading in developed countries. Severe pollution episodes with high particle concentration frequently happened in eastern urban China in recent years. Based on synchronous measurement of aerosol physical, chemical, and optical properties at the megacity of Shanghai for two months during autumn 2012, we studied MSE characteristics at high aerosol mass loading. Their relationships with mass concentrations and size distributions were examined. It was found that MSE values from the original US IMPROVE algorithm could not represent the actual aerosol characteristics in eastern China. It results in an underestimation of the measured ambient scattering coefficient by 36%. MSE values in Shanghai were estimated to be 3.5 +/- 0.55 m(2)/g for ammonia sulfate, 4.3 +/- 0.63 m(2)/g for ammonia nitrate, and 4.5 +/- 0.73 m(2)/g for organic matter, respectively. MSEs for three components increased rapidly with increasing mass concentration in low aerosol mass loading, then kept at a stable level after a threshold mass concentration of 12-24 MUg/m(3). During severe pollution episodes, particle growth from an initial peak diameter of 200-300 nm to a peak diameter of 500-600 nm accounts for the rapid increase in MSEs at high aerosol mass loading, that is, particle diameter becomes closer to the wavelength of visible lights. This study provides insights of aerosol scattering properties at high aerosol concentrations and implies the necessity of MSE localization for extinction apportionment, especially for the polluted regions. PMID- 25495051 TI - The maize brown midrib4 (bm4) gene encodes a functional folylpolyglutamate synthase. AB - Mutations in the brown midrib4 (bm4) gene affect the accumulation and composition of lignin in maize. Fine-mapping analysis of bm4 narrowed the candidate region to an approximately 105 kb interval on chromosome 9 containing six genes. Only one of these six genes, GRMZM2G393334, showed decreased expression in mutants. At least four of 10 Mu-induced bm4 mutant alleles contain a Mu insertion in the GRMZM2G393334 gene. Based on these results, we concluded that GRMZM2G393334 is the bm4 gene. GRMZM2G393334 encodes a putative folylpolyglutamate synthase (FPGS), which functions in one-carbon (C1) metabolism to polyglutamylate substrates of folate-dependent enzymes. Yeast complementation experiments demonstrated that expression of the maize bm4 gene in FPGS-deficient met7 yeast is able to rescue the yeast mutant phenotype, thus demonstrating that bm4 encodes a functional FPGS. Consistent with earlier studies, bm4 mutants exhibit a modest decrease in lignin concentration and an overall increase in the S:G lignin ratio relative to wild-type. Orthologs of bm4 include at least one paralogous gene in maize and various homologs in other grasses and dicots. Discovery of the gene underlying the bm4 maize phenotype illustrates a role for FPGS in lignin biosynthesis. PMID- 25495053 TI - Bipolar gold(III) complexes for solution-processable organic light-emitting devices with a small efficiency roll-off. AB - A new class of bipolar alkynylgold(III) complexes containing triphenylamine and benzimidazole moieties has been synthesized, characterized, and applied as phosphorescent dopants in the fabrication of solution-processable organic light emitting devices (OLEDs). The incorporation of methyl groups in the central phenyl unit has been found to rigidify the molecule to reduce nonradiative decay, yielding a high photoluminescence quantum yield of up to 75% in spin-coated thin films. In addition, the realization of highly efficient solution-processable OLEDs with an extremely small external quantum efficiency (EQE) roll-off has been demonstrated. At practical brightness level of 1000 cd m(-2), the optimized devices exhibited a high EQE of up to 10.0% and an extremely small roll-off of less than 1%. PMID- 25495052 TI - Using the unmet obstetric needs indicator to map inequities in life-saving obstetric interventions at the local health care system in Kenya. AB - BACKGROUND: Developing countries with high maternal mortality need to invest in indicators that not only provide information about how many women are dying, but also where, and what can be done to prevent these deaths. The unmet Obstetric Needs (UONs) concept provides this information. This concept was applied at district level in Kenya to assess how many women had UONs and where the women with unmet needs were located. METHODS: A facility based retrospective study was conducted in 2010 in Malindi District, Kenya. Data on pregnant women who underwent a major obstetric intervention (MOI) or died in facilities that provide comprehensive Emergency Obstetric Care (EmOC) services in 2008 and 2009 were collected. The difference between the number of women who experienced life threatening obstetric complications and those who received care was quantified. The main outcome measures in the study were the magnitude of UONs and their geographical distribution. RESULTS: 566 women in 2008 and 724 in 2009 underwent MOI. Of these, 185 (32.7%) in 2008 and 204 (28.1%) in 2009 were for Absolute Maternal Indications (AMI). The most common MOI was caesarean section (90%), commonly indicated by Cephalopelvic Disproportion (CPD)-narrow pelvis (27.6% in 2008; 26.1% in 2009). Based on a reference rate of 1.4%, the overall MOI for AMI rate was 1.25% in 2008 and 1.3% in 2009. In absolute terms, 22 (11%) women in 2008 and 12 (6%) in 2009, who required a life saving intervention failed to get it. Deficits in terms of unmet needs were identified in rural areas only while urban areas had rates higher than the reference rate (0.8% vs. 2.2% in 2008; 0.8% vs. 2.1% in 2009). CONCLUSIONS: The findings, if used as a proxy to maternal mortality, suggest that rural women face higher risks of dying during pregnancy and childbirth. This indicates the need to improve priority setting towards ensuring equity in access to life saving interventions for pregnant women in underserved areas. PMID- 25495054 TI - Community engagement and the human infrastructure of global health research. AB - BACKGROUND: Biomedical research is increasingly globalized with ever more research conducted in low and middle-income countries. This trend raises a host of ethical concerns and critiques. While community engagement (CE) has been proposed as an ethically important practice for global biomedical research, there is no agreement about what these practices contribute to the ethics of research, or when they are needed. DISCUSSION: In this paper, we propose an ethical framework for CE. The framework is grounded in the insight that relationships between the researcher and the community extend beyond the normal bounds of the researcher-research participant encounter and are the foundation of meaningful engagement. These relationships create an essential "human infrastructure" - a web of relationships between researchers and the stakeholder community-i.e., the diverse stakeholders who have interests in the conduct and/or outcomes of the research. Through these relationships, researchers are able to address three core ethical responsibilities: (1) identifying and managing non-obvious risks and benefits; (2) expanding respect beyond the individual to the stakeholder community; and (3) building legitimacy for the research project. SUMMARY: By recognizing the social and political context of biomedical research, CE offers a promising solution to many seemingly intractable challenges in global health research; however there are increasing concerns about what makes engagement meaningful. We have responded to those concerns by presenting an ethical framework for CE. This framework reflects our belief that the value of CE is realized through relationships between researchers and stakeholders, thereby advancing three distinct ethical goals. Clarity about the aims of researcher stakeholder relationships helps to make engagement programs more meaningful, and contributes to greater clarity about when CE should be recommended or required. PMID- 25495055 TI - Pyroglutamic acid stimulates DNA synthesis in rat primary hepatocytes through the mitogen-activated protein kinase pathway. AB - We purified pyroglutamic acid from human placental extract and identified it as a potent stimulator of rat primary hepatocyte DNA synthesis. Pyroglutamic acid dose dependently stimulated DNA synthesis, and this effect was inhibited by PD98059, a dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1) inhibitor. Therefore, pyroglutamic acid stimulated DNA synthesis in rat primary hepatocytes via MAPK signaling. PMID- 25495056 TI - Large-scale growth of well-aligned SiC tower-like nanowire arrays and their field emission properties. AB - Fabrication of well-aligned one-dimensional (1D) nanostrucutres is critically important and highly desired since it is the key step to realize the patterned arrays to be used as the display units. In the present work, we report the large scale and well-aligned growth of n-type SiC nanowire arrays on the 6H-SiC wafer substrates via pyrolysis of polymeric precursors assisted by Au catalysts. The obtained n-type SiC nanowires are highly qualified with sharp tips and numerous sharp corners around the wire bodies, which bring the emitters excellent field emission (FE) performance with low turn-on fields (1.50 V/MUm), low threshold fields (2.65 V/MUm), and good current emission stabilities (fluctuation <3.8%). The work abilities of the n-type SiC tower-like nanowire arrays under high temperature harsh environments have been investigated, suggesting that the resultant field emitters could be well serviced up to 500 degrees C. The temperature-enhanced FE behaviors could be attributed to the reduction of the work function induced by the rise of temperatures and the incorporated N dopants. It is believed that the present well-aligned n-type SiC tower-like nanowire arrays could meet nearly all stringent requirements for an ideal FE emitter with excellent FE properties, making their applications very promising in displays and other electronic nanodevices. PMID- 25495057 TI - Low surface energy plane exposed Co3O4 nanocubes supported on nitrogen-doped graphene as an electrocatalyst for efficient water oxidation. AB - Herein, we report a simple and scalable synthesis of Co3O4 nanocubes possessing exposed low surface energy planes supported on nitrogen-doped graphene (Co3O4 NC/NGr) by a hydrothermal method as an efficient electrocatalyst for water oxidation. Three different types of morphologies of Co3O4 (i.e., nanocubes, blunt edge nanocubes and spherical particles) have been synthesized by systematically varying the reaction time. Subsequently, their catalytic activity toward oxygen evolution reaction (OER) has been screened in alkaline medium. Among the three different morphologies, the intermediate architecture (i.e., the blunt edged nanocubes designated as Co3O4-NC/NGr-12h) has shown the highest OER activity. The catalyst displayed an overpotential (eta) of ~280 mV at 10 mA/cm(2) in 1 M KOH solution, which is lower than that of the other prepared samples such as Co3O4 NC/NGr-3h (~348 mV), Co3O4-NC/NGr-9h (~356 mV), Co3O4-NC/NGr-24h (~320 mV), Co3O4 NC/Gr-12h (~300 mV) and Co3O4 (~310 mV). Along with that, the electrochemical stability of the catalyst is also found to be remarkably good. The role of the low index planes of Co3O4 nanocubes (Co3O4-NC) and the importance of the doped nitrogen in the carbon framework for the uniform dispersion and direct coupling with Co3O4-NC have been examined. The controlled interplay of the exposed crystal planes of Co3O4 and its dispersion and synergistic interaction with the nitrogen doped graphene are found to be the decisive factors in bringing in the modulated OER activity of the system. PMID- 25495059 TI - 50th anniversary of the American College of Veterinary Surgeons. PMID- 25495060 TI - Japanese case of metastatic cutaneous Crohn's disease of the groin. PMID- 25495058 TI - Outcomes associated with nurse practitioners in collaborative practice with general practitioners in rural settings in Canada: a mixed methods study. AB - BACKGROUND: The formalized nurse practitioner (NP) role in British Columbia is relatively new with most roles implemented in primary care. The majority of primary care is delivered by physicians using the fee-for-service model. There is a shortage of general practitioners associated with the difficulties of recruitment and retention, particularly in rural and remote locations. The uptake of the primary care NP role has been slow due to challenges in understanding the extent of its contributions. This study aims to identify the outcomes associated with the NP role in collaborative primary care practice. METHODS: Three case studies where NPs were embedded into rural fee-for-service practices were undertaken to determine the outcomes at the practitioner, practice, community, and health services levels. Interviews, documents, and before and after data, were analyzed to identify changes in practise, access, and acute care service utilization. RESULTS: The results showed that NPs affected how care was delivered, particularly through the additional time afforded each patient visit, development of a team approach with interprofessional collaboration, and a change in style of practise from solo to group practise, which resulted in improved physician job satisfaction. Patient access to the practice improved with increased availability of appointments and practice staff experienced improved workplace relationships and satisfaction. At the community level, access to primary care improved for harder-to-serve populations and new linkages developed between the practice and their community. Acute care services experienced a statistically significant decrease in emergency use and admissions to hospital (P = 0.000). The presence of the NP improved their physician colleagues' desire to remain in their current work environment. CONCLUSIONS: This study identified the diversity of needs that can be addressed by the NP role. Namely, the importance of time to enhance patient care and its associated benefits, especially in the fee-for-service model; the value of the NP's role in the community; the acceptance of the clinical competence of NPs by their physician colleagues; the outcomes generated at the practice level in terms of organizational effectiveness and service provision; and substantiated the impact of the role in improving primary care access and reducing acute care utilization. PMID- 25495061 TI - Bayesian species delimitation combining multiple genes and traits in a unified framework. AB - Delimitation of species based exclusively on genetic data has been advocated despite a critical knowledge gap: how might such approaches fail because they rely on genetic data alone, and would their accuracy be improved by using multiple data types. We provide here the requisite framework for addressing these key questions. Because both phenotypic and molecular data can be analyzed in a common Bayesian framework with our program iBPP, we can compare the accuracy of delimited taxa based on genetic data alone versus when integrated with phenotypic data. We can also evaluate how the integration of phenotypic data might improve species delimitation when divergence occurs with gene flow and/or is selectively driven. These two realities of the speciation process are ignored by currently available genetic approaches. Our model accommodates phenotypic characters that exhibit different degrees of divergence, allowing for both neutral traits and traits under selection. We found a greater accuracy of estimated species boundaries with the integration of phenotypic and genetic data, with a strong beneficial influence of phenotypic data from traits under selection when the speciation process involves gene flow. Our results highlight the benefits of multiple data types, but also draws into question the rationale of species delimitation based exclusively on genetic data. PMID- 25495062 TI - Estrogen induces estrogen receptor alpha expression and hepatocyte proliferation in the livers of male mice. AB - Estrogens play pivotal roles in sexual development, growth, reproduction, and sex differentiation and have been implicated in a number of physiological processes in various tissues. Most of the effects of estrogens are mediated by the estrogen receptors alpha (ERalpha), beta (ERbeta), and G protein-coupled receptor 30 (GPR30). The liver is known to be a target tissue for estrogen signaling, but the physiological role of this signaling is not well characterized. Through analyses of an estradiol (E2)-treated hepatocyte cell line and mice, we showed that E2 signaling controls hepatocyte proliferation. Importantly, our data showed that the E2 signaling that is mediated through ERalpha is crucial for efficient liver regeneration after partial hepatectomy (PH). PH rapidly induced marked increases in circulating E2 and ERalpha transcripts in periportal hepatocytes, well before the onset of hepatocyte proliferation. Taken together, our results indicate that increased E2 is one of the initiating signals that trigger liver regeneration. We suggest that E2 treatment could be beneficial for stimulating liver regeneration in humans. PMID- 25495063 TI - A case of ovarian torsion in a patient carrier of a FSH receptor gene mutation previously affected by spontaneous ovarian hyperstimulation syndrome. AB - We here report a case of ovarian torsion in a patient with an history of two previous episodes of spontaneous ovarian hyperstimulation syndrome during her two pregnancies. A mutation of follicle-stimulating hormone receptor (FSHr) gene was identified in this patient and in other members of the family. Two years after her successful second pregnancy, the patient showed signs of severe thyroiditis during administration of oral contraceptive, with suppressed TSH and increased thyreoglobulin, in the absence of any abnormalities of the auto-antibodies. In few days, she developed severe pelvic pain and ultrasonographic evidence of increased ovarian volume. She underwent laparoscopy with unilateral adnexectomy for ovarian ischemic necrosis due to adnexal torsion. Our experience suggests that patients' carrier of a mutation of FSHr gene are at risk of ovarian pathologies also when non-pregnant and in the presence of low TSH levels. Further investigations are needed for an appropriate knowledge of typical and atypical manifestations of spontaneous ovarian hyperstimulation syndrome. PMID- 25495064 TI - Quantifying the epidemic spread of Ebola virus (EBOV) in Sierra Leone using phylodynamics. AB - Measuring epidemic parameters early in an outbreak is essential to inform control efforts. Using the viral genome sequence and collection date from 78 infections in the 2014 Ebola virus outbreak in Sierra Leone, we estimate key epidemiological parameters such as infectious period duration (approximately 71 hours) and date of the first case in Sierra Leone (approximately April 25th). We also estimate the effective reproduction number, Re, (approximately 1.26), which is the number of secondary infections effectively caused by an infected individual and accounts for public health control measures. This study illustrates that phylodynamics methods, applied during the initial phase of an outbreak on fewer and more easily attainable data, can yield similar estimates to count-based epidemiological studies. PMID- 25495065 TI - Effects of the Paced Auditory Serial Addition Task (PASAT) with different rates on autonomic nervous system responses and self-reported levels of stress. AB - To characterise self-reported levels of stress and autonomic responses in healthy humans evoked by different rates of the Paced Auditory Serial Addition Task (PASAT). Fifteen participants performed PASATs with different rates (3.6-, 2.4-, 1.6- or 1.2-s intervals) and a control task, in random order. Correct responses, self-reported levels of stress and autonomic responses to the PASATs were estimated. Increased PASAT rates were associated with decreases in correct responses (P < 0.001) and increases in self-reported levels of stress (P < 0.001). For autonomic responses, significant changes were seen in 10 variables during 2.4-s PASAT compared with the respective baseline; however, significant differences in relative changes from baseline were found between the 2.4-s PASAT and control task only for mean RR-intervals (P < 0.001), systolic and diastolic blood pressure (P = 0.002 and P = 0.006) and cardiac output (P < 0.001). Regarding comparison between the four PASATs, significant differences in the relative changes from baseline were seen between the 3.6-s PASAT and faster PASATs, for example mean RR-intervals, high-frequency power and respiration rate; however, there were no differences between the faster PASATs. The autonomic responses during the PASATs with different rates were quite similar for the faster PASATs (intervals < 2.4 s); however, the slowest 3.6-s PASAT evoked significantly less self-reported stress and autonomic arousal compared with the faster PASATs. Standardization of the PASAT rate may be important for studies on autonomic nervous system function and self-reported measures of stress. Future studies may test more complex interactions between stress, autonomic responses and pain responses. PMID- 25495066 TI - Worry and Rumination in Generalized Anxiety Disorder and Obsessive Compulsive Disorder. AB - Ample work has already been conducted on worry and rumination as negative thought processes involved in the etiology of most of the anxiety and mood related disorders. However, minimal effort has been exerted to investigate whether one type of negative thought process can make way for another type of negative thought process, and if so, how it subsequently results in experiencing a host of symptoms reflective of one or the other type of psychological distress. Therefore, the present study was taken up to investigate whether rumination mediates the relationship between worry and generalized anxiety disorder (GAD), and between worry and obsessive compulsive disorder (OCD) in two clinical groups. Self-report questionnaires tapping worry, rumination, generalized anxiety disorder (GAD), and obsessive compulsive disorder (OCD) were administered to a clinical sample of 60 patients aged 30-40. Worry, rumination, generalized anxiety disorder (GAD), and obsessive compulsive disorder (OCD) correlated substantially with each other, however, rumination did not mediate the relationship between worry and generalized anxiety disorder (GAD) and between worry and obsessive compulsive disorder (OCD). We also analyzed differences of outcome variables within two clinical groups. These results showed that worry and rumination were significantly different between GAD and OCD groups. PMID- 25495067 TI - Clinical predictors and time course of the improvement in beta-cell function with short-term intensive insulin therapy in patients with Type 2 diabetes. AB - AIMS: In patients with Type 2 diabetes, a short course of intensive insulin therapy can improve beta-cell function and even induce transient remission of diabetes. However, not all patients respond to this therapy. Although the achievement of fasting glucose < 7.0 mmol/l one day after stopping intensive insulin therapy can identify patients in whom beta-cell function has improved, we sought to determine clinical predictors for the early identification of such responders and the time course of response. METHODS: We pooled data from two studies in which 97 patients with Type 2 diabetes mellitus (median 3 years duration) and HbA1c 51 +/- 8.7 mmol/mol (6.8 +/- 0.8%) underwent 4-8 weeks of intensive insulin therapy, consisting of basal detemir and pre-meal insulin aspart. They were classified as responders (n = 74) or non-responders (n = 23), defined by the achievement of fasting glucose < 7.0 mmol/l after stopping intensive insulin therapy. RESULTS: On logistic regression analyses, duration of diabetes (odds ratio [OR] = 0.72, 95% confidence interval [CI] 0.56-0.92, P = 0.009) and baseline fasting glucose (OR = 0.40, 95% CI 0.24-0.68, P = 0.001) emerged as predictors of the likelihood of responding. Ninety per cent of patients with duration <= 4 years and fasting glucose <= 8.0 mmol/l responded to intensive insulin therapy. Despite having lower glucose levels during intensive insulin therapy, responders had less hypoglycaemia than non-responders (median 0.3 vs. 1.6 episodes/week, P < 0.0001), with rates of hypoglycaemia diverging sharply from the third week onwards. CONCLUSION: At baseline, shorter duration of diabetes and lower fasting glucose can identify patients most likely to benefit from short-term intensive insulin therapy. Most importantly, during therapy, responders had less hypoglycaemia from the third week onwards, despite lower glycaemia, suggesting that 2 weeks of intensive insulin therapy may be needed to improve endogenous islet function. PMID- 25495068 TI - Indonesian students' participation in an interprofessional learning workshop. AB - Interprofessional learning activities, such as workshops allow students to learn from, with and about each other. This study assessed the impact on Indonesian health students' attitudes towards interprofessional education (IPE) from participating in a workshop on medication safety. The students attended a two-day IPE workshop on medication safety. Thirty-five (48.6%) students completed pre /post-workshop surveys using a modified Readiness for Interprofessional Learning Scale (RIPLS) survey. The post-workshop survey also had a series of open-ended questions. Students' responses to each RIPLS statement pre-/post-workshop were compared, whilst their responses to open-ended questions in post-workshop survey were thematically analysed. Students reported positive attitudinal changes on statements of shared learning and teamwork sub-scale (Wilcoxon p value <0.05). Analysis of the open-ended questions indicated that students perceived the workshop as having improved their understanding on the importance of teamwork and communication skills. This study found that learning with other health students through an IPE workshop improved medical, nursing and pharmacy students' attitudes towards the importance of shared learning, teamwork and communication in healthcare service. PMID- 25495069 TI - T-helper 17 cytokines expression in leprosy skin lesions. PMID- 25495070 TI - A case of splenic rupture: a rare event after laparoscopic cholecystectomy. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is generally safe and well accepted. In rare cases, it is associated with complications (intra- e postoperative bleeding, visceral injury and surgical site infection). Splenic lesion has been reported only after direct trauma. We report an unusual case of splenic rupture presenting after "uncomplicated" LC. CASE PRESENTATION: A 77-year old woman presented with distended abdomen, tenderness in the left upper quadrant and severe anemia 12 hours after LC. Clinical examination revealed hypovolemic shock. Abdominal computed tomography confirmed the diagnosis of splenic rupture, and the patient required an urgent splenectomy through midline incision. The post operative course was uneventful and the patient was discharged on 7th postoperative day.Splenic injury rarely complicates LC. We postulate that congenital or post-traumatic adhesions of the parietal peritoneum to the spleen may have been stretched from the splenic capsule during pneumoperitoneum establishment, resulting in subcapsular hematoma and subsequent delayed rupture. CONCLUSIONS: Splenic rupture is an unusual but life-threatening complication of LC. Direct visualization of the spleen at the end of LC might be a useful procedure to aid early recognition and management in such cases. PMID- 25495071 TI - Pharmacological reactivation of p53 as a strategy to treat cancer. AB - It has been confirmed through studies using the technique of unbiased sequencing that the TP53 tumour suppressor is the most frequently inactivated gene in cancer. This finding, together with results from earlier studies, provides compelling evidence for the idea that p53 ablation is required for the development and maintenance of tumours. Genetic reconstitution of the function of p53 leads to the suppression of established tumours as shown in mouse models. This strongly supports the notion that p53 reactivation by small molecules could provide an efficient strategy to treat cancer. In this review, we summarize recent advances in the development of small molecules that restore the function of mutant p53 by different mechanisms, including stabilization of its folding by Apr-246, which is currently being tested in a Phase II clinical trial. We discuss several classes of compounds that reactivate wild-type p53, such as Mdm2 inhibitors, which are currently undergoing clinical testing, MdmX inhibitors and molecules targeting factors upstream of Mdm2/X or p53 itself. Finally, we consider the clinical applications of compounds targeting p53 and the p53 pathway. PMID- 25495072 TI - Impact of excess gestational and post-weaning energy intake on vascular function of swine offspring. AB - BACKGROUND: The development of long-term vascular disease can be linked to the intrauterine environment, and maternal nutrition during gestation plays a critical role in the future vascular health of offspring. The purpose of this investigation was to test the hypothesis that a high-energy (HE) gestational diet, HE post-weaning diet, or their combination will lead to endothelial dysfunction in offspring. METHODS: Duroc * Landrace gilts (n = 16) were assigned to either a HE (10,144 Kcal/day, n = 8) or normal energy (NE: 6721 Kcal/day, n = 8) diet throughout pregnancy. Piglets were placed on either a NE or HE diet during the growth phase. At 3 months of age femoral arteries were harvested from offspring (n = 47). Endothelial-dependent and -independent vasorelaxation was measured utilizing wire-myography and increasing concentrations of bradykinin (BK) and sodium nitroprusside (SNP), respectively. RESULTS: BK and SNP induced vasorelaxation were significantly reduced in the femoral arteries of gestational HE offspring. However, no effect for the post-weaning diet on BK and SNP induced vasorelaxation was seen. This investigation demonstrates that a HE diet prenatally diminishes both BK and SNP induced vasorelaxation in swine. CONCLUSIONS: These findings suggest that a HE gestational diet can play a critical role in the development of offspring's vascular function, predisposing them to endothelial dysfunction. This dysfunction may lead to atherosclerotic disease development later in life. PMID- 25495073 TI - How to adapt the implantation technique for the new SAPIEN 3 transcatheter heart valve design. AB - The new balloon-expandable Edwards SAPIEN 3 THV has significant design improvements requiring adjustments in the implantation technique as compared to the previous generation SAPIEN XT. Basically, the new valve requires less oversizing due to the outer skirt, which, if positioned underneath the annulus, can reduce the occurrence and severity of paravalvular leak (PVL). As with any transcatheter vale, a thorough assessment of the device-landing-zone, the surrounding structures, and the distribution of calcifications is of vast importance. Once the SAPIEN 3 valve is positioned with the initial orientation of the middle balloon marker at the level of the leaflet hinge points, the outer skirt will remain under the annulus, despite the foreshortening of the lower inflow portion of the valve. If there is an incomplete apposition, the outer skirt can conform to the anatomy, close the gaps, and reduce the risk of PVL. When calcifications are located on the edges of the annulus, PVL is common with the SAPIEN XT THV but dramatically reduced with the SAPIEN 3 THV. If the calcification extends from the annulus into the entire LVOT, there is always an incomplete apposition of the either valve frame; however, the resulting PVL is reduced by the outer skirt of the SAPIEN 3. In 165 consecutive SAPIEN 3 patients, 89.7% (n = 145) had none or a trace PVL and there were no patients with moderate or severe PVL. The new generation SAPIEN 3 valve allows more challenging anatomies to be treated, requires less oversizing, and can reduce PVL. PMID- 25495074 TI - Nucleolus precursor body (NPB): a distinct structure in mammalian oocytes and zygotes. AB - Nucleoli in mammalian oocytes and zygotes, sometimes referred to as nucleolus precursor bodies (NPBs), are compact and morphologically different from nucleoli in somatic cells. We applied a unique NPB analyzing method "enucleolation" technique to zygotes to remove the NPBs. It has been reported that oocyte NPBs are essential for embryonic development; in their absence, the oocytes complete maturation and can be fertilized, but no nucleoli are formed in the zygotes and embryos, leading to developmental failure. However, we found that when NPBs were removed from zygotes, the zygotes developed successfully to live-born pups. These results indicated that oocyte NPBs are essential for embryonic development, but zygote NPBs are not. In addition, the enucleolated zygotes formed somatic-type nucleoli during early embryonic development, demonstrating that somatic-type nucleoli do not originate from zygote NPBs. We summarize our recent investigation on NPBs, and provide additional comments and findings. PMID- 25495075 TI - The intelligent use and clinical benefits of electronic medical records in multiple sclerosis. AB - Electronic medical records (EMRs) are being quickly adopted in clinics around the world. This advancement can greatly enhance the clinical care of patients with multiple sclerosis (MS) by providing formats that allow easier review of medical documents and more structured avenues to store relevant information. MS clinicians should be involved with implementing and updating EMRs at their institutions to ensure EMR formats that benefit MS clinics. EMRs also provide opportunities for research studies of MS to access detailed, longitudinal data of MS disease course that would otherwise be difficult to collect. PMID- 25495077 TI - Characterizing variability of in vivo Raman spectroscopic properties of different anatomical sites of normal colorectal tissue towards cancer diagnosis at colonoscopy. AB - This study aims to characterize the in vivo Raman spectroscopic properties of normal colorectal tissues and to assess distinctive biomolecular variations of different anatomical locations in the colorectum for cancer diagnosis. We have developed a novel 785 nm excitation fiber-optic Raman endoscope that can simultaneously acquire in vivo fingerprint (FP) spectra (800-1800 cm(-1)) and high-wavenumber (HW) Raman spectra (2800-3600 cm(-1)) from the subsurface of colorectal tissue. We applied the FP/HW Raman endoscope for in vivo tissue Raman measurements of various normal colorectal anatomical locations (i.e., ascending colon (n = 182), transverse colon (n = 249), descending colon (n = 124), sigmoid (n = 212), and rectum (n = 362)) in 50 subjects. Partial least-squares (PLS) discriminant analysis (DA) was employed to evaluate the interanatomical variability. The normal colorectal tissue showed a subtle interanatomical variability in molecular constituents (i.e., proteins, lipids, and water content) and could be divided into three major clusterings: (1) ascending colon and transverse colon, (2) descending colon, and (3) sigmoid and rectum. The PLS-DA multiclass algorithms were able to identify different tissue sites with varying sensitivities (SE) and specificities (SP) (ascending colon: SE: 1.10%, SP: 91.02; transverse colon: SE: 14.06%, SP: 78.78; descending colon: SE: 40.32%, SP: 81.99; sigmoid: SE: 19.34%, SP: 87.90; rectum: SE: 71.55%, SP: 77.84). The interanatomical molecular variability was orders of magnitude less than neoplastic tissue transformation. Further PLS-DA modeling on in vivo FP/HW tissue Raman spectra yielded a diagnostic accuracy of 88.8% (sensitivity: 93.9% (93/99); specificity 88.3% (997/1129) for colorectal cancer detection. This work discloses that interanatomical Raman spectral variability of normal colorectal tissue is subtle compared to cancer tissue, and the simultaneous FP/HW Raman endoscopic technique has promising potential for real-time, in vivo diagnosis of colorectal cancer at the molecular level. PMID- 25495076 TI - Sixty years trying to define the malaria burden in Africa: have we made any progress? AB - Controversy surrounds the precise numbers of malaria deaths and clinical episodes in Africa. This would not have surprised malariologists working in Africa 60 years ago as they began to unravel the enigma that is 'malaria'. Malaria is a complex disease manifesting as a multitude of symptoms, degrees of severity and indirect morbid consequences. Clinical immunity develops quickly and the presence of infection cannot always be used to distinguish between malaria and other illnesses. During the 1950s and 1960s parasite prevalence was used in preference to statistics on malaria mortality and morbidity. An argument is made for a resurrection of this measure of the quantity of malaria across Africa as a more reliable means to understand the impact of control. PMID- 25495078 TI - The evolution of halophytes, glycophytes and crops, and its implications for food security under saline conditions. AB - The effective development of salt tolerant crops requires an understanding that the evolution of halophytes, glycophytes and our major grain crops has involved significantly different processes. Halophytes (and other edaphic endemics) generally arose through colonization of habitats in severe disequilibrium by pre adapted individuals, rather than by gradual adaptation from populations of 'glycophytes'. Glycophytes, by contrast, occur in low sodium ecosystems, where sodium was and is the major limiting nutrient in herbivore diets, suggesting that their evolution reflects the fact that low sodium individuals experienced lower herbivory and had higher fitness. For domestication/evolution of crop plants, the selective pressure was human imposed and involved humans co-opting functions of defense and reproductive security. Unintended consequences of this included loss of tolerance to various stresses and loss of the genetic variability needed to correct that. Understanding, combining and manipulating all three modes of evolution are now critical to the development of salt tolerant crops, particularly those that will offer food security in countries with few economic resources and limited infrastructure. Such efforts will require exploiting the genetic structures of recently evolved halophytes, the genetic variability of model plants, and endemic halophytes and 'minor' crops that already exist. PMID- 25495079 TI - Exploring the dynamics of design fluency in children with and without ADHD using artificial neural networks. AB - The neuropsychology of attention deficit/hyperactivity disorder (ADHD) has been extensively studied, with a general focus on global performance measures of executive function. In this study, we compared how global (i.e., endpoint) versus process (i.e., dynamic) measures of performance may help characterize children with and without ADHD using a design fluency task as a case study. The secondary goal was to compare the sensitivity of standard versus connectionist statistical models to group differences in cognitive data. Thirty-four children diagnosed with ADHD and 37 children without ADHD aged 8-11 years old were tested on the Five-Point Test. The continuous process measure of performance, indexed as the number of produced designs at each consecutive 1 minute interval during 5 minutes, was analyzed against the discrete process measure, that is, the number of designs between first and last intervals and the standard global performance measure of total number of produced designs. Results show that the continuous process measure distinguished the two groups better than the two other measures. The detailed observation of production patterns revealed a decreasing linear trajectory in children without ADHD that contrasts with the flat, but fluctuating productivity pattern of children with ADHD. With regards to the second goal, results show that the connectionist and standard methods are equally sensitive to group differences for the three types of measures. This illustrates the utility of quantitative process measures together with the connectionist method in neuropsychological research and suggests great potential for a dynamical approach to cognition. PMID- 25495080 TI - Interpersonal assessment of borderline personality disorder: preliminary findings. AB - We examined the reliability and validity of scores on an interpersonal measure of borderline personality disorder (BPD). Ratings on the Interpersonal Measure of Borderline Personality Disorder (IM-B) were based on nonverbal behaviors and interpersonal interactions occurring during clinical interviews with 276 adults. Scores on the IM-B exhibited good reliability. IM-B scores also displayed expected patterns of associations with scores on other measures of BPD, as well as with scores on measures of affective dysfunction, interpersonal pathology, and behavioral impairment associated with BPD, including indexes of maladaptive emotion regulation, interpersonal sensitivity, and self-harm. The pattern of associations for IM-B scores was quite similar to what would be expected for a dimensional measure of BPD symptoms. Scores on the IM-B were also associated with symptoms of disorders generally comorbid with BPD. Finally, IM-B scores contributed incrementally to the prediction of interpersonal dysfunction and suicidal ideation and behavior. Discussion focuses on implications for the assessment of BPD. PMID- 25495081 TI - Hot and not-so-hot females: reproductive state and thermal preferences of female Arizona Bark Scorpions (Centruroides sculpturatus). AB - For ectotherms, environmental temperatures influence numerous life history characteristics, and the body temperatures (Tb ) selected by individuals can affect offspring fitness and parental survival. Reproductive trade-offs may therefore ensue for gravid females, because temperatures conducive to embryonic development may compromise females' body condition. We tested whether reproduction influenced thermoregulation in female Arizona Bark Scorpions (Centruroides sculpturatus). We predicted that gravid females select higher Tb and thermoregulate more precisely than nonreproductive females. Gravid C. sculpturatus gain body mass throughout gestation, which exposes larger portions of their pleural membrane, possibly increasing their rates of transcuticular water loss in arid environments. Accordingly, we tested whether gravid C. sculpturatus lose water faster than nonreproductive females. We determined the preferred Tb of female scorpions in a thermal gradient and measured water loss rates using flow-through respirometry. Gravid females preferred significantly higher Tb than nonreproductive females, suggesting that gravid C. sculpturatus alter their thermoregulatory behaviour to promote offspring fitness. However, all scorpions thermoregulated with equal precision, perhaps because arid conditions create selective pressure on all females to thermoregulate effectively. Gravid females lost water faster than nonreproductive animals, indicating that greater exposure of the pleural membrane during gestation enhances the desiccation risk of reproductive females. Our findings suggest that gravid C. sculpturatus experience a trade-off, whereby selection of higher Tb and increased mass during gestation increase females' susceptibility to water loss, and thus their mortality risk. Elucidating the mechanisms that influence thermal preferences may reveal how reproductive trade-offs shape the life history of ectotherms in arid environments. PMID- 25495082 TI - Microstructural abnormality in white matter, regulatory T lymphocytes, and depressive symptoms after stroke. AB - BACKGROUND: The purpose of the present study was to investigate the existence of microstructure abnormalities in the white matter circuit in stroke patients and its relationship to depressive episodes. To target the prevention of depression, we also investigated the relationship between lymphocyte subsets and cerebral abnormalities in patients. METHODS: Participants included 18 patients with acute ischemic stroke and 22 healthy control subjects. Diffusion tensor imaging was performed. Whole-brain voxel-based analysis was used to compare fractional anisotropy (FA) between groups. Blood samples were obtained, and the lymphocyte subsets were evaluated using flow cytometry. Follow-up examinations were conducted on 12 patients at 6 months. RESULTS: FA was decreased in the bilateral anterior limb of the internal capsule in stroke patients. At the 6-month follow up examination, there was a significant increase in FA, which was associated with a lower depression scale score. Patients showed a decreased percentage of circulated regulatory T lymphocytes, and the degree of reduction was related to the decrease in the FA value in the internal capsule. CONCLUSIONS: FA reductions in the anterior limb of the internal capsule cause abnormality in the frontal subcortical circuits and confer a biological vulnerability, which in combination with environmental stressors results in the onset of depression. Our findings also demonstrated the possibility of preventing post-stroke depression by targeting the role of regulatory T lymphocytes in brain tissue repair and regeneration after stroke. PMID- 25495083 TI - Non-literal language deficits in mild cognitive impairment. AB - BACKGROUND: Verbal language deteriorates in Alzheimer's disease, contributing to dramatic disturbances in the ability to communicate. The presence of language disturbances may be detected at earlier phases of the neurodegenerative process, like mild cognitive impairment (MCI). In daily verbal interactions, people mostly use literal language, but sometimes they employ non-literal language, which requires listeners to interpret messages beyond the plain meaning of the words and can be quite demanding. In the present study, we tested the hypotheses that patients with MCI may have deficits in non-literal language, and these deficits are more pronounced than deficits in literal language. METHODS: Participants were recruited in a private memory clinic and senior universities. General cognitive evaluation included a comprehensive neuropsychological battery, the Mini-Mental State Examination, and the instrumental activities of daily living scale. Literal language was assessed with the semantic decision test, Token Test, and literal text comprehension test, and non-literal language with the proverbs comprehension, idiomatic expressions and non-literal text comprehension tests. RESULTS: Fifty-two participants with MCI and 31 controls were recruited. Patients with MCI had lower scores in all complex language tests, both literal (Token Test, semantic decision and literal text) and non-literal (proverbs, idiomatic expressions, and non-literal text), than the controls; the difference in literal text score was marginally significant. As much as 69% of MCI participants had deficits (performance below 1.5 SD of the mean) on at least one of the complex language tasks. Deficits were more frequent on the proverbs comprehension and semantic decision tests, and the deficits on these tests did not significantly differ from that on the Token Test. CONCLUSION: Patients with MCI are hindered in understanding complex language, both literal and non-literal. In daily living, these complex language deficits could compromise effective verbal interactions with the others. Amelioration of these deficits should be an important intervention target as part of a comprehensive rehabilitation strategy for patients with cognitive decline. PMID- 25495084 TI - From rural to urban areas: differences in behavioural and psychological symptoms of dementia in nursing home residents according to geographical location. AB - BACKGROUND: We determined whether the prevalence of behavioural and psychological symptoms of dementia (BPSD) in institutionalized older adults differed according to the geographical location of different facilities. METHODS: This cross sectional study covered 175 nursing homes (NH) in France (n = 6275; age, 86.0 +/- 8.2 years; women, 73.7%). Information on NH residents' health status and NH structure and internal organization were recorded by the NH staff. Each participant was coded for the presence or absence of the following BPSD: aggressive, screaming, and wandering behaviours. NH were geographically defined as rural (<2000 inhabitants), low urban (2000 <= inhabitants < 10 000), intermediate urban (10 000 <= inhabitants < 100 000), or high urban (inhabitants >= 100 000). RESULTS: Adjusted binary logistic regressions showed that, compared with residents living in rural NH, those living in NH located in high-urban areas had a significantly higher risk of aggressiveness (odds ratio = 1.33; 95% confidence interval = 1.06-1.67) and screaming (odds ratio = 1.43; 95% confidence interval = 1.05-1.95). The likelihood of aggressiveness was also higher in residents living in NH located in intermediate-urban areas (odds ratio = 1.36; 95% confidence interval = 1.13-1.65). CONCLUSIONS: Rurality seems to play a positive role in the expression of BPSD. If this hypothesis were confirmed, it would encourage NH staff to develop activities that explore rural potentials for the management of BPSD. PMID- 25495085 TI - Quality of life in nursing home residents with advanced dementia: a 2-year follow up. AB - BACKGROUND: Quality of life (QOL) in dementia has become increasingly recognized as an important clinical and policy concern, but little is known about the progression of QOL in patients with advanced dementia on psychogeriatric units of nursing homes. Therefore, the primary goal of the current study was to assess the evolution of QOL in advanced dementia patients on a psychogeriatric unit. METHODS: The QUALIDEM scale, a reliable and validated QOL instrument developed for patients with advanced dementia in residential settings who are unable to self-report, was assessed at baseline and 2 years later. Of the 75 patients with advanced dementia included at baseline, 32 patients participated at follow-up. RESULTS: Average QUALIDEM QOL scores did show a trend towards a significant improvement over a 2-year period. For 61.8% of the subjects at follow-up, the average scores improved. On the subscales that assessed 'feeling at home', 'social isolation' and 'negative affect', improvement was significant. CONCLUSIONS: Although it could be expected that QOL would decline over time in advanced dementia patients, results of the current study suggest that QOL is stable or improves despite the global cognitive deterioration, particularly in the more advanced stages of dementia. QOL is a distinctive domain of disease severity that should receive more attention in the advanced stages of dementia. PMID- 25495086 TI - Quality of life of older people in an urban slum of India. AB - OBJECTIVES: The aim of this study was to examine different domains of quality of life (QOL) and their relationship to sociodemographic characteristics among older people in an urban slum in India. MATERIALS AND METHODS: A cross-sectional study was conducted (n = 120). Selected individuals were interviewed, and their QOL was assessed by the World Health Organization Quality of Life-BREF questionnaire. Statistical analysis was then performed. RESULTS: Of those included in the study population, 61.7% were men, all were Hindus, 46.7% were members of the general caste, 19.2% were illiterate, 35% were unemployed, and 72.5% lived with their joint family (i.e. extended family). Mean scores in each domain studied did not significantly differ between the sexes, age groups, castes, and family types. Subjects with more education, who were married, and with greater income had significantly better QOL scores. Mean scores were also better in certain domains among persons who had their own income and who resided with their children. CONCLUSION: Having low education, being single, lacking personal income, and not living with their children significantly reduced QOL in the elderly subjects. Attention should be given to these factors to help elderly individuals age in a healthy manner. PMID- 25495087 TI - Determinants of oral health-related quality of life of the institutionalized elderly. AB - BACKGROUND: Diminished oral health of the institutionalized elderly has frequently been reported. This is not only of significance with regard to nutrition and general health, but it can also affect oral health-related quality of life. This paper evaluates the effects of oral and general conditions on oral health-related quality of life for the institutionalized elderly, as measured by the Geriatric Oral Health Assessment Index (GOHAI). MATERIALS AND METHODS: Ninety four residents of four long-term care homes in southern Germany agreed to participate in this study, and interviews were conducted using the GOHAI questionnaire. The Revised Oral Health Assessment Guide was applied to allocate participants into two groups: satisfactory oral health and poor oral health. To evaluate the effects of age, gender, number of chronic diseases, frequently taken drugs, care level, Mini-Mental State Examination score, periodontitis (for participants with their own teeth), pressures caused by prostheses, and type of denture worn, a linear regression model with the total GOHAI score was calculated with these determinants. RESULTS: The mean +/- SD GOHAI score was 53.3 +/- 6.2 in the satisfactory oral health group and 48.7 +/- 7.3 in the poor oral health group. Statistical analysis showed that the GOHAI scores were significantly different in satisfactory oral health and poor oral health groups (P = 0.030) and were affected by care level (P = 0.008) and type of dentures worn (P = 0.006). CONCLUSIONS: Within the limitations of this study, it can be concluded that oral health-related quality of life of the institutionalized elderly is low and is positively associated with better oral health. PMID- 25495088 TI - Risk-benefit analysis of antidepressant drug treatment in the elderly. AB - Depression in the elderly is a significant health issue that has the potential to seriously affect physical and emotional well-being. Therefore, the treatment of geriatric depression is necessary. Antidepressant treatment in older depressed patients is efficacious, but differences in the effectiveness of different classes of antidepressants have not been demonstrated. However, differences in tolerability profile are most recognizable in the elderly. With ageing, a series of changes occur in the elderly that modify both the pharmacokinetics and pharmacodynamics of antidepressants and may influence the efficacy, tolerability and safety of treatment in the elderly. Comorbidities require the use of other drugs, which increases the possibility of drug-drug interactions. Given these aspects, individualized therapy for each elderly patient is needed to achieve acceptable risk-benefit ratio. Effective treatment of depression in the elderly, which may require combined pharmacological with psychosocial treatment, can decrease both morbidity and mortality; it also may lead to reduced demands on family members and on health-care and social services. PMID- 25495089 TI - Transcranial direct current stimulation for depression in a 92-year-old patient: a case study. PMID- 25495090 TI - Isolation and characterization of Yersinia-specific bacteriophages from pig stools in Finland. AB - AIMS: Bacteriophages infect bacteria, and they are present everywhere in the world including the intestinal tracts of animals. Yersiniosis is a common foodborne infection caused by Yersinia enterocolitica and Yersinia pseudotuberculosis. As these bacteria are frequently isolated from pigs, we wanted to know whether Yersinia-specific bacteriophages are also present in the pig stools and, if so, whether there is a positive or negative association between the prevalence of the Yersinia phages and the pathogenic Yersinia in the stool samples. METHODS AND RESULTS: Altogether 793 pig stool samples collected between November 2010 and March 2012 from 14 Finnish pig farms were screened for the presence of bacteriophages able to infect Y. enterocolitica serotype O:3, O:5,27 or O:9 strains, or Y. pseudotuberculosis serotype O:1a, O:1b or O:3 strains. Yersinia phages were isolated from 90 samples from eight farms. Yersinia enterocolitica O:3 was infected by 59 phages, 28 phages infected serotypes O:3 and O:5,27, and eight phages infected serotypes O:3, O:5,27 and O:9, and Y. pseudotuberculosis O:1a by eight phages. Many phages originating from pigs in the same farm were identical based on their restriction enzyme digestion patterns; 20 clearly different phages were selected for further characterization. Host ranges of these phages were tested with 94 Yersinia strains. Six of the phages infected eight strains, 13 phages infected three strains, and one phage infected only one strain, indicating that the phages had a relatively narrow host range. CONCLUSIONS: There was a clear association between the presence of the host bacteria and specific phages in the stools. SIGNIFICANCE AND IMPACT OF THE STUDY: The isolated bacteriophages may have potential as biocontrol agents for yersiniosis in both humans and pigs in future, and as alternatives or in addition to antibiotics. To our knowledge, this is the first reported isolation of Yersinia-specific phages from pig stool samples. PMID- 25495091 TI - Positive is usually good, negative is not always bad: The effects of group affect on social integration and task performance. AB - Grounded in a social functional perspective, this article examines the conditions under which group affect influences group functioning. Using meta-analysis, the authors leverage heterogeneity across 39 independent studies of 2,799 groups to understand how contextual factors-group affect source (exogenous or endogenous to the group) and group life span (one-shot or ongoing)-moderate the influence of shared feelings on social integration and task performance. As predicted, results indicate that group positive affect has consistent positive effects on social integration and task performance regardless of contextual idiosyncrasies. The effects of group negative affect, on the other hand, are context-dependent. Shared negative feelings promote social integration and task performance when stemming from an exogenous source or experienced in a 1-shot group, but undermine social integration and task performance when stemming from an endogenous source or experienced in an ongoing group. The authors discuss implications of their findings and highlight directions for future theory and research on group affect. PMID- 25495092 TI - Heard it through the grapevine: indirect networks and employee creativity. AB - Social networks can be important sources of information and insights that may spark employee creativity. The cross-fertilization of ideas depends not just on access to information and insights through one's direct network-the people one actually interacts with--but at least as much on access to the indirect network one's direct ties connect one to (i.e., people one does not interact with directly, but with whom one's direct ties interact). We propose that the reach efficiency of this indirect network--its nonredundancy in terms of interconnections--is positively related to individual creativity. To help specify the boundaries of this positive influence of the indirect network, we also explore how many steps removed the indirect network still adds to creativity. In addition, we propose that the efficiency (nonredundancy) of one's direct network is important here, because more efficient direct networks give one access to indirect networks with greater reach efficiency. Our hypotheses were supported in a multilevel analysis of multisource survey data from 223 sales representatives nested within 11 divisions of a Chinese pharmaceutical company. This analysis also showed that the creative benefits of reach efficiency were evident for 3 and 4 degrees of separation but were greatest for indirect ties that depend only on one's direct ties. PMID- 25495093 TI - Insufficient effort responding: examining an insidious confound in survey data. AB - Insufficient effort responding (IER; Huang, Curran, Keeney, Poposki, & DeShon, 2012) to surveys has largely been assumed to be a source of random measurement error that attenuates associations between substantive measures. The current article, however, illustrates how and when the presence of IER can produce a systematic bias that inflates observed correlations between substantive measures. Noting that inattentive responses as a whole generally congregate around the midpoint of a Likert scale, we propose that Mattentive, defined as the mean score of attentive respondents on a substantive measure, will be negatively related to IER's confounding effect on substantive measures (i.e., correlations between IER and a given substantive measure will become less positive [or more negative] as Mattentive increases). Results from a personality questionnaire (Study 1) and a simulation (Study 2) consistently support the hypothesized confounding influence of IER. Using an employee sample (Study 3), we demonstrated how IER can confound bivariate relationships between substantive measures. Together, these studies indicate that IER can inflate the strength of observed relationships when scale means depart from the scale midpoints, resulting in an inflated Type I error rate. This challenges the traditional view that IER attenuates observed bivariate correlations. These findings highlight situations where IER may be a methodological nuisance, while underscoring the need for survey administrators and researchers to deter and detect IER in surveys. The current article serves as a wake-up call for researchers and practitioners to more closely examine IER in their data. PMID- 25495094 TI - Exploring qualitative training reactions: individual and contextual influences on trainee commenting. AB - Training reactions are the most common criteria used for training evaluation, and reaction measures often include opportunities for trainees to provide qualitative responses. Despite being widely used, qualitative training reactions are poorly understood. Recent trends suggest commenting is ubiquitous (e.g., tweets, texting, Facebook posts) and points to a currently untapped resource for understanding training reactions. In order to enhance the interpretation and use of this rich data source, this study explored commenting behavior and investigated 3 broad questions: who comments, under what conditions, and how do trainees comment? We explore both individual difference and contextual influences on commenting and characteristics of comments in 3 studies. Using multilevel modeling, we identified significant class-level variance in commenting in each of the 3 samples of trainees. Because commenting has only been considered at the individual level, our findings provide an important contribution to the literature. The shared experience of being in the same class appears to influence commenting in addition to individual differences, such as interest in the topic (Studies 1 and 2), satisfaction (Studies 2 and 3), and entity beliefs (Study 3). Furthermore, we demonstrated that item wording may have an impact on commenting (Study 3) and should be considered as a potential lever for training professionals to influence commenting behavior from trainees. Training professionals, particularly those who regularly administer training evaluation surveys, should be aware of nonresponse to open-ended items and how that may impact the information they collect, use, and present within their organizations. PMID- 25495095 TI - You don't always get what you want, and you don't always want what you get: An examination of control-desire for control congruence in transactional relationships. AB - In this research we develop a framework to examine the drivers of customers' desire for control over the sales relationship, and consequences of fit between perceived and desired control. Data collected in a lagged field study of 144 retailer manager (customer)-salesperson dyads were modeled using hierarchical linear modeling and response surface modeling techniques. Results from our analysis reveal that salesperson expertise drives retailers' desire for control in these relationships. In addition, while incongruence in perceived-desired control was negatively associated with both satisfaction and objective sales, retailer satisfaction was higher when both desired and perceived control were high. Further, as desired and perceived control over the sales relationship both increase, product sales initially decrease, and then increase, exhibiting a "U shaped" effect. Implications for both theory and practice are discussed. These include adaptive sales training to identify misalignment between desired and perceived control, optimization of cocreation strategies, incorporation of interorganizational relational constructs, exploration of triadic social network configurations, examination of unmet expectations, and the implications of assimilation-contrast theory. PMID- 25495096 TI - Synergistic Effect of Curcumin in Combination with Anticancer Agents in Human Retinoblastoma Cancer Cell Lines. AB - PURPOSE: Curcumin (diferuloylmethane), a phenolic compound obtained from the rhizome of the herb Curcuma longa, is known to have anti-proliferative and anti tumor properties. In this study, we evaluated the cytotoxic effect of curcumin alone and in combination with individual drugs like carboplatin, etoposide, or vincristine in a human retinoblastoma (RB) cancer cell line. MATERIALS AND METHODS: A drug-drug interaction was analyzed using the median effect/isobologram method and combination index values were used to characterize the interaction as synergistic or additive. We also performed the apoptosis and cell-cycle kinetics study with single drugs in combination with curcumin in a human RB cell lines (Y79 and Weri-Rb1). RESULTS: Curcumin caused concentration-dependent decrease in cell proliferation, cell kinetics, and also induced apoptosis in both the RB cell lines. When combination of curcumin with individual drugs like carboplatin or etoposide or vincristine was treated on to RB cells, both cell viability and cell cycling were reduced and increased apoptosis was noted, in comparison with single drug treatment. These effects were significant in both the cell lines, indicating the ability of curcumin to increase the sensitivity of RB cells to chemotherapy drugs. CONCLUSION: Our in vitro findings showed that the combination of curcumin with single drug treatment showed marked synergistic inhibitory effect against RB cell lines. These results suggest that curcumin can be used as a modulator which may have a potential therapeutic value for the treatment of RB cancer patients. PMID- 25495097 TI - Secular trends in age at menarche among women born between 1955 and 1985 in Southeastern China. AB - BACKGROUND: Improvements in socioeconomic conditions and population health have been linked to declining age at menarche. In China, secular trends in age at menarche following extensive economic reform during recent decades have not been thoroughly investigated. This study examined the overall trend in age at menarche and assessed differences in the rate of change of age at menarche over time, and between urban and rural populations and education levels in southeastern China. METHODS: Age at menarche was retrospectively collected from 1,167,119 Han Chinese women born 1955-1985, who registered in the Perinatal Health Care Surveillance System in 19 cities and counties in two southeast provinces during 1993-2005. Multivariable linear regression was used to estimate trends in age at menarche overall and stratified by urban/rural residence and education level. RESULTS: Age at menarche declined by 0.33 [95% CI 0.33, 0.32] years/decade overall, with the fastest decline in women born in 1966-1975. For the earliest birth cohorts (1955 1965), age at menarche declined faster in urban versus rural regions, and for women with high school education or above versus primary school or less. In contrast, age at menarche declined slower among urban women born 1976-1985, and among those with higher education born 1966-1985. CONCLUSIONS: Mean age at menarche declined for women born in 1955-1985 in southeast China. Further study is warranted to identify specific factors contributing to earlier age at menarche and associated health outcomes. PMID- 25495098 TI - Clinical effectiveness and clinical toxicity associated with platinum-based doublets in the first-line setting for advanced non-squamous non-small cell lung cancer in Chinese patients: a retrospective cohort study. AB - BACKGROUND: Real-world evidence lacks for clinical effectiveness and clinical toxicity associated with platinum-based doublets in the first-line setting for advanced non-squamous non-small cell lung cancer (advNS-NSCLC) in Chinese patients. METHODS: Patients receiving first-line chemotherapy for advNS-NSCLC in four Chinese tertiary care hospitals from 2007 to 2012 were retrospectively identified for chart review. Propensity score methods created best matched pairs for platinum/pemetrexed versus other platinum-based doublets for head-to-head comparisons of early treatment discontinuation (completed treatment cycles <4), treatment failure (progressive disease or early treatment discontinuation), and adverse events (AE). Conventional multiple logistic regression analyses were also performed to confirm the impact of the studied platinum-based doublets on early treatment discontinuation, treatment failure, and hematological AE using vinorelbine/platinum as reference. RESULTS: 1,846 patients were included to create propensity score matched treatment groups for platinum/pemetrexed versus docetaxel (95 pairs), paclitaxel (118 pairs), gemcitabine (199 pairs), and vinorelbine (72 pairs)-contained doublet, respectively. Platinum/pemetrexed was associated with significantly lower risks of early treatment discontinuation (odds ratio (OR) ranged from 0.239, p = 0.001 relative to platinum/docetaxel to 0.389, p = 0.003 relative to platinum/paclitaxel) and treatment failure (OR ranged from 0.257, p < 0.001 relative to platinum/paclitaxel to 0.381, p < 0.001 relative to platinum/gemcitabine) than the other four studied doublets. Platinum/pemetrexed was also associated with several significantly lower hematological AE rates, such as versus platinum/paclitaxel (any hematological AE: OR 0.508, p = 0.032), platinum/gemcitabine (i.e., any hematological AE: OR 0.383, p < 0.001; anemia: OR 0.357, p < 0.001; thrombocytopenia: OR 0.345, p < 0.001) or platinum/vinorelbine (i.e., neutropenia: OR 0.360, p = 0.046; anemia: OR 0.181, p = 0.014) in matched patients. Further conventional logistic regression analyses indicated that pemetrexed/platinum was ranked lowest for the risks of early treatment discontinuation (OR 0.326, p < 0.001), treatment failure (OR 0.460, p < 0.001), and any hematological AE (OR 0.329, p < 0.001). CONCLUSIONS: Pemetrexed plus platinum had significantly superior clinical effectiveness as compared to the other platinum-based doublets with third-generation cytotoxic agents and was also associated with several lower hematological toxicity rates than gemcitabine or vinorelbine-based doublet in the first-line setting for advNS-NSCLC in Chinese patients. PMID- 25495099 TI - ImmunoGlobulin galaxy (IGGalaxy) for simple determination and quantitation of immunoglobulin heavy chain rearrangements from NGS. AB - BACKGROUND: Sequence analysis of immunoglobulin heavy chain (IGH) gene rearrangements and frequency analysis is a powerful tool for studying the immune repertoire, immune responses and immune dysregulation in health and disease. The challenge is to provide user friendly, secure and reproducible analytical services that are available for both small and large laboratories which are determining VDJ repertoire using NGS technology. RESULTS: In this study we describe ImmunoGlobulin Galaxy (IGGalaxy)- a convenient web based application for analyzing next-generation sequencing results and reporting IGH gene rearrangements for both repertoire and clonality studies. IGGalaxy has two analysis options one using the built in igBLAST algorithm and the second using output from IMGT; in either case repertoire summaries for the B-cell populations tested are available. IGGalaxy supports multi-sample and multi-replicate input analysis for both igBLAST and IMGT/HIGHV-QUEST. We demonstrate the technical validity of this platform using a standard dataset, S22, used for benchmarking the performance of antibody alignment utilities with a 99.9 % concordance with previous results. Re-analysis of NGS data from our samples of RAG-deficient patients demonstrated the validity and user friendliness of this tool. CONCLUSIONS: IGGalaxy provides clinical researchers with detailed insight into the repertoire of the B-cell population per individual sequenced and between control and pathogenic genomes. IGGalaxy was developed for 454 NGS results but is capable of analyzing alternative NGS data (e.g. Illumina, Ion Torrent). We demonstrate the use of a Galaxy virtual machine to determine the VDJ repertoire for reference data and from B-cells taken from immune deficient patients. IGGalaxy is available as a VM for download and use on a desktop PC or on a server. PMID- 25495100 TI - Implication of plasma intermedin levels in patients who underwent first-time diagnostic coronary angiography: a single centre, cross-sectional study. AB - BACKGROUND: Intermedin (IMD) is involved in the prevention of atherosclerotic plaque progression, possessing cardioprotective effects from hypertrophy, fibrosis and ischemia-reperfusion injury. Elevated plasma IMD levels have been demonstrated in patients with acute coronary syndromes. No human study has examined the role of IMD in stable patients who underwent diagnostic coronary angiography with suspicion of coronary artery disease (CAD). Thus we investigated the role of IMD as a biomarker to discriminate patients with CAD and predict those with severe disease who require early and intensive therapeutic intervention before presenting with acute coronary syndrome. METHODS: Eligible two hundred and thirty-eight consecutive patients (123 males, mean age 58.4 +/- 10.0 years) who underwent first-time diagnostic coronary angiography were included in this study. Plasma concentrations of IMD were measured from arterial blood samples by the enzyme-linked immunosorbent assay. Patients were divided into three groups according to the presence and degree of CAD, consisting of 48 patients with normal coronary anatomy (Group 1), 111 patients with < 50% coronary stenosis (Group 2), and 79 patients with >= 50% stenosis in at least one of the major coronary arteries (group 3). The severity and extent of CAD was evaluated by calculations of the vessel, Gensini, and SYNTAX scores. RESULTS: Circulating plasma IMD levels in patients with CAD were significantly higher than those in patients without CAD (157.7 +/- 9.6, 134.8 +/- 11.9, and 117.6 +/- 7.9 pg/mL in groups 3, 2 and 1 respectively; p < 0.001). Besides, plasma IMD levels were correlated with Gensini and SYNTAX scores (rs = 0.742, and rs = 0.296, respectively; p < 0.05). The presence of >=50% coronary artery stenosis could be predicted if a cut-off value of 147.7 pg/mL for plasma IMD was used with 88.6% sensitivity and 88.7% specificity. Moreover, a plasma IMD level of <126.6 pg/mL could discriminate a patient with normal coronary arteries from patients with angiographically proven CAD with a sensitivity and specificity of 84.7%, and 83.3% respectively. CONCLUSIONS: We demonstrated that IMD might be used as a biomarker to predict CAD and its severity in patients who underwent first time diagnostic coronary angiography. PMID- 25495101 TI - The effect of hydration status on appetite and energy intake. AB - This study investigated the effect of hypohydration produced by exercise and sub optimal rehydration on appetite and energy intake. Ten males lost ~2% body mass through evening exercise in the heat (35 degrees C). Over the next 13 h, participants were re-fed and either rehydrated (RE: water equal to 175% of body mass loss (BML)) or remained hypohydrated (HYPO: 200 ml water), until the following morning. Urine samples, blood samples and subjective feelings were collected pre-exercise, post-exercise and 13 h post-exercise, with an ad libitum breakfast provided 13 h post-exercise. Total BML at 13 h post-exercise was greater during HYPO (2.8 (0.5)%) than RE (0.5 (0.5)%). Energy intake at the ad libitum breakfast was similar between trials (RE: 4237 (1459) kJ; HYPO: 4612 (1487) kJ; P = 0.436), with no difference in energy consumed in foods (P = 0.600) or drinks (P = 0.147). Total water ingestion at the ad libitum breakfast meal was greater during HYPO (1641 (367) ml) than RE (797 (275) ml) (P < 0.001), with this being explained by increased water intake through fluids (P < 0.001). Thirteen hours post-exercise, participants reported greater thirst (P < 0.001) and lower fullness (P < 0.01) during HYPO. Alterations in hydration status produced by exercise are unlikely to influence post-exercise food intake and consequently other aspects of recovery or adaptation. PMID- 25495102 TI - Theoretical investigation of the ionic selectivity of polyelectrolyte multilayer membranes in nanofiltration. AB - Polyelectrolyte multilayer membranes have proven to be promising materials for ion nanofiltration. In this work, we implement a continuum mesoscopic transport model developed in previous works (Szymczyk, A.; Zhu, H.; Balannec, B. Langmuir 2010, 26, 1214; Szymczyk, A.; Zhu, H.; Balannec, B. J. Phys. Chem. B 2010, 114, 10143) to investigate the pressure-driven transport of electrolyte mixtures through this kind of membrane. The model accounts for an inhomogeneous distribution of the fixed charge through an arbitrary number of polyelectrolyte bilayers. We show that accounting for the multiple bipolar charge distribution resulting from the layer-by-layer assembly of polyelectrolytes with opposite charge is responsible for the increase in the Na(+)/Mg(2+) selectivity reported experimentally with respect to conventional nanofiltration membranes. The model also allows the rationalizing of the seemingly contradictory experimental results reported in the literature (i.e., the increase or decrease in the selectivity with the number of bilayers or the existence of an optimum number of bilayers). It is shown, however, that the nonmonotonous variation of the ionic selectivity does not originate from the multibipolar distribution of the fixed charge through polyelectrolyte multilayer membranes but from the existence of an optimum skin layer thickness. PMID- 25495103 TI - Exciton energy transfer-based quantum dot fluorescence sensing array: "chemical noses" for discrimination of different nucleobases. AB - A novel exciton energy transfer-based fluorescence sensing array for the discrimination of different nucleobases was developed through target nucleobase triggered self-assembly of quantum dots (QDs). Four QD nanoprobes with different ligand receptors, including mercaptoethylamine, N-acetyl-l-cysteine, 2-dimethyl aminethanethiol, and thioglycolic acid, were created to detect and identify nucleobase targets. These QDs served as both selective recognition scaffolds and signal transduction elements for a biomolecule target. The extent of particle assembly, induced by the analyte-triggered self-assembly of QDs, led to an exciton energy transfer effect between interparticles that gave a readily detectable fluorescence quenching and distinct fluorescence response patterns. These patterns are characteristic for each nucleobase and can be quantitatively differentiated by linear discriminate analysis. Furthermore, a fingerprint-based barcode was established to conveniently discriminate the nucleobases. This pattern sensing was successfully used to identify nucleobase samples at unknown concentrations and five rare bases. In this "chemical noses" strategy, the robust characteristics of QD nanoprobes, coupled with the diversity of surface functionality that can be readily obtained using nanoparticles, provides a simple and label-free biosensing approach that shows great promise for biomedical applications. PMID- 25495104 TI - Prevalence and risk factors of Helicobacter pylori infection in Saudi children: a three-year prospective controlled study. AB - BACKGROUND: Helicobacter pylori (H. pylori) infection is the most common chronic infections. The risk factors for H. pylori infection in both developing and developed countries are closely related to poor living conditions in childhood. This study aimed to establish the prevalence of H. pylori infection and its associated risk factors among children in the western and central regions of Saudi Arabia. METHODS: A prospective cross-sectional study was performed among symptomatic children in National Guard hospitals who underwent esophagogastroduodenoscopy from 2010 to 2013. The gold standard diagnosis of H. pylori infection was histologic presence of the bacteria in the gastric biopsy. The variables analyzed as possible risk factors included demographic and living characteristics, socioeconomic status, potential mode of transmission, and clinical indications of H. pylori infection. RESULTS: A total of 303 children were included in the study. The overall prevalence of H. pylori infection was 49.8%. Among the studied variables, the following were positively associated with the presence of H. pylori in multivariable analyses: age above 10 years(OR = 11.84, 95% CI = 3.90-35.94, p < .0001), an income of <5000 SR (OR = 2.06, 95% CI = 1.07-3.95), more than eight persons in the household (OR = 3.46, 95% CI = 1.67 7.20), bed sharing (OR = 2.26, 95% CI = 1.32-3.86), and two affected parents (OR = 11.19, 95% CI = 1.29-97.27). Abdominal pain and anorexia were significant predictors of H. pylori infection (p = .005 and .009, respectively). CONCLUSION: Helicobacter pylori infection had a high prevalence among Saudi children in the cities of Jeddah and Riyadh. It was a relatively common cause of abdominal pain and anorexia. In this cohort of children, H. pylori infection was associated with variables indicative of a crowded environment and poor living conditions, further supporting the conclusion that improving socioeconomic conditions and designing a preventive health strategy in Saudi Arabia will likely protect children against this infection. PMID- 25495105 TI - Understanding the role of the OneLove campaign in facilitating drivers of social and behavioral change in southern Africa: a qualitative evaluation. AB - In the wake of the HIV and AIDS pandemic, health communication has played an important role in social and behavior change in HIV prevention and treatment efforts. Despite this significant role, it is not always clear how health communication influences individuals and communities to facilitate social and behavior change. Guided predominantly by Lewin's theory of change in the context of complexity thinking, and supported by qualitative evidence from Soul City Institute's midterm evaluation of the OneLove multimedia campaign in 9 southern African countries, this article illustrates how carefully designed health edutainment communication materials facilitate drivers of social and behavior change. Thus, researched and theory-based health communication aimed at behavior and social change remains an important pillar in HIV prevention and treatment, where personal and social agency remain key. PMID- 25495107 TI - Have prescription drug brand names become generic? PMID- 25495106 TI - Area deprivation and the prevalence of type 2 diabetes and obesity: analysis at the municipality level in Germany. AB - BACKGROUND: The objective of this study was to analyse the association between area deprivation at municipality level and the prevalence of type 2 diabetes (T2D) and obesity across Germany, controlling for individual socioeconomic status (SES). METHODS: The analyses are based on a large survey conducted in 2006. Information was included from 39,908 adults aged 20 years or above. Area deprivation was assessed using the German Index of Multiple Deprivation (GIMD) at municipality level. About 4,700 municipalities could be included and assigned to a deprivation quintile. Individual SES was assessed by income and educational level. Multilevel logistic models were used to control for individual SES and other potential confounders such as age, sex and physical activity. RESULTS: We found a positive association of area deprivation with T2D and obesity. Controlling for all individual-level variables, the odds ratios for municipalities in the most deprived quintile were significantly increased for T2D (OR 1.35; 95% CI 1.12-1.64) as well as for obesity (OR 1.14; 95% CI 1.02-1.26). Further analyses showed that these associations were relatively similar for both men and women. CONCLUSIONS: Based on a nationwide dataset, we were able to show that area deprivation at municipality level is significantly associated with the prevalence of T2D and obesity. It will be important to focus preventive efforts on very deprived municipalities. PMID- 25495108 TI - The correlation of family physician work with submitted codes and fees. AB - OBJECTIVES: The income disparity between primary care and other physicians has been attributed in part to the evaluation and management (E/M) rules written by CMS. The purpose of this study was to examine the relationship between family physicians' work and their actual coding practices and fees collected under these widely used rules. STUDY DESIGN: This was a direct observational time-motion study. METHODS: A diverse group of 15 family physicians were shadowed over consecutive patient visits at their ambulatory practices, usually for a half-day of clinic. Data about each visit were recorded, including time parameters; number of issues covered; number of labs, images, and chronic prescriptions ordered; the physician fee code from the Current Procedural Terminology (CPT) system that was submitted; the actual payer for each patient; and the actual fee collected. The primary outcome was the correlation between the time spent for each patient's care and coding/financial measures. RESULTS: The average total time a physician spent per patient including documentation time was 20.0 minutes. The average fee collected was $101.40, including patient co-pays. The correlation between the actual fee collected and the physician's time spent working on each patient's behalf was poor (R2 = 0.137, P < .001). There was a wide variation in times and fees for each CPT code category. CONCLUSIONS: The existing E/M rules and CPT coding system have created office visit fees that correlate poorly with family physician work. These findings provide another justification for disruptive primary care payment reform. PMID- 25495109 TI - Population targeting and durability of multimorbidity collaborative care management. AB - OBJECTIVES: A patient-centered collaborative care program for depression and uncontrolled diabetes and/or coronary heart disease (CHD) demonstrated improved clinical outcomes relative to usual care. We report clinically stratified analyses of patient outcomes to inform the duration and targeting of care management services for complex patients with multimorbidity. METHODS: A 12-month randomized controlled trial of a multimorbidity collaborative care program followed patients at 6, 12, 18, and 24 months for diabetes (glycated hemoglobin [A1C]), blood pressure (systolic; SBP), low-density lipoprotein (LDL) cholesterol, and depression (Symptoms Check List-20 score). Depressed patients with less favorable medical control (Patient Health Questionnaire-9 score > 10, A1C > 8.0 %, SBP > 140 mm Hg, and LDL cholesterol > 120 mg/dL) were compared with depressed patients with more favorable medical control to describe differential intervention benefits over time. RESULTS: In contrast to patients with more favorable baseline control, patients with depression and unfavorable control of A1C, SBP, and LDL at baseline showed improved outcomes as early as the 6-month follow-up assessment. Clinical benefits in the intervention group were largely sustained over the 24-month follow-up, except for some deterioration of glycemic control in intervention patients and trends toward improvement among controls over time. Among patients with depression and more favorable medical control at baseline, there were minimal between-group differences in medical disease outcomes. CONCLUSIONS: Clinical benefits of a multimorbidity collaborative care management program occurred early, and were only found among patients with poor control of baseline diabetes and CHD risk factors. Targeting may maximize reach and improve affordability of complex care management. PMID- 25495110 TI - Clinicians' views on displaying cost information to increase clinician cost consciousness. AB - OBJECTIVES: To evaluate 1) clinician attitudes towards incorporating cost information into decision making when ordering imaging studies; and 2) clinician reactions to the display of Medicare reimbursement information for imaging studies at clinician electronic order entry. STUDY DESIGN: Focus group study with inductive thematic analysis. METHODS: We conducted focus groups of primary care clinicians and subspecialty physicians (nephrology, pulmonary, and neurology) (N = 50) who deliver outpatient care in 12 hospital-based clinics and community health centers in an urban safety net health system. We analyzed focus group transcripts using an inductive framework to identify emergent themes and illustrative quotations. RESULTS: Clinicians believed that their knowledge of healthcare costs was low and wanted access to relevant cost information for reference. However, many clinicians believed it was inappropriate and unethical to consider costs in individual patient care decisions. Among clinicians' negative reactions toward displaying costs at order entry, 4 underlying themes emerged: 1) belief that ordering is already limited to clinically necessary tests; 2) importance of prioritizing responsibility to patients above that to the healthcare system; 3) concern about worsening healthcare disparities; and 4) perceived lack of accountability for healthcare costs in the system. CONCLUSIONS: Although clinicians want relevant cost information, many voiced concerns about displaying cost information at clinician order entry in safety net health systems. Alternative approaches to increasing cost-consciousness may be more acceptable to clinicians. PMID- 25495111 TI - Variation in hospital inpatient prices across small geographic areas. AB - OBJECTIVES: To examine whether market competition may influence the difference in the inpatient price per discharge between public (Medicare) and private payers across small geographic areas. STUDY DESIGN: Retrospective multivariate analysis. METHODS: Data came from the 2006 Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SIDs) in 162 counties from 6 states where an HCUP price-to-charge ratio (PCR) was available. The SIDs were linked with the Area Resource File, American Hospital Association Annual Survey Database, and US Census Bureau data files. Hospital inpatient prices were estimated by applying the HCUP PCR to total hospital charges. Payer-specific price comparisons were made for all discharges, an acute condition (acute myocardial infarction), and an elective condition (knee arthroplasty). Ordinary least squares models were used to examine the effect of market competition on the inpatient price per discharge by payer. RESULTS: Greater geographic variation was found in the inpatient price per discharge among private than public payers for most hospital services. Hospitals in more concentrated markets were associated with a higher price per discharge among knee arthroplasty discharges for both payers. CONCLUSIONS: Hospitals charged significantly higher prices to private than public payers. Because the payment policies from Medicare ultimately affect private payers, public policy efforts that take into consideration market-based approaches or payment reform may help to reduce price variations. PMID- 25495112 TI - Will Medicare Advantage payment reforms impact plan rebates and enrollment? AB - OBJECTIVES: To assess the relationship between Medicare Advantage (MA) plan rebates and enrollment and simulate the effects of Affordable Care Act (ACA) payment reforms. STUDY DESIGN AND METHODS: First difference regressions of county level MA payment and enrollment data from CMS from 2006 to 2010. RESULTS: A $10 decrease in the per member/per month rebate to MA plans was associated with a 0.20 percentage point (0.9%) decrease in MA penetration (P < .001) and a 7.1% decline in the average MA enrollee's risk score (P < .001). These effects are small overall, but larger in counties with low levels of traditional Medicare spending; a $10 decrease in monthly rebates was associated with a 0.64 percentage point decline in MA penetration and a 10% decrease in risk score. ACA reforms are predicted to reduce the level of rebates in lower-spending counties, leading to enrollment decreases of 1.7 to 1.9 percentage points in the lowest-spending counties. The simulation predicts that the disenrollment would come from MA enrollees with higher risk scores. CONCLUSIONS: MA enrollment responds to availability of supplemental benefits supported by rebates. ACA provisions designed to lower MA spending will predominantly affect Medicare beneficiaries living in counties where MA plans may be unable to offer a comparable product at a price similar to that of traditional Medicare. PMID- 25495113 TI - Medical cost burdens among nonelderly adults with asthma. AB - OBJECTIVES: We used the 2003-2009 Medical Expenditure Panel Survey to evaluate average annual total and out-of-pocket expenditures by nonelderly adults with asthma. STUDY DESIGN: We divided patients diagnosed with asthma into 4 groups, based on whether or not they had had an asthma attack in the previous year (a crude marker for disease severity) and whether or not they reported using treatment for their asthma. METHODS: For each group we calculated total and out of-pocket average annual spending for hospital inpatient, hospital outpatient, emergency department, and physician office care, as well as for prescription drugs. These averages were adjusted to account for differences in respondents' overall health (presence of other co-morbidities, self-reported health status, and self-reported activity limitations), sociodemographic characteristics (age, sex, race/ethnicity, income), and insurance status. RESULTS: We found that among the 4 groups, those who were receiving treatment but continued to experience asthma attacks had the highest total and out-of-pocket expenditures in all categories, consistent with their likely higher illness severity. However, patients who reported receiving treatment and did not experience attacks also reported relatively high adjusted total and out-of-pocket expenditures-most notably $536 per year out of pocket for prescription medications and $231 per year out of pocket for physician office visits. After adjustment, about the same proportion of patients in these 2 groups (13.5% who did not get treated and had attacks, and 13.8% who did get treated and avoided attacks) reported high financial burden. CONCLUSIONS: Patients may experience financial challenges to appropriate self-management of asthma, even when they are able to avoid exacerbations. PMID- 25495114 TI - Prenatal exposure to endocrine disrupting chemicals in relation to thyroid hormone levels in infants - a Dutch prospective cohort study. AB - BACKGROUND: Endocrine disrupting chemicals (EDCs) present in the environment may disrupt thyroid hormones, which in early life are essential for brain development. Observational studies regarding this topic are still limited, however as the presence of chemicals in the environment is ubiquitous, further research is warranted. The objective of the current study was to assess the association between exposure markers of various EDCs and thyroxine (T4) levels in newborns in a mother-child cohort in the Netherlands. METHODS: Exposure to dichlorodiphenyldichloroethylene (DDE), three di-2-ethylhexyl phthalate (DEHP) metabolites, hexachlorobenzene (HCB), polychlorinated biphenyl (PCB)-153, perfluorooctanesulfonic acid (PFOS), and perfluorooctanoic acid (PFOA) was determined in cord plasma or breast milk, and information on T4 levels in heel prick blood spots was obtained through the neonatal screening programme in the Netherlands. Linear regression models were composed to determine associations between each of the compounds and T4, which were stratified for gender and adjusted for a priori defined covariates. RESULTS: Mean T4 level was 86.9 nmol/L (n = 83). Girls in the highest quartile of DDE and PFOA exposure showed an increased T4 level compared to the lowest quartile with both crude and fully adjusted models (DDE > 107.50 ng/L, +24.8 nmol/L, 95% CI 0.79, 48.75; PFOA > 1200 ng/L, +38.6 nmol/L, 95% CI 13.34, 63.83). In boys a lower T4 level was seen in the second quartile of exposure for both PFOS and PFOA, however after fully adjusting the models these associations were attenuated. No effects were observed for the other compounds. CONCLUSION: DDE and perfluorinated alkyl acids may be associated with T4 in a sex-specific manner. These results should however be interpreted with caution, due to the relatively small study population. More research is warranted, as studies on the role of environmental contaminants in this area are still limited. PMID- 25495115 TI - Magnetic endoscope imaging in single-balloon enteroscopy. AB - BACKGROUND AND AIM: Magnetic endoscope imaging (MEI) provides continuous viewing of the position of the endoscope on a monitor without using X-ray and has already been established for colonoscopy. The aim of the present study was to evaluate a new MEI probe for enteroscopy. METHODS: In this prospective feasibility study, consecutive patients received single-balloon enteroscopy guided by the new MEI probe. Fluoroscopy was also used in all examinations. MEI images were compared to fluoroscopy images with respect to concordance of loop configuration by two independent observers after the examinations. Main outcome measurement was the rate of concordant MEI and fluoroscopy images with respect to loop configuration. RESULTS: In all 10 patients, single-balloon enteroscopy with MEI was carried out without any adverse events or technical difficulties. Concordance of MEI and fluoroscopy images was seen in 36/38 images (95%; 95% CI, 82-99%) by both observers. Overall agreement between the two observers was 95% (kappa = 0.47, 95% CI, -0.04-1). CONCLUSION: The use of MEI in single-balloon enteroscopy is safe and feasible. Detection and control of loops can be accurately achieved. PMID- 25495116 TI - AKE - the Accelerated k-mer Exploration web-tool for rapid taxonomic classification and visualization. AB - BACKGROUND: With the advent of low cost, fast sequencing technologies metagenomic analyses are made possible. The large data volumes gathered by these techniques and the unpredictable diversity captured in them are still, however, a challenge for computational biology. RESULTS: In this paper we address the problem of rapid taxonomic assignment with small and adaptive data models (< 5 MB) and present the accelerated k-mer explorer (AKE). Acceleration in AKE's taxonomic assignments is achieved by a special machine learning architecture, which is well suited to model data collections that are intrinsically hierarchical. We report classification accuracy reasonably well for ranks down to order, observed on a study on real world data (Acid Mine Drainage, Cow Rumen). CONCLUSION: We show that the execution time of this approach is orders of magnitude shorter than competitive approaches and that accuracy is comparable. The tool is presented to the public as a web application (url: https://ani.cebitec.uni-bielefeld.de/ake/ , username: bmc, password: bmcbioinfo). PMID- 25495117 TI - Easy preparation of self-assembled high-density buckypaper with enhanced mechanical properties. AB - A controlled assembly and alignment of carbon nanotubes (CNTs) in a high-packing density with a scalable way remains challenging. This paper focuses on the preparation of self-assembled and well-aligned CNTs with a densely packed nanostructure in the form of buckypaper via a simple filtration method. The CNT suspension concentration is strongly reflected in the alignment and assembly behavior of CNT buckypaper. We further demonstrated that the horizontally aligned CNT domain gradually increases in size when increasing the deposited CNT quantity. The resultant aligned buckypaper exhibited notably enhanced packing density, strength, modulus, and hardness compared to previously reported buckypapers. PMID- 25495118 TI - Practical recommendations for improvement of the physical health care of patients with severe mental illness. AB - OBJECTIVE: Health care for the physical health of patients with severe mental illness (SMI) needs to be improved. Therefore, we aimed to develop policy recommendations to improve this physical health care in the Netherlands based on consensus (general agreement) between the major stakeholders. METHOD: A modified Delphi was used to explore barriers and subsequently establish policy recommendations with all key stakeholders. Consensus was sought between patients with SMI, their family carers, general practitioners, and mental healthcare professionals--all experts in the everyday practice of health care. RESULTS: Consensus was reached on policy recommendations regarding (i) improvements in collaboration between healthcare professionals, (ii) the need for professional education on the specific medical risks of patients with SMI, and (iii) the distinguished responsibilities of general practitioners on the one hand and mental healthcare professionals on the other hand in taking care of patients' physical health. CONCLUSION: This article provides a range of policy recommendations that could lead to considerable improvements in the physical health of SMI patients. PMID- 25495119 TI - Probabilistic Linkage of Prehospital and Outcomes Data in Out-of-hospital Cardiac Arrest. AB - OBJECTIVE: Lack of longitudinal patient outcome data is an important barrier in emergency medical services (EMS) research. We aimed to demonstrate the feasibility of linking prehospital data from the California EMS Information Systems (CEMSIS) database to outcomes data from the California Office of Statewide Health Planning and Development (OSHPD) database for patients with out of-hospital cardiac arrest (OHCA). METHODS: We included patients age 18 years or older who sustained nontraumatic OHCA and were included in the 2010-2011 CEMSIS databases. The CEMSIS database is a unified EMS data collection system for California. The OSHPD database is a comprehensive data collection system for patient-level inpatient and emergency department encounters in California. OHCA patients were identified in the CEMSIS database using cardiac rhythm, procedures, medications, and provider impression. Probabilistic linkage blocks were created using in-hospital death or one of the following primary or secondary diagnoses (ICD-9-CM) in the OSHPD databases: cardiac arrest (427.5), sudden death (798), ventricular tachycardia (427.1), ventricular fibrillation (427.4), and acute myocardial infarction (410.xx). Blocking variables included incident date, gender, date of birth, age, and/or destination facility. Due to the volume of cases, match thresholds were established based on clerical record review for each block individually. Match variables included incident date, destination facility, date of birth, sex, race, and ethnicity. RESULTS: Of the 14,603 cases of OHCA we identified in CEMSIS, 91 (0.6%) duplicate records were excluded. Overall, 46% of the data used in the linkage algorithm were missing in CEMSIS. We linked 4,961/14,512 (34.2%) records. Linkage rates varied significantly by local EMS agency, ranging from 1.4 to 61.1% (OR for linkage 0.009-0.76; p < 0.0001). After excluding the local EMS agency with the outlying low linkage rate, we linked 4,934/12,596 (39.2%) records. CONCLUSION: Probabilistic linkage of CEMSIS prehospital data with OSHPD outcomes data was severely limited by the completeness of the EMS data. States and EMS agencies should aim to overcome data limitations so that more effective linkages are possible. PMID- 25495120 TI - Soybean DREB1/CBF-type transcription factors function in heat and drought as well as cold stress-responsive gene expression. AB - Soybean (Glycine max) is a globally important crop, and its growth and yield are severely reduced by abiotic stresses, such as drought, heat, and cold. The cis acting element DRE (dehydration-responsive element)/CRT plays an important role in activating gene expression in response to these stresses. The Arabidopsis DREB1/CBF genes that encode DRE-binding proteins function as transcriptional activators in the cold stress responsive gene expression. In this study, we identified 14 DREB1-type transcription factors (GmDREB1s) from a soybean genome database. The expression of most GmDREB1 genes in soybean was strongly induced by a variety of abiotic stresses, such as cold, drought, high salt, and heat. The GmDREB1 proteins activated transcription via DREs (dehydration-responsive element) in Arabidopsis and soybean protoplasts. Transcriptome analyses using transgenic Arabidopsis plants overexpressing GmDREB1s indicated that many of the downstream genes are cold-inducible and overlap with those of Arabidopsis DREB1A. We then comprehensively analyzed the downstream genes of GmDREB1B;1, which is closely related to DREB1A, using a transient expression system in soybean protoplasts. The expression of numerous genes induced by various abiotic stresses were increased by overexpressing GmDREB1B;1 in soybean, and DREs were the most conserved element in the promoters of these genes. The downstream genes of GmDREB1B;1 included numerous soybean-specific stress-inducible genes that encode an ABA receptor family protein, GmPYL21, and translation-related genes, such as ribosomal proteins. We confirmed that GmDREB1B;1 directly activates GmPYL21 expression and enhances ABRE-mediated gene expression in an ABA-independent manner. These results suggest that GmDREB1 proteins activate the expression of numerous soybean-specific stress-responsive genes under diverse abiotic stress conditions. PMID- 25495121 TI - Community perceptions, attitude, practices and treatment seeking behaviour for schistosomiasis in L. Victoria islands in Uganda. AB - BACKGROUND: Over 200,000 people, most of them infected with Schistosoma mansoni inhabit 150 islands in Lake Victoria in Uganda. Although a programme to control the disease has been ongoing since 2003, its implementation in islands is inadequate due to high transport costs on water. In 2011 and 2012, the Global Network for Neglected Tropical Diseases (GNNTD) through Schistosomiasis Control Initiative (SCI) provided financial support to ease treatment delivery on the islands and over the period, therapeutic coverage has been increasing. We conducted a study with an objective to assess community awareness of existence of the disease, its signs, symptoms, causes and transmission as well as attitude, practice and health seeking behavior. METHODS: This was a cross sectional descriptive study which used pre-tested interviewer administered questionnaire among purposively selected individuals in schools, health facilities and communities. Frequency distribution tables, graphs and cross tabulations were the main forms of data presentation. RESULTS: Our results showed that there are numerous challenges that must be overcome to achieve effective control of schistosomiasis in the islands. Many people especially young men are constantly on the move from island to island in search for richer fishing grounds and such groups are commonly known to miss treatment by mass chemotherapy. Unfortunately case management in health facilities is very poor; health facilities are few and understaffed mainly with unskilled personnel who are overburdened by other illnesses such as malaria and HIV and the supply of praziquantel in health facilities is inadequate. Furthermore, sanitation is appalling, no clean water and community knowledge about schistosomiasis is low even among biomedical staff. CONCLUSION: Rather than elimination, our results indicate that the programme should continue to target morbidity control beyond the 2020s until preventive measures have been instituted. The government should provide adequate trained health workers and stock praziquantel in all island health facilities. PMID- 25495122 TI - Chondroitin 4-O-sulfotransferases are required for cell adhesion and morphogenesis in the Ciona intestinalis embryo. AB - Chondroitin sulfate (CS) is a carbohydrate component of proteoglycans. Several types of sulfotransferases determine the pattern of CS sulfation, and thus regulate the biological functions of proteoglycans. The protochordate ascidians are the closest relatives of vertebrates, but the functions of their sulfotransferases have not been investigated. Here, we show that two chondroitin 4-O-sulfotransferases (C4STs) play important roles in the embryonic morphogenesis of the ascidian Ciona intestinalis. Ci-C4ST-like1 is predominantly expressed in the epidermis and muscle. Epidermal and muscle cells became spherical upon the injection of a Ci-C4ST-like1-specific morpholino oligo (MO), thus suggesting weakened cell adhesion. Co-injection of a Ci-C4ST-like1-expressing transgene rescued the phenotype, suggesting that the effects of the MO were specific. Ci C4ST-like3 was expressed in the central nervous system, muscle, and mesenchyme. A specific MO appeared to affect cell adhesion in the epidermis and muscle. Convergent extension movement of notochordal cells was also impaired. Forced expression of Ci-C4ST-like3 restored normal morphogenesis, suggesting that the effects of the MO were specific. The present study suggests that Ci-C4ST-like1 and Ci-C4ST-like3 are required for cell adhesion mainly in the epidermis and muscle. PMID- 25495123 TI - Evaluation of sour cherry (Prunus cerasus L.) fruits for their polyphenol content, antioxidant properties, and nutritional components. AB - Nutritional compounds (phenolic compounds, L-ascorbic acid), antioxidant activities, and physicochemical characteristics (fruit weight, dry matter, soluble solids, pH, acidity, total and reducing sugars) of 33 different sour cherry cultivars were studied. Polyphenols were identified by LC-PDA-QTOF/MS and quantified by UPLC-PDA-FL. A total of 41 polyphenolic compounds found were identified and presented as 14 flavan-3-ols, 11 anthocyanins, 5 hydroxycinnamic acids, 10 flavonols, and 1 flavon. The content of total polyphenols (TPs) ranged from 2982.51 ('Wisok' cultivar) to 1539.43 mg/100 g dry weight ('Erdi Nagygyupsilonmupsilonscu'cultivar). Flavan-3-ols, the major class of sour cherry polyphenols, represented ~ 40% of the TP compounds, whereas anthocyanins and hydroxycinnamic acids amounted for about 25% each. The content of l-ascorbic acid did not exceed 22.18 mg/100 g fresh matter. Some polish sour cherry cultivars (especially 'Agat', 'Ametyst', 'Wider', 'Winer', and 'Wisok') may be selected to promote the growth of cultivars with strong nutritional and phytochemical beneficial effects on human health. PMID- 25495124 TI - Effect of standardized training on the reliability of the Cochrane risk of bias assessment tool: a study protocol. AB - BACKGROUND: The Cochrane risk of bias (RoB) tool has been widely embraced by the systematic review community, but several studies have reported that its reliability is low. We aim to investigate whether training of raters, including objective and standardized instructions on how to assess risk of bias, can improve the reliability of this tool. We describe the methods that will be used in this investigation and present an intensive standardized training package for risk of bias assessment that could be used by contributors to the Cochrane Collaboration and other reviewers. METHODS/DESIGN: This is a pilot study. We will first perform a systematic literature review to identify randomized clinical trials (RCTs) that will be used for risk of bias assessment. Using the identified RCTs, we will then do a randomized experiment, where raters will be allocated to two different training schemes: minimal training and intensive standardized training. We will calculate the chance-corrected weighted Kappa with 95% confidence intervals to quantify within- and between-group Kappa agreement for each of the domains of the risk of bias tool. To calculate between-group Kappa agreement, we will use risk of bias assessments from pairs of raters after resolution of disagreements. Between-group Kappa agreement will quantify the agreement between the risk of bias assessment of raters in the training groups and the risk of bias assessment of experienced raters. To compare agreement of raters under different training conditions, we will calculate differences between Kappa values with 95% confidence intervals. DISCUSSION: This study will investigate whether the reliability of the risk of bias tool can be improved by training raters using standardized instructions for risk of bias assessment. One group of inexperienced raters will receive intensive training on risk of bias assessment and the other will receive minimal training. By including a control group with minimal training, we will attempt to mimic what many review authors commonly have to do, that is-conduct risk of bias assessment in RCTs without much formal training or standardized instructions. If our results indicate that an intense standardized training does improve the reliability of the RoB tool, our study is likely to help improve the quality of risk of bias assessments, which is a central component of evidence synthesis. PMID- 25495125 TI - Analysis of inflammatory cytokines in human blood, breath condensate, and urine using a multiplex immunoassay platform. AB - A change in the expression of cytokines in human biological media indicates an inflammatory response to external stressors and reflects an early step along the adverse outcome pathway (AOP) for various health endpoints. To characterize and interpret this inflammatory response, methodology was developed for measuring a suite of 10 different cytokines in human blood, exhaled breath condensate (EBC), and urine using an electrochemiluminescent multiplex Th1/Th2 cytokine immunoassay platform. Measurement distributions and correlations for eight interleukins (IL) (1beta, 2, 4, 5, 8, 10, 12p70 and 13), interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) were evaluated using 90 blood plasma, 77 EBC, and 400 urine samples collected from nominally healthy adults subjects in North Carolina in 2008-2012. The in vivo results show that there is sufficient sensitivity for characterizing all 10 cytokines at levels of 0.05-0.10 rhog/ml with a dynamic range up to 100 ng/ml across all three of these biological media. The measured in vivo results also show that the duplicate analysis of blood, EBC and urine samples have average estimated fold ranges of 2.21, 3.49, and 2.50, respectively, which are similar to the mean estimated fold range (2.88) for the lowest concentration (0.610 rhog/ml) from a series of spiked control samples; the cytokine method can be used for all three biological media. Nine out of the 10 cytokines measured in EBC were highly correlated within one another with Spearman rho coefficients ranging from 0.679 to 0.852, while the cytokines measured in blood had a mix of negative and positive correlations, ranging from -0.620 to 0.836. Almost all correlations between EBC and blood were positive. This work also represents the first successful within- and between-person evaluation of ultra trace-level inflammatory markers in blood, EBC, and urine. PMID- 25495126 TI - Structural waters in the minor and major grooves of DNA--a major factor governing structural adjustments of the A-T mini-helix. AB - The role of microhydration in structural adjustments of the AT-tract in B-DNA was studied at the B97-D/def2-SV(P) level. The (dA:dT)5 complexes with 10 water molecules in minor and 15 water molecules in major grooves were studied. The obtained network of hydrogen bonds revealed the dependence between the groove width and the types of water patterns. In the minor groove, the following patterns were observed: interstrand one-water bridges similar to that of the Dickerson "water spine" and interstrand two-water bridges. The network of structural waters in the major groove is more diverse than that in the minor groove, which agrees with crystallographic data. As the major groove is wider, it is enriched by water molecules forming two- and three-water bridges. Results suggest the nucleobase-water interactions in both grooves prevent AT-tract twisting and its "collapse" along the minor groove. Whereby, a helix structure with narrow minor and wide major grooves is formed. The structural waters affect the polynucleotide conformation so that it becomes similar to poly(dA).poly(dT) in fibers and acquires features of the A-tracts in DNA in solution. We suggest that formation of specific water patterns in both grooves is the factor responsible for stabilization of A-tracts with a narrowed minor groove, leading in turn to their strong intrinsic bending in DNA. PMID- 25495127 TI - Catalytic surface radical in dye-decolorizing peroxidase: a computational, spectroscopic and site-directed mutagenesis study. AB - Dye-decolorizing peroxidase (DyP) of Auricularia auricula-judae has been expressed in Escherichia coli as a representative of a new DyP family, and subjected to mutagenic, spectroscopic, crystallographic and computational studies. The crystal structure of DyP shows a buried haem cofactor, and surface tryptophan and tyrosine residues potentially involved in long-range electron transfer from bulky dyes. Simulations using PELE (Protein Energy Landscape Exploration) software provided several binding-energy optima for the anthraquinone-type RB19 (Reactive Blue 19) near the above aromatic residues and the haem access-channel. Subsequent QM/MM (quantum mechanics/molecular mechanics) calculations showed a higher tendency of Trp-377 than other exposed haem neighbouring residues to harbour a catalytic protein radical, and identified the electron-transfer pathway. The existence of such a radical in H2O2-activated DyP was shown by low-temperature EPR, being identified as a mixed tryptophanyl/tyrosyl radical in multifrequency experiments. The signal was dominated by the Trp-377 neutral radical contribution, which disappeared in the W377S variant, and included a tyrosyl contribution assigned to Tyr-337 after analysing the W377S spectra. Kinetics of substrate oxidation by DyP suggests the existence of high- and low-turnover sites. The high-turnover site for oxidation of RB19 (k(cat) > 200 s-1) and other DyP substrates was assigned to Trp-377 since it was absent from the W377S variant. The low-turnover site/s (RB19 k(cat) ~20 s 1) could correspond to the haem access-channel, since activity was decreased when the haem channel was occluded by the G169L mutation. If a tyrosine residue is also involved, it will be different from Tyr-337 since all activities are largely unaffected in the Y337S variant. PMID- 25495129 TI - Identification of a novel orally bioavailable phosphodiesterase 10A (PDE10A) inhibitor with efficacy in animal models of schizophrenia. AB - We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described. PMID- 25495128 TI - Programming thermoresponsiveness of NanoVelcro substrates enables effective purification of circulating tumor cells in lung cancer patients. AB - Unlike tumor biopsies that can be constrained by problems such as sampling bias, circulating tumor cells (CTCs) are regarded as the "liquid biopsy" of the tumor, providing convenient access to all disease sites, including primary tumor and fatal metastases. Although enumerating CTCs is of prognostic significance in solid tumors, it is conceivable that performing molecular and functional analyses on CTCs will reveal much significant insight into tumor biology to guide proper therapeutic intervention. We developed the Thermoresponsive NanoVelcro CTC purification system that can be digitally programmed to achieve an optimal performance for purifying CTCs from non-small cell lung cancer (NSCLC) patients. The performance of this unique CTC purification system was optimized by systematically modulating surface chemistry, flow rates, and heating/cooling cycles. By applying a physiologically endurable stimulation (i.e., temperature between 4 and 37 degrees C), the mild operational parameters allow minimum disruption to CTCs' viability and molecular integrity. Subsequently, we were able to successfully demonstrate culture expansion and mutational analysis of the CTCs purified by this CTC purification system. Most excitingly, we adopted the combined use of the Thermoresponsive NanoVelcro system with downstream mutational analysis to monitor the disease evolution of an index NSCLC patient, highlighting its translational value in managing NSCLC. PMID- 25495130 TI - Cell-penetrating hyperbranched polyprodrug amphiphiles for synergistic reductive milieu-triggered drug release and enhanced magnetic resonance signals. AB - The rational design of theranostic nanoparticles exhibiting synergistic turn-on of therapeutic potency and enhanced diagnostic imaging in response to tumor milieu is critical for efficient personalized cancer chemotherapy. We herein fabricate self-reporting theranostic drug nanocarriers based on hyperbranched polyprodrug amphiphiles (hPAs) consisting of hyperbranched cores conjugated with reduction-activatable camptothecin prodrugs and magnetic resonance (MR) imaging contrast agent (Gd complex), and hydrophilic coronas functionalized with guanidine residues. Upon cellular internalization, reductive milieu-actuated release of anticancer drug in the active form, activation of therapeutic efficacy (>70-fold enhancement in cytotoxicity), and turn-on of MR imaging (~9.6-fold increase in T1 relaxivity) were simultaneously achieved in the simulated cytosol milieu. In addition, guanidine-decorated hPAs exhibited extended blood circulation with a half-life up to ~9.8 h and excellent tumor cell penetration potency. The hyperbranched chain topology thus provides a novel theranostic polyprodrug platform for synergistic imaging/chemotherapy and enhanced tumor uptake. PMID- 25495131 TI - Impact of commercial precooking of common bean (Phaseolus vulgaris) on the generation of peptides, after pepsin-pancreatin hydrolysis, capable to inhibit dipeptidyl peptidase-IV. AB - The objective of this research was to determine the bioactive properties of the released peptides from commercially available precook common beans (Phaseolus vulgaris). Bioactive properties and peptide profiles were evaluated in protein hydrolysates of raw and commercially precooked common beans. Five varieties (Black, Pinto, Red, Navy, and Great Northern) were selected for protein extraction, protein and peptide molecular mass profiles, and peptide sequences. Potential bioactivities of hydrolysates, including antioxidant capacity and inhibition of alpha-amylase, alpha-glucosidase, dipeptidyl peptidase-IV (DPP-IV), and angiotensin converting enzyme I (ACE) were analyzed after digestion with pepsin/pancreatin. Hydrolysates from Navy beans were the most potent inhibitors of DPP-IV with no statistical differences between precooked and raw (IC50 = 0.093 and 0.095 mg protein/mL, respectively). alpha-Amylase inhibition was higher for raw Red, Navy and Great Northern beans (36%, 31%, 27% relative to acarbose (rel ac)/mg protein, respectively). alpha-Glucosidase inhibition among all bean hydrolysates did not show significant differences; however, inhibition values were above 40% rel ac/mg protein. IC50 values for ACE were not significantly different among all bean hydrolysates (range 0.20 to 0.34 mg protein/mL), except for Red bean that presented higher IC50 values. Peptide molecular mass profile ranged from 500 to 3000 Da. A total of 11 and 17 biologically active peptide sequences were identified in raw and precooked beans, respectively. Peptide sequences YAGGS and YAAGS from raw Great Northern and precooked Pinto showed similar amino acid sequences and same potential ACE inhibition activity. Processing did not affect the bioactive properties of released peptides from precooked beans. Commercially precooked beans could contribute to the intake of bioactive peptides and promote health. PMID- 25495132 TI - Lignans from the stems and leaves of Brandisia hancei and their effects on VEGF induced vascular permeability and migration of HRECs and DLAV formation in zebrafish. AB - In our continuing search for novel antiangiogenic agents, a new lignan glycoside, (7R,8R)-1-(4-O-beta-d-glucopyranosyl-3-methoxyphenyl)-2-{2-methoxy-4-[1-(E) propene-3-ol]-phenoxyl}-propane-1,3-diol (1), along with three known lignans (2 4), were isolated from the 80% EtOH extract of Brandisia hancei stems and leaves. These isolates (1-4) were subjected to an in vitro bioassay to evaluate their effects on vascular endothelial growth factor (VEGF)-induced vascular permeability and migration of human retinal endothelial cells (HRECs). Of the compounds tested, compound 1 resulted in the greatest reduction in VEGF-induced vascular permeability by about 31.5% at 10 MUM compared to the VEGF-treated control. In the migration assay, compounds 1 and 2 significantly decreased VEGF induced HREC migration. Furthermore, zebrafish embryos treated with compounds 1 and 2 showed mild reductions of dorsal longitudinal anastomotic vessel (DLAV) formation. PMID- 25495133 TI - Safety and toxicity concerns of orally delivered nanoparticles as drug carriers. AB - INTRODUCTION: The popularity of nanotechnology is increasing and revolutionizing extensively the drug delivery field. Nanoparticles, as carriers for oral delivery of drugs, have been claimed as the perfect candidates to overcome the poor bioavailability of most of the drugs by improving their solubility and/or permeability across biological barriers. However, this is still a promise to be fulfilled. AREAS COVERED: In this review, several nanosystems used as oral drug carriers are described along with their toxicological profiles. A number of nanoparticles based on different types of materials such as polymers, lipids, silica, silicon, carbon and metals are reviewed. Both in vitro and in vivo-based toxicological studies are discussed in this paper. EXPERT OPINION: Toxicological concerns have been raised in the past few years regarding the safety of the developed nanosystems. Assuming that most of the materials used are biocompatible and biodegradable, the toxicity caused by them when formulated into nanoparticles is usually neglected by the scientific community, existing only a few number of studies that approach the toxicity of the nanosystems. This is particularly important, because the materials that composed of the nanoparticles as well as their features such as size, charge and surface properties, will influence their pharmacokinetics after oral administration. PMID- 25495134 TI - One-year open-label safety evaluation of the fixed combination of ibuprofen and famotidine with a prospective analysis of dyspepsia. AB - OBJECTIVE: To assess the long-term safety of the single-tablet combination of ibuprofen 800 mg and famotidine 26.6 mg. RESEARCH DESIGN AND METHODS: A phase 3b open-label study (NCT00984815) was conducted in 86 adults requiring daily non steroidal anti-inflammatory drug (NSAID) administration for >=12 months. The combination tablet of ibuprofen/famotidine was self-administered orally three times daily for up to 54 consecutive weeks. Adverse events (AEs) were collected beginning at the first dose and continued through completion (54 weeks). The Severity of Dyspepsia Assessment (SODA) questionnaire was completed by patients to assess tolerability. RESULTS: Most patients (65%) finished the trial, with 76% contributing data at 6 months, and 21% withdrew due to adverse effects. Overall and gastrointestinal AE discontinuation rates (21% and 13%, respectively) were lower than that previously reported with ibuprofen 2400 mg given alone. Each of the SODA subscale scores demonstrated improvement by week 6 and improved statistically significantly at week 24 and week 54. Of the cardiovascular AEs, hypertension was reported most frequently (9/86, 9.3%), with 3.5% determined to be drug related. Twelve serious AEs were reported by 9 of 86 (10%) patients; two were considered possibly related to the study medication (unstable angina and gastric ulcer). There were no reports of serious gastrointestinal or CV complications. Most AEs were mild or moderate in severity and not considered drug related. CONCLUSIONS: These data, together with previously reported findings of a significant decrease in upper gastrointestinal endoscopic ulcer rate at 6 months, support the overall safety, compliance, and tolerability of this single-tablet formulation. PMID- 25495135 TI - Multicenter COMPACT study of COMplications in patients with sickle cell disease and utilization of iron chelation therapy. AB - BACKGROUND: Over the past few decades, lifespans of sickle cell disease (SCD) patients have increased; hence, they encounter multiple complications. Early detection, appropriate comprehensive care, and treatment may prevent or delay onset of complications. OBJECTIVE: We collected longitudinal data on sickle cell disease (SCD) complication rates and associated resource utilization relative to blood transfusion patterns and iron chelation therapy (ICT) use in patients aged >=16 years to address a gap in the literature. RESEARCH DESIGN AND METHODS: Medical records of 254 SCD patients >=16 years were retrospectively reviewed at three US tertiary care centers. MAIN OUTCOME MEASURES: We classified patients into cohorts based on cumulative units of blood transfused and ICT history: <15 units, no ICT (Cohort 1 [C1]), >=15 units, no ICT (Cohort 2 [C2]), and >=15 units with ICT (Cohort 3 [C3]). We report SCD complication rates per patient per year; cohort comparisons use rate ratios (RRs). RESULTS: Cohorts had 69 (C1), 91 (C2), and 94 (C3) patients. Pain led to most hospitalizations (76%) and emergency department (ED) (82%) visits. Among transfused patients (C2+C3), those receiving ICT were less likely to experience SCD complications than those who did not (RR [95% CI] C2 vs. C3: 1.33 [1.25-1.42]). Similar trends (RR [95% CI]) were observed in ED visits and hospitalizations associated with SCD complications (C2 vs. C3, ED: 1.94 [1.70-2.21]; hospitalizations: 1.61 [1.45-1.78]), but not in outpatient visits. CONCLUSIONS: Although the most commonly reported SCD complication among all patients was pain, patients who received ICT were less likely to experience pain and other complications than those who did not. These results highlight the need for increased patient and provider education on the importance of comprehensive disease management. PMID- 25495136 TI - Risk of recurrent venous thromboembolism among deep vein thrombosis and pulmonary embolism patients treated with warfarin. AB - OBJECTIVE: Guidelines for warfarin treatment of venous thromboembolism (VTE) recommend targeting an international normalized ratio (INR) level of 2-3. This study examines the association between INR levels and VTE recurrence among warfarin-treated patients. METHODS: A retrospective cohort study in the MedMining electronic health record database included adults treated with warfarin for VTE in 2004-2011. INR levels during warfarin use were categorized as below therapeutic range (<2), in range (2-3), or above range (>3), with time in each category estimated using the Rosendaal method. Recurrent VTE was noted from 30 days after the initial VTE to end of follow-up, which ranged up to 8 years. The incidence of recurrent VTE was calculated, and association with time-varying INR levels estimated using Cox models. RESULTS: Of 1753 qualifying patients, 867 had deep vein thrombosis, and 886 had pulmonary embolism. Mean age was 58 years, and 50.7% were female. Across all follow-up time, VTE recurrences were observed in 134 (7.6%) patients, at a rate of 3.2 (95% confidence interval [CI]: 0.7-9.1) events per 100 person-years. The risk of VTE recurrence was greater during time spent with INR <2 than with INR in the therapeutic range (hazard ratio [HR]: 3.37; 95% CI: 2.16-5.27). Low platelet counts also predicted greater risk of VTE recurrence (HR: 2.13; 95% CI: 1.24-3.67). LIMITATIONS: Exposure to warfarin and other anticoagulants was estimated based on prescription data and may be inaccurate. The study data include care within a single health system; thus, care received outside of the health system may be missing, and results may not be generalizable to the broader US population. CONCLUSIONS: Approximately 8% of patients experienced a recurrent VTE during follow-up. Subtherapeutic INR levels were associated with a more than three-fold increased risk of VTE recurrence. PMID- 25495137 TI - Evaluation of the effect of trypsin digestion buffers on artificial deamidation. AB - Nonenzymatic deamidation occurs readily under the condition of trypsin digestion, resulting in the identification of many artificial deamidation sites. To evaluate the effect of trypsin digestion buffers on artificial deamidation, we compared the three commonly used buffers Tris-HCl (pH 8), ammonium bicarbonate (ABC), and triethylammonium bicarbonate (TEAB), and ammonium acetate (pH 6), which was reported to reduce Asn deamidation. iTRAQ quantification on rat kidney tissue digested in these four buffers indicates that artificial Asn deamidation is produced in the order of ammonium acetate < Tris-HCl < ABC < TEAB, and Gln deamidation has no significant differences in all tested buffers. Label-free experiments show the same trend, while protein and unique peptide identification are comparable using these four buffers. To explain the differences of these four buffers in producing artificial Asn deamidation, we determined the half-life of Asn deamidation in these buffers using synthetic peptides containing -Asn-Gly- sequences. It is 51.4 +/- 6.0 days in 50 mM of ammonium acetate (pH 6) at 37 degrees C, which is about 23, 104, and 137 times that in Tris-HCl, ABC, and TEAB buffers, respectively. In conclusion, ammonium acetate (pH 6) is more suitable than other tested buffers for characterizing endogenous deamidation and N glycosylation. PMID- 25495138 TI - Glycomimetics versus multivalent glycoconjugates for the design of high affinity lectin ligands. PMID- 25495140 TI - Cryptic speciation within the Neotropical cichlid Geophagus brasiliensis (Quoy & Gaimard, 1824) (Teleostei Cichlidae): a new paradigm in karyotypical and molecular evolution. AB - The family Cichlidae is one of the most species-rich taxa in the Neotropics. However, the factors that determine these high levels of biodiversity remain unexplored. We have analyzed the morphological, cytogenetic, and molecular data from 62 specimens of a widespread cichlid, Geophagus brasiliensis, from three adjacent basins in southeastern Brazil. Morphological analyses did not show differences among specimens. The cytogenetic data indicate the occurrence of multiple nucleolar organizer regions and four sympatric karyotypes that differ in the first pair of chromosome morphology, in the Doce River Basin; whereas the karyotype from the Paraiba do Sul Basin is widely divergent. The molecular data- 616 bp fragment of cytochrome oxidase subunit I--revealed two haplogroups with the deepest genetic divergence (6.4%) ever reported within a nominal species in the Neotropical Region: One of the haplogroups is restricted to the quaternary lakes in the middle portion of the Doce Basin and the Mucuri River, whereas the other haplogroup is composed of haplotypes from elsewhere in the Doce Basin and the Paraiba do Sul Basin. These patterns suggest that G. brasiliensis undergoes a cryptic speciation process involving three major lineages that differ from the African explosive cichlid radiation. PMID- 25495139 TI - Low prevalence of methicillin resistant Staphylococcus aureus as determined by an automated identification system in two private hospitals in Nairobi, Kenya: a cross sectional study. AB - BACKGROUND: Staphylococcus aureus (S.aureus) is a major cause of both healthcare and community acquired infections. In developing countries, manual phenotypic tests are the mainstay for the identification of staphylococci with the tube and slide coagulase tests being relied upon as confirmatory tests for S. aureus. The subjectivity associated with interpretation of these tests may result in misidentification of coagulase negative staphylococci as S.aureus. Given that antibiotic resistance is more prevalent in CONS, this may result in over estimation of methicillin resistant S.aureus (MRSA) prevalence. METHODS: A review of susceptibility data from all non-duplicate S.aureus isolates generated between March 2011 and May 2013 by the Vitek-2 (bioMerieux) automated system was performed by the authors. The data was generated routinely from processed clinical specimens submitted to the microbiology laboratories for culture and sensitivity at the Aga Khan University Hospital and Gertrude's children's hospital both situated in Nairobi. RESULTS: Antimicrobial susceptibility data from a total of 731 non-duplicate S.aureus isolates was reviewed. Majority (79.2%) of the isolates were from pus swabs. Only 24 isolates were both cefoxitin and oxacillin resistant while 3 were resistant to oxacillin but susceptible to cefoxitin giving an overall MRSA prevalence of 3.7% (27/731). None of the isolates were resistant to mupirocin, linezolid, tigecycline, teicoplanin or vancomycin. CONCLUSION: The prevalence of MRSA in this study is much lower than what has been reported in most African countries. The significant change in antibiotic susceptibility compared to what has previously been reported in our hospital is most likely a consequence of the transition to an automated platform rather than a trend towards lower resistance rates. PMID- 25495142 TI - Sea-urchin-like Au nanocluster with surface-enhanced raman scattering in detecting epidermal growth factor receptor (EGFR) mutation status of malignant pleural effusion. AB - Somatic mutations in the epidermal growth factor receptor (EGFR) gene are common in patients with lung adenocarcinomas and are associated with sensitivity to the small-molecule tyrosine kinase inhibitors (TKIs). For 10%-50% of the patients who experienced malignant pleural effusion (MPE), pathological diagnosis might rely exclusively on finding lung cancer cells in the MPE. Current methods based on polymerase chain reaction were utilized to test EGFR mutation status of MPE samples, but the accuracy of the test data was very low, resulting in many patients losing the chance of TKIs treatment. Herein, we synthesized the sea urchin-like Au nanocluster (AuNC) with an average diameter of 92.4 nm, composed of 15-nm nanopricks. By introducing abundant sharp nanopricks, the enhancement factor of AuNC reached at 1.97 * 10(7). After capped with crystal violet (CV), polyethylene glycol, and EGFR mutation specific antibody, the AuNC-EGFR had excellent surface-enhanced Raman scattering (SERS) activity and EGFR mutation targeted recognition capability in lung cancer cells. Characteristic SERS signal at 1617 cm(-1) of CV was linear correlation with the number of H1650 cells, demonstrating the minimum detection limit as 25 cells in a 1-mL suspension. The gold mass in single H1650 cells exposed to AuNC-E746_750 for 2 h ranged from 208.6 pg to 231.4 pg, which approximately corresponded to 56-62 AuNCs per cell. Furthermore, SERS was preclinically utilized to test EGFR mutation status in MPE samples from 35 patients with lung adenocarcinoma. Principal component analysis (PCA) and the support vector machine (SVM) algorithm were constructed for EGFR mutation diagnostic analysis, yielding an overall accuracy of 90.7%. SERS measurement based on sea-urchin-like AuNC was an efficient method for EGFR mutation detection in MPE, and it might show great potential in applications such as predicting gene typing of clinical lung cancer in the near future. PMID- 25495141 TI - Gender, smoking and tobacco reduction and cessation: a scoping review. AB - Considerations of how gender-related factors influence smoking first appeared over 20 years ago in the work of critical and feminist scholars. This scholarship highlighted the need to consider the social and cultural context of women's tobacco use and the relationships between smoking and gender inequity. Parallel research on men's smoking and masculinities has only recently emerged with some attention being given to gender influences on men's tobacco use. Since that time, a multidisciplinary literature addressing women and men's tobacco use has spanned the social, psychological and medical sciences. To incorporate these gender related factors into tobacco reduction and cessation interventions, our research team identified the need to clarify the current theoretical and methodological interpretations of gender within the context of tobacco research. To address this need a scoping review of the published literature was conducted focussing on tobacco reduction and cessation from the perspective of three aspects of gender: gender roles, gender identities, and gender relations. Findings of the review indicate that there is a need for greater clarity on how researchers define and conceptualize gender and its significance for tobacco control. Patterns and anomalies in the literature are described to guide the future development of interventions that are gender-sensitive and gender-specific. Three principles for including gender-related factors in tobacco reduction and cessation interventions were identified: a) the need to build upon solid conceptualizations of gender, b) the importance of including components that comprehensively address gender related influences, and c) the importance of promoting gender equity and healthy gender norms, roles and relations. PMID- 25495144 TI - Dosage effect of high-amylose modifier gene(s) on the starch structure of maize amylose-extender mutant. AB - The objective of this study was to investigate how dosages of high-amylose modifier (HAM) gene(s) affected the structure of maize amylose extender (ae) mutant starch. GEMS-0067 (G), a homozygous mutant of ae and the HAM gene(s), and H99ae (H), an ae single mutant, were self-pollinated or inter-crossed to produce maize endosperms of G/G, G/H, H/G, and H/H with 3, 2, 1, and 0 doses of HAM gene(s), respectively. Endosperm starch was fractionated into amylopectin, amylose, and intermediate component (IC) of large and small molecular weights using 1-butanol precipitation of amylose followed by gel-permeation chromatography. Increases in the dosage of HAM gene(s) from 0 to 3 decreased the amylopectin content. The HAM-gene dosage significantly changed the branch chain length of small-molecular-weight IC, but had little effect on the branch chain length distributions of amylopectin and large-molecular-weight IC and the molecular structure of amylose. PMID- 25495143 TI - Palliative care case managers in primary care: a descriptive study of referrals in relation to treatment aims. AB - BACKGROUND: Three important elements of the World Health Organization (WHO) definition of palliative care are: 1) it includes patients who may have cure or life prolongation as treatment aims besides palliative care; 2) it is not exclusively for cancer patients; and 3) it includes attention to the medical, psychological, social, and spiritual needs of the patients and their families. Case managers (nurses with expertise in palliative care) may assist generalist primary care providers in delivery of good palliative care. OBJECTIVES: This study investigates the referral of patients to case managers in primary care with regard to the three elements mentioned: diagnosis, treatment aims, and needs as reflected in reasons given for referral. METHODS: In this cross-sectional survey in primary care among case managers and referrers to case management, case managers completed questionnaires for 687 patients; referrers completed 448 (65%). RESULTS: Most patients referred have a combination of treatment aims (69%). Life expectancy and functional status of patients are lower for those with a treatment aim of palliation. Almost all (96%) of those referred are cancer patients. A need for psychosocial support is frequently given as a reason for referral (66%) regardless of treatment aim. CONCLUSIONS: Referrals to case managers reflect two of three elements of the WHO definition. Mainly, patients are referred for support complementary to medical care, and relatively early in their disease trajectory. However, most of those referred are cancer patients. Thus, to fully reflect the definition, broadening the scope to reach other patient groups is important. PMID- 25495145 TI - RNA-Seq profile of flavescence doree phytoplasma in grapevine. AB - BACKGROUND: The phytoplasma-borne disease flavescence doree is still a threat to European viticulture, despite mandatory control measures and prophylaxis against the leafhopper vector. Given the economic importance of grapevine, it is essential to find alternative strategies to contain the spread, in order to possibly reduce the current use of harmful insecticides. Further studies of the pathogen, the vector and the mechanisms of phytoplasma-host interactions could improve our understanding of the disease. In this work, RNA-Seq technology followed by three de novo assembly strategies was used to provide the first comprehensive transcriptomics landscape of flavescence doree phytoplasma (FD) infecting field-grown Vitis vinifera leaves. RESULTS: With an average of 8300 FD mapped reads per library, we assembled 347 sequences, corresponding to 215 annotated genes, and identified 10 previously unannotated genes, 15 polycistronic transcripts and three genes supposedly localized in the gaps of the FD92 draft genome. Furthermore, we improved the annotation of 44 genes with the addition of 5'/3' untranslated regions. Functional classification revealed that the most expressed genes were either related to translation and protein biosynthesis or hypothetical proteins with unknown function. Some of these hypothetical proteins were predicted to be secreted, so they could be bacterial effectors with a potential role in modulating the interaction with the host plant. Interestingly, qRT-PCR validation of the RNA-Seq expression values confirmed that a group II intron represented the FD genomic region with the highest expression during grapevine infection. This mobile element may contribute to the genomic plasticity that is necessary for the phytoplasma to increase its fitness and endorse host adaptive strategies. CONCLUSIONS: The RNA-Seq technology was successfully applied for the first time to analyse the FD global transcriptome profile during grapevine infection. Our results provided new insights into the transcriptional organization and gene structure of FD. This may represent the starting point for the application of high-throughput sequencing technologies to study differential expression in FD and in other phytoplasmas with an unprecedented resolution. PMID- 25495147 TI - The influence of a sustained multifaceted approach to improve antibiotic prescribing in Slovenia during the past decade: findings and implications. AB - INTRODUCTION: Rising antibiotic resistance has become an increasing public health problem. There is a well-established correlation between antibiotic consumption and antimicrobial resistance. Consequently, measures to rationalize the prescribing of antibiotics should reduce the resistant strains. Following a 24% increase in antibiotic consumption at the end of the 1990s, multiple activities were designed and introduced by the Health Insurance Institute of Slovenia (ZZZS) and other organizations in Slovenia at the end of 1999. These activities reduced the antibiotic consumption by 18.7% by 2002. These measures have continued. OBJECTIVE: To study changes in antibiotic utilization from 1995 to 2012 alongside the multiple interventions and their consequences, including changes in resistance patterns. METHODS: This was a retrospective observational study involving all patients dispensed at least one ZZZS prescription for an antibiotic in Slovenia. Utilization was expressed in defined daily doses per thousand inhabitants per day. Multifaceted interventions were conducted over time involving all key stakeholder groups, that is, the Ministry of Health, ZZZS, physician groups and patients. These included comprehensive communication programs as well as prescribing restrictions for a number of antibiotics and classes. RESULTS: From 1999 to 2012, antibiotic consumption decreased by 2-9% per year, with an overall decrease of 31%. There were also appreciable structural changes. Overall antibiotic utilization and the utilization of 7 out of 10 antibiotics significantly decreased after multiple interventions. The resistance of Streptococcus pneumoniae to penicillin decreased in line with decreased utilization. However, its resistance to macrolides increased from 5.4 to 21% despite halving of its utilization. The resistance of Escherichia coli to fluoroquinolones doubled from 10 to 21% despite utilization decreasing by a third. Expenditures on antibiotics decreased by 53%. CONCLUSION: Multiple demand side measures introduced following increased utilization significantly decreased subsequent antibiotic utilization and associated costs. However, there was variable impact on antibiotic resistance. Additional targeted activities are planned to further reduce antibiotic prescribing and resistance. PMID- 25495146 TI - Participation of irradiated Anopheles arabiensis males in swarms following field release in Sudan. AB - BACKGROUND: The success of the sterile insect technique (SIT) depends the release of large numbers of sterile males, which are able to compete for mates with the wild male population within the target area. Unfortunately, the processes of colonisation, mass production and irradiation may reduce the competitiveness of sterile males through genetic selection, loss of natural traits and somatic damage. In this context, the capacity of released sterile Anopheles arabiensis males to survive, disperse and participate in swarms at occurring at varying distances from the release site was studied using mark-release-recapture (MRR) techniques. METHODS: In order to assess their participation in swarms, irradiated and marked laboratory-reared male mosquitoes were released 50, 100 or 200 m from the known site of a large swarm on three consecutive nights. Males were collected from this large swarm on subsequent nights. Over the three days a total of 8,100 males were released. Mean distance travelled (MDT), daily probability of survival and estimated population size were calculated from the recapture data. An effect of male age at the time of release on these parameters was observed. RESULTS: Five per cent of the males released over three days were recaptured. In two-, three- and four-day-old males, MDT was 118, 178 and 170 m, and the daily survival probability 0.95, 0.90 and 0.75, respectively. From the recapture data on the first day following each release, the Lincoln index gives an estimation of 32,546 males in the natural population. DISCUSSION: Sterile An. arabiensis males released into the field were able to find and participate in existing swarms, and possibly even initiate swarms. The survival probability decreased with the age of male on release but the swarm participation and the distance travelled by older males seemed higher than for younger males. The inclusion of a pre-release period may thus be beneficial to male competitiveness and increase the attractiveness of adult sexing techniques, such as blood spiking. PMID- 25495148 TI - Thermally triggered self-assembly of folded proteins into vesicles. AB - We report thermally triggered self-assembly of folded proteins into vesicles that incorporates globular proteins as building blocks. Leucine zipper coiled coils were combined with either globular proteins or elastin-like polypeptides as recombinant fusion proteins, which form "rod-coil" and "globule-rod-coil" protein complex amphiphiles. In aqueous solution, they self-assembled into hollow vesicles via temperature-responsive inverse phase transition. The characteristic of the protein vesicle membranes enables preferential encapsulation of simultaneously formed protein coacervate. Furthermore, the type of encapsulated cargo extends to small molecules and nanoparticles. Our approach offers a versatile strategy to create protein vesicles as vehicles with biological functionality. PMID- 25495149 TI - What a difference a decade has not made: the murky electronic structure of iron monocyanide (FeCN) and iron monoisocyanide (FeNC). AB - Formidable multireference character is known to exist in the quartet states of the neutral radicals iron monocyanide (FeCN) and iron monoisocyanide (FeNC), even more so than the controversial FeH radical (which is now definitively known to have a (4)Delta ground electronic state). In the initial theoretical study, it was found that the gas phase adiabatic (4)Delta <- (6)Delta transition energy plummeted with improving treatment of dynamical correlation, and final results suggested that FeCN ((4)Delta) and FeNC ((6)Delta) isomers have different ground electronic states. The (4)Delta ground state for FeCN has been since verified experimentally. In this work, an ab initio composite method employing coupled cluster theory up to full quadruple excitations (CCSDTQ) and large basis set CCSDT computations is compared to multireference configuration interaction (MRCI) energies at a level of sophistication far superior to the 2004 study [ DeYonker et al. J. Chem. Phys. 2004 , 120 , 4726 ]. Despite advances in the treatment of scalar relativistic effects, improved iron basis sets, and massive increases in computer processing power over the past decade, multireference methodologies still fail to find the correct ground state for FeCN, with large basis set MRCISD+Q results providing a qualitatively poor adiabatic (4)Delta <- (6)Delta transition energy, in error by nearly 5000 cm(-1). Coupled cluster theory with post-CCSD(T) additive corrections produces the (4)Delta FeCN ground state, with the (6)Delta state only 306 cm(-1) higher in energy. The ground electronic state of FeNC is computed to be (6)Delta and is only 45 cm(-1) higher in energy than the (4)Delta FeCN state while it is 741 cm(-1) lower in energy than the FeNC (4)Delta excited state. Surprisingly, an additional CCSDT additive correction for core-valence correlation shifts the FeNC transition energy in favor of a (4)Delta ground state, with a (4)Delta <- (6)Delta Te of 227 cm(-1). PMID- 25495150 TI - Full recovery case after 82 minutes out-of-hospital cardiac arrest: importance of chain of survival and predicting outcome. AB - A middle age man underwent immediate cardiopulmonary resuscitation (CPR) for ventricular fibrillation (VF) occurred in an ambulance. After arrival in a regional hospital, return of spontaneous circulation (ROSC) was achieved 82 minutes after the collapse. He was in coma even three hours after ROSC. So, he was transferred to our university hospital to receive therapeutic hypothermia (TH). An initial bispectral index (BIS) value suggested a favorable outcome. Thus we decided to aggressive therapies including TH of 34 degrees C for 48 hours, followed by a very slow rewarming at the rate of 1 degrees C per day. Eventually he was discharged from the hospital with good neurological state. This case shows us two points: 1) the importance of the chain of survival: CPR done immediately after the collapse, persistent CPR for refractory VF, followed by coronary interventions after ROSC, continuing care to the university hospital, 2) decision making for TH using BIS monitoring. PMID- 25495151 TI - Impact of hospital mergers on staff job satisfaction: a quantitative study. AB - BACKGROUND: Hospital mergers began in the UK in the late 1990s to deal with underperformance. Despite their prevalence, there is a lack of research on how such organizational changes affect the staff morale. This study aims to assess the impact of NHS hospital mergers between financial years 2009/10 and 2011/12 on staff job satisfaction and to identify factors contributing to satisfaction. METHODS: Data on staff job satisfaction were obtained from the annual NHS Staff Survey. A list of mergers was compiled using data provided by the Cooperation and Competition Panel and the Department of Health. Other sources of data included the NHS Hospital Estates and Facilities Statistics, the NHS 'Quarter' publication, official reports from health service regulators, individual hospitals' annual accounts, data from the NHS Information Centre and the NHS Recurrent Revenue Allocations Exposition Book. Only full mergers of acute and mental health hospitals were analyzed. Propensity scores were generated using observable factors likely to affect merger decision to select three comparable hospitals for every constituent hospital in a merger to act as a control group. A difference-in-difference was estimated between baseline (3 years before merger approval) and each subsequent year up to 4 years post-merger, controlling for work environment, drivers of job satisfaction, data year, type of hospital and occupation group. RESULTS: There were nine mergers during the study period. Only job satisfaction scores 1 to 2 years before (0.03 to 0.04 point) and 1 year after merger approval (0.06 point) were higher (P < 0.01) than baseline. Robustness testing produced consistent findings. Assuming other conditions were equal, an increase in autonomy, staff support, perceived quality and job clarity ratings would increase job satisfaction scores. Higher job satisfaction scores were also associated with being classified as medical, dental, management or administrative staff and working in a mental health trust. CONCLUSION: Hospital mergers have a small, transient positive impact on staff job satisfaction in the year immediately before and after merger approval. Continuous staff support and management of staff expectations throughout a merger may help to increase staff job satisfaction during the challenging period of merger. PMID- 25495153 TI - Conforming to coordinate: children use majority information for peer coordination. AB - Humans are constantly required to coordinate their behaviour with others. As this often relies on everyone's convergence on the same strategy (e.g., driving on the left side of the road), a common solution is to conform to majority behaviour. In this study, we presented 5-year-old children with a coordination problem: To retrieve some rewards, they had to choose the same of four options as a peer partner--in reality a stooge--whose decision they were unable to see. Before making a choice, they watched a video showing how other children from their partner's peer group had behaved; a majority chose the same option and a minority chose a different one. In a control condition, children watched the same video but could then retrieve the reward irrespective of their partner's choice (i.e., no coordination was necessary). Children followed the majority more often when coordination was required. Moreover, conformers mostly justified their choices by referring to the majority from the video demonstration. This study is the first to show that young children are able to strategically coordinate decisions with peers by conforming to the majority. PMID- 25495154 TI - Topological properties determined by atomic buckling in self-assembled ultrathin Bi(110). AB - Topological insulators (TIs) are a new type of electronic materials in which the nontrivial insulating bulk band topology governs conducting boundary states with embedded spin-momentum locking. Such edge states are more robust in a two dimensional (2D) TI against scattering by nonmagnetic impurities than in its three-dimensional (3D) variant, because in 2D the two helical edge states are protected from the only possible backscattering. This makes the 2D TI family a better candidate for coherent spin transport and related applications. While several 3D TIs are already synthesized experimentally, physical realization of 2D TI is so far limited to hybrid quantum wells with a tiny bandgap that does not survive temperatures above 10 K. Here, combining first-principles calculations and scanning tunneling microscopy/spectroscopy (STM/STS) experimental studies, we report nontrivial 2D TI phases in 2-monolayer (2-ML) and 4-ML Bi(110) films with large and tunable bandgaps determined by atomic buckling of Bi(110) films. The gapless edge states are experimentally detected within the insulating bulk gap at 77 K. The band topology of ultrathin Bi(110) films is sensitive to atomic buckling. Such buckling is sensitive to charge doping and could be controlled by choosing different substrates on which Bi(110) films are grown. PMID- 25495152 TI - The incidence and pattern of copollinator diversification in dioecious and monoecious figs. AB - Differences in breeding system are associated with correlated ecological and morphological changes in plants. In Ficus, dioecy and monoecy are strongly associated with different suites of traits (tree height, population density, fruiting frequency, pollinator dispersal ecology). Although approximately 30% of fig species are pollinated by multiple species of fig-pollinating wasps, it has been suggested that copollinators are rare in dioecious figs. Here, we test whether there is a connection between the fig breeding system and copollinator incidence and diversification by conducting a meta-analysis of molecular data from pollinators of 119 fig species that includes new data from 15 Asian fig species. We find that the incidence of copollinators is not significantly different between monoecious and dioecious Ficus. Surprisingly, while all copollinators in dioecious figs are sister taxa, only 32.1% in monoecious figs are sister taxa. We present hypotheses to explain those patterns and discuss their consequences on the evolution of this mutualism. PMID- 25495155 TI - What information is provided in Australian emergency departments about fitness-to drive after mild traumatic brain injury: a national survey. AB - BACKGROUND/AIM: Occupational therapists work together with their medical and nursing colleagues to ensure that patients are able to return to safe and legal driving upon discharge from the emergency department after a range of illnesses and/or injuries. This study aimed to determine the type of information that is provided nationally in emergency departments to people after mild traumatic brain injury (mTBI), with respect to fitness-to-drive. METHODS: Cross-sectional electronic survey mailed to all emergency departments in Australia (N = 110). Responses were invited from medical, nursing, and allied-health professionals. The survey asked respondents to comment about the existence and use of fitness-to drive management guidelines, as well as their opinion on when clearance should be given to return to driving post injury. RESULTS: 104 clinicians completed the survey; the majority of respondents were medical staff (n = 46, 51%) followed by allied-health staff (n = 23, 25%), with the highest response rate provided from Victoria (n = 41, 45%). Just over one-third of respondents' emergency departments (n = 34, 36%) recommended a period of 'no driving' after mTBI, and within these departments, this recommendation was usually provided by medical staff (n = 25, 80%). Consensus was not displayed with respect to the safest time to return to driving after mTBI. Opinions from respondents strongly suggested that a review of fitness-to-drive management guidelines was required for mTBI patients (n = 78, 88%). CONCLUSION: No consensus exists in the fitness-to-drive recommendations provided to patients after mTBI, and clinicians have reported the need for a review of fitness-to-drive management guidelines in Australian emergency departments. With their understanding about the complex interplay of the skills required for safe driving, occupational therapists are positioned to help guide the development of protocols in this area. PMID- 25495156 TI - Differential expression analysis of miRNA in peripheral blood mononuclear cells of patients with non-segmental vitiligo. AB - Vitiligo is a common depigmentary skin disease that may follow a pattern of multifactorial inheritance. The essential factors of its immunopathogenesis is thought to be the selective destruction of melanocytes. As a new class of microregulators of gene expression, miRNA have been reported to play vital roles in autoimmune diseases, metabolic diseases and cancer. This study sought to characterize the different miRNA expression pattern in the peripheral blood mononuclear cells (PBMC) of patients with non-segmental vitiligo (NSV) and healthy individuals and to examine their direct responses to thymosin alpha1 (Talpha1) treatment. The miRNA expression profile in the PBMC of patients with NSV was analyzed using Exiqon's miRCURY LNA microRNA Array. The differentially expressed miRNA were validated by real-time quantitative polymerase chain reaction. We found that the expression levels of miR-224-3p and miR-4712-3p were upregulated, and miR-3940-5p was downregulated in the PBMC. The common clinical immune modulator Talpha1 changed the miRNA expression profile. Our analysis showed that differentially expressed miRNA were associated with the mechanism of immune imbalance of vitiligo and that Talpha1 could play an important role in changing the expression of these miRNA in the PBMC of patients with NSV. This study provided further evidence that miRNA may serve as novel drug targets for vitiligo therapeutic evaluation. PMID- 25495157 TI - Impacts of emerging contaminants on surrounding aquatic environment from a youth festival. AB - The youth festival as we refer to Spring Scream, a large-scale pop music festival, is notorious for the problems of drug abuse and addiction. The origin, temporal magnitudes, potential risks and mass inputs of emerging contaminants (ECs) were investigated. Thirty targeted ECs were analyzed by solid-phase extraction and liquid chromatography coupled to tandem mass spectrometry (SPE-LC MS/MS). Sampling strategy was designed to characterize EC behavior in different stages (before and after the youth festival), based on multivariate data analysis to explore the contributions of contaminants from normal condition to the youth festival. Wastewater influents and effluents were collected during the youth festival (approximately 600 000 pop music fans and youth participated). Surrounding river waters are also sampled to illustrate the touristic impacts during peak season and off-season. Seasonal variations were observed, with the highest concentrations in April (Spring Scream) and the lowest in October (off season). Acetaminophen, diclofenac, codeine, ampicillin, tetracycline, erythromycin-H2O, and gemfibrozil have significant pollution risk quotients (RQs > 1), indicating ecotoxicological concerns. Principal component analysis (PCA) and weekly patterns provide a perspective in assessing the touristic impacts and address the dramatic changes in visitor population and drug consumption. The highest mass loads discharged into the aquatic ecosystem corresponded to illicit drugs/controlled substances such as ketamine and MDMA, indicating the high consumption of ecstasy during Spring Scream. PMID- 25495158 TI - Regeneration of corneal epithelium utilizing a collagen vitrigel membrane in rabbit models for corneal stromal wound and limbal stem cell deficiency. AB - PURPOSE: This study was performed to evaluate the potential of a collagen-based membrane, collagen vitrigel (CV), for reconstructing corneal epithelium in the stromal wound and limbal stem cell deficiency (LSCD) models. METHODS: Three groups of rabbits were used in the stromal wound model: CV affixed using fibrin glue (CV + FG group, n = 9), fibrin glue only (FG group, n = 3) and an untreated control group (n = 3). In the LSCD model, one group received CV containing human limbal epithelial cells (CV + hLEC group, n = 2) and the other was an untreated control (n = 1). Gross observation, including fluorescent staining, pathological examination, immunohistochemistry and electron microscopy, was used to evaluate the effect of CV on the corneal epithelium. RESULTS: In the stromal wound model, fluorescent staining showed that epithelial reconstruction occurred as rapidly in the CV + FG group as it did in the control group. The pathological examination proved that the CV supported a healthy corneal epithelium in the CV + FG group, whereas FG led to hypertrophy and inappropriate differentiation of corneal epithelium in the FG group. In the LSCD model, the corneas in the CV + hLEC group showed sustained tissue transparency with good epithelialization, low inflammatory response and reduced neovascularization. However, the control cornea was translucent and showed high amounts of inflammation and neovascularization. CONCLUSION: We have demonstrated that CV supports corneal epithelial differentiation and prevents epithelial hypertrophy, in addition to serving as a scaffold for hLEC transplantation, without complications. PMID- 25495159 TI - Integrative self-knowledge and marital satisfaction. AB - Married Iranian couples (N = 210) responded to the Integrative Self-Knowledge Scale along with a measure of marital satisfaction, the International Personality Item Pool (IPIP) Big Five, and an index of interpersonal problems. Integrative self-knowledge correlated positively with marital satisfaction, positively with all but the extraversion Big Five traits, and negatively with three indices of interpersonal problems. Integrative self-knowledge also mediated a number of personality relationships with marital satisfaction. Spouse-ratings of personality confirmed the adaptive implications of integrative self-knowledge for marriage. Linkages with questionnaire response styles supported the description of integrative self-knowledge as a measure of both self-insight and self development. Results confirmed the potential of integrative self-knowledge for studying self-regulatory processes and suggested that the enhancement of self knowledge may be a useful goal in efforts to strengthen marriages. PMID- 25495160 TI - Smoking on school property as a risk factor for substance use among adolescent smokers. AB - The purpose of the current study was to determine if smoking on high-school property was associated with increased risk for other substance use among U.S. adolescents. Secondary analyses were carried out with data from the 2011 Youth Risk Behavior Survey (YRBS, N = 15,503). Only adolescents who reported smoking at least one cigarette in the last 30 days were selected for analyses (n = 2531, 44% female). Alcohol, marijuana, and cocaine use was assessed among participants. Binary logistic regression analysis was carried out to examine the relationship between smoking on school property (yes versus no) with each of the substance use variables. Adolescent smokers who reported smoking on school property were significantly more likely to report substance use across all substances examined compared to smokers who did not smoke on campus. For example, campus smokers were 3.91 times more likely to use marijuana in their lifetime and 3.85 times more likely to have used crack or cocaine in their lifetime compared to smokers who did not smoke on campus. Health care providers who provide services to adolescents should screen for smoking on school property to help identify adolescents at increased risk for substance use. PMID- 25495161 TI - Assessing the factor structure of the Chinese conformity to masculine norms inventory. AB - The purpose of the present study was to examine the factor structure and assess the reliability of the Chinese Conformity to Masculine Norms Inventory-46 (CCMNI 46). Using a cohort of 254 Hong Kong-born Chinese males, scale reliability determination involved the internal consistencies of the entire instrument. Ages of respondents ranged from 18 to 81 years (M = 38.05; SD = 17.3). Confirmatory factor analysis provided support for the psychometric properties of the CCMNI-46, thus confirming the multidimensional structure of the CMNI-46 and the replicability of the CMNI using a Hong Kong Chinese sample. All items loaded onto the corresponding factor with the exception of one item from the emotional control subscale. The overall reliability of the CCMNI-46 was lower than previous Western studies and may well reflect the subtle diversity of masculinity across cultures. The findings offered psychometric support for use of the CCMNI-46 in research and practice regarding Hong Kong Chinese masculinity. The CCMNI-46 provides a useful template for the operationalization of masculine norms in Chinese society. PMID- 25495162 TI - The construct validity of the work-related flow inventory in a sample of Australian workers. AB - The purpose of this study was to examine the construct validity of the WOrk reLated Flow inventory (WOLF; Bakker, 2008). This instrument was administered to 711 men and women who were working in Queensland, Australia. The results from the confirmatory factor analysis showed that the WOLF has moderately acceptable construct validity, with the three-factor model being a borderline fit to the data. Tests of the convergent validity of the WOLF yielded satisfactory results. However, the analysis of the discriminant validity of the WOLF showed that the instrument poorly discriminated between work enjoyment and intrinsic work motivation. Follow-up exploratory factor analysis, using recommended procedures for determining the number of factors to extract, revealed a two-factor solution, with the work enjoyment and intrinsic work motivation items loading on the same factor. Drawing on literature on psychological flow and motivation, as well as the findings of the present study, questions are raised over the adequacy of the conceptual basis of the three-factor model of work-related flow, the discriminant validity of the WOLF subscales, and the appropriateness of the wording of several of this measure's items. Using alternative methods and measures to investigate flow in work settings is recommended. PMID- 25495163 TI - Emotional intelligence as a basis for self-esteem in young adults. AB - As self-esteem is likely to build on favorable social experiences, such as those derived from achievement (i.e., GPA) and social competence, emotional intelligence is likely to be pivotal in fostering social experiences conducive to self-esteem. Accordingly, emotional intelligence is likely to underlie social competence and mediate the contribution of achievement to self-esteem. This uncharted role is the focus of this study, which surveyed 405 undergraduates in Hong Kong, China. Results demonstrated the pivotal role of emotional intelligence. Essentially, emotional intelligence appeared to be a strong determinant of self-esteem and explain away the positive effect of social competence on self-esteem. The results imply the value of raising emotional intelligence in order to consolidate the basis for the young adult's self-esteem. PMID- 25495164 TI - Body Dissatisfaction and Eating Disorder Symptomatology: A Latent Structural Equation Modeling Analysis of Moderating Variables in 18-to-28-Year-Old Males. AB - Although body dissatisfaction is recognized as the strongest risk factor for eating disturbances, a majority of young males are body dissatisfied, but do not concomitantly report severe levels of eating disorder symptomatology. The present investigation was designed to examine five theoretically relevant variables (i.e., body checking, emotional dysregulation, perfectionism, insecure-anxious attachment, and self-esteem) as potential moderators of the relationship between body dissatisfaction and two critical components of male eating disorder symptomatology: drive for muscularity and bulimic behaviors. Data collected from 551 Italian males between 18 and 28 years old were analyzed using latent structural equation modeling. The authors found that emotional dysregulation, body checking, insecure-anxious attachment and perfectionism intensified the relationship between body dissatisfaction and each criterion variable representing male eating disorder symptomatology; the interactions accounted respectively for an additional 2%, 7%, 4% and 5% of variance in drive for muscularity and for an additional 6%, 4%, 5%, and 2% of the variance in bulimic behaviors. By contrast self-esteem weakened this relationship and the interactions accounted for an additional 3% of the variance in both drive for muscularity and bulimic behaviors. Implications of these findings for prevention and treatment of male eating disturbances are discussed. PMID- 25495166 TI - Cervical screening uptake in a dermatology cohort on immunosuppressive agents. PMID- 25495167 TI - Semitransparent polymer-based solar cells with aluminum-doped zinc oxide electrodes. AB - With the use of two transparent electrodes, organic polymer-fullerene solar cells are semitransparent and may be combined to parallel-connected multijunction devices or used for innovative applications like power-generating windows. A challenging issue is the optimization of the electrodes, to combine high transparency with adequate electric properties. In the present work, we study the potential of sputter-deposited aluminum-doped zinc oxide as an alternative to the widely used but relatively expensive indium tin oxide (ITO) as cathode material in semitransparent polymer-fullerene solar cells. Concerning the anode, we utilized an insulator-metal-insulator structure based on ultrathin Au films embedded between two evaporated MoO3 layers, with the outer MoO3 film (capping layer) serving as a light coupling layer. The performance of the ITO-free semitransparent polymer-fullerene solar cells was systematically studied as dependent on the thickness of the capping layer and the active layer as well as the illumination direction. These variations were found to have strong impact on the obtained photocurrent densities. We performed optical simulations of the electric field distribution within the devices using the transfer-matrix method, to analyze the origin of the current density variations in detail and provide deep insight into the device physics. With the conventional absorber materials studied here, optimized ITO-free and semitransparent devices reached 2.0% power conversion efficiency and a maximum optical transmission of 60%, with the device concept being potentially transferable to other absorber materials. PMID- 25495168 TI - The effect of Metformin on endometrial tumor-regulatory genes and systemic metabolic parameters in polycystic ovarian syndrome--a proof-of-concept study. AB - The aim of this proof-of-concept study was to determine the effects of three month Metformin therapy on the expression of tumor-regulatory genes (p53, cyclin D2 and BCL-2) in the endometrium of women with polycystic ovary syndrome (PCOS). A total of 40 women, aged between 21 and 45 years with PCOS (Rotterdam criteria) were recruited. The participants were assessed at pre- and 3-month-post-Metformin therapy for the menstrual regularities, weight reduction, Ferriman Galway scores, fasting blood glucose (FBG), total cholesterol, LDL, HDL and p53, BCL-2 and cyclin D2 gene expression. Five participants conceived spontaneously after the initial recruitment. Majority (68%) resumed regular menstrual cycles after Metformin. There were significant reduction in BMI (p = 0.001), weight (p = 0.001) and Ferriman Galway scores (p = 0.001). A significant improvement was seen in mean FBG (p = 0.002), total cholesterol (p = 0.001), LDL (p = 0.003) and HDL cholesterol levels (p = 0.015). Tumor suppressor gene (p53) was significantly up regulated after Metformin (10 out of 14 women), with p value 0.016. BCL-2 and cyclin D2 (oncogenes) were slightly up-regulated without significant difference (p = 0.119 and 0.155, respectively). In conclusion, Metformin therapy improved clinical and metabolic parameters in women with PCOS and up-regulated p53 tumor suppressor gene significantly. Further studies are however required to independently validate our findings. PMID- 25495169 TI - Very late relapse of Philadelphia chromosome positive acute megakaryoblastic leukemia. PMID- 25495170 TI - Trends in survival outcomes of B-lineage acute lymphoblastic leukemia in elderly patients: analysis of Surveillance, Epidemiology, and End Results database. AB - B-lineage acute lymphoblastic leukemia (B-ALL) in the elderly population is generally considered to have a poor prognosis. It is unclear whether their survival has improved in the current era. Using the Surveillance, Epidemiology, and End Results database, we selected 717 elderly patients (age>=60) with B-ALL diagnosed between 1992 and 2011. Overall survival (OS) was compared based on their period of diagnosis and age. Patients in the age group 60-69 had an improvement in OS over time, both 1-year OS (49.4% in 2002-2011 vs. 33.1% in 1992 2001) and 5-year OS (20.4% in 2002-2011 vs. 8.1% in 1992-2001, p=0.002). Patients>=70 years had no significant improvement in 1-year OS or 5-year OS (5 year OS 5.5% in 1992-2001 vs. 9.7% in 2002-2011, p=0.326). Hence, there are discrepancies in the improvement of OS among elderly patients with B-ALL. Further focus of research in elderly patients with B-ALL is needed to improve their outcome. PMID- 25495172 TI - Antithymocyte globulin for graft-versus-host disease prophylaxis: mistakenly maligned. PMID- 25495173 TI - Dasatinib-induced immunosuppression and recurrent respiratory tract infections. PMID- 25495174 TI - Mixed fields on RhD typing as an indication of loss of heterozygosity on chromosome 1p in acute myeloid leukemia. PMID- 25495175 TI - Invited review: Neuropathology of tauopathies: principles and practice. AB - Tauopathies are clinically, morphologically and biochemically heterogeneous neurodegenerative diseases characterized by the deposition of abnormal tau protein in the brain. The neuropathological phenotypes are distinguished based on the involvement of different anatomical areas, cell types and presence of distinct isoforms of tau in the pathological deposits. The nomenclature of primary tauopathies overlaps with the modern classification of frontotemporal lobar degeneration. Neuropathological phenotypes comprise Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, formerly called also as neurofibrillary tangle-only dementia, and a recently characterized entity called globular glial tauopathy. Mutations in the gene encoding the microtubule-associated protein tau are associated with frontotemporal dementia and parkinsonism linked to chromosome 17. In addition, further neurodegenerative conditions with diverse aetiologies may be associated with tau pathologies. Thus, the spectrum of tau pathologies and tauopathy entities expands beyond the traditionally discussed disease forms. Detailed multidisciplinary studies are still required to understand their significance. PMID- 25495176 TI - Faculty perceptions of key factors in interprofessional education. AB - Embedding interprofessional education (IPE) into academic programs presents structural, curricular and human factor challenges. Nurses and physicians comprise the dominant dyad in healthcare, and therefore nursing and medical faculty are key in guiding future IPE approaches. However, faculty experiences with IPE are rarely reported. This paper presents perceptions of medical and nursing faculty about key factors related to IPE for pre-licensure medical and nursing students. Semi-structured interviews with 32 faculty from three Midwest universities were analyzed thematically in this phenomenological study based on collaboration and cooperation theories. Findings clustered into six categories. Specific subthemes little discussed in the literature are addressed in detail. Study participants felt the most powerful interprofessional student experiences were authentic and faculty-facilitated, that constructive clinical environments were crucial, that curriculum design challenges included disparities between undergraduate and graduate education, and that leadership commitment to full-time and adjunct faculty engagement and development was imperative. PMID- 25495177 TI - Black and White men younger than 50 years of age demonstrate similar outcomes after radical prostatectomy. AB - BACKGROUND: Black men with prostate cancer are diagnosed at a younger age, present with more aggressive disease, and experience higher mortality. We sought to assess pathological features and biochemical recurrence (BCR) in young men undergoing radical prostatectomy (RP) to determine if there is a difference between black and white men closer to the time of disease initiation. METHODS: We identified 551 white and 99 black men at a tertiary cancer center who underwent RP at <=50 years of age. Baseline and pathological features were compared between the two groups. Cox proportional hazards models were utilized to examine the association of race and BCR, and Kaplan-Meier curves were generated to determine biochemical recurrence-free survival (bRFS). RESULTS: There were no differences in median age at surgery, biopsy Gleason score, or comorbidity. Black men had higher preoperative PSA (6.1 ng/ml vs 4.7 ng/ml, p = 0.004), but a greater percentage were cT1c (78% vs 63%), compared to white men. On multivariate analysis, black men demonstrated significantly lower odds of non-organ confined disease (OR 0.39; 95% CI: 0.18, 0.81; p = 0.01) and extracapsular extension (ECE) (OR 0.38; 95% CI: 0.18, 0.81, p = 0.01), and had no difference in Gleason score upgrading and seminal vesicle invasion compared to white men. There was no significant difference in bRFS in men with organ-confined disease; however, among men with locally advanced disease black men trended towards greater BCR (p = 0.052). Black men had 2-year bRFS of 56% vs 75% in white men. CONCLUSIONS: In this single institution study, there does not appear to be a racial disparity in outcomes among younger men who receive RP for prostate cancer. Black and white men in our cohort demonstrate similar bRFS with pathologically confirmed organ confined disease. There may be greater risk of BCR among black men locally advanced disease compared to white men, suggesting that locally advanced disease is biologically more aggressive in black men. PMID- 25495178 TI - Rosuvastatin treatment in stable chronic obstructive pulmonary disease (RODEO): a randomized controlled trial. AB - OBJECTIVES: The objective of this study was to examine whether statin therapy is associated with enhanced endothelium-dependent vascular function, improved pulmonary function and reduced systemic inflammation in patients with chronic obstructive pulmonary disease (COPD). DESIGN AND SETTING: This randomized, placebo-controlled, double-blind, parallel trial including patients with COPD was performed at two University hospitals in Norway. SUBJECTS, INTERVENTION AND MEASUREMENTS: Patients with stable COPD (n = 99) were assigned randomly to receive rosuvastatin 10 mg (n = 49) or matching placebo (n = 50) once daily for 12 weeks. The primary outcome measure was change in endothelium-dependent vascular function measured using peripheral arterial tonometry and expressed as the reactive hyperaemia index. Secondary end-points were change in pulmonary function, as assessed by forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC), and change in the circulating levels of the inflammatory markers interleukin-6 (IL6) and high-sensitivity C-reactive protein (hsCRP). RESULTS: In the overall study population, no significant between-group difference in change in endothelium-dependent vascular or pulmonary function was observed. Rosuvastatin therapy was associated with a reduction in hsCRP (-20% vs. 11%, P = 0.017) and an attenuation of the rise in IL6 concentration (8% vs. 30%, P = 0.028) compared with placebo. In a prespecified subgroup analysis of patients with a supra-median circulating hsCRP concentration (>1.7 mg L(-1) ), rosuvastatin was associated with improved endothelium-dependent vascular function (13% vs. 2%, P = 0.026). CONCLUSIONS: In stable COPD patients without the standard indications for statin therapy, rosuvastatin treatment is associated with a significant attenuation of systemic inflammation and improvement in endothelial-dependent vascular function in patients with evidence of systemic inflammation. PMID- 25495179 TI - Evaluation of pregnancy and delivery in 13 women who underwent resection of a sacrococcygeal teratoma during early childhood. AB - BACKGROUND: Sacrococcygeal teratoma resection often brings changes in pelvic anatomy and physiology with possible consequences for defecation, micturition and sexual function. It is unknown, whether these changes have any gynecological and obstetric sequelae. Until now four pregnancies after sacrococcygeal teratoma resection have been described and cesarean section has been suggested to be the method of choice for delivery. We evaluated the pregnancy course and mode of delivery in women previously treated for a sacrococcygeal teratoma. METHODS: The records of all patients who underwent sacrococcygeal teratoma resection after 1970 in one of the six pediatric surgical centers in the Netherlands were reviewed retrospectively. Women aged 18 years and older were eligible for participation. Patient characteristics, details about the performed operation and tumor histology were retrieved from the records. Consenting participants completed a questionnaire addressing fertility, pregnancy and delivery details. RESULTS: Eighty-nine women were eligible for participation; 20 could not be traced. Informed consent was received from 41, of whom 38 returned the completed questionnaire (92.7%). Thirteen of these 38 women conceived, all but one spontaneously. In total 20 infants were born, 17 by vaginal delivery and 3 by cesarean section, in one necessitated by previous intra-abdominal surgery as a consequence of sacrococcygeal teratoma resection. Conversion to a cesarean section was never necessary. None of the 25 women without offspring reported involuntary childlessness. CONCLUSIONS: There are no indications that resection of a sacrococcygeal teratoma in female patients is associated with reduced fertility: spontaneous pregnancy is possible and vaginal delivery is safe for mother and child, irrespective of the sacrococcygeal teratoma classification or tumor histology. PMID- 25495180 TI - Positional changes of a pluripotency marker gene during structural reorganization of fibroblast nuclei in cloned early bovine embryos. AB - Cloned bovine preimplantation embryos were generated by somatic cell nuclear transfer (SCNT) of bovine fetal fibroblasts with a silent copy of the pluripotency reporter gene GOF, integrated at a single site of a chromosome 13. GOF combines the regulatory Oct4/Pou5f1 sequence with the coding sequence for EGFP. EGFP expression served as a marker for pluripotency gene activation and was consistently detected in preimplantation embryos with 9 and more cells. Three dimensional radial nuclear positions of GOF, its carrier chromosome territory and non-carrier homolog were measured in nuclei of fibroblasts, and of day 2 and day 4 embryos, carrying 2 to 9 and 15 to 22 cells, respectively. We tested, whether transcriptional activation was correlated with repositioning of GOF toward the nuclear interior either with a corresponding movement of its carrier chromosome territory 13 or via the formation of a giant chromatin loop. A significant shift of GOF away from the nuclear periphery was observed in day 2 embryos together with both carrier and non-carrier chromosome territories. At day 4, GOF, its carrier chromosome territory 13 and the non-carrier homolog had moved back toward the nuclear periphery. Similar movements of both chromosome territories ruled out a specific GOF effect. Pluripotency gene activation was preceded by a transient, radial shift of GOF toward the nuclear interior. The persistent co-localization of GOF with its carrier chromosome territory rules out the formation of a giant chromatin loop during GOF activation. PMID- 25495182 TI - Clinical management of multiple sclerosis and neuromyelitis optica with therapeutic monoclonal antibodies: approved therapies and emerging candidates. AB - Therapeutic monoclonal antibodies (mAbs) are a relatively novel class of drugs that has substantially advanced immunotherapy for patients with multiple sclerosis. The advantage of these agents is that they bind specifically and exclusively to predetermined proteins or cells. Natalizumab was the first mAb in neurology to obtain approval. It is also considered one of the most potent options for annualized relapse rate reduction among available therapeutic options. Alemtuzumab is currently also approved in several countries. Several mAbs have been tested in clinical studies in multiple sclerosis. Here, we review the history of drug development of therapeutic mAbs and their classification. Furthermore, we outline the putative mechanisms of action, clinical evidence and safety of approved mAbs and those in different stages of clinical development in multiple sclerosis and neuromyelitis optica. PMID- 25495183 TI - One-dimensional approach to study kinetics of reversible binding of protein on capillary walls. AB - We introduce a method for kinetic characterization of reversible binding of protein onto the inner capillary wall. In essence, a short plug of the protein solution is propagated through the capillary by pressure, and the protein is detected at the distal capillary end. The signal versus time profile is fitted with a numerical model which uses the rate constants of adsorption, kad, and desorption, kde, as fitting parameters. The values of kad and kde which result in the best fit are considered to be the sought ones. We first used COMSOL multiphysics software to develop a numerical model with two-dimensional (2D) equations of mass transfer. Although 2D models in general can describe experiments more accurately than one-dimensional (1D) models, computing 2D models takes much more time (many hours to find two parameters: kad and kde). We used the fact that the capillary is narrow and long to develop a simplified model with 1D equations of mass transfer. Our comparison of the 1D and 2D models showed that the errors of the 1D approximation were less than 5%, whereas the computation of the 1D model was 100 times faster. We finally used the 1D approach to study kinetics of reversible binding of conalbumin to the uncoated fused-silica capillary walls. We determined kad, kde, and a diffusion coefficient, D. The obtained value of D is in excellent agreement with literature data which suggests that the values of kad and kde (for which there are no literature data) are also calculated correctly. Our approach for finding kad and kde will facilitate quantitative characterization of protein adsorption on capillary walls as well as properties of passivating materials used for capillary coating. PMID- 25495184 TI - Performance on the Test of Memory Malingering in children with neurological conditions. AB - Despite increasing interest in the use of performance validity tests with youth, relatively little is known about how children and adolescents with neurological diagnoses perform on these measures. The purpose of this study was to examine performance on the Test of Memory Malingering (TOMM) in a general pediatric neurologic sample. Data were obtained from 266 consecutive patients (mean age = 13.0, SD = 3.7, range = 5-18) referred for a neuropsychological assessment in a tertiary care pediatric hospital. As part of a broader neuropsychological battery, patients were administered the TOMM. In this sample, 94% of children passed the TOMM. Pass rate was 87% for 5-7 year-olds but was >= 90% for all other ages. Children with a history of stroke had the lowest pass rate (86%), with other diagnostic groups scoring >= 90%, including epilepsy, traumatic brain injury, and hydrocephalus. Lower TOMM performance was related to slower processing speed and weaker memory performance. The results support using the TOMM with children and adolescents who have neurological diagnoses. Caution may still be warranted when interpreting scores in those who are younger and/or who have more significant cognitive difficulty. PMID- 25495185 TI - Association of dietary glycemic index and glycemic load with endometrial cancer risk among Chinese women. AB - We evaluated the association of dietary glycemic index (GI) and glycemic load (GL) with the risk of endometrial cancer in a population-based, case-control study of 1199 endometrial cancer patients and 1212 age-frequency-matched controls in urban Shanghai, China, where diets are typically high in carbohydrates and have a high GL. Information on dietary habits, physical activity, and other relevant information was collected using a validated questionnaire, and anthropometric measurements were taken. Logistic regression was applied in the analysis. Dietary GI and GL were independently associated with risk for endometrial cancer but carbohydrate intake was unrelated to risk. Multivariable adjusted odds ratios (ORs) for increasing quartiles of intake were 1.0, 1.3, 1.4, and 2.2 [95% confidence interval (CI): 1.2-4.0] for dietary GL (P(trend) = 0.02) and 1.0, 1.2, 1.4, and 1.4 (95% CI: 1.0-2.0) for dietary GI (P(trend) = 0.02). High intake of staples, especially rice, was positively associated with endometrial cancer. The association with GI was more evident among lean and normal weight women, although the test for interaction was not significant. This study suggests that intake of high GL or GI foods, but not carbohydrates per se, may increase risk for endometrial cancer. PMID- 25495186 TI - Medicago truncatula symbiosis mutants affected in the interaction with a biotrophic root pathogen. PMID- 25495187 TI - Diversity and disparity through time in the adaptive radiation of Antarctic notothenioid fishes. AB - According to theory, adaptive radiation is triggered by ecological opportunity that can arise through the colonization of new habitats, the extinction of antagonists or the origin of key innovations. In the course of an adaptive radiation, diversification and morphological evolution are expected to slow down after an initial phase of rapid adaptation to vacant ecological niches, followed by speciation. Such 'early bursts' of diversification are thought to occur because niche space becomes increasingly filled over time. The diversification of Antarctic notothenioid fishes into over 120 species has become one of the prime examples of adaptive radiation in the marine realm and has likely been triggered by an evolutionary key innovation in the form of the emergence of antifreeze glycoproteins. Here, we test, using a novel time-calibrated phylogeny of 49 species and five traits that characterize notothenioid body size and shape as well as buoyancy adaptations and habitat preferences, whether the notothenioid adaptive radiation is compatible with an early burst scenario. Extensive Bayesian model comparison shows that phylogenetic age estimates are highly dependent on model choice and that models with unlinked gene trees are generally better supported and result in younger age estimates. We find strong evidence for elevated diversification rates in Antarctic notothenioids compared to outgroups, yet no sign of rate heterogeneity in the course of the radiation, except that the notothenioid family Artedidraconidae appears to show secondarily elevated diversification rates. We further observe an early burst in trophic morphology, suggesting that the notothenioid radiation proceeds in stages similar to other prominent examples of adaptive radiation. PMID- 25495188 TI - Growth hormone secretion decreases with age in paediatric Prader-Willi syndrome. AB - OBJECTIVE: Growth hormone deficiency is a common feature of Prader-Willi syndrome; however, biochemical deficiency is not uniformly demonstrated. Criteria for GH treatment in paediatric PWS vary with some countries requiring documentation of biochemical GH deficiency. Data regarding the significance of age in the interpretation of GH stimulation test results, particularly in infants, are lacking. We aimed to assess age-related trends in the prevalence of biochemical GH deficiency in infants and children with PWS. DESIGN: A retrospective chart review was conducted. Data from children with Prader-Willi syndrome that had GH stimulation tests performed at the Hospital for Sick Children in Toronto between the years 2000 and 2012 were collected. PATIENT: Charts of 47 children 0.4-15.5 years of age with PWS that had GH stimulation tests were reviewed. MEASUREMENTS: Biochemical GH status in relation to age and body mass index. RESULTS: Thirty-two of 47 patients (68%) were biochemically GH deficient. GH deficiency was significantly associated with older age (r = 0.45, P = 0.02) and higher body-mass-index z-score (r = 0.45, P = 0.02). Biochemical GH deficiency was less prevalent up to 18 months of age (3/11 27%) compared with older children (29/36 [81%]; P = 0.001). A higher prevalence of GH deficiency was also detected in obese patients (14/16 [88%]) compared with nonobese patients (18/31 [58%]; P = 0.04). CONCLUSIONS: The utility of performing GH stimulation tests as an indication of GH status under 18 months of age in Prader-Willi syndrome is questionable. If performed, results should be carefully interpreted in the context of age. PMID- 25495190 TI - Effects of graded levels of tannin-containing tropical tree leaves on in vitro rumen fermentation, total protozoa and methane production. AB - AIMS: This study was carried out to determine the effect of graded levels of tannin-containing tropical tree leaves, Autocarpus integrifolis, Azardirachta indica and Ficus bengalensis, on the in vitro rumen fermentation pattern, total protozoa and methane suppression in order to establish the optimum dose of these leaves for inclusion in the ruminant diets. METHODS AND RESULTS: The air-dried and ground samples of Au. integrifolis, Az. indica and Ficus bengalensis were subjected to in vitro incubation using 30 ml buffered rumen fluid at 0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0 and 30.0% (dry matter refers to moisture-free basis) of a total mixed ration (TMR: refers to mixture of roughage and concentrate containing cereals and oil cakes) devoid of tannin. The TMR for the experimental incubation was prepared by mixing 40 parts of ground Elusine coracana straw as roughage source with 60 parts of concentrate mixture. The leaves contained an average 130 g kg(-1) CP with 7.0 MJ of ME kg(-1) DM. The average neutral detergent fibre (NDF) content was <400 g kg(-1) DM. Highest total phenol (TP; g kg(-1) DM) was recorded in Az. indica (108) followed by F. bengalensis (103) and Au. integrifolis (76), and total tannin (TT) content also showed similar trend. However, condensed tannin (CT) was highest in F. bengalensis (260) followed by Au. integrifolis (186) and Az. indica (138). There was significant (P < 0.05) reduction in the NH3 concentration in the presence of all the leaves. Autocarpus integrifolis tannins did not cause inhibition of total volatile fatty acid (TVFA: refers to the concentration of volatile fatty acids, viz. acetic, butyric and propionic) concentration, whereas F. bengalensis and Az. indica tannins at higher level of incubation (>5.0%) reduced TVFA concentration. Protozoa (cells per mL) were similar at all levels of inclusion with Au. integrifolis, but reduced in case of F. bengalensis and Az. indica. As the level of tannin increased in the incubation medium, there was a linear reduction in methane concentration. Highest methane reduction (%) was recorded in incubations supplemented with Az. indica (61.5) followed by F. bengalensis (46.8) and Au. integrifolis (30.3). CONCLUSIONS: It was established from this study that tropical leaves of F. bengalensis, Au. integrifolis and Az. indica suppress methanogenesis. SIGNIFICANCE AND IMPACT OF THE STUDY: Ficus bengalensis, Au. integrifolis and Az. indica leaves are of interest in the enteric methane ameliorative strategies. Total mixed ration containing 10-15% ground F. bengalensis or Au. integrifolis or Az. indica leaves could be fed to ruminants to reduce enteric methanogenesis. However, in vivo trials need to be carried out to validate these in vitro results. PMID- 25495189 TI - TAZ regulates cell proliferation and epithelial-mesenchymal transition of human hepatocellular carcinoma. AB - The transcriptional coactivator with PDZ binding motif (TAZ) has been reported to be one of the nuclear effectors of Hippo-related pathways. TAZ is expressed in many primary tumors and could regulate many biological processes. However, little is known about the role of TAZ in hepatocellular carcinoma (HCC). In the current study, we show that TAZ regulates cellular proliferation and epithelial mesenchymal transition (EMT) of HCC. TAZ is overexpressed in HCC tissues and cell lines and upregulation of TAZ correlates with a lower overall survival rate of HCC patients after hepatic resection. TAZ knockdown results in inhibition of cancer cell proliferation through decreases in expression of stem cell markers (OCT4, Nanog, and SOX2). Reduction in HCC cell migration and invasion is also evident through reversal of EMT by increases E-cadherin expression, decreases in N-cadherin, vimentin, Snail, and Slug expression, and suppression of MMP-2 and MMP-9 expression. In a xenograft tumorigenicity model, TAZ knockdown could effectively inhibit tumor growth and metastasis through reversal of the EMT pathway. In conclusion, TAZ is associated with the proliferation and invasiveness of HCC cells, and the TAZ gene may contribute to a novel therapeutic approach against HCC. PMID- 25495191 TI - Signs and Symptoms of Dry Eye in Keratoconus Patients: A Pilot Study. AB - PURPOSE: To compare signs and symptoms of dry eye in keratoconus (KC) patients versus healthy subjects. METHODS: A total of 15 KC patients (KC group, n = 15 eyes) and 16 healthy subjects (control group, 16 eyes) were enrolled in this study. The Schirmer I test with no anesthetic, tear break-up time (TBUT), corneal staining characteristics, and ocular surface disease index (OSDI) scores were evaluated for both groups. Impression cytology, combined with/scanning laser confocal microscopy (LCM), was performed to evaluate goblet cell density, mucin cloud height (MCH), and goblet cell layer thickness (CLT). Finally, tear concentrations of di-adenosine tetraphosphate (Ap4A) were assessed. Results were statistically analyzed using Shapiro-Wilk and non-parametric Wilcoxon rank sum tests. Statistical significance was set at p < 0.05. RESULTS: KC patients had lower tear volumes and greater corneal staining than did healthy subjects (p < 0.05). OSDI scores were 44.96 +/- 8.65 and 17.78 +/- 6.50 for the KC and control groups, respectively (p < 0.05). We found no statistically significant differences in TBUT between groups. Impression cytology revealed lower goblet cell densities in KC group patients versus control group subjects (84.88 +/- 32.98 and 128.88 +/- 50.60 cells/mm,(2) respectively, p < 0.05). There was a statistically significant reduction in MCH and CLT in KC group patients compared with control group subjects. Ap4A tear concentrations were higher in KC group patients than in control group subjects (2.56 +/- 1.10 and 0.15 +/- 0.12 uM, respectively, p < 0.05). CONCLUSIONS: The parameters evaluated in this study indicate that KC patients suffer greater symptoms of dry eye and greater tear instability, primarily due to the decreased mucin production in their tears, than do healthy patients with no KC. PMID- 25495192 TI - Does South Korea have hidden female smokers: discrepancies in smoking rates between self-reports and urinary cotinine level. AB - BACKGROUND: Female smoking is perceived very negatively in East Asian countries such as South Korea, Japan, and China, as well as in Islamic countries. These countries' self-reported surveys (SRs) tend to produce results that underestimate the number of smokers, owing to the social desirability response bias. The present study seeks to assess South Korea, Europe, and the Americas, by comparing data from SRs with those from urinary cotinine samples. METHODS: Current smoking rates were calculated using the SRs and the urinary cotinine concentration (UCC) methods according to socioeconomic factors. In order to examine response accuracy regarding current smoking status in the SRs, participants who both completed the SRs and acquired UCC results were subject to analyses of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and difference ratio (DR) with respect to gender, age, region, economic level, household status, and the presence of chronic disease. RESULTS: Based on self reports, the current smoking rate among women was 7.1% (official smoking rates), while that according to the UCC was 18.2%; the rates for men were 47.8% and 55.1%, respectively. The sensitivity of males was 0.8553, the specificity 0.9768, PPV 0.9783, NPV 0.8465, and the difference ratio (DR) was 1.143. The sensitivity for females was 0.3670, the specificity 0.9956, PPV 0.9486, NPV 0.8761, and the DR was 2.6. These results exhibit a very low response alignment rate compared to males. CONCLUSION: This study shows that the actual female smoking rate is significantly higher than that reported officially, but also that the gap is decreasing steadily. Females exhibited a higher rate of false responses, which resulted in an underestimation of the female smoking rate. PMID- 25495193 TI - Metabolic characterization of triple negative breast cancer. AB - BACKGROUND: The aims of this study were to characterize the metabolite profiles of triple negative breast cancer (TNBC) and to investigate the metabolite profiles associated with human epidermal growth factor receptor-2/neu (HER-2) overexpression using ex vivo high resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS). Metabolic alterations caused by the different estrogen receptor (ER), progesterone receptor (PgR) and HER-2 receptor statuses were also examined. To investigate the metabolic differences between two distinct receptor groups, TNBC tumors were compared to tumors with ER(pos)/PgR(pos)/HER-2(pos) status which for the sake of simplicity is called triple positive breast cancer (TPBC). METHODS: The study included 75 breast cancer patients without known distant metastases. HR MAS MRS was performed for identification and quantification of the metabolite content in the tumors. Multivariate partial least squares discriminant analysis (PLS-DA) modeling and relative metabolite quantification were used to analyze the MR data. RESULTS: Choline levels were found to be higher in TNBC compared to TPBC tumors, possibly related to cell proliferation and oncogenic signaling. In addition, TNBC tumors contain a lower level of Glutamine and a higher level of Glutamate compared to TPBC tumors, which indicate an increase in glutaminolysis metabolism. The development of glutamine dependent cell growth or "Glutamine addiction" has been suggested as a new therapeutic target in cancer. Our results show that the metabolite profiles associated with HER-2 overexpression may affect the metabolic characterization of TNBC. High Glycine levels were found in HER-2(pos) tumors, which support Glycine as potential marker for tumor aggressiveness. CONCLUSIONS: Metabolic alterations caused by the individual and combined receptors involved in breast cancer progression can provide a better understanding of the biochemical changes underlying the different breast cancer subtypes. Studies are needed to validate the potential of metabolic markers as targets for personalized treatment of breast cancer subtypes. PMID- 25495194 TI - Echocardiographic evaluation of thalassemia intermedia patients in Duhok, Iraq. AB - BACKGROUND: Cardiac complications are among the most serious problems of thalassemia intermedia patients. The current study was initiated to address the latter issue through the study of the echocardiographic findings and correlate it with clinical characteristics of thalassemia intermedia patients in Duhok, Kurdistan region, Iraq. METHODS: An echocardiographic assessment of 61 beta thalassemia intermedia cases was performed. It included 30 males and 31 females, with a mean age 19.6 +/- 7.5 years. The standard echostudy of two-dimension and M mode measurements of cardiac chambers were done. The continuous doppler regurgitant jet of tricuspid and pulmonary valves were recorded. Left ventricle diastolic function was assessed by pulsed doppler of mitral valve inflow. To correlate the clinical with echocardiographic findings, patients were divided, according to tricuspid regurgitant velocity, into three groups (<2.5 m/sec, 2.5 2.9 m/sec and >=3 m/sec). RESULTS: Tricuspid regurgitant velocity <2.5 m/sec, 2.5 2.9 m/sec and >=3 m/sec occurred in 42(69%), 11(18%) and 8(13%) respectively. Comparing to other groups patients with tricuspid regurgitant velocity >=3 m/sec were older and included more males. They had lower hemoglobin levels, but higher ferritin levels. Their age at diagnosis and the age of the initiation of blood transfusion were later. Most of them had significant exertional dyspnea. They also had relatively lower left ventricle ejection fraction values. Right ventricular diameter and right atrial size were larger in the same group. Tricuspid regurgitant velocity as a continuous predictor was associated positively with age, cardiac volumes and pulmonary regurgitation though negatively associated with ejection fraction. CONCLUSIONS: Echo-derived right and left side cardiac complications are not uncommon in thalassemia intermedia patients. Therapeutic trails targeting these complications are indicated, and echocardiographic assessment is necessary to be offered early for thalassemia intermedia. PMID- 25495195 TI - Biocompatibilities and biodegradation of poly(3-hydroxybutyrate-co-3 hydroxyvalerate)s produced by a model metabolic reaction-based system. AB - BACKGROUND: This study evaluated the biocompatibilities of random and putative block poly(3-hydroxybutyrate-co-3-hydroxyvalerate)s (PHBVs) produced by a metabolic reaction-based system. The produced PHBVs were fractionated, and the copolymer sequence distributions were analyzed using (1)H and (13)C NMR spectroscopy. The thermal properties were analyzed using differential scanning calorimetry (DSC). Mechanical tests were conducted using a universal testing machine. The in vitro cytotoxicities of films composed of random PHBVs and putative block PHBVs were investigated against three types of mammalian cells. The surfaces of the copolymer films and the morphologies of the cells were qualitatively monitored using scanning electron microscopy (SEM) and atomic force microscopy (AFM). RESULTS: Films composed of poly(3-hydroxybutyrate) (PHB), random PHBVs, putative block PHBVs, polystyrene and polyvinylchloride were prepared and characterized. The diad and triad sequence distributions indicated that the PHBVs produced via the fed-batch cultivation using two different feed systems resulted in two types of copolymers: random PHBVs and putative block PHBVs. The monomer compositions and sequence distributions strongly affected the thermal and mechanical properties. The mechanical integrity and characteristics of the film surfaces changed with the HV content. Notably, the random PHBVs possessed different mechanical properties than the putative block PHBVs. The biocompatibilities of these films were evaluated in vitro against three types of mammalian cells: L292 mouse connective tissue, human dermal fibroblast and Saos-2 human osteosarcoma cells. None of the PHBV films exhibited cytotoxic responses to the three types of mammalian cells. Erosion of the PHA film surfaces was observed by scanning electron microscopy and atomic force microscopy. The production of transforming growth factor-beta-1 and interleukin-8 was also examined with regards to the usefulness of PHB and PHBV as biomaterials for regenerative tissue. The production of IL-8, which is induced by PHB and PHBVs, may be used to improve and enhance the wound-healing process because of deficiencies of IL-8 in the wound area, particularly in problematic wounds. CONCLUSION: Taken together, the results support the use of PHB and the random and putative block PHBVs produced in this study as potential biomaterials in tissue engineering applications for connective tissue, bone and dermal fibroblast reconstruction. PMID- 25495196 TI - Lower extremity kinematics of athletics curve sprinting. AB - Curve running requires the generation of centripetal force altering the movement pattern in comparison to the straight path run. The question arises which kinematic modulations emerge while bend sprinting at high velocities. It has been suggested that during curve sprints the legs fulfil different functions. A three dimensional motion analysis (16 high-speed cameras) was conducted to compare the segmental kinematics of the lower extremity during the stance phases of linear and curve sprints (radius: 36.5 m) of six sprinters of national competitive level. Peak joint angles substantially differed in the frontal and transversal plane whereas sagittal plane kinematics remained unchanged. During the prolonged left stance phase (left: 107.5 ms, right: 95.7 ms, straight: 104.4 ms) the maximum values of ankle eversion (left: 12.7 degrees , right: 2.6 degrees , straight: 6.6 degrees ), hip adduction (left: 13.8 degrees , right: 5.5 degrees , straight: 8.8 degrees ) and hip external rotation (left: 21.6 degrees , right: 12.9 degrees , straight: 16.7 degrees ) were significantly higher. The inside leg seemed to stabilise the movement in the frontal plane (eversion-adduction strategy) whereas the outside leg provided and controlled the motion in the horizontal plane (rotation strategy). These results extend the principal understanding of the effects of curve sprinting on lower extremity kinematics. This helps to increase the understanding of nonlinear human bipedal locomotion, which in turn might lead to improvements in athletic performance and injury prevention. PMID- 25495197 TI - Formation of bioinorganic complexes by the corrosive adsorption of (S)-proline on Ni/Au(111). AB - Nickel nanoparticles modified by the adsorption of chiral amino acids are known to be effective enantioselective heterogeneous catalysts. The leaching of nickel by amino acids has a number of potential effects including the induction of chirality in the nickel atoms left behind in the nanoparticle and the creation of catalytically active nickel complexes. The adsorption of (S)-proline onto Au(111) precovered by two-dimensional nickel nanoclusters was investigated by scanning tunneling microscopy, X-ray photoelectron spectroscopy, and high-resolution electron energy loss spectroscopy. Adsorption of (S)-proline at 300 K resulted in the corrosion of the nickel clusters, the oxidation of the leached nickel, and the on-surface formation of bioinorganic complexes, which are concluded to contain three prolinate species in an octahedral arrangement around the central Ni ion. Two distinguishable forms of nickel prolinate complexes were identified. One form self-assembles into 1-D chains, and the other form gives rise to porous 2-D islands. Octahedral complexes of the type M(AB)3 are intrinsically chiral, resulting in two pairs of enantiomers. The mirror symmetry of each pair of enantiomers is broken when, as in this study, the bidentate ligand itself possesses a chiral center. DFT calculations are used to examine the relative energies of each Ni(prolinate)3 complex as isolated gas phase species and isolated adsorbed species. PMID- 25495198 TI - Investigation of the persistence of nerve agent degradation analytes on surfaces through wipe sampling and detection with ultrahigh performance liquid chromatography-tandem mass spectrometry. AB - The persistence of chemical warfare nerve agent degradation analytes on surfaces is important, from indicating the presence of nerve agent on a surface to guiding environmental restoration of a site after a release. Persistence was investigated for several chemical warfare nerve agent degradation analytes on indoor surfaces and presents an approach for wipe sampling of surfaces, followed by wipe extraction and liquid chromatography-tandem mass spectrometry detection. Commercially available wipe materials were investigated to determine optimal wipe recoveries. Tested surfaces included porous/permeable (vinyl tile, painted drywall, and wood) and largely nonporous/impermeable (laminate, galvanized steel, and glass) surfaces. Wipe extracts were analyzed by ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). UPLC provides a separation of targeted degradation analytes in addition to being nearly four times faster than high-performance liquid chromatography, allowing for greater throughput after a large-scale contamination incident and subsequent remediation events. Percent recoveries from nonporous/impermeable surfaces were 60-103% for isopropyl methylphosphonate (IMPA), GB degradate; 61-91% for ethyl methylphosphonate (EMPA), VX degradate; and 60-98% for pinacolyl methylphosphonate (PMPA), GD degradate. Recovery efficiencies for methyl phosphonate (MPA), nerve agent degradate, and ethylhydrogen dimethylphosphonate (EHDMAP), GA degradate, were lower, perhaps due to matrix effects. Diisopropyl methylphosphonate, GB impurity, was not recovered from surfaces. The resulting detection limits for wipe extracts were 0.065 ng/cm(2) for IMPA, 0.079 ng/cm(2) for MPA, 0.040 ng/cm(2) for EMPA, 0.078 ng/cm(2) for EHDMAP, and 0.013 ng/cm(2) for PMPA. The data indicate that laboratories may hold wipe samples for up to 30 days prior to analysis. Target analytes were observed to persist on surfaces for at least 6 weeks. PMID- 25495199 TI - Low antibiotic resistance of Helicobacter pylori in The Netherlands. PMID- 25495200 TI - Communicating about cancer through Facebook: a qualitative analysis of a breast cancer awareness page. AB - Social media channels are increasingly being used for health communication and promotion. Social networking sites such as Facebook have become popular platforms for organizations to communicate health messages and encourage user participation around health topics. While the evaluation of social media's effectiveness in health promotion is beginning to emerge in the literature, few studies have examined actual interactions and user behaviors on Facebook Pages hosted by health organizations. The authors present a qualitative case study of a popular Facebook Page from a nonprofit organization devoted to raising awareness about breast cancer. With the goal of identifying the functions and uses of the Page, our study analyzes the content of Wall posts during Breast Cancer Awareness Month, October 2010. Common themes and characteristics are identified, including open mic communication, scarcity of health information, the commodification of breast cancer, unpredictable locations of conversation, and the use of gendered images and language. The findings have potential implications for health promotion efforts using social media platforms. PMID- 25495201 TI - Missing HIV prevention opportunities in South African children--a 7-year review. AB - BACKGROUND: The prevention of mother-to-child transmission (PMTCT) program in South Africa is now successful in ensuring HIV-free survival for most HIV-exposed children, but gaps in PMTCT coverage remain. The study objective was to identify missed opportunities for prevention of mother-to-child transmission of HIV using the four PMTCT stages outlined in National Guidelines. METHODS: This descriptive study enrolled HIV-exposed children who were below the age of 7 years and therefore born during the South African PMTCT era. The study site was in Gauteng, South Africa and enrolment was from June 2009 to May 2010. The clinical history was obtained through a structured caregiver interview and review of medical records and included socio-demographic data, medical history, HIV interventions, infant feeding information and HIV results. The study group was divided into the "single dose nevirapine" ("sdNVP") and "dual-therapy" (nevirapine & zidovudine) groups due to PMTCT program change in February 2008, with subsequent comparison between the groups regarding PMTCT steps during the preconception stage, antenatal care, labor and delivery and postpartum care. RESULTS: Two-hundred-and one HIV-exposed children were enrolled: 137 (68%) children were HIV infected and 64 (32%) were HIV uninfected. All children were born between 2002 and 2009, with 78 (39%) in the "sdNVP" and 123 (61%) in the "dual-therapy" groups. The results demonstrate significant improvements in antenatal HIV testing and PMTCT enrolment, known maternal HIV diagnosis at delivery, mother-infant antiretroviral interventions, infant HIV-diagnosis and cotrimoxazole prophylaxis. Missed opportunities without improvement include pre-conceptual HIV-services and family planning, tuberculosis screening, HIV disclosure, psychosocial support and postnatal care. Not receiving consistent infant feeding messaging was the only PMTCT component that worsened over time. CONCLUSIONS: Multiple missed opportunities for optimal PMTCT were identified, which collectively increase children's risk of HIV acquisition. Although HIV-testing and antiretroviral interventions improved, all PMTCT components need to be optimized to reach the goal of total pediatric HIV elimination. PMID- 25495202 TI - Conversion of psychological stress into cellular stress response: roles of the sigma-1 receptor in the process. AB - Psychiatrists empirically recognize that excessive or chronic psychological stress can result in long-lasting impairments of brain functions that partly involve neuronal cell damage. Recent studies begin to elucidate the molecular pathways activated/inhibited by psychological stress. Activation of the hypothalamic-pituitary-adrenal axis under psychological stress causes inflammatory oxidative stresses in the brain, in part due to elevation of cytokines. Psychological stress or neuropathological conditions (e.g., accumulation of beta-amyloids) trigger 'cellular stress responses', which promote upregulation of molecular chaperones to protect macromolecules from degradation. The unfolded protein response, the endoplasmic reticulum (ER)-specific cellular stress response, has been recently implicated in the pathophysiology of neuropsychiatric disorders and the pharmacology of certain clinically used drugs. The sigma-1 receptor is an ER protein whose ligands are shown to exert antidepressant-like and neuroprotective actions. Recent studies found that the sigma-1 receptor is a novel ligand-operated ER chaperone that regulates bioenergetics, free radical generation, oxidative stress, unfolded protein response and cytokine signaling. The sigma-1 receptor also regulates morphogenesis of neuronal cells, such as neurite outgrowth, synaptogenesis, and myelination, which can be perturbed by cellular stress. The sigma-1 receptor may thus contribute to a cellular defense system that protects nervous systems against chronic psychological stress. Findings from sigma receptor research imply that not only cell surface monoamine effectors but also intracellular molecules, especially those at the ER, may provide novel therapeutic targets for future drug developments. PMID- 25495203 TI - Pulmonary arterial hypertension: progress and challenges in the modern treatment era. AB - Pulmonary arterial hypertension (PAH) is a chronic, progressive disease with an estimated incidence of 2 cases per million individuals per year and a prevalence of approximately 10 to 15 cases per million individuals. PAH is more common in certain groups of patients, such as those with connective tissue disease and congenital heart disease, and is often overlooked in patients with these comorbidities. Treatment options in the United States have expanded to include 12 PAH-specific therapies, 3 of which were approved in 2013. As a result of treatment advancements, PAH patients are living longer. However, many challenges remain. Resource utilization in PAH, a primary driver of which is hospitalization, imposes a major economic burden on patients, payers, and society. Because change in 6-minute walk distance and other historical measures do not correlate well with the risk of hospitalization, guidelines favor more rigorous composite assessments of efficacy that take into account clinical worsening, including mortality and hospitalization. Stakeholders, including providers and payers, are tasked with selecting treatments with the best evidence of clinical benefit. Managing adherence to those therapies remains an important priority in improving clinical outcomes and reducing the overall clinical and economic burden of PAH. Future research that includes patient-reported outcomes, particularly those that reflect health-related quality of life, may be of particular relevance in this complex disease. PMID- 25495204 TI - A conceptual approach to a citizens' observatory--supporting community-based environmental governance. AB - In recent years there has been a trend to view the Citizens' Observatory as an increasingly essential tool that provides an approach for better observing, understanding, protecting and enhancing our environment. However, there is no consensus on how to develop such a system, nor is there any agreement on what a Citizens' Observatory is and what results it could produce. The increase in the prevalence of Citizens' Observatories globally has been mirrored by an increase in the number of variables that are monitored, the number of monitoring locations and the types of participating citizens. This calls for a more integrated approach to handle the emerging complexities involved in this field, but before this can be achieved, it is essential to establish a common foundation for Citizens' Observatories and their usage. There are many aspects to a Citizens' Observatory. One view is that its essence is a process that involves environmental monitoring, information gathering, data management and analysis, assessment and reporting systems. Hence, it requires the development of novel monitoring technologies and of advanced data management strategies to capture, analyse and survey the data, thus facilitating their exploitation for policy and society. Practically, there are many challenges in implementing the Citizens' Observatory approach, such as ensuring effective citizens' participation, dealing with data privacy, accounting for ethical and security requirements, and taking into account data standards, quality and reliability. These concerns all need to be addressed in a concerted way to provide a stable, reliable and scalable Citizens' Observatory programme. On the other hand, the Citizens' Observatory approach carries the promise of increasing the public's awareness to risks in their environment, which has a corollary economic value, and enhancing data acquisition at low or no cost. In this paper, we first propose a conceptual framework for a Citizens' Observatory programme as a system that supports and promotes community-based environmental governance. Next, we discuss some of the challenges involved in developing this approach. This work seeks to initiate a debate and help defining what is the Citizens' Observatory, its potential role in environmental governance, and its validity as a tool for environmental research. PMID- 25495205 TI - Overexpression of p53 but not Rb in the cytoplasm of neurons and small vessels in an autopsy of a patient with Cockayne syndrome. AB - Cockayne syndrome presents senescence-like changes starting in early infancy; however, the mechanism of premature aging remains unclear. In an autopsy of a 23 year-old woman with Cockayne syndrome, we evaluated the correlation between Cockayne pathology and the expression patterns of the senescence-associated proteins p53 and Rb. Neuropathological findings in this case revealed basal ganglia calcification, tigroid leukodystrophy, bizarre reactive astrocytes, severe cerebellar atrophy with loss of Purkinje cells, and arteriolar/neuronal calcifications in the hypothalamus. Multiple arteriolar calcifications and sclerotic changes were seen in the central nervous system and kidney, but the endothelium of the aorta and coronary arteries remained intact appropriately for the individual's age without any finding of arteriosclerosis. Overexpression of p53 protein was confirmed in the cytoplasm of neurons in the basal ganglia, thalamus, hypothalamus, hippocampus and cerebellum, of arteriolar endothelial cells of the cerebrum and renal glomerular capillaries, and of cutaneous epithelial cells. The distribution of p53 overexpression was coincident with that of pathological alteration, such as neuronal loss, calcification and atrophy. High expression of p53 was localized in the cytoplasm, not in the nucleus. In contrast to p53, Rb was not expressed in any senescence lesion. In terms of senescence, distinct differences are found among organs in a patient with Cockayne syndrome. This segmental progeria differs from natural aging, and implicates p53 overexpression in the etiology of CS. PMID- 25495207 TI - Self-organization of nanorods into ultra-long range two-dimensional monolayer end to-end network. AB - Highly uniform large-scale assembly of nanoscale building blocks can enable unique collective properties for practical electronic and photonic devices. We present a two-dimensional (2-D), millimeter-scale network of colloidal CdSe nanorods (NRs) in monolayer thickness through end-to-end linking. The colloidal CdSe NRs are sterically stabilized with tetradecylphosphonic acid (TDPA), and their tips are partially etched in the presence of gold chloride (AuCl3) and didecyldimethylammonium bromide (DDAB), which make them unwetted in toluene. This change in surface wetting property leads to spontaneous adsorption at the 2-D air/toluene interface. Anisotropy in both the geometry and the surface property of the CdSe NRs causes deformation of the NR/toluene/air interface, which derives capillary attraction between tips of neighboring NRs inward. As a result, the NRs confined at the interface spontaneously form a 2-D network composed of end-to-end linkages. We employ a vertical-deposition approach to maintain a consistent rate of NR supply to the interface during the assembly. The rate control turns out to be pivotal in the preparation of a highly uniform large scale 2-D network without aggregation. In addition, unprecedented control of the NR density in the network was possible by adjusting either the lift-up speed of the immersed substrate or the relative concentration of AuCl3 to DDAB. Our findings provide important design criteria for 2-D assembly of anisotropic nanobuilding blocks. PMID- 25495206 TI - Gene network inference using continuous time Bayesian networks: a comparative study and application to Th17 cell differentiation. AB - BACKGROUND: Dynamic aspects of gene regulatory networks are typically investigated by measuring system variables at multiple time points. Current state of-the-art computational approaches for reconstructing gene networks directly build on such data, making a strong assumption that the system evolves in a synchronous fashion at fixed points in time. However, nowadays omics data are being generated with increasing time course granularity. Thus, modellers now have the possibility to represent the system as evolving in continuous time and to improve the models' expressiveness. RESULTS: Continuous time Bayesian networks are proposed as a new approach for gene network reconstruction from time course expression data. Their performance was compared to two state-of-the-art methods: dynamic Bayesian networks and Granger causality analysis. On simulated data, the methods comparison was carried out for networks of increasing size, for measurements taken at different time granularity densities and for measurements unevenly spaced over time. Continuous time Bayesian networks outperformed the other methods in terms of the accuracy of regulatory interactions learnt from data for all network sizes. Furthermore, their performance degraded smoothly as the size of the network increased. Continuous time Bayesian networks were significantly better than dynamic Bayesian networks for all time granularities tested and better than Granger causality for dense time series. Both continuous time Bayesian networks and Granger causality performed robustly for unevenly spaced time series, with no significant loss of performance compared to the evenly spaced case, while the same did not hold true for dynamic Bayesian networks. The comparison included the IRMA experimental datasets which confirmed the effectiveness of the proposed method. Continuous time Bayesian networks were then applied to elucidate the regulatory mechanisms controlling murine T helper 17 (Th17) cell differentiation and were found to be effective in discovering well known regulatory mechanisms, as well as new plausible biological insights. CONCLUSIONS: Continuous time Bayesian networks were effective on networks of both small and large size and were particularly feasible when the measurements were not evenly distributed over time. Reconstruction of the murine Th17 cell differentiation network using continuous time Bayesian networks revealed several autocrine loops, suggesting that Th17 cells may be auto regulating their own differentiation process. PMID- 25495208 TI - Association of microRNA biogenesis pathway gene variants and alcohol dependence risk. AB - Alcohol dependence (AD) is a neuropsychiatric disorder to which both genetic and environmental factors contribute. Especially, multiple genetic factors are promising to explain the etiology of AD. microRNAs (miRNAs) are members of a family of noncoding small RNAs, which are thought to be responsible for the altered gene expression in neuropsychiatric disorders. We hypothesized that single nucleotide polymorphisms (SNPs) in the miRNA biogenesis pathway may result in dysregulation of miRNA levels inside the cell. The aim of this study was to test an association between miRNA biogenesis gene variants and AD risk. Real-time polymerase chain reaction genotyping experiment was conducted on DNA samples from 123 alcohol-dependent patients and 135 healthy controls. We found that AGO1 rs595961 (chi(2) = 9.066, p = 0.003; odds ratio [OR] = 0.459, 95% confidence interval [CI]: 0.275-0.768) and AGO2 rs4961280 (chi(2) = 4.111, p = 0.043; OR = 0.590, 95% CI: 0.353-0.986) G alleles have significantly altered the risk for AD, and also there is a significant association of GEMIN4 rs910924 (chi(2) = 5.291, p = 0.021; OR = 1.913, 95% CI: 1.094-3.344) T allele with the risk for AD. We also found statistically significant difference in AGO1 rs595961 (chi(2) = 11.139, p = 0.001) and DGCR8 rs1640299 (chi(2) = 13.001, p = 0.002) genotype frequencies between case-control groups. This is the first study to investigate the effects of SNPs in the miRNA biogenesis pathway on AD risk. In conclusion, we identified a significant association of miRNA biogenesis genes with altered AD risk, and these results could be a guide to research on the role of miRNAs in AD in the future. PMID- 25495210 TI - Surgical treatment of congenital thoracolumbar spondyloptosis in a 2-year-old child with vertebral column resection and posterior-only circumferential reconstruction of the spine column: case report. AB - Spondyloptosis refers to complete dislocation of a vertebral body onto another. The L5-S1 level is frequently affected. As this condition is rare, few published reports describing its clinical features and surgical outcomes exist, especially in the pediatric patient population. The authors report the presentation, pathological findings, and radiographic studies of a 2-year-old girl who presented to Texas Children's Hospital with a history since birth of progressive spastic paraparesis. Preoperative CT and MRI showed severe spinal cord compression associated with T11-12 spondyloptosis. The patient underwent a single stage posterior approach for complete resection of the dysplastic vertebral bodies at the apex of the spinal deformity with reconstruction and stabilization of the vertebral column using a titanium expandable cage and pedicle screws. At the 12-month follow-up, the patient remained neurologically stable without any radiographic evidence of instrumentation failure or loss of alignment. To the best of the authors' knowledge, there have been only 2 other children with congenital thoracolumbar spondyloptosis treated with the above-described strategy. The authors describe their case and review the literature to discuss the aggregate clinical features, surgical strategies, and operative outcomes for congenital thoracolumbar spondyloptosis. PMID- 25495209 TI - Community treatment orders: clinical and social outcomes, and a subgroup analysis from the OCTET RCT. AB - OBJECTIVE: Despite widespread use internationally, there is no convincing evidence that community treatment orders (CTO) (legal regimes making out-patient treatment compulsory), reduce readmission rates or have wider patient benefit. The primary and secondary outcomes of the Oxford Community Treatment Order Evaluation Trial (OCTET) (hospitalisation) showed no benefit. This article will, first, test the effect of community compulsion on wider clinical and social outcomes and on patients' experiences of services and the use of treatment pressure and second, explore differential effects in different groups of patients. METHOD: OCTET is a RCT of CTO effectiveness. Three hundred and thirty six patients were randomised and data for the 333 eligible patients were collected from interviews and medical records at baseline, 6 and 12 months. RESULTS: There was no significant difference at 12 months between the two arms in any of the reported outcomes, except a small difference in patients' view of the effectiveness of treatment pressure, which is unlikely to be clinically meaningful. Two statistically significant interactions were found in the subgroup analysis: symptoms interacted with age and with education, but no pattern was demonstrated. CONCLUSION: CTOs do not have benefit on any of the tested outcomes, or for any subgroup of patients. Their continued use should be carefully reconsidered. PMID- 25495212 TI - Comparison of osteogenic differentiation potential of human adult stem cells loaded on bioceramic-coated electrospun poly (L-lactide) nanofibres. AB - OBJECTIVES: To compare potential of four types of stem cell in tissue engineering and regenerative medicine applications, osteogenic capacity of newly introduced mesenchymal stem cells (MSCs) derived from buccal fat pads (BFP) (an adipose encapsulated mass of the oral cavity), was compared to those isolated from bone marrow (BM-MSCs), adipose tissue (AT-MSCs) and unrestricted somatic stem cells (USSCs). Cells were cultured on poly (L-lactide) (PLLA) nanofibres, Bio-Oss((r)) coated PLLA (PLLA-Bio), and culture plates (TCPS) as control. MATERIALS AND METHODS: Capacity of proliferation and osteogenic differentiation of the stem cells was investigated by MTT assay and common osteogenic markers, alkaline phosphatase activity, calcium mineral deposition and bone-related genes. RESULTS: Highest proliferation level was observed in cells cultured on PLLA-Bio, but with no significant difference between proliferation levels of the four types of stem cell. Over the period of study, BM-MSCs cultured on PLLA-Bio scaffolds exhibited greatest alkaline phosphatase (ALP) activity and mineralization with BFP-MSCs having the next closest results. However, AT-MSC had the lowest capacity for ALP activity and mineralization during osteogenic differentiation. Gene expression evaluation revealed that highest expression of three important bone-related genes was observed in stem cells cultured on bioceramic-coated nanofibrous scaffolds. CONCLUSIONS: Results indicated Bio-Oss-coated PLLA to compose most appropriate substrates to support proliferation and osteogenic differentiation of stem cells in vitro. BFP-MSCs demonstrated the same osteogenic differentiation capacity as other stem cells tested and thus hold very promising potential for applications in bone tissue engineering and regenerative medicine. PMID- 25495213 TI - Genotype harmonizer: automatic strand alignment and format conversion for genotype data integration. AB - BACKGROUND: To gain statistical power or to allow fine mapping, researchers typically want to pool data before meta-analyses or genotype imputation. However, the necessary harmonization of genetic datasets is currently error-prone because of many different file formats and lack of clarity about which genomic strand is used as reference. FINDINGS: Genotype Harmonizer (GH) is a command-line tool to harmonize genetic datasets by automatically solving issues concerning genomic strand and file format. GH solves the unknown strand issue by aligning ambiguous A/T and G/C SNPs to a specified reference, using linkage disequilibrium patterns without prior knowledge of the used strands. GH supports many common GWAS/NGS genotype formats including PLINK, binary PLINK, VCF, SHAPEIT2 & Oxford GEN. GH is implemented in Java and a large part of the functionality can also be used as Java 'Genotype-IO' API. All software is open source under license LGPLv3 and available from http://www.molgenis.org/systemsgenetics. CONCLUSIONS: GH can be used to harmonize genetic datasets across different file formats and can be easily integrated as a step in routine meta-analysis and imputation pipelines. PMID- 25495214 TI - Possible role of H1 histone in replication timing. AB - AT-rich repetitive DNA sequences become late replicating during cell differentiation. Replication timing is not correlated with LINE density in human cells (Ryba et al. 2010). However, short and properly spaced runs of oligo dA or dT present in nuclear matrix attachment regions (MARs) of the genome are good candidates for elements of AT-rich repetitive late replicating DNA. MAR attachment to the nuclear matrix is negatively regulated by chromatin binding of H1 histone, but this is counteracted by H1 phosphorylation, high mobility group proteins or, indirectly, core histone acetylation. Fewer MAR attachments correlates positively with longer average DNA loop size, longer replicons and an increase of late replicating DNA. PMID- 25495215 TI - Nitric oxide is a potential mediator of hepatic inflammation and fibrogenesis in autoimmune hepatitis. AB - BACKGROUND: Despite advances in the understanding of the pathophysiological basis of autoimmune hepatitis (AIH), it is still difficult to delineate the mechanisms involved in progression from hepatic inflammation toward fibrosis. Our aim was to study serum concentrations of NO in AIH of different histological severity and possible effects of immunosuppressive therapy on NO production. MATERIALS AND METHODS: We studied serum NO metabolites (NOx) in 47 consecutive patients with AIH and in 28 age- and sex-matched controls. RESULTS: Serum NOx concentrations were higher in AIH patients than in controls (10.3 (4.5-27.3 umol/L) vs. 4.3 (1.6 14.3 umol/L), p < 0.001). According to liver histology, median NOx concentrations were significantly higher in patients with severe interface hepatitis compared to patients with mild-moderate interface hepatitis (12.3 (4.5-27.3 umol/L) vs. 9.3 (4.6-20.3 umol/L), p = 0.029). Similarly, serum NOx concentrations were significantly higher in patients with advanced fibrosis than in those with early fibrosis (12.2 (4.6-27.3 umol/L) vs. 9.3 (6.6-12.8 umol/L), p = 0.018). NOx concentrations decreased in 16 AIH patients who were tested also after biochemical remission was achieved (12.6 (4.5-22.8 umol/L) at baseline and 5.9 (2.8-10.5 umol/L) after remission, p = 0.001). CONCLUSION: This study shows that serum NOx levels are associated with the histological severity of AIH. Hepatocyte inflammation and injury may activate hepatic stellate cells and kupffer cells, and the consequences may include release of NO, which ultimately promotes hepatic fibrosis. Immunosuppressive therapy inhibits this process and the production of NO. PMID- 25495217 TI - Electroporation threshold of POPC lipid bilayers with incorporated polyoxyethylene glycol (C12E8). AB - Electroporation relates to a phenomenon in which cell membranes are permeabilized after being exposed to high electric fields. On the molecular level, the mechanism is not yet fully elucidated, although a considerable body of experiments and molecular dynamic (MD) simulations were performed on model membranes. Here we present the results of a combined theoretical and experimental investigation of electroporation of palmitoy-oleoyl-phosphatidylcholine (POPC) bilayers with incorporated polyoxyethylene glycol (C12E8) surfactants. The experimental results show a slight increase of the capacitance and a 22% decrease of the voltage breakdown upon addition of C12E8 to pure POPC bilayers. These results were qualitatively confirmed by the MD simulations. They later revealed that the polyoxyethylene glycol molecules play a major role in the formation of hydrophilic pores in the bilayers above the electroporation threshold. The headgroup moieties of the latter are indeed embedded in the interior of the bilayer, which favors formation of water wires that protrude into its hydrophobic core. When the water wires extend across the whole bilayer, they form channels stabilized by the C12E8 head groups. These hydrophilic channels can transport ions across the membrane without the need of major lipid head-group rearrangements. PMID- 25495216 TI - Brain networks engaged in audiovisual integration during speech perception revealed by persistent homology-based network filtration. AB - The human brain naturally integrates audiovisual information to improve speech perception. However, in noisy environments, understanding speech is difficult and may require much effort. Although the brain network is supposed to be engaged in speech perception, it is unclear how speech-related brain regions are connected during natural bimodal audiovisual or unimodal speech perception with counterpart irrelevant noise. To investigate the topological changes of speech-related brain networks at all possible thresholds, we used a persistent homological framework through hierarchical clustering, such as single linkage distance, to analyze the connected component of the functional network during speech perception using functional magnetic resonance imaging. For speech perception, bimodal (audio visual speech cue) or unimodal speech cues with counterpart irrelevant noise (auditory white-noise or visual gum-chewing) were delivered to 15 subjects. In terms of positive relationship, similar connected components were observed in bimodal and unimodal speech conditions during filtration. However, during speech perception by congruent audiovisual stimuli, the tighter couplings of left anterior temporal gyrus-anterior insula component and right premotor-visual components were observed than auditory or visual speech cue conditions, respectively. Interestingly, visual speech is perceived under white noise by tight negative coupling in the left inferior frontal region-right anterior cingulate, left anterior insula, and bilateral visual regions, including right middle temporal gyrus, right fusiform components. In conclusion, the speech brain network is tightly positively or negatively connected, and can reflect efficient or effortful processes during natural audiovisual integration or lip-reading, respectively, in speech perception. PMID- 25495218 TI - Trehalose-6-phosphate synthase 1 is not the only active TPS in Arabidopsis thaliana. AB - Trehalose metabolism is essential for normal growth and development in higher plants. It is synthesized in a two-step pathway catalysed by TPS (trehalose-6 phosphate synthase) and trehalose phosphatase. Arabidopsis thaliana has 11 TPS or TPS-like proteins, which belong to two distinct clades: class I (AtTPS1-AtTPS4) and class II (AtTPS5-AtTPS11). Only AtTPS1 has previously been shown to have TPS activity. A. thaliana tps1? mutants fail to complete embryogenesis and rescued lines have stunted growth and delayed flowering, indicating that AtTPS1 is important throughout the life cycle. In the present study, we show that expression of AtTPS2 or AtTPS4 enables the yeast tps1? tps2? mutant to grow on glucose and accumulate Tre6P (trehalose 6-phosphate) and trehalose. Class II TPS genes did not complement the yeast mutant. Thus A. thaliana has at least three catalytically active TPS isoforms, suggesting that loss of Tre6P production might not be the only reason for the growth defects of A. thaliana tps1 mutants. PMID- 25495219 TI - Antimicrobial peptides with potential for biofilm eradication: synthesis and structure activity relationship studies of battacin peptides. AB - We report on the first chemical syntheses and structure-activity analyses of the cyclic lipopeptide battacin which revealed that conjugation of a shorter fatty acid, 4-methyl-hexanoic acid, and linearization of the peptide sequence improves antibacterial activity and reduces hemolysis of mouse blood cells. This surprising finding of higher potency in linear lipopeptides than their cyclic counterparts is economically beneficial. This novel lipopeptide was membrane lytic and exhibited antibiofilm activity against Pseudomonas aeruginosa, Staphylococcus aureus, and, for the first time, Pseudomonas syringe pv. actinidiae. The peptide was unstructured in aqueous buffer and dimyristoylphosphatidylcholine-polymerized diacetylene vesicles, with 12% helicity induced in 50% v/v of trifluoroethanol. Our results indicate that a well defined secondary structure is not essential for the observed antibacterial activity of this novel lipopeptide. A truncated pentapeptide conjugated to 4 methyl hexanoic acid, having similar potency against Gram negative and Gram positive pathogens was identified through alanine scanning. PMID- 25495220 TI - Monitoring morphological changes in 2D monolayer semiconductors using atom-thick plasmonic nanocavities. AB - Nanometer-sized gaps between plasmonically coupled adjacent metal nanoparticles enclose extremely localized optical fields, which are strongly enhanced. This enables the dynamic investigation of nanoscopic amounts of material in the gap using optical interrogation. Here we use impinging light to directly tune the optical resonances inside the plasmonic nanocavity formed between single gold nanoparticles and a gold surface, filled with only yoctograms of semiconductor. The gold faces are separated by either monolayers of molybdenum disulfide (MoS2) or two-unit-cell thick cadmium selenide (CdSe) nanoplatelets. This extreme confinement produces modes with 100-fold compressed wavelength, which are exquisitely sensitive to morphology. Infrared scattering spectroscopy reveals how such nanoparticle-on-mirror modes directly trace atomic-scale changes in real time. Instabilities observed in the facets are crucial for applications such as heat-assisted magnetic recording that demand long-lifetime nanoscale plasmonic structures, but the spectral sensitivity also allows directly tracking photochemical reactions in these 2-dimensional solids. PMID- 25495221 TI - Tunneling dendrimers. Enhancing charge transport through insulating layer using redox molecular objects. AB - Charge transport through an insulating layer was probed using ferrocenyl terminated dendrimers and scanning electrochemical microscopy. Experiments show that the passage through the layer is considerably enhanced when the transferred charges are brought globally to the surface by the ferrocenyl dendrimer instead of a single ferrocene molecule. This result shows that charge tunneling through an insulator could be promoted by a purely molecular nano-object. PMID- 25495222 TI - Feasibility of detecting aflatoxin B1 on inoculated maize kernels surface using Vis/NIR hyperspectral imaging. AB - The feasibility of using a visible/near-infrared hyperspectral imaging system with a wavelength range between 400 and 1000 nm to detect and differentiate different levels of aflatoxin B1 (AFB1 ) artificially titrated on maize kernel surface was examined. To reduce the color effects of maize kernels, image analysis was limited to a subset of original spectra (600 to 1000 nm). Residual staining from the AFB1 on the kernels surface was selected as regions of interest for analysis. Principal components analysis (PCA) was applied to reduce the dimensionality of hyperspectral image data, and then a stepwise factorial discriminant analysis (FDA) was performed on latent PCA variables. The results indicated that discriminant factors F2 can be used to separate control samples from all of the other groups of kernels with AFB1 inoculated, whereas the discriminant factors F1 can be used to identify maize kernels with levels of AFB1 as low as 10 ppb. An overall classification accuracy of 98% was achieved. Finally, the peaks of beta coefficients of the discrimination factors F1 and F2 were analyzed and several key wavelengths identified for differentiating maize kernels with and without AFB1 , as well as those with differing levels of AFB1 inoculation. Results indicated that Vis/NIR hyperspectral imaging technology combined with the PCA-FDA was a practical method to detect and differentiate different levels of AFB1 artificially inoculated on the maize kernels surface. However, indicated the potential to detect and differentiate naturally occurring toxins in maize kernel. PMID- 25495223 TI - Pre-mRNA splicing in cancer: the relevance in oncogenesis, treatment and drug resistance. AB - INTRODUCTION: Aberrant pre-mRNA splicing in cancer is emerging as an important determinant of oncogenesis, response to treatment and anticancer drug resistance. At the same time, the spliceosome has become a target for a novel class of pre clinical chemotherapeutics with a potential future application in cancer treatment. Taken together, these findings offer novel opportunities for the enhancement of the efficacy of cancer therapy. AREAS COVERED: This review presents a comprehensive overview of the molecular mechanisms involved in splicing and current developments regarding splicing aberrations in relation to several aspects of cancer formation and therapy. Identified mutations in the various components of the spliceosome and their implications for cancer prognosis are delineated. Moreover, the contribution of abnormal splicing patterns as well as deregulated splicing factors to chemoresistance is discussed, along with novel splicing-based therapeutic approaches. EXPERT OPINION: Significant progress has been made in deciphering the role of splicing factors in cancer including carcinogenesis and drug resistance. Splicing-based prognostic tools as well as therapeutic options hold great potential towards improvements in cancer therapy. However, gaining more in-depth molecular insight into the consequences of mutations in various components of the splicing machinery as well as of cellular effects of spliceosome inhibition is a prerequisite to establish the role of splicing in tumor progression and treatment options, respectively. PMID- 25495225 TI - DIGESTIF: a universal quality standard for the control of bottom-up proteomics experiments. AB - In bottom-up mass spectrometry-based proteomics analyses, variability at any step of the process, particularly during sample proteolysis, directly affects the sensitivity, accuracy, and precision of peptide detection and quantification. Currently, no generic internal standards are available to control the quality of sample processing steps. This makes it difficult to assess the comparability of MS proteomic data obtained under different experimental conditions. Here, we describe the design, synthesis, and validation of a universal protein standard, called DIGESTIF, that can be added to any biological sample. The DIGESTIF standard consists of a soluble recombinant protein scaffold to which a set of 11 artificial peptides (iRT peptides) with good ionization properties has been incorporated. In the protein scaffold, the amino acids flanking iRT peptide cleavage sites were selected either to favor or hinder protease cleavage. After sample processing, the retention time and relative intensity pattern of the released iRT peptides can be used to assess the quality of sample workup, the extent of digestion, and the performance of the LC-MS system. Thus, DIGESTIF can be used to standardize a broad spectrum of applications, ranging from simple replicate measurements to large-scale biomarker screening in biomedical applications. PMID- 25495226 TI - Renewable hydrogen production by alcohols reforming using plasma and plasma catalytic technologies: challenges and opportunities. PMID- 25495224 TI - Interleukin-1beta causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53. AB - BACKGROUND: Understanding how inflammation causes neuronal damage is of paramount importance in multiple sclerosis (MS) and in other neurodegenerative diseases. Here we addressed the role of the apoptotic cascade in the synaptic abnormalities and neuronal loss caused by the proinflammatory cytokines interleukin-1beta (IL 1beta) and tumor necrosis factor (TNF-alpha) in brain tissues, and disease progression caused by inflammation in relapsing-remitting MS (RRMS) patients. RESULTS: The effect of IL-1beta, but not of TNF-alpha, on glutamate-mediated excitatory postsynaptic currents was blocked by pifithrin-alpha (PFT), inhibitor of p53. The protein kinase C (PKC)/transient receptor potential vanilloid 1 (TRPV1) pathway was involved in IL-1beta-p53 interaction at glutamatergic synapses, as pharmacological modulation of this inflammation-relevant molecular pathway affected PFT effects on the synaptic action of IL-1beta. IL-1beta-induced neuronal swelling was also blocked by PFT, and IL-1beta increased the expression of p21, a canonical downstream target of activated p53.Consistent with these in vitro results, the Pro/Pro genotype of p53, associated with low efficiency of transcription of p53-regulated genes, abrogated the association between IL-1beta cerebrospinal fluid (CSF) levels and disability progression in RRMS patients. The interaction between p53 and CSF IL-1beta was also evaluated at the optical coherence tomography (OCT), showing that IL-1beta-driven neurodegenerative damage, causing alterations of macular volume and of retinal nerve fibre layer thickness, was modulated by the p53 genotype. CONCLUSIONS: Inflammatory synaptopathy and neurodegeneration caused by IL-1beta in RRMS patients involve the apoptotic cascade. Targeting IL-1beta-p53 interaction might result in significant neuroprotection in MS. PMID- 25495227 TI - Nonhatching Decapsulated Artemia Cysts As a Replacement to Artemia Nauplii in Juvenile and Adult Zebrafish Culture. AB - Feeding Artemia nauplii as the main nutrition source for zebrafish is a common practice for many research facilities. Culturing live feed can be time-consuming and requires additional equipment to be purchased, maintained, and cleaned. Nonhatching decapsulated Artemia cysts (decaps) are a commercially available product that can be fed directly to fish. Several other ornamental fish species have been successfully cultured using decaps. Replacing Artemia nauplii with decaps could reduce the overall time and costs associated with the operation of a zebrafish facility. The objective of this study was to determine if decaps could be a suitable replacement to Artemia nauplii in juvenile and adult zebrafish culture. Wild-type zebrafish were fed one of three dietary treatments: decaps only, nauplii only, or a standard consisting of nauplii plus a commercially prepared pellet food. Survival, growth (length and weight), and embryo production were analyzed between the treatments. Fish receiving the decap diet demonstrated a significantly higher growth and embryo production when compared to the fish receiving the nauplii-only diet. When comparing the decap fish to the standard fish, no significant difference was found in mean survival, mean weight at 90 days postfertilization, or mean embryo production. It was determined that nonhatching decapsulated Artemia cysts can be used as a suitable replacement to Artemia nauplii in juvenile and adult zebrafish culture. PMID- 25495228 TI - Natural attack rate of influenza in unvaccinated children and adults: a meta regression analysis. AB - BACKGROUND: The natural (i.e. unvaccinated population) attack rate of an infectious disease is an important parameter required for understanding disease transmission. As such, it is an input parameter in infectious disease mathematical models. Influenza is an infectious disease that poses a major health concern worldwide and the natural attack rate of this disease is crucial in determining the effectiveness and cost-effectiveness of public health interventions and informing surveillance program design. We estimated age stratified, strain-specific natural attack rates of laboratory-confirmed influenza in unvaccinated individuals. METHODS: Utilizing an existing systematic review, we calculated the attack rates in the trial placebo arms using a random effects model and a meta-regression analysis (GSK study identifier: 117102). RESULTS: This post-hoc analysis included 34 RCTs (Randomized Control Trials) contributing to 47 influenza seasons from 1970 to 2009. Meta-regression analyses showed that age and type of influenza were important covariates. The attack rates (95% CI (Confidence Interval)) in adults for all influenza, type A and type B were 3.50% (2.30%, 4.60%), 2.32% (1.47%, 3.17%) and 0.59% (0.28%, 0.91%) respectively. For children, they were 15.20% (11.40%, 18.90%), 12.27% (8.56%, 15.97%) and 5.50% (3.49%, 7.51%) respectively. CONCLUSIONS: This analysis demonstrated that unvaccinated children have considerably higher exposure risk than adults and influenza A can cause more disease than influenza B. Moreover, a higher ratio of influenza B:A in children than adults was observed. This study provides a new, stratified and up to-date natural attack rates that can be used in influenza infectious disease models and are consistent with previous published work in the field. PMID- 25495229 TI - Understanding the inverse care law: a register and survey-based study of patient deprivation and burnout in general practice. AB - INTRODUCTION: According to the inverse care law, there is a mismatch between patients' medical needs and medical care supply. As an example, the number of doctors is often lower in areas with high deprivation compared to areas with no deprivation, and doctors with a deprived patient population may experience a high work pressure, have insufficient time for comprehensive tasks and be at higher risk for developing burnout. The mechanisms responsible for the inverse care law might be mutually reinforcing, but we know very little about this process. In this study, the association between patient deprivation and burnout in the general practitioners (GPs) was examined. METHODS: Active GPs in the Central Denmark Region were invited to participate in a survey on job satisfaction and burnout and 601 GPs returned the questionnaire (72%). The Danish Regions provided information about which persons were registered with each practice, and information concerning socioeconomic characteristics for each patient on the list was obtained from Statistics Denmark. A composite deprivation index was also used. RESULTS: There was significantly more burnout among GPs in the highest quartile of the deprivation index compared to GPs in the lowest quartile (OR: 1.91; 95% CI: 1.06-3.44; p-value: 0.032). Among the eight variables included in the deprivation index, a high share of patients on social benefits was most strongly associated with burnout (OR: 2.62; 95% CI: 1.45-4.71; p-value: 0.001). CONCLUSIONS: A higher propensity of GP burnout was found among GPs with a high share of deprived patients on their lists compared to GPs with a low share of deprived patients. This applied in particular to patients on social benefits. This indicates that beside lower supply of GPs in deprived areas, people in these areas may also be served by GPs who are in higher risk of burnout and not performing optimally. PMID- 25495231 TI - One family: two very different end-of-life experiences. PMID- 25495232 TI - Species-specific chemosensory gene expression in the olfactory organs of the malaria vector Anopheles gambiae. AB - BACKGROUND: The malaria mosquito Anopheles gambiae has a high preference for human hosts, a characteristic that contributes greatly to its capacity for transmitting human malaria. A sibling species, An. quadriannulatus, has a quite different host preference and feeds mostly on bovids. For this reason it does not contribute to human malaria transmission. Host seeking in mosquitoes is modulated by the olfactory system, which is primarily housed in the antennae and maxillary palps. Therefore, the detection of differing host odors by sibling species may be reflected in the expression level of the olfactory genes involved. Accordingly, we compared the transcriptomes of the antennae and maxillary palps of An. gambiae and An. quadriannulatus. RESULTS: We identified seven relatively abundant olfactory receptors, nine ionotropic receptors and three odorant binding proteins that are substantially up-regulated in An. gambiae antennae. Interestingly, we find that the maxillary palps of An. gambiae contain a species-specific olfactory receptor, Or52, and five An. gambiae-specific gustatory receptors (AgGr48-52) that are relatively abundant. These five gustatory receptors are also expressed in An. gambiae antennae, although at lower level, indicating a likely role in olfaction, rather than gustation. We also document an approximately three-fold higher overall expression of olfaction genes in the maxillary palps of An. quadriannulatus, indicating an important role of this organ in the olfaction system of this species. Finally, the expression of the CO2 receptor genes is five to six-fold higher in the zoophilic An. quadriannulatus, implying a much higher sensitivity for detecting CO2. CONCLUSIONS: These results identify potential human host preference genes in the malaria vector An. gambiae. Interestingly, species-specific expression of several gustatory receptors in the olfactory organs indicate a role in olfaction rather than gustation. Additionally, a more expansive role for maxillary palps in olfaction is implicated than previously thought, albeit more so in the zoophilic An. quadriannulatus. PMID- 25495233 TI - Distribution and accumulative pattern of tetracyclines and sulfonamides in edible vegetables of cucumber, tomato, and lettuce. AB - Veterinary antibiotics can be released to environment by the animals' excretions, which thereby poses human health and ecological risks. Six antibiotics (tetracycline, oxytetracycline, chlortetracycline, sulfamethazine, sulfamethoxazole, and sulfadimethoxine) at three concentrations (5, 10, and 20 mg kg(-1) soil) were employed in pots filled with a loamy sand upland soil. Three types of vegetable seedlings, including cucumber (Cucumis sativus), cherry tomato (Solanum lycopersicum), and lettuce (Lactuca sativa), were also cultivated during 45 d in the greenhouse. All antibiotics taken up by tested plants showed negative effects on growth. Relatively high levels of tetracyclines and sulfonamides (SAs) were detected in the nonedible parts, roots, and leaves of cucumber and tomato, but fruit parts accumulated them lower than acceptable daily intake. Indeed, cucumber roots accumulated SAs by up to 94.6% of total addition (at 5 mg kg(-1) soil). PMID- 25495234 TI - A Key Opinion Leader interview: insight into the research and career of Dr KA Jacobson. PMID- 25495236 TI - The paradox of hydrogen-bonded anion-anion aggregates in oxoanions: a fundamental electrostatic problem explained in terms of electrophilic...nucleophilic interactions. AB - A theoretical study of anionic complexes formed by two partly deprotonated oxoacids joined by hydrogen bonds has been carried out at the MP2 computational level. In spite of the ionic repulsion, local energy minima are found both in the gas phase and in aqueous solution. Electrostatic potential and electron density topologies, and the comparison with neutral complexes formed by oxoacids, reveal that the ionization has no significant effect on the properties of the hydrogen bonds. The stability of the complexes in the gas phase is explained by attractive forces localized in a volume situated in the hydrogen bond and defined as the electrostatic attraction region (EAR) and determined by the topological analyses of the electron density and the electrostatic potential, and by the electric field lines. In solution, the strong anionic repulsion is mostly screened by the effect of the surrounding polar solvent, which only leads to a weak destabilizing interaction in the hydrogen bond region and finally favors the overall stability of the complexes. The anion-anion complexes have been compared with the corresponding neutral ones (as salts or protonated forms), showing that EAR remains unchanged along the series. PMID- 25495235 TI - Application of principal component analysis to multispectral-multimodal optical image analysis for malaria diagnostics. AB - BACKGROUND: Multispectral imaging microscopy is a novel microscopic technique that integrates spectroscopy with optical imaging to record both spectral and spatial information of a specimen. This enables acquisition of a large and more informative dataset than is achievable in conventional optical microscopy. However, such data are characterized by high signal correlation and are difficult to interpret using univariate data analysis techniques. METHODS: In this work, the development and application of a novel method which uses principal component analysis (PCA) in the processing of spectral images obtained from a simple multispectral-multimodal imaging microscope to detect Plasmodium parasites in unstained thin blood smear for malaria diagnostics is reported. The optical microscope used in this work has been modified by replacing the broadband light source (tungsten halogen lamp) with a set of light emitting diodes (LEDs) emitting thirteen different wavelengths of monochromatic light in the UV-vis-NIR range. The LEDs are activated sequentially to illuminate same spot of the unstained thin blood smears on glass slides, and grey level images are recorded at each wavelength. PCA was used to perform data dimensionality reduction and to enhance score images for visualization as well as for feature extraction through clusters in score space. RESULTS: Using this approach, haemozoin was uniquely distinguished from haemoglobin in unstained thin blood smears on glass slides and the 590-700 spectral range identified as an important band for optical imaging of haemozoin as a biomarker for malaria diagnosis. CONCLUSION: This work is of great significance in reducing the time spent on staining malaria specimens and thus drastically reducing diagnosis time duration. The approach has the potential of replacing a trained human eye with a trained computerized vision system for malaria parasite blood screening. PMID- 25495237 TI - Rwanda's evolving community health worker system: a qualitative assessment of client and provider perspectives. AB - BACKGROUND: Community health workers (CHWs) can play important roles in primary health care delivery, particularly in settings of health workforce shortages. However, little is known about CHWs' perceptions of barriers and motivations, as well as those of the beneficiaries of CHWs. In Rwanda, which faces a significant gap in human resources for health, the Ministry of Health expanded its community health programme beginning in 2007, eventually placing 4 trained CHWs in every village in the country by 2009. The aim of this study was to assess the capacity of CHWs and the factors affecting the efficiency and effectiveness of the CHW programme, as perceived by the CHWs and their beneficiaries. METHODS: As part of a larger report assessing CHWs in Rwanda, a cross-sectional descriptive study was conducted using focus group discussions (FGDs) to collect qualitative information regarding educational background, knowledge and practices of CHWs, and the benefits of community-based care as perceived by CHWs and household beneficiaries. A random sample of 108 CHWs and 36 beneficiaries was selected in 3 districts according to their food security level (low, middle and high). Qualitative and demographic data were analyzed. RESULTS: CHWs were found to be closely involved in the community, and widely respected by the beneficiaries. Rwanda's community performance-based financing (cPBF) was an important incentive, but CHWs were also strongly motivated by community respect. The key challenges identified were an overwhelming workload, irregular trainings, and lack of sufficient supervision. CONCLUSIONS: This study highlights the challenges and areas in need of improvement as perceived by CHWs and beneficiaries, in regards to a nationwide scale-up of CHW interventions in a resource-challenged country. Identifying and understanding these barriers, and addressing them accordingly, particularly within the context of performance-based financing, will serve to strengthen the current CHW system and provide key guidance for the continuing evolution of the CHW system in Rwanda. PMID- 25495238 TI - Vertigo in downhill mountain biking and road cycling. AB - Vertigo has been described after the practice of mountain bike. This study aimed to investigate the prevalence of vertigo following competitions or training sessions of downhill mountain biking (DMB) or road cycling (RC). One hundred and two DMB riders, 79 road cyclists and 73 control participants filled in a survey intended to evaluate the prevalence of vertigo in daily living activities and following competitions or training sessions. Vertigo causal factors (crashes, head trauma, fatigue, characteristics of the path/road ridden) were recorded. DMB riders and road cyclists did not report more vertigo during daily living activities than controls. But DMB riders older than 30 had more risk to report vertigo than age-matched road cyclists (OR: 5.06, 95% CI: 1.23-20.62). Road cyclists aged between 20 and 29 were 2.59-fold (95% CI: 1.06-6.27) more likely to report vertigo than controls. After competitions and training sessions, DMB riders were 2.33-fold (95% CI: 1.22-4.41) more likely to report vertigo than road cyclists. Vertigo causal factors were crash with head trauma in DMB riders and fatigue in road cyclists. Vertigo during daily living activities may be of concern for cyclists, particularly older DMB riders. The accumulation of impacts (crashes, vibrations) during the career of a DMB rider may generate micro traumatisms of the central nervous system and/or peripheral vestibular structures, particularly the otolith organs. In RC, the pathophysiological mechanisms generating vertigo might be effort-related disturbance of homeostasis. To avoid injuries, DMB riders should be aware that vertigo may occur at the end of training sessions or competitions. PMID- 25495239 TI - A neural reward prediction error revealed by a meta-analysis of ERPs using great grand averages. AB - Economic approaches to decision making assume that people attach values to prospective goods and act to maximize their obtained value. Neuroeconomics strives to observe these values directly in the brain. A widely used valuation term in formal learning and decision-making models is the reward prediction error: the value of an outcome relative to its expected value. An influential theory (Holroyd & Coles, 2002) claims that an electrophysiological component, feedback related negativity (FRN), codes a reward prediction error in the human brain. Such a component should be sensitive to both the prior likelihood of reward and its magnitude on receipt. A number of studies have found the FRN to be insensitive to reward magnitude, thus questioning the Holroyd and Coles account. However, because of marked inconsistencies in how the FRN is measured, a meaningful synthesis of this evidence is highly problematic. We conducted a meta analysis of the FRN's response to both reward magnitude and likelihood using a novel method in which published effect sizes were disregarded in favor of direct measurement of the published waveforms themselves, with these waveforms then averaged to produce "great grand averages." Under this standardized measure, the meta-analysis revealed strong effects of magnitude and likelihood on the FRN, consistent with it encoding a reward prediction error. In addition, it revealed strong main effects of reward magnitude and likelihood across much of the waveform, indicating sensitivity to unsigned prediction errors or "salience." The great grand average technique is proposed as a general method for meta-analysis of event-related potential (ERP). PMID- 25495241 TI - A mechanism of deficient interregional neural communication in schizophrenia. AB - Cognitive interference control is disrupted in schizophrenia (SZ). Neuroimaging studies relate interference control to 4-7 Hz (theta) neural activity in a network spanning prefrontal, anterior cingulate (ACC), and parietal cortices. The mechanism of communication in this network and how it is disrupted in schizophrenia are unclear. Behavioral performance and EEG theta oscillations were examined in a Stroop color-word interference task in 17 healthy controls (HC) and 14 SZ patients. Color-word incongruence induced less theta power increase in SZ than in HC around 400 ms and 600-900 ms after word onset in ACC, left middle frontal gyrus (MFG), and inferior parietal regions. Coupling of ACC theta phase to MFG gamma amplitude, indexing interregional communication, was weaker in SZ than in HC. Results suggest ACC-MFG theta power modulation as a mechanism of interference control that supports executive function and is disrupted in schizophrenia. PMID- 25495240 TI - The red death meets the abdominal bristle: polygenic mutation for susceptibility to a bacterial pathogen in Caenorhabditis elegans. AB - Understanding the genetic basis of susceptibility to pathogens is an important goal of medicine and of evolutionary biology. A key first step toward understanding the genetics and evolution of any phenotypic trait is characterizing the role of mutation. However, the rate at which mutation introduces genetic variance for pathogen susceptibility in any organism is essentially unknown. Here, we quantify the per-generation input of genetic variance by mutation (VM) for susceptibility of Caenorhabditis elegans to the pathogenic bacterium Pseudomonas aeruginosa (defined as the median time of death, LT50). VM for LT50 is slightly less than VM for a variety of life-history and morphological traits in this strain of C. elegans, but is well within the range of reported values in a variety of organisms. Mean LT50 did not change significantly over 250 generations of mutation accumulation. Comparison of VM to the standing genetic variance (VG) implies a strength of selection against new mutations of a few tenths of a percent. These results suggest that the substantial standing genetic variation for susceptibility of C. elegans to P. aeruginosa can be explained by polygenic mutation coupled with purifying selection. PMID- 25495242 TI - Non-occlusive mesenteric ischemia after chemotherapy for metastatic melanoma. PMID- 25495243 TI - Heteroagglomeration of oxide nanoparticles with algal cells: effects of particle type, ionic strength and pH. AB - Discharged oxide nanoparticles (NPs) have been shown toxic to unicellular algae, yet the research on heteroagglomeration between NPs and cells as an important precondition of the toxicity is scarce. This study for the first time investigated heteroagglomerations between various NPs and algal cells (Chlorella pyrenoidosa) and analyzed influencing factors including pH and ionic strength (IS) through cosettling experiment, transmission electron microscopic (TEM) observation, and Derjaguin-Landau-Verwey-Overbeek (DLVO) calculation. The examined NPs included anatase and rutile TiO2, microporous and spherical SiO2, and alpha-form and beta-form Al2O3. The results of cosettling experiments coincided well with the TEM observations, whereas the DLVO theory could only partly explain the NP-cell heteroagglomerations. The NP-cell heteroagglomeration for rutile TiO2 and beta-form Al2O3 was weak and insensitive to pH or IS. Preferential heteroagglomeration occurred at low pH or high IS for microporous SiO2, while marked heteroagglomeration only occurred under the neutral and low IS condition for anatase TiO2. The heteroagglomeration for spherical SiO2 was insensitive to pH but increased with increasing IS, while the heteroagglomeration for alpha-form Al2O3 occurred at low pH and irrelevant to IS. The work will shed new light on the bionano interfacial interaction and help to understand biological effects of NPs. PMID- 25495244 TI - Epidemiology of 411 140 cataract operations performed in public hospitals and private hospitals/clinics in Denmark between 2004 and 2012. AB - PURPOSE: To study the epidemiology and mortality in patients who had cataract surgery in public hospitals and private hospitals/clinics in Denmark between 2004 and 2012 and to assess the validity of the Danish cataract registries. METHODS: Register- and chart-based study. RESULTS: A total of 411 140 cataract operations were performed in 243 856 patients. Patients who had cataract surgery in public hospitals had an overall statistically significantly 62% higher mortality compared to patients who had cataract surgery in private hospitals/clinics. The decrease in mean age at first eye cataract surgery in private hospitals/clinics was statistically significantly greater compared to the decrease in mean age at first eye cataract surgery in public hospitals (p < 0.001). The median time interval between first and second eye cataract surgery decreased statistically significantly during the study period (p < 0.001) and was statistically significantly shorter in all calendar years for patients operated in private hospitals/clinics compared to patients operated in public hospitals (p < 0.001). In all, 46% of the cataract operations performed in private hospitals/clinics that led to cases of postoperative endophthalmitis were not registered in any registry. CONCLUSION: In general, patients who had cataract surgery in private hospitals/clinics were healthier, had first eye cataract surgery at an increasingly younger age and had a reduced time interval between cataract surgeries in the two eyes compared to patients who had cataract surgery in public hospitals. The lack of registration of cataract surgery by the private hospitals/clinics limits the quality of the registries. PMID- 25495245 TI - A review of introducing qualitative research in psychology. PMID- 25495246 TI - Oral squamous cell carcinoma and hyperkeratotic lesions with BRAF inhibitors. PMID- 25495247 TI - Novel composite layer based on electrospun polymer nanofibers for efficient light scattering. AB - We fabricated a PAN (polyacrylonitrile) NF (nanofiber)-embedded composite layer to adjust the light-control layer in light-emitting-diode (LED) and organic-light emitting-diode (OLED) lighting systems with unique optical characteristics, for effective light scattering. The newly designed light-control composite layers with a composition of PAN NF/SU-8 exhibited a change in the optical properties, which was identified by the diameter control of the NF using a simple process. The change in the optical properties was largely dependent on the embedded NF's features. Therefore, the NF can be applied in different types of lighting systems, depending on each lighting device's purpose. PMID- 25495248 TI - Preparation of 3-Acyl-4-arylcoumarins via Metal-Free Tandem Oxidative Acylation/Cyclization between Alkynoates with Aldehydes. AB - A new and efficient metal-free tandem acylation/cyclization of alkynoates with aldehydes was developed for the synthesis of 3-acyl-4-arylcoumarins. The reaction was achieved by the addition of acyl radical to alkynes and a C-H bond functionalization to form two new C-C bonds simultaneously. PMID- 25495249 TI - Supervised clustering of immunohistochemical markers to distinguish atypical and non-atypical endometrial hyperplasia. AB - The risk of endometrial hyperplasia (EH) progressing into endometrioid endometrial cancer ranges from 1% for simple EH without atypia (EHWA) to 46.2% for atypical EH (AEH). Differentiation between both entities is crucial to determine optimal management. As preoperative diagnosis of AEH can be difficult, we aimed to establish clusters of immunohistochemical markers to distinguish EHWA from AEH. We studied 13 immunohistochemical markers (steroid receptors, pro/anti apoptotic proteins, metalloproteinases (MMP), tissue inhibitor of metalloproteinase (TIMP), CD44 isoforms) known for their role in endometrial pathology. Using supervised clustering, we determined clusters of co-expressed proteins which contributed the most in differentiating EHWA from AEH. From 39 tissue samples (17 EHWA and 22 AEH), we found three clusters of co-expressed proteins: Cluster 1 included two proteins (over-expression of estrogen receptor (ER) and under-expression of progesterone receptor (PR) B in AEH compared to EHWA); Cluster 2: an ER, PR A, MMP-2 and TIMP-1 over-expression and a PR B and TIMP-2 under-expression; Cluster 3: over-expression of ER and MMP-7 and under expression of PR B and TIMP-2. AEH can be accurately distinguished from EHWA using a supervised clustering of immunohistochemical markers. This promising approach could be useful to improve the preoperative diagnosis of EH. PMID- 25495250 TI - Minimally invasive hepatobiliary surgery: pioneering investigations regarding surgical treatment of hepatobiliary disease. Introduction. PMID- 25495251 TI - Endovascular treatment of Budd-Chiari syndrome with hepatic vein obstruction in China. AB - Abstract Purpose: To evaluate characteristics of obstructions of the hepatic veins (HVs) in Chinese patients, technical aspects of puncture of the HVs, short- and mid-term outcomes, and complications of endovascular treatment. PATIENTS AND METHODS: Forty-eight HV patients with different degrees of symptoms and signs of portal hypertension were enrolled in our study. Endovascular treatments with balloon and stents were performed. Catheter-directed thrombolysis (CDT) was performed in patients with thrombosis in the HVs. For patients with lesions of both the HVs and the inferior vena cava (IVC), balloon expansions or stenting were performed at the IVC lesions also. RESULTS: Endovascular treatments were successful in 43 patients. The technically success rate was 89.6% (43/48). Fifteen patients underwent solely balloon expansions, 28 patients had balloon expansions and stentings, 5 patients underwent CDT, and 3 patients had implanted stents in the IVC lesions at the same time. The symptoms of portal hypertension were alleviated in 39 patients postoperatively. In the other 4 cases portal hypertension was mildly alleviated at discharge. Thirty-nine of the 43 patients were followed up for an average of 24+/-1.3 months (range, 6-62 months). Ascites were completely resolved in 32 cases, with a small amount of ascites in 4 patients and moderate to massive amounts in 3 patients. Hepatomegaly and splenomegaly completely disappeared in 30 patients and still could be touched in 6 patients. The HVs were patent in 29 patients. Restenosis and re-occlusion of the HVs appeared in 4 cases. All patients were successfully treated by endovascular treatments. CONCLUSIONS: Endovascular treatments for patients with obstruction of the HVs have a high technical success rate, fewer complications, and better short- and mid-term clinical outcome. The key to successful endovascular treatment is successful puncture of HVs. For patients who have occlusive lesions of HVs combined with occlusive IVC, recanalization of the lesions of the HVs could achieve good results. PMID- 25495252 TI - Single-port laparoscopic distal pancreatectomy: initial experience. AB - INTRODUCTION: Laparoscopic distal pancreatectomy has become the standard treatment of choice for pancreatic tail cystic and solid tumors when technically feasible. Technological advances have led to the development of single-port laparoscopic surgery, a safe alternative procedure. We present our experiences with single-port laparoscopic distal pancreatectomy. MATERIALS AND METHODS: We retrospectively reviewed clinical records and compared clinical outcomes in 40 patients diagnosed with a pancreatic tail mass between 2007 and 2013 who received either conventional laparoscopic (n=28) or single-port laparoscopic distal pancreatectomy (n=12). RESULTS: The mean surgery time in the single-port group (279.8+/-53.0 minutes) was significantly longer than in the conventional group (186.9+/-86.6 minutes) (P=.001). The mean duration of postoperative hospital stay in the single-port group (12.2+/-5.4 days) was also significantly longer than in the conventional group (8.3+/-4.7 days) (P=.028). The spleen was preserved more in the conventional group (60.7%) than in the single-port group (33.3%), but the difference was not significant (P=.112). There were no significant differences in intraoperative blood loss, tumor size, conversion rate, or postoperative complications between the two groups. CONCLUSIONS: Blood loss and postoperative complications of single-port laparoscopic distal pancreatectomy are similar to those of conventional laparoscopic distal pancreatectomy. Single-port laparoscopic distal pancreatectomy can be performed safely and effectively in select patients with pancreas tail neoplasms, but is associated with a longer surgery time and postoperative hospital stay. PMID- 25495253 TI - Commentary on "single-port laparoscopic distal pancreatectomy: initial experience". PMID- 25495254 TI - A clinical prediction score for diagnosing unilateral primary aldosteronism may not be generalizable. AB - BACKGROUND: A published clinical prediction score indicated that a unilateral adrenal adenoma and either hypokalemia or an estimated glomerular filtration rate of 100 ml/min/1.73 m2 was 100% specific for unilateral primary aldosteronism. This study aimed to validate this score in a separate cohort of patients with primary aldosteronism. METHODS: A review of patients with primary aldosteronism from June 2005 to July 2013 at a single center's hypertension clinic. One hundred twelve patients with primary aldosteronism underwent successful adrenal vein sampling and the 110 patients with full data available were included in the final analysis. Adrenal vein sampling was performed all patients desiring surgery by the simultaneous collection of sample prior to and 15 minutes after a cosyntropin infusion with a 3:1 aldosterone/cortisol ratio diagnosing unilateral primary aldosteronism. The derived score was applied to the cohort. Sensitivity and specificity were calculated for clinical prediction score of >=5 points. RESULTS: There were 64 patients found to have unilateral primary aldosteronism and 48 had bilateral disease. A score >=5 points had 64% sensitivity (95% confidence interval, 51-76) and 85% specificity (95% confidence interval, 71-94) for unilateral disease. Four patients had lateralization of primary aldosteronism to the side contralateral to the adenoma. CONCLUSIONS: The 100% specificity of the score for the unilateral origin of primary aldosteronism was not validated in this cohort with a score of >=5 points. At best, a high score in this prediction rule may be an additional tool for helping to confirm a decision to offer patients adrenal vein sampling. PMID- 25495255 TI - Gender-associated differential expression of cytokines in specific areas of the brain during helminth infection. AB - Intraperitoneal infection with Taenia crassiceps cysticerci in mice alters several behaviors, including sexual, aggressive, and cognitive function. Cytokines and their receptors are produced in the central nervous system (CNS) by specific neural cell lineages under physiological and pathological conditions, regulating such processes as neurotransmission. This study is aimed to determine the expression patterns of cytokines in various areas of the brain in normal and T. crassiceps-infected mice in both genders and correlate them with the pathology of the CNS and parasite counts. IL-4, IFN-gamma, and TNF-alpha levels in the hippocampus and olfactory bulb increased significantly in infected male mice, but IL-6 was downregulated in these regions in female mice. IL-1beta expression in the hippocampus was unaffected by infection in either gender. Our novel findings demonstrate a clear gender-associated pattern of cytokine expression in specific areas of the brain in mammals that parasitic infection can alter. Thus, we hypothesize that intraperitoneal infection is sensed by the CNS of the host, wherein cytokines are important messengers in the host-parasite neuroimmunoendocrine network. PMID- 25495256 TI - Effects of amniotic membrane extract on primary human corneal epithelial and limbal cells. AB - BACKGROUND: To assess the effects of amniotic membrane extract (AMX) on cellular activity of primary human corneal epithelial (HCE) cells under mechanical and oxidative stress, and on human limbal cells under oxidative stress. METHODS: Corneal mechanical stress was simulated with a linear scratch in confluent HCE cell plates, then incubated with 0.1% AMX for 48 and 72 h. Subjecting HCE cultures to 0.5 mmol/L tertiary-butylhydroperoxide for 1 h simulated an oxidative stress. 0.1% AMX-treated cultures were compared with controls at 24 and 48 h using cellular viability assay, along with 12-h AMX pretreatment and human limbal cell comparisons. RESULTS: Mechanical stress on HCE cultures revealed a statistically significant distance ratio at 48 and 72 h in favour of 0.1% AMX treated cultures (P = 0.021 and 0.035, respectively). Oxidative stress did not reveal any significant difference in cellular viability of AMX-treated versus control cultures. Twelve hour AMX pre-treatment prior to oxidative stress revealed a significant difference after 24 h from oxidative injury (73.3% AMX vs. 66.0% control, P = 0.035), but not after 48 h. Human limbal cells demonstrated significantly improved oxidative viability compared with HCE cells, with (91.0% vs. 82.0% control, P = 0.017) and without 0.1% AMX pre-treatment (91.2% vs. 83.7% control, P = 0.019). CONCLUSIONS: HCE cells treated with AMX healed faster after mechanical insult, suggesting a potential benefit in acute corneal injuries. Under oxidative stress, human limbal cells, a more proliferative cell type, showed superior viability compared with HCE cells. PMID- 25495257 TI - The experiences of participating in winter among youths with a physical disability compared with their typically developing peers. AB - BACKGROUND: Having a physical disability and using a wheelchair can create difficulties in navigating the physical and built environment, especially during winter when snow and ice become problematic. Little is known about the experiences of winter among youth who use an assistive mobility device. This study aimed to understand how youth with a physical disability experience winter, compared with typically developing peers. METHODS: A purposive sample of 25 youths (13 with a physical disability; 12 typically developing) completed a 2 week weather journal and photographs in two Canadian cities during winter. These data were used to guide semi-structured interviews with participants. RESULTS: Youths with disabilities experienced many similar challenges in winter, such as health and safety concerns and accessibility issues, compared with typically developing youth - but to a greater extent. Youths with disabilities reported more challenges going outdoors during winter and negative psychosocial impacts, including loneliness and increased dependence, compared with peers without a disability. They also, however, described developing several adaptive strategies to cope with these challenges. CONCLUSIONS: There is a strong need to remove physical and environmental barriers to facilitate the participation and inclusion of youth with disabilities in winter. PMID- 25495258 TI - Conditional cash transfer schemes in Nigeria: potential gains for maternal and child health service uptake in a national pilot programme. AB - BACKGROUND: This paper describes use of a Conditional Cash Transfer (CCT) programme to encourage use of critical MNCH services among rural women in Nigeria. METHODS: The CCT programme was first implemented as a pilot in 37 primary health care facilities (PHCs), in nine Nigerian states. The programme entitles women using these facilities up to N5,000 (approximately US$30) if they attend antenatal care (ANC), skilled delivery, and postnatal care. There are 88 other PHCs from these nine states included in this study, which implemented a standard package of supply upgrades without the CCT. Data on monthly service uptake throughout the continuum of care was collected at 124 facilities during quarterly monitoring visits. An interrupted time series using segmented linear regression was applied to estimate separately the effects of the CCT programme and supply package on service uptake. RESULTS: From April 2013-March 2014, 20,133 women enrolled in the CCT. Sixty-four percent of beneficiaries returned at least once after registration, and 80% of women delivering with skilled attendance returned after delivery. The CCT intervention is associated with a statistically significant increase in the monthly number of women attending four or more ANC visits (increase of 15.12 visits per 100,000 catchment population, p < 0.01; 95% confidence interval 7.38 to 22.85), despite a negative level effect immediately after the intervention began (-45.53/100,000 catchment population; p < 0.05; 95% CI -82.71 to -8.36). A statistically significant increase was also observed in the monthly number of women receiving two or more Tetanus toxoid doses during pregnancy (21.65/100,000 catchment population; p < 0.01; 95% CI 9.23 to 34.08). Changes for other outcomes with the CCT intervention (number of women attending first ANC visit; number of deliveries with skilled attendance; number of neonates receiving OPV at birth) were not found to be statistically significant. CONCLUSIONS: The results show that the CCT intervention is capable of significant effects on service uptake, although results for several outcomes of interest were inconclusive. Key lessons learnt from the pilot phase of implementation include a need to track beneficiary retention throughout the continuum of care as closely as possible, and avert loss to follow-up. PMID- 25495259 TI - Complement regulators in human disease: lessons from modern genetics. AB - First identified in human serum in the late 19th century as a 'complement' to antibodies in mediating bacterial lysis, the complement system emerged more than a billion years ago probably as the first humoral immune system. The contemporary complement system consists of nearly 60 proteins in three activation pathways (classical, alternative and lectin) and a terminal cytolytic pathway common to all. Modern molecular biology and genetics have not only led to further elucidation of the structure of complement system components, but have also revealed function-altering rare variants and common polymorphisms, particularly in regulators of the alternative pathway, that predispose to human disease by creating 'hyperinflammatory complement phenotypes'. To treat these 'complementopathies', a monoclonal antibody against the initiator of the membrane attack complex, C5, has received approval for use. Additional therapeutic reagents are on the horizon. PMID- 25495260 TI - Pharmacological approaches for Alzheimer's disease: neurotransmitter as drug targets. AB - Alzheimer's disease (AD) is the most common CNS disorder occurring worldwide. There is neither proven effective prevention for AD nor a cure for patients with this disorder. Hence, there is an urgent need to develop safer and more efficacious drugs to help combat the tremendous increase in disease progression. The present review is an attempt at discussing the treatment strategies and drugs under clinical trials governing the modulation of neurotransmitter. Therefore, looking at neurotransmitter abnormalities, there is an urge for developing the pharmacological approaches aimed at correcting those abnormalities and dysfunctioning. In addition, this review also discusses the drugs that are in Phase III trials for the treatment of AD. Despite advances in treatment strategies aimed at correcting neurotransmitter abnormalities, there exists a need for the development of drug therapies focusing on the attempts to remove the pathogenomic protein deposits, thus combating the disease progression. PMID- 25495261 TI - The bedside assessment practices of speech-language pathologists in adult dysphagia. AB - PURPOSE: The current study aimed to investigate what Australian speech-language pathologists frequently include in their bedside assessments in adult dysphagia, what factors influence these bedside assessments and whether they are consistent with the current evidence base. METHOD: These aims were achieved via an online questionnaire and a series of semi-structured interviews. In the questionnaire, respondents were asked to rate how frequently they utilized bedside assessment components on a scale of five ranging from never to always. RESULT: One hundred and forty practicing speech-language pathologists completed the online questionnaire in full. Eight interviews were then conducted. Respondents reported utilizing predominantly motor elements of their oro-motor examination with very few sensory elements being frequently utilized. Five main themes arose from the interviews including the influence of the individual patient and participant, the current evidence base, the participants' clinical practice and the participants' workplace. CONCLUSION: The findings from this research have implications for current clinical and education practices, in particular the impact of education and training and caseload demands on current practice. PMID- 25495262 TI - Unique designs, errors and strategies in the Five-Point Test: The contribution of age, phonemic fluency and visuospatial abilities in Italian children aged 6-11 years. AB - Performances on the Five-Point Test of 161 Italian children aged 6 to 11 years were investigated, along with phonemic fluency, visual-motor integration, visual perception, motor coordination, visuospatial memory, and fluid intelligence. Five Point Test accuracy was significantly related to phonemic fluency and visual motor integration, while phonemic fluency was linked to motor coordination. The two fluency measures increased linearly with age, but the developmental progression of Five-Point Test accuracy was less influenced by age. Different age effects were also found on the relationship between fluid intelligence and the two fluency measures. The inspection of qualitative aspects of Five-Point Test performance (errors and strategies) suggested that strategy usage enhanced both productivity and accuracy in children; age-related changes were observed in the relationship between the number of errors and the total number of designs produced. PMID- 25495263 TI - Resourcefulness in African American and Caucasian American Caregivers of Persons With Dementia: Associations With Perceived Burden, Depression, Anxiety, Positive Cognitions, and Psychological Well-Being. AB - PURPOSE: Providing care to persons with dementia can have negative effects on caregivers' physical and psychological well-being. This secondary analysis explored relationships among perceived burden, depression, anxiety, resourcefulness, and psychological well-being in 28 African American (AA) and 45 Caucasian American (CA) caregivers of persons with dementia. DESIGN AND METHODS: Descriptive, cross-sectional design was used to examine the hypothesized relationships in a sample of 73 caregivers. FINDINGS: CAs reported greater burden (t=-3.68, p<.001), more anxiety (t=-2.66, p<.01), depression (t=-2.21, p<.05), and hostility (t=-2.30, p<.05) than AAs. AAs reported higher scores than CAs on resourcefulness, positive cognitions, and psychological well-being. PRACTICE IMPLICATIONS: The study findings provided directions for the development of resourcefulness interventions to enhance the psychological well-being among dementia caregivers. PMID- 25495264 TI - An unusual colon atresia in a calf: at the junction of the distal loop and transverse colon. A brief overview. AB - Congenital defects are those abnormalities present at birth. During embryogenesis, many anomalies can occur. The primitive gut tube lengthens quickly and rotates, allowing the gastrointestinal tract acquire its final position and orientation. Because the colon of large animals is complex, most changes occur in this segment. Thus, in ruminants, colon atresia is the most frequent malformation, affecting mainly ascending colon, at the level of the spiral loop. There are no previous references about a very atypical colon atresia at the junction of distal loop and transverse colon, such we have described in a 5-day old calf, after a history of abdominal distention and absence of feces at birth, even with a patent anal opening. Atresia coli was detected at distal position of the typical colon atresia, at the junction of distal loop and transverse colon. In addition, the distal blind end was bent into a U-shape supported by the mesocolon. Besides the anatomical findings of this worthwhile atresia coli we discuss its possible etiology, in which local factors, such as a compromised blood supply during embryogenesis, are more consistent than genetic factors. Finding out the causes of atresia coli would help to reduce its incidence, lessen animal suffering and economic loss. PMID- 25495265 TI - Protein electrocatalysis for direct sensing of circulating microRNAs. AB - MicroRNAs (miRNAs) are potentially useful biomarkers for diagnosis, classification, and prognosis of many diseases, including cancer. Herein, we developed a protein-facilitated electrocatalytic quadroprobe sensor (Sens(PEQ)) for detection of miRNA signature of chronic lymphocytic leukemia (CLL) in human serum. The developed signal-ON sensor provides a compatible combination of two DNA adaptor strands modified with four methylene blue molecules and electrocatalysis using glucose oxidase in order to enhance the overall signal gain. This enhanced sensitivity provided the response necessary to detect the low abundant serum miRNAs without preamplification. The developed Sens(PEQ) is exquisitely sensitive to subtle pi-stack perturbations and capable of distinguishing single base mismatches in the target miRNA. Furthermore, the developed sensor was employed for profiling of three endogenous miRNAs characteristic to CLL, including hsa-miR-16-5p, hsa-miR-21-5p, and hsa-miR-150-5p in normal healthy serum, chronic lymphocytic leukemia Rai stage 1 (CLL-1), and stage 3 (CLL-3) sera, using a non-human cel-miR-39-3p as an internal standard. The sensor results were verified by conventional SYBR green-based quantitative reverse-transcription polymerase chain reaction (RT-qPCR) analysis. PMID- 25495267 TI - Impact of silicone and metal port-a-cath implants on superficial hyperthermia treatment quality. AB - PURPOSE: A port-a-cath is a device implanted under the skin for continuous drug administration. It is composed of a catheter and a silicone or metal reservoir. A simulation study was done to assess the impact of a port-a-cath implant on the quality of superficial hyperthermia treatments applied using the Lucite cone applicator (LCA). METHODS: Specific absorption rate (SAR) and temperature distributions were predicted using SEMCAD-X (version 14.8). We simulated 72 arrangements: two LCA-implant set-ups (central port-a-cath or at an edge below the LCA footprint), six translations of the LCA per set-up, two LCA orientations (Parallel or perpendicular electric field direction) per set-up, two implant materials (silicon or metal) and a control without port-a-cath. Treatment quality was quantified by the average 1 g SAR coverage (CV25%), i.e. volume within the 25% iso-SAR surface, and the volume within the 40 degrees C iso-temperature surface (CV40 degrees C). RESULTS: CV25% reduced with a silicon port-a-cath located below the LCA footprint. In the worst scenario, only 64% of the CV25% of the control set-up was achieved. For a metal port-a-cath below the LCA aperture, dramatic reductions of CV25% were predicted: worst scenario down to 12.1% of the control CV25%. For the CV40 degrees C the worst case values were 74.5% and 6.5%, for silicon and metal implants, respectively. CONCLUSIONS: A silicone port-a-cath below the LCA had a smaller effect on treatment quality than a metal implant. Based on this study we recommend verifying heating quality by 3D patient-specific treatment planning when a port-a-cath is located below the footprint of the applicator. PMID- 25495266 TI - When bad things happen to bad people: using disposition theory to explore the effects of cautionary tales. AB - Cautionary tales are a prevalent form of entertainment narrative in media saturated environments, yet they have received little empirical examination. Using disposition theory, this study manipulated affective disposition toward the protagonist in order to explore the effects of exposure to a cautionary tale on adoption of prosocial attitudes and behavioral intentions. A between-subjects experimental design was used with 2 conditions (positive/negative) and a control group (n = 305). Results provide evidence that exposure to cautionary tales positively influences adoption of attitudes and intentions to purchase a carbon monoxide detector and talk about accidental carbon monoxide poisoning. Affective disposition influenced identification with the protagonist, and perceptions that the protagonist deserved the negative consequences experienced in the cautionary tale narrative. Findings also suggest that identification mediates the relationship between affective disposition and perceived risk. PMID- 25495268 TI - Investigating mosquito net durability for malaria control in Tanzania - attrition, bioefficacy, chemistry, degradation and insecticide resistance (ABCDR): study protocol. AB - BACKGROUND: Long-Lasting Insecticidal Nets (LLINs) are one of the major malaria vector control tools, with most countries adopting free or subsidised universal coverage campaigns of populations at-risk from malaria. It is essential to understand LLIN durability so that public health policy makers can select the most cost effective nets that last for the longest time, and estimate the optimal timing of repeated distribution campaigns. However, there is limited knowledge from few countries of the durability of LLINs under user conditions. METHODS/DESIGN: This study investigates LLIN durability in eight districts of Tanzania, selected for their demographic, geographic and ecological representativeness of the country as a whole. We use a two-stage approach: First, LLINs from recent national net campaigns will be evaluated retrospectively in 3,420 households. Those households will receive one of three leading LLIN products at random (Olyset(r), PermaNet(r)2.0 or Netprotect(r)) and will be followed up for three years in a prospective study to compare their performance under user conditions. LLIN durability will be evaluated by measuring Attrition (the rate at which nets are discarded by households), Bioefficacy (the insecticidal efficacy of the nets measured by knock-down and mortality of mosquitoes), Chemical content (g/kg of insecticide available in net fibres) and physical Degradation (size and location of holes). In addition, we will extend the current national mosquito insecticide Resistance monitoring program to additional districts and use these data sets to provide GIS maps for use in health surveillance and decision making by the National Malaria Control Program (NMCP). DISCUSSION: The data will be of importance to policy makers and vector control specialists both in Tanzania and the SSA region to inform best practice for the maintenance of high and cost-effective coverage and to maximise current health gains in malaria control. PMID- 25495269 TI - Drug dose as mediator of treatment effect in antidepressant drug trials: the case of fluoxetine. AB - OBJECTIVE: This study aimed at investigating whether dose is a mediator of treatment effect in fluoxetine-randomized trials. Specifically, we investigated whether dose was higher in trials in which the aim was to demonstrate fluoxetine efficacy in comparison with older antidepressants and lower in trials in which the aim was to demonstrate a new drug's efficacy against fluoxetine. METHOD: We applied the model developed by Baron and Kenny to investigate the mediational role of drug dose on treatment effect. We included all randomized controlled trials comparing fluoxetine with other antidepressants as monotherapy in the acute-phase treatment of unipolar major depression. RESULTS: A total of 173 studies were included. In 76 comparisons (44%), fluoxetine was the experimental antidepressant. A metaregression analysis indicated that after adjusting for possible confounders, studies where fluoxetine was the experimental agent were associated with a significant advantage for fluoxetine. However, the Baron and Kenny model revealed no mediational role of drug dose in influencing treatment effect. CONCLUSION: The outcome of fluoxetine-randomized trials changed according to whether this drug was used as a new compound or as a reference. This finding cannot be attributed to antidepressants dose, as dose failed to emerge as mediator of treatment effect in the Baron and Kenny approach. PMID- 25495270 TI - Magnetic microwire probes for the magnetic rod interfacial stress rheometer. AB - The magnetic needle interfacial shear rheometer is a valuable tool for the study of the mechanical properties of thin fluid films or monolayers. However, it is difficult to differentiate the interfacial and subphase contributions to the drag on the needle. In principle, the problem can be addressed by decreasing the needle diameter, which decreases the bulk contribution while the interfacial contribution remains essentially the same. Here we show the results obtained when using a new type of needle, that of magnetic microwires with diameter approximately 10 times thinner than for commercial needles. We show that the lower inertia of the microwires calls for a new calibration procedure. We propose such a new calibration procedure based on the flow field solution around the needle introduced in refs 1 and 2. By measuring thin silicone oil films with well controlled interfacial viscosities as well as eicosanol (C20) and pentadecanoic acid (PDA, C15) Langmuir monolayers, we show that the new calibration method works well for standard needles as well as for the microwire probes. Moreover, we show that the analysis of the force terms contributing to the force on the needle helps to ascertain whether the measurements obtained are reliable for given surface shear viscosity values. We also show that the microwire probes have at least a 10-fold-lower resolution limit, allowing one to measure interfacial viscosities as low as 10(-7) N.m/s. PMID- 25495271 TI - Endoscopic endonasal dacryocystorhinostomy with ostial stent intubation following nasolacrimal duct stent incarceration. AB - PURPOSE: To study the feasibility of endoscopic endonasal dacryocystorhinostomy (EE-DCR) with novel lacrimal ostial stent (LOS) intubation for patients with chronic dacryocystitis with incarceration of a previously implanted nasolacrimal duct stent (NDS). METHODS: According to surgical procedure, 166 patients (167 eyes) were divided into two groups: EE-DCR with LOS intubation was performed on 126 patients (127 eyes) in the EE-DCR group; while external dacryocystorhinostomy (E-DCR) with silicone tube intubation was performed on 40 patients (40 eyes) in the E-DCR group. The LOS or silicone tube was retained for 3-6 months. All patients were followed up for 12-36 months. Success rate of tear drainage reconstruction (TDR) and complications were retrospectively compared. RESULTS: Excluding patients with early detachment of the LOS or the silicone tube, or with incomplete follow-up period, 117 patients (117 eyes) in the EE-DCR group and 36 patients (36 eyes) in the E-DCR group were included. The mean surgical time was 45.8 +/- 11.5 min in the EE-DCR group and 68.1 +/- 23.8 min in the E-DCR group (p < 0.001). Intraoperatively, the lacrimal sac was observed to become very small and its walls were thin, hyperemic and fragile, firmly attaching to the NDS by fibrous bands in all eyes. Upon final review, success rate of TDR was 83.8% (98/117) in the EE-DCR group, while 58.3% (21/36) in the E-DCR group (p < 0.01). Failure of TDR due to ostial closure by excessive fibrosis occurred in 14 out of 19 patients in the EE-DCR group, significantly less than the 11 out of 15 patients with failed TDR in the E-DCR group (chi(2 )= 6.959, p < 0.01). No significant difference existed in failures due to granuloma occluding the ostium or common canaliculus obstruction. CONCLUSION: EE-DCR with LOS intubation may be an effective procedure to manage the special subgroup of patients with chronic dacryocystitis with incarcerations of a previously implanted NDS. PMID- 25495272 TI - Reverse sequential therapy achieves a similar eradication rate as standard sequential therapy for Helicobacter pylori eradication: a randomized controlled trial. AB - BACKGROUND AND AIMS: Sequential therapy is a two-step therapy achieving a promising eradication rate for Helicobacter pylori infection. The rationale of sequential method has been proposed that amoxicillin weakens bacterial cell walls in the initial phase of treatment, preventing the development of drug efflux channels for clarithromycin and metronidazole used in the second phase. The aim of this prospective, randomized, controlled study was to investigate whether the efficacy of reverse sequential therapy was noninferior to sequential therapy in the treatment of H. pylori infection. METHODS: From January 2009 to December 2010, consecutive H. pylori-infected patients were randomly assigned to receive either sequential therapy (a 5-day dual therapy with pantoprazole plus amoxicillin, followed by a 5-day triple therapy with pantoprazole plus clarithromycin and metronidazole) or reverse sequential therapy (a 5-day triple therapy with pantoprazole plus clarithromycin and metronidazole, followed by a 5 day dual therapy with pantoprazole plus amoxicillin). H. pylori status was examined 6 weeks after the end of treatment by rapid urease and histology or urea breath test. RESULTS: One hundred and twenty-two H. pylori-infected participants were randomized to receive sequential (n = 60) or reverse sequential therapy (n = 62). The eradication rates, by intention-to-treat analysis, were similar: 91.9% (95% confidence interval (CI): 85.1-98.7%) for sequential therapy and 96.7% (95% CI: 92.2-101.2%) for reverse sequential therapy (p = .44). Per-protocol analysis also showed similar results: 91.8% (95% CI: 84.9-98.7%) for sequential group and 96.7% (95% CI: 92.2-101.2%) for reverse sequential therapy (p = .43). The two treatments exhibited comparable frequencies of adverse events (11.3% vs 6.7%, respectively) and drug compliance (98.4% vs 100%, respectively). The overall resistance rates of antibiotics were clarithromycin 10.5%, amoxicillin 0%, and metronidazole 44.2% of patients, respectively. The dual resistance rate of clarithromycin and metronidazole was 4.2%. Both therapies achieved a high eradication rate for clarithromycin-resistant strains (100% vs 100%, respectively) and metronidazole-resistant strains (81.8% vs 95%, respectively) by intention-to-treat analysis. CONCLUSIONS: Ten-day reverse sequential therapy and standard sequential therapy are equally effective for H. Pylori eradication. The finding indicates that the sequence of antibiotics administered in sequential therapy does not influence the efficacy of the treatment. PMID- 25495273 TI - Prognostic significance of metabolic tumor burden by positron emission tomography/computed tomography in patients with relapsed/refractory diffuse large B-cell lymphoma. AB - The aim of the present study was to investigate the feasibility of measuring metabolic tumor burden using [F-18] fluorodeoxyglucose ((18) F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with bendamustine rituximab. Because the standardized uptake value is a critical parameter of tumor characterization, we carried out a phantom study of (18) F-FDG PET/CT to ensure quality control for 28 machines in the 24 institutions (Japan, 17 institutions; Korea, 7 institutions) participating in our clinical study. Fifty-five patients with relapsed or refractory DLBCL were enrolled. The (18) F-FDG PET/CT was acquired before treatment, after two cycles, and after the last treatment cycle. Treatment response was assessed after two cycles and after the last cycle using the Lugano classification. Using this classification, remission was complete in 15 patients (27%) and incomplete in 40 patients (73%) after two cycles of therapy, and remission was complete in 32 patients (58%) and incomplete in 23 patients (42%) after the last treatment cycle. The percentage change in all PET/CT parameters except for the area under the curve of the cumulative standardized uptake value-volume histogram was significantly greater in complete response patients than in non-complete response patients after two cycles and the last cycle. The Cox proportional hazard model and best subset selection method revealed that the percentage change of the sum of total lesion glycolysis after the last cycle (relative risk, 5.24; P = 0.003) was an independent predictor of progression-free survival. The percent change of sum of total lesion glycolysis, calculated from PET/CT, can be used to quantify the response to treatment and can predict progression-free survival after the last treatment cycle in patients with relapsed or refractory DLBCL treated with bendamustine-rituximab. PMID- 25495275 TI - (Patho)physiology of cross-sex hormone administration to transsexual people: the potential impact of male-female genetic differences. AB - There is a limited body of knowledge of desired and undesired effects of cross sex hormones in transsexual people. Little attention has been given to the fact that chromosomal configurations, 46,XY in male-to-female transsexuals subjects (MtoF) and 46,XX in female-to-male transsexual subjects (FtoM), obviously, remain unchanged. These differences in their genomes cause sex differences in the functions of cells. This study reviews sex differences in metabolism/cardiovascular pathology, immune mechanisms, bone (patho)physiology and brain functions and examines whether they are, maybe partially, determined by genetic mechanisms rather than by (cross-sex) hormones. There do not appear to be major genetic impacts on the changes in bone physiology. Also immune functions are rather unaffected and the evidence for an increase of autoimmune disease in MtoF is preliminary. Brain functions of transsexuals may have differed from controls before cross-sex hormones; they do undergo shifts upon cross-sex hormone treatment, but there is no evidence for changes in sex-specific brain disease. The prevalence of cardiovascular disease is higher in MtoF receiving oestrogens than in FtoM receiving androgens. While type of oestrogen and route of administration might be significant, it is reasonable to speculate that nonhormonal/genetic factors play a role. PMID- 25495276 TI - A variant within the AQP1 3'-untranslated region is associated with running performance, but not weight changes, during an Ironman Triathlon. AB - The objective of this study was to test the association of the rs1049305 (G > C) variant within the 3'-untranslated region of the aquaporin 1 gene, AQP1, with changes in body weight, post-race serum sodium concentration and performance in Ironman triathletes. Five hundred and four male Ironman triathletes were genotyped for the rs1049305 variant within the AQP1 gene. Change in pre- and post race body weight was calculated for 470 triathletes and used as a proxy for changes in body fluid during the race, as well as to divide triathletes into biologically relevant weight-loss groups (0-3%, 3-5% and >5%). There were no rs1049305 genotype effects on post-race serum sodium concentrations (P = 0.647), pre-race weight (P = 0.610) nor relative weight change during the Ironman Triathlons (P = 0.705). In addition, there were no significant differences in genotype (P = 0.640) nor allele (P = 0.643) distributions between the weight loss groups. However, triathletes who carry a C-allele were found to complete the 42.2 km run stage faster (mean 286, s = 49 min) than triathletes with a GG genotype (mean 296, s = 47 min; P = 0.032). The AQP1 rs1049305 variant is associated with running performance, but not relative body weight change, during the 2000, 2001 and 2006 South African Ironman Triathlons. PMID- 25495277 TI - Differential detection of classical swine fever virus challenge strains in C strain vaccinated pigs. AB - BACKGROUND: Control of classical swine fever (CSF) by vaccination ideally requires that field strain infection can be detected irrespective of the vaccination status of the herd. To inform on the usefulness of molecular tests compatible with genetic Differentiation of Infected from Vaccinated Animals (DIVA) principles when using live-attenuated vaccines, tonsil homogenates from a vaccination-challenge experiment were analyzed using a differential real-time qRT PCR for the C-strain vaccine or real-time qRT-PCR assays developed to specifically detect the challenge strains used. RESULTS: In animals with high or moderate levels of blood viraemia, which were not, or not fully, protected by vaccination, challenge virus RNA was readily detected in tonsil homogenates. In three out of the seven vaccinated animals that had high or moderate viraemia, the vaccine strain RNA also could be detected but at lower levels. Lower but varying levels of challenge and/or vaccine virus RNA were detected in tonsil homogenate samples from animals with no or low-level viraemia, and in groups solely consisting of such animals, no transmission of infection to naive in-contact animals occurred. In one group of animals that were vaccinated 3 days prior to challenge, viraemia levels varied from high to absent and transmission of challenge virus to naive in-contact animals occurred. The DIVA assay revealed challenge virus in all tonsil homogenates from this group, even in those animals that did not have viraemia and were protected from clinical disease by vaccination. Such animals, particularly in a low biosecurity/informal farm setting, could constitute a risk for disease control in the field. CONCLUSIONS: Genetic DIVA testing is useful for detecting the presence of field virus infection especially in non-viraemic animals without overt clinical signs but which are incompletely protected by vaccination. Such tests could particularly be useful to inform decisions prior to and during cessation of a control strategy that employs vaccination. PMID- 25495278 TI - Sleep-related eating disorder and its associated conditions. AB - Sleep-related eating disorder (SRED) is a condition characterized by recurrent episodes of eating at the transition from night-time sleep to arousal. SRED patients describe eating in an out-of-control manner with preference for high caloric foods and sometimes with inedible or toxic items. Level of consciousness during SRED episodes ranges from partial consciousness to dense unawareness typical of somnambulistic episodes. SRED is sometimes associated with psychotropic medication, in particular sedative hypnotics, and other sleep disorders, including parasomnias, narcolepsy, and restless legs syndrome. Night eating syndrome (NES) is another important condition in the disordered night-time eating spectrum showing hyperphagia episodes at full arousal from nocturnal sleep without accompanying amnesia. NES could be considered an abnormality in the circadian rhythm of meal timing with a normal circadian timing of sleep onset. The two conditions often overlap and possibly share a common pathophysiology. Studies have suggested that central nervous system serotonin modulation may lead to an effective treatment of NES, while the anti-seizure medication topiramate may be an effective SRED treatment. PMID- 25495279 TI - Dual recognition unit strategy improves the specificity of the adenosine triphosphate (ATP) aptamer biosensor for cerebral ATP assay. AB - Adenosine triphosphate (ATP) aptamer has been widely used as a recognition unit for biosensor development; however, its relatively poor specificity toward ATP against adenosine-5'-diphosphate (ADP) and adenosine-5'-monophosphate (AMP) essentially limits the application of the biosensors in real systems, especially in the complex cerebral system. In this study, for the first time, we demonstrate a dual recognition unit strategy (DRUS) to construct a highly selective and sensitive ATP biosensor by combining the recognition ability of aptamer toward A nucleobase and of polyimidazolium toward phosphate. The biosensors are constructed by first confining the polyimidazolium onto a gold surface by surface initiated atom transfer radical polymerization (SI-ATRP), and then the aptamer onto electrode surface by electrostatic self-assembly to form dual-recognition unit-functionalized electrodes. The constructed biosensor based on DRUS not only shows an ultrahigh sensitivity toward ATP with a detection limit down to the subattomole level but also an ultrahigh selectivity toward ATP without interference from ADP and AMP. The constructed biosensor is used for selective and sensitive sensing of the extracellular ATP in the cerebral system by combining in vivo microdialysis and can be used as a promising neurotechnology to probing cerebral ATP concentration. PMID- 25495280 TI - Successful fibrinolytic treatment of prosthetic heart valve thrombosis using streptokinase. AB - OBJECTIVES: This study aims to evaluate the clinical outcome of fibrinolytic treatment of prosthetic valve thrombosis (PVT) with 'streptokinase' as a first line treatment for these cases. METHODS: The study group was 20 consecutive patients (10 females) diagnosed with PVT. The protocol for streptokinase administration was either accelerated (intravenous infusion of 0.5 million IU over 30 minutes followed by 0.15 million IU/h) or conventional (intravenous infusion of 0.25 million IU over 30 minutes followed by 0.15 million IU/h). Success of fibrinolytic therapy was defined as complete restoration of valve function in the presence or absence of complications. RESULTS: Eighteen patients (90%) had mitral PVT and two (10%) had aortic PVT. Thrombolytic therapy with streptokinase was successful in all but one case, with a total mortality of four cases (20%). In PVT episodes, before streptokinase therapy, the prosthetic valve areas (in all cases, mitral and aortic positions) were 0.82 +/- 0.21, 0.83 +/- 0.21, and 0.73 +/- 0.18 cm2; and the peak and mean transvalvular gradients were 38.7 +/- 16.7 and 25.4 +/- 8.7, 34.1 +/- 8.8 and 23.2 +/- 5.4, and 80.0 +/- 14.1 and 45.0 +/- 7.1 mmHg, respectively. After streptokinase therapy, the prosthetic valve area and peak and mean transvalvular gradients improved significantly (for all cases, mitral and aortic positions: valve area 2.17 +/- 0.58, 2.21 +/- 0.61, and 1.85 +/- 0.07 cm2, peak gradient 18.7 +/- 11.0, 16.4 +/- 7.7, and 39.0 +/- 18.4, and mean gradient 9.6 +/- 7.1, 8.2 +/- 5.3, and 22.0 +/- 11.3 mmHg, respectively; paired t-test, P<0.001 for pre- versus post-streptokinase infusion for all variables). CONCLUSION: Fibrinolytic therapy using streptokinase was an effective therapeutic strategy for the management of PVT and is a reasonable alternative to surgery. PMID- 25495281 TI - Anodic substitution reaction of proline derivatives using the 2,4,6 trimethoxyphenyl leaving group. AB - An efficient method for modifying a proline moiety through anodic carbon-carbon bond cleavage is developed. Use of the 2,4,6-trimethoxyphenyl (TMP) moiety as a leaving group at the 5-position allows the incorporation of various functional groups for modification in both the N- and C-terminal direction due to the stability of the N1-C5-C linkage. This approach also enables anodic substitution reactions using reactants with lower oxidation potential compared to N-carbonyl bonds. PMID- 25495282 TI - Alteration of N-glycan profiles in patients with chronic hepatitis and hepatocellular carcinoma. AB - AIM: Most of the modification of N-glycosylation reported in cancers including hepatocellular carcinoma (HCC) were based on the examinations of a small number of patients or particular proteins. The aim of this study is to reveal changes in whole serum N-glycan profiles systematically during the process of hepatocarcinogenesis and to elucidate their clinical application. METHODS: We analyzed sera from 105 patients with chronic hepatitis/liver cirrhosis (CH/LC) and age-/sex-matched healthy volunteers (HLT), as well as from 114 patients with HCC. Serum N-glycan profiles were measured comprehensively by a new, quantitative, high-throughput method and compared with clinical parameters. RESULTS: The total amount of N-glycan expression was significantly higher in patients with CH/LC than in HLT; however, no differences were observed between CH/LC and HCC patients. In HCC patients, multi-antennary glycans with fucose residues, particularly m/z 3195, were increased compared with CH/LC patients. The expression of m/z 3195 was high, especially in patients with a high number of intrahepatic lesions (>3), large tumor size (>3 cm), macroscopic vascular invasion or metastasis. The ratio of pairs of glycans on the same path of the biosynthesis pathway (m/z 3195/1914) showed a higher area under the receiver operator curve of 0.810 than any other single glycan to distinguish HCC from CH/LC. CONCLUSION: We demonstrate the full spectrum of the alterations of serum N glycans comprehensively in patients with liver disease, and elucidate the possible use of glycans as novel biomarkers of liver disease progression. PMID- 25495284 TI - The effect of anaerobic fungal inoculation on the fermentation characteristics of rice straw silages. AB - AIMS: To identify whether the supplement of anaerobic fungi isolates with cellulolytic activities accelerates the silage fermentation. METHODS AND RESULTS: Three fungal isolates with the highest cellulolytic activities among 45 strains of anaerobic fungal stock in our laboratory were selected and used as silage inoculants. The rice straw (RS) was ensiled for 10, 30, 60, 90 and 120 days with four treatments of anaerobic fungi derived from the control (no fungus), Piromyces M014 (isolated from the rumen of the Korean native goat), Orpinomyces R001 (isolated from the duodenum of Korean native cattle) and Neocallimastix M010 (isolated from the guts of termites), respectively. The silages inoculated with pure strains of fungi showed a higher fungal population (P < 0.05) when compared to the control silage. In situ ruminal DM disappearance of RS silage (RSS) was improved with fungal treatment. SEM observation showed live fungal cells inoculated in RS could survive during the ensiling process. Overall, this study indicated that the inoculation of anaerobic fungi decreased the cell wall content of the RSS and increased in situ dry matter disappearance. CONCLUSIONS: The supplementation of anaerobic fungi isolates to RSS as a silage inoculant improves the RSS quality. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study showing the potential application of supplement of anaerobic fungi isolated from the guts may be applied industrially as an alternate feed additive that improves the silage quality. PMID- 25495283 TI - Distance to Anopheles sundaicus larval habitats dominant among risk factors for parasitemia in meso-endemic Southwest Sumba, Indonesia. AB - BACKGROUND: The decline in intensity of malaria transmission in many areas now emphasizes greater importance of understanding the epidemiology of low to moderate transmission settings. Marked heterogeneity in infection risk within these populations creates opportunities to understand transmission and guide resource allocation to greater impact. METHODS: In this study, we examined spatial patterns of malaria transmission in a hypo- to meso-endemic area of eastern Indonesia using malaria prevalence data collected from a cross-sectional socio-demographic and parasitological survey conducted from August to November 2010. An entomological survey performed in parallel, identified, mapped, and monitored local anopheline larval habitats. RESULTS: A single spatial cluster of higher malaria prevalence was detected during the study period (relative risk=2.13; log likelihood ratio=20.7; P<0.001). In hierarchical multivariate regression models, risk of parasitemia was inversely correlated with distance to five Anopheles sundaicus known larval habitats [odds ratio (OR)=0.21; 95% confidence interval (CI)=0.14-0.32; P<0.001], which were located in a geographically restricted band adjacent to the coastline. Increasing distance from these sites predicted increased hemoglobin level across age strata after adjusting for confounders (OR=1.6; 95% CI=1.30-1.98; P<0.001). CONCLUSION: Significant clustering of malaria parasitemia in close proximity to very specific and relatively few An. sundaicus larval habitats has direct implications for local control strategy, policy, and practice. These findings suggest that larval source management could achieve profound if not complete impact in this region. PMID- 25495286 TI - Clinical skills development in student-run free clinic volunteers: a multi-trait, multi-measure study. AB - BACKGROUND: At Wayne State University School of Medicine (WSU SOM), the Robert R. Frank Student Run Free Clinic (SRFC) is one place preclinical students can gain clinical experience. There have been no published studies to date measuring the impact of student-run free clinic (SRFC) volunteerism on clinical skills development in preclinical medical students. METHODS: Surveys were given to first year medical students at WSU SOM at the beginning and end of Year 1 to assess perception of clinical skills, including self-confidence, self-reflection, and professionalism. Scores of the Year 1 Objective Structured Clinical Exam (OSCE) were compared between SRFC volunteers and non-volunteers. RESULTS: There were a total of 206 (68.2%) and 80 (26.5%) survey responses at the beginning and end of Year 1, respectively. Of the 80 students, 31 (38.7%) volunteered at SRFC during Year 1. Statistically significant differences were found between time points in self-confidence (p < 0.001) in both groups. When looking at self-confidence in skills pertaining to SRFC, the difference between groups was statistically significant (p = 0.032) at both time points. A total of 302 students participated in the Year 1 OSCE, 27 (9%) of which were SRFC volunteers. No statistically significant differences were found between groups for mean score (p = 0.888) and established level of rapport (p = 0.394). CONCLUSIONS: While this study indicated no significant differences in clinical skills in students who volunteer at the SRFC, it is a first step in attempting to measure clinical skill development outside of the structured medical school setting. The findings lend themselves to development of research designs, clinical surveys, and future studies to measure the impact of clinical volunteer opportunities on clinical skills development in future physicians. PMID- 25495285 TI - Prevalence of HMTV in breast carcinomas and unaffected tissue from Mexican women. AB - BACKGROUND: Breast cancer is a complex multifactorial genetic disease. Among other factors, race and, to an even greater extent, viruses are known to influence the development of this heterogeneous disease. It has been reported that MMTV-like (HMTV) gene sequences with a 90 to 98% homology to mouse mammary tumor virus are found in several populations with a prevalence range of 0 to 74%. In the Mexican population, 4.2% of patients with breast cancer exhibit the presence of HMTV (MMTV-like) sequences. The aim of this study was to evaluate the presence and current prevalence of retroviral HMTV (MMTV-like) sequences in breast cancer in Mexican women. METHODS: We used nested PCR and real-time PCR with a TaqMan probe. As a positive control, we used the C3H MMTV strain inserted into pBR322 plasmid. To confirm that we had identified the HMTV sequences, we sequenced the amplicons and compared these sequences with those of MMTV and HMTV (GenBank AF033807 and AF346816). RESULTS: A total of 12.4% of breast tumors were HMTV-positive, and 15.7% of the unaffected tissue samples from 458 patients were HMTV-positive. A total of 8.3% of the patients had both HMTV-positive tumor and adjacent tissues. The HMTV-positive samples presented 98% similarity to the reported HMTV sequence. CONCLUSIONS: These results confirm that the HMTV sequence is present in breast tumors and non-affected tissues in the Mexican population. HMTV should be considered a prominent causative agent of breast cancer. PMID- 25495287 TI - Trismus, xerostomia and nutrition status in nasopharyngeal carcinoma survivors treated with radiation. AB - The aims of the study were to: (1) examine levels of trismus, xerostomia and nutritional status; (2) compare levels of trismus, xerostomia and nutritional status in patients with nasopharyngeal carcinoma (NPC) receiving different types of radiation modalities; and (3) identify factors related to NPC survivors' risk status for malnutrition and existing malnutrition. A cross-sectional study with consecutive sampling was conducted. NPC survivors were recruited from otolaryngology/oncology outpatient clinics in a medical centre in Northern Taiwan. Study measures included (1) Mandibular Function Impairment Questionnaire, (2) Xerostomia Questionnaire, (3) Mini Nutrition Assessment, (4) Hospital Anxiety and Depression Scale - Depression subscale, and (5) Symptom Severity Scale. A total of 110 subjects were recruited. Those receiving intensity-modulated radiation therapy had less trismus and xerostomia than patients receiving two dimensional radiation therapy. Patients with female gender, advanced stage, completion of treatments within 1 year, higher levels of depression, more severe trismus and higher symptom severity tended to have malnutrition or were at risk of malnutrition. Trismus and xerostomia are long-term problems in some NPC survivors and may contribute to malnutrition. To better manage a patient's trismus and xerostomia and to enhance nutritional status, clinicians should develop a patient-specific care programme based on careful assessment and targeted measures to improve oral function and insure adequate nutritional intake. PMID- 25495288 TI - The use of goal attainment scaling in neuropsychological rehabilitation in multiple sclerosis. AB - PURPOSE: The overall objective was to apply the goal attainment scaling (GAS) in neuropsychological rehabilitation in multiple sclerosis (MS). The specific aims were to evaluate whether (1) GAS-rated goals are attained; (2) attaining goals is related to standardized rehabilitation outcome measures; and (3) GAS-rated goals can be mapped to the International Classification of Functioning, Disability, and Health (ICF). METHOD: 56 relapsing-remitting MS patients received neuropsychological rehabilitation conducted once a week for 13 consecutive weeks. The attainment of GAS-rated personal goals and the association between achievement of goals and standardized rehabilitation outcome were evaluated. Moreover, GAS-rated goals were mapped to the ICF. RESULTS: Median (interquartile range) GAS attainment T-score was 56.0 (50.0-62.0); 88.8% of personal goals set were fully achieved. The attainment of goals was not significantly associated with the outcome in majority of the standardized measures. Of the 182 meaningful concepts identified in the goals, 181 could be mapped to the ICF. CONCLUSIONS: GAS seems to be an appropriate outcome measure in neuropsychological rehabilitation in MS. GAS-rated personal goals were well achieved, and GAS was found to tap changes not covered with standardized outcome measures. Implications for Rehabilitation GAS seems to be an appropriate outcome measure in neuropsychological rehabilitation in MS. GAS-rated personal goals were well achieved, and GAS was found to tap changes in the areas not covered with standardized outcome measures. GAS seems to offer a possibility to take into account the specific needs of each individual patient. The ICF can be used to classify goals in neuropsychological rehabilitation in MS. PMID- 25495289 TI - Catalytic generation of alpha-CF3 enolate: direct catalytic asymmetric Mannich type reaction of alpha-CF3 amide. AB - The introduction of the CF3 unit is a common strategy for modifying pharmacokinetic properties and slowing metabolic degradation in medicinal chemistry. A catalytic and enantioselective addition of alpha-CF3 enolates allows for expeditious access to functionalized chiral building blocks with CF3 containing stereogenicity. To date, alpha-CF3 enolates have been a less explored class of nucleophiles because of rapid defluorination. The present study reveals that a designed alpha-CF3 amide enables a direct asymmetric Mannich-type reaction in a cooperative catalytic system. PMID- 25495290 TI - Authentication of Ginkgo biloba herbal dietary supplements using DNA barcoding. AB - Ginkgo biloba L. (known as ginkgo or maidenhair tree) is a phylogenetically isolated, charismatic, gymnosperm tree. Herbal dietary supplements, prepared from G. biloba leaves, are consumed to boost cognitive capacity via improved blood perfusion and mitochondrial function. A novel DNA mini-barcode assay was designed and validated for the authentication of G. biloba in herbal dietary supplements (n = 22; sensitivity = 1.00, 95% CI = 0.59-1.00; specificity = 1.00, 95% CI = 0.64-1.00). This assay was further used to estimate the frequency of mislabeled ginkgo herbal dietary supplements on the market in the United States of America: DNA amenable to PCR could not be extracted from three (7.5%) of the 40 supplements sampled, 31 of 37 (83.8%) assayable supplements contained identifiable G. biloba DNA, and six supplements (16.2%) contained fillers without any detectable G. biloba DNA. It is hoped that this assay will be used by supplement manufacturers to ensure that their supplements contain G. biloba. PMID- 25495291 TI - Autopsy case of spinocerebellar ataxia type 31 with severe dementia at the terminal stage. AB - Spinocerebellar ataxia type 31 (SCA31) is an autosomal dominant cerebellar ataxia commonly observed in Japan. However, few neuropathological examinations have been conducted. Here we report the case of a 76-year-old Japanese male SCA31 patient. He noticed dysarthria and difficulty walking at 65 years old. His symptoms subsequently deteriorated, although he could still walk with assistance at 70 years. At 73 years, when he could no longer walk, he was admitted to our hospital. He showed severe limb and truncal ataxia. His father and older brother had shown the same symptoms. Brain magnetic resonance imaging showed cerebellar atrophy of the anterior lobe and white matter hyperintensities. He was diagnosed with SCA31 by genetic analysis. Gradually, his cognitive functions and ability to communicate declined. He died of respiratory failure at the age of 76. Neuropathological examination revealed severe Purkinje cell loss that was accentuated in the anterior lobe of the cerebellum. Furthermore, the remaining Purkinje cells showed abnormal processes (that is, halo-like amorphous materials), as has been reported previously. Severe deposition of hyperphosphorylated tau-positive neurites, many senile plaques and amyloid angiopathy were observed in the neocortex. Our findings suggest that in SCA31, accelerated tau and amyloid pathology in the neocortex might induce dementia at the terminal stage. PMID- 25495293 TI - Peste, guerre et ideologie sans frontieres. PMID- 25495296 TI - Maternity care in general practice. PMID- 25495299 TI - Missing malaria? Potential obstacles to diagnosis and hypnozoite eradication. PMID- 25495301 TI - The Australian medical response to Typhoon Haiyan. PMID- 25495302 TI - Enabling the success of academic health science centres in Australia: where is the leadership? PMID- 25495303 TI - The future of Queensland's rural medical workforce. PMID- 25495304 TI - Closing the dental divide. PMID- 25495305 TI - The G20, human health and sustainability: an interview with Jeffrey D Sachs. PMID- 25495306 TI - Rural dental health care and the workforce challenges. PMID- 25495308 TI - Australian bat lyssavirus: implications for public health. AB - Australian bat lyssavirus (ABLV) infection in humans is rare but fatal, with no proven effective therapy. ABLV infection can be prevented by administration of a post-exposure prophylaxis regimen of human rabies immunoglobulin and rabies vaccine. All Australian bats (flying foxes and microbats) should be considered to be carrying ABLV unless proven otherwise. Any bat-related injury (bite, scratch or mucosal exposure to bat saliva or neural tissue) should be notified immediately to the relevant public health unit - no matter how small the injury or how long ago it occurred. Human-to-human transmission of ABLV has not been reported but is theoretically possible. Standard infection control precautions should be employed when managing patients with suspected or confirmed ABLV infection. PMID- 25495309 TI - A new blood glucose management algorithm for type 2 diabetes: a position statement of the Australian Diabetes Society. AB - Lowering blood glucose levels in people with type 2 diabetes has clear benefits for preventing microvascular complications and potential benefits for reducing macrovascular complications and death. Treatment needs to be individualised for each person with diabetes. This should start with selecting appropriate glucose and glycated haemoglobin targets, taking into account life expectancy and the patient's wishes. For most people, early use of glucose-lowering therapies is warranted. A range of recently available therapies has added to the options for lowering glucose levels, but this has made the clinical pathway for treating diabetes more complicated. This position statement from the Australian Diabetes Society outlines the risks, benefits and costs of the available therapies and suggests a treatment algorithm incorporating the older and newer agents. PMID- 25495310 TI - Patient safety and rapid response systems. AB - Attention was drawn to the safety of patients in acute care hospitals in the early 1990s when studies found large numbers of potentially preventable deaths. Errors were initially ascribed to individual doctors and nurses, but later it was recognised that errors were mainly related to failure of systems rather than individuals. Mortality is not necessarily a good measure of hospital safety. It depends more on the nature of the patient's underlying clinical state and the type of intervention than on the safety of the hospital, and its prevention (as a measure of patient safety) contributes to the failure of hospitals to recognise and appropriately manage patients who are naturally at the end of life. It is difficult to find agreement on the best ways to measure patient safety in hospitals and, as a result of the enormous resources devoted to improving and studying safety, it is difficult to show that patient safety has improved. However, the concept of safety is beginning to include post-hospital outcomes, such as quality of life. A rapid response system is an organisation-wide patient safety system which recognises the deterioration of a patient's condition and provides urgent and appropriate care. Evaluating the impact of a rapid response system can provide information on hospital safety, including potentially preventable deaths and cardiac arrests. PMID- 25495312 TI - An outbreak of enterovirus 71 in metropolitan Sydney: enhanced surveillance and lessons learnt. AB - OBJECTIVE: To report the findings of the enhanced surveillance set up in New South Wales in response to the recent outbreak of human enterovirus 71 (EV71) infection. DESIGN AND SETTING: A two-armed enhanced public health surveillance system including statewide emergency department surveillance and clinical surveillance at the Sydney Children's Hospitals Network. PARTICIPANTS: Children aged less than 10 years with suspected or confirmed enterovirus infection. MAIN OUTCOME MEASURES: Epidemiology of the outbreak, including weekly case counts, demographic information, geographic spread of the outbreak, and clinical presentation and progression. RESULTS: Statewide weekly case counts indicate that an epidemic of EV71 infection occurred in NSW from December 2012 until May 2013. Around 119 children were reported with disease severe enough to warrant admission to a tertiary Sydney children's hospital. Cases were spread throughout the Sydney metropolitan area and there is some evidence of geographic migration of the outbreak. Presenting features included fever, lethargy, myoclonus and skin rash. Only 24% of cases presented with classical hand, foot and mouth disease. CONCLUSIONS: EV71 infection is likely to continue to be a public health problem in Australia. Surveillance of routinely collected emergency department data can provide a useful indication of its activity in the community. PMID- 25495311 TI - Australia-wide point prevalence survey of the use and appropriateness of antimicrobial prescribing for children in hospital. AB - OBJECTIVES: To describe antimicrobial use in hospitalised Australian children and to analyse the appropriateness of this antimicrobial use. DESIGN: Multicentre single-day hospital-wide point prevalence survey, conducted in conjunction with the Antimicrobial Resistance and Prescribing in European Children study. SETTING: Eight children's hospitals across five Australian states, surveyed during late spring and early summer 2012. PATIENTS: Children and adolescents who were inpatients at 8 am on the day of the survey. MAIN OUTCOME MEASURES: Quantity and quality of antimicrobial prescribing. RESULTS: Of 1373 patients, 631 (46%) were prescribed at least one antimicrobial agent, 198 (31%) of whom were < 1 year old. The highest antimicrobial prescribing rates were in haematology and oncology wards (76% [95/125]) and paediatric intensive care units (55% [44/80]). Of 1174 antimicrobial prescriptions, 550 (47%) were for community-acquired infections, 175 (15%) were for hospital-acquired infections and 437 (37%) were for prophylaxis. Empirical treatment accounted for 72% of antimicrobial prescriptions for community-acquired infections and 58% for hospital-acquired infections (395 and 102 prescriptions, respectively). A total of 915 prescriptions (78%) were for antibacterials; antifungals and antivirals were predominantly used for prophylaxis. The most commonly prescribed antibacterials were narrow-spectrum penicillins (18% [164 prescriptions]), beta-lactam-beta-lactamase inhibitor combinations (15% [136]) and aminoglycosides (14% [128]). Overall, 957 prescriptions (82%) were deemed appropriate, but this varied between hospitals (range, 66% [74/112]) to 95% [165/174]) and specialties (range, 65% [122/187] to 94% [204/217]). Among surgical patients, 65 of 187 antimicrobial prescriptions (35%) were deemed inappropriate, and a common reason for this was excessive prophylaxis duration. CONCLUSION: A point prevalence survey is a useful cross sectional method for quantifying antimicrobial use in paediatric populations. The value is significantly augmented by adding assessment of prescribing quality. PMID- 25495313 TI - Leading the rebirth of the rural obstetrician. AB - OBJECTIVES: To understand the factors influencing the decisions of rural general practitioners and GP registrars to practise obstetrics, and to understand the impact on these decisions of an innovative obstetric training and support program in the Gippsland region of Victoria. DESIGN, SETTING AND PARTICIPANTS: Qualitative approach using semistructured interviews conducted in July and August 2013 and inductive content analysis. Participants were identified from training records over the previous 5 years for the Gippsland GP obstetric training and support program. Two questions were posed during interviews: What challenges face rural GPs in practising obstetrics? What impact has the Gippsland GP obstetric program had on GP obstetric career decisions? RESULTS: Of 60 people invited to participate, 22 agreed. Interviews ranged in duration from 40 to 90 minutes. The major themes that emerged on the challenges facing rural GPs in practising obstetrics were isolation, work-life balance and safety. The major themes that emerged on the impact of the Gippsland GP obstetric program were professional support, structured training and effective leadership. CONCLUSION: Rural GP obstetricians are challenged by isolation, the impact of their job on work-life balance, and safety. The support, training and leadership offered by the Gippsland expanded obstetric training program helped doctors to deal with these challenges. The Gippsland model of training offers a template for GP obstetric procedural training programs for other rural settings. PMID- 25495315 TI - An economic case for a cardiovascular polypill? A cost analysis of the Kanyini GAP trial. AB - OBJECTIVE: To measure the costs of a polypill strategy and compare them with those of usual care in people with established cardiovascular disease (CVD) or at similarly high cardiovascular risk. DESIGN: A within-trial cost analysis of polypill-based care versus usual care with separate medications, using data from the Kanyini Guidelines Adherence with the Polypill (GAP) trial and linked health service and medication administrative claims data. PARTICIPANTS: Kanyini GAP participants who consented to Australian Medicare record access. MAIN OUTCOME MEASURES: Mean health service and pharmaceutical expenditure per patient per year, estimated with generalised linear models. Costs during the trial (randomisation January 2010 - May 2012, median follow-up 19 months, maximum follow-up 36 months) were inflated to 2012 costs. RESULTS: Our analysis showed a statistically significantly lower mean pharmaceutical expenditure of $989 (95% CI, $648-$1331) per patient per year in the polypill arm compared with usual care (P < 0.001; adjusted, excluding polypill cost). No significant difference was shown in health service expenditure. CONCLUSIONS: This study provides evidence of significant cost savings to the taxpayer and Australian Government through the introduction of a CVD polypill strategy. The savings will be less now than during the trial due to subsequent reductions in the costs of usual care. Nonetheless, given the prevalence of CVD in Australia, the introduction of this polypill could increase considerably the efficiency of health care expenditure in Australia. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN126080005833347. PMID- 25495317 TI - Medical-setting deaths and the coroner: laws, penalties and guidelines. AB - We examine the law governing the reporting of medical-setting deaths to the Coroner throughout the Australian states and territories. We use a hypothetical case report to explore the different legal requirements for reporting a medical setting death and the varying penalties that apply for failing to report a reportable death. It is important for health practitioners to understand the law that applies in the state or territory in which they practice. Knowing when to report a medical-setting death requires not only medical knowledge but also legal analysis. On this basis, we recommend the development of coroners' guidelines in all jurisdictions to assist health practitioners in complying with their coronial reporting obligations. PMID- 25495316 TI - Firearms, mental illness, dementia and the clinician. AB - Clinicians have an obligation to report to state or territory police any concerns about risk of harm from patients with access to firearms. Dementia is an under recognised medical problem which may increase the risk of firearm injury or violence in those with such access. There are no guidelines for clinicians regarding mandatory screening for access to firearms, and currently the onus is on the firearm licence holder to declare any relevant medical conditions. We propose that clinicians should screen patients for firearm possession and use a combined capacity and risk assessment approach to evaluating fitness for firearm licences. PMID- 25495318 TI - The parable of Provence. PMID- 25495320 TI - Doctors for the Environment Australia: achievements and lessons learned. PMID- 25495321 TI - Viennese vibrations: doctors, lungs and opera. PMID- 25495322 TI - Colchicine--a short history of an ancient drug. PMID- 25495323 TI - Riding the buses. PMID- 25495324 TI - Remembering Vesalius. PMID- 25495327 TI - The surprising benefit of passive-aggressive behaviour at Christmas parties: being crowned king of the crackers. AB - OBJECTIVE: To test the effects of technique and attitude in pulling Christmas crackers. DESIGN, SETTING AND PARTICIPANTS: A binomial trial conducted at a Christmas-in-July dinner party involving five anonymous dinner guests, including two of the authors. MAIN OUTCOME MEASURE: Number of wins achieved by different strategies, with a win defined as securing the larger portion of the cracker. RESULTS: The previously "guaranteed" strategy for victory, employing a downwards angle towards the puller, failed to differentiate itself from random chance (win rate, 6/15; probability of winning, 0.40; 95% CI, 0.15-0.65). A novel passive aggressive strategy, in which one individual just holds on without pulling, provided a significant advantage (win rate, 11/12; probability of winning, 0.92; 95% CI, 0.76-1.00). CONCLUSION: The passive-aggressive strategy of failing to pull has a high rate of success at winning Christmas crackers; however, excessive adoption of this approach will result in a complete failure, with no winners at all. PMID- 25495328 TI - Christmas crackers. A diagnosis that will go down in history. PMID- 25495329 TI - Barking up the wrong tree: injuries due to falls from trees in Solomon Islands. AB - OBJECTIVE: To investigate tree-related injuries in Solomon Islands by the types of trees involved, who is affected and the types of injuries caused. DESIGN AND SETTING: Descriptive case series of all cases of injuries related to trees presenting to the National Referral Hospital in Honiara from 1994 to 2011. Data were collected by the attending clinician using a Trauma Epidemiology form, which provides information on age, sex, cause of injury and type of fracture. MAIN OUTCOME MEASURES: Number of injuries by tree type, sex and age. RESULTS: Of the 7651 injuries in the database, 1107 (14%) were caused by falls from trees. Falls from coconut trees led to the highest number of injuries, followed by falls from mango, guava, apple and nut trees. Overall, 85% of injuries occurred in individuals aged < 20 years. For injuries involving guava trees, 77% of patients were aged < 10 years, compared with 46% for the five most commonly involved tree types. Overall, 71% of injuries occurred among males. Of all injuries, 92% were fractures, 3% were dislocations and 5% were non-fracture, non-dislocation injuries. The arm (including wrist, elbow and hand) was the most common location of injury across all tree types. Distal radius fractures in the forearm were particularly common, as were ulna fractures. CONCLUSION: While mangos and guavas are undeniably delicious, the quest for their flesh can be hazardous. Children will always climb trees, but the search for food among children in lower-income settings may lead to higher rates of injury. PMID- 25495330 TI - The meaning of seven Christmases. PMID- 25495331 TI - What proof is in your Christmas pudding? Is caring under the influence possible? AB - OBJECTIVES: To determine the ethanol concentration of commonly available Christmas puddings, and to extrapolate the blood alcohol content (BAC) of typical health care professionals after Christmas lunch at the hospital. DESIGN AND SETTING: We conducted fractional distillation of Christmas puddings and analysed the distillate for ethanol content. We then applied standard pharmacological and physiological assumptions to assess predicted BAC in typical male and female health care professionals at our hospital. MAIN OUTCOME MEASURES: Ethanol concentration of each pudding; estimated BAC of health care professionals after ingestion and at the end of a 30-minute lunch break. RESULTS: The concentration of ethanol in common Christmas puddings ranged from 0.260 to 1.685 g per 125 mg slice. The concentration of ethanol per pudding was not greater than the stipulated specifications on the packaging, where shown. After pudding ingestion, the theoretical BAC of a typical 70 kg male and 60 kg female health care professional ranged from 0.001 to 0.004 g/dL and from 0.001 to 0.006 g/dL, respectively. Neither male nor female staff had a predicted BAC > 0.000 g/dL by the end of the lunch break. CONCLUSION: Christmas puddings contain ethanol that does not all evaporate during the cooking process. However, the rise in BAC after ingestion of a typical slice of Christmas pudding was negligible and unlikely to affect work performance or safety or impair a health care worker's ability to make complex decisions. PMID- 25495332 TI - SPoRE: a mathematical model to predict double strand breaks and axis protein sites in meiosis. AB - BACKGROUND: Meiotic recombination between homologous chromosomes provides natural combinations of genetic variations and is a main driving force of evolution. It is initiated via programmed DNA double-strand breaks (DSB) and involves a specific axial chromosomal structure. So far, recombination regions have been mainly determined by experiments, both expensive and time-consuming. RESULTS: SPoRE is a mathematical model that describes the non-uniform localisation of DSB and axis proteins sites, and distinguishes high versus low protein density. It is based on a combination of genomic signals, based on what is known from wet-lab experiments, whose contribution is precisely quantified. It models axis proteins accumulation at gene 5'-ends with a discrete approximation of their diffusion and convection along genes. It models DSB accumulation at approximated gene promoter positions with intergenic region length and GC-content. SPoRE can be used for prediction and it is parameterised in an obvious way that makes it easy to understand from a biological viewpoint. CONCLUSIONS: When compared to Saccharomyces cerevisiae experimental data, SPoRE predicts axis protein and DSB positions with high sensitivity and precision, axis protein density with an average local correlation r = 0.63 and DSB density with an average local correlation r = 0.62. SPoRE outbreaks previous DSB predictors, which are based on nucleotide patterning, and it reaches 85% of success rate in DSB prediction compared to 54% obtained by available tools on a benchmarked dataset.SPoRE is available at the address http://www.lcqb.upmc.fr/SPoRE/. PMID- 25495333 TI - Adherence to oral bisphosphonates: 30 more minutes in dosing instructions matter. AB - OBJECTIVES: Low adherence to treatment with bisphosphonates significantly impedes its effectiveness. The objectives were: (1) to compare adherence to oral weekly and monthly bisphosphonates with emphasis on dosing instructions; and (2) to study associations between adherence and beliefs about the bisphosphonate treatment among women >= 55 years. METHODS: A multicenter survey was performed in secondary-care patients with osteoporosis. Osteoporosis Specific Morisky Medication Adherence Scale (OS-MMAS), questions on compliance with five dosing instructions and Beliefs about Medicines Questionnaire (BMQ) Specific were used. RESULTS: As many as 363 questionnaires (response rate 95%) were analyzed. Respondents (mean age 69 years) were treated with weekly bisphosphonates (37%) or monthly ibandronate (63%). Based on OS-MMAS, 67% of respondents showed high adherence with no differences between the subgroups. Only 44% of respondents were compliant with all dosing instructions. Compliance with dosing instructions concerning time interval (fasting and staying upright) was 71% in weekly and 52% in monthly subgroups, respectively (p < 0.001). Compliance with dosing instructions correlated positively with education (p = 0.009). The mean BMQ necessity score of 18.4 was greater than the mean BMQ concerns score of 13.3. OS MMAS score correlated with necessity (p = 0.010). Persistence derived from OS MMAS correlated with both necessity (p = 0.014) and concerns (p = 0.041). CONCLUSION: Despite relatively high adherence to the treatment, most patients do not follow dosing instructions. Reduced bioavailability, particularly of monthly ibandronate, can be expected in clinical practice. Adherence-related outcomes are associated with beliefs about the oral treatment with bisphosphonates. PMID- 25495334 TI - Social networks and female reproductive choices in the developing world: a systematized review. AB - Continuing high global maternal mortality and morbidity rates in developing countries have resulted in an increasing push to improve reproductive health services for women. Seeking innovative ways for assessing how positive health knowledge and behaviors spread to this vulnerable population has increased the use of social network theories and analysis in health promotion research. Despite the increased research on social networks and health, no overarching review on social networks and maternal health literature in developing countries has been conducted. This paper attempts to synthesize this literature by identifying both published and unpublished studies in major databases on social networks and maternal and child health. This review examined a range of study types for inclusion, including experimental and non-experimental study designs including randomized controlled trials, non-randomized controlled trials, quasi experimental, cohort studies, case control studies, longitudinal studies, and cross-sectional observational studies. Only those that occurred in developing countries were included in the review. Eighteen eligible articles were identified; these were published between 1997 and 2012. The findings indicated that the most common social network mechanisms studied within the literature were social learning and social influence. The main outcomes studied were contraceptive use and fertility decisions. Findings suggest the need for continuing research on social networks and maternal health, particularly through the examination of the range of social mechanisms through which networks may influence health behaviors and knowledge, and the analysis of a larger variety of reproductive outcomes. PMID- 25495335 TI - Enhanced degradation of Herbicide Isoproturon in wheat rhizosphere by salicylic acid. AB - This study investigated the herbicide isoproturon (IPU) residues in soil, where wheat was cultivated and sprayed with salicylic acid (SA). Provision of SA led to a lower level of IPU residues in rhizosphere soil compared to IPU treatment alone. Root exudation of tartaric acid, malic acid, and oxalic acids was enhanced in rhizosphere soil with SA-treated wheat. We examined the microbial population (e.g., biomass and phospholipid fatty acid), microbial structure, and soil enzyme (catalase, phenol oxidase, and dehydrogenase) activities, all of which are associated with soil activity and were activated in rhizosphere soil of SA treated wheat roots. We further assessed the correlation matrix and principal component to figure out the association between the IPU degradation and soil activity. Finally, six IPU degraded products (derivatives) in rhizosphere soil were characterized using ultraperformance liquid chromatography with a quadrupole time-of-flight tandem mass spectrometer (UPLC/Q-TOF-MS/MS). A relatively higher level of IPU derivatives was identified in soil with SA-treated wheat than in soil without SA-treated wheat plants. PMID- 25495336 TI - 1alpha,25-dihydroxyvitamin D3 promotes osteogenic activity and downregulates proinflammatory cytokine expression in human periodontal ligament cells. AB - BACKGROUND AND OBJECTIVE: The aim of this study was to assess the impact of 1alpha,25-dihydroxyvitamin D3 (vitamin D3) on osteogenic and inflammatory properties of human periodontal ligament (PDL) cells and investigate underlying mechanisms. MATERIAL AND METHODS: Human PDL cells, obtained from four subjects, were stimulated with vitamin D3 for 4-48 h. The bone markers osteopontin and osteocalcin and proinflammatory cytokine/chemokine expression was determined by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Cytokine and chemokine expression was determined after stimulation with the inflammation promoter lipopolysaccharide (LPS) in the presence or absence of vitamin D3. Alkaline phosphatase activity was assessed using p nitrophenylphosphate substrate. RESULTS: Treatment with 30 ng/mL of vitamin D3, corresponding to an optimal plasma concentration of vitamin D, for 24 h had no effect on PDL cell number and morphology but increased PDL cell osteopontin and osteocalcin mRNA expression by about 70 and 40%, respectively, and, moreover, treatment with vitamin D3 for 48 h enhanced PDL cell alkaline phosphatase activity by about two times showing that vitamin D3 exerts pro-osteogenic effects in human PDL cells. Stimulation with LPS (1 MUg/mL) for 4 h increased PDL cell interleukin (IL)-6 cytokine and chemokine ligand 1 (CXCL1) chemokine mRNA expression several fold. The LPS-induced increase in IL-6 and CXCL1 transcripts was attenuated by vitamin D3 (30 ng/mL). Treatment with vitamin D3 (3-300 ng/mL) for 24 h reduced the LPS-evoked increase in PDL cell IL-6 protein by about 50%. Vitamin D3 (30 ng/mL) had no effect on LPS-induced IL-1beta and MCP-1 mRNA expression. CONCLUSIONS: Vitamin D3 promotes osteogenic differentiation but also downregulates inflammation promoter-induced IL-6 cytokine and CXCL1 chemokine expression in human PDL cells, suggesting that vitamin D3 both stimulates bone regeneration and antagonizes inflammation in human periodontal tissue. PMID- 25495337 TI - A New Assessment Framework for Transience in Hydrogeological Systems. AB - The importance of transience in the management of hydrogeologic systems is often uncertain. We propose a clear framework for determining the likely importance of transient behavior in groundwater systems in a management context. The framework incorporates information about aquifer hydraulics, hydrological drivers, and time scale of management. It is widely recognized that aquifers respond on different timescales to hydrological change and that hydrological drivers themselves, such as climate, are not stationary in time. We propose that in order to assess whether transient behavior is likely to be of practical importance, three factors need to be examined simultaneously: (1) aquifer response time, which can be expressed in terms of the response to a step hydrological change (taustep ) or periodic change (taucycle ); (2) temporal variation of the dominant hydrological drivers, such as dominant climatic systems in a region; (3) the management timescale and spatial scale of interest. Graphical tools have been developed to examine these factors in conjunction, and assess how important transient behavior is likely to be in response to particular hydrological drivers, and thus which drivers are most likely to induce transience in a specified management timeframe. The method is demonstrated using two case studies; a local system that responds rapidly and is managed on yearly to decadal timeframes and a regional system that exhibits highly delayed responses and was until recently being assessed as a high level nuclear waste repository site. Any practical groundwater resource problem can easily be examined using the proposed framework. PMID- 25495338 TI - Femoral component failure in the Oxford unicompartmental knee arthroplasty: a case report. AB - INTRODUCTION: The present case report describes a patient who presented with an early complication after a unicompartmental knee arthroplasty. It is not the first case in this subject but the unique aspect of this case report rests on the timing in which the failure occurred. CASE PRESENTATION: A 64-year-old Caucasian man received a medial unicompartmental knee arthroplasty (Oxford(r) Partial Knee) due to isolated anteromedial osteoarthritis of his right knee. His initial recovery was good, however, after 3 months he presented with acute pain and a locked knee. Radiographs showed a complete loosening and migration of the femoral component. During revision surgery no clear explanation was found for failure of the femoral component. CONCLUSIONS: The most likely explanation for loosening is the combination of peak stresses on the posterior facet of the femoral components of a unicompartmental knee arthroplasty in a patient in a cross-legged knee position causing bone-cement or cement-implant interface failure. Further research is necessary in prosthetic designs and applications of the unicompartmental knee arthroplasty to determine the origin of this early complication. PMID- 25495339 TI - Meso-substituted porphyrins for dye-sensitized solar cells. PMID- 25495340 TI - Are drug metabolites able to cause T-cell-mediated hypersensitivity reactions? AB - INTRODUCTION: Adverse drug reactions with an immune pathogenesis are a problem in the clinic and an impediment to drug development. T lymphocytes are believed to play a role in the pathogenesis; however, the nature of the drug interaction with immune receptors remains an area of debate. AREAS COVERED: This article reviews recent advances in our understanding of drug hypersensitivity focusing specifically on the way in which drugs are displayed in MHC molecules. Most drugs associated with a high incidence of reactions have been shown to form protein reactive metabolites. Hence, the relationship between drug metabolism and T-cell activation is discussed in detail. EXPERT OPINION: The role of metabolism in pathogenesis of immunological drug reactions has only been studied with a small number of drugs where synthetic metabolites are available for functional studies. In each case, metabolite-responsive T cells have been detected. However, the field is skewed by the fact that most research is conducted using the parent compound in metabolically inert cell systems. We propose that research efforts are directed towards the synthesis of drug metabolites and/or drug-protein conjugates. Furthermore, analytical methods need to be developed to relate metabolite exposure to the T-cell response. For now, our understanding of the chemical basis of drug hypersensitivity is incomplete. PMID- 25495342 TI - Next generation child neurologists. PMID- 25495341 TI - The function of phosphatidylinositol 5-phosphate 4-kinase gamma (PI5P4Kgamma) explored using a specific inhibitor that targets the PI5P-binding site. AB - NIH-12848 (NCGC00012848-02), a putative phosphatidylinositol 5-phosphate 4-kinase gamma (PI5P4Kgamma) inhibitor, was explored as a tool for investigating this enigmatic, low activity, lipid kinase. PI5P4K assays in vitro showed that NIH 12848 inhibited PI5P4Kgamma with an IC50 of approximately 1 MUM but did not inhibit the alpha and beta PI5P4K isoforms at concentrations up to 100 MUM. A lack of inhibition of PI5P4Kgamma ATPase activity suggested that NIH-12848 does not interact with the enzyme's ATP-binding site and direct exploration of binding using hydrogen-deuterium exchange (HDX)-MS (HDX-MS) revealed the putative PI5P binding site of PI5P4Kgamma to be the likely region of interaction. This was confirmed by a series of mutation experiments which led to the identification of a single PI5P4Kgamma amino acid residue that can be mutated to its PI5P4Ks alpha and beta homologue to render PI5P4Kgamma resistant NIH-12848 inhibition. NIH 12848 (10 MUM) was applied to cultured mouse principal kidney cortical collecting duct (mpkCCD) cells which, we show, express PI5P4Kgamma that increases when the cells grow to confluence and polarize. NIH-12848 inhibited the translocation of Na+/K+-ATPase to the plasma membrane that occurs when mpkCCD cells grow to confluence and also prevented reversibly their forming of 'domes' on the culture dish. Both these NIH-12848-induced effects were mimicked by specific RNAi knockdown of PI5P4Kgamma, but not that of PI5P4Ks alpha or beta. Overall, the data reveal a probable contribution of PI5P4Kgamma to the development and maintenance of epithelial cell functional polarity and show that NIH-12848 is a potentially powerful tool for exploring the cell physiology of PI5P4Ks. PMID- 25495344 TI - Effects of antibody to receptor activator of nuclear factor kappa-B ligand on inflammation and cartilage degradation in collagen antibody-induced arthritis in mice. AB - BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory disease that leads to destruction of both articular cartilage and bone tissues. In rheumatic joints, synoviocytes and T-lymphocytes as well as bone cells produce the receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL), which binds to RANK on the surface of osteoclasts and their precursor cells to induce differentiation and activation of osteoclasts. Hence, inhibition of RANKL may be a promising approach to suppress osteolysis in RA. On the other hand, RANKL production by lymphocytes indicates the possibility that its inhibition would be effective to suppress inflammation in RA. In addition, it has been reported that cathepsin K, a predominant cysteine protease in osteoclasts, is involved in cartilage destruction in RA model mice. Here, we evaluated the effects of an anti-RANKL antibody on inflammation in footpads and degradation of articular cartilage in RA model mice. RESULTS: We induced arthritis in mice by injection of anti-type II collagen antibodies and lipopolysaccharide (LPS). Inhibition of RANKL by an anti RANKL antibody (OYC1, Oriental Yeast, Tokyo, Japan) was confirmed by increased bone volume in the metaphysis of tibias. Swelling in either limb until day 14 was seen in 5 of 6 mice injected with anti-collagen antibodies and LPS without treatment with OYC1, while that was seen in 4 of 5 mice treated with OYC1. The average arthritis scores on day 14 in those groups were 2.17 and 3.00, respectively, indicating that OYC1 did not ameliorate inflammation in the limbs. Histological analyses indicated that OYC1 does not protect articular cartilage from destruction in mice with arthritis. CONCLUSIONS: Our present study failed to show the effectiveness of an anti-RANKL antibody to ameliorate inflammation in the limbs or protect articular cartilage from degradation in a collagen antibody induced arthritis mouse model. PMID- 25495345 TI - Retrospective review of superficial femoral artery stenting in diabetic patients: thiazolidinedione use may decrease reinterventions. AB - BACKGROUND: Diabetics are known to have inferior outcomes following peripheral vascular interventions. Thiazolidinediones are oral diabetic agents which improve outcomes following coronary bare metal stenting. No studies have been performed evaluating thiazolidinedione use and outcomes following lower extremity endovascular interventions. We hypothesize that diabetic patients taking thiazolidinediones at the time of primary superficial femoral artery (SFA) stenting have fewer reinterventions. METHODS: A retrospective review was performed to identify diabetic patients undergoing primary SFA stenting. The unit of analysis was the extremity. The primary outcome was freedom from target lesion revascularization stratified by thiazolidinedione use, evaluated by Kaplan Meier curves and a log rank test. A Cox proportional hazards model was constructed to determine variables associated with freedom from target lesion revascularization. RESULTS: SFA stents were placed in 138 extremities in 128 diabetic patients between August 1, 2001 and July 15, 2012. Twenty-four patients were taking thiazolidinediones at the time of SFA stenting. All patients taking thiazolidinediones had TASC A or B lesions. Twenty-seven extremities in the non thiazolidinedione group had TASC C or D lesions and were excluded to control for disease severity. Freedom from target lesion revascularization was significantly higher in diabetics taking thiazolidinediones at 2 years, 88.5% vs. 59.4%, P = 0.02, SE < 10%. Cox modeling identified a protective trend for thiazolidinedione use (thiazolidinedione use HR 0.33, 95% CI 0.09-1.13), whereas critical limb ischemia and insulin use were associated with trends for worse freedom from target lesion revascularization. CONCLUSIONS: This pilot, translation study demonstrates that diabetic patients taking thiazolidinediones at the time of primary SFA stenting have decreased reintervention rates at 2 years. These results may be explained by higher adiponectin levels or other anti-inflammatory effects in patients taking thiazolidinedione. National and regional quality improvement registries should consider collecting information regarding specific diabetic regimens and use of PPAR agonists such as cilostazol and fibrates. PMID- 25495346 TI - Interaction of Dark Excited States. Comparison of Computational Approaches. AB - A systematic theoretical study of the electronic interaction of dark excited states in a model system, formaldehyde dimer is reported. Using the fragment transition density scheme, we estimate the excitonic interaction in different configurations of the dimer. The excited state properties of the system are computed with several quantum mechanical methods. We show that the orbital interaction of the monomers rather than Coulomb interaction of their transition quadrupoles gives the major contribution to the coupling at intermolecular distances shorter than 5 A. It is found that the exitonic interaction alters drastically by conformational changes. Benchmark couplings computed with EOM CCSD, MS-CASPT2, CASSCF, TD DFT, CIS, and INDO/S and different basis sets are provided. The evaluation of the calculations shows that the TD cam-B3LYP scheme performs best, giving good estimates for all considered structures. In contrast, the TD B3LYP scheme leads to drastically overestimated values. The data obtained using the Tamm-Dancoff approximation are similar to the TD DFT results. CASSCF and CIS calculations underestimate the coupling, indicating that dynamic electron correlation may have a large effect on the short-range coupling. The INDO/S method fails to describe the excited state interaction both at short and long distances. PMID- 25495347 TI - Characterization of the developing small intestine in the absence of either GATA4 or GATA6. AB - BACKGROUND: Studies of adult mice lacking either GATA4 or GATA6 in the small intestine demonstrate roles for these factors in small intestinal biology. Deletion of Gata4 in the adult mouse intestine revealed an essential role for GATA4 in jejunal function. Deletion of Gata6 in the adult mouse ileum alters epithelial cell types and ileal enterocyte gene expression. The effect of deletion of Gata4 or Gata6 alone during embryonic small intestinal development, however, has not been examined. We recently demonstrated that loss of both factors in double conditional knockout embryos causes severe defects in jejunal development. Therefore, the goal of this study is to provide phenotypic analysis of the small intestine of single Gata4 and Gata6 conditional knockout embryos. RESULTS: Villin-Cre was used to delete Gata4 or Gata6 in the developing intestinal epithelium. Elimination of either GATA4 or GATA6 in the jejunum, where these factors are co-expressed, caused changes in enterocyte and enteroendocrine cell gene expression. Ectopic expression of markers of the ileal-specific bile acid metabolism pathway was induced in GATA4-deficient jejunum but not in GATA6 deficient jejunum. A subtle increase in goblet cells was also identified in jejunum of both mutants. In GATA6-deficient embryonic ileum, villus length was altered, and enterocyte gene expression was perturbed including ectopic expression of the colon marker Car1. Goblet cells were increased, and enteroendocrine cells were decreased. CONCLUSIONS: Overall, we show that aspects of the phenotypes observed in the small intestine of adult Gata4 and Gata6 conditional knockout mice emerge during development. The effect of eliminating GATA6 from the developing ileum was greater than that of eliminating either GATA4 or GATA6 from the developing jejunum likely reflecting functional redundancy between these factors in the jejunum. Although GATA4 and GATA6 functions overlap, our data also suggest unique functions for GATA4 and GATA6 within the developing intestine. GATA4 likely operates independently of GATA6 within the jejunum to regulate jejunal versus ileal enterocyte identity and consequently jejunal physiology. GATA6 likely regulates enteroendocrine cell differentiation cell autonomously whereas GATA4 affects this population indirectly. PMID- 25495348 TI - The potential of CXCL5 as a target for liver cancer - what do we know so far? AB - CXCL5, epithelial cell derived neutrophil attractant 78, is a CXC chemokine predominantly expressed on epithelial cells. It has specificity for CXCR2 receptors and is involved in the recruitment and activation of neutrophils. CXCL5 is considered a therapeutic target in liver cancer, since treatment with small interfering RNAs or antibodies against CXCL5 can suppress tumor growth, proliferation, migration and invasion. Experimental evidence demonstrated that CXCL5 antibodies could reduce the tumor growth and synergistically increase the efficiency of the tyrosine kinase inhibitor, Gefitinib, without the addition of toxicity. A number of challenges are encountered and should be considered during the development and clinical application of CXCL5 target-specific drugs. The specificity of CXCL5 as a therapeutic target for certain types and duration of cancer should be more carefully clarified, since it seems that CXCL5 is involved in many molecular pathways and crosstalk between targeted chemokines/receptors. The concept that CXCL5 serves as the therapeutic target for liver cancer was evidenced by preclinical studies, and is the beginning of CXCL5-based drug discovery and development. PMID- 25495349 TI - Alpha-1-antitrypsin deficiency panniculitis presenting with severe anasarca, pulmonary embolus and hypogammaglobulinaemia. PMID- 25495350 TI - Indoor air pollution exposure from use of indoor stoves and fireplaces in association with breast cancer: a case-control study. AB - BACKGROUND: Previous studies suggest that polycyclic aromatic hydrocarbons (PAHs) may adversely affect breast cancer risk. Indoor air pollution from use of indoor stoves and/or fireplaces is an important source of ambient PAH exposure. However, the association between indoor stove/fireplace use and breast cancer risk is unknown. We hypothesized that indoor stove/fireplace use in a Long Island, New York study population would be positively associated with breast cancer and differ by material burned, and the duration and timing of exposure. We also hypothesized that the association would vary by breast cancer subtype defined by p53 mutation status, and interact with glutathione S-transferases GSTM1, T1, A1 and P1 polymorphisms. METHODS: Population-based, case-control resources (1,508 cases/1,556 controls) were used to conduct unconditional logistic regression to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Breast cancer risk was increased among women reporting ever burning synthetic logs (which may also contain wood) in their homes (OR = 1.42, 95% CI 1.11, 1.84), but not for ever burning wood alone (OR = 0.93, 95% CI 0.77, 1.12). For synthetic log use, longer duration >7 years, older age at exposure (>20 years; OR = 1.65, 95% CI 1.02, 2.67) and 2 or more variants in GSTM1, T1, A1 or P1 (OR = 1.71, 95% CI 1.09, 2.69) were associated with increased risk. CONCLUSIONS: Burning wood or synthetic logs are both indoor PAH exposure sources; however, positive associations were only observed for burning synthetic logs, which was stronger for longer exposures, adult exposures, and those with multiple GST variant genotypes. Therefore, our results should be interpreted with care and require replication. PMID- 25495352 TI - Near-IR luminescence and field-induced single molecule magnet of four salen-type ytterbium complexes. AB - A series of rigid hexadentate salen-type (H2L) ytterbium complexes, namely, [Yb2L3(CH3OH)].3CH3CN (1), [Yb2LL'L"(CH3OH)(H2O)2](ClO4)2.CH3OH.H2O (2), [Yb2L(OAc)4(CH3OH)2].2CH3OH (3), and {[Yb2L(OAc)4].3H2O}n (4) (H2L = N,N'-bis(2 oxy-3-methoxybenzylidene)-1,2-phenylenediamine, HL' = 2-(2'-hydroxy-3'-methyloxy phenyl)benzimidazole and HL" = 3-methoxysalicylaldehyde) have been synthesized by reactions of H2L with multifarious Yb(3+) salts. X-ray crystallographic analyses demonstrate that complex 1 is of a triple-decker sandwich-type Yb2L3 structure with a ratio of H2L/Yb = 3:2, 2 and 3 possess the unique Yb2 core with a ratio of H2L/Yb = 2:2 and 1:2, respectively, 4 exhibits one dimensional coordination polymers in which the polymeric structures are formed by acetate (OAc(-)) groups. All complexes 1-4 exhibit near-IR luminescence, which can be rationalized on the basis of the disparate structural effects. The magnetic analysis unveils that all complexes 1-4 are of field-induced single-molecule magnet behavior with the energy barriers (Ueff/kB) of 14.5, 2.0, 9.5, and 2.4 K at 3 kOe direct current fields, respectively. PMID- 25495351 TI - Multidimensional fractionation is a requirement for quantitation of Golgi resident glycosylation enzymes from cultured human cells. AB - Glycosylation results from the concerted action of glycosylation enzymes in the secretory pathway. In general, gene expression serves as the primary control mechanism, but post-translational fine-tuning of glycosylation enzyme functions is often necessary for efficient synthesis of specific glycan epitopes. While the field of glycomics has rapidly advanced, there lacks routine proteomic methods to measure expression of specific glycosylation enzymes needed to fill the gap between mRNA expression and the glycomic profile in a "reverse genomics" workflow. Toward developing this workflow we enriched Golgi membranes from two human colon cancer cell lines by sucrose density centrifugation and further mass based fractionation by SDS-PAGE. We then applied mass spectrometry to demonstrate a doubling in the number of Golgi resident proteins identified, compared to the unenriched, low speed centrifuged supernatant of lysed cells. A total of 35 Golgi resident glycosylation enzymes, of which 23 were glycosyltransferases, were identified making this the largest protein database so far of Golgi resident glycosylation enzymes experimentally identified in cultured human cells. We developed targeted mass spectrometry assays for specific quantitation of many of these glycosylation enzymes. Our results show that alterations in abundance of glycosylation enzymes at the protein level were generally consistent with the resultant glycomic profiles, but not necessarily with the corresponding glycosyltransferase mRNA expression as exemplified by the case of O-glycan core 1 T synthase. PMID- 25495353 TI - Quantitative or qualitative carbon dioxide monitoring for manual ventilation: a mannequin study. AB - AIM: To compare the effectiveness of an in-line EtCO2 detector (DET) and a quantitative EtCO2 detector (CAP), both attached to a t-piece resuscitator, during PPV via a face mask. METHODS: Paediatric trainees were randomly assigned to determine the method of PPV they commenced with (No device (ND), DET or CAP). Participants used each method for 2 min. Participants were video-recorded to determine the amount of effective ventilations delivered with each method. RESULTS: Twenty-three paediatric trainees provided a total of 6035 ventilations, and 91.2% were deemed effective. The percentages of median effective ventilations with the ND, the DET and the CAP were 91.0%, 93.0% and 94.0%, respectively. Fourteen (61%) of the trainees indicated a preference for the DET method, 8 (35%) for the CAP method, and 1 (4%) of the trainees indicated a preference for the ND method. Capnography was the most effective method per patient. CONCLUSION: There was no adverse effect with the addition of EtCO2 detectors. Trainees favoured methods of EtCO2 monitoring during ventilation. The NeoStat device was the preferred device by the majority. The greatest efficacy was achieved with the capnography device. Capnography may enhance face mask ventilation. PMID- 25495354 TI - Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism. AB - BACKGROUND: Massively parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Inborn errors of metabolism (IEM) constitute a large group of monogenic disorders with highly variable clinical presentation, often with acute, nonspecific initial symptoms. In many cases irreversible damage can be reduced by initiation of specific treatment, provided that a correct molecular diagnosis can be rapidly obtained. MPS thus has the potential to significantly improve both diagnostics and outcome for affected patients in this highly specialized area of medicine. RESULTS: We have developed a conceptually novel approach for acute MPS, by analysing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization. We applied this novel methodology to an in house developed customized work flow enabling clinical-grade analysis of all IEM with a known genetic basis, represented by a database containing 474 disease genes which is continuously updated. As proof-of-concept, two patients were retrospectively analysed in whom diagnostics had previously been performed by conventional methods. The correct disease-causing mutations were identified and presented to the clinical team after 15 and 18 hours from start of sequencing, respectively. With this information available, correct treatment would have been possible significantly sooner, likely improving outcome. CONCLUSIONS: We have adapted MPS to fit into the dynamic, multidisciplinary work-flow of acute metabolic medicine. As the extent of irreversible damage in patients with IEM often correlates with timing and accuracy of management in early, critical disease stages, our novel methodology is predicted to improve patient outcome. All procedures have been designed such that they can be implemented in any technical setting and to any genetic disease area. The strategy conforms to international guidelines for clinical MPS, as only validated disease genes are investigated and as clinical specialists take responsibility for translation of results. As follow-up in patients without any known IEM, filters can be lifted and the full genome investigated, after genetic counselling and informed consent. PMID- 25495355 TI - Cost-effectiveness of point-of-care digital chest-x-ray in HIV patients with pulmonary mycobacterial infections in Nigeria. AB - BACKGROUND: Chest-x-ray is routinely used in the diagnosis of smear negative tuberculosis (TB). This study assesses the incremental cost per true positive test of a point-of-care digital chest-x-ray, in the diagnosis of pulmonary mycobacterial infections among HIV patients with presumed tuberculosis undetected by smear microscopy. METHODS: Consecutive patients with clinical suspicion of pulmonary tuberculosis were serially tested for Human immunodeficiency virus (HIV), their sputum examined for Acid Fast Bacilli then cultured in broth and solid media. Cultures characterized as tuberculous (M.tb) and non-tuberculous (NTM) mycobacteria by Hain assays were used as gold standards. A chest-x-ray was classified as: (1) consistent for TB, (2) not consistent for TB and (3) no pathology. RESULTS: Of the 1391 suspected cases enrolled, complete data were available for 952 (68%): 753/952 (79%) had negative smear tests while 150/753 (20%) had cultures positive for TB. Of those, 82/150 (55%) had chest-x-ray signs consistent with TB and 29/82 (35%) were positive for HIV. Within the co-infected, 9/29 (31%) had NTM infections. Among all suspects, the cost per positive case detected using smear microscopy test was $52.84; the overall incremental cost per positive case using chest-x-ray in smear negatives was $23.42, and in smear negative, HIV positive patients the cost was $15.77. CONCLUSION: Point-of-care chest-x-ray is a cost-effective diagnostic tool for smear negative HIV positive patients with pulmonary mycobacterial infection. PMID- 25495358 TI - Improvements in closeness, communication, and psychological distress mediate effects of couple therapy for veterans. AB - OBJECTIVE: Empirically based couple therapy results in significant improvements in relationship satisfaction for the average couple; however, further research is needed to identify mediators that lead to change and to ensure that improvements in mediators predict subsequent-not just concurrent-relationship satisfaction. In addition, given that much of the current literature on couple therapy examines outcomes in a research environment, it is important to examine mediators in a treatment-as-usual setting. METHOD: To address these questions, 161 heterosexual couples (322 individuals) received treatment-as-usual couple therapy at one of two Veteran Administration Medical Centers (M = 5.0 and 13.0 sessions at the two sites) and were assessed before every session. The majority of couples were married (85%) and had been together for a median of 7.8 years (SD = 13). Participants were primarily White, non-Hispanic (69%), African American (21%), and White, Hispanic/Latino (8%). RESULTS: Individuals' own self-reported improvements in communication, emotional closeness, and psychological distress (but not frequency of behaviors targeted in treatment) mediated the effect of treatment on their subsequent relationship satisfaction. When all significant mediators were examined simultaneously, improvements in men's and women's emotional closeness and men's psychological distress independently mediated subsequent relationship satisfaction. In contrast, improvements in earlier relationship satisfaction mediated the effect of treatment only on subsequent psychological distress. CONCLUSION: This study identifies unique mediators of treatment effects and shows that gains in mechanisms predict subsequent relationship satisfaction. Future investigations should focus on the role of emotional closeness and psychological distress-constructs that have often been neglected-in couple therapy. (PsycINFO Database Record PMID- 25495357 TI - Effects of behavioral and pharmacological therapies on peer reinforcement of deviancy in children with ADHD-only, ADHD and conduct problems, and controls. AB - OBJECTIVE: This study compared the unique and combined effects of evidence-based treatments for ADHD-stimulant medication and behavior modification-on children's rates of reinforcement for deviant peer behavior (RDPB). METHOD: Using a within subjects design, 222 elementary school-age children attending a summer treatment program, including 151 children with ADHD (127 male), with and without comorbid conduct problems, and 71 control children (57 male), received varying combinations of behavior modification (no, low-intensity, and high-intensity) and methylphenidate (placebo, 0.15 mg/kg, 0.30 mg/kg, and 0.60 mg/kg). RDPB was measured through direct observation and compared across all behavior modification and medication conditions. RESULTS: Children with ADHD reinforced the deviant behavior of their peers at a significantly higher rate than control children in the absence of either intervention. However, that difference largely disappeared in the presence of both behavior modification and medication. Both low and high intensity behavior modification, as well as medium (0.30 mg/kg) and high (0.60 mg/kg) doses of methylphenidate, significantly reduced the rate of ADHD children's RDPB to levels similar to the control group. CONCLUSIONS: Results indicate that although untreated children with ADHD do engage in RDPB at a greater rate than their non-ADHD peers, existing evidence-based interventions can substantially decrease the presence of RDPB, thereby limiting potential iatrogenic effects in group-based treatment settings. PMID- 25495359 TI - Cognitive therapy versus exposure therapy for hypochondriasis (health anxiety): A randomized controlled trial. AB - OBJECTIVE: Cognitive-behavioral therapy has proven to be highly effective in the treatment of hypochondriasis and health anxiety. However, little is known about which therapeutic interventions are most promising. The aim of the present study was to compare the efficacy of cognitive therapy (CT) with exposure therapy (ET). METHOD: Eighty-four patients with a diagnosis of hypochondriasis were randomly allocated to CT, ET, or a waiting list (WL) control group. The primary outcome measure was a standardized interview that evaluated hypochondriacal cognitions as well as behaviors conducted by independent diagnosticians. Several self-report questionnaires were evaluated as secondary outcome measures. Treatment success was evaluated at posttreatment and at 1-year follow-up. RESULTS: Both CT (Hedges's g = 1.01-1.11) and ET (Hedges's g = 1.21-1.24) demonstrated their efficacy in comparison with the WL in the primary outcome measure. Moreover, a significant reduction in depressive symptoms and bodily complaints was found in the secondary outcome measures for both treatments in comparison with the WL, but anxiety symptoms were only significantly reduced by ET. In a direct comparison, no significant differences were found between CT and ET in the primary or the secondary outcome measures. Regarding safety behaviors, we found a significantly larger improvement with ET than with CT in the completer analyses. CONCLUSIONS: The results suggest high efficacy of CT as well as ET in the treatment of hypochondriasis. Cognitive interventions were not a necessary condition for the change of dysfunctional cognitions. These findings are relevant to the conceptualization and psychotherapeutic treatment of hypochondriasis and health anxiety. PMID- 25495360 TI - Self-harm and suicidal behavior in borderline personality disorder with and without bulimia nervosa. AB - OBJECTIVE: Few studies have investigated whether a diagnosis of Bulimia nervosa (BN) confers additional risk of life-threatening behaviors such as self-harm and suicidal behavior in borderline personality disorder (BPD). METHOD: Participants were 483 treatment-seeking women diagnosed with BPD according to the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II; First, Gibbon, Spitzer, Williams, & Benjamin, 1997; Diagnostic and Statistical Manual of Mental Disorders, 4th ed.; APA, 1994) and admitted to the Norwegian Network of Psychotherapeutic Day Hospitals between 1996 and 2009. Of these, 57 (11.8%) women met DSM-IV diagnostic criteria for BN according to the Mini-International Neuropsychiatric Interview (M.I.N.I.; Sheehan et al., 1998) and they were compared with women with BPD and other Axis I disorders. RESULTS: We found that comorbid BN is uniquely and significantly associated with increased risk of suicidal behavior among women being treated for BPD. Findings underscore the importance of routinely screening for BN among women seeking treatment for BPD, as co-occurring bulimia appears to be a significant marker for immediate life threatening behaviors in this already high-risk population, which is a significant public health issue. A significantly greater proportion of women with BPD-BN reported suicidal ideation at intake (past 7 days), engaged in self-harm behavior during treatment, and attempted suicide during treatment. All bivariate associations remained significant in the logistic regression models after controlling for mood, anxiety, and substance-related disorders. CONCLUSION: The presence of a concurrent diagnosis of BN among women with BPD is significantly and uniquely associated with recent suicidal ideation, and self-harm behavior and suicide attempts during treatment after controlling for major classes of mental disorders. Co-occurring BN appears to represent a significant marker for immediate life-threatening behaviors in women seeking treatment for BPD. Extra vigilance and careful monitoring of suicidal behavior during treatment is important for these individuals, and routine screening for BN is warranted. PMID- 25495361 TI - Expanding the efficacy of Project UPLIFT: Distance delivery of mindfulness-based depression prevention to people with epilepsy. AB - OBJECTIVE: Depression affects about 16% of the U.S. population over a lifetime. People with chronic diseases have especially high rates of comorbid depression; 32% to 48% of people with epilepsy experience depression. This study evaluated the efficacy of a mindfulness-based cognitive therapy intervention for preventing major depressive disorder (MDD) episodes in people with epilepsy. METHOD: Participants (n = 128) were adults from Georgia, Michigan, Texas, and Washington with epilepsy and mild/moderate depressive symptoms. The 8-session weekly Project UPLIFT intervention, based on mindfulness-based cognitive therapy, was group delivered via Web or telephone. Using a randomized, controlled crossover design, participants were assigned to Project UPLIFT or a treatment-as-usual (TAU) waitlist and assessed at baseline, and after intervening in the intervention group (~10 weeks) and in the TAU group (~20 weeks). Assessments included valid self-report measures of depression and MDD, knowledge/skills, and satisfaction with life. RESULTS: The incidence of MDD episodes (new or relapse) from baseline to interim assessment was significantly lower in the intervention condition (0.0%) than in TAU (10.7%). Depressive symptoms decreased significantly more in the intervention condition than in TAU; Web and telephone did not differ. Change in knowledge/skills mediated the effect, which persisted over the 10 weeks of follow-up. Knowledge/skills and life satisfaction increased significantly more in the intervention condition than in TAU. CONCLUSIONS: Distance delivery of group mindfulness-based cognitive therapy can prevent episodes of MDD, reduce symptoms of depression, and increase life satisfaction in people with epilepsy. This intervention is easily modified for persons with other chronic diseases and other disparity populations. (PsycINFO Database Record PMID- 25495363 TI - Effect of Renal Transplantation in Restless Legs Syndrome. AB - OBJECTIVES: Restless legs syndrome is a disorder in which patients have irresistible urge to move legs during rest. Restless legs syndrome seems to be common in end-stage renal disease. After a successful renal transplant, symptoms ameliorate with renal function improvement and restless legs syndrome is seen less in this population. Here, we aimed to investigate restless legs syndrome frequency and associated factors in renal transplant patients. MATERIALS AND METHODS: In a cross-sectional study with 193 patients (116 hemodialysis patients, 45 transplant patients, and 32 controls), the presence of restless legs syndrome was assessed using the Restless Legs Syndrome Questionnaire. Medical history, demographic, and laboratory data were collected from the patients' medical records. Patients were questioned about the presence of restless legs syndrome using the Restless Legs Syndrome Questionnaire. Patients were evaluated with Beck Depression Scale for depression and Pittsburgh tests for sleep disturbances. RESULTS: While the rate of restless legs syndrome was similar between transplants and controls, it was significantly greater in hemodialysis patients. Hemodialysis patients and controls had similar depression scores that were higher compared with transplant patients. Pittsburgh score was similar in transplant patients and controls and significantly increased in the hemodialysis patients. The rate of insomnia was significantly higher in the hemodialysis patients compared with the other 2 groups. Logistic regression analysis revealed independent correlates of restless legs syndrome as insomnia, Beck depression score, and being on hemodialysis. Linear regression analysis showed that independent correlates of higher Pittsburgh score were higher depression score, higher age, and presence of restless legs syndrome. CONCLUSIONS: The prevalence of restless legs syndrome is significantly lower in transplant patients than it is in patients on maintenance dialysis. In renal transplant patients, restless legs syndrome frequency was found to be lower because of improved renal functions (normalization of uremia), psychological symptoms, and sleep disturbances. PMID- 25495364 TI - The microbiological gender gap in cystic fibrosis. PMID- 25495365 TI - Congress on women's health Trudy Bush lecture 2014: new insights into sex Hormones and Cardiovascular disease. AB - Many basic, mechanistic studies of how sex steroids alter vascular function proceeded from Dr. Bush's seminal epidemiologic observations that noncontraceptive use of estrogen reduced all-cause and cardiovascular mortality. However, translating findings from these basic science studies into clinical trials and clinical guidelines has been controversial. This commentary reviews the development of sex steroid vascular research, identifies mechanisms by which sex steroids affect vascular function, reviews findings from recent clinical hormone trials, and identifies challenges and the need for continued funding of such investigations. PMID- 25495366 TI - Gender differences in outcomes of patients with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is a common life-shortening genetic disease in which women have been described to have worse outcomes than males, particularly in response to respiratory infections with Pseudomonas aeruginosa. However, as advancements in therapies have improved life expectancy, this gender disparity has been challenged. The objective of this study is to examine whether a gender based survival difference still exists in this population and determine the impact of common CF respiratory infections on outcomes in males versus females with CF. METHODS: We conducted a retrospective cohort analysis of 32,766 patients from the United States Cystic Fibrosis Foundation Patient Registry over a 13-year period. Kaplan-Meier and Cox proportional hazards models were used to compare overall mortality and pathogen based survival rates in males and females. RESULTS: Females demonstrated a decreased median life expectancy (36.0 years; 95% confidence interval [CI] 35.0-37.3) compared with men (38.7 years; 95% CI 37.8 39.6; p<0.001). Female gender proved to be a significant risk factor for death (hazard ratio 2.22, 95% CI 1.79-2.77), despite accounting for variables known to influence CF mortality. Women were also found to become colonized earlier with several bacteria and to have worse outcomes with common CF pathogens. CONCLUSIONS: CF women continue to have a shortened life expectancy relative to men despite accounting for key CF-related comorbidities. Women also become colonized with certain common CF pathogens earlier than men and show a decreased life expectancy in the setting of respiratory infections. Explanations for this gender disparity are only beginning to be unraveled and further investigation into mechanisms is needed to help develop therapies that may narrow this gender gap. PMID- 25495367 TI - Enhancing uterine fibroid research through utilization of biorepositories linked to electronic medical record data. AB - BACKGROUND: Uterine leiomyomata (fibroids) affect up to 77% of women by menopause and account for $9.4 billion in yearly healthcare costs. Most studies rely on self-reported diagnosis, which may result in misclassification of controls since as many as 50% of cases are asymptomatic and thus undiagnosed. Our objective was to evaluate the performance and accuracy of a fibroid phenotyping algorithm constructed from electronic medical record (EMR) data, limiting to subjects with pelvic imaging. METHODS: Our study population includes women from a clinical population at Vanderbilt University Medical Center (2008-2012). Analyses were restricted to women 18 years and older with at least one fibroid diagnosis confirmed by imaging for cases or at least two separate pelvic imaging procedures without a diagnosis for controls. We randomly reviewed 218 records to evaluate the accuracy of our algorithm and assess the indications for pelvic imaging. Participant characteristics and indications for imaging were compared between cases and controls in unadjusted and adjusted logistic regression analyses. RESULTS: Our algorithm had a positive predictive value of 96% and negative predictive value of 98%. Increasing age (odds ratio=1.05, 95% confidence interval 1.03-1.08) and Black race (odds ratio=2.15, 95% confidence interval 1.18-3.94) were identified as risk factors for fibroids. The most common indications for imaging in both cases and controls were pain, bleeding, and reproductive factors, and the most common imaging modality was a pelvic ultrasound. CONCLUSIONS: These data suggest that using biorepositories linked to EMR data is a feasible way to identify populations of imaged women that facilitate investigations of fibroid risk factors. PMID- 25495369 TI - Infrared matrix isolation and theoretical studies of reactions of ozone with bicyclic alkenes: alpha-pinene, norbornene, and norbornadiene. AB - The reactions of ozone with three bicyclic alkenes, alpha-pinene, norbornene, and norbornadiene, were studied by low-temperature (14 K), argon matrix isolation infrared spectroscopy including (18)O isotope-labeling studies. Theoretical calculations of some of the proposed reaction intermediates and products were carried out using the Gaussian 09 suite of programs, applying density functional theory (DFT), the B3LYP functional, and the 6-311G++(d,2p) basis set. In the alpha-pinene/ozone system, the thermal reaction between alpha-pinene and ozone was too slow to observe under the twin-jet or merged-jet deposition conditions of these experiments. However, red light (lambda >= 600 nm) irradiation of the argon matrixes containing alpha-pinene and ozone caused new infrared peaks to appear that could be readily assigned to reaction products of alpha-pinene with O((3)P) resulting from ozone photolysis: alpha-pinene oxide (with an epoxide ring) and two isomeric ketones. Norbornene and norbornadiene were both found to react with ozone in the gas phase during twin-jet or merged-jet deposition of these mixtures with argon. New peaks observed in the infrared spectra were assigned to the primary ozonides, Criegee intermediates, and secondary ozonides of norbornene and norbornadiene, indicating that the bulk of these reactions proceeded via the "classic" Criegee mechanism for ozonolysis of alkenes. Calculated infrared frequencies and molecular energies support these conclusions. Ultraviolet irradiation of these mixtures resulted in complete decomposition of the early intermediates and the formation of acids, aldehydes, alcohols, carbon dioxide, and carbon monoxide. In any case, no evidence for "unusual" chemistry, prompted by the bicyclic nature of the reactants, was observed. PMID- 25495368 TI - Allostatic load in women with a history of low birth weight infants: the national health and nutrition examination survey. AB - BACKGROUND: The purpose of our study was to determine whether women of reproductive age with history of low birth weight (LBW) deliveries have higher allostatic load (AL), a measure of the cumulative toll of chronic stress, than those with normal-weight deliveries. METHODS: We used data from women ages 17-35 who responded to the National Health and Nutrition Examination Survey (NHANES) reproductive-health questionnaire, 1999-2006. Women reported history of LBW infants and those who were preterm. We classified preterm-LBW and term-LBW as surrogates for preterm birth (PTB) and small for gestational age (SGA), respectively. Normal weight included those without LBW infant history. We utilized nine biomarkers measured in NHANES to determine AL and used linear regression to compare unadjusted and adjusted means. RESULTS: We identified 877 women divided among SGA (2%), PTB (10%), and normal groups (88%). The SGA group had higher unadjusted and adjusted AL scores than did the normal group (2.82 +/- 0.35 vs. 1.92 +/- 0.07, p=0.011); women in the PTB group had higher AL scores than did the referent in adjusted analyses (2.58 +/- 0.21 vs. 1.92 +/- 0.07, p=0.001). CONCLUSIONS: Women with history of SGA or PTB had higher AL than did those with normal birth weight outcomes. This suggests a link between adverse pregnancy outcomes, chronic stress, and subclinical disease. PMID- 25495370 TI - Enantioselective total synthesis of (-)-maoecrystal V. AB - The enantioselective synthesis of maoecrystal V, a cytotoxic polycyclic diterpene, is described. Key reactions in the synthesis include an intramolecular Heck reaction, an oxidative cycloetherification, and an intermolecular Diels Alder reaction to forge the carbocyclic core in a concise and stereoselective manner. Late-stage amine and C-H oxidation is used to install the final functional groups required to complete the synthesis. PMID- 25495371 TI - Commentary on: Guidelines for the treatment of hypothyroidism. PMID- 25495373 TI - ELF score >=9.8 indicates advanced hepatic fibrosis and is influenced by age, steatosis and histological activity. AB - BACKGROUND & AIMS: There is increasing need to identify individuals with advanced liver fibrosis, who are at risk of complications such as hepatocellular carcinoma. The commercially available enhanced liver fibrosis (ELF) test provides a non-invasive assessment of fibrosis severity. This study was designed to determine the diagnostic accuracy of the manufacturer's cut-off value (>=9.8) in identifying advanced fibrosis. METHODS: The relationship between ELF score and fibrosis was examined using serum collected at time of liver biopsy for investigation of liver disease, particularly viral hepatitis. Fibrosis was staged using a modified METAVIR score. If available, liver tissue was recut and stained with Sirius red to determine collagen proportional area (CPA) and subsinusoidal fibrosis (SSF). RESULTS: Enhanced liver fibrosis score >=9.8 had a sensitivity of 74.4% and specificity 92.4% for detecting advanced fibrosis. In the whole cohort (n = 329), ELF score was more likely to incorrectly classify individuals if age was >=45 years and METAVIR inflammatory grade was 2 or 3 (adjusted OR, odds ratio 3.71 and 2.62 respectively). In contrast, ELF score was less likely to misclassify individuals in the presence of steatosis (OR 0.37). Neither SSF nor CPA explained the discordance in ELF score for patients with or without advanced fibrosis. CONCLUSION: Although ELF score >=9.8 reliably identifies advanced fibrosis in patients with chronic liver disease, both age and inflammatory activity need to be considered when interpreting the result. Importantly, ELF score performed well in the presence of steatosis and could thus be helpful in the assessment of fatty liver disease. PMID- 25495374 TI - Near-infrared spectroscopy reveals link between chronic physical activity and anterior frontal oxygenated hemoglobin in healthy young women. AB - Cerebrovascular and cognitive functioning peak developmentally in young adults, yet recent evidence indicates they may benefit on these fronts from regular engagement in physical activity. In light of epidemiological trends for increasingly sedentary lifestyles and the importance of optimal cerebrovascular and cognitive functioning, here we investigated relationships between physical activity levels, anterior frontal hemodynamics, and cognitive performance in 52 healthy young women. Analyses positively linked chronic physical activity level (CPAL) with anterior frontal oxygenated hemoglobin and cognitive inhibitory control, indicating regular physical activity may lead to hemodynamic and cognitive benefits, even in a cohort at developmental peak. In addition, higher anterior frontal oxygenated hemoglobin was linked to better performance for the most difficult cognitive task. Given the importance of oxygen availability for cognitive functioning, the current discovery of a relationship with CPAL may provide important insight toward understanding exercise-cognition links. PMID- 25495375 TI - Development of the morphology during functional stack build-up of P3HT:PCBM bulk heterojunction solar cells with inverted geometry. AB - Highly efficient poly(3-hexylthiophene-2,5-diyl) (P3HT):phenyl-C61-butyric acid methyl ester (PCBM) bulk heterojunction solar cells are achieved by using an inverted geometry. The development of the morphology is investigated as a function of the multilayer stack assembling during the inverted solar cell preparation. Atomic force microscopy is used to reveal the surface morphology of each stack, and the inner structure is probed with grazing incidence small-angle X-ray scattering. It is found that the smallest domain size of P3HT is introduced by replicating the fluorine-doped tin oxide structure underneath. The structure sizes of the P3HT:PCBM active layer are further optimized after thermal annealing. Compared to devices with standard geometry, the P3HT:PCBM layer in the inverted solar cells shows smaller domain sizes, which are much closer to the exciton diffusion length in the polymer. The decrease in domain sizes is identified as the main reason for the improvement of the device performance. PMID- 25495376 TI - Cognitive contributions to theory of mind ability in children with a traumatic head injury. AB - The objective of the current study is to examine the contribution of intellectual abilities, executive functions (EF), and facial emotion recognition to difficulties in Theory of Mind (ToM) abilities in children with a traumatic head injury. Israeli children with a traumatic head injury were compared with their non-injured counterparts. Each group included 18 children (12 males) ages 7-13. Measurements included reading the mind in the eyes, facial emotion recognition, reasoning the other's characteristics based on motive and outcome, Raven's Coloured Progressive Matrices, similarities and digit span (Wechsler Intelligence Scale for Children - Revised 95 subscales), verbal fluency, and the Behaviour Rating Inventory of Executive Functions. Non-injured children performed significantly better on ToM, abstract reasoning, and EF measures compared with children with a traumatic head injury. However, differences in ToM abilities between the groups were no longer significant after controlling for abstract reasoning, working memory, verbal fluency, or facial emotion recognition. Impaired ToM recognition and reasoning abilities after a head injury may result from other cognitive impairments. In children with mild and moderate head injury, poorer performance on ToM tasks may reflect poorer abstract reasoning, a general tendency to concretize stimuli, working memory and verbal fluency deficits, and difficulties in facial emotion recognition, rather than deficits in the ability to understand the other's thoughts and emotions. ToM impairments may be secondary to a range of cognitive deficits in determining social outcomes in this population. PMID- 25495377 TI - Comparison of Optimal Thermodynamic Models of the Tricarboxylic Acid Cycle from Heterotrophs, Cyanobacteria, and Green Sulfur Bacteria. AB - We have applied a new stochastic simulation approach to predict the metabolite levels, material flux, and thermodynamic profiles of the oxidative TCA cycles found in E. coli and Synechococcus sp. PCC 7002, and in the reductive TCA cycle typical of chemolithoautotrophs and phototrophic green sulfur bacteria such as Chlorobaculum tepidum. The simulation approach is based on modeling states using statistical thermodynamics and employs an assumption similar to that used in transition state theory. The ability to evaluate the thermodynamics of metabolic pathways allows one to understand the relationship between coupling of energy and material gradients in the environment and the self-organization of stable biological systems, and it is shown that each cycle operates in the direction expected due to its environmental niche. The simulations predict changes in metabolite levels and flux in response to changes in cofactor concentrations that would be hard to predict without an elaborate model based on the law of mass action. In fact, we show that a thermodynamically unfavorable reaction can still have flux in the forward direction when it is part of a reaction network. The ability to predict metabolite levels, energy flow, and material flux should be significant for understanding the dynamics of natural systems and for understanding principles for engineering organisms for production of specialty chemicals. PMID- 25495378 TI - Case of folliculotropic mycosis fungoides with prominent loss of T-cell antigens CD7 and CD26 in blood T cells. PMID- 25495379 TI - Performance of undergraduate dental students on ICDAS clinical caries detection after different learning strategies. AB - AIM: This study aimed to evaluate the effect of a digital learning tool on undergraduate dental students' performance in detecting dental caries using ICDAS. METHODS: An experimental digital learning tool (DLT) was created using digital photographs of sound and carious teeth. Thirty-nine students were divided into three groups (n = 13) and each assessed 12 randomly allocated patients before and after learning strategies: G1, ICDAS e-learning program; G2, ICDAS e learning program plus DLT; G3, no learning strategy. Students (n = 32) reassessed patients 2 weeks after training. RESULTS: Comparing before and after the learning strategies, any difference in the values of specificity and area under the ROC curve for all groups was found. Sensitivity was statistically significantly higher for G1 and G2. Comparing the groups, G2 showed a significant increase in sensitivity at the D2 and D3 thresholds. Spearman's correlations with the gold standard before and after the learning strategy were 0.60 and 0.61 for G1, 0.57 and 0.63 for G2, and 0.54 and 0.54 for G3, respectively. The Wilcoxon test showed a statistically significant difference between the values obtained before and after learning strategies for G1 and G2. CONCLUSIONS: Use of the DLT after the ICDAS e-learning program tended to increase the sensitivity of ICDAS used by undergraduate dental students. The DLT appeared to improve dental students' ability to use ICDAS. PMID- 25495380 TI - Lymphangiogenesis, the CCR7 receptor, and human atherosclerosis. PMID- 25495381 TI - Functional lymphatic collectors in breast cancer-related lymphedema arm. AB - BACKGROUND: The pathophysiology of breast cancer-related lymphedema (BCRL) is poorly understood. The present study evaluated the lymphatic collectors in the arms of patients with BCRL. METHODS AND RESULTS: In total, 123 patients with ipsilateral BCRL who had undergone magnetic resonance lymphangiography using gadobenate dimeglumine as a contrast agent were enrolled in this study. Morphological changes and the numbers of collecting lymphatic vessels were recorded. Associations between the number of visualized lymphatic collectors and edema accumulation, subcutis thickness, and the BCRL duration and latency were analyzed. Tortuous and significantly dilated lymphatic collectors were visualized in the lymphedematous arms of 104 patients (85%). The median number of visualized lymphatic collectors was four. The duration of BCRL was weakly but significantly correlated with the number of lymphatic collectors (rs=0.2054, p=0.0226). The differences in the tissue water content and thickness of the subcutis between the bilateral arms demonstrated moderate correlations with the number of collecting lymphatics (rs=0.31 and 0.35, respectively; p<0.01). More lymphatic collectors tended to be seen in more advanced cases. There was no statistical difference in the amount of lymphatic vessels among different breast cancer treatment methods. CONCLUSIONS: The number of functional remaining lymphatic collectors increases with the prolongation and severity of BCRL. This may imply persistent reactions of lymphatic collectors in response to lymphostasis. PMID- 25495382 TI - Three-dimensional camera system for measuring arm volume in women with lymphedema following breast cancer treatment. AB - BACKGROUND: Lymphedema is a common complication following breast cancer treatment, estimated to affect 20% of breast cancer survivors. The condition is associated with a number of symptoms, such as impaired range of motion and anxiety. A wide range of methods for determining the volume of the lymphedematous arm have been described. Circumference measurement (CM) is commonly used in clinics to appraise arm volume, while water displacement (WD) is often used in studies. The aim of the study was to assess the performance of a new method using 3D-technology in comparison to CM and WD. METHODS AND RESULTS: The study was performed on 25 subjects with lymphedema secondary to breast cancer treatment. Volumetric data from CM, WD, and the 3D-camera were gathered on all subjects. The measurements were performed by two physiotherapists, each subject being measured by one of the physiotherapist. Estimates of differences between the methods was calculated through analyzing the data collected from the three methods using mixed-design analyses of variance. The results indicated a tendency for the 3D camera to overestimate the volume in comparison the WD by 45.25 mL, 95% confidence interval (CI) -36.31 - 126.82 (p value 0.270). Conversely, CM showed a tendency to underestimate the volume compared to WD (-24.28 mL, CI -99.78 - 51.22, p value 0.521). Thus, no statistically significant difference was found between the methods. CONCLUSIONS: The 3D-camera is a viable method for measuring arm volume, performing on level with the established methods WD and CM. PMID- 25495383 TI - Validity and reliability of three-dimensional imaging for measuring the volume of the arm. AB - BACKGROUND: Lymphedema of the upper limb is a common complication after cancer treatment with axillary lymph node surgery and/or radiation. At this moment, there is no method that can identify lymphedema error free. Currently three dimensional (3D) imaging is used to measure volumes in aesthetic and maxillofacial surgery. This study aims to assess the validity and reliability of 3D volume measurements of the upper limb compared with the current gold standard (water displacement method). METHODS AND RESULTS: Thirty-three subjects were included which completed both measurements. The accuracy of the aforementioned methods was compared in a within subject design. The analysis showed a mean difference between the two measurements of -13.8 cc (SD 59.3), this volume difference was not significant (p=0.192). Both the intra- and inter-rater reliability of the 3D measurements were high (0.99). CONCLUSION: The 3D volume measurements of the arm are valid and reliable. Therefore we recommend the 3D method for measuring arm volumes. Since this method is now validated for arms without lymphedema, we plan to validate this new technique for patients with lymphedema. PMID- 25495384 TI - The importance of detection of subclinical lymphedema for the prevention of breast cancer-related clinical lymphedema after axillary lymph node dissection; a prospective observational study. AB - PURPOSE: Early detection and timely intervention have potential to reduce late stage lymphedema (LE) in patients with breast cancer undergoing axillary lymph node dissection (ALND). This study aims to determine if detection and early treatment of subclinical LE by using prospective monitoring with bioimpedance spectroscopy (BIS) can lead to reduced development of clinical LE. METHODS AND RESULTS: Subclinical LE was prospectively detected using an L-Dex((r)) U400 analyzer to measure BIS in 186 patients who underwent ALND between 2010 and 2013 through our LE monitoring program. Baseline measurements were obtained and at 3-6 month intervals for 5 years. Patients diagnosed with subclinical LE received short-term physical therapy, compression garments, and education about exercise, elevation, infection precautions, BMI, and hand usage. The control group had a preoperative baseline L-Dex((r)) measurement, but had only clinical follow-ups with circumferential arm measurements. Mean age and BMI were 56 years and 28.3 kg/m(2), respectively. The majority of the women underwent mastectomy (61%) and received chemotherapy (89%) and radiotherapy (77%). Thirty-three percent patients who had repeated L-Dex measurements were diagnosed with subclinical LE and received early intervention. Progression to clinical lymphedema occurred in 4.4% over an average of 20 months follow-up. In the control group, the incidence of clinical LE was 36.4%. CONCLUSION: Periodic monitoring of women at high risk for LE with BIS allows early detection and timely intervention for LE, which reduces the incidence of clinical LE from 36.4% to 4.4%. This may have implications for quality of life and health care costs. PMID- 25495387 TI - Conformational transition of a hairpin structure to G-quadruplex within the WNT1 gene promoter. AB - The role of G-quadruplexes (G4s) in biological systems has been widely studied. It is found that they have an important function in gene transcription and regulation. In this work, we have identified two topologies of hairpin and G4 structures formed by a native G-rich sequence (WT22: 5'-GGGCCACCGGGCAGGGGGCGGG 3') from the WNT1 promoter region using nuclear magnetic resonance (NMR) spectroscopy. With the help of site-specific isotope labeling, the topologies of these two structures are unambiguously characterized. Circular dichroism and NMR results are analyzed to determine the kinetics associated with the potassium ion induced hairpin-to-G4 transition, which is very slow-on the time scale of 4800 s compared to the previously reported folding kinetics of G4 formation. In addition, the free energies of the unfolding of these two structures are obtained using differential scanning calorimetry. Combining the kinetic and thermodynamic data, we have established the free energy landscape of this two-state folding system. Considering that similar conformational change may exist in other native G-rich sequences, this work highlights an important hairpin to G4 conformational transition which can be used in manipulation of gene regulation or ligand modulation in vivo. PMID- 25495388 TI - Silver-catalyzed C(sp2)-H functionalization/C-O cyclization reaction at room temperature. AB - Silver-catalyzed C(sp(2))-H functionalization/C-O cyclization has been developed. The scalable reaction proceeds at room temperature in an open flask. The present method exhibits good functional-group compatibility because of the mild reaction conditions. Using a AgNO3 catalyst and a (NH4)2S2O8 oxidant in CH2Cl2/H2O solvent, various lactones are obtained in good to excellent yields. A kinetic isotope effect (KIE) study indicates that the reaction may occur via a radical process. PMID- 25495389 TI - Fully automated sample preparation microsystem for genetic testing of hereditary hearing loss using two-color multiplex allele-specific PCR. AB - A fully automated microsystem consisting of a disposable DNA extraction and PCR microchip, as well as a compact control instrument, has been successfully developed for genetic testing of hereditary hearing loss from human whole blood. DNA extraction and PCR were integrated into a single 15-MUL reaction chamber, where a piece of filter paper was embedded for capturing genomic DNA, followed by in-situ PCR amplification without elution. Diaphragm microvalves actuated by external solenoids together with a "one-way" fluidic control strategy operated by a modular valve positioner and a syringe pump were employed to control the fluids and to seal the chamber during thermal cycling. Fully automated DNA extractions from as low as 0.3-MUL human whole blood followed by amplifications of 59-bp beta actin fragments can be completed on the microsystem in about 100 min. Negative control tests that were performed between blood sample analyses proved the successful elimination of any contamination or carryover in the system. To more critically test the microsystem, a two-color multiplex allele-specific PCR (ASPCR) assay for detecting c.176_191del16, c.235delC, and c.299_300delAT mutations in GJB2 gene that accounts for hereditary hearing loss was constructed. Two allele-specific primers, one labeled with TAMRA for wild type and the other with FAM for mutation, were designed for each locus. DNA extraction from blood and ASPCR were performed on the microsystem, followed by an electrophoretic analysis on a portable microchip capillary electrophoresis system. Blood samples from a healthy donor and five persons with genetic mutations were all accurately analyzed with only two steps in less than 2 h. PMID- 25495391 TI - Re: The Beneficial Effects of Doxycycline, an Inhibitor of Matrix Metalloproteinases, on Sulfur Mustard-induced Ocular Pathologies Depend on the Injury Stage. PMID- 25495390 TI - The second wave of the Controlled Antenatal Thyroid Screening (CATS II) study: the cognitive assessment protocol. AB - BACKGROUND: Children whose mothers had low thyroid hormone levels during pregnancy have been reported to have decreased cognitive function. The reported research is part of the follow-on study of the Controlled Antenatal Thyroid Screening Study (CATS I), a randomised controlled trial which investigated the impact of treated vs. untreated low thyroid hormone level in women during pregnancy with the primary outcome being the child's IQ at age 3. No significant differences in IQ were found between the treated and untreated groups. These children are now aged between 7 and 10 years and aspects of their cognitive functioning including their IQ are being reassessed as part of CATS II. METHODS/DESIGN: Cognitive assessments generate an IQ score and further tests administered will investigate long term memory function and motor coordination. The aim is to complete the assessments with 40% of the children born to mothers either in the treated or untreated low thyroid hormone groups (n = 120 per group). Also children born to mothers who had normal thyroid functioning during CATS I are being assessed for the first time (n = 240) to provide a comparison. Assessments are conducted either in the research facility or the participant's home. DISCUSSION: The study is designed to assess the cognitive functioning of children born to mothers with low thyroid hormone levels and normal thyroid functioning during pregnancy. This is the largest study of its type and also is distinguishable in its longitudinal design. The research has the potential to have a significant impact on public health policy in the UK; universal screening of thyroid hormone levels in pregnancy may be the recommendation. PMID- 25495392 TI - IDH2 mutation in gliomas including novel mutation. AB - Glioblastomas (GBMs) are the most aggressive type of primary brain tumors and provide a dismal prognosis. Thus far, several key genes have been identified in GBMs as prognostic and therapeutic targets. Mutations in two isocitrate dehydrogenase (IDH) genes, IDH1 and IDH2, commonly occur in low-grade gliomas and secondary high-grade gliomas, but are rare in primary GBMs. These mutations alter the catalytic activity of IDH proteins, promoting gliomagenesis. Gliomas with IDH1 or IDH2 mutation have better outcomes than do gliomas with wild-type IDH. The hot spots of IDH1 mutations (R132) and IDH2 mutations (R140 and R172) are well known and are considered as a possible biochemical explanation for the differing clinical characteristics of primary and secondary GBMs. We sought to find the incidence of IDH2 mutation and the characteristics of the gliomas with IDH2 mutation. Among 134 gliomas, which were operated in our hospital consecutively, we studied IDH1 and IDH2 mutations by Sanger sequencing and IDH2 mutation was identified in seven cases (5.2%, four oligodendrogliomas and three GBMs). IDH2 mutation was found in 3.3% of GBMs (3/90 cases) and 9.0% (4/44) of grades II to III gliomas. Here, we report the clinicopathological characteristics of the gliomas with IDH2 mutations including two cases of primary GBM carrying a novel missense IDH2 mutation (c. 484C>T, p. P162S). PMID- 25495393 TI - Ancient sedimentary structures in the <3.7 Ga Gillespie Lake Member, Mars, that resemble macroscopic morphology, spatial associations, and temporal succession in terrestrial microbialites. AB - Sandstone beds of the <3.7 Ga Gillespie Lake Member on Mars have been interpreted as evidence of an ancient playa lake environment. On Earth, such environments have been sites of colonization by microbial mats from the early Archean to the present time. Terrestrial microbial mats in playa lake environments form microbialites known as microbially induced sedimentary structures (MISS). On Mars, three lithofacies of the Gillespie Lake Member sandstone display centimeter to meter-scale structures similar in macroscopic morphology to terrestrial MISS that include "erosional remnants and pockets," "mat chips," "roll-ups," "desiccation cracks," and "gas domes." The microbially induced sedimentary-like structures identified in Curiosity rover mission images do not have a random distribution. Rather, they were found to be arranged in spatial associations and temporal successions that indicate they changed over time. On Earth, if such MISS occurred with this type of spatial association and temporal succession, they would be interpreted as having recorded the growth of a microbially dominated ecosystem that thrived in pools that later dried completely: erosional pockets, mat chips, and roll-ups resulted from water eroding an ancient microbial mat covered sedimentary surface; during the course of subsequent water recess, channels would have cut deep into the microbial mats, leaving erosional remnants behind; desiccation cracks and gas domes would have occurred during a final period of subaerial exposure of the microbial mats. In this paper, the similarities of the macroscopic morphologies, spatial associations, and temporal succession of sedimentary structures on Mars to MISS preserved on Earth has led to the following hypothesis: The sedimentary structures in the <3.7 Ga Gillespie Lake Member on Mars are ancient MISS produced by interactions between microbial mats and their environment. Proposed here is a strategy for detecting, identifying, confirming, and differentiating possible MISS during current and future Mars missions. PMID- 25495394 TI - Uncaria tomentosa (cat's claw) improves quality of life in patients with advanced solid tumors. AB - OBJECTIVE: Cat's claw (Uncaria tomentosa) is a native Amazon plant that exhibits anti-inflammatory and antitumor properties. We wanted to assess its activity for symptom management of terminal cancer patients. METHODS: This prospective phase II study assessed the effects of a 100-mg dose of a dry extract of U. tomentosa three times per day in patients with advanced solid tumors who had no further therapeutic options and a life expectancy of at least 2 months. The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ C30) and Functional Assessment of Chronic Illness Therapy - Fatigue questionnaires were used to assess the participants' quality of life, the Hospital Anxiety and Depression Scale questionnaire was used to assess anxiety and depression, and the Pittsburgh Sleep Quality Index was used to assess sleep quality. In addition, several biochemical and inflammatory parameters were analyzed. RESULTS: Fifty-one volunteers were recruited. Their median age was 64 (range, 33-85) years, and 47% of patients were female. More than 65% of patients had scores on the Karnofsky Performance Scale of 80% or less. Treatment improved the patients' overall quality of life (p=0.0411) and social functioning (p=0.0341), as assessed by the EORTC QLQ C-30, and reduced fatigue (p=0.0496) according to the Chalder Fatigue Questionnaire. None of the biochemical or inflammatory parameters assessed (interleukin-1 and -6, C-reactive protein, tumor necrosis factor-alpha, erythrocyte sedimentation rate, and alpha-1-acid glycoprotein) changed significantly. No tumor response was detected according to the Response Evaluation Criteria In Solid Tumors; however, the disease stabilized for more than 8 months in four participants. The medication was well tolerated by most patients. CONCLUSION: Use of cat's claw might be beneficial in patients with advanced cancer by improving their quality of life and reducing fatigue. The mechanism of action does not seem to be related to the anti-inflammatory properties of this plant. PMID- 25495395 TI - Depression and anxiety among left-behind children in China: a systematic review. AB - This study aimed to systematically review evidence of the prevalence and predictors of depression and anxiety among 'left-behind children' in rural China. The electronic databases PubMed/MEDLINE and Chinese National Knowledge Infrastructure/Wanfang (Chinese) were utilized to search for terms including 'depression' or 'depressive disorder', 'anxiety' or 'mental health', combined with 'left behind', 'children' and 'China'. High rates of psychological depression/anxiety have been reported among left-behind children compared with their age-matched peers. Prevalence rates of depression are reported to range from 12.1 to 51.4% and of anxiety are reported to range from 13.2 to 57.6%. Variability between studies is likely attributable to methodological variations relating to measures used and research setting. Potential predictors measured in studies include age and gender, types of being left, age/years of separation, socio-economic status, etc. These high rates of reported psychological problems among this group of young people suggest the need to develop more effective approaches to prevention and management. PMID- 25495396 TI - shRNA against PTEN promotes neurite outgrowth of cortical neurons and functional recovery in spinal cord contusion rats. AB - AIM: To explore neurite growth/regeneration and spinal cord injury repair after PTEN silencing via lentivirus-mediated RNAi. MATERIALS & METHODS: Cortical neurons were seeded on or adjacent to chondroitin sulfate proteoglycans. The length, number and crossing behavior of neurites were calculated. Lentivirus was locally injected into spinal cord contusion rats. The functional recovery and immunohistochemical staining were analyzed. RESULTS: Neurites with PTEN silencing exhibited significant enhancements in elongation, initiation and crossing ability when they encountered chondroitin sulfate proteoglycans in vitro. In vivo PTEN silencing improved functional recovery significantly, and promoted axon and synapse formation, but not scar formation. CONCLUSIONS: PTEN silencing may be promising for spinal cord injury repair. PMID- 25495398 TI - Statins and the neuromuscular system: a neurologist's perspective. AB - Statins intolerance is mainly due to their side effects on the neuromuscular system (primarily muscle). It has become an important issue because of the major cardiovascular risk reduction of this class of drugs. However, the facts related to these side effects are sometimes under-recognized or controversial. A literature review of the recent developments in the field is given. The clinical definition of statin myopathy and its presentation are not suitable for the myology field. Management and prevention are not validated. More genetic risk factors need to be established. Neurologists should become more involved in statin intolerance evaluation and management. PMID- 25495399 TI - Why is mesial temporal lobe epilepsy with Ammon's horn sclerosis becoming less common? PMID- 25495401 TI - Endoscopic dacryocystorhinostomy and obstructive sleep apnoea: the effects and outcomes of continuous positive airway pressure therapy. AB - BACKGROUND: This study aims to assess the effects and outcomes of continuous positive airway pressure (CPAP) therapy for obstructive sleep apnoea (OSA) in patients who have undergone endoscopic dacryocystorhinostomy (DCR). DESIGN: Retrospective series in a university setting. PARTICIPANTS: A total of 205 consecutive patients were included in this study. METHODS: A 10-year retrospective review was performed of 205 consecutive patients who had undergone powered endoscopic DCR for nasolacrimal duct obstruction. Patient notes were reviewed for demographic, clinical and surgical information. In addition, all patients were contacted and asked to complete a standardized telephone survey relating to OSA, CPAP use and associated symptoms. MAIN OUTCOME MEASURE: Effects of CPAP following DCR. RESULTS: Ten of the 205 patients undergoing DCR were identified to use CPAP for obstructive sleep apnoea. Eight patients were initiated on a nasal device, while two used a full-face mask. The mean CPAP pressures were 8 cm H20 (range: 6-10 cm H20). Eighty percent (8/10) of patients complained of symptoms from the use of their CPAP following DCR. The most commonly described symptom was that of air regurgitation in 70% of patients followed by ophthalmic symptoms in 60% (6/10). 50% (5/10) of patients discontinued their CPAP as a consequence of their symptoms with 20% (2/10) discontinuing because of intolerable ophthalmic symptoms. CONCLUSION: Symptoms from CPAP use post-endoscopic DCR are a common occurrence and may contribute to poor compliance with CPAP therapy. Detailed preoperative counseling with regards to CPAP use and its effects should be mandatory in known or at risk OSA patients undergoing DCR. PMID- 25495402 TI - The association between breastfeeding and childhood obesity: a meta-analysis. AB - BACKGROUND: The increase in childhood obesity is a serious public health concern. Several studies have indicated that breastfed children have a lower risk of childhood obesity than those who were not breastfed, while other studies have provided conflicting evidence. The objective of this meta-analysis was to investigate the association between breastfeeding and the risk of childhood obesity. METHODS: The PubMed, EMBASE and CINAHL Plus with Full Text databases were systematically searched from start date to 1st August 2014. Based on the meta-analysis, pooled adjusted odds ratio (AOR) and 95% confidence interval (CI) were calculated. I2 statistic was used to evaluate the between-study heterogeneity. Funnel plots and Fail-safe N were used to assess publication bias and reliability of results, and results from both Egger test and Begg test were reported. RESULTS: Twenty-five studies with a total of 226,508 participants were included in this meta-analysis. The studies' publication dates ranged from 1997 to 2014, and they examined the population of 12 countries. Results showed that breastfeeding was associated with a significantly reduced risk of obesity in children (AOR = 0.78; 95% CI: 0.74, 0.81). Categorical analysis of 17 studies revealed a dose-response effect between breastfeeding duration and reduced risk of childhood obesity. CONCLUSION: Results of our meta-analysis suggest that breastfeeding is a significant protective factor against obesity in children. PMID- 25495403 TI - The role of numerical and non-numerical cues in nonsymbolic number processing: Evidence from the line bisection task. AB - In line bisection tasks, adults and children bisect towards the numerically larger of two nonsymbolic numerosities [de Hevia, M. D., & Spelke, E. S. ( 2009 ). Spontaneous mapping of number and space in adults and young children. Cognition, 110, 198-207. doi:10.1016/j.cognition.2008.11.003]. However, it is not clear whether this effect is driven by number itself or rather by visual cues such as subtended area [Gebuis, T., & Gevers, W. ( 2011 ). Numbers and space: Indeed a cognitive illusion! A reply to de Hevia and Spelke ( 2009 ). Cognition, 121, 248-252. doi:10.1016/j.cognition.2010.09.008]. Furthermore, this effect has only been demonstrated with flanking displays of two and nine items. Here, we report three studies that examined whether this "spatial bias" effect occurs across a range of absolute and ratio numerosity differences; in particular, we examined whether the bias would occur when both flankers were outside the subitizing range. Additionally, we manipulated the subtended area of the stimulus and the aggregate surface area to assess the influence of visual cues. We found that the spatial bias effect occurred for a range of flanking numerosities and for ratios of 3:5 and 5:6 when subtended area was not controlled (Experiment 1). However, when subtended area and aggregate surface area were held constant, the biasing effect was reversed such that participants bisected towards the flanker with fewer items (Experiment 2). Moreover, when flankers were identical, participants bisected towards the flanker with larger subtended area or larger aggregate surface area (Experiments 2 and 3). On the basis of these studies, we conclude that the spatial bias effect for nonsymbolic numerosities is primarily driven by visual cues. PMID- 25495405 TI - Ultrasound assessment of gastric volume in the fasted pediatric patient undergoing upper gastrointestinal endoscopy: development of a predictive model using endoscopically suctioned volumes. AB - BACKGROUND: Aspiration of gastric contents can be a serious anesthetic-related complication. Gastric antral sonography prior to anesthesia may have a role in identifying pediatric patients at risk of aspiration. We examined the relationship between sonographic antral area and endoscopically suctioned gastric volumes, and whether a 3-point qualitative grading system is applicable in pediatric patients. METHODS: Fasted patients presenting to a pediatric hospital for upper gastrointestinal endoscopy were included in the study. Sonographic measurement of the antral cross-sectional area (CSA) in supine (supine CSA) and right lateral decubitus (RLD CSA) position was completed, and the antrum was designated as empty or nonempty. Gastric contents were endoscopically suctioned and measured. Multiple regression analysis was used to fit a mathematical model to estimate gastric volume. RESULTS: One hundred patients (aged 11-216 months) were included. The gastric antrum was measured in 94% and 99% of patients in the supine and RLD positions, respectively. Gastric antral CSA correlated with total gastric volume in both supine (rho = 0.63) and RLD (rho = 0.67) positions. A mathematical model incorporating RLD CSA and age (R(2) = 0.60) was determined as the best-fit model to predict gastric volumes. Increasing gastric antral grade (0 2) was associated with increasing gastric fluid volume. CONCLUSION: The results suggest that sonographic assessment of the gastric antrum provides useful information regarding gastric content (empty versus nonempty) and volume (ml.kg( 1) ) in pediatric patients. Results suggest that the three-point grading system may be a valuable tool to assess gastric 'fullness' based on a qualitative exam of the antrum. PMID- 25495406 TI - Polymorphic expression of CYP2C19 and CYP2D6 in the developing and adult human brain causing variability in cognition, risk for depression and suicide: the search for the endogenous substrates. PMID- 25495404 TI - Variant CJD. 18 years of research and surveillance. AB - It is now 18 years since the first identification of a case of vCJD in the UK. Since that time, there has been much speculation over how vCJD might impact human health. To date there have been 177 case reports in the UK and a further 51 cases worldwide in 11 different countries. Since establishing that BSE and vCJD are of the same strain of agent, we have also shown that there is broad similarity between UK and non-UK vCJD cases on first passage to mice. Transgenic mouse studies have indicated that all codon 129 genotypes are susceptible to vCJD and that genotype may influence whether disease appears in a clinical or asymptomatic form, supported by the appearance of the first case of potential asymptomatic vCJD infection in a PRNP 129MV patient. Following evidence of blood transfusion as a route of transmission, we have ascertained that all blood components and leucoreduced blood in a sheep model of vCJD have the ability to transmit disease. Importantly, we recently established that a PRNP 129MV patient blood recipient with an asymptomatic infection and limited PrP(Sc) deposition in the spleen could readily transmit disease into mice, demonstrating the potential for peripheral infection in the absence of clinical disease. This, along with the recent appendix survey which identified 16 positive appendices in a study of 32,441 cases, underlines the importance of continued CJD surveillance and maintaining control measures already in place to protect human health. PMID- 25495407 TI - SNPs and taxane toxicity in breast cancer patients. AB - AIM: In order to identify genetic variants associated with taxanes toxicity, a panel with 47 SNPs in 20 genes involved in taxane pathways was designed. PATIENTS & METHODS: Genomic DNA of 113 breast cancer patients was analyzed (70 taking docetaxel, 43 taking paclitaxel). RESULTS: Two SNPs associated with docetaxel toxicity were identified: CYP3A4*1B with infusion-related reactions; and ERCC1 Gln504Lys with mucositis (p<=0.01). Regarding paclitaxel toxicity: CYP2C8 HapC and CYP2C8 rs1934951 were associated with anemia; and ERCC1 Gln504Lys with neuropathy (p<=0.01). CONCLUSION: Genes involved in DNA repair mechanisms and reactive oxygen species levels influence taxane toxicity in cancer patients treated with chemotherapy schemes not containing platinum. These findings could lead to better treatment selection for breast cancer patients. PMID- 25495408 TI - CYP2D6 genetic polymorphisms in Southern Mexican Mayan Lacandones and Mestizos from Chiapas. AB - AIM: In previous CYP2D6 genotyping studies in Mexican-Amerindians a very low frequency of poor metabolizers (PMs) has been reported. Moreover, ultrarapid metabolizers (UMs) status has only been analyzed in some groups from Northern Mexico. MATERIALS & METHODS: In the present study we evaluated the hypothesis of low frequency of PMs in Mexican-Amerindians in Southern Mexican populations from Chiapas (Lacandones [ML] vs Mestizos [MM]). The frequency of UMs is also reported. CYP2D6 alleles *2, *3, *4, *5, *6, *10, *17, *35 and *41 and copy number variations were analyzed in 154 ML and 100 MM healthy volunteers. RESULTS: The PM frequency was 0% in MLs and 1% in MMs, and for UMs was 2.6% in MLs and 3% in MMs. CONCLUSION: The present data support previous findings reporting a very low frequency of CYP2D6 PMs in Mexican-Amerindians. Furthermore, the predicted UM phenotype in both MMs and MLs was lower than those reported for most Mexican populations. PMID- 25495409 TI - Effects of major transporter and metabolizing enzyme gene polymorphisms on carbamazepine metabolism in Chinese patients with epilepsy. AB - AIM: The present study aimed to evaluate the effects of SNPs of major transporter and metabolizing enzyme genes on carbamazepine (CBZ) metabolism in Chinese patients with epilepsy. MATERIALS & METHODS: For 210 epileptic patients treated with CBZ as monotherapy, nine SNPs in candidate genes ABCB1, CYP3A4, CYP3A5, POR and EPHX1 were analyzed by PCR-RFLP or direct sequencing. Serum concentrations of CBZ, carbamazepine-10,11-epoxide (CBZE) and carbamazepine-10,11-trans dihydrodiol (CBZD) were determined by HPLC. Dose-adjusted concentrations of CBZ (CDRCBZ), CBZE (CDRCBZE), CBZD (CDRCBZ D) and CBZD:CBZE ratio were used as evaluation parameters for CBZ metabolism. RESULTS: The ABCB1 c.3435C>T was significantly associated with the CDR of CBZ and its major metabolites. CYP3A4*1G and CYP3A5*3 could influence CBZ metabolism, while POR*28 had no effect on it. The EPHX1 c.416A>G and c.128G>C variants were significantly associated with CBZD:CBZE ratio. CONCLUSION: Our data suggest that certain polymorphisms of major transporter and metabolizing enzyme genes could in part influence interindividual variability of CBZ metabolism in Chinese patients with epilepsy. PMID- 25495410 TI - HLA-A*02:01:01/-B*35:01:01/-C*04:01:01 haplotype associated with lamotrigine induced maculopapular exanthema in Mexican Mestizo patients. AB - AIM: Several HLA alleles have been associated with antiepileptic drugs (AEDs) induced cutaneous adverse drug reactions (cADRs) in different populations; however, this has not been investigated in Mexican Mestizos (MM). Thus, the purpose of this preliminary study was to determine the association of HLA class I alleles with AED-induced cADRs in MM patients. MATERIALS & METHODS: This case control association study included 21 MM patients with phenytoin (PHT)-, carbamazepine (CBZ)-, or lamotrigine (LTG)-induced maculopapular exanthema (MPE) or Stevens-Johnson syndrome (SJS); 31 MM patients tolerant to the same AEDs; and 225 unrelated, healthy MM volunteers. HLA class I genotyping was performed. Differences in HLA allele frequencies between AED-induced cADR patients and AED tolerant patients were assessed. Frequencies of alleles possibly associated with AED-induced cADRs in MM patients were compared with those in MM population. RESULTS: The frequency of HLA-C*08:01 allele in PHT-induced MPE was higher than that in the PHT-tolerant group (pc=0.0179) or in the MM population (pc<0.0001). For the first time, HLA-A*02:01:01/-B*35:01:01/-C*04:01:01 haplotype was associated with LTG-induced MPE (pc=0.0048 for LTG-tolerant groups and pc<0.0001 for MM population). CONCLUSION: Our data suggest the HLA-A*02:01:01/-B*35:01:01/ C*04:01:01 haplotype may be a biomarker for LTG-induced MPE and the HLA-C*08:01 allele for PHT-induced MPE. We also identified HLA-A*01:01:01 and -A*31:01:02 as candidates alleles associated with CBZ-induced MPE in MM patients. However, further investigations are necessary to confirm these findings. PMID- 25495411 TI - Evaluation of the relationship between polymorphisms in CYP2C19 and the pharmacokinetics of omeprazole, pantoprazole and rabeprazole. AB - AIM: To evaluate the possible association between polymorphisms in CYP2C19 and the pharmacokinetics of omeprazole, rabeprazole and pantoprazole. MATERIALS & METHODS: 151 healthy volunteers were evaluated for polymorphisms in the CYP2C19 gene using real-time polymerase chain reaction. Plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. RESULTS: Carriers of the *2 allele displayed poor metabolism for all the PPIs studied (around 50% decrease in clearance). Subjects with the *17 allele showed a light increase in clearance compared with *1/*1 (not significant). CONCLUSION: CYP2C19*2 is associated with decreased clearance of all the PPIs, that could be associated with higher drug efficacy. CYP2C19*17 could increase clearance of these drugs, although the effect seems small. PMID- 25495414 TI - Retrospective evaluation of the efficacy of first-line treatment of advanced gastric cancer with docetaxel and oxaliplatin. AB - The incidence rate of gastric cancer is highest in China, where 5 in 10 new cases of stomach cancer across the world are diagnosed. Even though surgical management is the treatment of choice, it is not significantly effective due to advanced stage of the disease at diagnosis and the increased chances of primary tumor recurrence and metastasis to secondary organs. First-line chemotherapy of advanced gastric cancer patients recommend oxaliplatin and docetaxel; however, not much is known about their usage in Chinese patients. Therefore we retrospectively analyzed 199 cases of advanced gastric cancer (intestinal, diffuse, and mixed types) receiving either docetaxel or oxaliplatin-based first line chemotherapy. The end-points determined were objective response rate (ORR, sum of complete and partial responses), disease control rate (DCR, sum of complete response, partial response, and stable disease), median progression-free survival (mPFS), and median overall survival (OS) time. Both docetaxel and oxaliplatin-based chemotherapy exhibited improved ORR and DCR; however, the comparison of short-term objective efficacy (ORR and DCR) was not statistically significant (p > .05) between the two groups. Our results indicated that PFS and OS of intestinal-type gastric cancer were extended compared with diffuse-type and mixed-type gastric cancer. Adverse reactions were within the control range and after symptomatic treatment were significantly ameliorated. Both docetaxel and oxaliplatin-based chemotherapy thus had a robust treatment outcome and can prospectively be used as one of the effective chemotherapy regimens for advanced gastric cancer patients in China. PMID- 25495413 TI - Combining genetic and nongenetic biomarkers to realize the promise of pharmacogenomics for inflammatory diseases. AB - Many drugs used to treat inflammatory diseases are ineffective in a substantial proportion of patients. Identifying patients that are likely to respond to specific therapies would facilitate personalized treatment strategies that could improve outcomes while reducing costs and risks of adverse events. Despite these clear benefits, there are limited examples of predictive biomarkers of drug efficacy currently implemented into clinical practice for inflammatory diseases. We review efforts to identify genetic and nongenetic biomarkers of drug response in these diseases and consider potential benefits from combining multiple sources of biological data into multifeature predictive models. PMID- 25495415 TI - Mechanism-based discovery of novel substrates of haloalkane dehalogenases using in silico screening. AB - Substrate specificity is a key feature of enzymes determining their applicability in biomaterials and biotechnologies. Experimental testing of activities with novel substrates is a time-consuming and inefficient process, typically resulting in many failures. Here, we present an experimentally validated in silico method for the discovery of novel substrates of enzymes with a known reaction mechanism. The method was developed for a model system of biotechnologically relevant enzymes, haloalkane dehalogenases. On the basis of the parametrization of six different haloalkane dehalogenases with 30 halogenated substrates, mechanism based geometric criteria for reactivity approximation were defined. These criteria were subsequently applied to the previously experimentally uncharacterized haloalkane dehalogenase DmmA. The enzyme was computationally screened against 41,366 compounds, yielding 548 structurally unique compounds as potential substrates. Eight out of 16 experimentally tested top-ranking compounds were active with DmmA, indicating a 50% success rate for the prediction of substrates. The remaining eight compounds were able to bind to the active site and inhibit enzymatic activity. These results confirmed good applicability of the method for prioritizing active compounds-true substrates and binders-for experimental testing. All validated substrates were large compounds often containing polyaromatic moieties, which have never before been considered as potential substrates for this enzyme family. Whereas four of these novel substrates were specific to DmmA, two substrates showed activity with three other tested haloalkane dehalogenases, i.e., DhaA, DbjA, and LinB. Additional validation of the developed screening strategy with the data set of over 200 known substrates of Candida antarctica lipase B confirmed its applicability for the identification of novel substrates of other biotechnologically relevant enzymes with an available tertiary structure and known reaction mechanism. PMID- 25495416 TI - Efficacy of patient-administered mechanical and/or chemical plaque control protocols in the management of peri-implant mucositis. A systematic review. AB - AIM: To systematically assess the efficacy of patient-administered mechanical and/or chemical plaque control protocols in the management of peri-implant mucositis (PM). MATERIAL AND METHODS: Randomized (RCTs) and Controlled Clinical Trials (CCTs) were identified through an electronic search of three databases complemented by manual search. Identification, screening, eligibility and inclusion of studies was performed independently by two reviewers. Studies without professional intervention or with only mechanical debridement professionally administered were included. Quality assessment was performed by means of the Cochrane Collaboration's tool for assessing risk of bias. RESULTS: Eleven RCTs with a follow-up from 3 to 24 months were included. Definition of PM was lacking or heterogeneously reported. Complete resolution of PM was not achieved in any study. One study reported 38% of patients with complete resolution of PM. Surrogate end-point outcomes of PM therapy were often reported. The choice of control interventions showed great variability. The efficacy of powered toothbrushes, a triclosan-containing toothpaste and adjunctive antiseptics remains to be established. High quality of methods and reporting was found in four studies. CONCLUSIONS: Professionally- and patient-administered mechanical plaque control alone should be considered the standard of care in the management of PM. Therapy of PM is a prerequisite for the prevention of peri implantitis. PMID- 25495417 TI - New oral anticoagulants for nonvalvular atrial fibrillation in the elderly: Limited applicability in primary care. AB - BACKGROUND: Based on the results from randomized controlled trials (RCTs), new oral anticoagulants (NOACs) seem attractive alternatives to vitamin K antagonists (VKAs) because of their effectiveness, safety, and ease of use. However, the use of NOACs in unselected elderly patients with atrial fibrillation (AF) in primary care is arguable. OBJECTIVES: To assess the evidence for the effectiveness and safety of NOACs compared with VKAs in elderly patients with nonvalvular AF in primary care. METHODS: Starting from the meta-analysis of Ruff et al. (Lancet 2014;383:955-62), we used the GRADE-approach to make a transparent and explicit judgement of the quality of evidence. RESULTS: The meta-analysis reviewed four non-inferiority RCTs, including 58 634 AF patients with an average age of 70-73 years. Inconsistency of results, indirectness of evidence, and imprecision of risk reductions resulted in downgrading of the quality of evidence available from these studies. The quality of evidence for a decrease in all-cause stroke and systemic embolism (RR: 0.81; 95%CI: 0.73-0.91) for elderly patients using NOACs compared to VKAs in routine primary care was low. The quality of evidence for a lower risk for haemorrhagic stroke (RR: 0.49; 95% CI: 0.38-0.64) and for a lower risk of intracranial bleeding (RR: 0.48; 95% CI: 0.39-0.59) was moderate. CONCLUSION: There is uncertainty about effectiveness and safety of NOACs in unselected elderly patients with AF in primary care. Therefore, the balance between benefit and harm is still unclear. For this reason, routine use of NOACs is not recommended in elderly patients in primary care. PMID- 25495412 TI - Pharmacogenomics of antimicrobial agents. AB - Antimicrobial efficacy and toxicity varies between individuals owing to multiple factors. Genetic variants that affect drug-metabolizing enzymes may influence antimicrobial pharmacokinetics and pharmacodynamics, thereby determining efficacy and/or toxicity. In addition, many severe immune-mediated reactions have been associated with HLA class I and class II genes. In the last two decades, understanding of pharmacogenomic factors that influence antimicrobial efficacy and toxicity has rapidly evolved, leading to translational success such as the routine use of HLA-B*57:01 screening to prevent abacavir hypersensitivity reactions. This article examines recent advances in the field of antimicrobial pharmacogenomics that potentially affect treatment efficacy and toxicity, and challenges that exist between pharmacogenomic discovery and translation into clinical use. PMID- 25495418 TI - An examination of the relationship between health information use and health orientation in Korean mothers: focusing on the type of health information. AB - The present study explores the relationship between mothers' health information use and health orientation regarding their children's health. Given that the online mothering community (i.e., parenting websites) is currently an important source of parenting information for mothers of young children, the present study distinguishes between informal online health information provided by mothering communities and formal online health information provided by health-related websites to test for differences. An online survey of 533 Korean mothers of children between the ages of 0 and 3 years revealed that the frequency of health related website use (i.e., formal information) was associated with mothers' health consciousness and their health information orientation toward their children's health. The frequency of mothering community use (i.e., informal information) was associated with health information orientation, but not with health consciousness. Mass media use and contact with a health care professional for health information were not related to health consciousness or health information orientation. However, mothers' education level moderated the relationship between interpersonal communication and health consciousness, and between print media use and health information orientation. Results are discussed with an emphasis on the theoretical and practical implications of our findings. PMID- 25495419 TI - In vitro reactivation of latent HIV-1 by cytostatic bis(thiosemicarbazonate) gold(III) complexes. AB - BACKGROUND: A number of cytostatic agents have been investigated for the ability to reactivate latent viral reservoirs, which is a major prerequisite for the eradication of HIV-1 infection. Two cytostatic bis(thiosemicarbazonate) gold(III) complexes (designated 1 and 2) were tested for this potential in the U1 latency model of HIV-1 infection. METHODS: Cell viability in the presence or absence of 1 and 2 was determined using a tetrazolium dye and evidence of reactivation was assessed by p24 antigen capture following exposure to a latency stimulant, phorbol myristate acetate (PMA) and or test compounds. The latency reactivation mechanism was explored by determining the effect of the complexes on protein kinase C (PKC), histone deacetylases (HDAC) and proinflammatory cytokine production. RESULTS: The CC50 of the complexes in U1 cells were 0.53 +/- 0.12 MUM for 1 and 1.0 +/- 0.4 MUM for 2. In the absence of PMA and at non toxic concentrations of 0.2 and 0.5 MUM, 1 and 2 significantly (p <= 0.02) reactivated virus in U1 cells by 2.7 and 2.3 fold respectively. In comparison, a 2.6 fold increase (p = 0.03) in viral reactivation was observed for hydroxyurea (HU), which was used as a cytostatic and latent HIV reactivation control. Viral reactivation was absent for the complexes during co-stimulation with PMA indicating the lack of an additive effect between the chemicals as well as an absence of inhibition of PMA induced HIV reactivation but for HU inhibition of the stimulant's activity was observed (p = 0.01). Complex 1 and 2 activated PKC activity by up to 32% (p < 0.05) but no significant inhibition of HDAC was observed. Increases in TNF-alpha levels suggested that the reactivation of virus by the complexes may have been due to contributions from the latter and the activation of PKC. CONCLUSION: The ethyl group structural difference between 1 and 2 seems to influence bioactivity with lower active concentrations of 1, suggesting that further structural modifications should improve specificity. The cytostatic effect of 1 and 2 and now HIV reactivation from a U1 latency model is consistent with that of the cytostatic agent, HU. These findings suggest that the complexes have a potential dual (cytostatic and reactivation) role in viral "activation/elimination". PMID- 25495420 TI - Endometriosis presenting with right side hydroureteronephrosis only: a case report. AB - INTRODUCTION: Endometriosis can be defined as the presence of endometrial glandular and stromal tissue outside the uterus. Affected sites of endometriosis can even be the urinary tract. Here, we present the case of a 30-year-old woman with right ureteral endometriosis. This case was important due to the unusual localization and no signs of the disease except for hydroureteronephrosis. CASE PRESENTATION: A 30-year-old Caucasian woman with para 2 was admitted to our department for right side flank pain, dysuria and suprapubic pain. She had no complaints of vaginal discharge, bleeding or painful menstruation. Her menstrual cycles were normal and lasting for three to four days. She did not have a history of any surgical interventions. A physical examination revealed a right side costovertebral angle and suprapubic tenderness. Laboratory test results including a complete blood count, serum biochemical analysis, urine analysis and urine culture were normal. Urinary ultrasonography showed right side hydroureteronephrosis with renal cortical thinning. We suspected a right ureteral stone obstructing the ureter and a computed tomography scan was performed. The computed tomography scan revealed similar right side hydroureteronephrosis with obstruction of the ureter. No signs of stone were observed on the scan. Retrograde pyelography and diagnostic ureterorenoscopy were performed and they showed a focal stricture with a length of approximately 3 cm at the distal ureteral part and secondary hydroureteronephrosis. Open partial ureterectomy and ureteroneocystostomy with Boari flap were performed. The pathologic specimen of her ureter demonstrated intrinsic endometriosis of the right ureter with endometrial glandular cells and stromal tissue. CONCLUSIONS: Clinicians should suspect ureteral endometriosis in premenopausal women with unilateral or bilateral distal ureteral obstruction of uncertain cause. The main goals of the treatment should be preservation of renal function, relief of obstruction and prevention of recurrence. PMID- 25495421 TI - Potential mechanisms and clinical applications of mild hypothermia and electroconvulsive therapy on refractory status epilepticus. AB - Status epilepticus (SE) is an acute and severe neurological disorder. A small number of SE cases cannot be terminated by a sufficient therapeutic dose and duration of two to three common anticonvulsant therapies. The continuing seizures often lead to poor prognosis and a higher mortality rate. Novel non-drug treatment options to terminate SE are greatly needed. Induced hypothermia and electroconvulsive therapies are used to treat SE. There are many case studies and multiple experimental investigations of these methods in the literature. This article reviews the historical evolution, mechanisms, clinical applications and adverse reactions of SE, some of which have shown that both treatments are beneficial and relatively safe. The purpose of this paper is to provide alternative treatment methods for SE. PMID- 25495422 TI - Pentacyclic antibiotics from a tidal mud flat-derived actinomycete. AB - The combination of investigating a unique source of chemically prolific bacterium with an LC/MS-based bacterial strain selection approach resulted in the discovery of two new secondary metabolites, buanmycin (1) and buanquinone (2), from the culture of a marine Streptomyces strain, which was isolated from a tidal mudflat in Buan, Republic of Korea. The carbon backbone of buanmycin (1), comprising 20 quaternary carbons out of 30 total carbons, was determined via (13)C-(13)C COSY NMR analysis after labeling 1 with (13)C by culturing the bacterium with (13)C glucose. The complete structure of 1 was confidently elucidated, primarily based on 1D and 2D NMR spectroscopic and X-ray crystallographic analysis, as that of a new pentacyclic xanthone. The absolute configuration of the alpha-methyl serine unit in 1 was established by applying the advanced Marfey's method. The structure of buanquinone (2) was determined to be a new pentacyclic quinone based on NMR and MS spectroscopic data. Buanmycin exhibited potent cytotoxicity against colorectal carcinoma cells (HCT-116) and gastric carcinoma cells (SNU-638) with submicromolar IC50 values and strongly inhibited the pathogenic Gram-negative bacterium Salmonella enterica (MIC = 0.7 MUM). In particular, buanmycin demonstrated inhibition of sortase A, which is a promising target for antibiotic discovery. PMID- 25495423 TI - Fun with maths: exploring implications of mathematical models for malaria eradication. AB - Mathematical analyses and modelling have an important role informing malaria eradication strategies. Simple mathematical approaches can answer many questions, but it is important to investigate their assumptions and to test whether simple assumptions affect the results. In this note, four examples demonstrate both the effects of model structures and assumptions and also the benefits of using a diversity of model approaches. These examples include the time to eradication, the impact of vaccine efficacy and coverage, drug programs and the effects of duration of infections and delays to treatment, and the influence of seasonality and migration coupling on disease fadeout. An excessively simple structure can miss key results, but simple mathematical approaches can still achieve key results for eradication strategy and define areas for investigation by more complex models. PMID- 25495424 TI - What is rehabilitation potential? Development of a theoretical model through the accounts of healthcare professionals working in stroke rehabilitation services. AB - INTRODUCTION: Multi-disciplinary team members predict each patient's rehabilitation potential to maximise best use of resources. A lack of underpinning theory about rehabilitation potential makes it difficult to apply this concept in clinical practice. This study theorises about rehabilitation potential drawing on everyday decision-making by Health Care Professionals (HCPs) working in stroke rehabilitation services. METHODS: A clinical scenario, checked for face validity, was used in two focus groups to explore meaning and practice around rehabilitation potential. Participants were 12 HCPs working across the stroke pathway. Groups were co-facilitated, audio-recorded and fully transcribed. Analysis paid attention to data grounded in first-hand experience, convergence within and across groups and constructed a conceptual overview of HCPs' judgements about rehabilitation potential. RESULTS: Rehabilitation potential is predicted by observations of "carry-over" and functional gain and managed differently across recovery trajectories. HCPs' responses to rehabilitation potential judgements include prioritising workload, working around the system and balancing optimism and realism. Impacts for patients are streaming of rehabilitation intensity, rationing access to rehabilitation and a shifting emphasis between management and active rehabilitation. For staff, the emotional burden of judging rehabilitation potential is significant. Current service organisation restricts opportunities for feedback on the accuracy of previous judgements. CONCLUSION: Patients should have the opportunity to demonstrate rehabilitation potential by participation in therapy. As therapy resources are limited and responses to therapy may be context-dependent, early decisions about a lack of potential should not limit longer-term opportunities for rehabilitation. Services should develop strategies to enhance the quality of judgements through feedback to HCPs of longer-term patient outcomes. Implications for Rehabilitation Rehabilitation potential is judged at the level of individual patients (rather than population-based predictive models of rehabilitation outcome), draws on different sources of often experiential knowledge, and may be less than reliable. Decisions about rehabilitation potential may have far reaching consequences for individual patients, including the withdrawal of active rehabilitation in hospital or in the community and eventual care placement. A better understanding of what people mean by rehabilitation potential by all team members, and by patients and carers, may improve the quality of joint decision making and communication. PMID- 25495425 TI - Multiple tooth loss is associated with vascular cognitive impairment in subjects with acute ischemic stroke. AB - BACKGROUND AND OBJECTIVE: Emerging evidence shows that tooth loss is associated with cognitive impairment and dementia. Vascular cognitive impairment (VCI) is a common consequence of ischemic stroke. This study investigated the association of tooth loss with VCI in patients with acute stroke. MATERIAL AND METHODS: A total of 161 subjects with acute ischemic stroke were recruited. Within 1 wk after admission, fasting blood tests were undertaken and the number of teeth present was recorded. VCI was evaluated with the Montreal Cognitive Assessment (MoCA). RESULTS: The patients with loss of >= 8 teeth exhibited significantly lower MoCA values as compared to those with loss of <= 7 teeth (13.2 +/- 6.6 vs. 17.3 +/- 6.0, p < 0.001). Multivariate logistic regression analysis showed that loss of >= 8 teeth (OR = 3.1, 95% CI: 1.2-7.9, p = 0.02) and stroke history (OR = 3.8, 95% CI: 1.1-14.1, p = 0.04) were significantly associated with VCI (MoCA score <= 20.0). CONCLUSION: Within the limitations of this study, the current findings provide the first evidence that multiple tooth loss is independently associated with VCI in patients with acute ischemic stroke. PMID- 25495426 TI - The eta-class carbonic anhydrases as drug targets for antimalarial agents. AB - INTRODUCTION: The eta-class of carbonic anhydrases (CAs, EC 4.2.1.1) was recently discovered as the sixth genetic family of this metalloenzyme superfamily, and seems to be present only in various Plasmodium species, the malaria-provoking pathogens. The present review through detailed biochemical, kinetic and phylogenetic studies afford a clear view regarding the differences between eta- and the other CA families. AREAS COVERED: In this review, the authors underlined as the eta-CAs, like alpha-, gamma- and delta-class enzymes, have the Zn(II) ion coordinated by three histidine residues and a water molecule. They seem to be more closely related to the alpha-CAs, but there are notable differences between them, such as the lack of the proton shuttle residue (His64) and gatekeeper residues, Glu106 and Thr199 in the eta-CAs, which are conserved in all alpha-CAs. EXPERT OPINION: Plasmodium falciparum eta-CA showed a moderate but significant activity for the CO2 hydration reaction, with a kcat of 1.4 * 10(5)s(-1) and a kcat/Km of 5.4 * 10(6) M(-1) * s(-1). Several inhibition studies with anions and sulfonamides/sulfamates, allowed the identification of interesting lead compounds. The discovery of eta-CA-specific inhibitors may lead to novel such agents with a new mechanism of action. PMID- 25495427 TI - Receptor tyrosine kinase profiles and human papillomavirus status in oropharyngeal squamous cell carcinoma. AB - BACKGROUND: Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OSCCs) are two distinct entities. We defined the molecular profiles of druggable receptor tyrosine kinases (RTKs) in both groups. MATERIALS AND METHODS: E5 expression and RTK alterations were studied in 17 HPV positive and 59 HPV-negative formalin-fixed OSCCs. RTK activation was explored in further 12 frozen OSCCs. RESULTS: The HPV-positive OSCCs showed E5 expression and 33.3% expressed low level of HER2. The HPV-negative OSCCs showed HER2 expression (31.2%), increased HER2 gene copy number (46.51%, P = 0.045) and HER2 activation through HER2/EGFR heterodimerisation; HER3 (51.06%, P = 0.008) and neuregulin (65.63%; P = 0.03) expression, HER3 activation and HER3/EGFR heterodimerisation; and increased IGF-1R copy number (40.50%, P = 0.021), high IGF-1R cDNA values (P = 0.002), IGF-1R activation and expression of IGF1/2 and amphiregulin. PI3KCA mutations/expression/increased gene copy number and PTEN mutations were found in both groups, whereas PTEN gene loss was only observed in the HPV-positive cases. CONCLUSION: Human papillomavirus-positive and HPV-negative OSCC showed different RTK profiles. In HPV-positive cases, it would be interesting to study the expression of E5, which may modulate EGFR turnover and activate VEGF and PDGFRbeta. In HPV-negative cases, HER3 may be a promising druggable biomarker that deserves further investigation. PI3KCA and PTEN alterations encourage the promising clinical evaluation of PI3K/mTOR inhibitor activity in OSCC, particularly in HPV-positive/PI3KCA-mutated OSCCs because they may be driven by PI3KCA mutation alone. PMID- 25495428 TI - Development and assessment of multiplex high resolution melting assay as a tool for rapid single-tube identification of five Brucella species. AB - BACKGROUND: The zoonosis brucellosis causes economically significant reproductive problems in livestock and potentially debilitating disease of humans. Although the causative agent, organisms from the genus Brucella, can be differentiated into a number of species based on phenotypic characteristics, there are also significant differences in genotype that are concordant with individual species. This paper describes the development of a five target multiplex assay to identify five terrestrial Brucella species using real-time polymerase chain reaction (PCR) and subsequent high resolution melt curve analysis. This technology offers a robust and cost effective alternative to previously described hydrolysis-probe Single Nucleotide Polymorphism (SNP)-based species defining assays. RESULTS: Through the use of Brucella whole genome sequencing five species defining SNPs were identified. Individual HRM assays were developed to these target these changes and, following optimisation of primer concentrations, it was possible to multiplex all five assays in a single tube. In a validation exercise using a panel of 135 Brucella strains of terrestrial and marine origin, it was possible to distinguish the five target species from the other species within this panel. CONCLUSION: The HRM multiplex offers a number of diagnostic advantages over previously described SNP-based typing approaches. Further, and uniquely for HRM, the successful multiplexing of five assays in a single tube allowing differentiation of five Brucella species in the diagnostic laboratory in a cost effective and timely manner is described. However there are possible limitations to using this platform on DNA extractions direct from clinical material. PMID- 25495429 TI - Efficacy, effectiveness and side effects of medications used to prevent fractures. AB - There is an increasing number of effective therapies for fracture prevention in adults at risk of osteoporosis. However, shortcomings in the evidence underpinning our management of osteoporosis still exist. Evidence of antifracture efficacy in the groups of patients who most commonly use calcium and vitamin D supplements is lacking, the safety of calcium supplements is in doubt, and the safety and efficacy of high doses of vitamin D give cause for concern. Alendronate, risedronate, zoledronate and denosumab have been shown to prevent spine, nonspine and hip fractures; in addition, teriparatide and strontium ranelate prevent both spine and nonspine fractures, and raloxifene and ibandronate prevent spine fractures. However, most trials provide little information regarding long-term efficacy or safety. A particular concern at present is the possibility that oral bisphosphonates might cause atypical femoral fractures. Observational data suggest that the incidence of this type of fracture increases steeply with duration of bisphosphonate use, resulting in concern that the benefit-risk balance may become negative in the long term, particularly in patients in whom the osteoporotic fracture risk is not high. Therefore, reappraisal of ongoing use of bisphosphonates after about 5 years is endorsed by expert consensus, and 'drug holidays' should be considered at this time. Further studies are needed to guide clinical practice in this area. PMID- 25495430 TI - Mental Health Nurses' Attitudes and Perceived Self-Efficacy Toward Inpatient Aggression: A Cross-Sectional Study of Associations With Nurse-Related Characteristics. AB - PURPOSE: To explore mental health nurses' attitude and self-efficacy to adult inpatient aggression, and to explore the association with nurse-related characteristics. DESIGN AND METHOD: Cross-sectional study in a sample of 219 mental health nurses in nine psychiatric hospitals, with stepwise linear regression analysis to detect predictive models. FINDINGS: Female and less experienced nurses were less likely to blame patients for their behavior. Gender, burnout, secondary traumatic stress, and compassion satisfaction accounted for 26.2% of the variability in mental health nurses' self-efficacy toward aggression. PRACTICE IMPLICATIONS: There needs to be attention to professional quality of life for mental health nurses, to provide them with of self-efficacy and a positive attitude toward coping with aggression. PMID- 25495431 TI - Clearing the air: improving smoke-free policy compliance at the national oncology hospital in Armenia. AB - BACKGROUND: Smoke-free policies shown to reduce population exposure to secondhand smoke (SHS) are the norm in hospitals in many countries around the world. Armenia, a transition economy in the South Caucasus, has one of the highest male smoking rates in the European region. Although smoking in healthcare facilities has been banned since 2005, compliance with this ban has been poor due to lack of implementation and enforcement mechanisms and social acceptability of smoking. The study aimed to develop and test a model intervention to address the lack of compliance with the de jure smoking ban. The national oncology hospital was chosen as the intervention site. METHODS: This study used employee surveys and objective measurements of respirable particles (PM2.5) and air nicotine as markers of indoor air pollution before and after the intervention. The intervention developed in partnership with the hospital staff included an awareness campaign on SHS hazards, creation of no-smoking environment and building institutional capacity through training of nursing personnel on basics of tobacco control. The survey analysis included paired t-test and McNemar's test. The log-transformed air nicotine and PM2.5 data were analyzed using paired t-test. RESULTS: The survey showed significant improvement in the perceived quality of indoor air, reduced worksite exposure to SHS and increased employees' awareness of the smoke-free policy. The number of employees reporting compliance with the hospital smoke-free policy increased from 36.0% to 71.9% (p < 0.001). The overall indoor PM2.5 concentration decreased from 222 MUg/m3 GM (95% CI = 216 229) to 112 MUg/m3 GM (95% CI = 99-127). The overall air nicotine level reduced from 0.59 MUg/ m3 GM (95% CI = 0.38-0.91) to 0.48 MUg/ m3 GM (95% CI = 0.25 0.93). CONCLUSIONS: The three-faceted intervention developed and implemented in partnership with the hospital administration and staff was effective in reducing worksite SHS exposure in the hospital. This model can facilitate a tangible improvement in compliance with smoke-free policies as the first step toward a smoke-free hospital and serve as a model for similar settings in transition countries such Armenia that have failed to implement the adopted smoke-free policies. PMID- 25495434 TI - Personality disorders as an expression of the dimensional polarity in personality development in late adulthood women. AB - Relationships between Axis II personality disorders and Sidney Blatt constructs of dependency and self-criticism were explored in a late adulthood women sample. The sample consisted of 102 women (M = 72.07 years of age, SD = 7.04) who were administered two measures, the Personality Diagnostic Questionnaire-4+ and the Depressive Experiences Questionnaire. The histrionic, dependent, and obsessive compulsive personality disorder scales are shown to be significant predictors of dependency, and the narcissistic, borderline, and avoidant scales are significant predictors of self-criticism. The application of a dimensional interpersonal approach to psychopathology is discussed. PMID- 25495433 TI - Potential switchable circularly polarized luminescence from chiral cyclometalated platinum(II) complexes. AB - A series of chiral cyclometalated platinum(II) complexes, [Pt((-)-L1)(Dmpi)]Cl (( )-1), [Pt((+)-L1)(Dmpi)]Cl ((+)-1), [Pt((-)-L2)(Dmpi)]Cl ((-)-2), [Pt((+) L2)(Dmpi)]Cl ((+)-2), [Pt3((-)-L2)2(Dmpi)4](ClO4)4 ((-)-3), and [Pt3((+) L2)2(Dmpi)4](ClO4)4 ((+)-3) [(-)-L1 = (-)-4,5-pinene-6'-phenyl-2,2'-bipyridine, (+)-L1 = (+)-4,5-pinene-6'-phenyl-2,2'-bipyridine), (-)-L2 = (-)-1,3-bis(2-(4,5 pinene)pyridyl)benzene, (+)-L2 = (+)-1,3-bis(2-(4,5-pinene)pyridyl)benzene, Dmpi = 2,6-dimethylphenyl isocyanide], have been designed and synthesized. In aqueous solutions, (-)-1 and (+)-1 aggregate into one-dimensional helical chain structures through Pt...Pt, pi-pi, and hydrophobic-hydrophobic interactions. (-) 3 and (+)-3 represent a novel helical structure with Pt-Pt bonds. The formation of helical structures results in enhanced and distinct chiroptical properties as evidenced by circular dichroism spectra. Circularly polarized luminescence (CPL) was observed from the aggregates of (-)-1 and (+)-1 in water, as well as (-)-3 and (+)-3 in dichloromethane. The CPL activity can be switched reversibly (for ( )-1 and (+)-1) or irreversibly (for (-)-3 and (+)-3) by varying the temperature. PMID- 25495432 TI - American Geriatrics Society abstracted clinical practice guideline for postoperative delirium in older adults. AB - The abstracted set of recommendations presented here provides essential guidance both on the prevention of postoperative delirium in older patients at risk of delirium and on the treatment of older surgical patients with delirium, and is based on the 2014 American Geriatrics Society (AGS) Guideline. The full version of the guideline, American Geriatrics Society Clinical Practice Guideline for Postoperative Delirium in Older Adults is available at the website of the AGS. The overall aims of the study were twofold: first, to present nonpharmacologic and pharmacologic interventions that should be implemented perioperatively for the prevention of postoperative delirium in older adults; and second, to present nonpharmacologic and pharmacologic interventions that should be implemented perioperatively for the treatment of postoperative delirium in older adults. Prevention recommendations focused on primary prevention (i.e., preventing delirium before it occurs) in patients who are at risk for postoperative delirium (e.g., those identified as moderate-to-high risk based on previous risk stratification models such as the National Institute for Health and Care Excellence (NICE) guidelines, Delirium: Diagnosis, Prevention and Management. Clinical Guideline 103; London (UK): 2010 July 29). For management of delirium, the goals of this guideline are to decrease delirium severity and duration, ensure patient safety and improve outcomes. PMID- 25495435 TI - "Opening an emotional dimension in me": changes in emotional reactivity and emotion regulation in a case of executive impairment after left fronto-parietal damage. AB - Dysexecutive impairment is a common problem after brain injury, particularly after damage to the lateral surface of the frontal lobes. There is a large literature describing the cognitive deficits associated with executive impairment after dorsolateral damage; however, little is known about its impact on emotional functioning. This case study describes changes in a 72-year-old man (Professor F) who became markedly dysexecutive after a left fron-to-parietal stroke. Professor F's case is remarkable in that, despite exhibiting typical executive impairments, abstraction and working memory capacities were spared. Such preservation of insight-related capacities allowed him to offer a detailed account of his emotional changes. Quantitative and qualitative tools were used to explore changes in several well-known emotional processes. The results suggest that Professor F's two main emotional changes were in the domain of emotional reactivity (increased experience of both positive and negative emotions) and emotion regulation (down-regulation of sadness). Professor F related both changes to difficulties in his thinking process, especially a difficulty generating and manipulating thoughts during moments of negative arousal. These results are discussed in relation to the literature on executive function and emotion regulation. The relevance of these findings for neuropsychological rehabilitation and for the debate on the neural basis of emotional processes is addressed. PMID- 25495436 TI - Group psychotherapy's impact on trust in veterans with PTSD: a pilot study. AB - Interpersonal trust is fundamental for the recovery of trauma survivors and the effectiveness of group psychotherapy. Yet there is limited research on the relationship between interpersonal trust and group psychotherapy. Twenty-one male Vietnam combat veterans with posttraumatic stress disorder (PTSD) (6 in a long term process group [LTP], 10 in a short-term cognitive processing therapy group [CPT], and 5 treatment-as-usual controls) were evaluated before and after group psychotherapy using the Posttraumatic Stress Disorder Checklist-Military Version (PCL-M) and an in-vivo measure of interpersonal trust, the Iterated Trust Game. Three (14.3%) of the veterans were African American, 9 were Caucasian (42.9%), and 9 were Hispanic (42.9%); they averaged 61.9 years of age (SD = 1.8 years). Change in PCL-M scores differed by group (controls: -1.0 +/- 3.7; CPT: -15.5 +/- 6.8; LTP: -1.3 +/- 12.2; p = .003). CPT group subjects improved more than controls (p < .001) and trended toward more improvement than the LTP group (p = .081). Members of the LTP group, compared to nonprocess group participants, showed greater initial (p = .042), and posttherapy trust (p = .003). Posttreatment, interpersonal trust was significantly higher in the LTP than the CPT group (p < .001). These results suggest that CPT treatment may be better than LTP treatment for improving PTSD symptoms, but LTP therapy may be better than CPT therapy for improving interpersonal trust in veterans with PTSD. They suggest important roles for both group treatments and point to the value of interpersonal trust in successful recovery from PTSD. PMID- 25495437 TI - Determining adolescents' suitability for inpatient psychotherapy: utility of the clinician-rated Readiness for Inpatient Psychotherapy Scale with an adolescent inpatient sample. AB - Growing economic pressure on inpatient services for adolescents has resulted in fewer clinicians to provide individual psychotherapy. As a result, inpatient treatment trends have favored group psychotherapy modalities and psychopharmacological interventions. Currently, no clinician-rated measures exist to assist clinicians in determining who would be able to better utilize individual psychotherapy on inpatient units. The current study sought to demonstrate the utility of the Readiness for Inpatient Psychotherapy Scale with an adolescent inpatient sample. This study also used the RIPS as it is intended to be used in everyday practice. Results from the authors' analyses reveal that the RIPS demonstrates good psychometrics and interrater reliability, as well as construct validity. PMID- 25495439 TI - Membrane interface probe protocol for contaminants in low-permeability zones. PMID- 25495440 TI - Spatiotemporal analysis of particulate air pollution and ischemic heart disease mortality in Beijing, China. AB - BACKGROUND: Few studies have used spatially resolved ambient particulate matter with an aerodynamic diameter of <10 MUm (PM10) to examine the impact of PM10 on ischemic heart disease (IHD) mortality in China. The aim of our study is to evaluate the short-term effects of PM10 concentrations on IHD mortality by means of spatiotemporal analysis approach. METHODS: We collected daily data on air pollution, weather conditions and IHD mortality in Beijing, China during 2008 and 2009. Ordinary kriging (OK) was used to interpolate daily PM10 concentrations at the centroid of 287 township-level areas based on 27 monitoring sites covering the whole city. A generalized additive mixed model was used to estimate quantitatively the impact of spatially resolved PM10 on the IHD mortality. The co effects of the seasons, gender and age were studied in a stratified analysis. Generalized additive model was used to evaluate the effects of averaged PM10 concentration as well. RESULTS: The averaged spatially resolved PM10 concentration at 287 township-level areas was 120.3 +/- 78.1 MUg/m3. Ambient PM10 concentration was associated with IHD mortality in spatiotemporal analysis and the strongest effects were identified for the 2-day average. A 10 MUg/m3 increase in PM10 was associated with an increase of 0.33% (95% confidence intervals: 0.13%, 0.52%) in daily IHD mortality. The effect estimates using spatially resolved PM10 were larger than that using averaged PM10. The seasonal stratification analysis showed that PM10 had the statistically stronger effects on IHD mortality in summer than that in the other seasons. Males and older people demonstrated the larger response to PM10 exposure. CONCLUSIONS: Our results suggest that short-term exposure to particulate air pollution is associated with increased IHD mortality. Spatial variation should be considered for assessing the impacts of particulate air pollution on mortality. PMID- 25495441 TI - Emulsion PCR significantly improves nonequilibrium capillary electrophoresis of equilibrium mixtures-based aptamer selection: allowing for efficient and rapid selection of aptamer to unmodified ABH2 protein. AB - Nonequilibrium capillary electrophoresis of equilibrium mixtures (NECEEM), a homogeneous approach to select DNA aptamers, is among the most efficient partitioning techniques. In contrast with surface-based systematic evolution of ligands by exponential enrichment (SELEX) approaches, the ability of NECEEM to select aptamers to unmodified proteins in solution is preferable for identifying aptamers for eventual in vivo use. The high stringency and low sample volumes of NECEEM, although generally beneficial, can result in binding of very few aptamers, requiring highly efficient amplification to propagate them. When amplified with standard PCR, detectable library enrichment can fail due to the fast conversion of the aptamers into byproducts and preferential amplification of nonbinders. As an alternative, we proposed the use of emulsion PCR (ePCR), which is known to reduce byproduct formation, as a PCR mode for coupling with NECEEM partitioning. For the first time, we tested the advantages of ePCR in NECEEM based aptamer selection to a medically relevant DNA repair enzyme, ABH2. We report that the combination of ePCR with NECEEM allowed for the selection of aptamers in the first three rounds of SELEX, while SELEX with conventional PCR failed in a number of attempts. Selected aptamers to an unmodified ABH2 protein have potential use in diagnostics and as leads for anticancer cotherapies, used as enhancements of alkylating agents in chemotherapy. PMID- 25495442 TI - Categorizer: a tool to categorize genes into user-defined biological groups based on semantic similarity. AB - BACKGROUND: Communalities between large sets of genes obtained from high throughput experiments are often identified by searching for enrichments of genes with the same Gene Ontology (GO) annotations. The GO analysis tools used for these enrichment analyses assume that GO terms are independent and the semantic distances between all parent-child terms are identical, which is not true in a biological sense. In addition these tools output lists of often redundant or too specific GO terms, which are difficult to interpret in the context of the biological question investigated by the user. Therefore, there is a demand for a robust and reliable method for gene categorization and enrichment analysis. RESULTS: We have developed Categorizer, a tool that classifies genes into user defined groups (categories) and calculates p-values for the enrichment of the categories. Categorizer identifies the biologically best-fit category for each gene by taking advantage of a specialized semantic similarity measure for GO terms. We demonstrate that Categorizer provides improved categorization and enrichment results of genetic modifiers of Huntington's disease compared to a classical GO Slim-based approach or categorizations using other semantic similarity measures. CONCLUSION: Categorizer enables more accurate categorizations of genes than currently available methods. This new tool will help experimental and computational biologists analyzing genomic and proteomic data according to their specific needs in a more reliable manner. PMID- 25495443 TI - Relapse of acute lymphoblastic leukaemia (ALL). PMID- 25495444 TI - Histological and immunohistochemical characterization of the inflammatory and glial cells in the central nervous system of goat fetuses and adult male goats naturally infected with Neospora caninum. AB - BACKGROUND: Neospora caninum is an apicomplexan protozoan that is considered one of the main agents responsible for abortion in ruminants. The lesions found in the central nervous system (CNS) of aborted fetuses show multifocal necrosis, gliosis, and perivascular cuffs of mononuclear cells, but the inflammatory and glial cells have not been immunophenotypically characterized. The lesions in the CNS of infected adult animals have rarely been described. Therefore, in this study, we characterized the lesions, the immunophenotypes of the inflammatory and glial cells and the expression of MHC-II and PCNA in the CNS of goats infected with N. caninum. The CNS of eight aborted fetuses and six adult male goats naturally infected with N. caninum were analyzed with lectin histochemistry (RCA1) and immunohistochemistry (with anti-CD3, -CD79alpha, -GFAP, -MHC-II, and PCNA antibodies). All animals were the offspring of dams naturally infected with N. caninum. RESULTS: The microscopic lesions in the CNS of the aborted fetuses consisted of perivascular cuffs composed mainly of macrophages (RCA1(+)), rare T lymphocytes (CD3(+)), and rare B lymphocytes (CD79alpha(+)). Multifocal necrosis surrounded by astrocytes (GFAP(+)), gliosis composed predominantly of monocytic lineage cells (macrophages and microglia, RCA1(+)), and the cysts of N. caninum, related (or not) to the lesions were present. Similar lesions were found in four of the six male goats, and multinucleate giant cells related to focal gliosis were also found in three adult goats. Anti-GFAP immunostaining showed astrocytes characterizing areas of glial scarring. Cysts of N. caninum were found in three adult male goats. The presence of N. caninum was evaluated with histopathology, immunohistochemistry, and PCR. Immunohistochemistry demonstrated anti-PCNA labeling of macrophages and microglia in the perivascular cuffs and the expression of MHC-II by microglia and endothelial cells in the CNS of the aborted fetuses and adult male goats. CONCLUSIONS: Macrophages and microglia were the predominant inflammatory cells in the CNS of aborted fetuses and healthy adult male goats infected with N. caninum. Activated astrocytes were mainly associated with inflamed areas, suggesting that astrocytes were involved in the resolution of the lesions. PMID- 25495445 TI - Huntington's Disease (HD): Neurodegeneration of Brodmann's Primary Visual Area 17 (BA17). AB - Huntington's disease (HD), an autosomal dominantly inherited polyglutamine or CAG repeat disease along with somatomotor, oculomotor, psychiatric and cognitive symptoms, presents clinically with impairments of elementary and complex visual functions as well as altered visual-evoked potentials (VEPs). Previous volumetric and pathoanatomical post-mortem investigations pointed to an involvement of Brodmann's primary visual area 17 (BA17) in HD. Because the involvement of BA17 could be interpreted as an early onset brain neurodegeneration, we further characterized this potential primary cortical site of HD-related neurodegeneration neuropathologically and performed an unbiased estimation of the absolute nerve cell number in thick gallocyanin-stained frontoparallel tissue sections through the striate area of seven control individuals and seven HD patients using Cavalieri's principle for volume and the optical disector for nerve and glial cell density estimations. This investigation showed a reduction of the estimated absolute nerve cell number of BA17 in the HD patients (71,044,037 +/- 12,740,515 nerve cells) of 32% in comparison with the control individuals (104,075,067 +/- 9,424,491 nerve cells) (Mann-Whitney U-test; P < 0.001). Additional pathoanatomical studies showed that nerve cell loss was most prominent in the outer pyramidal layer III, the inner granular layers IVa and IVc as well as in the multiform layer VI of BA17 of the HD patients. Our neuropathological results in BA17 confirm and extend previous post-mortem, biochemical and in vivo neuroradiological HD findings and offer suitable explanations for the elementary and complex visual dysfunctions, as well as for the altered VEP observed in HD patients. PMID- 25495450 TI - MPAgenomics: an R package for multi-patient analysis of genomic markers. AB - BACKGROUND: Last generations of Single Nucleotide Polymorphism (SNP) arrays allow to study copy-number variations in addition to genotyping measures. RESULTS: MPAgenomics, standing for multi-patient analysis (MPA) of genomic markers, is an R-package devoted to: (i) efficient segmentation and (ii) selection of genomic markers from multi-patient copy number and SNP data profiles. It provides wrappers from commonly used packages to streamline their repeated (sometimes difficult) manipulation, offering an easy-to-use pipeline for beginners in R.The segmentation of successive multiple profiles (finding losses and gains) is performed with an automatic choice of parameters involved in the wrapped packages. Considering multiple profiles in the same time, MPAgenomics wraps efficient penalized regression methods to select relevant markers associated with a given outcome. CONCLUSIONS: MPAgenomics provides an easy tool to analyze data from SNP arrays in R. The R-package MPAgenomics is available on CRAN. PMID- 25495451 TI - Practices and determinants of delivery by skilled birth attendants in Bangladesh. AB - INTRODUCTION: Utilization of Skilled Birth Attendants (SBAs) at birth is low (20%) in Bangladesh. Birth attendance by SBAs is considered as the "single most important factor in preventing maternal deaths". This paper examined the practices and determinants of delivery by SBAs in rural Bangladesh. METHODS: The data come from the post-intervention survey of a cluster-randomized community controlled trial conducted to evaluate the impact of limited post-natal care (PNC) services on healthcare seeking behavior of women with a recent live birth in rural Bangladesh (n = 702). Multivariable logistic regression model was used to identify the potential determinants of delivery by SBAs. RESULTS: The respondents were aged between 16 and 45, with the mean age of 24.41 (+/- 5.03) years. Approximately one-third (30.06%) of the women had their last delivery by SBAs. Maternal occupation, parity, complications during pregnancy and antenatal checkup (ANC) by SBAs were the significant determinants of delivery by SBAs. Women who took antenatal care by SBAs were 2.62 times as likely (95% CI: 1.66, 4.14; p < 0.001) to have their delivery conducted by SBAs compared to those who did not, after adjusting for other covariates. CONCLUSION: Our findings suggest that ANC by SBAs and complications during pregnancies are significant determinants of delivery by SBAs. Measure should be in place to promote antenatal checkup by SBAs to increase utilization of SBAs at birth in line with achieving the Millennium Development Goal-5. Future research should focus in exploring the unmet need for, and potential barriers in, the utilization of delivery by SBAs. PMID- 25495452 TI - Oxidative nucleophilic cyclization of 2-alkynylanilines with thiophenols under metal-free conditions. AB - An oxidative nucleophilic cyclization of 2-alkynylanilines with thiophenols under metal-free conditions was developed. The one-pot two-step reaction involves a PhI(OAc)2-mediated oxidative dearomatization and a Bronsted acid promoted nucleophilic cyclization. DFT calculations were performed to understand the reaction pathway. PMID- 25495453 TI - Neurobehavioural assessment: a useful component of holistic care in single-suture craniosynostosis. PMID- 25495454 TI - Production of cis-11-eicosenoic acid by Mortierella fungi. AB - AIM: To find cis-11-eicosenoic acid (20:1omega9, EA)-producing micro-organisms. METHODS AND RESULTS: We found EA-producing fungi by screening about 300 fungal strains and identified a major fatty acid accumulated in the Mortierella fungi as EA by means of GC-MS analysis. In particular, Mortierella chlamydospora CBS 529.75 produced a high amount of EA (36.3 mg g(-1) of dried cells) on cultivation at 28 degrees C for 4 days and then at 12 degrees C for 3 days. In the result of lipid analysis, most of the EA was a component of triacylglycerols, not phospholipids. CONCLUSION: We found that M. chlamydospora CBS 529.75 was the best producer for the microbial production of EA. SIGNIFICANCE AND IMPACT OF THE STUDY: EA is beneficial as a raw material for medical supplies and a moisturizing component of cosmetic creams. This is the first report of microbial production of EA. PMID- 25495455 TI - Cardiovascular autonomic dysfunction and oxidative stress induced by fructose overload in an experimental model of hypertension and menopause. AB - BACKGROUND: Metabolic syndrome is characterized by the association of 3 or more risk factors, including: abdominal obesity associated with an excess of abdominal fat, insulin resistance, type 2 diabetes, dyslipidemia and hypertension. Moreover, the prevalence of hypertension and metabolic dysfunctions sharply increases after the menopause. However, the mechanisms involved in these changes are not well understood. Thus, the aim of this study was to assess the effects of fructose overload on cardiovascular autonomic modulation, inflammation and cardiac oxidative stress in an experimental model of hypertension and menopause. METHODS: Female SHR rats were divided into (n = 8/group): hypertensive (H), hypertensive ovariectomized (HO) and hypertensive ovariectomized undergoing fructose overload (100 g/L in drinking water) (FHO). Arterial pressure (AP) signals were directly recorded. Cardiac autonomic modulation was evaluated by spectral analysis. Oxidative stress was evaluated in cardiac tissue. RESULTS: AP was higher in the FHO group when compared to the other groups. Fructose overload promoted an increase in body and fat weight, triglyceride concentration and a reduction in insulin sensitivity. IL-10 was reduced in the FHO group when compared to the H group. TNF-alpha was higher in the FHO when compared to all other groups. Lipoperoxidation was higher and glutathione redox balance was reduced in the FHO group when compared to other groups, an indication of increased oxidative stress. A negative correlation was found between IL-10 and adipose tissue. CONCLUSION: Fructose overload promoted an impairment in cardiac autonomic modulation associated with inflammation and oxidative stress in hypertensive rats undergoing ovarian hormone deprivation. PMID- 25495457 TI - Generation of suppressive blood cells for control of allograft rejection. AB - Our previous studies in rats showed that incubation of monocytic dendritic cells (DCs) with the chemotherapeutic drug mitomycin C (MMC) renders the cells immunosuppressive. Donor-derived MMC-DCs injected into the recipient prior to transplantation prolonged heart allograft survival. Although the generation of DCs is labour-intensive and time-consuming, peripheral blood mononuclear cells (PBMCs) can be easily harvested. In the present study, we analyse under which conditions DCs can be replaced by PBMCs and examine their mode of action. When injected into rats, MMC-incubated donor PBMCs (MICs) strongly prolonged heart allograft survival. Removal of monocytes from PBMCs completely abrogated their suppressive effect, indicating that monocytes are the active cell population. Suppression of rejection was donor-specific. The injected MICs migrated into peripheral lymphoid organs and led to an increased number of regulatory T-cells (Tregs) expressing cluster of differentiation (CD) markers CD4 and CD25 and forkhead box protein 3 (FoxP3). Tolerance could be transferred to syngeneic recipients with blood or spleen cells. Depletion of Tregs from tolerogenic cells abrogated their suppressive effect, arguing for mediation of immunosuppression by CD4+CD25+FoxP3+ Tregs. Donor-derived MICs also prolonged kidney allograft survival in pigs. MICs generated from donor monocytes were applied for the first time in humans in a patient suffering from therapy-resistant rejection of a haploidentical stem cell transplant. We describe, in the present paper, a simple method for in vitro generation of suppressor blood cells for potential use in clinical organ transplantation. Although the case report does not allow us to draw any conclusion about their therapeutic effectiveness, it shows that MICs can be easily generated and applied in humans. PMID- 25495458 TI - Understanding the thermostability and activity of Bacillus subtilis lipase mutants: insights from molecular dynamics simulations. AB - Improving the thermostability of industrial enzymes is an important protein engineering challenge. Point mutations, induced to increase thermostability, affect the structure and dynamics of the target protein in several ways and thus can also affect its activity. There appears to be no general rules for improving the thermostabilty of enzymes without adversely affecting their enzymatic activity. We report MD simulations, of wild type Bacillus subtilis lipase (WT) and its six progressively thermostable mutants (2M, 3M, 4M, 6M, 9M, and 12M), performed at different temperatures, to address this issue. Less thermostable mutants (LTMs), 2M to 6M, show WT-like dynamics at all simulation temperatures. However, the two more thermostable mutants (MTMs) show the required flexibility at appropriate temperature ranges and maintain conformational stability at high temperature. They show a deep and rugged free-energy landscape, confining them within a near-native conformational space by conserving noncovalent interactions, and thus protecting them from possible aggregation. In contrast, the LTMs having marginally higher thermostabilities than WT show greater probabilities of accessing non-native conformations, which, due to aggregation, have reduced possibilities of reverting to their respective native states under refolding conditions. Our analysis indicates the possibility of nonadditive effects of point mutations on the conformational stability of LTMs. PMID- 25495456 TI - Nucleosome structure and function. PMID- 25495460 TI - Counseling psychology trainees' experiences with debt stress: a mixed methods examination. AB - Financial debt accrued by graduate psychology students has increased in recent years and is a chief concern among psychology trainees (El-Ghoroury, Galper, Sawaqdeh, & Bufka, 2012). This study examined debt stress among counseling psychology trainees using a complementary mixed methods research design. Qualitative analyses (N = 11) using the consensual qualitative research method (CQR; Hill, Thompson, & Williams, 1997; Hill et al., 2005) revealed six domains, 15 categories, and 34 subcategories. Domains included social class contributions, institutional contributions, long-term effects, coping mechanisms, personal relationships, and effect on well-being. The transactional model of stress and coping (Lazarus & Folkman, 1984) and social class worldview model (Liu, Soleck, Hopps, Dunston, & Pickett, 2004) guided quantitative analyses. Results of a path analysis (N = 285) indicated total debt and subjective social class were significant predictors of debt stress and that the relationship between debt stress and psychological distress was mediated by avoidant coping. Avoidant coping also moderated the association between debt stress and psychological distress. Results are discussed in relation to professional training and the career development of counseling psychology trainees. PMID- 25495459 TI - Use of a DVD to provide dietary and lifestyle information to pregnant women who are overweight or obese: a nested randomised trial. AB - BACKGROUND: We conducted a nested randomised trial to evaluate the effect of an educational DVD, providing information about healthy food choices and exercise during pregnancy, on diet and physical activity, among pregnant women who were overweight or obese. METHODS: We conducted a nested randomised trial within the context of the LIMIT randomised trial. Women were eligible with a singleton pregnancy between 10 and 20 weeks gestation, and body mass index at the time of their first antenatal appointment of >=25 kg/m(2). All women who were randomised to the Lifestyle Advice Group of the LIMIT trial received a series of consultations with both research dieticians and research assistants, in addition to standard written dietary and exercise materials (Standard Materials Group). Women randomised to the DVD Group received the same consultations and written materials, and additionally received an educational DVD (DVD Group). The primary study outcome was the Healthy Eating Index. Other study outcomes included physical activity, and gestational weight gain. Women completed a qualitative evaluation of all the materials provided. RESULTS: 1,108 women in the LIMIT Lifestyle Advice Group participated in the nested trial, with 543 women randomised to the DVD Group, and 565 women to the Standard Materials Group. Women who received the DVD compared with those who did not, had a higher mean Healthy Eating Index at 36 weeks gestation (73.6 vs 72.3; adjusted mean difference 1.2; 95% CI 0.2 to 2.3; p = 0.02), but not at 28 weeks gestation (73.2 vs 73.5; adjusted mean difference -0.1; 95% CI -1.1 to 0.9; p = 0.82). There were no statistically significant differences in physical activity or total gestational weight gain. While most women evaluated the materials positively, frequency of utilisation was poor. CONCLUSIONS: Ongoing attention to the delivery of information is required, particularly with the increased use and availability of digital and multi-media interactive technologies. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12607000161426. PMID- 25495461 TI - Health and quality of life outcomes. PMID- 25495464 TI - DNA Binding and Anticancer Activity of Novel Cyclometalated Platinum (II) Complexes. AB - This study describes anticancer activity and DNA binding properties of two cyclometalated platinum (II) complexes with non-leaving lipophilic ligands; deperotonated 2-phenylpryidine (ppy): C1 and deperotonated benzo[h]quinolone (bhq): C2. Both complexes demonstrate significant anticancer activity and were capable to stimulate Caspase-III activity in Jurkat cancer cells. The results of Acridine orange/Ethidium bromide(AO/EtB), along with those of Caspase-III activity suggest that these complexes can induce apoptosis in the cancer cells. Moreover, C1 with flexible chemical structure indicates considerably higher anticancer activity than C2 which possesses a higher structural rigidity. Additionally, C2 represents a complex which is in part inducing cancer cell death due to the cell injury (necrosis). The absorption spectra of DNA demonstrate a hypochromic effect in the presence of increasing concentration of these complexes, reflecting DNA structural alteration after drug binding. Also, EtB competition assay and docking results revealed partial intercalation and DNA groove binding for the metal complexes. Overall, from the therapeutic point of view, ppy containing platinum complex (C1) is a favored anticancer agent, because it induces signaling cell death (apoptosis) in cancer cells, and lacks the necrotic effect. PMID- 25495465 TI - Novel Triazolyl berberine derivatives prepared via CuAAC click chemistry: Synthesis, Anticancer Activity and Structure-Activity Relationships. AB - To search for novel anticancer agents, we designed and synthesized a series of new triazolyl berberine derivatives. The evaluation of all the synthesized compounds and their anticancer activities against a panel of four human cancer cell lines including MCF-7 (breast), MCF-7/ADR (breast), SW-1990 (pancreatic), SMMC-7721 (liver) and the non-cancer cell line HUVEC (human umbilical vein endothelial cell). The results showed that most of the compounds displayed better anticancer activities against MCF-7 and SMMC-7721 compared with berberine. Among these derivatives, compounds 5p and 5a exhibited the most potent inhibitory activities against the SMMC-7721 and SW-1990 cell lines with IC50 values of 14.861 +/- 2.4 MUM and 16.798 +/- 3.4 MUM. Furthermore, compounds 5p, 5a and 5n exhibited much better selectivity toward the normal cell line HUVEC than berberine. PMID- 25495462 TI - The gut microbiota of Colombians differs from that of Americans, Europeans and Asians. AB - BACKGROUND: The composition of the gut microbiota has recently been associated with health and disease, particularly with obesity. Some studies suggested a higher proportion of Firmicutes and a lower proportion of Bacteroidetes in obese compared to lean people; others found discordant patterns. Most studies, however, focused on Americans or Europeans, giving a limited picture of the gut microbiome. To determine the generality of previous observations and expand our knowledge of the human gut microbiota, it is important to replicate studies in overlooked populations. Thus, we describe here, for the first time, the gut microbiota of Colombian adults via the pyrosequencing of the 16S ribosomal DNA (rDNA), comparing it with results obtained in Americans, Europeans, Japanese and South Koreans, and testing the generality of previous observations concerning changes in Firmicutes and Bacteroidetes with increasing body mass index (BMI). RESULTS: We found that the composition of the gut microbiota of Colombians was significantly different from that of Americans, Europeans and Asians. The geographic origin of the population explained more variance in the composition of this bacterial community than BMI or gender. Concerning changes in Firmicutes and Bacteroidetes with obesity, in Colombians we found a tendency in Firmicutes to diminish with increasing BMI, whereas no change was observed in Bacteroidetes. A similar result was found in Americans. A more detailed inspection of the Colombian dataset revealed that five fiber-degrading bacteria, including Akkermansia, Dialister, Oscillospira, Ruminococcaceae and Clostridiales, became less abundant in obese subjects. CONCLUSION: We contributed data from unstudied Colombians that showed that the geographic origin of the studied population had a greater impact on the composition of the gut microbiota than BMI or gender. Any strategy aiming to modulate or control obesity via manipulation of this bacterial community should consider this effect. PMID- 25495466 TI - Design and synthesis of novel antineoplastic agents inspired from marine bromopyrrole alkaloids. AB - Azetidin-2-one, a beta -lactam four-membered heterocyclic ring is widely identified for its diverse medicinal properties. Ezetimibe a cholesterol absorption inhibitor and Aztreonam a potent cephalosporinase inhibitor proved the medicinal value of azetidin-2-ones. On the other hand marine bromopyrrole alkaloids are well known for their diverse biological significance. Hence twenty novel conjugates of azetidin-2-ones integrated with 4,5-dibromopyrrole motif were synthesized and screened for antineoplastic activity using MTT assay. Synthesized hybrids displayed good antineoplastic profile particularly towards breast cancer cell line MCF7, where hybrid 5e displayed maximum cytotoxicity (IC50 = 0.5 uM). The selective cytotoxicity displayed by these conjugates towards tested cancer cells with non-toxicity against normal human VERO cells indicated their potential for further antineoplastic drug development. PMID- 25495467 TI - A modified evidence-based practice- knowledge, attitudes, behaviour and decisions/outcomes questionnaire is valid across multiple professions involved in pain management. AB - BACKGROUND: A validated and reliable instrument was developed to knowledge, attitudes and behaviours with respect to evidence-based practice (EBB-KABQ) in medical trainees but requires further adaptation and validation to be applied across different health professionals. METHODS: A modified 33-item evidence-based practice scale (EBP-KABQ) was developed to evaluate EBP perceptions and behaviors in clinicians. An international sample of 673 clinicians interested in treatment of pain (mean age = 45 years, 48% occupational therapists/physical therapists, 25% had more than 5 years of clinical training) completed an online English version of the questionnaire and demographics. Scaling properties (internal consistency, floor/ceiling effects) and construct validity (association with EBP activities, comparator constructs) were examined. A confirmatory factor analysis was used to assess the 4-domain structure EBP knowledge, attitudes, behavior, outcomes/decisions). RESULTS: The EBP-KABQ scale demonstrated high internal consistency (Cronbach's alpha = 0.85), no evident floor/ceiling effects, and support for a priori construct validation hypotheses. A 4-factor structure provided the best fit statistics (CFI =0.89, TLI =0.86, and RMSEA = 0.06). CONCLUSIONS: The EBP-KABQ scale demonstrates promising psychometric properties in this sample. Areas for improvement are described. PMID- 25495469 TI - High-antibody-producing Chinese hamster ovary cells up-regulate intracellular protein transport and glutathione synthesis. AB - Chinese hamster ovary (CHO) cells are the preferred production host for therapeutic monoclonal antibodies (mAb) due to their ability to perform post translational modifications and their successful approval history. The completion of the genome sequence for CHO cells has reignited interest in using quantitative proteomics to identify markers of good production lines. Here we applied two different proteomic techniques, iTRAQ and SWATH, for the identification of expression differences between a high- and low-antibody-producing CHO cell lines derived from the same transfection. More than 2000 proteins were quantified with 70 of them classified as differentially expressed in both techniques. Two biological processes were identified as differentially regulated by both methods: up-regulation of glutathione biosynthesis and down-regulation of DNA replication. Metabolomic analysis confirmed that the high producing cell line displayed higher intracellular levels of glutathione. SWATH further identified up-regulation of actin filament processes and intracellular transport and down regulation of several growth-related processes. These processes may be important for conferring high mAb production and as such are promising candidates for targeted engineering of high-expression cell lines. PMID- 25495468 TI - Risk factors of pandemic influenza A/H1N1 in a prospective household cohort in the general population: results from the CoPanFlu-France cohort. AB - BACKGROUND: The CoPanFlu-France household cohort was set up in 2009 to identify risk factors of infection by the pandemic A/H1N1 (H1N1pdm09) virus in the general population. OBJECTIVES: To investigate the determinants of infection during the 2010-2011 season, the first complete influenza season of study follow-up for this cohort. PATIENTS/METHODS: Pre- and post-epidemic blood samples were collected for all subjects, and nasal swabs were obtained in all subjects from households where an influenza-like illness was reported. Cases were defined as either a fourfold increase in the serological titer or a laboratory-confirmed H1N1pdm09 on a nasal swab, with either RT-PCR or multiplex PCR. Risk factors for H1N1pdm09 infections were explored, without any pre-specified hypothesis, among 167 individual, collective and environmental covariates via generalized estimating equations modeling. We adopted a multimodel selection procedure to control for model selection uncertainty. RESULTS: This analysis is based on a sample size of 1121 subjects. The final multivariable model identified one risk factor (history of asthma, OR = 2.17; 95% CI: 1.02-4.62) and three protective factors: pre-epidemic serological titer (OR = 0.51 per doubling of the titer; 95% CI: 0.39-0.67), green tea consumption a minimum of two times a week (OR = 0.39; 95% CI: 0.18-0.84), and proportion of subjects in the household always covering their mouth while coughing/sneezing (OR = 0.93 per 10% increase; 95% CI: 0.86-1.00). CONCLUSION: This exploratory study provides further support of previously reported risk factors and highlights the importance of collective protective behaviors in the household. Further analyses will be conducted to explore these findings. PMID- 25495470 TI - Role of cytidine deaminase in toxicity and efficacy of nucleosidic analogs. AB - INTRODUCTION: Nucleosidic analogs such as pyrimidine and purine derivatives are mainstay in the field of treating cancers, both in adults and in children. All these drugs act as antimetabolite compounds, that is, they interfere with the ability of cancer cells to synthesize the nucleosides or the nucleotides necessary for proliferation and progression. As with most cytotoxics, maintaining patients in their therapeutic window is challenging, and predicting changes in drug exposure is critical to ensure an optimal efficacy/toxicity balance. AREAS COVERED: Among the antimetabolites, a small but widely prescribed number of drugs (i.e., gemcitabine, capecitabine, cytarabine, azacytidine) share a same metabolic pattern driven by a liver enzyme, cytidine deaminase (CDA), coded by a gene displaying several genetic and epigenetic polymorphisms. Consequently, CDA activity is erratic, ranging from deficient to ultra-rapid deaminator patients, with subsequent impact on drug pharmacokinetics and pharmacodynamics eventually. This review provides an update on the variety of clinical studies and case reports investigating on CDA status as a marker for clinical outcome in cancer patients treated with nucleosidic analogs. EXPERT OPINION: Whereas sorting patients on the basis of their CDA genotype remains tricky because of unclear genotype-to-phenotype relationships, developing functional strategies (i.e., phenotype-based status determination) could help to use CDA status as a biomarker for developing adaptive dosing strategies with nucleosidic analogs. PMID- 25495471 TI - Corrigendum. PMID- 25495472 TI - Actual practice of melanoma follow-up and treatment in Germany: results of a prospective, longitudinal cohort study. PMID- 25495473 TI - Nitrate Concentration near the Surface of Frozen Aqueous Solutions. AB - Photolysis of nitrate plays an important role in the emission of nitrogen oxides from snow and ice, which affects the composition of the overlying atmosphere. In order to quantify these reactions, it is necessary to know how much nitrate is available for photolysis near the surfaces of snow and ice. The concentration of nitrate excluded from frozen solutions of nitric acid, sodium nitrate, and magnesium nitrate was measured with attenuated total reflection infrared spectroscopy. Liquid water and nitrate were observed at and near the bottom surface of frozen aqueous solutions during annealing from -18 to -2 degrees C. At -2 degrees C, the nitrate concentration was determined to be ~1.0 mol/L for frozen NaNO(3) and Mg(NO(3))(2) solutions and ~0.8 mol/L for frozen HNO(3) solutions. At lower temperatures, nitrate concentration ranged from 1.6 to 3.7 mol/L. Ideal thermodynamics overestimates nitrate concentration at colder temperatures where the brine is highly concentrated for all solutions. The nitrate concentration at ice surfaces is well described by bulk freezing point depression data close to the melting point of ice and for nitric acid at colder temperatures. Effects of temperature and counterions and implications for modeling snow chemistry are discussed. PMID- 25495475 TI - Screening for oral potentially malignant disorders among areca (betel) nut chewers in Guam and Saipan. AB - BACKGROUND: The Mariana Islands, including Guam and Saipan, are home to many ethnic subpopulations of Micronesia. Oral cancer incidence rates vary among subpopulations, and areca (betel) nut chewing, a habit with carcinogenic risks, is common. Our objectives were to conduct a screening program to detect oral potentially malignant disorders (OPMD) in betel nut chewers, measure their betel nut chewing practices, and assess the prevalence of the oral human papillomavirus (HPV) infection in a subset of betel nut chewers in these islands. METHODS: A cross-section of 300 betel nut chewers >=18 years old [in Guam (n = 137) and in Saipan (n = 163)] were recruited between January 2011-June 2012. We collected demographic, socioeconomic, and oral behavioural characteristics. Latent class analysis was used to identify chewing patterns from selected chewing behaviours. Following calibration of OPMD against an expert, a registered oral hygienist conducted oral examinations by house to house visits and referred positive cases to the study dentist for a second oral examination. Buccal smears were collected from a subset (n = 123) for HPV testing. RESULTS: Two classes of betel nut chewers were identified on 7 betel nut behaviours, smoking, and alcohol use; a key difference between the two Classes was the addition of ingredients to the betel quid among those in Class 2. When compared on other characteristics, Class 1 chewers were older, had been chewing for more years, and chewed fewer nuts per day although chewing episodes lasted longer than Class 2 chewers. More Class 1 chewers visited the dentist regularly than Class 2 chewers. Of the 300 participants, 46 (15.3%; 3.8% for Class 1 and 19.4% for Class 2) had OPMD and one (0.3%) was confirmed to have squamous cell carcinoma. The prevalence of oral HPV was 5.7% (7/123), although none were high-risk types. CONCLUSIONS: We found two patterns of betel nut chewing behaviour; Class 2 had a higher frequency of OPMD. Additional epidemiologic research is needed to examine the relationship between pattern of chewing behaviours and oral cancer incidence. Based on risk stratification, oral screening in Guam and Saipan can be targeted to Class 2 chewers. PMID- 25495477 TI - Cu-catalyzed aerobic oxidative cyclization of guanidylpyridines and derivatives. AB - A new method for the straightforward synthesis of 2-amino-[1,2,4]triazolo[1,5 a]pyridines and derivatives is presented. The target products are synthesized in high yields from guanidylpyridines and analogues via copper-catalyzed N-N coupling. The present methodology shows a wide scope, tolerating not only different substituents on the pyridine ring but also different heterocylic rings such as pyrazines, pyrimidines, and pyridazines. PMID- 25495476 TI - RAB3GAP1 and RAB3GAP2 modulate basal and rapamycin-induced autophagy. AB - Macroautophagy is a degradative pathway that sequesters and transports cytosolic cargo in autophagosomes to lysosomes, and its deterioration affects intracellular proteostasis. Membrane dynamics accompanying autophagy are mostly elusive and depend on trafficking processes. RAB GTPase activating proteins (RABGAPs) are important factors for the coordination of cellular vesicle transport systems, and several TBC (TRE2-BUB2-CDC16) domain-containing RABGAPs are associated with autophagy. Employing C. elegans and human primary fibroblasts, we show that RAB3GAP1 and RAB3GAP2, which are components of the TBC domain-free RAB3GAP complex, influence protein aggregation and affect autophagy at basal and rapamycin-induced conditions. Correlating the activity of RAB3GAP1/2 with ATG3 and ATG16L1 and analyzing ATG5 punctate structures, we illustrate that the RAB3GAPs modulate autophagosomal biogenesis. Significant levels of RAB3GAP1/2 colocalize with members of the Atg8 family at lipid droplets, and their autophagy modulatory activity depends on the GTPase-activating activity of RAB3GAP1 but is independent of the RAB GTPase RAB3. Moreover, we analyzed RAB3GAP1/2 in relation to the previously reported suppressive autophagy modulators FEZ1 and FEZ2 and demonstrate that both reciprocally regulate autophagy. In conclusion, we identify RAB3GAP1/2 as novel conserved factors of the autophagy and proteostasis network. PMID- 25495478 TI - Non-invasive score system for fibrosis in chronic hepatitis: proposal for a model based on biochemical, FibroScan and ultrasound data. AB - BACKGROUND & AIMS: We elaborate a non-invasive score system for liver fibrosis (NISF), exploring its diagnostic performance and comparing its accuracy to FibroScan in patients with chronic viral hepatitis (CH) and non-alcoholic fatty liver disease (NAFLD). METHODS: Clinical, biochemical, elastographic and ultrasound parameters derived from patients with CH (n = 83) or NAFLD (n = 58), undergoing liver biopsy for fibrosis assessment, were prospectively collected as potential predictors of fibrosis. Each parameter was evaluated for its correlation with the liver biopsy (Gold Standard). Candidate predictors with good interobserver agreement and correlation with histological stages were combined into two algorithms (NISF) to predict fibrosis in chronic viral hepatitis and NAFLD. RESULTS: The CH-NISF included six parameters: bluntness of liver edges, irregularity of left lobe surface, diameter of segment 4, liver stiffness measurement, platelet count and ALT values. The ability of the model to discriminate F3-F4 vs F0-F1 stages and F2 vs F0-F1 was high (AUROC of 0.95 and 0.83 respectively) and better than FibroScan alone, especially in intermediate stages (F2 vs F0-F1), AUROC 0.83 vs 0.57 (P = 0.003). The resulting algorithm is available as mathematical formula, nomogram or free online link. [http://health.mafservizi.it/NISF_Calculator/liver.htm] The NAFLD-NISF included liver stiffness, platelet count and AST levels, had good ability to discriminate F0-F1 vs F2-F3-F4 stages (AUROC 0.86), however, not significantly higher than FibroScan. CONCLUSIONS: CH-NISF can be proposed as preliminary and easily available staging tool, superior to FibroScan alone in predicting histological fibrosis, especially in intermediate stages. Further validations are needed to improve NISF accuracy in NAFLD. PMID- 25495479 TI - Influence of surface structure on single or mixed component self-assembled monolayers via in situ spectroelectrochemical fluorescence imaging of the complete stereographic triangle on a single crystal Au bead electrode. AB - The use of a single crystal gold bead electrode is demonstrated for characterization of self-assembled monolayers (SAM)s formed on the bead surface expressing a complete set of face centered cubic (fcc) surface structures represented by a stereographic projection. Simultaneous analysis of many crystallographic orientations was accomplished through the use of an in situ fluorescence microscopic imaging technique coupled with electrochemical measurements. SAMs were prepared from different classes of molecules, which were modified with a fluorescent tag enabling characterization of the influence of electrical potential and a direct comparison of the influence of surface structure on SAMs adsorbed onto low index, vicinal and chiral surfaces. The assembly of alkylthiol, Aib peptide and DNA SAMs are studied as a function of the electrical potential of the interface revealing how the organization of these SAMs depend on the surface crystallographic orientation, all in one measurement. This approach allows for a simultaneous determination of SAMs assembled onto an electrode surface onto which the whole fcc stereographic triangle can be mapped, revealing the influence of intermolecular interactions as well as the atomic arrangement of the substrate. Moreover, this method enables study of the influence of the Au surface atom arrangement on SAMs that were created and analyzed, both under identical conditions, something that can be challenging for the typical studies of this kind using individual gold single crystal electrodes. Also demonstrated is the analysis of a SAM containing two components prepared using thiol exchange. The two component SAM shows remarkable differences in the surface coverage, which strongly depends on the surface crystallography enabling estimates of the thiol exchange energetics. In addition, these electrode surfaces enable studies of molecular adsorption onto the symmetry related chiral surfaces since more than one stereographic triangle can be imaged at the same time. The ability to observe a SAM modified surface that contains many complete fcc stereographic triangles will facilitate the study of the single and multicomponent SAMs, identifying interesting surfaces for further analysis. PMID- 25495480 TI - Modelling the impact of vaccination on infectious diseases dynamics. AB - This paper investigates consequences of vaccine implementation strategies for infectious diseases by a mathematical model. For an infectious disease, the degree of infection may vary widely among the individuals. Reports show that individuals belonging to certain groups possess considerably higher risk to infection. Incorporating this phenomenon into vaccination strategies, the host is categorized into different groups to measure the outcome of the vaccination. A mathematical model is proposed and analysed to evaluate this measure. Our results suggest that vaccinating a group with certain priority may lead to elimination of the disease effectively. The strategy is cost-effective as well. PMID- 25495481 TI - Construction of sole benzene ring porous aromatic frameworks and their high adsorption properties. AB - Porous organic frameworks (POFs), with their excellent performance in catalysis, electricity, sensor, gas storage, and separation, have attracted a great deal of attention from researchers all over the world. Generally, the monomers of POF materials require a rigid three-dimensional molecule configuration together with special functional groups, as well as being triggered by noble metal catalysts. Here we report a low-cost and easy-construction strategy for synthesizing PAF materials. A series of flat multi-benzene compounds are selected as building units, and those phenyl rings could couple together to form polymeric skeletons. The BET surface areas of resulting PAFs are moderate, ranging from 777 to 972 m(2) g(-1). However, they unexpectedly exhibit superior gas sorption capacities. At 1.0 bar and 77 K, the H2 uptake of PAF-48 reaches 215 cm(3) g(-1). In addition, PAF-49 shows excellent performance in carbon dioxide and methane sorption, with values of 104 and 35 cm(3) g(-1), respectively. With those adsorption properties, these PAF materials could be considered as potential candidates for energetic gas adsorbents. PMID- 25495482 TI - Overcoming the practical challenges of electroencephalography for very preterm infants in the neonatal intensive care unit. AB - AIM: Long-term electroencephalogram (EEG) recording is increasingly being used in the neonatal period, but application and maintenance of the EEG electrodes is challenging, especially in preterm infants. This study proposes a practical method of electrode application that can be used in the neonatal intensive care unit (NICU). METHODS: EEG recording in preterm infants of <32 weeks of gestational age is often challenging and requires careful preparation and strict adherence to NICU protocols. An effective technique for EEG application in preterm infants is to use prepackaged, sterile, disposable, flat-surfaced EEG electrodes. The use of these electrodes in combination with a continuous positive airway pressure hat provides good security for electrodes and good quality EEG recordings. It also limits the handling of the infant, while strictly adhering to infection control policies. RESULTS: Long-term monitoring for >72 h has been achieved using this technique. Important steps to consider are efficient preparation of the recording machine and materials, careful electrode application and infection control. CONCLUSION: A fast and effective method of EEG electrode placement is required for neonatal EEG monitoring. The practical techniques described in this article outline a reliable method of EEG electrode placement, suitable for even extremely preterm infants. PMID- 25495483 TI - The Investigation of HCV RNA in Tear Fluid and Aqueous Humor in Patients with Anti-HCV Antibody Positive Who Underwent Cataract Surgery. AB - PURPOSE: To obtain aqueous humor and tear fluid samples during cataract surgery of the hepatitis C virus (HCV)-antibody-positive patients in order to analyze them for HCV RNA and compare these measurements with serum HCV RNA levels. METHODS: Twenty-nine anti-HCV-positive patients were included this study. HCV RNA viral load levels were determined by commercial real-time polymerase chain reaction system. Antibodies to HCV were screened with the enzyme-linked immunosorbent assay (ELISA) using anti-HCV test kit. RESULTS: Log10 HCV RNA levels were found to be 6.00 +/- 1.06 IU/mL in serum, 2.76 +/- 0.36 IU/mL in the aqueous humor, and 1.91 +/- 0.93 IU/mL in tear fluid. No correlation was detected between samples for HCV RNA positivity (p = .390, kappa = .102). We have observed that, viral RNA was detected in the aqueous humor, while not in serum in one case, whereas viral RNA was detected in tear fluid but not in serum in another case. CONCLUSIONS: Although viral load detected in aqueous humor and tear fluid samples was considerably lower compared to the serum samples, it can still be important in terms of infectivity. PMID- 25495485 TI - Quantitative evidence for organic peroxy radical photochemistry at 254 nm. AB - Quantitative evidence is presented for the importance of alkyl peroxy photochemistry in the formation of secondary organic aerosol at 254 nm. Particles were generated by extensively oxidizing dodecanoic acid with photolytically generated hydroxyl radicals in a flow cell. The resulting particles were collected and analyzed for composition, which shows a lower contribution from multiply substituted parent molecules and much more decomposition product than expected from typical low-NOx oxidation mechanisms. Studies were performed at two separate reaction times, and kinetics modeling calculations were done using theoretical work from the combustion literature to estimate the branching of the photoexcited products. Extrapolation of the ethyl peroxy radical absorption spectrum compared to actinic flux measurements also shows that the alkyl peroxy radical absorption at ~310 nm leads to photochemical lifetimes under pristine tropospheric conditions that are comparable to predicted lifetimes from peroxy peroxy recombination reactions, particularly at higher altitudes. PMID- 25495484 TI - Usability testing of the Internet program: "Teens Taking Charge: Managing My Transplant Online". AB - Adolescents with SOT demonstrate high rates of medication non-adherence and higher rates of graft loss compared to all other age groups. Self-management interventions encompass information-based material designed to achieve disease related learning and changes in the participant's knowledge and skill acquisition, while providing social support. These interventions have had some success in chronic disease populations by reducing symptoms and promoting self efficacy and empowerment. Using findings from a needs assessment, an Internet based self-management program, Teens Taking Charge: Managing My Transplant Online, for youth with SOT was developed. This program contains information on transplant, self-management and transition skills, and opportunities for peer support. The purpose of this study was to determine the usability and acceptability of the initial three modules (Medication and Vaccines; Diet after Transplant; and Living with a Transplant Organ) of the online program from the perspectives of youth with SOT. Participants were recruited from SOT clinics at a large pediatric tertiary care center in Canada. Three iterative cycles (seven patients per iteration) of usability testing took place to refine the Web site prototype. Study procedures involved participants finding items from a standardized list of features and talking aloud about issues they encountered, followed by a semi-structured interview to generate feedback about what they liked and disliked about the program. All 21 patients (mean age = 14.9 yr) found the Web site content to be trustworthy, they liked the picture content, and they found the videos of peer experiences to be particularly helpful. Participants had some difficulties finding information within submodules and suggested a more simplistic design with easier navigation. This web-based intervention is appealing to teenagers and may foster improved self-management with their SOT. Nine additional teen and two parent modules are being developed, and the completed Web site will undergo usability testing. In the future, a randomized control trial will determine the feasibility and effectiveness of this online self-management program on adherence, self-efficacy, and transition skills. PMID- 25495486 TI - Theory and experiments for voltammetric and SECM investigations and application to ORR electrocatalysis at nanoelectrode ensembles of ultramicroelectrode dimensions. AB - Theoretical and experimental approaches to characterizing nanoelectrode (NE) ensembles of ultramicroelectrode dimensions (UME-NEEs) as a function of fraction of active area and random NE distribution are described. UME-NEEs were fabricated by addressing microregions of a gold-filled polycarbonate membrane through the UMEs of an underlying microfabricated addressable array. Results of Comsol Multiphysics 3D simulations based on randomly spaced NEs of 15 nm radius on a UME disk geometry of radii up to 5 MUm are shown for steady-state voltammetry (SSV) and scanning electrochemical microscopy (SECM) experiments. Analytical equations were developed to describe the diffusion-limited steady-state current and steady state voltammogram at an UME-NEE. These equations are shown to be in good agreement with the simulations and enabled evaluation of experimental SSVs. Comparison of experimental and simulated SECM approach curves, images, and tip voltammograms enabled the fraction of active area and distribution of NEs to be visualized and determined for individual UME-NEEs. Gold UME-NEEs are shown to be unique platforms for electrodeposition in forming nanoparticle electrodes (UME NPEs). Electrocatalysis results for the oxygen reduction reaction (ORR) on Pt UME NPEs in 0.1 M H2SO4 are also shown. PMID- 25495487 TI - Effective squaric acid dibutylester immunotherapy is associated with a reduction of skin infiltrating T-helper (Th)1 and Th17 cells in alopecia areata patients. PMID- 25495488 TI - Production of a Chaetomium globosum enolase monoclonal antibody. AB - Chaetomium globosum is a hydrophilic fungal species and a contaminant of water damaged building materials in North America. Methods to detect Chaetomium species include subjective identification of ascospores, viable culture, or molecular based detection methods. In this study, we describe the production and initial characterization of a monoclonal antibody (MAb) for C. globosum enolase. MAb 1C7, a murine IgG1 isotype MAb, was produced and reacted with recombinant C. globosum enolase (rCgEno) in an enzyme-linked immunosorbent assay and with a putative C. globosum enolase in a Western blot. Epitope mapping showed MAb 1C7 specific reactivity to an enolase decapeptide, LTYEELANLY, that is highly conserved within the fungal class Sordariomycetes. Cross-reactivity studies showed MAb 1C7 reactivity to C. atrobrunneum but not C. indicum. MAb 1C7 did not react with enolase from Aspergillus fumigatus, which is divergent in only two amino acids within this epitope. The results of this study suggest potential utility of MAb 1C7 in Western blot applications for the detection of Chaetomium and other Sordariomycetes species. PMID- 25495489 TI - Cardiac Sympathetic Dominance and Systemic Inflammation in COPD. AB - Cardiac autonomic dysfunction is an independent determinant of adverse outcomes in many diseases. The available literature on the relative changes in sympathetic and parasympathetic components in chronic obstructive pulmonary disease (COPD) is equivocal, the clinical and physiological correlates are poorly defined and association with markers of systemic inflammation has not been explored. As both autonomic dysfunction and systemic inflammation may contribute to cardiovascular morbidity in COPD, we hypothesized that these may be associated. Sixty three stable patients of COPD and 36 controls underwent spirometry, estimation of diffusion capacity, six-minute walk test and measurements of serum interleukin-6 (IL-6) and high-sensitivity C-Reactive protein. Cardiac autonomic activity was evaluated by standard five-minute heart rate variability (HRV) recordings to obtain time- and frequency-domain indices and the averaged heart rate. We observed that HRV indices of overall autonomic modulation, the standard deviation of time intervals between consecutive normal beats (SDNN) and total power, were greater in patients with higher levels of indices of both parasympathetic and sympathetic activity. The heart rate was significantly higher in patients indicating an overall sympathetic dominance and was inversely correlated with diffusion capacity. Serum IL-6 was inversely correlated with pNN50, an index of parasympathetic activity, and positively with LF/HF ratio, a measure of sympathetic: parasympathetic balance. None of the HRV indices was significantly correlated with physiological measures of severity. It was concluded that patients with COPD have increased cardiac autonomic modulation with sympathetic dominance. This is associated with decreased lung diffusion capacity and systemic inflammation. PMID- 25495491 TI - Perfecting breast-cancer treatment--incremental gains and musculoskeletal pains. PMID- 25495492 TI - First responders: dynamics of pre-gliotic Muller cell responses in the isolated adult rat retina. AB - PURPOSE: To explore the early reactions of the retinal Muller glia in response to retinal insult prior to gliotic remodeling and the sustained upregulation of intermediate filament glial fibrillary acidic protein (GFAP), which has traditionally been considered the most sensitive early indicator of reactive gliosis. METHODS: To study pre-gliotic events, we used a model of adult rat retinal explants and related the dynamic expression of GFAP as well as apoptosis, to four key regulators of retinal homeostasis (glutamine synthetase (GS), cellular retinaldehyde binding protein (CRALBP), basic fibroblast growth factor (bFGF), carbonic anhydrase II (CAII)) using immunohistochemistry. RESULTS: We found that a sustained GFAP upregulation couple with gliotic remodeling occurred comparatively late and that this phenomenon was preceded by an initial upregulation followed by depletion of GS, CRALBP, bFGF and CAII in retinal Muller cells. The initial increase of the regulatory proteins, seen after 1-12 h, preceded a first phase of moderate apoptosis, and their depletion after 48 h was followed by massive apoptosis and widespread GFAP upregulation in the Muller cells at 5 days. CONCLUSION: We conclude that, in the explant model, changes in the expression of the four homeostatic regulatory proteins as well as apoptotic cell death precedes sustained GFAP upregulation and reactive gliosis. Muller cell reactivity has been linked to several retinal conditions, and the herein provided novel information on the dynamics of pre-gliotic events in the lesioned retina may help us understand important pathological mechanisms crucial for future therapeutic intervention. PMID- 25495493 TI - Speed of Dog Adoption: Impact of Online Photo Traits. AB - The Internet has radically changed how dogs are advertised for adoption in the United States. This study was used to investigate how different characteristics in dogs' photos presented online affected the speed of their adoptions, as a proof of concept to encourage more research in this field. The study analyzed the 1st images of 468 adopted young and adult black dogs identified as Labrador Retriever mixed breeds across the United States. A subjective global measure of photo quality had the largest impact on time to adoption. Other photo traits that positively impacted adoption speed included direct canine eye contact with the camera, the dog standing up, the photo being appropriately sized, an outdoor photo location, and a nonblurry image. Photos taken in a cage, dogs wearing a bandana, dogs having a visible tongue, and some other traits had no effect on how fast the dogs were adopted. Improving the quality of online photos of dogs presented for adoption may speed up and possibly increase the number of adoptions, thereby providing a cheap and easy way to help fight the homeless companion animal population problem. PMID- 25495494 TI - Diurnal profiles of pedometer-determined physical activity in chronically ill and mobility-limited older adults: a cross-sectional study. AB - BACKGROUND: The aim of this study was to analyze diurnal profiles of physical activity for community-dwelling adults aged 70 years and over, and to explore the moderating effect of sex, age, morbidity, mobility limitation, and season on physical activity throughout the day. METHODS: A sample of 149 primary health care patients (mean age 79.5 +/- 5.2 years, 74.5% females) was included in the analyses. Participants' physical activity was measured on up to six consecutive days via Omron Walking Style Pro HJ-720IT-E2 pedometer. Step count per day and per hour, and pedometer wear time were descriptively analyzed. A repeated measures ANOVA with physical activity per hour as dependent variable was performed to analyze the moderating effect of sex, age, morbidity, mobility limitation, and season on diurnal profiles of physical activity. The diurnal profile for the total sample and adjusted diurnal profiles for subgroups are presented. RESULTS: Participants' daily step count averaged 3280 +/- 1873 steps/day. They wore the pedometer for 14.2 +/- 1.7 hours per day and walked on average 234 +/- 139 steps per hour. With respect to diurnal profiles, there were two peaks at 10-11 AM (mean [95%-confidence interval]: 382 [329-435] steps) and at 3-4 pm (313 [261-365] steps) interrupted by a period of lower activity with a low point at 1-2 pm (229 [190-268] steps). A mobility limitation, defined by use of a cane or a rollator, had a significant moderating effect (p = 0.0237) on diurnal physical activity. CONCLUSIONS: This is the first study to explore pedometer-determined diurnal profiles of physical activity in chronically ill and mobility-limited older adults. Prolonging periods of elevated physical activity in the afternoon while respecting individual daily routine and commitments could be one option for facilitating the integration of physical activity and for making it a habit in older adults' daily lives. The use of a walking aid seems to be an indicator for a quite low activity plateau during the second half of the day. People who use walking aids should be motivated to increase their physical activity during afternoon; this might help to increase the overall low physical activity level of this vulnerable subgroup of older adults. PMID- 25495495 TI - The comorbid relationship between migraine and epilepsy: a systematic review and meta-analysis. AB - A number of studies have suggested a pathophysiologic link between migraine and epilepsy. Our aim was to examine the relative lifetime prevalence of migraine in people with epilepsy (PWE) as well that of epilepsy in migraineurs. We carried out a systematic review, searching five electronic databases, specified bibliographies and conference abstracts in order to identify population-based studies that measured the lifetime co-prevalence of migraine and epilepsy. Two reviewers independently screened all titles and abstracts, carried out a risk of bias assessment and extracted the data. Meta-analyses were carried out using random effects models. Of the 3640 abstracts and titles screened, we identified 10 eligible studies encompassing a total of 1,548,967 subjects. Few of the studies used validated case ascertainment tools and there were inconsistent attempts to control for confounding. There was an overall 52% increase in the prevalence of migraine among PWE versus those without epilepsy [PR: 1.52 (95% CI: 1.29, 1.79)]. There was an overall 79% increase in the prevalence of epilepsy among migraineurs versus those without migraine [PR: 1.79 (95% CI: 1.43, 2.25)]. Subgroup analyses revealed that the method of ascertaining the epilepsy or migraine status of subjects was an important source of inter-study heterogeneity. Additional high quality primary studies are required, ones that use validated and accurate methods of case ascertainment as well as control for potential confounders. PMID- 25495496 TI - Planning considerations related to the organic contamination of Martian samples and implications for the Mars 2020 Rover. PMID- 25495498 TI - Safety of olmesartan in a patient with telmisartan-induced myotoxicity: a case report. PMID- 25495497 TI - Severe bleeding events in adults and children with primary immune thrombocytopenia: a systematic review. AB - BACKGROUND: The burden of severe bleeding in adults and children with immune thrombocytopenia (ITP) has not been established. OBJECTIVES: To describe the frequency and severity of bleeding events in patients with ITP, and the methods used to measure bleeding in ITP studies. PATIENTS/METHODS: We performed a systematic review of all prospective ITP studies that enrolled 20 or more patients. Two reviewers searched Medline, Embase, CINAHL and the Cochrane registry up to May 2014. Overall weighted proportions were estimated using a random effects model. Measurement properties of bleeding assessment tools were evaluated. RESULTS: We identified 118 studies that reported bleeding (n = 10 908 patients). Weighted proportions for intracerebral hemorrhage (ICH) were 1.4% for adults (95% confidence interval [CI], 0.9-2.1%) and 0.4% for children (95% CI, 0.2-0.7%; P < 0.01), most of whom had chronic ITP. The weighted proportion for severe (non-ICH) bleeding was 9.6% for adults (95% CI, 4.1-17.1%) and 20.2% for children (95% CI, 10.0-32.9%; P < 0.01) with newly-diagnosed or chronic ITP. Methods of reporting and definitions of severe bleeding were highly variable in primary studies. Two bleeding assessment tools (Buchanan 2002 for children; Page 2007 for adults) demonstrated adequate inter-rater reliability and validity in independent assessments. CONCLUSIONS: ICH was more common in adults and tended to occur during chronic ITP; other severe bleeds were more common in children and occurred at all stages of disease. Reporting of non-ICH bleeding was variable across studies. Further attention to ITP-specific bleeding measurement in clinical trials is needed to improve standardization of this important outcome for patients. PMID- 25495499 TI - Patient satisfaction after the treatment of glabellar lines with Botulinum toxin type A (Speywood Unit): a multi-centre European observational study. AB - BACKGROUND: Whilst the efficacy and safety of glabella complex treatment with botulinum toxin type A (Speywood Unit) [BoNT-A (s.U)] has been comprehensively studied, there are very few trials on patient-reported outcomes and patient satisfaction associated with this treatment. OBJECTIVE: To assess the level of patient satisfaction 3 weeks and 4 months after the treatment of glabellar lines with BoNT-A (s.U). METHODS: This is a multi-centre, prospective, non interventional observational study carried out in France, Germany, Spain and the United Kingdom. Subjects were eligible if the investigator had already decided to prescribe BoNT-A (s.U), according to the labelling. Subjects completed a questionnaire at both 3 weeks and 4 months after treatment. RESULTS: About 533 subjects completed at least one of the two questionnaires. About half of the subjects (47.9%) were naive to BoNT-A treatment of the glabella, while 50.6% had previously received another product. A high level of satisfaction was observed after the treatment, with 94.7% and 89.6% of subjects being satisfied or very satisfied with the aesthetic outcome at week 3 and month 4, respectively. Treatment was safe and well tolerated, as directly determined in the survey. Major reasons for satisfaction included the positive aesthetic outcome, a natural appearance, a rested look and comfort of injection. Most subjects felt the treatment brought them 'harmony', 'self-esteem/confidence' or 'youth'. Of the subjects who had previously been treated with another product, 51.2% considered the results obtained in the present study with BoNT-A (s.U) were better. CONCLUSION: Treatment of the glabellar lines with BoNT-A (s.U) led to a high level of patient satisfaction and a more positive self-perception up to 4 months after the treatment, regardless of whether the patients were naive or not to BoNT A treatment. PMID- 25495501 TI - Lactase genetic polymorphisms and coeliac disease in children: a cohort study. AB - BACKGROUND: Lactase activity declines during childhood in the majority of human populations leading to adult-type hypolactasia (AtH). C/T-13910 and G/A-22018 single nucleotide polymorphisms (SNPs) have been suggested to be associated with AtH in different human populations. Coeliac disease (CD) is an autoimmune condition characterized by damage to intestinal cells leading to ultimate deterioration. AIM: This study investigated the association between coeliac disease (CD) and SNPs leading to AtH in children from North India. SUBJECTS AND METHODS: Intestinal biopsies and saliva samples were obtained from 52 children with CD diagnosis and 102 control subjects. Biopsies were assayed for disaccharidase activities and samples were genotyped for given SNPs. RESULTS: Prevalence of C/C and G/G genotypes of AtH was almost equal in the CD and control group. The CD group had low lactase activity compared to the control group, irrespective of genotype at C/T -13910 and G/A -22018 SNPs (p < 0.05). For the control group, lactase activity was high in children with C/T + G/A genotypes compared to C/C + G/G (p < 0.05). CONCLUSION: There appears to be no significant correlation between C/T -13910 or G/A -22018 SNPs of AtH and CD. Children with C/C or G/G genotype of AtH may not be at greater risk of CD. PMID- 25495503 TI - Comprehensive dietary education in treated gout patients does not further improve serum urate. AB - BACKGROUND/AIM: This study aims to investigate the influence of dietary education in patients with gout on a stable dose of urate-lowering therapy (ULT). METHODS: Males and females aged >18 years with a history of gout, receiving an appropriate and stable dose of ULT, were recruited from two tertiary hospitals and randomised into two groups. The control group received basic advice regarding the importance of compliance with therapy and the benefit of weight loss. The intervention group received comprehensive dietary advice based on the British Society of Rheumatology Guidelines. Both groups received education at baseline and 3 months. Serum urate was measured at baseline, 3 months and 6 months, and a questionnaire was completed at baseline and at 6 months. The primary outcome of the study was to compare the change in serum urate between groups. RESULTS: Thirty patients were recruited into the study. There was no difference in serum urate between the control and intervention group at 6 months (0.29 mmol/L vs 0.29 mmol/L at baseline and 0.27 mmol/L vs 0.30 mmol/L at 6 months). The intervention group showed a statistically significant improvement in knowledge (8/13 in control group at baseline to 9/13 at 6 months vs 8/13 in intervention group at baseline to 12/13 at 6 months, P < 0.05) and self-reported dietary modification (1 in control vs 7 in intervention P < 0.05) at 6 months. CONCLUSION: This randomised controlled trial shows that in patients on ULT, providing education on diet does not lead to any clinically significant difference in serum urate at 6 months. PMID- 25495504 TI - Laser-induced nanoscale thermocapillary flow for purification of aligned arrays of single-walled carbon nanotubes. AB - Although aligned arrays of single-walled carbon nanotubes (SWNTs) have outstanding potential for use in broad classes of advanced semiconductor devices, the relatively large population of metallic SWNTs (m-SWNTs) that results from conventional growth techniques leads to significantly degraded performance. Recently reported methods based on thermocapillary effects that enable removal of m-SWNTs from such arrays offer exceptional levels of efficiency, but the procedures are cumbersome and require multiple processing steps. Here we present a simple, robust alternative that yields pristine arrays of purely semiconducting SWNTs (s-SWNTs) by use of irradiation with an infrared laser. Selective absorption by m-SWNTs coated with a thin organic film initiates nanoscale thermocapillary flows that lead to exposure only of the m-SWNTs. Reactive ion etching eliminates the m-SWNTs without damaging the s-SWNTs; removal of the film completes the purification. Systematic experimental studies and computational modeling of the thermal physics illuminates the essential aspects of this process. Demonstrations include use of arrays of s-SWNTs formed in this manner as semiconducting channel materials in statistically relevant numbers of transistors to achieve both high mobilities (>900 cm2 V(-1) s(-1)) and switching ratios (>10(4)). Statistical analysis indicates that the arrays contain at least 99.8% s SWNTs and likely significantly higher. PMID- 25495505 TI - Effects of a restrictive fluid regimen in pediatric patients undergoing major abdominal surgery. AB - OBJECTIVE: To investigate the effects of restrictive fluid regimen during major abdominal surgery in pediatric patients. BACKGROUND: In adults, a restrictive and goal-directed regimen as opposed to a liberal-fluid regimen results in better outcomes after various major surgical procedures. The different ratio of body fluid distribution in pediatric patients from those of adults may influence different needs of fluid. METHODS: This stratified, randomized, controlled trial was conducted in 25 pediatric patients (mean age <3 years) undergoing major abdominal surgery. Patients were allocated to two groups based on their perioperative fluid management. 'control group' received maintenance plus deficit plus interstitial space replacement plus ongoing loss, whereas 'restrictive group' had a similar treatment, but were given no interstitial space replacement. Intraoperative fluid resuscitation was guided by hemodynamics and base excess. Parameters recorded included hemodynamic variables, the volume and type of intravenous fluid, blood chemistry (including lactate, base excess, and electrolyte), chest X-ray, body weight, complications, and return of bowel function. RESULTS: Patients in control group needed significantly less additional fluid for resuscitation compared to restrictive group (0.62 +/- 3.51 ml . kg(-1) . h(-1) vs 5.04 +/- 4.16 ml . kg(-1) . h(-1) ; P = 0.012). In restrictive group, heart rates were higher (P = 0.012) and base excess showed more negative results (P = 0.049). There were no differences between the groups in terms of the total volume requirement, postoperative kidney function, chest X-ray, variation of body weight and the postoperative outcomes. CONCLUSIONS: Volume preload corresponding with an estimated interstitial space replacement was suitable for application to pediatric patients undergoing major abdominal surgery. PMID- 25495507 TI - Brine shrimp cytotoxicity and antimalarial activity of plants traditionally used in treatment of malaria in Msambweni district. AB - CONTEXT: In Kenya, most people use traditional medicine and medicinal plants to treat many diseases including malaria. To manage malaria, new knowledge and products are needed. Traditional herbal medicine has constituted a good basis for antimalarial lead discovery and drug development. OBJECTIVES: To determine in vivo antimalarial activity and brine shrimp toxicity of five medicinal plants traditionally used to treat malaria in Msambweni district, Kenya. MATERIALS AND METHODS: A 0.2 ml saline solution of 100 mg/kg aqueous crude extracts from five different plant parts were administered orally once a day and evaluated for their in vivo chemosuppressive effect using Plasmodium berghei berghei-infected Swiss mice for four consecutive days. Their safety was also determined using Brine shrimp lethality test: Grewia trichocarpa Hochst ex A. Rich (Tiliaceae) root, Dicrostachys cinerea (L) Wight et Am (Mimosaceae) root, Tamarindus indica L. (Caesalpiniaceae) stem bark, Azadirachta indica (L) Burn. (Meliaceae) root bark, and Acacia seyal Del. (Mimosaceae) root. RESULTS: Parasitaemia was as follows: A. indica, 3.1%; D. cinerea, 6.3%; T. indica, 25.1%; A. seyal, 27.8%; and G. trichocarpa, 35.8%. In terms of toxicity, A. indica root bark extract had an LC50 of 285.8 ug/ml and was considered moderately toxic. T. indica stem bark extract and G. trichocarpa root extract had an LC50 of 516.4 and 545.8 ug/ml, respectively, and were considered to be weakly toxic while A. seyal and D. cinerea root extracts had a LC50 >1000 ug/ml and were, therefore, considered to be non-toxic. DISCUSSION AND CONCLUSION: All extracts had antimalarial activity that was not significant compared to chloroquine (p >= 0.05). No extract was toxic to the arthropod invertebrate, Artemia salina L. (Artemiidae) larvae, justifying the continued use of the plant parts to treat malaria. PMID- 25495506 TI - Multimodal fluorescence microscopy of prion strain specific PrP deposits stained by thiophene-based amyloid ligands. AB - The disease-associated prion protein (PrP) forms aggregates which vary in structural conformation yet share an identical primary sequence. These variations in PrP conformation are believed to manifest in prion strains exhibiting distinctly different periods of disease incubation as well as regionally specific aggregate deposition within the brain. The anionic luminescent conjugated polythiophene (LCP), polythiophene acetic acid (PTAA) has previously been used to distinguish PrP deposits associated with distinct mouse adapted strains via distinct fluorescence emission profiles from the dye. Here, we employed PTAA and 3 structurally related chemically defined luminescent conjugated oligothiophenes (LCOs) to stain brain tissue sections from mice inoculated with 2 distinct prion strains. Our results showed that in addition to emission spectra, excitation, and fluorescence lifetime imaging microscopy (FLIM) can fruitfully be assessed for optical distinction of PrP deposits associated with distinct prion strains. Our findings support the theory that alterations in LCP/LCO fluorescence are due to distinct conformational restriction of the thiophene backbone upon interaction with PrP aggregates associated with distinct prion strains. We foresee that LCP and LCO staining in combination with multimodal fluorescence microscopy might aid in detecting structural differences among discrete protein aggregates and in linking protein conformational features with disease phenotypes for a variety of neurodegenerative proteinopathies. PMID- 25495490 TI - Adjuvant ovarian suppression in premenopausal breast cancer. AB - BACKGROUND: Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor-positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain. METHODS: We randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal. RESULTS: After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen-ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen-ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane-ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87). CONCLUSIONS: Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression. (Funded by Pfizer and others; SOFT ClinicalTrials.gov number, NCT00066690.). PMID- 25495508 TI - Evidence for the occurrence of gingival recession and non-carious cervical lesions as a consequence of traumatic toothbrushing. AB - AIM: To identify the best available evidence for the effect of toothbrushing on the initiation and progression of gingival recession and non-carious cervical lesions (NCCLs). METHODS: A protocol was developed for the questions: Does traumatic toothbrushing, compared to normal toothbrushing, lead to an increased prevalence of non-inflammatory gingival recession? [FQ1] and NCCLs? [FQ2]. The search covered four electronic databases. Bibliographies of review articles, relevant texts, World and European Workshops were screened. Hand searches were performed of the Journals of Clinical Periodontology, Periodontology, Periodontal Research and IADR abstracts. RESULTS: A meta-analysis included 159 subjects and showed that subjects who used MTBs (manual toothbrush) had greater gingival recession after 12 months when compared with those using PTBs (powered toothbrush). Thirteen cross-sectional studies identified the most frequent toothbrushing factors associated with gingival recession as being toothbrushing frequency, a horizontal or scrub toothbrushing method, bristle hardness, toothbrushing duration and the frequency of changing a toothbrush. The principal toothbrushing factors associated with NCCLs were toothbrushing method and frequency. CONCLUSION: The data to support or refute the association between toothbrushing and gingival recession and NCCLs remain largely inconclusive. PMID- 25495510 TI - Safety and clinical effects of EVP-6124 in subjects with Alzheimer's disease currently or previously receiving an acetylcholinesterase inhibitor medication. AB - Alzheimer's disease (AD) is a prevalent and currently incurable brain disease whose impact will continue to rise as the population ages. With limited treatment options, a variety of experimental therapies are currently in clinical trials. EVP-6124 (encenicline) is an alpha7 nicotinic acetylcholine receptor partial agonist under investigation for the symptomatic treatment of AD. EVP-6124 activates the alpha7 nicotinic acetylcholine receptor at low nanomolar brain concentrations and improves memory performance in rats. Treatment with EVP-6124 in Phase I and II trials involving patients with mild-to-moderate AD was well tolerated and showed statistically significant improvements compared with placebo on cognitive and functional measures. Two Phase III trials under the title COGNITIV AD will assess the efficacy and tolerability of EVP-6124 in patients with mild-to-moderate AD. Based on the completed clinical trials and proposed mechanism of action, EVP-6124 would appear to be a good candidate for therapy in combination with cholinesterase inhibitors. PMID- 25495509 TI - An exploration of China's mortality decline under Mao: A provincial analysis, 1950-80. AB - Between 1950 and 1980, China experienced the most rapid sustained increase in life expectancy of any population in documented global history. We know of no study that has quantitatively assessed the relative importance of the various explanations proposed for this gain in survival. We have created and analysed a new, province-level panel data set spanning the decades between 1950 and 1980 by combining historical information from China's public health archives, official provincial yearbooks, and infant and child mortality records contained in the 1988 National Survey of Fertility and Contraception. Although exploratory, our results suggest that gains in school enrolment and public health campaigns together are associated with 55-70 per cent of China's dramatic reductions in infant and under-5 mortality during our study period. These results underscore the importance of non-medical determinants of population health, and suggest that, in some circumstances, general education of the population may amplify the effectiveness of public health interventions. PMID- 25495512 TI - Epidemiology of anaphylaxis. AB - Knowledge about the epidemiology of anaphylaxis is based on data from various sources: clinical practice, large secondary clinical and administrative databases of primary care or hospitalized patients, and recent surveys with representative samples of the general population. As several similar results are often reported in several publications and populations, such findings are highly like to be robust. One such finding is that the incidence and prevalence of anaphylaxis are higher than previously thought. Publications from the last 5 years reveal an incidence of between 50 and 112 episodes per 100 000 person-years; estimated prevalence is 0.3-5.1% depending on the rigour of the definitions used. Figures are higher in children, especially those aged 0-4 years. Publications from various geographical areas based on clinical and administrative data on hospitalized patients suggest that the frequency of admissions due to anaphylaxis has increased (5-7-fold in the last 10-15 years). Other publications point to a geographic gradient in the incidence of anaphylaxis, with higher frequencies recorded in areas with few hours of sunlight. However, these trends could be the result of factors other than a real change in the incidence of anaphylaxis, such as changes in disease coding and in the care provided. Based on data from the records of voluntary declarations of death by physicians and from large national databases, death from anaphylaxis remains very infrequent and stands at 0.35-1.06 deaths per million people per year, with no increases observed in the last 10-15 years. Although anaphylaxis can be fatal, recurrence of anaphylaxis--especially that associated with atopic diseases and hymenoptera stings--affects 26.5-54% of patients. PMID- 25495511 TI - Biomedical and psychosocial factors influencing transtibial prosthesis fit: a Delphi survey among health care professionals. AB - PURPOSE: We aimed to reach consensus among professionals caring for prosthesis users, on definitions of biomedical and psychosocial factors, to assess their influence on fit of transtibial prosthesis and to identify new factors. METHOD: A three-round, internet-based, Delphi survey was conducted among experts recruited via the Dutch National Amputee and Prosthesis Work Group. The main outcome measure was consensus among care professionals on statements concerning new and presented biomechanical and psychosocial factors that influence transtibial prosthesis fit. RESULTS: Fifty-four experts participated in the survey, and consensus was reached on 67% (46/69) of all statements. Consensus on statements relevant for good prosthesis fit was reached in most of the statements concerning psychosocial factors and on statements concerning the biomedical factors "prosthesis support and suspension". Least consensus was reached on statements concerning the biomedical factor "skin problems and pain in the residual limb". CONCLUSIONS: Biomedical and psychosocial factors influence transtibial prosthesis fit. Consensus was reached among care professionals in a majority of the presented statements concerning these factors. Implications for Rehabilitation Prosthesis fit and comfort is suboptimal in many prosthesis users. Both biomedical and psychosocial factors influence fit. Biomedical and psychosocial factors should be checked during transtibial prosthesis prescription to achieve and maintain an optimal fit. Consensus on many factors influencing prosthesis fit is achieved among care professionals. Consensus was largest regarding prosthesis support and suspension and least regarding skin problems and pain in the residual limb. This consensus contributes to systematic assessment of prosthesis fit. PMID- 25495513 TI - Giant schwannoma with extensive scalloping of the lumbar vertebral body treated with one-stage posterior surgery: a case report. AB - INTRODUCTION: Schwannoma is a relatively common benign spinal cord and/or cauda equina tumor; however, giant cauda equina schwannoma with extensive scalloping of the lumbar vertebral body is a rare pathology, and the treatment strategy, including the use of surgical procedures, is controversial. In this report, we present a rare case of a giant lumbar schwannoma of the cauda equina with extremely large scalloping of the vertebral body, and we discuss the surgical strategy we used to treat this pathology. CASE PRESENTATION: A 42-year-old Japanese man presented to our department with complaints of a gait disturbance and muscle weakness in the left lower limb. His muscle strength in the proximal part of the left lower limb was grade 2 or 3/5, and he exhibited a mild urinary disturbance on the first visit. X-ray and computed tomography myelography of the lumbar spine showed an extremely large erosive lesion at the L3 vertebral body. Magnetic resonance imaging of the lumbar spine showed a large soft-tissue mass in the spinal canal at L2-L3 and the vertebral body at L3. A one-stage complete tumor resection and instrumented circumferential fusion were performed via a posterior approach, and a good outcome was achieved after the surgery. CONCLUSIONS: We performed one-stage posterior surgery in a patient with a giant cauda equina schwannoma with extensive scalloping of the vertebral body, and a good post-operative outcome was achieved. PMID- 25495514 TI - Antibacterial properties of Acinetobacter baumannii phage Abp1 endolysin (PlyAB1). AB - BACKGROUND: Acinetobacter baumannii has emerged as one of the most important hospital-acquired pathogens in the world, because of its resistance to almost all available antibiotic drugs. Endolysins from phages are attracting increasing interest as potential antimicrobial agents, especially for drug-resistant bacteria. We previously isolated and characterized Abp1, a virulent phage targeting the multidrug-resistant A. baumannii strain, AB1. METHODS: To evaluate the antimicrobial potential of endolysin from the Abp1 phage, the endolysin gene plyAB1 was cloned and over-expressed in Escherichia coli, and the lytic activity of the recombinant protein (PlyAB1) was tested by turbidity assessment and bacteria counting assays. RESULTS: PlyAB1 exhibits a marked lytic activity against A. baumannii AB1, as shown by a decrease in the number of live bacteria following treatment with the enzyme. Moreover, PlyAB1 displayed a highly specific lytic effect against all of the 48 hospital-derived pandrug-resistant A. baumannii isolates that were tested. These isolates were shown to belong to different ST clones by multilocus sequence typing. CONCLUSIONS: The results presented here show that PlyAB1 has potential as an antibiotic against drug resistant A. baumannii. PMID- 25495515 TI - Effects of epigallocatechin gallate on the cell-wall structure of Mycobacterial smegmatis mc2155. AB - Epigallocatechin gallate (EGCG) is the main component of green tea extracts that inhibits the growth of Mycobacterial smegmatis mc(2)155, and the mechanism is not clear. This study showed the effects of EGCG on the growth of mc(2)155. The content and the structure of EGCG in LB medium with mc(2)155 were identified by HPLC and LC/MS. Transmission electron microscopy was utilised to identify the cell envelope structure. As a result, the optional inhibition concentration was determined to be 20 MUg mL(-1). Most of EGCG was transferred into its isomeride in LB medium, but the inhibition effects against mc(2)155 had yet been maintained. The changes of cell envelope structure were showed after EGCG treatment for 18 h. The cell wall appeared to have a less electron-translucent zone, turn rougher and thicker. The results show that EGCG impacts the integrity of mycobacterial cell wall and is likely be a better prophylactic agent against tuberculosis. PMID- 25495516 TI - Synergistic antibacterial activity of the combination of the alkaloid sanguinarine with EDTA and the antibiotic streptomycin against multidrug resistant bacteria. AB - OBJECTIVES: Drug combinations consisting of the DNA intercalating benzophenanthridine alkaloid sanguinarine, the chelator EDTA with the antibiotic streptomycin were tested against several Gram-positive and Gram-negative bacteria, including multi-resistant clinical isolates. METHODS: Microdilution, checkerboard and time kill curve methods were used to investigate the antibacterial activity of the individual drugs and the potential synergistic activity of combinations. KEY FINDINGS: Sanguinarine demonstrated a strong activity against Gram-positive and Gram-negative bacteria (minimum inhibitory concentrations, MIC = 0.5-128 MUg/ml), while streptomycin was active against Gram negative strains (MIC = 2-128 MUg/ml). EDTA showed only bacteriostatic activity. Indifference to synergistic activity was seen in the two-drug combinations sanguinarine + EDTA and sanguinarine + streptomycin (fractional inhibitory concentration index = 0.1-1.5), while the three-drug combination of sanguinarine + EDTA + streptomycin showed synergistic activity against almost all the strains (except methicillin-resistant Staphylococcus aureus), as well as a strong reduction in the effective doses (dose reduction index = 2-16 times) of sanguinarine, EDTA and streptomycin. In time kill studies, a substantial synergistic interaction of the three-drug combination was detected against Escherichia coli and Klebsiella pneumoniae. CONCLUSIONS: The combination of drugs, which interfere with different molecular targets, can be an important strategy to combat multidrug resistant bacteria. PMID- 25495517 TI - The potential of targeting NMDA receptors outside the CNS. AB - INTRODUCTION: NMDA receptor (NMDAR) is an ionotropic glutamate receptor with a high permeability to calcium and a unique feature of controlling numerous calcium dependent processes. Apart from being widely distributed in the CNS, the presence of NMDAR and its potential significance in a variety of non-neuronal cells and tissues has become an interesting research topic. AREAS COVERED: The current review summarizes prevailing knowledge on the role of NMDARs in the kidney, bone and parathyroid gland, three main organs responsible for calcium homeostasis, as well as in the heart, an organ whose function is highly dependable on balanced intracellular calcium concentrations. The review also examines studies that have advanced our understanding of the therapeutic potential of NMDAR agonists and antagonists in renal, cardiovascular and bone pathologies. EXPERT OPINION: NMDARs have a preeminent role in many physiological and pathological processes outside the CNS. In certain organs and/or disease conditions, activating the NMDAR leads to beneficial effects for the target organ, whereas in other diseases cell signaling downstream of NMDAR activation can exacerbate their pathology. Therefore, targeting NMDARs therapeutically is rather intricate work, and surely requires more extensive investigation in order to properly tune up the diverse NMDAR's actions translating them into beneficial cellular responses. PMID- 25495518 TI - Revised stereochemistry of ficifolidione and its biological activities against insects and cells. AB - Ficifolidione (1), a moderately active insecticidal compound from two species of Myrtaceae, and its derivatives were synthesized to evaluate their insecticidal activity. X-ray crystallographic analyses and specific rotation values of ficifolidione and its C-4 (2) demonstrated that the structure of ficifolidione differs from the reported absolute structure; that is, the C-4 configuration of ficifolidione should have an S configuration. The reported insecticidal activity of ficifolidione (1) and its C-4 epimer (2) against adult houseflies (Musca domestica), mosquito larvae (Culex pipiens), and cutworms (Spodoptera litura) was not observed. The cytotoxicities of ficifolidione and its derivatives (1-4) against four cell lines, Sf9, Colon26, HL60, and Vero, were also measured because ficifolidione has a phloroglucinol-derived moiety, a motif that is often present in the structure of cytotoxic chemicals. Compound 1 exhibited IC50 values of ca. 32, 9, 3, and 12 MUM for Sf9, Colon26, HL60, and Vero cells, respectively, indicating that ficifolidione possesses selective cytotoxicity against the four cell lines. In HL60 cells treated with 1, DNA fragmentation and the activation of procaspase 3 were observed, suggesting that the cytotoxicity is induced by apoptosis. PMID- 25495519 TI - The genetic association study between polymorphisms in uncoupling protein 2 and uncoupling protein 3 and metabolic data in dogs. AB - BACKGROUND: The uncoupling proteins (UCPs) in the mitochondrial inner membrane are members of the mitochondrial anion carrier protein family that play an important role in energy homeostasis. Genetic association studies have shown that human UCP2 and UCP3 variants (SNPs and indels) are associated with obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome. The aim of this study was to examine the genetic association between polymorphisms in UCP2 and UCP3 and metabolic data in dogs. RESULTS: We identified 10 SNPs (9 intronic and 1 exonic) and 4 indels (intronic) in UCP2, and 13 SNPs (11 intronic and 2 exonic) and one indel (exonic) in UCP3, by DNA sequence analysis of 11 different dog breeds (n=119). An association study between these UCP2 and UCP3 variants and the biochemical parameters of glucose, total cholesterol, lactate dehydrogenase and triglyceride in Labrador Retrievers (n=50) showed that none of the UCP2 polymorphisms were significantly associated with the levels of these parameters. However, four UCP3 SNPs (intron 1) were significantly associated with total cholesterol levels. In addition, the allele frequencies of two of the four SNPs associated with higher total cholesterol levels in a breed that is susceptible to hypercholesterolemia (Shetland Sheepdogs, n=30), compared with the control breed (Shiba, n=30). CONCLUSION: The results obtained from a limited number of individuals suggest that the UCP3 gene in dogs may be associated with total cholesterol levels. The examination of larger sample sizes and further analysis will lead to increased precision of these results. PMID- 25495521 TI - Host-sensitized luminescence properties in CaNb2O6:Ln(3+) (Ln(3+) = Eu(3+)/Tb(3+)/Dy(3+)/Sm(3+)) phosphors with abundant colors. AB - A series of Ln(3+) (Ln(3+) = Eu(3+)/Tb(3+)/Dy(3+)/Sm(3+)) ion doped CaNb2O6 (CNO) phosphors have been prepared via the conventional high-temperature solid-state reaction route. The X-ray diffraction (XRD) and structure refinement, diffuse reflection, photoluminescence (PL), and fluorescent decay curves were used to characterize the as-prepared samples. Under UV radiation, the CNO host present a broad emission band from about 355 to 605 nm centered around 460 nm originating from the NbO6 octahedral groups, which has spectral overlaps with the excitation of f-f transitions of Eu(3+)/Tb(3+)/Dy(3+)/Sm(3+) in CNO:Eu(3+)/Tb(3+)/Dy(3+)/Sm(3+) samples. They show both host emission and respective emission lines derived from the characteristic f-f transitions of activators, which present different emission colors owing to the energy transfer from the NbO6 group in the host to Eu(3+)/Tb(3+)/Dy(3+)/Sm(3+) with increasing activator concentrations. The decreases of decay lifetimes of host emissions in CNO:Eu(3+)/Tb(3+)/Dy(3+)/Sm(3+) demonstrate the energy transfer from the hosts to Eu(3+)/Tb(3+)/Dy(3+)/Sm(3+). The energy transfer mechanisms in CNO:Eu(3+)/Tb(3+)/Dy(3+) phosphors have been determined to be a resonant type via dipole-dipole mechanisms. For CNO:Sm(3+), the metal-metal charge transfer transition (MMCT) might contribute to the different variations of decay lifetimes and emission intensity from CNO:Eu(3+)/Tb(3+)/Dy(3+) samples. The best quantum efficiency is 71.2% for CNO:0.01/0.02Dy(3+). The PL properties of as-prepared materials indicate the promising application in UV-pumped white-emitting lighting diodes field. PMID- 25495520 TI - Lambda-carrageenan treatment exacerbates the severity of cerebral malaria caused by Plasmodium berghei ANKA in BALB/c mice. AB - BACKGROUND: There is an urgent need to develop and test novel compounds against malaria infection. Carrageenans, sulphated polysaccharides derived from seaweeds, have been previously shown to inhibit Plasmodium falciparum in vitro. However, they are inflammatory and alter the permeability of the blood-brain barrier, raising concerns that their use as a treatment for malaria could lead to cerebral malaria (CM), a severe complication of the disease. In this work, the authors look into the effects of the administration of lambda-carrageenan to the development and severity of CM in BALB/c mice, a relatively non-susceptible model, during infection with the ANKA strain of Plasmodium berghei. METHODS: Five week-old female BALB/c mice were infected with P. berghei intraperitoneally. One group was treated with lambda-carrageenan (PbCGN) following the 4-day suppressive test protocol, whereas the other group was not treated (PbN). Another group of healthy BALB/c mice was similarly given lambda-carrageenan (CGN) for comparison. The following parameters were assessed: parasitaemia, clinical signs of CM, and mortality. Brain and other vital organs were collected and examined for gross and histopathological lesions. Evans blue dye assays were employed to assess blood brain barrier integrity. RESULTS: Plasmodium berghei ANKA-infected BALB/c mice treated with lambda-carrageenan died earlier than those that received no treatment. Histopathological examination revealed that intracerebral haemorrhages related to CM were present in both groups of infected BALB/c mice, but were more numerous in those treated with lambda-carrageenan than in mock-treated animals. Inflammatory lesions were also observed only in the lambda-carrageenan-treated mice. These observations are consistent with the clinical signs associated with CM, such as head tilt, convulsions, and coma, which were observed only in this group, and may account for the earlier death of the mice. CONCLUSION: The results of this study indicate that the administration of lambda-carrageenan exacerbates the severe brain lesions and clinical signs associated with CM in BALB/c mice infected with P. berghei ANKA. PMID- 25495522 TI - HIV testing among youth in a high-risk city: prevalence, predictors, and gender differences. AB - While HIV is prevalent among adolescents and young adults, testing levels remain low and little is known about gender differences in HIV testing. The objectives of this study were to describe the prevalence of past-year HIV testing and evaluate associations between HIV testing and individual- and partner-level factors by gender among heterosexually experienced youth (15-24 years) in Baltimore, Maryland (N = 352). Past-year HIV testing was prevalent (60.1%) and differed by gender (69.4% among women vs. 49.6% among men, p = 0.005). For women, African-American race (AOR 3.09) and recent older partner by <=2 years (AOR 4.04) were significantly associated with testing. Among men, only African-American race was associated with testing (OR 4.23), with no patterns identified based on risk behavior or perceived partner risk. HIV testing among adolescent and young adults was prevalent in this highly affected urban area. Findings emphasize the value of a gender lens, and provide direction for optimizing engagement in HIV testing. PMID- 25495523 TI - The echogenicity of nerve blockade needles. AB - We performed a prospective, randomised study to evaluate the echogenicity of 11 regional block needles when inserted into a gel phantom at 45 degrees in the ultrasound plane. Two hundred anaesthetists viewed in random sequence recordings of each needle as it was advanced into the phantom. Participants scored the needle for echogenicity on a scale of 0-10 and categorised the needle as 'hyperechoic' or 'standard'. The mean (95% CI) echogenicity score was 1.7 (1.4 2.0) units higher for three needles marketed as 'hyperechoic' compared with standard needles marketed by the same companies, p < 0.001. The odds ratios (95% CI) that an anaesthetist would categorise a needle as hyperechoic were: 5.3 (3.6 8.0) if the needle was marketed as hyperechoic, p < 0.001; and 1.7 (1.1-2.6) if regional anaesthetic experience was >= 1 year compared with < 1 year, p = 0.025. PMID- 25495524 TI - Prevalence of human papillomaviruses in the healthy oral mucosa of women with high-grade squamous intra-epithelial lesion and of their partners as compared to healthy controls. AB - Oral human papillomavirus (HPV) carriage rates were investigated in relation to genital HPV carriage in women with HPV-associated cervical lesions and male partner of such women, including several couples, in comparison with healthy individuals. Buccal and lingual mucosa of 60 males and 149 females with healthy oral mucosa and without known genital lesion, genital and oral mucosa of further 40 females with cervical high-grade squamous intraepithelial lesion (HSIL) and 34 male sexual partners of women with HSIL (including 20 couples) were sampled. HPV DNA was detected using MY/GP PCR. Genotype was determined by sequencing or restriction fragment length polymorphism. Virus copy numbers were determined by real-time PCR. Overall, oral HPV carriage rate was 5.7% (12/209) in healthy individuals; average copy number was 5.8 * 10(2) copies/1 MUg DNA; male and female rates were comparable. Oral carriage in women with HSIL was significantly higher, 20.0% (8/40, P = 0.003); males with partners with HSIL showed a carriage rate of 17.6% (6/34), copy numbers were similar to the healthy controls. In contrast, genital carriage rate (52.9%, 18/34 vs. 82.5%, 33/40; P = 0.006) and average copy number were lower in males (5.0 * 10(5) vs. 7.8 * 10(5) copies/1 MUg DNA; P = 0.01). Oral copy numbers in these groups and in healthy individuals were comparable. High-risk genotypes were dominant; couples usually had the same genotype in the genital sample. In conclusion, genital HPV carriage is a risk factor of oral carriage for the individual or for the sexual partner, but alone is not sufficient to produce an oral HPV infection in most cases. PMID- 25495527 TI - Ion mobility-mass spectrometry of lasso peptides: signature of a rotaxane topology. AB - Ion mobility mass spectrometry data were collected on a set of five class II lasso peptides and their branched-cyclic topoisomers prepared in denaturing solvent conditions with and without sulfolane as a supercharging agent. Sulfolane was shown not to affect ion mobility results and to allow the formation of highly charged multiply protonated molecules. Drift time values of low charged multiply protonated molecules were found to be similar for the two peptide topologies, indicating the branched-cyclic peptide to be folded in the gas phase into a conformation as compact as the lasso peptide. Conversely, high charge states enabled a discrimination between lasso and branched-cyclic topoisomers, as the former remained compact in the gas phase while the branched-cyclic topoisomer unfolded. Comparison of the ion mobility mass spectrometry data of the lasso and branched-cyclic peptides for all charge states, including the higher charge states obtained with sulfolane, yielded three trends that allowed differentiation of the lasso form from the branched-cyclic topology: low intensity of highly charged protonated molecules, even with the supercharging agent, low change in collision cross sections with increasing charge state of all multiply protonated molecules, and narrow ion mobility peak widths associated with the coexistence of fewer conformations and possible conformational changes. PMID- 25495525 TI - The ins and outs of metal homeostasis by the root nodule actinobacterium Frankia. AB - BACKGROUND: Frankia are actinobacteria that form a symbiotic nitrogen-fixing association with actinorhizal plants, and play a significant role in actinorhizal plant colonization of metal contaminated areas. Many Frankia strains are known to be resistant to several toxic metals and metalloids including Pb(2+), Al(+3), SeO2, Cu(2+), AsO4, and Zn(2+). With the availability of eight Frankia genome databases, comparative genomics approaches employing phylogeny, amino acid composition analysis, and synteny were used to identify metal homeostasis mechanisms in eight Frankia strains. Characterized genes from the literature and a meta-analysis of 18 heavy metal gene microarray studies were used for comparison. RESULTS: Unlike most bacteria, Frankia utilize all of the essential trace elements (Ni, Co, Cu, Se, Mo, B, Zn, Fe, and Mn) and have a comparatively high percentage of metalloproteins, particularly in the more metal resistant strains. Cation diffusion facilitators, being one of the few known metal resistance mechanisms found in the Frankia genomes, were strong candidates for general divalent metal resistance in all of the Frankia strains. Gene duplication and amino acid substitutions that enhanced the metal affinity of CopA and CopCD proteins may be responsible for the copper resistance found in some Frankia strains. CopA and a new potential metal transporter, DUF347, may be involved in the particularly high lead tolerance in Frankia. Selenite resistance involved an alternate sulfur importer (CysPUWA) that prevents sulfur starvation, and reductases to produce elemental selenium. The pattern of arsenate, but not arsenite, resistance was achieved by Frankia using the novel arsenite exporter (AqpS) previously identified in the nitrogen-fixing plant symbiont Sinorhizobium meliloti. Based on the presence of multiple tellurite resistance factors, a new metal resistance (tellurite) was identified and confirmed in Frankia. CONCLUSIONS: Each strain had a unique combination of metal import, binding, modification, and export genes that explain differences in patterns of metal resistance between strains. Frankia has achieved similar levels of metal and metalloid resistance as bacteria from highly metal-contaminated sites. From a bioremediation standpoint, it is important to understand mechanisms that allow the endosymbiont to survive and infect actinorhizal plants in metal contaminated soils. PMID- 25495528 TI - Accidental exposure to gas emissions from transit goods treated for pest control. AB - BACKGROUND: International phytosanitary standards ISPM 15 require (since 2007) fumigation or heat treatment for shipping and storage. Those dealing with fumigated freight might be accidentally exposed. In this paper we report a series of three accidents of six storage room workers in a medium sized company regularly importing electronic production parts from abroad. METHODS: Patients (n=6, aged from 32-54 yrs.) and control group (n=30, mean 40 yrs.) donated blood and urine samples. The fumigants: ethylene oxide, methyl bromide, chloropicrin, ethylene dichloride, other halo-alkanes and solvents were analyzed by headspace gas chromatography/mass spectrometry (GCMS). For the quantitation of long term exposure/s, macromolecular reaction products (hemoglobin adducts) were used (with GCMS) as molecular dosimeter; additionally 8-OHdG and circulating mtDNA (cmtDNA) were analyzed as nonspecific biological effect markers. RESULTS: The hemoglobin adducts N-methyl valine (MEV) and N-(2-hydroxy ethyl) valine (HEV) were elevated after exposure to the alkylating chemicals methyl bromide and ethylene oxide. Under the consideration of known elimination kinetics and the individual smoking status (biomonitored with nicotine metabolite cotinine and tobacco specific hemoglobin adduct: N-(2 cyan ethyl) valines, CEV), the data allow theoretical extrapolation to the initial protein adduct concentrations at the time of the accident (the MEV/CEV levels were from 1,616 pmol/g globin to 1,880 pmol/g globin and HEV/CEV levels from 1,407 pmol/g globin to 5,049 pmol/g globin, and correlated with inhaled 0.4-1.5 ppm ethylene oxide. These integrated, extrapolated internal doses, calculated on the basis of biological exposure equivalents, confirmed the clinical diagnosis for three patients, showing severe intoxication symptoms. Both, cmtDNA and 8-OHdG, as non-specific biomarkers of toxic effects, were elevated in four patients. CONCLUSION: The cases reported here, stress the importance of a suitable risk assessment and control measures. We put emphasis on the necessity of human biomonitoring guidelines and the urgency for the relevant limit values. PMID- 25495526 TI - Identification of synthetic lethality of PRKDC in MYC-dependent human cancers by pooled shRNA screening. AB - BACKGROUND: MYC family members are among the most frequently deregulated oncogenes in human cancers, yet direct therapeutic targeting of MYC in cancer has been challenging thus far. Synthetic lethality provides an opportunity for therapeutic intervention of MYC-driven cancers. METHODS: A pooled kinase shRNA library screen was performed and next-generation deep sequencing efforts identified that PRKDC was synthetically lethal in cells overexpressing MYC. Genes and proteins of interest were knocked down or inhibited using RNAi technology and small molecule inhibitors, respectively. Quantitative RT-PCR using TaqMan probes examined mRNA expression levels and cell viability was assessed using CellTiter Glo (Promega). Western blotting was performed to monitor different protein levels in the presence or absence of RNAi or compound treatment. Statistical significance of differences among data sets were determined using unpaired t test (Mann-Whitney test) or ANOVA. RESULTS: Inhibition of PRKDC using RNAi (RNA interference) or small molecular inhibitors preferentially killed MYC overexpressing human lung fibroblasts. Moreover, inducible PRKDC knockdown decreased cell viability selectively in high MYC-expressing human small cell lung cancer cell lines. At the molecular level, we found that inhibition of PRKDC downregulated MYC mRNA and protein expression in multiple cancer cell lines. In addition, we confirmed that overexpression of MYC family proteins induced DNA double-strand breaks; our results also revealed that PRKDC inhibition in these cells led to an increase in DNA damage levels. CONCLUSIONS: Our data suggest that the synthetic lethality between PRKDC and MYC may in part be due to PRKDC dependent modulation of MYC expression, as well as MYC-induced DNA damage where PRKDC plays a key role in DNA damage repair. PMID- 25495530 TI - Comparative analysis of corneal measurements obtained from a Scheimpflug camera and an integrated Placido-optical coherence tomography device in normal and keratoconic eyes. AB - PURPOSE: To assess the agreement between a Scheimpflug camera (Pentacam) and a combined Placido-optical coherence tomography device (Visante OMNI) in measuring corneal curvature, thickness and elevation values in normal and keratoconic eyes. METHODS: Corneal measurements of 110 normal eyes (one eye per subject) and 70 keratoconic eyes were obtained from both devices and compared. Agreement was determined using the Bland-Altman analysis 95% limits of agreement (LoA). RESULTS: The Pentacam measured significantly greater keratometry readings in the flattest (K1) and steepest meridians (K2) in normal and keratoconic eyes. The 95% LoA in normal eyes were -0.32 to 0.59 dioptres (D) (K1) and -0.41 to 0.74 D (K2). In keratoconic eyes, the 95% LoA were -1.35 to 1.92 D (K1) and -1.38 to 1.99 D (K2). The Pentacam recorded significantly higher central corneal thickness (CCT) values in both groups of eyes. The 95% LoA were -4.31 to 39.89 microns (MU) and 12.92 to 41.35 MU in normal and keratoconic eyes, respectively. Pentacam anterior and posterior corneal elevations were significantly greater in both groups of eyes. The devices demonstrated excellent repeatability and reproducibility for corneal curvature and thickness but not elevation measurements. CONCLUSIONS: The Pentacam measured significantly greater corneal curvature, thickness and elevation values compared to the Visante OMNI in normal and keratoconic eyes. The devices agree moderately for anterior corneal elevations in normal eyes and do not appear to be interchangeable for corneal measurements in clinical practice. PMID- 25495529 TI - Why We Should Not Be Indifferent to Specification Choices for Difference-in Differences. AB - OBJECTIVE: To evaluate the effects of specification choices on the accuracy of estimates in difference-in-differences (DID) models. DATA SOURCES: Process-of care quality data from Hospital Compare between 2003 and 2009. STUDY DESIGN: We performed a Monte Carlo simulation experiment to estimate the effect of an imaginary policy on quality. The experiment was performed for three different scenarios in which the probability of treatment was (1) unrelated to pre intervention performance; (2) positively correlated with pre-intervention levels of performance; and (3) positively correlated with pre-intervention trends in performance. We estimated alternative DID models that varied with respect to the choice of data intervals, the comparison group, and the method of obtaining inference. We assessed estimator bias as the mean absolute deviation between estimated program effects and their true value. We evaluated the accuracy of inferences through statistical power and rates of false rejection of the null hypothesis. PRINCIPAL FINDINGS: Performance of alternative specifications varied dramatically when the probability of treatment was correlated with pre intervention levels or trends. In these cases, propensity score matching resulted in much more accurate point estimates. The use of permutation tests resulted in lower false rejection rates for the highly biased estimators, but the use of clustered standard errors resulted in slightly lower false rejection rates for the matching estimators. CONCLUSIONS: When treatment and comparison groups differed on pre-intervention levels or trends, our results supported specifications for DID models that include matching for more accurate point estimates and models using clustered standard errors or permutation tests for better inference. Based on our findings, we propose a checklist for DID analysis. PMID- 25495531 TI - Kinematic analysis of forelimb and hind limb joints in clinically healthy sheep. AB - BACKGROUND: Variations associated with sex, age, velocity, breed and body geometry should be considered in the determination of kinematic parameters for a gait considered normal. Therefore, this study aimed to evaluate kinematic patterns of forelimbs and hind limbs in clinically normal sheep from two different age groups walking at a constant velocity. The hypothesis was that the age may influence sagittal plane kinematic patterns. Fourteen clinically healthy female sheep were divided into Group 1--seven animals aged from 8 to 12 months, and Group 2--seven animals aged above 5 years. Before starting data collection, the sheep were trained to be conducted for walking in a pre-determined space at constant velocity. A minimum of 5 valid trials were obtained from the right and left sides of each sheep. Data were analyzed by use of a motion-analysis program. Flexion and extension joint angles (maximum, minimum, displacement), and angular velocity (maximum, minimum) were determined for the shoulder, elbow, carpal, hip, stifle, and tarsal joints. RESULTS: Within each group, no significant differences were observed between the right and left limbs in all kinematic variables. Significant differences were observed in the following kinematic parameters between G1 and G2: minimum angle (G1 < G2), angular displacement (G1 > G2), maximum angular velocity (G1 > G2), minimum angular velocity (G1 > G2) of the carpus; angular displacement (G1 > G2), minimum angular velocity (G1 > G2) of the shoulder; minimum angle (G1 > G2), angular displacement (G1 < G2) of the tarsus; maximum angular velocity (G1 < G2) of the stifle; maximum angular velocity G1 > G2 of the hip. The lengths of both forelimbs and hind limbs differed between groups (G1 < G2). The Froude number differed between groups for forelimbs and hind limbs. CONCLUSIONS: In conclusion, sheep of two different ages walking at a constant velocity present, within the same group, similar kinematic data between sides, and exhibit some differences in kinematic variables that may be age related or body size. Further studies using sheep walking at similar Froude numbers are necessary to exclude the body size. PMID- 25495532 TI - Dynamic Changes of Microglia/Macrophage M1 and M2 Polarization in Theiler's Murine Encephalomyelitis. AB - Microglia and macrophages play a central role for demyelination in Theiler's murine encephalomyelitis (TME) virus infection, a commonly used infectious model for chronic-progressive multiple sclerosis. In order to determine the dynamic changes of microglia/macrophage polarization in TME, the spinal cord of Swiss Jim Lambert (SJL) mice was investigated by gene expression profiling and immunofluorescence. Virus persistence and demyelinating leukomyelitis were confirmed by immunohistochemistry and histology. Electron microscopy revealed continuous myelin loss together with abortive myelin repair during the late chronic infection phase indicative of incomplete remyelination. A total of 59 genes out of 151 M1- and M2-related genes were differentially expressed in TME virus-infected mice over the study period. The onset of virus-induced demyelination was associated with a dominating M1 polarization, while mounting M2 polarization of macrophages/microglia together with sustained prominent M1 related gene expression was present during the chronic-progressive phase. Molecular results were confirmed by immunofluorescence, showing an increased spinal cord accumulation of CD16/32(+) M1-, arginase-1(+) M2- and Ym1(+) M2-type cells associated with progressive demyelination. The present study provides a comprehensive database of M1-/M2-related gene expression involved in the initiation and progression of demyelination supporting the hypothesis that perpetuating interaction between virus and macrophages/microglia induces a vicious circle with persistent inflammation and impaired myelin repair in TME. PMID- 25495534 TI - Imaging cytokine targeting to the tumor/bone microenvironment in vivo. PMID- 25495536 TI - Determinants of fertility in Rwanda in the context of a fertility transition: a secondary analysis of the 2010 Demographic and Health Survey. AB - BACKGROUND: Major improvements to Rwanda's health system, infrastructure, and social programs over the last decade have led to a rapid fertility transition unique from other African countries. The total fertility rate fell from 6.1 in 2005 to 4.6 in 2010, with a 3-fold increase in contraceptive usage. Despite this rapid national decline, many women still have large numbers of children. This study investigates predictors of fertility during this fertility transition to inform policies that improve individuals' reproductive health and guide national development. METHODS: We used Poisson regression to separately model number of children born to ever married/cohabitated women (n = 8,309) and never married women (n = 1,220) age 15 to 49 based on 2010 Rwanda Demographic and Health Survey data. We used backward stepwise regression with a time offset to identify individual and household factors associated with woman's fertility level, accounting for sampling weights, clustering, and stratification. RESULTS: In ever married/cohabitating women, high fertility was significantly associated (p < 0.05) with the following variables: unmet need for contraception (IRR = 1.07), women's desire for children (5+ versus 0-2 children: IRR = 1.22), woman's number of siblings (8-20 versus 0-4: IRR = 1.03), and couples who desired different numbers of children (husband wants more: IRR = 1.04; husband wants fewer: IRR = 1.04). Low fertility in ever married/cohabitating women was associated with women's education (higher versus no education: IRR = 0.66), household wealth (highest versus lowest quintile: IRR = 0.93), and delayed sexual debut (25+ versus 8-18 years: IRR = 0.49). In never married women, low fertility was associated with education (higher versus no education: IRR = 0.22), household wealth (highest versus lowest quintile: IRR = 0.58), delayed sexual debut (25-49 versus 8-18 years: IRR = 0.43), and having an unmet need for contraception (IRR = 0.69). CONCLUSIONS: Although the study design does not allow causal conclusions, these results suggest several strategies to further reduce Rwanda's national fertility rate and support families to achieve their desired fertility. Strategies include policies and programs that promote delayed sexual debut via educational and economic opportunities for women, improved access to reproductive health information and services at schools and via health campaigns, and involvement of men in family planning decision making. PMID- 25495537 TI - solGS: a web-based tool for genomic selection. AB - BACKGROUND: Genomic selection (GS) promises to improve accuracy in estimating breeding values and genetic gain for quantitative traits compared to traditional breeding methods. Its reliance on high-throughput genome-wide markers and statistical complexity, however, is a serious challenge in data management, analysis, and sharing. A bioinformatics infrastructure for data storage and access, and user-friendly web-based tool for analysis and sharing output is needed to make GS more practical for breeders. RESULTS: We have developed a web based tool, called solGS, for predicting genomic estimated breeding values (GEBVs) of individuals, using a Ridge-Regression Best Linear Unbiased Predictor (RR-BLUP) model. It has an intuitive web-interface for selecting a training population for modeling and estimating genomic estimated breeding values of selection candidates. It estimates phenotypic correlation and heritability of traits and selection indices of individuals. Raw data is stored in a generic database schema, Chado Natural Diversity, co-developed by multiple database groups. Analysis output is graphically visualized and can be interactively explored online or downloaded in text format. An instance of its implementation can be accessed at the NEXTGEN Cassava breeding database, http://cassavabase.org/solgs. CONCLUSIONS: solGS enables breeders to store raw data and estimate GEBVs of individuals online, in an intuitive and interactive workflow. It can be adapted to any breeding program. PMID- 25495538 TI - In vitro aflatoxin B1 binding capacity by two Enterococcus faecium strains isolated from healthy dog faeces. AB - AIM: This study evaluated the binding capacity of aflatoxin B1 (AFB1 ) by two Enterococcus faecium strains (MF4 and GJ40) isolated from faeces from healthy dogs. MATERIALS AND METHODS: The binding assay was performed using 50 and 100 ppb of AFB1 analysing the effects of the viability, incubation time and pH on AFB1 binding. Binding stability was determined by washing three times the bacteria AFB1 complexes with phosphate buffer saline. RESULTS: Both GJ40 and MF4 strains have the ability to remove AFB1 from aqueous solution. Viable cells were slightly more effective in AFB1 binding than nonviable ones for both strains. Enterococcus faeciumGJ40 removes 24-27% and 17-24%, and Ent. faeciumMF4 removes 36-42% and 27 32% of AFB1 (50 and 100 ppb, respectively) throughout a 48 h incubation period. In general, the removal of AFB1 was highest at pH 7.00 for both strains. The stability of the bacteria-AFB1 complex formed was found to be high (up to 50% of AFB1 remained bounded in bacterial cell after three washes with phosphate buffered saline). CONCLUSION: The Ent. faecium strains assayed are capable of removing AFB1 under different conditions in vitro. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first AFB1 binding assay performed with Ent. faecium strains isolated from dog faeces, being an interesting strategy for AFB1 decontamination of pet food. PMID- 25495539 TI - Psychometric properties of functional balance tests in children: a literature review. AB - AIM: Identifying balance problems are the first step towards monitoring and rehabilitation. Therefore, this paper aims to make an overview of the psychometric properties of the functional balance tests available for children. METHOD: A literature search was performed in PubMED and Web of Science on 8 February 2014 and updated on 6 July 2014. A conceptual framework for functional balance tests was defined, taking balance control components and task constraints into account. The tests were selected for inclusion by consensus of 2-3 reviewers using the conceptual framework. RESULTS: Fourteen tests were investigated in 25 articles and analysed within the conceptual framework. The Timed Up and Go test, Pediatric Balance Scale, and Pediatric Reach Test are well investigated and all show good reliability. Validity remains unclear because of lack of a criterion standard to measure balance control. INTERPRETATION: Because of the lack of good methodological studies, strong evidence for the use of one or more functional balance tests in children cannot be provided. Moreover, it is necessary that a criterion standard to measure balance is established. PMID- 25495540 TI - Investigation of arc repressor DNA-binding specificity by comparative molecular dynamics simulations. AB - Transcription factors regulate gene expression through binding to specific DNA sequences. How transcription factors achieve high binding specificity is still not well understood. In this paper, we investigated the role of protein flexibility in protein-DNA-binding specificity by comparative molecular dynamics (MD) simulations. Protein flexibility has been considered as a key factor in molecular recognition, which is intrinsically a dynamic process involving fine structural fitting between binding components. In this study, we performed comparative MD simulations on wild-type and F10V mutant P22 Arc repressor in both free and complex conformations. The F10V mutant has lower DNA-binding specificity though both the bound and unbound main-chain structures between the wild-type and F10V mutant Arc are highly similar. We found that the DNA-binding motif of wild type Arc is structurally more flexible than the F10V mutant in the unbound state, especially for the six DNA base-contacting residues in each dimer. We demonstrated that the flexible side chains of wild-type Arc lead to a higher DNA binding specificity through forming more hydrogen bonds with DNA bases upon binding. Our simulations also showed a possible conformational selection mechanism for Arc-DNA binding. These results indicate the important roles of protein flexibility and dynamic properties in protein-DNA-binding specificity. PMID- 25495541 TI - Facile oxidation of primary amines to nitriles using an oxoammonium salt. AB - The oxidation of primary amines using a stoichiometric quantity of 4-acetamido 2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (1) in CH2Cl2 pyridine solvent at room temperature or at gentle reflux affords nitriles in good yield under mild conditions. The mechanism of the oxidation, which has been investigated computationally, involves a hydride transfer from the amine to the oxygen atom of 1 as the rate-limiting step. PMID- 25495542 TI - Absorption, Distribution, Metabolism, Excretion, and Toxicity Evaluation in Drug Discovery. 14. Prediction of Human Pregnane X Receptor Activators by Using Naive Bayesian Classification Technique. AB - The activation of pregnane X receptor (PXR), a member of the nuclear receptor (NR) superfamily, can mediate potential drug-drug interactions, and therefore, prediction of PXR activation is of great importance for evaluating drug metabolism and toxicity. In this study, based on 532 structurally diverse compounds, we present a comprehensive analysis with the aim to build accurate classification models for distinguishing PXR activators from nonactivators by using a naive Bayesian classification technique. First, the distributions of eight important molecular physicochemical properties of PXR activators versus nonactivators were compared, illustrating that the hydrophobicity-related molecular descriptors (AlogP and log D) show slightly better capability to discriminate PXR activators from nonactivators than the others. Then, based on molecular physicochemical properties, VolSurf descriptors, and molecular fingerprints, naive Bayesian classifiers were developed to separate PXR activators from nonactivators. The results demonstrate that the introduction of molecular fingerprints is quite essential to enhance the prediction accuracy of the classifiers. The best Bayesian classifier based on the 21 physicochemical properties, VolSurf descriptors, and LCFC_10 fingerprints descriptors yields a prediction accuracy of 92.7% for the training set based on leave-one-out (LOO) cross-validation and of 85.2% for the test set. Moreover, by exploring the important structural fragments derived from the best Bayesian classifier, we observed that flexibility is an important structural pattern for PXR activation. In addition, chemical compounds containing more halogen atoms, unsaturated alkanes chains relevant to pi-pi stacking, and fewer nitrogen atoms tend to be PXR activators. We believe that the naive Bayesian classifier can be used as a reliable virtual screening tool to predict PXR activation in the drug design and discovery pipeline. PMID- 25495543 TI - LC-REHAB: randomised trial assessing the effect of a new patient education method -learning and coping strategies--in cardiac rehabilitation. AB - BACKGROUND: Due to improved treatments and ageing population, many countries now report increasing prevalence in rates of ischemic heart disease and heart failure. Cardiac rehabilitation has potential to reduce morbidity and mortality, but not all patients complete. In light of favourable effects of cardiac rehabilitation it is important to develop patient education methods which can enhance adherence to this effective program. The LC-REHAB study aims to compare the effect of a new patient education strategy in cardiac rehabilitation called 'learning and coping' to that of standard care. Further, this paper aims to describe the theoretical basis and details of this intervention. METHODS/DESIGN: Open parallel randomised controlled trial conducted in three hospital units in Denmark among patients recently discharged with ischemic heart disease or heart failure. Patients are allocated to either the intervention group with learning and coping strategies incorporated into standard care in cardiac rehabilitation or the control group who receive the usual cardiac rehabilitation program. Learning and coping consists of two individual clarifying interviews, participation of experienced patients as educators together with health professionals and theory based, situated and inductive teaching. Usual care in cardiac rehabilitation is characterised by a structured deductive teaching style with use of identical pre-written slides in all hospital units. In both groups, cardiac rehabilitation consists of training three times a week and education once a week over eight weeks. The primary outcomes are adherence to cardiac rehabilitation, morbidity and mortality, while secondary outcomes are quality of life (SF-12, Health education impact questionnaire and Major Depression Inventory) and lifestyle and risk factors (Body Mass Index, waist circumference, blood pressure, exercise work capacity, lipid profile and DXA-scan). Data collection occurs four times; at baseline, at immediate completion of cardiac rehabilitation, and at three months and three years after the finished program. DISCUSSION: It is expected that learning and coping incorporated in cardiac rehabilitation will improve adherence in cardiac rehabilitation and may decrease morbidity and mortality. By describing learning and coping strategies the study aims to provide knowledge that can contribute to an increased transparency in patient education in cardiac rehabilitation. TRIAL REGISTRATION: Identifier NCT01668394. PMID- 25495545 TI - Side-chain packing interactions stabilize an intermediate of BAX protein against chemical and thermal denaturation. AB - Bcl-2-associated X (BAX) protein plays a gatekeeper role in transmitting apoptotic signaling from cytosol to mitochondria. However, little is known about its stability. This study reports a comprehensive investigation on the stability of BAX using spin-label ESR, CD, and ThermoFluor methods. Point mutations covering all of the nine helices of BAX were prepared. ESR study shows that BAX can be divided into two structural regions, each responding differently to the presence of guanidine hydrochloride (GdnHCl). The N-terminal region (helices 1-3) is denatured in 6 M GdnHCl, whereas the C-terminal region (helices 4-9) is resistant to the denaturing effects. The far-UV CD spectra show an appreciable amount of helical content of BAX at high temperatures. The magnitude of the near UV CD signal is increased with increasing temperature in either 0 or 6 M GdnHCl, indicating an enhancement of aromatic side-chain packing in the C-terminal region. Taken together with ThermoFluor results, we show that a core interior, wherein aromatic interactions are highly involved, within the C-terminal region plays an important role in stabilizing BAX against the denaturing effects. Collectively, we report a highly stable, indestructible intermediate state of BAX. Side-chain packing interactions are shown to be the major stabilizing force in determining BAX structure. PMID- 25495546 TI - Preschoolers' understanding of the role of communication and cooperation in establishing property rights. AB - Property as a social "agreement" comprises both a communicative component, in which someone makes a claim that she is entitled to some piece of property, and a cooperative component, in which others in the community respect that claim as legitimate. In the current study, preschool children were (a) given the opportunity to mark some objects as "theirs" (to claim them in the face of other fictitious children who would supposedly enter the room later); and (b) confronted with stickers in various spatial arrangements (e.g., piled up neatly vs. scattered), told that a fictitious child had previously chosen some for herself but had to suddenly leave the room, and then invited first to choose some stickers for themselves and second to identify which stickers had already been claimed by the fictitious child. Five-year-olds but not 3-year-olds were skillful in both of these tasks, demonstrating an understanding of the crucial role of communication in asserting property claims and the crucial role of cooperation in respecting them. PMID- 25495544 TI - Angiotensin-(1-7) prevents systemic hypertension, attenuates oxidative stress and tubulointerstitial fibrosis, and normalizes renal angiotensin-converting enzyme 2 and Mas receptor expression in diabetic mice. AB - We investigated the relationship between Ang-(1-7) [angiotensin-(1-7)] action, sHTN (systolic hypertension), oxidative stress, kidney injury, ACE2 (angiotensin converting enzyme-2) and MasR [Ang-(1-7) receptor] expression in Type 1 diabetic Akita mice. Ang-(1-7) was administered daily [500 MUg/kg of BW (body weight) per day, subcutaneously] to male Akita mice from 14 weeks of age with or without co administration of an antagonist of the MasR, A779 (10 mg/kg of BW per day). The animals were killed at 20 weeks of age. Age-matched WT (wild-type) mice served as controls. Ang-(1-7) administration prevented sHTN and attenuated kidney injury (reduced urinary albumin/creatinine ratio, glomerular hyperfiltration, renal hypertrophy and fibrosis, and tubular apoptosis) without affecting blood glucose levels in Akita mice. Ang-(1-7) also attenuated renal oxidative stress and the expression of oxidative stress-inducible proteins (NADPH oxidase 4, nuclear factor erythroid 2-related factor 2, haem oxygenase 1), pro-hypertensive proteins (angiotensinogen, angiotensin-converting enzyme, sodium/hydrogen exchanger 3) and profibrotic proteins (transforming growth factor-beta1 and collagen IV), and increased the expression of anti-hypertensive proteins (ACE2 and MasR) in Akita mouse kidneys. These effects were reversed by A779. Our data suggest that Ang-(1 7) plays a protective role in sHTN and RPTC (renal proximal tubular cell) injury in diabetes, at least in part, through decreasing renal oxidative stress-mediated signalling and normalizing ACE2 and MasR expression. PMID- 25495547 TI - Testing the vulnerability and scar models of self-esteem and depressive symptoms from adolescence to middle adulthood and across generations. AB - The vulnerability model states that low self-esteem functions as a predictor for the development of depressive symptoms whereas the scar model assumes that these symptoms leave scars in individuals resulting in lower self-esteem. Both models have received empirical support, however, they have only been tested within individuals and not across generations (i.e., between family members). Thus, we tested the scope of these competing models by (a) investigating whether the effects hold from adolescence to middle adulthood (long-term vulnerability and scar effects), (b) whether the effects hold across generations (intergenerational vulnerability and scar effects), and (c) whether intergenerational effects are mediated by parental self-esteem and depressive symptoms and parent-child discord. We used longitudinal data from adolescence to middle adulthood (N = 1,359) and from Generation 1 adolescents (G1) to Generation 2 adolescents (G2) (N = 572 parent-child pairs). Results from latent cross-lagged regression analyses demonstrated that both adolescent self-esteem and depressive symptoms were prospectively related to adult self-esteem and depressive symptoms 3 decades later. That is, both the vulnerability and scar models are valid over decades with stronger effects for the vulnerability model. Across generations, we found a substantial direct transmission effect from G1 to G2 adolescent depressive symptoms but no evidence for the proposed intergenerational vulnerability and scar effect or for any of the proposed mediating mechanisms. PMID- 25495548 TI - Quality of life ratings in dementia care--a cross-sectional study to identify factors associated with proxy-ratings. AB - OBJECTIVE: Quality of life (QoL) is one major outcome parameter in the care for people with dementia (PwD); however, their assessment is lacking a gold standard. The purpose of this study was to evaluate potential factors associated with nurse rated quality of life of PwD in nursing homes in Berlin, Germany. METHOD: An explorative cross-sectional study was performed in five nursing homes to evaluate QoL. Nurses rated the QoL for all residents with dementia by completing two different standardised assessments (ADRQL, QUALIDEM). Potential associated factors were evaluated concerning resident and nurse related factors. A fixed effects models of analysis of co-variance (ANCOVA) was used to analyse effects of assumed associated factors of the major outcome parameters ADRQL and QUALIDEM. Associated factors were severity of dementia (GDS), challenging behaviour (CMAI), and other characteristics. Regarding the nurses, burnout (MBI), satisfaction with life (SWLS), attitude (ADQ) and empathy toward residents (JSPE), as well as circumstances of the ratings and days worked in advance of the ratings were assessed. RESULTS: In total, 133 PwD and 88 nurses were included. Overall, the ratings show moderate to high QoL in every subscale independent of the instrument used. Assumed confounders relevantly influenced 14 out of 17 ratings. Predominantly, residents' challenging behaviour, nurses' burnout and satisfaction with life as well as the circumstances of the ratings are significant and clinically relevant associated factors. CONCLUSION: Assessing QoL of PwD is acknowledged as a central component of health care and health care research. In later stages of dementia, proxy-reported information obtained from quality of life questionnaires is and will continue to be essential in this research. However, methodological issues that underline this research - matters of measurement and instrument validity - must receive more attention. Associated factors in proxy-ratings have to be routinely assessed in order to get more valid and comparable estimates. PMID- 25495551 TI - Scalable surface area characterization by electrokinetic analysis of complex anion adsorption. AB - By means of the in situ electrokinetic assessment of aqueous particles in conjunction with the addition of anionic adsorbates, we develop and examine a new approach to the scalable characterization of the specific accessible surface area of particles in water. For alumina powders of differing morphology in mildly acidic aqueous suspensions, the effective surface charge was modified by carboxylate anion adsorption through the incremental addition of oxalic and citric acids. The observed zeta potential variation as a function of the proportional reagent additive was found to exhibit inverse hyperbolic sine-type behavior predicted to arise from monolayer adsorption following the Grahame Langmuir model. Through parameter optimization by inverse problem solving, the zeta potential shift with relative adsorbate addition revealed a nearly linear correlation of a defined surface-area-dependent parameter with the conventionally measured surface area values of the powders, demonstrating that the proposed analytical framework is applicable for the in situ surface area characterization of aqueous particulate matter. The investigated methods have advantages over some conventional surface analysis techniques owing to their direct applicability in aqueous environments at ambient temperature and the ability to modify analysis scales by variation of the adsorption cross section. PMID- 25495550 TI - A descriptive analysis of the indications for caesarean section in mainland China. AB - BACKGROUND: In recent decades we have observed a remarkable increase in the rate of caesarean section (CS) in both developed and developing countries, especially in China. However, the real reasons for this phenomenon are uncertain. Notably, the number of women requesting elective CS without accepted valid medical indication has also increased, generating a nationwide debate because several studies have shown that this may be the underlying cause of the increase in CS rates observed recently. Therefore, we carried out a multicentre, large-sample, cross-sectional study to describe the CS rate and indications for CS in mainland China during 2011. METHODS: This was a multicentre, large-sample, cross-sectional study of women who delivered infants in 39 hospitals in 14 provinces in China during 2011. We selected 111, 315 deliveries that occurred during 2011, excluding miscarriages or termination of pregnancy before 28 gestational weeks. RESULTS: The overall rate of CS in mainland China was 54.90%. The most common indication for CS was caesarean delivery on maternal request (CDMR; 28.43%), followed by cephalo-pelvic disproportion (14.08%), fetal distress (12.46%), previous CS (10.25%), malpresentation and breech presentation (6.56%), macrosomia (6.10%) and other indications (22.12%). CDMR accounted for 15.53% of all the deliveries and 28.43% of all CS deliveries in mainland China. CONCLUSIONS: CDMR appears to be a considerable driver behind the increasing CS rate in mainland China. The relaxation of China's "one-child policy" may translate into a greater number of CS because of previous CS delivery. To decrease the CS rate, we should first decrease the rate of CS on maternal request. Appropriate policies and guidelines should be considered to accomplish the goal. PMID- 25495549 TI - Rapid species-level identification of vaginal and oral lactobacilli using MALDI TOF MS analysis and 16S rDNA sequencing. AB - BACKGROUND: Lactobacillus represents a large genus with different implications for the human host. Specific lactobacilli are considered to maintain vaginal health and to protect from urogenital infection. The presence of Lactobacillus species in carious lesions on the other hand is associated with progressive caries. Despite their clinical significance, species-level identification of lactobacilli still poses difficulties and mostly involves a combination of different phenotypic and genotypic methods. This study evaluated rapid MALDI-TOF MS analysis of vaginal and oral Lactobacillus isolates in comparison to 16S rDNA analysis. RESULTS: Both methods were used to analyze 77 vaginal and 21 oral Lactobacillus isolates. The concordance of both methods was at 96% with five samples discordantly identified. Fifteen different Lactobacillus species were found in the vaginal samples, primarily L. iners, L. crispatus, L. jensenii and L. gasseri. In the oral samples 11 different species were identified, mostly L. salivarius, L. gasseri, L. rhamnosus and L. paracasei. Overall, the species found belonged to six different phylogenetic groups. For several samples, MALDI-TOF MS analysis only yielded scores indicating genus-level identification. However, in most cases the species found agreed with the 16S rDNA analysis result. CONCLUSION: MALDI-TOF MS analysis proved to be a reliable and fast tool to identify lactobacilli to the species level. Even though some results were ambiguous while 16S rDNA sequencing yielded confident species identification, accuracy can be improved by extending reference databases. Thus, mass spectra analysis provides a suitable method to facilitate monitoring clinically relevant Lactobacillus species. PMID- 25495554 TI - Virus Sensitivity Index of UV disinfection. AB - A new concept of Virus Sensitivity Index (VSI) is defined as the ratio between the first-order inactivation rate constant of a virus, ki, and that of MS2-phage during UV disinfection, kr. MS2-phage is chosen as the reference virus because it is recommended as a virus indicator during UV reactor design and validation by the US Environmental Protection Agency. VSI has wide applications in research, design, and validation of UV disinfection systems. For example, it can be used to rank the UV disinfection sensitivity of viruses in reference to MS2-phage. There are four major steps in deriving the equation between Hi/Hr and 1/VSI. First, the first-order inactivation rate constants are determined by regression analysis between Log I and fluence required. Second, the inactivation rate constants of MS2-phage are statistically analysed at 3, 4, 5, and 6 Log I levels. Third, different VSI values are obtained from the ki of different viruses dividing by the kr of MS2-phage. Fourth, correlation between Hi/Hr and 1/VSI is analysed by using linear, quadratic, and cubic models. As expected from the theoretical analysis, a linear relationship adequately correlates Hi/Hr and 1/VSI without an intercept. VSI is used to quantitatively predict the UV fluence required for any virus at any log inactivation (Log I). Four equations were developed at 3, 4, 5, and 6 Log I. These equations have been validated using external data which are not used for the virus development. At Log I less than 3, the equation tends to under-predict the required fluence at both low Log I such as 1 and 2 Log I. At Log I greater than 3 Log I, the equation tends to over-predict the fluence required. The reasons for these may very likely be due to the shoulder at the beginning and the tailing at the end of the collimated beam test experiments. At 3 Log I, the error percentage is less than 6%. The VSI is also used to predict inactivation rate constants under two different UV disinfection scenarios such as under sunlight and different virus aggregates. The correlation analysis shows that viruses will be about 40% more sensitive to sunlight than to UV254. On the other hand, virus size of 500 nm will reduce their VSI by 10%. This is the first attempt to use VSI to predict the required fluence at any given Log I. The equation can be used to quantitatively evaluate other parameters influencing UV disinfection. These factors include environmental species, antibiotic-resistant bacteria or genes, photo and dark repair, water quality such as suspended solids, and UV transmittance. PMID- 25495552 TI - Launching a virtual decision lab: development and field-testing of a web-based patient decision support research platform. AB - BACKGROUND: Over 100 trials show that patient decision aids effectively improve patients' information comprehension and values-based decision making. However, gaps remain in our understanding of several fundamental and applied questions, particularly related to the design of interactive, personalized decision aids. This paper describes an interdisciplinary development process for, and early field testing of, a web-based patient decision support research platform, or virtual decision lab, to address these questions. METHODS: An interdisciplinary stakeholder panel designed the web-based research platform with three components: a) an introduction to shared decision making, b) a web-based patient decision aid, and c) interactive data collection items. Iterative focus groups provided feedback on paper drafts and online prototypes. A field test assessed a) feasibility for using the research platform, in terms of recruitment, usage, and acceptability; and b) feasibility of using the web-based decision aid component, compared to performance of a videobooklet decision aid in clinical care. RESULTS: This interdisciplinary, theory-based, patient-centered design approach produced a prototype for field-testing in six months. Participants (n = 126) reported that: the decision aid component was easy to use (98%), information was clear (90%), the length was appropriate (100%), it was appropriately detailed (90%), and it held their interest (97%). They spent a mean of 36 minutes using the decision aid and 100% preferred using their home/library computer. Participants scored a mean of 75% correct on the Decision Quality, Knowledge Subscale, and 74 out of 100 on the Preparation for Decision Making Scale. Completing the web-based decision aid reduced mean Decisional Conflict scores from 31.1 to 19.5 (p < 0.01). CONCLUSIONS: Combining decision science and health informatics approaches facilitated rapid development of a web-based patient decision support research platform that was feasible for use in research studies in terms of recruitment, acceptability, and usage. Within this platform, the web-based decision aid component performed comparably with the videobooklet decision aid used in clinical practice. Future studies may use this interactive research platform to study patients' decision making processes in real-time, explore interdisciplinary approaches to designing web-based decision aids, and test strategies for tailoring decision support to meet patients' needs and preferences. PMID- 25495555 TI - Determining critical nutrient thresholds needed to control harmful cyanobacterial blooms in eutrophic Lake Taihu, China. AB - Nutrient overenrichment has led to dramatic increases in harmful cyanobacterial blooms, creating serious threats to drinking water supplies, ecological and economic sustainability of freshwater ecosystems. Nutrient-cyanobacterial bloom interactions were examined in eutrophic Lake Taihu, China. In situ microcosm nutrient dilution bioassays and mesocosm nutrient addition experiments were conducted to determine nitrogen (N) and phosphorus (P) concentration and load thresholds needed to control cyanobacterial bloom formation. Blooms were dominated by toxic, non N2 fixing Microcystis spp, from May to December. Dilution bioassays showed seasonality in nutrient limitation, with P-availability controlling prebloom spring conditions and N-availability controlling summer-fall blooms. Nutrient dilution and enrichment bioassays indicated that total nitrogen (TN) and total phosphorus (TP) concentration thresholds should be targeted at below 0.80 mg L(-1) and 0.05 mg L(-1), respectively, to limit intrinsic growth rates of Microcystis dominated blooms. Based on estimates of nutrient loading and observed stoichiometry of phytoplankton biomass, 61-71% TN and 20-46% TP reduction are necessary to bring Taihu's phytoplankton biomass to "acceptable" sub-bloom conditions of less than 20 MUg L(-1) chlorophyll a. PMID- 25495556 TI - Structural correlates of COMT Val158Met polymorphism in childhood ADHD: a voxel based morphometry study. AB - OBJECTIVES: The Val158-allele of the catechol-O-methyltransferase (COMT) Val158Met (rs4680) functional polymorphism has been identified as a risk factor for antisocial behaviour in attention-deficit/hyperactivity disorder (ADHD). Here, we used voxel-based morphometry to investigate the effects of Val158Met polymorphism on grey matter (GM) volumes in a sample of 7-13-year-old children. METHODS: MRI and genotype data were obtained for 38 children with combined-type ADHD and 24 typically developing (TD) children. Four regions of interest were identified: striatum, cerebellum, temporal lobe and inferior frontal gyrus (IFG). RESULTS: When compared to TD children, those with ADHD had a significant decrease of GM volume in the IFG. Volume in this region was negatively correlated with ratings of hyperactivity/impulsivity symptoms. Furthermore, the smaller GM volume in the IFG was attributed to the presence of the Met158-allele, as only children with ADHD carrying a Met158-allele exhibited such decrease in the IFG. Children with ADHD homozygotes for the Val158-allele presented increased GM volume in the caudate nucleus when compared with TD children. CONCLUSIONS: This study provides the first evidence of a modulation of ADHD-related GM volume alterations by Val158Met in two key regions, possibly mediating the relationship between Val158Met polymorphism and antisocial behaviour in children with ADHD. PMID- 25495557 TI - The prevalence of burning mouth syndrome: a population-based study. PMID- 25495558 TI - New insights into the role of the disordered WIP N-terminal domain revealed by NMR structural characterization. AB - WASp-interacting protein (WIP) is an intrinsically disordered 503-residue polypeptide with a key role in actin polymerization in activated T cells. Its interaction with actin is mediated by a pair of conserved actin binding motifs (ABMs) at the WIP N-terminus, a domain that has not been investigated in its unbound form. Here we use NMR to investigate the biophysical behavior of the N terminal ABM in WIP using protonless (13)C'-detected spectroscopy. Secondary chemical shifts, residual dipolar couplings and temperature effects identify residual structure throughout the ABM, which exhibits transient helical and beta strand character for residues 30-42 and 44-62, respectively. These observed structural propensities echo the structure observed in the actin-bound state of the ABM. Furthermore, residues preceding the canonical ABM (17-25) and conserved among WIP-related proteins exhibit transient beta-strand character, suggesting that the WIP(N) interaction epitope extends towards the N-terminal polyproline motif. This suggests a possible role for this region in mediating the WIP interaction with polyproline binders such as profilin. In revealing these features of the WIP ABM this study demonstrates the unique ability of NMR in characterizing unstructured domains and provides necessary information for further investigation of WIP-mediated protein-protein interactions. PMID- 25495559 TI - Retraction: "Chronic constipation-associated symptoms in Asians and non-Asians, and effects of 12-week prucalopride treatment: A pooled analysis of 4 randomized, placebo-controlled trials" by Suck Chei CHOI, Duo Wu ZOU, Mei Yun KE, Somchai LEELAKUSOLVONG, Jan TACK, Eamonn MM QUIGLEY, Andy LIU and Jin Yong KIM. PMID- 25495561 TI - 1,3-Diiodocalix[4]arene: synthesis by Ullmann-type iodination of 1,3-bistriflate ester of calix[4]arene, conformational analysis, and transformation into 1,3 dicarboxy-, diformyl-, and dialkylcalix[4]arenes. AB - A facile synthesis of 1,3-diiodocalix[4]arene 6 has been achieved by copper catalyzed iodination of the 1,3-bistriflate ester 2a of p-tert butylcalix[4]arene. After protection of the hydroxy groups with iodomethane, diiodide 6 is subjected to halogen-lithium exchange with butyllithium, followed by carbonation with CO2 or formylation with N-formylpiperidine and subsequent deprotection of the hydroxy groups to give novel dicarboxylic acid 11 or dialdehyde 16 in practical yields. The iodo groups of diiodide 6 pass through the calixarene macrocycle; the activation free energy for the conversion of the more stable syn conformer 6syn to the less stable anti conformer 6anti is DeltaG(?) = 104 kJ mol(-1) at 298 K. Dialdehyde 16 shows fast self-exchange between two equivalent species with a cone conformation, DeltaG(?), being 63.2 kJ mol(-1). Dicarboxylic acid 11 adopts a cone conformation and forms a dimer in solution as suggested by 1H NMR and X-ray crystallographic analyses. The arrangement of the iodide groups of compound 6 can be fixed predominantly to anti (17a and 17b) by introducing bulky alkyl groups (e.g., propyl groups) onto the hydroxy groups. The stereospecific alkylation of the iodo groups of the resulting di-O-alkylated anti 1,3-diiodides provides access to the anti-1,3-dialkylcalixarenes 19, which is otherwise difficult to obtain. PMID- 25495560 TI - Autophagy fosters myofibroblast differentiation through MTORC2 activation and downstream upregulation of CTGF. AB - Recent evidence suggests that autophagy may favor fibrosis through enhanced differentiation of fibroblasts in myofibroblasts. Here, we sought to characterize the mediators and signaling pathways implicated in autophagy-induced myofibroblast differentiation. Fibroblasts, serum starved for up to 4 d, showed increased LC3-II/-I ratios and decreased SQSTM1/p62 levels. Autophagy was associated with acquisition of markers of myofibroblast differentiation including increased protein levels of ACTA2/alphaSMA (actin, alpha 2, smooth muscle, aorta), enhanced gene and protein levels of COL1A1 (collagen, type I, alpha 1) and COL3A1, and the formation of stress fibers. Inhibiting autophagy with 3 different class I phosphoinositide 3-kinase and class III phosphatidylinositol 3 kinase (PtdIns3K) inhibitors or through ATG7 silencing prevented myofibroblast differentiation. Autophagic fibroblasts showed increased expression and secretion of CTGF (connective tissue growth factor), and CTGF silencing prevented myofibroblast differentiation. Phosphorylation of the MTORC1 target RPS6KB1/p70S6K kinase was abolished in starved fibroblasts. Phosphorylation of AKT at Ser473, a MTORC2 target, was reduced after initiation of starvation but was followed by spontaneous rephosphorylation after 2 d of starvation, suggesting the reactivation of MTORC2 with sustained autophagy. Inhibiting MTORC2 activation with long-term exposure to rapamycin or by silencing RICTOR, a central component of the MTORC2 complex abolished AKT rephosphorylation. Both RICTOR silencing and rapamycin treatment prevented CTGF and ACTA2 upregulation, demonstrating the central role of MTORC2 activation in CTGF induction and myofibroblast differentiation. Finally, inhibition of autophagy with PtdIns3K inhibitors or ATG7 silencing blocked AKT rephosphorylation. Collectively, these results identify autophagy as a novel activator of MTORC2 signaling leading to CTGF induction and myofibroblast differentiation. PMID- 25495562 TI - Non-invasive assessment of liver fibrosis in C282Y homozygous HFE hemochromatosis. AB - BACKGROUND & AIMS: C282Y homozygotes with serum ferritin (SF) levels >1000 MUg/L and/or increased serum transaminase levels are at risk of severe F3/F4 fibrosis. Current practical guidelines recommend liver biopsy in such individuals. This prospective observational cohort study aimed to evaluate non-invasive alternative means such as hyaluronic acid (HA) and transient elastography (TE) for the assessment of severe fibrosis in patients with SF >1000 MUg/L or elevated transaminases. METHODS: Between September 2005 and April 2013, 77 patients diagnosed C282Y homozygotes underwent a liver biopsy because of SF >1000 MUg/L and/or increased transaminases according to current guidelines, with concomitant TE. All of them had clinical and biological evaluation, including HA measurement in 52 cases. RESULTS: A total of 19.5% of patients had F3-F4 severe fibrosis. HA was higher in patients with severe fibrosis, but did not accurately predict severe fibrosis. TE was significantly higher in patients with severe fibrosis (17.2 vs. 4.9 kPa; P < 0.05) and was able to accurately predict fibrosis stage in 47/61 (77%) patients with valid measurement using a lower threshold of 6.4 kPa and an upper threshold of 13.9 kPa. Efficient assessment of severe fibrosis was not possible in patients with intermediate TE values. CONCLUSION: An algorithm that successively employed SF and TE can accurately classify severe fibrosis in 61% of patients, restricting the need for liver biopsy to the 39% of patients with intermediate or unvalid TE values. This algorithm should be validated in independent cohorts before extended use. PMID- 25495563 TI - Beauty, symmetry, and magnetocaloric effect-four-shell keplerates with 104 lanthanide atoms. AB - The hydrolysis of Ln(ClO4)3 in the presence of acetate leads to the assembly of the three largest known lanthanide-exclusive cluster complexes, [Nd104(ClO4)6(CH3COO)60(MU3-OH)168(MU4-O)30(H2O)112].(ClO4)18.(CH3CH2OH)8.xH2O (1, x ~ 158) and [Ln104(ClO4)6(CH3COO)56(MU3-OH)168(MU4 O)30(H2O)112].(ClO4)22.(CH3CH2OH)2.xH2O (2, Ln = Nd; 3, Ln = Gd; x ~ 140). The structure of the common 104-lanthanide core, abbreviated as Ln8@Ln48@Ln24@Ln24, features a four-shell arrangement of the metal atoms contained in an innermost cube (a Platonic solid) and, moving outward, three Archimedean solids: a truncated cuboctahedron, a truncated octahedron, and a rhombicuboctahedron. The magnetic entropy change of DeltaS(m) = 46.9 J kg(-1) K(-1) at 2 K for DeltaH = 7 T in the case of the Gd104 cluster is the largest among previously known lanthanide-exclusive cluster compounds. PMID- 25495564 TI - Is the digital divide an obstacle to e-health? An analysis of the situation in Europe and in Italy. AB - INTRODUCTION: The digital divide affecting elderly patients may compromise the diffusion of telemedicine systems for this age segment. It might be that the difficulties in the passage from trials to the effective distribution of telemedicine systems are also due to the awareness of a personal digital divide in the target population. MATERIALS AND METHODS: The analysis aims to estimate the number of people over the age of 50 years with potential cardiovascular problems able to access the Web. It made use of data from several sources (the Survey of Health, Ageing and Retirement in Europe and the Istituto Nazionale di Statistica Multiscopo Survey). Furthermore, with regard to Italy, the estimates obtained from official data were compared with those obtained in a survey investigating heart failure patients in Tuscany. RESULTS: In 2011, the percentage of people suffering from cardiovascular diseases and with Web access was 24% in Europe, with significant differences by country (ranging from 53% in Switzerland to below 20% in Italy, Spain, and Portugal). In Italy, however, the proportion of people with Web access increased from 2007 to 2011, and the survey in Tuscany showed that elderly people with limited information and communications technology skills overcame challenges and learned how to connect to the Web because they started to appreciate new technologies. CONCLUSIONS: The opportunity to use the Internet to monitor patients with chronic disease can serve as a challenge to reduce the digital divide gap and, furthermore, to increase their social and technological inclusion. PMID- 25495565 TI - Polyaniline-decorated {001} facets of Bi2O2CO3 nanosheets: in situ oxygen vacancy formation and enhanced visible light photocatalytic activity. AB - Polyaniline (PANI)-decorated {001} facets of Bi2O2CO3 nanosheets were synthesized by a low-temperature chemical method. We demonstrate that the strong interfacial interactions between Bi2O2CO3 {001} facets and PANI could promote in situ formation of oxygen vacancy at the interface confirmed by both density functional theory calculations and electron spin resonance experiments, which is due to the high oxygen density characteristic of Bi2O2CO3 {001} facets. In addition, such interfacial interaction also leads to a 0.38 eV positive shifting of the valence band of Bi2O2CO3. Importantly, the decorated PANI can stabilize these interfacial oxygen vacancies. Therefore, the migration and separation of photogenerated carriers have been improved significantly evidenced by electrochemical impedance spectroscopy, photoluminescence, and nanosecond time-resolved fluorescence-decay spectra, resulting in a 4.5 times higher activity toward photodegradation of Rhodamine B and a 6 times higher photocurrent density compared to their corresponding bare Bi2O2CO3. The finding of the in situ oxygen vacancy formation at the interface could provide some hints for the deep understanding of the interactions between PANI and crystal facets of semiconductors to develop highly efficient photocatalysts. PMID- 25495566 TI - Predictors of continued playing or singing--from childhood and adolescence to adult years. AB - AIM: Many individuals play an instrument or sing during childhood, but they often stop later in life. This study surveyed adults representative of the Swedish population about musical activities during childhood. METHODS: We asked 3820 adults (65% women) aged from 27 to 54 from the Swedish Twin Registry, who took extra music lessons to those provided at school, to fill in a web-based questionnaire. Factors analysed were the age they started studying music, the instrument they played, kind of teaching, institution and educational content, number of lessons and perceived characteristics of the lessons, the music environment during their childhood years and their preferred music genre. All variables were dichotomised. RESULTS: Factors strongly associated with continued playing or singing were male sex, young starting age, cultural family background, self-selected instrument, attending music classes and more than once a week, church-related or private education, pop, rock or classical music, playing by ear and improvisation. CONCLUSION: Several significant predictors determined whether a child continued to sing or play an instrument as an adult and many could be externally influenced, such as starting at a young age, taking music classes more than once a week, improvisation and the type of music they played. PMID- 25495567 TI - Translocator protein (TSPO) role in aging and Alzheimer's disease. AB - Cellular damage and deregulated apoptotic cell death lead to functional impairment, and a main consequence of these events is aging. Cellular damage is initiated by different stress/risk factors such as oxidative stress, inflammation, and heavy metals. These stress/risk factors affect the cellular homeostasis by altering methylation status of several aging and Alzheimer's disease associated genes; these effects can be manifested immediately after exposure to stress and at later stages of life. However, when cellular damage exceeds certain threshold levels apoptosis is initiated. This review discusses the stress factors involved in cellular damage and the role and potential of TSPO mediated cell death in aging as well as in Alzheimer's disease, which is also characterized by extensive cell death. Mitochondrial-mediated apoptotic death through the release of cytochrome c is regulated by TSPO, and increased expression of this protein is observed in both elderly people and in patients with Alzheimer's disease. TSPO forms and mediates opening of the mitochondrial membrane pore, mPTP and oxidizes cardiolipin, and these events lead to the leakage of apoptotic death mediators, such as cytochrome c, resulting in cell death. However, TSPO has many proposed functions and can also increase steroid synthesis, which leads to inhibition of inflammation and inhibition of the release of apoptotic factors, thereby decreasing cell damage and promoting cell survival. Thus, TSPO mediates apoptosis and decreases the cell damage, which in turn dictates the process of aging as well as the functionality of organs such as the brain. TSPO modulation with ligands in the Alzheimer's disease mouse model showed improvement in behavioral symptoms, and studies in Drosophila species showed increased cell survival and prolonged lifespan in flies after TSPO inhibition. These data suggest that since effects/signs of stress can manifest at any time, prevention through change in lifestyle and TSPO modulation could be potential strategies for altering both the aging process and the progression of Alzheimer's disease. PMID- 25495568 TI - Decrease of risk of developing symptoms of OAB in elderly men and women treated with loop diuretic for hypertensive disease using solifenacin. AB - OBJECTIVES: MATERIALS AND METHODS: Randomized double blind longitudinal study was performed from December 1, 2012 to June 15, 2013 in urological ward of gerontological hospital (Vladivostok city, Russian Federation). 378 men and women over 65 (average age: 69.8 (7.2)), who suffered from stage 1 (initial) hypertension, had participated in this study. During the treatment all patients, except for those who were assigned to the control group, received Loop Diuretic Furosemide dosed at 20-30 mg per day and Solifenacin dosed at 5 mg per day (First comparison group) and 10 mg per day (Second comparison group). Functional performance of lower urinary tract (LUT) at enrollment and at the end of the treatment was evaluated using ICIQ-SF questionnaires. During the whole period of treatment patients were keeping bladder diaries where records on frequency and volume of daily urinations, episodes of urgency (EU), episodes of incontinence (EI) and other symptoms were kept. RESULT: Comparison of data obtained from control group (7.2%), group of the patients treated with Furosemide and standard- dosed (11.1%) and low-dosed (16.2%) Solifenacin allows to draw conclusion on the absence of significant differences in number of patients with symptoms of OAB between these groups (p >= 0.05). At the same time percentage of patients with symptoms of OAB in the group treated only with Furosemide was significantly different from three other groups (p <= 0.05) and reached 46.1%. CONCLUSION: Risk of developing symptoms of OAB in elderly patients, whose hypertensive disease has been treated with loop diuretic for a long period of time, decreases significantly, provided antimuscarinic drug Solifencin is administered at the same time. Administration of low dosed Solifenacin is sufficient for significant decrease in risk of developing symptoms of overactive bladder. PMID- 25495569 TI - The prognostic utility of (18)F-FDG-PET metabolic tumor response after chemoradiotherapy for locally advanced head and neck cancer. PMID- 25495570 TI - Cervical cancer screening in the Faroe Islands. AB - BACKGROUND: The Faroe Islands have had nationally organised cervical cancer screening since 1995. Women aged 25-60 years are invited every third year. Participation is free of charge. Although several European overviews on cervical screening are available, none have included the Faroe Islands. Our aim was to provide the first description of cervical cancer screening, and to determine the screening history of women diagnosed with cervical cancer in the Faroe Islands. MATERIAL AND METHODS: Screening data from 1996 to 2012 were obtained from the Diagnostic Centre at the National Hospital of the Faroe Islands. They included information on cytology and HPV testing whereas information on histology was not registered consistently. Process indicators were calculated, including coverage rate, excess smears, proportion of abnormal cytological samples, and frequency of HPV testing. Data on cervical cancer cases were obtained from the Faroese Ministry of Health Affairs. The analysis of the screening history was undertaken for cases diagnosed in 2000-2010. RESULTS: A total of 52 457 samples were taken in 1996-2012. Coverage varied between 67% and 81% and was 71% in 2012. Excess smears decreased after 1999. At present, 7.0% of samples have abnormal cytology. Of all ASCUS samples, 76-95% were tested for HPV. A total of 58% of women diagnosed with cervical cancer did not participate in screening prior to their diagnosis, and 32% had normal cytology in the previous four years. CONCLUSION: Despite the difficult geographical setting, the organised cervical cancer screening programme in the Faroe Islands has achieved a relatively high coverage rate. Nevertheless, challenges, e.g. consistent histology registration and sending reminders, still exist. PMID- 25495571 TI - Environmental tobacco smoke exposure, urine CC-16 levels, and asthma outcomes among Chinese children. AB - BACKGROUND: Previous studies have shown the relationship between club cell secretory protein (Clara) (CC-16) and respiratory diseases. However, few studies have explored the associations between urine CC-16 levels and environmental tobacco smoke (ETS) exposure in children. The objective of this study was to evaluate whether ETS exposure is associated with CC-16 when stratified by asthma status. METHODS: In our study, CC-16 was measured on 537 children aged 9-15 from northeast China in 2011-2012 using the Human Clara Cell Protein ELISA kits. Doctor-diagnosed asthma was defined as having ever been diagnosed with asthma by a physician. The relationship between ETS exposure and urine CC-16 level was assessed using linear regression. RESULTS: When stratified by asthma status, a negative association between ETS exposure and urine CC-16 was observed after adjusting for the effects of the related covariates, with an adjusted beta coefficient [P value] = -0.31 [0.006] in the first 2 years of life and with an adjusted beta coefficient [P value] = -0.68 [0.004] in the first 2 years of life and current. CONCLUSIONS: Our study shows long-term exposure to ETS was associated with urinary CC-16 among children without asthma. PMID- 25495573 TI - Mechanism of the gaseous hydrolysis reaction of SO2: Effects of NH3 versus H2O. AB - Effects of ammonia and water molecules on the hydrolysis of sulfur dioxide are investigated by theoretical calculations of two series of the molecular clusters SO2-(H2O)n (n = 1-5) and SO2-(H2O)n-NH3 (n = 1-3). The reaction in pure water clusters is thermodynamically unfavorable. The additional water in the clusters reduces the energy barrier for the reaction, and the effect of each water decreases with the increasing number of water molecules in the clusters. There is a considerable energy barrier for reaction in SO2-(H2O)5, 5.69 kcal/mol. With ammonia included in the cluster, SO2-(H2O)n-NH3, the energy barrier is dramatically reduced, to 1.89 kcal/mol with n = 3, and the corresponding product of hydrated ammonium bisulfate NH4HSO3-(H2O)2 is also stabilized thermodynamically. The present study shows that ammonia has larger kinetic and thermodynamic effects than water in promoting the hydrolysis reaction of SO2 in small clusters favorable in the atmosphere. PMID- 25495572 TI - Outcomes in pediatric hepatitis C transplant recipients: analysis of the UNOS database. AB - HCV may lead to the development of ESLD in late childhood and, consequently, contributes to the need for liver transplantation. The aim of this study was to examine post-transplant outcomes in HCV-positive pediatric patients with ESLD from any cause and to determine the impact of the PELD scoring system, introduced in February 2002, on post-transplant patient and graft survival. A retrospective analysis of the UNOS database from 1994 to 2010 was performed to assess graft and patient survival in pediatric HCV-seropositive liver transplant recipients. Graft survival and patient survival comparing subjects in the pre-PELD era and post PELD era were analyzed using Kaplan-Meier statistics. Factors associated with survival were identified using Cox regression analysis. Of 120 pediatric HCV transplant recipients, 80 were transplanted in the pre-PELD era and 40 were transplanted post-PELD. Median serum total bilirubin, INR, and creatinine were 4.8 mg/dL, 1.6, and 0.7 mg/dL in the pre-PELD era vs. 5.5 mg/dL, 1.7, and 0.6 mg/mL, respectively, in the post-PELD era (p NS). One-yr graft survival in the pre-PELD vs. post-PELD era was 65.0% and 89.7%, respectively (p < 0.01); corresponding three-yr graft survival was 57.3% vs. 76.2% (p = 0.04). One-yr patient survival in the pre-PELD vs. post-PELD era was 79.0% and 97.5%, respectively (p < 0.01); corresponding three-yr survival was 79.0% vs. 89.4% (p = 0.17). Twenty-eight patients (23.3%) were retransplanted: 24 (30%) in the pre PELD era (median time to retransplant 272 days) and four (10%) in the post-PELD era (median time to retransplant 586 days). Early follow-up demonstrates a trend toward improved pediatric HCV liver transplant graft and patient survival in the post-PELD era. Superior outcomes may be attributed to pretransplant factors, improved surgical technique and better treatment options for HCV infection. PMID- 25495574 TI - Optical and electrochemical methods for determining the effective area and charge density of conducting polymer modified electrodes for neural stimulation. AB - Neural stimulation is used in the cochlear implant, bionic eye, and deep brain stimulation, which involves implantation of an array of electrodes into a patient's brain. The current passed through the electrodes is used to provide sensory queues or reduce symptoms associated with movement disorders and increasingly for psychological and pain therapies. Poor control of electrode properties can lead to suboptimal performance; however, there are currently no standard methods to assess them, including the electrode area and charge density. Here we demonstrate optical and electrochemical methods for measuring these electrode properties and show the charge density is dependent on electrode geometry. This technique highlights that materials can have widely different charge densities but also large variation in performance. Measurement of charge density from an electroactive area may result in new materials and electrode geometries that improve patient outcomes and reduce side effects. PMID- 25495575 TI - Changes in Clotting Time, Plasma Fibrinogen Levels, and Blood Viscosity After Administration of Ranibizumab for Treatment of Choroidal Neovascularization. AB - PURPOSE: To observe changes in clotting time, plasma fibrinogen levels, and blood viscosity after intravitreal ranibizumab (IVR) injection in patients with macular choroidal neovascularization (CNV). METHODS: A total of 77 patients were enrolled in the study. Patients were divided into a study group (n = 42 CNV patients) and a control group (n = 35 age- and gender-matched healthy subjects). Study group patients received IVR injections; control group patients received none. Clotting times, plasma fibrinogen levels and blood viscosity were evaluated before, and 1 week and 1 month after the first IVR injection, and again 1 month after the second injection in the study group, but only once in the control group. A paired sample t-test was used to analyze data at four time points in the study group. Study group patients were further categorized as those with neovascular age related macular degeneration (AMD subgroup) or CNV secondary to pathological myopia (PM subgroup). Indicators were also analyzed for each subgroup. RESULTS: There were no significant differences between study and control group patients in baseline values. Results showed that 1 week after the first IVR injection, the mean activated partial thromboplastin time (APTT) of study group patients was significantly reduced compared with baseline values (27.88 +/- 4.00 versus 30.70 +/- 5.56 s), respectively. Low-, median- and high-shear viscosity rates were increased significantly compared with baseline values. No statistically significant changes in tested indicators were found at other time points. In AMD subgroup patients, changes in all indicators were similar to those found overall. In contrast, only changes in median- and high-shear viscosity rates were statistically significant in PM subgroup patients. CONCLUSION: IVR injection may cause short-term fluctuations in APTT and blood viscosity in AMD patients. Further studies are needed to establish the long-term safety of IVR treatment. PMID- 25495576 TI - Pyruvate dehydrogenase complex (PDC) export from the mitochondrial matrix. AB - Studies on mitochondria protein import had revealed in detail molecular mechanisms of how peptides and proteins could be selectively targeted and translocated across membrane bound organelles. The opposite process of mitochondrial export, while known to occur in various aspects of cellular physiology and pathology, is less well understood. Two very recent reports have indicated that a large mitochondrial matrix protein complex, the pyruvate dehydrogenase complex (PDC) (or its component subunits), could be exported to the lysosomes and the nucleus, respectively. In the case of the latter, evidence was presented to suggest that the entire complex of 8-10 MDa could translocate in its entirety from the mitochondrial matrix to the nucleus upon mitogenic or stress stimuli. We discuss these findings in perspective to what is currently known about the processes of transport in and out of the mitochondrion. PMID- 25495577 TI - Flavonols, alkaloids, and antioxidant capacity of edible wild berberis species from patagonia. AB - There are 20 species of the Berberidaceae family described in Chile, whose fruits are edible and show high anthocyanin and hydroxycinnamic acid levels. Berberis microphylla G. Forst, commonly known as calafate, is the most extensively distributed. Flavonols and alkaloids in seed, pulp, skin, and whole calafate berry extracts and other Berberis were studied using HPLC-DAD-ESI-MS/MS and HPLC with fluorescence detector. Berry samples from different locations in Chilean Patagonia, including different phenological stages, were systematically addressed. Results were compared with other organs of the plant and with other Berberis species. Total flavonol concentration in calafate (n = 65) was 1.33 +/- 0.54 MUmol/g. Glycosyl metabolites of quercetin and isorhamnetin were the most abundant. Similar profiles were observed in calafate from distinct locations, but important differences were observed for the other edible Berberis species. Calafate pulp and skin have higher flavonol concentrations than seeds, and the maturation process reduced its levels. TEACCUPRAC and TEACABTS of whole calafate extracts and fractions are also explored. Finally, only berberine was detected in the fruit (0.001%), mainly in seeds. Results contribute to the promotion of this berry as a superfruit from Patagonia. PMID- 25495578 TI - Establishment of hepatitis E virus infection-permissive and -non-permissive human hepatoma PLC/PRF/5 subclones. AB - PLC/PRF/5 cells show limited permissiveness, meaning that almost all subclones are permissive; however, some subclones do not exhibit permissiveness for hepatitis E virus (HEV) infection. In this study, the single-cell cloning of PLC/PRF/5 was performed and heterogeneous subclones characterized. Notably, the efficiency of intracellular virus replication did not correlate with the permissiveness for HEV infection. However, as well as binding permissive subclones, virus-like particles bound non-permissive subclones on various levels, suggesting that these subclones have some deficiencies in the attachment and entry steps of infection. Our data would be useful for investigating the HEV life cycle. PMID- 25495580 TI - Health behaviour change of people living with HIV after a comprehensive community based HIV stigma reduction intervention in North-West Province in South Africa. AB - Abstract All over the world, health behaviour is considered a complex, far reaching and powerful phenomenon. People's lives are influenced by their own or others' health behaviour on a daily basis. Whether it has to do with smoking, drinking, pollution, global warming or HIV management, it touches lives and it challenges personal and community responses. Health behaviour, and health behaviour change, probably holds the key to many a person's immediate or prolonged life or death outcomes. The same can be said about communities, culture groups and nations. This SANPAD-funded study focused on research questions relating to health behaviour change for people living with HIV (PLWH) in the North-West Province in South Africa. It investigated whether a comprehensive community-based HIV stigma reduction intervention caused health behaviour change in PLWH. An quantitative single system research design with one pre- and four repetitive post-tests utilizing purposive sampling was used to test change-over time in the health behaviour of 18 PLWH. The results of the study indicated statistical and/or practical significant change-over-time. The intervention not only addressed the health behaviour of PLWH, but also their HIV stigma experiences, HIV signs and symptoms and their quality of life in the context of being HIV positive. The recommendations include popularization of the comprehensive community-based HIV stigma reduction intervention and extending it to include a second intervention to strengthen health behaviour and quality of life for PLWH in the community at large. PMID- 25495581 TI - Sexual and reproductive health perceptions and practices as revealed in the sexual history narratives of South African men living in a time of HIV/AIDS. AB - Abstract The frequent positioning of men's sexual risk-taking as driving the HIV/AIDS epidemic in South Africa has triggered interest in men's sexual and reproductive health (SRH) perceptions, attitudes, and practices. Much research, however, presents men as a homogenous group, and focuses on the quantifiable aspects of male sexual behaviors, providing an inadequate basis for understanding men's SRH needs and addressing the gendered aspects of HIV prevention. This study used sexual history narratives to yield more nuanced and contextualized understandings of male sexuality as it relates to SRH. Fifty sexual life history individual interviews and 10 focus-group discussions (FGDs) with men, as well as 25 sexual life history interviews with women, were conducted with participants purposively sampled from three age categories: (18-24, 25-55, and 55+ years), a wide range of cultural and racial backgrounds, and in urban and rural sites across 5 provinces in South Africa. Interviews and FGDs elicited stories of participant's early knowledge of sex and sexual experimentation and then explored sexual relationships and experiences in adulthood-including engagement with HIV risks and SRH management. The data were analyzed using a thematic approach. Many male participants conformed to dominant norms of masculinity associated with a high risk of sexually transmitted infections including HIV, such as having regular unprotected sex, reluctance to test for HIV, and poor SRH-seeking behaviors. Yet, the narrative accounts reveal instances of men taking steps to protect their own SRH and that of their partners, and the complex ways in which hegemonic gender norms influence men and women's SRH. Ultimately, the study points to the value of sexual biographies for gaining a deeper understanding of male sexuality, and the social structures, meanings, and experiences that underlie it. Such insights are critical to more effectively engaging men in HIV prevention efforts. PMID- 25495583 TI - Type of treatment of cardiac disorders--quality of life and heart-focused anxiety: The mediating role of illness perceptions. AB - The aim of the present research was to investigate the impact of illness perceptions on quality of life and heart-focused anxiety, in patients with cardiovascular disease (N = 106) admitted in the hospital, undergoing medication or who had undergone surgery. The influence of the type of treatment on the heart focused anxiety and on the quality of life was mediated by illness perceptions. Consequently, patients who have undergone cardiac surgery have a better quality of life and lower levels of heart-focused anxiety than those relying only on medication to treat their illness. PMID- 25495582 TI - Structural and biochemical analysis of the Hordeum vulgare L. HvGR-RBP1 protein, a glycine-rich RNA-binding protein involved in the regulation of barley plant development and stress response. AB - The timing of whole-plant senescence influences important agricultural traits such as yield and grain protein content. Post-transcriptional regulation by plant RNA-binding proteins is essential for proper control of gene expression, development, and stress responses. Here, we report the three-dimensional solution NMR structure and nucleic acid-binding properties of the barley glycine-rich RNA binding protein HvGR-RBP1, whose transcript has been identified as being >45-fold up-regulated in early-as compared to late-senescing near-isogenic barley germplasm. NMR analysis reveals that HvGR-RBP1 is a multidomain protein comprising a well-folded N-terminal RNA Recognition Motif (RRM) and a structurally disordered C-terminal glycine-rich domain. Chemical shift differences observed in 2D (1)H-(15)N correlation (HSQC) NMR spectra of full length HvGR-RBP1 and N-HvGR-RBP1 (RRM domain only) suggest that the two domains can interact both in-trans and intramolecularly, similar to what is observed in the tobacco NtGR-RBP1 protein. Further, we show that the RRM domain of HvGR-RBP1 binds single-stranded DNA nucleotide fragments containing the consensus nucleotide sequence 5'-TTCTGX-3' with low micromolar affinity in vitro. We also demonstrate that the C-terminal glycine-rich (HvGR) domain of Hv-GR-RBP1 can interact nonspecifically with ssRNA in vitro. Structural similarities with other plant glycine-rich RNA-binding proteins suggest that HvGR-RBP1 may be multifunctional. Based on gene expression analysis following cold stress in barley and E. coli growth studies following cold shock treatment, we conclude that HvGR-RBP1 functions in a manner similar to cold-shock proteins and harbors RNA chaperone activity. HvGR-RBP1 is therefore not only involved in the regulation of barley development including senescence, but also functions in plant responses to environmental stress. PMID- 25495584 TI - Examining Neurocognitive Function in Previously Concussed Interscholastic Female Soccer Players. AB - Awareness of sport-related concussions in soccer has gained recent attention in the medical community. Interestingly, purposeful heading-a unique yet strategic and inherent part of soccer-involves repeated subconcussive blows to the head. We divided 210 female interscholastic soccer players into control (CON [never concussed]) and experimental (EXP [previously concussed]) groups. We assessed neurocognitive performance using the Automated Neuropsychological Assessment Metrics computer program before and after the players' competitive season. Headers were recorded at all sanctioned matches. Data were analyzed using a series of one-way analyses of covariance and t tests. Both groups essentially played in the same number of games (EXP = 16.1 vs. CON = 16.1) and had an equal number of total headers (EXP = 24.9 vs. CON = 24.3). Additionally, headers per game were surprisingly low in both groups (1.4 in EXP vs. 1.3 in CON). Unexpectedly, there were no significant differences between the EXP and CON groups across all dependent variables measured (p > .05). This study suggests that although previously concussed players involve themselves in purposeful heading (i.e., subconcussive insults) throughout a competitive season, there appear to be no negative consequences on neuropsychological test performance or concussion-related symptoms. Additional research is needed to determine what may result during the course of a playing career. PMID- 25495585 TI - Creutzfeldt-Jakob disease associated with a V203I homozygous mutation in the prion protein gene. AB - We report a Japanese patient with Creutzfeldt-Jakob disease (CJD) with a V203I homozygous mutation of the prion protein gene (PRNP). A 73-year-old woman developed rapidly progressive gait disturbance and cognitive dysfunction. Four months after the onset, she entered a state of an akinetic mutism. Gene analysis revealed a homozygous V203I mutation in the PRNP. Familial CJD with a V203I mutation is rare, and all previously reported cases had a heterozygous mutation showing manifestations similar to those of typical sporadic CJD. Although genetic prion diseases with homozygous PRNP mutations often present with an earlier onset and more rapid clinical course than those with heterozygous mutations, no difference was found in clinical phenotype between our homozygous case and reported heterozygous cases. PMID- 25495586 TI - Why do electronic health records reveal oral anticoagulant prescription after haemorrhagic stroke? PMID- 25495587 TI - Levels of C-reactive protein (CRP) in patients with schizophrenia, unipolar depression and bipolar disorder. AB - OBJECTIVE: C-reactive protein (CRP) is the major acute-phase plasma protein. Studies show that patients with various mental disorders have elevated levels of CRP. The aim of the study was to determine differences in CRP serum level in patients with acute schizophrenia, unipolar depression, bipolar depression and bipolar mania. METHOD: Serum level of CRP was measured in 950 Caucasian inpatients (589 women, 62.0%; mean age 50.3 years). RESULTS: Mean concentration of CRP in study groups was: schizophrenia (n = 485) 5.30 mg/l, unipolar depression (n = 319) 5.61 mg/l, bipolar disorder (n = 146) 4.65 mg/l, bipolar depression (n = 114) 3.82 mg/l and bipolar mania (n = 32) 7.36 mg/l. There was no difference for CRP levels between patients with schizophrenia, unipolar depression, bipolar depression and bipolar mania (P = 0.58). The overall rate of being above the high level of CRP (set at 3.0 mg/l) was 35.7% for schizophrenia, 38.6% for unipolar depression, 40.4% for bipolar disorder, 40.4% for bipolar depression and 40.6% for bipolar mania. There were no significant differences in the risk of having high level of CRP between the clinical groups. The rate of patients being above high level was higher in women. We also found that in whole study group CRP level was positively correlated with age (P = 0.002). CONCLUSIONS: Although there is no statistically significant difference in CRP serum level between patients with schizophrenia, unipolar depression, bipolar depression and bipolar mania, our results show that more than one-third (37.4%) of all subjects had CRP level > 3 mg/l, which is the cut-off point for high cardiovascular risk. PMID- 25495588 TI - Association between family functioning and cognitive impairment among Chinese nonagenarians/centenarians. AB - AIM: We explored the association between family functioning and cognitive impairment in the very elderly aged 90-108 years. METHODS: The present study comprised data from subjects included in the 2005 Project of Longevity and Aging in Dujiangyan, China. Sociodemographic and family functioning data were collected, and cognitive function was assessed in all subjects using the Mini Mental State Examination. RESULTS: Data from 699 Chinese nonagenarians and centenarians were included. The prevalence of cognitive impairment was 62.8%. The prevalence of family dysfunction was 52.2%, including 8.6% severe and 43.6% moderate dysfunction. There were significant differences among individuals with different family functioning level with regard to cognitive function scores (P = 0.005) or cognitive impairment prevalence (P = 0.012). Subjects with cognitive impairment had lower family functioning scores than those without cognitive impairment (P = 0.004). Pearson's correlation analysis showed that family functioning scores were correlated with Mini-Mental State Examination scores (r = 0.13, P = 0.001). Multiple logistic regressions showed that severe family dysfunction was a risk factor for cognitive impairment. The effect remained after adjusting for sociodemographic status, life habits and metabolic indicators. CONCLUSIONS: Family functioning was related to cognitive impairment among Chinese nonagenarians and centenarians. We found that the higher the family functioning scores, the higher the Mini-Mental State Examination scores. Severe family dysfunction was associated with increased risk of cognitive impairment. PMID- 25495589 TI - Objectively measured physical activity and sedentary time in south Asian women: a cross-sectional study. AB - BACKGROUND: South Asian (SA) women in the United Kingdom (UK) are known to be at high risk for developing chronic diseases, and to have low levels of physical activity (PA). Increasing levels of PA and reducing sedentary time (ST) are recognized as factors to target in an effort to curb chronic disease morbidity and mortality. There is limited evidence documenting objectively measured PA/ST and their correlates in SA women. Therefore the purpose of this cross-sectional study was to objectively measure and report patterns of PA/ST among SA women in the UK and examine potential socio-demographic correlates of PA/ST. METHODS: 140 UK SA women (Pakistani and Bangladeshi) wore an accelerometer for 7 consecutive days. Anthropometric measurements and self-reported socio-demographic information were taken. RESULTS: Mean daily moderate-to-vigorous PA (MVPA) was 34.66 +/- 21.52 minutes and mean daily ST was 530.20 +/- 81.76 minutes, with an inverse correlation (r = -.270, N = 140, p < .001) showing that higher ST was associated with lower MVPA. The same was seen for light intensity PA (LPA) (r = -.610, N = 140, p < .001). MVPA was significantly higher for younger women (18-64.5 yrs), with 64.7% of older women (>=65 yrs) failing to meet PA guidelines (t = 3.101, p < 0.05). Overweight/obese women had lower levels of LPA, MVPA and higher ST (p < .001). Multiple linear regression analyses indicated 14.9% of the variance in MVPA was explained by age and waist circumference (F(2,138) = 6.41, p < 0.002). LPA and ST were significantly higher on weekend days than weekdays (p < .001), and MVPA was significantly higher on weekdays than weekend days. CONCLUSIONS: Results indicate higher levels of PA in this sample than previously assumed. High levels of LPA in this sample indicate the need for health promotion interventions to target not only duration, but also intensity of activity in this population to achieve PA recommendations. PMID- 25495590 TI - Effects provoked by chronic undernourishment on the fibre type composition and contractility of fast muscles in male and female developing rats. AB - In this study, we compare the effects of pre- and post-natal food deprivation on the relative proportion of fibre types and contractile responses in the extensor digitorum longus (EDL) muscle of female and male rats at different post-natal ages. EDL muscles from undernourished male (UM) rats showed a higher proportion of Type IIB than IIA fibres and larger normalized twitch responses (with respect to muscle weight) than those of controls (CM). In contrast, EDL muscles from control (CF) and undernourished female rats (UF) showed no significant differences in their fibre type composition and normalized twitch forces at most of the ages analysed. Our data are indicative that the EDL muscles from undernourished males are more susceptible to the effects exerted by low food income than the EDL muscles from female rats. It is proposed that changes in the reactive oxygen species (ROS) concentration and hormonal factors, due to undernutrition, are involved in the alterations observed in the fibre type composition and force production of EDL muscles in undernourished male rats and that estrogens may have an antioxidant protective role on the undernourished EDL muscles in female rats. PMID- 25495591 TI - Recombinant factor IX (BAX326) in previously treated paediatric patients with haemophilia B: a prospective clinical trial. AB - A newly developed recombinant factor IX (BAX326(1) ) was investigated for prophylactic use in paediatric patients aged <12 years with severe (FIX level <1%) or moderately severe (FIX level 1-2%) haemophilia B. The aim of this prospective clinical trial was to assess the safety, haemostatic efficacy and pharmacokinetic profile of BAX326 in previously treated paediatric patients. BAX326 was administered as prophylaxis twice a week for a period of 6 months, and on demand for treatment of bleeds. Safety was assessed by the occurrence of related AEs, thrombotic events and immunologic assessments. Efficacy was evaluated by annualized bleeding rate (ABR), and by treatment response rating (excellent, good, fair, none). PK was assessed over 72 h. None of the 23 treated paediatric subjects had treatment-related SAEs or AEs. There were no thrombotic events, inhibitory or specific binding antibodies against FIX, rFurin or CHO protein. Twenty-six bleeds (19 non-joint vs. 7 joint bleeds) occurred (mean ABR 2.7 +/- 3.14, median 2.0), of which 23 were injury-related. Twenty subjects (87%) did not experience any bleeds of spontaneous aetiology. Haemostatic efficacy of BAX326 was excellent or good for >96% of bleeds (100% of minor, 88.9% of moderate and 100% of major bleeds); the majority (88.5%) resolved after 1-2 infusions. Longer T1/2 and lower IR were observed in younger children (<6 years) compared to those aged 6 to 12 years. BAX326 administered as prophylactic treatment as well as for controlling bleeds is efficacious and safe in paediatric patients aged <12 years with haemophilia B. PMID- 25495592 TI - Efficacy of adjunctive anti-plaque chemical agents in managing gingivitis: a systematic review and meta-analysis. AB - AIM: The aim of this systematic review was to evaluate the efficacy of anti plaque chemical formulations for managing gingivitis, in 6-month, home-use, randomised clinical trials (RCTs). MATERIAL AND METHODS: A protocol was designed, including inclusion and exclusion criteria to identify RCTs assessing gingival and/or bleeding indices. Electronic and hand-searches identified relevant papers, which were screened and evaluated for inclusion. Full-papers were retrieved and relevant information was extracted (also plaque indices), including quality and risk of bias. Mean treatment effects were calculated to obtain weighted mean differences (WMD) and 95% confidence intervals. RESULTS: After the process of screening and selection, 87 articles with 133 comparisons, were included in the review. The additional effects of the tested products were statistically significant in terms of Loe & Silness gingival index (46 comparisons, WMD 0.217), modified gingival index (n = 23, -0.415), gingivitis severity index (n = 26, -14.939%) or bleeding index (n = 23, -7.626%), with significant heterogeneity. For plaque, additional effects were found for Turesky (66 studies, WMD -0.475), Silness & Loe (n = 26, -0.109), and plaque severity (n = 12, -23.4%) indices, with significant heterogeneity. CONCLUSION: Within the limitations of the present study, formulations with specific agents for chemical plaque control provide statistically significant improvements in terms of gingival, bleeding and plaque indices. PMID- 25495593 TI - Acute kidney injury associated with minimal change disease in systemic lupus erythematosus: a case report. AB - INTRODUCTION: In systemic lupus erythematosus, acute kidney injury is usually associated with severe lupus nephritis and rarely associated with other glomerular diseases. CASE PRESENTATION: We recently encountered a patient with acute kidney injury that was associated with minimal change disease in systemic lupus erythematosus. A 26-year-old Chinese woman who had a history of systemic lupus erythematosus presented with nephrotic syndrome and acute kidney injury. She fulfilled four of the American College of Rheumatology criteria for the classification of systemic lupus erythematosus. However, a renal biopsy revealed that there were no glomerular abnormalities or deposition of immune complex. Her generalized edema disappeared, and her high serum creatinine level decreased to normal after prednisolone therapy. CONCLUSION: Though the relationship between lupus and minimal change disease is still not defined, the possibility of systemic lupus erythematosus combined with minimal change disease must be differentiated in patients with lupus and severe proteinuria. PMID- 25495594 TI - Relationships between T cell and IgE/IgG4 epitopes of the Anisakis simplex major allergen Ani s 1. AB - BACKGROUND: Anisakiasis is a global disease caused by the consumption of raw or lightly cooked fish parasitized with third-stage Anisakis larvae. Anisakis simplex allergens may cause severe allergic reactions including angio-oedema, urticaria and anaphylaxis. Approximately 80% of allergic patients have allergen specific IgE against Ani s 1, and the diagnostic value of testing for antibodies to Ani s 1 has been extensively demonstrated. However, no previous studies have investigated the molecular aspects of the allergic response to Ani s 1. Knowledge of allergen-specific T cell and B cell (IgE and IgG4) epitopes is important for elucidating the immunological mechanisms underlying allergic responses, and for understanding why particular proteins behave as allergens. OBJECTIVE: To elucidate the main T cell- and B cell (IgE and IgG4)- binding regions of Ani s 1. METHODS: T cell epitopes were identified by peptide proliferation assays using T cell lines derived from peripheral blood mononuclear cells of 11 patients with Anisakis allergy, and IgE and IgG4 epitopes were identified by microarray immunoassay using sera from a different group of 11 patients with Anisakis allergy. RESULTS: Several T cell epitopes of Ani s 1 were identified, of which Ani s 1145-156 , Ani s 1151-162 and Ani s 1163-171 located at the C-terminal end of the protein were the most relevant. IgE and IgG4 recognized largely the same peptides, including Ani s 122-41 , Ani s 125-44 , Ani s 127-47 , Ani s 137-56 and Ani s 194-113 . CONCLUSIONS AND CLINICAL RELEVANCE: This is the first report describing the T cell epitopes of an important allergen of A. simplex, and the first B cell epitope study of this allergen in the Spanish population. This information can help to elucidate the mechanisms underlying the allergic response to Ani s 1, potentially leading to therapeutic and diagnostic advances. PMID- 25495595 TI - Synthesis of 13-amino telekin derivatives and their cytotoxic activity. AB - Telekin is a eudesmane sesquiterpene-lactone naturally occurring in many medicinal plants with antitumour and anti-inflammatory activity. In this study, a series of 13-amino derivatives of telekin have been synthesised through Michael addition reaction, and their relative configurations were exemplified by the single crystal X-ray diffraction of the dimethylamine adduct. The in vitro cytotoxicity against three tumour cell lines of these amine derivatives was evaluated. The piperidine and 4-hydroxypiperidine adducts displayed stronger cytotoxic activity than telekin. PMID- 25495596 TI - Osteoporosis in German men: a cost-of-illness study. AB - Costs of male osteoporosis may have increased due to population aging and change of treatment patterns. This cost-of-illness study provides a current estimate of the economic burden of male osteoporosis in Germany. Routine claims data from six German sickness funds were analyzed and extrapolated to the German statutory health insurance (SHI). For men above the age of 50 with at least one ICD-10 osteoporosis-related diagnosis or osteoporosis-related fracture in 2010, direct costs related to osteoporosis were considered based on a payer's perspective. Total direct costs attributable to osteoporosis amounted to ?728 million in 2010. The majority of these costs (71%) resulted from inpatient treatment due to fractures. Patients aged 75 and older caused approximately 63% of costs. Male osteoporosis represents a non-negligible economic burden for the German health care system. Targeted prevention and promotion measures should be offered both to men and women. PMID- 25495597 TI - Laboratory data of dog rabies in southern Cameroon from 2010 to 2013. AB - BACKGROUND: Dog rabies is endemic in most African countries and the risk of human rabies is estimated to be high in Cameroon according to WHO estimations in 2010. This study aimed to describe the circulation rabies virus (RABV) among dogs in the southern regions of Cameroon from 2010 to 2013 in a context, where mass vaccination campaigns are launched annually in order to control rabies in domestic animals including dogs and cats. FINDINGS: From 2010 to 2013, 93 animal specimens (dogs: 91, monkey: 1, pig: 1) originating from the southern regions of Cameroon were collected and tested for rabies virus at the Centre Pasteur of Cameroon by fluorescent antibody test (FAT) and virus isolation. Of the total dog specimens, 69.2% (63/91) originated from the central part of the southern regions and 50.5% (46/91) were from the capital city Yaounde. Overall, 74.2% (66/89) of dogs' specimens that could be tested were found rabies-positive while specimens from the monkey and pig were tested negative. Overall, dog rabies was repeatedly detected in the southern regions of Cameroon especially in the nation capital, Yaounde even though low specimen submission and geographic bias did not permit major conclusions about its actual rate, geographical and over time distribution. CONCLUSIONS: The results of this study indicate that rabies is endemic in the dog population which is of public health concern. Therefore, coordinated rabies control program should be conducted to reduce the rabies incidence in dogs and in humans. In addition, proper rabies surveillance program including reporting system should be established to monitor the success of the control program in Cameroon. PMID- 25495598 TI - The number of CCR5 expressing CD4+ T lymphocytes is lower in HIV-infected long term non-progressors with viral control compared to normal progressors: a cross sectional study. AB - BACKGROUND: The HIV co-receptors CXCR4 and CCR5 play an important role in HIV infection and replication. Therefore we hypothesize that long-term non progressors (LTNP) with viral control have lower expression of CCR5 and CXCR4 on CD4(+) cells, specifically on memory T-lymphocytes since they are the primary target cells of HIV. METHODS: In this cross-sectional study, we included five HIV infected LTNP with viral control (CD4 > 750 cell/MUl & HIV < 50 copies for >=2 years), thirteen HIV-infected and seven HIV-uninfected individuals at Radboud UMC Nijmegen, the Netherlands. We determined the CCR5 and CXCR4 expression among CD4(+) and CD8(+) lymphocyte subsets; memory (CD45RO(+)), naive (CD45RA(+)) cells and regulatory T-cells (CD4(+)CD25(high)FoxP3(+)). In addition, CCR5?32 polymorphism is related with disease progression and was therefore determined using polymerase chain reaction. RESULTS: The percentage of CCR5-expressing CD4(+) cells of LTNP was comparable with healthy controls; whereas HIV-infected individuals showed more CCR5-expressing cells. This was observed in memory and naive CD4(+) cells, but not in regulatory T-cells. The mean fluorescence intensity of CCR5-expressing CD4(+) cells was similar in all groups. All groups had comparable percentages of CXCR4-expressing cells. The mean fluorescence intensity of CXCR4-expressing cells was significantly higher in HIV-infected normally progressors in both memory and naive CD4(+) cells, but not in CD8(+) cells. The CCR5?32 polymorphism was not related to group. CONCLUSIONS: We show that HIV affects -directly or indirectly- the expression of CCR5 in CD4(+) T lymphocytes; yet this effect is not seen in LTNP with viral control. Avoiding upregulation of CCR5 could be an important method via which LTNP counteracts the effects of HIV and suppresses viral replication. Exploring how LTNP suppress the upregulation of CCR5 could be an important step for discovering new therapeutics. PMID- 25495599 TI - Combination therapy of Chinese herbal medicine Fructus Ligustri Lucidi with high calcium diet on calcium imbalance induced by ovariectomy in mice. AB - CONTEXT: Our previous biological study demonstrated that Fructus Ligustri Lucidi (FLL), the fruit of Ligustrum lucidum Ait. (Oleaceae), could be used to maintain calcium balance and prevent age-related osteoporosis since it effectively decreased calcium loss and increased calcium retention in rats. OBJECTIVE: This study investigates the combination effect of the Chinese herbal medicine FLL and a high calcium diet on calcium imbalance induced by ovariectomy in mice. MATERIALS AND METHODS: The ovariectomized (OVX) mice were orally treated with vehicle, FLL extract (700 mg/kg), milk powder (5 g/mice) fortified with calcium (1.0% Ca) and the combination of FLL with milk powder. After 6 weeks of treatment, urine, serum, and tibia were preserved for biochemical analysis and kidneys were taken for gene expression analysis. RESULTS: The combination treatment of FLL and a high calcium diet significantly increased bone calcium content (6.80 +/- 0.34 mg) by 22% (p < 0.05) and decreased urine calcium excretion (0.099 +/- 0.009 mg/mg) by 62% (p < 0.01) as compared with those of the OVX group (bone Ca, 5.57 +/- 0.31 mg; urine Ca/Cr, 0.261 +/- 0.017 mg/mg). The mRNA expression of renal calcium-binding protein-9k (CaBP-9k) and calcium-sensing receptor (CaSR) in combination treatment group was significantly up-regulated and down-regulated, respectively, as compared with those of the OVX group. CONCLUSION: The beneficial effects of this combination therapy on calcium balance of OVX mice were, at least partially, attributed to its regulation on mRNA expression of CaBP-9k and CaSR in kidney. PMID- 25495600 TI - Executive functioning deficits in young adult survivors of bronchopulmonary dysplasia. AB - PURPOSE: To assess long-term impairments of executive functioning in adult survivors of bronchopulmonary dysplasia (BPD). METHOD: Participants were assessed on measures of executive functioning, health-related quality of life (HRQoL) and social functioning. Survivors of BPD (n = 63; 34 males; mean age 24.2 years) were compared with groups comprising preterm (without BPD) (<1500 g; n = 45) and full term controls (n = 63). Analysis of variance was used to explore differences among groups for outcome measures. Multiple regression analyzes were performed to identify factors predictive of long-term outcomes. RESULTS: Significantly more BPD adults, compared with preterm and term controls, showed deficits in executive functioning relating to problem solving (OR: 5.1, CI: 1.4-19.3), awareness of behavior (OR: 12.7, CI: 1.5-106.4) and organization of their environment (OR: 13.0, CI: 1.6-107.1). Birth weight, HRQoL and social functioning were predictive of deficits in executive functioning. CONCLUSIONS: This study represents the largest sample of survivors into adulthood of BPD and is the first to show that deficits in executive functioning persist. Children with BPD should be assessed to identify cognitive impairments and allow early intervention aimed at ameliorating their effects. Implications for Rehabilitation Adults born preterm with very-low birth weight, and particularly those who develop BPD, are at increased risk of exhibiting defects in executive functioning. Clinicians and educators should be made aware of the impact that BPD can have on the long-term development of executive functions. Children and young adults identified as having BPD should be periodically monitored to identify the need for possible intervention. PMID- 25495601 TI - Preparation of sequence-controlled triblock copolymer-grafted silica microparticles by sequential-ATRP for highly efficient glycopeptides enrichment. AB - As one of the most important subproteomes in eukaryote cells, N-glycoproteins play crucial roles in various of biological processes and have long been considered closely correlated with the occurrence, progression, and metastasis of cancer. Comprehensive characterization of protein N-glycosylation and association of their aberrant patterns to the corresponding cancer stage may provide a unique way to discover new diagnostic biomarkers and therapeutic drug targets. However, the extremely complex nature of biological samples and relatively low abundance of N-glycosylated proteins makes the enrichment of glycoprotein/glycopeptide a prerequisite for large scale N-glycosylation identification. In this work, we prepared sequence controlled triblock copolymer grafted silica-microparticles (TCP-SMs) by sequential atom transfer radical polymerization (sequential-ATRP) of monosaccharides and zwitterionic-ion monomers for highly efficient and selective glycopeptides enrichment. The triblock copolymer is composed of sequence defined poly zwitterionic-ion, poly-N-acetylglucosamine and poly mannose blocks. The glycopolymer blocks carrying densely packed pendent sugars are excellent mimics of the natural carbohydrate clusters and may induce multivalent carbohydrate carbohydrate interaction (CCI) with the target glycopeptides. Therefore, increased retention of glycopeptides can be expected by the combination of CCI and zwitterionic-HILIC interaction. As a result, 1244 glycopeptides were identified after TCP-SMs enrichment from mouse liver, which are 65-120% higher than that obtained by homoglycopolymer or random-copolymer grafted silica microparticles prepared using the conventional free radical polymerization. These results demonstrate the critical role of sequence-defined block copolymer of TCP SMs for obtaining enhanced affinity toward glycopeptides and the potential of this sequential-ATRP strategy to integrate different affinity moieties into one enrichment material to achieve deeper coverage in protein PTM mapping. PMID- 25495602 TI - Intraoperative optimization to decrease postoperative PRBC transfusion in children undergoing craniofacial reconstruction. AB - BACKGROUND: Craniofacial reconstructive surgery for craniosynostosis is associated with large blood loss and intraoperative transfusion. This blood loss may continue through the initial postoperative period, potentially resulting in transfusion postoperatively. The purpose of this study is to determine if there is an association between any modifiable intraoperative factors and postoperative blood transfusion in this patient population. METHODS: A cohort of 55 pediatric patients who underwent primary craniofacial reconstruction at Vanderbilt Children's Hospital from January 1, 2013 to April 31, 2014 was analyzed. The authors analyzed 20 different demographic and perioperative variables for statistical associations with postoperative PRBC transfusion using multiple logistic regression with optimal models being selected by Bayesian model averaging. RESULTS: The optimal regression model only included initial PACU Hct as a predictor and showed a significant association between this variable and postoperative PRBC transfusion (odds ratio 0.69, 95% CI 0.55-0.87, P = 0.0016). Based on the average decrease in postoperative hematocrit (Hct) and the postoperative transfusion trigger, an initial PACU Hct threshold of 30 was calculated. In our patient sample, an initial PACU Hct above 30 was associated with a 50% decrease in the absolute risk of receiving a PRBC transfusion postoperatively. CONCLUSIONS: Based on this retrospective analysis, it may be justifiable to transfuse residual volume from previously exposed intraoperative PRBCs to a Hct above 30 to decrease the likelihood of subsequent blood transfusions from different donors in the postoperative period. PMID- 25495603 TI - Chaperone-usher fimbriae in a diverse selection of Gallibacterium genomes. AB - BACKGROUND: Fimbriae are bacterial cell surface organelles involved in the pathogenesis of many bacterial species, including Gallibacterium anatis, in which a F17-like fimbriae of the chaperone-usher (CU) family was recently shown to be an important virulence factor and vaccine candidate. To reveal the distribution and variability of CU fimbriae 22 genomes of the avian host-restricted bacteria Gallibacterium spp. were investigated. Fimbrial clusters were classified using phylogeny-based and conserved domain (CD) distribution-based approaches. To characterize the fimbriae in depth evolutionary analysis and in vitro expression of the most prevalent fimbrial clusters was performed. RESULTS: Overall 48 CU fimbriae were identified in the genomes of the examined Gallibacterium isolates. All fimbriae were assigned to gamma4 clade of the CU fimbriae of Gram-negative bacteria and were organized in four-gene clusters encoding a putative major fimbrial subunit, a chaperone, an usher and a fimbrial adhesin. Five fimbrial clusters (Flf-Flf4) and eight conserved domain groups were defined to accommodate the identified fimbriae. Although, the number of different fimbrial clusters in individual Gallibacterium genomes was low, there was substantial amino acid sequence variability in the major fimbrial subunit and the adhesin proteins. The distribution of CDs among fimbrial clusters, analysis of their flanking regions, and evolutionary comparison of the strains revealed that Gallibacterium fimbrial clusters likely underwent evolutionary divergence resulting in highly host adapted and antigenically variable fimbriae. In vitro, only the fimbrial subunit FlfA was expressed in most Gallibacterium strains encoding this protein. The absence or scarce expression of the two other common fimbrial subunits (Flf1A and Flf3A) indicates that their expression may require other in vitro or in vivo conditions. CONCLUSIONS: This is the first approach establishing a systematic fimbria classification system within Gallibacterium spp., which indicates a species-wide distribution of gamma4 CU fimbriae among a diverse collection of Gallibacterium isolates. The expression of only one out of up to three fimbriae present in the individual genomes in vitro suggests that fimbriae expression in Gallibacterium is highly regulated. This information is important for future attempts to understand the role of Gallibacterium fimbriae in pathogenesis, and may prove useful for improved control of Gallibacterium infections in chickens. PMID- 25495604 TI - Disulfiram-loaded immediate and extended release vaginal tablets for the localised treatment of cervical cancer. AB - OBJECTIVES: To develop and manufacture both immediate and sustained release vaginal tablets containing the anticancer drug disulfiram, which has the potential to be used as a non-invasive treatment for cervical cancer. METHODS: Disulfiram-loaded vaginal tablets were manufactured at pilot scale using the direct compression method. These tablets were tested in accordance with the European Pharmacopeia testing of solid dosage form guidelines. They were also tested using a biorelevant dissolution method as well as a dual-chambered release model designed to better mimic the dynamic nature of the vaginal vault. KEY FINDINGS: We have developed both immediate and sustained release vaginal tablets, which when manufactured at pilot scale are within the limits set by the European Pharmacopeia for the testing of solid dosage forms. Furthermore, these tablets are capable of releasing disulfiram in vitro using the dual-chambered release model at levels 25,000 times and 35,000 times greater than its IC50 concentration for the HeLa cervical cancer cell line. CONCLUSIONS: The successful pilot manufacture and testing of both the immediate and sustained release disulfiram loaded vaginal tablets warrant further investigation, using an in-vivo model, to assess their potential for use as a non-invasive treatment option for cervical cancer. PMID- 25495605 TI - A review of interventions addressing structural drivers of adolescents' sexual and reproductive health vulnerability in sub-Saharan Africa: implications for sexual health programming. AB - BACKGROUND: Young people particularly women are at increased risk of undesirable sexual and reproductive health (SRH) outcomes. Structural factors have been reported as driving some of these risks. Although several interventions have targeted some of the structural drivers for adolescent's SRH risk, little has been done to consolidate such work. This would provide a platform for coordinated efforts towards adolescent's SRH. We provide a narrative summary of interventions in sub-Saharan Africa (sSA) addressing the structural drivers of adolescents' SRH risk, explore pathways of influence, and highlight areas for further work. METHODS: 33 abstracts and summary reports were retrieved and perused for suitability. Fifteen documents met the inclusion criteria and were read in full. Papers and reports were manually reviewed and 15 interventions that met the criteria for inclusion were summarised in a table format. RESULTS: Most of the interventions addressed multiple structural factors, such as social norms, gender inequality, and poverty. Some interventions focused on reducing economic drivers that increased sexual risk behaviours. Others focused on changing social norms and thus sexual risk behaviours through communication. Social norms addressed included gender inequality, gender violence, and child socialisation. The interventions included components on comprehensive sexuality and behaviour change and communication and parenting, using different designs and evaluation methods. Important lessons from the narrative summary included the need for a flexible intervention design when addressing adolescents, the need for coordinated effort among different stakeholders. CONCLUSION: There are encouraging efforts towards addressing structural drivers among adolescents in (sSA). There is, however, a need for interventions to have a clear focus, indicate the pathways of influence, and have a rigorous evaluation strategy assessing how they work to reduce vulnerability to HIV. There is also a need for coordinated effort among stakeholders working on adolescent vulnerability in sSA. PMID- 25495606 TI - High frequency of activated NKp46(+) natural killer cells in patients with new diagnosed of latent autoimmune diabetes in adults. AB - To determine the potential association of different subsets of NK cells with the development of latent autoimmune diabetes of adults (LADA) in patients. The frequency of different subsets of NK and NKT cells, including IFN-gamma(+) and CD107a(+) NK and NKT cells, in 27 patients with newly diagnosed LADA and 20 healthy controls (HC) were determined by flow cytometry. The concentrations of serum autoantibodies against GAD65 were measured by direct radioligand assay. The potential association of the frequency of NK cells with clinical measures was analyzed. In comparison with that in the HC, significantly higher frequency of peripheral blood NK and NKp46(+) NK cells, but lower frequency of KIR3DL1(+) NK cells were detected in patients with newly diagnosed LADA (p < 0.0001, p < 0.0001, p = 0.0039, respectively). The percentages of inducible IFN-gamma(+) NK cells were significantly higher in the LADA patients than that in the HC (p < 0.0001). Moreover, the percentages of NKp46(+) NK cells were negatively correlated with the levels of fasting plasma C-peptide in patients (R = -0.4877, p = 0.0099). There was no significant difference in the frequency of spontaneous and inducible CD107a(+) between patients and controls. Our data indicate a higher frequency of activated NKp46(+) NK cells may be associated with the development of LADA in humans. PMID- 25495607 TI - The clinical and public health problem of relapse despite primaquine therapy: case review of repeated relapses of Plasmodium vivax acquired in Papua New Guinea. AB - BACKGROUND: Primaquine is the only drug available for preventing relapse following a primary attack by Plasmodium vivax malaria. This drug imposes several important problems: daily dosing over two weeks; toxicity in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; partner blood schizontocides possibly impacting primaquine safety and efficacy; cytochrome P-450 abnormalities impairing metabolism and therapeutic activity; and some strains of parasite may be tolerant or resistant to primaquine. There are many possible causes of repeated relapses in a patient treated with primaquine. CASE DESCRIPTION: A 56 year-old Caucasian woman from New Zealand traveled to New Ireland, Papua New Guinea for two months in 2012. One month after returning home she stopped daily doxycycline prophylaxis against malaria, and one week later she became acutely ill and hospitalized with a diagnosis of Plasmodium vivax malaria. Over the ensuing year she suffered four more attacks of vivax malaria at approximately two months intervals despite consuming primaquine daily for 14 days after each of those attacks, except the last. Genotype of the patient's cytochrome P-450 2D6 alleles (*5/*41) corresponded with an intermediate metabolizer phenotype of predicted low activity. DISCUSSION: Multiple relapses in patients taking primaquine as prescribed present a serious clinical problem, and understanding the basis of repeated therapeutic failure is a challenging technical problem. This case highlights these issues in a single traveler, but these problems will also arise as endemic nations approach elimination of malaria transmission. PMID- 25495608 TI - Incidence of lung cancer in patients with systemic sclerosis treated with extracorporeal photopheresis. AB - BACKGROUND: Extracorporeal photopheresis (ECP) improves skin sclerosis in systemic sclerosis (SSc) patients. SSc is associated with an increased risk of lung cancer. As ECP is supposed to exert immunomodulatory effects, a possible impact of ECP on the incidence of lung cancer in SSc patients was evaluated. METHODS: Seventy-one SSc patients treated with ECP at the Photopheresis Unit of the Department of Dermatology at the Medical University of Vienna between 1991 and 2013 were analyzed retrospectively. RESULTS: We calculated a standardized incidence ratio (SIR) for lung cancer in ECP-treated SSc patients of 2.34 [95% confidence interval (CI) 1.63-2.49]. This is in accordance with recent meta analyses demonstrating a significantly enhanced risk of lung carcinoma in SSc patients. Comparison of the lung cancer risks of these patients with our ECP treated patients revealed that ECP has no influence. Each patient with lung carcinoma had previously been diagnosed with lung involvement of the non-specific interstitial pneumonitis (NSIP) type. CONCLUSION: We confirm that SSc patients are at significantly increased risk for lung cancer. However, ECP does not influence this risk. NSIP may be a risk factor for lung cancer in SSc patients. PMID- 25495609 TI - An ongoing case-control study to evaluate the NHS Bowel Cancer Screening Programme. AB - BACKGROUND: Colorectal cancer is the third most common cause of cancer death in both males and females in England. A national bowel cancer screening programme was rolled out in England between 2006 and 2010. In the post-randomised controlled trials epoch, assessment of the impact of the programme using observational studies is needed. This study protocol was set up at the request of the UK Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis to evaluate the effect of the current bowel cancer screening programme on incidence of advanced primary colorectal cancer. METHODS/DESIGN: All incident cases of primary colorectal cancer in England will be included. Cases will be matched to controls with respect to sex, age, area of registration and year of first invitation to screening. Each evaluation round will cover a 2-year period, starting from January 2012, and ongoing thereafter. In the first instance, a pilot will be carried out in a single region. Variables related to colorectal tumour pathology will be obtained to enable selection and matching of cases and controls, and to allow analyses stratification by anatomical subsite within the bowel. Cases at Duke's stage B or worse will be considered as "advanced stage". The influence of sex will also be investigated. The incidence ratio observed in randomised controlled trials between controls (not invited) and non-attender invitees will be used to correct for self-selection bias overall. Screening participation at other national screening programmes (cervical, breast) will also be collected to derive a more contemporaneous adjustment factor for self selection bias and assess consistency in self-selection correction in female patients.Full ethical approval was obtained from the Health Research Authority. DISCUSSION: The case-control design is potentially prone to a number of biases. The size of the planned study, the design specifications and the development of analytical strategies to cope with bias should enable us to obtain accurate estimates of reduction in incidence of advanced stage disease. The results of analyses by sex and anatomical subsite may highlight the potential need for sex specific recommendations in the programme. PMID- 25495611 TI - Neonatal hypertonia - a diagnostic challenge. AB - In comparison to hypotonia, hypertonia is less commonly expressed in the neonatal period. The scientific literature on the causes of neonatal hypertonia is scant, with no suggested diagnostic algorithm easily available to clinicians. Aetiologies include conditions affecting the central nervous system and spine, and rare peripheral neuromuscular disorders leading to hypertonia. Aetiology onset may be antepartum, peripartum with either transient hypertonia or persistent hypertonia which may appear later, or from a postnatal event/disease. This review discusses neonatal hypertonia and a diagnostic approach to neonatal hypertonia is suggested. PMID- 25495610 TI - Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome. AB - BACKGROUND: Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). OBJECTIVE: In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. METHODS: We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. RESULTS: Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05-1.45) and 1.25 (95% CI 1.05-1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07-1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. CONCLUSIONS: In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance. PMID- 25495614 TI - Assessment of the amorphous "solubility" of a group of diverse drugs using new experimental and theoretical approaches. AB - The supersaturation potential of poorly water-soluble compounds is of interest in the context of solubility enhancing formulations for enhanced bioavailability. In this regard, the amorphous "solubility", i.e., the maximum increase in solution concentration that can be obtained relative to the crystalline form, is an important parameter, albeit a very difficult one to evaluate experimentally. The goal of the current study was to develop new approaches to determine the amorphous "solubility" and to compare the experimental values to theoretical predictions. A group of six diverse model compounds was evaluated using the solvent exchange method to generate an amorphous phase in situ, determining the concentration at which the amorphous material was formed. The theoretical estimation of the amorphous "solubility" was based on the thermal properties of the crystalline and amorphous phases, the crystalline solubility, and the estimated concentration of water in the water-saturated amorphous phase. The formation of an amorphous precipitate could be captured transiently for all six compounds and hence the amorphous "solubility" determined experimentally. A comparison of the experimental amorphous "solubility" values to those calculated theoretically showed excellent agreement, in particular when the theoretical estimate method treated the precipitated phase as a supercooled liquid, and took into account heat capacity differences between the two forms. The maximum supersaturation ratio in water was found to be highly compound dependent, varying between 4 for ibuprofen and 54 for sorafenib. This information may be useful to predict improvements in biological exposure for poorly water-soluble compounds formulated as amorphous solid dispersions or other formulations that rely on supersaturation. PMID- 25495612 TI - (+/-)-Torreyunlignans A-D, rare 8-9' linked neolignan enantiomers as phosphodiesterase-9A inhibitors from Torreya yunnanensis. AB - (+/-)-Torreyunlignans A-D (1a/1b-4a/4b), four pairs of new 8-9' linked neolignan enantiomers featuring a rare (E)-2-styryl-1,3-dioxane moiety, were isolated from the trunk of Torreya yunnanensis. The structures were determined by combined spectroscopic and chemical methods, and the absolute configurations were elucidated by ECD calculations. The compounds were screened by using tritium labeled adenosine 3',5'-cyclic monophosphate ([(3)H]-cGMP) as a substrate for inhibitory affinities against phosphodiesterase-9A (PDE9A), which is a potential target for the treatment of diabetes and Alzheimer's disease. All of the enantiomers exhibited inhibition against PDE9A with IC50 values ranging from 5.6 to 15.0 MUM. This is the first report of PDE9A inhibitors from nature. PMID- 25495615 TI - Optimism, community attachment and serostatus disclosure among HIV-positive men who have sex with men. AB - This study investigated the relationship between HIV health optimism (HHO) (the belief that health will remain good after HIV infection due to treatment efficacy), HIV-positive community attachment (HCA), gay community attachment (GCA) and serostatus disclosure to casual sex partners by HIV-positive men who have sex with men (MSM). Cross-sectional questionnaire data were gathered from 97 HIV-positive MSM attending an HIV treatment clinic in Dublin, Ireland. Based on self-reported disclosure to casual partners, participants were classified according to their pattern of disclosure (consistent, inconsistent or non disclosers). Multinomial logistic regression was used to assess HHO, HCA and GCA as predictors of participants' pattern of disclosure. Classification as a non discloser (compared to a consistent discloser) was associated with higher HHO, less HCA and greater GCA. Classification as an inconsistent discloser (compared to a consistent discloser) was associated with higher GCA. The study provided novel quantitative evidence for associations between the constructs of interest. The results suggest that (1) HHO is associated with reduced disclosure, suggesting optimism may preclude individuals reaping the benefits of serostatus disclosure and (2) HCA and GCA represent competing attachments with conflicting effects on disclosure behaviour. Limitations and areas for future research are discussed. PMID- 25495616 TI - Low prevalence of Neospora caninum and Toxoplasma gondii antibodies in dogs in Jilin, Henan and Anhui Provinces of the People's Republic of China. AB - BACKGROUND: Neospora caninum and Toxoplasma gondii are important pathogens of worldwide distribution. N. caninum is a major cause of abortion in cattle and dogs are main reservoirs because they excrete the environmentally resistant oocysts. Toxoplasmosis is a worldwide zoonosis and dogs are considered as sentinels for this parasite because of their close contact with people and cats; additionally dog meat is also used for human consumption in China. The aim of the present study was to assess the prevalence of N. caninum and T. gondii infection in dogs from China. A total of 425 countryside dog hearts in Jilin, Henan and Anhui provinces of the People's Republic of China were collected from slaughter houses in two batches; the first batch of 96 in October 2013, and the second batch of 329 in April 2014. Serum samples extracted from 96 dog hearts were tested for antibodies to N. caninum and from 425 dog hearts were tested for T. gondii antibodies in the modified agglutination tests (cut-off 1:25 for both), using respective antigens. RESULTS: Antibodies to N. caninum were 6 of 96 (6.25%) of dogs with titers of 1:25 in 2, 1:50 in 3, and 1:100 in 1. All seropositive dogs were more than 1 year old. Antibodies to T. gondii were found in 35 of 425 (8.24%) dogs with titers of 1:25 in 15, 1:50 in 14; and 1:100 in 6. CONCLUSION: The results of the present study indicated low prevalence of N. caninum and T. gondii antibodies in dogs of China, compared with Europe and America. Identification of the risk factors that underlie these differences may help prevention of neosporosis and toxoplasmosis. This is the first report of N. caninum infection in dogs from China. PMID- 25495618 TI - Indoleamine 2,3-dioxygenase inhibitors isolated from the sponge Xestospongia vansoesti: structure elucidation, analogue synthesis, and biological activity. AB - Two new IDO inhibitory meroterpenoids, xestolactone A (1) and xestosaprol O (2), have been isolated from the sponge Xestospongia vansoesti. Xestolactone A (1) has an unprecedented degraded meroterpenoid carbon skeleton. A short synthesis of the xestosaprol O (2) analogues 3 and 4 features the application of a rarely used photochemical coupling reaction. Synthetic analogue 3 is ~40 times more potent than the inspirational natural product 2. PMID- 25495617 TI - Ion mobility-derived collision cross section as an additional measure for lipid fingerprinting and identification. AB - Despite recent advances in analytical and computational chemistry, lipid identification remains a significant challenge in lipidomics. Ion-mobility spectrometry provides an accurate measure of the molecules' rotationally averaged collision cross-section (CCS) in the gas phase and is thus related to ionic shape. Here, we investigate the use of CCS as a highly specific molecular descriptor for identifying lipids in biological samples. Using traveling wave ion mobility mass spectrometry (MS), we measured the CCS values of over 200 lipids within multiple chemical classes. CCS values derived from ion mobility were not affected by instrument settings or chromatographic conditions, and they were highly reproducible on instruments located in independent laboratories (interlaboratory RSD < 3% for 98% of molecules). CCS values were used as additional molecular descriptors to identify brain lipids using a variety of traditional lipidomic approaches. The addition of CCS improved the reproducibility of analysis in a liquid chromatography-MS workflow and maximized the separation of isobaric species and the signal-to-noise ratio in direct-MS analyses (e.g., "shotgun" lipidomics and MS imaging). These results indicate that adding CCS to databases and lipidomics workflows increases the specificity and selectivity of analysis, thus improving the confidence in lipid identification compared to traditional analytical approaches. The CCS/accurate-mass database described here is made publicly available. PMID- 25495620 TI - The health challenges facing rural people and communities in Australia: what can psychology offer? PMID- 25495621 TI - Knowledge, skills and attitudes of rural and remote psychologists. AB - OBJECTIVE: To develop a list of knowledge, skills and attitudes (KSAs, components of competencies) considered required or desirable by rural and remote psychologists for rural and remote psychology practice. DESIGN: Semi-structured qualitative telephone interviews. Data were analysed thematically. SETTING: Rural and remote regions of South Australia. PARTICIPANTS: Nine registered psychologists living and working in rural and remote South Australia (as defined by ARIA++ classification categories excluding Highly Accessible communities). All participants were women. RESULTS: Seven competencies were identified, relating to two broad themes: 'Professional Isolation' (competencies arising from being the sole psychologist or one of few in the community); and 'rural life' (competencies relating to the need to manage features of the rural context). The seven competencies (managing professional development, supervision, the lack of other services, dual relationships, visibility, confidentiality and appreciation of the rural context) encompassed a number of corresponding and overlapping KSAs. Personality characteristics, including autonomy, resilience and confidence were also identified as important for working in rural areas. CONCLUSIONS: Competencies and KSAs identified were consistent with issues identified in previous research for rural and remote psychologists and other health professionals. The present study contributes by providing a comprehensive checklist of KSAs for rural practice identified by rural psychologists. With further development, the competencies outlined could be used in conjunction with rural placements as part of competency-based training. PMID- 25495622 TI - Therapeutic alliance in videoconferencing psychotherapy: a review. AB - Psychotherapy services are limited in remote and rural areas in Australia and across the globe. Videoconferencing has become well established as a feasible and acceptable mode of psychological treatment delivery. Therapeutic alliance (TA) is an essential factor underlying successful therapy across therapeutic models. In order to determine the state of knowledge regarding TA in psychotherapy via videoconferencing, a literature review was conducted on research studies that formally measured TA as primary, secondary or tertiary outcome measures over the past 23 years. The databases searched were Medline, PsycArticles, PsycINFO, PsycEXTRA and EMBASE. Searching identified 9915 articles that measured satisfaction, acceptability or therapeutic rapport, of which 23 met criteria for the review. Three studies were carried out in Australia, 11 in USA, 4 in Canada, 3 in Scotland and 2 in England. Studies overwhelmingly supported the notion that TA can be developed in psychotherapy by videoconference, with clients rating bond and presence at least equally as strongly as in-person settings across a range of diagnostic groups. Therapists also rated high levels of TA, but often not quite as high as that of their clients early in treatment. The evidence was examined in the context of important aspects of TA, including bond, presence, therapist attitudes and abilities, and client attitudes and beliefs. Barriers and facilitators of alliance were identified. Future studies should include observational measures of bond and presence to supplement self-report. PMID- 25495623 TI - 'Country women are resilient but. ...': Family planning access in rural Victoria. AB - OBJECTIVE: This study examined barriers to accessing three types of family planning service (emergency contraception, termination of pregnancy and options counselling) within the Grampians region of Victoria. In addressing the challenges faced by geographically marginalised women, the intention was to contribute to feminist psychological research in the field of women's health. DESIGN: The qualitative study drew on community and health psychology frameworks. Community psychology's ecological perspective takes into account the different contexts of people's lives, while the focus on psychosocial aspects of women's reproductive health behaviour places the study in a health psychology domain. SETTING: Grampians region of Victoria, Australia. PARTICIPANTS: Eleven professionals whose employment was connected to family planning services in Victoria. INTERVENTIONS: Semi-structured interviews. MAIN OUTCOME MEASURES: The study documented professionals' perceptions of facilitators and barriers to accessing family planning services in rural areas and the implications for women's psychosocial health and their ability to make timely decisions about a pregnancy. RESULTS: A thematic analysis confirmed that women in the Grampians region face many barriers including lack of local services, privacy, misinformation and judgmental service providers. While these issues could arise anywhere, the problem is compounded in rural areas by limited options and rural cultural pressures. CONCLUSIONS: This study highlights the complexity of many rural women's reproductive 'choices', and recommends plausible strategies to tackle barriers and facilitate access to family planning services. Reproductive health research can benefit from community and health psychology perspectives that consider psychosocial and cultural contexts as well as biomedical factors. PMID- 25495624 TI - Telepsychology in Australia: 20/20 vision. AB - The current roll-out of broadband across Australia provides new opportunities for psychologists to reach out to residents in remote and rural areas. With the advent of internet protocol (IP)-based videoconferencing, telepsychology is becoming more accessible and affordable, and a potential solution to those in remote areas who require access to specialist assessment and psychotherapy services. Telepsychology represents a high-quality/low-cost model of service delivery. Findings to date suggest that outcome might be equivalent to in-person therapy across a range of client groups both using standardised assessments and evidence-based therapies. Studies have consistently shown that clients rate high levels of satisfaction and therapeutic rapport. However, uptake among psychologists has been slow. This article provides a synthesis of the gradual growth of telepsychology in Australia. It identifies factors that hinder the development of telepsychology and outlines the main arguments for developing this as a model for the provision of psychology across remote and rural Australia. The authors draw on their own recent experiences in developing collaborative telepsychology services to make recommendations for the future of telepsychology in Australia. PMID- 25495625 TI - Regional use of the Australian Chronic Disease Dental Scheme. AB - OBJECTIVE: To determine whether a different number and type of services were provided in Australian regional areas under the Australian Government-funded Chronic Disease Dental Scheme (CDDS). DESIGN: Retrospective analysis of administrative payments data. SETTING: Australia. PARTICIPANTS: Patients receiving dental services under the Medicare CDDS. INTERVENTIONS: The CDDS. MAIN OUTCOME MEASURES: Number and type of services. METHOD: CDDS service categories Australian Statistical Geography Standard (ASGS) regions were collected by the Australian Department of Human Services between 2008 and 2013 and compared by Australian Bureau of Statistics ASGS estimated resident regional 2011 population, and by employed number of dentists, dental specialists and dental prosthetists from the 2011 National Health Workforce Dataset. RESULTS: Number of services provided was greatest in major cities (79.0%), followed by inner regional (15.4%), outer regional (5.2%) and remote/very remote Australia (0.4%). Number of services per head of population decreased from 1.088 in major cities to 0.16 in remote/very remote areas. Number of services provided per dental practitioner showed minimal variation between major city (1672), inner (1777) and outer regional (1627) areas, but was lower in remote/very remote areas (641). Crown and bridge, periodontic, endodontic and removable prostheses per dental practitioner were most frequently supplied in the major cities, but restorative care and oral surgery were more frequently supplied in inner and outer regional areas. CONCLUSION: The number of CDDS services provided declined with regional remoteness. There was a marked difference in the utilisation of the scheme between major cities and remote/very remote areas in both number and type of service levels. PMID- 25495626 TI - Clinical oral health of Australia's rural children in a sample attending school dental services. AB - OBJECTIVE: To examine the association between children's clinical oral health status and their residential location using the latest available data (2009) and to ascertain whether poor oral health among rural children is related to being Indigenous, having less access to fluoridated water or being of lower socioeconomic status (SES), than children from urban areas. DESIGN: Cross sectional survey. SETTING AND PARTICIPANT: Data were collected on 74, 467 children aged 5-12 years attending school dental services in Australia (data were not available for Victoria or New South Wales). MAIN OUTCOME MEASURES: Clinical oral health was determined by the mean number of permanent teeth with untreated caries, missing and filled permanent teeth, and the mean decayed, missing and filled permanent teeth index (DMFT) of 8 to 12-year-old-children and the mean number deciduous teeth with untreated caries, missing and filled deciduous teeth, and the mean decayed, missing and filled deciduous teeth index (dmft) of 5-10 year-olds. RESULTS: The multivariable models that included coefficients on whether the child was Indigenous, from an area with fluoridated water and SES, were controlled for age and sex. The mean DMFT of 8-12-year-old children and the mean dmft of 5-10-year-old-children were significantly higher in rural areas compared with urban centres after accounting for Indigenous status, fluoridated water and SES. CONCLUSION: Children's oral health was poorer in rural areas than in major city areas. PMID- 25495627 TI - Investigation into the effect of infrastructure on fly-in fly-out mining workers. AB - OBJECTIVE: To explore fly-in fly-out (FIFO) mining workers' attitudes towards the leisure time they spend in mining camps, the recreational and social aspects of mining camp culture, the camps' communal and recreational infrastructure and activities, and implications for health. DESIGN: In-depth semistructured interviews. SETTING: Individual interviews at locations convenient for each participant. PARTICIPANTS: A total of seven participants, one female and six males. The age group varied within 20-59 years. Marital status varied across participants. MAIN OUTCOME MEASURES: A qualitative approach was used to interview participants, with responses thematically analysed. Findings highlight how the recreational infrastructure and activities at mining camps impact participants' enjoyment of the camps and their feelings of community and social inclusion. RESULTS: Three main areas of need were identified in the interviews, as follows: (i) on-site facilities and activities; (ii) the role of infrastructure in facilitating a sense of community; and (iii) barriers to social interaction. CONCLUSION: Recreational infrastructure and activities enhance the experience of FIFO workers at mining camps. The availability of quality recreational facilities helps promote social interaction, provides for greater social inclusion and improves the experience of mining camps for their temporary FIFO residents. The infrastructure also needs to allow for privacy and individual recreational activities, which participants identified as important emotional needs. Developing appropriate recreational infrastructure at mining camps would enhance social interactions among FIFO workers, improve their well-being and foster a sense of community. Introducing infrastructure to promote social and recreational activities could also reduce alcohol-related social exclusion. PMID- 25495628 TI - Implementation of a multicomponent intervention to optimise patient safety through improved oxygen prescription in a rural hospital. AB - OBJECTIVE: To rationalise oxygen procedures in adult medical and surgical inpatients with a view to improving patient safety. DESIGN: Prospective pre- and post-intervention audit. SETTING: Manning Hospital, a rural referral hospital in Taree NSW. PARTICIPANTS: Pre-intervention: 82 patients aged 72.7 +/- 14.7 years. Post-intervention: 77 patients aged 73.6 +/- 12.4 years. INTERVENTION: A multicomponent intervention composed of implementation of a local hospital oxygen policy, introduction of a specific oxygen prescription chart and targeted staff education. MAIN OUTCOME MEASURES: Satisfactory oxygen prescription, monitoring and titration. RESULTS: Only 2/82 (2.4%) patients had satisfactory oxygen prescription specifying target saturation, device and initial flow rate before the intervention compared with 26/77 (34%) patients post-intervention (chi(2) = 56.88, df = 5, P < 0.0001). Percentage of patients with conditions predisposing to hypercapnic respiratory failure who were overtreated with oxygen dropped from 9/19 (47%) to 4/22 (18%) following the study intervention (chi(2) = 4.011, df = 1, P = 0.04). Oxygen therapy monitoring was satisfactory during the audit period, but oxygen titration was unsatisfactory and did not significantly improve following the intervention. CONCLUSIONS: A multicomponent intervention can achieve a significantly increased rate of satisfactory oxygen prescriptions specifying target saturation, including in those who are at risk of hypercapnic respiratory failure. PMID- 25495629 TI - Exploring a public-private partnership new-graduate physiotherapy recruitment program: a qualitative study. AB - OBJECTIVE: Difficulty in attracting allied health staff to rural areas is well known. In 2012, a small rural health facility and local private practice created an informal public-private partnership to recruit two new-graduate physiotherapists. Graduates were employed part-time in both the public and private sectors. DESIGN: This qualitative case study employed an appreciative enquiry framework to explore this partnership model. Three focus groups were held, and a combination of content and thematic analysis was used to derive and organise themes arising from the data. SETTING: A regional public health service and private physiotherapy practice in the Bega Valley region of south-eastern New South Wales, Australia. PARTICIPANTS: New-graduate and second-year physiotherapists (n = 5), private sector managers (n = 3), and public sector managers (n = 4). MAIN OUTCOME MEASURES: Perceived benefits of the partnership model and improvements that could be made to further develop the model. RESULTS: Organisational benefits of a shared public-private role included the ability to attract high-quality applicants to difficult-to-fill positions, reduced the risk of new-graduate attrition due to social isolation, enhanced networking between sectors, and enhanced staff skill development through a broad range of clinical and non-clinical experiences. The model relied on management flexibility and has potential to expand to other areas and professions. Dedicated funding support, targeted recruitment strategies and increased planning to ease the transition into the workplace would further enhance the model. CONCLUSIONS: An informal public-private partnership to overcome established workforce shortages has proven successful to the benefit of the new graduates and both the public and private sectors. PMID- 25495630 TI - Rural mental health matters. PMID- 25495631 TI - Report reveals rural children miss out on early intervention funds. PMID- 25495634 TI - Classical and nonclassical germanium environments in high-pressure BaGe5. AB - A new crystalline form of BaGe(5) was obtained at a pressure of 15(2) GPa in the temperature range from 1000(100) to 1200(120) K. Single-crystal electron and powder X-ray diffraction patterns indicate a body-centered orthorhombic structure (space group Imma, Pearson notation oI24) with unit cell parameters a = 8.3421(8) A, b = 4.8728(5) A, and c = 13.7202(9) A. The crystal structure of hp-BaGe(5) consists of four-bonded Ge atoms forming complex layers with Ge-Ge contacts between 2.560(6) and 2.684(3) A; the Ba atoms are coordinated by 15 Ge neighbors in the range from 3.341(6) to 3.739(4) A. Analysis of the chemical bonding using quantum chemical techniques in real space reveal charge transfer from the Ba cations to the anionic Ge species. Ge atoms having nearly tetrahedral environments show an electron-localizability-based oxidation number close to 0; the four-bonded Ge atoms with a Psi-pyramidal environment adopt a value close to 1-. In agreement with the calculated electronic density of states, the compound is a metallic conductor (electrical resistivity of ca. 240 MUOmega cm at 300 K), and magnetic susceptibility measurements evidence diamagnetic behavior with chi(0) = -95 * 10(-6) emu mol(-1). PMID- 25495633 TI - Exact reconstruction of gene regulatory networks using compressive sensing. AB - BACKGROUND: We consider the problem of reconstructing a gene regulatory network structure from limited time series gene expression data, without any a priori knowledge of connectivity. We assume that the network is sparse, meaning the connectivity among genes is much less than full connectivity. We develop a method for network reconstruction based on compressive sensing, which takes advantage of the network's sparseness. RESULTS: For the case in which all genes are accessible for measurement, and there is no measurement noise, we show that our method can be used to exactly reconstruct the network. For the more general problem, in which hidden genes exist and all measurements are contaminated by noise, we show that our method leads to reliable reconstruction. In both cases, coherence of the model is used to assess the ability to reconstruct the network and to design new experiments. We demonstrate that it is possible to use the coherence distribution to guide biological experiment design effectively. By collecting a more informative dataset, the proposed method helps reduce the cost of experiments. For each problem, a set of numerical examples is presented. CONCLUSIONS: The method provides a guarantee on how well the inferred graph structure represents the underlying system, reveals deficiencies in the data and model, and suggests experimental directions to remedy the deficiencies. PMID- 25495635 TI - Molecular and oenological characterization of Touriga Nacional non-Saccharomyces yeasts. AB - AIMS: The aim of this study was to evaluate non-Saccharomyces yeasts isolated from spontaneous fermenting musts of Touriga Nacional (TN), one of the most important Portuguese red grape variety, to improve and diversify TN wines. METHODS AND RESULTS: Two hundred and seventy nine isolates were assigned to 11 yeast species by conventional molecular and growth tests. Starmerella bacillaris was the most frequently detected yeast species, followed by Hanseniaspora guilliermondii and Hanseniaspora uvarum. Twenty-three isolates from 10 species were selected for oenological study, namely fermentation performance, physicochemical and quantitative descriptive sensory analysis of the wines produced. A significant species effect was observed for most of the variables evaluated, some species generating wines with quite interesting aromas. CONCLUSIONS: Candida diversa and S. bacillaris isolates produced wines with higher overall quality, higher balance and more intense and diverse aroma. Furthermore, S. bacillaris isolates generated wines with enhanced TN typical aroma, such as bergamot, violet and rock-rose, and were thus regarded as the most promising for improving TN wines. SIGNIFICANCE AND IMPACT OF STUDY: This study revealed the diversity of wine aroma profiles generated by non-Saccharomyces yeast isolates. This knowledge is particularly important given the growing trend from industry to use non-Saccharomyces yeasts as a tool for improving and diversifying the sensory characteristics of wine. PMID- 25495636 TI - Presenting simulation results in a nested loop plot. AB - BACKGROUND: Statisticians investigate new methods in simulations to evaluate their properties for future real data applications. Results are often presented in a number of figures, e.g., Trellis plots. We had conducted a simulation study on six statistical methods for estimating the treatment effect in binary outcome meta-analyses, where selection bias (e.g., publication bias) was suspected because of apparent funnel plot asymmetry. We varied five simulation parameters: true treatment effect, extent of selection, event proportion in control group, heterogeneity parameter, and number of studies in meta-analysis. In combination, this yielded a total number of 768 scenarios. To present all results using Trellis plots, 12 figures were needed. METHODS: Choosing bias as criterion of interest, we present a 'nested loop plot', a diagram type that aims to have all simulation results in one plot. The idea was to bring all scenarios into a lexicographical order and arrange them consecutively on the horizontal axis of a plot, whereas the treatment effect estimate is presented on the vertical axis. RESULTS: The plot illustrates how parameters simultaneously influenced the estimate. It can be combined with a Trellis plot in a so-called hybrid plot. Nested loop plots may also be applied to other criteria such as the variance of estimation. CONCLUSION: The nested loop plot, similar to a time series graph, summarizes all information about the results of a simulation study with respect to a chosen criterion in one picture and provides a suitable alternative or an addition to Trellis plots. PMID- 25495637 TI - Dermoscopic features of clear cell acanthoma: five new cases and a review of existing published cases. PMID- 25495638 TI - Does the singlet minus triplet spectrum with major photobleaching band near 680 682 nm represent an intact reaction center of Photosystem II? AB - We use both frequency- and time-domain low-temperature (5-20 K) spectroscopies to further elucidate the shape and spectral position of singlet minus triplet (triplet-bottleneck) spectra in the reaction centers (RCs) of Photosystem II (PSII) isolated from wild-type Chlamydomonas reinhardtii and spinach. It is shown that the shape of the nonresonant transient hole-burned spectrum in destabilized RCs from C. reinhardtii is very similar to that typically observed for spinach. This suggests that the previously observed difference in transient spectra between RCs from C. reinhardtii and spinach is not due to the sample origin but most likely due to a partial destabilization of the D1 and D2 polypeptides. This supports our previous assignments that destabilized RCs (referred to as RC680) (Acharya, K. et al. J. Phys. Chem. B 2012, 116, 4860-4870), with a major photobleaching band near 680-682 nm and the absence of a photobleaching band near 673 nm, do not represent the intact RC residing within the PSII core complex. Time-resolved absorption difference spectra obtained for partially destabilized RCs of C. reinhardtii and for typical spinach RCs support the above conclusions. The absence of clear photobleaching bands near 673 and 684 nm (where the PD1 chlorophyll and the active pheophytin (PheoD1) contribute, respectively) in picosecond transient absorption spectra in both RCs studied in this work indicates that the cation can move from the primary electron donor (ChlD1) to PD1 (i.e., PD1ChlD1(+)PheoD1(-) -> PD1(+)ChlD1PheoD1(-)). Therefore, we suggest that ChlD1 is the major electron donor in usually studied destabilized RCs (with a major photobleaching near 680-682 nm), although the PD1 path (where PD1 serves as the primary electron donor) is likely present in intact RCs, as discussed in Acharya, K. et al. J. Phys. Chem. B 2012, 116, 4860-4870. PMID- 25495639 TI - The interpersonal process model of demand/withdraw behavior. AB - The demand/withdraw interaction pattern is a destructive cycle of relationship communication behavior that is associated with negative individual and relationship outcomes. Demand/withdraw behavior is thought to be strongly linked to partners' emotional reactions, but current theories are inconsistent with empirical findings. The current study proposes the interpersonal process model of demand/withdraw behavior, which includes linkages between each partners' emotional reactions and the interpersonal behavior of demanding and withdrawing. Data come from problem solving discussions of 55 German couples with observationally coded demand/withdraw behavior and fundamental frequency (f0) to measure vocally encoded emotional arousal. Actor-partner interdependence models (Kenny, Kashy, & Cook, 2006) were used to examine associations among demand/withdraw behavior and f0 in the overall discussion and 5-min segments. Significant cross-partner associations emerged for demanding and withdrawing behavior across the whole conversation as well as within 5-min segments, and these associations are partially accounted for by each individual's f0. When behaviorally coded demanders expressed more vocal arousal, they demanded more and withdrew less while their partners withdrew more. In contrast, when behaviorally coded withdrawers expressed more vocal arousal, their partners demanded less and withdrew more. Findings demonstrate that demand/withdraw behavior varies between couples (i.e., some couples engage in a stronger demand/withdraw cycle than others) and between segments (i.e., when 1 partner increases demanding, the other increases withdrawing). Findings support key elements of the interpersonal process model, showing intra- and interpersonal pathways linking demand/withdraw behavior and emotion and demonstrate the importance of partners' behavioral roles in these linkages. PMID- 25495640 TI - Parent and adolescent intentions to disclose and links to positive social behavior. AB - Children's disclosure to parents as a buffer against antisocial behavior, and its parenting antecedents, have been extensively studied in recent years. The influence of parents' own disclosure on children's disclosure and positive social behavior has received little attention, however. We assessed mothers' (n = 149), fathers' (n= 105), and 12- to 14-year-old early adolescents' (n = 127) intentions to disclose about distress-related events and rule transgressions, their reasons for disclosing, and links to positive social behavior (assessed by mothers' ratings of willing compliance and by teachers' [n = 114] ratings of prosocial behavior). Parents reported that they disclosed to teach lessons or to encourage their children to disclose, whereas adolescents said they disclosed for comfort and advice. Child intention to disclose about distressing events mediated between mother (but not father) intention to disclose about these same issues and children's willing compliance, but not prosocial behavior in the classroom. Parent and child disclosure about rule transgressions were not related. PMID- 25495643 TI - Electronic structure of alloxan and its dimers: QM/QD simulations and quantum chemical topology analysis. AB - This study aims to identify the origin of the extra stability of alloxan, a biologically active pyrimidine. To achieve this goal, detailed DFT computations and quantum dynamics simulations have been performed to establish the most stable conformation and the global minimum structure on the alloxan potential energy surface. The effects of the solvent, basis set, and DFT method have been examined to validate the theoretical model adopted throughout the work. Two non-covalent intermolecular dimers of alloxan, the H-bonded and dipolar dimers, have been investigated at the omegaB97X-D and M06-2X levels of theory using the triple zeta 6-311++G** to establish their relative stability. Quantum chemical topology features and natural bond orbital analysis (NBO) have been performed to identify and characterize the forces that govern the structures and underlie the extra stability of alloxan. PMID- 25495641 TI - The burden of chronic mercury intoxication in artisanal small-scale gold mining in Zimbabwe: data availability and preliminary estimates. AB - BACKGROUND: Artisanal small-scale gold mining (ASGM) is a poverty-driven activity practiced in over 70 countries worldwide. Zimbabwe is amongst the top ten countries using large quantities of mercury to extract gold from ore. This analysis was performed to check data availability and derive a preliminary estimate of disability-adjusted life years (DALYs) due to mercury use in ASGM in Zimbabwe. METHODS: Cases of chronic mercury intoxication were identified following an algorithm using mercury-related health effects and mercury in human specimens. The sample prevalence amongst miners and controls (surveyed by the United Nations Industrial Development Organization in 2004 and the University of Munich in 2006) was determined and extrapolated to the entire population of Zimbabwe. Further epidemiological and demographic data were taken from the literature and missing data modeled with DisMod II to quantify DALYs using the methods from the Global Burden of Disease (GBD) 2004 update published by the World Health Organization (WHO). While there was no disability weight (DW) available indicating the relative disease severity of chronic mercury intoxication, the DW of a comparable disease was assigned by following the criteria 1) chronic condition, 2) triggered by a substance, and 3) causing similar health symptoms. RESULTS: Miners showed a sample prevalence of 72% while controls showed no cases of chronic mercury intoxication. Data availability is very limited why it was necessary to model data and make assumptions about the number of exposed population, the definition of chronic mercury intoxication, DW, and epidemiology. If these assumptions hold, the extrapolation would result in around 95,400 DALYs in Zimbabwe's total population in 2004. CONCLUSIONS: This analysis provides a preliminary quantification of the mercury-related health burden from ASGM based on the limited data available. If the determined assumptions hold, chronic mercury intoxication is likely to have been one of the top 20 hazards for population health in Zimbabwe in 2004 when comparing with more than 130 categories of diseases and injuries quantified in the WHO's GBD 2004 update. Improving data quality would allow more accurate estimates. However, the results highlight the need to reduce a burden which could be entirely avoided. PMID- 25495644 TI - Environmental photoinactivation of extracellular phosphatases and the effects of dissolved organic matter. AB - Alkaline phosphatases are ubiquitous extracellular enzymes in aquatic systems and play a central role in the biogeochemical cycling of phosphorus. Yet, the photochemical stability of phosphatase and effects of natural organic matter (DOM) are not completely understood. We demonstrate that phosphatase activity in natural biofilm samples decreased during sunlight exposure similar to well defined bacterial phosphatase solutions. Direct photoinactivation was slowed by more than 50% in the presence of redox-active dissolved organic matter (DOM, 10 mgC L(-1)) or a model antioxidant (esculetin, 50 MUM), even after light screening effects had been accounted for. Thus, DOM can not only inhibit enzymes (in the dark) or sensitize photodegradation by producing photochemically produced reactive intermediates but can also significantly quench direct photoinactivation of phosphatase. Our data further suggest that direct photooxidation of tryptophan residues within the protein structure are significantly involved in the photoinactivation of phosphatase because a loss of tryptophan-like fluorescence paralleled photoinactivation kinetics and because DOM acted as an antioxidant toward photoinactivation, a phenomenon recently established for the photooxidation of freely dissolved tryptophan. Thus, photoinactivation of phosphatase can be significantly slowed in the presence of naturally occurring antioxidants like DOM. The mechanistic link between tryptophan photooxidation and inactivation of phosphatase may have applicability to other extracellular enzymes but remains to be established. PMID- 25495642 TI - Mechanisms of intrinsic epileptogenesis in human gelastic seizures with hypothalamic hamartoma. AB - Human hypothalamic hamartoma (HH) is a rare developmental malformation often characterized by gelastic seizures, which are refractory to medical therapy. Ictal EEG recordings from the HH have demonstrated that the epileptic source of gelastic seizures lies within the HH lesion itself. Recent advances in surgical techniques targeting HH have led to dramatic improvements in seizure control, which further supports the hypothesis that gelastic seizures originate within the HH. However, the basic cellular and molecular mechanisms of epileptogenesis in this subcortical lesion are poorly understood. Since 2003, Barrow Neurological Institute has maintained a multidisciplinary clinical program to evaluate and treat patients with HH. This program has provided a unique opportunity to investigate the basic mechanisms of epileptogenesis using surgically resected HH tissue. The first report on the electrophysiological properties of HH neurons was published in 2005. Since then, ongoing research has provided additional insights into the mechanisms by which HH generate seizure activity. In this review, we summarize this progress and propose a cellular model that suggests that GABA mediated excitation contributes to epileptogenesis in HH lesions. PMID- 25495646 TI - Probiotic and prebiotic-probiotic PEC microparticles for sustaining and enhancing intestinal probiotic growth. AB - The aim of the study was to develop and evaluate Polyelectrolyte complex (PEC) microparticles composing Lactobacillus Acidophilus (probiotic) and Fructo oligosaccharide-Lactobacillus Acidophilus (prebiotic-probiotic), for sustaining and enhancing intestinal growth of probiotic bacteria. Gum Karaya-Chitosan(GK-CH) was used to fabricate PEC microparticles by extrusion method. The prepared microparticles were characterized for FT-IR, DSC and particle size and evaluated for percentage yield, swelling, surface morphology, entrapment rate and further studied for influence of prebiotic over probiotic growth. The fabricated PEC microparticles composed of Probiotic and Prebiotic- Probiotic have exhibited sustainability of probiotic bacteria for 12 hrs in GIT conditions and presence of prebiotic in the preparation enhanced the probiotic cell growth. Hence, it can be concluded that PEC between GK-CH was found to be successful in sustaining cell release and presence of prebiotic was found to enhance the probiotic cell growth. PMID- 25495645 TI - Silencing of ANGPTL 3 (angiopoietin-like protein 3) in human hepatocytes results in decreased expression of gluconeogenic genes and reduced triacylglycerol-rich VLDL secretion upon insulin stimulation. AB - Homozygosity of loss-of-function mutations in ANGPTL3 (angiopoietin-like protein 3)-gene results in FHBL2 (familial combined hypolipidaemia, OMIM #605019) characterized by the reduction of all major plasma lipoprotein classes, which includes VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), HDL (high-density lipoprotein) and low circulating NEFAs (non-esterified fatty acids), glucose and insulin levels. Thus complete lack of ANGPTL3 in humans not only affects lipid metabolism, but also affects whole-body insulin and glucose balance. We used wild-type and ANGPTL3-silenced IHHs (human immortalized hepatocytes) to investigate the effect of ANGPTL3 silencing on hepatocyte specific VLDL secretion and glucose uptake. We demonstrate that both insulin and PPARgamma (peroxisome-proliferator-activated receptor gamma) agonist rosiglitazone down-regulate the secretion of ANGPTL3 and TAG (triacylglycerol) enriched VLDL1-type particles in a dose-dependent manner. Silencing of ANGPTL3 improved glucose uptake in hepatocytes by 20-50% and influenced down-regulation of gluconeogenic genes, suggesting that silencing of ANGPTL3 improves insulin sensitivity. We further show that ANGPTL3-silenced cells display a more pronounced shift from the secretion of TAG-enriched VLDL1-type particles to secretion of lipid poor VLDL2-type particles during insulin stimulation. These data suggest liver-specific mechanisms involved in the reported insulin-sensitive phenotype of ANGPTL3-deficient humans, featuring lower plasma insulin and glucose levels. PMID- 25495647 TI - Regulation of Vibrio parahaemolyticus T3SS2 gene expression and function of T3SS2 effectors that modulate actin cytoskeleton. AB - Vibrio parahaemolyticus is a leading causative agent of seafood-borne gastroenteritis worldwide. Most clinical isolates from patients with diarrhoea possess two sets of genes for the type III secretion system (T3SS) on each chromosome (T3SS1 and T3SS2). T3SS is a protein secretion system that delivers effector proteins directly into eukaryotic cells. The injected effectors modify the normal cell functions by altering or disrupting the normal cell signalling pathways. Of the two sets of T3SS genes present in V. parahaemolyticus, T3SS2 is essential for enterotoxicity in several animal models. Recent studies have elucidated the biological activities of several T3SS2 effectors and their roles in virulence. This review focuses on the regulation of T3SS2 gene expression and T3SS2 effectors that specifically target the actin cytoskeleton. PMID- 25495648 TI - Synthesis of ortho-haloaminoarenes by aryne insertion of nitrogen-halide bonds. AB - A rapid and general access to ortho-haloaminoarenes has been developed by aryne insertion into N-chloramine, N-bromoamine, and N-iodoamine bonds via two complementary protocols harnessing fluoride-promoted 1,2-elimination of ortho trimethylsilyl aryltriflates. Typically, electron-deficient N-chloramines effectively react with aryne intermediates generated at elevated temperature with CsF, while less stable N-haloamines are found more efficient under milder, TBAF mediated aryne formation at room temperature. Both protocols demonstrate a good level of regioselectivity and functional group tolerance. Efforts to elucidate the mechanism of N-X insertion are also discussed. The practical value of this transformation is highlighted by rapid synthesis of novel analogues of the antipsychotic cariprazine. PMID- 25495649 TI - Treatment of two patients with generalized pustular psoriasis with the interleukin-1beta inhibitor gevokizumab. AB - Generalized pustular psoriasis (GPP) is a severe, potentially life-threatening inflammatory dermatosis, which is traditionally difficult to manage. Recent evidence suggests that interleukin (IL)-1 plays a central role in the disease pathogenesis, and thus makes the use of IL-1 inhibitors potentially effective. Two patients with severe, recalcitrant GPP were enrolled in an open-label, expanded access study to receive a new IL-1beta inhibitor, gevokizumab. The two patients had a respective 79% and 65% reduction in GPP area and severity index scores at weeks 4 and 12, with some improvements in quality-of-life instruments. There were no significant adverse events related to the study medication, although one patient developed an abscess in a haematoma secondary to an injury. Both patients showed substantial initial clinical response to gevokizumab, with no significant laboratory abnormalities noted. These cases illustrate the growing need for targeted, efficacious therapies for this severe, debilitating disease. Prospective randomized control studies are required to further assess the safety and efficacy of IL-1beta inhibitors for the treatment of GPP. PMID- 25495650 TI - Responsiveness of the Japanese Osteoporosis Quality of Life questionnaire in women with postmenopausal osteoporosis. AB - BACKGROUND: The Japanese Osteoporosis Quality of Life (JOQOL) questionnaire measures quality of life in Japanese patients with osteoporosis. However, several important aspects of the psychometric properties of individual domains, including responsiveness, have not been addressed to enable valid clinical application. This analysis examined the internal and external responsiveness of the JOQOL questionnaire. METHODS: This was a post hoc analysis of a 24-week prospective postmarketing study of raloxifene (60 mg/day) administered to postmenopausal Japanese women with osteoporosis (JapicCTI-070465). Internal responsiveness was assessed using Standardized Response Mean (SRM) statistics and changes in JOQOL domain scores. Patients were also stratified into those who did or did not achieve a minimal clinically important change (MCIC) in pain, assessed by a visual analogue scale for pain (VAS pain): comparisons were made between treated patients who achieved VAS pain reduction >= 20 mm versus VAS pain reduction < 20 mm. External responsiveness was assessed using Pearson's correlation coefficient (r) for changes in JOQOL domain scores with Short Form-8 Health Survey and European Quality of Life Instrument scores. RESULTS: Of 506 patients analyzed, 421 had a baseline value for VAS pain; of these, 152 patients (36.1%) had a MCIC, whereas 264 patients (62.7%) did not. The JOQOL domains pain, overall health, and falls/psychological factors had small to moderate SRM values (0.3-0.5) in all patients, but consistently showed significantly larger changes in patients whose pain score changes exceeded the MCIC. Together, these findings suggest some degree of internal responsiveness for these domains. However, activities of daily living domain had a SRM value as low as 0.2, and recreation/social activities and posture/physique domains had SRM values close to 0. Moderate correlation (defined as r >= 0.4 to < 0.6) was noted between the domains pain, activities of daily living, and overall health and some Short Form-8 Health Survey subscales and the European Quality of Life total score, suggesting external responsiveness of these domains. CONCLUSIONS: The inconsistent responsiveness among individual JOQOL domains in treated patients suggests the need for improving several JOQOL domains, especially the activities of daily living, recreation/social activities and posture/physique domains, before application to clinical research. PMID- 25495651 TI - New insights into PGC-1 coactivators: redefining their role in the regulation of mitochondrial function and beyond. AB - Members of the PGC-1 family of coactivators have been revealed as key players in the regulation of energy metabolism. Early gain- and loss-of-function studies led to the conclusion that all members of the PGC-1 family (PGC-1alpha, PGC-1beta and PRC) play redundant roles in the control of mitochondrial biogenesis by regulating overlapping gene expression programs. Regardless of this, all PGC-1 coactivators also appeared to differ in the stimuli to which they respond to promote mitochondrial gene expression. Although PGC-1alpha was found to be induced by different physiological or pharmacological cues, PGC-1beta appeared to be unresponsive to such stimuli. Consequently, it has long been widely accepted that PGC-1alpha acts as a mediator of mitochondrial biogenesis induced by cues that signal high-energy needs, whereas the role of PGC-1beta is restricted to the maintenance of basal mitochondrial function. By contrast, the function of PRC appears to be restricted to the regulation of gene expression in proliferating cells. However, recent studies using tissue-specific mouse models that lack or overexpress different PGC-1 coactivators have provided emerging evidence not only supporting new roles for PGC-1s, but also redefining some of the paradigms related to the precise function and mode of action of PGC-1 coactivators in mitochondrial biogenesis. The present review discusses some of the new findings regarding the control of mitochondrial gene expression by PGC-1 coactivators in a tissue-specific context, as well as newly-uncovered functions of PGC-1s beyond mitochondrial biogenesis, and their link to pathologies, such as diabetes, muscular dystrophies, neurodegenerative diseases or cancer. PMID- 25495652 TI - Networked-cage microcrystals for evaluation of host-guest interactions. AB - We have developed a new synthetic protocol for the preparation of a microcrystalline powder (median size: X50 = 25 MUm) of networked M6L4 cages 1a for the stationary phase of an affinity column on a greater than 50 g scale. Analogously to large single crystals 1b (X50 ~ 0.5 mm), microcrystals 1a accommodate guest molecules tetrathiafulvalene (TTF) and fullerene (C60) at up to 32 and 35 wt %, respectively. Importantly, the host-guest interactions within networked cages could be evaluated in terms of the retention time from HPLC analysis by using microcrystals 1a as the stationary phase. In this way, favorable guests for networked cages 1 and even solution M6L4 cage 2 could easily be assessed by HPLC. PMID- 25495653 TI - Microflow liquid chromatography coupled to mass spectrometry--an approach to significantly increase sensitivity, decrease matrix effects, and reduce organic solvent usage in pesticide residue analysis. AB - This manuscript reports a new pesticide residue analysis method employing a microflow-liquid chromatography system coupled to a triple quadrupole mass spectrometer (microflow-LC-ESI-QqQ-MS). This uses an electrospray ionization source with a narrow tip emitter to generate smaller droplets. A validation study was undertaken to establish performance characteristics for this new approach on 90 pesticide residues, including their degradation products, in three commodities (tomato, pepper, and orange). The significant benefits of the microflow-LC-MS/MS based method were a high sensitivity gain and a notable reduction in matrix effects delivered by a dilution of the sample (up to 30-fold); this is as a result of competition reduction between the matrix compounds and analytes for charge during ionization. Overall robustness and a capability to withstand long analytical runs using the microflow-LC-MS system have been demonstrated (for 100 consecutive injections without any maintenance being required). Quality controls based on the results of internal standards added at the samples' extraction, dilution, and injection steps were also satisfactory. The LOQ values were mostly 5 MUg kg(-1) for almost all pesticide residues. Other benefits were a substantial reduction in solvent usage and waste disposal as well as a decrease in the run time. The method was successfully applied in the routine analysis of 50 fruit and vegetable samples labeled as organically produced. PMID- 25495654 TI - Investigation of a new acetogen isolated from an enrichment of the tammar wallaby forestomach. AB - BACKGROUND: Forestomach fermentation in Australian marsupials such as wallabies and kangaroos, though analogous to rumen fermentation, results in lower methane emissions. Insights into hydrogenotrophy in these systems could help in devising strategies to reduce ruminal methanogenesis. Reductive acetogenesis may be a significant hydrogen sink in these systems and previous molecular analyses have revealed a novel diversity of putative acetogens in the tammar wallaby forestomach. RESULTS: Methanogen-inhibited enrichment cultures prepared from tammar wallaby forestomach contents consumed hydrogen and produced primarily acetate. Functional gene (formyltetrahydrofolate synthetase and acetyl-CoA synthase) analyses revealed a restricted diversity of Clostridiales species as the putative acetogens in the cultures. A new acetogen (growth on H2/CO2 with acetate as primary end product) designated isolate TWA4, was obtained from the cultures. Isolate TWA4 classified within the Lachnospiraceae and demonstrated >97% rrs identity to previously isolated kangaroo acetogens. Isolate TWA4 was a potent hydrogenotroph and demonstrated excellent mixotrophic growth (concomitant consumption of hydrogen during heterotrophic growth) with glycerol. Mixotrophic growth of isolate TWA4 on glycerol resulted in increased cell densities and acetate production compared to autotrophic growth. Co-cultures with an autotrophic methanogen Methanobrevibacter smithii revealed that isolate TWA4 performed reductive acetogenesis under high hydrogen concentration (>5 mM), but not at low concentrations. Under heterotrophic growth conditions, isolate TWA4 did not significantly stimulate methanogenesis in a co-culture with M. smithii contrary to the expectation for organisms growing fermentatively. CONCLUSIONS: The unique properties of tammar wallaby acetogens might be contributing factors to reduced methanogen numbers and methane emissions from tammar wallaby forestomach fermentation, compared to ruminal fermentation. The macropod forestomach may be a useful source of acetogens for future strategies to reduce methane emissions from ruminants, particularly if these strategies also include some level of methane suppression and/or acetogen stimulation, for example by harnessing mixotrophic growth capabilities. PMID- 25495655 TI - A qualitative study exploring newborn care behaviours after home births in rural Ethiopia: implications for adoption of essential interventions for saving newborn lives. AB - BACKGROUND: Ethiopia is among seven high-mortality countries which have achieved the fourth millennium development goal with over two-thirds reduction in under five mortality rate. However, the proportion of neonatal deaths continues to rise and recent studies reported low coverage of the essential interventions saving newborn lives. In the context of low uptake of health facility delivery, it is relevant to explore routine practices during home deliveries and, in this study, we explored the sequence of immediate newborn care practices and associated beliefs following home deliveries in rural communities in Ethiopia. METHODS: Between April-May 2013, we conducted 26 semi-structured interviews and 2 focus group discussions with eligible mothers, as well as a key informant interview with a local expert in traditional newborn care practices in rural Basona woreda (district) near the urban town of Debrebirhan, 120 km from Addis Ababa, Ethiopia. RESULTS: The most frequently cited sequence of newborn care practices reported by mothers with home deliveries in the rural Basona woreda was to tie the cord, immediately bath then dry the newborn, practice 'Lanka mansat' (local traditional practice on newborns), give pre-lacteal feeding and then initiate breastfeeding. For 'Lanka mansat', the traditional birth attendant applies mild pressure inside the baby's mouth on the soft palate using her index finger. This is performed believing that the baby will have 'better voice' and 'speak clearly' later in life. CONCLUSION: Coverage figures fail to tell the whole story as to why some essential interventions are not practiced and, in this study, we identified established norms or routines within the rural communities that determine the sequence of newborn care practices following home births. This might explain why some mothers delay initiation of breastfeeding and implementation of other recommended essential interventions saving newborn lives. An in-depth understanding of established routines is necessary, and community health extension workers require further training and negotiation skills in order to change the behaviour of mothers in practicing essential interventions while respecting local values and norms within the communities. PMID- 25495656 TI - Cholesterol modulates the interaction of the islet amyloid polypeptide with membranes. AB - The deposition of insoluble amyloid fibrils resulting from the aggregation of the human islet amyloid polypeptide (hIAPP) within the islet of Langerhans is a pathological feature of type 2 diabetes mellitus (T2DM). Increasing evidence indicates that biological membranes play a key role in amyloid aggregation, modulating among others the kinetics of amyloid formation, and being the target of toxic species generated during amyloid formation. In T2DM patients, elevated levels of cholesterol, an important determinant of the physical state of biological membranes, are observed in beta-cells and are thought to directly impair beta-cell function and insulin secretion. However, it is not known whether cholesterol enhances membrane-interaction or membrane-insertion of hIAPP. In this study, we investigated the effect of cholesterol incorporated in zwitterionic and anionic membranes. Our circular dichroism and liquid state NMR data reveal that 10-30% of cholesterol slightly affects the aggregational and conformational behaviour of hIAPP. Additional fluorescence results indicate that 10 and 20% of cholesterol slightly slow down the kinetics of oligomer and fibril formation while anionic lipids accelerate this kinetics. This behavior might be caused by differences in membrane insertion and therefore in membrane binding of hIAPP. The membrane binding affinity was evaluated using (1)H NMR experiments and our results show that the affinity of hIAPP for membranes containing cholesterol is significantly smaller than that for membranes containing anionic lipids. Furthermore, we found that hIAPP-induced membrane damage is synchronized to fibril formation in the absence and in the presence of cholesterol. PMID- 25495657 TI - A novel non-surgical, minimally invasive technique for parathyroid autotransplantation: a case report. AB - We present a case report of intramuscular autotransplantation of the parathyroid cell suspension acquired after total parathyroidectomy. A 15-yr-old female patient who had been undergoing hemodialysis due to chronic renal failure for eight yr was diagnosed with secondary hyperthyroidism and subsequently underwent total parathyroidectomy. The parathyroid cells were acquired from the resected tissues, processed through isolation and cultivation phases, and counted using a cell counter. A total of two million cells were injected into the left deltoid muscle using a 22-gauge needle. After surgery, five and 10 million cells were injected in the fifth and 12 week, respectively. The desired serum levels of parathyroid hormones and calcium were not achieved after the first two transplantations. In addition, there was no regression in the patient's symptoms. However, at four wk after the third transplantation, serum parathyroid hormone level did not decrease to <3 pg/mL, the patient was asymptomatic, and the oral treatment was stopped. Our findings indicate that this new technique is applicable because it is minimally invasive, and it can be easily repeated. PMID- 25495658 TI - Acceleration of small bowel transit in a canine hypermotility model with intestinal electrical stimulation. AB - OBJECTIVE: Few studies have been performed on the effect of intestinal electrical stimulation (IES) on intestinal dysmotility. This study aimed to investigate the small intestine transit (SIT) in a canine model of intestinal hypermotility when applying IES. METHOD: Six hound bitches were surgically prepared with two chronic intestinal fistulas, intestinal serosal electrodes of which the proximal pair was used for serosal IES. Pacing wires were attached to a manometric catheter for mucosal IES. A nitrogen oxide synthase inhibitor, Nomega-nitro-L-arginine (LNNA) was used to induce intestinal motility. SIT was measured during IES. The study consisted of four randomized sessions: session 1 (LNNA), session 2 (LNNA plus serosal IES), session 3 (LNNA plus mucosal IES) and session 4 (control). RESULTS: The intestine transit was slowed down from 31.7 +/- 6.1 min in the control session to 49.0 +/- 6.2 min after using LNNA (P = 0.003). Both mucosal and serosal IES accelerated SIT compared with the LNNA session. The SIT time was reduced to 17.7 +/- 3.4 min in the mucosal IES session (P = 0.006 vs. LNNA) and 27.5 +/- 6.3 min in the serosal IES session (P = 0.020 vs. LNNA). No difference was noted in the SIT time between mucosal and serosal IES (P = 0.128). CONCLUSION: IES significantly accelerates delayed SIT in a hypermotility model and intraluminal stimulation is as effective as a serosal one for IES, suggesting that IES may have a therapeutic potential for improving intestinal motility. PMID- 25495659 TI - Heparin induces an accumulation of atherogenic lipoproteins during hemodialysis in normolipidemic end-stage renal disease patients. AB - Dyslipidemias may account for the excess of cardiovascular mortality in end-stage renal disease (ESRD). Lipoprotein studies in ESRD patients are usually relative to prehemodialysis samples even if significative changes may occur after dialysis. In this study, we aimed to investigate the effects of ESRD on triglyceride-rich lipoproteins (TRL) subpopulations distribution and acute change following hemodialytic procedures, including the relative contribution of heparin administration. We selected a group of normolipidemic male middle-aged ESRD patients free of any concomitant disease affecting lipoprotein remnant metabolism compared with controls. We separated TRL subfractions according to density and apoE content and evaluated the changes of these particles after hemodialytic procedures with or without heparin. ESRD subjects had higher TRL subfractions, with the exception of apoE-rich particles, lower high-density lipoprotein (HDL) largest subclasses, and a smaller low-density lipoprotein peak particle size than controls. After a hemodialytic standard procedure with heparin, we demonstrated a significant reduction of triglyceride, an increase of HDL-cholesterol levels, and a raise of small very-low-density lipoprotein, intermediate-density lipoproteins (IDL), apoE-rich particles, and non-HDL-cholesterol levels. When hemodialysis was performed without heparin, no significant changes were observed. In the absence of concomitant hyperlipidemic triggers, ESRD patients show significant lipoprotein abnormalities before dialysis, but without any increased remnant particles concentrations. We speculate that hemodialysis, in particular heparin administration during this procedure, leads to a massive atherogenic TRLs production because of the acute stimulation of the dysfunctional lipolytic system not followed by an efficient removal, determining a recurrent lipoprotein remnant accumulation. PMID- 25495660 TI - Investigation of the effect of phosphogypsum amendment on two Arabidopsis thaliana ecotype growth and development. AB - The production of phosphoric acid from natural phosphate rock leads to an industrial waste called phosphogypsum (PG). About 5 tons of PG are generated per ton of phosphoric acid produced. This acidic waste (pH 2.2) is mostly disposed of by dumping into large stockpiles close to fertilizer production units, where they occupy large land areas that can cause serious environmental damages. Several attempts were made to test PG valorization via soil amendment because of its phosphate, sulphate and calcium content. The aim of the this study was to evaluate the potential use of PG as phosphate amendment in soil using two wild type Arabidopsis thaliana ecotypes (Wassilewskija and Colombia) as model plants. Plants were grown in a greenhouse for 30 days, on substrates containing various PG concentrations (0%, 15%, 25%, 40% and 50%). The growth rate and physiological parameters (fresh weight, phosphate and chlorophyll content) were determined. The data revealed that 15% PG did not alter plant survival and leaf's dry weight, and the inorganic phosphate (Pi) uptake by plant seemed to be efficient. However, some alterations in Chlorophyll a/Chlorophyll b ratio were noticed. Higher PG concentrations (40 and 50% PG) exhibited an enhanced negative effect on plant growth, survival and Pi uptake. These inhibitory effects of the substrates may be related to the acidity of the medium in addition to its Cd content. PMID- 25495661 TI - Risk factors for and progression of myopia in young Taiwanese men. AB - Abstract Purpose: To investigate the association between potential risk factors for myopia and its progression in young adult Taiwanese men. METHODS: A survey of male military conscripts (aged 18-24 years) was conducted from February 2010 to March 2011 in Taiwan. Participants underwent comprehensive eye examinations, including measurements of axial length and corneal radius by optical biometry and non-cycloplegic autorefraction. Participants also provided self-reported progression of myopia and information regarding potential risk factors, including age, parental myopia, educational level, close work, outdoor activities, and urbanization. RESULTS: Of 5145 eligible participants, 5048 (98.11%) provided refraction and questionnaire data; 2316 (45.88%) of the 5048 also had biometric measurements. The prevalence of myopia was 86.1% in this group, with a mean refractive error of -3.66 diopters (D). Of the 5048 participants, 1376 (27.3%) had experienced progression of their myopia during the past year. There were trends for a higher prevalence of myopia among older participants (p = 0.014), those with a history of parental myopia (p < 0.001), higher levels of education (p = 0.001), increased time spent reading (p < 0.001), less time outdoors (p = 0.003), and higher levels of urbanization (p = 0.010). However, only parental myopia, close work, and higher urbanization levels were significantly associated with self-reported progression of myopia. CONCLUSION: Older age, parental myopia, higher educational level, close work, fewer outdoor activities, and higher urbanization level were associated with the prevalence of myopia in Taiwanese men. PMID- 25495662 TI - Executive function impairment and recidivism in adult protective services clients referred for a decision making capacity assessment. AB - The objective of this study was to determine if recidivistic Adult Protective Services (APS) cases referred for a decision-making capacity assessment were more cognitively impaired than nonrecidivistic cases. A retrospective medical record review of neuropsychological and demographic data was gathered during decisional capacity assessments. Recidivistic clients were those referred to APS more than once; those with a single open case were nonrecidivistic. Mean neuropsychological test scores were compared between recidivistic (n = 138) and nonrecidivistic (n = 95) subjects. No significant differences were found for age, gender, ethnicity, education, or dwelling status. Both recidivistic and nonrecidivistic cases performed poorly in all cognitive domains. Recidivistic clients performed significantly worse on measures of executive function (CLOX1, EXIT25). Executive function impairments seem to be one risk factor for recidivism in APS referrals. With 60% of cases referred for decision capacity assessments being recidivistic, identifying risk factors may help identify when targeted interventions are indicated to preclude recurrence of abuse. PMID- 25495663 TI - Engineered mosquitoes to fight mosquito borne diseases: not a merely technical issue. AB - Malaria, dengue and other mosquito-borne diseases pose dramatic problems of public health, particularly in tropical and sub-tropical countries. Historically, vector control has been one of the most successfully strategies to eradicate some mosquito-borne diseases, as witnessed by malaria eradication in Mediterranean regions such as Italy and Greece. Vector control through insecticides has been used worldwide; unfortunately, it is losing effectiveness due to spread of resistances. Control of mosquito-borne diseases through field-releases of genetically engineered mosquitoes is an innovative and now feasible approach. Genetically modified mosquitoes have already been released into the wild in some regions, and protocols for this release are on hand in others. Local authorities are vigilant that transgenic insects in the field are safe for human and animal populations, and the public engagement in every control program is assuming a central role. PMID- 25495664 TI - Is pathology necessary to predict mortality among men with prostate-cancer? AB - BACKGROUND: Statistical models developed using administrative databases are powerful and inexpensive tools for predicting survival. Conversely, data abstraction from chart review is time-consuming and costly. Our aim was to determine the incremental value of pathological data obtained from chart abstraction in addition to information acquired from administrative databases in predicting all-cause and prostate cancer (PC)-specific mortality. METHODS: We identified a cohort of men with diabetes and PC utilizing population-based data from Ontario. We used the c-statistic and net-reclassification improvement (NRI) to compare two Cox- proportional hazard models to predict all-cause and PC specific mortality. The first model consisted of covariates from administrative databases: age, co-morbidity, year of cohort entry, socioeconomic status and rural residence. The second model included Gleason grade and cancer volume in addition to all aforementioned variables. RESULTS: The cohort consisted of 4001 patients. The accuracy of the admin-data only model (c-statistic) to predict 5 year all-cause mortality was 0.7 (95% CI 0.69-0.71). For the extended model (including pathology information) it was 0.74 (95% CI 0.73-0.75). This corresponded to a change in category of predicted probability of survival among 14.8% in the NRI analysis. The accuracy of the admin-data model to predict 5-year PC specific mortality was 0.76 (95% CI 0.74-0.78). The accuracy of the extended model was 0.85 (95% CI 0.83-0.87). Corresponding to a 28% change in the NRI analysis. CONCLUSIONS: Pathology chart abstraction, improved the accuracy in predicting all-cause and PC-specific mortality. The benefit is smaller for all cause mortality, and larger for PC-specific mortality. PMID- 25495665 TI - Surface modification of CoCr alloy using varying concentrations of phosphoric and phosphonoacetic acids: albumin and fibrinogen adsorption, platelet adhesion, activation, and aggregation studies. AB - CoCr alloy is commonly used in various cardiovascular medical devices for its excellent physical and mechanical properties. However, the formation of blood clots on the alloy surfaces is a serious concern. This research is focused on the surface modification of CoCr alloy using varying concentrations (1, 25, 50, 75, and 100 mM) of phosphoric acid (PA) and phosphonoacetic acid (PAA) to generate various surfaces with different wettability, chemistry, and roughness. Then, the adsorption of blood plasma proteins such as albumin and fibrinogen and the adhesion, activation, and aggregation of platelets with the various surfaces generated were investigated. Contact angle analysis showed PA and PAA coatings on CoCr provided a gradient of hydrophilic surfaces. FTIR showed PA and PAA were covalently bound to CoCr surface and formed different bonding configurations depending on the concentrations of coating solutions used. AFM showed the formation of homogeneous PA and PAA coatings on CoCr. The single and dual protein adsorption studies showed that the amount of albumin and fibrinogen adsorbed on the alloy surfaces strongly depend on the type of PA and PAA coatings prepared by different concentrations of coating solutions. All PA coated CoCr showed reduced platelet adhesion and activation when compared to control CoCr. Also, 75 and 100 mM PA-CoCr showed reduced platelet aggregation. For PAA coated CoCr, no significant difference in platelet adhesion and activation was observed between PAA coated CoCr and control CoCr. Thus, this study demonstrated that CoCr can be surface modified using PA for potentially reducing the formation of blood clots and improving the blood compatibility of the alloy. PMID- 25495666 TI - Safety of sublingual immunotherapy Timothy grass tablet in subjects with allergic rhinitis with or without conjunctivitis and history of asthma. AB - BACKGROUND: Patients with asthma may be more susceptible to adverse events (AEs) with sublingual immunotherapy tablet (SLIT-tablet) treatment, such as severe systemic reactions and asthma-related events. Using data from eight trials of grass SLIT-tablet in subjects with allergic rhinitis with/without conjunctivitis (AR/C), AE frequencies were determined in adults and children with and without reported asthma. METHODS: Data from randomized, double-blind, placebo-controlled trials of Timothy grass SLIT-tablet MK-7243 (2800 BAU/75 000 SQ-T, Merck/ALK Abello) were pooled for post hoc analyses. Subjects with uncontrolled and severe asthma were excluded from the trials. Frequencies for treatment-emergent AEs (TEAEs), local allergic swelling (mouth or throat), systemic allergic reactions, and asthma-related treatment-related AEs (TRAEs) were calculated. RESULTS: Among adults (n = 3314) and children (n = 881), 24% and 31%, respectively, had reported asthma. No serious local allergic swellings or serious systemic allergic reactions occurred in subjects with asthma treated with SLIT-tablet. There was no evidence of increased TEAEs, systemic allergic reactions, or severe local allergic swellings in adults or children with asthma treated with grass SLIT tablet versus subjects without asthma in or outside of pollen season. There were 6/120 asthma-related TRAEs assessed as severe with grass SLIT-tablet and 2/60 with placebo, without a consistent trend among subjects with and without asthma (5 and 3 events, respectively). CONCLUSIONS: In the AR/C subjects with reported well-controlled mild asthma included in these studies, grass SLIT-tablet did not increase TEAE frequency, severe local allergic swelling, or systemic allergic reactions versus subjects without asthma. There was no indication that treatment led to acute asthma worsening. PMID- 25495667 TI - Carbon nitride nanosheet-supported porphyrin: a new biomimetic catalyst for highly efficient bioanalysis. AB - A highly efficient biomimetic catalyst was fabricated based on ultrathin carbon nitride nanosheets (C3N4)-supported cobalt(II) proto-porphyrin IX (CoPPIX). The periodical pyridinic nitrogen units in C3N4 backbone could serve as electron donors for great affinity with Co(2+) in PPIX, which resembled the local electronic structure as vitamin B12 and heme cofactor of hemoglobin. UV-vis kinetics and electrochemistry revealed its competitive (electro)catalysis with conventional peroxidase, while X-ray photoelectron spectroscopy and theoretical calculations suggest that the rehybridization of Co 3d with N orbitals from the backside can result in significant changes in enthalpy and charge density, which greatly promoted the activity of CoPPIX. The prepared nanocatalyst was further conjugated with streptavidin via multiple amines on the edge plane of C3N4 for facile tagging. Using biotinylated molecular beacon as the capture probe, a sensitive electrochemiluminescence-based DNA assay was developed via the electroreduction of H2O2 as the coreactant after the hairpin unfolded by the target, exhibiting linearity from 1.0 fM to 0.1 nM and a detection limit of 0.37 fM. Our results demonstrate a new paradigm to rationally design inexpensive and durable biomimics for electrochemiluminescence quenching strategy, showing great promise in bioanalytical applications. PMID- 25495668 TI - Re: The Beneficial Effects of Doxycycline, an Inhibitor of Matrix Metalloproteinases, on Sulfur Mustard-induced Ocular Pathologies Depend on the Injury Stage. PMID- 25495669 TI - Symptoms of depression and anxiety before and after myocardial infarction: The HUNT 2 and HUNT 3 study. AB - The long-term effect of having a myocardial infarction (MI) and to what extent post-MI anxiety and depression can be attributed to pre-MI anxiety and depression are not known. Anxiety as an independent risk factor for the onset of MI is not clear and studies treating anxiety and depression as continuous variables are lacking. Baseline data in this prospective study were obtained from the Health Study of Nord-Trondelag County (HUNT 2). Anxiety and depression were measured with the Hospital Anxiety and Depression Scale (HADS) at HUNT 2. Age, gender, waist circumference, hypertension, total cholesterol, diabetes, and years of daily smoking were included as control variables. In the sample of 28,859 participants, 770 MI were reported in the follow-up study 5-8 years later (HUNT 3). The level of depressive symptoms at HUNT 2 was a significant and independent predictor of MI at HUNT 3, while symptoms of anxiety were not. Level of anxiety and depression at HUNT 3 was best predicted by baseline anxiety and depression. Having an MI had only a marginal effect on the levels of anxiety and depressive symptoms at HUNT 3. In the MI group, time since MI was not a significant predictor of anxiety and depression. PMID- 25495670 TI - Quantiferon TB-Gold conversion can predict active tuberculosis development in elderly nursing home residents. AB - AIM: The study was carried out on elderly nursing home residents in Taiwan. We assessed whether the serial QuantiFERON-TB Gold (QFT-G) assay and serial tuberculin skin test (TST) were reliable tools to predict or exclude the development of active tuberculosis (TB). METHODS: This prospective observational cohort study involved non-bacillus Calmette-Guerin-vaccinated 259 elderly nursing home residents free of active TB at baseline. Of these, 147 were eligible for follow up. Participants underwent serial QFT-G and TST at baseline and 2-year follow up, and were monitored for active TB over 5 years. Agreement between QFT-G and TST, incidence rate ratio, positive predictive value, and negative predictive value for progression to active TB were measured. RESULTS: During 5-year follow up, three participants developed active TB. The agreement between these two tests was 54.13% (K = 0.167, P = 0.001). The incidence rate ratio was 15.8 (P = 0.016) for the QFT-G-conversion group compared with the TST-positive group at baseline. Positive predictive value for QFT-G conversion groups was 25%. Negative predictive value was 100% for the TST-negative group at baseline. CONCLUSION: In the elderly nursing home residents, QFT-G conversion is a more reliable tool to predict the development of active TB. Meanwhile, TST is a valuable tool for predicting the chance of not developing active TB. PMID- 25495671 TI - Unchanged survival rates of Shadoo knockout mice after infection with mouse adapted scrapie. AB - Previous studies have demonstrated that Shadoo (Sho), a GPI-linked glycoprotein encoded by the Sprn gene with a membrane localization similar to PrP(C), is reduced in the brains of rodents with terminal prion disease. To determine the functional significance of Sho in prion disease pathogenesis, Sho-deficient mice were generated by gene targeting. Sho knockout and control wild-type (WT) mice were infected with themouse-adapted scrapie strains 22L or RML. No significant differences in survival, the incubation period of prion disease or other disease features were observed between Sho mutant and WT mice. In this model of prion disease, Sho removal had no effect on disease pathogenesis. PMID- 25495672 TI - Targeted ultraviolet B phototherapy: definition, clinical indications and limitations. AB - Targeted ultraviolet B (UVB) phototherapy is defined as UVB radiation applied only to clinically diseased skin, with sparing of adjacent normal skin, unlike conventional phototherapy, which involves irradiation of both diseased and normal skin. Targeted UVB radiation is a relatively new concept, which is now widely available because of advances in technology. Devices developed for targeted UVB phototherapy of the skin include the monochromatic excimer laser and lamp, both of which are now used by dermatologists in developed and developing countries. The aim of this review is to collate data from research studies on targeted phototherapy and to provide a concise description of currently available devices, their clinical indications and therapeutic efficacy. Additionally, potential adverse effects are summarized, and the limitations of these novel devices are highlighted. PMID- 25495673 TI - Linear and whorled naevoid hypermelanosis in a patient with trisomy 4 mosaicism. AB - Linear whorled naevoid hypermelanosis (LWNH) is a rare skin condition, characterized by swirls and whorls of hyperpigmented macules distributed in a reticulate pattern along the lines of Blaschko. We report a 2-year-old boy who presented with linear and whorled hyperpigmentation on his trunk and limbs, following the lines of Blaschko. Hyperkinesia and developmental speech-language impairment were also present. A biopsy specimen showed increased pigmentation within the basal keratinocytes without incontinentia pigmenti. No chromosomal abnormality was found in peripheral blood samples. Chromosomal analysis of skin fibroblasts detected trisomy 4 mosaicism. This case shows for the first time an association of LWNH with trisomy 4 mosaicism. LWNH should not be considered a single entity, but a cutaneous expression of mosaicism. PMID- 25495674 TI - Treatment of multiple periocular eccrine hidrocystomata: is botulinum toxin or electrocautery more effective? PMID- 25495675 TI - Genomic characterization of two novel HIV-1 second-generation recombinant forms among men who have sex with men in Beijing, China. AB - We report two different unique HIV-1 recombinant viruses from two HIV-positive men who have sex with men (MSM) in Beijing, China. Phylogenetic analysis of near full-length genomes (NFLG) showed that the unique recombinant forms (URFs) were comprised of gene regions from two circulating recombinant forms, CRF01_AE and CRF07_BC, both common in China. The parental CRF01_AE region of the recombinants clustered together with a previously described cluster 4 lineage of CRF01_AE. The CRF07_BC regions of both the recombinants clustered within the CRF07_BC radiation, but were distinct from other CRF07_BC reference sequences. The two recombinant forms had two breakpoints in common. The emergence of the two URFs indicates the ongoing generation of recombinant viruses involving CRF01_AE and CRF07_BC, and may provide insight into our understanding of the dynamics and complexity of the HIV-1 epidemic in China. PMID- 25495676 TI - Growth and haematological response of indigenous Venda chickens aged 8 to 13 weeks to varying dietary lysine to energy ratios. AB - The effect of feeding varying dietary lysine to energy levels on growth and haematological values of indigenous Venda chickens aged 8 - 13 weeks was evaluated. Four hundred and twenty Venda chickens (BW 362 +/- 10 g) were allocated to four dietary treatments in a completely randomized design. Each treatment was replicated seven times, and each replicate had fifteen chickens. Four maize-soya beans-based diets were formulated. Each diet had similar CP (150 g/kg DM) and lysine (8 g lysine/kg DM) but varying energy levels (11, 12, 13 and 14 MJ ME/kg DM). The birds were reared in a deep litter house; feed and water were provided ad libitum. Data on growth and haematological values were collected and analysed using one-way analysis of variance. Duncan's test for multiple comparisons was used to test the significant difference between treatment means (p < 0.05). A quadratic equation was used to determine dietary lysine to energy ratios for optimum parameters which were significant difference. Results showed that dietary energy level influenced (p < 0.05) feed intake, feed conversion ratio, live weight, haemoglobin and pack cell volume values of chickens. Dry matter digestibility, metabolizable energy and nitrogen retention not influenced by dietary lysine to energy ratio. Also, white blood cell, red blood cell, mean corpuscular volume, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration in female Venda chickens aged 91 days were not influenced by dietary lysine to energy ratio. It is concluded that dietary lysine to energy ratios of 0.672, 0.646, 0.639 and 0.649 optimized feed intake, growth rate, FCR and live weight in indigenous female Venda chickens fed diets containing 8 g of lysine/kg DM, 150 g of CP/kg DM and 11 MJ of ME/kg DM. This has implications in diet formulation for indigenous female Venda chickens. PMID- 25495678 TI - Characteristics of Executive Functioning in a Small Sample of Children With Tourette Syndrome. AB - Tourette syndrome (TS) is a disorder that involves at least one vocal tic and two or more motor tics; however, associated symptoms of obsessive-compulsive disorder (OCD) and attention-deficit disorder or attention-deficit hyperactivity disorder (ADHD) are common. Many children with TS exhibit educational difficulties and one possible explanation may be deficits in executive functioning. The focus of this study was to look at the severity of symptoms often associated with TS (tics and OCD and ADHD symptoms) and its potential relationship with the Behavior Rating Inventory of Executive Function (BRIEF) Parent Form in 11 children diagnosed with TS aged 8 to 14 years old. The parent of the child completed the BRIEF along with symptom measures evaluating tics, OCD behaviors, and ADHD symptoms. Despite relatively low mean scores on the symptom measures and just a few children exhibiting clinically significant scores on the BRIEF indexes, at least half the children exhibited abnormal scores on the Working Memory, Inhibit, and Shift subscales of the BRIEF. Varying patterns of relationships were found on the BRIEF subscales for each symptom severity scale. Results suggest that the BRIEF may be useful in determining the specific areas of difficulty in a population with variable symptomatology. PMID- 25495677 TI - The incidence of cardiovascular events after hospitalization due to CAP and their association with different inflammatory markers. AB - BACKGROUND: Late prognosis of Community-Acquired Pneumonia (CAP) patients is related to cardiovascular events. Persistence of inflammation-related markers, defined by high circulatory levels of interleukin 6 and 10 (IL-6/IL-10), is associated with a higher post-event mortality rate for CAP patients. However, association between these markers and other components of the immune response, and the risk of cardiovascular events, has not been adequately explored. The main objectives of this study are: 1) to quantify the incidence of cardiovascular disease, in the year post-dating their hospital admittance due to CAP and, 2) to describe the distribution patterns of a wide spectrum of inflammatory markers upon admittance to and release from hospital, and to determine their relationship with the incidence of cardiovascular disease. METHODS/DESIGN: A cohort prospective study. All patients diagnosed and hospitalized with CAP will be candidates for inclusion. The study will take place in the Universitary Hospital La Princesa, Spain, during two years. Two samples of blood will be taken from each patient: the first upon admittance and the second one prior to release, in order to analyse various immune agents. The main determinants are: pro adrenomedullin, copeptin, IL-1, IL-6, TNF-alpha, IL-17, IFN-gamma, IL-10 and TGF beta, E-Selectin, ICAM-1, VCAM-1 and subpopulations of peripheral T lymphocytes (T regulator, Th1 and Th17), together with other clinical and analytical variables. Follow up will start at admittance and finish a year after discharge, registering incidence of death and cardiovascular events. The main objective is to establish the predictive power of different inflammatory markers in the prognosis of CAP, in the short and long term, and their relationship with cardiovascular disease. DISCUSSION: The level of some inflammatory markers (IL 6/IL-10) has been proposed as a means to differentiate the degree of severity of CAP, but their association with cardiovascular risk is not well established. In this study we aim to define new inflammatory markers associated with cardiovascular disease that could be helpful for the prognosis of CAP patients, by describing the distribution of a wide spectrum of inflammatory mediators and analyzing their association with the incidence of cardiovascular disease and mortality one year after release from hospital. PMID- 25495679 TI - Increased IL-21 expression in chronic rhinosinusitis with nasalpolyps. AB - BACKGROUND: IL-21 is a key cytokine for regulating B cell immunity, which is involved in several inflammatory conditions. This study sought to define a role for IL-21 in activated B lymphocytes and enhanced tissue eosinophilia in NP tissues during the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: NP and uncinate process tissues were collected from 64 CRSwNP patients, 25 CRSsNP patients, and 29 control subjects. IL-21 expression was examined using IHC staining, qRT-PCR, flow cytometry, and ELISA, and its clinical implication was evaluated. Moreover, the effects of IL-21 on B cell differentiation and Ig production in cultured NP cells were examined in vitro. RESULTS: The mRNA and protein levels of IL-21 were significantly increased in polyp tissues compared with control tissues (P < 0.05). Polyp IL-21 level was significantly associated with polyp size, tissue eosinophilia and asthma comorbidity, and recurrence after surgery (P < 0.05). Both Th1 and Th17 cells were the main cellular sources of IL-21 in polyp tissues. The percentage of IL 21(+) CD4(+) cells was significantly higher in polyp tissues compared with control tissues and matched PBMCs (P < 0.01). Accordingly, the percentage of CD19(+) CD20(+/-) CD38(high) cells was significantly higher in polyp tissues compared with control tissues (P < 0.01). Moreover, recombinant IL-21 significantly increased the percentage of CD19(+) CD20(+/-) CD38(high) cells (plasmablasts) and IgG and IgA production in cultured NP cells in vitro (P < 0.05). CONCLUSION AND CLINICAL RELEVANCE: Increased IL-21 level in polyp tissues was associated with disease severity, local B cell activation, and immunoglobulin production, suggesting that IL-21 might play an important role in promoting persistent mucosal inflammation in CRSwNP patients. PMID- 25495680 TI - Improved prediction of inhibitor development in previously untreated patients with severe haemophilia A. AB - Treatment of previously untreated patients (PUPs) with severe haemophilia A is complicated by the formation of inhibitors. Prediction of PUPs with high risk is important to allow altering treatment with the intention to reduce the occurrence of inhibitors. An unselected multicentre cohort of 825 PUPs with severe haemophilia A (FVIII<0.01 IU mL(-1) ) was used. Patients were followed until 50 exposure days (EDs) or inhibitor development. All predictors of the existing prediction model including three new potential predictors were studied using multivariable logistic regression. Model performance was quantified [area under the curve (AUC), calibration plot] and internal validation (bootstrapping) was performed. A nomogram for clinical application was developed. Of the 825 patients, 225 (28%) developed inhibitors. The predictors family history of inhibitors, F8 gene mutation and an interaction variable of dose and number of EDs of intensive treatment were independently associated with inhibitor development. Age and reason for first treatment were not associated with inhibitor development. The AUC was 0.69 (95% CI 0.65-0.72) and calibration was good. An improved prediction model for inhibitor development and a nomogram for clinical use were developed in a cohort of 825 PUPs with severe haemophilia A. Clinical applicability was improved by combining dose and duration of intensive treatment, allowing the assessment of the effects of treatment decisions on inhibitor risk and potentially modify treatment. PMID- 25495681 TI - Validation of the World Health Organization Assessment Schedule II Chinese Traditional Version (WHODAS II CT) in persons with disabilities and chronic illnesses for Chinese population. AB - PURPOSE: The aim of this study is to test the psychometric properties and validity of the World Health Organization Assessment Schedule II Chinese Traditional Version (WHODAS II CT) in Traditional Chinese-speaking persons with disabilities and chronic illnesses. METHOD: The WHODAS II CT has been administrated to a sample of 1020 persons with disabilities and chronic illnesses. The construct validity, internal consistency, concurrent validity and convergent validity were evaluated. RESULTS: WHODAS II CT showed a satisfactory model fit for the second-order confirmatory factor analysis model (chi(2)/df = 3.05, root means square error of approximation = 0.053, comparative fit index = 0.912, standardized root mean square residual = 0.076), high internal consistency (Cronbach's alpha = 0.98), high correlation with all domains of Dartmouth Primary Care Cooperative Research Network/World Organization of National Colleges, Academies, and Academic Associations of General Practices/Family Physicians (COOP/WONCA) charts (partial correlation coefficient ranged from 0.26 to 0.74) and significance between persons with and without co-morbidity (all regression coefficients >0). CONCLUSIONS: WHODAS II CT is a reliable and valid instrument to measure the disability in persons with disabilities and chronic illnesses among Traditional Chinese-speaking population. A further study is required to validate the short version of WHODAS II in order to enhance its applicability in usual and clinical practices. Implications for Rehabilitation This is the first study to evaluate the reliability and validity of WHODAS II in persons with disability and chronic illnesses among Traditional Chinese-speaking population. The WHODAS II CT is a valid instrument in Chinese adults with disabilities and chronic illnesses. The WHODAS II CT is recommended to be used in population-based survey to investigate the health needs of persons with disabilities and chronic illnesses as well as in the rehabilitation programs as an outcome measure. PMID- 25495683 TI - Peri-implant health and disease. A systematic review of current epidemiology. AB - BACKGROUND: To develop preventive strategies addressing peri-implant diseases, a thorough understanding of the epidemiology is required. AIM: The aim was to systematically assess the scientific literature in order to evaluate the prevalence, extent and severity of peri-implant diseases. MATERIAL & METHODS: Data were extracted from identified studies. Meta-analyses for prevalence of peri implant mucositis and peri-implantitis were performed. The effect of function time and disease definition on the prevalence of peri-implantitis was evaluated by meta-regression analyses. Data on extent and severity of peri-implant diseases were estimated if not directly reported. RESULTS: Fifteen articles describing 11 studies were included. Case definitions for mucositis and peri-implantitis varied. The prevalence of peri-implant mucositis and peri-implantitis ranged from 19 to 65% and from 1 to 47%, respectively. Meta-analyses estimated weighted mean prevalences of peri-implant mucositis and peri-implantitis of 43% (CI: 32-54%) and 22% (CI: 14-30%), respectively. The meta-regression showed a positive relationship between prevalence of peri-implantitis and function time and a negative relationship between prevalence of peri-implantitis and threshold for bone loss. Extent and severity of peri-implant diseases were rarely reported. CONCLUSION: Future studies on the epidemiology of peri-implant diseases should consider (i) applying consistent case definitions and (ii) assessing random patient samples of adequate size and function time. PMID- 25495682 TI - Can administrative data be used to measure chemotherapy side effects? AB - Many of the issues with using data from clinical trials and observational studies for economic evaluations are highlighted in the case of chemotherapy side effects. We present the results of an observational cohort study using linked administrative data. The chemotherapy side effects identified in the administrative data are compared with patient self-reports of such events. The results of these comparisons are then used to guide a discussion of the issues surrounding the use of administrative data to identify clinical events for the population of economic models. Although the advantages of easy access and generalizability of the results make administrative data an attractive option for populating economic models, this is not always possible because of the limitations of these data. PMID- 25495684 TI - Pulmonary infection by Rhodococcus equi presenting with positive Ziehl-Neelsen stain in a patient with human immunodeficiency virus: a case report. AB - INTRODUCTION: Patients with human immunodeficiency virus carry a significant risk of contracting opportunistic infections. The worldwide increased incidence of tuberculosis has instituted pulmonary tuberculosis as an important diagnostic consideration in patients with human immunodeficiency virus presenting with lower respiratory tract infection. A positive result on the readily-available Ziehl Neelsen stain usually leads to the initiation of antituberculous treatment, since tuberculosis may exert a rapid and even fatal clinical progress in human immunodeficiency virus coinfection. However, a number of other acid-fast bacteria might be implicated as offending pathogens. This case highlights the importance of broadening the list of pathogens that can account for a positive Ziehl-Neelsen stain in this select group of patients. CASE PRESENTATION: We describe the case of a 34-year-old, Albanian man with untreated human immunodeficiency virus, presenting with clinical and radiologic signs of pulmonary tuberculosis and a positive Ziehl-Neelsen sputum specimen, who was finally diagnosed with pulmonary infection by Rhodococcus equi. CONCLUSIONS: Rhodococcus equi is a rare cause of pulmonary disease, even in patients with human immunodeficiency virus, and a positive Ziehl-Neelsen sputum specimen often misleads clinicians to more common organisms such as mycobacteria. A high index of suspicion, broadening the spectrum of optional pathogens, and effective communication between clinicians and microbiologists can ensure an efficient diagnostic and therapeutic approach. PMID- 25495685 TI - Neisseria meningitidis porA, fetA and fHbp gene distribution in Western Australia 2000 to 2011. AB - BACKGROUND: PorA, fetA and fHbp are three antigen encoding genes useful for meningococcal typing and FHbp is an important component of meningococcal B vaccines. METHODS: We performed sequence analysis of meningococcal porA, fetA and fHbp genes on 128 isolates from Western Australia, relating results to age, gender, race and geographic region. RESULTS: We found predominantly PorA subtypes P1.22,14-16 (n = 23) and P1.7-2,4 (n = 19); FetA subtypes F1-5 (n = 41), F3-6 (n = 11), F5-1 (n = 10), F5-2 (n = 9), F5-5 (n = 8), F3-3 (n = 8); and FHbp variant groups 1 (n = 65) and 2 (n = 44). PorA P1.22,14-16 and FHbp variant group 2 were associated with younger age and aboriginality. CONCLUSIONS: FHbp modular groups of the bivalent recombinant FHbp vaccine and the multicomponent 4CMenB vaccine make up 8.3% and 47.7% respectively of the examined serogroup B isolates from 2000-2011, however to estimate vaccine efficacy requires an account of all vaccine antigens and their levels of expression. PMID- 25495686 TI - A distinct chemokine axis does not account for enrichment of Foxp3(+) CD4(+) T cells in carcinogen-induced fibrosarcomas. AB - The frequency of CD4(+) Foxp3(+) regulatory T (Treg) cells is often significantly increased in the blood of tumour-bearing mice and people with cancer. Moreover, Treg cell frequencies are often higher in tumours compared with blood and lymphoid organs. We wished to determine whether certain chemokines expressed within the tumour mass selectively recruit Treg cells, thereby contributing to their enrichment within the tumour-infiltrating lymphocyte pool. To achieve this goal, the chemokine profile of carcinogen-induced fibrosarcomas was determined, and the chemokine receptor expression profiles of both CD4(+) Foxp3(-) and CD4(+) Foxp3(+) T cells were compared. These analyses revealed that the tumours are characterized by expression of inflammatory chemokines (CCL2, CCL5, CCL7, CCL8, CCL12, CXCL9, CXCL10 and CX3CL1), reflected by an enrichment of activated Foxp3(-) and Foxp3(+) T cells expressing T helper type 1-associated chemokine receptors. Notably, we found that CXCR3(+) T cells were significantly enriched in the tumours although curiously we found no evidence that CXCR3 was required for their recruitment. Instead, CXCR3 marks a population of activated Foxp3(-) and Foxp3(+) T cells, which use multiple and overlapping ligand receptor pairs to guide their migration to tumours. Collectively, these data indicate that enrichment of Foxp3(+) cells in tumours characterized by expression of inflammatory chemokines, does not occur via a distinct chemokine axis, thus selective chemokine blockade is unlikely to represent a meaningful therapeutic strategy for preventing Treg cell accumulation in tumours. PMID- 25495687 TI - Mapping and analysis of a novel candidate Fusarium wilt resistance gene FOC1 in Brassica oleracea. AB - BACKGROUND: Cabbage Fusarium wilt is a major disease worldwide that can cause severe yield loss in cabbage (Brassica olerecea). Although markers linked to the resistance gene FOC1 have been identified, no candidate gene for it has been determined so far. In this study, we report the fine mapping and analysis of a candidate gene for FOC1 using a double haploid (DH) population with 160 lines and a F2 population of 4000 individuals derived from the same parental lines. RESULTS: We confirmed that the resistance to Fusarium wilt was controlled by a single dominant gene based on the resistance segregation ratio of the two populations. Using InDel primers designed from whole-genome re-sequencing data for the two parental lines (the resistant inbred-line 99-77 and the highly susceptible line 99-91) and the DH population, we mapped the resistance gene to a 382-kb genomic region on chromosome C06. Using the F2 population, we narrowed the region to an 84-kb interval that harbored ten genes, including four probable resistance genes (R genes): Bol037156, Bol037157, Bol037158 and Bol037161 according to the gene annotations from BRAD, the genomic database for B. oleracea. After correcting the model of the these genes, we re-predicted two R genes in the target region: re-Bol037156 and re-Bol0371578. The latter was excluded after we compared the two genes' sequences between ten resistant materials and ten susceptible materials. For re-Bol037156, we found high identity among the sequences of the resistant lines, while among the susceptible lines, there were two types of InDels (a 1-bp insertion and a 10-bp deletion), each of which caused a frameshift and terminating mutation in the cDNA sequences. Further sequence analysis of the two InDel loci from 80 lines (40 resistant and 40 susceptible) also showed that all 40 R lines had no InDel mutation while 39 out of 40 S lines matched the two types of loci. Thus re-Bol037156 was identified as a likely candidate gene for FOC1 in cabbage. CONCLUSIONS: This work may lay the foundation for marker-assisted selection as well as for further function analysis of the FOC1 gene. PMID- 25495688 TI - Focus on fatigue amongst young adults with spastic cerebral palsy. AB - BACKGROUND: This study aimed to assess fatigue amongst young adults with spastic cerebral palsy (CP), to determine subgroups at risk for fatigue and to explore the relationship between fatigue and cardiopulmonary fitness and daily physical activity level. PARTICIPANTS: Young adults with spastic CP, Gross Motor Function Classification System (GMFCS) levels I to III, aged 16 to 24 years. METHODS: Fatigue (Fatigue Severity Scale) and self-reported daily physical activity (Physical Activity Scale for Individuals with Physical Disabilities) were assessed for 56 participants using questionnaires. Daily physical activity was objectively measured using accelerometry (Vitamove system) over 72 hours. Progressive maximal aerobic cycling was used to measure cardiopulmonary fitness. RESULTS: The mean Fatigue Severity Scale (FSS) score was 3.7 (SD 1.4). Forty percent of participants were fatigued, including 12.5% who were severely fatigued. Participants with bilateral CP (FSS = 4.2 (SD 1.4)) were more fatigued compared to those with unilateral CP (FSS = 3.1 (SD 1.3)) (p < 0.01). Levels of cardiopulmonary fitness (2.4 L/min (SD 0.8)) and daily physical activity (8.5% (SD 3.0)) were not significantly related to fatigue (respectively p = 0.10 and p = 0.55), although for cardiopulmonary fitness a trend was found. CONCLUSIONS: Fatigue is already present at a relatively young age amongst adults with CP, and CP subtype is a determinant of fatigue. We did not find significant evidence for a cross-sectional relation of fatigue with cardiopulmonary fitness or daily physical activity. TRIAL REGISTRATION: Nederland's trial register: NTR1785. PMID- 25495689 TI - Sassarandainol: a new neolignan and anti-inflammatory constituents from the stem of Sassafras randaiense. AB - A new neolignan, (R)-( - )-sassarandainol (1), together with 10 known compounds (2-11), was isolated from the stem of Sassafras randaiense. The structures were determined by spectroscopic techniques. Among these isolates, gamma-tocopherol (5), subamolide B (7) and beta-sitosterone (9) exhibited moderate iNOS inhibitory activity on nitrite production induced (%) value of 30.51, 28.68 and 16.96, respectively. PMID- 25495690 TI - The effect of 222-nm UVC phototesting on healthy volunteer skin: a pilot study. AB - BACKGROUND: Frequent topical antiseptic use to hands is now common in healthcare and other work environments. Inevitably, the use of such antiseptics will present an occupational risk for irritancy and allergic dermatitis. New, less irritant and even non-chemical antimicrobial approaches are under investigation. METHODS: A Sterilray disinfectant source (222 nm) conventionally used to sterilize equipment and work surfaces was assessed for tolerability in human skin. Using an escalating dosage study methodology, four skin phototype I and II healthy volunteers had their minimal erythema dose (MED) determined. Punch biopsies of irradiated sites were stained for cyclobutane pyrimidine dimers (CPD). The degree of CPD was compared with that in biopsies from unexposed skin and from areas exposed to UVB (280-315 nm) radiation. RESULTS: Calibrated spectral measurements revealed emission at a peak wavelength of 222 nm with 97% emission at wavelengths less than 250 nm. At low doses below the threshold bacteriostatic effect, the source was capable of inducing both erythema and CPD formation in human skin. In two individuals, cells in the basal layer were not shielded by the overlying tissue as indicated by the presence of CPD. CONCLUSION: The source showed an erythemogenic or CPD potential at lower doses than those required to reach the reported threshold bacteriostatic effect. PMID- 25495691 TI - Potential nephroprotective effects of the Chinese herb Angelica sinensis against cisplatin tubulotoxicity. AB - CONTEXT: Acute kidney injury (AKI) is often encountered in patients receiving cisplatin (CisPt), a chemotherapeutic drug that induces numerous toxic side effects. Techniques used to limit nephrotoxicity during CisPt treatment are not fully effective; about a third of patients experience AKI. New nephroprotective strategies, including pharmacological approaches, must be developed. OBJECTIVE: The present study investigated the nephroprotective potential of Angelica sinensis (Oliv.) Diels (Apiaceae) root towards CisPt tubulotoxicity. MATERIALS AND METHODS: HK-2 cells were incubated with CisPt (10 uM) and/or with a methanolic extract of A. sinensis (AS). Nephroprotective capacity was evaluated by means of cellular viability (resazurin assay) and apoptosis (annexin-V/PI staining), oxidative stress generation (H2DCF-DA oxidation), Ki-67 index (immunofluorescence), cell cycle analysis (DNA staining), cell migration rate (scratch assay), extracellular matrix deposition (collagen determination), and beta-catenin relocalization. RESULTS: CisPt decreased cell viability [76% versus Ctrl], which was associated with an increased apoptosis. Simultaneous treatment with 50 ug/ml AS enhanced cell survival [84% versus Ctrl] and decreased the apoptosis rate. AS could not alleviate CisPt-induced oxidative stress; but doses of 5 and 50 ug/ml raised the Ki-67 index [135 and 244% versus Ctrl] and cell migration rates [1.2 and 1.3-fold versus Ctrl]. Finally, both doses of AS limited the amount of collagen deposition [121.6 and 119.6% for 5 and 50 ug/ml, respectively, versus 131.0% for CisPt-treated cells] and prevented the relocalization of beta-catenin from the membrane to the nucleus. CONCLUSION: These results confirm the nephroprotective potential of A. sinensis and require further investigations aiming at identifying its active compounds. PMID- 25495692 TI - Gallbladder adenocarcinoma with sarcoid-like reaction in regional lymph nodes: report of a case. AB - BACKGROUND: Sarcoid-like reaction is often seen in various types of carcinoma, not only in the primary tumor, but also in regional lymph nodes, and can occur at any time, not only at the time of diagnosis, but also after treatment. However, few cases of hepatopancreatobiliary carcinoma, and no cases of gallbladder cancer with sarcoid-like reaction involving the lymph nodes have been described. This report is the first report of a sarcoid-like reaction involving the lymph nodes in a case of gallbladder cancer. CASE PRESENTATION: We encountered a rare case of gall bladder cancer with sarcoid-like reaction in the lymph nodes. Since regional lymph node swelling that was difficult to differentiate from metastasis was found preoperatively, swollen nodes were examined histologically using frozen sections. Based on this histology, the swollen nodes were diagnosed as showing sarcoid reaction and therefore extended lymphadenectomy was avoided. The patient did not receive any adjuvant chemotherapy and has shown no recurrence of disease as of 4 years after surgery. CONCLUSION: Distinguishing between metastasis and sarcoid like reaction in lymph nodes by preoperative imaging is still difficult. The present case shows that it is important to histologically examine swollen nodes by biopsy or by sampling before deciding on the treatment strategy for gall bladder cancer with swollen lymph nodes. PMID- 25495693 TI - The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist. AB - The clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A PubMed literature search was performed for perampanel. Congress abstract data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5-2.5 h later; its bioavailability is ~100%. Although the rate of perampanel absorption is slowed by food co-ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2 12 mg); perampanel is 95% protein-bound to albumin and alpha1-acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half-life is ~105 h, whereas the calculated effective half-life is 48 h. These half-life values allow for once daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, half-life decreases to 25 h. Clearance values are not significantly different in adolescents (~13.0 ml/min) and the elderly (~10.5 ml/min) compared with adults (10.9 ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4-inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable contraceptive method. Overall, perampanel has a favorable clinical pharmacology profile, which should aid its clinical use. PMID- 25495694 TI - A cis-acting element in the promoter of human ether a go-go 1 potassium channel gene mediates repression by calcitriol in human cervical cancer cells. AB - The human ether a go-go 1 potassium channel (hEAG1) is required for cell cycle progression and proliferation of cancer cells. Inhibitors of hEAG1 activity and expression represent potential therapeutic drugs in cancer. Previously, we have shown that hEAG1 expression is downregulated by calcitriol in a variety of cancer cells. Herein, we provided evidence on the regulatory mechanism involved in such repressive effect in cells derived from human cervical cancer. Our results indicate that repression by calcitriol occurs at the transcriptional level and involves a functional negative vitamin D response element (nVDRE) E-box type in the hEAG1 promoter. The described mechanism in this work implies that a protein complex formed by the vitamin D receptor-interacting repressor, the vitamin D receptor, the retinoid X receptor, and the Williams syndrome transcription factor interact with the nVDRE in the hEAG1 promoter in the absence of ligand. Interestingly, all of these transcription factors except the vitamin D receptor interacting repressor are displaced from hEAG1 promoter in the presence of calcitriol. Our results provide novel mechanistic insights into calcitriol mode of action in repressing hEAG1 gene expression. PMID- 25495697 TI - Calculation of incubation period and serial interval from multiple outbreaks of Marburg virus disease. AB - BACKGROUND: Marburg viruses have been responsible for a number of outbreaks throughout sub-Saharan Africa, as well as a number of laboratory infections. Despite many years of experience with the viruses, little is known about several important epidemiologic parameters relating to the development of Marburg virus disease. The analysis uses pooled data from all Marburg cases between 1967 and 2008 to develop estimates for the incubation period and the clinical onset serial interval (COSI). METHODS: Data were obtained from original outbreak investigation forms (n=406) and from published data (n=45). Incubation periods were calculated for person-to-person exposure, for laboratory-acquired infections, and for presumed zoonotic exposures. Similar analysis was conducted for COSI, using only cases with unambiguous person-to-person transmission where both the primary and the secondary case patients had well-defined illness onsets. RESULTS: Seventy-six cases were retained for the incubation period analysis. Incubation periods ranged from a minimum of 2 days in the case of two laboratory workers to a maximum of at least 26 days for a person-to-person household transmission. Thirty-eight cases were retained for COSI analysis. The median COSI was 11 days, with an interquartile range of 8 to 15. CONCLUSIONS: This study extends the maximum known incubation period of Marburg virus disease to 26 days. The analysis was severely hampered by a lack of completeness in epidemiologic data. It is necessary to prioritize obtaining more accurate epidemiologic data in future outbreaks; greater use of COSI may facilitate an improved understanding of outbreak dynamics in Marburg and other diseases. PMID- 25495696 TI - Array-based discovery of aptamer pairs. AB - Affinity reagent pairs that recognize distinct epitopes on a target protein can greatly improve the sensitivity and specificity of molecular detection. Importantly, such pairs can be conjugated to generate reagents that achieve two site "bidentate" target recognition, with affinities greatly exceeding either monovalent component. DNA aptamers are especially well-suited for such constructs, because they can be linked via standard synthesis techniques without requiring chemical conjugation. Unfortunately, aptamer pairs are difficult to generate, primarily because conventional selection methods preferentially yield aptamers that recognize a dominant "hot spot" epitope. Our array-based discovery platform for multivalent aptamers (AD-MAP) overcomes this problem to achieve efficient discovery of aptamer pairs. We use microfluidic selection and high throughput sequencing to obtain an enriched pool of aptamer sequences. Next, we synthesize a custom array based on these sequences, and perform parallel affinity measurements to identify the highest-affinity aptamer for the target protein. We use this aptamer to form complexes that block the primary binding site on the target, and then screen the same array with these complexes to identify aptamers that bind secondary epitopes. We used AD-MAP to discover DNA aptamer pairs that bind distinct sites on human angiopoietin-2 with high affinities, even in undiluted serum. To the best of our knowledge, this is the first work to discover new aptamer pairs using arrays. We subsequently conjugated these aptamers with a flexible linker to construct ultra-high-affinity bidentate reagents, with equilibrium dissociation constants as low as 97 pM: >200-fold better than either component aptamer. Functional studies confirm that both aptamers critically contribute to this ultrahigh affinity, highlighting the promise of such reagents for research and clinical use. PMID- 25495698 TI - Comparison of a mobile phone-based malaria reporting system with source participant register data for capturing spatial and temporal trends in epidemiological indicators of malaria transmission collected by community health workers in rural Zambia. AB - BACKGROUND: Timeliness, completeness, and accuracy are key requirements for any surveillance system to reliably monitor disease burden and guide efficient resource prioritization. Evidence that electronic reporting of malaria cases by community health workers (CHWs) meet these requirements remains limited. METHODOLOGY: Residents of two adjacent rural districts in Zambia were provided with both passive and active malaria testing and treatment services with malaria rapid diagnostic tests (RDTs) and artemisinin-based combination therapy by 42 CHWs serving 14 population clusters centred around public sector health facilities. Reference data describing total numbers of RDT-detected infections and diagnostic positivity (DP) were extracted from detailed participant register books kept by CHWs. These were compared with equivalent weekly summaries relayed directly by the CHWs themselves through a mobile phone short messaging system (SMS) reporting platform. RESULTS: Slightly more RDT-detected malaria infections were recorded in extracted participant registers than were reported in weekly mobile phone summaries but the difference was equivalent to only 19.2% (31,665 versus 25,583, respectively). The majority (81%) of weekly SMS reports were received within one week and the remainder within one month. Overall mean [95% confidence limits] difference between the numbers of register-recorded and SMS reported RDT-detected malaria infections per CHW per week, as estimated by the Bland Altman method, was only -2.3 [-21.9, 17.2]. The mean [range] for both the number of RDT-detected malaria infections (86 [0, 463] versus 73.6 [0, 519], respectively)) and DP (22.8% [0.0 to 96.3%] versus 23.2% [0.4 to 75.8%], respectively) reported by SMS were generally very consistent with those recorded in the reference paper-based register data and exhibited similar seasonality patterns across all study clusters. Overall, mean relative differences in the SMS reports and reference register data were more consistent with each other for DP than for absolute numbers of RDT-detected infections, presumably because this indicator is robust to variations in patient reporting rates by location, weather, season and calendar event because these are included in both the nominator and denominator. DISCUSSION/CONCLUSION: The SMS reports captured malaria transmission trends with adequate accuracy and could be used for population-wide, continuous, longitudinal monitoring of malaria transmission. PMID- 25495699 TI - Drug permeation through skin is inversely correlated with carrier gel rigidity. AB - Controlled release plays an essential role in formulating topical and transdermal drug delivery systems. In this study, we correlated the skin permeation of Sesamin, a lipophilic drug, with the rheological properties of two different organogel carriers, i.e., low molecular weight gelling agent N-lauroyl-l-glutamic acid di-n-butylamide (GP-1) and Carbopol polymeric gels. Although these two gels have distinct network structures, they share the same trend: the more rigid the gel network and the higher the gelator concentration, the lower the steady flux of Sesamin through skin. This negative correlation lies in the fact that organogel network hinders the diffusion of drug to the gel-skin interface; as a result, the depletion zone near the interface is non-negligible and contributes to the resistance of the whole diffusion system, and thus, the permeation flux is reduced. More interestingly, the dependence of the steady flux against gel complex modulus at the linear viscoelastic region followed a "universal" power law regardless of the gel types, i.e., 1/J = 1/J0 + a(G*)(epsilon)/C0 with a = 11.25, epsilon = 0.21 +/- 0.03 for GP-1 gels, and a = 0.16, epsilon = 1.05 +/- 0.06 for Carbopol gels, J0 is the steady flux without gel (G* = 0), and C0 is the initial concentration of drug in gels. The empirical formulae are crucial in developing transdermal organogel systems with controlled release of drug content through readily obtainable data of their rheological properties. The explanation for the power law dependence of the steady flux on gel complex modulus is discussed. PMID- 25495700 TI - Tablets compressed with gastric floating pellets coated with acrylic resin for gastro retention and sustained release of famotidine: in-vitro and in-vivo study. AB - OBJECTIVES: The aim of this study was to prepare a disintegrating gastric floating tablet composed of floating pellets coated with acrylic resin to prolong the gastric residence time and increase the oral bioavailability of famotidine. METHODS: The gastric floating pellets containing famotidine, stearyl alcohol and microcrystalline cellulose (1 : 10 : 1) were prepared by extrusion-spheronization process and coated with acrylic resin, then compressed into tablets with Avicel PH 301 pellets and cross-linked polyvinylpyrrolidone. The coating weight, volume ratio of Eudragit RL30 D and RS30 D and solid content of coating fluid were optimized by Box-Behnken design. KEY FINDINGS: In 0.1 M HCl, tablets can immediately disintegrate into pellets which can remain floating and sustained drug releasing over 12 h. The AUC0-infinity of famotidine gastric floating pellets (7776.52 +/- 1065.93 h ng/ml) administered into rats was significantly higher than that of marketed rapid release tablets Xingfading(r) (Xingyi, Shanghai, China) (4166.23 +/- 312.43 h ng/ml), while the relative bioavailability was 187.01 +/- 22.81%. CONCLUSIONS: The experimental results indicated that the optimized formulation did offer a new gastro retention and sustained release approach to enhance the oral absorption of famotidine. PMID- 25495701 TI - PAR1-stimulated platelet releasate promotes angiogenic activities of endothelial progenitor cells more potently than PAR4-stimulated platelet releasate. AB - BACKGROUND: Endothelial progenitor cells (EPCs) are important for endothelial regeneration and angiogenesis. Thrombin protease-activated receptor 1 (PAR1) PAR1 and PAR4 stimulation induces selective release of platelet proangiogenic and antiangiogenic regulators. OBJECTIVE: To investigate if PAR1-stimulated platelet releasate (PAR1-PR) and PAR4-PR regulate angiogenic properties of EPCs in different manners. METHODS AND RESULTS: EPCs were generated from peripheral mononuclear cell culture. Washed platelets (2 * 10(9) mL(-1)) were stimulated by PAR1-activating peptide (PAR1-AP; 10 MUmol L(-1)) or PAR4-AP (100 MUmol L(-1)) to prepare PAR1-PR and PAR4-PR, respectively. PAR1-PR or PAR4-PR had little influence on EPC proliferation. EPC migration experiments using a modified Boyden chamber showed that both platelet releasates facilitated EPC migration. As for in vitro tube formation on Matrigel, PAR1-PR and PAR4-PR similarly enhanced capillary-like network formation of EPCs in the complete EPC medium containing 10% FBS and a cocktail of growth factors, while PAR1-PR more profoundly increased EPC tube formation in basal culture medium supplemented with only 0.5% FBS than did PAR4-PR. The latter was confirmed in the murine angiogenesis model of subcutaneous Matrigel implantation. Moreover, blockade of vascular endothelial growth factor, stromal cell-derived factor 1alpha, or matrix metalloproteinases attenuated EPC migration and tube formation, suggesting a cooperation of these factors in the enhancements. CONCLUSIONS: PAR1-PR enhances vasculogenesis more potently than PAR4-PR, and the enhancements require a cooperation of multiple platelet-derived angiogenic regulators. PMID- 25495702 TI - Psychosocial challenges of young people affected by HIV: experiences from Hamilton County, Chattanooga, Tennessee. AB - The number of young people affected by HIV and AIDS in Tennessee has steadily grown over the last few years. As a response to this situation, several organizations are working hard to address the needs of families impacted by HIV and AIDS. However, a close examination of some of the services provided suggests that young people within these families are ignored. Most of the services are geared toward HIV and AIDS-infected adult members of these families. Young people within these household are not targeted, and little is known about psychosocial challenges they experience in living with HIV-positive parents or guardians. In an attempt to address this gap, this small-scale qualitative study investigated the psychosocial challenges of young people affected by HIV and AIDS as a result of living with HIV-positive parents or guardians. Perceived sense of depression, experiencing stigma, self-blame, and lack of communication and loneliness were challenges that young people faced regularly. PMID- 25495704 TI - A bitter pill to swallow: esophageal lesions after PVI may not be what we expected. PMID- 25495703 TI - QUDeX-MS: hydrogen/deuterium exchange calculation for mass spectra with resolved isotopic fine structure. AB - BACKGROUND: Hydrogen/deuterium exchange (HDX) coupled to mass spectrometry permits analysis of structure, dynamics, and molecular interactions of proteins. HDX mass spectrometry is confounded by deuterium exchange-associated peaks overlapping with peaks of heavy, natural abundance isotopes, such as carbon-13. Recent studies demonstrated that high-performance mass spectrometers could resolve isotopic fine structure and eliminate this peak overlap, allowing direct detection and quantification of deuterium incorporation. RESULTS: Here, we present a graphical tool that allows for a rapid and automated estimation of deuterium incorporation from a spectrum with isotopic fine structure. Given a peptide sequence (or elemental formula) and charge state, the mass-to-charge ratios of deuterium-associated peaks of the specified ion is determined. Intensities of peaks in an experimental mass spectrum within bins corresponding to these values are used to determine the distribution of deuterium incorporated. A theoretical spectrum can then be calculated based on the estimated distribution of deuterium exchange to confirm interpretation of the spectrum. Deuterium incorporation can also be detected for ion signals without a priori specification of an elemental formula, permitting detection of exchange in complex samples of unidentified material such as natural organic matter. A tool is also incorporated into QUDeX-MS to help in assigning ion signals from peptides arising from enzymatic digestion of proteins. MATLAB-deployable and standalone versions are available for academic use at qudex-ms.sourceforge.net and agarlabs.com . CONCLUSION: Isotopic fine structure HDX-MS offers the potential to increase sequence coverage of proteins being analyzed through mass accuracy and deconvolution of overlapping ion signals. As previously demonstrated, however, the data analysis workflow for HDX-MS data with resolved isotopic fine structure is distinct. QUDeX-MS we hope will aid in the adoption of isotopic fine structure HDX-MS by providing an intuitive workflow and interface for data analysis. PMID- 25495705 TI - Use of in vivo induced antigen technology to identify genes from Aeromonas salmonicida subsp. salmonicida that are specifically expressed during infection of the rainbow trout Oncorhynchus mykiss. AB - BACKGROUND: Aeromonas salmonicida is a major fish pathogen associated with mass mortalities in salmonid fish. In the present study, we applied In Vivo Induced Antigen Technology (IVIAT), a technique that relies on antibodies adsorbed against in vitro cultures of the pathogen, to a clinical isolate of A. salmonicida subsp. salmonicida. RESULTS: The results from IVIAT allowed identification of four proteins that were upregulated in the fish samples: A UDP 3-O-acyl-N-acetylglucosamine deacetylase, an RNA polymerase sigma factor D as well as TonB and a hypothetical protein. Subsequent investigations were performed using real-time PCR and cDNA synthesised from infected spleen, liver and anterior kidneys. These confirmed that the transcription level of each of these genes was significantly upregulated during the infection process compared to bacteria in vitro. CONCLUSIONS: The present studied identified four genes that were upregulated during the infectious process and are likely to play a role in the virulence of A. salmonicida. Because these are antigenic they might constitute potential targets for the development of new vaccine as well as therapeutic agents. PMID- 25495706 TI - High-energy photon activation tandem mass spectrometry provides unprecedented insights into the structure of highly sulfated oligosaccharides extracted from macroalgal cell walls. AB - Extreme ultraviolet photon activation tandem mass spectrometry (MS) at 69 nm (18 eV) was used to characterize mixtures of oligo-porphyrans, a class of highly sulfated oligosaccharides. Porphyrans, hybrid polymers whose structures are far from known, continue to provide a challenge for analytical method development. Activation by 18 eV photons led to a rich fragmentation of the oligo-porphyrans, with many cross-ring and glycosidic cleavages. In contrast to multistage MSn strategies such as activated electron photodetachment dissociation, a single step of irradiation by energetic UV of multiply charged anions led to a complete fragmentation of the oligo-porphyrans. In both ionization modes, the sulfate groups were retained on the backbone, which allowed the pattern of these modifications along the porphyran backbone to be described in unprecedented detail. Many structures released by the enzymatic degradation of the porphyran were completely resolved, including isomers. This work extends the existing knowledge of the structure of porphyrans. In addition, it provides a new demonstration of the potential of activation by high-energy photons for the structural analysis of oligosaccharides, even in unseparated mixtures, with a particular focus on sulfated compounds. PMID- 25495707 TI - The concurrence of subacute cutaneous lupus erythematosus and hand-foot syndrome in a patient undergoing capecitabine chemotherapy. AB - We describe an unusual case of subacute cutaneous lupus erythematosus concurrent with hand-foot syndrome, apparently associated with capecitabine treatment. We hypothesise that subacute cutaneous lupus erythematosus and hand-foot syndrome may occur in a novel overlap syndrome. PMID- 25495708 TI - Vision-based body tracking: turning Kinect into a clinical tool. AB - PURPOSE: Vision-based body tracking technologies, originally developed for the consumer gaming market, are being repurposed to form the core of a range of innovative healthcare applications in the clinical assessment and rehabilitation of movement ability. Vision-based body tracking has substantial potential, but there are technical limitations. METHOD: We use our "stories from the field" to articulate the challenges and offer examples of how these can be overcome. RESULTS: We illustrate that: (i) substantial effort is needed to determine the measures and feedback vision-based body tracking should provide, accounting for the practicalities of the technology (e.g. range) as well as new environments (e.g. home). (ii) Practical considerations are important when planning data capture so that data is analysable, whether finding ways to support a patient or ensuring everyone does the exercise in the same manner. (iii) Home is a place of opportunity for vision-based body tracking, but what we do now in the clinic (e.g. balance tests) or in the home (e.g. play games) will require modifications to achieve capturable, clinically relevant measures. CONCLUSIONS: This article articulates how vision-based body tracking works and when it does not to continue to inspire our clinical colleagues to imagine new applications. Implications for Rehabilitation Vision-based body tracking has quickly been repurposed to form the core of innovative healthcare applications in clinical assessment and rehabilitation, but there are clinical as well as practical challenges to make such systems a reality. Substantial effort needs to go into determining what types of measures and feedback vision-based body tracking should provide. This needs to account for the practicalities of the technology (e.g. range) as well as the opportunities of new environments (e.g. the home). Practical considerations need to be accounted for when planning capture in a particular environment so that data is analysable, whether it be finding a chair substitute, ways to support a patient or ensuring everyone does the exercise in the same manner. The home is a place of opportunity with vision-based body tracking, but it would be naive to think that we can do what we do now in the clinic (e.g. balance tests) or in the home (e.g. play games), without appropriate modifications to what constitutes a practically capturable, clinically relevant measure. PMID- 25495709 TI - Catalysis and chemodivergence in the interrupted, formal homo-Nazarov cyclization using allylsilanes. AB - A chemodivergent, Lewis acid catalyzed allylsilane interrupted formal homo Nazarov cyclization is disclosed. With catalytic amounts of SnCl4 and in the presence of allyltrimethylsilane, a formal Hosomi-Sakurai-type allylation of the oxyallyl cation intermediate is observed. A variety of functionalized donor acceptor cyclopropanes and allylsilanes were shown to be amenable to the reaction transformation and the allyl products were formed in up to 92% yield. Under dilute reaction conditions with stoichiometric SnCl4 and at reduced temperatures, an unusual formal [3 + 2]-cycloaddition between the allylsilane and the oxyallyl cation occurred to give hexahydrobenzofuran products in up to 69% yield. PMID- 25495711 TI - N-Heterocyclic carbenes: versatile second cyclometalated ligands for neutral iridium(III) heteroleptic complexes. AB - With 2-(2,4-difluorophenyl)pyridine (dfppy) as the first cyclometalated ligand and different monoanionic N-heterocyclic carbenes (NHCs) as the second cyclometalated ligands, 16 blue or greenish-blue neutral iridium(III) phosphorescent complexes, (dfppy)2Ir(NHC), were synthesized efficiently. The obtained Ir(III) complexes display typical phosphorescence of 455-485 nm with quantum yields up to 0.73. By modifying the phenyl moiety in the NHCs with electron-withdrawing substituents (e.g., -F or -CF3) or replacing it with N heteroaromatic rings (pyridine or pyrimidine), the HOMO-LUMO gaps are broadened, and the emissions shift to the more blue region accordingly. Furthermore, to extend the application scope of NHCs as the second cyclometalated ligands, five other Ir(III) complexes from blue to red were synthesized with different first cyclometalated ligands. Finally, the organic light-emitting diodes using one blue emitter exhibit a maximum current efficiency of 37.83 cd A(-1), an external quantum efficiency of 10.3%, and a maximum luminance of 8709 cd m(-2). Our results demonstrate that NHCs as the second cyclometalated ligands are good candidates for the achievement of efficient phosphorescent Ir(III) complexes and corresponding devices. PMID- 25495710 TI - Generating GPS activity spaces that shed light upon the mobility habits of older adults: a descriptive analysis. AB - BACKGROUND: Measuring mobility is critical for understanding neighborhood influences on older adults' health and functioning. Global Positioning Systems (GPS) may represent an important opportunity to measure, describe, and compare mobility patterns in older adults. METHODS: We generated three types of activity spaces (Standard Deviation Ellipse, Minimum Convex Polygon, Daily Path Area) using GPS data from 95 older adults in Vancouver, Canada. Calculated activity space areas and compactness were compared across sociodemographic and resource characteristics. RESULTS: Area measures derived from the three different approaches to developing activity spaces were highly correlated. Participants who were younger, lived in less walkable neighborhoods, had a valid driver's license, had access to a vehicle, or had physical support to go outside of their homes had larger activity spaces. Mobility space compactness measures also differed by sociodemographic and resource characteristics. CONCLUSIONS: This research extends the literature by demonstrating that GPS tracking can be used as a valuable tool to better understand the geographic mobility patterns of older adults. This study informs potential ways to maintain older adult independence by identifying factors that influence geographic mobility. PMID- 25495712 TI - Creating groups with similar expected behavioural response in randomized controlled trials: a fuzzy cognitive map approach. AB - BACKGROUND: Controlling bias is key to successful randomized controlled trials for behaviour change. Bias can be generated at multiple points during a study, for example, when participants are allocated to different groups. Several methods of allocations exist to randomly distribute participants over the groups such that their prognostic factors (e.g., socio-demographic variables) are similar, in an effort to keep participants' outcomes comparable at baseline. Since it is challenging to create such groups when all prognostic factors are taken together, these factors are often balanced in isolation or only the ones deemed most relevant are balanced. However, the complex interactions among prognostic factors may lead to a poor estimate of behaviour, causing unbalanced groups at baseline, which may introduce accidental bias. METHODS: We present a novel computational approach for allocating participants to different groups. Our approach automatically uses participants' experiences to model (the interactions among) their prognostic factors and infer how their behaviour is expected to change under a given intervention. Participants are then allocated based on their inferred behaviour rather than on selected prognostic factors. RESULTS: In order to assess the potential of our approach, we collected two datasets regarding the behaviour of participants (n = 430 and n = 187). The potential of the approach on larger sample sizes was examined using synthetic data. All three datasets highlighted that our approach could lead to groups with similar expected behavioural changes. CONCLUSIONS: The computational approach proposed here can complement existing statistical approaches when behaviours involve numerous complex relationships, and quantitative data is not readily available to model these relationships. The software implementing our approach and commonly used alternatives is provided at no charge to assist practitioners in the design of their own studies and to compare participants' allocations. PMID- 25495713 TI - 2013 Southeastern Regional ACS Meeting. Nanochemistry and spectroscopy: symposium honoring Mostafa El-Sayed. PMID- 25495714 TI - Juveniles' Miranda comprehension: Understanding, appreciation, and totality of circumstances factors. AB - This study examined juvenile justice-involved youths' understanding and appreciation of the Miranda warnings' rights to silence and legal counsel using the Miranda Rights Comprehension Instruments (Goldstein, Zelle, & Grisso, 2012). It also examined the relationships between totality of circumstances factors and understanding and appreciation of rights. Data were collected from 183 youths (140 boys) in pre- and postadjudication facilities in 2 states. Overall, youths demonstrated greater difficulty on measures of appreciation than understanding, with particular deficits in their abilities to comprehend the abstract concept of the right to silence. Results varied slightly by instrument, highlighting the importance of a multimodal assessment of these complex abilities. Examination of totality of circumstances factors identified relationships between some factors (e.g., age, verbal IQ, academic achievement) and Miranda comprehension, but revealed that other factors (e.g., gender, number of previous arrests) were not significantly related to Miranda understanding or appreciation. The findings support a nuanced conceptualization of Miranda rights comprehension that acknowledges the complexity of understanding and appreciating the warnings. Empirical analyses also support the continued use of some totality of circumstances factors and abandonment of others. Findings underscore the necessity of multimodal assessment and interpretation when conducting capacity to waive Miranda rights evaluations. PMID- 25495715 TI - Static-99R reporting practices in sexually violent predator cases: Does norm selection reflect adversarial allegiance? AB - We surveyed experts (N = 109) who conduct sexually violent predator (SVP) evaluations to obtain information about their Static-99R score reporting and interpretation practices. Although most evaluators reported providing at least 1 normative sample recidivism rate estimate, there were few other areas of consensus. Instead, reporting practices differed depending on the side for which evaluators typically performed evaluations. Defense evaluators were more likely to endorse reporting practices that convey the lowest possible level of risk (e.g., routine sample recidivism rates, 5-year recidivism rates) and the highest level of uncertainty (e.g., confidence intervals, classification accuracy), whereas prosecution evaluators were more likely to endorse practices suggesting the highest possible level of risk (e.g., high risk/need sample recidivism rates, 10-year recidivism rates). Reporting practices from state-agency evaluators tended to be more consistent with those of prosecution evaluators than defense evaluators, although state-agency evaluators were more likely than other evaluators to report that it was at least somewhat difficult to choose an appropriate normative comparison group. Overall, findings provide evidence for adversarial allegiance in Static-99R score reporting and interpretation practices. PMID- 25495716 TI - From the shadows into the light: How pretrial publicity and deliberation affect mock jurors' decisions, impressions, and memory. AB - This 2-part study explored how exposure to negative pretrial publicity (Neg-PTP) influences the jury process, as well as possible mechanisms responsible for its biasing effects on decisions. Study Part A explored how PTP and jury deliberations affect juror/jury verdicts, memory, and impressions of the defendant and attorneys. One week before viewing a criminal trial mock-jurors (N = 320 university students) were exposed to Neg-PTP or unrelated crime stories (No PTP). Two days later deliberating jurors came to a group decision, whereas nondeliberating jurors completed an unrelated task before making an individual decision. Neg-PTP jurors were more likely to vote guilty, make memory errors, and rate the defendant lower in credibility. Deliberation reduced Neg-PTP jurors' memory accuracy and No-PTP jurors' guilty verdicts (leniency bias). Jurors' memory and ratings of the defendant and prosecuting attorney significantly mediated the effect of PTP on guilt ratings. Study Part B content analyzed 30 mock-jury deliberations and explored how PTP influenced deliberations and ultimately jury decisions. Neg-PTP juries were more likely than No-PTP juries to discuss ambiguous trial evidence in a proprosecution manner and less likely to discuss judicial instructions and lack of evidence. All Neg-PTP juries mentioned PTP, after instructed otherwise, and rarely corrected jury members who mentioned PTP. Discussion of ambiguous trial evidence in a proprosecution manner and lack of evidence significantly mediated the effect of PTP on jury-level guilt ratings. Together the findings suggest that judicial admonishments and deliberations may not be sufficient to reduce PTP bias, because of memory errors, biased impressions, and predecisional distortion. PMID- 25495717 TI - Riluzole is a promising pharmacological inhibitor of bilirubin-induced excitotoxicity in the ventral cochlear nucleus. AB - BACKGROUND AND PURPOSE: Bilirubin encephalopathy as a result of hyperbilirubinemia is a devastating neurological disorder that occurs mostly in the neonatal period. To date, no effective drug treatment is available. Glutamate mediated excitotoxicity is likely an important factor causing bilirubin encephalopathy. Thus, drugs suppressing the overrelease of glutamate may protect the brain against bilirubin excitotoxicity. Riluzole is a prescription drug known for its antiglutamatergic function. This study was conducted in the rat's ventral cochlear nucleus, a structure highly sensitive to bilirubin toxicity, to find whether riluzole can be used to inhibit bilirubin toxicity. EXPERIMENTAL APPROACH: Electrophysiology changes were detected by perforated patch clamp technique. Calcium imaging using Rhod-2-AM as an indicator was used to study the intracellular calcium. Cell apoptosis and necrosis were measured by PI/Hoechst staining. KEY RESULTS: In the absence of bilirubin, riluzole effectively decreased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and suppressed neuronal firing but did not change the amplitude of sEPSC and glutamate-activated currents (I(Glu)). Moreover, riluzole inhibited bilirubin induced increases in the frequency of sEPSC and neuronal firing. Riluzole could prevent the bilirubin-induced increase in intracellular calcium, mediated by AMPA and NMDA receptors. Furthermore, riluzole significantly reduced bilirubin-induced cell death. CONCLUSIONS AND IMPLICATIONS: These data suggest that riluzole can protect neurons in the ventral cochlear nucleus from bilirubin-induced hyperexcitation and excitotoxicity through reducing presynaptic glutamate release. PMID- 25495718 TI - Conformational changes and allosteric communications in human serum albumin due to ligand binding. AB - It is well recognized that knowledge of structure alone is not sufficient to understand the fundamental mechanism of biomolecular recognition. Information of dynamics is necessary to describe motions involving relevant conformational states of functional importance. We carried out principal component analysis (PCA) of structural ensemble, derived from 84 crystal structures of human serum albumin (HSA) with different ligands and/or different conditions, to identify the functionally important collective motions, and compared with the motions along the low-frequency modes obtained from normal mode analysis of the elastic network model (ENM) of unliganded HSA. Significant overlap is observed in the collective motions derived from PCA and ENM. PCA and ENM analysis revealed that ligand selects the most favored conformation from accessible equilibrium structures of unliganded HSA. Further, we analyzed dynamic network obtained from molecular dynamics simulations of unliganded HSA and fatty acids- bound HSA. Our results show that fatty acids-bound HSA has more robust community network with several routes to communicate among different parts of the protein. Critical nodes (residues) identified from dynamic network analysis are in good agreement with allosteric residues obtained from sequence-based statistical coupling analysis method. This work underscores the importance of intrinsic structural dynamics of proteins in ligand recognition and can be utilized for the development of novel drugs with optimum activity. PMID- 25495719 TI - How to choose first-line treatment for men with predominant storage lower urinary tract symptoms: a prospective randomised comparative study. AB - AIMS: To compare the therapeutic effects and identify predictors of successful treatment of first-line antimuscarinic and alpha-blocker monotherapy for men with predominant storage lower urinary tract symptoms (LUTS). METHODS: This prospective randomised comparative study included men aged >= 40 years with a total IPSS >= 8, IPSS storage subscore (IPSS-S) >= voiding subscore (IPSS-V) and PVR <= 250 ml. Subjects were randomised to receive tolterodine 4 mg or doxazosin 4 mg daily for 12 weeks. The primary end-point included changes of total IPSS, IPSS subscore and global response assessment (GRA) after treatment. The secondary end-points included comparisons of baseline parameters between patients with a GRA >= 1 and GRA < 1. All adverse events were also recorded. RESULTS: This study was completed by 163 patients. The IPSS-T, IPSS-S and quality of life index decreased significantly in both groups. An improved outcome (GRA >= 1) at 4 weeks was reported in 51/74 patients (68.9%) receiving doxazosin and 69/89 patients (77.5%) receiving tolterodine. The rate of improved outcome in patients with a TPV < 40 ml was significantly higher in tolterodine group (73.3% vs. 57.6%, p = 0.040). Patients with tolterodine treatment failure (GRA < 1) had higher baseline IPSS-V and IPSS intermittency domain, whereas patients with doxazosin treatment failure had a higher baseline IPSS urgency domain. CONCLUSIONS: The rate of improved outcome was comparable between first-line tolterodine and doxazosin monotherapy for male storage LUTS. Antimuscarinic monotherapy was suggested for men with smaller prostate volume and higher urgency symptom scores, whereas alpha blocker monotherapy was suggested for those with higher voiding symptom scores. PMID- 25495721 TI - A taxonomic framework for assessing governance challenges and environmental effects of integrated food-energy systems. AB - Predominant forms of food and energy systems pose multiple challenges to the environment as current configurations tend to be structured around centralized one-way through-put of materials and energy. In addition, these configurations can introduce vulnerability to input material price and supply shocks as well as contribute to localized food insecurity and lost opportunities for less environmentally harmful forms of local economic development. One proposed form of system transformation involves locally integrating "unclosed" material and energy loops from food and energy systems. Such systems, which have been termed integrated food-energy systems (IFES), have existed in diverse niche forms but have not been systematically studied with respect to technological, governance, and environmental differences. As a first step in this process, we have constructed a taxonomy of IFES archetypes by using exploratory data analysis on a collection of IFES cases. We find that IFES may be classified hierarchically first by their primary purpose-food or energy production-and subsequently by degree and direction of vertical supply chain coordination. We then use this taxonomy to delineate potential governance challenges and pose a research agenda aimed at understanding what role IFES may play in food and energy system transformation and ultimately what policies may encourage IFES adoption. PMID- 25495720 TI - Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55 80 years with type 2 diabetes. AB - AIMS: The long-term efficacy and safety of canagliflozin, a sodium glucose co transporter 2 inhibitor, was evaluated over 104 weeks in patients aged 55-80 years with type 2 diabetes mellitus (T2DM) inadequately controlled on a stable antihyperglycaemic agent regimen. METHODS: In this randomized, double-blind, phase III study, patients received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period (N = 714) and a 78-week extension period (n = 624). Efficacy endpoints at week 104 included change from baseline in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and systolic blood pressure, and percent change from baseline in body weight and fasting plasma lipids. Safety was assessed by adverse event (AE) reports. RESULTS: At week 104, canagliflozin 100 and 300 mg were associated with reductions in HbA1c versus placebo (-0.32 and -0.43% vs 0.17%, respectively; overall mean baseline, 7.7%) and more patients achieved HbA1c <7.0% with canagliflozin 100 and 300 mg than with placebo (35.8 and 41.9% vs 20.3%, respectively). Reductions in FPG, body weight and systolic blood pressure, and increases in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were seen with canagliflozin compared with placebo. The overall incidence rates of AEs over 104 weeks were 88.0, 89.8 and 86.1% with canagliflozin 100 and 300 mg and placebo, respectively; serious AE rates were low across treatment groups. The incidence rates of urinary tract infections, genital mycotic infections and osmotic diuresis- and volume depletion related AEs were higher with canagliflozin than with placebo. CONCLUSION: Canagliflozin improved glycaemic control, reduced body weight and systolic blood pressure, and was generally well tolerated in patients aged 55-80 years with T2DM over 104 weeks. PMID- 25495722 TI - Demographic and clinical differences between unilateral and bilateral forms of naevoid telangiectasia: a retrospective study with review of the literature. PMID- 25495723 TI - Reliability and validity of the Japanese version of the self-stigma scale in patients with type 2 diabetes. AB - BACKGROUND: Self-stigma has been highlighted and researched in relation to patients with chronic illnesses, as it may have a negative impact on their treatment adherence. However, self-stigma has not yet been investigated in patients with type 2 diabetes. In order to evaluate the extent to which patients with type 2 diabetes experience self-stigma, which may result in their poor self care management, there is a need for a specific tool to measure self-stigma in patients with type 2 diabetes. This study assessed the psychometric properties of a Japanese version of the Self-Stigma Scale (SSS-J) in patients with type 2 diabetes. METHODS: The reliability and validity of the SSS-J were evaluated using a consecutive sample of 210 outpatients with type 2 diabetes from university hospitals and from hospitals or clinics specializing in diabetes treatment. Confirmatory factor analysis was conducted to assess the factors theorized by the original Self-Stigma Scale. Cronbach's alpha for internal reliability and Pearson's correlations for construct validity were used for evaluation of psychometric properties. Pearson's correlations for test-retest reliability of the SSS-J were also performed. RESULTS: Confirmatory factor analysis verified the three-factor structure of the SSS-J, consisting of cognitive, affective, and behavioral subscales. The model fit indices were as follows: the goodness-of-fit index was 0.78, the adjusted goodness-of-fit index was 0.70, the comparative fit index was 0.88, and the root mean square error of approximation was 0.07. Cronbach's alpha of the SSS-J was 0.96 (cognitive: alpha = 0.92; affective: alpha = 0.93; behavioral: alpha = 0.83). The SSS-J was associated with self-esteem (r = -0.43, p < 0.01), self-efficacy (r = -0.38, p < 0.01), and depressive symptoms (r = 0.39, p < 0.01). The 2-week test-retest reliability demonstrated satisfactory stability (r = 0.76, p < 0.01). CONCLUSIONS: The SSS-J is reliable and valid for assessment of the extent of self-stigma in Japanese patients with type 2 diabetes. PMID- 25495724 TI - Biocatalytic route to chiral acyloins: P450-catalyzed regio- and enantioselective alpha-hydroxylation of ketones. AB - P450-BM3 and mutants of this monooxygenase generated by directed evolution are excellent catalysts for the oxidative alpha-hydroxylation of ketones with formation of chiral acyloins with high regioselectivity (up to 99%) and enantioselectivity (up to 99% ee). This constitutes a new route to a class of chiral compounds that are useful intermediates in the synthesis of many kinds of biologically active compounds. PMID- 25495726 TI - BioSpotlight / Citations. PMID- 25495725 TI - Valeriana officinalis root extract suppresses physical stress by electric shock and psychological stress by nociceptive stimulation-evoked responses by decreasing the ratio of monoamine neurotransmitters to their metabolites. AB - BACKGROUND: In this study, we investigate the effects of valerian root extracts (VE) on physical and psychological stress responses by utilizing a communication box. METHODS: Eight-week-old ICR mice received oral administration of VE (100 mg/kg/0.5 ml) or equal volume of distilled water in every day for 3 weeks prior to being subjected to physical or psychological stress for 3 days, which are induced by communication box developed for physical electric shock and psychological stress by nociceptive stimulation-evoked responses. The stress condition was assessed by forced swimming test and serum corticosterone levels. In addition, norepinephrine (NE), serotonin (5-HT), and their metabolites such as 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) and 5 hydroxyindoleacetic acid (5-HIAA) were measured in the hippocampus and amygdala at 1 h after final stress condition, respectively. RESULTS: Immobility time and corticosterone levels were significantly increased in both the physical and psychological stress groups compared to the control group. The administration of VE significantly reduced these parameters in both the physical and psychological stress groups. In addition, compared to the control group, physical and psychological stress groups showed significantly increased levels of MHPG-SO4 and 5-HIAA in the hippocampus and amygdala, respectively. The administration of VE significantly suppressed the increase of MHPG-SO4 and 5-HIAA in the two stress groups. CONCLUSION: These results suggest that VE can suppress physical and psychological stress responses by modulating the changes in 5-HT and NE turnover in the hippocampus and amygdala. PMID- 25495727 TI - The green fields of chromatography. AB - Researchers are finding that chromatographic separations that use less solvent and stationary phase provide cheaper, more efficient, and more sensitive results. Sarah Webb explores how these changes are leading to the "greening" of chromatography. PMID- 25495728 TI - Bovine thrombin enhances the efficiency and specificity of polymerase chain reaction. AB - The polymerase chain reaction (PCR) has become one of the central techniques in molecular biology since its invention. However, PCR can be fraught with difficulties in various situations, and it is desirable to find novel PCR enhancers suitable for universal applications. Here we show that bovine thrombin (BT), a well-known coagulation protein, is exceptionally effective at preventing the formation of primer dimers and enhancing the formation of the desired PCR products. The PCR enhancement effects of BT were demonstrated by testing various types of samples, including low-copy synthetic single-stranded DNAs (ssDNAs), synthetic ssDNA pools, human genomic DNA, and hepatitis B virus genomic DNA. In addition, BT was also able to effectively relieve PCR inhibition by nanomaterial inhibitors such as gold nanoparticles (AuNPs) and graphene oxide (GO). Compared with BSA, one of the most popular PCR enhancers, BT was more effective and required concentrations 18-178 times less than that of BSA to achieve a similar level of PCR enhancement. PMID- 25495730 TI - Staining and embedding of human chromosomes for 3-d serial block-face scanning electron microscopy. AB - The high-order structure of human chromosomes is an important biological question that is still under investigation. Studies have been done on imaging human mitotic chromosomes using mostly 2-D microscopy methods. To image micron-sized human chromosomes in 3-D, we developed a procedure for preparing samples for serial block-face scanning electron microscopy (SBFSEM). Polyamine chromosomes are first separated using a simple filtration method and then stained with heavy metal. We show that the DNA-specific platinum blue provides higher contrast than osmium tetroxide. A two-step procedure for embedding chromosomes in resin is then used to concentrate the chromosome samples. After stacking the SBFSEM images, a familiar X-shaped chromosome was observed in 3-D. PMID- 25495729 TI - Assessing and reducing sources of gene expression variability in Staphylococcus epidermidis biofilms. AB - Gene expression quantification can be a useful tool in studying the properties of bacterial biofilms. Unfortunately, techniques such as RNA extraction, cDNA synthesis, and quantitative PCR (qPCR) can introduce variability into mRNA transcript measurements, obscuring biologically relevant results. Here we sought to identify the steps that impair accurate gene expression quantification from Staphylococcus epidermidis biofilm samples. We devised an experimental setup that could be used to determine the contribution of each experimental step to the variability of mRNA transcript measurement. Among factors tested, biofilm growth contributed the most bias to gene expression quantification. Additional experiments demonstrated that pooling biofilms together reduced this variability, resulting in more accurate gene expression analysis results. We therefore recommend pooling in order to reduce the variability associated with gene expression quantification from biofilm samples. PMID- 25495731 TI - Automation of the cytokinesis-block micronucleus cytome assay by laser scanning cytometry and its potential application in radiation biodosimetry. AB - Here we describe the adaptation of laser scanning cytometry (LSC) to measure micronuclei (MN) automatically in lymphocytes. MN frequencies were determined in irradiated human lymphocytes using the cytokinesis-block technique, and the results from LSC were compared with visual scoring results obtained from slides of cells stained using Fast Green and 4',6-diamidino-2-phenylindole (DAPI). This fluorescent approach allowed clear identification of binucleated cells and detection of MN. The dose responses measured visually and by LSC showed similar trends and correlated positively (r = 0.9689; P < 0.0001). High-content analysis was developed to further automatically score MN within mono-, tri- and tetra nucleated cells and to determine the nuclear division index and nuclear circularity values. The high-throughput nature of LSC can provide unique advantages in future DNA damage diagnostics in experimental and epidemiological studies. Importantly, it allows for co-detection of other biomarkers of interest within a single lymphocyte, and further development of this capability is anticipated. PMID- 25495732 TI - Discrimination of SNPs in GC-rich regions using a modified hydrolysis probe chemistry protocol. AB - Allelic discrimination using TaqMan 5'-nuclease assay chemistry has been in routine use for many years, and the catalog of Life Technologies' predesigned SNP genotyping assays now exceeds 4 million entries. However, predesigned assays are often not available for genomic regions with a high GC content, nor can an assay necessarily be designed in this type of region using the manufacturer's design pipelines. Additionally, when an assay is available, the performance can be poor when using standard protocols. Here we report a modified allelic discrimination protocol for variants that reside in extremely GC-rich (GC > 75%) regions. The approach resolves fluorescent signal from reference and variant alleles, allowing all samples to be successfully assigned a genotype call. This protocol modification adds an extra step to the standard workflow, but the increased time is a productive compromise to generate high-quality data. PMID- 25495733 TI - Structural and functional analysis of yeast Crh1 and Crh2 transglycosylases. AB - Covalent cross-links between chitin and glucan at the yeast cell wall are created by the transglycosylase activity of redundant proteins Crh1 and Crh2, with cleavage of beta-1,4 linkages of the chitin backbone and transfer of the generated molecule containing newly created reducing end onto the glucan acceptor. A three-dimensional structure of Crh1 was generated by homology modeling based on the crystal structure of bacterial 1,3-1,4-beta-d-glucanase, followed by site-directed mutagenesis to obtain molecular insights into how these enzymes achieve catalysis. The residues of both proteins that are involved in their catalytic and binding activities have been characterized by measuring the ability of yeast cells expressing different versions of these proteins to transglycosylate oligosaccharides derived from beta-1,3-glucan, beta-1,6-glucan and chitin to the chitin at the cell wall. Within the catalytic site, residues E134 and E138 of Crh1, as well as E166 and E170 of Crh2, corresponding to the nucleophile and general acid/base, and also the auxiliary D136 and D168 of Crh1 and Crh2, respectively, are shown to be essential for catalysis. Mutations of aromatic residues F152, Y160 and W219, located within the carbohydrate-binding cleft of the Crh1 model, also affect the transglycosylase activity. Unlike Crh1, Crh2 contains a putative carbohydrate-binding module (CBM18) of unknown function. Modeling and functional analysis of site-directed mutant residues of this CBM identified essential amino acids for protein folding and stability, as well as residues that tune the catalytic activity of Crh2. PMID- 25495734 TI - Topology-guided design and syntheses of highly stable mesoporous porphyrinic zirconium metal-organic frameworks with high surface area. AB - Through a topology-guided strategy, a series of Zr6-containing isoreticular porphyrinic metal-organic frameworks (MOFs), PCN-228, PCN-229, and PCN-230, with ftw-a topology were synthesized using the extended porphyrinic linkers. The bulky porphyrin ring ligand effectively prevents the network interpenetration which often appears in MOFs with increased linker length. The pore apertures of the structures range from 2.5 to 3.8 nm, and PCN-229 demonstrates the highest porosity and BET surface area among the previously reported Zr-MOFs. Additionally, by changing the relative direction of the terminal phenyl rings, this series replaces a Zr8 cluster with a smaller Zr6 cluster in a topologically identical framework. The high connectivity of the Zr6 cluster yields frameworks with enhanced stability despite high porosity and ultralarge linker. As a representative example, PCN-230, constructed with the most extended porphyrinic linker, shows excellent stability in aqueous solutions with pH values ranging from 0 to 12 and demonstrates one of the highest pH tolerances among all porphyrinic MOFs. This work not only presents a successful example of rational design of MOFs with desired topology, but also provides a strategy for construction of stable mesoporous MOFs. PMID- 25495735 TI - Nanopores suggest a negligible influence of CpG methylation on nucleosome packaging and stability. AB - Nucleosomes are the fundamental repeating units of chromatin, and dynamic regulation of their positioning along DNA governs gene accessibility in eukaryotes. Although epigenetic factors have been shown to influence nucleosome structure and dynamics, the impact of DNA methylation on nucleosome packaging remains controversial. Further, all measurements to date have been carried out under zero-force conditions. In this paper, we present the first automated force measurements that probe the impact of CpG DNA methylation on nucleosome stability. In solid-state nanopore force spectroscopy, a nucleosomal DNA tail is captured into a pore and pulled on with a time-varying electrophoretic force until unraveling is detected. This is automatically repeated for hundreds of nucleosomes, yielding statistics of nucleosome lifetime vs electrophoretic force. The force geometry, which is similar to displacement forces exerted by DNA polymerases and helicases, reveals that nucleosome stability is sensitive to DNA sequence yet insensitive to CpG methylation. Our label-free method provides high throughput data that favorably compares with other force spectroscopy experiments and is suitable for studying a variety of DNA-protein complexes. PMID- 25495736 TI - Nanoparticle-Based Therapy in Genomics. AB - In the modern era, humankind is making daily progress through industrialization. As various types of diseases are prevailing worldwide, scientists are using many approaches to manage these diseases, such as gene therapy. A nanoparticle (NP) based approach is an example of a modern method used to address several pathologies. This modern therapeutic approach aims not only at safely transferring the drug of choice to the site of interest in a biological system but also at ensuring the biocompatibility of these NPs. Hence, various coating methodologies are being employed to avoid NP toxicity as well as immunoreactivity. This short review covers the latest approaches and advances in this biomedical field. Among nanomaterials, gold NPs (GNPs) are comprehensively employed as a diagnostic tool for the treatment and management of diseases such as cancer. PMID- 25495738 TI - Application of Proteomic Tools in Modern Nanotechnological Approaches Towards Effective Management of Neurodegenerative Disorders. AB - Neurodegeneration is the progressive loss of structure or function of neurons leading to neuronal death, usually associated with ageing. Some of the common neurodegenerative disorders include Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and Huntington's disease. Due to recent advancements in highthroughput technologies in various disciplines such as genomics, epigenomics, metabolomics and proteomics, there has been a great demand for detection of specific macromolecules such as hormones, drug residues, miRNA, DNA, antibodies, peptides, proteins, pathogens and xenobiotics at nano-level concentrations for in-depth understanding of disease mechanisms as well as for the development of new therapeutic strategies. The present review focuses on the management of agerelated neurodegenerative disorders using proteomics and nanotechnological approaches. In addition, this review also highlights the metabolism and disposition of nano-drugs and nano-enabled drug delivery in neurodegenerative disorders. PMID- 25495737 TI - Protein engineering: a new frontier for biological therapeutics. AB - Protein engineering holds the potential to transform the metabolic drug landscape through the development of smart, stimulusresponsive drug systems. Protein therapeutics are a rapidly expanding segment of Food and Drug Administration approved drugs that will improve clinical outcomes over the long run. Engineering of protein therapeutics is still in its infancy, but recent general advances in protein engineering capabilities are being leveraged to yield improved control over both pharmacokinetics and pharmacodynamics. Stimulus- responsive protein therapeutics are drugs which have been designed to be metabolized under targeted conditions. Protein engineering is being utilized to develop tailored smart therapeutics with biochemical logic. This review focuses on applications of targeted drug neutralization, stimulus-responsive engineered protein prodrugs, and emerging multicomponent smart drug systems (e.g., antibody-drug conjugates, responsive engineered zymogens, prospective biochemical logic smart drug systems, drug buffers, and network medicine applications). PMID- 25495740 TI - Symptomatic contralateral subdural hygromas after decompressive craniectomy: plausible causes and management protocols. AB - OBJECT: Contralateral subdural hygromas are occasionally observed after decompressive craniectomies (DCs). Some of these hygromas are symptomatic, and the etiology and management of these symptomatic contralateral subdural collections (CLDCs) present surgical challenges. The authors share their experience with managing symptomatic CLSDCs after a DC. METHODS: During a 10 month period, 306 patients underwent a DC. Of these patients, 266 had a head injury, 25 a middle cerebral artery infarction (that is, a thrombotic stroke), and 15 an infarction due to a vasospasm (resulting from an aneurysmal subarachnoid hemorrhage [SAH]). Seventeen patients (15 with a head injury and 2 with an SAH) developed a CLSDC, and 7 of these patients showed overt symptoms of the fluid collection. These patients were treated with a trial intervention consisting of bur hole drainage followed by cranioplasty. If required, a ventriculo- or thecoperitoneal shunt was inserted at a later time. RESULTS: Seven patients developed a symptomatic CLSDC after a DC, 6 of whom had a head injury and 1 had an SAH. The average length of time between the DC and CLSDC formation was 24 days. Fluid drainage via a bur hole was attempted in the first 5 patients. However, symptoms in these patients improved only temporarily. All 7 patients (including the 5 in whom the bur hole drainage had failed and 2 directly after the DC) underwent a cranioplasty, and the CLSDC resolved in all of these patients. The average time it took for the CLSDC to resolve after the cranioplasty was 34 days. Three patients developed hydrocephalus after the cranioplasty, requiring a diversion procedure, and 1 patient contracted meningitis and died. CONCLUSIONS: Arachnoid tears and blockage of arachnoid villi appear to be the underlying causes of a CLSDC. The absence of sufficient fluid pressure required for CSF absorption after a DC further aggravates such fluid collections. Underlying hydrocephalus may appear as subdural collections in some patients after the DC. Bur hole drainage appears to be only a temporary measure and leads to recurrence of a CLSDC. Therefore, cranioplasty is the definitive treatment for such collections and, if performed early, may even avert CLSDC formation. A temporary ventriculostomy or an external lumbar drainage may be added to aid the cranioplasty and may be removed postoperatively. Ventriculoperitoneal or thecoperitoneal shunting may be required for patients in whom a hydrocephalus manifests after cranioplasty and underlies the CLSDC. PMID- 25495741 TI - Endoscopic endonasal transsphenoidal approach to pituitary adenomas. PMID- 25495739 TI - Detection of third and sixth cranial nerve palsies with a novel method for eye tracking while watching a short film clip. AB - OBJECT: Automated eye movement tracking may provide clues to nervous system function at many levels. Spatial calibration of the eye tracking device requires the subject to have relatively intact ocular motility that implies function of cranial nerves (CNs) III (oculomotor), IV (trochlear), and VI (abducent) and their associated nuclei, along with the multiple regions of the brain imparting cognition and volition. The authors have developed a technique for eye tracking that uses temporal rather than spatial calibration, enabling detection of impaired ability to move the pupil relative to normal (neurologically healthy) control volunteers. This work was performed to demonstrate that this technique may detect CN palsies related to brain compression and to provide insight into how the technique may be of value for evaluating neuropathological conditions associated with CN palsy, such as hydrocephalus or acute mass effect. METHODS: The authors recorded subjects' eye movements by using an Eyelink 1000 eye tracker sampling at 500 Hz over 200 seconds while the subject viewed a music video playing inside an aperture on a computer monitor. The aperture moved in a rectangular pattern over a fixed time period. This technique was used to assess ocular motility in 157 neurologically healthy control subjects and 12 patients with either clinical CN III or VI palsy confirmed by neuro-ophthalmological examination, or surgically treatable pathological conditions potentially impacting these nerves. The authors compared the ratio of vertical to horizontal eye movement (height/width defined as aspect ratio) in normal and test subjects. RESULTS: In 157 normal controls, the aspect ratio (height/width) for the left eye had a mean value +/- SD of 1.0117 +/- 0.0706. For the right eye, the aspect ratio had a mean of 1.0077 +/- 0.0679 in these 157 subjects. There was no difference between sexes or ages. A patient with known CN VI palsy had a significantly increased aspect ratio (1.39), whereas 2 patients with known CN III palsy had significantly decreased ratios of 0.19 and 0.06, respectively. Three patients with surgically treatable pathological conditions impacting CN VI, such as infratentorial mass effect or hydrocephalus, had significantly increased ratios (1.84, 1.44, and 1.34, respectively) relative to normal controls, and 6 patients with supratentorial mass effect had significantly decreased ratios (0.27, 0.53, 0.62, 0.45, 0.49, and 0.41, respectively). These alterations in eye tracking all reverted to normal ranges after surgical treatment of underlying pathological conditions in these 9 neurosurgical cases. CONCLUSIONS: This proof of concept series of cases suggests that the use of eye tracking to detect CN palsy while the patient watches television or its equivalent represents a new capacity for this technology. It may provide a new tool for the assessment of multiple CNS functions that can potentially be useful in the assessment of awake patients with elevated intracranial pressure from hydrocephalus or trauma. PMID- 25495742 TI - Complications of contralateral C-7 transfer through the modified prespinal route for repairing brachial plexus root avulsion injury: a retrospective study of 425 patients. AB - OBJECT: In this report, the authors review complications related to the modified prespinal route in contralateral C-7 transfer for repairing brachial plexus nerve root avulsion injury and suggest a prevention strategy. METHODS: A retrospective, nonselected amalgamation of every case of modified contralateral C-7 transfer through the prespinal route was undertaken. The study population comprised 425 patients treated between February 2002 and August 2009. The patients were managed according to a standardized protocol by one senior professor. The surgical complications were grouped into one of the following categories: those associated with tunnel making through the prespinal route, those related to the dissection and transection of the contralateral C-7 nerve root, and those that occurred in the postoperative period. RESULTS: The study population included 379 male and 46 female patients whose average age was 21 years (range 3 months to 56 years). A total of 401 patients were diagnosed with traumatic brachial plexus injury, the leading cause of which was motor vehicle accident, and 24 patients were diagnosed with obstetrical brachial plexus palsy. The contralateral C-7 nerve root was cut at the proximal side of the division portion of the middle trunk in 15 cases and sectioned at the distal end of the anterior and posterior divisions in 410 cases. The overall incidence of complications was 5.4% (23 of 425). Complications associated with making a prespinal tunnel occurred in 12 cases, including severe bleeding due to vertebral artery injury during the procedure in 2 cases (0.47%), temporary recurrent laryngeal nerve palsy in 5 cases (1.18%), pain and numbness in the donor upper extremity during swallowing in 4 cases (0.94%), and dyspnea caused by thrombosis of the brainstem 42 hours postoperatively in 1 case (0.24%); this last patient died 38 days after the operation. Complications related to exploration and transection of the contralateral C-7 nerve root occurred in 11 cases, including deficiency in extensor strength of the fingers and thumb in 4 cases (0.94%) due to injury to the posterior division of the lower trunk, unbearable pain on the donor upper extremity in 3 cases (0.71%), Horner's syndrome in 2 children (0.47%) who suffered birth palsy, a section of C-6 nerve root mistaken as C-7 in l case (0.24%), and atrophy of the sternocostal part of the pectoralis major in 1 case (0.24%). CONCLUSIONS: The most serious complications of using the modified prespinal route in contralateral C-7 transfer were vertebral artery laceration and injury to the posterior division of the lower trunk. The prevention of such complications is necessary to popularize this surgical procedure and attain good long-term clinical results. PMID- 25495743 TI - Clinical factors associated with venous thromboembolism risk in patients undergoing craniotomy. AB - OBJECT Patients undergoing craniotomy are at risk for developing venous thromboembolism (VTE). The safety of anticoagulation in these patients is not clear. The authors sought to identify risk factors predictive of VTE in patients undergoing craniotomy. METHODS The authors reviewed a national surgical quality database, the American College of Surgeons National Surgical Quality Improvement Program. Craniotomy patients were identified by current procedural terminology code. Clinical factors were analyzed to identify associations with VTE. RESULTS Four thousand eight hundred forty-four adult patients who underwent craniotomy were identified. The rate of VTE in the cohort was 3.5%, including pulmonary embolism in 1.4% and deep venous thrombosis in 2.6%. A number of factors were found to be statistically significant in multivariate binary logistic regression analysis, including craniotomy for tumor, transfer from acute care hospital, age >= 60 years, dependent functional status, tumor involving the CNS, sepsis, emergency surgery, surgery time >= 4 hours, postoperative urinary tract infection, postoperative pneumonia, on ventilator >= 48 hours postoperatively, and return to the operating room. Patients were assigned a score based on how many of these factors they had (minimum score 0, maximum score 12). Increasing score was predictive of increased VTE incidence, as well as risk of mortality, and time from surgery to discharge. CONCLUSIONS Patients undergoing craniotomy are at low risk of developing VTE, but this risk is increased by preoperative medical comorbidities and postoperative complications. The presence of more of these clinical factors is associated with progressively increased VTE risk; patients possessing a VTE Risk Score of >= 5 had a greater than 20-fold increased risk of VTE compared with patients with a VTE score of 0. PMID- 25495744 TI - Simulation in neurosurgical education: where next? PMID- 25495745 TI - Predictors of excellent functional outcome in aneurysmal subarachnoid hemorrhage. AB - OBJECT: Case fatality rates after aneurysmal subarachnoid hemorrhage (aSAH) have decreased over time, and many patients treated with modern paradigms return to a normal life. However, there is little information on predictors of excellent functional outcome after aSAH. In this study, the authors investigated predictors of excellent outcome in a modern consecutive series of patients with aSAH. METHODS: A retrospective review was conducted of patients with aSAH admitted between 2001 and 2013. The primary outcome measure was excellent functional outcome, defined as modified Rankin Scale (mRS) score of 0 or 1 at last follow-up within 1 year of aSAH. RESULTS: Three hundred seventy-three patients were identified with posthospital follow-up. Excellent outcome was noted in 236 patients (63.3%), including an mRS score of 0 in 122 (32.7%) and an mRS score of 1 in 114 (30.6%). On univariate analysis, the following factors were associated with an excellent outcome: indicators of less severe bleeding, such as better World Federation of Neurosurgical Societies grade at any of the times of assessment, better modified Fisher grade, and absence of intracerebral hemorrhage (ICH), intraventricular hemorrhage (IVH), and symptomatic hydrocephalus; aneurysm treatment with coil embolization; absence of symptomatic vasospasm, delayed cerebral ischemia, and radiological infarction; absence of in-hospital seizures; lack of need for CSF diversion; fewer hours with fever; less severe anemia; and absence of transfusion. On multivariable analysis, the 4 variables that were most strongly associated with excellent outcome were presence of good clinical grade after neurological resuscitation, absence of ICH on initial CT scan, blood transfusion during the hospitalization, and radiological infarctions on final brain imaging. CONCLUSIONS: Excellent outcomes (mRS score 0-1) can be achieved in the majority of patients with aSAH. The likelihood of excellent outcome is predicted by good clinical condition after resuscitation, absence of ICH on presentation, no evidence of infarction on brain imaging, and absence of blood transfusion during hospitalization. PMID- 25495746 TI - Hepadnavirus detected in bile and liver samples from domestic pigs of commercial abattoirs. AB - BACKGROUND: Preliminary studies showed the prevalence of a virus similar to human hepatitis B virus (HBV-like) in swine from farms in China and the molecular evidence of Hepadnavirus infection in domestic pigs herds in Brazil. In this study, we genetically characterize the swine Hepadnavirus strains in swine from slaughterhouses located in certified abattoirs from Rio de Janeiro State, Brazil and evaluate its hepatotropic potential. RESULTS: Bile and liver samples from swine were positive for partial genome amplification (ORF S and ORF C), direct sequencing and viral load quantification. Sequencing of the gene encoding the surface antigen allowed classification of Hepadnavirus into genotypes, similar to HBV genotype classification. Indirect immunofluorescence confirmed the presence of HBsAg antigen in liver tissue sections. CONCLUSIONS: So far our data suggest that commercial swine house an HBV-like virus and this relevant finding should be considered in studies on the origin and viral evolution. PMID- 25495747 TI - Primary Care Triple P for parents of NICU graduates with behavioral problems: a randomized, clinical trial using observations of parent-child interaction. AB - BACKGROUND: Preterm-born or asphyxiated term-born children show more emotional and behavioral problems at preschool age than term-born children without a medical condition. It is uncertain whether parenting intervention programs aimed at the general population, are effective in this specific group. In earlier findings from the present trial, Primary Care Triple P was not effective in reducing parent-reported child behavioral problems. However, parenting programs claim to positively change child behavior through enhancement of the parent-child interaction. Therefore, we investigated whether Primary Care Triple P is effective in improving the quality of parent-child interaction and increasing the application of trained parenting skills in parents of preterm-born or asphyxiated term-born preschoolers with behavioral problems. METHODS: For this pragmatic, open randomized clinical trial, participants were recruited from a cohort of infants admitted to the neonatal intensive care units of two Dutch hospitals. Children aged 2-5 years, with a gestational age <32 weeks and/or birth weight <1500 g and children with a gestational age 37-42 weeks and perinatal asphyxia were included. After screening for a t-score >=60 on the Child Behavior Checklist, children were randomly assigned to Primary Care Triple P (n = 34) or a wait-list control group (n = 33). Trial outcomes were the quality of parent-child interaction and the application of trained parenting skills, both scored from structured observation tasks. RESULTS: There was no effect of the intervention on either of the observational outcome measures at the 6-month trial endpoint. CONCLUSIONS: Primary Care Triple P, is not effective in improving the quality of parent-child interaction nor does it increase the application of trained parenting skills in parents of preterm-born or asphyxiated term-born children with behavioral problems. Further research should focus on personalized care for these parents, with an emphasis on psychological support to reduce stress and promote self-regulation. TRIAL REGISTRATION: Netherlands National Trial Register NTR2179 . Registered 26 January 2010. PMID- 25495749 TI - Changing patterns of drug-resistant Shigella isolates in egypt. AB - BACKGROUND: The emergence of multidrug resistance (MDR) is a serious problem in treating shigellosis. There are limited existing data examining the change in the antimicrobial resistance profile of Shigella in Egypt. We previously reported that 58% of the Shigella isolates in Egypt were resistant to at least one member of the three different antimicrobial groups. This study was performed to determine the antimicrobial resistance profile of Shigella, determine their possible mechanisms of resistance, and compare their resistance profile to those reported 20 years ago. PATIENTS AND METHODS: Stool samples were collected from 500 subjects and processed for the isolation and identification of Shigella. The susceptibility of the isolates to 11 different antimicrobials was determined using the disc diffusion method. RESULTS: Of 500 stool cultures, 24 (4.8%) samples were positive for Shigella. There was a high percentage of resistance to ampicillin (88%), tetracycline (83%), and sulfamethoxazole-trimethoprim (75%). Also, there was a moderate percentage of resistance to chloramphenicol (46%), streptomycin (42%), ceftazidime (33%), and cefotaxime (25%). A lower percentage of resistance was recorded for amikacin, nalidixic acid (17% each), and ofloxacin (7%), while no resistance was found to ciprofloxacin (0%). Twenty-one of the isolates (88%) were resistant to at least three different antimicrobial groups (indicating MDR). The average number of antimicrobial agents to which the Shigella isolates were resistant was 4.3+/-1.4, while it was 3.4+/-1.5 in the same locality in 1994. CONCLUSION: These data demonstrate that there is a marked increase in MDR and change in the resistance patterns of Shigella over the past 20 years. PMID- 25495750 TI - Topology specific stabilization of promoter over telomeric G-quadruplex DNAs by bisbenzimidazole carboxamide derivatives. AB - Various potential G-quadruplex forming sequences present in the genome offer a platform to modulate their function by means of stabilizing molecules. Though G quadruplex structures exhibit diverse structural topologies, the presence of G quartets as a common structural element makes the design of topology specific ligands a daunting task. To address this, the subtle structural variations of loops and grooves present in the quadruplex structures can be exploited. To this end, we report the design and synthesis of quadruplex stabilizing agents based on bisbenzimidazole carboxamide derivatives of pyridine, 1,8-naphthyridine, and 1,10 phenanthroline. The designed ligands specifically bind to and stabilize promoter quadruplexes having parallel topology over any of the human telomeric quadruplex topologies (parallel, hybrid, or antiparallel) and duplex DNAs. CD melting studies indicate that ligands could impart higher stabilization to c-MYC and c KIT promoter quadruplexes (up to 21 degrees C increment in Tm) than telomeric and duplex DNAs (DeltaTm <= 2.5 degrees C). Consistent with a CD melting study, ligands bind strongly (Kb = ~10(4) to 10(5) M(-1)) to c-MYC quadruplex DNA. Molecular modeling and dynamics studies provide insight into how the specificity is achieved and underscore the importance of flexible N-alkyl side chains attached to the benzimidazole-scaffold in recognizing propeller loops of promoter quadruplexes. Overall, the results reported here demonstrate that the benzimidazole scaffold represents a potent and powerful side chain, which could judiciously be assembled with a suitable central core to achieve specific binding to a particular quadruplex topology. PMID- 25495748 TI - An Integrated Risk Reduction Intervention can reduce body mass index in individuals being treated for bipolar I disorder: results from a randomized trial. AB - OBJECTIVES: We conducted a randomized, controlled trial comparing the efficacy of an Integrated Risk Reduction Intervention (IRRI) to a control condition with the objective of improving mood stability and psychosocial functioning by reducing cardiometabolic risk factors in overweight/obese patients with bipolar I disorder. METHODS: A total of 122 patients were recruited from our outpatient services and randomly allocated to IRRI (n = 61) or psychiatric care with medical monitoring (n = 61). Individuals allocated to IRRI received psychiatric treatment and assessment, medical monitoring by a nurse, and a healthy lifestyle program from a lifestyle coach. Those allocated to the control condition received psychiatric treatment and assessment and referral, if indicated, for medical problems. A mixed-effects model was used to examine the impact of the interventions on body mass index (BMI). Exploratory moderator analyses were used to characterize those individuals likely to benefit from each treatment approach. RESULTS: Analyses were conducted on data for the IRRI (n = 58) and control (n = 56) participants with >= 1 study visit. IRRI was associated with a significantly greater rate of decrease in BMI (d = -0.51, 95% confidence interval: -0.91 to 0.14). Three variables (C-reactive protein, total cholesterol, and instability of total sleep time) contributed to a combined moderator of faster decrease in BMI with IRRI treatment. CONCLUSIONS: Overweight/obese patients with bipolar disorder can make modest improvements in BMI, even when taking medications with known potential for weight gain. Our finding that a combination of three baseline variables provides a profile of patients likely to benefit from IRRI will need to be tested further to evaluate its utility in clinical practice. PMID- 25495751 TI - Hepatic arterial infusion chemotherapy with cisplatin and sorafenib in hepatocellular carcinoma patients unresponsive to transarterial chemoembolization: a propensity score-based weighting. AB - OBJECTIVE: We aimed to evaluate the efficacy and tolerability of hepatic arterial infusion chemotherapy (HAIC) using cisplatin as an alternative to sorafenib for the treatment of hepatocellular carcinoma (HCC) patients who had not responded to transarterial chemoembolization (TACE). METHODS: Medical records of 127 consecutive HCC patients without extrahepatic metastasis (cisplatin, n = 44; sorafenib, n = 83) who had not responded to prior TACE at four institutions were retrospectively reviewed. An inverse probability of treatment weighting using propensity scoring was used to adjust for the selection bias. RESULTS: Severe adverse events accounting for treatment discontinuation occurred in 2.3% of the patients in the cisplatin group and 32.5% of those in the sorafenib group. The median overall survival (OS) period was 11.2 months (95% CI 4.8-17.7) in the cisplatin group and 10.2 months (95% CI 8.8-11.5) in the sorafenib group, respectively. After an inverse probability of treatment weighting adjustment, the survival outcome of the HAIC treatment group was not inferior to that of the sorafenib treatment group (hazard ratio 0.758; 95% CI 0.471-1.219, P = 0.253). CONCLUSION: HAIC with cisplatin can be an alternative treatment for the selection of HCC patients who have not responded to prior TACE and cannot tolerate sorafenib. PMID- 25495752 TI - Use of novel oral anticoagulants in patients with end-stage renal disease. PMID- 25495753 TI - The impact of Ni, Co and Mo supplementation on methane yield from anaerobic mono digestion of maize silage. AB - The objective of this experimental study was to demonstrate the impact of trace metal supplementation, namely nickel (Ni), cobalt (Co) and molybdenum (Mo), on the methane yields obtained from batch mesophilic anaerobic digestion of maize silage as mono-substrate. The maize silage used in this experimental work initially lacked Ni and Co. Trace metal concentration selected was 0.1 and 0.5 mg/L for Ni and Co, respectively, while it was 0.05 and 0.25 mg/L for Mo. The supplementation by Ni, Co and Mo, individually or in combination at different doses, seemed to improve the methane yields for mono-digestion of maize silage and particularly, the highest methane yield of 0.429 L CH4/g VSadded was obtained, when Ni, Co and Mo were supplemented together at concentrations of 0.5, 0.5 and 0.25 mg/L, respectively. PMID- 25495754 TI - Pharmacokinetics of flavanone glycosides after ingestion of single doses of fresh squeezed orange juice versus commercially processed orange juice in healthy humans. AB - Orange juice is a rich source of flavonoids considered beneficial to cardiovascular health in humans. The objective of this study was to analyze the pharmacokinetics of the main flavanone glycosides, hesperidin and narirutin, in humans after the consumption of two styles of orange juice, fresh-squeezed (FOJ) and commercially processed (POJ), differing in their amounts of soluble and insoluble forms of these compounds. Healthy human subjects consumed 11.5 mL/kg body weight of FOJ, and after an interval of 30 days, consumed the same quantity of POJ. The results showed that there were no significant differences in the Tmax of the pharmacokinetic curves for the metabolites of hesperidin and narirutin following the consumption of the two styles of juices, and corrected for differences in doses in the POJ and FOJ, there were also no significant differences in the AUC and Cmax values and percent absorption of these compounds. PMID- 25495755 TI - Vision screening by teachers in southern Indian schools: testing a new "all class teacher" model. AB - AIM: To study the effectiveness and cost of a new school vision screening program involving all class teachers (ACTs) compared with the standard program involving a limited number of selected teachers (STs) in Southern India. METHODS: A total of 12 schools were selected for intervention and 12 schools were matched as controls, from in and around Pondicherry, India. Teachers in both the intervention arm (ACTs) and the standard arm (STs) were trained to identify students between the ages of 6 and 17 years with visual acuity <=20/30 in either eye or obvious ocular abnormalities and refer them to an ophthalmic team. The ophthalmic team, including an ophthalmologist, visited the schools to examine all children referred by teachers, provided medical treatment or a prescription for glasses, or referred them to the base hospital if required. RESULTS: ACTs (761 teachers) screened 39,357 children (97.7%) and STs (156 teachers) screened 38,469 children (95.7%). ACTs found significantly fewer screen-positive children (n = 3806, 9.7%) than the STs (n = 6387, 16.6%; p < 0.001), but had a significantly larger number of children with actual vision loss and other ocular pathology (2231, 5.7% and 1554, 4.0%, respectively, p < 0.001). More children from ACTs than STs reached the base hospital for further investigation within 3 months (p < 0.001). The cost of screening per child with actual ocular pathology was estimated to be US$1.91 for ACTs and US$4.83 for STs. CONCLUSIONS: A school vision screening program involving ACTs resulted in more efficient screening than a program involving STs at about a third of the cost and also improved compliance with hospital referral. PMID- 25495756 TI - Profilin1 activity in cerebellar granule neurons is required for radial migration in vivo. AB - Neuron migration defects are an important aspect of human neuropathies. The underlying molecular mechanisms of such migration defects are largely unknown. Actin dynamics has been recognized as an important determinant of neuronal migration, and we recently found that the actin-binding protein profilin1 is relevant for radial migration of cerebellar granule neurons (CGN). As the exploited brain-specific mutants lacked profilin1 in both neurons and glial cells, it remained unknown whether profilin1 activity in CGN is relevant for CGN migration in vivo. To test this, we capitalized on a transgenic mouse line that expresses a tamoxifen-inducible Cre variant in CGN, but no other cerebellar cell type. In these profilin1 mutants, the cell density was elevated in the molecular layer, and ectopic CGN occurred. Moreover, 5-bromo-2'-deoxyuridine tracing experiments revealed impaired CGN radial migration. Hence, our data demonstrate the cell autonomous role of profilin1 activity in CGN for radial migration. PMID- 25495757 TI - Health Professionals' readiness to implement electronic medical record system at three hospitals in Ethiopia: a cross sectional study. AB - BACKGROUND: Electronic medical record systems are being implemented in many countries to support healthcare services. However, its adoption rate remains low, especially in developing countries due to technological, financial, and organizational factors. There is lack of solid evidence and empirical research regarding the pre implementation readiness of healthcare providers. The aim of this study is to assess health professionals' readiness and to identify factors that affect the acceptance and use of electronic medical recording system in the pre implementation phase at hospitals of North Gondar Zone, Ethiopia. METHODS: An institution based cross-sectional quantitative study was conducted on 606 study participants from January to July 2013 at 3 hospitals in northwest Ethiopia. A pretested self-administered questionnaire was used to collect the required data. The data were entered using the Epi-Info version 3.5.1 software and analyzed using SPSS version 16 software. Descriptive statistics, bi-variate, and multi variate logistic regression analyses were used to describe the study objectives and assess the determinants of health professionals' readiness for the system. Odds ratio at 95% CI was used to describe the association between the study and the outcome variables. RESULTS: Out of 606 study participants only 328 (54.1%) were found ready to use the electronic medical recording system according to our criteria assessment. The majority of the study participants, 432 (71.3%) and 331(54.6%) had good knowledge and attitude for EMR system, respectively. Gender (AOR = 1.87, 95% CI: [1.26, 2.78]), attitude (AOR = 1.56, 95% CI: [1.03, 2.49]), knowledge (AOR = 2.12, 95% CI: [1.32, 3.56]), and computer literacy (AOR =1.64, 95% CI: [0.99, 2.68]) were significantly associated with the readiness for EMR system. CONCLUSIONS: In this study, the overall health professionals' readiness for electronic medical record system and utilization was 54.1% and 46.5%, respectively. Gender, knowledge, attitude, and computer related skills were the determinants of the presence of a relatively low readiness and utilization of the system. Increasing awareness, knowledge, and skills of healthcare professionals on EMR system before system implementation is necessary to increase its adoption. PMID- 25495758 TI - Photolysis of phenylalanine in the presence of oxidized carbon nanotubes. AB - Photolyses at 254 nm of phenylalanine (Phe) in aqueous solutions, were carried out in the presence of oxidized carbon nanotubes modified by the reaction with SO2 (mNTO). Kinetics of the photolyses were followed by UV spectrophotometry at 220 nm, and the products were characterized by HPLC, XPS, and (13)C-SSNMR. The ratio of the initial rates of photolysis in the presence and absence of mNTO, k*/ko*, showed a systematic decrease. The photolytic decay of Phe occurs with minor formation of tyrosine. The mass of nanotubes produced an exponential attenuation of the photolytic decomposition of Phe. Total carbon analyses (TCA) showed no inorganic carbon formation after the photolyses. The first-order rate constant of photofunctionalization of mNTO by the insertion of phenylalanine onto the nanotube matrix was calculated from TCA to be kin = 30.1 min(-1). Comparison of the XPS spectra of the mNTO before and after the photolysis, using the atom inventory technique, suggests the insertion of Phe along with the extrusion of a sulfide radical anion ((*)S(-)) which undergo subsequent oxidation to SO4(2-). The obtained results show the effects of mNTO on the photolysis of Phe and provide a new method of photofunctionalization of carbon materials, modified by the intermediates of the reduction of SO2, with an organic moiety. PMID- 25495759 TI - The influence of childhood traffic-related air pollution exposure on asthma, allergy and sensitization: a systematic review and a meta-analysis of birth cohort studies. AB - The impact of early childhood traffic-related air pollution (TRAP) exposure on development of asthma and allergies remains unclear. Birth cohort studies are the best available study design to answer this question, but the evidence from such studies has not been synthesized to date. We conducted a systematic review and meta-analyses of published birth cohort studies to understand the association between early childhood TRAP exposure, and subsequent asthma, allergies and sensitization. Increased longitudinal childhood exposure to PM2.5 and black carbon was associated with increasing risk of subsequent asthma in childhood (PM2.5 : OR 1.14, 95%CI 1.00 to 1.30 per 2 MUg/m(3) and black carbon: OR 1.20, 95%CI 1.05 to 1.38 per 1 * 10(-5) m(-1) ). Also, early childhood exposure to TRAP was associated with development of asthma across childhood up to 12 years of age. The magnitude of these associations increased with age, and the pattern was prominent for PM2.5 . Increasing exposure to PM2.5 was associated with sensitization to both aero- and food allergens. There was some evidence that TRAP was associated with eczema and hay fever. In summary, exposure to TRAP was related to asthma and allergic diseases. However, the substantial variability across studies warrants long-term birth cohort studies with regular repeated follow-ups to confirm these findings. PMID- 25495760 TI - Polymeric micelles encapsulating fisetin improve the therapeutic effect in colon cancer. AB - The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) was discovered to possess antitumor activity, revealing its potential value in future chemotherapy. However, its poor water solubility makes it difficult for intravenous administration. In this study, the monomethyl poly(ethylene glycol)-poly(epsilon caprolactone) (MPEG-PCL) copolymer was applied to prepare nanoassemblies of fisetin by a self-assembly procedure. The prepared fisetin micelles gained a mean particle size of 22 +/- 3 nm, polydisperse index of 0.163 +/- 0.032, drug loading of 9.88 +/- 0.14%, and encapsulation efficiency of 98.53 +/- 0.02%. Compared with free fisetin, fisetin micelles demonstrated a sustained and prolonged in vitro release behavior, as well as enhanced cytotoxicity, cellular uptake, and fisetin induced apoptosis in CT26 cells. As for in vivo studies, fisetin micelles were more competent for suppressing tumor growth and prolonging survival time than free fisetin in the subcutaneous CT26 tumor model. Furthermore, histological analysis, terminal deoxynucleotidyl transferase-mediated nick-end labeling assay, immunohistochemical detection of Ki-67, and microvessel density detection were conducted, demonstrating that fisetin micelles gained increased tumor apoptosis induction, proliferation suppression, and antiangiogenesis activities. In conclusion, we have successfully produced a MPEG-PCL-based nanocarrier encapsulating fisetin with enhanced antitumor activity. PMID- 25495761 TI - The relative importance of avoidance and restoration-oriented stressors for grief and depression in bereaved parents. AB - Previous research has identified a number of individual risk factors for parental bereavement including the sex of the parent, the sex of the child, avoidance focussed coping style and time since death. These factors emerged from research where variables were tested univariately and their relative importance is currently unknown. The current research, therefore, aims to investigate which risk factors are important, multivariately, for the outcomes of grief and depression in parents following the death of their child. Psychosocial measures were completed by 106 bereaved parents four years post-loss, recruited from death records in Scotland. The cause of the child's death included long-term illness and stillbirths as well as sudden and violent deaths. In multivariate regression analyses, depression was predicted by higher avoidance-focussed coping and higher number of restoration-oriented stressors such as relationship difficulties, problems at work and financial issues. Grief was predicted by higher avoidance, restoration stressors and level of continuing bonds. The present study adds to the knowledge about the phenomenon of parental bereavement with participants recruited directly from death records rather than through support, clinical or obituary sources. Factors previously found to be associated with outcomes when tested univariately such as sudden, violent death or sex of the parent were not significant when tested multivariately. This study highlights that different vulnerability factors exist for grief and depression in bereaved parents. PMID- 25495762 TI - The Effect of Systemic Tamsulosin Hydrochloride on Choroidal Thickness Measured by Enhanced Depth Imaging Spectral Domain Optical Coherence Tomography. AB - BACKGROUND: To evaluate the effects of selective alpha1A-adrenoceptor antagonist tamsulosin hydrochloride on choroidal thickness using enhanced depth imaging spectral-domain optical coherence tomography (EDI-OCT). METHODS: This is a prospective observational study including 29 eyes of 29 patients with newly diagnosed benign prostatic hyperplasia. Choroidal thickness and retrobulbar ocular blood flow measurements were performed at baseline and after 3 months of treatment. Results were analyzed by the masked observer. RESULTS: The mean subfoveal choroidal thickness (275.8-291.9 um) and thicknesses 750 um nasal (257.9-270.4 um) and 750 um temporal (262.4-277.0 um) to the fovea were significantly increased after 3 months of treatment (p < 0.001). No statistically significant change was found in retrobulbar ocular blood flow. CONCLUSIONS: Tamsulosin causes a significant increase in EDI-OCT-based choroidal thickness measurements. This increase might be associated with choroidal vasodilation in consequence of blockade of sympathetic alpha1A-adrenoceptors, which is critical for the maintenance of vascular tone and resistance in the choroidal vascular architecture. This should be kept in mind when choroidal disease and its response to treatment are followed by EDI-OCT imaging. PMID- 25495763 TI - Association of dietary fat intake with the risk of hip fractures in an elderly Chinese population: A matched case-control study. AB - AIM: The aim of the present study was to examine the association between dietary fat intake and the risk of hip fractures in an elderly Chinese population. METHODS: A case-control study of 646 patients with newly diagnosed hip fractures and 646 controls, matched by age (+/-3 years) and sex, was carried out among elderly Chinese (55-80 years) in Guangdong, China. Their dietary fat intake was measured and calculated using a 79-item food-frequency questionnaire. RESULTS: After adjusting for potential confounders, a dose-dependent increased risk of hip fractures was found to be associated with higher intakes of total fat, animal fat, saturated fatty acids and mono-unsaturated fatty acids (P for trend < 0.005). The adjusted odds ratios (95% confidence intervals) for hip fractures from a comparison of extreme quartiles were 1.92 (1.26-2.92) for total fat, 2.60 (1.70-3.99) for animal fat, 1.95 (1.30-2.93) for saturated fatty acids and 2.22 (1.46-3.39) for animal mono-unsaturated fatty acids, respectively. No significant association was observed for plant fat or polyunsaturated fatty acids (P for trend = 0.063 for plant fat and 0.174 for polyunsaturated fatty acids). CONCLUSIONS: Our findings suggest that higher consumption of total fat and animal fat rich in saturated fatty acids might increase the risk of hip fractures in elderly Chinese. PMID- 25495765 TI - Possible association between actinic keratosis and the rs7208422 (c.917A->T, p.N306l) polymorphism of the EVER2 gene in patients without epidermodysplasia verruciformis. AB - BACKGROUND: Mutations of the EVER1 and EVER2 genes cause epidermodysplasia verruciformis (EV), a genodermatosis associated with squamous cell carcinoma (SCC). Recently, it has been found that the rs7208422 (c.917A->T, p.N306l) polymorphism in the EVER2 gene is related to an increased risk of SCC in patients with conditions other than EV. We hypothesized that this polymorphism might be also associated with actinic keratoses (AK). AIM: To determine whether the rs7208422 polymorphism of the EVER2 gene is associated with AK in non-EV patients. METHODS: We genotyped rs7208422 in 65 patients with AK and 274 controls, using reverse transcription PCR. RESULTS: We detected a trend towards an association between AK and the TT genotype of rs7208422; the frequency of this genotype was 38.5% in patients with AK and 26.3% in controls (OR = 1.75, P < 0.06 for recessive model of inheritance). We also found an association between rs7208422 TT and both the age at which AK appeared and the extent of the AK. This variant was more frequent in patients who had AK onset before the age of 70 years compared with those whose age of onset was above 70 years (OR = 3.14, P = 0.03 for the recessive model; OR = 2.05, P = 0.04 for allelic comparison) and more frequent in AK involving > 3 body areas (OR = 3.14, P = 0.03 for the recessive model; OR = 2.34, P = 0.01 for allelic comparison). These associations remained significant in a multivariate regression analysis, showing that both parameters were independently associated with the TT genotype (P = 0.031). CONCLUSIONS: This study indicates a potential role of the rs7208422 (c.917A->T, P.N306l) polymorphism of the EVER2 gene in AK. PMID- 25495764 TI - In vitro amplification of scrapie and chronic wasting disease PrP(res) using baculovirus-expressed recombinant PrP as substrate. AB - Protein misfolding cyclic amplification (PMCA) is an in vitro simulation of prion replication, which relies on the use of normal brain homogenate derived from host species as substrate for the specific amplification of abnormal prion protein, PrP(Sc). Studies showed that recombinant cellular PrP, PrP(C), expressed in Escherichia coli lacks N-glycosylation and an glycophosphatidyl inositol anchor (GPI) and therefore may not be the most suitable substrate in seeded PMCA reactions to recapitulate prion conversion in vitro. In this study, we expressed 2 PRNP genotypes of sheep, V136L141R154Q171 and A136F141R154Q171, and one genotype of white-tailed deer (Q95G96, X132,Y216) using the baculovirus expression system and evaluated their suitability as substrates in seeded-PMCA. It has been reported that host-encoded mammalian RNA molecules and divalent cations play a role in the pathogenesis of prion diseases, and RNA molecules have also been shown to improve the sensitivity of PMCA assays. Therefore, we also assessed the effect of co-factors, such as prion-specific mRNA molecules and a divalent cation, manganese, on protein conversion. Here, we report that baculovirus-expressed recombinant PrP(C) shows a glycoform and GPI-anchor profile similar to mammalian brain-derived PrP(C) and supports amplification of PrP(Sc) and PrP(CWD) derived from prion-affected animals in a single round of seeded PMCA in the absence of exogenous co-factors. Addition of species-specific in vitro transcribed PrP mRNA molecules stimulated the conversion efficiency resulting in increased PrP(Sc) or PrP(CWD) production. Addition of 2 to 20 MUM of manganese chloride (MnCl2) to unseeded PMCA resulted in conversion of recombinant PrP(C) to protease-resistant PrP. Collectively, we demonstrate, for the first time, that baculovirus expressed sheep and deer PrP can serve as a substrate in protein misfolding cyclic amplification for sheep and deer prions in the absence of additional exogenous co-factors. PMID- 25495766 TI - Short communication: The Veterans Aging Cohort Study Index is an effective tool to assess baseline frailty status in a contemporary cohort of HIV-infected persons. AB - The Veterans Aging Cohort Study (VACS) Index has previously been used to identify frail HIV-infected persons. However, data demonstrating the independent association between the VACS Index and baseline frailty status is lacking. Furthermore, the ability of the VACS Index to also reflect transitions in frailty status over time is unknown. We used data from the Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN Study) to determine independent association of baseline frailty status with the VACS Index. We also evaluated VACS Index changes with frailty status transitions over time. We included 303 participants (median age 48 years, 76% men, 57% non-Hispanic white, 91% with plasma HIV RNA <400 copies/ml, and median CD4(+) cell count 595 cells/ml) with baseline and follow-up frailty assessments and used the Fried's criteria to define frailty status. There were 184 (61%) nonfrail, 112 (37%) prefrail, and seven (2%) frail participants at baseline. Prefrail/frail participants had significantly higher median VACS Index scores compared with nonfrail participants (18 versus 10, p<0.001). In multivariable analysis, prefrailty/frailty was independently associated with a higher VACS Index score (odds ratio 1.025, p=0.019). After a median follow-up of 12 months, participants who remained prefrail/frail compared to those who remained nonfrail continued to have higher median VACS Index scores. The VACS Index score did not significantly change with transitions in frailty status over time. Our study highlights the potential utility of the VACS Index in frailty assessment within the clinical setting. PMID- 25495768 TI - Hyperkyphosis and back pain are not associated with prevalent vertebral fractures in women with osteoporosis. AB - Vertebral fractures (VFs) are the clinical consequence of spinal osteoporosis and may be associated with back pain and aggravated kyphosis. However, the relative importance of VFs as an underlying cause of kyphosis and chronic back pain is not known. The aim of this study was to investigate the relationship between prevalent VFs and the size of kyphosis, and back pain in osteoporotic women. Thirty-six women, aged 74.6 +/- 8.3 years, were consecutively recruited from the osteoporosis unit at Uppsala University Hospital. The patients had 1-9 radiographic verified VFs. Tragus wall distance (TWD) and numeric rating scale were used to measure kyphosis and pain. All patients had a hyperkyphosis (TWD >= 10 cm). Notably, there were no associations between numbers or location of VFs versus size of kyphosis (rho = 0.15, p = 0.4; rho = -0.27, p = 0.12) or severity of back pain (rho = -0.08, p = 0.66; rho = 0.16, p = 0.35). Furthermore, no association was evident between kyphosis and back pain (rho = -0.02, p = 0.89). There was, however, an association between size of kyphosis and age (R = 0.44, p = 0.008). In conclusion, these data suggest that prevalent VFs are not significantly associated with kyphosis or chronic back pain, in patients with manifest spinal osteoporosis. PMID- 25495767 TI - Effects of FGF10 on bovine oocyte meiosis progression, apoptosis, embryo development and relative abundance of developmentally important genes in vitro. AB - Fibroblast growth factor (FGF10) acts at the cumulus oocyte complex, increasing the expression of cumulus cell expansion-related genes and oocyte competency genes. We tested the hypothesis that addition of FGF10 to the maturation medium improves oocyte maturation, decreases the percentage of apoptotic oocytes and increases development to the blastocyst stage while increasing the relative abundance of developmentally important genes (COX2, CDX2 and PLAC8). In all experiments, oocytes were matured for 22 h in TCM-199 supplemented with 0, 2.5, 10 or 50 ng/ml FGF10. In Experiment 1, after maturation, oocytes were stained with Hoechst to evaluate meiosis progression (metaphase I, intermediary phases and extrusion of the first polar body) and submitted to the TUNEL assay to evaluate apoptosis. In Experiment 2, oocytes were fertilized and cultured to the blastocyst stage. Blastocysts were frozen for analysis of COX2, CDX2 and PLAC8 relative abundance. In Experiment 1, 2.5 ng/ml FGF10 increased (p < 0.05) the percentage of oocytes with extrusion of the first polar body (35%) compared to 0, 10 and 50 ng/ml FGF10 (21, 14 and 12%, respectively) and FGF10 decreased the percentage of oocytes that were TUNEL positive in all doses studied. In Experiment 2, there was no difference in the percentage of oocytes becoming blastocysts between treatments and control. Real-time RT-PCR showed a tendency of 50 ng/ml FGF10 to increase the relative abundance of COX2 and PLAC8 and of 10 ng/ml FGF10 to increase CDX2. In conclusion, the addition of FGF10 to the oocyte maturation medium improves oocyte maturation in vitro, decreases the percentage of apoptotic oocytes and tends to increase the relative abundance of developmentally important genes. PMID- 25495769 TI - A randomized clinical trial comparing pulsed ultrasound and erythromycin phonophoresis in the treatment of patients with chronic rhinosinusitis. AB - Therapeutic ultrasound, an important physiotherapy modality, has been used successfully in the treatment of patients with chronic rhinosinusitis (CRS). No study has compared pulsed ultrasound (PUS) with erythromycin phonophoresis (EP). The aim of this randomized, double-blind, parallel group study with concealed allocation was to compare PUS with EP. Sixty CRS patients were randomly allocated into two groups. Group 1 had PUS and Group 2 had EP. Patients were treated 3 days a week for 10 sessions over 4 weeks. The severity of nine CRS symptoms was self rated by patients on an ordinal scale of 0-3 (absent, mild, moderate or severe) at baseline and after the 10th treatment session. Individual symptom scores were summed to obtain a "Total Symptom Score" (TSS). The outcome measure included percentage improvement in the TSS. A statistically significant improvement in TSS occurred with both PUS and EP therapy groups (p < 0.05). The percentage improvement in the EP group was statistically greater than in the PUS group (67.2 versus 49.3%) (p = 0.03). The effect sizes in both therapy groups were large; PUS: d = 1.36 and EP: d = 2.15. EP was found to be superior over PUS therapy. PMID- 25495770 TI - Executive Function Performance for Children With Epilepsy Localized to the Frontal or Temporal Lobes. AB - Research with adults with epilepsy consistently indicates deficits in executive function (EF). There is less research specific to children with epilepsy and EF. The purpose of this study was to consider EF deficits in children with complex partial epilepsy and complex partial with secondary generalization epilepsy with onset localized to the frontal or temporal lobes. This was a retrospective study of 28 children followed in an outpatient pediatric epilepsy clinic who were consecutively referred for neuropsychological assessment, which included measures of EF. The sample was predominantly White and male, with a mean age of 12.88 years (SD = 1.64) and mean cognitive ability of 89.39 (SD = 13.41). Comparison of right-temporal, left-temporal, and frontal groups yielded significant differences (p = .01) between the left-temporal and frontal groups on the Wisconsin Card Sorting Test (WCST) Categories with the frontal group demonstrating the greatest deficits. Although mean differences were not significant, the frequency of impaired performance by the frontal group on the Attention/Concentration Index was greater than in the temporal groups. Results indicate that for children with complex partial and complex partial with secondary generalized seizures localized to the frontal and temporal lobes, there is an increased likelihood for impaired EF evident on the WCST, but not on others. Implications of these findings for prevention and intervention are discussed. PMID- 25495772 TI - Local IgE in non-allergic rhinitis. AB - Local allergic rhinitis (LAR) is characterized by the presence of a nasal Th2 inflammatory response with local production of specific IgE antibodies and a positive response to a nasal allergen provocation test (NAPT) without evidence of systemic atopy. The prevalence has been shown to be up to 25% in subjects affected with rhinitis with persistence, comorbidity and evolution similar to allergic rhinitis. LAR is a consistent entity that does not evolve to allergic rhinitis with systemic atopy over time although patients have significant impairment in quality of life and increase in the severity of nasal symptoms over time. Lower airways can be also involved. The diagnosis of LAR is based mostly on demonstration of positive response to NAPT and/or local synthesis of specific IgE. Allergens involved include seasonal or perennial such as house dusts mites, pollens, animal epithelia, moulds (alternaria) and others. Basophils from peripheral blood may be activated by the involved allergens suggesting the spill over of locally synthesized specific IgE to the circulation. LAR patients will benefit from the same treatment as allergic patients using antihistamines, inhaled corticosteroids and IgE antagonists. Studies on immunotherapy are ongoing and will determine its efficacy in LAR in terms of symptoms improvement and evolution of the natural course of the disease. PMID- 25495771 TI - Pulsed direct and constant direct currents in the pilocarpine iontophoresis sweat chloride test. AB - BACKGROUND: The classic sweat test (CST) is the golden standard for cystic fibrosis (CF) diagnosis. Then, our aim was compare the production and volume of sweat, and side effects caused by pulsed direct current (PDC) and constant direct current (CDC). To determine the optimal stimulation time (ST) for the sweat collection. To verify the PDC as CF diagnosis option. METHODS: Prospective study with cross-sectional experimental intervention. Experiment 1 (right arm): PDC and CDC. ST at 10 min and sweat collected at 30 min. Currents of 0.5; 0.75; 1.0 and 1.5 mA and frequencies of 0, 200, 1,000 and 5,000 Hz applied. Experiment 2 (left arm): current of 1.0 mA, ST at 5 and 10 min and sweat collected at 15 and 30 min with frequencies of 0; 200; 1,000 and 5,000 Hz applied Experiments 1 and 2 were performed with current density (CD) from 0.07 to 0.21 mA/cm2. Experiment 3: PDC was used in typical CF patients with two CFTR mutations screened and or with CF diagnosis by rectal biopsy and patients with atypical CF. RESULTS: 48 subjects (79.16% female) with average of 29.54 +/- 8.87 years old were enrolled. There was no statistical difference between the interaction of frequency and current in the sweat weight (p = 0.7488). Individually, positive association was achieved between weight sweat and stimulation frequency (p = 0.0088); and current (p = 0.0025). The sweat production was higher for 10 min of stimulation (p = 0.0023). The sweat collection was better for 30 min (p = 0.0019). The skin impedance was not influenced by ST and sweat collection (p > 0.05). The current frequency was inversely associated with the skin impedance (p < 0.0001). The skin temperature measured before stimulation was higher than after (p < 0.0001). In Experiment 3 (29 subjects) the PDC showed better kappa index compared to CDC (0.9218 versus 0.5205, respectively). CONCLUSIONS: The performance of the CST with CDC and PDC with CD of 0.14 to 0.21 mA/cm2 showed efficacy in steps of stimulation and collection of sweat, without side effects. The optimal stimulation time and sweat collection were, respectively, 10 and 30 min. PMID- 25495773 TI - Acquired von Willebrand syndrome in paediatric patients with congenital heart disease: challenges in the diagnosis and management of this rare condition. PMID- 25495774 TI - Rett syndrome: establishing a novel outcome measure for walking activity in an era of clinical trials for rare disorders. AB - BACKGROUND: Rett syndrome is a pervasive neurological disorder with impaired gait as one criterion. This study investigated the capacity of three accelerometer type devices to measure walking activity in Rett syndrome. METHODS: Twenty-six participants (mean 18 years, SD 8) wore an Actigraph, ActivPAL and StepWatch Activity Monitor (SAM) during a video-taped session of activities. Agreement was determined between step-counts derived from each accelerometer and observation. Repeatability of SAM-derived step counts was determined using pairs of one-minute epochs during which the same participant was observed to walk with the same cadence. RESULTS: The mean difference (limit of agreement) for the Actigraph, ActivPAL and SAM were -41 (SD 33), -16 (SD 21) and -1 (SD 16) steps/min, respectively. Agreement was influenced by a device/cadence interaction (p < 0.001) with greater under-recording at higher cadences. For SAM data, repeatability of step-count pairs was excellent (intraclass correlation coefficient 0.91, 95% CI 0.79-0.96). The standard error of measurement was 6 steps/min and we would be 95% confident that a change >=17 steps/min would be greater than within-subject measurement error. CONCLUSIONS: The capacity of the SAM to measure physical activity in Rett syndrome allows focus on participation based activities in clinical practice and clinical trials. Implications for Rehabilitation Many girls and women with Rett syndrome are able to walk on their own or with assistance but with altered movement patterns. Validated measures of physical activity, such as step counts, have potential to monitor function during daily life. Compared with other forms of accelerometer-type devices, such as ActiGraph and ActivPAL, the StepWatch Activity Monitor (SAM) measured step counts with good accuracy and repeatability. The capacity of the SAM to measure physical activity in Rett syndrome allows focus on participation-based activities in clinical practice and clinical trials. PMID- 25495775 TI - Cost-effectiveness analysis of 5-fluorouracil 0.5%/salicylic acid 10% in the treatment of actinic keratosis in Spain. AB - OBJECTIVE: The aim of this study is to conduct a cost-effectiveness analysis of 5 fluorouracil 0.5%/salicylic acid 10% (5-FU/SA) in the treatment of isolated hyperkeratotic actinic keratosis lesions in Spain. METHODS: An analytical decision-making model was constructed to compare whether 5-FU/SA was a cost effective option compared with cryotherapy from the perspective of the Spanish National Health System with a time horizon of 6 months. Costs were expressed in 2014 euros. RESULTS: The cost of patients with hyperkeratotic actinic keratosis treated with 5-FU/SA or cryotherapy was ?266 and ?285, respectively. 5-FU/SA was associated with higher rates of treatment success and, consequently, more quality adjusted life years, than cryotherapy. Therefore, 5-FU/SA was the dominant treatment, as it was associated with a lower treatment cost and greater effectiveness than cryotherapy. CONCLUSIONS: Economically, 5-FU/SA was a dominant option compared with cryotherapy in the treatment of isolated hyperkeratotic actinic keratosis lesions in Spain. PMID- 25495776 TI - Toward a selective, sensitive, fast-responsive, and biocompatible two-photon probe for hydrogen sulfide in live cells. AB - Hydrogen sulfide has emerged as an exciting endogenous gasotransmitter in addition to nitric oxide and carbon dioxide. Noninvasive detection methods for hydrogen sulfide thus become indispensable tools for studying its diverse roles in biological systems. Accordingly, fluorescent probes for hydrogen sulfide have received great attention in recent years. A practically useful fluorescent probe for bioimaging of hydrogen sulfide should be selective, sensitive, fast responsive, biocompatible, observable in the biological optical window, and capable of deep-tissue imaging. These sensing properties, however, are extremely difficult to achieve at the same time. Disclosed here is the two-photon fluorescent probe that meets all of these criteria. The probe belongs to a Michael acceptor system, which raised a serious selectivity issue over the competing biothiols such as cysteine and glutathione. We have addressed the selectivity issue by optimizing the electronic and steric interactions between biothiols and the probe, in addition to achieving very high sensitivity, fast response, and biocompatibility. Also, the sensing mechanism suggested in the literature was revised. The probe thus enables us to image the endogenously produced hydrogen sulfide with negligible interference from other biothiols in live cells. The excellent sensing properties of the probe combined with its capability of bioimaging thus make it a practically useful tool for further studying biological roles of hydrogen sulfide. PMID- 25495777 TI - Management of dentine hypersensitivity: efficacy of professionally and self administered agents. AB - CONTEXT: The gold standard treatment modality for dentine hypersensitivity has not yet been established. This review examines the effectiveness of self and professionally applied treatments for the reduction in pain from dentine hypersensitivity. MATERIALS AND METHODS: Electronic (three databases) and hand searches were performed 14-21 July 2014 to identify randomized controlled trials for the treatment of dentine hypersensitivity. RESULTS: This systematic review provided numerous treatment modalities for dentine hypersensitivity. Eleven agents and 105 Randomized Controlled Trials were robust enough to be included. The studies varied considerably in design, observation period, active agents, formulation of the whole agent, negative and positive controls and comparator products investigated. The stimuli used were predominantly airblast and tactile or thermal. Due to the heterogeneity between the studies and lack of direct comparison between agents there was insufficient data to undertake a meta analysis to compare agents for meaningful conclusions. Best available evidence for each treatment agent has been documented as a narrative. CONCLUSIONS: Treatments including stannous fluoride, arginine, calcium sodium phosphosilicate and strontium toothpaste appear to be clinically effective for the treatment of dentine hypersensitivity compared to comparators and controls. There is limited evidence to confirm the relative effectiveness of individual professionally applied agents. PMID- 25495778 TI - Lymphoepithelioma-like carcinoma of the bladder: a case report. AB - INTRODUCTION: Lymphoepitheliomas are malignant epithelial tumors of the nasopharynx characterized by an important lymphoid proliferation at histological examination. Lymphoepithelioma-like carcinoma is a rare tumor of the bladder for which the therapeutic strategy is not clearly defined. CASE PRESENTATION: We report the case of a 64-year-old Moroccan man who presented with macroscopic hematuria. Investigations revealed a muscle-invasive lymphoepithelioma-like carcinoma of the bladder. Therefore he underwent a radical cystoprostatectomy with a good outcome. CONCLUSION: This case illustrates pathogenic, clinical and therapeutic features of this unusual tumor. PMID- 25495779 TI - Daptomycin versus linezolid for treatment of vancomycin-resistant enterococcal bacteremia: systematic review and meta-analysis. AB - BACKGROUND: Linezolid, which has bacteriostatic activity, is approved for the treatment of vancomycin-resistant enterococci (VRE) infections. Meanwhile, daptomycin exerts bactericidal activity against VRE, but is not approved for the treatment of VRE bacteremia. Only a few studies with small sample sizes have compared the effectiveness of these drugs for treatment of VRE bacteremia. METHODS: PubMed, EMBASE, and the Cochrane Library were searched for studies of VRE bacteremia treatment published before January 1, 2014. All studies reporting daptomycin and linezolid treatment outcomes simultaneously were included. The endpoints were mortality and microbiological cure. The adjusted odds ratios (aORs) of mortality in daptomycin- and linezolid-treated patients were extracted if available. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for all outcomes using a random-effects model. RESULTS: Thirteen studies (532 patients receiving daptomycin, 656 patients receiving linezolid) met the selection criteria. All studies had retrospective cohort designs and relatively small sample sizes. Eight studies compared the aORs of mortality in daptomycin- and linezolid-treated patients. Four studies were published as conference papers and there was significant heterogeneity among these studies (I2 = 63%, p = 0.04). Daptomycin use was not associated with better microbiological cure (daptomycin vs. linezolid, OR: 0.67, 95% CI: 0.42-1.06, p = 0.09). However, mortality was higher in patients receiving daptomycin (OR: 1.43, 95% CI: 1.09 1.86, p = 0.009). Subgroup analysis of studies that reported aORs indicated that daptomycin was associated with higher mortality (OR: 1.59, 95% CI: 1.02-2.50, p = 0.04). There was no evidence of publication bias, but all enrolled studies were retrospective, had small sample sizes, and had substantial limitations. CONCLUSIONS: Although limited data is available, the current meta-analysis shows that linezolid treatment for VRE bacteremia was associated with a lower mortality than daptomycin treatment. However, the results should be interpreted cautiously because of limitations inherent to retrospective studies and the high heterogeneity among studies. A large randomized trial is needed to confirm the present results. PMID- 25495780 TI - Knockdown of T-bet expression in Mart-127-35 -specific T-cell-receptor-engineered human CD4(+) CD25(-) and CD8(+) T cells attenuates effector function. AB - Gene transfer to create tumour epitope-specific cytolytic T cells for adoptive immunotherapy of cancer remains an area of active inquiry. When the Mart-127-35 specific DMF5 T-cell receptor (TCR) is transferred into peripheral human CD4(+) T cells, the reprogrammed cells exhibit a T helper type 1 (Th1) phenotype with significant multifactorial effector capabilities. The T-bet transcription factor plays an important role in determination of the Th1 differentiation pathway. To gain a deeper understanding of how T-bet controls the outcome of human T-cell reprogramming by gene transfer, we developed a system for examining the effects of short hairpin RNA-mediated T-bet gene knockdown in sorted cell populations uniformly expressing the knockdown construct. In this system, using activated peripheral human CD4(+) CD25(-) and CD8(+) T cells, T-bet knockdown led to attenuation of the interferon-gamma response to both antigen-specific and non specific TCR stimulation. The interleukin-2 (IL-2) antigen-specific response was not attenuated by T-bet knockdown. Also, in TCR-reprogrammed CD8(+) cells, the cytolytic effector response was attenuated by T-bet knockdown. T-bet knockdown did not cause redirection into a Th2 differentiation pathway, and no increased IL 4, IL-10, or IL-17 response was detected in this system. These results indicate that T-bet expression is required for maintenance of the CD4(+) CD25(-) and CD8(+) effector phenotypes in TCR-reprogrammed human T cells. They also suggest that the activation protocol necessary for transduction with retrovectors and lentivectors may commit the reprogrammed cells to the Th1 phenotype, which cannot be altered by T-bet knockdown but that there is, nevertheless, a continuous requirement of T-bet expression for interferon-gamma gene activation. PMID- 25495782 TI - Contributions of lower extremity kinematics to trunk accelerations during moderate treadmill running. AB - BACKGROUND: Trunk accelerations during running provide useful information about movement economy and injury risk. However, there is a lack of data regarding the key biomechanical contributors to these accelerations. The purpose was to establish the biomechanical variables associated with root mean square (RMS) accelerations of the trunk. METHODS: Eighteen healthy males (24.0 +/- 4.2 yr; 1.78 +/- 0.07 m; 79.7 +/- 14.8 kg) performed treadmill running with high resolution accelerometer measurement at the lumbar spine and full-body optical motion capture. We collected 60 sec of data at three speeds (2.22, 2.78, 3.33 m ? s(-1)). RMS was calculated for medio-lateral (ML), anterio-posterior (AP), vertical (VT), and the resultant Euclidean scalar (RES) acceleration. From motion capture, we calculated 14 kinematic variables, including mean sagittal plane joint angles at foot contact, mid-stance, and toe-off. Principal components analysis (PCA) was used to form independent components comprised of combinations of the original variables. Stepwise regressions were performed on the original variables and the components to determine contributions to RMS acceleration in each axis. RESULTS: Significant speed effects were found for RMS-accelerations in all axes (p < 0.05). Regressions of the original variables indicated from 4 to 5 variables associated with accelerations in each axis (R2 = 0.71 to 0.82, p < 0.001). The most prominent contributing variables were associated with the late flight and early stance phase. PCA reduced the data into four components. Component 1 included all hip angles before mid-stance and component 2 was primarily associated with propulsion. Regressions indicated key contributions from components 1 and 2 to ML, VT, and RES acceleration (p < 0.05). CONCLUSIONS: The variables with highest contribution were prior to mid-stance and mechanically relate to shock absorption and attenuation of peak forces. Trunk acceleration magnitude is associated with global running variables, ranging from energy expenditure to forces lending to the mechanics of injury. These data begin to delineate running gait events and offer relationships of running mechanics to those structures more proximal in the kinetic chain. These relationships may provide insight for technique modification to maximize running economy or prevent injury. PMID- 25495783 TI - Chemical composition, antimicrobial and insecticidal activities of the essential oils of Conyza linifolia and Chenopodium ambrosioides. AB - Two essential oil-containing plants growing wildly in Egypt: Conyza linifolia (Willd.) Tackh. (Asteraceae) and Chenopodium ambrosioides L. (Chenopodiaceae) were subjected to essential oil analysis and biological investigation. The essential oils from both plants were prepared by hydrodistillation, and GC/MS was employed for volatiles profiling. This study is the first to perform GC/MS analysis of C. linifolia essential oil growing in Egypt. C. linifolia essential oil contained mainly sesquiterpenes, while that of C. ambrosioides was rich in monoterpenes. Ascaridole, previously identified as the major component of the latter, was found at much lower levels. In addition, the oils were investigated for their antimicrobial activity against two Gram positive and two Gram negative bacteria, and one fungus. The insecticidal activities of both oils, including mosquitocidal and pesticidal potentials, were also evaluated. The results of biological activities encourage further investigation of the two oils as antimicrobial and insecticidal agents of natural origin. PMID- 25495781 TI - Flower development and sex specification in wild grapevine. AB - BACKGROUND: Wild plants of Vitis closely related to the cultivated grapevine (V. v. vinifera) are believed to have been first domesticated 10,000 years BC around the Caspian Sea. V. v. vinifera is hermaphrodite whereas V. v. sylvestris is a dioecious species. Male flowers show a reduced pistil without style or stigma and female flowers present reflexed stamens with infertile pollen. V. vinifera produce perfect flowers with all functional structures. The mechanism for flower sex determination and specification in grapevine is still unknown. RESULTS: To understand which genes are involved during the establishment of male, female and complete flowers, we analysed and compared the transcription profiles of four developmental stages of the three genders. We showed that sex determination is a late event during flower development and that the expression of genes from the ABCDE model is not directly correlated with the establishment of sexual dimorphism. We propose a temporal comprehensive model in which two mutations in two linked genes could be players in sex determination and indirectly establish the Vitis domestication process. Additionally, we also found clusters of genes differentially expressed between genders and between developmental stages that suggest a role involved in sex differentiation. Also, the detection of differentially transcribed regions that extended existing gene models (intergenic regions) between sexes suggests that they may account for some of the variation between the subspecies. CONCLUSIONS: There is no evidence of differences of expression levels in genes from the ABCDE model that could explain the shift from hermaphroditism to dioecy. We propose that sex specification occurs after floral organ identity has been established and therefore, sex determination genes might be having an effect downstream of the ABCDE model genes.For the first time a full transcriptomic analysis was performed in different flower developmental stages in the same individual. Our experimental approach enabled us to create a comprehensive catalogue of transcribed genes across developmental stages and genders that will contribute for future work in sex determination in seed plants. PMID- 25495784 TI - UVA irradiation of the eye modulates the contact hypersensitivity of the skin and intestines by affecting mast cells in mice. AB - BACKGROUND: Ultraviolet A (UVA) irradiation before allergic sensitization induces immunosuppression, but the precise mechanism remained unclear. In this study, we examined the influence of UVA irradiation of the eye on contact hypersensitivity (CHS) and the role of mast cells in CHS. METHODS: We used two types of haptens, fluorescein isothiocyanate (FITC: a Th2 type hapten) and 4-ethoxymethylene-2 phenyl-2-oxazolin-5-one (oxazolone: a Th1 type hapten). A 300 kJ/m(2) dose of UVA irradiation was delivered to the eyes. After UVA irradiation, we sensitized abdominal shaved skin and challenged the ear epidermis and colons of these mice with each hapten. RESULTS: After UVA irradiation, the CHS of the skin and colon were not inhibited in the FITC-sensitized mice. However, in the oxazolone sensitized mice, only the CHS of the skin was inhibited by UVA irradiation. The inflammation of the colon became more severe after UVA irradiation. In mast cell deficient (W/Wv) mice sensitized to FITC, the CHS was weaker than that in WT mice. Moreover, the reduction of immunosuppression in ear swelling was seen for one of the two models they used. CONCLUSIONS: These results suggest that the mast cells induced by UVA irradiation of the eye have different roles in the epidermis and colon and have different responses to different haptens. PMID- 25495785 TI - Metronomic oral cyclophosphamide (MOC) in the salvage therapy of heavily treated recurrent ovarian cancer patients: a retrospective, multicenter study. AB - BACKGROUND: The aim of this multicenter, retrospective study was to evaluate the efficacy and safety of metronomic oral cyclophosphamide (MOC) in heavily treated, relapsed ovarian cancer (ROC) patients. METHODS: oral cyclophosphamide (Endoxan(r), Baxter, Italy) was administered at the dose of 50 mg daily, continuously. Treatment-related toxicity and response to treatment were assessed by the NCI-CTC criteria, and RECIST criteria, respectively. Progression-free (PFS), and overall survival (OS) were also assessed. RESULTS: 54 patients were analyzed: 20 patients (37.0%) were considered primarily platinum refractory/resistant, while 34 patients (63.0%) were defined as platinum sensitive; 79.6% of patients had received >=2 previous lines before starting MOC. The objective response rate (ORR) was 20.4%. Eleven patients (20.4%) experienced stable disease and 8 of them had a response duration >=6 months. A total of 32 patients (59.2.%) progressed during treatment. Median PFS was 4 months, and the 12-month PFS rate was 19.6%; median OS was 13 months, and the 12-month OS rate was 51.5% . Patients responding to MOC showed a more favorable PFS (median = 17 months) compared to patients with stabilization (median = 6 months) or progression of disease (median = 3 months) (p value = 0.0001). Median OS of responding patients was 30 months compared to 11 months in cases achieving stabilization, or progression of disease (median = 8 months) (p value = 0.0001). Only 1 patient experienced grade 3 anemia. Non-hematological grade 3 toxicity was registered in 2 patients. CONCLUSIONS: MOC could provide a valid alternative in terms of risk/benefit ratio in the palliative treatment of heavily treated ROC patients. PMID- 25495786 TI - Long-term seizure outcome in 211 patients with focal cortical dysplasia. AB - OBJECTIVE: Focal cortical dysplasia (FCD) is currently recognized as the most common cause of neocortical pharmacoresistant epilepsy. Epilepsy surgery has become an increasingly successful treatment option. Herein, the largest patient cohort reported to date is analyzed regarding long-term outcome and factors relevant for long-term seizure control. METHODS: Two hundred eleven children and adults undergoing epilepsy surgery for histologically proven FCD and a follow-up period of 2-12 years were analyzed regarding the longitudinal course of seizure control, effects of FCD type, localization, magnetic resonance imaging (MRI), timing of surgery, and postoperative antiepileptic treatment. RESULTS: After 1 year, Engel class I outcome was achieved in 65% of patients and the percentage of seizure-free patients remained stable over the following (up to 12) years. Complete resection of the assumed epileptogenic area, lower age at surgery, and unilobar localization were positive prognostic indicators of long-term seizure freedom. Seizure recurrence was 12% after the first year, whereas 8% achieved late seizure freedom either following additional introduction of antiepileptic drugs (AEDs) (4%), a reoperation (2%), or a running down phenomenon (2%). Thirty nine percent of patients had a reduction of AED from polytherapy to monotherapy or a complete cessation of AED treatment. Late seizure relapse was seen in nine patients during reduction of AEDs (i.e., in 12% of all patients with AED tapering); in four of them seizures persisted after reestablishment of antiepileptic medication. SIGNIFICANCE: Postoperative long-term seizure outcome was favorable in patients with FCD and remained stable in 80% of patients after the first postoperative year. Several preoperative factors revealed to be predictive for the postoperative outcome and may help in the preoperative counseling of patients with FCD and in the selection of ideal candidates for epilepsy surgery. PMID- 25495787 TI - The Editor's swan song. PMID- 25495789 TI - Profiling and relative quantitation of phosphoinositides by multiple precursor ion scanning based on phosphate methylation and isotopic labeling. AB - Phosphoinositides, the phosphorylated derivatives of phosphatidylinositol (PtdIns), are key regulators of many fundamental biological processes, including cell growth, proliferation, and motility. Here, we present a novel method for rapid, sensitive, and simultaneous profiling of phosphatidylinositol trisphosphate (PtdInsP3), phosphatidylinositol bisphosphate (PtdInsP2), and phosphatidylinositol phosphate (PtdInsP) of different fatty acid compositions. This method is based on a technique called "charged diacylglycerol fragment ion specific multiple precursor ion scanning" (DAG(+)-specific MPIS), coupled with prior phosphate methylation. Using DAG(+)-specific MPIS, we were able to identify 32 PtdIns, 28 PtdInsP, 30 PtdInsP2, and 3 PtdInsP3 molecular species from bovine brain extracts or prostatic cancer cell lines in an efficient and time-saving manner. Our analysis revealed a large range of fatty acyl compositions in phosphoinositides not obtained previously from mammalian samples. We also developed a method that involves isotopic labeling of endogenous phosphoinositides with deuterated diazomethane (CD2N2) for quantitation of phosphoinositides. CD2N2 was generated in situ through acid-catalyzed H/D exchange and methanolysis of trimethylsilyl diazomethane (TMS-diazomethane). Phosphoinositides, extracted from a PC3 prostatic cancer cell line, were labeled either with CH2N2 or CD2N2 and mixed in known proportions for DAG(+)-specific MPIS-based mass spectrometry (MS) analysis. The results indicate that isotopic labeling is capable of providing accurate quantitation of PtdInsP3, PtdInsP2, and PtdInsP with adequate linearity as well as high reproducibility with an average coefficient variation of 18.9%. More importantly, this new methods excluded the need for multiple phosphoinositide internal standards. DAG(+)-specific MPIS and isotopic labeling based MS analysis of phosphoinositides offers unique advantages over existing approaches and presents a powerful tool for research of phosphoinositide metabolism. PMID- 25495790 TI - A curated review of recent literature of biomarkers used for assessing air pollution exposures and effects in humans. AB - This is a cross-sectional review of biomarkers used in air pollution research from January 2009 through December 2012. After an initial keyword search in PubMed retrieving 426 articles, a comprehensive abstract review identified 54 articles of experimental design that used biomarkers of exposure or effect in human studies in the area of air pollution research during this specified time period. A thorough bibliographic search of the included articles retrieved an additional 65 articles meeting the inclusion criteria. This review presents these 119 studies and the 234 biomarkers employed in these air pollution research investigations. Data presented are 70 biomarkers of exposure with 54% relating to polycyclic aromatic hydrocarbons, 36% volatile organic carbons, and 10% classified as other. Of the 164 biomarkers of effect, 91 and 130 were used in investigating effects of short-term and chronic exposure, respectively. Results of biomarkers used in short-term exposure describe different lag times and pollutant components such as primary and secondary pollutants, and particle number associated with corresponding physiological mechanisms including airway inflammation, neuroinflammation, ocular, metabolic, early endothelial dysfunction, coagulation, atherosclerosis, autonomic nervous system, oxidative stress, and DNA damage. The review presents three different exposure scenarios of chronic, occupational, and extreme exposure scenarios (indoor cooking) with associated biomarker findings presented in three broad categories of (1) immune profile, (2) oxidative stress, and (3) DNA damage. This review offers a representation of the scope of data being explored by air pollution researchers through the use of biomarkers and has deliberately been restricted to this particular subject rather than an extensive or in-depth review. This article provides a contextualization of air pollution studies conducted with biomarkers in human subjects in given areas while also integrating this complex body of information to offer a useful review for investigators in this field of study. PMID- 25495791 TI - Pseudomonas aeruginosa keratitis misdiagnosed as fungal keratitis by in vivo confocal microscopy: a case report. AB - BACKGROUND: To report a case of non-typical Pseudomonas aeruginosa keratitis that was misdiagnosed as fungal keratitis by in vivo confocal microscopy. CASE PRESENTATION: A 37-year-old Chinese woman presented with a 2-week history of increasing pain and redness of the right eye. She was started on hourly topical fortified tobramycin and levofloxacin by the referring doctor without improvement. She denied any improvement of her symptoms and signs. On examination, she had a large central corneal ulcer extending to the peripheral cornea. Further symptoms included a satellite lesion, intense conjunctival injection and marked corneal oedema. The corneal scrape was not performed initially because of the deep infiltrate in the stroma. The patient was examined by in vivo confocal microscopy. Confocal microscopy images showed hyper reflective, thin, and branching interlocking linear structures in the stroma that were 5-8 MUm in width and 200-400 MUm in length. The morphology was consistent with that of fungus. However, the histopathological examination, Gram stain, and culture of the cornea only confirmed the presence of a Pseudomonas species within the deep strom. No fungal element was found. The pathogen was sensitive to ciprofloxacin, gentamicin, levofloxacin, tobramycin and amikacin. CONCLUSION: This case reports the potential for a false positive finding of fungus in Pseudomonas aeruginosa keratitis and emphasizes the importance of bacterial culture and antibiotic susceptibility testing in the management of microbial keratitis. PMID- 25495793 TI - Modeling the drug release from hydrogel-based matrices. AB - In this work the behavior of hydrogel-based matrices, the most widespread systems for oral controlled release of pharmaceuticals, has been mathematically described. In addition, the calculations of the model have been validated against a rich set of experimental data obtained working with tablets made of hydroxypropyl methylcellulose (a hydrogel) and theophylline (a model drug). The model takes into account water uptake, hydrogel swelling, drug release, and polymer erosion. The model was obtained as an improvement of a previous code, describing the diffusion in concentrated systems, and obtaining the erosion front (which is a moving boundary) from the polymer mass balance (in this way, the number of fitting parameters was also reduced by one). The proposed model was found able to describe all the observed phenomena, and then it can be considered a tool with predictive capabilities, useful in design and testing of new dosage systems based on hydrogels. PMID- 25495792 TI - PfRON3 is an erythrocyte-binding protein and a potential blood-stage vaccine candidate antigen. AB - BACKGROUND: Erythrocyte invasion by merozoites is an essential step in Plasmodium falciparum infection and leads to subsequent disease pathology. Proteins both on the merozoite surface and secreted from the apical organelles (micronemes, rhoptries and dense granules) mediate the invasion of erythrocytes; some of the molecules have been regarded as targets in the development of an anti-malaria vaccine. Recently, a subgroup of rhoptry neck proteins (PfRON2, PfRON4 and PfRON5) associated with the microneme protein apical membrane antigen AMA1 has been described as components of the moving junction complex that assists merozoite invasion into erythrocytes. However, unlike PfRON2, PfRON4 and PfRON5, the latest study suggested that PfRON3 might be located in the rhoptry bulb and participates in a novel PfRON complex (PfRON2, 3 and 4), but does not form a complex with AMA1. Additionally, the full-length PfRON3 protein possesses three transmembrane regions at the N-terminus, which is highly conserved among RON3 orthologues in the genus Plasmodium, Toxoplasma gondii and Eimeria tenella. Overall, these findings suggest that PfRON3 may play an important role in merozoite invasion into erythrocytes. RESULTS: PfRON3 was primarily expressed during the late trophozoite stage, with a peak in transcription levels at 40 hours post-invasion. The subcellular localization of PfRON3 was confirmed that it is a merozoite rhoptry bulb protein. Additionally, the recombinant form of PfRON3 protein bound to the erythrocyte and was recognized by sera collected from malaria endemic areas in Africa, and anti-PfRON3 antibodies significantly inhibited merozoite invasion into erythrocytes. METHODS: The expression of PfRON3 was analysed via real-time quantitative PCR, and the recombinant PfRON3 proteins were generated with an Escherichia coli expression system. The subcellular localization of PfRON3 was assessed with immunoelectron microscopy and immunofluorescence assay (IFA). The recognition PfRON3 by malaria immune sera was analysed with an enzyme-linked immunosorbent assay (ELISA). Erythrocyte-binding assays were performed using recombinant PfRON3 proteins and invasion inhibition assays were carried out with PfRON3-specific antibodies. CONCLUSION: This study confirmed that PfRON3 is a rhoptry protein with an erythrocyte-binding property, which is likely associated red blood cell invasion. PfRON3 is a potential vaccine candidate. PMID- 25495794 TI - Hepatoprotective effect of fermented ginseng and its major constituent compound K in a rat model of paracetamol (acetaminophen)-induced liver injury. AB - OBJECTIVES: This work aimed at evaluating the effect of fermented ginseng (FG) and fermented red ginseng (FRG) against rat liver injury caused by paracetamol (acetaminophen (APAP)). METHODS: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the serum and histopathological changes in the liver were analysed to determine the degree of liver injury. Deoxyribonucleic acid (DNA) microarray analysis was performed to compare gene expression levels altered in the rat livers. Phosphorylated Jun-N-terminal kinase (JNK) in human hepatocellular carcinoma (HepG2) cells were detected using western blot analysis to investigate the anti-inflammatory activity of compound K. KEY FINDINGS: Pretreatment with FG, containing compound K at high concentration, attenuated AST as well as ALT levels in rats, while no obvious effect was observed in the group that received FRG, whose content of compound K was lower than that of FG. In addition, the results of our histopathological analysis were consistent with changes in the serum biochemical analysis. DNA microarray analysis indicated that JNK- and glutathione S-transferase (GST)-related genes were involved in the hepatotoxicity. Notably, compound K, a major ginsenoside in FG, inhibited the phosphorylation of JNK in HepG2 cells. CONCLUSIONS: FG was shown to possess hepatoprotective activity against paracetamol (APAP)-induced liver injury better than FRG. Compound K might play an important role for an anti-inflammatory activity of FG by inhibiting JNK signalling in the liver. PMID- 25495796 TI - An assessment of HIV treatment outcomes among utilizers of semi-mobile clinics in rural Kenya. AB - HIV/AIDS is a major cause of morbidity and mortality in Africa, and rates of retention in treatment are low. Some research has shown that mobile clinics are effective in connecting people in rural areas with health care. We compared HIV outcomes between HIV-positive patients who chose to access treatment from a regional hospital to those who chose care in one of four semi-mobile clinics closer to where they live. The subjects for this analysis were HIV-positive residents in West Pokot accessing care at one of four semi-mobile sites (Kabichbich, Chepareria, Kacheliba, and Sigor) or at the regional hospital in Kapenguria. We examined four outcome variables between the two groups: (1) retention in HIV treatment, (2) change in CD4 count, (3) adherence to ARVs, and (4) deaths. The patients who chose semi-mobile clinic care were less well educated, poorer, and sicker than those who chose to continue care in the regional hospital. There were no statistically significant differences between the groups in any of the four outcome measures. Although the population of patients attending semi-mobile clinics was on average poorer and sicker than those attending the hospital, their outcomes were similar. Care at the semi mobile clinics did not result in significantly different outcomes from care in the district hospital. This program showed that semi-mobile clinics are a viable alternative to hospital care for very ill, isolated populations, but further measures must be taken to improve retention and adherence in these settings. PMID- 25495795 TI - The pharmacokinetics of a B-domain truncated recombinant factor VIII, turoctocog alfa (NovoEight(r)), in patients with hemophilia A. AB - BACKGROUND: Turoctocog alfa (NovoEight((r))) is a human recombinant coagulation factor VIII (rFVIII) for the treatment of patients with hemophilia A. OBJECTIVES: To evaluate the pharmacokinetics of turoctocog alfa in all age groups across clinical trials. PATIENTS/METHODS: Data from previously treated patients with severe hemophilia A (FVIII activity level of <= 1%) with no history of FVIII inhibitors, in a non-bleeding state, were included. The pharmacokinetics were assessed following a wash-out period and a subsequent single intravenous 50 IU kg(-1) dose of turoctocog alfa. Blood was sampled during a 48-h period postdose. Standard pharmacokinetic (PK) parameters were estimated on the basis of plasma FVIII activity vs. time (PK profiles) with non-compartmental methods. Furthermore, a population PK analysis was conducted. RESULTS: Data from 76 patients (aged 1-60 years) enrolled globally across six clinical trials were included, totaling 105 turoctocog alfa PK profiles. Single-dose PK results 3-6 months after the first dose of turoctocog alfa were comparable with the results obtained after the first dose. Similar PK characteristics were shown for different lots and strengths of the drug product. Overall, area under the plasma concentration (activity) curve from administration to infinity (AUC) and t1(/2) tended to increase with increasing age, with lower AUC and shorter t(1/2) being seen in children than in adolescents and adults. The PK profiles of turoctocog alfa and other commercially available plasma-derived FVIII and rFVIII products were similar in all age groups. CONCLUSIONS: The PK characteristics of turoctocog alfa have been thoroughly studied, and shown to be consistent over time, reproducible between different lots and strengths of drug product, and similar to those observed for other FVIII products. PMID- 25495797 TI - Diterpenes from a Chinese collection of the brown alga Dictyota plectens. AB - Twenty-seven diterpenes of six chemical classes, including seven new diterpenes (1, 2, 6, 10, 11, 16, and 19), have been isolated from a collection of the brown alga Dictyota plectens from the South China Sea. The structures of the new diterpenes were elucidated by extensive spectroscopic analysis and by comparison with reported data. In the in vitro assays, 9, 12, 14, 16, and 22 showed inhibitory activity against HIV-1 replication with IC50 values of 16.1-30.5 MUM, compounds 5, 13, 24, and 26 exhibited anti-H5N1 activity with inhibition rates of 50%-62% at 30.0 MUM, and 12 and 24 also showed potent inhibition against LPS induced NO production with inhibition rates of 90% and 86%, respectively, at 10.0 MUM. PMID- 25495798 TI - Methodology for the inference of gene function from phenotype data. AB - BACKGROUND: Biomedical ontologies are increasingly instrumental in the advancement of biological research primarily through their use to efficiently consolidate large amounts of data into structured, accessible sets. However, ontology development and usage can be hampered by the segregation of knowledge by domain that occurs due to independent development and use of the ontologies. The ability to infer data associated with one ontology to data associated with another ontology would prove useful in expanding information content and scope. We here focus on relating two ontologies: the Gene Ontology (GO), which encodes canonical gene function, and the Mammalian Phenotype Ontology (MP), which describes non-canonical phenotypes, using statistical methods to suggest GO functional annotations from existing MP phenotype annotations. This work is in contrast to previous studies that have focused on inferring gene function from phenotype primarily through lexical or semantic similarity measures. RESULTS: We have designed and tested a set of algorithms that represents a novel methodology to define rules for predicting gene function by examining the emergent structure and relationships between the gene functions and phenotypes rather than inspecting the terms semantically. The algorithms inspect relationships among multiple phenotype terms to deduce if there are cases where they all arise from a single gene function. We apply this methodology to data about genes in the laboratory mouse that are formally represented in the Mouse Genome Informatics (MGI) resource. From the data, 7444 rule instances were generated from five generalized rules, resulting in 4818 unique GO functional predictions for 1796 genes. CONCLUSIONS: We show that our method is capable of inferring high-quality functional annotations from curated phenotype data. As well as creating inferred annotations, our method has the potential to allow for the elucidation of unforeseen, biologically significant associations between gene function and phenotypes that would be overlooked by a semantics-based approach. Future work will include the implementation of the described algorithms for a variety of other model organism databases, taking full advantage of the abundance of available high quality curated data. PMID- 25495799 TI - What currents underlie pulmonary vein automaticity? PMID- 25495800 TI - Spatial localization of the first and last enzymes effectively connects active metabolic pathways in bacteria. AB - BACKGROUND: Although much is understood about the enzymatic cascades that underlie cellular biosynthesis, comparatively little is known about the rules that determine their cellular organization. We performed a detailed analysis of the localization of E.coli GFP-tagged enzymes for cells growing exponentially. RESULTS: We found that out of 857 globular enzymes, at least 219 have a discrete punctuate localization in the cytoplasm and catalyze the first or the last reaction in 60% of biosynthetic pathways. A graph-theoretic analysis of E.coli's metabolic network shows that localized enzymes, in contrast to non-localized ones, form a tree-like hierarchical structure, have a higher within-group connectivity, and are traversed by a higher number of feed-forward and feedback loops than their non-localized counterparts. A Gene Ontology analysis of these enzymes reveals an enrichment of terms related to essential metabolic functions in growing cells. Given that these findings suggest a distinct metabolic role for localization, we studied the dynamics of cellular localization of the cell wall synthesizing enzymes in B. subtilis and found that enzymes localize during exponential growth but not during stationary growth. CONCLUSIONS: We conclude that active biochemical pathways inside the cytoplasm are organized spatially following a rule where their first or their last enzymes localize to effectively connect the different active pathways and thus could reflect the activity state of the cell's metabolic network. PMID- 25495801 TI - Successful treatment of Dowling-Degos disease using intense pulsed light. AB - Dowling-Degos disease (DDD) is a rare inherited pigmentary disorder characterised by reticulate pigmentation at flexural sites. No treatment modality has yet been established as a definitive method for the effective elimination of lentigines in DDD. We present a case of a 24-year old woman with DDD treated successfully using intense pulsed light as a novel management strategy. PMID- 25495803 TI - Using robots in "Hands-on" academic activities: a case study examining speech generating device use and required skills. AB - PURPOSE: A 12-year-old girl, Emily, with complex communication needs and severe physical limitations, controlled a Lego robot from a speech-generating device (SGD) to do various "hands-on" academic activities. Emily's teacher and assistive technology (AT) team thought that controlling a robot would motivate Emily to "use her SGD more". METHOD: A descriptive case study was used because the integration of communication and manipulation technologies is not yet understood. Target activities and goals were chosen by Emily's teacher and AT team. Emily performed several manipulative math activities and engaged in an "acting" activity aimed at increasing her message length. The competency skills needed to control a robot from the SGD were examined, as well as stakeholder satisfaction with the robot system. RESULTS: Emily generated up to 0.4 communication events and 7 robot commands per minute in the activities. Her length of utterance was usually one-word long, but she generated two- and three-word utterances during some activities. Observations of Emily informed a framework to describe the competency skills needed to use SGDs to control robots. Emily and her teacher expressed satisfaction with robot use. CONCLUSION: Robot use could motivate students to build SGD operational skills and learn educational concepts. Implications for Rehabilitation Controlling a robot from a speech-generating device (SGD) could increase students' motivation, engagement and understanding in learning educational concepts, because of the hands-on enactive approach. The robot and SGD system was acceptable to the participant and teacher and elicited positive comments from classmates. Thus, it may provide a way for children with disabilities to link with the curriculum and with other students in the classroom. Controlling a robot via SGD presents opportunities to improve augmentative and alternative communication operational, linguistic, social and strategic skills. Careful choice of activities will ensure that the activity requirements focus on the desired target skill, e.g. drawing or playing board games could be helpful to build operational skills and acting out stories could be helpful for building linguistic skills. PMID- 25495804 TI - Regioselective synthesis of vinyl halides, vinyl sulfones, and alkynes: a tandem intermolecular nucleophilic and electrophilic vinylation of tosylhydrazones. AB - A diazo species is trapped in an intermolecular fashion by two independent ion species in tandem at the carbene center to install an electrophile and a nucleophile on the same carbon. This metal-free concept, which is unprecedented, has been illustrated by regioselective synthesis of a variety of vinyl halides, vinyl sulfones, and alkyne derivatives. PMID- 25495806 TI - Is non-obstructive coronary artery disease clinically important? PMID- 25495805 TI - Vasodilator beta-blockers: a different class of antihypertensive agents? PMID- 25495802 TI - Amphipols outperform dodecylmaltoside micelles in stabilizing membrane protein structure in the gas phase. AB - Noncovalent mass spectrometry (MS) is emerging as an invaluable technique to probe the structure, interactions, and dynamics of membrane proteins (MPs). However, maintaining native-like MP conformations in the gas phase using detergent solubilized proteins is often challenging and may limit structural analysis. Amphipols, such as the well characterized A8-35, are alternative reagents able to maintain the solubility of MPs in detergent-free solution. In this work, the ability of A8-35 to retain the structural integrity of MPs for interrogation by electrospray ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) is compared systematically with the commonly used detergent dodecylmaltoside. MPs from the two major structural classes were selected for analysis, including two beta-barrel outer MPs, PagP and OmpT (20.2 and 33.5 kDa, respectively), and two alpha-helical proteins, Mhp1 and GalP (54.6 and 51.7 kDa, respectively). Evaluation of the rotationally averaged collision cross sections of the observed ions revealed that the native structures of detergent solubilized MPs were not always retained in the gas phase, with both collapsed and unfolded species being detected. In contrast, ESI-IMS-MS analysis of the amphipol solubilized MPs studied resulted in charge state distributions consistent with less gas phase induced unfolding, and the presence of lowly charged ions which exhibit collision cross sections comparable with those calculated from high resolution structural data. The data demonstrate that A8-35 can be more effective than dodecylmaltoside at maintaining native MP structure and interactions in the gas phase, permitting noncovalent ESI-IMS-MS analysis of MPs from the two major structural classes, while gas phase dissociation from dodecylmaltoside micelles leads to significant gas phase unfolding, especially for the alpha-helical MPs studied. PMID- 25495807 TI - Novel perspectives in clinical cardiology and cardiac surgery. AB - The International Conference on Clinical & Experimental Cardiology was held in San Antonio (TX, USA) on 14-16 April 2014. This was the fourth meeting and had the theme 'Novel Perspectives on Clinical Cardiology and Cardiac Surgery' with sessions in heart disease, congenital heart disease, cardiac therapeutic agents, biophysics and systems biology, current research, and interventional cardiology, providing an interactive forum for discussion of science and clinical practices. Presentations by delegates from Africa, Saudi Arabia, India, China, Japan, Australia, Europe, South America, in addition to Canada and the USA, provided an opportunity for collaboration but also an appreciation of the challenges for treatment in remote locations as well as distance between health facilities. PMID- 25495808 TI - A vascular physician's view of venous thromboembolism and apixaban. AB - Alexander Cohen speaks to Wing Han Wu, Commissioning Editor: Dr Cohen is a vascular physician and epidemiologist involved in clinical work, designing, managing and analyzing clinical trials from Phase I to IV. He is the Chairman and member of many international steering committees for multicenter trials, and epidemiological and pharmaco-economic studies. Dr Cohen graduated with honors in Medicine and Surgery from the University of Melbourne, Australia (MBBS). He achieved his fellow of the Royal Australasian College of Physicians (FRACP) in 1990, and received an MSc in Epidemiology in 1991 from the University of London. His MSc thesis in 1991 was on the Metabolic Syndrome in South Asia. In 1998, he achieved MD with a thesis on Epidemiology of VTE and Thromboprophylaxis. He has written or co-authored over 300 publications since 1990, including 40 publications in The Lancet and New England Journal of Medicine. PMID- 25495809 TI - Future cardiopulmonary resuscitation: should we adopt dedicated systems of care? PMID- 25495810 TI - Transcatheter mitral valve therapies for mitral regurgitation: are we getting closer? PMID- 25495811 TI - Randomized double-blind placebo-controlled trial of perhexiline in heart failure with preserved ejection fraction syndrome. AB - Recently heart failure with preserved ejection fraction (HFpEF) has emerged as a huge epidemic. Increasing evidence shows the role of energy deficiency in the pathophysiology of HFpEF. In the current study, we hypothesize that the use of metabolic modulator perhexiline would correct myocardial energy deficiency and improve exercise capacity and diastolic abnormalities in patients with this syndrome. PMID- 25495812 TI - New oral anticoagulants in patients undergoing atrial flutter radiofrequency catheter ablation: an observational study. AB - AIM: Atrial flutter (AFL) ablation requires optimal periprocedural anticoagulation in order to minimize thromboembolic events/bleeding risk. This study describes the characteristics of patients receiving new oral anticoagulants before AFL ablation and assesses complications. METHODS: This multicenter, retrospective study reports ischemic and hemorrhagic predischarge, postprocedural complications. RESULTS: We evaluated 60 patients (62.3% male; mean age: 69.2 +/- 9.7 years; CHA2DS2-VASc score: 2.44 +/- 1.46, HAS-BLED score: 1.14 +/- 0.7). Twenty-one (35.0%) and 23 patients (38.3%) received twice-daily dabigatran 110 or 150 mg; 16 patients (26.6%) received once-daily rivaroxaban (15 mg [n = 5] or 20 mg [n = 11]). Four cases of postprocedural minor bleeding were reported. CONCLUSION: This is the first study assessing new oral anticoagulants for periprocedural anticoagulation, specifically in patients undergoing AFL ablation. No major bleeding was reported. Further prospective investigation is warranted. PMID- 25495813 TI - Does aortic valve disease etiology predict postoperative atrial fibrillation in patients undergoing aortic valve surgery? AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is one of the most common complications of cardiac surgery and is associated with increased mortality and morbidity. METHODS: We analyzed 830 patients without prior atrial fibrillation who underwent aortic valve replacement for aortic stenosis and/or aortic regurgitation. RESULTS: The incidence of POAF was 38%. The patients with POAF were older, predominately male and hypertensive. The incidence of POAF was significantly different according to the valve etiology. At multivariate analysis, rheumatic and degenerative aortic valve etiologies were independent predictors of POAF. CONCLUSION: Aortic valve disease etiology affects the development of POAF. Rheumatic and degenerative etiologies have a higher risk of developing POAF independently of other clinical, functional and hemodynamic variables. PMID- 25495814 TI - An objective comparison between bivalirudin and heparin during peripheral vascular interventions. AB - Patients undergoing percutaneous peripheral interventions are at increased risk for thrombotic complications hence the routine use of periprocedural anticoagulants. There is currently no American College of Cardiology/American Heart Association guidelines for periprocedural anticoagulants use in percutaneous peripheral interventions. Historically, unfractionated heparin has been the most common periprocedural anticoagulant used during percutaneous peripheral interventions. There may be a role for more predictable periprocedural anticoagulants in percutaneous peripheral interventions as has been demonstrated in percutaneous coronary interventions. Our review focuses on the evidence supporting the use of bivalirudin in percutaneous peripheral interventions. PMID- 25495815 TI - Preoperative evaluation before MitraClip(r): present and future perspective. AB - Mitral regurgitation (MR) is the second most common heart valve disease worldwide. Currently, the management of MR is based on medical therapy (including biventricular pacing), surgery (mitral valve replacement or repair) and percutaneous therapy. However, in spite of guideline recommendations, 50% of individuals assessed in the Euro Heart Survey were not referred to surgical intervention due to comorbidities or real or perceived high risks for cardiac surgery; thus, in recent years, the focus of research has shifted to the development of percutaneous approaches to treat severe MR in order to restore valve function in a minimally invasive fashion. Among these techniques, the percutaneous mitral valve repair procedure using the MitraClip((r)) system (Abbott Vascular, IL, USA) is one of the most promising. Usually, patient selection for MitraClip implantation is based on careful echocardiographic assessment of valve disease; however, although definitive data are lacking, evidence is mounting for a multiparametric approach including the evaluation of the functional status of patients. PMID- 25495816 TI - Atrial fibrillation in the elderly: a review. AB - Atrial fibrillation (AF) is common in the elderly population. Elderly patients with AF are often asymptomatic, may have atypical presentation or may present with heart failure or thromboembolic complications. The optimal management strategy of AF in the elderly population is challenging. We present an overview of AF in elderly patients, in particular addressing the pros and cons of various management strategies, and provide a practical approach within the guidelines. PMID- 25495817 TI - Challenges in cardiology research in pregnancy. AB - Research in pregnancy is challenging as it involves a special 'vulnerable' group due to the involvement of the mother and the fetus. These challenges, which are inherent in studying pregnancy in physiologic and pathologic states, have contributed to the scant research in pregnancy. Until recently, most studies in pregnancy were nonrandomized and retrospective in nature, representing prevailing clinical standards of practice and clinicians' biases. Prospective studies were generally limited to single centers, comprising of small sample sizes and were observational in nature, rather than randomized studies involving therapy. Ethical and legal factors, research mandates, patient factors, the protracted nature of pregnancy, institutional commitment to research, interdisciplinary clinical and research collaboration, funding support, administrative issues and the level of involvement of national cardiac and obstetric and gynecological societies have been barriers to research in pregnancy in developed countries. Even prospective observational studies are difficult to perform due the difficulties involved with obtaining consent, study recruitment and follow-up. Misconceptions regarding research have led to a lack of participation by women. The longitudinal nature of prospective studies in pregnancy, the problems associated with enrolling women before pregnancy and in the first trimester and the failure to understand the commitment required by the patient, as well as many social factors, have led to increased drop-out rates during pregnancy, as well as difficulty with follow-up in the post-partum state. These factors, along with the failure to supplement funding support due to longer study periods than anticipated, have led to studies of small sample sizes. Understanding patient factors that lead to a lack of participation in research or dropping out following initial consent could help make research participation more conducive for pregnant women. The involvement of national societies in the planning and funding of multicenter studies, interdepartmental and interinstitutional collaboration, institutional and extramural funding support and patient incentives are crucial for shortening study duration and ensuring adequacy of sample sizes for successful research in pregnancy. National health service structures, such as those found in Europe and Canada, makes multicenter collaboration for prospective studies more feasible than for countries such as the USA, in which the fees-for-service system is used. Utilization of telemedicine and handheld ultrasound systems and participation in prospective multicenter registries could not only improve the clinical care of pregnant women in underdeveloped countries, but also provide a platform for research during pregnancy. Multicenter and even global registries supported by European cardiac societies have been formed recently that are beginning to bring forth much-needed data regarding pathological states, such as peripartum cardiomyopathy and pregnancy in congenital heart disease. Such studies are largely confined to non US countries and have started seeing participation from underdeveloped countries. Studies on pregnancy in connective tissue disorders, older women, post chemoradiation therapy or organ transplantation and in the HIV state remain limited. PMID- 25495818 TI - Modern advances in cardiovascular imaging: cardiac computed tomography and cardiovascular MRI in pericardial disease. AB - The pericardium is characterized by a two-layer sac that surrounds the heart and provides an enclosed, lubricated space. Diseases of the pericardium may occur due to active inflammation, scar, calcification or effusion. While clinical, ECG and hemodynamic evaluation have been the established methods for the diagnosis of pericardial disease, advances in cardiac computed tomography and cardiovascular MRI provide complementary tools for diagnostic, prognostic and therapeutic assessment. PMID- 25495819 TI - An update on primary findings and new designs in biotherapy studies for acute myocardial infarction. AB - Treatment of acute myocardial infarction in the future should focus not only on improving acute treatment, as it has been done over the past decades, but also on secondary prevention of left ventricular dysfunction and/or progression to heart failure by preserving left ventricular shape, avoiding left ventricular remodeling and stimulating cardiac regeneration. Biotherapies with adult stem cells and bone marrow-derived endothelial cell progenitors, combined or not with biomaterials, and new drugs are under investigation and will probably be part of routine clinical practice for patients suffering from myocardial infarction in the near future. PMID- 25495820 TI - MiRNAs as potential molecular targets in heart failure. AB - Pathogenesis of heart diseases is associated with an altered expression profile of hundreds of genes. miRNAs are a newly identified layer of gene regulation operating at the post-transcriptional level by pairing to complementary base sequences in target mRNAs. Genetic data have identified the roles of miRNAs in basic pathological processes associated with heart failure: apoptosis, fibrosis, myocardial hypertrophy and cardiac remodeling. Many reports demonstrated that aberrantly expressed miRNAs and their modulation have effects on cardiac insufficiency. Here, we overview the advances in miRNAs as potential targets in the modulation of the heart failure phenotype. miRNA-based therapy holds great promise as a future strategy for treating heart diseases and identifying emerging signaling pathways responsible for the progression of heart failure. PMID- 25495821 TI - The role of O-GlcNAc transferase in regulating the gene transcription of developing and failing hearts. AB - Heart failure treatment currently centers on symptom management, primarily through reductions in systemic blood pressure and fluid retention. The O-linked attachment of beta-N-acetylglucosamine to cardiac proteins is increased in cardiovascular disease and heart failure, and O-GlcNAc transferase (OGT) is the enzyme that catalyzes this addition. Deletion of OGT is embryonically lethal, and cardiomyocyte-specific OGT knockdown causes the exacerbation of heart failure. Stem cell therapy is currently a major focus of heart failure research, and it was recently discovered that OGT is intricately involved with stem cell differentiation. This article focuses on the relationship of OGT with epigenetics and pluripotency, and integrates OGT with several emerging areas of heart failure research, including calcium signaling. PMID- 25495822 TI - Effects of renal denervation on atrial arrhythmogenesis. AB - Atrial fibrillation is the most common sustained arrhythmia and is associated with significant morbidity and mortality. In addition to mechanisms such as atrial stretch and atrial remodeling, the activity of the autonomic nervous system has also been suggested to contribute to the progression from paroxysmal to persistent atrial fibrillation. Catheter-based renal denervation was introduced as a minimally invasive approach to reduce renal and whole body sympathetic activation with accompanying blood pressure reduction and left ventricular morphological and functional improvement in drug-resistant hypertension. This review focuses on the potential effects of renal denervation on different arrhythmogenic mechanisms in the atrium and discusses potential anti remodeling effects in atrial fibrillation patients with hypertension, heart failure and sleep apnea. PMID- 25495824 TI - Discovery of a 240 million year old nematode parasite egg in a cynodont coprolite sheds light on the early origin of pinworms in vertebrates. AB - BACKGROUND: We report the discovery of a nematode parasite egg (Nemata: Oxyurida) from a coprolite closely associated with the remains of several species of Cynodontia, dated to 240 million years old. This finding is particularly significant because this is the oldest record of an oxyurid nematode yet discovered, and because the cynodonts are considered a stem-group of the mammals. METHODS: We extracted material from a fully mineralized coprolite by both scraping the surface, and removing fragments from its interior with clean dental instruments used a single time. A single drop of glycerol from a new vial was added as a clearing reagent. Each slide was sealed with wax and examined with an optical microscope at 100* to 400* magnification. RESULTS: From one coprolite, 550 slides were examined; from 275 of these slides, sediment was examined that was scraped from the surface of the coprolite, and from the other 275 slides, material was examined that was extracted from the interior of the coprolite. All microscopic structures encountered were photographed, measured, and identified when possible. CONCLUSIONS: From the coprolite examined, we discovered an egg representing a new species of pinworm that, based on the egg structure, clearly places it in the family Heteroxynematidae. Nematodes of the order Oxyurida have very constrained life-histories, occurring only in animals that are not strictly carnivorous and also ingest large amounts of plant material. This fact enabled us to determine which species of cynodont, from several collected at the site in Brazil, are most likely the depositors of the coprolite, and therefore were the putative host of the parasite. PMID- 25495825 TI - Field-induced slow relaxation in a monometallic manganese(III) single-molecule magnet. AB - High-field electron paramagnetic resonance spectroscopy shows that the structurally distorted Mn(III) ion in Na5[Mn(L-tart)2].12H2O (1; L-tart = L tartrate) has a significant negative axial zero-field splitting and a small rhombic anisotropy (~1% of D). Alternating-current magnetic susceptibility measurements demonstrate that 1, which contains isolated Mn(III) centers, displays slow relaxation of its magnetization under an applied direct-current magnetic field. PMID- 25495823 TI - Developing ovarian cancer stem cell models: laying the pipeline from discovery to clinical intervention. AB - Despite decades of research, ovarian cancer is still associated with unacceptably high mortality rates, which must be addressed by novel therapeutic approaches. One avenue through which this may be achieved is targeting of tumor-initiating 'Cancer Stem Cells' (CSCs). CSCs are sufficient to generate primary and recurrent disease through extensive rounds of asymmetric division, which maintain the CSC pool while producing the tissues that form the bulk of the tumor. CSCs thrive in the harsh tumor niche, are generally refractory to therapeutic intervention and closely-linked to the Epithelial-Mesenchymal Transition process, which facilitates invasion and metastasis. While it is well-accepted that CSC-targeting must be assessed as a novel therapeutic avenue, few ovarian CSC models have been developed due to perceived and actual difficulties associated with the process of 'CSC Discovery'. In this article we review contemporary approaches to CSC Discovery and argue that this process should start with an understanding of the specific challenges associated with clinical intervention, laying the pipeline backwards towards CSC Discovery. Such an approach would expedite the bridging of the gap between laboratory isolation and clinical targeting of ovarian CSCs. PMID- 25495826 TI - Patients' and carers' experiences of interacting with home haemodialysis technology: implications for quality and safety. AB - BACKGROUND: Little is known about patients' and carers' experiences of interacting with home haemodialysis (HHD) technology, in terms of user experience, how the design of the technology supports safety and fits with home use, and how the broader context of service provision impacts on patients' use of the technology. METHODS: Data were gathered through ethnographic observations and interviews with 19 patients and their carers associated with four different hospitals in the UK, using five different HHD machines. All patients were managing their condition successfully on HHD. Data were analysed qualitatively, focusing on themes of how individuals used the machines and how they managed their own safety. RESULTS: Findings are organised by three themes: learning to use the technology, usability of the technology, and managing safety during dialysis. Home patients want to live their lives fully, and value the freedom and autonomy that HHD gives them; they adapt use of the technology to their lives and their home context. They also consider the machines to be safe; nevertheless, most participants reported feeling scared and having to learn through mistakes in the early months of dialysing at home. Home care nurses and technicians provide invaluable support. Although participants reported on strategies for anticipating problems and keeping safe, perceived limitations of the technology and of the broader system of care led some to trade off safety against immediate quality of life. CONCLUSIONS: Enhancing the quality and safety of the patient experience in HHD involves designing technology and the broader system of care to take account of how individuals manage their dialysis in the home. Possible design improvements to enhance the quality and safety of the patient experience include features to help patients manage their dialysis (e.g. providing timely reminders of next steps) and features to support communication between families and professionals (e.g. through remote monitoring). PMID- 25495827 TI - Effects of purified alginate sponge on the regeneration of chondrocytes: in vitro and in vivo. AB - Regeneration science has been studied using tissue engineering techniques due to the self-renewal difficulties of damaged or degenerated cartilage. A scaffold with biodegradability and biocompatibility features plays a key role in developing cartilage tissue similar to human biological materials. Herein, we have fabricated three-dimensional sponge using purified alginate for the regeneration of chondrocytes cells and formation of cartilage. We demonstrated that the alginate purification can effectively minimize inflammatory reaction through reducing the content of mannuronic acid causing immune rejection. Cartilage regeneration research was performed using three-dimensional non purified and purified alginate sponges synthesized by modified Korbutt method. In vitro cell viability and specific gene expression in the cartilage cells were investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and reverse transcriptase-polymerase chain reaction (RT-PCR) after seeding chondrocytes on the as-fabricated sponges. Specific extracellular matrix (ECM) of chondrocytes, sGAG, and the content of collagen were also measured. Histological staining was carried out after purified alginate sponge seeded with chondrocytes and was implanted in subcutaneous nude mouse followed by extraction. Compared to the non-purified ones, the purified alginate sponges showed positive effects on maintaining affinities and phenotype of chondrocytes. From these results, it can be suggested that the purified alginate sponges provide a promising platform for cartilage regeneration. PMID- 25495829 TI - Dual task performance in Huntington's disease: A comparison of choice reaction time tasks. AB - OBJECTIVE: This study investigated whether dual tasks make disproportionately high demands in Huntington's disease (HD) compared with controls, and also tested the Multiple Resources Theory. METHOD: Thirteen HD participants and 13 controls completed 2 dual task sets that varied in difficulty and complexity: Set 1 paired simple choice reaction time (RT) with digit forward, and Set 2 paired complex choice RT with digit backward. RESULTS: We found that HD participants were overall slower; however, although they maintained similar levels of accuracy in the simple choice RT tasks with controls, their accuracy decreased in the complex choice RT tasks. In addition, we found that HD participants were more susceptible to speed-accuracy trade-offs. Despite that, they did not show greater dual task costs than controls. CONCLUSIONS: Overall, our findings do not support the Multiple Resources Theory, but they do provide some support for the Unitary Resource Theory and the attentional impairment hypothesis. PMID- 25495828 TI - Negative social interactions and risk of mild cognitive impairment in old age. AB - OBJECTIVE: To test the hypothesis that negative social interaction is associated with increased risk of mild cognitive impairment and rate of cognitive decline. METHODS: Participants were 529 older people without cognitive impairment at study onset. They completed annual evaluations that included assessment of negative social interactions (e.g., unsympathetic behavior, rejection), cognitive testing, and clinical classification of mild cognitive impairment. RESULTS: During a mean of 4.8 years of follow-up (SD = 2.5), 198 individuals (37.4%) developed mild cognitive impairment. In a proportional hazards model, higher baseline frequency of negative social interactions (M = 1.51, SD = 0.43, skewness = 1.60) was associated with higher risk of developing mild cognitive impairment (hazard ratio = 1.53, 95% confidence interval: 1.13, 2.07). Results were similar after adjustment for depressive symptoms, social network size, social activity, and loneliness. This association was mainly due to neglect and rejection. There was no change in negative social interaction rate over time (estimate = -0.003, SE = 0.004, p = .508). Higher baseline level of negative social interaction was associated with lower initial level of global cognition (estimate = -0.096, SE = 0.034, p = .005) but not with cognitive decline (estimate = -0.018, SE = 0.011, p = .098). A higher mean level of negative interactions across the study period was robustly related to faster cognitive decline (estimate = -0.036, SE = 0.012, p = .002). CONCLUSION: Frequent negative social interactions may be a risk factor for mild cognitive impairment and cognitive decline in old age. PMID- 25495830 TI - Relations between volumetric measures of brain structure and attentional function in spina bifida: utilization of robust statistical approaches. AB - OBJECTIVE: Weak structure-function relations for brain and behavior may stem from problems in estimating these relations in small clinical samples with frequently occurring outliers. In the current project, we focused on the utility of using alternative statistics to estimate these relations. METHOD: Fifty-four children with spina bifida meningomyelocele performed attention tasks and received MRI of the brain. Using a bootstrap sampling process, the Pearson product-moment correlation was compared with 4 robust correlations: the percentage bend correlation, the Winsorized correlation, the skipped correlation using the Donoho Gasko median, and the skipped correlation using the minimum volume ellipsoid estimator. RESULTS: All methods yielded similar estimates of the relations between measures of brain volume and attention performance. The similarity of estimates across correlation methods suggested that the weak structure-function relations previously found in many studies are not readily attributable to the presence of outlying observations and other factors that violate the assumptions behind the Pearson correlation. CONCLUSIONS: Given the difficulty of assembling large samples for brain-behavior studies, estimating correlations using multiple, robust methods may enhance the statistical conclusion validity of studies yielding small, but often clinically significant, correlations. PMID- 25495831 TI - A late-emerging auditory deficit in autism. AB - OBJECTIVE: Individuals with autism spectrum disorders (ASD) show enhanced perceptual and memory abilities in the domain of pitch, but also perceptual deficits in other auditory domains. The present study investigated their skills with respect to "echoic memory," a form of short-term sensory memory intimately tied to auditory perception, using a developmental perspective. METHOD: We tested 23 high-functioning participants with ASD and 26 typically developing (TD) participants, distributed in two age groups (children vs. young adults; mean ages: ~11 and ~21 years). By means of an adaptive psychophysical procedure, we measured the longest period for which periodic (i.e., repeated) noise could be reliably discriminated from nonperiodic (i.e., plain random) noise. On each experimental trial, a single noise sample was presented to the participant, who had to classify this sound as periodic or nonperiodic. RESULTS: The TD adults performed, on average, much better than the other three groups, who performed similarly overall. As a function of practice, the measured thresholds improved for the TD participants, but did not change for the ASD participants. Thresholds were not correlated to performance in a test assessing verbal memory. The variance of the participants' response biases was larger among the ASD participants than among the TD participants. CONCLUSION: The results mainly suggest that echoic memory takes a long time to fully develop in TD humans, and that this development stops prematurely in persons with ASD. PMID- 25495832 TI - Residual decline in cognition after adjustment for common neuropathologic conditions. AB - OBJECTIVE: Neurodegenerative and cerebrovascular conditions are common in old age and are associated with cognitive decline. However, considerable heterogeneity remains in residual decline (i.e., person-specific trajectories of cognitive decline adjusted for these common neuropathologic conditions). The present study aimed to characterize profiles of residual decline in late life cognition. METHOD: Up to 19 waves of longitudinal cognitive data were collected from 876 autopsied participants from 2 ongoing clinical-pathologic cohort studies of aging. Uniform neuropathologic examinations quantified measures of Alzheimer's disease, cerebral infarcts, Lewy body disease, and hippocampal sclerosis. Random effects mixture models characterized latent profiles of residual decline in global cognition. RESULTS: We identified 4 latent groups, and each group demonstrated distinct residual decline profiles. On average, 44% of the participants had little or no decline, 35% showed moderate decline, 13% showed severe decline and the rest (8%) had substantial within-subject fluctuation of longitudinal cognitive measures. These latent groups differed in psychological, experiential and neurobiologic factors that have been previously shown to be associated with cognitive decline. Specifically, compared with nondecliners, decliners had more depressive symptoms, were more socially isolated; were less engaged in cognitive or physical activities; and had lower density of noradrenergic neurons in locus ceruleus. CONCLUSIONS: After controlling for common dementia related pathologies, considerable residual variability remains in cognitive aging trajectories and this variability is not random but rather is related to markers of cognitive and neural reserve. The mixture modeling approach provides a powerful tool to identify latent groups with distinct cognitive trajectories. PMID- 25495833 TI - Differential effects of goal cues on everyday action errors in Alzheimer's disease versus Parkinson's disease dementia. AB - OBJECTIVE: Prior research has shown that individuals with Parkinson's disease dementia (PDD) show a different pattern of error types on everyday tasks compared with individuals with Alzheimer's disease (AD). This study evaluated whether these groups would respond differently to cues designed to remind participants of task goals and improve performance of everyday tasks (i.e., goal cues). METHOD: Participants with PDD (n = 20) and AD (n = 20), and a comparison group of individuals with Parkinson's disease and no dementia (n = 20), were administered performance-based tasks of everyday functioning that allowed for the quantification of errors before and after the presentation of goal cues. RESULTS: AD participants showed a significantly greater response to the goal cues as compared with individuals with PDD. The goal cues facilitated the completion of task goals but did not promote error correction (i.e., the undoing of errors that had been made earlier during the task). CONCLUSIONS: Not all dementia patients respond similarly to cues designed to improve everyday functioning. Understanding patients' specific form of everyday action impairment is crucial for developing individualized interventions that target specific functional deficits. PMID- 25495834 TI - A comparison of adult outcomes for males compared to females following pediatric traumatic brain injury. AB - OBJECTIVE: To identify the association between traumatic brain injury (TBI) and internalizing and externalizing problem behaviors and determine if these apply equally to males and females. METHOD: The association between adult psychosocial functioning and childhood TBI for males and females was examined using groups with a history of childhood TBI (mild or moderate/severe) or orthopedic injury (injury age, 1-17, assessed 18-31 at >5 years postinjury), including rates of depression and anxiety disorders, substance abuse/dependence and offending behavior. Repeated-measures logistic regression was used to determine if the rates of internalizing and externalizing problem behaviors varied by group and sex. RESULTS: Overall rates of problem behaviors were significantly greater for both moderate/severe TBI (OR = 4.00) and mild TBI (OR = 3.60) groups compared with orthopedic controls. Females were significantly more likely than males to report a history of internalizing problems (OR = 2.22), whereas males were more likely than females to report externalizing problems (OR = 2.10). The sex difference in internalizing/externalizing problems was found consistently across TBI groups and controls. CONCLUSIONS: Childhood TBI is associated with psychosocial problems in adulthood, regardless of injury severity. How deficits are expressed differs between the sexes, with important implications for interventions strategies. PMID- 25495835 TI - Multimedia educational tools for cognitive surgical skill acquisition in open and laparoscopic colorectal surgery: a randomized controlled trial. AB - AIM: Conventional teaching in surgical training programmes is constrained by time and cost, and has room for improvement. This study aimed to determine the effectiveness of a multimedia educational tool developed for an index colorectal surgical procedure (anterior resection) in teaching and assessment of cognitive skills and to evaluate its acceptability amongst general surgical trainees. METHOD: Multimedia educational tools in open and laparoscopic anterior resection were developed by filming multiple operations which were edited into procedural steps and substeps and then integrated onto interactive navigational platforms using Adobe(r) Flash(r) Professional CS5 10.1. A randomized controlled trial was conducted on general surgical trainees to evaluate the effectiveness of online multimedia in comparison with conventional 'study day' teaching for the acquisition of cognitive skills. All trainees were assessed before and after the study period. Trainees in the multimedia group evaluated the tools by completing a survey. RESULTS: Fifty-nine trainees were randomized but 27% dropped out, leaving 43 trainees randomized to the multimedia group (n = 25) and study day group (n = 18) who were available for analysis. Posttest scores improved significantly in both groups (P < 0.01). The change in scores (mean +/- SD) in the multimedia group was not significantly different from the study day group (6.02 +/- 5.12 and 5.31 +/- 3.42, respectively; P = 0.61). Twenty-five trainees completed the evaluation survey and experienced an improvement in their decision making (67%) and in factual and anatomical knowledge (88%); 96% agreed that the multimedia tool was a useful additional educational resource. CONCLUSION: Multimedia tools are effective for the acquisition of cognitive skills in colorectal surgery and are well accepted as an educational resource. PMID- 25495836 TI - Inhibition of G protein-coupled receptor 81 (GPR81) protects against ischemic brain injury. AB - AIM: Lactates accumulate in ischemic brains. G protein-coupled receptor 81 (GPR81) is an endogenous receptor for lactate. We aimed to explore whether lactate is involved in ischemic injury via activating GPR81. METHODS: N2A cells were transfected with GFP-GPR81 plasmids 24 h previously, and then treated with GPR81 antagonist 3-hydroxy-butyrate (3-OBA) alone or cotreated with agonists lactate or 3, 5-dihydroxybenzoic acid (3, 5-DHBA) during 3 h of oxygen-glucose deprivation (OGD). Adult male C57BL/6J mice and primary cultured cortical neurons were treated with 3-OBA at the onset of middle cerebral artery occlusion (MCAO) or OGD, respectively. RESULTS: The GPR81 overexpression increased the cell vulnerability to ischemic injury. And GPR81 antagonism by 3-OBA significantly prevented cell death and brain injury after OGD and MCAO, respectively. Furthermore, inhibition of GPR81 reversed ischemia-induced apoptosis and extracellular signal-regulated kinase (ERK) signaling may be involved in the neuroprotection. CONCLUSIONS: G protein-coupled receptor 81 (GPR81) inhibition attenuated ischemic neuronal death. Lactate may aggravate ischemic brain injury by activating GPR81. GPR81 antagonism might be a novel therapeutic strategy for the treatment of cerebral ischemia. PMID- 25495837 TI - New Insights into the N2O formation mechanism over Pt-BaO/Al2O3 model catalysts using H2 as a reductant. AB - The N2O formation mechanism was investigated over a Pt-BaO/Al2O3 catalyst applied on light-duty diesel vehicles using H2 as a reductant in the absence and presence of H2O. In the absence of H2O, N2O forms mainly at the initial phase of lean NOx trapping; while in the presence of H2O, N2O appears mainly at the beginning of the rich reduction phase. In the lean period, N2O is formed via the gaseous NO/O2 reacting with the adsorbed H and NH3 that are formed during the previous rich period. The N2O formation in the rich period is insignificant in the absence of H2O but is greatly enhanced by the presence of H2O. The amount of N2O formed is proportional to the H2O level in the feed, and its formation is favored at low temperatures. Our FTIR data show that H2O enhances the rate of nitrite/nitrate reduction during the rich regeneration, which increases the amount of released NOx, an oxygen source for N2O formation. Our temperature-programmed experiments indicate that H2O competes with NH3 for adsorption sites on Pt surface. This competitive adsorption may increase the NH3 desorption rate at low temperatures in the rich phase and make Pt surface more accessible to NO. PMID- 25495838 TI - Extensive lentigo simplex, linear epidermolytic naevus and epidermolytic naevus comedonicus caused by a somatic mutation in KRT10. PMID- 25495839 TI - Vitamin D replacement and type 2 diabetes mellitus. AB - The objective of this paper is to review the evidence testing the possible benefit of vitamin D replacement on diabetes control and complications. Type 2 diabetes mellitus (DM 2) has become a significant global health care problem and its reported incidence is increasing at an alarming rate. Despite the improvement in therapy and development of new drugs, treatment is still not optimal especially with the associated adverse effects of most of the available drugs. New efforts are shifted toward disease prevention and a search for safer drugs. New mounting evidence is associating low vitamin D to diabetes mellitus and as such many studies were conducted to test the effect of vitamin D replacement on incidence of diabetes, diabetes control as well as diabetes complications. Although these studies present several limitations, vitamin D replacement seems to have beneficial effect on all aspects of diabetes: incidence, control and complications. Further longer term and more powered controlled trials are necessary to draw firmer conclusions on this beneficial role of vitamin D treatment on DM. PMID- 25495841 TI - A stable N-heterocyclic carbene organocatalyst for hydrogen/deuterium exchange reactions between pseudoacids and deuterated chloroform. AB - It was observed that the stable and commercially available N-heterocyclic carbene (NHC) 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, the so-called IDipp, catalyzes hydrogen/deuterium exchange reactions between pseudoacids and chloroform-d1, while the analogous saturated NHC 1,3-bis(2,4,6 trimethylphenyl)imidazolin-2-ylidene, the so-called SIMes, is inefficient for the same transformation. Experimental and computational DFT studies allowed these differences of reactivity to be attributed to the relative stability of the corresponding azolium-trichloromethyl anion ion pairs: in the former case, the complex evolves toward dissociation of the ions to produce an aromatic azolium cation and a basic trichloromethyl anion, while in the latter case, it evolves by ion recombination to give the product of formal carbene C-H insertion into the C H bond of chloroform. These results provide a rationale for some early intuitions and observations of Wanzlick, Arduengo, and others on the reactivity of NHCs with chloroform as well as a simple organocatalytic method for the deuteration of pseudoacids (pKa,DMSO = 14-19) with chloroform-d1. PMID- 25495840 TI - Mapping the functional assessment of cancer therapy-breast (FACT-B) to the 5 level EuroQoL Group's 5-dimension questionnaire (EQ-5D-5L) utility index in a multi-ethnic Asian population. AB - PURPOSE: To develop an algorithm for mapping the Functional Assessment of Cancer Therapy-Breast (FACT-B) to the 5-level EuroQoL Group's 5-dimension questionnaire (EQ-5D-5L) utility index. METHODS: A survey of 238 breast cancer patients in Singapore was conducted. Models using various regression methods with or without recognizing the upper boundary of utility values at 1 were fitted to predict the EQ-5D-5L utility index based on the five subscale scores of the FACT-B. Data from a follow-up survey of these patients were used to validate the results. RESULTS: A model that maps the physical, emotional, functional well-being and the breast cancer concerns subscales of the FACT-B to the EQ-5D-5L utility index was derived. The social well-being subscale was not associated to the utility index. Although theoretical assumptions may not be valid, ordinary least square outperformed other regression methods. The mean predicted utility index within each performance status level at follow-up deviated from the observed mean less than the minimally important difference of EQ-5D for cancer patients. CONCLUSIONS: The mapping algorithm converts the FACT-B to the EQ-5D utility index. This enables oncologists, clinical researchers and policy makers to obtain a quantitative utility summary of a patient's health status when only the FACT-B is assessed. PMID- 25495843 TI - Theoretical Insights into the Impact of Ru Catalyst Anchors on the Efficiency of Photocatalytic CO2 Reduction on Ta2O5. AB - We present a computational study of the dynamical and electronic structure origins of the impact of anchoring groups, PO3H2, COOH, and OH, on the efficiency of photochemical CO2 reduction in Ru(di-X-bpy)(CO)2Cl2/Ta2O5 systems. Recent experimental studies indicate that the efficiency may not directly correlate with the driving force for electron transfer (ET) in these systems, prompting the need for further investigation of the role of anchor groups. Our analysis shows that there are at least two key roles of the anchor in determining the efficiency of CO2 reduction by the Ru complex. First, depending on local steric interactions, different tilting angles and their fluctuations may emerge for different anchors, affecting the magnitude of the donor-acceptor coupling. Second, depending on localization of acceptor states on the anchor, determined by the anchor's tendency to form conjugate subsystems, the yields of ET to the catalytic center may vary, directly affecting the photocatalytic efficiency. Finally, our calculations indicate that surface modeling with N-doping and many-body effects are needed to describe the ET process in the systems properly. N-doping imparts the Ta2O5 surface with a dipole moment, while Coulomb and exchange contributions to the electron-hole interaction can produce excitons that should be taken into account. PMID- 25495842 TI - Systematic review of prostate cancer risk and association with consumption of fish and fish-oils: analysis of 495,321 participants. AB - INTRODUCTION: Fish-oils have a potential role in inflammation, carcinogenesis inhibition and favourable cancer outcomes. There has been increasing interest in the relationship of diet with cancer incidence and mortality, especially for eicosapantaenoic acid (EPA) and docosahexaenoic acid (DHA). This systematic analysis of the literature aims to review evidence for the roles of dietary-fish and fish-oil intake in prostate-cancer (PC) risk, aggressiveness and mortality. METHODS: A systematic-review, following PRISMA guidelines was conducted. PubMed, MEDLINE and Embase were searched to explore PC-risk, aggressiveness and mortality associated with dietary-fish and fish-oil intake. 37 studies were selected. RESULTS: A total of 495,321 (37-studies) participants were investigated. These revealed various relationships regarding PC-risk (n = 31), aggressiveness (n = 8) and mortality (n = 3). Overall, 10 studies considering PC-risk found significant inverse trends with fish and fish-oil intake. One found a dose-response relationship whereas greater intake of long-chain-polyunsaturated fatty acids increased risk of PC when considering crude odds-ratios [OR: 1.36 (95% CI: 0.99 1.86); p = 0.014]. Three studies addressing aggressiveness identified significant positive relationships with reduced risk of aggressive cancer when considering the greatest intake of total fish [OR 0.56 (95% CI 0.37-0.86)], dark fish and shellfish-meat (p < 0.0001), EPA (p = 0.03) and DHA (p = 0.04). Three studies investigating fish consumption and PC-mortality identified a significantly reduced risk. Multivariate-OR (95% CI) were 0.9 (0.6-1.7), 0.12 (0.05-0.32) and 0.52 (0.30-0.91) at highest fish intakes. CONCLUSIONS: Fish and fish-oil do not show consistent roles in reducing PC incidence, aggressiveness and mortality. Results suggest that the specific fish type and the fish-oil ratio must be considered. Findings suggest the need for large intervention randomised placebo controlled trials. PMID- 25495844 TI - Root of Polygonum cuspidatum extract reduces progression of diabetes-induced mesangial cell dysfunction via inhibition of platelet-derived growth factor-BB (PDGF-BB) and interaction with its receptor in streptozotocin-induced diabetic rats. AB - BACKGROUND: Platelet-derived growth factor-BB (PDGF-BB) is highly expressed in the renal tissues of patients with diabetic nephropathy, and it plays an important role in the initiation and progression of diabetic nephropathy. The aim of this study was to evaluate the protective effects of root of Polygonum cuspidatum extract (PCE) on early renal glomerular proliferation in streptozotocin (STZ)-induced diabetic rats. METHODS: PCE (100, 350 mg/kg/day) was administered to diabetic rats for 16 weeks. Blood glucose and albuminuria were measured. Renal histology, alpha-smooth muscle actin (alpha-SMA), and proliferating cell nuclear antigen (PCNA) expression levels were also examined. RESULTS: After 16 weeks of treatment with PCE, severe hyperglycemia and albuminuria were observed in the diabetic rats. The expressions levels of alpha SMA and PCNA proteins were significantly increased in the glomeruli of the diabetic rats. The expression levels of PDGF-BB and its receptor expressions were greatly increased in the glomeruli of the diabetic rats. However, PCE markedly reduced albuminuria in the diabetic rats. PCE inhibited alpha-SMA and PCNA up regulation and ameliorated PDGF-BB and PEGFR-beta protein expression in the diabetic rats. In addition, the binding of PDGF-BB/PDGFR-beta was inhibited by PCE as shown by an in vitro assay. CONCLUSIONS: These results suggest that PCE has an inhibitory effect on mesangial proliferation in diabetic renal tissues via the inhibition of the interaction of PDGF-BB with its receptor. PCE may have beneficial effects in preventing the progression of diabetic nephropathy. PMID- 25495846 TI - Effect of interface atomic structure on the electronic properties of nano-sized metal-oxide interfaces. AB - We report that the size dependence of electronic properties at nanosized metal semiconducting oxide interfaces is significantly affected by the interface atomic structure. The properties of interfaces with two orientations are compared over size range of 20-200 nm. The difference in interface atomic structure leads to electronic structure differences that alter electron transfer paths. Specifically, interfaces with a higher concentration of undercoordinated Ti result in enhanced tunneling due to the presence of defect states or locally reduced tunnel barrier widths. This effect is superimposed on the mechanisms of size dependent properties at such small scales. PMID- 25495845 TI - Nestor-Guillermo Progeria Syndrome: a biochemical insight into Barrier-to Autointegration Factor 1, alanine 12 threonine mutation. AB - BACKGROUND: Premature aging syndromes recapitulate many aspects of natural aging and provide an insight into this phenomenon at a molecular and cellular level. The progeria syndromes appear to cause rapid aging through disruption of normal nuclear structure. Recently, a coding mutation (c.34G > A [p.A12T]) in the Barrier to Autointegration Factor 1 (BANF1) gene was identified as the genetic basis of Nestor-Guillermo Progeria syndrome (NGPS). This mutation was described to cause instability in the BANF1 protein, causing a disruption of the nuclear envelope structure. RESULTS: Here we demonstrate that the BANF1 A12T protein is indeed correctly folded, stable and that the observed phenotype, is likely due to the disruption of the DNA binding surface of the A12T mutant. We demonstrate, using biochemical assays, that the BANF1 A12T protein is impaired in its ability to bind DNA while its interaction with nuclear envelope proteins is unperturbed. Consistent with this, we demonstrate that ectopic expression of the mutant protein induces the NGPS cellular phenotype, while the protein localizes normally to the nuclear envelope. CONCLUSIONS: Our study clarifies the role of the A12T mutation in NGPS patients, which will be of importance for understanding the development of the disease. PMID- 25495848 TI - Helpful self-management strategies to cope with enduring depression from the patients' point of view: a concept map study. AB - BACKGROUND: Despite the development of various self-management programmes that attempt to ameliorate symptoms of patients with chronic major depressive disorder (MDD), little is known about what these patients perceive as helpful in their struggle during daily live. The present study aims to explore what patients believe they can do themselves to cope with enduring MDD besides professional treatment, and which self-management strategies patients perceive as being most helpful to cope with their MDD. METHODS: We used concept mapping, a method specifically designed for the conceptualisation of a specific subject, in this case patients' point of view (n = 25) on helpful self-management strategies in their coping with enduring MDD. A purposive sample of participants was invited at the Academic Medical Center and through requests on several MDD-patient websites in the Netherlands. Participants generated strategies in focus group discussions which were successively clustered on a two-dimensional concept map by hierarchical cluster analysis. RESULTS: Fifty strategies were perceived as helpful. They were combined into three meta-clusters each comprising two clusters: A focus on the depression (sub clusters: Being aware that my depression needs active coping and Active coping with professional treatment); An active lifestyle (sub clusters: Active self-care, structure and planning and Free time activities) and Participation in everyday social life (sub clusters: Social engagement and Work-related activities). CONCLUSIONS: MDD patients believe they can use various strategies to cope with enduring MDD in daily life. Although current developments in e-health occur, patients emphasise on face-to-face treatments and long-term relations, being engaged in social and working life, and involving their family, friends, colleagues and clinicians in their disease management. Our findings may help clinicians to improve their knowledge about what patients consider beneficial to cope with enduring MDD and to incorporate these suggested self-management strategies in their treatments. PMID- 25495847 TI - A web-based intervention to support self-management of patients with type 2 diabetes mellitus: effect on self-efficacy, self-care and diabetes distress. AB - BACKGROUND: Management of diabetes mellitus is complex and involves controlling multiple risk factors that may lead to complications. Given that patients provide most of their own diabetes care, patient self-management training is an important strategy for improving quality of care. Web-based interventions have the potential to bridge gaps in diabetes self-care and self-management. The objective of this study was to determine the effect of a web-based patient self-management intervention on psychological (self-efficacy, quality of life, self-care) and clinical (blood pressure, cholesterol, glycemic control, weight) outcomes. METHODS: For this cohort study we used repeated-measures modelling and qualitative individual interviews. We invited patients with type 2 diabetes to use a self-management website and asked them to complete questionnaires assessing self-efficacy (primary outcome) every three weeks for nine months before and nine months after they received access to the website. We collected clinical outcomes at three-month intervals over the same period. We conducted in-depth interviews at study conclusion to explore acceptability, strengths and weaknesses, and mediators of use of the website. We analyzed the data using a qualitative descriptive approach and inductive thematic analysis. RESULTS: Eighty-one participants (mean age 57.2 years, standard deviation 12) were included in the analysis. The self-efficacy score did not improve significantly more than expected after nine months (absolute change 0.12; 95% confidence interval -0.028, 0.263; p = 0.11), nor did clinical outcomes. Website usage was limited (average 0.7 logins/month). Analysis of the interviews (n = 21) revealed four themes: 1) mediators of website use; 2) patterns of website use, including role of the blog in driving site traffic; 3) feedback on website; and 4) potential mechanisms for website effect. CONCLUSIONS: A self-management website for patients with type 2 diabetes did not improve self-efficacy. Website use was limited. Although its perceived reliability, availability of a blog and emailed reminders drew people to the website, participants' struggles with type 2 diabetes, competing priorities in their lives, and website accessibility were barriers to its use. Future interventions should aim to integrate the intervention seamlessly into the daily routine of end users such that it is not seen as yet another chore. PMID- 25495849 TI - 4q27 as a psoriasis susceptibility locus in the Northeastern Chinese Han population. AB - Psoriasis is an autoimmune inflammatory skin disease with genetic components. Chromosome 4q27 is related to many autoimmune diseases, however, the relationship between psoriasis and 4q27 has not been fully established yet. The objective of this study is to investigate the association between chromosome 4q27 and psoriasis in the Northeastern Chinese Han population. Four common single nucleotide polymorphisms (rs2069762, rs4833837, rs6840978, and rs7684187) from chromosome 4q27 were genotyped in 400 psoriasis cases and 398 controls from the Northeastern Chinese Han population using the Multiplex SNaPSHOT method. Single nucleotide polymorphism and haplotype frequencies were analyzed using spss 13.0. Our data indicated that rs2069762 GG, TG genotypes [GG: odds ratio (OR) = 2.6875, 95% confidence interval (CI) = 1.5948-4.5290, P < 0.0001; TG: OR = 1.6159, 95% CI = 1.2044-2.1681, P = 0.0013], and H3 haplotype (OR = 1.717, 95% CI = 1.050-2.808, P = 0.030) increased the risk of psoriasis. Furthermore, rs4833837 GG, GA genotypes (GG: OR = 0.2071, 95% CI = 0.0685-0.6266, P = 0.0022; GA: OR = 0.4711, 95% CI = 0.3289-0.6746, P < 0.0001), and H5 haplotype (OR = 0.482, 95% CI = 0.238 0.978, P = 0.039) were identified as protective factors for psoriasis. 4q27 polymorphisms are associated with psoriasis in the Northeastern Chinese Han population. PMID- 25495850 TI - Is some better than none: are TEG and TGA profiles different in severe FVIII deficient patients with inhibitors? AB - Severe factor VIII (FVIII)-deficient patients with and without FVIII inhibitors cannot be distinguished using FVIII levels. The FVIII assay is sensitive to detect factor levels below 1%. While severe FVIII-deficient, non-inhibitor patients have FVIII < 1%, they may retain unmeasurable residual factor activity. In contrast, inhibitor patients have a FVIII antibody that presumably fully eliminates FVIII activity. It is unknown whether thromboelastography (TEG) and thrombin generation assay (TGA) can differentiate between patients with FVIII < 1% with and without the presence of FVIII inhibitors. The primary objective was to discern whether TEG and TGA could differentiate between severe FVIII-deficient patients with and without the presence of FVIII inhibitors. A secondary objective was to correlate TEG and TGA to annualized bleeding rates. This observational study performed TEG and TGA in healthy volunteers (N = 15), severe FVIII deficient (N = 15) and severe FVIII-deficient patients with inhibitors (N = 15). Kaolin-activated TEG was better at differentiating reaction time (31.3 vs. 120 min respectively, P = 0.004) and kinetics time (6.1 vs. 23.1 min respectively, P = 0.028) between the non-inhibitor and inhibitor patients. TEG activated by tissue factor in plasma-containing corn trypsin inhibitor failed to differentiate groups. The TGA failed to differentiate peak thrombin, endogenous thrombin potential and lag time between groups. There was no correlation between TEG and TGA with annualized bleeding rates. Kaolin-activated TEG, but not TGA, differentiated between severe FVIII-deficient patients with and without inhibitors. These assays did not find a correlation to annualized bleeding rate. PMID- 25495851 TI - Skatole remediation potential of Rhodopseudomonas palustris WKU-KDNS3 isolated from an animal waste lagoon. AB - Skatole (3MI) is a major contributor to the malodor emission resulting from ruminant and human faeces. The remediation of malodor has been a major challenge for the animal production industry. In this investigation, a pure culture of purple nonsulphur bacterium capable of degrading 3MI was isolated from a swine waste lagoon using an enrichment technique and identified as Rhodopseudomonas palustris WKU-KDNS3 based on 16S rRNA analysis and UV-visible spectroscopy. The cell structure of the organism was confirmed by transmission electron microscopy. Growth profile and 3MI removal pattern were determined using media supplemented with 0.1 MUmol 3MI under short-term and long-term aerobic growth conditions. The organism grew on 3MI media as luxuriantly as control (without 3MI). Growth of R. palustris WKU-KDNS3 demonstrated a significant reduction in the level of 3MI (>48%) in 72 h. The level of 3MI dropped further by >93% of the total concentration present in the medium in 21 days. Skatole remediation potential of R. palustris WKU-KDNS3 can be judiciously utilized in various animal and industrial waste treatment systems. SIGNIFICANCE AND IMPACT OF THE STUDY: Odour pollution is a serious environmental problem, particularly in the agriculture industry, and technologies based on chemical remediation are less effective and cost prohibitive. In this study, the newly isolated Rhodopseudomonas palustris strain WKU-KDNS3 causes biodegradation of 3-methylindole (skatole), which is one of the most offensive odorants present in wastewater lagoons. Aerobic degradation of this widely spread aromatic pollutant by Rhodopseudomonas strain is a significant finding that enhances the present understanding about metabolic versatility of purple photosynthetic nonsulphur bacteria. The remediation potential of R. palustris WKU-KDNS3 can also be gainfully utilized in various waste treatment facilities. PMID- 25495852 TI - Clinical Features, Risk Factors, and Treatments of Microsporidial Epithelial Keratitis. AB - OBJECTIVE: To report the clinical manifestations, risk factors, and treatments of microsporidial epithelial keratitis in Thailand. METHODS: Twenty eyes of 19 patients were diagnosed and the clinical presentations, risk factors, and management were analyzed. RESULTS: Of 19 patients, six patients (32%) had no apparent risk factors. Predisposing factors included soil exposure (6/19, 32%), water contamination (6/19, 32%), and eye liner (1/19, 4%). Twelve cases (63%) were detected in the rainy season. All cases presented with disseminated, punctated, elevated, epithelial keratitis. Corneal scrapings with Gram chromotrope staining were positive in all patients. Moxifloxacin 0.5% eye drops were given and all 16 patients experienced complete resolution. Three recurrent cases were resolved with only topical moxifloxacin without corneal scraping or swabbing. CONCLUSIONS: Predisposing factors were not found in some patients; thus, corneal scraping with staining should be considered in cases having a high index of suspicion. The incidence is increased during the rainy season; therefore, clinicians should have more awareness during these times. Debridement with topical moxifloxacin eye drops, without any systemic medication, may be an effective treatment. Corneal scraping or swabbing may not be required in recurrences. PMID- 25495853 TI - 5-hydroxymethylfurfural conversion by fungal aryl-alcohol oxidase and unspecific peroxygenase. AB - Oxidative conversion of 5-hydroxymethylfurfural (HMF) is of biotechnological interest for the production of renewable (lignocellulose-based) platform chemicals, such as 2,5-furandicarboxylic acid (FDCA). To the best of our knowledge, the ability of fungal aryl-alcohol oxidase (AAO) to oxidize HMF is reported here for the first time, resulting in almost complete conversion into 2,5-formylfurancarboxylic acid (FFCA) in a few hours. The reaction starts with alcohol oxidation, yielding 2,5-diformylfuran (DFF), which is rapidly converted into FFCA by carbonyl oxidation, most probably without leaving the enzyme active site. This agrees with the similar catalytic efficiencies of the enzyme with respect to oxidization of HMF and DFF, and its very low activity on 2,5 hydroxymethylfurancarboxylic acid (which was not detected by GC-MS). However, AAO was found to be unable to directly oxidize the carbonyl group in FFCA, and only modest amounts of FDCA are formed from HMF (most probably by chemical oxidation of FFCA by the H2 O2 previously generated by AAO). As aldehyde oxidation by AAO proceeds via the corresponding geminal diols (aldehyde hydrates), the various carbonyl oxidation rates may be related to the low degree of hydration of FFCA compared with DFF. The conversion of HMF was completed by introducing a fungal unspecific heme peroxygenase that uses the H2 O2 generated by AAO to transform FFCA into FDCA, albeit more slowly than the previous AAO reactions. By adding this peroxygenase when FFCA production by AAO has been completed, transformation of HMF into FDCA may be achieved in a reaction cascade in which O2 is the only co substrate required, and water is the only by-product formed. PMID- 25495854 TI - Total serum IgE level influences oral food challenge tests for IgE-mediated food allergies. AB - Probability curves predicting oral food challenge test (OFC) results based on specific IgE levels are widely used to prevent serious allergic reactions. Although several confounding factors are known to affect probability curves, the main factors that affect OFC outcomes are currently unclear. We hypothesized that an increased total IgE level would reduce allergic reactivity. Medical records of 337 and 266 patients who underwent OFCs for 3.5 g boiled hen's egg white and 3.1 ml raw cow's milk, respectively, were examined retrospectively. We subdivided the patients into three groups based on total IgE levels and age by percentile (<25th, 25-75th, and >75th percentiles), and logistic regression analyses were performed on each group. Patients with higher total IgE levels were significantly less responsive. In addition, age did not significantly affect the OFC results. Therefore, total IgE levels should be taken into account when predicting OFC results based on food-specific IgE levels. PMID- 25495855 TI - Long-term outcome in patients with obscure gastrointestinal bleeding after capsule endoscopy. AB - OBJECTIVE: This study aimed to identify the risk factors associated with rebleeding and long-term outcomes after capsule endoscopy (CE) for obscure gastrointestinal bleeding (OGIB) in a follow-up study. METHODS: Data of consecutive patients who underwent CE due to OGIB from June 2002 to January 2012 were retrospectively reviewed. The Cox proportional hazard model was used to evaluate the risk factors associated with rebleeding, while Kaplan-Meier survival curves and the log-rank test were used to analyze cumulative rebleeding rates. RESULTS: The overall rebleeding rate after CE in patients with OGIB was 28.6% (97/339) during a median follow-up of 48 months (range 12-112 months). Multivariate analysis showed that age >=60 years (hazard ratio [HR] 2.473, 95% confidence interval [CI] 1.576-3.881, P = 0.000), positive CE findings (HR 3.393, 95% CI 1.931-5.963, P = 0.000), hemoglobin <=70 g/L before CE (HR 2.010, 95% CI 1.261-3.206, P = 0.003), nonspecific treatments (HR 2.500, 95% CI 1.625-3.848, P = 0.000) and the use of anticoagulants, antiplatelet or non-steroidal anti inflammatory drugs after CE (HR 2.851, 95% CI 1.433-5.674, P = 0.003) were independent risk factors associated with rebleeding. Univariate analysis showed that chronic hepatitis was independently associated with rebleeding in CE negative patients (P = 0.021). CONCLUSIONS: CE has a significant impact on the long-term outcome of patients with OGIB. Further investigation and close follow up in patients with OGIB and those with negative CE findings are necessary. PMID- 25495856 TI - Retinal photography screening programs to prevent vision loss from diabetic retinopathy in rural and urban Australia: a review. AB - PURPOSE: This review assessed the effectiveness of diabetic retinopathy (DR) screening programs, using retinal photography in Australian urban and rural settings, and considered implications for public health strategy and policy. METHODS: An electronic search of MEDLINE, PubMed, and Embase for studies published between 1 January 1996 and the 30 June 2013 was undertaken. Key search terms were "diabetic retinopathy," "screening," "retinal photography" and "Australia." RESULTS: Twelve peer-reviewed publications were identified. The 14 DR screening programs identified from the 12 publications were successfully undertaken in urban, rural and remote communities across Australia. Locations included a pathology collection center, and Indigenous primary health care and Aboriginal community controlled organizations. Each intervention using retinal photography was highly effective at increasing the number of people who underwent screening for DR. The review identified that prior to commencement of the screening programs a median of 48% (range 16-85%) of those screened had not undergone a retinal examination within the recommended time frame (every year for Indigenous people and every 2 years for non-Indigenous people in Australia). A median of 16% (range 0-45%) of study participants had evidence of DR. CONCLUSIONS: This review has shown there have been many pilot and demonstration projects in rural and urban Australia that confirm the effectiveness of retinal photography-based screening for DR. PMID- 25495857 TI - Long-term controlled release of PLGA microparticles containing antidepressant mirtazapine. AB - The aim of the study was to prepare PLGA microparticles for prolonged release of mirtazapine by o/w solvent evaporation method and to evaluate effects of PVA concentration and organic solvent choice on microparticles characteristics (encapsulation efficiency, drug loading, burst effect, microparticle morphology). Also in vitro drug release tests were performed and the results were correlated with kinetic model equations to approximate drug release mechanism. It was found that dichloromethane provided microparticles with better qualities (encapsulation efficiency 64.2%, yield 79.7%). Interaction between organic solvent effect and effect of PVA concentration was revealed. The prepared samples released the drug for 5 days with kinetics very close to that of zero order (R(2 )= 0.9549 - 0.9816). According to the correlations, the drug was probably released by a combination of diffusion and surface erosion, enhanced by polymer swelling and chain relaxation. PMID- 25495858 TI - Muscle function in aged women in response to a water-based exercises program and progressive resistance training. AB - AIM: The purpose of the present study was to determine the effects of a water based exercise program on muscle function compared with regular high-intensity resistance training. METHODS: Older women (n = 87) were recruited from the local community. The inclusion criteria were, to be aged 60 years or older, able to walk and able to carry out daily living activities independently. Participants were randomly assigned to one of the following groups: water-based exercises (WBG), resistance training (RTG) or control (CG). The experimental groups carried out 12 weeks of an excise program performed on water or on land. The dynamic strength, the isometric peak, and rate of torque development for the lower limbs were assessed before and after interventions. RESULTS: The water-based program provided a similar improvement in dynamic strength in comparison with resistance training. The isometric peak torque increased around the hip and ankle joints in the water-based group, and around the knee joint in the resistance-training group (P < 0.05). The rate of torque development increased only in the water-based group around the hip extensors muscles (P < 0.05). CONCLUSIONS: Water-based programs constitute an attractive alternative to promote relevant strength gains using moderate loads and fast speed movements, which were also effective to improve the capacity to generate fast torques. PMID- 25495859 TI - Explaining low rates of sustained use of siphon water filter: evidence from follow-up of a randomised controlled trial in Bangladesh. AB - OBJECTIVE: To assess sustained siphon filter usage among a low-income population in Bangladesh and study relevant motivators and barriers. METHODS: After a randomised control trial in Bangladesh during 2009, 191 households received a siphon water filter along with educational messages. Researchers revisited households after 3 and 6 months to assess filter usage and determine relevant motivators and barriers. Regular users were defined as those who reported using the filter most of the time and were observed to be using the filter at follow-up visits. Integrated behavioural model for water, sanitation and hygiene (IBM-WASH) was used to explain factors associated with regular filter use. RESULTS: Regular filter usage was 28% at the 3-month follow-up and 21% at the 6-month follow-up. Regular filter users had better quality water at the 6-month, but not at the 3 month visit. Positive predictors of regular filter usage explained through IBM WASH at both times were willingness to pay >US$1 for filters, and positive attitude towards filter use (technology dimension at individual level); reporting boiling drinking water at baseline (psychosocial dimension at habitual level); and Bengali ethnicity (contextual dimension at individual level). Frequently reported barriers to regular filter use were as follows: considering filter use an additional task, filter breakage and time required for water filtering (technology dimension at individual level). CONCLUSION: The technological, psychosocial and contextual dimensions of IBM-WASH contributed to understanding the factors related to sustained use of siphon filter. Given the low regular usage rate and the hardware-related problems reported, the contribution of siphon filters to improving water quality in low-income urban communities in Bangladesh is likely to be minimal. PMID- 25495860 TI - Bioorthogonal tetrazine-mediated transfer reactions facilitate reaction turnover in nucleic acid-templated detection of microRNA. AB - Tetrazine ligations have proven to be a powerful bioorthogonal technique for the detection of many labeled biomolecules, but the ligating nature of these reactions can limit reaction turnover in templated chemistry. We have developed a transfer reaction between 7-azabenzonorbornadiene derivatives and fluorogenic tetrazines that facilitates turnover amplification of the fluorogenic response in nucleic acid-templated reactions. Fluorogenic tetrazine-mediated transfer (TMT) reaction probes can be used to detect DNA and microRNA (miRNA) templates to 0.5 and 5 pM concentrations, respectively. The endogenous oncogenic miRNA target mir 21 could be detected in crude cell lysates and detected by imaging in live cells. Remarkably, the technique is also able to differentiate between miRNA templates bearing a single mismatch with high signal to background. We imagine that TMT reactions could find wide application for amplified fluorescent detection of clinically relevant nucleic acid templates. PMID- 25495861 TI - Split-bolus versus triphasic multidetector-row computed tomography technique in the diagnosis of hepatic focal nodular hyperplasia: a case report. AB - INTRODUCTION: Computed tomography and magnetic resonance imaging are able to demonstrate and to diagnose hepatic focal nodular hyperplasia when a typical pattern of a well-circumscribed lesion with a central scar is present.Our aim is to propose the split-bolus multidetector-row computed tomography technique as an alternative to the conventional triphasic technique in the detection and characterization of focal nodular hyperplasia to reduce the radiation dose to the patient.To the best of our knowledge, this is the first report regarding the application of the split-bolus computed tomography technique in the evaluation of hepatic focal nodular hyperplasia. CASE PRESENTATION: We describe a case of focal nodular hyperplasia of the liver in a 53-year-old Caucasian woman (weight 75Kg) with a colorectal adenocarcinoma histologically confirmed. An innovative split bolus multidetector-row computed tomography technique was used that, by splitting intravenous contrast material in two boli, combined two phases (hepatic arterial phase and portal venous phase) in a single pass; a delayed (5 minutes) phase was obtained to compare the findings with that of triphasic multidetector-row computed tomography. CONCLUSIONS: Split-bolus multidetector-row computed tomography was able to show the same appearance of the lesion as the triphasic multidetector-row computed tomography technique.This is the first case demonstrating the effectiveness of the split-bolus multidetector-row computed tomography technique in the detection and characterization of focal nodular hyperplasia with a significant reduction in radiation dose to the patient with respect to triphasic multidetector-row computed tomography technique. PMID- 25495862 TI - Intensive weight loss combining flexible dialysis with a personalized, ad libitum, coach-assisted diet program. A "pilot" case series. AB - Obesity is a growing problem on dialysis. The best approach to weight loss has not been established. The risks of malnutrition may offset the advantages of weight loss. Personalized hemodialysis schedules, with an incremental approach, are gaining interest; to date, no studies have explored its potential in allowing weight loss. This case series reports on combining flexible, incremental hemodialysis, and intensive weight loss. SETTING: a small Dialysis Unit, following incremental personalized schedules (2-6 sessions/week, depending on residual function), tailored to an equivalent renal clearance >12 mL/min. Four obese and two overweigh patients (5 male, 1 female; age: 40-63 years; body mass index [BMI] 31.1 kg/m(2)) were enrolled in a coach-assisted weight loss program, with an "ad libitum" approach (3-6 foods/day chosen on the basis of their glycemic index and glycemic load). The diet consists of 8 weeks of rapid weight loss followed by 8-12 weeks of maintenance; both phases can be repeated. This study measures weight loss, side effects, and patients' opinions. Over 12-30 months, all patients lost weight (median -10.3 kg [5.7-20], median DeltaBMI-3.2). Serum albumin (pre-diet 3.78; post-diet 3.83 g/dL), hemoglobin (pre-diet 11; post diet 11.2 g/dL), and acid-base balance (HCO(3) pre-diet: 23.3; post-diet: 23.4 mmol/L) remained stable, with decreasing needs for erythropoietin and citrate or bicarbonate supplements. Calcium-phosphate-parathyroid hormone (PTH) balance improved (PTH-pre 576; post 286 pg/mL). Three out of 4 hypertensive patients discontinued, 1 decreased antihypertensives. None experienced severe side effects. Patient satisfaction was high (9 on a 0-10 analog scale). Personalized, incremental hemodialysis schedules allow patient enrollment in intensive personalized weight loss programs, with promising results. PMID- 25495863 TI - Japanese nurse practitioner practice and outcomes in a nursing home. AB - AIM: By describing the practice of a Japanese nurse practitioner, this descriptive case study discusses role development and outcomes before and after the intervention. BACKGROUND: One of the first Japanese nurse practitioners intervened at a nursing home during the government-designated trial period for nurse practitioner practice. CONCLUSION: Because of the nurse practitioner's meticulous observation and timely care provision to the residents in collaboration with the physician and the other staff in the facility, comparative data showed improvement in daily health status management of every resident and decreased deterioration of residents' health conditions requiring ambulance transfer and hospitalization. PMID- 25495864 TI - An exploratory mixed methods analysis of adherence predictors following acute coronary syndrome. AB - Adherence to cardiac health behaviors is a critical predictor of prognosis in the months following an acute coronary syndrome (ACS). However, there has been minimal concomitant study of multiple nonadherence risk factors, as assessed via record review, structured assessments, and qualitative interviews, among hospitalized ACS patients. Accordingly, we completed an exploratory mixed methods study with 22 individuals who were admitted for ACS and had suboptimal pre-ACS adherence to physical activity, heart-healthy diet, and/or medications, defined by a Medical Outcomes Study Specific Adherence Scale (MOS SAS) score <15/18. During hospitalization, participants underwent quantitative assessments of sociodemographic, medical, and psychological variables, followed by in-depth semi structured interviews to explore intentions, plans, and perceived barriers related to post-discharge health behavior changes. The MOS SAS was readministered at 3 months and participants were designated as persistently nonadherent (MOS SAS <15; n = 9) or newly adherent (n = 13). Interviews were transcribed and coded by trained raters via content analysis, and quantitative variables were compared between groups using chi-square analysis and independent-samples t-tests. On our primary qualitative analysis, we found that participants with vaguely described intentions/plans regarding health behavior change, and those who focused on barriers to change that were perceived as static, were more likely to be persistently nonadherent. On exploratory quantitative analyses, greater medical burden, diabetes, depressive symptoms, and low optimism/positive affect at baseline were associated with subsequent post-ACS nonadherence (all p < .05). In conclusion, this appears to be the first study to prospectively examine all of these constructs in hospitalized ACS patients, and we found that specific factors were associated with nonadherence to key health behaviors 3 months later. Therefore it may be possible to predict future nonadherence in ACS patients, even during hospitalization, and specific interventions during admission may be indicated to prevent adverse outcomes among patients at highest risk for post-ACS nonadherence. PMID- 25495865 TI - Assessment of the Ocular Response Analyzer as an Instrument for Measurement of Intraocular Pressure and Corneal Biomechanics. AB - PURPOSE: The purpose of this study is to provide better understanding of the Ocular Response Analyzer (ORA) and how reliable it is to produce intraocular pressure (IOP) measurements that are free of the effects of corneal stiffness parameters, and stiffness estimates that are independent of IOP. MATERIALS AND METHODS: A numerical parametric study that closely represents the in-vivo conditions of the human eye and the ORA procedure was conducted to determine the correlation coefficient r(2) between ORA output and the values of true IOP and a number of stiffness parameters, namely corneal thickness, curvature and age. For the purpose of this exercise, the ORA output was put in the form k1P1+k2P2 where k1 and k2 were variables and P1 and P2 were ORA's measured applanation pressures. Two separate clinical datasets involving Moorfields Eye Hospital, London and the University of New South Wales, Sydney participants, respectively, were used to validate the numerical results. RESULTS: The numerical study results show a strong association between (k1P1 + k2P2) and the true IOP over a wide range of k1 and k2 values apart from a narrow region approximately extending from (k1 = +2, k2 = -2) to (k1 = -2, k2 = +2). On the other hand, (k1. P1 + k2. P2) was found to have a strong association with CCT, R and age (the stiffness parameters) over the same narrow region, beyond which the association was weak. Similar trends were found with the two clinical datasets. CONCLUSIONS: The results of this study show the potential of the ORA to provide reliable IOP measurements with weak dependence on the cornea's stiffness parameters and the considerably reduced reliability in producing stiffness estimates that are unaffected by IOP values. PMID- 25495866 TI - Enrichment and activity of methanotrophic microorganisms from municipal wastewater sludge. AB - In this study, methanotrophic microorganisms were enriched from a municipal wastewater sludge taken from an Upflow Anaerobic Sludge Blanket reactor. The enrichment was performed in a sequencing batch reactor (SBR) with an autotrophic medium containing nitrite and nitrate. The microbial community composition of the inoculum and of the enrichment culture after 100 days of SBR operation was investigated and compared with the help of data obtained from 454 pyrosequencing analyses. The nitrite and nitrate removal efficiencies were 68% and 53%, respectively, probably due to heterotrophic denitrification. Archaeal cells of the anaerobic methanotrophic Archaic (ANME)-I and ANME-II groups were detected by polymerase chain reaction throughout the whole cultivation period. Pyrosequencing analysis showed that community composition was different among the two samples analysed. The dominant phyla found in the inoculum were Synergistestes, Firmicutes and Euryarchaeota, while Planctomycetes, Verrucomicrobia, Chloroflexi and Proteobacteria prevailed in the enriched biomass. The cultivation conditions decreased Methanobacterium abundance from 8% to 1%, and enriched for methanotrophic bacteria such as Methylocaldum, Methylocistis and Methylosinus. Sequences of Methylocaldum sp. accounted for 2.5% of the total reads. The presence and high predominance of Verrucomicrobia in the enriched biomass suggested that other unknown methanotrophic species related to that phylum might also have occurred in the reactor. Anaerobic methane oxidation activity was measured for both samples, and showed that the activity of the enrichment culture was nearly three times higher than the activity of the inoculum. Taken together, these results showed that the inoculum type and cultivation conditions were properly suited for methanotrophic enrichment. PMID- 25495867 TI - Quality of life in mothers of preschoolers with high-functioning pervasive developmental disorders. AB - BACKGROUND: Parents of children with pervasive developmental disorders (PDD) are likely to experience serious distress. The aims of this study were to (i) assess distress among mothers of preschoolers with high-functioning PDD (HFPDD); and (ii) examine its relation to the child's behavioral characteristics. METHODS: Participants were 30 mothers of preschoolers with HFPDD, and 30 mothers of a matched control group. Short Form 36 Health Survey Questionnaire (version 2), and the Strengths and Difficulties Questionnaire were used for assessment. The children's autistic traits were assessed using the total number of items for the DSM-IV-TR autistic disorder diagnosis. RESULTS: Mothers in the HFPDD group were more distressed mentally than physically. Neither physical nor mental distress in the group was related to the child's autistic traits, while their mental distress was significantly related to the child's behavior problems. CONCLUSIONS: Mothers in the HFPDD group were at increased risk of impaired mental wellbeing. Maternal mental distress in the group was significantly related to general behavior problems, but not to autistic traits in the child. PMID- 25495868 TI - Itolizumab provides sustained remission in plaque psoriasis: a 5-year follow-up experience. AB - There is an unmet need for psoriasis therapies that provide long-term remission. Itolizumab is a humanized recombinant anti-CD6 monoclonal antibody shown to be effective in psoriasis. We report a patient who received itolizumab in a phase 2 clinical trial, and experienced long-term remission. At baseline, the patient's Psoriasis Area and Severity Index (PASI) was 12.2, and Physician's Global Assessment (PGA) score was 3. After 8 weeks of treatment, the patient achieved 97% improvement in PASI. She continued to have >= 90% improvement, initially for 4 weeks (follow-up phase), and later for 20 weeks (follow-up extension phase). She continued to visit the hospital after the final study visit; her most recent visit was on 10 May 2013. PGA results during the visits revealed sustained response for 4 years and 5 months after stopping itolizumab. Itolizumab could be therefore an important treatment option for moderate to severe psoriasis, with potential to provide long-lasting remission. PMID- 25495869 TI - Prevention of aggregation and renaturation of carbonic anhydrase via weak association with octadecyl- or azobenzene-modified poly(acrylate) derivatives. AB - The prevention of aggregation during renaturation of urea-denatured carbonic anhydrase B (CAB) via hydrophobic and Coulomb association with anionic polymers was studied in mixed solutions of CAB and amphiphilic poly(acrylate) copolymers. The polymers were derivatives of a parent poly(acrylic acid) randomly grafted with hydrophobic side groups (either 3 mol % octadecyl group, or 1-5 mol % alkylamidoazobenzene photoresponsive groups). CAB:polymer complexes were characterized by light scattering and fluorescence correlation spectroscopy in aqueous buffers (pH 7.75 or 5.9). Circular dichroism and enzyme activity assays enabled us to study the kinetics of renaturation. All copolymers, including the hydrophilic PAA parent chain, provided a remarkable protective effect against CAB aggregation during renaturation, and most of them (but not the octadecyl-modified one) markedly enhanced the regain of activity as compared to CAB alone. The significant role of Coulomb binding in renaturation and comparatively the lack of efficacy of hydrophobic association was highlighted by measurements of activity regain before and after in situ dissociation of hydrophobic complexes (achieved by phototriggering the polarity of azobenzene-modified polymers under exposure to UV light). In the presence of polymers (CAB:polymer of 1:1 w/w ratio) at concentration ~0.6 g L(-1), the radii of the largest complexes were similar to the radii of the copolymers alone, suggesting that the binding of CAB involves one or a few polymer chain(s). These complexes dissociated by dilution (0.01 g L( 1)). It is concluded that prevention of irreversible aggregation and activity recovery were achieved when marginally stable complexes are formed. Reaching a balanced stability of the complex plays the main role in CAB renaturation, irrespective of the nature of the binding (by Coulomb association, with or without contribution of hydrophobic association). PMID- 25495871 TI - How to cure AIDS: feeling the elephant. PMID- 25495870 TI - Thioredoxin reductase activity may be more important than GSH level in protecting human lens epithelial cells against UVA light. AB - This study compares the abilities of the glutathione (GSH) and thioredoxin (Trx) antioxidant systems in defending cultured human lens epithelial cells (LECs) against UVA light. Levels of GSH were depleted with either L-buthionine-(S,R) sulfoximine (BSO) or 1-chloro-2,4-dinitrobenzene (CDNB). CDNB treatment also inhibited the activity of thioredoxin reductase (TrxR). Two levels of O2 , 3% and 20%, were employed during a 1 h exposure of the cells to 25 J cm(-2) of UVA radiation (338-400 nm wavelength, peak at 365 nm). Inhibition of TrxR activity by CDNB, combined with exposure to UVA light, produced a substantial loss of LECs and cell damage, with the effects being considerably more severe at 20% O2 compared to 3%. In contrast, depletion of GSH by BSO, combined with exposure to UVA light, produced only a slight cell loss, with no apparent morphological effects. Catalase was highly sensitive to UVA-induced inactivation, but was not essential for protection. Although UVA light presented a challenge for the lens epithelium, it was well tolerated under normal conditions. The results demonstrate an important role for TrxR activity in defending the lens epithelium against UVA light, possibly related to the ability of the Trx system to assist DNA synthesis following UVA-induced cell damage. PMID- 25495872 TI - Glucocorticoids regulate the metabolic hormone FGF21 in a feed-forward loop. AB - Hormones such as fibroblast growth factor 21 (FGF21) and glucocorticoids (GCs) play crucial roles in coordinating the adaptive starvation response. Here we examine the interplay between these hormones. It was previously shown that FGF21 induces corticosterone levels in mice by acting on the brain. We now show that this induces the expression of genes required for GC synthesis in the adrenal gland. FGF21 also increases corticosterone secretion from the adrenal in response to ACTH. We further show that the relationship between FGF21 and GCs is bidirectional. GCs induce Fgf21 expression in the liver by acting on the GC receptor (GR). The GR binds in a ligand-dependent manner to a noncanonical GR response element located approximately 4.4 kb upstream of the Fgf21 transcription start site. The GR cooperates with the nuclear fatty acid receptor, peroxisome proliferator-activated receptor-alpha, to stimulate Fgf21 transcription. GR and peroxisome proliferator-activated receptor-alpha ligands have additive effects on Fgf21 expression both in vivo and in primary cultures of mouse hepatocytes. We conclude that FGF21 and GCs regulate each other's production in a feed-forward loop and suggest that this provides a mechanism for bypassing negative feedback on the hypothalamic-pituitary-adrenal axis to allow sustained gluconeogenesis during starvation. PMID- 25495873 TI - Activation of Gq/11 in the mouse corpus luteum is required for parturition. AB - Mice with a deletion of Galpha(q/11) in granulosa cells were previously shown to be subfertile. They also have a reduced ovulatory response due to a deficiency in the ability of the activated LH receptor to fully induce the granulosa cell progesterone receptor. Because this conditional deletion of Galpha(q/11) will interfere with the actions of any G protein-coupled receptor that activates G(q/11) in granulosa or luteal cells, we sought to determine whether the actions of other hormones that contribute to fertility were also impaired. We focused our attention on prostaglandin F2 (PGF2)alpha, because this hormone is known to activate phospholipase C (a prominent Galpha(q/11) effector) in luteal cells and because the action of PGF2alpha on luteal cells is the first step in the murine parturition pathway. Our data show that the conditional deletion of Galpha(q/11) from granulosa cells prevents the ability of PGF2alpha to induce Akr1c18 in luteal cells. Akr1c18 codes for 20alpha-hydroxysteroid dehydrogenase, an enzyme that inactivates progesterone. The PGF2alpha-mediated induction of this enzyme towards the end of pregnancy increases the inactivation of progesterone and precipitates parturition in mice. Thus, the conditional deletion of Galphaq/11 from granulosa/luteal cells prevents the progesterone withdrawal that occurs at the end of pregnancy and impairs parturition. This novel molecular defect contributes to the subfertile phenotype of the mice with a deletion of Galpha(q/11) from granulosa cells. PMID- 25495874 TI - Management and outcome in adult intramedullary spinal cord tumours: a 20-year single institution experience. AB - BACKGROUND: Several uncertainties remain concerning the management of intramedullary spinal cord tumours (IMSCTs). These include the timing and extent of resection, its interrelated functional outcome, and the adequate use and timing of radiation therapy and/or chemotherapy. In this retrospective study we report on all adult cases involving IMSCTs treated from 1987 to 2007 in our institution to validate our treatment strategy for IMSCTs. Pre- and post operative functional performance was classified according to the McCormick scale. RESULTS: A total of 70 adult cases with IMSCTs consisting of ependymoma (39), astrocytoma (11), carcinoma metastasis (8), haemangioblastoma (5), cavernoma (3) and others (4) were reviewed. Mean age was 46.8 years (range, 18-79 years), and mean follow-up was 4.5 years (range, 1-195 months). The proportion of localisation in descending order was thoracic (36%), cervical (33%), cervicothoracic (19%) and conus region (13%), with 45 gross total resections, 22 partial resections and three biopsies. Surgery-related morbidity with worsening postoperative symptoms occurred immediately in 13 patients (18.6%). The preoperative McCormick grade correlated significantly with the early postoperative grade and the grade at follow-up (chi2-test; p=0.001). None of the patients with preserved intraoperative evoked potentials exhibited significant postoperative deterioration. The degree of resection was correlated with progression-free survival (Duncan test; p=0.05). Most patients with malignant tumours, namely anaplastic ependymoma (3), astrocytoma (2) or metastatic lesions (5), underwent postoperative radiation therapy. Six patients (one anaplastic ependymoma, two anaplastic astrocytomas and three metastatic lesions) received postoperative chemotherapy. CONCLUSIONS: IMSCTs should be operated on when symptoms are mild. We recommend evoked potential-guided microsurgical total resection of ependymomas and other benign lesions; partial resection or biopsy followed by adjuvant therapy should be confined to patients with high-grade astrocytomas, whereas resection or biopsy with adjuvant therapy is the best option for metastatic lesions. PMID- 25495876 TI - Results From Three Performance Validity Tests in Children With Intellectual Disability. AB - If we wish to conclude that failure on a performance validity test (PVT) is a false positive for poor effort, we must have evidence that the person is truly incapable of passing the test because of cognitive impairment. We must show that they have a diagnostic condition that is sufficient to account fully for failure on that test. The purpose of the current study was to evaluate the performance of children with a primary diagnosis of intellectual disability (ID) on the Word Memory Test (WMT), the Medical Symptom Validity Test (MSVT), and the Nonverbal Medical Symptom Validity Test (Green, 2003 , 2004 , 2008b ; Green & Astner, 1995 ). If a Full-Scale IQ (FSIQ) less than 70 could account for failure on these tests in adults, then children with ID would also fail them. In fact, the children with ID in the current study did not fail the WMT or MSVT as long as they had at least a Grade 3 reading level. Also, the children with ID did not fail these tests any more often than did children of significantly higher intelligence. The data suggest that an FSIQ in the range of 48 to 70 is not sufficient to explain failure on these PVTs by children or adults. PMID- 25495875 TI - Effect of professional mechanical plaque removal performed on a long-term, routine basis in the secondary prevention of periodontitis: a systematic review. AB - AIMS: To systematically review the evidence evaluating the efficacy of long-term, routine, professional mechanical plaque removal (PMPR) in the prevention of periodontitis progression. METHODS: A literature search was conducted to identify prospective studies evaluating the effect of PMPR in periodontitis patients undergoing active periodontal therapy and enrolled in a maintenance programme including PMPR for at least 3 years. RESULTS: No RCTs evaluating the efficacy of the intervention when compared with no treatment during maintenance were found. Nineteen prospective studies assessing the effect of PMPR as part of the supportive therapy were included. In general, studies reported no to low incidence of tooth loss during follow-up. The weighted mean yearly rate of tooth loss was 0.15 +/- 0.14 and 0.09 +/- 0.08 for follow-up of 5 years or 12-14 years, respectively, with no significant differences between groups. Mean clinical attachment loss was <1 mm at follow-up ranging from 5 to 12 years. CONCLUSIONS: Supportive therapy, which encompasses PMPR, may limit the incidence and yearly rate of tooth loss as well as the loss in clinical attachment in patients treated for periodontitis. However, whether and to what extent the intervention may impact on long-term periodontal parameters still needs to be assessed. PMID- 25495877 TI - Physical activity perceptions and beliefs following total hip and knee arthroplasty: a qualitative study. AB - BACKGROUND: Despite improvements in pain and physical capacity experienced by patients following total hip arthroplasty (THA) and total knee arthroplasty (TKA), recent studies suggest that levels of physical activity may not change. This study aimed to qualitatively explore people's beliefs and perspectives about physical activity at 6 months following THA or TKA for the treatment of osteoarthritis (OA). METHODS: Semi-structured interviews were conducted with 10 participants (age range 51-78 years) at 6 months post-arthroplasty surgery. Participants were recruited from a concurrent larger quantitative study examining quantitative physical activity levels via accelerometers. Interviews were transcribed, coded and analysed using a thematic approach. RESULTS: Participants described greater capacity to be physically active post-surgery despite no increase in objective measures. Three themes emerged from the interviews relating to the participants perspective of physical activity after surgery: (1) physical activity is for enjoying living; (2) new limitations on physical activity: age and comorbidities; and (3) personal beliefs about physical activity: it is enough to know you can. CONCLUSION: Individual beliefs and perceptions are important in understanding factors influencing physical activity following THA and TKA. Health practitioners should examine this when developing management plans aimed at optimizing physical activity. PMID- 25495878 TI - Phosphorus binding with ferric citrate is associated with fewer hospitalizations and reduced hospitalization costs. AB - BACKGROUND: Ferric citrate (FC) is a new phosphorus binder shown to increase serum iron stores while reducing intravenous iron and erythropoiesis-stimulating agent usage. Such reductions could lower hospitalization rates and associated costs. METHODS: Hospitalizations during a Phase III trial were compared between FC and active control (AC). Hospitalization costs were estimated using the 2013 US Renal Data System Annual Data Report. RESULTS: 34.6% of FC patients were hospitalized at least once versus 45.6% of the AC group (risk reduction 24.2%; p = 0.02). There were 181 unique hospitalizations in the FC group versus 239 in the AC group, for a difference of 58 hospitalizations. Total potential savings was US$ 867,622 in hospitalization costs in the FC group. If the hospitalization reduction in our study was applied to the general end-stage renal disease population, this could translate into a savings of US$ 3002/patient/year. CONCLUSIONS: Patients receiving FC experienced fewer hospitalizations with the potential for significant savings. PMID- 25495879 TI - Antioxidant activities and phenolics profiling of different parts of Carica papaya by LCMS-MS. AB - This article deals with the comparison of the antioxidant activity of aqueous extracts of various parts of Carica papaya L. The evaluation of total phenolic content and total flavonoid content revealed high antioxidant potential of the seeds and fruits. The free radical-scavenging potential of the aqueous extracts indicated the seeds to have better DPPH-scavenging activity than fruits. The results were augmented by the FRAP activity as well. The phenolics present in the extracts were separated and identified as 5-hydroxy feruloyl quinic acid, acetyl p-coumaryl quinic acid, quercetin-3-O-rhamnoside, syringic acid hexoside, 5 hydroxy caffeic quinic acid, peonidin-3-O-glucoside, sinapic acid-O-hexoside, cyaniding-3-O-glucose and methyl feruloyl glycoside by LCMS-MS technique. PMID- 25495880 TI - Vitiligo treatment update. AB - Vitiligo is a common depigmenting disease that can affect the skin and mucosal surfaces. Various treatments have been used over the years with varying repigmentation rates. This review looks at the evidence of commonly used therapies for vitiligo. PMID- 25495881 TI - Implication of FKBP6 for male fertility in horses. AB - In stallions, impaired acrosome reaction (IAR) may often cause subfertility. Single nucleotide polymorphisms (SNPs) within FK506-binding protein (FKBP6) seem to be associated with IAR in stallions. However, their effect on stallion fertility has not yet been quantified. Using whole-genome sequence data of seven stallions, we searched FKBP6 for mutations to perform an association study in Hanoverian stallions with estimated breeding values for the paternal component of the pregnancy rate per oestrus cycle (EBV-PAT) as target trait. Genotyping five exonic mutations within FKBP6 revealed a significant association of the SNP g.11040379C>A (p.167H>N) with EBV-PAT in 216 Hanoverian stallions. The difference among the two homozygous genotypes was 7.62% in EBV-PAT, corresponding to one standard deviation of EBV-PAT. In conclusion, in Hanoverian stallions, the FKBP6 associated SNP g.11040379C>A confers higher conception rates in A/A homozygous and lower conception rates in C/C homozygous Hanoverian stallions. Thus, an FKBP6 associated missense mutation is significantly associated with stallion fertility. PMID- 25495882 TI - Diagnostic practice of psychogenic nonepileptic seizures (PNES) in the pediatric setting. AB - OBJECTIVE: No formal guidelines for diagnosing psychogenic nonepileptic seizures (PNES) in children exist, and little is known about the clinical practice of diagnosing PNES in the pediatric setting. We therefore performed a national survey as a first step to document pediatricians' current diagnostic practice for PNES. METHODS: A questionnaire was distributed to all pediatricians (n=64) working in the field of neuropediatrics and/or social pediatrics in the Danish hospital setting to uncover their use of terminology and of the International Classification of Diseases, 10th Revision (ICD-10) codes as well as their clinical diagnostic approach to pediatric PNES. The questionnaire included questions on 18 history and 24 paroxysmal event characteristics. RESULTS: The response rate was 95% (61/64). There was no consensus on which terminology and diagnostic codes to use. Five history characteristics (psychosocial stressors/trauma, sexual abuse, paroxysmal events typically occur in stressful situations, no effect of antiepileptic drugs, and physical abuse) and six paroxysmal event characteristics (resisted eyelid opening, avoidance/guarding behavior, paroxysmal events occur in the presence of others, closed eyes, rarely injury related to paroxysmal event, and absence of postictal change) were agreed to be very predictive of PNES by at least 50% of the pediatricians. Supplementary diagnostic tests such as blood chemistry measurements (e.g., blood glucose or acute phase reactants; i.e., white blood cell count and C-reactive protein) and electrocardiography were inconsistently used. Only 49% of the respondents reported to use video-electroencephalography (VEEG) frequently as part of their diagnostic procedure. SIGNIFICANCE: To our knowledge, this is the first national survey that offers a systematic insight into the diagnostic practices for children with PNES in the hospital setting. The results demonstrate a need for clinical guidelines to improve and systematize the diagnostic approach for PNES in children. PMID- 25495883 TI - Highly-sensitive amplification-free analysis of multiple miRNAs by capillary electrophoresis. AB - Sets of deregulated microRNAs (miRNAs), termed miRNA signatures, are promising biomarkers for cancer. Validation of miRNA signatures requires a technique that is accurate, sensitive, capable of detecting multiple miRNAs, fast, robust, and not cost-prohibitive. Direct quantitative analysis of multiple miRNAs (DQAMmiR) is a capillary electrophoresis (CE)-based hybridization assay that was suggested as a methodological platform for validation and clinical use of miRNA signatures. While satisfying the other requirements, DQAMmiR is not sufficiently sensitive to detect low-abundance miRNAs. Here, we solve this problem by combining DQAMmiR with the preconcentration technique, isotachophoresis (ITP). The sensitivity improved 100 times (to 1 pM) allowing us to detect low-abundance miRNAs in an RNA extract. Importantly, ITP-DQAMmiR can be performed in a fully automated mode using a commercial CE instrument making it suitable for practical applications. PMID- 25495885 TI - Understanding mixed sequence DNA recognition by novel designed compounds: the kinetic and thermodynamic behavior of azabenzimidazole diamidines. AB - Sequence-specific recognition of DNA by small organic molecules offers a potentially effective approach for the external regulation of gene expression and is an important goal in cell biochemistry. Rational design of compounds from established modules can potentially yield compounds that bind strongly and selectively with specific DNA sequences. An initial approach is to start with common A.T bp recognition molecules and build in G.C recognition units. Here we report on the DNA interaction of a synthetic compound that specifically binds to a G.C bp in the minor groove of DNA by using an azabenzimidazole moiety. The detailed interactions were evaluated with biosensor-surface plasmon resonance (SPR), isothermal calorimetric (ITC), and mass spectrometry (ESI-MS) methods. The compound, DB2277, binds with single G.C bp containing sequences with sub nanomolar potency and displays slow dissociation kinetics and high selectivity. A detailed thermodynamic and kinetic study at different experimental salt concentrations and temperatures shows that the binding free energy is salt concentration dependent but essentially temperature independent under our experimental conditions, and binding enthalpy is temperature dependent but salt concentration independent. The results show that in the proper compound structural context novel heterocyclic cations can be designed to strongly recognize complex DNA sequences. PMID- 25495886 TI - Incidence of food anaphylaxis in people with food allergy: a systematic review and meta-analysis. AB - BACKGROUND: Food allergy is a common cause of anaphylaxis, but the incidence of anaphylaxis in food allergic people is unknown. METHODS: We undertook a systematic review and meta-analysis, using the inverse variance method. Two authors selected studies by consensus, independently extracted data and assessed study quality using the Newcastle-Ottawa assessment scale. We searched Medline, Embase, PsychInfo, CINAHL, Web of Science, LILACS and AMED between January 1946 and September 2012 and recent conference abstracts. We included registries, databases or cohort studies which described the number of food anaphylaxis cases in a defined population and time period and applied an assumed population prevalence of food allergy. RESULTS: We included data from 34 studies. There was high heterogeneity between study results, possibly due to variation in study populations, anaphylaxis definition and data collection methods. In food allergic people, medically coded food anaphylaxis had an incidence rate of 0.14 per 100 person-years (95% CI 0.05, 0.35; range 0.01, 1.28). In sensitivity analysis using different estimated food allergy prevalence, the incidence varied from 0.11 to 0.21 per 100 person-years. At age 0-19, the incidence rate for anaphylaxis in food allergic people was 0.20 (95% CI 0.09, 0.43; range 0.01, 2.55; sensitivity analysis 0.08, 0.39). At age 0-4, an incidence rate of up to 7.00 per 100 person years has been reported. In food allergic people, hospital admission due to food anaphylaxis had an incidence rate of 0.09 (95% CI 0.01, 0.67; range 0.02, 0.81) per 1000 person-years; 0.20 (95% CI 0.10, 0.43; range 0.04, 2.25) at age 0-19 and 0.50 (0.26, 0.93; range 0.08, 2.82) at age 0-4. CONCLUSION: In food allergic people, the incidence of food allergic reactions which are coded as anaphylaxis by healthcare systems is low at all ages, but appears to be highest in young children. PMID- 25495884 TI - N-acetylaspartate normalization in bipolar depression after lamotrigine treatment. AB - OBJECTIVES: The aim of the present study was to examine N-acetylaspartate (NAA), a general marker of neuronal viability, and total NAA (tNAA), the combined signal of NAA and N-acetylaspartylglutamate, in bipolar depression before and after lamotrigine treatment. Given that NAA is synthesized through direct acetylation of aspartate by acetyl-coenzyme A-l-aspartate-N-acetyltransferase, we hypothesized that treatment with lamotrigine would be associated with an increase in NAA level. METHODS: Patients with bipolar depression underwent two-dimensional proton magnetic resonance spectroscopy of the anterior cingulate at baseline (n = 15) and after 12 weeks of lamotrigine treatment (n = 10). A group of age-matched healthy controls (n = 9) underwent scanning at baseline for comparison. RESULTS: At baseline, patients with bipolar depression had significantly lower NAA [mean standard deviation (SD) = 1.13 (0.21); p = 0.02] than controls [mean (SD) = 1.37 (0.27)]. Significant increases in NAA [mean (SD) = 1.39 (0.21); p = 0.01] and tNAA [mean (SD) = 1.61 (0.25); p = 0.02] levels were found after 12 weeks of lamotrigine treatment. CONCLUSIONS: These data suggest an NAA deficit in bipolar depression that is normalized after lamotrigine treatment. Future research is warranted to evaluate whether baseline NAA level is a potential biomarker for identifying lamotrigine response patterns and whether this functional brain change has an associated clinical response. PMID- 25495888 TI - Structure-based design of a B cell antigen from B. pseudomallei. AB - Burkholderia pseudomallei is the etiological agent of melioidosis, a severe endemic disease in South-East Asia, causing septicemia and organ failure with high mortality rates. Current treatments and diagnostic approaches are largely ineffective. The development of new diagnostic tools and vaccines toward effective therapeutic opportunities against B. pseudomallei is therefore an urgent priority. In the framework of a multidisciplinary project tackling melioidosis through reverse and structural vaccinology, BPSL1050 was identified as a candidate for immunodiagnostic and vaccine development based on its reactivity against the sera of melioidosis patients. We determined its NMR solution structure and dynamics, and by novel computational methods we predicted immunogenic epitopes that once synthesized were able to elicit the production of antibodies inducing the agglutination of the bacterium and recognizing both BPSL1050 and B. pseudomallei crude extracts. Overall, these results hold promise for novel chemical biology approaches in the discovery of new diagnostic and prophylactic tools against melioidosis. PMID- 25495887 TI - Transcriptome profiling and pathway analysis of genes expressed differentially in participants with or without a positive response to topiramate treatment for methamphetamine addiction. AB - BACKGROUND: Developing efficacious medications to treat methamphetamine dependence is a global challenge in public health. Topiramate (TPM) is undergoing evaluation for this indication. The molecular mechanisms underlying its effects are largely unknown. Examining the effects of TPM on genome-wide gene expression in methamphetamine addicts is a clinically and scientifically important component of understanding its therapeutic profile. METHODS: In this double-blind, placebo controlled clinical trial, 140 individuals who met the DSM-IV criteria for methamphetamine dependence were randomized to receive either TPM or placebo, of whom 99 consented to participate in our genome-wide expression study. The RNA samples were collected from whole blood for 50 TPM- and 49 placebo-treated participants at three time points: baseline and the ends of weeks 8 and 12. Genome-wide expression profiles and pathways of the two groups were compared for the responders and non-responders at Weeks 8 and 12. To minimize individual variations, expression of all examined genes at Weeks 8 and 12 were normalized to the values at baseline prior to identification of differentially expressed genes and pathways. RESULTS: At the single-gene level, we identified 1054, 502, 204, and 404 genes at nominal P values < 0.01 in the responders vs. non-responders at Weeks 8 and 12 for the TPM and placebo groups, respectively. Among them, expression of 159, 38, 2, and 21 genes was still significantly different after Bonferroni corrections for multiple testing. Many of these genes, such as GRINA, PRKACA, PRKCI, SNAP23, and TRAK2, which are involved in glutamate receptor and GABA receptor signaling, are direct targets for TPM. In contrast, no TPM drug targets were identified in the 38 significant genes for the Week 8 placebo group. Pathway analyses based on nominally significant genes revealed 27 enriched pathways shared by the Weeks 8 and 12 TPM groups. These pathways are involved in relevant physiological functions such as neuronal function/synaptic plasticity, signal transduction, cardiovascular function, and inflammation/immune function. CONCLUSION: Topiramate treatment of methamphetamine addicts significantly modulates the expression of genes involved in multiple biological processes underlying addiction behavior and other physiological functions. PMID- 25495890 TI - Ligand-directed stearic acid grafted chitosan micelles to increase therapeutic efficacy in hepatic cancer. AB - Targeted delivery system would be an interesting platform to enhance the therapeutic effect and to reduce the side effects of anticancer drugs. In this study, we have developed lactobionic acid (LA)-modified chitosan-stearic acid (CS SA) (CSS-LA) to deliver doxorubicin (DOX) to hepatic cancer cells. The average particle size of CSS-LA/DOX was ~100 nm with a high entrapment efficiency of >95%. Drug release studies showed that DOX release from pH-sensitive micelles is significantly faster at pH 5.0 than at pH 7.4. The LA conjugated micelles showed enhanced cellular uptake in HepG2 and BEL-7402 liver cancer cells than free drug and unconjugated micelles. Consistently, CSS-LA/DOX showed enhanced cell cytotoxicity in these two cell lines. Annexin-V/FITC and PI based apoptosis assay showed that the number of living cells greatly reduced in this group with marked presence of necrotic and apoptotic cells. LA-conjugated carrier induced typical chromatic condensation of cells; membrane blebbing and apoptotic bodies began to appear. In vivo, CSS-LA/DOX showed an excellent tumor regression profile with no toxic side effects. The active targeting moiety, long circulation profile, and EPR effect contributed to its superior anticancer effect in HepG2 based tumor. Our results showed that polymeric micelles conjugated with LA increased the therapeutic availability of DOX in the liver cancer cell based solid tumor without any toxic side effects. The active targeting ligand conjugated nanoparticulate system could be a promising therapeutic strategy in the treatment of hepatic cancers. PMID- 25495889 TI - Home-based Computer Assisted Arm Rehabilitation (hCAAR) robotic device for upper limb exercise after stroke: results of a feasibility study in home setting. AB - BACKGROUND: Home-based robotic technologies may offer the possibility of self directed upper limb exercise after stroke as a means of increasing the intensity of rehabilitation treatment. The current literature has a paucity of robotic devices that have been tested in a home environment. The aim of this research project was to evaluate a robotic device Home-based Computer Assisted Arm Rehabilitation (hCAAR) that can be used independently at home by stroke survivors with upper limb weakness. METHODS: hCAAR device comprises of a joystick handle moved by the weak upper limb to perform tasks on the computer screen. The device provides assistance to the movements depending on users ability. Nineteen participants (stroke survivors with upper limb weakness) were recruited. Outcome measures performed at baseline (A0), at end of 8-weeks of hCAAR use (A1) and 1 month after end of hCAAR use (A2) were: Optotrak kinematic variables, Fugl Meyer Upper Extremity motor subscale (FM-UE), Action Research Arm Test (ARAT), Medical Research Council (MRC) and Modified Ashworth Scale (MAS), Chedoke Arm and Hand Activity Inventory (CAHAI) and ABILHAND. RESULTS: Two participants were unable to use hCAAR: one due to severe paresis and the other due to personal problems. The remaining 17 participants were able to use the device independently in their home setting. No serious adverse events were reported. The median usage time was 433 minutes (IQR 250 - 791 min). A statistically significant improvement was observed in the kinematic and clinical outcomes at A1. The median gain in the scores at A1 were by: movement time 19%, path length 15% and jerk 19%, FM-UE 1 point, total MAS 1.5 point, total MRC 2 points, ARAT 3 points, CAHAI 5.5 points and ABILHAND 3 points. Three participants showed clinically significant improvement in all the clinical outcomes. CONCLUSIONS: The hCAAR feasibility study is the first clinical study of its kind reported in the current literature; in this study, 17 participants used the robotic device independently for eight weeks in their own homes with minimal supervision from healthcare professionals. Statistically significant improvements were observed in the kinematic and clinical outcomes in the study. PMID- 25495891 TI - Awareness, knowledge and self-care practices toward glaucoma among final year health science university students in Ghana. AB - BACKGROUND: In the absence of adequate services, patients have to rely on the few health professionals that they do come into contact with to advise them on their treatment options. The aim of this study was to determine the level of awareness and knowledge of glaucoma, and the association between these factors and self care practices among final year health science university students in Ghana. METHOD: A cross-sectional survey involving the use of a structured questionnaire was conducted among 273 final year students (67 per cent) studying at any one of eight health science programs in three selected public universities in Ghana. RESULTS: All 273 respondents were aware of glaucoma but only 37.7 per cent had knowledge of it. The majority (65.9 per cent) defined glaucoma as raised intraocular pressure, and confused glaucoma with ocular hypertension. Over half (56.8 per cent) had acquired their knowledge of glaucoma during the course of their training. The media also played a major role in glaucoma awareness; however, it played a limited role in impacting on the knowledge of glaucoma. Only 28.6 per cent of respondents had previously undergone glaucoma screening. CONCLUSION: Although all respondents were aware of glaucoma, their level of knowledge of glaucoma was low. Self-care practices were also generally poor among the respondents. This information may be useful for glaucoma health education in Ghana. PMID- 25495893 TI - Copper-catalyzed three-component synthesis of benzothiazolethiones from o iodoanilines, isocyanide, and potassium sulfide. AB - An efficient copper catalyzed strategy for the synthesis of a variety of benzothiazolethione derivatives has been developed. In the presence of CuCl, the three-component reaction of o-iodoanilines and K2S with p-toluenesulfonylmethyl isocyanide proceeded smoothly to obtain the corresponding benzothiazolethiones in good to excellent isolated yields. Notably, isocyanide functioned as a carbon source and K2S functioned as a sulfur source in this reaction. PMID- 25495894 TI - Genetic variations in the annexin A5 gene and the risk of pregnancy-related venous thrombosis. AB - BACKGROUND: Annexin A5 is a natural anticoagulant assumed to have thrombomodulary functions as it shields phospholipid layers from coagulation complexes. It was recently shown that the M2 haplotype within the annexin A5 gene (ANXA5) promoter reduces the transcriptional activity of the gene. In a previous report, the M2 haplotype was found to be associated with pregnancy-related venous thrombosis (VT). OBJECTIVES: To investigate whether the M1 or M2 haplotypes or other genetic variations in ANXA5 are associated with pregnancy-related VT. PATIENTS/METHODS: We investigated samples from 313 cases and 353 controls included in the VIP study, which is a case-control study of pregnancy-related VT. We analyzed tag single nucleotide polymorphisms (SNPs) selected from the CEU population (Utah Residents with Northern and Western European Ancestry) of HapMap and the M1 and the M2 haplotypes of the promoter. Odds ratios for VT were calculated for each haplotype with the wild type as the reference and for each tag SNP with the most common genotype as reference. RESULTS: We did not find any association between genetic variants in ANXA5 and the risk of pregnancy related VT, but some of the genetic variants were not in Hardy-Weinberg equilibrium. CONCLUSION: Neither the M1/M2 haplotypes nor the tag SNPs in ANXA5 were convincingly associated with pregnancy related VT, but other studies in this field are needed. PMID- 25495895 TI - Electron acceptor-dependent respiratory and physiological stratifications in biofilms. AB - Bacterial respiration is an essential driving force in biogeochemical cycling and bioremediation processes. Electron acceptors respired by bacteria often have solid and soluble forms that typically coexist in the environment. It is important to understand how sessile bacteria attached to solid electron acceptors respond to ambient soluble alternative electron acceptors. Microbial fuel cells (MFCs) provide a useful tool to investigate this interaction. In MFCs with Shewanella decolorationis, azo dye was used as an alternative electron acceptor in the anode chamber. Different respiration patterns were observed for biofilm and planktonic cells, with planktonic cells preferred to respire with azo dye while biofilm cells respired with both the anode and azo dye. The additional azo respiration dissipated the proton accumulation within the anode biofilm. There was a large redox potential gap between the biofilms and anode surface. Changing cathodic conditions caused immediate effects on the anode potential but not on the biofilm potential. Biofilm viability showed an inverse and respiration dependent profile when respiring with only the anode or azo dye and was enhanced when respiring with both simultaneously. These results provide new insights into the bacterial respiration strategies in environments containing multiple electron acceptors and support an electron-hopping mechanism within Shewanella electrode respiring biofilms. PMID- 25495896 TI - Long-term, open-label, safety study of once-daily ropinirole extended/prolonged release in early and advanced Parkinson's disease. AB - Long-term safety of once-daily ropinirole extended/prolonged release (ropinirole XL/PR) was evaluated in subjects with early and advanced Parkinson's disease (PD) in this study, 101468/248. Subjects (n = 419) who completed one of three prior studies evaluating ropinirole XL/PR for the treatment of PD were enrolled in this open-label, multicenter, extension study, and were to be followed for up to 73 months. Ropinirole XL/PR was titrated/continued, and adjusted as appropriate during the maintenance phase (maximum 24 mg/d). Levodopa (L-dopa) and other nondopamine agonist PD medications were permitted. Safety outcomes that were investigated included frequency of adverse events (AEs). Subjects' preference regarding once daily versus three times daily study medication regimens was also investigated in a subset of the study population. The median duration of ropinirole XL/PR exposure was 1275 d. Most subjects (87%) reported at least one AE, with the most common (>= 10%) AEs being, back pain (14%), hallucinations (13%), somnolence (11%) and peripheral edema (11%). Twenty-five percent of subjects discontinued the study prematurely due to an AE during the treatment period. Long-term treatment with ropinirole XL/PR was not associated with any new or unexpected safety concerns in patients with early and advanced PD, and a majority of subjects preferred the once-daily dosing regimen. PMID- 25495897 TI - A population-based cohort study on adherence to practice guidelines for adjuvant chemotherapy in colorectal cancer. AB - BACKGROUND: The value of adjuvant chemotherapy in colorectal cancer is well studied, and guidelines have been established. Little is known about how treatment guidelines are implemented in the everyday clinical setting. METHODS: This national population-based study on nearly 34,000 patients with colorectal cancer evaluates the adherence to present clinical guidelines for adjuvant chemotherapy. Virtually all patients with colorectal cancer in Sweden during the years 2007-2012 and data from the Swedish Colorectal Cancer Registry were included. RESULTS: In colon cancer stage III, adherence to national guidelines was associated with lower age, presence of multidisciplinary team (MDT) conference, low co-morbidity, and worse N stage. The MDT forum also affected whether or not high-risk stage II colon cancer patients were considered for adjuvant chemotherapy. Rectal cancer patients both in stage II and III were considered for adjuvant chemotherapy less often than colon cancer patients, but the same factors influenced the decision. Adjuvant chemotherapy was started later than eight weeks after surgery in 30% of colon cancer patients and in 38% of rectal cancer patients. CONCLUSIONS: In Sweden, the adherence to national guidelines for adjuvant chemotherapy in colon cancer stage III is acceptable in younger and healthier patients. MDT conferences are of major importance and affect whether patients are recommended for adjuvant chemotherapy. Special consideration needs to be given to certain subgroups of patients, particularly older patients and patients with poorly differentiated tumors. There is a need to shorten the waiting time until start of chemotherapy. PMID- 25495898 TI - Who is not using condoms among HIV-positive patients in treatment in the largest city in Brazil? AB - Data on risky sexual behaviors in people living with HIV/AIDS (PLWHA) is still scarce in some populations around the world. The purpose of this study was to assess the factors associated with the use of condoms in a representative sample of PLWHA in outpatient treatment in the city of Sao Paulo. Six hundred and sixty seven HIV-positive patients (383 men and 284 women) who were being treated at eight centers participated in this study. Data were collected using a sociodemographic survey, the Beck depression and anxiety inventories, a survey of alcohol and other drugs use, the Alcohol Use Disorders Identification Test, a sexual behavior survey, and the Sexual Risk Behavior Assessment Schedule. The majority of study participants were sexually active (almost 62% of the sample had at least one sexual partner in the last three months), and at least one-fourth engaged in unsafe sex (25.3% did not use condoms during at least one instance of anal and/or vaginal intercourse in the past three months). Multivariate logistic regression showed that engaging in unprotected sex was more likely among females (p < .001), persons with an HIV-positive partner (p < .001), and people using cannabis before sex (p = .002). These findings should stimulate health-care workers to create specific groups for women, seroconcordant couples, and cannabis users to discuss condom use, as they seem to be vulnerable groups. PMID- 25495899 TI - Complex DSBs: A need for resection. PMID- 25495901 TI - Construction of the Myrioneuron alkaloids: a total synthesis of (+/-) myrioneurinol. AB - A strategy has been developed that culminated in a stereoselective total synthesis of the tetracyclic antimalarial Myrioneuron alkaloid myrioneurinol. The synthesis relies on three highly diastereoselective reactions, including an intramolecular chelation-controlled Michael spirocyclization of an N-Cbz-lactam titanium enolate to an alpha,beta-unsaturated ester for construction of the A/D ring system and the attendant C5 (quaternary), C6 relative stereochemistry; a malonate enolate conjugate addition to a nitrosoalkene in order to install the appropriate functionality and establish the configuration at C7; and an intramolecular aza-Sakurai reaction to form the B-ring and the accompanying C9 and C10 stereocenters. PMID- 25495900 TI - Functional genomics and microbiome profiling of the Asian longhorned beetle (Anoplophora glabripennis) reveal insights into the digestive physiology and nutritional ecology of wood feeding beetles. AB - BACKGROUND: Wood-feeding beetles harbor an ecologically rich and taxonomically diverse assemblage of gut microbes that appear to promote survival in woody tissue, which is devoid of nitrogen and essential nutrients. Nevertheless, the contributions of these apparent symbionts to digestive physiology and nutritional ecology remain uncharacterized in most beetle lineages. RESULTS: Through parallel transcriptome profiling of beetle- and microbial- derived mRNAs, we demonstrate that the midgut microbiome of the Asian longhorned beetle (Anoplophora glabripennis), a member of the beetle family Cerambycidae, is enriched in biosynthetic pathways for the synthesis of essential amino acids, vitamins, and sterols. Consequently, the midgut microbiome of A. glabripennis can provide essential nutrients that the beetle cannot obtain from its woody diet or synthesize itself. The beetle gut microbiota also produce their own suite of transcripts that can enhance lignin degradation, degrade hemicellulose, and ferment xylose and wood sugars. An abundance of cellulases from several glycoside hydrolase families are expressed endogenously by A. glabripennis, as well as transcripts that allow the beetle to convert microbe-synthesized essential amino acids into non-essential amino acids. A. glabripennis and its gut microbes likely collaborate to digest carbohydrates and convert released sugars and amino acid intermediates into essential nutrients otherwise lacking from their woody host plants. CONCLUSIONS: The nutritional provisioning capabilities of the A. glabripennis gut microbiome may contribute to the beetles' unusually broad host range. The presence of some of the same microbes in the guts of other Cerambycidae and other wood-feeding beetles suggests that partnerships with microbes may be a facilitator of evolutionary radiations in beetles, as in certain other groups of insects, allowing access to novel food sources through enhanced nutritional provisioning. PMID- 25495902 TI - Differences in the binding of copper(I) to alpha- and beta-synuclein. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of abnormal alpha-synuclein (alphaS) deposits in the brain. Alterations in homeostasis and metal-induced oxidative stress may play a crucial role in the progression of alphaS amyloid assembly and pathogenesis of PD. Contrary to alphaS, beta-synuclein (betaS) is not involved in the PD etiology. However, it has been suggested that the betaS/alphaS ratio is altered in PD, indicating that a correct balance of these two proteins is implicated in the inhibition of alphaS aggregation. alphaS and betaS share similar abilities to coordinate Cu(II). In this study, we investigated and compared the interaction of Cu(I) with the N terminal portion of betaS and alphaS by means of NMR, circular dichroism, and X ray absorption spectroscopies. Our data show the importance of M10K mutation, which induces different Cu(I) chemical environments. Coordination modes 3S1O and 2S2O were identified for betaS and alphaS, respectively. These new insights into the bioinorganic chemistry of copper and synuclein proteins are a basis to understand the molecular mechanism by which betaS might inhibit alphaS aggregation. PMID- 25495903 TI - Immunoproteomic characterisation of Mycoplasma mycoides subspecies capri by mass spectrometry analysis of two-dimensional electrophoresis spots and western blot. AB - OBJECTIVES: Mycoplasma mycoides subspecies capri is one of the causative agents of contagious agalactia in goats. The disease is characterised by mastitis, pneumonia, arthritis, keratitis and in acute cases septicaemia. No vaccine is currently available that has been demonstrated to prevent disease. METHODS: This study used two-dimensional electrophoresis to separate proteins from whole-cell preparations and tandem mass spectrometry to identify them. KEY FINDINGS: In total, 145 spots were successfully identified corresponding to 74 protein identities. Twenty of these proteins were found to be immunogenic by western blot analysis using a pooled serum sample from experimentally infected goats. CONCLUSIONS: Six proteins were found to have a less than 95% amino acid similarity to a closely related Mycoplasma species showing that they warrant further evaluation in development of diagnostic tests. These proteins were a dihydrolipoamide acetyltransferase component of the pyruvate dehydrogenase complex, phosphoglycerate kinase, pyrimidine-nucleoside phosphorylase, 30S ribosomal protein S6, ribulose-phosphate 3-epimerase and D-lactate dehydrogenase. PMID- 25495904 TI - PCR amplification of a triple-repeat genetic target directly from whole blood in 15 minutes as a proof-of-principle PCR study for direct sample analysis for a clinically relevant target. AB - BACKGROUND: Most PCR-based diagnostics are still considered time- and labor intensive due to disparate purification, amplification, and detection steps. Advancements in PCR enzymes and buffer chemistry have increased inhibitor tolerance, facilitating PCR directly from crude samples. Obviating the need for DNA purification, while lacking a concentration step, these direct sample methods are particularly apt for human genetic testing. However, direct PCR protocols have traditionally employed thermal cyclers with slow ramp rates and conservative hold times that significantly increase an assay's time-to-result. For this proof of-principle study, our objective was to significantly reduce sample preparation and assay time for a PCR-based genetic test, for myotonic dystrophy type 1 (DM1), by pairing an inhibitor-resistant enzyme mix with a rapid thermal cycler to analyze samples directly in whole blood. METHODS: DM1 genetic screening was done with an adapted conventional PCR approach that employed the Streck Philisa(r) Thermal Cycler, the inhibitor-resistant NEBNext(r) High-Fidelity 2X PCR Master Mix, and agarose gel electrophoresis or an Agilent 2100 Bioanalyzer for detection. The Gene LinkTM Myotonic Dystrophy GenemerTM Kit was used as a reference assay kit to evaluate the rapid assay. RESULTS: In this work, a rapid and direct PCR assay testing 10% whole blood as template has been developed as an exclusionary screening assay for DM1, a triple-repeat genetic disorder. PCR amplification was completed in 15 minutes using 30 cycles, including in situ hot start/cell lysis. Out of the 40 donors screened, this assay identified 23 (57.5%) as DM1 negative suggesting no need for further testing. These data are 100% concordant with data collected using the commercially available Gene Link GenemerTM Kit per the kit-specific PCR protocol. CONCLUSIONS: The PCR assay described in this study amplified DM1 short tandem repeats in 15 minutes. By eliminating sample purification and slower conventional PCR protocols, we demonstrated how adaptation of current PCR technology and chemistries can produce a simple-to-use exclusionary screening assay that is independent of up-front sample prep, improving a clinical lab technician's time-to-result. We envision this direct and rapid methodology could be applied to other conventional PCR based genetic tests and sample matrices where genomic DNA is targeted for analysis within a given molecular diagnostic platform. PMID- 25495905 TI - Is there a link between overactive bladder and the metabolic syndrome in women? A systematic review of observational studies. AB - OBJECTIVES: To conduct a systematic review to determine whether there is an association between metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) or overactive bladder (OAB) in women. METHODS: We systematically reviewed English language observational studies on the effect of MetS (or component factors) on the presence of OAB or LUTS in women. We searched PubMed, Web of Science and The Cochrane Library with no date restrictions, checked reference lists and undertook citation searches in PubMed and Google Scholar. Studies were assessed for risk of bias. Because of heterogeneity, results were not pooled, but are reported narratively. RESULTS: Of 27 included studies, only three looked at the link between MetS and OAB. The rest looked at links between OAB and components of MetS such as obesity or insulin resistance (n = 10), between MetS and urinary symptoms (n = 3) and between urinary symptoms and components of MetS, such as obesity (n = 14). Evidence is currently limited, but it does suggest that there may be important links between MetS and OAB and components of MetS such as obesity. CONCLUSIONS: The literature on MetS and OAB or LUTS in women is limited, and poor quality. However, the evidence available on obesity appears to support MetS as a contributor and predictor of LUTS in women. Many of the women with LUTS will be overweight and will have features of the MetS, if looked for. This provides not only an opportunity to encourage weight loss as an adjunct to therapy for the OAB symptoms but also a window of opportunity to address cardiovascular risk factors and prevent future cardiovascular morbidity and mortality. PMID- 25495906 TI - Pretreatment of chemically-synthesized Abeta42 affects its biological activity in yeast. AB - The tendency of amyloid beta (Abeta42) peptide to misfold and aggregate into insoluble amyloid fibrils in Alzheimer's disease (AD) has been well documented. Accumulation of Abeta42 fibrils has been correlated with abnormal apoptosis and unscheduled cell division which can also trigger the death of neuronal cells, while oligomers can also exhibit similar activities. While investigations using chemically-synthesized Abeta42 peptide have become common practice, there appear to be differences in outcomes from different preparations. In order to resolve this inconsistency, we report 2 separate methods of preparing chemically synthesized Abeta42 and we examined their effects in yeast. Hexafluoroisopropanol pretreatment caused toxicity while, ammonium hydroxide treated Abeta42 induced cell proliferation in both C. glabrata and S. cerevisiae. The hexafluoroisopropanol prepared Abeta42 had greater tendency to form amyloid on yeast cells as determined by thioflavin T staining followed by flow cytometry and microscopy. Both quiescent and non-quiescent cells were analyzed by these methods of peptide preparation. Non-quiescent cells were susceptible to the toxicity of Abeta42 compared with quiescent cells (p < 0.005). These data explain the discrepancy in the previous publications about the effects of chemically synthesized Abeta42 on yeast cells. The effect of Abeta42 on yeast cells was independent of the size of the peptide aggregates. However, the Abeta42 pretreatment determined whether the molecular conformation of peptide resulted in proliferation or toxicity in yeast based assays. PMID- 25495907 TI - CLAST: CUDA implemented large-scale alignment search tool. AB - BACKGROUND: Metagenomics is a powerful methodology to study microbial communities, but it is highly dependent on nucleotide sequence similarity searching against sequence databases. Metagenomic analyses with next-generation sequencing technologies produce enormous numbers of reads from microbial communities, and many reads are derived from microbes whose genomes have not yet been sequenced, limiting the usefulness of existing sequence similarity search tools. Therefore, there is a clear need for a sequence similarity search tool that can rapidly detect weak similarity in large datasets. RESULTS: We developed a tool, which we named CLAST (CUDA implemented large-scale alignment search tool), that enables analyses of millions of reads and thousands of reference genome sequences, and runs on NVIDIA Fermi architecture graphics processing units. CLAST has four main advantages over existing alignment tools. First, CLAST was capable of identifying sequence similarities ~80.8 times faster than BLAST and 9.6 times faster than BLAT. Second, CLAST executes global alignment as the default (local alignment is also an option), enabling CLAST to assign reads to taxonomic and functional groups based on evolutionarily distant nucleotide sequences with high accuracy. Third, CLAST does not need a preprocessed sequence database like Burrows-Wheeler Transform-based tools, and this enables CLAST to incorporate large, frequently updated sequence databases. Fourth, CLAST requires <2 GB of main memory, making it possible to run CLAST on a standard desktop computer or server node. CONCLUSIONS: CLAST achieved very high speed (similar to the Burrows-Wheeler Transform-based Bowtie 2 for long reads) and sensitivity (equal to BLAST, BLAT, and FR-HIT) without the need for extensive database preprocessing or a specialized computing platform. Our results demonstrate that CLAST has the potential to be one of the most powerful and realistic approaches to analyze the massive amount of sequence data from next-generation sequencing technologies. PMID- 25495908 TI - Prostate cancer patients gradually advance goals for rehabilitation after radical prostatectomy: applying a lines-of-defense model to rehabilitation. AB - Following tumor surgery, urinary incontinence challenges prostate cancer patients' functional health. Adjustments of functional goals (lines of defense [LoDs]) were examined during rehabilitation from incontinence. A conceptual model proposing stepwise and distinct upward adjustments of LoDs, ranging from minimizing discomfort (lowest LoD) to protecting self-reliance (highest LoD), was investigated. Within 7 months following the onset of incontinence, 175 patients completed questionnaires at 4 occasions. A theory-based hierarchy was imposed on time-invariant latent classes of LoD-endorsements. As incontinence receded, patients transitioned upward through the hierarchy of LoD-classes, matched LoDs to concurrent incontinence levels, and thus promptly claimed independent functioning with physical improvements. PMID- 25495909 TI - Comparison of the canine corneal epithelial cell sheets cultivated from limbal stem cells on canine amniotic membrane, atelocollagen gel, and temperature responsive culture dish. AB - OBJECTIVE: The current study compared canine corneal epithelial cell sheets cultivated from limbal stem cells on amniotic membrane, atelocollagen gel, and temperature-responsive culture dish. PROCEDURES: We collected limbal epithelial cells from the intact eyes of beagles and cultivated the cells on denuded canine amniotic membranes, temperature-responsive cell culture labware, and collagen gel with 3T3 feeder cells. Immunofluorescence staining for Ki-67 was used to analyze the capacity of cell proliferation in the sheets. Immunofluorescence staining was also performed for the corneal epithelium-specific marker cytokeratin 3 and putative stem cell markers ABCG2 and p63. Reverse-transcription polymerase chain reaction (RT-PCR) was performed to detect ABCG2 and p63. RESULTS: The growth rates of the cultivated cells, or the times it took them to reach confluency, were different for the three scaffolds. The cultivated sheet on the temperature responsive dish consisted of 2-3 layers, while those on the collagen gel and on the amniotic membrane consisted of 5-8 layers. The basal layer cells grown on all three scaffolds expressed putative stem cell markers. In real-time RT-PCR analysis, the highest level of p63 was observed in the sheets grown on collagen gel. CONCLUSIONS: In this study, the cells cultured on the collagen gel demonstrated a capacity for cell proliferation, and the expressions of stem cells in the sheets suggested that collagen gel is the most suitable carrier for clinical use. PMID- 25495910 TI - Serum cystatin C is a determinant of central pressure augmentation index measured by oscillometric method in renal transplant recipients. AB - BACKGROUND: Serum cystatin C (ScysC) may help predicting cardiovascular outcome not only through its ability to detect renal dysfunction but also through its potential connection to others factors that are directly related to cardiovascular diseases. We explored the potential association of ScysC with arterial stiffness--a major contributor to cardiovascular disease--in renal transplant recipients (RTR). METHODS: Traditional and non-traditional cardio vascular risk factors were collected from 215 stable RTR whom arterial stiffness was evaluated by the measure of the augmentation index of central pressure (AIx) determined by the arteriograph device. Serum creatinine and ScysC were measured the same day using standardized methods. Association between ScysC and AIx was examined in univariate and multivariate linear regression analysis. RESULTS: In univariate analysis, ScysC was strongly associated with AIx. This relationship was not confounded by age, gender, length of time spent on dialysis and transplantation vintage. Adjustment on the level of GFR estimated by the MDRD Study equation attenuated but did not abolish the association between ScysC and AIx. CONCLUSIONS: In conclusion, ScysC is an independent predictor of AIx in RTR. Our data suggest that arterial stiffness may partially mediate the association between ScysC and cardiovascular risk in renal transplantation. PMID- 25495912 TI - Empathy in Dentistry: How Attitudes and Interaction With Older Adults Make a Difference. AB - The development of empathy and positive attitudes are essential elements of professional education. This study explored the nature of empathy and its association with attitudes about, and exposure to older patients in a sample of dental students. Students completed an adapted version of the Jefferson Scale of Physician Empathy (JSPE), the Aging Semantic Differential (ASD) and answered questions about their exposure to older people. Factor analysis was used to identify four factors: (1) Empathy is Valuable, (2) Empathy is Demonstrated, (3) Empathy is not Influential, and (4) Empathy is Difficult to Accomplish. Higher empathy scores were related to the ASD subscale attitude of acceptability of aging and to greater exposure to older adults outside of clinical practice. There were no demographic predictors of higher empathy scores. PMID- 25495911 TI - Acute and chronic efficacy of bumetanide in an in vitro model of posttraumatic epileptogenesis. AB - BACKGROUND: Seizures triggered by acute injuries to the developing brain respond poorly to first-line medications that target the inhibitory chloride-permeable GABAA receptor. Neuronal injury is associated with profound increases in cytoplasmic chloride ([Cl(-)]i) resulting in depolarizing GABA signaling, higher seizure propensity and limited efficacy of GABAergic anticonvulsants. The Na(+) K(+)-2Cl(-) (NKCC1) cotransporter blocker bumetanide reduces [Cl(-)]i and causes more negative GABA equilibrium potential in injured neurons. We therefore tested both the acute and chronic efficacy of bumetanide on early posttraumatic ictal like epileptiform discharges and epileptogenesis. METHODS: Acute hippocampal slices were used as a model of severe traumatic brain injury and posttraumatic epileptogenesis. Hippocampal slices were then incubated for 3 weeks. After a 1 week latent period, slice cultures developed chronic spontaneous ictal-like discharges. The anticonvulsant and anti-epileptogenic efficacy of bumetanide, phenobarbital, and the combination of these drugs was studied. RESULTS: Bumetanide reduced the frequency and power of early posttraumatic ictal-like discharges in vitro and enhanced the anticonvulsant efficacy of phenobarbital. Continuous 2-3 weeks administration of bumetanide as well as phenobarbital in combination with bumetanide failed to prevent posttraumatic ictal-like discharges and epileptogenesis. CONCLUSIONS: Our data demonstrate a persistent contribution of NKCC1 cotransport in posttraumatic ictal-like activity, presumably as a consequence of chronic alterations in neuronal chloride homeostasis and GABA mediated inhibition. New strategies for more effective reduction in posttraumatic and seizure-induced [Cl(-)]i accumulation could provide the basis for effective treatments for posttraumatic epileptogenesis and the resultant seizures. PMID- 25495913 TI - An electrochemical biosensor for sensitive detection of microRNA-155: combining target recycling with cascade catalysis for signal amplification. AB - In this work, a new electrochemical biosensor based on catalyzed hairpin assembly target recycling and cascade electrocatalysis (cytochrome c (Cyt c) and alcohol oxidase (AOx)) for signal amplification was constructed for highly sensitive detection of microRNA (miRNA). It is worth pointing out that target recycling was achieved only based on strand displacement process without the help of nuclease. Moreover, porous TiO2 nanosphere was synthesized, which could offer more surface area for Pt nanoparticles (PtNPs) enwrapping and enhance the amount of immobilized DNA strand 1 (S1) and Cyt c accordingly. With the mimicking sandwich type reaction, the cascade catalysis amplification strategy was carried out by AOx catalyzing ethanol to acetaldehyde with the concomitant formation of high concentration of H2O2, which was further electrocatalyzed by PtNPs and Cyt c. This newly designed biosensor provided a sensitive detection of miRNA-155 from 0.8 fM to 1 nM with a relatively low detection limit of 0.35 fM. PMID- 25495914 TI - The relationship between physical functional capacity and lung function in obese children and adolescents. AB - BACKGROUND: There is no consensus regarding obesity repercussions for lung function in children and adolescents. Therefore, the aim of the study was to determine whether obesity is associated with poor physical conditioning and damaged lung function in children and adolescents, and to correlate lung function with six-minute walk test (6MWT) results. METHODS: This cross-sectional study included 38 obese subjects of both sexes, ranging between 5 and 17 years of age, as well as 56 control subjects paired by sex and age for the 6MWT, and 39 subjects for spirometry. Subjects performed spirometry according to the guidelines of the American Thoracic Society (ATS) and the European Respiratory Society. The obese group repeated spirometry after receiving bronchodilator (BD) treatments. Physical performance was evaluated via the 6MWT according to ATS guidelines. RESULTS: The obese group demonstrated lower forced expiratory volumes in the first second compared with the control group based on forced vital capacity indices (p < 0.01), findings consistent with airway obstruction in 36.8% of patients in the obese group. Walking distances were shorter in the obese group than in the control group. Changes in lung function did not correlate directly with performance on the 6MWT among obese patients. However, there was a correlation between lung function and variables indicative of effort during exercise. CONCLUSION: In the present study, the obese group walked shorter distances and demonstrated lower values in some markers of lung function. However, there is no relationship between their physical conditions and these test results. Therefore, we cannot conclusively state that poor physical performance results from damaged pulmonary function. PMID- 25495915 TI - Cellular micromotion monitored by long-range surface plasmon resonance with optical fluctuation analysis. AB - Long-range surface plasmon resonance (LRSPR) is a powerful biosensing technology due to a substantially larger probing depth into the medium and sensitivity, compared with conventional SPR. We demonstrate here that LRSPR can provide sensitive noninvasive measurement of the dynamic fluctuation of adherent cells, often referred to as the cellular micromotion. Proof of concept was achieved using confluent layers of 3T3 fibroblast cells and MDA-MB-231 cancer cells. The slope of the power spectral density (PSD) of the optical fluctuations was calculated to determine the micromotion index, and significant differences were measured between live and fixed cell layers. Furthermore, the performances of LRSPR and conventional surface plasmon resonance (cSPR) were compared with respect to micromotion monitoring. Our study showed that the micromotion index of cells measured by LRSPR sensors was higher than when measured with cSPR, suggesting a higher sensitivity of LRSPR to the micromotion of cells. To investigate further this finding, simulations were conducted to establish the relative sensitivities of LRSPR and cSPR to membrane fluctuations. Increased signal intensity was predicted for LRSPR in comparison to cSPR, suggesting that membrane fluctuations play a significant role in the optical micromotion measured in LRSPR. Analogous to cellular micromotion measured using impedance techniques, LRSPR micromotion has the potential to provide important biological information on the metabolic activity and viability of adherent cells. PMID- 25495916 TI - Erratum. PMID- 25495917 TI - Tetronic((r))-based composite hydrogel scaffolds seeded with rat bladder smooth muscle cells for urinary bladder tissue engineering applications. AB - Natural hydrogels such as collagen offer desirable properties for tissue engineering, including cell adhesion sites, but their low mechanical strength is not suitable for bladder tissue regeneration. In contrast, synthetic hydrogels such as poly (ethylene glycol) allow tuning of mechanical properties, but do not elicit protein adsorption or cell adhesion. For this reason, we explored the use of composite hydrogel blends composed of Tetronic (BASF) 1107-acrylate (T1107A) in combination with extracellular matrix moieties collagen and hyaluronic acid seeded with bladder smooth muscle cells (BSMC). This composite hydrogel supported BSMC growth and distribution throughout the construct. When compared to the control (acellular) hydrogels, mechanical properties (peak stress, peak strain, and elastic modulus) of the cellular hydrogels were significantly greater. When compared to the 7-day time point after BSMC seeding, results of mechanical testing at the 14-day time point indicated a significant increase in both ultimate tensile stress (4.1-11.6 kPa) and elastic modulus (11.8-42.7 kPa) in cellular hydrogels. The time-dependent improvement in stiffness and strength of the cellular constructs can be attributed to the continuous collagen deposition and reconstruction by BSMC seeded in the matrix. The composite hydrogel provided a biocompatible scaffold for BSMC to thrive and strengthen the matrix; further, this trend could lead to strengthening the construct to match the mechanical properties of the bladder. PMID- 25495918 TI - Primary care clinicians' perceptions about antibiotic prescribing for acute bronchitis: a qualitative study. AB - BACKGROUND: Clinicians prescribe antibiotics to over 65% of adults with acute bronchitis despite guidelines stating that antibiotics are not indicated. METHODS: To identify and understand primary care clinician perceptions about antibiotic prescribing for acute bronchitis, we conducted semi-structured interviews with 13 primary care clinicians in Boston, Massachusetts and used thematic content analysis. RESULTS: All the participants agreed with guidelines that antibiotics are not indicated for acute bronchitis and felt that clinicians other than themselves were responsible for overprescribing. Barriers to guideline adherence included 6 themes: (1) perceived patient demand, which was the main barrier, although some clinicians perceived a recent decrease; (2) lack of accountability for antibiotic prescribing; (3) saving time and money; (4) other clinicians' misconceptions about acute bronchitis; (5) diagnostic uncertainty; and (6) clinician dissatisfaction in failing to meet patient expectations. Strategies to decrease inappropriate antibiotic prescribing included 5 themes: (1) patient educational materials; (2) quality reporting; (3) clinical decision support; (4) use of an over-the-counter prescription pad; and (5) pre-visit triage and education by nurses to prevent visits. CONCLUSIONS: Clinicians continued to cite patient demand as the main reason for antibiotic prescribing for acute bronchitis, though some clinicians perceived a recent decrease. Clinicians felt that other clinicians were responsible for inappropriate antibiotic prescribing and that better pre-visit triage by nurses could prevent visits and change patients' expectations. PMID- 25495919 TI - Immunotherapy with the trifunctional anti-CD20 x anti-CD3 antibody FBTA05 (Lymphomun) in paediatric high-risk patients with recurrent CD20-positive B cell malignancies. AB - Children with B cell malignancies refractory to standard therapy are known to have a poor prognosis and very limited treatment options. Here, we report on the treatment and follow-up of ten patients diagnosed with relapsed or refractory mature B-cell Non Hodgkin Lymphoma (B-NHL), Burkitt leukaemia (B-AL) or pre B acute lymphoblastic leukaemia (pre B-ALL). All children were treated with FBTA05 (now designated Lymphomun), an anti-CD3 x anti-CD20 trifunctional bispecific antibody (trAb) in compassionate use. Within individual treatment schedules, Lymphomun was applied (a) after allogeneic stem cell transplantation (allo-SCT, n = 6) to induce sustained long-term remission, or (b) stand alone prior to subsequent chemotherapy to eradicate residual disease before allo-SCT (n = 4). Nine of ten children displayed a clinical response: three stable diseases (SD), one partial remission (PR) and five induced or sustained complete remissions (CR). Five of these nine responders died during follow-up. The other patients still maintain CR with a current overall survival of 874-1424 days (median: 1150 days). In conclusion, despite the dismal clinical prognosis of children refractory to standard therapy, immunotherapy with Lymphomun resulted in a favourable clinical outcome in this cohort of refractory paediatric patients. PMID- 25495920 TI - Mechanism of the intramolecular charge transfer state formation in all-trans-beta apo-8'-carotenal: influence of solvent polarity and polarizability. AB - In this work we analyzed the infrared and visible transient absorption spectra of all-trans-beta-apo-8'-carotenal in several solvents, differing in both polarity and polarizability at different excitation wavelengths. We correlate the solvent dependence of the kinetics and the band shape changes in the infrared with that of the excited state absorption bands in the visible, and we show that the information obtained in the two spectral regions is complementary. All the collected time-resolved data can be interpreted in the frame of a recently proposed relaxation scheme, according to which the major contributor to the intramolecular charge transfer (ICT) state is the bright 1Bu(+) state, which, in polar solvents, is dynamically stabilized through molecular distortions and solvent relaxation. A careful investigation of the solvent effects on the visible and infrared excited state bands demonstrates that both solvent polarity and polarizability have to be considered in order to rationalize the excited state relaxation of trans-8'-apo-beta-carotenal and clarify the role and the nature of the ICT state in this molecule. The experimental observations reported in this work can be interpreted by considering that at the Franck-Condon geometry the wave functions of the S1 and S2 excited states have a mixed ionic/covalent character. The degree of mixing depends on solvent polarity, but it can be dynamically modified by the effect of polarizability. Finally, the effect of different excitation wavelengths on the kinetics and spectral dynamics can be interpreted in terms of photoselection of a subpopulation of partially distorted molecules. PMID- 25495922 TI - Association of mortality with out-of-hours admission in patients with perforated peptic ulcer. AB - BACKGROUND: Perforated peptic ulcer is a serious emergency surgical condition. The aim of the present nationwide cohort study was to evaluate the association between mortality and out-of-hours admission in patients surgically treated for perforated peptic ulcer. METHODS: All Danish patients surgically treated for benign gastric or duodenal perforated peptic ulcer in Denmark between September 1, 2011 and August 31, 2013 were included. Patients were identified through The Danish Clinical Register of Emergency Surgery. The association between 90-day mortality and time and day of admission and surgery was assessed by crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of 726 patients were included. Median age was 69.5 years (range 18.2-101.7), and 569 of the 726 patients (78.4%) had at least one coexisting disease. Adjusted ORs and 95% CIs between 90-day mortality and admission in daytime vs. nighttime and weekday vs. weekend were 1.0 (0.7-1.5) and 1.2 (0.8-1.8), respectively. Adjusted ORs with 95% CI between surgery in daytime vs. nighttime and weekday vs. weekend were 0.9 (0.6-1.3) and 1.2 (0.8-1.8), respectively. Sensitivity analysis was consistent with the primary analysis. The overall 90-day mortality rate was 25.6% (186/726). CONCLUSION: No statistically significant adjusted association between 90-day mortality and out-of-hours admission was found in patients surgically treated for perforated peptic ulcer. PMID- 25495921 TI - Propolis--based chitosan varnish: drug delivery, controlled release and antimicrobial activity against oral pathogen bacteria. AB - BACKGROUND: Dental caries is the most prevalent oral disease in several Asian and Latin American countries. It is an infectious disease and different types of bacteria are involved in the process. Synthetic antimicrobials are used against this disease; however, many of these substances cause unwarranted undesirable effects like vomiting, diarrhea and tooth staining. Propolis, a resinous substance collected by honeybees, has been used to control the oral microbiota. So, the objective of this study was to develop and characterize sustained-release propolis-based chitosan varnish useful on dental cariogenic biofilm prevention, besides the in vitro antimicrobial activity. METHODS: Three formulations of propolis - based chitosan varnish (PCV) containing different concentrations (5%, 10% and 15%) were produced by dissolution of propolis with chitosan on hydro alcoholic vehicle. Bovine teeth were used for testing adhesion of coatings and to observe the controlled release of propolis associated with varnish. It was characterized by infrared spectroscopy, scanning electron microscopy, casting time, diffusion test in vitro antimicrobial activity and controlled release. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were tested for the main microorganisms involved in the cariogenic biofilm through the microdilution test in 96-well plates. RESULTS: The formulations presented a tooth surface adherence and were able to form films very fast on bovine tooth surface. Also, propolis-based chitosan varnishes have shown antimicrobial activity similar to or better than chlorhexidine varnish against all oral pathogen bacteria. All microorganisms were sensitive to propolis varnish and chitosan. MIC and MBC for microorganisms of cariogenic biofilme showed better results than chlorhexidine. Propolis active components were released for more than one week. CONCLUSION: All developed formulations turn them, 5%, 10% and 15% propolis content varnish, into products suitable for clinical application on dental caries prevention field, deserving clinical studies to confirm its in vivo activity. PMID- 25495923 TI - Next generation sequencing in non-small cell lung cancer: new avenues toward the personalized medicine. AB - Non-small cell lung cancer (NSCLC) is one of the most common causes of cancer related death worldwide. Based on the patient's stage of disease, treatment options include surgery, radiotherapy, and chemotherapy. Although chemotherapy remains the main therapeutic approach for advanced NSCLC, targeted therapy represents a good chance of treatment for this subgroup of patients. Currently this approach is based on previous evaluation of clinically relevant mutations and the Sanger sequencing is the main approach to assign mutational status and to guide the appropriate treatment; however this tool is characterized by a low sensitivity. Recently, the advent of next-generation sequencing (NGS) has dramatically revolutionized the molecular knowledge of cancer by increasing the feasibility and possibility to sequence DNA ranging from large scale studies to targeted regions. This review reports an overview of different applications of the NGS as novel approach to study NSCLC, thereby providing information about mutational spectrum of this cancer in order to identify novel targetable mutations and to predict the emergence of drug resistance. All studies demonstrated several advantages of this approach over the traditional tools. In particular the NGS was also able to reveal mutations in low percentage, and to screen the mutational status of different critical samples such as biopsies, cytological samples and circulating plasma DNA, offering innovative diagnostic opportunities. Despite several problems have to be overcome toward the personalized therapy, the NGS represents a highly attractive system to identify mutations improving the outcome of patients with this deadly disease. PMID- 25495924 TI - MicroRNAs as tools and effectors for patient treatment in gastrointestinal carcinogenesis. AB - In the last 20 years, microRNAs (miRNAs) have become the most promising class of diagnostic and prognostic biomarkers for human cancer. From a therapeutic perspective, advances in the understanding of the molecular role of miRNAs in the pathological processes have significantly influenced the selection of new therapeutic modalities. Moreover, the intrinsic characteristics that confer stability to miRNAs in vitro, allow a longer molecular/structural resistance and activity in vivo. Preclinical models have consistently underlined the feasibility and efficacy of miRNA-based therapies, either alone or in combination with current targeted therapies. The appealing strength of such therapeutic option dwells in miRNAs' ability to concurrently target multiple genes, frequently in the context of a specific network/pathway. This property allows miRNA-based therapy to be extremely efficient in regulating distinct biological processes relevant to normal and pathological cell homeostasis. The purpose of this review is to summarize the role of miRNAs in gastrointestinal carcinogenesis and their potential use as novel biomarkers and therapeutics. PMID- 25495925 TI - Grapevine species from varied native habitats exhibit differences in embolism formation/repair associated with leaf gas exchange and root pressure. AB - Drought induces xylem embolism formation, but grapevines can refill non functional vessels to restore transport capacity. It is unknown whether vulnerability to embolism formation and ability to repair differ among grapevine species. We analysed in vivo embolism formation and repair using x-ray computed microtomography in three wild grapevine species from varied native habitats (Vitis riparia, V. arizonica, V. champinii) and related responses to measurements of leaf gas exchange and root pressure. Vulnerability to embolism formation was greatest in V. riparia, intermediate in V. arizonica and lowest in V. champinii. After re-watering, embolism repair was rapid and pronounced in V. riparia and V. arizonica, but limited or negligible in V. champinii even after numerous days. Similarly, root pressure measured after re-watering was positively correlated with drought stress severity for V. riparia and V. arizonica (species exhibiting embolism repair) but not for V. champinii. Drought-induced reductions in transpiration were greatest for V. riparia and least in V. champinii. Recovery of transpiration after re-watering was delayed for all species, but was greatest for V. champinii and most rapid in V. arizonica. These species exhibit varied responses to drought stress that involve maintenance/recovery of xylem transport capacity coordinated with root pressure and gas exchange responses. PMID- 25495927 TI - Research in haemophilia B--approaching the request for high evidence levels in a rare disease. AB - Payers in European countries request studies with high levels of evidence for decision making also for rare diseases like haemophilia B (HB). The objective of the study was to determine the status quo of current studies in HB regarding the overall level of evidence generated. The methods used for performing the study were systematic literature research in EMBASE and MEDLINE, search terms 'HB' and 'factor IX' (FIX). The inclusion criteria were journal articles (JA), conference abstracts (CA), English language, published between January 2009 and March 2013, studies only; screening of titles, abstracts, full texts subsequently. ClinicalTrials.gov search: unpublished registered trials (RT) concerning HB or FIX. The analysis was performed on research topic, sponsor, recruitment status and study design. Screening of 1639 hits yielded 31 JA describing 35 studies, and 62 CA. FIX was subject of 21 studies (60.0%) and 29 CA (46.8%). Seven studies focused on various aspects of HB, six on haemophilia studies with separate HB data. Screening of 173 hits from ClinicalTrials.gov yielded 42 RT. Overall, 32 RT (76.2%) related to FIX. Measurement of health-related quality of life (HRQoL) was identified in none of these studies, four CA (6.5%), four RT (9.5%). Randomized study design was found in one study (2.9%), four RT (9.5%). Three studies (8.6%) and seven RT (16.7%) were prospective, observational and comparative. The majority of published clinical studies do not meet payers' expectations for evidence. Therefore, clinical investigation concepts addressing randomization, outcomes research including HRQoL and comparison of therapy options should be discussed. Refined statistical methods and exploitation of complementary real life data sources may fill current evidence gaps concerning rare diseases. PMID- 25495926 TI - Stage 1 of the meaningful use incentive program for electronic health records: a study of readiness for change in ambulatory practice settings in one integrated delivery system. AB - BACKGROUND: Meaningful Use (MU) provides financial incentives for electronic health record (EHR) implementation. EHR implementation holds promise for improving healthcare delivery, but also requires substantial changes for providers and staff. Establishing readiness for these changes may be important for realizing potential EHR benefits. Our study assesses whether provider/staff perceptions about the appropriateness of MU and their departments' ability to support MU-related changes are associated with their reported readiness for MU related changes. METHODS: We surveyed providers and staff representing 47 ambulatory practices within an integrated delivery system. We assessed whether respondent's role and practice-setting type (primary versus specialty care) were associated with reported readiness for MU (i.e., willingness to change practice behavior and ability to document actions for MU) and hypothesized predictors of readiness (i.e., perceived appropriateness of MU and department support for MU). We then assessed associations between reported readiness and the hypothesized predictors of readiness. RESULTS: In total, 400 providers/staff responded (response rate approximately 25%). Individuals working in specialty settings were more likely to report that MU will divert attention from other patient-care priorities (12.6% vs. 4.4%, p = 0.019), as compared to those in primary-care settings. As compared to advanced-practice providers and nursing staff, physicians were less likely to have strong confidence in their department's ability to solve MU implementation problems (28.4% vs. 47.1% vs. 42.6%, p = 0.023) and to report strong willingness to change their work practices for MU (57.9% vs. 83.3% vs. 82.0%, p < 0.001). Finally, provider/staff perceptions about whether MU aligns with departmental goals (OR = 3.99, 95% confidence interval (CI) = 2.13 to 7.48); MU will divert attention from other patient-care priorities (OR = 2.26, 95% CI = 1.26 to 4.06); their department will support MU-related change efforts (OR = 3.99, 95% CI = 2.13 to 7.48); and their department will be able to solve MU implementation problems (OR = 2.26, 95% CI = 1.26 to 4.06) were associated with their willingness to change practice behavior for MU. CONCLUSIONS: Organizational leaders should gauge provider/staff perceptions about appropriateness and management support of MU-related change, as these perceptions might be related to subsequent implementation. PMID- 25495928 TI - Lanthanide(III) complexes with a reinforced cyclam ligand show unprecedented kinetic inertness. AB - Lanthanide(III) complexes of a cross-bridged cyclam derivative containing two picolinate pendant arms are kinetically inert in very harsh conditions such as 2 M HCl, with no dissociation being observed for at least 5 months. Importantly, the [Ln(dota)](-) complexes, which are recognized to be extremely inert, dissociate under these conditions with lifetimes in the range ca. 1 min to 12 h depending upon the Ln(3+) ion. X-ray diffraction studies reveal octadentate binding of the ligand to the metal ion in the [Eu(cb-tedpa)](+) complex, while (1)H and (13)C NMR experiments in D2O point to the presence of a single diastereoisomer in solution with a very rigid structure. The structure of the complexes in the solid state is retained in solution, as demonstrated by the analysis of the Yb(3+)-induced paramagnetic shifts. PMID- 25495929 TI - Normalization of environmental metagenomic DNA enhances the discovery of under represented microbial community members. AB - Normalization is a procedure classically employed to detect rare sequences in cellular expression profiles (i.e. cDNA libraries). Here, we present a normalization protocol involving the direct treatment of extracted environmental metagenomic DNA with S1 nuclease, referred to as normalization of metagenomic DNA: NmDNA. We demonstrate that NmDNA, prior to post hoc PCR-based experiments (16S rRNA gene T-RFLP fingerprinting and clone library), increased the diversity of sequences retrieved from environmental microbial communities by detection of rarer sequences. This approach could be used to enhance the resolution of detection of ecologically relevant rare members in environmental microbial assemblages and therefore is promising in enabling a better understanding of ecosystem functioning. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first testing 'normalization' on environmental metagenomic DNA (mDNA). The aim of this procedure was to improve the identification of rare phylotypes in environmental communities. Using hypoliths as model systems, we present evidence that this post-mDNA extraction molecular procedure substantially enhances the detection of less common phylotypes and could even lead to the discovery of novel microbial genotypes within a given environment. PMID- 25495930 TI - Enhanced Pb Absorption by Hordeum vulgare L. and Helianthus annuus L. Plants Inoculated with an Arbuscular Mycorrhizal Fungi Consortium. AB - The effect of an arbuscular mycorrhizal fungi (AMF) consortium conformed by (Glomus intraradices, Glomus albidum, Glomus diaphanum, and Glomus claroideum) on plant growth and absorption of Pb, Fe, Na, Ca, and (32)P in barley (Hordeum vulgare L.) and sunflower (Helianthus annuus L.) plants was evaluated. AMF-plants and controls were grown in a substrate amended with powdered Pb slag at proportions of 0, 10, 20, and 30% v/v equivalent to total Pb contents of 117; 5,337; 13,659, and 19,913 mg Pb kg(-1) substrate, respectively. Mycorrhizal root colonization values were 70, 94, 98, and 90%, for barley and 91, 97, 95, and 97%, for sunflower. AMF inoculum had positive repercussions on plant development of both crops. Mycorrhizal barley absorbed more Pb (40.4 mg Pb kg(-1)) shoot dry weight than non-colonized controls (26.5 mg Pb kg(-1)) when treated with a high Pb slag dosage. This increase was higher in roots than shoots (650.0 and 511.5 mg Pb kg(-1) root dry weight, respectively). A similar pattern was found in sunflower. Plants with AMF absorbed equal or lower amounts of Fe, Na and Ca than controls. H. vulgare absorbed more total P (1.0%) than H. annuus (0.9%). The arbuscular mycorrizal consortium enhanced Pb extraction by plants. PMID- 25495931 TI - Phytoextraction of risk elements by willow and poplar trees. AB - To characterize the phytoextraction efficiency of two clones of willow trees (Salix x smithiana Willd., Salix rubens) and two clones of poplar trees (Populus nigra x maximowiczii, Populus nigra Wolterson) were planted in contaminated soil (0.4-2.0 mg Cd.kg(-1), 78-313 mg Zn.kg(-1), 21.3-118 mg Cu.kg(-1)). Field experiment was carried out in Czech Republic. The study investigated their ability to accumulate heavy metals (Cd, Zn, and Cu) in harvestable plant parts. The poplars produced higher amount of biomass than willows. Both Salix clones accumulated higher amount of Cd, Zn and Cu in their biomass (maximum 6.8 mg Cd.kg(-1), 909 mg Zn.kg(-1), and 17.7 mg Cu.kg(-1)) compared to Populus clones (maximum 2.06 mg Cd.kg(-1), 463 mg Zn.kg(-1), and 11.8 mg Cu.kg(-1)). There were no significant differences between clones of individual species. BCs for Cd and Zn were greater than 1 (the highest in willow leaves). BCs values of Cu were very low. These results indicate that Salix is more suitable plant for phytoextraction of Cd and Zn than Populus. The Cu phytoextraction potential of Salix and Populus trees was not confirmed in this experiment due to low soil availability of this element. PMID- 25495933 TI - Effects of Reductants on Phytoextraction of Chromium (VI) by Ipomoea aquatica. AB - Reductants are often used to reduce Cr(VI) in chemical treatments, yet the effects of the reductants on Cr(VI) phytoremediation are not fully understood. This study investigates the effects of different reductants on Cr(VI) phytoremediation by Ipomoea aquatica in simulated solution with 3 mg L(-1) of Cr(VI), pH0 of 6, and an incubation time of 5 days. Results indicate that the applications of S2O3(2-), Fe0, and Fe2+ at low doses notably increased root Cr concentrations, which were obviously higher than that those in the control (Cr6+ alone). However, high reductant concentrations decreased bioaccumulation of Cr in the roots and shoots of the plant. Statistical results indicate that Cr concentrations were significantly and negatively correlated with Fe concentrations in the roots and shoots of the plant (p<0.05). This suggest that Fe accumulation inhibited Cr accumulation in the plant. A Cr(VI) concentration of 3 mg L(-1) caused short, brown lateral roots with tip necrosis, leaf chlorosis, and noticeable shoot wilting. The leaf necrosis and shoot wilting is caused by oxidative damage of lateral roots by Cr(VI) rather than by the reactive oxygen species generated by the oxidative stress. Addition of the reductants effectively reduced these plant injuries. PMID- 25495932 TI - Effects of Indole-3-Acetic Acid (IAA), a Plant Hormone, on the Ryegrass Yield and the Removal of Fluoranthene from Soil. AB - A soil culture experiment was conducted to determine whether a plant hormone, indole-3-acetic acid (IAA), could influence fluoranthene (Flu) removal from soil. Four treatments were utilized: (i) unplanted soil (CK), (ii) soil planted with ryegrass (P), (iii) soil planted with ryegrass and treated with 0.24 mg kg(-1) IAA (P+0.24), (iv) soil planted with ryegrass and treated with 2.4 mg kg(-1) IAA (P+2.4). The Flu initial concentration was 200 mg kg(-1). After 3 months, the percentage of Flu removal and plant root biomass were significantly increased under the P+2.4 and the removal rate was 35.68%. The total Flu content in plants was higher than that in the other treatments. The Flu concentration was significantly increased in the shoots, but not significantly altered in the roots. The highest translocation factor was observed in the P+2.4. Increase in number of bacteria, actinomycetes and fungi were observed in the planted treatments, and the amount of fungi was significantly increased in P+2.4. Flu removal was related to the Flu in ryegrass, and was insignificantly correlated with the stimulation of soil microflora, which suggesting that IAA may work mainly on improving plant growth, the Flu uptake, and eventually leading to enhanced remediation of Flu polluted soil. PMID- 25495935 TI - Utilization of grasses for potential biofuel production and phytoremediation of heavy metal contaminated soils. AB - This research focuses on investigating the use of common biofuel grasses to assess their potential as agents of long-term remediation of contaminated soils using lead as a model heavy metal ion. We present evidence demonstrating that switch grass and Timothy grass may be potentially useful for long-term phytoremediation of heavy metal contaminated soils and describe novel techniques to track and remove contaminants from inception to useful product. Enzymatic digestion and thermochemical approaches are being used to convert this lignocellulosic feedstock into useful product (sugars, ethanol, biocrude oil+biochar). Preliminary studies on enzymatic hydrolysis and fast pyrolysis of the Switchgrass materials that were grown in heavy metal contaminated soil and non-contaminated soils show that the presence of lead in the Switchgrass material feedstock does not adversely affect the outcomes of the conversion processes. These results indicate that the modest levels of contaminant uptake allow these grass species to serve as phytoremediation agents as well as feedstocks for biofuel production in areas degraded by industrial pollution. PMID- 25495934 TI - Effect of Organic Manures on the Growth of Cymbopogon citratus and Chrysopogon zizanioides for the Phytoremediation of Chromite-Asbestos Mine Waste: A Pot Scale Experiment. AB - The abandoned chromite-asbestos mines are located in the Roro hills, West Singhbhum, Jharkhand, India, where mining operation ceased in 1983, and since then these mines are causing environmental pollution. The present study was planned to phytoremediate these metalloid and metal contaminated mine waste by using two aromatic grasses, Cymbopogon citratus and Chrysopogon zizanioides by applying different proportions of amendments (chicken manure, farmyard manure and garden soil). Mine waste has neutral pH, low electrical conductivity and organic carbon with higher concentration of total metals (Cr and Ni) as compared to soil. Application of manures resulted significant improvements of mine waste characteristics and plant growth, reduction in the availability of total extractable toxic metals (Cr, Ni) and increase in Mn, Zn and Cu concentration in the substrate. The maximum growth and biomass production for C. citratus and C. zizanioides were found in T-IV combination comprising of mine waste (90%), chicken manure (2.5%), farmyard manure (2.5%) and garden soil (5%). Addition of T IV combination also resulted in low Cr and Ni accumulation in roots and reduction in translocation to shoots. Study indicates that C. citratus and C. zizanioides can be used for phytostabilization of abandoned chromite-asbestos mine waste with amendments. PMID- 25495936 TI - Neotyphodium Endophyte Changes Phytoextraction of Zinc in Festuca arundinacea and Lolium perenne. AB - The effect of Neotyphodium endophytes on growth parameters and zinc (Zn) tolerance and uptake was studied in two grass species of Festuca arundinacea and Lolium perenne. Plants were grown under different Zn concentrations (control, 200, 400, 800, and 1800 mg kg(-1)) in potted soil for 5 months. The results showed that the number of plant tillers was 85 and 51% greater in endophyte infected Festuca (FaEI) and Lolium (LpEI), respectively, compared to their endophyte free (EF) plants. Roots and shoots dry weights in infected Festuca were 87 and 9% greater than non-infected counterparts but in opposite, EF Lolium had 47 and 8% greater root and shoot dry weights than LpEI. Endophyte infected Festuca and Lolium improved chlorophyll fluorescence as Fv/Fm at high concentrations of Zn, showing their better chlorophyll functions and significant reduction of Zn stress in endophyte infected plants. Shoots of endophyte infectedFestuca had 82% greater concentration of Zn than EF Festuca when grown in soil containing 1800 mg kg(-1) Zn. Festuca and Lolium may tolerate high Zn concentration in soil without reduction in shoot and root growth. Endophyte infection in Festuca may help the grass accumulate and transport more Zn in aboveground parts under Zn-stress, thereby aiding phytoremediation of contaminated soils. PMID- 25495937 TI - Variation in Heavy Metal Accumulation and Genetic Diversity at a Regional Scale Among Metallicolous and Non-Metallicolous Populations of the Facultative Metallophyte Biscutella laevigata subsp. laevigata. AB - Biscutella laevigata is a facultative metallophyte, with populations on non metalliferous and metalliferous soils. Some of its metallicolous populations have been shown to hyperaccumulate thallium or lead in nature. Only Tl hyperaccumulation has been experimentally confirmed. We aimed to compare the patterns of metal (hyper)accumulation and genetic diversity among populations of B. laevigata subsp. laevigata in NE Italy. None of the populations exhibited foliar hyperaccumulation of Cu, Zn, or Pb. The root-to-shoot accumulation rates for these metals were unchanged or decreased rather than enhanced in the metallicolous populations, in comparison with the non-metallicolous ones. Hyperaccumulation of Tl was confined to the population of the Cave del Predil mine. This population was genetically very distinct from the others, as demonstrated by AFLP-based cluster analysis. The two other mine populations did not surpass the threshold for Tl hyperaccumulation, but showed enhanced foliar Tl concentrations and root-to-shoot translocation rates, in comparison with the non metallicolous populations. Genetic analysis suggested that adaptation to metalliferous soil must have been independently evolved in the metallicolous populations. PMID- 25495938 TI - Wild flora of mine tailings: perspectives for use in phytoremediation of potentially toxic elements in a semi-arid region in Mexico. AB - The aim of this research was to identify wild plant species applicable for remediation of mine tailings in arid soils. Plants growing on two mine tailings were identified and evaluated for their potential use in phytoremediation based on the concentration of potentially toxic elements (PTEs) in roots and shoots, bioconcentration (BCF) and translocation factors (TF). Total, water-soluble and DTPA-extractable concentrations of Pb, Cd, Zn, Cu, Co and Ni in rhizospheric and bulk soil were determined. Twelve species can grow on mine tailings, accumulate PTEs concentrations above the commonly accepted phytotoxicity levels, and are suitable for establishing a vegetation cover on barren mine tailings in the Zimapan region. Pteridium sp. is suitable for Zn and Cd phytostabilization. Aster gymnocephalus is a potential phytoextractor for Zn, Cd, Pb and Cu; Gnaphalium sp. for Cu and Crotalaria pumila for Zn. The species play different roles according to the specific conditions where they are growing at one site behaving as a PTEs accumulator and at another as a stabilizer. For this reason and due to the lack of a unified approach for calculation and interpretation of bioaccumulation factors, only considering BCF and TF may be not practical in all cases. PMID- 25495939 TI - Use of Arbuscular Mycorrhiza and Organic Amendments to Enhance Growth of Macaranga peltata (Roxb.) Mull. Arg. in Iron Ore Mine Wastelands. AB - Macaranga peltata (Roxb.) Mull. Arg. is a disturbance tolerant plant species with potential in mine wasteland reclamation. Our study aims at studying the phyto extraction potential of M. peltata and determining plant-soil interaction factors effecting plant growth in iron ore mine spoils. Plants were grown in pure mine spoil and spoil amended with Farm Yard Manure (FYM) and Vermicompost (VC) along with arbuscular mycorrhizal (AM) species Rhizophagus irregularis. Pure and amended mine spoils were evaluated for nutrient status. Plant growth parameters and foliar nutrient contents were determined at the end of one year. FYM amendment in spoil significantly increased plant biomass compared to pure mine spoil and VC amended spoil. Foliar Fe accumulation was recorded highest (594.67 MUg/g) in pure spoil with no mortality but considerably affecting plant growth, thus proving to exhibit phyto-extraction potential. FYM and VC amendments reduced AM colonization (30.4% and 37% resp.) and plants showed a negative mycorrhizal dependency (-30.35 and -39.83 resp.). Soil pH and P levels and, foliar Fe accumulation are major factors determining plant growth in spoil. FYM amendment was found to be superior to VC as a spoil amendment for hastening plant growth and establishment in iron ore mine spoil. PMID- 25495940 TI - Abundance and Activity of 16S rRNA, AmoA and NifH Bacterial Genes During Assisted Phytostabilization of Mine Tailings. AB - Mine tailings in semiarid regions are highly susceptible to erosion and are sources of dust pollution and potential avenues of human exposure to toxic metals. One constraint to revegetation of tailings by phytostabilization is the absence of microbial communities critical for biogeochemical cycling of plant nutrients. The objective of this study was to evaluate specific genes as in situ indicators of biological soil response during phytoremediation. The abundance and activity of 16S rRNA, nifH, and amoA were monitored during a nine month phytostabilization study using buffalo grass and quailbush grown in compost amended, metalliferous tailings. The compost amendment provided a greater than 5 log increase in bacterial abundance, and survival of this compost-inoculum was more stable in planted treatments. Despite increased abundance, the activity of the introduced community was low, and significant increases were not detected until six and nine months in quailbush, and unplanted compost and buffalo grass treatments, respectively. In addition, increased abundances of nitrogen-fixation (nifH) and ammonia-oxidizing (amoA) genes were observed in rhizospheres of buffalo grass and quailbush, respectively. Thus, plant establishment facilitated the short term stabilization of introduced bacterial biomass and supported the growth of two key nitrogen-cycling populations in compost-amended tailings. PMID- 25495941 TI - Effect of Different Amendments on Growing of Canna indica L. Inoculated with AMF on Mining Substrate. AB - Canna indica L. (CiL) was used here in phytoremediation of mining soils. Our work evaluated the effect of AMF (i) on the growth and (ii) on the uptake of heavy metals (HM). The tests were conducted in the greenhouse on mining substrates collected from the Kettara mine (Morocco). The mine soil was amended by different proportions of agricultural soil and compost and then inoculated with two isolates of AMF (IN1) and (IN2) of different origins. After six months of culture, the results show that on mining soils (100%) only AMF (IN2) was able to colonize the roots of CiL with a frequency of 40+/-7% and an intensity of 6.5+/ 1.5%. Also, the lowest values of shoot and root dry biomass are obtained on these mining soils with respectively 0.30 g and 0.27 g. In contrast, the accumulation of HM was higher and reached more than 50% of that contained in the mining soils, the highest values with 138 mg kg(-1) Cu2+, Zn2+ 270 mg kg(-1) and 1.38 mg kg(-1) Cd was recorded. These results indicate that the colonization of CiL roots by AMF (IN2) could significantly improve its potential to be used in phytoremediation of polluted soil. PMID- 25495943 TI - Posterior-only spinal release combined with derotation, translation, segmental correction, and an in situ rod-contouring technique for treatment of severe and rigid scoliosis. AB - OBJECT: The object of this study was to review the effectiveness in treating severe and rigid scoliosis with posterioronly spinal release combined with derotation, translation, segmental correction, and an in situ rod-contouring technique. METHODS: Twenty-eight patients with severe and rigid scoliosis (Cobb angle>70 degrees and flexibility<30%) were retrospectively enrolled between June 2008 and June 2010. The average age of the patients was 17.1 years old (range 12 22 years old), 18 were female, and 10 were male. Etiological diagnoses were idiopathic in 24 patients, neuromuscular in 2 patients, and Marfan syndrome in 2 patients. All patients underwent posterior spinal release, derotation, translation, segmental correction, and an in situ rod-contouring technique. The scoliosis Cobb angle in the coronal plane, kyphosis Cobb angle, apex vertebral translation, and trunk shift were evaluated preoperatively and postoperatively. RESULTS: The average operative time was 241.8+/-32.1 minutes and estimated blood loss was 780.5+/-132.6 ml. The average scoliosis Cobb angle in the coronal plane was corrected from 85.7 degrees (range 77 degrees -94 degrees ) preoperatively to 33.1 degrees (range 21 degrees -52 degrees ) postoperatively, with a correction ratio of 61.3%. The average kyphosis Cobb angle was 64.5 degrees (range 59 degrees -83 degrees ) preoperatively, which was decreased to 42.6 degrees (range 34 degrees -58 degrees ) postoperatively, with a correction ratio of 33.9%. After an average of 24 months of follow-up (range 13-30 months), no major complications were observed in these patients, except screw pullout of the upper thoracic vertebrae in 2 patients and screw penetration into the apical vertebrae in 1 patient. CONCLUSIONS: Posterior spinal release combined with derotation, translation, segmental correction, and an in situ rod-contouring technique has proved to be a promising new technique for rigid scoliosis, significantly correcting the scoliosis and accompanied by fewer complications. PMID- 25495942 TI - CXCL16 suppresses liver metastasis of colorectal cancer by promoting TNF-alpha induced apoptosis by tumor-associated macrophages. AB - BACKGROUND: Inhibition of metastasis through upregulation of immune surveillance is a major purpose of chemokine gene therapy. In this study, we focused on a membrane-bound chemokine CXCL16, which has shown a correlation with a good prognosis for colorectal cancer (CRC) patients. METHODS: We generated a CXCL16 expressing metastatic CRC cell line and identified changes in TNF and apoptosis related factors. To investigate the effect of CXCL16 on colorectal liver metastasis, we injected SL4-Cont and SL4-CXCL16 cells into intraportal vein in C57BL/6 mice and evaluated the metastasis. Moreover, we analyzed metastatic liver tissues using flow cytometry whether CXCL16 expression regulates the infiltration of M1 macrophages. RESULTS: CXCL16 expression enhanced TNF-alpha-induced apoptosis through activation of PARP and the caspase-3-mediated apoptotic pathway and through inactivation of the NF-kappaB-mediated survival pathway. Several genes were changed by CXCL16 expression, but we focused on IRF8, which is a regulator of apoptosis and the metastatic phenotype. We confirmed CXCL16 expression in SL4-CXCL16 cells and the correlation between CXCL16 and IRF8. Silencing of IRF8 significantly decreased TNF-alpha-induced apoptosis. Liver metastasis of SL4-CXCL16 cells was also inhibited by TNF-alpha-induced apoptosis through the induction of M1 macrophages, which released TNF-alpha. Our findings suggest that the accumulation of M1 macrophages and the enhancement of apoptosis by CXCL16 might be an effective dual approach against CRC liver metastasis. CONCLUSIONS: Collectively, this study revealed that CXCL16 regulates immune surveillance and cell signaling. Therefore, we provide the first evidence of CXCL16 serving as an intracellular signaling molecule. PMID- 25495944 TI - The adverse effects of sorafenib in patients with advanced cancers. AB - Sorafenib is the first multi-kinase inhibitor (TKI) approved for the treatment of advanced hepatocellular cancer (HCC) and metastatic renal cell cancer (RCC) and is increasingly being used to treat patients with well-differentiated radioiodine resistant thyroid cancer (DTC). Sorafenib demonstrates targeted activity on several families of receptor and non-receptor tyrosine kinases that are involved in angiogenesis, tumour growth and metastatic progression of cancer. Sorafenib treatment results in long-term efficacy and low incidence of life-threatening toxicities. Although sorafenib has demonstrated many benefits in patients, the adverse effects cannot be ignored. The most common treatment-related toxicities include diarrhoea, fatigue, hand-foot skin reaction and hypertension. Most of these toxicities are considered mild to moderate and manageable to varying degrees; however, cardiovascular events might lead to death. In this MiniReview, we summarize the adverse effects of sorafenib that commonly occur in patients with advanced cancers. PMID- 25495945 TI - Feral ferrets (Mustela furo) as hosts and sentinels of tuberculosis in New Zealand. AB - The control and eventual eradication of bovine tuberculosis (TB) poses major challenges in New Zealand, given the variety of wildlife species susceptible to TB, many of which are capable of onwards transmission of Mycobacterium bovis infection. Here we discuss the role of feral ferrets (Mustela furo), focussing on potential transmission or risk pathways that have implications for management of TB. Firstly inter-specific transmission to ferrets. Ferrets scavenge potentially infected wildlife, including other ferrets, thus prevalence of TB can be amplified through ferrets feeding on tuberculous carcasses, particularly brushtail possums (Trichosurus vulpecula). Secondly intra-specific transmission between ferrets. The rate of ferret-ferret transmission depends on population density, and in some places ferret densities exceed the estimated threshold for disease persistence. TB can therefore potentially be maintained independently of other sources of infection. Thirdly transmission from ferrets to other wildlife. These include the main wildlife maintenance host, brushtail possums, that will occasionally scavenge potentially tuberculous ferret carcasses. Fourthly transmission from ferrets to livestock. This is considered to occur occasionally, but the actual rate of transmission has never been measured. Fifthly geographical spread. M. bovis-infected ferrets can travel large distances and cause new outbreaks of TB at locations previously free of TB, which may have caused an expansion of TB-endemic areas. Ferrets play a complex role in the TB cycle in New Zealand; they are capable of contracting, amplifying and transmitting M. bovis infection, sometimes resulting in ferret populations with a high prevalence of TB. However, ferret population densities are usually too low to sustain infection independently, and transmission to other wildlife or livestock appears a rarer event than with possums. Nevertheless, management of ferrets remains a key part of the National Pest Management Strategy for TB. Control is prudent where M. bovis-infected ferret populations exist in high numbers, to reduce the onward transmission risk of any self-sustained infection to livestock. When ferret numbers are well below the theoretical disease maintenance threshold, ferret control is still sometimes warranted because of the animals' ability to acquire infection when young and, through dispersal, transport it outside TB-endemic areas. Ferrets can also be used as disease sentinels for TB, especially in areas where alternative sentinel species are rare or expensive to survey, and when sampling of possums is not cost-effective. PMID- 25495946 TI - Patient safety culture among nurses. AB - BACKGROUND: Patient safety is considered to be crucial to healthcare quality and is one of the major parameters monitored by all healthcare organizations around the world. Nurses play a vital role in maintaining and promoting patient safety due to the nature of their work. AIMS: The purpose of this study was to investigate nurses' perceptions about patient safety culture and to identify the factors that need to be emphasized in order to develop and maintain the culture of safety among nurses in Oman. METHODS: A descriptive and cross-sectional design was used. Patient safety culture was assessed by using the Hospital Survey on Patient Safety Culture among 414 registered nurses working in four major governmental hospitals in Oman. Descriptive statistics and general linear regression were employed to assess the association between patient safety culture and demographic variables. RESULTS: Nurses who perceived more supervisor or manager expectations, feedback and communications about errors, teamwork across hospital units, and hospital handoffs and transitions had more overall perception of patient safety. Nurses who perceived more teamwork within units and more feedback and communications about errors had more frequency of events reported. Furthermore, nurses who had more years of experience and were working in teaching hospitals had more perception of patient safety culture. CONCLUSION: Learning and continuous improvement, hospital management support, supervisor/manager expectations, feedback and communications about error, teamwork, hospital handoffs and transitions were found to be major patient safety culture predictors. Investing in practices and systems that focus on improving these aspects is likely to enhance the culture of patient safety in Omani hospitals and others like them. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Strategies to nurture patient safety culture in Omani hospitals should focus upon building leadership capacity that support open communication, blame free, team work and continuous organizational learning. PMID- 25495947 TI - Load and distribution of organic matter and nutrients in a separated household wastewater stream. AB - Wastewater from a source-separated sanitation system connected to 24 residential flats was analysed for the content of organic matter and nutrients and other key parameters for microbiological processes used in the treatment and reuse of wastewater. Black water (BW) was the major contributor to the total load of organic matter and nutrients in the wastewater, accounting for 69% of chemical oxygen demand (COD), 83% of total nitrogen (N) and 87% of phosphorus (P). With a low COD/N ratio and high content of free ammonia, treating BW alone is a challenge in traditional biological nitrogen removal approaches. However, its high nitrogen concentration (1.4-1.7 g L(-1)) open up for nutrient reuse as well as for novel, more energy efficient N-removal technologies. Grey water (GW) contained low amounts of nutrients relative to organic matter, and this may limit biological treatment processes under certain conditions. GW contains a higher proportion of soluble, readily degradable organic substances compared with BW, which facilitates simple, decentralized treatment approaches. The concentration of organic matter and nutrients varied considerably between our study and other studies, which could be related to different toilet flushing volumes and water use habits. The daily load per capita, on the other hand, was found to be in line with most of the reported studies. PMID- 25495948 TI - The influence of early sexual debut and pubertal timing on psychological distress among Taiwanese adolescents. AB - This study examined the relative influence of early sexual debut (ESD) and pubertal timing on psychological distress from adolescence to young adulthood in Taiwan, a non-Western society with a distinct cultural and family context. Data were from a cohort sample of 15-year-olds (N = 2595) first interviewed in 2000, with four follow-ups during a 7-year period. Psychological distress was assessed by a reduced form of the Symptom Checklist-90 Revised. ESD was defined by first intercourse at age 15 or younger. Multivariate analyses via growth curve modeling found a greater increase in psychological distress over time in adolescents with ESD (beta = .28, p < .05). Early-pubertal adolescents were at greater risk for the onset of psychological distress (beta = .46, p < .05). Further, early pubertal adolescents with an ESD appeared to be especially likely to be distressed (beta = 3.39, p < .05). In addition, analyses showed a non-linear trajectory of psychological distress between the ages of 15 and 22, with distress escalating (beta = .45, p < .001) as age increased before tapering off as adolescents became young adults (beta = -.03, p < .001). Results suggest the contributing influence of both ESD and pubertal timing on distress trajectories, independent of parental and family characteristics. PMID- 25495949 TI - RPE65 Mutations in Two Japanese Families with Leber Congenital Amaurosis. AB - PURPOSE: To investigate genetic and clinical features of patients with Leber congenital amaurosis (LCA) caused by RPE65 mutations. METHODS: Five Japanese families with LCA were recruited. We performed complete ophthalmic examinations, with optical coherence tomography, fundus autofluorescence imaging, and full field electroretinography (ERG). Genetic analysis was performed with whole-exome sequencing analysis and Sanger sequencing. RESULTS: We identified RPE65 mutations in two unrelated LCA patients from two families. Case 1: A 5-month-old girl was diagnosed with LCA because of nystagmus, loss of vision and non-recordable ERG. She was the only one affected in her non-consanguineous family, and exhibited novel compound heterozygous RPE65 mutations (c.177C>G, p.H59Q and c.183_184insT, p.D62X). Case 2: A 30-year-old woman, who had night blindness and poor ocular pursuit during the first year of life, exhibited severe retinal degeneration and non-recordable ERG. She was the only affected in her non-consanguineous family, and showed a homozygous RPE65 mutation (c.1543C>T, p.R515W). CONCLUSIONS: By using whole-exome sequencing analysis, three RPE65 mutations were identified in two Japanese patients with LCA. This approach would be useful for identification of disease-causing mutations of LCA. PMID- 25495950 TI - Multicollinearity in spatial genetics: separating the wheat from the chaff using commonality analyses. AB - Direct gradient analyses in spatial genetics provide unique opportunities to describe the inherent complexity of genetic variation in wildlife species and are the object of many methodological developments. However, multicollinearity among explanatory variables is a systemic issue in multivariate regression analyses and is likely to cause serious difficulties in properly interpreting results of direct gradient analyses, with the risk of erroneous conclusions, misdirected research and inefficient or counterproductive conservation measures. Using simulated data sets along with linear and logistic regressions on distance matrices, we illustrate how commonality analysis (CA), a detailed variance partitioning procedure that was recently introduced in the field of ecology, can be used to deal with nonindependence among spatial predictors. By decomposing model fit indices into unique and common (or shared) variance components, CA allows identifying the location and magnitude of multicollinearity, revealing spurious correlations and thus thoroughly improving the interpretation of multivariate regressions. Despite a few inherent limitations, especially in the case of resistance model optimization, this review highlights the great potential of CA to account for complex multicollinearity patterns in spatial genetics and identifies future applications and lines of research. We strongly urge spatial geneticists to systematically investigate commonalities when performing direct gradient analyses. PMID- 25495951 TI - Effect of ethylenediaminetetraacetic acid gel on the incidence of dentinal cracks caused by three novel nickel-titanium systems. AB - The aim of this study is to evaluate the incidence of crack formation while using Reciproc, WaveOne and Twisted File Adaptive with and without ethylenediaminetetraacetic acid (EDTA) gel. Seventy extracted mandibular premolars were included. The teeth were decoronated until roots of 16 mm were obtained. Samples were distributed into seven groups: group 1, no canal preparation (control); other groups were instrumented so; group 2, Reciproc; group 3, Reciproc + EDTA; group 4, WaveOne; group 5, WaveOne + EDTA; group 6, Twisted File Adaptive; group 7, Twisted File Adaptive + EDTA. Roots were horizontally sectioned from 3, 6 and 9 mm from apex and observed under stereomicroscope. The number and the incidence of cracks were recorded and statistically analysed with chi-squared and Kruskal-Wallis tests. Control group did not reveal any cracks. Crack formation with three novel Ni-Ti instruments was similar. Using EDTA gel did not reduce crack occurrence. PMID- 25495952 TI - The tap-tpg gene pair on the linear plasmid functions to maintain a linear topology of the chromosome in Streptomyces rochei. AB - Streptomyces rochei 7434AN4 carries three linear plasmids, pSLA2-L (211 kb), pSLA2-M (113 kb) and pSLA2-S (18 kb), their complete nucleotide sequences having been determined. Restriction and sequencing analysis revealed that the telomere sequences at both ends of the linear chromosome are identical to each other, are 98.5% identical to the right end sequences of pSLA2-L and pSLA2-M up to 3.1 kb from the ends and have homology to those of typical Streptomyces species. Mutant 2-39, which lost all the three linear plasmids, was found to carry a circularized chromosome. Sequence comparison of the fusion junction and both deletion ends revealed that chromosomal circularization occurred by terminal deletions followed by nonhomologous recombination. Curing of pSLA2-L from strain 51252, which carries only pSLA2-L, also resulted in terminal deletions in newly obtained mutants. The tap-tpg gene pair, which encodes a telomere-associated protein and a terminal protein for end patching, is located on pSLA2-L and pSLA2-M but has not hitherto been found on the chromosome. These results led us to the idea that the tap-tpg of pSLA2-L or pSLA2-M functions to maintain a linear chromosome in strain 7434AN4. This hypothesis was finally confirmed by complementation and curing experiments of the tap-tpg of pSLA2-M. PMID- 25495953 TI - Digital plethysmography and arginine metabolism in prehypertension: effect of nebivolol therapy. AB - Prehypertension is an important phenotype for cardiovascular risk and development of established hypertension. To better understand the early circulatory changes in this group, the authors studied 34 patients with prehypertension (blood pressure 120-139/80-89 mm Hg) using digital plethysmography for measurement of blood flow and reactive hyperemic index (RHI). Arterial augmentation index (AI) was also measured. Because prehypertension is associated with endothelial dysfunction and decreased availability of nitric oxide (NO), indices of arginine metabolism (l-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, and l-citrulline) were measured. Nebivolol (5 mg/d), a vasodilating beta1 -antagonist with beta3 -agonist activity, was studied in a double-blind fashion for 8 weeks. Nebivolol increases the bioavailability of NO. Prehypertension was associated with normal RHI and baseline digital blood flow. AI was abnormal and associated with diastolic blood pressure. ADMA concentration was increased at baseline. After 8 weeks of nebivolol therapy, RHI, ADMA, symmetric dimethylarginine, and AI showed no significant change, but digital blood flow and l-citrulline levels were significantly increased. Prehypertension is associated with increased ADMA and evidence of increased arterial stiffness and preserved RHI. Nebivolol therapy is associated with digital vasodilation and increased NO production, as depicted by increased levels of l-citruline and mean digital blood flow. PMID- 25495954 TI - Baseline Anterior Segment Parameters Associated with the Long-term Outcome of Laser Peripheral Iridotomy. AB - PURPOSE: To investigate the baseline anterior segment (AS) parameters determined by AS optical coherence tomography (AS OCT) in the prediction of long-term outcome of laser peripheral iridotomy (LPI) in primary angle closure suspect (PACS) eyes Methods: Participants were imaged at pre-LPI and at 2 weeks and 3 years post-LPI using AS OCT. Based on these images, anterior chamber depth (ACD), iris curvature (IC), anterior chamber width (ACW), iris thickness at 750 um from the scleral spur (IT750), lens vault (LV), and iris area (IA) were estimated using the Image J software (version 1.46). Proportional change (%) in angle opening distance at 750 um from the scleral spur (AOD750) was used as an outcome measure for LPI. Univariate and multivariate regression analyses were performed to evaluate baseline AS parameters associated with changes in AOD750. RESULTS: A total of 39 PACS eyes were included. At 2 weeks post-LPI, thinner IT750 (p = 0.006) and less AOD750 (p < 0.001) at baseline were related to a greater AOD750 change. When assessed at 3 years post-LPI, thinner IT750 (p = 0.039) and less AOD750 (p = 0.003) at baseline were associated with a greater AOD750 change. CONCLUSIONS: Thin peripheral iris and less AOD750 at baseline were associated with greater changes in longitudinal assessment after LPI. PACS eyes with thick peripheral iris at baseline showed less AOD750 change at both early and late follow up after LPI; therefore, such eyes should be followed with caution despite successful LPI. PMID- 25495955 TI - Exertional fat embolism after hip joint replacement: a case report. AB - INTRODUCTION: We present the case of a patient with exertional fat embolism on isolated exercise of his right leg two and four months after right total hip joint replacement. His immediate post-operative period had also been complicated by an acute episode of chest pain and hypotension, treated as acute coronary syndrome. To the best of our knowledge, this is the first reported case of exertional fat embolism following orthopedic surgery. CASE PRESENTATION: A 71 year-old Caucasian man underwent elective cementless total right hip joint replacement. His acute post-operative period was complicated by an episode of chest pain and hypotension. This was treated as acute coronary syndrome. Two months later, a routine stress echocardiography demonstrated a shower of small, echodense bubbles in his right heart, reproduced on exercise of his right leg but not his left. Computed tomography pulmonary angiography excluded pulmonary thromboemboli. A technetium-99m colloid scan confirmed pulmonary fat emboli. Similar findings occurred again four months after the operation but had resolved at six months. CONCLUSIONS: Fat embolism is a well-described phenomenon in the acute setting after long-bone trauma or intramedullary manipulation, and the rare fat embolism syndrome can be fatal. Exertional fat embolism months after joint replacement, however, is an undescribed phenomenon that may have implications in the sub-acute post-operative phase. This may be of particular interest to those involved in orthopedics, cardiology and rehabilitation, but the large volume of patients undergoing joint replacements may broaden the clinical scope of this unusual presentation far beyond these specialties. PMID- 25495957 TI - Subjective Cognitive Complaints in Parkinson Disease Without Dementia: A Preliminary Study. AB - Little is known about the subjective cognitive complaints of individuals with Parkinson disease (PD). Such complaints have become a topic of interest recently as they play a role in the diagnosis of neurocognitive disorders. The aim of this preliminary study was to determine whether a sample of nondemented individuals with PD reported significantly more difficulties with multiple elements of cognition than a control sample and to assess the relation between their ratings and demographics, motor symptom severity, neuropsychological test performance, and measures of depression and anxiety. Forty nondemented individuals with PD and 27 healthy individuals completed a questionnaire assessing everyday cognitive difficulties. Independent t tests indicated that individuals with PD reported significantly more cognitive complaints in general and in specific tasks involving complex attention, executive function, processing speed, and verbal fluency but not memory. Questionnaire ratings significantly correlated with measures assessing anxiety, verbal memory, processing speed, and verbal fluency. Results suggest that it is important to ask individuals with PD about cognitive complaints across several cognitive domains and also inquire about symptoms of anxiety, which may be related to their self-reported cognitive difficulties. PMID- 25495956 TI - "Every drug goes to treat its own disease..." - a qualitative study of perceptions and experiences of taking anti-retrovirals concomitantly with anti malarials among those affected by HIV and malaria in Tanzania. AB - BACKGROUND: Little is known about how people living with human immunodeficiency virus (HIV) experience malaria and the concomitant use of anti-malarial treatments with anti-retrovirals (ARVs). An understanding of how patients make sense of these experiences is important to consider in planning and supporting the clinical management and treatment for co-infected individuals. METHODS: A qualitative study was conducted in Tanzania alongside a clinical trial of concomitant treatment for HIV and malaria co-infection. Focus group discussions were held with people receiving treatment for HIV and/or malaria, and in-depth interviews with health workers responsible for HIV care and members of the clinical trial team. Data were analysed inductively to identify themes and develop theoretical narratives. RESULTS: Results suggest that people living with HIV perceived malaria to be more harmful to them due to their compromised immune status but saw the disease as unavoidable. For those enrolled in the clinical controlled study, taking anti-malarials together with ARVs was largely seen as unproblematic, with health workers' advice and endorsement of concomitant drug taking influential in reported adherence. However, perceptions of drug strength appeared to compel some people not enrolled in the clinical study to take the drugs at separate times to avoid anticipated harm to the body. CONCLUSIONS: Management of HIV and malaria concurrently often requires individuals to cross the domains of different disease programmes. In the context of a trial concerned with both diseases, patients experienced the support of clinicians in guiding and reassuring them about when and how to take drugs concomitantly. This points towards the need to continue to strive for integrated care for patients with HIV. PMID- 25495958 TI - Simultaneous determination of stable carbon, oxygen, and hydrogen isotopes in cellulose. AB - A technological development is described through which the stable carbon-, oxygen , and nonexchangeable hydrogen-isotopic ratios (delta(13)C, delta(18)O, delta(2)H) are determined on a single carbohydrate (cellulose) sample with precision equivalent to conventional techniques (delta(13)C 0.150/00, delta(18)O 0.300/00, delta(2)H 3.00/00). This triple-isotope approach offers significant new research opportunities, most notably in physiology and medicine, isotope biogeochemistry, forensic science, and palaeoclimatology, when isotopic analysis of a common sample is desirable or when sample material is limited. PMID- 25495959 TI - Identification and determination of flavonoids, carotenoids and chlorophyll concentration in Cynodon dactylon (L.) by HPLC analysis. AB - Cynodon dactylon (L.) is a potent medicinal plant in the traditional and current Indian medicinal systems. The objective of this research was to find out the levels of flavonoids, carotenoids and chlorophyll b in C. dactylon leaves by high performance liquid chromatography (HPLC) equipped with a diode array detector. HPLC analysis revealed that total carotenoid and total flavonoid concentration were 62 mg/100 g and 249.1 MUg/g, respectively. The mean chlorophyll b was 85.1 mg/100 g in C. dactylon. Among the flavonoids, quercetin (164.7 MUg/g) was the major flavonoid followed by kaempferol (48.2 MUg/g), rutin (18.4 MUg/g), catechin (12.1 MUg/g) and myricetin (5.7 MUg/g). Of the carotenoids, beta-carotene (35.2 mg/100 g) was predominant followed by lutein (17.0 mg/100 g), violaxanthin (5.8 mg/100 g) and zeaxanthin (4.2 mg/100 g). Chlorophyll b concentration was 85.1 mg/100 g in C. dactylon. The results of this investigation should be useful information for further pharmacological studies. PMID- 25495960 TI - The association between suicide ideation and sensory impairment among elderly Koreans. AB - OBJECTIVES: The purpose of this cross-sectional study was to examine the relationship between sensory impairment and suicide ideation among elderly Koreans. METHODS: Data from the 2010-2012 Korea National Health and Nutrition Examination Survey V was used. Participants included 3636 older adults (>=65 years) who received hearing and vision tests; participants also completed assessments of covariates and suicide ideation. RESULTS: The risk of suicide ideation was 1.43-1.65 times higher among participants with visual impairment than in those without impairment. Moreover, the risk was 1.60-1.76 times higher among those with both auditory and visual impairments than the risk for those without any impairment. CONCLUSION: This study found an association between sensory impairment and suicide ideation in elderly individuals. Therefore, it seems necessary that interventions that reduce or prevent sensory impaired elders' suicide ideation are needed, which may be an indicator of mental health problems or poor quality of life. PMID- 25495961 TI - Diagnosis, prognosis and management of erythrodermic cutaneous T-cell lymphoma. AB - Erythroderma describes complete or near-complete skin surface erythema of any cause. Cutaneous T-cell lymphoma accounts for a minority of cases of erythroderma and consists of erythrodermic mycosis fungoides, Sezary syndrome. Both adult T cell leukemia/lymphoma and T-cell prolymphocytic leukemia can also rarely present with erythroderma. Diagnosis may be extremely challenging because benign disorders may have overlapping features with those of lymphoma. Prognosis is poor with median survival of approximately 2 years. The evidence base for therapeutic approaches relies on cohorts and case series and more recently Phase II trials. Improved patient selection and identification of appropriate conditioning regimens for reduced intensity allogeneic hematopoetic transplant are likely to improve survival, although a significant number of patients may not be fit for transplant because of advanced age and comorbidities. PMID- 25495962 TI - Professional mechanical plaque removal for prevention of periodontal diseases in adults--systematic review update. AB - AIM: To update previous systematic review investigating effect of professional mechanical plaque removal (PMPR) on prevention of periodontal diseases. METHODS: Search for randomized controlled trials: 2004 to April 2014. Screening and data abstraction conducted independently/in duplicate and narrative synthesis. RESULTS: From 1655 titles and abstracts, 24 full-text articles screened and three new studies were eligible. Low-to moderate strength of evidence suggests that in adults, PMPR, particularly if combined with oral hygiene instructions (OHI), may achieve greater changes in measures of dental plaque and gingival bleeding/inflammation than no treatment. Moderate strength of evidence suggests there is no additional benefit to plaque and gingival bleeding outcomes from PMPR over that achieved by repeated and thorough OHI. There is no evidence from RCTs to inform on prevention of periodontitis. Low strength of evidence suggests that more frequent PMPR is associated with improved plaque and bleeding outcomes and possibly less annual attachment loss. CONCLUSIONS: There are insufficient data to inform directly on the effect of PMPR on primary prevention of periodontitis. However, in relation to gingival health, new studies strengthen the evidence that there is little value in providing PMPR without OHI. In fact, repeated, thorough OHI can achieve a similar benefit to repeated PMPR. PMID- 25495963 TI - Antiplatelet drugs and platelet reactivity: is it time to halt clinical research on tailored strategies? AB - Personalized medicine of antiplatelet drugs in cardiovascular patients has led to a significant enthusiasm. Indeed, numerous longitudinal studies showed an association between high platelet reactivity and the recurrence of ischemic events. The first small randomized trials of P2Y12 blockers tailored to each patient's platelet reactivity yielded encouraging reductions of coronary stent thrombosis in high-risk populations. The discovery of genetic variants contributing to the pharmacodynamic effect of clopidogrel has then paved the way toward a personalized antiplatelet therapy based on reliable and stable genetic tests. This enthusiasm was soon tempered by large interventional trials demonstrating that a platelet function testing-based strategy did not improve clinical outcome and that genetic variants discovered up to now only explained a small part of the pharmacodynamic effect of clopidogrel, thus limiting its clinical use. Looking back to the most recent trials, their target populations and the type of clinical setting, it seems that the one-size-fits all policy regarding antiplatelet drugs may be well acceptable for low-risk patients. On the contrary, integration of the clinical setting as well as other risk factors may help to identify subgroups of patients who could derive a benefit from a truly personalized management of antiplatelet therapy. PMID- 25495965 TI - How to help women at risk for acute stress disorder after childbirth. AB - For some women, childbirth is a traumatic experience that results in significant mental and emotional distress. Whether owing to birth complications, postpartum events such as hemorrhage or pre-existing risk factors such as past history of sexual abuse or rape, the emotional effects of childbirth trauma can lead to acute stress disorder (ASD). To provide the best care for women after childbirth, it's imperative that nurses be able to identify signs of ASD and intervene appropriately. There are many things nurses can do to help women in what could be the most vulnerable time of their lives. PMID- 25495964 TI - Probing the DNA structural requirements for facilitated diffusion. AB - DNA glycosylases perform a genome-wide search to locate damaged nucleotides among a great excess of undamaged nucleotides. Many glycosylases are capable of facilitated diffusion, whereby multiple sites along the DNA are sampled during a single binding encounter. Electrostatic interactions between positively charged amino acids and the negatively charged phosphate backbone are crucial for facilitated diffusion, but the extent to which diffusing proteins rely on the double-helical structure DNA is not known. Kinetic assays were used to probe the DNA searching mechanism of human alkyladenine DNA glycosylase (AAG) and to test the extent to which diffusion requires B-form duplex DNA. Although AAG excises epsilonA lesions from single-stranded DNA, it is not processive on single stranded DNA because dissociation is faster than N-glycosidic bond cleavage. However, the AAG complex with single-stranded DNA is sufficiently stable to allow for DNA annealing when a complementary strand is added. This observation provides evidence of nonspecific association of AAG with single-stranded DNA. Single strand gaps, bubbles, and bent structures do not impede the search by AAG. Instead, these flexible or bent structures lead to the capture of a nearby site of damage that is more efficient than that of a continuous B-form duplex. The ability of AAG to negotiate these helix discontinuities is inconsistent with a sliding mode of diffusion but can be readily explained by a hopping mode that involves microscopic dissociation and reassociation. These experiments provide evidence of relatively long-range hops that allow a searching protein to navigate around DNA binding proteins that would serve as obstacles to a sliding protein. PMID- 25495967 TI - A pilot study of prenatal care visits blended group and individual for women with low income. AB - Healthy Pregnancy, Healthy Childbirth, Healthy Parenting (HPCP) is a blended prenatal care model that integrates group visits with individual prenatal visits. While group prenatal care has been found to have a positive impact on pregnancy outcomes, current models may not be feasible or desirable in all clinical settings. HPCP offers one educational group visit each trimester to improve knowledge of self-care during pregnancy and of childbirth and infant care. The program was piloted among women with low income in a southern metropolitan area. This article presents the findings of a pilot study that examined maternal knowledge acquisition and subsequent changes in self-efficacy and satisfaction with care. Suggestions for future use of a blended model for the delivery of prenatal care are shared. PMID- 25495968 TI - Addressing sexual violence through preventive nursing practice. AB - Approximately 1 in 20 women will experience sexual violence at some point in her life. The negative health consequences to women can be serious and lifelong, prompting the Centers for Disease Control and Prevention and the World Health Organization to declare sexual violence a public health problem. Nurses, in their provision of care to individuals and communities, can contribute to improved outcomes related to the problem of sexual violence through the application of preventive care practices. PMID- 25495969 TI - Facilitating skin-to-skin contact in the operating room after cesarean birth. AB - We implemented an evidence-based practice change to provide early skin-to-skin contact (SSC) in non-emergent, full-term cesarean surgical births among low-risk healthy women. There were three aims of this project: (1) To develop a protocol for health care professionals' roles in providing SSC in the operating room; (2) To implement the protocol; and (3) To evaluate the process of implementation of the evidence-based intervention. The "champion team" concept was crucial to the project's success. PMID- 25495970 TI - A cost-effective approach to simulation-based team training in obstetrics. AB - Many larger facilities regularly stage obstetric drills in modern simulation departments equipped with expensive simulators. Despite lacking these resources, we wanted to provide effective simulation training at our rural hospital. A team of clinicians and educators developed a cost-effective and time-efficient simulation drill for nurses, which included both a didactic review and a simulation day. The drill included obstetric providers and incorporated scenarios for shoulder dystocia, neonatal resuscitation and postpartum hemorrhage. This was a successful multidisciplinary learning experience that was high in creativity and teamwork, but low in cost. PMID- 25495971 TI - Management of neonatal abstinence syndrome in the newborn nursery. AB - Maternal drug use and neonatal abstinence syndrome (NAS) are being seen across the United States. NAS occurs with withdrawal disturbances in response to the cessation of the pregnancy exposure. The clinical presentation of a newborn with NAS can include gastrointestinal, neurologic, vasomotor and respiratory symptoms. Assessment of newborns with NAS can often present as a challenge to maternal child nurses. Treatment can include supportive care as well as pharmacologic therapies. PMID- 25495972 TI - A potential method to lower risk for surgical site infection during cesarean birth. AB - It's common practice to use a preparation containing chlorhexidine to prepare the surgical site before cesarean birth. We observed an interaction between ultrasound gel, used for electronic fetal heart monitoring before birth, and chlorhexidine. This interaction creates the potential for surgical site infection. Using isopropyl alcohol to thoroughly remove all gel before application of chlorhexidine was associated with reduced rates of postsurgical infection at our institution. PMID- 25495973 TI - Potential drug interaction between Rho(D) immune globulin and live virus vaccine. AB - Women often receive Rho(D) immune globulin as well as a live virus vaccine in the immediate postpartum period. The immune globulin product has the potential to interfere with appropriate immune response to the vaccine. Here we describe our approach to identifying and following up on this often overlooked potential drug interaction. PMID- 25495974 TI - Sharing the wisdom of nursing by writing for publication. AB - Nurses share their experiences, wisdom and insights through storytelling. Writing these stories for publication can serve to extend the reach of nursing practice. Writing for publication is a skill that all nurses can develop. It could be considered a professional obligation, as well as an act of generosity. The process of writing involves selecting a topic, working through an initial draft, reviewing, revising and finally submitting for publication. For the nursing profession to contribute fully to the advancement of health care, nurses need to present themselves as competent, thoughtful leaders able to express themselves clearly and effectively. Writing for publication helps accomplish this goal. PMID- 25495976 TI - Position statement discourages induction of labor without medical indications. PMID- 25495977 TI - From the emergency room to the birthing room. PMID- 25495978 TI - Enhancing antibiotic activity to combat resistant Gram-negative bacteria: what's next? PMID- 25495979 TI - The potential of 12/15-lipoxygenase inhibitors in stroke therapy. PMID- 25495980 TI - The search for a common structural moiety among selected pharmacological correctors of the mutant CFTR chloride channel. AB - BACKGROUND: The F508del mutation impairs the trafficking of CFTR from endoplasmic reticulum to plasma membrane and is responsible of a severe form of cystic fibrosis. Trafficking can be improved by small organic molecules called 'correctors'. MATERIALS & METHODS: By different synthetic ways, we prepared 4 chloroanisole and 2-(4-chloroanisol-2-yl)aminothiazole derivatives. Such compounds were ineffective as correctors but we could find a sign of activity in an intermediate. In the meantime, we found a common pharmacophoric moiety present in four known correctors. RESULTS: Following this structural indication, we synthesized a small set of new molecules endowed with a significant, even if not great, F508del-CFTR rescue activity. CONCLUSION: The cited structural feature seems interesting in the search of new correctors. To corroborate this observation, later on we found a new pyrazine derivative (Novartis) endowed with a potent activity as corrector and having the cited common design. PMID- 25495981 TI - Pharmacophore modeling for COX-1 and -2 inhibitors with LigandScout in comparison to Discovery Studio. AB - BACKGROUND: Pharmacophore modeling has become an integrated tool in drug discovery. However, no prospective study compares the performance of the available software. METHODS: The two widely used pharmacophore modeling and screening software programs Discovery Studio and LigandScout were used to generate, validate, and prospectively apply COX-1 and -2 models. Selected virtual hits were tested in cell-free enzymatic assays. The correct retrieval of active compounds was compared. RESULTS: In the enzymatic testing, 10.5% of the tested hits for COX-2 and 6.6% of the predicted compounds for COX-1 were active. To directly compare the two models, both based on the same PDB entry, were selected for virtual screening. The two programs yielded vastly different hit lists, but both predicted active compounds. CONCLUSION: To obtain a comprehensive selection of active compounds, more than one program should be used for modeling. PMID- 25495982 TI - Isoxazolotacrines as non-toxic and selective butyrylcholinesterase inhibitors for Alzheimer's disease. AB - BACKGROUND: Owing to the complex nature of Alzheimer's disease, there is a renewed and growing search for multitarget non-toxic tacrines as simple, easily available drugs in order to stop the progress and development of the disease. RESULTS: This paper describes our preliminary results on the synthesis, in vitro biochemical evaluation and molecular modeling of isoxazolotacrines as potential drugs for the treatment of Alzheimer's disease. Novel 3-phenyl-5,6,7,8 tetrahydroisoxazolo[5,4-b]quinolin-4-amine (OC41) is a promising, 31% less toxic than tacrine in HepG2 cells, and selective reversible human butyrylcholinesterase inhibitor (IC50 = 5.08 +/- 1.12 uM), also showing good drug-like properties according to the absorption, Distribution, Metabolism, Excretion, Toxicity analysis. CONCLUSION: A new family of non-hepatotoxic permeable tacrine analogs, showing selective butyrylcholinesterase inhibition, have been discovered for the potential treatment of Alzheimer's disease. PMID- 25495983 TI - "Too little, too late?" Will inhibitors of the hepatitis C virus p7 ion channel ever be used in the clinic? AB - Hepatitis C virus (HCV) p7 is a virus-coded ion channel, or 'viroporin'. p7 is an essential HCV protein, promoting infectious virion production, and this process can be blocked by prototypic p7 inhibitors. However, prototype potency is weak and effects in clinical trials are unsatisfactory. Nevertheless, recent structural studies render p7 amenable to modern drug discovery, with studies supporting that effective drug-like molecules should be achievable. However, burgeoning HCV therapies clear infection in the majority of treated patients. This perspective summarizes current understanding of p7 channel function and structure, pertaining to the development of improved p7 inhibitors. We ask, 'is this too little, too late', or could p7 inhibitors play a role in the long-term management of HCV disease? PMID- 25495985 TI - Utilizing diversity-oriented synthesis in antimicrobial drug discovery. AB - The development of resistance to existing antimicrobials has created a threat to human health that is not being addressed through our current drug pipeline. Limitations with the use of commercial vendor libraries and natural products have created a need for new types of small molecules to be screened in antimicrobial assays. Diversity oriented synthesis (DOS) is a strategy for the efficient generation of compound collections with a high degree of structural diversity. Diversity-oriented synthesis molecules occupy the middle ground of both complexity and efficiency of synthesis between natural products and commercial libraries. In this review we focus upon the use of diversity-oriented synthesis compound collections for the discovery of new antimicrobial agents. PMID- 25495984 TI - Targeting SH2 domains in breast cancer. AB - Breast cancer is among the most commonly diagnosed cancer types in women worldwide and is the second leading cause of cancer-related disease in the USA. SH2 domains recruit signaling proteins to phosphotyrosine residues on aberrantly activated growth factor and cytokine receptors and contribute to cancer cell cycling, metastasis, angiogenesis and so on. Herein we review phosphopeptide mimetic and small-molecule approaches targeting the SH2 domains of Grb2, Grb7 and STAT3 that inhibit their targets and reduce proliferation in in vitro breast cancer models. Only STAT3 inhibitors have been evaluated in in vivo models and have led to tumor reduction. Taken together, these studies suggest that targeting SH2 domains is an important approach to the treatment of breast cancer. PMID- 25495986 TI - Histone methylases as novel drug targets: developing inhibitors of EZH2. AB - Post-translational modifications of histones (so-called epigenetic modifications) play a major role in transcriptional control and normal development, and are tightly regulated. Disruption of their control is a frequent event in disease. In particular, the methylation of lysine 27 on histone H3 (H3K27), induced by the methylase EZH2, emerges as a key control of gene expression and a major regulator of cell physiology. The identification of driver mutations in EZH2 has already led to new prognostic and therapeutic advances, and new classes of potent and specific inhibitors for EZH2 show promising results in preclinical trials. This review examines the roles of histone lysine methylases and demethylases in cells and focuses on the recent knowledge and developments about EZH2. PMID- 25495988 TI - Two orders of magnitude improvement in detection limit of lateral flow assays using isotachophoresis. AB - Lateral flow immunoassays (LFA) are one of the most prevalent point-of-care (POC) diagnostics due to their simplicity, low cost, and robust operation. A common criticism of LFA tests is that they have poor detection limits compared to those of analytical techniques, like ELISA, which confines their application as a diagnostic tool. The low detection limit of LFA and associated long equilibration times are due to kinetically limited surface reactions that result from low target concentration. Here, we use isotachophoresis (ITP), a powerful electrokinetic preconcentration and separation technique, to focus target analytes into a thin band and transport them to the LFA capture line, resulting in a dramatic increase in the surface reaction rate and equilibrium binding. We show that ITP is able to improve the limit of detection (LoD) of LFA by 400-fold for 90 s assay time and by 160-fold for a longer 5 min time scale. ITP-enhanced LFA (ITP-LF) also shows up to 30% target extraction from 100 MUL of the sample, whereas conventional LFA captures less than 1% of the target. ITP improves the LoD of LFA to the level of some lab-based immunoassays, such as ELISA, and may provide sufficient analytical sensitivity for application to a broader range of analytes and diseases that require higher sensitivity and lower detection limits. PMID- 25495989 TI - The relationship between HIV and prevalence of disabilities in sub-Saharan Africa: systematic review (FA). AB - OBJECTIVE: To systematically review evidence on the prevalence and risk of disabilities among children and adults living with HIV in sub-Saharan Africa. METHODS: Articles were identified from 1980 to June 2013 through searching seven electronic databases. Epidemiological studies conducted in sub-Saharan Africa that explored the association between HIV status and general disability or specific impairments, with or without an HIV-uninfected comparison group, were eligible for inclusion. RESULTS: Of 12 867 records initially identified, 61 papers were deemed eligible for inclusion. The prevalence of disability was high across age groups, impairment types and study locations. Furthermore, 73% of studies using an HIV- comparator found significantly lower levels of functioning in people living with HIV (PLHIV). By disability type, the results were as follows: (i) for studies measuring physical impairments (n = 14), median prevalence of limitations in mobility and motor function among PLHIV was 25.0% (95% CI: 21.8-28.2%). Five of eight comparator studies found significantly reduced functioning among PLHIV; for arthritis, two of three studies which used an HIV- comparison group found significantly increased prevalence among PLHIV; (ii) for sensory impairment studies (n = 17), median prevalence of visual impairment was 11.2% (95%CI: 9.5-13.1%) and hearing impairment was 24.1% (95%CI: 19.2-29.0%) in PLHIV. Significantly increased prevalence among PLHIV was found in one of four (vision) and three of three studies (hearing) with comparators; (iii) for cognitive impairment in adults (n = 30), median prevalence for dementia was 25.3% (95% CI: 22.0-28.6%) and 40.9% (95% CI: 37.7-44.1%) for general cognitive impairment. Across all types of cognitive impairment, twelve of fourteen studies found a significant detrimental effect of HIV infection; (iv) for developmental delay in children with HIV (n = 20), median prevalence of motor delay was 67.7% (95% CI: 62.2-73.2%). All nine studies that included a comparator found a significant difference between PLHIV and controls; for cognitive development and global delay, a significant detrimental effect of HIV was found in five of six and one of two studies, respectively. In the nine cohort studies comparing vertically infected and uninfected children, eight showed a significant gap in development over time in children with HIV. Finally, fifteen of thirty-one (48%) studies found a statistically significant dose-response relationship between indicators of disease progression (CD4 or WHO stage) and disability. CONCLUSIONS: HIV is widespread in sub-Saharan Africa and the evidence suggests that it is linked to disabilities, affecting a range of body structures and functions. More research is needed to better understand the implications of HIV-related disability for individuals, their families as well as those working in the fields of disability and HIV so that appropriate interventions can be developed. PMID- 25495990 TI - Low antibiotic resistance rates and high genetic heterogeneity of Escherichia coli isolates from urinary tract infections of diabetic patients in Tunisia. AB - Antimicrobial resistance phenotypes, tetracycline, sulphonamide resistance genes, and integrons were analysed in 48 Escherichia coli isolates recovered from urine cultures of diabetic patients in Tunisia. Twenty-one were susceptible to all antibiotics tested. High rates of resistance were observed for amoxicillin (39.5%), trimethoprim-sulphamethoxazole (33.3%), sulphonamide (33.3%), and tetracycline (31.2%). Resistance to imipenem was not detected, and ESBL producing isolates were not recovered. Our analysis assigned 26, 13, 3, and 5 isolates to phylogroups A, B1, B2, and D, respectively. It is worthy to note that all the resistant isolates belonged to phylogroups A (15 isolates) and B1 (12 isolates), while for the 21 susceptible isolates, phylogroups A, B1, B2, and D were found in 11, 2, 3, and 5 isolates, respectively. Among 15 tetracycline-resistant isolates, the tetA and tetB genes were detected in three and four isolates, respectively. Among 17 sulphonamide resistant isolates, 12, 3, and 1 isolates harboured sul1, sul2, and sul3, respectively. sul1 and sul2 genes occurred simultaneously in three isolates. Integrons were detected in 11 isolates. Ten isolates harboured the class 1 integron and three the class 2 integron. The variable regions (VRs) of the class 1 integrons were analysed in the 10 in1-positive isolates, and the following gene cassette arrangements were detected: dfrA12-orfF-aadA2-cmIA1-aadA1 qacH-IS440-sul3 (one isolate), dfrA15-aadA1 (three isolates), dfrA5 (one isolate), dfrA17- aadA5 (one isolate), dfrA1-aadA1 (one isolate), and dfrA14 (one isolate). The VR of class 2 integron was analysed in the in2-positive isolates, and only one gene cassette arrangement was detected, dfrA1-sat-aadA1. Pulsed field gel electrophoresis (PFGE) analysis of resistant isolates showed that all were unrelated. Our results highlight the moderate antibiotic resistance in the clinical isolates as well as their heterogeneous genetic background. PMID- 25495987 TI - miRNA-based therapies: strategies and delivery platforms for oligonucleotide and non-oligonucleotide agents. AB - The discovery of miRNAs as important regulatory agents for gene expression has expanded the therapeutic opportunities for oligonucleotides. In contrast to siRNA, miRNA-targeted therapy is able to influence not only a single gene, but entire cellular pathways or processes. It is possible to supplement downregulated or non-functional miRNAs by synthetic oligonucleotides, as well as alleviating effects caused by overexpression of malignant miRNAs through artificial antagonists, either oligonucleotides or small molecules. Chemical oligonucleotide modifications together with an efficient delivery system seem to be mandatory for successful therapeutic application. While miRNA-based therapy benefits from the decades of research spent on other therapeutic oligonucleotides, there are some specific challenges associated with miRNA therapy, mainly caused by the short target sequence. The current status and recent progress of miRNA-targeted therapeutics is described and future challenges and potential applications in treatment of cancer and viral infections are discussed. PMID- 25495991 TI - Therapeutic effects of GM1 on Parkinson's disease in rats and its mechanism. AB - OBJECTIVE: To observe the effects of GM1 on apomorphine (APO)-induced rotational behavior and the expression of inflammatory factors in 6-hydroxydopamine-induced Parkinson's disease (PD) rat models. METHODS: Mature and healthy Wistar rats of either sex with body weight of 150-200 g were randomly divided into control group, PD+APO group and PD+APO+GM1 group (10 mg/kg of GM1, intraperitoneally, once a day, for 14 days; each group with 15 rats). PD rat models were prepared by injecting 6-hydroxydopamine into rat's right striatum, and then rotational behavior was induced by intraperitoneal injection of APO 7 days after operation. Rat rotational behavior was observed, and mRNA and protein levels of interleukin 1beta (IL-1beta) and interleukin-1Ra (IL-1Ra) were determined, respectively, by RT-PCR and Western blot. RESULTS: Compared with PD+APO group, the rotational behavior was significantly relieved in PD+APO+GM1 group (p < 0.05). Compared with control group, mRNA and protein expressions of IL-1beta in the striatum significantly increased in PD+APO group (p < 0.05). However, mRNA and protein expressions of IL-1beta significantly decreased in PD+APO+GM1 group compared with PD+APO group (p < 0.05), but mRNA and protein expressions of IL-1beta were also higher in PD+APO+GM1 group than in control group (p < 0.05). mRNA and protein expressions of IL-1Ra in the striatum were significantly higher in PD+APO+GM1 group than in PD+APO group (p < 0.05). CONCLUSION: GM1 can inhibit inflammatory reaction through decreasing mRNA and protein expressions of IL-1beta and increasing mRNA and protein expressions of IL-1Ra with the therapeutic effects on PD. PMID- 25495992 TI - Association between two alpha-2-macroglobulin gene polymorphisms and Parkinson's disease: a meta-analysis. AB - PURPOSE: Due to the controversial results in assessment of the association between alpha-2-Macroglobulin gene (A2M) polymorphisms and Parkinson's disease (PD), we performed a meta-analysis to evaluate the relationship between two A2M variants (rs669 and rs3832852) and PD. METHODS: All eligible studies were retrieved in PubMed, Web of Science, Embase and PDGene databases. Data were extracted by two investigators independently. All the four genetic models were used for rs669 and rs3832852. RESULTS: A total of 877 PD patients and 1296 controls from six studies were included for rs669 polymorphisms. The combined odds ratio (OR) indicated that rs669 polymorphisms were likely associated increased risk of PD only in dominant genetic models (OR = 1.41, CI = 1.03-1.92), especially in Asian subgroup (OR = 1.97, CI = 1.03-3.75). Five studies containing 772 PD patients and 1178 controls were identified for rs3832852 polymorphisms. The result suggested that rs3832852 polymorphisms were not associated with PD in all genetic models. CONCLUSIONS: Our data indicate that the rs669 (A/G) polymorphisms in A2M gene are associated with increased risk in PD. To further validate the association of A2M polymorphisms with PD, more studies with larger samples are required. PMID- 25495993 TI - Alcohol consumption in the elderly and risk of dementia related death--a Norwegian prospective study with a 17-year follow-up. AB - PURPOSE: The aim of this study was to determine the association between alcohol intake and risk of dementia related death, taking into account relevant confounding and mediating factors. MATERIALS AND METHODS: Data was obtained from a Norwegian prospective study with a 17-year follow-up. The study population comprised 25,635 participants aged between 60 and 80 years at the time of examination from the Cohort of Norway (CONOR). Cox regression was used to investigate the association between alcohol use and dementia related death. RESULTS: Nearly half (12,139) of the study population died during follow-up, of which 1,224 had a diagnosis of dementia on their death certificate. The risk of dementia related death was significantly higher among abstainers than among individuals that drank alcohol once per month (HR = 1.33, 95% CI = 1.14-1.56, p < 0.001, in a fully adjusted model). Respondents with missing information regarding alcohol consumption (representing 5% of the study population) had the highest risk of dementia related death (HR = 1.60, 95% CI = 1.28-2.00, p < 0.001) and also significantly higher mortality rates due to alcohol-related causes (HR = 1.41, 95% CI = 1.03-1.93, p = 0.031) and other causes (HR = 1.32, 95% CI = 1.21 1.43, p < 0.001), all compared to those drinking alcohol no more than once per month. CONCLUSION: These findings suggest that the risk of dementia related death is significantly higher among elderly abstainers than among those who drink alcohol, after adjusting for relevant confounders. However, care should be taken in interpretation of data due to missing information on drinking frequency, as this missing-group might have a large share of the heavy drinkers in the study cohort. PMID- 25495994 TI - Skin dryness in apparently healthy human skin is associated with decreased expression of bleomycin hydrolase in the stratum corneum. AB - BACKGROUND: Maintenance of water balance in the stratum corneum (SC) is determined by the content of intercellular lipids and natural moisturizing factors (NMFs) in corneocytes. AIM: To investigate the association between the NMFs and (pro)filaggrin and the proteases responsible for the processing of (pro)filaggrin to NMFs in the SC of hydrated and dry skin areas of healthy human subjects. METHODS: The SC hydration state and the transepidermal water loss (TEWL) were measured using a Corneometer and a Tewameter, respectively. Proteases, (pro)filaggrin and NMFs were extracted from SC samples obtained by tape-stripping of the tested skin. Expression levels of (pro)filaggrin were determined by dot blotting and western blotting, and total NMFs by ultra-high performance liquid chromatography. Expression of the proteases caspase-14, calpain-1 and bleomycin hydrolase was measured by western blotting. RESULTS: The levels of (pro)filaggrin were not significantly different between hydrated and dry skin, whereas the level of total NMFs was significantly reduced in dry skin. A negative correlation between (pro)filaggrin and NMFs was found in dry skin (Pearson correlation coefficient r = - 0.57, *P < 0.05). Bleomycin hydrolase expression was significantly decreased in the SC of dry skin. CONCLUSIONS: These results suggest that the low hydration state of dry skin may be due to the reduction in (pro)filaggrin degradation caused by decreased bleomycin hydrolase expression. PMID- 25495995 TI - Ion-unquenchable and thermally "on-off" reversible room temperature phosphorescence of 3-bromoquinoline induced by supramolecular gels. AB - Ion-unquenchable and thermally on-off reversible room temperature phosphorescence (RTP) can be induced by entrapping 3-bromoquinoline (3-BrQ) into supramolecular gels formed by the self-assembly of a sorbitol derivative (DBS). In comparison with conventional substrates inducing RTP, the gel state 3-BrQ/DBS can produce strong RTP due to the efficient restriction of the vibration of 3-BrQ. Notably, the rather inconvenient deoxygenation is no longer necessary in the preparation of 3-BrQ/DBS gels. The produced RTP was found to be very fast to reach stable, not depending on the standing time. As a reference, in the liquid state of 3 BrQ/sodium deoxycholate (NaDC), stable RTP can be observed after standing for 5 h. The investigation of RTP quenching indicates that the mechanism of RTP induced by DBS gels mainly involves the microenvironment in which 3-BrQ is located. 3-BrQ was entrapped in the hydrophobic 3D network structure of DBS gels, thereby restricting the motion and collision of 3-BrQ and avoiding RTP quenching and additionally quenching by ions. Furthermore, the RTP of 3-BrQ/DBS gels show an excellent "on-off" effect at 10 or 80 degrees C. This indicates that the solid DBS gel is beneficial for the preparation of RTP sensor devices. PMID- 25495996 TI - Evaluation of an in-house HIV-1 drug resistance genotypic testing for using dried blood spot specimens in China. AB - OBJECTIVES: We evaluated an In-house assay for HIV-1 drug resistance genotyping by using DBS samples in China. METHODS: The amplification sensitivity was assessed using 79 DBS specimens with plasma viral load ranging from 1,000 to 6,000 copies/ml. Precision was assessed using 5 DBS specimens with 5 replicates tested in one test run. Reproducibility was evaluated using other 5 DBS specimens with 5 replicates genotyped in 5 test runs. Nucleotide sequence identity and the degree of concordance in detecting drug resistance mutations were assessed within and between test runs. In addition, nucleotide sequence and drug resistance mutations were compared between 64 matched plasma and DBS specimens. RESULTS: The amplification rate of DBS specimens with plasma viral load of 1,000-6,000 copies/ml was 96.2% (76/79). The nucleotide sequence identity was 99.7+/-0.34% and 99.6+/-0.25% within and between test runs, respectively. Moreover, there was a near perfect agreement of detecting drug resistance mutations intra- and inter- test runs with kappa value of 0.972 and 0.963, respectively. Between 64 pairs of plasma and DBS specimens, the nucleotide identity was excellent with 99.5+/ 0.34%. As compared to the results of plasma specimens, the sensitivity and specificity for detecting drug resistance mutations in DBS specimens were 99.4 % (95% CI, 97.4-99.8%) and 99.8% (95% CI, 99.7-99.9%), respectively. Totally 15 discordant drug resistance mutations were found. Among them, 53.3 % (8/15) were caused by mixture base. CONCLUSION: The In-house HIVDR genotyping assay could be used for testing DBS samples with viral load above 1,000 copies/ml in China and had a low intra- and inter- assay variability. DBS is an excellent alternative to plasma for HIV-1 drug resistance genotyping at population levels in China. PMID- 25495997 TI - Soluble Klotho is not independently associated with cardiovascular disease in a population of dialysis patients. AB - BACKGROUND: Dialysis patients suffer from a high burden of cardiovascular disease (CVD). Partly this is due to progressive deterioration of calcium-phosphate homeostasis. Previous studies suggested that besides FGF-23, low levels of Klotho, a protein linked to aging, might constitute a key factor in this detrimental relationship. The purpose of the present study was to determine the relationship between serum Klotho (sKlotho) and the presence of CVD in dialysis patients. METHODS: Plasma levels of sKlotho were measured in a cohort of dialysis patients and related to left ventricular (LV) dysfunction (defined as a LV ejection fraction<45%) and LV mass using echocardiography. Coronary artery disease (CAD) and calcification score were assessed using computed tomography angiography. Abdominal aortic calcification score (AACscore) was measured by abdominal X-ray. RESULTS: We included 127 dialysis patients, 67+/-7 years old, 76% male, 67% on hemodialysis, median sKlotho 460 pg/mL (25th-75th percentile 350 620 pg/mL). Patients with a low sKlotho (<460 pg/mL) showed significantly more CAD (81% versus 61%; p=0.02) and LV dysfunction (19% versus 3%; p<0.01). However, after adjusting for confounders, sKlotho was not independently associated with the presence of CVD or the AACscore. CONCLUSIONS: In the present cohort of dialysis patients, sKlotho was not independently associated with CVD. However, patients with a low sKlotho level (<460 pg/mL) did show CAD and LV dysfunction more frequently. Therefore, while sKlotho might be a marker for CVD in dialysis patients, the current data does not support a direct cardioprotective effect of sKlotho. PMID- 25495998 TI - Cervical cancer screening in adolescents: an evidence-based internet education program for practice improvement among advanced practice nurses. AB - BACKGROUND: The literature reports great variation in the knowledge levels and application of the recent changes of cervical cancer screening guidelines into clinical practice. Evidence-based screening guidelines for the prevention and early detection of cervical cancer offers healthcare providers the opportunity to improve practice patterns among female adolescents by decreasing psychological distress as well as reducing healthcare costs and morbidities associated with over-screening. PURPOSE: The purpose of this pilot intervention study was to determine the effects of a Web-based continuing education unit (CEU) program on advanced practice nurses' (APNs) knowledge of current cervical cancer screening evidence-based recommendations and their application in practice. This paper presents a process improvement project as an example of a way to disseminate updated evidence-based practice guidelines among busy healthcare providers. METHODS: This Web-based CEU program was developed, piloted, and evaluated specifically for APNs. The program addressed their knowledge level of cervical cancer and its relationship with high-risk human papillomavirus. It also addressed the new cervical cancer screening guidelines and the application of those guidelines into clinical practice. FINDINGS: Results of the study indicated that knowledge gaps exist among APNs about cervical cancer screening in adolescents. However, when provided with a CEU educational intervention, APNs' knowledge levels increased and their self-reported clinical practice behaviors changed in accordance with the new cervical cancer screening guidelines. LINKING EVIDENCE TO PRACTICE: Providing convenient and readily accessible up-to-date electronic content that provides CEU enhances the adoption of clinical practice guidelines, thereby decreasing the potential of the morbidities associated with over-screening for cervical cancer in adolescents and young women. PMID- 25496000 TI - Fractionated microneedle radiofrequency for treatment of primary axillary hyperhidrosis: A sham control study. AB - BACKGROUND/ OBJECTIVE: Primary axillary hyperhidrosis (PAH) creates social stress in patients. Although there are several options for treating PAH, only surgical modalities have conferred a permanent solution. This study evaluated the clinical effectiveness of fractionated microneedle radiofrequency (FMR) treatment for PAH. METHODS: This study is based on a single-blind, sham control comparative design. In all, 25 patients with severe PAH underwent three sessions of FMR at 3-week intervals. One side was treated with FMR while the other was sham controlled. Efficacy was evaluated using the hyperhidrosis disease severity scale (HDSS), sweating intensity visual analogue scale (VAS) and patient satisfaction at baseline, 3 weeks after each session and at 3 months after the last. Skin biopsies were obtained from two enrolled patients. RESULTS: The HDSS and VAS demonstrated significant improvement after treatment on the treated side in comparison with the control side. The mean +/- SD of the HDSS after 21 weeks were 1.87 +/- 0.61 and 3.38 +/- 0.49 (P < 0.001) for the treated and the controlled side, respectively. The follow-up evaluation revealed that 79% of the patients showed a 1 or 2-score decrease in HDSS. In total, 80% of patients reported more than 50% satisfaction at the end of the study. Histopathological findings showed a decrease of the number of the sweat glands in the treated side, confirming the above findings. CONCLUSIONS: Treatment of PAH with FMR as a non-invasive modality can be a safe option with positive therapeutic effects on HDSS without any long lasting side effects. PMID- 25496001 TI - A comparative study on the effects of amphiphilic and hydrophilic polymers on the release profiles of a poorly water-soluble drug. AB - This paper reports the use of two crystalline polymers, an amphiphilic Pluronic(r) F-127 (PF-127) and a hydrophilic poly(ethylene glycol) (PEG6000) as drug delivery carriers for improving the drug release of a poorly water-soluble drug, fenofibrate (FEN), via micelle formation and formation of a solid dispersion (SD). In 10% PF-127 (aq.), FEN showed an equilibrium solubility of ca. 0.6 mg/mL, due to micelle formation. In contrast, in 10% PEG6000 (aq.), FEN only exhibited an equilibrium solubility of 0.0037 mg/mL. FEN-loaded micelles in PF 127 were prepared by direct dissolution and membrane dialysis. Both methods only yielded a highest drug loading (DL) of 0.5%. SDs of FEN in PF-127 and PEG6000, at DLs of 5-80%, were prepared by solvent evaporation. In-vitro dissolution testing showed that both micelles and SDs significantly improved FEN's release rate. The SDs of FEN in PF-127 showed significantly faster release than crystalline FEN, when the DL was as high as 50%, whereas SDs of PEG6000 showed similar enhancement in the release rate when the DL was not more than 20%. The DSC thermograms of SDs of PF-127 exhibited a single phase transition peak at ca. 55-57 degrees C when the DL was not more than 50%, whereas those in PEG6000 exhibited a similar peak at ca. 61-63 degrees C when the DL was not more than 35%. When the DL exceeded 50% for SDs of PF-127 and 35% for SDs of PEG6000, DSC thermograms showed two melting peaks for the carrier polymer and FEN, respectively. FT-IR studies revealed that PF-127 has a stronger hydrophobic-hydrophobic interaction with FEN than PEG6000. It is likely that both dispersion and micelle formation contributed to the stronger effect of PF-127 on enhancing the release rate of FEN in its SDs. PMID- 25495999 TI - Muscarinic excitation of parvalbumin-positive interneurons contributes to the severity of pilocarpine-induced seizures. AB - OBJECTIVE: A common rodent model in epilepsy research employs the muscarinic acetylcholine receptor (mAChR) agonist pilocarpine, yet the mechanisms underlying the induction of pilocarpine-induced seizures (PISs) remain unclear. Global M1 mAChR (M1 R) knockout mice are resistant to PISs, implying that M1 R activation disrupts excitation/inhibition balance. Parvalbumin-positive (PV) inhibitory neurons express M1 Rs, participate in cholinergically induced oscillations, and can enter a state of depolarization block (DB) during epileptiform activity. Here, we test the hypothesis that pilocarpine activation of M1 Rs expressed on PV cells contributes to PISs. METHODS: CA1 PV cells in PV-CRE mice were visualized with a floxed YFP or hM3Dq-mCherry adeno-associated virus, or by crossing PV-CRE mice with the RosaYFP reporter line. To eliminate M1 Rs from PV cells, we generated PV-M1 knockout (KO) mice by crossing PV-CRE and floxed M1 mice. Action potential (AP) frequency was monitored during application of pilocarpine (200 MUm). In behavioral experiments, locomotion and seizure symptoms were recorded in wild-type (WT) or PV-M1 KO mice during PISs. RESULTS: Pilocarpine significantly increased AP frequency in CA1 PV cells into the gamma range. In the continued presence of pilocarpine, a subset (5/7) of PV cells progressed to DB, which was mimicked by hM3Dq activation of Gq-receptor signaling. Pilocarpine-induced depolarization, AP firing at gamma frequency, and progression to DB were prevented in CA1 PV cells of PV-M1 KO mice. Finally, compared to WT mice, PV-M1 KO mice were associated with reduced severity of PISs. SIGNIFICANCE: Pilocarpine can directly depolarize PV+ cells via M1 R activation, but a subset of these cells progress to DB. Our electrophysiologic and behavioral results suggest that this mechanism is active during PISs, contributing to a collapse of PV-mediated gamma-aminobutyric acid (GABA)ergic inhibition, dysregulation of excitation/inhibition balance, and increased susceptibility to PISs. PMID- 25496002 TI - Extensive duplication of the Wolbachia DNA in chromosome four of Drosophila ananassae. AB - BACKGROUND: Lateral gene transfer (LGT) from bacterial Wolbachia endosymbionts has been detected in ~20% of arthropod and nematode genome sequencing projects. Many of these transfers are large and contain a substantial part of the Wolbachia genome. RESULTS: Here, we re-sequenced three D. ananassae genomes from Asia and the Pacific that contain large LGTs from Wolbachia. We find that multiple copies of the Wolbachia genome are transferred to the Drosophila nuclear genome in all three lines. In the D. ananassae line from Indonesia, the copies of Wolbachia DNA in the nuclear genome are nearly identical in size and sequence yielding an even coverage of mapped reads over the Wolbachia genome. In contrast, the D. ananassae lines from Hawaii and India show an uneven coverage of mapped reads over the Wolbachia genome suggesting that different parts of these LGTs are present in different copy numbers. In the Hawaii line, we find that this LGT is underrepresented in third instar larvae indicative of being heterochromatic. Fluorescence in situ hybridization of mitotic chromosomes confirms that the LGT in the Hawaii line is heterochromatic and represents ~20% of the sequence on chromosome 4 (dot chromosome, Muller element F). CONCLUSIONS: This collection of related lines contain large lateral gene transfers composed of multiple Wolbachia genomes that constitute >2% of the D. ananassae genome (~5 Mbp) and partially explain the abnormally large size of chromosome 4 in D. ananassae. PMID- 25496003 TI - Diagnostic value of active protraction and retraction for sternoclavicular joint pain. AB - BACKGROUND: Sternoclavicular joint (SCJ) arthropathy is an uncommon cause of mechanical pain. The aim of this study is to evaluate the diagnostic value of two active clinical tests for localizing the sternoclavicular joint as the source of mechanical pain. METHODS: All patients between June 2011 and October 2013 that visited the orthopedic departments of three hospitals with atraumatic pain in the area of the SC joint were evaluated. Local swelling, pain at palpation, pain during arm elevation and two newly described tests (pain during active scapular protraction and retraction) were evaluated. CT images were evaluated. The patients were then divided into two groups according to whether they had a >=50% decrease in pain following the SCJ injection. Sensitivity and specificity for local swelling, the four clinical tests and CT-scan were measured. RESULTS: Forty eight patients were included in this study and SC joint pain was confirmed in 44. The tests with highest sensitivity were pain on palpation, (93% sensitivity) and pain during active scapular protraction (86%). CT-scan showed a sensitivity of 84%. Local swelling showed a high specificity (100%). CONCLUSION: Pain at the SCJ during active scapular protraction is a good clinical diagnostic tool for SC arthropathy. PMID- 25496004 TI - Axillary fine needle aspiration cytology is a sensitive and highly specific technique for the detection of axillary lymph node metastasis: a meta-analysis and systematic review. AB - BACKGROUND: Fine needle aspiration cytology (FNAC) of axillary lymphadenopathy is a helpful tool in the pre-operative diagnosis of breast cancer patients with axillary lymphadenopathy. To date, no published meta-analysis or systematic review has been performed to assess its overall value. We therefore conducted a meta-analysis to establish the overall diagnostic value of FNAC for axillary lymph node metastasis. METHODS: After a review and quality assessment of 31 studies, published either in Chinese or English, the sensitivity, specificity and other measurements of accuracy of FNAC of axillary lymphadenopathy were pooled using random-effects models. A summary of the receiver-operating characteristic curves was used to summarize overall accuracy. RESULTS: We provided the following estimated values for FNAC in the diagnosis of axillary lymph node metastasis: sensitivity, 0.63 [95% confidence interval (CI), 0.61-0.65]; specificity, 0.99 (95% CI, 0.99-0.99); positive likelihood ratio, 26.52 (95% CI, 18.42-38.18); negative likelihood ratio, 0.34 (95% CI, 0.29-0.40); diagnostic odds ratio, 76.73 (95% CI, 51.98-113.28). CONCLUSIONS: FNAC has adequate sensitivity and high specificity in the diagnosis of axillary lymph node metastasis. A positive axillary FNA result could potentially alter disease management. PMID- 25496005 TI - Prognostic factors for long-term poor outcomes after acute ischemic stroke in very old age (>80 years) patients: Total cholesterol level might differently influence long-term outcomes after acute ischemic stroke at ages above 80 years. AB - AIM: We investigated the differences in determinant factors for functional outcomes between patients aged >80 years and those aged <80 years after acute ischemic stroke (AIS). In particular, we would like to know the differential impacts of initial total cholesterol (TC) levels between the two groups. METHODS: We defined a poor outcome as 3-6 modified Rankin Scale 90 days after AIS. RESULTS: In the present study, 2772 participants were enrolled. Among them, 374 patients (13.5%) were aged >80 years, and 1061 patients had a poor outcome 90 days after AIS. The proportion was significantly higher in patients aged >80 years than in those aged <80 years after AIS. Regarding factors relating to poor outcomes, previous history of stroke, stroke severity and stroke subtypes of ischemic stroke were independent factors in patients aged <80 years, and the stroke severity and initial TC level independently influenced the outcome for patients aged >80 years. In particular, risk of poor outcome adjusted for age, stroke severity and subtypes of ischemic stroke for patients (OR [95% CI]) in the first quartile range (<=157 mg%) were 2.21 (1.06-4.62), in the third quartile range (184-210 mg%) 2.76 (1.27-6.01) and in the fourth quartile range (>=211 mg%) 2.75 (1.21-6.24) compared with those in the second quartile range (158-183 mg%) in patients aged >80 years. CONCLUSIONS: There were also some differences in related factors regarding occurrences of poor outcome between the two groups. In particular, the initial TC level might play a crucial role for the outcome after AIS in the very old population. PMID- 25496006 TI - Mental illness, mass shootings, and the politics of American firearms. AB - Four assumptions frequently arise in the aftermath of mass shootings in the United States: (1) that mental illness causes gun violence, (2) that psychiatric diagnosis can predict gun crime, (3) that shootings represent the deranged acts of mentally ill loners, and (4) that gun control "won't prevent" another Newtown (Connecticut school mass shooting). Each of these statements is certainly true in particular instances. Yet, as we show, notions of mental illness that emerge in relation to mass shootings frequently reflect larger cultural stereotypes and anxieties about matters such as race/ethnicity, social class, and politics. These issues become obscured when mass shootings come to stand in for all gun crime, and when "mentally ill" ceases to be a medical designation and becomes a sign of violent threat. PMID- 25496008 TI - Moderators of the longitudinal relationship between the perceived physical environment and outside play in children: the KOALA birth cohort study. AB - OBJECTIVES: Promoting unstructured outside play is a promising vehicle to increase children's physical activity (PA). This study investigates if factors of the social environment moderate the relationship between the perceived physical environment and outside play. STUDY DESIGN: 1875 parents from the KOALA Birth Cohort Study reported on their child's outside play around age five years, and 1516 parents around age seven years. Linear mixed model analyses were performed to evaluate (moderating) relationships among factors of the social environment (parenting influences and social capital), the perceived physical environment, and outside play at age five and seven. Season was entered as a random factor in these analyses. RESULTS: Accessibility of PA facilities, positive parental attitude towards PA and social capital were associated with more outside play, while parental concern and restriction of screen time were related with less outside play. We found two significant interactions; both involving parent perceived responsibility towards child PA participation. CONCLUSION: Although we found a limited number of interactions, this study demonstrated that the impact of the perceived physical environment may differ across levels of parent responsibility. PMID- 25496007 TI - A randomized, placebo-controlled study of the NS5B inhibitor beclabuvir with peginterferon/ribavirin for HCV genotype 1. AB - Beclabuvir is a potent, non-nucleoside inhibitor of the HCV NS5B RNA polymerase, with nanomolar activity against HCV genotypes 1, 3, 4, 5 and 6 in vitro. This study evaluated the efficacy and safety of beclabuvir, in combination with peginterferon alfa-2a (pegIFN) and ribavirin (RBV), in HCV genotype 1. In this randomized (1:1:1), double-blinded, placebo-controlled, dose-ranging phase 2a study, 39 treatment-naive patients chronically infected with HCV genotype 1 were treated for 48 weeks with beclabuvir (75 mg or 150 mg) plus pegIFN (180 MUg) and RBV (1000 mg/day [<75 kg] or 1200 mg/day [>= 75 kg]) vs pegIFN/RBV alone. The primary efficacy endpoint of extended rapid virologic response (undetectable HCV RNA at treatment weeks 4 and 12) was achieved by 76.9% (10/13) of patients receiving beclabuvir 75 mg and 38.5% (5/13) receiving beclabuvir 150 mg vs 0% receiving pegIFN/RBV alone. Higher response rates were observed among patients receiving beclabuvir 75 mg for all secondary efficacy endpoints, including sustained virologic response at follow-up weeks 12 or 24. Three patients experienced virologic breakthrough on treatment, all in the beclabuvir 150-mg treatment group. Beclabuvir was well tolerated at both doses, with the most commonly observed adverse events (headache, fatigue, nausea, decreased appetite, irritability, depression and insomnia) consistent with those observed with pegIFN/RBV. In conclusion, beclabuvir was both effective and well tolerated when administered in combination with pegIFN/RBV for the treatment of chronic HCV GT 1, supporting the study of beclabuvir as part of an all-oral regimen for HCV GT1. PMID- 25496009 TI - The Slx4-Dpb11 scaffold complex: coordinating the response to replication fork stalling in S-phase and the subsequent mitosis. AB - Replication fork stalling at DNA lesions is a common problem during the process of DNA replication. One way to allow the bypass of these lesions is via specific recombination-based mechanisms that involve switching of the replication template to the sister chromatid. Inherent to these mechanisms is the formation of DNA joint molecules (JMs) between sister chromatids. Such JMs need to be disentangled before chromatid separation in mitosis and the activity of JM resolution enzymes, which is under stringent cell cycle control, is therefore up-regulated in mitosis. An additional layer of control is facilitated by scaffold proteins. In budding yeast, specifically during mitosis, Slx4 and Dpb11 form a cell cycle kinase-dependent complex with the Mus81-Mms4 structure-selective endonuclease, which allows efficient JM resolution by Mus81. Furthermore, Slx4 and Dpb11 interact even prior to joining Mus81 and respond to replication fork stalling in S-phase. This S-phase complex is involved in the regulation of the DNA damage checkpoint as well as in early steps of template switch recombination. Similar interactions and regulatory principles are found in human cells suggesting that Slx4 and Dpb11 may have an evolutionary conserved role organizing the cellular response to replication fork stalling. PMID- 25496010 TI - Urinary excretion of phthalate metabolites in school children of China: implication for cumulative risk assessment of phthalate exposure. AB - We analyzed 13 metabolites of 9 phthalates in urine of 782 Chinese school children aged 8-11 years and estimated the daily intake for phthalates based on urinary metabolite levels. The daily intakes were compared with acceptable intake levels to calculate the hazard quotient (HQ) for single phthalate. Finally, the cumulative risk for each child was assessed by means of a hazard index (HI) which is the sum of HQs. Overall, 11 metabolites were found in at least 85% of the urine samples with the highest median concentration of 47.1 ng/mL (93.4 MUg/g creatinine) for mono-n-butyl phthalate (MnBP). Monooctyl phthalate (MOP) and monoisononyl phthalate (MiNP) were not detectable. The cumulative risk assessment covering di(2-ethylhexyl) phthalate (DEHP), di-n-butyl phthalate (DnBP), di isobutyl phthalate (DiBP), and butyl-benzyl phthalate (BBzP) demonstrated that 19.8% (volume model-based) and 40.3% (creatinine model-based) of the children exceeded 1 for the HI based on tolerable daily intake (TDI) values (considered as potential adverse antiandrogenic effect). Furthermore, at least 36% of the children from the manufacturing-intensive region had a HI higher than 1. The results indicate that Chinese children are widely exposed to phthalates and those from manufacturing-intensive regions are probably at a high risk of cumulative phthalate exposure. PMID- 25496011 TI - Biodegradable protein-based rockets for drug transportation and light-triggered release. AB - We describe a biodegradable, self-propelled bovine serum albumin/poly-l-lysine (PLL/BSA) multilayer rocket as a smart vehicle for efficient anticancer drug encapsulation/delivery to cancer cells and near-infrared light controlled release. The rockets were constructed by a template-assisted layer-by-layer assembly of the PLL/BSA layers, followed by incorporation of a heat-sensitive gelatin hydrogel containing gold nanoparticles, doxorubicin, and catalase. These rockets can rapidly deliver the doxorubicin to the targeted cancer cell with a speed of up to 68 MUm/s, through a combination of biocatalytic bubble propulsion and magnetic guidance. The photothermal effect of the gold nanoparticles under NIR irradiation enable the phase transition of the gelatin hydrogel for rapid release of the loaded doxorubicin and efficient killing of the surrounding cancer cells. Such biodegradable and multifunctional protein-based microrockets provide a convenient and efficient platform for the rapid delivery and controlled release of therapeutic drugs. PMID- 25496012 TI - Estimating the workload associated with symptoms-based ovarian cancer screening in primary care: an audit of electronic medical records. AB - BACKGROUND: Ovarian cancer is the most lethal gynaecological malignancy in the United Kingdom (UK). Studies have found that many women with ovarian cancer have symptoms for several months before diagnosis. Using a symptoms-based tool to diagnose ovarian cancer (OC) earlier is appealing, but may increase general practitioner (GP) workload because the symptoms are typically vague and non specific. This study aimed to provide estimates of the GP workload associated with offering symptoms-based ovarian cancer screening. METHODS: A cross-sectional analysis of electronic records from four general practices in England, UK. We downloaded anonymous data on women aged 45-74 who consulted over one week to estimate the proportion who would be offered 'screening' according to the UK National Institute for Health and Care Excellence (NICE) guidelines and a symptoms index (Index 2) over one year. We used previous consultations (censoring women with no prior symptom at the date of their last recorded consultation) to estimate the proportion of women presenting with a new (not recorded in previous 12 months) NICE symptom each year. RESULTS: Data were obtained from 19,558 women. The proportion presenting over one week varied between practices (5%-14%), however, the proportion with an OC symptom was similar (17% overall). Over one year, an estimated 51.8% (95% CI 44.0%-59.7%) would present with an OC symptom, 26.6% (95% CI 19.3%-35.1%) with a NICE symptom and 20.3% (95% CI 13.7%-28.5%) with an Index 2 symptom. Each year, an estimated 11.9% (95% CI 5.0%-18.3%) of women would present with a new NICE symptom. CONCLUSION: One in two women aged 45 74 present to primary care at least once a year with an OC symptom, 11.9% with a new NICE symptom. This would be comparable to 2 to 8 yearly screening (depending on what symptoms triggered testing). PMID- 25496013 TI - The association between bone mineral density and higher body mass index in men. AB - BACKGROUND: A number of studies have identified that higher body mass index is associated with higher bone mineral density. However, a small number of previous studies have indicated an association between higher body mass index (> 35 kg/m(2)) and lower bone mineral density. No previous study has investigated the association between higher body mass index and bone mineral density in a large male population. METHODS: Data of men aged over 50 years of age who attended for a dual energy X-ray absorptiometry scan at a UK teaching hospital were collated. The population was divided according to body mass index increments of 5 kg/m(2). The mean bone mineral density of both the lumbar spine and femoral neck was ascertained for each body mass index category. Multiple linear regression analysis, adjusted for age, was used to investigate for an association between body mass index and bone mineral density. RESULTS: Data of 1263 men were collated. Increasing body mass index was associated with increasing bone mineral density of both the lumbar spine and femoral neck up to 35 kg/m(2); further increase in body mass index was not associated with an increasing bone mineral density. CONCLUSIONS: The beneficial effect upon bone mineral density of increasing body mass index exists up to 35 kg/m(2); a body mass index higher than 35 kg/m(2) is not associated with further increase in bone mineral density. PMID- 25496014 TI - Xanthoma disseminatum associated with inflammatory arthritis and synovitis--a rare association. AB - Xanthoma disseminatum (XD) is a rare, benign, non-Langerhans cell histiocytosis characterized by disseminated xanthomatous lesions with a predilection for the face, flexures, and mucosae. Approximately 100 cases have been reported in the literature. We report XD in an 8-year-old boy with symmetric synovitis and arthritis involving the wrists and knees. This case is interesting in view of the association between arthritis and synovitis and XD, which to our knowledge has not been reported in the literature. This case has to be differentiated from multicentric histiocytosis, another non-Langerhans cell histiocytosis, in which joint involvement is common. PMID- 25496015 TI - A statistical approach to quantification of genetically modified organisms (GMO) using frequency distributions. AB - BACKGROUND: According to Regulation (EU) No 619/2011, trace amounts of non authorised genetically modified organisms (GMO) in feed are tolerated within the EU if certain prerequisites are met. Tolerable traces must not exceed the so called 'minimum required performance limit' (MRPL), which was defined according to the mentioned regulation to correspond to 0.1% mass fraction per ingredient. Therefore, not yet authorised GMO (and some GMO whose approvals have expired) have to be quantified at very low level following the qualitative detection in genomic DNA extracted from feed samples. As the results of quantitative analysis can imply severe legal and financial consequences for producers or distributors of feed, the quantification results need to be utterly reliable. RESULTS: We developed a statistical approach to investigate the experimental measurement variability within one 96-well PCR plate. This approach visualises the frequency distribution as zygosity-corrected relative content of genetically modified material resulting from different combinations of transgene and reference gene Cq values. One application of it is the simulation of the consequences of varying parameters on measurement results. Parameters could be for example replicate numbers or baseline and threshold settings, measurement results could be for example median (class) and relative standard deviation (RSD). All calculations can be done using the built-in functions of Excel without any need for programming. The developed Excel spreadsheets are available (see section 'Availability of supporting data' for details). In most cases, the combination of four PCR replicates for each of the two DNA isolations already resulted in a relative standard deviation of 15% or less. CONCLUSIONS: The aims of the study are scientifically based suggestions for minimisation of uncertainty of measurement especially in -but not limited to- the field of GMO quantification at low concentration levels. Four PCR replicates for each of the two DNA isolations seem to be a reasonable minimum number to narrow down the possible spread of results. PMID- 25496016 TI - mRNA destabilizing factors: tristetraprolin expression at the porcine maternal fetal interface. AB - PROBLEM: To evaluate the expression of the tristetraprolin family and their selected targets during porcine pregnancy. METHOD OF STUDY: Using qPCR and Western blot, mRNA and protein levels were compared between endometrium and chorioallantoic membrane (CAM) associated with healthy and impaired conceptuses at gestation day (gd) 20 and gd50, respectively. Immunohistochemistry was performed to determine localization of TIS11 family members at gd20 and 50. RESULTS: Multiple significant differences (P < 0.05) in TIS11 family transcripts were observed in the aforementioned comparisons. GM-CSF was significantly higher in healthy endometrium and CAM from impaired conceptus attachment sites. TNF alpha was elevated in CAM as compared to endometrium at gd50, regardless of conceptus health status. Immunohistochemical staining shows TIS11 family expressed in the glandular and luminal epithelium, as well as stromal cells in the uterus. CONCLUSIONS: The shift in the expression of tristetraprolin (TTP) and TIS11D points to a potential role of these genes in regulating spontaneous fetal loss. PMID- 25496017 TI - A diferrous dithiolate as a model of the elusive H(ox)(inact) state of the [FeFe] hydrogenases: an electrochemical and theoretical dissection of its redox chemistry. AB - The reduction of the Fe(II)Fe(II) complex [Fe2(CO)2{P(OMe)3}2(kappa(2)-IMe-CH2 IMe)(MU-CO)(MU-pdt)](2+) (2P(2+); pdt = S(CH2)3S), which is a synthetic model of the H cluster of the [FeFe] hydrogenases in its inactive state, has been investigated electrochemically and theoretically (by density functional theory, DFT) in order to determine the mechanisms, intermediates, and products of the related processes. The electrochemical reduction of 2P(2+) occurs according to an ECE-type reaction where the intervening chemical step is the loss of one P(OMe)3 ligand. This outcome, which is based on cyclic voltammetric experiments, is strongly supported by DFT calculations that provide additional information on the intermediates and the energetics of the reactions involved. The electrochemical reoxidation of the neutral product of the reduction follows an EEC process where the chemical step is the binding of P(OMe)3 to a dicationic intermediate. DFT calculations reveal that this intermediate has an unusual geometry wherein one of the two C-H bonds of a side methylene from the pdt group forms an agostic interaction with one Fe center. This interaction is crucial to stabilize the 32e( ) diferrous center and concomitantly to preserve Fe(II) from binding of weakly coordinating species. Nonetheless, it could be displaced by a relatively stronger electron donor such as H2, which could be relevant for the design of new oxidation catalysts. PMID- 25496018 TI - High throughput exome coverage of clinically relevant cardiac genes. AB - BACKGROUND: Given the growing use of whole-exome sequencing (WES) for clinical diagnostics of complex human disorders, we evaluated coverage of clinically relevant cardiac genes on WES and factors influencing uniformity and depth of coverage of exonic regions. METHODS: Two hundred and thirteen human DNA samples were exome sequenced via Illumina HiSeq using different versions of the Agilent SureSelect capture kit. 50 cardiac genes were further analyzed including 31 genes from the American College of Medical Genetics (ACMG) list for reporting of incidental findings and 19 genes associated with congenital heart disease for which clinical testing is available. Gene coordinates were obtained from two databases, CCDS and Known Gene and compared. Read depth for each region was extracted from the exomes and used to assess capture variability between kits for individual genes, and for overall coverage. GC content, gene size, and inter sample variability were also tested as potential contributors to variability in gene coverage. RESULTS: All versions of capture kits (designed based on Consensus coding sequence) included only 55% of known genomic regions for the cardiac genes. Although newer versions of each Agilent kit showed improvement in capture of CCDS regions to 99%, only 64% of Known Gene regions were captured even with newer capture kits. There was considerable variability in coverage of the cardiac genes. 10 of the 50 genes including 6 on the ACMG list had less than the optimal coverage of 30X. Within each gene, only 32 of the 50 genes had the majority of their bases covered at an interquartile range >=30X. Heterogeneity in gene coverage was modestly associated with gene size and significantly associated with GC content. CONCLUSIONS: Despite improvement in overall coverage across the exome with newer capture kit versions and higher sequencing depths, only 50% of known genomic regions of clinical cardiac genes are targeted and individual gene coverage is non-uniform. This may contribute to a bias with greater attribution of disease causation to mutations in well-represented and well-covered genes. Improvements in WES technology are needed before widespread clinical application. PMID- 25496019 TI - Rearrangement of quinoxalin-2-ones when exposed to enamines generated in situ from ketones and ammonium acetate: method for the synthesis of 1 (pyrrolyl)benzimidazolones. AB - The reaction of 3-benzoylquinoxalin-2(1H)-ones with enamines (generated in situ from ammonium acetate and the corresponding methylaryl(hetaryl)ketones) proceeds smoothly to give the corresponding substituted 1-(pyrrolyl)benzimidazolone derivatives in moderate yields through the novel rearrangement of 3 benzoylquinoxalin-2(1H)-ones involving a dual cleavage of the C3?N4 and C2-C3 bonds under mild conditions. PMID- 25496020 TI - Biofilm removal from implants supported restoration using different instruments: a 6-month comparative multicenter clinical study. AB - OBJECTIVES: The aim of this study was to compare the efficacy of different instruments on biofilm removal from implant supported restorations. MATERIALS AND METHODS: The study was designed as comparative multicenter clinical study including patients proceeding from the Milan, Naples, and Buenos Aires, with a peri-implant mucositis. Implants enrolled for the study were allocated in 4 groups and treated with ultrasonic scalers with plastic tips, with titanium curettes, with airflow with glycine powder, and with rubber cup and polishing paste, respectively. mPI was assessed at baseline, immediately after therapy, at 1, 3, and 6 months. mBI, PD, and REC were assessed at baseline, 1, 3, and 6 months. All parameters were recorded on six sites per implant. Kruskal-Wallis and Mann-Whitney tests were used to compare groups and centers. A generalized linear model for repeated measures was chosen for inter-group comparison. An intra-group comparison was performed with repeated measure ANOVA test to assess differences between baseline and recalls. RESULTS: A total of 89 patients (39 males, 50 females) were enrolled in the study, and 141 implants were available for the analysis. 55 implants were enrolled in University of Buenos Aires, 32 in University of Milan, and 54 in University of Naples. There were no significant differences between the four groups in inflammatory status reduction of peri implant mucosa. CONCLUSIONS: Non-surgical therapy is effective in reducing peri implant mucositis. Sonic scaler with plastic tip and rubber cup with polishing paste showed higher efficacy when compared with titanium curettes or airflow with glycine powder. PMID- 25496021 TI - Loss of vinculin and membrane-bound beta-catenin promotes metastasis and predicts poor prognosis in colorectal cancer. AB - BACKGROUND: Loss of cell-cell adhesion is important for the development of cancer invasion and metastasis. Vinculin, a key adhesion-related protein, can affect metastasis and prognosis in several tumours. Here, we determined the biological roles of vinculin in the metastasis of colorectal cancer (CRC) and evaluated its clinical significance as a potential disease biomarker. METHODS: The expression level of vinculin in CRC cell lines and tissues was measured using Real-Time PCR and western blotting. Moreover, vinculin function was analysed using Transwell assays and in vivo metastasis assays in gain- and loss-of-function experiments. Furthermore, the impact of vinculin together with membrane-bound beta-catenin on the prognosis of 228 CRC patients was investigated by immunohistochemistry. Additionally, the expression of epithelial-mesenchymal transition (EMT) indicators was verified by immunohistochemistry in CRC tissues obtained from these patients. RESULT: Vinculin expression was found to be significantly downregulated in highly metastatic CRC cell lines and metastatic tissues. Both in vitro and in vivo experiments showed that vinculin suppressed invasion, migration and metastasis in CRC cells and that this suppression could be attenuated by silencing beta-catenin. Moreover, the expression of vinculin and membrane-bound beta-catenin were positively correlated in CRC tissues, and lack of vinculin expression emerged as an independent prognostic factor in patients with CRC. Finally, the loss of vinculin and membrane-bound beta-catenin was associated with node metastasis, organ metastasis and expression of EMT indicators. CONCLUSION: Our results suggest that vinculin may play specific roles in the EMT and metastasis of CRC and that loss of vinculin could be used as a prognostic factor for CRC. PMID- 25496022 TI - Studies on antidiarrhoeal, antispasmodic and bronchodilator activities of Operculina turpethum Linn. AB - BACKGROUND: Traditionally, Operculina turpethum has been used in a wide range of ailments such as, gastrointestinal disturbances and asthma. It is found in China, South Asia, Pacific Islands, and Australia. This study was aimed to provide a possible pharmacological basis for the medicinal use of O. turpethum in gut and airways disorders. METHODS: Castor oil-induced diarrhoeal mice model and isolated tissue preparations such as, rabbit jejunum and guinea-pig tracheal preparations were used to test the antidiarrhoeal, antispasmodic and bronchodilator effects and the possible mode of action(s) of the 70% aqueous-ethanolic extract of O. turpethum black variety (OTB). RESULTS: In the castor oil-induced diarrhoea in mice, the crude extract of OTB caused a dose-dependent (300-1000 mg/kg) protection from diarrhoea, similar to that of loperamide. In isolated rabbit jejunum preparations, OTB produced a dose-dependent inhibition of spontaneous and high K+(80 mM)-induced contractions with resultant median effective concentrations (EC50 with 95% confidence interval) of 1.04 mg/ml (0.59-1.54) and 0.12 mg/ml (0.10-0.15; n = 4) respectively, thus showing more potency against K+. Pretreatment of the tissue with OTB (0.01 and 0.03 mg/ml) caused a rightward shift in the concentration response curves of Ca++, similar to that of verapamil. In isolated guinea-pig tracheal preparations, OTB caused inhibition of carbachol and high K+-induced constriction at similar concentrations with respective EC50 value of 0.66 mg/ml (0.53-0.82) and 0.59 mg/ml (0.45-0.62). Activity-directed fractionation revealed that the ethyl acetate fraction was more potent than the parent crude extract and hexane fraction. CONCLUSION: These results suggest that the crude extract of O. turpethum possesses antidiarrhoeal, antispasmodic and bronchodilator activities, mediated possibly through the presence of Ca++ antagonist like constituent(s), though additional mechanism(s) cannot be ruled out. Thus, this study provides the evidence for the medicinal use of plant in diarrhoea and asthma. PMID- 25496023 TI - Whether vitamin A supplementation is effective in T-bet and IFN-gamma gene expression reduction? AB - BACKGROUND: The aim of present study is evaluation of vitamin A supplementation efficacy on IFN-gamma and T-bet gene expression in atherosclerotic patients. METHODS: Thirty-one patients and 15 healthy controls participated in this study. Healthy control and patients in Vitamin A group received 25 000 IU retinyl palmitate daily for 4 months. Control patients also received 1 pearl of placebo per day up to 4 months. Gene expression levels were assessed by real-time PCR using SYBR green detection method. RESULTS: IFN-gamma gene expression in fresh cells of patients taking vitamin A declined slightly (0.85-fold, p = 0.068), whereas the expression of this gene was increased in patients taking placebo, and in healthy control subjects 1.2-fold (p = 0.267) and 1.7-fold (p = 0.580), respectively. There were no significant difference (p = 0.159) between 3 groups in terms of IFN-gamma gene expression in cells stimulated with PHA. In order to determine whether PHA stimulation of PBMCs in vitro had an effect on T-bet expression, we measured the difference between the 3 groups of studied. The results showed significant differences between the groups (p = 0.046). IFN-gamma gene expression in cells activated with ox-LDL in healthy control subjects and patients taking vitamin A, was reduced 0.43 (p = 0.0001) and 0.41 (p = 0.001) respectively, but in placebo patients was increased 2.2-fold (p = 0.959). CONCLUSION: Considering role of vitamin A on suppression of Th1 cells in atherosclerotic patients, it can be concluded that vitamin A supplementation may be advantageous for these patients. PMID- 25496024 TI - Development of an in vitro model for the analysis of bovine endometrium using simple techniques. AB - This study aimed to develop an in vitro model for the analysis of the bovine endometrium. Immunofluorescent staining revealed that the hetero-spheroids and the cultured explants showed almost similar structure in the localization of bovine endometrial epithelial cells and endometrial stromal cells, except the glandular-like structure of the epithelial cells inside the explants. Gelatin zymography revealed that the hetero-spheroids did not express matrix metalloproteinases (MMPs) after 4 days of culture, but strong MMP expressions were observed in the cultured explants until 7 days of culture. Additionally, expression of progesterone receptor (PR), estrogen receptor alpha (ERalpha), type I interferon receptor 1 (IFNAR1) and 2 (IFNAR2) messenger RNA was observed both in the homo- and hetero-spheroids. The expression of oxytocin receptor (OTR) mRNA in E2 and E2+P4 (1,3,5(10)-Estratrien-3, 17beta-diol + 4-Pregnen-3, 20-dinone) treated groups were significantly (P < 0.05) higher than that of the control group of spheroids. In case of cultured explants, the expression of PR and OTR mRNA were significantly (P < 0.05) higher in E2 treated groups compared to the control groups. Hepatocyte growth factor (HGF) mRNA expression was also higher in P4 treated groups at 10 days in culture (P < 0.05). In a nutshell, the in vitro model developed in this study for the analysis of the endometrium may provide a new platform for extensive research on bovine endometrial function. PMID- 25496025 TI - One-pot protocol to functionalized benzopyrrolizidine catalyzed successively by Rh2(OAc)4 and Cu(OTf)2: a transition metal-Lewis acid catalysis relay. AB - 4-N-allylarylpropylamino-1-sulfonyl triazoles are converted to structurally unique benzopyrrolizidinyl sulfonamides in a one-pot operation. Intramolecular capture of rhodium carbene with arylamino nitrogen gives rise to the formation of an ammonium ylide immediate. A [2,3]- or [1,2]-rearrangement occurs to give a 2 allylpyrrolidinyl-2-carbimine intermediate which undergoes Cu(OTf)2 catalyzed aza Friedel-Crafts cyclization to finish a highly functionalized tricyclic system decorated with a synthetically difficult quaternary carbon center, a sulfonamide group, and an allyl segment. PMID- 25496026 TI - Molecular properties determining unbound intracellular and extracellular brain exposure of CNS drug candidates. AB - In the present work we sought to gain a mechanistic understanding of the physicochemical properties that influence the transport of unbound drug across the blood-brain barrier (BBB) as well as the intra- and extracellular drug exposure in the brain. Interpretable molecular descriptors that significantly contribute to the three key neuropharmacokinetic properties related to BBB drug transport (Kp,uu,brain), intracellular accumulation (Kp,uu,cell), and binding and distribution in the brain (Vu,brain) for a set of 40 compounds were identified using partial least-squares (PLS) analysis. The tailoring of drug properties for improved brain exposure includes decreasing the polarity and/or hydrogen bonding capacity. The design of CNS drug candidates with intracellular targets may benefit from an increase in basicity and/or the number of hydrogen bond donors. Applying this knowledge in drug discovery chemistry programs will allow designing compounds with more desirable CNS pharmacokinetic properties. PMID- 25496027 TI - Skin temperature changes during a footbath in patients who had had a stroke with consequent sensory impairment. AB - AIM: The objectives of this study were to examine skin temperature changes on the unaffected and affected sides as well as changes in perceived temperature and comfort during a footbath in patients who had had a stroke with consequent sensory impairment. METHODS: The study used a quasi-experimental design in which the results of intervention for patients who had had a stroke and healthy adults were compared. The subjects were 20 patients who had had a stroke with consequent sensory impairment and 20 healthy adults. RESULTS: Before the footbath, the skin temperature of the dorsum of the foot on the affected side of the patient who had had a stroke was lower than that of the foot on the unaffected side. Five minutes after the start of the footbath, however, the relationship reversed, with the skin temperature on the affected side increasing in parallel with the water temperature. After the footbath, the dorsum skin temperature on the affected side was again lower than that on the unaffected side. In healthy adults, a difference was found in dorsum skin temperature between the left and right feet. In contrast with patients who had had a stroke, no reversal of the sides was found with the lower and higher temperature. CONCLUSION: Unlike in the healthy adults, the skin temperature of the patients who had had a stroke with consequent sensory impairment was susceptible to changes in the external environment. However, no significant changes in the physiological indices were seen, while perceived temperature and comfort remained at high levels after the footbath. PMID- 25496028 TI - The spread of injectate during saphenous nerve block at the adductor canal: a cadaver study. AB - BACKGROUND: The spread of injectate during a saphenous nerve block at the adductor canal has not been clearly described. METHODS: We examined the spread of 15 ml dyed injectate during ultrasound-guided saphenous nerve blocks at the adductor canal in 15 unembalmed cadavers' lower limbs followed by comparative dissections of the same limbs. RESULTS: The spread of the injectates was determined by the fascial limits and the muscles surrounding the adductor canal. The anteromedial limit of the adductor canal (the roof) was found to be a continuous fascia, with a thin proximal part and a thicker distal part (the vastoadductor membrane) covering the canal from the apex of the femoral triangle to the adductor hiatus. The fascial limits of the adductor canal formed a conduit around the femoral neurovascular bundle. The dyed aqueous injectate spread throughout the entire adductor canal to the femoral triangle and reached 1-2 cm into the popliteal fossa. Injections superficial to the adductor canal spread over the femoral artery within the subsartorial fat compartment resembling the injections within the canal but with ultrasonographic distinct features. These injections spread only half the length of the adductor canal. The only nerve observed within the adductor canal was the saphenous nerve. CONCLUSIONS: Injection of 15 ml dye was sufficient to spread throughout the adductor canal and beyond both proximally and distally. Distinct ultrasonographic features could be identified separating a subsartorial injection from an injection within the adductor canal with consequent differences in the spread. PMID- 25496029 TI - Revealing DNA interactions with exogenous agents by surface-enhanced Raman scattering. AB - The standard protocols for DNA analysis largely involve polymerase chain reaction (PCR). However, DNA structures bound to chemical agents cannot be PCR-amplified, and therefore any sequence changes induced by external agents may be neglected. Thus, the development of analytical tools capable of characterizing the biochemical mechanisms associated with chemically induced DNA damage is demanded for the rational design of more effective chemotherapy drugs, understanding the mode of actions of carcinogenic chemicals, and monitoring the genotypic toxicology of environments. Here we report a fast, high-throughput, low-cost method for the characterization and quantitative recognition of DNA interactions with exogenous agents based on surface-enhanced Raman scattering spectroscopy. As representative chemical agents, we selected a chemotherapeutic drug (cisplatin) which forms covalent adducts with DNA, a duplex intercalating agent (methylene blue), and a cytotoxic metal ion (Hg(II)) which inserts into T:T mismatches. Rich structural information on the DNA complex architecture and properties is provided by the unique changes of their SERS spectra, which also offer an efficient analytical tool to quantify the extent of such binding. PMID- 25496030 TI - Phase I/II study exploring ImMucin, a pan-major histocompatibility complex, anti MUC1 signal peptide vaccine, in multiple myeloma patients. AB - ImMucin, a 21-mer cancer vaccine encoding the signal peptide domain of the MUC1 tumour-associated antigen, possesses a high density of T- and B-cell epitopes but preserves MUC1 specificity. This phase I/II study assessed the safety, immunity and clinical response to 6 or 12 bi-weekly intradermal ImMucin vaccines, co administered with human granulocyte-macrophage colony-stimulating factor to 15 MUC1-positive multiple myeloma (MM) patients, with residual or biochemically progressive disease following autologous stem cell transplantation. Vaccination was well tolerated; all adverse events were temporal grade 1 2 and spontaneously resolved. ImMucin vaccination induced a robust increase in gamma-interferon (IFN gamma-producing CD4+ and CD8+ T-cells (<=80-fold), a pronounced population of ImMucin multimer CD8+ T-cells (>2%), a 9.4-fold increase in peripheral blood mononuclear cells proliferation and 6.8-fold increase in anti-ImMucin antibodies, accompanied with T-cell and antibody-dependent cell-mediated cytotoxicity. A significant decrease in soluble MUC1 levels was observed in 9/10 patients. Stable disease or improvement, persisting for 17.5-41.3 months (ongoing) was achieved in 11/15 patients and appeared to be associated with low-intermediate PDL1 (CD274) bone marrow levels pre- and post-vaccination. In summary, ImMucin, a highly tolerable cancerous vaccine, induces robust, diversified T- and B-cell ImMucin specific immunity in MM patients, across major histocompatibility complex barrier, resulting in at least disease stabilization in most patients. PMID- 25496031 TI - LED-based UV absorption detector with low detection limits for capillary liquid chromatography. AB - A 260 nm deep UV LED-based absorption detector with low detection limits was developed and integrated with a small nanoflow pumping system. The detector is small in size (5.2 * 3.0 cm) and weighs only 85 g (without electronics). This detector was specifically designed and optimized for on-column detection to minimize extra-column band broadening. No optical reference was included due to the low drift in the signal. Two ball lenses, one of which was integrated with the LED, were used to increase light throughput through the capillary column. Stray light was minimized by the use of a band-pass filter and an adjustable slit. Signals down to the parts per billion level (nanomolar) were easily detected with a short-term noise level of 4.4 MUAU, confirming a low limit of detection and low noise. The detection limit for adenosine-5'-monophosphate was 230 times lower than any previously reported values. Good linearities (3 orders of magnitude) were obtained using sodium anthraquinone-2-sulfonate, adenosine-5' monophosphate, dl-tryptophan, and phenol. The LC system was demonstrated by performing isocratic separation of phenolic compounds using a monolithic capillary column (16.5 cm * 150 MUm i.d.) synthesized from poly(ethylene glycol) diacrylate. PMID- 25496032 TI - NFAT targets signaling molecules to gene promoters in pancreatic beta-cells. AB - Nuclear factor of activated T cells (NFAT) is activated by calcineurin in response to calcium signals derived by metabolic and inflammatory stress to regulate genes in pancreatic islets. Here, we show that NFAT targets MAPKs, histone acetyltransferase p300, and histone deacetylases (HDACs) to gene promoters to differentially regulate insulin and TNF-alpha genes. NFAT and ERK associated with the insulin gene promoter in response to glucagon-like peptide 1, whereas NFAT formed complexes with p38 MAPK (p38) and Jun N-terminal kinase (JNK) upon promoters of the TNF-alpha gene in response to IL-1beta. Translocation of NFAT and MAPKs to gene promoters was calcineurin/NFAT dependent, and complex stability required MAPK activity. Knocking down NFATc2 expression, eliminating NFAT DNA binding sites, or interfering with NFAT nuclear import prevented association of MAPKs with gene promoters. Inhibiting p38 and JNK activity increased NFAT-ERK association with promoters, which repressed TNF-alpha and enhanced insulin gene expression. Moreover, inhibiting p38 and JNK induced a switch from NFAT-p38/JNK-histone acetyltransferase p300 to NFAT-ERK-HDAC3 complex formation upon the TNF-alpha promoter, which resulted in gene repression. Histone acetyltransferase/HDAC exchange was reversed on the insulin gene by p38/JNK inhibition in the presence of glucagon-like peptide 1, which enhanced gene expression. Overall, these data indicate that NFAT directs signaling enzymes to gene promoters in islets, which contribute to protein-DNA complex stability and promoter regulation. Furthermore, the data suggest that TNF-alpha can be repressed and insulin production can be enhanced by selectively targeting signaling components of NFAT-MAPK transcriptional/signaling complex formation in pancreatic beta-cells. These findings have therapeutic potential for suppressing islet inflammation while preserving islet function in diabetes and islet transplantation. PMID- 25496034 TI - Why dieting should die. PMID- 25496035 TI - Attrition and the management of pediatric obesity: an integrative review. AB - BACKGROUND: A key challenge in managing pediatric obesity is the high degree of program attrition, which can reduce therapeutic benefits and contribute to inefficient health services delivery. Our aim was to document and characterize predictors of, and reasons for, attrition in pediatric obesity management. METHODS: We searched literature published until January 2014 in five databases (CINAHL, EMBASE, MEDLINE, PsycINFO, and Scopus). Articles were included if they were English, included participants 0-18 years of age, focused on pediatric obesity management, incorporated lifestyle and behavioral changes without pharmacotherapy, provided attrition data, and reported information about predictors of, and/or reasons for, attrition from family-based interventions provided in research or clinical settings. Twenty-three articles (n=20 quantitative; n=2 qualitative; n=1 mixed methods) met our inclusion criteria. Clarity of study aims, objectives, methods, and data analysis were appraised using Bowling's checklist. RESULTS: Attrition varied according to definition (minimum to maximum, 4-83%; median, 37%). There were few consistent predictors of attrition between studies, although dropout was higher among US-based families receiving public health insurance. Older children were also more likely to discontinue care, but sex and baseline weight status did not predict attrition. The most commonly reported reasons for attrition were logistical barriers and programs not meeting families' needs. CONCLUSIONS: Developing and evaluating strategies designed to minimize the risk of attrition, especially among families who receive public health insurance and older boys and girls, are needed to optimize the effectiveness of pediatric obesity management. PMID- 25496033 TI - Farnesoid X receptor antagonizes JNK signaling pathway in liver carcinogenesis by activating SOD3. AB - The farnesoid X receptor (FXR) is a key metabolic and homeostatic regulator in the liver. In the present work, we identify a novel role of FXR in antagonizing c Jun N-terminal kinase (JNK) signaling pathway in liver carcinogenesis by activating superoxide dismutase 3 (SOD3) transcription. Compared with wild-type mouse liver, FXR(-/-) mouse liver showed elevated JNK phosphorylation. JNK1 deletion suppressed the increase of diethylnitrosamine-induced tumor number in FXR(-/-) mice. These results suggest that JNK1 plays a key role in chemical induced liver carcinogenesis in FXR(-/-) mice. We found that ligand-activated FXR was able to alleviate H2O2or tetradecanoylphorbol acetate-induced JNK phosphorylation in human hepatoblastoma (HepG2) cells or mouse primary hepatocytes. FXR ligand decreased H2O2-induced reactive oxygen species (ROS) levels in wild-type but not FXR(-/-) mouse hepatocytes. FXR knockdown abolished the inhibition of 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4 isoxazolyl]methoxy]phenyl]ethenyl]-Benzoic acid (GW4064) on JNK phosphorylation and ROS production induced by H2O2in HepG2 cells. The gene expression of SOD3, an antioxidant defense enzyme, was increased by FXR activation in vitro and in vivo. An FXR-responsive element, inverted repeat separated by 1 nucleotide in SOD3 promoter, was identified by a combination of transcriptional reporter assays, EMSAs, and chromatin immunoprecipitation assays, which indicated that SOD3 could be a direct FXR target gene. SOD3 knockdown abolished the inhibition of GW4064 on JNK phosphorylation induced by H2O2in HepG2 cells. In summary, FXR may regulate SOD3 expression to suppress ROS production, resulting in decreasing JNK activity. These results suggest that FXR, as a novel JNK suppressor, may be an attractive therapeutic target for liver cancer treatment. PMID- 25496037 TI - Retraction of "Modeling potential effects of reduced calories in kids' meals with toy giveaways". PMID- 25496036 TI - Order of magnitude misestimation of weight effects of children's meal policy proposals. PMID- 25496038 TI - Global invasion history of the tropical fire ant: a stowaway on the first global trade routes. AB - Biological invasions are largely thought to be contemporary, having recently increased sharply in the wake of globalization. However, human commerce had already become global by the mid-16th century when the Spanish connected the New World with Europe and Asia via their Manila galleon and West Indies trade routes. We use genetic data to trace the global invasion of one of the world's most widespread and invasive pest ants, the tropical fire ant, Solenopsis geminata. Our results reveal a pattern of introduction of Old World populations that is highly consistent with historical trading routes suggesting that Spanish trade introduced the tropical fire ant to Asia in the 16th century. We identify southwestern Mexico as the most likely source for the invasive populations, which is consistent with the use of Acapulco as the major Spanish port on the Pacific Ocean. From there, the Spanish galleons brought silver to Manila, which served as a hub for trade with China. The genetic data document a corresponding spread of S. geminata from Mexico via Manila to Taiwan and from there, throughout the Old World. Our descriptions of the worldwide spread of S. geminata represent a rare documented case of a biological invasion of a highly invasive and globally distributed pest species due to the earliest stages of global commerce. PMID- 25496039 TI - The HIV cascade of care in Georgia: implications for countries in Eastern Europe and Central Asia (EECA). PMID- 25496040 TI - Opportunities for social workers in the patient centered medical home. AB - The Patient Centered Medical Home (PCMH) has been hailed as one method of improving chronic care outcomes in the United States. A number of studies have underscored the importance of the social work role within the PCMH, yet little existing research explores the social worker as a driver of improved patient care. The Pennsylvania Chronic Care Initiative was created with a primary goal of increasing the number of practices that were recognized as PCMH by the National Committee for Quality Assurance. This article describes findings from in-depth qualitative interviews with representatives from seven primary care practices, in which the authors examined barriers and facilitators to implementation of the initiative. Barriers to implementation included small practice size, payer-driven care, not having a strong physician champion, variability within patient populations, and high implementation costs. Facilitators included having a social worker coordinate behavioral health services, clinical nurse case managers, preexisting models of outcomes-driven care, and being part of an integrated health delivery and financing system. Recommendations strengthening the role of medical social workers in primary care practices are discussed. PMID- 25496042 TI - Formulation and evaluation of floating mucoadhesive alginate beads for targeting Helicobacter pylori. AB - OBJECTIVES: There are various obstacles in the eradication of Helicobacter pylori infections, including low antibiotic levels and poor accessibility of the drug at the site of the infection. This study describes the preparation and characterisation of novel floating mucoadhesive alginate beads loaded with clarithromycin for delivery to the gastric mucosa to improve the eradication of this microorganism. METHODS: Calcium alginate beads were prepared by ionotropic gelation. The formulation was modified through addition of oil and coating with chitosan to improve floating, mucoadhesion and modify drug release. KEY FINDINGS: Scanning electron microscopy confirmed the sphericity of the beads with X-ray microtomography showing the three-dimensional structure of the beads with the layered internal structure of the bead and the even distribution of the drug within the bead. This formulation combined two gastro-retentive strategies, and produced excellent in-vitro floating, mucoadhesive and drug release characteristics. Enhanced stability of the beads in phosphate buffer raises a potential for the modified formulations to be targeted to regions of higher pH within the gastrointestinal tract. Drug release from these beads was sustained through an unstirred mucin layer simulating in-vivo conditions under which the H. pylori resides in the gastric mucosa. CONCLUSIONS: This novel formulation will ensure retention for a longer period in the stomach than conventional formulations and control drug release, ensuring high local drug concentrations, leading to improved eradication of the bacteria. PMID- 25496041 TI - Design of chemically stable, potent, and efficacious MDM2 inhibitors that exploit the retro-mannich ring-opening-cyclization reaction mechanism in spiro-oxindoles. AB - Inhibition of the MDM2-p53 protein-protein interaction is being actively pursued as a new anticancer therapeutic strategy, and spiro-oxindoles have been designed as a class of potent and efficacious small-molecule inhibitors of this interaction (MDM2 inhibitors). Our previous study showed that some of our first generation spiro-oxindoles undergo a reversible ring-opening-cyclization reaction that, from a single compound in protic solution, results in an equilibrium mixture of four diastereoisomers. By exploiting the ring-opening-cyclization reaction mechanism, we have designed and synthesized a series of second generation spiro-oxindoles with symmetrical pyrrolidine C2 substitution. These compounds undergo a rapid and irreversible conversion to a single, stable diastereoisomer. Our study has yielded compound 31 (MI-1061), which binds to MDM2 with Ki = 0.16 nM, shows excellent chemical stability, and achieves tumor regression in the SJSA-1 xenograft tumor model in mice. PMID- 25496043 TI - Structural and permeation kinetic correlations in PdCuAg membranes. AB - Addition of Ag is a promising way to enhance the H2 permeability of sulfur tolerant PdCu membranes for cleanup of coal-derived hydrogen. We investigated a series of PdCuAg membranes with at least 70 atom % Pd to elucidate the interdependence between alloy structure and H2 permeability. Membranes were prepared via sequential electroless plating of Pd, Ag, and Cu onto ceramic microfiltration membranes and subsequent alloying at elevated temperatures. Alloy formation was complicated by a wide miscibility gap in the PdCuAg phase diagram at the practically feasible operation temperatures. X-ray diffraction showed that the lattice constants of the fully alloyed ternary alloys obey Vegard's law closely. In general, H2 permeation rates increased with increasing Ag and decreasing Cu content of the membranes in the investigated temperature range. Detailed examination of the permeation kinetics revealed compensation between activation energy and pre-exponential factor of the corresponding H2 permeation laws. The origin of this effect is discussed. Further analysis showed that the activation energy for H2 permeation decreases overall with increasing lattice constant of the ternary alloy. The combination of these correlations results in a structure-function relationship that will facilitate rational design of PdCuAg membranes. PMID- 25496044 TI - Parents and teachers reporting on a child's emotional and behavioural problems following severe traumatic brain injury (TBI): the moderating effect of time. AB - BACKGROUND: Gathering information from parents and teachers following paediatric traumatic brain injury (TBI) has substantial clinical value for diagnostic decisions. Yet, a multi-informant approach has rarely been addressed when evaluating children at the chronic stage post-injury. In the current study, the goals were to examine (1) differences between parents' and teachers' reports on a child's emotional and behavioural problems and (2) the effect of time elapsed since injury on each rater's report. METHODS: A sample of 42 parents and 42 teachers of children following severe TBI completed two standard rating scales. Receiver Operating Characteristic (ROC) curves were used to determine whether time elapsed since injury reliably distinguished children falling above and below clinical levels. RESULTS: Emotional-behavioural scores of children following severe TBI fell within normal range, according to both teachers and parents. Significant differences were found between parents' reports relatively close to the time of injury and 2 years post-injury. However, no such differences were observed in teachers' ratings. CONCLUSIONS: Parents and teachers of children following severe TBI differ in their reports on a child's emotional and behavioural problems. The present study not only underscores the importance of multiple informants, but also highlights, for the first time, the possibility that informants' perceptions may vary across time. PMID- 25496045 TI - Risk of tuberculosis, serious infection and lymphoma with disease-modifying biologic drugs in rheumatoid arthritis patients in Taiwan. AB - AIM: To determine the risk of adverse events in rheumatoid arthritis (RA) patients treated with biological disease-modifying anti-rheumatic drugs (bDMARD) versus traditional DMARDs (tDMARD). METHOD: This retrospective study used Taiwan's National Health Insurance Research Database to capture data for adult patients diagnosed with RA between 1 January 1999 and 31 December 2009 and treated with tDMARD or bDMARD. The endpoints were patients with cases of an inpatient serious bacterial infection (SBI), diagnosis of tuberculosis (TB) or lymphoma. Within the bDMARD cohort, individual bDMARDS with adequate data were also compared (adalimumab and etanercept). Propensity-score matching was used to adjust for significant (P <= 0.05) patient characteristics. Incidence rate ratios (IRR) of SBI/TB/lymphoma cases versus non-cases were adjusted for exposure time (rate per 100,000 patient-years) and 95% confidence intervals were constructed to assess whether IRRs differed from 1.0. RESULTS: Of 34,947 potential patients, 7888 tDMARD, 3459 bDMARD (including 1492 etanercept and 746 adalimumab) patients were matched for analysis. A total of 2150 cases were identified and of these 1711 were SBI, 406 as TB and 33 as lymphoma. For all cases except SBI, the IRR (95% CI) was higher for bDMARD versus tDMARD (SBI 1.04 [0.89-1.19]; TB 2.67 [2.12 3.34]; lymphoma 3.24 [1.37-7.06]). Excepting lymphoma, IRR was higher for adalimumab versus etanercept (SBI 1.83 [1.19-2.77]; TB 2.35 [1.29-4.15]; lymphoma 1.49 [0.03-18.66]). CONCLUSIONS: There was a higher risk for specified infections and lymphoma with bDMARD versus tDMARD and adalimumab versus etanercept. PMID- 25496046 TI - Development of risk perception and substance use of tobacco, alcohol and cannabis among adolescents and emerging adults: evidence of directional influences. AB - BACKGROUND: While several studies have investigated the relationship between risk perception and substance use, surprisingly little is known about mutual influences between both variables over time. OBJECTIVES: The present study aimed to explore two different hypotheses separately for tobacco, alcohol and cannabis: influences from risk perception on behavior (motivational hypothesis) and influences from behavior on risk perception (risk reappraisal hypothesis). METHODS: A prospective and longitudinal cross-lagged panel design was used with substance use and risk perception measured five times over the course of 10 years. Participants were 318 German youths aged 14-15 at the beginning of the study. Risk perception and substance use frequency were measured using self reports. RESULTS: Structural equation modeling indicated significant influences of risk perception on substance use behavior for all substances, which supports the motivational hypothesis. Changes in risk perception predict changes in future substance use of tobacco, alcohol and cannabis. Specifically for cannabis, influences of substance use on risk perception can also be shown, thus, supporting the risk reappraisal hypothesis. CONCLUSIONS: While there is support for the rationale behind adequate risk perception as a goal of preventive interventions, the possibility of risk reappraisal should not be neglected, especially regarding illicit substances. PMID- 25496047 TI - Crystallization behavior of single isotactic poly(methyl methacrylate) chains visualized by atomic force microscopy. AB - We have, for the first time, successfully visualized the crystallization behavior of a single isolated polymer chain at the molecular level by atomic force microscopy (AFM). Previously, we found that isotactic poly(methyl methacrylate) (it-PMMA) formed two-dimensional folded chain crystals composed of double stranded helices upon compression of its Langmuir monolayer on a water surface, and the molecular images of the crystals deposited on mica were clearly visualized by AFM (Kumaki, J.; et al. J. Am. Chem. Soc. 2005, 127, 5788). In the present study, a high-molecular-weight it-PMMA was diluted in a monolayer of an it-PMMA oligomer which cannot crystallize at the experimental temperature due to its low molecular weight. At a low surface pressure, isolated amorphous chains of the high-molecular-weight it-PMMA solubilized in the oligomer monolayer were observed. On compression, the isolated chains converted to crystals composed of a single chain, typically some small crystallites linked by an amorphous chain like a necklace. Detailed AFM observations of the crystals indicated that the crystalline nuclei preferentially formed at the ends of the chains, and the size of the nuclei was almost independent of the molecular weight of it-PMMA over a wide range. At an extremely slow compression, crystallization was promoted, resulting in crystallization of the whole chain. The crystallization behavior of a single isolated chain provides new insights in understanding the polymer crystallization process. PMID- 25496048 TI - Comparing clinical effectiveness and drug toxicity with hydrochlorothiazide and chlorthalidone using two potency ratios in a managed care population. AB - This study compared the clinical effectiveness and drug toxicity of chlorthalidone and hydrochlorothiazide. Electronic health records and claims data were used to identify patients initially prescribed chlorthalidone or hydrochlorothiazide. A total of 214 patients prescribed chlorthalidone 25 mg were matched with 428 patients prescribed hydrochlorothiazide 25 mg (1:1 potency ratio) and 214 patients prescribed hydrochlorothiazide 50 mg (1:2 potency ratio). Mean systolic blood pressure/diastolic blood pressure values at least 30 days after initial prescription were lower with chlorthalidone (132.2/74 mm Hg) compared with hydrochlorothiazide 25 mg (137.0/77.5 mm Hg) and hydrochlorothiazide 50 mg (138.6/78.5 mm Hg) (P<.05 for all comparisons). Goal systolic blood pressure/diastolic blood pressure values were achieved in a higher percentage of patients prescribed chlorthalidone (45.0%/78.3%) than with either hydrochlorothiazide 25 mg (32.1%/63.9%) or hydrochlorothiazide 50 mg (32.8%/68.9%) (P<.05 for all comparisons). Mean serum potassium was 3.94 mEq/L with chlorthalidone 25 mg, 4.13 mEq/L with hydrochlorothiazide 25 mg (P<.01 vs chlorthalidone), and 3.96 mEq/L with hydrochlorothiazide 50 mg. These findings indicate that chlorthalidone 25 mg is associated with a better antihypertensive response than hydrochlorothiazide 25 mg or 50 mg, without clinically significant differences in serum potassium. PMID- 25496049 TI - A mechanistic model of COR15 protein function in plant freezing tolerance: integration of structural and functional characteristics. AB - Plants as sessile organisms are strongly challenged by environmental stresses. Many plants species are able to cold-acclimate, acquiring higher freezing tolerance upon exposure to low but non-freezing temperatures. Among a plethora of adaptational processes, this involves the accumulation of cold regulated (COR) proteins that are assumed to stabilize and protect cellular structures during freezing. However, their molecular functions are largely unknown. We recently reported a comprehensive study of 2 intrinsically disordered cold regulated chloroplast proteins, COR15A and COR15B from Arabidopsis thaliana. They are necessary for full cold acclimation. During freezing, they stabilize leaf cells through folding and binding to chloroplast membranes. Contrary to evidence from in-vitro experiments, they play no role in enzyme stabilization in vivo. Elucidating these major functional and structural characteristics and estimation of protein abundance allow us to propose a detailed model for the mode of action of the two COR15 proteins. PMID- 25496050 TI - A role for the FtsQLB complex in cytokinetic ring activation revealed by an ftsL allele that accelerates division. AB - The cytokinetic apparatus of bacteria is initially formed by the polymerization of the tubulin-like FtsZ protein into a ring structure at midcell. This so-called Z-ring facilitates the recruitment of many additional proteins to the division site to form the mature divisome machine. Although the assembly pathway leading to divisome formation has been well characterized, the mechanisms that trigger cell constriction remain unclear. In this report, we study a 'forgotten' allele of ftsL from Escherichia coli, which encodes a conserved division gene of unknown function. We discovered that this allele promotes the premature initiation of cell division. Further analysis also revealed that the mutant bypasses the requirement for the essential division proteins ZipA, FtsK and FtsN, and partially bypasses the need for FtsA. These findings suggest that rather than serving simply as a protein scaffold within the divisome, FtsL may play a more active role in the activation of the machine. Our results support a model in which FtsL, along with its partners FtsB and FtsQ, function as part of a sensing mechanism that promotes the onset of cell wall remodeling processes needed for the initiation of cell constriction once assembly of the divisome complex is deemed complete. PMID- 25496051 TI - A systematic review of nurse-related social network analysis studies. AB - BACKGROUND: Nurses frequently work as part of both uni- and multidisciplinary teams. Communication between team members is critical in the delivery of quality care. Social network analysis is increasingly being used to explore such communication. AIM: To explore the use of social network analysis involving nurses either as subjects of the study or as researchers. METHODS: Standard systematic review procedures were applied to identify nurse-related studies that utilize social network analysis. A comparative thematic approach to synthesis was used. Both published and grey literature written in English, Spanish and Portuguese between January 1965 and December 2013 were identified via a structured search of CINAHL, SciELO and PubMed. In addition, Google and Yahoo search engines were used to identify additional grey literature using the same search strategy. RESULTS: Forty-three primary studies were identified with literature from North America dominating the published work. So far it would appear that no author or group of authors have developed a programme of research in the nursing field using the social network analysis approach although several authors may be in the process of doing so. LIMITATIONS: The dominance of literature from North America may be viewed as problematic as the underlying structures and themes may be an artefact of cultural communication norms from this region. CONCLUSIONS: The use of social network analysis in relation to nursing and by nurse researchers has increased rapidly over the past two decades. The lack of longitudinal studies and the absence of replication across multiple sites should be seen as an opportunity for further research. IMPLICATION FOR NURSING AND HEALTH POLICY: This analytical approach is relatively new in the field of nursing but does show considerable promise in offering insights into the way information flows between individuals, teams, institutions and other structures. An understanding of these structures provides a means of improving communication. PMID- 25496053 TI - Data-driven synthesis of proteolysis-resistant peptide hormones. AB - Peptide hormones are key physiological regulators, and many would make terrific drugs; however, the therapeutic use of peptides is limited by poor metabolism including rapid proteolysis. To develop novel proteolysis-resistant peptide hormone analogs, we utilize a strategy that relies on data from simple mass spectrometry experiments to guide the chemical synthesis of proteolysis-resistant analogs (i.e., data-driven synthesis). Application of this strategy to oxyntomodulin (OXM), a peptide hormone that stimulates insulin secretion from islets and lowers blood glucose in vivo, defined the OXM cleavage site in serum, and this information was used to synthesize a proteolysis-resistant OXM analog (prOXM). prOXM and OXM have similar activity in binding and glucose stimulated insulin secretion assays. Furthermore, prOXM is also active in vivo. prOXM reduces basal glucose levels and improves glucose tolerance in mice. The discovery of prOXM suggests that proteolysis-resistant variants of other important peptide hormones can also be found using this strategy to increase the number of candidate therapeutic peptides. PMID- 25496052 TI - Interactive balance training integrating sensor-based visual feedback of movement performance: a pilot study in older adults. AB - BACKGROUND: Wearable sensor technology can accurately measure body motion and provide incentive feedback during exercising. The aim of this pilot study was to evaluate the effectiveness and user experience of a balance training program in older adults integrating data from wearable sensors into a human-computer interface designed for interactive training. METHODS: Senior living community residents (mean age 84.6) with confirmed fall risk were randomized to an intervention (IG, n = 17) or control group (CG, n = 16). The IG underwent 4 weeks (twice a week) of balance training including weight shifting and virtual obstacle crossing tasks with visual/auditory real-time joint movement feedback using wearable sensors. The CG received no intervention. Outcome measures included changes in center of mass (CoM) sway, ankle and hip joint sway measured during eyes open (EO) and eyes closed (EC) balance test at baseline and post intervention. Ankle-hip postural coordination was quantified by a reciprocal compensatory index (RCI). Physical performance was quantified by the Alternate Step-Test (AST), Timed-up-and-go (TUG), and gait assessment. User experience was measured by a standardized questionnaire. RESULTS: After the intervention sway of CoM, hip, and ankle were reduced in the IG compared to the CG during both EO and EC condition (p = .007-.042). Improvement was obtained for AST (p = .037), TUG (p = .024), fast gait speed (p = . 010), but not normal gait speed (p = .264). Effect sizes were moderate for all outcomes. RCI did not change significantly. Users expressed a positive training experience including fun, safety, and helpfulness of sensor-feedback. CONCLUSIONS: Results of this proof-of-concept study suggest that older adults at risk of falling can benefit from the balance training program. Study findings may help to inform future exercise interventions integrating wearable sensors for guided game-based training in home- and community environments. Future studies should evaluate the added value of the proposed sensor-based training paradigm compared to traditional balance training programs and commercial exergames. TRIAL REGISTRATION: http://www.clinicaltrials.govNCT02043834. PMID- 25496054 TI - The developmental effects of extremely low frequency electric fields on visual and somatosensory evoked potentials in adult rats. AB - The purpose of our study was to investigate the developmental effects of extremely low frequency electric fields (ELF-EFs) on visual evoked potentials (VEPs) and somatosensory-evoked potentials (SEPs) and to examine the relationship between lipid peroxidation and changes of these potentials. In this context, thiobarbituric acid reactive substances (TBARS) levels were determined as an indicator of lipid peroxidation. Wistar albino female rats were divided into four groups; Control (C), gestational (prenatal) exposure (Pr), gestational+ postnatal exposure (PP) and postnatal exposure (Po) groups. Pregnant rats of Pr and PP groups were exposed to 50 Hz electric field (EF) (12 kV/m; 1 h/day), while those of C and Po groups were placed in an inactive system during pregnancy. Following parturition, rats of PP and Po groups were exposed to ELF-EFs whereas rats of C and Pr groups were kept under the same experimental conditions without being exposed to any EF during 68 days. On postnatal day 90, rats were prepared for VEP and SEP recordings. The latencies of VEP components in all experimental groups were significantly prolonged versus C group. For SEPs, all components of PP group, P2, N2 components of Pr group and P1, P2, N2 components of Po group were delayed versus C group. As brain TBARS levels were significantly increased in Pr and Po groups, retina TBARS levels were significantly elevated in all experimental groups versus C group. In conclusion, alterations seen in evoked potentials, at least partly, could be explained by lipid peroxidation in the retina and brain. PMID- 25496055 TI - Evaluation of single and multilayered reactive zones for heavy metals removal from stormwater. AB - In this paper, the ability of granular activated carbon (GAC), silica spongolite (SS) and zeolite (Z) to remove heavy metals from aqueous solutions has been investigated through column tests. The breakthrough times for a mobile tracer that does not sorb to the material for SS, GAC and layered SS, Z and GAC were as follows: 2.54*10(4) s, 2.38*10(4) s and 3.02*10(4) s. The breakthrough time (tbR) for Ni was in the range from tbR=1.70*10(6) s for SS, through tbR=3.98*10(5) s for the layered bed, to tbR=8.75*10(5) s for GAC. The breakthrough time for Cd was in the range from tbR=1.83*10(5) s for GAC to tbR=1.30*10(6) s for SS, Z, GAC. During the experiment, the concentration of Cd, Cu, Pb and Zn in the solution from a column filled with construction aggregate and the concentration of Pb, and Cu in a filtrate from the column filled with several materials was close to zero. The reduction in metal ions removal was due to high pH values of the solution (above 8.00). In addition, during the testing period, an increase in Cd and Zn concentrations in the filtrate from the column filled with the layered bed was observed, but at the end of the experiment the concentrations did not reach the maximum values. The test results suggest that the multilayered permeable reactive barrier is the most effective technology for long time effective removal of heavy metals. PMID- 25496057 TI - Concurrence of myotonic dystrophy and epilepsy: a case report. AB - INTRODUCTION: Myotonic dystrophy is a clinically and genetically heterogeneous multisystem disorder with a prevalence of 1 in 8000 in the general population. CASE PRESENTATION: A 25-year-old Ethiopian man presented with symptoms of myotonia, muscle wasting, gait problems, frontal baldness, and family history characterizing the hereditary disorder myotonic dystrophy. He had been on treatment for idiopathic generalized epilepsy for over 15 years. A needle electromyography showed insertional classic myotonic discharges. A nerve conduction study showed mild axonal sensorimotor polyneuropathy. His muscle biopsy showed marked increase of internalized nuclei, severely atrophic muscle fibers, muscle fiber necrosis and regeneration of isolated muscle fibers, architectural changes, and a preferential atrophy of type I fibers. CONCLUSION: This is a rare occurrence of two distinctive hereditary diseases. PMID- 25496056 TI - Association between HIF-1alpha C1772T/G1790A polymorphisms and cancer susceptibility: an updated systematic review and meta-analysis based on 40 case control studies. AB - BACKGROUND: HIF-1 (hypoxia-inducible factor 1) is a transcriptional activator that functions as a critical regulator of oxygen homeostasis. Recently, a large number of epidemiological studies have investigated the relationship between HIF 1alpha C1772T/G1790A polymorphisms and cancer susceptibility. However, the results remain inconclusive. Therefore, we performed a meta-analysis on all of the available case-control studies to systematically summarize the possible association. METHODS: A literature search was performed using PubMed and the Web of Science database to obtain relevant published studies. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the relationship between HIF-1alpha C1772T/G1790A polymorphisms and cancer susceptibility were calculated using fixed- and random-effects models when appropriate. Heterogeneity tests, sensitivity analyses and publication bias assessments were also performed in our meta-analysis. RESULTS: A total of 40 studies met the inclusion criteria were included in the meta-analysis: 40 studies comprised of 10869 cases and 14289 controls for the HIF-1alpha C1772T polymorphism and 30 studies comprised of 7117 cases and 10442 controls for the HIF-1alpha G1790A polymorphism. The results demonstrated that there were significant association between the HIF-1alpha C1772T polymorphism and cancer susceptibility under four genetic models (TT vs. CC: OR = 1.63, 95% CI = 1.02-2.60; CT + TT vs. CC: OR = 1.15, 95% CI = 1.01-1.34; TT vs. CT + CC: OR = 2.11, 95% CI = 1.32-3.77; T vs. C: OR = 1.21, 95% CI = 1.04 1.41). Similarly, the statistically significant association between the HIF 1alpha G1790A polymorphism and cancer susceptibility was found to be consistently strong in all of the genetic models. Moreover, increased cancer risk was observed when the data were stratified by cancer type, ethnicity and the source of controls. CONCLUSIONS: This meta-analysis demonstrates that both the C1772T and G1790A polymorphisms in the HIF-1alpha gene likely contribute to increased cancer susceptibility, especially in the Asian population and in breast cancer, lung cancer, pancreatic cancer and oral cancer. However, further research is necessary to evaluate the relationship between these polymorphisms and cancer risk. PMID- 25496058 TI - Technical survey of the French role in multichannel cochlear implant development. AB - The objective of this review is to remind the ENT community of the essential role of the French teams in the development and finalization of the multi-electrode cochlear implant (MCI), which has deliberately been neglected, and to repair the oblivion into which France was curiously cast at the end of the last century. It aims to underline significant scientific publications from the researchers who played key roles in the development of MCIs. In conclusion, the Parisian team of the ENT Lab in Saint Antoine Hospital in Paris can claim priority for its work in five regards. We were the first: (1) to plot in 1976 a frequency map of the whole length of three living human cochleas; (2) on September 22, 1976, to set up total cochlear implantation in a deaf adult male with eight electrodes; (3) on March 16, 1977, to apply for a patent for an implantable hearing aid in humans; (4) to describe sound signal processing (SSP) for a functional cochlear implant able to supply totally deaf patients with speech discrimination without the help of lip reading; (5) in 1983, to experimentally demonstrate why it was necessary to place a cochlear implant as early as possible, in case of profound neonatal deafness. An injustice has occurred. These facts will be brought to the knowledge of the scientific community. PMID- 25496059 TI - A genotypically distinct, melanic variant of Anopheles arabiensis in Sudan is associated with arid environments. AB - BACKGROUND: Anopheles arabiensis, an important malaria vector in Sudan and other countries in sub-Saharan Africa, exhibits considerable ecological and behavioural plasticity allowing it to survive in the harsh conditions of arid regions. It has been shown that adult populations of An. arabiensis in the semi-desert habitat of western Khartoum State survive through the long dry season in a state of partial aestivation, characterized by limited feeding activity and a degree of arrested ovarian development. Anopheles arabiensis in these sites occurs in two phenotypic forms. One is large and heavily melanized, the other has the typical characteristics of An. arabiensis as found elsewhere in Africa. The extent of genetic variation in these forms was examined in widely separated locations in Sudan, including Kassala, Gedaref and the Northern States between 1998 and 1999 and 2004 and 2006. METHODS: Each mosquito specimen was identified using standard morphological keys and a species-specific PCR test. Sequence variation in a 660 bp fragment of the mtDNA ND5 coding region was examined and the extent of genetic divergence between the forms was estimated from FST values using DNASP version 4.9. TCS 1.13 software was used to determine the genealogical relationships and to reflect clustering among mtDNA haplotypes. RESULTS: The melanic and normal forms were found in sympatry in Kassala, Gedaref and Khartoum states, with the melanic form commonest in the hottest and most arid areas. Both forms were encountered in the periods of study: 1998-1999, and 2004-2006. Only ten specimens of An. arabiensis were collected from the Northern State in February 2006, all of which were of the normal form.Based on the ND5 analysis, there was a marked subdivision between the normal and melanic forms (FST = 0.59). Furthermore, the melanic form showed more genetic variability, as measured by haplotype diversity (0.95) compared with the normal form (0.57), suggesting larger effective population. CONCLUSIONS: This is the first demonstration of correspondent phenotypic and genetic structuring in An. arabiensis. The high level of genetic differentiation shown by the mtDNA ND5 locus suggests that the two forms may represent separate species. It is hypothesized that the melanic form is better adapted to hot and arid environments. PMID- 25496060 TI - Comparison of Cognitive Functions Between Obstructive Sleep Apnea Syndrome and Simple Snoring Patients: OSAS May Be a Modifiable Risk Factor for Cognitive Decline. AB - By comparing neurocognitive test results from patients with obstructive sleep apnea syndrome (OSAS) and those from patients with simple snoring, we aimed to establish whether OSAS negatively influences cognition. Patients with mild-to severe OSAS (n = 29) and nonhypoxic simple-snoring patients (n = 30) were admitted to the study. All participants in both groups were evaluated with polysomnography and neurocognitive tests, including the Stroop Test, Rey Auditory Verbal Learning Test, Judgment of Line Orientation, Trail-Making Test, and Symbol Digit Modalities Test (SDMT). Significant differences were identified between the groups for test scores on the Rey 1, SDMT, and Stroop tests. We propose that accurate OSAS diagnosis and treatment might help to prevent cognitive decline. PMID- 25496061 TI - Delayed circadian phase is linked to glutamatergic functions in young people with affective disorders: a proton magnetic resonance spectroscopy study. AB - BACKGROUND: While the association between affective disorders and sleep and circadian disturbance is well established, little is known about the neurobiology underpinning these relationships. In this study, we sought to determine the relationship between a marker of circadian rhythm and neuronal integrity (N Acetyl Aspartate, NAA), oxidative stress (glutathione, GSH) and neuronal-glial dysfunction (Glutamate + Glutamine, Glx). METHODS: Fifty-three young adults (age range 15-33 years, mean = 21.8, sd = 4.3) with emerging affective disorders were recruited from a specialized tertiary referral service. Participants underwent clinical assessment and actigraphy monitoring, from which sleep midpoint was calculated as a marker of circadian rhythm. Proton magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC). The metabolites NAA, GSH and Glx were obtained, and expressed as a ratio to Creatine. RESULTS: Neither NAA or GSH were associated with sleep midpoint. However, higher levels of ACC Glx were associated with later sleep midpoints (rho = 0.35, p = 0.013). This relationship appeared to be independent of age and depression severity. CONCLUSIONS: This study is the first to demonstrate that delayed circadian phase is related to altered glutamatergic processes. It is aligned with animal research linking circadian rhythms with glutamatergic neurotransmission as well as clinical studies showing changes in glutamate with sleep interventions. Further studies may seek to examine the role of glutamate modulators for circadian misalignment. PMID- 25496063 TI - Naloxegol , a new drug for the treatment of opioid-induced constipation. AB - INTRODUCTION: With increasing chronic opioid use, opioid-induced constipation (OIC) is becoming a relevant clinical challenge. Presently, only few treatments have been demonstrated to be more effective than placebo in treating OIC but most of them have a restricted clinical application because of side effects. Naloxegol , an orally administered, peripherally acting, MU-opioid receptor antagonist (PAMORA), was developed for the treatment of OIC. AREA COVERED: This review summarizes published information and presentations at meetings on the effects of naloxegol in OIC. Pharmacodynamic studies have demonstrated that naloxegol inhibits gastrointestinal opioid effects while preserving central analgesic actions. Phase II and Phase III studies in patients with non-cancer OIC have confirmed the efficacy of naloxegol to inhibit OIC, and the most consistent efficacy was seen with the 25 mg dose once daily. Adverse events were mainly gastrointestinal in origin and usually transient and mild. There were no signs of opioid withdrawal in the studies. Safety and tolerability were also shown in a long-term safety study. Regulatory authorities have recently approved the use of naloxegol in OIC. EXPERT OPINION: Naloxegol is the first approved, orally available PAMORA. The drug has the potential to substantially improve management of OIC patients. PMID- 25496064 TI - Clinical implications of glycoproteomics for Acinetobacter baumannii. AB - The opportunistic human pathogen Acinetobacter baumannii persists in the healthcare setting because of its ability to survive exposure to various antimicrobial and sterilization agents. A. baumannii's ability to cause multiple infection types complicates diagnosis and treatment. Rapid detection of A. baumannii infections would likely improve treatment outcomes. Recently published Acinetobacter glycoproteomic data show the prevalence of O-linked glycoproteins, suggesting the possibility for an O-glycan-based detection technology. O-glycan biosynthesis is required for protein glycosylation and capsular polysaccharide production in A. baumannii. Recent publications demonstrate key roles for protein glycosylation and capsular polysaccharide in the pathogenicity of A. baumannii. Targeted antimicrobial development against O-glycan biosynthesis may produce new effective treatment options for A. baumannii infections. Here, we discuss how the data gathered through Acinetobacter glycoproteomics can be used to develop technologies for rapid diagnosis and reveal potential antimicrobial targets. In addition, we consider the efficacy of glycoconjugate vaccine development against A. baumannii. PMID- 25496065 TI - Rural Christians' view of sickness treatment behavior: a case study from a Shandong village, China. AB - There are few studies of Christian views of disease and treatment behavior in rural China. Based on Village G in Shandong Province, this paper describes how, under conditions of rural social and medical deprivation, Christians regard physical (routi) and mental (jingshen) sickness as resulting from disturbances to communal peace. Sickness occurs when everyday sinful words and actions allow the devil to enter or when God uses the devil to test worshippers' beliefs. In either case, it is the devil who directly causes sickness. Christian treatment is through scripture, communal and individual prayer, and expurgation. Diagnosis and treatment thus reflect both theodicy and the emergence of a kind of devil culture in the context of rural social crises. PMID- 25496062 TI - Persistently high glucose levels in young children with type 1 diabetes. AB - OBJECTIVES: The aim of the study was to characterize glucose levels and variability in young children with type 1 diabetes (T1D). METHODS: A total of 144 children of 4-10 yr old diagnosed with T1D prior to age 8 were recruited at five DirecNet centers. Participants used a continuous glucose monitor (CGM) every 3 months during an 18-month study. Among the 144 participants, 135 (mean age 7.0 yr, 47% female) had a minimum of 48 h of CGM data at more than five of seven visits and were included in analyses. CGM metrics for different times of day were analyzed. RESULTS: Mean hemoglobin A1c (HbA1c) at the beginning and end of the study was 7.9% (63 mmol/mol). Fifty percent of participants had glucose levels >180 mg/dL (10.0 mmol/L) for >12 h/d and >250 mg/dL (13.9 mmol/L) for >6 h/d. Median time <70 mg/dL (3.9 mmol/L) was 66 min/d and <60 mg/dL (3.3 mmol/L) was 39 min/d. Mean amplitude of glycemic excursions (MAGE) was lowest overnight (00:00 06:00 hours). The percent of CGM values 71-180 mg/dL (3.9-10.0 mmol/L) and the overall mean glucose correlated with HbA1c at all visits. There were no differences in CGM mean glucose or coefficient of variation between the age groups of 4 and <6, 6 and <8, and 8 and <10. CONCLUSIONS: Suboptimal glycemic control is common in young children with T1D as reflected by glucose levels in the hyperglycemic range for much of the day. New approaches to reduce postprandial glycemic excursions and increase time in the normal range for glucose in young children with T1D are critically needed. Glycemic targets in this age range should be revisited. PMID- 25496066 TI - Risk indicators for peri-implant mucositis: a systematic literature review. AB - OBJECTIVES: To examine the existing evidence in identifying risk indicators in the aetiology of peri-implant mucositis. MATERIAL AND METHODS: A search was performed in PubMed, Web of Science (WOS) and The Cochrane Library databases for articles published until June 2014. RESULTS: This search gave 3135 results of which 15 studies fulfilled the inclusion criteria. The current review revealed that only a few studies provided data on risk indicators for the development of peri-implant mucositis. Based on the data available, there is evidence that plaque is a risk indicator for peri-implant mucositis. Smoking has also been identified as an independent risk indicator whereas the overall evidence for surface roughness, residual cement, the dimension of the keratinized tissue and time of implant in function is weak. There are limited data available to support systemic conditions as risk indicators for peri-implant mucositis. CONCLUSIONS: Plaque accumulation at implants will result in development of peri-implant mucositis. Smoking should also be considered as a risk indicator for the development of peri-implant mucositis. PMID- 25496068 TI - Surface-bubble-modulated liquid chromatography: a new approach for manipulation of chromatographic retention and investigation of solute distribution at water/hydrophobic interfaces. AB - In this paper, we present a new chromatographic method termed surface-bubble modulated liquid chromatography (SBMLC), that has a hybrid separation medium incorporated with surface nanobubbles. Nanobubbles or nanoscale gas phases can be fixed at the interface between water and a hydrophobic material by delivering water into a dry column packed with a nanoporous material. The incorporation of a gas phase at the hydrophobic surface leads to the formation of the hybrid separation system consisting of the gas phase, hydrophobic moieties, and the water/hydrophobic interface or the interfacial water. One can change the volume of the gas phase by pressure applied to the column, which in turn alters the area of water/hydrophobic interface or the volume of the interfacial water, while the amount of the hydrophobic moiety remains constant. Therefore, this strategy provides a novel technique not only for manipulating the separation selectivity by pressure but also for elucidating the mechanism of accumulation or retention of solute compounds in aqueous solutions by a hydrophobic material. We evaluate the contributions of the interfacial water at the surface of an octadecyl bonded silica and the bonded layer itself to the retention of various solute compounds in aqueous solutions on the column packed with the material by SBMLC. The results show that the interfacial water formed at the hydrophobic surface has a key role in retention even though its volume is rather small. The manipulation of the separation selectivity of SBMLC for some organic compounds by pressure is demonstrated. PMID- 25496067 TI - X-ray crystallographic structure of BshC, a unique enzyme involved in bacillithiol biosynthesis. AB - Bacillithiol is produced by many Gram-positive bacteria via a pathway utilizing the enzymes BshA, BshB, and BshC. Here we report the 1.77 A resolution crystal structure of BshC, the putative cysteine ligase in bacillithiol production. The structure reveals that BshC contains a core Rossmann fold with connecting peptide motifs (CP1 and CP2) and a unique alpha-helical coiled-coil domain that facilitates dimerization. The model contains citrate and glycerol in the canonical active site and ADP in a second binding pocket. The overall structure and bound ligands give insight into the function of this unique enzyme. PMID- 25496069 TI - Evaluation of the Microsemi CRP, an automated hematology analyzer for rapid 3 part WBC differential and CRP using whole blood. AB - INTRODUCTION: We evaluated the basic performance of Microsemi CRP, an unique automated hematology analyzer which can simultaneously measure CBC including 3 part WBC differential (3-Diff) and CRP using whole blood treated with EDTA-2K anticoagulant. METHOD: We found that it produced generally the acceptable results for all parameters performed (repeatability, reproducibility, linearity, interference effect, carry over, and correlation) using control materials, fresh human whole bloods, and serum samples. RESULTS: CBC data examined using Microsemi CRP showed the good correlation with the previous model, Micros CRP200 (r ? 0.9), and also those obtained using the routine analyzer, ADVIA 2120i (r ? 0.989). Concerning the 3-Diff, both GRA (%) and LYM (%) showed the excellent correlation coefficient between Microsemi CRP and Micros CRP200 (r ? 0.992) as well as ADVIA 2120i (r ? 0.957). MON (%) showed good correlation between Microsemi CRP and Micros CRP200 (r = 0.959), but lower correlation between Microsemi CRP and ADVIA 2120 i (r = 0.471). CRP data showed the good correlation with HITACHI7600 (r ? 0.997) and Micros CRP200 (r ? 0.997). CONCLUSION: From these findings, we concluded that Microsemi CRP seemed the convenient laboratory analyzer in the setting of point of care testing (POCT) especially at NICU or primary care unit. PMID- 25496070 TI - Compounding diagnostic delays: a qualitative study of point-of-care testing in South Africa. AB - OBJECTIVES: Successful point-of-care (POC) testing (completion of test-and-treat cycle in one patient encounter) has immense potential to reduce diagnostic and treatment delays, and improve patient and public health outcomes. We explored what tests are done and how in public/private, rural/urban hospitals and clinics in South Africa and whether they can ensure successful POC testing. METHODS: This qualitative research study examined POC testing across major diseases in Cape Town, Durban and Eastern Cape. We conducted 101 semi-structured interviews and seven focus group discussions with doctors, nurses, community health workers, patients, laboratory technicians, policymakers, hospital managers and diagnostic manufacturers. RESULTS: In South Africa, diagnostics are characterised by a centralised system. Most tests conducted on the spot can be made to work successfully as POC tests. The majority of public/private clinics and smaller hospitals send samples via couriers to centralised laboratories and retrieve results the same way, via internet, fax or phone. The main challenge to POC testing lies in transporting samples and results, while delays risk patient loss from diagnostic/treatment pathways. Strategies to deal with associated delays create new problems, such as artificially prolonged turnaround times, strains on human resources and quality of testing, compounding additional diagnostic and treatment delays. CONCLUSIONS: For POC testing to succeed, particular characteristics of diagnostic ecosystems and adaptations of professional practices to overcome associated challenges must be taken into account. PMID- 25496071 TI - Developing a national food defense guideline based on a vulnerability assessment of intentional food contamination in Japanese food factories using the CARVER+Shock vulnerability assessment tool. AB - The awareness of food terrorism has increased following the September 11, 2001 terrorist attacks in New York City, United States, and many measures and policies dealing with this issue have been established worldwide. Suspected deliberate food-poisoning crimes have occurred in Japan, although they are not regarded as acts of food terrorism. One area of concern is that the small- to medium-sized companies that dominate Japan's food industry are extremely vulnerable to deliberate food poisoning. We conducted a literature research on food defense measures undertaken by the World Health Organization and in the United States and Europe. Using the Carver+Shock vulnerability assessment tool, eight food factories and related facilities in Japan were evaluated and we found the level of awareness of food defense to be low and the measures inappropriate. On the basis of this evaluation, we developed a set of guidelines that Japanese food companies can use to help develop their food defense strategies and to serve as a reference in considering specific measures. PMID- 25496073 TI - The TNFAIP3 polymorphism rs610604 both associates with the risk of psoriasis vulgaris and affects the clinical severity. AB - BACKGROUND: Genome-wide association studies in white and Chinese Han populations have found that the single-nucleotide polymorphism (SNP) rs610604, at the tumour necrosis factor (TNF)-alpha-induced protein 3 (TNFAIP3) locus, is associated with psoriasis, and is also associated with response to TNF blockade in psoriasis. AIM: To examine whether this SNP is also associated with the clinical traits of psoriasis vulgaris (PV). METHODS: A hospital-based case-control study was performed, which involved 647 subjects [351 patients with PV and 296 healthy controls (HC)]. The rs610604 variants were typed using a SNaPshot assay. RESULTS: Both the G allele and the dominant model genotype (GG + GT) of rs610604 were associated with risk of PV (OR = 1.53; P = 0.01 and OR = 1.68, P < 0.01, respectively). In genotype-phenotype analysis, both the G allele and the GG + GT genotype were also associated with the clinical severity of PV. Severe cases [Psoriasis Area and Severity Index (PASI) > 6] had a higher frequency of the G allele and the GG + GT genotype compared with mild cases (PASI <= 6) (OR = 2.03, P = 0.001 and OR = 2.46, P < 0.001, respectively). In addition, rs610604 was significantly associated with almost all of the phenotypes in subphenotype control analyses. CONCLUSIONS: SNP rs610604 in the TNFAIP3 locus is associated with the clinical severity of PV in a Chinese Han population. PMID- 25496074 TI - A United Kingdom national survey of trends in ectopic pregnancy management. PMID- 25496072 TI - Effects of climate change on Salmonella infections. AB - BACKGROUND: Climate change and global warming have been reported to increase spread of foodborne pathogens. To understand these effects on Salmonella infections, modeling approaches such as regression analysis and neural network (NN) were used. METHODS: Monthly data for Salmonella outbreaks in Mississippi (MS), Tennessee (TN), and Alabama (AL) were analyzed from 2002 to 2011 using analysis of variance and time series analysis. Meteorological data were collected and the correlation with salmonellosis was examined using regression analysis and NN. RESULTS: A seasonal trend in Salmonella infections was observed (p<0.001). Strong positive correlation was found between high temperature and Salmonella infections in MS and for the combined states (MS, TN, AL) models (R(2)=0.554; R(2)=0.415, respectively). NN models showed a strong effect of rise in temperature on the Salmonella outbreaks. In this study, an increase of 1 degrees F was shown to result in four cases increase of Salmonella in MS. However, no correlation between monthly average precipitation rate and Salmonella infections was observed. CONCLUSION: There is consistent evidence that gastrointestinal infection with bacterial pathogens is positively correlated with ambient temperature, as warmer temperatures enable more rapid replication. Warming trends in the United States and specifically in the southern states may increase rates of Salmonella infections. PMID- 25496075 TI - Volume-based metabolic tumor response to neoadjuvant chemotherapy is associated with an increased risk of recurrence in breast cancer. AB - PURPOSE: To evaluate the prognostic value of a volume-based metabolic tumor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. MATERIALS AND METHODS: This study was approved by the institutional review board, with waivers of informed consent. One hundred sixty-seven patients (mean age, 44 years; range, 22-68 years) with clinical stage II or III breast cancer who underwent fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography scans at baseline and after completion of neoadjuvant chemotherapy between July 2006 and June 2013 were selected. The association between the metabolic response parameters and the disease-free survival was assessed by using a Cox proportional hazards regression model and time-dependent receiver operating characteristic curve analysis. Metabolic response parameters included the maximum standardized uptake value (SUVmax), the total metabolic tumor volume (MTVtotal), and the relative decrease in SUVmax and MTVtotal. RESULTS: In the Cox model, posttreatment SUVmax (P = .029) and MTVtotal (P = .028) and relative decreases in SUVmax (P = .032) and MTVtotal (P = .005) after neoadjuvant chemotherapy were significantly associated with disease-free survival after adjusting for pretreatment clinical stage, yp stage, and tumor subtype. In the time-dependent receiver operating characteristic curve analysis, MTVtotal after neoadjuvant chemotherapy had the highest association with outcome compared with the other parameters (P < .001). MTVtotal of up to 0.2 cm(3) after neoadjuvant chemotherapy was significantly associated with a favorable outcome in patients who did not achieve pathologic complete response after neoadjuvant chemotherapy. CONCLUSION: The volume-based metabolic tumor response to neoadjuvant chemotherapy is associated with an increased risk of recurrence, regardless of tumor subtype and pathologic tumor response. PMID- 25496076 TI - Remote loading of aloe emodin in gemini-based cationic liposomes. AB - Anthraquinone compound aloe-emodin (AE) has shown antineoplastic, antibacterial, antiviral, and anti-inflammatory properties and scavenging activity on free radicals. Because of these therapeutic features, AE has been attracting increasing interest and could be applied in the curing of many diseases. However, until now the physicochemical features of this compound have not been fully investigated; furthermore, its wide application might be hindered by its scarce solubility in aqueous media (~19 MUM). The inclusion of AE in nanocarriers, such as cationic liposomes, could allow its delivery effectively and selectively to target sites, reducing side effects in the remaining tissues. In this work, the weak acid nature of AE, because of its two phenolic functions, was exploited to load it remotely in the internal aqueous phase of liposomes in response to a difference in pH between the inside and outside of the liposomes, pHin > pHout. The inclusion of AE in gemini-based cationic liposomes by the acetate gradient method was obtained at high AE/lipid ratios (up to 1:30). PMID- 25496078 TI - Emergency management of traumatic dental injuries in 42 countries. AB - Availability and quality of emergency services for traumatic dental injuries (TDI) are important as the prognosis of TDI is decided at the place of accident or during the first hours after the injury has occurred. AIM: To report how emergency services for TDI are provided in some places around the world. SUBJECTS AND METHODS: This is a preliminary observational study of descriptive character. One-hundred and three participants from 83 cities in 42 countries described the emergency services in their city by answering a questionnaire related to: (1) availability of advice per telephone at the place of the accident; (2) availability of emergency treatment resources at different times of the day; and; (3) assessment of competence level of the person carrying out the service. Answers and comments were scored with regard to availability and level of competence. RESULTS: 62% of the participants were not satisfied with their current emergency services. 50% reported organized emergency telephone service always available. 43% of the advice given by phone was from professionals with dental training. An organized on-call 24/7 service was available in 33%. Treatment of TDI within the first hour was available in 53%. A competent dentist was available in 40%. 56% reported compromised competency outside office hours. Places with a well-organized system built on a well-developed first-line care managed by trauma-trained general dentists, ideally on a 24/7 basis, supported by on-call specialists outside office working hours, achieved the highest scores. CONCLUSIONS: With all the limitations of a preliminary questionnaire study, we can conclude that there is a need to perform more comprehensive well-designed studies in this field to understand more of the varying quality of emergency services worldwide. The major problem today seems to be related to limited availability and competence, especially outside office working hours. PMID- 25496077 TI - MicroRNA in prostate cancer: functional importance and potential as circulating biomarkers. AB - BACKGROUND: This non-systematic review article aims to summarise the progress made in understanding the functional consequences of microRNA (miRNA) dysregulation in prostate cancer development, and the identification of potential miRNA targets as serum biomarkers for diagnosis or disease stratification. RESULTS: A number of miRNAs have been shown to influence key cellular processes involved in prostate tumourigenesis, including apoptosis-avoidance, cell proliferation and migration and the androgen signalling pathway. An overlapping group of miRNAs have shown differential expression in the serum of patients with prostate cancer of varying stages compared with unaffected individuals. The majority of studies thus far however, involve small numbers of patients and have shown variable and occasionally conflicting results CONCLUSION: MiRNAs show promise as potential circulating biomarkers in prostate cancer, but larger prospective studies are required to validate particular targets and better define their clinical utility. PMID- 25496079 TI - Necrostatin-1 alleviates reperfusion injury following acute myocardial infarction in pigs. AB - BACKGROUND: In rodents, it has previously been shown that necrostatin-1 (Nec-1) inhibits RIP1, a central regulator of programmed necrosis, thereby decreasing cell death and reducing infarct size (IS) after ischaemia/reperfusion (I/R) injury. To address unanswered questions on feasibility and efficacy of Nec-1 in a large animal model, we assessed the effects of Nec-1 in a porcine I/R model, relevant to human disease. MATERIALS AND METHODS: In Dalland landrace pigs (69 +/ 3 kg), I/R injury was induced by a 75-min surgical ligation of the left circumflex coronary artery (LCx). Ten minutes prior to reperfusion, pigs were randomly allocated to different Nec-1 doses (1.0 mg/kg or 3.3 mg/kg) or vehicle treatment (control, CTRL). Functional endpoints and immunohistological analyses were performed 24 h after reperfusion. RESULTS: Nec-1 3.3 mg/kg significantly reduced IS (n = 6; 24.4 +/- 15.6%) compared to Nec-1 1.0 mg/kg (n = 5; 54.8 +/- 16.9%) or CTRLs (n = 6; 62.1 +/- 26.6%; P = 0.016). In line, LV ejection fraction (LVEF) was significantly higher in Nec-1 3.3 mg/kg, copared to Nec-1 1.0 mg/kg or CTRL treated animals (50.0 +/- 12.0% vs. 32.5 +/- 12.9% vs. 31.9 +/- 6.6%, respectively, P = 0.015). Hemodynamically, a preserved contractility was observed [end-systolic volume at 100 mmHg (ESV100 )] at 24-h follow-up (87.6 +/- 17.3 mL vs. 74.5 +/- 41.1 mL vs. 56.8 +/- 11.8 mL, respectively, P = 0.032), reflecting improved cardiac function. CONCLUSIONS: In the pig model of I/R injury, intravenous administration of Nec-1 prior to reperfusion was an effective and above all practical therapeutic strategy that significantly reduced IS and preserved left ventricular function. These data highlight the potential of cardioprotection as a promising adjuvant therapy in the setting of early reperfusion following I/R injury. PMID- 25496080 TI - Cutaneous non-tuberculous mycobacterial infection in patients with chronic graft versus-host disease: A case series. AB - We report the first case series of allogeneic haematopoietic stem-cell transplant patients with graft versus host disease who developed cutaneous non-tuberculous mycobacteria infection. A multidisciplinary approach, reduction of immunosuppressive medications, combination of antibiotics, close skin surveillance and excision of suitable lesions are recommended in this specific subgroup. PMID- 25496081 TI - Genomic resources for the endangered Hawaiian honeycreepers. AB - BACKGROUND: The Hawaiian honeycreepers are an avian adaptive radiation containing many endangered and extinct species. They display a dramatic range of phenotypic variation and are a model system for studies of evolution, conservation, disease dynamics and population genetics. Development of a genome-scale resources for this group would augment the quality of research focusing on Hawaiian honeycreepers and facilitate comparative avian genomic research. RESULTS: We assembled the genome sequence of a Hawaii amakihi (Hemignathus virens),and identified ~3.9 million single nucleotide polymorphisms (SNPs) in the genome. Using the amakihi genome as a reference, we also identified ~156,000 SNPs in RAD tag (restriction site associated DNA) sequencing of five honeycreeper species (palila [Loxioides bailleui], Nihoa finch [Telespiza ultima], iiwi [Vestiaria coccinea], apapane [Himatione sanguinea], and amakihi). SNPs are distributed throughout the amakihi genome, and the individual sequenced shows several large regions of low heterozygosity on chromosomes 1, 5, 6, 8 and 11. SNPs from RAD tag sequencing were also found throughout the genome but were found to be more densely located on microchromosomes, apparently a result of differential distribution of the particular site recognized by restriction enzyme BseXI. CONCLUSIONS: The amakihi genome sequence will be useful for comparative avian genomics research and provides a significant resource for studies in such areas as disease ecology, evolution, and conservation genetics. The genome sequences will enable mapping of transcriptome data for honeycreepers and comparison of gene sequences between avian taxa. Researchers will be able to use the large number of SNP markers to genotype honeycreepers in regions of interest or across the whole genome. There are enough markers to enable use of methods such as genome-wide association studies (GWAS) that will allow researchers to make connections between phenotypic diversity of honeycreepers and specific genetic variants. Genome-wide markers will also help resolve phylogenetic and population genetic questions in honeycreepers. PMID- 25496082 TI - Activation of intervertebral disc cells by co-culture with notochordal cells, conditioned medium and hypoxia. AB - BACKGROUND: Notochordal cells (NC) remain in the focus of research for regenerative therapy for the degenerated intervertebral disc (IVD) due to their progenitor status. Recent findings suggested their regenerative action on more mature disc cells, presumably by the secretion of specific factors, which has been described as notochordal cell conditioned medium (NCCM). The aim of this study was to determine NC culture conditions (2D/3D, fetal calf serum, oxygen level) that lead to significant IVD cell activation in an indirect co-culture system under normoxia and hypoxia (2% oxygen). METHODS: Porcine NC was kept in 2D monolayer and in 3D alginate bead culture to identify a suitable culture system for these cells. To test stimulating effects of NC, co-cultures of NC and bovine derived coccygeal IVD cells were conducted in a 1:1 ratio with no direct cell contact between NC and bovine nucleus pulposus cell (NPC) or annulus fibrosus cells (AFC) in 3D alginate beads under normoxia and hypoxia (2%) for 7 and 14 days. As a positive control, NPC and AFC were stimulated with NC-derived conditioned medium (NCCM). Cell activity, glycosaminoglycan (GAG) content, DNA content and relative gene expression was measured. Mass spectrometry analysis of the NCCM was conducted. RESULTS: We provide evidence by flow cytometry that monolayer culture is not favorable for NC culture with respect to maintaining NC phenotype. In 3D alginate culture, NC activated NPC either in indirect co-culture or by addition of NCCM as indicated by the gene expression ratio of aggrecan/collagen type 2. This effect was strongest with 10% fetal calf serum and under hypoxia. Conversely, AFC seemed unresponsive to co-culture with pNC or to the NCCM. Further, the results showed that hypoxia led to decelerated metabolic activity, but did not lead to a significant change in the GAG/DNA ratio. Mass spectrometry identified connective tissue growth factor (CTGF, syn. CCN2) in the NCCM. CONCLUSIONS: Our results confirm the requirement to culture NC in 3D to best maintain their phenotype, preferentially in hypoxia and with the supplementation of FCS in the culture media. Despite these advancements, the ideal culture condition remains to be identified. PMID- 25496083 TI - Use of low-level laser therapy (808 nm) to muscle fatigue resistance: a randomized double-blind crossover trial. AB - OBJECTIVE: The purpose of this study was to investigate whether low-level laser (light) therapy (LLLT) can provide fatigue resistance via maximum repetitions (RM) with an isokinetic dynamometer, and decrease electromyography fatigue index (EFI). BACKGROUND DATA: LLLT has been used to increase muscle performance when applied before or after intense exercises. MATERIALS AND METHODS: This study was a randomized, double-blind, crossover trial with placebo. Seven young men (21+/-3 years of age) who were clinically healthy, were allocated into two groups: active laser (LLLT) and placebo laser (Placebo). Both groups were assessed at baseline, at one training session, and at the end of this study. Baseline and final assessments recorded the number of RM of knee flexion-extensions using an isokinetic dynamometer at 60 degrees/sec in conjunction with EFI recorded by median frequency. The training sessions consisted of three sets of 20 RM of knee flexion-extensions using an isokinetic dynamometer at 60 degrees/sec plus LLLT (808 nm, 100 mW, 4 J), or placebo, applied to quadriceps femoris muscles between sets, and after the last series of this exercise. After 1 week (washout period), all volunteers were exchanged among groups and then all assessments were repeated. RESULTS: LLLT group increased RM (52%; p=0.002) with a small EFI for the vastus medialis (p=0.004) and rectus femoris (p=0.004). CONCLUSIONS: These results suggest an increased muscle fatigue resistance when LLLT is applied during rest intervals, and after the last series of intense exercises. PMID- 25496084 TI - Effects of near infrared laser radiation associated with photoabsorbing cream in preventing white spot lesions around orthodontic brackets: an in vitro study. AB - OBJECTIVE: The present study aims to investigate the effect of a low-power infrared laser on the inhibition of bovine enamel demineralization around orthodontic brackets. BACKGROUND DATA: Near infrared lasers have been suggested as alternative approaches because they may produce an increase in resistance to dental caries. METHODS: Forty-eight blocks of enamel obtained from bovine incisor teeth were divided into six groups: Group 1 (control), without treatment; Group 2 (C), photoabsorbing cream; Group 3 (CF), photoabsorbing cream with fluoride; Group 4 (L), irradiation with low-level infrared laser (lambda=830 nm) at an energy density of 4.47 J/cm2; Group 5 (L+C), photoabsorbing cream followed by low level infrared laser irradiation; and Group 6 (L+CF), photoabsorbing cream with fluoride followed by low-level infrared laser irradiation. After these procedures, the enamel blocks received an assortment of orthodontic brackets and were then submitted to pH cycling to simulate a highly cariogenic challenge. The enamel surface demineralization around the orthodontic brackets, according to the different treatments, was quantified by fluorescence loss analysis by quantitative light-induced fluorescence (QLF). The fluorescence loss, expressed as DeltaF (percentage of loss fluorescence), was statistically examined by analysis of variance and the Tukey test. RESULTS: The control group (-10.48+/ 2.85) was statistically similar to Group C (-14.52+/-7.80), which presented the lowest values of DeltaF when compared with Groups FC (-3.67+/-3.21), L (-2.79+/ 1.68), CL (-1.05+/-0:50), and CFL (-0.60+/-0:43). However, Groups FC, L, CL, and CFL showed no statistically significant differences among them. CONCLUSIONS: It can be concluded that both the low-level infrared laser and photoabsorbing cream with fluoride were effective in inhibiting the development of caries in enamel around orthodontic brackets, even in situations of high cariogenic challenge. PMID- 25496085 TI - Effect of low-level laser therapy in reducing dentinal hypersensitivity and pain following periodontal flap surgery. AB - OBJECTIVE: This randomized controlled double-blinded split mouth study sought to compare the levels of dentinal hypersensitivity (DH) and pain after 660 nm laser irradiation in test and control sites following periodontal flap surgery. BACKGROUND DATA: Dentinal hypersensitivity and pain are the two main causes of discomfort after periodontal flap surgery. The analgesic and desensitising property of low-level lasers can be used to reduce postoperative complications following periodontal flap surgery. MATERIALS AND METHODS: Thirty patients were enrolled in this study. Periodontal flap surgery was performed on 60 sites. The test site was randomly determined for laser irradiation, and was irradiated by a sweeping motion of 660 nm laser (25 mW, 4.5 J) for 3 min for 3 consecutive days. The control site served as a placebo. Although the laser was used in a similar motion in the control sites, it was not activated postoperatively. A visual analogue scale (VAS) and verbal rating scale (VRS) for pain and DH were recorded for both sites in each patient, on the 1st, 3rd, 5th, and 7th days following flap surgery. RESULTS: There was statistically significant decrease in both DH and pain in the laser-irradiated site on the 7th day following periodontal flap surgery, as compared with the control site (p<0.05). CONCLUSIONS: Postoperative DH and pain following periodontal surgery can be reduced by using low-level laser therapy. PMID- 25496086 TI - A systematic review and evaluation of measures for suicidal ideation and behaviors in population-based research. AB - The use of measures of suicidal ideation and behavior with sound measurement properties is critical in identifying people most at risk of suicide. In particular, brief self-report measures of suicidal ideation and behaviors are needed for use in large-scale population-based research and in the development and evaluation of suicide prevention programs in the community. This review aimed to identify and recommend psychometrically sound self-report measures of suicidal ideation and behaviors that could be used in population-based research of adults. To identify existing self-report measures for adult use, a systematic search was conducted using MEDLINE (Medical Literature Analysis and Retrieval System Online) and PsycINFO (Psychological Information Database) databases. Abstracts, reference lists, and previous review papers were screened. Once measures were identified, we used a hierarchical criterion-based approach to assess their utility, psychometric properties, and appropriateness for population-based research. Nineteen measures were evaluated against 6 criteria. Three brief measures that met all criteria of the evaluation and demonstrated adequate psychometric properties were the Depressive Symptom Index Suicidality Subscale (DSI-SS), Suicidal Behaviors Questionnaire-Revised (SBQ-R), and Suicidal Ideation Attributes Scale (SIDAS). None of the comprehensive measures met all criteria for use in population-based studies, due to financial costs imposed on use, although the Beck Scale for Suicide Ideation (BSSI) and the Adult Suicidal Ideation Questionnaire (ASIQ) had considerable evidence of psychometric robustness. Suicide researchers are encouraged to further establish the validity of scores on these measures across diverse adult populations. PMID- 25496087 TI - Defining early positive response to psychotherapy: An empirical comparison between clinically significant change criteria and growth mixture modeling. AB - Several different approaches have been applied to identify early positive change in response to psychotherapy so as to predict later treatment outcome and length as well as use this information for outcome monitoring and treatment planning. In this study, simple methods based on clinically significant change criteria and computationally demanding growth mixture modeling (GMM) are compared with regard to their overlap and uniqueness as well as their characteristics in terms of initial impairment, therapy outcome, and treatment length. The GMM approach identified a highly specific subgroup of early improving patients. These patients were characterized by higher average intake impairments and higher pre- to posttreatment score differences. Although being more specific for the prediction of treatment success, GMM was much less sensitive than clinically significant and reliable change criteria. There were no differences between the groups with regard to treatment length. Because each of the approaches had specific advantages, results suggest a combination of both methods for practical use in routine outcome monitoring and treatment planning. PMID- 25496088 TI - Predictive validity of the Short-Term Assessment of Risk and Treatability for violent behavior in outpatient forensic psychiatric patients. AB - It remains unclear whether prediction of violence based on historical factors can be improved by adding dynamic risks, protective strengths, selection of person specific key strengths or critical vulnerabilities, and structured professional judgment (SPJ). We examine this in outpatient forensic psychiatry with the Short Term Assessment of Risk and Treatability (START) at 3 and 6 months follow-up. An incident occurred during 33 (13%) out of 252 3-month and 44 (21%) out of 211 6 month follow-up periods (n = 188 unique clients). Pearson correlations for all predictor variables were in the expected directions. Prediction of recidivism based on historical factor ratings (odds ratio [OR] = 1.10) could not be improved through the addition of dynamic risk, protective strength, or key or critical factor scores (all ORs ns). The addition of the SPJ improved the model to modest accuracy (area under the curve [AUC] = .64) but made no independent significant contribution (OR = 1.55, p = .21) for the 3-month follow-up. For the 6-month follow-up, SPJ scores also increased predictive accuracy to modest (AUC = .67) and made a significant independent contribution to the prediction of the outcome (OR = 1.98, p = .04). Multicollinearity limits were unviolated. Limitations apply, however, results are similar to those from clinical, researcher rated samples and are discussed in the light of setting specific characteristics. Although it is too early to advocate implementing risk assessment instruments in clinical practice, we can conclude that clinicians in a heterogeneous outpatient forensic psychiatric setting can achieve similar results with the START as clinicians and research staff in more homogeneous inpatient settings. PMID- 25496089 TI - Genetic associations of Nrf2-encoding NFE2L2 variants with Parkinson's disease - a multicenter study. AB - BACKGROUND: The transcription factor Nrf2, encoded by the NFE2L2 gene, is an important regulator of the cellular protection against oxidative stress. Parkinson's disease is a neurodegenerative disease highly associated with oxidative stress. In a previously published study, we reported associations of NFE2L2 haplotypes with risk and age at onset of idiopathic Parkinson's disease in a Swedish discovery material and a Polish replication material. Here, we have extended the replication study and performed meta-analyses including the Polish material and four new independent European patient-control materials. Furthermore, all SNPs included in the haplotype windows were investigated individually for associations with Parkinson's disease in meta-analyses including all six materials. METHODS: Totally 1038 patients and 1600 control subjects were studied. Based on previous NFE2L2 haplotype associations with Parkinson's disease, five NFE2L2 tag SNPs were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. The impact of individual SNPs and haplotypes on risk and age at onset of Parkinson's disease were investigated in each material individually and in meta-analyses of the obtained results. RESULTS: Meta-analyses of NFE2L2 haplotypes showed association of haplotype GAGCAAAA, including the fully functional promoter haplotype AGC, with decreased risk (OR = 0.8 per allele, p = 0.012) and delayed onset (+1.1 years per allele, p = 0.048) of Parkinson's disease. These results support the previously observed protective effect of this haplotype in the first study. Further, meta-analyses of the SNPs included in the haplotypes revealed four NFE2L2 SNPs associated with age at onset of Parkinson's disease (rs7557529 G > A, -1.0 years per allele, p = 0.042; rs35652124 A > G, -1.1 years per allele, p = 0.045; rs2886161 A > G, -1.2 years per allele, p = 0.021; rs1806649 G > A, +1.2 years per allele, p = 0.029). One of these (rs35652124) is a functional SNP located in the NFE2L2 promoter. No individual SNP was associated with risk of Parkinson's disease. CONCLUSION: Our results support the hypothesis that variation in the NFE2L2 gene, encoding a central protein in the cellular protection against oxidative stress, may contribute to the pathogenesis of Parkinson's disease. Functional studies are now needed to explore these results further. PMID- 25496090 TI - Cooling water before panicle initiation increases chilling-induced male sterility and disables chilling-induced expression of genes encoding OsFKBP65 and heat shock proteins in rice spikelets. AB - In rice (Oryza sativa L.), chilling-induced male sterility increased when plants experienced low water temperature (Tw , 18 degrees C for 14 d) before panicle initiation. The number of mature pollen grains after chilling at the booting stage (12 degrees C for 5 d) was only 45% of total pollen grains in low-Tw plants, whereas it was 71% in normal-Tw plants (Tw not controlled; approximately 23 degrees C under air temperature of 26 degrees C/21 degrees C, day/night). Microarray and quantitative PCR analyses showed that many stress-responsive genes (including OsFKBP65 and genes encoding the large heat shock protein OsHSP90.1, heat-stress transcription factors and many small heat shock proteins) were strongly up-regulated by chilling in normal-Tw spikelets, but were unaffected or even down-regulated by chilling in low-Tw spikelets. OsAPX2 and genes encoding some other antioxidant enzymes were also significantly down-regulated by low Tw in chilled spikelets. The levels of lipid peroxidation products (malondialdehyde equivalents) were significantly increased in low-Tw spikelets by chilling. Ascorbate peroxidase activity in chilled spikelets was significantly lower in low Tw plants than in normal-Tw plants. Our data suggest that an OsFKBP65-related chilling response, which protects proteins from oxidative damage, is indispensable for chilling tolerance but is lost in low-Tw spikelets. PMID- 25496091 TI - Overexpression of SpWRKY1 promotes resistance to Phytophthora nicotianae and tolerance to salt and drought stress in transgenic tobacco. AB - WRKY transcription factors are key regulatory components of plant responses to biotic and abiotic stresses. SpWRKY1, a pathogen-induced WRKY gene, was isolated from tomato (Solanum pimpinellifolium L3708) using in silico cloning and reverse transcriptase-polymerase chain reaction (RT-PCR) methods. SpWRKY1 expression was significantly induced following oomycete pathogen infection and treatment with salt, drought, salicylic acid (SA), methyl jasmonate (MeJA) and abscisic acid (ABA). Overexpression of SpWRKY1 in tobacco conferred greater resistance to Phytophthora nicotianae infection, as evidenced by lower malondialdehyde (MDA) content; relative electrolyte leakage (REL); higher chlorophyll content; and higher peroxidase (POD, EC 1.11.1.7), superoxide dismutase (SOD, EC 1.15.1.1) and phenylalanine ammonia-lyase (PAL, EC 4.3.1.24) activities. This resistance was also coupled with enhanced expression of SA- and JA-associated genes (NtPR1, NtPR2, NtPR4, NtPR5 and NtPDF1.2), as well as of various defense-related genes (NtPOD, NtSOD and NtPAL). In addition, transgenic tobacco plants also displayed an enhanced tolerance to salt and drought stresses, mainly demonstrated by the transgenic lines exhibiting lower accumulation of MDA content and higher POD (EC 1.11.1.7), SOD (EC 1.15.1.1) activities, chlorophyll content, photosynthetic rate and stomatal conductance, accompanied by enhanced expression of defense-related genes (NtPOD, NtSOD, NtLEA5, NtP5CS and NtNCED1) under salt and drought stresses. Overall, these findings suggest that SpWRKY1 acts as a positive regulator involved in tobacco defense responses to biotic and abiotic stresses. PMID- 25496092 TI - Clinical validity of the estimated energy requirement and the average protein requirement for nutritional status change and wound healing in older patients with pressure ulcers: A multicenter prospective cohort study. AB - AIM: Adequate nutritional intake is essential for pressure ulcer healing. Recently, the estimated energy requirement (30 kcal/kg) and the average protein requirement (0.95 g/kg) necessary to maintain metabolic balance have been reported. The purpose was to evaluate the clinical validity of these requirements in older hospitalized patients with pressure ulcers by assessing nutritional status and wound healing. METHODS: This multicenter prospective study carried out as a secondary analysis of a clinical trial included 194 patients with pressure ulcers aged >=65 years from 29 institutions. Nutritional status including anthropometry and biochemical tests, and wound status by a structured severity tool, were evaluated over 3 weeks. Energy and protein intake were determined from medical records on a typical day and dichotomized by meeting the estimated average requirement. Longitudinal data were analyzed with a multivariate mixed effects model. RESULTS: Meeting the energy requirement was associated with changes in weight (P < 0.001), arm muscle circumference (P = 0.003) and serum albumin level (P = 0.016). Meeting the protein requirement was associated with changes in weight (P < 0.001) and serum albumin level (P = 0.043). These markers decreased in patients who did not meet the requirement, but were stable or increased in those who did. Energy and protein intake were associated with wound healing for deep ulcers (P = 0.013 for both), improving exudates and necrotic tissue, but not for superficial ulcers. CONCLUSIONS: Estimated energy requirement and average protein requirement were clinically validated for prevention of nutritional decline and of impaired healing of deep pressure ulcers. PMID- 25496093 TI - A liver mass in a case of gastrointestinal stromal tumour of the stomach is not always a metastasis. PMID- 25496094 TI - Cellular iron homeostasis and therapeutic implications of iron chelators in cancer. AB - Iron metabolism and homeostasis are imperative for the maintenance of normal physiological activities due to the element's critical involvement in a wide variety of crucial biological processes like cellular respiration, metabolic pathways, DNA replication, repair, detoxification, neurotransmission and cellular signaling. Being a key contributor of crucial machineries regulating cellular proliferation and survival, it facilitates the process of tumor growth and development. Thus, tumor cells strive to acquire higher amount of iron than non malignant cells to satisfy their elevated rate of metabolism. Perhaps, not surprisingly chelation of this metal ion was thought to be effective in treating cancer, but due to a variety of side effects, the use of iron chelators was clinically insignificant. However, discovery of various new classes of iron chelators with lesser side effects and selective toxicity towards cancer cells has revived the possibilities of using iron chelators in anti-cancer therapy. In this review, we have discussed the role of iron in promoting malignant mechanisms and the prospects of usage of different classes of iron chelators in cancer therapeutics. PMID- 25496095 TI - Time to pass the baton. PMID- 25496096 TI - Stochastic age-related epigenetic drift in the pathogenesis of idiopathic pulmonary fibrosis. PMID- 25496097 TI - Transfusion-induced lung endothelial injury: a DAMP death? PMID- 25496098 TI - Chronic sirolimus therapy for lymphangioleiomyomatosis. PMID- 25496099 TI - Bridging the gap: merging clinical and inflammatory phenotypes with epithelial gene expression profiles in asthma. PMID- 25496101 TI - Fibrocytes and progression of fibrotic lung disease. Ready for showtime? PMID- 25496100 TI - Interleukin-33: a potential link between rhinovirus infections and asthma exacerbation. PMID- 25496102 TI - Live and let die: targeting alveolar epithelial cell proliferation in pulmonary fibrosis. PMID- 25496103 TI - An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults. AB - RATIONALE: Profound muscle weakness during and after critical illness is termed intensive care unit-acquired weakness (ICUAW). OBJECTIVES: To develop diagnostic recommendations for ICUAW. METHODS: A multidisciplinary expert committee generated diagnostic questions. A systematic review was performed, and recommendations were developed using the Grading, Recommendations, Assessment, Development, and Evaluation (GRADE) approach. MEASUREMENT AND MAIN RESULTS: Severe sepsis, difficult ventilator liberation, and prolonged mechanical ventilation are associated with ICUAW. Physical rehabilitation improves outcomes in heterogeneous populations of ICU patients. Because it may not be feasible to provide universal physical rehabilitation, an alternative approach is to identify patients most likely to benefit. Patients with ICUAW may be such a group. Our review identified only one case series of patients with ICUAW who received physical therapy. When compared with a case series of patients with ICUAW who did not receive structured physical therapy, evidence suggested those who receive physical rehabilitation were more frequently discharged home rather than to a rehabilitative facility, although confidence intervals included no difference. Other interventions show promise, but fewer data proving patient benefit existed, thus precluding specific comment. Additionally, prior comorbidity was insufficiently defined to determine its influence on outcome, treatment response, or patient preferences for diagnostic efforts. We recommend controlled clinical trials in patients with ICUAW that compare physical rehabilitation with usual care and further research in understanding risk and patient preferences. CONCLUSIONS: Research that identifies treatments that benefit patients with ICUAW is necessary to determine whether the benefits of diagnostic testing for ICUAW outweigh its burdens. PMID- 25496104 TI - Cavitary lung nodules in a patient with prior squamous cell carcinoma of the submandibular gland. PMID- 25496105 TI - Using exhaled nitric oxide and serum periostin as a composite marker to identify severe/steroid-insensitive asthma. PMID- 25496106 TI - Reduction of airway smooth muscle mass by bronchial thermoplasty in patients with severe asthma. PMID- 25496107 TI - The in vivo environment accelerates generation of resuscitation-promoting factor dependent mycobacteria. PMID- 25496108 TI - Caffeine therapy for apnea of prematurity: long-term effect on sleep by actigraphy and polysomnography. PMID- 25496109 TI - Reply: caffeine therapy for apnea of prematurity: long-term effect on sleep by actigraphy and polysomnography. PMID- 25496110 TI - Pulmonary artery intimal sarcoma. PMID- 25496111 TI - Catamenial hemothorax in a patient with multiple sclerosis. PMID- 25496112 TI - Insomnia. PMID- 25496113 TI - Investigating drug-target association and dissociation mechanisms using metadynamics-based algorithms. AB - CONSPECTUS: This Account highlights recent advances and discusses major challenges in the field of drug-target recognition, binding, and unbinding studied using metadynamics-based approaches, with particular emphasis on their role in structure-based design. Computational chemistry has significantly contributed to drug design and optimization in an extremely broad range of areas, including prediction of target druggability and drug likeness, de novo design, fragment screening, ligand docking, estimation of binding affinity, and modulation of ADMET (absorption, distribution, metabolism, excretion, toxicity) properties. Computationally driven drug discovery must continuously adapt to keep pace with the evolving knowledge of the factors that modulate the pharmacological action of drugs. There is thus an urgent need for novel computational approaches that integrate the vast amount of complex information currently available for small (bio)organic compounds, biologically relevant targets and their complexes, while also accounting accurately for the thermodynamics and kinetics of drug target association, the intrinsic dynamical behavior of biomolecular systems, and the complexity of protein-protein networks. Understanding the mechanism of drug binding to and unbinding from biological targets is fundamental for optimizing lead compounds and designing novel biologically active ones. One major challenge is the accurate description of the conformational complexity prior to and upon formation of drug-target complexes. Recently, enhanced sampling methods, including metadynamics and related approaches, have been successfully applied to investigate complex mechanisms of drugs binding to flexible targets. Metadynamics is a family of enhanced sampling techniques aimed at enhancing the rare events and reconstructing the underlying free energy landscape as a function of a set of order parameters, usually referred to as collective variables. Studies of drug binding mechanisms have predicted the most probable association and dissociation pathways and the related binding free energy profile. In addition, the availability of an efficient open-source implementation, running on cost effective GPU (i.e., graphical processor unit) architectures, has considerably decreased the learning curve and the computational costs of the methods, and increased their adoption by the community. Here, we review the recent contributions of metadynamics and other enhanced sampling methods to the field of drug-target recognition and binding. We discuss how metadynamics has been used to search for transition states, to predict binding and unbinding paths, to treat conformational flexibility, and to compute free energy profiles. We highlight the importance of such predictions in drug discovery. Major challenges in the field and possible solutions will finally be discussed. PMID- 25496114 TI - Cognitive function and endogenous cytokine levels in children with chronic hepatitis C. AB - Little is known about how hepatitis C (HCV) infection affects cognitive function in children. The aim of the study was to assess the impact of HCV infection on cognitive function of children with normal liver functions and their relationships to endogenous IFN-alpha, IL-6 and TNF-alpha. IFN-alpha, IL-6 and TNF-alpha were measured and the Arabic version of the Stanford-Binet test used to assess cognitive functions in 35 children with HCV infection and 23 controls. Serum levels of IL-6 and IFN-alpha were significantly higher in patients compared to controls. There was a significant effect on vocabulary, comprehension, and abstract visual reasoning, quantitative reasoning and bead memory tests, as well as total short-term memory and intelligence quotient in patients compared to controls. There was a significant positive correlation between IFN-alpha and IL 6. Also there were significant negative correlations between IFN-alpha and Abstract visual reasoning test, Quantitative reasoning test, Bead memory test, Total short-term memory and Intelligence quotient; and between IL-6 and Abstract visual reasoning test, Quantitative reasoning test and Intelligence quotient. There was no significant correlation between TNF-alpha and any of the cognitive functions. Cytokine levels were not related to demographic characteristics of the patients or viral load (PCR). Children with chronic hepatitis C infection in its early stages showed signs of cognitive impairment, with the memory tasks being mostly affected. There was a significant correlation between endogenous cytokines and cognitive impairment in these children. Further studies are needed to define the effect of successful antiviral treatment. PMID- 25496116 TI - Surface catalyzed oxidative oligomerization of 17beta-estradiol by Fe(3+) saturated montmorillonite. AB - With widespread detection of endocrine disrupting compounds including hormones in wastewater, there is a need to develop cost-effective remediation technologies for their removal from wastewater. Previous research has shown that Fe(3+) saturated montmorillonite is effective in quickly transforming phenolic organic compounds such as pentachlorophenol, phenolic acids, and triclosan via surface catalyzed oligomerization. However, little is known about its effectiveness and reaction mechanisms when reacting with hormones. In this study, the reaction kinetics of Fe(3+)-saturated montmorillonite catalyzed 17beta-estradiol (betaE2) transformation was investigated. The transformation products were identified using liquid chromatography coupled with mass spectrometry, and their structures were further confirmed using computational approach. Rapid betaE2 transformation in the presence of Fe(3+)-saturated montmorillonite in an aqueous system was detected. The disappearance of betaE2 follows first-order kinetics, while the overall catalytic reaction follows the second-order kinetics with an estimated reaction rate constant of 200 +/- 24 (mmol betaE2/g mineral)(-1) h(-1). The half life of betaE2 in this system was estimated to be 0.50 +/- 0.06 h. betaE2 oligomers were found to be the major products of betaE2 transformation when exposed to Fe(3+)-saturated montmorillonite. About 98% of betaE2 were transformed into betaE2 oligomers which are >10(7) times less water-soluble than betaE2 and, therefore, are much less bioavailable and mobile then betaE2. The formed oligomers quickly settled from the aqueous phase and were not accumulated on the reaction sites of the interlayer surfaces of Fe(3+)-saturated montmorillonite, the major reason for the observed >84% betaE2 removal efficiency even after five consecutive usages of the same of Fe(3+)-saturated montmorillonite. The results from this study clearly demonstrated that Fe(3+)-saturated montmorillonite has a great potential to be used as a cost-effective material for efficient removal of phenolic organic compounds from wastewater. PMID- 25496117 TI - Systematic review: the management of hepatic cyst infection. AB - BACKGROUND: Cyst infection is a severe complication of hepatic cystic disease. However, an evidence-based treatment strategy is not available. AIM: To assess the available treatment strategies and provide a treatment advice for de novo hepatic cyst infection. METHODS: We systematically searched PubMed (1948-2014), EMBASE (1974-2014), and the Cochrane Library (until 2014) for studies involving humans (>=18 years) treated for a hepatic cyst infection. We extracted data on patient characteristics, treatment and follow-up. RESULTS: We identified 41 articles; all were case series or case reports, implicating a high risk of bias. We included 54 hepatic cyst infection cases (male 39%; mean age 63 +/- 12 years; diabetes 6%; dialysis 19%; transplant recipients 30%). Initial therapy consisted of antimicrobial (56%), percutaneous (31%) or surgical treatment (13%). We identified 42 antimicrobial regimens consisting of 23 different combinations. Most used antibiotic classes were quinolones (34%) and cephalosporins (34%). Antimicrobials failed in 70% of cases, eventually requiring percutaneous or surgical treatment in, respectively, 37% and 27%. Recurrent hepatic cyst infection was frequent (20%). Median time to recurrence was 8 weeks (IQR 3-24 weeks). In 46%, recurrence occurred in renal transplant recipients. Cyst infection related deaths occurred in 9%, of whom 40% were on dialysis. CONCLUSIONS: The literature shows that treatment of hepatic cyst infection is highly heterogeneous. We recommend first line treatment with oral ciprofloxacin. In case of failure, percutaneous cyst drainage needs to be considered. PMID- 25496118 TI - Fabrication of novel nitrogen-doped graphene-hollow AuPd nanoparticle hybrid films for the highly efficient electrocatalytic reduction of H2O2. AB - Hollow AuPd (hAuPd) alloy nanoparticles (NPs) were prepared through simultaneous reduction of HAuCl4 and Na2PdCl4 using Co NPs as sacrificial template (i.e., reductant). Then, the hAuPd NPs were assembled on nitrogen-doped graphene (NG) to prepare an NG-hAuPd hybrid film. The obtained NG-hAuPd composite showed higher electrocatalytic activity toward the reduction of H2O2, compared with graphene hAuPd hybrid, NG-solid AuPd hybrid, and hAuPd NPs. The enhanced performance was related to the hollow structure of hAuPd NPs and the synergistic effect between NG and hAuPd NPs. Under optimum conditions, the NG-hAuPd hybrid film showed a linear response to H2O2 in the range of 0.1-20 MUM, with a sensitivity of 5095.5 MUA mM(-1) cm(-2)and a comparable detection limit of 0.02 MUM (S/N = 3). These results demonstrated that the NG-hAuPd composite was a promising electrocatalytic material for constructing sensors, etc. PMID- 25496115 TI - ERRbeta splice variants differentially regulate cell cycle progression. AB - Orphan receptors comprise nearly half of all members of the nuclear receptor superfamily. Despite having broad structural similarities to the classical estrogen receptors, estrogen-related receptors (ERRs) have their own unique DNA response elements and functions. In this study, we focus on 2 ERRbeta splice variants, short form ERRbeta (ERRbetasf) and ERRbeta2, and identify their differing roles in cell cycle regulation. Using DY131 (a synthetic agonist of ERRbeta), splice-variant selective shRNA, and exogenous ERRbetasf and ERRbeta2 cDNAs, we demonstrate the role of ERRbetasf in mediating the G1 checkpoint through p21. We also show ERRbetasf is required for DY131-induced cellular senescence. A key novel finding of this study is that ERRbeta2 can mediate a G2/M arrest in response to DY131. In the absence of ERRbeta2, the DY131-induced G2/M arrest is reversed, and this is accompanied by p21 induction and a G1 arrest. This study illustrates novel functions for ERRbeta splice variants and provides evidence for splice variant interaction. PMID- 25496121 TI - What is Ebola? AB - On 23 March 2014, the World Health Organization first announced a new Ebola virus outbreak that started in December 2013 in the eastern part of the Republic of Guinea. Human infections shortly emerged in Liberia, Sierra Leone, and Nigeria. On 30 September 2014, the Centers for Disease Control and Prevention confirmed through laboratory testing the first Ebola virus infection diagnosed in the USA, in a patient who travelled from West Africa to Texas. On 6 October 2014, the first human infection occurring outside of Africa was reported, in a Spanish nurse who treated two priests, both of whom died, and on 23 October 2014, the first human infection was reported in New York City. To date, the 2014 Ebola virus outbreak is the longest, largest, and most persistent one since 1976, when the virus was first identified in humans, and the number of human cases exceeded, as of mid-September 2014, the cumulative number of infections from all the previous outbreaks. The early clinical presentation overlaps with other infectious diseases, opening differential diagnosis difficulties. Understanding the transmission routes and identifying the natural reservoir of the virus are additional challenges in studying Ebola hemorrhagic fever outbreaks. Ebola virus is as much a public health challenge for developing countries as it is for the developed world, and previous outbreaks underscored that the relative contribution of the risk factors may differ among outbreaks. The implementation of effective preparedness plans is contingent on integrating teachings from previous Ebola virus outbreaks with those from the current outbreak and with lessons provided by other infectious diseases, along with developing a multifaceted inter-disciplinary and cross-disciplinary framework that should be established and shaped by biomedical as well as sociopolitical sciences. PMID- 25496119 TI - Therapeutic potential of human embryonic stem cell transplantation in patients with cerebral palsy. AB - BACKGROUND: The present study evaluated the efficacy and safety of human embryonic stem cell (hESC) therapy in patients with CP. MATERIALS AND METHODS: This analysis included patients (30 days-18 yr) with documented diagnosis of CP. The study consisted of four treatment phases (T1, T2, T3, T4) separated by gap phases. Efficacy of hESC therapy was evaluated based on Gross Motor Function Classification Scores Expanded and Revised (GMFCS-E & R; 1-good to 5-bad). RESULTS: Ninety one patients were included and all received hESC therapy in T1, 66 patients returned for T2, 38 patients for T3, and 15 patients for T4. Overall, 30.2% patients achieved GMFCS-E & R score 1 during the study with different number of patients achieving GMFCS score 1 by the end of each treatment phase (T1: 6 [6.6%]; T2: 7 [10.6%]; T3: 11 [28.9%]; and T4: 5 [33.3%]). All patients in up to 2 yr (n = 10), 2-4 yr (n = 10), 4-6 yr (n = 9), and 6-12 yr (n = 8) age groups except one of the 5 patients in the age group of 12-18 yr transitioned from GMFCS-E & R score 5 to lower scores by end of T1. Most patients transitioned to GMFCS-E & R score 2 (n = 34) from higher scores by end of T2. Eleven patients achieved GMFCS-E & R score 1 by end of T3. No serious adverse events were observed. CONCLUSION: Use of hESC therapy in patients with CP is effective and safe. hESC therapy has demonstrated significant improvement in GMFCS-E & R scale. PMID- 25496120 TI - Development of a family physician impact assessment tool in the district health system of the Western Cape Province, South Africa. AB - BACKGROUND: Policy makers in Africa are ambivalent about the need for family physicians to strengthen district health services. Evidence on the impact of family physicians is therefore needed. The aim was to develop a tool to evaluate the impact of family physicians on district health services according to the six expected roles that have been defined nationally. METHODS: Mixed methods were used to develop, validate, pilot and test the reliability of the tool in the Western Cape Province, South Africa. An expert panel validated the content and construction of the tool. The tool was piloted by 94 respondents who evaluated eight family physicians. Cronbach alpha scores were calculated to test the reliability of the tool. The impact of these family physicians in the pilot study was also analysed. RESULTS: A draft tool was successfully developed, validated, and proved reliable (Cronbach alpha >0.8). The overall scores (scale of 1-4) were: Care provider = 3.5, Consultant = 3.4, Leader and champion of clinical governance = 3.4, Capacity builder = 3.3, Clinical trainer and supervisor = 3.2 and Champion of community-orientated primary care (COPC) = 3.1. The impact on COPC was significantly less than the impact of other roles (p < 0.05). CONCLUSION: The Family Physician Impact Evaluation Tool can be used to measure the impact of family physicians in South Africa. The pilot study shows that the family physicians are having most impact in terms of clinical care and clinical governance, and a lesser impact in terms of clinical training, capacity-building and especially COPC. PMID- 25496122 TI - A rare variant of type I truncus arteriosus: truncus arteriosus with anterior origin of a main pulmonary artery. PMID- 25496123 TI - Low molecular weight heparin modulates maternal immune response in pregnant women and mice with thrombophilia. AB - PROBLEM: Thrombophilia is associated with pregnancy complications. Treatment with low molecular weight heparin (LMWH) improves pregnancy outcome, but the underlying mechanisms are not clear. METHODS OF STUDY: We analyzed Treg frequency in blood from thrombophilic pregnancies treated with LMWH (n = 32) or untreated (n = 33) and from healthy pregnancies (n = 39) at all trimesters. Additionally, we treated pregnant wild-type, heterozygous and homozygous factor-V-Leiden (FVL) mice with LMWH or PBS and determined Treg frequency, pro-/anti-inflammatory cytokine levels and Caspase-3-activity in placenta and decidua. RESULTS: Treg frequencies were increased in second and third trimester in LMWH-treated thrombophilic pregnancies compared to controls. Treg levels were comparable to those of normal pregnancies. Homozygous FVL mice had decreased decidual Tregs compared to wild-type mice. LMWH treatment normalized Tregs and was associated with increased decidual IL-10 mRNA. LMWH diminished Caspase-3-activity in mice of all genotypes. CONCLUSION: We demonstrated anti-apoptotic and anti-inflammatory effects of LMWH in pregnant FVL mice. LMWH increased Treg levels in mice and humans, which suggests benefits of LMWH treatment for thrombophilic women during pregnancy. PMID- 25496124 TI - Electronic effects of ligand substitution on spin crossover in a series of diiminoquinonoid-bridged Fe(II)2 complexes. AB - A series of four isostructural Fe(II)2 complexes, [(TPyA)2Fe2((X)L)](2+) (TPyA = tris(2-pyridylmethyl)amine; (X)L(2-) = doubly deprotonated form of 3,6 disubstituted-2,5-dianilino-1,4-benzoquinone; X = H, Br, Cl, and F), were synthesized to enable a systematic study of electronic effects on spin crossover behavior. Comparison of X-ray diffraction data for these complexes reveals the sole presence of high-spin Fe(II) at 225 K and mixtures of high-spin and low-spin Fe(II) at 100 K, which is indicative of incomplete spin crossover. In addition, crystal packing diagrams show that these complexes are well-isolated from one another in the solid state, owing primarily to the presence of bulky tetra(aryl)borate counteranions, such that spin crossover is likely not significantly affected by intermolecular interactions. Variable-temperature dc magnetic susceptibility data confirm the structural observations and reveal that 54(1), 56(1), 62(1), and 84(1)% of Fe(II) centers remain high-spin even below 65 K. Moreover, fits to magnetic data provide crossover temperatures of T1/2 = 160(1), 124(1), 121(1), and 110(1) K for X = H, Br, Cl, and F, respectively, along with enthalpies of DeltaH = 11.4(3), 8.5(3), 8.3(3), and 7.5(2) kJ/mol, respectively. These parameters decrease with increasing electronegativity of X and thus increasing electron-withdrawing character of (X)L(2-), suggesting that the observed trends originate primarily from inductive effects of X. Moreover, when plotted as a function of the Pauling electronegativity of X, both T1/2 and DeltaH undergo a linear decrease. Further analyses of the low-temperature magnetic data and variable-temperature Mossbauer spectroscopy suggest that the incomplete spin crossover behavior in [(TPyA)2Fe2((X)L)](2+) is best described as a transition from purely [FeHS-FeHS] (HS = high-spin) complexes at high temperature to a mixture of [FeHS-FeHS] and [FeHS-FeLS] (LS = low-spin) complexes at low temperature, with the number of [FeHS-FeHS] species increasing with decreasing electron-withdrawing character of (X)L(2-). PMID- 25496126 TI - Kiwi: a tool for integration and visualization of network topology and gene-set analysis. AB - BACKGROUND: The analysis of high-throughput data in biology is aided by integrative approaches such as gene-set analysis. Gene-sets can represent well defined biological entities (e.g. metabolites) that interact in networks (e.g. metabolic networks), to exert their function within the cell. Data interpretation can benefit from incorporating the underlying network, but there are currently no optimal methods that link gene-set analysis and network structures. RESULTS: Here we present Kiwi, a new tool that processes output data from gene-set analysis and integrates them with a network structure such that the inherent connectivity between gene-sets, i.e. not simply the gene overlap, becomes apparent. In two case studies, we demonstrate that standard gene-set analysis points at metabolites regulated in the interrogated condition. Nevertheless, only the integration of the interactions between these metabolites provides an extra layer of information that highlights how they are tightly connected in the metabolic network. CONCLUSIONS: Kiwi is a tool that enhances interpretability of high throughput data. It allows the users not only to discover a list of significant entities or processes as in gene-set analysis, but also to visualize whether these entities or processes are isolated or connected by means of their biological interaction. Kiwi is available as a Python package at http://www.sysbio.se/kiwi and an online tool in the BioMet Toolbox at http://www.biomet-toolbox.org. PMID- 25496125 TI - Overexpression of miR-21-5p as a predictive marker for complete tumor regression to neoadjuvant chemoradiotherapy in rectal cancer patients. AB - BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by radical surgery is the preferred treatment strategy for locally advanced rectal cancer. However, complete tumor regression is observed in a significant proportion of patients after nCRT, making them ideal candidates for alternative treatment strategies to this considerably morbid procedure. Identification of such patients based on clinical findings (complete clinical response - cCR) is difficult mainly because it relies on subjective clinical and imaging studies. Our goal was to identify biomarkers capable of predicting complete response to nCRT. METHODS: We analyzed miRNA expression profile using deep sequencing in rectal tumor biopsies prior to nCRT. Differential expression was investigated by EdgeR for a training (n = 27) and a validation (n = 16) set of patients to identify miRNAs associated with treatment response (complete vs. incomplete). In vitro experiments with two cancer cell lines were also performed in order to evaluate the possible role of miRNAs on response to nCRT. RESULTS: We found 4 miRNAs differentially expressed between complete and incomplete responders to nCRT. In addition, validation was performed using an independent group of patients and miR-21-5p was confirmed as being overexpressed in complete responders. Overall sensitivity and specificity of miR-21-5p expression in predicting complete response to nCRT was 78% and 86% respectively. Interestingly, in a subset of patients with cCR followed by early local recurrence, the expression level of miR-21-5p was considerably low, similarly to incomplete responders. We also found SATB1, a miR-21-5p target gene and known multidrug resistance gene, whose expression was inversely correlated with miR-21-5p expression. Finally, we performed functional experiments and showed that miR-21-5p and SATB1 may be directly involved with poor response to nCRT in rectal cancer patients. CONCLUSIONS: This study suggests miR-21-5p as a promising predictive biomarker, which should aid in the selection of patients with cCR to nCRT that potentially could be spared from radical surgery. PMID- 25496127 TI - Synthesis of fused 1-aminoindole polycycles by a sequence of palladium-catalyzed N-H and C(sp2)-H arylations. AB - An efficient Pd-catalyzed selective intramolecular arylation of functionalized N,N'-substituted 1-aminoindoles has been reported. In all cases, the reactions take place rapidly in DMA and efficiently proceed in the presence of a Pd(OAc)2/Dpephos catalytic system, furnishing the fused indolo[2,1-a]phthalazines in high yields. Additionally, the one-pot double C-H arylation at positions C-2 and C-3 of N,N'-substituted 1-aminoindoles is effective and leads to unknown complex scaffolds of biological interest. PMID- 25496128 TI - Ranolazine inhibits NaV1.5-mediated breast cancer cell invasiveness and lung colonization. AB - BACKGROUND: Na(V)1.5 voltage-gated sodium channels are abnormally expressed in breast tumours and their expression level is associated with metastatic occurrence and patients' death. In breast cancer cells, Na(V)1.5 activity promotes the proteolytic degradation of the extracellular matrix and enhances cell invasiveness. FINDINGS: In this study, we showed that the extinction of Na(V)1.5 expression in human breast cancer cells almost completely abrogated lung colonisation in immunodepressed mice (NMRI nude). Furthermore, we demonstrated that ranolazine (50 MUM) inhibited Na(V)1.5 currents in breast cancer cells and reduced Na(V)1.5-related cancer cell invasiveness in vitro. In vivo, the injection of ranolazine (50 mg/kg/day) significantly reduced lung colonisation by Na(V)1.5-expressing human breast cancer cells. CONCLUSIONS: Taken together, our results demonstrate the importance of Na(V)1.5 in the metastatic colonisation of organs by breast cancer cells and indicate that small molecules interfering with Na(V) activity, such as ranolazine, may represent powerful pharmacological tools to inhibit metastatic development and improve cancer treatments. PMID- 25496129 TI - Evaluation of the influence exerted by different dental specialty backgrounds and measuring instrument reproducibility on esthetic aspects of maxillary implant supported single crown. AB - OBJECTIVE: To evaluate the influence exerted by different dental specialty backgrounds as well as the validity and reproducibility of the Pink Esthetic Score/White Esthetic Score (PES/WES) and the modified Implant Crown Aesthetic Index (mod-ICAI) on the assessment of esthetic aspects of maxillary implants supported single-tooth prosthesis. MATERIAL AND METHODS: A total of fourteen examiners (Two orthodontists, two prosthodontists, two oral surgeons, two periodontists, two dental technicians, two dental assistants, and two postgraduate students in Implant Dentistry evaluated 20 photographs of single implant-supported crowns and five photographs of unrestored teeth of esthetic zone in a two part study. The examiners assessed the photographs with each index (Pink Esthetic Score/White Esthetic Score and modified Implant Crown Aesthetic Index), twice with a week's interval. Orders of photographs were rearranged in the second assessment. RESULTS: Kruskal-Wallis test results showed significant differences among all the six specialties (P <= 0.001). DAs and periodontists had significantly better ratings than other specialties with both indices. Prosthodontists had the lowest mean rank scores regardless of the index. Interobserver agreement was also lowest between the two prosthodontists (4-28%), rest of the groups had low-to-moderate agreement (20-80%) when limited allowance was accepted. With mod-ICAI, more interobserver agreement was noted within the specialty group than with PES/WES. CONCLUSIONS: The PES/WES and the modified ICAI can be reliable estimates of esthetic outcomes. The assessor degree of specialization affected the esthetic evaluation with both the PES/WES and the modified ICAI. DAs and periodontists were identified to provide more favorable ratings than other specialties while prosthodontists were most critical in this study. With modified ICAI, more interobserver agreement within specialty resulted. The interexaminer agreement may be increased if more tolerance of 1-2 points is considered. PMID- 25496131 TI - A minute amount of s-puckered sugars is sufficient for (6-4) photoproduct formation at the dinucleotide level. AB - The di-2'-alpha-fluoro analogue of thymidylyl(3',5')thymidine, synthesized to probe the effect of a minimum amount of S conformer on the photoreactivity of dinucleotides, is endowed with only 3% and 8% of S sugar conformation at its 5'- and 3'-end, respectively. This analogue gives rise to the (6-4) photoproduct as efficiently as the dithymine dinucleotide (74% and 66% at the 5'- and 3'-end, respectively) under 254 nm. Our results suggest that the 5'-N, 3'-S conformer gives rise to the (6-4) photoproduct. PMID- 25496132 TI - Physiometabolic responses to road transport in weaned piglets for a short period and the effects of straw bedding. AB - The aim of the study was to evaluate the physiometabolic responses to stress in hybrid suckling piglets that were weaned and transported at different ages on a paved road under two vehicle conditions: with and without a layer of straw bedding. The piglets were weaned and transported at the following ages: 8, 15 and 22 days. The duration of each trip was 1 h. The piglets in each group were further divided into two sub-groups for two distinct experimental transport conditions: (1) over the road with straw bedding; and (2) over the same road but without straw bedding. A total of three repetitions were performed for each experimental condition. In order to assess their responses to weaning- and transport-induced stress, the study evaluated a thorough physiometabolic blood profile. The 8- and 15-day-old piglets transported without straw bedding showed increases in their pCO2, blood glucose, blood lactate levels and the percentage of hematocrit, but a decrease of pO2 upon arrival (P < 0.05). In contrast, the 22 day-old piglets transported on the same road with straw bedding were able to re establish their blood concentrations of lactate, pCO2, pO2, Na+, K+, Ca2+ and pH during the trip (P < 0.05). PMID- 25496130 TI - Chemical composition and biological activity of Rubus idaeus shoots--a traditional herbal remedy of Eastern Europe. AB - BACKGROUND: The young shoots of Rubus idaeus are traditionally used as a herbal remedy in common cold, fever and flu-like infections yet there is no research concerning this plant material. The aim of the study was to evaluate the chemical composition and biological properties of raspberry shoots from 11 cultivar varieties. METHODS: The methanol extracts were subjected to chromatographic analysis using HPLC-DAD-ESI-MS, and two-dimensional 'comprehensive' LCxLC techniques. The biological activity of the shoot extract from the 'Willamette' cultivar variety was evaluated. Antioxidant activity was tested using DPPH and phosphomolybdenum assay. Antimicrobial activity was estimated towards 15 strains of human pathogenic bacteria using broth microdilution method. Cytotoxic activity was tested using MTT cell viability assay. RESULTS: The dominating compounds identified in the shoots of R. idaeus were ellagic acid (26.1 - 106.8 mg/100 g) and sanguiin H-6 (139.2 - 633.1 mg/100 g). The best separation of compounds present in the analysed polyphenol complex, was achieved by 'comprehensive' LCxLC method using Nucleodur Sphinx RP column in the first dimension and Chromolith Performance column in the second dimension. The shoot extract was found to be a strong antioxidant (EC50 19.4 MUg/ml, AAE 427.94 mg/g) and displayed the strongest bactericidal properties towards Corynebacterium diphtheriae. The extract revealed higher cytotoxic activity towards the HL-60 cells (IC50 110 MUg/ml) than HeLa (IC50 300 MUg/ml). CONCLUSIONS: The shoots of R. idaeus stand out as a valuable source of sanguiin H-6 and ellagic acid and possess a number of biological properties including antioxidative, antimicrobial and cytotoxic. PMID- 25496133 TI - Traceless stereoinduction for the enantiopure synthesis of substituted-2 cyclopentenones. AB - The pseudoenantiomeric 4-O-Boc- and 4-OPMP-cyclopent-2-enones, readily available from hydroxymethylenefurane on multigram scale, are demonstrated to be exceptional building blocks for the synthesis of enantiopure 4-alkyl-5-(1' hydroxyalkyl) substituted 2-cyclopentenones and derivatives thereof. The 4-OR substituent acts as a traceless stereoinducing element, conferring not only 1,2- but also 1,4-stereocontrol with excellent selectivity. The methodology developed here was applied for the rapid synthesis of natural products and biologically active 2-cyclopentenones such as TEI-9826, guaianes, and pseudoguaianolides. PMID- 25496135 TI - MCI of different etiologies differ on the Cognitive Assessment Battery. AB - OBJECTIVES: The study aims to investigate whether patients with mild cognitive impairment (MCI) who have significant vascular disease (MCI-vas) differ from those with no significant vascular disease (MCI-nov) in terms of cognitive profile when assessed with the cognitive assessment battery (CAB). MATERIALS AND METHODS: Seventy patients clinically diagnosed with MCI were included in the study, 32 were classified as MCI-vas, and 38 as MCI-nov, together with 40 healthy controls. CAB consists of six short tests measuring speed and attention, memory, visuospatial functions, language, and executive functions. RESULTS: The healthy controls performed better than both MCI groups on CAB. MCI-vas patients were significantly older and had fewer years of education than MCI-nov patients. When adjusted for age and education, MCI-vas performed significantly worse than MCI nov on memory, language, and executive tests. CONCLUSIONS: The results suggest that CAB can differentiate between MCI patients with and without vascular disease and that their cognitive profiles differ. Furthermore, CAB classified the patients as vascular and non-vascular MCI with good sensitivity and specificity. PMID- 25496134 TI - The transcriptional signatures of cells from the human Peyronie's disease plaque and the ability of these cells to generate a plaque in a rat model suggest potential therapeutic targets. AB - INTRODUCTION: The success of medical therapies for Peyronie's disease (PD) has not been optimal, possibly because many of them went directly to clinical application without sufficient preclinical scientific research. Previous studies revealed cellular and molecular pathways involved in the formation of the PD plaque and in particular the role of the myofibroblast. AIMS: The current work aimed to determine under normal and fibrotic conditions what differentiates PD cells from tunica albuginea (TA) and corpora cavernosa (CC) cells by defining their global transcriptional signatures and testing in vivo whether PD cells can generate a PD-like plaque. METHODS: Human TA, PD, and CC cells were grown with transforming growth factor beta 1 (TGFbeta1; TA+, PD+, CC+) or without it (TA-, PD-, CC-) and assayed by (i) immunofluorescence, Western blot and RT-PCR for myofibroblast, smooth muscle cell and stem cell markers; (ii) collagen content; and (iii) DNA microarray analysis. The ability of PD+ cells to induce a PD-like plaque in an immuno-suppressed rat model was assessed by Masson trichrome and Picrosirius Red stainings. MAIN OUTCOMES MEASURES: Fibroproliferative features of PD cells and identification of related key genes as novel targets to reduce plaque size. RESULTS: Upon TGFbeta1stimulation, collagen levels were increased by myofibroblasts in the PD+ but not in the CC+ cells. The transcriptional signature of the PD- cells identified fibroproliferative, myogenic (myofibroblasts), inflammatory, and collagen turnover genes that differentiate them from TA- or CC- cells and respond to TGFbeta1 with a PD+ fibrotic phenotype, by upregulation of IGF-1, ACTG2, MYF5, ACTC1, PSTN, COL III, MMP3, and others. The PD+ cells injected into the TA of the rat induce a PD-like plaque. CONCLUSIONS: This suggests a novel combination therapy to eliminate a PD plaque by targeting the identified genes to (i) improve collagenase action by stimulating endogenous metalloproteinases specific to key collagen types and (ii) counteract fibromatosis by inhibiting myofibroblast generation, proliferation, and/or apoptosis. PMID- 25496136 TI - The genomic landscape of chronic lymphocytic leukaemia: biological and clinical implications. AB - Chronic lymphocytic leukaemia (CLL) remains at the forefront of the genetic analysis of human tumours, principally due its prevalence, protracted natural history and accessibility to suitable material for analysis. With the application of high-throughput genetic technologies, we have an unbridled view of the architecture of the CLL genome, including a comprehensive description of the copy number and mutational landscape of the disease, a detailed picture of clonal evolution during pathogenesis, and the molecular mechanisms that drive genomic instability and therapeutic resistance. This work has nuanced the prognostic importance of established copy number alterations, and identified novel prognostically relevant gene mutations that function within biological pathways that are attractive treatment targets. Herein, an overview of recent genomic discoveries will be reviewed, with associated biological and clinical implications, and a view into how clinical implementation may be facilitated. PMID- 25496137 TI - Toward fundamentals of confined catalysis in carbon nanotubes. AB - An increasing number of experimental studies have demonstrated that metal or metal oxide nanoparticles confined inside carbon nanotubes (CNTs) exhibit different catalytic activities with respect to the same metals deposited on the CNT exterior walls, with some reactions enhanced and others hindered. In this article, we describe the concept of confinement energy, which enables prediction of confinement effects on catalytic activities in different reactions. Combining density functional theory calculations and experiments by taking typical transition metals such as Fe, FeCo, RhMn, and Ru as models, we observed stronger strains and deformations within the CNT channels due to different electronic structures and spatial confinement. This leads to downshifted d-band states, and consequently the adsorption of molecules such as CO, N2, and O2 is weakened. Thus, the confined space of CNTs provides essentially a unique microenvironment due to the electronic effects, which shifts the volcano curve of the catalytic activities toward the metals with higher binding energies. The extent of the shift depends on the specific metals and the CNT diameters. This concept generalizes the diverse effects observed in experiments for different reactions, and it is anticipated to be applicable to an even broader range of reactions other than redox of metal species, CO hydrogenation, ammonia synthesis and decomposition discussed here. PMID- 25496139 TI - Identification and characterization of Acidithiobacillus ferrooxidans YY2 and its application in the biodesulfurization of coal. AB - The acidophilic Fe-oxidizing and S-oxidizing bacterium YY2 was isolated from the acid drainage of a coalmine. Based on morphological and physiological characteristics and phylogenetic analysis, it was identified as Acidithiobacillus ferrooxidans. Significant differences were observed in the oxidation efficiency and cell morphology when YY2 was cultured in 9K medium with ferrous ion (Fe(2+)), elemental sulfur (S(0)), and pyrite as the sole energy source. YY2 exhibited marked Fe(2+) oxidation activity; 44.2 g . L(-1) FeSO4 . 7H2O was completely oxidized in 30 h, but the rates of S(0) and pyrite oxidization were slower. After 20 days, the efficiencies of oxidizing 10 g . L(-1) S(0) and 10 g . L(-1) pyrite were approximately 9.6% and 20%, respectively. Cells cultured in pyrite as substrate secreted more extracellular polymeric substances than they did when cultured in Fe(2+) or S(0). Additionally, 75% total sulfur removal and 86% pyritic sulfur removal was achieved in a sequencing batch reactor of biodesulfurization of coal. PMID- 25496138 TI - Uncertainties about laparoscopic myomectomy during pregnancy: A lack of evidence or an inherited misconception? A critical literature review starting from a peculiar case. AB - OBJECTIVE: The aim of this report was to perform a critical review of the literature about feasibility, safety, limitations and contraindications of laparoscopic myomectomy during pregnancy starting from a peculiar case of a 15 weeks pregnant woman affected by a symptomatic large myoma. CASE REPORT: A 35 year-old Caucasian-nulliparous-woman was referred to our unit at nine weeks of gestation for abdominal heaviness and constipation. The ultrasound examination revealed the presence of a 24 cm pedunculated myoma. The initial management was conservative until the achievement of 15 gestational weeks, when the worsening of abdominal pain led to the need of a laparoscopic myomectomy. Intraoperative blood loss was 600 ml and operating-time was 150 minutes (70 minutes were required for the morcellement); the postoperative course was normal. The pregnancy evolved regularly and, at 41 weeks, the patient delivered by urgent caesarean section (because intrapartum fetal heart rate abnormalities) a healthy male baby weighing 4460 gr. Both post-partum and puerperium period had a regular course. CONCLUSION: Laparoscopic myomectomy is feasible and safe during pregnancy for both mother and fetus and vaginal delivery should not be contraindicated. Evidence from our and other reported cases suggests that, during pregnancy, laparoscopic myomectomy should be considered the best surgical choice when subserous peduncolated myomas are symptomatic. PMID- 25496140 TI - Characterization of DNA-conjugated compounds using a regenerable chip. AB - DNA-encoded chemical library (DECL) technology has emerged as a new avenue in the field of drug discovery. Combined with high-throughput sequencing, DECL selection experiments can provide not only many lead compounds but also insights into the structure-affinity relationship. However, the counts of individual DNA codes reflect, but cannot be used to precisely rank, the binding affinities of the corresponding compounds to protein targets. Herein, we describe a chip-based approach to realize an automated high-throughput assay for the kinetic characterization of the interaction between DNA-conjugated small organic compounds and protein targets. Importantly, this method can be applied to both single-pharmacophore DECLs and self-assembled dual-pharmacophore DECLs. PMID- 25496142 TI - Contextually appropriate measurement as the basis for culturally appropriate interventions: a case study in Managua, Nicaragua. AB - Despite recent advances in U.S. health care, racial and ethnic minorities experience significantly worse health and mental health outcomes. Policy responses to this problem are based on available research, which is often premised on a misinterpretation of the cultural concepts that underlie people's health and mental health. Health researchers often rely upon measurements with questionable cultural validity. This contributes to a lack of understanding of health disparities that nondominant populations experience and creates obstacles to the development of effective policies to alleviate them. Even statistically valid or literally translated measurements often fail to account for different social and cultural contexts and/or neglect to consider vital information about the population studied or its history. This article reports on the content validity of measures used in a study that investigated predictors of mental health in Managua, Nicaragua. Results reveal a polarized response structure and lack of cultural relevance in underlying concepts measured. PMID- 25496141 TI - Switching from zidovudine/lamivudine to tenofovir/emtricitabine improves fat distribution as measured by fat mass ratio. AB - OBJECTIVES: Fat mass ratio (FMR) has been suggested as an objective indicator of abnormal body fat distribution in HIV infection. Although it could provide more comprehensive information on body fat changes than limb fat mass, FMR has scarcely been used in clinical trials examining body fat distribution in HIV infected patients. METHODS: A subanalysis of a controlled, randomized clinical trial in virologically suppressed HIV-1-infected men switching from zidovudine (ZDV)/lamivudine (3TC) to emtricitabine (FTC)/tenofovir (TDF) versus continuing on ZDV/3TC was carried out. FMR was assessed by dual X-ray absorptiometry (DEXA) for a period of 72 weeks. Lipoatrophy was defined as FMR >= 1.5. Multivariate linear regression models for the change in FMR from baseline were fitted. RESULTS: Sixty-five men were randomized and treated (28 in the FTC/TDF arm and 37 in the ZDV/3TC arm), and 57 completed the study (25 and 32 in each arm, respectively). In the FTC/TDF arm, adjusted mean FMR decreased by 0.52 at week 72 (P = 0.014), and in the ZDV/3TC arm it increased by 0.13 (P = 0.491; P between arms = 0.023). Among subjects with lipoatrophy (baseline FMR >= 1.5), adjusted FMR decreased by 0.76 (P = 0.003) in the FTC/TDF arm and increased by 0.21 (P = 0.411; P between arms = 0.009) in the ZDV/3TC arm. Baseline FMR and treatment group were significant predictors (P < 0.05) of post-baseline changes in FMR. CONCLUSIONS: Switching from ZDV/3TC to FTC/TDF led to an improvement in FMR, compared with progressive worsening of FMR in subjects receiving ZDV/3TC, showing that fat mass not only increased but was also distributed in a healthier way after the switch. PMID- 25496143 TI - Combined effects of alternariols mixture on human colon carcinoma cells. AB - Mycotoxins are naturally occurring contaminants encountered at high levels in a wide variety of agricultural products intended for human and animal consumptions. Various Alternaria mycotoxins may occur simultaneously in small grain cereals. Considering the concomitant production of alternariol (AOH) and alternariol monomethyl ether (AME), it is expected that humans and animals are exposed to the mixture rather than to individual compounds. Therefore, we studied the interactive effects of binary mixture of alternariols (AOH and AME) on the human intestinal cell line, HCT116 cells. Exposure of HCT116 cells to low cytotoxic alternariols doses, resulted in a moderate cytotoxicity manifested by a loss in the cell viability mediated by an activation of the mitochondrial apoptotic process, associated with the opening of mitochondrial permeability transition pore (PTP) and the loss of the mitochondrial transmembrane potential (DeltaPsim). However, when combined, they exert a significant increase in their toxic potential. Altogether, our study showed that AOH and AME combination is obviously additive. PMID- 25496145 TI - A good year for Biopreservation and Biobanking. PMID- 25496146 TI - What are some of the ELSI challenges of international collaborations involving biobanks, global sample collection, and genomic data sharing and how should they be addressed? PMID- 25496144 TI - Fluorescent protein-mediated colour polymorphism in reef corals: multicopy genes extend the adaptation/acclimatization potential to variable light environments. AB - The genomic framework that enables corals to adjust to unfavourable conditions is crucial for coral reef survival in a rapidly changing climate. We have explored the striking intraspecific variability in the expression of coral pigments from the green fluorescent protein (GFP) family to elucidate the genomic basis for the plasticity of stress responses among reef corals. We show that multicopy genes can greatly increase the dynamic range over which corals can modulate transcript levels in response to the light environment. Using the red fluorescent protein amilFP597 in the coral Acropora millepora as a model, we demonstrate that its expression increases with light intensity, but both the minimal and maximal gene transcript levels vary markedly among colour morphs. The pigment concentration in the tissue of different morphs is strongly correlated with the number of gene copies with a particular promoter type. These findings indicate that colour polymorphism in reef corals can be caused by the environmentally regulated expression of multicopy genes. High-level expression of amilFP597 is correlated with reduced photodamage of zooxanthellae under acute light stress, supporting a photoprotective function of this pigment. The cluster of light-regulated pigment genes can enable corals to invest either in expensive high-level pigmentation, offering benefits under light stress, or to rely on low tissue pigment concentrations and use the conserved resources for other purposes, which is preferable in less light-exposed environments. The genomic framework described here allows corals to pursue different strategies to succeed in habitats with highly variable light stress levels. In summary, our results suggest that the intraspecific plasticity of reef corals' stress responses is larger than previously thought. PMID- 25496147 TI - Implementation of an error-reporting module within a biorepository IT application to enhance operations. AB - The Collaborative (formerly the Cooperative) Human Tissue Network (CHTN) is a federally funded service oriented grant that provides high-quality biospecimens and services to the research community. The CHTN consists of six institutions located throughout the United States to assist investigators in obtaining research specimens required for basic research. The CHTN divisions have similar operating goals: however, each division is responsible for maintaining operations at their local institutions. This requires the divisions to identify ways to maintain and sustain operations in a challenging federally funded environment, especially when the number of investigators requesting services drives the operation. Sustainability plans and goals are often times patched together out of necessity rather than taking a thoughtful approach by clearly defining and aligning activities with business strategy and priorities. The CHTN Western Division at Vanderbilt University Medical Center (CHTN-WD) has responded to this challenge of biospecimen resource sustainability in the face of diminished funding by continually identifying ways to innovate our processes through IT enhancements and requiring that the innovation produce measurable and relevant criteria for credibly reporting our operations progress and performance issues. With these overarching goals in mind, CHTN-WD underwent a Lean Six Sigma (LSS) series to identify operational inefficiencies that could be addressed with redesigning workflow and innovating the processes using IT solutions. The result of this internal collaborative innovation process was the implementation of an error-reporting module (ERM) hosted within our biorepository donor IT application, which allowed staff to report errors immediately; determine the operational area responsible; assess the severity of the error; determine course of action; determine if standard operating procedure (SOPs) revisions were required; and through automated e-mails, alert the area personnel responsible. The module provides a data-reporting feature by date range and area of operation for management and analysis. PMID- 25496148 TI - Biobank bootstrapping: is biobank sustainability possible through cost recovery? AB - BACKGROUND: The pre-eminent goal of biobanks is to accelerate scientific discovery and support improvements in healthcare through the supply of high quality biospecimens to enable excellent science. Despite the need for retrospective future-proofed cancer repositories, they are presented with significant fiscal challenges. While it was once thought that biobanks could recover most, if not all, operational costs through distribution fees, biobanks have been consistently unable to fully realize this dream. METHODS: Using data from three mature Canadian cancer biobanks, common attributes and assumptions related to cost recovery were evaluated. The values were entered into a simple financial model to determine the cost recovery potential for biobanks. RESULTS: Over a 5-year period analyzed, aliquots from almost 40% (8990) of 23055 cases collected have been distributed in whole or in part to researchers. The financial modeling demonstrates that, based on values derived from the real life experiences of three major Canadian biobanks, full cost recovery through distribution is not feasible. A more realistic, experience based, expectation of cost recovery from distribution fees is in the range of 5%-25%, and this range is lower if only academic research is supported as opposed to also supporting industry researchers. CONCLUSIONS: Biobanks are expensive and, to mitigate costs, are frequently challenged to operate under "self-sustainable" financial models. However, the only possible route to self-sustainability through distribution fees in today's market would require an almost exclusive targeting of commercial researchers and, even then, evidence suggests this is an impossible goal to attain. Support for biobanks should recognize that they exist to further development of personalized treatments and diagnostics essential for precision medicine. For biobanks to continue to achieve this goal, pro bono publicum, funders need to be aware of the full funding requirements of biobanks and create appropriate funding streams. PMID- 25496149 TI - Assessing the financial, operational, and social sustainability of a biobank: the Wales Cancer Bank case study. AB - Biobank sustainability is a multi-faceted concept that many biobanks are wrestling with to justify their continued existence. After 10 years of operation, the Wales Cancer Bank is faced with a potential reduction in grant funding that will result in the need for a restructured approach to patient consenting, sample collection, and sample issue. A review is currently in progress, using evidence from the last 12 months, to inform the decisions that will be taken at the end of 2014 regarding the biobank's future. The information presented details the areas under consideration for revision with the perceived costs and benefits associated with the amendment. Not all outcomes are currently known, and some decisions will be made once the level of future funding is confirmed. The process of assessment has proved to be a valuable exercise and has highlighted the need for biobanks to regularly evaluate strategic principles and operating procedures using sustainability as a denominator. PMID- 25496150 TI - Construction of a business model to assure financial sustainability of biobanks. AB - Biobank-suisse (BBS) is a collaborative network of biobanks in Switzerland. Since 2005, the network has worked with biobank managers towards a Swiss biobanking platform that harmonizes structures and procedures. The work with biobank managers has shown that long-term, sustainable financing is difficult to obtain. In this report, three typical biobank business models are identified and their characteristics analyzed. Five forces analysis was used to understand the competitive environment of biobanks. Data provided by OECD was used for financial estimations. The model was constructed using the business model canvas tool. The business models identified feature financing influenced by the economic situation and the research budgets in a given country. Overall, the competitive environment for biobanks is positive. The bargaining power with the buyer is negative since price setting and demand prediction is difficult. In Switzerland, the healthcare industry collects approximately 5600 U.S. dollars per person and year. If each Swiss citizen paid 0.1% (or 5 U.S. dollars) of this amount to Swiss biobanks, 45 million U.S. dollars could be collected. This compares to the approximately 10 million U.S. dollars made available for cohort studies, longitudinal studies, and pathology biobanks through science funding. With the same approach, Germany, the United States, Canada, France, and the United Kingdom could collect 361, 2634, 154, 264, and 221 million U.S. dollars, respectively. In Switzerland and in other countries, an annual fee less than 5 U.S. dollars per person is sufficient to provide biobanks with sustainable financing. This inspired us to construct a business model that not only includes the academic and industrial research sectors as customer segment, but also includes the population. The revenues would be collected as fees by the healthcare system. In Italy and Germany, a small share of healthcare spending is already used to finance selected clinical trials. The legal frameworks could serve as templates for the business model proposed here. PMID- 25496151 TI - Biobanking sustainability--experiences of the Australian Breast Cancer Tissue Bank (ABCTB). AB - Sustainability of biorepositories is a key issue globally. This article is a description of the different strategies and mechanisms used by the Australian Breast Cancer Tissue Bank (ABCTB) in developing and operating the resource since its inception in 2005. ABCTB operates according to a hub and spoke model, with a central management hub that is responsible for overall management of the resource including financial, ethical, and legal processes, researcher applications for material, clinical follow-up, information/database activities, and security. A centralized processing laboratory also operates from the hub site where DNA and RNA extractions are performed, digital imaging of stained tumor sections occurs, and specimens are assembled for dispatch for research projects. ABCTB collection sites where donors are identified, consent obtained, and specimens collected and processed for initial storage are located across Australia. Each of the activities of the resource requires financial support and different sources of revenue, some of which are allocated to a specific function of the ABCTB. Different models are in use at different collection centers where local variations may exist and local financial support may sometimes be obtained. There is also significant in-kind support by clinics and diagnostic and research facilities that house the various activities of the resource. However, long-term financial commitment to ensure the survival of the resource is not in place, and forward planning of operations remains challenging under these circumstances. PMID- 25496152 TI - DNA storage under high temperature conditions does not affect performance in human leukocyte antigen genotyping via next-generation sequencing (DNA integrity maintained in extreme conditions). AB - BACKGROUND: Stable dry-state storage of DNA is desirable to minimize required storage space and to reduce electrical and shipping costs. DNA purified from various commercially available dry-state stabilization matrices has been used successfully in downstream molecular applications (e.g., quantitative polymerase chain reaction [qPCR], microarray, and sequence-based genotyping). However, standard DNA storage conditions still include freezing of DNA eluted in aqueous buffers or nuclease-free water. Broad implementation of dry-state, long-term DNA storage requires enhancement of such dry-state DNA stabilization products to control for temperature fluctuations at specimen collection, transit, and storage. This study tested the integrity of genomic DNA subjected to long-term storage on GenTegra(TM) DNA stabilization matrices (GenTegra LLC, Pleasanton, CA) at extreme conditions, as defined by a 4-year storage period at ambient temperature with an initial incubation for 7 months at 37 degrees C, 56 degrees C, or ambient temperature. Subsequently, purified DNA performance and integrity were measured by qPCR and next-generation sequencing (NGS)-based human leokocyte antigen (HLA) genotyping. RESULTS: High molecular weight genomic DNA samples were recovered from the GenTegra product matrix and exhibited integrity comparable to a highly characterized commercial standard under assessment by qPCR. Samples were genotyped for classical HLA loci using next generation sequencing-based methodolgy on the Roche 454 GS Junior instrument. Amplification efficiency, sequence coverage, and sequence quality were all comparable with those produced from a cell line DNA sequenced as a control. No significant differences were observed in the mean, median, or mode quality scores between samples and controls (p>=0.4). CONCLUSIONS: Next generation HLA genotyping was chosen to test the integrity of GenTegra-treated genomic DNA due to the requirment for long sequence reads to genotype the highly polymorphic classical HLA genes. Experimental results demonstrate the efficacy of the GenTegra product as a suitable genomic DNA preservation tool for collection and long-term biobanking of DNA at fluctuating and high temperatures. PMID- 25496153 TI - Factors that may influence the willingness of cancer patients to consent for biobanking. AB - BACKGROUND: Broad or general consent given by cancer patients for their tissue, blood, and clinical information to be stored in institutional biorepositories is fundamental to enable future ethical translational cancer research. The decision to consent for biobanking will contribute to the development of advanced diagnostic and prognostic tests, as well as new therapies to improve patient outcomes. While the rate of patient participation in biobanking programs is generally reported as high worldwide, few studies have investigated factors that may influence this decision. Biobanking at our medical research institute, an associated public (government-run) university hospital, and private hospital has been established for over 20 years, with collection of certain tumor types embedded in the research culture of these institutions. In this study, we investigated factors that may influence a cancer patient's decision to give broad consent for biobanking of their specimens. METHODS: Data on patient consent were collected over a 6-month period from both government and private hospitals associated with our medical research institute. Factors considered included gender, patient age at surgery, type of malignancy (breast, duodenal, cervical, endometrial, gastric, liver, esophageal, ovarian, pancreatic, pelvic, uterine, or vulval), type of institution where surgery was performed, and timing of consent. RESULTS: Of 171 cancer patients, 159 (93%) gave broad consent for biobanking of their tissue and blood specimens for future cancer research projects receiving ethical and scientific approval. None of the factors analyzed was shown to influence a patient's decision to contribute biological specimens and clinical data to a biorepository for future medical research. CONCLUSION: Biobanking for future ethically and scientifically approved research projects in an established institution is an initiative that receives strong support from patients undergoing cancer surgery, independent of factors including gender, age, type of tumor, type of institution where surgery was performed, or timing of consent. PMID- 25496154 TI - Access to biobanks: harmonization across biobank initiatives. AB - PURPOSE: The current study investigates whether access arrangements relevant for biobanking contain clear information on key access conditions. It furthermore assesses the extent to which these access conditions are harmonized across biobank initiatives. METHODS: A comparative analysis was conducted of access arrangements developed by 26 organizations, 36 biobank networks, and 20 biobanks worldwide. RESULTS: The study demonstrates a lack of clear information on 21 key access conditions relevant for biobanking. Furthermore, it confirms that the harmonization across biobank initiatives is limited. CONCLUSION: Many biobank initiatives need to be more transparent on how they apply the studied access conditions. PMID- 25496155 TI - Traditional and electronic informed consent for biobanking: a survey of U.S. biobanks. AB - Biobanks face unique challenges obtaining consent from biospecimen contributors. Electronic consent (e-consent) presents one option for streamlining the biobank consent process, and improving contributor understanding of consent information. An e-mail survey was conducted to establish the extent of current biobank e consent and interest in future use of e-consent. A total of 235 biobanks were surveyed and 65 (28%) responded with a fully completed survey. Few of these 65 biobanks (8%) reported using e-consent; however, the majority (75%) were interested in e-consent. Many (48%) biobanks were in discussions with institutional stakeholders about using e-consent in the future. Anticipated benefits of e-consent included improved efficiency and increased enrollment. Perceived barriers to e-consent adoption included lack of funding, issues with human subjects approval, and factors affecting user uptake (e.g., computer literacy). Biobanks using e-consent reported cost, technology issues, and difficulty training staff as barriers to e-consent adoption. Traditional consenting methods (e.g., face-to-face, phone, and mail) continued to be used at biobanks reporting use of e-consent. The survey results suggest strong interest in e-consent among U.S. biobanks, and a need to consider a range of implementation issues, including user preferences and receptivity; institutional and technical support; integration with clinical data networks; electronic signature capture; and what type of e-consent to implement. Biobanks will need evidence-based guidance for purposes of addressing these issues, so that e consent processes enhance efficiency, as well as contributor receptivity, understanding, and trust. PMID- 25496156 TI - Laboratory detective work identifies a mishandling problem in sample aliquoting. AB - Data from a recent ovarian cancer biomarker study using serum aliquots from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial Biorepository showed that CA125II concentrations in these aliquots were significantly lower than those previously measured in the same subjects from the same blood draw. We designed an experiment to investigate whether samples used in the study (reference study) were compromised during the aliquoting process. We measured CA125II in the "sister" vials created during the same aliquoting process as the reference study aliquot, and in "cousin" vials newly aliquoted from another parent vial from the same blood draw, from 15 healthy controls in the study. Because the sister vials were created in a specific order, we also assessed whether there was a CA125II concentration gradient among the sisters. The Wilcoxon signed-rank test was used to test the statistical significance of the observed differences. Mean CA125II concentration (volume-averaged) was greater in the sisters than the cousins in all 15 subjects (p<0.001). The mean coefficient of variation was 0.25 (range: 0.12-0.43) in the sisters and 0.11 (range: 0.-1.1) in the cousins (p<0.008). The mean ratio of CA125II in the 5(th) aliquoted versus the 3(rd) aliquoted sister vial was 1.66 (1.25-2.5, p<0.001). These data suggest that the parent vials were not adequately mixed before they were aliquoted. CA125II in serum can partially precipitate to form a concentration gradient in long-term storage. Rigorous vortexing after thawing and before aliquoting is thus critical. PMID- 25496157 TI - Biobanco-IMM, Lisbon Academic Medical Centre. PMID- 25496158 TI - International Society for Biological and Environmental Repositories (ISBER) tools for the biobanking community. PMID- 25496159 TI - Psychological distress and the development of hypertension over 5 years in black South Africans. AB - Alarming increases in the incidence of hypertension in many low- and middle income countries are related to alcohol overuse. It is unclear whether alcohol overuse is a symptom of psychological distress. The authors assessed psychological distress in Africans and its relationship with a 5-year change in blood pressure (BP), independent of alcohol intake. The authors followed 107 Africans with optimal BP (<=120/80 mm Hg) (aged 35-75 years) over 5 years. Alcohol intake (self-report and serum gamma-glutamyl transferase) and nonspecific psychological distress (Kessler Screening Scale for Psychological Distress [K6]) were assessed. The K6 predicted hypertension development (P=.019), and its individual component "nervous" increased a participant's risk two-fold to become hypertensive (hazard ratio, 2.00 [1.23-3.26]). By entering K6 and gamma-glutamyl transferase into multivariable-adjusted regression models for change in systolic BP, both were independently associated with change in systolic BP. Psychological distress and scoring high on being nervous predicted the development of hypertension over 5 years, independent of alcohol intake. PMID- 25496161 TI - Association analysis between 8-oxoguanine DNA glycosylase genetic variants and endometrial cancer susceptibility in Chinese Han population. AB - OBJECTIVES: Numerous epidemiologic studies demonstrate that 8-oxoguanine DNA glycosylase gene (hOGG1) is an important candidate gene for the development of endometrial cancer (EC). The objective of this study is to evaluate the potential association between hOGG1 genetic variants and the susceptibility to EC. METHODS: In total, 218 EC patients and 243 cancer-free controls were recruited in this study. KEY FINDINGS: Our data indicate that the hOGG1 c.269C > A and c.828A > G genetic variants are statistically associated with the increased susceptibility to EC (for c.269C > A, AA vs CC: odds ratio (OR) = 2.14, 95% confidence interval (CI), 1.21 to 3.78, P = 0.008; A vs C: OR = 1.43, 95% CI, 1.09 to 1.88, P = 0.010; for c.828A > G, GG vs AA: OR = 2.31, 95% CI, 1.24 to 4.30, P = 0.008; G vs A: OR = 1.35, 95% CI, 1.03 to 1.78, P = 0.032). The A allele and AA genotype of c.269C > A and G allele and GG genotype of c.828A > G genetic variants could contribute to the susceptibility to EC. CONCLUSION: Taken together, our findings suggest that the hOGG1 c.269C > A and c.828A > G genetic variants are significantly associated with EC susceptibility in Chinese Han populations and might be used as molecular markers for assessing the risk of EC. PMID- 25496160 TI - Roles for both FtsA and the FtsBLQ subcomplex in FtsN-stimulated cell constriction in Escherichia coli. AB - Escherichia coli FtsN is a bitopic membrane protein that is essential for triggering active cell constriction. A small periplasmic subdomain ((E) FtsN) is required and sufficient for function, but its mechanism of action is unclear. We isolated extragenic (E) FtsN*-suppressing mutations that restore division in cells producing otherwise non-functional variants of FtsN. These mapped to the IC domain of FtsA in the cytoplasm and to small subdomains of the FtsB and FtsL proteins in the periplasm. All FtsB and FtsL variants allowed survival without (E) FtsN, but many then imposed a new requirement for interaction between the cytoplasmic domain of FtsN ((N) FtsN) and FtsA. Alternatively, variants of FtsA, FtsB or FtsL acted synergistically to allow cell division in the complete absence of FtsN. Strikingly, moreover, substitution of a single residue in FtsB (E56) proved sufficient to rescue DeltaftsN cells as well. In FtsN(+) cells, (E) FtsN* suppressing mutations promoted cell fission at an abnormally small cell size, and caused cell shape and integrity defects under certain conditions. This and additional evidence support a model in which FtsN acts on either side of the membrane to induce a conformational switch in both FtsA and the FtsBLQ subcomplex to de-repress septal peptidoglycan synthesis and membrane invagination. PMID- 25496163 TI - Th-17 related regulatory network in the pathogenesis of Arab patients with systemic lupus erythematosus and lupus nephritis. AB - AIM: The present study aimed to identify the genes involved in the pathogenesis of systemic lupus erythematosus (SLE) in Arabs by investigating a panel of 84 genes related to the t helper (Th)17-related regulatory network and to further explore the expression levels of serum interleukin (IL)-17A and IL-17F in a studied cohort. A comparative analysis of gene expression profile in SLE and lupus nephritis (LN) patients against that of healthy controls (HC) was performed. METHOD: A quantitative real-time polymerase chain reaction (PCR) (Th17 autoimmunity and inflammation) array analysis was performed in peripheral white blood cells of 66 SLE patients under specific medical treatment and 30 age/gender/ethnically matched healthy controls. Statistical analysis was carried out using the RT(2) Profiler TM PCR Data Analysis tool. RESULTS: The analysis of Th17 pathway revealed 14 genes (IL-17A, IL-17C, IL-17D, IL-17F, IL-18, IL-12RB2, IL-23R, CCL2, CCL20, CXCL5, MMP3, RORC, STAT4 and TRAF6) that are differentially expressed in SLE and HC (fold change [FC] < 2, P < 0.0006). No significant difference in expression profiles was observed between SLE and LN. A significant difference in serum concentration of IL-17A (P = 0.002) and IL-17F (P = 0.002) was observed between SLE (13.91 +/- 4.25) and LN (18.26 +/- 4.24). CONCLUSION: Our study is the first to investigate a panel of 84 genes related to Th17 regulatory pathway in Arab SLE subjects and the first to explore the effect of current immunosuppression regimens on Th17 regulatory pathway. It paves the way for understanding the etiology of SLE and autoimmune diseases in general. PMID- 25496164 TI - Expression of gastrin-releasing peptide by excitatory interneurons in the mouse superficial dorsal horn. AB - BACKGROUND: Gastrin-releasing peptide (GRP) and its receptor have been shown to play an important role in the sensation of itch. However, although GRP immunoreactivity has been detected in the spinal dorsal horn, there is debate about whether this originates from primary afferents or local excitatory interneurons. We therefore examined the relation of GRP immunoreactivity to that seen with antibodies that label primary afferent or excitatory interneuron terminals. We tested the specificity of the GRP antibody by preincubating with peptides with which it could potentially cross-react. We also examined tissue from a mouse line in which enhanced green fluorescent protein (EGFP) is expressed under control of the GRP promoter. RESULTS: GRP immunoreactivity was seen in both primary afferent and non-primary glutamatergic axon terminals in the superficial dorsal horn. However, immunostaining was blocked by pre-incubation of the antibody with substance P, which is present at high levels in many nociceptive primary afferents. EGFP+ cells in the GRP-EGFP mouse did not express Pax2, and their axons contained the vesicular glutamate transporter 2 (VGLUT2), indicating that they are excitatory interneurons. In most cases, their axons were also GRP immunoreactive. Multiple-labelling immunocytochemical studies indicated that these cells did not express either of the preprotachykinin peptides, and that they generally lacked protein kinase Cgamma, which is expressed by a subset of the excitatory interneurons in this region. CONCLUSIONS: These results show that GRP is expressed by a distinct population of excitatory interneurons in laminae I II that are likely to be involved in the itch pathway. They also suggest that the GRP immunoreactivity seen in primary afferents in previous studies may have resulted from cross-reaction of the GRP antibody with substance P or the closely related peptide neurokinin A. PMID- 25496165 TI - Functional antigen matching in corneal transplantation: matching for the HLA-A, B and -DRB1 antigens (FANCY) - study protocol. AB - BACKGROUND: Penetrating keratoplasty can commonly restore vision in corneal blindness. However, immunological graft reactions may induce irreversible graft failure in a substantial percentage. Repeat keratoplasties in turn are associated with increased risk of graft failure and possibly irreversible blindness. Topical as well as systemic immunosuppressants are administered for prophylaxis. However, severe adverse effects limit long-term usage. By contrast, matching for transplantation antigens might be effective for a long time. METHODS: FANCY is a prospective, controlled, randomised, double-blind, multi-centre clinical trial with two parallel arms. The primary objective is to evaluate superiority of the proposed HLA matching strategy in comparison to random graft assignment with respect to the primary endpoint 'time to first endothelial graft rejection'. Relevant inclusion criteria are age over 18 years and waiting for penetrating or endothelial lamellar keratoplasty. The most important exclusion criteria are abuse of medication and/or drugs and an anticipated waiting time for an HLA match longer than 6 months. After randomisation, patients either receive a HLA-matched graft (experimental intervention) or a random graft (control intervention). The calculated sample size is 620 patients. The trial started in 2009 with a recruitment period of 24 months. A total of 654 patients were included during this time. DISCUSSION: The primary goal of FANCY is to assess whether histocompatibility matching is feasible and effective in the broad clinical routine. However, during the course of the trial, the landscape of keratoplasty changed due to the rise of Descemet Membrane Endothelial Keratoplasty (DMEK). Nowadays, immune reactions are confined mostly to the 'high-risk' subgroups. If we would design FANCY in 2014, we would narrow down the inclusion criteria to include only the high risk patients and accept longer waiting times for a matching donor here. TRIAL REGISTRATION: The unique identifying number of the FANCY trial is NCT00810472. PMID- 25496167 TI - Reorientational jump dynamics and its connections to hydrogen bond relaxation in molten acetamide: an all-atom molecular dynamics simulation study. AB - Here we report results from our molecular dynamics simulations on orientational relaxation and hydrogen bond dynamics of molten acetamide. Signatures for orientational jumps have been detected with jump barrier estimated to be ~0.7 kBT. Simulated orientational relaxations indicate deviations from hydrodynamics and this deviation has been ascribed to the detected orientational jumps. Simulated free energy surfaces obtained at various distances between the rotating acetamide and its initial and final H-bond acceptors have been found to be symmetric double-well in nature at the transition state. H-bond relaxation times obtained from our simulations corroborate well with the time scales associated with the jump and waiting time distributions, suggesting an interrelationship between jump dynamics and H-bond fluctuations. Jump angle distributions are asymmetric and depict long tails extending to large angles. PMID- 25496166 TI - Interfacing microwells with nanoliter compartments: a sampler generating high resolution concentration gradients for quantitative biochemical analyses in droplets. AB - Analysis of concentration dependencies is key to the quantitative understanding of biological and chemical systems. In experimental tests involving concentration gradients such as inhibitor library screening, the number of data points and the ratio between the stock volume and the volume required in each test determine the quality and efficiency of the information gained. Titerplate assays are currently the most widely used format, even though they require microlitre volumes. Compartmentalization of reactions in pico- to nanoliter water-in-oil droplets in microfluidic devices provides a solution for massive volume reduction. This work addresses the challenge of producing microfluidic-based concentration gradients in a way that every droplet represents one unique reagent combination. We present a simple microcapillary technique able to generate such series of monodisperse water-in-oil droplets (with a frequency of up to 10 Hz) from a sample presented in an open well (e.g., a titerplate). Time-dependent variation of the well content results in microdroplets that represent time capsules of the composition of the source well. By preserving the spatial encoding of the droplets in tubing, each reactor is assigned an accurate concentration value. We used this approach to record kinetic time courses of the haloalkane dehalogenase DbjA and analyzed 150 combinations of enzyme/substrate/inhibitor in less than 5 min, resulting in conclusive Michaelis-Menten and inhibition curves. Avoiding chips and merely requiring two pumps, a magnetic plate with a stirrer, tubing, and a pipet tip, this easy-to-use device rivals the output of much more expensive liquid handling systems using a fraction (~100-fold less) of the reagents consumed in microwell format. PMID- 25496168 TI - A typology of drug selling among young adults in the United States. AB - BACKGROUND: Although studies have found that young adults who sell drugs are more likely to be involved in risky behaviors than those who do not sell drugs, there has been relatively little research that has explored heterogeneity among young adults who sell drugs. METHODS: Using a pooled sample of 18 to 25 year olds from the National Survey on Drug Use and Health (2006-2010) who report past-year drug selling (N = 5,373), this study employs latent profile analysis to specify latent groups and assess the correlates of group membership. RESULTS: Findings indicate substantial differences among young adults who sell drugs. In particular, the analysis found four groups of drug sellers: normative (49.6%), club drug users (23.6%), polysubstance users (16.0%), and criminal offenders (10.8%). Club drug users were characterized by high levels of ecstasy and hallucinogen use, polysubstance users were more likely to be depressed and anxious, White and female than the other groups. Criminal offenders were overwhelmingly male and more likely to be comprised of African-Americans and Hispanics. CONCLUSIONS: RESULTS indicate that drug selling in early adulthood varies substantially. Contrary to media and popular notions most drug sellers are not involved in crime and polysubstance using drug sellers are in clear need of mental health services. Further, most drug sellers in this age range are White. Findings suggest that policy efforts that operate under the assumption of homogeneity of drug selling may be misguided. PMID- 25496169 TI - Association between personality disorders traits and problematic cannabis use in adolescents. AB - BACKGROUND: There are few studies on the contribution of personality disorder traits to cannabis use disorders in adolescents. OBJECTIVES: The aim of the study was to evaluate the association of personality disorder traits to problematic cannabis use. METHODS: Participants were 111 high school students who completed self-report questionnaires, mainly the Cannabis Use Disorders Identification Test, assessing problematic cannabis use, and the Personality Diagnostic Questionnaire using the scales evaluating personality disorders most often linked to adolescent cannabis use. RESULTS: A multiple regression analysis showed that personality disorder traits explained a high part of the variance in problematic cannabis use symptoms. Schizotypal and borderline personality traits were positively associated to problematic cannabis use symptoms after adjustment for anxious and depressive symptoms. CONCLUSIONS: This study suggests the importance of evaluating personality disorder traits in studies of risk factors or consequences of problematic cannabis use. PMID- 25496170 TI - Smoking processes, panic, and depressive symptoms among treatment-seeking smokers. AB - OBJECTIVES: The present study evaluated the relative contribution of panic and depressive symptoms in relation to past cessation difficulties and smoking motives among treatment-seeking daily smokers. METHODS: The sample included 392 treatment-seeking daily smokers (47.07% female; Mage = 35.48; SD = 13.56), who reported smoking an average of 10 or more cigarettes daily for at least one year. RESULTS: Findings indicated that panic and depressive symptoms were significantly associated with quit problems as well as addictive and negative affect motives for smoking. However, depressive symptoms were not associated with habitual smoking motives. CONCLUSIONS: Differential patterns of associations with smoking based processes imply that although panic and depression are related, there are important distinctions. Such data highlight the need for additional research to examine the putative role of panic and depressive symptoms in relation to smoking behaviors to further elucidate the mechanisms through which panic, depression, and smoking impact one another. PMID- 25496171 TI - Development of the human infrahepatic inferior caval and azygos venous systems. AB - Differences in opinion regarding the development of the infrahepatic inferior caval and azygos venous systems in mammals centre on the contributions of 'caudal cardinal', 'subcardinal', 'supracardinal', 'medial and lateral sympathetic line' and 'sacrocardinal' veins. The disagreements appear to arise from the use of topographical position rather than developmental origin as criterion to define separate venous systems. We reinvestigated the issue in a closely spaced series of human embryos between 4 and 10 weeks of development. Structures were visualized with the Amira((r)) reconstruction and Cinema4D((r)) remodelling software. The vertebral level and neighbouring structures were used as topographic landmarks. The main results were that the caudal cardinal veins extended caudally from the common cardinal vein between CS11 and CS15, followed by the development of the subcardinal veins as a plexus sprouting ventrally from the caudal cardinal veins. The caudal cardinal veins adapted their course from lateral to medial relative to the laterally expanding lungs, adrenal glands, definitive kidneys, sympathetic trunk and umbilical arteries between CS15 and CS18, and then became interrupted in the part overlaying the regressing mesonephroi (Th12-L3). The caudal part of the left caudal cardinal vein then also regressed. The infrarenal part of the inferior caval vein originated from the right caudal cardinal vein, while the renal part originated from subcardinal veins. The azygos veins developed from the remaining cranial part of the caudal cardinal veins. Our data show that all parts of the inferior caval and azygos venous systems developed directly from the caudal cardinal veins or from a plexus sprouting from these veins. PMID- 25496172 TI - Glycoconjugate vaccines: an update. AB - INTRODUCTION: Globally, the three main pathogens causing serious infections are Haemophilus influenzae type b, Streptococcus pneumoniae and Neisseria meningitidis. Over the last 5 years, new vaccines protecting against these bacteria have been developed and introduced in various countries. AREAS COVERED: This review describes the recently licensed glycoconjugates being used to protect against these encapsulated bacteria. Immunogenicity and safety data that led to licensure or licensure expansion of these glycoconjugates are discussed in addition to the resultant impact on the disease burden. EXPERT OPINION: The maintenance of robust immunisation programmes with high uptake rates is important in maintaining low rates of disease. Epidemiological surveillance systems are essential in monitoring any changes in infectious disease trends and in identifying emerging infections such as from non-typeable H. influenzae, pneumococcal serotype replacement disease and changes in the epidemiology of meningococcal serogroups. This is important to guide future vaccine development. Accessibility of these glycoconjugate vaccines in resource poor regions, which bear the highest disease burden from these pathogens, remains challenging largely due to high vaccine pricing. Recent aids from public and private funding, tiered vaccine pricing and the transfer of vaccine technology have helped in introducing these vaccines where they are most needed. PMID- 25496173 TI - Trichloroethylene degradation by persulphate with magnetite as a heterogeneous activator in aqueous solution. AB - Iron oxide-magnetite (Fe3O4) as a heterogeneous activator to activate persulphate anions (S2O8(2-)) for trichloroethylene (TCE) degradation was investigated in this study. The experimental results showed that TCE could be completely oxidized within 5 h by using 5 g L(-1) magnetite and 63 mM S2O8(2-), indicating the effectiveness of the process for TCE removal. Various factors of the process, including. (S2O8(2-) and magnetite dosages, and initial solution pH, were evaluated, and TCE degradation fitted well to the pseudo-first-order kinetic model. The calculated kinetic rate constant was increased with increasing S2O8(2 ) and magnetite dosages, but it was independent of solution pH. In addition, the changes of magnetite morphology examined by scanning electron microscopy and X ray powder diffraction, respectively, confirmed the slight corrosion with alpha Fe2O3 coated on the magnetite surface. The probe compounds tests clearly identified the generation of the reactive oxygen species in the system. While the free radical quenching studies further demonstrated that *SO4- and *OH were the major radicals responsible for TCE degradation, whereas *O2- contributed less in the system, and therefore the roles of reactive oxygen species on TCE degradation mechanisms were proposed accordingly. To our best knowledge, this is the first time the performance and mechanism of magnetite-activated persulphate oxidation for TCE degradation are reported. The findings of this study provided a new insight into the heterogeneous catalysis mechanism and showed a great potential for the practical application of this technique in in situ TCE-contaminated groundwater remediation. PMID- 25496174 TI - The dissolution and solid-state behaviours of coground ibuprofen-glucosamine HCl. AB - The cogrinding technique is one of most effective methods for improving the dissolution of poorly water-soluble drugs and it is superior to other approaches from an economical as well as an environmental standpoint, as the technique does not require any toxic organic solvents. Present work explores the role of d glucosamine HCl (GL) as a potential excipient to improve dissolution of a low melting point drug, ibuprofen (Ibu), using physical mixtures and coground formulations. The dissolution of the poorly soluble drug has been improved by changing the ratio of Ibu:GL and also grinding time. The results also showed that although GL can enhance the solubility of Ibu, it also reduces pH around the Ibu particles which led to poor dissolution performance when the concentration of GL is high. The effect of GL on the solubility of Ibu could be misleading if the pH of the final solution was not measured. Grinding reduced the particle size of GL significantly but in case of Ibu it was less effective. Solid state analysis (XRPD, DSC, and FT-IR) showed that ibuprofen is stable under grinding conditions, but the presence of high concentration of GL in samples subjected to high grinding times caused changes in FT-IR spectrum of Ibu which could be due to intermolecular hydrogen bond or esterification between the carboxylic acid group in the ibuprofen and hydroxyl group in the GL. PMID- 25496175 TI - The second and third phases of caloric nystagmus. AB - CONCLUSION: The second and third phases of caloric nystagmus occur at a high rate. We can explain this phenomenon based on the hydrostatic pressure theory involved in perilymph. OBJECTIVES: To clarify the incidence of the second and third phases of caloric nystagmus, and to measure their intensity. METHODS: The subjects were 12 healthy humans. The right ear was stimulated using iced water. The first phase of caloric nystagmus was recorded in a supine position. Immediately after the cessation of the first phase, each subject was repositioned to a prone position, and the second phase was recorded. Immediately after the halt of the second phase, each subject was repositioned to a supine position, and the third phase was recorded. Nystagmus was analyzed using three-dimensional video-oculography. RESULTS: The mean value of maximum slow-phase velocity (MSV) of the first phase was 27.2 degrees /s. All subjects revealed the second phase, and the direction was toward the right. The mean value of MSV was 7.2 degrees /s. Nine subjects (75%) showed the third phase, and the direction was toward the left. The mean value of MSV was 2.7 degrees /s. PMID- 25496176 TI - Effect of pneumococcal conjugate vaccination on nasopharyngeal carriage in children with early onset of acute otitis media - a randomized controlled trial. AB - CONCLUSION: Although children vaccinated with heptavalent pneumococcal conjugate vaccine (PCV) had fewer episodes of acute otitis media (AOM), this trial was unable to prove a simultaneous decrease in nasopharyngeal carriage. OBJECTIVE: Carriage rates of AOM pathogens in the nasopharynx are high among children, and colonization is the first step towards infection. The possible impact of PCV on carriage is therefore of interest, particularly in children with recurrent AOM. The aims of this study were to examine the effect of heptavalent PCV on carriage of AOM pathogens in children at high risk of developing recurrent disease, and to monitor carriage of resistant pathogens in vaccinated and unvaccinated children. METHODS: A total of 109 children with an onset of AOM before 6 months of age, 89 of whom developed recurrent disease, were enrolled in a trial. Fifty-two children were vaccinated and all were closely monitored for 3 years. RESULTS: There was no difference statistically between vaccinated children and controls concerning the carriage of any of the major AOM pathogens. There was evidence of within-child clustering for S. pneumoniae (p = 0.002) and H. influenzae (p < 0.001), indicating that children continued to carry either species over time. Resistance rates were generally low and comparable with national levels. PMID- 25496177 TI - Effect of absorbable gelatin sponge in the middle ear: in vitro and in vivo animal model. AB - CONCLUSION: GelitaSpon gelatin sponge (GS) showed faster reabsorption than gelfoam (GF) in vitro, and GS-packed middle ears resulted in a faster hearing recovery and less inflammation than the ears packed with GF soaked in saline. Soaking GF sponges with boric acid (BA) appeared to offset the inflammatory response of saline-soaked GF, making this inflammatory response comparable to that of GS-packed ears. OBJECTIVE: To describe the reabsorption and inflammatory effects of absorbable gelatin sponge in the middle ear. METHODS: For in vitro evaluation, GF and GS were used as disks immersed in saline solution or 3% BA and placed in gel. Images were captured with a microscope and processed using image processing Toolbox. For in vivo tests, 16 female albino Sprague Dawley rats were divided into four groups: bulla opening; GF + 0.9% saline; GF + BA; and GS + 0.9% saline. An anterior approach to the right bulla was used for surgery. Preoperative and postoperative auditory brainstem response thresholds were measured. RESULTS: In vitro, there was marked degradation of GF by day 14, while GS showed complete degradation by the third day. In vivo, hearing recovery occurred by day 21. GF produced a more severe inflammatory response, which could be reduced by treating the GF with BA. PMID- 25496178 TI - Herbal drug BNO 1016 is safe and effective in the treatment of acute viral rhinosinusitis. AB - CONCLUSION: Daily intake of 480 mg of BNO 1016 for 15 days is an effective treatment in acute viral rhinosinusitis. OBJECTIVES: The pooled efficacy data of two similar randomized placebo-controlled clinical trials were analyzed. Safety was evaluated on the basis of the individual trials. METHODS: The efficacy analysis was based on 589 patients. Treatment was performed orally with either 3 * 160 mg BNO 1016 (n = 294) or 3 * placebo (n = 295) for 15 days. In both trials patients underwent five visits to the investigational sites. Symptoms were evaluated according to the EPOS 2012 guideline. Ultrasonography was used to confirm the diagnosis at onset of treatment and the remission of symptoms at the last visit. Efficacy was evaluated by the investigator as the mean major symptom score (MSS) at the end of treatment (visit 5, day 14). Patients reported symptoms and social/emotional consequences of rhinosinusitis using a quality of life questionnaire (SNOT-20 GAV). RESULTS: MSS improved during the treatment period by a mean of 10.02 +/- 1.61 score points to 2.47 +/- 2.55 for BNO 1016 and of 9.87 +/- 1.52 to 3.63 +/- 3.63 for placebo. Differences between treatment groups at end of therapy (1.16 +/- 3.14 score points; p < 0.0001) and patient-assessed quality of life (p = 0.0015) were statistically significant in favor of BNO 1016. PMID- 25496179 TI - Aberrant methylation and expression of DAPk1 in human hypopharyngeal squamous cell carcinoma. AB - CONCLUSION: These findings indicate that in hypopharyngeal squamous cell carcinoma (HSCC), hypermethylation and down-regulation of death-associated protein kinase-1 (DAPk1) are common events, which are associated with a poor prognosis. OBJECTIVES: This study aimed to investigate the methylation and expression of DAPk1, a tumor suppressor gene, in HSCC, and explore its clinical significance. METHODS: The tumor and adjacent non-tumor tissues were collected from 53 patients with HSCC. The methylation status of DAPk1 was detected by methylation-specific polymerase chain reaction (MSP), and expression of DAPk1 was determined with real-time reverse transcriptase polymerase chain reaction (RT PCR), immunohistochemistry, and Western blot at mRNA or protein levels. Correlations between the findings and patients' clinicopathological parameters were further evaluated. RESULTS: The methylation ratio of DAPk1 in tumor tissues (60.38%) was significantly higher than that in the adjacent non-tumor tissues (26.42%) (p = 0.001), while DAPk1 expression in the tumors was down-regulated markedly (real-time RT-PCR, p = 0.002; immunohistochemistry, p = 0.006; Western blot, p < 0.001). DAPk1 methylation was negatively correlated with its mRNA expression (p = 0.002, r = -0.521). Both hypermethylation and down-regulation of DAPk1 were closely related to lymph node metastasis (p = 0.001 and 0.001, respectively), advanced TNM stage (p = 0.009 and 0.019, respectively), and low survival rates (p = 0.031 and 0.045, respectively). PMID- 25496180 TI - Combined endoscopic and transcutaneous approach for immobile parotid stones. AB - CONCLUSION: Salivary stones in the parotid gland that are not amenable to endoscopic extraction can safely be removed by a combined, endoscopic-external approach. OBJECTIVE: Limitations for endoscopic removability of salivary stones from the parotid gland are immobile stones in the deeper salivary duct system. A combined endoscopic and transcutaneous approach gives access to these stones with possible preservation of the parotid gland. METHODS: A total of 10 consecutive patients were treated using the combined approach for the management of sialolithiasis of the parotid gland. The patients had previously undergone a sialendoscopy under local anesthesia and were proven to have large, immobile salivary stones in the salivary duct. RESULTS: In all patients, the procedure was successfully conducted with extraction of impacted stones. In 60% of the patients, a temporary stenting of the salivary duct was performed. All patients showed good clinical results with restored drainage of the salivary duct system and preserved gland function. PMID- 25496181 TI - Electrochemotherapy - possible benefits and limitations to its use in the head and neck region. AB - CONCLUSION: Electrochemotherapy (ECT) is an efficacious treatment. It should, however, be used with some caution in the treatment of head and neck cancer. OBJECTIVES: To assess local tumor control, safety, survival, and functional outcome after treatment of cancer in the head and neck region with ECT. METHODS: Four patients with primary T2 cancer of the oral cavity or oropharynx and one patient with a metastasis of renal cancer in the masseter muscle were treated with ECT with intratumorally administered bleomycin. Control biopsies were carried out 2 months after treatment. Postoperative radiotherapy was performed based on tumor T-stage and the depth of tumor infiltration. Serious adverse events and treatment malfunctions were recorded. The follow-up time was 24 months for the surviving patients and 20 months overall. The PSS-HN scale was used to assess the functional outcome. RESULTS: No local recurrence was recorded in any patient during the follow-up. However, only one patient was treated with ECT alone. There were four serious adverse events: one nearly lethal bleeding, two cases of osteoradionecrosis, and a fistula. One patient died from distant metastasis. The other patients were tumor-free both locally and overall at 24 months. The median functional outcome in all parameters was worse 1 year after treatment. PMID- 25496182 TI - Clinical outcomes of nedaplatin and S-1 treatment with concurrent radiotherapy in advanced head and neck cancer. AB - CONCLUSION: Nedaplatin and S-1 treatment with concurrent radiotherapy was effective, with acceptable toxicities. This regimen does not require extensive intravenous hydration and continuous infusion. Nedaplatin and S-1 may contribute to better clinical outcomes and improve quality of life for patients. OBJECTIVES: We retrospectively analyzed the clinical efficacy and toxicity of concurrent chemoradiotherapy with nedaplatin and S-1 for head and neck squamous cell cancer. METHODS: Forty-six patients with oropharyngeal, hypopharyngeal, and laryngeal cancer were treated with S-1 on days 1 through 14 and nedaplatin on day 1 every 4 weeks for two cycles of radiotherapy. Therapeutic responses and adverse events were assessed. RESULTS: Primary site tumors and neck lymph nodes exhibited complete response rates of 91% and 64.3%, respectively. The 4-year relapse-free survival and overall survival rates were 76.2% and 85.3%, respectively. The main grade 3 and 4 toxicities were mucositis (30%), leukopenia (30%), anorexia (22%), dermatitis (15%), and thrombocytopenia (9%). PMID- 25496183 TI - Activity-guided investigation of Carissa carandas (L.) roots for anti inflammatory constituents. AB - The present study was structured to investigate the anti-inflammatory potential of the extracts, fractions and compounds isolated from Carissa carandas (L.) roots. Bioassay guided fractionation of methanol extract based on inhibitory potential towards proinflammatory mediators (TNF-alpha, IL-1beta and nitric oxide (NO)) led to the identification of stigmasterol (1), lupeol (2), oleanolic acid (3), carissone (4) and scopoletin (5) as potential anti-inflammatory agents. Carissone (4) (IC50 = 20.1 +/- 2.69 MUg/mL) and scopoletin (5) (IC50 = 24.6 +/- 1.36 MUg/mL) exhibited significant inhibition of NO production comparable to specific NO inhibitor (L-NAME; IC50 = 19.82 +/- 1.64 MUg/mL) without affecting the cell viability. Also, 4 and 5 at a concentration of 30 MUM were found to inhibit 41.88-53.44% of TNF-alpha and IL-1beta. To the best of our knowledge, this is the first report displaying the anti-inflammatory effects of C. carandas (L.) roots, partially mediated by inhibition of TNF-alpha, IL-1beta and NO. PMID- 25496184 TI - Alterations in circadian/seasonal rhythms and vegetative functions are related to suicidality in DSM-5 PTSD. AB - BACKGROUND: Alterations in rhythmicity and vegetative functions have been reported as correlates of suicidality, particularly in patients with mood disorders. No investigation has addressed their impact on patients with post traumatic stress disorder (PTSD). Aim of the present study was to fulfill this gap. METHODS: Sixty-five out- and inpatients with DSM-5 PTSD were assessed by using the Mood Spectrum-Self Report-Lifetime Version (MOODS-SR), a questionnaire for lifetime mood spectrum symptomatology including alterations in circadian/seasonal rhythms and vegetative functions. Six items of the MOODS-SR were combined and dichotomized to assess suicidal ideation and/or attempts. RESULTS: Significant and positive associations were found between symptoms of lifetime dysregulations in rhythmicity and vegetative functions and suicidal ideation and/or attempts. All MOODS-SR sub-domains (rhythmicity, sleep, appetite/weight, sexual function, physical symptoms) were associated with an increased likelihood of suicidal ideation, but only changes in appetite/weight were associated with greater odd ratios of suicide attempts (OR = 2.099, 95% CI 1.148-3.841). CONCLUSIONS: Our results suggest that lifetime dysregulations in rhythmicity and vegetative functions may represent correlates of suicidality in patients with DSM-5 PTSD. PMID- 25496185 TI - Microsatellite markers reveal low levels of population sub-structuring of Plasmodium falciparum in southwestern Nigeria. AB - BACKGROUND: Genetic diversity studies provide evidence of Plasmodium falciparum differentiation that could affect fitness and adaptation to drugs and target antigens for vaccine development. This study describes the genetic structure of P. falciparum populations in urban and rural sites from southwestern Nigeria. METHODOLOGY: Ten neutral microsatellite loci were genotyped in 196 P. falciparum infections from three localities: Aramoko-Ekiti, a rural community; Lekki, an urban location and Badagry, a peri-urban border settlement. Analysis was performed on the genetic diversity, linkage disequilibrium, population structure and inter-population differentiation. RESULTS: Allelic diversity values were similar across all populations, with mean expected heterozygosity (HE) values between 0.65 and 0.79. No matching multilocus haplotypes were found and analysis of multilocus LD showed no significant index of association. Genetic differentiation between populations was low (PhiPT = 0.017). CONCLUSION: The absence of detectable population structure of P. falciparum in southwestern Nigeria is evident in the lack of significant differentiation between populations separated by about 200 km. This implies that a fairly uniform malaria control strategy may be effective over a wide geographic range in this highly endemic region. However, more wide-scale survey across the country will be required to inform malaria control in this large and densely populated endemic region. PMID- 25496187 TI - Efficacy of professionally administered plaque removal with or without adjunctive measures for the treatment of peri-implant mucositis. A systematic review and meta-analysis. AB - FOCUSED QUESTION: In patients with peri-implant mucositis, what is the efficacy of professionally administered plaque removal (PAPR) with adjunctive measures on changing signs of inflammation compared with PARP alone? MATERIALS AND METHODS: After electronic database and hand search, 19 full-text articles were independently screened by two reviewers. Finally, a total of seven studies fulfilled the inclusion criteria. The weighted mean difference (WMD) in bleeding on probing- (BOP) (primary outcome), gingival index- (GI) and probing pocket depth- (PD) reductions was estimated (random effect model). RESULTS: WMD in BOP reduction between test and control groups amounted to -8.16% [SD = 4.61; p = 0.07; 95% CI (-17.20, 0.88)] not favouring adjunctive antiseptic or antibiotic (local, systemic) therapy over PAPR alone. WMD in GI and PD reductions amounted to -0.12 [SD = 0.13; p = 0.34; 95% CI (-0.38, 0.13)] and -0.056 mm [SD = 0.10; p = 0.60; 95% CI (-0.27, 0.16)] not favouring adjunctive (antiseptics, systemic antibiotics, air abrasive device) over control measures respectively. Most studies evaluated reported on residual BOP and GI scores after therapy. CONCLUSIONS: Adjunctive therapy may not improve the efficacy of PAPR in reducing BOP, GI and PD scores at mucositis sites. Despite clinically important improvements, a complete disease resolution may not be expected by any of the treatment protocols investigated. PMID- 25496186 TI - Complex phenotype with social communication disorder caused by mosaic supernumerary ring chromosome 19p. AB - BACKGROUND: Deletions or duplications of chromosome 19 are rare and there is no previous report in the literature of a ring chromosome derived from proximal 19p. Copy Number Variants (CNVs) responsible for complex phenotypes with Social Communication Disorder (SCD), may contribute to improve knowledge about the distinction between intellectual deficiency and autism spectrum disorders. CASE PRESENTATION: We report the clinical and cytogenetic characterization of a patient (male, 33 years-old, first child of healthy Portuguese non-consanguineous parents) presenting with a complex phenotype including SCD without intellectual deficiency and carrying a mosaic supernumerary ring chromosome 19p. Microarray Based Comparative Genomic Hybridization and Fluorescence in situ Hybridization were performed. Genetic analysis showed a large mosaic interstitial duplication 19p13.12p12 of the short arm of chromosome 19, spanning 8.35 Mb. Our data suggested a putative association between psychosocial dysfunction and mosaic pure trisomy 19p13.2p12. CONCLUSION: This clinical report demonstrated the need to analyze more discreet trait-based subsets of complex phenotypes to improve the ability to detect genetic effects. To address this question and the broader issue of deciphering the yet unknown genetic contributors to complex phenotype with SCD, we suggest performing systematic psychological and psychiatric assessments in patients with chromosomal abnormalities. PMID- 25496188 TI - Molecular cloning and characterization of a novel carotenoid cleavage dioxygenase 1 from Lycium chinense. AB - Carotenoids are key precursor for aroma compounds in plants. Although the fruit of Lycium chinense contains numerous carotenoids, the formation mechanism of aroma compounds in L. chinense is still poorly understood. In this study, a new carotenoid cleavage dioxygenase (termed LmCCD1) was identified from the leaves of L. chinense. Expression analysis by semiquantitative PCR reveals that LmCCD1 gene is expressed in different tissues of L. chinense, and dominant expression of LmCCD1 gene was found in leaves, flowers, and ripe fruits. In addition, the expression level of LmCCD1 in fruits is in accordance with the content of beta ionone. Finally, recombinantly expressed LmCCD1 can cleave beta-carotene and lycopene to produce beta-ionone and pseudoionone in in vitro assays. These results indicate that LmCCD1 a novel carotenoids cleavage dioxygenase gene that may regulate the metabolic pathways responsible for aroma metabolite production (such as beta-ionone and pseudoionone) in L. chinense has been identified. PMID- 25496190 TI - Results From Three Performance Validity Tests (PVTs) in Adults With Intellectual Deficits. AB - Previous studies of performance on the Word Memory Test (WMT; Green, 2003 ; Green & Astner, 1995 ) in adults with very low intelligence have provided conflicting evidence. Most studies suggest that a Full-Scale IQ (FSIQ) less than 70 cannot explain failure on the WMT, but Shandera et al. ( 2010 ) suggest that many adults with mental retardation (MR) cannot pass the WMT. If so, we would expect adults with such low intelligence to fail the WMT at a high rate, even if they were motivated to perform well. In the current study, parents with an FSIQ of 70 or less, who were seeking custody of their children, rarely failed the WMT or the Medical Symptom Validity Test (MSVT; Green, 2004 ). They did not fail the WMT or MSVT any more often than adults of higher intelligence. On the other hand, adults with an external incentive to appear impaired scored significantly lower on the WMT and MSVT than did parents with an incentive to look good. The data strongly suggest that MR with an FSIQ in the range of 46 to 70 is not sufficient to explain failure on these performance validity tests by adults. PMID- 25496189 TI - Associations between a History of Traumatic Brain Injuries and Current Cigarette Smoking, Substance Use, and Elevated Psychological Distress in a Population Sample of Canadian Adults. AB - This study describes the prevalence of reported history of traumatic brain injury (TBI) and its association with reports of current substance use, cigarette smoking, and psychological distress among Canadian adults in a population sample. A cross-sectional sample of 1999 Ontario adults 18-93 years of age were surveyed by telephone in 2011 as part of the Center for Addiction and Mental Health's ongoing representative survey of adult mental health and substance use in Ontario, Canada. Loss of consciousness for at least 5 min or at least one overnight hospitalization resulting from symptoms associated with the TBI injury represented minimum criteria for TBI. An estimated 16.8% (95% confidence interval, 14.8, 19.0) of adults reported a TBI in their lifetime. Men had higher prevalence of TBI than women. Adults who reported a history of TBI had higher odds of reported past-year daily smoking (adjusted odds ratio [AOR] = 2.15), using cannabis (AOR = 2.80) and nonmedical opioids (AOR = 2.90), as well as screened significantly for recent elevated psychological distress (AOR = 1.97) in the past few weeks, compared to adults without a history of TBI. Co-occurrence of a history of TBI with current elevated psychological distress and substance use warrants vigilance among medical practitioners to assess the possibility of a history of TBI during reviews of the history leading to the occurrence of these conditions. PMID- 25496191 TI - Number of conspecifics and reproduction in the invasive plant Eschscholzia californica (Papaveraceae): is there a pollinator-mediated Allee effect? AB - The component Allee effect has been defined as 'a positive relationship between any measure of individual fitness and the number or density of conspecifics'. Larger plant populations or large patches have shown a higher pollinator visitation rate, which may give rise to an Allee effect in reproduction of the plants. We experimentally tested the effect of number of conspecifics on reproduction and pollinator visitation in Eschscholzia californica Cham., an invasive plant in Chile. We then built patches with two, eight and 16 flowering individuals of E. californica (11 replicates per treatment) in an area characterised by dominance of the study species. We found that E. californica exhibits a component Allee effect, as the number of individuals of this species has a positive effect on individual seed set. However, individual fruit production was not affected by the number of plants examined. Pollinator visitation rate was also independent of the number of plants, so this factor would not explain the Allee effect. This rate was positively correlated with the total number of flowers in the patches. We also found that the number of plants did not affect the seed mass or proportion of germinated seeds in the patches. Higher pollen availability in patches with 16 plants and pollination by wind could explain the Allee effect. The component Allee effect identified could lead to a weak demographic Allee effect that might reduce the rate of spread of E. californica. Knowledge of this would be useful for management of this invasive plant in Chile. PMID- 25496192 TI - Gene-deleted live-attenuated Trypanosoma cruzi parasites as vaccines to protect against Chagas disease. AB - Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. This illness is now becoming global, mainly due to congenital transmission, and so far, there are no prophylactic or therapeutic vaccines available to either prevent or treat Chagas disease. Therefore, different approaches aimed at identifying new protective immunogens are urgently needed. Live vaccines are likely to be more efficient in inducing protection, but safety issues linked with their use have been raised. The development of improved protozoan genetic manipulation tools and genomic and biological information has helped to increase the safety of live vaccines. These advances have generated a renewed interest in the use of genetically attenuated parasites as vaccines against Chagas disease. This review discusses the protective capacity of genetically attenuated parasite vaccines and the challenges and perspectives for the development of an effective whole-parasite Chagas disease vaccine. PMID- 25496193 TI - Stability of coagulation proteins in lyophilized plasma. AB - INTRODUCTION: External quality assessment (EQA) is an important component of quality assurance for laboratory tests of haemostasis. Lyophilization of plasma confers stability of labile clotting factors, allowing valid comparison of results between participating centres. However, elevated ambient temperatures in some geographical areas could affect the stability of lyophilized samples in transit. METHODS: The effect on lyophilized plasma samples of consistent elevated temperature with respect to haemostasis tests was determined in a single centre. The temperature to which packages were exposed during transit was also monitored. RESULTS: Survey packages were exposed to average temperatures up to 31.9 degrees C and maximum temperatures up to 39.7 degrees C over delivery periods between 1 and 8 weeks. In-house studies revealed samples to be stable over a 6-week period at a constant 30 degrees C, and only small changes were observed for samples exposed to 37 degrees C for 4 weeks. 6-week storage at 37 degrees C was associated with average changes of up to 15% in factor assay activity. CONCLUSION: Lyophilized EQA material employed in UK NEQAS surveys is stable under conditions encountered for the majority of participants, but in cases of delayed delivery of samples, the effect of temperature on sample integrity must be considered when assessing laboratory performance. PMID- 25496194 TI - Radiosurgery alone versus radiosurgery plus whole-brain irradiation for very few cerebral metastases from lung cancer. AB - BACKGROUND: It is unclear whether patients with few cerebral metastases benefit from whole-brain irradiation added to radiosurgery. Since primary tumors disseminating to the brain show different behavior, this question should be answered separately for each tumor type. This study compared both treatments in patients with 1-3 cerebral metastases from lung cancer. METHODS: Ninety-eight patients receiving radiosurgery alone were retrospectively compared to 50 patients receiving radiosurgery plus whole-brain irradiation for local control, distant cerebral control and overall survival. Ten other characteristics were additionally considered including radiosurgery dose, age, gender, Eastern Cooperative Oncology Group (ECOG) performance score, histology, number of cerebral metastases, maximum diameter of all cerebral metastases, site of cerebral metastases, extra-cerebral metastases, and interval from lung cancer diagnosis to irradiation. RESULTS: The treatment approach had no significant impact on local control (p = 0.61). On multivariate analysis of local control, ECOG performance score was significant (risk ratio [RR]: 2.10; p < 0.001). The multivariate analysis of distant brain control revealed significant positive associations with radiosurgery plus whole-brain irradiation (RR: 4.67; p < 0.001) and one cerebral metastasis (RR: 2.62; p < 0.001). Treatment approach was not significantly associated with overall survival (p = 0.32). On multivariate analysis, significant associations with overall survival were found for maximum diameter of all cerebral metastases (RR: 1.81; p = 0.008), extra-cerebral metastases (RR: 2.98; p < 0.001), and interval from lung cancer diagnosis to irradiation (RR: 1.19; p < 0.001). CONCLUSION: Addition of whole-brain irradiation to radiosurgery significantly improved distant brain control in patients with few cerebral metastases from lung cancer. This improvement did not translate into better overall survival. PMID- 25496195 TI - Risk factors of Pneumocystis pneumonia in solid organ recipients in the era of the common use of posttransplantation prophylaxis. AB - Pneumocystis pneumonia (PCP) in solid organ transplant (SOT) recipients becomes rare in the immediate posttransplantation period thanks to generalized prophylaxis. We aimed to identify the predictive factors for PCP in the era of universal prophylaxis and to propose a strategy for preventing PCP beyond the first year after transplantation. In a retrospective case-control study, 33 SOT cases with PCP diagnosed between 2004 and 2010 were matched with two controls each to identify risk factors for PCP by uni- and multivariate analysis. All the patients benefited from 6 months of posttransplantation trimethoprim sulfamethoxazole prophylaxis. Most PCP in SOT patients occurred during the second year posttransplantation (33%). By univariate analysis, age, nonuse of tacrolimus, total and CD4 lymphocyte counts, gamma-globulin concentration and cytomegalovirus (CMV) infection appeared to be PCP risk factors. In the final multivariate analysis, age (adjusted odds ratio [OR] 3.7, 95% confidence interval [CI]: 1.3-10.4), CMV infection (OR: 5.2, 95% CI: 1.8-14.7) and total lymphocyte count (OR: 3.9, 95% CI: 1.4-10.7) were found to be independently associated with PCP. The second year posttransplantation appeared to be the new period of highest risk of PCP. Age, CMV viremia and lymphocytes were the most pertinent predictive criteria to evaluate the risk of PCP in clinical practice. PMID- 25496197 TI - Self-directed care: participants' service utilization and outcomes. AB - OBJECTIVE: Self-directed care (SDC) is a mental health service delivery model in which participants budget the state dollars allotted for their care to purchase the goods and services they deem most appropriate for achieving their recovery goals. This study examines the demographic characteristics, service utilization patterns, and outcomes of individuals enrolled in the Florida Self-Directed Care (FloridaSDC) program, which is the oldest and most established SDC program in the United States for individuals diagnosed with a severe and persistent mental illness. METHOD: This is a naturalistic descriptive study in which demographic, service utilization, and outcome data (i.e., Functional Assessment Rating Scale (FARS) scores, days in the community, days worked, monthly income, discharge status) were collected from the clinical and fiscal records of 136 FloridaSDC participants. RESULTS: Key findings suggest that FloridaSDC participants had very little income and largely utilized their budgets to subsidize their living expenses. Though most participants did not work or earn income and very few left the program due to employment, participants' FARS scores improved modestly and nearly all participants remained in the community throughout the study period. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Participants' service purchases were rational given the poverty in which they live, and their outcomes did not suffer when they controlled decisions regarding their service needs. These findings highlight the utility and value of the personalized budgeting and individualized planning components of SDC. Findings also point to the need for practitioners to implement innovative strategies to enhance participants' employment readiness and supported employment opportunities. (PsycINFO Database Record PMID- 25496198 TI - Rising to the challenge of first episode psychosis: the NIMH Recovery After Initial Schizophrenia Episode (RAISE) initiative. AB - This editorial reviews the challenges of treating people who first experience a psychotic episode, and the core elements of effective programs for these individuals. It then describe the NIMH Recovery After Initial Schizophrenia Episode (RAISE) initiative, and other related developments in the U.S., and their implications for psychiatric rehabilitation practitioners. PMID- 25496196 TI - Microarray analysis of the Escherichia coli response to CdTe-GSH Quantum Dots: understanding the bacterial toxicity of semiconductor nanoparticles. AB - BACKGROUND: Most semiconductor nanoparticles used in biomedical applications are made of heavy metals and involve synthetic methods that require organic solvents and high temperatures. This issue makes the development of water-soluble nanoparticles with lower toxicity a major topic of interest. In a previous work our group described a biomimetic method for the aqueous synthesis of CdTe-GSH Quantum Dots (QDs) using biomolecules present in cells as reducing and stabilizing agents. This protocol produces nanoparticles with good fluorescent properties and less toxicity than those synthesized by regular chemical methods. Nevertheless, biomimetic CdTe-GSH nanoparticles still display some toxicity, so it is important to know in detail the effects of these semiconductor nanoparticles on cells, their levels of toxicity and the strategies that cells develop to overcome it. RESULTS: In this work, the response of E. coli exposed to different sized-CdTe-GSH QDs synthesized by a biomimetic protocol was evaluated through transcriptomic, biochemical, microbiological and genetic approaches. It was determined that: i) red QDs (5 nm) display higher toxicity than green (3 nm), ii) QDs mainly induce expression of genes involved with Cd+2 stress (zntA and znuA) and tellurium does not contribute significantly to QDs-mediated toxicity since cells incorporate low levels of Te, iii) red QDs also induce genes related to oxidative stress response and membrane proteins, iv) Cd2+ release is higher in red QDs, and v) QDs render the cells more sensitive to polymyxin B. CONCLUSION: Based on the results obtained in this work, a general model of CdTe-GSH QDs toxicity in E. coli is proposed. Results indicate that bacterial toxicity of QDs is mainly associated with cadmium release, oxidative stress and loss of membrane integrity. The higher toxicity of red QDs is most probably due to higher cadmium content and release from the nanoparticle as compared to green QDs. Moreover, QDs treated cells become more sensitive to polymyxin B making these biomimetic QDs candidates for adjuvant therapies against bacterial infections. PMID- 25496199 TI - Sensory processing, participation, and recovery in adults with serious mental illnesses. AB - OBJECTIVE: People with serious mental illnesses (SMI) have different sensory processing patterns compared to the general population. The purpose of the study was to examine the relationship between different sensory processing patterns and community participation and recovery-oriented outcomes to inform the development of innovative rehabilitation interventions, including those resulting in more accommodating environments. METHODS: A quasi-experimental, comparative research design was conducted by using data obtained from 95 adults with SMI who received public mental health services. Participants completed a sensory processing profile and measures of community participation, recovery, and quality of life. Comparisons were made between sensory profile categories for each dependent variable using multivariate analyses of variance. RESULTS: The category with more evidence of self-reported low registration and sensory sensitivity than most reported less participation and lower levels of recovery than did their peers with processing patterns in typical ranges. The category with more self-reported sensory sensitivity than most reported lower quality of life. Finally, the category in the "similar" to "more than most" range on self-reported sensory seeking had higher levels of participation and recovery. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Assessment of sensory processing patterns in adults with SMI can inform sensory-based interventions that might result in greater community participation and other recovery outcomes. Interventions can include those that seek to enhance person-environment fit by altering the environment, as well as interventions that enhance adaptive sensory responses to external stimuli. PMID- 25496200 TI - Affective forecasting in schizophrenia: comparing predictions to real-time Ecological Momentary Assessment (EMA) ratings. AB - OBJECTIVE: "Affective forecasting" refers to the predictions people make about future affective experiences. These predictions influence decision making, which in turn might impact individuals' level of functioning, goal-directed behavior, and pursuit of potentially rewarding activities. In the current study, we explored affective forecasting in people diagnosed with schizophrenia. METHOD: Twenty-four participants with schizophrenia or schizoaffective disorder were asked to provide affective forecasts for an upcoming week. They were subsequently given a handheld mobile device that prompted them to complete "in-the-moment" positive affect (i.e., feeling active, excited, interested) and negative affect (i.e., jittery, scared, hostile, upset, guilty) ratings 6 times daily, over the next 7 days. Paired-sample t tests were used to compare forecasts to average weekly momentary ratings. RESULTS: Participants expected more emotionally charged weeks than they actually experienced-both positive affect forecasts and negative affect forecasts were more intense than the average weekly ratings. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The findings of the study have implications for psychiatric rehabilitation; outlining the differences between consumer forecasts (e.g., excessively pessimistic predictions, unrealistic expectations) and actual experience can serve as a component of psychosocial interventions, including motivational interviewing, goal setting, thought challenging, and vocational rehabilitation. Mobile technologies can be incorporated for short-term data collection in the context of these rehabilitation efforts. PMID- 25496201 TI - Education and training column: communities of practice. AB - TOPIC: This column describes the key components of a community of practice, with examples from the experience of 1 such group. PURPOSE: A community of practice is a potentially useful model for developing and disseminating knowledge about psychiatric rehabilitation and to supplement the short-term training sessions that typically constitute psychiatric rehabilitation workforce development. SOURCES USED: This description draws from published material on communities of practice and the authors' experience. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Communities of practice are receiving increased attention for workforce development, and guidelines do exist for making these communities effective in achieving their aims. The development of such learning communities provides members with a chance for professional development, but also the opportunity to develop greater overall capacity of the mental health system by sharing knowledge and expertise across organizational lines. PMID- 25496202 TI - Structure-property relationships in an iridium(III) bis(terpyridine) complex with extended conjugated side chains. AB - Iridium(III) bis(terpyridine) complexes are known as excellent triplet emitters with emission lifetimes in the order of microseconds. We report the homoleptic complex [IrL2](3+) (L = 4'-(4-2,5-bis(octyloxy)-4-styrylphenyl)ethinyl)phenyl) 2,2':6',2"-terpyridine) that shows no detectable phosphorescence at room temperature but shows fluorescence. Emission spectra of [IrL2](3+) depend on the excitation wavelength. The origin of this behavior is studied with the help of results from (TD-)DFT calculations and is attributed to the selective excitation of different rotamers and isomers. Femtosecond-transient absorption experiments give further support for this interpretation as the specific excited-state absorption features of Z- and E-stilbene motives can be identified. PMID- 25496203 TI - Buddhist social networks and health in old age: A study in central Thailand. AB - AIM: Religious social networks are well known for their capacity to improve individual health, yet the effects of friendship networks within the Buddhist context remain largely unknown. The present study aimed to compare health status and social support in community-dwelling older adults according to their level of Buddhist social network (BSN) involvement, and to examine the association between BSN involvement and functional health among older adults. METHODS: A cross sectional survey was carried out among 427 Buddhist community-dwelling older adults aged >=60 years in Nakhon Pathom, Thailand. Data were collected from home based personal interviews using a structured questionnaire. Health status was defined according to the measures of basic and advanced activities of daily living (ADL), the 15-item Geriatric Depression Scale and subjective quality of life. Perceived social support was assessed across the four dimensions of tangible, belonging, emotional and information support. Multiple logistic regression was used for analysis. RESULTS: Older adults with BSN involvement reported better functional, mental and social health status, and perceived greater social support than those without BSN involvement. In addition, BSN involvement was positively associated with independence in basic and advanced ADL. After adjusting for age, sex, education, income, morbidity and depressive symptoms, BSN showed a strong association with advanced ADL and a weak association with basic ADL. CONCLUSION: The results show that involvement in BSN could contribute positively to functional health, particularly with regard to advanced ADL. Addressing the need for involvement in these networks by older adults might help delay functional decline and save on healthcare costs. PMID- 25496205 TI - Evaluation of nasal patency by acoustic rhinometry after repair of complete unilateral cleft lip and palate. AB - PURPOSE: The aim of the current study was to evaluate nasal patency by acoustic rhinometry in children aged 4-8 years with repaired complete unilateral cleft lip and palate (UCLP) compared with an age-matched control group without cleft lip and palate (CLP). METHODS: This comparative cross-sectional study was conducted at a tertiary care teaching hospital and a private ENT clinic in Porto Alegre, southern Brazil. The case group consisted of 38 children who had undergone surgery for complete UCLP (mean age, 6.44 years), and the control group of 21 children without CLP (mean age, 6.21 years) recruited among patients seeking medical care for ear diseases at the private clinic. Acoustic rhinometry was performed in all children after administration of oxymetazoline hydrochloride (2 * 0.25 mg/mL) for nasal vasoconstriction. RESULTS: The minimal cross-sectional area and nasal volume of the cleft side were smaller than those of the non-cleft side in the case group (p = 0.001). When the two groups were compared, the non cleft side in the case group did not differ from the control group (p = 0.175), but the minimal cross-sectional area and volume of the cleft nasal cavity were smaller than the mean values of the two nostrils of controls (p = 0.001). CONCLUSION: In conclusion, our findings show that nasal patency on the cleft side is impaired in children surgically treated for complete UCLP. PMID- 25496204 TI - Does removal of CU-IUD in patients with biofilm forming candida really maintain regression of clinical symptoms? AB - OBJECTIVE: To evaluate whether symptoms and recurrence would differ with and without Cu-IUD removal in patients with concomitant biofilm forming Candida spp. METHODS: The data of 270 consecutive patients wearing TCu380A Cu-IUD were evaluated. Among these patients, 100/270 were found to have Candida spp. isolated from the tail of Cu-IUD or vaginal samples. These patients were investigated in four groups: Group 1 (n = 24; Biofilm (+), Cu-IUD removed), Group 2 (n = 14; Biofilm (+), Cu-IUD not removed), Group 3 (n = 29; Biofilm (-), Cu-IUD removed), Group 4 (n = 33; Biofilm (-), Cu-IUD not removed). Patients in each group were followed for clinical signs and symptoms for 8-16 months and compared to each other. RESULTS: Symptoms, physical findings and candida positivity have decreased statistically significantly in Group 1 one year after removal of Cu-IUD (95.8% vs. 4.2%, p < 0.01; 95.8% vs. 4.2%, p < 0.01; 100% vs. 8.3%, p < 0.01 respectively). In Group 2, symptoms, physical findings and candida positivity have decreased after follow-up, but without a statistical significance. In Group 3, all the parameters have decreased, but only decrease in candida positivity has reached statistical significance (100% vs. 48.3%, p < 0.01). In Group 4 - as in Group 1- symptoms, physical findings and candida positivity have decreased statistically significantly (48.5% vs. 18.2%, p = 0.01; 72.7% vs. 48.5%, p = 0.05; 100% vs. 51.5%, p < 0.01 respectively). CONCLUSION: Biofilm forming microorganisms should be considered in the management of vaginal infections or symptoms for safer use of intrauterine devices. PMID- 25496206 TI - A prospective study of trends in consumption of cigarettes and alcohol among adults in a rural Ugandan population cohort, 1994-2011. AB - OBJECTIVES: To characterise trends over time in smoking and alcohol consumption in a rural Ugandan population between 1994 and 2011. METHODS: We used self reported data from a long-standing population cohort - the General Population Cohort. From 1989 to 1999, the study population comprised about 10 000 residents of 15 adjacent villages. From 1999, 10 more villages were added, doubling the population. Among adults (>=13 years, who comprise about half of the total study population), data on smoking were collected in 1994/1995, 2008/2009 and in 2010/2011. Data on alcohol were collected in 1996/1997, 2000/2001, 2009/2010 and 2010/2011. RESULTS: The reported prevalence of smoking among men was 17% in 1994/1995, 14% in 2008/2009 and 16% in 2010/2011; equivalent figures for women were 1.5%, 1% and 2%. In the most recent time period, for both sexes combined, prevalence of smoking increased from 1.5% in those aged <29 years, to 18% in those 50+ years (P < 0.001); prevalence was 14.8% in the lowest tertile of socio economic status, decreasing to 3.7% in the highest (P < 0.001). For alcohol consumption, current drinking was reported by 39% in 1996/1997, 35% in 2000/2001 and 28% in 2010/2011; men were more likely to drink than women (32.9% vs. 23.5% in 2010/2011) and consumption increased with age (P < 0.001); and was associated with low socio-economic status, riskier sexual behaviour and being HIV positive (P < 0.001). CONCLUSIONS: In this rural Ugandan population, consumption of cigarettes and alcohol is higher among men than women, increases with age and is more frequent among those with low socio-economic status. We find no evidence of increases in either exposure over time. PMID- 25496207 TI - Antimicrobial resistance: impact on clinical and economic outcomes and the need for new antimicrobials. AB - INTRODUCTION: Antimicrobial resistance is a well-recognized global threat; thus, the development of strong infection control policies coupled with antimicrobial stewardship strategies and new therapies is required to reverse this process. In its 2013 report on antimicrobial resistance, the Centers for Disease Control and Prevention focused on this problem while presenting estimated annual rates of infections with antimicrobial-resistant organisms and their related mortality rates. Whereas some resistant pathogens were considered less threatening, others such as carbapenem-resistant Enterobacteriaceae were associated with higher mortality rates owing to limited treatment options. AREAS COVERED: An overview of the most common antimicrobial-resistant pathogens, focusing on risk factors for acquisition, clinical and economic outcomes, as well as current treatment options. Strategies to optimize antimicrobial therapy with currently available agents, in addition to newly developed antimicrobials are also discussed. EXPERT OPINION: The emergence of pathogens with a variety of resistance mechanisms has intensified the challenges associated with infection control and treatment strategies. Therefore, prudent use of currently available antimicrobial agents, as well as implementing measures to limit spread of resistance is paramount. Although several new antimicrobials have been recently approved or are in the pipeline showing promise in the battle against resistance, the appropriate use of these agents is required as the true benefits of these treatments are to be recognized in the clinical care setting. PMID- 25496208 TI - Role of Drosophila retinoblastoma protein instability element in cell growth and proliferation. AB - The RB tumor suppressor, a regulator of the cell cycle, apoptosis, senescence, and differentiation, is frequently mutated in human cancers. We recently described an evolutionarily conserved C-terminal "instability element" (IE) of the Drosophila Rbf1 retinoblastoma protein that regulates its turnover. Misexpression of wild-type or non-phosphorylatable forms of the Rbf1 protein leads to repression of cell cycle genes. In contrast, overexpression of a defective form of Rbf1 lacking the IE (DeltaIE), a stabilized but transcriptionally less active form of the protein, induced ectopic S phase in cell culture. To determine how mutations in the Rbf1 IE may induce dominant effects in a developmental context, we assessed the impact of in vivo expression of mutant Rbf1 proteins on wing development. DeltaIE expression resulted in overgrowth of larval wing imaginal discs and larger adult wings containing larger cells. In contrast, a point mutation in a conserved lysine of the IE (K774A) generated severely disrupted, reduced wings. These contrasting effects appear to correlate with control of apoptosis; expression of the pro-apoptotic reaper gene and DNA fragmentation measured by acridine orange stain increased in flies expressing the K774A isoform and was suppressed by expression of Rbf1DeltaIE. Intriguingly, cancer associated mutations affecting RB homologs p130 and p107 may similarly induce dominant phenotypes. PMID- 25496209 TI - Adverse drug events identified by triggers at a teaching hospital in Brazil. AB - BACKGROUND: Adverse drug events (ADEs) are one of the most frequent causes of patient harm resulting from medical interventions, especially among inpatients. This study aimed to evaluate the incidence of ADEs and characterise them in terms of degree of harm, medication implicated and patient symptoms, at a Brazilian university hospital. METHODS: This is a retrospective study of chart review. The method, developed by the Institute for Healthcare Improvement, uses triggers to identify possible ADEs. The study population comprised adult inpatients at least 15 years old. Obstetric patients and those hospitalised for less than 48 hours were excluded. Time spent in the intensive care unit was not considered for the purposes of this study. Patients were selected on the basis of simple random sampling of records of patients discharged from January to July 2008. The records selected were reviewed by a multidisciplinary team. The indicators of ADE incidence were patients with ADEs and ADE rate per 100 patients. Patients with and without ADE were compared in the bivariate analysis. To identify the drugs classes most often associated with events, the number of prescriptions of each class of drug was related to the number of events assigned to it. RESULTS: The 240 inpatients studied were of mean age 50.8 (SD = 20.0) years, and mostly male (63.8%). A total of 44 ADEs were identified in 35 patient records, with 14.6% of patients presenting ADE and a rate of 18.3% ADEs per 100 patients. The most frequent were skin rash and nausea and vomiting, but severe ADEs were also identified. In the bivariate analysis long hospital stay and use of 10 or more drugs were associated with the occurrence of ADEs (p-value < 0.01). The drug classes associated with the highest number of events were anti-infective. CONCLUSION: About 1/6 of the hospitalized patients in a teaching hospital showed adverse events what is, by itself, cause for concern. Increased number of prescribed drugs and greater period of hospitalization appear to favour the occurrence of these events. In the future studies with higher number of patients may offer evidences of the association. PMID- 25496210 TI - Distal regulation of heme binding of heme oxygenase-1 mediated by conformational fluctuations. AB - Heme oxygenase-1 (HO-1) is an enzyme that catalyzes the oxidative degradation of heme. Since free heme is toxic to cells, rapid degradation of heme is important for maintaining cellular health. There have been useful mechanistic studies of the HO reaction based on crystal structures; however, how HO-1 recognizes heme is not completely understood because the crystal structure of heme-free rat HO-1 lacks electron densities for A-helix that ligates heme. In this study, we characterized conformational dynamics of HO-1 using NMR to elucidate the mechanism by which HO-1 recognizes heme. NMR relaxation experiments showed that the heme-binding site in heme-free HO-1 fluctuates in concert with a surface exposed loop and transiently forms a partially unfolded structure. Because the fluctuating loop is located over 17 A distal from the heme-binding site and its conformation is nearly identical among different crystal structures including catalytic intermediate states, the function of the loop has been unexamined. In the course of elucidating its function, we found interesting mutations in this loop that altered activity but caused little change to the conformation. The Phe79Ala mutation in the loop changed the conformational dynamics of the heme binding site. Furthermore, the heme binding kinetics of the mutant was slower than that of the wild type. Hence, we concluded that the distal loop is involved in the regulation of the conformational change for heme binding through the conformational fluctuations. Similar to other enzymes, HO-1 effectively promotes its function using the identified distal sites, which might be potential targets for protein engineering. PMID- 25496211 TI - Formation of layer-by-layer assembled titanate nanotubes filled coating on flexible polyurethane foam with improved flame retardant and smoke suppression properties. AB - A fire blocking coating made from chitosan, titanate nanotubes and alginate was deposited on a flexible polyurethane (FPU) foam surface by a layer-by-layer assembly technique in an effort to reduce its flammability. First, titanate nanotubes were prepared by a hydrothermal method. And then the coating growth was carried out by alternately submerging FPU foams into chitosan solution, titanate nanotubes suspension and alginate solution. The mass gain of coating on the surface of FPU foams showed dependency on the concentration of titanate nanotubes suspension and the trilayers's number. Scanning electron microscopy indicated that titanate nanotubes were distributed well on the entire surface of FPU foam and showed a randomly oriented and entangled network structure. The cone calorimeter result indicated that the coated FPU foams showed reduction in the peak heat release rate (peak HRR), peak smoke production rate (peak SPR), total smoke release (TSR) and peak carbon monoxide (CO) production compared with those of the control FPU foam. Especially for the FPU foam with only 5.65 wt % mass gain, great reduction in peak HRR (70.2%), peak SPR (62.8%), TSR (40.9%) and peak CO production (63.5%) could be observed. Such a significant improvement in flame retardancy and the smoke suppression property for FPU foam could be attributed to the protective effect of titanate nanotubes network structure formed, including insulating barrier effect and adsorption effect. PMID- 25496212 TI - Reduced Myeloid-derived Suppressor Cells in the Blood and Endometrium is Associated with Early Miscarriage. AB - PROBLEM: The contribution of myeloid-derived suppressor cells (MDSC) in patients suffering from early or recurrent miscarriage is unknown. MDSC are implicated in modulation of T-cell response in healthy pregnancies; however, the role of MDSC in patients suffering from miscarriage has not been studied. We hypothesized that MDSC play major role in inducing maternal-fetal tolerance and this tolerance is compromised in patients suffering from miscarriage. METHOD OF STUDY: MDSC level was assessed by flow cytometry and immunostaining in blood and endometrial decidua, respectively. Activation of T cells was determined by MTT proliferation and IL-2 ELISA assays. RESULTS AND CONCLUSION: The miscarriage patients harbor reduced level of functionally suppressive MDSC in blood and endometrium as compared to healthy control women with successful pregnancies. These results suggest MDSC regulate maternal tolerance in healthy pregnancies and that drug inducing MDSC could have therapeutic implication in the miscarriage patients. PMID- 25496213 TI - Urticarial vasculitis in a French bulldog. PMID- 25496214 TI - New insight into microgel-stabilized emulsions using transmission X-ray microscopy: nonuniform deformation and arrangement of microgels at liquid interfaces. AB - Microgel-covered interfaces, e.g., in emulsions, have attracted much interest lately. Different imaging techniques have been used to image these interfaces, either flat or curved, to investigate their properties and appearance. Techniques such as cryogenic scanning electron microscopy (cryo-SEM) and confocal microscopy have provided valuable insight into microgel-covered systems but still have some disadvantages such as part of the microgels being trapped in vitrified liquid or the need for fluorescent markers. Some of these disadvantages can be overcome by using transmission X-ray microscopy (TXM), which has the advantage of allowing the investigation of adsorbed and free microgels simultaneously. We used TXM to acquire tomographic image series of microgel-covered droplets and calculated 3D reconstructions from these image stacks. As a result, we could show that microgels deform anisotropically and penetrate the oil droplets in the hydrated state. Additionally, 3D reconstruction gives an idea of the arrangement of microgels adsorbed to oil droplets and reveals that droplet stabilization is possible without full coverage of the interface with polymer segments. PMID- 25496215 TI - The Added Value of Statistical Modeling of Backscatter Properties in the Management of Breast Lesions at US. AB - PURPOSE: To develop a classification method based on the statistical backscatter properties of tissues that can be used as an ancillary tool to the usual Breast Imaging Reporting and Data System (BI-RADS) classification for solid breast lesions identified at ultrasonography (US). MATERIALS AND METHODS: This study received institutional review board approval, and all subjects provided informed consent. Eighty-nine women (mean age, 50 years; age range, 22-82 years) with 96 indeterminate solid breast lesions (BI-RADS category 4-5; mean size, 13.2 mm; range, 2.6-44.7 mm) were enrolled. Prior to biopsy, additional radiofrequency US images were obtained, and a 3-second cine sequence was used. The research data were analyzed at a later time and were not used to modify patient management decisions. The lesions were segmented manually, and parameters of the homodyned K distribution (alpha, k, and MUn values) were extracted for three regions: the intratumoral zone, a 3-mm supratumoral zone, and a 5-mm infratumoral zone. The Mann-Whitney rank sum test was used to identify parameters with the best discriminating value, yielding intratumoral alpha, supratumoral k, and infratumoral MUn values. RESULTS: The 96 lesions were classified as follows: 48 BI-RADS category 4A lesions, 16 BI-RADS category 4B lesions, seven BI-RADS category 4C lesions, and 25 BI-RADS category 5 lesions. There were 24 cancers (25%). The area under the receiver operating characteristic curve was 0.76 (95% confidence interval: 0.65, 0.86). Overall, 24% of biopsies (in 17 of 72 lesions) could have been spared. By limiting analysis to lesions with a lower likelihood of malignancy (BI-RADS category 4A-4B), this percentage increased to 26% (16 of 62 lesions). Among benign lesions, the model was used to correctly classify 10 of 38 fibroadenomas (26%) and three of seven stromal fibroses (43%). CONCLUSION: The statistical model performs well in the classification of solid breast lesions at US, with the potential of preventing one in four biopsies without missing any malignancy. PMID- 25496216 TI - Fluorine MR Imaging of Inflammation in Atherosclerotic Plaque in Vivo. AB - PURPOSE: To preliminarily test the hypothesis that fluorine 19 ((19)F) magnetic resonance (MR) imaging enables the noninvasive in vivo identification of plaque inflammation in a mouse model of atherosclerosis, with histologic findings as the reference standard. MATERIALS AND METHODS: The animal studies were approved by the local animal ethics committee. Perfluorocarbon (PFC) emulsions were injected intravenously in a mouse model of atherosclerosis (n = 13), after which (19)F and anatomic MR imaging were performed at the level of the thoracic aorta and its branches at 9.4 T. Four of these animals were imaged repeatedly (at 2-14 days) to determine the optimal detection time. Repeated-measures analysis of variance with a Tukey test was applied to determine if there was a significant change in (19)F signal-to-noise ratio (SNR) of the plaques and liver between the time points. Six animals were injected with a PFC emulsion that also contained a fluorophore. As a control against false-positive results, wild-type mice (n = 3) were injected with a PFC emulsion, and atherosclerotic mice were injected with a saline solution (n = 2). The animals were sacrificed after the last MR imaging examination, after which high-spatial-resolution ex vivo MR imaging and bright-field and immunofluorescent histologic examination were performed. RESULTS: (19)F MR signal was detected in vivo in plaques in the aortic arch and its branches. The SNR was found to significantly increase up to day 6 (P < .001), and the SNR of all mice at this time point was 13.4 +/- 3.3. The presence of PFC and plaque in the excised vessels was then confirmed both through ex vivo (19)F MR imaging and histologic examination, while no signal was detected in the control animals. Immunofluorescent histologic findings confirmed the presence of PFC in plaque macrophages. CONCLUSION: (19)F MR imaging allows the noninvasive in vivo detection of inflammation in atherosclerotic plaques in a mouse model of atherosclerosis and opens up new avenues for both the early detection of vulnerable atherosclerosis and the elucidation of inflammation mechanisms in atherosclerosis. PMID- 25496217 TI - TLR4 and NALP3 inflammasome in the development of endothelial dysfunction in uraemia. AB - BACKGROUND: The increased cardiovascular risk present in chronic kidney disease (CKD) is related to the development of endothelial dysfunction, whose mechanisms are still unclear. Accumulation of toxins and proinflammatory cytokines may constitute danger-associated molecular patterns (DAMP) to which endothelial cells are continuously exposed. Potential involvement of mechanisms recognizing DAMP, such as TLR and inflammasomes, has been explored. MATERIALS AND METHODS: Endothelial cells in culture were exposed to sera samples collected from patients with CKD: (i) stages 4-5 not on dialysis (PreD), (ii) on maintenance haemodialysis (HD) and (iii) peritoneal dialysis (PD). Changes in TLR4 and ICAM-1 expression, reactive oxygen species (ROS) production and TLR4 signalling were explored. Assembly of NALP3 inflammasome components was also investigated. RESULTS: TLR4 was expressed at the cell surface and increased significantly in response to PreD, HD and PD sera, paralleling with the activation of the cell stress protein Akt and the inflammation-related transcription factor NFkappaB, with elevated surface ICAM-1 expression and ROS production. TLR4 blockade partially decreased these effects. Exposure of cells to uraemic sera induced assembly of NALP3 components, with caspase-1 activation, especially in response to HD and PD sera. CONCLUSIONS: TLR4 and NALP3 inflammasomes, crucial elements of innate immunity, contribute to the development and perpetuation of endothelial dysfunction in response to the uraemic toxicity. These mechanisms constitute potential therapeutic targets to improve endothelial dysfunction and to reduce the increased cardiovascular risk in CKD. PMID- 25496219 TI - Gemcitabine and vinorelbine treatment in cutaneous T-cell lymphoma in four patients. AB - Treatment options for advanced stage cutaneous T-cell lymphoma (CTCL) are limited by the their efficacy and side-effects profile. Gemcitabine, a pyrimidine analogue, has been reported to be efficacious in CTCL. Most of the studies published used gemcitabine as a single agent in treating advanced CTCL. Our small case series demonstrated that a combination of gemcitabine and vinorelbine induced partial remission in all four patients with refractory or advanced CTCL, although the effects were not sustained for a long duration (2-6 months). Two patients had neutropenia and one had acute hepatitis, requiring discontinuation of treatment. PMID- 25496218 TI - Hypocretin/Orexin regulation of dopamine signaling and cocaine self administration is mediated predominantly by hypocretin receptor 1. AB - Extensive evidence suggests that the hypocretins/orexins influence cocaine reinforcement and dopamine signaling via actions at hypocretin receptor 1. By comparison, the involvement of hypocretin receptor 2 in reward and reinforcement processes has received relatively little attention. Thus, although there is some evidence that hypocretin receptor 2 regulates intake of some drugs of abuse, it is currently unclear to what extent hypocretin receptor 2 participates in the regulation of dopamine signaling or cocaine self-administration, particularly under high effort conditions. To address this, we examined the effects of hypocretin receptor 1, and/or hypocretin receptor 2 blockade on dopamine signaling and cocaine reinforcement. We used in vivo fast scan cyclic voltammetry to test the effects of hypocretin antagonists on dopamine signaling in the nucleus accumbens core and a progressive ratio schedule to examine the effects of these antagonists on cocaine self-administration. Results demonstrate that blockade of either hypocretin receptor 1 or both hypocretin receptor 1 and 2 significantly reduces the effects of cocaine on dopamine signaling and decreases the motivation to take cocaine. In contrast, blockade of hypocretin receptor 2 alone had no significant effects on dopamine signaling or self-administration. These findings suggest a differential involvement of the two hypocretin receptors, with hypocretin receptor 1 appearing to be more involved than hypocretin receptor 2 in the regulation of dopamine signaling and cocaine self administration. When considered with the existing literature, these data support the hypothesis that hypocretins exert a permissive influence on dopamine signaling and motivated behavior via preferential actions on hypocretin receptor 1. PMID- 25496220 TI - Practical approach to physical-chemical acid-base management. Stewart at the bedside. AB - The late Peter Stewart developed an approach to the analysis of acid-base disturbances in biological systems based on basic physical-chemical principles. His key argument was that the traditional carbon dioxide/bicarbonate analysis with just the use of the Henderson-Hasselbalch equation does not account for the important role in the regulation of H(+) concentration played by strong ions, weak acids and water itself. Acceptance of his analysis has been limited because it requires a complicated set of calculations to account for all the variables and it does not provide simple clinical guidance. However, the analysis can be made more pragmatic by using a series of simple equations to quantify the major processes in acid-base disturbances. These include the traditional PCO2 component and the addition of four metabolic processes, which we classify as "water effects," "chloride-effects," "albumin effects," and "others." Six values are required for the analysis: [Na(+)], [Cl(-)], pH, Pco2, albumin concentration, and base excess. The advantage of this approach is that it gives a better understanding of the mechanisms behind acid-base abnormalities and more readily leads to clinical actions that can prevent or correct the abnormalities. We have developed a simple free mobile app that can be used to input the necessary values to use this approach at the bedside (Physical/Chemical Acid Base Calculator). PMID- 25496221 TI - Exposure of two Eutrema salsugineum (Thellungiella salsuginea) accessions to water deficits reveals different coping strategies in response to drought. AB - Eutrema salsugineum is an extremophile related to Arabidopsis. Accessions from Yukon, Canada and Shandong, China, were evaluated for their tolerance to water deficits. Plants were exposed to two periods of water deficit separated by an interval of re-watering and recovery. All plants took the same time to wilt during the first drought exposure but Yukon plants took 1 day longer than Shandong plants following the second drought treatment. Following re-watering and turgor recovery, solute potentials of Shandong leaves returned to predrought values while those of Yukon leaves were lower than predrought levels consistent with having undergone osmotic adjustment. Polar metabolites profiled in re watered plants showed that different metabolites are accumulated by Yukon and Shandong plants recovering from a water deficit with glucose more abundant in Yukon and fructose in Shandong leaves. The drought-responsive expression of dehydrin genes RAB18, ERD1, RD29A and RD22 showed greater changes in transcript abundance in Yukon relative to Shandong leaves during both water deficits and recovery with the greatest difference in expression appearing during the second drought. We propose that the initial exposure of Yukon plants to drought renders them more resilient to water loss during a subsequent water deficit leading to delayed wilting. Yukon plants also established a high leaf water content and increased specific leaf area during the second deficit. Shandong plants undergoing the same treatment regime do not show the same beneficial drought tolerance responses and likely use drought avoidance to cope with water deficits. PMID- 25496222 TI - Investigating the sustainability of careers in academic primary care: a UK survey. AB - BACKGROUND: The UK National Health Service (NHS) is undergoing institutional reorganisation due to the Health and Social Care Act-2012 with a continued restriction on funding within the NHS and clinically focused academic institutions. The UK Society for Academic Primary Care (SAPC) is examining the sustainability of academic primary care careers within this climate and preliminary qualitative work has highlighted individual and organisational barriers. This study seeks to quantify the current situation for academics within primary care. METHODS: A survey of academic primary care staff was undertaken. Fifty-three academic primary care departments were selected. Members were invited to complete a survey which contained questions about an individual's career, clarity of career pathways, organisational culture, and general experience of working within the area. Data were analysed descriptively with cross-tabulations between survey responses and career position (early, mid-level, senior), disciplinary background (medical, scientist), and gender. Pearson chi-square test was used to determine likelihood that any observed difference between the sets arose by chance. RESULTS: Responses were received from 217 people. Career pathways were unclear for the majority of people (64%) and 43% of the workforce felt that the next step in their career was unclear. This was higher in women (52% vs. men 25%; chi(2)(3) = 14.76; p = 0.002) and higher in those in early career (50% vs. senior career, 25%) and mid-career(45%; vs. senior career; chi(2)(6) = 29.19, p < 0.001). The workforce appeared geographically static but unstable with only 50% of people having their contract renewed or extended. The majority of people (59%) have never been promoted by their institution. There were perceptions of gender equality even in the context of females being underrepresented in senior positions (19% vs. males 39%; chi(2)(3) = 8.43, p = 0.015). Despite these findings, the majority of the workforce reported positive organisational and cultural experiences. CONCLUSIONS: Sustainability of a academic primary care career is undermined by unclear pathways and a lack of promotion. If the discipline is to thrive, there is a need to support early and mid-career individuals via greater transparency of career pathways. Despite these findings staff remained positive about their careers. PMID- 25496224 TI - Vitamin K and other markers of micronutrient status in morbidly obese patients before bariatric surgery. AB - BACKGROUND: Micronutrient deficiencies occur in morbidly obese patients. The aim of this study was to assess vitamin deficiencies prior to bariatric surgery including vitamin K about which there is little data in this population. METHODS: A prospective assessment of 118 consecutive patients was performed. Clinical allied with haematological and biochemical variables were measured. Micronutrients measured included vitamins K1 , PIVKA-II (protein-induced in vitamin K absence factor II), vitamin D, vitamin B12 (holotranscobalamin), iron, transferrin and folate. RESULTS: Patients were aged 49 +/- 11 [mean (SD, standard deviation)] years, body mass index (BMI) 50 +/- 8 kg/m(2), 66% female and 78% Caucasian. Hypertension was present in 47% and type 2 diabetes in 32%. Vitamin D supplements had been prescribed in 8%. Micronutrient insufficiencies were found for vitamin K (40%), vitamin D (92%) and vitamin B12 (25%), and also iron (44%) and folate (18%). Normocalcaemic vitamin D insufficiency with secondary hyperparathyroidism was present in 18%. Iron and transferrin levels were associated with age, sex and estimated glomerular filtration rate. Vitamin K levels were associated with age, and inversely with BMI and diabetes mellitus; and PIVKA-II with smoking, triglycerides and liver function markers. Vitamin D levels were associated with statin use and prescription of supplements and inversely with BMI. Vitamin B12 levels were associated with ethnicity and HbA1c. CONCLUSION: Micronutrient status shows differing relationships with age, gender and BMI. Vitamin K insufficiency was present in 40% and not related to deficiencies in other vitamins or micronutrients. Vitamin D and vitamin K supplementation should be considered prebariatric surgery in patients with diabetes or severe insulin resistance. PMID- 25496223 TI - Construction of a synthetic phage-displayed Nanobody library with CDR3 regions randomized by trinucleotide cassettes for diagnostic applications. AB - BACKGROUND: Nanobodies (Nbs) have proved their great value as therapeutic molecules and clinical diagnostic tools. Although the routine procedure to obtain Nbs is to immunize camels with antigens, it is unavailable to immunize a camel when the antigens are highly toxic, pathogenic or nonimmunogenic. A synthetic phage display library is an alternative to generate Nbs against such targets, besides all the other ones. METHODS: We constructed a large and diverse synthetic phage display Nanobody (Nb) library based on the conserved camel single-domain antibody fragment (VHH) framework of cAbBCII10. Diversity was introduced in the complementarity-determining region 3 (CDR3) by means of randomization of synthetic oligonucleotides. Then human prealbumin (PA) and neutrophil gelatinase associated lipocalin (NGAL) were used to select specific Nbs from this library. Furthermore, a sandwich enzyme-linked immunosorbent assay (ELISA) was developed to detect PA based on horseradish peroxidase (HRP)-conjugated anti-PA Nb isolated from this study and another biotinylated anti-PA Nb obtained from an immune library, in our previous study. RESULTS: A large and diverse synthetic phage display Nb library with CDR3 regions randomized by trinucleotide cassettes was constructed. The library size was 1.65 * 10(9) CFU/mL and the correct insertion ratio was nearly 100%. A Nb against human PA and against NGAL was successfully isolated from the synthetic library. The obtained anti-PA Nb was effectively used to develop a sandwich ELISA for PA detection and it demonstrated a working range from 50 to 1000 ng/mL, with a limit of detection (LOD) of 27.1 ng/mL. CONCLUSION: This proposed novel synthetic library was a good source for obtaining some antigen-specific Nbs. This approach could provide crucial support to an immune library and a naive library in the acquisition of specific Nbs, potentially functioning as a great resource for medical diagnostic applications. In addition, we have successfully developed a novel sandwich ELISA to detect PA, which could provide great assistance for clinical PA detection. PMID- 25496225 TI - A retrospective 15-year review: survival advantage after switching to sirolimus in hepatitis C virus infected liver graft recipients. AB - BACKGROUND: The use of sirolimus-based immune suppression in liver transplantation, particularly in hepatitis C virus (HCV)-infected recipients, remains contentious. There is some evidence that sirolimus retards hepatic fibrosis, is renal sparing and may be of benefit in preventing hepatocellular carcinoma (HCC) recurrence. Sirolimus has not been adopted by many transplant centres because of persistent concerns regarding an increased risk of hepatic artery thrombosis, graft loss and death with de novo sirolimus. AIM: To review the impact of switching to sirolimus monotherapy in HCV-infected liver recipients with respect to survival, graft loss and hepatic fibrosis. METHODS: A retrospective review of 190 patients from a single centre undergoing first liver transplantation for HCV over 15 years. 113 patients were switched from calcineurin inhibitor (CNI)-based therapy to low-dose sirolimus monotherapy at a median of 15 months after transplantation for HCV-related fibrosis (72%), renal impairment (14%) or high-risk HCC (5%). RESULTS: Patients switched to sirolimus had improved survival (P < 0.001) and slower progression to cirrhosis (P = 0.001). In patients with HCC (n = 91), sirolimus duration rather than strategy was an independent predictor of survival (P = 0.001) and extended time to HCC recurrence (33 vs. 16 months). Patients switched for renal dysfunction showed improvement in serum creatinine (140-108 MUmol/L, P = 0.001). Those remaining on CNI-therapy were more likely to develop post-transplant diabetes (P = 0.03). CONCLUSION: These data suggest selective switching to low-dose sirolimus monotherapy in HCV-positive liver recipients improves clinical outcome. PMID- 25496226 TI - Comparison of self-reported pain intensity, sleeping difficulty, and treatment outcomes of patients with myofascial temporomandibular disorders by age group: a prospective outcome study. AB - BACKGROUND: Subjective symptoms of temporomandibular disorders (TMDs) have rarely been studied by age group. We aimed to compare self-reported pain intensity, sleeping difficulty, and treatment outcomes of patients with myofascial TMDs among three age groups. METHODS: The study population included 179 consecutive patients (151 women and 28 men) who underwent comprehensive clinical examinations at a university-based orofacial pain center. They were classified into myofascial pain subgroups based on the Research Diagnostic Criteria for Temporomandibular Disorders. They were stratified by age group: M1, under 20 years; M2, 20-39 years; and M3, 40 years and older. The patients scored their pretreatment symptoms (first visit) and post-treatment symptoms (last visit) on a form composed of three items that assessed pain intensity and one item that assessed sleeping difficulty. Their treatment options (i.e., pharmacotherapy, physical therapy, and orthopedic appliances) and duration were recorded. All variables were compared between sexes in each group and between the age groups by using the Kruskal-Wallis test, the Mann-Whitney U test, the chi-square test, and analysis of variance (p < 0.05). RESULTS: No significant sex differences were found in any age group. Only sleeping difficulty was significantly different before treatment (p = 0.009). No significant differences were observed in the treatment options or treatment duration. After treatment, the intensity of jaw/face pain and headache and sleeping difficulty was significantly reduced in groups M2 and M3, but only the intensity of jaw/face pain was significantly decreased in group M1. The changes in the scores of pain intensity and sleeping difficulty were not different between the groups. CONCLUSIONS: Pain intensity does not differ by age group, but older patients with myofascial TMDs had greater sleeping difficulties. However, there were no differences between the age groups in the treatment outcomes. Clinicians should carefully consider the age-related characteristics of patients with myofascial TMDs when developing appropriate management strategies. PMID- 25496227 TI - Three-dimensional echocardiography enhances diagnostic accuracy of supramitral ring. AB - Real time three-dimensional echocardiography (RT3DE) allows for accurate morphological characterization of congenital heart disease and complements two dimensional (2D) echocardiography. Accurate evaluation of the mitral valve and supramitral ring prior to surgery aids the surgeon in successful resection of the ring and repair of associated mitral valve abnormalities. We report a case of congenital mitral valve stenosis from a supramitral ring in a young child using real time three-dimensional transesophageal echocardiography. PMID- 25496228 TI - Paraquat reduces natural killer cell activity via metallothionein induction. AB - Paraquat (PQ), one of the most widely used herbicides, has been used for several decades in agriculture. Some studies suggest that PQ has effects on the immune system. Moreover, previous studies have shown that PQ imparted some immunosuppressive effects. In the present study, cytotoxicity assays using splenic NK cells from mice treated for 28 days with PQ (at 0.2, 1, and 5 mg/kg) were performed to determine whether PQ altered the function of NK cells. Given that PQ was expected to induce an immunosuppressive effect, it was hypothesized that a gene involved in cellular metal ion homeostasis, metallothionein-1 (MT-1), could play an important role in this outcome. This belief was based on the fact that MT1 encodes a protein responsible for zinc ion homeostasis, and that a reduction in free zinc ion levels impairs NK cell function. The results showed that PQ treatments led to increased MT expression in several organs (liver, kidneys, testes) and in splenocytes, caused a reduction of both free zinc ions in sera and in free intracellular zinc, and reduced the expression of GATA-3, a zinc finger transcription factor important for maturation and activity of T-cells and NK cells. These results provide a basis for a new molecular mechanism to describe potential immunosuppressive effects of PQ in vivo. PMID- 25496229 TI - Quantitative trait loci mapping and transcriptome analysis reveal candidate genes regulating the response to ozone in Arabidopsis thaliana. AB - As multifaceted molecules, reactive oxygen species (ROS) are known to accumulate in response to various stresses. Ozone (O3 ) is an air pollutant with detrimental effect on plants and O3 can also be used as a tool to study the role of ROS in signalling. Genetic variation of O3 sensitivity in different Arabidopsis accessions highlights the complex genetic architecture of plant responses to ROS. To investigate the genetic basis of O3 sensitivity, a recombinant inbred line (RIL) population between two Arabidopsis accessions with distinct O3 sensitivity, C24 (O3 tolerant) and Te (O3 sensitive) was used for quantitative trait loci (QTL) mapping. Through analysis of QTL mapping combined with transcriptome changes in response to O3 , we identified three causal QTLs and several potential candidate genes regulating the response to O3 . Based on gene expression data, water loss and stomatal conductance measurement, we found that a combination of relatively low stomatal conductance and constitutive activation of salicylic acid (SA)-mediated defence signalling were responsible for the O3 tolerance in C24. Application of exogenous SA prior to O3 exposure can mimic the constitutive SA signalling in C24 and could attenuate O3 -induced leaf damage in the sensitive Arabidopsis accessions Te and Cvi-0. PMID- 25496230 TI - Chlorinated dibenzo-p-dioxin and dibenzofuran congener and homologue distributions in tree bark from Sauget, Illinois, U.S. AB - Polychlorinated dibenzo-p-dioxins (PCDD) and dibenzofurans (PCDF) are ubiquitous urban/industrial contaminants found in tree bark, which acts as a long-term passive atmospheric sampler. Twenty seven bark samples (tree age 8-92 years) were collected from residential and industrial areas near Sauget, IL to identify the trends of 2,3,7,8-Cl PCDD & PCDF congener distributions, toxic equivalents (TEQ), and PCDD & PCDF homologue distributions. The Sauget area is heavily industrialized, with a long history of chlorine production, and is the largest single contributor to air pollution exposure risk in St. Louis. Analysis of seven 2,3,7,8 Cl-substituted PCDD and 10 PCDF congeners showed ?PCDD7 ranging from 2214 to 71821 pg g(-1) lipid and ?PCDF10 from 355 to 13707 pg g(-1) lipid, the highest in trees <20 years old in both cases. OctaCCD and octaCDF respectively dominated ?PCDD7 (89% average) and ?PCDF10 (57% average). The 2,3,7,8-Cl congener profiles showed slight differences among samples showing that all were affected by similar sources but at different magnitudes. ?TEQ ranged from 35 to 624 pg g(-1) lipid, dominated by 1,2,3,7,8-PeCDD (average = 41.3% of total TEQ). Tetra-Cl through hepta-Cl homologues were dominated by non-2,3,7,8-Cl compounds for both CDD and CDF. Homologue profiles for 26 samples had a "sink" profile dominated by octaCDD, whereas one sample showed effects of a local source. PMID- 25496231 TI - Hepatic involvement in congenital cytomegalovirus infection - infrequent yet significant. AB - Congenital cytomegalovirus (cCMV) infection can reside in many organ systems; however, the virus has a particular predilection towards inhabiting the reticuloendothelial system, especially the liver. Specific studies focusing only on hepatic involvement in infants with cCMV are lacking. We report our experience with a large cohort of infants treated in our hospital clinic due to cCMV and hepatic involvement. Hepatic involvement was defined either as hepatitis (elevated alanine transaminases (ALT) >80 units/L without cholestatic disease) or cholestatic disease (elevated ALT >80 units/L combined with direct bilirubin >2 mg/dL). During the study period, 198 infants were diagnosed with symptomatic cCMV in our clinic. Hepatic involvement was observed in 13 infants (6.6%); 7 (3.5%) with hepatitis and 6 (3%) with cholestatic disease. Maternal primary infection with cytomegalovirus during pregnancy was diagnosed in 7 (53.8%) of the 13 infants, nonprimary in 3 (23.1%) and unknown in 3 (23.1%). Among these 13 infants, central nervous system (CNS) involvement was observed in 11 (84.6%) and hearing impairment in 7 (53.8%). Treatment with an antiviral agent was initiated in all cases. Gradual improvement of hepatic enzymes and cholestasis was observed over a prolonged period. We found that the incidence of hepatic involvement in infants with cCMV is much less frequent than previously reported. The hepatic involvement in these infants may manifest in two different ways, and thus, a high index of suspicion and a stepwise approach will help in correctly diagnosing these infants. Antiviral treatment due to CNS involvement is warranted and prognosis is excellent. PMID- 25496232 TI - In situ experiments to reveal the role of surface feature sidewalls in the Cassie Wenzel transition. AB - Waterproof and self-cleaning surfaces continue to attract much attention as they can be instrumental in various different technologies. Such surfaces are typically rough, allowing liquids to contact only the outermost tops of their asperities, with air being entrapped underneath. The formed solid-liquid-air interface is metastable and, hence, can be forced into a completely wetted solid surface. A detailed understanding of the wetting barrier and the dynamics of this transition is critically important for the practical use of the related surfaces. Toward this aim, wetting transitions were studied in situ at a set of patterned perfluoropolyether dimethacrylate (PFPEdma) polymer surfaces exhibiting surface features with different types of sidewall profiles. PFPEdma is intrinsically hydrophobic and exhibits a refractive index very similar to water. Upon immersion of the patterned surfaces into water, incident light was differently scattered at the solid-liquid-air and solid-liquid interface, which allows for distinguishing between both wetting states by dark-field microscopy. The wetting transition observed with this methodology was found to be determined by the sidewall profiles of the patterned structures. Partial recovery of the wetting was demonstrated to be induced by abrupt and continuous pressure reductions. A theoretical model based on Laplace's law was developed and applied, allowing for the analytical calculation of the transition barrier and the potential to revert the wetting upon pressure reduction. PMID- 25496234 TI - Palladium-catalyzed ortho-sulfonylation of 2-aryloxypyridines and subsequent formation of ortho-sulfonylated phenols. AB - A palladium-catalyzed direct sulfonylation of 2-aryloxypyridines on the ortho position of the benzene ring was developed using 2-pyridyloxyl as the directing group and sulfonyl chlorides as sulfonylation reagents. The protocol was available for both electron-rich and electron-deficient substrates. The ortho sulfonylated phenol was synthesized expediently from the sulfonylation product by the removal of the pyridyl group. PMID- 25496233 TI - Probenecid as a sensitizer of bisphosphonate-mediated effects in breast cancer cells. AB - BACKGROUND: Anti-resorptive bisphosphonates (BP) are used for the treatment of osteoporosis and bone metastases. Clinical studies indicated a benefit in survival and tumor relapse in subpopulations of breast cancer patients receiving zoledronic acid, thus stimulating the debate about its anti-tumor activity. Amino bisphosphonates in nM concentrations inhibit farnesyl pyrophosphate synthase leading to accumulation of isopentenyl pyrophosphate (IPP) and the ATP/pyrophosphate adduct ApppI, which induces apoptosis in osteoclasts. For anti tumor effects MUM concentrations are needed and a sensitizer for bisphosphonate effects would be beneficial in clinical anti-tumor applications. We hypothesized that enhancing intracellular pyrophosphate accumulation via inhibition of probenecid-sensitive channels and transporters would sensitize tumor cells for bisphosphonates anti-tumor efficacy. METHOD: MDA-MB-231, T47D and MCF-7 breast cancer cells were treated with BP (zoledronic acid, risedronate, ibandronate, alendronate) and the pyrophosphate channel inhibitors probenecid and novobiocin. We determined cell viability and caspase 3/7 activity (apoptosis), accumulation of IPP and ApppI, expression of ANKH, PANX1, ABCC1, SLC22A11, and the zoledronic acid target gene and tumor-suppressor KLF2. RESULTS: Treatment of MDA-MB-231 with BP induced caspase 3/7 activity, with zoledronic acid being the most effective. In MCF-7 and T47D either BP markedly suppressed cell viability with only minor effects on apoptosis. Co-treatment with probenecid enhanced BP effects on cell viability, IPP/ApppI accumulation as measurable in MCF-7 and T47D cells, caspase 3/7 activity and target gene expression. Novobiocin co-treatment of MDA-MB-231 yielded identical results on viability and apoptosis compared to probenecid, rendering SLC22A family members as candidate modulators of BP effects, whereas no such evidence was found for ANKH, ABCC1 and PANX1. CONCLUSIONS: In summary, we demonstrate effects of various bisphosphonates on caspase 3/7 activity, cell viability and expression of tumor suppressor genes in breast cancer cells. Blocking probenecid and novobiocin-sensitive channels and transporters enhances BP anti-tumor effects and renders SLC22A family members as good candidates as BP modulators. Further studies will have to unravel if treatment with such BP sensitizers translates into preclinical and clinical efficacy. PMID- 25496235 TI - Sleep and breathing disorders in myotonic dystrophy type 2. AB - OBJECTIVES: In patients who exhibit myotonic dystrophy type 1 (DM1), sleep disorders and breathing impairments are common; however, in those with DM type 2 (DM2), limited studies on polysomnography (PSG) and none on phrenic compound motor action potential (CMAP) have been performed, which is the aim of this study. MATERIALS AND METHODS: Sixteen patients with DM2 were questioned about respiratory symptoms. They underwent PSG with morning arterial gas analyses (AGA). Respiratory functions and phrenic CMAPs were studied. The data were compared to those of 16 healthy controls and 25 patients with DM1. RESULTS: Daytime tiredness is the most common symptom, but orthopnea was reported in 13% of patients with DM2. A detailed sleep architecture analysis revealed a significantly greater proportion of time in stage 3 and REM sleep, and a shorter time in stage 2 in the DM2 than in controls. Lower respiratory volumes and pressures, abnormalities in AGA, night oxygen desaturation and higher EtCO2 are present in DM2, but are less pronounced than in the DM1 population. Small CMAP amplitudes were presented in 12% of patients with DM2, correlating with smaller respiratory functions and poorer sleep quality. AHI was abnormal in 38% of DM2, mainly due to obstructive apneas. PSG did not reveal hypoventilation. CONCLUSIONS: Diaphragm weakness and sleep apneas might be present in patients with DM2; therefore, we suggest regular questioning about symptoms of respiratory insufficiency and monitoring of phrenic CMAP. PSG should be recorded, when patients have suggestive symptoms, abnormalities in AGA or higher BMI. PMID- 25496236 TI - Recent Advances in Asymmetric Catalytic Methods for the Formation of Acyclic alpha,alpha-Disubstituted alpha-Amino Acids. AB - Because of their greater stability and unique conformational properties, unnatural amino acids are highly valued by pharmaceutical, biological, and organic chemists. This synopsis surveys the various catalytic methods used to access enantioenriched, acyclic alpha,alpha-disubstituted alpha-amino acids with a focus on the processes developed since 2007, when the last major reviews in this area were published. PMID- 25496237 TI - Testosterone replacement therapy in men with prostate cancer: a time-varying analysis. AB - INTRODUCTION: The use of testosterone replacement therapy (TRT) in men with prostate cancer is controversial given concerns of androgen-related cancer progression. Although emerging evidence suggests that TRT may be safe in this setting, no study has investigated dose-related effects. AIM: We used time varying analysis to determine whether increasing TRT exposure is associated with worse outcomes. METHODS: Using linked Surveillance, Epidemiology, and End Results Medicare data, we identified 149,354 men diagnosed with prostate cancer from 1991 to 2007. Subjects treated with TRT were stratified by duration of treatment. Weighted propensity score methods were used to adjust for differences between groups. A Cox proportional hazards model was constructed to assess the effect of injectable TRT exposure on outcomes. MAIN OUTCOME MEASURE: Overall mortality (OM), prostate cancer-specific mortality (PCSM), and use of salvage androgen deprivation therapy (ADT). RESULTS: Men treated with TRT, regardless of duration, did not experience higher OM or PCSM (all hazard ratio [HR] <1.0, all P <= 0.002). We found no difference in use of salvage ADT in the <= 30-day and 31-60 day groups compared with no-TRT (HR 1.23 and 1.05, P=0.06 and 0.81, respectively), whereas it was lower for men on long-term TRT (HR 0.70, P=0.04). CONCLUSIONS: TRT following prostate cancer diagnosis and treatment does not increase mortality or the use of salvage ADT. Using time-varying analysis, we demonstrate that longer duration of TRT is not associated with adverse mortality or greater need for ADT. PMID- 25496238 TI - KO(t)Bu-mediated aerobic transition-metal-free regioselective beta-arylation of indoles: synthesis of beta-(2-/4-nitroaryl)-indoles. AB - A KO(t)Bu-mediated intermolecular oxidative C-C coupling of nitroarenes with indoles is presented in DMSO at room temperature in an open flask. By using this mild and economical methodology, syntheses of beta-(2/4-nitroaryl)-indoles with sensitive functionalities such as bromo, iodo, cyano, and nitro were achieved chemo- and regioselectively. Synthesized beta-(2/4-nitroaryl) indoles were transformed into densely functionalized biindoles, indoloindoles, and (4 aminoaryl)-indoles which demonstrate post-transformation utility of the developed methodology. PMID- 25496240 TI - A series of M(II)Cu(II)3 stars (M = Mn, Ni, Cu, Zn) exhibiting unusual magnetic properties. AB - The work in this report describes the syntheses, electrospray ionization mass spectromtery, structures, and experimental and density functional theoretical (DFT) magnetic properties of four tetrametallic stars of composition [M(II)(Cu(II)L)3](ClO4)2 (1, M = Mn; 2, M = Ni; 3, M = Cu; 4, M = Zn) derived from a single-compartment Schiff base ligand, N,N'-bis(salicylidene)-1,4 butanediamine (H2L), which is the [2 + 1] condensation product of salicylaldehyde and 1,4-diaminobutane. The central metal ion (Mn(II), Ni(II), Cu(II), or Zn(II)) is linked with two MU2-phenoxo bridges of each of the three [Cu(II)L] moieties, and thus the central metal ion is encapsulated in between three [Cu(II)L] units. The title compounds are rare or sole examples of stars having these metal-ion combinations. In the cases of 1, 3, and 4, the four metal ions form a centered isosceles triangle, while the four metal ions in 2 form a centered equilateral triangle. Both the variable-temperature magnetic susceptibility and variable field magnetization (at 2-10 K) of 1-3 have been measured and simulated contemporaneously. While the Mn(II)Cu(II)3 compound 1 exhibits ferromagnetic interaction with J = 1.02 cm(-1), the Ni(II)Cu(II)3 compound 2 and Cu(II)Cu(II)3 compound 3 exhibit antiferromagnetic interaction with J = -3.53 and -35.5 cm(-1), respectively. Variable-temperature magnetic susceptibility data of the Zn(II)Cu(II)3 compound 4 indicate very weak antiferromagnetic interaction of -1.4 cm(-1), as expected. On the basis of known correlations, the magnetic properties of 1-3 are unusual; it seems that ferromagnetic interaction in 1 and weak/moderate antiferromagnetic interaction in 2 and 3 are possibly related to the distorted coordination environment of the peripheral copper(II) centers (intermediate between square-planar and tetrahedral). DFT calculations have been done to elucidate the magnetic properties. The DFT-computed J values are quantitatively (for 1) or qualitatively (for 2 and 3) matched well with the experimental values. Spin densities and magnetic orbitals (natural bond orbitals) correspond well with the trend of observed/computed magnetic exchange interactions. PMID- 25496239 TI - Severe vitamin D deficiency is associated with frequent exacerbations and hospitalization in COPD patients. AB - BACKGROUND: Acute exacerbations of COPD (AECOPD) are common and strongly influence disease severity and relative healthcare costs. Vitamin D deficiency is frequent among COPD patients and its contributory role in disease exacerbations is widely debated. Our aim was to assess the relationship of serum vitamin D levels with COPD severity and AECOPD. METHODS: Serum vitamin D (25-hydroxyvitamin D) levels were measured in 97 COPD patients and related to lung function, comorbidities, FEV1 decline, AECOPD and hospital admission during the previous year. RESULTS: Most patients (96%) had vitamin D deficiency, which was severe in 35 (36%). No significant relationship was found between vitamin D and FEV1 or annual FEV1 decline. No difference between patients with and without severe vitamin D deficiency was found in age, gender, BMI, smoking history, lung function, and comorbidities, apart from osteoporosis (60.9% in severe deficiency vs 22.7%, p = 0.001). In multiple logistic regression models, severe deficiency was independently associated with AECOPD [adjusted odds ratios (aOR) of 30.5 (95% CI 5.55, 168), p < 0.001] and hospitalization [aOR 3.83 (95% CI 1.29, 11.4), p = 0.02]. The odds ratio of being a frequent exacerbator if having severe vitamin D deficiency was 18.1 (95% CI 4.98, 65.8) (p < 0.001), while that of hospitalization was 4.57 (95% CI 1.83, 11.4) (p = 0.001). CONCLUSIONS: In COPD patients severe vitamin D deficiency was related to more frequent disease exacerbations and hospitalization during the year previous to the measurement of vitamin D. This association was independent of patients' characteristics and comorbidities. PMID- 25496241 TI - Commercial cuts and chemical and sensory attributes of meat from crossbred Boer goats fed sunflower cake-based diets. AB - This study aimed to evaluate sunflower cake feed in commercial cut yields and chemical and sensory attributes of goat meat. Thirty-two castrated male goats were distributed in four levels (0, 8, 16 and 24%) of sunflower cake supplementation. The animals were slaughtered and the carcasses were placed in a cold chamber and sectioned into five anatomical regions corresponding to commercial cuts. Samples of the Longissimus lumborum muscle were analyzed for chemical composition and sensory quality. The chemical composition and pH were not affected by the treatments. The smell, taste and 'goatiness' of the aroma and flavor of the meat were also unaffected by the treatments. The appearance, tenderness and juiciness of the meat differed by treatment. The highest level (24%) of sunflower cake increased meat tenderness; however, according to the tasters there was reduced softness, although none of the samples were rejected by the tasters. Sunflower cake can be added to the diet at a level of up to 16% without altering the quantitative and qualitative attributes of the meat. PMID- 25496242 TI - Angelica sinensis extract inhibits RANKL-mediated osteoclastogenesis by down regulated the expression of NFATc1 in mouse bone marrow cells. AB - BACKGROUND: Destructive erosion of bone or osteolysis is a major complication of inflammatory conditions such as rheumatoid arthritis (RA), periodontal disease, and periprosthetic osteolysis. Natural plant-derived products have received recent attention as potential therapeutic and preventative drugs in human disease. METHODS: The effect of Angelica sinensis (AS) extract on RANKL-induced osteoclast differentiation was examined in this study. The osteoclast precursor cell line bone marrow macrophages (BMMs) was cultured and stimulated with RANKL followed by treatment with AS at several doses. Gene expression profiles of c Fos, c-Jun, NFATc1, TRAP, and OSCAR were sequentially evaluated. RESULTS: AS extract inhibited RANKL-mediated osteoclast differentiation in BMMs in a dose dependent manner without any evidence of cytotoxicity. AS extract strongly inhibited p38, ERK, JNK, p65 phosphorylation and I-kappaB degradation in RANKL stimulated BMMs. AS extract also inhibited the mRNA expression of c-Fos, c-Jun, NFATc1, TRAP, and OSCAR in RANKL-treated BMMs. Moreover, RANKL-induced c-Fos, c Jun and NFATc1 protein expression was suppressed by AS extract. CONCLUSIONS: These results collectively suggested that AS extract demonstrated inhibitory effects on RANKL-mediated osteoclast differentiation in bone marrow macrophages in vitro, indicating that AS may therefore serve as a useful drug in the prevention of bone loss. PMID- 25496243 TI - Impact of placement and restoration timing on single-implant esthetic outcome - a randomized clinical trial. AB - AIM: The objective of this randomized clinical trial was to investigate the influence of the time of implant placement (immediate vs. early) and the time of restoration (immediate vs. early) on esthetic outcome in maxillary anterior single implants. MATERIAL AND METHODS: Forty-eight patients with a single failing incisor in the maxilla and a natural contralateral site were randomly distributed into four groups. Treatment variations affected the time of implant placement (immediate or early) as well as the time of restoration (immediate or early) - in detail, group 1a with immediate implant placement and immediate temporary restoration, group 1b with immediate implant placement and early restoration, group 2a with early implant placement and immediate temporary restoration, and group 2b with early implant placement and early restoration. All patients received the final prosthetic restoration 10-12 weeks after implant placement. Standardized photographs were taken eight months after tooth extraction. Five competent observers analyzed the esthetic outcome according to the PES after Furhauser. For statistical analysis, the Kruskal-Wallis test and Dunn's post hoc test were applied. Interobserver reliability was evaluated by Krippendorff's alpha. RESULTS: The overall scores of the four treatment groups revealed PES values of 8.47 (SD 2.08, group 1a), 7.93 (SD 3.21, group 1b), 6.62 (SD 3.24, group 2a), and 8.10 (SD 3.25, group 2b). The differences between groups 2a and 1a and between groups 2a and 2b were statistically significant (P = 0.015 and P = 0.047). The single parameter analysis displayed a certain range of fluctuation and heterogeneity. CONCLUSIONS: Immediate implant placement and restoration appear to be a viable alternative to early implant placement if an experienced surgeon is entrusted with the implantation procedure. PMID- 25496244 TI - Emerging trends in prostate cancer literature: medical progress or marketing hype? PMID- 25496245 TI - Cardioprotective role of H3R agonist imetit on isoproterenol-induced hemodynamic changes and oxidative stress in rats. AB - The cardioprotective role of histamine H3 receptor (H3R) agonist imetit (IMT) in isoproterenol (ISO)-induced alterations of hemodynamic and oxidative stress was investigated in Wistar rats. In this study, rats were treated with IMT (5 and 10 mg/kg, per orally [p.o.]), carvedilol (10 mg/kg, p.o.) and ISO control group (normal saline) for 7 d, with concurrent subcutaneous administration of ISO (85 mg/kg) at 24 h interval on last two consecutive days whereas control group was administered with vehicle only. ISO significantly attenuated cardiac antioxidant enzymes superoxide dismutase, catalase and increased plasma cardiac injury biomarkers creatine kinase-MB, alanine transaminase and aspartate transaminase. ISO also altered cardiac activity as evidenced by decrease in blood pressure (34.60%) and increase in heart rate (11.40%). The damage due to oxidative stress was revealed by histopathology alterations such as myocyte necrosis, myofibrillar degeneration and pyknotic nucleus. However, pre-treatment with IMT demonstrated restoration of hemodynamic alterations along with significant preservation of antioxidants and myocyte injury-specific marker enzymes. Furthermore, protective effect of IMT was reconfirmed by the histopathological salvage of myocardium. Results of the present study demonstrated the cardioprotective potential of IMT, as evidenced by favorable improvement in ISO-induced hemodynamic, plasma cardiac biomarkers and tissue antioxidant status along with maintenance of integrity of myocardium. PMID- 25496247 TI - Diversion of methadone and buprenorphine from opioid substitution treatment: patients who regularly sell or share their medication. AB - Diversion-the practice of patients selling or sharing their medication-is a much debated problem of opioid substitution treatment. Regular diversion by patients was studied at 11 opioid substitution treatment programs in the south of Sweden. Using quantitative and qualitative data, it was investigated whether those patients differ from other patients, their motives for and means of diversion, and who the recipients are. Regular diverters are a small, yet heterogeneous group. Continued illicit drug use, however, stands out as a common risk factor. Pecuniary need and a desire to help friends are other important motives. The client base mainly consists of people from the regular diverters' own drug milieus. PMID- 25496246 TI - Bronchoscopic intervention as a main treatment for tracheobronchial adenoid cystic carcinoma. AB - BACKGROUND: Bronchial adenoid cystic carcinoma (ACC) is a rare disease with low malignancy and indolent progression. Airway obstruction caused by ACC can be resolved by endoscopic procedures. The efficacy of different techniques of bronchoscopic interventions for ACC has not been determined. MATERIAL AND METHODS: From November 2004 to March 2012, ACC patients, mainly treated with different techniques of bronchoscopic interventions in our hospital, were reviewed. RESULTS: The study included 37 ACC patients. Five patients (13.5%) with intra-luminal type underwent bronchoscopic therapies for a median of three times (range 1-6 times). Thirty-two patients (86.5%) with mixed type underwent bronchoscopic interventions for a median of 14 times (range 4-20 times). The dyspnea index was significantly improved after the first endoscopic procedure. The overall five- and ten-year survival rate was 85.9% and 45.9%, respectively, similar to surgery-dominant treatments. CONCLUSIONS: The present study demonstrates that different procedures of bronchoscopic interventions, as main treatments for ACC, are as effective as surgery-dominant treatment. More prospective and multicentric studies are required to confirm these favorable results, which may influence the therapeutic strategy for ACC in the future. PMID- 25496248 TI - Heuristic cognitive diagnosis when the Q-matrix is unknown. AB - Cognitive diagnosis models of educational test performance rely on a binary Q matrix that specifies the associations between individual test items and the cognitive attributes (skills) required to answer those items correctly. Current methods for fitting cognitive diagnosis models to educational test data and assigning examinees to proficiency classes are based on parametric estimation methods such as expectation maximization (EM) and Markov chain Monte Carlo (MCMC) that frequently encounter difficulties in practical applications. In response to these difficulties, non-parametric classification techniques (cluster analysis) have been proposed as heuristic alternatives to parametric procedures. These non parametric classification techniques first aggregate each examinee's test item scores into a profile of attribute sum scores, which then serve as the basis for clustering examinees into proficiency classes. Like the parametric procedures, the non-parametric classification techniques require that the Q-matrix underlying a given test be known. Unfortunately, in practice, the Q-matrix for most tests is not known and must be estimated to specify the associations between items and attributes, risking a misspecified Q-matrix that may then result in the incorrect classification of examinees. This paper demonstrates that clustering examinees into proficiency classes based on their item scores rather than on their attribute sum-score profiles does not require knowledge of the Q-matrix, and results in a more accurate classification of examinees. PMID- 25496249 TI - Structural evolution of 2D microporous covalent triazine-based framework toward the study of high-performance supercapacitors. AB - A series of nitrogen-containing micropore-donimated materials, porous triazine based frameworks (PTFs), are constructed through the structural evolution of a 2D microporous covalent triazine-based framework. The PTFs feature predictable and controllable nitrogen doping and pore structures, which serve as a model-like system to more deeply understand the heteroatom effect and micropore effect in ionic liquid-based supercapacitors. The experimental results reveal that the nitrogen doping can enhance the supercapacitor performance mainly through affecting the relative permittivity of the electrode materials. Although microspores' contribution is not as obvious as the doped nitrogen, the great performances of the micropore-dominated PTF suggest that micropore-dominated materials still have great potential in ionic liquid-based supercapacitors. PMID- 25496250 TI - Metabolic profiling of bile acids in human and mouse blood by LC-MS/MS in combination with phospholipid-depletion solid-phase extraction. AB - To obtain a more comprehensive profile of bile acids (BAs) in blood, we developed an ultrahigh performance liquid chromatography/multiple-reaction monitoring-mass spectrometry (UPLC-MRM-MS) method for the separation and detection of 50 known BAs. This method utilizes phospholipid-depletion solid-phase extraction as a new high-efficiency sample preparation procedure for BA assay. UPLC/scheduled MRM-MS with negative ion electrospray ionization enabled targeted quantitation of 43 and 44 BAs, respectively, in serum samples from seven individuals with and without fasting, as well as in plasma samples from six cholestatic gene knockout mice and six age- and gender-matched wild-type (FVB/NJ) animals. Many minor BAs were identified and quantitated in the blood for the first time. Method validation indicated good quantitation precision with intraday and interday relative standard deviations of <=9.3% and <=10.8%, respectively. Using a pooled human serum sample and a pooled mouse plasma sample as the two representative test samples, the quantitation accuracy was measured to be 80% to 120% for most of the BAs, using two standard-substance spiking approaches. To profile other potential BAs not included in the 50 known targets from the knockout versus wild-type mouse plasma, class-specific precursor/fragment ion transitions were used to perform UPLC-MRM-MS for untargeted detection of the structural isomers of glycine- and taurine-conjugated BAs and unconjugated tetra-hydroxy BAs. As a result, as many as 36 such compounds were detected. In summary, this UPLC-MRM-MS method has enabled the quantitation of the largest number of BAs in the blood thus far, and the results presented have revealed an unexpectedly complex BA profile in mouse plasma. PMID- 25496251 TI - Is it possible to identify gender and ethnicity via hair elements? PMID- 25496252 TI - 8th GCC: consolidated feedback to US FDA on the 2013 draft FDA guidance on bioanalytical method validation. AB - The 8th GCC Closed Forum for Bioanalysis was held in Baltimore, MD, USA on 5 December 2013, immediately following the 2013 AAPS Workshop (Crystal City V): Quantitative Bioanalytical Methods Validation and Implementation--The 2013 Revised FDA Guidance. This GCC meeting was organized to discuss the contents of the draft revised FDA Guidance on bioanalytical method validation that was published in September 2013 and consolidate the feedback of the GCC members. In attendance were 63 senior-level participants, from seven countries, representing 46 bioanalytical CRO companies/sites. This event represented a unique opportunity for CRO bioanalytical experts to share their opinions and concerns regarding the draft FDA Guidance, and to build unified comments to be provided to the FDA. PMID- 25496253 TI - Targeting an acid labile aspartyl-prolyl amide bond as a viable alternative to trypsin digestion to generate a surrogate peptide for LC-MS/MS analysis. AB - BACKGROUND: FGF21-AdPKE is a fusion protein and functionally inactivated in vivo by cleavage around the C-terminus. It is important to quantify the intact active protein in serum. RESULTS & DISCUSSION: Taking advantage of a uniquely acid labile aspartyl-prolyl amide bond, we developed an acid hydrolysis procedure based on heating FGF21-AdPKE in dilute formic acid to generate a surrogate peptide encompassing the last 17 amino acids at the C-terminus. The monkey serum samples were extracted with an immunocapture procedure with an antibody specific for AdPKE. The calibration range was 200-50000 ng/ml. The assay accuracy and precision were between 92.8-99.8% and 3.9-14.5%, respectively. The method was applied to analyze incurred serum samples from a cynomolgus monkey toxicokinetic study involving administration of FGF21-AdPKE. CONCLUSION: A method of combining immunocapture and acid hydrolysis to quantify a therapeutic protein in biological fluids was developed. PMID- 25496254 TI - Determination of tamoxifen and endoxifen in dried blood spots using LC-MS/MS and the effect of coated DBS cards on recovery and matrix effects. AB - BACKGROUND: We developed an HPLC-MS/MS method to quantify tamoxifen (2.5-250 ng/ml) and its metabolite (Z)-endoxifen (0.5-50 ng/ml) in dried blood spots. RESULTS: Extraction recovery of both analytes from Whatman DMPK-A cards was 100% and consistent over time, however, recovery of (Z)-endoxifen from Whatman 903 cards was incomplete and increased upon storage. When SDS, a constituent of the DMPK-A coating, was present during the extraction, recovery improved. The method using DMPK-A cards was validated using bioanalytical guidelines. Additionally, influence of haematocrit (0.29-0.48 L/L), spot volume (20-50 ul) and homogeneity was within limits and both analytes were stable in DBS for at least 4 months. CONCLUSIONS: The method for the quantification of tamoxifen and (Z)-endoxifen in DBS collected on DMPK-A cards was successfully validated. PMID- 25496255 TI - First MEPS/HPLC assay for the simultaneous determination of venlafaxine and O desmethylvenlafaxine in human plasma. AB - BACKGROUND: A new high-performance liquid chromatography-fluorescence detection assay based on microextraction by packed sorbent as sample preparation approach is described to quantify venlafaxine (VEN) and its main metabolite [O desmethylvenlafaxine (ODV)]in human plasma. METHODS & RESULTS: Chromatographic separation of the target analytes (VEN and ODV) and internal standard (licarbazepine) was achieved in less than 6 min on a reverse-phase C18 column using isocratic elution. Calibration curves were linear in the ranges of 10-1000 ng ml(-1) for VEN and 20-1000 ng ml(-1) for ODV. The method was successfully applied to real plasma samples. CONCLUSION: This microextraction by packed sorbent/high-performance liquid chromatography-fluorescence detection assay offers a cost-effective tool that can be applied for therapeutic drug monitoring and also support other pharmacokinetic-based studies in humans. PMID- 25496257 TI - Analytical platforms in vitreoretinal proteomics. AB - Current proteomic technologies can effectively be used to study the proteins of the vitreous body and retina in health and disease. The use of appropriate samples, analytical platform and bioinformatic method are essential factors to consider when undertaking such studies. Certain proteins may hinder the detection and evaluation of more relevant proteins associated with pathological processes if not carefully considered, particularly in the sample preparation and data analysis stages. The utilization of more than one quantification technique and database search program to expand the level of proteome coverage and analysis will help to generate more robust and worthwhile results. This review discusses important aspects of sample processing and the use of label and label-free quantitative proteomics strategies applied to the vitreous and retina. PMID- 25496256 TI - 2014 White Paper on recent issues in bioanalysis: a full immersion in bioanalysis (Part 1--small molecules by LCMS). AB - The 2014 8th Workshop on Recent Issues in Bioanalysis (8th WRIB), a 5-day full immersion in the evolving field of bioanalysis, took place in Universal City, California, USA. Close to 500 professionals from pharmaceutical and biopharmaceutical companies, contract research organizations and regulatory agencies worldwide convened to share, review, discuss and agree on approaches to address current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches and immunogenicity. From the prolific discussions held during the workshop, specific recommendations are presented in this 2014 White Paper. As with the previous years' editions, this paper acts as a practical tool to help the bioanalytical community continue advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2014 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for small molecule bioanalysis using LCMS. Part 2 (Hybrid LBA/LCMS, Electronic Laboratory Notebook and Regulatory Agencies' input) and Part 3 (Large molecules bioanalysis using LBA and Immunogenicity) will be published in the upcoming issues of Bioanalysis. PMID- 25496258 TI - A comparative study of fatty acid profile and formation of biofilm in Geobacillus gargensis exposed to variable abiotic stress. AB - Understanding bacterial fatty acid (FA) profile has a great taxonomic significance as well as clinical importance for diagnosis issues. Both the composition and nature of membrane FAs change under different nutritional, biotic and (or) abiotic stresses, and environmental stress. Bacteria produce both odd carbon as well as branched-chain fatty acids (BCFAs). This study was designed to examine the effect of abiotic pressure, including salinity, temperature, pH, and oxinic stress on the growth, development, and FA profile in thermophilic Geobacillus gargensis. Under these stresses, 3 parametric ratios, 2-methyl fatty acids/3-methyl fatty acids (iso-/anteiso-FAs), BCFAs/straight-chain saturated fatty acids (SCSFA), and SCSFAs/straight-chain unsaturated fatty acids (SCUFA), in addition to total lipids affected by variable stresses were measured. Our results indicate that the ratio of total iso-/anteiso-FAs increased at the acidic pH range of 4.1-5.2 and decreased with increasing pH. The reverse was true for salt stress when iso-/anteiso-FAs ratio increased with salt concentration. The BCFAs/SCSFAs and SCSFAs/SCUFAs ratios increased at neutral and alkaline pH and high salt concentration, reduced incubation time, and comparatively high temperature (55-65 degrees C) of the growth medium. The bacterial total lipid percentage deceased with increasing salt concentration, incubation period, but it increased with temperature. The formation of extracellular polymeric substances was observed under all stress conditions and with the addition of sodium dodecyl sulfate (2 and 5 mmol/L) to the growth medium. The membrane phospholipid composition of the bacterium was analyzed by thin-layer chromatography. PMID- 25496261 TI - Deep thrombophlebitis masked by peripheral arthritis in Henoch-Schonlein purpura. PMID- 25496260 TI - Validation of the Chinese version of the dementia screening questionnaire for individuals with intellectual disabilities (DSQIID-CV). AB - BACKGROUND: An increasing number of people with intellectual disabilities (ID) are at risk of developing age-related disorders such as dementia because of a dramatic increase in life expectancy in this population in the recent years. There is no validated dementia screening instrument for Chinese people with ID. The Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID) was reported to be a valid, user-friendly, easy-to-use observer-rated instrument. It was developed in the UK and has good psychometric properties. Validation of a Chinese version of the DSQIID will facilitate its application among the Chinese population. METHOD: The DSQIID was translated into the Chinese version (DSQIID-CV). By purposive sampling, service users with ID aged 40 years or over were recruited through two large centres serving adults with ID in Hong Kong. Carers who had taken care of the participants continuously for the past 6 months were invited to complete the DSQIID-CV. All participants were examined by qualified psychiatrists to determine the presence or absence of dementia. RESULTS: Two hundred people with ID whose age ranged between 40 and 73 years (mean 51 years, SD=7.34 years) were recruited to the study. A clinical diagnosis of dementia was established in 13 participants. An overall total score of 22 as a screening cut-off provided the optimum levels of specificity (0.995) and sensitivity (0.923). The DSQIID-CV showed good internal consistency (alpha=0.945) for all its 53 items, and excellent test-retest reliability (0.978, n=46) and inter-rater reliability (1.000, n=47). Exploratory factor analysis resulted in a four-factor solution explaining 45% of the total variance. CONCLUSIONS: The DSQIID-CV is shown to have robust psychometric properties. It is the first valid and reliable dementia screening instrument for Chinese adults with ID. PMID- 25496259 TI - The bypass of ZipA by overexpression of FtsN requires a previously unknown conserved FtsN motif essential for FtsA-FtsN interaction supporting a model in which FtsA monomers recruit late cell division proteins to the Z ring. AB - Assembly of the divisome in Escherichia coli occurs in two temporally distinct steps. First, FtsZ filaments attached to the membrane through interaction with FtsA and ZipA coalesce into a Z ring at midcell. Then, additional proteins are recruited to the Z ring in a hierarchical manner to form a complete divisome, activated by the arrival of FtsN. Recently, we proposed that the interaction of FtsA with itself competes with its ability to recruit downstream division proteins (both require the IC domain of FtsA) and ZipA's essential function is to promote the formation of FtsA monomers. Here, we tested whether overexpression of a downstream division protein could make ZipA dispensable, presumably by shifting the FtsA equilibrium to monomers. Only overexpression of FtsN bypassed ZipA and a conserved motif in the cytoplasmic domain of FtsN was required for both the bypass and interaction with FtsA. Also, this cytoplasmic motif had to be linked to the periplasmic E domain of FtsN to bypass ZipA, indicating that linkage of FtsA to periplasmic components of the divisome through FtsN was essential under these conditions. These results are used to further elaborate our model for the role of FtsA in recruiting downstream division proteins. PMID- 25496265 TI - Fructose containing sugars do not raise blood pressure or uric acid at normal levels of human consumption. AB - The impact of fructose, commonly consumed with sugars by humans, on blood pressure and uric acid has yet to be defined. A total of 267 weight-stable participants drank sugar-sweetened milk every day for 10 weeks as part of their usual, mixed-nutrient diet. Groups 1 and 2 had 9% estimated caloric intake from fructose or glucose, respectively, added to milk. Groups 3 and 4 had 18% of estimated caloric intake from high fructose corn syrup or sucrose, respectively, added to the milk. Blood pressure and uric acid were determined prior to and after the 10-week intervention. There was no effect of sugar type on either blood pressure or uric acid (interaction P>.05), and a significant time effect for blood pressure was noted (P<.05). The authors conclude that 10 weeks of consumption of fructose at the 50th percentile level, whether consumed as pure fructose or with fructose-glucose-containing sugars, does not promote hyperuricemia or increase blood pressure. PMID- 25496263 TI - Wider impacts of a 10-week community cooking skills program--Jamie's Ministry of Food, Australia. AB - BACKGROUND: Jamie's Ministry of Food (JMoF) Australia is a 10-week community based cooking skills program which is primarily aimed at increasing cooking skills and confidence and the promotion of eating a more nutritious diet. However, it is likely that the program influences many pathways to behaviour change. This paper explores whether JMoF impacted on known precursors to healthy cooking and eating (such as attitudes, knowledge, beliefs, cooking enjoyment and satisfaction and food purchasing behaviour) and whether there are additional social and health benefits which arise from program participation. METHODS: A mixed method, quasi-experimental longitudinal evaluation with a wait-list control was conducted. Intervention participants were measured using repeated questionnaires at three time points; before and after the program and at six month follow-up. Control participants completed the questionnaire 10 weeks before their program and at program commencement. Quantitative analysis used a linear mixed model approach and generalised linear models for repeated measures using all available data. Qualitative methods involved 30-minute repeated semi structured interviews with a purposively selected sample, analysed thematically. RESULTS: Statistically significant differences between groups and over time were found for a reduction of take away/fast food weekly purchasing (P = 0.004), and increases in eating meals at the dinner table (P = 0.01), cooking satisfaction (P = 0.01), and the ability to prepare a meal in 30 minutes (P < 0.001) and from basics that was low in cost (P < 0.001). The qualitative findings supported the quantitative results. Repeat qualitative interviews with fifteen participants indicated increased confidence and skills gained from the program to prepare meals from scratch as well as increases in family involvement in cooking and meal times at home. CONCLUSIONS: Jamie's Ministry of Food, Australia resulted in improvements in participants' food and cooking attitudes and knowledge, food purchasing behaviours and social interactions within the home environment, which were sustained six months after the program. TRIAL REGISTRATION: Australian and New Zealand Trial registration number: ACTRN12611001209987. PMID- 25496266 TI - Free Energy Calculations of Crystalline Hard Sphere Complexes Using Density Functional Theory. AB - Recently developed fundamental measure density functional theory (FMT) is used to study binary hard sphere (HS) complexes in crystalline phases. By comparing the excess free energy, pressure, and phase diagram, we show that the fundamental measure functional yields good agreements to the available simulation results of AB, AB2, and AB13 crystals. Furthermore, we use this functional to study the HS models of five binary crystals, Cu5Zr(C15b), Cu51Zr14(beta), Cu10Zr7(phi), CuZr(B2), and CuZr2(C11b), which are observed in the Cu-Zr system. The FMT functional gives a well-behaved minimum for most of the hard sphere crystal complexes in the two-dimensional Gaussian parameter space, namely a crystalline phase. However, the current version of FMT functional (White Bear) fails to give a stable minimum for the structure Cu10Zr7(phi). We argue that the observed solid phases for the HS models of the Cu-Zr system are true thermodynamic stable phases and can be used as a reference system in perturbation calculations. PMID- 25496262 TI - Involvement of Rho GTPases and their regulators in the pathogenesis of hypertension. AB - Proper regulation of arterial blood pressure is essential to allow permanent adjustment of nutrient and oxygen supply to organs and tissues according to their need. This is achieved through highly coordinated regulation processes controlling vascular resistance through modulation of arterial smooth muscle contraction, cardiac output, and kidney function. Members of the Rho family of small GTPases, in particular RhoA and Rac1, have been identified as key signaling molecules playing important roles in several different steps of these regulatory processes. Here, we review the current state of knowledge regarding the involvement of Rho GTPase signaling in the control of blood pressure and the pathogenesis of hypertension. We describe how knockout models in mouse, genetic, and pharmacological studies in human have been useful to address this question. PMID- 25496264 TI - Regioselective glucuronidation of gingerols by human liver microsomes and expressed UDP-glucuronosyltransferase enzymes: reaction kinetics and activity correlation analyses for UGT1A9 and UGT2B7. AB - OBJECTIVES: To determine the reaction kinetics for regioselective glucuronidation of gingerols (i.e. 6-, 8- and 10-gingerol) by human liver microsomes and expressed UDP-glucuronosyltransferase (UGT) enzymes, and to identify the main UGT enzymes involved in regioselective glucuronidation of gingerols. METHODS: The rates of glucuronidation were determined by incubating the gingerols with uridine diphosphoglucuronic acid-supplemented microsomes. Kinetic parameters were derived by fitting an appropriate model to the data. Activity correlation analyses were performed to identify the main UGT enzymes contributing to hepatic metabolism of gingerols. KEY FINDINGS: Glucuronidation at the 4'-OH group was much more favoured than that at 5-OH. The degree of position preference was compound dependent; the catalytic efficiency ratios of 4'-O- to 5-O-glucuronidation were 9.1, 19.7 and 2.9 for 6-, 8- and 10-gingerol, respectively. UGT1A8 (an intestinal enzyme), UGT1A9 and UGT2B7 were the enzymes showing the highest activity towards gingerols. Formation of 5-O-glucuronide was mainly catalysed by UGT1A9. UGT2B7 was the only enzyme that generated glucuronides at both 4'-OH and 5-OH sites, although a strong position preference was observed with 4'-OH (>=80.2%). Further, activity correlation analyses indicated that UGT2B7 and UGT1A9 were primarily responsible for 4'-O-glucuronidation and 5-O-glucuronidation of gingerols in the liver, respectively. CONCLUSIONS: Gingerols were metabolized by multiple hepatic and gastrointestinal UGT enzymes. Also, UGT1A9 and 2B7 were the main contributors to regioselective glucuronidation of gingerols in the liver. PMID- 25496268 TI - Antioxidant Capacities of Flavones and Benefits in Oxidative-Stress Related Diseases. AB - Flavonoids, a group of secondary metabolites widely distributed in the plant kingdom, have been acknowledged for their interesting medicinal properties. Among them, natural flavones, as well as some of their synthetic derivatives, have been shown to exhibit several biological activities, including antioxidant, anti inflammatory, antitumor, anti-allergic, neuroprotective, cardioprotective and antimicrobial. The antioxidant properties of flavones allow them to demonstrate potential application as preventive and attenuating agents in oxidative stress, i.e., a biological condition that is closely associated to aging processes and to several diseases. Some flavones interfere in distinct oxidative-stress related events by directly reducing the levels of intracellular free radicals (hydroxyl, superoxide and nitric oxide) and/or of reactive species (e.g. hydrogen peroxide, peroxynitrite and hypochlorous acid) thus preventing their amplification and the consequent damage of other biomolecules such as lipids, proteins and DNA. Flavones can also hinder the activity of central free radical-producing enzymes, such as xanthine oxidase and nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) or inducible nitric oxide synthase (iNOS) and can even modulate the intracellular levels of oxidant and/or antioxidant enzymes. The evaluation of flavones antioxidant ability has been extensively determined in chemical or biological in vitro models, but in vivo therapy with individual flavones or with flavones-enriched extracts has also been reported. The present manuscript revises relevant studies focusing the preventive effects of flavones on stress-related diseases, namely the neurological and cardiovascular diseases and diabetes and its associated complications. PMID- 25496267 TI - Effect of 5-n-alkylresorcinol extracts from durum wheat whole grain on the growth of fusarium head blight (FHB) causal agents. AB - In an approach toward the identification of ecofriendly compounds for fusarium head blight biocontrol, the in vitro antifungal activity of 5-n-alkylresorcinol (AR) extracts, obtained from durum wheat intact kernels, was tested. In comparison with ethyl acetate and acetone extracts containing AR, total inhibition of Fusarium graminearum spore germination was observed with cyclohexane extract, which also exhibited a significant fungistatic activity against F. graminearum, Fusarium culmorum, Fusarium avenaceum, and Fusarium poae. Additionally, the study of the influence of such variables as predrying of seeds and durum wheat genotype on AR cyclohexane extract properties allowed the association of its highest antifungal activity with the AR homologue composition and, in particular, with the presence of a higher C21:0/C23:0 ratio. The interesting finding of this study suggests a potential application of the AR homologues in crop protection systems and could be an important step toward the development of commercial formulations suitable to the prevention of fungal diseases. PMID- 25496269 TI - Is there a role for antioxidants in the prevention of infection-associated carcinogenesis and in the treatment of infection-driven tumors? AB - Causative connections between infections and cancer are ascertained for several types of viruses, bacteria, and parasites. The mechanisms of cancer induction in chronically infected inflamed tissues strongly implicate oxygen- and nitrogen centered reactive species, and an impairment of redox-sensitive molecular pathways involved in the tumorigenic transformation, tumor growth, altered immune defense, and in the mechanisms of tumor cell death and survival. Here, we briefly reviewed mechanistic data on carcinogenesis and tumor progression of three major infection-associated tumors, human papillomavirus-induced cervical cancer, hepatitis B virus-positive hepatocarcinoma, and Helicobacter pylori-positive gastric cancer. Notwithstanding the contradictory results of clinical studies on cancer chemoprevention with long-term, high dosage antioxidant vitamin/micronutrient supplementation, natural and synthetic agents with proven capacity to affect redox-dependent molecular pathways still hold the promise for preventing/delaying carcinogenesis initiation, as well as the overt malignancy evolution from dysplastic/ aplastic stages. Novel directions for a targeted antioxidant-based approach to the reduction of persistent infection-driven cancer risk stems from the current knowledge of critical factors in the host-microbe interaction leading to oncogenesis. An emerging role of redox active substances in the chemotherapy of tumors relies on their stimulating effects towards TRAIL related apoptosis and the induction of intracellular oxidative stress. PMID- 25496270 TI - Electrochemically driven supramolecular interaction of quinones and ferrocifens: an example of redox activation of bioactive compounds. AB - This review discusses the state of the art, challenges and perspectives in recent applications of electrochemistry in the life sciences. It deals mainly with the elucidation of molecular mechanisms of drug action, drug design and development, involving electron transfer, pharmaco-electrochemistry (the combination of electrochemical and pharmacological assays), and electrochemical studies of membrane models and drug delivery. It aims to shed light on the question: does electrochemistry really contribute to this area? It includes a general introduction for the use of electrochemistry in the life sciences, with a focus on how electrochemistry can uniquely provide both kinetic and thermodynamic information. A number of studies are reported in the literature and from the authors' laboratories, including the investigation of biooxidative/bioreductive activation of pro-drugs, DNA alkylation, electrochemically- based release of reactive oxygen and nitrogen species, with a particular emphasis on quinones, ferrocifens and compounds with mixed-functionality. Within the context of drug delivery and bioavailability, the electrochemical investigation of supramolecular interactions of the chosen classes of compounds with cyclodextrins and lipid bilayers, in relation to their solubilization and vectorization was also carried out. The updated examples herein illustrate how relevant and challenging the integration of electrochemistry, supramolecular and materials chemistry, biochemistry and medical knowledge for the design and development of redox selective molecular approaches is. Many questions related to these fields are still unclear and the search for selectivity toward redox therapeutic agents remains of expanding interest. This review hopes to stimulate researchers to become more involved in this fruitful interface between electrochemistry and the life sciences. PMID- 25496271 TI - Melatonin Redox Activity. Its Potential Clinical application in Neurodegenerative Disorders. AB - Neurodegeneration is the hallmark of many chronic progressive neurogical disorders characterized by specific clinical, morphological and biochemical features. Central nervous system is very sensitive to oxidative stress, which is considered as a key factor of neurodegenerative disorders. Therefore, many therapeutical strategies are focused on molecules with redox activity to re establish the equilibrium between pro and antioxidants. Due to the fact that melatonin readily crosses the blood- brain-barrier, concomitant with its safety profile at the highest dosages makes this dietary supplement very useful in possible clinical application in neurodegeneration. Melatonin is currently marketed in several countries as a dietary supplement with no prescription. Clinical trials have shown different effectiveness of melatonin supplementation in several disorders, including neurodegenerative disorders. Melatonin has unique biochemical properties such as scavenging of hydroxyl, carbonate, alkoxyl, peroxyl and aryl cation radicals and stimulation of activities main antioxidative enzymes (glutathione peroxidase, superoxide dismutase etc.). Moreover, it can suppress nitric oxide synthase. The present paper highlighted the potential clinical role of melatonin in main neurodegenerative diseases including Alzheimer disease, Parkinson disease, amylotrophic lateral sclerosis and multiple sclerosis. Moreover, in this review the main molecular aspects of melatonin in brain cell protection and survival mechanisms were discussed. Therefore, melatonin is regarded as a potential therapeutical agent in clinical application in neurodegenerative disorders, but this findings needs to be confirmed by the larger, more well-designed clinical trials. PMID- 25496272 TI - Antioxidant supplementation on cancer risk and during cancer therapy: an update. AB - Radiation and some chemotherapeutic agents used in conventional cancer treatment generate reactive oxygen species (ROS), and a high ROS level diminishes cellular antioxidant capacity and leads to apoptosis and cancer cell death. Antioxidant supplements are consumed widely by cancer patients in order to prevent toxic side effects of cancer treatment to normal tissues and organs. However, the effects of antioxidant supplementation in cancer therapy were largely disappointing. There is still no consensus on the efficacy and safety of dietary antioxidant supplementation during conventional cancer therapy. In some studies, antioxidant supplements did not reduce the risk for cancer or prevent tumour growth; at the contrary, these interventions resulted in some cases to be harmful to the patients. Therefore, a guidance on antioxidant supplementation based on large clinical trials is urgently needed in order to obtain the best possible care and to avoid risky treatments for cancer patients. PMID- 25496273 TI - The Competence Of 7,8-Diacetoxy-4-Methylcoumarinand Other Polyphenolic Acetates In Mitigating The Oxidative Stress And Their Role In Angiogenesis. AB - The potential role of polyphenolic acetate (PA) in causing diverse biological and pharmacological actions has been well studied in our laboratory. Our investigations, for the first time, established the role of calreticulin transacetylase (CRTAase) in catalyzing the acetylation of nitric oxide synthase (NOS) by Pas leading to robust activation of NOS. 7, 8-Diacetoxy-4-methylcoumarin (DAMC) and other acetoxycoumarins augmented the expression of thioredoxin (TRX) and vascular endothelial growth factor (VEGF) in human peripheral blood mononuclear cells (PBMCs). These findings substantiated our earlier observations that DAMC was a superb inducer of angiogenesis. The enhanced expression of thioredoxin reductase (TRXR) and diminished expression of thioredoxin interacting protein (TRXIP) leading to increased expression and activity of TRX in PBMCs due to the action of DAMC was revealed by real time RT-PCR analysis. The possible activation of TRX due to acetylation was confirmed by the fact that TRX activity of PBMCs was enhanced by variousacetoxycoumarins in tune with their affinities to CRTAase as substrates. DAMC caused enhanced production of NO by way of acetylation of NOS as mentioned above and thereby acted as an inducer of VEGF. Real time RT-PCR and VEGF ELISA results also revealed the overexpression of TRX. DAMC and other PAs were found to reduce the oxidative stress in cells as proved by significant reduction of intracellular ROS levels. Thus, the crucial role of TRX in DAMC-induced angiogenesis with the involvement of VEGF was established. PMID- 25496275 TI - Computational Studies of Free Radical-Scavenging Properties of Phenolic Compounds. AB - For more than half a century free radical-induced alterations at cellular and organ levels have been investigated as a probable underlying mechanism of a number of adverse health conditions. Consequently, significant research efforts have been spent for discovering more effective and potent antioxidants / free radical scavengers for treatment of these adverse conditions. Being by far the most used antioxidants among natural and synthetic compounds, mono- and polyphenols have been the focus of both experimental and computational research on mechanisms of free radical scavenging. Quantum chemical studies have provided a significant amount of data on mechanisms of reactions between phenolic compounds and free radicals outlining a number of properties with a key role for the radical scavenging activity and capacity of phenolics. The obtained quantum chemical parameters together with other molecular descriptors have been used in quantitative structure-activity relationship (QSAR) analyses for the design of new more effective phenolic antioxidants and for identification of the most useful natural antioxidant phenolics. This review aims at presenting the state of the art in quantum chemical and QSAR studies of phenolic antioxidants and at analysing the trends observed in the field in the last decade. PMID- 25496277 TI - Differential impact of infection control strategies on rates of resistant hospital-acquired pathogens in critically ill surgical patients. AB - BACKGROUND: There were two major outbreaks of multi-drug resistant Acinetobacter baumannii (MDRA) in our general surgery and trauma intensive care units (ICUs) in 2004 and 2011. Both required aggressive multi-faceted interventions to control. We hypothesized that the infection control response may have had a secondary benefit of reducing rates of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and Clostridium difficile (C. diff). METHODS: We analyzed data retrospectively from a prospective infection control database at a major university hospital and calculated the incidence rates of nosocomial MRSA, VRE, and C. diff before and after the two MDRA outbreaks (2004 and 2011) in the general surgery and trauma ICUs, and two unaffected control ICUs: thoracic surgery ICU and medical ICU. We tracked incidence rates in 6 mos segments for 24 mos per outbreak and created a composite variable of "any resistant pathogen" for comparison. RESULTS: The incidence rates of "any resistant pathogen" were significantly lower in the general surgery ICU after both outbreaks (24 to 11 cases per 1000 patient days in 2004, p=0.045 and 7.7 >4.0 cases per 1000 patient days in 2011, p=0.04). This did not persist after 6 mos. The trauma ICU's rate of "any resistant pathogen" did not change after either outbreak (16 ->16.5 cases per 1000 patient days in 2004, p=0.44 and 4.6 >1.9 cases per 1000 patient days in 2011, p=0.41). The rates in the control ICUs were unchanged during the study periods. CONCLUSIONS: Rates of resistant pathogens were lower in the general surgery ICU after response to MDRA outbreaks in both 2004 and 2011 although the rates increased again with time. There were no changes in rates of resistant pathogens in the trauma ICU after MDRA outbreaks in 2004 and 2011. Outbreak responses may have a differential impact in general surgery ICU versus trauma ICUs. PMID- 25496279 TI - Risk factor assessment tools for the prevention of periodontitis progression a systematic review. AB - OBJECTIVES: (i) To identify characteristics of currently published patient-based tools used to assess levels of risk for periodontitis progression and (ii) systematically review the evidence documenting the use of patient-based risk assessment tools for predicting periodontitis progression. MATERIAL AND METHODS: A systematic review was prepared on the basis of an electronic search of the literature supplemented with manually searching the relevant journals of the latest 5 years. Prospective and retrospective cohort studies were included as no randomized controlled clinical trials were available. RESULTS: The search identified 336 titles, and 19 articles were included in this systematic review. The search identified five different risk assessment tools. Results of nine of 10 cohort studies reporting outcomes of 2110 patients indicate that risk assessment tools are able to identify subjects with different probability of periodontitis progression and/or tooth loss. Subjects with higher risk scores showed more progression of periodontitis and tooth loss. CONCLUSIONS: In treated populations, results of patient-based risk assessments, for example periodontal risk calculator (PRC) and periodontal risk assessment (PRA), predicted periodontitis progression and tooth loss in various populations. Additional research on the utility of risk assessment and results in improving patient management are needed. PMID- 25496280 TI - Dynamic evolution of the alpha (alpha) and beta (beta) keratins has accompanied integument diversification and the adaptation of birds into novel lifestyles. AB - BACKGROUND: Vertebrate skin appendages are constructed of keratins produced by multigene families. Alpha (alpha) keratins are found in all vertebrates, while beta (beta) keratins are found exclusively in reptiles and birds. We have studied the molecular evolution of these gene families in the genomes of 48 phylogenetically diverse birds and their expression in the scales and feathers of the chicken. RESULTS: We found that the total number of alpha-keratins is lower in birds than mammals and non-avian reptiles, yet two alpha-keratin genes (KRT42 and KRT75) have expanded in birds. The beta-keratins, however, demonstrate a dynamic evolution associated with avian lifestyle. The avian specific feather beta-keratins comprise a large majority of the total number of beta-keratins, but independently derived lineages of aquatic and predatory birds have smaller proportions of feather beta-keratin genes and larger proportions of keratinocyte beta-keratin genes. Additionally, birds of prey have a larger proportion of claw beta-keratins. Analysis of alpha- and beta-keratin expression during development of chicken scales and feathers demonstrates that while alpha-keratins are expressed in these tissues, the number and magnitude of expressed beta-keratin genes far exceeds that of alpha-keratins. CONCLUSIONS: These results support the view that the number of alpha- and beta-keratin genes expressed, the proportion of the beta-keratin subfamily genes expressed and the diversification of the beta keratin genes have been important for the evolution of the feather and the adaptation of birds into multiple ecological niches. PMID- 25496281 TI - Intrinsically disordered proteins (IDPs) in trypanosomatids. AB - BACKGROUND: Proteins are composed of one or more amino acid chains and exhibit several structure levels. IDPs (intrinsically disordered proteins) represent a class of proteins that do not fold into any particular conformation and exist as dynamic ensembles in their native state. Due to their intrinsic adaptability, IDPs participate in many regulatory biological processes, including parasite immune escape. Using the information from trypanosomatids proteomes, we developed a pipeline for the identification, characterization and analysis of IDPs. The pipeline employs six disorder prediction methodologies and integrates structural and functional annotation information, subcellular location prediction and physicochemical properties. At the core of the IDP pipeline, there is a relational database that describes the protein disorder knowledge in a logically consistent manner. RESULTS: The results obtained from the IDP pipeline showed that Leishmania and Trypanosoma species have approximately 70% and 55% IDPs, respectively. Our results indicate that IDPs in trypanosomatids contain disorder promoting amino acids and order-promoting amino acids. The functional annotation analysis demonstrated enrichment of selected Gene Ontology terms. A relevant association was observed between the disordered residue numbers within predicted IDPs and their subcellular location, lack of transmembrane domains and lack of predicted function. We validated our computational findings with 2D electrophoresis designed for IDP identification and found that 100% of the identified protein spots were predicted in silico. CONCLUSIONS: Because there is no pipeline or database addressing IDPs in trypanosomatids, the pipeline described here represents the first attempt to establish possible correlations between protein function and structural disorder in these eukaryotes. Interestingly, all significant associations detected in the contingency analysis were observed when the protein disorder content reached approximately 40%. The exploratory data analysis allowed us to develop hypotheses regarding the IDPs' association with key biological features of these parasites, including transcription and transcriptional regulation, RNA processing and splicing, and cytoskeleton. PMID- 25496282 TI - Geissoschizine methyl ether N-oxide, a new alkaloid with antiacetylcholinesterase activity from Uncaria rhynchophylla. AB - Geissoschizine methyl ether N-oxide, a new oxindole alkaloid, along with 14 known alkaloids, was isolated from the aerial part of Uncaria rhynchophylla. Their structures were identified by comprehensive spectral methods, including 2D NMR experiments, and confirmed by comparing with the literature data. In vitro acetylcholinesterase (AChE) inhibitory activity assay showed that the new compound exhibited anti-AChE activity with IC50 value of 23.4 MUM. PMID- 25496283 TI - Randomized Trial of Family Therapy Versus Nonfamily Treatment for Adolescent Behavior Problems in Usual Care. AB - A major focus of implementation science is discovering whether evidence-based approaches can be delivered with fidelity and potency in routine practice. This randomized trial compared usual care family therapy (UC-FT), implemented without a treatment manual or extramural support as the standard-of-care approach in a community clinic, to nonfamily treatment (UC-Other) for adolescent conduct and substance use disorders. The study recruited 205 adolescents (M age = 15.7 years; 52% male; 59% Hispanic American, 21% African American) from a community referral network, enrolling 63% for primary mental health problems and 37% for primary substance use problems. Clients were randomly assigned to either the UC-FT site or one of five UC-Other sites. Implementation data confirmed that UC-FT showed adherence to the family therapy approach and differentiation from UC-Other. Follow-ups were completed at 3, 6, and 12 months postbaseline. There was no between-group difference in treatment attendance. Both conditions demonstrated improvements in externalizing, internalizing, and delinquency symptoms. However, UC-FT produced greater reductions in youth-reported externalizing and internalizing among the whole sample, in delinquency among substance-using youth, and in alcohol and drug use among substance-using youth. The degree to which UC FT outperformed UC-Other was consistent with effect sizes from controlled trials of manualized family therapy models. Nonmanualized family therapy can be effective for adolescent behavior problems within diverse populations in usual care, and it may be superior to nonfamily alternatives. PMID- 25496284 TI - Anaerobic metabolism of the agro-pesticide nitroxinil by bovine ruminal fluid. AB - Metabolism of three different agro-pesticides widely used in Uruguay, the insecticides imidacloprid and thiamethoxam and the antiparasite nitroxinil, by bovine ruminal fluid, as supply of anaerobic microorganims, was studied. Complete ruminal fluid was incubated with each of the agrochemicals in different conditions, varying time, nutrients, and nitroethane supplementation as methanogenesis modificator. Only biotransformation was detected for nitroxinil in some of the studied variables. In the optimized condition only one product was generated and the chemical structure of this main metabolite was elucidated using combined spectroscopies evidencing a structural motive unrelated with the products of the corresponding mammal biotransformation results of reduction, and substitution processes. The ruminal generation of the metabolite was confirmed. In order to employ this anaerobic microbial system as potential bioremediator of agrochemical-contaminated soils, the toxicity, against mammal cells, and the mutagenicity, using Ames test, of the product of biotransformation were studied. The lack of toxic effects encouraged us to propose the ruminal system as a plausible system for agrochemicals bioremediation. PMID- 25496285 TI - Awareness of salt restriction and actual salt intake in hypertensive patients at a hypertension clinic and general clinic. AB - The purpose of the present study was to investigate awareness of salt restriction and actual salt intake in hypertensive patients at a hypertension clinic and general clinic. Subjects included 330 patients, with a mean age of 69+/-12 years, who were followed at a hypertension clinic and 200 patients, with a mean age of 67+/-11 years, who were followed at a general clinic. We estimated 24-h salt excretion using spot urine samples and checked the awareness of salt intake using a self-description questionnaire. The number of antihypertensive drugs available at the hypertension clinic was significantly higher than that at the general clinic (2.2+/-1.1 versus 1.6+/-0.9, p<0.01); however, no significant difference was observed in office systolic blood pressure between the two groups. Urinary salt excretion was significantly lower at the hypertension clinic than at the general clinic (8.7+/-2.5 versus 9.3+/-2.5 g/d, p<0.01). The rate of achievement of salt intake<6 g/d was 15% at the hypertension clinic and 6% at the general clinic. In patients with excessive salt intake (>=10 g/d), 28% of patients at the hypertensive clinic and 23% at the general clinic thought that their salt intake was low. Urinary salt excretion in hypertensive patients was lower at a hypertensive clinic than at a general clinic. This may be due to the professional nutritional guidance at the hypertension clinic. However, most patients could not comply with the guidelines, and the awareness of salt restriction in patients with excessive salt intake was low. PMID- 25496286 TI - Inhibitory effect of D3 dopamine receptor on migration of vascular smooth muscle cells induced by synergistic effect of angiotensin II and aldosterone. AB - OBJECTIVE: The abnormal migration of vascular smooth muscle cells (VSMCs) has been implicated to contribute to lesion formation in the adult vasculature. The renin-angiotensin-aldosterone system (RAAS) is intensively involved in the pathogenesis of a variety of cardiovascular diseases. There are increasing pieces of evidence for interactions between RAAS and dopamine receptors. We hypothesize that the D3 receptor has an inhibitory effect on angiotensin II (Ang II)/aldosterone-induced VSMC migration. METHOD: In this study, embryonic thoracic aortic smooth muscle cells were cultured. VSMC migration was determined by the Boyden chamber and wound healing assays. RESULTS: VSMC migration was increased by Ang II (10(-10)-10(-7) mol/L) in a concentration-dependent manner, but not by aldosterone (10(-10)-10(-7) mol/L), and a synergistic effect of Ang II (10(-10) mol/L)/aldosterone (10(-10)mol/L) was also observed in VSMC migration. The migratory effects of Ang II alone/with aldosterone were attenuated by the activation of D3 receptors (10(-10)-10(-7) mol/L), although a D3 receptor agonist, PD128907, by itself, had no effect on VSMC migration. The inhibitory effect of the D3 receptor on Ang II/ aldosterone-mediated VSMC migration was blocked by the blocker of PKA (14-22 amide, 10(-7) mol/L), indicating that PKA was involved in the signaling pathway. CONCLUSION: These results indicate that activation of vascular D3 receptors inhibits Ang II/aldosterone-induced VSMC migration through the PKA signal pathway, which may be important in the regulation of vascular remodeling. PMID- 25496287 TI - Association between transforming growth factor beta1 and atrial fibrillation in essential hypertensive patients. AB - BACKGROUND: Transforming growth factor beta1 (TGFbeta1) was one of the main factors for accelerating atrial fibrosis and has been reported with significantly higher level in plasma of the patients with essential hypertension (EH), especially in those with target organ damage. The contribution of TGFbeta1 in the pathogenesis of atrial fibrillation (AF) in EH patients remains unknown. METHODS: 75 EH patients with documented AF were divided into the paroxysmal AF group (EH+pAF, n = 44) or the chronic AF group (EH+cAF, n = 31), and 37 EH patients with sinus rhythm (SR) were assigned into the EH+SR group. All data including EH duration, blood pressure, lipids, glucose and left atrial diameter (LAD) measured by ultrasonic cardiogram were recorded. The serum levels of TGFbeta1 and connective tissue growth factor (CTGF) were detected, and compared with normal controls (NC group, n = 36). RESULTS: The serum levels of TGFbeta1 and CTGF in all EH groups were significantly higher than those in the NC group (p < 0.001, respectively). Among the EH groups, TGFbeta1 and CTGF levels were highest in the cAF group, followed by the pAF and the SR groups (p < 0.005). However, no significant difference was observed in TGFbeta1 and CTGF levels between the cAF group and the pAF group. The serum TGFbeta1 in AF patients was independently correlated with LAD, the presence of AF, aldosterone, CTGF and age. CONCLUSION: The serum TGFbeta1 promotes CTGF synthesis and causes left atrial enlargement and remodeling, which is possibly involved in the pathogenesis of AF in EH patients. PMID- 25496288 TI - Quantifying the economic benefits of prevention in a healthcare setting with severe financial constraints: the case of hypertension control. AB - Hypertension significantly contributes to the increased cardiovascular morbidity and mortality, thus leading to rising healthcare costs. The objective of this study was to quantify the clinical and economic benefits of optimal systolic blood pressure (SBP), in a setting under severe financial constraints, as in the case of Greece. Hence, a Markov model projecting 10-year outcomes and costs was adopted, in order to compare two scenarios. The first one depicted the "current setting", where all hypertensives in Greece presented an average SBP of 164 mmHg, while the second scenario namely "optimal SBP control" represented a hypothesis in which the whole population of hypertensives would achieve optimal SBP (i.e. <140 mmHg). Cardiovascular events' occurrence was estimated for four sub-models (according to gender and smoking status). Costs were calculated from the Greek healthcare system's perspective (discounted at a 3% annual rate). Findings showed that compared to the "current setting", universal "optimal SBP control" could, within a 10-year period, reduce the occurrence of non-fatal events and deaths, by 80 and 61 cases/1000 male smokers; 59 and 37 cases/1000 men non-smokers; whereas the respective figures for women were 69 and 57 cases/1000 women smokers; and accordingly, 52 and 28 cases/1000 women non-smokers. Considering health expenditures, they could be reduced by approximately ?83 million per year. Therefore, prevention of cardiovascular events through BP control could result in reduced morbidity, thereby in substantial cost savings. Based on clinical and economic outcomes, interventions that promote BP control should be a health policy priority. PMID- 25496289 TI - High prevalence of metabolic syndrome in a middle-aged and elderly population with prehypertension in Tianjin. AB - BACKGROUND: Prehypertension has been reported as being correlated with future cardiovascular risk and end-organ damage in middle-aged and elderly persons, and also playing an important role in metabolic syndrome (MetS). The association between prehypertension and MetS has rarely been reported among urban adults in Tianjin, China. METHODS: In this cross-sectional study, a total of 1176 participants aged 40-70 years (524 males and 652 females) were enrolled after excluding participants with hypertension or treated hypertension. Participants were divided into two groups [optimal blood pressure (BP) and prehypertension] based on the classification of BP from the JNC-7. The definition of MetS was as per the International Diabetes Federation standard. An adjusted logistic regression model was used to assess relationships between prehypertension and MetS. RESULTS: The prehypertension group had a significantly higher odds ratio (OR) than the optimal BP group for abnormal waist circumference (WC), fasting plasma glucose (FPG) and triglycerides (TG). In addition, the prehypertension group had a higher OR (3.12; 95% confidence interval 2.34-4.18) for having MetS after adjusting for potential confounders. CONCLUSIONS: The risk of having MetS was significantly associated with prehypertension in middle-aged and elderly persons in Tianjin. Stricter control of BP in this age group is warranted. PMID- 25496290 TI - Feasibility and acceptability of cognitive adaptation training for first-episode psychosis. AB - AIM: Cognitive and functioning impairments are present early in the course of psychotic disorder and remain one of the greatest treatment challenges. Cognitive adaptation training (CAT) is a compensatory approach to psychosocial intervention that is underpinned by a model that incorporates the role of cognition in daily functioning. CAT has established effectiveness in chronic schizophrenia but has received limited investigation in first-episode psychosis (FEP). The aim of this study was to examine the feasibility and acceptability of CAT in young people with FEP. METHODS: This was a single-arm feasibility study of CAT conducted at the Early Psychosis Prevention and Intervention Centre, Melbourne, Australia. Five FEP participants received manually guided CAT from a fully trained CAT therapist. A range of feasibility and acceptability measures were recorded throughout the study, including participant and case manager satisfaction ratings. RESULTS: All participants completed the CAT intervention and session attendance rates were very high (95.3%). Participants and their case managers indicated strong satisfaction with CAT as indicated by positive mean ratings on all satisfaction items, although there was a greater range in the participant ratings. Importantly, CAT did not have a negative effect on existing case management, with case managers reporting that CAT enhanced their treatment. CONCLUSIONS: This study provides evidence that CAT is a highly feasible and acceptable intervention in FEP, which may be easily integrated within existing services. The effectiveness of CAT in improving functional outcomes in FEP is worthy of investigation in a larger trial. PMID- 25496291 TI - The epidermal growth factor receptors as biological targets in penile cancer. AB - Penile cancer is a rare disease, with an incidence that is higher in less developed countries and is in the range of 1 - 10 per 100000 men worldwide. Early diagnosis is essential for cure, as 5 year cancer-specific survival is 90 - 100 % in patients with intraepithelial neoplasms and in those with low-grade superficial tumors without lymphovascular invasion, but it drops to 30% in men with multiple mobile or bilateral inguinal lymph nodes. The EGFR family plays a major role in penile cancer biology, with distinct receptors being involved in HPV-positive and -negative tumors. A number of anti-EGFR agents were used in penile cancer patients outside the context of a clinical trial, mainly as a salvage treatment after failure of first-line chemotherapy. A total of 28 patients received anti-EGFR monoclonal antibodies, with 50% of them showing a response to treatment, and a median PFS of ~ 3 months. The rarity of the disease poses great challenge in terms of education and awareness of the general population, planning of preventive measures on a large scale, as well as conduction of prospective trials and approval of high-cost biological therapy. PMID- 25496292 TI - Composite endpoints for malaria case-management: not simplifying the picture? AB - Rapid diagnostic tests (RDTs) for infection with Plasmodium spp. offer two main potential advantages related to malaria treatment: 1) ensuring that individuals with malaria are promptly treated with an effective artemisinin-based combination therapy, and 2) ensuring that individuals without malaria do not receive an anti malarial they do not need (and instead receive a more appropriate treatment). Some studies of the impact of RDTs on malaria case management have combined these two different successes into a binary outcome describing 'correct management'. However combining correct management of positives and negatives into a single summary measure can be misleading. The problems, which are analogous to those encountered in the evaluation of diagnostic tests, can largely be avoided if data for patients with and without malaria are presented and analysed separately. Where a combined metric is necessary, then one of the established approaches to summarise the performance of diagnostic tests could be considered, although these are not without their limitations. Two graphical approaches to help understand case management performance are illustrated. PMID- 25496293 TI - Expression of Mitogen-Activated Protein Kinases in Chronic Subdural Hematoma Outer Membranes. AB - Growth factors and inflammatory cytokines activate the mitogen-activated protein kinase (MAPK) cascade. Previous studies have shown that chronic subdural hematoma (CSDH) fluid contains these factors and cytokines. In this study, expression of three major MAPK cascade transmitters in the outer membrane of CSDH was assessed. Eleven patients whose outer membrane and CSDH fluid were successfully obtained during trepanation surgery were included in this study. Expression of extracellular signal-regulated kinase (ERK), phosphorylated (p)-ERK, p38, p-p38, c-Jun N-terminal kinase (JNK), p-JNK, and actin was examined by Western blot and immunostaining. We examined whether CSDH fluid could activate MAPKs in cultured endothelial cells (ECs) or fibroblasts in vitro. Western blot analysis showed that p-ERK was present in all samples, whereas p-p38 and p-JNK were detected, but not in all cases. Immunostaining showed that all three p-MAPKs were expressed in vascular endothelium. However, only p-ERK was expressed in fibroblasts. Expression of p-extracellular signal-regulated kinase kinase (MEK) and p-ERK in ECs and fibroblasts was significantly induced immediately after treatment with CSDH fluid, whereas p-p38 and p-JNK expression was significantly induced in ECs 60 min after treatment, but not in fibroblasts. Activation of MEK was significantly inhibited by treatment with antibodies directed against interleukin 6 and vascular endothelial growth factor in ECs, but not in fibroblasts. Inflammatory cytokines and growth factors in CSDH fluids might activate major MAPKs in ECs, which might be associated with neovascularization in the outer membrane of CSDH. These MAPK pathways could become novel targets for treatment of CSDHs. PMID- 25496294 TI - Ultrafiltration biofeedback guided by blood volume monitoring to reduce intradialytic hypotensive episodes in hemodialysis: study protocol for a randomized controlled trial. AB - BACKGROUND: Fluid removal during dialysis, also known as ultrafiltration (UF), leads to intradialytic hypotension (IDH) in a significant number of patients treated with hemodialysis (HD) and is associated with an increase in morbidity and mortality. At present, there are no accepted standards of practice for the prevention or treatment of IDH. Relative blood volume monitoring (BVM) is based on the concept that the hematocrit increases with UF, relative to the patient's baseline hematocrit. The use of BVM biofeedback, whereby the HD machine automatically adjusts the rate of UF based on the relative blood volume, has been proposed for the prevention of IDH. METHODS/DESIGN: This is a 22-week randomized crossover trial. Participants undergo a 4-week run-in phase to standardize medications and dialysis prescriptions. Subsequently, participants are randomized to standard HD or to BVM biofeedback for a period of 8 weeks followed by a 2-week washout phase before crossing over. The dialysis prescription remains identical for both arms. The primary outcome is the frequency of symptomatic IDH as defined by an abrupt drop in the systolic blood pressure of >= 20 mm Hg accompanied by headache, dizziness, loss of consciousness, thirst, dyspnea, angina, muscle cramps or vomiting. Secondary outcomes include the number of symptomatic IDH episodes and any reduction in IDH episodes, nursing interventions, dialysis adequacy, total body water, extra- and intracellular fluid volumes, brain natriuretic peptide and cardiac troponin levels, blood pressure, antihypertensive medication use, patient symptoms and quality of life. DISCUSSION: Our study will determine the impact of using BVM biofeedback to prevent IDH and other serious adverse events in susceptible patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT01988181 (6 November 2013). PMID- 25496297 TI - Parapharyngodon n. spp. (Nematoda: Pharyngodonidae) parasites of hylid frogs from Mexico and review of species included in the genus. AB - Two new species of Parapharyngodon Chatterji, 1933 , parasitizing 3 species of hylid frogs (Diaglena spatulata, Triprion petasatus, and Trachycephalus typhonius) from Mexico are described. The 2 new species share the presence of a gubernaculum with Parapharyngodon lamothei and belong to the group of those species with short spicule; both differ from the remaining species of the genus in the papillar pattern on ventrolateral and dorsal lips and in the thickness of cuticular annulations and cuticular ornamentation in the female specimens. These are the third and fourth reports of Parapharyngodon spp. parasitizing hylid frogs. In addition to the egg characteristics, we propose that length of the lateral alae is also a taxonomically relevant feature to differentiate species of the genus. A bibliographic review of all species historically assigned to Parapharyngodon is given, including those that have been declared species inquirenda, or transferred to other genera and those that are considered valid. PMID- 25496298 TI - Effective management of lower divisional pain in trigeminal neuralgia using balloon traction. AB - Percutaneous balloon compression (PBC) of the trigeminal ganglion uses a differential injury of axons to interfere with the nerve's ability to transmit signals. In our experience, patients with lower divisional pain (V3) are often more difficult to control using PBC. We describe a modification to the PBC technique for patients with lower division (V3) pain, and present our experience to date. PMID- 25496296 TI - Differential experiences of discrimination among ethnoracially diverse persons experiencing mental illness and homelessness. AB - BACKGROUND: This mixed methods study explored the characteristics of and experiences with perceived discrimination in an ethnically diverse urban sample of adults experiencing homelessness and mental illness. METHODS: Data were collected in Toronto, Ontario, as part of a 4-year national randomized field trial of the Housing First treatment model. Rates of perceived discrimination were captured from survey questions regarding perceived discrimination among 231 ethnoracially diverse participants with moderate mental health needs. The qualitative component included thirty six in-depth interviews which explored how individuals who bear these multiple identities of oppression navigate stigma and discrimination, and what affects their capacity to do so. RESULTS: Quantitative analysis revealed very high rates of perceived discrimination related to: homelessness/poverty (61.5%), race/ethnicity/skin colour (50.6%) and mental illness/substance use (43.7%). Immigrants and those who had been homeless three or more years reported higher perceived discrimination on all three domains. Analysis of qualitative interviews revealed three common themes related to navigating these experiences of discrimination among participants: 1) social distancing; 2) old and new labels/identities; and, 3) 'homeland' cultures. CONCLUSIONS: These study findings underscore poverty and homelessness as major sources of perceived discrimination, and expose underlying complexities in the navigation of multiple identities in responding to stigma and discrimination. TRIAL REGISTRATION: Current Controlled Trials ISRCTN42520374 . Registered 18 August 2009. PMID- 25496295 TI - Annual research review: Optimal outcomes of child and adolescent mental illness. AB - BACKGROUND: 'Optimal outcomes' of child and adolescent psychiatric disorders may mean the best possible outcome, or the best considering a child's history. Most research into the outcomes of child and adolescent psychiatric disorder concentrates on the likelihood of adult illness and disability given an earlier history of psychopathology. METHODS: In this article, we review the research literature (based on a literature search using PubMed, RePORT and Google Advanced Scholar databases) on including optimal outcomes for young people with a history of anxiety, depression, attention-deficit/hyperactivity disorder, conduct disorder, oppositional defiant disorder, or substance use disorders in childhood or adolescence. We consider three types of risks that these children may run later in development: future episodes of the same disorder, future episodes of a different disorder, and functional impairment. The impact of treatment or preventative interventions on early adult functioning is briefly reviewed. RESULTS: We found that very few studies enabled us to answer our questions with certainty, but that in general about half of adults with a psychiatric history were disorder-free and functioning quite well in their 20s or 30s. However, their chance of functioning well was less than that of adults without a psychiatric history, even in the absence of a current disorder. CONCLUSIONS: Among adults who had a psychiatric disorder as a child or adolescent, about half can be expected to be disorder-free as young adults, and of these about half will be free of significant difficulties in the areas of work, health, relationships, and crime. Optimal outcomes are predicted by a mixture of personal characteristics and environmental supports. PMID- 25496299 TI - A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency. AB - BACKGROUND: Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder associated with intellectual disability in one-third of cases. Recent findings support Mendelian inheritance in subgroups of patients with the disease. The purpose of this study was to identify a novel genetic cause of paraplegic CP with intellectual disability in a consanguineous Pakistani family. METHODS: We performed whole-exome sequencing (WES) in two brothers with CP and intellectual disability. Analysis of AP4M1 mRNA was performed using quantitative real-time PCR on total RNA from cultured fibroblasts. The brothers were investigated clinically and by MRI. RESULTS: We identified a novel homozygous AP4M1 mutation c.194_195delAT, p.Y65Ffs*50 in the affected brothers. Quantitative RT-PCR analysis showed markedly reduced AP4M1 mRNA levels suggesting partial non-sense mediated mRNA decay. Several clinical and MRI features were consistent with AP-4 complex deficiency. However, in contrast to previously reported cases with AP4M1 mutations our patients show an aggressive behavior and a relatively late onset of disease. CONCLUSION: This study shows an AP4M1 mutation associated with aggressive behavior in addition to mild dysmorphic features, intellectual disability, spastic paraparesis and reduced head circumference. Our findings expand the clinical spectrum associated with AP-4 complex deficiency and the study illustrates the importance of MRI and WES in the diagnosis of patients with CP and intellectual disability. PMID- 25496300 TI - Effect of Flumorph on F-Actin Dynamics in the Potato Late Blight Pathogen Phytophthora infestans. AB - Oomycetes are fungal-like pathogens that cause notorious diseases. Protecting crops against oomycetes requires regular spraying with chemicals, many with an unknown mode of action. In the 1990s, flumorph was identified as a novel crop protection agent. It was shown to inhibit the growth of oomycete pathogens including Phytophthora spp., presumably by targeting actin. We recently generated transgenic Phytophthora infestans strains that express Lifeact-enhanced green fluorescent protein (eGFP), which enabled us to monitor the actin cytoskeleton during hyphal growth. For analyzing effects of oomicides on the actin cytoskeleton in vivo, the P. infestans Lifeact-eGFP strain is an excellent tool. Here, we confirm that flumorph is an oomicide with growth inhibitory activity. Microscopic analyses showed that low flumorph concentrations provoked hyphal tip swellings accompanied by accumulation of actin plaques in the apex, a feature reminiscent of tips of nongrowing hyphae. At higher concentrations, swelling was more pronounced and accompanied by an increase in hyphal bursting events. However, in hyphae that remained intact, actin filaments were indistinguishable from those in nontreated, nongrowing hyphae. In contrast, in hyphae treated with the actin depolymerizing drug latrunculin B, no hyphal bursting was observed but the actin filaments were completely disrupted. This difference demonstrates that actin is not the primary target of flumorph. PMID- 25496301 TI - Impact of Laurel Wilt, Caused by Raffaelea lauricola, on Leaf Gas Exchange and Xylem Sap Flow in Avocado, Persea americana. AB - Laurel wilt, caused by Raffaelea lauricola, is a destructive disease of avocado (Persea americana). The susceptibility of different cultivars and races was examined previously but more information is needed on how this host responds to the disease. In the present study, net CO2 assimilation (A), stomatal conductance of H2O (gs), transpiration (E), water use efficiency (WUE), and xylem sap flow rates were assessed in cultivars that differed in susceptibility. After artificial inoculation with R. lauricola, there was a close relationship between symptom development and reductions in A, gs, E, WUE, and mean daily sap flow in the most susceptible cultivar, 'Russell', and significantly greater disease and lower A, gs, E, WUE, and sap flow rates were usually detected after 15 days compared with the more tolerant 'Brogdon' and 'Marcus Pumpkin'. Significant differences in preinoculation A, gs, E, and WUE were generally not detected among the cultivars but preinoculation sap flow rates were greater in Russell than in Brogdon and Marcus Pumpkin. Preinoculation sap flow rates and symptom severity for individual trees were correlated at the end of an experiment (r=0.46), indicating that a plant's susceptibility to laurel wilt was related to its ability to conduct water. The potential management of this disease with clonal rootstocks that reduce sap flow rates is discussed. PMID- 25496302 TI - Genomic analyses of cherry rusty mottle group and cherry twisted leaf-associated viruses reveal a possible new genus within the family betaflexiviridae. AB - It is demonstrated that closely related viruses within the family Betaflexiviridae are associated with a number of diseases that affect sweet cherry (Prunus avium) and other Prunus spp. Cherry rusty mottle-associated virus (CRMaV) is correlated with the appearance of cherry rusty mottle disease (CRMD), and Cherry twisted leaf-associated virus (CTLaV) is linked to cherry twisted leaf disease (CTLD) and apricot ringpox disease (ARPD). Comprehensive analysis of previously reported full genomic sequences plus those determined in this study representing isolates of CTLaV, CRMaV, Cherry green ring mottle virus, and Cherry necrotic rusty mottle virus revealed segregation of sequences into four clades corresponding to distinct virus species. High-throughput sequencing of RNA from representative source trees for CRMD, CTLD, and ARPD did not reveal additional unique virus sequences that might be associated with these diseases, thereby further substantiating the association of CRMaV and CTLaV with CRMD and CTLD or ARPD, respectively. Based on comparison of the nucleotide and amino acid sequence identity values, phylogenetic relationships with other triple-gene block-coding viruses within the family Betaflexiviridae, genome organization, and natural host range, a new genus (Robigovirus) is suggested. PMID- 25496304 TI - Decision-making regarding organ donation in Korean adults: A grounded-theory study. AB - The aim of this study was to identify the hidden patterns of behavior leading toward the decision to donate organs. Thirteen registrants at the Association for Organ Sharing in Korea were recruited. Data were collected using in-depth interview and the interview transcripts were analyzed using Glaserian grounded theory methodology. The main problem of participants was "body attachment" and the core category (management process) was determined to be "pursuing life." The theme consisted of four phases, which were: "hesitating," "investigating," "releasing," and "re-discovering. " Therefore, to increase organ donations, it is important to find a strategy that will create positive attitudes about organ donation through education and public relations. These results explain and provide a deeper understanding of the main problem that Korean people have about organ donation and their management of decision-making processes. These findings can help care providers to facilitate the decision-making process and respond to public needs while taking into account the sociocultural context within which decisions are made. PMID- 25496305 TI - Bronchiectasis in children from Qikiqtani (Baffin) Region, Nunavut, Canada. AB - RATIONALE: Bronchiectasis not related to cystic fibrosis is common in indigenous populations globally, but it has not been studied in Canadian indigenous children. OBJECTIVE: The objective of this study was to describe bronchiectasis in Canadian Inuit children and examine potentially causal factors. METHODS: We described the clinical features of bronchiectasis in Canadian Inuit children residing in the Qikiqtani (Baffin) Region, Nunavut, Canada, by performing a retrospective chart review of children from this region. Patients had computed tomography-confirmed bronchiectasis and were diagnosed at the Children's Hospital of Eastern Ontario, Ottawa, Canada, the regional tertiary center, between 1998 and 2011. MEASUREMENTS AND MAIN RESULTS: We identified 17 cases of bronchiectasis. We conservatively estimated the prevalence at 202/100,000 children. Bronchiectasis was strongly associated with lower respiratory tract infection (LRTI) in infancy. Reported environmental tobacco smoke exposure and overcrowding in the home appeared to be common. The left lower lobe was the most common lung lobe involved. Haemophilus influenza, Streptococcus, and Streptococcus pneumoniae were commonly isolated. The range of FEV1 values measured during pulmonary function testing was 46-108% predicted. CONCLUSIONS: Previous researchers have reported that Canadian Inuit children have markedly elevated rates of LRTI early in life. Our study suggests that this may lead to long-term pulmonary sequelae. Preventing LRTI in Inuit infants may both prevent acute, severe illness and reduce their risk of developing permanent lung damage. PMID- 25496303 TI - A blinded, randomized clinical trial comparing the efficacy and safety of oclacitinib and ciclosporin for the control of atopic dermatitis in client-owned dogs. AB - BACKGROUND: Ciclosporin is approved for the treatment of atopic dermatitis (AD) in dogs and has been shown to be safe and effective. Placebo-controlled studies suggest that oclacitinib is a safe and effective alternative therapy. HYPOTHESIS/OBJECTIVES: To evaluate the efficacy and safety of oclacitinib, in comparison to ciclosporin, for the control of AD in a blinded, randomized clinical trial, incorporating a noninferiority test at day 28. ANIMALS: A total of 226 client-owned dogs with a history of AD from eight sites were enrolled. METHODS: Enrolled animals were randomized to receive oral oclacitinib (0.4-0.6 mg/kg twice daily for 14 days, then once daily) or oral ciclosporin (3.2-6.6 mg/kg once daily) for 12 weeks. Owners assessed pruritus using an enhanced visual analog scale (VAS), and veterinarians assessed dermatitis using the Canine Atopic Dermatitis Extent and Severity Index (CADESI)-02. RESULTS: On days 1, 2, 7, 14, 28, 56 and 84, the percentage reduction from baseline for owner-assessed pruritus changed from 25.6 to 61.0% in the oclacitinib group compared with 6.5 to 61.5% in the ciclosporin group; differences were significant at all time points up to day 28. On day 56, ciclosporin-treated dogs showed a similar decrease in pruritus to oclacitinib-treated dogs. On day 14, the percentage reduction from baseline CADESI-02 was significantly greater in the oclacitinib group (58.7%) than in the ciclosporin group (43.0%). Three times as many adverse events attributed to gastrointestinal signs were reported in the ciclosporin group compared with the oclacitinib group. CONCLUSIONS AND CLINICAL IMPORTANCE: In this study of treatment for canine AD, oclacitinib had a faster onset of action and a lower frequency of gastrointestinal side effects compared with ciclosporin. PMID- 25496306 TI - Association between left ventricular mechanics and heart rate variability in untreated hypertensive patients. AB - The authors sought to investigate left ventricular (LV) mechanics and heart rate variability (HRV), and their relationship, in untreated hypertensive patients. A total of 63 untreated hypertensive patients and 45 healthy patients were included. All patients underwent 24-hour Holter monitoring and echocardiographic examination (two- and three-dimensional). All parameters of time and frequency domain of HRV were decreased in the hypertensive patients. Two-dimensional LV longitudinal and circumferential deformation was significantly reduced in hypertensive patients. Three-dimensional LV strain in all three directions as well as area strain were reduced in the hypertensive group. In two different models of multivariate regression, two-dimensional LV longitudinal and circumferential strain, as well as three-dimensional LV area strain, remained associated with HRV parameters independently of LV structural and functional parameters. This study showed that LV mechanics and HRV were significantly impaired in untreated hypertensive patients. Two- and three-dimensional echocardiographic LV deformation were independently associated with HRV parameters in the whole study population. PMID- 25496307 TI - Transition to retirement and participation in mainstream community groups using active mentoring: a feasibility and outcomes evaluation with a matched comparison group. AB - BACKGROUND: This paper reports on the feasibility and outcomes of a transition to retirement programme for older adults with disability. Without activities and social inclusion, retirees with disability are likely to face inactivity, isolation and loneliness. METHODS: Matched intervention and comparison groups each consisted of 29 older individuals with disability. There were 42 men and 16 women with a mean age of 55.6 years While attending their individual mainstream community group 1 day per week, intervention group participants received support from community group members trained as mentors. We assessed participants' loneliness, social satisfaction, depression, life events, quality of life, community participation, social contacts, and work hours before and 6 months after joining a community group. RESULTS: Twenty-five (86%) of the intervention group attended their community group weekly for at least 6 months. They increased their community participation, made an average of four new social contacts and decreased their work hours. Intervention participants were more socially satisfied post-intervention than comparison group members. CONCLUSIONS: The results demonstrate that participation in mainstream community groups with support from trained mentors is a viable option for developing a retirement lifestyle for older individuals with disability. PMID- 25496308 TI - B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) mediate CD40-independent help by memory CD4 T cells. AB - Donor-reactive memory T cells undermine organ transplant survival and are poorly controlled by immunosuppression or costimulatory blockade. Memory CD4 T cells provide CD40-independent help for the generation of donor-reactive effector CD8 T cells and alloantibodies (alloAbs) that rapidly mediate allograft rejection. The goal of this study was to investigate the role of B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) in alloresponses driven by memory CD4 T cells. The short-term neutralization of BAFF alone or BAFF plus APRIL synergized with anti-CD154 mAb to prolong heart allograft survival in recipients containing donor-reactive memory CD4 T cells. The prolongation was associated with reduction in antidonor alloAb responses and with inhibited reactivation and helper functions of memory CD4 T cells. Additional depletion of CD8 T cells did not enhance the prolonged allograft survival suggesting that donor-reactive alloAbs mediate late graft rejection in these recipients. This is the first report that targeting the BAFF cytokine network inhibits both humoral and cellular immune responses induced by memory CD4 T cells. Our results suggest that reagents neutralizing BAFF and APRIL may be used to enhance the efficacy of CD40/CD154 costimulatory blockade and improve allograft survival in T cell sensitized recipients. PMID- 25496309 TI - SQSTM1/p62 regulates the expression of junctional proteins through epithelial mesenchymal transition factors. AB - The epithelial to mesenchymal transition (EMT) is an essential process during development and during tumor progression. Here, we observed the accumulation of the selective autophagy receptor and signaling adaptor sequestosome-1 (SQSTM1/p62) during growth factor-induced EMT in immortalized and tumor-derived epithelial cell lines. Modulation of the p62 level regulated the expression of junctional proteins. This effect was dependent on the ubiquitin-associated domain of p62, which stabilized the TGFbeta/Smad signaling co-activator Smad4 and the EMT transcription factor Twist. This study highlights a novel function of p62 in a major epithelial phenotypic alteration. PMID- 25496310 TI - Psychological characteristics of patients with myotonic dystrophy type 1. AB - OBJECTIVES: Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy. It is associated with motor symptoms but patients also display non-motor symptoms such as particular personality traits. Studies have reported mixed results about personality characteristics which may be attributable to small sample sizes, different disease severity of groups studied, and use of different questionnaires or method. This study aimed to describe the psychological characteristics of a large cohort of patients with DM1, to characterize those at risk of developing a psychiatric disorder, and to compare characteristics between two DM1 phenotypes, a mild and more severe adult-onset phenotype. METHODS: Two hundred patients with DM1 (152 adult-onset; 48 mild) were asked to complete questionnaires assessing personality traits, psychological symptoms, self-esteem, and suicidal risk. Neurological and neuropsychological assessments were performed to compare personality characteristics to clinical and cognitive measures. RESULTS: Patients with DM1 globally showed personality traits and psychological symptoms in the average range compared to normative data, with normal levels of self-esteem and suicidal ideation. However, 27% of patients were found to be at high risk of developing a psychiatric disorder. Moreover, psychological traits differed across phenotypes, with the most severe phenotype tending to show more severe psychological symptoms. The presence of higher phobic anxiety and lower self-esteem was associated with lower education, a higher number of CTG repeats, more severe muscular impairment, and lower cognitive functioning (P < 0.001). CONCLUSIONS: Different phenotypes should thus be taken into account in clinical settings for individual management of patients and optimizing therapeutic success. PMID- 25496311 TI - A phospholipid complex to improve the oral bioavailability of flavonoids. AB - AIM: A phospholipid complex (TFH-PC) was prepared to increase the oral bioavailability of isorhamnetin, kaempferol, and quercetin from TFH (total flavones of Hippophae rhamnoides L.). METHODS: Solvent evaporation was used to prepare TFH-PC. Relevant parameters were investigated based on the complexation rate of isorhamnetin, kaempferol, and quercetin. Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray power diffraction (X-RPD), and scanning electron microscopy (SEM) were used for characterization. Solubility, octanol-water partition coefficient (log P), dissolution rate, and in vivo pharmacokinetics were also investigated. RESULTS: TFH-PC was successfully prepared in tetrahydrofuran with a drug to phospholipid ratio of 1:1, reaction temperature of 20 degrees C, and a reaction time of 1 h. The complexation rates of isorhamnetin, kaempferol, and quercetin were 97.7%, 95.97%, and 92.23%, respectively. FT-IR, DSC, X-RPD, and SEM confirmed the formation of TFH-PC. The aqueous solubilities of the three flavonoids in TFH-PC increased 22.0-26.8-fold compared with TFH. The dissolution of isorhamnetin, kaempferol, and quercetin in TFH-PC was 84.32%, 90.77%, and 100% within 10 min, respectively, greatly improved over TFH. After oral administration of TFH-PC in rats, the bioavailability of isorhamnetin, kaempferol, and quercetin in TFH-PC relative to TFH was 223%, 172%, and 242%, respectively. CONCLUSION: The oral absorption of isorhamnetin, kaempferol, and quercetin was significantly improved in TFH-PC, mainly due to increased solubility and dissolution rate. This phospholipid complex shows potential for oral delivery of the flavonoids in TFH. PMID- 25496312 TI - Structural and functional consequences of buserelin-induced enteric neuropathy in rat. AB - BACKGROUND: Women treated with gonadotropin-releasing hormone (GnRH) analogs may develop enteric neuropathy and dysmotility. Administration of a GnRH analog to rats leads to similar degenerative neuropathy and ganglioneuritis. The aim of this study on rat was to evaluate the early GnRH-induced enteric neuropathy in terms of distribution of neuronal subpopulations and gastrointestinal (GI) function. METHODS: Forty rats were given the GnRH analog buserelin (20 MUg, 1 mg/ml) or saline subcutaneously, once daily for 5 days, followed by 3 weeks of recovery, representing one treatment session. Two weeks after the fourth treatment session, the animals were tested for GI transit time and galactose absorption, and fecal weight and fat content was analyzed. After sacrifice, enteric neuronal subpopulations were analyzed. Blood samples were analyzed for zonulin and antibodies against GnRH and luteinizing hormone, and their receptors. RESULTS: Buserelin treatment transiently increased the body weight after 5 and 9 weeks (p < 0.001). Increased estradiol in plasma and thickened uterine muscle layers indicate high estrogen activity. The numbers of both submucous and myenteric neurons were reduced by 27%-61% in ileum and colon. The relative numbers of neurons containing calcitonin gene-related peptide (CGRP), cocaine- and amphetamine-related transcript (CART), galanin, gastrin-releasing peptide (GRP), neuropeptide Y (NPY), nitric oxide synthase (NOS), serotonin, substance P (SP), vasoactive intestinal peptide (VIP) or vesicular acetylcholine transporter (VAchT), and their nerve fiber density, were unchanged after buserelin treatment, but the relative number of submucous neurons containing somatostatin tended to be increased (p = 0.062). The feces weight decreased in buserelin-treated rats (p < 0.01), whereas feces fat content increased (p < 0.05), compared to control rats. Total GI transit time, galactose absorption, zonulin levels in plasma, and antibody titers in serum were unaffected by buserelin treatment. CONCLUSIONS: A marked enteric neuronal loss with modest effects on GI function is found after buserelin treatment. Increased feces fat content is suggested an early sign of dysfunction. PMID- 25496313 TI - Radioprotective effects of mitochondria-targeted antioxidant SkQR1. AB - We show here that mitochondria-targeted antioxidant composed of plastoquinone conjugated through hydrocarbon linker with cationic rhodamine 19 (SkQR1) protected against nuclear DNA damage induced by gamma radiation in K562 erythroleukemia cells. We also demonstrate that SkQR1 prevented the early (1 h postirradiation) accumulation of phosphorylated histone H2AX (gamma-H2AX) an indicator of DNA double-strand break formation, as well as the radiation-induced increase in chromosomal aberrations. These data suggested that nuclear DNA damage induced by gamma radiation may be mediated by mitochondrial reactive oxygen species (ROS) production. We show that SkQR1 suppressed delayed accumulation of ROS 32 h after irradiation probably by inhibiting mitochondrial ROS-induced ROS release mechanisms. This suggests that mitochondria-targeted antioxidants may protect cells from the late consequences of radiation exposure related to delayed oxidative stress. We have previously reported that SkQRl is the substrate of multidrug resistance pump P-glycoproten (Pgp 170) and selectively protects Pgp 170-negative cells against oxidative stress. In line with this finding, we demonstrate here that SkQR1 did not protect Pgp170-positive K562 subline against DNA damage induced by gamma radiation. The selective radioprotection of normal Pgp 170-negative cells by mitochondria-targeted antioxidants could be a promising strategy to increase the efficiency of radiotherapy for multidrug-resistant tumors. PMID- 25496314 TI - The two-dimensional Monte Carlo: a new methodologic paradigm for dose reconstruction for epidemiological studies. AB - Retrospective dose estimation, particularly dose reconstruction that supports epidemiological investigations of health risk, relies on various strategies that include models of physical processes and exposure conditions with detail ranging from simple to complex. Quantification of dose uncertainty is an essential component of assessments for health risk studies since, as is well understood, it is impossible to retrospectively determine the true dose for each person. To address uncertainty in dose estimation, numerical simulation tools have become commonplace and there is now an increased understanding about the needs and what is required for models used to estimate cohort doses (in the absence of direct measurement) to evaluate dose response. It now appears that for dose-response algorithms to derive the best, unbiased estimate of health risk, we need to understand the type, magnitude and interrelationships of the uncertainties of model assumptions, parameters and input data used in the associated dose estimation models. Heretofore, uncertainty analysis of dose estimates did not always properly distinguish between categories of errors, e.g., uncertainty that is specific to each subject (i.e., unshared error), and uncertainty of doses from a lack of understanding and knowledge about parameter values that are shared to varying degrees by numbers of subsets of the cohort. While mathematical propagation of errors by Monte Carlo simulation methods has been used for years to estimate the uncertainty of an individual subject's dose, it was almost always conducted without consideration of dependencies between subjects. In retrospect, these types of simple analyses are not suitable for studies with complex dose models, particularly when important input data are missing or otherwise not available. The dose estimation strategy presented here is a simulation method that corrects the previous deficiencies of analytical or simple Monte Carlo error propagation methods and is termed, due to its capability to maintain separation between shared and unshared errors, the two-dimensional Monte Carlo (2DMC) procedure. Simply put, the 2DMC method simulates alternative, possibly true, sets (or vectors) of doses for an entire cohort rather than a single set that emerges when each individual's dose is estimated independently from other subjects. Moreover, estimated doses within each simulated vector maintain proper inter relationships such that the estimated doses for members of a cohort subgroup that share common lifestyle attributes and sources of uncertainty are properly correlated. The 2DMC procedure simulates inter-individual variability of possibly true doses within each dose vector and captures the influence of uncertainty in the values of dosimetric parameters across multiple realizations of possibly true vectors of cohort doses. The primary characteristic of the 2DMC approach, as well as its strength, are defined by the proper separation between uncertainties shared by members of the entire cohort or members of defined cohort subsets, and uncertainties that are individual-specific and therefore unshared. PMID- 25496315 TI - Frequent co-inactivation of the SWI/SNF subunits SMARCB1, SMARCA2 and PBRM1 in malignant rhabdoid tumours. AB - AIMS: Malignant rhabdoid tumours (MRTs) are highly aggressive malignancies of early infancy characterized by inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodelling complex. The aim of this study was to explore the status of multiple key subunits of the SWI/SNF complex in MRTs. METHODS AND RESULTS: We screened the key subunits of the SWI/SNF complex, including SMARCB1, SMARCA2, PBRM1, SMARCA4, and ARID1A, in four MRTs by immunohistochemistry, sequencing, and fluorescence in-situ hybridization (FISH). Complete loss of SMARCB1, SMARCA2 and PBRM1 expression and corresponding mutations in the same genes were observed in all cases. The mutations included seven missense, three same-sense, four frameshift and two truncating mutations. FISH revealed heterozygous deletion of SMARCB1 in one case, and monoploidy of chromosome 22, which harbours SMARCB1, in another case. Furthermore, trisomy of chromosome 9, which harbours SMARCA2, was observed in two cases. Abnormality of PBRM1 was not found in any case. CONCLUSIONS: We report, for the first time, co-inactivation and frequent mutations of SMARCB1, SMARCA2 and PBRM1 in MRTs. Multiple subunit abnormalities of the SWI/SNF complex potentially act together to contribute to the tumorigenesis of MRTs, which provides unique insights into this disease. PMID- 25496316 TI - Cardiac safety of tiotropium in patients with COPD: a combined analysis of Holter ECG data from four randomised clinical trials. AB - BACKGROUND: Tiotropium is generally well tolerated; however, there has been debate whether antimuscarinics, particularly tiotropium administered via Respimat((r)) Soft Mist(TM) Inhaler, may induce cardiac arrhythmias in a vulnerable subpopulation with cardiovascular comorbidity. The aim of this study was to provide evidence of the cardiac safety of tiotropium maintenance therapy. METHODS: Combined analysis of Holter electrocardiogram (ECG) data from clinical trials of tiotropium in chronic obstructive pulmonary disease (COPD). Trials in the Boehringer Ingelheim clinical trials database conducted between 2003 and 2012, involving tiotropium HandiHaler((r)) 18 MUg and/or tiotropium Respimat((r)) (1.25-, 2.5-, 5.0- and 10-MUg doses) were reviewed. All trials involving Holter ECG monitoring during this period were included in the analysis. Men and women aged >= 40 years with a smoking history of >= 10 pack-years, and a clinical diagnosis of COPD were included. Holter ECGs were evaluated for heart rate (HR), supraventricular premature beats (SVPBs), ventricular premature beats (VPBs) and pauses. Quantitative and categorical end-points were derived for each of the Holter monitoring days. RESULTS: Four trials (n = 727) were included in the analysis. Respimat((r)) (1.25-10 MUg) or HandiHaler((r)) (18 MUg) was not associated with changes in HR, SVPBs, VPBs and pauses compared with placebo or the pretreatment baseline period. In terms of cardiac arrhythmia end-points, there was no evidence for an exposure-effect relationship. CONCLUSIONS: In this analysis, tiotropium maintenance therapy administered using Respimat((r)) (1.25 10 MUg) or HandiHaler((r)) (18 MUg) once daily for periods of up to 48 weeks was well tolerated with no increased risk of cardiac arrhythmia in patients with COPD. PMID- 25496317 TI - Fully automated synthesis of DNA-binding Py-Im polyamides using a triphosgene coupling strategy. AB - The fully automated solid-phase synthetic strategy of hairpin pyrrole-imidazole polyamides is described. A key advance is the development of methodology for the application of triphosgene as a coupling agent in the automated synthesis of hairpin polyamides without racemization. This automated methodology is compatible with all the typical building blocks, enabling the facile synthesis of polyamide libraries in good yield (9-15%) and crude purity. PMID- 25496319 TI - Protective effect of aqueous extracts from Rhizopus oryzae on liver injury induced by carbon tetrachloride in rats. AB - Hepatoprotective effects of Rhizopus oryzae/ U-1 aqueous extract (RU) were demonstrated in carbon tetrachloride (CCl4 )-induced liver-injured rats. In order to investigate the RU effects, the rats were administered RU at a dose of 10 or 100 mg/kg of body weight for 10 days before induction of the liver injury by oral administration of CCl4 (125 mg/kg body weight). (i) Pretreatment with RU caused a significant decrease in serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities that were increased by the administration of CCl4 . (ii) RU pretreatment (100 mg/kg) increased 5-bromo-2'-deoxyuridine incorporation at 48 h after CCl4 treatment in hepatocytes. (iii) Histological hematoxylin and eosin staining of the liver showed that RU pretreatment reduced the damage induced by CCl4 administration. (iv) Reverse transcriptase PCR analysis showed RU retreatment caused a transient but significant increase in hepatocyte growth factor (HGF) and a sustained and significant increase in insulin-like growth factor-I (IGF-I) gene expression in hepatocytes injured by CCl4 treatment. From these results, we conclude that oral pre-administration of RU was effective to suppress liver injury induced by the subsequent oral CCl4 administration, and RU-induced increase in IGF-I and HGF gene expression may be, even in part, involved in biological actions of RU in rats. PMID- 25496318 TI - SWS2 visual pigment evolution as a test of historically contingent patterns of plumage color evolution in warblers. AB - Distantly related clades that occupy similar environments may differ due to the lasting imprint of their ancestors-historical contingency. The New World warblers (Parulidae) and Old World warblers (Phylloscopidae) are ecologically similar clades that differ strikingly in plumage coloration. We studied genetic and functional evolution of the short-wavelength-sensitive visual pigments (SWS2 and SWS1) to ask if altered color perception could contribute to the plumage color differences between clades. We show SWS2 is short-wavelength shifted in birds that occupy open environments, such as finches, compared to those in closed environments, including warblers. Phylogenetic reconstructions indicate New World warblers were derived from a finch-like form that colonized from the Old World 15 20 Ma. During this process, the SWS2 gene accumulated six substitutions in branches leading to New World warblers, inviting the hypothesis that passage through a finch-like ancestor resulted in SWS2 evolution. In fact, we show spectral tuning remained similar across warblers as well as the finch ancestor. Results reject the hypothesis of historical contingency based on opsin spectral tuning, but point to evolution of other aspects of visual pigment function. Using the approach outlined here, historical contingency becomes a generally testable theory in systems where genotype and phenotype can be connected. PMID- 25496320 TI - LEIGC long non-coding RNA acts as a tumor suppressor in gastric carcinoma by inhibiting the epithelial-to-mesenchymal transition. AB - BACKGROUND: Long non-coding RNAs have been shown to have critical regulatory roles in cancer biology. However, the contributions of lncRNAs to gastric cancer remain largely unknown. METHODS: The differential expression of lncRNAs in gastric cancer and paired non-cancerous tissues were identified by microarray and validated using quantitative real-time PCR. Gastric samples from patients with gastric cancer were further analyzed for levels of a specifically downregulated lncRNA (termed as LEIGC). RESULTS: We found that there were significantly lower levels of LEIGC expression in cancer tissue than in adjacent non-cancerous tissues in human gastric cancers (P < 0.01). Overexpression of LEIGC suppressed tumor growth and cell proliferation, and enhanced the sensitivity of gastric cancer cells to 5-fluorouracil (5-FU), whereas knockdown of LEIGC showed the opposite effect. We further demonstrated LEIGC functions by inhibiting the epithelial-to-mesenchymal transition (EMT) in gastric cancer. CONCLUSIONS: Our data suggested that LEIGC is a tumor-suppressing lncRNA in gastric cancer, and led us to propose that lncRNAs may play important regulatory roles in cancer development and progression. PMID- 25496321 TI - Expression of bioactive lysophospholipids and processing enzymes in the vitreous from patients with proliferative diabetic retinopathy. AB - BACKGROUND: The bioactive lysophospholipids phosphatidic acid (PA), lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) have been implicated in mediating cell migration, proliferation and apoptosis, inflammation, angiogenesis and fibrosis. This study was conducted to measure the levels of PA, LPA, LPA-producing enzymes phospholipase A1/A2 (PLA1A/PLA2, respectively) and acylgylycerol kinase (AGK), the S1P receptor S1PR1, the S1P catabolising enzyme S1P lyase (SPL) and 5-lipoxygenase in the vitreous fluid from patients with proliferative diabetic retinopathy (PDR). In addition, we investigated the correlations between the levels of PA and LPA and the levels of the inflammatory and endothelial dysfunction biomarker soluble vascular cell adhesion molecule-1 (sVCAM-1). METHODS: Vitreous samples from 34 PDR and 29 nondiabetic patients were studied by biochemical and enzyme-linked immunosorbent assays and Western blot analysis. RESULTS: PA, LPA and sVCAM-1 levels in vitreous samples from PDR patients were significantly higher than those in nondiabetic patients. Significant correlations were observed between levels of LPA and levels of PA and sVCAM-1. Western blot analysis revealed a significant increase in the expression of PLA1A, AGK, S1PR1 and SPL in vitreous samples from PDR patients compared to nondiabetic controls, whereas PLA2 and 5-lipoxygenase were not detected. CONCLUSIONS: Our findings suggest that the enzymatic activities of PLA1A and AGK might be responsible for increased synthesis of LPA in PDR and that PLA1A, but not PLA2 is responsible for deacylation of PA to generate LPA. S1PR1 and SPL might regulate inflammatory, angiogenic and fibrogenic responses in PDR. PMID- 25496322 TI - Heterogeneous genetic diversity pattern in Plasmodium vivax genes encoding merozoite surface proteins (MSP) -7E, -7F and -7L. AB - BACKGROUND: The msp-7 gene has become differentially expanded in the Plasmodium genus; Plasmodium vivax has the highest copy number of this gene, several of which encode antigenic proteins in merozoites. METHODS: DNA sequences from thirty six Colombian clinical isolates from P. vivax (pv) msp-7E, -7F and -7L genes were analysed for characterizing and studying the genetic diversity of these pvmsp-7 members which are expressed during the intra-erythrocyte stage; natural selection signals producing the variation pattern so observed were evaluated. RESULTS: The pvmsp-7E gene was highly polymorphic compared to pvmsp-7F and pvmsp-7L which were seen to have limited genetic diversity; pvmsp-7E polymorphism was seen to have been maintained by different types of positive selection. Even though these copies seemed to be species-specific duplications, a search in the Plasmodium cynomolgi genome (P. vivax sister taxon) showed that both species shared the whole msp-7 repertoire. This led to exploring the long-term effect of natural selection by comparing the orthologous sequences which led to finding signatures for lineage-specific positive selection. CONCLUSIONS: The results confirmed that the P. vivax msp-7 family has a heterogeneous genetic diversity pattern; some members are highly conserved whilst others are highly diverse. The results suggested that the 3'-end of these genes encode MSP-7 proteins' functional region whilst the central region of pvmsp-7E has evolved rapidly. The lineage-specific positive selection signals found suggested that mutations occurring in msp-7s genes during host switch may have succeeded in adapting the ancestral P. vivax parasite population to humans. PMID- 25496323 TI - Alpinetin enhances cholesterol efflux and inhibits lipid accumulation in oxidized low-density lipoprotein-loaded human macrophages. AB - Alpinetin is a natural flavonoid abundantly present in the ginger family. Here, we investigated the effect of alpinetin on cholesterol efflux and lipid accumulation in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 macrophages and human peripheral blood monocyte-derived macrophages (HMDMs). After exposing THP-1 macrophages to alpinetin, cholesterol efflux was determined by liquid scintillator. The mRNA and protein levels of peroxisome proliferator activated receptor gamma (PPAR-gamma), liver X receptor alpha (LXR-alpha), ATP binding cassette transporter A1 (ABCA1), and ABCG1 and scavenger receptor class B member 1 were determined by reverse-transcriptase PCR (RT-PCR) and Western blot analysis, respectively. Alpinetin promoted apolipoprotein A-I- and high-density lipoprotein-mediated cholesterol efflux and elevated PPAR-gamma and LXR-alpha mRNA and protein expression in a dose-dependent fashion in ox-LDL-treated THP-1 macrophages and HMDMs. Small interfering RNA-mediated silencing of PPAR-gamma or LXR-alpha dose dependently reversed alpinetin-increased cholesterol efflux in THP 1 macrophages, indicating the involvement of PPAR-gamma and LXR-alpha in alpinetin-promoted cholesterol efflux. Alpinetin inhibited ox-LDL-induced lipid accumulation and enhanced the expression of ABCA1 and ABCG1 mRNA and protein, which was reversed by specific knockdown of PPAR-gamma or LXR-alpha. Taken together, our results reveal that alpinetin exhibits positive effects on cholesterol efflux and inhibits ox-LDL-induced lipid accumulation, which might be through PPAR-gamma/LXR-alpha/ABCA1/ABCG1 pathway. PMID- 25496324 TI - Synthetic approach toward complexity of sialic acid-containing glycans. AB - The biological relevance of sialic acid-containing glycans (sialo-glycans) to various interactions at the cell surface has increased the demand for the supply of structurally defined sialo-glycans. Due to their unique structures, the stereoselective synthesis of glycosides of sialic acid is inherently difficult, which makes the synthetic approach to synthesize diverse and complex sialo glycans far from successful. However, the gap between the chemical and natural synthesis of complex sialo-glycans is narrowing through the emergence of synthetic methods. This review highlights recent progress made in the synthesis of complex sialo-glycans via cutting-edge synthetic methods. PMID- 25496325 TI - Novel antitumor cisplatin and transplatin derivatives containing 1-methyl-7 azaindole: synthesis, characterization, and cellular responses. AB - The current work investigates the effect of new bifunctional and mononuclear Pt(II) compounds, the cis- and trans-isomers of [PtCl2(NH3)(L)] (L = 1-methyl-7 azaindole, compounds 1 and 2, respectively), on growth and viability of human carcinoma cells as well as their putative mechanism(s) of cytotoxicity. The results show that substitution of 1-methyl-7-azaindole for ammine in cisplatin or transplatin results in an increase of the toxic efficiency, selectivity for tumor cells in cisplatin-resistant cancer cells, and activation of the trans geometry. The differences in the cytotoxic activities of 1 and 2 were suggested to be due to their different DNA binding mode, different capability to induce cell cycle perturbations, and fundamentally different role of transcription factor p53 in their mechanism of action. Interestingly, both isomers make it possible to detect their cellular uptake and distribution in living cells by confocal microscopy without their modification with an optically active tag. PMID- 25496326 TI - SmI2-mediated radical coupling strategy to Securinega alkaloids: total synthesis of (-)-14,15-dihydrosecurinine and formal total synthesis of (-)-securinine. AB - The asymmetric total synthesis of (-)-14,15-dihydrosecurinine and the formal total synthesis of (-)-securinine were accomplished starting from an easily available malimide. A concise SmI2-mediated radical coupling strategy has been developed to construct the bridged alpha-hydroxy 6-azabicyclo[3.2.1]octanone in four steps with high diastereoselectivity. PMID- 25496327 TI - Uncovering the cathepsin system in heart failure patients submitted to Left Ventricular Assist Device (LVAD) implantation. AB - BACKGROUND: In end-stage heart failure (HF), the implantation of a left ventricular assist device (LVAD) is able to induce reverse remodeling. Cellular proteases, such as cathepsins, are involved in the progression of HF. The aim of this study was to evaluate the role of cathepsin system in HF patients supported by LVAD, in order to determine their involvement in cardiac remodeling. METHODS: The expression of cysteine (CatB, CatK, CatL, CatS) and serine cathepsin (CatG), and relative inhibitors (Cystatin B, C and SerpinA3, respectively) was determined in cardiac biopsies of 22 patients submitted to LVAD (pre-LVAD) and compared with: 1) control stable chronic HF patients on medical therapy at the moment of heart transplantation without prior LVAD (HT, n = 7); 2) patients supported by LVAD at the moment of transplantation (post-LVAD, n = 6). RESULTS: The expression of cathepsins and their inhibitors was significantly higher in pre-LVAD compared to the HT group and LVAD induced a further increase in the cathepsin system. Significant positive correlations were observed between cardiac expression of cathepsins and their inhibitors as well as inflammatory cytokines. In the pre LVAD group, a relationship of cathepsins with dilatative etiology and length of hospitalization was found. CONCLUSIONS: A parallel activation of cathepsins and their inhibitors was observed after LVAD support. The possible clinical importance of these modifications is confirmed by their relation with patients' outcome. A better discovery of these pathways could add more insights into the cardiac remodeling during HF. PMID- 25496328 TI - Think UV, not heat! AB - BACKGROUND: Australia has the highest incidence of skin cancer in the world, a preventable disease caused primarily by exposure to ultraviolet radiation (UVR) in sunlight. Health promotion strategies play a significant role in sun protection. OBJECTIVES: To assess the understanding of a population sample as to the time of year that the sun was 'at its most burning' in Melbourne, Australia. METHODS: A cross-sectional study was performed using questionnaires completed at corporate skin checks, conducted on 668 participants during 2011 to 2013. RESULTS: Only a minority (n = 82, 12%) gave the correct theoretical answer; the summer solstice or 21-22 December, while another 38% (n = 254) correctly named December and January as the times when the UVR is actually highest. In all, 18% (n = 122) said February was the month when the temperature is hottest and 170 (25%) either mentioned the period May-August when UVR is negligible in Melbourne or had no idea, including saying 'all year round'. There was no significant difference in this knowledge between different age groups. CONCLUSION: One quarter of participants did not understand that sunburn was related to high levels of UVR, which occur in summer. Almost one-fifth associated the heat of February with the highest UVR. Understanding these concepts is important for Australians residing in cooler parts of southern Australia, as UVR levels may be high and yet the temperature may be relatively cool. There needs to be more emphasis on UVR in sun awareness campaigns to prompt sun-protective behaviour. PMID- 25496330 TI - From mindful attention to social connection: The key role of emotion regulation. AB - Effective emotion regulation is important for high-quality social functioning. Recent laboratory-based evidence suggests that mindfulness may enhance emotion regulation in socioemotional contexts; however, little is known about mindful emotion regulation during in vivo social interactions. In a study of romantic couples, we assessed each partner's mindfulness and top-down attentional efficiency (with an Emotional Go/No-Go task) prior to sampling emotions and perceived connection with others during day-to-day social interactions. Analyses revealed that mindfulness-related differences in top-down attentional efficiency on the Emotional Go/No-Go predicted positive emotion during daily social interactions. In turn, positive emotion and two additional indices of social emotion regulation each mediated the relation between actor mindfulness and perceived social connection. In corresponding analyses, neither trait reappraisal nor suppression use predicted the outcomes, and all mindfulness relations held controlling for these strategies. Findings support a framework for investigating mindfulness and higher-quality social functioning, for which mindful emotion regulation may be key. PMID- 25496329 TI - Retrospective Analysis of Interobserver Spatial Variability in the Localization of Broca's and Wernicke's Areas Using Three Different fMRI Language Paradigms. AB - PURPOSE: To determine interobserver spatial variability in language area localization using three commonly employed language tasks. MATERIALS AND METHODS: With institutional review board approval, 125 fMRI time series from 50 different clinical language cases were retrospectively reviewed by three blinded readers who selected 3-dimensional points representing the perceived center of Wernicke's and Broca's areas using three language tasks (semantic decision, SD; sentence comprehension, SC; and silent word generation, WG). Point dispersion values were then calculated using the perimeter of the 3-dimensional triangle defined by the three readers' selections. RESULTS: After resolving interobserver laterality disagreements, there was no difference in spatial variability between the three tasks (P = .069). The SD task had the fewest interobserver laterality disagreements (P = .028) and the SC task had fewer failed localizations for Broca's area (P = .050) and Wernicke's area (P = .013). CONCLUSION: While there were no differences between interobserver spatial variability in language area localization between the three tasks, language task choice impacts the accuracy of fMRI language area identification because tasks vary in their rates of interobserver laterality disagreements and failed localizations. A combination of tasks including one with low laterality disagreements (eg, SD) and one with few failed localizations (eg, SC) may offer the best combination. PMID- 25496331 TI - A promising CpG adjuvant-loaded nanoparticle-based vaccine for treatment of dust mite allergies. PMID- 25496332 TI - Evaluation of epratuzumab as a biologic therapy in systemic lupus erythematosus. AB - B cells play a key role in the pathogenesis of systemic lupus erythematosus. Some of the current biologic therapies target B cells or B-cell activating factors. Epratuzumab is a humanized monoclonal antibody, which targets CD22 on B cells. This review focuses on the safety and efficacy of epratuzumab in systemic lupus erythematosus based on the information from various published clinical trials and presentations at international meetings. Epratuzumab acts as a B-cell modulator through inhibition of B-cell receptor signaling. It has been shown to be efficacious in open-label and Phase I and Phase II randomized controlled trials. The drug has steroid-sparing properties and treatment is associated with significant improvements in Health Related Quality of Life and its safety profile is comparable to placebo. PMID- 25496333 TI - Ramucirumab: targeting angiogenesis in the treatment of gastric cancer. AB - Gastroesophageal cancer is responsible for over 1 million deaths annually worldwide; for patients with advanced disease treatment options are limited. Angiogenesis is an attractive therapeutic target that has been successfully exploited in other cancers. Ramucirumab, a fully humanized monoclonal antibody targeting VEGFR-2 has demonstrated efficacy as a single agent and in combination with paclitaxel in two large randomized trials (REGARD and RAINBOW) for the treatment of advanced previously treated gastroesophageal cancer. In combination with paclitaxel chemotherapy ramucirumab treated patients demonstrated increased rates of neutropenia, and ramucirumab is also associated with hypertension consistent with other antiangiogenic agents. Ramucirumab has been US FDA approved for patients with advanced gastroesophageal cancer who have progressed during or after treatment with fluoropyrimidine- or platinum-containing chemotherapy. PMID- 25496334 TI - Mogamulizumab and the treatment of CCR4-positive T-cell lymphomas. AB - Glyco-engineering has been developed to enhance the pharmacological properties of monoclonal antibodies (mAbs) resulting in superior immune effector function. Mogamulizumab is the first approved glyco-engineered therapeutic antibody and first approved mAb to target the CC chemokine receptor 4 (CCR4). CCR4 is principally expressed on Tregs and helper T cells (Th) where it functions to induce homing of these leukocytes to sites of inflammation. Tregs play an essential role in maintaining immune balance; however, in malignancy, Tregs impair host antitumor immunity and provide a favorable environment for tumors to grow. CCR4 is highly expressed by aggressive peripheral T-cell lymphomas (PTCLs), particularly adult T-cell leukemia/lymphoma (ATL) and cutaneous T-cell lymphomas (CTCLs). Mogamulizumab is a humanized anti-CCR4 mAb with a defucosylated Fc region that enhances antibody-dependent cellular cytotoxicity (ADCC). In addition, mogamulizumab depletes CCR4(+) Tregs, potentially evoking antitumor immune responses by autologous effector cells. This ability is highly pertinent as subsets of malignant T cells are believed to function as CD4(+) Tregs, overexpressing CCR4. Clinical trials with mogamulizumab have demonstrated clinical efficacy and tolerability for the treatment of relapsed/refractory aggressive T-cell lymphomas, previously associated with very poor outcomes. PMID- 25496336 TI - Immunotherapy and lung cancer: current developments and novel targeted therapies. AB - Non-small-cell lung cancer (NSCLC) is a highly prevalent and aggressive disease. In the metastatic setting, major advances include the incorporation of immunotherapy and targeted therapies into the clinician's therapeutic armamentarium. Standard chemotherapeutic regimens have long been reported to interfere with the immune response to the tumor; conversely, antitumor immunity may add to the effects of those therapies. The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. Recently, many trials addressed the role of such therapies for metastatic NSCLC treatment: ipilimumab, tremelimumab, nivolumab and lambrolizumab are immunotherapeutic agents of main interest in this field. In addition, anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, ganglioside vaccines, tumor cell vaccines and dendritic cell vaccines, emerged as potent inducers of immune response against the tumor. The current work aims to address the most recent developments regarding these innovative immunotherapies and their implementation in the treatment of metastatic NSCLC. PMID- 25496337 TI - Validated method for the analysis of goji berry, a rich source of zeaxanthin dipalmitate. AB - In the present study an HPLC-DAD method was developed for the determination of the main carotenoid, zeaxanthin dipalmitate, in the fruits of Lycium barbarum. The aim was to develop and optimize an extraction protocol to allow fast, exhaustive, and repeatable extraction, suitable for labile carotenoid content. Use of liquid N2 allowed the grinding of the fruit. A step of ultrasonication with water removed efficiently the polysaccharides and enabled the exhaustive extraction of carotenoids by hexane/acetone 50:50. The assay was fast and simple and permitted the quality control of a large number of commercial samples including fruits, juices, and a jam. The HPLC method was validated according to ICH guidelines and satisfied the requirements. Finally, the overall method was validated for precision (% RSD ranging between 3.81 and 4.13) and accuracy at three concentration levels. The recovery was between 94 and 107% with RSD values <2%, within the acceptable limits, especially if the difficulty of the matrix is taken into consideration. PMID- 25496335 TI - Beyond regulatory T cells: the potential role for IL-2 to deplete T-follicular helper cells and treat autoimmune diseases. AB - Low-dose IL-2 administration suppresses unwanted immune responses in mice and humans, thus evidencing the potential of IL-2 to treat autoimmune disorders. Increased Tregs activity is one of the potential mechanisms by which low-dose IL 2 immunotherapy induces immunosuppression. In addition, recent data indicate that IL-2 may contribute to prevent unwanted self-reactive responses by preventing the developing of T-follicular helper cells, a CD4(+) T-cell subset that expands in autoimmune disease patients and promotes long-term effector B-cell responses. Here we discuss the mechanisms underlying the clinical benefits of low-dose IL-2 administration, focusing on the role of this cytokine in promoting Treg-mediated suppression and preventing self-reactive T-follicular helper cell responses. PMID- 25496339 TI - Particulate inorganic adjuvants: recent developments and future outlook. AB - OBJECTIVES: To review the state of the art and assess future potential in the use of inorganic particulates as vaccine adjuvants. KEY FINDINGS: An adjuvant is an entity added to a vaccine formulation to ensure that robust immunity to the antigen is inculcated. The inclusion of an adjuvant is typically vital for the efficacy of vaccines using inactivated organisms, subunit and DNA antigens. With increasing research efforts being focused on subunit and DNA antigens because of their improved safety profiles, the development of appropriate adjuvants is becoming ever more crucial. Despite this, very few adjuvants are licensed for use in humans (four by the FDA, five by the European Medicines Agency). The most widely used adjuvant, alum, has been used for nearly 90 years, yet its mechanism of action remains poorly understood. In addition, while alum produces a powerful antibody Th2 response, it does not provoke the cellular immune response required for the elimination of intracellular infections or cancers. New adjuvants are therefore needed, and inorganic systems have attracted much attention in this regard. SUMMARY: In this review, the inorganic adjuvants currently in use are considered, and the efforts made to date to understand their mechanisms of action are summarised. We then move on to survey the literature on inorganic particulate adjuvants, focusing on the most interesting recent developments in this area and their future potential. PMID- 25496338 TI - Self-efficacy mediates the effects of topiramate and GRIK1 genotype on drinking. AB - Previous studies indicate that topiramate reduces alcohol use among problem drinkers, with one study showing that the effect was moderated by a polymorphism (rs2832407) in GRIK1, the gene encoding the GluK1 kainate subunit. We examined whether the interactive effect of medication and genotype (1) altered the association between daily self-efficacy and later-day drinking; and (2) had an indirect effect on drinking via self-efficacy. In a 12-week, placebo-controlled trial of topiramate, we used daily interactive voice response technology to measure self-efficacy (i.e. confidence in avoiding heavy drinking later in the day) and drinking behavior in 122 European-American heavy drinkers. Topiramate's effects on both self-efficacy and drinking level were moderated by rs2832407. C allele homozygotes treated with topiramate showed higher levels of self-efficacy and lower levels of nighttime drinking across the 12-week trial. Further, the interactive effect of topiramate and genotype on mean nighttime drinking levels was mediated by mean levels of self-efficacy. By modeling topiramate's effects on nighttime drinking across multiple levels of analysis, we found that self efficacy, a key psychologic construct, mediated the effect of topiramate, which was moderated by rs2832407 genotype. Thus, it may be possible to use an individualized assessment (i.e. genotype) to select treatment to optimize the reduction in heavy drinking and thereby provide a personalized treatment approach. PMID- 25496340 TI - Annual research review: Secular trends in child and adolescent mental health. AB - BACKGROUND: Child and adolescent mental health problems are common, associated with wide-ranging functional impairments, and show substantial continuities into adult life. It is therefore important to understand the extent to which the prevalence of mental health problems has changed over time, and to identify reasons behind any trends in mental health. SCOPE AND METHODOLOGY: This review evaluates evidence on whether the population prevalence of child and adolescent mental health problems has changed. The primary focus of the review is on epidemiological cross-cohort comparisons identified by a systematic search of the literature (using the Web of Knowledge database). FINDINGS: Clinical diagnosis and treatment of child and adolescent psychiatric disorders increased over recent decades. Epidemiological comparisons of unselected population cohorts using equivalent assessments of mental health have found little evidence of an increased rate of ADHD, but cross-cohort comparisons of rates of ASD are lacking at this time. Findings do suggest substantial secular change in emotional problems and antisocial behaviour in high-income countries, including periods of increase and decrease in symptom prevalence. Evidence from low- and middle-income countries is very limited. Possible explanations for trends in child and adolescent mental health are discussed. The review also addresses how cross cohort comparisons can provide valuable complementary information on the aetiology of mental illness. PMID- 25496341 TI - Construction of a dairy microbial genome catalog opens new perspectives for the metagenomic analysis of dairy fermented products. AB - BACKGROUND: Microbial communities of traditional cheeses are complex and insufficiently characterized. The origin, safety and functional role in cheese making of these microbial communities are still not well understood. Metagenomic analysis of these communities by high throughput shotgun sequencing is a promising approach to characterize their genomic and functional profiles. Such analyses, however, critically depend on the availability of appropriate reference genome databases against which the sequencing reads can be aligned. RESULTS: We built a reference genome catalog suitable for short read metagenomic analysis using a low-cost sequencing strategy. We selected 142 bacteria isolated from dairy products belonging to 137 different species and 67 genera, and succeeded to reconstruct the draft genome of 117 of them at a standard or high quality level, including isolates from the genera Kluyvera, Luteococcus and Marinilactibacillus, still missing from public database. To demonstrate the potential of this catalog, we analysed the microbial composition of the surface of two smear cheeses and one blue-veined cheese, and showed that a significant part of the microbiota of these traditional cheeses was composed of microorganisms newly sequenced in our study. CONCLUSIONS: Our study provides data, which combined with publicly available genome references, represents the most expansive catalog to date of cheese associated bacteria. Using this extended dairy catalog, we revealed the presence in traditional cheese of dominant microorganisms not deliberately inoculated, mainly Gram-negative genera such as Pseudoalteromonas haloplanktis or Psychrobacter immobilis, that may contribute to the characteristics of cheese produced through traditional methods. PMID- 25496343 TI - Optical injection of gold nanoparticles into living cells. AB - The controlled injection of nanoscopic objects into living cells with light offers promising prospects for the development of novel molecular delivery strategies or intracellular biosensor applications. Here, we show that single gold nanoparticles from solution can be patterned on the surface of living cells with a continuous wave laser beam. In a second step, we demonstrate how the same particles can then be injected into the cells through a combination of plasmonic heating and optical force. We find that short exposure times are sufficient to perforate the cell membrane and inject the particles into cells with a survival rate of >70%. PMID- 25496344 TI - MRI sensing of neurotransmitters with a crown ether appended Gd(3+) complex. AB - Molecular magnetic resonance imaging (MRI) approaches that detect biomarkers associated with neural activity would allow more direct observation of brain function than current functional MRI based on blood-oxygen-level-dependent contrast. Our objective was to create a synthetic molecular platform with appropriate recognition moieties for zwitterionic neurotransmitters that generate an MR signal change upon neurotransmitter binding. The gadolinium complex (GdL) we report offers ditopic binding for zwitterionic amino acid neurotransmitters, via interactions (i) between the positively charged and coordinatively unsaturated metal center and the carboxylate function and (ii) between a triazacrown ether and the amine group of the neurotransmitters. GdL discriminates zwitterionic neurotransmitters from monoamines. Neurotransmitter binding leads to a remarkable relaxivity change, related to a decrease in hydration number. GdL was successfully used to monitor neural activity in ex vivo mouse brain slices by MRI. PMID- 25496342 TI - Applying Tai Chi as a rehabilitation program for stroke patients in the recovery phase: study protocol for a randomized controlled trial. AB - BACKGROUND: As the second commonest cause of death and a major cause of disability worldwide, stroke has greatly influenced patients' quality of life and created a huge public health burden. As a special form of physical activity that has been widely practiced in China, and even throughout the world, Tai Chi may be favorable for the rehabilitation of stroke patients. Several studies have been conducted to investigate the rehabilitative effects of Tai Chi for stroke patients, but none of them have been focused on the recovery phase (2 to 24 weeks) of stroke. METHODS/DESIGN: This study is an assessor-blinded randomized controlled trial. A total of 50 eligible participants will be randomly assigned to either a control group or a Tai Chi group. Patients in the control group will receive standard, conventional rehabilitation therapies, and a combination of Tai Chi and conventional rehabilitation programs will be applied in the Tai Chi group. The recovery of motor impairment, functional activity and balance abilities as measured with the Fugl-Meyer Assessment, Barthel Index and Berg Balance Scale will be assessed as primary outcome measures. The secondary outcome measures to be used are the scores on the Stroke-Specific Quality of Life Scale, the National Institutes of Health Stroke Scale and the objective parameters of the RSscan footscan gait system. All assessments will be conducted at baseline, 4 weeks after the rehabilitation course and at the end of 3-month follow-up. DISCUSSION: The results of this study will provide preliminary evidence regarding the efficacy and feasibility of Tai Chi as an additional rehabilitative program for stroke patients in the recovery phase. TRIAL REGISTRATION: Chinese Clinical Trial Register ID: ChiCTR-TRC-13003661 (7 October 2013). PMID- 25496345 TI - Reduced port laparoscopic gastrectomy: a review, techniques, and perspective. AB - Reduced port laparoscopic surgery has been used increasingly. It is a concept that has grown out of the various efforts aimed at minimally invasive surgery, with SILS being the ultimate reduced port technique. Reduced port laparoscopic surgery has been used to perform sleeve gastrectomy in bariatric surgery and excision of benign gastric submucosal tumor, applications that generally do not require lymph node dissection or complicated reconstruction. It can be done safely, result in a permanent cure, and offer good cosmetic outcomes. Reduced port laparoscopic surgery for gastric cancer has a short history, and its usefulness has not yet been fully established. This review describes the present situation and challenges faced as well as standardized procedures and the future prospects of reduced port laparoscopic gastrectomy for gastric cancer, which my team performs almost daily. These aspects of reduced port laparoscopic surgery are presented in light of the literature. PMID- 25496346 TI - Broad ligament perivascular epithelioid tumour presenting with haemoperitoneum. PMID- 25496347 TI - Could mycobacterial Hsp70-containing fusion protein lead the way to an affordable therapeutic cancer vaccine? AB - Cancer vaccine development efforts have recently gained momentum, but most vaccines showing clinical impact in human trials tend to be based on technology approaches that are very costly and difficult to produce at scale. With the projected doubling of the incidence of cancer and its related cost of care in the U.S. over the next two decades, the widespread clinical use of such vaccines will prove difficult to justify. Heat shock protein-based vaccines have shown the potential to elicit clinically meaningful immunologic responses in cancer, but the predominant development approach - heat shock protein-peptide complexes derived from a patient's own tumor - face similar challenges of cost and scalability. New innovative modalities for deploying heat shock proteins in cancer vaccines may open the door to vaccines that can generate potent cytotoxic responses against multiple tumor targets and can be made in a cost-effective and scalable manner. PMID- 25496348 TI - One-dimensional CdS/TiO2 nanofiber composites as efficient visible-light-driven photocatalysts for selective organic transformation: synthesis, characterization, and performance. AB - CdS/TiO2 heterojunction nanofibers have been successfully synthesized through the photodeposition of CdS on 1D TiO2 nanofibers that were prepared via a facile electrospinning method. The as-synthesized samples showed high photocatalytic activities upon selectively oxidizing a series of alcohols into corresponding aldehydes under visible light irradiation. TEM observations revealed that CdS was closely grown on the TiO2 nanofibers. Moreover, it was found that the CdS/TiO2 nanofibers that were photodeposited for 4 h exhibited the highest catalytic activity, with a conversion of 22% and a selectivity of 99%, which were much higher than those of commercial CdS. In addition, we also discuss the photoabsorption performance and the reaction mechanism of the photocatalytic oxidation of alcohols. PMID- 25496349 TI - An item response theory analysis of the sexual compulsivity scale and its correspondence with the hypersexual disorder screening inventory among a sample of highly sexually active gay and bisexual men. AB - INTRODUCTION: Numerous scales and assessments are available to assess sexual compulsivity (SC). AIM: This study sought to conduct an item response theory (IRT) analysis of the Sexual Compulsivity Scale (SCS) to provide evidence about its measurement precision at the various levels of the SC construct in a sample of highly sexually active gay and bisexual men (GBM). METHODS: SCS data from a sample of 202 GBM who are highly sexually active but who vary in their experiences of SC symptoms were modeled using Samejima's polytomous graded response IRT model. To describe the performance of the SCS relative to the Hypersexual Disorder Screening Inventory (HDSI), SCS scores were compared with participants' corresponding HDSI results to determine sensitivity, specificity, positive and negative predictive values, and accuracy. MAIN OUTCOME MEASURES: This study examined the correspondence between the SCS and the HDSI, a diagnostic instrument for the screening of hypersexuality. RESULTS: IRT analyses indicated that, although two of the SCS items had low reliability, the SCS as a whole was reliable across much of the SC continuum. Scores on the SCS and the HDSI were highly correlated; however, no potential cutoffs on the SCS corresponded strongly with the polythetic scoring criteria of the HDSI. CONCLUSION: Comparisons of SCS scores with HDSI results indicated that the SCS itself could not serve as a substitute for the HDSI and would incorrectly classify a substantial number of individuals' levels of hypersexuality. However, the SCS could be a useful screening tool to provide a preliminary screening of people at risk for meeting criteria on the HDSI. Combining the SCS and the HDSI may be an appropriate evaluation strategy in classifying GBM as negative on both (i.e., "non hypersexual/non-SC"), positive on the SCS only (i.e., "at risk"), and positive on both the SCS and the HDSI (i.e., "problematic hypersexuality/SC"). PMID- 25496350 TI - Expression patterns of superficial epidermal adhesion molecules in an experimental dog model of acute atopic dermatitis skin lesions. AB - BACKGROUND: The stratum corneum is critical for providing a functional skin barrier, especially in humans and dogs with atopic dermatitis. An effective barrier also depends upon intact corneodesmosomes and superficial epidermal tight junctions. HYPOTHESIS/OBJECTIVES: To study the expression of selected corneodesmosome, desmosome, tight and adherens junction proteins in an experimental model of acute atopic dermatitis skin lesions in dogs. METHODS: Control and house dust mite (HDM) allergen-containing patches (two types of patches) were applied to the skin of six Maltese-beagle atopic dogs hypersensitive to HDM. Patches were left on for 48 h, and biopsies were collected 24 h after removal. Frozen skin sections were stained by indirect immunofluorescence for corneodesmosin, desmoglein-1, desmocollin-1, claudin-1 and E-cadherin. Immunostains were assessed for their extent, intensity and patterns; they were compared between HDM and control patches on the same dogs. RESULTS: The immunostaining for E-cadherin, desmocollin-1 and desmoglein-1 was homogeneous, intercellular and continuous in all control and HDM patches. The immunoreactivity of corneodesmosin and claudin-1 was heterogeneous and reduced in intensity in 12 of 12 and eight of 12 HDM patches, respectively, in contrast to a normal expression seen in all control samples (Fisher's test, P < 0.001). CONCLUSIONS AND CLINICAL IMPORTANCE: These observations suggest that HDM allergens, via proteolytic digestion and/or because of induced allergic inflammation, affect the expression and possible function of corneodesmosomal and tight junction proteins. Ensuing intercellular junction alterations might promote an abnormally increased penetration of allergens through the epidermis. PMID- 25496351 TI - Autonomous metabolomics for rapid metabolite identification in global profiling. AB - An autonomous metabolomic workflow combining mass spectrometry analysis with tandem mass spectrometry data acquisition was designed to allow for simultaneous data processing and metabolite characterization. Although previously tandem mass spectrometry data have been generated on the fly, the experiments described herein combine this technology with the bioinformatic resources of XCMS and METLIN. As a result of this unique integration, we can analyze large profiling datasets and simultaneously obtain structural identifications. Validation of the workflow on bacterial samples allowed the profiling on the order of a thousand metabolite features with simultaneous tandem mass spectra data acquisition. The tandem mass spectrometry data acquisition enabled automatic search and matching against the METLIN tandem mass spectrometry database, shortening the current workflow from days to hours. Overall, the autonomous approach to untargeted metabolomics provides an efficient means of metabolomic profiling, and will ultimately allow the more rapid integration of comparative analyses, metabolite identification, and data analysis at a systems biology level. PMID- 25496352 TI - Construction of tetracyclic 3-spirooxindole through cross-dehydrogenation of pyridinium: applications in facile synthesis of (+/-)-corynoxine and (+/-) corynoxine B. AB - A facile and straightforward method was developed to construct the fused tetracyclic 3-spirooxindole skeleton, which exists widely in natural products. The formation of the tetracyclic 3-spirooxindole structure was achieved through a transition-metal-free intramolecular cross-dehydrogenative coupling of pyridinium, which were formed in situ by the condensation of 3-(2 bromoethyl)indolin-2-one derivatives with 3-substituted pyridines. As examples of the application of this new methodology, two potentially medicinal natural products, (+/-)-corynoxine and (+/-)-corynoxine B, were efficiently synthesized in five scalable steps. PMID- 25496353 TI - A transcranial magnetic stimulation study on response activation and selection in spatial conflict. AB - In choice reaction tasks, subjects typically respond faster when the relative spatial positions of stimulus and response correspond than when they do not, even when spatial information is irrelevant to the task (e.g. in the Simon task). Cognitive models attribute the Simon effect to automatic response activation elicited by spatial information, which facilitates or competes with the controlled selection of the correct response as required by task demands. In the present study, we investigated the role of the dorsal premotor cortex (PMd) in response activation and selection during spatial conflict. We applied single pulse transcranial magnetic stimulation (TMS) to the PMd of the right and left hemispheres during the execution of a Simon task, at different times after the onset of the visual stimulus. The results showed that TMS produced a different effect on subjects' performance in two separate time windows. When TMS was applied at an early time [160-ms stimulus onset asynchrony (SOA)], we observed suppression of the Simon effect, resulting from a delay of corresponding trials. When TMS was applied at a late time (220 and 250-ms SOA), we observed an increase in the Simon effect, resulting from a delay of non-corresponding trials. These outcomes revealed that the PMd is involved both in the activation of the spatially triggered response and in response selection during spatial conflict. PMID- 25496354 TI - A trial of devices for urinary incontinence after treatment for prostate cancer. AB - OBJECTIVE: To compare the performance of three continence management devices and absorbent pads used by men with persistent urinary incontinence (>1 year) after treatment for prostate cancer. PATIENTS AND METHODS: Randomised, controlled trial of 56 men with 1-year follow-up. Three devices were tested for 3 weeks each: sheath drainage system, body-worn urinal (BWU) and penile clamp. Device and pad performance were assessed. Quality of life (QoL) was measured at baseline and follow-up with the King's Health Questionnaire. Stated (intended use) and revealed (actual use) preference for products were assessed. Value-for-money was gathered. RESULTS: Substantial and significant differences in performance were found. The sheath was rated as 'good' for extended use (e.g. golf and travel) when pad changing is difficult; for keeping skin dry, not leaking, not smelling and convenient for storage and travel. The BWU was generally rated worse than the sheath and was mainly used for similar activities but by men who could not use a sheath (e.g. retracted penis) and was not good for seated activities. The clamp was good for short vigorous activities like swimming/exercise; it was the most secure, least likely to leak, most discreet but almost all men described it as uncomfortable or painful. The pads were good for everyday activities and best for night-time use; most easy to use, comfortable when dry but most likely to leak and most uncomfortable when wet. There was a preference for having a mixture of products to meet daytime needs; around two-thirds of men were using a combination of pads and devices after testing compared with baseline. CONCLUSIONS: This is the first trial to systematically compare different continence management devices for men. Pads and devices have different strengths, which make them particularly suited to certain circumstances and activities. Most men prefer to use pads at night but would choose a mixture of pads and devices during the day. Device limitations were important but may be overcome by better design. PMID- 25496355 TI - High capacity and high density functional conductive polymer and SiO anode for high-energy lithium-ion batteries. AB - High capacity and high density functional conductive polymer binder/SiO electrodes are fabricated and calendered to various porosities. The effect of calendering is investigated in the reduction of thickness and porosity, as well as the increase of density. SiO particle size remains unchanged after calendering. When compressed to an appropriate density, an improved cycling performance and increased energy density are shown compared to the uncalendered electrode and overcalendered electrode. The calendered electrode has a high density of ~1.2 g/cm(3). A high loading electrode with an areal capacity of ~3.5 mAh/cm(2) at a C/10 rate is achieved using functional conductive polymer binder and simple and effective calendering method. PMID- 25496356 TI - Association between frequency of oral and denture cleaning and personality in edentulous older adults. AB - AIM: The purpose of the present study was to clarify the relationship between the frequency of oral and denture cleaning and personality in edentulous older adults. METHODS: Participants were 54 edentulous older adults using maxillary and mandibular complete dentures without any problems. A questionnaire was used to establish the frequency of mechanical oral cleaning and mechanical denture cleaning using a denture brush. A personality survey was carried out using a questionnaire based on Eysenck's questionnaire on factors of introversion/extroversion and emotional stability/instability. Stepwise logistic regression analyses were used to identify which characteristic factors were significantly associated with frequency of mechanical denture or oral cleaning after all participants were categorized into two groups by frequency of cleaning, in accordance with the criterion of the median. RESULTS: The mean frequencies of mechanical oral and denture cleaning were 0.93 +/- 1.18 times per day and 1.83 +/ 1.19 times per day, respectively. Activity/inactivity, which was a factor relating to introversion/extroversion, was associated with frequency of oral cleaning (odds ratio 2.473, P = 0.001). Activity/inactivity, which was a factor relating to introversion/extroversion, and anaclisis/autonomy, which was a factor relating to emotional stability/instability, were associated with frequency of denture cleaning (odds ratio 1.310, P = 0.001; odds ratio 1.392, P = 0.011, respectively). CONCLUSIONS: The present study showed that personality including activity/inactivity and anaclisis/autonomy influence the frequency of oral and denture cleaning. These findings suggest the necessity of providing an effective method of oral health care based on each person's personality. Geriatr Gerontol Int 2015; 15: 1258-1263. PMID- 25496357 TI - Effects of curcumin and tannic acid on the aluminum- and lead-induced oxidative neurotoxicity and alterations in NMDA receptors. AB - Exposure to aluminum (Al) and lead (Pb) can cause brain damage. Also, Pb and Al exposure alters N-methyl-d-aspartate receptor (NMDAR) subunit expression. Polyphenols such as tannic acid and curcumin are very efficient chelator for metals. The effects of curcumin and tannic acid (polyphenols) on Al(3+)- and Pb(2+)-induced oxidative stress were examined by investigating lipid peroxidation (LPO) levels, antioxidant enzyme activities, acetyl cholinesterase (AChE) activity and also NMDA receptor subunits 2A and 2B concentrations in the brain tissue of rats sub-chronically. Rats were divided into seven groups as control, Al, Pb, aluminum-tannic acid treatment (AlT), aluminum-curcumin treatment (AlC), lead-tannic acid treatment (PbT) and lead-curcumin treatment (PbC). After 16 weeks of treatment, LPO levels in the brain and hippocampus were higher in Al(3+) exposed rats than that of Pb(2+)-exposed group. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in brain tissue of Al- and Pb-exposed rats increased significantly compared with control, while catalase (CAT) and AChE activities decreased. It was observed that metal exposure affected NR2A concentrations more than NR2B concentrations and also that polyphenol treatments increased these receptor protein concentrations. PMID- 25496358 TI - 2-(Phenylazo)pyridineplatinum(II) catecholates showing photocytotoxicity, nuclear uptake, and glutathione-triggered ligand release. AB - Platinum(II) complexes [Pt(pap)(an-cat)] (1) and [Pt(pap)(py-cat)] (2) with 2 (phenylazo)pyridine (pap), 4-[2-[(anthracen-9-ylmethylene)amino]ethyl]benzene-1,2 diol (H2an-cat), and 4-[2-[(pyren-1-ylmethylene)amino]ethyl]benzene-1,2-diol (H2py-cat) were prepared, and their photoinduced cytotoxicity was studied. The complexes were found to release catecholate ligand in the presence of excess glutathione (GSH), resulting in cellular toxicity in the cancer cells. The catecholate complex [Pt(pap)(cat)] (3) was prepared and used as a control. Complex 3, which is structurally characterized by X-ray crystallography, has platinum(II) in a distorted square-planar geometry. The complexes are redox active, showing responses near 0.6 and 1.0 V versus SCE in N,N dimethylformamide/0.1 M tetrabutylammonium perchlorate corresponding to a two step catechol oxidation process and at -0.3 and -1.3 V for reduction of the pap ligand. Complex 1 showed remarkable light-induced cytotoxicity in HaCaT (human skin keratinocytes) and MCF-7 (human breast cancer) cells, giving IC50 value of ~5 MUM in visible light of 400-700 nm and >40 MUM in the dark. The 2',7' dichlorofluorescein diacetate (DCFDA) assay showed the generation of reactive oxygen species (ROS), which seems to trigger apoptosis, as is evident from the annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) assay. The fluorescence microscopic images showed significant nuclear localization of the complexes and free ligands. A mechanistic study revealed possible reduction of the coordinated azo bond of pap by cellular GSH, releasing the catecholate ligand and resulting in remarkable photochemotherapeutic action of the complexes. PMID- 25496359 TI - Trade-Offs in Improving Biofuel Tolerance Using Combinations of Efflux Pumps. AB - Microbes can be engineered to produce next-generation biofuels; however, the accumulation of toxic biofuels can limit yields. Previous studies have shown that efflux pumps can increase biofuel tolerance and improve production. Here, we asked whether expressing multiple pumps in combination could further increase biofuel tolerance. Pump overexpression inhibits cell growth, suggesting a trade off between biofuel and pump toxicity. With multiple pumps, it is unclear how the fitness landscape is impacted. To address this, we measured tolerance of Escherichia coli to the biojet fuel precursor alpha-pinene in one-pump and two pump strains. To support our experiments, we developed a mathematical model describing toxicity due to biofuel and overexpression of pumps. We found that data from one-pump strains can accurately predict the performance of two-pump strains. This result suggests that it may be possible to dramatically reduce the number of experiments required for characterizing the effects of combined biofuel tolerance mechanisms. PMID- 25496360 TI - Pharmacotherapy for treatment of retinal vein occlusion. PMID- 25496361 TI - Protective efficacy of recombinant exotoxin A--flagellin fusion protein against Pseudomonas aeruginosa infection. AB - Pseudomonas aeruginosa is an opportunistic bacterium that causes serious nosocomial infection in immunocompromised patients. The aim of this study was to prepare a fusion protein consisting of exotoxin A (ExoA) and flagellin (Fla) from P. aeruginosa and to evaluate its potential as a vaccine candidate against P. aeruginosa infection. The genes encoding for ExoA and Fla proteins were cloned in frame and expressed in Escherichia coli. The recombinant ExoA-Fla fusion protein was purified by Ni-NTA affinity chromatography. Mice were immunized subcutaneously with ExoA, Fla, and ExoA-Fla fusion proteins, and the humoral immune response was evaluated by ELISA method. The immunized and control group mice were challenged with a 2* LD50 (7.5 * 10(7) CFU) of P. aeruginosa for the protection assay. The results indicated that vaccination with Fla, ExoA, and ExoA Fla fusion proteins produced a significant amount of specific immunoglobulin G antibodies. Immunization of mice with ExoA-Fla fusion protein showed significant protection against intraperitoneal challenge with 7.5 * 10(7) CFU (2* LD50) P. aeruginosa. Results of this study suggest that recombinant ExoA-Fla fusion protein is a highly immunogenic protective protein showing promise as a vaccine candidate against P. aeruginosa. PMID- 25496362 TI - Olive oil and its phenolic constituent tyrosol attenuates dioxin-induced toxicity in peripheral blood mononuclear cells via an antioxidant-dependent mechanism. AB - Olive oil (OO) and its phenolic compounds are reported to possess many potential biological effects, which are ascribed to its powerful antioxidant property. In this study, we have assessed whether OO and its phenolic compound tyrosol (TY) could mitigate 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced oxidative damages in peripheral blood mononuclear cells (PBMC). The results showed that exposure of PBMC to 10 nM TCDD caused significant cell death and elevated cellular concentrations of reactive oxygen species and lipid peroxidation. Comet assay indicated that OO and TY protected DNA damage against dioxin toxicity. In addition, alterations in levels of antioxidant enzymes were substantially prevented by OO and TY. TCDD-induced CYP1A1 activity and loss of mitochondrial membrane potential were significantly reduced by the administration of OO and TY. The results suggested that dietary modifications incorporating diets rich in OO and associated phenolics could prove beneficial in protecting individuals against toxicity induced by dioxins. PMID- 25496364 TI - Generation of an Attenuated, Cross-Protective Pepino mosaic virus Variant Through Alignment-Guided Mutagenesis of the Viral Capsid Protein. AB - Mild variants of many viruses are able to protect infected plants from subsequent invasion by more severe variants of the same viruses through a process known as cross-protection. In the past, the cross-protective viral variants were commonly derived from mild field isolates that were sometimes genetically heterogeneous, providing variable levels of cross-protection. Here, we report a novel approach to rapidly generate cross-protective variants of the tomato-infecting Pepino mosaic virus (PepMV) independently of the availability of mild field isolates. Our approach sought to attenuate PepMV by mutating less conserved amino acid residues of the abundantly produced capsid protein (CP). These less-conserved amino acid residues were identified through multiple alignments of CPs of six potexviruses including PepMV, and were altered systematically to yield six PepMV mutants. These mutants were subsequently inoculated onto the model plant Nicotiana benthamiana, as well as tomato, to evaluate their accumulation levels, symptom severities, and cross-protection potentials. The mutant KD, in which the threonine (T) and alanine (A) residues at CP positions 66 and 67 were replaced with lysine (K) and aspartic acid (D), respectively, were found to accumulate to low levels in infected plants, cause very mild symptoms, and effectively protect both N. benthamiana and tomato against secondary infections by wild-type PepMV. These data suggest that our approach represents a simple, fast, and reliable way of generating attenuated viral variants capable of cross-protection. PMID- 25496366 TI - Indolinooxazolidine: a versatile switchable unit. AB - The design of multiresponsive systems continues to arouse a lot of interest. In such multistate/multifunctional systems, it is possible to isomerize a molecular system from one metastable state to another by application of different stimulation such as light, heat, proton, or electron. In this context, some researches deal with the design of multimode switch where a same interconversion between two states could be induced by using indifferently two or more different kind of stimuli. Herein, we demonstrate that the association of an indolinooxazolidine moiety with a bithiophene unit allows the development of a new trimode switch. A reversible conversion between a colorless closed form and a colorful open form can be equally performed by light, proton, or electrical stimulation. In addition, the oxidation of this system allows the generation of a third metastable state. PMID- 25496365 TI - T cell receptor binding affinity governs the functional profile of cancer specific CD8+ T cells. AB - Antigen-specific T cell receptor (TCR) gene transfer via patient-derived T cells is an attractive approach to cancer therapy, with the potential to circumvent immune regulatory networks. However, high-affinity tumour-specific TCR clonotypes are typically deleted from the available repertoire during thymic selection because the vast majority of targeted epitopes are derived from autologous proteins. This process places intrinsic constraints on the efficacy of T cell based cancer vaccines and therapeutic strategies that employ naturally generated tumour-specific TCRs. In this study, we used altered peptide ligands and lentivirus-mediated transduction of affinity-enhanced TCRs selected by phage display to study the functional properties of CD8(+) T cells specific for three different tumour-associated peptide antigens across a range of binding parameters. The key findings were: (i) TCR affinity controls T cell antigen sensitivity and polyfunctionality; (ii) supraphysiological affinity thresholds exist, above which T cell function cannot be improved; and (iii) T cells transduced with very high-affinity TCRs exhibit cross-reactivity with self derived peptides presented by the restricting human leucocyte antigen. Optimal system-defined affinity windows above the range established for natural tumour specific TCRs therefore allow the enhancement of T cell effector function without off-target effects. These findings have major implications for the rational design of novel TCR-based biologics underpinned by rigorous preclinical evaluation. PMID- 25496367 TI - An investigation into the ameliorating effect of black soybean extract on learning and memory impairment with assessment of neuroprotective effects. AB - BACKGROUND: The physiological effects of the non-anthocyanin fraction (NAF) in a black soybean seed coat extract on Abeta-induced oxidative stress were investigated to confirm neuroprotection. In addition, we examined the preventive effect of NAF on cognitive defects induced by the intracerebroventricular (ICV) injection of Abeta. METHODS: Levels of cellular oxidative stress were measured using 2',7'-dichlorofluorescein diacetate (DCF-DA). Neuronal cell viability was investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assay. To investigate in vivo anti-amnesic effects of NAF by using Y-maze and passive avoidance tests, the learning and memory impairment in mice was induced by Abeta. After in vivo assays, acetylcholinesterase (AChE) activity and level of malondialdehyde (MDA) in the mouse brain were determined to confirm the cognitive effect. Individual phenolics of NAF were qualitatively analyzed by using an ultra-performance liquid chromatography (UPLC) Accurate-Mass Quadrupole Time of-Flight (Q-TOF) UPLC/MS. RESULTS: A NAF showed cell protective effects against oxidative stress-induced cytotoxicity. Intracellular ROS accumulated through Abeta1-40 treatment was significantly reduced in comparison to cells only treated with Abeta1-40. In MTT and LDH assay, the NAF also presented neuroprotective effects on Abeta1-40 treated cytotoxicity. Finally, the administration of this NAF in mice significantly reversed the Abeta1-40-induced cognitive defects in in vivo behavioral tests. After behavioral tests, the mice brains were collected in order to examine lipid peroxidation and AChE activity. AChE, preparation was inhibited by NAF in a dose-dependent manner. MDA generation in the brain homogenate of mice treated with the NAF was decreased. Q-TOF UPLC/MS analyses revealed three major phenolics from the non-anthocyanin fraction; epicatechin, procyanidin B1, and procyanidin B2. CONCLUSIONS: The results suggest that the NAF in black soybean seed coat extracts may improve the cytotoxicity of Abeta in PC12 cells, possibly by reducing oxidative stress, and also have an anti-amnesic effect on the in vivo learning and memory deficits caused by Abeta. Q-TOF UPLC/MS analyses showed three major phenolics; (-)-epicatechin, procyanidin B1, and procyanidin B2. Above results suggest that (-)-epicatechins are the major components, and contributors to the anti-amnesic effect of the NAF from black soybean seed coat. PMID- 25496368 TI - Exploring anal self-examination as a means of screening for anal cancer in HIV positive men who have sex with men: a qualitative study. AB - BACKGROUND: Anal cancer is relatively common in HIV-positive men who have sex with men(MSM). However there are no clear guidelines on how to effectively screen for anal cancer. As earlier diagnosis of anal cancer is associated with increased survival, innovative ways such as utilizing anal self-examination to identify anal cancer should be explored. METHOD: Semi-structured interviews were conducted with 20 HIV-positive MSM from a range of ages (35 to 78 years). This study explored acceptability and barriers to implementing ASE as a method of anal cancer screening. Framework analysis was used to identify themes. RESULTS: Seventeen out of 20 men had conducted an ASE before--six (35%) were for medical reasons, six (35%) for sexual reasons, three (18%) for both medical and sexual reasons, and two (12%) for cleaning purposes. Only 5 men were currently confident in detecting an abnormality. Whilst men were generally comfortable with the idea of utilizing ASE as a means for detecting anal cancer, potential barriers identified operated at three levels: attitudinal (discomfort with any anal examinations, anxiety about finding an abnormality, preference for health professional examination), knowledge (lack of awareness of anal cancer risk and ignorance of anal cancer symptoms) and practical (inadequate physical flexibility, importance of hygiene). CONCLUSION: ASE may be an acceptable means for anal cancer detection in HIV-positive MSM but training in detecting abnormalities is needed. The preference for health professional examination and inadequate physical flexibility may preclude its use for some men. Future trials to confirm its wider acceptability will be needed before undertaking an effectiveness trial for detecting anal cancer. PMID- 25496370 TI - Behaviour change counselling for tobacco use cessation and promotion of healthy lifestyles: a systematic review. AB - AIM: To systematically assess the efficacy of oral health behaviour change counselling for tobacco use cessation (TUC) and the promotion of healthy lifestyles. MATERIALS AND METHODS: Systematic Reviews, Randomized (RCTs), and Controlled Clinical Trials (CCTs) were identified through an electronic search of four databases complemented by manual search. Identification, screening, eligibility and inclusion of studies were performed independently by two reviewers. Quality assessment of the included publications was performed according to the AMSTAR tool for the assessment of the methodological quality of systematic reviews. RESULTS: A total of seven systematic reviews were included. With the exception of inadequate oral hygiene, the following unhealthy lifestyles related with periodontal diseases were investigated: tobacco use, unhealthy diets, harmful use of alcohol, physical inactivity, and stress. Brief interventions for TUC were shown to be effective when applied in the dental practice setting while evidence for dietary counselling and the promotion of other healthy lifestyles was limited or non-existent. CONCLUSIONS: While aiming to improve periodontal treatment outcomes and the maintenance of periodontal health current evidence suggests that tobacco use brief interventions conducted in the dental practice setting were effective thus underlining the rational for behavioural support. PMID- 25496369 TI - Clinical, biochemical and histological differences between HIV-associated NAFLD and primary NAFLD: a case-control study. AB - BACKGROUND: There are limited data regarding the clinical, biochemical and liver histological characteristics of patients with HIV-associated nonalcoholic fatty liver disease (NAFLD), and whether this entity differs in presentation and severity from primary NAFLD AIM: To examine the clinical and histological differences between HIV-associated NAFLD and primary NAFLD. METHODS: This is a cross-sectional, case-control study comparing patients with HIV-associated NAFLD vs. patients with primary NAFLD. HIV-infected patients were identified from a database of consecutive liver biopsies performed at the University of California at San Diego, over a 13-year period. HIV-infected patients with biopsy-proven NAFLD were selected as cases, after exclusion of other causes of liver disease and hepatic steatosis. Age-sex-matched controls with biopsy-proven primary NAFLD were randomly identified from the same pathology database. All biopsies underwent a standardised, detailed, histological research evaluation by a liver pathologist who was blinded to clinical and case-control status. RESULTS: Compared to age-sex matched patients with primary NAFLD (n = 33), patients with HIV-associated NAFLD (n = 33) had significantly higher mean aspartate aminotransferase (P < 0.001), alanine aminotransferase (P < 0.001), alkaline phosphatase (P = 0.003) and serum triglycerides (P = 0.024). Similarly, compared to age-sex-matched primary NAFLD, patients with HIV-associated NAFLD had significantly higher rates of definite steatohepatitis (37% vs. 63%, P = 0.04), and more features of liver injury, including lobular inflammation (<0.001) and acidophil bodies (<0.001). CONCLUSION: Compared to age-sex-matched primary NAFLD, HIV-associated NAFLD has increased severity of liver disease and a higher prevalence of NASH. PMID- 25496372 TI - Pathogenetic Mechanisms of Neurogenic Pulmonary Edema. AB - Neurogenic pulmonary edema (NPE) is a life-threatening complication of central nervous system (CNS) injuries. This review summarizes current knowledge about NPE etiology and pathophysiology with an emphasis on its experimental models, including our spinal cord compression model. NPE may develop as a result of activation of specific CNS trigger zones located in the brainstem, leading to a rapid sympathetic discharge, rise in systemic blood pressure, baroreflex-induced bradycardia, and enhanced venous return resulting in pulmonary vascular congestion characterized by interstitial edema, intra-alveolar accumulation of transudate, and intra-alveolar hemorrhages. The potential etiological role of neurotransmitter changes in NPE trigger zones leading to enhanced sympathetic nerve activity is discussed. Degree of anesthesia is a crucial determinant for the extent of NPE development in experimental models because of its influence on sympathetic nervous system activity. Sympathetic hyperactivity is based on the major activation of either ascending spinal pathways by spinal cord injury or NPE trigger zones by increased intracranial pressure. Attenuation of sympathetic nerve activity or abolition of reflex bradycardia completely prevent NPE development in our experimental model. Suggestions for future research into NPE pathogenesis as well as therapeutic potential of particular drugs and interventions are discussed. PMID- 25496371 TI - Chronic and Episodic Stress in Children of Depressed Mothers. AB - The goal of this study was to examine chronic and episodic stress in children of mothers with and without a history of major depressive disorder (MDD) during the children's lives. Participants were 255 mothers selected according to their history of MDD (present vs. absent during child's life) and their children (age 8 14; 53% girls, 81% Caucasian). Mothers' and children's histories of MDD were assessed using diagnostic interviews, and their depressive symptoms were assessed via self-report measures. Children's levels of chronic and episodic stress were assessed using a semistructured contextual threat interview. Children of mothers with a history of recurrent MDD, compared to single MDD or no depression, experienced more chronic stress within several domains including peers, mother child relations, and other family member relations as well as greater episodic dependent interpersonal stress. Each of these group differences was maintained after excluding children with a history of MDD themselves and controlling for their current depressive symptoms. However, only the group difference in chronic peer stress was maintained when controlling for mothers' current depression. The results suggest that children exposed to recurrent maternal MDD experience higher levels of both chronic and episodic stress, at least some of which they contribute to themselves (dependent interpersonal stress) and which is at least partially independent of the effects of children's depression. In addition, much of this stress is associated primarily with current depression in the mother, though it appears that chronic peer stress may remain elevated even after the remission of maternal depression. PMID- 25496373 TI - Anatomical and/or pathological predictors for the "incorrect" classification of red dot markers on wrist radiographs taken following trauma. AB - OBJECTIVE: To establish the prevalence of red dot markers in a sample of wrist radiographs and to identify any anatomical and/or pathological characteristics that predict "incorrect" red dot classification. METHODS: Accident and emergency (A&E) wrist cases from a digital imaging and communications in medicine/digital teaching library were examined for red dot prevalence and for the presence of several anatomical and pathological features. Binary logistic regression analyses were run to establish if any of these features were predictors of incorrect red dot classification. RESULTS: 398 cases were analysed. Red dot was "incorrectly" classified in 8.5% of cases; 6.3% were "false negatives" ("FNs")and 2.3% false positives (FPs) (one decimal place). Old fractures [odds ratio (OR), 5.070 (1.256 20.471)] and reported degenerative change [OR, 9.870 (2.300-42.359)] were found to predict FPs. Frykman V [OR, 9.500 (1.954-46.179)], Frykman VI [OR, 6.333 (1.205-33.283)] and non-Frykman positive abnormalities [OR, 4.597 (1.264-16.711)] predict "FNs". Old fractures and Frykman VI were predictive of error at 90% confidence interval (CI); the rest at 95% CI. CONCLUSION: The five predictors of incorrect red dot classification may inform the image interpretation training of radiographers and other professionals to reduce diagnostic error. Verification with larger samples would reinforce these findings. ADVANCES IN KNOWLEDGE: All healthcare providers strive to eradicate diagnostic error. By examining specific anatomical and pathological predictors on radiographs for such error, as well as extrinsic factors that may affect reporting accuracy, image interpretation training can focus on these "problem" areas and influence which radiographic abnormality detection schemes are appropriate to implement in A&E departments. PMID- 25496374 TI - Key points of basic theories and clinical practice in rAd-p53 ( Gendicine TM) gene therapy for solid malignant tumors. AB - INTRODUCTION: Wild-type p53 gene is an essential cancer suppressor gene which plays an important role in carcinogenesis and malignant progressions. The p53 gene family participates in almost all the key procedures of cancer biology, such as programmed cell death, angiogenesis, metabolism and epithelial-mesenchymal transition. The mutation or functional defects of the p53 gene family are detected in most of the solid malignant tumors, and the restoration of the p53 gene by adenovirus-mediated gene therapy becomes a promising treatment for cancer patients now. AREAS COVERED: In the present review, the potential therapeutic effects of recombinant adenovirus p53 rAd-p53 ( Gendicine TM) were reviewed to explore the biological mechanism underlying the adenovirus-mediated p53 gene therapy. Then, the key points of the drug administration were discussed, including the routes of administration, dosage calculation and treatment cycles, based on findings of the preclinical and clinical trials in order to establish a standard treatment for the p53 gene therapy. EXPERT OPINION: As an important part of the combined therapy for the cancer patients, the adenovirus-mediated p53 gene therapy was blossomed to be a promising treatment strategy. A new evaluation criteria and guideline for the gene therapy is urgently needed for the further clinical practice. PMID- 25496375 TI - Synergy in monoclonal antibody neutralization of HIV-1 pseudoviruses and infectious molecular clones. AB - BACKGROUND: Early events in HIV infection are still poorly understood; virus derived from acute infections, the transmitted/founders IMCs, could provide more reliable information as they represent strains that established HIV infection in vivo, and therefore are investigated to elucidate potentially shared biological features. METHODS: This study examined synergy in neutralization by six monoclonal antibodies targeting different domains in gp120 and gp41 and assayed in pairwise combination against 11 HIV-1 clade B strains, either Env pseudoviruses (PV, n = 5) or transmitted/founder infectious molecular clones (T/F IMCs, n = 6). Three of the early-infection env tested as PV were juxtaposed with T/F viruses derived from the same three patients, respectively. RESULTS: All antibodies reaching IC50 were assayed pairwise (n = 50). T/F IMCs showed overall lower sensitivity to neutralization by single antibodies than PV, including within the three patient-matched pairs. Remarkably, combination index (CI) calculated using the Chow and Talalay method indicated synergy (CI < 0.9) in 42 data sets, and occurred in T/F IMC at similar proportions (15 of 17 antibody-T/F IMC combinations tested) as in pseudoviruses (27 of 33). CI values indicative of additivity and low-level antagonism were seen in 5 and 3 cases, respectively. Most pairs showed comparable synergic neutralizing effects on both virus groups, with the 4E10 + PG16 pair achieving the best synergic effects. Variability in neutralization was mostly observed on pseudovirus isolates, suggesting that factors other than virus isolation technology, such as env conformation, epitope accessibility and antibody concentration, are likely to affect polyclonal neutralization. CONCLUSIONS: The findings from this study suggest that inhibitory activity of bNAbs can be further augmented through appropriate combination, even against viruses representing circulating strains, which are likely to exhibit a less sensitive Tier 2 neutralization phenotype. This notion has important implications for the design and development of anti-Env bNAb-inducing vaccines and polyclonal sera for passive immunization. PMID- 25496376 TI - Tattoo-based noninvasive glucose monitoring: a proof-of-concept study. AB - We present a proof-of-concept demonstration of an all-printed temporary tattoo based glucose sensor for noninvasive glycemic monitoring. The sensor represents the first example of an easy-to-wear flexible tattoo-based epidermal diagnostic device combining reverse iontophoretic extraction of interstitial glucose and an enzyme-based amperometric biosensor. In-vitro studies reveal the tattoo sensor's linear response toward physiologically relevant glucose levels with negligible interferences from common coexisting electroactive species. The iontophoretic biosensing tattoo platform is reduced to practice by applying the device on human subjects and monitoring variations in glycemic levels due to food consumption. Correlation of the sensor response with that of a commercial glucose meter underscores the promise of the tattoo sensor to detect glucose levels in a noninvasive fashion. Control on-body experiments demonstrate the importance of the reverse iontophoresis operation and validate the sensor specificity. This preliminary investigation indicates that the tattoo-based iontophoresis-sensor platform holds considerable promise for efficient diabetes management and can be extended toward noninvasive monitoring of other physiologically relevant analytes present in the interstitial fluid. PMID- 25496379 TI - Single-pill combination therapy in the initial treatment of marked hypertension: a propensity-matched analysis. AB - BACKGROUND: Many drugs combinations are available and equally recommended for the initial treatment of patients with marked blood pressure (BP) elevation and high cardiovascular risk. HYPOTHESIS: To investigate safety and efficacy of such combination therapies. METHODS: Prospectively collected data were retrospectively reviewed, inclusion criteria were: initial single-pill combination therapy, availability of clinical and echocardiographic 6-month follow-up. Six treatment groups were identified: Enalapril 20 mg+ Hydrochlorothiazide 12.5 mg (E/H), E 20 mg + Lercanidipine 10 mg (E/L), Ramipril 2.5 mg+ H 12.5 mg (R/H), Perindopril 5 mg+ Amlodipine 5 mg (P/A), Olmesartan 40 mg+ H 12.5 mg (O/H) and Telmisartan 40 mg+ H 12.5 mg (T/H). To avoid selection bias a Propensity score (goodness of fit: c-statistic 0.78, p = 0.0001) was used to select comparable cohorts of patients (n = 142 each). RESULTS: After 4 weeks of treatment BP goal was achieved by 624/852 (73.2%) patients, and adverse events were registered in 24/852 (2.8%) patients. After 6 months, 562/624 (90.1%) patients maintained the BP goal. Six month responder rate was significantly higher in the E/L (69.0%) and P/A (68.3%) groups (p = 0.05); especially among diabetics (52.0% and 51.0%, respectively; p = 0.003). Patients receiving E/L (-19.8 +/- 3.2 mmHg) and P/A (-19.9 +/- 4.6 mmHg) showed greater reductions of diastolic BP (p = 0.03); whereas reductions of systolic BP were similar between treatment groups (p = 0.46). Echocardiographic follow-up revealed greater left ventricular reverse remodeling among patients receiving ACE-inhibitors (E/L, R/H, E/H and P/A), but this trend did not reach statistical significance. CONCLUSIONS: Single-pill fixed-dose combination therapies are highly effective and safe in the study settings. Best clinical and echocardiographic outcomes were noted among patients receiving E/L, R/H and P/A. PMID- 25496377 TI - Novel DNA methylation profiles associated with key gene regulation and transcription pathways in blood and placenta of growth-restricted neonates. AB - Fetal growth is determined by the feto-placental genome interacting with the maternal in utero environment. Failure of this interplay leads to poor placental development and fetal growth restriction (FGR), which is associated with future metabolic disease. We investigated whether whole genome methylation differences existed in umbilical cord blood and placenta, between gestational-matched, FGR, and appropriately grown (AGA) neonates. Using the Infinium HumanMethylation450 BeadChip(r), we found that DNA from umbilical cord blood of FGR born at term (n = 19) had 839 differentially methylated positions (DMPs) that reached genome-wide significance compared with AGA (n = 18). Using gestational age as a continuous variable, we identified 76,249 DMPs in cord blood (adj. P < 0.05) of which 121 DMPs were common to the 839 DMPs and were still evident when comparing 12 FGR with 12 AGA [39.9 +/- 1.2 vs. 40.0 +/- 1.0 weeks (mean +/- SD), respectively]. A total of 53 DMPs had a beta methylation difference >10% and 25 genes were co methylated more than twice within 1000 base pairs. Gene Ontology (GO) analysis of DMPs supported their involvement in gene regulation and transcription pathways related to organ development and metabolic function. A similar profile of DMPs was found across different cell types in the cord blood. At term, no DMPs between FGR and AGA placentae reached genome-wide significance, validated with an external dataset. GO analysis of 284 pre-term, placental DMPs associated with autophagy, oxidative stress and hormonal responses. Growth restricted neonates have distinct DNA methylation profiles in pre-term placenta and in cord blood at birth, which may predispose to future adult disease. PMID- 25496380 TI - Comparison of aldosterone synthesis in adrenal cells, effect of various AT1 receptor blockers with or without atrial natriuretic peptide. AB - Bifunctional angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) that can block the activation of not only AT1 receptor, but also neprilysin, which metabolizes vasoactive peptides including atrial natriuretic peptide (ANP), are currently being developed. However, the usefulness of the inactivation of ANP in addition to the AT1 receptor with regard to aldosterone (Ald) synthesis is not yet clear. We evaluated the inhibitory effects of various ARBs combined with or without ANP on Ang II-induced adrenal Ald synthesis using a human adrenocortical cell line (NCI-H295R). Ang II increased Ald synthesis in a dose- and time dependent manner. Ald synthesis induced by Ang II was completely blocked by azilsartan, but not PD123319 (AT2 receptor antagonist). CGP42112 AT2 receptor agonist did not affect Ald synthesis. While most ARBs block Ang II-induced Ald synthesis to different extents, azilsartan and olmesartan have similar blocking effects on Ald synthesis. The different effects of ARBs were particularly observed at 10(-7) and 10(-8 )M. ANP attenuated Ang II-induced Ald synthesis, and ANP-mediated attenuation of Ang II-induced Ald synthesis were blocked by inhibitors of G-protein signaling subtype 4 and protein kinase G. ANP (10(-8) and 10(-7 )M) without ARBs inhibited Ald synthesis, and the combination of ANP (10(-7 )M) and ARB (10(-8 )M) had an additive effect with respect to the inhibition of Ald synthesis. In conclusions, ARBs had differential effects on Ang II-induced Ald synthesis, and ANP may help to block Ald synthesis when the dose of ARB is not sufficient to block its secretion. PMID- 25496381 TI - Asymmetric dimethylarginine is associated with carotid atherosclerosis in patients with essential hypertension. AB - This study was to assess the relationship between asymmetric dimethylarginine (ADMA) and carotid atherosclerosis in patients with essential hypertension. A total of 182 individuals with never-treated essential hypertension and 182 age matched healthy controls were studied. Plasma ADMA levels, mean intima-media thickness (IMT) and plaque score were significantly greater in hypertensive patients than normotensive controls. ADMA was positively correlated with mean IMT. On multiple logistic regression analysis, ADMA was a crucial independent predictor of carotid plaque formation (plaque score >=1.1). Our results suggest that increased levels of ADMA are associated with the development of carotid atherosclerosis in hypertensive patients. PMID- 25496382 TI - Awareness of salt restriction is not reflected in the actual salt intake in Japanese hypertensive patients. AB - OBJECTIVES: The Japanese guidelines for hypertension management recommend reducing salt intake to <6 g/day for hypertensive patients. However, it is not currently known whether hypertensive patients' awareness of the recommended reduced salt diet correlates with their actual intake. Therefore, the purpose of this study was to investigate the relationship between actual salt intake of Japanese hypertensive patients and their awareness of the recommended guidelines for reduced dietary salt intake. METHODS: In total, 236 outpatients (146 males and 90 females) with a mean age 69.7 +/- 12.5 years were included in this study. Daily dietary salt intake was estimated using sodium and creatinine concentrations detected in spot urine samples. The patients filled out a questionnaire regarding their awareness of recommended salt restriction for hypertension management. The questionnaire distinguished the patients' awareness of recommended salt restriction in four levels (low, moderate, high and very high). RESULTS: The mean estimated salt intake was 9.72 +/- 2.43 g/day. Patients' awareness regarding salt intake in all levels provided in the questionnaire did not correlate with actual salt intake (p = 0.731). CONCLUSION: Our results demonstrated that Japanese hypertensive outpatients consumed higher levels of salt than the target value recommended by Japanese guidelines. There was no correlation between actual salt intake and patients' awareness of the recommended reduction in salt. These results suggest that monitoring salt intake and informing patients of their actual salt intake are necessary for effective hypertension management. PMID- 25496383 TI - CompPhy: a web-based collaborative platform for comparing phylogenies. AB - BACKGROUND: Collaborative tools are of great help in conducting projects involving distant workers. Recent web technologies have helped to build such tools for jointly editing office documents and scientific data, yet none are available for handling phylogenies. Though a large number of studies and projects in evolutionary biology and systematics involve collaborations between scientists of different institutes, current tree comparison visualization software and websites are directed toward single-user access. Moreover, tree comparison functionalities are dispersed between different software that mainly focus on high level single tree visualization but to the detriment of basic tree comparison features. RESULTS: The web platform presented here, named CompPhy, intends to fill this gap by allowing collaborative work on phylogenies and by gathering simple advanced tools dedicated to tree comparison. It offers functionalities for tree edition, tree comparison, supertree inference and data management in a collaborative environment. The latter aspect is a specific feature of the platform, allowing people located in different places to work together at the same time on a common project. CompPhy thus proposes shared tree visualization, both synchronous and asynchronous tree manipulation, data exchange/storage, as well as facilities to keep track of the progress of analyses in working sessions. Specific advanced comparison tools are also available, such as consensus and supertree inference, or automated branch swaps of compared trees. As projects can be readily created and shared, CompPhy is also a tool that can be used easily to interact with students in a educational setting, either in the classroom or for assignments. CONCLUSIONS: CompPhy is the first web platform devoted to the comparison of phylogenetic trees allowing real-time distant collaboration on a phylogenetic/phylogenomic project. This application can be accessed freely with a recent browser at the following page of the ATGC bioinformatics platform: http://www.atgc-montpellier.fr/compphy/ . PMID- 25496384 TI - Epidermal polymeric immunoglobulin receptors: leads from intraepidermal neutrophilic IgA dermatosis-type IgA pemphigus. AB - In this study, we attempted to identify unknown autoantigen for intraepidermal neutrophilic IgA dermatosis-type IgA pemphigus by novel IgA-specific immunoprecipitation. Mass-spectrometry study identified polymeric immunoglobulin receptor (PIGR) as the candidate protein, and we confirmed that PIGR expressed in both epidermis and cultured keratinocytes. Eukaryotic recombinant protein of PIGR expressed in COS7 cells was reacted with both patient and normal sera, indicating that PIGR binds physiologically to IgA. To detect antigen-specific binding by IgA autoantibodies, we performed several experiments using deglycosylated PIGR and F(ab)2 fragments from patient sera. However, these analyses suggested that patient IgA bound physiologically, but not immunologically, to PIGR. Nevertheless, our study provided two important insights. Newly developed IgA immunoprecipitation system should be a useful tool in the future study of identification of antigens for IgA autoantibodies. Detection of epidermal PIGR in this study confirmed previous results and indicated possible immunological role of PIGR in epidermis. PMID- 25496385 TI - TRALI: reducing its risk while trying to understand its causes. PMID- 25496386 TI - Transfusion medicine illustrated. A predecessor of the current blood bank pneumatic tube delivery system. PMID- 25496387 TI - Things aren't always as they seem: what the randomized trials of red blood cell transfusion tell us about adverse outcomes. PMID- 25496388 TI - Are current regulations for quality control of cryoprecipitate still appropriate for the 21st century? PMID- 25496389 TI - Thromboembolic events associated with immune globulin preparations: spontaneous pharmacovigilance data versus claims-based data. PMID- 25496390 TI - The Se(w) FUT2 mutation A385T does not result in a nonsecretor allele. PMID- 25496391 TI - Plasma exchange complications in patients treated for thrombotic thrombocytopenia purpura-hemolytic uremic syndrome: 2011 to 2014. PMID- 25496392 TI - Is there a subgroup of long-term evolution among patients with advanced lung cancer?: hints from the analysis of survival curves from cancer registry data. AB - BACKGROUND: Recently, with the access of low toxicity biological and targeted therapies, evidence of the existence of a long-term survival subpopulation of cancer patients is appearing. We have studied an unselected population with advanced lung cancer to look for evidence of multimodality in survival distribution, and estimate the proportion of long-term survivors. METHODS: We used survival data of 4944 patients with non-small-cell lung cancer (NSCLC) stages IIIb-IV at diagnostic, registered in the National Cancer Registry of Cuba (NCRC) between January 1998 and December 2006. We fitted one-component survival model and two-component mixture models to identify short- and long- term survivors. Bayesian information criterion was used for model selection. RESULTS: For all of the selected parametric distributions the two components model presented the best fit. The population with short-term survival (almost 4 months median survival) represented 64% of patients. The population of long-term survival included 35% of patients, and showed a median survival around 12 months. None of the patients of short-term survival was still alive at month 24, while 10% of the patients of long-term survival died afterwards. CONCLUSIONS: There is a subgroup showing long-term evolution among patients with advanced lung cancer. As survival rates continue to improve with the new generation of therapies, prognostic models considering short- and long-term survival subpopulations should be considered in clinical research. PMID- 25496393 TI - Blending online therapy into regular face-to-face therapy for depression: content, ratio and preconditions according to patients and therapists using a Delphi study. AB - BACKGROUND: Blending online modules into face-to-face therapy offers perspectives to enhance patient self-management and to increase the (cost-)effectiveness of therapy, while still providing the support patients need. The aim of this study was to outline optimal usage of blended care for depression, according to patients and therapists. METHODS: A Delphi method was used to find consensus on suitable blended protocols (content, sequence and ratio). Phase 1 was an explorative phase, conducted in two rounds of online questionnaires, in which patients' and therapists' preferences and opinions about online psychotherapy were surveyed. In phase 2, data from phase 1 was used in face-to-face interviews with therapists to investigate how blended therapy protocols could be set up and what essential preconditions would be. RESULTS: Twelve therapists and nine patients completed the surveys. Blended therapy was positively perceived among all respondents, especially to enhance the self-management of patients. According to most respondents, practical therapy components (assignments, diaries and psycho-education) may be provided via online modules, while process-related components (introduction, evaluation and discussing thoughts and feelings), should be supported face-to-face. The preferred blend of online and face-to-face sessions differs between therapists and patients; most therapists prefer 75% face to-face sessions, most patients 50 to 60%. The interviews showed that tailoring treatment to individual patients is essential in secondary mental health care, due to the complexity of their problems. The amount and ratio of online modules needs to be adjusted according to the patient's problems, skills and characteristics. Therapists themselves should also develop skills to integrate online and face-to-face sessions. CONCLUSIONS: Blending online and face-to-face sessions in an integrated depression therapy is viewed as a positive innovation by patients and therapists. Following a standard blended protocol, however, would be difficult in secondary mental health care. A database of online modules could provide flexibility to tailor treatment to individual patients, which asks motivation and skills of both patients and therapists. Further research is necessary to determine the (cost-)effectiveness of blended care, but this study provides starting points and preconditions to blend online and face-to-face sessions and create a treatment combining the best of both worlds. PMID- 25496394 TI - Non-alcoholic fatty liver disease associated with gallstones in females rather than males: a longitudinal cohort study in Chinese urban population. AB - BACKGROUND: Whether non-alcoholic fatty liver disease (NAFLD) is a risk factor for gallstones remains uncertain. Few longitudinal or cohort studies have been used to identify this relationship. The aim of this study was to confirm the association between NAFLD and gallstones in a longitudinal cohort of urban dwellers in China. METHODS: To elucidate the association between NAFLD and gallstones, we fitted a generalized estimating equation (GEE) model in a large scale longitudinal cohort over 6 years, which included 11,200 participants with at least three regular health check-ups. RESULTS: A total of 498 cases of gallstones occurred during the 6-year follow-up, which resulted in a total incidence density of 12.73 per 1000 person-years (498/39, 135.5 person-years). The GEE analyses confirmed and clarified the association between NAFLD and gallstones (relative risk (RR) = 1.2381, 95% confidence interval (CI) = 1.003 1.528, P = 0.047) after adjusting for other potential confounding factors, especially in females (RR = 1.707, 95% CI = 1.245-2.341, P = 0.001). CONCLUSIONS: NAFLD is associated with gallstones in an urban Chinese population from the middle to upper socioeconomic strata. Moreover, this association is more strongly apparent in females than in males. Further cohort studies must be conducted to confirm this association in the general population. PMID- 25496395 TI - Using intervention mapping to deconstruct cognitive work hardening: a return-to work intervention for people with depression. AB - BACKGROUND: Mental health related work disability leaves are increasing at alarming rates with depression emerging as the most common mental disorder in the workforce. Treatments are available to alleviate depressive symptoms and associated functional impacts; however, they are not specifically aimed at preparing people to return to work. Cognitive work hardening (CWH) is a novel intervention that addresses this gap in the health care system. This paper presents a theoretical analysis of the components and underlying mechanisms of CWH using Intervention Mapping (IM) as a tool to deconstruct its elements. METHODS: The cognitive sequelae of depression and their relevance to return-to work (RTW) are examined together with interpersonal skills and other work-related competencies that affect work ability. IM, a tool typically used to create programs, is used to deconstruct an existing program, namely CWH, into its component parts and link them to theories and models in the literature. RESULTS: CWH has been deconstructed into intervention elements which are linked to program performance objectives through underlying theoretical models. In this way, linkages are made between tools and materials of the intervention and the overall program objective of 'successful RTW for people with depression'. An empirical study of the efficacy of CWH is currently underway which should provide added insight and understanding into this intervention. CONCLUSIONS: The application of IM to CWH illustrates the theoretical underpinnings of the treatment intervention and assists with better understanding the linkage between intervention elements and intervention objective. Applying IM to deconstruct an existing program (rather than create a program) presents an alternate application of the IM tool which can have implications for other programs in terms of enhancing understanding, grounding in theoretical foundations, communicating program design, and establishing a basis for program evaluation and improvement. PMID- 25496397 TI - A feasibility study of behavioural activation for depressive symptoms in adults with intellectual disabilities. AB - BACKGROUND: Important work has been carried out adapting cognitive behavioural therapy for people with intellectual disabilities. However, there is a lack of alternative psychological therapies available for people with intellectual disabilities and emotional difficulties. Behavioural activation for depression is less reliant on verbal communication and focuses on increasing purposeful activity and reducing avoidance. METHOD: This feasibility study involved the development and piloting of an adapted manual of behavioural activation for people with intellectual disabilities. The intervention consisted of 10-12 sessions and a key adaptation was that the therapist worked with the clients alongside a significant other in their life, either a paid carer or family member. Baseline, post-intervention (3 months after entering the study) and 6 month quantitative follow-up data were obtained. Primary outcome data were gathered, concerning depressive symptoms, participants' levels of activity and general well-being. RESULTS: Twenty-three adults with intellectual disabilities with symptoms of depression were recruited from specialist health services. In terms of acceptability, the behavioural activation intervention was well received and only two individuals dropped out, with a further two lost to follow-up. The main measures of depression appeared to be sensitive to change. Pre- to post intervention data showed a significant reduction in self-report of depressive symptoms with a strong effect size (r = 0.78), that was maintained at follow-up (r = 0.86). Positive change was also obtained for informant reports of depressive symptoms from pre- to post-intervention, with a strong effect size (r = 0.7). Once again, this positive change was maintained at follow-up (r = 0.72). CONCLUSIONS: The study suggested that behavioural activation may be a feasible and worthwhile approach to tackling depression in people with intellectual disabilities. However, a randomised controlled trial would be required to establish its effectiveness, with more sensitive measurement of change in activity. PMID- 25496398 TI - Stevens-Johnson syndrome and toxic epidermal necrolysis: follow-up of pulmonary function after remission. AB - BACKGROUND: Acute-stage specific bronchial epithelial detachment has been described in 27% of patients with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). OBJECTIVES: To assess the pulmonary function of patients with SJS/TEN after remission. METHODS: Analysis of pulmonary function tests (PFTs) performed during the usual follow-up of patients with SJS/TEN managed in a referral centre from April 2007 to January 2010. RESULTS: Of 58 patients admitted, 32 underwent PFTs (17 male, 15 female). The median time from the acute stage to PFTs was 3 months (interquartile range 1-18). Three patients had grade 2 dyspnoea. Eighteen patients (56%) had abnormal PFTs, including 13 patients (41%) with moderately altered diffusion capacity for carbon monoxide (DLCO ) normalized by the alveolar volume (VA) (giving the ratio KCO , which equals DLCO /VA) and five patients with decreased total lung capacity. No airway obstruction was observed. Patients with decreased KCO had higher initial detached body surface area than others (30% vs. 10%, P = 0.006), as did those with decreased DLCO (25% vs. 10%; P = 0.054). There were correlations between detached body surface area and both KCO (r = -0.41, P = 0.026) and DLCO (r = -0.47, P = 0.011). Among 10 patients with decreased KCO on the first PFT, eight patients had a sustained decrease in KCO on a second PFT. CONCLUSIONS: More than half of patients with SJS/TEN displayed abnormalities on PFTs, mainly diffusion impairment, which was associated with higher initial skin surface detachment. These abnormalities were mostly asymptomatic and remained stable over time. PMID- 25496401 TI - Gene expression profiling of coelomic cells and discovery of immune-related genes in the earthworm, Eisenia andrei, using expressed sequence tags. AB - The coelomic cells of the earthworm consist of leukocytes, chlorogocytes, and coelomocytes, which play an important role in innate immunity reactions. To gain insight into the expression profiles of coelomic cells of the earthworm, Eisenia andrei, we analyzed 1151 expressed sequence tags (ESTs) derived from the cDNA library of the coelomic cells. Among the 1151 ESTs analyzed, 493 ESTs (42.8%) showed a significant similarity to known genes and represented 164 unique genes, of which 93 ESTs were singletons and 71 ESTs manifested as two or more ESTs. From the 164 unique genes sequenced, we found 24 immune-related and cell defense genes. Furthermore, real-time PCR analysis showed that levels of lysenin-related proteins mRNA in coelomic cells of E. andrei were upregulated after the injection of Bacillus subtilis bacteria. This EST data-set would provide a valuable resource for future researches of earthworm immune system. PMID- 25496402 TI - The relative roles of cultural drift and acoustic adaptation in shaping syllable repertoires of island bird populations change with time since colonization. AB - In birds, song divergence often precedes and facilitates divergence of other traits. We assessed the relative roles of cultural drift, innovation, and acoustic adaptation in divergence of island bird dialects, using silvereyes (Zosterops lateralis). In recently colonized populations, syllable diversity was not significantly lower than source populations, shared syllables between populations decreased with increasing number of founder events, and dialect variation displayed contributions from both habitat features and drift. The breadth of multivariate space occupied by recently colonized Z. l. lateralis populations was comparable to evolutionarily old forms that have diverged over thousands to hundreds of thousands of years. In evolutionarily old subspecies, syllable diversity was comparable to the mainland and the amount of variation in syllable composition explained by habitat features increased by two- to threefold compared to recently colonized populations. Together these results suggest that cultural drift influences syllable repertoires in recently colonized populations, but innovation likely counters syllable loss from colonization. In evolutionarily older populations, the influence of acoustic adaptation increases, possibly favoring a high diversity of syllables. These results suggest that the relative importance of cultural drift and acoustic adaptation changes with time since colonization in island bird populations, highlighting the value of considering multiple mechanisms and timescale of divergence when investigating island song divergence. PMID- 25496399 TI - Behavioral weight loss and physical activity intervention in obese adults with asthma. A randomized trial. AB - RATIONALE: The effect of weight loss on asthma in obese adults warrants rigorous investigation. OBJECTIVES: To examine an evidence-based, practical, and comprehensive lifestyle intervention targeting modest weight loss and increased physical activity for asthma control. METHODS: The trial randomized 330 obese adults with uncontrolled asthma to receive usual care enhanced with a pedometer, a weight scale, information about existing weight management services at the participating clinics, and an asthma education DVD, or with these tools plus the 12-month intervention. MEASUREMENTS AND MAIN RESULTS: The primary outcome was change in Asthma Control Questionnaire (ACQ) scores from baseline to 12 months. Participants (mean [SD] age, 47.6 [12.4] yr) were 70.6% women, 20.0% non-Hispanic black, 20.3% Hispanic/Latino, and 8.2% Asian/Pacific Islander. At baseline, they were obese (mean [SD] body mass index, 37.5 [5.9] kg/m(2)) and had uncontrolled asthma (Asthma Control Test score, 15.1 [3.8]). Compared with control subjects, intervention participants achieved significantly greater mean weight loss (+/-SE) (intervention, -4.0 +/- 0.8 kg vs. control, -2.1 +/- 0.8 kg; P = 0.01) and increased leisure-time activity (intervention, 418.2 +/- 110.6 metabolic equivalent task-min/wk vs. control, 178.8 +/- 109.1 metabolic equivalent task min/wk; P = 0.05) at 12 months. But between-treatment mean (+/-SE) differences were not significant for ACQ changes (intervention, -0.3 +/- 0.1 vs. control, 0.2 +/- 0.1; P = 0.92) from baseline (mean [SD], 1.4 [0.8]), nor for any other clinical asthma outcomes (e.g., spirometric results and asthma exacerbations). Among all participants regardless of treatment assignment, weight loss of 10% or greater was associated with a Cohen d effect of 0.76 and with 3.78 (95% confidence interval, 1.72-8.31) times the odds of achieving clinically significant reductions (i.e., >=0.5) on ACQ as stable weight (<3% loss or gain from baseline). The effects of other weight change categories were small. CONCLUSIONS: Moderately and severely obese adults with uncontrolled asthma can safely participate in evidence-based lifestyle intervention for weight loss and active living. The modest average weight and activity improvements are comparable to those shown to reduce cardiometabolic risk factors in studies of similar interventions in other populations but are not associated with significant net benefits for asthma control or other clinical asthma outcomes in the current population. Instead, weight loss of 10% or greater may be required to produce clinically meaningful improvement in asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00901095). PMID- 25496400 TI - Relation of plasma PCSK9 levels to lipoprotein subfractions in patients with stable coronary artery disease. AB - BACKGROUND: Plasma PCSK9 levels was positively associated with low-density lipoprotein (LDL) cholesterol (LDL-C) and atherosclerosis, while PCSK9 may also be implicated in the metabolism of lipoprotein subfractions. The study was to examine the association of plasma PCSK9 with lipoprotein subfractions in patients with stable coronary artery disease (CAD). METHODS: A total of 281 consecutive, stable CAD patients who were not treated with lipid-lowering drugs were enrolled. The baseline clinical characteristics were collected, the plasma PCSK9 levels were determined using ELISA, and the LDL and high-density lipoprotein (HDL) subfractions were analyzed by Lipoprint System. The association of plasma PCSK9 levels with the lipoprotein subfractions was investigated. RESULTS: In the overall population, plasma PCSK9 levels were positively associated with the concentration of LDL-C, intermediate LDL-C, small LDL-C, and LDL score, while negatively correlated with mean LDL particle size. PCSK9 levels were positively associated with the concentration of HDL-C, intermediate HDL-C and small HDL-C. Multivariable regression analysis revealed that the plasma PCSK9 levels were significantly and independently associated with the concentration of intermediate LDL-C (beta=0.152, p=0.013), small LDL-C (beta=0.179, p=0.004), LDL score (beta=0.121, p=0.043), and mean LDL particle size (beta=-0.130, p=0.035), while not HDL subfractions. Interestingly, when investigated in male and female patients separately, these relationships were only found in male but not in female, and the small HDL-C exhibited an association with PCSK9 levels in male patients (beta=0.149, p=0.045). CONCLUSIONS: PCSK9 levels were independently associated with the changes of lipoprotein subfractions, suggesting a potential interaction between PCSK9 and lipoprotein subfractions in CAD. PMID- 25496403 TI - Counting missing values in a metabolite-intensity data set for measuring the analytical performance of a metabolomics platform. AB - Metabolomics requires quantitative comparison of individual metabolites present in an entire sample set. Unfortunately, missing intensity values in one or more samples are very common. Because missing values can have a profound influence on metabolomic results, the extent of missing values found in a metabolomic data set should be treated as an important parameter for measuring the analytical performance of a technique. In this work, we report a study on the scope of missing values and a robust method of filling the missing values in a chemical isotope labeling (CIL) LC-MS metabolomics platform. Unlike conventional LC-MS, CIL LC-MS quantifies the concentration differences of individual metabolites in two comparative samples based on the mass spectral peak intensity ratio of a peak pair from a mixture of differentially labeled samples. We show that this peak pair feature can be explored as a unique means of extracting metabolite intensity information from raw mass spectra. In our approach, a peak-pair peaking algorithm, IsoMS, is initially used to process the LC-MS data set to generate a CSV file or table that contains metabolite ID and peak ratio information (i.e., metabolite-intensity table). A zero-fill program, freely available from MyCompoundID.org , is developed to automatically find a missing value in the CSV file and go back to the raw LC-MS data to find the peak pair and, then, calculate the intensity ratio and enter the ratio value into the table. Most of the missing values are found to be low abundance peak pairs. We demonstrate the performance of this method in analyzing an experimental and technical replicate data set of human urine metabolome. Furthermore, we propose a standardized approach of counting missing values in a replicate data set as a way of gauging the extent of missing values in a metabolomics platform. Finally, we illustrate that applying the zero-fill program, in conjunction with dansylation CIL LC-MS, can lead to a marked improvement in finding significant metabolites that differentiate bladder cancer patients and their controls in a metabolomics study of 109 subjects. PMID- 25496405 TI - Long-term safety and efficacy of rituximab in 7 Japanese patients with ANCA associated vasculitis. AB - OBJECTIVES: The safety and efficacy of rituximab were examined in a multicenter open-label pilot study in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan. METHODS: Patients with refractory AAV were administered a rituximab infusion at a weekly dose of 375 mg/m(2) for 4 weeks. All patients also received oral daily prednisolone. The primary outcome was complete remission, which was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 or 1. RESULTS: The mean age of the 7 patients was 57 (range, 34 71) years. The mean follow-up period after rituximab treatment was 62.9 (range, 4.8-81) months. The mean BVAS at entry was 16.7 (range, 2-34). Complete remission occurred in all cases, except in 1 case in which the patient died, with a significant decline in BVAS from baseline at 12 months after initiation of rituximab. Rituximab reduced granulomatous orbital involvement in a patient with granulomatosis with polyangiitis. Relapse occurred in five patients. Adverse events included de novo hepatitis B in one patient, cancer (hepatocellular carcinoma and prostate cancer) in two patients, and transient visual disturbance, atypical mycobacterial infection, urinary tract infection, sepsis, and cytomegalovirus infection. Two patients died due to recurrent infections and airway obstruction, caused by an AAV lesion. CONCLUSIONS: Rituximab had a beneficial effect on refractory AAV in Japanese patients, but several adverse effects occurred during rituximab treatment. PMID- 25496404 TI - Predictive value of bone destruction and duration of clinical remission for subclinical synovitis in rheumatoid arthritis patients. AB - OBJECTIVES: Treatment for rheumatoid arthritis (RA) should aim to achieve full remission. The aim of this study was to investigate predictors of persistent subclinical synovitis and whether longer clinical remission is effective in reducing subclinical synovitis. METHODS: Forty-four RA patients who achieved DAS28ESR clinical remission for at least 3 months were enrolled in this study and underwent ultrasound examination of 22 joints (bilateral proximal interphalangeal joints, metacarpophalangeal joints, and wrists); bilateral hand X-ray; and blood examination. The severity of synovial effusion, synovial hypertrophy, and blood flow were semi-quantitatively graded from 0 to 3 using gray-scale (GS) and power Doppler (PD) modes. RESULTS: Among patients with DAS28ESR-defined clinical remission, 59.1% (26/44) demonstrated residual synovitis (>= PD1) in at least one joint. Genant-modified total Sharp score (TSS) demonstrated the highest statistical difference between patients with and without residual subclinical synovitis (p = 0.0057), and full remission was only observed in patients with low TSS. A nonsignificant trend for decreased residual synovitis with longer sustained clinical remission was also observed (p = 0.724). CONCLUSION: Residual synovitis can persist during clinical remission, particularly in patients with progressive bone destruction. Early treatment and longer sustained clinical remission prior to bone destruction are critical for full remission. PMID- 25496406 TI - Successful treatment with tocilizumab of a psoriasiform skin lesion induced by etanercept in a patient with juvenile idiopathic arthritis. PMID- 25496407 TI - Issues associated with the Ministry of Health, Labour and Welfare diagnostic criteria for antineutrophil cytoplasmic antibody-associated vasculitides: Reclassification of patients in the prospective cohort study of Remission Induction Therapy in Japanese patients with ANCA-associated vasculitides according to the MHLW criteria. PMID- 25496408 TI - In vivo confocal scanning laser microscopy in patients with primary Sjogren's syndrome: A monocentric experience. AB - AIMS: (i) To analyze the in vivo corneal structure and sub-basal plexus nerves in patients with primary Sjogren's syndrome (pSS) and no-SS dry eye by confocal scanning laser microscopy (CSLM) and (ii) to correlate CSLM findings with tear function tests and with patients' subjective dryness. METHODS: Seventeen patients with pSS, 16 no-SS dry eye, and 20 healthy volunteers were included. CSLM parameters taken into consideration included: basal epithelial integrity, corneal thickness, epithelial cellular density, keratocyte activation, and sub-basal plexus morphology. Statistical analysis was carried out using SPSS-13 (Chicago IL, USA). RESULTS: CSLM pachymetric data and the superficial epithelium cell density were significantly lower in pSS versus no-SS dry eye (p < 0.0001); keratocyte activation and sub-basal nerve abnormalities were also more frequent in pSS patients (p < 0.0001). CSLM findings well correlated with both the ocular test results and the patients' perception of ocular dryness at the baseline and over the follow-up. CONCLUSION: CSLM might be a useful novel tool in the assessment of the involvement of the lachrymal functional unit in pSS. PMID- 25496409 TI - Pulmonary infections following immunosuppressive treatments during hospitalization worsen the short-term vital prognosis for patients with connective tissue disease-associated interstitial pneumonia. AB - OBJECTIVE: Connective tissue disease-associated interstitial pneumonia (CTD-IP) significantly affects the mortality of patients with CTD. The purpose of the present study is to identify causes and risk factors for death during hospitalization for immunosuppressive treatment of CTD-IP. METHODS: A multicenter, retrospective study was conducted that collected data from patients with CTD who had been hospitalized for commencing or intensifying immunosuppressive treatment of CTD-IP using a standardized case report form. Risk factors were identified using the Cox proportional hazard regression model. RESULTS: A total of 322 CTD-IP patients were enrolled with rheumatoid arthritis (n = 84), systemic lupus erythematosus (n = 13), polymyositis (n = 33), dermatomyositis (n = 69), systemic sclerosis (n = 55), mixed connective tissue disease (n = 21), microscopic polyangiitis (n = 19), and overlap syndrome (n = 28). Of the 42 patients who died during hospitalization, 22 died from CTD-IP, 15 from CTD-IP and pulmonary infection, 2 from pulmonary infection, and 3 from other causes. Age >= 65 years and development of pulmonary infections after commencing or intensifying immunosuppressive treatments were identified as risk factors for death during hospitalization after adjusting for covariates. CONCLUSION: Careful consideration of the benefit-risk balance of immunosuppressive treatment for CTD IP is indispensable for improving the short-term vital prognosis of these patients. PMID- 25496411 TI - Global Advisory Panel on the Future of Nursing (GAPFON) and Global Health. PMID- 25496410 TI - Quantitative analysis of skeletal muscle mass in patients with rheumatic diseases under glucocorticoid therapy--comparison among bioelectrical impedance analysis, computed tomography, and magnetic resonance imaging. AB - OBJECTIVES: To determine the availability of bioelectrical impedance analysis (BIA), computed tomography (CT), and magnetic resonance imaging (MRI) for measurement of skeletal muscle mass in patients with rheumatic diseases and quantitatively assess skeletal muscle loss after glucocorticoid (GC) treatment. METHODS: The data from 22 patients with rheumatic diseases were retrospectively obtained. The muscle mass of body segments was measured with a BIA device in terms of skeletal muscle mass index (SMI). Cross-sectional area (CSA) was obtained from CT and MRI scans at the mid-thigh level using the image analysis program. We further assessed the data of three different measurements before and after GC treatment in 7 patients with rheumatic diseases. RESULTS: SMI of whole body was significantly correlated with estimated muscle volume and mid-thigh muscle CSA with CT and MRI (p < 0.01). Significant correlations between SMI and mid-thigh muscle CSA of each leg were also found (p < 0.01). All the three measurements were negatively correlated with GC dosage (p < 0.01). Significant decline in mid-thigh muscle CSA with CT and MRI was found after GC treatment in 7 patients (p < 0.02). Those patients showed significant decline in SMI of whole body after GC treatment, but not in SMI of each leg. On the other hand, significant correlations between mid-thigh muscle CSA with CT and MRI were found before and after GC treatment (p < 0.01). CONCLUSIONS: GC-related skeletal muscle loss could be quantitatively assessed with BIA, CT, or MRI in patients with rheumatic diseases, and CT and MRI appeared to be more accurate than BIA. PMID- 25496412 TI - Synthesis and biological evaluation of furanoallocolchicinoids. AB - A series of conformationally flexible furan-derived allocolchicinoids was prepared from commercially available colchicine in good to excellent yields using a three-step reaction sequence. Cytotoxicity studies indicated the potent activity of two compounds against human epithelial and lymphoid cell lines (AsPC 1, HEK293, and Jurkat) as well as against Wnt-1 related murine epithelial cell line W1308. The results of in vitro experiments demonstrated that the major effect of these compounds was the induction of cell cycle arrest in the G2/M phase as a direct consequence of effective tubulin binding. In vivo testing of the most potent furanoallocolchicinoid 10c using C57BL/6 mice inoculated with Wnt 1 tumor cells indicated significant inhibition of the tumor growth. PMID- 25496413 TI - Perivascular Enhancement in a Patient with Neuromyelitis Optica Spectrum Disease during an Optic Neuritis Attack. AB - We present a case with neuromyelitis optica spectrum disease (NMOSD) who had perivascular enhancement during an optic neuritis attack. Cloud-like enhancement, pencil-thin enhancement, and leptomeningeal enhancement have been defined as specific enhancement patterns to neuromyelitis optica (NMO). Perivascular enhancement has not been described before in NMO/NMOSD. This finding suggests that perivascular enhancement may also be seen in NMO/NMOSD patients. PMID- 25496414 TI - Experiences of UK patients with hepatitis C virus infection accessing phlebotomy: A qualitative analysis. AB - This study provides an understanding of the experiences and perceptions of phlebotomy in people with infection who have venous damage related to injecting drug use with the aim of improving their care. Narrative interviews were conducted with 10 attendees of a phlebotomy service within an acute Trust in the south-west of England. The participants had hepatitis C infection and poor venous access due to current or former drug use. Interview audiotapes were analyzed, and the themes - conflict, emotional responses, the patient as expert, and offering solutions - were identified. In the context of this study, we discuss the difficulties associated with phlebotomy, which might explain why individuals with hepatitis C infection and venous damage disengage from health services and are less likely to undertake antiviral treatment. This research adds to the literature on phlebotomy for vulnerable groups, and recommends hepatitis C virus clinics within drug agencies, the need to review training and policy, and the development of "phlebotomy passports" to enable continuity of care between services. PMID- 25496415 TI - Increased dietary alpha-linolenic acid has sex-specific effects upon eicosapentaenoic acid status in humans: re-examination of data from a randomised, placebo-controlled, parallel study. AB - BACKGROUND: There is a metabolic pathway by which mammals can convert the omega-3 (n-3) essential fatty acid alpha-linolenic acid (ALA) into longer-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). As far as we know there are currently no studies that have specifically examined sex differences in the LC n-3 PUFA response to increased dietary ALA intake in humans, although acute studies with isotope labelled ALA identified that women have a significantly greater capacity to synthesise EPA and DHA from ALA compared to men. FINDINGS: Available data from a placebo-controlled, randomised study were re-examined to identify whether there are sex differences in the LC n-3 PUFA response to increased dietary ALA intake in humans. There was a significant difference between sexes in the response to increased dietary ALA, with women having a significantly greater increase in the EPA content of plasma phospholipids (mean +2.0% of total fatty acids) after six months of an ALA-rich diet compared to men (mean +0.7%, P = 0.039). Age and BMI were identified as predictors of response to dietary ALA among women. CONCLUSIONS: Women show a greater increase in circulating EPA than men during increased dietary ALA consumption. Further understanding of individual variation in the response to dietary ALA could inform nutrition advice, with recommendations being specifically tailored according to habitual diet, sex, age and BMI. PMID- 25496416 TI - Nosocomial Clostridium difficile-associated diarrhoea in Assiut University Children's Hospital, Egypt. AB - BACKGROUND: There are no large epidemiological studies of Clostridium difficile associated disease (CDAD) in hospitalised children. AIM: To describe the frequency, demography, clinical features and outcome of nosocomial CDAD in children admitted to Assiut University Children's Hospital, Egypt. PATIENTS AND METHODS: In this descriptive cross-sectional study, 72 children developed nosocomial diarrhoea between April 2010 and March 2011. A medical history, clinical assessment and culture for Clostridium difficile and direct toxin detection from stool samples by enzyme immuno-assay were undertaken in all patients. RESULTS: CDAD was diagnosed in 17 (23.6%) patients. Those aged <=12 months were the most commonly affected (eight, 47%). The main cause of admission was respiratory disorders (eight, 47% of cases), followed by surgical problems (three, 17.7%). Ten patients (58.8%) had severe symptoms. There were no statistically significant differences between any of the demographic or laboratory data for children with CDAD and children with other causes of nosocomial diarrhoea. None of the patients developed complications. Seven children with CDAD (41.2%) had recurrence. CONCLUSION: CDAD is an important cause of nosocomial diarrhoea in children in Assiut University Children's Hospital. Established guidelines should be followed in all hospitals to minimise exposure to the pathogen. Physicians can do much to reduce the risk of a severe outcome in children by early identification and rapid management. Further research should be undertaken to identify the risk factors for recurrence. PMID- 25496417 TI - Synthesis and pharmacological evaluation of [(3)H]HS665, a novel, highly selective radioligand for the kappa opioid receptor. AB - Herein we report the radiolabeling and pharmacological investigation of a novel radioligand, the N-cyclobutylmethyl substituted diphenethylamine [(3)H]HS665, designed to bind selectively to the kappa opioid peptide (KOP) receptor, a target of therapeutic interest for the treatment of a variety of human disorders (i.e., pain, affective disorders, drug addiction, and psychotic disorders). HS665 was prepared in tritium-labeled form by a dehalotritiated method resulting in a specific activity of 30.65 Ci/mmol. Radioligand binding studies were performed to establish binding properties of [(3)H]HS665 to the recombinant human KOP receptor in membranes from Chinese hamster ovary cells stably expressing human KOP receptors (CHOhKOP) and to the native neuronal KOP receptor in guinea pig brain membranes. Binding of [(3)H]HS665 was specific and saturable in both tissue preparations. A single population of high affinity binding sites was labeled by [(3)H]HS665 in membranes from CHOhKOP cells and guinea pig brain with similar equilibrium dissociation constants, Kd, 0.45 and 0.64 nM, respectively. Average receptor density of [(3)H]HS665 recognition sites were 5564 and 154 fmol/mg protein in CHOhKOP cells and guinea pig brain, respectively. This study shows that the new radioligand distinguishes and labels KOP receptors specifically in neuronal and cellular systems expressing KOP receptors, making this molecule a valuable tool in probing structural and functional mechanisms governing ligand KOP receptor interactions in both a recombinant and native in vitro setting. PMID- 25496418 TI - Severe Puumala virus infection in a patient with a lymphoproliferative disease treated with icatibant. AB - Early identification of patients at risk of a severe course of hantaviral disease and lack of effective medication represent a global challenge in the treatment of this emerging infection. We describe a 67-year-old female patient with a history of chronic lymphoproliferative disease involving the spleen and an extremely severe acute Puumala hantavirus infection. She was treated with the bradykinin receptor antagonist icatibant and recovered. She is the second patient with a spleen abnormality and severe Puumala infection treated with icatibant in our hospital. We suggest that patients with spleen abnormalities may be more susceptible to severe hantavirus disease. The activation of the kinin-kallikrein system and the formation of bradykinin in hantavirus-infected endothelial cells indicate that the role of bradykinin receptor antagonist icatibant in the treatment of hantavirus disease is worth studying. PMID- 25496419 TI - First and stereoselective synthesis of an alpha-(2->5)-linked disaccharide of 3 deoxy-D-manno-oct-2-ulosonic acid (Kdo). AB - Resistance of bacterial pathogens toward antibiotics has revived interest in lipopolysaccharide (LPS) motifs as potential therapeutic targets. The LPS of several pathogenic Acinetobacter strains comprises a 4,5-branched Kdo trisaccharide containing an uncommon (2->5)-linkage. In this contribution the first stereoselective glycosylation method for obtaining an alpha-Kdo-(2->5) alpha-Kdo disaccharide in good yield is highlighted. The synthetic approach used for accessing this linkage type will allow for future studies of the immunoreactivity associated with this unique bacterial Kdo inner core structure. PMID- 25496420 TI - Local destabilization of the metal-binding region in human copper-zinc superoxide dismutase by remote mutations is a possible determinant for progression of ALS. AB - More than 100 distinct mutations in the gene CuZnSOD encoding human copper-zinc superoxide dismutase (CuZnSOD) have been associated with familial amyotrophic lateral sclerosis (fALS), a fatal neuronal disease. Many studies of different mutant proteins have found effects on protein stability, catalytic activity, and metal binding, but without a common pattern. Notably, these studies were often performed under conditions far from physiological. Here, we have used experimental conditions of pH 7 and 37 degrees C and at an ionic strength of 0.2 M to mimic physiological conditions as close as possible in a sample of pure protein. Thus, by using NMR spectroscopy, we have analyzed amide hydrogen exchange of the fALS-associated I113T CuZnSOD variant in its fully metalated state, both at 25 and 37 degrees C, where (15)N relaxation data, as expected, reveals that CuZnSOD I113T exists as a dimer under these conditions. The local dynamics at 82% of all residues have been analyzed in detail. When compared to the wild-type protein, it was found that I113T CuZnSOD is particularly destabilized locally at the ion binding sites of loop 4, the zinc binding loop, which results in frequent exposure of the aggregation prone outer beta-strands I and VI of the beta-barrel, possibly enabling fibril or aggregate formation. A similar study (Museth, A. K., et al. (2009) Biochemistry, 48, 8817-8829) of amide hydrogen exchange at pH 7 and 25 degrees C on the G93A variant also revealed a selective destabilization of the zinc binding loop. Thus, a possible scenario in ALS is that elevated local dynamics at the metal binding region can result in toxic species from formation of new interactions at local beta-strands. PMID- 25496421 TI - AMPK-dependent autophagic activation is probably involved in the mechanism of resveratrol exerting therapeutic effects for Alzheimer's disease. PMID- 25496422 TI - JAN and the publishing landscape. PMID- 25496424 TI - Beyond Rab GTPases Legionella activates the small GTPase Ran to promote microtubule polymerization, pathogen vacuole motility, and infection. AB - Legionella spp. are amoebae-resistant environmental bacteria that replicate in free-living protozoa in a distinct compartment, the Legionella-containing vacuole (LCV). Upon transmission of Legionella pneumophila to the lung, the pathogens employ an evolutionarily conserved mechanism to grow in LCVs within alveolar macrophages, thus triggering a severe pneumonia termed Legionnaires' disease. LCV formation is a complex and robust process, which requires the bacterial Icm/Dot type IV secretion system and involves the amazing number of 300 different translocated effector proteins. LCVs interact with the host cell's endosomal and secretory vesicle trafficking pathway. Accordingly, in a proteomics approach as many as 12 small Rab GTPases implicated in endosomal and secretory vesicle trafficking were identified and validated as LCV components. Moreover, the small GTPase Ran and its effector protein RanBP1 have been found to decorate the pathogen vacuole. Ran regulates nucleo-cytoplasmic transport, spindle assembly, and cytokinesis, as well as the organization of non-centrosomal microtubules. In L. pneumophila-infected amoebae or macrophages, Ran and RanBP1 localize to LCVs, and the small GTPase is activated by the Icm/Dot substrate LegG1. Ran activation by LegG1 leads to microtubule stabilization and promotes intracellular pathogen vacuole motility and bacterial growth, as well as chemotaxis and migration of Legionella-infected cells. PMID- 25496425 TI - Process evaluation of the implementation of dementia-specific case conferences in nursing homes (FallDem): study protocol for a randomized controlled trial. AB - BACKGROUND: Challenging behaviors exhibited by individuals with dementia might result from an unmet need that they cannot communicate directly due to cognitive restrictions. A dementia-specific case conference represents a promising means of analyzing and exploring these unmet needs. The ongoing FallDem study is a stepped wedged, cluster-randomized trial evaluating the effects of two different types of dementia-specific case conferences on the challenging behaviors of nursing home residents. This study protocol describes the process evaluation that is conducted, along with the FallDem study.The goal of the process evaluation is to explain potential discrepancies between expected and observed outcomes, and to provide insights into implementation processes and recruitment strategies, as well as the contexts and contextual factors that promote or inhibit the implementation of dementia-specific case conferences. METHODS/DESIGN: The process evaluation will use a mixed-method design comprising longitudinal elements, in which quantitative and qualitative data will be gathered. Qualitative data will be analyzed using content analysis, documentary analysis and a documentary method. Quantitative data (standardized questionnaires) will be analyzed using descriptive statistics. Both types of data will complement one another and provide a more comprehensive picture of the different objects under investigation. DISCUSSION: The process evaluation will allow for a comprehensive understanding of the changing processes and mechanisms underlying the 'black box' of the complex intervention of the FallDem study. These findings will provide practical knowledge regarding issues related to the implementation of dementia specific case conferences in nursing homes. TRIAL REGISTRATION: Current Controlled Trials identifier: ISRCTN20203855, registered on 10th July 2013. PMID- 25496426 TI - Anatomical study of blood supply to the cervical spinal cord in the guinea pig. AB - The aim of this study was to describe the arterial arrangement of the cervical spinal cord in the guinea pig. The study was carried out on 20 adult English self guinea pigs using corrosion and dissection technique. Batson's corrosion casting kit no. 17((c)) was used as a casting medium. The origin of the ventral spinal artery from the left vertebral artery was found on average in 35% of the cases and from the right vertebral artery on average in 40% of the cases. The ventral spinal artery with origin from the anastomosis of two medial branches was found on average in 25% of the cases. The presence of ventral radicular branches of rami spinales entering the ventral spinal artery in the cervical region was observed in 42% of the cases on the right side and in 58% of the cases on the left side. The presence of dorsal radicular branches of rami spinales that reached the spinal cord was observed in 63% of the cases on the left side and in 37% of the cases on the right side. The number of radicular branches supplying the spinal cord is greater in guinea pig than in humans. PMID- 25496427 TI - Long-term risk of malignancy in the neovagina created using colon graft in vaginal agenesis - A case report. PMID- 25496428 TI - Environmental script affects lateral asymmetry of word recognition: A study of French-Hebrew bilinguals tested in Israel and in France. AB - A written word is identified more easily when it is presented in the right than in the left visual field. This right visual field superiority (RVFS) may be explained by the left hemisphere's role in reading and by reading direction in left-to-right scripts. However, the comparison of left-to-right and right-to-left scripts had not resulted in systematic differences. It had also been found that the linguistic environment has an effect on visuospatial bias. We hypothesized that the linguistic environment might also affect RVFS. In an identification task, French and Hebrew words were presented in each visual field to four groups of 24 neurologically healthy participants, all of whom read French and Hebrew as a first or second language: native French speakers in France, native French speakers in Israel, native Hebrew speakers in Israel, and native Hebrew speakers in France. Results showed a greater RVFS with French than with Hebrew words in all groups except the native Hebrew speakers in Israel. Thus, at least for native Hebrew speakers, the country where participants lived also had an effect on the differential RVFS between languages, suggesting an effect of environmental script or reading practice. PMID- 25496429 TI - Prenatal testosterone excess decreases neurokinin 3 receptor immunoreactivity within the arcuate nucleus KNDy cell population. AB - Prenatal exposure of the female ovine foetus to excess testosterone leads to neuroendocrine disruptions in adulthood, as demonstrated by defects in responsiveness with respect to the ability of gonadal steroids to regulate gonadotrophin-releasing hormone (GnRH) secretion. In the ewe, neurones of the arcuate nucleus (ARC), which co-expresses kisspeptin, neurokinin B (NKB) and dynorphin (termed KNDy cells), play a key role in steroid feedback control of GnRH and show altered peptide expression after prenatal testosterone treatment. KNDy cells also co-localise NKB receptors (NK3R), and it has been proposed that NKB may act as an autoregulatory transmitter in KNDy cells where it participates in the mechanisms underlying steroid negative-feedback. In addition, recent evidence suggests that NKB/NK3R signalling may be involved in the positive feedback actions of oestradiol leading to the GnRH/luteinising hormone (LH) surge in the ewe. Thus, we hypothesise that decreased expression of NK3R in KNDy cells may be present in the brains of prenatal testosterone-treated animals, potentially contributing to reproductive defects. Using single- and dual-label immunohistochemistry we found NK3R-positive cells in diverse areas of the hypothalamus; however, after prenatal testosterone treatment, decreased numbers of NK3R immunoreactive (-IR) cells were seen only in the ARC. Moreover, dual label confocal analyses revealed a significant decrease in the percentage of KNDy cells (using kisspeptin as a marker) that co-localised NK3R. To investigate how NKB ultimately affects GnRH secretion in the ewe, we examined GnRH neurones in the preoptic area (POA) and mediobasal hypothalamus (MBH) for the presence of NK3R. Although, consistent with earlier findings, we found no instances of NK3R co-localisation in GnRH neurones in either the POA or MBH; in addition, > 70% GnRH neurones in both areas were contacted by NK3R-IR presynaptic terminals suggesting that, in addition to its role at KNDy cell bodies, NKB may regulate GnRH neurones by presynaptic actions. In summary, the finding of decreased NK3R within KNDy cells in prenatal testosterone-treated sheep complements previous observations of decreased NKB and dynorphin in the same population, and may contribute to deficits in the feedback control of GnRH/LH secretion in this animal model. PMID- 25496430 TI - Evaluation of quality improvement for cesarean sections caesarean section programmes through mixed methods. AB - BACKGROUND: The rate of avoidable caesarean sections (CS) could be reduced through multifaceted strategies focusing on the involvement of health professionals and compliance with clinical practice guidelines (CPGs). Quality improvements for CS (QICS) programmes (QICS) based on this approach, have been implemented in Canada and Spain. OBJECTIVES: Their objectives are as follows: 1) Toto identify clusters in each setting with similar results in terms of cost consequences, 2) Toto investigate whether demographic, clinical or context characteristics can distinguish these clusters, and 3) Toto explore the implementation of QICS in the 2 regions, in order to identify factors that have been facilitators in changing practices and reducing the use of obstetric intervention, as well as the challenges faced by hospitals in implementing the recommendations. METHODS: Descriptive study with a quantitative and qualitative approach. 1) Cluster analysis at patient level with data from 16 hospitals in Quebec (Canada) (n = 105,348) and 15 hospitals in Andalusia (Spain) (n = 64,760). The outcome measures are CS and costs. For the cost, we will consider the intervention, delivery and complications in mother and baby, from the hospital perspective. Cluster analysis will be used to identify participants with similar patterns of CS and costs based, and t tests will be used to evaluate if the clusters differed in terms of characteristics: Hospital level (academic status of hospital, level of care, supply and demand factors), patient level (mother age, parity, gestational age, previous CS, previous pathology, presentation of the baby, baby birth weight). 2) Analysis of in-depth interviews with obstetricians and midwives in hospitals where the QICS were implemented, to explore the differences in delivery-related practices, and the importance of the different constructs for positive or negative adherence to CPGs. Dimensions: political/management level, hospital level, health professionals, mothers and their birth partner. DISCUSSION: This work sets out a new approach for programme evaluation, using different techniques to make it possible to take into account the specific context where the programmes were implemented. PMID- 25496431 TI - NOX1 deficiency in apolipoprotein E-knockout mice is associated with elevated plasma lipids and enhanced atherosclerosis. AB - Nicotinamide adenine dinucleotide phosphate oxidases (NOX) are enzymes that generate reactive oxygen species (ROS). NOX2 activity in the vascular wall is elevated in hypercholesterolemia, and contributes to oxidative stress and atherogenesis. Here we examined the role of another NOX isoform, NOX1, in atherogenesis in apolipoprotein E-knockout (APOE(-/-)) mice fed a Western diet for 14 weeks. Although NOX1 mRNA expression was unchanged in aortas from APOE(-/ ) versus wild-type mice, expression of the NOX1-specific organizer, NOXO1, was diminished, consistent with an overall reduction in NOX1 activity in APOE(-/-) mice. To examine the impact of a further reduction in NOX1 activity, APOE(-/-) mice were crossed with NOX1(-/y) mice to generate NOX1(-/y)/APOE(-/-) double knockouts. NOX1 deficiency in APOE(-/-) mice was associated with 30-50% higher plasma very-low-density lipoprotein (VLDL)/LDL and triglyceride levels (P < 0.01). Vascular ROS levels were also elevated by twofold in NOX1(-/y)/APOE(-/-) versus APOE(-/-) mice (P < 0.05), despite no changes in expression of other NOX subunits. Although en face analysis of the descending aorta revealed no differences in plaque area between NOX1(-/y)/APOE(-/-) and APOE(-/-) mice, intimal thickening in the aortic sinus was increased by 40% (P < 0.05) in the double-knockouts. Moreover, NOX1 deficiency was associated with a less stable plaque phenotype; aortic sinus lesions contained 60% less collagen (P < 0.01), 40% less smooth muscle (P < 0.01), and 2.5-fold higher levels of matrix metalloproteinase-9 (P < 0.001) than lesions in APOE(-/-) mice. Thus, these data, which suggest a protective role for NOX1 against hyperlipidemia and atherosclerosis in APOE(-/-) mice, highlight the complex and contrasting roles of different NOX isoforms (e.g., NOX2 versus NOX1) in vascular pathology. PMID- 25496432 TI - Association between advanced oxidation protein products and 5-year mortality risk among amazon riparian elderly population. AB - Proteins are important targets of several modifications caused by oxidative stress, leading to structural changes and consequently partial or total loss of their functions. The oxidized proteins include advanced oxidation protein products (AOPP) derived from oxidation-modified albumin, as well as fibrinogen and lipoproteins. An increase in AOPP levels indicates an oxidative stress state and the presence of coexisting inflammation. Several investigations have also suggested an association between high AOPP levels and aging-related diseases. However, the link between elevated AOPP levels and elderly mortality risk has not yet been investigated. Here, we report on a 5-year longitudinal study that investigated the potential association between AOPP levels and mortality using a population-based representative sample of riparian elders living in Brazilian Amazon region (Maues-AM). Age, sex, socioeconomic and cultural conditions, chronic morbidities, polypharmacy, and previous morbidities were also tested as potential confounders. The AOPP levels were measured in 540 (84.78%) individuals, all of whom were followed over a 5-year period in order to establish the mortality rate. Within this study period, 74 (13.7%) elders died and 466 (86.3%) survived. The AOPP levels were higher among the elders who died within the 5-year period (46.27 +/- 40.6 mmol/L) compared with those who survived (36.79 +/- 20.84 mmol/L) (p = 0.002). The analysis confirmed the link between high AOPP levels and mortality risk, independent of other intervenient factors. These results suggest that elevated AOPP levels could be used to predict mortality risk in elderly patients. PMID- 25496433 TI - Emotional health and coping in spina bifida after goal management training: a randomized controlled trial. AB - OBJECTIVE: Executive function impairments are common after spina bifida (SB) and potentially have a detrimental effect on the individual's emotional health and coping. Goal management training (GMT) is a cognitive rehabilitation method for improving executive function. The purpose of this study was to determine the efficacy of GMT on aspects of perceived emotional health and coping in individuals with SB. METHOD: Thirty-eight adult subjects with SB were included in this randomized controlled trial. Inclusion was based upon the presence of executive functioning complaints. Experimental subjects (n = 24) received 21 hr of GMT, with efficacy of GMT being compared with results of subjects in a wait list condition (n = 14). Four self-report questionnaires assessing emotional health and coping were utilized as outcome measures. All subjects were assessed at baseline, postintervention, and at 6-month follow-up. RESULTS: Findings indicated positive effects of GMT relative to the control group on measures of emotional health. Of note, the GMT group showed significant improvement, compared with control subjects, on a self-report inventory of depressive and anxiety symptoms after training, lasting at least 6 months posttreatment. Furthermore, both groups showed improvements after training on mental health components of health-related quality of life. Finally, the GMT group showed a significant increase in task-focused coping and a decrease in avoidant coping after training compared with pretreatment baseline assessment scores. CONCLUSIONS: Overall, findings indicate that by us a compensatory intervention to manage executive dysfunction, effective and lasting benefits can be achieved with regard to aspects of perceived emotional health and coping. PMID- 25496434 TI - Predictors of anxiety in multiple sclerosis. AB - PURPOSE/OBJECTIVES: The aims of this study were to (1) identify the predictors of symptoms of anxiety, and (2) evaluate the differential association of somatic and nonsomatic symptoms of depression on anxiety over time in persons with multiple sclerosis (MS). METHOD/DESIGN: Participants were 513 persons with MS who previously enrolled in a study exploring the experience of living with MS and completed a 4-month follow-up survey. The main outcome measure used was the Hospital Anxiety and Depression Scale-Anxiety. Demographic, disease-associated variables (time since onset of MS, Expanded Disability Status Scale Mobility, pain, and fatigue), and Time 1 psychological variables were entered into a hierarchical regression model to examine predictors at baseline for anxiety symptoms at Time 2. RESULTS: A large portion of the sample was White (92%), female (82%), and had relapsing-remitting MS (57%). After adjusting for demographic and disease related variables, anxiety (beta <.001), employment (beta = .07), and nonsomatic depressive symptoms (beta = .10) at baseline significantly predicted anxiety at Time 2, ps < .05. Interactions revealed significant effects for time since onset of MS and somatic symptoms as well as time since onset and nonsomatic symptoms, ps < .05. Nonsomatic symptoms were more linked to anxiety early in the disease and somatic symptoms were more prominently linked to anxiety later in the disease. CONCLUSIONS: Findings suggest that nonsomatic symptoms of depression and employment predict anxiety in MS. The relationship between different aspects of depression and anxiety may change over the course of the disease. PMID- 25496435 TI - Association between age, distress, and orientations to happiness in individuals with disabilities. AB - PURPOSE/OBJECTIVE: To determine how age and distress are associated in individuals with disabilities, and how happiness and its components (meaning, pleasure, and engagement) mediate or moderate this relationship. RESEARCH METHOD/DESIGN: These were cross-sectional analyses of survey data from 508 community-dwelling adults with a variety of self-reported health conditions and functional disabilities. Measures included the Orientations to Happiness Questionnaire and items from the Behavior Risk Factor Surveillance System. RESULTS: Greater distress was associated with lower global happiness in both mediation and moderation models. The mediation model showed that middle-aged participants (age: 45-64) scored lowest in global happiness, and the effect of age on distress was partially mediated by happiness. None of the happiness components mediated the relationship of age on distress. The moderation model showed a significant interaction effect for age and global happiness on distress, where younger participants low on happiness were significantly more distressed. Of the three happiness components, only meaning was significantly associated with distress. There was a significant interaction between age and meaning, where participants who were younger and scored low on the meaning scale reported significantly higher distress. CONCLUSIONS/IMPLICATIONS: Findings from this study lay groundwork for the development of clinical interventions to address distress in individuals with functional disabilities. Middle-aged and younger people with disabilities may be particularly affected by lower levels of happiness and might benefit from psychological interventions that focus on increasing overall well being and providing meaning and purpose in life. PMID- 25496436 TI - Guidelines for competency development and measurement in rehabilitation psychology postdoctoral training. AB - OBJECTIVE: This study describes the results of a multidisciplinary conference (the Baltimore Conference) that met to develop consensus guidelines for competency specification and measurement in postdoctoral training in rehabilitation psychology. METHODS: Forty-six conference participants were chosen to include representatives of rehabilitation psychology training and practice communities, representatives of psychology accreditation and certification bodies, persons involved in medical education practice and research, and consumers of training programs (students). RESULTS: Consensus education and training guidelines were developed that specify the key competencies in rehabilitation psychology postdoctoral training, and structured observation checklists were developed for their measurement. DISCUSSION: This study continues the development of more than 50 years of thinking about education and training in rehabilitation psychology and builds on the existing work to further advance the development of guidelines in this area. The conference developed aspirational guidelines for competency specification and measurement in rehabilitation psychology postdoctoral training (i.e., for studying the outcomes of these training programs). Structured observation of trainee competencies allows examination of actual training outcomes in relation to intended outcomes and provides a methodology for studying how program outcomes are related to program structures and processes so that program improvement can occur. Best practices in applying program evaluation research methods to the study of professional training programs are discussed. PMID- 25496437 TI - Impaired vigilance is associated with erectile dysfunction in patients with sleep apnea. AB - INTRODUCTION: Erectile dysfunction (ED) is frequent in patients with obstructive sleep apnea (OSA) and may act as a surrogate of endothelial dysfunction. Furthermore, impairments of vigilance and sustained attention are also commonly associated with OSA. AIM: The purpose of this study was to evaluate whether there is an association between ED and sustained attention deficits. METHODS: A prospective cross-sectional cohort of 401 male in-patients undergoing diagnostic polysomnography for suspected OSA and a 25-minute sustained attention test was analyzed. ED was assessed using the 15-item International Index of Erectile Function (IIEF-15) questionnaire. The Epworth Sleepiness Scale (ESS) served as a measure of daytime sleepiness. MAIN OUTCOME MEASURE: Severity of impaired erectile function (EF) assessed by the IIEF-15, core task parameters of the sustained attention test (i.e., CR: correct reactions; V-CR: variation of correct reactions, CE: commission errors, RT: reaction time; V-RT: variation of reaction times). RESULTS: Three hundred eighty-one consecutive patients presenting for in lab polysomnography were included in the analysis. Impaired EF was diagnosed in 246 patients (65%). With increasing impairment of EF, patients scored significantly worse in all vigilance test parameters and demonstrated more severely diminished vigilance (normal EF: 11.9%, moderately impaired EF: 24.1%, and severely impaired EF: 34.9%). Multivariate regression analyses including established risk factors for ED, OSA, or sleepiness revealed a significant independent association between lower scores for EF and impairments on the following vigilance test variables: odds ratio (95% confidence interval) for V CR: 0.52 (0.34-0.81), CE: 0.87 (0.80-0.95), and V-RT: 0.91 (0.87-0.96). The ESS was independently associated with both measures of performance instability: odds ratio for V-CR: 6.94 (2.97-16.23) and V-RT: 1.28 (1.14-1.44). CONCLUSIONS: In OSA patients, the severity of impaired EF was associated with impaired vigilance performance, independent of other known risk factors for ED or OSA and not mediated by sleepiness. Potentially, the findings suggest a direct relationship between vascular or endothelial dysfunction and impairments in both EF and neurobehavioral cognitive function. PMID- 25496439 TI - Design, characterization, and evaluation of intranasal delivery of ropinirole loaded mucoadhesive nanoparticles for brain targeting. AB - CONTEXT: Parkinson disease (PD) is a common, progressive neurodegenerative disorder, characterized by marked depletion of striatal dopamine and degeneration of dopaminergic neurons in the substantia nigra. OBJECTIVE: The purpose of the present study was to investigate the possibility of targeting an anti-Parkinson's drug ropinirole (RH) to the brain using polymeric nanoparticles. MATERIALS AND METHODS: Ropinirole hydrochloride (RH)-loaded chitosan nanoparticles (CSNPs) were prepared by an ionic gelation method. The RH-CSNPs were characterized for particle size, polydispersity index (PDI), zeta potential, loading capacity, entrapment efficiency in vitro release study, and in vivo distribution after intranasal administration. RESULTS AND DISCUSSION: The RH-CSNPs showed sustained release profiles for up to 18 h. The RH concentrations (% Radioactivity/g) in the brain following intranasal administration (i.n.) of RH-CSNPs were found to be significantly higher at all the time points compared with RH solution. The concentration of RH was highest in the liver (7.210 +/- 0.52), followed by kidneys (6.862 +/- 0.62), intestine (4.862 +/- 0.45), and lungs (4.640 +/- 0.92) in rats following i.n. administration of RH-CSNPs. Gamma scintigraphy imaging in rats was performed to ascertain the localization of drug in the brain following intranasal administration of formulations. The brain/blood ratios obtained (0.251 +/- 0.09 and 0.386 +/- 0.57 of RH (i.n.) and RH-CSNPs (i.n.), respectively) at 0.5 h are indicative of direct nose to brain transport, bypassing the blood-brain barrier (BBB). CONCLUSION: The novel formulation showed the superiority of nose to brain delivery of RH using mucoadhesive nanoparticles compared with other delivery routes reported earlier. PMID- 25496438 TI - G-protein-coupled receptor 137 accelerates proliferation of urinary bladder cancer cells in vitro. AB - Urinary bladder cancer is a worldwide concern because of its level of incidence and recurrence. To search an effective therapeutic strategy for urinary bladder cancer, it is important to identify proteins involved in tumorigenesis that could serve as potential targets for diagnosis and treatment. G-protein-coupled receptors (GPRs) constitute a large protein family of receptors that sense molecules outside the cell and activate signal transduction pathways and cellular responses inside the cell. GPR137 is a newly discovered human gene encoding orphan GPRs. In this study, we aimed to investigate the physiological role of GPR137 in urinary bladder cancer. The effect of GPR137 on cell growth was examined via an RNA interference (RNAi) lentivirus system in two human urinary bladder cancer cell lines BT5637 and T24. Lentivirus-mediated RNAi could specifically suppressed GPR137 expression in vitro, resulting in alleviated cell viability and impaired colony formation, as well as blocks G0/G1 and S phases of the cell cycle. These results suggested GPR137 as an essential player in urinary bladder cancer cell growth, and it may serve as a potential target for gene therapy in the treatment of urinary bladder cancer. PMID- 25496440 TI - Synthesis of phase-pure U2N3 microspheres and its decomposition into UN. AB - Uranium mononitride (UN) is important as a nuclear fuel. Fabrication of UN in its microspherical form also has its own merits since the advent of the concept of accident-tolerant fuel, where UN is being considered as a potential fuel in the form of TRISO particles. However, not many processes have been well established to synthesize kernels of UN. Therefore, a process for synthesis of microspherical UN with a minimum amount of carbon is discussed herein. First, a series of single phased microspheres of uranium sesquinitride (U2N3) were synthesized by nitridation of UO2+C microspheres at a few different temperatures. Resulting microspheres were of low-density U2N3 and decomposed into low-density UN. The variation of density of the synthesized sesquinitrides as a function of its chemical composition indicated the presence of extra (interstitial) nitrogen atoms corresponding to its hyperstoichiometry, which is normally indicated as alpha-U2N3. Average grain sizes of both U2N3 and UN varied in a range of 1-2.5 MUm. These also had a considerably large amount of pore spacing, indicating the potential sinterability of UN toward its use as a nuclear fuel. PMID- 25496442 TI - Association between waist circumference and self-reported disability among Chinese adults aged 90 years and older. AB - AIM: To investigate the relationship between waist circumference (WC) and activities of daily living (ADL)/instrumental activities of daily living (IADL) disability among nonagenarians and centenarians. METHODS: We analyzed data obtained from a cross-sectional study carried out in 870 older Chinese adults aged 90 years and older in Dujiangyan, a town in West China. The participants were divided into four groups according to their sex and WC quartile. The ADL and IADL disabilities were measured using the physical self-maintenance scale and Lawton and Brody's IADL scale, respectively. RESULTS: We included 233 men and 505 women in this statistical analysis. The prevalence of ADL or IADL disability was 53.6% in men and 71.3% in women. Participants in the highest WC quartile group (WC >=83.0 cm for men or WC >=82.0 cm for women) had higher prevalence of ADL or IADL disability compared with those in the lowest WC quartile group (WC <73.0 cm for men or WC <70.5 cm for women). Adjusting for relevant confounders, the highest quartile group showed significantly increased odds ratios for either ADL (1.7 for men and 2.1 for women) or IADL disability (odds ratios 3.3 for men and 2.0 for women) compared with the lowest quartile group. CONCLUSION: Among Chinese older adults aged 90 years and older, both men and women in the highest quartile of WC were at higher risk of ADL or IADL disability compared with those in the lowest quartile of WC. Geriatr Gerontol Int 2015; 15: 1249-1257. PMID- 25496443 TI - Hormone replacement therapy, renal function and heart ultrasonographic parameters in postmenopausal women: an observational study. AB - BACKGROUND AND AIM: A certain degree of impaired kidney function is related to an increased cardiovascular risk. The cardiovascular protection exerted in the postmenopausal state by the hormone replacement therapy (HRT) is debated. No studies have so far explored the relationship between menopause, renal function and cardiovascular risk profile in healthy menopausal women in relation with HRT. SUBJECTS AND METHODS: A total of 362 postmenopausal healthy women with normal albumin excretion rate were recruited and divided into two groups (HRT+ and HRT-) according to the presence or absence of HRT. All participants underwent a complete routine biochemical analyses and an echocardiogram. RESULTS: Clinical characteristics of the two groups were similar, but HRT+ showed a significantly higher estimated glomerular filtration rate (GFR; by CKD-EPI formula). Regarding the heart ultrasonography, HRT+ had a significantly lower size of the aortic root and left atrium diameter (p = 0.038 and p = 0.012, respectively); no differences were found in the ejection fraction and Left Ventricular Mass Index (LVMI). In the whole study group, eGFR correlated inversely with LVMI and with the size of the aortic root (both p < 0.0001), being GFR the only determinant of the former by a stepwise regression. Dividing the study population according to an eGFR cut off (> 80 and < 80 ml/min/1.73 m(2)); > 80 women, in comparison with < 80, showed a significantly lower LVMI and lower size of aortic bulb, further reduced in the HRT+. CONCLUSION: In a cohort of healthy, drug-naive, postmenopausal women, HRT seems to positively affect glomerular filtration and is associated with lower values of left ventricular mass and aortic root size, thus offering a further mechanism through female hormones exert cardioprotection. PMID- 25496441 TI - Histone acetyltransferase PCAF regulates inflammatory molecules in the development of renal injury. AB - Kidney diseases, including chronic kidney disease (CKD) and acute kidney injury (AKI), are associated with inflammation. The mechanism that regulates inflammation in these renal injuries remains unclear. Here, we demonstrated that p300/CBP-associated factor (PCAF), a histone acetyltransferase, was overexpressed in the kidneys of db/db mice and lipopolysaccharide (LPS)-injected mice. Moreover, elevated histone acetylation, such as H3K18ac, and up-regulation of some inflammatory genes, such as ICAM-1, VCAM-1, and MCP-1, were found upon these renal injuries. Furthermore, increased H3K18ac was recruited to the promoters of ICAM-1, VCAM-1, and MCP-1 in the kidneys of LPS-injected mice. In vitro studies demonstrated that PCAF knockdown in human renal proximal tubule epithelial cells (HK-2) led to downregulation of inflammatory molecules, including VCAM-1, ICAM-1, p50 subunit of NF-kappaB (p50), and MCP-1 mRNA and protein levels, together with significantly decreased H3K18ac level. Consistent with these, overexpression of PCAF enhanced the expression of inflammatory molecules. Furthermore, PCAF deficiency reduced palmitate-induced recruitment of H3K18ac on the promoters of ICAM-1 and MCP-1, as well as inhibited palmitate-induced upregulation of these inflammatory molecules. In summary, the present work demonstrates that PCAF plays an essential role in the regulation of inflammatory molecules through H3K18ac, which provides a potential therapeutic target for inflammation-related renal diseases. PMID- 25496444 TI - Osteonecrosis of the femoral head: using CT, MRI and gross specimen to characterize the location, shape and size of the lesion. AB - OBJECTIVE: To investigate the accuracy of using CT and MRI to characterize lesions of osteonecrosis of the femoral head (ONFH). METHODS: Coronal CT and MRI scans were performed on 30 femoral head specimens collected from 23 patients who had undertaken hip arthroplasty owing to ONFH. The results were compared with findings from coronal sectional gross specimens. Two radiologists independently measured the volume of necrotic lesions from CT and MR images using computer software, and the results were averaged. The volume of specimens' necrotic lesion was measured using the water displacement method. RESULTS: There was a high degree of consistency between CT, MRI and the coronal sectional gross specimen on the location, shape and spatial structure of lesions. Differences of the lesion volume measured from CT and MR images were not statistically significant between two radiologists. The necrotic lesion volumes measured from CT and MR images and gross specimens were 22.07 +/-5.35, 22.21 +/- 5.15 and 21.12 +/-4.96 cm(3), respectively, and the differences were not statistically significant (F = 0.396; p = 0.674). CONCLUSION: For patients with ONFH in Association Research Circulation Osseous stage III or above, CT and MRI can accurately display the characterization of lesion. ADVANCES IN KNOWLEDGE: The size and location of necrotic lesions are major factors associated with femoral head collapse. CT is superior to MRI in identifying subchondral fracture. CT can help diagnose and predict the prognosis of ONFH. PMID- 25496445 TI - Potential toxicity of phthalic acid esters plasticizer: interaction of dimethyl phthalate with trypsin in vitro. AB - Dimethyl phthalate (DMP) is widely used as a plasticizer in industrial processes and has been reported to possess potential toxicity to the human body. In this study, the interaction between DMP and trypsin in vitro was investigated. The results of fluorescence, UV-vis, circular dichroism, and Fourier transform infrared spectra along with cyclic voltammetric measurements indicated that the remarkable fluorescence quenching and conformational changes of trypsin resulted from the formation of a DMP-trypsin complex, which was driven mainly by hydrophobic interactions. The molecular docking and trypsin activity assay showed that DMP primarily interacted with the catalytic triad of trypsin and led to the inhibition of trypsin activity. The dimensions of the individual trypsin molecules were found to become larger after binding with DMP by atomic force microscopy imaging. This study offers a comprehensive picture of DMP-trypsin interaction, which is expected to provide insights into the toxicological effect of DMP. PMID- 25496446 TI - Electroacupuncture stimulation at sub-specific acupoint and non-acupoint induced distinct brain glucose metabolism change in migraineurs: a PET-CT study. AB - BACKGROUND: Acupuncture has analgesic effect to most pain conditions. Many neuroimaging studies were conducted to explore acupoint specificity in pain and other condition, but till now there is still discrepancy. Based on our previous finding, this study investigated the brain metabolism changes of acupuncture analgesia induced by sub-specific acupoint and non-acupoint stimulation. METHODS: 30 migraineurs were included and randomly assigned to 3 groups: Acupuncture Group (AG), Sham Acupuncture Group (SAG) and Migraine Group (MG). In AG, a combination sub-specific points of Shaoyang meridians, Luxi (TE19), San Yangluo (TE8), and Xi Yangguan (GB33) has been stimulated with electroacupuncture, while non-acupoints for SAG were used and MG received no treatment. Positron emission tomography with computed tomography (PET-CT) was used to identify differences in brain glucose metabolism between groups. RESULTS: In the AG, brain glucose metabolism increase compared with the MG was observed in the middle frontal gyrus, postcentral gyrus, the precuneus, parahippocampus, cerebellum and middle cingulate cortex (MCC), and decrease were observed in the left hemisphere of Middle Temporal Cortex (MTC).In the SAG, compared with MG, glucose metabolism increased in the poster cingulate cortex (PCC), insula, inferior temporal gyrus, MTC, superior temporal gyrus, postcentral gyrus, fusiform, inferior parietal lobe, superior parietal lobe, supramarginal gyrus, middle occipital lobe, angular and precuneus; while, decreased in cerebellum, parahippocampus. CONCLUSIONS: Acupuncture stimulation at both sub-specific acupoint and non-acupoint yields ameliorating effect to migraine pain, but with evidently differed central mechanism as measured by PET CT. The pattern of brain glucose metabolism change in acupoint is pertinent and targeted, while in non-acupoint that was disordered and randomized. These finding may provide new perspectives into the validation of acupoint specificity, optimizing acupuncture analgesia and revealing central mechanism of acupuncture analgesia by neuroimaging measurement. TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trial Registry, with registration no. ChiCTR TRC-11001813. PMID- 25496448 TI - Comparison of direct and indirect costs of abnormal uterine bleeding treatment with global endometrial ablation and hysterectomy. AB - AIM: The objective was to compare abnormal uterine bleeding (AUB) direct healthcare costs and indirect work absence or short-term disability costs associated with treatment with second-generation global endometrial ablation (GEA) or hysterectomy. METHODS: Women aged 30-55 years with AUB who underwent GEA or hysterectomy during 2006-2010 were identified in the Truven Health MarketScan((r)) Commercial and Health and Productivity Management databases. RESULTS & CONCLUSION: Two-thirds (66.3%) of the 61,602 study patients underwent GEA compared with hysterectomy (33.7%). Hysterectomy patients had higher treatment costs (US$12,147 vs 5837; p < 0.001), higher annual absenteeism costs (US$7543 vs 5621; p < 0.001), were four-times more likely to have a short-term disability claim (84 vs 21%; p < 0.001) and had higher per-patient short-term disability costs (US$5744 vs 1361; p < 0.001). Overall hysterectomy costs were approximately twice those of GEA. PMID- 25496447 TI - Transcriptome analysis of the effect of Vibrio alginolyticus infection on the innate immunity-related complement pathway in Epinephelus coioides. AB - BACKGROUND: Orange-spotted grouper (Epinephelus coioides) with protogynous hermaphroditic features are one of the most economically important aquaculture species in Taiwan. However, larvae stage grouper are susceptible to infection by the bacterial pathogen Vibrio alginolyticus. To better understand the molecular mechanisms of the immune response to V. alginolyticus in Epinephelus coioides larvae, we used high-throughput deep sequencing technology to study the effect of infection on gene expression. RESULTS: A total of 114,851,002 reads were assembled, consisting of 9,687,355,560 nucleotides; these were further assembled into 209,082 contigs with a mean length of 372 bp. Gene ontology (GO) analysis of the transcriptome revealed 12 cellular component subcategories, 16 molecular function subcategories, and 42 biological process subcategories (P value <0.05). A total of 32664 Epinephelus coioides genes were mapped to the Kyoto Encyclopedia of Genes and Genomes (KEGG); 1504 differentially expressed genes (DEGs) were subsequently identified, in 12 categories (P value <0.05). Vibrio infection affected the expression of genes involved in complementation, coagulation cascades, pathogen (Staphylococcus aureus) infection, phagosome activity, antigen processing, and the antigen presentation pathway. CONCLUSION: We conclude that the complement pathway of innate immunity and the hepicidin antimicrobial peptide may play important roles in the defense of Epinephelus coioides larvae against V. alginolyticus, and the immune response may activate at 4 h after bacterial infection. These results implicate the complement pathway signal pathway in immunity during V. alginolyticus infection at early developmental stages, enhancing our understanding of the mechanisms underlying the immune response to Vibrio infection in Epinephelus coioides. PMID- 25496449 TI - Understanding nitric acid-induced changes in the arrangement of monomeric and polymeric methacryloyl diglycolamides on their affinity toward f-element ions. AB - Assembled diglycolamides (DGAs) have a strong affinity toward f-element ions at high nitric acid concentrations. Small angle X-ray scattering studies revealed that nitric acid concentration dependent changes occur in the geometrical arrangement of the DGA units of monomeric methacryloyl-DGA and the corresponding polymeric DGA. Cylindrical aggregates of methacryloyl-DGA were formed in 10:1 n dodecane:1-decanol (added for solubility reasons) upon equilibration with nitric acid. The lengths and diameters of the cylindrical methacryloyl-DGA aggregates increased on varying the nitric acid concentration from 3 to 4 mol L(-1). This resulted in an increase of the distribution coefficient (D) of Eu(3+) ions from 72 to 197. The physical structure of cross-linked (10 mol %) poly(methacryloyl DGA) reorganized distinctly upon equilibration with nitric acid. In this case, also the DEu(3+) values increased significantly from 147 mL g(-1) at 1 mol L(-1) HNO3 to ~4000 mL g(-1) at 4 mol L(-1) HNO3. Hydrogen bonds between the outer sphere of Eu(3+)/Am(3+)/Pu(4+) nitrate and DGA units provide stabilization in the hydrophobic environment. This results in enhancement of their extraction upon increasing nitric acid concentration both in the organic phase as well as in the polymer matrix. Though monomeric and polymeric methacryloyl-DGA are different in their physical assembling, the normalized DI values for a same f-element ion upon varying HNO3 concentrations show remarkably similar patterns in both forms. In addition, the unusual stoichiometry deduced from the slopes of the log D vs log[HNO3] curves at fixed nitrate concentration seems to suggest that the normal extraction mechanism may not be operating in the hydrogen bonded DGA assemblies. PMID- 25496450 TI - Effectiveness of hexaminolevulinate fluorescence cystoscopy for the diagnosis of non-muscle-invasive bladder cancer in daily clinical practice: a Spanish multicentre observational study. AB - OBJECTIVE: To assess the sensitivity and specificity of blue-light cystoscopy (BLC) with hexaminolevulinate as an adjunct to white-light cystoscopy (WLC) vs WLC alone for the detection of non-muscle-invasive bladder cancer (NMIBC), in routine clinical practice in Spain. PATIENTS AND METHOD: An intra-patient comparative, multicentre, prospective, observational study. Adults with suspected or documented primary or recurrent NMIBC at eight Spanish centres were included in the study. All patients were examined with WLC followed by BLC with hexaminolevulinate. We evaluated the detection rate of bladder cancer lesions by WLC and BLC with hexaminolevulinate, overall and by tumour stage and compared with histological examination of the biopsied lesions. Sensitivity and specificity was calculated. RESULTS: In all, 1,569 lesions were identified from 283 patients: 621 were tumour lesions according to histology and 948 were false positives. Of the 621 tumour lesions, 475 were detected by WLC (sensitivity 76.5%, 95% confidence interval [CI] 73.2-79.8) and 579 were detected by BLC (sensitivity 93.2%, 95% CI 91.0-95.1; P < 0.001). There was a significant improvement in the sensitivity in the detection of all types of NMIBC lesions with BLC compared with WLC. Of 219 patients with tumours, 188 had NMIBC [highest grade: carcinoma in situ (CIS), n = 36; Ta, n = 87; T1, n = 65). CIS lesions were identified more with BLC (n = 27) than with WLC [n = 19; sensitivity: BLC 75.0% (95% CI 57.8-87.9) vs WLC 52.8% (95% CI 35.5-69.6); P = 0.021]. Results varied across centres. CONCLUSIONS: This study shows that improvement in diagnosis of NMIBC, mainly CIS and Ta tumours, obtained with BLC with hexaminolevulinate as an adjunct to WLC vs WLC alone can be shown in routine clinical practice. PMID- 25496451 TI - Highly enantioselective, intermolecular hydroamination of allenyl esters catalyzed by bifunctional phosphinothioureas. AB - Bifunctional phosphinothiourea catalysts have been developed successfully for the highly regio- and enantioselective gamma-hydroamination of allenyl and propargyl esters with N-methoxy carbamate nucleophiles to yield alpha,beta-unsaturated gamma-amino acid ester products. In the case of propargyl ester substrates, the reaction proceeds through reversible phosphinothiourea-catalyzed isomerization to the corresponding allenyl ester. The high enantioselectivity of the process is attributed to a cooperative conjugate addition of a thiourea-bound carbamate anion to a vinyl phosphonium ion resulting from covalent activation of the allenyl ester substrate. PMID- 25496452 TI - Dynamic characteristics of silver nanoparticles in physiological fluids: toxicological implications. AB - The field of nanotoxicology has made tremendous progress identifying novel and potentially adverse biological effects following nanomaterial (NM) exposure. However, one facet yet to be satisfactorily explored is how a physiological environment modifies NM physicochemical properties, thus introducing novel complexities associated with solid phase material exposures. In this study, artificial alveolar, lysosomal, and interstitial fluids were used to identify environmental-specific modulations to the properties and behavior of hydrocarbon coated (Ag-HC) and polysaccharide-coated (Ag-PS) silver NMs. As inhalation is a common route of exposure, an alveolar macrophage cell model with deposition dosages representing approximately 2.5 months and 10 years of occupational exposure (0.5 and 25 ng/mL, respectively) were employed. Following dispersion in the artificial fluids, the Ag-HC and Ag-PS NMs demonstrated significant alterations to morphology, aggregation patterns, and particle reactivity. However, the Ag-PS also demonstrated a loss of particle coating, which elicited increased cytotoxicity, phagocytosis, and inflammation not associated with the original Ag-PS. This study demonstrated that in a physiological system NMs undergo considerable modulation, introducing a scenario where the toxicity of NMs may increase over time due to internal bioconditions. These findings highlight the critical influence that the dynamic and insoluble nature of NMs have on bioeffects and the importance of characterizing this behavior. PMID- 25496454 TI - Surface double phase network modified lithium rich layered oxides with improved rate capability for Li-ion batteries. AB - Poor rate capability and cycling performance are the major barriers to the application of lithium rich layered oxides (LLOs) as the next generation cathodes materials for lithium-ion batteries. In this paper, a novel surface double phase network modification has been applied to enhance the rate property of Li1.2Co0.13Ni0.13Mn0.54O2 (LR) via flexible electrostatic heterocoagulation and thermal treatment. The template action of multiwalled carbon nanotubes (MWCNTs) network on LR clusters results in the spinel phase network formation at the interface between the LR and MWCNTs. The phase transformation process from layered component toward spinel phase is identified through the detailed investigation of the interface using high-resolution transmission electron microscopy, fast Fourier transformation, and the detailed analysis on the transformation of simulated diffraction patterns. The double phases stretch two sets of networks with both fine Li ion and electron conductivity onto and within the clusters of LR, lowering the surface resistance, reducing the electrochemical polarization, and as a result, significantly enhancing the rate capability of LR. The double phase network modification, combining MWCNT coagulation and spinel phase modification, has profound potential in accelerating kinetics for LLOs. PMID- 25496453 TI - Gold nanoparticles stabilized with MPEG-grafted poly(l-lysine): in vitro and in vivo evaluation of a potential theranostic agent. AB - As the number of diagnostic and therapeutic applications utilizing gold nanoparticles (AuNPs) increases, so does the need for AuNPs that are stable in vivo, biocompatible, and suitable for bioconjugation. We investigated a strategy for AuNP stabilization that uses methoxypolyethylene glycol-graft-poly(l-lysine) copolymer (MPEG-gPLL) bearing free amino groups as a stabilizing molecule. MPEG gPLL injected into water solutions of HAuCl4 with or without trisodium citrate resulted in spherical (Zav = 36 nm), monodisperse (PDI = 0.27), weakly positively charged nanoparticles (AuNP3) with electron-dense cores (diameter: 10.4 +/- 2.5 nm) and surface amino groups that were amenable to covalent modification. The AuNP3 were stable against aggregation in the presence of phosphate and serum proteins and remained dispersed after their uptake into endosomes. MPEG-gPLL stabilized AuNP3 exhibited high uptake and very low toxicity in human endothelial cells, but showed a high dose-dependent toxicity in epithelioid cancer cells. Highly stable radioactive labeling of AuNP3 with (99m)Tc allowed imaging of AuNP3 biodistribution and revealed dose-dependent long circulation in the blood. The minor fraction of AuGNP3 was found in major organs and at sites of experimentally induced inflammation. Gold analysis showed evidence of a partial degradation of the MPEG-gPLL layer in AuNP3 particles accumulated in major organs. Radiofrequency-mediated heating of AuNP3 solutions showed that AuNP3 exhibited heating behavior consistent with 10 nm core nanoparticles. We conclude that PEG pPLL coating of AuNPs confers "stealth" properties that enable these particles to exist in vivo in a nonaggregating, biocompatible state making them suitable for potential use in biomedical applications such as noninvasive radiofrequency cancer therapy. PMID- 25496455 TI - Changes in prevalence of periodontitis in two German population-based studies. AB - AIM: We aimed to assess changes of periodontal status in Germany. MATERIALS & METHODS: The Studies of Health in Pomerania (SHIP) are two cross-sectional population-based studies conducted during 1997-2001 (SHIP-0, 20-81 years, n = 3736) and 2008-2012 (SHIP-Trend, 20-84 years, n = 3622) in northeast Germany. The German Oral Health Studies (DMS, 35-44 and 65-74 years) are national cross sectional population-based surveys conducted in 1997 (DMS III, n = 1454) and 2005 (DMS IV, n = 1668), whose results were separately reported for West and East Germany. Prevalences, percentages and numbers of teeth affected were defined. RESULTS: In SHIP, prevalence of attachment loss (AL) >= 3 mm decreased from 89.7% (95% confidence interval (CI): 88.6-90.8) to 85.1% (95%CI: 83.9-86.3) (p < 0.05) and the mean extent reduced from 62.8% (95%CI: 61.7-63.8) to 55.9% (95%CI: 54.9 56.9) (p < 0.05). Probing depth (PD) >= 4 mm and the respective extent remained unchanged. In West Germany, AL >= 3 mm decreased for 35-44-year-olds and increased for 65-74-year-olds (p < 0.05). In SHIP and DMS, the number of teeth in dentates increased significantly in all age groups. CONCLUSIONS: Prevalences and extents of AL improved almost in all age categories in SHIP and West German adults, whereas PDs remained unchanged. Nonetheless, the improvement of periodontal conditions implies an increase of treatment needs regarding moderately diseased teeth because of simultaneous increases of the number of present teeth. PMID- 25496456 TI - Mutations in FA2H in three Arab families with a clinical spectrum of neurodegeneration and hereditary spastic paraparesis. PMID- 25496457 TI - Elevated expression of histone demethylase PHF8 associates with adverse prognosis in patients of laryngeal and hypopharyngeal squamous cell carcinoma. AB - AIM: Overexpression of histone demethylase PHF8 has been reported to function as an oncoprotein in many cancers; however, the implications of PHF8 involvement in laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) remain unclear. This study aims to explore the expression of PHF8 and its clinical significance in LHSCC. MATERIALS & METHODS: Western blotting and immunohistochemistry were performed to evaluate PHF8 protein expression in fresh and archived LHSCC samples. Global expressions of H3K27 and H3K9 methylation were analyzed in a cell line with PHF8 siRNA treatment. RESULTS & CONCLUSION: In our study, PHF8 was upregulated in fresh LHSCC tissues. Immunohistochemical staining revealed that the expression of PHF8 was positively associated with T classification, clinical stage, primary tumor position and tumor relapse. Survival analysis demonstrated that high PHF8 expression was significantly associated with shorter overall survival and disease-free survival. Moreover, PHF8 regulates the levels of H3K9me2 and H3K27me2 in LHSCC. Taken together, PHF8 might be a novel prognostic marker for this disease. PMID- 25496458 TI - Velocity of DNA during translocation through a solid-state nanopore. AB - While understanding translocation of DNA through a solid-state nanopore is vital for exploiting its potential for sensing and sequencing at the single-molecule level, surprisingly little is known about the dynamics of the propagation of DNA through the nanopore. Here we use linear double-stranded DNA molecules, assembled by the DNA origami technique, with markers at known positions in order to determine for the first time the local velocity of different segments along the length of the molecule. We observe large intramolecular velocity fluctuations, likely related to changes in the drag force as the DNA blob unfolds. Furthermore, we observe an increase in the local translocation velocity toward the end of the translocation process, consistent with a speeding up due to unfolding of the last part of the DNA blob. We use the velocity profile to estimate the uncertainty in determining the position of a feature along the DNA given its temporal location and demonstrate the error introduced by assuming a constant translocation velocity. PMID- 25496459 TI - High prevalence of dyslipidemia and associated risk factors among rural Chinese adults. AB - BACKGROUND: Dyslipidemia is a key independent modifiable risk factor for Cardiovascular Disease, which is a leading contributor to morbidity and mortality in most developed and developing countries. This study was designed to investigate the current epidemiological features of dyslipidemia among adults in rural China. METHODS: Between January 2013 and August 2013, we conducted a cross sectional study involving 11,956 subjects with age>=35 years in a general Chinese population. Permanent residents of the population were invited to participate in the study and the response rate was at 85.3%. Dyslipidemia was identified based on serum lipids levels following the standards proposed by the National Cholesterol Education Program Adult Treatment Panel III. Multivariate logistic regression analysis was used to evaluate the associated risk factors for dyslipidemia. RESULTS: Within the study population, 16.4% had high TC, 13.8% had low HDL-C, 7.6% had high LDL-C, and 17.3% had high TG concentrations. Prevalence of lipid abnormality (including borderline dyslipidemia and dyslipidemia) was 47.8%, 13.8%, 25.7% and 30.7% for TC, HDL-C, LDL-C and TG, respectively. Detailed analysis indicated that 36.9% of this population had at least one type of dyslipidemia and 64.4% had at least one type of abnormal lipid concentration. Thus, this study observed an alarmingly higher prevalence of lipid abnormality, in a relatively large population, compared to previous studies. Further, we determined that not all of the risk factors studied, including age, gender, hypertension, diabetes mellitus, obesity, smoking, drinking, education level, marital status, and family income, influenced dyslipidemia to the same extent. CONCLUSIONS: Our present study, in a population of 11,956 adults in Liaoning Providence, demonstrated a very high prevalence of dyslipidemia, which represented an alarming rise since the publication of our previous study and other similar studies around the world, which report lower levels. We also examined various risk factors for dyslipidemia, many of which are modifiable risk factors for Cardiovascular Disease (CVD), to provide a comprehensive view that will help in designing strategies to slow the rapid spread and promote effective measures to treat dyslipidemia. Our ultimate goal is to prevent the increasing prevalence of lipid abnormality and reduce the burden of CVD in rural China. PMID- 25496460 TI - Two methods for one-point anchoring of a linear polysaccharide on a gold surface. AB - Two strategies to achieve a one-point anchoring of a hydrolyzed pullulan (P9000) on a gold surface are compared. The first strategy consists of forming a self assembled monolayer of a 6-amino-1-hexanethiol (AHT) and then achieving reductive amination on the surface between the aminated surface and the aldehyde of the polysaccharide reductive end sugar. The second consists of incorporating a thiol function at the extremity of the pullulan (via the same reductive amination), leading to P9000-AHT and then immobilizing it on gold by a spontaneous reaction between solid gold and thiol. The modified pullulan was characterized by NMR and size-exclusion chromatography coupled to a light-scattering detector. P9000-AHT appears to be in a disulfide dimer form in solution but recovers its unimer form with dithiothreitol (DTT) treatment. The comparison of the two strategies by contact angle and XPS revealed that the second strategy is more efficient for the pullulan one-point anchoring. P9000-AHT even in its dimer form is easily grafted onto the surface. The grafted polymer seems to be more in a coil conformation than in a rigid brush. Furthermore, QCM measurements highlighted that the second strategy leads to a grafting density of around 3.5 * 10(13) molecules.cm(-2) corresponding to a high surface coverage. The elaboration of a dense and oriented layer of polysaccharides covalently linked to a gold surface might enhance the use of such modified polysaccharides in various fields. PMID- 25496461 TI - Evidence for microRNA-mediated regulation of steroidogenesis by hypoxia. AB - Environmental hypoxia can occur in both natural and occupational environments. Over the recent years, the ability of hypoxia to cause endocrine disruption via perturbations in steroid synthesis (steroidogenesis) has become increasingly clear. To further understand the molecular mechanism underlying hypoxia-induced endocrine disruption, the steroid-producing human cell line H295R was used to identify microRNAs (miRNAs) affecting steroidogenic gene expression under hypoxia. Hypoxic treatment of H295R cells resulted in the downregulation of seven steroidogenic genes and one of these, CYP19A1 (aromatase), was shown to be regulated by the transcription factor hypoxia-inducible factor-1 (HIF-1). Using bioinformatic and luciferase reporter analyses, miR-98 was identified to be a CYP19A1-targeting miRNA from a subset of HIF-1-inducible miRNAs. Gain- and loss of-function analysis suggested that under hypoxia, the increased expression of miR-98 led to the downregulation of CYP19A1 mRNA and protein expression and that it may have contributed to a reduction in estradiol (E2) production. Intriguingly, luciferase reporter assays using deletion constructs of a proximal 5'-flanking region of miR-98 did not reveal a hypoxia-responsive element (HRE) containing promoter. Overall, this study provided evidence for the role of miRNAs in regulating steroidogenesis and novel insights into the molecular mechanisms of hypoxia-induced endocrine disruption. PMID- 25496462 TI - Evaluation of insulin resistance in idiopathic hirsutism compared with polycystic ovary syndrome patients and healthy individuals. AB - INTRODUCTION: Hirsutism is defined as the excessive male-pattern growth of hair in women. Hirsutism is often idiopathic or the consequence of polycystic ovary syndrome (PCOS). Insulin resistance is common in PCOS (especially in obese patients) but the association between insulin resistance and idiopathic hirsutism (IH) is not clear. The aim of this study was to investigate the rate of insulin resistance in IH, compared with healthy individuals and patients with PCOS. METHODS: The study included three groups, patients with idiopathic hirsutism, PCOS and healthy women. Each group included 30 non-obese women. Fasting blood sugar (FBS), insulin level and insulin resistance (estimated by the homeostasis model assessment [HOMA-IRIR]) were compared in the three groups. RESULTS: There was a significant difference between the age of the women with IH compared with two other groups. There were no significant difference in levels of serum insulin (P = 0.49, HOMA-IR (P = 0.47) and prevalence of insulin resistance (P = 0.07) in the three groups. The age-adjusted prevalence of insulin resistance was similar in the three groups. CONCLUSION: Insulin resistance was no more frequent in IH patients than in healthy control groups. PMID- 25496463 TI - Effects of tofacitinib on nucleic acid metabolism in human articular chondrocytes. AB - OBJECTIVE: In our previous screening of chondrocyte protein profiles, the amount of adenosine monophosphate deaminase (AMPD) 2 was found to be decreased by tofacitinib. Extending the study, here we confirmed the decrease of AMPD2 by tofacitinib and further investigated effects of tofacitinib on purine nucleotide metabolism. METHODS: Human articular chondrocytes and a chondrosarcoma cell line: OUMS-27 were stimulated with tofacitinib. Then the levels of AMPD2 and its related enzymes were investigated by Western blot. The levels of AMP and adenosine were assessed by mass spectrometry. RESULTS: We confirmed the significant decrease of AMPD2 by tofacitinib in chondrocytes (p = 0.025). The levels of adenosine kinase and 5'-nucleotidase were decreased in chondrocytes, although they did not meet statistical significance (p = 0.067 and p = 0.074, respectively). The results from OUMS-27 were similar to those from the chondrocytes. The cellular adenosine levels were significantly decreased by tofacitinib in OUMS-27 (p = 0.014). The cellular AMP levels were increased, although they did not meet statistical significance in OUMS-27 (p = 0.066). CONCLUSION: Our data indicate that tofacitinib increases the cellular levels of adenosine, which is known to have anti-inflammatory activity, through the downregulation of AMPD2. This would be a novel functional aspect of tofacitinib. PMID- 25496464 TI - Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study. AB - OBJECTIVES: To evaluate oral tofacitinib versus placebo for treatment of active rheumatoid arthritis in Japanese patients with inadequate response to disease modifying antirheumatic drugs. METHODS: In this double-blind, placebo-controlled, randomized, parallel-group, 12-week, phase 2 study (clinicaltrials.gov NCT00687193), 317 patients received tofacitinib: 1, 3, 5, 10, or 15 mg as monotherapy or placebo twice daily (BID). PRIMARY ENDPOINT: response rate by American College of Rheumatology (ACR) >= 20% improvement criteria (ACR20) at week 12. RESULTS: ACR20 response rates: 37.7% (20/53), 67.9% (36/53), 73.1% (38/52), 84.9% (45/53), and 90.7% (49/54) with tofacitinib: 1, 3, 5, 10, and 15 mg BID, respectively, versus 15.4% (8/52) with placebo (p < 0.01; all doses). Dose-dependent ACR20 responses with tofacitinib versus placebo occurred from week 2 onward (p < 0.05). Changes from baseline in 28-joint disease activity score using erythrocyte sedimentation rate improved with tofacitinib versus placebo from week 4 (p < 0.01; all doses). Six tofacitinib patients experienced treatment related serious adverse events (AEs). Most common treatment-emergent AEs: nasopharyngitis (10% vs 12%) and hyperlipidemia (5% vs 0%). Serum creatinine, hemoglobin, and total-, low-, and high-density lipoprotein-cholesterol levels increased with tofacitinib. CONCLUSIONS: Tofacitinib produced dose-dependent ACR20 responses and reduced disease activity. The safety profile was consistent with that reported from global monotherapy trials. PMID- 25496465 TI - Using environmental health officers' opinions to inform the source attribution of enteric disease: further analysis of the "most likely source of infection". AB - BACKGROUND: Policies and programs are needed to mitigate the burden of enteric disease in Canada. Source attribution, a goal of FoodNet Canada, can inform such strategies and can be accomplished with the information provided by expert opinion. This includes environmental health officers' (EHOs) opinions on the "most likely source of infection" (MLSI) of confirmed cases of enteric disease that are investigated by the Fraser Health Authority in British Columbia, FoodNet Canada's second sentinel site. METHODS: Exposure data from the MLSI were categorized into ten groups and summarized for five enteric disease groups using endemic cases in the first analysis, and a combination of endemic and international travel cases for the second analysis. An exploratory analysis was also conducted on risk setting information in the MLSI. The final analysis involved using a logistic regression model (Wald test) to describe the inherent biases in the data. RESULTS: Exposure proportions, by disease group, were similar to those of an analysis of MLSI data from FoodNet Canada's Ontario sentinel site. Food exposure represented the greatest proportion of overall enteric disease (32.0%), as well as for salmonellosis (45.0%), verotoxigenic E. coli (VTEC) infection (38.1%), and campylobacteriosis (30.0%) cases. The majority of parasitic diseases (41.2%) were attributed to water exposure. Food safety practices and consuming unpasteurized products were more frequently reported for campylobacteriosis (19.7% and 5.4%, respectively) compared to other enteric diseases. More VTEC infection was attributed to domestic travel (4.8%) than the other enteric diseases. Among endemic and international travel-related cases combined, VTEC infection was attributed more to endemic food exposure (35.5%) than international travel (16.1%), but similar proportions of campylobacteriosis were attributed to endemic food exposure (25.1%) and international travel (25.1%). Variations existed in the exposure and risk setting information that EHOs included in the MLSI, and in their propensity to enter food sources over other types of exposures. CONCLUSIONS: Results from the MLSI analysis for exposure, risk setting, and EHO bias, are valid contributions for informing source attribution. Important considerations from this work, including strategies to standardize and improve the quality of MLSI data, will enhance source attribution hypotheses. PMID- 25496466 TI - Prevalence of Type VI Secretion System in Spanish Campylobacter jejuni Isolates. AB - Infections from Campylobacter jejuni pose a serious public health problem and are now considered the leading cause of foodborne bacterial gastroenteritis throughout the world. Sequencing of C. jejuni genomes has previously allowed a number of loci to be identified, which encode virulence factors that aid survival and pathogenicity. Recently, a Type VI secretion system (T6SS) consisting of 13 conserved genes was described in C. jejuni strains and recognised to promote pathogenicity and adaptation to the environment. In this study, we determined the presence of this T6SS in 63 Spanish C. jejuni isolates from the food chain and urban effluents using whole-genome sequencing. Our findings demonstrated that nine (14%) strains harboured the 13 ORFs found in prototype strain C. jejuni 108. Further studies will be necessary to determine the prevalence and importance of T6SS-positive C. jejuni strains. PMID- 25496467 TI - Photosynthetic leaf area modulates tiller bud outgrowth in sorghum. AB - Shoot branches or tillers develop from axillary buds. The dormancy versus outgrowth fates of buds depends on genetic, environmental and hormonal signals. Defoliation inhibits bud outgrowth indicating the role of leaf-derived metabolic factors such as sucrose in bud outgrowth. In this study, the sensitivity of bud outgrowth to selective defoliation was investigated. At 6 d after planting (6 DAP), the first two leaves of sorghum were fully expanded and the third was partially emerged. Therefore, the leaves were selectively defoliated at 6 DAP and the length of the bud in the first leaf axil was measured at 8 DAP. Bud outgrowth was inhibited by defoliation of only 2 cm from the tip of the second leaf blade. The expression of dormancy and sucrose-starvation marker genes was up-regulated and cell cycle and sucrose-inducible genes was down-regulated during the first 24 h post-defoliation of the second leaf. At 48 h, the expression of these genes was similar to controls as the defoliated plant recovers. Our results demonstrate that small changes in photosynthetic leaf area affect the propensity of tiller buds for outgrowth. Therefore, variation in leaf area and photosynthetic activity should be included when integrating sucrose into models of shoot branching. PMID- 25496468 TI - Antibody titres against canine papillomavirus 1 peak around clinical regression in naturally occurring oral papillomatosis. AB - BACKGROUND: Most forms of canine papillomatosis are believed to be associated with papillomavirus infections. Canine papillomavirus type 1 (CPV1) is considered to be responsible for most oral cases and several forms of cutaneous papillomatosis. HYPOTHESIS/OBJECTIVES: The aim of this study was to evaluate cases of naturally occurring oral papillomatosis with regard to the type of virus involved, antibody induction and remission time. METHODS: Forty dogs showing different degrees of classical oral papillomatosis were included as a single study group. Tissue and serum samples were acquired upon initial presentation; serum samples were collected again upon remission (n = 13) and after 3 months of convalescence (n = 4). None of the dogs underwent antiviral therapy. Tissue samples were tested by PCR to detect CPV DNA, while serum samples were tested using a specific enzyme-linked immunosorbent assay for antibodies against the L1 capsid protein of CPV1. RESULTS: All tissue samples were positive for CPV1 DNA, and 87.5% of all serum samples contained measurable levels of antibody against the virus (cut-off value 0.3). The average optical density measured in the enzyme linked immunosorbent assay was 0.51 at initial presentation, 1.65 upon remission and 0.83 at 3 months postrecovery. Time to clinical regression varied between 1 month and 1 year. CONCLUSIONS AND CLINICAL IMPORTANCE: These data support existing evidence for a high prevalence of CPV1 in canine oral papillomatosis. The healing process seems to correlate with a strong antibody response, and antibody titres peaked around the time of clinical recovery. In contrast to previous data from laboratory settings, the variation in remission time was very high. PMID- 25496469 TI - Fast determination of Ziziphora tenuior L. essential oil by inorganic-organic hybrid material based on ZnO nanoparticles anchored to a composite made from polythiophene and hexagonally ordered silica. AB - In this paper, for the first time, an inorganic-organic hybrid material based on ZnO nanoparticles was anchored to a composite made from polythiophene and hexagonally ordered silica (ZnO/PT/SBA-15) for use in solid-phase fibre microextraction (SPME) of medicinal plants. A homemade SPME apparatus was used for the extraction of volatile components of Ziziphora tenuior L. A simplex method was used for optimisation of five different parameters affecting the efficiency of the extraction. The main constituents extracted by ZnO/PT/SBA-15 and PDMS fibres and hydrodistillation (HD) methods, respectively, included pulegone (51.25%, 53.64% and 56.68%), limonene (6.73%, 6.58% and 8.3%), caryophyllene oxide (5.33%, 4.31% and 4.53%) and 1,8-cineole (4.21%, 3.31% and 3.18%). In comparison with the HD method, the proposed technique could equally monitor almost all the components of the sample, in an easier way, in a shorter time and requiring a much lower amount of the sample. PMID- 25496470 TI - Efficient delivery of long-chain fatty aldehydes from the Nostoc punctiforme acyl acyl carrier protein reductase to its cognate aldehyde-deformylating oxygenase. AB - A two-step pathway consisting of an acyl-acyl carrier protein (ACP) reductase (AAR) and an aldehyde-deformylating oxygenase (ADO) allows various cyanobacteria to convert long-chain fatty acids into hydrocarbons. AAR catalyzes the two electron, NADPH-dependent reduction of a fatty acid attached to ACP via a thioester linkage to the corresponding fatty aldehyde, while ADO transforms the fatty aldehyde to a Cn-1 hydrocarbon and C1-derived formate. Considering that heptadec(a/e)ne is the most prevalent hydrocarbon produced by cyanobacterial ADOs, the insolubility of its precursor, octadec(a/e)nal, poses a conundrum with respect to its acquisition by ADO. Herein, we report that AAR from the cyanobacterium Nostoc punctiforme is activated almost 20-fold by potassium and other monovalent cations of similar ionic radius, and that AAR and ADO form a tight isolable complex with a Kd of 3 +/- 0.3 MUM. In addition, we show that when the aldehyde substrate is supplied to ADO by AAR, efficient in vitro turnover is observed in the absence of solubilizing agents. Similarly to studies by Lin et al. with AAR from Synechococcus elongatus [Lin et al. (2013) FEBS J. 280, 4773 4781], we show that catalysis by AAR proceeds via formation of a covalent intermediate involving a cysteine residue that we have identified as Cys294. Moreover, AAR specifically transfers the pro-R hydride of NADPH to the Cys294 thioester intermediate to afford its aldehyde product. Our results suggest that the interaction between AAR and ADO facilitates either direct transfer of the aldehyde product of AAR to ADO or formation of the aldehyde product in a microenvironment allowing for its efficient uptake by ADO. PMID- 25496471 TI - Evidence update on the treatment of overweight and obesity in children and adolescents. AB - Childhood obesity is associated with increased medical and psychosocial consequences and mortality and effective interventions are urgently needed. Effective interventions are urgently needed. This article reviews the evidence for psychological treatments of overweight and obesity in child and adolescent populations. Studies were identified through searches of online databases and reference sections of relevant review articles and meta-analyses. Treatment efficacy was assessed using established criteria, and treatments were categorized as well-established, probably efficacious, possibly efficacious, experimental, or of questionable efficacy. Well-established treatments included family-based behavioral treatment (FBT) and Parent-Only Behavioral Treatment for children. Possibly efficacious treatments include Parent-Only Behavioral Treatment for adolescents, FBT-Guided Self-Help for children, and Behavioral Weight Loss treatment with family involvement for toddlers, children, and adolescents. Appetite awareness training and regulation of cues treatments are considered experimental. No treatments are considered probably efficacious, or of questionable efficacy. All treatments considered efficacious are multicomponent interventions that include dietary and physical activity modifications and utilize behavioral strategies. Treatment is optimized if family members are specifically targeted in treatment. Research supports the use of multicomponent lifestyle interventions, with FBT and Parent-Only Behavioral Treatment being the most widely supported treatment types. Additional research is needed to test a stepped care model for treatment and to establish the ideal dosage (i.e., number and length of sessions), duration, and intensity of treatments for long-term sustainability of healthy weight management. To improve access to care, the optimal methods to enhance the scalability and implementability of treatments into community and clinical settings need to be established. PMID- 25496472 TI - Microarray analysis for differentially expressed genes of patients undergoing total knee arthroplasty with ischemia preconditioning. AB - BACKGROUND: Ischemia preconditioning (IPC) has been proved as a powerful method of protecting tissues against ischemia reperfusion insults. We aimed to elucidate the mechanism of IPC in ischemia reperfused tissues. METHODS: GSE21164 containing 16 muscle biopsies taken from the operative knee of four IPC-treated patients and four control at the onset of surgery (T?=?0) and 1 h into surgery (T?=?1) undergoing primary total knee arthroplasty was downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between IPC group and control were screened with Limma package in R language. KEGG pathway enrichment analysis was performed by the DAVID online tool. Meanwhile, potential regulatory microRNAs (miRNAs) for downregulated DEGs and targets of transcription factors for upregulated DEGs were screened out. Based on the above DEGs, protein-protein interaction (PPI) networks were constructed by the STRING software. RESULTS: Significantly upregulated DEGs at T1 were mainly enriched in asthma and p53 signaling pathway. Meanwhile, significantly enriched transcriptional factor NOTCH1 at T1 and GABP at T0 were obtained. Moreover, miRNA analysis showed that targets of miR141/200a were enriched in downregulated DEGs both at T0 and T1. Mostly, RPA1 and JAK2 in PPI network at T1 were with higher degree. CONCLUSIONS: In our study, obtained DEGs, regulatory transcriptional factors, and miRNA might play a vital role in the protection of ischemia reperfusion injury. This finding will provide a deeper understanding to the mechanism of IPC. PMID- 25496473 TI - Pyrosequencing analysis of free-living and attached bacterial communities in Meiliang Bay, Lake Taihu, a large eutrophic shallow lake in China. AB - To elucidate the relationship between particle-attached (PA, >= 5.0 MUm) and free living (FL, 0.2-5.0 MUm) bacterial communities, samplings were collected seasonally from November 2011 to August 2012 in Meiliang Bay, Lake Taihu, China. We used 454 pyrosequencing of 16S rRNA genes to study bacterial diversity and structure of PA and FL communities. The analysis rendered 37,985 highly qualified reads, subsequently assigned to 1755 operational taxonomic units (97% similarity) for the 8 samples. Although 27 high-level taxonomic groups were obtained, the 3 dominant phyla (Proteobacteria, Actinobacteria, and Bacteroidetes) comprised about 75.9% and 82.4% of the PA and FL fractions, respectively. Overall, we found no significant differences between community types, as indicated by ANOSIM R statistics (R = 0.063, P > 0.05) and the Parsimony test (P = 0.222). Dynamics of bacterial communities were correlated with changes in concentrations of total suspended solids (TSS) and total phosphorus (TP). In summer, a significant taxonomic overlap in the 2 size fractions was observed when Cyanobacteria, a major contributor of TSS and TP, dominated in the water, highlighting the potential rapid exchange between PA and FL bacterial populations in large shallow eutrophic lakes. PMID- 25496474 TI - Receptor-mediated endocytosis of macromolecules and strategy to enhance their transport in alveolar epithelial cells. AB - INTRODUCTION: Pulmonary delivery is an attractive administration route for therapeutic proteins and peptides. In this context, endocytosis/transcytosis at the distal lung epithelial barrier is an important process in the pulmonary absorption of therapeutic macromolecules. The alveolar epithelium is comprised of type I and type II cells. Understanding the transport mechanisms in these cells is essential for the development of efficient pulmonary delivery systems of therapeutic macromolecules. AREAS COVERED: Endocytic pathways for albumin and insulin in alveolar epithelial cells and possible receptors for the endocytosis are discussed. Strategies to enhance the endocytosis and pulmonary absorption of macromolecules are also discussed, by focusing on the effects of cationic poly(amino acid)s. EXPERT OPINION: Although the surface area occupied by type II cells in alveoli is much smaller than that covered by type I cells, type II cells may significantly contribute to the endocytosis/transcytosis of macromolecules such as albumin. Identification of the receptors involved in the cellular uptake of each macromolecule is prerequisite for the understanding and regulation of its transport into and across alveolar epithelial cells. Establishment of novel in vitro culture cell models of type I and type II cells would be a great help for the future advance of this research field. PMID- 25496475 TI - Post-acute traumatic brain injury rehabilitation: effects on outcome measures and life care costs. AB - Rehabilitation is the predominant post-acute treatment for patients with traumatic brain injury (TBI). We retrospectively evaluated the effectiveness of post-acute TBI rehabilitation by comparing outcome measures and life care cost with that of patients with cerebrovascular accident (CVA) who underwent a multidisciplinary rehabilitation program within the same facility. To better assess the effects of rehabilitation, we only included patients with no benefit limitations from the insurance carrier. Functional effectiveness was determined by comparing outcome scales, which included the Disability Rating Scale, Mayo Portland Inventory, Occupational Status Scale, Living Status Scale, and the Centre for Neuro Skills Scale. Cost-effectiveness was determined by having certified life care planners create separate cost projections from the admission and discharge patient files. This allowed us to compare cost projections with and without rehabilitation for each patient. Significant decreases in the cost projections, i.e., rehabilitation savings (RS), were found after rehabilitation for TBI. These RS were equivalent to those of patients with CVA. Likewise, equivalent improvements were found on all of the outcome scales for both brain injury groups. We also evaluated if the latency from TBI to admission in the rehabilitation program had an influence on outcome. Cost and functional effectiveness was more marked when rehabilitation was initiated within the first year after TBI. The effects of age of TBI were also evaluated. Although RS were most marked in younger patients, improvements in outcome measures were observed in all age groups after post-acute rehabilitation. PMID- 25496477 TI - Study of lead-induced neurotoxicity in neural cells differentiated from adipose tissue-derived stem cells. AB - In recent years, the use of stem cells as a new tool to create an in vitro model for toxicological studies has been considered. Adipose tissue-derived stem cells (ADSCs) are mesenchymal stem cells which have been extracted from adipose tissue by a less invasive method and rapidly propagated in culture medium compared with other sources. These cells have the capacity to differentiate into different cell lineage in vitro including neural cells. The aim of this study was to investigate the effect of lead exposure at various stages of differentiation on the neural differentiation of ADSCs. Third-passaged ADSCs were differentiated to neural cell in differentiation medium during 16 d. The ADSCs were exposed to lead (0.1-100 ug/ml) before differentiation and during differentiation on days 1, 7 and 14. The cell viability was assessed by MTT assay after 48 h. Also expression of beta tubulin III protein and Nestin, NeuN, NF70, Synaptophysin genes were evaluated at the end of differentiation in all treated groups. The results showed that lead had no effect on viability of undifferentiated ADSCs but differentiating cells showed various sensitivities to lead exposure and cells were more vulnerable to lead exposure at early stage of differentiation. Also, lead exposure at different stages of differentiation had various effects on gene expressions. Our study indicated that neural cells differentiated from ADSCs in vitro are sensitive to neurotoxic effect of lead as well-known developmental neurotoxicant, and then ADSCs could be a candidate as an alternative method for assessing neurodevelopmental toxicity potential of chemicals. PMID- 25496476 TI - Pan-African phylogeny of Mus (subgenus Nannomys) reveals one of the most successful mammal radiations in Africa. AB - BACKGROUND: Rodents of the genus Mus represent one of the most valuable biological models for biomedical and evolutionary research. Out of the four currently recognized subgenera, Nannomys (African pygmy mice, including the smallest rodents in the world) comprises the only original African lineage. Species of this subgenus became important models for the study of sex determination in mammals and they are also hosts of potentially dangerous pathogens. Nannomys ancestors colonized Africa from Asia at the end of Miocene and Eastern Africa should be considered as the place of their first radiation. In sharp contrast with this fact and despite the biological importance of Nannomys, the specimens from Eastern Africa were obviously under-represented in previous studies and the phylogenetic and distributional patterns were thus incomplete. RESULTS: We performed comprehensive genetic analysis of 657 individuals of Nannomys collected at approximately 300 localities across the whole sub-Saharan Africa. Phylogenetic reconstructions based on mitochondrial (CYTB) and nuclear (IRBP) genes identified five species groups and three monotypic ancestral lineages. We provide evidence for important cryptic diversity and we defined and mapped the distribution of 27 molecular operational taxonomic units (MOTUs) that may correspond to presumable species. Biogeographical reconstructions based on data spanning all of Africa modified the previous evolutionary scenarios. First divergences occurred in Eastern African mountains soon after the colonization of the continent and the remnants of these old divergences still occur there, represented by long basal branches of M. (previously Muriculus) imberbis and two undescribed species from Ethiopia and Malawi. The radiation in drier lowland habitats associated with the decrease of body size is much younger, occurred mainly in a single lineage (called the minutoides group, and especially within the species M. minutoides), and was probably linked to aridification and climatic fluctuations in middle Pliocene/Pleistocene. CONCLUSIONS: We discovered very high cryptic diversity in African pygmy mice making the genus Mus one of the richest genera of African mammals. Our taxon sampling allowed reliable phylogenetic and biogeographic reconstructions that (together with detailed distributional data of individual MOTUs) provide a solid basis for further evolutionary, ecological and epidemiological studies of this important group of rodents. PMID- 25496478 TI - Reactivity of catecholamine-driven Fenton reaction and its relationships with iron(III) speciation. AB - INTRODUCTION: Fenton reaction is the main source of free radicals in biological systems. The reactivity of this reaction can be modified by several factors, among these iron ligands are important. Catecholamine (dopamine, epinephrine, and norepinephrine) are able to form Fe(III) complexes whose extension in the coordination number depends upon the pH. Fe(III)-catecholamine complexes have been related with the development of several pathologies. METHODS: In this work, the ability of catecholamines to enhance the oxidative degradation of an organic substrate (veratryl alcohol, VA) through Fenton and Fenton-like reactions was studied. The initial VA degradation rate at different pH values and its relationship to the different iron species present in solution were determined. Furthermore, the oxidative degradation of VA after 24 hours of reaction and its main oxidation products were also determined. RESULTS: The catecholamine-driven Fenton and Fenton-like systems showed higher VA degradation compared to unmodified Fenton or Fenton-like systems, which also showed an increase in the oxidation state of the VA degradation product. All of this oxidative degradation takes place at pH values lower than 5.50, where the primarily responsible species would be the Fe(III) mono-complex. CONCLUSION: The presence of Fe(III) mono complex is essential in the ability of catecholamines to increase the oxidative capacity of Fenton systems. PMID- 25496479 TI - A study of seroprevalence and rates of asymptomatic viremia of severe fever with thrombocytopenia syndrome virus among Chinese blood donors. AB - BACKGROUND: Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne pathogen that can cause fatal severe fever with thrombocytopenia syndrome, was first identified in China in 2009. Limited evidence suggests that SFTSV can be transmitted between humans via blood contact, raising concerns over transfusion safety. A study of donor samples from three Chinese blood centers was conducted to investigate the seroprevalence and rate of SFTSV viremia among Chinese blood donors. STUDY DESIGN AND METHODS: From April 16 to October 31, 2012, a total of 17,208 plasma samples were collected from donors at Xinyang (located in an SFTSV-endemic area), Mianyang, and Luoyang Blood Centers. Assessment of anti-SFTSV total antibody was performed on all samples using enzyme-linked immunosorbent assay. Repeat-reactive samples were tested for SFTSV RNA using reverse transcription (RT)-real-time polymerase chain reaction (PCR) assay with Taqman probes. In addition, 9960 of the Xinyang samples were tested in pools of 4 by the same PCR method and each of the samples in a reactive pool was tested individually. RESULTS: Donor seroreactivity rates were as follows: Xinyang, 0.54% (80/14,752); Mianyang, 0.27% (3/1130); and Luoyang, 0.28% (3/1326). All seroreactive samples were negative on RT-PCR single-sample testing. Two RT-PCR-reactive donor samples were identified, both with estimated viral load of less than 20 plaque-forming units/mL. The RNA prevalence rate for SFTSV among donors in Xinyang was 0.02%. CONCLUSION: This was the first multiregion study of SFTSV sero- and viral prevalence among Chinese blood donors. Viral prevalence was low and no seroreactive sample was viremic, suggesting a limited impact of SFTSV on blood safety in China. PMID- 25496481 TI - Authors and readers beware the dark side of Open Access. PMID- 25496480 TI - Huachansu injection inhibits metastasis of pancreatic cancer in mice model of human tumor xenograft. AB - BACKGROUND: Huachansu injection (HCS) is a water-soluble preparation made from Bufo gargarizans's skin, which has been widely used in clinics for tumor therapy in China. Though the anti-cancer activity of HCS has been verified through studies in vitro and in vivo, there is little research about its potential anti metastasis effect. The primary objective of this study was to assess the effects of HCS on both the invasion of pancreatic cancer cells in vitro and on the progression of liver metastasis in vivo in this study. METHODS: HCS anti metastasis potential was accessed using both assay of Cell viability and invasion in vitro, and then further Establishing xenograft model in nude mice. In the cell based assay, mRNA and protein expression of MMP-2, MMP-9 and VEGF was detected by semi-quantitative RT-PCR and western blotting. In animal experiment, liver metastasis nodules and change of liver-body ratio was observed. Meanwhile, correlation of the CA19-9 and CEA content in serum with the progression of liver metastasis was analyzed. RESULT: We observed that HCS prevented the invasion of cancer cells, with inhibiting the expressions of MMP-2 and MMP-9, and reduced not only the number of metastasis nodules but the ratio of liver-body weight as well. Furthermore, HCS decreased the expression of MMP-2, MMP-9 and VEGF in liver metastasis, while also reducing CA19-9 contents in serum. In addition, correlation analysis indicated that the level of CA19-9 in serum was closely related to the number of liver metastasis nodules. CONCLUSION: Our experimental results suggest that HCS has some anti-metastasis potential to suppress the growth of liver metastasis by decreasing the expression of MMP-2 and MMP-9 as well as VEGF. PMID- 25496482 TI - Functional lung avoidance for individualized radiotherapy (FLAIR): study protocol for a randomized, double-blind clinical trial. AB - BACKGROUND: Although radiotherapy is a key component of curative-intent treatment for locally advanced, unresectable non-small cell lung cancer (NSCLC), it can be associated with substantial pulmonary toxicity in some patients. Current radiotherapy planning techniques aim to minimize the radiation dose to the lungs, without accounting for regional variations in lung function. Many patients, particularly smokers, can have substantial regional differences in pulmonary ventilation patterns, and it has been hypothesized that preferential avoidance of functional lung during radiotherapy may reduce toxicity. Although several investigators have shown that functional lung can be identified using advanced imaging techniques and/or demonstrated the feasibility and theoretical advantages of avoiding functional lung during radiotherapy, to our knowledge this premise has never been tested via a prospective randomized clinical trial. METHODS/DESIGN: Eligible patients will have Stage III NSCLC with intent to receive concurrent chemoradiotherapy (CRT). Every patient will undergo a pre treatment functional lung imaging study using hyperpolarized 3He MRI in order to identify the spatial distribution of normally-ventilated lung. Before randomization, two clinically-approved radiotherapy plans will be devised for all patients on trial, termed standard and avoidance. The standard plan will be designed without reference to the functional state of the lung, while the avoidance plan will be optimized such that dose to functional lung is as low as reasonably achievable. Patients will then be randomized in a 1:1 ratio to receive either the standard or the avoidance plan, with both the physician and the patient blinded to the randomization results. This study aims to accrue a total of 64 patients within two years. The primary endpoint will be a pulmonary quality of life (QOL) assessment at 3 months post-treatment, measured using the functional assessment of cancer therapy-lung cancer subscale. Secondary endpoints include: pulmonary QOL at other time-points, provider-reported toxicity, overall survival, progression-free survival, and quality-adjusted survival. DISCUSSION: This randomized, double-blind trial will comprehensively assess the impact of functional lung avoidance on pulmonary toxicity and quality of life in patients receiving concurrent CRT for locally advanced NSCLC. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02002052. PMID- 25496483 TI - Enhanced clinical pharmacy service targeting tools: risk-predictive algorithms. AB - RATIONALE, AIMS AND OBJECTIVES: This study aimed to determine the value of using a mix of clinical pharmacy data and routine hospital admission spell data in the development of predictive algorithms. Exploration of risk factors in hospitalized patients, together with the targeting strategies devised, will enable the prioritization of clinical pharmacy services to optimize patient outcomes. METHODS: Predictive algorithms were developed using a number of detailed steps using a 75% sample of integrated medicines management (IMM) patients, and validated using the remaining 25%. IMM patients receive targeted clinical pharmacy input throughout their hospital stay. The algorithms were applied to the validation sample, and predicted risk probability was generated for each patient from the coefficients. Risk threshold for the algorithms were determined by identifying the cut-off points of risk scores at which the algorithm would have the highest discriminative performance. Clinical pharmacy staffing levels were obtained from the pharmacy department staffing database. RESULTS: Numbers of previous emergency admissions and admission medicines together with age-adjusted co-morbidity and diuretic receipt formed a 12-month post-discharge and/or readmission risk algorithm. Age-adjusted co-morbidity proved to be the best index to predict mortality. Increased numbers of clinical pharmacy staff at ward level was correlated with a reduction in risk-adjusted mortality index (RAMI). CONCLUSIONS: Algorithms created were valid in predicting risk of in-hospital and post-discharge mortality and risk of hospital readmission 3, 6 and 12 months post discharge. The provision of ward-based clinical pharmacy services is a key component to reducing RAMI and enabling the full benefits of pharmacy input to patient care to be realized. PMID- 25496484 TI - Spleen nodules: a potential hallmark of Visceral Leishmaniasis in young children. AB - BACKGROUND: Visceral leishmaniasis (VL) is a severe disease caused by Leishmania infantum in the Mediterranean basin, and is associated with considerable morbidity and mortality. Infantile VL may begin suddenly, with high fever and vomiting, or insidiously, with irregular daily fever, anorexia, and marked splenomegaly. Delays in diagnosis of VL are common, highlighting the need for increased awareness of clinicians for VL in endemic European countries. CASE PRESENTATION: We report 4 cases of young children in northern Italy presenting with persistent fever of unknown origin and diagnosed with VL by serological and molecular methods. At the time of diagnosis, these patients showed an unusual echographic pattern characterized by multiple iso-hypoechoic nodules associated with splenomegaly. CONCLUSION: We suggest that detection of spleen nodules represents a signature of VL in infants, thus helping to diagnose systemic Leishmania infantum infection in children. PMID- 25496485 TI - The effect of a regional care model on cardiac catheterization rates in patients with Acute Coronary Syndromes. AB - BACKGROUND: Patients with ACS often present to community hospitals without on site cardiac catheterization and revascularization therapies. Transfer to specialized cardiac procedural centers is necessary to provide access to these procedures. We evaluated process of care within a regional care model by comparing cardiac catheterization and revascularization rates and outcomes in ACS patients presenting to community and interventional hospitals. METHODS: We evaluated a total of 6154 patients with ACS admitted to Southern Alberta hospitals (where a distinct regional care model for ACS exists) between January 1, 2005 and December 31, 2009. We compared cardiac catheterization and revascularization rates during index hospitalization among patients admitted to community and interventional hospitals. Thirty day and 1-year survival were also evaluated. RESULTS: Catheterization was performed more often in patients presenting to community hospitals compared to the interventional facility (respectively 69.5% and 51.4%, p < 0.0001). Catheterization within 72 hours of admission occurred in 48% of patients presenting to the interventional center and in 68.3% of community patients (P < 0.0001). In patients undergoing catheterization, revascularization (PCI and/or CABG) was also performed more frequently in the community group (74.5% vs 56.1%, P < 0.0001). Risk adjusted mortality rates were the same for patients undergoing cardiac catheterization regardless of hospital of initial presentation. CONCLUSION: ACS patients presenting to community centers associated with a regional care model had effective access to cardiac catheterization and revascularization. These findings support the importance of regional initiatives and processes of care that facilitate access to cardiac catheterization for all ACS patients. PMID- 25496486 TI - Abietic acid inhibits UVB-induced MMP-1 expression in human dermal fibroblast cells through PPARalpha/gamma dual activation. AB - Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors and consist of three isotypes: PPARalpha, PPARbeta/delta and PPARgamma. PPARs are expressed in various cell types in the skin, including keratinocytes, fibroblasts and infiltrating immune cells. Thus, these receptors are highly studied in dermato-endocrine research, and their ligands are targets for the treatment of various skin disorders, such as photoageing and chronological ageing of skin. Intensive studies have revealed that PPARalpha/gamma functions in photoageing and age-related inflammation by regulating matrix metalloproteinases (MMPs) via nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1). However, the detailed mechanism of PPARalpha/gamma's role in photoageing has not yet been elucidated. In this study, we confirmed that abietic acid (AA) is a PPARalpha/gamma dual ligand and significantly decreased UVB-induced MMP-1 expression by downregulating UVB-induced MAPK signalling and downstream transcription factors, subsequently reducing IkappaBalpha degradation and blocking NF-kappaB p65 nuclear translocation in Hs68 human dermal fibroblast cells. Treatment of cells with AA and GW6471 or bisphenol A diglycidyl ether (BADGE), PPARalpha or PPARgamma antagonists, respectively, reversed the effect on UVB-induced MMP-1 expression and inflammatory signalling pathway activation. Taken together, our data suggest that AA acts as a PPARalpha/gamma dual activator to inhibit UVB-induced MMP-1 expression and age-related inflammation by suppressing NF-kappaB and the MAPK/AP-1 pathway and can be a useful agent for improving skin photoageing. PMID- 25496487 TI - Pharmacometabolomics of l-carnitine treatment response phenotypes in patients with septic shock. AB - RATIONALE: Sepsis therapeutics have a poor history of success in clinical trials, due in part to the heterogeneity of enrolled patients. Pharmacometabolomics could differentiate drug response phenotypes and permit a precision medicine approach to sepsis. OBJECTIVES: To use existing serum samples from the phase 1 clinical trial of l-carnitine treatment for severe sepsis to metabolically phenotype l carnitine responders and nonresponders. METHODS: Serum samples collected before (T0) and after completion of the infusion (T24, T48) from patients randomized to either l-carnitine (12 g) or placebo for the treatment of vasopressor-dependent septic shock were assayed by untargeted (1)H-nuclear magnetic resonance metabolomics. The normalized, quantified metabolite data sets of l-carnitine- and placebo-treated patients at each time point were compared by analysis of variance with post-hoc testing for multiple comparisons. Pathway analysis was performed to statistically rank metabolic networks. MEASUREMENTS AND MAIN RESULTS: Thirty eight metabolites were identified in all samples. Concentrations of 3 hydroxybutyrate, acetoacetate, and 3-hydroxyisovalerate were different at T0 and over time in l-carnitine-treated survivors versus nonsurvivors. Pathway analysis of pretreatment metabolites revealed that synthesis and degradation of ketone bodies had the greatest impact in differentiating l-carnitine treatment response. Analysis of all patients based on pretreatment 3-hydroxybutyrate concentration yielded distinct phenotypes. Using the T0 median 3-hydroxybutyrate level (153 MUM), patients were categorized as either high or low ketone. l-Carnitine-treated low-ketone patients had greater use of carnitine as evidenced by lower post treatment l-carnitine levels. The l-carnitine responders also had faster resolution of vasopressor requirement and a trend toward a greater improvement in mortality at 1 year (P = 0.038) compared with patients with higher 3 hydroxybutyrate. CONCLUSIONS: The results of this preliminary study, which were not readily apparent from the parent clinical trial, show a unique metabolite profile of l-carnitine responders and introduce pharmacometabolomics as a viable strategy for informing l-carnitine responsiveness. The approach taken in this study represents a concrete example for the application of precision medicine to sepsis therapeutics that warrants further study. PMID- 25496488 TI - Biomechanical testing of a unique built-in expandable anterior spinal internal fixation system. AB - BACKGROUND: Expandable screws have greater pullout strength than conventional screws. The purpose of this study was to compare the biomechanical stability provided by a new built-in expandable anterior spinal fixation system with that of 2 commonly used anterior fixation systems, the Z-Plate and the Kaneda, in a porcine partial vertebral corpectomy model. METHODS: Eighteen porcine thoracolumbar spine specimens were randomly divided into 3 groups of 6 each. A vertebral wedge osteotomy was performed by removing the anterior 2/3 of the L1 vertebral body and the T15/L1 disc. Vertebrae were fixed with the Z-Plate, Kaneda, or expandable fixation system. The 3-dimensional spinal range of motion (ROM) of specimens in the intact state (prior to osteotomy), injured state (after osteotomy), and after internal fixation were recorded. The pullout strength and maximum torque of common anterior screws, the expandable anterior fixation screw unexpanded, and the expandable anterior fixation screw expanded was tested. RESULTS: After internal fixation, the expandable device and Z-plate system exhibited higher left bending motion than the Kaneda system (5.50 degrees and 5.37 degrees vs. 5.04, p = 0.001 and 0.008, respectively), and the Z-plate and Kaneda groups had significantly higher left axial and right axial rotation ROM as compared to the expandable device group (left axial rotation: 5.23 degrees and 5.02 degrees vs. 4.53 degrees ; right axial rotation: 5.23 degrees and 5.08 degrees vs. 4.49 degrees ). The maximum insertion torque of the expandable device was significantly greater than of a common screw (5.10 vs. 3.75 Ns). The maximum pullout force of the expandable device expanded was significantly higher than that of the common screw and the expandable device unexpanded (3,035.48 N vs. 1,827.38 N and 2,333.49 N). CONCLUSIONS: The built-in anterior fixation system provides better axial rotational stability as compared to the other 2 systems, and greater maximum torque and pullout strength than a common fixation screw. PMID- 25496489 TI - Intrinsic foot muscle and plantar tissue changes in type 2 diabetes mellitus. AB - BACKGROUND: Diabetes mellitus is a metabolic disorder with involvement of the neurovascular and muscular system. Peripheral neuropathy (PN) is thought to be the principal cause of foot complications in type 2 diabetes mellitus (T2DM). However, foot evaluation using ultrasonography early in the course of diabetes has not gained due importance. The aim of the present study was to evaluate the thickness of intrinsic foot muscles, plantar skin, plantar fascia, and plantar fat pad in T2DM subjects with and without PN using musculoskeletal ultrasonography. METHODS: This study was conducted in 30 T2DM subjects with and without PN and 30 age-matched non-diabetes mellitus (NDM) subjects. After detailed clinical evaluation, high-frequency musculoskeletal ultrasonography was used to measure the thickness of the intrinsic foot muscles and plantar tissue thickness under the metatarsals. Data were analyzed using independent t-tests to compare T2DM groups with NDM subjects, and one-way ANOVA followed by Tukey's honestly significant difference test for between- and within-group analyses. RESULTS: There was a significant reduction in the thickness of the intrinsic foot muscles and plantar tissue in T2DM compared with NDM subjects (P < 0.05). However, there were differences in intrinsic foot muscle and plantar tissue thickness between T2DM subjects with and without PN. CONCLUSION: There was a substantial decrease in intrinsic foot muscle and plantar tissue thickness in T2DM compared with NDM subjects, indicating that structural changes appear in the foot before PN develops. The techniques used in this study cannot exclude the possibility that neuropathic changes that are clinically undetectable may develop in parallel with changes in plantar tissues. PMID- 25496491 TI - Saccharification of rice straw by cellulase from a local Trichoderma harzianum SNRS3 for biobutanol production. AB - BACKGROUND: Rice straw has shown to be a promising agricultural by-product in the bioconversion of biomass to value-added products. Hydrolysis of cellulose, a main constituent of lignocellulosic biomass, is a requirement for fermentable sugar production and its subsequent bioconversion to biofuels such as biobutanol. The high cost of commercial enzymes is a major impediment to the industrial application of cellulases. Therefore, the use of local microbial enzymes has been suggested. Trichoderma harzianum strains are potential CMCase and beta glucosidase producers. However, few researches have been reported on cellulase production by T. harzianum and the subsequent use of the crude cellulase for cellulose enzymatic hydrolysis. For cellulose hydrolysis to be efficiently performed, the presence of the whole set of cellulase components including exoglucanase, endoglucanase, and beta-glucosidase at a considerable concentration is required. Biomass recalcitrance is also a bottleneck in the bioconversion of agricultural residues to value-added products. An effective pretreatment could be of central significance in the bioconversion of biomass to biofuels. RESULTS: Rice straw pretreated using various concentrations of NaOH was subjected to enzymatic hydrolysis. The saccharification of rice straw pretreated with 2% (w/v) NaOH using crude cellulase from local T. harzianum SNRS3 resulted in the production of 29.87 g/L reducing sugar and a yield of 0.6 g/g substrate. The use of rice straw hydrolysate as carbon source for biobutanol fermentation by Clostridium acetobutylicum ATCC 824 resulted in an ABE yield, ABE productivity, and biobutanol yield of 0.27 g/g glucose, 0.04 g/L/h and 0.16 g/g glucose, respectively. As a potential beta-glucosidase producer, T. harzianum SNRS3 used in this study was able to produce beta-glucosidase at the activity of 173.71 U/g substrate. However, for cellulose hydrolysis to be efficient, Filter Paper Activity at a considerable concentration is also required to initiate the hydrolytic reaction. According to the results of our study, FPase is a major component of cellulose hydrolytic enzyme complex system and the reducing sugar rate-limiting enzyme. CONCLUSION: Our study revealed that rice straw hydrolysate served as a potential substrate for biobutanol production and FPase is a rate limiting enzyme in saccharification. PMID- 25496492 TI - Methacrylate Copolymers with Liquid Crystalline Side Chains for Organic Gate Dielectric Applications. AB - Polymers for all-organic field-effect transistors are under development to cope with the increasing demand for novel materials for organic electronics. Besides the semiconductor, the dielectric layer determines the efficiency of the final device. Poly(methyl methacrylate) (PMMA) is a frequently used dielectric. In this work, the chemical structure of this material was stepwise altered by incorporation of cross-linkable and/or self-organizing comonomers to improve the chemical stability and the dielectric properties. Different types of cross linking methods were used to prevent dissolution, swelling or intermixing of the dielectric e.g. during formation processes of top electrodes or semiconducting layers. Self-organizing comonomers were expected to influence the dielectric/semiconductor interface, and moreover, to enhance the chemical resistance of the dielectric. Random copolymers were obtained by free radical and reversible addition-fragmentation chain transfer (RAFT) polymerization. With 6-[4 (4'-cyanophenyl)phenoxy]alkyl side chains having hexyl or octyl spacer, thermotropic liquid crystalline (LC) behavior and nanophase separation into smectic layers was observed, while copolymerization with methyl methacrylate induced molecular disorder. In addition to chemical, thermal and structural properties, electrical characteristics like breakdown field strength (EBD) and relative permittivity (k) were determined. The dielectric films were studied in metal-insulator-metal setups. EBD appeared to be strongly dependent on the type of electrode used and especially the ink formulation. Cross-linking of PMMA yielded an increase in EBD up to 4.0 MV/cm with Ag and 5.7 MV/cm with PEDOT: PSS electrodes because of the increased solvent resistance. The LC side chains reduce the ability for cross-linking resulting in decreased breakdown field strengths. PMID- 25496490 TI - Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The kinase inhibitor nintedanib specific for vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) significantly reduced the rate of decline of forced vital capacity versus placebo. AIM: To determine the in vitro effect of nintedanib on primary human lung fibroblasts. METHODS: Fibroblasts were isolated from lungs of IPF patients and from non fibrotic controls. We assessed the effect of VEGF, PDGF-BB and basic FGF (bFGF) +/- nintedanib on: (i) expression/activation of VEGFR, PDGFR, and FGFR, (ii) cell proliferation, secretion of (iii) matrix metalloproteinases (MMP), (iv) tissue inhibitor of metalloproteinase (TIMP), and (v) collagen. RESULTS: IPF fibroblasts expressed higher levels of PDGFR and FGFR than controls. PDGF-BB, bFGF, and VEGF caused a pro-proliferative effect which was prevented by nintedanib. Nintedanib enhanced the expression of pro-MMP-2, and inhibited the expression of TIMP-2. Transforming growth factor-beta-induced secretion of collagens was inhibited by nintedanib. CONCLUSION: Our data demonstrate a significant anti-fibrotic effect of nintedanib in IPF fibroblasts. This effect consists of the drug's anti proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced. PMID- 25496494 TI - Critical V2O5/TeO2 Ratio Inducing Abrupt Property Changes in Vanadium Tellurite Glasses. AB - Transition metal containing glasses have unique electrical properties and are therefore often used for electrochemical applications, such as in batteries. Among oxide glasses, vanadium tellurite glasses exhibit the highest electronic conductivity and thus the high potential for applications. In this work, we investigate how the dynamic and physical properties vary with composition in the vanadium tellurite system. The results show that there exists a critical V(2)O(5) concentration of 45 mol %, above which the local structure is subjected to a drastic change with increasing V(2)O(5), leading to abrupt changes in both hardness and liquid fragility. Electronic conductivity does not follow the expected correlation to the valence state of the vanadium as predicted by the Mott-Austin equation but shows a linear correlation to the mean distance between vanadium ions. These findings could contribute to designing optimum vanadium tellurite compositions for electrochemical devices. The work gives insight into the mechanism of electron conduction in the vanadium tellurite systems. PMID- 25496493 TI - Targeted cancer immunotherapy via combination of designer bispecific antibody and novel gene-engineered T cells. AB - BACKGROUND: Redirection of T lymphocytes against tumor antigens can induce dramatic regression of advanced stage malignancy. The use of bispecific antibodies (BsAbs) that bind both the T-cell receptor (TCR) and a target antigen is one promising approach to T-cell redirection. However, BsAbs indiscriminately bind all CD3+ T-cells and trigger TCR activation in the absence of parallel costimulatory signals required to overcome T-cell unresponsiveness or anergy. METHODS: To address these limitations, a combination platform was designed wherein a unique BsAb referred to as frBsAb exclusively engages T-cells engineered to express a novel chimeric receptor comprised of extracellular folate receptor fused to intracellular TCR and CD28 costimulatory signaling domains in tandem; a BsAb-binding immune receptor (BsAb-IR). As a surrogate TCR, the BsAb-IR allows for concomitant TCR and costimulatory signaling exclusively in transduced T-cells upon engagement with specific frBsAbs, and can therefore redirect T-cells on command to desired antigen. Human primary T-cells were transduced with lentiviral vector and expanded for 14-18 days. BsAb-IRs were harvested and armed with frBsAbs to test for redirected cytotoxicity against CD20 positive cancer cell lines. RESULTS: Using frBsAbs specific for CD20 or HER2, the lytic activity of primary human T-cells expressing the BsAb-IR was specifically redirected against CD20+ leukemic cells or HER2+ epithelial cancer cells, respectively, while non-engineered T-cells were not activated. Notably, elimination of the CD28 costimulatory domain from the BsAb-IR construct significantly reduced frBsAb redirected antitumor responses, confirming that frBsAbs are capable of delivering simultaneous TCR activation and costimulatory signals to BsAb-IR T-cells. CONCLUSION: In summary, our results establish the proof of concept that the combination of BsAbs with optimized gene-engineered T-cells provides the opportunity to specify and augment tumor antigen-specific T-cell activation and may improve upon the early success of conventional BsAbs in cancer immunotherapy. PMID- 25496495 TI - Spatially dependent lattice deformations for dislocations at the edges of graphene. AB - We show that dislocations located at the edge of graphene cause different lattice deformations to those located in the bulk lattice. When a dislocation is located near an edge, a decrease in the rippling and increase of the in-plane rotation occurs relative to the dislocations in the bulk. The increased in-plane rotation near the edge causes bond rotations at the edge of graphene to reduce the overall strain in the system. Dislocations were highly stable and remained fixed in their position even when located within a few lattice spacings from the edge of graphene. We study this behavior at the atomic level using aberration-corrected transmission electron microscopy. These results show detailed information about the behavior of dislocations in 2D materials and the strain properties that result. PMID- 25496496 TI - Another year. PMID- 25496497 TI - Retinoic acids change gene expression profiles of bovine intramuscular adipocyte differentiation, based on microarray analysis. AB - Beef marbling is caused by intramuscular deposition and it is an economically important trait in the beef industry. Vitamin A (VA) is an important feed supplement for cattle, but it can hinder marbling if provided in excess. In cattle, VA forms various derivatives such as all-trans retinoic acid (ATRA) and 9 cis retinoic acid (9cRA). Therefore, we investigated the genes involved in bovine intramuscular adipogenesis after VA treatment with ATRA and 9cRA. Differential gene expression levels were validated by microarray analysis in a clonal bovine intramuscular preadipocyte (BIP) cell line derived from the intramuscular adipose tissue of Japanese Black cattle. BIP cells were harvested 6 days after adipogenic stimulation with either 1 MUmol/L ATRA, 1 MUmol/L 9cRA or non-retinoic acid control. The ATRA- and 9cRA-treated cells exhibited reduced transcription of genes involved in the circulatory system and muscle development compared with the no retinoic acid (RA) treatment. In addition, the ATRA- and 9cRA-treated cells exhibited increased transcription of genes involved in the immune system, protein kinase B signaling and responses to various stimuli. These results demonstrate the lower expression of muscle development in ATRA- and 9cRA-treated BIP cells during adipogenesis. PMID- 25496500 TI - Single patch multilayer aortic annular repair for destructive infective endocarditis. AB - Active infective endocarditis may progress to annular abscess formation. We describe a patch annuloplasty technique to treat the fragile aortic root tissue in these patients. PMID- 25496499 TI - Pregnancy outcomes in Southeast Asian migrant workers at Southern Thailand. AB - This retrospective study was conducted to determine the pregnancy outcomes and identify predictive factors of adverse outcomes in pregnant migrant workers who delivered at Songklanagarind Hospital from January 2002 to December 2012. Two hundred and forty migrant worker pregnancies were enrolled. Pre-eclampsia, gestational diabetes mellitus, pre-term birth and foetal intrauterine growth restriction found were 15, 7.9, 13.7 and 3.7%, respectively. No stillbirth was found. Apgar score was =8, was experienced by 33.9 percent of participants. Poor SROH was associated with high levels of psychological distress, being older, being female, and usually visiting a dentist because of a problem. In the multivariable model, factors that were significantly associated with poor SROH after adjustment for other covariates included having a high level of psychological distress (OR 2.74, 95% CI 1.25-6.00), being female (OR 2.22, 95% CI 1.03-4.78), and usually visiting a dentist because of a problem (OR 3.57, 95% CI 1.89-6.76). CONCLUSIONS: Poor self rated oral health and high levels of psychological distress were both highly frequent among this vulnerable population. Psychological distress was significantly associated with poor self-rated oral health after adjustment for confounding. PMID- 25496504 TI - Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials. AB - BACKGROUND: Inhaled nitric oxide (INO), a selective pulmonary vasodilator, has revolutionized the treatment of neonatal hypoxemic respiratory failure (NHRF). However, there is lack of sustained improvement in 30 to 46% of infants. Aerosolized prostaglandins I2 (PGI2) and E1 (PGE1) have been reported to be effective selective pulmonary vasodilators. The objective of this study was to evaluate the feasibility of a randomized controlled trial (RCT) of inhaled PGE1 (IPGE1) in NHRF. METHODS: Two pilot multicenter phase II RCTs are included in this report. In the first pilot, late preterm and term neonates with NHRF, who had an oxygenation index (OI) of >=15 and <25 on two arterial blood gases and had not previously received INO, were randomly assigned to receive two doses of IPGE1 (300 and 150 ng/kg/min) or placebo. The primary outcome was the enrollment of 50 infants in six to nine months at 10 sites. The first pilot was halted after four months for failure to enroll a single infant. The most common cause for non enrollment was prior initiation of INO. In a re-designed second pilot, co administration of IPGE1 and INO was permitted. Infants with suboptimal response to INO received either aerosolized saline or IPGE1 at a low (150 ng/kg/min) or high dose (300 ng/kg/min) for a maximum duration of 72 hours. The primary outcome was the recruitment of an adequate number of patients (n = 50) in a nine-month period, with fewer than 20% protocol violations. RESULTS: No infants were enrolled in the first pilot. Seven patients were enrolled in the second pilot; three in the control, two in the low-dose IPGE1, and two in the high-dose IPGE1 groups. The study was halted for recruitment futility after approximately six months as enrollment targets were not met. No serious adverse events, one minor protocol deviation and one pharmacy protocol violation were reported. CONCLUSIONS: These two pilot RCTs failed to recruit adequate eligible newborns with NHRF. Complex management RCTs of novel therapies for persistent pulmonary hypertension of the newborn (PPHN) may require novel study designs and a longer period of time from study approval to commencement of enrollment. TRIAL REGISTRATION: CLINICALTRIALS.GOV: Pilot one: NCT number: 00598429 registered on 10 January 2008. Last updated: 3 February 2011. Pilot two: NCT number: 01467076 17 October 2011. Last updated: 13 February 2013. PMID- 25496508 TI - Association between human cytomegalovirus antibody levels, and essential hypertension and functional status in elderly Koreans. AB - AIM: To evaluate the relationship between human cytomegalovirus (HCMV) antibody status, and hypertension and functional status among elderly Koreans. METHODS: Patients aged >=65 years were prospectively enrolled from March 2011 to February 2012 at a 2000-bed university hospital. We collected data including CD4+ and CD8+ T-lymphocyte count, and functional status by measuring basic activities of daily living and instrumental activities of daily living for all patients. In addition, HCMV immunoglobulin G levels were analyzed using enzyme-linked fluorescent assay. RESULTS: During the study period, 103 patients (51 men), who were admitted for treatment of infections or other diseases, were enrolled. Multivariate analysis showed that body mass index and HCMV immunoglobulin G antibody titers were independent factors associated with hypertension in elderly patients (OR 1.347, 95% CI 1.113-1.630, P = 0.002; OR 1.023, 95% CI 1.001-1.047, P = 0.042, respectively). In univariate linear correlations, HCMV antibody levels were positively correlated with systolic blood pressure levels (r = 0.303, P = 0.002), CD8+ T-lymphocyte count (r = 0.313, P = 0.001) and instrumental activities of daily living scores (r = 0.217, P = 0.028). In addition, HCMV immunoglobulin G titers were inversely associated with estimated glomerular filtration rate (r = 0.268, P = 0.006). These four variables remained independently significant in multivariate correlation analysis. CONCLUSION: These findings could provide insight into the important role of HCMV in the pathogenesis of essential hypertension and decreased functional status in the elderly. PMID- 25496509 TI - Foetal "black bone" MRI: utility in assessment of the foetal spine. AB - OBJECTIVE: Foetal CT has recently been added to the foetal imaging armamentarium, but this carries with it the risks of ionizing radiation, both to the mother and the foetus. Foetal "black bone" MRI is a new technique that allows assessment of the foetal skeleton without the risk of exposure to ionizing radiation and is a potential new sequence in foetal MRI examination. METHODS: Retrospective review of all foetal MRI studies over the past 4- to 5-year period identified 36 cases where susceptibility weighted imaging was used. Cases were selected from this group to demonstrate the potential utility of this sequence. RESULTS: This sequence is most frequently useful not only in the assessment of spinal abnormalities, most commonly the bony abnormalities in myelomeningocele, but also in cases of scoliosis, segmentation anomalies and sacrococcygeal teratoma. CONCLUSION: Although the utility of this sequence is still being evaluated, it provides excellent contrast between the mineralized skeleton and surrounding soft tissues compared with standard half Fourier acquisition single-shot turbo-spin echo sequences. Further assessment is required to determine whether black bone MRI can more accurately evaluate the level of bony defect in spina bifida aperta, an important prognostic factor. Potential further uses include the assessment of skeletal dysplasias, evaluation of the skull base and craniofacial skeleton in certain congenital anomalies and the post-mortem evaluation of the foetal skeleton potentially obviating the need for necropsy. ADVANCES IN KNOWLEDGE: Foetal black bone MRI can be performed using susceptibility weighted imaging and allows better demonstration of the mineralized skeleton compared with standard sequences. PMID- 25496510 TI - Perception of men's beauty and attractiveness by women with low sexual desire. AB - INTRODUCTION: Despite the high prevalence of hypoactive sexual desire disorder (HSDD), especially among women, this sexual disorder remains poorly understood. Among the multiple factors possibly involved in HSDD, particularities in the cognitive evaluations of social stimuli need to be better characterized. Especially, beauty and attractiveness judgments, two dimensions of interpersonal perception that are related but differ on their underlying motivational aspects, may vary according to the level of sexual desire. AIM: The main goal of this study was to investigate whether women with and without HSDD differ in their evaluations of beauty and attractiveness of men's faces and voices. METHODS: Young women from the general population (controls, n = 16) and with HSDD (patients, n = 16) took part in the study. They were presented with a series of neutral/nonerotic voices and faces of young men from the GEneva Faces And Voices database. MAIN OUTCOME MEASURES: Ratings of beauty (i.e., assessments of aesthetic pleasure) and of attractiveness (i.e., assessments of the personal propensity to feel attracted to someone) and the frequency to which the participants pressed a key to see or listen to each stimulus again were the main outcome measures. RESULTS: Ratings of attractiveness were lower than ratings of beauty in both groups of women. The dissociation between beauty and attractiveness was larger in women with HSDD than in control participants. Patients gave lower attractiveness ratings than the controls and replayed the stimuli significantly less often. CONCLUSION: These results suggest that women with HSDD are characterized by specific alterations of the motivational component of men's perception, very early in the process of interpersonal relationships. Our findings have significant implications, both in better understanding the specific cognitive processes underlying hypoactive sexual desire and more largely the evaluative processes involved in human mate choice. PMID- 25496511 TI - Intracranial markers of emotional valence processing and judgments in music. AB - The involvement of the amygdala and orbitofrontal cortex in the processing of valenced stimuli is well established. However, less is known about the extent to which activity in these regions reflects a stimulus' physical properties, the individual subjective experience it evokes, or both. We recorded cortical electrical activity from five epileptic patients implanted with depth electrodes for presurgical evaluation while they rated "consonant" and "dissonant" musical chords using a "pleasantness" scale. We compared the pattern of responses in the amygdala and orbitofrontal cortex when trials were sorted by pleasantness judgments relative to when they were sorted by the acoustic properties known to influence emotional reactions to musical chords. This revealed earlier differential activity in the amygdala in the physical properties-based, relative to in the judgment-based, analyses. Thus, our results demonstrate that the amygdala has, first and foremost, a high initial sensitivity to the physical properties of valenced stimuli. The finding that differentiations in the amygdala based on pleasantness ratings had a longer latency suggests that in this structure, mediation of emotional judgment follows accumulation of sensory information. This is in contrast to the orbitofrontal cortex where sensitivity to sensory information did not precede differentiation based on affective judgments. PMID- 25496512 TI - Ligand-sensitive but not ligand-diagnostic: evaluating Cr valence-to-core X-ray emission spectroscopy as a probe of inner-sphere coordination. AB - This paper explores the strengths and limitations of valence-to-core X-ray emission spectroscopy (V2C XES) as a probe of coordination environments. A library was assembled from spectra obtained for 12 diverse Cr complexes and used to calibrate density functional theory (DFT) calculations of V2C XES band energies. A functional dependence study was undertaken to benchmark predictive accuracy. All 7 functionals tested reproduce experimental V2C XES energies with an accuracy of 0.5 eV. Experimentally calibrated, DFT calculated V2C XES spectra of 90 Cr compounds were used to produce a quantitative spectrochemical series showing the V2C XES band energy ranges for ligands comprising 18 distinct classes. Substantial overlaps are detected in these ranges, which complicates the use of V2C XES to identify ligands in the coordination spheres of unknown Cr compounds. The ligand-dependent origins of V2C intensity are explored for a homologous series of [Cr(III)(NH3)5X](2+) (X = F, Cl, Br, and I) to rationalize the variable intensity contributions of these ligand classes. PMID- 25496513 TI - Isocitrate dehydrogenase 1 R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype. AB - The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause of CIMP in colorectal cancer. The IDH1 mutational hotspot was screened in 86 CIMP-positive and 80 CIMP-negative cancers. The entire coding sequence was examined in 81 CIMP-positive colorectal cancers. Forty-seven cancers varying by CIMP-status and IDH1 mutation status were examined using Illumina 450K DNA methylation microarrays. The R132C IDH1 mutation was detected in 4/166 cancers. All IDH1 mutations were in CIMP cancers that were BRAF mutant and microsatellite stable (4/45, 8.9%). Unsupervised hierarchical cluster analysis identified an IDH1 mutation-like methylation signature in approximately half of the CIMP-positive cancers. IDH1 mutation appears to cause CIMP in a small proportion of BRAF mutant, microsatellite stable colorectal cancers. This study provides a precedent that a single gene mutation may cause CIMP in colorectal cancer, and that this will be associated with a specific epigenetic signature and clinicopathological features. PMID- 25496514 TI - Enhancing cognitive-behavioural therapy for recurrent headache: design of a randomised controlled trial. AB - BACKGROUND: We have argued against the traditional approach of counselling avoidance of all triggers of headaches and migraine. Problems with this approach include the impossibility of avoiding all triggers and the high costs associated with trying to do so, and that avoidance could lead to reduced tolerance for the triggers. We have developed an alternative approach called Learning to Cope with Triggers (LCT) that encourages avoidance of triggers that are detrimental to health and wellbeing, but uses exposure to other triggers to desensitise headache sufferers to the triggers. This approach has been shown to be more effective than advising avoidance of all triggers. Trigger management is only one component of a comprehensive treatment program and the current study is designed to evaluate a new approach to treating headaches in which LCT has been integrated into an established cognitive-behavioural therapy (CBT) package (LCT/CBT). METHODS/DESIGN: A target sample of 120 adult participants who suffer from migraine or tension-type headache, at least six days per month, and have done so for at least 12 months will be recruited. Participants will be randomly assigned to one of three groups: LCT/CBT; Avoid/CBT (CBT combined with instructions to avoid all triggers); and waiting-list control. Measures will include: daily diaries for recording headaches, triggers and medication consumption; headache disability and quality of life; trigger avoidance; locus of control and self efficacy; and coping strategies. Treatment will involve 12 60-minute sessions scheduled weekly. Assessment will be completed before and after treatment, and at 4 and 12 month follow-up. The data will be analysed to determine which approach is most effective, and predictors of response to treatment. DISCUSSION: Migraine and tension-type headache are common and can be disabling. CBT has been demonstrated to be an efficacious treatment for both disorders. However, there is room for improvement. This study aims to increase the efficacy of behavioural approaches and identify factors predictive of a positive response. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12614000435684 . PMID- 25496515 TI - Endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer diagnosis and staging. AB - Lung cancer is one of the most prevalent types of cancer in the world. A complete diagnosis of lung cancer involves tissue acquisition for pathological subtype, molecular diagnosis and accurate staging of the disease to guide appropriate therapy. Real-time endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is minimally invasive and relatively safe procedure, which can be done on an outpatient basis under moderate sedation. EBUS-TBNA has been shown to be a safe modality to obtain tissue for diagnosis, staging and molecular profiling in lung cancer. EBUS-TBNA stands out in comparison with other modalities for tissue acquisition in lung cancer. EBUS-TBNA performed with the patient under moderate sedation yields sufficient tissue for sequential molecular analysis in most patients. In this review, we describe the role of EBUS-TBNA in various aspects of diagnosis and staging of lung cancer in the present era along with its future aspects. PMID- 25496516 TI - Site-specific metabolic phenotypes in metastatic breast cancer. AB - BACKGROUND: The purpose of this study was to examine the expression of metabolism related proteins according to metastatic site in metastatic breast cancer and to assess the implication of site-specific differential expression. METHODS: A tissue microarray containing 162 cases of metastatic breast cancer (52 lung metastasis, 47 bone metastasis, 39 brain metastasis, and 24 liver metastasis) was constructed. It was subject to immunohistochemical staining of the following proteins: Glycolysis-related: Glut-1, hexolinase II, carbonic anhydrase (CA) IX, and monocarboxylate transporter (MCT) 4; glutaminolysis-related: glutaminase (GLS) 1, glutamate dehydrogenase (GDH), and amino acid transporter (ASCT) 2; mitochondrial metabolism-related: ATP synthase, succinate dehydrogenase (SDH)A, and SDHB; and serine/glycine metabolism related: phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT), phosphoserine phosphatase (PSPH), glycine decarboxylase (GLDC), and serine hydroxymethyltransferase (SHMT). RESULTS: The expression levels of glycolysis-related-proteins (Glut-1, hexokinase II, CAIX, and MCT4) differed according to metastatic site, with higher expression seen in the brain and lower expression in the bone and liver (p < 0.001, 0.001, 0.009, and <0.001, respectively). Differences in metabolic phenotype were analyzed according to metastasis site. Glycolysis type was most frequently encountered in the brain and lung (p < 0.001). In univariate analysis, the factors associated with shorter overall survival were CAIX positivity (p = 0.044), PSPH positivity (p = 0.045), and SHMT1 positivity (p = 0.002), as well as serine/glycine type (p = 0.041). CONCLUSIONS: Differences in metabolic features according to metastatic site were seen in metastatic breast cancer, with the glycolysis phenotype found predominantly in the brain and lung and the non glycolysis phenotype in the bone and liver. PMID- 25496517 TI - Characterization of immunomodulatory activities of honey glycoproteins and glycopeptides. AB - Recent evidence suggests an important role for natural honey in modulating immune response. To identify active components responsible, this study investigated the immunomodulatory properties of glycoproteins and glycopeptides fractionated from Ziziphus honey. Honey proteins/peptides were fractionated by size exclusion chromatography into five peaks with molecular masses in the range of 2-450 kDa. The fractionated proteins exhibited potent, concentration-dependent inhibition of reactive oxygen species production in zymosan-activated human neutrophils (IC50 = 6-14 ng/mL) and murine macrophages (IC50 = 2-9 ng/mL). Honey proteins significantly suppressed the nitric oxide production by LPS-activated murine macrophages (IC50 = 96-450 ng/mL). Moreover, honey proteins inhibited the phagocytosis latex bead macrophages. The production of pro-inflammatory cytokines IL-1beta and TNF-alpha by human monocytic cell line in the presence of honey proteins was analyzed. Honey proteins did not affect the production of IL-1beta; however, TNF-alpha production was significantly suppressed. These findings indicated that honey glycoproteins and glycopeptides significantly interfere with molecules of the innate immune system. PMID- 25496519 TI - Tumour necrosis factor-alpha/interleukin-10 ratio in patients with obstructive sleep apnoea hypopnoea syndrome. AB - OBJECTIVE: To explore the significance of the tumour necrosis factor alpha/interleukin-10 ratio and the effect of continuous positive airway pressure in patients with different degrees of obstructive sleep apnoea hypopnoea syndrome severity. METHOD: This study comprised 135 patients with obstructive sleep apnoea hypopnoea syndrome and 94 control subjects. RESULTS: Tumour necrosis factor-alpha and tumour necrosis factor-alpha/interleukin-10 ratio values were significantly higher in the obstructive sleep apnoea hypopnoea syndrome group than in the control group, but interleukin-10 was significantly lower. Tumour necrosis factor alpha/interleukin-10 ratio values increased in line with the severity of obstructive sleep apnoea hypopnoea syndrome. In multivariate analysis, the tumour necrosis factor-alpha/interleukin-10 ratio correlated positively with the apnoea hypopnoea index and all indices of obstructive sleep apnoea hypopnoea syndrome, except for age, body mass index and neck circumference. After one month of continuous positive airway pressure therapy, levels of tumour necrosis factor alpha decreased; interleukin-10 showed no change. CONCLUSION: The results suggest that inflammation is activated and anti-inflammatory cytokines are decreased in obstructive sleep apnoea hypopnoea syndrome patients. Tumour necrosis factor alpha/interleukin-10 ratio may prove useful for severity monitoring and management of obstructive sleep apnoea hypopnoea syndrome patients, and may reduce the need for polysomnography. PMID- 25496518 TI - Whole exome sequencing of a single osteosarcoma case--integrative analysis with whole transcriptome RNA-seq data. AB - BACKGROUND: Osteosarcoma (OS) is a prevalent primary malignant bone tumour with unknown etiology. These highly metastasizing tumours are among the most frequent causes of cancer-related deaths. Thus, there is an urgent need for different markers, and with our study, we were aiming towards finding novel biomarkers for OS. METHODS: For that, we analysed the whole exome of the tumorous and non-tumour bone tissue from the same patient with OS applying next-generation sequencing. For data analysis, we used several softwares and combined the exome data with RNA seq data from our previous study. RESULTS: In the tumour exome, we found wide genomic rearrangements, which should qualify as chromotripsis-we detected almost 3,000 somatic single nucleotide variants (SNVs) and small indels and more than 2,000 copy number variants (CNVs) in different chromosomes. Furthermore, the somatic changes seem to be associated to bone tumours, whereas germline mutations to cancer in general. We confirmed the previous findings that the most significant pathway involved in OS pathogenesis is probably the WNT/beta-catenin signalling pathway. Also, the IGF1/IGF2 and IGF1R homodimer signalling and TP53 (including downstream tumour suppressor gene EI24) pathways may have a role. Additionally, the mucin family genes, especially MUC4 and cell cycle controlling gene CDC27 may be considered as potential biomarkers for OS. CONCLUSIONS: The genes, in which the mutations were detected, may be considered as targets for finding biomarkers for OS. As the study is based on a single case and only DNA and RNA analysis, further confirmative studies are required. PMID- 25496520 TI - Detection of Vibrio cholerae O1 and O139 in environmental waters of rural Bangladesh: a flow-cytometry-based field trial. AB - Presence of Vibrio cholerae serogroups O1 and O139 in the waters of the rural area of Matlab, Bangladesh, was investigated with quantitative measurements performed with a portable flow cytometer. The relevance of this work relates to the testing of a field-adapted measurement protocol that might prove useful for cholera epidemic surveillance and for validation of mathematical models. Water samples were collected from different water bodies that constitute the hydrological system of the region, a well-known endemic area for cholera. Water was retrieved from ponds, river waters, and irrigation canals during an inter epidemic time period. Each sample was filtered and analysed with a flow cytometer for a fast determination of V. cholerae cells contained in those environments. More specifically, samples were treated with O1- and O139-specific antibodies, which allowed precise flow-cytometry-based concentration measurements. Both serogroups were present in the environmental waters with a consistent dominance of V. cholerae O1. These results extend earlier studies where V. cholerae O1 and O139 were mostly detected during times of cholera epidemics using standard culturing techniques. Furthermore, our results confirm that an important fraction of the ponds' host populations of V. cholerae are able to self-sustain even when cholera cases are scarce. Those contaminated ponds may constitute a natural reservoir for cholera endemicity in the Matlab region. Correlations of V. cholerae concentrations with environmental factors and the spatial distribution of V. cholerae populations are also discussed. PMID- 25496521 TI - Solvation and hydration of the ceramide headgroup in a non-polar solution. AB - The microscopic hydration of the ceramide headgroup has been determined using a combination of experimental-both NMR and neutron diffraction techniques and computational techniques-empirical potential structure refinement (EPSR) and molecular dynamics (MD). The addition of water to ceramide in chloroform solutions disrupts the chloroform solvation of the ceramide headgroup, and the water forms distinct pockets of density. Specifically, water is observed to preferentially hydrate the two hydroxyl groups and the carbonyl oxygen over the amide NH motif. Further assessment of the location and orientation of the water molecules bound to the ceramide headgroup makes it clear that the strongly solvated carbonyl moiety of the amide bond creates an anchor from which water molecules can bridge via hydrogen bonding interactions to the hydroxyl groups. Moreover, a significant difference in the hydration of the two hydroxyl groups indicates that water molecules are associated with the headgroup in such a way that they bridge between the carbonyl motif and the nearest neighbor hydroxyl group. PMID- 25496522 TI - The effect of long or chopped straw on pig behaviour. AB - In the EU, pigs must have permanent access to manipulable materials such as straw, rope, wood, etc. Long straw can fulfil this function, but can increase labour requirements for cleaning pens, and result in problems with blocked slatted floors and slurry systems. Chopped straw might be more practical, but what is the effect on pigs' behaviour of using chopped straw instead of long straw? Commercial pigs in 1/3 slatted, 2/3 solid pens of 15 pigs were provided with either 100 g/pig per day of long straw (20 pens) or of chopped straw (19 pens). Behavioural observations were made of three focal pigs per pen (one from each of small, medium and large weight tertiles) for one full day between 0600 and 2300 h at each of ~40 and ~80 kg. The time spent rooting/investigating overall (709 s/pig per hour at 40 kg to 533 s/pig per hour at 80 kg), or directed to the straw/solid floor (497 s/pig per hour at 40 kg to 343 s/pig per hour at 80 kg), was not affected by straw length but reduced with age. Time spent investigating other pigs (83 s/pig per hour at 40 kg), the slatted floor (57 s/pig per hour) or pen fixtures (21 s/pig per hour) was not affected by age or straw length. Aggressive behaviour was infrequent, but lasted about twice as long in pens with chopped straw (2.3 s/pig per hour at 40 kg) compared with pens with long straw (1.0 s/pig per hour at 40 kg, P=0.060). There were no significant effects of straw length on tail or ear lesions, but shoulders were significantly more likely to have minor scratches with chopped straw (P=0.031), which may reflect the higher levels of aggression. Smaller pigs showed more rooting/investigatory behaviour, and in particular directed towards the straw/solid floor and the slatted floor than their larger pen-mates. Females exhibited more straw and pen fixture-directed behaviour than males. There were no effects of pig size or sex on behaviour directed towards other pigs. In summary, pigs spent similar amounts of time interacting with straw/solid floor when long and chopped straw were provided, and most aspects of pig-directed behaviour and injuries were not affected by straw length. There was an increase in pigs with minor shoulder lesions with chopped straw, perhaps because of increased aggression. The use of chopped straw as an enrichment material for pigs warrants further investigation in larger and more detailed studies. PMID- 25496523 TI - The Role of Parental ADHD in Sustaining the Effects of a Family-School Intervention for ADHD. AB - This study investigated the extent to which parental Attention Deficit/Hyperactivity Disorder (ADHD) symptoms impact child and parent outcomes following a multimodal family-school intervention, the Family School Success (FSS) program, when compared to an active-control condition (CARE). Participants were 139 children with ADHD (67% male; 91% non-Hispanic; 77% Caucasian; Grades 2 6) and their primary caretaker (91% female; ages 26-59) who participated in a randomized clinical trial evaluating the efficacy of FSS. Associations were examined between parent-reported ADHD symptoms at baseline and intervention outcomes reported by parents and teachers after treatment and at a 3-month follow up, including child homework and classroom impairments, child ADHD and oppositional defiant disorder symptoms, parenting behaviors, and parent-teacher relationship quality. Across both treatment conditions, parental ADHD was not associated with parent or child outcomes at postassessment. However, differences emerged between the two treatment groups at follow-up for parents with ADHD, particularly when an empirically supported symptom cutoff was used to identify parents at risk for having ADHD. In FSS, but not in CARE, parental ADHD was associated with declines in treatment gains in the quality of the parent-teacher relationship and the child's homework performance. Parents at risk for ADHD had difficulty maintaining treatment effects for themselves and their child in the FSS intervention but not in CARE. The supportive and educational components central to the CARE intervention may be helpful in promoting the sustainability of psychosocial interventions for children with ADHD who have parents with elevated ADHD symptoms. PMID- 25496525 TI - The role of transperineal template biopsies of the prostate in the diagnosis of prostate cancer: a review. AB - The incidence of prostate cancer has shown a significant increase, highlighting the importance of early diagnosis. Current practice considers histological diagnosis a necessity in the majority of the cases. The limitations of transrectal biopsies led to the development of the promising transperineal prostatic biopsies. The latter offers a safer approach by avoiding the rectum, utilizing brachytherapy template grid to detect anterior zone disease and provides accurate prostatic mapping by systematically sampling the whole gland. It also helps to direct biopsies based on images obtained from previous prostate scanning and identify those eligible for focal therapy to direct focal treatment accurately. The current literature provides enough reassurance that transperineal template biopsies are effective, efficient and superior to the traditional and inaccurate transrectal biopsies. The absence of consensus on the technical aspect of template biopsies is a drawback, yet it highlights the need to develop robust guidelines to standardize the procedure. PMID- 25496526 TI - Nasal-type extranodal natural killer/T-cell lymphoma presenting as a solitary non healing lower leg ulcer. AB - Nasal-type extranodal natural killer/T-cell lymphoma (ENTCL) is an aggressive form of non-Hodgkin's lymphoma with a poor prognosis. Primary cutaneous lesions of ENTCL usually present as nodules or infiltrative plaques. The presentation of ENTCL as a solitary ulcer, in the absence of other cutaneous lesions and systemic symptoms and signs, is extremely rare and may be easily misdiagnosed. In this report, we describe an unusual case of ENTCL with a diagnostically challenging clinical presentation as a solitary non-healing leg ulcer in an elderly woman. PMID- 25496524 TI - How SLX4 cuts through the mystery of HIV-1 Vpr-mediated cell cycle arrest. AB - Vpr is one of the most enigmatic viral auxiliary proteins of HIV. During the past twenty years, several activities have been ascribed to this viral protein, but one, its ability to mediate cell cycle arrest at the G2 to M transition has been the most extensively studied. Nonetheless, the genuine role of Vpr and its pathophysiological relevance in the viral life cycle have remained mysterious. Recent work by Laguette et al. (Cell 156:134-145, 2014) provides important insight into the molecular mechanism of Vpr-mediated G2 arrest. This study highlights for the first time how Vpr recruits the SLX4 endonuclease complex and how Vpr-induced inappropriate activation of this complex leads to G2 arrest. Here, we will discuss these findings in the light of previous work to show how they change the view of Vpr's mechanism of action. We will also discuss how these findings open new questions towards the understanding of the biological function of Vpr regarding innate immune sensing. PMID- 25496527 TI - Inhibitory control and moral emotions: relations to reparation in early and middle childhood. AB - This study examined links between inhibitory control, moral emotions (sympathy and guilt), and reparative behavior in an ethnically diverse sample of 4- and 8 year-olds (N = 162). Caregivers reported their children's reparative behavior, inhibitory control, and moral emotions through a questionnaire, and children reported their guilt feelings in response to a series of vignettes depicting moral transgressions. A hypothesized meditation model was tested with inhibitory control relating to reparative behavior through sympathy and guilt. In support of this model, results revealed that high levels of inhibitory control were associated with high levels of reparative behavior through high levels of sympathy and guilt. However, the mediation of inhibitory control to reparation through guilt was significant for 4-year-olds only. Results are discussed in relation to the temperamental, regulatory, and affective-moral precursors of reparative behavior in early and middle childhood. PMID- 25496528 TI - Children's moral emotions, narratives, and aggression: relations with maternal discipline and support. AB - Children who attribute more positive emotions to hypothetical moral victimizers are typically more aggressive and have more behavior problems. Little is known, however, about when individual differences in these moral emotion attributions first emerge or about maternal correlates of these differences. In this study, 63 4-6-year-olds judged how they would feel after victimizing peers for gain and enacted event conclusions using narrative methods adapted from the MacArthur Story Stem Battery. In addition, children's mothers completed assessments of their disciplinary styles and social support, and children's aggressive tendencies were assessed based on ratings from mothers and a second familiar adult. Results revealed that most preschoolers expected to feel happy after their victimizing acts, but variations in happy victimization were unrelated to children's aggression. Several of children's narrative themes, including making amends (e.g., apologizing, reparations), aggressive acts, and mentions of death/killing, however, were related to children's aggression. Moreover, two maternal disciplinary dimensions, higher warmth and reasoning, as well as greater social support were also related to lower child aggression. Children's emotion attributions and moral narratives, however, were unrelated to maternal disciplinary practices or social support. PMID- 25496529 TI - Knowledge of memory aging across the lifespan. AB - The authors examined knowledge of normal and pathological memory aging in a lifespan sample of 198 individuals who ranged in age from 13 to 88 years. Participants completed the Knowledge of Memory Aging Questionnaire (Cherry, Brigman, Hawley, & Reese, 2003). The authors hypothesized that high school students would be less knowledgeable about memory aging issues than college students, middle-aged, and community-dwelling older adults. Consistent with this hypothesis, response accuracy was lower for high school students compared to their older counterparts. Follow-up analyses revealed that high school students' responses to a subset of questions that tap ageist views of adult cognition were less accurate than the other age groups, implying a response bias toward stereotypical images of memory aging. Implications for research and the design of instructional materials to increase people's knowledge about normative changes in adult cognition are discussed. PMID- 25496531 TI - Comparative analysis of EPA and DHA in fish oil nutritional capsules by GC-MS. AB - BACKGROUND: Fish oil is a popular nutritional product consumed in Hong Kong. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the two main bioactive components responsible for the health benefits of fish oil. Market survey in Hong Kong demonstrated that various fish oil capsules with different origins and prices are sold simultaneously. However, these capsules are labelled with same ingredient levels, namely EPA 180 mg/g and DHA 120 mg/g. This situation makes the consumers very confused. To evaluate the quality of various fish oil capsules, a comparative analysis of the contents of EPA and DHA in fish oil is crucial. METHODS: A gas chromatography-mass spectrometry (GC-MS) method was developed for identification and determination of EPA and DHA in fish oil capsules. A comprehensive validation of the developed method was conducted. Ten batches of fish oil capsules samples purchased from drugstores of Hong Kong were analyzed by using the developed method. RESULTS: The present method presented good sensitivity, precision and accuracy. The limits of detection (LOD) for EPA and DHA were 0.08 ng and 0.21 ng, respectively. The relative standard deviation (RSD) values of EPA and DHA for repeatability tests were both less than 1.05%; and the recovery for accuracy test of EPA and DHA were 100.50% and 103.83%, respectively. In ten fish oil samples, the contents of EPA ranged from 39.52 mg/g to 509.16 mg/g, and the contents of DHA ranged from 35.14 mg/g to 645.70 mg/g. CONCLUSION: The present method is suitable for the quantitative analysis of EPA and DHA in fish oil capsules. There is a significant variation in the contents of the quantified components in fish oil samples, and there is not a linear relationship between price and contents of EPA and DHA. Strict supervision of the labelling of the fish oil capsules is urgently needed. PMID- 25496532 TI - The global burden of headache in children and adolescents - developing a questionnaire and methodology for a global study. AB - BACKGROUND: Burden of headache has been assessed in adults in countries worldwide, and is high, but data for children and adolescents are sparse. The objectives of this study were o develop a questionnaire and methodology for the global estimation of burden of headache in children and adolescents, to test these in use and to present preliminary data. METHODS: We designed structured questionnaires for mediated-group self-administration in schools by children aged 6-11 years and adolescents aged 12-17 years. In two pilot studies, we offered the questionnaires to pupils in Vienna and Istanbul. We performed face-to-face interviews in a randomly selected subsample of 199 pupils to validate the headache diagnostic questions. RESULTS: Data were collected from 1,202 pupils (mean 13.9 +/- 2.4 years; 621 female, 581 male). The participation rate was 81.1% in Istanbul, 67.2% in Vienna. The questionnaire proved acceptable: <=5% of participants disagreed partially or totally with its length, comprehensibility or simplicity. The sensitivity, specificity, positive and negative predictive values ranged between 0.71 and 0.76 for migraine and between 0.61 and 0.85 for tension type headache (TTH). Cronbach's alpha was 0.83. The 1-year prevalence of headache was 89.3%, of migraine 39.3% and of TTH 37.9%. The prevalence of headache on >=15 days/month was 4.5%. One fifth (20.7%) of pupils with headache lost >=1 day of school during the preceding 4 weeks and nearly half (48.8%) reported >=1 day when they could not do activities they had wanted to. The vast majority of pupils with headache experienced difficulties in coping with headache and in concentrating during headache. Quality of life was poorer in pupils with headache than in those without. CONCLUSION: These pilot studies demonstrate the usefulness of the questionnaires and feasibility of the methodology for assessing the global burden of headache in children and adolescents, and predict substantial impact of headache in these age groups. PMID- 25496533 TI - Is Wnt5a overexpression sufficient for generating a psoriasis-like phenotype in transgenic mice? PMID- 25496534 TI - Experimental infection of a periodical cicada (Magicicada cassinii) with a parasitoid (Emblemasoma auditrix) of a proto-periodical cicada (Okanagana rimosa). AB - BACKGROUND: The proto-periodical cicada Okanagana rimosa is subject to infection by the acoustically orientating parasitoid fly Emblemasoma auditrix. Furthermore, it is also the only known host of E. auditrix. Here we test the question, whether the highly adapted parasitoid can also infect other cicadas, like the periodical cicada (Magicicada cassinii) and which steps of the parasitization process can be completed. The experiments might also reveal whether such a parasitoid could hypothetically have been involved in the evolution of periodicity. RESULTS: The hearing threshold of E. auditrix matches with the spectrum of the calling song of M. cassinii, indicating potential host localization. Behaviourally, host localization is possible by the parasitoid as it approaches a loudspeaker broadcasting the buzz part of the calling song of M. cassinii. Magicicada cassinii is readily accepted as host and for host infection the parasitoid uses the same behavioural sequence as for its host O. rimosa. A larva is deposited into the timbal of the cicada. By contrast to O. rimosa the development of the fly larva is delayed and eventually suppressed in M. cassinii. CONCLUSIONS: The host range of E. auditrix is mainly determined by acoustic parameters. This filter is important, as other sensory cues seem not to be involved in the host selection process and larva will not develop in unsuited host. Although the recent parasitoid-host system seems to be stable in terms of coexistence of both species, an acoustically hunting parasitoid could have been a selective force during evolution of prime numbered periodicity in cicadas. PMID- 25496536 TI - Caparinia tripilis in African hedgehog (Atelerix albiventris). PMID- 25496535 TI - Investigating the biological response of human mesenchymal stem cells to titanium surfaces. AB - BACKGROUND: We have investigated the behaviour of a newly characterised population of haemarthrosis fluid-derived human mesenchymal stem cells (HF-hMSCs) with titanium (Ti) surfaces. METHODS: HF-hMSCs were seeded onto round cannulated interference (RCI; Smith and Nephew) screws or control Ti discs and cultured under pro-osteogenic conditions. RESULTS: Electron microscopy showed the attachment and spreading of HF-hMSCs across both Ti surfaces during the early stages of osteogenic culture; however, cells were exclusively localised to the basal regions within the vertex of the Ti screws. In the later stages of culture, an osteoid matrix was deposited on the Ti surfaces with progressive culture expansion and matrix deposition up the sides and the top of the Ti Screws. Quantification of cellular content revealed a significantly higher number of cells within the Ti screw cultures; however, there was no difference in the cellular health. Conversely, alizarin red staining used as both a qualitative and quantitative measure of matrix calcification was significantly increased in Ti disc cultures compared to those of Ti screws. CONCLUSIONS: Our results suggest that the gross topography of the metal implant is able to create microenvironment niches that have an influence on cellular behaviour. These results have implications for the design of advanced tissue engineering strategies that seek to use cellular material to enhance biological remodelling and healing following tissue reconstruction. PMID- 25496537 TI - A Thailand case study based on quantitative assessment: does a national lead agency make a difference in pre-hospital care development in middle income countries? AB - BACKGROUND: Emergency Medical Institute of Thailand (EMIT) has been established as a national lead agency to improve emergency medical service systems since December 2008. However up to now, there has not been any published systematic assessment of its performance to guide further policy decisions. METHODS: This study assesses the 4-year pre-hospital care coverage and performance in Thailand after EMIT establishment. The assessment makes use of 1,171,564 records from a national data set for pre-hospital care i.e., Information Technology for Emergency Medical Service System (ITEMS) in 2012. RESULTS: Comparing with historical data, we found evidence indicating the national lead agency making differences in two basic requirements of pre-hospital care i.e., the coverage was increased by at least 1.4 times higher than the majority reported figures among 11 out of the total 13 regions of the country at baseline; and mean total response time for critical-coded patients, the longest in our study, is 1.6 times shorter than previously reported figure in 2008 (48.46 minutes). Analysis of the national data set also revealed quite substantial missing values indicating a need for further improvement. When historical data was not available, we compared our findings with international figures. Over triage rate of 28.4% for advanced life support (ALS) ambulance was found which is roughly a third of that reported in Taiwan. Almost all patients were stabilized and/or treated regardless of being transferred to hospitals in contrast to the scenarios in the U.S. systems which may probably be due to different payment mechanism. Relying on circumstantial evidences, we identified probable stagnation in pre-hospital care coverage for patients visiting emergency department after the establishment of the lead agency. CONCLUSIONS: This national data assessment shows progression in certain basic pre-hospital care requirements in Thailand. However, it needs regular systematic evaluation and there is still room for improvement of pre-hospital care systems such as increasing coverage, more equitable distribution of the coverage, faster response times, especially for patients with critical code, information system, cost-effectiveness study as well as further specific qualitative researches to guide further development of policy and intervention. PMID- 25496538 TI - High-efficiency BODIPY-based organic photovoltaics. AB - A benzannulated boron dipyrromethene (BODIPY, bDIP) molecule exhibiting strong absorption at 640 nm was synthesized. The organic dye was used in an organic solar cell as the electron donor with C60 as the acceptor. The BODIPY dye demonstrated the best performance in lamellar architecture (indium tin oxide (ITO)/bDIP/C60/bathocuproine/Al), giving power conversion efficiency up to 4.5% with short-circuit current (JSC) of 8.7 mA/cm(2) and an open-circuit voltage (VOC) of 0.81 V. Neutron reflectivity experiments were performed on the bilayer film to investigate the thickness dependence of JSC. A 13 nm mixed layer was found to be present at the donor/acceptor interface in the bilayer device, formed when the C60 was deposited onto a room temperature bDIP film. Planar-mixed heterojunction devices were fabricated to understand the extent of spontaneous mixing between the donor and acceptor materials. The native mixed region in the bilayer device was shown to most resemble 1:3 bDIP:C60 layer in the structure: (ITO/bDIP/bDIP:C60 blend/C60/bathocuproine/Al). PMID- 25496539 TI - Severe tricuspid valve regurgitation is not an innocent finding to be ignored! PMID- 25496540 TI - LGE patterns in pulmonary hypertension do not impact overall mortality. AB - OBJECTIVES: The goal of this study was to determine the prognostic value of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) features in patients with pulmonary hypertension. BACKGROUND: The prognostic significance of LGE in the clinical assessment of patients with pulmonary hypertension remains uncertain. METHODS: Consecutive patients with suspected pulmonary hypertension seen at a specialist pulmonary hypertension referral center who underwent right heart catheterization and CMR with LGE imaging within 48 h were identified. Short axis late-enhancement imaging was performed using a 3-dimensional gradient spoiled echocardiography sequence on a 1.5-T scanner. Three groups were identified: 1) no late enhancement of the myocardium; 2) late enhancement at the right ventricular insertion points (LGE-IP); and 3) late enhancement involving the right ventricular insertion points and the interventricular septum (LGE-S). RESULTS: Of 194 patients, 162 had pulmonary hypertension. LGE was identified in 135 of 162 (83%) patients with pulmonary hypertension, and 47 (29%) of patients demonstrated LGE-S. Patients with LGE-S had significantly higher right ventricular end-diastolic volume index (p = 0.013) and lower mixed venous oxygen saturation (p = 0.045) than patients with LGE-IP alone. The presence of LGE-S (p = 0.022), but not LGE-IP alone, right ventricular end-systolic volume (p = 0.045), right ventricular ejection fraction (p = 0.034), mixed venous oxygen saturation (p = 0.021), mean right atrial pressure (0.027), and male sex (p = 0.002) predicted mortality. At multivariate analysis, male sex was the only significant predictor of mortality independent of covariate predictors (p = 0.027). CONCLUSIONS: The presence of LGE at the right ventricular insertion points is suggestive of the presence of pulmonary hypertension. LGE may also be more extensive, involving the septum; however, after multivariable analysis including other factors associated with pulmonary hypertension, septal LGE was not associated with an increase in overall mortality. PMID- 25496542 TI - Separating the VAT from the FAT: new insights into the cardiometabolic risks of obesity. PMID- 25496541 TI - Prediction of prognosis in pulmonary hypertension using CMR: what happens where the right and left ventricles meet? PMID- 25496543 TI - Examining Achilles' heel: improving response rates with cardiac resynchronization therapy. PMID- 25496544 TI - The left atrial appendage: anatomy, function, and noninvasive evaluation. AB - The left atrial appendage (LAA) is a finger-like extension originating from the main body of the left atrium. Atrial fibrillation (AF) is the most common clinically important cardiac arrhythmia, occurring in approximately 0.4% to 1% of the general population and increasing with age to >8% in those >80 years of age. In the presence of AF thrombus, formation often occurs within the LAA because of reduced contractility and stasis; thus, attention should be given to the LAA when evaluating and assessing patients with AF to determine the risk for cardioembolic complications. It is clinically important to understand LAA anatomy and function. It is also critical to choose the optimal imaging techniques to identify or exclude LAA thrombi in the setting of AF, before cardioversion, and with current and emerging transcatheter therapies, which include mitral balloon valvuloplasty, pulmonary vein isolation, MitraClip (Abbott Laboratories, Abbott Park, Illinois) valve repair, and the implantation of LAA occlusion and exclusion devices. In this review, we present the current data regarding LAA anatomy, LAA function, and LAA imaging using the currently available noninvasive imaging modalities. PMID- 25496545 TI - Adult left ventricular noncompaction: reappraisal of current diagnostic imaging modalities. AB - Left ventricular noncompaction (LVNC) cardiomyopathy is morphologically characterized by prominent myocardial trabeculations and deep recesses. The precise stage of development and the natural history of the disorder are not fully understood. Studies in heart failure patients demonstrate a high prevalence of myocardial trabeculations, raising the potential diagnosis of LVNC. Given the high prevalence compared with other primary cardiomyopathies, it is unclear whether the myocardial morphology is representative of LVNC or merely epiphenomena associated with increased cardiac pre-load. Imaging modalities including echocardiography and cardiac magnetic resonance imaging facilitate identification and assessment for LVNC; however, current diagnostic criteria are based on small cohorts and are liable to result in an overdiagnosis of LVNC. This review re-evaluates current diagnostic criteria and their potential impact on overdiagnosis of LVNC in low-risk populations. PMID- 25496546 TI - Applications of cardiac CT in the tetralogy of Fallot patient. PMID- 25496547 TI - Incremental prognostic value of estimated LV end-diastolic volume by cardiac CT. PMID- 25496548 TI - Cardiopulmonary changes in healthy children residing at high altitude in China. PMID- 25496549 TI - 3D image reconstruction of histopathological structure of atherosclerotic plaque using a novel technique with film tomography. PMID- 25496550 TI - Tricuspid regurgitation severity associated with positioning of RV lead or other etiology assessed by intracardiac echocardiography. PMID- 25496551 TI - Reply: Tricuspid regurgitation severity associated with positioning of RV lead or other etiology assessed by intracardiac echocardiography. PMID- 25496552 TI - Imaging findings in aortic intramural hematoma. PMID- 25496553 TI - Finding the sweet spot for CRT. PMID- 25496554 TI - Environmental heterogeneity generates opposite gene-by-environment interactions for two fitness-related traits within a population. AB - Theory predicts that environmental heterogeneity offers a potential solution to the maintenance of genetic variation within populations, but empirical evidence remains sparse. The live-bearing fish Xiphophorus variatus exhibits polymorphism at a single locus, with different alleles resulting in up to five distinct melanistic "tailspot" patterns within populations. We investigated the effects of heterogeneity in two ubiquitous environmental variables (temperature and food availability) on two fitness-related traits (upper thermal limits and body condition) in two different tailspot types (wild-type and upper cut crescent). We found gene-by-environment (G * E) interactions between tailspot type and food level affecting upper thermal limits (UTL), as well as between tailspot type and thermal environment affecting body condition. Exploring mechanistic bases underlying these G * E patterns, we found no differences between tailspot types in hsp70 gene expression despite significant overall increases in expression under both thermal and food stress. Similarly, there was no difference in routine metabolic rates between the tailspot types. The reversal of relative performance of the two tailspot types under different environmental conditions revealed a mechanism by which environmental heterogeneity can balance polymorphism within populations through selection on different fitness-related traits. PMID- 25496555 TI - Cost-effective strategies for rural community outreach, Hawaii, 2010-2011. AB - Three strategies designed to maximize attendance at educational sessions on chronic disease medication safety in older adults in rural areas were implemented sequentially and compared for cost-effectiveness: 1) existing community groups and events, 2) formal advertisement, and 3) employer-based outreach. Cost effectiveness was measured by comparing overall cost per attendee recruited and number of attendees per event. The overall cost per attendee was substantially higher for the formal advertising strategy, which produced the lowest number of attendees per event. Leveraging existing community events and employers in rural areas was more cost-effective than formal advertisement for recruiting rural community members. PMID- 25496556 TI - Prevalence of sleep duration on an average school night among 4 nationally representative successive samples of American high school students, 2007-2013. AB - Consistency, quality, and duration of sleep are important determinants of health. We describe sleep patterns among demographically defined subgroups from the Youth Risk Behavior Surveillance System reported in 4 successive biennial representative samples of American high school students (2007 to 2013). Across the 4 waves of data collection, 6.2% to 7.7% of females and 8.0% to 9.4% of males reported obtaining 9 or more hours of sleep. Insufficient duration of sleep is pervasive among American high school students. Despite substantive public health implications, intervention research on this topic has received little attention. PMID- 25496558 TI - The role of fear and disgust in predicting the effectiveness of television advertisements that graphically depict the health harms of smoking. AB - INTRODUCTION: Antismoking television advertisements that depict the graphic health harms of smoking are increasingly considered best practices, as exemplified by the Centers for Disease Control and Prevention's current national campaign. Evaluation of responses to these widely used advertisements is important to determine advertisements that are most effective and their mechanisms of action. Our study tested the hypothesis that advertisements rated highest in fear- and disgust-eliciting imagery would be rated as the most effective. METHODS: Our laboratory study included 144 women and men aged 18 to 33; 84% were current nonsmokers. All participants viewed 6 antismoking television advertisements that depicted the health harms of smoking; they rated their responses of fear and disgust and the effectiveness of the advertisements. We used multilevel modeling to test the effects of the following in predicting effectiveness: fear, disgust, the fear-disgust interaction, the advertisement, and the participant's sex and smoking status. Follow-up analyses examined differences in ratings of fear, disgust, and effectiveness. RESULTS: Advertisement, fear, disgust, and the fear-disgust interaction were each significant predictors of effectiveness. Smoking status and sex were not significant predictors. The 3 advertisements that elicited the highest ratings of fear and disgust were rated the most effective. CONCLUSION: Our findings support the hypothesis that antismoking advertisements of health harms that elicit the greatest responses of fear or disgust are the most effective. When advertisements elicit high ratings of both fear and disgust, advertisements with graphic imagery are effective, whereas advertisements without graphic imagery are not. PMID- 25496557 TI - Engaging traditional medicine providers in colorectal cancer screening education in a chinese american community: a pilot study. AB - INTRODUCTION: Although colorectal cancer (CRC) screening is effective in preventing colon cancer, it remains underused by Asian Americans. Because Chinese Americans often use traditional Chinese medicine (TCM), we conducted a pilot study to explore the feasibility and acceptability of having TCM providers deliver education about CRC screening. METHODS: Four TCM providers (2 herbalists and 2 acupuncturists) were trained to deliver small-group educational sessions to promote CRC screening. Each provider recruited 15 participants aged 50 to 75. Participants completed a baseline survey on CRC-related knowledge, attitudes, and behaviors and then attended one 2-hour educational session delivered by the providers in Cantonese or Mandarin. Three months later, participants completed a postintervention survey. RESULTS: Sixty participants were recruited from the San Francisco Chinatown neighborhood. The average age was 62.4 years. Most participants had limited English proficiency (96.7%), annual household income less than $20,000 per year (60%), and low educational attainment (65.1% < high school education). At postintervention (n = 57), significant increases were found in having heard of CRC (from 52.6% to 79.0%, P < .001) and colon polyps (from 64.9% to 84.2%, P < .001). Knowledge regarding screening frequency recommendations also increased significantly. The rate of ever having received any CRC screening test increased from 71.9% to 82.5% (P <.001). The rate of up-to date screening increased from 70.2% to 79.0% (P = .04). CONCLUSION: The findings suggest that TCM providers can be trained to deliver culturally and linguistically appropriate outreach on CRC screening within their community. Participants reached by TCM providers increased CRC knowledge and self-reported CRC screening. PMID- 25496559 TI - Rituximab therapy in pemphigus foliaceus: report of 12 cases and review of recent literature. PMID- 25496560 TI - The effects of Cordyceps sinensis phytoestrogen on estrogen deficiency-induced osteoporosis in ovariectomized rats. AB - BACKGROUND: Isoflavones are naturally occurring plant chemicals belonging to the "phytoestrogen" class. The aim of the present study was to examine the effects of isoflavones obtained from Cordyceps sinensis (CSIF) on development of estrogen deficiency-induced osteoporosis in ovariectomized rats. METHODS: After the rats were treated orally with CSIF, serum alkaline phosphatase (ALP), tartarate resistant acid phosphatase (TRAP), serum osteocalcin (OC), homocysteine (HCY), C terminal crosslinked telopeptides of collagen type I (CTX), estradiol and interferongamma (IFN-gamma) level were examined. At the same time, the urine calcium, plasma calcium, plasma phosphorus and the mass of uterus, thymus and body were also examined. RESULTS: The beneficial effects of CSIF on improvement of osteoporosis in rats were attributable mainly to decrease ALP activity, TRAP activity, CTX level and IFN-gamma level. At the same time, CSIF also increase the OC and estradiol level in ovariectomized osteopenic rats. The histological examination clearly showed that dietary CSIF can prevent bone loss caused by estrogen deficiency. CONCLUSION: The significant estrogenic activity of CSIF demonstrated that CSIF has significant estrogenic effects in OVX rats. PMID- 25496561 TI - Impacts of genetic correlation on the independent evolution of body mass and skeletal size in mammals. AB - BACKGROUND: Mammals show a predictable scaling relationship between limb bone size and body mass. This relationship has a genetic basis which likely evolved via natural selection, but it is unclear how much the genetic correlation between these traits in turn impacts their capacity to evolve independently. We selectively bred laboratory mice for increases in tibia length independent of body mass, to test the hypothesis that a genetic correlation with body mass constrains evolutionary change in tibia length. RESULTS: Over 14 generations, we produced mean tibia length increases of 9-13%, while mean body mass was unchanged, in selectively bred mice and random-bred controls. Using evolutionary scenarios with different selection and quantitative genetic parameters, we also found that this genetic correlation impedes the rate of evolutionary change in both traits, slowing increases in tibia length while preventing decreases in body mass, despite the latter's negative effect on fitness. CONCLUSIONS: Overall, results from this ongoing selection experiment suggest that parallel evolution of relatively longer hind limbs among rodents, for example in the context of strong competition for resources and niche partitioning in heterogeneous environments, may have occurred very rapidly on geological timescales, in spite of a moderately strong genetic correlation between tibia length and body mass. PMID- 25496562 TI - Factors explaining priority setting at community mental health centres: a quantitative analysis of referral assessments. AB - BACKGROUND: Clinicians at Norwegian community mental health centres assess referrals from general practitioners and classify them into three priority groups (high priority, low priority, and refusal) according to need where need is defined by three prioritization criteria (severity, effect, and cost effectiveness). In this study, we seek to operationalize the three criteria and analyze to what extent they have an effect on clinical-level priority setting after controlling for clinician characteristics and organisational factors. METHODS: Twenty anonymous referrals were rated by 42 admission team members employed at 14 community mental health centres in the South-East Health Region of Norway. Intra-class correlation coefficients were calculated and logistic regressions were performed. RESULTS: Variation in clinicians' assessments of the three criteria was highest for effect and cost-effectiveness. An ordered logistic regression model showed that all three criteria for prioritization, three clinician characteristics (education, being a manager or not, and "guideline awareness"), and the centres themselves (fixed effects), explained priority decisions. The relative importance of the explanatory factors, however, depended on the priority decision studied. For the classification of all admitted patients into high- and low-priority groups, all clinician characteristics became insignificant. For the classification of patients, into those admitted and non admitted, one criterion (effect) and "being a manager or not" became insignificant, while profession ("being a psychiatrist") became significant. CONCLUSIONS: Our findings suggest that variation in priority decisions can be reduced by: (i) reducing the disagreement in clinicians' assessments of cost effectiveness and effect, and (ii) restricting priority decisions to clinicians with a similar background (education, being a manager or not, and "guideline awareness"). PMID- 25496563 TI - Iron nanoparticle-induced activation of plasma membrane H(+)-ATPase promotes stomatal opening in Arabidopsis thaliana. AB - Engineered nanomaterials (ENMs) enable the control and exploration of intermolecular interactions inside microscopic systems, but the potential environmental impacts of their inevitable release remain largely unknown. Plants exposed to ENMs display effects, such as increase in biomass and chlorophyll, distinct from those induced by exposure to their bulk counterparts, but few studies have addressed the mechanisms underlying such physiological results. The current investigation found that exposure of Arabidopsis thaliana to nano zerovalent iron (nZVI) triggered high plasma membrane H(+)-ATPase activity. The increase in activity caused a decrease in apoplastic pH, an increase in leaf area, and also wider stomatal aperture. Analysis of gene expression indicated that the levels of the H(+)-ATPase isoform responsible for stomatal opening, AHA2, were 5-fold higher in plants exposed to nZVI than in unexposed control plants. This is the first study to show that nZVI enhances stomatal opening by inducing the activation of plasma membrane H(+)-ATPase, leading to the possibility of increased CO2 uptake. PMID- 25496565 TI - Reinvestigation of the stereochemistry of the C-glycosidic ellagitannins, vescalagin and castalagin. AB - The stereochemistry of the C-glycosidic ellagitannins, vescalagin and castalagin, has been reinvestigated using computational methods. DFT calculations of their (1)H and (13)C NMR spectra, as well as TDDFT calculations of the ECD spectra of their des-hexahydroxydiphenoyl analogues, revealed that the structure of the triphenoyl moiety of vescalagin and castalagin should be revised. PMID- 25496564 TI - Association between dietary calcium and phosphorus intakes, dietary calcium/phosphorus ratio and bone mass in the Korean population. AB - BACKGROUND: Osteoporosis has become a major public health issue. Among various factors affected bone health, not only dietary calcium and phosphorus intakes, but also the dietary calcium/phosphorus ratio could relate to bone health. Therefore, we evaluated whether dietary calcium and phosphorus intakes, and dietary calcium/phosphorus ratio are associated with bone mass in Korean adults >= 20 years of age. METHODS: The analysis used data from the Korean National Health and Nutrition Examination Survey, a cross-sectional survey of Korean civilians, conducted from January to December 2010. A total of 4,935 participants (2,309 men and 2,626 women) were analyzed in this study. Dietary calcium and phosphorus intakes of the participants were estimated using 24-h dietary recall. Bone mass densities for the whole body, femoral neck, and lumbar spine were measured by dual-energy X-ray absorptiometry. RESULTS: Dietary calcium intake and dietary calcium/phosphorus ratio were positively related to bone mass density for femoral neck in men >= 50 years of age (p = 0.046 and 0.041, respectively). Dietary calcium intake showed positive associations with bone mass density for whole body in premenopausal women (p = 0.022). CONCLUSIONS: Increased calcium intake and high dietary calcium/phosphorus ratio might have favorable effects on bone mass in Korean adults. Additional gender- and age-specific studies are needed to further identify the influence of calcium and phosphorus intakes, and the dietary calcium/phosphorus ratio on bone mass. PMID- 25496566 TI - Changes in protein expression across laboratory and field experiments in Geobacter bemidjiensis. AB - Bacterial extracellular metal respiration, as carried out by members of the genus Geobacter, is of interest for applications including microbial fuel cells and bioremediation. Geobacter bemidjiensis is the major species whose growth is stimulated during groundwater amendment with acetate. We have carried out label free proteomics studies of G. bemidjiensis grown with acetate as the electron donor and either fumarate, ferric citrate, or one of two hydrous ferric oxide mineral types as electron acceptor. The major class of proteins whose expression changes across these conditions is c-type cytochromes, many of which are known to be involved in extracellular metal reduction in other, better-characterized Geobacter species. Some proteins with multiple homologues in G. bemidjiensis (OmcS, OmcB) had different expression patterns than observed for their G. sulfurreducens homologues under similar growth conditions. We also compared the proteome from our study to a prior proteomics study of biomass recovered from an aquifer in Colorado, where the microbial community was dominated by strains closely related to G. bemidjiensis. We detected an increased number of proteins with functions related to motility and chemotaxis in the Colorado field samples compared to the laboratory samples, suggesting the importance of motility for in situ extracellular metal respiration. PMID- 25496567 TI - Supramolecular solubilization of cyclodextrin-modified carbon nano-onions by host guest interactions. AB - Small carbon nano-onions (CNOs, 6-12 shells) were prepared in high yields and functionalized with carboxylic groups by chemical oxidation and reacted with betaCD-NH2 to yield CNOs decorated with betaCDs. A biocompatibile dextran polymer with graphted ferrocene groups was employed for the supramolecular self-assembly on the betaCD-CNO surfaces. The betaCDs act as hosts and the polymer ferrocene groups as guests (Fc-Dex) by the formation of inclusion complexes. After their assembly these nanostructures were soluble in aqueous solutions. The resulting product was characterized by transmission electron microscopy (TEM), thermogravimetric analysis (TGA), and FT-IR and Raman spectroscopies. Moreover, the deposition of successive layers on the surface of the particles was monitored using DLS measurements and zeta potentials. Through-space interactions between the Fc moieties and the CNO cores and the influence of an additional dextran betaCD outer layer were measured electrochemically. PMID- 25496568 TI - Connexin43 enhances the expression of osteoarthritis-associated genes in synovial fibroblasts in culture. AB - BACKGROUND: Recent work has shown that the gap junction protein connexin43 (Cx43) is upregulated in cells of the joint during osteoarthritis (OA). Here we examined if the OA-associated increase in Cx43 expression impacts the function of synovial fibroblasts by contributing to the production of catabolic and inflammatory factors that exacerbate joint destruction in arthritic disease. METHODS: Using rabbit and human synovial fibroblast cell lines, we examined the effects of Cx43 overexpression and Cx43 siRNA-mediated knockdown on the gene expression of OA associated matrix metalloproteinases (MMP1 and MMP13), aggrecanases (ADAMTS4 and ADAMTS5), and inflammatory factors (IL1, IL6 and PTGS2) by quantitative real time RT-PCR. We examined collagenase activity in conditioned media of cultured synovial cells following Cx43 overexpression. Lastly, we assessed the interplay between Cx43 and the NFkappaB cascade by western blotting and gene expression studies. RESULTS: Increasing Cx43 expression enhanced the gene expression of MMP1, MMP13, ADAMTS4, ADAMTS5, IL1, IL6 and PTGS2 and increased the secretion of collagenases into conditioned media of cultured synovial fibroblasts. Conversely, knockdown of Cx43 decreased expression of many of these catabolic and inflammatory genes. Modulation of Cx43 expression altered the phosphorylation of the NFkappaB subunit, p65, and inhibition of NFkappaB with chemical inhibitors blocked the effects of increased Cx43 expression on the mRNA levels of a subset of these catabolic and inflammatory genes. CONCLUSIONS: Increasing or decreasing Cx43 expression alone was sufficient to alter the levels of catabolic and inflammatory genes expressed by synovial cells. The NFkappaB cascade mediated the effect of Cx43 on the expression of a subset of these OA-associated genes. As such, Cx43 may be involved in joint pathology during OA, and targeting Cx43 expression or function may be a viable therapeutic strategy to attenuate the catabolic and inflammatory environment of the joint during OA. PMID- 25496569 TI - Socio-demographic, behavioural and cognitive correlates of work-related sitting time in German men and women. AB - BACKGROUND: Sitting time is ubiquitous for most adults in developed countries and is most prevalent in three domains: in the workplace, during transport and during leisure time. The correlates of prolonged sitting time in workplace settings are not well understood. Therefore, the aim of this study was to examine the gender specific associations between the socio-demographic, behavioural and cognitive correlates of work-related sitting time. METHODS: A cross-sectional sample of working German adults (n = 1515; 747 men; 43.5 +/- 11.0 years) completed questionnaires regarding domain-specific sitting times and physical activity (PA) and answered statements concerning beliefs about sitting. To identify gender specific correlates of work-related sitting time, we used a series of linear regressions. RESULTS: The overall median was 2 hours of work-related sitting time/day. Regression analyses showed for men (beta = -.43) and for women (beta = .32) that work-related PA was negatively associated with work-related sitting time, but leisure-related PA was not a significant correlate. For women only, transport-related PA (beta = -.07) was a negative correlate of work-related sitting time, suggesting increased sitting times during work with decreased PA in transport. Education and income levels were positively associated, and in women only, age (beta = -.14) had a negative correlation with work-related sitting time. For both genders, TV-related sitting time was negatively associated with work-related sitting time. The only association with cognitive correlates was found in men for the belief 'Sitting for long periods does not matter to me' (beta = .10) expressing a more positive attitude towards sitting with increasing sitting durations. CONCLUSIONS: The present findings show that in particular, higher educated men and women as well as young women are high-risk groups to target for reducing prolonged work-related sitting time. In addition, our findings propose considering increasing transport-related PA, especially in women, as well as promoting recreation-related PA in conjunction with efforts to reduce long work-related sitting times. PMID- 25496570 TI - Afebrile meningoencephalitis with transient central facial paralysis due to Toscana virus infection, southeastern France, 2014 [corrected]. AB - We report a case of meningoencephalitis caused by Toscana virus (TOSV) with central facial paralysis lasting over two days acquired in south-eastern France. The patient was not febrile either before or during the course of the disease. The diagnosis was established by both real-time RT-PCR and virus isolation with complete genome sequencing. This case emphasises the need to consider TOSV in non febrile neurological syndromes in people living in or having travelled to the Mediterranean area. PMID- 25496571 TI - Preparedness for admission of patients with suspected Ebola virus disease in European hospitals: a survey, August-September 2014. AB - In response to the Ebola virus disease (EVD) outbreak in West Africa, the World Health Organization has advised all nations to prepare for the detection, investigation and management of confirmed and suspected EVD cases in order to prevent further spread through international travel. To gain insights into the state of preparedness of European hospitals, an electronic survey was circulated in August-September 2014 to 984 medical professionals representing 736 hospitals in 40 countries. The survey addressed the willingness and capacity to admit patients with suspected EVD as well as specific preparedness activities in response to the current Ebola crisis. Evaluable responses were received from representatives of 254 (32%) hospitals in 38 countries, mostly tertiary care centres, of which 46% indicated that they would admit patients with suspected EVD. Patient transfer agreements were in place for the majority of hospitals that would not admit patients. Compared with non-admitting hospitals, admitting hospitals were more frequently engaged in various preparedness activities and more often contained basic infrastructural characteristics such as admission rooms and laboratories considered important for infection control, but some gaps and concerns were also identified. The results of this survey help to provide direction towards further preparedness activities and prioritisation thereof. PMID- 25496572 TI - Human and entomological surveillance of Toscana virus in the Emilia-Romagna region, Italy, 2010 to 2012. AB - Toscana virus (TOSV), transmitted by phlebotomine sandflies, is recognised as one of the most important causes of viral meningitis in summer in Mediterranean countries. A surveillance plan based on both human and entomological surveys was started in 2010 in the Emilia-Romagna region, Italy. Clinical samples from patients with neurological manifestations were collected during 2010 to 2012. The surveillance protocol was improved during these years, allowing the detection of 65 human infections. Most of these infections were recorded in hilly areas, where sandflies reach the highest density. Entomological sampling around the homes of the patients resulted in a low number of captured sandflies, while later sampling in a hilly area with high number of human cases (n=21) resulted in a larger number of captured sandflies. Using this approach, 25,653 sandflies were sampled, of which there were 21,157 females, which were sorted into 287 pools. TOSV RNA was detected by real-time PCR in 33 of the pools. The results highlighted the role of Phlebotomus perfiliewi as the main vector of TOSV and a potential link between vector density and virus circulation. This integrated system shows that an interdisciplinary approach improves the sensitiveness and effectiveness of health surveillance. PMID- 25496573 TI - Improving surveillance of sexually transmitted infections using mandatory electronic clinical reporting: the genitourinary medicine clinic activity dataset, England, 2009 to 2013. AB - A new electronic surveillance system for sexually transmitted infections (STIs) was introduced in England in 2009. The genitourinary medicine clinic activity dataset (GUMCAD) is a mandatory, disaggregated, pseudo-anonymised data return submitted by all STI clinics across England. The dataset includes information on all STI diagnoses made and services provided alongside demographic characteristics for every patient attendance at a clinic. The new system enables the timely analysis and publication of routine STI data, detailed analyses of risk groups and longitudinal analyses of clinic attendees. The system offers flexibility so new codes can be introduced to help monitor outbreaks or unusual STI activity. From January 2009 to December 2013 inclusive, over twenty-five million records from a total of 6,668,648 patients of STI clinics have been submitted. This article describes the successful implementation of this new surveillance system and the types of epidemiological outputs and analyses that GUMCAD enables. The challenges faced are discussed and forthcoming developments in STI surveillance in England are described. PMID- 25496578 TI - Letter from the editor. PMID- 25496574 TI - Overcoming healthcare workers vaccine refusal--competition between egoism and altruism. AB - Vaccination reduces the risk of becoming infected with and transmitting pathogens. The role of healthcare workers (HCWs) in controlling and limiting nosocomial infections has been stressed repeatedly. This has also been recognised at a political level, leading the European Council of Ministers in 2009 to encourage coverage of 75% seasonal influenza vaccine in HCWs. Although there are policies, recommendations and well-tolerated vaccines, still many HCWs refuse to get vaccinated. This article uses literature from psychology and behavioural economics to understand vaccination decisions and the specific situation of HCWs. HCWs are expected to be highly motivated to protect others. However, their individual vaccination decisions follow the same principles (of weighting individual risks) as everyone else's vaccination decisions. This will lead to decisional conflict in a typical social dilemma situation, in which individual interests are at odds with collective interests. Failure to get vaccinated may be the result. If we understand the motivations and mechanisms of HCWs' vaccine refusal, interventions and campaigns may be designed more effectively. Strategies to increase HCWs' vaccine uptake should be directed towards correcting skewed risk perceptions and activating pro-social motivation in HCWs. PMID- 25496579 TI - An ageing population poses dental challenges. AB - In this narrative review paper, we summarise what is known about the oral health of older people, with a specific focus on the most common oral conditions in that age group. After that, the implications for older people's oral care are considered, along with ways of developing and maintaining a gerodontologically capable and responsive workforce and oral care delivery system. PMID- 25496580 TI - Oral health status and complete denture status of independent-living Singaporean elderly residing in a community home. AB - AIM: Past studies have examined the oral health status of elderly Singaporean adults residing in long term care facilities and living in residential housing but no oral health research has been conducted on elderly Singaporeans residing in community homes. The aim of this paper is to report on the oral health status and complete denture status of a group of free living (community dwelling) elderly in Singapore from the AWWA Community Home for Senior Citizens, and investigate the relation between the clinical findings and demographic data. MATERIALS AND METHODS: This research used a cross-sectional design and was conducted in the month of December 2011. Consenting residents of the AWWA home who were over the age of 60 participated in this study. Sampling strategy was census. Two calibrated interviewers collected demographic information from the participants and four calibrated dentists conducted extra-oral and intra-oral soft tissue examinations along with assessment of dentition, periodontal and denture status. STATISTICAL ANALYSIS: All data were input into Microsoft Excel 2010(TM) and analysed in SPSS 21.0(TM). Descriptive analysis and bivariate analysis were performed on the demographic factors and other variables of interest. The Spearman's test, Mann-Whitney U and Chi-Square test were used to examine the correlation between the clinical findings and age, gender and education level respectively. RESULTS: Among the 70 participants, two subjects (2.9%) had complete dentition, 34 (48.6%) were partially dentate, and 34 (48.6%) had no teeth. The mean number of teeth among the partially dentate participants was 11.28 while the mean number of anterior, posterior and total occlusal contacts were 1.61, 2.17 and 3.78 respectively. The mean number of decayed teeth (DT) and filled teeth (FT) were 2.81 and 0.25, giving a mean DFT score of 3.06. The mean Root Caries Index was 0.13. Periodontal examination revealed that only 5 (13.9%) individuals had healthy periodontal tissues, while 2 (5.6%) had the highest score of 1, 9 (25.0%) had the highest score of 2, 11 (30.6%) had the highest score of 3 and 7 (19.4%) had the highest score of 4. Amongst the partially dentate, 14 had dentures and 20 had none. There were 34 edentulous participants and 23 had at least one denture while 11 did not have any complete dentures. The most frequent unsatisfactory finding for complete dentures was inadequate retention of the mandibular dentures. When the dentures were grouped into those that were satisfactory and those that had at least one unsatisfactory factor, 11 of the 26 maxillary dentures and 17 of the 23 mandibular dentures fell to the latter category. Analysis revealed that there was a correlation between age and the number of teeth with a correlation coefficient of -0.43 (p=0.01) and age with the mean DFT, -0.33 (p=0.05). CONCLUSION: The findings of this study revealed a high treatment need for this group of elderly. PMID- 25496581 TI - Factors contributing to tooth loss among the elderly: A cross sectional study. AB - BACKGROUND: The present study evaluates the influence of several demographic, health, personal, and clinical factors on the number of missing teeth in old age sample. METHODS: The number of patients included was 259; they received a full mouth examination and answered a questionnaire provided by one examiner. All the variables related to teeth loss based on the literature were included. These variables focused on age, gender, race, marital status, clinical attachment level, pocket depth, year of smoking, number of cigarettes smoked per day, number of medications, root decay, coronal decay, health status, and year of education. Statistical analysis involved stepwise multivariate linear regression. RESULTS: Teeth loss was statistically associated with clinical attachment level (CAL)(p value 0.0001), pocket depth (PD) (0.0007) and education level (0.0048). When smoking was included in the model, age was significantly associated with teeth loss (0.0037). At least one of these four factors was also related to teeth loss in several specific groups such as diabetes mellitus, male, and White. The multiple linear regressions for all the proposed variables showed that they contributed to teeth loss by about 23%. CONCLUSIONS: It can be concluded that less education or increased clinical attachment level loss may increase number of missing teeth. Additionally, age may cause teeth loss in the presence of smoking. PMID- 25496582 TI - Challenges in anaesthesia for elderly. AB - The segment of elderly individuals comprises a growing proportion of the global population. Health care systems and health care providers worldwide need to understand the specific challenges related to treatment of this heterogeneous patient population. The process of ageing is complex and under constant influence by numerous factors, for which reason the way human age is extremely individual. It is important to understand and acknowledge how elderly differ from younger adults, and how management needs to be modified and tailored to the individual patient in order to improve outcomes. The goal of treatment of an elderly patient is not necessarily to increase human longevity regardless of the consequences, but to increase active longevity free from disability and functional dependence. For older people, deterioration in function can be devastating and is often precipitated by a stressful event such as an acute episode of illness or injury. Therefore a mainstay of treatment of the aged is prevention of functional decline. In this review, we will outline the extreme variability in the aging process, and its implications for tailoring the perioperative care for the elderly. We will provide an overview of the challenges, when dealing with the aged surgical population with emphasis on postoperative cognitive changes. PMID- 25496583 TI - Clinical issues in occlusion - Part I. AB - Good occlusal practise provides an important cornerstone to optimal patient care. Occlusal problems can manifest in different areas of dentistry but these are more apparent when there are restorative aspects to the patient's problem. This review highlights areas of restorative dentistry where the appreciation of occlusal aspects can optimise diagnosis and follow up care. PMID- 25496584 TI - Diagnosis of oral pigmentations and malignant transformations. AB - BACKGROUND: Oral pigmentation is a common finding in the mouth. Pigmentation can be either normal or abnormal discoloration of oral mucous membrane. The purpose of this review mainly focuses on the main oral pigmented lesions, in order to help the clinicians establish a better approach towards the patients with pigmented oral lesions and to provide thorough knowledge regarding such lesions for patient reassurance, early definitive diagnosis and prompt treatment. METHODS: Relevant data concerning oral pigmented lesions, clinical features and the possibility of malignant transformation of such lesions were reviewed thoroughly from pubmed literature published in English. Pigmented lesions affecting the skin were not included in our review. RESULTS: Few pigmented lesions have been identified and their tendency to become malignant has been reported in the literature. The oral lesions showing malignant transformation reported were mostly case series. Unfortunately, due to lack of long-term studies, follow ups and randomized controlled studies in this respect it was difficult to draw a statistical analysis. This information is quite crucial for general dental practitioners to improve their understanding regarding oral lesions and to differentiate between normal and diseased conditions, so that they can master the skill of differential diagnosis, definitive diagnosis and prompt treatment. CONCLUSION: Oral pigmentation may present as focal, multifocal or diffused macular or tumefactive lesions. They may greatly vary in color as blue, purple, brown, gray or black depending on the quantity and site of melanin in the tissues [1]. Etiology of pigmentation can be multi factorial. Mostly pigmentation is physiologic but at times it can be a precursor of severe diseases. Lesions may be caused by localized harmless accumulations of melanin, hemosiderin or exogenous metals or they may be a sign of underlying systemic or genetic disease. A few lesions may be associated with life-threatening medical conditions that require immediate intervention. The differential diagnosis for any pigmented lesion is extensive, as it includes examples of endogenous and exogenous pigmentations. Although biopsy is a helpful and necessary aid in the diagnosis of focally pigmented lesions, with diffuse pigmentation lesions require a thorough dental and medical history and laboratory investigations. PMID- 25496585 TI - Endodontic irrigant as a root conditioning agent: An in vitro scanning electron microscopic study evaluating the ability of MTAD to remove smear layer from periodontally affected root surfaces. AB - BACKGROUND: Instrumentation of the root surface, results in formation of a smear layer of organic and mineralized debris which serves as a physical barrier, inhibiting new connective tissue attachment to the root surface. The present study advocates the use of an endodontic irrigant MTAD (mixture of tetracycline, citric acid and detergent) as a root conditioning agent. The main aim of the study was to compare the root conditioning ability of an endodontic irrigant MTAD (mixture of tetracycline, acid and detergent) with 17% EDTA (ethylenediaminetetraacetic acid). MATERIALS AND METHODS: Sixty freshly extracted human single rooted teeth with confirmed periodontal involvement were selected for this study and decoronated. The apical third of each root was removed and the remaining root was sectioned longitudinally to produce a 6mm to 8mm long tooth section. The root surface was then instrumented by hand using a sharp Gracey 1-2 periodontal curette with 6-8 strokes per area to achieve a smooth glass-like surface. A total of 60 specimens were prepared which were randomly divided into three groups (n=20). Each group received the root conditioning treatments as follows: All specimens were prepared for SEM and scored according to the presence of smear layer. RESULTS AND CONCLUSIONS: MTAD removed the smear layer successfully from the root surfaces. The mean smear score for samples treated with Biopure MTAD was lower than those treated with EDTA, (p=0.04). MTAD can be used as a root conditioning agent with efficient smear layer removal ability and known antimicrobial and anticollagenase activity. PMID- 25496586 TI - Complications associated with the occurrence and treatment of impacted maxillary canines. AB - BACKGROUND: The aim of this study was to evaluate the complications associated with the occurrence and treatment of impacted maxillary canines. METHODS: This retrospective study was conducted on 533 Southern Chinese children and adolescents who attended the Paediatric Dentistry and Orthodontics Clinics and had at least one impacted maxillary canine. The study material included all the documentation files and radiographs of these patients. Complications that had been recorded in the clinical and surgical notes and that could be diagnosed from the available radiographs were noted. The data obtained were descriptively analyzed. RESULTS: The most frequently reported phenomenon associated with the occurrence of impacted maxillary canine (prior to surgical treatment) was root resorption of an adjacent permanent tooth in 22 (4.1%) patients. The most frequently reported sequelae observed after any surgical procedure was swelling of the soft tissues around the operation site which often persisted for 48h as seen in 76 (18.8%) patients. Complications reported most commonly after any form of surgery included post-operative bleeding: 7(1.7%), hematoma: 7(1.7%), post operative pain: 6(1.5%) and purulent discharge: 6(1.5%), post-operative complications in relation to surgical exposure and bonding of an attachment which included breakage of ligature wire: 5.7%; de-bonding of the attachment: 4.3% and inability to bond the attachment during surgery: 1.4% occurred rarely. CONCLUSIONS: The frequency of root resorption of teeth adjacent to an impacted maxillary canine was low. Swelling of the soft tissue 48h post-operatively was the most commonly occurring complication after surgical intervention. PMID- 25496587 TI - Gingival crevicular fluid levels of Matrix Metalloproteinase-1 (MMP-1) and Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) in periodontal health and disease. AB - BACKGROUND: Matrix Metalloproteinases (MMPs) are directly responsible for pathogenesis of periodontal diseases and their activity is regulated by Tissue Inhibitor of Metalloproteinases (TIMPs). This study was aimed to evaluate changes in gingival crevicular fluid (GCF) levels of MMP-1 and TIMP-1 in periodontal health and disease. MATERIALS AND METHOD: Clinical parameters were recorded and GCF samples were collected from 30 subjects with chronic generalised periodontitis and 20 periodontally healthy subjects. Subjects with periodontitis underwent scaling and root planing (SRP). GCF samples were collected and clinical parameters were recorded again after 1 month of SRP. GCF levels of MMP-1 and TIMP 1 were detected by ELISA. RESULTS: GCF levels of MMP-1 were significantly increased in subjects with periodontitis at baseline (P0) as compared to periodontally healthy subjects (C). GCF levels of MMP-1 reduced significantly in subjects with periodontitis after treatment (P1) as compared to P0. GCF levels of TIMP-1 were significantly reduced in P0 as compared to C. GCF levels of TIMP-1 increased significantly in P1 as compared to P0. CONCLUSION: Substantial elevation in GCF levels of MMP-1 and reduction in TIMP-1 were found in periodontitis as compared to healthy subjects. GCF levels of MMP-1 and TIMP-1 improved significantly after treatment. PMID- 25496588 TI - Complete denture copy technique-A practical application. AB - The copy denture technique is a misnomer for the clinical and laboratory procedures involved in making complete dentures that replicate most of the features of the original prosthesis. The aim is to replicate the good features of an otherwise successful prosthesis that now requires replacement and to alter the poor features and so it is strictly speaking not a copy. There are many purported advantages to this technique which include reduced treatment time, increased patient acceptance especially for the elderly who may not adapt so well to a new prosthesis, maintenance of tooth position and vertical dimension. A typical case is presented illustrating the clinical stages involved with a discussion of the merits of this technique. PMID- 25496589 TI - Delayed replantation of avulsed tooth with 15-hours extra-oral time: 3-year follow-up. AB - BACKGROUND: Avulsion is one of the most serious injuries of the tooth which is most commonly seen in young children and occurs in the upper front teeth. Immediate transplantation of the avulsed tooth is recommended treatment and results in good prognosis although this may not be always possible. CASE REPORT: The present case highlights the 3-year follow-up of delayed replantation (after 15h) of maxillary central incisor which was avulsed due to trauma. The complications seen in the present case were ankylosis and inflammatory resorption, but clinically the tooth was asymptomatic and maintains the esthetics of the individual signifying the importance of delayed replantation even after prolonged extra-oral time. CLINICAL IMPLICATIONS AND CONCLUSION: Although complications like ankylosis or root resorption may be unavoidable, delayed replantation of avulsed tooth may be a good alternative to prosthesis (implant or fixed partial denture) till the growth is completed due to preservation of the alveolar bone and psychological benefit to the patient. Also efforts should be made to educate and update children, teachers and parents regarding management of avulsed tooth at accident site and also the dentists regarding its management in dental office. PMID- 25496590 TI - Patient induced unusual metallic obturation of the root canal of permanent maxillary central incisor with an immature apex - A rare case report. AB - Discovery of multiple foreign objects in the root canal is unusual and their removal is often difficult and challenging procedure. Entrapment of the foreign object in the pulp chamber or in root canal usually occur accidentally in children with the habit of chewing or placing various objects in the oral cavity. Clinically it was often encountered in tooth with wide carious lesion, exposed pulp chamber due to trauma or tooth left open for the drainage during root canal treatment. This impacted foreign body may act as a potential source of pain or infection. The attempt to retrieve such foreign object from the root canal with immature apex increases the risk of its displacement into periapical area. The present case report describes an unusual case of a patient with two metallic sewing needles inadvertently broken down in the root canal of the permanent maxillary left central incisor and it's successful retrieval by non-surgical endodontic treatment. PMID- 25496591 TI - Rapid fabrication of silicone orbital prosthesis using conventional methods. AB - Restoration of orbital defects with silicone prosthesis has been a well documented and accepted treatment option. Adhesive retained prosthesis offer the patients with adequate retention and treatment satisfaction. However, marginal breakdown and discoloration are common problems associated with these prostheses, necessitating their refabrication. Fabrication of a silicone orbital prosthesis is time consuming and requires multiple clinical and laboratory procedures. This technical article describes simple and cost effective steps for rapid fabrication of a silicone prosthesis using conventional methods. PMID- 25496592 TI - A Core Gene Set Describes the Molecular Basis of Mutualism and Antagonism in Epichloe spp. AB - Beneficial plant-fungal interactions play an important role in the ability of plants to survive changing environmental conditions. In contrast, phytopathogenic fungi fall at the opposite end of the symbiotic spectrum, causing reduced host growth or even death. In order to exploit beneficial interactions and prevent pathogenic ones, it is essential to understand the molecular differences underlying these alternative states. The association between the endophyte Epichloe festucae and Lolium perenne (perennial ryegrass) is an excellent system for studying these molecular patterns due to the existence of several fungal mutants that have an antagonistic rather than a mutualistic interaction with the host plant. By comparing gene expression in a wild-type beneficial association with three mutant antagonistic associations disrupted in key signaling genes, we identified a core set of 182 genes that show common differential expression patterns between these two states. These gene expression changes are indicative of a nutrient-starvation response, as supported by the upregulation of genes encoding degradative enzymes, transporters, and primary metabolism, and downregulation of genes encoding putative small-secreted proteins and secondary metabolism. These results suggest that disruption of a mutualistic symbiotic interaction may lead to an elevated uptake and degradation of host-derived nutrients and cell-wall components, reminiscent of phytopathogenic interactions. PMID- 25496593 TI - Insights into the polerovirus-plant interactome revealed by coimmunoprecipitation and mass spectrometry. AB - Identification of host proteins interacting with the aphidborne Potato leafroll virus (PLRV) from the genus Polerovirus, family Luteoviridae, is a critical step toward understanding how PLRV and related viruses infect plants. However, the tight spatial distribution of PLRV to phloem tissues poses challenges. A polyclonal antibody raised against purified PLRV virions was used to coimmunoprecipitate virus-host protein complexes from Nicotiana benthamiana tissue inoculated with an infectious PLRV cDNA clone using Agrobacterium tumefaciens. A. tumefaciens-mediated delivery of PLRV enabled infection and production of assembled, insect-transmissible virus in most leaf cells, overcoming the dynamic range constraint posed by a systemically infected host. Isolated protein complexes were characterized using high-resolution mass spectrometry and consisted of host proteins interacting directly or indirectly with virions, as well as the nonincorporated readthrough protein (RTP) and three phosphorylated positional isomers of the RTP. A bioinformatics analysis using ClueGO and STRING showed that plant proteins in the PLRV protein interaction network regulate key biochemical processes, including carbon fixation, amino acid biosynthesis, ion transport, protein folding, and trafficking. PMID- 25496594 TI - Deregulation of Plant Cell Death Through Disruption of Chloroplast Functionality Affects Asexual Sporulation of Zymoseptoria tritici on Wheat. AB - Chloroplasts have a critical role in plant defense as sites for the biosynthesis of the signaling compounds salicylic acid (SA), jasmonic acid (JA), and nitric oxide (NO) and as major sites of reactive oxygen species production. Chloroplasts, therefore, regarded as important players in the induction and regulation of programmed cell death (PCD) in response to abiotic stresses and pathogen attack. The predominantly foliar pathogen of wheat Zymoseptoria tritici is proposed to exploit the plant PCD, which is associated with the transition in the fungus to the necrotrophic phase of infection. In this study virus-induced gene silencing was used to silence two key genes in carotenoid and chlorophyll biosynthesis, phytoene desaturase (PDS) and Mg-chelatase H subunit (ChlH). The chlorophyll-deficient, PDS- and ChlH-silenced leaves of susceptible plants underwent more rapid pathogen-induced PCD but were significantly less able to support the subsequent asexual sporulation of Z. tritici. Conversely, major gene (Stb6)-mediated resistance to Z. tritici was partially compromised in PDS- and ChlH-silenced leaves. Chlorophyll-deficient wheat ears also displayed increased Z. tritici disease lesion formation accompanied by increased asexual sporulation. These data highlight the importance of chloroplast functionality and its interaction with regulated plant cell death in mediating different genotype and tissue-specific interactions between Z. tritici and wheat. PMID- 25496595 TI - Rhizoxin analogs contribute to the biocontrol activity of a newly isolated pseudomonas strain. AB - Two strains of Pseudomonas sp., Os17 and St29, were newly isolated from the rhizosphere of rice and potato, respectively, by screening for 2,4 diacetylphloroglucinol producers. These strains were found to be the same species and were the closest to but different from Pseudomonas protegens among the sequenced pseudomonads, based on 16S ribosomal RNA gene and whole-genome analyses. Strain Os17 was as effective a biocontrol agent as reported for P. protegens Cab57, whereas strain St29 was less effective. The whole-genome sequences of these strains were obtained: the genomes are organized into a single circular chromosome with 6,885,464 bp, 63.5% G+C content, and 6,195 coding sequences for strain Os17; and with 6,833,117 bp, 63.3% G+C content, and 6,217 coding sequences for strain St29. Comparative genome analysis of these strains revealed that the complete rhizoxin analog biosynthesis gene cluster (approximately 79 kb) found in the Os17 genome was absent from the St29 genome. In an rzxB mutant, which lacks the polyketide synthase essential for the production of rhizoxin analogs, the growth inhibition activity against fungal and oomycete pathogens and the plant protection efficacy were attenuated compared with those of wild-type Os17. These findings suggest that rhizoxin analogs are important biocontrol factors of this strain. PMID- 25496596 TI - Exophiala angulospora Causes Systemic Mycosis in Atlantic Halibut: a Case Report. AB - Filamentous black yeasts from the genus Exophiala are ubiquitous, opportunistic pathogens causing both superficial and systemic mycoses in warm- and cold-blooded animals. Infections by black yeasts have been reported relatively frequently in a variety of captive and farmed freshwater and marine fishes. In November 2012, moribund and recently dead, farm-raised Atlantic Halibut Hippoglossus hippoglossus were necropsied to determine the cause of death. Histopathology revealed that three of seven fish were affected by a combination of an ascending trans-ductual granulomatous mycotic nephritis, necrotizing histiocytic encephalitis, and in one fish the addition of a fibrogranulomatous submucosal branchitis. Microbial cultures of kidney using selective mycotic media revealed pure growth of a black-pigmenting septated agent. Application of molecular and phenotypic taxonomy methodologies determined that all three isolates were genetically consistent with Exophiala angulospora. This is the first report of E. angulospora as the causal agent of systemic mycosis in Atlantic Halibut. PMID- 25496597 TI - Associations between breakfast eating habits and health-promoting lifestyle, suboptimal health status in Southern China: a population based, cross sectional study. AB - BACKGROUND: Suboptimal health status (SHS) is the intermediate health state between health and disease, refers to medically undiagnosed or functional somatic syndromes, and has been a major global public health challenge. However, both the etiology and mechanisms associated with SHS are still unclear. Breakfast eating behavior is a dietary pattern marker and previous studies have presented evidence of associations between failure to consume breakfast and increased diseases. Accordingly, in view of the significance of breakfast eating behaviors with respect to health status, the associations between breakfast eating habits and healthy lifestyle, SHS require further elucidation. METHODS: A cross-sectional survey was conducted within a clustered sample of 24,159 individuals aged 12-80 years in 2012-13 within the population of Southern China. Breakfast eating habits were categorically defined by consumption frequency ('scarcely, sometimes or always'). Health-promoting lifestyle was assessed via the health-promoting lifestyle profile (HPLP-II). SHS was evaluated using the medical examination report and Sub-health Measurement Scale V1.0 (SHMS V1.0). RESULTS: Of the 24,159 participants, the prevalence rates for the 'health' , 'SHS' , and 'disease' were 18.8%, 46.0%, and 35.2%, respectively. Overall, 19.6% of participants reported 'scarce' breakfast eating habits, with frequent breakfast eaters scoring higher on both HPLP-II and SHMS V1.0. After demographic adjustment, regression analyses revealed a significant association between breakfast eating habits and healthy lifestyle (p <0.001). There were lower levels of breakfast consumption regularity amongst individuals with SHS than those with disease. Categorically 'scarce' breakfast eaters were approximately three times more likely to be assigned SHS (OR: 2.745, 95% CI: 2.468-3.053), while infrequent breakfast eaters ('sometimes') were just less than twice as likely to be assessed as being of SHS (OR: 1.731, 95% CI: 1.595-1.879). CONCLUSIONS: Breakfast eating habits are significantly associated with a healthy lifestyle, and appear to be a useful predictor of a healthy lifestyle. Irregular breakfast eating habits are related to an increased risk of SHS; increased breakfast eating frequency may contribute to lowering the prevalence of SHS in Southern China. PMID- 25496598 TI - Barriers to shared decisions in the most serious of cancers: a qualitative study of patients with pancreatic cancer treated in the UK. AB - BACKGROUND: Less than 20% of patients with pancreatic cancer present with localized, potentially curable tumours. Even when potentially curative surgery is possible, mortality is high. Only 20-25% of patients who have had resected ductal adenocarcinoma of the pancreatic head survive 5 years. Other treatments include chemotherapy, radiotherapy and palliative care. AIM: To explore patients' perceptions of barriers to shared decision making in a condition in which shared decision making might be difficult. METHOD: Thematic analysis of narrative interviews with 32 people diagnosed with pancreatic cancer in the UK; interviews with a social scientist, usually in people's homes. RESULTS: We found that barriers to shared decisions include the idea that investigations are conducted to determine whether the patient qualifies for surgery, rather than to establish whether surgery is an option to consider; a sense of being pressured to accept treatment, a sense that in a life-threatening situation, there are no 'real options'; and the confusion that can be caused when clinical opinions differ. CONCLUSION: We need to ask how patients can be expected to engage in an informed, shared decision if they are made to feel that they are one of the 'winners' if they qualify for surgery. When each treatment decision might have serious consequences for a patient's remaining months, we suggest that there is a particularly strong imperative to make sure that the patient is not subject to other people's assumptions about what is best for them and that patients are offered the opportunity to share in decisions. PMID- 25496599 TI - Evidence for GC-biased gene conversion as a driver of between-lineage differences in avian base composition. AB - BACKGROUND: While effective population size (Ne) and life history traits such as generation time are known to impact substitution rates, their potential effects on base composition evolution are less well understood. GC content increases with decreasing body mass in mammals, consistent with recombination-associated GC biased gene conversion (gBGC) more strongly impacting these lineages. However, shifts in chromosomal architecture and recombination landscapes between species may complicate the interpretation of these results. In birds, interchromosomal rearrangements are rare and the recombination landscape is conserved, suggesting that this group is well suited to assess the impact of life history on base composition. RESULTS: Employing data from 45 newly and 3 previously sequenced avian genomes covering a broad range of taxa, we found that lineages with large populations and short generations exhibit higher GC content. The effect extends to both coding and non-coding sites, indicating that it is not due to selection on codon usage. Consistent with recombination driving base composition, GC content and heterogeneity were positively correlated with the rate of recombination. Moreover, we observed ongoing increases in GC in the majority of lineages. CONCLUSIONS: Our results provide evidence that gBGC may drive patterns of nucleotide composition in avian genomes and are consistent with more effective gBGC in large populations and a greater number of meioses per unit time; that is, a shorter generation time. Thus, in accord with theoretical predictions, base composition evolution is substantially modulated by species life history. PMID- 25496601 TI - Understanding pressurized metered dose inhaler performance. AB - INTRODUCTION: Deepening the current understanding of the factors governing the performance of the pressurized metered dose inhaler (pMDI) has the potential to benefit patients by providing improved drugs for current indications as well as by enabling new areas of therapy. Although a great deal of work has been conducted to this end, our knowledge of the physical mechanisms that drive pMDI performance remains incomplete. AREAS COVERED: This review focuses on research into the influence of device and formulation variables on pMDI performance metrics. Literature in the areas of dose metering, atomization and aerosol evolution and deposition is covered, with an emphasis on studies of a more fundamental nature. Simple models which may be of use to those developing pMDI products are summarized. EXPERT OPINION: Although researchers have had good success utilizing an empirically developed knowledge base to predict pMDI performance, such knowledge may not be applicable when pursuing innovations in device or formulation technology. Developing a better understanding of the underlying mechanisms is a worthwhile investment for those working to enable the next generation of pMDI products. PMID- 25496602 TI - Surgical removal of an intracardiac sewing needle in a 13-month-old Chinese girl: report of a case. AB - Abstract Introduction: Sewing needles, albeit a rare case of penetrating cardiac injury, are highly lethal, especially in children, because it is difficult to diagnose and treat. We herein present the case of a 13-month-old girl who was injured by a sewing needle inserted in the myocardium, which probably is the first report from mainland China.Case presentation: The 13-month-old girl was referred to our hospital with a range of symptoms, such as convulsions, diarrhea, and cough. Chest X-ray and echocardiogram revealed a needle located below the aortic valve, passing through the ventricular septum and aortic root. Surgical removal of the needle was performed under extracorporeal circulation. No hemorrhage or arrhythmia was seen, so the operation was ended, and the patient was discharged 8 days after the surgery. Conclusion: An early diagnosis and intervention proved to be life-saving for this penetrating cardiac injury. Hopefully, this case could provide a reference for the treatment of similar situations. PMID- 25496600 TI - Factors determining the smooth flow and the non-operative time in a one-induction room to one-operating room setting. AB - RATIONALE, AIMS AND OBJECTIVES: What factors determine the use of an anaesthesia preparation room and shorten non-operative time? METHODS: A logistic regression is applied to 18 751 surgery records from AZ Sint-Jan Brugge AV, Belgium, where each operating room has its own anaesthesia preparation room. Surgeries, in which the patient's induction has already started when the preceding patient's surgery has ended, belong to a first group where the preparation room is used as an induction room. Surgeries not fulfilling this property belong to a second group. A logistic regression model tries to predict the probability that a surgery will be classified into a specific group. Non-operative time is calculated as the time between end of the previous surgery and incision of the next surgery. A log linear regression of this non-operative time is performed. RESULTS: It was found that switches in surgeons, being a non-elective surgery as well as the previous surgery being non-elective, increase the probability of being classified into the second group. Only a few surgery types, anaesthesiologists and operating rooms can be found exclusively in one of the two groups. Analysis of variance demonstrates that the first group has significantly lower non-operative times. Switches in surgeons, anaesthesiologists and longer scheduled durations of the previous surgery increases the non-operative time. A switch in both surgeon and anaesthesiologist strengthens this negative effect. Only a few operating rooms and surgery types influence the non-operative time. CONCLUSION: The use of the anaesthesia preparation room shortens the non-operative time and is determined by several human and structural factors. PMID- 25496603 TI - A comparison of methods for the detection of the r'(s) haplotype. AB - BACKGROUND: The r'(s) haplotype is found in 5% to 15% of individuals of African descent. Persons with this haplotype have a partial C antigen and weakened e and can produce anti-C or other "e-like" alloantibodies. Thus, for these chronically transfused patients, accurate detection of the r'(s) haplotype is important for selection of matched units. STUDY DESIGN AND METHODS: African-American donors were genotyped using the human erythrocyte antigen (HEA) microarray. Samples (n = 125) identified as "possible r'(s) " were then tested by IDCORE XT and RHD and RHCE microarrays. DNA sequencing was used to resolve discordant samples. The genotyping results were compared to serologic testing using a monoclonal anti-C reagent (Clone MS24). RESULTS: Of the 125 possible r'(s) samples identified by HEA, only 94 (75%) were confirmed by both RHD and RHCE microarrays. The IDCORE XT accurately detected 93 of 94 (99%) of the confirmed r'(s) and had no false positives. DNA sequencing of the one discordant sample revealed the presence of a compound heterozygote with RHD* DIII.4/RHCE*ceVS.02 as one haplotype and r'(s) Type 2 as the other. The 31 unconfirmed r'(s) samples carried RHCE*ceVS.03 not linked to the hybrid RHD-CE-D. This occurred most often with RHD*DIIIa (55%) or RHD*01 (19%) and rarely with DIII.4, DIII.6, DAU3, and weak D Type 14. Serologic testing with anti-C gave 100% concordance with the r'(s) samples. CONCLUSIONS: The predominant type of r'(s) in African-Americans is Type 1, which can be detected either by a reagent anti-C containing Clone MS24 or by IDCORE XT. However, serology cannot differentiate between a normal C allele and the hybrid. PMID- 25496604 TI - Prediction of mortality using a multi-bed vascular calcification score in the Diabetes Heart Study. AB - BACKGROUND: Vascular calcified plaque, a measure of subclinical cardiovascular disease (CVD), is unlikely to be limited to a single vascular bed in patients with multiple risk factors. Consideration of vascular calcified plaque as a global phenomenon may allow for a more accurate assessment of the CVD burden. The aim of this study was to examine the utility of a combined vascular calcified plaque score in the prediction of mortality. METHODS: Vascular calcified plaque scores from the coronary, carotid, and abdominal aortic vascular beds and a derived multi-bed score were examined for associations with all-cause and CVD mortality in 699 European-American type 2 diabetes (T2D) affected individuals from the Diabetes Heart Study. The ability of calcified plaque to improve prediction beyond Framingham risk factors was assessed. RESULTS: Over 8.4 +/- 2.3 years (mean +/- standard deviation) of follow-up, 156 (22.3%) participants were deceased, 74 (10.6%) from CVD causes. All calcified plaque scores were significantly associated with all-cause (HR: 1.4-1.8; p < 1x10(-5)) and CVD mortality (HR: 1.5-1.9; p < 1*10(-4)) following adjustment for Framingham risk factors. Associations were strongest for coronary calcified plaque. Improvement in prediction of outcome beyond Framingham risk factors was greatest using coronary calcified plaque for all-cause mortality (AUC: 0.720 to 0.757, p = 0.004) and the multi-bed score for CVD mortality (AUC: 0.731 to 0.767, p = 0.008). CONCLUSIONS: Although coronary calcified plaque and the multi-bed score were the strongest predictors of all-cause mortality and CVD-mortality respectively in this T2D-affected sample, carotid and abdominal aortic calcified plaque scores also significantly improved prediction of outcome beyond traditional risk factors and should not be discounted as risk stratification tools. PMID- 25496605 TI - Is knee extension strength a better predictor of functional performance than handgrip strength among older adults in three different settings? AB - BACKGROUND: The first purpose was to examine whether knee extension strength is a better predictor of functional performance than handgrip strength among older adults (>=60 years). The second purpose was to identify functionally relevant cut off values for muscle strength. METHODS: 770 community-dwelling older adults, 104 older adults living in assisted living facilities and 73 nursing home residents were included. Static strength, expressed in kg/kg body weight (BW), was measured using two field tests: handgrip (GRIP/BW) and knee extension (KNEE/BW) test. Functional performance was assessed with 6-Minute Walk Distance (6MWD, N=947) and modified Physical Performance Test (mPPT, N=152). RESULTS: Both GRIP/BW and KNEE/BW were positively correlated with functional performance in all settings (p<0.05). In the community and nursing homes, both strength variables equally contributed to functional performance. In assisted living facilities, KNEE/BW (R(2)6MWD=0.39 and R2mPPT=0.35) was clearly a better predictor of functional performance than GRIP/BW (R(2)6MWD=0.15 and R2mPPT=0.12). GRIP/BW had no added value to KNEE/BW in order to explain the variance in functional performance. Functionally relevant cut-off values for static strength, for men and women respectively, were set at 0.40 and 0.31 for KNEE/BW and at 0.43 and 0.31 for GRIP/BW. CONCLUSIONS: Handgrip and knee extension strength are both important predictors of functional performance in older adults. In assisted living facilities only, knee extension strength was clearly more predictive than handgrip strength. Both cut-off values appear to be highly sensitive to screen for functionally relevant muscle weakness in older adults. PMID- 25496607 TI - Optimization of Zn(x)Fe(3-x)O4 hollow spheres for enhanced microwave attenuation. AB - We report here the composition optimization of Zn(x)Fe(3-x)O4 hollow nanospheres for enhancing microwave attenuation. Zn(x)Fe(3-x)O4 hollow nanospheres were synthesized through a simple solvothermal process. The maximum magnetization moment of 91.9 emu/g can be obtained at x = 0.6. The composite filled with Zn0.6Fe2.4O4 exhibited the bandwidth of 3.21-8.33 GHz for RL < -10 dB and a maximum relative bandwidth (Wp,max) of 88.6% at optimized thickness t0 = 0.34 cm. The enhancement should be attributed to the enhanced permeability resonance at high frequency. This optimized hollow material is very promising to be used as a mass efficient and broadband microwave attenuation material. PMID- 25496606 TI - Cross-sectional study of glycemic control among adults with type 2 diabetes. AB - Type 2 diabetes mellitus is a chronic condition, a global concern, and a serious issue in Sri Lanka, where there is little data regarding the influence of dietary control, exercise, and adherence to medication behaviors among adults diabetes. In this cross-sectional, descriptive study, we identified current factors influencing glycemic control and glycemic control behavior among adults with diabetes. A total of 230 people attending diabetes clinics in a tertiary hospital and a primary care institute were administered the self-report Diabetes Information Form, assessing their socioeconomic and medical information and glycemic control behaviors. Data were analyzed by frequency distribution, percentages, mean scores, and standard deviation. The results indicated that most participants had not achieved the recommended fasting blood glucose level (< 126 mg/dL). Although dietary control was practised by 72%, regular exercise was not practised by 85%, and while 77% reported adhering to regular medication, they still had poor glycemic control. The findings highlight the need for health professionals to adopt new strategies for diabetes education to overcome issues related to misconceptions and barriers in providing diabetes care in Sri Lanka. PMID- 25496608 TI - Neuroanniversary 2015. PMID- 25496610 TI - The line of Gennari--sometimes history gets it right. PMID- 25496613 TI - Abstracts of the Hunter Cancer Research Alliance Annual Symposium 2014, November 21, 2014, New Lambton Heights, New South Wales, Australia. PMID- 25496614 TI - Human papillomavirus prevalence and type distribution among women attending routine gynecological examinations in Saudi Arabia. AB - BACKGROUND: Cervical cancer (CC) is caused by persistent infection with high-risk (HR) human papillomavirus (HPV) types. In Saudi Arabia which has a population of 6.5 million women over the age of 15 years, approximately 152 new cases of CC are diagnosed and 55 women die from the disease annually. Nevertheless current epidemiological data for HPV in this population are limited. This study evaluated the prevalence and type distribution of HPV and documented the awareness of HPV infection and health-related behavior among Saudi and non-Saudi women attending routine examination. METHODS: This was an observational, epidemiological cross sectional study conducted between April 2010 and December 2011 at three hospitals in Saudi Arabia. Cervical samples from women aged >=15 years, who were attending routine gynecological examinations were collected and tested for HPV-DNA by polymerase chain reaction and typed using the SPF10 DEIA/LiPA25 system. Two questionnaires on health-related behavior and awareness of HPV infection were completed. RESULTS: A total of 417 women, mean age (standard deviation) 41.9 (+/ 10.4) years, were included in the final analysis, of whom 77% (321/417) were Saudi nationals. HPV-DNA was detected in 9.8% women (41/417, 95% confidence interval [CI]: 7.1-13.1). The prevalence of any HR-HPV by age was: 25-34 years: 3.0%; 35-44 years: 4.5%; 45-54 years: 3.2%; >55 years: 10.9%. The most prevalent HR-HPV-types were: HPV-68/73 (5 cases); HPV-18 (4 cases); HPV-16 (3 cases). The most prevalent low risk (LR) types were HPV-6 (4 cases); HPV-42, HPV-53 and HPV 54 (2 cases each). The prevalence of HPV was higher among non-Saudi nationals vs. Saudi nationals (16.7% vs. 7.8%, P = 0.0234). No statistically significant risk factors were identified: 32.2% (101/314) women were aware of HPV and 89.9% (285/317) showed an interest in HPV vaccination. CONCLUSION: The overall prevalence of HPV was 9.8% in Saudi Arabia, but was higher in women over 55 years, as well as in non-Saudi nationals. These data provide a reference for public health authorities and may also help in determining future policies for the prevention of CC. CLINICAL TRIAL REGISTRATION: NCT01213459. PMID- 25496615 TI - A randomized controlled trial of the effectiveness of a postnatal psychoeducation programme on self-efficacy, social support and postnatal depression among primiparas. AB - AIM: To examine the effectiveness of a postnatal psychoeducation programme in enhancing maternal self-efficacy and social support and reducing postnatal depression among primiparas. BACKGROUND: Primiparas experience various challenges during the early postnatal period with low self-efficacy, depression and lack of social support. Support in the form of postnatal educational programmes is needed to improve these outcomes of primiparas. DESIGN: A randomized controlled two group pre-test-post-test design was adopted. METHODS: Data were collected from June-December 2012 in a public hospital in Singapore from 122 primiparas, who were randomly assigned to the intervention (n = 61) or control group (n = 61). The intervention group received postnatal psychoeducation programme and routine care while the control group received routine care only. The Maternal Parental Self-Efficacy scale, Perinatal Infant Care Social Support scale and Edinburgh Postnatal Depression Scale were used to measure outcomes of maternal parental self-efficacy, social support and postnatal depression. The mean percentage changes of all three outcome variables from baseline to 6 and 12 weeks postpartum between groups were used when performing repeated measures multivariate analysis of covariance. RESULTS: The intervention group had significantly higher scores of maternal parental self-efficacy and social support and lower scores of postnatal depression at 6 and 12 weeks postpartum when compared with the control group. CONCLUSION: The postnatal psychoeducation programme was effective in improving maternal outcomes and hence could be introduced as routine care with ongoing evaluation in the postnatal period. Future studies could focus on the effects of this programme on other populations. TRIAL REGISTRATION NO: ISRCTN15886353. PMID- 25496616 TI - International coordination of large-scale human induced pluripotent stem cell initiatives: Wellcome Trust and ISSCR workshops white paper. AB - There is growing recognition of the potential value of human induced pluripotent stem cells (hiPSC) for understanding disease and identifying drugs targets. This has been reflected in the establishment of multiple large-scale hiPSC initiatives worldwide. Representatives of these met recently at a workshop supported by the Welcome Trust in the UK and in a focus session at the 2014 ISSCR annual meeting in Vancouver. The purpose was to discuss strategies for making thousands of hiPSC lines widely available with as few restrictions as possible while retaining financial viability and donor privacy. The outcome of these discussions is described here. PMID- 25496617 TI - Conservative treatment of uterine fistula with abdominal abscess after caesarean section. PMID- 25496618 TI - Surgical repair of a large saccular left main coronary artery aneurysm. PMID- 25496619 TI - World Neurosurgery. Neuroendoscopy refinements & innovation in endoscopic skull base surgery. Introduction. PMID- 25496620 TI - The endoscopic endonasal approach for extradural and intradural clivus lesions. AB - OBJECTIVE: To report the use of the endoscopic transnasal transclival approach to treat tumors involving the clivus region. METHODS: The clinical records of 38 patients with clivus lesions were retrospectively reviewed to determine the surgical technique used. All patients were surgically treated using any of the options of the endoscopic transnasal transclival approach at the Sao Paulo Skull Base Center from 2000-2011. A transsphenoidal, transpterygoidal, retropharyngeal, or a combination of approaches was chosen based on the tumor topography. RESULTS: Chordomas were the most frequent tumor (26 of 38), followed by chondrosarcoma (2 of 38). Biopsy only was performed in 6 patients with metastasis to the clivus, and 1 patient with fibrous dysplasia underwent a planned partial resection. Gross total resection (GTR) was achieved in 15 of 31 (48%) patients with indications for GTR. For centrally located tumors, GTR was achieved in 75% (15 of 20 patients). Fistula was the most frequent complication (6 of 31; 19%) but was much lower in the most recent series using the nasoseptal flap (1 of 16; 6%). Tumors with lateral extensions or with previous treatment had the worst results. The presence of intradural extension was not a limiting factor for GTR. CONCLUSION: Endoscopic transnasal surgery is an alternative approach to treatment of clivus lesions, and, in expert hands, this technique can obtain good results. Lateral extension and previous treatment were factors that could make the surgery more difficult. Intradural extension did not limit the radicality of the removal. PMID- 25496621 TI - The transition from microscopic to endoscopic transsphenoidal surgery in high caseload neurosurgical centers: the experience of Foch Hospital. AB - OBJECTIVE: To report the experience of 1 hospital in the transition from the microscopic approach to the endoscopic endonasal approach for pituitary disease and skull base tumor surgery. METHODS: From 2006 to August 2011, 1000 procedures to treat pituitary disease and skull base tumors were performed in our department by a single neurosurgeon using the endoscopic endonasal approach. RESULTS: The endonasal endoscopic approach for pituitary adenoma surgery decreased nasal complications, increased patient comfort by avoiding postoperative nasal packing, provided a better view of the intrasellar and suprasellar areas, obtained the same endocrinologic results as the microscopic approach, provided better control of the invasion of the cavernous sinus, and allowed removal of tumors of the cavernous sinus in some cases. CONCLUSIONS: It is important to separate the 2 approaches, the endoscopic endonasal transsellar approach and the endoscopic endonasal extended approach, and to avoid unnecessary extended approaches. The use of an endoscopic endonasal approach has added value for lesions localized between the tuberculum sellae and the odontoid. The added value of endoscopic endonasal approaches for lesions in front of the tuberculum sellae is less clear and must be evaluated in the future. PMID- 25496622 TI - Advantages and limitations of endoscopic endonasal approaches to the skull base. AB - BACKGROUND: The anatomy of the skull base is extremely complex with an abundance of critical neurovascular bundles and their corresponding foramina as well as the insertions and origins of multiple masticatory and craniocervical muscles. These anatomic intricacies increase the difficulty of surgery within this area. METHODS: Advantages and disadvantages of endoscopic endonasal approaches (EEAs) based on the authors' sequential learning and experience are described. RESULTS: EEAs offer the advantages of using preexistent air spaces that enable accessing various areas of the skull base, while avoiding external incisions or scars and obviating the need for the translocation of the maxillofacial skeleton. In addition, EEAs are well suited to preserve neurologic, visual, and masticatory functions as well as cosmesis. However, the sinonasal corridor must be expanded and optimized to access the skull base adequately, facilitate the reconstruction of the surgical defect, avoid sinonasal complications, and minimize sequelae. Important considerations can limit or indicate the approach, such as the nature of the pathology, including location, diagnosis, and vascularity; patient characteristics, including age and medical comorbidities; surgeon attributes, including training, experience, and expertise; the resultant need to reconstruct large skull base defects and feasible alternatives to do so; and institutional resources, including adjunctive services, an intensive care unit, and operating room equipment. CONCLUSIONS: EEAs are important techniques in contemporary skull base surgery. Understanding the indications for and limitations of these approaches help to maximize outcomes. PMID- 25496623 TI - Endonasal endoscopic approaches to the paramedian skull base. AB - OBJECTIVE: To describe the technical and anatomic nuances related to endoscopic endonasal approaches (EEAs) to the paramedian skull base. METHODS: Surgical indications, limitations, and technical aspects pertaining to EEAs designed to access areas oriented in the coronal plane are systematically reviewed with special attention to caveats, pitfalls, and common complications and how to avoid them. Case examples are presented. RESULTS: The paramedian skull base may be divided into anterior (corresponding to the orbit and its contents), middle (corresponding to the middle cranial, pterygopalatine, and infratemporal fossae), and posterior (includes the craniovertebral junction lateral to the occipital condyles and the jugular foramen) segments. EEAs to the anterior segment offer access to the intraconal orbital space and the optic canal. A transpterygoid corridor typically precedes EEAs to the middle and posterior paramedian approaches. EEAs to the middle segment provide wide exposure of the petrous apex, middle cranial fossa (including cavernous sinus and Meckel cave), and infratemporal and pterygopalatine fossae. Finally, EEAs to the posterior segment access the hypoglossal canal, occipital condyle, and jugular foramen. CONCLUSIONS: Approaches to the paramedian skull base are the most challenging and complex of all endoscopic endonasal techniques. Because of their technical complexity, it is recommended that surgeons master endoscopic endonasal anatomic approaches oriented to median structures (sagittal plane) before approaching paramedian (coronal plane) pathologies. PMID- 25496624 TI - The supraorbital endoscopic approach for aneurysms. AB - OBJECTIVE: To review our surgical experience in minimally invasive transcranial endoscope-assisted microsurgical treatment of intracranial aneurysms, using the supraorbital keyhole craniotomy. METHODS: The supraorbital keyhole approach was performed through an eyebrow skin incision in 793 cases for treatment of 989 intracranial aneurysms. Of patients, 474 were operated on after subarachnoid hemorrhage, and 319 were operated on under elective conditions. After lateral frontobasal burr hole trephination, a limited subfrontal craniotomy was created. To achieve adequate intraoperative exposure through the limited approach, endoscopes were used routinely. Surgical outcome was assessed using the modified Rankin scale. RESULTS: The transcranial endoscope-assisted microneurosurgery technique was used routinely via a supraorbital approach. In 152 operations (19.1%), the endoscope provided important visual information in the vicinity of the aneurysm, revealing subsequent clip repositioning. The results of incidental aneurysms were excellent with a modified Rankin scale score <=2 in 96.52%. The overall outcome of ruptured aneurysms was good with a modified Rankin scale score <=2 in 72.2% of patients. There were no approach-related intraoperative or postoperative complications. CONCLUSIONS: The minimally invasive supraorbital keyhole approach allowed safe surgical treatment of intracranial aneurysms, including after subarachnoid hemorrhage. The markedly improved endoscopic visualization increased the assessment of clip placement with ideal control of surrounding vessels including perforators for identification of incorrect clip position. PMID- 25496625 TI - Endoscopic endonasal surgery for nonadenomatous sellar/parasellar lesions. AB - INTRODUCTION: This article demonstrates the experience with endoscopic transphenoidal anterior skull base surgery for lesions other than pituitary adenomas. The spectrum of lesions, results, and complications are presented. PATIENTS AND METHODS: This series includes patients with 102 lesions other than pituitary adenomas operated upon using the endoscopic approach. The results and complications were reviewed retrospectively. RESULTS: The most common lesions treated were Rathke Cleft Cysts (n = 39) and craniopharyngiomas (n = 18) in a total of 82 tumors. There were 8 patients with inflammatory lesions, and the remainder had a variety of unusual pathologies. Complications other than diabetes insipidus (n = 12) were uncommon, with 6 postoperative cerebrospinal fluid leaks. CONCLUSIONS: The endoscopic anterior skull base approach is highly effective in treating a large variety of lesions other than pituitary adenomas. The adoption of the nasoseptal flap for closure has markedly reduced the incidence of spinal fluid leaks, and is used routinely for lesions that violate the intracranial compartment. PMID- 25496626 TI - Contemporary indications for transsphenoidal pituitary surgery. AB - OBJECTIVE: To analyze current indications for transsphenoidal pituitary surgery. METHODS: The current literature regarding transsphenoidal surgery for all subtypes of pituitary adenomas and other sellar lesions was examined. Alternate approaches for pituitary surgery were also reviewed. RESULTS: Transsphenoidal surgery continues to be the mainstay of surgical treatment for pituitary tumors, and has good outcomes in experienced hands. Pre- and postoperative management of pituitary tumors remains an important part of the treatment of patients with pituitary tumors. CONCLUSIONS: Even as medical and surgical treatment for pituitary tumors evolves, transsphenoidal surgery remains a mainstay of treatment. Outcomes after transshenoidal surgery have improved over time. Neurosurgeons must be aware of the indications, risks and alternatives to transsphenoidal pituitary surgery. PMID- 25496627 TI - The transition from microscopic to endoscopic transsphenoidal surgery: the experience at Brigham and Women's Hospital. AB - OBJECTIVE: As interest and enthusiasm for the use of the endoscope in transsphenoidal anterior skull base and pituitary surgery increases, neurosurgeons are increasingly adopting endoscopic technology and associated novel concepts. Often this involves a transition from the standard operating microscope as the main means of visualization to the operating endoscope (2D or 3D) during surgery. METHODS: The authors' experience with this transition is described, including the rationale, advantages and disadvantages of the two surgical techniques. RESULTS: The successful use of endoscopic surgery for a large variety of pathological problems involving the anterior skull base and the pituitary region is presented. Perceived advantages for the patient and the surgeon are described, as is the occasional need for transition back to the microscopic approach. CONCLUSIONS: The endoscopic approach and its allied technology are here to stay. They are useful and occasionally preferable methods for treating a variety of suitable lesions involving the anterior skull base. The importance of incorporating the basic principles of skull base surgery is emphasized. PMID- 25496628 TI - The transition from microscopic to endoscopic transsphenoidal surgery in high case load neurosurgical centers: the Groote Schuur Hospital experience. PMID- 25496629 TI - Endoscopic anatomy of the skull base explored through the nose. AB - OBJECTIVE: Different surgical approaches have been used over the years in order to access skull base. The endoscopic endonasal approach represents a direct and minimally invasive approach to the suprasellar, retrosellar, and retroclival space, with the advantage of avoid brain retraction and visualize safely and effectively the surgical target. The present contribution aims to provide anatomical details of the skull base as seen from below (i.e., via an endoscopic endonasal approach). METHODS: Five human cadaver heads were dissected. The anatomical neurovascular structures within the skull base were visualized and carefully described from an endoscopic endonasal view. The advantages and limitations of the endoscopic endonasal route were discussed as well. RESULTS: The entire skull base region, as seen from the endoscopic endonasal viewpoint, has been divided in 4 main regions: anterior skull base, middle skull base, posterior skull base and parasellar area. CONCLUSION: The development of endoscopic techniques has opened different perspectives over the skull base surgery. Endonasal surgery provides access to a wide range of skull base lesions via a natural surgical corridor (i.e., the nasal cavities). PMID- 25496630 TI - The retrosigmoid endoscopic approach for cerebellopontine-angle tumors and microvascular decompression. PMID- 25496631 TI - Endoscopic endonasal surgery for malignancies of the anterior cranial base. AB - OBJECTIVE: Data from several centers worldwide have demonstrated that transnasal endoscopic surgery performed with or without a transcranial approach is capable of achieving radical resection of selected sinonasal malignancies. We report our experience with endoscopic management of sinonasal cancers, with emphasis on naso ethmoidal malignancies encroaching on the anterior skull base. METHODS: Major series reporting results concerning the endoscopic endonasal approach with or without craniectomy for treatment of sinonasal and anterior skull base cancers were reviewed. Preoperative work-up, indications and exclusion criteria, surgical techniques, postoperative management, and adjuvant therapy are reported. RESULTS: In the 2 largest series analyzed, the most common malignancies were adenocarcinoma (28%), olfactory neuroblastoma (14.5%), and squamous cell carcinoma (13.5%). The 5-year disease-specific survival rate ranged from 81.9% 87%, with no major differences in the mean follow-up time (34.1 months vs. 37 months). CONCLUSIONS: Endoscopic endonasal resection performed with or without a transcranial approach, when properly planned and in expert hands, has an accepted role with precise indications in the surgeon's armamentarium for the treatment of sinonasal and skull base malignancies. PMID- 25496632 TI - Endoscopic endonasal surgery for pituitary adenomas. AB - BACKGROUND: Pituitary surgery is a continuous evolving specialty of the neurosurgeons' armamentarium, which requires precise anatomic knowledge, technical skills, and integrated culture of the pituitary pathophysiology. Actually it cannot be considered only from a technical standpoint, but rather a procedure resulting from the close cooperation among different specialists (e.g., ophthalmologists, neuroradiologists, endocrinologists, neurosurgeons, otorhinolaryngologists, anesthesiologists, neurophysiologists, pathologists, instrument manufacturers). METHODS: The "pure" endoscopic endonsal surgery is a procedure performed through the nose, with the endoscope alone throughout the whole approach and without any transsphenoidal retractor. The procedure consists of three main aspects: exposure of the lesion, removal of the relevant pathology, and reconstruction, going through three different steps, the nasal, the sphenoid, and the sellar phases. CONCLUSIONS: The endoscopic approach offers some advantages due to the endoscope itself: a superior close-up view of the relevant anatomy and an enlarged working angle are provided with an increased panoramic vision inside the surgical area. Concerning results in terms of mass removal, relief of clinical symptoms, cure of the underlying disease, and complication rate, these are, at least, similar to those reported in the major microsurgical series, but patient compliance is by far better. Besides the advantages to the patients, the surgeons-because of the wider and closer view of the surgical target area and the increase of the scientific activity as from the peer-reviewed literature on the topic in the past 10 years, the smoothing of interdisciplinary cooperation-, and the institutions (shorter postoperative hospital stay and increase of the case load)- the adoption of endoscopy in transsphenoidal surgery has gained a strong foothold. PMID- 25496633 TI - The role of the endoscopic endonasal route in the management of craniopharyngiomas. AB - BACKGROUND: Craniopharyngiomas represent one of the major challenges of neurosurgery. Surgical management of craniopharyngiomas classically required various transcranial approaches with the transsphenoidal route reserved for very selected cases. With the widespread use of endoscopes in endonasal surgery in the past decade, the extended endoscopic endonasal transtuberculum and transplanum approaches have been proposed as an alternative surgical route for removal of different types of suprasellar tumors, including solid craniopharyngiomas in patients with normal pituitary function and small sella. METHODS: A detailed report is presented of the technique used by the authors for the endoscopic endonasal approach for the resection of craniopharyngiomas. For each type of craniopharyngioma, hints and anatomic "main landmarks" are provided throughout each step of the procedure. CONCLUSIONS: The endoscopic endonasal approach offers advantages in the management of craniopharyngiomas that historically have been approached via the transsphenoidal route (i.e., purely intrasellar or intra suprasellar infradiaphragmatic, preferably cystic lesions in patients with panhypopituitarism). Use of the "extended" endoscopic endonasal approach overcomes the limits of the transsphenoidal route to the sella enabling the management of different purely suprasellar and retrosellar cystic/solid craniopharyngiomas, regardless of the sellar size or pituitary function. PMID- 25496634 TI - A three-dimensional computer-based perspective of the skull base. AB - OBJECTIVE: To describe our designed protocol for the reconstruction of three dimensional (3D) models applied to various endoscopic endonasal approaches that allows performing a 3D virtual dissection of the desired approach and analyzing and quantifying critical surgical landmarks. METHODS: All human cadaveric heads were dissected at the Laboratory of Surgical Neuroanatomy of the University of Barcelona. The dissection anatomic protocol was designed as follows: 1) virtual surgery simulation systems, 2) navigated cadaver dissection, and 3) postdissection analysis and quantification of data. RESULTS: The virtual dissection of the selected approach, the preliminary exploration of each specimen, the real dissection laboratory experience, and the analysis of data retrieved during the dissection step provide a complete method to improve general knowledge of the main endoscopic endonasal approaches to the skull base, at the same time allowing the development of new surgical techniques. CONCLUSIONS: The methodology for surgical training in the anatomic laboratory described in this article has proven to be very effective, producing a depiction of anatomic landmarks as well as 3D visual feedback that improves the study, design, and execution in various neurosurgical approaches. The Dextroscope as a virtual surgery simulation system can be used as a preoperative planning tool that can allow the neurosurgeon to perceive, practice reasoning, and manipulate 3D representations using the transsphenoidal perspective acquiring specifically visual information for endoscopic endonasal approaches to the skull base. The Dextroscope also can be used as an advanced tool for analytic purposes to perform different types of measurements between surgical landmarks before, during, and after dissection. PMID- 25496635 TI - Endoscopic approaches to the craniovertebral junction and odontoid process. AB - BACKGROUND: The microsurgical transoral approach has traditionally been the preferred access for ventral decompression of the craniovertebral junction. This natural corridor, although direct, may be a challenging approach because of potential morbidities. The evolution of endoscopic methods in skull base surgeries has reduced morbidity and improved results. Endoscopic approaches are also being used for ventral decompression at the craniovertebral junction. Some technical modifications in this approach are described. METHODS: An endoscope is inserted endonasally for a panoramic view of the entire area of interest, from the sphenoid to second cervical vertebra. Image guidance systems are used in all cases to guide the resection. The soft palate is retracted away with a rubber catheter sling when both nasal and oral corridors are being used. Various mucosal flaps are raised for access and reconstruction. Actual decompression can be done through the nasal or oral corridors based on the relationship of the pathology to the palate. Reconstruction is done using standard principles with the vascularized flaps, fat, and fibrin glue. RESULTS: Reduced surgical morbidity by avoiding palatal split and good postoperative healing are some of the advantages of this modified endoscopic technique. Better surgical exposure and a wide perspective facilitate the decompression. However, as with all newer perspectives, a learning curve exists. CONCLUSIONS: Used judiciously, this modified endoscopic approach to the craniovertebral junction and odontoid process is minimally invasive and adds to the surgeon's armamentarium. PMID- 25496636 TI - Comprehensive management of the paranasal sinuses in patients undergoing endoscopic endonasal skull base surgery. AB - OBJECTIVE: The endonasal route often provides the most direct and safe approach to skull base pathology. In this article we review the literature with regard to management of the paranasal sinuses in the setting of skull base surgery. METHODS: We describe our institutional experience and review the literature of concurrent management of the sinusitis in patients undergoing endoscopic skull base surgery. RESULTS: Patients should be optimized preoperatively to ensure the endonasal route is a safe corridor to enter the intracranial cavity. Often the paranasal sinuses can be surgically addressed at the same time as endoscopic skull base surgery. We describe the technical details of management of the paranasal sinuses when addressing skull base pathology. CONCLUSIONS: Careful management of the paranasal sinuses throughout the peri-operative course is paramount to optimizing sinonasal function and safety. PMID- 25496637 TI - From craniofacial resection to endonasal endoscopic removal of malignant tumors of the anterior skull base. AB - OBJECTIVE: To review the current literature and provide our institutional approach and opinion on the indications and limitations of traditional open craniofacial resection (CFR) and a minimally invasive pure endonasal endoscopic approach for anterior skull base tumors concentrating primarily on malignant lesions. METHODS: Based on 3 decades of experience with both open and more recently endoscopic techniques, we examined our current practice in treating tumors and other lesions involving the skull base and our current indications and limitations in the use of these techniques. We conducted a retrospective chart analysis to see which operative techniques were used for malignant tumors of the anterior skull base in the last 10 years at our institution. RESULTS: There were 30 cases identified. Traditional CFR was performed in 16, a pure endoscopic resection was performed in 9, and an endoscopic procedure combined with a frontal craniotomy was performed in 5. Gross total resection was achieved in 83.3% in the CFR group and 75% in the pure endoscopic resection group. Near-total resection was 10% in the CFR group and 33.3% in pure endoscopic resection group. Of the 5 patients who underwent a combined approach, 80% had gross total resection, and 20% had near-total resection. CONCLUSIONS: Both traditional CFR and the endonasal endoscopic approach offer advantages and disadvantages. Both approaches can achieve good results with appropriate patient selection. Numerous important factors, including location and the extent of tumor, should be taken into consideration when considering either approach. The most important determinant of outcome is the ability to achieve gross total resection with microscopic negative margins rather than the type of approach used. In the future, skull base surgeons will need to be familiar with and capable of offering both techniques to the patient. PMID- 25496638 TI - Segments of the internal carotid artery during endoscopic transnasal and open cranial approaches: can a uniform nomenclature apply to both? AB - BACKGROUND: The classic anatomic view of the course of the internal carotid artery (ICA) and its segments familiar to neurosurgeons by a 3-dimensional microscopic cranial view may be challenging to understand when seen in the unique 2-dimensional view of transnasal endoscopic surgery. OBJECTIVE: We re-examined our 1996 classification of 7 (C1-C7) segments of the ICA, comparing the arterial course in cadaveric dissections for both a transnasal endoscopic transpenoidal approach and frontotemporal craniotomy. METHODS: Five formalin-fixed cadaveric heads injected with colored silicone underwent thin-cut computed tomographic scanning for bony and vascular analysis. The ICA's intracranial course viewed by transnasal endoscopic dissection was compared with the view of a bilateral frontotemporal crantiotomy, from the petrous (C2) to communicating (C7) segments. RESULTS: Refinement of our 1996 ICA classification provides an anatomical understanding for endoscopic exposures transnasally along an inferior skull base trajectory. The changing course of the ICA, initially termed loop is now termed bend (i.e., implying a change in direction). Four bends are described as the ICA enters into the skull base as C2, C3-C4, C4, and C4-C5. We discuss delineation of certain problematic ICA segments and identify landmarks for endoscopic endonasal approaches. CONCLUSIONS: Our classification of the segments of the ICA achieves consistency without sacrificing either clinical or anatomic accuracy for either transcranial or endoscopic approaches. Universal application of this established nomenclature can avoid new and misleading terms, respects anatomical landmarks delineating segments, and provides a universal language for clear communication between disciplines. PMID- 25496639 TI - The supraorbital endoscopic approach for tumors. AB - OBJECTIVE: To describe the indications, technical nuances, and techniques for complication avoidance for the supraorbital keyhole approach with endoscopic assistance. The supraorbital eyebrow craniotomy provides minimally invasive access to a wide range of frontal fossa, parasellar, and some middle and posterior fossae tumors. This approach is considered ideal for removal of many, if not most, planum and tuberculum sellae meningiomas, some olfactory groove meningiomas, and suprasellar craniopharyngiomas, particularly tumors with far lateral extensions. It is also ideal for many intraaxial tumors, including metastases and gliomas arising from the orbitofrontal, frontal pole, and medial temporal lobe regions. The use of endoscopy further extends the range and versatility of this keyhole approach and is considered an essential adjunct for allowing safe and maximal tumor removal. PMID- 25496640 TI - Indications and limitations of the endoscopic endonasal approach for anterior cranial base meningiomas. AB - OBJECTIVE: To describe the decision-making and the surgical strategy in the resection of anterior skullbase meningiomas. METHODS: Details of the microsurgical and endoscopic approach to anterior skullbase meningiomas are presented. RESULTS: Small and midsize olfactory groove, planum sphenoidale, and tuberculum sellae meningiomas can be removed via an endonasal endoscopic approach, an alternative option to the transcranial microsurgical approach. The choice of approach depends on tumor size and location, involvement of important neurovascular structures, and, most importantly, the surgeon's preference and experience. In my opinion, in most meningiomas, the endonasal approach has no advantage compared with the transcranial approach. Disadvantages of the endonasal approach are the discomfort after surgery and the prolonged recovery phase because of the nasal morbidity, which requires intensive nasal care. Compared with the eyebrow approach, the trauma to the nasal cavity, paranasal sinuses, and skull base is greater, and the risk of cerebrospinal fluid leak is higher. CONCLUSION: For most skull base meningiomas, I usually prefer the endoscope assisted microsurgical transcranial approach which combines the advantages of the operating microscope with the advantages of the endoscope. The endonasal approach is beneficial for small tumors located below or behind the chiasm. PMID- 25496641 TI - The endoscopic endonasal approach to repair of iatrogenic and noniatrogenic cerebrospinal fluid leaks and encephaloceles of the anterior cranial fossa. AB - OBJECTIVE: The current approach for the diagnosis and repair of spontaneous and traumatic anterior skull-base defects is oulined, highlighting the controversies that exist in the field and describing the strategies required to access different segments of the anterior cranial fossa. METHODS: We reviewed the literature concerning endoscopic management of anterior skull-base defects. These publications have been combined with our own experience repairing cerebrospinal fluid (CSF) leaks and encephaloceles that developed spontaneously, traumatically, or intentionally as a result of endoscopic skull-base surgery. RESULTS: We present a systematic methodology for the repair of these defects. We have divided our surgical approach into four separate corridors. These are the transnasal, transsphenoidal, transethmoidal, and transmaxillary corridors. Dissection strategies vary for each corridor, but with a combination of approaches, all areas of the anterior skull base can be accessed. Skull-base defects are successfully repaired with a multilayered closure that often involves use of a vascularized pedicled mucosal flap. Adoption of this technique has decreased our rate of postoperative CSF leak from 5.9%-3.1%. CONCLUSIONS: Endoscopic endonasal repair of CSF leaks and encephaloceles has evolved significantly during the past decade. The versatility of different endoscopic approaches through the four endonasal corridors allows for the endoscopic repair of almost all skull-base defects. The use of vascularized pedicled mucosal flaps has evolved to cover these defects as part of multilayered closure strategies. PMID- 25496642 TI - An advanced navigation protocol for endoscopic transsphenoidal surgery. AB - OBJECTIVE: To report our clinical experience with an advanced navigation protocol that provides seamless integration into the operating workflow of endoscopic transsphenoidal surgery. PATIENTS AND METHODS: From 32 consecutive cases of endoscopic transsphenoidal surgery, an optimal setup of continuous electromagnetic instrument navigation was created. Additionally, our standard multimodality image navigation of T1-weighted magnetic resonance (MR) images for soft tissue, MR angiogram for vascular structures, and computed tomography (CT) for solid bone was advanced by the addition of a CT surface rendering for fine paranasal sinus structures. The anatomic structures visualized and their clinical impacts were compared between standard and advanced visualization protocol. Bone windowed CT images served as reference. The accuracy of the navigation setup was assessed by intraoperative landmark tests. Potential tissue shift was calculated by comparing pre- and postoperative MR angiograms of 20 macroadenomas. RESULTS: After a learning curve of 2 cases (1 ferromagnetic interference and 1 dislocation of the patient reference tracker), the advanced navigation protocol was feasible in 30 cases. Advanced multimodality imaging was able to visualize significantly finer paranasal sinus structures than multimodality image navigation without CT surface rendering, equal to bone-windowed CT images (P < 0.001, McNemar test). This was found helpful for orientation in cases of complex sphenoid sinus anatomy. The accuracy of the advanced navigation setup corresponded to standard optic navigation with skull fixation. A tissue shift of median 2 mm (range 0-9 mm) was observed in the posterior genu of the internal carotid arteries after tumor resection. CONCLUSIONS: The advanced navigation protocol permits continuous suction-tracked navigation guidance during endoscopic transsphenoidal surgery and optimal visualization of solid bone, fine paranasal sinus structures, soft-tissue and vascular structures. This may add to the safety of the procedure especially in cases of anatomical variations and in cases of recurrent adenomas with distorted anatomy. PMID- 25496643 TI - Fe(III) hydroxide nucleation and growth on quartz in the presence of Cu(II), Pb(II), and Cr(III): metal hydrolysis and adsorption. AB - Fe(III) hydroxide nanoparticles are an essential carrier for aqueous heavy metals. Particularly, iron hydroxide precipitation on mineral surfaces can immobilize aqueous heavy metals. Here, we used grazing-incidence small-angle X ray scattering (GISAXS) to quantify nucleation and growth of iron hydroxide on quartz in 0.1 mM Fe(NO3)3 solution in the presence of Na(+), Cu(2+), Pb(2+), or Cr(3+) at pH = 3.7 +/- 0.1. In 30 min, the average radii of gyration (R(g)) of particles on quartz grew from around 2 to 6 nm in the presence of Na(+) and Cu(2+). Interestingly, the particle sizes remained 3.3 +/- 0.3 nm in the presence of Pb(2+), and few particles formed in the presence of Cr(3+). Quartz crystal microbalance dissipation (QCM-D) measurements showed that only Cr(3+) adsorbed onto quartz, while Cu(2+) and Pb(2+) did not. Cr(3+) adsorption changed the surface charge of quartz from negative to positive, thus inhibiting the precipitation of positively charged iron hydroxide on quartz. Masses and compositions of the precipitates were also quantified. This study provided new insights on interactions among quartz, iron hydroxide, and metal ions. Such information is helpful not only for environmental remediation but also for the doping design of iron oxide catalysts. PMID- 25496644 TI - Outcomes of singleton and twin pregnancies complicated by pre-existing diabetes and gestational diabetes: A population-based study in Alberta, Canada, 2005-11. AB - BACKGROUND: We assessed the prevalence and pregnancy outcomes of pre-existing diabetes mellitus (pre-DM) and gestational diabetes mellitus (GDM) in Alberta, Canada, 2005-11. METHODS: 327 198 singleton and 5552 twin pregnancies resulting in live births or stillbirths were included. The odds ratios of adverse outcomes were evaluated comparing pre-DM with no diabetes and GDM with no diabetes, controlling for maternal characteristics. RESULTS: Diabetes complicated 6.3% of pregnancies, with 88% being GDM. In singleton pregnancies, pre-DM and GDM were associated with increased risks of pre-eclampsia (adjusted odds ratio [aOR] = 3.38 and 1.83, respectively), cesarean delivery (aOR 2.53, 1.55), spontaneous preterm (aOR 4.20, 1.71), and labor-induced preterm (aOR 3.82, 2.00) in the mother, and macrosomia (aOR 2.11, 1.30), shoulder dystocia (aOR 1.54, 1.32), congenital anomalies (aOR 1.61, 1.20), and neonatal intensive care unit (NICU) admissions (aOR 3.81, 1.60) in the infants. In addition, pre-DM was associated with an increased likelihood of stillbirth (aOR 3.73) and neonatal death (aOR 2.00) compared with non-diabetic pregnancies. In twin pregnancies, pre-DM was associated with increased risks of spontaneous (aOR 3.54) and labor-induced (aOR 3.57) preterm births, large for gestational age (LGA) infants (aOR 3.73), congenital anomalies (aOR 3.05) and NICU admissions (aOR 2.91); GDM was associated with an increased risk of pre-eclampsia (aOR 1.54), cesarean delivery (aOR 1.57), and LGA infants (aOR 1.63). CONCLUSIONS: Pre-existing diabetes confers higher risks than GDM. Diabetes is associated with adverse outcomes in singleton and twin pregnancies, and the increased risks are generally similar or less in twins, probably due to their higher "baseline" risks and closer clinical monitoring. PMID- 25496645 TI - DNA-protein crosslink repair: proteases as DNA repair enzymes. AB - DNA-protein crosslinks (DPCs) are highly toxic DNA lesions because they interfere with DNA transactions. The recent discovery of a yeast protease that processes DPCs proteolytically raises the question whether DPC proteases also exist in higher eukaryotes. We argue here that the yeast enzyme, Wss1 (weak suppressor of smt3), is a member of a protease family whose mammalian representative is Spartan (SprT-like domain-containing protein)/DVC1 (DNA damage protein targeting VCP). DPC proteases may thus be common to all eukaryotes where they function as novel guardians of the genome. PMID- 25496646 TI - A case-cohort study of recurrent salivary adenoid cystic carcinoma after iodine 125 brachytherapy and resection treatment. AB - Recurrent adenoid cystic carcinoma (rAdCC) can be challenging to be treated with brachytherapy, although brachytherapy is safe and effective in treating head and neck cancers. Patients of adenoid cystic carcinoma (AdCC), who underwent resection and iodine 125 ((125)I) radioactive seed implantation, were recruited for this study. Clinical data, surgical details of resection and seed implantation, histologic characteristics, and prognosis were studied. There were 16 rAdCC cases among 140 cases of AdCC treated with brachytherapy and resection. The mean follow-up duration for the recurrent cases was 61 months. The 3-year local control rate of rAdCC was 51.6%, and the overall disease-specific survival rate was 49.4%. Eight patients showed distant metastasis (50%, 8/16). The histologic grades of 10 rAdCCs were upgraded (62.5%, 10/16).Two cases displayed sarcomatous transformation after brachytherapy (1.4%, 2/140). Although the overall local control rate and survival rate were relatively favorable, some rAdCCs with an aggressive phenotype appeared to respond poorly to (125)I seed implantation. Preventive adjuvant chemotherapy should be prescribed for these rAdCCs. PMID- 25496647 TI - New findings from prospective studies. PMID- 25496648 TI - HfSe2 thin films: 2D transition metal dichalcogenides grown by molecular beam epitaxy. AB - In this work, we demonstrate the growth of HfSe2 thin films using molecular beam epitaxy. The relaxed growth criteria have allowed us to demonstrate layered, crystalline growth without misfit dislocations on other 2D substrates such as highly ordered pyrolytic graphite and MoS2. The HfSe2 thin films exhibit an atomically sharp interface with the substrates used, followed by flat, 2D layers with octahedral (1T) coordination. The resulting HfSe2 is slightly n-type with an indirect band gap of ~ 1.1 eV and a measured energy band alignment significantly different from recent DFT calculations. These results demonstrate the feasibility and significant potential of fabricating 2D material based heterostructures with tunable band alignments for a variety of nanoelectronic and optoelectronic applications. PMID- 25496649 TI - Inhibition of GPR30 by estriol prevents growth stimulation of triple-negative breast cancer cells by 17beta-estradiol. AB - BACKGROUND: Due to the lack of ERalpha, triple negative breast cancers (TNBCs) are not susceptible to endocrine therapy using antiestrogens. However, the majority of TNBCs express the membrane bound estrogen receptor GPR30. We have recently shown that knock-down of GPR30 expression prevented growth stimulation of TNBC cell lines by 17beta-estradiol. Now we analyzed whether specific inhibition of GPR30 represents a new option for therapy of TNBC. METHODS: Growth of TNBC cells was assessed using Alamar-blue colorimetric assay. Activation of c Src and EGF-receptor was assessed using Western blots. Expression of c-fos, cyclin D1 and aromatase was quantified by RT-PCR. Galpha-specific signaling of GPR30 was analyzed by electrophoretic mobility shift assay. RESULTS: HCC1806 cells showed the highest GPR30 expression, in HCC70 cells it was clearly lower, in MDA-MB-231 cells it was lowest. 10-8 M 17beta-estradiol significantly increased proliferation of HCC1806 cells to 134 +/- 12% of control (p < 0.01). Proliferation of HCC70 cells was slightly increased to 116 +/- 8% of control. Estriol significantly reduced cell number of HCC1806 cells to 16 +/- 12% (p < 0.01). Cell number of HCC70 cells and of MDA-MB-231 cells was reduced to 68 +/- 25% and to 61 +/- 10%, respectively.Activity of Src kinase increased to 150 +/- 10% (p < 0.05) by 10-8 M 17beta-estradiol treatment in HCC1806 and to 220 +/- 20% in HCC70 cells (p < 0.01). Estriol treatment completely inhibited 17beta estradiol-induced p-src activation. Transactivation of EGF-receptor increased by estradiol treatment to 350% in HCC1806 and to 280% in HCC70 cells. Estriol completely suppressed EGF-receptor transactivation. c-fos expression increased to 260% and to 190%, respectively. Estriol reduced this induction to 160% (HCC1806) and below control in HCC70 cells. Cyclin D1 was induced to 290% (HCC1806) and 170% (HCC70) and completely inhibited by estriol. 17beta-estradiol increased CREB phosphorylation to 400%. Binding of phospho-CREB to a CRE of cyclin D1 was enhanced to 320%. CONCLUSION: Specific pharmacological inhibition of GPR30 might become a promising targeted therapy for TNBC in future. PMID- 25496650 TI - [Consequences of mechanical ventilation on diaphragmatic function]. AB - INTRODUCTION: Mechanical ventilation is associated with ventilator-induced diaphragmatic dysfunction (VIDD) in animal models and also in humans. BACKGROUND: The main pathophysiological pathways implicated in VIDD seems to be related to muscle inactivity but may also be the consequence of high tidal volumes. Systemic insults from side effects of medication, infection, malnutrition and hypoperfusion also play a part. The diaphragm is caught in the cross-fire of ventilation-induced and systemic-induced dysfunctions. Intracellular consequences of VIDD include oxidative stress, proteolysis, impaired protein synthesis, autophagy activation and excitation-contraction decoupling. VIDD can be diagnosed at the bedside using non-invasive magnetic stimulation of the phrenic nerves which is the gold standard. Other techniques involve patient's participation such as respiratory function tests or ultrasound examination. CONCLUSION AND PERSPECTIVES: At this date, only spontaneous ventilatory cycles and perhaps phrenic nerve stimulation appear to diminish the severity of VIDD in humans but several pathways are currently being examined using animal models. Specific pharmacological options are currently under investigation in animal models. PMID- 25496651 TI - The Cochlear Baha 4 Attract System - design concepts, surgical technique and early clinical results. AB - Bone conduction implant systems utilize osseointegrated fixtures to transmit sound through the bones of the skull. They allow patients with hearing loss to receive acoustic signals directly to the inner ear, bypassing the outer and middle ear. The new CochlearTM Baha((r)) Attract System (Cochlear Bone Anchored Solutions AB, Molnlycke, Sweden) has been designed as a non-skin penetration hearing implant. The system uses magnetic coupling to hold the external sound processor in place and transmit acoustic energy. An implantable magnet is anchored to the skull via a single osseointegrated fixture, maximizing the efficiency of energy sound transfer. The interposed soft tissue is protected by a SoftWear pad that evenly distributes pressure in order to minimize the risk of pressure necrosis. This article summarizes the design features and early clinical results of the Baha 4 Attract System and provides context as to its place in the broader hearing aid market. PMID- 25496652 TI - ACE and sIL-2R correlate with lung function improvement in sarcoidosis during methotrexate therapy. AB - INTRODUCTION: In sarcoidosis, the search for disease activity markers that correlate with treatment response is ongoing. The aim of this study was to investigate the pattern of two proposed markers, serum angiotensin-converting enzyme (ACE) and soluble IL-2 receptor (sIL-2R) during methotrexate (MTX) therapy in sarcoidosis patients. MATERIALS AND METHODS: We analysed 114 sarcoidosis patients who used MTX for six months, consisting of a subgroup of 76 patients with a pulmonary indication for treatment and a subgroup of 38 patients with an extra-pulmonary indication. ACE and sIL-2R serum levels were measured at baseline and after six months of treatment. Correlation coefficients (R) and odds ratios (ORs) were calculated to study the correlation and predictive effect of serum ACE and sIL-2R levels for pulmonary improvement. RESULTS: High baseline levels of ACE correlated significantly with lung function improvement after treatment (R = 0.45, p < 0.0001; stronger in the pulmonary subgroup R 0.57, p < 0.0001). ACE baseline levels >90 U/l predicted a 10% improvement in overall lung function (OR 3.55; CI 1.34-9.38), with the highest prediction level for 10% improvement in DLCO (OR 4.63; CI 1.23-17.4). After six months of MTX, mean ACE decreased with 17.2 U/l (p < 0.0001) and sIL-2R with 1850 pg/ml (p < 0.0001). Decreases in both ACE and sIL-2R correlated with an increase in lung function. The strongest correlation was found with change in DLCO in the pulmonary subgroup (ACE R = 0.63, P < 0.0001; sIL-2R R = 0.56, P < 0.0001). CONCLUSION: Baseline and serial serum ACE and sIL-2R levels correlate well with lung function improvement during MTX treatment. Serial measurements of these biomarkers are helpful in monitoring treatment effects in sarcoidosis patients. PMID- 25496653 TI - Endless validation of diagnostic imaging modalities to assess acute coronary syndrome: has the time finally come for computed tomography angiography? PMID- 25496654 TI - Obstructive sleep apnea syndrome: An important piece in the puzzle of cardiovascular risk factors. AB - The obstructive sleep apnea syndrome (OSA) is a clinical entity characterized by recurring episodes of apnea and/or hypopnea during sleep, due to a total or partial collapse, respectively, of the upper airway. This collapse originates a set of pathophysiological changes that determine the appearance of several cardiovascular complications. OSA contributes for the development of hypertension, heart failure, arrhythmias and coronary heart disease. Nowadays it is recognized to be an important public health problem, taking into account not just its repercussions but also its prevalence, since the main risk factor for the disease is obesity, a growing problem worldwide, both in developed and developing countries. The present review summarizes the current knowledge about OSA, as regards its definition, pathophysiology, clinical manifestations, diagnosis, cardiovascular effects and treatment. PMID- 25496655 TI - [The continuum of COPD and cardiovascular risk: A global scenario of disease]. AB - Chronic obstructive pulmonary disease (COPD) is a serious public health problem in our country. COPD is a treatable and preventable disease which is underdiagnosed. The EPISCAN study revealed a prevalence of 10.2% in Spain between individuals of 40-80 years, with 73% underdiagnosis. In Primary Care occupies 8.5% of all queries with a high economic impact. These patients exhibit some degree of systemic inflammation characterized by increased plasma levels of some inflammatory mediators such as IL-1, IL-6, IL-8, CRP and TNF, which are also related to endothelial disorders and arteriosclerosis. In the continuum of COPD, comorbidities most frequently appear are: ischemic heart disease, heart failure, stroke, hypertension, type 2 diabetes mellitus, renal failure, osteoporosis, myopathy, anxiety, depression, cognitive impairment, malnutrition, anemia and lung cancer. PMID- 25496656 TI - Interplays between the cell wall and phytohormones in interaction between plants and necrotrophic pathogens. AB - The plant cell wall surrounds every cell in plants. During microbial infection, the cell wall provides a dynamic interface for interaction with necrotrophic phytopathogens as a rich source of carbohydrates for the growth of pathogens, as a physical barrier restricting the progression of the pathogens, and as an integrity sensory system that can activate intracellular signaling cascades and ultimately lead to a multitude of inducible host defense responses. Studies over the last decade have provided evidence of interplays between the cell wall and phytohormone signaling. This review summarizes the current state of knowledge about the cell wall-phytohormone interplays, with the focus on auxin, cytokinin, brassinosteroids, and abscisic acid, and discuss how they impact the outcome of plant-necrotrophic pathogen interaction. PMID- 25496657 TI - Hepatitis C virus and lipid droplets: finding a niche. AB - Hepatitis C virus (HCV) causes serious liver disease in chronically infected individuals. Infectious virions are released from hepatocytes as lipoprotein complexes, indicating that the virus interacts with very low density lipoprotein (VLDL) assembly to propagate. The primary source of lipid for incorporation into VLDL is cytoplasmic lipid droplets (LDs). This organelle is targeted by two virus encoded proteins as part of a process essential for virion morphogenesis. Moreover, LDs regulate infection. A common condition in HCV-infected individuals is steatosis, characterized by an accumulation of LDs. The mechanisms underlying development of steatosis include direct effects of the virus on lipid metabolism. This review reveals new insights into HCV infection and a further twist to the growing list of functions performed by LDs. PMID- 25496658 TI - A practical methodology to measure unbiased gas chromatographic retention factor vs. temperature relationships. AB - Compound identification continues to be a major challenge. Gas chromatography mass spectrometry (GC-MS) is a primary tool used for this purpose, but the GC retention information it provides is underutilized because existing retention databases are experimentally restrictive and unreliable. A methodology called "retention projection" has the potential to overcome these limitations, but it requires the retention factor (k) vs. T relationship of a compound to calculate its retention time. Direct methods of measuring k vs. T relationships from a series of isothermal runs are tedious and time-consuming. Instead, a series of temperature programs can be used to quickly measure the k vs. T relationships, but they are generally not as accurate when measured this way because they are strongly biased by non-ideal behavior of the GC system in each of the runs. In this work, we overcome that problem by using the retention times of 25 n-alkanes to back-calculate the effective temperature profile and hold-up time vs. T profiles produced in each of the six temperature programs. When the profiles were measured this way and taken into account, the k vs. T relationships measured from each of two different GC-MS instruments were nearly as accurate as the ones measured isothermally, showing less than two-fold more error. Furthermore, temperature-programmed retention times calculated in five other laboratories from the new k vs. T relationships had the same distribution of error as when they were calculated from k vs. T relationships measured isothermally. Free software was developed to make the methodology easy to use. The new methodology potentially provides a relatively fast and easy way to measure unbiased k vs. T relationships. PMID- 25496660 TI - Strengthening moral reasoning through dedicated ethics training in dietetic preparatory programs. AB - Moral reasoning skills, associated with the ability to make ethical decisions effectively, must be purposively fostered. Among health professionals, enhanced moral reasoning is linked to superior clinical performance. Research demonstrates that moral reasoning is enhanced through dedicated, discussion-based ethics education offered over a period of 3-12 weeks. Current dietetic students and practicing dietitians seeking to strengthen their moral reasoning skills can undertake elective ethics education. Further research within dietetic preparatory programs is warranted to better inform the development and implementation of ethics courses. PMID- 25496661 TI - The effect of farrowing environment and previous experience on the maternal behaviour of sows in indoor pens and outdoor huts. AB - Outdoor farrowing huts facilitate a less restricted maternal behaviour in sows compared with sows kept indoors in farrowing pens. The aim of our study was to investigate whether there are behavioural differences between primiparous sows kept outdoors in farrowing huts and indoors in pens, and whether the maternal behaviour during the second parity, when all sows were kept outdoors in farrowing huts, would differ between sows that have experienced the indoor or the outdoor environment, respectively, during their first parturition. A total of 26 Yorkshire*Swedish Landrace sows were studied. Of these, 11 sows were housed outdoors in farrowing huts during both parturitions (group=OUTOUT). The other 15 sows were kept indoors in a barn with single farrowing pens during their first parturition. During their second parturition, sows were kept outdoors in farrowing huts (group=INOUT). The behaviour was video recorded from 2 h prepartum to 48 h postpartum. The sows' responsiveness to playbacks of a piglet's screams was tested on days 2 to 3 postpartum. Parity 1: during the last 2 h prepartum, OUTOUT sows had a higher proportion of observations in the sternal lying position (P<0.01). During parturition, OUTOUT sows changed posture more often (P<0.05) and were lying less (P<0.05) than INOUT sows. All sows in both groups responded with 'lifting head' towards the playback of piglet scream, whereas 100% of OUTOUT sows and only 43% of INOUT sows thereafter were 'getting up' (P <0.01). Parity 2: There were no behavioural differences between INOUT and OUTOUT sows. In conclusion, it is not problematic for a second parity sow with initial maternal experience from an indoor farrowing pen to be kept outdoors in farrowing huts during its following farrowing. PMID- 25496659 TI - The impact of clinical heterogeneity in schizophrenia on genomic analyses. AB - Though clinically useful, the diagnostic systems currently employed are not well equipped to capture the substantial clinical heterogeneity observed for most psychiatric disorders, as exemplified by the complex psychotic disorder(s) that Bleuler aptly labeled the "Group of Schizophrenias". The clinical heterogeneity associated with schizophrenia has likely frustrated decades of attempts to illuminate the underlying genetic architecture, although recent genome-wide association studies have begun to provide valuable insight into the role of common genetic risk variants. Here we demonstrate the importance of using diagnostic information to identify a core form of the disorder and to eliminate potential comorbidities in genetic studies. We also demonstrate why applying a diagnostic screening procedure to the control dataset to remove individuals with potentially related disorders is critical. Additionally, subjects may participate in multiple studies at different institutions or may have genotype data released by more than one research group. It is thus good practice to verify that no identical subjects exist within or between samples prior to conducting any type of genetic analysis to avoid potential confounding of results. While the availability of genomic data for large collections of subjects has facilitated many investigations that would otherwise not have been possible, we clearly show why one must use caution when acquiring data from publicly available sources. Although the broad vs. narrow debate in terms of phenotype definition in genetic analyses will remain, it is likely that both approaches will yield different results and that both will have utility in resolving the genetic architecture of schizophrenia. PMID- 25496662 TI - Learning, motor skill, and long-range correlations. AB - Long-range correlations have been evidenced in a number of experiments, generally using overlearned and overpracticed tasks. The authors hypothesized that long range correlation could represent the byproduct of learning. They analyzed the series of periods produced by a group of expert and a group of novices during prolonged trials on a ski simulator. Results showed a very low variability in expert's series, as compared to novices. Fractal analyses showed that fluctuations were significantly more structured and correlated in experts. These results suggest that learning could be conceived as the progressive installation of complexity in the system. PMID- 25496663 TI - Reprint of: Dream vs. reality: seven case-studies on the desirability and feasibility of cross-border hospital collaboration in Europe. AB - Despite being a niche phenomenon, cross-border health care collaboration receives a lot of attention in the EU and figures visibly on the policy agenda, in particular since the policy process which eventually led to the adoption of Directive 2011/24/EU. One of the underlying assumptions is that cross-border collaboration is desirable, providing justification to both the European Commission and to border-region stakeholders for promoting it. The purpose of this paper is to question this assumption and to examine the role of actors in pushing (or not) for cross-border collaboration. The analysis takes place in two parts. First, the EU policies to promote cross-border collaboration and the tools employed are examined, namely (a) use of European funds to sponsor concrete border-region collaboration projects, (b) use of European funds to sponsor research which gives visibility to cross-border collaboration, and (c) use of the European Commission's newly acquired legal mandate to encourage "Member States to cooperate in cross-border health care provision in border-regions" (Art. 10) and support "Member States in the development of European reference networks between health care providers and centres of expertise" (Art. 12). Second, evidence gathered in 2011-2013 from seven European border-regions on hospital cross-border collaboration is systematically reviewed to assess the reality of cross-border collaboration - can it work and when, and why do actors engage in cross-border collaboration? The preliminary findings suggest that while the EU plays a prominent role in some border-region initiatives, cross-border collaboration needs such a specific set of circumstances to work that it is questionable whether it can effectively be promoted. Moreover, local actors make use of the EU (as a source of funding, legislation or legitimisation) to serve their needs. PMID- 25496665 TI - Ultrasonographic evaluation of adrenal gland size compared to body weight in normal dogs. AB - The accepted cut-off value for adrenal gland maximum diameter of 0.74 cm to distinguish adrenal gland enlargement in dogs regardless of body weight may not be appropriate for small to medium breed dogs. The purpose of the current retrospective study was to examine adrenal gland dimensions as a function of body weight in healthy dogs in three weight categories (< 10 kg, 10-30 kg, and > 30 kg) representing small, medium, and large breeds, respectively, to establish greater confidence in determining if adrenal gland size is abnormal. The measurements of length (sagittal plane), cranial and caudal pole thickness (sagittal and transverse planes), and caudal pole width (transverse plane) of both adrenal glands were obtained ultrasonographically in clinically healthy dogs (n = 45) with 15 dogs in each weight group. Findings support our hypothesis that adrenal gland size correlates with body weight in normal dogs, and more precise reference intervals should be created for adrenal gland size by categorizing dogs as small, medium, or large breed. The caudal pole thickness of either adrenal gland in a sagittal plane was the best dimension for evaluating adrenal gland size based on low variability, ease, and reliability in measurement. PMID- 25496664 TI - Molecular signatures that correlate with induction of lens regeneration in newts: lessons from proteomic analysis. AB - BACKGROUND: Amphibians have the remarkable ability to regenerate missing body parts. After complete removal of the eye lens, the dorsal but not the ventral iris will transdifferentiate to regenerate an exact replica of the lost lens. We used reverse-phase nano-liquid chromatography followed by mass spectrometry to detect protein concentrations in dorsal and ventral iris 0, 4, and 8 days post lentectomy. We performed gene expression comparisons between regeneration and intact timepoints as well as between dorsal and ventral iris. RESULTS: Our analysis revealed gene expression patterns associated with the ability of the dorsal iris for transdifferentiation and lens regeneration. Proteins regulating gene expression and various metabolic processes were enriched in regeneration timepoints. Proteins involved in extracellular matrix, gene expression, and DNA associated functions like DNA repair formed a regeneration-related protein network and were all up-regulated in the dorsal iris. In addition, we investigated protein concentrations in cultured dorsal (transdifferentiation competent) and ventral (transdifferentiation-incompetent) iris pigmented epithelial (IPE) cells. Our comparative analysis revealed that the ability of dorsal IPE cells to keep memory of their tissue of origin and transdifferentiation is associated with the expression of proteins that specify the dorso-ventral axis of the eye as well as with proteins found highly expressed in regeneration timepoints, especially 8 days post-lentectomy. CONCLUSIONS: The study deepens our understanding in the mechanism of regeneration by providing protein networks and pathways that participate in the process. PMID- 25496666 TI - Inappropriate use of urinary catheters among hospitalized elderly patients: Clinician awareness is key. AB - AIM: To investigate incidence, reasons, risk factors and outcomes for inappropriate use of urinary catheters in hospitalized elderly patients. METHODS: The prospective study enrolled 321 patients aged 65 years and older with a urinary catheter placed within 24 h of hospitalization. Collected data included characteristics of patients and catheter use, reasons for urinary catheter use, mortality, length of hospital stay, time to first removal of catheter, catheter remaining in place at discharge, catheter-associated urinary tract infections and complications, change of activities of daily living, and new admission to nursing home after discharge. RESULTS: The use of 418 urinary catheters was observed. Among these patients with a total of 1958 urinary catheter-days, 1035 (52.8%) urinary catheter-days were inappropriate in hospitalized elderly patients. Inappropriate catheter use occurred mostly in women and surgical patients, and was associated with initially inappropriate catheter use and lack of medical documentation. "Convenience of care" was the most common reason for inappropriate catheter use. Inappropriate use was a significant predictor for longer hospital stay, delayed timing of first removal of catheter, increased rate of catheterization in place at discharge, increased incidence of catheter-associated urinary tract infections and catheter-related complications, and decline in activities of daily living. CONCLUSIONS: The study highlights a considerable percentage of inappropriate use of urinary catheters and its association with adverse outcomes in hospitalized elderly patients. Efforts to improve quality of documentation by clinicians and to emphasize catheterization education for patients and caregivers are necessary to reduce the incidence of inappropriate urinary catheter use. Geriatr Gerontol Int 2015; 15: 1235-1241. PMID- 25496667 TI - Genome-wide shRNA screening identifies host factors involved in early endocytic events for HIV-1-induced CD4 down-regulation. AB - BACKGROUND: Down-modulation of the CD4 receptor is one of the hallmarks of HIV-1 infection and it is believed to confer a selective replicative advantage to the virus in vivo. This process is mainly mediated by three viral proteins: Env, Vpu and Nef. To date, the mechanisms that lead to CD4 depletion from the surface of infected cells during HIV-1 infection are still only partially characterized. In this study, we sought to identify and characterize cellular host factors in HIV-1 induced CD4 down-modulation. RESULTS: To identify host factors involved in CD4 down-regulation, we used a whole genome-targeting shRNA lentiviral library in HeLa CD4+ cells expressing Nef as an inducer of CD4 down-modulation. We identified 55 genes, mainly encoding for proteins involved in various steps of clathrin-mediated endocytosis. For confirmation and further selection of the hits we performed several rounds of validation, using individual shRNA lentiviral vectors with a different target sequence for gene knock-down in HIV-1-infected T cells. By this stringent validation set-up, we could demonstrate that the knock down of DNM3 (dynamin 3), SNX22 (sorting nexin 22), ATP6AP1 (ATPase, H+ Transporting, Lysosomal Accessory Protein 1), HRBL (HIV-Rev binding protein Like), IDH3G (Isocitrate dehydrogenase), HSP90B1 (Heat shock protein 90 kDa beta member 1) and EPS15 (Epidermal Growth Factor Receptor Pathway Substrate 15) significantly increases CD4 levels in HIV-infected SupT1 T cells compared to the non-targeting shRNA control. Moreover, EPS15, DNM3, IDH3G and ATP6AP1 knock-down significantly decreases HIV-1 replication in T cells. CONCLUSIONS: We identified seven genes as cellular co-factors for HIV-1-mediated CD4 down-regulation in T cells. The knock-down of four out of seven of these genes also significantly reduces HIV-1 replication in T cells. Next to a role in HIV-mediated CD4 down regulation, these genes might however affect HIV-1 replication in another way. Our findings give insights in the HIV-1-mediated CD4 down-regulation at the level of the plasma membrane and early endosomes and identify four possible new HIV-1 replication co-factors. PMID- 25496668 TI - Imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. AB - OBJECTIVE: The objective of the study was to describe the imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) on computed tomography (CT). MATERIALS AND METHODS: Electronic medical records were searched for patients with pathology-proven DIPNECH who had a CT available for review. Eleven patients were included. RESULTS: The most common finding on CT was small pulmonary nodules which were present in all patients and were multiple (>=5) in 7/11 patients. Other CT findings included mosaic pattern attenuation and bronchial wall thickening/bronchiectasis. CONCLUSION: DIPNECH should be considered as a diagnostic possibility when multiple small pulmonary nodules are identified on CT, particularly if there is an associated carcinoid tumor. PMID- 25496669 TI - Gastric large cell neuroendocrine carcinoma with venous tumor thrombus: the value of PET/CT and contrast-enhanced computed tomography. AB - Venous involvement is commonly detected microscopically on gastric neuroendocrine carcinomas (NECs), but related imaging studies have been rarely documented. We report a rare case of gastric large cell NEC with tumor thrombi in gastric and splenic veins, elevated serum alpha fetoprotein, and multiple hepatic nodules. In this case, (18)F-fluorodeoxyglucose positron emission tomography combined with contrast-enhanced computed tomography provided valuable information on tumor staging. PMID- 25496670 TI - Deconstructing and reconstructing theory of mind. AB - Usage of the term 'theory of mind' (ToM) has exploded across fields ranging from developmental psychology to social neuroscience and psychiatry research. However, its meaning is often vague and inconsistent, its biological bases are a subject of debate, and the methods used to study it are highly heterogeneous. Most crucially, its original definition does not permit easy downward translation to more basic processes such as those studied by behavioral neuroscience, leaving the interpretation of neuroimaging results opaque. We argue for a reformulation of ToM through a systematic two-stage approach, beginning with a deconstruction of the construct into a comprehensive set of basic component processes, followed by a complementary reconstruction from which a scientifically tractable concept of ToM can be recovered. PMID- 25496671 TI - Subcortical white matter infarcts predict 1-year outcome of fatigue in stroke. AB - BACKGROUND: Fatigue is common in stroke survivors. Lesion location may influence the risk of poststroke fatigue (PSF) but it is uncertain whether location has an impact on the prognosis of PSF. This study examined the association between PSF outcome and infarct location. METHODS: The study sample comprised 435 Chinese patients with acute ischemic stroke admitted to the acute stroke unit of a university affiliated regional hospital in Hong Kong. Three and fifteen months after the onset of the index stroke a research assistant administered the Fatigue Severity Scale (FSS). PSF was defined as a FSS score of 4.0 or above. Of the 139 patients with PSF three months poststroke, 97 (69.8%) attended the 15-month follow-up, when 50 (51.5%) patients still had PSF ('non-remitters') and 47 (48.5%) did not report fatigue ('remitters'). The presence and location of infarcts were evaluated with magnetic resonance imaging. RESULTS: In comparison with the remitters, the non-remitters were more likely to have subcortical white matter infarcts (40.0% vs 21.3%, p = 0.046). These infarcts remained an independent predictor of non-remission of PSF in the multivariate analysis, with an odds ratio of 4.208 (p = 0.011). CONCLUSIONS: The results suggest that subcortical white matter infarcts may influence the outcome of PSF. Further investigations are needed to explore whether infarcts have any impact on the response of PSF to pharmacological or psychological interventions. PMID- 25496673 TI - Effect of sequential medium with fibroblast growth factor-10 and follicle stimulating hormone on in vitro development of goat preantral follicles. AB - A sequential medium with fibroblast growth factor-10 (FGF-10) and follicle stimulating hormone (FSH) was evaluated on the survival, ultrastructure, activation and growth rate of caprine preantral follicles submitted to long-term culture, aiming to establish an ideal in vitro culture system. Ovarian fragments were cultured for 16 days in alpha-MEM(+) alone or supplemented with FGF-10 and/or FSH added sequentially on different days of culture. Ovarian fragments were cultured during the first (days 0-8) and second (days 8-16) halves of the culture period, generating 10 treatments: alpha-MEM(+)/alpha-MEM(+) (cultured control), FSH/FSH, FSH/FGF-10, FSH/FSH+FGF-10, FGF-10/FGF-10, FGF-10/FSH, FGF 10/FSH+FGF-10, FSH+FGF-10/FSH+FGF-10, FSH+FGF-10/FSH and FSH+FGF-10/FGF-10. Follicle morphology, viability and ultrastructure were analyzed. The FSH/FGF-10 treatment showed a higher (P<0.05) percentage of normal follicles compared to all other treatments. In addition, follicles from the FSH/FGF-10 treatment maintained ultrastructural integrity after the culture period. After 16 days of culture, the FSH/FGF-10 and FSH/FSH treatments showed a higher percentage of activation compared to the cultured control (alpha-MEM(+)/alpha-MEM(+)). Moreover, the FSH/FGF-10 treatment promoted greater follicular and oocyte diameters compared to the fresh control. In conclusion, this study showed that a sequential medium with FSH followed by FGF-10 (FSH/FGF-10 and FSH/FSH) maintains follicular viability and ultrastructure and promotes transition from the primordial to primary stage (activation) and growth in goat preantral follicles cultured in vitro. PMID- 25496672 TI - Study on matrix metalloproteinase 1 and 2 gene expression and NO in dairy cows with ovarian cysts. AB - The objective of this study was to investigate how changes in total nitric oxide (NO) and ovarian matrix metalloproteinase (MMP)-1 and MMP-2 correlated with luteinizing hormone (LH) and estradiol (E2) in infertile dairy cows with ovarian cysts. Holstein cows (n=21 infertile cows and 19 fertile) were studied during their estrous phase to minimize hormone fluctuations. Blood LH, E2 and NO were measured. Expression of the MMP-1 and MMP-2 genes in the ovaries was measured by real-time PCR and immunohistochemistry. LH, E2 and NO were less in infertile cows with ovarian cysts than in fertile cows (P<0.05). The mRNAs of MMP-1 and MMP-2 were less in infertile cows with ovarian cysts than in fertile cows (P<0.05). The immunohistochemical results showed that MMP-1 and MMP-2 genes were expressed in different parts of the ovarian tissues, including granulosa and theca cells of preovulatory follicles, epithelial follicular cells of small follicles, stromal cells and endothelial cells of blood vessels. The results showed that a decrease in MMP-1 and MMP-2 gene expression is accompanied with a decrease in NO concentrations in infertile cows affected with ovarian cysts. The expression of these marker genes might be risk factors of infertility in cows and might correlate with the hormonal profile. The present study suggests that the abnormal expression of the MMP-1/2 gene might be an important marker of ovarian follicular cysts in dairy cows. PMID- 25496674 TI - Effects of lignocaine on pressor response to laryngoscopy and endotracheal intubation during general anaesthesia in rigid suspension laryngoscopy. AB - OBJECTIVE: This study aimed to compare the effects of topical and systemic lignocaine on the circulatory response to direct laryngoscopy performed under general anaesthesia. METHODS: Ninety-nine patients over 20 years of age, with a physical status of I-II (classified according to the American Society of Anesthesiologists), were randomly allocated to 3 groups. One group received 5 ml of 0.9 per cent physiological saline intravenously, one group received 1.5 mg/kg lignocaine intravenously, and another group received seven puffs of 10 per cent lignocaine aerosol applied topically to the airway. Mean arterial pressures, heart rates and peripheral oxygen saturations were recorded, and changes in mean arterial pressure and heart rate ratios were calculated. RESULTS: Changes in the ratios of mean arterial pressure and heart rate were greater in the saline physiological group than the other groups at 1 minute after intubation. Changes in the ratios of mean arterial pressure (at the same time point) were greater in the topical lignocaine group than in the intravenous lignocaine group, but this finding was not statistically significant. CONCLUSION: Lignocaine limited the haemodynamic responses to laryngoscopy and endotracheal intubation during general anaesthesia in rigid suspension laryngoscopy. PMID- 25496675 TI - Modification of a Braided Support Catheter into a Rapid Exchange System for Navigation of a Distal Protection Device through Significant Vascular Tortuosity. AB - Cerebral embolic protection devices (EPD) reduce the rate of periprocedural thromboembolic complications and are currently used in all carotid artery stenting (CAS) procedures. However, tortuous vascular anatomy of the internal carotid artery (ICA) may prevent navigation of distal EPDs, thereby leading to inadequate cerebral protection. We present a case in which significant tortuosity of the ICA distal to the stenotic lesion precluded navigation of currently available distal EPDs. During a CAS procedure, significant vascular tortuosity of the distal cervical ICA was noted which prevented navigation of currently available distal EPDs due to catheter kinking. In order to overcome this anatomic barrier, a novel rapid exchange catheter system (RECS) was created using a modified DAC 038 braided catheter through which a distal EPD and microguidewire were placed. This newly devised RECS allowed navigation of the distal EPD past the tortuous ICA bend and successful completion of the CAS procedure without periprocedural complications. We demonstrate that modification of currently available devices can, in select cases, effectively address cases of significant vascular tortuosity which limit the use of conventional distal EPDs. PMID- 25496676 TI - Microcatheter looping facilitates access to both the acutely angled parent artery and cerebral aneurysms for effective embolization. AB - Aneurysms with an acutely angled parent artery are difficult to access for coiling. This study aimed to investigate the safety and effectiveness of microcatheter looping for embolization of cerebral aneurysms with access difficulty. Ten patients (male:female=5:5) with cerebral aneurysms treated with the microcatheter looping technique were analyzed retrospectively. The parent artery formed an acute angle with the major artery in five aneurysms. The microcatheter was looped into a "alpha" loop for treatment in the anterior temporal artery aneurysm and a "U" loop in the remaining nine aneurysms. All ten aneurysms were successfully treated with the microcatheter looping technique. The microcatheter tip was successfully navigated into the aneurysm sac and remained stable throughout the embolization process. All aneurysms were occluded with total occlusion in five and near-total occlusion in five, and the parent artery remained patent in all cases. No complications occurred peri-procedurally. The Glasgow Outcome Scale was 5 in all patients before discharge. Follow-up angiography six to 12 months later revealed a good occlusion status of the aneurysms. The microcatheter looping technique is effective when the conventional embolization technique fails to treat cerebral aneurysms with difficult access especially when the parent artery forming an acute angle with the major artery exacerbates difficult access to the aneurysms. PMID- 25496678 TI - Contrast-Enhanced and Time-of-Flight MR Angiographic Assessment of Endovascular Coiled Intracranial Aneurysms at 1.5 T. AB - This study evaluated contrast-enhanced magnetic resonance angiography (CE-MRA) and three-dimensional time-of-flight magnetic resonance angiography (3D-TOF-MRA) through comparisons with digital subtraction angiography (DSA) for the follow-up of intracranial aneurysms treated with detachable coils. Sixty-seven patients with 79 aneurysms underwent 3D-TOF-MRA, CE-MRA, and catheter angiography one year after coiling. Two independent observers classified recanalization status on images as neck or body remnant or no recanalization. For 3D-TOF-MRA and CE-MRA, the intermodality agreement, interobserver agreement, and correlation with angiography were assessed. Sixty-seven patients with 79 coiled aneurysms agreed to participate in the study. Three aneurysms could not be detected on 3D-TOF-MRA, so they were excluded from this study. Interobserver agreement was very good for 3D-TOF-MRA and CE-MRA (kappa (kappa): 0.87, 0.94, respectively). Correlation of TOF-MRA with angiography was good (kappa: 0.76). Correlation of CE-MRA with angiography was excellent (kappa: 0.91). The sensitivity and specificity of TOF MRA were 92% and 98%, respectively. The sensitivity and specificity of CE-MRA were 96% and 98%, respectively. After selective embolization of intracranial aneurysms, CE-MRA is useful and comparable to DSA in the assessment of aneurysmal recanalization. Agreement with the gold standard is stronger with CE-MRA than with 3D-TOF-MRA. PMID- 25496677 TI - Hybrid y stenting with the waffle-cone. A technical note. AB - Endovascular treatment of wide-neck bifurcation aneurysms is challenging and often requires adjunctive techniques and devices. We report our experience with the hybrid Y stenting with the waffle-cone technique, combining Y stent-assisted coiling and waffle-cone stenting techniques. This approach has been described only in a single case report using a combination of open and closed cell stents. We describe four cases treated by hybrid Y stenting with the waffle-cone procedure with a variation from the originally reported technique, consisting in deploying two closed cell stents. All patients were successfully treated without complications. We propose hybrid Y stenting with the waffle-cone for the treatment of wide-neck bifurcation aneurysms as a bailout technique after failure of Y stent-assisted coiling. PMID- 25496679 TI - Will Fluoroscopic Follow-up after Stent-Assisted Coiling of Cerebral Aneurysms Provide Information on Recanalization? AB - Fluoroscopic images for comparison (FICs) can be easily obtained for follow-up on an outpatient basis. This study retrospectively assessed the diagnostic performance of a set of FICs for evaluation of recanalization after stent assisted coiling, with digital subtraction angiography (DSA) as the reference standard. A total of 124 patients harboring 144 stent-assisted coiled aneurysms were included. At least one month postembolization they underwent follow-up angiograms comprising a routine frontal and lateral DSA and a working-angle DSA. For analysis, FICs should be compared with the mask images of postprocedural DSAs to find recanalization. Instead of FIC acquisition, the mask images of follow-up DSAs were taken as a substitute because of the same view-making processes as FICs, full availability, and perfect coincidence with follow-up DSAs. Two independent readers evaluated a set of 169 FICs and DSA images for the presence of recanalization one month apart. Sensitivity, specificity, and interreader agreement were determined. Recanalization occurred in 24 (14.2%) cases. Of these, nine (5.3%) cases were found to have significant recanalization in need of retreatment. Sensitivity and specificity rates were 79.2% (19 of 24) and 95.9% (139 of 145) respectively for reader 1, and 66.7% (16 of 24) and 97.9% (142 of 145) for reader 2. Minimal recanalization was identified in seven out of all eight false negative cases. Excluding minimally recanalized cases in no need for retreatment from the recanalization group, calculation resulted in high sensitivity and specificity of over 94% for both readers. Interreader agreement between the two readers was excellent (96.4%; kappa = 0.84). FICs may be a good imaging modality to detect significant recanalization of stent-assisted coiled aneurysms. PMID- 25496680 TI - Effect of the Interaction between Recanalization and Collateral Circulation on Functional Outcome in Acute Ischaemic Stroke. AB - Identification of patients with acute ischaemic stroke who could most benefit from arterial recanalization after endovascular treatment remains an unsettled issue. Although several classifications of collateral circulation have been proposed, the clinical role of collaterals is still debated. We evaluated the effect of the collateral circulation in relation to recanalization as a predictor of clinical outcome. Data were prospectively collected from 103 patients consecutively treated for proximal middle cerebral or internal carotid artery occlusion. The collateral circulation was evaluated with a novel semiquantitative qualitative score, the Careggi collateral score (CCS), in six grades. Both CCS and recanalization grades (TICI) were analysed in relation to clinical outcome. A statistical analysis was performed to evaluate the effect of interaction between recanalization and collateral circulation on clinical outcome. Out of the 103 patients, 37 (36.3%) had poor collaterals, and 65 (63.7%) had good collaterals. Patients with good collaterals had lower basal National Institute of Health Stroke Scale (NIHSS), more distal occlusion, smaller lesions at 24h CT scan and better functional outcome. After multivariate analysis, the interaction between recanalization and collateral grades was significantly stronger as a predictor of good outcome (OR 6.87, 95% CI 2.11-22.31) or death (OR 4.66, 95%CI 1.48-14.73) compared to the effect of the single variables. Collaterals showed an effect of interaction with the recanalization grade in determining a favourable clinical outcome. Assessment of the collateral circulation might help predict clinical results after recanalization in patients undergoing endovascular treatment for acute ischaemic stroke. PMID- 25496681 TI - Color-coded digital subtraction angiography in the management of a rare case of middle cerebral artery pure arterial malformation. A technical and case report. AB - The advent of flow dynamics and the recent availability of perfusion analysis software have provided new diagnostic tools and management possibilities for cerebrovascular patients. To this end, we provide an example of the use of color coded angiography and its application in a rare case of a patient with a pure middle cerebral artery (MCA) malformation. A 42-year-old male chronic smoker was evaluated in the emergency room due to sudden onset of severe headache, nausea, vomiting and left-sided weakness. Head computed tomography revealed a right basal ganglia hemorrhage. Cerebral digital subtraction angiography (DSA) showed a right middle cerebral artery malformation consisting of convoluted and ectatic collateral vessels supplying the distal middle cerebral artery territory-M1 proximally occluded. An associated medial lenticulostriate artery aneurysm was found. Brain single-photon emission computed tomography with and without acetazolamide failed to show problems in vascular reserve that would indicate the need for flow augmentation. Twelve months after discharge, the patient recovered from the left-sided weakness and did not present any similar events. A follow-up DSA and perfusion study using color-coded perfusion analysis showed perforator aneurysm resolution and adequate, albeit delayed perfusion in the involved vascular territory. We propose a combined congenital and acquired mechanism involving M1 occlusion with secondary dysplastic changes in collateral supply to the distal MCA territory. Angiographic and cerebral perfusion work-up was used to exclude the need for flow augmentation. Nevertheless, the natural course of this lesion remains unclear and long-term follow-up is warranted. PMID- 25496682 TI - Curative glubran 2 embolization of cerebral arteriovenous malformations patient selection and initial results. AB - The liquid embolic agents currently used for embolization of cerebral arteriovenous malformations are Onyx and NBCA. Glubran 2, a cyanoacrylate-based synthetic glue, has recently been applied for embolization of cerebral arteriovenous malformations (AVMs). We report the clinical results of selected cerebral AVMs treated with Glubran 2 targeting for curative embolization. Between October 2011 and March 2013, 31 patients with cerebral AVMs were selected for curative embolization with Glubran 2. There were 19 men and 12 women with a mean age of 32 years (range 4-65 years). Initial clinical presentation included hemorrhage in 28 and seizures in three patients. AVM location was frontal in eight patients, parietal in four, occipital in eight temporal in six, cerebellar in two and cerebellar vermis in three patients. Follow-up was performed clinically and with angiography examination at three to six months. Clinical outcomes were evaluated based on the modified Rankin Scale (mRS). A mean of 2.5 (range, 1-12) feeding pedicles were embolized per patient. Complete angiographic obliteration of AVM was achieved in 27 patients. A hemorrhagic complication was observed in one patient, an ischemic complication in one patient and technical complications in four patients. There was no procedure-related disabling neurological deficit or death at discharge. Additional gamma knife radiosurgery was performed in five patients, including one patient with recurrent AVM. All of the patients had favorable clinical outcomes at three to six month follow-up (mRS<=2). The curative embolization technique with Glubran 2 for selected cerebral AVMs achieved a high initial complete obliteration rate with an acceptable complication frequency. PMID- 25496683 TI - Treatment of complex intracranial aneurysms using flow-diverting silk(r) stents. An analysis of 32 consecutive patients. AB - This study describes the peri-procedural and late complications and angiographic follow-up results of 32 patients with 34 complex aneurysms treated with flow diverter Silk stents in a single centre. In this retrospective study, 40 Silk stents (SS) were implanted in 34 complex intracranial aneurysms in 32 patients. In our series, 20 (58.8%) carotid-ophthalmic internal carotid artery (ICA), six (17.6%) cavernous ICA, two (5.9%) supraclinoid ICA, two (5.9%) petrosal ICA (the same patient- bilateral) and four (11.8%) posterior circulation aneurysms were treated. One of the posterior circulation lesions was a fenestrated-type aneurysm. Twenty wide-necked, saccular; eight neck remnant; four fusiform and two blister-like aneurysms were included in our series. SS were successfully implanted in all patients (100%). Misdeployment occurred in 17.6% of patients. In two of these patients adequate stent openness was achieved via Hyperglide balloon dilatation. Coil embolization in addition to SS placement was utilized in four aneurysms. One patient (3%) experienced transient morbidity due to a thromboembolic event and there was one mortality (3%) due to remote intraparenchymal haemorrhage. Complete occlusion of 27/33 (81.8 %) and 29/33 (87.9 %) aneurysms was achieved six and 12 months after the procedure, respectively. In-stent intimal hyperplasia was detected in 6.1 % patients. Flow diverter Silk stent implantation is an effective method of treating complex aneurysms with acceptable mortality and morbidity rates. Complete occlusion is achieved in most of the complex aneurysms. PMID- 25496684 TI - Technical failure of giant supraclinoid aneurysm after internal carotid artery occlusion. A report of three cases. AB - We describe three cases of technical failure in patients with giant supraclinoid aneurysm treated with internal carotid artery (ICA) occlusion. Case 1 was a 65 year-old woman who presented with a two-month history of headache accompanied by blurred vision of the left eye. Case 2 was a 43-year-old woman who presented with a six-month history of headache accompanied by blurred vision of the right eye. Case 3 was a 21-year-old man admitted due to headache and blurred vision of the left eye, accompanied by left oculomotor nerve palsy for three months. Cerebral angiography revealed giant supraclinoid aneurysms in these patients. All of them were treated with ICA occlusion. One case had recurrent headache symptoms after the first procedure and was retreated. Two cases suffered from post-procedural intracranial hemorrhagic complications. Before ICA occlusion for giant supraclinoid aneurysm, balloon occlusion test was used to evaluate the collateral anastomosis between the external carotid artery (ECA) and the ICA, and still plays an important role in preventing treatment failure. PMID- 25496685 TI - Endovascular treatment of internal carotid artery pseudo-aneurysm presenting with epistaxis. A case report. AB - Recurrent epistaxis is a rare presentation of internal carotid artery C4/C5 segment pseudo-aneurysm rupture. We describe a case of a traumatic internal carotid artery pseudo-aneurysm with recurrent epistaxis as a leading symptom that was finally managed with endovascular treatment with stent-assisted coil placement. Clopidogrel and acetylsalicylic acid orally were introduced in the therapy for further stent thrombosis prevention and epistaxis did not recur on six-month follow-up. Endovascular treatment with stent-assisted coil placement seems to be a good method for pseudo-aneurysm treatment while keeping the lumen of the parent artery patent. PMID- 25496686 TI - Anatomical risk factors for ischemic lesions associated with carotid artery stenting. AB - The purpose of this study was to investigate the anatomical risk factors for ischemic lesions detected by diffusion-weighted imaging (DWI) associated with carotid artery stenting (CAS). DWI was performed within four days after CAS in 50 stenotic lesions between January 2008 and September 2013. We retrospectively analyzed the correlation between the anatomical factors and ischemic lesions associated with CAS. Post-procedural DWI revealed new ischemic lesions after 24 (48%) of the 50 CAS procedures. All three patients with common carotid artery tortuosity, defined as the presence of severe angulation (less than 90 degrees) in the common carotid artery, developed new ischemic lesions. However, there were no significant differences between the patients with and without tortuosity, likely due to the small number of cases. Meanwhile, seven of eight patients with internal carotid artery tortuosity, defined as the presence of severe angulation (less than 90 degrees) in the cervical segment of the internal carotid artery, developed new ischemic lesions. A multivariate analysis showed internal carotid artery tortuosity (odds ratio: 11.84, 95% confidence interval: 1.193-117.4, P= 0.035) to be an independent risk factor for the development of ischemic lesions associated with CAS. Anatomical factors, particularly severe angulation of the internal carotid artery, have an impact on the risk of CAS. The indications for CAS should be carefully evaluated in patients with these factors. PMID- 25496687 TI - Stent fracture and occlusion after treatment of symptomatic vertebral artery ostium stenosis with a self-expanding device. A case report. AB - Endovascular stenting with a balloon expandable device is currently the preferred treatment modality for symptomatic proximal vertebral artery stenosis, but high rates of in-stent restenosis remain a major problem, for which stent fracture might be a contributing factor. Limited reports showed that placement of self expanding stents in the proximal vertebral artery might reduce restenosis; no stent fracture has been reported to date. We describe here a new case of fracture and occlusion of a self-expanding stent after endovascular treatment of symptomatic vertebral artery ostium stenosis. PMID- 25496688 TI - Bilateral migration of open-cell design carotid stents in the early post procedure period: a rare complication. AB - We describe migration of bilateral carotid stents in a 63-year-old man shortly after stenting. Carotid stent migration was found four days post-procedure on the right side and one day post-procedure on the left side on angiography and duplex ultrasound, respectively. This is the first reported case of bilateral carotid artery stenting complicated by bilateral proximal migration of open-cell design stents in the early post-procedure period. PMID- 25496689 TI - Anatomically based approach for endovascular treatment of vertebro-vertebral arteriovenous fistula. AB - Vertebro-vertebral arteriovenous fistula (VV-AVF) is a rare vascular disorder with an abnormal high-flow shunt between the extracranial vertebral artery (VA), its muscular or radicular branches and an adjacent vein. To date, there are no guidelines on the best treatment for VV-AVF. We present our experience of VV-AVF treatment with covered stents in three patients and detachable coils in two patients. One patient with fistula at the V3 segment had rapid fistula recurrence one week after covered stent treatment. The possible causes of failed treatment in this patient are discussed. The currently available treatment modalities for VV-AVF are also summarized after a literature review. At the end of this article, we propose a new concept of anatomically based approach for endovascular treatment of VV-AVF. Fistula in the V1-2 segments of vertebral artery could be treated safely and effectively by covered stent with the benefit of preserving VA patency. Embolization with variable embolizers should be considered first for fistula in the V3 segment because of the tortuous course and flexibility of the VA in this segment. PMID- 25496690 TI - Ruptured isolated spinal artery aneurysms. Report of two cases and review of the literature. AB - Isolated spinal artery aneurysms are exceedingly rare vascular lesions thought to be related to dissection of the arterial wall. We describe two cases presenting with spinal subarachnoid haemorrhage that underwent conservative management. In the first patient the radiculomedullary branch involved was feeding the anterior spinal artery at the level of D3 and thus, neither endovascular nor surgical approach was employed. Control angiography was performed at seven days and at three months, demonstrating complete resolution of the lesion. In our second case, neither the anterior spinal artery or the artery of Adamkiewicz could be identified during angiography, thus endovascular management was deemed contraindicated. Magnetic resonance imaging showed a stable lesion in the second patient. No rebleeding or other complications were seen. In comparison to intracranial aneurysms, spinal artery aneurysms tend to display a fusiform appearance and lack a clear neck in relation to the likely dissecting nature of the lesions. Due to the small number of cases reported, the natural history of these lesions is not well known making it difficult to establish the optimal treatment approach. Various management strategies may be supported, including surgical and endovascular treatment, but It would seem that a wait and see approach is also viable, with control angiogram and treatment decisions based on the evolution of the lesion. PMID- 25496691 TI - Dural arteriovenous shunt development in patients with vein of galen malformation. AB - Dural arteriovenous fistulas (DAVF) associated with our series of patients with vein of Galen malformations (VOGM) are analyzed and discussed. We retrospectively analyzed 87 consecutive cases of VOGM treated between May 2002 and December 2011 and identified 26 patients with DAVF. We gathered information from the clinical case records, angiographic images, MRI on presentation and during follow-up. The findings were analyzed to aid discussion. Among 87 patients treated by multi stage endovascular embolization, age range from newborn to 19 years, 26(30%) had DAVF. In seven patients (8%), DAVF were found on initial angiogram and were all into the VOGM. Nineteen (21%) DAVF found on follow-up angiograms were all into the VOGM and distant locations. Sprouting and non-sprouting angiogenesis resulted in the formation of a network of vessels around partially thrombosed VOGM, recruiting blood from the surrounding dura mater resulting in a secondary network on the dura mater supplied by the blood vessels of dura mater in the region or from its natural collaterals. Embolization targeting DAVFs was done in 13 (52%) with complete cure in eight (32%) and recurrence in five (20%). Among 12 non embolized patients (48%), eight (32%) had spontaneous regression with continued treatment of VOGM. In others, the DAVF either remained stable or progressed. DAVF associated with VOGM represent the dural response to angiogenic stimuli. They are observed to regress spontaneously or mature while continuing to treat the primary feeders of VOGM. It is important to include the external carotid system during angiograms. Persistent DAVF with residual VOGM that do not have access though the pial vessels are used as a conduit to treat the dural shunt and to achieve obliteration of residual VOGM at later stages of treatment. PMID- 25496692 TI - Endovascular treatment of a ruptured flow aneurysm of the heubner artery as part of a moyamoya collateral network in a young patient with an occluded middle cerebral artery. AB - A young woman with an occluded middle cerebral artery presented with a ruptured flow aneurysm distal on a Heubner artery as part of a moyamoya collateral network. Leptomeningeal collateral supply was tested by occlusion of the A1 origin of the Heubner artery. This test occlusion demonstrated ample collateral leptomeningeal supply over the hemispheres to the M2. Subsequently, the Heubner artery harbouring the aneurysm could be safely proximally occluded with coils. PMID- 25496694 TI - Migration of a fractured inferior vena cava filter strut to the right ventricle of the heart: a case report. AB - A 23 year old woman presented with sudden onset retrosternal chest pain following an attempt to move a heavy object from her vehicle. Multiple fractured struts of an inferior vena cava filter were identified in the distal right and left pulmonary artery branches, and in the free wall of the right ventricle. A small pericardial effusion was noted. Because of the depth of penetration into the right ventricle, it was perceived not to be amenable to endovascular retrieval. Over several days of observation, she continued to have progressive retrosternal and left shoulder pain. She underwent exploratory sternotomy and extraction of a strut that was partially protruding from the right ventricle and abrading the diaphragmatic pericardium. The patient recovered quite well and was discharged on the third postoperative day. PMID- 25496693 TI - Radiological changes in infantile dissecting anterior communicating artery aneurysm treated endovascularly. A case report and five-year follow-up. AB - Intracranial aneurysms are extremely rare in infants, and to our knowledge only seven infants treated for ruptured spontaneous dissecting aneurysms have been reported. Good outcomes have been achieved with endovascular treatment of infantile aneurysm. We the endovascular treatment of a one-month-old girl for ruptured dissecting aneurysm located in the anterior communicating artery, and the unique radiological changes that were observed during the perioperative and follow-up periods. These changes suggest that blood coagulation and fibrinolytic response play a part in the repair and healing processes of dissecting aneurysms. Careful neuroradiological surveys are needed for pediatric dissecting aneurysms treated endovascularly. PMID- 25496695 TI - Widespread contamination of coastal sediments in the Transmanche Channel with anti-androgenic compounds. AB - This study analysed the levels of androgen receptor antagonist activity in extracts of coastal sediments sampled from estuaries in southern UK and northern France. Anti-androgenic (AA) activity varied between <0.2 and 224.3+/-38.4MUg flutamide equivalents/g dry weight of sediment and was significantly correlated with the total organic carbon and silt content of samples. AA activity was detected in tissues extracts of clams, Scrobicularia plana, sampled from a contaminated estuary, some of which was due to uptake of a series of 4 or 5 ring polycyclic aromatic hydrocarbons (PAHs). Initial studies also indicated that fractionated extracts of male, but not female, clams also contained androgen receptor agonist activity due to the presence of dihydrotestosterone in tissues. This study reveals widespread contamination of coastal sediments of the Transmanche region with anti-androgenic compounds and these contaminants should be investigated for their potential to disrupt sexual differentiation in aquatic organisms. PMID- 25496696 TI - More jellyfish everybody? PMID- 25496697 TI - Fate of Deepwater Horizon oil in Alabama's beach system: understanding physical evolution processes based on observational data. AB - The impact of MC252 oil on northern Gulf of Mexico (GOM) beaches from the 2010 Deepwater Horizon (DWH) catastrophe was extensive along Alabama's beaches. While considerable amount of cleanup has occurred along these beaches, as of August 2014, DWH oil spill residues continue to be found as surface residual balls (SRBs), and also occasionally as submerged oil mats (SOMs). Four years of field observations informing the fate and transport of DWH SRBs in Alabama's beach system are presented here, along with a conceptual framework for describing their physical evolution processes. The observation data show that SRBs containing MC252 residues currently remain in Alabama's beach system, although their relationship to SOMs is not fully known. Based on our field observations we conclude that small DWH SRBs are likely to persist for several years along the Alabama shoreline. PMID- 25496698 TI - Family Accommodation Scale for Obsessive-Compulsive Disorder-Interviewer-Rated (FAS-IR), Brazilian Portuguese version: internal consistency, reliability, and exploratory factor analysis. AB - OBJECTIVE: To examine the psychometric properties of the Brazilian Portuguese version of the Family Accommodation Scale for Obsessive-Compulsive Disorder Interviewer-Rated (FAS-IR). METHOD: A total of 114 family members of patients with obsessive-compulsive disorder (OCD) were assessed. The following analyses of the FAS-IR were carried out: internal consistency, inter-rater and test-retest reliability, and exploratory factor analysis. RESULTS: The Brazilian Portuguese version of the FAS-IR showed excellent inter-rater reliability (intraclass correlation coefficient [ICC]=0.94) and acceptable test-retest reliability (ICC=0.77), with no significant differences in FAS-IR scores. Factor analysis produced three factors for the scale. However, factor loadings were not well defined within each factor, and the factors did not have distinct constructs. Thus, a global analysis approach was chosen, revealing good internal consistency of the scale as a whole (Cronbach's alpha=0.805). CONCLUSIONS: The Brazilian Portuguese FAS-IR showed sound psychometric properties for the evaluation of family accommodation, and is, therefore, a reliable instrument for use in research and clinical practice. PMID- 25496699 TI - Big data in wildlife research: remote web-based monitoring of hibernating black bears. AB - BACKGROUND: Numerous innovations for the management and collection of "big data" have arisen in the field of medicine, including implantable computers and sensors, wireless data transmission, and web-based repositories for collecting and organizing information. Recently, human clinical devices have been deployed in captive and free-ranging wildlife to aid in the characterization of both normal physiology and the interaction of animals with their environment, including reactions to humans. Although these devices have had a significant impact on the types and quantities of information that can be collected, their utility has been limited by internal memory capacities, the efforts required to extract and analyze information, and by the necessity to handle the animals in order to retrieve stored data. RESULTS: We surgically implanted miniaturized cardiac monitors (1.2 cc, Reveal LINQTM, Medtronic Inc.), a newly developed human clinical system, into hibernating wild American black bears (N = 6). These devices include wireless capabilities, which enabled frequent transmissions of detailed physiological data from bears in their remote den sites to a web-based data storage and management system. Solar and battery powered telemetry stations transmitted detailed physiological data over the cellular network during the winter months. The system provided the transfer of large quantities of data in near-real time. Observations included changes in heart rhythms associated with birthing and caring for cubs, and in all bears, long periods without heart beats (up to 16 seconds) occurred during each respiratory cycle. CONCLUSIONS: For the first time, detailed physiological data were successfully transferred from an animal in the wild to a web-based data collection and management system, overcoming previous limitations on the quantities of data that could be transferred. The system provides an opportunity to detect unusual events as they are occurring, enabling investigation of the animal and site shortly afterwards. Although the current study was limited to bears in winter dens, we anticipate that future systems will transmit data from implantable monitors to wearable transmitters, allowing for big data transfer on non-stationary animals. PMID- 25496700 TI - Plasma mRNA expression levels of BRCA1 and TS as potential predictive biomarkers for chemotherapy in gastric cancer. AB - OBJECTIVE: Personalized chemotherapy based on predictive biomarkers can maximize efficacy. However, tumor tissue obtained at the time of initial diagnosis will not reflect genetic alterations observed at the time of disease progression. We have examined whether plasma mRNA levels can be a surrogate for tumor levels in predicting chemosensitivity. METHODS: In 150 gastric cancer patients, mRNA levels of BRCA1 and TS were assessed in plasma and paired tumor tissue. The Mann-Whitney U-test was used to compare mRNA expression levels between tumor samples exhibiting in vitro sensitivity or resistance to docetaxel and pemetrexed. All statistical tests were two-sided. RESULTS: There were significant correlations between plasma and tumor mRNA levels of BRCA1 (rho = 0.696, P < 0.001) and TS (rho = 0.620, P < 0.001). BRCA1 levels in plasma (docetaxel-sensitive: 1.25; docetaxel-resistant: 0.50, P < 0.001) and tumor (docetaxel-sensitive: 8.81; docetaxel-resistant: 4.88, P < 0.001) were positively associated with docetaxel sensitivity. TS levels in plasma (pemetrexed-sensitive: 0.90; pemetrexed resistant: 1.82, P < 0.001) and tumor (pemetrexed-sensitive: 6.56; pemetrexed resistant: 16.69, P < 0.001) were negatively associated with pemetrexed sensitivity. CONCLUSIONS: Plasma mRNA expression levels mirror those in the tumor and may have a promising role as potential predictive biomarkers for chemotherapy. PMID- 25496701 TI - Features of migraine aura in teenagers. AB - BACKGROUND: Complex migraine aura in teenagers can be complicated to diagnose. The aim of this study was to present detailed features of migraine aura in teenage migraineurs. METHODS: This cross-sectional study was conducted in the period from 2008 till 2013. A total number of 40 teenage migraineurs (20 females and 20 males) met criteria for this study. The patients were interviewed using a specially designed questionnaire for collecting data about migraine aura features. Main outcome measures were frequency of visual, somatosensory and higher cortical dysfunction (HCD) symptoms in teenage migraineurs population during the aura, and also within each individual. RESULTS: Visual aura was reported in every attack, followed by somatosensory (60%) and dysphasic (36.4%) aura. Scintillating scotoma and blurry vision were mostly reported and predominant visual symptoms. The most common somatosensory symptom was numbness in hand. HCD were reported by 22 (55%) patients. Slowed speech was mostly reported symptom of HCD, followed by dyslexia, deja vu phenomenon, color dysgnosia, and dyspraxia. In patients with HCD, aura frequency per year (6.18 +/- 3.17 vs. 3.33 +/- 2.03, p = 0.003) and prevalence of somatosensory symptoms (77.3% vs. 38.9%, p = 0.014) were significantly higher than in patients without HCD. CONCLUSIONS: Aura symptoms vary to a great extent in complexity in teenage migraineurs. Consequently, results obtained in this study provide useful information for clinicians when faced with unusual migraine aura. PMID- 25496702 TI - TGF-beta2 secretion from RPE decreases with polarization and becomes apically oriented. AB - Retinal pigmented epithelium (RPE) secretes transforming growth factor beta 1 and 2 (TGF-beta1 and -beta2) cytokines involved in fibrosis, immune privilege, and proliferative vitreoretinopathy (PVR). Since RPE cell polarity may be altered in various disease conditions including PVR and age-related macular degeneration, we determined levels of TGF-beta from polarized human RPE (hRPE) and human stem cell derived RPE (hESC-RPE) as compared to nonpolarized cells. TGF-beta2 was the predominant isoform in all cell culture conditions. Nonpolarized cells secreted significantly more TGF-beta2 supporting the contention that loss of polarity of RPE in PVR leads to rise of intravitreal TGF-beta2. Active TGF-beta2, secreted mainly from apical side of polarized RPE, represented 6-10% of total TGF-beta2. In conclusion, polarity is an important determinant of TGF-beta2 secretion in RPE. Low levels of apically secreted active TGF-beta2 may play a role in the normal physiology of the subretinal space. Comparable secretion of TGF-beta from polarized hESC-RPE and hRPE supports the potential for hESC-RPE in RPE replacement therapies. PMID- 25496703 TI - Using winter 2009-2010 to assess the accuracy of methods which estimate influenza related morbidity and mortality. AB - We used the winter of 2009-2010, which had minimal influenza circulation due to the earlier 2009 influenza A(H1N1) pandemic, to test the accuracy of ecological trend methods used to estimate influenza-related deaths and hospitalizations. We aggregated weekly counts of person-time, all-cause deaths, and hospitalizations for pneumonia/influenza and respiratory/circulatory conditions from seven healthcare systems. We predicted the incidence of the outcomes during the winter of 2009-2010 using three different methods: a cyclic (Serfling) regression model, a cyclic regression model with viral circulation data (virological regression), and an autoregressive, integrated moving average model with viral circulation data (ARIMAX). We compared predicted non-influenza incidence with actual winter incidence. All three models generally displayed high accuracy, with prediction errors for death ranging from -5% to -2%. For hospitalizations, errors ranged from -10% to -2% for pneumonia/influenza and from -3% to 0% for respiratory/circulatory. The Serfling and virological models consistently outperformed the ARIMAX model. The three methods tested could predict incidence of non-influenza deaths and hospitalizations during a winter with negligible influenza circulation. However, meaningful mis-estimation of the burden of influenza can still result with outcomes for which the contribution of influenza is low, such as all-cause mortality. PMID- 25496704 TI - Well-defined star-shaped conjugated macroelectrolytes as efficient electron collecting interlayer for inverted polymer solar cells. AB - A star-shaped monodisperse conjugated macroelectrolyte grafted with cationic side chains, TrNBr, was designed, synthesized, and utilized as efficient electron collecting cathode interlayers for inverted polymer solar cells. A neutral one composed of identical star-shaped conjugated backbone, TrOH, was also investigated for comparison. The surface properties and the function as interfacial layers on modulating the work function of bottom electrode (indium tin oxide) were systematically studied. Both interfacial electron-selective materials show strongly thickness-dependent performance for inverted polymer solar cells, and the best performance could be achieved via optimizing the thickness with 2.4 nm of TrNBr and 8.7 nm of TrOH. Parallel investigations of optimized TrNBr and TrOH interlayer in inverted architecture with active blend layer of poly(3-hexylthiophene):indene-C60 bisadduct (P3HT:ICBA) demonstrated a remarkable power conversion efficiency (PCE) enhancement (PCE of 4.88% for TrNBr and 4.74% for TrOH) in comparison with those of conventional noninverted devices using Ca/Al cathodes (3.94%) and inverted devices with sol-gel ZnO buffer layer (4.21%). In addition, the inverted devices using the TrNBr and TrOH interlayer exhibited improved device stability in contrast to conventional noninverted devices using Ca/Al cathodes. PMID- 25496705 TI - Missing data in substance abuse research? Researchers' reporting practices of sexual orientation and gender identity. AB - BACKGROUND: Lesbian, gay, bisexual, and transgender individuals are at higher risk for substance use and substance use disorders than heterosexual individuals and are more likely to seek substance use treatment, yet sexual orientation and gender identity are frequently not reported in the research literature. The purpose of this study was to identify if sexual orientation and gender identity are being reported in the recent substance use literature, and if this has changed over time. METHOD: The PsycINFO and PubMed databases were searched for articles released in 2007 and 2012 using the term "substance abuse" and 200 articles were randomly selected from each time period and database. Articles were coded for the presence or absence of sexual orientation and gender identity information. RESULTS: Participants' sexual orientation was reported in 3.0% and 4.9% of the 2007 and 2.3% and 6.5% of the 2012 sample, in PsycINFO and PubMed sample articles, respectively, while non-binary gender identity was reported in 0% and 1.0% of the 2007 sample and 2.3% and 1.9% of the 2012 PsycINFO and PubMed sample articles. There were no differences in rates of reporting over time. CONCLUSIONS: Sexual orientation and gender identity are rarely reported in the substance abuse literature, and there has not been a change in reporting practices between 2007 and 2012. Recommendations for future investigators in reporting sexual orientation and gender identity are included. PMID- 25496706 TI - High-risk behaviors after release from incarceration among people who inject drugs in St. Petersburg, Russia. AB - BACKGROUND: Injection drug use, infectious disease, and incarceration are inextricably linked in Russia. We aimed to identify factors associated with time to relapse (first opioid injection after release from prison) and using a non sterile, previously used syringe at relapse in a sample of people who inject drugs in St. Petersburg. METHODS: We collected data on time from release to relapse among individuals with a history of incarceration, a subsample of a larger study among people who inject drugs. Proportional hazards and logistic regression were used to identify factors associated with time to relapse and injection with a non-sterile previously used syringe at relapse, respectively. RESULTS: The median time to relapse after release was 30 days. Factors that were independently associated with relapsing sooner were being a native of St. Petersburg compared to not being native (AHR: 1.64; 95% CI 1.15-2.33), unemployed at relapse compared to employed (AHR: 4.49; 95% CI 2.96-6.82) and receiving a previous diagnosis of HBV and HCV compared to no previous diagnosis (AHR: 1.49; 95% CI 1.03-2.14). Unemployment at relapse was also significant in modeling injection with a non-sterile, previously used syringe at relapse compared to those who were employed (AOR: 6.80; 95% CI 1.96-23.59). CONCLUSIONS: Unemployment was an important correlate for both resuming opioid injection after release and using a non-sterile previously used syringe at relapse. Linkage to medical, harm reduction, and employment services should be developed for incarcerated Russian people who inject drugs prior to release. PMID- 25496709 TI - A commentary on "brain vessels mummification in an individual of ancient Egypt" by Isidro et al., 2014. PMID- 25496708 TI - Cardiac arrest survivors treated with or without mild therapeutic hypothermia: performance status and quality of life assessment. AB - BACKGROUND: Hypoxic-ischaemic encephalopathy is the main determinant of clinical outcome after cardiac arrest. The study was designed to determine long-term neurological and psychological status in cardiac arrest survivors, as well as to compare neuropsychological outcomes between patients treated with mild therapeutic hypothermia (MTH) and patients who did not undergo hypothermia treatment. METHODS: The article describes a single-center, retrospective, observational study on 28 post-cardiac arrest adult patients treated in the cardiac intensive care unit who qualified for MTH vs. 37 control group patients, hospitalized at the same center following cardiac arrest in the preceding years and fulfilling criteria for induced hypothermia, but who were not treated due to unavailability of the method at that time. Disability Rating Scale (DRS), Barthel Index and RAND-36 were used to assess performance status and quality of life in both study groups after hospital discharge. RESULTS: There were no statistically significant differences in physical functioning found between groups either at the end of hospital treatment or at long-term follow-up (DRS: p = 0.11; Barthel Index: p = 0.83). In long-term follow-up, MTH patients showed higher vitality (p = 0.02) and reported fewer complaints on role limitations due to emotional problems (p = 0.04) compared to the control group. No significant differences were shown between study groups in terms of physical capacity and independent functioning. CONCLUSION: To conclude, in long-term follow-up, MTH patients showed higher vitality and reported fewer complaints on role limitations due to emotional problems compared to the control group. This suggest that MTH helps to preserve global brain function in cardiac arrest survivors. However, the results can be biased by a small sample size and variable observation periods. PMID- 25496707 TI - Treatment outcomes for substance use disorder among women of reproductive age in Massachusetts: a population-based approach. AB - INTRODUCTION: Longitudinal patterns of treatment utilization and relapse among women of reproductive age with substance use disorder (SUD) are not well known. In this statewide report spanning seven years we describe SUD prevalence, SUD treatment utilization, and differences in subsequent emergency department (ED) use and post-treatment relapse rates by type of treatment: none, 'acute only' (detoxification/stabilization), or 'ongoing' services. METHODS: We linked a statewide dataset of hospital discharge, observation stay and ED records with SUD treatment admission records from hospitals and freestanding facilities, and birth/fetal death certificates, in Massachusetts, 2002-2008. We aggregated episodes into individual woman records, identified evidence of SUD and treatment, and tested post-treatment outcomes. RESULTS: Nearly 150,000 (8.5%) of 1.7 million Massachusetts women aged 15-49 were identified as SUD-positive. Nearly half of SUD-positive women (71,533 or 48.3%) had evidence of hospital or facility-based SUD treatment; among these, 12% received acute care/detoxification only while 88% obtained 'ongoing' treatment. Treatment varied by substance type; women with dual diagnosis and those with opiate use were least likely to receive 'ongoing' treatment. Treated women were older and less likely to have a psychiatric history or chronic illness. Women who received 'acute only' services were more likely to relapse (12.4% vs. 9.6%) and had a 10% higher rate of ED visits post-treatment than women receiving 'ongoing' treatment. CONCLUSIONS: Many Massachusetts women of reproductive age need but do not receive adequate SUD treatment. 'Ongoing' services beyond detoxification/stabilization may reduce the likelihood of post treatment relapse and/or reliance on the ED for subsequent medical care. PMID- 25496711 TI - Combining bimodal presentation schemes and buzz groups improves clinical reasoning and learning at morning report. AB - Morning reports offer opportunities for intensive work-based learning. In this controlled study, we measured learning processes and outcomes with the report of paediatric emergency room patients. Twelve specialists and 12 residents were randomised into four groups and discussed the same two paediatric cases. The groups differed in their presentation modality (verbal only vs. verbal + text) and the use of buzz groups (with vs. without). The verbal interactions were analysed for clinical reasoning processes. Perceptions of learning and judgment of learning were reported in a questionnaire. Diagnostic accuracy was assessed by a 20-item multiple-choice test. Combined bimodal presentation and buzz groups increased the odds ratio of clinical reasoning to occur in the discussion of cases by a factor of 1.90 (p = 0.013), indicating superior reasoning for buzz groups working with bimodal materials. For specialists, a positive effect of bimodal presentation was found on perceptions of learning (p < 0.05), and for residents, a positive effect of buzz groups was found on judgment of learning (p < 0.005). A positive effect of bimodal presentation on diagnostic accuracy was noted in the specialists (p < 0.05). Combined bimodal presentation and buzz group discussion of emergency cases improves clinicians' clinical reasoning and learning. PMID- 25496710 TI - Quantification of functional hand grip using electromyography and inertial sensor derived accelerations: clinical implications. AB - BACKGROUND: Assessing hand injury is of great interest given the level of involvement of the hand with the environment. Knowing different assessment systems and their limitations generates new perspectives. The integration of digital systems (accelerometry and electromyography) as a tool to supplement functional assessment allows the clinician to know more about the motor component and its relation to movement. Therefore, the purpose of this study was the kinematic and electromyography analysis during functional hand movements. METHOD: Ten subjects carried out six functional movements (terminal pinch, termino lateral pinch, tripod pinch, power grip, extension grip and ball grip). Muscle activity (hand and forearm) was measured in real time using electromyograms, acquired with the Mega ME 6000, whilst acceleration was measured using the AcceleGlove. RESULTS: Electrical activity and acceleration variables were recorded simultaneously during the carrying out of the functional movements. The acceleration outcome variables were the modular vectors of each finger of the hand and the palm. In the electromyography, the main variables were normalized by the mean and by the maximum muscle activity of the thenar region, hypothenar, first interosseous dorsal, wrist flexors, carpal flexors and wrist extensors. CONCLUSIONS: Knowing muscle behavior allows the clinician to take a more direct approach in the treatment. Based on the results, the tripod grip shows greater kinetic activity and the middle finger is the most relevant in this regard. Ball grip involves most muscle activity, with the thenar region playing a fundamental role in hand activity. CLINICAL RELEVANCE: Relating muscle activation, movements, individual load and displacement offers the possibility to proceed with rehabilitation by individual component. PMID- 25496712 TI - How we developed and piloted an electronic key features examination for the internal medicine clerkship based on a US national curriculum. AB - BACKGROUND: Key features examinations (KFEs) have been used to assess clinical decision making in medical education, yet there are no reports of an online KFE based on a national curriculum for the internal medicine clerkship. What we did: The authors developed and pilot tested an electronic KFE based on the US Clerkship Directors in Internal Medicine core curriculum. Teams, with expert oversight and peer review, developed key features (KFs) and cases. EVALUATION: The exam was pilot tested at eight medical schools with 162 third and fourth year medical students, of whom 96 (59.3%) responded to a survey. While most students reported that the exam was more difficult than a multiple choice question exam, 61 (83.3%) students agreed that it reflected problems seen in clinical practice and 51 (69.9%) students reported that it more accurately assessed the ability to make clinical decisions. CONCLUSIONS: The development of an electronic KFs exam is a time-intensive process. A team approach offers built-in peer review and accountability. Students, although not familiar with this format in the US, recognized it as authentically assessing clinical decision-making for problems commonly seen in the clerkship. PMID- 25496713 TI - How we implemented an analytical support clinic to strengthen student research capacity in Zambia. AB - BACKGROUND: Research outputs in sub-Saharan Africa may be limited by a scarcity of clinical research expertise. In Zambia, clinical and biomedical postgraduate students are often delayed in graduation due to challenges in completing their research dissertations. We sought to strengthen institutional research capacity by supporting student and faculty researchers through weekly epidemiology and biostatistics clinics. METHODS: We instituted a weekly Analytical Support Clinic at the University of Zambia, School of Medicine. A combination of biostatisticians, clinical researchers and epidemiologists meet weekly with clients to address questions of proposal development, data management and analysis. Clinic sign-in sheets were reviewed. RESULTS: 109 students and faculty members accounted for 197 visits to the Clinic. Nearly all clients (107/109, 98.2%) were undergraduate or postgraduate students. Reasons for attending the Clinic were primarily for proposal development (46.7%) and data management/analysis (42.1%). The most common specific reasons for seeking help were data analysis and interpretation (36.5%), development of study design and research questions (26.9%) and sample size calculation (21.8%). CONCLUSIONS: The Analytical Support Clinic is an important vehicle for strengthening postgraduate research through one-on-one and small group demand-driven interactions. The clinic approach supplements mentorship from departmental supervisors, providing specific expertise and contextual teaching. PMID- 25496714 TI - Ammonia as an in situ sanitizer: inactivation kinetics and mechanisms of the ssRNA virus MS2 by NH3. AB - Sanitizing human and animal waste (e.g., urine, fecal sludge, or grey water) is a critical step in reducing the spread of disease and ensuring microbially safe reuse of waste materials. Viruses are particularly persistent pathogens and can be transmitted through inadequately sanitized waste. However, adequate storage or digestion of waste can strongly reduce the number of viruses due to increases in pH and uncharged aqueous ammonia (NH3), a known biocide. In this study we investigated the kinetics and mechanisms of inactivation of the single-stranded RNA virus MS2 under temperature, pH and NH3 conditions representative of waste storage. MS2 inactivation was mainly controlled by the activity of NH3 over a pH range of 7.0-9.5 and temperatures lower than 40 degrees C. Other bases (e.g., hydroxide, carbonate) additionally contributed to the observed reduction of infective MS2. The loss in MS2 infectivity could be rationalized by a loss in genome integrity, which was attributed to genome cleavage via alkaline transesterification. The contribution of each base to genome transesterification, and hence inactivation, could be related to the base pKa by means of a Bronsted relationship. The Bronsted relationship in conjunction with the activity of bases in solution enabled an accurate prediction of MS2 inactivation rates. PMID- 25496715 TI - The role of melanin pigment in melanoma. PMID- 25496716 TI - Economic evaluation of ivabradine in the treatment of chronic heart failure in Greece. AB - BACKGROUND: The objective of our study was to assess the cost-effectiveness of ivabradine plus standard care (SoC) in chronic heart failure (CHF) patients with sinus rhythm and a baseline heart rate >= 75 b.p.m. in Greece, in comparison with current SoC alone. METHODS: An existing cost-effectiveness model consisting of two health states, was adapted to the Greek health care setting. All clinical inputs of the model (i.e. mortality rates, hospitalization rates, NYHA class distribution and utility values) were estimated from SHIFT trial data. All costing data used in the model reflects the year 2013 (in ?). An incremental cost effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained was calculated. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. The horizon of analysis was over patient life time and both cost and outcomes were discounted at 3.5% per year. The analysis was conducted from a Greek third party-payer perspective. RESULTS: The Markov analysis revealed that the discounted quality-adjusted survival was 4.27 and 3.99 QALYs in the ivabradine plus SoC and SoC alone treatment arms, respectively. The cumulative lifetime total cost per patient was ?8,665 and ?5,873, for ivabradine plus SoC and SoC alone, respectively. The ICER for ivabradine plus SoC versus SoC alone was estimated as ?9,986 per QALY gained. The PSA showed that the likelihood of ivabradine plus SoC being cost-effective at a threshold of ?36,000/QALY was found to be 95%. CONCLUSIONS: Ivabradine plus SoC may be regarded as a cost-effective option for the treatment in CHF patients in Greece. PMID- 25496718 TI - Response to "Seat belt injury causing bisection of the breast: a case report". PMID- 25496717 TI - Identification of single nucleotide polymorphisms in Toll-like receptor candidate genes associated with tuberculosis infection in water buffalo (Bubalus bubalis). AB - BACKGROUND: Toll-like receptors play a key role in innate immunity by recognizing pathogens and activating appropriate responses. Pathogens express several signal molecules (pathogen-associated molecular patterns, PAMPs) essential for survival and pathogenicity. Recognition of PAMPs triggers an array of anti-microbial immune responses through the induction of various inflammatory cytokines. The objective of this work was to perform a case-control study to characterize the distribution of polymorphisms in three candidate genes (toll-like receptor 2, toll-like receptor 4, toll-like receptor 9) and to test their role as potential risk factors for tuberculosis infection in water buffalo (Bubalus bubalis). RESULTS: The case-control study included 184 subjects, 59 of which resulted positive to both intradermal TB test and Mycobacterium bovis isolation (cases) and 125 resulted negative to at least three consecutive intradermal TB tests. The statistical analysis indicated that two polymorphisms exhibited significant differences in allelic frequencies between cases and controls. Indeed, the TT genotype at TLR9 2340 C > T locus resulted significantly associated with susceptibility to bovine tuberculosis (P = 0.030, OR = 3.31, 95% CI = 1.05 10.40). One polymorphism resulted significantly associated with resistance to the disease, and included the CC genotype, at the TLR4 672 A > C locus (P = 0.01, OR = 0.26, 95% CI = 0.08-0.80). Haplotype reconstruction of the TLR2 gene revealed one haplotype (CTTACCAGCGGCCAGTCCC) associated with disease resistance (P = 0.04, OR = 0.51, 95% CI = 0.27-0.96), including the allelic variant associated with disease resistance. CONCLUSIONS: The work describes novel mutations in bubaline TLR2, TLR4 and TLR9 genes and presents their association with M. bovis infection. These results will enhance our ability to determine the risk of developing the disease by improving the knowledge of the immune mechanisms involved in host response to mycobacterial infection, and will allow the creation of multiple layers of disease resistance in herds by selective breeding. PMID- 25496719 TI - Diagnosing PIP breast implant failure: a prospective analysis of clinical and ultrasound accuracy. AB - INTRODUCTION: The risk of Poly Implant Prosthesis (PIP) breast implant failure has been quantified by the Department of Health as 2-6 times greater than other brands. In the UK, removal of PIP breast implants is recommended when failure is suspected from patient history or clinical findings. Owing to conflicting reports of accuracy in current literature, ultrasound is not recommended as a routine investigation. We aimed to evaluate the accuracy of patient history, clinical impression, and ultrasound at diagnosing implant failure in a large consecutive series of women against the reference standard. We aimed to provide evidence in response to current guidelines and help guide best practice. METHODS: All patients from January 2012-January 2013 who underwent PIP breast implant explantation at the Spire Murrayfield Hospital were prospectively evaluated. Operative findings were correlated to pre-operative results of patient history, clinical impression and ultrasound imaging. Sensitivity, specificity and accuracy were calculated with 95% confidence intervals. RESULTS: A total of 192 women who underwent 384 PIP implant explantations from January 2012 to January 2013 were included. Twenty-three patients (12.0%) reported a positive patient history pre operatively. In 35 patients (18%), failure was pre-operatively diagnosed clinically. Intra-operatively, 80 implants (21%) in 63 women (33%) had failed. The sensitivity of patient history, clinical impression and ultrasound was 12%, 34%, and 91%, respectively. The specificity was 88%, 89%, and 97%, respectively. Ultrasound was 96% accurate at diagnosing PIP implant failure, whilst patient history and clinical impression were 63% and 71% accurate, respectively. CONCLUSION: Ultrasound provides a far more reliable test of implant failure than patient history or clinical impression. Considering the availability, cost and number of women in the UK with PIP implants, we would recommend high-resolution ultrasound be implemented as a routine investigation. PMID- 25496720 TI - Compounds leached from quinoa seeds inhibit matrix metalloproteinase activity and intracellular reactive oxygen species. AB - OBJECTIVE: Quinoa (Chenopodium quinoa Willd.) is a seed crop rich in bioactive compounds including phytoecdysones (especially 20-hydroxyecdysone, 20HE), polyphenols, proteins and essential fatty acids. We previously reported a method to leach and concentrate quinoa bioactives into a complex phytochemical mixture termed quinoa leachate (QL). Here, we aimed to determine the effect of QL and its chemically distinct fractions on five biochemical endpoints relevant to skin care applications: (i) cell viability, (ii) matrix metalloproteinase (MMP) mRNA expression, (iii) MMP enzymatic activity, (iv) tyrosinase enzymatic activity and (v) intracellular reactive oxygen species (ROS) production. METHODS: Quinoa leachate was fractionated and chemically characterized using column chromatography and liquid chromatography-mass spectrometry (LC-MS). Cell viability was determined using a MTT assay in four mammalian cell lines. MMP-1 mRNA expression was assessed in human dermal fibroblasts (HDF) via qRT-PCR. The enzymatic activity of MMP-9 and tyrosinase was measured using fluorometric and colorimetric in vitro assays, respectively. Lipopolysaccharide (LPS)-induced ROS production was determined in human dermal fibroblasts by fluorescence intensity of an oxidant-sensitive probe. RESULTS: Quinoa leachate was separated into three fractions: (i) carbohydrate-rich fraction (QL-C; 71.3% w/w of QL); (ii) phytoecdysone, polyphenol and protein-rich fraction (QL-P, 13.3% w/w of QL); (iii) oil-rich fraction (QL-O, 10.8% w/w of QL). QL did not reduce cell viability in any of the four cell lines tested. QL, QL-P and QL-O each significantly inhibited MMP-1 mRNA expression in HDF at a concentration of 5 MUg mL(-1) . QL and QL-P also significantly inhibited MMP-9 enzymatic activity, whereas QL-P demonstrated significant tyrosinase enzymatic inhibition. Furthermore, QL, QL-P, QL-O and 20HE significantly inhibited intracellular ROS production. CONCLUSION: This study is the first to demonstrate the MMP, tyrosinase and ROS inhibiting properties of multiple different phytochemical components derived from quinoa seeds. Our work indicates that quinoa phytochemicals may play a role in the treatment and prevention of skin ageing through a multiplicity of effects. PMID- 25496721 TI - Joint motion quality in vibroacoustic signal analysis for patients with patellofemoral joint disorders. AB - BACKGROUND: Chondromalacia, lateral patellar compression syndrome and osteoarthritis are common patellofemoral joint disorders leading to functional and/or structural disturbances in articular surfaces. The objective of the study was to evaluate their impact on joint motion quality via the vibroacoustic signal generated during joint movement analysis. METHODS: Seventy-three patients (30 with chondromalacia, 21 with lateral patellar compression syndrome, and 22 with osteoarthritis) and 32 healthy controls were tested during flexion/extension knee motion for vibroacoustic signals using an acceleration sensor. Estimated parameters: variation of mean square (VMS), difference between mean of four maximum and mean of four minimum values (R4), power spectral density for frequency of 50-250 Hz (P1) and 250-450 Hz (P2) were analyzed. RESULTS: Vibroacoustic signals recorded for particular disorders were characterized by significantly higher values of parameters in comparison to the control group. Moreover, differences were found among the various types of patellofemoral joint disturbances. Chondromalacia and osteoarthritis groups showed differences in all parameters examined. In addition, osteoarthritis patients exhibited differences in VMS, P1 and P2 values in comparison to lateral patellar compression syndrome patients. However, only the value of R4 was found to differ between knees with lateral patellar compression syndrome and those with chondromalacia. CONCLUSION: Our results suggest that particular disorders are characterized by specific vibroacoustic patterns of waveforms as well as values of analyzed parameters. PMID- 25496722 TI - The topological pressure-temperature phase diagram of ritonavir, an extraordinary case of crystalline dimorphism. AB - A topological pressure-temperature phase diagram involving the phase relationships of ritonavir forms I and II has been constructed using experimental calorimetric and volumetric data available from the literature. The triple point I-II-liquid is located at a temperature of about 407 K and a pressure as extraordinarily small as 17.5 MPa (175 bar). Thus, the less soluble solid phase (form II) will become metastable on increasing pressure. At room temperature, form I becomes stable around 100 MPa indicating that form II may turn into form I at a relatively low pressure of 1000 bar, which may occur under processing conditions such as mixing or grinding. This case is a good example for which a proper thermodynamic evaluation trumps "rules of thumb" such as the density rule. PMID- 25496723 TI - Understanding HIV infection for the design of a therapeutic vaccine. Part I: Epidemiology and pathogenesis of HIV infection. AB - HIV infection leads to a gradual loss CD4+ T lymphocytes comprising immune competence and progression to AIDS. Effective treatment with combined antiretroviral drugs (cART) decreases viral load below detectable levels but is not able to eliminate the virus from the body. The success of cART is frustrated by the requirement of expensive life-long adherence, accumulating drug toxicities and chronic immune activation resulting in increased risk of several non-AIDS disorders, even when viral replication is suppressed. Therefore there is a strong need for therapeutic strategies as an alternative to cART. Immunotherapy, or therapeutic vaccination, aims to increase existing immune responses against HIV or induce de novo immune responses. These immune responses should provide a functional cure by controlling viral replication and preventing disease progression in the absence of cART. The key difficulty in the development of an HIV vaccine is our ignorance of the immune responses that control of viral replication, and thus how these responses can be elicited and how they can be monitored. Part one of this review provides an extensive overview of the (patho-) physiology of HIV infection. It describes the structure and replication cycle of HIV, the epidemiology and pathogenesis of HIV infection and the innate and adaptive immune responses against HIV. Part two of this review discusses therapeutic options for HIV. Prevention modalities and antiretroviral therapy are briefly touched upon, after which an extensive overview on vaccination strategies for HIV is provided, including the choice of immunogens and delivery strategies. PMID- 25496725 TI - Underwater drag-reducing effect of superhydrophobic submarine model. AB - To address the debates on whether superhydrophobic coatings can reduce fluid drag for underwater motions, we have achieved an underwater drag-reducing effect of large superhydrophobic submarine models with a feature size of 3.5 cm * 3.7 cm * 33.0 cm through sailing experiments of submarine models, modified with and without superhydrophobic surface under similar power supply and experimental conditions. The drag reduction rate reached as high as 15%. The fabrication of superhydrophobic coatings on a large area of submarine model surfaces was realized by immobilizing hydrophobic copper particles onto a precross-linked polydimethylsiloxane (PDMS) surface. The pre-cross-linking time was optimized at 20 min to obtain good superhydrophobicity for the underwater drag reduction effect by investigating the effect of pre-cross-linking on surface wettability and water adhesive property. We do believe that superhydrophobic coatings may provide a promising application in the field of drag-reducing of vehicle motions on or under the water surface. PMID- 25496724 TI - Stereochemistry and neuropharmacology of a 'bath salt' cathinone: S-enantiomer of mephedrone reduces cocaine-induced reward and withdrawal in invertebrates. AB - Knowledge about the neuropharmacology of mephedrone (MEPH) applies primarily to the racemate, or street form of the drug, but not to its individual enantiomers. Here, through chemical isolation of MEPH enantiomers and subsequent behavioral characterization in established invertebrate (planarian) assays, we began separating adverse effects of MEPH from potential therapeutic actions. We first compared stereotypical and environmental place conditioning (EPC) effects of racemic MEPH, S-MEPH, and R-MEPH. Stereotypy was enhanced by acute treatment (100 1000 MUM) with each compound; however, S-MEPH was less potent and efficacious than racemate and R-MEPH. Both R-MEPH (10, 100, 250 MUM) and racemate (100 MUM) produced EPC, but S-MEPH was ineffective at all concentrations (10-100 MUM). After showing that S-MEPH lacked rewarding efficacy, we investigated its ability to alter three of cocaine's behavioral effects (EPC, withdrawal, and stereotypy). Cocaine (1 MUM) produced EPC that was abolished when S-MEPH (100 MUM) was administered after cocaine conditioning. Spontaneous withdrawal from chronic cocaine exposure caused a reduction in motility that was not evident during acute or continuous cocaine treatment but was attenuated by S-MEPH (100 MUM) treatment during the cocaine abstinence interval. Acute stereotypy produced by 1 mM cocaine, nicotine or racemic MEPH was not affected by S-MEPH (10-250 MUM). The present results obtained using planarian assays suggest that the R-enantiomer of MEPH is predominantly responsible for its stimulant and rewarding effects and the S-enantiomer is capable of antagonizing cocaine's addictive-like behaviors without producing rewarding effects of its own. PMID- 25496726 TI - Association between the introduction of a new cystic fibrosis inhaled antibiotic class and change in prevalence of patients receiving multiple inhaled antibiotic classes. AB - BACKGROUND: In 2010, aztreonam for inhalation solution joined aminoglycosides and colistimethate as a new cystic fibrosis (CF) chronic inhaled antimicrobial therapy. We studied how the introduction of this new inhaled antibiotic class changed the management of US CF patients. METHODS: The use of inhaled aminoglycosides, colistimethate, and aztreonam among patients followed in the CF Foundation Patient Registry was analyzed by age group, lung disease stage, and microbiologic status both annually, and at individual visits between 2009 and 2012. RESULTS: The overall prevalence of inhaled antibiotic use did not change during the period, but the prevalence of annual and any visit treatment with >1 inhaled antibiotic class more than doubled. Adults, those with advanced lung disease, and those with >1 Pseudomonas aeruginosa respiratory culture were more likely to receive >1 antibiotic class. CONCLUSIONS: Inhaled antibiotic management of US CF patients has dramatically changed in association with the introduction of a third inhaled antibiotic class. PMID- 25496727 TI - Effects of Spirulina platensis supplementation on lipid profile in HIV-infected antiretroviral naive patients in Yaounde-Cameroon: a randomized trial study. AB - BACKGROUND: Cardiovascular diseases (CVD) and metabolic alterations are among the majors public health concern that have been reported in people living with HIV infections. Factors contributing to cardio metabolic syndrome in HIV include body fat distribution, dyslipidemia, insulin resistance, cardiovascular dysfunction and inflammation. The aim of the study was to determine the effect of Spirulina platensis (Cyanobacteriaceae) supplementation versus local diet on lipid profile in HIV-infected antiretroviral-naive patients. METHODS: A prospective single blind, randomized, multicentre study was conducted from February 2010 to December 2012. A total of 320 HIV antiretroviral-naive patients were screened and 169 were recruited in this study. Patients were randomized and received either Spirulina supplementation combined with local diet (n=82) or local diet only (n=87). Age, weight, body mass index (BMI), lipid profile, CD4 count, and local food intake variables were assessed on three separate occasions (three, six and twelve months). RESULTS: An average age of the patients was 35.6+/-9 years. The majority of participants were female 67.1%. Regarding the lipid profile, there is a significant increase in HDL-cholesterol and a significant decrease in total cholesterol, LDL-cholesterol and triglycerides in the group of patients who consumed Spirulina platensis. A change in the atherogenic index defined by the ratio CT/HDL-C substitutable by LDL-C/HDL-C and the TC/HDL decreased significantly from 10.83 at baseline to 2.22 after 12 months (p=0.21 and p<0.0001) in the patients taking Spirulina. CONCLUSIONS: Nutritional supplementation with Spirulina combined with a quantitative and qualitative balanced diet for at least six months can retard an exposition to lipid abnormalities in HIV-infected antiretroviral-naive patients. Further studies are recommended on a large group of people not infected with HIV and exposed to cardiovascular risk factors. PMID- 25496729 TI - Characterization of the endemic equilibrium and response to mutant injection in a multi-strain disease model. AB - We explore a model of an antigenically diverse infection whose otherwise identical strains compete through cross-immunity. We assume that individuals may produce upon infection different numbers of antibody types, each of which matches the antigenic configuration of a particular epitope, and that one matching antibody type grants total immunity against a challenging strain. In order to reduce the number of equations involved in the analytic description of the dynamics, we follow the strategy proposed by Kryazhimskiy et al. (2007) and apply a low-order closure reminiscent of a pair approximation. Using this approximation, we go beyond the numerical studies of Kryazhimskiy et al. (2007) and explore the analytic properties of the ensuing model in the absence of mutation. We characterize its endemic equilibrium, comparing with the results of agent based simulations of the full model to assess the performance of the closure assumption. We show that a particular choice of immune response leads to a degenerate endemic equilibrium, where different strain prevalences may exist, breaking the symmetry of the model. Finally we study the behavior of the system under the injection of mutant strains. We find that the build up of diversity from a single founding strain is extremely unlikely for different choices of the population's immune response. PMID- 25496728 TI - Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia. AB - Cancer is a clonal evolutionary process, caused by successive accumulation of genetic alterations providing milestones of tumor initiation, progression, dissemination, and/or resistance to certain therapeutic regimes. To unravel these milestones we propose a framework, tumor evolutionary directed graphs (TEDG), which is able to characterize the history of genetic alterations by integrating longitudinal and cross-sectional genomic data. We applied TEDG to a chronic lymphocytic leukemia (CLL) cohort of 70 patients spanning 12 years and show that: (a) the evolution of CLL follows a time-ordered process represented as a global flow in TEDG that proceeds from initiating events to late events; (b) there are two distinct and mutually exclusive evolutionary paths of CLL evolution; (c) higher fitness clones are present in later stages of the disease, indicating a progressive clonal replacement with more aggressive clones. Our results suggest that TEDG may constitute an effective framework to recapitulate the evolutionary history of tumors. PMID- 25496731 TI - Adding ecology to particle capture models: numerical simulations of capture on a moving cylinder in crossflow. AB - The particle capture efficiency, eta, of systems that remove suspended particles from ambient flow (e.g. suspension feeding, abiotic pollination) has been studied using static collectors in steady flows. Particle deposition on collectors moving due to fluid flow remains largely unknown, despite its ecological relevance. We used numerical modeling to simulate particle deposition on a 2D circular cylinder subject to flow-induced oscillation in a cross flow. Using parameter values relevant to wind pollination and other natural biological systems, we examined the influence of the direction, amplitude and frequency of the oscillation, the Stokes number (Stk=0.01-5, characterizing particle behavior), as well as the Reynolds number (Re=662 and 3309, characterizing flow regime) in steady and unsteady flow, on eta. The numerical model was validated with empirical results for parts of the parameter space. Particle capture occurred via "inertial impaction", "direct interception" and "leeward deposition", as well as via a new mechanism, "collector chasing" for moving collectors. The eta of an oscillating cylinder varied significantly relative to a static cylinder, depending on the parameters used, and on the magnitude of a numerical error that caused loss of particles. This variance of eta was due to a change in relative momentum between the particle and the moving collector, which depends on Re, Stk and the oscillation parameters. Collector oscillation transverse to oncoming flow direction strongly increased eta, whereas collector motion parallel to flow had little effect on capture efficiency. The oscillation also changed leeward capture significantly in some cases. For most conditions, however, leeward deposition was small. Results suggest that collector motion could have significant influence on the particle capture efficiency of natural systems, which indicates the need to incorporate these ecologically more relevant findings into current models. Empirical studies, however, are still necessary to validate these results and provide reliable data. PMID- 25496730 TI - Contribution of HIV-1 genomes that do not integrate to the basic reproductive ratio of the virus. AB - Recent experimental data indicate that HIV-1 DNA that fails to integrate (from now on called uDNA) can by itself successfully produce infectious offspring virions in resting T cells that become activated after infection. This scenario is likely important at the initial stages of the infection. We use mathematical models to calculate the relative contribution of unintegrated and integrated viral DNA to the basic reproductive ratio of the virus, R0, and the models are parameterized with preliminary data. This is done in the context of both free virus spread and transmission of the virus through virological synapses. For free virus transmission, we find that under preliminary parameter estimates, uDNA might contribute about 20% to the total R0. This requires that a single copy of uDNA can successfully replicate. If the presence of more than one uDNA copy is required for replication, uDNA does not contribute to R0. For synaptic transmission, uDNA can contribute to R0 regardless of the number of uDNA copies required for replication. The larger the number of viruses that are successfully transmitted per synapse, however, the lower the contribution of uDNA to R0 because this increases the chances that at least one virus integrates. Using available parameter values, uDNA can maximally contribute 20% to R0 in this case. We argue that the contribution of uDNA to virus reproduction might also be important for continued low level replication of HIV-1 in the presence of integrase inhibitor therapy. Assuming a 20% contribution of uDNA to the overall R0, our calculations suggest that R0=1.6 in the absence of virus integration. While these are rough estimates based on preliminary data that are currently available, this analysis provides a framework for future experimental work which should directly measure key parameters. PMID- 25496732 TI - Global dynamic analysis of a H7N9 avian-human influenza model in an outbreak region. AB - In 2013 in China a new type of avian influenza virus, H7N9, began to infect humans and had aroused severe fatality in the infected humans. We know that the spread is from poultry to humans, and the H7N9 avian influenza is low pathogenic in the poultry world but highly pathogenic in the human world, but the transmission mechanism is unclear. Since it has no signs of human-to-human transmission and outbreaks are isolated in some cities in China, in order to investigate the transmission mechanism of human infection with H7N9 avian influenza, an eco-epidemiological model in an outbreak region is proposed and analyzed dynamically. Researches and reports show that gene mutation makes the new virus be capable of infecting humans, therefore the mutation factor is taken into account in the model. The global dynamic analysis is conducted, different thresholds are identified, persistence and global qualitative behaviors are obtained. The impact of H7N9 avian influenza on the people population is concerned. Finally, the numerical simulations are carried out to support the theoretical analysis and to investigate the disease control measures. It seems that we may take people's hygiene and prevention awareness factor as a significant policy to achieve the aim of both the disease control and the economic returns. PMID- 25496733 TI - Achilles tendinopathy alters stretch shortening cycle behaviour during a sub maximal hopping task. AB - OBJECTIVES: To describe stretch shortening cycle behaviour of the ankle and lower limb in patients with Achilles tendinopathy (AT) and establish differences with healthy volunteers. DESIGN: Between-subjects case-controlled. METHODS: Fifteen patients with AT (mean age 41.2+/-12.7 years) and 11 healthy volunteers (CON) (mean age 23.2+/-6.7 years) performed sub-maximal single-limb hopping on a custom built sledge-jump system. Using 3D motion analysis and surface EMG, temporal kinematic (lower limb stiffness, ankle angle at 80ms pre-contact, ankle angle at contact, peak ankle angle, ankle stretch amplitude) and EMG measures (onset, offset and peak times relative to contact) were captured. Data between AT and CON were compared statistically using a linear mixed model. RESULTS: Patients with AT exhibited significantly increased lower limb stiffness when compared to healthy volunteers (p<0.001) and their hopping range was shifted towards a more dorsiflexed position (p<0.001). Furthermore, ankle stretch amplitude was greater in AT compared with healthy volunteers (p<0.001). A delay in muscle activity was also observed; soleus onset (p<0.001), tibialis anterior peak (p=0.026) and tibialis anterior offset (p<0.001) were all delayed in AT compared with CON. CONCLUSIONS: These findings indicate that patients with AT exhibit altered stretch-shortening cycle behaviour during sub-maximal hopping when compared with healthy volunteers. Patients with AT hop with greater lower limb stiffness, in a greater degree of ankle dorsiflexion and have a greater stretch amplitude. Likewise, delayed muscle activity is evident. These findings have implications in terms of informing the understanding of the pathoaetiology and management of AT. PMID- 25496734 TI - Morphological and physiological responses of maize (Zea mays) exposed to sand contaminated by phenanthrene. AB - Phytoremediation is promising, but depends on clearly understanding contaminants' impact on plant functioning. We therefore focused on the impact of polycyclic aromatic hydrocarbons (PAH) on cultivated plants and understanding the impact of phenanthrene (PHE) on maize functioning (Zea mays). Cultivation was conducted under controlled conditions on artificially contaminated sand with PHE levels increasing from 50 to 750 mg PHE kg(-1). After four weeks, plants exposed to levels above 50 mg PHE kg(-1) presented decreased biomasses and reduced photosynthetic activity. These modifications were associated with higher biomass allocations to roots and lower ones to stems. The leaf biomass proportion was similar, with thinner blades than controls. PHE-exposed plant showed modified root architecture, with fewer roots of 0.2 and 0.4 mm in diameter. Leaves were potassium-deplete, but calcium, phosphorus, magnesium and zinc-enriched. Their content in nitrogen, iron, sulfur and manganese was unaffected. These responses resembled those of water-stress, although water contents in plant organs were not affected by PHE and water supply was not limited. They also indicated a possible perturbation of both nutritional functioning and photosynthesis. PMID- 25496735 TI - An evaluation on different origins of natural organic matters using various anodes by electrocoagulation. AB - In this investigation, natural organic matters (NOM) of different origins (commercial, terrestrial and natural water) were treated by electrocoagulation (EC) process using aluminum, iron and hybrid electrodes. Electrode type effect on removal efficiency was observed for each NOM (commercial, terrestrial, and natural). The results were presented as dissolved organic carbon (DOC) (mg L(-1)) and UV/VIS absorbance (cm(-1)). The specific UV absorbance (SUVA) was determined before and after treatment of water. The lowest effluent concentration was obtained as 5.05 mg L(-1) with hybrid electrode for natural NOM source at its original pH 7.3. In addition, among the metal types, the best UV-abs-254 removal efficiency was obtained as 92.4% with 0.0312 cm(-1) by hybrid electrode at the end of the process. The color removal efficiency of water occurred successfully by Al and hybrid electrodes. Aquatic NOM source was the most resistant to EC treatment with DOC reduction of 71.1%, 59.8%, and 68.6% for Al, Fe and hybrid electrodes, respectively. Zeta potential and floc size of colloids were observed during the process for the determination of destabilization level of natural organic matters in EC process. Fast coagulation or flocculation and incipient instability were formed during electrolysis time for Al and Fe electrode, respectively. SUVA value was reduced to below 2 for three NOM sources studied. The EC process was shown to be a viable for different NOM sources with various metals. PMID- 25496736 TI - Binding mechanism of arsenate on rutile (110) and (001) planes studied using grazing-incidence EXAFS measurement and DFT calculation. AB - Characterization of contaminant molecules on different exposed crystal planes is required to conclusively describe its behavior on mineral surfaces. Here, the structural properties and relative stability of arsenate adsorbed on rutile TiO2 (110) and (001) surfaces were investigated using grazing-incidence extended X-ray absorption fine structure (GI-EXAFS) spectra and periodic density functional theory (DFT) calculation. The combined results indicated that arsenate mainly formed inner-sphere bidentate binuclear (BB) and monodentate mononuclear (MM) complexes on both surfaces, but the orientational polar angles of arsenate on the (110) surface were commonly smaller than that on the (001) surface for the two adsorption modes. The DFT calculation showed that the (110) plane had a higher affinity toward arsenate than the (001) plane, suggesting that, for a given adsorption mode (i.e., MM or BB structure), a small polar angle was more favorable for arsenate stabilized on the rutile surfaces. PMID- 25496737 TI - Spinosad in the native stingless bee Melipona quadrifasciata: regrettable non target toxicity of a bioinsecticide. AB - The risks imposed by novel insecticides, mainly bioinsecticides, are largely unknown despite their increased use and their perceived environmental safety, which is based on their natural origin. Furthermore, unlike honeybees, native pollinator species have received little attention. In the present study, the lethal and sublethal effects of the neonicotinoid imidacloprid and the bioinsecticide spinosad were assessed in the stingless bee species Meliponaquadrifasciata, an important native pollinator in the Neotropical region. The adult stingless bee workers exhibited high oral insecticide susceptibility, with LD50s of 23.54 and 12.07 ng a.i./bee for imidacloprid and spinosad, respectively. Imidacloprid also impaired worker respiration and overall group activity and flight, while spinosad significantly impaired only worker flight despite exhibiting higher oral toxicity to adult workers than imidacloprid. These findings indicate the hazardous nature not only of imidacloprid but also the bioinsecticide spinosad to adult workers of the native pollinator M. quadrifasciata. Therefore, bioinsecticides should not be exempted from risk assessment analysis due to their lethal and sublethal components. PMID- 25496738 TI - Occurrence of perfluoroalkyl acids in environmental waters in Vietnam. AB - This is the first nationwide study of perfluoroalkyl acids (PFAAs) in environmental waters in Vietnam. Twenty-eight river water and 22 groundwater samples collected in four major cities and 14 river water samples from the Red River were screened to investigate the occurrence and sources of 16 PFAAs. Perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) were the most prevalent of 11 detected PFAAs with maximum concentrations in urban river water of 5.3, 18 and 0.93ngL(-1), respectively, and in groundwater of 8.2, 4.5 and 0.45ngL(-1), respectively. PFAAs in the Red River water were detected at low levels. PFAA concentrations in river water were higher in the rainy season than in the dry season, possibly due to storm water runoff, a common phenomenon in Southeast Asian countries. The highest concentrations of PFAAs in river water were observed in samples from highly populated and industrialized areas, perhaps sourced from sewage. The PFAA concentrations observed were similar to those in other Southeast Asian countries, but lower than in developed nations. From the composition profiles of PFAAs, industrial products containing PFAAs imported from China and Japan might be one of the major sources of PFAAs in the Vietnamese aquatic environment. According to the health-based values and advisory issued by the United States Environmental Protection Agency (USEPA), the concentrations of detected PFAAs in this study do not pose an immediate health risk to humans and aquatic organisms. PMID- 25496739 TI - Mercury methylation coupled to iron reduction by dissimilatory iron-reducing bacteria. AB - Iron reduction and mercury methylation by dissimilatory iron-reducing bacteria (DIRB), Geobacter sulfurreducens and Shewanella oneidensis, were studied, and the relationship of mercury methylation coupled to iron reduction was determined. The ability of both bacteria for reducing iron was tested, and Fe(III) reduction occurred with the highest rate when ferric oxyhydroxide was used as a terminal electron acceptor. G. sulfurreducens had proven to mediate the production of methylmercury (MeHg), and a notable increase of MeHg following the addition of inorganic Hg was observed. When the initial concentration of HgCl2 was 500nM, about 177.03nM of MeHg was determined at 8d after G. sulfurreducens inoculation. S. oneidensis was tested negligible for Hg methylation and only 12.06nM of MeHg was determined. Iron reduction could potentially influence Hg methylation rates. The increase in MeHg was consistent with high rate of iron reduction, indicating that Fe(III) reduction stimulated the formation of MeHg. Furthermore, the net MeHg concentration increased at low Fe(III) additions from 1.78 to 3.57mM, and then decreased when the added Fe(III) was high from 7.14 to 17.85mM. The mercury methylation rate was suppressed with high Fe(III) additions, which might have been attributable to mercury complexation and low availability. PMID- 25496740 TI - Use of lead isotopes to identify sources of metal and metalloid contaminants in atmospheric aerosol from mining operations. AB - Mining operations are a potential source of metal and metalloid contamination by atmospheric particulate generated from smelting activities, as well as from erosion of mine tailings. In this work, we show how lead isotopes can be used for source apportionment of metal and metalloid contaminants from the site of an active copper mine. Analysis of atmospheric aerosol shows two distinct isotopic signatures: one prevalent in fine particles (<1MUm aerodynamic diameter) while the other corresponds to coarse particles as well as particles in all size ranges from a nearby urban environment. The lead isotopic ratios found in the fine particles are equal to those of the mine that provides the ore to the smelter. Topsoil samples at the mining site show concentrations of Pb and As decreasing with distance from the smelter. Isotopic ratios for the sample closest to the smelter (650m) and from topsoil at all sample locations, extending to more than 1km from the smelter, were similar to those found in fine particles in atmospheric dust. The results validate the use of lead isotope signatures for source apportionment of metal and metalloid contaminants transported by atmospheric particulate. PMID- 25496742 TI - Transfer of oxytetracycline from swine manure to three different aquatic plants: implications for human exposure. AB - Little is known regarding the potential for pharmaceuticals including antibiotics to be accumulated in edible aquatic plants and enter the human food chain. This work investigates the transfer of a widely used veterinary antibiotic, oxytetracycline (OTC), from swine manure to aquatic plants by firstly characterizing desorption from swine manure to water and fitting data to both nonlinear and linear isotherms. Bioconcentration of OTC from water was then quantified with aquatic plants of contrasting morphology and growth habit viz. watermeal (Wolffia globosa Hartog and Plas), cabomba (Cabomba caroliniana A. Gray) and water spinach (Ipomoea aquatica Forsk.). Watermeal and water spinach are widely consumed in Southeast Asia. The OTC desorption and bioconcentration data were used to provide the first quantitative estimates of human exposure to OTC from a manure-water-aquatic plant route. Results show that under certain conditions (plants growing for 15d in undiluted swine manure effluent (2% w/v solids) and an initial OTC swine manure concentration of 43mgkg(-1) (dry weight)), this pathway could provide a significant fraction (>48%) of the acceptable daily intake (ADI) for OTC. While effluent dilution, lower OTC manure concentrations and not all plant material consumed being contaminated would be expected to diminish the proportion of the ADI accumulated, uptake from aquatic plants should not be ignored when determining human exposure to antibiotics such as OTC. PMID- 25496741 TI - Effect of linoleic acid sustained-release microspheres on Microcystis aeruginosa antioxidant enzymes activity and microcystins production and release. AB - The objective of this work was to identify the optimal dose range for good anti algal effect of linoleic acid (LA) sustained-release microspheres and investigate their impact on the antioxidant enzymes (super oxide dismutase, Catalase and Peroxidase) activity changes of Microcystis aeruginosa, as well as the production and release of microcystins (MCs). Based on measured changes in algal cell density and inhibitory ratio (IR), the optimal dose of LA microspheres was 0.3 g L(-1) with over 90% of IR in this study. The Chlorophyll a content and antioxidant enzymes activity in the LA microspheres group decreased markedly until beyond the minimal detection limit after 16 d and 9 d, respectively. In addition, LA microspheres demonstrated no significant impact on the extracellular release of MCs during the culturing period. The amount of intracellular microcystin-LR (MC-LR) per 10(6) algal cells in LA microspheres group was highest among all groups during the whole experimental process. Under the sustained stress of LA released from LA microspheres, the LA microspheres could decrease the production and release of algal toxins. There was no increase in the total amount of MC-LR in the algal cell culture medium. These indicated that LA sustained-release microspheres represent a high degree of ecological safety and their practical applications for the treatment of water undergoing algal blooms need further study. PMID- 25496743 TI - Elucidating triplet-sensitized photolysis mechanisms of sulfadiazine and metal ions effects by quantum chemical calculations. AB - Sulfadiazine (SDZ) mainly proceeds triplet-sensitized photolysis with dissolved organic matter (DOM) in the aquatic environment. However, the mechanisms underlying the triplet-sensitized photolysis of SDZ with DOM have not been fully worked out. In this study, we investigated the mechanisms of triplet-sensitized photolysis of SDZ(0) (neutral form) and SDZ(-) (anionic form) with four DOM analogues, i.e., fluorenone (FL), thioxanthone (TX), 2-acetonaphthone (2-AN), and 4-benzoylbenzoic acid (CBBP), and three metal ions (i.e., Mg(2+), Ca(2+), and Zn(2+)) effects using quantum chemical calculations. Results indicated that the triplet-sensitized photolysis mechanism of SDZ(0) with FL, TX, and 2-AN was hydrogen transfer, and with CBBP was electron transfer along with proton transfer (for complex SDZ(0)-CBBP2) and hydrogen transfer (for complex SDZ(0)-CBBP1). The triplet-sensitized photolysis mechanisms of SDZ(-) with FL, TX, and CBBP was electron transfer along with proton transfer, and with 2-AN was hydrogen transfer. The triplet-sensitized photolysis product of both SDZ(0) and SDZ(-) was a sulfur dioxide extrusion product (4-(2-iminopyrimidine-1(2H)-yl)aniline), but the formation routs of the products for SDZ(0) and SDZ(-) were different. In addition, effects of the metal ions on the triplet-sensitized photolysis of SDZ(0) and SDZ(-) were different. The metal ions promoted the triplet-sensitized photolysis of SDZ(0), but inhibited the triplet-sensitized photolysis of SDZ(-). PMID- 25496744 TI - The neonicotinoid pesticide imidacloprid and the dithiocarbamate fungicide mancozeb disrupt the pituitary-thyroid axis of a wildlife bird. AB - Thyroid is an important homeostatic regulator of metabolic activities as well as endocrine mechanisms including those of reproduction. Present investigation elucidated the thyroid disrupting potential of a neonicotinoid imidacloprid and a dithiocarbamate mancozeb in a seasonally breeding wildlife bird, Red Munia (Amandava amandava) who is vulnerable to these two pesticides through diet (seed grains and small insects). Adult male birds were exposed to 0.5% LD50 mgkg( 1)bwd(-1) of both the pesticides through food for 30days during the preparatory and breeding phases. Weight, volume and histopathology of thyroid gland were distinctly altered. Disruption of thyroid follicles reflected in nucleus-to cytoplasm ratio (N/C) in epithelial and stromal cells, epithelial cell hypertrophy and altered colloid volume. Impairment of thyroid axis was pesticide and phase specific as evident from the plasma levels of thyroid (T4 and T3) and pituitary (TSH) hormones. In preparatory phase, plasma TSH was increased in response to decrease of T4 on mancozeb exposure showing responsiveness of the hypothalamic-pituitary-thyroid (HPT) axis to feedback regulation. On imidacloprid exposure, however, plasma levels of both T4 and TSH were decreased indicating non functioning of negative feedback mechanism. Increased plasma T3 in response to both the pesticides exposure might be due to synthesis from non-thyroidal source(s) in a compensatory response to decrease level of T4. In breeding phase, impairment of HPT axis was more pronounced as plasma T4, T3 and TSH were significantly decreased in response to both mancozeb and imidacloprid. Thus, low dose pesticide exposure could affect the thyroid homeostasis and reproduction. PMID- 25496745 TI - Emission of perfluoroalkyl carboxylic acids (PFCA) from heated surfaces made of polytetrafluoroethylene (PTFE) applied in food contact materials and consumer products. AB - Polytetrafluoroethylene (PTFE) has been widely discussed as a source of perfluorooctanoic acid (PFOA), which has been used in the production of fluoropolymers. PTFE may also contain unintended perfluoroalkyl carboxylic acids (PFCAs) caused by thermolysis of PTFE, which has been observed at temperatures above 300 degrees C. Common PTFE coated food contact materials and consumer goods are operated at temperatures above 200 degrees C. However, knowledge on possible emissions of PFCAs is limited. Therefore, it was the aim of this study to investigate and evaluate the emission of PFCAs from PTFE coated products with both, normal use and overheating scenarios. Four pans, claimed to be PFOA free, and nine consumer products were investigated. At normal use conditions (<230 degrees C), emissions from PTFE surfaces were trapped for 1h. Overheating scenarios (>260 degrees C) recorded emissions during a 30min heating of empty pans on a stove. Emissions were analyzed by LC-ESI-MS. Results indicate the emission of PFCAs, whereas no perfluorinated sulfonic acids were traced. At normal use conditions total emissions of PFCAs accounted for 4.75ng per hour. Overheated pans, however, released far higher amounts with up to 12190ng PFCAs per hour at 370 degrees C. Dominating contributors where PFBA and PFOA at normal use and PFBA and PFPeA during overheating. Temperature seems to be the main factor controlling the emission of PFCAs. A worst case estimation of human exposure revealed that emissions of PFCAs from heated PTFE surfaces would be far below the TDI of 1500ng PFOA per kg body weight. PMID- 25496746 TI - Possible contribution of chronic inflammation in the induction of cancer in rheumatic diseases. AB - Several chronic inflammatory conditions and autoimmune diseases involving different organs and tissues have been found at risk of progression to cancer. A wide array of proinflammatory cytokines, prostaglandins, nitric oxide products, and matricellular proteins are closely involved in premalignant and malignant transition of cells almost always in a background of chronic inflammation. Interestingly, epigenetic perturbations (i.e. miRNA aberrations, altered DNA methylation) together with important steroid hormone metabolic changes (i.e. oestrogens), or the altered vitamin D concentrations that may unbalance the immune / inflammatory response, have been found linked to the risk and severity in several chronic inflammatory conditions, as well as in cancer. In particular, it is evident, that not only the parent oestrogen but also oestrogen metabolites should be taken into account when this process is evaluated, specially the formation of catecholoestrogen metabolites, that are capable of forming either stable or depurinating DNA adducts, which can cause extensive DNA damage. It is interesting that today the successful treatment of several chronic immune/inflammatory rheumatic diseases is obtained also by using medications initially developed for their use in oncology. The circadian increase of growth factors, specially during the late night, in both chronic inflammation and in cancer patients, as well as the presence of oestrogen-regulated circadian mechanisms, suggests further important links. PMID- 25496747 TI - Ultrasonographic evaluation of entheses in patients with spondyloarthritis: a systematic literature review. AB - OBJECTIVES: Enthesitis represents a characteristic features of spondyloarthritis (SpA) and, in the context of the early management of the disease, its reliable assessment has emerged as a central issue. Musculoskeletal ultrasonography (US) has proven to be of value in the assessment of peripheral entheses. Our aim was to systematically review the literature from 2010 to 2013 in order to summarise the evidence on the evaluation of entheses by US in patients with diagnosed or suspected SpA. METHODS: PubMed and Embase were searched developing a search strategy based on terms related to SpA and US. The target population were patients with SpA or suspected SpA, the intervention was entheseal US, the outcomes were the prevalence of US abnormalities, the reliability, the diagnostic accuracy, the sensitivity to change. The possible comparators were clinical evaluation and other imaging techniques. Cohort studies (cross-sectional or longitudinal), case-control studies, diagnostic accuracy studies, systematic literature reviews and meta-analyses were eligible for inclusion. RESULTS: Out of 3368 retrieved references, 34 papers were finally included. 22 of which reported information on the prevalence of US findings, yielding highly variable results. US was sufficiently reliable, as reported in 6 papers. A minority of studies reported data on sensitivity to change, which was good, and on the application of US for differential diagnosis and diagnosis of SpA, thus demonstrating the value of US also in this context. CONCLUSIONS: US confirms its validity and reliability in the assessment of entheseal involvement in patients with SpA. Further application in the help of diagnosis will be provided by future research. PMID- 25496749 TI - Potential side effects to GLP-1 agonists: understanding their safety and tolerability. AB - INTRODUCTION: Glucagon-like peptide 1 receptor (GLP-1Rx) agonists might elicit unwelcome side effects and concerns have recently been raised about their safety. AREAS COVERED: Available evidence about safety, tolerability and potential adverse events relative to GLP-1Rx agonists presently used. We searched the MEDLINE database using the terms: 'GLP-1 receptor agonists', 'Incretin therapy side effects', 'exenatide', ' liraglutide', 'exenatide long-acting release', 'lixisenatide'. Articles were selected on the basis of the study design and importance, in the light of authors' clinical experience and personal judgment. The main safety concern about GLP-1Rx agonists use is the possible association with increased risk of pancreatitis and/or tumors. This concern stems mainly from limited observations in animal models not confirmed in similar studies. Furthermore, clinical studies reporting association between GLP-1Rx agonist use and pancreatitis/cancer are marred by several biases and both clinical trials and post-marketing analyses failed to demonstrate a significant association. EXPERT OPINION: As stated by both FDA and EMA, the safety concerns emerged so far about GLP-1RX agonists should not affect present prescribing habits. Thus, although a strict data monitoring must be encouraged, they should not prevent access to the benefits of an innovative treatment, such as GLP-1Rx agonists use, to a large diabetic population still confronted with unmet needs. PMID- 25496750 TI - Transient presence of clonal chromosomal aberrations in Ph-negative cells in patients with chronic myeloid leukemia remaining in deep molecular response on tyrosine kinase inhibitor treatment. AB - Advancements in treatment of chronic myeloid leukemia (CML) turned this formerly fatal neoplasm into a manageable chronic condition. Therapy with tyrosine kinase inhibitors (TKIs) often leads to significant reduction of disease burden, known as the deep molecular response (DMR). Herein, we decided to analyze the cohort of CML patients treated in our center with TKIs, who obtain and retain DMR for a period longer than 24 months. The aim of the study was to evaluate the frequency of clonal cytogenetic aberrations in Philadelphia-negative (Ph-) cells in patients with DMR during TKI treatment. The analyzed data was obtained during routine molecular and cytogenetic treatment monitoring, using G-banded trypsin and Giemsa stain (GTG) karyotyping and reverse transcription quantitative PCR. We noticed that approximately 50% of patients (28 of 55) in DMR had, at some follow up point, transient changes in the karyotype of their Ph- bone marrow cells. In 9.1% of cases (5 of 55), the presence of the same aberrations was observed at different time points. The most frequently appearing aberrations were monosomies of chromosomes 19, 20, 21, and Y. Statistical analysis suggests that the occurrence of such abnormalities in CML patients correlates with the TKI treatment time. PMID- 25496751 TI - Is there evidence for recommending specific intravenous immunoglobulin formulations? A systematic review of head-to-head randomized controlled trials. AB - Intravenous immunoglobulins (IVIG) have been used for several licensed and off label indications. Each IVIG product is a unique formulation of IgG and excipients, making them distinct products. How these differences impact on individual IVIG product efficacy and safety are not well established but can be investigated by head-to-head randomized controlled trials (RCT). A systematic review of head-to-head RCT comparing different formulations of IVIG, regardless of the target condition and outcomes investigated. Two reviewers screened 4084 citations retrieved from MEDLINE, Embase, Cochrane and LILACS, and 23 citations were fully-text evaluated. Eight trials were included. The clinical conditions, outcomes and risk of bias were assessed. Of the eight trials included only two investigated products that are currently on the market. One evaluated two Grifols brands used in patients with primary immunodeficiency and another evaluated two Baxter brands used in patients with chronic inflammatory demyelinating polyradiculoneuropathy. There were no differences between the formulations for the outcomes evaluated. In the other trials, either the manufacturers were acquired by other companies or the formulation was withdrawn from the market. As consequence, evidence concerning these products could not be considered. The quality of the studies was low, showing high risk of bias. Direct evidence about the different IVIGs is scarce and, at present, there is no scientific evidence that can be applied for a specific brand or formulation. Further comparative effectiveness studies are highly desirable for a better understanding of the differences in safety and efficacy of IVIGs. PMID- 25496752 TI - Partial agonist activity of R3(BDelta23-27)R/I5 at RXFP3--investigation of in vivo and in vitro pharmacology. AB - Relaxin family peptide receptor 3 (RXFP3) is a G-protein coupled receptor mainly expressed in the brain and involved in appetite regulation. Previous studies in lean Wistar rats during the light phase have shown that the chimeric peptide R3(BDelta23-27)R/I5 suppresses food intake stimulated by an RXFP3 agonist, but has no effect on food intake when administered alone. We wanted to further investigate if R3(BDelta23-27)R/I5 on its own is able to antagonize the basal tone of the relaxin-3/RXFP3 system and therefore characterized the pharmacology of R3(BDelta23-27)R/I5 in vivo and in vitro. R3(BDelta23-27)R/I5 was intracerebroventricularly (ICV) injected in diet induced obese (DIO) Wistar rats and food intake was automatically measured during the dark phase when feeding drive is high. In our hands, R3(BDelta23-27)R/I5 alone did not have a significant effect on food intake during 24h following administration. Consistent with previous results, relaxin-3 stimulated food intake in satiated lean rats. R3(BDelta23-27)R/I5 was characterized in vitro using [(35)S]-GTPgammaS binding and cAMP assays, both assessing Galphai-protein mediated signalling, and dynamic mass redistribution (DMR) assays capturing the integrated cell response. R3(BDelta23-27)R/I5 showed partial agonist activity in all three functional assays. Thus, since R3(BDelta23-27)R/I5 displays partial RXFP3 agonist properties in vitro, further in vivo studies including additional tool compounds are needed to address if antagonizing relaxin-3/RXFP3 basal tone is a therapeutically relevant mechanism to regulate food intake and body weight. PMID- 25496753 TI - Faecal metabolomic fingerprint after moderate consumption of red wine by healthy subjects. AB - Faecal metabolome contains information on the metabolites found in the intestine, from which knowledge about the metabolic function of the gut microbiota can be obtained. Changes in the metabolomic profile of faeces reflect, among others, changes in the composition and activity of the intestinal microorganisms. In an effort to improve our understanding of the biological effects that phenolic compounds (including red wine polyphenols) exert at the gut level, in this foodomic study we have undertaken a metabolome characterization of human faeces after moderate consumption of red wine by healthy subjects for 4 weeks. Namely, a nontargeted metabolomic approach based on the use of UHPLC-TOF MS was developed to achieve the maximum metabolite information on 82 human faecal samples. After data processing and statistical analysis, 37 metabolites were related to wine intake, from which 20 could be tentatively or completely identified, including the following: (A) wine compounds, (B) microbial-derived metabolites of wine polyphenols, and (C) endogenous metabolites and/or others derived from other nutrient pathways. After wine consumption, faecal metabolome was fortified in flavan-3-ols metabolites. Also, of relevance was the down regulation of xanthine and bilirubin-derived metabolites such as urobilinogen and stercobilin after moderate wine consumption. As far as we know, this is the first study of the faecal metabolome after wine intake. PMID- 25496754 TI - Spatiotemporal interactions between wild boar and cattle: implications for cross species disease transmission. AB - Controlling infectious diseases at the wildlife/livestock interface is often difficult because the ecological processes driving transmission between wildlife reservoirs and sympatric livestock populations are poorly understood. Thus, assessing how animals use their environment and how this affects interspecific interactions is an important factor in determining the local risk for disease transmission and maintenance. We used data from concurrently monitored GPS collared domestic cattle and wild boar (Sus scrofa) to assess spatiotemporal interactions and associated implications for bovine tuberculosis (TB) transmission in a complex ecological and epidemiological system, Donana National Park (DNP, South Spain). We found that fine-scale spatial overlap of cattle and wild boar was seasonally high in some habitats. In general, spatial interactions between the two species were highest in the marsh-shrub ecotone and at permanent water sources, whereas shrub-woodlands and seasonal grass-marshlands were areas with lower predicted relative interactions. Wild boar and cattle generally used different resources during winter and spring in DNP. Conversely, limited differences in resource selection during summer and autumn, when food and water availability were limiting, resulted in negligible spatial segregation and thus probably high encounter rates. The spatial gradient in potential overlap between the two species across DNP corresponded well with the spatial variation in the observed incidence of TB in cattle and prevalence of TB in wild boar. We suggest that the marsh-shrub ecotone and permanent water sources act as important points of TB transmission in our system, particularly during summer and autumn. Targeted management actions are suggested to reduce potential interactions between cattle and wild boar in order to prevent disease transmission and design effective control strategies. PMID- 25496755 TI - Working memory performance is reduced in children with congenital adrenal hyperplasia. AB - Individuals with classic congenital adrenal hyperplasia (CAH) experience impaired glucocorticoid production and are treated postnatally with glucocorticoids. Prior research with animals and other human populations indicates that glucocorticoids can influence memory, particularly working memory. We tested the hypothesis that children with CAH would show reduced working memory. Children in the United Kingdom, aged 7-11years, with classical CAH (31 girls, 26 boys) were compared to their unaffected relatives (30 girls, 20 boys) on a test of working memory, the Digit Span test. Vocabulary was also assessed to measure verbal intelligence for control purposes. Children with CAH showed reduced working memory performance compared to controls, on both components of the Digit Span test: p=.008 for Digit Span Forward, and p=.027 for Digit Span Backward, and on a composite score, p=.004. These differences were of moderate size (d=.53 to .70). Similar differences were also seen in a subset of 23 matched pairs of children with CAH and their relatives (d=.78 to .92). There were no group differences on Vocabulary. Glucocorticoid abnormality, including treatment effects, could be responsible for the reduced Digit Span performance in children with CAH. Other factors related to CAH, such as salt-wasting crises, could also be involved. Additional research is needed to identify the cause of the memory reduction, which will help to determine if more rapid diagnosis or more precise glucocorticoid treatment would help prevent memory reduction. Educational interventions might also be considered for children with CAH. PMID- 25496756 TI - Behavioral responses to pups in males with different reproductive experiences are associated with changes in central OT, TH and OTR, D1R, D2R mRNA expression in mandarin voles. AB - Male rodents behave differently toward pups because of different sexual and/or paternal experiences; however, the mechanisms underlying these responses are not well understood. Using socially monogamous mandarin voles (Microtus mandarinus) we investigated the behavioral responses of males with different reproductive experiences (virgin males, paired males and new fathers) to new born pups. Central levels of neuropeptide oxytocin (OT), tyrosine hydroxylase (TH), as well as oxytocin receptor (OTR), dopamine 1-type receptor (D1R) and dopamine 2-type receptor (D2R) mRNA expression in the nucleus accumbens and medial amygdala were also measured in these males. Our data showed that new fathers exhibited more approaching behavior and contained more OT-immunoreactive and TH-immunoreactive neurons. In addition to increased OTR mRNA expression in the nucleus accumbens and medial amygdala, new fathers had higher D1R and D2R mRNA expression in the nucleus accumbens, and less D1R and D2R mRNA expression in the medial amygdala than paired males. These results demonstrate that males with different reproductive experiences display different behavioral responses to pups and that these differences are associated with altered OT and dopamine, and their receptors in specific brain regions. PMID- 25496757 TI - Variations in the hospital management of self-harm and patient outcome: a multi site observational study in England. AB - INTRODUCTION: Studies have shown wide variations in delivery of self-harm services but it is unclear how these relate to important outcomes such as self harm repetition. METHODS: Data were collected on self-harm presentations and hospital management from 31 hospitals in England. Key staff were interviewed about service provision for self-harm patients and responses were mapped to a 21 item service quality scale. Our main outcome was repeat hospital-presenting self harm within six months. RESULTS: 6347 individuals presented with 7599 episodes of self-harm during a three month period in 2010-2011. Re-attendance with self-harm within six months of index episode occurred in 21% (1308/6347) of individuals (range between hospitals 9-27%). We found little association between clinical management at hospital level (i.e. proportion of episodes receiving psychosocial assessment, medical or psychiatric admission, and referral to statutory or non statutory services) and repetition rate. The median score on service quality scale was 14.5 (range between hospitals 10.5-19). There was no evidence of correlation between total service quality score and repetition of self-harm (Spearman's r=-0.06, p=0.73) or between individual service items and repetition. LIMITATIONS: We did not explore certain aspects of service provision e.g. quality of psychosocial assessments and length of admission. Hospital presentation for repeat self-harm may not be the most reliable measure of service quality. CONCLUSION: At aggregate level aspects of management and service structures did not appear to be associated with self-harm repetition rates. Future research should focus on better understanding the processes underlying the delivery of services at hospital level and their relationship to outcome. PMID- 25496758 TI - Panic attacks in minority Americans: the effects of alcohol abuse, tobacco smoking, and discrimination. AB - BACKGROUND: Lifetime prevalence of panic attacks is estimated at 22.7%, and research on the correlates and causes of depression, anxiety, and other mental illnesses have yielded mixed results in minority groups. Therefore, the purpose of this study is to evaluate the relationship between panic attacks, minority status, and nativity by focusing on the effects of health lifestyle behaviors and discrimination. METHODS: Multivariate analysis was performed using logistic regression, which was used to estimate the probability of meeting the criteria for panic attacks (n=17,249). RESULTS: Demographic and socioeconomic variables had significant associations; females had over 2.4 times higher odds than males of meeting the criteria for panic attacks. The more frequently respondents were treated as dishonest, less smart, with disrespect, threatened, or called names, the more likely they met the criteria for panic attacks. Additionally, smoking and alcohol abuse were significant predictors of panic attacks. Those who abused alcohol have over 2 times the odds of having panic attacks. Similarly, smokers had 52% higher odds of panic attacks than non-smokers. LIMITATIONS: The primary limitation of this project was the lack of a true acculturation measure with a secondary limitation being the inability to determine respondents' legal status. CONCLUSIONS: Key findings were that health lifestyle choices and exposure to discrimination significantly affected the chance of having panic attacks. Nativity was protective; however, its effect was counteracted by exposure to discrimination or engagement in smoking behavior or alcohol abuse. Thus, this study offers insight into contextual factors for clinicians caring for racial and ethnic minorities diagnosed with panic attacks. PMID- 25496760 TI - Mode-dependent stochastic stability criteria of fuzzy Markovian jumping neural networks with mixed delays. AB - This paper investigates the stochastic stability of fuzzy Markovian jumping neural networks with mixed delays in mean square. The mixed delays include time varying delay and continuously distributed delay. By using the Lyapunov functional method, Jensen integral inequality, the generalized Jensen integral inequality, linear convex combination technique and the free-weight matrix method, several novel sufficient conditions are derived to ensure the global asymptotic stability of the equilibrium point of the considered networks in mean square. The proposed results, which do not require the differentiability of the activation functions, can be easily checked via Matlab software. Finally, two numerical examples are given to demonstrate the effectiveness and less conservativeness of our theoretical results over existing literature. PMID- 25496759 TI - Hippocampal structure and function in individuals with bipolar disorder: a systematic review. AB - INTRODUCTION: Bipolar disorder (BD) is a psychiatric disorder accompanied by deficits in declarative memory. Given the importance of the hippocampus in declarative memory, it is not surprising that BD patients have been reported to show hippocampal abnormalities. OBJECTIVES: Review evidence about structural and functional hippocampal abnormalities in BD. METHODS: Systematic review of studies comparing BD patients and healthy controls with respect to hippocampal structure or function. RESULTS: Twenty-five studies were included, together involving 1043 patients, 21 of which compared patients to controls. Decrease in hippocampal volume was found in four of 18 studies using adult samples, and two of three samples using adolescents. Four studies revealed localized hippocampal deficits. Meta-analysis revealed a significant but small effect with lower hippocampal volumes when comparing all BD patients with controls. Lithium treatment was associated with larger hippocampal volumes across studies. The three functional studies yielded contradictory evidence. LIMITATIONS: Studies were only cross sectional in nature and all used MRI or fMRI to investigate hippocampal volume or function. Heterogeneous patients groups and different methodologies for hippocampal segmentation, may have contributed to difficulties when comparing the different studies. CONCLUSIONS: There seems to be a small reduction in hippocampal volume in BD, which perhaps is more pronounced in early-onset BD and is counteracted by a neuroprotective effect of lithium treatment. However, how these structural abnormalities relate to functional deficits is largely unclear. Given the few functional neuroimaging studies and given the lack of congruence in these results, further investigation of especially hippocampal function in BD is recommended. PMID- 25496762 TI - Surgical treatment of a mycotic pseudoaneurysm of the transverse arch using a rifampicin-impregnated dacron patch in an infant. AB - We describe a case of successful treatment of mycotic pseudoaneurysm of the transverse aortic arch in a male infant. The aneurysm was resected and the defect was repaired using a patch made from a rifampicin-impregnated Dacron graft. PMID- 25496763 TI - Increased haemodynamic adrenergic load with isoflurane anaesthesia in type 2 diabetic and obese rats in vivo. AB - BACKGROUND: Increasing numbers of type 2 diabetic and obese patients with enhanced rates of cardiovascular complications require surgical interventions, however they have a higher incidence of perioperative haemodynamic complications, which has been linked to adrenergic dysfunction. Therefore, we aimed to determine how alpha- and beta-adrenoceptor (AR)-mediated haemodynamic responses are affected by isoflurane anaesthesia in experimental type 2 diabetes and obesity in vivo. METHODS: Sixteen-week old male Zucker type 2 Diabetic Fatty (ZDF) rats, Zucker Obese rats and their lean counterparts (n = 7-9 per group) were instrumented with radio telemeters to record blood pressure and heart rate and with vascular access ports for non-invasive intravenous drug delivery in vivo. Haemodynamic effects of alpha-AR (phenylephrine; 1-100 MUg x kg(-1)) or beta-AR (dobutamine; 2-120 MUg x kg(-1)) stimulation were assessed under conscious and anaesthetised (isoflurane; 2%) conditions. RESULTS: Vascular alpha-AR sensitivity was increased in both diabetic (non-diabetic 80 +/- 3 vs. diabetic 95 +/- 4 DeltammHg at 100 MUg x kg(-1); p < 0.05) and obese (lean 65 +/- 6 vs. obese 84 +/ 6 DeltammHg at 20 MUg x kg(-1); p < 0.05) conscious rats. Interestingly, anaesthesia exacerbated and prolonged the increased alpha-AR function in both diabetic and obese animals (non-diabetic 51 +/- 1 vs. diabetic 68 +/- 4 DeltammHg, lean 61 +/- 5 vs. obese 84 +/- 2 DeltammHg at 20 MUg x kg(-1); p < 0.05). Meanwhile, beta-AR chronotropic sensitivity was reduced in conscious diabetic and obese rats (non-diabetic 58 +/- 7 vs. diabetic 27 +/- 8 Deltabpm, lean 103 +/- 12 vs. obese 61 +/- 9 Deltabpm at 15 MUg x kg(-1); p < 0.05). Anaesthesia normalised chronotropic beta-AR responses, via either a limited reduction in obese (lean 51 +/- 3 vs. obese 66 +/- 5 Deltabpm; NS at 15 MUg x kg( 1)) or increased responses in diabetic animals (non-diabetic 49 +/- 8 vs. diabetic 63 +/- 8 Deltabpm, at 15 MUg x kg(-1); NS at 15 MUg x kg(-1)). CONCLUSIONS: Long term metabolic stress, such as during type 2 diabetes and obesity, alters alpha- and beta-AR function, its dynamics and the interaction with isoflurane anaesthesia. During anaesthesia, enhanced alpha-AR sensitivity and normalised beta-AR function may impair cardiovascular function in experimental type 2 diabetes and obesity. PMID- 25496764 TI - Toxicological assessment of kretek cigarettes Part 6: the impact of ingredients added to kretek cigarettes on smoke chemistry and in vitro toxicity. AB - Mainstream smoke (MS) from experimental kretek cigarettes with three ingredient mixes at low (typical use level) and high (2.5 or 3 times that level) inclusion rates was compared to a control kretek cigarette of identical construction (cloves and humectants), but without the addition of ingredients. 350 ingredients, commonly used in various combinations and in a limited number in a given brand in the manufacture of marketed kretek cigarettes were assessed. The MS composition of the kretek cigarettes was characterized by a comprehensive set of analytes (55 smoke constituents). Furthermore, the smoke was assessed in vitro for its cytotoxicity in the Neutral Red Uptake assay (particle phase and gas/vapor phase separately) in mouse embryo BALB/c 3T3 cells, and for mutagenicity/genotoxicity in the Salmonella typhimurium reverse mutation assay and the mammalian cell mouse lymphoma TK assay in L5178Y cells, the latter with and without metabolic activation. There were some statistically significant differences in the yield of smoke constituents (increases as well as decreases, nearly all of them less than +/- 20%) as a result of the addition of the ingredient mixes. However, the addition of the three different mixes of ingredients to the experimental kreteks did not change the in vitro cytotoxicity and mutagenicity/genotoxicity of the smoke, when compared to the control kretek cigarette. PMID- 25496765 TI - Acceptability of a 'guidebook' for the management of Osteoarthritis: a qualitative study of patient and clinician's perspectives. AB - BACKGROUND: Written information can be of benefit to both practitioners and patients and the provision of quality information is emphasised as a core intervention by United Kingdom National Institute of Clinical Excellence (NICE) OA guidelines. Researchers, patients and HCPs developed an 'OA guidebook' to provide; a) a balanced source of information for patients; b) a resource to aid practitioners when discussing self-management. This study aimed to evaluate the acceptability and usefulness of the OA guidebook as part of complex intervention to deliver NICE OA guidelines in General Practice. METHODS: The intervention comprises a series of consultations with GPs and practice nurses in which supported self-management is offered to patients. Eight practices in the West Midlands and North West of England were recruited to take part: four control practices and four intervention practices. Semi-structured interviews were undertaken with patients (n = 29), GPs (n = 9) and practice nurses (n = 4) from the intervention practices to explore experiences of the intervention and use of the guidebook. Data were analysed using thematic analysis and constant comparison of data within and across interviews. RESULTS: GPs thought the guidebook helped provide patients with information about OA aetiology, prognosis and self management. Thus, it backed up key messages they provided patients during consultations. GPs also found the guidebook helped them 'close off' consultations. Nurses also thought the guidebook helped them describe OA disease processes in consultations. Patients valued the explanations of disease onset, process and prognosis. The use of 'real' people and 'real life' situations contained within the guidebook made self-management strategies seem more tangible. A sense of inclusion and comfort was obtained from knowing other people encountered similar problems and feelings. CONCLUSION: An OA specific written information guidebook was deemed acceptable and useful to practitioners and patients alike as part of the MOSAICS study. Findings reinforce the utility of this model of patient information as a resource to support patients living with chronic illnesses. An OA guidebook featuring a mixture of lay and professional information developed by professionals and lay people is useful and could effectively be used more widely in usual care. PMID- 25496766 TI - Reconstruction of gross avian genome structure, organization and evolution suggests that the chicken lineage most closely resembles the dinosaur avian ancestor. AB - BACKGROUND: The availability of multiple avian genome sequence assemblies greatly improves our ability to define overall genome organization and reconstruct evolutionary changes. In birds, this has previously been impeded by a near intractable karyotype and relied almost exclusively on comparative molecular cytogenetics of only the largest chromosomes. Here, novel whole genome sequence information from 21 avian genome sequences (most newly assembled) made available on an interactive browser (Evolution Highway) was analyzed. RESULTS: Focusing on the six best-assembled genomes allowed us to assemble a putative karyotype of the dinosaur ancestor for each chromosome. Reconstructing evolutionary events that led to each species' genome organization, we determined that the fastest rate of change occurred in the zebra finch and budgerigar, consistent with rapid speciation events in the Passeriformes and Psittaciformes. Intra- and interchromosomal changes were explained most parsimoniously by a series of inversions and translocations respectively, with breakpoint reuse being commonplace. Analyzing chicken and zebra finch, we found little evidence to support the hypothesis of an association of evolutionary breakpoint regions with recombination hotspots but some evidence to support the hypothesis that microchromosomes largely represent conserved blocks of synteny in the majority of the 21 species analyzed. All but one species showed the expected number of microchromosomal rearrangements predicted by the haploid chromosome count. Ostrich, however, appeared to retain an overall karyotype structure of 2n=80 despite undergoing a large number (26) of hitherto un-described interchromosomal changes. CONCLUSIONS: Results suggest that mechanisms exist to preserve a static overall avian karyotype/genomic structure, including the microchromosomes, with widespread interchromosomal change occurring rarely (e.g., in ostrich and budgerigar lineages). Of the species analyzed, the chicken lineage appeared to have undergone the fewest changes compared to the dinosaur ancestor. PMID- 25496768 TI - Implementation of field cardio-respiratory measurements to assess energy expenditure in Arabian endurance horses. AB - Measurements of respiratory exchanges in genuine exercise conditions are undoubtedly of interest to further define the energy needs of endurance horses. However, the equine K4b2, the gas exchanges portable device validated for equines, has not been used in Arabian endurance horses yet. Therefore, the objective of this study was to implement field cardio-respiratory measurements in such horses using the equine K4b2 in order to assess energy expenditure (EE). Measurements of heart rate (HR), oxygen uptake (VO2), carbon dioxide production (VCO2), respiratory frequency (RF), tidal volume (VT) and minute expired volume (VE) were carried out at rest and during a 20-min submaximal incremental field exercise in five trained Arabian endurance horses equipped with the K4b2 system. The relationship between HR and VO2 was determined for each horse. EE of the exercise session was calculated from direct VO2 measurements and individual HR VO2 regression. Out of the five horses, four tolerated the equipment. Respiratory and metabolic variables at rest and during exercise, as well as EE measured at the different gaits, were consistent with reported values in exercising horses: VO2 ranged from 4.8 to 54.1 ml/min per kg from rest to canter, respectively, and EE from 82 to 1095 J/min per kg BW. The 20-min exercise session EE accounted for 6258 and 6332 J from direct VO2 measurements and individual HR-VO2 regression, respectively, which did not differ significantly. Providing an adaptation period and several technical adjustments, the present equine K4b2 could be used to assess EE in Arabian endurance horses in a controlled environment. The prediction of EE from the individual VO2-HR relationship might be an alternative method to evaluate EE when VO2 measurements are not possible. PMID- 25496769 TI - Assessment of tuberculosis surveillance by capture-recapture in the Balearic Islands, Spain, 2005-2007. AB - The tuberculosis surveillance system in the Balearic Islands was assessed from 2005 to 2007. Applying the capture-recapture method the completeness of this system was evaluated to be 58.4%. When a new electronic recorded data was included in Primary Health Care, up to 66.5% was obtained. This new source of data increased the detected cases of pulmonary tuberculosis from 572 to 681. As a result, the estimated annual incidence rate increases from 18.9 cases/10(5) to 22.6 cases/10(5) [95% CI, 20.9-24.3], similar to figures issued by WHO. PMID- 25496767 TI - Comparing Open Radical Cystectomy and Robot-assisted Laparoscopic Radical Cystectomy: A Randomized Clinical Trial. AB - BACKGROUND: Open radical cystectomy (ORC) and urinary diversion in patients with bladder cancer (BCa) are associated with significant perioperative complication risk. OBJECTIVE: To compare perioperative complications between robot-assisted radical cystectomy (RARC) and ORC techniques. DESIGN, SETTING, AND PARTICIPANTS: A prospective randomized controlled trial was conducted during 2010 and 2013 in BCa patients scheduled for definitive treatment by radical cystectomy (RC), pelvic lymph node dissection (PLND), and urinary diversion. Patients were randomized to ORC/PLND or RARC/PLND, both with open urinary diversion. Patients were followed for 90 d postoperatively. INTERVENTION: Standard ORC or RARC with PLND; all urinary diversions were performed via an open approach. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcomes were overall 90-d grade 2 5 complications defined by a modified Clavien system. Secondary outcomes included comparison of high-grade complications, estimated blood loss, operative time, pathologic outcomes, 3- and 6-mo patient-reported quality-of-life (QOL) outcomes, and total operative room and inpatient costs. Differences in binary outcomes were assessed with the chi-square test, with differences in continuous outcomes assessed by analysis of covariance with randomization group as covariate and, for QOL end points, baseline score. RESULTS AND LIMITATIONS: The trial enrolled 124 patients, of whom 118 were randomized and underwent RC/PLND. Sixty were randomized to RARC and 58 to ORC. At 90 d, grade 2-5 complications were observed in 62% and 66% of RARC and ORC patients, respectively (95% confidence interval for difference, -21% to -13%; p=0.7). The similar rates of grade 2-5 complications at our mandated interim analysis met futility criteria; thus, early closure of the trial occurred. The RARC group had lower mean intraoperative blood loss (p=0.027) but significantly longer operative time than the ORC group (p<0.001). Pathologic variables including positive surgical margins and lymph node yields were similar. Mean hospital stay was 8 d in both arms (standard deviation, 3 and 5 d, respectively; p=0.5). Three- and 6-mo QOL outcomes were similar between arms. Cost analysis demonstrated an advantage to ORC compared with RARC. A limitation is the setting at a single high-volume, referral center; our findings may not be generalizable to all settings. CONCLUSIONS: This trial failed to identify a large advantage for robot-assisted techniques over standard open surgery for patients undergoing RC/PLND and urinary diversion. Similar 90-d complication rates, hospital stay, pathologic outcomes, and 3- and 6-mo QOL outcomes were observed regardless of surgical technique. PATIENT SUMMARY: Of 118 patients with bladder cancer who underwent radical cystectomy, pelvic lymph node dissection, and urinary diversion, half were randomized to open surgery and half to robot-assisted laparoscopic surgery. We compared the rate of complications within 90 d after surgery for the open group versus the robotic group and found no significant difference between the two groups. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01076387, www.clinicaltrials.gov. PMID- 25496770 TI - Acinetobacter baumannii OxPhos inhibitors as selective anti-infective agents. AB - The Gram-negative bacterium Acinetobacter baumannii is an opportunistic pathogen in humans and infections are poorly treated by current therapy. Recent emergence of multi-drug resistant strains and the lack of new antibiotics demand an immediate action for development of new anti-Acinetobacter agents. To this end, oxidative phosphorylation (OxPhos) was identified as a novel target for drug discovery research. Consequently, a library of ~10,000 compounds was screened using a membrane-based ATP synthesis assay. One hit identified was the 2 iminobenzimidazole 1 that inhibited the OxPhos of A. baumannii with a modestly high selectivity against mitochondrial OxPhos, and displayed an MIC of 25MUM (17MUg/mL) against the pathogen. The 2-iminobenzimidazole 1 was found to inhibit the type 1 NADH-quinone oxidoreductase (NDH-1) of A. baumannii OxPhos by a biochemical approach. Among various derivatives that were synthesized to date, des-hydroxy analog 5 is among the most active with a relatively tight SAR requirement for the N'-aminoalkyl side chain. Analog 5 also showed less cytotoxicity against NIH3T3 and HepG2 mammalian cell lines, demonstrating the potential for this series of compounds as anti-Acinetobacter agents. Additional SAR development and target validation is underway. PMID- 25496771 TI - CD44 antibody-mediated amelioration of murine immune thrombocytopenia (ITP): mouse background determines the effect of FcgammaRIIb genetic disruption. AB - BACKGROUND: Several monoclonal antibodies to CD44 can successfully ameliorate murine immune thrombocytopenia (ITP). As these antibodies may be a potential replacement for intravenous immune globulin (IVIG) in the treatment of ITP and other autoimmune diseases, an understanding of their mechanisms of action is important. The role of the inhibitory Fc receptor (FcgammaRIIb) in the mechanism of action of IVIG and therapeutic CD44 antibodies remains uncertain. To assess if FcgammaRIIb in splenic macrophages plays a critical role in the action of these two therapeutics, splenectomized mice and mice genetically deficient in FcgammaRIIb on different backgrounds were evaluated. STUDY DESIGN AND METHODS: Thrombocytopenia was induced in FcgammaRIIb-deficient mice on B6;129S, C57BL/6, and BALB/C backgrounds, as well as splenectomized mice and control mice by platelet (PLT) antibody. PLT counts were enumerated before and after treatment with anti-CD44, red blood cell antibodies, or IVIG. RESULTS: Anti-CD44 is ineffective at inhibiting thrombocytopenia in B6;129S FcgammaRIIb-deficient mice but, like IVIG, is effective in splenectomized mice and FcgammaRIIb-deficient mice on the BALB/C and C57BL/6 background. CONCLUSION: These data suggest that 1) the B6;129S background itself is unlikely to be the sole reason for anti-CD44's inability to function in B6;129S FcgammaRIIb-deficient mice, 2) the simple loss of macrophage FcgammaRIIb expression alone is insufficient to explain anti-CD44 ameliorative function, and 3) a combination of mouse background genes in addition to FcgammaRIIb genetic disruption may affect the ability of anti-CD44 to function therapeutically. Similarities between IVIG and anti-CD44 mechanisms suggest that patients responsive to IVIG may also potentially respond to anti-CD44 treatment. PMID- 25496772 TI - BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid. AB - BACKGROUND: The recently discovered small-molecule BI-2 potently blocks HIV-1 infection. BI-2 binds to the N-terminal domain of HIV-1 capsid. BI-2 utilizes the same capsid pocket used by the small molecule PF74. Although both drugs bind to the same pocket, it has been proposed that BI-2 uses a different mechanism to block HIV-1 infection when compared to PF74. FINDINGS: This work demonstrates that BI-2 destabilizes the HIV-1 core during infection, and prevents the binding of the cellular factor CPSF6 to the HIV-1 core. CONCLUSIONS: Overall this short form paper suggests that BI-2 is using a similar mechanism to the one used by PF74 to block HIV-1 infection. PMID- 25496773 TI - Tunable charge-trap memory based on few-layer MoS2. AB - Charge-trap memory with high-kappa dielectric materials is considered to be a promising candidate for next-generation memory devices. Ultrathin layered two dimensional (2D) materials like graphene and MoS2 have been receiving much attention because of their fantastic physical properties and potential applications in electronic devices. Here, we report on a dual-gate charge-trap memory device composed of a few-layer MoS2 channel and a three-dimensional (3D) Al2O3/HfO2/Al2O3 charge-trap gate stack. Because of the extraordinary trapping ability of both electrons and holes in HfO2, the MoS2 memory device exhibits an unprecedented memory window exceeding 20 V. Importantly, with a back gate the window size can be effectively tuned from 15.6 to 21 V; the program/erase current ratio can reach up to 10(4), allowing for multibit information storage. Moreover, the device shows a high endurance of hundreds of cycles and a stable retention of ~ 28% charge loss after 10 years, which is drastically lower than ever reported MoS2 flash memory. The combination of 2D materials with traditional high-kappa charge-trap gate stacks opens up an exciting field of nonvolatile memory devices. PMID- 25496774 TI - Prioritisation of wildlife pathogens to be targeted in European surveillance programmes: Expert-based risk analysis focus on ruminants. AB - This study attempted to develop a list of priority pathogens. It is part of a European Union (EU) project dedicated to the surveillance of emerging or re emerging pathogens of wildlife. Partners of the consortium established an initial list of 138 pathogens of concern, which was reduced to a smaller list of 65 pathogens likely to affect ruminants (i.e., the most costly animal group in the EU over the last 15 years). These 65 pathogens underwent a two-step, expert-based risk analysis: 92 experts graded them with respect to their global importance for animal welfare, species conservation, trade/economic impacts and public health. In step 2, the top 15 pathogens from step 1 were assessed by 69 experts considering seven weighted epidemiological criteria (pathogen variability, host specificity, potential for contagion, speed of spread, presence in Europe, difficulty of surveillance in wildlife and persistence in the environment) for which four options were possible. The responses concerned a wide geographic coverage. The resulting top-list pathogens were ranked as follows: 1. Salmonella enterica, 2. Coxiella burnetii, 3. foot-and-mouth disease virus, 4. Mycobacterium bovis, 5. bluetongue virus, and 6. European tick-borne encephalitis virus. The influence of the characteristics of the respondents, the importance of the levels of uncertainty/variability and the implication of the results are discussed. This work highlights the relevance of developing such lists for preparedness. PMID- 25496775 TI - Standardized analysis of German cattle mortality using national register data. AB - In a retrospective cohort study of national register data, 1946 randomly selected holdings, with 286,912 individual cattle accumulating 170,416 animal-years were analyzed. The sample was considered to represent the national herd in Germany 2012. Within each holding, individual cattle records were stratified by current age (<=21 days, 3-6 weeks, 6-12 weeks, 3-6 months, 6-12 months, 1-2, 2-4, 4-8, and >8 years), sex, breed (intensive milk, less intensive milk, and beef), and mean monthly air temperature (<10 degrees C and >=10 degrees C). Holdings were categorized by size (<100 and >=100 animal-years), calving rate, slaughter rate, and federal state. 8027 on-site deaths (excluding slaughter for human consumption) were recorded, with cattle aged <6 months, 6-24 months, and >2 years contributing 50.0%, 15.4%, and 34.6% of deaths, respectively. Poisson regression and generalized estimating equations (gee) accounting for intra-herd clustering were used to model the number of deaths. In both models, most age bands differed significantly, with highest rates in calves <=21 days, falling to lowest rates in 1-2 year olds, and rising again thereafter in females. Males exhibited higher mortality than females from birth to 2 years. All breed categories differed significantly with lowest rates in beef and highest in intensive milk breeds. Larger holdings, temperatures <=10 degrees C, calving rates >0-0.5 per animal year were all associated with higher mortality. Via interaction, intensive and less intensive milk breed cattle aging 6 weeks to 6 months and intensive milk breed females >4 years were associated with higher mortality. There were no significant differences between federal states and slaughter rates. The standardized deviations of modeled dead cattle numbers from occurred deaths per calendar year per holding were calculated and a 95% reference range of deviations constructed. This approach makes a standardized active monitoring and surveillance system regardless of herd size possible, offering a useful, inexpensive and easy implementable aid in the detection of holdings deviant from mortality levels of the national herd. PMID- 25496776 TI - From biological models to economic optimization. AB - This article addresses the additional challenges being faced when biological models are used as a basis for decision support in livestock herds. The challenges include dealing with uncertain information, observation costs, herd dynamics and methodological issues in relation to the computational methods applied particularly in the dynamic case. The desired key property of information included in models is that it can be used as the basis for unbiased prediction of the future performance of the animals. Often there will be a tradeoff between uncertainty and costs in the sense that the level of uncertainty can be reduced (for instance through additional tests) at some cost. Thus, the decision about which (and how many) tests to perform can be seen as an optimization problem in itself. Another way of expressing the tradeoff is to talk about the value of information which can sometimes be assessed by modeling different approaches and levels of detail in data collection. Various optimization methods of relevance to herd health management are discussed with the main emphasis on decision graphs in the static case and Markov decision processes (dynamic programming) in a dynamic context. PMID- 25496778 TI - Unlicensed motorcycling of high school adolescents in Dehaghan county (Isfahan Province of Iran). AB - BACKGROUND: Unlicensed motorcycling increases the chances of accidents in adolescents. There are many behavioral and non-behavioral factors involved in adolescents' unlicensed motorcycling which were not addressed in research yet completely. METHODS: The cross-sectional study aimed to determine prevalence and related factors of unlicensed motorcycling on 500 unlicensed male high school adolescents in Dehaghan, who entered in the study by census. Demographic and motorcycling information were collected via self-report questionnaire, and its content validity was approved by a panel of experts. The statistical analyses of the data included Pearson Correlation Coefficient, chi-square, independent samples t-test and ANOVA with Tukey post hoc test. RESULTS: The prevalence of unlicensed motorcycling among participants was 74.2% and mean age at first motorcycling experience was 11.97+/-1.97 years ranged from 8 to 17. Of the motorcyclist participants, 59.6% owned their personal motorcycle. Most motorcycle passengers (62.8%) were adolescent's friends, and the most frequently expressed reason for use of motorcycle was fun and entertainment (54.2%). Age at first motorcycling experience was lower among rural adolescents than urban adolescents. However, unlicensed motorcycling was more prevalent among urban adolescents than rural ones. The relationship between living status, father's job, mother's job and age at first motorcycling experience was insignificant (P>0.05). However, mean age at first motorcycling experience among students of humanities, technical disciplines, and general first year was lower than that among students of natural sciences and math. CONCLUSION: High prevalence of unlicensed motorcycling and significant role of family and social environments on adolescents' high-risk motorcycling without license, is indicative of the need for interventions at all levels of peers, family, and schools and also establishing new driving regulations in Iran. PMID- 25496780 TI - Functional interactions of dopamine cell groups reflect personality, sex, and social context in highly social finches. AB - Dopamine (DA) is well known for its involvement in novelty-seeking, learning, and goal-oriented behaviors such as social behavior. However, little is known about how DA modulates social processes differentially in relation to sex and behavioral phenotype (e.g., personality). Importantly, the major DA cell groups (A8-A15) are conserved across all amniote vertebrates, and thus broadly relevant insights may be obtained through investigations of avian species such as zebra finches (Taeniopygia guttata), which express a human-like social organization based on biparental nuclear families that are embedded within larger social groups. We here build upon a previous study that quantified multidimensional personality structures in male and female zebra finches using principal components analysis (PCA) of extensive behavioral measures in social and nonsocial contexts. These complex dimensions of behavioral phenotype can be characterized as Social competence/dominance, Gregariousness, and Anxiety. Here we analyze Fos protein expression in DA neuronal populations in response to social novelty and demonstrate that the Fos content of multiple dopamine cell groups is significantly predicted by sex, personality, social context, and their interactions. In order to further investigate coordinated neuromodulation of behavior across multiple DA cell groups, we also conducted a PCA of neural variables (DA cell numbers and their phasic Fos responses) and show that behavioral PCs are associated with unique suites of neural PCs. These findings demonstrate that personality and sex are reflected in DA neuron activity and coordinated patterns of neuromodulation arising from multiple DA cell groups. PMID- 25496779 TI - Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression. AB - Stress during pregnancy has a wide variety of negative effects in both human [1] and animal offspring [2]. These effects are especially apparent in various forms of learning and memory such as object recognition [3] and spatial memory [4]. The cognitive effects of prenatal stress (PNS) may be mediated through epigenetic changes such as histone acetylation and DNA methylation [5]. As such, the present study investigated the effects of chronic unpredictable PNS on memory and epigenetic measures in adult offspring. Mice that underwent PNS exhibited impaired spatial memory in the Morris water maze, as well as sex-specific changes in levels of DNA methyltransferase (DNMT) 1 protein, and acetylated histone H3 (AcH3) in the hippocampus, and serum corticosterone. Male mice exposed to PNS exhibited decreased hippocampal AcH3, whereas female PNS mice displayed a further reduction in AcH3, as well as heightened hippocampal DNMT1 protein levels and corticosterone levels. These data suggest that PNS may epigenetically reduce transcription in the hippocampus, particularly in females in whom this effect may be related to increased baseline stress hormone levels, and which may underlie the sexual dimorphism in rates of mental illness in humans. PMID- 25496777 TI - Genomic signatures of near-extinction and rebirth of the crested ibis and other endangered bird species. AB - BACKGROUND: Nearly one-quarter of all avian species is either threatened or nearly threatened. Of these, 73 species are currently being rescued from going extinct in wildlife sanctuaries. One of the previously most critically-endangered is the crested ibis, Nipponia nippon. Once widespread across North-East Asia, by 1981 only seven individuals from two breeding pairs remained in the wild. The recovering crested ibis populations thus provide an excellent example for conservation genomics since every individual bird has been recruited for genomic and demographic studies. RESULTS: Using high-quality genome sequences of multiple crested ibis individuals, its thriving co-habitant, the little egret, Egretta garzetta, and the recently sequenced genomes of 41 other avian species that are under various degrees of survival threats, including the bald eagle, we carry out comparative analyses for genomic signatures of near extinction events in association with environmental and behavioral attributes of species. We confirm that both loss of genetic diversity and enrichment of deleterious mutations of protein-coding genes contribute to the major genetic defects of the endangered species. We further identify that genetic inbreeding and loss-of-function genes in the crested ibis may all constitute genetic susceptibility to other factors including long-term climate change, over-hunting, and agrochemical overuse. We also establish a genome-wide DNA identification platform for molecular breeding and conservation practices, to facilitate sustainable recovery of endangered species. CONCLUSIONS: These findings demonstrate common genomic signatures of population decline across avian species and pave a way for further effort in saving endangered species and enhancing conservation genomic efforts. PMID- 25496783 TI - Does reward unpredictability reflect risk? AB - Most decisions made in real-life situations are risky because they are associated with possible negative consequences. Current models of decision-making postulate that the occasional, unpredictable absence of reward that may result from free choice is a negative consequence interpreted as risk by organisms in laboratory situations. I argue that such a view is difficult to justify because, in most experimental paradigms, reward omission does not represent a cost for the decision-maker. Risk only exists when unpredictability may cause a potential loss of own limited resources, whether energetic, social, financial, and so on. Thus, the experimental methodologies used to test humans and non-humans relative to risk-taking seem to be limited to studying the effects of reward uncertainty in the absence of true decision cost. This may have important implications for the conclusions that can be drawn with respect to the neurobehavioural determinants of risk-taking in real-life situations. PMID- 25496781 TI - Lifelong bilingualism and neural reserve against Alzheimer's disease: a review of findings and potential mechanisms. AB - Alzheimer's disease (AD) is a progressive brain disorder that initially affects medial temporal lobe circuitry and memory functions. Current drug treatments have only modest effects on the symptomatic course of the disease. In contrast, a growing body of evidence suggests that lifelong bilingualism may delay the onset of clinical AD symptoms by several years. The purpose of the present review is to summarize evidence for bilingualism as a reserve variable against AD and discuss potential underlying neurocognitive mechanisms. Evidence is reviewed suggesting that bilingualism may delay clinical AD symptoms by protecting frontostriatal and frontoparietal executive control circuitry rather than medial temporal lobe memory circuitry. Cellular and molecular mechanisms that may contribute to bilingual cognitive reserve effects are discussed, including those that may affect neuronal metabolic functions, dynamic neuronal-glial interactions, vascular factors, myelin structure and neurochemical signaling. Future studies that may test some of these potential mechanisms of bilingual CR effects are proposed. PMID- 25496782 TI - Abnormal functional connectivity density in Parkinson's disease. AB - The pathology of Parkinson's disease (PD) is not confined to the nigrostriatal pathway, but also involves widespread cerebral cortical areas. Using seed-based resting state functional connectivity, many previous studies have demonstrated that PD patients have abnormal functional integration. However, this technique strongly relies on a priori selection of the seed regions and may miss important unpredictable findings. Using an ultrafast voxel-wise functional connectivity density approach, this study performed a whole brain functional connectivity analysis to investigate the abnormal resting-state functional activities in PD patients. Compared with healthy controls, PD patients exhibited decreased short range functional connectivity densities in regions that were mainly located in the ventral visual pathway and decreased long-range functional connectivity densities in the right middle and superior frontal gyrus, which have been speculated to be associated with visual hallucinations and cognitive dysfunction, respectively. PD patients also exhibited increased short- and long-range functional connectivity densities in the bilateral precuneus and posterior cingulate cortex, which may represent a compensatory process for maintaining normal brain function. The observed functional connectivity density alterations might be related to the disturbed structural connectivity of PD patients, leading to abnormal functional integration. Our results suggest that functional connectivity density mapping may provide a useful means to assess PD-related neurodegeneration and to study the pathophysiology of PD. PMID- 25496784 TI - Adolescent exposure to cocaine, amphetamine, and methylphenidate cross-sensitizes adults to methamphetamine with drug- and sex-specific effects. AB - The increasing availability, over-prescription, and misuse and abuse of ADHD psychostimulant medications in adolescent populations necessitates studies investigating the long-term effects of these drugs persisting into adulthood. Male and female C57Bl/6J mice were exposed to amphetamine (AMPH) (1.0 and 10 mg/kg), methylphenidate (MPD) (1.0 and 10 mg/kg), or cocaine (COC) (5.0 mg/kg) from postnatal day 22 to 31, which represents an early adolescent period. After an extended period of drug abstinence, adult mice were challenged with a subacute methamphetamine (METH) dose (0.5 mg/kg), to test the long-term effects of adolescent drug exposures on behavioral cross-sensitization using an open field chamber. There were no sex- or dose-specific effects on motor activity in adolescent, saline-treated controls. However, AMPH, MPD, and COC adolescent exposures induced cross-sensitization to a subacute METH dose in adulthood, which is a hallmark of addiction and a marker of long-lasting plastic changes in the brain. Of additional clinical importance, AMPH-exposed male mice demonstrated increased cross-sensitization to METH in contrast to the female-specific response observed in MPD-treated animals. There were no sex-specific effects after adolescent COC exposures. This study demonstrates differential drug, dose, and sex-specific alterations induced by early adolescent psychostimulant exposure, which leads to behavioral alterations that persist into adulthood. PMID- 25496785 TI - N-acetyl cysteine does not modify the sensitization of the rewarding effect of amphetamine as assessed with frequency-modulated 50-kHz vocalization in the rat. AB - A satisfactory pharmacological cure for addictions to psychostimulants has not yet been developed. Because of the well-known role of changes in the corticoaccumbal and corticostriatal glutamatergic system(s) in drug seeking and relapses in psychostimulant addiction, much hope is presently linked to the use of agents that restore glutamate homeostasis. In this regard, one of the most promising agents is N-acetyl cysteine, which has been shown to reverse some changes in neuroplasticity associated with psychostimulant addiction/dependence. In this study, we used the enhancement of locomotor activity and the induction of frequency-modulated 50-kHz ultrasonic vocalization (FM 50-kHz USV) to test the possible stimulant properties of N-acetyl cysteine itself in various experimental settings (acute and subchronic administration in amphetamine-naive and amphetamine-pretreated rats) and the capacity of N-acetyl cysteine to attenuate both the rewarding effects of amphetamine and the behavioral sensitization to this stimulant in rats showing considerable differences in their susceptibility to the FM 50-kHz USV sensitization. Our data showed no stimulant properties of N acetyl cysteine and no acute effect of the drug on the rewarding properties of amphetamine. Moreover, no effect of N-acetyl cysteine on the pre-existing sensitization of the FM 50-kHz USV and locomotor activity responses to amphetamine were observed, independent of the susceptibility of the rats to the FM 50-kHz USV sensitization. Hence, N-acetyl cysteine seems to be ineffective at reversing the neurobiological changes underlying the sensitization of these responses to amphetamine in rats. PMID- 25496787 TI - [Cellular senescence and pulmonary disease: COPD as an example]. AB - The biological mechanisms of aging, and more specifically cellular senescence, are increasingly a subject of research. Cellular senescence may be a common determinant of many age-related diseases, including some chronic lung diseases such as chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis. Many arguments suggest that these diseases are associated with premature senescence of lung cells, which may be involved in the pathophysiology of respiratory alterations. Furthermore, these diseases are associated with systemic manifestations, such as bone loss, muscle wasting and atherosclerosis, which impact on symptoms and prognosis. Whether these alterations are related to a common pathogenic mechanism or develop independently in patients with COPD remains an open question. In this review, we will focus on cellular senescence and COPD. Two concepts will be discussed: (1) the role of cell senescence in the pathophysiology of lung destruction, vascular remodeling and inflammation in COPD, (2) the possible link between the pulmonary and systemic manifestations of COPD which could reflect a general process of accelerated aging. PMID- 25496788 TI - [Pulmonary manifestations in HIV-infected patients: a diagnostic approach]. AB - The spectrum of pulmonary diseases that can affect human immunodeficiency virus (HIV)-infected patients is wide and includes both HIV and non-HIV-related conditions. Opportunistic infections and neoplasms remain a major concern even in the current era of combination antiretroviral therapy. Although these diseases have characteristic clinical and radiological features, there can be considerable variation in these depending on the patient's CD4 lymphocyte count. The patient's history, physical examination, CD4 count and chest radiograph features must be considered in establishing an appropriate diagnostic algorithm. In this article, we propose different diagnostic approaches HIV infected to patients with respiratory symptoms depending on their clinico-radiological pattern. PMID- 25496789 TI - [Smoking cessation and social deprivation]. AB - Smoking is a major of public health policy issue; one in two lifelong smokers will die from a disease related to tobacco use. In France, smoking is responsible for more than 70,000 deaths every year. The benefits linked to stopping smoking include reduced mortality and morbidity related to the use of tobacco. Recent data show an increase in the prevalence of smoking in the lowest socioeconomic population. Tobacco control needs a better understanding of the determinants of smoking in this population, which are also factors in the failure of cessation attempts. Based on international literature, this review specifies the educational and socioeconomic factors involved in tobacco smoking and in the result of an attempt to quit. Its aim is to propose ways to improve the management of smoking cessation in a socially deprived population. PMID- 25496790 TI - [Smoking cessation in smokers with chronic obstructive pulmonary disease]. AB - One out of two smokers who smoke throughout their lifetime will die from a disease related to smoking. Tobacco smoking therefore represents a major global public health issue. Smoking is the leading cause of chronic obstructive pulmonary disease (COPD). Projections for 2020 indicate that by then, COPD will have become the third cause of death and the fifth cause of disability worldwide. Stopping smoking reduces the risk of developing COPD and is an essential treatment for this inflammatory disease. Smoking cessation decreases the prevalence of respiratory symptoms, number of hospitalizations, and decline in FEV1, as well as exacerbation frequency and overall mortality. Among the patients, 38-77% with COPD are smokers. Their daily cigarette consumption and level of nicotine dependence are often high. The combination of high intensity behavioral interventions and medication treatments (nicotine replacement therapy, varenicline, bupropion) is the most effective strategy for smokers with COPD. In contrast, behavioral interventions without medication are not more effective than simple advice to stop. Two factors seem to predict the success of the attempt to quit in smokers with COPD: a strong motivation to quit and the use of smoking cessation medications. PMID- 25496791 TI - [The patient with lung cancer in intensive care]. AB - In Western countries, lung cancer (LC) is the most common cause of cancer death. It is present in 15-20% of patients admitted to the ICU with a neoplastic condition. The purpose of this article is to review the causes of admission to ICU of patients with LC, their prognosis and the results of different life support techniques. Most studies include mixed populations of non-small cell (NSCLC) and small-cell lung cancers (SCLC). However, there is preponderance of NSCLC (70%) and LC of advanced or metastatic stages, reflecting the distribution in the general population of LC. The cause of admission of LC patients to ICU is most often of respiratory origin. The ICU mortality rate currently ranges from 13 to 47% and the hospital mortality rate from 24 to 65%. The predictors of in hospital mortality are mainly severity scores, organ dysfunction, general condition (performance status), respiratory distress and the need for mechanical ventilation or vasopressor drugs. When considering the long-term mortality, it is the features of the cancer (presence of metastases, cancer progression) that are important predictive factors. PMID- 25496792 TI - [Pulmonary alveolar proteinosis]. AB - Alveolar proteinosis (AP) is a rare disease characterized by alveolar accumulation of surfactant components, which impairs gas exchange. AP is classified into three groups: auto-immune AP defined by the presence of plasma autoantibodies anti-GM-CSF, the most frequent form (90% of all AP); secondary AP, mainly occurring as a consequence of haematological diseases, or following on from toxic inhalation or infections, and genetic AP, which affects almost exclusively children. AP diagnosis is suspected where chest CT-scan demonstrates interstitial lung disease with a crazy paving aspect; and confirmed by bronchoalveolar lavage, which has a milky appearance and contains periodic acid Schiff positive proteinaceous alveolar deposits. The use of surgical lung biopsy to confirm AP is less frequent nowadays. In this context, positive antibodies against GM-CSF indicates an auto-immune etiology of the AP. Concerning management, whole lung lavage is the gold standard therapy. In refractory AP, new treatments are available such as subcutaneous or inhaled GM-CSF supplementation, or rituximab infusions. The clinical course is unpredictable. Spontaneous improvement or even cure can occur, and the 5-year actuarial survival is 95%. The most frequent complications are infectious etiology. PMID- 25496793 TI - [Impact of lung cancer treatments on renal function]. AB - INTRODUCTION: Renal failure in patients with lung cancer may be multifactorial: related to the patients and their comorbidities, direct tumor compression or the toxicity of cancer treatments and other associated medications. This literature review is intended to describe the state of knowledge regarding the nephrotoxicity of treatments used in thoracic oncology. FINDINGS: The majority of chemotherapy treatments are potentially nephrotoxic. Cisplatin and pemetrexed exhibit mainly renal tubular toxicity, while vascular renal impairment is found with gemcitabine and bevacizumab. Cisplatin results in acute renal failure in 30% of patients. Renal protective strategies (compliance with recommendations, limitation of nephrotoxic treatments, hydration, magnesium supplementation) must be employed systematically. Targeted therapies do not require any adjustment of the dosage in case of moderate or severe renal insufficiency but adapting the doses of biphosphonates to renal function is necessary. CONCLUSION: This review highlights the need for monitoring of renal function in patients with lung cancer during treatment with chemotherapy or biphosphonates. PMID- 25496794 TI - [Haut Conseil de la Sante publique (HCSP). Guidance on the benefits and risks of the electronic cigarette or e-cigarette in the general population (25 April 2014)]. PMID- 25496795 TI - You have a message! Social networking as a motivator for FLS training. AB - OBJECTIVES: Despite evidence supporting the value of the Fundamentals of Laparoscopic Surgery (FLS) curriculum, surgical educators still find it challenging to motivate residents to practice. Wiggio is an online networking and collaboration tool that allows learners to track performance, see what their peers are doing, and send and receive updates. The purpose of this study was to assess whether using Wiggio increases practice and improves performance of the FLS manual skills. DESIGN: After baseline FLS testing, residents were randomized into control (C) and Wiggio (W) groups. The practice events, time spent practicing, and best scores were recorded. Residents in the W group interacted with each other via the Wiggio website. The website moderator sent motivational messages, calendar reminders, and FLS-related articles. The best times and progress graphs for each resident were also posted online. After 4 weeks, all residents underwent final FLS testing and filled out a questionnaire. SETTING: The study was performed in a tertiary care center, at the Steinberg-Bernstein Centre for Minimally Invasive Surgery at the Montreal General Hospital. PARTICIPANTS: Postgraduate year-1 and postgraduate year-2 general surgery residents with no or minimal FLS simulator experience were included. RESULTS: Of the 15 eligible residents, 14 participated, with 7 residents in each group. The FLS scores were similar at baseline (C = 56.9 [+/-14.2], W = 57. 6 [+/-14.7]; p = 0.93). During the study period, twice as many residents in the W group practiced compared with those in the C group (4 vs 2); W-group residents reported more practice events than the C-group residents did (14 vs 4) and spent more time practicing in the laboratory (1035 vs 480 minutes). These results did not reach statistical significance. During practice sessions, proficiency scores were achieved for 40% of the tasks in the W group compared with 8.6% in the C group; however, this difference was also not significant. There was no difference in the FLS scores in both groups at the end of the study. The moderator spent an average of 6.5 minutes per day sending messages and managing the Wiggio website. CONCLUSIONS: Participation in Wiggio seems to increase practice events and time spent training on FLS. Social networking may play a role in surgical education and learner motivation; however, the optimal use of Web 2.0 tools in resident education is not yet fully understood. PMID- 25496797 TI - What is in a number? The Personal Impact of Epilepsy Scale (PIES). PMID- 25496796 TI - The Mini-BESTest--a clinically reproducible tool for balance evaluations in mild to moderate Parkinson's disease? AB - BACKGROUND: The Mini-BESTest is a clinical balance test that has shown a high sensitivity in detecting balance impairments in elderly with Parkinson's disease (PD). However, its reproducibility between different raters and between test occasions has yet to be investigated in a clinical context. Moreover, no one has investigated the reproducibility of the Mini-BESTest's subcomponents (i.e. anticipatory postural adjustments; postural responses; sensory orientation and dynamic gait). We aimed to investigate the inter-rater and test-retest reproducibility (reliability as well as agreement) of the Mini-BESTest, as well as its subcomponents, in elderly with mild to moderate PD, performed under conditions assimilating clinical practice. METHOD: This was an observational measurement study with a test-retest design. Twenty-seven individuals with idiopathic PD (66 - 80 years, mean age: 73; Hoehn & Yahr: 2-3; 1-15 years since diagnosis) were included. Two test administrators, having different experiences with the Mini-BESTest, administered the test individually, in separate rooms in a hospital setting. For the test-retest assessment, all participants returned 7 days after the first test session to perform the Mini-BESTest under similar conditions. Intra-class correlation coefficients (ICC2.1), standard error of measurement (SEMagreement), and smallest real difference (SRD) were analyzed. RESULTS: The Mini-BESTest showed good reliability for both inter-rater and test retest reproducibility (ICC = 0.72 and 0.80). Regarding agreement, the measurement error (SRD) was found to be 4.1 points (accounting for 15% of the maximal total score) for inter-rater reproducibility and 3.4 points (12% of the maximal total score) for test-retest reproducibility. The investigation of the Mini-BESTest's subcomponents showed a similar pattern for both inter-rater and test-retest reproducibility, where postural responses had the largest proportional measurement error, and sensory orientation showed the highest agreement. CONCLUSIONS: Our findings indicate that the Mini-BESTest is able to distinguish between individuals with mild to moderate PD; however, when used in clinical balance assessments, the large measurement error needs to be accounted for. PMID- 25496798 TI - Sleep, epilepsy, and autism. AB - The purpose of this review article is to explore the links between sleep and epilepsy and the treatment of sleep problems in children with autism spectrum disorder (ASD). Epilepsy and sleep have bidirectional relationships, and problems with both are highly prevalent in children with ASD. Literature is reviewed to support the view that sleep is particularly important to address in the context of ASD. Identification and management of sleep disorders may improve seizure control and challenging behaviors. In closing, special considerations for evaluating and treating sleep disorders in children with ASD and epilepsy are reviewed. This article is part of a Special Issue entitled "Autism and Epilepsy". PMID- 25496799 TI - Mediation analysis of health-related quality of life among people living with HIV infection in China. AB - The effects of stigma, social support, and depressive symptoms on health-related quality of life are well documented in the literature, but how these psychological factors interact with each other, and the combined effects when taken together on the health-related quality of life for people living with HIV, remain unclear. This cross-sectional study investigated 114 people living with HIV who were taking antiretroviral medication using the HIV/AIDS-related Stigma Scale (Chinese version), the Social Support Rating Scale, the Center for Epidemiological Studies Depression Scale, and the Medical Outcomes Study-HIV health survey. Multiple linear regression analyses were used to examine the mediation effect of the psychosocial factors on health-related quality of life. Results showed that stigma and social support did not have direct effects, but indirect effects on health-related quality of life through a full mediation effect of depressive symptoms. The results indicate that interventions targeting depression might be the most effective approach to improving health-related quality of life among people living with HIV who are taking antiretroviral medication in China. PMID- 25496800 TI - Redox physical oncology: intersections between redox and the physical environment in cancer. PMID- 25496801 TI - Proteomic and functional analyses of the venom of Porthidium lansbergii lansbergii (Lansberg's hognose viper) from the Atlantic Department of Colombia. AB - The venom of the Lansberg's hognose pitviper, Porthidium lansbergii lansbergii, a species found in the northern region of Colombia, is poorly known. Aiming to increase knowledge on Porthidium species venoms, its proteomic analysis and functional evaluation of in vitro and in vivo activities relevant to its toxicity were undertaken. Out of 51 protein components resolved by a combination of RP HPLC and SDS-PAGE, 47 were assigned to 12 known protein families. In similarity with two previously characterized venoms from species within this genus, Porthidium nasutum and Porthidium ophryomegas, that of P. lansbergii lansbergii was dominated by metalloproteinases, although in lower proportion. A common feature of the three Porthidium venoms appears to be a high content of disintegrins. Proteins not previously observed in Porthidium venoms belong to the vascular endothelium growth factor, phosphodiesterase, and phospholipase B families. P. lansbergii lansbergii venom showed relatively weak lethal activity to mice, and induced a moderate local myotoxicity, but considerable hemorrhage. Its isolated VEGF component showed potent edema-inducing activity in the mouse footpad assay. Significant thrombocytopenia, but no other major hematological changes, were observed in envenomed mice. In vitro, this venom lacked coagulant effect on human plasma, and induced a potent inhibition of platelet aggregation which was reproduced by its purified disintegrin components. Phospholipase A2 and proteolytic activities were also demonstrated. Overall, the compositional and functional data herein described for the venom of P. lansbergii lansbergii may contribute to a better understanding of envenomings by this pitviper species, for which specific clinical information is lacking. BIOLOGICAL SIGNIFICANCE: Porthidium lansbergii lansbergii is estimated to be responsible for nearly 20% of snakebite envenoming cases at the Atlantic Department of Colombia, but the identity and functional properties of its venom components are largely unknown. This study provides the first combined proteomic and functional analyses of the venom of this pitviper, which may contribute to a better understanding of the features of envenomings by this species. PMID- 25496803 TI - Biomarkers for assessing population and individual health and disease related to stress and adaptation. AB - Biomarkers are important in stress biology in relation to assessing individual and population health. They facilitate tapping meaningfully into the complex, non linear interactions that affect the brain and multiple systems of the body and promote adaptation or, when dysregulated, they can accelerate disease processes. This has demanded a multifactorial approach to the choice of biomarkers. This is necessary in order to adequately describe and predict how an individual embedded in a particular social and physical environment, and with a unique genotype and set of lifetime experiences, will fare in terms of health and disease risk, as well as how that individual will respond to an intervention. Yet, at the same time, single biomarkers can have a predictive or diagnostic value when combined with carefully designed longitudinal assessment of behavior and disease related to stress. Moreover, the methods of brain imaging, themselves the reflection of the complexity of brain functional architecture, have provided new ways of diagnosing, and possibly differentiating, subtypes of depressive illness and anxiety disorders that are precipitated or exacerbated by stress. Furthermore, postmortem assessment of brain biomarkers provides important clues about individual vulnerability for suicide related to depression and this may lead to predictive biomarkers to better treat individuals with suicidal depression. Once biomarkers are available, approaches to prevention and treatment should take advantage of the emerging evidence that activating brain plasticity together with targeted behavioral interventions is a promising strategy. PMID- 25496802 TI - Concentrations of the vitamin D metabolite 1,25(OH)2D and odds of metabolic syndrome and its components. AB - AIM: Few epidemiological studies have investigated the association between circulating concentrations of the active vitamin D metabolite 1,25(OH)2D and metabolic syndrome. We sought to determine whether blood levels of 1,25(OH)2D are associated with metabolic syndrome and its individual components, including waist circumference, triglycerides, blood pressure, and glucose, and high-density lipoprotein. We also investigated these associations for the more abundant precursor vitamin D metabolite, 25(OH)D. METHODS: Participants from two completed clinical trials of colorectal neoplasia with available metabolic syndrome data and blood samples for measurement of 1,25(OH)2D (n=1048) and 25(OH)D (n=2096) were included. Cross-sectional analyses of the association between concentrations of 1,25(OH)2D, 25(OH)D, metabolic syndrome, and its components were conducted. RESULTS: A statistically significant inverse association was observed for circulating concentrations of 1,25(OH)2D and metabolic syndrome, with adjusted ORs (95% CIs) of 0.73 (0.52-1.04) and 0.52 (0.36-0.75) for the second and third tertiles of 1,25(OH)2D, respectively (p-trend <0.001). Significant inverse relationships were also observed between 1,25(OH)2D and high triglycerides (p trend <0.001), and low high-density lipoprotein (p-trend <0.001). For 25(OH)D concentrations, significant inverse associations were found for metabolic syndrome (p-trend <0.01), high waist circumference (p-trend <0.04) and triglyceride levels (p-trend <0.01). Participants with 25(OH)D >=30 ng/ml and in the highest tertile of 1,25(OH)2D demonstrated significantly lower odds of metabolic syndrome, with an OR (95% CI) of 0.38 (0.19-0.75) compared to those in the lowest category for both metabolites. CONCLUSION: These results provide new evidence that the relatively rarely-studied active hormonal form of vitamin D, 1,25(OH)2D, is associated with metabolic syndrome and its components, and confirm prior findings for 25(OH)D. The finding that 1,25(OH)2D is related to high density lipoprotein, while 25(OH)D is not, suggests that there may be an independent mechanism of action for 1,25(OH)2D in relation to metabolic dysregulation. PMID- 25496804 TI - Synthesis, biological evaluation and 3D-QSAR study of novel 4,5-dihydro-1H pyrazole thiazole derivatives as BRAF(V600E) inhibitors. AB - Many reports implied that the BRAF serine/threonine kinase was mutated in various types of human tumors, which were related with cell growth, survival and differentiation. To provide new therapeutic opportunities, a series of novel 4,5 dihydro-1H-pyrazole derivatives (6a-10d) containing thiazole moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. All compounds were evaluated in vitro for anticancer activities against WM266.4 human melanoma cell line and breast cancer MCF-7 cell line. Compound 10d displayed the most potential antiproliferative activity with an IC50 value of 0.12MUM against cell line WM266.4 and 0.16MUM against MCF-7 with positive control Sorafenib. Results of the inhibitory activity against BRAF(V600E) revealed that compound 10d was bearing the best bioactivity with IC50 of 0.05MUM as well. On the basis of the result of flow cytometry, with the dose of compound 10d increasing, more and more cancer cell gradually encountered apoptosis or died, which indicated the compound 10d could induce remarkable apoptosis of MCF-7 and WM266.4 cells in a dose dependent manner. Furthermore, docking simulation of inhibitor analogues and 3D-QSAR modeling provided potential binding model and further knowledge of pharmacophore. PMID- 25496805 TI - Design, synthesis and biological activity of a novel Rutin analogue with improved lipid soluble properties. AB - Recent interest in flavonoids has increased greatly due to their biological and pharmacological activities. Flavonoids, consist of a large group of low molecular weight polyphenolic substances, naturally occurring in fruits, vegetables, tea, and wine, and are an integral part of the human diet. Rutin is a common dietary flavonoid that is widely consumed worldwide from plant-derived beverages and foods as traditional and folk medicine remedy as well. Rutin exhibit important pharmacological activities, including anti-oxidation, anti-inflammation, anti diabetic, anti-adipogenic, neuroprotective and hormone therapy. Here, we present the synthesis, antimicrobial, antiproliferative and pro-apoptotic effect on human leukemic K562 cells of compound R2, a new semi-synthetic derivative of Rutin as compared to Rutin itself. The new derivative was also included in finished topical formulations to evaluate a potential application to the dermatology field in view of the antioxidant/antimicrobial/antiinflammatory properties. Stability studies were performed by HPLC; PCL assay and ORAC tests were used to determine the antioxidant activity. R2 presented an antioxidant activity very close to that of the parent Rutin while bearing much better lipophilic character. Regarding antiproliferative effects on the human K562 cell line, R2 was found to be more effective than parent Rutin. Preliminary experiments demonstrated that R2 inhibits NF-kB activity and promotes cellular apoptosis. PMID- 25496806 TI - Synthesis and hybridization property of a boat-shaped pyranosyl nucleic acid containing an exocyclic methylene group in the sugar moiety. AB - A boat-shaped pyranosyl nucleic acid (BsNA) having an exocyclic methylene group in the sugar moiety was synthesized to investigate the possibility that the axial H3' of original BsNA is the cause of its duplex destabilization. The synthesized BsNA analog was chemically stable against various nucleophiles. From the thermal stability of duplex oligonucleotides including the BsNA analog, it was found that the duplex-forming ability can be sensitive to the size of functional groups at the 3'-position. PMID- 25496807 TI - Synthesis, structural characterization and effect on human granulocyte intracellular cAMP levels of abscisic acid analogs. AB - The phytohormone abscisic acid (ABA), in addition to regulating physiological functions in plants, is also produced and released by several mammalian cell types, including human granulocytes, where it stimulates innate immune functions via an increase of the intracellular cAMP concentration ([cAMP]i). We synthesized several ABA analogs and evaluated the structure-activity relationship, by the systematical modification of selected regions of these analogs. The resulting molecules were tested for their ability to inhibit the ABA-induced increase of [cAMP]i in human granulocytes. The analogs with modified configurations at C-2' and C-3' abrogated the ABA-induced increase of the [cAMP]i and also inhibited several pro-inflammatory effects induced by exogenous ABA on granulocytes and monocytes. Accordingly, these analogs could be suitable as novel putative anti inflammatory compounds. PMID- 25496808 TI - Synthesis of prenylated quinolinecarboxylic acid derivatives and their anti obesity activities. AB - Mitochondrial uncoupling is one of the therapeutic strategies used to control energy metabolism in various metabolic diseases and in obesity. Ppc-1 (1), a prenylated quinolinecarboxylic acid isolated from cellular slime molds, shows uncoupling activity in vitro and anti-obesity activity in vivo. In this study, we synthesized Ppc-1 (1) and its derivatives, and revealed the structure-activity relationship of uncoupling activities. The triprenylated compound 18 showed mitochondrial uncoupling activity that was more potent than that of Ppc-1 (1). Compound 18 also suppressed weight gain in mice without undesired effects such as lesions on tissues. These results indicate that compound 18 could be used as a seed compound for new anti-obesity drugs. PMID- 25496811 TI - One-generation reproduction study of esterified propoxylated glycerol (EPG) administered in the feed to CD(r) (Sprague-Dawley) rats. AB - This one-generation study assessed the potential of esterified propoxylated glycerol (EPG) to affect reproduction and offspring development in rats. Male and female Crl:CD(SD)BR rats (30/sex/group) were exposed to EPG at 0, 0.5, 1, and 2g/kg bw/day or at 5% (w/w) in the diet prior to (13 weeks), during, and after two consecutive matings. For dams, exposure continued through gestation and lactation; F1a and F1b pups were weaned to the respective diet (for up to 91 days). No consistent treatment-related effects were observed in: body weights/gains; feed consumption; clinical observations; mating indices; survival, growth and development of litters, litter sizes, body weights, sex ratios (lower % males/litter at 1 and 2g/kg bw/day), acquisition of developmental landmarks, behavioral indices, or histology of selected organs. Lower serum vitamin D, liver vitamin A, and liver vitamin E levels were seen in some EPG-treated groups. None of the reductions were judged to be biologically significant. A/G ratio was greater among males receiving 2g/kg bw/day and 5%. In the absence of any other related effects, the biological significance of this finding is doubtful. PMID- 25496810 TI - Dissociating the semantic function of two neighbouring subregions in the left lateral anterior temporal lobe. AB - We used fMRI in 35 healthy participants to investigate how two neighbouring subregions in the lateral anterior temporal lobe (LATL) contribute to semantic matching and object naming. Four different levels of processing were considered: (A) recognition of the object concepts; (B) search for semantic associations related to object stimuli; (C) retrieval of semantic concepts of interest; and (D) retrieval of stimulus specific concepts as required for naming. During semantic association matching on picture stimuli or heard object names, we found that activation in both subregions was higher when the objects were semantically related (mug-kettle) than unrelated (car-teapot). This is consistent with both LATL subregions playing a role in (C), the successful retrieval of amodal semantic concepts. In addition, one subregion was more activated for object naming than matching semantically related objects, consistent with (D), the retrieval of a specific concept for naming. We discuss the implications of these novel findings for cognitive models of semantic processing and left anterior temporal lobe function. PMID- 25496809 TI - Management of endocrino-metabolic dysfunctions after allogeneic hematopoietic stem cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation). Among side effects, the endocrine complications may be classified as 1) hormonal endocrine deficiencies (particularly gonado- and somatotropic) related to delayed consequences of chemo- and above all radiotherapy, with their consequences on growth, puberty, bone and fertility); 2) auto-immune diseases, particularly dysthyroidism; 3) secondary tumors involving either endocrine glands (thyroid carcinoma) or dependent on hormonal status (breast cancer, meningioma), favored by immune dysregulation and radiotherapy; 4) metabolic complications, especially steroid-induced diabetes and dyslipidemia with their increased cardio-vascular risk. These complications are intricate. Moreover, hormone replacement therapy can modulate the cardio-vascular or the tumoral risk of patients, already increased by radiotherapy and chemotherapy, especially steroids and anthracyclins... Therefore, patients and families should be informed of these side effects and of the importance of a long term follow-up requiring a multidisciplinary approach. PMID- 25496812 TI - Extracorporeal membrane oxygenation in near-drowning patients with cardiac or pulmonary failure. AB - BACKGROUND: The aim of this study was to determine the early outcomes of using extracorporeal membrane oxygenation (ECMO) in near-drowning patients with cardiac or pulmonary failure. METHODS: This study was based on data from 9 patients including 2 children (mean age 33; 8 males, 1 female) who received ECMO after near-drowning between 2008 and 2013. Veno-arterial or veno-arteriovenous ECMO was used in 2 patients with sustained cardiac arrest and veno-venous ECMO was used in 7 patients with severe acute respiratory distress syndrome (ARDS). The means of the partial arterial oxygen pressure (PaO2), Murray score, sequential organ failure assessment (SOFA) score, and simplified acute physiology score II (SAPS II) prior to ECMO were 59.7 +/- 9.9 mmHg on 100% oxygen, 3.5 +/- 0.6, 11.4 +/- 1.9, and 73.0 +/- 9.2, respectively. RESULTS: The PaO2 mean improved to 182 +/- 152 mmHg within 2 h post-ECMO. The mean of SOFA score and SAPS-II decreased significantly to 8.6 +/- 3.2 (p = 0.013) and 46.4 +/- 5.1 (p = 0.008), respectively, at 24 h post-ECMO with mean flow rate of 3.9 +/- 0.8 l/min. ECMO was weaned at a mean duration of 188 (range, 43-672) h in all patients. Seven patients were discharged home without neurological sequelae, while 2 patients who had hypoxic brain damage died after further referral. The overall survival with favourable neurological outcomes at 3 months was 77.8%. There were no complications related to ECMO. CONCLUSIONS: ECMO was safe and effective for patients with ongoing cardiac arrest or ARDS after a near-drowning incident and can be used as a resuscitative strategy in near-drowning patients with cardiac or pulmonary failure resistant to conventional ventilator therapy. PMID- 25496813 TI - An unusual complication of a duodenal ulcer. PMID- 25496814 TI - A rare vascular tumor of the liver. PMID- 25496815 TI - Esophageal intraluminal baseline impedance differentiates gastroesophageal reflux disease from functional heartburn. AB - BACKGROUND & AIMS: Mucosal integrity can be assessed in patients with gastroesophageal reflux disease (GERD) by measuring intraluminal baseline impedance (BI). However, it is not clear whether BI is abnormal in patients with functional heartburn (FH), or can be used to distinguish them from patients with GERD. We compared differences in BI between patients with FH vs GERD. METHODS: We performed a prospective study of 52 patients (16 men; mean age, 55 y; range, 23 78 y) seen at a tertiary university hospital from February 2009 through December 2012. Thirty-five patients had GERD (19 had nonerosive reflux disease [NERD], 16 had erosive reflux disease [ERD]) and 17 had FH. All patients discontinued proton pump inhibitor therapy and then underwent esophagogastroduodenoscopy and multichannel intraluminal impedance and pH monitoring. BI was assessed at 3, 5, 7, 9, 15, and 17 cm proximal to the lower esophageal sphincter in recumbent patients. Biopsy specimens were taken from 3 cm above the gastroesophageal junction; histology analysis was performed to identify and semiquantitatively score (scale, 0-3) dilated intercellular spaces. RESULTS: Baseline impedance in the distal esophagus was significantly lower in patients with NERD or erosive reflux disease (ERD) than FH (P = .0006). At a cut-off value of less than 2100 Omega, BI measurements identified patients with GERD with 78% sensitivity and 71% specificity, with positive and negative predictive values of 75%. Also in the proximal esophagus, reduced levels of BI levels were found only in patients with ERD. There were negative correlations between level of BI and acid exposure time (r = -0.45; P = .0008), number of acidic reflux episodes (r = -0.45; P = .001), and proximal extent (r = -0.40; P = .004). Biopsy specimens from patients with NERD or ERD had significant increases in dilation of intercellular spaces, compared with those from patients with FH; there was an inverse association between dilated intercellular spaces and BI in the distal esophagus (r = -0.28; P = .06). CONCLUSIONS: Measurement of BI in the lower esophagus can differentiate patients with ERD or NERD from patients with FH (78% sensitivity and 71% specificity), and therefore should be considered as a diagnostic tool for patients with proton pump inhibitor-refractory reflux. Low levels of BI are associated with increased exposure to acid and dilation of intercellular spaces, indicating that BI is a marker of mucosal integrity. PMID- 25496817 TI - Effects of anxiety and depression in patients with gastroesophageal reflux disease. AB - BACKGROUND & AIMS: Increased levels of anxiety and depression have been associated with esophageal hyperalgesia and an increased risk of gastroesophageal reflux disease (GERD). We investigated the effects of anxiety and depression on GERD symptoms and the perception of reflux episodes in a well-characterized group of patients. METHODS: We performed a prospective study of 225 consecutive patients who had symptoms of GERD evaluated. Patients underwent ambulatory 24 hour pH impedance monitoring, and levels of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. RESULTS: GERD was diagnosed in 147 patients (78 patients had functional heartburn); 36 patients were hypersensitive to gastroesophageal reflux. Among patients with GERD, increased levels of anxiety were associated with more severe retrosternal pain and retrosternal burning. Furthermore, increased levels of anxiety and depression each were associated with lower scores of the mental component of quality of life questionnaire. Levels of anxiety or depression were not associated with the number of reflux symptoms reported during 24-hour pH impedance monitoring or with the number of symptoms associated with a reflux event. Among GERD patients with hypersensitivity to reflux, levels of anxiety and depression and decreases in quality of life were similar to those of other patients with GERD. Patients with functional heartburn had higher levels of anxiety than patients with GERD. CONCLUSIONS: In patients with GERD, increased levels of anxiety are associated with increased severity of retrosternal pain and heartburn and reduced quality of life. Patients with GERD with hypersensitivity to gastroesophageal reflux have similar levels of anxiety and similar quality-of-life scores as other patients with GERD. PMID- 25496816 TI - L-carnitine Reduces Muscle Cramps in Patients With Cirrhosis. AB - We performed a prospective study to evaluate the ability of L-carnitine, which is involved in the beta-oxidation of fatty acids, to reduce muscle cramps in patients with cirrhosis. Consecutive patients with cirrhosis and muscle cramps were given L-carnitine 300 mg, 3 times/day (900 mg/day, n = 19) or 4 times/day (1200 mg/day, n = 23) for 8 weeks. The frequency of muscle cramps was assessed by questionnaires, and the degree of muscle cramping was assessed by using the visual analogue scale (VAS). Muscle cramping was reduced in 88.1% of all subjects at the end of the 8-week study period and disappeared for 28.6% of patients. Overall VAS scores decreased significantly from 69.9 +/- 22.5 at baseline to 26.2 +/- 29.1 after 8 weeks (P < .0001). The dose of L-carnitine was significantly associated with percentages of patients with reduced muscle cramps after 8 weeks (43.5% in the 1200 mg/day group vs 10.5% in the 900 mg/day group, P = .037) and VAS scores at 8 weeks (9.9 +/- 13.5 in the 1200 mg/day group vs 39.6 +/- 31.9 in the 900 mg/day group, P = .003). No adverse events were reported. Therefore, L carnitine appears to be safe and effective for reducing liver cramps in patients with cirrhosis. PMID- 25496818 TI - Memory and PTPIP51--a new protein in hippocampus and cerebellum. AB - Previously the expression of Protein Tyrosine Phosphatase Interacting Protein 51 (PTPIP51) in mouse brain was reported. Here, we investigated PTPIP51 mRNA and protein in two of the brain regions namely the hippocampus and the cerebellum of mouse brains. On a cellular level both the protein and the mRNA were related to the pyramidal cells of the hippocampal formation, the granular cells of the dentate gyrus and the cells of the adjacent strata. In the cerebellum PTPIP51 was traced in Purkinje cells, the cells of the molecular layer and the granular layer. On a subcellular level only partial co-localization was seen for the endoplasmic reticulum, but not with mitochondria. In addition the interactome of PTPIP51 was analysed. In hippocampal cells a strong interaction with PTP1B and vesicle-associated membrane protein-associated protein B (VAPB) was detected. A somewhat differing interaction profile was found in the cerebellum, where high interaction levels were found for 14-3-3, diacylglycerol kinase alpha (DGKalpha), NFkappaB and PTP1B. These interaction partners represent specific signalling pathways linked to building memory. PTPIP51 can be associated with nerve growth factor signalling, dendritic and axonal growth, synaptogenesis, and all processes needed for memory formation. Moreover, in HT-22 mouse hippocampal cells PTPIP51 expression was induced by administrating the fibroblast growth factor 1 (FGF-1), which is known to take part in learning/memory processes. Knocking down p38-MAPK also led to an up-regulation of PTPIP51 probably resembling a compensative mechanism. Thus, a possible connection to the processing of memories can be anticipated. Differences in the interaction profile in both regions may be attributed to the actual/local differences in memory formation. PMID- 25496819 TI - Dilution and volatilization of groundwater contaminant discharges in streams. AB - An analytical solution to describe dilution and volatilization of a continuous groundwater contaminant plume into streams is developed for risk assessment. The location of groundwater plume discharge into the stream (discharge through the side versus bottom of the stream) and different distributions of the contaminant plume concentration (Gaussian, homogeneous or heterogeneous distribution) are considered. The model considering the plume discharged through the bank of the river, with a uniform concentration distribution was the most appropriate for risk assessment due to its simplicity and limited data requirements. The dilution and volatilization model is able to predict the entire concentration field, and thus the mixing zone, maximum concentration and fully mixed concentration in the stream. It can also be used to identify groundwater discharge zones from in stream concentration measurement. The solution was successfully applied to published field data obtained in a large and a small Danish stream and provided valuable information on the risk posed by the groundwater contaminant plumes. The results provided by the dilution and volatilization model are very different to those obtained with existing point source models, with a distributed source leading to a larger mixing length and different concentration field. The dilution model can also provide recommendations for sampling locations and the size of impact zones in streams. This is of interest for regulators, for example when developing guidelines for the implementation of the European Water Framework Directive. PMID- 25496820 TI - Fringe-controlled biodegradation under dynamic conditions: quasi 2-D flow-through experiments and reactive-transport modeling. AB - Biodegradation in contaminated aquifers has been shown to be most pronounced at the fringe of contaminant plumes, where mixing of contaminated water and ambient groundwater, containing dissolved electron acceptors, stimulates microbial activity. While physical mixing of contaminant and electron acceptor by transverse dispersion has been shown to be the major bottleneck for biodegradation in steady-state plumes, so far little is known on the effect of flow and transport dynamics (caused, e.g., by a seasonally fluctuating groundwater table) on biodegradation in these systems. Towards this end we performed experiments in quasi-two-dimensional flow-through microcosms on aerobic toluene degradation by Pseudomonas putida F1. Plume dynamics were simulated by vertical alteration of the toluene plume position and experimental results were analyzed by reactive-transport modeling. We found that, even after disappearance of the toluene plume for two weeks, the majority of microorganisms stayed attached to the sediment and regained their full biodegradation potential within two days after reappearance of the toluene plume. Our results underline that besides microbial growth, also maintenance and dormancy are important processes that affect biodegradation performance under transient environmental conditions and therefore deserve increased consideration in future reactive-transport modeling. PMID- 25496821 TI - Recurrent laryngeal papillomatosis with oesophageal involvement in a 2 year old boy: successful treatment with the quadrivalent human papillomatosis vaccine. AB - Authors present a case report of a 2-year-old boy with recurrent laryngeal papillomatosis with oesophageal involvement due to human papilloma virus types 6 and 11, who needed surgical treatment every 4-6 weeks, altogether 11 times. After detailed immunological evaluation of basic immunological parameters, and in vitro detection of good responses to routine childhood immunization, a therapeutic vaccination has been decided with a 4-valent HPV vaccine. Following the third vaccine dose both laryngeal and oesophageal lesions disappeared completely, and for 2 years follow-up no papillomas could be detected. Vaccination could be a promising method in the treatment of RRP in children. PMID- 25496822 TI - Cholesteatoma in Danish children - a national study of changes in the incidence rate over 34 years. AB - OBJECTIVE: To describe temporal trends in the incidence rate of surgically treated middle ear cholesteatoma in Danish children from 1977 to 2010. METHODS: Data on surgically treated middle ear cholesteatoma was drawn from the Danish National Patient Register. A change in incidence rate over time was examined using Poisson regression analysis, while the cumulative incidence proportion was estimated using life-tables. RESULTS: A total of 5850 cases of surgically treated middle ear cholesteatoma distributed among 3874 children aged 0-15 years were identified. From 1977 to 2002 the age-standardized incidence rates for first-time surgically treated middle ear cholesteatoma increased from 8 to 15 per 100,000 person-years with an estimated annual increase of 1.8% (95% confidence interval (CI) 1.3-2.2%). From 2002 to 2010 the rates decreased from 15 to 10 per 100,000 person-years with an annual decrease of 5.4% (95% CI 3.2-7.5%). Age-specific incidence rates were at maximum around the age of 9 years during the whole period. The estimated cumulative incidence proportion at age 16 years based on the 2010 age-specific incidence rates was 0.16% (95% CI 0.09-0.32%) compared with 0.20% (95% CI 0.11-0.37%) based on the 2000 age-specific incidence rates. CONCLUSION: From 2002 to 2010 there was a decrease in the incidence rate of first time surgically treated middle ear cholesteatoma. The decrease was preceded by a significant increase in the incidence rate of middle ear ventilation tube insertion. However, further studies are needed to find possible explanations for the decrease. PMID- 25496823 TI - Preliminary evidence of an interaction between the CRISPLD2 gene and non syndromic cleft lip with or without cleft palate (nsCL/P) in Xinjiang Uyghur population, China. AB - BACKGROUND: Non-syndromic cleft lip with or without cleft palate (nsCL/P) is a common birth defect results from the genetic factors alone or interactions with environmental changes. Single nucleotide polymorphisms (SNPs) of CRISPLD2 gene have been found to be an etiologic factor in the development of nsCL/P. However, few studies to date focused on the association of genetic variation of CRISPLD2 gene with nsCL/P, and the results are conflicting based on the different study population. The main purpose of the present study was to investigate the association between the CRISPLD2 gene and nsCL/P in Xinjiang Uyghur population. METHODS: Eighteen SNPs were screened in a group of 200 patients with nsCL/P and in a control group consisting of 180 unaffected individuals by next generation sequencing using MiSeq Benchtop Sequencer (Illumina). RESULTS: Our case-control association analysis showed that the SNP marker rs1546124 showed statistically significant differences in genotype (CC vs. CG vs. GG P=0.004) and allele frequencies (49% vs. 37.8% OR=1.58; 95% CI=1.19-2.1, P=0.002) between nsCL/P and controls. Under the recessive model of inheritance, the GG homozygotes had an OR of 2.4 (95% CI=1.37-4.18; P=0.002), and the result of significance was maintained even after multiple testing correction. Haplotype combinations of CACC were significantly more frequent in the nsCL/P patients than in controls (P=0.037). Finally, the MDR analysis identified the two-SNP model including rs1546124 and rs4782675 as best combination of possibly interactive polymorphisms (P<0.001). CONCLUSION: Our results demonstrate that genetic polymorphism of CRISPLD2 gene is associated with an increased risk of nsCL/P in a Xinjiang Uyghur population. PMID- 25496824 TI - Dose monitoring using the DICOM structured report: assessment of the relationship between cumulative radiation exposure and BMI in abdominal CT. AB - AIM: To perform a systematic, large-scale analysis using the Digital Imaging and Communication in Medicine structured report (DICOM-SR) to assess the relationship between body mass index (BMI) and radiation exposure in abdominal CT. MATERIALS AND METHODS: A retrospective analysis of DICOM-SR of 3121 abdominal CT examinations between April 2013 and March 2014 was performed. All examinations were conducted using a 128 row CT system. Patients (mean age 61 +/- 15 years) were divided into five groups according to their BMI: group A <20 kg/m(2) (underweight), group B 20-25 kg/m(2) (normal weight), group C 25-30 kg/m(2) (overweight), group D 30-35 kg/m(2) (obese), and group E > 35 kg/m(2) (extremely obese). CT dose index (CTDIvol) and dose-length product (DLP) were compared between all groups and matched to national diagnostic reference values. RESULTS: The mean CTDIvol and DLP were 5.4 +/- 2.9 mGy and 243 +/- 153 mGy.cm in group A, 6 +/- 3.6 mGy and 264 +/- 179 mGy.cm in group B, 7 +/- 3.6 mGy and 320 +/- 180 mGy.cm in group C, 8.1 +/- 5.2 mGy and 375 +/- 306 mGy.cm in group D, and 10 +/- 8 mGy and 476 +/- 403 mGy.cm in group E, respectively. Except for group A versus group B, CTDIvol and DLP differed significantly between all groups (p<0.05). Significantly more CTDIvol values exceeded national diagnostic reference values in groups D and E (2.1% and 6.3%) compared to group B (0.5%, p<0.05). CONCLUSION: DICOM-SR is a comprehensive, fast, and reproducible way to analyse dose-related data at CT. It allows for automated evaluation of radiation dose in a large study population. Dose exposition is related to the patient's BMI and is increased by up to 96% for extremely obese patients undergoing abdominal CT. PMID- 25496825 TI - Human keratinocytes restrict chikungunya virus replication at a post-fusion step. AB - Transmission of chikungunya virus (CHIKV) to humans is initiated by puncture of the skin by a blood-feeding Aedes mosquito. Despite the growing knowledge accumulated on CHIKV, the interplay between skin cells and CHIKV following inoculation still remains unclear. In this study we questioned the behavior of human keratinocytes, the predominant cell population in the skin, following viral challenge. We report that CHIKV rapidly elicits an innate immune response in these cells leading to the enhanced transcription of type I/II and type III interferon genes. Concomitantly, we show that despite viral particles internalization into Rab5-positive endosomes and efficient fusion of virus and cell membranes, keratinocytes poorly replicate CHIKV as attested by absence of nonstructural proteins and genomic RNA synthesis. Accordingly, human keratinocytes behave as an antiviral defense against CHIKV infection rather than as a primary targets for initial replication. This picture significantly differs from that reported for Dengue and West Nile mosquito-borne viruses. PMID- 25496826 TI - Foot-and-mouth disease vaccination induces cross-reactive IFN-gamma responses in cattle that are dependent on the integrity of the 140S particles. AB - Interferon-gamma (IFN-gamma) recall responses against foot-and-mouth disease virus (FMDV) in FMD vaccinated cattle are utilized to study T-lymphocyte immunity against this virus. Here, a recall IFN-gamma assay based on a commercial ELISA was set up using 308 samples from naive and vaccinated cattle. The assay was used to study cross-reactive responses between different FMDV vaccine strains. Blood samples from cattle immunized with monovalent vaccines containing A24/Cruzeiro/Brazil/55, A/Argentina/2001 or O1/Campos/Brazil/58 strains were tested using purified-inactivated FMDV from homologous and heterologous strains. A24/Cruzeiro was the most efficient IFN-gamma inducer in all vaccinated animals, both when included in the vaccine or as stimulating antigen. We demonstrate that this was mainly due to the structural stability of the whole viral particle. These results show that IFN-gamma production relies on the presence of 140S particles that can maintain their integrity along the incubation process in vitro, and throughout the vaccine's shelf-life, when used in vivo. PMID- 25496827 TI - Tuberculosis in swine co-infected with Mycobacterium avium subsp. hominissuis and Mycobacterium bovis in a cluster from Argentina. AB - SUMMARY In Argentina little is known about the epidemiology of tuberculosis (TB) infection in swine. We characterized the epidemiological dynamics of Mycobacterium avium complex (MAC) infection in a swine population of Argentina using molecular tools and spatial analysis techniques. Isolates (n = 196) obtained from TB-like lesions (n = 200) were characterized by polymerase chain reaction. The isolates were positive to either M. bovis (IS6110) (n = 160) or M. avium (IS1245) (n = 16) while the remaining 20 (10.2%) isolates were positive to both M. bovis and M. avium. The detection of both bacteria together suggests co infection at the animal level. In addition, MAC-positive isolates (n = 36) were classified as M. avium subsp. avium (MAA) (n = 30) and M. avium subsp. hominissuis (MAH) (n = 6), which resulted in five genotypes when they were typed using mycobacterial interspersed repetitive unit, variable number of tandem repeats (MIRU-VNTR). One significant (P = 0.017) spatial clustering of genotypes was detected, in which the proportion of MAH isolates was larger than expected under the null hypothesis of even distribution of genotypes. These results show that in Argentina the proportion of TB cases in pigs caused by M. avium is larger than that reported in earlier studies. The proportion of M. bovis-MAC co infections was also higher than in previous reports. These results provide valuable information on the epidemiology of MAC infection in swine in Argentina. PMID- 25496828 TI - Diagnostic evaluation, monitoring, and perioperative management of spinal cord compression in patients with Morquio syndrome. AB - Mucopolysaccharidosis IVA is an autosomal recessive condition caused by mutations in the GALNS gene, which encodes N-acetylgalactosamine-6-sulfatase, also called galactosamine-6-sulfatase (GALNS). A reduction in or absence of effective GALNS leads to faulty catabolism of keratan sulfate and chondroitin-6-sulfate within the lysosome; their accumulation causes cell, tissue, and organ dysfunction. The connective tissue, cartilage, ligaments, and bone of patients with Morquio A syndrome are particularly affected. Patients with Morquio A syndrome are at high risk of neurological complications because of their skeletal abnormalities; many patients are in danger of cervical myelopathy due to odontoid hypoplasia and ligamentous laxity leading to atlantoaxial subluxation. The multisystemic involvement of patients with Morquio A syndrome requires treatment by multidisciplinary teams; not all members of these teams may be aware of the potential for subluxation and quadriparesis. A multinational, multidisciplinary panel of 10 skeletal dysplasia or Morquio A syndrome specialists convened in Miami, FL on December 7 and 8, 2012 to develop consensus recommendations for early identification and effective management of spinal cord compression, for anesthesia and surgical best practices, and for effectual cardiac and respiratory management in patients with Morquio A syndrome. The target audience for these recommendations includes any physician who may encounter a patient with Morquio A syndrome, however doctors who do not have access to the full spectrum of specialists and resources needed to support patients with Morquio A syndrome should attempt to refer patients to a center that does. Physicians who manage Morquio A syndrome or comorbid conditions within specialty centers should review these expert panel recommendations and fully understand the implications of spinal cord instability for their own practices. PMID- 25496829 TI - Differential effects of olanzapine and clozapine on plasma levels of adipocytokines and total ghrelin. AB - Second-generation antipsychotics (SGAs) have been associated with an increased liability for weight gain and metabolic side effects. Among SGAs, clozapine and olanzapine had great liability to induce weight gain and metabolic adverse reactions. Leptin, adiponectin, and total ghrelin play important roles in energy homeostasis and are suggested to be biomarkers of metabolic disturbances. The purpose of the present study was to investigate the differential effects of antipsychotics (olanzapine and clozapine) on the levels of adipocytokines (leptin and adiponectin) and total ghrelin. Three hundred and thirty-three patients with schizophrenia under clozapine or olanzapine monotherapy were recruited. Control participants were recruited from a healthy community population based on a health investigation (N=119). Fasting blood samples for glucose, cholesterol, triglycerides, leptin, adiponectin, and total ghrelin were analyzed. There were significant differences in the levels of cholesterol, triglycerides, and glucose between these three groups. Post hoc comparisons showed that the olanzapine group had the highest levels of cholesterol and triglycerides. The levels of leptin, adiponectin, and total ghrelin were also significantly different between the three groups after controlling age and body mass index (BMI). Post hoc comparisons showed that the olanzapine group had the lowest levels of adiponectin and total ghrelin. The present study found that the uses of olanzapine and clozapine were associated with changes in adipocytokines and total ghrelin, even after adjusting potential confounding factors. Olanzapine had greater influences on adiponectin and total ghrelin than clozapine. The changes in adipocytokines and total ghrelin were a direct effect of antipsychotics on hormonal pathways of energy homeostasis, rather than the result of weight gain. PMID- 25496830 TI - Effects of rimonabant on the development of single dose-induced behavioral sensitization to ethanol, morphine and cocaine in mice. AB - RATIONALE: The endocannabinoid system has been implicated in the neurobiological mechanism underlying drug addiction, especially the primary rewarding dopamine dependent processes. Therefore, endocannabinoid receptor antagonists, such as the CB1 cannabinoid antagonist rimonabant, have been proposed as candidates for preventive addiction therapies. OBJECTIVES: Investigate the possible involvement of CB1 receptors in the development of behavioral sensitization to ethanol, morphine and cocaine in mice. METHODS: We compared the effects of different doses of rimonabant (0.3, 1, 3 and 10mg/kg) on spontaneous locomotor activity in the open-field, hyperlocomotion induced by acute administration of ethanol (1.8g/kg), morphine (20mg/kg) or cocaine (10mg/kg) and on subsequent drug-induced locomotor sensitization using a two-injection protocol in mice. We also investigated a possible depressive-like effect of an acute rimonabant challenge at the highest dose and its potential anxiogenic property. RESULTS: At the highest dose, rimonabant abolished ethanol- and cocaine-induced hyperlocomotion and behavioral sensitization without modifying spontaneous and central locomotor activity or inducing depressive-like behavior on the forced swim test in mice. The other doses of rimonabant also selectively blocked acute ethanol-induced central hyperlocomotion. Although rimonabant at 0.3 and 1mg/kg potentiated the central hyperlocomotion induced by acute morphine injection, it was effective in attenuating morphine-induced behavioral sensitization at all doses. CONCLUSIONS: Because the neural basis of behavioral sensitization has been proposed to correspond to some components of addiction, our findings indicate that the endocannabinoid system might be involved in ethanol, cocaine and morphine abuse. PMID- 25496831 TI - Brahma regulates the Hippo pathway activity through forming complex with Yki-Sd and regulating the transcription of Crumbs. AB - The Hippo signaling pathway restricts organ size by inactivating the Yorkie (Yki)/Yes-associated protein (YAP) family proteins. The oncogenic Yki/YAP transcriptional coactivator family promotes tissue growth by activating target gene transcription, but the regulation of Yki/YAP activation remains elusive. In mammalian cells, we identified Brg1, a major subunit of chromatin-remodeling SWI/SNF family proteins, which interacts with YAP. This finding led us to investigate the in vivo functional interaction of Yki and Brahma (Brm), the Drosophila homolog of Brg1. We found that Brm functions at the downstream of Hippo pathway and interacts with Yki and Scalloped (Sd) to promotes Yki-dependent transcription and tissue growth. Furthermore, we demonstrated that Brm is required for the Crumbs (Crb) dysregulation-induced Yki activation. Interestingly, we also found that crb is a downstream target of Yki-Brm complex. Brm physically binds to the promoter of crb and regulates its transcription through Yki. Together, we showed that Brm functions as a critical regulator of Hippo signaling during tissue growth and plays an important role in the feedback loop between Crb and Yki. PMID- 25496832 TI - EPO gene expression promotes proliferation, migration and invasion via the p38MAPK/AP-1/MMP-9 pathway by p21WAF1 expression in vascular smooth muscle cells. AB - The use of recombinant human erythropoietin (rHuEpo) can lead to hypertrophy and hyperplasia, and has induced the proliferation of vascular smooth muscle cells (VSMCs). The effect of the EPO gene in the migration and invasion of VSMCs remains unclear. In this study, overexpression of the EPO gene increased the DNA synthesis and phosphorylation of ERK1/2 and p38MAPK in VSMCs. In addition, EPO gene expression induced the migration and invasion of VSMCs via the expression of MMP-9 by the activation of NF-kappaB and AP-1 binding. A blockade of p38MAPK by specific p38MAPK inhibitor SB203580 led to a suppression of the increased DNA synthesis, migration, and invasion of VSMCs that was induced by the EPO gene. SB203580 treatment blocked the increased expression of MMP-9 through the binding activity of AP-1. Transfection of the EPO gene with VSMCs was associated with the up-regulation of cyclin D1/CDK4, cyclin E/CDK2, and p21WAF1, and with the down regulation of p27KIP1. The specific suppression of p21WAF1 expression by siRNA rescued the enhancement of DNA synthesis via the phosphorylation of p38MAPK and the increase in migration and invasion through AP-1-mediated MMP-9 expression in EPO gene transfectants. These novel findings demonstrate that p21WAF1 regulates the proliferation, migration and invasion of VSMC induced by EPO gene. PMID- 25496833 TI - The effects of short term dietary restriction on haematological responses and leukocyte gene expression of anovulatory and ovulatory beef heifers. AB - The study objective was to characterise the impact of negative energy balance (NEB) on immune-stress responsiveness in beef heifers. A short term (18-day) dietary restriction model was used. Dietary restriction (0.4 maintenance (Mn) energy requirements) induced abrupt onset of anoestrus in nine heifers (Restricted Anovulatory; RA) while nineteen heifers maintained oestrous cyclicity (Restricted Ovulatory; RO). In addition a control (C) group of 12 heifers received a higher level of feeding (1.2 Mn). Haematological related biomarkers of husbandry stress, leukocyte gene expression of seven cytokine genes and five immunological biomarkers were investigated. After 18 days of differential feeding of the heifers alterations in eosinophil and monocyte numbers and altered expression of CXCL8, IL2 and TNFalpha could be attributed to diet restriction. More specifically, changes in these five variables were found in heifers that became anovulatory (RA) and are therefore considered to be more sensitive biomarkers to an energy deficit. PMID- 25496834 TI - Bioactive compound synthesis of Ag nanoparticles from leaves of Melia azedarach and its control for mosquito larvae. AB - Larvicidal activity of synthesized Ag nanoparticles using 2,7.bis[2 [diethylamino]-ethoxy]fluorence isolate from the Melia azedarach leaves against Aedes aegypti and Culex quinquefasciatus. Six fractions were collected and concentrated, fraction three showed a single spot on TLC which was found to be a pure compound. The structures were elucidated by analyses of UV, MS, and NMR spectral data. The maximum mortality was fluorence against A. aegypti and C. quinquefasciatus (LC50 = 7.94, LC90 = 23.82 ppm and LC50 = 13.58 and LC90 = 40.03 ppm). The synthesized nanoparticles were characterized and confirmed as Ag nanoparticles by using UV-visible spectroscopy, XRD and HRTEM analysis. The maximum activity was observed in synthesized AgNPs against A. aegypti and C. quinquefasciatus (LC50 = 4.27 and 3.43 ug/mL; LC90 = 12.61 and 10.29 ug/mL). Rephrase test was studied to analyze the toxicological effects of Mesocyclops pehpeiensis for 24 h at synthesized AgNPs. This method is considered as an innovative alternative approach that can be used to control mosquitoes. PMID- 25496835 TI - A histomorphologic predictive model for axillary lymph node metastasis in preoperative breast cancer core needle biopsy according to intrinsic subtypes. AB - The aim of this study is construction of a pathologic nomogram that can predict axillary lymph node metastasis (LNM) for each intrinsic subtype of breast cancer with regard to histologic characteristics in breast core needle biopsy (CNB) for use in routine practice. A total of 534 CNBs with invasive ductal carcinoma classified into 5 intrinsic subtypes were enrolled. Eighteen clinicopathological characteristics and 8 molecular markers used in CNB were evaluated for construction of the best predictive model of LNM. In addition to conventional parameters including tumor multiplicity (P < .001), tumor size (P < .001), high histologic grade (P = .035), and lymphatic invasion (P = .017), micropapillary structure (P < .001), the presence of small cell-like crush artifact (P = .001), and overexpression of HER2 (P = .090) and p53 (P = .087) were proven to be independent predictive factors for LNM. A combination of 8 statistically independent parameters yielded the strongest predictive performance with an area under the curve of 0.760 for LNM. A combination of 6 independent variables, including tumor number, tumor size, histologic grade, lymphatic invasion, micropapillary structure, and small cell-like crush artifact produced the best predictive performance for LNM in luminal A intrinsic subtype (area under the curve, 0.791). Thus, adding these combinations of clinical and morphologic parameters in preoperative CNB is expected to enhance the accuracy of prediction of LNM in breast cancer, which might serve as another valuable tool in determining optimal surgical strategies for breast cancer patients. PMID- 25496836 TI - Implications of the legalization of non-commercial surrogacy for local kinship and motherhood in Vietnamese society. AB - Until recently, surrogacy was banned in Vietnam for all cases. The government, however, has altered its position on reproductive technology and will soon legalize non-commercial surrogacy among relatives. Motherhood is highly venerated in Vietnamese society and, under this local kinship conception, gestational process is of paramount importance in establishing a connection between the fetus and the woman. The implications of this new government decision for local kinship, motherhood and the individuals concerned will be discussed. PMID- 25496837 TI - Inhibition of dipeptidyl peptidase-IV enzyme activity protects against myocardial ischemia-reperfusion injury in rats. AB - BACKGROUND: We investigated whether attenuating dipeptidyl peptidase-IV (DPP4) enzyme activity protected rat heart from ischemia-reperfusion (IR) injury (40-min left anterior descending coronary artery ligation followed by 72 h reperfusion). METHODS AND RESULTS: Adult male Fischer 344 rats (n = 24) were equally divided into sham-control (WT-SC), WT-IR, and WT-IR-Sita (oral sitagliptin 400 mg/kg/day for 3 days) groups, whereas adult male DPP4-deficiency (DPP4(D)) rats (n = 16) were equally divided into DPP4(D)-SC and DPP4(D)-IR groups. Animals were sacrificed at 72 h after reperfusion with collection of heart specimens. Infarct area (H&E), collagen deposition (Sirius-red stain), fibrotic area (Masson's trichrome), and fluorescent-ROS intensity (H2DCFDA-labeling myocardium) of left ventricle were significantly higher in WT-IR than those in other groups, significantly higher in WT-IR-Sita and DPP4(D)-IR groups than in WT-SC and DPP4(D)-SC groups (all p < 0.001), but there was no difference between the latter two groups. Protein expressions of oxidative stress (oxidized protein), reactive oxygen species (NOX-1, NOX-2), inflammation (TNF-alpha, NF-kappaB, MMP-9, VCAM 1), apoptosis (mitochondrial Bax, cleaved caspase-3 and PARP), myocardial damage markers (cytosolic cytochrome-C, gamma-H2AX), and number of inflammatory cells (CD14+, CD68+, CD40+ cells) showed a pattern identical to that of histological changes among all groups (all p < 0.005), whereas markers of anti-apoptosis (Bcl 2) and mitochondrial integrity (mitochondrial cytochrome-C) as well as left ventricular ejection fraction showed an opposite pattern (all p < 0.001). Protein expressions of anti-oxidants (HO-1, NQO-1), angiogenesis factors (SDF-1alpha, CXCR4), and glycogen-like-peptide-1-receptor were significantly higher inWT-IR Sita and DPP4(D)-IR than those in other groups (all p <0.001). CONCLUSION: Abrogation of DPP4 activity protects against myocardial IR injury and preserved heart function. PMID- 25496838 TI - A comparative analysis of the structural, functional and biological differences between Mouse and Human Nerve Growth Factor. AB - NGF is the prototype member of the neurotrophin family of proteins that promote the survival and growth of selected neurons in the central and peripheral nervous systems. As for all neurotrophins, NGF is translated as a pre-pro-protein. Over the years, NGF and proNGF of either human or mouse origin, given their high degree of homology, have been exploited for numerous applications in biomedical sciences. The mouse NGF has been considered the golden-standard for bioactivity. Indeed, due to evolutionary relatedness to human NGF and to its ready availability and by assuming identical properties to its human counterpart, the mouse NGF, isolated and purified from sub-maxillary glands, has been tested not only in laboratory practice and in preclinical models, but it has also been evaluated in several human clinical trials. Aiming to validate this assumption, widely believed, we performed a comparative study of the biochemical and biophysical properties of the mouse and human counterparts of NGF and proNGF. The mature and the precursor proteins of either species strikingly differ in their biophysical profiles and, when tested for ligand binding to their receptors, in their in vitro biological activities. We provide a structural rationale that accounts for their different functional behaviors. Despite being highly conserved during evolution, NGF and proNGF of mouse and human origins show distinct properties and therefore special care must be taken in performing experiments with cross-species systems in the laboratory practice, in developing immunoassays, in clinical trials and in pharmacological treatments. PMID- 25496839 TI - Somatic mutations of the ATP1A1 gene and aldosterone-producing adenomas. AB - Primary aldosteronism is the most common form of secondary hypertension. It affects approximately 10% of patients with hypertension and causes greater cardiovascular morbidity and mortality compared to essential hypertension of similar severity and duration. The cause of primary aldosteronism in about half of these patients is an aldosterone-producing adenoma; over half of these adenomas have mutations in one of several ion channels and pumps, including the potassium channel KCNJ5, calcium channel Cav1.3, alpha1 subunit of the sodium potassium ATPase, and membrane calcium ATPase 3. This review concentrates on the molecular and physiological mechanisms by which mutations of the ATP1A1 gene increase aldosterone production. PMID- 25496840 TI - Desmoplakin is involved in organization of an adhesion complex in peripheral nerve regeneration after injury. AB - Peripheral nerves have the unique capability to regenerate after injury. Insights into regeneration of peripheral nerves after injury may have implications for neurodegenerative diseases of the nervous system. In this study, we analyzed the expression and function of desmoplakin in peripheral nerve regeneration. Desmoplakin was upregulated in spinal cord motoneurons after sciatic nerve injury. Conditional ablation of desmoplakin in motoneurons demonstrated that desmoplakin is necessary for normal motor regeneration. SiRNA and desmoplakin deletion-constructs revealed a role of desmoplakin in neurite extension in vitro. A complex of N-cadherin, plakoglobin, desmoplakin and vimentin was shown in motoneuronal cell cultures and peripheral nerves after injury in vivo. Motor nerve fiber regeneration and localization of N-cadherin and vimentin to axonal growth fronts were reduced in conditionally desmoplakin-ablated mice. These data indicate a function of desmoplakin in motor nerve regeneration by linking N cadherin to intermediate filaments in regenerating motor axons. PMID- 25496841 TI - GDNF preconditioning can overcome Schwann cell phenotypic memory. AB - While it is known that Schwann cells (SCs) provide cues to enhance regeneration following peripheral nerve injury, the effect of SC phenotypic memory (muscle or cutaneous nerve-derived) on enhancing axonal regeneration and functional recovery has been unclear in the literature. In particular, differences between muscle and cutaneous nerve-derived SC may encourage specific motor or sensory axonal guidance in cell/tissue transplantation therapies. Thus, the goal of this study was to determine whether phenotypically matched combinations of neurons and SCs stimulate greater axonal extension compared to mismatched combinations (i.e. motor neurons/muscle nerve-derived SCs vs. motor neurons/cutaneous nerve-derived SCs). Additionally, the effect of glial cell line-derived neurotrophic factor (GDNF) treatment on SC-neuron interaction was also evaluated. In order to examine these interactions, microfluidic devices were used to assess the effects of soluble factors secreted from SCs on neurons. Unlike traditional co-culture methods, the devices allow for easier quantification of single neurite extension over long periods of time, as well as easy cell and media sampling of pure populations for biochemical analyses. Results demonstrated longer neurite growth when neurons are cultured with phenotype matched SCs, suggesting that SCs are capable of retaining phenotypic memory despite a prolonged absence of axonal contact. Furthermore, the negative effect of mismatched cultures can be overcome when mismatched SCs are preconditioned with GDNF. These results suggest that treatment of SCs with GDNF could enhance their ability to promote regeneration through mismatched grafts frequently used in clinical settings. PMID- 25496842 TI - Diagnosis of incidental thyroid nodules on 18F-fluorodeoxyglucose positron emission tomography imaging: are these significant? AB - OBJECTIVE: To determine the prevalence of thyroid malignancy in the first UK case series of patients with incidentally detected thyroid lesions on 18F fluorodeoxyglucose positron emission tomography imaging. METHODS: A total of 235 patients were evaluated with 18F-fluorodeoxyglucose positron emission tomography imaging. Incidental focal uptake in the thyroid gland was identified in nine patients (3.8 per cent). A retrospective review of their case notes was conducted. RESULTS: The rate of malignancy was 55 per cent. The mean and standard deviation of the maximum standardised uptake value was 13.1 +/- 7.3 in those patients with malignancy and a nodule identified as positive on positron emission tomography. This value was 2.8 +/- 1.2 in those patients without malignancy but with a nodule identified as positive on positron emission tomography (p = 0.01). A palpable thyroid nodule was more likely in those with malignant lesions (p = 0.14). CONCLUSION: The prevalence of incidental thyroid lesions found on 18F fluorodeoxyglucose positron emission tomography in patients with other primary malignancies is low, but the incidence of malignancy in these patients is high. Patients with a palpable thyroid nodule, focal uptake on 18F-fluorodeoxyglucose positron emission tomography and an increased maximum standardised uptake value require further investigation. PMID- 25496843 TI - The association between pentraxin 3 in maternal circulation and pathological intrauterine fetal growth restriction. AB - OBJECTIVE: To assess the diagnostic accuracy of maternal serum pentraxin 3 (PTX3) in identifying pathological intrauterine fetal growth restriction (IUFGR) among women presented in the third trimester of pregnancy with a small for gestational age (SGA) fetus. STUDY DESIGN: This case control study was conducted in Ain-Shams University Maternity Hospital, Abbasiya Square, Cairo, Egypt and included women diagnosed at the third trimester of pregnancy as having a SGA fetus. Cases included pregnant women with pathological IUFGR, while women with physiologically SGA fetus were included in the control group. Diagnosis of antenatal SGA fetus was based on the presence of abdominal circumference <10th percentile. Pathological IUFGR was provisionally diagnosed antenatally by the presence of falling percentiles on serial ultrasound scans and then the definitive diagnosis was established postnatally after comprehensive neonatal evaluation. Maternal venous blood samples were collected from the eligible participants, once at the time of enrollment, to assess serum PTX3 levels using enzyme-linked immunosorbent assay (ELISA). Both groups were then followed up till delivery to confirm the diagnosis. RESULTS: Among the 68 pregnant included in the study, PTX3 was found to be significantly elevated in women with SGA fetus due to pathological IUFGR (n=34) than those with physiologically SGA fetus (n=34) [6.5 ng/ml (2.5-11.0) versus 1.2 ng/ml (0.8-2.5) respectively], with a best cutoff value of >=1.3 ng/ml [sensitivity of 85.3% (95% confidence interval (CI), 68.9-95.0) and a specificity of 73.5% (95% CI, 55.6-87.1)]. Using multivariable binary logistic regression model, amniotic fluid index (AFI) (P=0.010), estimated fetal weight (EFW) (P=0.016), PTX3 level (P=0.041), and umbilical artery pulsatility index (UA-PI) (P=0.027) were all found to be independent diagnostic markers for pathological IUFGR. CONCLUSION: PTX3 is a promising marker that deserves further evaluation as it may differentiate normal and abnormal fetal growth among women presenting at third trimester of pregnancy with a SGA fetus. PMID- 25496844 TI - OASI: a preventable injury? AB - OBJECTIVE: The aim of this study was to determine risk factors for obstetric anal sphincter injury and whether any of them were modifiable. STUDY DESIGN: This was a retrospective review of 2572 women (cases=1286; controls=1286) that took place over a 10 year period at a University teaching hospital. Maternal (Age, Parity, BMI and ethnicity), Obstetric (gestational age, assistance during delivery, episiotomy) and fetal (weight) risk factors were analyzed using logistic regression model presented as odds ratio (OR) with 95% confidence intervals (CI). Both univariate and multivariate analyses were conducted with outcome variables comparing cases and controls. Cases without instrumental deliveries were also compared to controls to exclude for the effect of assisted delivery. RESULTS: This study shows that in addition to instrumental delivery, primiparity (OR 9.8; CI 7.8-12.3), episiotomy (OR 8.6; CI 6.4-11.6), gestational age over 41 weeks (OR 1.5; CI 1.2-1.9), fetal weight over 4 kg (OR 3.2; CI 2.3-4.4) and Asian ethnicity (OR 1.9; CI 1.4-2.7) were all strongly associated with OASI. A raised BMI over 30 appeared to have a protective effect (OR 0.4; CI 0.2-0.5). CONCLUSIONS: Most risk factors related to OASI are non-modifiable however gestational age and episiotomy are modifiable risk factors. PMID- 25496845 TI - Protease-activated-receptor 1 polymorphisms correlate with risk for unexplained recurrent pregnancy loss: a pilot study querying an association beyond coagulation. AB - BACKGROUND: Recurrent pregnancy loss (RPL) has been associated with impaired maternal-fetal communication. Protease-activated-receptor 1 (PAR1) is critical for trophoblast invasion and establishment unrelated to its role in vascular biology. OBJECTIVES: To analyze whether polymorphisms of PAR1 [-1426C/T], [ 506I/D], and/or IVS[-14A/T] are associated with unexplained RPL. PATIENTS/METHODS: A case-control pilot study conducted in 39 healthy women with history of unexplained RPL and 98 women with a full-term, uncomplicated deliveries and no history of RPL. RESULTS: Women with RPL were significantly more likely to be heterozygous for [-1426C/T] (12.8% versus 3.2%; p=0.049); the heterozygous state for IVS[-14A/T] was also more common (15.4% versus 4.4%; p=0.064). There was no difference between groups for [-506I/D] genotypes. The functional consequence for [-1426C/T] and IVS[-14A/T] polymorphisms is underscored by the markedly low PAR1 mRNA levels in those women. Bioinformatics indicate generation of a new consensus motif for repressor Kruppel-like factor 3 (KLF3) in [-1426T]. Moreover, chromatin immunoprecipitation (ChIP) analysis confirmed a physical association between KLF3 protein and the hPar1 DNA obtained from women with the [-1426C/T] polymorphism. CONCLUSIONS: We hypothesize that the significantly low PAR1 levels impact placenta establishment and consequently pregnancy outcome, thereby profiling a novel risk factor for unexplained RPL. PMID- 25496846 TI - Gender specific intrapartum and neonatal outcomes for term babies. AB - OBJECTIVE: The purpose of this study is to document the gender specific intrapartum and neonatal outcomes in term, singleton, appropriately grown babies. STUDY DESIGN: De-identified, routinely collected data of all women meeting inclusion criteria between 2001 and 2011 were examined (n=9223). Inclusion criteria were public (non-insured), primiparous women who had delivered singleton, appropriately grown babies at term. In this retrospective cohort study, we estimated 95% confidence intervals. Outcomes measured were maternal demographics, mode of delivery, birthweight, APGAR score, cord blood acidemia, respiratory distress, any resuscitation requirement, nursery admission and stillbirth rates. RESULTS: The sex ratio of male babies was 1.05:1 (4718 males; 4505 females, p=0.85). Male babies were more likely to be delivered by instrumental (p=0.004) or caesarean (p<0.001). Birthweight was found to be a significant influencing factor on mode of delivery. Even after adjusting for birthweight, male babies were more likely to be delivered by instrumental delivery (OR 1.24, p<0.001), as well as by emergency caesarean for failure to progress (OR 1.24, p=0.04) and fetal distress (OR 1.38, p<0.001). Male babies, despite having greater birthweights than female babies (p<0.001), were more likely to have lower APGAR scores at 5 min (p=0.004), require neonatal resuscitation (p<0.001), develop respiratory distress (p=0.005) and require nursery admission (p<0.001). No statistical difference between male and female babies was found for cord blood acidemia (p=0.58) or stillbirth (p=0.49). CONCLUSION: This large cohort study demonstrates that term, appropriately grown male babies in primiparous pregnancies fare more poorly in the intrapartum and neonatal periods than female babies. Even when birthweight was accounted for, male babies still required higher rates of intervention in the intrapartum and neonatal periods. This suggests gender may play an independent role in influencing pregnancy outcomes, although the underlying contributing physiology is not definitively established. The gender of the baby perhaps should be considered when counselling parents in the antepartum period. PMID- 25496847 TI - [A rare cause of back pain and fever]. PMID- 25496848 TI - Systematic review of the incidence of inferior alveolar nerve injury in bilateral sagittal split osteotomy and the assessment of neurosensory disturbances. AB - Extreme variation in the reported incidence of inferior alveolar nerve (IAN) disturbances suggests that neurosensory disturbances after orthognathic surgery have not been evaluated adequately. Here we review the reported incidence of IAN injury after orthognathic surgery and assess recently reported methods for evaluating sensory disturbances. A search was conducted of the English-language scientific literature published between 1 January 1990 and 31 December 2013 using the Limo KU Leuven search platform. Information on various aspects of assessing IAN injury was extracted from 61 reports. In 16 reports (26%), the incidence of injury was not indicated. Preoperative IAN status was not assessed in 22 reports (36%). The IAN assessor was described in detail in 21 reports (34%), while information on the training of the assessors was mentioned in only two reports (3%). Subjective evaluation was the most common method for assessing neurosensory deficit. We conclude that the observed wide variation in the reported incidence of IAN injury is due to a lack of standardized assessment procedures and reporting. Thus, an international consensus meeting on this subject is needed in order to establish a standard-of-care method. PMID- 25496850 TI - Behaviour of the buccal crestal bone levels after immediate placement of implants subjected to immediate loading. AB - The aim of this study was to measure changes in buccal alveolar crestal bone levels after immediate placement and loading of dental implants with Morse taper prosthetic abutments after tooth extraction. This study followed the STROBE guidelines regarding prospective cohort studies. The sample comprised 12 patients with a mean age of 45 years, in whom a central or upper lateral incisor was indicated for extraction. Prior to extraction, computed tomography (CT) analysis was carried out to assess the presence of the buccal bone crest. CT scans were performed at 24 h and at 6 months after immediate implant placement and immediate loading. The distance from the most apical point of the implant platform to the buccal bone crest was assessed at the two time points. The buccal bone crest height was evaluated at three points in the mesio-distal direction: (1) the centre point of the alveolus, (2) 1mm mesial to the centre point, and (3) 1 mm distal to the centre point. The values obtained were subjected to statistical analysis, comparing the distances from the bone crest to the implant platform for the two time points. After 6 months there was a statistically significant, non uniform reduction in height at the level of the crest of the buccal bone in the cervical direction. It is concluded that the buccal bone crest of the immediate implants that replaced the maxillary incisors underwent apical resorption when subjected to immediate loading. PMID- 25496849 TI - Applicability of human dental follicle cells to bone regeneration without dexamethasone: an in vivo pilot study. AB - The aim of this study was to investigate the capacity of human dental follicle cells (hDFCs) for bone formation in vivo. hDFCs were obtained from wisdom teeth extracted from patients aged 14 and 22 years. hDFCs from the 5th to 8th passages were grown in three-dimensional (3D) culture using gelatin sponges. Cells were transplanted onto the calvaria of F344/NJcl-rnu/rnu male rats (immunodeficient rats). Haematoxylin and eosin (HE) staining and immunohistochemistry were performed, and newly formed bone was evaluated by micro-computed tomography (micro-CT). HE staining showed newly formed bone in 3D culture. Immunohistochemistry showed bone morphogenetic protein 2 (BMP-2), runt-related transcription factor 2 (RUNX2), and osterix staining in areas with newly formed bone. Furthermore, micro-CT showed that, in comparison to controls, transplanted hDFCs promoted better bone quality and bone mineral density (BMD 582 +/- 131.1 vs. 300.5 +/- 77.7 mg/cm(3); P=0.039), bone mineral content (BMC 5.6 +/- 1.1 vs. 2.1 +/- 0.4 mg; P = 0.006), bone volume (BV 9.7 +/- 0.5 * 10(-3) vs. 7.0 +/- 0.4 * 10(-3) cm(3); P = 0.002), BMC/total volume (TV) (399.9 +/- 76.3 vs. 147.7 +/- 30.8 mg/cm(3); P = 0.006), and BV/TV (69.1 +/- 3.6% vs. 49.6 +/- 3.1%; P=0.002). This suggests that human dental follicles are potentially useful for regenerative therapy. PMID- 25496851 TI - ALPPS: challenging the concept of unresectability--a systematic review. AB - INTRODUCTION: Hepatic resection for malignancy is limited by the amount of liver parenchyma left behind. As a result, two-staged hepatectomy and portal vein occlusion (PVO) have become part of the treatment algorithm. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been recently described as a method to stimulate rapid and profound hypertrophy. MATERIALS AND METHODS: A systematic review of the literature pertaining to ALPPS was undertaken. Peer-reviewed articles relating to portal vein ligation (PVL) and in situ split (ISS) of the parenchyma were included. RESULTS: To date, ALPPS has been employed for a variety of primary and metastatic liver tumors. In early case series, the perioperative morbidity and mortality was unacceptably high. However with careful patient selection and improved technique, many centers have reported a 0% 90-day mortality. The benefits of ALPPS include hypertrophy of 61-93% over a median 9-14 days, 95-100% completion of the second stage, and high likelihood of R0 resection (86-100%). DISCUSSION: ALPPS is only indicated when a two-stage hepatectomy is necessary and the future liver remnant (FLR) is deemed inadequate (<30%). Use in patients with poor functional status, or advanced age (>70 years) is cautioned. Discretion should be used when considering this in patients with pathology other than colorectal liver metastases (CRLM), especially hilar tumors requiring biliary reconstruction. Biliary ligation during the first stage and routine lymphadenectomy of the hepatoduodenal ligament should be avoided. CONCLUSIONS: A consensus on the indications and contraindications for ALPPS and a standardized operative protocol are needed. PMID- 25496852 TI - MicroRNAs associated with initiation and progression of colonic polyp: a feasibility study. AB - INTRODUCTION: Colorectal cancer is the third most common neoplasm worldwide. The sequential progression of colorectal cancer from adenoma to carcinoma highlights that opportunities exist to alter the natural course of disease progression. The aim of this study was to characterize the expression levels of microRNAs linked to development and progression of colorectal neoplasia. Patient, Design, Patients & Methods: MicroRNA expression signature was developed for RNA extracted from freshly frozen tumour and adjacent normal tissue (n = 5). Based on differential expression and literature search, hsa-miR-135b was selected for further characterisation in different types of colonic polyps and cancer tissue. Formalin Fixed Paraffin Embedded tissue were studied for miRNA expression, KRAS, BRAF, PIK3CA mutations, and immuno-histochemistry for APC and p53 proteins for normal colon (n=11), hyperplastic polyps (n=11), high grade adenomas (n=10), low grade adenomas (n=34) and adenocarcinoma (n=13). RESULTS: CRC tissue had significantly higher expression levels of hsa-miR-135b (p=0.0017) than their adjacent paired normal tissues (mean increase=8.90 fold, 95% CI=2.98-26.50). Linear trend analysis showed a progressive increase in expression level of hsa-miR-135b across normal epithelium, low grade adenomas, high grade adenomas and carcinomas (p=0.0007, R squared 0.16, slope -0.35). KRAS mutant colonic polyps and cancer tissue had significantly higher (3.04 fold, 95% CI=1.23-7.46) expression levels of hsa-miR-135b compared to polyps and cancers with non mutant KRAS gene (p=0.001). Whereas, hsa-miR-135b expression levels were significantly lower in colonic polyp and cancer tissue stained positively for APC proteins (p<0.001). CONCLUSION: There is a progressive increase in expression levels of hsa-miR-135b correlating with the sequential progression of normal epithelium to adenoma and carcinoma. Expression levels of hsa-miR-135b correlate with expression of APC proteins in colorectal tissue suggesting its role in tumour initiation. HIGHLIGHTS: This study highlights the role of tissue microRNAs for their role in the development of colorectal carcinoma. Identification of tissue specific microRNAs will help is designing microRNAs based gene therapies to control the development and progression of colonic neoplasia. PMID- 25496853 TI - Current progress in xenotransplantation and organ bioengineering. AB - Organ transplantation represents a unique method of treatment to cure people with end-stage organ failure. Since the first successful organ transplant in 1954, the field of transplantation has made great strides forward. However, despite the ability to transform and save lives, transplant surgery is still faced with a fundamental problem the number of people requiring organ transplants is simply higher than the number of organs available. To put this in stark perspective, because of this critical organ shortage 18 people every day in the United States alone die on a transplant waiting list (U.S. Department of Health & Human Services, http://organdonor.gov/about/data.html). To address this problem, attempts have been made to increase the organ supply through xenotransplantation and more recently, bioengineering. Here we trace the development of both fields, discuss their current status and highlight limitations going forward. Ultimately, lessons learned in each field may prove widely applicable and lead to the successful development of xenografts, bioengineered constructs, and bioengineered xeno-organs, thereby increasing the supply of organs for transplantation. PMID- 25496854 TI - Management of blunt liver trauma in 134 severely injured patients. AB - BACKGROUND: In haemodynamic stable patients without an acute abdomen, nonoperative management (NOM) of blunt liver injuries (BLI) has become the standard of care with a reported success rate of between 80 and 100%. Concern has been expressed about the potential overuse of NOM and the fact that failed NOM is associated with higher mortality rate. The aim of this study was to evaluate factors that might indicate the need for surgical intervention, and to assess the efficacy of NOM. METHODS: A single centre prospective study between 2008 and 2013 in a level-1 Trauma Centre. One hundred thirty four patients with BLI were diagnosed on CT-scan or at laparotomy. The median ISS was 25 (range 16-34). RESULTS: Thirty five (26%) patients underwent an early exploratory laparotomy. The indication for surgery was haemodynamic instability in 11 (31%) patients, an acute abdomen in 16 (46%), and 8 (23%) patients had CT findings of intraabdominal injuries, other than the hepatic injury, that required surgical repair. NOM was initiated in 99 (74%) patients, 36 patients had associated intraabdominal solid organ injuries. Seven patients developed liver related complications. Five (5%) patients required a delayed laparotomy (liver related (3), splenic injury (2)). NOM failure was not related to the presence of shock on admission (p=1000), to the grade of liver injury (p=0.790) or associated intraabdominal injuries (p=0.866). CONCLUSION: Physiologic behaviour or CT findings dictated the need for operative intervention. NOM of BLI has a high success rate (95%). Nonoperative management of BLI should be considered in patients who respond to resuscitation, irrespective of the grade of liver trauma. Associated intraabdominal solid organ injuries do not exclude NOM. PMID- 25496855 TI - Indications and results of emergency surgical airways performed by a physician staffed helicopter emergency service. AB - BACKGROUND: Airway management is essential in critically ill or injured patients. In a "can't intubate, can't oxygenate" scenario, an emergency surgical airway (ESA), similar to a cricothyroidotomy, is the final step in airway management. This procedure is infrequently performed in the prehospital or clinical setting. The incidence of ESA may differ between physician- and non-physician-staffed emergency medical services (EMS). We examined the indications and results of ESA procedures among our physician-staffed EMS compared with non-physician-staffed services. METHODS: Data for all forms of airway management were obtained from our EMS providers and analyzed and compared with data from non-physician-staffed EMS found in the literature. RESULTS: Among 1871 patients requiring a secured airway, the incidence of a surgical airway was 1.6% (n=30). Fourteen patients received a primary ESA. In 16 patients, a secondary ESA was required after failed endotracheal intubation. The total prehospital ESA tracheal access success rate was 96.7%. CONCLUSION: The incidence of ESA in our patient population was low compared with those reported in the literature from non-physician-staffed EMS. Advanced intubation skills might be a contributing factor, thus reducing the number of ESAs required. PMID- 25496856 TI - Gaps and opportunities in the management of the young femoral neck fracture. AB - Femoral neck fractures in young adults are difficult to treat. There are substantial gaps in our knowledge regarding treatment and prevention of young adult femoral neck fractures. Avoiding malunion or nonunion of these fractures after fixation remains a challenge. Currently available fixation techniques may allow for healing to occur, but in a shortened position, with negative consequences on gait mechanics and physical function. Osteonecrosis remains a problem, affecting up to half of patients who sustain femoral neck fractures. Achieving reliable healing may require a reconsideration of fracture fixation implants as well as biological methods to address metabolic, endocrine, and/or genetic abnormalities that may be present in the young adult femoral neck fracture patient. Also, prevention of low-energy femoral neck fractures (e.g. stress fracture) remains an area ripe for investigation. PMID- 25496857 TI - Management of advanced plexiform neurofibromatosis of the foot presenting with skeletal deformation and intractable pain: an indication for proximal amputation. AB - Plexiform neurofibromas of the foot are rare and often present with significant pain, deformity, and functional impairment secondary to their locally invasive behavior. While treatment has traditionally focused on attempts at radical resection, a lack of consensus among surgeons has hindered the establishment of a well-defined algorithm to guide the management of these highly co-morbid peripheral nerve sheath tumors. We present the case of an advanced plexiform neurofibroma of the right foot in a 24-year-old male with neurofibromatosis type 1. The patient presented following accelerated tumor growth with extensive osseous erosion, intractable pain, and progressive ankle instability that limited his capacity to ambulate and wear shoes. A modified transtibial amputation with a vascularized fibular bone graft (Ertl procedure) was performed without complication. Following graduated rehabilitation, postoperatively, the patient regained functional independence and was able to ambulate without pain in a customized prosthesis after 3 months. Plexiform neurofibromas of the foot present a complex challenge for foot and ankle surgeons. On the basis of our experience and previously reported cases, we advocate for amputation over aggressive attempts at advanced limb salvage for patients with extensive skeletal destruction, joint instability, and/or intractable pain caused by tumor mass effect. PMID- 25496858 TI - [Research of relationship between antiviral efficacy on chronic hepatitis C and the application time and dose of ribavirin]. AB - OBJECTIVE: To perform a preliminarily study on the relationship between the duration and dosage of ribavirin treatment and its antiviral effect against chronic hepatitis C. METHODS: A total of 69 patients with chronic hepatitis C whose hemogloblin (HGB) level had decreased to 100 g/L were divided into two groups for receiving a reduced dosage of ribavirin when their HGB level fell to less than or equal to 100 g/L or for withdrawal of the ribavirin treatment when their HGB level fell to less than or equal to 80 g/L (restricted group), or for receiving a reduced dosage when the HGB level fell to less than or equal to 80 g/L or for withdrawal of the ribavirin treatment when the HGB level fell below less than or equal to 60 g/L (adjusted group).The rates of sustained virological response (SVR), relapse, and incidence of adverse effects were statistically compared between the two groups. RESULTS: The adjusted group had a significantly higher SVR rate than the restricted group (91.17% vs.74.29%, P = 0.049). At the 2 year follow-up after treatment withdrawal, there were significantly less cases of relapse in the adjusted group than in the restricted group (23.07% vs.6.45%, P = 0.038).The adjusted group had lower incidence rates of severe anemia and cardiovascular events but there was no significant difference from these rates in the restricted group (P more than 0.05).Subgroup analysis of the adjusted group showed that the patients with HCV-RNA baseline level of less than 5 lg copy/ml had a significantly higher SVR rate than the patients with HCV-RNA baseline level of more than 5 lg copy/ml (100% vs.76.92%, P = 0.021), and that the patients infected with non genotype-1 had a significantly higher SVR rate than patients infected with genotype-1 (100% vs.70.00%, P = 0.005). CONCLUSION: When patients with chronic hepatitis C develop anemia during the course of anti-HCV ribavirin therapy with Peg-IFNat2a, adjustment of the ribavirin treatment duration and dosage can increase the likelihood of achieving and sustaining SVR and decrease the rate of relapse; these treatment adjustments are not associated with changes in severe adverse effects.The adjustment approach, however, shows more benefit for patients with lower viral load and non genotype-1 infection. PMID- 25496859 TI - [Location of the binding position for HBV X protein functional interaction with cytochrome C oxidase III]. AB - OBJECTIVE: To identify the binding site position of the hepatitis B virus (HBV) X protein (HBx) functional interaction with the cytochrome C oxidase subunit III (COX III, a key regulator of mitochondrial function) by using a yeast two-hybrid system. METHODS: Two fragments of HBx mutants (X1 1-72aa and X2 1-117aa) were amplified by PCR and inserted into the bait plasmid pAS2-1.The resultant mutant plasmids were transfected into yeast cells using the lithium acetate-method.PCR and gene sequencing were used to confirm that the mutant fragments were expressed properly in yeast cells.Western blotting was used to verify that the mutant proteins were translated accurately in the yeast cells.Filter assay was used to exclude autoactivated mutants.Hybridization in solid medium and beta-gal activity detection were used to determine the precise position of the binding site for HBx and COX III interaction. RESULTS: The two mutant plasmids containing HBx 1-72aa and 1-117aa respectively were successfully constructed and the mutants were both properly expressed and translated in yeast cells; no autoactivated mutants were detected throughout the experimental process.The binding site of HBx and COX III was found to be encompass the amino acids 72 through 117 of HBx. CONCLUSION: Amino acids 72 through 117 of HBx are the key domain of the HBx functional interaction With COX III; this domain may represent a useful target for molecular based therapies to treat HBV-related diseases. PMID- 25496860 TI - [Comparative study of transient elastography versus real-time tissue elastography for assessment of liver fibrosis in patients with chronic liver disease]. AB - OBJECTIVE: To compare the abilities of transient elastography (TE) versus real time tissue elastography (RTE) for assessing liver fibrosis in patients with chronic liver disease. METHODS: Ninetytwo patients with chronic liver disease were enrolled in the study, and included 77 cases of chronic hepatitis B, 4 cases of chronic hepatitis C, 4 cases of autoimmune liver disease, 2 cases of primary biliary cirrhosis, I case of abnormal bile duct development, and 4 cases of unknown etiology.All patients were assessed by both TE and RTE in a single day.The correlation coefficient of liver fibrosis level and the receiver operating characteristic (ROC) curve of S more than 2 and =4 of TE and RTE were determined.The values were compared using findings fiom pathological analysis as reference. RESULTS: The correlation coefficient of liver fibrosis level was significantly higher for TE (r =0.755, 95% CI:0.651-0.831, P =0.000) than for RTE (r=0.481, 95% CI:0.306-0.624, P =0.000) (Z=3.07, P =0.002).The areas under the ROC curves for S more than 2 and =4 were 0.903 and 0.740 for TE and 0.915 and 0.786 for RTE, respectively, indicating that the performance of TE was superior to that of RTE. CONCLUSION: TE was superior to RTE for assessment of liver fibrosis. PMID- 25496861 TI - [Evaluation of markers associated with primary biliary cirrhosis in a population of anti-mitochondrial antibody-M2-positive individuals]. AB - OBJECTIVE: To explore the distribution of the main clinical symptoms and signs of primary biliary cirrhosis (PBC) in a population of individuals with positivity for anti-mitochondrial antibody-M2 (AMA-M2). METHODS: A total of 20 970 persons who participated in routine health examinations at our hospital were tested for presence and level of antinuclear antibodies (ANAs) using an indirect immunofluorescence (IIF) assay and of AMA-M2 by western blotting. The chi-square test was used for statistical analysis. RESULTS: Titers of ANAs more than 1:320 were detected in 1 243 of all the study participants, with 156 of those individuals having detectable AMA-M2.The overall rate ofAMA-M2 positivity was 0.74%, with a significantly higher rate among female subjects (males:0.3% (32/10 550) vs.females:1.2% (124/10 420); x2=55.85, P less than 0.05). Among the AMA-M2 positive population there were 66 cases of abnormal liver function, 58 cases of increased alkaline phosphatase, 72 cases of abnormal findings for routine blood testing, 47 cases of gallbladder disease history, 49 cases of diabetes history, 22 cases of allergy, 75 cases of abdominal discomfort, 38 cases of weakness, 3 cases of jaundice, and 11 cases of pruritus. There were significant differences between the AMA-M2-negative individuals and the AMA-M2-positive individuals. CONCLUSION: Among the general population, individuals with substandard states of health, such as those with abnormal findings in routine blood tests and abnormal liver function, should be screened for AMA-M2. This screening will facilitate early diagnosis of PBC and timely initiation of disease management, improving the patient's life quality of life and prolonging their life. PMID- 25496862 TI - [Preoperative risk factors of portal venous thrombosis after splenectomy and gastric pericardial devascularization for portal hypertension]. AB - OBJECTIVE: To investigate the preoperative risk factors of portal venous thrombosis (PVT) after splenectomy and gastric pericardial devascularization in patients with liver cirrhosis and portal hypertension. METHODS: Clinical data was collected for 127 patients who underwent splenectomy and gastric pericardial devascularization for portal hypertension at our hospital between January 2010 and December 2012.The patient data were analyzed retrospectively according to patient status of presence or absence of PVT postoperatively.The preoperative risk factors of PVT were statistically analyzed. RESULTS: There were no significant differences between the postoperative PVT-positive and-negative groups in regards to sex, age, receipt of emergency surgery, presence of ascites, admission to hospital for upper gastrointestinal bleeding, grade of esophageal gastric varices, Child-Pugh classification, spleen vein diameter, liver function (as determined by levels of alanine aminotransferase, total bilirubin, direct bilirubin, albumin, globulin, cholinesterase, and gamma-glutamyltransferase), renal function (as determined by creatinine level), and coagulation function (as determined by prothrombin time, prothrombin activity degree, activated partial thromboplastin time, international normalized ratio, fibrinogen, thrombin time, and antithrombin III).However, there were significant differences between the groups for the parameters of postoperative PVT presence, upper gastric bleeding history, aspartate aminotransferase level, and blood urea nitrogen level (all P less than 0.05).Portal vein diameter and history of upper gastric bleeding were both identified as independent risk factors for PVT (P less than 0.05).Incidence of postoperative PVT was higher in patients who had portal vein diameter > 13.15 mm (cutoff value of 13.75 mm) and in patients who had a history of upper gastric bleeding. CONCLUSION: Portal vein diameter and history of upper gastric bleeding were independent risk factors for PVT occurrence after splenectomy and gastric pericardial devascularization in patients with liver cirrhosis and portal hypertension. PMID- 25496863 TI - [Clinical significance of HLA-DRB1 and HLA-DPB1 gene polymorphisms in cirrhosis patients]. AB - OBJECTIVE: To investigate the genetic association between cirrhosis and polymorphisms in the genes encoding major histocompatibility complex, class II (HLA)-DR beta 1 (DRB1) and HLA-DP beta 1 (DPB1). METHODS: A population of 168 parent/offspring trios, in which the proband had a diagnosis of hepatitis B virus infection with clinical signs of cirrhosis.The HLA-DRB1 and DPB 1 gene polymorphisms of rs24755213 and rs202176660 were detected by PCR and single nucleotide polymorphism (SNP) genotyping.Correlation analysis and haplotype relative risk analysis were carried out. RESULTS: A/G genotypes were detected in rs24755213 of HLA-DRB1 and C/T genotypes were detected in rs202176660 of DPB1.The rs24755213 allele was associated with cirrhosis (P=0.014), with the G allele identified as a protective factor (Z=-2.33) and the A allele identified as a hazard factor (Z=2.33).The rs202176660 allele was also associated with cirrhosis (P =0.026), with the T allele identified as a protective factor (Z=-2.06) and the C allele identified as a hazard factor (Z=2.06).The haplotypes of G/T and A/C in rs24755213 and rs202176660 respectively were associated with cirrhosis (P =0.037 and 0.002, Z=-2.12 and 2.09 respectively). CONCLUSION: In this group of Chinese patients with hepatitis B virus-related cirrhosis, polymorphisms in the HLA-DRB 1 and DPB1 genes were associated with cimhosis. PMID- 25496864 TI - [Construction and validation of a dual-luciferase reporter gene system for screening and evaluating anti-liver fibrosis drugs that inhibit transcription of the gene encoding collagen I, chain a1]. AB - OBJECTIVE: To construct a dual-reporter gene system that will be applicable for use as a tool to screen and evaluate therapeutic drug compounds that inhibit transcription of the gene encoding collagen I, chain at1 (COL1A1). METHODS: The full-length eDNA of transforming growth factor beta1 (TGFbeta1) was cloned by RT PCR and inserted into two vectors, pcDNA3.1 and pJW4303, for construction of two eukaryotic expression vectors, pcDNA3.1-TGFbeta1 and pJW4303-TGFbeta1.Next, the promoter region of COL1A1, cloned by PCR using human genome DNA as template, was inserted into the vector pGL4.29 to construct the reporter gene vector, pGL4.29 COL1A1 promoter.All three recombinant vectors were verified by restriction enzyme digestion and DNA sequencing.Either the pcDNA3.1-TGFbeta1 or pJW4303-TGFbeta1 vector along with the pGL4.29-COL1A1 promoter vector or a pRL-null, control reporter, vector were co-transfected into the LX-2 human hepatic stellate cells to establish the transcription-activated dualreporter gene system.This system was used as a cell model for screening anti-liver fibrosis compounds that inhibit the transcription of COL1A1.Dexamethasone, a model drug that is known to inhibit the expression of COL1A1, was used as a control to validate the dual-reporter gene system. RESULTS: The two TGFbeta1-expressing vectors and the reporter gene vector containing the promoter region of COL1A1 were successfully constructed.The results of a dual-reporter gene assay showed that TGFbeta1 co-expression increased the activity of the COL1A1 promoter by above 200-fold (t =21.78, P =0.0001), whereas in the absence of TGF31 co-expression the activity was below 2 fold (t =3.396, P =0.0274).The transcriptionactivated dual-reporter gene system was successfully established.The model drug, dexamethasone, effectively inhibited the activity of the COL 1A1 promoter in dose-dependent manner; the activity decreased 29.6% with 10 mumol/L dexamethasone (t =4.140, P =0.0144) and 53.9% with 100 mumol/L (t =6.193, P =0.0035). CONCLUSION: The dual-luciferase reporter system of TGFbeta1 and COL1A1 co-expression developed here can be used as a cell model to screen and evaluate anti-liver fibrosis compounds that inhibit activity of the COL1A1. PMID- 25496865 TI - [Family history of liver cancer increases the risk of liver cancer incidence: a 20-year prospective cohort study in Qidong, China]. AB - OBJECTIVE: To evaluate whether first-degree family history of liver cancer plays a role in liver cancer incidence by prospective evaluation of a patient cohort in Qidong, China over a 20-year period. METHODS: In May 1992, 708 hepatitis B surface antigen (HBsAg) carriers and 730 HBsAg-negadve controls from Qidong city were enrolled for participation in a prospective cohort study ending in November 2012.Follow-up was carried out every 6 to 12 months, and evaluations included serum assays to measure concentrations of alpha fetoprotein (AFP), HBsAg and alanine aminotransferase (ALT), as well as abdominal ultrasound to assess liver disease.The relationship between baseline (study entry) information of patients with first-degree family history of liver cancer and liver cancer incidence during the two decades of study was statistically assessed. RESULTS: There were 172 newly diagnosed liver cancer cases in the cohort during 25 753 person-years (py) of follow-up, representing an incidence of 667.88/100 000 py.The incidence rates of liver cancer among participants with or without liver cancer family history were 1 244.36/100 000 py and 509.70/100 000 py respectively, and the between-group difference reached the threshold for statistical significance (P less than 0.01, Relative Risk (RR):2.44, 95% Confidence Interval (CI):1.80 3.31).The incidence rates of liver cancer among participants who had a sibling with liver cancer and participants who had a parent with liver cancer were not significantly different (P > 0.05), but the liver cancer incidence among participants who had a mother with liver cancer was significantly higher than that of participants who had a father with liver cancer (P < 0.05, RR:1.86, 95% CI:1.03-3.36). Among the participants with liver cancer family history, 56.52% (39/69) were diagnosed before 50 years old, and this rate was significantly higher than that of participants without a family history of liver cancer (40.78%, 42/103, P less than 0.05).The incidence rate of liver cancer among the participants who were family history-positive and HBsAg-positive was significantly higher than that of participants who were family history-negative but HBsAg-positive (P < 0.01, RR:1.75, 95% CI:1.29-2.38), and was 59.59 times higher than for participants who were family history-negative and HBsAgnegative.Subgroup analysis of liver cancer incidence among participants who were family history-positive but HBsAg-negative and participants who were family history-negative and HBsAg-negative produced anRR of 2.60, but there was no statistically significant difference between the two subgroups (P > 0.05).At the study's end, the incidence rates of liver cancer for the different subgroups were 32.21% for the family history-positive and HBsAgpositive participants, 19.80% for the family history-negative and HBsAg-positive participants, 1.71% for the family history-positive and HBsAg-negative participants, and 0.65% for the family history-negative and HBsAg-negative participants. CONCLUSION: First-degree family history of liver cancer is a risk factor of liver cancer in Chinese patients from Qidong, and exhibits synergism with HBsAg-positivity for incidence of liver cancer. PMID- 25496866 TI - [Influence of GLP-1 on oxidative stress injury in non-alcoholic fatty liver disease rats]. AB - OBJECTIVE: To investigate the effects of glucagon-like peptide-1 (GLP-1) on liver oxidative stress injury using a rat model of non-alcoholic fatty liver disease. METHODS: Sixty male Sprague-Dawley rats were fed 12 weeks of either a diet of normal chow (NC), for use as controls (n =15) or high-fat chow (HF), for use as models (n =45).The NC rats were administered normal saline, while the HF rats were treated with either normal saline (NS), for use as untreated model controls (n =10), low-dose GLP-1 (LG, 50 mutg/kg; n =10), mid-dose GLP-1 (MG, 100 mutg/kg; n =10), or high-dose GLP-1 (HG, 200 mug/kg; n =10); all treatments lasted for 4 weeks.The rats' weight, levels of serum biochemical markers (triglycerides, total cholesterol, high-density lipoproteincholesterol, low-density lipoprotein cholesterol, alanine arninotransferase, and aspartate aminotransferase), levels of superoxide dismutase (SOD) and malondialdehyde (MDA), and expression of CYP2E1 mRNA and protein in liver homogenates were measured.The F test, t-test, least significant difference test and Dunnett's T3 test were used for statistical analyses. RESULTS: Compared with the NC group, the rars in the NS group showed significantly lower SOD (165.81 +/- 11.64 vs.192.89 +/- 16.53 U/mg, P < 0.05), significantly higher MDA (7.30 +/- 1.79 vs.3.10 +/- 1.30 nmol/ mg, P < 0.05), and significantly higher expressions of CYP2E1 mRNA and protein (both P < 0.05).After GLP1 treatment, the rats in the LG, MG and HG groups showed increased levels of SOD (compared to the NS group; 171.44 +/- 9.80 vs.177.66 +/- 14.77 vs.186.17 +/- 15.43 U/mg; only the HG group had P < 0.05), significantly decreased levels of MDA (compared to the NS group; 5.16 +/- 1.45 vs.4.08 +/- 1.22 vs.3.31 +/- 1.14 nmol/mg; all P < 0.05], and decreased levels of CYP2E1 mRNA and protein expressions (CYP2E1 mRNA:only the HG group had P < 0.05; CYP2E1 protein: both the MG and HG groups had P < 0.05). CONCLUSION: GLP-1 treatment can improve oxidative stress injury, suggesting its potential as a therapeutic agent for non-alcoholic fatty liver disease. PMID- 25496867 TI - [Pharmacoeconomic profiles of four hepatoprotective drugs used for the treatment of drug-induced liver injury]. AB - OBJECTIVE: To perform a pharmacoeconomic evaluation of the efficacies of therapeutic schemes involving four hepatoprotective drugs for the treatment of drug-induced liver injury (DILI). METHODS: The principle of decision tree analysis in pharmacoeconomics was applied to perform a retrospective analysis using a meta-analyses approach to evaluate the data from randomized controlled trials of four common therapeutic schemes.The key parameters for evaluating efficacy and safety of each were identified by searching the official data, relevant literature and expert opinions, and included the parameters of consumption and unit cost with respect to a variety of health resources. RESULTS: The hepatoprotective drug showing the greatest efficacy (4.5118) and safety for treating DILI was bicyclol; this drug also had a lower incremental cost effectiveness ratio (ICER; 245.0118) than the other three therapeutic schemes.The tioproninenteric-coated tablet had the lowest cost (296.9536) among the four, but also had the worst efficacy (4.1352). Bicyclol had the lowest cost/benefit ratio (5.32) and ICER (4.93) among all the therapeutic schemes evaluated.Sensitivity analyses confirmed the robustness of these results. CONCLUSION: According to this pharmacoeconomic evaluation, the bicyclol therapeutic strategy is the most cost effective choice for DILI. PMID- 25496868 TI - Cathepsin D deficiency induces oxidative damage in brain pericytes and impairs the blood-brain barrier. AB - Recent evidence suggests that peripheral blood mononuclear cells (PBMCs) contribute to the pathogenesis of neuropathological changes in patients with neuronal ceroid lipofuscinosis (NCL) and lysosomal storage diseases. In order to examine the possible increase in the permeability of the blood-brain-barrier (BBB) and resultant infiltration of PBMCs due to cathepsin D (CatD) deficiency, a process underlying the onset of congenital NCL, we examined structural changes in brain vessels in CatD-/- mice. Consequently, the mean diameter of the brain vessels in the cerebral cortex on postnatal day 24 (P24) was significantly larger in CatD-/- mice than in wild-type mice. Furthermore, the mean number of brain pericytes in CatD-/- mice began to decline significantly on P16 and almost disappeared on P24, and oxidative DNA damage was first detected in brain pericytes on P12. Examinations with electron microscopy revealed that brain pericytes were laden with dense granular bodies, cytoplasmic vacuoles and lipid droplets. The infiltration of PBMCs characterized by segmented nucleus laden with dense granular bodies was also noted in the cerebral cortex of CatD-/- mice. When primary cultured microglia prepared from enhanced green fluorescent protein (GFP) expressing transgenic rats were injected into the common carotid artery, GFP positive microglia were detected in the brain parenchyma of CatD-/-, but not wild type, mice. Moreover, pepstatin A, a specific aspartic protease inhibitor, induced mitochondria-derived reactive oxygen species (ROS) production in the isolated brain pericytes, which decreased the cell viability. These observations suggest that increased lysosomal storage due to CatD deficiency causes oxidative damage in brain pericytes, subsequently resulting in an increased vessel diameter, enhanced permeability of the BBB and the infiltration of PBMCs. Therefore, protecting brain pericytes against lysosomal storage-induced oxidative stress may represent an alternative treatment strategy for congenital NCL. PMID- 25496869 TI - Prophylactic efficacy of fluoxetine, escitalopram, sertraline, paroxetine, and concomitant psychotherapy in major depressive disorder: outcome after long-term follow-up. AB - The acute efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder (MDD) is well established; however their role in longer-term prevention of recurrence remains unconfirmed. This study aims at examining: the prophylactic efficacy of four commonly used SSRIs in MDD in a naturalistic setting with long-term follow-up, the effect of concomitant cognitive behavioral therapy (CBT), and the predictors of outcome. In a prospective cohort study, 387 patients who either remitted or responded following treatment with four different SSRIs-fluoxetine, escitalopram, sertraline and paroxetine-were followed up over several years. During an average follow-up period of 34.5 months, 76.5% of patients experienced MDD recurrence. Escitalopram and fluoxetine showed a numerically higher prophylactic efficacy than paroxetine and sertraline but the difference was statistically insignificant. The prophylactic efficacy for SSRI-only treatment was limited, with a recurrence rate of 82.0%, compared to 59.0% of patient recurrence rate in concomitant Cognitive Behavioral Therapy (CBT). The relatively small size of the CBT group and the lack of randomization may undermine the extrapolation of its findings to clinical practice. Nevertheless, the study preliminary data may help in defining the clinical utility of antidepressants and CBT in the prophylaxis from MDD recurrence. PMID- 25496871 TI - Alzheimer's disease risk variant in CLU is associated with neural inefficiency in healthy individuals. AB - INTRODUCTION: Genome-wide association studies identify rs11136000 in the CLU gene, which codes for Apolipoprotein J/Clusterin, as a significant risk variant for Alzheimer's disease (AD). However, the mechanisms by which this variant confers susceptibility remain relatively unknown. METHODS: Eighty-five healthy Caucasian participants underwent functional magnetic resonance imaging during a working memory (WM) task and were genotyped for CLU rs11136000/APOE loci. RESULTS: Here we show that young individuals with the CLU rs11136000 risk variant (C) have higher activation levels in memory-related prefrontal and limbic areas during a WM task. We also found subtle reductions in gray matter in the right hippocampal formation in carriers of the risk variant. DISCUSSION: We suggest that this pattern of multimodal imaging results may reflect incipient structural differences and inefficient functional activation. This study supports accumulating evidence suggesting that genetic risk for AD affects the neural networks associated with memory in healthy individuals. PMID- 25496870 TI - The transcription factor Pitx2 positions the embryonic axis and regulates twinning. AB - Embryonic polarity of invertebrates, amphibians and fish is specified largely by maternal determinants, which fixes cell fates early in development. In contrast, amniote embryos remain plastic and can form multiple individuals until gastrulation. How is their polarity determined? In the chick embryo, the earliest known factor is cVg1 (homologous to mammalian growth differentiation factor 1, GDF1), a transforming growth factor beta (TGFbeta) signal expressed posteriorly before gastrulation. A molecular screen to find upstream regulators of cVg1 in normal embryos and in embryos manipulated to form twins now uncovers the transcription factor Pitx2 as a candidate. We show that Pitx2 is essential for axis formation, and that it acts as a direct regulator of cVg1 expression by binding to enhancers within neighbouring genes. Pitx2, Vg1/GDF1 and Nodal are also key actors in left-right asymmetry, suggesting that the same ancient polarity determination mechanism has been co-opted to different functions during evolution. PMID- 25496872 TI - Hospital admissions, outpatient visits and healthcare costs of community-dwellers with Alzheimer's disease. AB - BACKGROUND: Detailed data on the health care service use of people with Alzheimer's disease (AD) are scarce. METHODS: We assessed the health care service use of all community-dwelling persons with clinically verified AD diagnosis, residing in Finland on December 31, 2005 (n = 27,948) in comparison to matched cohort without AD. Hospitalization data during 2006-2009 were extracted from the National Hospital Discharge Register. RESULTS: Comorbidity-adjusted incidence rate ratios; IRR (95% CI) were 1.25 (1.22-1.28) for inpatient admissions and 0.72 (0.68-0.77) for outpatient visits. People with AD had more general health care admissions (IRR, 95%CI 1.73, 1.67-1.80) but less admissions to specialty units 0.82 (0.79-0.85) than the non-AD group, with psychiatry being the only specialty with more admissions in the AD group. People with AD had 16 more hospital days/person-year. CONCLUSIONS: It would be important to assess whether inpatient hospitalizations of AD patients could be decreased by better targeting of outpatient services and whether other conditions are underdiagnosed or undertreated among persons with AD. PMID- 25496874 TI - Melatonin plays a critical role in inducing B lymphocyte proliferation of the bursa of Fabricius in broilers via monochromatic lights. AB - To study the role of melatonin in the monochromatic light-induced B lymphocyte proliferation of bursa, a total of 360 newly hatched broilers, including intact, sham-operated, and pinealectomized groups, were exposed to blue light (BL), green light (GL), red light (RL) and white light (WL) from a light-emitting diode system for 14d. Both in vivo and in vitro studies showed that the percentage of proliferating cell nuclear antigen (PCNA)-immunoreactive lymphocytes and the lymphocyte proliferation in response to lipopolysaccharide in the bursa of broilers in the GL intact group was the highest values among the different intact groups with altered plasma melatonin levels. Additionally, the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and total antioxidant capability (T-AOC) were the highest, whereas malondialdehyde (MDA) content and inducible nitric oxide synthase (iNOS) expression were significantly decreased in the GL intact group. After pinealectomy, the levels of SOD, GSH-Px and T-AOC decreased remarkably in the various light-treatment groups, whereas the MDA content and iNOS expression significantly increased. The administration of exogenous melatonin (250pg/mL) in vitro also significantly enhanced the bursal B lymphocyte proliferation. These findings suggest that GL illumination effectively elevates the antioxidative capacity to promote B lymphocyte proliferation of bursa in young broilers, which might depend on enhanced melatonin secretion. PMID- 25496873 TI - Carriers of a common variant in the dopamine transporter gene have greater dementia risk, cognitive decline, and faster ventricular expansion. AB - INTRODUCTION: Genetic variants in DAT1, the gene encoding the dopamine transporter (DAT) protein, have been implicated in many brain disorders. In a recent case-control study of Alzheimer's disease (AD), a regulatory polymorphism in DAT1 showed a significant association with the clinical stages of dementia. METHODS: We tested whether this variant was associated with increased AD risk, and with measures of cognitive decline and longitudinal ventricular expansion, in a large sample of elderly participants with genetic, neurocognitive, and neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: The minor allele-previously linked with increased DAT expression in vitro-was more common in AD patients than in both individuals with mild cognitive impairment and healthy elderly controls. The same allele was also associated with poorer cognitive performance and faster ventricular expansion, independently of diagnosis. DISCUSSION: These results may be due to reduced dopaminergic transmission in carriers of the DAT1 mutation. PMID- 25496878 TI - Dementia warning for the Asia-Pacific region. PMID- 25496876 TI - Enhanced photocatalytic activity of sprayed Au doped ferric oxide thin films for salicylic acid degradation in aqueous medium. AB - Various doping percentage of Au were successfully introduced into the Fe2O3 photocatalysts via a spray pyrolysis method different. The effect of Au doping on photoelectrochemical, structural, optical and morphological properties of these deposited thin films is studied. The PEC characterization shows that, the photocurrent increases gradually with increasing Au content initially up to 2at.% indicating the maximum values of short circuit current (Isc) and open circuit voltage (Voc) are (Isc=90MUA and Voc=220.5mV) and then decreases after exceeding the optimal Au doping content. Therefore, the photocurrent of Au doped Fe2O3 photocatalysts can be adjusted by the Au content. Deposited films are polycrystalline with a rhombohedral crystal structure having (104) preferred orientation. SEM and AFM images show deposited thin films are compact and uniform. The photocatalytic activities of the Fe2O3 and Au:Fe2O3 photocatalyst were evaluated by photoelectrocatalytic degradation of salicylic acid under sunlight irradiation. The results show that the Au:Fe2O3 thin film photocatalyst exhibited about 45% more degradation of pollutants than the pure Fe2O3. Thus, in Au doped Fe2O3 photocatalysts, the interaction between Au and Fe2O3 reduces the recombination of photogenerated charge carriers and improve the photocatalytic activity. PMID- 25496875 TI - Riboflavin-sensitized photooxidation of Ceftriaxone and Cefotaxime. Kinetic study and effect on Staphylococcus aureus. AB - Trace amounts of the widely used beta-lactam antibiotics (Atbs) in waste water may cause adverse effects on the ecosystems and contribute to the proliferation of antibiotic-resistant bacteria. On these grounds, kinetic and mechanistic aspects of photosensitized degradation of Ceftriaxone (Cft) and Cefotaxime (Ctx), have been studied in pure water by stationary and time-resolved techniques. Additionally, possible implications of these photoprocesses on the antimicrobial activity of the Atbs have also been investigated. Photoirradiation of aqueous solutions of Cft and Ctx produces the degradation of both Atbs in the presence of Riboflavin (vitamin B2), a well known pigment dissolved in natural aquatic systems. The process occurs through Type I and Type II mechanisms, with effective prevalence of the former. The participation of O2(-), OH and O2((1)Deltag) is supported by experiments of oxygen consumption carried out in the presence of specific scavengers for such reactive oxygen species. Microbiological assays exhibit a parallelism between the rate of Cft and Ctx photodegradation and the loss of their bactericidal capacity on Staphylococcus aureus strains. Results contribute to both understanding kinetic and mechanism aspects of the degradation and predicting on natural decay of Atbs waste water-contaminants. PMID- 25496879 TI - Stroke: an emphasis on guidelines. PMID- 25496880 TI - Alzheimer's disease and other dementias: advances in 2014. PMID- 25496881 TI - Headache research in 2014: Advancing migraine therapy. PMID- 25496882 TI - Epilepsy: redefining the boundaries. PMID- 25496884 TI - MS and related disorders: looking for markers of phenotypes. PMID- 25496883 TI - Movement disorders: discoveries in pathophysiology and therapy. PMID- 25496885 TI - Neuromuscular diseases: progress in gene discovery drives diagnostics and therapeutics. PMID- 25496886 TI - Concussion research: new horizons. PMID- 25496887 TI - Paediatric neurology: from molecular mechanisms to targeted treatments. PMID- 25496888 TI - Sleep: what the day owes the night. PMID- 25496889 TI - CNS infections in 2014: Guns, germs, and will. PMID- 25496890 TI - Pain: from new perspectives to novel treatments. PMID- 25496891 TI - A multidisciplinary approach in neurofibromatosis 1. PMID- 25496892 TI - A multidisciplinary approach in neurofibromatosis 1. PMID- 25496893 TI - A multidisciplinary approach in neurofibromatosis 1--authors' reply. PMID- 25496894 TI - Site of effect of LY2951742 for migraine prophylaxis. PMID- 25496895 TI - Site of effect of LY2951742 for migraine prophylaxis--authors' reply. PMID- 25496896 TI - Michel Ferrari: game, set, and match in headache research. PMID- 25496897 TI - Migraine and headache. PMID- 25496898 TI - Migraine pathophysiology: lessons from mouse models and human genetics. AB - Migraine is a common, disabling, and undertreated episodic brain disorder that is more common in women than in men. Unbiased genome-wide association studies have identified 13 migraine-associated variants pointing at genes that cluster in pathways for glutamatergic neurotransmission, synaptic function, pain sensing, metalloproteinases, and the vasculature. The individual pathogenetic contribution of each gene variant is difficult to assess because of small effect sizes and complex interactions. Six genes with large effect sizes were identified in patients with rare monogenic migraine syndromes, in which hemiplegic migraine and non-hemiplegic migraine with or without aura are part of a wider clinical spectrum. Transgenic mouse models with human monogenic-migraine-syndrome gene mutations showed migraine-like features, increased glutamatergic neurotransmission, cerebral hyperexcitability, and enhanced susceptibility to cortical spreading depression, which is the electrophysiological correlate of aura and a putative trigger for migraine. Enhanced susceptibility to cortical spreading depression increased sensitivity to focal cerebral ischaemia, and blocking of cortical spreading depression improved stroke outcome in these mice. Changes in female hormone levels in these mice modulated cortical spreading depression susceptibility in much the same way that hormonal fluctuations affect migraine activity in patients. These findings confirm the multifactorial basis of migraine and might allow new prophylactic options to be developed, not only for migraine but potentially also for migraine-comorbid disorders such as epilepsy, depression, and stroke. PMID- 25496899 TI - Functional MRI of migraine. AB - Migraine is a disabling neurological condition manifesting with attacks of headache, hypersensitivities to visual, auditory, olfactory and somatosensory stimuli, nausea, and vomiting. Exposure to sensory stimuli, such as odours, visual stimuli, and sounds, commonly triggers migraine attacks, and hypersensitivities to sensory stimuli are prominent during migraine attacks, but can persist with less magnitude between attacks. Functional MRI (fMRI) has been used to investigate the mechanisms that lead to migraine sensory hypersensitivities by measuring brain responses to visual, olfactory, and painful cutaneous stimulation, and functional connectivity analyses have investigated the functional organisation of specific brain regions and networks responsible for sensory processing. These studies have consistently shown atypical brain responses to sensory stimuli, absence of the normal habituating response between attacks, and atypical functional connectivity of sensory processing regions. Identification of the mechanisms that lead to migraine sensory hypersensitivities and that trigger migraine attacks in response to sensory stimuli might help to better understand neural dysfunction in migraine and provide new targets for migraine prevention, and could provide fMRI biomarkers that indicate early responses to preventive therapy. PMID- 25496900 TI - Paediatric stroke: pressing issues and promising directions. AB - Stroke occurs across the lifespan with unique issues in the fetus, neonate, and child. The past decade has seen substantial advances in paediatric stroke research and clinical care, but many unanswered questions and controversies remain. The pathobiology of perinatal stroke needs to be better understood if prevention strategies are to be realised. Similarly, enhanced understanding of the mechanisms underlying childhood stroke, including cerebral arteriopathies, could inform the development of mechanism-specific treatments. Emerging clinical trials, including studies of neonatal sinovenous thrombosis and childhood arterial stroke, offer the hope of evidence-based treatment options in the near future. Early recognition of stroke in children is a key educational target for both the public and health-care professionals, and has translational potential to advance the application of neuroprotective, thrombolytic, and antithrombotic interventions and rehabilitation strategies to the earliest possible timepoints after stroke onset, improving outcomes and quality of life for affected children and their families. PMID- 25496902 TI - Tau imaging: early progress and future directions. AB - Use of selective in-vivo tau imaging will enable improved understanding of tau aggregation in the brain, facilitating research into causes, diagnosis, and treatment of major tauopathies such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, and some variants of frontotemporal lobar degeneration. Neuropathological studies of Alzheimer's disease show a strong association between tau deposits, decreased cognitive function, and neurodegenerative changes. Selective tau imaging will allow the in-vivo exploration of such associations and measure the global and regional changes in tau deposits over time. Such imaging studies will comprise non-invasive assessment of the spatial and temporal pattern of tau deposition over time, providing insight into the role tau plays in ageing and helping to establish the relation between cognition, genotype, neurodegeneration, and other biomarkers. Once validated, selective tau imaging might be useful as a diagnostic, prognostic, and progression biomarker, and a surrogate marker for the monitoring of efficacy and patient recruitment for anti-tau therapeutic trials. PMID- 25496903 TI - Sensitive and critical periods during neurotypical and aberrant neurodevelopment: a framework for neurodevelopmental disorders. AB - During sensitive and critical periods, the brain undergoes significant plasticity from the level of individual synapses and neuronal networks up to the level of behaviour. Both sensitive and critical periods during neurotypical development of the young animal provide a framework to the early temporally-regulated modifications that occur in the nervous system. In neurodevelopmental disorders (NDD), notably autistic syndromes and intellectual disability, children exhibit developmental delays in motor, social and sensory processes and often miss key developmental milestones. In corresponding genetic NDD mouse models, recent data reveal temporally-regulated and in some cases, transient impairments in many neuronal and behavioural phenotypes during development. However, the mechanisms underlying these impairments in NDDs and their potential links with neurobiological mechanisms governing neurotypical development are not fully investigated. This article highlights the potential for the use of known critical and sensitive periods during vertebrate development to investigate and advance our understanding of the neural bases underlying impairments in these developmental disorders of the nervous system. PMID- 25496901 TI - Wilson's disease and other neurological copper disorders. AB - The copper metabolism disorder Wilson's disease was first defined in 1912. Wilson's disease can present with hepatic and neurological deficits, including dystonia and parkinsonism. Early-onset presentations in infancy and late-onset manifestations in adults older than 70 years of age are now well recognised. Direct genetic testing for ATP7B mutations are increasingly available to confirm the clinical diagnosis of Wilson's disease, and results from biochemical and genetic prevalence studies suggest that Wilson's disease might be much more common than previously estimated. Early diagnosis of Wilson's disease is crucial to ensure that patients can be started on adequate treatment, but uncertainty remains about the best possible choice of medication. Furthermore, Wilson's disease needs to be differentiated from other conditions that also present clinically with hepatolenticular degeneration or share biochemical abnormalities with Wilson's disease, such as reduced serum ceruloplasmin concentrations. Disordered copper metabolism is also associated with other neurological conditions, including a subtype of axonal neuropathy due to ATP7A mutations and the late-onset neurodegenerative disorders Alzheimer's disease and Parkinson's disease. PMID- 25496904 TI - Fetal programming of schizophrenia: select mechanisms. AB - Mounting evidence indicates that schizophrenia is associated with adverse intrauterine experiences. An adverse or suboptimal fetal environment can cause irreversible changes in brain that can subsequently exert long-lasting effects through resetting a diverse array of biological systems including endocrine, immune and nervous. It is evident from animal and imaging studies that subtle variations in the intrauterine environment can cause recognizable differences in brain structure and cognitive functions in the offspring. A wide variety of environmental factors may play a role in precipitating the emergent developmental dysregulation and the consequent evolution of psychiatric traits in early adulthood by inducing inflammatory, oxidative and nitrosative stress (IO&NS) pathways, mitochondrial dysfunction, apoptosis, and epigenetic dysregulation. However, the precise mechanisms behind such relationships and the specificity of the risk factors for schizophrenia remain exploratory. Considering the paucity of knowledge on fetal programming of schizophrenia, it is timely to consolidate the recent advances in the field and put forward an integrated overview of the mechanisms associated with fetal origin of schizophrenia. PMID- 25496905 TI - Why is obesity such a problem in the 21st century? The intersection of palatable food, cues and reward pathways, stress, and cognition. AB - Changes in food composition and availability have contributed to the dramatic increase in obesity over the past 30-40 years in developed and, increasingly, in developing countries. The brain plays a critical role in regulating energy balance. Some human studies have demonstrated increased preference for high fat and high sugar foods in people reporting greater stress exposure. We have examined neurochemical changes in the brain in rodent models during the development of obesity, including the impact of obesity on cognition, reward neurocircuitry and stress responsiveness. Using supermarket foods high in fat and sugar, we showed that such a diet leads to changes in neurotransmitters involved in the hedonic appraisal of foods, indicative of an addiction-like capacity of foods high in fat and/or sugar. Importantly, withdrawal of the palatable diet led to a stress-like response. Furthermore, access to this palatable diet attenuated the physiological effects of acute stress (restraint), indicating that it could act as a comfort food. In more chronic studies, the diet also attenuated anxiety like behavior in rats exposed to stress (maternal separation) early in life, but these rats may suffer greater metabolic harm than rats exposed to the early life stressor but not provided with the palatable diet. Impairments in cognitive function have been associated with obesity in both people and rodents. However, as little as 1 week of exposure to a high fat, high sugar diet selectively impaired place but not object recognition memory in the rat. Excess sugar alone had similar effects, and both diets were linked to increased inflammatory markers in the hippocampus, a critical region involved in memory. Obesity-related inflammatory changes have been found in the human brain. Ongoing work examines interventions to prevent or reverse diet-induced cognitive impairments. These data have implications for minimizing harm caused by unhealthy eating. PMID- 25496907 TI - The early detection of lung cancer during follow-up of patients undergoing endobronchial one-way valve treatment for emphysema. AB - We describe the early detection of lung cancer during the follow-up of two emphysematous patients undergoing endobronchial treatment with one-way valves for severe dyspnea. In both cases, the lung function improvement achieved after the valves placement allowed their surgical treatment. In additional to standard follow-up for evaluating the progression of emphysema, such patients should be enrolled in a screening program. It may allow the early detection of lung cancer with the possibility for surgery in accordance with respiratory function of patient. PMID- 25496908 TI - [Coexisting systemic lupus erythematosus and sickle cell disease: case report and literature review]. AB - OBJECTIVE: To report a case of coexisting systemic lupus erythematosus (SLE) and sickle cell disease (SCD) with a review of the literature on the topic. METHODOLOGY: Report of case and research of the association between SLE and SCD in literature through scientific articles in health sciences databases, such as LILACS, MEDLINE/Pubmed and Scielo, until May 2012. Descriptors used: 1. Sickle cell anemia; 2. Sickle cell disease; 3. Systemic lupus erythematosus; 4. Hemoglobinopathies. RESULTS: The authors describe an association between SLE and SS hemoglobinopathy in an eight-year-old female patient displaying articular, hematologic and neuropsychiatric manifestations during clinical evolution. Forty five cases of association between SLE and SCD are described in literature, mostly adult (62.2%), women (78%) and with the SS phenotype in 78% of the cases, and different clinical manifestations. Compared with our patient, articular, hematologic and neuropsychiatric manifestations were present in 76%, 36% and 27% of the cases, respectively. CONCLUSION: SLE and SCD are chronic diseases that have several clinical and laboratory findings in common, meaning difficult diagnosis and difficulty in finding the correct treatment. Although the association between these diseases is not common, it is described in literature, so it is imperative that physicians who treat such diseases be alert to this possibility. PMID- 25496909 TI - Evaluating the risk of avian influenza introduction and spread among poultry exhibition flocks in Australia. AB - Some practices undertaken by poultry exhibitors, such as allowing wild birds to contact domestic birds, the high frequency of bird movements and the lack of appropriate isolation for incoming birds, pose a risk for disease introduction and spread. The aim of the current study was to quantitatively assess the probability of introduction of low pathogenic avian influenza (LPAI) viruses from wild waterfowl into poultry exhibition flocks and the subsequent spread to other poultry flocks. Exposure and consequence assessments, using scenario trees and Monte Carlo stochastic simulation modelling, were conducted to identify potential pathways of introduction and spread and calculate the probabilities of these pathways occurring. Input parameters were estimated from two recently conducted cross-sectional studies among poultry exhibitors in Australia (Dusan et al., 2010; Hernandez-Jover et al., 2013) and other scientific literature. According to reported practices of poultry exhibitors and the LPAI prevalence in wild birds in Australia, this assessment estimates a median (5-95%) probability of exposure of a bird kept by a poultry exhibitor of 0.004 (0.003-0.005). Due to the higher susceptibility of infection of turkeys and waterfowl, this probability is higher in flocks keeping these bird species than in those keeping chickens or pigeons only. Similarly, once exposure has occurred, establishment of infection and subsequent spread are more likely in those flocks keeping waterfowl and turkeys than in those keeping chicken and pigeons only. Spread through movement of birds is the most likely pathway of spread, followed by contaminated fomites, wild birds and airborne spread. The median probability of LPAI spread through movement of birds in flocks keeping waterfowl and turkeys was estimated to be 0.280 (0.123 0.541) and 0.230 (0.104-0.421), respectively. A lower probability was estimated for chicken (0.087; 0.027-0.202) and pigeon (0.0003; 3.0*10(-5)-0.0008) flocks. The sensitivity analysis indicates that the prevalence of LPAI in wild waterfowl and the probability of contact of domestic birds with wild waterfowl are the most influential parameters on the probability of exposure; while the probability of spread is mostly influenced by the probability of movement of birds and the probability of the exhibitor detecting and reporting LPAI. To minimize the potential risk of AI introduction and spread, poultry exhibitors should prevent contact of domestic birds with wild birds, and implement appropriate biosecurity practices. In addition, adequate extension services are required to improve exhibitors' abilities to recognize diseases and reporting behaviour. PMID- 25496910 TI - Acanthamoeba keratitis: 10-year study at a tertiary eye care center in Hong Kong. AB - PURPOSE: To review clinical presentation, investigation results and treatment outcomes of patients with Acanthamoeba keratitis (AK) at a tertiary eye care center in Hong Kong. METHODS: A retrospective case review was performed for cases of Acanthamoeba keratitis diagnosed at the Prince of Wales Hospital, Hong Kong over a 10-year period. RESULTS: Fifteen eyes of 13 patients were treated for AK over the study period. 12 out of 13 patients (92.3%) were contact lens wearers. All patients presented with blurred vision and pain, while 9 patients (69.2%) presented with redness of the affected eye. The most common ocular sign was diffuse corneal haze or ground glass appearance of the cornea (69.2%) followed by anterior chamber inflammation (53.8%), ring infiltrate (38.4%), epithelial defect (38.4%), perineural infiltrates (30.7%) and satellite lesions (15.3%). Acanthamoeba was detected on corneal scrapings in 4 eyes and on confocal microscopy in 4 eyes. The mean duration of treatment was 140 +/- 50.8 days. Surgical intervention was required in two cases due to uncontrolled eye infection and progressive corneal thinning. All patients had improvement in visual acuity after treatment. CONCLUSIONS: Patients with AK exhibited a wide spectrum of clinical characteristics. Improper care and usage of contact lenses is a major risk factor for Acanthamoeba keratitis. Diagnosis of AK remained a challenge. Timely diagnosis and appropriate treatment with amoebicidal drugs can improve the outcomes of Acanthamoeba keratitis. PMID- 25496911 TI - Cell penetrating peptide TAT can kill cancer cells via membrane disruption after attachment of camptothecin. AB - Attachment of traditional anticancer drugs to cell penetrating peptides is an effective strategy to improve their application in cancer treatment. In this study, we designed and synthesized the conjugates TAT-CPT and TAT-2CPT by attaching camptothecin (CPT) to the N-terminus of the cell penetrating peptide TAT. Interestingly, we found that TAT-CPT and especially TAT-2CPT could kill cancer cells via membrane disruption, which is similar to antimicrobial peptides. This might be because that CPT could perform as a hydrophobic residue to increase the extent of membrane insertion of TAT and the stability of the pores. In addition, TAT-CPT and TAT-2CPT could also kill cancer cells by the released CPT after they entered cells. Taken together, attachment of CPT could turn cell penetrating peptide TAT into an antimicrobial peptide with a dual mechanism of anticancer action, which presents a new strategy to develop anticancer peptides based on cell penetrating peptides. PMID- 25496912 TI - Inducible expression of enhanced green fluorescent protein by interleukin-1alpha, interleukin-1beta and Toll-like receptor 2 promoters in goat mammary epithelial cells in response to bacterial challenges. AB - The development of a bacteria-inducible expression system has several advantages compared with persistent expression of anti-bacterial proteins in milk to prevent and treat mastitis. The present study determined whether mastitis responsive promoters could regulate enhanced green fluorescent protein (EGFP) expression in goat mammary epithelial cells (GMECs) in response to challenges with Escherichia coli, Staphylococcus aureus or Streptococcus agalactiae. The level of expression of interleukin (IL)-1alpha was significantly increased in GMECs challenged with E. coli, S. aureus or S. agalactiae compared with untreated GMECs. IL-1beta was induced by E. coli and S. aureus, while Toll-like receptor 2 (TLR2) was induced by E. coli only. GMECs were transfected with IL-1alpha, IL-1beta and TLR2 promoter-EGFP reporter gene lentiviral expression vectors and the levels of expression of EGFP were measured by flow cytometry and Western blot analysis after bacterial challenge. EGFP expression driven by the IL-1alpha and IL-1beta promoters was higher in GMECs challenged with E. coli, S. aureus or S. agalactiae than in untreated GMECs. There were no differences in EGFP expression driven by the TLR2 promoter between GMECs challenged with S. aureus or S. agalactiae and untreated GMECs, but EGFP expression was significantly increased in GMECs challenged with E. coli. Overall, these results indicate that the promoters of some bacteria-inducible genes can regulate EGFP expression in GMECs in response to bacterial challenges. This bacteria-inducible expression strategy could be used for production of mastitis resistant animals by regulating the expression of anti-bacterial proteins in the mammary gland. PMID- 25496913 TI - alpha-L-fucosidase enhances capacitation-associated events in porcine spermatozoa. AB - The activity of alpha-L-fucosidase in oviductal fluid increases around the time of ovulation. alpha-L-fucosidase is also associated with the spermatozoal plasma membrane and its substrate, fucose, has been identified in the zona pellucida (ZP) and on the spermatozoal surface, suggesting a role in fertilisation. The aim of the present study was to investigate the role of exogenous alpha-L-fucosidase during fertilisation. Porcine oocytes were incubated with fucosidase and later subjected to in vitro fertilisation (IVF). No effect on the percentage of oocytes fertilised was observed, although there was a slight decrease in spermatozoa-ZP binding. Fucosidase was then added to IVF medium, and spermatozoa and oocytes were co-incubated for 15 min. A significant increase in spermatozoa-ZP binding and penetration was observed, suggesting a role of the enzyme in the fertilisation ability of spermatozoa. In addition, fluorescence intensity and the patterns of spermatozoa membrane-associated alpha-L-fucosidase distribution, as assessed by indirect immunofluorescence, were not affected by the presence or absence of exogenous enzyme, suggesting an independent role for the exogenous and spermatozoa-associated enzymes. Addition of exogenous alpha-L-fucosidase increased the spermatozoal intracellular ionised calcium concentration and tyrosine phosphorylation, suggesting a role in promoting capacitation and, at the same time, protecting spermatozoa from a premature acrosome reaction. Thus, alpha L-fucosidase enhances capacitation-associated events in porcine spermatozoa. PMID- 25496914 TI - Big dung beetles dig deeper: trait-based consequences for faecal parasite transmission. AB - Observational evidence suggests that burial of faeces by dung beetles negatively influences the transmission of directly transmitted gastrointestinal helminths. However, the mechanistic basis for these interactions is poorly characterised, limiting our ability to understand relationships between beetle community composition and helminth transmission. We demonstrate that beetle body size and sex significantly impact tunnel depth, a key variable affecting parasite survival. Additionally, high parasite loads reduce the depth of beetle faeces burial, suggesting that the local prevalence of parasites infecting beetles may impact beetle ecosystem function. Our study represents a first step towards a mechanistic understanding of a potentially epidemiologically relevant ecosystem function. PMID- 25496915 TI - Road crash fatality rates in France: a comparison of road user types, taking account of travel practices. AB - BACKGROUND: Travel practices are changing: bicycle and motorized two-wheeler (MTW) use are rising in some of France's large cities. These are cheaper modes of transport and therefore attractive at a time of economic crisis, but they also allow their users to avoid traffic congestion. At the same time, active transport modes such as walking and cycling are encouraged because they are beneficial to health and reduce pollution. It is therefore important to find out more about the road crash risks of the different modes of transport. To do this, we need to take account of the number of individuals who use each, and, even better, their travel levels. METHOD: We estimated the exposure-based fatality rates for road traffic crashes in France, on the basis of the ratio between the number of fatalities and exposure to road accident risk. Fatality data were obtained from the French national police database of road traffic casualties in the period 2007-2008. Exposure data was estimated from the latest national household travel survey (ENTD) which was conducted from April 2007 to April 2008. Three quantities of travel were computed for each mode of transport: (1) the number of trips, (2) the distance traveled and (3) the time spent traveling. Annual fatality rates were assessed by road user type, age and sex. RESULTS: The overall annual fatality rates were 6.3 per 100 million trips, 5.8 per billion kilometers traveled and 0.20 per million hours spent traveling. The fatality rates differed according to road user type, age and sex. The risk of being killed was 20 to 32 times higher for motorized two-wheeler users than for car occupants. For cyclists, the risk of being killed, both on the basis of time spent traveling and the number of trips was about 1.5 times higher than for car occupants. Risk for pedestrians compared to car occupants was similar according to time spent traveling, lower according to the number of trips and higher according to the distance traveled. People from the 17-20 and 21-29 age groups and those aged 70 and over had the highest rates. Males had higher rates than females, by a factor of between 2 and 3. CONCLUSION: When exposure is taken into account, the risks for motorized two-wheeler users are extremely high compared to other types of road user. This disparity can be explained by the combination of speed and a lack of protection (except for helmets). The differential is so great that prevention measures could probably not eliminate it. The question that arises is as follows: with regard to public health, should not the use of MTW, or at least of motorcycles, be deterred? The difference between the fatality risk of cyclists and of car occupants is much smaller (1.5 times higher); besides, there is much room for improvements in cyclist safety, for instance by increasing the use of helmets and conspicuity equipment. Traffic calming could also benefit cyclists, pedestrians and perhaps moped users. PMID- 25496906 TI - Found in translation: Understanding the biology and behavior of experimental traumatic brain injury. AB - The aim of this review is to discuss in greater detail the topics covered in the recent symposium entitled "Traumatic brain injury: laboratory and clinical perspectives," presented at the 2014 International Behavioral Neuroscience Society annual meeting. Herein, we review contemporary laboratory models of traumatic brain injury (TBI) including common assays for sensorimotor and cognitive behavior. New modalities to evaluate social behavior after injury to the developing brain, as well as the attentional set-shifting test (AST) as a measure of executive function in TBI, will be highlighted. Environmental enrichment (EE) will be discussed as a preclinical model of neurorehabilitation, and finally, an evidence-based approach to sports-related concussion will be considered. The review consists predominantly of published data, but some discussion of ongoing or future directions is provided. PMID- 25496917 TI - Restoring testosterone levels by adding dehydroepiandrosterone to a drospirenone containing combined oral contraceptive: II. Clinical effects. AB - OBJECTIVES: Combined oral contraceptives (COCs) decrease androgen levels, including testosterone (T), which may be associated with sexual dysfunction and mood complaints in some women. We have shown that 'co-administration' of dehydroepiandrosterone (DHEA) to a drospirenone (DRSP)-containing COC restored total T levels to baseline and free T levels by 47%. Here we describe the effects on sexual function, mood and quality of life of such an intervention. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled study in 99 healthy COC starters. A COC containing 30 mcg ethinylestradiol (EE) and 3 mg DRSP was used for three cycles, followed by six cycles of the same COC combined with 50 mg/day DHEA or placebo. Subjects completed the Moos Menstrual Distress Questionnaire (MDQ), the McCoy Female Sexuality Questionnaire and the short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Safety and tolerability, including effects on skin, were evaluated. RESULTS: The addition of DHEA induced small but significant improvements compared to placebo in the MDQ score for autonomic reactions during the menstrual (-2.0 vs. 0.71; p=0.05) and the premenstrual phase (-3.1 vs. 2.9; p=0.01) and for behavior during the intermenstrual phase (-1.4 vs. 3.6; p=0.02). A significant difference was found in the MDQ score for arousal during the premenstrual phase in favor of placebo (-5.0 vs. 1.0; p=0.01). There were no statistically significant differences between groups for the MSFQ and Q-LES-Q scores. DHEA 'co administration' resulted in an acceptable safety profile. DHEA negated the beneficial effect of the COC on acne according to the subjects' self-assessment. CONCLUSIONS: 'Co-administration' with DHEA did not result in consistent improvements in sexual function, mood and quality of life indicators in women taking EE/DRSP. Retrospectively, the 50 mg dose of DHEA may be too low for this COC. IMPLICATIONS: A well-balanced judgment of the clinical consequences of normalizing androgens during COC use may require complete normalization of free T. PMID- 25496918 TI - Enabling plant synthetic biology through genome engineering. AB - Synthetic biology seeks to create new biological systems, including user-designed plants and plant cells. These systems can be employed for a variety of purposes, ranging from producing compounds of industrial or therapeutic value, to reducing crop losses by altering cellular responses to pathogens or climate change. To realize the full potential of plant synthetic biology, techniques are required that provide control over the genetic code - enabling targeted modifications to DNA sequences within living plant cells. Such control is now within reach owing to recent advances in the use of sequence-specific nucleases to precisely engineer genomes. We discuss here the enormous potential provided by genome engineering for plant synthetic biology. PMID- 25496916 TI - A HIV-1 Tat mutant protein disrupts HIV-1 Rev function by targeting the DEAD-box RNA helicase DDX1. AB - BACKGROUND: Previously we described a transdominant negative mutant of the HIV-1 Tat protein, termed Nullbasic, that downregulated the steady state levels of unspliced and singly spliced viral mRNA, an activity caused by inhibition of HIV 1 Rev activity. Nullbasic also altered the subcellular localizations of Rev and other cellular proteins, including CRM1, B23 and C23 in a Rev-dependent manner, suggesting that Nullbasic may disrupt Rev function and trafficking by intervening with an unidentified component of the Rev nucleocytoplasmic transport complex. RESULTS: To seek a possible mechanism that could explain how Nullbasic inhibits Rev activity, we used a proteomics approach to identify host cellular proteins that interact with Nullbasic. Forty-six Nullbasic-binding proteins were identified by mass spectrometry including the DEAD-box RNA helicase, DDX1. To determine the effect of DDX1 on Nullbasic-mediated Rev activity, we performed cell-based immunoprecipitation assays, Rev reporter assays and bio-layer interferometry (BLI) assays. Interaction between DDX1 and Nullbasic was observed by co-immunoprecipitation of Nullbasic with endogenous DDX1 from cell lysates. BLI assays showed a direct interaction between Nullbasic and DDX1. Nullbasic affected DDX1 subcellular distribution in a Rev-independent manner. Interestingly overexpression of DDX1 in cells not only restored Rev-dependent mRNA export and gene expression in a Rev reporter assay but also partly reversed Nullbasic induced Rev subcellular mislocalization. Moreover, HIV-1 wild type Tat co immunoprecipitated with DDX1 and overexpression of Tat could rescue the unspliced viral mRNA levels inhibited by Nullbasic in HIV-1 expressing cells. CONCLUSIONS: Nullbasic was used to further define the complex mechanisms involved in the Rev dependent nuclear export of the 9 kb and 4 kb viral RNAs. All together, these data indicate that DDX1 can be sequestered by Nullbasic leading to destabilization of the Rev nucleocytoplasmic transport complex and decreased levels of Rev-dependent viral transcripts. The outcomes support a role for DDX1 in maintenance of a Rev nuclear complex that transports viral RRE-containing mRNA to the cytoplasm. To our knowledge Nullbasic is the first anti-HIV protein that specifically targets the cellular protein DDX1 to block Rev's activity. Furthermore, our research raises the possibility that wild type Tat may play a previously unrecognized but very important role in Rev function. PMID- 25496920 TI - Gastric dilatation and volvulus in dogs. Foreword. PMID- 25496919 TI - The fundamental tradeoff in genomes and proteomes of prokaryotes established by the genetic code, codon entropy, and physics of nucleic acids and proteins. AB - BACKGROUND: Mutations in nucleotide sequences provide a foundation for genetic variability, and selection is the driving force of the evolution and molecular adaptation. Despite considerable progress in the understanding of selective forces and their compositional determinants, the very nature of underlying mutational biases remains unclear. RESULTS: We explore here a fundamental tradeoff, which analytically describes mutual adjustment of the nucleotide and amino acid compositions and its possible effect on the mutational biases. The tradeoff is determined by the interplay between the genetic code, optimization of the codon entropy, and demands on the structure and stability of nucleic acids and proteins. CONCLUSION: The tradeoff is the unifying property of all prokaryotes regardless of the differences in their phylogenies, life styles, and extreme environments. It underlies mutational biases characteristic for genomes with different nucleotide and amino acid compositions, providing foundation for evolution and adaptation. PMID- 25496921 TI - Inherited and predisposing factors in the development of gastric dilatation volvulus in dogs. AB - This review article summarizes what is known as well as what is undetermined concerning the inherited and environmental pathogenesis of gastric dilatation volvulus in dogs. The disorder primarily affects large and giant, deep-chested breeds. A concise description of a typical dog affected with gastric dilatation volvulus is presented. PMID- 25496922 TI - The relationship between gastrointestinal motility and gastric dilatation volvulus in dogs. AB - Gastric dilatation-volvulus (GDV) is a devastating disease that most commonly affects large and giant-breed dogs. Though a number of risk factors have been associated with the development of GDV, the etiology of GDV remains unclear. Abnormal gastric motility patterns and delayed gastric emptying have been previously described in dogs following GDV. Work evaluating the effects of gastropexy procedures and changes to gastric motility after experimental GDV has not found the same changes as those found in dogs with naturally occurring GDV. Although the role of abnormal gastric motility in dogs with GDV will need to be clarified with additional research, such study is likely to be facilitated by improved access to and development of noninvasive measurement techniques for the evaluation of gastric emptying and other motility parameters. In particular, the availability of Food and Drug Administration-approved wireless motility devices for the evaluation of gastrointestinal motility is particularly promising in the study of GDV and other functional gastrointestinal diseases of large and giant breed dogs. PMID- 25496923 TI - Cardiovascular and systemic effects of gastric dilatation and volvulus in dogs. AB - Gastric dilatation and volvulus (GDV) is a common emergency condition in large and giant breed dogs that is associated with high morbidity and mortality. Dogs with GDV classically fulfill the criteria for the systemic inflammatory response syndrome (SIRS) and can go on to develop multiple organ dysfunction syndrome (MODS). Previously reported organ dysfunctions in dogs with GDV include cardiovascular, respiratory, gastrointestinal, coagulation and renal dysfunction. Cardiovascular manifestations of GDV include shock, cardiac arrhythmias and myocardial dysfunction. Respiratory dysfunction is also multifactorial, with contributory factors including decreased respiratory excursion due to gastric dilatation, decreased pulmonary perfusion and aspiration pneumonia. Gastrointestinal dysfunction includes gastric necrosis and post-operative gastrointestinal upset such as regurgitation, vomiting, and ileus. Coagulation dysfunction is another common feature of MODS in dogs with GDV. Disseminated intravascular coagulation can occur, putting them at risk of complications associated with thrombosis in the early hypercoagulable state and hemorrhage in the subsequent hypocoagulable state. Acute kidney injury, acid-base and electrolyte disturbances are also reported in dogs with GDV. Understanding the potential for systemic effects of GDV allows the clinician to monitor patients astutely and detect such complications early, facilitating early intervention to maximize the chance of successful management. PMID- 25496924 TI - Plasma lactate concentration as a prognostic biomarker in dogs with gastric dilation and volvulus. AB - Initial and serial plasma lactate concentrations can be used to guide decision making in individual dogs with GDV but care is necessary in phrasing conversations with owners. Published data suggests that survival is more likely and the chance of complications less in dogs with an initial plasma lactate of <4 mmol/L. An initial lactate >6 mmol/L makes gastric necrosis and greater expense more likely. However, because of the overlap between groups and the good overall survival rates, exploratory laparotomy should always be recommended irrespective of the plasma lactate concentration. Falls in plasma lactate of greater than ~40% after fluid resuscitation are likely to indicate better survival. If the initial plasma lactate concentration is moderately to severely increased (5->10 mmol/L) and a sustained increase in plasma lactate occurs after fluid resuscitation, the cause should be aggressively pursued. Many dogs with persistent hyperlactatemia over 24-48 hours do not survive. PMID- 25496925 TI - Gastropexy for prevention of gastric dilatation-volvulus in dogs: history and techniques. AB - Gastric dilatation-volvulus (GDV) is a common and catastrophic disease of large and giant-breed dogs. Treatment of GDV includes medical stabilization followed by prompt surgical repositioning of the stomach in its normal anatomic position. To prevent reoccurrence, gastropexy is used to securely adhere the stomach to the body wall. Effective gastropexy decreases the recurrence of GDV from as high as 80% to less than 5%. The purpose of this article is to describe the history, indications, and techniques for gastropexy. Gastropexy was first reported in veterinary medicine in 1971 for the management of gastric reflux, and later in 1979 for treating and preventing the recurrence of GDV. Gastropexy is indicated in all dogs that undergo surgical correction of GDV. Additionally, prophylactic gastropexy should be strongly considered at the time of surgery in dogs undergoing splenectomy for splenic torsion and potentially other splenic pathology, and in dogs of at-risk breeds, such as Great Danes, that are undergoing exploratory celiotomy for any reason owing to evidence for increased risk of GDV in these patients. Although there are numerous techniques described, gastropexy is always performed on the right side of the abdomen, near the last rib. Ensuring an anatomically correct gastropexy location is vital to prevent postoperative complications such as partial pyloric outflow obstruction. Gastropexy can be performed as part of an open surgical approach to the abdomen or using a minimally invasive technique. When combined with surgical correction of GDV, gastropexy is almost always performed as an open procedure. The stomach is repositioned, the abdomen explored, and then a permanent gastropexy is performed. Techniques used for open gastropexy include incisional, belt-loop, circumcostal, and incorporating gastropexy, as well as gastrocolopexy. Each of these has been described later. Incisional gastropexy is currently the most commonly performed method of surgical gastropexy in dogs; it is quick, relatively easy, safe, and effective. Minimally invasive techniques for gastropexy are often used when gastropexy is performed as an elective, isolated procedure. Minimally invasive techniques include the grid approach, endoscopically guided miniapproach, and laparoscopic gastropexy. Laparoscopic gastropexy is the least invasive alternative; however, it requires special equipment and significant surgical expertise to perform. The authors consider it a veterinarian's responsibility to educate the owners of at-risk large and giant dog breeds about prophylactic gastropexy given such a favorable risk-benefit profile. PMID- 25496926 TI - Postoperative management of dogs with gastric dilatation and volvulus. AB - The objective of the study was to review the veterinary literature for evidence based and common clinical practice supporting the postoperative management of dogs with gastric dilatation and volvulus (GDV). GDV involves rapid accumulation of gas in the stomach, gastric volvulus, increased intragastric pressure, and decreased venous return. GDV is characterized by relative hypovolemic distributive and cardiogenic shock, during which the whole body may be subjected to inadequate tissue perfusion and ischemia. Intensive postoperative management of the patients with GDV is essential for survival. Therapy in the postoperative period is focused on maintaining tissue perfusion along with intensive monitoring for prevention and early identification of ischemia-reperfusion injury (IRI) and consequent potential complications such as hypotension, cardiac arrhythmias, acute kidney injury (AKI), gastric ulceration, electrolyte imbalances, and pain. In addition, early identification of patients in need for re-exploration owing to gastric necrosis, abdominal sepsis, or splenic thrombosis is crucial. Therapy with intravenous lidocaine may play a central role in combating IRI and cardiac arrhythmias. The most serious complications of GDV are associated with IRI and consequent systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Other reported complications include hypotension, AKI, disseminated intravascular coagulation, gastric ulceration, and cardiac arrhythmias. Despite appropriate medical and surgical treatment, the reported mortality rate in dogs with GDV is high (10%-28%). Dogs with GDV that are affected with gastric necrosis or develop AKI have higher mortality rates. PMID- 25496927 TI - The Sterile Elastic Exsanguination Tourniquet vs. the Pneumatic Tourniquet for Total Knee Arthroplasty. AB - We compared the sterile elastic exsanguination tourniquet and the pneumatic tourniquet for total knee arthroplasty. 145 patients were operated on using a pneumatic tourniquet and 166 with the sterile elastic exsanguination tourniquet. Patients with the sterile elastic exsanguination tourniquet had a smaller decrease in hemoglobin on post-operative days one (P<0.028) and three (P<0.045). The amount of blood collected from drains at 24h was significantly lower in the sterile elastic exsanguination group. A trend towards a higher rate of wound complications within 3months following the operation was found in the pneumatic tourniquet group. The sterile elastic exsanguination tourniquet works at least as good as the pneumatic one. PMID- 25496928 TI - Not all "continuous femoral nerve blocks" are equivalent. PMID- 25496929 TI - Prevalence of deep vein thrombosis and pulmonary embolism treated with mechanical compression device after total hip arthroplasty. AB - Several reports have suggested that there is a strikingly low prevalence of deep vein thrombosis (DVT) and pulmonary embolism (PE) after total hip arthroplasty (THA) in Asian patients. We determined the prevalence of DVT and PE after the use of a mechanical compression device only without pharmacological thromboprophylaxis in 459 patients (516 hips). The overall prevalence of DVT was 4.8% (27 of 561 hips). Nine of 27 hips had proximal thrombi. Three patients (0.7%) had asymptomatic PE. In our patients, combinations of absent thrombophilic polymorphisms with low clinical prothrombotic risk factors led to a low prevalence of DVT and virtually no symptomatic PE. Therefore, mechanical compression device only suffices to prevent DVT and PE in Asian patients. PMID- 25496930 TI - An uncemented iso-elastic monoblock acetabular component: preliminary results. AB - Little is known about the clinical application of highly cross-linked polyethylene (HXLPE) blended with vitamin E. This study evaluates an uncemented iso-elastic monoblock cup with vitamin E blended HXLPE. 112 patients were followed up for 2years. 95.5% completed the follow-up. The mean VAS score for patient satisfaction was 8.8 and the mean Harris Hip Score was 94.2. In 7 cases initial gaps behind the cup were observed, which disappeared completely during follow-up in 6 cases. The mean femoral head penetration rate was 0.055mm/year. No adverse reactions or abnormal mechanical behavior was observed with the short term use of vitamin E blended HXLPE. This study shows the promising performance of this cup and confirms the potential of vitamin E blended HXLPE. PMID- 25496931 TI - Does sickle cell disease increase risk of adverse outcomes following total hip and knee arthroplasty? A nationwide database study. AB - Sickle cell disease (SCD) is associated with impaired vascular function and progressive vaso-occlusive injury to bones. We used the Nationwide Inpatient Sample to identify all THA and TKA admissions between 1998 and 2010. After controlling for patient age, gender, insurance, race, and comorbidities, the risk of complication among admissions with SCD was 152% higher (P<0.001) for THA and 137% higher (P=0.001) for TKA. Patients with SCD had a length of stay that was 42% longer (P<0.001) for THA and 20% longer for TKA (P<0.001), and hospital charges that were 19% higher (P<0.001) for THA and 16% higher (P=0.001) for TKA. Orthopedic surgeons should counsel potential THA and TKA candidates with SCD of these risks prior to admission. PMID- 25496932 TI - A bilateral advantage for maintaining objects in visual short term memory. AB - Research has shown that attentional pre-cues can subsequently influence the transfer of information into visual short term memory (VSTM) (Schmidt, B., Vogel, E., Woodman, G., & Luck, S. (2002). Voluntary and automatic attentional control of visual working memory. Perception & Psychophysics, 64(5), 754-763). However, studies also suggest that those effects are constrained by the hemifield alignment of the pre-cues (Holt, J. L., & Delvenne, J.-F. (2014). A bilateral advantage in controlling access to visual short-term memory. Experimental Psychology, 61(2), 127-133), revealing better recall when distributed across hemifields relative to within a single hemifield (otherwise known as a bilateral field advantage). By manipulating the duration of the retention interval in a colour change detection task (1s, 3s), we investigated whether selective pre-cues can also influence how information is later maintained in VSTM. The results revealed that the pre-cues influenced the maintenance of the colours in VSTM, promoting consistent performance across retention intervals (Experiments 1 & 4). However, those effects were only shown when the pre-cues were directed to stimuli displayed across hemifields relative to stimuli within a single hemifield. Importantly, the results were not replicated when participants were required to memorise colours (Experiment 2) or locations (Experiment 3) in the absence of spatial pre-cues. Those findings strongly suggest that attentional pre-cues have a strong influence on both the transfer of information in VSTM and its subsequent maintenance, allowing bilateral items to better survive decay. PMID- 25496933 TI - Presentation of noise during acute restraint stress attenuates expression of immediate early genes and arginine vasopressin in the hypothalamic paraventricular nucleus but not corticosterone secretion in rats. AB - The present study investigated the effect of acoustic stimulation on the activation of the hypothalamic-pituitary-adrenal (HPA) axis in rats submitted to acute restraint stress, through semi-quantitative histochemical analysis of expression of immediate early gene products (c-Fos, JunB and phosphorylated c Jun) and arginine vasopressin (AVP) hnRNA in the paraventricular nucleus (PVN). Simultaneous presentation of white or pink noise with restraint resulted in a significant attenuation of stress-induced c-Fos and JunB expression in the dorsal body of dorsal medial parvicellular subdivision (mpdd) of the PVN, as compared with restraint without noise. However, this presentation did not change phosphorylation of c-Jun and the plasma corticosterone level. Moreover, white noise presentation during restraint led to a reduction in the number of c-Fos- or JunB-expressing corticotropin-releasing hormone (CRH) neurons and the number of neurons expressing AVP hnRNA in the mpdd. Dual-histochemical labeling revealed co expression of c-Fos and JunB, as well as JunB and AVP hnRNA in mpdd neurons. These data suggest that acoustic stimuli have an attenuation effect on the restraint-induced activation of neuroendocrine CRH neurons, resulting in the reduction in AVP production as an adaptation of HPA axis to repeated stress. PMID- 25496934 TI - Decompressive hemicraniectomy with or without clot evacuation for large spontaneous supratentorial intracerebral hemorrhages. AB - OBJECTIVE: The management of patients with supra-tentorial intracerebral hemorrhage (ICH) remains controversial. Here we critically evaluate the safety, feasibility, and outcomes following decompressive hemicraniectomy (HC) with or without clot evacuation in the management of patients with large ICHs. METHODS: We analyzed data from 73 consecutive patients managed with a HC for a spontaneous ICH. All relevant patient variables at initial presentation and management were compiled. Variables were modeled as independent regressors against the three month Glasgow Outcome Score using a multivariate logistic regression model. RESULTS: Over 7 years, HC was performed in 73 patients with clot evacuation in 86% and HC alone in 14%. The average ICH volume was 81 cc and the median HC surface area was 105 cm(2). 26 patients were comatose at initial presentation. Three-month functional outcomes were favorable in 29%, unfavorable in 44% and 27% of patients expired. Admission Glasgow Coma Scale (p = 0.003), dominant hemisphere ICH location (p = 0.01) and hematoma volume (p = 0.002) contributed significantly to the outcome, as estimated by a multivariate analysis. Eight surgical complications occurred. CONCLUSIONS: Early HC with or without clot evacuation is feasible and safe for managing spontaneous ICH. Our experience in this uncontrolled retrospective series, the largest such series in the modern era, suggests that it may be of particular benefit in patients with large non dominant hemisphere ICH who are not moribund at presentation. Our findings suggest that a prospective randomized trial of HC vs. craniotomy for ICH be conducted. PMID- 25496935 TI - Diagnosis and management of dural arteriovenous fistulas: a 10 years single center experience. AB - OBJECTIVES: Dural arteriovenous fistulas (DAVFs) are a challenging condition in vascular neurosurgery. Disease natural history and its management is still debated. In the present paper we report our center series on DAVFs over a period of 10 years. Our data were compared with relevant literature. PATIENT AND METHODS: Our series includes 45 cases: 14 cavernous sinus, 11 transverse-sigmoid, 8 patients tentorial, 6 anterior cranial fossa, 5 patients spinal, 1 patient foramen magnum. RESULTS AND CONCLUSIONS: DVAFs distribution, clinical presentation and hemorrhagic risk are discussed. Cavernous sinus DAVFs are the most common site in our series. Other locations in order of frequency are transverse-sigmoid sinus, tentorial, anterior cranial fossa, spinal and foramen magnum. The majority of patients presented with non-aggressive symptoms. 18% presented with intracranial hemorrhage: all the hemorrhages occurred in high grade DAVFs. For most patients, endovascular treatment, transarterial or transvenous, was the first option. Surgery was performed for the anterior cranial fossa DAVFs and other complex lesions draining mostly transverse-sigmoid sinus and tentorium. In 7% of cases a combination of endovascular+surgical treatment was used. Our series has been carefully analyzed in comparison 'side by side' with most relevant literature on DVAFs, focusing particularly on management strategies, therapeutic options and risks related to treatment. PMID- 25496936 TI - Examining the latent class structure of CO2 hypersensitivity using time course trajectories of panic response systems. AB - BACKGROUND AND OBJECTIVES: Carbon dioxide (CO2) hypersensitivity is hypothesized to be a robust endophenotypic marker of panic spectrum vulnerability. The goal of the current study was to explore the latent class trajectories of three primary response systems theoretically associated with CO2 hypersensitivity: subjective anxiety, panic symptoms, and respiratory rate (fR). METHODS: Participants (n = 376; 56% female) underwent a maintained 7.5% CO2 breathing task that included three phases: baseline, CO2 air breathing, and recovery. Growth mixture modeling was used to compare response classes (1...n) to identify the best-fit model for each marker. Panic correlates also were examined to determine class differences in panic vulnerability. RESULTS: For subjective anxiety ratings, a three-class model was selected, with individuals in one class reporting an acute increase in anxiety during 7.5% CO2 breathing and a return to pre-CO2 levels during recovery. A second, smaller latent class was distinguished by elevated anxiety across all three phases. The third class reported low anxiety reported during room air, a mild increase in anxiety during 7.5% CO2 breathing, and a return to baseline during recovery. Latent class trajectories for fR yielded one class whereas panic symptom response yielded two classes. LIMITATIONS: This study examined CO2 hypersensitivity in one of the largest samples to date, but did not ascertain a general population sample thereby limiting generalizability. Moreover, a true resting baseline measure of fR was not measured. CONCLUSIONS: Two classes potentially representing different risk pathways were observed. Implications of results will be discussed in the context of panic risk research. PMID- 25496938 TI - Experimental evolution: prospects and challenges. PMID- 25496937 TI - Asymmetries and relationships between dynamic loading, muscle strength, and proprioceptive acuity at the knees in symptomatic unilateral hip osteoarthritis. AB - INTRODUCTION: High joint loading, knee muscle weakness, and poor proprioceptive acuity are important factors that have been linked to knee osteoarthritis (OA). We previously reported that those with unilateral hip OA and bilateral asymptomatic knees are more predisposed to develop progressive OA in the contralateral knee relative to the ipsilateral knee. In the present study, we evaluate asymmetries in muscle strength and proprioception between the limbs and also evaluate relationships between these factors and joint loading that may be associated with the asymmetric evolution of OA in this group. METHODS: Sixty-two participants with symptomatic unilateral hip OA and asymptomatic knees were evaluated for muscle strength, joint position sense and dynamic joint loads at the knees. Muscle strength and proprioception were compared between limbs and correlations between these factors and dynamic joint loading were evaluated. Subgroup analyses were also performed in only those participants that fulfilled criteria for severe hip OA. RESULTS: Quadriceps muscle strength was 15% greater, and in the severe subgroup, proprioceptive acuity was 25% worse at the contralateral compared to ipsilateral knee of participants with unilateral hip OA (P <0.05). In addition, at the affected limb, there was an association between decreased proprioceptive acuity and higher knee loading (Spearman's rho = 0.377, P = 0.007) and between decreased proprioceptive acuity and decreased muscle strength (Spearman's rho = -0.328, P = 0.016). CONCLUSIONS: This study demonstrated asymmetries in muscle strength and proprioception between the limbs in a unilateral hip OA population. Early alterations in these factors suggest their possible role in the future development of OA at the contralateral 'OA predisposed knee' in this group. Furthermore, the significant association observed between proprioception, loading, and muscle strength at the affected hip limb suggests that these factors may be interrelated. PMID- 25496939 TI - Effect of cobalt enrichment on growth and hydrocarbon accumulation of Botryococcus braunii with immobilized biofilm attached cultivation. AB - The effects of cobalt enrichment on the growth and hydrocarbon accumulation were studied with biofilm attached cultivation. Under biofilm attached cultivation conditions, the microalga Botryococcus braunii survived high concentration of cobalt (50* normal level). The crude hydrocarbon content as well as the long C chain component (C31) increased under Co enrichment treatment indicating the activity of key enzyme that catalyze hydrocarbon synthesis might be enhanced by Co enrichment. The reduced carbohydrate and protein contents accompanied by increased hydrocarbon content for Co enrichment treatment indicating the Co was also an effective factor that controls the carbon flow of B. braunii. Under Co enrichment treatment, totally 1473.9 MUmol of Co element was consumed to produce one gram of algal biomass, indicating this attached cultivation method is high efficient in heavy metal elements removal. PMID- 25496940 TI - Understanding the impact of influent nitrogen concentration on granule size and microbial community in a granule-based enhanced biological phosphorus removal system. AB - To better understand the effect of influent nitrogen concentration on granule size and microbial community in a granule-based enhanced biological phosphorus removal system, three influent nitrogen concentrations were tested while carbon concentration was an unlimited factor. The results show that although ammonium and phosphate were well removed in the tested nitrogen concentration range (20-50 mg L(-1)), granule size, the amount of phosphate accumulating organisms (PAOs) and microbial activity were affected significantly. A possible mechanism for the effect of influent nitrogen concentration on granule size is proposed based on the experimental results. The increase in proteins/polysaccharides ratio caused by high influent nitrogen concentration plays a crucial role in granule breakage. The small granule size then weakens simultaneous nitrification-denitrification, which further causes higher nitrate concentration in the effluent and lower amount of PAOs in sludge. Consequently, phosphate concentration in the anaerobic phase decreases, which plays the secondary role in granule breakage. PMID- 25496941 TI - Assessing nitrogen transformation processes in a trickling filter under hydraulic loading rate constraints using nitrogen functional gene abundances. AB - A study was conducted of treatment performance and nitrogen transformation processes in a trickling filter (TF) used to treat micro-polluted source water under variable hydraulic loading rates (HLRs), ranging from 1.0 to 3.0 m(3)/m(2) d. The TF achieved high and stable COD (97.7-99.3%) and NH4(+)-N (67.3-92.7%) removal efficiencies. Nitrification and anaerobic ammonium oxidation were the dominant nitrogen removal processes in the TF. Path analysis indicated that amoA/anammox and amoA/(narG+napA) were the two key functional gene groups driving the major processes for NH4(+)-N and NO2(-)-N, respectively. The analysis also revealed that anammox/amoA and nxrA/(nirK+nirS) were the two key functional gene groups affecting processes associated with the NO3(-)-N transformation rate. The direct and indirect effect of functional gene groups further confirmed that nitrogen transformation processes are coupled at the molecular level, resulting in a mutual contribution to nitrogen removal in the TF. PMID- 25496942 TI - Development and validation of a screening procedure of microalgae for biodiesel production: application to the genus of marine microalgae Nannochloropsis. AB - Nannochloropsis has emerged as a promising alga for biodiesel production. However, the genus consists of 6 species and hundreds of strains making strain selection a challenge. Furthermore, oil productivity is instrumental to economic viability of any algal strain for industrial production, which is dependent on growth rate and oil content. In most cases, these two parameters have been studied independently. Thus, the goal of this study is to provide a combined method for evaluating strain performance in specially designed photobioreactors together with an in-depth lipidomic analyses. The nine strains of Nannochloropsis tested showed considerable variations in productivity and lipidomics highlighting the importance of strain selection. Finally, Nannochloropsis gaditana CCMP527 and Nannochloropsis salina CCMP537 emerged as the two most promising strains, with an oil content of 37 and 27 dry wt% after 11-day nitrogen starvation, respectively, resulting in TAG productivity of 13*10(-3) and 18*10(-3) kg m(-3) d(-1), respectively. PMID- 25496943 TI - Submersible microbial desalination cell for simultaneous ammonia recovery and electricity production from anaerobic reactors containing high levels of ammonia. AB - High ammonia concentration in anaerobic reactors can seriously inhibit the anaerobic digestion process. In this study, a submersible microbial desalination cell (SMDC) was developed as an innovative method to lower the ammonia level in a continuous stirred tank reactor (CSTR) by in situ ammonia recovery and electricity production. In batch experiment, the ammonia concentration in the CSTR decreased from 6 to 0.7 g-N/L during 30 days, resulting in an average recovery rate of 80 g-N/m(2)/d. Meanwhile, a maximum power density of 0.71+/-0.5 W/m(2) was generated at 2.85 A/m(2). Both current driven NH4(+) migration and free NH3 diffusion were identified as the mechanisms responsible for the ammonia transportation. With an increase in initial ammonia concentration and a decrease in external resistance, the SMDC performance was enhanced. In addition, the coexistence of other cations in CSTR or cathode had no negative effect on the ammonia transportation. PMID- 25496944 TI - Growth optimisation of microalga mutant at high CO2 concentration to purify undiluted anaerobic digestion effluent of swine manure. AB - Growth rate of the microalga Chlorella PY-ZU1 mutated by nuclear irradiation was optimised for use in the purification of undiluted anaerobic digestion effluent of swine manure (UADESM) with 3745 mg L(-1) chemical oxygen demand (COD) and 1135 mg L(-1) total nitrogen content. The problem of accessible carbon in UADESM was solved by continuous introduction of 15% (v/v) CO2. Adding phosphorus to UADESM and aeration of UADESM before inoculation both markedly reduced the lag phase of microalgal growth. In addition, the biomass yield and average growth rate of Chlorella PY-ZU1 increased significantly to 4.81 g L(-1) and 601.2 mg L(-1) d( 1), respectively, while the removal efficiencies of total phosphorus, COD and ammonia nitrogen increased to 95%, 79% and 73%, respectively. Thus, the findings indicate that Chlorella PY-ZU1 can be used for effective purification of UADESM, while the biomass can be safely used as animal feed supplement. PMID- 25496945 TI - Enhancing of sugar cane bagasse hydrolysis by Annulohypoxylon stygium glycohydrolases. AB - The aim of this study was to develop a bioprocess for the production of beta glucosidase and pectinase from the fungus Annulohypoxylon stygium DR47. Media optimization and bioreactor cultivation using citrus bagasse and soybean bran were explored and revealed a maximum production of 6.26 U/mL of pectinase at pH 4.0 and 10.13 U/mL of beta-glucosidase at pH 5.0. In addition, the enzymes extracts were able to replace partially Celluclast 1.5L in sugar cane bagasse hydrolysis. Proteomic analysis from A. stygium cultures revealed accessory enzymes, mainly belong to the families GH3 and GH54, that would support enhancement of commercial cocktail saccharification yields. This is the first report describing bioreactor optimization for enzyme production from A. stygium with a view for more efficient degradation of sugar cane bagasse. PMID- 25496946 TI - Corn stover semi-mechanistic enzymatic hydrolysis model with tight parameter confidence intervals for model-based process design and optimization. AB - Uncertainty associated to the estimated values of the parameters in a model is a key piece of information for decision makers and model users. However, this information is typically not reported or the confidence intervals are too large to be useful. A semi-mechanistic model for the enzymatic saccharification of dilute acid pretreated corn stover is proposed in this work, the model is a modification of an existing one providing a statistically significant improved fit towards a set of experimental data that includes varying initial solid loadings (10-25% w/w) and the use of the pretreatment liquor and washed solids with or without supplementation of key inhibitors. A subset of 8 out of 17 parameters was identified, showing sufficiently tight confidence intervals to be used in uncertainty propagation and model analysis, without requiring interval truncation via expert judgment. PMID- 25496947 TI - The effects of initial substrate concentration, C/N ratio, and temperature on solid-state anaerobic digestion from composting rice straw. AB - This study investigated the possibilities of improving the biogasification from solid-state anaerobic digestion (SS-AD) of composting rice straw (RS) based on the optimized digestion temperature, initial substrate concentration (ISC) and C/N ratio. RS compounds, such as lignin, cellulose, and hemicellulose, were significantly degraded after composting. A significant interactive effect of temperature, ISC and C/N ratio was found on the biogasification of SS-AD of composting RS, and a maximum biogas production was achieved at 35.6 degrees C, with a 20% ISC and a C/N ratio of 29.6:1. The verification experiment confirmed the optimization results. High-throughput sequencing analysis indicated that microbial communities in the SS-AD mainly consist of Methanobacteria, Bacteroidia, Clostridia, Betaproteobacteria, and Gammaproteobacteria. A dominant Methanobacteria was shifted from Methanobacterium to Methanoculleus during the SS AD process. This study provides novel information about the interdependent effects and microbial behavior of AD. PMID- 25496948 TI - Effects of salinity build-up on biomass characteristics and trace organic chemical removal: implications on the development of high retention membrane bioreactors. AB - This study investigated the impact of salinity build-up on the performance of membrane bioreactor (MBR), specifically in terms of the removal and fate of trace organic chemicals (TrOCs), nutrient removal, and biomass characteristics. Stepwise increase of the influent salinity, simulating salinity build-up in high retention MBRs, adversely affected the metabolic activity in the bioreactor, thereby reducing organic and nutrient removal. The removal of hydrophilic TrOCs by MBR decreased due to salinity build-up. By contrast, with the exception of 17alpha-ethynylestradiol, the removal of all hydrophobic TrOCs was not affected at high salinity. Moreover, salinity build-up had negligible impact on the residual accumulation of TrOCs in the sludge phase except for a few hydrophilic compounds. Additionally, the response of the biomass to salinity stress also dramatically enhanced the release of both soluble microbial products (SMP) and extracellular polymeric substances (EPS), leading to severe membrane fouling. PMID- 25496949 TI - Coordinated response of photosynthesis, carbon assimilation, and triacylglycerol accumulation to nitrogen starvation in the marine microalgae Isochrysis zhangjiangensis (Haptophyta). AB - The photosynthetic performance, carbon assimilation, and triacylglycerol accumulation of Isochrysis zhangjiangensis under nitrogen-deplete conditions were studied to understand the intrinsic correlations between them. The nitrogen deplete period was divided into two stages based on the photosynthetic parameters. During the first stage, carbon assimilation was not reduced compared with that under favorable conditions. The marked increase in triacylglycerols and the variation in the fatty acid profile suggested that triacylglycerols were mainly derived from de novo synthesized acyl groups. In the second stage, the triacylglycerol content continued increasing while the carbohydrate content decreased from 44.0% to 26.3%. These results indicated that the intracellular conversion of carbohydrates to triacylglycerols occurred. Thus, we propose that sustainable carbon assimilation and incremental triacylglycerol production can be achieved by supplying appropriate amounts of nitrogen in medium to protect the photosynthetic process from severe damage using the photosynthetic parameters as indicators. PMID- 25496951 TI - Effect of the addition of calcium hydroxide on the hydrothermal-mechanochemical treatment of Eucalyptus. AB - The effect of Ca(OH)2 addition on optimization of hydrothermal-mechanochemical pretreatment, which combines hydrothermal and milling treatments, was examined. The highest glucose yield of 90% was achieved in the ball-milled specimen previously treated at 170 degrees C in the presence of 20% Ca(OH)2 per substrate weight. The specific surface area of the substrate was closely correlated with glucose yield, and a larger specific surface area was obtained when treating the specimen at 170 degrees C in the presence of Ca(OH)2 compared to treatment at 170 degrees C without Ca(OH)2. Although the Ca(OH)2-treated specimen was relatively unaffected by delignification, the cleavage of the ester bonds between lignin and hemicellulose was confirmed by FT-IR. This suggests that Ca(OH)2 weakens the substrate structure by loosening the bonds between lignin and hemicellulose as the mechanism to increase the specific surface area regardless of the high lignin content, facilitating the fibrillation of fibers with mechanical milling. PMID- 25496950 TI - Isolation of microalgae tolerant to polybrominated diphenyl ethers (PBDEs) from wastewater treatment plants and their removal ability. AB - The present study isolated microalgae with tolerance to polybrominated diphenyl ethers (PBDEs) from wastewater aiming to discover isolates with high removal abilities. Nine isolates, Chlorella (STCh and SICh), Parachlorella (STPa1 and STPa2), Scenedesmus (STSc, TPSc1 and TPSc2), Nitzschia palea (YLBa) and Mychonastes (TPMy), were obtained. Four isolates, SICh, STCh, STPa1 and TPSc1, were very tolerant, and their growth was not affected by DE-71 and BDE-209 mixtures (5:1) at low (6 MUg L(-1)), medium (60 MUg L(-1)) or even high (600 MUg L(-1)) levels for 7 days. The removal of PBDEs by one of the tolerant isolates, SICh, was the highest, with 82-90% removal at the end of 7-days exposure. SICh also accumulated more PBDEs than the other isolates. Bioaccumulation and biotransformation were important for PBDE removal. This is the first study isolated PBDE-tolerant microalgae from wastewater and obtained a Chlorella isolate, SICh, with high tolerance and removal ability. PMID- 25496952 TI - Physiological response of Clostridium ljungdahlii DSM 13528 of ethanol production under different fermentation conditions. AB - In this study, cell growth, gene expression and ethanol production were monitored under different fermentation conditions. Like its heterotrophical ABE-producing relatives, a switch from acidogenesis to solventogenesis of Clostridium ljungdahlii during the autotrophic fermentation with CO/CO2 could be observed, which occurred surprisingly in the late-log phase rather than in the transition phase. The gene expression profiles indicated that aor1, one of the putative aldehyde oxidoreductases in its genome played a critical role in the formation of ethanol, and its transcription could be induced by external acids. Moreover, a low amount of CaCO3 was proved to have positive influences on the cell density and substrate utilization, followed by an increase of over 40% ethanol and 30% acetate formation. PMID- 25496953 TI - Investigating the mechanisms of biochar's removal of lead from solution. AB - The objective of this study was to investigate the relationship between Pb(2+) adsorption and physicochemical properties of biochars produced at different pyrolytic temperatures. Ten biochars were prepared from peanut shell (PS) and Chinese medicine material residue (MR) at 300-600 degrees C. Adsorption kinetics and isotherms were determined, and the untreated and Pb(2+)-loaded biochars were analyzed by FTIR, SEM-EDX and XRD. Functional groups complexation, Pb(2+)-pi interaction and precipitation with minerals jointly contributed to Pb(2+) adsorption on these biochars. New mineral precipitates (e.g., Pb2(SO4)O and Pb4(CO3)2(SO4)(OH)2) formed during Pb(2+) sorption. For high-temperature biochars (?500 degrees C), Pb(2+) sorption via complexation reduced, but the contribution of Pb(2+)-pi interaction was enhanced. Dramatic reduction of Pb(2+) sorption on demineralized biochars indicated the dominant role of minerals. These results are useful for screening effective biochars as engineered sorbents to remove or immobilize Pb(2+) in polluted water and soil. PMID- 25496954 TI - Hydrothermal carbonisation of sewage sludge: effect of process conditions on product characteristics and methane production. AB - Hydrothermal carbonisation of primary sewage sludge was carried out using a batch reactor. The effect of temperature and reaction time on the characteristics of solid (hydrochar), liquid and gas products, and the conditions leading to optimal hydrochar characteristics were investigated. The amount of carbon retained in hydrochars decreased as temperature and time increased with carbon retentions of 64-77% at 140 and 160 degrees C, and 50-62% at 180 and 200 degrees C. Increasing temperature and treatment time increased the energy content of the hydrochar from 17 to 19 MJ/kg but reduced its energy yield from 88% to 68%. Maillard reaction products were identified in the liquid fractions following carbonisations at 180 and 200 degrees C. Theoretical estimates of the methane yields resulting from the anaerobic digestion of the liquid by-products are also presented and optimal reaction conditions to maximise these identified. PMID- 25496955 TI - Combustion behavior of different kinds of torrefied biomass and their blends with lignite. AB - In this study, the combustion behavior of different kinds of torrefied biomass (lignocellulosic and animal wastes) and their blends with lignite was investigated via non-isothermal thermogravimetric method under air atmosphere. For comparison, combustion characteristics of raw biomasses were also determined. Torrefaction process improved the reactivity of char combustion step of biomasses. Characteristic combustion parameters for blends showed non-additivity behavior. It was found that the mixture of torrefied biomasses and lignite at a ratio of 1:1 had a lower ignition and burnout temperature than the coal-only sample. Although no interactions were observed between the lignite and torrefied biomass at initial step of combustion, a certain degree of interaction between the components occurred at char combustion step. Kinetic parameters of combustion were calculated by using the Coats Redfern model. Overall, this study showed that poultry litters can be used as a substitute fuel in coal/biomass co-firing systems by blending with lignocellulosic biomass. PMID- 25496956 TI - Advanced treatment of landfill leachate using anaerobic-aerobic process: organic removal by simultaneous denitritation and methanogenesis and nitrogen removal via nitrite. AB - A novel biological system coupling an UASB and a SBR was established to treat landfill leachate. In order to enhance organics and nitrogen removal, simultaneous denitritation and methanogenesis (SDM) was performed in the UASB. Free ammonia (FA) inhibition on nitrite-oxidizing bacteria (NOB) and process control was used to achieve nitrite pathway in the SBR. Results over 623 days showed that the maximum organic removal rate in the UASB and the maximum ammonium oxidization rate in the SBR was 12.7 kgCOD/m(3) d and 0.96 kgN/m(3) d, respectively. The system achieved COD, TN, and NH4(+)-N removal efficiencies of 93.5%, 99.5%, and 99.1%, respectively. By using FA inhibition coupled with process control, the nitrite pathway was started-up in the SBR at low temperatures (14.0-18.2 degrees C) and was maintained for 142 days at temperatures below 15 degrees C (the lowest level was 9.0 degrees C). The predominant ammonia-oxidizing bacteria (AOB) explains essentially stable nitritation obtained. PMID- 25496957 TI - Strategies for improving water use efficiency of livestock production in rain-fed systems. AB - Livestock production is a major consumer of fresh water, and the influence of livestock production on global fresh water resources is increasing because of the growing demand for livestock products. Increasing water use efficiency of livestock production, therefore, can contribute to the overall water use efficiency of agriculture. Previous studies have reported significant variation in livestock water productivity (LWP) within and among farming systems. Underlying causes of this variation in LWP require further investigation. The objective of this paper was to identify the factors that explain the variation in LWP within and among farming systems in Ethiopia. We quantified LWP for various farms in mixed-crop livestock systems and explored the effect of household demographic characteristics and farm assets on LWP using ANOVA and multilevel mixed-effect linear regression. We focused on water used to cultivate feeds on privately owned agricultural lands. There was a difference in LWP among farming systems and wealth categories. Better-off households followed by medium households had the highest LWP, whereas poor households had the lowest LWP. The variation in LWP among wealth categories could be explained by the differences in the ownership of livestock and availability of family labor. Regression results showed that the age of the household head, the size of the livestock holding and availability of family labor affected LWP positively. The results suggest that water use efficiency could be improved by alleviating resource constraints such as access to farm labor and livestock assets, oxen in particular. PMID- 25496958 TI - The COMT Val/Met polymorphism modulates effects of tDCS on response inhibition. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is increasingly discussed as a new option to support the cognitive rehabilitation in neuropsychiatric disorders. However, the therapeutic impact of tDCS is limited by high inter-individual variability. Genetic factors most likely contribute to this variability by modulating the effects of tDCS. OBJECTIVES: We aimed to investigate the influence of the COMT Val(108/158)Met polymorphism on cathodal tDCS effects on executive functioning. METHODS: Cathodal tDCS was applied to the left dorsolateral prefrontal cortex (dlPFC) during the performance of a parametric Go/No-Go test. RESULTS: We demonstrate an impairing effect of cathodal tDCS to the dlPFC on response inhibition. This effect was only found in individuals homozygous for the Val-allele of the COMT Val(108/158)Met polymorphism. No effects of stimulation on executive functions in Met-allele carriers were detected. CONCLUSION: Our data indicate that i) cathodal, excitability reducing tDCS, interferes with inhibitory cognitive control, ii) the left dlPFC is critically involved in the neuronal network underlying the control of response inhibition, and iii) the COMT Val(108/158)Met polymorphism modulates the impact of cathodal tDCS on inhibitory control. Together with our previous finding that anodal tDCS selectively impairs set-shifting abilities in COMT Met/Met homozygous individuals, these results indicate that genetic factors modulate effects of tDCS on cognitive performance. Therefore, future tDCS research should account for genetic variability in the design and analysis of neurocognitive as well as therapeutic applications to reduce the variability of results and facilitate individualized neurostimulation approaches. PMID- 25496959 TI - [2013 Guidelines ACC/AHA cardiovascular risk. Incomplete evidence and failed attempt at simplification]. AB - After almost a decade, finally Guidelines for the management of hypercholesterolemia in adults by the AHA/ACC were published. The substantial change in the paradigm of this new recommendation is the treatment decision basically statin, based on a recalculation of cardiovascular risk. Four groups were identified and based on them different statins indication, according to the power applied. As is apparent, have been used only randomized clinical trials (RCT) as the sole basis for the drafting of these new guidelines. Two basic issues are reviewed and revised in the following article: leaving aside other types of evidence to generate the recommendation and on the other hand the attempt to simplify the interpretation and management of this condition. We stress the need for any recommendation to clinical reasoning to interpret different scenarios involved in each patient. PMID- 25496960 TI - Lung adenocarcinoma harboring concomitant EGFR mutation and EML4-ALK fusion that benefits from three kinds of tyrosine kinase inhibitors: a case report and literature review. PMID- 25496961 TI - Frontal association cortex is engaged in stimulus integration during associative learning. AB - The frontal association cortex (FrA) is implicated in higher brain function. Aberrant FrA activity is likely to be involved in dementia pathology. However, the functional circuits both within the FrA and with other regions are unclear. A recent study showed that inactivation of the FrA impairs memory consolidation of an auditory fear conditioning in young mice. In addition, dendritic spine remodeling of FrA neurons is sensitive to paired sensory stimuli that produce associative memory. These findings suggest that the FrA is engaged in neural processes critical to associative learning. Here we characterize stimulus integration in the mouse FrA during associative learning. We experimentally separated contextual fear conditioning into context exposure and shock, and found that memory formation requires protein synthesis associated with both context exposure and shock in the FrA. Both context exposure and shock trigger Arc, an activity-dependent immediate-early gene, expression in the FrA, and a subset of FrA neurons was dually activated by both stimuli. In addition, we found that the FrA receives projections from the perirhinal (PRh) and insular (IC) cortices and basolateral amygdala (BLA), which are implicated in context and shock encoding. PRh and IC neurons projecting to the FrA were activated by context exposure and shock, respectively. Arc expression in the FrA associated with context exposure and shock depended on PRh activity and both IC and BLA activities, respectively. These findings indicate that the FrA is engaged in stimulus integration and contributes to memory formation in associative learning. PMID- 25496962 TI - A dwarf male reversal in bone-eating worms. AB - Darwin hypothesized that sexes in a species should be similar unless sexual selection, fecundity selection, or resource partitioning has driven them apart. Male dwarfism has evolved multiple times in a range of animals, raising questions about factors that drive such extreme size dimorphism. Ghiselin noted that dwarf males are more common among smaller marine animals, and especially among sedentary and sessile species living at low densities, where mates are difficult to find, or in deep-sea environments with limited energy sources. These benefits of male dwarfism apply well to Osedax (Annelida: Siboglinidae), bone-eating marine worms. Osedax males, notable for extreme sexual size dimorphism (SSD), are developmentally arrested larvae that produce sperm from yolk reserves. Harems of dwarf males reside in the lumen of the tube surrounding a female. Herein, we describe Osedax priapus n. sp., a species that deviates remarkably by producing males that anchor into, and feed on, bone via symbiont-containing "roots," just like female Osedax. Phylogenetic analyses revealed O. priapus n. sp. as a derived species, and the absence of dwarf males represents a character reversal for this genus. Some dwarf male features are retained due to functional and morphological constraints. Since O. priapus n. sp. males are anchored in bone, they possess an extensible trunk that allows them to roam across the bone to contact and inseminate females. Evolutionary and ecological implications of a loss of male dwarfism are discussed. PMID- 25496963 TI - Increased affluence explains the emergence of ascetic wisdoms and moralizing religions. AB - BACKGROUND: Between roughly 500 BCE and 300 BCE, three distinct regions, the Yangtze and Yellow River Valleys, the Eastern Mediterranean, and the Ganges Valley, saw the emergence of highly similar religious traditions with an unprecedented emphasis on self-discipline and asceticism and with "otherworldly," often moralizing, doctrines, including Buddhism, Jainism, Brahmanism, Daoism, Second Temple Judaism, and Stoicism, with later offshoots, such as Christianity, Manichaeism, and Islam. This cultural convergence, often called the "Axial Age," presents a puzzle: why did this emerge at the same time as distinct moralizing religions, with highly similar features in different civilizations? The puzzle may be solved by quantitative historical evidence that demonstrates an exceptional uptake in energy capture (a proxy for general prosperity) just before the Axial Age in these three regions. RESULTS: Statistical modeling confirms that economic development, not political complexity or population size, accounts for the timing of the Axial Age. CONCLUSIONS: We discussed several possible causal pathways, including the development of literacy and urban life, and put forward the idea, inspired by life history theory, that absolute affluence would have impacted human motivation and reward systems, nudging people away from short-term strategies (resource acquisition and coercive interactions) and promoting long term strategies (self-control techniques and cooperative interactions). PMID- 25496964 TI - Neural control of wing coordination in flies. AB - At the onset of each flight bout in flies, neural circuits in the CNS must rapidly integrate multimodal sensory stimuli and synchronously engage hinges of the left and right wings for coordinated wing movements. Whereas anatomical and physiological investigations of flight have been conducted on larger flies, molecular genetic studies in Drosophila have helped identify neurons that mediate various levels of flight control. However, neurons that might mediate bilateral coordination of wing movements to precisely synchronize left and right wing engagement at flight onset and maintain their movement in perfect coordination at rapid frequencies during flight maneuvers remain largely unexplored. Wing coordination could be directly modulated via bilateral sensory inputs to motoneurons of steering muscles and/or through central interneurons. Using a Ca(2+)-activity-based GFP reporter, we identified three flight-activated central dopaminergic interneurons in the ventral ganglion, which connect to and activate motoneurons that innervate a pair of direct-steering flight muscles. The activation of these newly identified dopaminergic interneurons is context specific. Whereas bilateral wing engagement for flight requires these neurons, they do not control unilateral wing extension during courtship. Thus, independent central circuits function in the context of different natural behaviors to control the motor circuit for Drosophila wing movement. PMID- 25496966 TI - Amygdala/hippocampal activation during the menstrual cycle: evidence for lateralization of effects across different tasks. AB - Variations in hormonal levels between the follicular and the luteal phase of the female menstrual cycle are associated with variations in emotional and cognitive aspects of behavior. The functional neural correlates of these cycle-related variations have been explored in previous neuroimaging studies. We summarize the existing findings of functional magnetic resonance imaging (fMRI) studies to identify regions of increased brain activation in the follicular or luteal phases of the cycle that are concordant across studies. Eleven fMRI studies reporting coordinates of higher brain activation in one of the two main cycle phases were included in the analysis. Activation likelihood estimation was used to determine concordance. We found higher left amygdala/hippocampal activation during the luteal phase and higher right amygdala/hippocampal activation during the follicular phase. Additionally, the anterior cingulate cortex and temporal pole showed increased activation during the luteal phase and the superior temporal gyrus during the follicular phase. The observed pattern of cycle-dependent functional lateralization of the amygdala/hippocampal complex is consistent with findings on cycle-related behavioral variations and on sex differences in lateralization of activity in amygdala and hippocampus. PMID- 25496965 TI - Methylmercury exposure during early Xenopus laevis development affects cell proliferation and death but not neural progenitor specification. AB - Methylmercury (MeHg) is a widespread environmental toxin that preferentially and adversely affects developing organisms. To investigate the impact of MeHg toxicity on the formation of the vertebrate nervous system at physiologically relevant concentrations, we designed a graded phenotype scale for evaluating Xenopus laevis embryos exposed to MeHg in solution. Embryos displayed a range of abnormalities in response to MeHg, particularly in brain development, which is influenced by both MeHg concentration and the number of embryos per ml of exposure solution. A TC50 of ~50MUg/l and LC50 of ~100MUg/l were found when maintaining embryos at a density of one per ml, and both increased with increasing embryo density. In situ hybridization and microarray analysis showed no significant change in expression of early neural patterning genes including sox2, en2, or delta; however a noticeable decrease was observed in the terminal neural differentiation genes GAD and xGAT, but not xVGlut. PCNA, a marker for proliferating cells, was negatively correlated with MeHg dose, with a significant reduction in cell number in the forebrain and spinal cord of exposed embryos by tadpole stages. Conversely, the number of apoptotic cells in neural regions detected by a TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay was significantly increased. These results provide evidence that disruption of embryonic neural development by MeHg may not be directly due to a loss of neural progenitor specification and gene transcription, but to a more general decrease in cell proliferation and increase in cell death throughout the developing nervous system. PMID- 25496967 TI - Musicogenic and spontaneous seizures: EEG analyses with hippocampal depth electrodes. AB - Musicogenic seizure is classified as a rare form of complex reflex seizures. We present a patient with musicogenic seizures from whom invasive recordings were obtained using subdural arrays, as well as hippocampal depth electrodes. Interestingly, this patient had both spontaneous seizures and musicogenic seizures, and they originated from different hippocampi. Due to bilateral independent musicogenic seizures and spontaneous seizures, our patient was not eligible for surgery, but vagal nerve stimulation treatment was almost successful. [Published with video sequence]. PMID- 25496968 TI - Polarization of macrophages induced by Toxoplasma gondii and its impact on abnormal pregnancy in rats. AB - Toxoplasma gondii infection is the leading cause of fetal intrauterine growth retardation among the five kinds of pathogens termed as TORCH, including Toxoplasma, Rubella virus, Cytomegalo virus, herpes virus and others during pregnancy. Pathogens infect the fetus through the placenta. T. gondii infection may result in congenital toxoplasmosis, miscarriage, stillbirth, and preemie, and increase pregnancy complications. Adaptive immune response induced by T. gondii infection stimulates T cells and macrophages to produce high levels of cytokines. Physiologically, the microenvironment of pregnancy was Th2-dominant. Here we set up a pregnant Sprague-Dawley rat model, and reported the polarization of macrophages induced by genotype Chinese 1 strain (Wh6) of Toxoplasma, and its adverse impact on pregnancy. The results showed that Wh6 infection pre- or in gestation both led to abnormal pregnancy outcomes. Peritoneal macrophages in pre gestation infection were polarized toward classically activated macrophages (M1), while in-gestation infection drove macrophages to polarize toward M2 activation. The Th2-dominant immune response in pregnant rat somewhat inhibits the excessive bias of the macrophages toward M1, and partially, toward M2. Infection of pre- and in-gestation may alter the physiological immune microenvironment in pregnant rats, giving rise to abnormal pregnancy outcomes. PMID- 25496970 TI - In vivo effect of insulin on the hormone production of immune cells in mice - gender differences. AB - The immune cells of rat and man synthesize, store and secrete hormones, characteristic to the endocrine glands. In the present experiments female and male CD1 mice were treated with 10 IU/kg insulin sc. (the controls with normal saline) and after 30 min peritoneal fluid was gained. The cells of the peritoneal fluid (lymphocytes and the monocyte-granulocyte group) were studied by immunocytochemical flow-cytometry to adrenocorticotropic hormone (ACTH), triiodothyronine (T3), histamine and serotonin content. In the female mice each hormone level was significantly lower in the insulin-treated animals, except histamine in the monocyte-granulocyte group. In the insulin-treated male animals, the hormone levels were similar to the control. The results 1) support the previously hypothesized hormonal network in the immune system, 2) justify that the insulin effect is not species dependent and 3) call attention to the sex, species and organ differences in the response. PMID- 25496971 TI - Virulence factors, antimicrobial susceptibility and molecular characterization of Streptococcus agalactiae isolated from pregnant women. AB - Forty-one Streptococcus agalactiae isolates collected from pregnant women at 35 37 weeks of gestation were analysed for their capsular types, antimicrobial resistance determinants, distribution of virulence factors and genetic relatedness using PCR and multiplex PCR. Capsular type III was predominant (65.8%), followed by capsular type II (14.6%), Ib (7.3%), and V(4.9%). All isolates were susceptible to penicillin, vancomycin, linezolid and quinupristin dalfopristin. Resistance to tetracycline, erythromycin and clindamycin were found in 97.6%, 24.4%, and 14.6% of isolates, respectively. The most common antimicrobial resistance gene was tetM found in 97.6% of the isolates followed by ermTR and ermB found in 12% and 7.3% of isolates, respectively. The most common virulence gene was hly (100%), followed by scpB (97.6%), bca (97.6%), rib (53.65%) and bac (4.9%). The insertion sequence IS1548 was found in 63.4% of isolates. By multi locus variable number of tandem repeat analysis (MLVA) typing, 30 different allelic profiles or MLVA types (MTs) were identified. The most frequent was the MT1 (5/41, 12.2%) and followed by MT2 (4/41, 9.75%). Our data revealed that population structure of these isolates is highly diverse and indicates different MLVA types. PMID- 25496972 TI - Antimicrobial susceptibility and genotyping analysis of Hungarian Neisseria gonorrhoeae strains in 2013. AB - Emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae is a major public health concern worldwide. The current study aims to determine the antimicrobial resistance in N. gonorrhoeae and associated molecular typing to enhance gonococcal antimicrobial surveillance in Hungary. In the National N. gonorrhoeae Reference Laboratory of Hungary 187 N. gonorrhoeae infections were detected in 2013, antibiograms were determined for all the isolated strains, and 52 (one index strain from every sexually contact related group) of them were also analysed by the N. gonorrhoeae multi-antigen sequence typing (NG-MAST) method. Twenty-two different NG-MAST sequence types (STs) were identified, of which 8 STs had not been previously described. In Hungary, the highly diversified gonococcal population displayed high resistance to penicillin, ciprofloxacin and tetracycline (the antimicrobials previously recommended for gonorrhoea treatment). Resistance to the currently recommended extended spectrum cephalosporines were rare: only two of the expected strains, an ST 1407 and an ST 210, had cefixime MIC above the resistance breakpoint. By the revision of our National Treatment Guideline, it must be considered, that the azithromycin resistance is about 60% among the four most frequently isolated STs in Hungary. PMID- 25496973 TI - Thiolated pyrimidine nucleotides may interfere thiol groups concentrated at lipid rafts of HIV-1 infected cells. AB - Upon HIV infection, cells become activated and cell surface thiols are present in increased number. Earlier we demonstrated in vitro anti-HIV effect of thiolated pyrimidine nucleotide UD29, which interferes thiol function. To further analyse the redox processes required for HIV-1 entry and infection, toxicity assays were performed using HIV-1 infected monolayer HeLaCD4-LTR/ beta-gal cells and suspension H9 T cells treated with several thiolated nucleotide derivatives of UD29. Selective cytotoxicity of thiolated pyrimidines on HIV-1 infected cells were observed. Results indicate that thiolated pyrimidine derivates may interfere with -SH (thiol) groups concentrated in lipid rafts of cell membrane and interacts HIV-1 infected (activated) cells resulting in a selective cytotoxicity of HIV-1 infected cells, and reducing HIV-1 entry. PMID- 25496975 TI - Dose-specific transcriptional responses in thyroid tissue in mice after (131)I administration. AB - INTRODUCTION: In the present investigation, microarray analysis was used to monitor transcriptional activity in thyroids in mice 24 h after (131)I exposure. The aims of this study were to 1) assess the transcriptional patterns associated with (131)I exposure in normal mouse thyroid tissue and 2) propose biomarkers for (131)I exposure of the thyroid. METHODS: Adult BALB/c nude mice were i.v. injected with 13, 130 or 260 kBq of (131)I and killed 24h after injection (absorbed dose to thyroid: 0.85, 8.5, or 17 Gy). Mock-treated mice were used as controls. Total RNA was extracted from thyroids and processed using the Illumina platform. RESULTS: In total, 497, 546, and 90 transcripts were regulated (fold change >=1.5) in the thyroid after 0.85, 8.5, and 17 Gy, respectively. These were involved in several biological functions, e.g. oxygen access, inflammation and immune response, and apoptosis/anti-apoptosis. Approximately 50% of the involved transcripts at each absorbed dose level were dose-specific, and 18 transcripts were commonly detected at all absorbed dose levels. The Agpat9, Plau, Prf1, and S100a8 gene expression displayed a monotone decrease in regulation with absorbed dose, and further studies need to be performed to evaluate if they may be useful as dose-related biomarkers for 131I exposure. CONCLUSION: Distinct and substantial differences in gene expression and affected biological functions were detected at the different absorbed dose levels. The transcriptional profiles were specific for the different absorbed dose levels. We propose that the Agpat9, Plau, Prf1, and S100a8 genes might be novel potential absorbed dose-related biomarkers to (131)I exposure of thyroid. ADVANCES IN KNOWLEDGE: During the recent years, genomic techniques have been developed; however, they have not been fully utilized in nuclear medicine and radiation biology. We have used RNA microarrays to investigate genome-wide transcriptional regulations in thyroid tissue in mice after low, intermediate, and high absorbed doses from (131)I exposure in vivo. Using this approach, we have identified novel biological responses and potential absorbed dose-related biomarkers to (131)I exposure. Our research shows the importance of embracing technological advances and multi disciplinary collaboration in order to apply them in radiation therapy, nuclear medicine, and radiation biology. IMPLICATIONS ON PATIENT CARE: This work may contribute with new knowledge of potential normal tissue effects or complications that may occur after exposure to ionizing radiation in diagnostic and therapeutic nuclear medicine, and due to radioactive fallout or accident with radionuclide spread. PMID- 25496976 TI - Results from the French National Esophageal Atresia register: one-year outcome. AB - BACKGROUND: The aim of the present national prospective population-based study was to assess the early morbidity of esophageal atresia (EA). METHODS: All 38 multidisciplinary French centers that care for patients with EA returned a specific questionnaire about the 1-year outcome for each patient. This information was centralized, checked, and entered into a database. RESULTS: From the total population of 307 EA patients born in 2008 and 2009, data about the 1 year outcome were obtained from 301 (98%) patients, of whom 4% were lost to follow-up and 5% died. Medical complications occurred in 34% of the patients: anastomotic leaks (8%), recurrent tracheoesophageal fistula (4%), and anastomotic stenosis (22%); all of the latter group needed dilation (median, 2 dilations/patient). A new hospitalization was required for 59% of patients (2.5 hospitalizations/patient) for digestive (52%) or respiratory (48%) reasons. Twelve percent of patients required antireflux surgery at a median age of 164 days (range, 33-398 days), and 1% underwent an aortopexy for severe tracheomalacia. The weight/age Z-score was -0.8 (range, -5.5 to 3.7 months) at 12 months. Fifteen percent of patients were undernourished at 12 months of age, whereas 37% presented with respiratory symptoms and 15% had dysphagia at the last follow-up. Significant independent factors associated with medical complications were anastomotic esophageal tension (p = .0009) and presence of a gastrostomy (p = .0002); exclusive oral feeding at discharge was associated with a decreased risk of complications (p = .007). CONCLUSIONS: Digestive and respiratory morbidities remain frequent during the first year of life and are associated with difficult anastomosis and lack of full oral feeding. PMID- 25496977 TI - Behavioral in-effectiveness of high frequency electromagnetic field in mice. AB - The present investigation was carried out with an objective to study the influence of high frequency electromagnetic field (HF-EMF) on anxiety, obsessive compulsive disorder (OCD) and depression-like behavior. For exposure to HF-EMF, non-magnetic material was used to fabricate the housing. Mice were exposed to HF EMF (2.45GHz), 60min/day for 7 or 30 or 60 or 90 or 120days. The exposure was carried out by switching-on inbuilt class-I BLUETOOTH device that operates on 2.45GHz frequency in file transfer mode at a peak density of 100mW. Mice were subjected to the assessment of anxiety, OCD and depression-like behavior for 7 or 30 or 60 or 90 or 120days of exposure. The anxiety-like behavior was assessed by elevated plus maze, open field test and social interaction test. OCD-like behavior was assessed by marble burying behavior, whereas depression-like behavior was assessed by forced swim test and tail suspension test. The present experiment demonstrates that up to 120days of exposure to HF-EMF does not produce anxiety, OCD and depression-like behavior in mice. PMID- 25496978 TI - Immobility behavior during the forced swim test correlates with BNDF levels in the frontal cortex, but not with cognitive impairments. AB - The forced swim test (FST) is widely used to evaluate the antidepressant-like activity of compounds and is sensitive to stimuli that cause depression-like behaviors in rodents. The immobility behavior observed during the test has been considered to represent behavioral despair. In addition, some studies suggest that the FST impairs rats' performance on cognitive tests, but these findings have rarely been explored. Thus, we investigated the effects of the FST on behavioral tests related to neuropsychiatric diseases that involve different cognitive components: novel object recognition (NOR), the object location test (OLT) and prepulse inhibition (PPI). Brain-derived neurotrophic factor (BDNF) levels in the frontal cortex and hippocampus were evaluated. The rats were forced to swim twice (15-min session followed by a 5-min session 24h later) and underwent cognitive tests 24h after the last swimming exposure. The FST impaired the rats' performance on the OLT and reduced the PPI and acoustic startle responses, whereas the NOR was not affected. The cognitive impairments were not correlated with an immobility behavior profile, but a significant negative correlation between the frontal BDNF levels and immobility behavior was identified. These findings suggest a protective role of BDNF against behavioral despair and demonstrate a deleterious effect of the FST on spatial memory and pre attentive processes, which point to the FST as a tool to induce cognitive impairments analogous to those observed in depression and in other neuropsychiatric disorders. PMID- 25496979 TI - Paternal line multigenerational passage of altered risk assessment behavior in female but not male rat offspring of mothers fed a low protein diet. AB - Maternal low protein (MLP) diets in pregnancy and lactation impair offspring brain development and modify offspring behavior. We hypothesized multigenerational passage of altered behavioral outcomes as has been demonstrated following other developmental programming challenges. We investigated potential multigenerational effects of MLP in rat pregnancy and/or lactation on offspring risk assessment behavior. Founder generation mothers (F0) ate 20% casein (C) or restricted (R) 10% casein diet, providing four groups: CC, RR, CR, and RC (first letter pregnancy, second letter lactation diet) to evaluate offspring (F1) effects influenced by MLP in F0. On postnatal day (PND 250), F1 males were mated to non-colony siblings producing F2. On PND 90, F2 females (in diestrous) and F2 males were tested in the elevated plus maze (EPM) and open field. Corticosterone was measured at PND 110. Female but not male CR and RC F2 made more entries and spent more time in EPM open arms than CC females. Overall activity was unchanged as observed in male F1 fathers. There were no open field differences in F2 of either sex, indicating that multigenerational MLP effects are due to altered risk assessment, not locomotion. MLP in pregnancy reduced F1 male and F2 female corticosterone. We conclude that MLP in pregnancy and/or lactation increases the innate tendency to explore novel environments in F2 females via the paternal linage, suggesting lower levels of caution and/or higher impulsiveness to explore unknown spaces. Further studies will be necessary to identify the epigenetic modifications in the germ line through the paternal linage. PMID- 25496980 TI - Abnormal regional homogeneity in young adult suicide attempters with no diagnosable psychiatric disorder: a resting state functional magnetic imaging study. AB - Many young adults who attempt suicide have no discernible mental illness, suggesting an etiology distinct from other psychiatric disorders. Neurological anomalies associated with a history of suicidal behavior may predict future risk. In the present study, we explored changes in neural circuit organization associated with suicidal behavior by comparing local synchronization of resting state functional magnetic resonance imaging signals in suicide attempters without a psychiatric diagnosis (SA group, 19.84+/-1.61 years, n=19) with those in healthy controls (HC group, 20.30+/-1.72 years, n=20) using regional homogeneity (ReHo) analysis. The SA group exhibited significantly lower mean ReHo in the left (L) fusiform and supraorbital inferior frontal gyri, L hippocampus, bilateral parahippocampal and middle frontal gyri, right (R) angular gyrus, and cerebellar lobules RVIII, RII, and LVI compared with the HC group. Conversely, in the SA group, ReHo was higher in the R supraorbital middle frontal gyrus, R inferior parietal lobe, and L precuneus. The SA group also had significantly higher total Barratt Impulsiveness Scale scores compared with the HC group. Local functional connectivity is altered in multiple regions of the cerebral cortex, limbic system, and cerebellum of suicidal young adults. Elucidating the functional deficits associated with these ReHo changes may clarify the pathophysiological mechanisms of suicidal behavior and assist in identifying high-risk individuals. PMID- 25496981 TI - First-line therapy in atypical hemolytic uremic syndrome: consideration on infants with a poor prognosis. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare and heterogeneous disorder. The first line treatment of aHUS is plasma therapy, but in the past few years, the recommendations have changed greatly with the advent of eculizumab, a humanized monoclonal anti C5-antibody. Although recent recommendations suggest using it as a primary treatment for aHUS, important questions have arisen about the necessity of immediate use of eculizumab in all cases. We aimed to draw attention to a specific subgroup of aHUS patients with rapid disease progression and high mortality, in whom plasma therapy may not be feasible. METHODS: We present three pediatric patients of acute complement-mediated HUS with a fatal outcome. Classical and alternative complement pathway activity, levels of complement factors C3, C4, H, B and I, as well as of anti-factor H autoantibody and of ADAMTS13 activity were determined. The coding regions of CFH, CFI, CD46, THBD, CFB and C3 genes were sequenced and the copy number of CFI, CD46, CFH and related genes were analyzed. RESULTS: We found severe activation and consumption of complement components in these patients, furthermore, in one patient we identified a previously not reported mutation in CFH (Ser722Stop), supporting the diagnosis of complement-mediated HUS. These patients were not responsive to the FFP therapy, and all cases had fatal outcome. CONCLUSION: Taking the heterogeneity and the variable prognosis of atypical HUS into account, we suggest that the immediate use of eculizumab should be considered as first-line therapy in certain small children with complement dysregulation. PMID- 25496982 TI - Synergistic antiarrhythmic effect of combining inhibition of Ca2+-activated K+ (SK) channels and voltage-gated Na+ channels in an isolated heart model of atrial fibrillation. AB - BACKGROUND: Application of antiarrhythmic compounds is limited by both proarrhythmic and extracardiac toxicities, as well as incomplete antiarrhythmic efficacy. An improved antiarrhythmic potential may be obtained by combining antiarrhythmic drugs with different modes of action, and a reduction of the adverse effect profile could be an additional advantage if compound concentrations could be reduced. OBJECTIVE: The purpose of this study was to test the hypothesis that combined inhibition of Ca(2+)-activated K(+) channels (SK channels) and voltage-gated Na(+) channels, in concentrations that would be subefficacious as monotherapy, may prevent atrial fibrillation (AF) and have reduced proarrhythmic potential in the ventricles. METHODS: Subefficacious concentrations of ranolazine, flecainide, and lidocaine were tested alone or in combination with the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol 2-amine (ICA) in a Langendorff-perfused guinea pig heart model in which AF was induced after acetylcholine application and burst pacing. RESULTS: AF duration was reduced when both flecainide and ranolazine were combined with ICA in doses that did not reduce AF as monotherapy. At higher concentrations, both flecainide and ranolazine revealed proarrhythmic properties. CONCLUSION: A synergistic effect in AF treatment was obtained by combining low concentrations of SK and Na(+) channel blockers. PMID- 25496983 TI - Further refinement of torsades de pointes. PMID- 25496984 TI - Preclinical evaluation of implantable cardioverter-defibrillator developed for magnetic resonance imaging use. AB - BACKGROUND: Many patients with an implantable cardioverter-defibrillator (ICD) have indications for magnetic resonance imaging (MRI). However, MRI is generally contraindicated in ICD patients because of potential risks from hazardous interactions between the MRI and ICD system. OBJECTIVE: The purpose of this study was to use preclinical computer modeling, animal studies, and bench and scanner testing to demonstrate the safety of an ICD system developed for 1.5-T whole-body MRI. METHODS: MRI hazards were assessed and mitigated using multiple approaches: design decisions to increase safety and reliability, modeling and simulation to quantify clinical MRI exposure levels, animal studies to quantify the physiologic effects of MRI exposure, and bench testing to evaluate safety margin. RESULTS: Modeling estimated the incidence of a chronic change in pacing capture threshold >0.5 V and 1.0 V to be less than 1 in 160,000 and less than 1 in 1,000,000 cases, respectively. Modeling also estimated the incidence of unintended cardiac stimulation to occur in less than 1 in 1,000,000 cases. Animal studies demonstrated no delay in ventricular fibrillation detection and no reduction in ventricular fibrillation amplitude at clinical MRI exposure levels, even with multiple exposures. Bench and scanner testing demonstrated performance and safety against all other MRI-induced hazards. CONCLUSION: A preclinical strategy that includes comprehensive computer modeling, animal studies, and bench and scanner testing predicts that an ICD system developed for the magnetic resonance environment is safe and poses very low risks when exposed to 1.5-T normal operating mode whole-body MRI. PMID- 25496985 TI - Efficacy and safety of flecainide for ventricular arrhythmias in patients with Andersen-Tawil syndrome with KCNJ2 mutations. AB - BACKGROUND: Andersen-Tawil syndrome (ATS) is an autosomal dominant genetic or sporadic disorder characterized by ventricular arrhythmias (VAs), periodic paralyses, and dysmorphic features. The optimal pharmacological treatment of VAs in patients with ATS remains unknown. OBJECTIVE: We evaluated the efficacy and safety of flecainide for VAs in patients with ATS with KCNJ2 mutations. METHODS: Ten ATS probands (7 females; mean age 27 +/- 11 years) were enrolled from 6 institutions. All of them had bidirectional VAs in spite of treatment with beta blockers (n = 6), but none of them had either aborted cardiac arrest or family history of sudden cardiac death. Twenty-four-hour Holter recording and treadmill exercise test (TMT) were performed before (baseline) and after oral flecainide therapy (150 +/- 46 mg/d). RESULTS: Twenty-four-hour Holter recordings demonstrated that oral flecainide treatment significantly reduced the total number of VAs (from 38,407 +/- 19,956 to 11,196 +/- 14,773 per day; P = .003) and the number of the longest ventricular salvos (23 +/- 19 to 5 +/- 5; P = .01). At baseline, TMT induced nonsustained ventricular tachycardia (n = 7) or couplets of premature ventricular complex (n = 2); treatment with flecainide completely (n = 7) or partially (n = 2) suppressed these exercise-induced VAs (P = .008). In contrast, the QRS duration, QT interval, and U-wave amplitude of the electrocardiogram were not altered by flecainide therapy. During a mean follow-up of 23 +/- 11 months, no patients developed syncope or cardiac arrest after oral flecainide treatment. CONCLUSION: This multicenter study suggests that oral flecainide therapy is an effective and safe means of suppressing VAs in patients with ATS with KCNJ2 mutations, though the U-wave amplitude remained unchanged by flecainide. PMID- 25496986 TI - The effect of supervised exercise therapy on physical activity and ambulatory activities in patients with intermittent claudication. AB - OBJECTIVE/BACKGROUND: Intermittent claudication (IC) is associated with a reduction in physical activity (PA) and a more rapid functional decline leading to a higher mortality rate compared with healthy individuals. Supervised exercise therapy (SET) is known to increase the walking capacity of patients with IC. However, it is unclear whether SET increases PA. The aim of this study was to investigate the effect of SET on PA levels and ambulatory activities in patients with IC. METHODS: Patients newly diagnosed with IC were requested to wear an activity monitor 1 week prior to and 1 week immediately after 3 months of SET. The primary outcome was the percentage of patients meeting the minimum recommendations of PA (American College of Sports Medicine [ACSM]/American Heart Association [AHA] recommendation for public health of >= 67 metabolic equivalents [METs]/min/day, in bouts of >= 10 min) at baseline and after 3 months of SET. Additionally, daily PA level (METs/min), duration of ambulatory activities, daily number of steps, pain free walking distance (PFWD), maximal walking distance (MWD), and Short Form Health Survey (SF-36) health surveys were compared before and after SET. RESULTS: Data from 41 participants were available for analysis. A higher number of participants met the ACSM minimum recommendation for PA at the 3 month follow up (baseline: 43%; 3 months: 63%; p = .003). Despite significant increases in PFWD (baseline: 210 m; 3 months: 390 m; p = .001), MWD (baseline: 373 m; 3 months: 555 m; p = .002) and physical functioning score (SF-36) following SET, no increase in the mean daily PA level was found (395 +/- 220 vs. 411 +/- 228 METs/min; p = .43). Furthermore, the total number of steps and time spent in ambulatory activities did not change following SET. CONCLUSION: Three months of SET for IC leads to more patients meeting the ACSM/AHA public health minimum recommendations for PA. Assessment of PA could be incorporated as an outcome parameter in future research comparing different treatment modalities for peripheral arterial disease. PMID- 25496987 TI - Fitting perception in and to cognition. AB - Perceptual modules adapt at evolutionary, lifelong, and moment-to-moment temporal scales to better serve the informational needs of cognizers. Perceptual learning is a powerful way for an individual to become tuned to frequently recurring patterns in its specific local environment that are pertinent to its goals without requiring costly executive control resources to be deployed. Mechanisms like predictive coding, categorical perception, and action-informed vision allow our perceptual systems to interface well with cognition by generating perceptual outputs that are systematically guided by how they will be used. In classic conceptions of perceptual modules, people have access to the modules' outputs but no ability to adjust their internal workings. However, humans routinely and strategically alter their perceptual systems via training regimes that have predictable and specific outcomes. In fact, employing a combination of strategic and automatic devices for adapting perception is one of the most promising approaches to improving cognition. PMID- 25496989 TI - Splitting of IVP bovine blastocyst affects morphology and gene expression of resulting demi-embryos during in vitro culture and in vivo elongation. AB - Embryo splitting might be used to increase offspring yield and for molecular analysis of embryo competence. How splitting affects developmental potential of embryos is unknown. This research aimed to study the effect of bovine blastocyst splitting on morphological and gene expression homogeneity of demi-embryos and on embryo competence during elongation. Grade I bovine blastocyst produced in vitro were split into halves and distributed in nine groups (3 * 3 setting according to age and stage before splitting; age: days 7-9; stage: early, expanded and hatched blastocysts). Homogeneity and survival rate in vitro after splitting (12 h, days 10 and 13) and the effect of splitting on embryo development at elongation after embryo transfer (day 17) were assessed morphologically and by RT-qPCR. The genes analysed were OCT4, SOX2, NANOG, CDX2, TP1, TKDP1, EOMES, and BAX. Approximately 90% of split embryos had a well conserved defined inner cell mass (ICM), 70% of the halves had similar size with no differences in gene expression 12 h after splitting. Split embryos cultured further conserved normal and comparable morphology at day 10 of development; this situation changes at day 13 when embryo morphology and gene expression differed markedly among demi-embryos. Split and non-split blastocysts were transferred to recipient cows and were recovered at day 17. Fifty per cent of non-split embryos were larger than 100 mm (33% for split embryos). OCT4, SOX2, TP1 and EOMES levels were down-regulated in elongated embryos derived from split blastocysts. In conclusion, splitting day-8 blastocysts yields homogenous demi-embryos in terms of developmental capability and gene expression, but the initiation of the filamentous stage seems to be affected by the splitting. PMID- 25496988 TI - How cognitive theory guides neuroscience. AB - The field of cognitive science studies latent, unobservable cognitive processes that generate observable behaviors. Similarly, cognitive neuroscience attempts to link latent cognitive processes with the neural mechanisms that generate them. Although neural processes are partially observable (with imaging and electrophysiology), it would be a mistake to 'skip' the cognitive level and pursue a purely neuroscientific enterprise to studying behavior. In fact, virtually all of the major advances in understanding the neural basis of behavior over the last century have relied fundamentally on principles of cognition for guiding the appropriate measurements, manipulations, tasks, and interpretations. We provide several examples from the domains of episodic memory, working memory and cognitive control, and decision making in which cognitive theorizing and prior experimentation has been essential in guiding neuroscientific investigations and discoveries. PMID- 25496990 TI - Sphincter saving and abdomino-perineal resections following neoadjuvant chemoradiation in locally advanced low rectal cancer. AB - BACKGROUND: The improvement in surgical techniques alongside neoadjuvant chemoradiation enabled more patients with low rectal cancer to have sphincter preservation. STUDY AIM: To compare the oncologic and functional outcome in patients with locally advanced low rectal cancer treated by neoadjuvant chemoradiation followed by sphincter saving resection (SSR) against those who underwent abdomino-perineal resection (APR). PATIENTS AND METHODS: A total of 111 patients with low rectal cancer were included in the study. Sixty-one consented patients who prospectively underwent SSR, from Jan 2008 to Jan 2013, and a retrospective group, formed of 50 patients, selected from cases seen at NCI, with comparable demographic, clinical and pathologic criteria, who underwent APR from Jan 2003 to Jan 2008. All lesions were <5 cm from anal verge. All 111 patients received preoperative chemoradiation and total mesorectal excision. RESULTS: All tumors were located at a median of 3.6 cm (range 2.5-4.5 cm) for the SSR group, and 3.5 cm (range 2.5-4.6 cm) for the APR group, from the anal verge. The median follow-up was 34 months (range 1-60 months) for both groups. The difference in disease recurrence and OS between the APR and SSR groups were both statistically insignificant. CONCLUSION: In low rectal cancer, the sphincter preservation appears to have nearly the same oncologic outcome compared to APR, this might be attributed to the small sample size and short follow up period. However, patients with sphincter preservation have certainly demonstrated an indisputable better functional outcome, in terms of stoma avoidance and adequate continence. PMID- 25496992 TI - Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is an invasive cancer with a high rate of recurrence and metastasis. Agents with anti-proliferative as well as anti metastatic activity will be ideal for effective treatment. Here, we demonstrated that berberine, an isoquinoline alkaloid, harbored potent anti-metastatic and anti-proliferative activities in vivo. Using an orthotopic model of HCC (MHCC 97L), which spontaneously develops lung metastases (one of the most common sites of HCC metastasis), we found that berberine treatment (10mg/kg/2days) significantly reduced lung metastasis from the liver tumors by ~85% (quantitated by bioluminescence emitted from lung metastases). Histological examination also confirmed the reduced incidence and number of lung metastases in berberine treated mice. Furthermore, berberine effectively suppressed extra-tumor invasion of the primary HCC implant into the surrounding normal liver tissue, illustrating its potent anti-metastatic action in vivo. Consistent with previous reports in other cancer, berberine's anti-tumor activity was accompanied by suppression of cellular proliferation, invasiveness and HIF-1alpha/VEGF signaling. Strikingly, further mechanistic investigation revealed that berberine exerted profound inhibitory effect on the expression of Id-1, which is a key regulator for HCC development and metastasis. Berberine could suppress the transcription level of Id-1 through inhibiting its promotor activity. Specific downregulation of Id-1 by knocking down its RNA transcripts in HCC cells inhibited cellular growth, invasion and VEGF secretion, demonstrating the functional relevance of Id-1 downregulation induced by berberine. Lastly, berberine's anti-proliferative and anti-invasive activities could be partially rescued by Id-1 overexpression in HCC models, revealing a novel anti-cancer/anti-invasive mechanism of berberine via Id 1 suppression. PMID- 25496993 TI - Muscle-specific GSK-3beta ablation accelerates regeneration of disuse-atrophied skeletal muscle. AB - Muscle wasting impairs physical performance, increases mortality and reduces medical intervention efficacy in chronic diseases and cancer. Developing proficient intervention strategies requires improved understanding of the molecular mechanisms governing muscle mass wasting and recovery. Involvement of muscle protein- and myonuclear turnover during recovery from muscle atrophy has received limited attention. The insulin-like growth factor (IGF)-I signaling pathway has been implicated in muscle mass regulation. As glycogen synthase kinase 3 (GSK-3) is inhibited by IGF-I signaling, we hypothesized that muscle specific GSK-3beta deletion facilitates the recovery of disuse-atrophied skeletal muscle. Wild-type mice and mice lacking muscle GSK-3beta (MGSK-3beta KO) were subjected to a hindlimb suspension model of reversible disuse-induced muscle atrophy and followed during recovery. Indices of muscle mass, protein synthesis and proteolysis, and post-natal myogenesis which contribute to myonuclear accretion, were monitored during the reloading of atrophied muscle. Early muscle mass recovery occurred more rapidly in MGSK-3beta KO muscle. Reloading-associated changes in muscle protein turnover were not affected by GSK-3beta ablation. However, coherent effects were observed in the extent and kinetics of satellite cell activation, proliferation and myogenic differentiation observed during reloading, suggestive of increased myonuclear accretion in regenerating skeletal muscle lacking GSK-3beta. This study demonstrates that muscle mass recovery and post-natal myogenesis from disuse-atrophy are accelerated in the absence of GSK 3beta. PMID- 25496994 TI - JNK inhibition of VMAT2 contributes to rotenone-induced oxidative stress and dopamine neuron death. AB - Treatment with rotenone, both in vitro and in vivo, is widely used to model dopamine neuron death in Parkinson's disease upon exposure to environmental neurotoxicants and pesticides. Mechanisms underlying rotenone neurotoxicity are still being defined. Our recent studies suggest that rotenone-induced dopamine neuron death involves microtubule destabilization, which leads to accumulation of cytosolic dopamine and consequently reactive oxygen species (ROS). Furthermore, the c-Jun N-terminal protein kinase (JNK) is required for rotenone-induced dopamine neuron death. Here we report that the neural specific JNK3 isoform of the JNKs, but not JNK1 or JNK2, is responsible for this neuron death in primary cultured dopamine neurons. Treatment with taxol, a microtubule stabilizing agent, attenuates rotenone-induced phosphorylation and presumably activation of JNK. This suggests that JNK is activated by microtubule destabilization upon rotenone exposure. Moreover, rotenone inhibits VMAT2 activity but not VMAT2 protein levels. Significantly, treatment with SP600125, a pharmacological inhibitor of JNKs, attenuates rotenone inhibition of VMAT2. Furthermore, decreased VMAT2 activity following in vitro incubation of recombinant JNK3 protein with purified mesencephalic synaptic vesicles suggests that JNK3 can inhibit VMAT2 activity. Together with our previous findings, these results suggest that rotenone induces dopamine neuron death through a series of sequential events including microtubule destabilization, JNK3 activation, VMAT2 inhibition, accumulation of cytosolic dopamine, and generation of ROS. Our data identify JNK3 as a novel regulator of VMAT2 activity. PMID- 25496995 TI - Deciphering the role of exosomes in tuberculosis. AB - Exosomes were originally described as small vesicles released from reticulocytes during the maturation process. These 40-200 nm microvesicles were hypothesized to be a mechanism for the removal of membrane proteins in lieu of intracellular degradation by Harding et al. (1984) and Johnstone et al. (1987) [1,2]. Exosomes can be distinguished from other extracellular vesicles (ectosomes, apoptotic blebs) based on their size and the protein indicators intercalated in their membrane (also, linking their derivation from the endocytic pathway) by Simpson (2012) [3]. The exact role which exosomes play in cell-to-cell communication and immune modulation is a topic of intense study. However, the focus of most reports has been directed towards discovering aberrations in exosomal protein and RNA content linked to disease onset and progression, and also primarily related to cancer. Nonetheless, exosomes are now documented to be released from a wide variety of cell types by Mathivanan et al. (2012), Simpson et al. (2012) and Kalra et al. (2012) [4-6] and have been isolated from all bodily fluids; thus, exosomes are an excellent source of biomarkers. Here we describe the discoveries related to the role exosomes play in tuberculosis disease, as well as translational work in vaccine development and how circulation of these dynamic vesicles can be harnessed for diagnostic purposes. PMID- 25496996 TI - The cell-membrane prothrombinase, fibrinogen-like protein 2, promotes angiogenesis and tumor development. AB - The aim of the study was to further investigate the role of fibrinogen-like protein 2 (FGL-2), a transmembrane prothrombinase that directly cleaves prothrombin to thrombin, in angiogenesis and tumor development and the mechanism(s) underlying these processes. To study angiogenesis HUVEC clones with decreased fgl-2 mRNA were generated by specific siRNA. To study tumorigenesis SCID mice were implanted with intact (wild type) and fgl-2-silenced PC-3 clones. IFN-gamma treated HUVEC expressing increased fgl-2 mRNA exhibited significant capillary sprouting that was not inhibited by hirudin, whereas fgl-2 silencing completely inhibited blood-vessel formation. Tumors (poorly differentiated carcinoma) developed in all 12 mice injected with wild type PC-3 compared with 8/12 mice injected with the fgl-2-silenced PC-3 clone. The tumors developed by fgl-2-silenced PC-3 clones were smaller and less aggressive and contained significantly fewer blood vessels (p<0.05). All tumors' sections were negative for thrombin staining, indicating that FGL-2-induced tumorigenesis was not mediated by thrombin. In fgl-2-silenced tumors there was a decrease in fgl-2 mRNA (p=0.02) and ERK1/2 phosphorylation (p<0.05) by 80% and a 20%, respectively. The mechanism underlying these processes, studied in PC-3 clones, revealed that fgl-2 silencing was associated with a 65% decrease in FGF-2 mRNA (p<0.01) and a 30% down regulation of ERK1/2 phosphorylation (p<0.05). Together, these results suggest that FGL-2 mediates angiogenesis and tumorigenesis not by thrombin mediated mechanism but rather through FGF-2/ERK signaling pathway. FGL-2 may serve as a valuable therapeutic target in the future. PMID- 25496997 TI - Endothelial and platelet microparticles in patients with antiphospholipid antibodies. AB - BACKGROUND: The antiphospholipid syndrome (APS) is the association of thrombosis and recurrent pregnancy loss and/or pregnancy morbidity with persistent antiphospholipid antibodies (aPL). Previous studies of microparticles in patients with APS/aPL have mainly been small and findings, contradictory. OBJECTIVES: To quantify endothelial and platelet microparticle levels in patients with isolated antiphospholipid antibodies or primary antiphospholipid syndrome (PAPS). PATIENTS/METHODS: We measured endothelial and platelet microparticle levels by flow cytometry in 66 aPL/PAPS patients and 18 healthy controls. RESULTS: Levels of circulating platelet (CD41 and CD61) and endothelial microparticles (CD51 and CD105) were significantly increased in patients with PAPS and aPL compared to healthy controls. There were correlations between platelet and endothelial microparticles levels in all patients with aPL. CONCLUSIONS: Platelet and endothelial microparticles are increased in all patient groups within this cohort of patients aPL. Whether they may have a role in the pathogenesis of APS merits further study. PMID- 25496998 TI - Prediction of the pathogenicity of antithrombin sequence variations by in silico methods. AB - Computational prediction tools have been developed to aid in the interpretation of novel sequence variations, but their utility within the diagnostic setting of antithrombin (AT) deficiency has not been evaluated to date. The aim of our study was to test the performance of different bioinformatic tools (Meta-SNP, MutPred, nsSNPAnalyzer, PANTHER, PhD-SNP, PMut, SIFT, SNAP, SNPs&Go, PolyPhen-2, PON-P2, and PredictSNP) in predicting the pathogenicity of AT sequence variations. We analysed all naturally occurring SERPINC1 missense mutations that have been previously characterised to be damaging with regard to the secretion or function of the AT molecule. Additionally, we analysed all reported non-synonymous exonic polymorphisms within SERPINC1 with a population allele frequency >1.0%. The in silico tools had accuracies of 62-96%, sensitivities of 59-98%, and specificities of 33-100% for the prediction of the pathogenicity of AT sequence variations; receiver operating characteristic analysis had area under the curves between 0.54 0.97. When mutations were grouped according to their effect on the phenotype of AT deficiency [type I or type II with a thrombin (IIRS) or heparin (IIHBS) binding defect or pleiotropic effects (IIPE)], we observed the lowest performance characteristics of the tools for mutations causing AT deficiency type IIHBS. Only three tools (MutPred, PhD-SNP, PolyPhen-2) detected mutants causing type IIHBS AT deficiency with high sensitivity (93%), the sensitivities of the other tools ranged between 36% and 79%. This study demonstrates that bioinformatic tools are useful for pathogenicity prediction for AT sequence variations, but they have substantially different performance characteristics, particularly for type IIHBS AT deficiency. PMID- 25496999 TI - Genes expressed in coronary thrombi are associated with ischemic time in patients with acute myocardial infarction. AB - INTRODUCTION: Reports on the content of aspirated coronary thrombi have until now mainly focused on cellular components. We investigated the genetic expression of selected mediators and proteases actively involved in the pathophysiological process of acute myocardial infarction in aspirated coronary thrombi. MATERIALS AND METHODS: In this cross-sectional study, RNA from coronary thrombi in 67 subjects with acute myocardial infarction was isolated. Gene expression arrays of selected markers were performed by RT-PCR with relative quantification. RESULTS: Twenty of 22 markers were expressed in >50% of the samples. The relative quantification of P-selectin correlated negatively to total ischemic time (p=0.01), while genes related to fibrinolysis (t-PA, u-PA, PAI-1), inflammation (PTX3, CXCL9, MCP-1, IL18, TNFalpha) and plaque instability (MMP-2 and TIMP-1) correlated positively to total ischemic time (all<0.05). Long ischemic time (>4.0 hours) associated with a relative reduction in the expression of P-selectin and a relative increase in the expression of t-PA, u-PA, PAI-1, PTX3, CXCL9, MCP-1, IL 18, TNFalpha, MMP-2 and TIMP-1. The presence of type 2 diabetes associated with 3.2-fold increased PAI-1 expression (adjusted p=0.033), while the presence of hypertension associated with about 50% reduction of IL-8 and TIMP-1. Smoking and overweight did not affect any markers. CONCLUSIONS: The gene expression profile from coronary thrombi differed according to ischemic time, shown by reduced content of platelet markers and increased content of fibrinolytic, inflammatory and plaque instability mediators over time. Patients with type 2 diabetes showed increased expression of PAI-1, indicative of reduced fibrinolysis. PMID- 25497000 TI - A study of the noncollinear ultrasonic-wave-mixing technique under imperfect resonance conditions. AB - Geometrical and material property changes cause deviations in the resonant conditions used for noncollinear wave mixing. These deviations are predicted and observed using the SV(omega1)+L(omega2)->L(omega1+omega2) interaction, where SV and L are the shear vertical and longitudinal waves, respectively, and omega1, omega2 are their frequencies. Numerical predictions, performed for the scattered secondary field in the far field zone, show three field features of imperfect resonance conditions: (1) rotation of a scattered beam, (2) decrease in the beam amplitude, and (3) beam splitting. The response of the nonlinear ultrasonic wave mixing technique is verified experimentally in two ways: (1) detection of a kissing bond between two polyvinyl chloride (PVC) plates, and (2) detection of subsurface micro-cracks in polymethyl methacrylate (PMMA). A predominant decrease in nonlinear wave energy is observed in both experiments. Beam rotation and splitting is observed in the kissing-bond experiment, while a minor increase in the nonlinear wave energy up to 100% is observed in the micro-cracked PMMA specimen. PMID- 25497001 TI - The reflection of guided waves from simple dents in pipes. AB - Guided elastic waves have been anticipated as a rapid screening technique for pipe inspection. Dents occurring in pipes are a severe problem which may lead to the possibility of pipe failure. A study of the reflection characteristics of guided waves from dents of varying geometrical profile in pipes is investigated through experiments. Dented region is represented by a series of circumferential cross-sections and its geometric parameters are described by axial length and the maximum and minimum outer diameters. Both single and double sided dents are mechanically simulated in hollow aluminum pipes and then experimentally tested by exciting the longitudinal L(0,2) mode. A quantitative parameter, so-called deformation rate relating to the maximum and minimum outer diameters of the dents is defined to evaluate the effect of the extent of the deformation on the reflection. For both types of dents, it is shown that the reflection coefficients of the L(0,2) mode are all approximately a linear function of their respective deformation rates. Mode conversion occurs at the dents and reflections of the F(1,3) mode are identified. The results show that the amplitude of the reflected F(1,3) mode is generally higher when the dent has stronger non-axisymmetric features. PMID- 25497002 TI - The anisotropic propagation of ultrasonic guided waves in composite materials and implications for practical applications. AB - Ultrasonic guided wave propagation in anisotropic attenuative materials like CFRP (carbon fibre reinforced polymer) is much more complicated than in isotropic materials. Propagation phenomena need to be understood and quantified before reliable NDE (Non-destructive Evaluation)/SHM (Structural Health Monitoring) inspection systems can be realized. The propagation characteristics: energy velocity, dispersion, mode coupling, energy focusing factor and attenuation are considered in this paper. Concepts of minimum resolvable distance and sensitivity maps are extended to anisotropic attenuative materials in order to provide the means for comparison of different guided wave modes in composite materials. The paper is intended to serve as a framework for evaluating and comparing different modes and choosing the optimum operating conditions (frequency, sensor layout) for possible NDE/SHM applications on composite materials. Fundamental guided wave modes in the low frequency regime for highly anisotropic CFRP plates are investigated experimentally and theoretically and the implications for NDE/SHM are discussed. PMID- 25497003 TI - Laser vibrometer measurement of guided wave modes in rail track. AB - The ability to measure the individual modes of propagation is very beneficial during the development of guided wave ultrasound based rail monitoring systems. Scanning laser vibrometers can measure the displacement at a number of measurement points on the surface of the rail track. A technique for estimating the amplitude of the individual modes of propagation from these measurements is presented and applied to laboratory and field measurements. The method uses modal data from a semi-analytical finite element model of the rail and has been applied at frequencies where more than twenty propagating modes exist. It was possible to measure individual modes of propagation at a distance of 400 m from an ultrasonic transducer excited at 30 kHz on operational rail track and to identify the modes that are capable of propagating large distances. PMID- 25497004 TI - Analysis of temperature dependence of background phase errors in phase-contrast cardiovascular magnetic resonance. AB - BACKGROUND: The accuracy of phase-contrast cardiovascular magnetic resonance (PC CMR) can be compromised by background phase errors. It is the objective of the present work to provide an analysis of the temperature dependence of background phase errors in PC-CMR by means of gradient mount temperature sensing and magnetic field monitoring. METHODS: Background phase errors were measured for various temperatures of the gradient mount using magnetic field monitoring and validated in a static phantom. The effect of thermal changes during k-space acquisition was simulated and confirmed with measurements in a stationary phantom. RESULTS: The temperature of the gradient mount was found to increase by 20-30 K during PC-CMR measurements of 6-12 min duration. Associated changes in background phase errors of up to 11% or 0.35 radian were measured at 10 cm from the magnet's iso-center as a result of first order offsets. Zeroth order phase errors exhibited little thermal dependence. CONCLUSIONS: It is concluded that changes in gradient mount temperature significantly modify background phase errors during PC-CMR with high gradient duty cycle. Since temperature increases significantly during the first minutes of scanning the results presented are also of relevance for single-slice or multi-slice PC-CMR scans. The findings prompt for further studies to investigate advanced correction methods taking into account gradient temperature and/or the use of concurrent field-monitoring to map gradient-induced fields throughout the scan. PMID- 25497005 TI - Improving interprofessional collaboration: evaluation of implicit attitudes in the surgeon-nurse relationship. AB - BACKGROUND: Optimizing the surgeon-nurse relationship to improve interprofessional communication is increasingly recognized as an essential component of patient care. The increasing number of women surgeons has altered the surgeon-nurse dynamic, which has traditionally been a male-female relationship. In particular, this shift has raised the issue of whether implicit perceptions regarding gender and demeanor influence the interactions between surgeons and nurses. Therefore, the purpose of this study was to understand nurses' implicit perceptions of surgeons, with a particular focus on gender and gender-normative demeanor. We defined two types of demeanor: communal, which is classically associated with women and includes being supportive and nurturing, and agentic, which is a male-associated trait that includes being direct and assertive. METHODS: We administered surveys to 1701 nurses at the main campus of our institution. Each survey had one of eight possible scenarios; all began with a short description of a surgeon who was described as accomplished and well trained, then varied by surgeon gender (male/female), surgeon demeanor (agentic/communal) and type of surgery (breast cancer/lung cancer). Using a 0 to 5 scale, respondents rated their perception of the surgeon through five questions. These five items were averaged to create a composite perception score scaled from 0 to 5. RESULTS: We received 493 surveys. The overall average perception score was 3.8+/-0.99. Respondents had a statistically significant preference for the communal surgeon (4.1+/-0.91) versus the agentic surgeon (3.6+/-1.0, p<0.001). There were no significant main effects of surgeon gender or surgery type. CONCLUSION: Nurses demonstrated a significant preference for communal surgeons, regardless of surgeon gender. PMID- 25497006 TI - Diagnostic clinical relevance of developmental pluripotency-associated 2 (DPPA2) in colorectal cancer. AB - INTRODUCTION: Colorectal cancer (CRC) is one of the most important common causes of cancer-related death globally and reorganization of regulatory mechanisms controlling initiation, progression and metastasis of the CRC is critical to improve the prognosis, diagnosis and effective therapeutic treatment of the patients. One of the newly identified pluripotency genes which is expressed specifically in pluripotent stem cells is developmental pluripotency-associated 2 (DPPA2). It may play important roles in the maintenance of pluripotency of ESCs and is associated with abnormal cell growth and cancer formation. METHODS: Protein expression of DPPA2 was specifically analyzed in tumors and their margin normals of colorectal epithelium in 50 new cases CRC patients by immunohistochemical staining. RESULTS: DPPA2 protein was significantly overexpressed in 60% of samples (30 of 50, P<0.01). This level of protein expression was significantly correlated to the depth of tumor invasion (p=0.047) and the stage of tumor progression (p=0.028). DISCUSSION: Due to existence of transcriptional linkage between DPPA2/Nanog and OCT4 in mouse ESCs, our results suggest that a pluripotency transcriptional network consisting of SALL4/OCT4/DPPA2/Nanog, as similar as ESCs, is activated in CRC which not only play essential roles in maintenance of stemness state and self-renewal characteristics of tumor cells, but also in progression of CRC cells through advanced stages leading to increase depth of tumor cell invasion. CONCLUSION: DPPA2 protein expression is correlated with different indices of poor prognosis and may be introduced as a new therapeutic marker in adjuvant therapy of colorectal cancer. PMID- 25497007 TI - Left colon acute diverticulitis: an update on diagnosis, treatment and prevention. AB - Diverticulosis of the colon is a common disease with an increasing incidence in Western Countries. It represents a significant burden for National Health Systems in terms of costs. Most people with diverticulosis remain asymptomatic, about one quarter of them will develop an episode of symptomatic diverticular disease and up to 5% an episode of acute diverticulitis (AD). AD shows an increasing prevalence. Recently, progresses have been reached about the etiology, pathogenesis, natural course of diverticular disease and its complications; improvements about the diagnosis and treatment of AD have been achieved. However, the treatment options are not well defined because of a lack of solid evidence: there are few systematic reviews and well conducted trials to guide decision making in the treatment of AD and in the prevention of its recurrences. This review describes the recent evidence about diagnosis, treatment and prevention of AD. PMID- 25497008 TI - Cancer stem cells, lymphangiogenesis, and lymphatic metastasis. AB - Although current opinion indicates that tumor-induced lymphangiogenesis plays a key role in promoting the initial spread of malignant tumors, the mechanism that underlies lymphatic spread is not clear. The recent discovery of cancer stem cells (CSCs) in human tumors has challenged our current understanding of tumor recurrence, drug resistance, and metastasis, and opens up new research directions on how cancer cells are capable of switching from dormancy to malignancy. CSCs can be directly and indirectly involved in tumor-induced lymphangiogenesis and ultimately promote lymphatic metastasis. However, the details and the possible relationship between CSCs, lymphangiogenesis, and lymphatic metastasis remain ambiguous, and the origin of tumor lymphatic endothelial cells is controversial. Elucidation of these factors may provide useful information for future research and cancer treatment. In this article, we summarize current knowledge of CSCs, tumor-induced lymphangiogenesis, and lymphatic metastasis and attempt to find an association between key molecular and cellular mechanisms. We provide an overview of CSCs and lymphatic vasculature as potential therapeutic targets. CSC- and lymphatic vasculature-targeted therapy may bring new hope for cancer treatment. PMID- 25497009 TI - Dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitor is an effective radiosensitizer for colorectal cancer. AB - The present study was aimed to investigate whether combination of molecular targeting therapy, a dual PI3K/mTOR inhibitor (BEZ235), with radiation can enhance the radiosensitivity of colorectal cancer cells (CRC). K-RAS mutant CRC cells (HCT 116 and SW 620) and wild type CRC cells (HT 29) were irradiated with different dose of radiation (0-6 Gy). The synergistic effects of combining radiation with different concentration of BEZ235 (0-10 nM) pretreatment were demonstrated by cell survival assay. When comparing with radiation alone and BEZ235 alone, the combination of BEZ235 pretreatment and radiation resulted in an increased percentage of sub-G1 phase cells, and an increased number of gamma H2AX/cell (DNA double strand breaks). Radiation up-regulated AKT/mTOR signaling pathway, including the activation of phospho (p)-AKT, p-mTOR, p-eIF4E, and p rpS6; and this activated AKT/mTOR signaling pathway was attenuated by BEZ235 pretreatment. In addition, BEZ235 blocked double strand break repair induced by radiation through attenuating the activation of ATM and DNA-PKcs and sensitized CRC cells to radiation. In vivo model, the tumor size and the expression pattern of p-mTOR, p-eIF4E, and p-rpS6 were significantly decreased in combined group than radiation alone or BEZ235 alone. Our findings indicate that the administration of BEZ235 before radiation enhances the radiotherapeutic effect of CRC cells both in vitro and in vivo. PMID- 25497014 TI - Glutamine synthetase isoforms in nitrogen-fixing soybean nodules: distinct oligomeric structures and thiol-based regulation. AB - Legume root nodule glutamine synthetase (GS) catalyzes the assimilation of ammonia produced by nitrogen fixation. Two GS isoform subtypes (GS1beta and GS1gamma) are present in soybean nodules. GS1gamma isoforms differ from GS1beta isoforms in terms of their susceptibility to reversible inhibition by intersubunit disulfide bond formation between C159 and C92 at the shared active site at subunit interfaces. Although nodule GS enzymes share 86% amino acid sequence identity, analytical ultracentrifugation experiments showed that GS1gamma is a dodecamer, whereas the GS1beta is a decamer. It is proposed that this difference contributes to the differential thiol sensitivity of each isoform, and that GS1gamma1 may be a target of thiol-based regulation. PMID- 25497012 TI - miR-466 is putative negative regulator of Coxsackie virus and Adenovirus Receptor. AB - This study aimed at elucidating how Coxsackie B virus (CVB) perturbs the host's microRNA (miRNA) regulatory pathways that lead to antiviral events. The results of miRNA profiling in rat pancreatic cells infection models revealed that rat rno miR-466d was up-regulated in CVB infection. Furthermore, in silico studies showed that Coxsackie virus and Adenovirus Receptor (CAR), a cellular receptor, was one of the rno-miR-466d targets involved in viral entry. Subsequent experiments also proved that both the rno-miR-466d and the human hsa-miR-466, which are orthologs of the miR-467 gene family, could effectively down-regulate the levels of rat and human CAR protein expression, respectively. PMID- 25497011 TI - The bacterial cell division regulators MinD and MinC form polymers in the presence of nucleotide. AB - The Min system of proteins, consisting of MinC, MinD and MinE, is essential for normal cell division in Escherichia coli. MinC forms a polar gradient to restrict placement of the division septum to midcell. MinC localization occurs through a direct interaction with MinD, a membrane-associating Par-like ATPase. MinE stimulates ATP hydrolysis by MinD, thereby releasing MinD from the membrane. Here, we show that MinD forms polymers with MinC and ATP without the addition of phospholipids. The topological regulator MinE induces disassembly of MinCD polymers. Two MinD mutant proteins, MinD(K11A) and MinD(DeltaMTS15), are unable to form polymers with MinC. PMID- 25497013 TI - Glutamate 270 plays an essential role in K(+)-activation and domain closure of Thermus thermophilus isopropylmalate dehydrogenase. AB - The mutant E270A of Thermus thermophilus 3-isopropylmalate dehydrogenase exhibits largely reduced (~1%) catalytic activity and negligible activation by K(+) compared to the wild-type enzyme. A 3-4 kcal/mol increase in the activation energy of the catalysed reaction upon this mutation could also be predicted by QM/MM calculations. In the X-ray structure of the E270A mutant a water molecule was observed to take the place of K(+). SAXS and FRET experiments revealed the essential role of E270 in stabilisation of the active domain-closed conformation of the enzyme. In addition, E270 seems to position K(+) into close proximity of the nicotinamide ring of NAD(+) and the electron-withdrawing effect of K(+) may help to polarise the aromatic ring in order to aid the hydride-transfer. PMID- 25497010 TI - Restoration of IRF1-dependent anticancer effects by MEK inhibition in human cancer cells. AB - Interferon regulatory factor (IRF1) is a potent antiviral, antitumor and immune regulatory protein. Recently, we found that activated Ras/MEK inhibits antiviral response by downregulating IRF1 expression and renders cancer cells susceptible to oncolytic viruses. In this study, we sought to determine whether IRF1 downregulation underlies oncogenesis induced by Ras/MEK activation in human cancer cells. Treatment of the MEK inhibitor U0126 promoted IRF1 expression in 7 of 11 cancer cell lines we tested. IRF1 promotion was also observed in human cancer cell lines treated with different MEK inhibitors or with RNAi oligonucleotides against extracellular signal-regulated kinases (ERKs). Restoration of the expression of antitumor genes, p27 and p53 upregulated modulator of apoptosis (PUMA), by MEK inhibition was less in IRF1 shRNA knockdown cancer cells than in vector control cancer cells, suggesting that Ras/MEK targets IRF1 for the downregulation of the antitumor genes. Moreover, apoptosis induction by U0126 was significantly reduced in IRF1 shRNA knockdown cells than vector control cells. This study demonstrates that IRF1 expression is suppressed by activated Ras/MEK in human cancer cells and that IRF1 plays essential roles in apoptosis induced by Ras/MEK inhibition. PMID- 25497015 TI - Osteopontin-integrin alpha(v)beta(3) axis is crucial for 5-fluorouracil resistance in oral squamous cell carcinoma. AB - Clinical applications of a chemotherapeutic agent, 5-fluorouracil (5-FU) in oral squamous cell carcinoma (OSCC) have been limited because of drug resistance. This study aimed to identify novel mechanisms of 5-FU resistance. Here we found increased osteopontin (OPN) gene expression in OSCC tissues with resistance to 5 FU-based chemoradiotherapy. OPN overexpression in OSCC cells led to 5-FU resistance and abrogated the prosurvival effect of the drug in a mouse xenograft model. OPN-induced 5-FU resistance required integrin alphavbeta3. Targeting integrin alphavbeta3 reversed the resistance in a 5-FU-resistant clone highly expressing OPN. Our data suggest that the OPN-integrin alphavbeta3 axis is crucial for 5-FU resistance in OSCC. PMID- 25497016 TI - Cdc42 induces EGF receptor protein accumulation and promotes EGF receptor nuclear transport and cellular transformation. AB - Cdc42 is a Ras-related small GTP-binding protein. A previous study has shown that Cdc42 binding to the gamma subunit of the coatomer protein complex (gammaCOP) is essential for Cdc42-regulated cellular transformation, but the molecular mechanism involved is not well understood. Here, we demonstrate that constitutively-active Cdc42 binding to gammaCOP induced the accumulation of epithelial growth factor receptor (EGFR) in the cells, sustained EGF-stimulated extracellular signal-regulated kinase (ERK), JUN amino-terminal kinase (JNK) and phosphoinositide 3-kinase (PI3K) signaling and promoted cell division. Moreover, constitutive Cdc42 activity facilitated the nuclear translocation of EGFR, and this indicates a novel mechanism through which Cdc42 might promote cellular transformation. PMID- 25497021 TI - Two nitro derivatives of azabenzo[a]pyrene N-oxide: electronic properties and their relation to mutagenic activity. AB - The equilibrium geometries, relative energies, IR and Raman spectra, vertical ionization potentials (IP), vertical electron affinities (EA), dipole moments (MU), electronic dipole polarizabilities (alpha), and molecular electrostatic potentials (MEP) of two species that show very high mutagenicity, 1-nitro-6 azabenzo[a]pyrene N-oxide (1-N-6-ABPO) and 3-nitro-6-azabenzo[a]pyrene N-oxide (3 N-6-ABPO), are investigated by means of Density Functional Theory (DFT) using B3LYP functional with different basis sets. The 3-N-6-ABPO isomer was estimated to be much more mutagenic in Salmonella typhimurium tester strain TA98 (396,000 revertants/nmol) than 1-N-6-ABPO (36100 revertants/nmol) (Fukuhara et al., 1992). The results show that for both isomers the structural, energetic, and vibrational properties are similar. The orientation of the nitro group with respect to the plane of the aromatic system as well as the nitroreduction and oxidation reaction and polarizability seem not be important for the determination of different mutagenic behavior of these isomers. However, the dipole moment of 3-N-6-ABPO is about 3 times that of 1-N-6-ABPO. The larger dipole moment and the different electronic charge distribution of 3-N-6-ABPO compared to 1-N-6-ABPO imply stronger electrostatic and inductive molecular interactions so that the active site of the enzyme involved in the mutagenic activation can more effectively bind 3-N-6-ABPO compared to 1-N-6-ABPO. PMID- 25497017 TI - Downregulation of striatin leads to hyperphosphorylation of MAP2, induces depolymerization of microtubules and inhibits proliferation of HEK293T cells. AB - Microtubules are tubular polymers of alpha/beta-tubulin that are involved in the maintenance of cell shape, motility, and intracellular transport and in the segregation of chromosomes during cell division. Microtubules are dynamic structures, and their assembly is regulated by phosphoproteins called microtubule associated proteins (MAPs). We propose that striatin, a protein belonging to the striatin family of proteins, is involved in regulation of microtubules. In HEK293T cells, striatin colocalizes with microtubules and stably associates with PP2Ac. Inhibition of striatin expression results in hyperphosphorylation of MAP2 and destabilizes microtubules. Striatin-induced destabilization of microtubules inhibited the proliferation of HEK293T cells and caused the accumulation of cells in the G0/G1 phase of the cell cycle. These results suggest that the PP2A/striatin complex modulates microtubule dynamics by regulating MAP2 phosphorylation. PMID- 25497018 TI - Tumor necrosis factor-alpha reduces beta-amyloid accumulation primarily by lowering cellular prion protein levels in a brain endothelial cell line. AB - Disruption of beta-amyloid (Abeta) transport across the blood-brain barrier is thought to cause Abeta accumulation in the brain, thus leading to the development of Alzheimer's disease (AD). As AD patients show increased serum tumor necrosis factor-alpha (TNFalpha) levels, we examined the effect of TNFalpha on the function and expression of Abeta transport-related proteins including cellular prion protein (PrP(C)) in the mouse brain microvascular endothelial cell line MBEC4. TNFalpha decreased PrP(C) levels and intracellular radiolabeled Abeta. Similarly, anti-prion protein antibody also decreased radiolabeled Abeta. These results suggest that TNFalpha lowers PrP(C) levels, which in turn, reduces Abeta in the brain endothelium. PMID- 25497020 TI - Removal of 1,2-dichlorobenzene from water emulsion using adsorbent catalysts and its regeneration. AB - Purification of emulsions of 1,2-dichlorobenzene (1,2-DCB) by carbon-based adsorbent catalysts has been studied. The cycle of purification includes: (1) adsorption of 1,2-DCB from the aqueous phase and (II) reductive regeneration by hydrodechlorination of the adsorbed 1,2-DCB by molecular hydrogen in the liquid phase. 1,2-DCB adsorption from aqueous solutions has been found to proceed by the mechanism of volume filling of pores. The rate of hydrodechlorination was shown to correlate with the particle size of the active component: the finer the particles, the higher the activity of the adsorbent catalyst. Pd/FAS with an average Pd particle size of 2.8 nm was found to be the most efficient catalyst. PMID- 25497019 TI - Purification of olive mill wastewater phenols through membrane filtration and resin adsorption/desorption. AB - Olive tree cultivation has a long history in the Mediterranean countries, and even today consists an important cultural, economic, and environmental aspect of the area. The production of olive oil through 3-phase extraction systems, leads to the co-production of large quantities of olive mill wastewater (OMW), with toxic compounds that inhibit its biodegradation. Membrane filtration has been used for the exploitation of this byproduct, through the isolation of valuable phenolic compounds. In the current work, a fraction of the waste occurring from a membrane process was used. More specifically the reverse osmosis concentrate, after a nanofiltration, containing the low-molecular-weight compounds, was further treated with resin adsorption/desorption. The non ionic XAD4, XAD16, and XAD7HP resins were implemented, for the recovery of phenols and their separation from carbohydrates. The recovered phenolic compounds were concentrated through vacuum evaporation reaching a final concentration of 378 g/L in gallic acid equivalents containing 84.8 g/L hydroxytyrosol. PMID- 25497022 TI - Effects of chlorination operating conditions on trihalomethane formation potential in polyaluminum chloride-polymer coagulated effluent. AB - In this study, coagulation performance of polyaluminum chloride (PAC) and PAC lignin acrylamide (PAC+LAM) in reservoir water treatment was contrastively analyzed. Effects of operating conditions including chlorine dose, contact time and pH on the formation potential of trihalomethanes (THMs) during chlorination in coagulated effluent were also investigated. Comparing with PAC, PAC+LAM achieved higher efficiency in the removal of THMs precursors. TTHM yield in unfiltered water samples (UW) was greater than that of filtered water (FW) due to the residual dissolved organic matter (DOM) in the suspended particles or micro flocs. Meanwhile, operating conditions during chlorination had a significant influence on THMs formation potential. With chlorine dose rising, mass ratio of CHCl3 to TTHM increased, whereas that of CHBr2Cl decreased due to higher Cl2/Br( ) molar ratio. TTHM and CHCl3 levels rose with the increase of pH. Under a given chlorination condition, there was a minor effect of contact time on THM speciation. PMID- 25497024 TI - Simultaneous treatment of NO and SO2 with aqueous NaClO2 solution in a wet scrubber combined with a plasma electrostatic precipitator. AB - NO and SO2 gases that are generally produced in thermal power plants and incinerators were simultaneously removed by using a wet scrubber combined with a plasma electrostatic precipitator. The wet scrubber was used for the absorption and oxidation of NO and SO2, and non-thermal plasma was employed for the electrostatic precipitation of aerosol particles. NO and SO2 gases were absorbed and oxidized by aerosol particles of NaClO2 solution in the wet scrubber. NO and SO2 reacted with the generated NaClO2 aerosol particles, NO2 gas, and aqueous ions such as NO2(-), NO3(-), HSO3(-), and SO4(2-). The aerosol particles were negatively charged and collected on the surface of grounded anode in the plasma electrostatic precipitator. The NO and SO2 removal efficiencies of the proposed system were 94.4% and 100% for gas concentrations of 500 mg/m(3) and a total gas flow rate of 60 Nm(3)/h, when the molar flow rate of NaClO2 and the gas-liquid contact time were /min and 1.25 s, respectively. The total amount and number of aerosol particles in the exhaust gas were reduced to 7.553 MUg/m(3) and 210/cm(3) at the maximum plasma input power of 68.8 W, which are similar to the values for clean air. PMID- 25497023 TI - Synthesis, characterization and application of poly(acrylamide-co methylenbisacrylamide) nanocomposite as a colorimetric chemosensor for visual detection of trace levels of Hg and Pb ions. AB - In this study, a new colorimetric chemosensor based on TiO2/poly(acrylamide-co methylenbisacrylamide) nanocomposites was designed for determination of mercury and lead ions at trace levels in environmental samples. The removal and preconcentration of lead and mercury ions on the sorbent was achieved due to sharing an electron pair of N and O groups of polymer chains with the mentioned heavy metal ions. The hydrogel sensor was designed by surface modification of a synthesized TiO2 nanoparticles using methacryloxypropyltrimethoxysilan (MAPTMS), which provided a reactive C=C bond that polymerized the acrylamide and methylenbisacrylamide. The sorbent was characterized using X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscope (SEM), EDS analysis and Fourier transform in frared (FT-IR) spectrometer. This nanostructured composite with polymer shell was developed as a sensitive and selective sorbent for adsorption of mercury and lead ions from aqueous solution at optimized condition. This method involves two-steps: (1) preconcentration of mercury and lead ions by the synthesized sorbent and (2) its selective monitoring of the target ions by complexation with dithizone (DZ). The color of the sorbent in the absence and presence of mercury and lead ions shifts from white to violet and red, respectively. The detection limit of the synthesized nanochemosensor for mercury and lead ions was 1 and 10 MUg L(-1), respectively. The method was successfully applied for trace detection of mercury and lead ions in tap, river, and sea water samples. PMID- 25497027 TI - Reduction process of Cr(VI) by Fe(II) and humic acid analyzed using high time resolution XAFS analysis. AB - The initial reduction behavior of Cr(VI) to Cr(III) has not been clearly understood due to its rapid reduction reaction. In order to study the reduction process of Cr(VI) in detail, we applied quick X-ray absorption fine structure (QXAFS) analysis to observe how Cr(VI) was reduced to Cr(III) by Fe(II) and humic acid (HA) with time. The Cr(VI) concentration was analyzed every 60s, and the plots of ln(Cr(VI)/Cr(VI)0) versus time were used to evaluate the reduction process based on their linearity. Reduction by Fe(II) showed a linear relation, whereas reduction by HA showed a nonlinear relation. With combined Fe(II) and HA, the linearity was unlike those of Fe(II) and HA individually. The reduction rate was not constant. The structure of Fe(II) produced by HA during the Cr(VI) reduction was investigated by using Mossbauer spectroscopy, which showed that Fe(II) produced by HA reduction of Fe(III) had the same structure as the initial Fe(II). HA can reduce Fe(III) back to Fe(II), and reproduced Fe(II) reduces Cr(VI). For Cr(VI) reduction by combined Fe(II) and HA, each reductant contribute differently: Fe(II) directly contributes to the Cr(VI) reaction, whereas HA reduces both Cr(VI) and Fe(III). PMID- 25497025 TI - Photodegradation of malachite green under simulated and natural irradiation: kinetics, products, and pathways. AB - In this work photodegradation rates and pathways of malachite green were studied under simulated and solar irradiation with the goal of assessing the potential of photolysis as a removal mechanism in real aquatic environment. Factors influencing the photodegradation process were investigated, including pH, humic acid, Fe(2+), Ca(2+), HCO3(-), and NO3(-), of which favorable conditions were optimized by the orthogonal array design under simulated sunlight irradiation in the presence of dissolved oxygen. The degradation processes of malachite green conformed to pseudo first-order kinetics and their degradation rate constants were between 0.0062 and 0.4012 h(-1). Under solar irradiation, the decolorization efficiency of most tests can reach almost 100%, and relatively thorough mineralization could be observed. Forty degradation products were detected by liquid chromatography-mass spectrometry, and thirteen small molecular products were identified by gas chromatography-mass spectrometry. Based on the analyses of the degradation products and calculation of the frontier electron density, the pathways were proposed: decomposition of conjugated structure, N-demethylation reactions, hydroxyl addition reactions, the removal of benzene ring, and the ring opening reaction. This study has provided a reference, both for photodegradation of malachite green and future safety applications and predictions of decontamination of related triphenylmethane dyes under real conditions. PMID- 25497029 TI - Succession of microbial community and enhanced mechanism of a ZVI-based anaerobic granular sludge process treating chloronitrobenzenes wastewater. AB - The combined zero-valent iron (ZVI) and upflow anaerobic sludge blanket (UASB) process is established for the treatment of chloronitrobenzenes (ClNBs) wastewater, and the succession of microbial community and its enhanced mechanism are investigated in the study. Results showed that compared with the control UASB (R1), the stable COD removal, ClNBs transformation, and dechlorination occurred in the combined system (R2) when operated at influent COD and 3,4 Dichloronitrobenzene (3,4-DClNB) loading rates of 4200-7700 g m(-3) d(-1) and 6.0 70.0 g m(-3) d(-1), and R2 had the better shock resistance and buffering capacity for the anaerobic acidification. The dechlorination for the intermediate products of p-chloroanaline (p-ClAn) to analine (AN) occurred in R2 reactor after 45 days, whereas it did not occur in R1 after a long-term operation. The novel ZVI-based anaerobic granular sludge (ZVI-AGS) was successfully developed in the combined system, and higher microbial activities including ClNB transformation and H2/CH4 production were achieved simultaneously. The dominant bacteria were closely related to the groups of Megasphaera, Chloroflexi, and Clostridium, and the majority of archaea were correlated with the groups of Methanosarcinalesarchaeon, Methanosaetaconcilii, and Methanothrixsoehngenii, which are capable of reductively dechlorinating PCB, HCB, and TCE in anaerobic niche and EPS secretion. PMID- 25497031 TI - Facile preparation of hierarchically porous diatomite/MFI-type zeolite composites and their performance of benzene adsorption: the effects of NaOH etching pretreatment. AB - Hierarchically porous diatomite/MFI-type zeolite (Dt/Z) composites with excellent benzene adsorption performance were prepared. The hierarchical porosity was generated from the microporous zeolite coated at the surface of diatom frustules and from the macroporous diatomite support. A facile NaOH etching method was employed for the first time to treat the frustule support, followed by hydrothermal growth of MFI-type zeolite at the surface of frustules previously seeded with nanocrystalline silicalite-1 (Sil-1). NaOH etching enlarged the pores on diatom frustules and further increased the coated zeolite contents (W(z)). The central macropore size of the diatom frustules increased from approximately 200 500 nm to 400-1000 nm after NaOH etching. The W(z) could reach 61.2%, while the macroporosity of the composites was largely preserved due to more voids for zeolite coating being formed by NaOH etching. The Dt/Z composites exhibited higher benzene adsorption capacity per unit mass of zeolite and less mass transfer resistance than Sil-1, evaluated via a method of breakthrough curves. These results demonstrate that etching of a diatomite support is a facile but crucial process for the preparation of Dt/Z composites, enabling the resulting composites to become promising candidates for uses in volatile organic compounds emission control. PMID- 25497030 TI - Heterogeneous photo-Fenton degradation of acid red B over Fe2O3 supported on activated carbon fiber. AB - Fe2O3 supported on activated carbon fiber (Fe2O3/ACF) was prepared via an impregnation method and characterized by X-ray diffraction, scanning electron microscopy and BET analysis. The results indicated that Fe2O3 with small particle size was highly dispersed on the surface of the ACF and the introduction of Fe2O3 did not change the ACF pore structure. Fe2O3/ACF exhibited a higher Fenton efficiency for the degradation of acid red B (ARB), especially under simulated solar irradiation. Complete decoloration of the ARB solution and 43% removal of TOC could be achieved within 200 min under optimal conditions. It was verified that more OH radicals were generated in the photo-assisted Fenton process and involved as active species in ARB degradation. FTIR analysis indicated that the degradation of ARB was initiated through the cleavage of -N=N-, followed by hydroxylation and opening of phenyl rings to form aliphatic acids, and further oxidation of aliphatic acids would produce CO2 and H2O. Moreover, Fe2O3/ACF maintained its activity after being reused 4 times and the release of iron from the catalyst was found to be insignificant during the Fenton and photo-Fenton processes, indicating that Fe2O3/ACF had good long-term stability. PMID- 25497032 TI - Investigation on properties of Pd/CeO2-ZrO2-Pr2O3 catalysts with different Ce/Zr molar ratios and its application for automotive emission control. AB - Pd/CeO2-ZrO2-Pr2O3 (CZP) catalysts with different Ce/Zr molar ratios were synthesized and systematically investigated by XRD, N2 adsorption-desorption, XPS, H2-TPR, OSC and in situ DRIFTS techniques. The results of XPS, in situ DRIFTS, etc., show that the number of oxygen vacancies increases with the increasing Zr content and thus leads to the enhanced metal-support interaction and the accelerative formation rate of nitrate, formate, acetate and carbonate species, resulting in improving catalytic performance for HC and NO elimination, especially for Pd/CZP catalysts with Ce/Zr from 1/2 to 1/3. While Pd/CZP catalysts with higher OSC value (Ce/Zr=4/1-1/2) exhibit better catalytic activity of CO and NO2 elimination. An appropriate concentration of Zr facilitates the diffusion of Pr from the surface to the bulk of the CZP supports, thus forming more homogeneous CZP solid solution and improving the structure/textual stability, which promotes the thermal stability of catalysts. Pd/CZP catalysts with Ce/Zr from 2/1 to 1/2 exhibit good thermal stability. PMID- 25497033 TI - Using physiologically based pharmacokinetic models to estimate the health risk of mixtures of trihalomethanes from reclaimed water. AB - To estimate the health risk of mixture of trihalomethanes (THMs) from reclaimed water during toilet flushing, the interaction-based Hazard Index (HI(interaction based)) and the mixture carcinogenic risk (CRM) according to tissue dose were conducted through the integrated use of both the exposure concentrations model and the physiologically based pharmacokinetic (PBPK) model of THMs. Monte Carlo simulations were employed to implement the probabilistic risk analysis and sensitivity analysis. Nine samples were analyzed, which were collected from J Water Reclamation Plant (JWRP) in Tianjin of China. The results indicated that the mean HI(interaction-based) (=0.85) was lower than the acceptable risk level (=1). The probability that the HI(interaction-based) exceeded the acceptable risk level is 22.97%. For carcinogenic risk, the CRM ranges from 9.41*10(-7) to 3.54*10(-5), with a mean of 5.49*10(-6). Moreover, the probability of exceeding the acceptable risk level (1*10(-6)) is near 100%. And the values of HI(interaction-based) from sample no. 1, 5, and 7 exceeded 1, while the values of CRM for all samples exceeded 1*10(-6). Consequently, the reclaimed water used for flushing toilets should be paid more attention, though non-carcinogenic effect is relatively small. Furthermore, the concentrations of DBCM had greater impact on both the carcinogenic and non-carcinogenic risk based on sensitivity analysis. PMID- 25497034 TI - Synthesis, characterization, and secondary sludge dewatering performance of a novel combined silicon-aluminum-iron-starch flocculant. AB - Flocculation is one of the most widely used cost-effective pretreatment method for sludge dewatering, and a novel environmentally friendly and efficient flocculant is highly desired in the sludge dewatering field. In this study, a novel combined silicon-aluminum-ferric-starch was synthesized by grafting silicon, aluminum, and iron onto a starch backbone. The synthesized starch flocculant was characterized using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy, X-ray powder diffraction, and thermogravimetric analysis. The dewatering performance of secondary sludge was evaluated according to the capillary suction time, settling volume percentage, and specific resistance to filtration. The results indicated that the copolymer exhibited: (1) a good dewatering efficiency over a wide pH range of 3.0-11.0, (2) superior sludge dewatering performance compared to those of polyaluminum chloride (PACl), polyacrylamide (PAM), ferric chloride, and (3) a discontinuous surface with many channels or voids that helps to mobilize the impermeable thin layer of secondary sludge during filter pressing. Such a novel copolymer is a promising green flocculant for secondary sludge dewatering applications. PMID- 25497038 TI - Adipose tissue dysregulation and metabolic consequences in childhood and adolescent obesity: potential impact of dietary fat quality. AB - Evidence suggests that at a population level, childhood and adolescent obesity increase the long-term risk of chronic diseases such as type 2 diabetes and CVD. At an individual level, however, the metabolic consequences of obesity in youth vary immensely. Despite comparable BMI, some adolescents develop impaired glucose tolerance while others maintain normal glucose homeostasis. It has been proposed that the variation in the capacity to store lipid in the subcutaneous adipose tissue (SAT) may partially discriminate metabolically healthy from unhealthy obesity. In positive energy balance, a decreased capacity to expand SAT may drive lipid accumulation to visceral adipose tissue, liver and skeletal muscle. This state of lipotoxicity is associated with chronic low-grade inflammation, insulin resistance and dyslipidaemia. The present review examines the differential adipose tissue development and function in children and adolescents who exhibit metabolic dysregulation compared with those who are protected. Additionally, the role of manipulating dietary fat quality to potentially prevent and treat metabolic dysfunction in obesity will be discussed. The findings of the present review highlight the need for further randomised controlled trials to establish the effect of dietary n-3 PUFA on the metabolic phenotype of obese children and adolescents. Furthermore, using a personalised nutrition approach to target interventions to those at risk of, or those with established metabolic dysregulation may optimise the efficacy of modifying dietary fat quality. PMID- 25497036 TI - Characterization and improved solar light activity of vanadium doped TiO2/diatomite hybrid catalysts. AB - V-doped TiO2/diatomite composite photocatalysts with different vanadium concentrations were synthesized by a modified sol-gel method. The diatomite was responsible for the well dispersion of TiO2 nanoparticles on the matrix and consequently inhibited the agglomeration. V-TiO2/diatomite hybrids showed red shift in TiO2 absorption edge with enhanced absorption intensity. Most importantly, the dopant energy levels were formed in the TiO2 bandgap due to V(4+) ions substituted to Ti(4+) sites. The 0.5% V-TiO2/diatomite photocatalyst displayed narrower bandgap (2.95 eV) compared to undoped sample (3.13 eV) and other doped samples (3.05 eV) with higher doping concentration. The photocatalytic activities of V doped TiO2/diatomite samples for the degradation of Rhodamine B under stimulated solar light illumination were significantly improved compared with the undoped sample. In our case, V(4+) ions incorporated in TiO2 lattice were responsible for increased visible-light absorption and electron transfer to oxygen molecules adsorbed on the surface of TiO2 to produce superoxide radicals O2(-), while V(5+) species presented on the surface of TiO2 particles in the form of V2O5 contributed to e(-)-h(+) separation. In addition, due to the combination of diatomite as support, this hybrid photocatalyst could be separated from solution quickly by natural settlement and exhibited good reusability. PMID- 25497037 TI - Nuclear waste viewed in a new light; a synchrotron study of uranium encapsulated in grout. AB - How do you characterise the contents of a sealed nuclear waste package without breaking it open? This question is important when the contained corrosion products are potentially reactive with air and radioactive. Synchrotron X-rays have been used to perform micro-scale in-situ observation and characterisation of uranium encapsulated in grout; a simulation for a typical intermediate level waste storage packet. X-ray tomography and X-ray powder diffraction generated both qualitative and quantitative data from a grout-encapsulated uranium sample before, and after, deliberately constrained H2 corrosion. Tomographic reconstructions provided a means of assessing the extent, rates and character of the corrosion reactions by comparing the relative densities between the materials and the volume of reaction products. The oxidation of uranium in grout was found to follow the anoxic U+H2O oxidation regime, and the pore network within the grout was observed to influence the growth of uranium hydride sites across the metal surface. Powder diffraction analysis identified the corrosion products as UO2 and UH3, and permitted measurement of corrosion-induced strain. Together, X ray tomography and diffraction provide means of accurately determining the types and extent of uranium corrosion occurring, thereby offering a future tool for isolating and studying the reactions occurring in real full-scale waste package systems. PMID- 25497028 TI - In silico understanding of the cyclodextrin-phenanthrene hybrid assemblies in both aqueous medium and bacterial membranes. AB - The explicit-solvent molecular dynamic (MD) simulation and adaptive biased forces (ABF) methods were employed to systemically study the structural and thermodynamic nature of the beta-cyclodextrin (betaCD) monomer, phenanthrene (Phe) monomer, and their inclusion complexes in both the aqueous and membrane environments, aiming at clarifying the atomic-level mechanisms underlying in the CD-enhanced degradation of polycyclic aromatic hydrocarbons (PAHs) by bacteria. Simulations showed that betaCD and Phe monomers could associate together to construct two distinctive assemblies, i.e, betaCD1-Phe1 and betaCD2-Phe1, respectively. The membrane-involved equilibrium simulations and the data of potential of mean forces (PMFs) further confirmed that Phe monomer was capable of penetrating through the membranes without confronting any large energy barrier, whereas, the single betaCD and betaCD-involved assemblies were unable to pass across the membranes. These observations clearly suggested that betaCD only served as the carrier to enhance the bioavailability of Phe rather than the co substrate in the Phe biodegradation process. The Phe-separation PMF profiles indicated that the maximum of the Phe uptake by bacteria would be achieved by the "optimal" betaCD:Phe molar ratio, which facilitated the maximal formation of betaCD1-Phe1 inclusion and the minimal construction of betaCD2-Phe1 complex. PMID- 25497026 TI - Visible and near-infrared reflectance spectroscopy is of limited practical use to monitor soil contamination by heavy metals. AB - In recent years, several authors have suggested repeatedly that visible and near infrared reflectance spectroscopy (VNIRS) could be an advantageous alternative to traditional wet-laboratory methods for the measurement of heavy metal concentrations in soils. In this comment, we argue that, on the contrary, VNIRS is of limited practical use in such a context and should not serve as an excuse to get rid of direly needed laboratory facilities. The key reasons are that VNIRS spectra are irremediably insensitive to the presence of heavy metals, that the effect of soil moisture and surface rugosity on VNIR sensing still has to be satisfactorily accounted for, and finally that VNIRS probes an extremely thin layer of soil at the surface, which is generally irrelevant in terms of plant growth. Given these intrinsic limitations, it seems indicated to put the persistent VNIRS myth to rest, and to explore other measurement techniques that may have more potential. PMID- 25497035 TI - Response to "Visible and near-infrared reflectance spectroscopy is of limited practical use to monitor soil contamination by heavy metals" by Philippe C. Baveye. PMID- 25497039 TI - Would a student midwife run postnatal clinic make a valuable addition to midwifery education in the UK?--a systematic review. AB - BACKGROUND: There is growing evidence in the UK that some National Health Service improvements, particularly in the postnatal period, are having an impact on the quality and variety of student midwives' clinical experiences, making it challenging for them to meet the standards set by the regulatory body for midwives and receive a licence to practice. A possible solution to this may be the introduction of a Student Midwife integrated Learning Environment (SMiLE) focusing upon the delivery of postnatal care (PN) through a student run clinic. OBJECTIVE: To identify the current state of knowledge, regarding the educational outcomes of students who engage with student run clinics (SRC) and the satisfaction of clients who attend them. Search strategy--BNI, CINAHL, EMBASE, and MEDLINE were searched for articles published until April 2014. SELECTION CRITERIA: Studies, nationally and internationally, were carried out on healthcare students running their own clinics. Outcome measures were the evaluation of educational outcomes of students and client satisfaction were included. DATA COLLECTION AND ANALYSIS: Data were extracted, analysed and synthesised to produce a summary of knowledge, regarding the effectiveness of SRCs. MAIN RESULTS: 6 studies were selected for this review. AUTHORS' CONCLUSIONS: The findings that SRC can offer advantages in improving educational outcomes of students and provide an effective service to clients are encouraging. However, given the limited number of high-quality studies included in this review, further research is required to investigate the effectiveness of SRC. PMID- 25497045 TI - Brazilian Journal of Pulmonology and Portuguese Journal of Pulmonology: strengthening ties in respiratory science. PMID- 25497040 TI - Investigating critical care nurses' perception regarding enteral nutrition. AB - BACKGROUND: Evidences showed that nurses lack the needed knowledge to administer nutritional care. Besides, nutritional information was found to be incomplete in patients' record, and nurses' responsibilities regarding EN were not well understood. In Jordan, literature regarding nurses' perceptions of EN is scarce. AIM: To investigate critical care nurses' perceptions regarding enteral nutrition (EN) of critically-ill adult patients. METHODS: A descriptive, cross-sectional, comparative design was used to collect data from 151 Jordanian critical care nurses utilizing the Nurses' Perception of Enteral Nutrition Questionnaire. RESULTS: Nurses in private hospitals scored the highest in regard to responsibility and support from documentation. Education, internet, and nursing school were the primary sources of EN knowledge. Besides, female nurses differ significantly from male nurses in regard to the perception of responsibility of EN. CONCLUSION: Awareness of responsibility, supportive documentation system, and implementation of the current evidences of EN in the actual daily practices can be used to improve EN practices. PMID- 25497042 TI - DNA methylation patterns of protein coding genes and long noncoding RNAs in female schizophrenic patients. AB - Schizophrenia (SCZ) is a complex mental disorder contributed by both genetic and epigenetic factors. Long noncoding RNAs (lncRNAs) was recently found playing an important regulatory role in mental disorders. However, little was known about the DNA methylation of lncRNAs, although numerous SCZ studies have been performed on genetic polymorphisms or epigenetic marks in protein coding genes. We presented a comprehensive genome wide DNA methylation study of both protein coding genes and lncRNAs in female patients with paranoid and undifferentiated SCZ. Using the methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq), 8,163 and 764 peaks were identified in paranoid and undifferentiated SCZ, respectively (p < 1 * 10-5). Gene ontology analysis showed that the hypermethylated regions were enriched in the genes related to neuron system and brain for both paranoid and undifferentiated SCZ (p < 0.05). Among these peaks, 121 peaks were located in gene promoter regions that might affect gene expression and influence the SCZ related pathways. Interestingly, DNA methylation of 136 and 23 known lncRNAs in Refseq database were identified in paranoid and undifferentiated SCZ, respectively. In addition, ~20% of intergenic peaks annotated based on Refseq genes were overlapped with lncRNAs in UCSC and gencode databases. In order to show the results well for most biological researchers, we created an online database to display and visualize the information of DNA methyation peaks in both types of SCZ (http://www.bioinfo.org/scz/scz.htm). Our results showed that the aberrant DNA methylation of lncRNAs might be another important epigenetic factor for SCZ. PMID- 25497046 TI - Portuguese Journal of Pulmonology as a journal open to a variety of respiratory research. PMID- 25497041 TI - Eight novel mutations in MLC1 from 18 Iranian patients with megalencephalic leukoencephalopathy with subcortical cysts. AB - Megalencephalic leukoencephalopathy with subcortical cysts (MLC) (MIM #604004) is a rare autosomal recessive neurological disorder characterized by macrocephaly, motor and cognitive decline, ataxia, spasticity and occasional seizures. Magnetic resonance imaging (MRI) shows diffusely abnormal and swollen white matter of the cerebral hemispheres and subcortical cysts in the anterior temporal and frontoparietal region. Mutations in MLC1(22q13.33) and GLIALCAM have been identified in patients with MLC. Mutations in MLC1 account for approximately 75% of the cases. MLC was suspected in eighteen Iranian patients from sixteen families based on positive clinical findings including macrocephaly beginning in the first year, neurocognitive deterioration, seizure or loss of consciousness after minor head trauma. All except two were born to consanguineous parents. Brain MRI images were compatible with MLC and confirmed the diagnosis. Sequencing of entire coding region of MLC1 was performed for seventeen patients and mutations in MLC1 were detected in all of them. Eight novel mutations and seven previously reported mutations were identified. This report shows that MLC is relatively common in Iranian population, as expected for rare diseases with high inbreeding, with a surprisingly high frequency of novel mutations. PMID- 25497043 TI - Long-term change of disease behavior in Papillon-Lefevre syndrome: seven years follow-up. AB - Papillon-Lefevre syndrome (PLS) is an autosomal recessive disease, characterized by severe periodontitis and palmoplantar hyperkeratosis. Mutations in the cathepsin C (CTSC) gene are the causative genetic factor. PLS starts at very early age, however, the age associated change of PLS has never been characterized. In this report, four PLS patients with CTSC mutations were followed up for seven years, periodontal condition and serum immunoglobulins (Igs) were recorded. Results showed that periodontal inflammation of PLS peaked at teenage years, but declined with time. At the same time the serum IgE change was consistent with the change, suggesting the possibility of using IgE as a monitoring index for PLS inflammation level, or to develop new target for therapy. PMID- 25497044 TI - Molecular characterization of a cohort of 73 patients with infantile spasms syndrome. AB - Infantile Spasms syndrome (ISs) is a characterized by epileptic spasms occurring in clusters with an onset in the first year of life. West syndrome represents a subset of ISs that associates spasms in clusters, a hypsarrhythmia EEG pattern and a developmental arrest or regression. Aetiology of ISs is widely heterogeneous including many genetic causes. Many patients, however, remain without etiological diagnosis, which is critical for prognostic purpose and genetic counselling. In the present study, we performed genetic screening of 73 patients with different types of ISs by array-CGH and molecular analysis of 5 genes: CDKL5, STXBP1, KCNQ2, and GRIN2A, whose mutations cause different types of epileptic encephalopathies, including ISs, as well as MAGI2, which was suggested to be related to a subset of ISs. In total, we found a disease-causing mutation or CNV (Copy Number Variation) in 15% of the patients. These included 6 point mutations found in CDKL5 (n = 3) and STXBP1 (n = 3), 3 microdeletions (10 Mb in 2q24.3, 3.2 Mb in 5q14.3 including the region upstream to MEF2C, and 256 kb in 9q34 disrupting EHMT1), and 2 microduplications (671 kb in 2q24.3 encompassing SCN2A, and 11.93 Mb in Xq28). In addition, we discuss 3 CNVs as potential risk factors, including one 16p12.1 deletion, one intronic deletion of the NEDD4 gene, and one intronic deletion of CALN1 gene. The present findings highlight the efficacy of combined cytogenetic and targeted mutation screening to improve the diagnostic yield in patient with ISs. PMID- 25497047 TI - Demographic and delivery characteristics associated with obstetric fistula in Kigali, Rwanda. AB - OBJECTIVE: To assess the characteristics of Rwandan women undergoing surgical correction of obstetric fistula. METHODS: A retrospective, cross-sectional study was conducted of women undergoing surgery to repair obstetric fistula as part of a program run by the International Organization for Women and Development in Kigali, Rwanda, between April 1, 2010, and February 28, 2011. Data were collected from medical records, including demographics, obstetric history, and results of the physical examination. RESULTS: A total of 65 women underwent fistula surgery in the study period. Among 59 women for whom relevant data were available, 43 (73%) reported that the fetus did not survive the pregnancy during which the fistula developed. Delivery had occurred in a healthcare facility for 49 (82%) of 60 women. Delivery was by cesarean in 31 (48%) women included in the analyses. Cervicovesical or uterovesical fistula occurred more frequently among women who underwent cesarean delivery (9 [29%]) than among those who underwent vaginal delivery (3 [9%] of 34; P=0.04). There was no difference in the number of fetal or neonatal deaths between the two groups (P=0.2). CONCLUSION: Approximately half of the women in the sample delivered by cesarean, and these women were more likely to have a fistula involving the uterus or cervix. PMID- 25497051 TI - Mother-baby friendly birthing facilities initiative. PMID- 25497048 TI - Coverage and distribution of obstetricians and gynecologists in Nigeria. AB - OBJECTIVE: To determine the number, regional spread, and population ratio of obstetricians and gynecologists (OB/GYNs) in Nigeria. METHODS: Data for the present descriptive study were collected between July 1, 2012, and December 31, 2013, as part of a national survey of OB/GYNs. Information was obtained about characteristics, qualifications, place of work, primary employer, subspecialty interest, and type of practice. RESULTS: In total, 968 OB/GYNs were identified, of whom 846 (87.4%) were male. The estimated national population in 2013 was 175651197, which meant that there was one OB/GYN for every 181 458 individuals. Lagos State had the highest number of OB/GYNs (179 [18.5%]), whereas Yobe State had only 2 (0.2%) and Jigawa State 1 (0.1%). The geopolitical region with the highest number of OB/GYNs was the South West (315 [32.5%]), whereas the North East had the lowest number (45 [4.6%]). CONCLUSION: The number of OB/GYNs in Nigeria is inadequate in view of the population size, and coverage varies greatly in different states. Efforts to improve maternal health and reduce the maternal mortality ratio should include more investment in training, engagement, and equitable distribution of OB/GYNs in all parts of the country. PMID- 25497049 TI - Reproductive and gynecologic health after uterine artery embolization for postabortion hemorrhage. PMID- 25497050 TI - Safety of induced abortions at less than 12 weeks of pregnancy in Japan. AB - OBJECTIVE: To assess the safety of various methods of induced abortion when used before 12 weeks of pregnancy in Japan. METHODS: A retrospective study was undertaken of induced abortions conducted between January 1 and December 31, 2012. Questionnaires were sent to 4154 institutions that employed doctors who were licensed to conduct induced abortions. Information was obtained about the numbers of induced abortions performed before 12 weeks, methods, complications, and routine management. RESULTS: Completed questionnaires from 2434 institutions showed that 100 851 induced abortions had been performed. Vacuum aspiration (VA) was used in 20 458 (20.3%) abortions, VA with sharp curettage in 47 148 (46.8%), dilatation and curettage (D&C) in 32 958 (32.7%), and medical abortion in 287 (0.3%). Overall, 358 complications were reported (355.0 per 100000 procedures). The rate of complications was significantly higher after D&C than after VA and after VA with sharp curettage (P<0.001 for both). However, incomplete abortion requiring repeat procedures was the only complication that was significantly associated with D&C (P<0.001). CONCLUSION: D&C can be safely used for induced abortion before 12 weeks of pregnancy, but changing from D&C to VA could reduce incomplete abortions and improve the safety of induced abortions before 12 weeks of pregnancy in Japan. PMID- 25497052 TI - Availability, utilization, and quality of emergency obstetric care services in Bauchi State, Nigeria. AB - OBJECTIVE: To report the availability, utilization, and quality of emergency obstetric care (EmOC) services in Bauchi State, Nigeria. METHODS: Between June and July 2012, a cross-sectional survey of health facilities was conducted. Data on the performance of EmOC services between June 2011 and May 2012 were obtained from records of 20 general hospitals and 39 primary healthcare centers providing delivery services. Additionally, structured interviews with facility managers were conducted. RESULTS: Only 6 (10.2%) of the 59 facilities met the UN requirements for EmOC centers. None of the three senatorial zones in Bauchi State had the minimum acceptable number of five EmOC facilities per 500 000 population. Overall, 10 517 (4.4%) of the estimated 239 930 annual births took place in EmOC facilities. Cesarean delivery accounted for 3.6% (n=380) of the 10 517 births occurring in EmOC facilities and 0.2% of the 239 930 expected live births. Only 1416 (3.9%) of the expected 35 990 obstetric complications were managed in EmOC facilities. Overall, 45 (3.2%) of 1416 women with major direct obstetric complications treated at EmOC facilities died. Among 379 maternal deaths, 317 (83.6%) were attributable to major direct obstetric complications. CONCLUSION: Availability, utilization, and quality of EmOC services in Bauchi State, Nigeria, are suboptimal. The health system's capacity to manage emergency obstetric complications needs to be strengthened. PMID- 25497053 TI - Refractory trigeminal neuralgia treatment outcomes following CyberKnife radiosurgery. AB - INTRODUCTION: A handful of studies have reported outcomes with CyberKnife radiosurgery (CKRS) for the treatment of trigeminal neuralgia. However, the follow-up has been short with no minimum follow-up required and have included patients with short duration of symptoms. Here we report our institutional experience on patients with a minimum follow-up of 1 year and a median follow-up of 28 months (mean 38.84 months). METHODS: Twenty-five patients with medically and surgically intractable TN received CKRS with a mean marginal radiation dose of 64 Gy applied to an average isodose line of 86% of the affected trigeminal nerve. Follow-up data were obtained by clinical examination and telephone questionnaire. Outcome results were categorized based on the Barrow Neurological Institute (BNI) pain scale with BNI I-III considered to be good outcomes and BNI IV-V considered as treatment failure. BNI facial numbness score was used to assess treatment complications. RESULTS: A large proportion of patients (42.9%) reported pain relief within 1 month following CKRS treatment. The mean time to recurrence of severe pain was 27.8 months (range 1-129 months). At median follow up of 28 months (mean 38.84 months), actuarial rate of freedom from severe pain (BNI >= III) was 72%. At last follow-up 2 (8%) patients had freedom from any pain and no medications (BNI I) and the majority (48%) had some pain that was adequately controlled with medications. Seven patients (28%) had no response to treatment and continued to suffer from severe pain (BNI IV or V). Patient's diabetic status and overall post-treatment BNI facial numbness scores were statistically significant predictors of treatment outcomes. CONCLUSION: CKRS represents an acceptable salvage option for with medically and/or surgically refractory patients. Even patients with severely debilitating symptoms may experience significant and sustained pain relief after CKRS. Particularly, CKRS remains an attractive option in patients who are not good surgical candidates or possibly even failed surgical therapy. This data should help in setting realistic expectations for weighing the various available treatment options. PMID- 25497054 TI - Biosequestration of atmospheric CO2 and flue gas-containing CO2 by microalgae. AB - The unceasing rise of greenhouse gas emission has led to global warming and climate change. Global concern on this phenomenon has put forward the microalgal based CO2 sequestration aiming to sequester carbon back to the biosphere, ultimately reducing greenhouse effects. Microalgae have recently gained enormous attention worldwide, to be the valuable feedstock for renewable energy production, due to their high growth rates, high lipid productivities and the ability to sequester carbon. The photosynthetic process of microalgae uses atmospheric CO2 and CO2 from flue gases, to synthesize nutrients for their growth. In this review article, we will primarily discuss the efficiency of CO2 biosequestration by microalgae species, factors influencing microalgal biomass productions, microalgal cultivation systems, the potential and limitations of using flue gas for microalgal cultivation as well as the bio-refinery approach of microalgal biomass. PMID- 25497055 TI - Torrefaction of cedarwood in a pilot scale rotary kiln and the influence of industrial flue gas. AB - Torrefaction of cedarwood was performed in a pilot-scale rotary kiln at various temperatures (200, 230, 260 and 290 degrees C). The torrefaction properties, the influence on the grindability and hydroscopicity of the torrefied biomass were investigated in detail as well as the combustion performance. It turned out that, compared with raw biomass, the grindability and the hydrophobicity of the torrefied biomass were significantly improved, and the increasing torrefaction temperature resulted in a decrease in grinding energy consumption and an increase in the proportion of smaller-sized particles. The use of industrial flue gas had a significant influence on the behavior of cedarwood during torrefaction and the properties of the resultant solid products. To optimize the energy density and energy yield, the temperature of torrefaction using flue gas should be controlled within 260 degrees C. Additionally, the combustion of torrefied samples was mainly the combustion of chars, with similar combustion characteristics to lignite. PMID- 25497056 TI - Critical comparison of different model structures for the applied simulation of the anaerobic digestion of agricultural energy crops. AB - Different model structures were compared to simulate the characteristic process variables of the anaerobic digestion of maize, sugar beet and grain silage. Depending on the type and number of the required components, it can be shown that in comparison to the complex Anaerobic Digestion Model No. 1 (ADM1) different simplified model structures can describe the gas production rate, ammonia nitrogen and acetate concentration or pH value equally well. Since the reduction of the predominantly fast kinetics of the methanogenesis, acetogenesis or acidogenesis will only have little effect on the simulation of the specific gas production, it can be proven that the hydrolysis is the rate-limiting step during the uninhibited anaerobic digestion of complex particulate substrates. However, the stoichiometric comparison reveals that the model protein gelatine is not suitable for a representative characterization of agricultural energy crops. PMID- 25497058 TI - Heterotrophic microalgae cultivation to synergize biodiesel production with waste remediation: progress and perspectives. AB - Microalgae are inexhaustible feedstock for synthesis of biodiesel rich in polyunsaturated fatty acids (PUFA) and valuable bioactive compounds. Their cultivation is critical in sustaining the global economy in terms of human consumption of food and fuel. When compared to autotrophic cultivation, heterotrophic systems are more suitable for producing high cell densities of microalgae for accumulation of large quantities of lipids (triacylglycerols) which can be converted into biodiesel. Consorted efforts are made in this communication to converge recent literature on heterotrophic cultivation systems with simultaneous wastewater treatment and algal oil production. Challenges faced during large scale production and limiting factors which hinder the microalgae growth are enumerated. A strategic deployment of integrated closed loop biorefinery concept with multi-product recovery is proposed to exploit the full potential of algal systems. Sustainable algae cultivation is essential to produce biofuels leading to green future. PMID- 25497059 TI - Enzyme kinetics determined by single-injection isothermal titration calorimetry. AB - The purposes of this paper are (a) to examine the effect of calorimeter time constant (tau) on heat rate data from a single enzyme injection into substrate in an isothermal titration calorimeter (ITC), (b) to provide information that can be used to predict the optimum experimental conditions for determining the rate constant (k2), Michaelis constant (KM), and enthalpy change of the reaction (DeltaRH), and (c) to describe methods for evaluating these parameters. We find that KM, k2 and DeltaRH can be accurately estimated without correcting for the calorimeter time constant, tau, if (k2E/KM), where E is the total active enzyme concentration, is between 0.1/tau and 1/tau and the reaction goes to at least 99% completion. If experimental conditions are outside this domain and no correction is made for tau, errors in the inferred parameters quickly become unreasonable. A method for fitting single-injection data to the Michaelis-Menten or Briggs Haldane model to simultaneously evaluate KM, k2, DeltaRH, and tau is described and validated with experimental data. All four of these parameters can be accurately inferred provided the reaction time constant (k2E/KM) is larger than 1/tau and the data include enzyme saturated conditions. PMID- 25497057 TI - Omega-3 fatty acid production from enzyme saccharified hemp hydrolysate using a novel marine thraustochytrid strain. AB - In this work, a newly isolated marine thraustochytrid strain, Schizochytrium sp. DT3, was used for omega-3 fatty acid production by growing on lignocellulose biomass obtained from local hemp hurd (Cannabis sativa) biomass. Prior to enzymatic hydrolysis, hemp was pretreated with sodium hydroxide to open the biomass structure for the production of sugar hydrolysate. The thraustochytrid strain was able to grow on the sugar hydrolysate and accumulated polyunsaturated fatty acids (PUFAs). At the lowest carbon concentration of 2%, the PUFAs productivity was 71% in glucose and 59% in the sugars hydrolysate, as a percentage of total fatty acids. Saturated fatty acids (SFAs) levels were highest at about 49% of TFA using 6% glucose as the carbon source. SFAs of 41% were produced using 2% of SH. This study demonstrates that SH produced from lignocellulose biomass is a potentially useful carbon source for the production of omega-3 fatty acids in thraustochytrids, as demonstrated using the new strain, Schizochytrium sp. DT3. PMID- 25497061 TI - Non-fatal extensive cerebral venous thrombosis as a complication of adenotonsillectomy. AB - Adenotonsillectomy, a common ambulatory surgical procedure performed in the pediatric population, may at times lead to serious postoperative complications. The case of a 10-year-old with extensive cerebral venous thrombosis (CVT) following routine adenotonsillectomy is presented and the likely risk factors are discussed. Recent literature regarding CVT in children will be reviewed. To our knowledge, there are no previous reports in the Otolaryngology literature of extensive CVT as a complication of adenotonsillectomy. This clinical entity is more common than previously thought. Awareness and a high index of suspicion and initiation of timely management can reduce the risk of potentially fatal outcomes. PMID- 25497062 TI - The association between pediatric general emergency department visits and post operative adenotonsillectomy hospital return. AB - PURPOSE: To define the association between pre-operative general emergency department visits, gender, and pre-operative diagnosis with post-operative emergency department return following adenotonsillectomy. METHODS: Retrospective chart review of 1468 pediatric patients who underwent adenotonsillectomy at a tertiary pediatric hospital between 2011 and 2013. RESULTS: There was a significant relationship between patients who visited the ED pre-operatively, 25% (N=96) returned to the ED post-procedure, compared to 10% who did not have a pre operative ED visit. There was an overall significant relation between having a pre-operative visit (chi(2)=53.6, df=1, p<0.001), female gender (female=56.9%; male=43.1%; chi(2)=4.2, df=1, p=0.04), and having a preoperative diagnosis of recurrent strep tonsillitis (OSA and RST=18%; RST=17.5%; OSA=11.8%; chi(2)=12.8, p=0.002) and having a post-operative ED visit. CONCLUSION: Generalized pre operative visits along with gender and diagnosis of recurrent streptococcal tonsillitis were found to be positively associated with post-operative ED visits for common post-operative complaints. PMID- 25497060 TI - Selective autophagy: xenophagy. AB - Xenophagy is an autophagic phenomenon that specifically involves pathogens and other non-host entities. Although the understanding of the relationship between autophagosomes and invading organisms has grown significantly in the past decade, the exact steps to confirm xenophagy has been not been thoroughly defined. Here we describe a methodical approach to confirming autophagy, its interaction with bacterial invasion, as well as the specific type of autophagic formation (i.e. autophagosome, autolysosome, phagolysosome). Further, we argue that xenophagy is not limited to pathogen interaction with autophagosome, but also non-microbial entities such as iron. PMID- 25497063 TI - Histamine skin reactivity increases with body mass index in Korean children. AB - OBJECTIVE: Histamine skin prick testing is most commonly used to diagnose immunoglobulin E (IgE)-mediated allergic diseases, and histamine reactivity is used as a standardized positive control in the interpretation of a skin prick test. However, reactivity to histamine differs among individuals for reasons that are poorly understood. The present study aimed to evaluate the potential association between body mass index (BMI) and histamine skin reactivity in children. METHODS: A total of 451 children (246 boys, 205 girls) aged 7-8 years were enrolled in this study. The skin prick test was performed with 26 aeroallergens commonly found in Korea. Other information was collected, including sex, age, BMI, parental allergy history, and parental smoking status. Multivariate analysis was used to confirm the association between histamine skin reactivity and BMI. RESULTS: The histamine wheal size was revealed to be associated with BMI (Spearman's Rho 0.161, p<0.001). This association was confirmed by multivariate analysis, after adjusting for sex, age, parental allergy history, parental smoking status, and allergic sensitization (coefficient B 0.071, 95% confidence interval 0.030-0.112). CONCLUSIONS: Skin responses to histamine were primarily correlated with increased BMI. Further studies are needed to understand the clinical implication of BMI when interpreting the results of skin prick test. PMID- 25497065 TI - Optical dissection of brain circuits with patterned illumination through the phase modulation of light. AB - Brain function relies on electrical signaling among ensembles of neurons. These signals are encoded in space - neurons are organized in complex three-dimensional networks - and in time-cells generate electrical signals on a millisecond scale. How the spatial and temporal structure of these signals controls higher brain functions is largely unknown. The recent advent of novel molecules that manipulate and monitor electrical activity in genetically identified cells provides, for the first time, the ability to causally test the contribution of specific cell subpopulations in these complex brain phenomena. However, most of the commonly used approaches are limited in their ability to illuminate brain tissue with high spatial and temporal precision. In this review article, we focus on one technique, patterned illumination through the phase modulation of light using liquid crystal spatial light modulators (LC-SLMs), which has the potential to overcome some of the major limitations of current experimental approaches. PMID- 25497064 TI - Threshold segmentation algorithm for automatic extraction of cerebral vessels from brain magnetic resonance angiography images. AB - BACKGROUND: Cerebrovascular segmentation plays an important role in medical diagnosis. This study was conducted to develop a threshold segmentation algorithm for automatic extraction and volumetric quantification of cerebral vessels on brain magnetic resonance angiography (MRA) images. NEW METHODS: The MRA images of 10 individuals were acquired using a 3 Tesla MR scanner (Intera-achieva SMI-2.1, Philips Medical Systems). Otsu's method was used to divide the brain MRA images into two parts, namely, foreground and background regions. To extract the cerebral vessels, we performed the threshold segmentation algorithm on the foreground region by comparing two different statistical distributions. Automatically segmented vessels were compared with manually segmented vessels. RESULTS: Different similarity metrics were used to assess the changes in segmentation performance as a function of a weighted parameter w used in segmentation algorithm. Varying w from 2 to 100 resulted in a false positive rate ranging from 117% to 3.21%, and a false negative rate ranging from 8.23% to 28.97%. The Dice similarity coefficient (DSC), which reflected the segmentation accuracy, initially increased and then decreased as w increased. The suggested range of values for w is [10, 20] given that the maximum DSC (e.g., DSC=0.84) was obtained within this range. COMPARISON WITH EXISTING METHOD(S): The performance of our method was validated by comparing with manual segmentation. CONCLUSION: The proposed threshold segmentation method can be used to accurately and efficiently extract cerebral vessels from brain MRA images. Threshold segmentation may be used for studies focusing on three-dimensional visualization and volumetric quantification of cerebral vessels. PMID- 25497067 TI - Exploring prostate cancer survivors' self-management behaviours and examining the mechanism effect that links coping and social support to health-related quality of life, anxiety and depression: a prospective longitudinal study. AB - OBJECTIVE: Little is known about the influence of psycho-social factors on health related quality of life (HRQoL), anxiety and depression in men affected by prostate cancer. Developing an understanding in this area can help to identify men who are at high risk of inadequate support and suggest directions for appropriately targeted interventions. Moreover, little is known about how men affected by prostate cancer mobilise social support in their self-management behaviours over time. This is the first study to test the effects of coping and social support on HRQoL and emotional outcome, and assessed the self-management behaviours of men affected by prostate cancer overtime. METHODS: The study population was 74 prostate cancer patients with a mean age of 67.3 (SD 7.9) years and mixed treatment modalities. The EORTC QLQ-C30, PR25 and HADS were used to assess the dependant variables before treatment and at six months follow-up. Statistical analysis was performed in SPSS version 17.0 using parametric tests and non-parametric tests. RESULTS: A significant decline in quality of life was observed at 6 months post diagnosis (p < 0.001). Perceived social support before radical treatment was the most important social support construct that predicted better global quality of life and less depression at six months, explaining approximately 30% of the variance. Despite men's self-management efforts and use of social support overtime, self-management self-efficacy significantly reduced at six months (p < 0.05). CONCLUSION: These findings provide support towards the development of a psycho-social intervention study to improve quality of life, self-management self-efficacy and improve patients' symptom management. PMID- 25497068 TI - Limitations of 18F-2-deoxy-D-glucose positron emission tomography in N1 detection in patients with pathologic stage II-N1 and implications for management. AB - BACKGROUND: The definitive use of 18F-2-deoxy-d-glucose positron emission tomography (FDG-PET) to detect nodal metastasis in patients with early-stage non small cell lung cancer (NSCLC) being evaluated for local nonsurgical management, such as stereotactic body radiation therapy and minimally invasive percutaneous ablative therapies, underscores the importance of diagnosing N1 disease by FDG PET. The purpose of this study was to evaluate FDG-PET in the detection of N1 disease and to determine if FDG-PET-positive N1 disease predicts poor survival in patients with pathologic stage II-N1 NSCLC. METHODS: We reviewed all patients who underwent surgical resection for lung cancer at MD Anderson Cancer Center from 2000 to 2011 who had pathologic stage T1 to T2 and N1 disease and a preoperative FDG-PET. We compared the clinicopathologic characteristics and survival of patients who had PET-positive N1 and PET-negative N1 disease. RESULTS: A total of 104 patients met the inclusion criteria. The pathologic stage in 87 patients was IIA (T1a N1, T1b N1 or T2a N1) and in 17 patients was IIB (T2b N1). Only 25 of 104 patients (24%) had PET-positive N1 disease. There was no clinical or pathologic difference between the patients who had PET-positive N1 and PET negative N1 disease. No significant difference was found in the survival rates between patients from the PET-positive N1 and the PET-negative N1 groups (p = 0.9). CONCLUSIONS: FDG-PET has poor sensitivity in detecting N1 disease, and N1 positive disease on FDG-PET does not have an effect on survival. FDG-PET should not be used alone to determine management in patients with early-stage non-small cell lung cancer being evaluated for local nonsurgical management. PMID- 25497069 TI - Determining factors in diagnosing pulmonary sarcoidosis by endobronchial ultrasound-guided transbronchial needle aspiration. AB - BACKGROUND: Although the role of endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) in pulmonary sarcoidosis has previously been investigated, the determining factors in diagnosing sarcoidosis by EBUS-TBNA without rapid on-site evaluation (ROSE) are unclear. METHODS: Patients with clinically and radiographically suspected sarcoidosis underwent EBUS-TBNA without ROSE in a prospective study. Presence of non-caseating epithelioid cell granulomas was pathologic evidence of sarcoidosis. RESULTS: The EBUS-TBNA was performed in 120 patients, 111 of whom had confirmed sarcoidosis. For the patients with sarcoidosis (62 stage I, 49 stage II) EBUS-TBNA provided sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 93.69%, 100%, 100%, 56.25%, and 94.17%, respectively, in the diagnosis of sarcoidosis. Diagnostic yield of EBUS-TBNA for sarcoidosis was associated with disease stage, but not associated with serum angiotensin converting enzyme level, number of lymph node stations sampled per patient, or total number of passes performed per patient. At EBUS-TBNA, 284 mediastinal and hilar lymph nodes were aspirated in 111 patients. Multivariate logistic regression revealed that short-axis diameter and more than 1 needle pass per lymph node were independent risk factors associated with positive pathology. No major procedure-related complications were observed. CONCLUSIONS: Endobronchial ultrasound-guided transbronchial needle aspiration is a safe procedure with high sensitivity for diagnosing sarcoidosis, having a higher diagnostic yield in stage I than stage II. To obtain a higher diagnostic yield of EBUS-TBNA in pulmonary sarcoidosis without ROSE, operators should select the largest mediastinal or hilar lymph node accessible and puncture with 3 to 5 passes. PMID- 25497066 TI - Lemierre's syndrome: a pharyngotonsillitis complication. PMID- 25497070 TI - Hospital readmission after pulmonary lobectomy is not affected by surgical approach. AB - BACKGROUND: The aim of this study is to identify the predictors of hospital readmission or early unplanned return to clinic within 30 days of discharge after pulmonary lobectomy. METHODS: The medical records of patients undergoing lobectomy by the thoracic surgery service between January 2009 and July 2012 were reviewed. All lobectomies were included irrespective of the etiology of disease. Multivariate logistic regression methods were used to identify predictors of readmission and or early unplanned return to clinic. RESULTS: Two hundred thirteen patients underwent a pulmonary lobectomy during the study period (median age, 67 years). Pathologic diagnosis was malignant in 94% of the patients and benign in 6%. Minimally invasive approaches were used in 69% of the patients, whereas open thoracotomy was used in 31%. Median hospital length of stay was 4 days, and postoperative mortality occurred in 1 patient (0.5%). The Charlson comorbidity index was 1 +/- 1. Predicted postoperative forced expiratory volume in 1 second and diffusing capacity of the lung for carbon monoxide were 68% +/- 18% and 64% +/- 17%, respectively. Postoperative complications occurred in 31% of patients; 13% required readmission to the hospital within 30 days of discharge or early unplanned return to clinic. Predictors of readmission or early unplanned return to clinic were unplanned transfer to the intensive care unit (odds ratio, 10.4; 95% confidence interval, 1.1 to 103.5; p = 0.04) and Charlson comorbidity index greater than 0 (odds ratio, 1.5; 95% confidence interval, 1.04 to 2.03; p = 0.03). Readmission or early unplanned return to clinic was independent of surgical approach (p = 0.32). CONCLUSIONS: Patients who require a postoperative transfer to the intensive care unit or with higher Charlson comorbidity index are at higher risk for hospital readmission after pulmonary lobectomy. Readmission was not affected by the surgical approach. Whether a different strategy to follow up for these high-risk patients can prevent readmission remains to be determined. PMID- 25497072 TI - Management of benign dynamic "A-shape" tracheal stenosis: a retrospective study of 60 patients. AB - BACKGROUND: Benign tracheal stenosis complicates tracheal intubation or tracheostomy in 0.6% to 65% of cases. Surgical resection is the standard treatment. Endoscopic management is used for inoperable patients with 17% to 69% success. Dynamic "A-shape" tracheal stenosis (DATS) results in a dynamic stenosis with anterior fracture of tracheal cartilage and frequently associated posterior malacia. We report the results of our multidisciplinary management. METHODS: Sixty patients with DATS were included. Management decision was made during initial bronchoscopy. When suitable, patients were referred to thoracic surgery for tracheal resection. Posterior localized tracheomalacia was treated with laser photocoagulation of the posterior tracheal wall. Tracheal stents were placed if the stenosis persisted after laser treatment. The choice of stent (straight silicone, hour-glass shaped silicone, T-tube, or fully-covered self-expandable metallic stent) was based on operator's judgment. After 12 to 18 months, stents were removed. If the stenosis persisted after stent removal, surgery was reconsidered. If surgery was not possible, a stent was replaced. In case of satisfactory result, a stent was replaced only after recurrence. Stable patients after treatment were considered as success, requirement of long-term tracheostomy or T tube as failure, and long-term stent as partial success. RESULTS: All patients developed DATS after tracheostomy. Thirty-three patients had posterior tracheomalacia. In 13 patients, mild stenosis required only endoscopic surveillance. Two patients were referred to thoracic surgery for tracheal resection surgery. Endoscopic management was the initial therapy in 45 patients (75%) and was considered successful in 23 patients (51%), partially successful in 10 (22%), and failed in 12 (27%). Five patients with successful outcomes required only laser therapy. Overall 70 stents were placed in 35 patients, with a migration rate of 31%. CONCLUSIONS: The DATS management was successful in 63%. Stent migration was frequent. Posterior tracheomalacia was successfully treated in selected cases, avoiding stent placement. PMID- 25497071 TI - Effects of scaffold material used in cardiovascular surgery on mesenchymal stem cells and cardiac progenitor cells. AB - BACKGROUND: Polytetrafluoroethylene (PTFE) and porcine small intestinal submucosa (pSIS) are patch materials used in congenital heart surgery. Porcine SIS is an extracellular-matrix scaffold that may interact with stem or progenitor cells. To evaluate this, we determined the in vitro effects of pSIS and PTFE on human bone marrow mesenchymal stromal cells (MSCs) and cardiac progenitor cells (CPCs) in 3 areas; cell proliferation, angiogenic growth-factor production, and differentiation. METHODS: Human MSCs and CPCs were seeded onto pSIS and PTFE patches. Cell-seeded patches were cultured and then assessed for cell viability and proliferation and supernatant vascular endothelial growth factor A (VEGFA) levels. Cell proliferation was quantified by MTT assay (3-[4,5-dimethylthiazol-2 yl]-2,5-diphenyltetrazolium bromide). Quantitative real-time polymerase chain reaction was performed on cell-seeded scaffolds to determine relative changes in gene expression related to angiogenesis and cardiogenesis. RESULTS: The MSCs and CPCs were able to attach and proliferate on pSIS and PTFE. The proliferation rate of each cell type was similar on pSIS. Total RNA isolation was only possible from the cell-seeded pSIS patches. The MSC VEGFA production was increased by pSIS. Porcine SIS promoted an angiogenic gene profile in MSCs and an early cardiogenic profile in CPCs. CONCLUSIONS: Both PTFE and pSIS allow for varying degrees of cell proliferation. Porcine SIS elicits different phenotypical responses in MSCs as compared with CPCs, which indicates that pSIS may be a bioactive scaffold that modulates stem cell activation and proliferation. These findings highlight the differences in scaffold material strategies and suggest potential advantages of bioactive approaches. PMID- 25497073 TI - Comparison of the oncologic outcomes of anatomic segmentectomy and lobectomy for early-stage non-small cell lung cancer. AB - Interest has been renewed in segmentectomy for non-small cell lung cancer (NSCLC). However, whether the oncologic outcomes are comparable with lobectomy is conflicting. To assess the evidence base, a systematic search identified 31 comparative studies for meta-analysis. No higher local or distant recurrence in segmentectomy compared with lobectomy. Nevertheless, worse outcomes in overall and recurrence-free survival for patients treated with segmentectomy were found. Lobectomy conferred a significant survival advantage compared with segmentectomy for stage I. However, segmentectomy was more suitable for stage IA NSCLC, with survivals equivalent to lobectomy. Further randomized controlled trials are needed to confirm the results. PMID- 25497074 TI - The value of adding laboratory data to coronary artery bypass grafting registry data to improve models for risk-adjusting provider mortality rates. AB - BACKGROUND: Clinical databases are currently being used for calculating provider risk-adjusted mortality rates for coronary artery bypass grafting (CABG) in a few states and by the Society for Thoracic Surgeons. These databases contain very few laboratory data for purposes of risk adjustment. METHODS: For 15 hospitals, New York's CABG registry data from 2008 to 2010 were linked to laboratory data to develop statistical models comparing risk-adjusted mortality rates with and without supplementary laboratory data. Differences between these two models in discrimination, calibration, and outlier status were compared, and correlations in hospital risk-adjusted mortality rates were examined. RESULTS: The discrimination of the statistical models was very similar (c = 0.785 for the registry model and 0.797 for the registry/laboratory model, p =0.63). The correlation between hospital risk-adjusted mortality rates by use of the two models was 0.90. The registry/laboratory model contained three additional laboratory variables: alkaline phosphatase (ALKP), aspartate aminotransferase (AST), and prothrombin time (PT). The registry model yielded one hospital with significantly higher mortality than the statewide average, and the registry/laboratory model yielded no outliers. CONCLUSIONS: The clinical models with and without laboratory data had similar discrimination. Hospital risk adjusted mortality rates were essentially unchanged, and hospital outlier status was identical. However, three laboratory variables, ALKP, AST, and PT, were significant independent predictors of mortality, and they deserve consideration of addition to CABG clinical databases. PMID- 25497075 TI - Is transfusion associated with graft occlusion after cardiac operations? AB - BACKGROUND: Packed red blood cell (RBC) transfusions are associated with increased mortality after coronary artery bypass grafting (CABG) but not after cardiac valve operations. Transfusions are associated with increased strokes and deep venous thromboses after cardiac operations as well as increased peripheral vascular graft thrombosis. The purpose of this study was to determine if RBC transfusions were associated with a greater hazard of an occluded graft developing after CABG. METHODS: Patients who underwent symptom-driven coronary artery angiography after CABG were analyzed using Cox models and propensity scoring to compare outcomes based on the RBC transfusion status during their index CABG hospitalization. RESULTS: We analyzed 940 patients. We found that patients who received transfusions were more likely to have occluded grafts on angiography (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.03-1.50; p = 0.02). After adjusting for other factors, we found that RBC transfusion was associated with about a 20% increased hazard of graft occlusion (HR, 1.21; 95% CI,1.07-1.37; p = 0.003). CONCLUSIONS: Perioperative RBC transfusion is associated with graft occlusion after CABG at both the patient and graft levels. These results add to the growing body of evidence that homologous RBC transfusion is not risk free but is associated with a variety of adverse effects including midterm graft failure. PMID- 25497076 TI - An active lifestyle induces positive antioxidant enzyme modulation in peripheral blood mononuclear cells of overweight/obese postmenopausal women. AB - AIMS: The aim of this study was to investigate the effects of an active lifestyle on mitochondrial functioning, viability, bioenergetics, and redox status markers in peripheral blood mononuclear cells (PBMC) of overweight/ obese postmenopausal women. MATERIALS AND METHODS: We performed a cross-sectional study with postmenopausal women aged 45-64 years and body mass index N 25 kg/m2, divided into physically active (n = 23) and sedentary (n = 12) groups. Mitochondria functioning and viability, bioenergetics and redox status parameters were assessed in PBMC with spectrophotometric and fluorometric assays. KEY FINDINGS: No differences were found in the enzyme activity of complexes I and II of the electron transport chain (ETC), mitochondrial superoxide dismutase (MnSOD) activity, methyl-tetrazolium reduction levels and reduced glutathione and oxidized glutathione levels between the groups. However, the physically active group presented higher levels of reactive oxygen species (ROS) (P= 0.04) and increased catalase (CAT) (P= 0.029), total (P= 0.011) and cytosolic SOD (CuZnSOD) (P= 0.009) activities. SIGNIFICANCE: An active lifestyle that includes aerobic exercise for at least 30 min, three times per week may improve antioxidant enzyme activities in PBMC in overweight/obese postmenopausal women, without changes in the activity of the ETC enzymes. However, this low intensity physical activity is not able to induce relevant mitochondrial adaptations. PMID- 25497077 TI - Is there a relationship between the presence of ponticulus posticus and elongated styloid process? AB - This study aimed to determine if there is a possible relationship concerning the presence of ponticulus posticus (PP) in patients with elongated styloid process (ESP) on three-dimensional cone beam computed tomography (CBCT) images. The presence or absence of the PP (whether partial or complete) was determined and noted as a positive or negative finding. Then, the patients with PP were evaluated for ESP. For this purpose, 3-D CBCT scanning digital images of 542 patients having ESP (247 males and 295 females) were examined retrospectively. There was a significant relationship between the presence of PP and ESP (P=.03). The results of this study suggest that there is a significant correlation between the presence of PP and ESP. To our knowledge, this is the first study investigating the relationship between the two disorders in the literature. PMID- 25497079 TI - Stress and fear responses in the teleost pallium. AB - Evolution has resulted in behavioural responses to threat which show extensive similarities between different animal species. The reaction to predator cues is one example of such prevailing responses, and functional homologies to mammalian limbic regions involved in threat-sensitive behaviour have been found in the teleost telencephalon. The dorsolateral (Dl) and dorsomedial (Dm) regions of the pallium are thought to perform hippocampus and amygdala-like functions respectively. To what degree these regions are involved in the neuroendocrine responses to stress and predator cues however remains largely unknown. In the present study the involvement of Dl and Dm in such responses was investigated by exposing Nile tilapia (Oreochromis niloticus) to a standardized confinement stress and to skin extract from conspecifics. Nile tilapia develops a characteristic anticipatory behaviour to hand feeding, and effects of skin extract on this behaviour and locomotor activity were studied to characterise threat sensitive behaviour. Nile tilapia responded behaviourally to conspecific alarm cues by reducing feeding anticipatory behaviour. This may reflect a general elevation of alertness, and further studies combining skin extract with other challenges are needed to reveal neuroendocrine effects associated with this predator cue. Confinement stress resulted in an elevation of cortisol and serotonin (5-hydroxytryptamine, 5-HT) metabolism in both Dl and Dm. A similar tendency was observed in fish exposed to chemical alarm cues, but this effect did not reach the level of statistical significance. Hence, limbic responses to stress and fear, akin to those seen in extant mammals, are also present in the teleost lineage. PMID- 25497082 TI - Attenuated or absent HRV response to postural change in subjects with primary insomnia. AB - Previous studies have compared rest heart rate variability (HRV) between insomniacs and good sleepers, but the results have not been consistent. The altered HRV behavior in response to postural change was considered useful as another sensitive measure for evaluating the autonomic nervous function, however, to our knowledge, no study was found using HRV response to postural change in primary insomnia. Our study aimed to examine HRV response to postural change maneuver (PCM) in both primary insomniacs and controls between 22 and 39 years of age to gain insights into the characteristics of the autonomic nervous system (ANS) function in primary insomnia subjects. HRV was recorded for 5 min at seated rest, and then, the subjects quickly stood up from a seated position in up to 3s and remained standing for 15 min. HRV was recorded at the following times: seated rest and 0-5 min, 5-10 min and 10-15 min in the standing position. In primary insomnia subjects, attenuated or absent HRV response to postural change was identified, the increase in LF/HF ratio and the decrease in HF and SD1 from seated to standing were much slower than in the normal controls. In conclusion, this study provided evidence of the possible bi-directional relationship between insomnia and autonomic nervous system (ANS) function, which will move us closer to developing a new sensitive method for measuring autonomic impairment and early sympathetic damage in primary insomnia subjects. PMID- 25497081 TI - Taste preferences and taste thresholds to classical taste substances in the carnivorous fish, kutum Rutilus frisii kutum (Teleostei: Cyprinidae). AB - The objective of this study was to compare the taste preferences in the closely related sympatric fish species with different feeding patterns. For this purpose, palatability for four classical taste substances was evaluated for carnivorous kutum Rutilus frisii kutum and the results were compared with the taste preferences of the omnivorous roach Rutilus rutilus which had been studied earlier. In addition, the threshold concentration and the dose-response relationship of the most palatable tastants were evaluated and the ability of kutum to differentiate food with tastants in different concentrations was estimated. It was found that citric acid significantly increases the agar gel pellet consumption within the range of concentrations from 0.01M to 0.52M; the pellets with a concentration of 0.026M were the most palatable. The pellet consumption is significantly different if the concentration of citric acid in the pellets differs more than two times. The absolute threshold concentration is 0.01M, or 2.74MUg of citric acid per pellet. Sucrose and NaCl have deterrent taste at the highest concentrations tested (0.29 and 1.73M, respectively). Both substances are palatable at 10 times lower concentrations and become indifferent after further gradual decrease in their concentration. CaCl2 decreases the pellets consumption at 0.9M but is an indifferent tastant at lower concentrations (0.45, 0.09 and 0.045M). The number of rejections and repeated grasps of a food pellet is fewness and is not related to the pellet's palatability, while the retention time of pellet in the oral cavity positively and highly correlates with the pellet's palatability. Kutum have opposite taste preferences for most substances tested in comparison with the roach. It indicates that the taste preferences mediated by the oral taste receptors are different in closely related sympatric fish displayed diet divergences. PMID- 25497080 TI - Environmental modulation of same-sex affiliative behavior in female meadow voles (Microtus pennsylvanicus). AB - The effects of temperature and food availability on social bonds and group formation are poorly understood. Because seasonal transitions in female social behavior facilitate the assembly of winter groups in meadow voles, we explored the role of same-sex female associations in winter sociality. To examine the effects of winter typical environmental conditions on same-sex female affiliative behavior, paired female meadow voles were housed in varying combinations of day length, temperature, and food availability for 7weeks and then tested for social preference. In short days (SDs), lower ambient temperature increased huddling with unfamiliar females without interfering with existing social bonds, whereas lower temperature disrupted the retention of bonds in long days (LDs). Mild food restriction with no discernible effects on body mass enhanced affiliative behavior in SDs, but not LDs. A second experiment examined the effects of sex and day length on the propensity to aggregate with unfamiliar same-sex voles. Compared to LD females and SD males, SD females spent more time in group huddles with unfamiliar voles and displayed no social preference. These outcomes indicate that winter-like conditions enhance affiliative behavior between females and that pre-existing social bonds do not preclude integration into new winter social groups. The adaptive value of these behaviors is discussed. PMID- 25497083 TI - Electrical stimulation for pain relief in knee osteoarthritis: systematic review and network meta-analysis. AB - OBJECTIVE: To investigate the efficacy of different electrical stimulation (ES) therapies in pain relief of patients with knee osteoarthritis (OA). METHOD: Electronic databases including MEDLINE, Embase and Cochrane Library were searched through for randomized controlled trials (RCTs) comparing any ES therapies with control interventions (sham or blank) or with each other. Bayesian network meta analysis was used to combine both the direct and indirect evidence on treatment effectiveness. RESULTS: 27 trials and six kinds of ES therapies, including high frequency transcutaneous electrical nerve stimulation (h-TENS), low-frequency transcutaneous electrical nerve stimulation (l-TENS), neuromuscular electrical stimulation (NMES), interferential current (IFC), pulsed electrical stimulation (PES), and noninvasive interactive neurostimulation (NIN), were included. IFC is the only significantly effective treatment in terms of both pain intensity and change pain score at last follow-up time point when compared with the control group. Meanwhile, IFC showed the greatest probability of being the best option among the six treatment methods in pain relief. These estimates barely changed in sensitivity analysis. However, the evidence of heterogeneity and the limitation in sample size of some studies could be a potential threat to the validity of results. CONCLUSION: IFC seems to be the most promising pain relief treatment for the management of knee OA. However, evidence was limited due to the heterogeneity and small number of included trials. Although the recommendation level of the other ES therapies is either uncertain (h-TENS) or not appropriate (l-TENS, NMES, PES and NIN) for pain relief, it is likely that none of the interventions is dangerous. LEVEL OF EVIDENCE: LevelII, systematic review and network meta analysis of RCTs. PMID- 25497084 TI - C1QBP negatively regulates the activation of oncoprotein YBX1 in the renal cell carcinoma as revealed by interactomics analysis. AB - The Y-box-binding protein 1 (YBX1) plays a critical role in tumorigenesis by promoting cell proliferation, overriding cell-cycle check points, and enhancing genomic instability. In this study, the interactome of YBX1 in renal cell carcinoma (RCC) was analyzed by coimmunoprecipitation and mass spectrometry to better understand its function and regulatory mechanism. A total of 129 proteins were identified as potential YBX1 binding partners. The interaction between the complement component 1, q subcomponent binding protein (C1QBP), and YBX1 was further confirmed by immunoprecipitation and Western blotting. Knockdown of C1QBP enhanced the phosphorylation of YBX1and its nuclear translocation, indicating that C1QBP negatively regulated YBX1 activation. The clinical significance of these two proteins was analyzed in the tissues from 52 RCC patients by immunohistochemistry. Expression of YBX1 was markedly elevated in the carcinoma tissues, and its nuclear expression was associated with histological T stage and metastasis. Meanwhile, the level of C1QBP in the carcinoma tissues was significantly lower than that in the adjacent healthy tissues, which was negatively correlated with the nuclear localization of YBX1 in the RCC tissues (P = 0.011). These data suggest that C1QBP is a novel regulator of YBX1, and the expression of C1QBP and the nuclear expression of YBX1 could both be used as independent prognostic makers for cancer progression in the RCC patients. The proteomics data have been deposited to the ProteomeXchange with identifier PXD001493. PMID- 25497085 TI - Longitudinal change in white matter microstructure in Huntington's disease: The IMAGE-HD study. AB - OBJECTIVE: To quantify 18-month changes in white matter microstructure in premanifest (pre-HD) and symptomatic Huntington's disease (symp-HD). To investigate baseline clinical, cognitive and motor symptoms that are predictive of white matter microstructural change over 18months. METHOD: Diffusion tensor imaging (DTI) data were analyzed for 28 pre-HD, 25 symp-HD, and 27 controls scanned at baseline and after 18months. Unbiased tract-based spatial statistics (TBSS) methods were used to identify longitudinal changes in fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) of white matter. Stepwise linear regression models were used to identify baseline clinical, cognitive, and motor measures that are predictive of longitudinal diffusion changes. RESULTS: Symp-HD compared to controls showed 18-month reductions in FA in the corpus callosum and cingulum white matter. Symp-HD compared to pre-HD showed increased RD in the corpus callosum and striatal projection pathways. FA in the body, genu, and splenium of the corpus callosum was significantly associated with a baseline clinical motor measure (Unified Huntington's Disease Rating Scale: total motor scores: UHDRS-TMS) across both HD groups. This measure was also the only independent predictor of longitudinal decline in FA in all parts of the corpus callosum across both HD groups. CONCLUSIONS: We provide direct evidence of longitudinal decline in white matter microstructure in symp-HD. Although pre-HD did not show longitudinal change, clinical symptoms and motor function predicted white matter microstructural changes for all gene positive subjects. These findings suggest that loss of axonal integrity is an early hallmark of neurodegenerative changes which are clinically relevant. PMID- 25497078 TI - Examination of the perception of sweet- and bitter-like taste qualities in sucralose preferring and avoiding rats. AB - Sucralose avoiding rats detect a bitter-like taste quality in concentrations of sucralose that are strongly preferred over water by sucralose preferring rats. Here, we investigated whether sucralose preferrers (SP) also detect a bitter-like quality in sucralose that may be masked by an increased perception of sucralose's sweet-like quality. A microstructural analysis of sucralose intake revealed that, at concentrations they avoided in preference tests, sucralose avoiders (SA) consumed smaller and fewer bouts of sucralose than SP. Interestingly, the concentration-dependent increase in sucralose preference in SP was not associated with larger bouts or increased lick rate, two measures that are expected to increase with increasing perceived sweetness. This suggests that SP can detect an aversive quality in sucralose, but this perception of a presumably bitter-like quality may be masked by increased salience of a sweet-like quality that sustains high levels of intake in SP. Further evidence for increased sweet-taste perception in SP, relative to SA, was obtained in a second study in which SP consumed more of a palatable sweet-milk diet than SA. These are the first data to suggest that SP are not blind to the bitter-like quality in sucralose, and that there may be differences in sweet-taste perception between SP and SA. PMID- 25497086 TI - Alarmins MRP8 and MRP14 induce stress tolerance in phagocytes under sterile inflammatory conditions. AB - Hyporesponsiveness by phagocytes is a well-known phenomenon in sepsis that is frequently induced by low-dose endotoxin stimulation of Toll-like receptor 4 (TLR4) but can also be found under sterile inflammatory conditions. We now demonstrate that the endogenous alarmins MRP8 and MRP14 induce phagocyte hyporesponsiveness via chromatin modifications in a TLR4-dependent manner that results in enhanced survival to septic shock in mice. During sterile inflammation, polytrauma and burn trauma patients initially present with high serum concentrations of myeloid-related proteins (MRPs). Human neonatal phagocytes are primed for hyporesponsiveness by increased peripartal MRP concentrations, which was confirmed in murine neonatal endotoxinemia in wild-type and MRP14(-/-) mice. Our data therefore indicate that alarmin-triggered phagocyte tolerance represents a regulatory mechanism for the susceptibility of neonates during systemic infections and sterile inflammation. PMID- 25497087 TI - Genome-wide bisulfite sequencing in zygotes identifies demethylation targets and maps the contribution of TET3 oxidation. AB - Fertilization triggers global erasure of paternal 5-methylcytosine as part of epigenetic reprogramming during the transition from gametic specialization to totipotency. This involves oxidation by TET3, but our understanding of its targets and the wider context of demethylation is limited to a small fraction of the genome. We employed an optimized bisulfite strategy to generate genome-wide methylation profiles of control and TET3-deficient zygotes, using SNPs to access paternal alleles. This revealed that in addition to pervasive removal from intergenic sequences and most retrotransposons, gene bodies constitute a major target of zygotic demethylation. Methylation loss is associated with zygotic genome activation and at gene bodies is also linked to increased transcriptional noise in early development. Our data map the primary contribution of oxidative demethylation to a subset of gene bodies and intergenic sequences and implicate redundant pathways at many loci. Unexpectedly, we demonstrate that TET3 activity also protects certain CpG islands against methylation buildup. PMID- 25497089 TI - Microglia dictate the impact of saturated fat consumption on hypothalamic inflammation and neuronal function. AB - Diets rich in saturated fat produce inflammation, gliosis, and neuronal stress in the mediobasal hypothalamus (MBH). Here, we show that microglia mediate this process and its functional impact. Although microglia and astrocytes accumulate in the MBH of mice fed a diet rich in saturated fatty acids (SFAs), only the microglia undergo inflammatory activation, along with a buildup of hypothalamic SFAs. Enteric gavage specifically with SFAs reproduces microglial activation and neuronal stress in the MBH, and SFA treatment activates murine microglia, but not astrocytes, in culture. Moreover, depleting microglia abrogates SFA-induced inflammation in hypothalamic slices. Remarkably, depleting microglia from the MBH of mice abolishes inflammation and neuronal stress induced by excess SFA consumption, and in this context, microglial depletion enhances leptin signaling and reduces food intake. We thus show that microglia sense SFAs and orchestrate an inflammatory process in the MBH that alters neuronal function when SFA consumption is high. PMID- 25497090 TI - Diversity of cortical interneurons in primates: the role of the dorsal proliferative niche. AB - Evolutionary elaboration of tissues starts with changes in the genome and location of the stem cells. For example, GABAergic interneurons of the mammalian neocortex are generated in the ventral telencephalon and migrate tangentially to the neocortex, in contrast to the projection neurons originating in the ventricular/subventricular zone (VZ/SVZ) of the dorsal telencephalon. In human and nonhuman primates, evidence suggests that an additional subset of neocortical GABAergic interneurons is generated in the cortical VZ and a proliferative niche, the outer SVZ. The origin, magnitude, and significance of this species-specific difference are not known. We use a battery of assays applicable to the human, monkey, and mouse organotypic cultures and supravital tissue to identify neuronal progenitors in the cortical VZ/SVZ niche that produce a subset of GABAergic interneurons. Our findings suggest that these progenitors constitute an evolutionary novelty contributing to the elaboration of higher cognitive functions in primates. PMID- 25497088 TI - HSV-1 remodels host telomeres to facilitate viral replication. AB - Telomeres protect the ends of cellular chromosomes. We show here that infection with herpes simplex virus 1 (HSV-1) results in chromosomal structural aberrations at telomeres and the accumulation of telomere dysfunction-induced DNA damage foci (TIFs). At the molecular level, HSV-1 induces transcription of telomere repeat containing RNA (TERRA), followed by the proteolytic degradation of the telomere protein TPP1 and loss of the telomere repeat DNA signal. The HSV-1-encoded E3 ubiquitin ligase ICP0 is required for TERRA transcription and facilitates TPP1 degradation. Small hairpin RNA (shRNA) depletion of TPP1 increases viral replication, indicating that TPP1 inhibits viral replication. Viral replication protein ICP8 forms foci that coincide with telomeric proteins, and ICP8-null virus failed to degrade telomere DNA signal. These findings suggest that HSV-1 reorganizes telomeres to form ICP8-associated prereplication foci and to promote viral genomic replication. PMID- 25497091 TI - MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. AB - KRAS mutation, which occurs in ~ 95% of pancreatic ductal adenocarcinoma (PDA), has been shown to program tumor metabolism. MCT4 is highly upregulated in a subset of PDA with a glycolytic gene expression program and poor survival. Models with high levels of MCT4 preferentially employ glycolytic metabolism. Selectively in such "addicted" models, MCT4 attenuation compromised glycolytic flux with compensatory induction of oxidative phosphorylation and scavenging of metabolites by macropinocytosis and autophagy. In spite of these adaptations, MCT4 depletion induced cell death characterized by elevated reactive oxygen species and metabolic crisis. Cell death induced by MCT4-depletion was augmented by inhibition of compensatory pathways. In xenograft models, MCT4 had a significant impact on tumor metabolism and was required for rapid tumor growth. Together, these findings illustrate the metabolic diversity of PDA described by MCT4, delineate pathways through which this lactate transporter supports cancer growth, and demonstrate that PDA can be rationally targeted based on metabolic addictions. PMID- 25497092 TI - PCAF improves glucose homeostasis by suppressing the gluconeogenic activity of PGC-1alpha. AB - PGC-1alpha plays a central role in hepatic gluconeogenesis and has been implicated in the onset of type 2 diabetes. Acetylation is an important posttranslational modification for regulating the transcriptional activity of PGC 1alpha. Here, we show that PCAF is a pivotal acetyltransferase for acetylating PGC-1alpha in both fasted and diabetic states. PCAF acetylates two lysine residues K328 and K450 in PGC-1alpha, which subsequently triggers its proteasomal degradation and suppresses its transcriptional activity. Adenoviral-mediated expression of PCAF in the obese mouse liver greatly represses gluconeogenic enzyme activation and glucose production and improves glucose homeostasis and insulin sensitivity. Moreover, liver-specific knockdown of PCAF stimulates PGC 1alpha activity, resulting in an increase in blood glucose and hepatic glucose output. Our results suggest that PCAF might be a potential pharmacological target for developing agents against metabolic disorders associated with hyperglycemia, such as obesity and diabetes. PMID- 25497093 TI - Functional and developmental identification of a molecular subtype of brain serotonergic neuron specialized to regulate breathing dynamics. AB - Serotonergic neurons modulate behavioral and physiological responses from aggression and anxiety to breathing and thermoregulation. Disorders involving serotonin (5HT) dysregulation are commensurately heterogeneous and numerous. We hypothesized that this breadth in functionality derives in part from a developmentally determined substructure of distinct subtypes of 5HT neurons each specialized to modulate specific behaviors. By manipulating developmentally defined subgroups one by one chemogenetically, we find that the Egr2-Pet1 subgroup is specialized to drive increased ventilation in response to carbon dioxide elevation and acidosis. Furthermore, this subtype exhibits intrinsic chemosensitivity and modality-specific projections-increasing firing during hypercapnic acidosis and selectively projecting to respiratory chemosensory but not motor centers, respectively. These findings show that serotonergic regulation of the respiratory chemoreflex is mediated by a specialized molecular subtype of 5HT neuron harboring unique physiological, biophysical, and hodological properties specified developmentally and demonstrate that the serotonergic system contains specialized modules contributing to its collective functional breadth. PMID- 25497094 TI - Mycobacterium tuberculosis proteome microarray for global studies of protein function and immunogenicity. AB - Poor understanding of the basic biology of Mycobacterium tuberculosis (MTB), the etiological agent of tuberculosis, hampers development of much-needed drugs, vaccines, and diagnostic tests. Better experimental tools are needed to expedite investigations of this pathogen at the systems level. Here, we present a functional MTB proteome microarray covering most of the proteome and an ORFome library. We demonstrate the broad applicability of the microarray by investigating global protein-protein interactions, small-molecule-protein binding, and serum biomarker discovery, identifying 59 PknG-interacting proteins, 30 bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) binding proteins, and 14 MTB proteins that together differentiate between tuberculosis (TB) patients with active disease and recovered individuals. Results suggest that the MTB rhamnose pathway is likely regulated by both the serine/threonine kinase PknG and c-di-GMP. This resource has the potential to generate a greater understanding of key biological processes in the pathogenesis of tuberculosis, possibly leading to more effective therapies for the treatment of this ancient disease. PMID- 25497095 TI - Physiological roles for mafr-1 in reproduction and lipid homeostasis. AB - Maf1 is a conserved repressor of RNA polymerase (Pol) III transcription; however, its physiological role in the context of a multicellular organism is not well understood. Here, we show that C. elegans MAFR-1 is functionally orthologous to human Maf1, represses the expression of both RNA Pol III and Pol II transcripts, and mediates organismal fecundity and lipid homeostasis. MAFR-1 impacts lipid transport by modulating intestinal expression of the vitellogenin family of proteins, resulting in cell-nonautonomous defects in the developing reproductive system. MAFR-1 levels inversely correlate with stored intestinal lipids, in part by influencing the expression of the lipogenesis enzymes fasn-1/FASN and pod 2/ACC1. Animals fed a high carbohydrate diet exhibit reduced mafr-1 expression and mutations in the insulin signaling pathway genes daf-18/PTEN and daf-16/FoxO abrogate the lipid storage defects associated with deregulated mafr-1 expression. Our results reveal physiological roles for mafr-1 in regulating organismal lipid homeostasis, which ensure reproductive success. PMID- 25497098 TI - Differential regulation of the heat shock factor 1 and DAF-16 by neuronal nhl-1 in the nematode C. elegans. AB - In the nematode Caenorhabditis elegans, insulin/insulin-like growth factor 1 (IGF 1) signaling (IIS) reduction hyperactivates the transcription factors DAF-16 and heat shock factor 1 (HSF-1), creating long-lived, stress-resistant worms that are protected from proteotoxicity. How DAF-16 executes its distinct functions in response to IIS reduction is largely obscure. Here, we report that NHL-1, a member of the TRIM-NHL protein family, acts in chemosensory neurons to promote stress resistance in distal tissues by DAF-16 activation but is dispensable for the activation of HSF-1. The expression of nhl-1 is regulated by the IIS, defining a neuronal regulatory circuit that controls the organismal stress response. The knockdown of nhl-1 protects nematodes that express the Alzheimer disease-associated Abeta peptide from proteotoxicity but has no effect on lifespan. Our findings indicate that DAF-16- and HSF-1-regulated heat-responsive mechanisms are differentially controlled by neurons and show that one neuronal protein can be involved in the activation of different stress responses in remote tissues. PMID- 25497097 TI - Hand2 is an essential regulator for two Notch-dependent functions within the embryonic endocardium. AB - The basic-helix-loop-helix (bHLH) transcription factor Hand2 plays critical roles during cardiac morphogenesis via expression and function within myocardial, neural crest, and epicardial cell populations. Here, we show that Hand2 plays two essential Notch-dependent roles within the endocardium. Endocardial ablation of Hand2 results in failure to develop a patent tricuspid valve, intraventricular septum defects, and hypotrabeculated ventricles, which collectively resemble the human congenital defect tricuspid atresia. We show endocardial Hand2 to be an integral downstream component of a Notch endocardium-to-myocardium signaling pathway and a direct transcriptional regulator of Neuregulin1. Additionally, Hand2 participates in endocardium-to-endocardium-based cell signaling, with Hand2 mutant hearts displaying an increased density of coronary lumens. Molecular analyses further reveal dysregulation of several crucial components of Vegf signaling, including VegfA, VegfR2, Nrp1, and VegfR3. Thus, Hand2 functions as a crucial downstream transcriptional effector of endocardial Notch signaling during both cardiogenesis and coronary vasculogenesis. PMID- 25497100 TI - RFX6 regulates insulin secretion by modulating Ca2+ homeostasis in human beta cells. AB - Development and function of pancreatic beta cells involve the regulated activity of specific transcription factors. RFX6 is a transcription factor essential for mouse beta cell differentiation that is mutated in monogenic forms of neonatal diabetes. However, the expression and functional roles of RFX6 in human beta cells, especially in pathophysiological conditions, are poorly explored. We demonstrate the presence of RFX6 in adult human pancreatic endocrine cells. Using the recently developed human beta cell line EndoC-betaH2, we show that RFX6 regulates insulin gene transcription, insulin content, and secretion. Knockdown of RFX6 causes downregulation of Ca(2+)-channel genes resulting in the reduction in L-type Ca(2+)-channel activity that leads to suppression of depolarization evoked insulin exocytosis. We also describe a previously unreported homozygous missense RFX6 mutation (p.V506G) that is associated with neonatal diabetes, which lacks the capacity to activate the insulin promoter and to increase Ca(2+) channel expression. Our data therefore provide insights for understanding certain forms of neonatal diabetes. PMID- 25497096 TI - Rfx6 maintains the functional identity of adult pancreatic beta cells. AB - Increasing evidence suggests that loss of beta cell characteristics may cause insulin secretory deficiency in diabetes, but the underlying mechanisms remain unclear. Here, we show that Rfx6, whose mutation leads to neonatal diabetes in humans, is essential to maintain key features of functionally mature beta cells in mice. Rfx6 loss in adult beta cells leads to glucose intolerance, impaired beta cell glucose sensing, and defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway, including glucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca(2+) channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of "disallowed" genes, a group usually specifically repressed in adult beta cells, and thus to the maintenance of beta cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to beta cell failure in humans. PMID- 25497102 TI - Ultrasound follow-up of posttraumatic injuries of the sagittal band of the dorsal hood treated by a conservative approach. AB - Traumatic dislocation of the extensor tendon over the metacarpophalangeal (MCP) joint is a rare problem in patients without rheumatoid disorders. The common extensor tendon is stabilized on the metacarpal head by components of the dorsal hood (DH). A tear in the sagittal bands, allows (sub)luxation of the tendon. To ensure appropriate treatment, the identification of the damaged structures is essential. Ultrasound (US) is a valuable method in the evaluation of DH injuries and in the follow-up for evaluation of healing or lack of healing of the lesions. We report three cases with partial rupture of the sagittal band of the DH: two cases in the index finger and one case in the long finger, which caused pain and swelling and was diagnosed with US. The patients were treated conservatively and the pain resolved after 9 months in case 1, 3 months in case 2 and 6 months in case 3. The follow-up at one year revealed painless full range of motion and no residual subluxation during the dynamic ultrasound. PMID- 25497101 TI - Genomic and functional overlap between somatic and germline chromosomal rearrangements. AB - Genomic rearrangements are a common cause of human congenital abnormalities. However, their origin and consequences are poorly understood. We performed molecular analysis of two patients with congenital disease who carried de novo genomic rearrangements. We found that the rearrangements in both patients hit genes that are recurrently rearranged in cancer (ETV1, FOXP1, and microRNA cluster C19MC) and drive formation of fusion genes similar to those described in cancer. Subsequent analysis of a large set of 552 de novo germline genomic rearrangements underlying congenital disorders revealed enrichment for genes rearranged in cancer and overlap with somatic cancer breakpoints. Breakpoints of common (inherited) germline structural variations also overlap with cancer breakpoints but are depleted for cancer genes. We propose that the same genomic positions are prone to genomic rearrangements in germline and soma but that timing and context of breakage determines whether developmental defects or cancer are promoted. PMID- 25497099 TI - A pathway switch directs BAFF signaling to distinct NFkappaB transcription factors in maturing and proliferating B cells. AB - BAFF, an activator of the noncanonical NFkappaB pathway, provides critical survival signals during B cell maturation and contributes to B cell proliferation. We found that the NFkappaB family member RelB is required ex vivo for B cell maturation, but cRel is required for proliferation. Combined molecular network modeling and experimentation revealed Nfkb2 p100 as a pathway switch; at moderate p100 synthesis rates in maturing B cells, BAFF fully utilizes p100 to generate the RelB:p52 dimer, whereas at high synthesis rates, p100 assembles into multimeric IkappaBsome complexes, which BAFF neutralizes in order to potentiate cRel activity and B cell expansion. Indeed, moderation of p100 expression or disruption of IkappaBsome assembly circumvented the BAFF requirement for full B cell expansion. Our studies emphasize the importance of p100 in determining distinct NFkappaB network states during B cell biology, which causes BAFF to have context-dependent functional consequences. PMID- 25497103 TI - Paper - a potential platform in pharmaceutical development. AB - Paper is predominantly composed of cellulose fibers that have an inherent ability to wick fluids by capillary action; it provides an interesting diagnostic platform that is inexpensive, easily obtained, and eco-friendly. Paper has been used in various types of biologically relevant applications including paper-based molecular assays, paper-based ELISA (P-ELISA), paper-based nucleic acid assays, and paper-based cell assays. Based on recent successes with the use of paper as a platform, we contend that paper is not only very suitable for diagnostics but could provide a more advantageous platform than current plastics-based platforms for drug discovery, and would be useful for accomplishing in vitro pre-compound screening steps while offering a possible solution to several economic obstacles inherent in the pharmaceutical industry. PMID- 25497104 TI - Oral and lip cancer in solid organ transplant patients--a cohort study from a Swedish Transplant Centre. AB - OBJECTIVES: Previous large studies have shown that solid organ transplant (SOT) patients have an increased risk of developing malignancies. Few studies have compared the prognosis for SOT patients who develop cancer with that of non transplanted cancer patients. In this study we have investigated the increased risk of oral and lip cancer in SOT patients and also compared the relative survival between SOT patients and non-SOT patients with oral and lip cancer. PATIENTS AND METHODS: From the patient registers at the Transplant Institute at Sahlgrenska University Hospital, records of 4604 SOT patients from 1965 to 2010 were collected. These patient records were linked to the nationwide Swedish Cancer Register and compared to those of the normal population regarding the risk of developing oral and lip cancer, and also to non-SOT patients with lip and oral cancer. A Poisson regression model was used to compare the relative survival between SOT and non-SOT patients with oral and lip cancer. RESULTS: We observed 17 oral cancers (expected 2.69) and 34 lip cancers (expected 0.78) in the cohort. The standardized incidence ratio (SIR) for oral cancer was 6.32 (95% CI, 3.7 10.1) and 43.7 (95% CI, 30.3-61.1) for lip cancer. Relative five-year survival for lip cancer was lower for SOT patients compared to non-SOT patients (p<0.001). CONCLUSION: This study shows that SOT patients have a higher risk of developing both oral and lip cancer, and in addition, that SOT patients with lip cancer have a worse prognosis. PMID- 25497106 TI - Induction chemotherapy in squamous cell carcinoma of the head and neck: saved by the bell? PMID- 25497105 TI - Looking beyond the CRT paradigm: why induction chemotherapy is worthy of pursuit. PMID- 25497107 TI - Screen printing as a scalable and low-cost approach for rigid and flexible thin film transistors using separated carbon nanotubes. AB - Semiconducting single-wall carbon nanotubes are very promising materials in printed electronics due to their excellent mechanical and electrical property, outstanding printability, and great potential for flexible electronics. Nonetheless, developing scalable and low-cost approaches for manufacturing fully printed high-performance single-wall carbon nanotube thin-film transistors remains a major challenge. Here we report that screen printing, which is a simple, scalable, and cost-effective technique, can be used to produce both rigid and flexible thin-film transistors using separated single-wall carbon nanotubes. Our fully printed top-gated nanotube thin-film transistors on rigid and flexible substrates exhibit decent performance, with mobility up to 7.67 cm2 V(-1) s(-1), on/off ratio of 10(4)~10(5), minimal hysteresis, and low operation voltage (<10 V). In addition, outstanding mechanical flexibility of printed nanotube thin-film transistors (bent with radius of curvature down to 3 mm) and driving capability for organic light-emitting diode have been demonstrated. Given the high performance of the fully screen-printed single-wall carbon nanotube thin-film transistors, we believe screen printing stands as a low-cost, scalable, and reliable approach to manufacture high-performance nanotube thin-film transistors for application in display electronics. Moreover, this technique may be used to fabricate thin-film transistors based on other materials for large-area flexible macroelectronics, and low-cost display electronics. PMID- 25497108 TI - Children's health and vulnerability in outdoor microclimates: A comprehensive review. AB - BACKGROUND: Children are routinely identified as a vulnerable population in environmental health risk assessments, experiencing adverse health outcomes due to exposure to a suite of atmospheric constituents. OBJECTIVE: To provide a substantive overview of the research literature pertaining to biometeorological effects on children. Key information areas within urban environmental health research related to atmospheric variables (heat, air pollution, radiation) are assessed and integrated to better understand health outcomes and vulnerabilities in children. Critical avenues for improvement and understanding of children's health related to such biophysical parameters are also identified. METHODS: This comprehensive review assesses past and current primary studies, organizational reports, educational books, and review articles. Emphasis is placed on the differential ambient exposures to temperature, air pollution, and radiation within urban microclimates commonly used by children (e.g., schoolyards, urban parks), and the resulting health impacts. DISCUSSION: Exposure to heat, air pollution, and radiation are often enhanced in urban areas, specifically under the current design of the majority of outdoor child play places. Many heat indices, energy budget models, and health outcome studies fail to adequately parameterize children, yet those that do find enhanced vulnerability to ambient stressors, particularly heat and air pollution. Such environmental exposures relate strongly to behavior, activity, asthma, obesity, and overall child well being. Current research indicates that a changing climate, growing urban population, and unsustainable design are projected to pose increasing complications. CONCLUSIONS: Evidence-based research to link children's health, physiology, and behavior to atmospheric extremes is an important future research avenue, underscoring the fact that children are among the population groups disproportionately affected by ambient extremes. However, current methods and population-based models lack child-specific inputs and outputs, as well as designated thresholds for accurate predictions of child health impacts. More substantive evidence is needed for applicable child-specific policies and guidelines. PMID- 25497109 TI - Chemical contaminants in swimming pools: Occurrence, implications and control. AB - A range of trace chemical contaminants have been reported to occur in swimming pools. Current disinfection practices and monitoring of swimming pool water quality are aimed at preventing the spread of microbial infections and diseases. However, disinfection by-products (DBPs) are formed when the disinfectants used react with organic and inorganic matter in the pool. Additional chemicals may be present in swimming pools originating from anthropogenic sources (bodily excretions, lotions, cosmetics, etc.) or from the source water used where trace chemicals may already be present. DBPs have been the most widely investigated trace chemical contaminants, including trihalomethanes (THMs), haloacetic acids (HAAs), halobenzoquinones (HBQs), haloacetonitriles (HANs), halonitromethanes (HNMs), N-nitrosamines, nitrite, nitrates and chloramines. The presence and concentrations of these chemical contaminants are dependent upon several factors including the types of pools, types of disinfectants used, disinfectant dosages, bather loads, temperature and pH of swimming pool waters. Chemical constituents of personal care products (PCPs) such as parabens and ultraviolet (UV) filters from sunscreens have also been reported. By-products from reactions of these chemicals with disinfectants and UV irradiation have been reported and some may be more toxic than their parent compounds. There is evidence to suggest that exposure to some of these chemicals may lead to health risks. This paper provides a detailed review of various chemical contaminants reported in swimming pools. The concentrations of chemicals present in swimming pools may also provide an alternative indicator to swimming pool water quality, providing insights to contamination sources. Alternative treatment methods such as activated carbon filtration and advanced oxidation processes may be beneficial in improving swimming pool water quality. PMID- 25497110 TI - Clostridium difficile toxin B inhibits the secretory response of human mast cell line-1 (HMC-1) cells stimulated with high free-Ca2+ and GTPgammaS. AB - Clostridium difficile toxins A and B (TcdA and TcdB) belong to the class of large clostridial cytotoxins and inactivate by glucosylation some low molecular mass GTPases of the Rho-family (predominantly Rho, Rac and Cdc42), known as regulators of the actin cytoskeleton. TcdA and B also represent the main virulence factors of the anaerobic gram-positive bacterium that is the causal agent of pseudomembranous colitis. In our study, TcdB was chosen instead of TcdA for the well-known higher cytotoxic potency. Inactivation of Rho-family GTPases by this toxin in our experimental conditions induced morphological changes and reduction of electron-dense mast cell-specific granules in human mast cell line-1 (HMC-1) cells, but not cell death or permeabilisation of plasma-membranes. Previously reported patch-clamp dialysis experiments revealed that high intracellular free Ca(2+) and GTPgammaS concentrations are capable of inducing exocytosis as indicated by significant membrane capacitance (Cm) increases in HMC-1 cells. In this study, we investigated the direct effects of TcdB upon HMC-1 cell "stimulated" Cm increase, as well as on "constitutive" secretion of hexosaminidase and interleukin-16 (IL-16). Compared to untreated control cells, HMC-1 cells incubated with TcdB for 3-24h exhibited a significant reduction of the mean absolute and relative Cm increase in response to free-Ca(2+) and GTPgammaS suggesting an inhibition of secretory processes by TcdB. In conclusion, the HMC-1 cell line represents a suitable model for the study of direct effects of C. difficile toxins on human mast cell secretory activity. PMID- 25497111 TI - N-acetyl cysteine improves the effects of corticosteroids in a mouse model of chlorine-induced acute lung injury. AB - Chlorine (Cl2) causes tissue damage and a neutrophilic inflammatory response in the airways manifested by pronounced airway hyperreactivity (AHR). The importance of early anti-inflammatory treatment has previously been addressed. In the previous study, both high-dose and low-dose of dexamethasone (DEX) decreased the risk of developing delayed effects, such as persistent lung injuries, while only high-dose treatment could significantly counteract acute-phase effects. One aim of this study was to evaluate whether a low-dose of DEX in combination with the antioxidant N-acetyl cysteine (NAC) and if different treatments (Triptolide, Reparixin and Rolipram) administered 1h after Cl2-exposure could improve protection against acute lung injury in Cl2-exposed mice. BALB/c mice were exposed to 300 ppm Cl2 during 15 min. Assessment of AHR and inflammatory cells in bronchoalveolar lavage was analyzed 24h post exposure. Neither of DEX nor NAC reduced the AHR and displayed only minor effects on inflammatory cell influx when given as separate treatments. When given in combination, a protective effect on AHR and a significant reduction in inflammatory cells (neutrophils) was observed. Neither of triptolide, Reparixin nor Rolipram had an effect on AHR but Triptolide had major effect on the inflammatory cell influx. Treatments did not reduce the concentration of either fibrinogen or plasminogen activator inhibitor-1 in serum, thereby supporting the theory that the inflammatory response is not solely limited to the lung. These results provide a foundation for future studies aimed at identifying new concepts for treatment of chemical-induced lung injury. Studies addressing combination of anti-inflammatory and antioxidant treatment are highly motivated. PMID- 25497112 TI - Maternal exposure to hexachlorophene targets intermediate-stage progenitor cells of the hippocampal neurogenesis in rat offspring via dysfunction of cholinergic inputs by myelin vacuolation. AB - Hexachlorophene (HCP) is known to induce myelin vacuolation corresponding to intramyelinic edema of nerve fibers in the central and peripheral nervous system in animals. This study investigated the effect of maternal exposure to HCP on hippocampal neurogenesis in rat offspring using pregnant rats supplemented with 0 (controls), 100, or 300 ppm HCP in the diet from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, the numbers of T box brain 2(+) progenitor cells and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling(+) apoptotic cells in the hippocampal subgranular zone (SGZ) decreased in female offspring at 300 ppm, which was accompanied by myelin vacuolation and punctate tubulin beta-3 chain staining of nerve fibers in the hippocampal fimbria. In addition, transcript levels of the cholinergic receptor, nicotinic beta 2 (Chrnb2) and B-cell CLL/lymphoma 2 (Bcl2) decreased in the dentate gyrus. HCP-exposure did not alter the numbers of SGZ proliferating cells and reelin- or calcium-binding protein-expressing gamma-aminobutyric acid (GABA) ergic interneuron subpopulations in the dentate hilus on PND 21 and PND 77. Although some myelin vacuolation remained, all other changes observed in HCP exposed offspring on PND 21 disappeared on PND 77. These results suggest that maternal HCP exposure reversibly decreases type-2b intermediate-stage progenitor cells via the mitochondrial apoptotic pathway in offspring hippocampal neurogenesis at 300 ppm HCP. Neurogenesis may be affected by dysfunction of cholinergic inputs into granule cell lineages and/or GABAergic interneurons as indicated by decreased transcript levels of Chrnb2 and numbers of Chrnb2(+) interneurons caused by myelin vacuolation in the septal-hippocampal pathway. PMID- 25497113 TI - Microcystin-LR induced thyroid dysfunction and metabolic disorders in mice. AB - There is growing evidence that microcystins (MCs) act as hazardous materials and can disrupt the endocrine systems of animals. However, the response of thyroid function and the related energy metabolism following MCs exposure is still unknown. In the present study, mice were injected intraperitoneally (i.p.) with doses of either 5 or 20 MUg/kg MC-LR for 4 weeks. We report, for the first time, that mice exposed to 20 MUg/kg MC-LR showed disrupted glucose, triglyceride and cholesterol metabolism with obvious symptoms of hyperphagia, polydipsia, and weight loss. The circulating thyroid hormone (TH) levels in mice following MC-LR exposure were detected. Significantly increased free triiodothyronine (FT3) and decreased free thyroxin (FT4) were largely responsible for the physiological aberrations and metabolic disorders observed in mice after the 20 MUg/kg MC-LR exposure. Increased expression of TH receptor (Tralpha) and mTOR expression in the brain after the 20 MUg/kg MC-LR exposure suggests that the increased FT3 enhanced mTOR signaling subsequently led to hyperphagia and elevated energy expenditure in mice. Furthermore, several genes involved in glucose homeostasis and lipid metabolism, which have been identified affected by TH, were also differentially expressed after MC-LR exposure. The above results clearly showed that mice exposed to MC-LR experienced thyroid dysfunction and its downstream functional changes, and are useful to better understand the endocrine toxicity of MC-LR to mammals or even humans. PMID- 25497114 TI - Changes in leukocyte subsets of pregnant gilts experimentally infected with porcine reproductive and respiratory syndrome virus and relationships with viral load and fetal outcome. AB - In spite of more than two decades of extensive research, the understanding of porcine reproductive and respiratory syndrome virus (PRRSv) immunity is still incomplete. A PRRSv infection of the late term pregnant female can result in abortions, early farrowings, fetal death, and the birth of weak, congenitally infected piglets. The objectives of the present study were to investigate changes in peripheral blood mononuclear cell populations in third trimester pregnant females infected with type 2 PRRSv (NVSL 97-7895) and to analyze potential relationships with viral load and fetal mortality rate. PRRSv infection caused a massive, acute drop in total leukocyte counts affecting all PBMC populations by two days post infection. Except for B cells, cell counts started to rebound by day six post infection. Our data also show a greater decrease of naive B cells, T helper cells and cytolytic T cells than their respective effector or memory counterparts. Absolute numbers of T cells and gammadelta T cells were negatively associated with PRRSv RNA concentration in gilt serum over time. Additionally, absolute numbers of T helper cells may be predictive of fetal mortality rate. The preceding three leukocyte populations may therefore be predictive of PRRSv related pathological outcomes in pregnant gilts. Although many questions regarding the immune responses remain unanswered, these findings provide insight and clues that may help reduce the impact of PRRSv in pregnant gilts. PMID- 25497116 TI - In memoriam of Prof. Josue A. Nunez (1924-2014). PMID- 25497115 TI - Effects of sodium benzoate, a widely used food preservative, on glucose homeostasis and metabolic profiles in humans. AB - Sodium benzoate is a widely used preservative found in many foods and soft drinks. It is metabolized within mitochondria to produce hippurate, which is then cleared by the kidneys. We previously reported that ingestion of sodium benzoate at the generally regarded as safe (GRAS) dose leads to a robust excursion in the plasma hippurate level [1]. Since previous reports demonstrated adverse effects of benzoate and hippurate on glucose homeostasis in cells and in animal models, we hypothesized that benzoate might represent a widespread and underappreciated diabetogenic dietary exposure in humans. Here, we evaluated whether acute exposure to GRAS levels of sodium benzoate alters insulin and glucose homeostasis through a randomized, controlled, cross-over study of 14 overweight subjects. Serial blood samples were collected following an oral glucose challenge, in the presence or absence of sodium benzoate. Outcome measurements included glucose, insulin, glucagon, as well as temporal mass spectrometry-based metabolic profiles. We did not find a statistically significant effect of an acute oral exposure to sodium benzoate on glucose homeostasis. Of the 146 metabolites targeted, four changed significantly in response to benzoate, including the expected rise in benzoate and hippurate. In addition, anthranilic acid, a tryptophan metabolite, exhibited a robust rise, while acetylglycine dropped. Although our study shows that GRAS doses of benzoate do not have an acute, adverse effect on glucose homeostasis, future studies will be necessary to explore the metabolic impact of chronic benzoate exposure. PMID- 25497117 TI - Modulatory effects of bombyxin on ecdysteroidogenesis in Bombyx mori prothoracic glands. AB - In the present study, we investigated the modulatory effects of ecdysteroidogenesis of prothoracic glands (PGs) by bombyxin, an endogenous insulin-like peptide in the silkworm, Bombyx mori. The results showed that bombyxin stimulated ecdysteroidogenesis during a long-term incubation period and in a dose-dependent manner. Moreover, the injection of bombyxin into day 4-last instar larvae increased ecdysteroidogenesis 24h after the injection, indicating its possible in vivo function. Phosphorylation of the insulin receptor and Akt, and the target of rapamycin (TOR) signaling were stimulated by bombyxin, and stimulation of Akt phosphorylation and TOR signaling appeared to be dependent on phosphatidylinositol 3-kinase (PI3K). Bombyxin inhibited the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK), and the inhibition appeared to be PI3K-independent. Bombyxin-stimulated ecdysteroidogenesis was blocked by either an inhibitor of PI3K (LY294002) or a chemical activator of AMPK (5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, AICAR), indicating involvement of the PI3K/Akt and AMPK signaling pathway. Bombyxin did not stimulate extracellular signal-regulated kinase (ERK) signaling of PGs. Bombyxin, but not prothoracicotropic hormone (PTTH) stimulated cell viability of PGs. In addition, bombyxin treatment also affected mRNA expression levels of insulin receptor, Akt, AMPKalpha, -beta, and -gamma in time-dependent manners. These results suggest that bombyxin modulates ecdysteroidogenesis in B. mori PGs during development. PMID- 25497118 TI - Does heterospecific seminal fluid reduce fecundity in interspecific copulation between seed beetles? AB - Reproductive interference through mating between related species can cause fitness reduction and affect population dynamics of the interacting species. In experimental matings between two seed beetles, Callosobruchus chinensis and Callosobruchus maculatus, C. maculatus females, but not C. chinensis females, suffer from significant loss of fecundity when conspecific mating is followed by heterospecific mating. We hypothesized that male traits associated with sexual conflict, which are often harmful to females, pleiotropically affect fitness of heterospecific females through interspecific mating. We examined the effect of ejaculate of C. chinensis males on C. maculatus females as the cause of the fecundity loss in C. maculatus females due to interspecific copulation. We found that frequent interspecific copulation occurred between C. maculatus females and C. chinensis males, but not between C. chinensis females and C. maculatus males, resulting in frequent interspecific ejaculate transfer from C. chinensis males to C. maculatus females. However, injection of the extract from C. chinensis male reproductive organs into C. maculatus females did not significantly affect C. maculatus fecundity compared with saline injection, indicating that the effect of the heterospecific ejaculate transfer on fecundity is negligible. We suggest that other harmful male traits such as genital spines of C. chinensis males are mainly responsible for the fecundity reduction in C. maculatus females that have experienced interspecific mating. PMID- 25497119 TI - Which benefits and harms of preoperative radiotherapy should be addressed? A Delphi consensus study among rectal cancer patients and radiation oncologists. AB - BACKGROUND AND PURPOSE: We previously found considerable variation in information provision on preoperative radiotherapy (PRT) in rectal cancer. Our aims were to reach consensus among patients and oncologists on which benefits/harms of PRT should be addressed during the consultation, and to assess congruence with daily clinical practice. MATERIALS AND METHODS: A four-round Delphi-study was conducted with two expert panels: (1) 31 treated rectal cancer patients and (2) 35 radiation oncologists. Thirty-seven possible benefits/harms were shown. Participants indicated whether addressing the benefit/harm was (1) essential, (2) desired, (3) not necessary, or (4) to be avoided. Consensus was assumed when ?80% of the panel agreed. Results were compared to 81 audio-taped consultations. RESULTS: The panels reached consensus that six topics should be addressed in all patients (local control, survival, long term altered defecation pattern and faecal incontinence, perineal wound healing problems, advice to avoid pregnancy), three in male patients (erectile dysfunction, ejaculation disorder, infertility), and four in female patients (vaginal dryness, pain during intercourse, menopause, infertility). On average, less than half of these topics were addressed in daily clinical practice. CONCLUSIONS: This study showed substantial overlap between benefits/harms that patients and oncologists consider important to address during the consultation, and at the same time poor congruence with daily clinical practice. PMID- 25497120 TI - Corpus callosum and motor development in healthy term infants. AB - BACKGROUND: Corpus callosum atrophy has been associated with cognitive and motor deficits in elderly people. However, the role of the corpus callosum in infant development is unclear. The aim of this study was to assess the impact of corpus callosum size on motor development in infants. METHODS: We investigated cerebral ultrasonograms performed on healthy infants aged 4 to 6 months. The correlation between the development of rolling over and corpus callosum size was calculated for determining odds ratios. Covariates, including gestational age, sex, age in months, and head circumference were tested using logistic regression. RESULTS: We investigated 244 cerebral ultrasonograms performed on term infants from 2009 to 2011. The percentage of rolling over development in the examined infants increased with age (47.8%, 78.4%, and 97.5% at ages 4, 5, and 6 months, respectively). There was no significant difference in the development of rolling over between male (67.9%) and female (73.6%) children or among different gestational age groups. After the other covariates in the logistic model were adjusted, only age and corpus callosum size (length and thickness) were significantly associated with the development of rolling over: 3.86 times the odds (confidence interval, 2.1 to 7.0) for age in months, 1.14 times the odds (confidence interval, 1.0 to 1.3) for corpus callosum length, and 3.92 times the odds (confidence interval, 1.6 to 9.6) for corpus callosum thickness. CONCLUSIONS: Corpus callosum size is positively associated with the development of rolling over in healthy term infants, independent of the gestational age, sex, age, and head circumference. PMID- 25497121 TI - Vitamin D supplementation in children with epilepsy and intellectual disability. AB - BACKGROUND: Children with epilepsy and intellectual disability have an increased risk of vitamin D deficiency. In this patient group, it is neither clear which factors are associated with the level of 25-hydroxyvitamin D nor what the therapeutic results are when Dutch guidelines are followed. METHODS: This retrospective study included 30 patients who, in October 2012, were residents of the children's wards of a tertiary epilepsy center in The Netherlands (Kempenhaeghe). From November 2012 onward they received cholecalciferol supplementation in doses that met or exceeded Dutch guidelines. At baseline, after 6, and 15 months, serum 25-hydroxyvitamin D concentration was measured. RESULTS: At baseline, the vitamin D status in 11 (36.7%) residents was found to be deficient, in 10 (33.3%) to be insufficient and in 9 (30.0%) sufficient. Supplementation dose, diet, body mass index, intellectual disability, and mobility were significantly associated with baseline 25-hydroxyvitamin D concentrations. The mean 25-hydroxyvitamin D concentration increased significantly from 57.40 +/- 22.00 nmol/L at baseline to 89.47 +/- 26.77 nmol/L after 15 months (P < 0.001). In spite of supplementation ranging from 400 to 1200 IU/day, 64% of the residents in the deficient category and 30% of those with an insufficient level at baseline failed to attain a sufficient vitamin D status after 15 months. CONCLUSIONS: Not all residents reached a sufficient vitamin D status after supplementation at least equal to the amount recommended by the Dutch guidelines. In a high-risk population, such as our residents, we advise monitoring 25-hydroxyvitamin D concentrations, adjusting supplementation accordingly and following patients to ensure they reach sufficiency. PMID- 25497122 TI - Neurodevelopmental outcome after extreme prematurity: a review of the literature. AB - BACKGROUND: Advances in obstetric and neonatal medical care and assisted reproductive technology have increased the rates of preterm birth, decreased preterm mortality rates, and lowered the limit of viability. However, morbidity in survivors, including neurodevelopmental disabilities, has increased, especially in extremely preterm infants born at <=25 weeks' gestation. A better understanding of the prevalence and patterns of adverse neurodevelopmental outcomes in extremely preterm infants is important for patient care, counseling of families, and research. METHODS: The PubMed and Ovid Medline databases were searched for full text articles published between 1999 and 2013 in English that reported neurodevelopmental outcomes after extreme prematurity, and a review of identified relevant cohort studies was performed. RESULTS: Extreme prematurity of 22 to 25 weeks' gestation is associated with an overall high mortality of >=50%. High rates (17% to 59%) of severe neurodevelopmental disabilities occur among survivors on short-term follow-up. The rates of surviving unimpaired or minimally impaired are 6% to 20% for live-born infants at <=25 weeks' gestation and <5% for infants born at 22 and 23 weeks' gestation. Long-term adverse outcomes after extreme prematurity include intellectual disability (5% to 36%), cerebral palsy (9% to 18%), blindness (0.7% to 9%), and deafness (2% to 4%). Milder degrees of disability involving cognition, behavior, and learning are increasingly recognized among older preterm children, teens, and young adults. CONCLUSIONS: Infants who are born at <=25 weeks' gestation, especially those born at 22 and 23 weeks' gestation, have a very low likelihood of surviving little or no impairment. Nearly half of surviving extremely premature infants have significant neurodevelopmental disabilities on short- and long-term follow-up. Instituting early intervention programs, providing family support, and establishing special educational school programs can pay high dividends and lead to brighter futures and, hence, help improve neurodevelopmental outcome of preterm infants. PMID- 25497123 TI - The estimated cost of "no-shows" in an academic pediatric neurology clinic. AB - OBJECTIVE: Missed appointments ("no-shows") represent an important source of lost revenue for academic medical centers. The goal of this study was to examine the costs of "no-shows" at an academic pediatric neurology outpatient clinic. METHODS: This was a retrospective cohort study of patients who missed appointments at an academic pediatric neurology outpatient clinic during 1 academic year. Revenue lost was estimated based on average reimbursement for different insurance types and visit types. RESULTS: The yearly "no-show" rate was 26%. Yearly revenue lost from missed appointments was $257,724.57, and monthly losses ranged from $15,652.33 in October 2013 to $27,042.44 in January 2014. CONCLUSIONS: The yearly revenue lost from missed appointments at the academic pediatric neurology clinic represents funds that could have been used to improve patient access and care. Further work is needed to develop strategies to decrease the no-show rate to decrease lost revenue and improve patient care and access. PMID- 25497124 TI - An atypical case of Canavan disease with stroke-like presentation. AB - BACKGROUND: Canavan disease is an autosomal recessive leukodystrophy caused by a deficiency of aspartoacylase. The disease has a severe course, with death occurring in the first few years of life. Atypical patients with mild courses have been reported, but acute presentations similar to stroke have not been well described. PATIENT DESCRIPTION: We present a boy who presented at 4 months of age with seizures after an episode of cardiopulmonary arrest is discussed. RESULTS: He was initially thought to have an ischemic watershed stroke based on his initial clinical presentation and magnetic resonance imaging. However, biochemical and follow-up radiologic evaluation were consistent with mild Canavan disease. DNA sequencing of the ASPA gene indicated one known mutation (A305E) and a novel mutation, L30V. Follow-up magnetic resonance imaging did not reveal the atrophy which would have been expected with watershed ischemia. Magnetic resonance spectroscopy demonstrated elevated N-acetyl aspartate to creatinine and N-acetyl aspartate to choline ratios. At 4 years of age, he was normocephalic, with mild clumsiness, speech delay, and seizures. CONCLUSIONS: This child's unusual acute presentation, along with his prolonged mild course, raises questions about the relationship between biochemical signs of abnormal aspartoacylase function and clinical findings. This patient highlights the need for long-term clinical follow-up of children with mild Canavan disease to clarify the significance of these biochemical abnormalities. PMID- 25497126 TI - What we know but do not understand about nidovirus helicases. AB - Helicases are versatile NTP-dependent motor proteins of monophyletic origin that are found in all kingdoms of life. Their functions range from nucleic acid duplex unwinding to protein displacement and double-strand translocation. This explains their participation in virtually every metabolic process that involves nucleic acids, including DNA replication, recombination and repair, transcription, translation, as well as RNA processing. Helicases are encoded by all plant and animal viruses with a positive-sense RNA genome that is larger than 7 kb, indicating a link to genome size evolution in this virus class. Viral helicases belong to three out of the six currently recognized superfamilies, SF1, SF2, and SF3. Despite being omnipresent, highly conserved and essential, only a few viral helicases, mostly from SF2, have been studied extensively. In general, their specific roles in the viral replication cycle remain poorly understood at present. The SF1 helicase protein of viruses classified in the order Nidovirales is encoded in replicase open reading frame 1b (ORF1b), which is translated to give rise to a large polyprotein following a ribosomal frameshift from the upstream ORF1a. Proteolytic processing of the replicase polyprotein yields a dozen or so mature proteins, one of which includes a helicase. Its hallmark is the presence of an N-terminal multi-nuclear zinc-binding domain, the nidoviral genetic marker and one of the most conserved domains across members of the order. This review summarizes biochemical, structural, and genetic data, including drug development studies, obtained using helicases originating from several mammalian nidoviruses, along with the results of the genomics characterization of a much larger number of (putative) helicases of vertebrate and invertebrate nidoviruses. In the context of our knowledge of related helicases of cellular and viral origin, it discusses the implications of these results for the protein's emerging critical function(s) in nidovirus evolution, genome replication and expression, virion biogenesis, and possibly also post-transcriptional processing of viral RNAs. Using our accumulated knowledge and highlighting gaps in our data, concepts and approaches, it concludes with a perspective on future research aimed at elucidating the role of helicases in the nidovirus replication cycle. PMID- 25497128 TI - Biosynthesis of lactosylfructoside by an intracellular levansucrase from Bacillus methylotrophicus SK 21.002. AB - Lactosylfructoside is a functional oligosaccharide consisting of D-glucose, D galactose, and D-fructose. In this work, lactosylfructoside was biosynthesized from sucrose as a fructosyl donor and lactose as an acceptor by an intracellular levansucrase derived from strain Bacillus methylotrophicus (B. methylotrophicus) SK21.002. The trisaccharide was purified from the product using a high performance liquid chromatography (HPLC) system and was confirmed to be lactosylfructoside by nuclear magnetic resonance (NMR) spectroscopy. The biosynthesis conditions (such as pH, temperature, enzyme dosage, substrate concentrations, and the concentration ratio of the two substrates) for lactosylfructoside production were optimized. The optimum conditions for lactosylfructoside preparation were a pH of 6.5, temperature of 37 degrees C, and enzyme dosage of 8 U/g substrates. The concentration of substrates (total lactose and sucrose) was 400mg/mL, and the ratio of lactose to sucrose was 1:1. The optimum time for lactosylfructoside production was 20 h, the yield of lactosylfructoside under the optimal conditions was 143 mg/mL, and the lactosylfructoside conversion efficiency was 36%. PMID- 25497125 TI - Genome-scale identification and characterization of moonlighting proteins. AB - BACKGROUND: Moonlighting proteins perform two or more cellular functions, which are selected based on various contexts including the cell type they are expressed, their oligomerization status, and the binding of different ligands at different sites. To understand overall landscape of their functional diversity, it is important to establish methods that can identify moonlighting proteins in a systematic fashion. Here, we have developed a computational framework to find moonlighting proteins on a genome scale and identified multiple proteomic characteristics of these proteins. RESULTS: First, we analyzed Gene Ontology (GO) annotations of known moonlighting proteins. We found that the GO annotations of moonlighting proteins can be clustered into multiple groups reflecting their diverse functions. Then, by considering the observed GO term separations, we identified 33 novel moonlighting proteins in Escherichia coli and confirmed them by literature review. Next, we analyzed moonlighting proteins in terms of protein protein interaction, gene expression, phylogenetic profile, and genetic interaction networks. We found that moonlighting proteins physically interact with a higher number of distinct functional classes of proteins than non moonlighting ones and also found that most of the physically interacting partners of moonlighting proteins share the latter's primary functions. Interestingly, we also found that moonlighting proteins tend to interact with other moonlighting proteins. In terms of gene expression and phylogenetically related proteins, a weak trend was observed that moonlighting proteins interact with more functionally diverse proteins. Structural characteristics of moonlighting proteins, i.e. intrinsic disordered regions and ligand binding sites were also investigated. CONCLUSION: Additional functions of moonlighting proteins are difficult to identify by experiments and these proteins also pose a significant challenge for computational function annotation. Our method enables identification of novel moonlighting proteins from current functional annotations in public databases. Moreover, we showed that potential moonlighting proteins without sufficient functional annotations can be identified by analyzing available omics-scale data. Our findings open up new possibilities for investigating the multi-functional nature of proteins at the systems level and for exploring the complex functional interplay of proteins in a cell. REVIEWERS: This article was reviewed by Michael Galperin, Eugine Koonin, and Nick Grishin. PMID- 25497127 TI - Understanding history, and not repeating it. Neuroprotection for acute ischemic stroke: from review to preview. AB - BACKGROUND: Neuroprotection for ischemic stroke is a growing field, built upon the elucidation of the biochemical pathways of ischemia first studied in the 1970s. Beginning in the early 1990s, means by which to pharmacologically intervene and counteract these pathways have been sought, though with little clinical success. Through a comprehensive review of translations from laboratory to clinic, we aim to evaluate individual mechanisms of action, while highlighting potential barriers to success that will guide future research. METHODS: The MEDLINE database and The Internet Stroke Center clinical trials registry were queried for trials involving the use of neuroprotective agents in acute ischemic stroke in human subjects. For the purpose of the review, neuroprotective agents refer to medications used to preserve or protect the potentially ischemic tissue after an acute stroke, excluding treatments designed to re-establish perfusion. This excludes mechanical or pharmacological thrombolytics, anti-thrombic medications, or anti-platelet therapies. RESULTS: This review summarizes previously trialed neuroprotective agents, including but not limited to glutamate neurotransmission blockers, anti-oxidants, GABA agonists, leukocyte migration blockers, various small cation channel modulators, narcotic antagonists, and phospholipid membrane stabilizers. We outline key biochemical steps in ischemic injury that are the proposed areas of intervention. The agents, time to administration of therapeutic agent, follow-up, and trial results are reported. DISCUSSION: Stroke trials in humans are burdened with a marked heterogeneity of the patient population that is not seen in animal studies. Also, trials to date have included patients that are likely treated at a time outside of the window of efficacy for neuroprotective drugs, and have not effectively combined thrombolysis with neuroprotection. Through an evaluation of the accomplishments and failures in neuroprotection research, we propose new methodologies, agents, and techniques that may provide new routes for success. PMID- 25497129 TI - Contact ion pairs and solvent-separated ion pairs from D-mannopyranosyl and D glucopyranosyl triflates. AB - The chemical nature of contact ion pairs and solvent-separated ion pairs from 2,3,4,6-tetra-O-methyl-alpha-D-mannopyranosyl triflate was investigated at the DFT(M06-2X) level of theory. Comparison of the present results to those obtained for the D-glucopyranosyl counterpart in our previous study indicated that the ion pairs from the D-mannopyranosyl triflate adopt B2,5-like conformations more preferably than those from the D-glucopyranosyl triflate. Similarly, 1,6-anhydro D-mannopyranosyl dioxacarbenium ions bearing a (1)C4 conformation were shown to be more stable than the D-glucopyranosyl counterparts. PMID- 25497131 TI - Synthesis, anticandidal activity of N(3)-(4-methoxyfumaroyl)-(S)-2,3 diaminopropanoic amide derivatives--novel inhibitors of glucosamine-6-phosphate synthase. AB - Novel FMDP amides 4-6 have been synthesized and tested against Candida strains. The anticandidal activity has been confined only to Candida albicans. Anticandidal activity of the tested amides has correlated with their inhibitory activity of glucosamine-6-phosphate synthase in cell free extract from C. albicans. PMID- 25497130 TI - Synthesis and antiproliferative activity of novel polynuclear heterocyclic compounds derived from 2,3-diaminophenazine. AB - 2,3-Diaminophenazine 1 was used as a precursor for the preparation of some novel phenazine derivatives such as imidazo[4,5-b]phenazine-2-thione 2, its methylthio 3, ethyl 1-aryl-3H-[1,2,4]triazolo[2,3-a]imidazo[4,5-b]phenazines 8a-c, ethyl (2Z)-[3-aminophenazin-2-yl)amino](phenylhydrazono)ethanoate 9, pyrazino[2,3 b]phenazine derivatives 10, 12, 15-17, [1,4]diazepino[2,3-b]phenazine derivatives 13, 14, 2,3-dibenzoylaminophenazine 18, 1H-Imidazo[4,5-b]phenazine derivatives 20, 23a-c, 24, 25 and 4-[(E)-(3-amino phenazin-2-yl)diazenyl] derivatives 27-29. All compounds were tested as inhibitors of the proliferation of human lung carcinoma and colorectal cancer cell lines through inhibition of Tyrosine Kinases. Most of compounds exert good activity against the two cancer cell lines. Five compounds (1, 2, 3, 25 and 28) were found to possess the same activity as the standard drug Cisplatin. PMID- 25497132 TI - Design, synthesis and biological evaluation of a class of bioisosteric oximes of the novel dual peroxisome proliferator-activated receptor alpha/gamma ligand LT175. AB - The effects resulting from the introduction of an oxime group in place of the distal aromatic ring of the diphenyl moiety of LT175, previously reported as a PPARalpha/gamma dual agonist, have been investigated. This modification allowed the identification of new bioisosteric ligands with fairly good activity on PPARalpha and fine-tuned moderate activity on PPARgamma. For the most interesting compound (S)-3, docking studies in PPARalpha and PPARgamma provided a molecular explanation for its different behavior as full and partial agonist of the two receptor isotypes, respectively. A further investigation of this compound was carried out performing gene expression studies on HepaRG cells. The results obtained allowed to hypothesize a possible mechanism through which this ligand could be useful in the treatment of metabolic disorders. The higher induction of the expression of some genes, compared to selective agonists, seems to confirm the importance of a dual PPARalpha/gamma activity which probably involves a synergistic effect on both receptor subtypes. PMID- 25497134 TI - What health care is learning from the aviation industry. PMID- 25497133 TI - Quadriceps arthrogenic muscle inhibition: the effects of experimental knee joint effusion on motor cortex excitability. AB - INTRODUCTION: Marked weakness of the quadriceps muscles is typically observed following injury, surgery or pathology affecting the knee joint. This is partly due to ongoing neural inhibition that prevents the central nervous system from fully activating the quadriceps, a process known as arthrogenic muscle inhibition (AMI). This study aimed to further investigate the mechanisms underlying AMI by exploring the effects of experimental knee joint effusion on quadriceps corticomotor and intracortical excitability. METHODS: Seventeen healthy volunteers participated in this study. Transcranial magnetic stimulation was used to measure quadriceps motor evoked potential area, short-interval intracortical inhibition, intracortical facilitation and cortical silent period duration before and after experimental knee joint effusion. Joint effusion was induced by the intraarticular infusion of dextrose saline into the knee. RESULTS: There was a significant increase in quadriceps motor evoked potential area following joint infusion, both at rest (P = 0.01) and during voluntary muscle contraction (P = 0.02). Cortical silent period duration was significantly reduced following joint infusion (P = 0.02). There were no changes in short interval intracortical inhibition or intracortical facilitation over time (all P > 0.05). CONCLUSIONS: The results of this study provide no evidence for a supraspinal contribution to quadriceps AMI. Paradoxically, but consistent with previous observations in patients with chronic knee joint pathology, quadriceps corticomotor excitability increased after experimental knee joint effusion. The increase in quadriceps corticomotor excitability may be at least partly mediated by a decrease in gamma aminobutyric acid (GABA)-ergic inhibition within the motor cortex. PMID- 25497135 TI - Domestic minor sex trafficking: what the PNP needs to know. AB - Human trafficking is a major global public health problem and represents a substantial human rights violation. Human trafficking has been receiving attention in both the lay media and professional literature. Human trafficking can include commercial sex, forced labor, child soldiers, and stealing of human organs. One form of human trafficking represents a significant American pediatric health problem: domestic minor sex trafficking (DMST). DMST is the commercial sexual abuse of children by selling, buying, or trading their sexual service. This continuing education article will define DMST and discuss it in terms of prevalence, risk factors, and practice implications for the pediatric nurse practitioner. PMID- 25497136 TI - Premature guinea pigs: a new paradigm to investigate the late-effects of preterm birth. AB - Preterm birth is common and the associated short-term morbidity well described. The adult-onset consequences of preterm birth are less clear, but cardiovascular and metabolic health may be adversely affected. Although large animal models of preterm birth addressing important short-term issues exist, long-term studies are hampered by significant logistical constraints. Current small animal models of prematurity require terminal caesarean section of the mother; both caesarean birth and early maternal care modify offspring adult cardio-metabolic function. We describe a novel method for inducing preterm labour in guinea pigs. With support comparable to that received by moderately preterm human infants, preterm pups are viable. Growth trajectories between preterm and term-born pups differ significantly; between term equivalent age and weaning ex-preterm animals demonstrate increased weight and ponderal index. We believe this novel paradigm will significantly improve our ability to investigate the cardio-metabolic sequelae of preterm birth throughout the life course and into the second generation. PMID- 25497137 TI - Learning experience of Chinese nursing students in an online clinical English course: qualitative study. AB - The low English proficiency of Chinese nurse/nursing students affects their performance when they work in English-speaking countries. However, limited resources are available to help them improve their workplace English, i.e. English used in a clinical setting. To this end, it is essential to look for an appropriate and effective means to assist them in improving their clinical English. The objective of this study is to evaluate the learning experience of Chinese nursing students after they have completed an online clinical English course. Focus group interview was used to explore their learning experience. 100 students in nursing programs at Tung Wah College were recruited. The inclusion criteria were: (1) currently enrolled in a nursing program; and (2) having clinical experience. Eligible participants self-registered for the online English course, and were required to complete the course within 3 months. After that, semi-structured interviews were conducted on students whom completed the whole and less than half of the course. One of the researchers joined each of the interviews as a facilitator and an observer. Thematic analysis was used to analyze the data. Finally, 7 themes emerged from the interviews: technical issues, adequacy of support, time requirement, motivation, clarity of course instruction, course design, and relevancy of the course. Participants had varied opinions on the 2 themes: motivation and relevancy of the course. Overall, results of this study suggest that the online English course helped students improve their English. Factors which support their learning are interactive course design, no time constraint, and relevancy to their work/study. Factors which detracted from their learning are poor accessibility, poor technical and learning support and no peer support throughout the course. PMID- 25497138 TI - A systematic review of clinical assessment for undergraduate nursing students. AB - BACKGROUND: Consolidated clinical practicum prepares pre-registration nursing students to function as beginning practitioners. The clinical competencies of final-year nursing students provide a key indication of professional standards of practice and patient safety. Thus, clinical assessment of nursing students is a crucial issue for educators and administrators. OBJECTIVE: The aim of this systematic review was to explore the clinical competency assessment for undergraduate nursing students. DATA SOURCES: PubMed, CINAHL, ScienceDirect, Web of Science, and EBSCO were systematically searched from January 2000 to December 2013. METHODS: The systematic review was in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Published quantitative and qualitative studies that examined clinical assessment practices and tools used in clinical nursing education were retrieved. Quality assessment, data extraction, and analysis were completed on all included studies. RESULTS: This review screened 2073 titles, abstracts and full-text records, resulting in 33 included studies. Two reviewers assessed the quality of the included studies. Fourteen quantitative and qualitative studies were identified for this evaluation. The evidence was ordered into emergent themes; the overarching themes were current practices in clinical assessment, issues of learning and assessment, development of assessment tools, and reliability and validity of assessment tools. CONCLUSION: There is a need to develop a holistic clinical assessment tool with reasonable level of validity and reliability. Clinical assessment is a robust activity and requires collaboration between clinical partners and academia to enhance the clinical experiences of students, the professional development of preceptors, and the clinical credibility of academics. PMID- 25497140 TI - Multidisciplinary perspective on the management of appendiceal adenocarcinoma: case review of 10 patients from a university hospital and current considerations. AB - BACKGROUND: Adenocarcinoma of the vermiform appendix is rare. It constitutes less than 0.5% of all gastrointestinal malignancies. Pathologically, appendiceal neoplasms are categorized into various subtypes depending on cell lineage. PATIENTS AND METHODS: We considered a case series of appendiceal invasive adenocarcinomas from 2004 to 2013 managed in a teaching hospital. We discuss our management dilemmas, given the lack of randomized controlled trial data that exist. A detailed look at the histopathology, case series, and literature is presented. RESULTS: Ideal standards ought to be constructed for the management of this rare pathology, with a particular focus on exploring the indications and potential benefits, as well as difficulties, of ileocolic lymphadenectomy. CONCLUSION: Appendiceal adenocarcinoma ought to be managed in the same way as a cecal adenocarcinoma. PMID- 25497139 TI - Integrating learning assessment and supervision in a competency framework for clinical workplace education. AB - Although competency-based education is well established in health care education, research shows that the competencies do not always match the reality of clinical workplaces. Therefore, there is a need to design feasible and evidence-based competency frameworks that fit the workplace reality. This theoretical paper outlines a competency-based framework, designed to facilitate learning, assessment and supervision in clinical workplace education. Integration is the cornerstone of this holistic competency framework. PMID- 25497141 TI - Recommendations for reporting gait studies. PMID- 25497142 TI - 27-Hydroxycholesterol up-regulates CD14 and predisposes monocytic cells to superproduction of CCL2 in response to lipopolysaccharide. AB - We investigated the possibility that a cholesterol-rich milieu can accelerate response to pathogen-associated molecular patterns in order to elucidate mechanisms underlying aggravation of atherosclerosis after bacterial infection. The consumption of a high-cholesterol diet resulted in enhanced the expression of CD14 in arteries of ApoE(-/-) mice. 27-Hydroxycholesterol (27OHChol), the most abundant cholesterol oxide in atherosclerotic lesions, induced the significant expression of CD14 by THP-1 monocytic cells, but not by vascular smooth muscle cells or Jurkat T cells. Additions of lipopolysaccharide (LPS) to 27OHChol treated THP-1 monocytic cells resulted in superinduction in terms of the gene transcription of CCL2 and the secretion of its gene product. In contrast, cholesterol did not cause increased the expression of CD14 in the aforementioned cells, and the addition of LPS to cholesterol-treated monocytic cells did not result in enhanced the expression of CCL2. The conditioned medium isolated from THP-1 cells exposed to 27OHChol plus LPS further induced the migration of monocytic cells in comparison with conditioned media obtained from THP-1 cells treated with 27OHChol or LPS alone. Treatment with 27OHChol also resulted in the enhanced secretion of MMP-9 and soluble CD14 (sCD14), and the secretion of sCD14 was blocked by a selective MMP-9 inhibitor. The inhibition of the ERK pathway resulted in significantly attenuated the secretion of sCD14 via mechanisms that were distinct from those by PI3K inhibition. We propose that 27OHChol can prime monocytes/macrophages by up-regulation of CD14 such that LPS-mediated inflammatory reaction is accelerated, thereby contributing to aggravated development of atherosclerotic lesions by enhancing recruitment of monocytic cells after infection with Gram-negative bacteria. PMID- 25497143 TI - Incidence of myocardial infarction, stroke, and death in patients with age related macular degeneration treated with intravitreal anti-vascular endothelial growth factor therapy. AB - PURPOSE: To describe the rates of myocardial infarction (MI), stroke, and mortality in patients who have treatment with intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections for age-related macular degeneration (AMD). DESIGN: A retrospective population linkage study. METHOD: We identified patients aged 40 years and above who received treatment with intravitreal anti-VEGF injections for AMD from January 1, 2008 to December 31, 2011 at the Singapore National Eye Centre. We used a national record linkage database to identify patients who developed MI, stroke, and all-cause mortality after the first injection, excluding those with previous MI or stroke at baseline from the respective analysis. We compared rates of MI, stroke, and mortality to that of the total Singapore population. RESULTS: A total of 1182 individuals had an intravitreal anti-VEGF injection included in this analysis, with the majority receiving bevacizumab (n = 1011). Overall, 19 patients developed MI, 16 developed stroke, and there were 43 mortalities, giving an age-adjusted incidence rate of 350.2 per 100 000 person-years for MI, 299.3 per 100 000 person-years for stroke, and 778.9 per 100 000 person-years for mortality. This is comparable to the weighted incidence rates of the Singapore population (427.1 per 100 000 person years for MI, 340.4 per 100 000 person-years for stroke, and 921.3 per 100 000 person-years for mortality). CONCLUSION: The incidence rate of MI, stroke, and death in this cohort of AMD patients treated with anti-VEGF was low, and was not significantly higher than the age-adjusted incidence rate of these events in the Singapore population. PMID- 25497144 TI - Trends in long head biceps tenodesis. AB - BACKGROUND: Tenodesis of the long head of the biceps tendon has become a popular surgical treatment option for patients with pain or instability attributed to a diseased or unstable biceps tendon. No previous studies have characterized the practice patterns of surgeons performing biceps tenodesis in the United States. PURPOSE: To investigate current trends in both arthroscopic and open biceps tenodesis across time, sex, age, and region of the United States as well as associated charges. STUDY DESIGN: Descriptive epidemiology study. METHODS: Patients who underwent biceps tenodesis (Current Procedural Terminology [CPT] codes 23430 and 29828) for the years 2008 through 2011 were identified using the PearlDiver Patient Record Database, including both private-payer and Medicare data. These cohorts were then assessed for associated diagnoses using International Classification of Diseases, 9th Revision, codes and concomitant procedures using CPT codes. These searches yielded procedural volumes, sex and age distribution, regional volumes, and average per-patient charges. A chi(2) linear-by-linear association analysis, Student t test, and linear regression were used for comparisons, with P < .05 considered significant. RESULTS: A total of 44,932 biceps tenodesis procedures were identified from 2008-2011. The incidence of biceps tenodesis procedures per 100,000 database patients increased 1.7-fold over the study period, from 8178 in 2008 to 14,014 in 2011 (P < .0001). An increase in the overall percentage volume was noted in patients aged 60-69 years (P = .039) and 20-29 years (P = .016). The overall charges for arthroscopic tenodesis increased at a rate significantly greater than that of open tenodesis (P < .0001). Rotator cuff tear or sprain, bicipital tenosynovitis, biceps tendon rupture, superior labral lesion, and osteoarthritis were the most common diagnoses associated with biceps tenodesis procedures. A significant increase in isolated biceps tenodesis was also observed over the study period, from 1967 patients in 2008 to 3565 patients in 2011, representing a 1.8-fold increase. CONCLUSION: The incidence of biceps tenodesis has increased yearly from 2008 2011. Arthroscopic tenodesis has emerged as a more popular technique. Charges associated with the procedure have increased significantly. Significant regional variations in procedural incidences exist. PMID- 25497145 TI - Correlation of meniscal and articular cartilage injuries in children and adolescents with timing of anterior cruciate ligament reconstruction. AB - BACKGROUND: In pediatric patients, anterior cruciate ligament (ACL) reconstruction is controversial; however, delaying surgery until skeletal maturity is complete may increase the risk of secondary meniscal and articular cartilage injury. PURPOSE: To assess the risk of meniscal and chondral injuries with delay of ACL reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Records were reviewed in patients younger than 17 years (median age, 14 years) who had ACL reconstruction. Patients were consecutively enrolled and assigned to 1 of 3 surgical groups based on timing of surgery: acute (<6 weeks after surgery), subacute (6-12 weeks), or chronic (>3 months). The type and grade of meniscal injuries was documented according to the International Society of Arthroscopy, Knee Surgery, and Orthopaedic Sports Medicine (ISAKOS) meniscal classification criteria. International Cartilage Repair Society (ICRS) criteria were used to document location and grade of chondral injuries. Associations between patient characteristics and meniscal injury were tested using rank sum and chi-square tests. Regression analyses were conducted to model incidence and severity of lateral and medial meniscal tears. There were 130 patients who had 135 ACL reconstructions between the years of 2000 and 2012. RESULTS: Sixty-two ACL injuries were treated acutely, 37 were subacute, and 36 were chronic. Meniscal injuries (n = 112) included 70 lateral and 42 medial tears. Time to surgery had bivariate association with lateral and medial meniscal tears (P = .016 and .007, respectively). Independent risk factors for incidence of lateral meniscal tears were younger age (P = .028) and return to sports activities before surgery (P = .007). Patients with 1 episode of instability had 3-fold higher odds of higher grade lateral meniscal tear (95% CI, 1.30-7.60). Compared with acute reconstruction, subacute and chronic reconstruction patients had 1.45 and 2.82 times higher odds, respectively, of lateral meniscal tear severity (P = .12). Independent risk factors for incidence of medial meniscal tears were female sex (P = .03), older age (P = .01), and any episode of instability (P = .01). Adjusted odds ratio for medial meniscal tear was 4.7 for an instability episode (vs no episode; P = .01). Adjusted odds ratio for increased severity of medial meniscal tears included any instability episode, 5.6 (P < .01); playing sports before reconstruction, 15.2 (P < .01); and time to surgery greater than 3 months, 4.3 (P = .046). Seventeen patients had 23 chondral injuries. The risk factors for chondral injury included increased time to surgery (P = .005) and any instability episode (P = .001). For increased grade of chondral injury, risk factors were time to surgery (P <= .001) and any instability episode (P = .003). CONCLUSION: Delayed ACL reconstruction increased the risks of secondary meniscal and chondral injuries in this population of pediatric patients. PMID- 25497146 TI - Myoclonic status epilepticus as a presentation of caspr2 antibody-associated autoimmune encephalitis. AB - We present a case of autoimmune encephalitis associated with antibodies targeting contact in-associated protein-like 2. This case is notable because of the presentation with myoclonic status epilepticus and the prolonged clinical course of refractory seizures, which are demonstrated in the accompanying videos, and not previously associated with this condition. Treatment with prednisone, intravenous immunoglobulin, plasma exchange, rituximab, cyclophosphamide, and mycophenolate mofetil resulted in significant functional improvement. Historically, myoclonic status epilepticus is associated with a grave prognosis and minimal chance of meaningful recovery. This case demonstrates that autoimmune encephalitis remains an important differential diagnosis in patients with such a presentation, and that early recognition and the appropriate institution of immunotherapy can result in seizure control and functional recovery. [Published with video sequences]. PMID- 25497147 TI - Ultrastructural differences in pretangles between Alzheimer disease and corticobasal degeneration revealed by comparative light and electron microscopy. AB - Pretangles are defined under the light microscope as diffuse and granular tau immunoreactivity in neurons in tissue from patients with Alzheimer disease (AD) or corticobasal degeneration (CBD) and are considered to be a premature stage before neurofibrillary tangle formation. However, the ultrastructure of pretangles remains to be described. To clarify the similarities and differences between pretangles from patients with AD and CBD (AD-pretangles and CBD pretangles, respectively), we examined cortical pretangles in tissue from patients with each of diseases. For direct light and electron microscopic (LM/EM) correlation of the pretangles, we used quantum dot nanocrystals (QDs) with dual fluorescent and electron-dense properties. We first identified tau-labeled pretangles on fluorescence LM and subsequently examined the same neurons on EM. Energy dispersive X-ray spectrometry (EDX) color mapping identified selenium (Se) and cadmium (Cd) as elementary components of QDs and highlighted each QD particle clearly against gray-scale EM images. With these methods, we were successful for the first time in demonstrating accurately that LM-defined pretangles are tau positive straight filaments sparsely distributed throughout neuronal cytoplasm and neurites in both AD and CBD at the EM level. Notably, AD-pretangles showed a strong tendency to form fibrillary tangles even at an early stage, whereas pretangles or Pick-like inclusions in tissue from patients with CBD did not even at an advanced stage. In conclusion, AD-pretangles and CBD-pretangles showed essential differences at the EM level. PMID- 25497149 TI - [Editors' commentary: Nutrition, malnutrition, nutrition therapy]. PMID- 25497148 TI - [Anaesthetic management in a paediatric patient with a difficult airway due to epidermolysis bullosa dystrophica]. AB - Dystrophic epidermolysis bullosa (DEB) is a rare inherited disorder characterized by blistering after minimal trauma. These blisters tend to form dystrophic scars, leading to limiting and life-threatening sequelae. The anaesthetic management of patients with DEB is a challenge, even for the most experienced anaesthesiologists, but basic principles can help us prepare the plan of care. The main goals are to prevent trauma/infection of skin/mucous, and to establish a secure airway without causing bullae. Patient positioning and the instruments used to monitor vital signs and administering anaesthetic agents can cause new lesions. It is advisable to lubricate the instruments and to avoid adhesive material and shearing forces on the skin. Besides the implications of the comorbidities, there is a potential difficult intubation and difficult vascular access. Acute airway obstruction can occur due to airway instrumentation. We report the case of a patient diagnosed with EBD difficult airway and undergoing correction of syndactylyl and dental extractions. PMID- 25497150 TI - [The measureable clinical signs of malnutrition: the clinical significance of body composition - bioimpedance - analysis]. AB - Undernutrition, or more precisely: malnutrition results in worse outcome in clinical practice. Recognition and treatment of different forms of malnutrition are not unconditionally easy in the daily routine, however, it could lead to significant improvement in the outcome. This review summarizes the most frequent forms of malnutrition and demonstrates the advantages of the systematic use of bioelectrical impedance analysis in patients undergoing chronic treatment either in hospitals or outpatient care. The importance of the method is still underestimated in Hungary as well as many other countries. PMID- 25497151 TI - [Pharmaconutrition: pharmacological approach to nutrition therapy]. AB - Reviewing the literature of nutrition therapy one can conclude that during the last decade the pharmacological action of several nutrients has been demonstrated. However, research activity is still at the beginning and it could be verified in a restricted number of nutrients only that in which conditions (illnesses), dose and duration we can expect therapeutic effect in addition to nutrition. The examples of glutamine, arginine, taurine, leucine, omega-3 fatty acids, however, support the possibility that complex reactions and treatment results observed in certain patients are not purely due to nutritional support but the consequence of additional pharmacological action as well. Evaluation of results of therapeutic intervention is especially difficult because in the everyday practice physicians try to use several therapeutic modalities that can be beneficial for the patient. Therefore, retrospective separation of beneficial components of the therapeutic agents is almost impossible. Only well designed, randomized and multicentric studies can verify specific therapeutic action of certain ingredients ie. nutrients. PMID- 25497152 TI - [Indications and practice of enteral nutrition]. AB - Malnutrition in hospitalised patients has a significant and disadvantageous impact on treatment outcome. If possible, enteral nutrition with an energy/protein-balanced nutrient should be preferred depending on the patient's condition, type of illness and risk factors. The aim of the nutrition therapy is to increase the efficacy of treatment and shorten the length of hospital stay in order to ensure rapid rehabilitation. In the present review the authors summarize the most important clinical and practical aspects of enteral nutrition therapy. PMID- 25497153 TI - [Artificial nutrition in gastrointestinal diseases]. AB - The association between nutrition and intestinal function is based on facts. The main function of the gut is to digest and absorb nutrients in order to maintain life. Consequently, chronic gastrointestinal diseases commonly result in malnutrition and increased morbidity and mortality. Chronic malnutrition impairs digestive and absorptive function. Parenteral and enteral nutritions are effective therapeutic modalities in several diseases. In cases of gastrointestinal malfunctions, nutrition has a direct therapeutic role. The benefit of nutrition therapy is similar to medical treatment in patients with pancreatitis, Crohn disease, hepatic failure, and in those with gastrointestinal fistulas. Nutrition has both supportive and therapeutic roles in the management of chronic gastrointestinal diseases. With the development of modern techniques of nutritional support, the morbidity and mortality associated with chronic gastrointestinal diseases can be reduced. PMID- 25497154 TI - [Neurological diseases and nutrition -- what can we do?]. AB - Neurological diseases and nutrition are in complex relationship. In the first part of this review the nutritional consequences of acute neurological diseases is presented, with special emphasis on traumatic injuries of the nervous system and stroke. Nutritional therapy of these patients is described in detail. In addition, chronic, degenerative neurological pathological conditions are also discussed, including nutritional consequences and possibilities of therapy. Some ethical and legal issues are also considered. The second part of this review article describes neurological consequences of nutritional problems, both deficits of macro- and micronutrients and toxic effects. PMID- 25497155 TI - [Nutrition in critical illness]. AB - Critically ill patients are often unable to eat by themselves over a long period of time, sometimes for weeks. In the acute phase, serious protein-energy malnutrition may develop with progressive muscle weakness, which may result in assisted respiration of longer duration as well as longer stay in intensive care unit and hospital. In view of the metabolic processes, energy and protein intake targets should be defined and the performance of metabolism should be monitored. Enteral nutrition is primarily recommended. However, parenteral supplementation is often necessary because of the disrupted tolerance levels of the gastrointestinal system. Apparently, an early parenteral supplementation started within a week would be of no benefit. Some experts believe that muscle loss can be reduced by increased target levels of protein. Further studies are needed on the effect of immune system feeding, fatty acids and micronutrients. PMID- 25497156 TI - [Clinical nutrition therapy in patients with short bowel syndrome in line with principles of personalized medicine]. AB - Home parenteral nutrition administered in selected care centres has been financed in Hungary since January, 2013. The authors discuss diagnostic issues, treatment and nutrition therapy of short bowel syndrome patients in line with the principles of personalised medicine. The most severe form of short bowel syndrome occurs in patients having jejunostomy, whose treatment is discussed separately. The authors give a detailed overview of home parenteral feeding, its possible complications, outcomes and adaptation of the remaining bowel. They describe how their own care centre operates where they administer home parenteral nutrition to 12 patients with short bowel syndrome (5 females and 7 males aged 51.25+/-14.4 years). The body mass index was 19.07+/-5.08 kg/m2 and 20.87+/-3.3 kg/m2, skeletal muscle mass was 25.7+/-6.3 kg and 26.45+/-5.38 kg, and body fat mass was 14.25+/-8.55 kg and 11.77+/-2.71 kg at the start of home parenteral nutrition and presently, respectively. The underlying conditions of short bowel syndrome were tumours in 4 patients, bowel ischaemia in four patients, surgical complications in three patients, Crohn's disease in one patient, and Crohn's disease plus tumour in one patient. PMID- 25497158 TI - Late side-effects after curative intent radiotherapy: Identification of hypersensitive patients for personalized strategy. AB - Radiation therapy undeniably enhances local control and thus improves overall survival in cancer patients. However, some long-term cancer survivors (less than 10%) develop severe late radio-induced toxicities altering their quality of life. Therefore, there is a need to identify patients who are sensitive to those toxicities and who could benefit from adapted care. In this review, we address all available techniques aiming to detect patients' hyper-radiosensitivity and present the scientific rationales these techniques are based on. PMID- 25497157 TI - 29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype. AB - PMM2-CDG (formerly known as CDG Ia) a deficiency in phosphomannomutase, is the most frequent congenital disorder of glycosylation. The phenotype encompasses a wide range of neurological and non-neurological manifestations comprising cerebellar atrophy and intellectual deficiency. The phenotype of the disorder is well characterized in children but the long term course of the disease is unknown and the phenotype of late onset forms has not been comprehensively described. We thus retrospectively collected the clinical, biological and radiological data of 29 French PMM2-CDG patients aged 15 years or more with a proven molecular diagnosis (16 females and 13 males). In addition, thirteen of these patients were reexamined at the time of the study to obtain detailed information. 27 of the 29 patients had a typical PMM2-CDG phenotype, with infantile hypotonia, strabismus, developmental delay followed by intellectual deficiency, epilepsy, retinitis pigmentosa and/or visceral manifestations. The main health problems for these patients as teenagers and in adulthood were primary ovarian insufficiency, growth retardation, coagulation anomalies and thrombotic events, skeletal deformities and osteopenia/osteoporosis, retinitis pigmentosa, as well as peripheral neuropathy. Three patients had never walked and three lost their ability to walk. The two remaining patients had a late-onset phenotype unreported to date. All patients (n = 29) had stable cerebellar atrophy. Our findings are in line with those of previous adult PMM2-CDG cohorts and points to the need for a multidisciplinary approach to the follow up of PMM2-CDG patients to prevent late complications. Additionally, our findings add weight to the view that PMM2-CDG may be diagnosed in teenage/adult patients with cerebellar atrophy, even in the absence of intellectual deficiency or non-neurological involvement. PMID- 25497159 TI - Spatio-temporal factors influencing the occurrence of Syngamus trachea within release pens in the South West of England. AB - Syngamus trachea is a pathogenic tracheal nematode that causes syngamiasis in wild and game birds, especially when birds are managed at high densities. Despite its pathogenic nature, very little is known about its epidemiology and relationship with ambient temperature and humidity. The spatial and temporal modelling of disease was undertaken on two pheasant estates within the South West of England from April 2014 to August 2014. Significant differences between the mean numbers of eggs per gram of soil were identified between pens at both site 1 and site 2 but did not differ significantly between sites. Egg abundance was significantly associated with soil moisture content, with greater egg survival between years in pens with higher average volumetric soil moisture content. Previous years stocking density and pen age were also associated with greater egg survival between years with more eggs being recovered in pens with greater stocking densities, and pens that had been sited longer. The greatest model to explain the variation in the numbers of eggs per gram of soil per pen was a combination of soil moisture content, stocking density and pen age. Larval recovery differed significantly between sites. Larval abundance was significantly and positively associated with temperature and relative humidity at site 1. Similarly, temperature and humidity were also positively and significantly associated with larval abundance at site 2. Rainfall did not influence larval recovery at either site 1 or site 2. The model with the greatest ability to explain larval abundance at both sites, was a combination of temperature, humidity and rainfall. Infection status (positive faecal egg counts) was significantly and positively associated with larval abundance at both sites, but rainfall was only positively associated at site 1. Temperature and humidity were positively associated with infection status at site 2, but not at site 1. The present study highlights the influence of climatic variables on both egg survival and larval abundance, and could therefore be used to develop more targeted treatment strategies around periods of higher disease risk. The frequent use of release pens is a clear factor in the epidemiology of syngamiasis, and it is recommended that pens be rested and/or rotated in order to reduce infection pressure in subsequent flocks. PMID- 25497160 TI - Amaranth proteins foaming properties: Film rheology and foam stability - Part 2. AB - In this work the influence of pH and ionic strength on the stability of foams prepared with amaranth protein isolate was analyzed. The behaviour observed was related to the physico-chemical and structural changes undergone by amaranth protein as a result of those treatments. The results obtained show that foams prepared at acidic pH were more stable than the corresponding to alkaline pH. At pH 2.0 the foams presented higher times and more volumes of drainage. This behaviour is consistent with the characteristics of the interfacial film, which showed a higher viscoelasticity and a greater flexibility at acidic pH than alkaline pH value, which in turn increased by increasing the concentration of proteins in the foaming solution. It is also important to note that the presence of insoluble protein is not necessarily detrimental to the properties of the foam. Detected changes in the characteristics of the interfacial film as in the foam stability have been attributed to the increased unfolding, greater flexibility and net charge of amaranth proteins at acidic conditions. PMID- 25497161 TI - Bacteria encapsulated in layered double hydroxides: towards an efficient bionanohybrid for pollutant degradation. AB - A soft chemical process was successfully used to immobilize Pseudomonas sp. strain ADP (ADP), a well-known atrazine (herbicide) degrading bacterium, within a Mg2Al-layered double hydroxide host matrix. This approach is based on a simple, quick and ecofriendly direct coprecipitation of metal salts in the presence of a colloidal suspension of bacteria in water. It must be stressed that by this process the mass ratio between inorganic and biological components was easily tuned ranging from 2 to 40. This ratio strongly influenced the biological activity of the bacteria towards atrazine degradation. The better results were obtained for ratios of 10 or lower, leading to an enhanced atrazine degradation rate and percentage compared to free cells. Moreover the biohybrid material maintained this biodegradative activity after four cycles of reutilization and 3 weeks storage at 4 degrees C. The ADP@MgAl-LDH bionanohybrid materials were completely characterized by X-ray diffraction (XRD), FTIR spectroscopy, thermogravimetric analysis and scanning and transmission electronic microscopy (SEM and TEM) evidencing the successful immobilization of ADP within the inorganic matrix. This synthetic approach could be readily extended to other microbial whole-cell immobilization of interest for new developments in biotechnological systems. PMID- 25497162 TI - Patients with hematologic malignancies have many reasons to die during extracorporeal membrane oxygenation. PMID- 25497163 TI - Omental Teratoma Misdiagnosed as Gossypiboma. PMID- 25497164 TI - Treatment of Asherman's syndrome in an outpatient hysteroscopy setting. AB - OBJECTIVE: To evaluate the feasibility and success rate of treating Asherman syndrome in an outpatient hysteroscopy unit. DESIGN: Retrospective case series (Canadian Task Force classification III). SETTING: The outpatient hysteroscopy clinic at Ottawa Hospital from November 26, 2008, to January 31, 2014. PATIENTS: Patients undergoing treatment for Asherman syndrome. INTERVENTIONS: All cases of hysteroscopic adhesiolysis were reviewed. MEASUREMENTS AND MAIN RESULTS: Demographic data were collected by a retrospective chart review including patients' age, obstetric history, referring complaint, etiology of Asherman syndrome, antecedent treatment, and outcome measures when available. The severity of Asherman syndrome was determined based on the March classification by the operating surgeon. Analgesia used during the procedure was recorded. Twenty patients were treated for Asherman syndrome in the outpatient hysteroscopy suite. There were a total of 38 procedures (adhesiolysis or diagnostic hysteroscopies) performed for this indication in the patient set. The most common etiologies for intrauterine adhesions were previous curettage (60%) and previous missed abortion (45%). Outcomes were available for 19 patients. All of the patients had normal menses after treatment. Eighty-four percent of patients had either no adhesions or mild adhesions at their final hysteroscopy. Six patients had a spontaneous pregnancy after treatment, and 5 went on to have a term delivery to date. In terms of analgesia used for the procedure, 89% of patients had preoperative nonsteroidal anti-inflammatory drugs, 2.8% required intravenous fentanyl and midazolam, and 5.6% required oral lorazepam. CONCLUSION: This series showed that Asherman syndrome may be successfully treated in an outpatient hysteroscopy setting outside the operating room and without general or regional anesthesia. PMID- 25497165 TI - A comparison of hysteroscopic mechanical tissue removal with bipolar electrical resection for the management of endometrial polyps in an ambulatory care setting: preliminary results. AB - STUDY OBJECTIVE: To assess and compare efficacy, pain, and the learning curve associated with diagnostic therapeutic hysteroscopy using mechanical tissue removal versus bipolar electrical resection in the management of endometrial polyps in an ambulatory care setting. DESIGN: A randomized controlled clinical trial (Canadian Task Force classification I). SETTING: Hospital de Igulada, Barcelona, Spain. PATIENTS: A total of 133 patients diagnosed with endometrial polyp(s) were included and randomly assigned to 1 of the 2 hysteroscopic methods. Criteria assessed were total hysteroscopy time, full polypectomy procedure time, pain experienced by patients, and learning curve of staff in training. MEASUREMENTS AND MAIN RESULTS: The average time to perform total hysteroscopy using the mechanical tissue removal system (TRUCLEAR 5.0 System; Smith & Nephew Inc., Andover, MD) was 6 minutes 49 seconds versus 11 minutes 37 seconds required for the bipolar electrosurgery system (GYNECARE VERSAPOINT; Ethicon Inc, Somerville, NJ) (p < .01). Results for complete polypectomy time favored the TRUCLEAR System at 3 minutes 7 seconds over the VERSAPOINT System at 8 minutes 25 seconds (p < .01). If a successful procedure is predicated on access to cavity, visualization, and complete resection and excision of endometrial polyp, the mechanical TRUCLEAR Tissue Removal System shows a higher success rate than the VERSAPOINT Bipolar Electrosurgery System at 92% and 77%, respectively. Analysis of pain using the visual analog scale revealed no significant differences between the 2 techniques (p > .05). A study of the residents' learning curve showed a higher level of autonomy with hysteroscopy using the TRUCLEAR Tissue Removal System with which residents showed a higher level of confidence compared with hysteroscopy with the VERSAPOINT Bipolar Electrosurgery System. CONCLUSION: In hysteroscopic polypectomy, the mechanical tissue removal system was significantly faster, achieved a greater success rate for complete polypectomy, and required a shorter learning curve from staff being trained in the management of endometrial polyps when compared with bipolar electrical resection. PMID- 25497166 TI - Identification of the impact of crime on physical activity depends upon neighbourhood scale: multilevel evidence from 203,883 Australians. AB - Equivocal findings on crime as a deterrent for physical activity may be due to effects of geographic scale on exposure measurement. To investigate this hypothesis, physical activity was measured in 203,883 Australians and linked to standardised crime counts within small ('Census Collection Districts'; approx. 330 residents) and larger areas ('Statistical Local Areas'; approx. 32,000 residents). A median rate ratio of 2.26 indicated substantive geographic variation in moderate-to-vigorous physical activity (MVPA). Adjusting for confounders, multilevel negative binomial regression reported lower MVPA with more crime consistently in small, but not in larger areas. Reducing small pockets of local crime may encourage more physically active lifestyles. PMID- 25497167 TI - Putting the party down on paper: a novel method for mapping youth drug use in private settings. AB - This article proposes a novel method for generating context-rich knowledge about 'hard-to-access' places. We ground our discussion in a recent qualitative study of social settings of youth drug use in Denmark. The study confirmed that private house parties are common sites of youth drug use, although these parties presented limited opportunities for fieldwork. In response, a 'map-task' was introduced to the study to complement fieldwork and interviews. We assess the most significant methodological and epistemological features of this map-task, and explore how it may to used to conduct observations 'from a distance' in hard to-access places. Further, we argue that the map-task has a number of analytical and logistical advantages for scholars interested in the health and social aspects of 'hidden' phenomena, such as youth drug use. PMID- 25497168 TI - Autotrophic hydrogen-producing biofilm growth sustained by a cathode as the sole electron and energy source. AB - It is still unclear whether autotrophic microbial biocathode biofilms are able to self-regenerate under purely cathodic conditions without any external electron or organic carbon sources. Here we report on the successful development and long term operation of an autotrophic biocathode whereby an electroactive biofilm was able to grow and sustain itself with CO2 as a sole carbon source and using the cathode as electron source, with H2 as sole product. From a small inoculum of 15 mg COD (in 250 mL), containing 30.3% Archaea, the bioelectrochemical system operating at -0.5 V vs. SHE enabled an estimated biofilm growth of 300 mg as COD over a period of 276 days. A dramatic change in the microbial population was observed during this period with Archaea disappearing completely (<0.1% of population). The predominant phyla enriched were Proteobacteria (57.3%), Firmicutes (12.4%), Bacteroidetes (11.6%) and Actinobacteria (1.1%). Up to 9.2 L H2 m(-2) day(-1) (1.88 A m(-2)) was achieved when the cathode potential was decreased to -0.75 V vs. SHE. This study demonstrates that purely autotrophic biofilm growth coupled to proton reduction to hydrogen alone can be sustained with a cathode as the sole electron source, while avoiding the development of H2 consuming microorganisms such as methanogens and acetogens. PMID- 25497169 TI - Eculizumab effect on the hemostatic state in patients with paroxysmal nocturnal hemoglobinuria. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by a hypercoagulable state associated with acute hemolysis. Eculizumab is used to reduce the intensity of intravascular hemolysis in PNH patients. The hemostatic status of three patients with PNH was assessed during eculizumab treatment by D-dimer assay and the global assays: thromboelastography (TEG), thrombin generation test (TGT), and thrombodynamics (TD). In the state of hemolytic crisis before the therapy D-dimer concentration was increased in two patients accompanied by hypercoagulation changes in TEG parameter angle (alpha). TD parameter the clot growth velocity (V) revealed hypercoagulability while TGT parameter ETP was within the normal range in all patients. The lactate dehydrogenase (LDH) activity decreased during the 8months of eculizumab therapy. The physical health was improved, the frequency of hemolytic crisis decreased. Patients periodically exhibited hypercoagulable state: the mean values alpha=38+/-11 degrees (with normal range 20-40 degrees ), ETP=1311+/-442nM.min (with normal range 800-1560nM.min), V=31+/-4MUm/min (with normal range 20-29MUm/min). During the eculizumab therapy two patients had the repeated clinical manifestation of acute hemolytic crisis, the parameters of the global tests were increased compared to the previous measurement. The global hemostasis tests TEG, TGT and TD revealed hypercoagulability in patients with PNH during eculizumab therapy. PMID- 25497171 TI - [Disparity of French Emergency medical services equipment: disparity of funding allocation or of management quality?]. PMID- 25497170 TI - Characteristics of Chinese rural young suicides: who did not have a strong intent to die. AB - BACKGROUND: In exploration of the risk factors of the Chinese rural young suicide, previous researchers found low prevalence of mental problems, high degree of impulsivity, and great proportion of lethal pesticide consumption. It noticed that some of the young suicides in rural China did not intend to die from the suicidal behavior which was only instrumentally used for certain gains. AIMS: This study aims to look into the characteristics of those young suicides who did not really intend to die and compare them with those young suicides who had a strong intent to die. METHODS: Subjects were 386 suicides aged 15-34years in the rural areas of three provinces in China. The data were obtained by psychological autopsy method. The degree of suicidal intent of the subjects was evaluated by the first 8 items of Beck's Suicide Intent Scale (SIS). RESULTS: It was found that those suicides that had a strong intent of death were more likely to have higher age, more years of education, live alone, and suffer mental disease. On the other hand, the low intent suicides were more likely to have pesticides at home and to be impulsive. In other words, pesticides and impulsivity killed some Chinese rural young men and women who did not really want to die by suicide. CONCLUSION: Findings of the study may be translated into practical measures in suicide prevention in China as well as elsewhere in the world. PMID- 25497172 TI - [Multimodal approach to enhance filter lifespan: are all actions equal?]. PMID- 25497173 TI - Physical activity and cognitive function of community Chinese elderly in Hong Kong (HK) and Guangzhou (GZ). AB - BACKGROUND: Some studies demonstrated that physical activity may have beneficial effect on cognitive function. The objective of the study was to estimate the association between physical activity and cognitive function in community dwelling elderly Chinese in Hong Kong (HK) and Guangzhou (GZ). METHODS: In the neighborhood of HK and GZ, a convenience sample of 557 (260 in HK and 297 in GZ) older persons without dementia aged over 60 years (73.4 +/- 6.5) was recruited. Physical activity was measured using a checklist. Information on physical activity participation, cognitive function, and other variables were collected. Multivariate linear regression analyses were performed to evaluate the association between physical activity and cognitive function. RESULTS: Total number of physical activities showed significant association with the delayed recall test (p 0.05) CONCLUSION: Physical activity may not be associated with better cognitive function among elderly Chinese independently of other factors. PMID- 25497174 TI - Removal of total and antibiotic resistant bacteria in advanced wastewater treatment by ozonation in combination with different filtering techniques. AB - Elimination of bacteria by ozonation in combination with charcoal or slow sand filtration for advanced sewage treatment to improve the quality of treated sewage and to reduce the potential risk for human health of receiving surface waters was investigated in pilot scale at the sewage treatment plant Eriskirch, Baden Wuerttemberg/Germany. To determine the elimination of sewage bacteria, inflowing and leaving wastewater of different treatment processes was analysed in a culture based approach for its content of Escherichia coli, enterococci and staphylococci and their resistance against selected antibiotics over a period of 17 month. For enterococci, single species and their antibiotic resistances were identified. In comparison to the established flocculation filtration at Eriskirch, ozonation plus charcoal or sand filtration (pilot-scale) reduced the concentrations of total and antibiotic resistant E. coli, enterococci and staphylococci. However, antibiotic resistant E. coli and staphylococci apparently survived ozone treatment better than antibiotic sensitive strains. Neither vancomycin resistant enterococci nor methicillin resistant Staphylococcus aureus (MRSA) were detected. The decreased percentage of antibiotic resistant enterococci after ozonation may be explained by a different ozone sensitivity of species: Enterococcus faecium and Enterococcus faecalis, which determined the resistance-level, seemed to be more sensitive for ozone than other Enterococcus-species. Overall, ozonation followed by charcoal or sand filtration led to 0.8-1.1 log-units less total and antibiotic resistant E. coli, enterococci and staphylococci, as compared to the respective concentrations in treated sewage by only flocculation filtration. Thus, advanced wastewater treatment by ozonation plus charcoal or sand filtration after common sewage treatment is an effective tool for further elimination of microorganisms from sewage before discharge in surface waters. PMID- 25497175 TI - Removal of Hg(II) by poly(1-vinylimidazole)-grafted Fe3O4@SiO2 magnetic nanoparticles. AB - Fe3O4@SiO2 magnetic nanoparticles modified by grafting poly(1-vinylimidazole) oligomer (FSPV) was fabricated as a novel adsorbent to remove Hg(II) from water. Fourier transform infra-red spectroscopy confirmed the successful grafting of oligomer, and thermogravimetric analysis showed FSPV had a high grafting yield with organic content of 22.8%. Transmission electron microscopy image displayed that FSPV particles were polymer-coated spheres with size of 10-20 nm. With saturation magnetization of 44.7 emu/g, FSPV particles could be easily separated from water with a simple magnetic process in 5 min. The Hg(II) adsorption capacity of FSPV was found to be 346 mg/g at pH 7 and 25 degrees C in 10 mM NaCl. Moreover, the removal of Hg(II) by FSPV was not obviously affected by solution pH (from 4 to 10) or humic acid (up to 8 mg/L as TOC). The presence of seven common ions including Na(+), K(+), Ca(2+), Mg(2+), Cl(-), NO3(-), and SO4(2 ) (up to 100 mM ionic strength) slightly increased the adsorption of Hg(II) by FSPV. X-ray photoelectron spectroscopy analysis revealed that the N atom of the imidazole ring was responsible for the bonding with Hg(II), whereas the bonding of Hg with N did not result in cleavage of Hg-Cl bond in HgCl2 and HgClOH. The regeneration of Hg(II)-loaded FSPV could be achieved with 0.5 M HCl rapidly in 10 min, and the removal of Hg(II) maintained above 94% in five consecutive adsorption-desorption cycles. Therefore, FSPV could serve as a promising adsorbent for Hg(II) removal from water. PMID- 25497176 TI - [Erectile dysfunction evaluation after brachytherapy for low risk prostate adenocarcinoma: prospective study of patients with a baseline IIEF5>16]. AB - PURPOSE: To evaluate erectile function (EF) prospectively from 1 to 2 years post brachytherapy in patients with a baseline IIEF5 score>16. METHODS: Between 2007 and 2012, 179 patients underwent an exclusive brachytherapy for localised low risk prostate adenocarcinoma. Neo-adjuvant hormotherapy (15.6%) and post brachytherapy intake phosphodiesterase inhibitors (PDE5i) were not considered as exclusion criteria. EF was evaluated via a scoring questionnaire IIEF5 before the surgical implantation, at month 12 and 24 post-operation. Only patients with an initial IIEF5 score>16 were included. RESULTS: Of the 179 patients, 102 (57%) had a baseline IIEF5>16. At 12 months, 51.1% maintained an IIEF5>16 and 24.5% had a mild to moderate erectile dysfunction (ED), so that a total of 75.6% with IIEF5>=12. About 18% of patients had used PDE5i. At 24 months, 53.2% had an IIEF5>16 and 80.6% had an IIEF5>=12. Severe ED was reported in only 14.5% of the patients. The mean IIEF5 was 16.2 with an average decline of 5 points from the initial stage. All patients who were treated with PDE5i (27%) could have sexual intercourse. EF at baseline was reported as the only predictive factor of ED in multivariate analysis, 70% of patient without ED initially, had an IIEF5>16 at 1 and 2 years. CONCLUSION: Severe ED was quite rare (14%) during the first 2 years post-brachytherapy and more than half of patients maintained an IIEF5>16. The main predictive factor was the erectile function at baseline. LEVEL OF EVIDENCE: 4. PMID- 25497178 TI - 3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets. AB - The aim of this study was to explore the potential of fused-deposition 3 dimensional printing (FDM 3DP) to produce modified-release drug loaded tablets. Two aminosalicylate isomers used in the treatment of inflammatory bowel disease (IBD), 5-aminosalicylic acid (5-ASA, mesalazine) and 4-aminosalicylic acid (4 ASA), were selected as model drugs. Commercially produced polyvinyl alcohol (PVA) filaments were loaded with the drugs in an ethanolic drug solution. A final drug loading of 0.06% w/w and 0.25% w/w was achieved for the 5-ASA and 4-ASA strands, respectively. 10.5mm diameter tablets of both PVA/4-ASA and PVA/5-ASA were subsequently printed using an FDM 3D printer, and varying the weight and densities of the printed tablets was achieved by selecting the infill percentage in the printer software. The tablets were mechanically strong, and the FDM 3D printing was shown to be an effective process for the manufacture of the drug, 5 ASA. Significant thermal degradation of the active 4-ASA (50%) occurred during printing, however, indicating that the method may not be appropriate for drugs when printing at high temperatures exceeding those of the degradation point. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of the formulated blends confirmed these findings while highlighting the potential of thermal analytical techniques to anticipate drug degradation issues in the 3D printing process. The results of the dissolution tests conducted in modified Hank's bicarbonate buffer showed that release profiles for both drugs were dependent on both the drug itself and on the infill percentage of the tablet. Our work here demonstrates the potential role of FDM 3DP as an efficient and low-cost alternative method of manufacturing individually tailored oral drug dosage, and also for production of modified-release formulations. PMID- 25497177 TI - Biodistribution of nanostructured lipid carriers: a tomographic study. AB - This study describes the preparation, characterization, and biodistribution of radiolabelled nanostructured lipid carriers (NLCs) especially designed for in vivo tomographic study. A preliminary formulative study was conducted in order to incorporate (99m)Tc based tracer in NLCs. At this aim a (99m)Tc complex containing a terminal (99m)Tc = N multiple bond ([(99m)Tc]N-DBODC2) has been synthesized and included in NLCs produced by a stirring and ultrasonication method. The morphological and dimensional characteristics of the produced NLCs have been accurately investigated by a number of specific techniques, including: cryogenic transmission electron microscopy, X-ray, photon correlation spectroscopy and sedimentation field flow fractionation. The obtained NLCs were employed for achieving in vivo tomographic images of the rat body by small-animal SPECT scanner that enabled the investigation of NLC biodistribution after intraperitoneal, intravenous, intranasal and oral administration. NLC production protocol allowed to firmly encapsulate the radiotracer within the nanoparticles. In vivo studies evidenced that NLC remained stable in vivo, suggesting their suitability as controlled release system for drugs and radiochemical for therapeutic and diagnostic purposes. Moreover the high resolution images obtained by the SPECT technique allowed to detect NLC presence in brown fat tissue, suggesting NLC therapeutic application for treating human obesity and related metabolic disorders. PMID- 25497179 TI - Phenol esterase activity of porcine skin. AB - The alkyl esters of plant-derived phenols may serve as slow-release sources for cutaneous delivery of antioxidants. The ability of skin esterases to hydrolyze phenolic esters was examined. Esters of tyrosol and hydroxytyrosol were prepared from decanoic and lipoic acids. Ferulic acid was esterified with octadecanol, glycerol, and dioleoylglycerol. These phenolic derivatives were treated in taurodeoxycholate microemulsion and unilamellar liposomes with ex vivo porcine skin and an aqueous extract of the skin. Extracted esterases hydrolyzed the microemulsions at rates in the order: tyrosyl lipoate > tyrosyl decanoate > hydroxytyrosyl lipoate > hydroxytyrosyl decanoate. The tyrosyl decanoate was subject to comparatively little hydrolysis (10-30% after 24h) when incorporated into liposomes, while hydroxytyrosyl decanoate in liposomes was not hydrolyzed at all by the skin extract. Ferulate esters were not hydrolyzed by the extract in aqueous buffer, microemulsion, nor liposomes. Tyrosyl decanoate applied topically to skin explants in microemulsion were readily hydrolyzed within 4h, while hydrolysis was minimal when applied in liposomes. These findings indicate that porcine skin displays a general esterase activity toward medium-chain esters of tyrosol and hydroxytyrosol, which can be moderated by the physiochemical properties of the lipid vehicle, but no feruloyl esterase activity. PMID- 25497180 TI - Referral-making in the current landscape of abortion access. PMID- 25497181 TI - Outcome of salvage hepatic resection for recurrent hepatocellular carcinoma after radiofrequency ablation therapy. AB - BACKGROUND: Although radiofrequency ablation (RFA) is an effective local ablative technique for the treatment of hepatocellular carcinoma (HCC), the optimal treatment for recurrence after RFA has not been established. METHODS: Between September 2002 and December 2011, 46 hepatectomies (salvage group) were performed for intrahepatic (local or multifocal) recurrent HCC after RFA. The difference between the imaging findings before RFA and at the time of salvage resection, especially in the Local recurrent group, and the short-term and long-term outcomes after salvage surgery were analyzed retrospectively by comparing them with those for a matched control group (n = 46) and with those of patients who underwent a second hepatic resection for HCC recurrence after an initial hepatic resection during the same period (n = 155). RESULTS: The tumor-occupying region was more distributed widely before the salvage resection compared with that before RFA, and a more extensive operation would have been required (rather than the RFA) in the local group. An evaluation of the short-term outcomes revealed that salvage resection required a longer operative time and was associated with a greater frequency of morbidity. The long-term outcomes of the salvage group were poorer than those of patients who underwent repeat hepatic resection for HCC recurrence after an initial hepatic resection. CONCLUSION: The indications for RFA should be determined carefully, because recurrence after RFA may be associated with a more aggressive pattern of recurrence, and the long-term results after salvage resection are unsatisfactory. PMID- 25497183 TI - Impact of maternal obesity on perinatal and childhood outcomes. AB - Maternal obesity is of major consequence, affecting every aspect of maternity care including both short- and long-term effects on the health of the offspring. Obese mothers are at a higher risk of developing gestational diabetes and pre eclampsia, potentially exposing the foetus to an adverse intrauterine environment. Maternal obesity is linked to foetal macrosomia, resulting in increased neonatal and maternal morbidity. Foetal macrosomia is a result of a change in body composition in the neonate with an increase in both percentage fat and fat mass. Maternal obesity and gestational weight gain are associated with childhood obesity, and this effect extends into adulthood. Childhood obesity in turn increases chances of later life obesity, thus type 2 diabetes, and cardiovascular disease in the offspring. Further clinical trials of lifestyle and, potentially, pharmacological interventions in obese pregnant women are required to determine whether short- and long-term adverse effects for the mother and child can be reduced. PMID- 25497184 TI - Universal health coverage post-2015: putting people first. PMID- 25497182 TI - Transcriptional regulation of heterogeneous nuclear ribonucleoprotein K gene expression. AB - Heterogeneous nuclear ribonucleoprotein K (hnRNP K) is importantly involved in the regulation of development, DNA damage response, and several human diseases. The molecular mechanisms that control the expression of hnRNP K are largely unknown. In the present study, we investigated the detailed mechanism of the transcriptional regulation of human hnRNP K gene. Two activating and one repressive elements located in the proximal segment of the transcriptional initiation site were identified in hnRNP K gene. A 19 bp-region was responsible for the inhibitory activities of the repressor element. Twenty proteins were identified by DNA-affinity purification and mass spectrometry analyses as binding partners of the primary activating element in the hnRNP K promoter. Chromatin immunoprecipitation and EMSA analysis confirmed the binding of Sp1 with hnRNP K promoter. Sp1 enhanced the promoter activity, increased the expression of hnRNP K, and reduced the mRNA level of angiotensinogen, a gene known to be negatively regulated by hnRNP K. In summary, the current study characterized the promoter elements that regulate the transcription of human hnRNP K gene, identified 20 proteins that bind to the primary activating element of hnRNP K promoter, and demonstrated a functional effect of Sp1 on hnRNP K transcription. PMID- 25497185 TI - Drug labelling and pregnancy. PMID- 25497186 TI - Consequences of a competitive research culture. PMID- 25497187 TI - Health and climate change: the end of the beginning? PMID- 25497189 TI - Remembering the Indian Ocean tsunami. PMID- 25497190 TI - David Evans: putting universal health coverage on the agenda. PMID- 25497191 TI - Ebola in Africa: beyond epidemics, reproductive health in crisis. PMID- 25497192 TI - Patient safety after partial and total knee replacement. PMID- 25497193 TI - Prevalence of overweight and obesity in children and adults. PMID- 25497194 TI - The debate on electronic cigarettes. PMID- 25497195 TI - Education of health professionals in China. PMID- 25497196 TI - Prevalence of overweight and obesity in children and adults - authors' reply. PMID- 25497197 TI - Education of health professionals in China. PMID- 25497198 TI - Education of health professionals in China - author's reply. PMID- 25497199 TI - Transgender patients need better protection in China. PMID- 25497200 TI - Austerity and its consequences on cancer screening in Greece. PMID- 25497201 TI - Acute compartment syndrome secondary to rhabdomyolysis in a sickle cell trait patient. PMID- 25497202 TI - Pharmacovigilance bolstered in the Arab world. PMID- 25497204 TI - How the virophage compels the need to readdress the classification of microbes. AB - The discovery of Mimivirus opened the door to reclassifying viruses and microorganisms. Because the definition of a virus had been based on their putative small size, giant viruses have been widely neglected, as have their own viral parasites: the virophage. Current studies show that giant viruses can be found worldwide in the soil, water, animals and humans. Their existence forces us to create new classifications, the most recent being TRUC, to accommodate the existence of four branches of microorganisms, i.e., bacteria, archaea, eukaryotes and giant viruses. PMID- 25497205 TI - Evaluation of a comprehensive cardiovascular magnetic resonance protocol in young adults late after the arterial switch operation for d-transposition of the great arteries. AB - BACKGROUND: In adults with prior arterial switch operation (ASO) for d transposition of the great arteries, the need for routine coronary artery assessment and evaluation for silent myocardial ischemia is not well defined. In this observational study we aimed to determine the value of a comprehensive cardiovascular magnetic resonance (CMR) protocol for the detection of coronary problems in adults with prior ASO for d-transposition of the great arteries. METHODS: Adult ASO patients (>=18 years of age) were recruited consecutively. Patients underwent a comprehensive stress perfusion CMR protocol that included measurement of biventricular systolic function, myocardial scar burden, coronary ostial assessment and myocardial perfusion during vasodilator stress by perfusion CMR. Single photon emission computed tomography (SPECT) was performed on the same day as a confirmatory second imaging modality. Stress studies were visually assessed for perfusion defects (qualitative analysis). Additionally, myocardial blood flow was quantitatively analysed from mid-ventricular perfusion CMR images. In unclear cases, CT coronary angiography or conventional angiography was done. RESULTS: Twenty-seven adult ASO patients (mean age 23 years, 85% male, 67% with a usual coronary pattern; none with a prior coronary artery complication) were included in the study. CMR stress perfusion was normal in all 27 patients with no evidence of inducible perfusion defects. In 24 cases the coronary ostia could conclusively be demonstrated to be normal. There was disagreement between CMR and SPECT for visually-assessed perfusion defects in 54% of patients with most disagreement due to false positive SPECT. CONCLUSIONS: Adult ASO survivors in this study had no CMR evidence of myocardial ischemia, scar or coronary ostial abnormality. Compared to SPECT, CMR provides additional valuable information about the coronary artery anatomy. The data shows that the asymptomatic and clinically stable adult ASO patient has a low pre-test probability for inducible ischemia. In this situation it is likely that routine evaluation with stress CMR is unnecessary. PMID- 25497207 TI - Neurological and cardiac responses after treatment with miglustat and a ketogenic diet in a patient with Sandhoff disease. AB - Sandhoff disease is a progressive neurodegenerative disorder characterized by accumulation of GM2 gangliosides. We describe a 6-year-old male with coarse facial features, developmental delay, refractory seizures, hypertrophic cardiomyopathy, who was later found to have Sandhoff disease. Previous studies have revealed that caloric restriction in combination with miglustat increased survival and motor behavior in mouse model of Sandhoff disease. These findings suggest that combination therapy may result in improved outcomes for patients with Sandhoff. Initiation of treatment with miglustat and a ketogenic diet was followed by improvement of the patient's seizure control and cardiac function. Further clinical investigation is required to better determine the benefit of management in late-onset forms of Sandhoff disease. PMID- 25497206 TI - Associated noncardiac congenital anomalies among cases with congenital heart defects. AB - Cases with congenital heart defects (CHD) often have other associated anomalies. The purpose of this investigation was to assess the prevalence and the types of associated anomalies in CHD in a defined population. The anomalies associated with CHD were collected in all live births, stillbirths and terminations of pregnancy during 26 years in 346,831 consecutive pregnancies of known outcome in the area covered by our population based registry of congenital anomalies. Of the 4005 cases with CHD born during this period (total prevalence of 115.5 per 10,000), 1055 (26.3%) had associated major anomalies. There were 354 (8.8%) cases with chromosomal abnormalities including 218 trisomies 21, and 99 (2.5%) nonchromosomal recognized dysmorphic conditions. There were no predominant recognized dysmorphic conditions, but VACTERL association. However, other recognized dysmorphic conditions were registered including Noonan syndrome, fetal alcohol syndrome, and skeletal dysplasias. Six hundred and two (15.0%) of the cases had non syndromic, non chromosomal multiple congenital anomalies (MCA). Anomalies in the urinary tract, the musculoskeletal, the digestive, and the central nervous systems were the most common other anomalies. Prenatal diagnosis was obtained in 18.7% of the pregnancies. In conclusion the overall prevalence of associated anomalies, which was one in four infants, emphasizes the need for a thorough investigation of cases with CHD. A routine screening for other anomalies may be considered in infants and in fetuses with CHD. One should be aware that the anomalies associated with CHD can be classified into a recognizable anomaly, syndrome or pattern in one out of nine cases with CHD. PMID- 25497208 TI - Most frequent mutation c.3402delC (p.Ala1135GlnfsX13) among Wilson disease patients in Venezuela has a wide distribution and two old origins. AB - Wilson disease is an infrequent autosomal recessive disorder caused by mutations in the ATP7B gene (13q14.3) producing pathologic phenotypes due to copper accumulation in critical tissues. The aim of the research was to probe Wilson disease genetic epidemiology in Venezuela, through the identification in diagnosed index cases, of ATP7B locus mutations, their geographic distribution, frequency, in-phase haplotypes and probable ethnic ancestry. During the last three decades 33 independent Wilson disease families from the country at large were ascertained and diagnosed through severely reduced ceruloplasmin activity, higher urinary copper excretion, and specific clinical signs. Molecular studies of the ATP7B gene were accomplished in 26 of the families. Disease prevalence was estimated as 1:94,000 families between 1985 and 2013, showing geographic aggregation in the state of Zulia with 1:27,000 families in it. DNA analysis in 26 families revealed 13 different mutations. The c.3402delC was the most frequent one (26.9%), presenting two independent in-phase haplotypes, both of likely European descent; which is followed by the not previously reported p.G691V (9.6%) and by the frequent European H1069Q (7.7%). Known mutations c.51 + 4A > T, c.1285 + 5G > T, M645R, T788I, V845SfsX28, T977M, L1088X, T1220M, R1319X and a novel P767L showed frequencies between 5.8 and 1.9%. Despite the ample mutation heterogeneity for Wilson disease in the country, the findings provide a diagnostic algorithm to ease mutation assessment in new patients; the predominant c.3402delC displayed wide geographic distribution and two genetic origins. PMID- 25497210 TI - Biosynthesis of cyclosporins and other natural peptidyl prolyl cis/trans isomerase inhibitors. AB - BACKGROUND: Peptidyl-prolyl-cis/trans-isomerases (PPIases) are ubiquitously expressed and have been implicated in a wide range of biological functions. Their inhibition is beneficial in immunosuppression, cancer treatment, treatment of autoimmune diseases, protozoan and viral infections. SCOPE OF REVIEW: Three classes of PPIases are known, each class having their own specific inhibitors. This review will cover the present knowledge on the biosynthesis of the natural PPIase inhibitors. These include for the cyclophilins: the cyclosporins, the analogues of peptolide SDZ 214-103 and the sanglifehrins; for the FKBPs: ascomycin, rapamycin and FK506 and for the parvulins the naphtoquinone juglone. MAJOR CONCLUSIONS: Over the last thirty years much progress has been made in understanding PPIase function and the biosynthesis of natural PPIase inhibitors. Non-immunosuppressive analogues were discovered and served as lead compounds for the development of novel antiviral drugs. There are, however, still unsolved questions which deserve further research into this exciting field. GENERAL SIGNIFICANCE: As all the major natural inhibitors of the cyclophilins and FKBPs are synthesized by complex non-ribosomal peptide synthetases and/or polyketide synthases, total chemical synthesis is not a viable option. Thus, fully understanding the modular enzyme systems involved in their biosynthesis may help engineering enzymes capable of synthesizing novel PPIase inhibitors with improved functions for a wide range of conditions. This article is part of a Special Issue entitled Proline-directed Foldases: Cell signaling catalysts and drug targets. PMID- 25497209 TI - Impaired autophagy induces chronic atrophic pancreatitis in mice via sex- and nutrition-dependent processes. AB - BACKGROUND & AIMS: Little is known about the mechanisms of the progressive tissue destruction, inflammation, and fibrosis that occur during development of chronic pancreatitis. Autophagy is involved in multiple degenerative and inflammatory diseases, including pancreatitis, and requires the protein autophagy related 5 (ATG5). We created mice with defects in autophagy to determine its role in pancreatitis. METHODS: We created mice with pancreas-specific disruption of Atg5 (Ptf1aCreex1;Atg5F/F mice) and compared them to control mice. Pancreata were collected and histology, immunohistochemistry, transcriptome, and metabolome analyses were performed. ATG5-deficient mice were placed on diets containing 25% palm oil and compared with those on a standard diet. Another set of mice received the antioxidant N-acetylcysteine. Pancreatic tissues were collected from 8 patients with chronic pancreatitis (CP) and compared with pancreata from ATG5 deficient mice. RESULTS: Mice with pancreas-specific disruption of Atg5 developed atrophic CP, independent of beta-cell function; a greater proportion of male mice developed CP than female mice. Pancreata from ATG5-deficient mice had signs of inflammation, necrosis, acinar-to-ductal metaplasia, and acinar-cell hypertrophy; this led to tissue atrophy and degeneration. Based on transcriptome and metabolome analyses, ATG5-deficient mice produced higher levels of reactive oxygen species than control mice, and had insufficient activation of glutamate dependent metabolism. Pancreata from these mice had reduced autophagy, increased levels of p62, and increases in endoplasmic reticulum stress and mitochondrial damage, compared with tissues from control mice; p62 signaling to Nqo1 and p53 was also activated. Dietary antioxidants, especially in combination with palm oil derived fatty acids, blocked progression to CP and pancreatic acinar atrophy. Tissues from patients with CP had many histologic similarities to those from ATG5 deficient mice. CONCLUSIONS: Mice with pancreas-specific disruption of Atg5 develop a form of CP similar to that of humans. CP development appears to involve defects in autophagy, glutamate-dependent metabolism, and increased production of reactive oxygen species. These mice might be used to identify therapeutic targets for CP. PMID- 25497211 TI - Spontaneously hyperactive MEK-Erk pathway mediates paradoxical facilitation of cell proliferation in mild hypoxia. AB - BACKGROUND: Oxygen is important for common eukaryotic cells to generate ATP. Pathophysiological conditions such as ischemic diseases cause tissue hypoxia. In addition, oxygen availability in deep tissues is supposed to be far lower than surrounding atmosphere even in healthy animals, and the oxygen partial pressures in most normal tissues are estimated to be around 40-50mmHg, so-called mild hypoxia. Recent studies have demonstrated that mild hypoxia has distinct effects on living cells from severe hypoxia. For instance, mild hypoxia was reported to promote cell reprogramming. Although severe hypoxia is known to inhibit cell proliferation, mild hypoxia has been paradoxically demonstrated to increase cell proliferation. However, it has not been clarified by which molecular mechanisms mild hypoxia evokes the discontinuous increment of cell proliferation. METHODS: We established experimental conditions showing the opposite influences of mild and severe hypoxia on cell proliferation using undifferentiated Caco2 human colon carcinoma cells in order to clarify the underlying molecular mechanism. RESULTS: The basal activity of Erk, which is a typical mediator of mitogenic signals, is spontaneously increased specifically in cells exposed to mild hypoxia, and inhibition of MEK, an upstream kinase of the Erk, completely inhibited the mild hypoxia-induced enhancement of cell proliferation. CONCLUSIONS: Spontaneous hyperactivation of the MEK-Erk pathway by mild hypoxia should be the plausible molecular mechanism of the paradoxical promotion of cell proliferation. GENERAL SIGNIFICANCE: Our findings will provide clues to the molecular basis of mild hypoxia-evoked phenomena such as cell reprogramming. PMID- 25497212 TI - Real-time protein NMR spectroscopy and investigation of assisted protein folding. AB - BACKGROUND: During protein-folding reactions toward the native structure, short lived intermediate states can be populated. Such intermediates expose hydrophobic patches and can self-associate leading to non-productive protein misfolding. A major focus of current research is the characterization of short-lived intermediates and how molecular chaperones enable productive folding. Real-time NMR spectroscopy, together with the development of advanced methods, is reviewed here and the potential these methods have to characterize intermediate states as well as interactions with molecular chaperone proteins at single-residue resolution is highlighted. SCOPE OF REVIEW: Various chaperone interactions can guide the protein-folding reaction and thus are important for protein structure formation, stability, and activity of their substrates. Chaperone-assisted protein folding, characterization of intermediates, and their molecular interactions using real-time NMR spectroscopy will be discussed. Additionally, recent advances in NMR methods employed for characterization of high-energy intermediates will be discussed. MAJOR CONCLUSIONS: Real-time NMR combines high resolution with kinetic information of protein reactions, which can be employed not only for protein-folding studies and the characterization of folding intermediates but also to investigate the molecular mechanisms of assisted protein folding. GENERAL SIGNIFICANCE: Real-time NMR spectroscopy remains an effective tool to reveal structural details about the interaction between chaperones and transient intermediates. Methodologically, it provides in-depth understanding of how kinetic intermediates and their thermodynamics contribute to the protein-folding reaction. This review summarizes the most recent advances in this field. This article is part of a Special Issue titled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. PMID- 25497213 TI - Molecular recognition in naphthoquinone derivatives - G-quadruplex complexes by NMR. AB - BACKGROUND: G-quadruplexes have become important drug-design targets for the treatment of various human disorders such as cancer, diabetes and cardiovascular diseases. Recently, G-quadruplex structures have been visualized in the DNA of human cells and appeared to be dynamically sensitive to the cell cycle and stabilized by small molecule ligands. A small library of isoxazolo naphthoquinones (1a-h), which exhibited a strong antiproliferative activity on different cancer cell lines, was studied as potential ligands of G-quadruplex DNA. METHODS: The DNA binding properties of a series of the selected compounds have been analyzed by fluorescence assays. NMR/modeling studies were performed to describe the complexes between G-quadruplex DNA sequences and two selected compounds 1a and 1b. RESULTS: 1a and 1b in the presence of G-quadruplexes, d(T(2)AG(3)T)(4), d(TAG(3)T(2)A)(4) and d(T(2)G(3)T(2))(4), showed good ability of intercalation and the formation of complexes with 2:1 stoichiometry. 1a showed an important interaction with the sequence Pu22 belonging to the promoter of oncogenes c-myc. CONCLUSIONS: The ligands directly interact with the external G tetrads of the G-quadruplexes, without alterations in the structure of the G quadruplex core. The role of the adenine moieties over the G-tetrads in the stabilization of the complexes was discussed. GENERAL SIGNIFICANCE: The results obtained suggested that the strong antiproliferative activity of isoxazolo naphthoquinones is not due to the Hsp90 inhibition, but mainly to the interaction at the level of telomeres and/or at the level of gene promoter. These findings can be used as a basis for the rational drug design of new anticancer agents. PMID- 25497214 TI - Cytoplasmic peptide:N-glycanase cleaves N-glycans on a carboxypeptidase Y mutant during ERAD in Saccharomyces cerevisiae. AB - BACKGROUND: Endoplasmic reticulum (ER)-associated degradation (ERAD) is a pathway by which misfolded or improperly assembled proteins in the ER are directed to degradation. The cytoplasmic peptide:N-glycanase (PNGase) is a deglycosylating enzyme that cleaves N-glycans from misfolded glycoproteins during the ERAD process. The mutant form of yeast carboxypeptidase Y (CPY*) is an ERAD model substrate that has been extensively studied in yeast. While a delay in the degradation of CPY* in yeast cells lacking the cytoplasmic PNGase (Png1 in yeast) was evident, the in vivo action of PNGase on CPY* has not been detected. METHODS: We constructed new ERAD substrates derived from CPY*, bearing epitope tags at both N- and C-termini and examined the degradation intermediates observed in yeast cells with compromised proteasome activity. RESULTS: The occurrence of the PNGase-mediated deglycosylation of intact CPY* and its degradation intermediates was evident. A major endoproteolytic reaction on CPY* appears to occur between amino acid 400 and 404. CONCLUSIONS: The findings reported herein clearly indicate that PNGase indeed releases N-glycans from CPY* during the ERAD process in vivo. GENERAL SIGNIFICANCE: This report implies that the PNGase-mediated deglycosylation during the ERAD process may occur more abundantly than currently envisaged. PMID- 25497215 TI - Optimal vitamin D levels in Crohn's disease: a review. AB - Vitamin D deficiency is common among patients with Crohn's disease. Serum 25 hydroxyvitamin D (25(OH)D) is the best measure of an individual's vitamin D status and current cut-off ranges for sufficiency are debatable. Several factors contribute to vitamin D deficiency in Crohn's disease. These include inadequate exposure to sunlight, inadequate dietary intake, impaired conversion of vitamin D to its active metabolite, increased catabolism, increased excretion and genetic variants in vitamin D hydroxylation and transport. The effects of low 25(OH)D on outcomes other than bone health are understudied in Crohn's disease. The aim of the present review is to discuss the potential roles of vitamin D and the possible levels required to achieve them. Emerging evidence suggests that vitamin D may have roles in innate and adaptive immunity, in the immune-pathogenesis of Crohn's disease, prevention of Crohn's disease-related hospitalisations and surgery, in reducing disease severity and in colon cancer prevention. The present literature appears to suggest that 25(OH)D concentrations of >=75 nmol/l may be required for non-skeletal effects; however, further research on optimal levels is required. PMID- 25497216 TI - Rodent selectivity of piperidine-4-yl-1H-indoles, a series of CC chemokine receptor-3 (CCR3) antagonists: insights from a receptor model. AB - Rodent selectivity data of piperidine-4-yl-1H-indoles, a series of CC chemokine receptor-3 (CCR3) antagonists, are presented and discussed as part of an overall optimization effort within this lead compound class. Although attachment of an acidic moiety to the 1-position of the indole led to an overall balanced in vitro profile, in particular reducing inhibition of the hERG channel, potency on the rat and mouse receptor worsened. These findings could be rationalized in the context of a CCR3 homology model. PMID- 25497217 TI - A synthesis of new, bi-labeled peptides for quantitative proteomics. AB - Isotopically labeled peptides are often used in proteomics as internal reference allowing quantification of peptides by isotopic dilution method. Although the synthesis of peptides labeled with stable isotopes is relatively simple, there are several factors limiting application of these standards in proteomic research: cost of labeled derivatives of amino acids, time needed to obtain labeled peptide and problems with quantification of the standard. To solve these problems we developed a method of synthesis of peptides labeled with heavy oxygen and with a dabsyl moiety. The chromophoric group facilitates the determination of peptide concentration while sequence of peptide allows enzymatic cleavage of fragment containing dabsyl from peptide leaving "natural" sequence with incorporated (18)O atoms. The approach proposed herein is based on the "analytical construct" concept. The experiments performed on model peptides demonstrated that response factors in HPLC analysis of labeled peptides does not depend on the sequence and tryptic hydrolysis of obtained conjugates is completed in minutes producing labeled standards useful in quantitative proteomics. BIOLOGICAL SIGNIFICANCE: The reported method allows for a cheap and efficient synthesis of peptides labeled with heavy isotopes, and for their precise quantification. Peptides of our design are stable, and the isotopic label, which is a part of the peptide backbone, is stable as well. Moreover, they can be quickly quantified in solution at any time, so the possible decomposition of standard or a non-uniform distribution of the peptide in lyophylisate does not pose a problem. Therefore, we deem our synthesis to be useful for a broad range of quantitative proteomics methods. In addition, the procedure described herein allows direct application of crude peptides as the analytical standards. The elimination of expensive and time-consuming chromatographic purification reduces the cost of AQUA peptides and gives the possibility of a rapid preparation of large libraries of proteolytic fragments. PMID- 25497218 TI - Exoproteome of Aspergillus flavus corneal isolates and saprophytes: identification of proteoforms of an oversecreted alkaline protease. AB - Aspergillus flavus infects the human eye leading to keratitis. Extracellular proteins, the earliest proteins that come in contact with the host and virulence related exoproteins, were identified in the fungus isolated from infected cornea. Virulence of the corneal isolates was tested in the Galleria mellonella larvae model and those isolates showing higher virulence were taken for subsequent exoproteome analysis. High resolution two-dimensional electrophoresis and mass spectrometry were used to generate A. flavus exoproteome reference map as well as to profile most of the exoproteins. Analysis of the identified proteins clearly shows the major biological processes that they are involved in. Nearly 50% of the exoproteins possess catalytic activity and one of these, an alkaline serine protease (Alp1) is present in high abundance as well as multiple proteoforms. Many proteins in the A. flavus exoproteome have been shown to be virulence factors in other pathogens indicating the probable role for these proteins in the corneal infection as well. Interestingly, the majority of the exoproteins do not have secretory signal indicating that they are secreted through the non-classical pathway. Thus, this study provides a clue to the early strategies employed by the pathogen to establish an infection in an immunocompetent host. BIOLOGICAL SIGNIFICANCE: The outcome of a fungal infection in an immunocompetent human eye depends on the ability of the fungus to overcome the host defense and propagate itself. In this process, the earliest events with respect to the fungal proteins involved include the secretory proteins of the invading organism. As a first step towards understanding the role of the extracellular proteins, exoproteome profile of the fungal isolates was generated. The fungal isolates from cornea showed a distinct pattern of the exoproteome when compared to the saprophyte. Since corneal isolates also showed higher virulence in the insect larval model, presumably the proteins elaborated by the corneal isolates are virulence related. One of the abundant proteins is an alkaline serine protease and this protein exists as multiple proteoforms. This study reports the comprehensive profile of exoproteome and reveals proteins that are potential virulence factors. PMID- 25497219 TI - Proteomic analysis on the antibacterial activity of a Ru(II) complex against Streptococcus pneumoniae. AB - Streptococcus pneumoniae is a Gram-positive pathogen that causes a variety of infection diseases in human. In this project, we determined the antibacterial activity of a Ru(II) complex X-03 against S. pneumoniae in vitro, by comparing its toxicity to host cells A549 and HBE. We performed two-dimensional gel electrophoresis (2-DE)-based proteomic analysis to characterize the protein alterations in S. pneumoniae after treatment with X-03. In total, 50 proteins exhibiting significant differential expressions were identified. RT-PCR was used to confirm the expression differences for selected proteins. Bioinformatics analysis on the proteomic alterations suggested that Ru(II) complex X-03 may obstruct bacterial fatty acid synthesis and oxidation-reduction process to suppress the growth of S. pneumoniae. Metal-uptake experiments revealed that iron acquisition pathway in the bacterium may be interfered by X-03. These results provide useful clues for further investigations on the mechanism of the antibacterial action of metal compounds. BIOLOGICAL SIGNIFICANCE: The appearance of bacterial strains with broad antibiotic resistance is becoming an alarming global health concern. The development of novel efficient antibacterial compound is urgently needed. In the present study, we found that Ru(II) complex X-03 has a significant antibacterial activity and applied proteomic technology combined with bioinformatics analysis to investigate its antimicrobial mechanism in S. pneumoniae. Many proteins were found to be dysregulated, implicating that X-03 may affect various molecular pathways leading to the inhibition of bacterial growth. Metal-uptake experiments demonstrated that X-03 treatment reduced the iron content in the bacterium, suggesting the interference with iron acquisition systems by the complex. This disturbance in iron acquisition may directly or indirectly induce the proteomic response that involved many pathways. In addition, X-03 could selectively suppress Gram-positive bacteria but execute less cytotoxicity to Gram-negative bacteria, with almost no effect on human cells, implicating its potential to be developed as a specific antimicrobial agent. These results provide useful information for further investigations on the mechanism of the antibacterial action of metal drugs and development of efficient antibacterial drugs. PMID- 25497221 TI - Neural correlates of planning performance in patients with schizophrenia- relationship with apathy. AB - Patients with schizophrenia often suffer from apathy: a quantitative reduction of voluntary, goal-directed behaviors that impairs daily functioning. We hypothesized that schizophrenia patients with high levels of apathy would show decreased activation in brain regions involved in planning and goal-directed behavior. Patients with schizophrenia or psychotic spectrum disorder (n=47) and healthy controls (n=20) performed the Tower of London (ToL) task during fMRI scanning using arterial spin labeling. To investigate the relationship between apathy and planning in patients, a proxy measure of apathy based on the Positive and Negative syndrome Scale was regressed against the task-related brain activation. Brain activation was also compared between patients and healthy controls. Higher levels of apathy were associated with less task-related activation within the inferior parietal lobule precuneus and thalamus. Compared to controls, patients showed lower activation in lateral prefrontal regions, parietal and motor areas, and a higher activation of medial frontal areas. Apathy was related to abnormal activation in thalamus and parietal regions during the ToL task. This supports the hypothesis that impaired function of brain regions involved in planning and goal-directed behavior may underlie apathy in schizophrenia. Moreover, impaired lateral prefrontal activation in schizophrenia patients compared to controls is consistent with the hypofrontality model of schizophrenia. In contrast, stronger medial frontal activation in patients may be related to increased effort to perform a task with conflicting task solutions. PMID- 25497220 TI - Oligometastases in prostate cancer: restaging stage IV cancers and new radiotherapy options. AB - There are various subgroups of patients with metastatic prostate cancer: polymetastatic, oligometastatic, or oligo-recurrent cancers whose progression follows different courses and for whom there are different treatment options. Knowledge of tumor dissemination pathways and different genetic and epigenetic tumor profiles, as well as their evolution during disease progression, along with new diagnostic and therapeutic advances has allowed us to address these situations with local ablative treatments such as stereotactic body radiation therapy or stereotactic radiosurgery. These treatments provide high rates of local control with low toxicity in metastatic spread for primary cancers including those of pulmonary, digestive, and renal origin, while these types of treatments are still emerging for cancers of prostatic origin. There are several retrospective studies showing the effectiveness of such treatments in prostate cancer metastases, which has led to the emergence of prospective studies on the issue and even some phase II studies intended to prevent or delay systemic treatments such as chemotherapy. Here we collect together and review these past experiences and the studies currently underway. These types of radiotherapy treatments redefine how we approach extracranial metastatic disease and open up new possibilities for combination therapy with new systemic treatment agents. PMID- 25497223 TI - Abnormal, affect-specific modulatory effects on early auditory processing in schizophrenia: magnetoencephalographic evidence. AB - Abnormalities in the perception and identification of emotions have frequently been reported in schizophrenia. Hemodynamic neuroimaging studies found functional abnormalities in cortical and subcortical brain circuits that are involved in normal affective processing, but the temporal dynamics of abnormal emotion processing in schizophrenia remain largely elusive. To investigate this issue, we recorded early auditory evoked field components by means of whole-head magnetoencephalography that were in response to emotion-associated tones in seventeen patients with schizophrenia and in seventeen healthy, matched controls. Forty-two click-like tones (conditioned stimuli; CS) acquired differential emotional meaning through an affective associative learning procedure by pairing each CS three times with either pleasant, unpleasant or neutral auditory scenes. As expected, differential affect-specific modulation in patients vs. controls was evident, starting at the auditory N1m onset latency of approximately 70ms, extending to 230ms. While controls showed the expected enhanced processing of emotion associated CS, patients revealed an inverted pattern with reduced processing of arousal, when compared to neutral stimuli, in the right prefrontal cortex. The present finding suggests impairments in the prioritization of emotionally salient vs. non-salient stimuli in patients with schizophrenia. Dysfunction in higher cognitive processes and behavior in schizophrenia may therefore reflect dysfunction in fundamental, early emotion processing stages. PMID- 25497222 TI - Hippocampal dysfunction during declarative memory encoding in schizophrenia and effects of genetic liability. AB - Declarative memory (DM) impairments are reported in schizophrenia and in unaffected biological relatives of patients. However, the neural correlates of successful and unsuccessful encoding, mediated by the medial temporal lobe (MTL) memory system, and the influence of disease-related genetic liability remain under explored. This study employed an event-related functional MRI paradigm to compare activations for successfully and unsuccessfully encoded associative face name stimuli between 26 schizophrenia patients (mean age: 33, 19m/7f), 30 controls (mean age: 29, 24m/6f), and 14 unaffected relatives of patients (mean age: 40, 5m/9f). Compared to controls or unaffected relatives, patients showed hyper-activations in ventral visual stream and temporo-parietal cortical association areas when contrasting successfully encoded events to fixation. Follow-up hippocampal regions-of-interest analysis revealed schizophrenia-related hyper-activations in the right anterior hippocampus during successful encoding; contrasting successful versus unsuccessful events produced schizophrenia-related hypo-activations in the left anterior hippocampus. Similar hippocampal hypo activations were observed in unaffected relatives during successful versus unsuccessful encoding. Post hoc analyses of hippocampal volume showed reductions in patients, but not in unaffected relatives compared to controls. Findings suggest that DM encoding deficits are attributable to both disease-specific and genetic liability factors that impact different components of the MTL memory system. Hyper-activations in temporo-occipital and parietal regions observed only in patients suggest the influence of disease-related factors. Regional hyper- and hypo-activations attributable to successful encoding occurring in both patients and unaffected relatives suggest the influence of schizophrenia-related genetic liability factors. PMID- 25497224 TI - Expression and characterization of myristoylated preS1-conjugated nanocages for targeted cell delivery. AB - Lipid modification of proteins plays key roles in cellular signaling pathways. We describe the development of myristoylated preS1-nanocages (myr-preS1-nanocages) that specifically target human hepatocyte-like HepaRG cells in which a specific receptor-binding peptide (preS1) is joined to the surface of naturally occurring ferritin cages. Using a genetic engineering approach, the preS1 peptide was joined to the N-terminal regions of the ferritin cage via flexible linker moieties. Myristoylation of the preS1 peptide was achieved by co-expression with yeast N-myristoyltransferase-1 in the presence of myristic acid in Escherichia coli cells. The myristoylated preS1-nanocages exhibited significantly greater specificity for human hepatocyte-like HepaRG cells than the unmyristoylated preS1 nanocages. These results suggest that the lipid-modified nanocages have great potential for effective targeted delivery to specific cells. PMID- 25497226 TI - Death: past, present, and future. PMID- 25497227 TI - Current treatment strategies for inhibiting mTOR in cancer. AB - Mammalian target of rapamycin (mTOR) is a Ser/Thr kinase that regulates a wide range of functions, including cell growth, proliferation, survival, autophagy, metabolism, and cytoskeletal organization. mTOR activity is dysregulated in several human disorders, including cancer. The crucial role of mTOR in cancer cell biology has stimulated interest in mTOR inhibitors, placing mTOR on the radar of the pharmaceutical industry. Several mTOR inhibitors have already undergone clinical trials for treating tumors, without great success, although mTOR inhibitors are approved for the treatment of some types of cancer, including advanced renal cell carcinoma. However, the role of mTOR inhibitors in cancer treatment continues to evolve as new compounds are continuously being disclosed. Here we review the three classes of mTOR inhibitors currently available for treating cancer patients. Moreover, we highlight efforts to identify markers of resistance and sensitivity to mTOR inhibition that could prove useful in the emerging field of personalized medicine. PMID- 25497228 TI - The effects of "The Work" meditation (Byron Katie) on psychological symptoms and quality of life--a pilot clinical study. AB - OBJECTIVES: "The Work" is a meditative technique that enables the identification and investigation of thoughts that cause an individual stress and suffering. Its core is comprised of four questions and turnarounds that enable the participant to experience a different interpretation of reality. We assessed the effect of "The Work" meditation on quality of life and psychological symptoms in a non clinical sample. DESIGN: This study was designed as a single-group pilot clinical trial (open label). Participants (n = 197) enrolled in a nine-day training course ("The School for The Work") and completed a set of self-administered measures on three occasions: before the course (n = 197), after the course (n = 164), and six months after course completion (n = 102). OUTCOME MEASURES: Beck Depression Inventory-II (BDI-II), Subjective Happiness Scale (SHS), Quality of Life Inventory (QOLI), Quick Inventory of Depressive Symptomatology-Self Report (QIDS SR16), Outcome Questionnaire 45.2 (OQ-45.2), State-Trait Anger Expression Inventory-2 (STAXI-2), and State-Trait Anxiety Inventory (STAI). RESULTS: A mixed models analysis revealed significant positive changes between baseline compared to the end of the intervention and six-month follow-up in all measures: BDI-II (t = 10.24, P < .0001), SHS (t = -9.07, P <.0001), QOLI (t = -5.69, P < .0001), QIDS SR16 (t = 9.35, P < .0001), OQ-45.2 (t = 11.74, P < .0001), STAXI-2 (State) (t = 3.69, P = .0003), STAXI-2 (Trait) (t = 7.8, P < .0001), STAI (State) (t = 11.46, P < .0001), and STAI (Trait) (t = 10.75, P < .0001). CONCLUSIONS: The promising results of this pilot study warrant randomized clinical trials to validate "The Work" meditation technique as an effective intervention for improvement in psychological state and quality of life in the general population. PMID- 25497231 TI - Therapeutic potential of combined anti-IL-1beta IgY and anti-TNF-alpha IgY in guinea pigs with allergic rhinitis induced by ovalbumin. AB - We have previously demonstrated that anti-IL-1beta immunoglobulin yolk(IgY) inhibits pathological responses in allergic asthma guinea pigs induced by ovalbumin(OVA). This study aims to determine whether the combined blockade of IL 1beta and TNF-alpha can more effectively inhibit allergic inflammation in allergic rhinitis(AR) guinea pigs induced by OVA. Healthy guinea pigs treated with saline were used as the healthy control. The AR guinea pigs induced by OVA were randomly divided into (1) the AR model group containing negative control animals treated with intranasal saline; (2) the 0.1% non-specific IgY treatment group treated with non-specific IgY; (3) the 0.1% anti-TNF-alpha IgY treatment group treated with 0.1% anti-TNF-alpha IgY; (4) the 0.1% anti-IL-1beta IgY treatment group treated with 0.1% anti-IL-1beta IgY; (5) the 0.1% combined anti IL-1beta IgY and anti-TNF-alpha IgY treatment group treated with 0.1% combined anti-IL-1beta IgY and anti-TNF-alpha IgY; and (6) the fluticasone propionate treatment group treated with fluticasone propionate. Cytokines were measured using an enzyme-linked immunosorbent assay. The results showed that IL-1beta, IL 5, IL-9, IL-13, IL-18, IL-22, IL-33, TNF-alpha, TGF-beta1 and OVA-specific IgE levels in the peripheral blood (PB) and nasal lavage fluid (NLF) significantly decreased at 2h, 4h or 8h in the 0.1% combined anti-IL-1beta IgY and anti-TNF alpha IgY treatment group compared to the AR model group and the 0.1% non specific IgY treatment group (P<0.05). The data suggest that blockade of IL-1beta and TNF-alpha by intranasal instillation of combined anti-IL-1beta IgY and anti TNF-alpha IgY could be a potential alternative strategy for preventing and treating allergic rhinitis. PMID- 25497232 TI - Optimisation of protein microarray techniques for analysis of the plasma proteome: minimisation of non-specific binding interactions. AB - Components of the plasma proteome, particularly serum albumin, have been shown to compromise the accuracy of protein microarray technologies through non-specific binding interactions. Optimisation of array conditions is imperative to help address these problems. Here we demonstrate how modifications to array printing conditions and processing methodology can influence the reliability of data output. In particular, we demonstrate that whilst some glycerol is necessary to maintain specific binding signals, it also increases non-specific binding of albumin. Concentrations of 20% glycerol in the printing buffers are therefore recommended. The findings presented here provide opportunities for increased accuracy in plasma protein detection for possible future diagnostic applications. PMID- 25497229 TI - Structural basis for ligand and innate immunity factor uptake by the trypanosome haptoglobin-haemoglobin receptor. AB - The haptoglobin-haemoglobin receptor (HpHbR) of African trypanosomes allows acquisition of haem and provides an uptake route for trypanolytic factor-1, a mediator of innate immunity against trypanosome infection. In this study, we report the structure of Trypanosoma brucei HpHbR in complex with human haptoglobin-haemoglobin (HpHb), revealing an elongated ligand-binding site that extends along its membrane distal half. This contacts haptoglobin and the beta subunit of haemoglobin, showing how the receptor selectively binds HpHb over individual components. Lateral mobility of the glycosylphosphatidylinositol anchored HpHbR, and a ~50 degrees kink in the receptor, allows two receptors to simultaneously bind one HpHb dimer. Indeed, trypanosomes take up dimeric HpHb at significantly lower concentrations than monomeric HpHb, due to increased ligand avidity that comes from bivalent binding. The structure therefore reveals the molecular basis for ligand and innate immunity factor uptake by trypanosomes and identifies adaptations that allow efficient ligand uptake in the context of the complex trypanosome cell surface. PMID- 25497233 TI - Sexual behaviour, drug use and health service use by young Noongar people in Western Australia: a snapshot. AB - Background This study aimed to describe sexual health behaviour, alcohol and other drug use, and health service use among young Noongar people in the south west of Western Australia. METHOD: A cross-sectional survey was undertaken among a sample of 244 Noongar people aged 16-30 years. RESULTS: The sample was more disadvantaged than the wider Noongar population. Sexual activity was initiated at a young age, 18% had two or more casual sex partners in the previous 12 months, with men more likely to have done so than women (23% vs 14%). Condoms were always or often carried by 57% of men and 37% of women, and 36% of men and 23% of women reported condom use at last sex with a casual partner. Lifetime sexually transmissible infection diagnosis was 14%. Forty percent currently smoked tobacco and 25% reported risky alcohol consumption on a weekly and 7% on an almost daily basis. Cannabis was used by 37%, 12% used drugs in addition to cannabis and 11% reported recently injecting drugs. In the previous 12 months, 66% had a health check and 31% were tested for HIV or sexually transmissible infections. Additionally, 25% sought advice or assistance for mental health or alcohol and other drug issues. DISCUSSION: Although some respondents engaged in risky sexual behaviour, alcohol and other drug use or both, most did not. Particularly encouraging was the engagement of respondents with the health care system, especially among those engaging in risky behaviours. The results confound negative stereotypes of Aboriginal people and demonstrate a level of resilience among respondents. PMID- 25497230 TI - Molecular insights into RNA and DNA helicase evolution from the determinants of specificity for a DEAD-box RNA helicase. AB - How different helicase families with a conserved catalytic 'helicase core' evolved to function on varied RNA and DNA substrates by diverse mechanisms remains unclear. In this study, we used Mss116, a yeast DEAD-box protein that utilizes ATP to locally unwind dsRNA, to investigate helicase specificity and mechanism. Our results define the molecular basis for the substrate specificity of a DEAD-box protein. Additionally, they show that Mss116 has ambiguous substrate-binding properties and interacts with all four NTPs and both RNA and DNA. The efficiency of unwinding correlates with the stability of the 'closed state' helicase core, a complex with nucleotide and nucleic acid that forms as duplexes are unwound. Crystal structures reveal that core stability is modulated by family-specific interactions that favor certain substrates. This suggests how present-day helicases diversified from an ancestral core with broad specificity by retaining core closure as a common catalytic mechanism while optimizing substrate-binding interactions for different cellular functions. PMID- 25497235 TI - Value of oral effervescent powder administration for multidetector CT evaluation of esophageal cancer. AB - PURPOSE: To assess the value of oral effervescent powder (EP) for evaluation of esophageal distension, and for detection and staging of esophageal cancer with contrast-enhanced CT. MATERIALS AND METHODS: 84 patients without esophageal pathology and 52 patients with histological confirmed diagnosis of esophageal cancer were included in this prospective IRB-approved study. Half of the patients in both groups received EP prior to CT. Esophageal distension was assessed by planimetry of the inner (IA) and outer area (OA). Two blinded readers evaluated the datasets separately with regard to diagnosis of esophageal cancer (yes/no) and staging (T0-T4), if applicable. Distension results were compared (t-Test). In patients with cancer sensitivity, specificity, NPV and PPV were calculated. CT staging results were compared to histopathology (Cohen-k). RESULTS: IA and IA/OA were significantly larger after EP as compared to the group without EP (p<0.05). Sensitivity, specificity, NPV and PPV for cancer detection cancer were as follows: 78%/78%, 98%/98%, 95%/95%, 87%/87% with EP; 60%/68%, 98%/98%, 94%/94%, 80%/83% without EP. Staging with EP was good (k=0.84/0.67) and moderate without EP (k=0.58/0.59). CONCLUSIONS: Administration of EP prior to CT results in good distension of the esophagus, and improves detection and staging of esophageal cancer, as compared to control studies without EP. PMID- 25497234 TI - Evaluation of dual energy spectral CT in differentiating metastatic from non metastatic lymph nodes in rectal cancer: Initial experience. AB - OBJECTIVES: To investigate the value of dual energy spectral CT (DEsCT) imaging in differentiating metastatic from non-metastatic lymph nodes in rectal cancer. METHODS: Fifty-five patients with rectal cancer underwent the arterial phase (AP) and portal venous phase (PP) contrast-enhanced DEsCT imaging. The virtual monochromatic images and iodine-based material decomposition images derived from DEsCT imaging were interpreted for lymph nodes (LNs) measurement. The short axis diameter and the normalized iodine concentration (nIC) of metastatic and non metastatic LNs were measured. The two-sample t test was used to compare the short axis diameters and nIC values of metastatic and non-metastatic LNs. ROC analysis was performed to assess the diagnostic performance. RESULTS: One hundred and fifty two LNs including 92 non-metastatic LNs and 60 metastatic LNs were matched using the radiological-pathological correlation. The mean short axis diameter of metastatic LNs was significantly larger than that of the non-metastatic LNs (7.28+/-2.28mm vs. 4.90+/-1.64mm, P<0.001). The mean nIC value for metastatic LNs was significantly lower than that of non-metastatic LNs (0.24+/-0.08 vs. 0.34+/ 0.21, P=0.001 in AP; 0.47+/-0.18 vs. 0.64+/-0.17, P<0.001 in PP). Combining nIC (PP) with the short axis diameter, the overall accuracy could be improved to 82.9%. CONCLUSIONS: With the combination of nIC value in PP and conventional size criterion, dual energy spectral imaging may be used to differentiate metastatic from non-metastatic lymph nodes in rectal cancer. PMID- 25497236 TI - Genotype distribution of Mycoplasma hyopneumoniae in swine herds from different geographical regions. AB - Genetic heterogeneity of Mycoplasma hyopneumoniae in pigs has been reported, however there has been limited reproducibility on the molecular methods employed so far. The aim of this study was to modify and standardize a high-resolution multiple locus variable number tandem repeat analysis (MLVA), to investigate the genetic variability of M. hyopneumoniae circulating in the United States of America (USA), Brazil, Mexico and Spain. The MLVA was standardized on the basis of the number of tandem repeats in two Mycoplasma adhesins, P97 and P146, which are proteins involved in the adherence of the pathogen to cilia. A total of 355 samples obtained from the four countries were analyzed. The Simpson's diversity index for the assay was D=0.976 when samples from all countries were combined. A large number of MLVA types (n=139) were identified, suggesting that multiple M. hyopneumoniae variants are circulating in swine. The locus P97 had 17 different types with 2-18 repeats. The P146 locus showed higher heterogeneity, with 34 different types, ranging from 7 to 48 repeats. MLVA types that presented more than 30 repeats in P146 were found in Spain and Brazil, while shorter repeats were observed in the USA and Mexico. This simplified MLVA method proved to be an efficient tool for typing M. hyopneumoniae with a high degree of stability, repeatability, and discriminatory power. In conclusion, M. hyopneumoniae showed a high variable number tandem repeat heterogeneity and this assay can be applied in molecular epidemiology investigations within farms and productions systems. PMID- 25497237 TI - The protoxin Cry1Ac of Bacillus thuringiensis improves the protection conferred by intranasal immunization with Brucella abortus RB51 in a mouse model. AB - Brucellosis is a zoonotic disease affecting many people and animals worldwide. Preventing this infection requires improving vaccination strategies. The protoxin Cry1Ac of Bacillus thuringiensis is an adjuvant that, in addition to increasing the immunogenicity of different antigens, has shown to be protective in different models of parasitic infections. The objective of the present study was to test whether the intranasal co-administration of pCry1Ac with the RB51 vaccine strain of Brucella abortus confers protection against an intranasal challenge with the virulent strain B. abortus 2308 in BALB/c mice. The results showed that co administration of pCry1Ac and RB51, increased the immunoprotection conferred by the vaccine as evidenced by the following: (1) decrease of the splenic bacterial load when challenged intranasally with the virulent strain; (2) greater in vivo cytotoxic activity in response to the transference of previously infected cells; (3) further proliferation of cytotoxic TCD8+ cells in response to stimulation with heat-inactivated bacteria; (4) increased production of TNF-alpha and IFN gamma; and (5) significant IgG2a response. These results indicate that the use of the Cry1Ac protein as a mucosal adjuvant via the intranasal route can be a promising alternative for improving current RB51 vaccine against brucellosis. PMID- 25497238 TI - Diversity and health status specific fluctuations of intrauterine microbial communities in postpartum dairy cows. AB - For the interpretation of clinical findings of endometritis and the development of disease prevention and intervention strategies a better understanding of the dynamics and interactions within intrauterine bacterial communities in healthy and diseased cows is required. To gain deeper insights into fluctuations within the uterine microbiota, intrauterine samples were collected from 122 cows at the day of calving, days 3, 9, 15, 21 and 28 postpartum. A total of 2052 bacterial isolates were identified by Fourier-transform-infrared spectroscopy. This culturomics-based approach showed that the aerobic uterine microflora comprised a huge diversity of bacteria belonging to 202 different species, representing 76 genera, with members of the genus Staphylococcus (24.2%) being predominant. On species level the uterine microflora was dominated by Trueperella pyogenes (13.2%), Escherichia coli (11.2%), Staphylococcus xylosus (5.4%), Bacillus pumilus (5.2%) and Streptococcus uberis (4.9%). Comparative analysis of uterine bacteria from cows with different vaginal discharge scores (VDS) revealed health status specific temporal microbial diversifications. Although the intrauterine flora of all VDS groups was dominated by T. pyogenes, E. coli and Staphylococcus spp., the relative number of bacteria differed between VDS groups. The presence of T. pyogenes on days 15 and 21 significantly increased the risk of VDS 2 and 3 at day 21, whereas Staphylococci at day 9 reduced the likelihood of VDS 3 (P<0.05). This study demonstrates that intrauterine bacterial infections are highly dynamic processes and that bacterial species follow specific patterns of progression, which require further research to decipher their potential role in uterine disease development. PMID- 25497239 TI - Molecular cloning, tissue distribution, and immune function of goose TLR7. AB - TLR7 is a transmembrane endosomal protein that plays an essential role in innate antiviral responses via the recognition of conserved viral molecular patterns. Here, we cloned the full-length cDNA of goose TLR7 and carried out a molecular characterization of goose TLR7. The goose TLR7 gene is 3900 bp and encodes a 1045 amino acid protein with high homology to poultry (93% to duck and 83% to chicken). Similar conclusions were made by phylogenetic analysis. The predicted protein secondary structure of goose TLR7 contained a conserved Toll/interleukin 1 receptor domain and characteristic leucine-rich repeat regions, which has also been reported for duck TLR7. Additionally, the tissue distribution of goose TLR7 suggests that immune-associated tissues, especially the cecal tonsil and bursa of Fabricius, have high goose TLR7 expression levels. Goose TLR7 is abundantly expressed in lung tissues, which is distinct from its expression in chickens. Similar to duck TLR7, goose spleen mononuclear cells (MNCs) exposed to the mammalian TLR7 agonists R848 and Imiquimod showed significant induction of the production of proinflammatory cytokines and IFN-alpha. New type gosling viral enteritis virus (NGVEV) infection resulted in high mRNA expression levels of goose TLR7 in the spleen. By contrast, no direct interaction between NGVEV and goose TLR7 was detected after infecting goose spleen MNCs with NGVEV in vitro. However, triggering of goose TLR7 resulted in the rapid up-regulation of proinflammatory cytokines and anti-viral molecules, suggesting that goose TLR7 plays an important role in anti-viral defense. PMID- 25497241 TI - Anger and mental stress-induced myocardial ischemia: mechanisms and clinical implications. PMID- 25497240 TI - Transition from apixaban to warfarin--addressing excess stroke, systemic embolism, and major bleeding. PMID- 25497242 TI - Comparison of conventional and high-sensitivity troponin in patients with chest pain: a collaborative meta-analysis. AB - BACKGROUND: Multiple studies have evaluated the diagnostic and prognostic performance of conventional troponin (cTn) and high-sensitivity troponin (hs cTn). We performed a collaborative meta-analysis comparing cTn and hs-cTn for diagnosis of acute myocardial infarction (AMI) and assessment of prognosis in patients with chest pain. METHODS: MEDLINE/PubMed, Cochrane CENTRAL, and EMBASE were searched for studies assessing both cTn and hs-cTn in patients with chest pain. Study authors were contacted and many provided previously unpublished data. RESULTS: From 17 included studies, there were 8,644 patients. Compared with baseline cTn, baseline hs-cTn had significantly greater sensitivity (0.884 vs 0.749, P < .001) and negative predictive value (NPV; 0.964 vs 0.935, P < .001), whereas specificity (0.816 vs 0.938, P < .001) and positive predictive value (0.558 vs 0.759, P < .001) were significantly reduced. Based on summary receiver operating characteristic curves, test performance for the diagnosis of AMI was not significantly different between baseline cTn and hs-cTn (0.90 [95% CI 0.85 0.95] vs 0.92 [95% CI 0.90-0.94]). In a subanalysis of 6 studies that alternatively defined AMI based on hs-cTn, cTn had lower sensitivity (0.666, P < .001) and NPV (0.906, P < .001). Elevation of baseline hs-cTn, but negative baseline cTn, was associated with increased risk of death or nonfatal myocardial infarction during follow-up (P < .001) compared with both negative. CONCLUSION: High-sensitivity troponin has significantly greater early sensitivity and NPV for the diagnosis of AMI at the cost of specificity and positive predictive value, which may enable early rule in/out of AMI in patients with chest pain. Baseline hs-cTn elevation in the setting of negative cTn is also associated with increased nonfatal myocardial infarction or death during follow-up. PMID- 25497243 TI - Rationale and design of the Clinical Evaluation of Magnetic Resonance Imaging in Coronary heart disease 2 trial (CE-MARC 2): a prospective, multicenter, randomized trial of diagnostic strategies in suspected coronary heart disease. AB - BACKGROUND: A number of investigative strategies exist for the diagnosis of coronary heart disease (CHD). Despite the widespread availability of noninvasive imaging, invasive angiography is commonly used early in the diagnostic pathway. Consequently, approximately 60% of angiograms reveal no evidence of obstructive coronary disease. Reducing unnecessary angiography has potential financial savings and avoids exposing the patient to unnecessary risk. There are no large scale comparative effectiveness trials of the different diagnostic strategies recommended in international guidelines and none that have evaluated the safety and efficacy of cardiovascular magnetic resonance. TRIAL DESIGN: CE-MARC 2 is a prospective, multicenter, 3-arm parallel group, randomized controlled trial of patients with suspected CHD (pretest likelihood 10%-90%) requiring further investigation. A total of 1,200 patients will be randomized on a 2:2:1 basis to receive 3.0-T cardiovascular magnetic resonance-guided care, single-photon emission computed tomography-guided care (according to American College of Cardiology/American Heart Association appropriate-use criteria), or National Institute for Health and Care Excellence guidelines-based management. The primary (efficacy) end point is the occurrence of unnecessary angiography as defined by a normal (>0.8) invasive fractional flow reserve. Safety of each strategy will be assessed by 3-year major adverse cardiovascular event rates. Cost-effectiveness and health-related quality-of-life measures will be performed. CONCLUSIONS: The CE-MARC 2 trial will provide comparative efficacy and safety evidence for 3 different strategies of investigating patients with suspected CHD, with the intension of reducing unnecessary invasive angiography rates. Evaluation of these management strategies has the potential to improve patient care, health-related quality of life, and the cost-effectiveness of CHD investigation. PMID- 25497244 TI - Clinical events after transitioning from apixaban versus warfarin to warfarin at the end of the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. AB - BACKGROUND: We sought to assess the occurrence of events after blinded study drug discontinuation and transition to open-label vitamin K antagonist (VKA) in ARISTOTLE. METHODS: At the end of ARISTOTLE, blinded study drug was stopped, and open-label VKA was recommended. For patients completing the trial on blinded study drug, a 2-day bridging period with apixaban or apixaban placebo was recommended (while beginning open-label VKA). Outcomes were assessed during the 30 days after stopping blinded study drug. RESULTS: Of the 6,809 patients in the apixaban group and 6,588 in the warfarin group who completed the trial on study drug, there were 21 strokes or systemic emboli (4.02%/year) and 26 major bleeding (4.97%/year) events in the apixaban group (transitioning to VKA) and 5 strokes or systemic emboli (0.99%/year) and 10 major bleeding (1.97%/year) events in the warfarin group (continuing on VKA), with most of the imbalance between groups being after the first week. Similar results were seen in the first 30 days of the trial where warfarin-naive patients starting warfarin had a higher rate of stroke or systemic emboli (5.41%/year) than warfarin-experienced patients (1.42%/year), a pattern not seen when starting apixaban. No similar increase in events with apixaban versus warfarin was seen during temporary or permanent study drug discontinuation during the trial. CONCLUSIONS: The excess in thrombotic and bleeding events in the apixaban group after study drug discontinuation appears to be related to an increased risk associated with the initiation of a VKA rather than a direct effect of apixaban. Whether >=2 days of apixaban bridging improves outcomes during VKA transition is unknown and deserves further evaluation. PMID- 25497245 TI - High-sensitivity cardiac troponin T and the risk of incident atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study. AB - INTRODUCTION: Structural changes in the heart are known risk factors for atrial fibrillation (AF). An association between high-sensitivity cardiac troponin T (hs cTnT), a marker of myocardial cell damage measured with a high-sensitivity assay, and the risk of AF could have implications for AF risk stratification. OBJECTIVE: To estimate the association between hs-cTnT and the risk of incident AF in the ARIC study, a prospective cohort of middle-aged adults from 4 US communities. METHODS: Study included 10,584 participants (mean age 62.7 years) free of AF in 1996 to 1998 and followed through 2008. Atrial fibrillation was defined using International Classification of Diseases codes from hospitalizations and death certificates. Participants with undetectable hs-cTnT levels (58%) were assigned the lower limit of measurement (5 ng/L). Net reclassification improvement was used to examine the discriminative ability of hs-cTnT for 10-year AF risk prediction (categories: <5%, 5%-15%, and >15%). RESULTS: A total of 920 incident AF cases were observed for 109,227 person-years. After adjustment, a 1-SD difference in ln(hs-cTnT) was associated with a hazard ratio of 1.16 (95% CI 1.10 1.23). Compared with those with undetectable levels, participants with hs-cTnT >=14 ng/L had a hazard ratio of 1.78 (95% CI 1.43-2.24). Addition of hs-cTnT to known AF predictors did not increase the c statistic appreciably (0.756 vs 0.758) or improve risk stratification (net reclassification improvement 0.4%, 95% CI 1.4% to 2.3%). CONCLUSIONS: High-sensitivity cTnT level is associated with an increased incidence rate of AF but did not improve risk stratification. PMID- 25497246 TI - Accuracy and validation of an automated electronic algorithm to identify patients with atrial fibrillation at risk for stroke. AB - BACKGROUND: There is no universally accepted algorithm for identifying atrial fibrillation (AF) patients and stroke risk using electronic data for use in performance measures. METHODS: Patients with AF seen in clinic were identified based on International Classification of Diseases, Ninth Revision(ICD-9) codes. CHADS(2) and CHA(2)DS(s)-Vasc scores were derived from a broad, 10-year algorithm using IICD-9 codes dating back 10 years and a restrictive, 1-year algorithm that required a diagnosis within the past year. Accuracy of claims-based AF diagnoses and of each stroke risk classification algorithm were evaluated using chart reviews for 300 patients. These algorithms were applied to assess system-wide anticoagulation rates. RESULTS: Between 6/1/2011, and 5/31/2012, we identified 6,397 patients with AF. Chart reviews confirmed AF or atrial flutter in 95.7%. A 1-year algorithm using CHA(2)DS(2)-Vasc score >=2 to identify patients at risk for stroke maximized positive predictive value (97.5% [negative predictive value 65.1%]). The PPV of the 10-year algorithm using CHADS(2) was 88.0%; 12% those identified as high-risk had CHADS(2) scores <2. Anticoagulation rates were identical using 1-year and 10-year algorithms for patients with CHADS(2) scores >=2 (58.5% on anticoagulation) and CHA(2)DS(2)-Vasc scores >=2 (56.0% on anticoagulation). CONCLUSIONS: Automated methods can be used to identify patients with prevalent AF indicated for anticoagulation but may have misclassification up to 12%, which limits the utility of relying on administrative data alone for quality assessment. Misclassification is minimized by requiring comorbidity diagnoses within the prior year and using a CHA(2)DS(2)-Vasc based algorithm. Despite differences in accuracy between algorithms, system-wide anticoagulation rates assessed were similar regardless of algorithm used. PMID- 25497247 TI - Procedure timing as a predictor of inhospital adverse outcomes from implantable cardioverter-defibrillator implantation: insights from the National Cardiovascular Data Registry. AB - BACKGROUND: Implantable cardioverter-defibrillator (ICD) procedures performed later in the day and on weekends/holidays may be associated with adverse events due to a variety of factors including operator fatigue, handoffs, reduced staffing, and limited resource availability. We sought to determine whether patients implanted with ICDs in the afternoon/evening and on weekends/holidays are at increased risk for adverse events. METHODS: We studied 148,004 first-time ICD recipients in the National Cardiovascular Data Registry-ICD Registry implanted between April 2010 and March 2012. Using hierarchical multivariable logistic regression adjusting for patient, implanting physician, and hospital characteristics, we examined the association between both ICD implant start time and day of week with any complication, a prolonged hospital stay, and mortality. RESULTS: Most ICD implants (52.6%; n = 77,853) were performed in the morning (6 am-12 pm) and during the regular workweek (97.5%; n = 144,266). After multivariable adjustment, ICD recipients implanted in the afternoon (12 pm-5 pm)/evening (5 pm-6 am) compared with the morning experienced a greater odds of any complication (odds ratio [OR] 1.08; 95% CI 1.01-1.15; P = .0168), hospital stay >1 day (OR 1.29; 95% CI 1.25-1.33; P < .0001) but not inhospital death (OR 1.06; 95% CI 0.88-1.27; P = .5322). Implantable cardioverter-defibrillator recipients implanted on weekend/holidays compared with the mid-workweek also experienced a significantly greater odds of hospital stay >1 day (OR 1.40; 95% CI 1.29-1.53; P < .0001), no statistically significant differences in total complications (OR 1.14; 95% CI 0.96-1.36; P = .1371), and a trend toward more inhospital death (OR 1.52; 95% CI 0.98-2.38; P = .0642). CONCLUSIONS: In a large, real-world population, ICD recipients implanted in the afternoon/evening and on weekends/holidays more often experienced adverse events, particularly prolonged hospital stays. PMID- 25497248 TI - P-wave indices and atrial fibrillation: cross-cohort assessments from the Framingham Heart Study (FHS) and Atherosclerosis Risk in Communities (ARIC) study. AB - BACKGROUND: Atrial fibrillation (AF) is associated with increased morbidity. P wave indices (PWIs) measure atrial electrical function and are associated with AF. Study of PWI has been limited to single-cohort investigations, and their contributions to risk enhancement are unknown. METHODS: We examined PWI from the FHS and ARIC study. We calculated 10-year AF risk using adjusted Cox models. We conducted cross-cohort meta-analyses for the PWI estimates and assessed their contributions to risk discrimination (c statistic), net reclassification index, and integrated discrimination improvement. RESULTS: After exclusions, the analysis included 3,110 FHS (62.6 +/- 9.8 years, 56.9% women) and 8,254 ARIC participants (62.3 +/- 5.6 years, 57.3% women, 20.3% black race). Over 10 years, 217 FHS and 458 ARIC participants developed AF. In meta-analysis, P-wave duration >120 milliseconds was significantly associated with AF (hazard ratio 1.55, 95% CI 1.29-1.85) compared with <=120 milliseconds. P-wave area was marginally but not significantly related to AF (hazard ratio 1.31, 95% CI 0.95-1.80). P-wave terminal force was strongly associated with AF in ARIC but not FHS. P-wave indices had a limited contribution toward predictive risk beyond traditional risk factors and markers. CONCLUSIONS: P-wave indices are intermediate phenotypes for AF. They are associated with AF in cross-cohort meta-analyses but contribute minimally toward enhancing risk prediction. PMID- 25497249 TI - Off-hour admission and outcomes for patients with acute myocardial infarction undergoing percutaneous coronary interventions. AB - BACKGROUND: Prior studies have suggested that patients with acute myocardial infarction (AMI) who are admitted during off-hours (weekends, nights and holidays) have higher mortality when compared with patients admitted during regular hours. METHODS: We analyzed consecutive patients with AMI (ST-elevation myocardial infarction [STEMI] and non-STEMI) who were treated with percutaneous coronary interventions from January 1998 to June 2010 at an academic medical center. Multivariable logistic regression models were used to estimate the association between off-hour admission and clinical outcomes adjusted for demographic and clinical variables. RESULTS: There were 3,422 and 2,664 patients with AMI admitted during off-hours and regular hours, respectively. Patients admitted during off-hours were more likely to have STEMI (56% vs 48%, P < .001), have cardiogenic shock at presentation (6% vs 4%, P = .002), and develop shock after presentation (6% vs 5%, P = .004). After multivariable analyses, off-hour admission was not significantly associated with in-hospital mortality (odds ratio [OR] 1.12, 95% CI 0.84-1.49), 30-day mortality (OR 1.12, 0.87-1.45), or 30-day readmissions (OR 1.01, 0.84-1.20) but was significantly associated with composite major complications and any of emergent coronary artery bypass graft surgery, ventricular arrhythmia, stroke/transient ischemic attack, and gastrointestinal/retroperitoneal/intracranial bleeding (OR 1.27, 1.05-1.55, P = .015). There was no significant time trend in the adjusted mortality difference between off-hours and regular hours. The results were not different between STEMI and non-STEMI. CONCLUSIONS: Patients who were admitted during off-hours did not have higher mortality or readmission rates as compared with ones admitted during regular hours at an academic medical center. PMID- 25497250 TI - Three-year clinical outcome of patients with bifurcation treatment with second generation Resolute and Xience V stents in the randomized TWENTE trial. AB - BACKGROUND: Only limited data from large randomized clinical trials have been published on the long-term performance of second-generation drug-eluting stents in bifurcation lesions. METHODS: We investigated in patients in the randomized TWENTE trial the long-term safety and efficacy of treating bifurcation lesions with 2 widely applied second-generation drug-eluting stents, the zotarolimus eluting Resolute stent (Medtronic Inc, Santa Rosa, CA) and the everolimus-eluting Xience V stent (Abbott Vascular, Santa Clara, CA). Three-year follow-up was available in 99.3%. Patients were categorized into treatment for >=1 bifurcation lesion versus treatment for nonbifurcation lesions only. RESULTS: Among the 1,391 patients of the TWENTE trial, 362 (26%) were treated for bifurcation lesions. At 3-year follow-up, target-vessel failure did not differ between patients treated for bifurcation versus nonbifurcation lesions (13.1% vs 12.6%; P = .84), whereas the periprocedural myocardial infarction rate was higher in patients with bifurcation lesions (6.9% vs 3.1%; P < .01). Of the 362 patients with bifurcation lesion treatment, 179 (49.4%) were treated with Resolute and 183 (50.6%) with Xience V. There was no significant difference in target-vessel failure between the Resolute and Xience V groups with bifurcation treatment (13.6% vs 12.6%; P = .78), and their incidence of definite-or-probable stent thrombosis was low and similar (1.1% vs 0.5%, respectively; P = .62). CONCLUSION: Despite a significant difference in periprocedural myocardial infarction, 3-year clinical outcome after implantation of second-generation stents was favorable and similar for patients with and without bifurcation lesions. In addition, we observed no difference in long-term clinical outcome after bifurcation lesion treatment with Resolute and Xience V stents. PMID- 25497251 TI - National trends in stroke after acute myocardial infarction among Medicare patients in the United States: 1999 to 2010. AB - BACKGROUND: Stroke is a common and important adverse event after acute myocardial infarction (AMI) in the elderly. It is unclear whether the risk of stroke after AMI has changed with improvements in treatments and outcomes for AMI in the last decade. METHODS: To assess trends in risk of stroke after AMI, we used a national sample of Medicare data to identify Fee-for-Service patients (n = 2,305,441) aged >=65 years who were discharged alive after hospitalization for AMI from 1999 to 2010. RESULTS: We identified 57,848 subsequent hospitalizations for ischemic stroke and 4,412 hospitalizations for hemorrhagic stroke within 1 year after AMI. The 1-year rate of ischemic stroke decreased from 3.4% (95% CI 3.3%-3.4%) to 2.6% (2.5%-2.7%; P < .001). The risk-adjusted annual decline was 3% (hazard ratio, 0.97; [0.97-0.98]) and was similar across all age and sex-race groups. The rate of hemorrhagic stroke remained stable at 0.2% and did not differ by subgroups. The 30-day mortality for patients admitted with ischemic stroke after AMI decreased from 19.9% (18.8%-20.9%) to 18.3% (17.1%-19.6%) and from 48.3% (43.0% 53.6%) to 45.7% (40.3%-51.2%) for those admitted with hemorrhagic stroke. We observed a decrease in 1-year mortality from 37.8% (36.5%-39.1%) to 35.3% (33.8% 36.8%) for ischemic stroke and from 66.6% (61.4%-71.5%) to 60.6% (55.1%-65.9%) for hemorrhagic stroke. CONCLUSIONS: From 1999 to 2010, the 1-year risk for ischemic stroke after AMI declined, whereas the risk of hemorrhagic stroke remained unchanged. However, 30-day and 1-year mortality continued to be high. PMID- 25497252 TI - Sex, adverse cardiac events, and infarct size in anterior myocardial infarction: an analysis of intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction (INFUSE-AMI). AB - BACKGROUND: Women are more likely than men to experience adverse cardiac events after ST-elevation myocardial (STEMI). Whether differences in infarct size or reperfusion contribute to sex differences in outcomes is unknown. METHODS: We compared baseline and procedural characteristics, angiographic and electrocardiographic indices of reperfusion, microvascular obstruction, infarct size, and clinical outcomes in 118 women and 334 men with anterior STEMI enrolled in the INFUSE-AMI randomized trial of intralesion abciximab and aspiration thrombectomy (NCT00976521). Infarct size was assessed by cardiac magnetic resonance imaging at 30 days, and clinical end points were adjudicated by an independent committee. RESULTS: Women were older, were more commonly affected by hypertension and renal impairment, and had a 50.5-minute longer delay to reperfusion. There were no differences in infarct size, microvascular obstruction, or reperfusion success. At 30 days, major adverse cardiac events (MACE), defined as death, reinfarction, new-onset severe heart failure, or rehospitalization for heart failure, were more common in women (11.1% vs 5.4%, hazard ratio 2.09, 95% CI 1.03-4.27, P = .04). After multivariable adjustment, age, but not sex or time to reperfusion, was an independent predictor of MACE. CONCLUSIONS: In the INFUSE-AMI randomized trial, women with anterior STEMI experienced a higher rate of MACE, attributable to older age. Despite longer delay from symptom onset to reperfusion therapy, there was no difference between women and men in infarct size or reperfusion success. PMID- 25497253 TI - Hemoglobin levels and new-onset heart failure in the community. AB - BACKGROUND: In established cardiovascular disease and heart failure (HF), low hemoglobin levels are associated with unfavorable outcome. Whether hemoglobin levels are associated with the development of new-onset HF in the population is unclear. This study sought to investigate the relationship between hemoglobin levels and development of new-onset HF in the community. METHODS: In 6,744 patients from PREVEND, a prospective, community-based, cohort study, we analyzed the relationship between hemoglobin levels and the risk of new-onset HF. RESULTS: Mean age (+/-SD) was 53 +/- 12 years, 49.8% was male, and mean hemoglobin level was 13.7 +/- 1.2 g/dL. During a median follow-up of 8.3 years (interquartile range 7.8-8.9), 217 subjects (3.2%) were newly diagnosed with HF. The association between hemoglobin levels and the risk for new-onset HF was U shaped (P< .001), remaining significant after full adjustment in a multivariable model with established cardiovascular risk factors (P= .015). Furthermore, a increased annual HF incidence was already observed in subjects with high-normal hemoglobin levels (men >16 g/dL or women >15 g/dL; P= .041), whereas on the other side of the distribution, only severe anemia (men <11 g/dL or women <10 g/dL; P= .018) was associated with a higher annual incidence. CONCLUSIONS: The impact of hemoglobin level on the risk of new-onset HF in the community is best described as U shaped. Interestingly, higher hemoglobin levels, already within the high reference range, are associated with an increased incidence. This in contrast to anemia, where a higher annual HF incidence was only observed for severe anemia. PMID- 25497254 TI - Cardiac rehabilitation in African Americans: evidence for poorer outcomes compared with whites, especially in women and diabetic participants. AB - BACKGROUND: Cardiac rehabilitation (CR) improves coronary artery disease risk factors and mortality. Outcomes after CR in African Americans (AAs) compared with whites have not been studied extensively. METHODS: A total of 1,096 patients (169 AAs, 927 whites) were enrolled in a 36-session CR program for ischemic heart disease or postcardiac surgery. The program consisted of exercise, lifestyle modification, and pharmacotherapy. RESULTS: After CR, quality of life, blood pressure, and low-density lipoprotein cholesterol improved significantly in both AAs and whites, although to a lesser degree in AAs. Whites also had significant improvements in weight and triglyceride concentrations. Overall, mean peak exercise capacity, measured in metabolic equivalents (METs), improved by only 1.6 (95% CI 1.3-1.8) in AAs compared with 2.4 (2.3-2.6) in CCs (P< .001 for AAs vs CCs). African American women had the least improvement in METs, but changes were still significant (1.1 [CI 0.9-1.4]). The subgroup with the least improvement in METs was AA diabetic patients (1.4 (CI 1.1-1.7]). CONCLUSION: African Americans derive a significant benefit from CR, but not to the same degree as whites, based on changes in risk factors and in exercise capacity. Within both ethnic groups, both women and diabetic patients appeared to have markedly less improvement. PMID- 25497255 TI - Cardiovascular prognosis in patients with type 2 diabetes: contribution of heart and kidney subclinical damage. AB - BACKGROUND: Left ventricular hypertrophy (LVH) and kidney damage (abnormal urinary albumin-to-creatinine ratio [uACR] or estimated glomerular filtration rate [eGFR]) are predictive of major cardiovascular events (MACE) in patients with type 2 diabetes (T2D) but are rarely used in cardiovascular score calculators. Our study aimed to assess their respective prognostic values for MACE and the additive information they provide to score calculators. METHODS: A total of 1298 T2D (43% women) aged 65 (SD 11) years were followed up for a median of 65 months, with MACE as a primary composite end point: cardiovascular death, nonfatal myocardial infarction, or stroke. Electrocardiogram (ECG)-derived LVH was defined using Sokolow, Gubner, and Cornell product indexes; uACR was considered as abnormal if >2.5 mg/mmol in men or >3.5 mg/mmol in women and eGFR if <60 mL/min per 1.73 m(2). RESULTS: Urinary albumin-to-creatinine ratio was higher in subjects with electrocardiographic LVH (ECG-LVH) than in subjects without (median [interquartile range] 7.61 [43.48] and 2.56 [10.53], respectively; P < .0001). After adjustment for age, history of myocardial infarction, and peripheral artery disease, ECG-LVH and kidney damage were strong predictors for MACE (adjusted hazard ratio [1.64; 95% CI 1.23-2.20], [1.90; 95% CI 1.43-2.53], and [1.85; 95% CI 1.42-2.41] for ECG-LVH, uACR, and eGFR, respectively). Net reclassification improvement was higher with the model including both ECG-LVH and uACR than models with ECG-LVH alone (P < .0001) or uACR alone (P < .0001). In addition, using cardiovascular risk calculators (Framingham score and others), we observed an additional prognostic value of ECG LVH for each one of them. CONCLUSIONS: Electrocardiographic LVH is complementary to kidney damage for MACE prediction in T2D. PMID- 25497256 TI - Association between anger and mental stress-induced myocardial ischemia. AB - BACKGROUND: Mental stress-induced myocardial ischemia is associated with adverse prognosis in coronary artery disease patients. Anger is thought to be a trigger of acute coronary syndromes and is associated with increased cardiovascular risk; however, little direct evidence exists for a link between anger and myocardial ischemia. METHODS: [(99m)Tc]-sestamibi single-photon emission tomography was performed at rest, after mental stress (a social stressor with a speech task) and after exercise/pharmacologic stress. Summed scores of perfusion abnormalities were obtained by observer-independent software. A summed-difference score, the difference between stress and rest scores, was used to quantify myocardial ischemia under both stress conditions. The Spielberger's State-Trait Anger Expression Inventory was used to assess different anger dimensions. RESULTS: The mean age was 50 years, 50% were female, and 60% were non-white. After adjusting for demographic factors, smoking, coronary artery disease severity, depressive, and anxiety symptoms, each IQR increment in state-anger score was associated with 0.36 U-adjusted increase in ischemia as measured by the summed-difference score (95% CI 0.14-0.59); the corresponding association for trait anger was 0.95 (95% CI 0.21-1.69). Anger expression scales were not associated with ischemia. None of the anger dimensions was related to ischemia during exercise/pharmacologic stress. CONCLUSION: Anger, both as an emotional state and as a personality trait, is significantly associated with propensity to develop myocardial ischemia during mental stress but not during exercise/pharmacologic stress. Patients with this psychologic profile may be at increased risk for silent ischemia induced by emotional stress, and this may translate into worse prognosis. PMID- 25497257 TI - Incorporating patient preferences into clinical trial design: results of the opinions of patients on treatment implications of new studies (OPTIONS) project. AB - BACKGROUND: Traditionally, clinical outcomes comprising composite end points in cardiovascular trials are assigned equal weights in statistical analyses. However, the importance of weighting outcomes according to their relative severity is now recognized. This study aimed to elicit patients' perceptions of the importance of cardiovascular outcomes and treatment complications and compare them with those of clinicians. METHODS AND RESULTS: Interviewer-administered surveys, including rating, ranking, point-allocation and trade-off exercises, were conducted in 52 adults with confirmed coronary disease or previous myocardial infarction. Patients viewed "death" as the most severe cardiovascular outcome, followed by cardiogenic shock, congestive heart failure (CHF), and repeat myocardial infarction (re-MI), the same pattern observed in clinician responses in a previous study. Most patients were willing to accept a 3-fold increase in risk of systemic bleed (SB) or nonfatal intracranial hemorrhage (ICH) for a 20% reduction in risk of cardiogenic shock or 60% reduction in risk of CHF, but only a 2-fold increase in the risk of SB or ICH for a 20% reduction in risk of CHF or 60% reduction in risk of re-MI and no increase in risk of SB or ICH for a 20% reduction in risk of re-MI. Similar patterns were seen in a previous study of trade-offs in clinicians. CONCLUSIONS: Although patients' preferences appear to be comparable with those of clinicians, patients may be less willing than clinicians to tolerate potential treatment complications. The methods used in this study offer a feasible approach to incorporating patient preferences into cardiovascular trials and warrant further investigation in broader patient populations. PMID- 25497258 TI - Targeted versus standard feedback: results from a randomized quality improvement trial. AB - BACKGROUND: Quality improvement is central to improving the care of patients with cardiovascular disease; however, the optimum type of data feedback to support such efforts is unknown. METHODS: Over 26 months, 149 eligible Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines hospitals were randomized to receive either standard (n = 76 control) or targeted (n = 73 intervention) performance feedback reports for acute myocardial infarction patient care. Each report summarized performance on identified metrics (providing hospitals with detailed data on their 3 lowest-performing quality metrics, relative to their peers). Intervention sites received 5 targeted feedback reports. Overall composite performance was compared between cohorts at end of study and as a change from baseline. RESULTS: Intervention (n = 60) and control (n = 64) hospitals that completed the study had similar baseline performance (median score 83.7% vs 84.2%). Over 26 months of follow-up, the change in overall composite score across hospitals was neutral (median 0.1% [interquartile range {IQR} -2.4% to 3.3%]). There was no difference in observed improvement in either the intervention (median -0.2% [IQR-2.6% to 3.3%]) or control (median 0.1% [IQR -2.2% to 3.4%]) hospitals. CONCLUSIONS: We were unable to demonstrate that targeted performance feedback reports lead to more rapid care improvements than standard reports. Future directions should explore the relationship between hospital self-selection of targeted metrics and the identification and promulgation of less common metrics--particularly those that reflect processes of care. PMID- 25497259 TI - Cost of informal caregiving for patients with heart failure. AB - BACKGROUND: Heart failure is a serious health condition that requires a significant amount of informal care. However, informal caregiving costs associated with heart failure are largely unknown. METHODS: We used a study sample of noninstitutionalized US respondents aged >=50 years from the 2010 HRS (n = 19,762). Heart failure cases were defined by using self-reported information. The weekly informal caregiving hours were derived by a sequence of survey questions assessing (1) whether respondents had any difficulties in activities of daily living or instrumental activities of daily living, (2) whether they had caregivers because of reported difficulties, (3) the relationship between the patient and the caregiver, (4) whether caregivers were paid, and (5) how many hours per week each informal caregiver provided help. We used a 2-part econometric model to estimate the informal caregiving hours associated with heart failure. The first part was a logit model to estimate the likelihood of using informal caregiving, and the second was a generalized linear model to estimate the amount of informal caregiving hours used among those who used informal caregiving. Replacement approach was used to estimate informal caregiving cost. RESULTS: The 943 (3.9%) respondents who self-reported as ever being diagnosed with heart failure used about 1.6 more hours of informal caregiving per week than those who did not have heart failure (P < .001). Informal caregiving hours associated with heart failure were higher among non Hispanic blacks (3.9 hours/week) than non-Hispanic whites (1.4 hours/week). The estimated annual informal caregiving cost attributable to heart failure was $3 billion in 2010. CONCLUSION: The cost of informal caregiving was substantial and should be included in estimating the economic burden of heart failure. The results should help public health decision makers in understanding the economic burden of heart failure and in setting public health priorities. PMID- 25497260 TI - Impact of drug-eluting stents on the comparative effectiveness of coronary artery bypass surgery and percutaneous coronary intervention. AB - BACKGROUND: Drug-eluting stents (DES) have largely replaced bare-metal stents (BMS) for percutaneous coronary intervention (PCI). It is uncertain, however, whether introduction of DES had a significant impact on the comparative effectiveness of PCI versus coronary artery bypass graft surgery (CABG) for death and myocardial infarction (MI). METHODS: We identified Medicare beneficiaries aged >=66 years who underwent multivessel CABG or multivessel PCI and matched PCI and CABG patients on propensity score. We defined the BMS era as January 1999 to April 2003 and the DES era as May 2003 to December 2006. We compared 5-year outcomes of CABG and PCI using Cox proportional hazards models, adjusting for baseline characteristics and year of procedure and tested for a statistically significant interaction (P(int)) of DES era with treatment (CABG or PCI). RESULTS: Five-year survival improved from the BMS era to the DES era by 1.2% for PCI and by 1.1% for CABG, and the CABG:PCI hazard ratio was unchanged (0.90 vs 0.90; P(int) = .96). Five-year MI-free survival improved by 1.4% for PCI and 1.1% for CABG, with no change in the CABG:PCI hazard ratio (0.81 vs 0.82; P(int) = .63). By contrast, survival-free of MI or repeat coronary revascularization improved from the BMS era to the DES era by 5.7% for PCI and 0.9% for CABG, and the CABG:PCI hazard ratio changed significantly (0.50 vs 0.57, P(int) <= .0001). CONCLUSIONS: The introduction of DES did not alter the comparative effectiveness of CABG and PCI with respect to hard cardiac outcomes. PMID- 25497261 TI - Left ventricular hypertrophy and cardiovascular disease risk prediction and reclassification in blacks and whites: the Atherosclerosis Risk in Communities Study. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is a major independent predictor of cardiovascular disease (CVD) survival and is more prevalent in blacks than whites. In a large biracial population, we evaluated the ability of electrocardiography (ECG)-determined LVH (ECG-LVH) to reclassify CVD/coronary heart disease (CHD) events beyond traditional risk factors in blacks and whites. METHODS: The analysis included 14,489 participants (mean age 54 +/- 5.7 years; 43.5% men; 26% black) from the ARIC cohort, with baseline (1987-1989) ECG, followed up for 10 years. Predicted risk for incident CVD and CHD were estimated using the 10-year Pooled Cohort and Framingham risk equations (base models 1A/1B), respectively. Models 2A and 2B included respective base model plus LVH by "any" of 10 traditional ECG-LVH criteria. Net reclassification improvement (NRI) was calculated, and the distribution of risk was compared using models 2A and 2B versus models 1A and 1B, respectively. RESULTS: There were 792 (5.5%) 10-year Pooled Cohort CVD events and 690 (4.8%) 10-year Framingham CHD events. Left ventricular hypertrophy defined by any criteria was associated with CVD and CHD events (hazard ratio [95% CI] 1.62 [1.38-1.90] and 1.56 [1.32-1.86], respectively]. Left ventricular hypertrophy did not significantly reclassify or improve C statistic in models 2A/B (C statistics 0.767/0.719; NRI = 0.001 [P = not significant]), compared with the base models 1A/B (C statistics 0.770/0.718), respectively. No racial interactions were observed. CONCLUSIONS: In this large cohort of black and white participants, ECG-LVH was associated with CVD/CHD risk but did not significantly improve CVD and CHD events risk prediction beyond the new Pooled Cohort and most used Framingham risk equations in blacks or whites. PMID- 25497263 TI - Antistreptokinase antibodies and outcome of fibrinolytic therapy with streptokinase for left-sided prosthetic valve thrombosis. AB - BACKGROUND: Left-sided prosthetic valve thrombosis (PVT) is a serious complication of valve replacement. In developing countries, fibrinolysis with streptokinase (SK) is often used as the first line of treatment. Anti streptokinase (anti-SK) antibodies are widely prevalent in the general population, but their effect on the efficacy and outcome of fibrinolysis with SK in patients with PVT is not known. METHODS: Patients with rheumatic heart disease and prosthetic valve replacement presenting with a first episode of left-sided PVT were enrolled. All patients underwent fibrinolysis with SK. An indirect enzyme-linked immunosorbent assay was used to detect anti-SK antibodies before fibrinolysis. Relationship of these antibodies to the outcome of fibrinolysis was evaluated. RESULTS: Forty-four patients treated for left-sided PVT were included. Thrombosis affected 33 mitral and 11 aortic prosthetic valves. On fibrinolysis with SK, 32 (73%) patients achieved complete success, whereas it was unsuccessful in the remaining 12 patients. There were 3 bleeding events, 1 stroke, and 3 deaths. Mean anti-SK antibody levels were not significantly different between patients who had complete success and those who did not (8.81 +/- 2.43 vs 7.67 +/ 1.26 Au/mL; P = .13) and did not correlate with the outcome after adjustment with other variables. Patients in New York Heart Association class III or IV had a greater chance of failed fibrinolytic therapy, even after adjustment for other prognostic variables (odds ratio 9.0; 95% CI 1.29-63.02; P = .027). CONCLUSION: Anti-SK antibody titers are not associated with success of fibrinolytic therapy using SK in patients with left-sided PVT. PMID- 25497262 TI - Effects of egg ingestion on endothelial function in adults with coronary artery disease: a randomized, controlled, crossover trial. AB - BACKGROUND: Prevailing recommendations call for restricting intake of dietary cholesterol and eggs for those at risk of heart disease, despite accumulating evidence challenging this association. Our prior studies showed no short-term adverse effects of daily egg intake on cardiac risk factors in at-risk adults. OBJECTIVE: We conducted this study to determine effects of daily egg consumption in adults with established coronary artery disease (CAD). METHODS: Randomized, controlled, single-blind, crossover trial of 32 adults (mean age, 67 years; 6 women, 26 men) with CAD assigned to 1 of 6 possible sequence permutations of 3 different treatments (breakfast with 2 eggs, breakfast with 1/2 cup Egg Beaters, ConAgra Foods, St. Louis, MO, or a high-carbohydrate breakfast part of an ad libitum diet) for 6 weeks, with 4-week washout periods. The primary outcome measure was endothelial function measured as flow-mediated dilatation. RESULTS: Compared with the control breakfast (ie, high-carbohydrate breakfast), daily consumption of eggs showed no adverse effects on flow-mediated dilatation (7.2% +/- 2.9% vs 7.5% +/- 2.9%, P = .33), lipids (total cholesterol: 158.3 +/- 28.6 mg/dL vs 156.2 +/- 27.4 mg/dL, P = .49), blood pressure (systolic blood pressure: 132.8 +/- 14.1 mm Hg or vs 135.5 +/- 14.9 mm Hg, P = .52; diastolic blood pressure: 77.2 +/- 6.1 mm Hg vs 76.7 +/- 6.9 mm Hg, P = .86), or body weight (90.8 +/- 17.5 kg vs 91.8 +/- 17.1 kg, P = .92). No outcomes differed (P > .05) between eggs and Egg Beaters. CONCLUSIONS: We found no evidence of adverse effects of daily egg ingestion on any cardiac risk factors in adults with CAD over a span of 6 weeks. PMID- 25497264 TI - Long-term clinical and angiographic outcomes in patients with diabetes undergoing coronary artery bypass graft surgery: results from the Project of Ex-vivo Vein Graft Engineering via Transfection IV trial. AB - BACKGROUND: There is limited information about the association between diabetes, its treatment, and long-term angiographic and clinical outcomes in patients undergoing coronary artery bypass graft surgery (CABG). We evaluated the association of diabetes and its treatment with 1-year angiographic graft failure and 5-year clinical outcomes in patients undergoing CABG. METHODS: Using data from 3,014 patients in PREVENT IV, we analyzed angiographic and clinical outcomes in patients with and without diabetes and among those who did and did not receive insulin before CABG. Logistic regression and Cox proportional hazards models were used to adjust for differences in baseline variables. RESULTS: Overall, 1,139 (37.8%) patients had diabetes. Of these, 305 (26.8%) received insulin. One-year rates of vein graft failure were similar in patients with and without diabetes but, among diabetics, tended to be higher in patients who received insulin compared with those who did not. At 5 years, rates of death, myocardial infarction, or revascularization were higher among patients with compared with those without diabetes (adjusted hazard ratio 1.57; 95% CI 1.26-1.96; P < .001) and, among diabetics, higher among those who received insulin (adjusted hazard ratio 1.15; 95% CI 1.02-1.30; P = .02). CONCLUSIONS: Patients with diabetes had similar rates of vein graft failure but worse clinical outcomes than patients without diabetes. Patients who received insulin had significantly worse clinical outcomes than patients who did not receive insulin. Further studies to better understand the mechanism behind these findings and to improve the outcomes of patients with insulin-requiring diabetes undergoing CABG surgery are warranted. PMID- 25497265 TI - Recognition of biomarker identified high-risk patients in the acute medically ill venous thromboembolism prevention with extended duration betrixaban study resulting in a protocol amendment. PMID- 25497266 TI - Estimated prevalence of implanted electrophysiologic devices in patients with heart failure. PMID- 25497267 TI - Ischemic postconditioning for acute myocardial infarction: standardized end points to reduce the potential selection bias. PMID- 25497268 TI - The use of positive expiratory pressure therapy does not appear to be effective in people hospitalised with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). PMID- 25497269 TI - Timed Up and Go test in musculoskeletal conditions. PMID- 25497270 TI - Endothelial progenitor cells from peripheral blood support bone regeneration by provoking an angiogenic response. AB - Neovascularization is crucial for fracture healing and plays an important role in long-time graft survival in tissue engineering applications. Endothelial progenitor cells (EPCs) can be isolated from peripheral blood avoiding donor site morbidity, which makes them attractive for autologous cell-based engineering of neovessels. However, contradictory results are published concerning the vasculogenic potential of this cell type. We could previously show that implanted human endothelial vein cells (HUVECs) gave rise to the formation of a complex functional human neovasculature in a heterotopic (subcutaneous) as well as in an orthotopic (calvarial defect) model of severe combined immunodeficiency (SCID) mice, where vessel formation could even be increased by coimplanting mesenchymal stem cells (MSCs) functioning as perivascular cells. In this study, we investigated whether coimplantation of MSCs which have been predifferentiated in vitro into SMCs (SMC-MSCs) may enable pbEPCs to form blood vessels upon implantation and, if this would be the case, whether the resulting enhanced vascularization may support bone regeneration. For this purpose, pbEPCs and SMC MSCs were mono- or cocultured in collagen matrices and seeded into scaffolds consisting of decalcified processed bovine cancellous bone (PBCB, Tutobone). Neovascularization and osteogenesis were evaluated using a calvarial bone defect model in SCID mice. Our experiments could show that the missing vasculogenic potential of pbEPCs is not rescued by coimplantation of SMCs derived from MSCs predifferentiated along the vascular smooth muscle lineage. However, implantation of both cell types alone, or in combination induced an angiogenic response, which correlated in a positive manner with bone formation within the implants. PMID- 25497271 TI - The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity. AB - Under pathological conditions, microglia, the resident CNS immune cells, become reactive and release pro-inflammatory cytokines and neurotoxic factors. We investigated whether this phenotypic switch includes changes in the expression of the L-type voltage-gated calcium channel (VGCC) in a rat model of N-methyl-D aspartate-induced hippocampal neurodegeneration. Double immunohistochemistry and confocal microscopy evidenced that activated microglia express the L-type VGCC. We then analyzed whether BV2 microglia express functional L-type VGCC, and investigated the latter's role in microglial cytokine release and phagocytic capacity. Activated BV2 microglia express the CaV1.2 and CaV1.3 subunits of the L type VGCC determined by reverse transcription-polymerase chain reaction, Western blot and immunocytochemistry. Depolarization with KCl induced a Ca2+ entry facilitated by Bay k8644 and partially blocked with nifedipine, which also reduced TNF-alpha and NO release by 40%. However, no nifedipine effect on BV2 microglia viability or phagocytic capacity was observed. Our results suggest that in CNS inflammatory processes, the L-type VGCC plays a specific role in the control of microglial secretory activity. PMID- 25497272 TI - Chronic lymphocytic leukemia of the genital tract. PMID- 25497274 TI - Successful eltrombopag treatment of refractory idiopathic thrombocytopenic purpura associated with Crohn disease. PMID- 25497273 TI - Interleukin-23 receptor genetic polymorphisms and ulcerative colitis susceptibility: A meta-analysis. AB - OBJECTIVE: The interleukin-23 receptor (IL-23R) polymorphism has been implicated in susceptibility to ulcerative colitis (UC), but the results remain inconclusive. This study was designed to evaluate whether IL-23R polymorphisms were associated with UC susceptibility. METHODS: CNKI, WanFang Data, PubMed, MEDLINE, Web of Science, Google Scholar, EBSCO, CBM database and EMBASE were searched until 31 June 2014 for eligible studies on eight IL-23R polymorphisms: rs11209026, rs7517847, rs1209032, rs2201841, rs1343151, rs1088967, rs1495965 and rs1004819. Meta-analysis from all eligible case-control studies was performed to assess the purported associations. Meta-analysis was performed by using the RevMan 5.2 software and STATA package version 12.0. RESULTS: Sixteen studies with 5438 cases and 7380 controls were included. Overall, our analysis found that variant minor alleles for single nucleotide polymorphisms (SNPs) rs11209026 (Arg381Gln) (dominant model: GG+TG vs. TT, P=0.02, OR=0.71, 95%CI: 0.53-0.94); rs7517847 (recessive model: GG vs. TT, P=0.04, OR=0.80, 95%CI: 0.65-0.99) and rs11209032 [dominant model: GA+AA vs. GG (P=0.04, OR=1.31, 95% CI: 1.01-1.26); AA vs. GG: (P=0.04, OR=1.21, 95% CI: 1.01-1.45)] of IL-23R were associated with UC risk. In stratification analysis by ethnicity, we observed that the rs11209026 and rs7517847 polymorphism of IL-23R could protect against development of UC among Caucasian populations [rs11209026: dominant model (P=0.01, OR=0.69, 95%CI: 0.52-0.92); rs7517847: GG vs. TT (P=0.002, OR=0.69, 95%CI: 0.54-0.87); recessive model (P=0.004, OR=0.73, 95% CI: 0.59-0.90)]; the rs11209032 were associated with a greater risk for UC in Caucasian populations [dominant model (P=0.04, OR=1.13, 95%CI: 1.00-1.26)]; the rs1088967 were associated with a lower risk for UC among Asian populations [dominant model (P=0.04, OR=0.73, 95%CI: 0.54-0.99)]. Moreover, meta-analysis revealed no association between the four alleles of the rs2201841, rs1004819, rs1495965 and rs1343151 polymorphisms and the risk of developing UC in Caucasian and Asian populations. CONCLUSION: Our meta-analysis supports that two polymorphisms (rs11209026 and rs7517847) in the IL-23 gene may be considered to be protective factors against developing UC among Caucasian populations; while the rs11209032 polymorphisms may increase the risk of UC among Caucasian populations; furthermore, the rs1088967 polymorphisms in the IL-23 gene may be considered to be protective factors against developing UC among Asian populations. Further large case-control studies especially concerning ethnicity differences and genotype-phenotype interaction should be performed to clarify possible roles of IL-23R in UC. PMID- 25497275 TI - WITHDRAWN: Association of TNF-alpha-308G>A polymorphisms with hepatocellular carcinoma in Han Chinese population: A systematic review and meta-analysis. AB - The Editor and Publisher of "Clinics and Research in Hepatology and Gastroenterology" have decided to withdraw this article because they consider that it has been accepted based upon the positive advice of at least one faked reviewer report. This manipulation of the peer-review process represents a clear violation of the fundamentals of peer review, our publishing policies, and publishing ethics standards. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. The Publisher apologizes for any inconvenience this may cause. PMID- 25497277 TI - Guidelines and guidance in lipid modification. PMID- 25497276 TI - Effects of dietary salt levels on monocytic cells and immune responses in healthy human subjects: a longitudinal study. AB - Increasing evidence indicated that excess salt consumption can impose risks on human health and a reduction in daily salt intake from the current average of approximately 12 g/d to 5-6 g/d was suggested by public health authorities. The studies on mice have revealed that sodium chloride plays a role in the modulation of the immune system and a high-salt diet can promote tissue inflammation and autoimmune disease. However, translational evidence of dietary salt on human immunity is scarce. We used an experimental approach of fixing salt intake of healthy human subjects at 12, 9, and 6 g/d for months and examined the relationship between salt-intake levels and changes in the immune system. Blood samples were taken from the end point of each salt intake period. Immune phenotype changes were monitored through peripheral leukocyte phenotype analysis. We assessed immune function changes through the characterization of cytokine profiles in response to mitogen stimulation. The results showed that subjects on the high-salt diet of 12 g/d displayed a significantly higher number of immune cell monocytes compared with the same subjects on a lower-salt diet, and correlation test revealed a strong positive association between salt-intake levels and monocyte numbers. The decrease in salt intake was accompanied by reduced production of proinflammatory cytokines interleukin (IL)-6 and IL-23, along with enhanced producing ability of anti-inflammatory cytokine IL-10. These results suggest that in healthy humans high-salt diet has a potential to bring about excessive immune response, which can be damaging to immune homeostasis, and a reduction in habitual dietary salt intake may induce potentially beneficial immune alterations. PMID- 25497278 TI - Guideline-adherence and perspectives in the acute management of unstable angina - Initial results from the German chest pain unit registry. AB - BACKGROUND: We investigated the current management of unstable angina pectoris (UAP) in certified chest pain units (CPUs) in Germany and focused on the European Society of Cardiology (ESC) guideline-adherence in the timing of invasive strategies or choice of conservative treatment options. More specifically, we analyzed differences in clinical outcome with respect to guideline-adherence. METHOD: Prospective data from 1400 UAP patients were collected. Analyses of high risk criteria with indication for invasive management and 3-month clinical outcome data were performed. Guideline-adherence was tested for a primarily conservative strategy as well as for percutaneous coronary intervention (PCI) within <24 and <72h after admission. RESULTS: Overall guideline-conforming management was performed in 38.2%. In UAP patients at risk, undertreatment caused by an insufficient consideration of risk criteria was obvious in 78%. Reciprocally, overtreatment in the absence of adequate risk markers was performed in 27%, whereas a guideline-conforming primarily conservative strategy was chosen in 73% of the low-risk patients. Together, the 3-month major adverse coronary and cerebrovascular events (MACCE) were low (3.6%). Nonetheless, guideline-conforming treatment was even associated with significantly lower MACCE rates (1.6% vs. 4.0%, p<0.05). CONCLUSION: The data suggest an inadequate adherence to ESC guidelines in nearly two thirds of the patients, particularly in those patients at high to intermediate risk with secondary risk factors, emphasizing the need for further attention to consistent risk profiling in the CPU and its certification process. PMID- 25497279 TI - MiR-score: a novel 6-microRNA signature that predicts survival outcomes in patients with malignant pleural mesothelioma. AB - BACKGROUND: Prognosis of malignant pleural mesothelioma (MPM) is poor, and predicting the outcomes of treatment is difficult. Here we investigate the potential of microRNA expression to estimate prognosis of MPM patients. METHODS: Candidate microRNAs from microarray profiling of tumor samples from 8 long (median: 53.7 months) and 8 short (median: 6.4 months) survivors following extrapleural pneumonectomy (EPP) were validated by RT-qPCR in 48 additional EPP samples. Kaplan-Meier log ranking was used to further explore the association between microRNA expression and overall survival (OS). Binary logistic regression was used to construct a microRNA signature (miR-Score) that was able to predict an OS of >=20 months. Performance of the miR-Score was evaluated by receiver operating characteristic (ROC) curve analysis and validated in a series of 43 tumor samples from patients who underwent palliative surgery [pleurectomy/decortication (P/D)]. RESULTS: The miR-Score, using expression data of six microRNAs (miR-21-5p, -23a-3p, -30e-5p, -221-3p, -222-3p, and -31-5p), enabled prediction of long survival with an accuracy of 92.3% for EPP and 71.9% for palliative P/D. Hazard ratios for score-negative patients were 4.12 (95% CI: 2.03-8.37) for EPP and 1.93 (95% CI: 1.01-3.69) for P/D. Importantly, adding the miR-Score to a set of clinical selection criteria (histology, age, gender) increased predictive accuracy in the independent validation set from 76.3% for clinical factors only to 87.3%. CONCLUSIONS: This study has identified a novel 6 microRNA signature (miR-Score) that can accurately predict prognosis of MPM patients. PMID- 25497281 TI - First-line crizotinib shows promise in patients with NSCLC. PMID- 25497282 TI - NICE guidelines to family doctors on diagnosis of pneumonia. PMID- 25497283 TI - Mexico's complex respiratory public health picture. PMID- 25497280 TI - The histone chaperone HJURP is a new independent prognostic marker for luminal A breast carcinoma. AB - BACKGROUND: Breast cancer is a heterogeneous disease with different molecular subtypes that have varying responses to therapy. An ongoing challenge in breast cancer research is to distinguish high-risk patients from good prognosis patients. This is particularly difficult in the low-grade, ER-positive luminal A tumors, where robust diagnostic tools to aid clinical treatment decisions are lacking. Recent data implicating chromatin regulators in cancer initiation and progression offers a promising avenue to develop new tools to help guide clinical decisions. METHODS: Here we exploit a published transcriptome dataset and an independent validation cohort to correlate the mRNA expression of selected chromatin regulators with respect to the four intrinsic breast cancer molecular subtypes. We then perform univariate and multivariate analyses to compare the prognostic value of a panel of chromatin regulators to Ki67, a currently utilized proliferation marker. RESULTS: Unsupervised hierarchical clustering revealed a gene cluster containing several histone chaperones and histone variants highly expressed in the proliferative subtypes (basal-like, HER2-positive, luminal B) but not in the luminal A subtype. Several chromatin regulators, including the histone chaperones CAF-1 (subunits p150 and p60), ASF1b, and HJURP, and the centromeric histone variant CENP-A, associated with local and metastatic relapse and poor patient outcome. Importantly, we find that HJURP can discriminate favorable and unfavorable outcome within the luminal A subtype, outperforming the currently utilized proliferation marker Ki67, as an independent prognostic marker for luminal A patients. CONCLUSIONS: The integration of chromatin regulators as clinical biomarkers, in particular the histone chaperone HJURP, will help guide patient substratification and treatment options for low-risk luminal A breast carcinoma patients. PMID- 25497284 TI - Patients with lung disease at risk of bowel disease. PMID- 25497285 TI - Arcobacter ebronensis sp. nov. and Arcobacter aquimarinus sp. nov., two new species isolated from marine environment. AB - Two strains recovered from mussels (F128-2(T)) and sea water (W63(T)) were characterized as Arcobacter sp., but they could not be assigned to any known species using the molecular identification methods specific for this genus (16S rDNA-RFLP and m-PCR) and rpoB gene analysis. The 16S rRNA gene sequence similarity to the type strains of all Arcobacter species ranged from 92.2% to 96.7% with strain F128-2(T), and from 94.1% to 99.4% with strain W63(T), the most similar being A. bivalviorum (CECT 7835(T)) and A. defluvii (CECT 7697(T)), respectively. The phylogenetic analyses of 16S rRNA, and the concatenated sequences of gyrB, gyrA, rpoB, atpA and hsp60 genes confirmed that strains F128 2(T) and W63(T) belonged to two new lineages within the genus Arcobacter. Moreover, both strains showed differential phenotypic characteristics and MALDI TOF mass spectra from all other Arcobacter species. Therefore, it has been demonstrated the existence of two new Arcobacter species and the proposed names are Arcobacter ebronensis (type strain F128-2(T)=CECT 8441(T)=LMG 27922(T)), and Arcobacter aquimarinus (type strain W63(T)=CECT 8442(T)=LMG 27923(T)). PMID- 25497286 TI - Assessment of serum biomarkers in rats after exposure to pesticides of different chemical classes. AB - There is increasing emphasis on the use of biomarkers of adverse outcomes in safety assessment and translational research. We evaluated serum biomarkers and targeted metabolite profiles after exposure to pesticides (permethrin, deltamethrin, imidacloprid, carbaryl, triadimefon, fipronil) with different neurotoxic actions. Adult male Long-Evans rats were evaluated after single exposure to vehicle or one of two doses of each pesticide at the time of peak effect. The doses were selected to produce similar magnitude of behavioral effects across chemicals. Serum or plasma was analyzed using commercial cytokine/protein panels and targeted metabolomics. Additional studies of fipronil used lower doses (lacking behavioral effects), singly or for 14 days, and included additional markers of exposure and biological activity. Biomarker profiles varied in the number of altered analytes and patterns of change across pesticide classes, and discriminant analysis could separate treatment groups from control. Low doses of fipronil produced greater effects when given for 14 days compared to a single dose. Changes in thyroid hormones and relative amounts of fipronil and its sulfone metabolite also differed between the dosing regimens. Most cytokine changes reflected alterations in inflammatory responses, hormone levels, and products of phospholipid, fatty acid, and amino acid metabolism. These findings demonstrate distinct blood-based analyte profiles across pesticide classes, dose levels, and exposure duration. These results show promise for detailed analyses of these biomarkers and their linkages to biological pathways. PMID- 25497288 TI - Novel curcumin analogue 14p protects against myocardial ischemia reperfusion injury through Nrf2-activating anti-oxidative activity. AB - BACKGROUND: Alleviating the oxidant stress associated with myocardial ischemia reperfusion has been demonstrated as a potential therapeutic approach to limit ischemia reperfusion (I/R)-induced cardiac damage. Curcumin, a natural compound with anti-oxidative activity, exerts beneficial effect against cardiac I/R injury, but poor chemical and metabolic stability. Previously, we have designed and synthesized a series of mono-carbonyl analogues of curcumin (MACs) with high stability. This study aims to find new anti-oxidant MACs and to demonstrate their effects and mechanisms against I/R-induced heart injury. METHODS: H9c2 cells challenged with H2O2 or TBHP were used for in vitro bio-screening and mechanistic studies. The MDA, H2O2 and SOD levels in H9C2 cells were determined, and the cell viability was assessed by MTT assay. Myocardial I/R mouse models administrated with or without the compound were used for in vivo studies. RESULTS: The in vitro cell-based screening showed that curcumin analogues 8d and 14p exhibited strong anti-oxidative effects. Pre-treatment of H9c2 cells with 14p activated Nrf2 signaling pathway, attenuated H2O2-increased MDA and SOD level, followed by the inhibition of TBHP-induced cell death and Bax/Bcl-2-caspase-3 pathway activation. Silencing Nrf2 significantly reversed the protective effects of 14p. In in vivo animal model of myocardial I/R, administration of low dose 14p (10mg/kg) reduced infarct size and myocardial apoptosis to the same extent as the high dose curcumin (100mg/kg). CONCLUSION: These data support the novel curcumin analogue 14p as a promising antioxidant to decrease oxidative stress and limit myocardial ischemia reperfusion injury via activating Nrf2. PMID- 25497287 TI - Phosphoramide mustard exposure induces DNA adduct formation and the DNA damage repair response in rat ovarian granulosa cells. AB - Phosphoramide mustard (PM), the ovotoxic metabolite of the anti-cancer agent cyclophosphamide (CPA), destroys rapidly dividing cells by forming NOR-G-OH, NOR G and G-NOR-G adducts with DNA, potentially leading to DNA damage. A previous study demonstrated that PM induces ovarian DNA damage in rat ovaries. To investigate whether PM induces DNA adduct formation, DNA damage and induction of the DNA repair response, rat spontaneously immortalized granulosa cells (SIGCs) were treated with vehicle control (1% DMSO) or PM (3 or 6MUM) for 24 or 48h. Cell viability was reduced (P<0.05) after 48h of exposure to 3 or 6MUM PM. The NOR-G OH DNA adduct was detected after 24h of 6MUM PM exposure, while the more cytotoxic G-NOR-G DNA adduct was formed after 48h by exposure to both PM concentrations. Phosphorylated H2AX (gammaH2AX), a marker of DNA double stranded break occurrence, was also increased by PM exposure, coincident with DNA adduct formation. Additionally, induction of genes (Atm, Parp1, Prkdc, Xrcc6, and Brca1) and proteins (ATM, gammaH2AX, PARP-1, PRKDC, XRCC6, and BRCA1) involved in DNA repair were observed in both a time- and dose-dependent manner. These data support that PM induces DNA adduct formation in ovarian granulosa cells, induces DNA damage and elicits the ovarian DNA repair response. PMID- 25497289 TI - [Epidural extraskeletal Ewing sarcoma. Case report and literature review]. AB - Ewing sarcoma is a malignant tumour of the bone that sometimes presents extraskeletal involvement, with the epidural location being rare. We report the case of a 45-year-old woman with paresthesia, paresis and urinary retention. Magnetic resonance imaging showed an epidural mass from C6 to D3. Laminectomy from C7 to D2 and partial resection of the lesion was performed. Pathological analysis was consistent with Ewing sarcoma. The patient received chemotherapy and radiotherapy, without evidence of disease at 8 months follow-up. A review of the literature on all published cases of extraskeletal Ewing sarcoma with epidural involvement is presented. PMID- 25497290 TI - Cranioplasty after decompressive craniectomy. A prospective series analyzing complications and clinical improvement. AB - BACKGROUND: Cranioplasty is carried out for cosmetic reasons and for protection, but it may also lead to some neurological improvement after the bone flap placement. Complications of cranioplasty are more frequent than expected for a scheduled neurosurgical procedure. We tried to identify factors associated with both complications and improvement after cranioplasty. METHODS: We prospectively studied the cranioplasties performed in our hospital from November 2009 to November 2013. Patients whose initial reason for bone removal was tumor infiltration were excluded. Demographic, clinical and radiological data were collected. The NIH Stroke Scale and Barthel Self-Care Index scores were obtained both before and within 72 h after cranioplasty. The outcome measures were the occurrences of complications and clinical improvement. RESULTS: Fifty-five cranioplasties were performed. The material used for the cranioplasty was autologous bone in 42 cases, polyetheretherketone (PEEK) in 7 and methacrylate in 6. The average size of the bone defect was 69.5 (19.5-149.5) cm2. The time elapsed between decompressive craniectomy and cranioplasty was 309 (25-1217) days. There were 10 complications (7 severe and 3 mild), an 18.2% complication rate. Statistically significant risk factors of complications were identified as a Barthel<=70 (Odds ratio [OR] 22; 2.5-192; P=0.005), age over 45 years (OR 13.5; 1.5-115; P=0.01) and early surgery (<=85 days; OR 8; 1.69-37.03, P=0.004). After multivariate analysis, Barthel<=70 and age over 45 years remained independent predictors of complications. Twenty-two (40%) of the 55 patients showed objective improvement. Early surgery (<85 days) increased the likelihood of improvement (OR 4.67; 1.05-20.83; P=0.035). Larger bone defects seemed to be related with improvement, but differences in defect size were not statistically significant (75.3 vs 65.6 cm2; P=0.1). CONCLUSIONS: The complication rate of cranioplasty is higher than for other elective neurosurgical procedures. Older age, poorer functional situation (worse Barthel index score) and early surgery (<=85 days) are independent risk factors for complications. However, cranioplasty produces clinical benefits beyond protection and esthetic improvement. Earlier surgery and larger bone defects seem to increase the likelihood of clinical improvement. PMID- 25497291 TI - Eco-friendly aqueous core surface-modified nanocapsules. AB - In this work, positively charged nanocapsules have been developed for potential ocular delivery exploiting the deposition of PLA onto the droplet surface of a W/O nanoemulsion prepared by the reversed procedure of the PIT method. PLA in combination with different amounts of various oils and surfactants have been studied in order to select the best formulation for polymeric nanocapsule preparation. The traditional visual observation together with the Turbiscan((r)) technology were exploited in order to identify the best combination of polymer/oil for nanocapsule preparation. Two different primary surfactants (Span((r)) 60 and Span((r)) 80) have been tested to select their influence on the field of existence of the nanoemulsion by the construction of the pseudoternary phase diagrams. Cationic hybrid NC have been prepared by the addition of a coating layer of DDAB. The physico-chemical and morphological properties of all the prepared nanocapsules have been evaluated and compared by PCS, DSC and AFM. Therefore, positively charged nanocapsules can be easily prepared by a simple eco friendly technique that exploits biocompatible materials avoiding a large input of mechanical energy as a potential ocular delivery systems for hydrophilic compounds or gene materials. PMID- 25497292 TI - A novel folic acid-conjugated TiO2-SiO2 photosensitizer for cancer targeting in photodynamic therapy. AB - In this paper, a novel folic acid-conjugated silica-coated titanium dioxide (TiO2 SiO2) photosensitizer was synthesized and characterized using various analytical instruments. The photosensitizer was further assessed with regards to its photoreactivity, cellular and hemocompatibility, cell internalization, and phototoxicity. Conjugating folic acid with TiO2-SiO2 has shown a significantly improved compatibility of the nanoparticles with the mouse fibroblast cells (L929) at 24 h. An improved compatibility with the human nasopharyngeal epidermoid cancer (KB) cells was also demonstrated, but to a slightly reduced degree. Enhanced cell internalization was well demonstrated in the TiO2-SiO2 folate nanoparticles. Upon exposure to UV light, TiO2-SiO2 folate nanoparticles maintained a high level photodynamic reactivity and yielded a 38-43% photo killing of KB cells. The photo-killing effect increased with increasing dosage in the investigated concentration range of 50-100 MUg ml(-1). PMID- 25497293 TI - CDC proposes stronger endorsement of male circumcision. PMID- 25497294 TI - High quality resuscitation bundles include real-time audiovisual CPR feedback. PMID- 25497295 TI - Prediction of hospitalization due to heart diseases by supervised learning methods. AB - BACKGROUND: In 2008, the United States spent $2.2 trillion for healthcare, which was 15.5% of its GDP. 31% of this expenditure is attributed to hospital care. Evidently, even modest reductions in hospital care costs matter. A 2009 study showed that nearly $30.8 billion in hospital care cost during 2006 was potentially preventable, with heart diseases being responsible for about 31% of that amount. METHODS: Our goal is to accurately and efficiently predict heart related hospitalizations based on the available patient-specific medical history. To the best of our knowledge, the approaches we introduce are novel for this problem. The prediction of hospitalization is formulated as a supervised classification problem. We use de-identified Electronic Health Record (EHR) data from a large urban hospital in Boston to identify patients with heart diseases. Patients are labeled and randomly partitioned into a training and a test set. We apply five machine learning algorithms, namely Support Vector Machines (SVM), AdaBoost using trees as the weak learner, logistic regression, a naive Bayes event classifier, and a variation of a Likelihood Ratio Test adapted to the specific problem. Each model is trained on the training set and then tested on the test set. RESULTS: All five models show consistent results, which could, to some extent, indicate the limit of the achievable prediction accuracy. Our results show that with under 30% false alarm rate, the detection rate could be as high as 82%. These accuracy rates translate to a considerable amount of potential savings, if used in practice. PMID- 25497296 TI - Brain functional changes across the different phases of bipolar disorder. AB - BACKGROUND: Little is known about how functional imaging changes in bipolar disorder relate to different phases of the illness. AIMS: To compare cognitive task activation in participants with bipolar disorder examined in different phases of illness. METHOD: Participants with bipolar disorder in mania (n = 38), depression (n = 38) and euthymia (n = 38), as well as healthy controls (n = 38), underwent functional magnetic resonance imaging during performance of the n-back working memory task. Activations and de-activations were compared between the bipolar subgroups and the controls, and among the bipolar subgroups. All participants were also entered into a linear mixed-effects model. RESULTS: Compared with the controls, the mania and depression subgroups, but not the euthymia subgroup, showed reduced activation in the dorsolateral prefrontal cortex, the parietal cortex and other areas. Compared with the euthymia subgroup, the mania and depression subgroups showed hypoactivation in the parietal cortex. All three bipolar subgroups showed failure of de-activation in the ventromedial frontal cortex. Linear mixed-effects modelling revealed a further cluster of reduced activation in the left dorsolateral prefrontal cortex in the patients; this was significantly more marked in the mania than in the euthymia subgroup. CONCLUSIONS: Bipolar disorder is characterised by mood state-dependent hypoactivation in the parietal cortex. Reduced dorsolateral prefrontal activation is a further feature of mania and depression, which may improve partially in euthymia. Failure of de-activation in the medial frontal cortex shows trait-like characteristics. PMID- 25497297 TI - Monoamine oxidase A gene promoter methylation and transcriptional downregulation in an offender population with antisocial personality disorder. AB - BACKGROUND: Antisocial personality disorder (ASPD) is characterised by elevated impulsive aggression and increased risk for criminal behaviour and incarceration. Deficient activity of the monoamine oxidase A (MAOA) gene is suggested to contribute to serotonergic system dysregulation strongly associated with impulsive aggression and antisocial criminality. AIMS: To elucidate the role of epigenetic processes in altered MAOA expression and serotonin regulation in a population of incarcerated offenders with ASPD compared with a healthy non incarcerated control population. METHOD: Participants were 86 incarcerated participants with ASPD and 73 healthy controls. MAOA promoter methylation was compared between case and control groups. We explored the functional impact of MAOA promoter methylation on gene expression in vitro and blood 5-HT levels in a subset of the case group. RESULTS: Results suggest that MAOA promoter hypermethylation is associated with ASPD and may contribute to downregulation of MAOA gene expression, as indicated by functional assays in vitro, and regression analysis with whole-blood serotonin levels in offenders with ASPD. CONCLUSIONS: These results are consistent with prior literature suggesting MAOA and serotonergic dysregulation in antisocial populations. Our results offer the first evidence suggesting epigenetic mechanisms may contribute to MAOA dysregulation in antisocial offenders. PMID- 25497298 TI - Frequency of delusional infestation by proxy and double delusional infestation in veterinary practice: observational study. AB - BACKGROUND: Nothing is known about the prevalence of delusional infestation in veterinary practice and the consequences for psychiatrists. AIMS: We attempted to examine the frequency of delusional infestation among pet owners presenting their animals to veterinary clinics. METHOD: We conducted a survey among 32 663 veterinary clinicians who were members of the Veterinary Information Network. RESULTS: The respondents had seen 724 suspected cases of delusional infestation by proxy in a pet. The clients were mainly White, female and 30-60 years old. They presented mainly dogs and cats, and the alleged infestation was mainly with arthropods or worms. Also, 252 clients claimed to be affected themselves; we termed this 'double delusional infestation'. CONCLUSIONS: Delusional infestation is seen frequently in veterinary practice. Psychiatrists need to be aware that patients may have pets they believe are infested. PMID- 25497299 TI - Youth mental health after civil war: the importance of daily stressors. AB - BACKGROUND: Recent evidence suggests that post-conflict stressors in addition to war trauma play an important role in the development of psychopathology. AIMS: To investigate whether daily stressors mediate the association between war exposure and symptoms of post-traumatic stress and depression among war-affected youth. METHOD: Standardised assessments were conducted with 363 Sierra Leonean youth (26.7% female, mean age 20.9, s.d. = 3.38) 6 years post-war. RESULTS: The extent of war exposures was significantly associated with post-traumatic stress symptoms (P<0.05) and a significant proportion was explained by indirect pathways through daily stressors (0.089, 95% CI 0.04-0.138, P<0.001). In contrast, there was little evidence for an association from war exposure to depression scores (P = 0.127); rather any association was explained via indirect pathways through daily stressors (0.103, 95% CI 0.048-0.158, P<0.001). CONCLUSIONS: Among war-affected youth, the association between war exposure and psychological distress was largely mediated by daily stressors, which have potential for modification with evidence-based intervention. PMID- 25497300 TI - Right superior temporal gyrus volume in adolescents with a history of suicide attempt. AB - The extent to which observed differences in emotion processing and regulation neural circuitry in adolescents with a history of suicide attempt are paralleled by structural differences is unknown. We measured brain cortical thickness and grey- and white-matter volumes in 100 adolescents: 28 with a history of suicide attempt and major depressive disorder (MDD); 31 with a history of MDD but no suicide attempt; and a healthy control group (n = 41). The first group compared with controls showed reduction in grey-matter volume in the right superior temporal gyrus (BA38), a region important for social emotion processing. PMID- 25497301 TI - Lifetime hypertension as a predictor of brain structure in older adults: cohort study with a 28-year follow-up. AB - BACKGROUND: Hypertension is associated with an increased risk of dementia and depression with uncertain longitudinal associations with brain structure. AIMS: To examine lifetime blood pressure as a predictor of brain structure in old age. METHOD: A total of 190 participants (mean age 69.3 years) from the Whitehall II study were screened for hypertension six times (1985-2013). In 2012-2013, participants had a 3T-magnetic resonance imaging (MRI) brain scan. Data from the MRI were analysed using automated and visual measures of global atrophy, hippocampal atrophy and white matter hyperintensities. RESULTS: Longitudinally, higher mean arterial pressure predicted increased automated white matter hyperintensities (P<0.002). Cross-sectionally, hypertensive participants had increased automated white matter hyperintensities and visually rated deep white matter hyperintensities. There was no significant association with global or hippocampal atrophy. CONCLUSIONS: Long-term exposure to high blood pressure predicts hyperintensities, particularly in deep white matter. The greatest changes are seen in those with severe forms of hypertension, suggesting a dose response pattern. PMID- 25497304 TI - A district general hospital experience of palliative biliary stenting. AB - BACKGROUND: Palliative management of malignant pancreaticobiliary (PB) disease typically takes the form of endoscopic biliary stenting with a covered metal stent. We set out to assess outcomes from endoscopic biliary stenting (endoscopic retrograde cholangiopancreatography, ERCP) for malignant disease in our district general hospital (DGH). METHODS: We identified patients with malignant PB disease who underwent primary ERCP between 2011 and 2012. Case notes were reviewed for clinical outcomes and involvement of palliative care. RESULTS: 38 patients underwent biliary stenting in this period. Median age was 75.6 years (53.6-99.8 years). 35 stents were placed for primary PB malignancy. 31 of these stents were covered metal stents and 6 were uncovered. Bilirubin decreased from a median of 218 to 112 umol/L (median decrease 55 umol/L). Complications occurred in the following 13 cases: 7 blocked stents (18.9%), 2 of which were associated with sepsis; 2 cases of stent migration (8.1%); 3 cases of biliary sepsis (8.1%) and 1 episode of pancreatitis (2.7%). Subsequently, 12 patients underwent a single repeat ERCP and 1 patient underwent 3 further ERCPs. Median survival following ERCP and stent was 78 days (10-806). 28 patients (76%) were known to the hospital palliative care team. CONCLUSIONS: Our DGH provides local service with complication rates comparable to those described in the literature. This allows care of patients with limited prognosis to be treated close to home. The majority of stent complications and mortality occur within 3 months. Input from the palliative care team is useful when considering whether a patient has a prognosis long enough to benefit from the procedure. PMID- 25497302 TI - Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload. AB - BACKGROUND: Obesity leads to metabolic heart disease (MHD) that is associated with a pathologic increase in myocardial fatty acid (FA) uptake and impairment of mitochondrial function. The mechanism of mitochondrial dysfunction in MHD, which results in oxidant production and decreased energetics, is poorly understood but may be related to excess FAs. Determining the effects of cardiac FA excess on mitochondria can be hindered by the systemic sequelae of obesity. Mice with cardiomyocyte-specific overexpression of the fatty acid transport protein FATP1 have increased cardiomyocyte FA uptake and develop MHD in the absence of systemic lipotoxicity, obesity or diabetes. We utilized this model to assess 1) the effect of cardiomyocyte lipid accumulation on mitochondrial structure and energetic function and 2) the role of lipid-driven transcriptional regulation, signaling, toxic metabolite accumulation, and mitochondrial oxidative stress in lipid induced MHD. METHODS: Cardiac lipid species, lipid-dependent signaling, and mitochondrial structure/function were examined from FATP1 mice. Cardiac structure and function were assessed in mice overexpressing both FATP1 and mitochondrial targeted catalase. RESULTS: FATP1 hearts exhibited a net increase (+12%) in diacylglycerol, with increases in several very long-chain diacylglycerol species (+160-212%, p<0.001) and no change in ceramide, sphingomyelin, or acylcarnitine content. This was associated with an increase in phosphorylation of PKCalpha and PKCdelta, and a decrease in phosphorylation of AKT and expression of CREB, PGC1alpha, PPARalpha and the mitochondrial fusion genes MFN1, MFN2 and OPA1. FATP1 overexpression also led to marked decreases in mitochondrial size (-49%, p<0.01), complex II-driven respiration (-28.6%, p<0.05), activity of isolated complex II (-62%, p=0.05), and expression of complex II subunit B (SDHB) (-60% and -31%, p<0.01) in the absence of change in ATP synthesis. Hydrogen peroxide production was not increased in FATP1 mitochondria, and cardiac hypertrophy and diastolic dysfunction were not attenuated by overexpression of catalase in mitochondria in FATP1 mice. CONCLUSIONS: Excessive delivery of FAs to the cardiac myocyte in the absence of systemic disorders leads to activation of lipid-driven signaling and remodeling of mitochondrial structure and function. PMID- 25497303 TI - Single-walled carbon nanotubes increase pandemic influenza A H1N1 virus infectivity of lung epithelial cells. AB - BACKGROUND: Airborne exposure to nanomaterials from unintended occupational or environmental exposures or as a consequence of product use may lead to adverse health effects. Numerous studies have focused on single-walled carbon nanotubes (SWCNTs) and their ability to cause pulmonary injury related to fibrosis, and cancer; however few studies have addressed their impact on infectious agents, particularly viruses that are known for causing severe disease. Here we have demonstrated the ability of pristine SWCNTs of diverse electronic structure to increase the susceptibility of small airway epithelial cells (SAEC) to pandemic influenza A H1N1 infection and discerned potential mechanisms of action driving this response. METHODS: Small airway epithelial cells (SAEC) were exposed to three types of SWCNTs with varying electronic structure (SG65, SG76, CG200) followed by infection with A/Mexico/4108/2009 (pH1N1). Cells were then assayed for viral infectivity by immunofluorescence and viral titers. We quantified mRNA and protein levels of targets involved in inflammation and anti-viral activity (INFbeta1, IL-8, RANTES/CCL5, IFIT2, IFIT3, ST3GAL4, ST6GAL1, IL-10), localized sialic acid receptors, and assessed mitochondrial function. Hyperspectral imaging analysis was performed to map the SWCNTs and virus particles in fixed SAEC preparations. We additionally performed characterization analysis to monitor SWCNT aggregate size and structure under biological conditions using dynamic light scattering (DLS), static light scattering (SLS). RESULTS: Based on data from viral titer and immunofluorescence assays, we report that pre-treatment of SAEC with SWCNTs significantly enhances viral infectivity that is not dependent on SWCNT electronic structure and aggregate size within the range of 106 nm - 243 nm. We further provide evidence to support that this noted effect on infectivity is not likely due to direct interaction of the virus and nanoparticles, but rather a combination of suppression of pro-inflammatory (RANTES) and anti-viral (IFIT2, IFIT3) gene/protein expression, impaired mitochondrial function and modulation of viral receptors by SWCNTs. CONCLUSIONS: Results of this work reveal the potential for SWCNTs to increase susceptibility to viral infections as a mechanism of adverse effect. These data highlight the importance of investigating the ability of carbon-nanomaterials to modulate the immune system, including impacts on anti-viral mechanisms in lung cells, thereby increasing susceptibility to infectious agents. PMID- 25497305 TI - Temporal distribution of accumulated metal mixtures in two feral fish species and the relation with condition metrics and community structure. AB - The present study investigated temporal influences on metal distribution in gudgeon (Gobio gobio) and roach (Rutilus rutilus), and its relation to condition metrics and fish community structure. Fish communities were sampled in two seasons (autumn and spring) during two successive years and the Index of Biotic Integrity (IBI) was calculated. Cadmium, Cu, Pb, Zn and As concentrations were measured in gill, liver, kidney and muscle, and condition factor (CF) and hepatosomatic index (HSI) were measured. Cadmium (max. 39.0 MUg g(-1) dw) and Zn (max 2502 MUg g(-1) dw) were most strongly stored in kidney and liver and periodical influences on metal accumulation were observed. CF appeared to be a stable metric related to accumulated metal-mixtures and was best related to hepatic levels, while the HSI was less useful. Relations between single metal accumulation and IBI were influenced by sample period, however, when taking into account multiple metals periodical influences disappeared. PMID- 25497306 TI - Damage cost of the Dan River coal ash spill. AB - The recent coal ash spill on the Dan River in North Carolina, USA has caused several negative effects on the environment and the public. In this analysis, I report a monetized value for these effects after the first 6 months following the spill. The combined cost of ecological damage, recreational impacts, effects on human health and consumptive use, and esthetic value losses totals $295,485,000. Because the environmental impact and associated economic costs of riverine coal ash spills can be long-term, on the order of years or even decades, this 6-month assessment should be viewed as a short-term preview. The total cumulative damage cost from the Dan River coal ash spill could go much higher. PMID- 25497307 TI - Perfluoroalkyl substances detected in the world's southernmost marine mammal, the Weddell seal (Leptonychotes weddellii). AB - This study investigates concentrations of 18 perfluoroalkyl substances (PFAS) in blood plasma of adult lactating Weddell seals (Leptonychotes weddellii) (n = 10) from McMurdo Sound, Antarctica. Perfluoroundecanoic acid (PFUnDA) was detected in all samples at concentrations ranging from 0.08 to 0.23 ng/ml. Perfluorooctane sulfonate (PFOS), perfluorohexanoate (PFHxA) and perfluorotridecanoate (PFTriDA) were sporadically detected, while the remaining compounds were below the limit of detection. This is the first report of detectible concentrations of PFASs in an endemic Antarctic marine mammal species. We suggest that the pollutants have been subjected to long range atmospheric transportation and/or derive from a local source. A review of these and published data indicate that perfluoroalkyl carboxylates (PFCAs) dominate in biotic PFAS patterns in species feeding south of the Antarctic Circumpolar Current (ACC), whereas PFOS was the major PFAS detected in species feeding predominantly north of the current. PMID- 25497308 TI - Humidity plays an important role in the PM2.5 pollution in Beijing. AB - Heavily-polluted PM2.5 (fine particulate matter) episodes frequently impacting Beijing, especially during winter, have become a substantial concern. We found that during winter, the daily variation of PM2.5 in Beijing tracked the pattern of relative humidity (RH). With the increase of PM2.5 (or RH), water-soluble components (especially inorganic ions) became more abundant, and the water soluble organic carbon to organic carbon ratios increased. The nitrate to sulfate ratios also exhibited dependence on RH, and were higher than those measured about a decade ago, consistent with the increasing trend of nitrogen oxides emissions. Surprisingly, the ratios of water-insoluble organic carbon to elemental carbon showed significant increase at high RH levels, presumably indicating the formation of secondary organic aerosol that is not soluble in water. In addition, humid winters were occasionally identified during 1996-2013 which are expected to be favorable for the formation of air pollution episodes with high PM2.5 concentrations. PMID- 25497309 TI - Making music in the operating theatre. PMID- 25497310 TI - Reducing the negative valence of stressful memories through emotionally valenced, modality-specific tasks. AB - BACKGROUND AND OBJECTIVES: People who perform a cognitively demanding secondary task while recalling a distressing memory often experience the memory as less emotional, vivid, or accurate during subsequent recollections. In this experiment, we tested whether the emotional valence (positive versus neutral) and sensory modality (visual, auditory, or both) of a secondary task diminishes the emotionality, vividness, and accuracy of memory of distressing videos. METHODS: Participants (N = 156) viewed a distressing video and were then randomized to one of six groups in a 2 (Emotional Valence: positive, neutral) * 3 (Modality: visual, auditory, combined) design. Participants were then exposed to an amusing or a neutral clip that was visual, auditory, or audiovisual. They were asked to recall the distressing video during exposure to the clip. Participants rated the emotionality and vividness of their memory of the distressing video, and completed recognition tests regarding its visual and auditory details before and after exposure to the secondary clip. RESULTS: Participants who recalled the distressing video while exposed to the amusing clip rated their memory of the distressing video as less distressing (but not less vivid or accurate) than did participants exposed to the neutral clip. Modality had no significant effects Limitations. Participants were not trauma survivors, and the memories targeted were stressful, but subtraumatic. CONCLUSIONS: Inducing positive emotion during recollection of distressing memories may diminish the emotional distress prompted by subsequent recollection. PMID- 25497311 TI - In vitro dry powder inhaler formulation performance considerations. AB - It has long been desired to match airflow conditions during formulation evaluation to those of relevance to lung deposition. In this context several strategies have been adopted involving sampling at different: flow rate (without consideration of flow conditions, e.g. shear, Reynolds number, work function); pressure drop (with and without consideration of flow conditions) and; flow rate and pressure drop. Performance testing has focused on the influence of these sampling conditions on delivered dose uniformity and aerodynamic particle size distribution. However, in order to be physiologically relevant it is also important to know when the drug was delivered with respect to initiation of airflow as variation in this parameter would influence lung deposition. A light obscuration method of detecting the dose delivered from a dry powder inhaler while sampling for aerodynamic particle size distributions (APSD) by inertial impaction has been developed. Four formulations of albuterol sulfate and budesonide in sieved and milled lactose, respectively, were dispersed and their rate of delivery monitored. The differences observed have the potential to impact the site of delivery in the lungs. The rate of delivery of drug is clearly an important companion measurement to delivered dose and APSD if the intent is to predict the similarity of in vivo performance of dry powder inhaler products. PMID- 25497312 TI - Irinophore CTM, a lipid nanoparticulate formulation of irinotecan, improves vascular function, increases the delivery of sequentially administered 5-FU in HT 29 tumors, and controls tumor growth in patient derived xenografts of colon cancer. AB - PURPOSE: A liposomal formulation of irinotecan, Irinophore CTM (IrCTM) is efficacious in a panel of tumor models, normalizes tumor vasculature, and increases the accumulation of a second drug in the same tumor. We now show that Irinophore CTM is also effective against patient derived xenografts (PDX) of colon cancer, and examine the kinetics of vascular normalization in the HT-29 tumor model and assess how these changes might be used with 5-FU sequentially. MATERIALS AND METHODS: Rag2M mice bearing HT-29 tumors were treated with IrCTM (25mg/kg; Q7D*3) for up to three weeks. Groups of tumors were harvested for analysis at 7, 14 and 21days after the start of treatment. Drug and lipid levels in the tumor were evaluated using HPLC and scintillation counts, respectively. Changes in tumor morphology (H&E), vasculature (CD31), perfusion (Hoechst 33342) and apoptosis (TUNEL) were quantified using microscopy. The accumulation of a second drug ([(14)C]-5-FU, 40mg/kg) given 3h before sacrifice was determined using liquid scintillation. The efficacy of IrCTM (Q7D*3) followed by 5-FU treatment (Q7D*3) was assessed in mice bearing established HT-29 tumors. The efficacy of IrCTM was also evaluated in primary human colorectal tumors grown orthotopically in NOD-SCID mice. RESULTS: Following a single dose of IrCTM the active lactone forms of irinotecan and its metabolite SN-38 were measurable in HT 29 tumors after 7days. The treatment reduced tumor cell density and increased apoptosis. Hoechst 33342 perfusion and accumulation of [(14)C]-5-FU in the treated tumors increased significantly on days 7 and 14. This was accompanied by an increase in the number of endothelial cells relative to total nuclei in the tumor sections. Pre-treatment with IrCTM (Q7D*3) followed by 5-FU (Q7D*3) delayed the time taken for tumors to reach 1cm(3) by 9days (p<0.05). IrCTM was just as effective as free irinotecan when used on patient derived xenografts of colorectal cancer. CONCLUSIONS: Treatment with IrCTM reduces tumor cell viability and appears to normalize the vascular function of the tumor after a single treatment cycle. A concomitant increase in the accumulation of a second drug (5 FU) in the tumor was observed in tumors from IrCTM treated animals and this was correlated with changes in vascular structure consistent with normalization. The treatment effects of sequential 5-FU dosing following IrCTM are additive with no additional toxicity in contrast to previous studies where concurrent 5-FU and IrCTM treatment exacerbated 5-FU toxicity. The studies with PDX tumors also indicate that IrCTM is just as effective as free irinotecan on PDX tumors even though the delivered dose is halved. PMID- 25497313 TI - Immediate remediation of heavy metal (Cr(VI)) contaminated soil by high energy electron beam irradiation. AB - This work developed an immediate and high-performance remediation method for Cr(VI) contaminated soil (CCS) using high energy electron beam (HEEB) irradiation. The result indicated that, compared with gamma-ray irradiation, HEEB irradiation displayed a significant reduction efficiency on Cr(VI) in CCS to Cr(III) with substantially lower toxicity, which was mainly attributed to the reduction effects of electrons, hydrated electrons, and reductive radicals generated in the irradiation process of HEEB. This work could provide a one-step and effective method for the remediation of heavy metal contaminated soil (HMCS). PMID- 25497314 TI - Study of microbial perchlorate reduction: considering of multiple pH, electron acceptors and donors. AB - Bioremediation of perchlorate-cotaminated water by a heterotrophic perchlorate reducing bacterium creates a multiple electron acceptor-donor system. We experimentally determined the perchlorate reduction by Azospira sp. KJ at multiple pH, electron acceptors and donors systems; this was the aim of this study. Perchlorate reduction was drastically inhibited at the pH 6.0, and the maximum reduction of perchlorate by Azospira sp. KJ was observed at pH value of 8.0. Perchlorate reduction was retarded in ClO4(-)-ClO3(-), ClO4(-)-ClO3(-)-NO3( ),and ClO4(-)-NO3(-) acceptor systems, while being completely inhibited by the additional O2 in the ClO4(-)-O2 acceptor system. The reduction proceeded as an order of ClO3(-), ClO4(-), and NO3(-) in the ClO4(-)-ClO3(-)-NO3(-) system. K(S), v(max), and q(max) obtained at different e(-) acceptor and donor conditions are calculated as 140.5-190.6 mg/L, 8.7-13.2 mg-perchlorate/L-h, and 0.094-0.16 mg perchlorate/mg-DW-h, respectively. PMID- 25497315 TI - Transport, fate, and stimulating impact of silver nanoparticles on the removal of Cd(II) by Phanerochaete chrysosporium in aqueous solutions. AB - Despite the knowledge about increasing discharge of silver nanoparticles (AgNPs) into wastewater and its potential toxicity to microorganisms, the interaction of AgNPs with heavy metals in the biological removal process remains poorly understood. This study focused on the effect of AgNPs (hydrodynamic diameter about 24.3+/-0.37 nm) on the removal of cadmium (Cd(II)) by using a model white rot fungus species, Phanerochaete chrysosporium. Results showed that the biological removal capacity of Cd(II) increased with the concentration of AgNPs increasing from 0.1 mg/L to 1 mg/L. The maximum removal capacity (4.67 mg/g) was located at 1 mg/L AgNPs, and then decreased with further increasing AgNPs concentration, suggesting that an appropriate concentration of AgNPs has a stimulating effect on the removal of Cd(II) by P. chrysosporium instead of an inhibitory effect. Results of Ag(+) and total Ag concentrations in the solutions together with those of SEM and XRD demonstrated that added AgNPs had undergone oxidative dissolution and transported from the solution to the surface of fungal mycelia (up to 94%). FTIR spectra confirmed that amino, carboxyl, hydroxyl, and other reducing functional groups were involved in Cd(II) removal, AgNPs transportation, and the reduction of Ag(+) to AgNPs. PMID- 25497316 TI - Different tolerances to chemical contaminants between unicellular and colonial morph of Microcystis aeruginosa: excluding the differences among different strains. AB - In order to ascertain the different tolerances to chemical contaminants in one strain of Microcystis with different morphology, unicellular and colonial Microcystis in one strain was obtained from different conditions of light intensity and temperature. The samples were divided into 8 groups including control (no chemical addition), CuSO4, chloromycetin, and linear alkylbenzene sulfonatelas (LAS) treatments. The cell density, cell viability, superoxide dismutase (SOD), and malonaldehyde of Microcystis were analyzed. It was observed that cell density of both unicellular and colonial Microcystis increased from the beginning to day-5 in the control and the CuSO4 treatments. However, the growth of Microcystis was significantly inhibited in the culture with chloromycetin and LAS treatments. Notably, the inhibition rate was significantly high in unicellular Microcystis relative to the colonial Microcystis. The esterase activity in all the treatments decreased dramatically relating to the control. In addition, the esterase activity in colonial Microcystis was significantly higher than that of the unicellular Microcystis in all the treatments. Although there were no significant differences in activities of SOD between the two morphologies in the control treatments, in all the other treatments, significant differences were observed. The results proved that colony formation of Microcystis could be considered as a strategy in response to chemical stress. PMID- 25497317 TI - Novel HCN sorbents based on layered double hydroxides: sorption mechanism and performance. AB - Layered double hydroxides (LDHs) and layered double oxides (LDOs) have been prepared and used as sorbents for hydrogen cyanide (HCN). Based on results from sorbent optimization experiments, the optimal performance for HCN removal was found in Ni-Al LDH. As evidenced by fixed-bed sorption studies, the Ni-Al LDO with the greatest surface area showed better performance and outperformed products calcined at 200, 400, or 500 degrees C, whereas, the Ni-Al LDH showed a more twofold higher sorption capacity than the Ni-Al LDO. Investigation of the mechanisms between HCN and sorbents reveals that the HCN removal by the Ni-Al LDH and Ni-Al LDO leads to the formation of the complex anion, [Ni(CN)4](2-). Nevertheless, the [Ni(CN)4](2-) can enter interlayer region of the Ni-Al LDH due to its anion exchangeability, which endows this LDH with more binding sites, not only on its external surfaces, but also on its internal surfaces located in the interlayer region. In contrast, [Ni(CN)4](2-) were only adsorbed on the external surface of the Ni-Al LDO. As a result, the sorption capacity of the Ni-Al LDH for HCN is twice as high as that of the Ni-Al LDO, which is at 21.55 mg/g. PMID- 25497318 TI - Dry powder inhalers: physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol. AB - The purpose of this work was to evaluate the physicochemical and inhalation characteristics of different size fractions of a promising carrier, i.e., freeze dried mannitol (FDM). FDM was prepared and sieved into four size fractions. FDMs were then characterized in terms of micromeritic, solid-state and bulk properties. Dry powder inhaler (DPI) formulations were prepared using salbutamol sulphate (SS) and then evaluated in terms of drug content homogeneity and in vitro aerosolization performance. The results showed that the crystalline state of mannitol was maintained following freeze-drying for all size fractions of FDM. All FDM particles showed elongated morphology and contained mixtures of alpha-, beta- and delta-mannitol. In comparison to small FDM particles, FDMs with larger particle sizes demonstrated narrower size distributions, higher bulk and tap densities, lower porosities and better flowability. Regardless of particle size, all FDMs generated a significantly higher (2.2-2.9-fold increase) fine particle fraction (FPF, 37.5 +/- 0.9%-48.6 +/- 2.8%) of SS in comparison to commercial mannitol. The FPFs of SS were related to the shape descriptors of FDM particles; however, FPFs did not prove quantitative apparent relationships with either particle size or powder bulk descriptors. Large FDM particles were more favourable than smaller particles because they produced DPI formulations with better flowability, better drug content homogeneity, lower amounts of the drug depositing on the throat and contained lower fine-particle-mannitol. Optimized stable DPI formulations with superior physicochemical and pharmaceutical properties can be achieved using larger particles of freeze-dried mannitol (FDM). PMID- 25497319 TI - Topical delivery of acetyl hexapeptide-8 from different emulsions: influence of emulsion composition and internal structure. AB - Acetyl hexapeptide-8 (AH-8) is a well-known component of anti-aging products and was recently explored as a promising topical treatment of blepharospasm. Although AH-8 appears in a variety of cosmetic products, its skin penetration is sparsely studied and controversially discussed. Therefore, the aim of the present study was to investigate the influence of the vehicle type on the AH-8 delivery to the skin. Besides skin permeation experiments with Franz type diffusion cells, the spatial distribution of AH-8 in the stratum corneum after a real in-use application was investigated by in vitro tape stripping on porcine ear skin. By applying LC-MS/MS for quantification of AH-8, we demonstrated that a multiple water-in-oil-in-water (W/O/W) emulsion can significantly increase penetration of AH-8 into porcine skin compared to simple O/W and W/O emulsions. The internal structure of the developed multiple emulsion was confirmed by electron microscopic investigations and NMR self diffusion studies. In general, a clear superiority of water-rich W/O/W and O/W emulsions over an oil-rich W/O emulsion in terms of dermal delivery of AH-8 was found. This enhanced delivery of AH-8 could be explained by an increased absorption of the water-rich emulsions into the skin, confirmed by combined ATR-FTIR and tape stripping experiments. PMID- 25497321 TI - Cell-size maintenance: universal strategy revealed. AB - How cells maintain a stable size has fascinated scientists since the beginning of modern biology, but has remained largely mysterious. Recently, however, the ability to analyze single bacteria in real time has provided new, important quantitative insights into this long-standing question in cell biology. PMID- 25497320 TI - The presence of meniscal lesions is a strong predictor of neuropathic pain in symptomatic knee osteoarthritis: a cross-sectional pilot study. AB - INTRODUCTION: Pain in osteoarthritis (OA) has been classically attributed to joint structural damage. Disparity between the degree of radiographic structural damage and the severity of symptoms implies that factors other than the joint pathology itself contribute to the pain. Peripheral and central sensitization have been suggested as two of the underlying mechanisms that contribute to pain in OA. The aim of this study was to explore in symptomatic knee OA patients, the structural changes assessed by magnetic resonance imaging (MRI) that could be used as markers of neuropathic pain (NP). METHODS: This cross-sectional observational pilot study included 50 knee OA patients with moderate to severe pain (VAS >=40) in the target knee. The presence of NP was determined based on the PainDETECT questionnaire. Among the 50 patients included, 25 had PainDETECT score <=12 (unlikely NP), 9 had PainDETECT score between 13 and 18 (uncertain NP) and 16 had PainDETECT score >=19 (likely NP). WOMAC, PainDETECT, and VAS pain scores as well as knee MRI were assessed. RESULTS: Data showed no significant difference in demographic characteristics between the three groups. However, a positive and statistically significant association was found between the WOMAC pain (P <0.001), function (P <0.001), stiffness (P = 0.007) and total (P <0.001) scores as well as higher VAS pain score (P = 0.023), and PainDETECT scores. Although no difference was found in the cartilage volume between groups, the presence of meniscal extrusion in both medial (P = 0.006) and lateral (P = 0.023) compartments, and presence of meniscal tears in the lateral compartment (P = 0.011), were significantly associated with increasing PainDETECT score. Moreover, the presence of bone marrow lesions in the lateral plateau and the extent of the synovial membrane thickness in the lateral recess were associated with increasing PainDETECT scores (P = 0.032, P = 0.027, respectively). CONCLUSIONS: In this study, meniscal lesions, particularly extrusion, were found to be among the strongest risk factors for NP in knee OA patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01733277. Registered 16 November 2012. PMID- 25497322 TI - Continuous versus pulse neutron induced gamma spectroscopy for soil carbon analysis. AB - Neutron induced gamma spectra analysis (NGA) provides a means of measuring carbon in large soil volumes without destructive sampling. Calibration of the NGA system must account for system background and the interference of other nuclei on the carbon peak at 4.43 MeV. Accounting for these factors produced measurements in agreement with theoretical considerations. The continuous NGA mode was twice as fast and just as accurate as the pulse mode, thus this mode was preferable for routine soil carbon analysis. PMID- 25497323 TI - Improved peak shape fitting in alpha spectra. AB - Peak overlap is a recurrent issue in alpha-particle spectrometry, not only in routine analyses but also in the high-resolution spectra from which reference values for alpha emission probabilities are derived. In this work, improved peak shape formulae are presented for the deconvolution of alpha-particle spectra. They have been implemented as fit functions in a spreadsheet application and optimum fit parameters were searched with built-in optimisation routines. Deconvolution results are shown for a few challenging spectra with high statistical precision. The algorithm outperforms the best available routines for high-resolution spectrometry, which may facilitate a more reliable determination of alpha emission probabilities in the future. It is also applicable to alpha spectra with inferior energy resolution. PMID- 25497324 TI - Cross-sections for (p,x) reactions on natural chromium for the production of (52,52m,54)Mn radioisotopes. AB - The production of positron-emitting isotopes of manganese is potentially important for developing contrast agents for dual-modality positron emission tomography and magnetic resonance (PET/MR) imaging, as well as for in vivo imaging of the biodistribution and toxicity of manganese. The decay properties of (52)Mn make it an excellent candidate for these applications, and it can easily be produced by bombardment of a chromium target with protons or deuterons from a low-energy biomedical cyclotron. Several parameters that are essential to this mode of production-target thickness, beam energy, beam current, and bombardment time-depend heavily on the availability of reliable, reproducible cross-section data. This work contributes to the routine production of (52g)Mn for biomedical research by contributing experimental cross-sections for natural chromium ((nat)Cr) targets for the (nat)Cr(p,x)(52g)Mn reaction, as well as for the production of the radiocontaminants (52m,54)Mn. PMID- 25497325 TI - Target optimization for the photonuclear production of radioisotopes. AB - In this paper we discuss the optimum shape of a target for photonuclear production of radioisotopes using an electron linear accelerator. Different target geometries such as right cylinder, conical frustum, Gaussian volume of revolution and semi-ellipsoid have been considered for the production of (67)Cu via (68)Zn(gamma,p)(67)Cu photonuclear reaction. The specific activity (SA) of (67)Cu was simulated for each target shape. Optimum ratio of radius to height for cylindrical targets was found to be between 0.2 and 0.25 for target masses ranging from 20 g to 100 g. It was shown that while some unconventional target shapes, such as semi-elliptical volume of revolution, result in slightly higher specific activities than cylindrical targets, the advantage is not significant and is outweighed by the complexity of the target production and handling. Power deposition into the target was modeled and the trade-off between the maximization of (67)Cu yield and the minimization of target heating has been discussed. The (67)Cu case can easily be extended for production of many other isotopes. PMID- 25497326 TI - APOE and mild cognitive impairment: the Framingham Heart Study. AB - BACKGROUND: The risk apolipoprotein E-4 (APOE4) poses for mild cognitive impairment (MCI) may vary based on the neuropsychological definition of MCI. SETTING: A community-based cohort study. METHODS: Using two psychometric neuropsychological impairment definitions, we examined APOE4 and prevalent MCI among older adults or pre-MCI among middle-aged adults. Neuropsychological, clinical and genetic data were collected on 2,239 Framingham Offspring Cohort participants free from clinical stroke or dementia (62+/-9 years; 54% women). Prevalent amnestic MCI was defined from neuropsychological performances>=1.5 SD below the mean based on (i) age and education or (ii) age and Wide Range Achievement Test-3 Reading (WRAT-3 Reading) performance adjustment. RESULTS: In the entire sample, multivariable-adjusted logistic regressions found that APOE4 was associated with amnestic MCI when using the age and WRAT Reading definition (odds ratio [OR]=1.7, P=0.002) but not the age and education definition (OR=1.0, P=0.90). Results were modified by age, such that APOE4 was associated with amnestic MCI in participants>=65 years using both the age and WRAT Reading definition (OR=2.4, P<0.001) and the age and education definition (OR=1.7, P=0.04). CONCLUSION: APOE4 risk for prevalent amnestic MCI varies depending on the definition of objective neuropsychological impairment for MCI. Our findings support existing literature emphasising the need to refine MCI neuropsychological profiling methods. PMID- 25497328 TI - The complexity of DNA double strand break is a crucial factor for activating ATR signaling pathway for G2/M checkpoint regulation regardless of ATM function. AB - DNA double strand break (DSB) repair pathway choice following ionizing radiation (IR) is currently an appealing research topic, which is still largely unclear. Our recent paper indicated that the complexity of DSBs is a critical factor that enhances DNA end resection. It has been well accepted that the RPA-coated single strand DNA produced by resection is a signaling structure for ATR activation. Therefore, taking advantage of high linear energy transfer (LET) radiation to effectively produce complex DSBs, we investigated how the complexity of DSB influences the function of ATR pathway on the G2/M checkpoint regulation. Human skin fibroblast cells with or without ATM were irradiated with X rays or heavy ion particles, and dual-parameter flow cytometry was used to quantitatively assess the mitotic entry at early period post radiation by detecting the cells positive for phosphor histone H3. In ATM-deficient cells, ATR pathway played a pivotal role and functioned in a dose- and LET-dependent way to regulate the early G2/M arrest even as low as 0.2Gy for heavy ion radiation, which indicated that ATR pathway could be rapidly activated and functioned in an ATM-independent, but DSB complexity-dependent manner following exposure to IR. Furthermore, ATR pathway also functioned more efficiently in ATM-proficient cells to block G2 to M transition at early period of particle radiation exposure. Accordingly, in contrast to ATM inhibitor, ATR inhibitor had a more effective radiosensitizing effect on survival fraction following heavy ion beams as compared with X ray radiation. Taken together, our results reveal that the complexity of DSBs is a crucial factor for the activation of ATR pathway for G2/M checkpoint regulation, and ATM-dependent end resection is not essential for the activation. PMID- 25497330 TI - A method to accurately quantitate intensities of (32)P-DNA bands when multiple bands appear in a single lane of a gel is used to study dNTP insertion opposite a benzo[a]pyrene-dG adduct by Sulfolobus DNA polymerases Dpo4 and Dbh. AB - Quantitating relative (32)P-band intensity in gels is desired, e.g., to study primer-extension kinetics of DNA polymerases (DNAPs). Following imaging, multiple (32)P-bands are often present in lanes. Though individual bands appear by eye to be simple and well-resolved, scanning reveals they are actually skewed-Gaussian in shape and neighboring bands are overlapping, which complicates quantitation, because slower migrating bands often have considerable contributions from the trailing edges of faster migrating bands. A method is described to accurately quantitate adjacent (32)P-bands, which relies on having a standard: a simple skewed-Gaussian curve from an analogous pure, single-component band (e.g., primer alone). This single-component scan/curve is superimposed on its corresponding band in an experimentally determined scan/curve containing multiple bands (e.g., generated in a primer-extension reaction); intensity exceeding the single component scan/curve is attributed to other components (e.g., insertion products). Relative areas/intensities are determined via pixel analysis, from which relative molarity of components is computed. Common software is used. Commonly used alternative methods (e.g., drawing boxes around bands) are shown to be less accurate. Our method was used to study kinetics of dNTP primer-extension opposite a benzo[a]pyrene-N(2)-dG-adduct with four DNAPs, including Sulfolobus solfataricus Dpo4 and Sulfolobus acidocaldarius Dbh. Vmax/Km is similar for correct dCTP insertion with Dpo4 and Dbh. Compared to Dpo4, Dbh misinsertion is slower for dATP (~20-fold), dGTP (~110-fold) and dTTP (~6-fold), due to decreases in Vmax. These findings provide support that Dbh is in the same Y-Family DNAP class as eukaryotic DNAP kappa and bacterial DNAP IV, which accurately bypass N(2)-dG adducts, as well as establish the scan-method described herein as an accurate method to quantitate relative intensity of overlapping bands in a single lane, whether generated from (32)P-signals or by other means (e.g., staining). PMID- 25497327 TI - Analysis of microRNA from archived formalin-fixed paraffin-embedded specimens of amyotrophic lateral sclerosis. AB - BACKGROUND: MicroRNAs (miRNAs) are noncoding small RNAs that regulate gene expression. This study investigated whether formalin-fixed paraffin-embedded (FFPE) specimens from postmortem cases of neurodegenerative disorders would be suitable for miRNA profiling. RESULTS: Ten FFPE samples from 6 cases of amyotrophic lateral sclerosis (ALS) and 4 neurologically normal controls were selected for miRNA analysis on the basis of the following criteria for RNA quality: (i) a postmortem interval of less than 6 hours, (ii) a formalin fixation time of less than 4 weeks, (iii) an RNA yield per sample of more than 500 ng, and (iv) sufficient quality of the RNA agarose gel image. An overall RNA extraction success rate was 46.2%. For ALS, a total of 364 miRNAs were identified in the motor cortex, 91 being up-regulated and 233 down-regulated. Target genes were predicted using miRNA bioinformatics software, and the data applied to ontology analysis. This indicated that one of the miRNAs up-regulated in ALS (miR-338-3p) had already been identified in leukocytes, serum, cerebrospinal fluid and frozen spinal cord from ALS patients. CONCLUSION: Although analysis was possible for just under half of the specimens examined, we were able to show that informative miRNA data can be derived from archived FFPE samples from postmortem cases of neurodegenerative disorders. PMID- 25497329 TI - Proteome-wide analysis of SUMO2 targets in response to pathological DNA replication stress in human cells. AB - SUMOylation is a form of post-translational modification involving covalent attachment of SUMO (Small Ubiquitin-like Modifier) polypeptides to specific lysine residues in the target protein. In human cells, there are four SUMO proteins, SUMO1-4, with SUMO2 and SUMO3 forming a closely related subfamily. SUMO2/3, in contrast to SUMO1, are predominantly involved in the cellular response to certain stresses, including heat shock. Substantial evidence from studies in yeast has shown that SUMOylation plays an important role in the regulation of DNA replication and repair. Here, we report a proteomic analysis of proteins modified by SUMO2 in response to DNA replication stress in S phase in human cells. We have identified a panel of 22 SUMO2 targets with increased SUMOylation during DNA replication stress, many of which play key functions within the DNA replication machinery and/or in the cellular response to DNA damage. Interestingly, POLD3 was found modified most significantly in response to a low dose aphidicolin treatment protocol that promotes common fragile site (CFS) breakage. POLD3 is the human ortholog of POL32 in budding yeast, and has been shown to act during break-induced recombinational repair. We have also shown that deficiency of POLD3 leads to an increase in RPA-bound ssDNA when cells are under replication stress, suggesting that POLD3 plays a role in the cellular response to DNA replication stress. Considering that DNA replication stress is a source of genome instability, and that excessive replication stress is a hallmark of pre neoplastic and tumor cells, our characterization of SUMO2 targets during a perturbed S-phase should provide a valuable resource for future functional studies in the fields of DNA metabolism and cancer biology. PMID- 25497331 TI - Spheroid cultures promote the stemness of corneal stromal cells. AB - Several culture methods generated spheroids of rabbit and mouse corneal stromal cells (CSCs) in vitro. In this study, rabbit CSC spheroids were positively expressed the mesenchymal and stem cell phenotypes, which contained immunopositive for vimentin (a mesenchymal cell marker) and CD34 (a stem cell marker), as well as mRNA expression of nestin (a neural stem cell marker) and Nanog (a stem cell marker), in suspension or adherent cultures that were induced by methylcellulose, a rotary cell culture system (RCCS) or reprogramming proteins and VPA. Mouse CSCs showed poor growth and hardly formed spheroids after treatment with methylcellulose or reprogramming proteins and VPA. Our work has laid a promising foundation to elucidate CSCs and the further use of CSC spheroids for reprogramming, bioprinting and tissue engineering. PMID- 25497332 TI - Excess mortality from mental, neurological and substance use disorders in the Global Burden of Disease Study 2010. AB - AIMS: Mortality-associated burden of disease estimates from the Global Burden of Disease 2010 (GBD 2010) may erroneously lead to the interpretation that premature death in people with mental, neurological and substance use disorders (MNSDs) is inconsequential when evidence shows that people with MNSDs experience a significant reduction in life expectancy. We explore differences between cause specific and excess mortality of MNSDs estimated by GBD 2010. METHODS: GBD 2010 cause-specific death estimates were produced using the International Classification of Diseases death-coding system. Excess mortality (all-cause) was estimated using natural history models. Additional mortality attributed to MNSDs as underlying causes but not captured through GBD 2010 methodology is quantified in the comparative risk assessments. RESULTS: In GBD 2010, MNSDs were estimated to be directly responsible for 840 000 deaths compared with more than 13 million excess deaths using natural history models. CONCLUSIONS: Numbers of excess deaths and attributable deaths clearly demonstrate the high degree of mortality associated with these disorders. There is substantial evidence pointing to potential causal pathways for this premature mortality with evidence-based interventions available to address this mortality. The life expectancy gap between persons with MNSDs and the general population is high and should be a focus for health systems reform. PMID- 25497333 TI - Generation and structural validation of a library of diverse xyloglucan-derived oligosaccharides, including an update on xyloglucan nomenclature. AB - Xyloglucans are structurally complex plant cell wall polysaccharides that are involved in cell growth and expansion, energy metabolism, and signaling. Determining the structure-function relationships of xyloglucans would benefit from the availability of a comprehensive and structurally diverse collection of rigorously characterized xyloglucan oligosaccharides. Here, we present a workflow for the semi-preparative scale generation and purification of neutral and acidic xyloglucan oligosaccharides using a combination of enzymatic and chemical treatments and size-exclusion chromatography. Twenty-six of these oligosaccharides were purified to near homogeneity and their structures validated using a combination of matrix-assisted laser desorption/ionization mass spectrometry, high-performance anion exchange chromatography, and 1H nuclear magnetic resonance spectroscopy. Mass spectrometry and analytical chromatography were compared as methods for xyloglucan oligosaccharide quantification. 1H chemical shifts were assigned using two-dimensional correlation spectroscopy. A comprehensive update of the nomenclature describing xyloglucan side-chain structures is provided for reference. PMID- 25497334 TI - Montmorillonite K-10 promoted synthesis of chiral dioxa-caged compounds derived from levoglucosenone. AB - A short and efficient methodology for the synthesis of chiral dioxa-caged compounds from levoglucosenone, a biomass-derived enone, is herein presented. The key transformation, that involves a cascade 3-step cationic cyclization, was efficiently carried out in high yields and selectivities by Montmorillonite K-10 catalysis. The usefulness of K-10 in related semi-pinacol rearrangements to obtain pyran-3-ones is also shown. Interesting differences in the reactivity pattern was found for epimeric alcohols, and the origins of these findings were determined by DFT calculations. PMID- 25497335 TI - Selective glycosylation of steroidal saponins by Arthrobacter nitroguajacolicus. AB - In this study seven strains of the genus Arthrobacter were screened by biotransformation to discover glycosylating patterns on steroid saponins. A strain of Arthrobacter nitroguajacolicus (CPCC 203516) was found to have the ability of fructosylation. Crude enzyme of the strain was extracted for the further study of conversion characteristics and patterns. Sucrose was used as a non-activated sugar donor, and fifteen steroidal saponins were involved. Nine furostan saponins of the substrates were converted, and ten products were isolated and identified. Based on the HR-ESI-MS, 1D, and 2D NMR spectral data, one fructosyl was added to furostan saponins at C6-OH of 26-O-beta-D glucopyranosyl by A. nitroguajacolicus for all nine products. One product was distinguished by an additional fructosyl at the position of C6-OH on the first added fructosyl. Spirostan saponins of the substrates could not be converted. Steroidal saponins embracing a fructosyl are quite rare according to other reports based on similar studies. This study successfully converted furostan saponins into new compounds. PMID- 25497337 TI - Structural identification of 4-benzyl-voglibose hydrochloride monohydrate using NMR and single-crystal X-ray diffraction methods. AB - The chemical structure studies on an important related substance of voglibose have been carried out using NMR spectroscopy and single crystal X-ray crystallography. For the structure identification study, hydrochloride monohydrate of this compound was isolated and purified. Its molecular structure was characterized and analyzed using 1D (1H NMR, 13C NMR, and DEPT) and 2D (1H,1H COSY, HSQC, HMBC, TOCSY, and ROESY) NMR spectra. The signal crystal structure was detected by X-ray crystallography. All results indicated this related substance of voglibose was C17H27NO7.HCl.H2O, 5,6-dideoxy-4-benzyl-5-{[2-hydroxy-1 (hydroxymethyl)ethy]amino}-1-C-(hydroxymethyl)-D-epi-inositol hydrochloride monohydrate. PMID- 25497336 TI - One-pot SSA-catalyzed beta-elimination: an efficient and inexpensive protocol for easy access to the glycal of sialic acid. AB - Neu5Ac2en1Me per-OAc, the fully protected glycal of sialic acid, is a key intermediate in the discovery of therapeutics and diagnostics, including anti influenza drugs and proteolysis resistant peptidomimetic foldamers. The synthesis of this sialic acid derivative, however, still relies on standard sugar chemistry that utilizes multi-step methodologies. Herein we report a facile and highly efficient microwave-assisted preparation of Neu5Ac1Me using silica sulfuric acid (SSA) as solid-supported acid catalyst that is one- to two-orders of magnitude faster than standard procedures. We also describe the microwave-assisted and SSA catalyzed one-pot, rapid, solvent free reaction that combines both peracetylation and beta-elimination reactions in one step to generate the glycal from Neu5Ac1Me. We coined the term One-pot SSA-catalyzed Technology for beta-Elimination Protocol (OneSTEP) to describe this least laborious, most efficient, and practical preparation to date of Neu5Ac2en1Me per-OAc in terms of yield, time, reagent cost, and waste generation. PMID- 25497338 TI - Structural studies of the exopolysaccharide from Lactobacillus plantarum C88 using NMR spectroscopy and the program CASPER. AB - Some lactic acid bacteria, such as those of the Lactobacillus genus, have the ability to produce exopolysaccharides (EPSs) that confer favorable physicochemical properties to food and/or beneficial physiological effects on human health. In particular, the EPS of Lactobacillus plantarum C88 has recently demonstrated in vitro antioxidant activity and, herein, its structure has been investigated using NMR spectroscopy and the computer program CASPER (Computer Assisted Spectrum Evaluation of Regular polysaccharides). The pentasaccharide repeating unit of the O-deacetylated EPS consists of a trisaccharide backbone, >4)-alpha-D-Galp-(1->2)-alpha-D-Glcp-(1->3)-beta-D-Glcp-(1->, with terminal D-Glc and D-Gal residues (1.0 and 0.8 equiv per repeating unit, respectively) extending from O3 and O6, respectively, of the ->4)-alpha-D-Galp-(1-> residue. In the native EPS an O-acetyl group is present, 0.85 equiv per repeating unit, at O2 of the alpha-linked galactose residue; thus the repeating unit of the EPS has the following structure: ->4)[beta-D-Glcp-(1->3)][beta-D-Galp-(1->6)]alpha-D-Galp2Ac (1->2)-alpha-D-Glcp-(1->3)-beta-D-Glcp-(1->. These structural features, and the chain length (~10(3) repeating units on average, determined in a previous study), are expected to play an important role in defining the physicochemical properties of the polymer. PMID- 25497339 TI - Structural investigation of a uronic acid-containing polysaccharide from abalone by graded acid hydrolysis followed by PMP-HPLC-MSn and NMR analysis. AB - A new strategy was applied to elucidate the structure of a polysaccharide from abalone gonad (AGSP). It was hydrolyzed by 0.05 M, 0.2 M, 0.5 M, and 2.0 M TFA at 100 degrees C for 1 h, sequentially. Every hydrolysate was ultrafiltrated (3000 Da) to collect oligo- and monosaccharides, and the final retentate was further hydrolyzed with 2.0 M TFA at 110 degrees C and 121 degrees C for 2 h, respectively. 1-Phenyl-3-methyl-5-pyrazolone (PMP) derivatization followed by HPLC-MSn analysis was applied to detect the sugar residues in these hydrolysates, which allowed proposing their location in the polysaccharide structure. The retentate after 0.5 M TFA hydrolysis was confirmed as the polysaccharide backbone, and it was further analyzed by 1D and 2D NMR spectroscopy. Thus, the structural elucidation of AGSP was accomplished, and it has a backbone of ->4) beta-GlcA(1->2)-alpha-Man(1-> repeating unit with Fuc, Xyl and Gal in the branch. The analytical strategy demonstrated was useful to characterize the structure of polysaccharides. PMID- 25497340 TI - Synthesis and characterization of copolyanhydrides of carbohydrate-based galactaric acid and adipic acid. AB - A series of copolyanhydrides, consisting of 2,3,4,5-tetra-O-acetylgalactaric acid (AGA) and adipic acid (AA) as monomer units, was polymerized. Synthesis of AGA monomer consisted of two steps. First, O-acetylation of galactaric acid secondary hydroxyl groups was performed using acetic anhydride as a reagent. Acetic anhydride was then further used as a reagent in the synthesis of diacetyl mixed anhydride of AGA. Polymerizations were conducted as bulk condensation polymerization at 150 degrees C. Thermal properties of the copolymers varied depending on monomer composition. Increase in the AGA content had a clear increasing effect on the Tg. A similar increasing effect was observed in Tm. The degree of crystallinity decreased as AGA content increased. There was a slightly lowering tendency in the molecular weights of the obtained polymers when the AGA content in the polymerization mixtures increased. The described synthesis route shows that bio-based aldaric acid monomers are potential candidates for the adjustment of thermal properties of polyanhydrides. PMID- 25497341 TI - 20 years of leptin: from the discovery of the leptin gene to leptin in our therapeutic armamentarium. PMID- 25497342 TI - Leptin resistance and diet-induced obesity: central and peripheral actions of leptin. AB - Obesity is a chronic disease that represents one of the most serious global health burdens associated to an excess of body fat resulting from an imbalance between energy intake and expenditure, which is regulated by environmental and genetic interactions. The adipose-derived hormone leptin acts via a specific receptor in the brain to regulate energy balance and body weight, although this protein can also elicit a myriad of actions in peripheral tissues. Obese individuals, rather than be leptin deficient, have in most cases, high levels of circulating leptin. The failure of these high levels to control body weight suggests the presence of a resistance process to the hormone that could be partly responsible of disturbances on body weight regulation. Furthermore, leptin resistance can impair physiological peripheral functions of leptin such as lipid and carbohydrate metabolism and nutrient intestinal utilization. The present document summarizes those findings regarding leptin resistance development and the role of this hormone in the development and maintenance of an obese state. Thus, we focused on the effect of the impaired leptin action on adipose tissue, liver, skeletal muscle and intestinal function and the accompanying relationships with diet-induced obesity. The involvement of some inflammatory mediators implicated in the development of obesity and their roles in leptin resistance development are also discussed. PMID- 25497344 TI - From leptin to other adipokines in health and disease: facts and expectations at the beginning of the 21st century. AB - This year marks the 20th anniversary of the discovery of leptin, which has tremendously stimulated translational obesity research. The discovery of leptin has led to realizations that have established adipose tissue as an endocrine organ, secreting bioactive molecules including hormones now termed adipokines. Through adipokines, the adipose tissue influences the regulation of several important physiological functions including but not limited to appetite, satiety, energy expenditure, activity, insulin sensitivity and secretion, glucose and lipid metabolism, fat distribution, endothelial function, hemostasis, blood pressure, neuroendocrine regulation, and function of the immune system. Adipokines have a great potential for clinical use as potential therapeutics for obesity, obesity related metabolic, cardiovascular and other diseases. After 20 years of intense research efforts, recombinant leptin and the leptin analog metreleptin are already available for the treatment of congenital leptin deficiency and lipodystrophy. Other adipokines are also emerging as promising candidates for urgently needed novel pharmacological treatment strategies not only in obesity but also other disease states associated with and influenced by adipose tissue size and activity. In addition, prediction of reduced type 2 diabetes risk by high circulating adiponectin concentrations suggests that adipokines have the potential to be used as biomarkers for individual treatment success and disease progression, to monitor clinical responses and to identify non-responders to anti-obesity interventions. With the growing number of adipokines there is an increasing need to define their function, molecular targets and translational potential for the treatment of obesity and other diseases. In this review we present research data on adipose tissue secreted hormones, the discovery of which followed the discovery of leptin 20 years ago pointing to future research directions to unravel mechanisms of action for adipokines. PMID- 25497345 TI - Structural characterization of the catalytic site of a Nilaparvata lugens delta class glutathione transferase. AB - Glutathione transferases (GSTs) are a major class of detoxification enzymes that play a central role in the defense against environmental toxicants and oxidative stress. Here, we studied the crystal structure of a delta-class glutathione transferase from Nilaparvata lugens, nlGSTD, to gain insights into its catalytic mechanism. The structure of nlGSTD in complex with glutathione, determined at a resolution of 1.7A, revealed that it exists as a dimer and its secondary and tertiary structures are similar to those of other delta-class GSTs. Analysis of a complex between nlGSTD and glutathione showed that the bound glutathione was localized to the glutathione-binding site. Site-directed mutagenesis of nlGSTD mutants indicated that amino acid residues Ser11, His52, Glu66, and Phe119 contribute to catalytic activity. PMID- 25497343 TI - The role of leptin in regulating bone metabolism. AB - Leptin was initially best known for its role in energy homeostasis and regulation of energy expenditure. In the past few years we have realized that leptin also plays a major role in neuroendocrine regulation and bone metabolism. Here, we review the literature the indirect and direct pathways through which leptin acts to influence bone metabolism and discuss bone abnormalities related to leptin deficiency in both animal and human studies. The clinical utility of leptin in leptin deficient individuals and its potential to improve metabolic bone disease are also discussed. We are beginning to understand the critical role leptin plays in bone metabolism; future randomized studies are needed to fully assess the potential and risk-benefit of leptin's use in metabolic bone disease particularly in leptin deficient individuals. PMID- 25497346 TI - Alarin in cranial autonomic ganglia of human and rat. AB - Extrinsic and intrinsic sources of the autonomic nervous system contribute to choroidal innervation, thus being responsible for the control of choroidal blood flow, aqueous humor production or intraocular pressure. Neuropeptides are involved in this autonomic control, and amongst those, alarin has been recently introduced. While alarin is present in intrinsic choroidal neurons, it is not clear if these are the only source of neuronal alarin in the choroid. Therefore, we here screened for the presence of alarin in human cranial autonomic ganglia, and also in rat, a species lacking intrinsic choroidal innervation. Cranial autonomic ganglia (i.e., ciliary, CIL; pterygopalatine, PPG; superior cervical, SCG; trigeminal ganglion, TRI) of human and rat were prepared for immunohistochemistry against murine and human alarin, respectively. Additionally, double staining experiments for alarin and choline acetyltransferase (ChAT), tyrosine hydroxilase (TH), substance P (SP) were performed in human and rat ganglia for unequivocal identification of ganglia. For documentation, confocal laser scanning microscopy was used, while quantitative RT-PCR was applied to confirm immunohistochemical data and to detect alarin mRNA expression. In humans, alarin-like immunoreactivity (alarin-LI) was detected in intrinsic neurons and nerve fibers of the choroidal stroma, but was lacking in CIL, PPG, SCG and TRI. In rat, alarin-LI was detected in only a minority of cranial autonomic ganglia (CIL: 3.5%; PPG: 0.4%; SCG: 1.9%; TRI: 1%). qRT-PCR confirmed the low expression level of alarin mRNA in rat ganglia. Since alarin-LI was absent in human cranial autonomic ganglia, and only present in few neurons of rat cranial autonomic ganglia, we consider it of low impact in extrinsic ocular innervation in those species. Nevertheless, it seems important for intrinsic choroidal innervation in humans, where it could serve as intrinsic choroidal marker. PMID- 25497347 TI - Poly(ADP-ribose) polymerases as modulators of mitochondrial activity. AB - Mitochondria are essential in cellular stress responses. Mitochondrial output to environmental stress is a major factor in metabolic adaptation and is regulated by a complex network of energy and nutrient sensing proteins. Activation of poly(ADP-ribose) polymerases (PARPs) has been known to impair mitochondrial function; however, our view of PARP-mediated mitochondrial dysfunction and injury has only recently fundamentally evolved. In this review, we examine our current understanding of PARP-elicited mitochondrial damage, PARP-mediated signal transduction pathways, transcription factors that interact with PARPs and govern mitochondrial biogenesis, as well as mitochondrial diseases that are mediated by PARPs. With PARP activation emerging as a common underlying mechanism in numerous pathologies, a better understanding the role of various PARPs in mitochondrial regulation may help open new therapeutic avenues. PMID- 25497348 TI - Effects of the gut microbiota on bone mass. AB - The gut microbiota (GM), the commensal bacteria living in our intestine, performs numerous useful functions, including modulating host metabolism and immune status. Recent studies demonstrate that the GM is also a regulator of bone mass and it is proposed that the effect of the GM on bone mass is mediated via effects on the immune system, which in turn regulates osteoclastogenesis. Under normal conditions, the skeleton is constantly remodeled by bone-forming osteoblasts (OBs) and bone-resorbing osteoclasts (OCLs), and imbalances in this process may lead to osteoporosis. Here we review current knowledge on the possible role for the GM in the regulation of bone metabolism and propose that the GM might be a novel therapeutic target for osteoporosis and fracture prevention. PMID- 25497349 TI - A decade of norovirus genetic diversity in Belgium. AB - Outbreaks of norovirus-associated gastroenteritis occur during all seasons and in various locations, and are recognized as one of the most common causes of nonbacterial food-borne infections. The molecular epidemiology of norovirus infections has not been well characterized in Belgium. To study the incidence of norovirus infections and the nature of the circulating genotypes, 3080 specimens were collected from patients with acute gastroenteritis between 2004 and 2014. Norovirus was detected with RT-PCR in 554 samples (18%). The circulating strains were genotyped based on the variability in the 5' end of the capsid gene (region C). The GII.4 genotype, which is detected predominantly worldwide, was also the most prevalent genotype in our study (87%). This study shows a high frequency and genetic diversity of norovirus in patients with acute gastroenteritis in health care facilities in Flanders, Belgium. PMID- 25497350 TI - Identification and characterization of regions of difference between the Salmonella Gallinarum biovar Gallinarum and the Salmonella Gallinarum biovar Pullorum genomes. AB - Salmonella Gallinarum is the causative agent of fowl typhoid, a severe septicaemic disease that affects birds of all ages, whereas S. Pullorum causes pullorum disease, a systemic disorder affecting primarily young birds. A proportion of birds with pullorum disease become carriers and are thereby able to transmit S. Pullorum vertically. Although these two pathogens cause distinct diseases, they are otherwise phenotypically and genetically similar. Therefore, the small variations that lead to the differences in virulence must have a genetic basis which currently is unknown. In the present study, we compared the genome sequences of S. Gallinarum (strains: SG287/91 and SG9) and S. Pullorum (strains: SP_CDC, SP_RKS, SP_FCAV, SP_S06) and identified 223 regions of difference (RODs), characterized by indels which were detected by using the software Artemis Comparison Tool. Some of the RODs led to pseudogenes frequently formed by frameshifts and premature stop codons in genes primarily involved in virulence and metabolism. We further verified the presence of some conserved RODs by PCR in 26 isolates of S. Gallinarum and 17 of S. Pullorum in order to extrapolate data analyses from genome comparison to field strains. The variations observed in virulence-related genes of S. Gallinarum and S. Pullorum appear not to be sufficient to explain the differences between the distinct biology of infection of fowl typhoid and pullorum disease. Thus, we suggest that the identified pseudogenes affecting metabolism might play a greater role during infection than previously thought. PMID- 25497351 TI - Molecular epidemiology of noroviruses detected in Nepalese children with acute diarrhea between 2005 and 2011: increase and predominance of minor genotype GII.13. AB - Noroviruses, an important cause of acute gastroenteritis, possess a highly divergent genome which was classified into five genogroups and dozens of genotypes. However, changes in genotype distribution over time were poorly understood, particularly in developing countries. We therefore conducted a molecular epidemiological study which characterized the norovirus strains detected in 4437 Nepalese children with acute diarrhea between November 2005 and January 2011 to gain insight into how their genotypes changed over time. Of the 356 samples positive for noroviruses, 277 (78%) were successfully genotyped into 22 capsid genotypes; GII.4 (n=113), GII.3 (n=38) and GII.13 (n=37) were the majority. Interestingly, GII.13 accounted for only 1.7% (4/230) between 2005 and 2008 (period 1) but increased substantially to 26.2% (33/126) between 2009 and 2011 (period 2). Phylogenetic analysis of the VP1 nucleotide sequences of 35 GII.13 strains indicated that they clustered into two lineages named NPL2008 and NPL2009 to which two period 1 strains and 33 period 2 strains belonged, respectively. Lineage NPL2009 contained GII.13 strains that were detected in a large-scale gastroenteritis outbreak in Germany in 2012. Both Nepalese and German VP1 sequences carried two substitutions, H378N and V394Q, in the putative histo blood group antigen (HBGA)-binding sites. As to the polymerase genotypes of Nepalese strains, the period 1 strains possessed GII.Pm, but the period 2 strains possessed GII.P13, GII.P16, and GII.P21. Together with recent reports on the predominance of GII.P13/GII.13 and GII.P16/GII.13 in India and GII.P16/GII.13 in European countries, this study predicts that genotype GII.13 which was previously regarded as a minor genotype has a potential to become an epidemiologically important genotype. PMID- 25497352 TI - Isolation, molecular and phylogenetic analysis of encephalomyocarditis virus strain GS01 in China. AB - Encephalomyocarditis virus (EMCV) is a small non-enveloped, single-stranded RNA virus. It can infect many host species and cause acute myocarditis and respiratory failure in piglets, reproductive failure in pregnant sows. Diseases caused by EMCV currently affect the swine industry worldwide. In this study, an EMCV strain was isolated from an aborted fetus in western China. It was identified by reverse-transcription polymerase chain reaction (RT-PCR) and genome sequencing. The subsequent results showed that the virus could produce a specific cytopathic effect on BHK-21 cells and could cause severe clinical symptoms and pathological changes in mice. Complete genome sequencing and multiple sequence alignment indicated that the GS01 strain was 79.9-99.9% identical with other isolates worldwide. Phylogenetic analysis showed that EMCV isolates fell into five clusters: lineage 1, 2, 3, 4, and 5 based on the nucleotide sequences of the entire ORF and VP3/VP1 junction, as well as 3D gene. GS01 isolate was grouped into lineage 1. The results of this study confirmed that an EMCV strain GS01 isolated from an aborted pig fetus in western China was fatal to mice and provided new epidemiologic data on EMCV in China. PMID- 25497353 TI - A new member of the Pteropine Orthoreovirus species isolated from fruit bats imported to Italy. AB - A novel member of the Pteropine Orthoreovirus species has been isolated and sequenced for the whole genome from flying foxes (Pteropus vampyrus) imported to Italy from Indonesia. The new isolate named Indonesia/2010 is genetically similar to Melaka virus which has been the first virus of this species to be shown to be responsible for human respiratory disease. Our findings highlight the importance of flying foxes as vectors of potentially zoonotic viruses and the biological hazard that lies in the import of animals from geographical areas that are ecologically diverse from Europe. PMID- 25497354 TI - Impacts of dredged-material disposal on the coastal soft-bottom macrofauna, Saronikos Gulf, Greece. AB - Dredged sediments derived by the low course and estuary of the metropolitan river of Athens (Kifissos River) were dumped every day for 21 months to an open-sea site in the Saronikos Gulf. The spoil-ground and surrounding area was monitored prior, during and post to dumping for 24 months, over 6-month intervals. Dumping significantly changed the granulometry of the pre-existing superficial sediments to finer-grained only in the spoil ground and increased the sediment contamination load (aliphatic, polycyclic aromatic hydrocarbons and heavy metals) throughout the study area. Microtox(r) SPT showed that sediment toxicity levels were high at almost all sampling stations. During dumping, burial of natural soft bottom habitats degraded severely the communities of the spoil-ground resulting in an almost azoic state, as well as significantly declined the species number and abundance of benthic communities in locations up to 3.2 km away from the spoil-ground, due to dispersion of the spoil and smothering. Benthic indices on the surrounding sites were significantly correlated with hydrocarbon concentrations and sediment toxicity levels. Post to dumping, the macrofauna communities of the spoil-ground were still significantly degraded, but the surrounding areas showed patterns of recovery. However, the high concentrations of aliphatic, polycyclic aromatic hydrocarbons and levels of toxicity persisted in the sediments after the ceasing of dumping operations in the study area, implying the ecological hazard imposed on the area. PMID- 25497355 TI - Current irrigation practices in the central United States reduce drought and extreme heat impacts for maize and soybean, but not for wheat. AB - In this study, we assessed the adaptive effects of irrigation on climatic risks for three crops (maize, soybean, and wheat) at the regional scale from 1981 to 2012 in the Central US. Based on yields of 183 counties for maize, 121 for soybean and 101 for wheat, statistical models were developed for irrigated, rainfed and county-level yields. Results show that irrigation has a statistically significant effect on abating detrimental climate impacts, specifically drought and extreme heat, in maize and soybean but not in wheat. On average, irrigation reduces the negative influences of extreme heat by around 7.2% for maize and 5.0% for soybean yields for each additional 10 degree-days above the optimal temperature for each crop. This is approximately two-thirds of the negative effects of extreme heat under rainfed management. The remaining third of the yield reduction is caused by heat damage that cannot be alleviated by irrigation. No significant differences were detected between county yields and irrigated yields for maize and soybean, suggesting that the existing irrigation practices were reasonably efficient. Efforts to mitigate future climate risks for these two crops should focus on improving the heat sensitivity contributing to the yield losses from heat damage. In contrast, the existing irrigation does not improve the resilience of wheat to climate risks. Both increased temperature and drought were critical to wheat production, which was potentially caused by relatively poor irrigation supplies for wheat. Further enhancement of wheat yield may be possible through improved irrigation management. PMID- 25497356 TI - Nitrous oxide emissions from cattle excreta applied to a Scottish grassland: effects of soil and climatic conditions and a nitrification inhibitor. AB - Dung and urine excreted onto grasslands are a major source of nitrous oxide (N2O). These N2O emissions stem from inefficient utilisation of nitrogen (N) ingested by ruminants, and the inability of pasture to utilise the deposited N. Predicted growth in dairy and meat consumption means that there is a requirement to quantify N2O emissions, and investigate emission reduction mechanisms. Three 12 month 'seasonal' experiments were undertaken at Crichton, SW Scotland, where N2O emissions were measured from applications of cattle urine, dung, artificial urine and urine+a nitrification inhibitor (NI), dicyandiamide (DCD). The three application timings were 'spring', 'summer' and 'autumn', representative of early , mid- and late grazing seasons. N2O emissions were measured from static chambers for 12 months. The aim was to quantify emissions from cattle excreta, and determine their dependence on the season of application, and the respective contribution of dung and urine to total excreta emissions. Measurement from NI amended urine was made to assess DCD's potential as an emission mitigation tool. Emissions were compared to the IPCC's default emission factor (EF) of 2% for cattle excreted N. Mean annual cumulative emissions from urine were the highest when applied in summer (5034 g N2O-N ha(-1)), with lower emissions from spring (1903 g N2O-N ha(-1)) and autumn (2014 g N2O-N ha(-1)) application, most likely due to higher temperatures and soil moisture conducive to both nitrification and denitrification in the summer months. Calculated EFs were significantly greater from urine (1.1%) than dung (0.2%) when excreta was applied in summer, and EFs varied with season of application, but in all experiments were lower than the IPCC default of 2%. These results support both lowering and disaggregating this EF into individual EFs for dung and urine. Addition of DCD to urine caused no significant reduction in emissions, suggesting that more research is required into its use as a mitigation option. PMID- 25497357 TI - Hypervolemia increases release of atrial natriuretic peptide and shedding of the endothelial glycocalyx. AB - INTRODUCTION: Acute normovolemic hemodilution (ANH) and volume loading (VL) are standard blood-sparing procedures. However, VL is associated with hypervolemia, which may cause tissue edema, cardiopulmonary complications and a prolonged hospital stay. The body reacts to hypervolemia with release of atrial natriuretic peptide (ANP) from the heart. ANP has been shown to deteriorate the endothelial glycocalyx, a vital part of the vascular permeability barrier. The aim of the present study was to evaluate and compare ANP release and damage to the glycocalyx during ANH and VL. METHODS: ANH or VL with 6% hydroxyethyl starch 130/0.4 was administered prior to elective surgery in patients of good cardiopulmonary health (n =9 in each group). We measured concentrations of ANP in plasma and of three main constituent parts of the glycocalyx (hyaluronan, heparan sulfate and syndecan 1) in serum before and after ANH or VL. Heparan sulfate and syndecan 1 levels in urine were also determined. RESULTS: In contrast to ANH, VL (20 ml/kg) induced a significant release of ANP (approximately +100%, P <0.05) and increased the serum concentration of two glycocalyx constituents, hyaluronan and syndecan 1 (both by about 80%, P <0.05). Elevation of syndecan 1 was also detected in the urine of patients undergoing VL, but no increase was found in patients undergoing ANH. Heparan sulfate levels were not influenced by either procedure. CONCLUSION: These data suggest that hypervolemia increases the release of ANP and causes enhanced shedding of the endothelial glycocalyx. This perturbation must be expected to impair the vascular barrier, implying that VL may not be as safe as generally assumed and that it should be critically evaluated. PMID- 25497358 TI - Focal EEG slowing and chorea: electroclinical clues to the diagnosis of anti NMDAR encephalitis. AB - Variations in clinical presentation can lead to delays in the diagnosis and initiation of treatment of anti-N-methyl-D-aspartate receptor encephalitis. Most patients have an EEG study performed early in the course of their illness. Although not specific, there may be clues in the electroclinical features that should alert clinicians and electroencephalographers to the possibility of this diagnosis. This case is a reminder that anti- anti-N-methyl-D-aspartate receptor encephalitis may present initially with a movement disorder as the sole symptom, without features of an encephalopathy. In addition, it adds to the growing body of evidence that recognition of certain electroclinical clues may shorten the time to diagnosis. [Published with video sequence]. PMID- 25497359 TI - Treatment of motor and behavioural symptoms in three Lesch-Nyhan patients with intrathecal baclofen. AB - Current therapies for the Lesch-Nyhan Syndrome (OMIM: 300322) are off-label and experimental, often leading to inconsistent outcomes. We here report the effects of an intrathecal baclofen therapy, carried out at the Scientific Institute Eugenio Medea (Lecco, Italy), on three patients who no longer received benefit from previous therapies. This treatment, as expected, ameliorated the motor symptoms and, unexpectedly, it also improved behavioural components. This result may involve a functional interaction between baclofen and dopamine, complemented by an anxiolytic effect. Our observations provide the rationale for the use of intrathecal baclofen administration in the therapy of the Lesch-Nyhan Syndrome. PMID- 25497361 TI - Metabolic engineering of antibiotic factories: new tools for antibiotic production in actinomycetes. AB - Actinomycetes are excellent sources for novel bioactive compounds, which serve as potential drug candidates for antibiotics development. While industrial efforts to find and develop novel antimicrobials have been severely reduced during the past two decades, the increasing threat of multidrug-resistant pathogens and the development of new technologies to find and produce such compounds have again attracted interest in this field. Based on improvements in whole-genome sequencing, novel methods have been developed to identify the secondary metabolite biosynthetic gene clusters by genome mining, to clone them, and to express them in heterologous hosts in much higher throughput than before. These technologies now enable metabolic engineering approaches to optimize production yields and to directly manipulate the pathways to generate modified products. PMID- 25497360 TI - Temporal characteristics of melanopsin inputs to the human pupil light reflex. AB - Rods, cones and melanopsin containing intrinsically photosensitive retinal ganglion cells (ipRGCs) operate in concert to regulate pupil diameter. The temporal properties of intrinsic ipRGC signalling are distinct to those of rods and cones, including longer latencies and sustained signalling after light offset. We examined whether the melanopsin mediated post-illumination pupil response (PIPR) and pupil constriction were dependent upon the inter-stimulus interval (ISI) between successive light pulses and the temporal frequency of sinusoidal light stimuli. Melanopsin excitation was altered by variation of stimulus wavelength (464 nm and 638 nm lights) and irradiance (11.4 and 15.2 log photons cm(-2) s(-1)). We found that 6s PIPR amplitude was independent of ISI and temporal frequency for all melanopsin excitation levels, indicating complete summation. In contrast to the PIPR, the maximum pupil constriction increased with increasing ISI with high and low melanopsin excitation, but time to minimum diameter was slower with high melanopsin excitation only. This melanopsin response to briefly presented pulses (16 and 100 ms) slows the temporal response of the maximum pupil constriction. We also demonstrate that high melanopsin excitation attenuates the phasic peak-trough pupil amplitude compared to conditions with low melanopsin excitation, indicating an interaction between inner and outer retinal inputs to the pupil light reflex. We infer that outer retina summation is important for rapidly controlling pupil diameter in response to short timescale fluctuations in illumination and may occur at two potential sites, one that is presynaptic to extrinsic photoreceptor input to ipRGCs, or another within the pupil control pathway if ipRGCs have differential temporal tuning to extrinsic and intrinsic signalling. PMID- 25497363 TI - Educational interventions to improve cytology visual diagnostic reasoning measured by eye tracking. AB - The teaching of visual diagnostic reasoning skills, to date, has been conducted in a largely unstructured apprenticeship manner. The purpose of this study was to assess if the introduction of two educational interventions improved the visual diagnostic reasoning skills of novices. These were (1) the active use of key diagnostic features and (2) image repetition. A pre-test and post-test research design was used to compare the two teaching interventions to a traditional teaching group and an expert group using eye tracking as an assessment method. The time to diagnosis and the percentage of time spent viewing an area of diagnostic interest (AOI) were compared using independent t-tests, paired t tests, and analysis of covariance (ANCOVA). Diagnostic accuracy as a dichotomous variable was compared using Chi-square tables. Students taught in an active learning manner with image repetition behaved most like experts, with no significant difference from experts for percentage of time spent in the AOIs and a significantly faster time to diagnosis than experts (p<.017). Our results from the educational interventions suggest a greater level of improvement in the eye tracking of students that were taught key diagnostic features in an active learning forum and were shown multiple case examples. PMID- 25497364 TI - [Ketoacidosis at time of diagnosis of type 1 diabetes in children and adolescents: effect of a national prevention campaign]. AB - The aim of the study was to evaluate, after the first year of a national information campaign, the effect on the frequency and severity of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes (T1D) in children and adolescents in France. The following data were collected during a 2-year period in people younger than 15 years of age at diagnosis of T1D, in 146 pediatric centers: age, sex, duration of symptoms, patient's previous care, clinical and biological signs, and family history of T1D. DKA was defined as pH<7.30 or bicarbonate<15mmol/L, severe DKA as pH<7.10 or bicarbonate <5mmol/L. During the 2nd year, an information campaign targeting health professionals and families was launched with the objective of reducing the time to diagnosis. Data were compared between the year before the campaign (year 0) and the first year of the campaign (year 1). The number of new cases of T1D was 1299 for year 0 and 1247 for year 1. Between year 0 and year 1, the rate of DKA decreased from 43.9% to 40.5% (P=0.08), exclusively due to the decrease of severe DKA from 14.8 to 11.4% (P=0.01). In the 0- to 5-year-old and 5- to 10-year-old age groups, the relative decrease in the rate of DKA was 13% and 15%, and 23% and 41% for severe DKA, respectively. In patients referred to the hospital by a pediatrician or who came at the family's initiative, the decrease was 34% and 7%, and 39% and 32% for severe DKA, respectively. No change was observed in the 10- to 15-year-old group or in those children who were referred by a general practitioner. In multivariate analyses, a higher DKA rate was associated with the young age of the child (<5 years), being hospitalized at the parents' initiative rather than being referred by a doctor, and the absence of a family history of T1D. A higher rate of severe DKA was associated with these last two factors but not with the child's age. The frequency of DKA at diagnosis of type 1 diabetes remains high in children and adolescents, but the first year of an information campaign decreased it. The results have also helped better define the strategy and targets of the continuing prevention campaign, to more efficiently reduce the morbidity and mortality of T1D at diagnosis in children and adolescents in France. PMID- 25497365 TI - [Emergence of G12 rotavirus diarrhea in childhood in Libreville]. PMID- 25497362 TI - Predictors of change in quality of life in older adults with generalized anxiety disorder. AB - BACKGROUND: Quality of life (QOL) is lower in older adults with generalized anxiety disorder (GAD). QOL generally improves following cognitive-behavioral treatment for GAD. Little is known, however, about additional variables predicting changes in QOL in older adults with GAD. This study examined predictors of change in QOL among older participants in a randomized clinical trial of cognitive behavioral therapy (CBT) for GAD, relative to enhanced usual care (EUC). METHODS: Hierarchical multilevel mixed-model analyses were used to examine inter-individual and intra-individual factors that predicted QOL over time. Predictors were categorized into treatment, personal and clinical characteristics. RESULTS: QOL improved over time, and there was significant variability between participants in change in QOL. Controlling for treatment condition, baseline general self-efficacy, baseline social support, within-person variation in worry and depression and average levels of depression across different time points predicted changes in QOL. CONCLUSIONS: QOL has increasingly been used as an outcome measure in treatment outcome studies to focus on overall improvement in functioning. Attention to improvement in symptoms of depression and worry, along with psychosocial variables, such as social support and self efficacy, may help improve QOL in older adults with GAD. This study was a secondary study of data from a randomized clinical trial (NCT00308724) registered with clinical.trials.gov. PMID- 25497366 TI - [Alveolar capillary dysplasia with misalignment of pulmonary veins: a fatal cause of refractory neonatal cyanosis]. AB - Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare neonatal pathology that combines refractory hypoxemia with severe pulmonary arterial hypertension, and leads to death every time. Histologic examination of lung tissue confirms the diagnosis and is characterized by a decreased number of pulmonary capillaries, immature lobular development, and abnormal proximity between pulmonary arteries and veins. This abnormal proximity is responsible for an arteriovenous shunt. We report five cases confirmed by postmortem histology, which occurred over 14 years in Lower Normandy (France). The cumulative incidence is therefore of 1.8 for 100,000 births. In these five cases, the first symptoms appeared during the first hour of life and death occurred before 24h in four of five cases. The patient with the longest survival had mild histological lesions and delayed emergence of the first symptoms. Genitourinary and gastrointestinal anomalies were associated with ACD/MPV in two cases, and bilateral pulmonary hypoplasia in three cases. Optimized invasive ventilation, pulmonary vasodilators, vasoactive drugs, and pulmonary surfactant did not improve survival. Extracorporeal membrane oxygenation (ECMO) was not used. We present a review of the literature on ACD/MPV, a clinical and histological entity little known to both clinicians and pathologists, whereas a premortem diagnosis is possible and genetic counseling in affected families can be suggested. PMID- 25497367 TI - [Sports-related concussions in youths]. AB - Mild head trauma can be associated with concussion, defined as transient brain function impairment without radiological findings. Sports-related concussion is also reported in pediatrics (rugby, ice hockey, football, boxing, etc.). Misdiagnosis can lead to persistent neurocognitive signs with athletic and academic problems. Consensual tools are available, but they are not well-known by first-line doctors, coaches, and patients or parents. Concussed players should not be allowed to return to the field on the same day. Return to play should be gradual over 3weeks or more. School activities may need to be modified to favor cognitive rest. Prevention is based on risk information and knowledge transfer, rule changes, and protective helmets, whose effectiveness is not always proven. PMID- 25497368 TI - [Skin-to-skin care in the delivery room: impact of SpO2 monitoring]. AB - BACKGROUND: Skin-to-skin care in the delivery room increases mother-newborn bonding, reduces the newborn's stress level, and facilitates breastfeeding. However, a few reports of life-threatening events in newborn infants during skin to-skin care have prompted suggestions that SpO2 monitoring may be of value in the delivery room. The present study compared SpO2 monitoring with standard clinical practices during skin-to-skin care in the delivery room. The midwife's opinion and the mother's anxiety level were assessed for both procedures. MATERIALS AND METHODS: The midwife's opinion was measured on a Likert scale and the mother's anxiety level was measured on the State-Trait Anxiety Inventory Y-A and Y-B scales. Two procedures (standard clinical practice vs. SpO2 monitoring) were compared prospectively in two consecutive 3-month periods. RESULTS: Seventy case report forms were completed for the "standard clinical practice" group and 62 were completed for the "SpO2 monitoring" group. The care procedure was considered to be satisfactory or quite satisfactory in 60 cases (96.8%) in the "SpO2 monitoring" group and in 57 cases (81.4%; P<0.05) in the "standard clinical practice" group. There was no significant difference between the groups in terms of the mean maternal anxiety level. CONCLUSION: SpO2 monitoring during skin-to skin care in the delivery room was well accepted by the midwife. Relative to standard clinical practice alone, SpO2 monitoring was not associated with elevated maternal anxiety levels. PMID- 25497369 TI - Endogenous airway mucins carry glycans that bind Siglec-F and induce eosinophil apoptosis. AB - BACKGROUND: Sialic acid-binding, immunoglobulin-like lectin (Siglec) F is a glycan-binding protein selectively expressed on mouse eosinophils. Its engagement induces apoptosis, suggesting a pathway for ameliorating eosinophilia in the setting of asthma and other eosinophil-associated diseases. Siglec-F recognizes sialylated sulfated glycans in glycan-binding assays, but the identities of endogenous sialoside ligands and their glycoprotein carriers in vivo are unknown. OBJECTIVES: To use mouse lung-derived materials to isolate, biochemically identify, and biologically characterize naturally occurring endogenous glycan ligands for Siglec-F. METHODS: Lungs from normal and mucin-deficient mice, as well as mouse tracheal epithelial cells, were investigated in vitro and in vivo for the expression of Siglec-F ligands. Western blotting and cytochemistry used Siglec-F-Fc as a probe for directed purification, followed by liquid chromatography-tandem mass spectrometry of recognized glycoproteins. Purified components were tested in mouse eosinophil-binding assays and flow cytometry based cell death assays. RESULTS: We detected mouse lung glycoproteins that bound to Siglec-F; binding was sialic acid dependent. Proteomic analysis of Siglec-F binding material identified Muc5b and Muc4. Cross-affinity enrichment and histochemical analysis of lungs from mucin-deficient mice assigned and validated the identity of Muc5b as one glycoprotein ligand for Siglec-F. Purified mucin preparations carried sialylated and sulfated glycans, bound to eosinophils and induced their death in vitro. Mice conditionally deficient in Muc5b displayed exaggerated eosinophilic inflammation in response to intratracheal installation of IL-13. CONCLUSIONS: These data identify a previously unrecognized endogenous anti-inflammatory property of airway mucins by which their glycans can control lung eosinophilia through engagement of Siglec-F. PMID- 25497371 TI - Internucleosomal DNA fragmentation in wild emmer wheat is catalyzed by S1-type endonucleases translocated to the nucleus upon induction of cell death. AB - Leaves of cereal plants display nucleosomal fragmentation of DNA attributed to the action of nucleases induced during program cell death (PCD). Yet, the specific nuclease activity responsible for generating double strand DNA breaks (DSBs) that lead to DNA fragmentation has not been fully described. Here, we characterized a Ca2+/Mg2+-dependent S1-type endonuclease activity in leaves of wild emmer wheat (Triticum dicoccoides Koern.) capable of introducing DSBs as demonstrated by the conversion of supercoiled plasmid DNA into a linear duplex DNA. In-gel nuclease assay revealed a nuclease of about 35 kDa capable of degrading both single stranded DNA and RNA. We further showed that the endonuclease activity can be purified on Concanavalin A and treatment with peptide-N-glycosidase F (PNGase F) did not abolish its activity. Furthermore, ConA-associated endonuclease was capable of generating nucleosomal DNA fragmentation in tobacco nuclei. Since S1-type endonucleases lack canonical nuclear localization signal it was necessary to determine their subcellular localization. To this end, a cDNA encoding for a putative 34 kDa S1-type nuclease, designated TaS1-like (TaS1L) was synthesized based on available sequence data of Triticum aestivum and fused with RFP. Introduction into protoplasts showed that TaS1L-RFP is cytoplasmic 24h post transformation but gradually turn nuclear at 48 h concomitantly with induction of cell death. Our results suggest that DNA fragmentation occurring in leaves of wild emmer wheat may be attributed to S1-type endonuclease(s) that reside in the cytoplasm but translocate to the nucleus upon induction of cell death. PMID- 25497370 TI - Insights into epigenetic regulation of microRNA-155 expression in multiple myeloma. AB - CONTEXT: MiR-155 plays a critical role in the development of B-cell malignancies. Previous studies have shown a deregulation of miR-155 in specific cytogenetic subtypes of multiple myeloma (MM). However, the mechanisms that regulate miR-155 expression in MM are not fully understood. OBJECTIVE: In the present study, we explored the regulation of miRNA-155 in MM by DNA methylation mechanisms and the impact of miR-155 expression in survival of MM patients. METHOD: Primary samples were obtained from 95 patients with newly diagnosed myeloma. Methylation was analyzed by Methylation Specific PCR, sequencing of bisulfite treated DNA and luciferase assay. RESULTS: qRT-PCR analysis revealed that miR-155 was differentially expressed in MM and its upregulation was associated with longer survival. DNA methylation of CpG island present in the first exon of miR-155 host gene was associated with its low expression in MM cell lines and patient samples. Our results showed for the first time that in vitro methylation of part of the promoter and first exon abrogated the miR-155 expression. We further showed that miR-155 expression in MM cell lines was increased by demethylating 5-aza-dC treatment and decreased by RNA-directed DNA methylation. Additionally, we found that LPS "immunological challenge" was insufficient to induce miR-155 expression in MM cell lines with methylated DNA around transcription start site (TSS). CONCLUSION: This study provides evidence that DNA methylation contributes to miR 155 expression in myeloma cells. Interestingly, the survival data showed an association between miR-155 expression and outcome of MM. PMID- 25497372 TI - Large coronary intramural hematomas: a case series and focused literature review. AB - Isolated spontaneous coronary intramural hematoma is a unique subset of spontaneous coronary artery dissection that is characterized by a hemorrhage limited to the medial-adventitial layers, causing subsequent hematoma formation without visible intimal flaps. It is an infrequent and serious coronary vessel wall pathology, with poorly understood underlying pathogenic mechanisms. Affected individuals may present with a broad spectrum of symptoms ranging from acute coronary syndromes (ACS) to cardiogenic shock or even sudden cardiac death. The disease entity causes challenges in terms of both diagnostics and treatment strategy. Coronary intramural hematomas can also occur iatrogenically, as a complication to percutaneous coronary intervention (PCI). Coronary angiography (CAG) has limited diagnostic value in the absence of intimal dissections, and lesions are often angiographically ambiguous. Intravascular ultrasound (IVUS) is an important diagnostic tool in establishing the correct diagnosis, as it provides a complete vessel wall assessment, and enables morphometric information regarding the magnitude and severity of the underlying hematoma. Due to the rarity of this clinical scenario, no randomized, controlled trials exist to guide treatment, and no consensus regarding management is available. Currently, treatment strategies are based on a case-by-case clinical assessment, and experiences described in previous, limited retrospective studies and case reports. PMID- 25497374 TI - Tormentic acid reduces inflammation in BV-2 microglia by activating the liver X receptor alpha. AB - Tormentic acid (TA) has been reported to have anticancer, anti-inflammatory and anti-atherogenic properties. However, the effects of TA on neuroinflammation have not been reported. In this study, we investigated whether TA inhibited lipopolysaccharide (LPS)-induced inflammatory response in BV2 microglia cells. BV2 microglia cells were treated with TA for 1h before exposure to LPS. The expression of inducible nitric oxide synthase (iNOS), Cyclooxygenase-2 (COX-2), Nuclear factor kappaB (NF-kappaB) and liver X receptor alpha (LXRalpha) was detected by western blotting. The expression of cytokines Tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) was detected by enzyme-linked immunosorbent assays (ELISA). Results showed that TA inhibited nitric oxide (NO), prostaglandin E2 (PGE2) production by inhibiting iNOS and COX-2 expression. TA also inhibited LPS-induced inflammatory cytokines TNF-alpha and IL-1beta expression. Furthermore, TA could activate LXRalpha and inhibit LPS-induced NF kappaB activation. Knowdown of LXRalpha reversed the anti-inflammatory effects of TA. In conclusion, our results indicate that TA exerts an anti-inflammatory effect on LPS-stimulated BV2 microglia cells by activating LXRalpha. PMID- 25497373 TI - Prostate volume and implant configuration during 48 hours of temporary prostate brachytherapy: limited effect of oedema. AB - BACKGROUND: In pulsed-dose rate prostate brachytherapy the dose is delivered during 48 hours after implantation, making the treatment sensitive to oedematic effects possibly affecting dose delivery. The aim was to study changes in prostate volume during treatment by analysing catheter configurations on three subsequent scans. METHODS: Prostate expansion was determined for 19 patients from the change in spatial distribution of the implanted catheters, using three CT scans: a planning CT (CT1) and two CTs after 24 and 48 hours (CT2, CT3). An additional 4 patients only received one repeat CT (after 24 hours). The mean radial distance (MRD) of all dwell positions to the geometric centre of all dwell positions used was calculated to evaluate volume changes. From three implanted markers changes in inter-marker distances were assessed. The relative shifts of all dwell positions were determined using catheter- and marker-based registrations. Wilcoxon signed-rank tests were performed to compare the results from the different time points. RESULTS: The MRDs measured on the two repeat CTs were significantly different from CT1. The mean prostate volume change derived from the difference in MRD was +4.3% (range -9.3% to +15.6%) for CT1-CT2 (p < .05) and +4.4% (range -7.5% to +16.3%) for CT1-CT3 (p < .05). These values represented a mean increase of 1.2 cm(3) in the first 24 hours and 1.5 cm(3) in the subsequent 24 hours. There was no clear sign of prostate expansion from the change in inter-marker distance (CT1-CT2: 0.2 +/- 1.8 mm; CT1-CT3: 0.6 +/- 2.2 mm). Catheter configuration remained stable; shifts in catheter positions were largest in the C-C direction: 0 +/- 1.8 mm for CT1-CT2 and 0 +/- 1.4 mm for CT2 CT3. CONCLUSIONS: The volume changes derived from catheter displacements were small and therefore considered clinically insignificant. Implant configuration remains stable during 2 days of treatment, confirming the safety of this technique. PMID- 25497375 TI - Mineralocorticoid receptor haplotype, oral contraceptives and emotional information processing. AB - BACKGROUND: Oral contraceptives (OCs) affect mood in some women and may have more subtle effects on emotional information processing in many more users. Female carriers of mineralocorticoid receptor (MR) haplotype 2 have been shown to be more optimistic and less vulnerable to depression. AIM: To investigate the effects of oral contraceptives on emotional information processing and a possible moderating effect of MR haplotype. METHODS: Cross-sectional study in 85 healthy premenopausal women of West-European descent. RESULTS: We found significant main effects of oral contraceptives on facial expression recognition, emotional memory and decision-making. Furthermore, carriers of MR haplotype 1 or 3 were sensitive to the impact of OCs on the recognition of sad and fearful faces and on emotional memory, whereas MR haplotype 2 carriers were not. LIMITATIONS: Different compounds of OCs were included. No hormonal measures were taken. Most naturally cycling participants were assessed in the luteal phase of their menstrual cycle. CONCLUSIONS: Carriers of MR haplotype 2 may be less sensitive to depressogenic side-effects of OCs. PMID- 25497376 TI - United Kingdom nationwide study of avascular necrosis of the jaws including bisphosphonate-related necrosis. AB - We aimed to record all new patients who presented to departments of oral surgery, oral medicine, and oral and maxillofacial surgery, and to dental hospitals in the UK, with avascular necrosis of the jaws including bisphosphonate-related necrosis (BRONJ) over a 2-year period (1 June 2009-31 May 2011). They were eligible irrespective of age, cause, or coexisting conditions. Data on incidence, clinical characteristics, risk factors, and coexisting conditions were collected. A total of 383 cases were registered: 369 were described as BRONJ, 5 as avascular necrosis, and 9 were unknown. Bisphosphonates had been given orally in 207 (56%), intravenously in 125 (34%), both orally and intravenously in 27 (7%), and was unknown in 9 (2%); one had been given denosumab. The main risk factor was dental extraction, and the mandible was commonly affected. The median duration of administration until onset of BRONJ was 3 years in those treated intravenously and 4 years in those treated orally. Levels of engagement with the study varied between regions, and extrapolation from the 2 most involved (Merseyside and Northern Ireland) found around 8.2-12.8 cases/million/year, which is 508-793 patients/year across the UK. To our knowledge this is one of the first studies to estimate national rates of BRONJ. It confirms that the risk and incidence are low. With changes in trends for antiresorptive bone medication, and increasing numbers of elderly people, it would be useful to repeat the registration in the future. PMID- 25497378 TI - Evaluation of aneurysm-associated wall shear stress related to morphological variations of circle of Willis using a microfluidic device. AB - Although microfluidic systems have been important tools in analytical chemistry, life sciences, and medical research, their application was rather limited for drug-screening and biosensors. Here, we described a microfluidic device consisting of a multilayer micro-channel system that represented the hemodynamic cerebral vascular system. We analyzed wall shear stresses related to aneurysm formation in the circle of Willis (CoW) and their morphological variations using this system. This device was controlled by pneumatic valves, which occluded various major arteries by closing the associated channels. The hemodynamic analysis indicated that higher degrees of shear stress occurred in an anterior communicating artery (ACoA), particularly in the hypoplastic region of the posterior communicating artery (PCoA) and the P1 segment. Furthermore, occlusion of a common carotid artery (CCA) or a middle cerebral artery (MCA) increased the shear stress, whereas occlusion of a vertebral artery (VA) decreased the shear stress. These results indicate that the morphological variation of the CoW may affect aneurysm formation resulting from increased wall shear stress. Therefore, the technique described in this paper provides a novel method to investigate the hemodynamics of complex cerebral vascular systems not accessible from previous clinical studies. PMID- 25497377 TI - Methods for determining hip and lumbosacral joint centers in a seated position from external anatomical landmarks. AB - A global coordinate system (GCS) method is proposed to estimate hip and lumbosacral joint centers (HJC and LSJC) from at least three distances between joint center of interest and target anatomic landmarks (ALs). The distances from HJC and LSJC to relevant pelvis and femur ALs were analyzed with respect to usual pelvis and femur scaling dimensions. Forty six pelves and related pairs of femurs from a same sample of adult specimens were examined. The corresponding regression equations were obtained. These equations can be used to estimate HJC and LSJC in conditions where a very limited number of ALs are available: for example, during seated posture analysis as performed in the automotive industry. Compared to currently existing HJC and LSJC methods from ALs, the proposed method showed better results with an average error less than 11 mm. PMID- 25497379 TI - In vivo strain assessment of the abdominal aortic aneurysm. AB - The only criteria currently used to inform surgical decision for abdominal aortic aneurysms are maximum diameter (>5.5 cm) and rate of growth, even though several studies have identified the need for more specific indicators of risk. Patient specific biomechanical variables likely to affect rupture risk would be a valuable addition to the science of understanding rupture risk and prove to be a life saving benefit for patients. Local deformability of the aorta is related to the local mechanical properties of the wall and may provide indication on the state of weakening of the wall tissue. We propose a 3D image-based approach to compute aortic wall strain maps in vivo. The method is applicable to a variety of imaging modalities that provide sequential images at different phases in the cardiac cycle. We applied the method to a series of abdominal aneurysms imaged using cine-MRI obtaining strain maps at different phases in the cardiac cycle. These maps could be used to evaluate the distensibility of an aneurysm at baseline and at different follow-up times and provide an additional index to clinicians to facilitate decisions on the best course of action for a specific patient. PMID- 25497380 TI - Why should cancer biologists care about tRNAs? tRNA synthesis, mRNA translation and the control of growth. AB - Transfer RNAs (tRNAs) are essential for mRNA translation. They are transcribed in the nucleus by RNA polymerase III and undergo many modifications before contributing to cytoplasmic protein synthesis. In this review I highlight our understanding of how tRNA biology may be linked to the regulation of mRNA translation, growth and tumorigenesis. First, I review how oncogenes and tumour suppressor signalling pathways, such as the PI3 kinase/TORC1, Ras/ERK, Myc, p53 and Rb pathways, regulate Pol III and tRNA synthesis. In several cases, this regulation contributes to cell, tissue and body growth, and has implications for our understanding of tumorigenesis. Second, I highlight some recent work, particularly in model organisms such as yeast and Drosophila, that shows how alterations in tRNA synthesis may be not only necessary, but also sufficient to drive changes in mRNA translation and growth. These effects may arise due to both absolute increases in total tRNA levels, but also changes in the relative levels of tRNAs in the overall pool. Finally, I review some recent studies that have revealed how tRNA modifications (amino acid acylation, base modifications, subcellular shuttling, and cleavage) can be regulated by growth and stress cues to selectively influence mRNA translation. Together these studies emphasize the importance of the regulation of tRNA synthesis and modification as critical control points in protein synthesis and growth. This article is part of a Special Issue entitled: Translation and Cancer. PMID- 25497381 TI - Roles of the translation initiation factor eIF2alpha serine 51 phosphorylation in cancer formation and treatment. AB - Cells respond to various forms of stress by activating anti-proliferative pathways, which allow them to correct the damage caused by stress before re entering proliferation. If the damage, however, is beyond repair, stressed cells are eliminated from the host by undergoing death. The balance between cell survival and death is essential for cancer formation and is determined by several key pathways that impact on different stages of gene expression. In recent years, it has become evident that phosphorylation of the alpha (alpha) subunit of the translation initiation factor eIF2 at serine 51 (eIF2alphaS51P) is an important determinant of cell fate in response to stress. Induction of eIF2alphaS51P is mediated by a family of four kinases namely, HRI, PKR, PERK and GCN2, each of which responds to distinct forms of stress. Increased eIF2alphaS51P results in a global inhibition of protein synthesis but at the same time enhances the translation of select mRNAs encoding for proteins that control cell adaptation to stress. Short-term induction of eIF2alphaS51P has been associated with cell survival whereas long-term induction with cell death. Studies in mouse and human models of cancer have provided compelling evidence that eIF2alphaS51P plays an essential role in stress-induced tumorigenesis. Increased eIF2alphaS51P exhibits cell autonomous as well as immune regulatory effects, which can influence tumor growth and the efficacy of anti-tumor therapies. The findings suggest that eIF2alphaS51P may be of prognostic value and a suitable target for the design and implementation of effective anti-tumor therapies. This article is part of a Special Issue entitled: Translation and Cancer. PMID- 25497382 TI - Epigenetic regulation of p14ARF and p16INK4A expression in cutaneous and uveal melanoma. AB - Inactivation of p14ARF and p16INK4A by epigenetic changes in cutaneous and uveal melanoma has been here investigated. Compared with melanocytes, p14ARF mRNA reduction and p16INK4A inactivation were frequently noticed. No association between p14ARF promoter methylation and mRNA levels was found, whereas aberrant p16INK4A methylation was associated with gene silencing (p<0.001). Comparative analysis within melanomas of different Breslow's thicknesses showed that drastic reductions in p14ARF and p16INK4A expression appeared at the level of thin/intermediate and intermediate/thick transitions. The effects of 5-aza-2' deoxycytidine (5-aza-dC) and suberanilohydroxamic acid (SAHA) on in vivo binding of DNA methyltransferases (DNMTs) and acetyl histone H3/H4 to p14ARF and p16INK4A promoters were tested together with the impact of ectopic expression of p14ARF and p16INK4A on cell proliferation, migration, and invasion. SAHA treatment induced H3 and H4 hyperacetylation at the p14ARF promoter followed by increased p14ARF expression, whereas exposure to 5-aza-dC decreased the recruitment of DNMT1 and DNMT3b at the p16INK4A promoter and reactivated p16INK4A. Studies on promoter-associated di-methyl histone H3 (Lys4) levels ruled out an involvement of this epigenetic trait on p14ARF and p16INK4A expression. The enforced expression of p14ARF or p16INK4A and, even more so, their co-expression, significantly reduced cell proliferation, migration and invasion. Our data pinpoint: i) a frequent impairment of p14ARF and p16INK4A gene expression by epigenetic modifications in melanoma; ii) histone hypoacetylation as the dominant mechanism of p14ARF silencing; and iii) 5' CpG promoter methylation as the major mechanism of p16INK4A gene inactivation. Collectively, our data suggest that selected epi-drugs may be useful in melanoma treatment. PMID- 25497383 TI - Acceptability and feasibility of phone follow-up with a semiquantitative urine pregnancy test after medical abortion in Moldova and Uzbekistan. AB - OBJECTIVE: To evaluate the feasibility and acceptability of phone follow-up with a home semiquantitative pregnancy test and standardized checklist, and compare the alternative method of follow-up with in-clinic follow-up after medical abortion. STUDY DESIGN: Two thousand four hundred women undergoing medical abortion with mifepristone and misoprostol in Moldova and Uzbekistan were randomized to phone or clinic follow-up. All women in the clinic group returned to the clinic 2 weeks later. Women randomized to phone follow-up used a semiquantitative pregnancy test at the initial visit and repeated the test at home 2 weeks later when they also filled out a symptom checklist. Women were called at 2 weeks to review the test results and checklist. Participants who screened "positive" were referred to clinic to verify abortion completion. RESULTS: Most women in the phone group were successfully contacted on the phone (97.6%). Staff were unable to contact one woman in the phone follow-up group, and all women in clinic group returned to the clinic. The ongoing pregnancy rate was similar in both groups (0.4-0.6%), and the semiquantitative pregnancy test identified all ongoing pregnancies in the phone follow-up group. Women in the phone group found the test and checklist easy to use, and most (76.1%) preferred phone follow-up in the future. Overall, 92.8% of women in the phone group did not undergo in-clinic follow-up. CONCLUSION: Phone follow-up with a semiquantitative urine pregnancy test and symptom checklist is a feasible and a highly effective approach in identifying ongoing pregnancy after medical abortion. IMPLICATIONS: The semiquantitative pregnancy test can make home follow-up after medical abortion possible for many women and provide reassurance that ongoing pregnancies will be detected. PMID- 25497384 TI - pERK1/2 immunofluorescence in rat dorsal horn and paraventricular nucleus neurons as a marker for sensitization and inhibition in the pain pathway. AB - The aim of the present study was to investigate whether the phosphorylation of ERK1/2 in the rat lumbar dorsal horn and in the parvocellularis part of the paraventricular nucleus can be used to visualize neuronal activity. pERK1/2 fluorescence-immunohistochemistry is specifically suited to mirror neuronal activity in the pain pathway following an acute noxious stimulation. The rat hind paw was either stimulated by noxious heat or by a sequence of mustard oil and noxious heat. Two and 10 min after the thermal stimulation a 3-4-fold increase in cells with pERK1/2 immunoreactivity was observed in lamina I/II of the L3-L5 dorsal horn. The combination of mustard oil with heat led to a 5-6-fold increase in the pERK1/2 signal. The pERK1/2 immunoreactivity in the parvocellularis part of the paraventricular nucleus increased by 2-fold following the heat stimulus, with no further increase following the sequential mustard oil and heat stimulus. A pretreatment with the opioid analgesic morphine or the NMDA antagonist MK-801 markedly attenuated ERK1/2 phosphorylation in both areas of the pain pathway. The present findings support the concept that the pERK1/2 immunofluorescence signal can be used as a quantitative marker for sensitization or inhibition in the pain pathway at spinal and hypothalamic level. PMID- 25497385 TI - [How I do... laparoscopic management of presumed benign giant ovarian cyst]. PMID- 25497386 TI - [Can caesarean delivery prevent cerebral palsy? Medico-legal implications of a French ecological study]. AB - OBJECTIVE: For a long time, the benefit of a caesarean delivery in the prevention of cerebral palsy (CP) has been put forward, which was based on the assumption that CP is due to asphyxia in more than 50 % of the cases. However, from register based data, this rate has been estimated less than 4 %. The aim of this study was to evaluate whether the rate of caesarean sections for fetal indication was correlated with the prevalence rate of CP in a French county. PATIENTS AND METHODS: This was an ecological study of register-based prevalence estimates of children with CP (postnatal cases excluded) born between 1997 and 2003 in a French county compared with the rates of caesarean section for fetal distress obtained from the maternal and infant protection service of the county. RESULTS: Whilst the rate of caesarean section for fetal indication increased by 44% during the period studied, the prevalence of CP remained nearly stable around 1.5 per 1000 live births. There was no correlation between caesarean section and CP prevalence (r'=-0.36, P=0.43). DISCUSSION AND CONCLUSION: The present study was in accordance with the results of a recent meta-analysis which concluded that emergency and prophylactic caesarean deliveries were not efficient in the prevention of CP. Indication of caesarean delivery for foetal heart rhythm anomaly, which is the most relevant cause for the growing rate of caesarean sections, should be justified by additional examinations in ambivalent cases, in order not to consider it as defensive medicine, which is ethically and therefore juridically blameworthy. PMID- 25497387 TI - The a subunit asymmetry dictates the two opposite rotation directions in the synthesis and hydrolysis of ATP by the mitochondrial ATP synthase. AB - The main and best known role of the mitochondrial ATP synthase is to synthesize ATP by exploiting the transmembrane electrochemical gradient of protons and their downhill movement. However, under different conditions, the same enzyme can also switch to the opposite function of ATP hydrolysis and exploits its energy to pump protons against their gradient and energize the membrane. The change in functionality is linked to the change of direction of rotation of the two matched sectors of this unique complex, namely the hydrophilic F1, which performs the catalysis, and the hydrophobic membrane-embedded FO, which channels protons. Accordingly, viewed from the matrix side, ATP synthesis is driven by counterclockwise rotation and ATP hydrolysis by clockwise rotation of the FO rotor which is transmitted to F1. ATP dissipation through this mechanism features some diseases such as myocardial ischemia. Increasing evidence shoulders the hypothesis that the asymmetry of the a subunit of FO and particularly the steric arrangement of the two inner semi-channels for protons, play a key role in conferring to the coupled bi-functional complex the ability to reverse rotation by switching from ATP synthesis to ATP hydrolysis and vice versa. Accordingly, the conserved steric arrangement of the chiral a subunit of FO yields the same direction of rotation for all the ATP synthases. According to this hypothesis, the a subunit chirality imposes the direction of rotation of the rotor according to the proton gradient across the membrane. It seems likely that the direction of rotation of the membrane-embedded c-ring, which is adjacent to the a-subunit and acts as a rotor, may be under multiple control, being rotation essential to make the whole enzyme machinery work. However, the asymmetric features of the a subunit would make it the master regulator, thus directly determining which of the two functions, ATP production or ATP dissipation, will be performed. The handedness of a subunit should be considered in drug design to counteract tissue damage under all pathological conditions linked to functional impairment of ATP synthase. PMID- 25497388 TI - A gedanken experiment to find a neuroanatomical model for post-traumatic stress disorder. AB - Post-traumatic stress disorder is a persistent stress syndrome in which abnormal brain physiology persists long after cessation of the acute psychological event that causes it. Normal physiological homeostasis depends on equilibria. The basic unit of equilibrium is the negative feedback loop (NFL) and the simplest way to disrupt homeostasis would be to break an NFL. The resulting model requires two nuclei in the brain reciprocally-connected in an NFL, one of which, in response to the perception of overwhelming threats or demands, generates rapid pacemaker firing which leads to excitotoxic cell death in the other. The injured nucleus must also be able to undergo neurogenesis, which would explain clinical recovery. The relevant site of neurogenesis is the hippocampus, which is reciprocally connected with the dorsal raphe nucleus (DRN), a serotonergic pacemaker nucleus which has been shown to light up on PET scan (i.e. undergo burst firing) in response to stress. The model postulates that the DRN delivers an excitotoxic blow to the hippocampus. Then, via a second pathway, it promotes neurogenesis. The model incorporates potential sites of action for several psychoactive drugs, including anti-depressants and lithium, which promote neurogenesis; and valproate and atypical anti-psychotics, which block excitotoxicity. The theory has the advantage of being formulated in terms of how the brain actually works, i.e. through the interaction between pacemakers and processed sensory input from the outside world. It also directs pharmacological thinking to the role played by pacemakers and pacemaker currents. PMID- 25497389 TI - The potential use of cholestyramine to reduce the risk of developing Clostridium difficile-associated diarrhoea in patients receiving long-term intravenous ceftriaxone. AB - Intravenous pharmacotherapy with the third-generation cephalosporin ceftriaxone is unfortunately associated with a relatively high incidence of Clostridium difficile-associated diarrhoea. Cholestyramine (colestyramine) is an anion binding resin which can bind luminal C.difficile toxin A (TcdA) and toxin B (TcdB) and which may be beneficial in the treatment of recurrent antibiotic associated pseudomembranous colitis. We therefore hypothesised that concomitant oral cholestyramine might reduce the risk of C.difficile-associated diarrhoea in patients receiving long-term intravenous ceftriaxone. A pilot study was carried out in which it was found that only three out of 46 (6.5%) such patients being treated with 2 g ceftriaxone daily for Lyme borreliosis, who also received 4 g cholestyramine daily, developed C.difficile-associated diarrhoea. This is smaller than a published report of the incidence of this complication in six out of 26 (23.1%) patients following 1-3 days' treatment with 1 g intravenous ceftriaxone, but without oral cholestyramine (p=0.06). We therefore recommend that a larger, double-blind placebo-controlled trial be carried out to test this hypothesis. PMID- 25497390 TI - Cardiopulmonary resuscitation in pectus excavatum patients: is it time to say more? PMID- 25497391 TI - Ultrasound guided chest compressions during cardiopulmonary resuscitation. PMID- 25497392 TI - Therapeutic hypothermia associated with stent thrombosis: is Kounis mast cell activation-associated syndrome the culprit? PMID- 25497393 TI - A systematic review of the outcomes reported in cardiac arrest clinical trials: the need for a core outcome set. AB - BACKGROUND: There is a limited guidance for outcome reporting for cardiac arrest trials. This review was conducted to explore the degree of variation and identify trends in outcome reporting. METHODS: Randomised controlled trials enrolling patients with cardiac arrest (2002-2012) were identified by applying a search strategy to four databases. Titles, abstracts and short-listed studies were independently assessed for eligibility. Data on the primary and secondary outcome measures, details of outcome reporting and reproducibility were extracted. RESULTS: 61 studies matched the inclusion criteria. There was wide variation in the focus, method and timing of assessment. Outcomes most commonly reported across studies were: survival (85.2%), activities (52.5%), body structure or function (41.0%), and processes of care (26.2%). Over 160 individual outcomes were reported including 39 different reports of survival measures of which 11 were measurements of ROSC (return of spontaneous circulation). Twenty different assessments of activity limitation were reported; only one was patient-reported. Many assessments were poorly defined or non-reproducible. The majority of outcomes were assessed up to hospital discharge (89.3%). There was no one outcome measure that was assessed across all trials. CONCLUSIONS: Outcome reporting in cardiac arrest RCTs lacks consistency and transparency. Guidance for improved outcome reporting is urgently required to reduce this heterogeneity in reporting, improve the quality of assessment in clinical trials, and to support the synthesis of trial data. The results highlight the importance of working towards a core outcome set for cardiac arrest clinical trials to maximise the utility of future research. PMID- 25497395 TI - Resuscitation duty cycle in out-of-hospital cardiac arrest: is 40 the new 50? PMID- 25497394 TI - Racial disparities in outcomes following PEA and asystole in-hospital cardiac arrests. AB - AIM: To define the racial differences present after PEA and asystolic IHCA and explore factors that could contribute to this disparity. METHODS: We analyzed PEA and asystolic IHCA in the Get-With-The-Guidelines-Resuscitation database. Multilevel conditional fixed effects logistic regression models were used to estimate the relationship between race and survival to discharge and return of spontaneous circulation (ROSC), sequentially controlling for hospital, patient demographics, comorbidities, arrest characteristic, process measures, and interventions in place at time of arrest. RESULTS: Among the 561 hospitals, there were 76,835 patients who experienced IHCA with an initial rhythm of PEA or asystole (74.8% white, 25.2% black). Unadjusted ROSC rate was 55.1% for white patients and 54.1% for black patients (unadjusted OR: 0.94 [95% CI, 0.90-0.98], p=0.016). Survival to discharge was 12.8% for white patients and 10.4% for black patients (unadjusted OR: 0.83 [95% CI, 0.78-0.87], p<0.001). After adjusting for temporal trends, patient characteristics, hospital, and arrest characteristics, there remained a difference in survival to discharge (OR: 0.85 [95% CI, 0.79 0.92]) and rate of ROSC (OR: 0.88 [95% CI, 0.84-0.92]). Black patients had a worse mental status at discharge after survival. Rates of DNAR placed after survival from were lower in black patients with a rate of 38.3% compared to 44.5% in white patients (p<0.001). CONCLUSION: Black patients are less likely to experience ROSC and survival to discharge after PEA or asystole IHCA. Individual patient characteristics, event characteristics, and hospital characteristics don't fully explain this disparity. It is possible that disease burden and end-of life preferences contribute to the racial disparity. PMID- 25497396 TI - Personalising nutritional guidance for more effective behaviour change. AB - Improving diet and other lifestyle behaviours has considerable potential for reducing the global burden of non-communicable diseases, promoting better health across the life-course and increasing wellbeing. However, realising this potential will require the development, testing and implementation of much more effective behaviour change interventions than are used conventionally. Evidence based, personalised (or stratified) interventions which incorporate effective behaviour change techniques (BCT) and which are delivered digitally are likely to be an important route to scalable and sustainable interventions. Progress in developing such interventions will depend on the outcomes of research on: (i) the best bases for personalisation of dietary advice; (ii) identification of BCT which are proven to enhance intervention efficacy; (iii) suitable platforms (digital-based tools) for collection of relevant participant characteristics (e.g. socioeconomic information, current diet and lifestyle and dietary preferences) linked with intelligent systems which use those characteristics to offer tailored feedback and advice in a cost-effective and acceptable manner. Future research should focus on such interventions aiming to reduce health inequalities and to improve overall public health. PMID- 25497397 TI - Rotarod training in mice is associated with changes in brain structure observable with multimodal MRI. AB - The brain has been shown to remain structurally plastic even throughout adulthood. However, little is known how motor-skill training affects different MRI modalities in the adult mouse brain. The aim of this study is to investigate whether rotarod training, a simple motor training task taken from the standard test battery, is associated with structural plasticity observable with different MRI modalities in adult C57BL/6 mice. The rotarod is a standard test that taxes motor coordination and balance. We use T2-weighted MRI followed by deformation based morphometry to assess local volume and fractional anisotropy (FA) derived from diffusion MRI to assess microstructure ex-vivo. Using deformation-based morphometry we found that the hippocampus, frontal cortex and amygdala are larger in rotarod-trained mice compared to untrained controls. Surprisingly, the cerebellum and white matter in the corpus callosum underlying the primary motor cortex are smaller after training. We also found that the volume of the motor cortex is positively correlated with better rotarod performance. Diffusion imaging indicates group differences and behavioral correlations with FA, a measure of microstructure. Trained mice have higher FA in the hippocampus. Better rotarod performance is associated with higher FA in the hippocampus and lower FA in the primary visual cortex. This is the first study to reveal the substantial structural reorganization of the adult mouse brain following only a relatively brief period of motor-skill training by using complementary measures of microstructure and volume. PMID- 25497399 TI - Novel valosin containing protein mutation in a Swiss family with hereditary inclusion body myopathy and dementia. PMID- 25497398 TI - How number line estimation skills relate to neural activations in single digit subtraction problems. AB - The Number Line (NL) task requires judging the relative numerical magnitude of a number and estimating its value spatially on a continuous line. Children's skill on this task has been shown to correlate with and predict future mathematical competence. Neurofunctionally, this task has been shown to rely on brain regions involved in numerical processing. However, there is no direct evidence that performance on the NL task is related to brain areas recruited during arithmetical processing and that these areas are domain-specific to numerical processing. In this study, we test whether 8- to 14-year-old's behavioral performance on the NL task is related to fMRI activation during small and large single-digit subtraction problems. Domain-specific areas for numerical processing were independently localized through a numerosity judgment task. Results show a direct relation between NL estimation performance and the amount of the activation in key areas for arithmetical processing. Better NL estimators showed a larger problem size effect than poorer NL estimators in numerical magnitude (i.e., intraparietal sulcus) and visuospatial areas (i.e., posterior superior parietal lobules), marked by less activation for small problems. In addition, the direction of the activation with problem size within the IPS was associated with differences in accuracies for small subtraction problems. This study is the first to show that performance in the NL task, i.e. estimating the spatial position of a number on an interval, correlates with brain activity observed during single digit subtraction problem in regions thought to be involved in numerical magnitude and spatial processes. PMID- 25497400 TI - European Medicines Agency review of ataluren for the treatment of ambulant patients aged 5 years and older with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene. PMID- 25497401 TI - A novel mitochondrial DNA m.7507A>G mutation is only pathogenic at high levels of heteroplasmy. AB - We present a Dutch family with a novel disease-causing mutation in the mitochondrial tRNA(Ser(UCN)) gene, m.7507A>G. The index patient died during the neonatal period due to cardio-respiratory failure and fatal lactic acidosis. A second patient, his cousin, has severe hearing loss necessitating cochlear implants and progressive exercise intolerance. Laboratory investigations of both patients revealed combined deficiencies of the enzyme complexes of the mitochondrial respiratory chain in several tissues. Reduced levels of fully assembled complexes I and IV in fibroblasts by BN-PAGE associated with (near) homoplasmic levels of the m.7507A>G mutation in several tissues and a severe reduction in the steady-state level of mt-tRNA(Ser(UCN)) in fibroblasts were observed. The novel mitochondrial DNA mutation was shown to segregate with disease; several healthy maternal family members showed high heteroplasmy levels (up to 76 +/- 4% in blood and 68 +/- 4% in fibroblasts) which did not lead to any alterations in the activities of the enzyme complexes of the respiratory chain in fibroblasts or clinical signs and symptoms. We hereby conclude that the m.7507A>G mutation causes a heterogeneous clinical phenotype and is only pathogenic at very high levels of mtDNA heteroplasmy. PMID- 25497402 TI - Preventing Opioid Misuse and Potential Abuse: The Nurse's Role in Patient Education. AB - Nurses play a vital role in providing patient education for proper use of opioids. This descriptive study was designed to explore nurses' knowledge of opioids. Nurses in two large urban East Coast medical centers in the United States were invited to participate in the study, and 133 nurses completed the survey in its entirety. Registered nurses' knowledge of and attitudes about opioid use were assessed using a 48-item web-based questionnaire sent via e-mail. Frequencies were computed for all items on the questionnaire. Chi-squared testing was used to analyze data for all questions that fewer than 50% of participants answered correctly. The results of this study revealed a pain management knowledge gap among nurses caring for patients who are receiving opioid analgesics. This gap includes patient assessment; pharmacologic management; use of adjuvant medications; risks of addiction; risks of respiratory depression; and disposal and storage of opioid analgesics. Only 25% of the nurses answered 50% of the survey questions correctly. Demographic variables such as experience working as a nurse and length of time as a nurse did not influence how nurses performed on the questionnaire, nor did educational level. However, nurses who received education on opioids as a separate class of medication answered a higher percentage of questions correctly than those who did not receive education on opioids. The results of this study reveal a knowledge gap and nurses' lack of sufficient information about opioids that may affect their ability to provide effective medication instructions to their patients. PMID- 25497405 TI - Acute cholecystitis in the sick patient. PMID- 25497406 TI - Subjective report of eye fixations during serial search. AB - Humans readily introspect upon their thoughts and their behavior, but how reliable are these subjective reports? In the present study, we explored the consistencies of and differences between the observer's subjective report and actual behavior within a single trial. On each trial of a serial search task, we recorded eye movements and the participants' beliefs of where their eyes moved. The comparison of reported versus real eye movements revealed that subjects successfully reported a subset of their eye movements. Limits in subjective reports stemmed from both the number and the type of eye movements. Furthermore, subjects sometimes reported eye movements they actually never made. A detailed examination of these reports suggests that they could reflect covert shifts of attention during overt serial search. Our data provide quantitative and qualitative measures of observers' subjective reports and reveal experimental effects of visual search that would otherwise be inaccessible. PMID- 25497407 TI - Mmp1a and Mmp1b are not functional orthologs to human MMP1 in cigarette smoke induced lung disease. AB - Matrix Metalloproteinase 1 (MMP1, collagenase-1) expression is implicated in a number of diseased states including emphysema and malignant tumors. The cigarette smoke induced expression of this interstitial collegenase has been studied extensively and its inhibition proposed as a novel therapeutic treatment for tobacco related diseases such as chronic obstructive pulmonary disease (COPD) and lung cancer. However, a limitation in MMP1 research is the inability to take advantage of natural in vivo studies as most research has been performed in vitro or via animal models expressing human forms of the gene due to the lack of a rodent ortholog of MMP1. The present study examines the function of two possible mouse orthologs of human MMP1 known as Mmp1a and Mmp1b. Using genomic sequence analysis and expression analysis of these enzymes, the data demonstrate that neither MMP1a nor MMP1b behave in the same manner as human MMP1 in the presence of cigarette smoke. These findings establish that the two commonly proposed orthologs of MMP1, Mmp1a and Mmp1b, provide substantial limitations for use in examining MMP1 induced lung disease in mouse models of cigarette smoke emphysema. PMID- 25497408 TI - The changing landscape of genetic testing for hereditary breast and ovarian cancer. PMID- 25497409 TI - Hereditary breast and ovarian cancer syndrome: considering the complexities. AB - HBOC is the most common and well-described hereditary breast cancer syndrome and is often at the center of professional recommendations, accreditation standards, and insurance company coverage policies. A person's BRCA gene mutation status may alter their decisions about surgical treatment, eligibility for a clinical trial, and their approach to cancer risk reduction and screening. The potential for knowledge gained from undergoing BRCA gene testing is great, but there are limitations and pitfalls of which patients should be aware before providing informed consent, including the possibility of uncertain or uninformative results, potential for psychological distress, and effect on family members. As such, it is important for clinicians across the health care spectrum to be able to appropriately identify patients at risk of having HBOC, understand the effect that this diagnosis has on their patients with and without cancer, and be able to identify resources to support their patients throughout genetic testing process. PMID- 25497410 TI - Beyond BRCA1 and BRCA2. AB - A hereditary breast cancer syndrome can present in a variety of ways ranging from an index case of early-onset breast cancer to an incidental finding during an endoscopy or a dermatological examination. A comprehensive review of the patient's personal and family history is essential to accurately assess the risk for a hereditary cancer syndrome. Clinicians should be aware of the wide variety of hereditary breast cancer syndromes beyond BRCA1 and BRCA2-associated HBOC. Failure to identify a rare hereditary breast cancer syndrome can lead to additional cancer diagnoses in the patient or relatives that might have been prevented with appropriately aggressive management and screening. Effective identification and management of patients with a hereditary breast cancer syndrome requires a team approach. The use of cancer gene panels, although they can be beneficial in many cases, may also reveal incidental information, unexpected diagnoses, and inconclusive findings. Patients should be offered comprehensive counseling about the potential impact of this type of genetic testing before deciding to pursue a gene panel test. This counseling should include information about the numerous genetic syndromes analyzed. When performed in the context of thorough pretest and posttest counseling, genetic testing is a powerful tool that can aid the patient, his or her family members, and their physicians in making appropriate medical management decisions. PMID- 25497411 TI - Hereditary colorectal cancer: more common than you think. PMID- 25497412 TI - The genetics of endocrine neoplasia. AB - The hereditary endocrine neoplasias are characterized by the development of benign or malignant tumors in more than one endocrine tissue. These tumors typically occur at a younger age than sporadic endocrine tumors and follow an autosomal dominant pattern of inheritance. Because of the age-related penetrance and extreme phenotypic variability both within and between families, clinicians cannot always rely on the family history to make the diagnosis. Recognition of the features of a hereditary endocrine syndrome can allow for appropriate and timely risk assessment, genetic counseling and genetic testing, and identification of at-risk family members who may benefit from early and regular screening. PMID- 25497413 TI - Novel genus-specific broad range primers for the detection of furoviruses, hordeiviruses and rymoviruses and their application in field surveys in South East Australia. AB - A number of viruses from the genera Furovirus, Hordeivirus and Rymovirus are known to infect and damage the four major temperate cereal crops, wheat, barley, sorghum and oats. Currently, there is no active testing in Australia for any of these viruses, which pose a significant biosecurity threat to the phytosanitary status of Australia's grains industry. To address this, broad spectrum PCR assays were developed to target virus species within the genera Furovirus, Hordeivirus and Rymovirus. Five sets of novel genus-specific primers were designed and tested in reverse-transcription polymerase chain reaction assays against a range of virus isolates in plant virus diagnostic laboratories in both Australia and New Zealand. Three of these assays were then chosen to screen samples in a three-year survey of cereal crops in western Victoria, Australia. Of the 8900 cereal plants screened in the survey, all were tested free of furoviruses, hordeiviruses and rymoviruses. To date, there were no published genus-specific primers available for the detection of furoviruses, hordeiviruses and rymoviruses. This study shows for the first time a broad-spectrum molecular test being used in a survey for exotic grain viruses in Australia. Results from this survey provide important evidence of the use of this method to demonstrate the absence of these viruses in Victoria, Australia. The primer pairs reported here are expected to detect a wide range of virus species within the three genera. PMID- 25497415 TI - Expression and evolution of hexamerins from the tobacco hornworm, Manduca sexta, and other Lepidoptera. AB - Hexamerins are large hemolymph-proteins that accumulate during the late larval stages of insects. Hexamerins have emerged from hemocyanin, but have lost the ability to bind oxygen. Hexamerins are mainly considered as storage proteins for non-feeding stages, but may also have other functions, e.g. in cuticle formation, transport and immune response. The genome of the hornworm Manduca sexta harbors six hexamerin genes. Two of them code for arylphorins (Msex2.01690, Msex2.15504) and two genes correspond to a methionine-rich hexamerin (Msex2.10735) and a moderately methionine-rich hexamerin (Msex2.01694), respectively. Two other genes do not correspond to any known hexamerin and distantly resemble the arylphorins (Msex2.01691, Msex2.01693). Five of the six hexamerin genes are clustered within ~45 kb on scaffold 00023, which shows conserved synteny in various lepidopteran genomes. The methionine-rich hexamerin gene is located at a distinct site. M. sexta and other Lepidoptera have lost the riboflavin-binding hexamerin. With the exception of Msex2.01691, which displays low mRNA levels throughout the life cycle, all hexamerins are most highly expressed during pre-wandering phase of the 5th larval instar of M. sexta, supporting their role as storage proteins. Notably, Msex2.01691 is most highly expressed in the brain, suggesting a divergent function. Phylogenetic analyses showed that hexamerin evolution basically follows insect systematics. Lepidoptera display an unparalleled diversity of hexamerins, which exceeds that of other hexapod orders. In contrast to previous analyses, the lepidopteran hexamerins were found monophyletic. Five distinct types of hexamerins have been identified in this order, which differ in terms of amino acid composition and evolutionary history: i. the arylphorins, which are rich in aromatic amino acids (~20% phenylalanine and tyrosine), ii. the distantly related arylphorin-like hexamerins, iii. the methionine-rich hexamerins, iv. the moderately methionine rich hexamerins, and v. the riboflavin binding hexamerins. PMID- 25497416 TI - Introduction to the special issue on chemosignals and reproduction. PMID- 25497414 TI - Comparing viral metagenomics methods using a highly multiplexed human viral pathogens reagent. AB - Unbiased metagenomic sequencing holds significant potential as a diagnostic tool for the simultaneous detection of any previously genetically described viral nucleic acids in clinical samples. Viral genome sequences can also inform on likely phenotypes including drug susceptibility or neutralization serotypes. In this study, different variables of the laboratory methods often used to generate viral metagenomics libraries were compared for their abilities to detect multiple viruses and generate full genome coverage. A biological reagent consisting of 25 different human RNA and DNA viral pathogens was used to estimate the effect of filtration and nuclease digestion, DNA/RNA extraction methods, pre-amplification and the use of different library preparation kits on the detection of viral nucleic acids. Filtration and nuclease treatment led to slight decreases in the percentage of viral sequence reads and number of viruses detected. For nucleic acid extractions silica spin columns improved viral sequence recovery relative to magnetic beads and Trizol extraction. Pre-amplification using random RT-PCR while generating more viral sequence reads resulted in detection of fewer viruses, more overlapping sequences, and lower genome coverage. The ScriptSeq library preparation method retrieved more viruses and a greater fraction of their genomes than the TruSeq and Nextera methods. Viral metagenomics sequencing was able to simultaneously detect up to 22 different viruses in the biological reagent analyzed including all those detected by qPCR. Further optimization will be required for the detection of viruses in biologically more complex samples such as tissues, blood, or feces. PMID- 25497417 TI - Sexually active males prevent the display of seasonal anestrus in female goats. AB - A well-defined season of sexual rest controlled by photoperiod is observed in female sheep and goats during spring and summer, delineating their "anestrous season"; bucks also decrease sexual activity at about the same time. Nutrition and/or socio-sexual stimuli play only secondary roles. However, the presence of sexually active males can reduce the length of seasonal anestrus. Whether it can also completely suppress anestrus has not been investigated. Here we tested this in goats in 3 experiments, using bucks rendered sexually active out of season by exposure to long days. The continuous presence of these males prevented goats to display seasonal anestrus: 12/14 females cycled the year round, vs. 0/13 and 0/11 for females with un-treated bucks or without bucks (experiment 1). When active bucks were removed, females immediately entered anestrus (7/7 stopped ovulating vs. 1/7 if maintained with active bucks; experiment 2). Finally, 7/7 anestrous does with bucks in sexual rest since 1.5months commenced cycling rapidly during mid-anestrous, when these bucks became sexually active following a treatment with artificial long days, vs. 0/7 with un-treated bucks or no bucks (experiment 3). The presence/withdrawal of active bucks had a highly significant effect in the three experiments (P<=0.002). Therefore, the presence of a mating opportunity can completely override the photoperiodic inhibition of reproduction of females throughout the anestrous season. Results suggest that we must re-evaluate the relative contributions of photoperiod vs. other external cues in controlling seasonal reproduction, thus offering new non-pharmaceutical ways for controlling out-of-season reproduction in small ruminants. PMID- 25497418 TI - Cross-reactivity of Nocardia spp. in the fungal (1-3)-beta-d-glucan assay performed on cerebral spinal fluid. AB - Cerebral spinal fluid from a patient affected by a brain abscess caused by Nocardia abscessus gave a positive result for (1-3)-beta-d-glucan (BG) assay, in absence of any fungal infection. This study aimed to assess whether Nocardia spp. show cross-reactivity with BG assay. All Nocardia spp. analyzed provided positive reactions. PMID- 25497419 TI - Antimicrobial treatment and outcomes of critically ill patients with OXA-48like carbapenemase-producing Enterobacteriaceae infections. AB - We report on the clinical characteristics, antimicrobial therapy, and outcomes of 20 critically ill patients with severe OXA-48like infections. Carbapenem-based therapy demonstrated improved survival (odds ratio = 5.0) as compared with non carbapenem therapy. Risk factors for mortality included Acute Physiology and Chronic Health Evaluation III score and length of stay, highlighting the significant influence of comorbidities and severity of underlying illness on outcomes. PMID- 25497420 TI - Characterization of recombinant pectate lyase refolded from inclusion bodies generated in E. coli BL21(DE3). AB - Pectate lyase (EC 4.2.2.2) gene from Bacillus subtilis RCK was cloned and expressed in Escherichia coli to maximize its production. In addition to soluble fraction, bioactive pectate lyase was also obtained from inclusion body aggregates by urea solubilization and refolding under in vitro conditions. Enzyme with specific activity ~3194IU/mg and ~1493IU/mg were obtained from soluble and inclusion bodies (IBs) fraction with recovery of 56% and 74% in terms of activity, respectively. The recombinant enzyme was moderately thermostable (t1/2 60min at 50 degrees C) and optimally active in wider alkaline pH range (7.0 10.5). Interaction of protein with its cofactor CaCl2 was found to stimulate the change in tertiary structure as revealed by near UV CD spectra. Intrinsic tryptophan fluorescence spectra indicated that tryptophan is involved in substrate binding and there might be independent binding of Ca(2+) and polygalacturonic acid to the active site. The recombinant enzyme was found to be capable of degrading pectin and polygalacturonic acid. The work reports novel conditions for refolding to obtain active recombinant pectate lyase from inclusion bodies and elucidates the effect of ligand and substrate binding on protein conformation by circular dichroism (CD) and fluorescence spectrofluorometry. PMID- 25497421 TI - Developmental mechanisms channeling cortical evolution. AB - Increase in the area and neuron number of the cerebral cortex over evolutionary time systematically changes its computational properties. One of the fundamental developmental mechanisms generating the cortex is a conserved rostrocaudal gradient in duration of neuron production, coupled with distinct asymmetries in the patterns of axon extension and synaptogenesis on the same axis. A small set of conserved sensorimotor areas with well-defined thalamic input anchors the rostrocaudal axis. These core mechanisms organize the cortex into two contrasting topographic zones, while systematically amplifying hierarchical organization on the rostrocaudal axis in larger brains. Recent work has shown that variation in 'cognitive control' in multiple species correlates best with absolute brain size, and this may be the behavioral outcome of this progressive organizational change. PMID- 25497422 TI - Sexual risk and healthcare seeking behaviour in young Aboriginal and Torres Strait Islander people in North Queensland. AB - Background Compared with non-Indigenous Australians, Aboriginal and Torres Strait Islander people have higher rates of sexually transmissible infections (STI). The identification of the sexual risk and healthcare seeking behaviours of young Aboriginal and Torres Strait Islander people in a regional Australian setting was sought. METHODS: A cross-sectional survey of 155 young Aboriginal and Torres Strait Islander people (16-24 years) in Townsville was conducted. RESULTS: Most participants (83%) reported ever having had sex, with a median age of 15 years at first sex and a range from 9 to 22 years. While young men reported more sexual partners in the last 12 months than young women, they were also more likely to report condom use at the last casual sex encounter (92% vs 68%, P=0.006). Young women were significantly more likely than young men to report never carrying condoms (35% vs 16%); however, they were more likely to have had STI testing (53% vs 28%, P=0.004). Of those reporting previous STI testing, 29% reported ever being diagnosed with an STI. CONCLUSIONS: The sample of young Aboriginal and Torres Strait Islander people reported an early age at first sex, variable condom use and low uptake of STI testing. The high prevalence of self-reported STI diagnoses indicate a need for opportunistic sexual health education and efforts designed to promote the uptake of STI screening in this group. PMID- 25497423 TI - Sperm sex-sorting and preservation for managing the sex ratio and genetic diversity of the southern white rhinoceros (Ceratotherium simum simum). AB - White rhinoceros ejaculates (n=9) collected by electroejaculation from four males were shipped (10 degrees C, 12h) to develop procedures for the production of chilled and frozen-thawed sex-sorted spermatozoa of adequate quality for artificial insemination (AI). Of all electroejaculate fractions, 39.7% (31/78) exhibited high quality post-collection (>=70% total motility and membrane integrity) and of those, 54.8% (17/31) presented reduced in vitro quality after transport and were retrospectively determined to exhibit urine-contamination (>=21.0MUg creatinine/ml). Of fractions analyzed for creatinine concentration, 69% (44/64) were classified as urine-contaminated. For high quality non contaminated fractions, in vitro parameters (motility, velocity, membrane, acrosome and DNA integrity) of chilled non-sorted and sorted spermatozoa were well-maintained at 5 degrees C up to 54h post-collection, whereby >70% of post transport (non-sorted) or post-sort (sorted) values were retained. By 54h post collection, some motility parameters were higher (P<0.05) for non-sorted spermatozoa (total motility, rapid velocity, average path velocity) whereas all remaining motion parameters as well as membrane, acrosome and DNA integrity were similar between sperm types. In comparison with a straw method, directional freezing resulted in enhanced (P<0.05) motility and velocity of non-sorted and sorted spermatozoa, with comparable overall post-thaw quality between sperm types. High purity enrichment of X-bearing (89+/-6%) or Y-bearing (86+/-3%) spermatozoa was achieved using moderate sorting rates (2540+/-498X-spermatozoa/s; 1800+/-557Y-spermatozoa/s). Collective in vitro characteristics of sorted-chilled or sorted-frozen-thawed spermatozoa derived from high quality electroejaculates indicate acceptable fertility potential for use in AI. PMID- 25497424 TI - Sericin supplementation improves semen freezability of buffalo bulls by minimizing oxidative stress during cryopreservation. AB - The variety of mammalian cells has been successfully cryopreserved by use of the silk protein sericin due to its strong free-radical-scavenging and potent antioxidant activity. The present study was conducted to examine the protective role of sericin on buffalo spermatozoa during cryopreservation. Semen of four breeding bulls was collected twice a week using artificial vagina technique. The ejaculates of four bulls were pooled, divided into five equal fractions, diluted with the extender supplemented with different concentrations of sericin (0, 0.25, 0.5, 1.5 and 2%) and then cryopreserved. Post-thawed motility was objectively assessed by computer assisted sperm analyzer. Sperm plasma membrane integrity was assessed by hypo-osmotic swelling test (HOST). Malondialdehyde (MDA) concentration, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were determined in frozen-thawed extended seminal plasma by spectrophotometry. The extender supplemented with 0.25, 0.5 and 1% sericin resulted in the higher sperm motility and GPx acivity. Furthermore, plasma membrane integrity and SOD activity were found to be higher (P<0.05) in group supplemented with 0.25 and 0.5% sericin (P<0.05). The MDA concentration was found to be significantly lower (P<0.05) in 0.25 and 0.5% sericin treated groups than control and other treated groups. In conclusion, the supplementation of 0.25-0.5% sericin in semen extender improves frozen-thawed semen quality through protecting sperm from oxidative stress. PMID- 25497425 TI - Peak centiles of chlorpyrifos surface-water concentrations in the NAWQA and NASQAN programs. AB - We provide upper bound estimates for peak centiles of surface water chlorpyrifos concentration readings within spatial, temporal, and land-use domains of the United States Geological Survey (USGS) National Water-Quality Assessment (NAWQA) and National Stream Quality Accounting Network (NASQAN) programs. These datasets have large overall sample sizes but variable sampling frequencies and, for chlorpyrifos, extremely high levels of non-detections. Point and interval estimates are provided for the 90th, 95th, 99th, and the 99.9th centiles, given sufficient sample size. Overall upper bound estimates for the NAWQA program over the period 1992-2011 for the 90th, 95th, 99th, and 99.9th centiles are <0.005, 0.0066, 0.0214, and 0.0852 ug/L, respectively. The estimation method is based on a survey sampling approach, finding centiles of pooled data across aggregates of site-years. Although the population quantity estimated by a pooled data centile is not the easily interpretable average of population site-year centiles, we provide strong support that it bounds this average by a combination of theory, comparison of NAWQA aggregate and direct estimates, and using modeled populations. PMID- 25497426 TI - Search for over 2000 current and legacy micropollutants on a wastewater infiltration site with a UPLC-high resolution MS target screening method. AB - A target screening method using ultra high performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) was developed. The method was applied to 14 groundwater and 11 surface water samples of a former wastewater infiltration site, where raw wastewater was applied until 1985 and treated wastewater is applied since 2005. The measured data are compared with mass spectrometric data of over 2000 organic micropollutants (OMPs), including pharmaceuticals, personal care products, pesticides, industrial chemicals and metabolites of these classes. A total number of 151 and 159 OMPs were detected in groundwater and surface water, respectively, of which 12 have not been reported before in these matrices. Among these 12 compounds were 11 pharmaceuticals and one personal care product. The identity of 55 of the detected OMPs (35%) was verified by analysis of standard compounds. Based on the distribution in the study area, two groups of OMPs were clearly distinguished: current OMPs introduced with treated municipal wastewater since 2005 and legacy OMPs originating from infiltration of untreated wastewater until 1985. A third group included OMPs contained in historic as well as in current wastewater. During infiltration, OMPs with molecular mass >500 g/mol and log DOW > 3.9 were preferentially removed. Speciation had a strong impact with cationic OMPs showing high, neutral OMPs medium and anionic OMPs lowest elimination during infiltration. This target screening method proved useful to study a wide range of compounds, even in retrospect and at sites with poorly documented history and with a complex and variable hydrological situation. PMID- 25497427 TI - Direct electrochemical oxidation of ammonia on graphite as a treatment option for stored source-separated urine. AB - Electrolysis can be a viable technology for ammonia removal from source-separated urine. Compared to biological nitrogen removal, electrolysis is more robust and is highly amenable to automation, which makes it especially attractive for on site reactors. In electrolytic wastewater treatment, ammonia is usually removed by indirect oxidation through active chlorine which is produced in-situ at elevated anode potentials. However, the evolution of chlorine can lead to the formation of chlorate, perchlorate, chlorinated organic by-products and chloramines that are toxic. This study focuses on using direct ammonia oxidation on graphite at low anode potentials in order to overcome the formation of toxic by-products. With the aid of cyclic voltammetry, we demonstrated that graphite is active for direct ammonia oxidation without concomitant chlorine formation if the anode potential is between 1.1 and 1.6 V vs. SHE (standard hydrogen electrode). A comparison of potentiostatic bulk electrolysis experiments in synthetic stored urine with and without chloride confirmed that ammonia was removed exclusively by continuous direct oxidation. Direct oxidation required high pH values (pH > 9) because free ammonia was the actual reactant. In real stored urine (pH = 9.0), an ammonia removal rate of 2.9 +/- 0.3 gN.m(-2).d(-1) was achieved and the specific energy demand was 42 Wh.gN(-1) at an anode potential of 1.31 V vs. SHE. The measurements of chlorate and perchlorate as well as selected chlorinated organic by-products confirmed that no chlorinated by-products were formed in real urine. Electrode corrosion through graphite exfoliation was prevented and the surface was not poisoned by intermediate oxidation products. We conclude that direct ammonia oxidation on graphite electrodes is a treatment option for source separated urine with three major advantages: The formation of chlorinated by products is prevented, less energy is consumed than in indirect ammonia oxidation and readily available and cheap graphite can be used as the electrode material. PMID- 25497428 TI - Investigation on thiosulfate-involved organics and nitrogen removal by a sulfur cycle-based biological wastewater treatment process. AB - Thiosulfate, as an intermediate of biological sulfate/sulfite reduction, can significantly improve nitrogen removal potential in a biological sulfur cycle based process, namely the Sulfate reduction-Autotrophic denitrification Nitrification Integrated (SANI((r))) process. However, the related thiosulfate bio-activities coupled with organics and nitrogen removal in wastewater treatment lacked detailed examinations and reports. In this study, S2O3(2-) transformation during biological SO4(2-)/SO3(2-) co-reduction coupled with organics removal as well as S2O3(2-) oxidation coupled with chemolithotrophic denitrification were extensively evaluated under different experimental conditions. Thiosulfate is produced from the co-reduction of sulfate and sulfite through biological pathway at an optimum pH of 7.5 for organics removal. And the produced S2O3(2-) may disproportionate to sulfide and sulfate during both biological S2O3(2-) reduction and oxidation most possibly carried out by Desulfovibrio-like species. Dosing the same amount of nitrate, pH was found to be the more direct factor influencing the denitritation activity than free nitrous acid (FNA) and the optimal pH for denitratation (7.0) and denitritation (8.0) activities were different. Spiking organics significantly improved both denitratation and denitritation activities while minimizing sulfide inhibition of NO3(-) reduction during thiosulfate-based denitrification. These findings in this study can improve the understanding of mechanisms of thiosulfate on organics and nitrogen removal in biological sulfur cycle-based wastewater treatment. PMID- 25497429 TI - Transport of U(VI) through sediments amended with phosphate to induce in situ uranium immobilization. AB - Phosphate amendments can be added to U(VI)-contaminated subsurface environments to promote in situ remediation. The primary objective of this study was to evaluate the impacts of phosphate addition on the transport of U(VI) through contaminated sediments. In batch experiments using sediments (<2 mm size fraction) from a site in Rifle, Colorado, U(VI) only weakly adsorbed due to the dominance of the aqueous speciation by Ca-U(VI)-carbonate complexes. Column experiments with these sediments were performed with flow rates that correspond to a groundwater velocity of 1.1 m/day. In the absence of phosphate, the sediments took up 1.68-1.98 MUg U/g of sediments when the synthetic groundwater influent contained 4 MUM U(VI). When U(VI)-free influents were then introduced with and without phosphate, substantially more uranium was retained within the column when phosphate was present in the influent. Sequential extractions of sediments from the columns revealed that uranium was uniformly distributed along the length of the columns and was primarily in forms that could be extracted by ion exchange and contact with a weak acid. Laser induced fluorescence spectroscopy (LIFS) analysis along with sequential extraction results suggest adsorption as the dominant uranium uptake mechanism. The response of dissolved uranium concentrations to stopped-flow events and the comparison of experimental data with simulations from a simple reactive transport model indicated that uranium adsorption to and desorption from the sediments was not always at local equilibrium. PMID- 25497430 TI - New insight into the aetiology of testicular germ cell tumours. PMID- 25497431 TI - Evaluation and management of greater trochanter pain syndrome. AB - Greater trochanteric pain syndrome is an enigmatic but common cause of lateral hip symptoms in middle-aged active women. The most common manifestation of this syndrome is a degenerative tendinopathy of the hip abductors similar to the intrinsic changes seen with rotator cuff pathology in the shoulder. There are no definitive tests to isolate the underlying pathology and palpation is a non specific means by which to differentiate the source of the pain generator. The physical examination must comprehensively evaluate for a cluster of potential impairments and contributing factors that will need to be addressed to effectively manage the likely functional limitations and activity challenges the syndrome presents to the patient. Compressive forces through increased tension in the iliotibial band should be avoided. Intervention strategies should include education regarding postural avoidance, activity modifications, improvement of lumbopelvic control, and a patient approach to resolving hip joint restrictions and restoring the tensile capabilities of the deep rotators and abductors of the hip. A number of reliable and validated hip-specific self-report outcome tools are available to baseline a patient's status and monitor their progress. Further investigations to identify the epidemiological risk factors, establish effective treatment strategies, and predict prognosis are warranted. PMID- 25497432 TI - How ketamine helps to overcome depression. AB - Genetically modified mice shed new light on how ketamine can target NMDA receptors in the brain to reduce the symptoms of depression. PMID- 25497434 TI - The taste of togetherness. AB - The larvae of fruit flies produce pheromones to control whether they are attracted to others of the same species or whether they avoid members of a different species. PMID- 25497433 TI - Evolved differences in larval social behavior mediated by novel pheromones. AB - Pheromones, chemical signals that convey social information, mediate many insect social behaviors, including navigation and aggregation. Several studies have suggested that behavior during the immature larval stages of Drosophila development is influenced by pheromones, but none of these compounds or the pheromone-receptor neurons that sense them have been identified. Here we report a larval pheromone-signaling pathway. We found that larvae produce two novel long chain fatty acids that are attractive to other larvae. We identified a single larval chemosensory neuron that detects these molecules. Two members of the pickpocket family of DEG/ENaC channel subunits (ppk23 and ppk29) are required to respond to these pheromones. This pheromone system is evolving quickly, since the larval exudates of D. simulans, the sister species of D. melanogaster, are not attractive to other larvae. Our results define a new pheromone signaling system in Drosophila that shares characteristics with pheromone systems in a wide diversity of insects. PMID- 25497435 TI - Incidentally. PMID- 25497436 TI - Surgical education and global health: call to action. PMID- 25497437 TI - Surgical subinternships: bridging the chiasm between medical school and residency: a position paper prepared by the Subcommittee for Surgery Subinternship and the Curriculum Committee of the Association for Surgical Education. AB - BACKGROUND: Surgery subinternship rotations are clinical rotations intended to provide senior medical students with experiential exposure and increased autonomy during the care of surgical patients in clinical settings. Due to the lack of guidelines from national surgical organizations, these rotations remain largely unstructured and unstandardized with wide variability in the goals and experiences they provide for medical students. METHODS: Through synthesis of the literature and by applying an iterative process among members of the subcommittee for surgery subinternship and the curriculum committee of the Association for Surgical Education (ASE) consensus recommendations were established. RECOMMENDATIONS: Five defined domains were identified as essential for establishing surgery subinternship rotations. These are: administrative structure, goals and objectives, curricular elements, instructional methods, and assessment tools. CONCLUSIONS: These recommendations should serve as a blue print for establishing a structured, educationally sound, and rewarding clinical rotation for medical students. Applying these recommendations may also provide educators with opportunities for scholarships and academic advancement. PMID- 25497438 TI - Debriefing 101: training faculty to promote learning in simulation-based training. AB - BACKGROUND: Debriefing is recognized as essential for successful simulation-based training. Unfortunately, its effective use is variable. We developed a train the trainer workshop to teach key evidence-based components of effective debriefing. METHOD: A workshop focusing on best practices for debriefing in surgical simulation-based training was developed for the 2012 Annual Meeting of the Association for Surgical Education. Content emphasized key theoretical concepts related to and evidence-based components of an effective debriefing. Additionally, the workshop incorporated experiential learning via active debriefing following a simulated scenario. RESULTS: Content of the workshop emphasized effective debriefing as the key to learning in simulation-based education. Key elements of debriefing for educators to keep in mind include the following: approach, learning environment, engagement of learners, reaction, reflection, analysis, diagnosis, and application. CONCLUSIONS: Effective debriefing is an essential skill for educators involved in surgical simulation based training. Without it, learning opportunities are missed. Training the trainer in effective debriefing is essential to ensure standardization of practice. PMID- 25497439 TI - Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia. AB - Increasing evidence suggests that the tetracycline antibiotic minocycline has neuroprotective effects and is a potential treatment for schizophrenia. However, the mechanisms of action of minocycline in the CNS remain elusive. The aim of this study was to investigate the effects of minocycline on brain morphology and cerebral perfusion in patients with recent-onset schizophrenia after 12months of a randomized double-blind, placebo-controlled clinical trial of minocycline add on treatment. This study included 24 outpatients with recent-onset schizophrenia randomized for 12months of adjuvant treatment with minocycline (200mg/d) or placebo. MRI (1.5T) and [(99m)Tc]-ECD SPECT brain scans were performed at the end of the 12-month of trial. Between-condition comparisons of SPECT and MRI brain images were performed using statistical parametric mapping and analyzed by voxel based morphometry (VBM). Minocycline adjuvant treatment significantly reduced positive and negative symptoms when compared with placebo. The VBM analysis of MRI scans showed that the patients in the placebo group had significant lower gray matter volumes in the midposterior cingulate cortex and in the precentral gyrus in comparison with the patients in the minocycline group. In addition, a decreased ECD uptake in the minocycline condition was observed in fronto-temporal areas. These results suggest that minocycline may protect against gray matter loss and modulate fronto-temporal areas involved in the pathophysiology of schizophrenia. Furthermore, minocycline add-on treatment may be a potential treatment in the early stages of schizophrenia and may ameliorate clinical deterioration and brain alterations observed in this period. PMID- 25497441 TI - Dysfunctional plasmalogen dynamics in the plasma and platelets of patients with schizophrenia. AB - BACKGROUND: Based upon the concept of a prodromal risk syndrome for first psychosis, intense efforts are being applied to define potential biomarkers of disease onset in schizophrenia. One such tentative biomarker may be plasmalogens, complex structural glycerophospholipids that serve multiple functions in all cells. METHODS: To further investigate this possibility, we undertook a lipidomics analysis of choline and ethanolamine plasmalogens in the plasma and platelets of 23 patients with schizophrenia and 27 age-matched controls. RESULTS: Plasma levels of both choline and ethanolamine plasmalogens were decreased by 23 to 45% in patients with schizophrenia. In platelets, from patients with schizophrenia, ethanolamine plasmalogens also were decreased while choline plasmalogen levels were increased. Levels of docosahexaenoic acid (DHA) were decreased by approximately 30% both in plasma and platelets. CONCLUSIONS: Our results suggest that alterations in lipid transport or lipid remodeling/metabolism of plasmalogens are present in schizophrenia and that changes in the steady-state levels of these complex lipid pools may be involved in altered neuronal function. PMID- 25497442 TI - Brain structure in people at ultra-high risk of psychosis, patients with first episode schizophrenia, and healthy controls: a VBM study. AB - Early intervention research in schizophrenia has suggested that brain structural alterations might be present in subjects at high risk of developing psychosis. The heterogeneity of regional effects of these changes, which is established in schizophrenia, however, has not been explored in prodromal or high-risk populations. We used high-resolution MRI and voxel-based morphometry (VBM8) to analyze grey matter differences in 43 ultra high-risk subjects for psychosis (meeting ARMS criteria, identified through CAARMS interviews), 24 antipsychotic naive first-episode schizophrenia patients and 49 healthy controls (groups matched for age and gender). Compared to healthy controls, resp., first-episode schizophrenia patients had reduced regional grey matter in left prefrontal, insula, right parietal and left temporal cortices, while the high-risk group showed reductions in right middle temporal and left anterior frontal cortices. When dividing the ultra-high-risk group in those with a genetic risk vs. those with attenuated psychotic symptoms, the former showed left anterior frontal, right caudate, as well as a smaller right hippocampus, and amygdala reduction, while the latter subgroup showed right middle temporal cortical reductions (each compared to healthy controls). Our findings in a clinical psychosis high-risk cohort demonstrate variability of brain structural changes according to subgroup and background of elevated risk, suggesting frontal and possibly also hippocampal/amygdala changes in individuals with genetic susceptibility. Heterogeneity of structural brain changes (as seen in schizophrenia) appears evident even at high-risk stage, prior to potential onset of psychosis. PMID- 25497443 TI - Duration of ultrasound-mediated enhanced plasma membrane permeability. AB - Ultrasound (US) induced cavitation can be used to enhance the intracellular delivery of drugs by transiently increasing the cell membrane permeability. The duration of this increased permeability, termed temporal window, has not been fully elucidated. In this study, the temporal window was investigated systematically using an endothelial- and two breast cancer cell lines. Model drug uptake was measured as a function of time after sonication, in the presence of SonoVueTM microbubbles, in HUVEC, MDA-MB-468 and 4T1 cells. In addition, US pressure amplitude was varied in MDA-MB-468 cells to investigate its effect on the temporal window. Cell membrane permeability of HUVEC and MDA-MB-468 cells returned to control level within 1-2 h post-sonication, while 4T1 cells needed over 3h. US pressure affected the number of cells with increased membrane permeability, as well as the temporal window in MDA-MB-468 cells. This study shows that the duration of increased membrane permeability differed between the cell lines and US pressures used here. However, all were consistently in the order of 1-3 h after sonication. PMID- 25497440 TI - California Verbal Learning Test-II performance in schizophrenia as a function of ascertainment strategy: comparing the first and second phases of the Consortium on the Genetics of Schizophrenia (COGS). AB - The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) showed performance deficits in learning and memory on the California Verbal Learning Test, Second Edition (CVLT-II) in individuals with schizophrenia (SZ), compared to healthy comparison subjects (HCS). A question is whether the COGS-1 study, which used a family study design (i.e. studying relatively intact families), yielded "milder" SZ phenotypes than those acquired subsequently in the COGS-2 case-control design that did not recruit unaffected family members. CVLT II performance was compared for the COGS-1 and COGS-2 samples. Analyses focused on learning, recall and recognition variables, with age, gender and education as covariates. Analyses of COGS-2 data explored effects of additional covariates and moderating factors in CVLT-II performance. 324 SZ subjects and 510 HCS had complete CVLT-II and covariate data in COGS-1, while 1356 SZ and 1036 HCS had complete data in COGS-2. Except for recognition memory, analysis of covariance showed significantly worse performance in COGS-2 on all CVLT-II variables for SZ and HCS, and remained significant in the presence of the covariates. Performance in each of the 5 learning trials differed significantly. However, effect sizes comparing cases and controls were comparable across the two studies. COGS-2 analyses confirmed SZ performance deficits despite effects of multiple significant covariates and moderating factors. CVLT-II performance was worse in COGS-2 than in COGS-1 for both the SZ and the HCS in this large cohort, likely due to cohort effects. Demographically corrected data yield a consistent pattern of performance across the two studies in SZ. PMID- 25497444 TI - Biocompatibility of poly(D,L-lactic-co-hydroxymethyl glycolic acid) microspheres after subcutaneous and subcapsular renal injection. AB - Poly(D,L-lactic-co-hydroxymethyl glycolic acid) (PLHMGA) is a biodegradable copolymer with potential as a novel carrier in polymeric drug delivery systems. In this study, the biocompatibility of PLHMGA microspheres (PLHMGA-ms) was investigated both in vitro in three different cell types (PK-84, HK-2 and PTECs) and in vivo at two implantation sites (by subcutaneous and subcapsular renal injection) in rats. Both monodisperse (narrow size distribution) and polydisperse PLHMGA-ms were prepared with volume weight mean diameter of 34 and 17 MUm, respectively. Mono and polydisperse PLHMGA-ms showed good cytocompatibility properties upon 72 h incubation with the cells (100 MUg microspheres/600 MUL/cell line). A mild foreign body reaction was seen shortly after subcutaneous injection (20 mg per pocket) of both mono and polydisperse PLHMGA-ms with the presence of mainly macrophages, few foreign body giant cells and myofibroblasts. This transient inflammatory reaction diminished within 28 days after injection, the time-point at which the microspheres were degraded. The degradation profile is comparable to the in vitro degradation time of the microspheres (i.e., within 35 days) when incubated at 37 degrees C in phosphate buffered saline. Subcapsular renal injection of monodisperse PLHMGA-ms (10 mg) in rats was characterized with similar inflammatory patterns compared to the subcutaneous injection. No cortical damage was observed in the injected kidneys. In conclusion, this study demonstrates that PLHMGA-ms are well tolerated after in vivo injection in rats. This makes them a good candidate for controlled delivery systems of low-molecular weight drugs as well as protein biopharmaceuticals. PMID- 25497445 TI - Effect of male and female body mass index on pregnancy and live birth success after in vitro fertilization. AB - OBJECTIVE: To assess the effects of both male and female body mass index (BMI), individually and combined, on IVF outcomes. DESIGN: Prospective cohort study. SETTING: University fertility center. PATIENT(S): All couples undergoing first fresh IVF cycles, 2005-2010, for whom male and female weight and height information were available (n = 721 couples). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Embryologic parameters, clinical pregnancy, and live birth incidence. RESULT(S): The average male BMI among the study population was 27.5 +/- 4.8 kg/m(2) (range, 17.3-49.3 kg/m(2)), while the average female BMI (n = 721) was 25.2 +/- 5.9 kg/m(2) (range, 16.2-50.7 kg/m(2)). Neither male nor female overweight (25-29.9 kg/m(2)), class I obese (30-34.9 kg/m(2)), or class II/III obese (>=35 kg/m(2)) status was significantly associated with fertilization rate, embryo score, or incidence of pregnancy or live birth compared with normal weight (18.5-24.9 kg/m(2)) status after adjusting for male and female age, partner BMI, and parity. Similar null findings were found between combined couple BMI categories and IVF success. CONCLUSION(S): Our findings support the notion that weight status does not influence fecundity among couples undergoing infertility treatment. Given the limited and conflicting research on BMI and pregnancy success among IVF couples, further research augmented to include other adiposity measures is needed. PMID- 25497446 TI - Adolescent and adult uterine volume and uterine artery Doppler blood flow among subjects treated with bone marrow transplantation or chemotherapy in pediatric age: a case-control study. AB - OBJECTIVE: To compare uterine and ovarian volumes and uterine artery (UA) Doppler blood flow among women who were treated with antineoplastic regimens when pediatric aged versus healthy controls. DESIGN: Case-control study. SETTING: Tertiary obstetric and gynecologic center. PATIENT(S): One hundred twenty-seven women who were treated for childhood cancer with bone marrow transplantation (BMT) and?or chemotherapy and total body irradiation (TBI) and 64 age-matched healthy controls. INTERVENTION(S): Ultrasonographic and clinical evaluations. MAIN OUTCOME MEASURE(S): Uterine and ovarian volume, detection of follicles, and UA pulsatility index (PI). RESULT(S): Median uterus and ovarian volumes were reduced by 64% (95% CI, 56.6-70.6) and 83.6% (95% CI, 79.6-86.7), respectively, among cases compared with controls. Median UA PI among cases was increased by 30.3% (95% CI, 19.6-40.8) compared with controls. Ovarian follicles were identified in 24 (18.9%) of 127 cases and 25 (39%) of 64 controls. Uterine volume was reduced after TBI (percent reduction 81.9%; 95% CI, 71.8-87.8) or busulfan (percentage reduction 67.4%; 95% CI, 58.5-75.6) compared with those who had not received a conditioning regimen (percentage reduction 24.4%; 95% CI, 7.6-38.2). The only factors independently associated with reduced uterine and ovarian volumes compared with controls were TBI, busulfan, and BMT. The worst effect on UA PI resulted from BMT and a diagnosis of hematologic disease. CONCLUSION(S): Bone marrow transplantation as main treatment and TBI and busulfan as conditioning regimens had the worst effect on uterine and ovarian sizes compared with controls. These data should be considered in counseling families on preserving future fertility in children undergoing BMT. PMID- 25497447 TI - Searching for metastases in ovarian tissue before autotransplantation: a tailor made approach. AB - OBJECTIVE: To exclude minimal residual disease in remaining ovarian tissue after harvesting the ovarian cortex for cryopreservation, by means of a tailor-made approach. DESIGN: Retrospective case series. SETTING: Hospital laboratory. PATIENT(S): We evaluated the ovarian and tubal tissue from 47 cancer patients (breast cancer, [non-]Hodgkin lymphoma; osteo-, Ewing, myxoid lipo-, and oropharyngeal synovial sarcoma; cervical, rectal, and esophageal cancer), who had stored ovarian tissue for fertility preservation. INTERVENTION(S): Immunohistochemistry (IHC) with tumor-related antibodies and genetic mutation analysis were performed to detect micrometastases by multiple sectioning at three levels of the paraffin-embedded formalin-fixed material. Molecular assays were performed with the use of tissue between these three levels of sectioning. MAIN OUTCOME MEASURE(S): Detection of micrometastases in ovaries. RESULT(S): We analyzed 847 ovarian slides to detect isolated tumor cells (ITCs) or micrometastases by IHC. In only one case (1/47) were ITCs detected in the fallopian tube. That patient had an intra-abdominal metastatic esophageal carcinoma. Additional DNA analyses of breast and rectal cancer, Ewing sarcoma, and human papilloma virus in cervical patients did not show evidence of micrometastases in the ovarian tissue. CONCLUSION(S): The tailor-made approach consisted of patient-specific tumor markers which were used to search for ovarian micrometastases. We found evidence of metastatic disease within the fallopian tube of a patient with intraperitoneal metastatic esophageal adenocarcinoma. PMID- 25497448 TI - Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. AB - Bidirectional somatic cell-oocyte signaling is essential to create a changing intrafollicular microenvironment that controls primordial follicle growth into a cohort of growing follicles, from which one antral follicle is selected to ovulate a healthy oocyte. Such intercellular communications allow the oocyte to determine its own fate by influencing the intrafollicular microenvironment, which in turn provides the necessary cellular functions for oocyte developmental competence, which is defined as the ability of the oocyte to complete meiosis and undergo fertilization, embryogenesis, and term development. These coordinated somatic cell-oocyte interactions attempt to balance cellular metabolism with energy requirements during folliculogenesis, including changing energy utilization during meiotic resumption. If these cellular mechanisms are perturbed by metabolic disease and/or maternal aging, molecular damage of the oocyte can alter macromolecules, induce mitochondrial mutations, and reduce adenosine triphosphate production, all of which can harm the oocyte. Recent technologies are now exploring transcriptional, translational, and post-translational events within the human follicle with the goal of identifying biomarkers that reliably predict oocyte quality in the clinical setting. PMID- 25497449 TI - Birth weight is associated with inner cell mass grade of blastocysts. AB - OBJECTIVE: To determine the relationship between blastocyst growth parameters and birth weight. DESIGN: Cohort study. SETTING: University-affiliated fertility center. PATIENT(S): In vitro patients who delivered a singleton after a single blastocyst transfer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Birth weight adjusted for gestational age at delivery and gender, with adjusted birth weight examined for association with blastocyst scores and grades. RESULT(S): After standard in vitro fertilization (IVF) and thawed embryo transfers, greater birth weight was associated with a higher inner cell mass grade. The grade of the trophectoderm and stage of the blastocyst did not relate to weight. CONCLUSION(S): Embryonic growth as early as day 5 can predict the progress of fetal development as measured by birth weight. PMID- 25497450 TI - The Great Recession, insurance mandates, and the use of in vitro fertilization services in the United States. AB - OBJECTIVE: To investigate the relationship between economic activities, insurance mandates, and the use of in vitro fertilization (IVF) in the United States. DESIGN: We examined the correlation between the coincident index (a proxy for overall economic conditions) and IVF use at the national level from 2000 to 2011. We then analyzed the relationship at the state level through longitudinal regression models. The base model tested the correlation at the state level. Additional models examined whether this relationship was affected, both separately and jointly, by insurance mandates and the Great Recession. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Direction and magnitude of the relationship between the coincident index and IVF use, and influences of insurance mandates and the Great Recession. RESULT(S): The coincident index was positively correlated with IVF use at the national level (correlation coefficient = 0.89). At the state level, an increase of one unit in the coincident index was associated with an increase of 16 IVF cycles per 1 million women, with a significantly greater increase in IVF use in states with insurance mandates than in states without mandates (27 versus 15 IVF cycles per 1 million women). The Great Recession did not alter the relationship between the coincident index and IVF use. CONCLUSION(S): Our study demonstrates a positive relationship between the economy and IVF use, with greater magnitude in states with insurance mandates. This relationship was not affected by the Great Recession regardless of mandated insurance coverage. PMID- 25497451 TI - The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor. AB - The alpha7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of neurological disorders including chronic pain and inflammatory diseases. Since alpha7 can function as a ligand-gated ion channel, drug development initially focused on ligands that were selective activators of the alpha7 ion channel. However, the best alpha7 drugs for chronic pain and inflammation indications may not be ion channel activators but rather "silent agonists", which bind to the receptor but preferentially induce non-conducting states that modulate signal transduction in non-neuronal cells. One such compound is NS6740. We show that NS6740 selectively induces prolonged desensitization of alpha7 nAChRs. There are two forms of alpha7 desensitization that can be distinguished by their sensitivity to the positive allosteric modulators (PAMs). At high concentrations, NS6740 preferentially induces PAM-insensitive desensitization, which over the course of several minutes reverts to the sensitive form. NS6740 was tested in several pain models after in vivo administration in the mouse. Although it had no effects in acute thermal pain, NS6740 induced significant dose- and time-dependent antinociceptive activity in formalin- and acetic acid-induced nociceptive behaviors as well as in the chronic constrictive nerve injury (CCI) model for neuropathic pain. The antinociceptive activity of NS6740 in these models was alpha7-dependent. In addition, NS6740 administration reversed pain-induced aversion, an important affective component of pain. The time and concentration dependence of the effects were consistent with NS6740 induction of PAM-insensitive non-conducting states, suggesting that signal transduction required for analgesia is accomplished by alpha7 receptors in that conformation. PMID- 25497452 TI - Programmed deep brain stimulation synchronizes VTA gamma band field potential and alleviates depressive-like behavior in rats. AB - Deep brain stimulation (DBS) significantly alleviates symptoms in various neurological disorders. Current research focuses on developing programmed stimulation protocols for customization to individual symptoms. However, the therapeutic mechanism of action of programmed DBS (pDBS) is poorly understood. We previously demonstrated that pDBS in the ventral tegmental area (VTA) normalizes molecular and behavioral abnormalities in the Flinders Sensitive Line (FSL) rat model for depression. Herein, we examined the effect of a short-duration, low frequency DBS template on local field potential (LFP) synchronization patterns along the anterior-posterior axis of the VTA of FSL rats, and correlation of this effect with depressive-like behavior, as compared with non-programmed, continuous low-frequency DBS (npDBS). We used the wavelet phase coherence (WPC) measure for effective representation of time and frequency of LFP patterns, and the forced swim test to measure immobility (despair). Baseline WPC values were lower in FSLs as compared with SD controls, at the low and high gamma frequency range (above 30 Hz). Baseline immobility scores for FSL rats were higher than those of SD rats, while pDBS, and not npDBS, significantly reduced FSL immobility scores to control SD levels, up to day 14. pDBS also significantly increased the change (between baseline and day 14) in WPC values, in beta, low gamma and high gamma frequency ranges. The change in high gamma (60-100 Hz) WPC values correlated with improvement in depressive-like behavior. Our results suggest that programmed DBS of the VTA increases interaction among local neuronal populations, an effect that may underlie the normalization of depressive-like behavior. PMID- 25497453 TI - Comparative biochemical characterization of the monoacylglycerol lipase inhibitor KML29 in brain, spinal cord, liver, spleen, fat and muscle tissue. AB - Monoacylglycerol lipase (MAGL) is part of the endocannabinoid and the prostaglandin signaling system. MAGL degrades the endocannabinoid 2 arachidonoylglycerol (2-AG) into glycerol and arachidonic acid. MAGL-induced arachidonic acid is the primary source for prostaglandin synthesis in the brain. 2-AG mainly induces neuroprotective and anti-inflammatory effects, whereas prostaglandins are related to pro-inflammatory effects inducing neurotoxicity. Therefore, inhibition of MAGL represents a promising target for neurological diseases characterized by inflammation. However, as 2-AG is an agonist for the cannabinoid receptor 1 (CB1), inhibition of MAGL might be associated with unwanted cannabimimetic effects. Here, we show that oral administration of KML29, a highly selective inhibitor of MAGL, induced large and dose-dependent changes in 2-AG levels in vivo in brain and spinal cord of mice. Of note, MAGL inhibition by KML29 induced a decrease in prostaglandin levels in brain and most peripheral tissues but not in the spinal cord. MAGL expression was highest in fat, liver and brain, whereas the cytosolic phospholipase A2 (cPLA2), a further enzyme responsible for arachidonic acid production, was highly expressed in spinal cord, muscle and spleen. In addition, high doses (10 mg/kg) of KML29 induced some cannabimimetic effects in vivo in the tetrad test, including hypothermia, analgesia and hypomotility without induction of cataleptic behavior. In summary, inhibition of MAGL by KML29 represents a promising strategy for targeting the cannabinoid and prostaglandin system of the brain with only a moderate induction of cannabimimetic effects. PMID- 25497454 TI - Short-term inhibition of 11beta-hydroxysteroid dehydrogenase type 1 reversibly improves spatial memory but persistently impairs contextual fear memory in aged mice. AB - High glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11beta-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11beta-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design. Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11beta-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals. PMID- 25497455 TI - A flexible reporter system for direct observation and isolation of cancer stem cells. AB - Many tumors are hierarchically organized with a minority cell population that has stem-like properties and enhanced ability to initiate tumorigenesis and drive therapeutic relapse. These cancer stem cells (CSCs) are typically identified by complex combinations of cell-surface markers that differ among tumor types. Here, we developed a flexible lentiviral-based reporter system that allows direct visualization of CSCs based on functional properties. The reporter responds to the core stem cell transcription factors OCT4 and SOX2, with further selectivity and kinetic resolution coming from use of a proteasome-targeting degron. Cancer cells marked by this reporter have the expected properties of self-renewal, generation of heterogeneous offspring, high tumor- and metastasis-initiating activity, and resistance to chemotherapeutics. With this approach, the spatial distribution of CSCs can be assessed in settings that retain microenvironmental and structural cues, and CSC plasticity and response to therapeutics can be monitored in real time. PMID- 25497457 TI - Clinical trials in uremia-time to reappraise. AB - The construct of any road map of the progress of medical knowledge reveals a long and tortuous road, full of errors, misapprehensions, blind alleys, and a perpetual shuffling between authority, heresy, and reason; but one of continuous growth and steady progress, albeit at variable pace and achievement at different periods of history. Numerous factors account for this cumulative progress, notable among which are the transmission, scientification, and mathematization of medical knowledge that ultimately account for the progressive evolution of medical care over time, from its primitive beginnings in antiquity to its present sophisticated state of accomplishment. It was the mathematical precision provided by quantification and statistical analysis that established certainty in medicine and ultimately changed the conjectural art of clinical practice to a disciplined science founded on clinical investigation, especially in therapeutics. Randomized clinical trials (RCTs) introduced in the 1950s have since been instrumental in establishing certainty in the practice of medicine. Regrettably, the proliferation of RCTs driven by biased hypotheses and pharmaceutical-industrial interests have created serious flaws in the results of the onslaught of new RCTs that need to be reappraised. Another unfortunate trade-off during this evolution has been neglect of the individual patient's inborn biological variation from the norm, mean, or median, an omission that has come to erode the personal in medical care. PMID- 25497456 TI - C-MYC transcriptionally amplifies SOX2 target genes to regulate self-renewal in multipotent otic progenitor cells. AB - Sensorineural hearing loss is caused by the loss of sensory hair cells and neurons of the inner ear. Once lost, these cell types are not replaced. Two genes expressed in the developing inner ear are c-Myc and Sox2. We created immortalized multipotent otic progenitor (iMOP) cells, a fate-restricted cell type, by transient expression of C-MYC in SOX2-expressing otic progenitor cells. This activated the endogenous C-MYC and amplified existing SOX2-dependent transcripts to promote self-renewal. RNA-seq and ChIP-seq analyses revealed that C-MYC and SOX2 occupy over 85% of the same promoters. C-MYC and SOX2 target genes include cyclin-dependent kinases that regulate cell-cycle progression. iMOP cells continually divide but retain the ability to differentiate into functional hair cells and neurons. We propose that SOX2 and C-MYC regulate cell-cycle progression of these cells and that downregulation of C-MYC expression after growth factor withdrawal serves as a molecular switch for differentiation. PMID- 25497458 TI - Carbapenem-resistant Enterobacteriaceae and the correlation between carbapenem and fluoroquinolone usage and resistance in the US military health system. AB - Whether carbapenem or fluoroquinolone usage is correlated with carbapenem resistant Enterobacteriaceae (CRE) has not been investigated at the level of an entire US nationwide managed health care system. We analyzed 75 million person years of surveillance and 1,969,315 cultures from all 266 hospitals in the geographically dispersed US military health system. Incidences of CRE remained under 1 case per 100,000 person-years. Incidences of CRE increased relative to 2005 baseline levels in 3 of 7 subsequent years, then decreased in 2012 (P<0.05). Incident proportions of carbapenem resistance (CR) differed significantly among years, geographical regions, and bacterial species. Although use and resistance strongly correlated (R>0.80) for several "drug-bug" combinations, none were significant at the national or facility level. One exception was that inpatient consumption of fluoroquinolones was significantly correlated (P=0.0007) with CR in Escherichia coli when data from the major referral centers of the Southern and Northern regions were combined. PMID- 25497459 TI - Evaluation of pooled ocular and vaginal swabs by the Cepheid GeneXpert CT/NG assay for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae compared to the GenProbe Aptima Combo 2 Assay. AB - Ocular swabs from Tanzania were tested for Chlamydia trachomatis (CT), and self collected vaginal swabs collected through a home collection program, iwantthekit.org, were tested for Neisseria gonorrhoeae and CT to evaluate Cepheid GeneXpert for the use of pooling multiple specimens before testing. GeneXpert shows to be a promising test for pooling. PMID- 25497460 TI - Epidemiology and antibiotic susceptibility of aerococci in urinary cultures. AB - In this study, we present population-based data regarding the prevalence of aerococci in clinical urinary samples. During a 3-month period, all aerococcal isolates from urinary samples from 2 clinical microbiology laboratories were collected. We identified 64 Aerococcus urinae isolates and 40 Aerococcus sanguinicola isolates, which correlates with an incidence of 33 cases of aerococcal bacteriuria per 100,000 inhabitants per year. The median age was 83years for all patients with aerococcal bacteriuria, which was significantly higher than for patients with Escherichia coli or Enterococcus faecalis bacteriuria. Sex was almost equally distributed between men and women with aerococcal bacteriuria, whereas females dominated in E. coli bacteriuria. The aerococcal isolates displayed low MICs for ampicillin, cefalotin, mecillinam, and nitrofurantoin. Most A. sanguinicola isolates were resistant to ciprofloxacin, whereas most A. urinae isolates had low MICs. Clinical studies are needed to establish clinical breakpoints and optimal treatment. PMID- 25497461 TI - Visual scanning and recognition of Chinese, Caucasian, and racially ambiguous faces: contributions from bottom-up facial physiognomic information and top-down knowledge of racial categories. AB - Recent studies have shown that participants use different eye movement strategies when scanning own- and other-race faces. However, it is unclear (1) whether this effect is related to face recognition performance, and (2) to what extent this effect is influenced by top-down or bottom-up facial information. In the present study, Chinese participants performed a face recognition task with Chinese, Caucasian, and racially ambiguous faces. For the racially ambiguous faces, we led participants to believe that they were viewing either own-race Chinese faces or other-race Caucasian faces. Results showed that (1) Chinese participants scanned the nose of the true Chinese faces more than that of the true Caucasian faces, whereas they scanned the eyes of the Caucasian faces more than those of the Chinese faces; (2) they scanned the eyes, nose, and mouth equally for the ambiguous faces in the Chinese condition compared with those in the Caucasian condition; (3) when recognizing the true Chinese target faces, but not the true target Caucasian faces, the greater the fixation proportion on the nose, the faster the participants correctly recognized these faces. The same was true when racially ambiguous face stimuli were thought to be Chinese faces. These results provide the first evidence to show that (1) visual scanning patterns of faces are related to own-race face recognition response time, and (2) it is bottom-up facial physiognomic information that mainly contributes to face scanning. However, top-down knowledge of racial categories can influence the relationship between face scanning patterns and recognition response time. PMID- 25497462 TI - [Analysis of the medical prescription in institutionalised patients]. AB - OBJECTIVES: To evaluate/assess the therapeutic concordance/agreement with prescribed medication in patients institutionalized diagnoses in two periods of time as well as the characteristics of this prescription. MATERIAL AND METHODS: Observational and descriptive study. Prescribing and clinical diagnoses of institutionalized patients were analyzed. These patients were treated by the same physicians during the period of time with a one-year interval (2010-2011), offering prescribing information in this period. RESULTS: A total of 81 patients (78% women), mean age 84+/-7 years, and 5+/-2 diagnoses per patient. The number of drugs per patient was more than 8 in the 2 periods, being higher in 2011 compared to 2010. From all the prescription, we found that 8.88% in 2010 and 9.3% in 2011 are included as "limited clinical value" drugs. In 2010, it sees a concordance of 86.71+/-13.75 against 87.17+/-14.58 in 2011, it means, 87% of patients are treated with drugs in agreement with their diagnoses, representing an increase of 0.47 in 2011 regarding 2010. No statistically significant differences between the 2 years. CONCLUSIONS: The prescriptions in institutionalized patients are very high and the number of drugs per patient increased after information. When we analyzed prescriptions we underline a high percentage of drugs included in the group of limited clinical value (citicoline). A significant percentage of prescriptions don't correspond with diagnoses avaiable in their clinical history. PMID- 25497464 TI - Theoretical evaluation of wall teichoic acids in the cavitation-mediated pores formation in Gram-positive bacteria subjected to an electric field. AB - BACKGROUND: Electroporation is a method of choice to transform living cells. The ability of electroporation to transfer small or large chemicals across the lipid bilayer membrane of eukaryotic cells or Gram-negative bacteria relies on the formation of transient pores across the membrane. To exist, these pores rely on an insulator (the bilayer membrane) and the presence of a potential difference on either side of the membrane mediated by an external electric field. In Gram positive bacteria, however, the wall is not an insulator but pores can still form when an electric field is applied. Past works have shown that the electrostatic charge of teichoic acids, a major wall component; sensitizes the wall to pore formation when an external electric field is applied. These results suggest that teichoic acids mediate the formation of defects in the wall of Gram-positive bacteria. METHODS: We model the electrostatic repulsion between teichoic acids embedded in the bacterial wall composed of peptidoglycan when an electric field is applied. The repulsion between teichoic acids gives rise to a stress pressure that is able to rupture the wall when a threshold value has been reached. The size of such small defects can diverge leading to the formation of pores. RESULTS: It is demonstrated herein that for a bonding energy of about ~1-10 k(B)T between peptidoglycan monomers an intra-wall pressure of about ~5-120 k(B)T/nm(3) generates spherical defects of radius ~0.1-1 nm diverging in size to create pores. CONCLUSION: The electrostatic cavitation of the bacterial wall theory has the potential to highlight the role of teichoic acids in the formation pores, providing a new step in the understanding of electroporation in Gram-positive bacteria without requiring the use of an insulator. PMID- 25497463 TI - Free-living ciliates from epiphytic tank bromeliads in Mexico. AB - The ciliate diversity of Mexican bromeliads is poorly known. We studied the ciliate community of two species of epiphytic tank bromeliads from 48 individuals of Tillandsia heterophylla and four of T. prodigiosa. The bromeliads occurred on over 22 tree host species. Samples were collected during 2009 and 2010 in a mountain cloud forest and in two coffee plantations and in a pine-oak forest. The ciliates were identified in live and protargol preparations. We recorded 61 ciliate species distributed in 39 genera grouped in eight classes. Ten species were frequent in the 52 samples (20 +/- 3.2) and Leptopharynx bromeliophilus was the most frequent recorded in 25 samples. Thirty-three species are new for the fauna of Mexico, 24 species have been recorded for the first time in tank bromeliads. The classes Spirotrichea, Oligohymenophorea and Colpodea presented the highest number of species, 16, 14, and 12, respectively. Colpoda was the most species-rich genus being present with six species. A low similarity between areas and seasons was obtained with Jaccard's index. We conclude that the two bromeliads species host a rich ciliate diversity whose knowledge contributes to the question of ciliate distribution and specifically, in tank bromeliads. PMID- 25497466 TI - Relationship between semen production and medical comorbidity. AB - OBJECTIVE: To study the relationship between semen quality and current health status in a cohort of men evaluated for infertility. DESIGN: Cross-sectional study. SETTING: Fertility clinic. PATIENT(S): Nine thousand three hundred eighty seven men evaluated for infertility between 1994 and 2011. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Charlson comorbidity index, medical diagnoses by organ system. RESULT(S): At the time of evaluation, 9,387 men with a mean age of 38 years had semen data available. Of these men, 44% had at least one medical diagnosis unrelated to infertility. When stratifying the cohort by the Charlson comorbidity index (CCI), differences in all measured semen parameters were identified. Men with a higher CCI had lower semen volume, concentration, motility, total sperm count, and morphology scores. In addition, men with diseases of the endocrine, circulatory, genitourinary, and skin diseases all showed significantly higher rates of semen abnormalities. Upon closer examination of diseases of the circulatory system, men with hypertensive disease, peripheral vascular and cerebrovascular disease, and nonischemic heart disease all displayed higher rates of semen abnormalities. CONCLUSION(S): The current report identified a relationship between medical comorbidites and male semen production. Although genetics help guide a man's sperm production, his current condition and health play an important role. PMID- 25497467 TI - First reported case of sextuplets conceived via letrozole for ovulation induction. AB - OBJECTIVE: To report the first case of sextuplets conceived via letrozole during ovulation induction. DESIGN: Case report. SETTING: Private fertility clinic. PATIENT(S): A 32-year-old female with a history of secondary infertility and polycystic ovary syndrome. INTERVENTION(S): Letrozole, 7.5 mg, on cycle days 3-7 after a progesterone-induced menses. MAIN OUTCOME MEASURE(S): Clinical pregnancy. RESULT(S): Sexchorionic-sexamniotic pregnancy. CONCLUSION(S): High-order multiple gestations are possible with letrozole ovulation induction, so patients should be counseled appropriately and follicle monitoring considered. PMID- 25497468 TI - Variation in response to short-term antidepressant treatment between patients with continuous and non-continuous cycling bipolar disorders. AB - OBJECTIVES: The study aimed to compare effectiveness and safety of short-term antidepressant treatment between patients with continuous (CCC) and non continuous (N-CCC) cycling bipolar disorders. METHODS: The study sample included 101 patients with bipolar disorder, 22 (21.8%) CCC and 79 (78.2%) N-CCC. Response was defined as a HDRS21 total score <7 at 12 weeks of treatment and remission as a >=50% reduction of baseline HDRS21 total score sustained for 8 weeks. RESULTS: Compared with N-CCC patients, CCC patients achieved a significantly lower percentage of response (respectively 50% vs. 82.3%, chi2=9.6, p=0.002) and remission (respectively 40.9% vs. 69.6%, chi2=6.11, p=0.013). Adjusted logistic regression analysis indicated that CCC patients were 4.3 times more likely to be non-responders and 3.3 times more likely to be non-remitters than N-CCC patients. CONCERNING: AD safety, 1 (5.0%) CCC patient committed a suicide attempt and AD emerging switch was observed in 2 patients with N-CCC (2.5%) and in 1 with CCC (4.5%). LIMITATIONS: The observational nature of the study, retrospective assessment of course, and unblinded outcomes assessment. CONCLUSIONS: Our findings indicate that the presence or absence of a free interval identifies two different forms of bipolar disorders with different response not only to prophylactic treatment, as previously reported, but also to short-term ADs. We submit that clinicians should take into consideration their patients' pattern of cycling when prescribing short-term AD treatment. Moreover, subtypes of bipolar disorders might be used as moderators of treatment response in studies assessing the efficacy or the effectiveness of antidepressant treatment. PMID- 25497469 TI - Rate of suicide and suicide attempts and their relationship to unemployment in Thessaloniki Greece (2000-2012). AB - INTRODUCTION: Recently there was a debate concerning the relationship between the economic crisis and an increase in attempted and completed suicides in Europe and especially in Greece. The aim of the current study was to calculate the rates of attempted and completed suicide per year in the county of Thessaloniki, Macedonia, northern Greece, for the years 2000-12, and to investigate their relationship with unemployment. MATERIAL AND METHODS: The archive of the Emergency Outpatient Units of three hospitals was investigated and the results were projected to the county population. Data from the Hellenic statistics authority concerning regional general population and suicides and unemployment were used. RESULTS: The rate of attempted suicides was 16.69-40.34 per 10(5) inhabitants for males and 41.43-110.82 for females. Medication was the preferred method for 95.93%. The completed suicide rates varied from 3.62 to 5.47 for males and from 0.19 to 1.95 per 10(5) inhabitants for females. The male attempt rate correlated negatively with regional male unemployment (-0.63). For females the respected value was similar (-0.72). Concerning competed suicide rates, the respected values were 0.34 and 0.65. The attempt was repeated by 15.34%; almost half-repeated within the same year and 75% within two years. The female to male ratio varied significantly across years with 2:1 (more females) being the probable value for attempts and 1:3.6 (more males) for completed suicides. CONCLUSION: This is the first study from Greece reporting rates on the basis of hospital archives. Attempt and suicide rates are low in Greece. Attempts are negatively and suicides are positively correlated with unemployment. PMID- 25497470 TI - Molecular imaging of striatal dopamine transporters in major depression--a meta analysis. AB - BACKGROUND: Increasing studies have revealed the dopamine transporter (DAT) availability altered in striatum associated with major depression. However, the results remain inconsistent. METHODS: To assess the alteration of striatal DAT availability in major depression, we performed a meta-analysis based on 12 case control molecular imaging studies, including a total of 209 depressed patients and 314 healthy controls. Hedges' g and corresponding 95% confidence intervals (CIs) for striatal DAT availability in major depression compared with controls were estimated. RESULTS: Our meta-analysis revealed no evidence for the alteration of striatal DAT availability in major depression (Hedges' g=0.09, CI 95% from -0.43 to 0.61, P=0.73). Meta-regression analyses suggested that there were no moderating effects for age, gender, year of publication, sample size, medication exposures and severity of depression on the hedges'g values for striatal DAT availability. LIMITATIONS: The results should be treated with caution because of the significant heterogeneity and the potential interference of confounding factors in this meta-analysis. CONCLUSIONS: Our results showed no altered striatal DAT availability in major depression and indicated that striatal DAT may not implicated in the pathophysiology of major depression. PMID- 25497465 TI - Clinical characteristics and course of patients with diabetes entering cardiac rehabilitation. AB - BACKGROUND: Using data from the Italian SurveY on carDiac rEhabilitation (ISYDE 2008), this study provides insight into the level of implementation of Cardiac Rehabilitation (CR) in patients with diabetes. METHODS: Data from 165 CR units were collected online from January 28th to February 10th, 2008. RESULTS: The study cohort consisted of 2281 patients (66.9 +/- 12 yrs); 475 (69.7 +/- 10 yrs, 74% male) patients with diabetes and 1806 (66.2 +/- 12 yrs, 72% male) non diabetic patients. Compared to non-diabetic patients, patients with diabetes were older and showed more comorbidity [myocardial infarction (32% vs. 19%, p < 0.0001), peripheral artery disease (10% vs. 5%, p < 0.0001), chronic obstructive pulmonary disease (20% vs. 11%, p < 0.0001), chronic kidney disease (20% vs. 6%, p < 0.0001), and cognitive impairment (5% vs. 2%, p = 0.0009), respectively], and complications during CR [re-infarction (3% vs. 1%, p = 0.04), acute renal failure (9% vs. 4%, p < 0.0001), sternal revision (3% vs. 1%, p = 0.01), inotropic support/mechanical assistance (7% vs. 4%, p = 0.01), respectively]; a more complex clinical course and interventions with less functional evaluation and a different pattern of drug therapy at hospital discharge. Notably, in 51 (3%) and in 104 (6%) of the non-diabetic cohort, insulin and hypoglycemic agents were prescribed, respectively, at hospital discharge from CR suggesting a careful evaluation of the glycemic metabolism during CR program, independent of the diagnosis at the admission. Mortality was similar among diabetic compared to non diabetic patients (1% vs. 0.5%, p = 0.23). CONCLUSIONS: This survey provided a detailed overview of the clinical characteristics, complexity and more severe clinical course of diabetic patients admitted to CR. PMID- 25497471 TI - Clinical characteristics and temperament influences on 'happy' euphoric and 'snappy' irritable bipolar hypo/manic mood states. AB - BACKGROUND: While mood elevation and euphoria are the most commonly described phenotypic descriptors of hypo/mania, irritability and anger may dominate. This study was designed to pursue possible determinants of such differing states. METHODS: Patients with bipolar I or II disorder were assigned to an 'irritable/snappy' or 'euphoric/happy' sub-set on the basis of their dominant hypo/manic symptoms. Group differences were examined across clinical, personality, lifestyle and illness impact measures. RESULTS: The two sub-sets did not differ on age of depression onset, family history of mood disorders, or depression severity and impairment. The snappy sub-set reported higher levels of irritability in depressed phases and were more likely to have a comorbid anxiety disorder. Their hypo/manic episodes were shorter and they were more likely to be hospitalized at such times. On a temperament measure they scored as more irritable and self-focussed and as less cooperative and effective - indicative of higher levels of disordered personality functioning. LIMITATIONS: Some comparison analyses were undertaken on a reduced sample size, giving rise to power issues. Our bipolar I and II diagnoses deviated to some extent from DSM-5 criteria in not imposing duration criteria for hypo/manic episodes. CONCLUSIONS: Findings support a spectrum model for the bipolar disorders linking temperament to bipolar symptomatic state and which may have treatment implications. PMID- 25497472 TI - Beliefs of people taking antidepressants about the causes of their own depression. AB - BACKGROUND: The beliefs of people receiving treatment about the causes of their own mental health problems are researched less often than the causal beliefs of the public, but have important implications for relationships with prescribers, treatment choices and recovery. METHOD: An online survey on a range of beliefs about depression, and experiences with antidepressants, was completed by 1829 New Zealand adults prescribed anti-depressants in the preceding five years, 97.4% of whom proceeded to take antidepressants. RESULTS: Six of 17 beliefs about the causes of their own depression were endorsed by more than half the sample: chemical imbalance, family stress, work stress, heredity, relationship problems and distressing events in childhood. There were some marked differences in content, structure and level of conviction of beliefs about one's own depression and the sample's previously published beliefs about depression in general. There were also significant differences between the beliefs of demographic groupings. Regression analyses revealed that self-reported effectiveness of the antidepressants was positively associated with bio-genetic causal beliefs. The quality of the relationship with the prescribing doctor was positively related to a belief in chemical imbalance as a cause and negatively related to a belief in unemployment as a cause. LIMITATIONS: The convenience sample may have been biased towards a favourable view of bio-genetic explanations, since 83% reported that the medication reduced their depression. CONCLUSIONS: People experiencing depression hold complex, multifactorial and idiosyncratic sets of beliefs about the causes of their own depression, apparently based at least in part on their own life experiences and circumstances. Exploring those beliefs may enhance the doctor-patient relationship and selection of appropriate treatment modality. PMID- 25497474 TI - Prefrontal cortex activation is associated with a discrepancy between self- and observer-rated depression severities of major depressive disorder: a multichannel near-infrared spectroscopy study. AB - BACKGROUND: Studies on major depressive disorder (MDD) show that the degree of correlation between the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HAMD) varies widely. We aimed to determine whether this discrepancy reflects specific functional abnormalities in the frontotemporal cortex. METHODS: Mildly depressed or euthymic patients with MDD (n=52), including 21 patients with MDD with the discrepancy, i.e., those with low HAMD17 scores (<=13) but high BDI II scores (>28), and 31 patients without the discrepancy, i.e., those with low HAMD17 scores and low BDI-II scores (<=28), participated in the study along with 48 control subjects. Regional changes of oxygenated hemoglobin (oxy-Hb) levels during a verbal fluency task (VFT) were monitored using a 52-channel near infrared spectroscopy (NIRS) device. RESULTS: In the frontotemporal regions, mean oxy-Hb changes induced by the VFT were significantly smaller in patients with MDD than in control subjects. In 5 channels within frontal regions, the increase in mean oxy-Hb levels was significantly greater in MDD patients with the BDI-HAMD discrepancy than in those without the discrepancy. In 6 channels within the frontal region of the patients with MDD, significant positive correlations were observed between mean oxy-Hb changes and BDI total scores (rho=0.38-0.59; P<0.05, false discovery rate corrected). LIMITATIONS: Our findings required replication in severely depressed patients, particularly those with melancholia. CONCLUSIONS: The distinct pattern of activation of the prefrontal cortex suggests that MDD with the BDI-HAMD discrepancy is pathophysiologically different from MDD without the discrepancy. PMID- 25497473 TI - Pre-treatment insomnia as a predictor of single and combination antidepressant outcomes: a CO-MED report. AB - BACKGROUND: Most patients with major depressive disorder (MDD) report clinically significant sleep problems. Pre-treatment insomnia has been associated with poorer treatment outcomes in some antidepressant trials, leading to suggestions that combined treatment regimens may be more successful in this subgroup. This study investigated this question using data from the CO-MED trial. METHODS: Adult outpatients with chronic and/or recurrent MDD were randomly assigned in 1:1:1 ratio to 28 weeks of single-blind, placebo-controlled antidepressant treatment with (1) escitalopram+placebo, (2) bupropion-sustained-release+escitalopram, or (3) venlafaxine-extended-release+mirtazapine. We compared baseline characteristics, tolerability, and treatment outcomes at 12 and 28 weeks for patients with and without pre-treatment insomnia. RESULTS: Of the 665 evaluable patients, the majority (88.3%) reported significant pre-treatment insomnia. Those with pre-treatment insomnia were more likely to be female (69.3% vs. 57.7%) and African-American (29.1% vs. 11.8%). Those with pre-treatment insomnia symptoms reported higher rates of concurrent anxiety disorders, lower rates of alcohol and substance use disorders, and greater impairment in psychosocial functioning. The two groups did not differ in either tolerability or treatment outcomes among the three antidepressant treatments. CONCLUSIONS: Insomnia symptoms, while common in patients with chronic/recurrent MDD were not predictive of response, remission, or tolerability with either single or combined antidepressant medications. PMID- 25497476 TI - Computation of epidemic final size distributions. AB - We develop a new methodology for the efficient computation of epidemic final size distributions for a broad class of Markovian models. We exploit a particular representation of the stochastic epidemic process to derive a method which is both computationally efficient and numerically stable. The algorithms we present are also physically transparent and so allow us to extend this method from the basic SIR model to a model with a phase-type infectious period and another with waning immunity. The underlying theory is applicable to many Markovian models where we wish to efficiently calculate hitting probabilities. PMID- 25497477 TI - A possible mechanism for the attainment of out-of-phase periodic dynamics in two chaotic subpopulations coupled at low dispersal rate. AB - Much research in metapopulation dynamics has concentrated on identifying factors that affect coherence in spatially structured systems. In this regard, conditions for the attainment of out-of-phase dynamics have received considerable attention, due to the stabilizing effect of asynchrony on global dynamics. At low to moderate rates of dispersal, two coupled subpopulations with intrinsically chaotic dynamics tend to go out-of-phase with one another and also become periodic in their dynamics. The onset of out-of-phase dynamics and periodicity typically coincide. Here, we propose a possible mechanism for the onset of out-of phase dynamics, and also the stabilization of chaos to periodicity, in two coupled subpopulations with intrinsically chaotic dynamics. We suggest that the onset of out-of-phase dynamics is due to the propensity of chaotic subpopulations governed by a steep, single-humped one-dimensional population growth model to repeatedly reach low subpopulation sizes that are close to a value Nt = A (A ? equilibrium population size, K) for which Nt( + 1) = K. Subpopulations with very similar low sizes, but on opposite sides of A, will become out-of-phase in the next generation, as they will end up at sizes on opposite sides of K, resulting in positive growth for one subpopulation and negative growth for the other. The key to the stabilization of out-of-phase periodic dynamics in this mechanism is the net effect of dispersal placing upper and lower bounds to subpopulation size in the two coupled subpopulations, once they have become out-of-phase. We tested various components of this proposed mechanism by simulations using the Ricker model, and the results of the simulations are consistent with predictions from the hypothesized mechanism. Similar results were also obtained using the logistic and Hassell models, and with the Ricker model incorporating the possibility of extinction, suggesting that the proposed mechanism could be key to the attainment and maintenance of out-of-phase periodicity in two-patch metapopulations where each patch has local dynamics governed by a single-humped population growth model. PMID- 25497480 TI - Anticipatory sensitization to repeated stressors: the role of initial cortisol reactivity and meditation/emotion skills training. AB - Anticipation may play a role in shaping biological reactions to repeated stressors-a common feature of modern life. We aimed to demonstrate that: (a) individuals who display a larger cortisol response to an initial stressor exhibit progressive anticipatory sensitization, showing progressively higher cortisol levels before subsequent exposures, and (b) attention/emotional skills training can reduce the magnitude of this effect on progressive anticipatory sensitization. Female school teachers (N=76) were randomly assigned to attention/emotion skills and meditation training or to a control group. Participants completed 3 separate Trier Social Stress Tests (TSST): at baseline (Session 1), post-training (Session 2), and five months post (Session 3). Each TSST session included preparing and delivering a speech and performing an arithmetic task in front of critical evaluators. In each session participants' salivary cortisol levels were determined before and after the stressor. Control participants with larger cortisol reactivity to the first stressor showed increasing anticipatory (pre-stressor) cortisol levels with each successive stressor exposure (TSST session)-suggesting progressive anticipatory sensitization. Yet this association was absent in the training group. Supplementary analyses indicated that these findings occurred in the absence of group differences in cortisol reactivity. Findings suggest that the stress response can undergo progressive anticipatory sensitization, which may be modulated by attention/emotion-related processes. An important implication of the construct of progressive anticipatory sensitization is a possible self perpetuating effect of stress reactions, providing a candidate mechanism for the translation of short-to-long-term stress reactions. PMID- 25497475 TI - A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment. AB - While active tuberculosis (TB) is a treatable disease, many complex factors prevent its global elimination. Part of the difficulty in developing optimal therapies is the large design space of antibiotic doses, regimens and combinations. Computational models that capture the spatial and temporal dynamics of antibiotics at the site of infection can aid in reducing the design space of costly and time-consuming animal pre-clinical and human clinical trials. The site of infection in TB is the granuloma, a collection of immune cells and bacteria that form in the lung, and new data suggest that penetration of drugs throughout granulomas is problematic. Here we integrate our computational model of granuloma formation and function with models for plasma pharmacokinetics, lung tissue pharmacokinetics and pharmacodynamics for two first line anti-TB antibiotics. The integrated model is calibrated to animal data. We make four predictions. First, antibiotics are frequently below effective concentrations inside granulomas, leading to bacterial growth between doses and contributing to the long treatment periods required for TB. Second, antibiotic concentration gradients form within granulomas, with lower concentrations toward their centers. Third, during antibiotic treatment, bacterial subpopulations are similar for INH and RIF treatment: mostly intracellular with extracellular bacteria located in areas non permissive for replication (hypoxic areas), presenting a slowly increasing target population over time. Finally, we find that on an individual granuloma basis, pre treatment infection severity (including bacterial burden, host cell activation and host cell death) is predictive of treatment outcome. PMID- 25497481 TI - Analyzing the history of Cognition using Topic Models. AB - Very few articles have analyzed how cognitive science as a field has changed over the last six decades. We explore how Cognition changed over the last four decades using Topic Models. Topic Models assume that every word in every document is generated by one of a limited number of topics. Words that are likely to co-occur are likely to be generated by a single topic. We find a number of significant historical trends: the rise of moral cognition, eyetracking methods, and action, the fall of sentence processing, and the stability of development. We introduce the notion of framing topics, which frame content, rather than present the content itself. These framing topics suggest that over time Cognition turned from abstract theorizing to more experimental approaches. PMID- 25497478 TI - Nanometer-long Ge-imogolite nanotubes cause sustained lung inflammation and fibrosis in rats. AB - BACKGROUND: Ge-imogolites are short aluminogermanate tubular nanomaterials with attractive prospected industrial applications. In view of their nano-scale dimensions and high aspect ratio, they should be examined for their potential to cause respiratory toxicity. Here, we evaluated the respiratory biopersistence and lung toxicity of 2 samples of nanometer-long Ge-imogolites. METHODS: Rats were intra-tracheally instilled with single wall (SW, 70 nm length) or double wall (DW, 62 nm length) Ge-imogolites (0.02-2 mg/rat), as well as with crocidolite and the hard metal particles WC-Co, as positive controls. The biopersistence of Ge imogolites and their localization in the lung were assessed by ICP-MS, X-ray fluorescence, absorption spectroscopy and computed micro-tomography. Acute inflammation and genotoxicity (micronuclei in isolated type II pneumocytes) was assessed 3 d post-exposure; chronic inflammation and fibrosis after 2 m. RESULTS: Cytotoxic and inflammatory responses were shown in bronchoalveolar lavage 3 d after instillation with Ge-imogolites. Sixty days after exposure, a persistent dose-dependent inflammation was still observed. Total lung collagen, reflected by hydroxyproline lung content, was increased after SW and DW Ge-imogolites. Histology revealed lung fibre reorganization and accumulation in granulomas with epithelioid cells and foamy macrophages and thickening of the alveolar walls. Overall, the inflammatory and fibrotic responses induced by SW and DW Ge imogolites were more severe (on a mass dose basis) than those induced by crocidolite. A persistent fraction of Ge-imogolites (15% of initial dose) was mostly detected as intact structures in rat lungs 2 m after instillation and was localized in fibrotic alveolar areas. In vivo induction of micronuclei was significantly increased 3 d after SW and DW Ge-imogolite instillation at non inflammatory doses, indicating the contribution of primary genotoxicity. CONCLUSIONS: We showed that nm-long Ge-imogolites persist in the lung and promote genotoxicity, sustained inflammation and fibrosis, indicating that short high aspect ratio nanomaterials should not be considered as innocuous materials. Our data also suggest that Ge-imogolite structure and external surface determine their toxic activity. PMID- 25497482 TI - Manifesto for a new (computational) cognitive revolution. AB - The cognitive revolution offered an alternative to merely analyzing human behavior, using the notion of computation to rigorously express hypotheses about the mind. Computation also gives us new tools for testing these hypotheses - large behavioral databases generated by human interactions with computers and with one another. This kind of data is typically analyzed by computer scientists, who focus on predicting people's behavior based on their history. A new cognitive revolution is needed, demonstrating the value of minds as intervening variables in these analyses and using the results to evaluate models of human cognition. PMID- 25497484 TI - Italy's gynaecologists demand government action to protect women's abortion rights. PMID- 25497485 TI - Deformable image registration for defining the postimplant seroma in permanent breast seed implant brachytherapy. AB - PURPOSE: To demonstrate the benefit of deformable image registration (DIR) to define postimplant seromas in permanent breast seed implants (PBSIs) by adapting preimplant seromas to postimplant images. METHODS AND MATERIALS: Planning and Day 0 CT scans from 15 consecutive PBSI patients were included. Seromas were contoured on the preimplant CTs. After implant, DIR (MIM Maestro; MIM Software, Inc., Cleveland, OH) was used to adapt preimplant seromas to postimplant scans. Resulting seromas were evaluated for accuracy and adjusted if required, and pre- and postimplant seroma volumes were recorded and compared. DIR was validated by assessing the spatial correspondence of surgical clips pre- and postimplant in eight cases. Retrospectively, rigid registration was also investigated. RESULTS: Surgical clip location corresponded between pre- and postimplant images with a median agreement of <1.0 mm. The seroma defined using DIR was an acceptable rendering of the postimplant seroma in 9 of 15 cases, and in the remaining six cases, minor alterations (mean, 1.0 +/- 0.2 mm) were made. Mean change in seroma volumes between preimplant and postimplant imaging was -6.1 +/- 26.4%. Rigid registration exhibited unacceptable variability, with poor concordance in postimplant seroma between different observers (median conformity index, 26.5%; range, 0-52.7%). CONCLUSIONS: Deformable image registration can be used to adapt the preimplant seroma to postimplant PBSI images and is recommended for implant quality assurance in PBSI. Using deformable registration avoids uncertainties associated with poor seroma visualization and interobserver variability when rigid registration is performed. The accurate deformation of implanted surgical clips demonstrates the reliability of deformable image registration for PBSI. PMID- 25497486 TI - Investigation of the milling capabilities of the F10 Fine Grind mill using Box Behnken designs. AB - Size reduction or milling of the active is often the first processing step in the design of a dosage form. The ability of a mill to convert coarse crystals into the target size and size distribution efficiently is highly desirable as the quality of the final pharmaceutical product after processing is often still dependent on the dimensional attributes of its component constituents. The F10 Fine Grind mill is a mechanical impact mill designed to produce unimodal mid-size particles by utilizing a single-pass two-stage size reduction process for fine grinding of raw materials needed in secondary processing. Box-Behnken designs were used to investigate the effects of various mill variables (impeller, blower and feeder speeds and screen aperture size) on the milling of coarse crystals. Response variables included the particle size parameters (D10, D50 and D90), span and milling rate. Milled particles in the size range of 5-200 MUm, with D50 ranging from 15 to 60 MUm, were produced. The impeller and feeder speeds were the most critical factors influencing the particle size and milling rate, respectively. Size distributions of milled particles were better described by their goodness-of-fit to a log-normal distribution (i.e. unimodality) rather than span. Milled particles with symmetrical unimodal distributions were obtained when the screen aperture size was close to the median diameter of coarse particles employed. The capacity for high throughput milling of particles to a mid-size range, which is intermediate between conventional mechanical impact mills and air jet mills, was demonstrated in the F10 mill. Prediction models from the Box Behnken designs will aid in providing a better guide to the milling process and milled product characteristics. PMID- 25497487 TI - Sustained intravitreal delivery of connexin43 mimetic peptide by poly(D,L-lactide co-glycolide) acid micro- and nanoparticles--Closing the gap in retinal ischaemia. AB - Recent research has shown that transient block of connexin43 (Cx43) hemichannels by mimetic peptides (MP) after retinal ischaemia inhibits uncontrolled hemichannel opening causing blood-brain barrier permeability and endothelial cell loss, and consequently provides improved retinal ganglion cell (RGC) survival. However, the highly hydrophilic character and potentially poor stability of native peptides can limit efficient delivery in a clinical setting. The present study investigated the ability of intravitreally injected Cx43 MP encapsulated into slow-release poly(lactic-co-glycolic) acid (PLGA) nano-(Nps) and microparticles (Mps) to promote RGC survival in a retinal ischaemia-reperfusion rat model. The particle size was around 113 nm (Nps) and 9 MUm (Mps), respectively, with Cx43 MP entrapment efficiencies of 70% (Nps) and 97% (Mps). A triphasic in vitro release profile was observed with an initial burst of surface bound Cx43 MP followed by slow release due to polymer erosion and further drug release at the point of complete particle breakdown, with 100% release achieved after 63 (Nps) and 112 (Mps) days, respectively. Nps showed the most promising results on both Cx43 down-regulation and RGC rescue in this acute injury model. Mps treatment, on the other hand, was unable to down regulate the initial inflammatory response possibly due to trapping of the bigger particles in the vitreous and the much slower release of Cx43 MP from these particles, but displayed a delayed effect on Cx43 regulation and RGC preservation due to the sustained release. PMID- 25497488 TI - Particle engineering to enhance or lessen particle uptake by alveolar macrophages and to influence the therapeutic outcome. AB - The alveolar macrophages defend the lung against airborne pollutants and infectious microorganisms. Recent advances in the understanding of the role of macrophages in generation of immunological and inflammatory responses have established that alveolar macrophages could be used as targets for drug delivery. Enhanced uptake of particulate drug carriers by macrophages could be beneficial in pathological conditions such as tuberculosis and HIV where infectious microorganisms utilize macrophages as a safe haven and a vehicle to further infections. In contrary, to achieve prolonged residence time, extended drug release and in desired situations, increased systemic absorption, drug carrying particles that can avoid recognition and uptake by alveolar macrophages may prove to be significantly advantageous. Drug targeting to macrophages can achieve superior therapeutic efficacy for the treatment of medical conditions that involve tumorigenesis, inflammation and infections. Various particulate carriers containing therapeutic agents have been used to deliver drugs to the macrophages residing in the lung. Particulate systems have also been engineered to facilitate or avoid uptake by macrophages. But pathological conditions to be treated and drug delivery goals dictate the engineering approach for reducing or enhancing uptake by macrophages. In this review, we have summarized the influence of various physicochemical properties--composition, size, shape, pegylation and presence or absence of surface ligands--of particulate carriers on their uptake by macrophages. We have also described the macrophage biology and strategies that have been used to influence uptake and avoidance of particulate carriers by macrophages. PMID- 25497489 TI - Clinician-friendly lower extremity physical performance measures in athletes: a systematic review of measurement properties and correlation with injury, part 1. The tests for knee function including the hop tests. AB - OBJECTIVE: To review the measurement properties of physical performance tests (PPTs) of the knee as each pertain to athletes, and to determine the relationship between PPTs and injury in athletes age 12 years to adult. METHODS: A search strategy was constructed by combining the terms 'lower extremity' and synonyms for 'performance test', and names of performance tests with variants of the term 'athlete'. In this, part 1, we report on findings in the knee. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were followed and the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist was used to critique the methodological quality of each paper. A second measure was used to analyse the quality of the measurement properties of each test. RESULTS: In the final analysis, we found 29 articles pertinent to the knee detailing 19 PPTs, of which six were compiled in a best evidence synthesis. The six tests were: one leg hop for distance (single and triple hop), 6 m timed hop, crossover hop for distance, triple jump and single leg vertical jump. The one leg hop for distance is the most often studied PPT. There is conflicting evidence regarding the validity of the hop and moderate evidence that the hop test is responsive to changes during rehabilitation. No test has established reliability or measurement error as assessed by the minimal important change or smallest detectable change. No test predicts knee injury in athletes. CONCLUSIONS: Despite numerous published articles addressing PPTs at the knee, there is predominantly limited and conflicting evidence regarding the reliability, agreement, construct validity, criterion validity and responsiveness of commonly used PPTs. There is a great opportunity for further study of these tests and the measurement properties of each in athletes. PMID- 25497490 TI - 1,2,4-triazolo[1,5-a]quinoxaline derivatives and their simplified analogues as adenosine A3 receptor antagonists. Synthesis, structure-affinity relationships and molecular modeling studies. AB - The 1,2,4-triazolo[1,5-a]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2-15). This study produced some interesting compounds endowed with good hA3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA3 receptor-ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16-23). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor-ligand interaction, have a very low hA3 adenosine receptor affinity, the only exception being compound 23 (1-[3 (4-methoxyphenyl)-1-phenyl-1H-1,2,4-triazol-5-yl]-3-phenylurea) endowed with a Ki value in the micro-molar range and high hA3 selectivity versus both hA1 and hA2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5 a]quinoxalines as hA3AR antagonists (compounds 24-27). These derivatives, though lacking the classical structural requirements for the anchoring at the hA3 receptor site, show high hA3 affinity and in some case selectivity versus hA1 and hA2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor. PMID- 25497492 TI - Electron vortex beams prepared by a spiral aperture with the goal to measure EMCD on ferromagnetic films via STEM. AB - X-ray magnetic circular dichroism is a well established method to study element specific magnetic properties of a material, while electron magnetic circular dichroism (EMCD), which is the electron wave analogue to XMCD, is scarcely used today. Recently discovered electron vortex beams, that carry a discrete orbital angular momentum (OAM) L, are also predicted to reveal dichroic signals. Since electron beams can be easily focused down to sub-nanometer diameters, this novel technique promises the possibility to quantitatively determine local magnetic properties with unrivalled lateral resolution. As the spiralling wave front of the electron vortex beam has an azimutally growing phase shift of up to 2pi and a phase singularity in its axial center, specially designed apertures are needed to generate such non-planar electron waves. We report on the preparation and successful implementation of spiral apertures into the condenser lens system of an aberration-corrected FEI Titan(3) 80-300 transmission electron microscope (TEM). This setup allows to perform scanning TEM (STEM) with vortex beams carrying user-selected OAM. First experiments on the interaction of the vortex beam with a poly-crystalline sample are presented. Within the achieved signal to noise ratio no EMCD signal has been detected. This finding is supported by simulations of inelastic scattering of a beam generated by spiral aperture. PMID- 25497493 TI - Quantitative investigation of SiGeC layers using atom probe tomography. AB - The quantification of carbon and germanium in a Si/SiGeC multilayer structure using atom probe tomography has been investigated as a function of analysis conditions. The best conditions for quantitative results are obtained using an intermediate electric field and laser power. Carbon evaporation shows strong spatial and temporal correlation. By using multi-ion event analysis, an evaporation mechanism is put forward to explain the modification of mass spectra as a function of electric field and laser power. PMID- 25497494 TI - Detecting and extracting clusters in atom probe data: a simple, automated method using Voronoi cells. AB - The analysis of the formation of clusters in solid solutions is one of the most common uses of atom probe tomography. Here, we present a method where we use the Voronoi tessellation of the solute atoms and its geometric dual, the Delaunay triangulation to test for spatial/chemical randomness of the solid solution as well as extracting the clusters themselves. We show how the parameters necessary for cluster extraction can be determined automatically, i.e. without user interaction, making it an ideal tool for the screening of datasets and the pre filtering of structures for other spatial analysis techniques. Since the Voronoi volumes are closely related to atomic concentrations, the parameters resulting from this analysis can also be used for other concentration based methods such as iso-surfaces. PMID- 25497495 TI - Proteomic analysis of rat plasma with experimental autoimmune uveitis based on label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS). AB - Uveitis is a severe autoimmune eye disease that can cause intraocular inflammation even lead to severe vision loss, and the occurrence of uveitis can be closely associated with abnormal expression of proteins. However, the abnormally expressed proteins involved in uveitis are not well identified. Using liquid chromatography-tandem mass spectrometry technique, we examined the alterations in proteomic expression profiling in rat plasma specimens related to experimental autoimmune uveitis (EAU) versus normal samples. In addition, the experimental verification was further performed using enzyme-linked immunosorbent assay (ELISA) for abnormally expressed proteins in EAU rat plasma. The results indicate that 62 proteins were upregulated and 106 proteins were downregulated in plasma from EAU rats compared with those in saline-treated samples. In the meantime, we observed that the plasma level of complement component 3 in EAU rats was upregulated versus saline-treated rats (from 92.32MUg/mL to 168.92MUg/mL), whereas the level of interleukin-1 receptor accessory protein was downregulated (from 1120.97pg/mL to 798.39pg/mL), and these results were highly in agreement with those of mass spectrometry determination. Taken together, our results indicate that liquid chromatography-tandem mass spectrometry analysis possesses a good resolution for peptides in plasma, and the findings will provide the baseline plasma dataset for EAU rats and the relevant information can contribute to future studies on the understanding the mechanism of uveitis. PMID- 25497491 TI - Models of alpha-synuclein aggregation in Parkinson's disease. AB - Parkinson's disease (PD) is not only characterized by motor disturbances but also, by cognitive, sensory, psychiatric and autonomic dysfunction. It has been proposed that some of these symptoms might be related to the widespread pathology of alpha-synuclein (alpha-syn) aggregation in different nuclei of the central and peripheral nervous system. However, the pathogenic formation of alpha-syn aggregates in different brain areas of PD patients is poorly understood. Most experimental models of PD are valuable to assess specific aspects of its pathogenesis, such as toxin-induced dopaminergic neurodegeneration. However, new models are required that reflect the widespread and progressive formation of alpha-syn aggregates in different brain areas. Such alpha-syn aggregation is induced in only a few animal models, for example perikaryon inclusions are found in rats administered rotenone, aggregates with a neuritic morphology develop in mice overexpressing either mutated or wild-type alpha-syn, and in Smad3 deficient mice, aggregates form extensively in the perikaryon and neurites of specific brain nuclei. In this review we focus on alpha-syn aggregation in the human disorder, its genetics and the availability of experimental models. Indeed, evidences show that dopamine (DA) metabolism may be related to alpha-syn and its conformational plasticity, suggesting an interesting link between the two pathological hallmarks of PD: dopaminergic neurodegeneration and Lewy body (LB) formation. PMID- 25497496 TI - Improved determination of malonaldehyde by high-performance liquid chromatography with UV detection as 2,3-diaminonaphthalene derivative. AB - A rapid, specific and simple procedure is proposed for the determination of free malonaldehyde (MA) contained in fish tissue. The method is the optimization of the reaction of MA with 2,3-diaminonaphthalene to afford a naphtodiazepinium ion that present a UV absorption at 311nm, useful for MA determination by HPLC with UV detection. The reaction proceeds in the presence of 25% acetonitrile at 37 degrees C in 20min at pH 2 using 2,4-pentanedione as internal standard. The method has been applied to homogenized samples of canned mackerel fillets that were treated with 2,3-diaminonaphthalene in an acidic aqueous:acetonitrile mixture. The produced naphtodiazepinium ion was extracted in acetonitrile by a salting-out homogeneous liquid-liquid extraction. A standard calibration was carried out in the range 0.625-10nmol/g. The reliability of the procedure is demonstrated by linearity (r(2)=0.998), limit of detection (0.16nmol/g), limit of quantification (0.22nmol/g), repeatibility (RSD 5.57%), and intermediate precision (RSD 8.92%). PMID- 25497497 TI - Reference-free corrosion damage diagnosis in steel strands using guided ultrasonic waves. AB - This study presents a nondestructive evaluation method based on guided ultrasonic waves (GUW) to quantify corrosion damage of prestressing steel strands. Specifically, a reference-free algorithm is proposed to estimate the strand's cross-section loss by using dispersion curves, continuous wavelet transform, and wave velocity measurements. Accelerated corrosion tests are carried out to validate the proposed approach. Furthermore, the propagation of Heisenberg uncertainty to diameter measurement is also investigated. The method can reasonably estimate the wires' diameter without any baseline as a reference. PMID- 25497499 TI - Proceedings of the Bovine Respiratory Disease Symposium 2014: new approaches to bovine respiratory disease prevention, management, and diagnosis. PMID- 25497498 TI - Fabrication of an optical lens array using ultraviolet light and ultrasonication. AB - A technique to form an optical lens array using an ultraviolet (UV)-curable resin and ultrasound was investigated. A UV-curable gel film was formed on a glass plate having four lead zirconate titanate (PZT) transducers. Excitation of the transducers generated a lattice flexural vibration mode on the glass plate. The acoustic radiation force acted to deform the surface of the gel film, so that a lens array could be fabricated on the gel film. The lens array was exposed to UV light under ultrasonication to cure the UV-curable film. The quality factor of the transducer resonance was decreased upon curing of the resin film because the cured resin dampened the vibration of the plate. The acoustic characteristics of the UV-curable gel film were measured by using an ultrasound pulse technique at the MHz range. The sound speed of the gel increased from 987 to 1006 m/s (increase of 1.9%) as the UV exposure time increased. The attenuation coefficient also increased and the larger attenuation of the resin caused the lens array to have a lower quality factor. PMID- 25497500 TI - The monster we don't see: subclinical BRD in beef cattle. AB - Bovine respiratory disease (BRD) is the most expensive disease affecting United States cattle. Recently weaned calves are the focus of prevention and treatment research. Identifying affected cattle early in the course of BRD is difficult. Intervention during the early stages of BRD improves treatment outcomes; however, cattle as prey animals are excellent at hiding signs of disease, especially if the caregiver has not gained their trust. Depression, appetite loss, and changes in respiratory character are the principal signs used to identify BRD. Rectal temperatures from cattle pulled for treatment are a final measure of evaluation. Cattle suffering from subclinical BRD frequently escape identification and treatment. Observations of lungs at packing plants for anterior ventral (AV) lesions frequently document higher BRD incidence rates than observed pre-harvest, suggesting subclinical BRD is common. Data from numerous studies document lower average daily gains (ADG) from cattle with AV lung lesions at packing plants that were not treated for BRD compared with cattle with normal lungs. Scoring lung lesions at the packing plant can be a useful tool for gaining insight into BRD incidence. Data indicate that BRD lowers ADG by 0.2 lbs on average, and lowers the USDA Quality Grade by 50 marbling points. PMID- 25497502 TI - Control of BRD in large dairy calf populations. AB - Bovine respiratory disease (BRD) is a leading cause of morbidity and mortality in dairy calves. As the number of calves being raised on the dairy farm or at a calf raising operation has become larger, both opportunity and risk have increased. Opportunities for applying economies of size and scale exist in these large dairy calf populations while meeting specific needs of the dairy calf. BRD control requires effective biosecurity and biocontainment efforts, adequate passive transfer of immunoglobulins, a strategic immunization program, and appropriate diagnostic strategies for ongoing disease surveillance. These components are necessary to achieve an evidence-based approach for preventing and reducing severity of BRD cases. Proper nutrition, housing, and environmental management are important for achieving optimal dairy calf health and performance. Good record keeping and analysis of outcomes are needed to document dairy calf health and performance and to efficiently identify new problems that require attention in these large dairy calf populations. Proper management of calves to prevent and control BRD requires careful planning and follow through to achieve those results but will likely pay big dividends in improved calf health and future productivity. PMID- 25497501 TI - How stress alters immune responses during respiratory infection. AB - Fall-weaned calves entering the feedlot experience a variety of psychological and physical stressors, including maternal separation, transportation, social mixing, restraint, and dietary changes. Mixing calves from multiple sources also exposes them to respiratory pathogens at a time when maternal immunity has waned. Using an experimental bovine respiratory disease (BRD) challenge, we analyzed the effects of specific stressors on clinical disease and immune responses following bovine herpes virus (BHV-1/IBR) infection of naive calves. Transportation stress was compared to either abrupt weaning plus transportation or transportation following a two-step weaning process. Transportation alone significantly (P < 0.05) increased BHV-1 shedding in nasal secretions despite elevated interferon gamma production in the upper respiratory tract. In contrast, abrupt weaning and transportation, significantly (P < 0.05) increased serum haptoglobin on day 3 post-infection (PI) and blood leukocyte tumor necrosis factor alpha secretion on day 5 PI. These systemic responses were reduced by instituting a two-step weaning process 4 days prior to transportation and BHV-1 infection. In conclusion, these observations are consistent with earlier studies implicating weaning and transportation as stressors contributing to BRD severity and mortality. Current studies also revealed that different stressors or combination of stressors have distinct effects on host responses to viral infection in naive calves. PMID- 25497503 TI - Factors that influence producer decisions to implement management strategies. AB - Cow-calf enterprises in the USA are widely divergent in size, locale, resource availability, management skill, and market focus. Furthermore, variation exists in dependence on the cow-calf enterprise as a primary source of income, perception about the utility of a particular management practice or technology, and assessment of cost: benefit resulting from implementation impact decisions. Enterprises with larger cow inventories, greater dependence on income from the cattle enterprise, and that retain ownership further into the supply chain beyond the cow-calf operation are more likely to institute management protocols such as vaccination programs, defined calving seasons, and reproductive technologies. Successful cow-calf managers place the highest priority on herd nutrition, pasture and range management, herd health, financial management marketing, production management, and genetics. Management practices are more likely to be adopted when they align with a manager's perception of the utility, labor availability, favorable cost: benefit outcomes and profit motivation. PMID- 25497504 TI - Association of depression and anxiety symptoms with functional disability and disability days in a community sample with type 2 diabetes. AB - BACKGROUND: There is a well-documented association between depression and disability in people with diabetes. However, less is known about the possible association of co-occurring anxiety on these associations. OBJECTIVE: The objective of this study was to assess the association of elevated anxiety or depression symptoms or both with functional disability and frequent disability days in a community sample with type 2 diabetes. METHODS: The participants were 1999 people with diabetes who completed the baseline portion of the Evaluation of Diabetes Treatment study. Functional disability was assessed using the World Health Organization Disability Assessment Schedule II. Frequent disability days were assessed using a cutoff score >=14 on a question assessing functional disability in the past month from the Healthy Days Core Module. Depression and anxiety were assessed with the Patient Health Questionnaire and General Anxiety Questionnaire with cutoff scores >=10 applied to create groups. Additional questions examined diabetes complications, chronic conditions, and sociodemographic characteristics. RESULTS: Fully adjusted logistic regression analyses demonstrated an increased likelihood of reporting functional disability for all groups with high anxiety or depressive symptoms or both. Groups with high depressive symptoms with and without high anxiety symptoms were also more likely to report frequent disability days. CONCLUSIONS: Results indicate that elevated anxiety and depression symptoms are important factors associated with increased functional disability and frequent disability days in people with diabetes. PMID- 25497505 TI - Continuation of clozapine during chemotherapy: a case report and review of literature. PMID- 25497506 TI - An insatiable desire for tofu: a case of restless legs and unusual pica in iron deficiency anemia. PMID- 25497507 TI - Quetiapine-induced hyperglycemic crisis and severe hyperlipidemia: a case report and review of the literature. PMID- 25497508 TI - SSRI discontinuation syndrome following bariatric surgery: a case report and focused literature review. PMID- 25497509 TI - The early-career consultation psychiatrist: the role in global settings. PMID- 25497510 TI - The early-career consultation psychiatrist: preparing psychiatry residents for the integrated care wave. PMID- 25497511 TI - QTc prolongation and haloperidol: just how risky is this drug? PMID- 25497513 TI - Older age is a strong predictor for poor outcome in intracerebral haemorrhage: the INTERACT2 study. AB - BACKGROUND AND PURPOSE: Global ageing contributes greatly to the burden of stroke. We investigated the influence of age on the baseline profile and on outcomes in acute intracerebral haemorrhage (ICH) among participants of the INTERACT2 study. METHODS: INTERACT2 was an international, randomised controlled trial in 2839 patients with spontaneous ICH within 6 h of onset and elevated systolic blood pressure (SBP; 150-220 mmHg) who were allocated to receive intensive (target SBP <140 mmHg within 1 h) or guideline-recommended (target SBP <180 mmHg) blood pressure lowering treatment. Stroke severity was assessed with the National Institutes of Health Stroke Scale. Poor outcome was defined as death or major disability ('dependency', modified Rankin Scale scores 3-6) at 90 days. Health-related quality of life (HRQoL) was assessed with the European Quality of Life-5 Dimensions (EQ-5D) questionnaire. Associations between age and outcomes were analysed in multivariable logistic regression models. RESULTS: Stroke severity increased in categories of older age (P-trend 0.002). Stroke patients over 75 years old were four times more likely to die or be disabled at 90 days than those <52 years when other confounders were accounted for (odds ratio 4.36, 95% confidence interval 3.12-6.08). Older age was also associated with decreasing HRQoL, across mobility, self-care, usual activities and depression (all P-trend <0.001), and pain or discomfort (P-trend 0.022). CONCLUSION: In the INTERACT2 cohort, older people had more severe ICH and worse outcomes (death, major disability and HRQoL). These data will help guide clinicians manage older people with haemorrhagic stroke. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov (NCT00716079). PMID- 25497512 TI - Ebola virus disease. PMID- 25497514 TI - Floral biology and ovule and seed ontogeny of Nymphaea thermarum, a water lily at the brink of extinction with potential as a model system for basal angiosperms. AB - BACKGROUND AND AIMS: Nymphaea thermarum is a member of the Nymphaeales, of one of the most ancient lineages of flowering plants. This species was only recently described and then declared extinct in the wild, so little is known about its reproductive biology. In general, the complete ontogeny of ovules and seeds is not well documented among species of Nymphaea and has never been studied in the subgenus Brachyceras, the clade to which N. thermarum belongs. METHODS: Flowers and fruits were processed for brightfield, epifluorescence and confocal microscopy. Flower morphology, with emphasis on the timing of male and female functions, was correlated with key developmental stages of the ovule and the female gametophyte. Development of the seed tissues and dynamics of polysaccharide reserves in the endosperm, perisperm and embryo were examined. KEY RESULTS: Pollen release in N. thermarum starts before the flower opens. Cell walls of the micropylar nucellus show layering of callose and cellulose in a manner reminiscent of transfer cell wall patterning. Endosperm development is ab initio cellular, with micropylar and chalazal domains that embark on distinct developmental trajectories. The surrounding maternal perisperm occupies the majority of seed volume and accumulates starch centrifugally. In mature seeds, a minute but fully developed embryo is surrounded by a single, persistent layer of endosperm. CONCLUSIONS: Early male and female function indicate that N. thermarum is predisposed towards self-pollination, a phenomenon that is likely to have evolved multiple times within Nymphaea. While formation of distinct micropylar and chalazal developmental domains in the endosperm, along with a copious perisperm, characterize the seeds of most members of the Nymphaeales, seed ontogenies vary between and among the constituent families. Floral biology, life history traits and small genome size make N. thermarum uniquely promising as an early-diverging angiosperm model system for genetic and molecular studies. PMID- 25497515 TI - Randomized controlled trials in adult traumatic brain injury: a review of compliance to CONSORT statement. AB - OBJECTIVE: To describe the extent to which adherence to Consolidated Standards of Reporting Trials (CONSORT) statement in randomized controlled trials (RCTs) in adult traumatic brain injury (TBI) has improved over time. DATA SOURCES: MEDLINE, PsycINFO, and CINAHL databases were searched from inception to September 2013. STUDY SELECTION: Primary report of RCTs in adult TBI. The quality of reporting on CONSORT checklist items was examined and compared over time. Study selection was conducted by 2 researchers independently. Any disagreements were solved by discussion. DATA EXTRACTION: Two reviewers independently conducted data extraction based on a set of structured data extraction forms. Data regarding the publication years, size, locations, participation centers, intervention types, intervention groups, and CONSORT checklist items were extracted from the including trials. DATA SYNTHESIS: Of 105 trials reviewed, 38.1%, 5.7%, and 32.4% investigated drugs, surgical procedures, and rehabilitations as the intervention of interest, respectively. Among reports published between the 2 periods 2002 and 2010 (n=51) and 2011 and September 2013 (n=16), the median sample sizes were 99 and 118; 39.2% and 37.5% of all reports detailed implementation of the randomization process; 60.8% and 43.8% provided information on the method of allocation concealment; 56.9% and 31.3% stated how blinding was achieved; 15.7% and 43.8% reported information regarding trial registration; and only 2.0% and 6.3% stated where the full trial protocol could be accessed, all respectively. CONCLUSIONS: Reporting of several important methodological aspects of RCTs conducted in adult TBI populations improved over the years; however, the quality of reporting remains below an acceptable level. The small sample sizes suggest that many RCTs are likely underpowered. Further improvement is recommended in designing and reporting RCTs. PMID- 25497516 TI - Lifetime prevalence of chronic health conditions among persons with spinal cord injury. AB - OBJECTIVE: To assess lifetime prevalence of 7 chronic health conditions (CHCs) among a cohort of adults with chronic traumatic spinal cord injury (SCI). DESIGN: Cross-sectional. SETTING: Rehabilitation hospital. PARTICIPANTS: Adults with SCI who were >=18 years of age, were >=1 year postinjury, and had residual neurologic effects impeding full recovery (n=1678). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: CHCs were measured using questions from the Behavioral Risk Factor Surveillance System for diabetes (not including gestational), heart attack (also called a myocardial infarction), angina or coronary artery disease, stroke, hypertension (not including during pregnancy), high blood cholesterol, or cancer. RESULTS: Of participants, 49.5% reported having at least 1 CHC, with 23.2% reporting >=2 CHCs. The most frequently reported CHC was high cholesterol (29.3%) followed by hypertension (28.7%) and diabetes (11.8%). Although the prevalence of CHCs significantly increased with increasing age, only hypertension and cancer were significantly associated with years postinjury. Four CHCs (diabetes, coronary artery disease, hypertension, high cholesterol) were significantly related to mobility status as measured by injury level and ambulatory status. However, after controlling for age, years postinjury, sex, and race, mobility status became nonsignificant in relation to coronary artery disease, but it remained significantly associated with diabetes, hypertension, and high cholesterol. CONCLUSIONS: Clinicians should be aware of the risk of CHCs in persons with SCI and should screen for these conditions and regular maintenance activities related to SCI. PMID- 25497518 TI - Natural forces as agents: reconceptualizing the animate-inanimate distinction. AB - Research spanning multiple domains of psychology has demonstrated preferential processing of animate as compared to inanimate entities--a pattern that is commonly explained as due to evolutionarily adaptive behavior. Forces of nature represent a class of entities that are semantically inanimate but which behave as if they are animate in that they possess the ability to initiate movement and cause actions. We report an eye-tracking experiment demonstrating that natural forces are processed like animate entities during online sentence processing: they are easier to integrate with action verbs than instruments, and this effect is mediated by sentence structure. The results suggest that many cognitive and linguistic phenomena that have previously been attributed to animacy may be more appropriately attributed to perceived agency. To the extent that this is so, the cognitive potency of animate entities may not be due to vigilant monitoring of the environment for unpredictable events as argued by evolutionary psychologists but instead may be more adequately explained as reflecting a cognitive and linguistic focus on causal explanations that is adaptive because it increases the predictability of events. PMID- 25497517 TI - Acceleration metrics are responsive to change in upper extremity function of stroke survivors. AB - OBJECTIVES: To (1) determine whether acceleration metrics derived from monitoring outside of treatment are responsive to change in upper extremity (UE) function; and secondarily to (2) compare metric values during task-specific training and while in the free-living environment, and (3) establish metric associations with an in-clinic measure of movement capabilities. DESIGN: Before-after observational study. SETTING: Inpatient hospital (primary purpose); outpatient hospital (secondary purpose). PARTICIPANTS: Individuals (n=8) with UE hemiparesis <30 days poststroke (primary purpose); individuals (n=27) with UE hemiparesis >=6 months poststroke (secondary purpose). INTERVENTION: The inpatient sample was evaluated for UE movement capabilities and monitored with wrist-worn accelerometers for 22 hours outside of treatment before and after multiple sessions of task-specific training. The outpatient sample was evaluated for UE movement capabilities and monitored during a single session of task-specific training and the subsequent 22 hours outside clinical settings. MAIN OUTCOME MEASURES: Action Research Arm Test (ARAT) and acceleration metrics quantified from accelerometer recordings. RESULTS: Five metrics improved in the inpatient sample, along with UE function as measured on the ARAT: use ratio, magnitude ratio, variation ratio, median paretic UE acceleration magnitude, and paretic UE acceleration variability. Metric values were greater during task-specific training than in the free-living environment, and each metric was strongly associated with ARAT score. CONCLUSIONS: Multiple metrics that characterize different aspects of UE movement are responsive to change in function. Metric values are different during training than in the free living environment, providing further evidence that what the paretic UE does in the clinic may not generalize to what it does in everyday life. PMID- 25497519 TI - 18-month-olds comprehend indirect communicative acts. AB - From soon after their first birthdays young children are able to make inferences from a communicator's referential act (e.g., pointing to a container) to her overall social goal for communication (e.g., to inform that a searched-for toy is inside; see Behne, Carpenter, & Tomasello, 2005; Behne, Liszkowski, Carpenter, & Tomasello, 2012). But in such cases the inferential distance between referential act and communicative intention is still fairly close, as both container and searched-for toy lie in the direction of the pointing gesture. In the current study we tested 18- and 26-month-old children in a situation in which referential act and communicative goal were more distant: In the midst of a game, the child needed a certain toy. The experimenter then held up a key (that they knew in common ground could be used to open a container) to the child ostensively. In two control conditions the experimenter either inadvertently moved the key and so drew the child's attention to it non-ostensively or else held up the key for her own inspection intentionally but non-communicatively. Children of both ages took only the ostensive showing of the key, not the accidental moving or the non ostensive but intentional inspection of the key, as an indirect request to take the key and open the container to retrieve the toy inside. From soon after they start acquiring language young children thus are able to infer a communicator's social goal for communication not only from directly-referential acts, but from more indirect communicative acts as well. PMID- 25497521 TI - How many kinds of reasoning? Inference, probability, and natural language semantics. AB - The "new paradigm" unifying deductive and inductive reasoning in a Bayesian framework (Oaksford & Chater, 2007; Over, 2009) has been claimed to be falsified by results which show sharp differences between reasoning about necessity vs. plausibility (Heit & Rotello, 2010; Rips, 2001; Rotello & Heit, 2009). We provide a probabilistic model of reasoning with modal expressions such as "necessary" and "plausible" informed by recent work in formal semantics of natural language, and show that it predicts the possibility of non-linear response patterns which have been claimed to be problematic. Our model also makes a strong monotonicity prediction, while two-dimensional theories predict the possibility of reversals in argument strength depending on the modal word chosen. Predictions were tested using a novel experimental paradigm that replicates the previously-reported response patterns with a minimal manipulation, changing only one word of the stimulus between conditions. We found a spectrum of reasoning "modes" corresponding to different modal words, and strong support for our model's monotonicity prediction. This indicates that probabilistic approaches to reasoning can account in a clear and parsimonious way for data previously argued to falsify them, as well as new, more fine-grained, data. It also illustrates the importance of careful attention to the semantics of language employed in reasoning experiments. PMID- 25497520 TI - Pigeons acquire multiple categories in parallel via associative learning: a parallel to human word learning? AB - Might there be parallels between category learning in animals and word learning in children? To examine this possibility, we devised a new associative learning technique for teaching pigeons to sort 128 photographs of objects into 16 human language categories. We found that pigeons learned all 16 categories in parallel, they perceived the perceptual coherence of the different object categories, and they generalized their categorization behavior to novel photographs from the training categories. More detailed analyses of the factors that predict trial-by trial learning implicated a number of factors that may shape learning. First, we found considerable trial-by-trial dependency of pigeons' categorization responses, consistent with several recent studies that invoke this dependency to claim that humans acquire words via symbolic or inferential mechanisms; this finding suggests that such dependencies may also arise in associative systems. Second, our trial-by-trial analyses divulged seemingly irrelevant aspects of the categorization task, like the spatial location of the report responses, which influenced learning. Third, those trial-by-trial analyses also supported the possibility that learning may be determined both by strengthening correct stimulus-response associations and by weakening incorrect stimulus-response associations. The parallel between all these findings and important aspects of human word learning suggests that associative learning mechanisms may play a much stronger part in complex human behavior than is commonly believed. PMID- 25497522 TI - Effects of prediction and contextual support on lexical processing: prediction takes precedence. AB - Readers may use contextual information to anticipate and pre-activate specific lexical items during reading. However, prior studies have not clearly dissociated the effects of accurate lexical prediction from other forms of contextual facilitation such as plausibility or semantic priming. In this study, we measured electrophysiological responses to predicted and unpredicted target words in passages providing varying levels of contextual support. This method was used to isolate the neural effects of prediction from other potential contextual influences on lexical processing. While both prediction and discourse context influenced ERP amplitudes within the time range of the N400, the effects of prediction occurred much more rapidly, preceding contextual facilitation by approximately 100 ms. In addition, a frontal, post-N400 positivity (PNP) was modulated by both prediction accuracy and the overall plausibility of the preceding passage. These results suggest a unique temporal primacy for prediction in facilitating lexical access. They also suggest that the frontal PNP may index the costs of revising discourse representations following an incorrect lexical prediction. PMID- 25497523 TI - Language influences number processing--a quadrilingual study. AB - Reading/writing direction or number word formation influence performance even in basic numerical tasks such as magnitude comparison. However, so far the interaction of these language properties has not been evaluated systematically. In this study we tested English, German, Hebrew, and Arab participants realizing a natural 2 * 2 design of reading/writing direction (left-to-right vs. right-to left) and number word formation (non-inverted vs. inverted, i.e., forty-seven vs. seven-and-forty). Symbolic number magnitude comparison was specifically influenced by the interaction of reading/writing direction and number word formation: participants from cultures where reading direction and the order of tens and units in number words are incongruent (i.e., German and Hebrew) exhibited more pronounced unit interference in place-value integration. A within group comparison indicated that this effect was not due to differences in education. Thus, basic cultural differences in numerical cognition were driven by natural language variables and their specific combination. PMID- 25497524 TI - Multi-modal distraction: insights from children's limited attention. AB - How does the multi-sensory nature of stimuli influence information processing? Cognitive systems with limited selective attention can elucidate these processes. Six-year-olds, 11-year-olds and 20-year-olds engaged in a visual search task that required them to detect a pre-defined coloured shape under conditions of low or high visual perceptual load. On each trial, a peripheral distractor that could be either compatible or incompatible with the current target colour was presented either visually, auditorily or audiovisually. Unlike unimodal distractors, audiovisual distractors elicited reliable compatibility effects across the two levels of load in adults and in the older children, but high visual load significantly reduced distraction for all children, especially the youngest participants. This study provides the first demonstration that multi-sensory distraction has powerful effects on selective attention: Adults and older children alike allocate attention to potentially relevant information across multiple senses. However, poorer attentional resources can, paradoxically, shield the youngest children from the deleterious effects of multi-sensory distraction. Furthermore, we highlight how developmental research can enrich the understanding of distinct mechanisms controlling adult selective attention in multi-sensory environments. PMID- 25497525 TI - Short- and long-term mortality and hospital readmissions among patients with new hospitalization for heart failure: A population-based investigation from Italy. AB - OBJECTIVE: Predictors of mortality and readmission among patients hospitalized for the first time for heart failure (HF) were investigated for a large, unselected population. METHODS: The cohort of 13,171 patients in the Lombardy Region (Italy), all of whom were aged 50years or older and survived their first hospitalization for HF during 2011, were followed after discharge. Mortality and readmission within 30days and one year of index discharge were investigated. Kaplan-Meier estimator and Cox model were respectively used to estimate the cumulative proportions of patients experiencing the outcomes and the hazard ratio (HR) for the association between selected covariates and time of outcome onset. RESULTS: Within 30days of index discharge, 4.7% and 4.3% of the cohort members died or were readmitted for HF, respectively, while 22.6% and 57.2% of them died or were readmitted for any cause within one year of index discharge. Older age was an independent predictor of mortality at both 30days and one year. One-year mortality was affected by the use of diuretics, mineralocorticoid receptor antagonists and antigout preparations and by previous hospitalization for respiratory and cerebrovascular diseases. Younger age, use of antidiabetics, diuretics, other antihypertensives, NSAIDs and antigout preparations and previous hospitalization for renal, respiratory, coronary heart and cerebrovascular disease, were independent predictors of hospital readmission. CONCLUSION: Short- and long-term mortality and readmissions after first hospitalization for HF are high and heterogeneous across different patient subgroups. Characterization of hospitalized HF is very important in assisting clinicians in decision-making and targeting treatment of high-risk patients. PMID- 25497526 TI - The German CPU Registry: Dyspnea independently predicts negative short-term outcome in patients admitted to German Chest Pain Units. AB - BACKGROUND: While dyspnea is a common symptom in patients admitted to Chest Pain Units (CPUs) little is known about the impact of dyspnea on their outcome. The purpose of this study was to evaluate the impact of dyspnea on the short-term outcome of CPU patients. METHODS: We analyzed data from a total of 9169 patients admitted to one of the 38 participating CPUs in this registry between December 2008 and January 2013. Only patients who underwent coronary angiography for suspected ACS were included. 2601 patients (28.4%) presented with dyspnea. RESULTS: Patients with dyspnea at admission were older and frequently had a wide range of comorbidities compared to patients without dyspnea. Heart failure symptoms in particular were more common in patients with dyspnea (21.0% vs. 5.3%, p<0.05) at admission. Importantly, in patients presenting with dyspnea the 3month mortality was fourfold higher compared to patients without dyspnea (8.6% vs. 2.1%, p<0.05, OR death: 4.40 95% CI 3.14-6.03). Interestingly, the mortality estimated from the GRACE risk score was below the actual mortality assessed after the 3month follow-up. After adjustment for the GRACE risk score or for heart failure, dyspnea remained highly predictive of death and myocardial infarction within 3months (OR death adjusted for heart failure: 2.99 95% CI 1.99-4.47 and OR death adjusted for GRACE risk score: 3.37 95% CI 2.27-4.99). CONCLUSION: Dyspnea is a common symptom in CPU patients. Our data show that dyspnea is associated with a fourfold higher 3month mortality which is underestimated by the established ACS risk scores. To improve their predictive value we therefore propose to add dyspnea as an item to common risk scores. PMID- 25497527 TI - Individual-patient visit-by-visit office and ambulatory blood pressure measurements over 24months in patients undergoing renal denervation for hypertension. AB - BACKGROUND: Renal denervation (RDN) is a promising treatment option in addition to medical antihypertensive treatment in patients suffering from resistant hypertension. Despite the growing interest in RDN, only few long-term results are published so far. METHODS: We systematically investigated the effects of RDN on ABPM in a consecutive series of patients with resistant hypertension out to 24 months. Office BP measurements and ABPM assessment were offered at 3, 6, 12 and 24 months. The patients with an average systolic BP reduction of more than 10 mmHg in office BP 6months after RDN were classified as responders. Additional to this classical responder concept, we categorized response to RDN by an individual patient visit-by-visit evaluation of office BP and 24-hour-BP, separately. RESULTS: We included 32 patients. In 21 patients (65.6%) we found a mean systolic BP reduction >10 mmHg in office BP six months after RDN. These patients were classified as responders. In responders, mean office BP dropped from 175.3 +/- 15.9/96 +/- 14.2 mmHg to 164.8 +/- 24.4/93.2 +/- 10.4 mmHg (p=0.040/p=0.323) and mean 24-h BP in ABPM decreased from 146.8 +/- 17.0/89.1 +/- 11 mmHg to 136.8 +/- 15.0/83.2 +/- 10.7 mmHg after 24 months (p=0.034/p=0.014). Additionally, we performed a visit-by-visit evaluation of all patients and results were divided in larger-than-median and smaller-than-median response. By this evaluation, we found a high variation of office BP reductions and the 24-hour BP results demonstrated a significant BP reduction in patients with larger-than-median response, which sustained over the 24 months of follow-up. CONCLUSIONS: In contrast to the observed variation of office BP measurements, ABPM demonstrated a reproducible and sustained significant BP reduction in patients with larger-than-median response to RDN. PMID- 25497528 TI - Reply to the letter "Prognostic value of late gadolinium enhancement in cardiomyopathy: Causative risk factor or surrogate marker?". PMID- 25497529 TI - Catheter ablation of longstanding persistent atrial fibrillation: Let sleeping dogs lie. PMID- 25497530 TI - Prognosis of arrhythmia patients with implantable cardioverter-defibrillator with special reference to heart rate and QRS duration. PMID- 25497531 TI - Association of nonculprit plaque characteristics with transient slow flow phenomenon during percutaneous coronary intervention. AB - BACKGROUND: The slow flow (SF) phenomenon is more prevalent in patients with acute coronary syndrome (ACS), who frequently exhibit vulnerable plaques in remote coronary arteries. We aimed to clarify the impact of nonculprit plaque characteristics on the occurrence of SF using multidetector computed tomography (MDCT). METHODS: The study population comprised 180 consecutive patients with non ST-segment elevation ACS (NSTE-ACS) who underwent MDCT before intervention. The characteristics of culprit and nonculprit lesions were compared between patients with and without SF. RESULTS: SF was observed in 43 (23.8%) of the 180 patients. The prevalence of positive remodeling (PR), low-attenuation plaque (LAP), and napkin-ring sign (NRS) in culprit lesion was significantly higher in the SF group than in the non-SF group (86.1% vs. 39.4%; p<0.001, 81.4% vs. 18.3%; p<0.001, and 65.1% vs. 16.1%; p<0.001, respectively). The same result was observed for nonculprit lesions (58.1% vs. 14.6%; p<0.001, 45.2% vs. 6.6%; p<0.001, and 14.3% vs. 4.9%; p<0.04, respectively). Multivariate analysis revealed LAP [odds ratio (OR), 12.8; 95% confidence interval (CI), 3.7-54.7; p<0.001], and NRS (OR, 5.1; 95% CI, 1.3-25.3; p=0.03) in culprit lesions and PR (OR, 4.7; 95% CI, 1.1-22.2; p=0.04) in nonculprit lesions were independently associated with SF. CONCLUSIONS: The plaque characteristics of nonculprit lesions are associated with the occurrence of SF during percutaneous coronary intervention. Assessment of plaque characteristics of both culprit and nonculprit lesions using MDCT may be useful for the prediction of SF. PMID- 25497532 TI - Detection of multiregional transient myocardial ischaemia using a novel 80 electrode body surface Delta map. PMID- 25497533 TI - Wolff-Parkinson-White syndrome with bundle branch and fascicular block: The diagnostic clue of electrocardiogram. PMID- 25497534 TI - Differences in neurohormonal activity partially explain the obesity paradox in patients with heart failure: The role of sympathetic activation. AB - BACKGROUND: Obese patients with chronic Heart Failure (HF) have better outcome than their lean counterparts, although little is known about the pathophysiology of this obesity paradox. Our aim was to evaluate the hypothesis that patients with chronic HF and obesity (defined as body mass index (BMI)>=30kg/m(2)), may have an attenuated neurohormonal activation in comparison with non-obese patients. METHODS AND RESULTS: The present study is the post-hoc analysis of a cohort of 742 chronic HF patients from a single-center study evaluating sympathetic activation by measuring baseline levels of norepinephrine (NE). Obesity was present in 33% of patients. Higher BMI and obesity were significantly associated with lower NE levels in multivariable linear regression models adjusted for covariates (p<0.001). Addition to NE in multivariate Cox proportional hazard models attenuated the prognostic impact of BMI in terms of outcomes. Finally, when we explored the prognosis impact of raised NE levels (>70th percentile) carrying out a separate analysis in obese and non-obese patients we found that in both groups NE remained a significant independent predictor of poorer outcomes, despite the lower NE levels in patients with chronic HF and obesity: all-cause mortality hazard ratio=2.37 (95% confidence interval, 1.14-4.94) and hazard ratio=1.59 (95% confidence interval, 1.05-2.4) in obese and non-obese respectively; and cardiovascular mortality hazard ratio=3.08 (95% confidence interval, 1.05-9.01) in obese patients and hazard ratio=2.08 (95% confidence interval, 1.42-3.05) in non-obese patients. CONCLUSION: Patients with chronic HF and obesity have significantly lower sympathetic activation. This finding may partially explain the obesity paradox described in chronic HF patients. PMID- 25497536 TI - Treatment of Kounis syndrome. PMID- 25497535 TI - Troponin T: Correlation with location and volume of acute brain infarction. AB - BACKGROUND: The troponin T (cTnT) is frequently elevated in acute ischemic stroke (AIS) patients. However, the relationship, if any, between the cTnT level and brain infarction remains to be established. The aim was to investigate the possible correlation between the location and volume of brain infarction and the cardiac cTnT serum level in AIS patients. METHODS: The study consisted of consecutive AIS patients admitted within 12h of stroke onset. The location and volume of the acute ischemic lesion was assessed with magnetic resonance imaging. Standard laboratory tests, including cTnT and repeated electrocardiograms, were performed at admission and after 4h. Correlations between the cTnT level and the location and volume of brain infarction and baseline parameters were tested with a Spearman correlation coefficient. Univariate and multiple logistic regression analysis (LRA) were used to determine the possible predictors of cTnT elevation. RESULTS: Out of the 200 enrolled patients, elevated cTnT was present in 71 (36%). No correlation was found between the cTnT serum levels and the location (P>0.05) nor volume of brain infarction (r=0.05, P=0.48). LRA identified creatinine (OR: 1.26 per 10MUmol/L increase; 95% CI: 1.043-1.524), NT-proBNP (OR: 1.05 per 100MUg/L increase; 95% CI: 1.018-1.093) and male gender (OR: 3.674; 95% CI: 1.025 13.164) as significant independent predictors of pathological elevation of cTnT. CONCLUSIONS: Although elevated cTnT serum level is relatively frequent in AIS patients within the first 12h of stroke onset, it is not related to the location or volume of brain infarction. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov (No. NCT01541163). PMID- 25497537 TI - Elevated mitochondrial membrane potential of circulating monocyte-platelet aggregates in patients with coronary heart disease. PMID- 25497538 TI - A massive pericardial effusion in a cancer patient. PMID- 25497539 TI - Cardiac programming in rats submitted to leptin treatment during lactation. PMID- 25497540 TI - Obstructive sleep apnea and the risk of ischemic stroke in patients with atrial fibrillation. PMID- 25497541 TI - RETRACTED: Correlation between the number and origin of circulating microparticles and fibrin clot properties in patients with coronary artery disease. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted after the journal was approached by its authors bringing important matters to our attention. It has been retracted due to the fact that following this publication there appeared concerns about provenance of the data presented and the authorship of this paper. PMID- 25497542 TI - Combined drug-eluting stent and supplementary paclitaxel-eluting balloon application at side branch ostium for in-stent restenotic true bifurcation lesion. PMID- 25497543 TI - Blood pressure abnormalities in adults born moderately preterm and their children. PMID- 25497544 TI - Exercise cardiac power and the risk of sudden cardiac death in a long-term prospective study. AB - BACKGROUND: Little is known about exercise cardiac power and the risk of sudden cardiac death. The aim of this study was to examine the relationship of exercise cardiac power (ECP), defined as a ratio of directly measured maximal oxygen uptake with peak systolic blood pressure during exercise, with the risk for sudden cardiac death (SCD). METHODS: This prospective study was based on 2358 men who participated in exercise stress test at baseline. During an average follow-up of 20 years 205 SCDs occurred. RESULTS: Men with ECP (<8.2 mL/mmHg, lowest quartile) had a 4.6-fold (95% CI 2.8-7.5, p<0.001) increased risk of SCD as compared to with ECP in the highest quartile (>12.8mL/mmHg) after adjusting for age and examination years. Men with low ECP (<8.2mL/mmHg) had markedly increased risk of SCD (RR 3.9, 95% CI 2.19-7.14, p<0.001) after adjustment for conventional risk factors and left ventricular hypertrophy, whereas for progressive adjustment for resting systolic blood pressure, the respective risk among men with lowest ECP was 2.5 (95% CI 1.46-4.22, p<0.001). After adding ECP in the multivariate model, the Harrell C-index increased from 0.760 to 0.778 showing the significant incremental value of ECP in predicting SCD. The integrated discrimination improvement was 0.014 (p=0.004). CONCLUSIONS: Low ECP provides a non-invasive and easily available measure for the prediction of SCD and may help in identifying men with high risk for SCD. PMID- 25497545 TI - Oleuropein prevents angiotensin II-mediated: Human vascular progenitor cell depletion. PMID- 25497546 TI - Implantable cardioverter defibrillator lead placement in the right ventricular outflow tract in a patient with Brugada syndrome and persistent left superior vena cava. PMID- 25497547 TI - A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. AB - We use in situ Hi-C to probe the 3D architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1 kb resolution. We find that genomes are partitioned into contact domains (median length, 185 kb), which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ~10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs "facing" one another. The inactive X chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats. PMID- 25497549 TI - Renalase is a novel target gene of hypoxia-inducible factor-1 in protection against cardiac ischaemia-reperfusion injury. AB - AIMS: Renalase, an enzyme that can metabolize catecholamine, was recently reported to attenuate the ischaemia/reperfusion (I/R)-induced cardiac injury. This work was undertaken to investigate the functions and regulation mechanisms of renalase in protection against cardiac I/R injury. METHODS AND RESULTS: An elevated level of renalase was found in C57BL/6 mice challenged with I/R injury. Then, we generated a mouse model with cardiac administration of cholesterol conjugated renalase siRNA followed by I/R operation. The mice treated with renalase siRNA exhibited increased infarction size and decreased cardiac function compared with the scramble siRNA group. Subsequently, we identified four potential hypoxia-inducible factor-1 alpha (HIF-1alpha)-binding motifs in the promoter of renalase through bioinformatics approaches. Dual-luciferase reporter assay, electrophoretic mobility shift assay, chromatin immunoprecipitation assay, and western blot were conducted and demonstrated that renalase was a novel target gene of HIF-1alpha. Furthermore, administration of renalase reduced the infarct area and rescued the deterioration of cardiac function in myocardial HIF-1alpha knockdown mice subjected to I/R injury. In addition, the levels of norepinephrine in serum as well as nicotinamide adenine dinucleotide (NAD(+)) and ATP in myocardium were determined, which implied that cardiac protection of renalase against I/R may be related, at least in part, to its metabolism of catecholamine and regulation of energy. CONCLUSION: These findings have revealed renalase as a novel target gene of HIF-1alpha in protection against myocardial I/R injury, which provided a basis for therapeutic strategies for enhancing cardiomyocyte survival in patients associated with ischaemic heart diseases. PMID- 25497548 TI - High-resolution sequencing and modeling identifies distinct dynamic RNA regulatory strategies. AB - Cells control dynamic transitions in transcript levels by regulating transcription, processing, and/or degradation through an integrated regulatory strategy. Here, we combine RNA metabolic labeling, rRNA-depleted RNA-seq, and DRiLL, a novel computational framework, to quantify the level; editing sites; and transcription, processing, and degradation rates of each transcript at a splice junction resolution during the LPS response of mouse dendritic cells. Four key regulatory strategies, dominated by RNA transcription changes, generate most temporal gene expression patterns. Noncanonical strategies that also employ dynamic posttranscriptional regulation control only a minority of genes, but provide unique signal processing features. We validate Tristetraprolin (TTP) as a major regulator of RNA degradation in one noncanonical strategy. Applying DRiLL to the regulation of noncoding RNAs and to zebrafish embryogenesis demonstrates its broad utility. Our study provides a new quantitative approach to discover transcriptional and posttranscriptional events that control dynamic changes in transcript levels using RNA sequencing data. PMID- 25497550 TI - Marine n-3 PUFAs modulate IKs gating, channel expression, and location in membrane microdomains. AB - AIMS: Polyunsaturated fatty n-3 acids (PUFAs) have been reported to exhibit antiarrhythmic properties. However, the mechanisms of action remain unclear. We studied the electrophysiological effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on IKs, and on the expression and location of Kv7.1 and KCNE1. METHODS AND RESULTS: Experiments were performed using patch-clamp, western blot, and sucrose gradient techniques in COS7 cells transfected with Kv7.1/KCNE1 channels. Acute perfusion with both PUFAs increased Kv7.1/KCNE1 current, this effect being greater for DHA than for EPA. Similar results were found in guinea pig cardiomyocytes. Acute perfusion of either PUFA slowed the activation kinetics and EPA shifted the activation curve to the left. Conversely, chronic EPA did not modify Kv7.1/KCNE1 current magnitude and shifted the activation curve to the right. Chronic PUFAs decreased the expression of Kv7.1, but not of KCNE1, and induced spatial redistribution of Kv7.1 over the cell membrane. Cholesterol depletion with methyl-beta-cyclodextrin increased Kv7.1/KCNE1 current magnitude. Under these conditions, acute EPA produced similar effects than those induced in non-cholesterol-depleted cells. A ventricular action potential computational model suggested antiarrhythmic efficacy of acute PUFA application under IKr block. CONCLUSIONS: We provide evidence that acute application of PUFAs increases Kv7.1/KCNE1 through a probably direct effect, and shows antiarrhythmic efficacy under IKr block. Conversely, chronic EPA application modifies the channel activity through a change in the Kv7.1/KCNE1 voltage-dependence, correlated with a redistribution of Kv7.1 over the cell membrane. This loss of function may be pro-arrhythmic. This shed light on the controversial effects of PUFAs regarding arrhythmias. PMID- 25497555 TI - Genotype effect on lifespan following vitellogenin knockdown. AB - Honey bee workers display remarkable flexibility in the aging process. This plasticity is closely tied to behavioral maturation. Workers who initiate foraging behavior at earlier ages have shorter lifespans, and much of the variation in total lifespan can be explained by differences in pre-foraging lifespan. Vitellogenin (Vg), a yolk precursor protein, influences worker lifespan both as a regulator of behavioral maturation and through anti-oxidant and immune functions. Experimental reduction of Vg mRNA, and thus Vg protein levels, in wild type bees results in precocious foraging behavior, decreased lifespan, and increased susceptibility to oxidative damage. We sought to separate the effects of Vg on lifespan due to behavioral maturation from those due to immune and antioxidant function using two selected strains of honey bees that differ in their phenotypic responsiveness to Vg gene knockdown. Surprisingly, we found that lifespans lengthen in the strain described as behaviorally and hormonally insensitive to Vg reduction. We then performed targeted gene expression analyses on genes hypothesized to mediate aging and lifespan: the insulin-like peptides (Ilp1 and 2) and manganese superoxide dismutase (mnSOD). The two honey bee Ilps are the most upstream components in the insulin-signaling pathway, which influences lifespan in Drosophila melanogaster and other organisms, while manganese superoxide dismutase encodes an enzyme with antioxidant functions in animals. We found expression differences in the llps in fat body related to behavior (llp1 and 2) and genetic background (Ilp2), but did not find strain by treatment effects. Expression of mnSOD was also affected by behavior and genetic background. Additionally, we observed a differential response to Vg knockdown in fat body expression of mnSOD, suggesting that antioxidant pathways may partially explain the strain-specific lifespan responses to Vg knockdown. PMID- 25497556 TI - Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: a systematic review and meta-analysis. AB - PURPOSE: To perform a systematic review and meta-analysis to compare the clinical outcomes and toxicity of hepatocellular carcinoma (HCC) patients treated with charged particle therapy (CPT) with those of individuals receiving photon therapy. METHODS: We identified relevant clinical studies through searching databases. Primary outcomes of interest were overall survival (OS) at 1, 3, 5 years, progression-free survival (PFS), and locoregional control (LC) at longest follow-up. RESULTS: 73 cohorts from 70 non-comparative observational studies were included. Pooled OS was significantly higher at 1, 3, 5 years for CPT than for conventional radiotherapy (CRT) [relative risk (RR) 1.68, 95% CI 1.22-2.31; p<0.001; RR 3.46, 95% CI: 1.72-3.51, p<0.001; RR 25.9, 95% CI: 1.64-408.5, p=0.02; respectively]. PFS and LC at longest follow-up was also significantly higher for CPT than for CRT (p=0.013 and p<0.001, respectively), while comparable efficacy was found between CPT and SBRT in terms of OS, PFS and LC at longest follow-up. Additionally, high-grade acute and late toxicity associated with CPT was lower than that of CRT and SBRT. CONCLUSION: Survival rates for CPT are higher than those for CRT, but similar to SBRT in patients with HCC. Toxicity tends to be lower for CPT compared to photon radiotherapy. PMID- 25497557 TI - Heart dose reduction by prone deep inspiration breath hold in left-sided breast irradiation. AB - BACKGROUND AND PURPOSE: Cardiac disease has been related to heart dose after left sided breast radiotherapy. This trial evaluates the heart sparing ability and feasibility of deep inspiration breath hold (DIBH) in the prone position for left sided whole breast irradiation (WBI). MATERIALS AND METHODS: Twelve patients underwent CT-simulation in supine shallow breathing (SB), supine DIBH, prone SB and prone DIBH. A validation cohort of 38 patients received prone SB and prone DIBH CT-scans; the last 30 patients were accepted for prone DIBH treatment. WBI was planned with a prescription dose of 40.05 Gy. RESULTS: DIBH was able to reduce (p<0.001) heart dose in both positions, with results for prone DIBH at least as favorable as for supine DIBH. Mean heart dose was lowered from 2.2 Gy for prone SB to 1.3 Gy for prone DIBH (p<0.001), while preserving the lung sparing ability of prone positioning. Moreover prone DIBH nearly consistently reduced mean heart dose to less then 2 Gy, regardless of breast volume. All patients were able to perform the simulation procedure, 28/30 patients were treated with prone DIBH. CONCLUSIONS: This trial demonstrates the ability and feasibility of prone DIBH to acquire optimal heart and lung sparing for left sided WBI. PMID- 25497558 TI - Phase II trial of recombinant human endostatin in combination with concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer. AB - PURPOSE: The objective of this study was to evaluate the efficacy and safety of Endostar combined with concurrent chemoradiotherapy (CCRT) in patients with stage III non-small-cell lung cancer (NSCLC). METHODS: Patients with unresectable stage III NSCLC were treated with Endostar (7.5mg/m(2)/d) for 7days at weeks 1, 3, 5, and 7, while two cycles of docetaxel (65mg/m(2)) and cisplatin (65mg/m(2)) were administered on days 8 and 36, with concurrent thoracic radiation to a dose of 60 66Gy. Primary end points were short-term efficacy and treatment-related toxicity. RESULTS: Fifty patients were enrolled into the study, and 48 were assessable. Of the 48 patients, 83% had stage IIIB and 65% had N3 disease. Median follow-up was 25.0months. Overall response rate was 77%. The estimated median progression-free survival (PFS) was 9.9months, and the estimated median overall survival (OS) was 24.0months. The 1-, 2-, and 3-year local control rates were 75%, 67%, and 51%, PFS rates were 48%, 27%, and 16%, and OS rates were 81%, 50%, and 30%, respectively. All toxicities were tolerable with proper treatment. CONCLUSIONS: The combination of Endostar with CCRT for locally advanced NSCLC patients was feasible and showed promising survival and local control rates. PMID- 25497559 TI - A review of the equine age-related changes in the immune system: comparisons between human and equine aging, with focus on lung-specific immune-aging. AB - The equine aging process involves many changes to the immune system that may be related to genetics, the level of nutrition, the environment and/or an underlying subclinical disease. Geriatric horses defined as horses above the age of 20, exhibit a decline in body condition, muscle tone and general well-being. It is not known whether these changes contribute to decreased immune function or are the result of declining immune function. Geriatric years are characterized by increased susceptibility to infections and a reduced antibody response to vaccination as a result of changes in the immune system. Humans and horses share many of these age-related changes, with only a few differences. Thus, inflamm aging and immunosenescence are well-described phenomena in both human and equine research, particularly in relation to the peripheral blood and especially the T cell compartment. However, the lung is faced with unique challenges because of its constant interaction with the external environment and thus may not share similarities to peripheral blood when considering age-related changes in immune function. Indeed, recent studies have shown discrepancies in cytokine mRNA and protein expression between the peripheral blood and bronchoalveolar lavage immune cells. These results provide important evidence that age-related immune changes or 'dys-functions' are organ-specific. PMID- 25497560 TI - [The value of cooperation]. PMID- 25497561 TI - [New production partners for Swiss Archive for Veterinary Medicine (SAT) and thanks to publisher Hans Huber]. PMID- 25497562 TI - Diagnostic imaging and endoscopic finding in dogs and cats with gastric tumors: a review. AB - Medical imaging is an essential part of the diagnostic workup of many gastrointestinal disorders. This paper reviews imaging and endoscopy of gastric tumors in dogs and cats and the techniques used. The appearance of the normal as well as the various aspects of gastric tumors are described for these different modalities. Plain radiography is widely available but has limited diagnostic value. Contrast radiography has higher sensitivity but is laborious and time consuming. Ultrasonography (if an adequate acoustic window is available), endosonography and endoscopy are the most appropriate modalities for diagnosing gastric tumors. They are especially useful when obtaining samples for cytologic or histopathologic examination, because the imaging modalities do not always differentiate between inflammatory or infectious conditions and neoplastic disorders. Hydro-helical CT was found helpful for evaluating the location and local invasiveness of the lesion. Ultrasonography and endoscopy are useful modalities for taking adequate biopsies. PMID- 25497563 TI - [Usefulness of lactate dehydrogenase concentration in thoracic and abdominal fluid of dogs]. AB - The aims of this study were to investigate the usefulness of LDH measurement in effusions in dogs to classify the fluid as exudate or transudate and to classify the fluid based on the pathophysiological mechanism. In thoracic (n = 107) and abdominal (n = 199) fluid of dogs cell count, protein and LDH concentrations were measured. The fluid was retrospectively categorized into exudate (group A), protein-poor (B) or protein-rich transudate (C) as well as based on pathophysiology into the following five groups (group 1 - 5): hemorrhagic, chylous, inflammatory, oncotic and congestive. In thoracic and abdominal fluid LDH concentrations were significantly higher in group A compared to group B and C. There was a significant difference of LDH concentration between the groups 1 to 5 in both thoracic and abdominal fluid, however there was a large overlap between the five groups. While fluid LDH measurement in dogs is helpful to distinguish exudate from transudate it is only of little help to elucidate the pathophysiological cause. PMID- 25497564 TI - Comparison of accuracy of pregnancy-associated glycoprotein (PAG) concentration in blood and milk for early pregnancy diagnosis in cows. AB - The aim of this study was to compare two methods of early pregnancy diagnosis by determining pregnancy-associated glycoprotein (PAG) concentration in blood and PAG concentration in milk. Blood and milk samples were obtained on days 0 (AI day), 14, 21, 28, 35, 49, 63, 77, 91 and 105 of gestation from 60 lactating Holstein Frisian cows from one herd, carrying live fetuses. To determine PAG concentration a specific RIA system (RIA-706) was used. PAG concentration in blood and milk increased after 28 days of pregnancy, with blood concentrations being significantly higher than in milk. However, the accuracy of both tests at this time point was similar (sensitivity: 92 % in blood, 93 % in milk; specificity 53 % and 60 % respectively). None of the tests were able to detect open cows properly at this stage. On day 35 of gestation sensitivity (100 % for blood, 97 % for milk) and specificity (100 % for blood, 100 % for milk) were high enough to be used for reliable pregnancy diagnosis. The accuracy (sensitivity and specificity) for PAG concentrations in blood and milk for the rest of the study was 100 %. Our investigation shows that PAG determination in milk is a stress free and non-invasive method for early pregnancy diagnosis in cattle. PMID- 25497565 TI - Transient Fanconi syndrome with severe polyuria and polydipsia in a 4-year old Shih Tzu fed chicken jerky treats. AB - Acquired Fanconi syndrome is characterized by inappropriate urinary loss of amino acids, bicarbonate, electrolytes, and water. It has recently been described in dogs fed chicken jerky treats from China, a new differential diagnosis to the classical inciting infectious diseases (e.g. leptospirosis, pyelonephritis) and toxins. A dog fed exclusively chicken jerky treats purchased in Switzerland was presented to our clinic with severe polyuria, polydipsia and profound electrolyte and acid base disturbances. Other inciting causes of Fanconi syndrome were ruled out. The requirement of a very intensive supportive treatment in this dog stands in contrast to treatment of chronic forms of Fanconi syndrome as described in the Basenji. This intensive therapy and the associated monitoring can be a real challenge and a limiting factor for the prognosis of acquired Fanconi syndrome. Veterinarians should be aware of the risk of excessive feeding of chicken jerky treats. PMID- 25497566 TI - [Anesthesia and Analgesia in small animals and pets]. PMID- 25497567 TI - [Active participation in the first veterinary - Osteopathy Congress of EVSO ]. PMID- 25497568 TI - [From the GST- Presidents' Conference from October 23, 2014]. PMID- 25497569 TI - [The responsibility of the veterinarian in the supply of veterinary medicines]. PMID- 25497571 TI - A joined role of canopy and reversal cells in bone remodeling--lessons from glucocorticoid-induced osteoporosis. AB - Successful bone remodeling demands that osteoblasts restitute the bone removed by osteoclasts. In human cancellous bone, a pivotal role in this restitution is played by the canopies covering the bone remodeling surfaces, since disruption of canopies in multiple myeloma, postmenopausal- and glucocorticoid-induced osteoporosis is associated with the absence of progression of the remodeling cycle to bone formation, i.e., uncoupling. An emerging concept explaining this critical role of canopies is that they represent a reservoir of osteoprogenitors to be delivered to reversal surfaces. In postmenopausal osteoporosis, this concept is supported by the coincidence between the absence of canopies and scarcity of cells on reversal surfaces together with abortion of the remodeling cycle. Here we tested whether this concept holds true in glucocorticoid-induced osteoporosis. A histomorphometric analysis of iliac crest biopsies from patients exposed to long-term glucocorticoid treatment revealed a subpopulation of reversal surfaces corresponding to the characteristics of arrest found in postmenopausal osteoporosis. Importantly, these arrested reversal surfaces were devoid of canopy coverage in almost all biopsies, and their prevalence correlated with a deficiency in bone forming surfaces. Taken together with the other recent data, the functional link between canopies, reversal surface activity, and the extent of bone formation surface in postmenopausal- and glucocorticoid-induced osteoporosis, supports a model where bone restitution during remodeling demands recruitment of osteoprogenitors from the canopy onto reversal surfaces. These data suggest that securing the presence of functional local osteoprogenitors deserves attention in the search of strategies to prevent the bone loss that occurs during bone remodeling in pathological situations. PMID- 25497570 TI - AMP-activated protein kinase (AMPK) activity negatively regulates chondrogenic differentiation. AB - Chondrocytes are derived from mesenchymal stem cells, and play an important role in cartilage formation. Sex determining region Y box (Sox) family transcription factors are essential for chondrogenic differentiation, whereas the intracellular signal pathways of Sox activation have not been clearly elucidated. AMP-activated protein kinase (AMPK) is a serine-threonine kinase generally regarded as a key regulator of cellular energy homeostasis. It is known that the catalytic alpha subunit of AMPK is activated by upstream AMPK kinases (AMPKKs) including liver kinase B1 (LKB1). We have previously reported that AMPK is a negative regulator of osteoblastic differentiation. Here, we have explored the role of AMPK in chondrogenic differentiation using in vitro culture models. The phosphorylation level of the catalytic AMPK alpha subunit significantly decreased during chondrogenic differentiation of primary chondrocyte precursors as well as ATDC-5, a well-characterized chondrogenic cell line. Treatment with metformin, an activator of AMPK, significantly reduced cartilage matrix formation and inhibited gene expression of sox6, sox9, col2a1 and aggrecan core protein (acp). Thus, chondrocyte differentiation is functionally associated with decreased AMPK activity. PMID- 25497573 TI - Chemotherapy-induced pulmonary hypertension: role of alkylating agents. AB - Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents. PMID- 25497572 TI - Tibia and radius bone geometry and volumetric density in obese compared to non obese adolescents. AB - Childhood obesity is associated with biologic and behavioral characteristics that may impact bone mineral density (BMD) and structure. The objective was to determine the association between obesity and bone outcomes, independent of sexual and skeletal maturity, muscle area and strength, physical activity, calcium intake, biomarkers of inflammation, and vitamin D status. Tibia and radius peripheral quantitative CT scans were obtained in 91 obese (BMI>97th percentile) and 51 non-obese adolescents (BMI>5th and <85th percentiles). Results were converted to sex- and race-specific Z-scores relative to age. Cortical structure, muscle area and muscle strength (by dynamometry) Z-scores were further adjusted for bone length. Obese participants had greater height Z-scores (p<0.001), and advanced skeletal maturity (p<0.0001), compared with non-obese participants. Tibia cortical section modulus and calf muscle area Z-scores were greater in obese participants (1.07 and 1.63, respectively, both p<0.0001). Tibia and radius trabecular and cortical volumetric BMD did not differ significantly between groups. Calf muscle area and strength Z-scores, advanced skeletal maturity, and physical activity (by accelerometry) were positively associated with tibia cortical section modulus Z-scores (all p<0.01). Adjustment for muscle area Z-score attenuated differences in tibia section modulus Z-scores between obese and non-obese participants from 1.07 to 0.28. After multivariate adjustment for greater calf muscle area and strength Z-scores, advanced maturity, and less moderate to vigorous physical activity, tibia section modulus Z-scores were 0.32 (95% CI -0.18, 0.43, p=0.06) greater in obese, vs. non-obese participants. Radius cortical section modulus Z-scores were 0.45 greater (p=0.08) in obese vs. non obese participants; this difference was attenuated to 0.14 with adjustment for advanced maturity. These findings suggest that greater tibia cortical section modulus in obese adolescents is attributable to advanced skeletal maturation and greater muscle area and strength, while less moderate to vigorous physical activities offset the positive effects of these covariates. The impact of obesity on cortical structure was greater at weight bearing sites. PMID- 25497575 TI - Non-convulsive status epilepticus in the elderly. AB - Altered mental state is a very common presentation in the elderly admitted to the emergency department. It has been determined that about 16% of patients aged 60 or older with confusion of unknown origin have non-convulsive status epilepticus. The diagnosis of non-convulsive status epilepticus is difficult in the elderly because possible aetiologies of confusion may present with the same clinical picture. Non-convulsive status epilepticus in the elderly carries major morbidity and mortality, attributable primarily to aetiology, and treatment is complex, involving treatment of the aetiology and concomitant medical illnesses, whilst balancing the side effects and drug interactions of antiepileptic drugs. PMID- 25497574 TI - Extensive clinical, hormonal and genetic screening in a large consecutive series of 46,XY neonates and infants with atypical sexual development. AB - BACKGROUND: One in 4500 children is born with ambiguous genitalia, milder phenotypes occur in one in 300 newborns. Conventional time-consuming hormonal and genetic work-up provides a genetic diagnosis in around 20-40% of 46,XY cases with ambiguous genitalia. All others remain without a definitive diagnosis. The investigation of milder cases, as suggested by recent reports remains controversial. METHODS: Integrated clinical, hormonal and genetic screening was performed in a sequential series of 46, XY children, sex-assigned male, who were referred to our pediatric endocrine service for atypical genitalia (2007-2013). RESULTS: A consecutive cohort of undervirilized 46,XY children with external masculinization score (EMS) 2-12, was extensively investigated. In four patients, a clinical diagnosis of Kallmann syndrome or Mowat-Wilson syndrome was made and genetically supported in 2/3 and 1/1 cases respectively. Hormonal data were suggestive of a (dihydro)testosterone biosynthesis disorder in four cases, however no HSD17B3 or SRD5A2 mutations were found. Array-CGH revealed a causal structural variation in 2/6 syndromic patients. In addition, three novel NR5A1 mutations were found in non-syndromic patients. Interestingly, one mutation was present in a fertile male, underlining the inter- and intrafamilial phenotypic variability of NR5A1-associated phenotypes. No AR, SRY or WT1 mutations were identified. CONCLUSION: Overall, a genetic diagnosis could be established in 19% of non-syndromic and 33% of syndromic cases. There is no difference in diagnostic yield between patients with more or less pronounced phenotypes, as expressed by the external masculinisation score (EMS). The clinical utility of array-CGH is high in syndromic cases. Finally, a sequential gene-by-gene approach is time consuming, expensive and inefficient. Given the low yield and high expense of Sanger sequencing, we anticipate that massively parallel sequencing of gene panels and whole exome sequencing hold promise for genetic diagnosis of 46,XY DSD boys with an undervirilized phenotype. PMID- 25497576 TI - Atmospheric mercury in the Canadian Arctic. Part I: a review of recent field measurements. AB - Long-range atmospheric transport and deposition are important sources of mercury (Hg) to Arctic aquatic and terrestrial ecosystems. We review here recent progress made in the study of the transport, transformation, deposition and reemission of atmospheric Hg in the Canadian Arctic, focusing on field measurements (see Dastoor et al., this issue for a review of modeling studies on the same topics). Redox processes control the speciation of atmospheric Hg, and thus impart an important influence on Hg deposition, particularly during atmospheric mercury depletion events (AMDEs). Bromine radicals were identified as the primary oxidant of atmospheric Hg during AMDEs. Since the start of monitoring at Alert (NU) in 1995, the timing of peak AMDE occurrence has shifted to earlier times in the spring (from May to April) in recent years, and while AMDE frequency and GEM concentrations are correlated with local meteorological conditions, the reasons for this timing-shift are not understood. Mercury is subject to various post depositional processes in snowpacks and a large portion of deposited oxidized Hg can be reemitted following photoreduction; how much Hg is deposited and reemitted depends on geographical location, meteorological, vegetative and sea-ice conditions, as well as snow chemistry. Halide anions in the snow can stabilize Hg, therefore it is expected that a smaller fraction of deposited Hg will be reemitted from coastal snowpacks. Atmospheric gaseous Hg concentrations have decreased in some parts of the Arctic (e.g., Alert) from 2000 to 2009 but at a rate that was less than that at lower latitudes. Despite numerous recent advances, a number of knowledge gaps remain, including uncertainties in the identification of oxidized Hg species in the air (and how this relates to dry vs. wet deposition), physical-chemical processes in air, snow and water-especially over sea ice-and the relationship between these processes and climate change. PMID- 25497577 TI - Highly cited works in skull base neurosurgery. AB - OBJECTIVE: Citation analysis can be used to evaluate an article's impact on its discipline. This study characterizes the most-cited articles related to skull base surgery. METHODS: The 100 most-cited skull base neurosurgery articles in all journals were examined. A separate listing of the top 100 most-cited articles in dedicated skull base journals was also examined. The following information was recorded for each article: number of authors, country of origin, citation-count adjusted for number of years in print, topic, and level of evidence. RESULTS: The 100 overall most-cited articles appeared in 25 journals. The top 100 most-cited articles in dedicated skull base journals appeared in 3 journals. Publication dates ranged from 1965-2006 for the overall list and 1993-2010 for the dedicated skull base list. Citations ranged from 11-59 (mean, 19) for the dedicated skull base list and 115-487 for the overall list (mean, 175). The average time-adjusted citation count was 8.4 for the overall list and 2 for the dedicated skull base journal list. CONCLUSIONS: An original article in a nondedicated skull base journal related to the subspecialty of skull base with a citation count of 150 or more and time-adjusted citation count of 10 can be considered a high-impact publication. An original article in a dedicated skull base periodical having a total citation count of 20 or more and an average citation count of 2 per year or more can be considered a high impact publication. PMID- 25497578 TI - Molecular mechanism of tanshinone IIA and cryptotanshinone in platelet anti aggregating effects: an integrated study of pharmacology and computational analysis. AB - Tanshinone IIA and cryptotanshinone are two pharmacologically active diterpenoids extracted from the roots of Salvia milthiorriza Bunge, a plant used in Chinese traditional medicine for the treatment of some cardiovascular and cerebrovascular disease. Until now, the molecular mechanisms of action of these two diterpenoids on platelets are partially known. To clarify this aspect, here we utilized an integrated study of pharmacology and computational analysis. Our results demonstrate that cryptotanshinone is able to inhibit in a concentration dependent manner the rat platelet aggregation and also is endowed of Gi-coupled P2Y12 receptor antagonist as demonstrated by docking studies. This computational method was also performed for tanshinone IIA demonstrating even for this diterpenoid an interaction with the same receptor. The findings from our study enable a better understanding of tanshinone IIA and cryptotanshinone biological properties, which could ultimately lead to the development of novel pharmaceutical strategies for the treatment and/or prevention of some cardiovascular disease. PMID- 25497579 TI - Improving quantification using curtain flow chromatography columns in the analysis of labile compounds: a study on amino acids. AB - The performance of curtain flow chromatography column technology with MS detection was evaluated for the analysis of labile compounds. The curtain flow column design allows for separations that are faster and/or more sensitive than conventional columns, depending on how exactly the curtain flow column is configured. For example, when mass spectral detection is employed, the curtain flow column can yield separations that are 5-times faster than conventional columns when the curtain flow and the conventional columns have the same internal diameter. Or when the internal diameter of the conventional column is reduced in order to yield the same analytical through-put as the curtain flow column, the sensitivity on the curtain flow column can be as much as 66-fold higher than the conventional column. As a consequence of the higher analytical through-put less standardization is required in the analysis of labile compounds because less sample degradation is apparent. Consequently the sample integrity is preserved yielding data of a higher quality. PMID- 25497580 TI - Analyte quantification with comprehensive two-dimensional gas chromatography: assessment of methods for baseline correction, peak delineation, and matrix effect elimination for real samples. AB - Comprehensive two-dimensional gas chromatography (GC*GC) is used widely to separate and measure organic chemicals in complex mixtures. However, approaches to quantify analytes in real, complex samples have not been critically assessed. We quantified 7 PAHs in a certified diesel fuel using GC*GC coupled to flame ionization detector (FID), and we quantified 11 target chlorinated hydrocarbons in a lake water extract using GC*GC with electron capture detector (MUECD), further confirmed qualitatively by GC*GC with electron capture negative chemical ionization time-of-flight mass spectrometer (ENCI-TOFMS). Target analyte peak volumes were determined using several existing baseline correction algorithms and peak delineation algorithms. Analyte quantifications were conducted using external standards and also using standard additions, enabling us to diagnose matrix effects. We then applied several chemometric tests to these data. We find that the choice of baseline correction algorithm and peak delineation algorithm strongly influence the reproducibility of analyte signal, error of the calibration offset, proportionality of integrated signal response, and accuracy of quantifications. Additionally, the choice of baseline correction and the peak delineation algorithm are essential for correctly discriminating analyte signal from unresolved complex mixture signal, and this is the chief consideration for controlling matrix effects during quantification. The diagnostic approaches presented here provide guidance for analyte quantification using GC*GC. PMID- 25497582 TI - Mass transfer coefficients determination from linear gradient elution experiments. AB - A procedure to estimate mass transfer coefficients in linear gradient elution chromatography is presented and validated by comparison with experimental data. Mass transfer coefficients are traditionally estimated experimentally through the van Deemter plot, which represents the HETP as a function of the fluid velocity. Up to now, the HETP was obtained under isocratic elution conditions. Unfortunately, isocratic elution experiments are often not suitable for large biomolecules which suffer from severe mass transfer hindrances. Yamamoto et al. were the first to propose a semi-empirical equation to relate HETPs measured from linear gradient elution experiments to those obtained under isocratic conditions [7]. Based on his pioneering work, the approach presented in this work aims at providing an experimental procedure supported by simple equations to estimate reliable mass transfer parameters from linear gradient elution chromatographic experiments. From the resolution of the transport model, we derived a rigorous analytical expression for the HETP in linear gradient elution chromatography. PMID- 25497581 TI - Roles of inorganic oxide nanoparticles on extraction efficiency of electrospun polyethylene terephthalate nanocomposite as an unbreakable fiber coating. AB - In the present work, the roles of inorganic oxide nanoparticles on the extraction efficiency of polyethylene terephthalate-based nanocomposites were extensively studied. Four fiber coatings based on polyethylene terephthalate nanocomposites containing different types of nanoparticles along with a pristine polyethylene terephthalate polymer were conveniently electrospun on stainless steel wires. The applicability of new fiber coatings were examined by headspace-solid phase microextraction of some environmentally important volatile organic compound such as benzene, toluene, ethylbenzene and xylene (BTEX), as model compounds, from aqueous samples. Subsequently, the extracted analytes were transferred into a gas chromatography by thermal desorption. Parameters affecting the morphology and capability of the prepared nanocomposites including the type of nanoparticles and their doping levels along with the coating time were optimized. Four types of nanoparticles including Fe3O4, SiO2, CoO and NiO were examined as the doping agents and among them the presence of SiO2 in the prepared nanocomposite was prominent. The homogeneity and the porous surface structure of the SiO2 polyethylene terephthalate nanocomposite were confirmed by scanning electron microscopy indicating that the nanofibers diameters were lower than 300 nm. In addition, important parameters influencing the extraction and desorption process such as temperature and extraction time, ionic strength and desorption conditions were optimized. Eventually, the developed method was validated by gas chromatography-mass spectrometry. Under optimized conditions, the relative standard deviation values for a double distilled water spiked with the selected volatile organic compounds at 50 ng L(-1) were 2-7% (n=3) while the limits of detection were between 0.7 and 0.9 ng L(-1). The method was linear in the concentration range of 10 to 1,000 ng L(-1) (R(2)>0.9992). Finally, the developed method was applied to the analysis of Kalan dam and tap water samples and the relative recovery values were found to be in the range of 86-102%. PMID- 25497583 TI - Optimization of the stopping-power-ratio to Hounsfield-value calibration curve in proton and heavy ion therapy. AB - For CT-based dose calculation in ion therapy a link between the attenuation coefficients of photons and the stopping-power of particles has to be provided. There are two commonly known approaches to establish such a calibration curve, the stoichiometric calibration and direct measurements with tissue substitutes or animal samples. Both methods were investigated and compared. As input for the stoichiometric calibration the data from ICRP-report 23 were compared to newly available data from ICRP-report 110. By employing the newer data no relevant difference could be observed. The differences between the two acquisition methods (direct measurement and stoichiometric calibration) were systematically analyzed and quantified. The most relevant change was caused by the exchange of carbon and oxygen content in the substitutes in comparison to the data of the ICRP-reports and results in a general overshoot of the Bragg peak. The consequence of the differences between the calibration curves was investigated with treatment planning studies and iso-range surfaces. Range differences up to 6mm in treatment plans of the head were observed. Additionally two improvements are suggested which increase the accuracy of the calibration curve. PMID- 25497584 TI - Correlation of degree of hypothyroidism with survival outcomes in patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors. AB - BACKGROUND: Hypothyroidism is a common adverse effect of vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in patients with metastatic renal cell carcinoma (mRCC). Some studies have shown an association with improved survival. However, hypothyroidism severity has not been correlated with survival outcomes. We report the incidence and severity of VEGFR TKI therapy-associated hypothyroidism in correlation with the survival outcomes of patients with mRCC. PATIENTS AND METHODS: A retrospective analysis of patients with mRCC who received VEGFR-TKIs (2004 through 2013) was conducted from a single institutional database. Hypothyroidism, progression-free survival (PFS), and overall survival (OS) were assessed. Univariate and multivariate analyses were performed using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: Of 125 patients with mRCC, 65 were eligible. Their median age was 59 years (range, 45-79 years), and 46 (70.8%) were male. Hypothyroidism occurred in 25 patients (38.5%), of whom 13 had a peak thyroid-stimulating hormone (TSH) level > 10 mIU/L during treatment. The median OS was significantly longer in patients with a peak TSH > 10 mIU/L than in patients with a peak TSH of <= 10 mIU/L (not reached vs. 21.4 months, P = .005). On multivariate analysis, risk criteria, number of previous therapies, and severe hypothyroidism (TSH > 10 mIU/L) during VEGFR-TKI therapy remained significant for improvements in PFS and OS. CONCLUSION: The severity of VEGFR-TKI therapy-associated hypothyroidism (TSH > 10 mIU/L) was associated with improved survival outcomes in patients with mRCC and should not necessitate a dose reduction or therapy discontinuation. PMID- 25497585 TI - Increasing volume of non-neoplastic parenchyma in partial nephrectomy specimens is associated with chronic kidney disease upstaging. AB - INTRODUCTION: We examined the effect of non-neoplastic parenchymal volumes (NNPVs) in partial nephrectomy (PN) surgical specimens on long-term postoperative renal function. PN for renal cortical neoplasms has demonstrated superior long term renal function outcomes compared with radical nephrectomy. Minimizing the distance between the surgical margin and tumor will reduce the NNPV removed. The role of NNPV on postoperative outcomes has been preliminarily investigated, with varying results. Thus, we sought to determine the association between the NNPV removed and postoperative chronic kidney disease (CKD) staging. MATERIALS AND METHODS: Our institutional database was queried for patients who had undergone PN from 1990 to 2012. The demographic and pathologic data were collected. The ellipsoid formula was used to calculate the surgical specimen and tumor volumes, which were then subtracted from each other to determine the NNPV. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula. Binary logistic regression analysis was used to determine the predictors of postoperative CKD upstaging according to the eGFR. RESULTS: A total of 584 patients meeting the inclusion criteria had undergone PN. On binary logistic regression analysis, controlling for age, tumor volume, surgical modality, and preoperative CKD stage, an increasing NNPV in the surgical specimen was independently associated with postoperative CKD upstaging (odds ratio, 1.004; P = .007). CONCLUSION: An increasing NNPV removed during PN correlated with CKD upstaging using the eGFR; therefore, additional emphasis should be placed on healthy parenchymal preservation, with long-term follow-up to ensure adequate oncologic outcomes. PMID- 25497586 TI - Radiotherapy in Prostate Cancer Patients With Pelvic Lymphocele After Surgery: Clinical and Dosimetric Data of 30 Patients. AB - INTRODUCTION: The purpose of the study was to evaluate the feasibility of irradiation after prostatectomy in the presence of asymptomatic pelvic lymphocele. PATIENTS AND METHODS: The inclusion criteria for this study were: (1) patients referred for postoperative (adjuvant or salvage) intensity modulated radiotherapy (IMRT; 66-69 Gy in 30 fractions); (2) detection of postoperative pelvic lymphocele at the simulation computed tomography [CT] scan; (3) no clinical symptoms; and (4) written informed consent. Radiotherapy toxicity and occurrence of symptoms or complications of lymphocele were analyzed. Dosimetric data (IMRT plans) and the modification of lymphocele volume during radiotherapy (cone beam CT [CBCT] scan) were evaluated. RESULTS: Between January 2011 and July 2013, in 30 of 308 patients (10%) treated with radiotherapy after prostatectomy, pelvic lymphocele was detected on the simulation CT. The median lymphocele volume was 47 cm(3) (range, 6-467.3 cm(3)). Lymphocele was not included in planning target volume (PTV) in 8 cases (27%). Maximum dose to lymphocele was 57 Gy (range, 5.7-73.3 Gy). Radiotherapy was well tolerated. In all but 2 patients, lymphoceles remained asymptomatic. Lymphocele drainage-because of symptom occurrence-had to be performed in 2 patients during IMRT and in one patient, 7 weeks after IMRT. CBCT at the end of IMRT showed reduction in lymphocele volume and position compared with the initial data (median reduction of 37%), more pronounced in lymphoceles included in PTV. CONCLUSION: Radiotherapy after prostatectomy in the presence of pelvic asymptomatic lymphocele is feasible with acceptable acute and late toxicity. The volume of lymphoceles decreased during radiotherapy and this phenomenon might require intermediate radiotherapy plan evaluation. PMID- 25497587 TI - Chimeric flaps pedicled with the lateral circumflex femoral artery for individualised reconstruction of through-and-through oral and maxillofacial defects. AB - Reconstruction of through-and-through oral and maxillofacial defects has always been difficult. We have evaluated the feasibility and reconstructive efficacy of chimeric flaps pedicled with the lateral circumflex femoral artery in the reconstruction of 41 through-and-through oral and maxillofacial defects after resections for cancer. There were 29 chimeric anterolateral thigh and anterolateral thigh flaps and 12 chimeric anterolateral thigh and anteromedial thigh flaps, the sizes of which ranged from 5*8 to 9*11 cm. The chimeric flaps provided separate flaps to reconstruct the intraoral mucosa and extraoral skin defects, and 40/41 of them survived. The appearance and function were satisfactory in all patients after the reconstruction. Chimeric flaps pedicled with the lateral circumflex femoral artery are a good choice for the reconstruction of through-and-through oral and maxillofacial defects. PMID- 25497588 TI - Systematic investigation of the toxic mechanism of PFOA and PFOS on bovine serum albumin by spectroscopic and molecular modeling. AB - Perfluorinated compounds (PFCs), an emerging class of globally environmental contaminations, pose a great threat to humans with wide exposure from food and other potential sources. The effects of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) on bovine serum albumin (BSA) under normal physiological conditions were characterized by fluorescence, UV-Vis absorption, Fourier transform infrared (FT-IR) spectroscopy and molecular docking methods. The fluorescence study suggested that the fluorescence quenching of BSA by PFCs was a static procedure forming a PFCs-BSA complex. The negative values of enthalpy change (DeltaH) and entropy change (DeltaS) indicated that van der Waals forces and hydrogen bonds were the dominant intermolecular forces in the binding of PFCs to BSA. The displacement experiments of site markers and molecular docking revealed that the binding of PFOA to BSA took place in sub-domain IIA (Sudlow site I) whereas PFOS was mainly located in the sub-domain IIIA (Sudlow site II) and partially bound into site I. Furthermore, the results of UV-Vis and FT-IR spectra demonstrated that the microenvironment and the secondary structure of BSA were changed in the presence of PFCs. These results indicated that PFCs indeed impact the conformation of BSA and PFOS was more toxic than PFOA, which were supported by theoretical molecular modeling methods. PMID- 25497589 TI - Quality of life in people with cognitive impairment: nursing homes versus home care. AB - BACKGROUND: The evaluation of quality of life (QoL) among older adults has become increasingly important, and living arrangements play a pivotal role in determining the QoL of people with cognitive impairment (PWCI). Although informal care (home-based) is favored, transition to formal care (residential care) often becomes necessary, especially in the later stages of cognitive impairment. The primary objective was to compare the QoL of PWCI in the community and nursing homes. Additionally, factors differentiate the QoL of PWCI in these two settings were identified. METHODS: This is a quasi-experimental study design involving 219 older adults with cognitive impairment, aged 60-89 years old from both nursing home and home care. Participants completed the EUROPE Health Interview Survey-QoL (WHO-8), the Short Mini-Mental State Examination (SMMSE), the Barthel Index (BI), the Geriatric Depression Scale (GDS-15), and the Friendship Scale (FS). RESULTS: There were significant differences in QoL, depression, social connectedness (p < 0.01) and cognitive functions (p = 0.01) between home care recipients and nursing home participants. No significant differences were observed with regards to health condition, co morbidities and physical functions between study cohorts. CONCLUSIONS: Older adults with cognitive impairment living at home experienced higher QoL, had better cognitive function, were less depressed and reported higher social connectedness compared to those living in institutional care. Therefore, support should be provided in enabling home care and empowering caregivers to provide better care for PWCI. PMID- 25497590 TI - Mortality and cause of death in a cohort of people who had ever injected drugs in Glasgow: 1982-2012. AB - BACKGROUND: To describe all-cause and cause-specific mortality in a cohort of people who had ever injected drugs (PWID) with a low prevalence of HIV over 20-30 years. METHODS: Using a retrospective study design, identifying data from a cohort of PWID recruited between 1982 and 1993 through in-patient drug treatment services were linked to National Records for Scotland deaths data using probabilistic record linkage. We report all-cause and cause-specific mortality rates; standardized mortality ratios (SMR) across time, gender and age were estimated. RESULTS: Among 456 PWID, 139 (30.5%) died over 9024 person-years (PY) of follow-up. Mortality within the cohort was almost nine times higher than the general population, and remained elevated across all age groups. The greatest excess mortality rate was in the youngest age group, who were 15-24 years of age (SMR 31.6, 95% CI 21.2-47.1). Drug-related deaths declined over time and mortality was significantly higher among HIV positive participants. Although SMRs declined with follow-up, the SMR of the oldest age group (45-60) was 4.5 (95% CI 3.0-6.9). There were no significant differences in all-cause mortality rates between participants who were 25 years and older at cohort entry compared to younger participants. CONCLUSION: Mortality rates remained higher than the general population across all age groups. Screening services that identify a history of injecting drug use may be an opportunity to address risk factors faced by an ageing population of PWID and potentially have implications for future health care planning. PMID- 25497591 TI - The effects of GSK-3beta blockade on ketamine self-administration and relapse to drug-seeking behavior in rats. AB - RATIONALE: The role of glycogen synthase kinase-3 (GSK-3) has recently been implicated in the neurochemical mechanism underlying ketamine-induced neuronal toxicity and behavioral disturbance. OBJECTIVES: The primary goal of the present study was to determine the role of GSK-3beta in ketamine self-administration (SA) and relapse to drug-seeking behavior after abstinence. METHODS: In Experiment 1, the level of phosphorylated GSK-3beta (p-GSK-3beta) and total GSK-3beta (t-GSK 3beta) was determined in various brain areas following 14 days of ketamine SA. In Experiments 2 and 3, the effects of a GSK-3beta inhibitor, SB216763 (2 and 4 mg/kg) and a GSK-3 inhibitor, lithium (LiCl, 100mg/kg) on the responding maintained by 0.5mg/kg/infusion ketamine SA were evaluated. In Experiments 4 and 5, rats underwent ketamine SA for 14 days followed by a 10-day abstinence period. The animals were treated with 2 or 4 mg/kg GSK-3beta inhibitor, or 100mg/kg LiCl during the cue-induced relapse test. Seven days later, animals received the same drug treatment and underwent the drug-induced relapse test. Finally, the effect of saline and DMSO on locomotor activity was evaluated in Experiment 6. RESULTS: Ketamine SA significantly decreased the ratio p-GSK-3beta and t-GSK-3beta (p-GSK 3beta:t-GSK-3beta) in the caudate putamen, nucleus accumbens, and ventral tegmental area. Both SB216763 and LiCl decreased responding on a progressive ratio schedule, but not on a fixed ratio schedule. Cue-induced relapse was suppressed only by 4mg/kg SB216763, whereas drug-induced relapse was inhibited by 2, 4 mg/kg SB216763 and LiCl. However, inactive responses were also suppressed by LiCl during progressive ratio and drug-induced relapse testing. CONCLUSIONS: SB216763 was effective at decreasing ketamine SA under the PR schedule and reducing drug-seeking behavior after abstinence. PMID- 25497592 TI - Retention rates of levetiraceram in Chinese children and adolescents with epilepsy. AB - BACKGROUND: Levetiracetam (Lev) is a new antiepileptic drugs, proved to be effective and tolerance in regulatory trials, but these controlled trials do not always predict how useful a drug will be in day to day clinical practice, Retention rates can provide a better indication of efficacy and tolerability in everyday use. METHODS: Totally 124 patients with more than 3 months disease course were enrolled in the study from June 2007 to December 2007. The LEV dose ranged from 10 to 60 mg/kg per day. Follow up visit were performed at 6 months, 12 months, 24 months and 36 months, and treatment effects, adverse effects were recorded. RESULTS: The LEV retention rates at 6, 12, 24, and 36 months were 93.5% (116/124), 84.7% (105/124), 65.3% (81/124), and 58.9% (73/124), respectively. The predominant causes of withdrawal were lack of efficacy (62.7%) and serious adverse effects (17.6%). In addition, 48.6% (51/105), 60.5% (49/81) and 72.6% (53/73) patients were seizure-free for 12 months, 24 months and 36 months, respectively. In this study, 75 (60.5%) patients experienced at least one side effect. The most common side effects observed were irritability 38.7% (29/75), somnolence 17.3% (13/75), learning disability 16.0% (12/75), anorexia 17.3% (13/75), somnipathy 13.3% (10/75), and abnormal behavior 13.3% (10/75). CONCLUSIONS: Our study revealed the high retention rate of LEV in Chinese children and adolescents with epilepsy. PMID- 25497593 TI - Adaptive behavior in 10-11 year old children born preterm with a very low birth weight (VLBW). AB - AIMS: The aims were to compare adaptive behavior in 10-11 year old VLBW children with and without cerebral palsy (CP) to term-born children, and examine its relationship with neonatal factors and infant motor repertoire in VLBW children without CP. METHODS: Twenty-eight VLBW children without CP, 10 VLBW children with CP and 31 term-born control children were examined at 10-11 years using the parent-reported Vineland Adaptive Behavior Scales-II. The Adaptive Behavior Composite Score, based on communication, daily living skills and socialization, was adjusted for sex, socioeconomic status (SES), cognitive (WISC-III) and motor function (MABC-2). Associations with neonatal variables and infant motor repertoire were also examined. RESULTS: Adaptive Behavior Composite scores were significantly lower in the two VLBW groups (with CP: 72.5 +/- 15.9; without CP: 92.2 +/- 12.3) than in the control group (105.7 +/- 17.5). The latter difference was still significant after adjustment for sex, SES, WISC-III and MABC-2. Among VLBW children without CP, an abnormal infant motor repertoire at 14 weeks post term age was significantly associated with a lower Adaptive Behavior Composite score at 10-11 years of age (r(2) = 0.20, p = 0.03). CONCLUSION: VLBW children have challenges regarding adaptive behavior. Specific attention may be needed to reveal such problems in VLBW children without major disabilities like CP, as these children had impaired adaptive function that could not be explained by their SES, cognitive or motor functions. PMID- 25497594 TI - Role of IP3 receptor signaling in cell functions and diseases. AB - IP3 receptor (IP3R) was found to release Ca(2+) from non-mitochondrial store but the exact localization and the mode of action of IP3 remained a mystery. IP3R was identified to be P400 protein, a protein, which was missing in the cerebellum of ataxic mutant mice lacking Ca(2+) spikes in Pukinje cells. IP3R was an IP3 binding protein and was a Ca(2+) channel localized on the endoplasmic reticulum. Full-length cDNA of IP3R type 1 was initially cloned and later two other isoforms of IP3R (IP3R type 2 and type 3) were cloned in vertebrates. Interestingly, the phosphorylation sites, splicing sites, associated molecules, IP3 binding affinity and 5' promoter sequences of each isoform were different. Thus each isoform of IP3 receptor plays a role as a signaling hub offering a unique platform for matching various functional molecules that determines different trajectories of cell signaling. Because of this distinct role of each isoform of IP3R, the dysregulation of IP3 receptor causes various kinds of diseases in human and rodents such as ataxia, vulnerability to neuronal degeneration, heart disease, exocrine secretion deficit, taste perception deficit. Moreover, IP3 was found not only to release Ca(2+), but also to release IRBIT (IP3receptor binding protein released with inositol trisphosphate) essential for the regulation of acid-base balance, RNA synthesis and ribonucleotide reductase. PMID- 25497595 TI - A switching formation strategy for obstacle avoidance of a multi-robot system based on robot priority model. AB - This paper describes a switching formation strategy for multi-robots with velocity constraints to avoid and cross obstacles. In the strategy, a leader robot plans a safe path using the geometric obstacle avoidance control method (GOACM). By calculating new desired distances and bearing angles with the leader robot, the follower robots switch into a safe formation. With considering collision avoidance, a novel robot priority model, based on the desired distance and bearing angle between the leader and follower robots, is designed during the obstacle avoidance process. The adaptive tracking control algorithm guarantees that the trajectory and velocity tracking errors converge to zero. To demonstrate the validity of the proposed methods, simulation and experiment results present that multi-robots effectively form and switch formation avoiding obstacles without collisions. PMID- 25497596 TI - Neuroretinitis secondary to Bartonella henselae in the emergent setting. PMID- 25497597 TI - Parkinsonism in GTP cyclohydrolase 1 mutation carriers. PMID- 25497598 TI - Exome sequencing in undiagnosed inherited and sporadic ataxias. AB - Inherited ataxias are clinically and genetically heterogeneous, and a molecular diagnosis is not possible in most patients. Having excluded common sporadic, inherited and metabolic causes, we used an unbiased whole exome sequencing approach in 35 affected individuals, from 22 randomly selected families of white European descent. We defined the likely molecular diagnosis in 14 of 22 families (64%). This revealed de novo dominant mutations, validated disease genes previously described in isolated families, and broadened the clinical phenotype of known disease genes. The diagnostic yield was the same in both young and older onset patients, including sporadic cases. We have demonstrated the impact of exome sequencing in a group of patients notoriously difficult to diagnose genetically. This has important implications for genetic counselling and diagnostic service provision. PMID- 25497601 TI - Control of appetite and energy intake by SCFA: what are the potential underlying mechanisms? AB - In recent years, there has been a renewed interest in the role of dietary fibre in obesity management. Much of this interest stems from animal and human studies which suggest that an increased intake of fermentable fibre can suppress appetite and improve weight management. A growing number of reports have demonstrated that the principal products of colonic fermentation of dietary fibre, SCFA, contribute to energy homeostasis via effects on multiple cellular metabolic pathways and receptor-mediated mechanisms. In particular, over the past decade it has been identified that a widespread receptor system exists for SCFA. These G-protein coupled receptors, free fatty acid receptor (FFAR) 2 and FFAR3 are expressed in numerous tissue sites, including the gut epithelium and adipose tissue. Investigations using FFAR2- or FFAR3-deficient animal models suggest that SCFA mediated stimulation of these receptors enhances the release of the anorectic hormones peptide tyrosine tyrosine and glucagon-like peptide-1 from colonic L cells and leptin from adipocytes. In addition, the SCFA acetate has recently been shown to have a direct role in central appetite regulation. Furthermore, the SCFA propionate is a known precursor for hepatic glucose production, which has been reported to suppress feeding behaviour in ruminant studies through the stimulation of hepatic vagal afferents. The present review therefore proposes that an elevated colonic production of SCFA could stimulate numerous hormonal and neural signals at different organ and tissue sites that would cumulatively suppress short-term appetite and energy intake. PMID- 25497603 TI - Weight-bearing asymmetry in individuals post-hip fracture during the sit to stand task. AB - BACKGROUND: Individuals post hip fracture decrease force on the involved limb during sit to stand tasks, creating an asymmetry in vertical ground reaction force. Joint specific differences that underlie asymmetry of the vertical ground reaction force are unknown. The purpose of this study was to compare differences in vertical ground reaction force variables and joint kinetics at the hip and knee in participants post-hip fracture, who were recently discharged from homecare physical therapy to controls. METHODS: Forty-four community-dwelling older adults, 29 who had a hip fracture and 15 elderly control participant's completed the sit to stand task on an instrumented chair with 3 force plates. T tests were used to compare clinical tests (Berg Balance Scale, activity balance confidence and gait speed, isokinetic knee strength) and vertical ground reaction force variables. Two-way analyses of variance compared vertical ground reaction force variables and kinetics at the hip and knee between hip fracture and elderly control groups. Pearson correlation coefficients were used to determine correlations between clinical and vertical ground reaction force variables. FINDINGS: Vertical ground reaction force variables were significantly lower on the involved side for the hip fracture group compared to the uninvolved side and controls. Lower involved side hip and knee moments and power contributed to lower involved side vertical ground reaction force. Vertical ground reaction force variables and strength had moderate to high correlations with clinical measures. INTERPRETATION: Uninvolved side knee moments and powers were the largest contributors to asymmetrical vertical ground reaction force in participants post hip fracture. The association of vertical ground reaction force variables and clinical measures of function suggesting reducing vertical ground reaction force asymmetry may contribute to higher levels of function post-hip fracture. Functional and strength training should target the involved knee to reduce vertical ground reaction force asymmetry. PMID- 25497602 TI - Proctitis following stereotactic body radiation therapy for prostate cancer. AB - BACKGROUND: Proctitis after radiation therapy for prostate cancer remains an ongoing clinical challenge and critical quality of life issue. SBRT could minimize rectal toxicity by reducing the volume of rectum receiving high radiation doses and offers the potential radiobiologic benefits of hypofractionation. This study sought to evaluate the incidence and severity of proctitis following SBRT for prostate cancer. METHODS: Between February 2008 and July 2011, 269 men with clinically localized prostate cancer were treated definitively with SBRT monotherapy at Georgetown University Hospital. All patients were treated to 35-36.25Gy in 5 fractions delivered with the CyberKnife Radiosurgical System (Accuray). Rectal bleeding was recorded and scored using the CTCAE v.4. Telangiectasias were graded using the Vienna Rectoscopy Score (VRS). Proctitis was assessed via the Bowel domain of the Expanded Prostate Index Composite (EPIC)-26 at baseline and at 1, 3, 6, 9, 12, 18 and 24 months post SBRT. RESULTS: The median age was 69 years with a median prostate volume of 39 cc. The median follow-up was 3.9 years with a minimum follow-up of two years. The 2-year actuarial incidence of late rectal bleeding >= grade 2 was 1.5%. Endoscopy revealed VRS Grade 2 rectal telangiectasias in 11% of patients. All proctitis symptoms increased at one month post-SBRT but returned to near-baseline with longer follow-up. The most bothersome symptoms were bowel urgency and frequency. At one month post-SBRT, 11.2% and 8.5% of patients reported a moderate to big problem with bowel urgency and frequency, respectively. The EPIC bowel summary scores declined transiently at 1 month and experienced a second, more protracted decline between 6 months and 18 months before returning to near-baseline at two years post-SBRT. Prior to treatment, 4.1% of men felt their bowel function was a moderate to big problem which increased to 11.5% one month post-SBRT but returned to near-baseline at two years post-SBRT. CONCLUSIONS: In this single institution cohort, the rate and severity of proctitis observed following SBRT is low. QOL decreased on follow-up; however, our results compare favorably to those reported for patients treated with alternative radiation modalities. Future prospective randomized studies are needed to confirm these observations. PMID- 25497604 TI - Survival outcome of stage I ovarian clear cell carcinoma with lympho-vascular space invasion. AB - BACKGROUND: The clinical impact of lympho-vascular space invasion (LVSI) in early stage ovarian clear cell carcinoma (OCCC) is not well understood. Given the distinct tumor biology and survival patterns of OCCC, the significance of LVSI on survival outcome and treatment response was examined in OCCC. METHODS: A multicenter study was conducted to examine stage IA-IC3 OCCC cases that underwent primary surgical staging including lymphadenectomy. LVSI status was determined from archived histopathology slides, correlated with clinico-pathological results, chemotherapy patterns, and survival outcomes. RESULTS: LVSI was observed in 47 (20.3%) among 232 cases. In univariate analysis, LVSI was associated with older age (p=0.042), large tumor size (p=0.048), and stage IC (p=0.035). In survival analysis, LVSI was associated with decreased disease-free survival (DFS, 5-year rate, 70.6% versus 92.1%, p=0.0004) and overall survival (OS, 78.8% versus 93.3%, p=0.008) on univariate analysis. After controlling for age, tumor size, stage, and chemotherapy use, LVSI remained an independent prognostic factor for decreased survival outcomes (DFS, hazard ratio [HR] 4.35, 95% confidence interval [CI] 1.73-10.9, p=0.002; and OS, HR 4.73, 95%CI 1.60-14.0, p=0.015). Among 210 cases who received postoperative chemotherapy, while regimen type did not impact survival outcome regardless of LVSI status (DFS, p=0.63), the number of administered cycles showed a survival benefit towards >=6cycles for patients with LVSI-positive tumors (DFS, p=0.009; and OS, p=0.016). CONCLUSION: LVSI is an important marker to predict survival outcome of stage I OCCC. Regardless of chemotherapy type, patients with stage I OCCC showing LVSI may benefit from receiving postoperative chemotherapy. PMID- 25497606 TI - [Digital metastasis as an unusual primary symptom of cancer]. AB - We describe a rare case in which the presenting symptom of lung cancer was an ulcerating tumour in a patient's distal 4th finger. Such acrometastatic lesions represent only 0.1% of all metastatic osseous involvement and have been described in relation to various cancer types. Symptoms can mimic those of a localized infection and consequently the condition is frequently overlooked or mistreated. This case serves as a reminder that metastases should be considered in patients with refractory digital lesions, not least among high-risk groups. PMID- 25497605 TI - [Lead poisoning occurs among Danish workers]. AB - Lead poisoning still occurs among Danish workers. The Danish Working Environment Authority guideline regulates working with lead, and in Denmark there is an occupational threshold blood lead concentration of 1.0 micromol/l. In this case daily window frame lead paint removal work and guideline neglect caused significant lead exposure. Three months work resulted in a peak blood lead concentration of 3.28 micromol/l and prolonged symptoms of mild to moderate lead poisoning. General practitioners must be aware of the continuous risk of lead poisoning and refer to an occupational and environmental department. PMID- 25497607 TI - [Focal hepatic peliosis without evident aetiology]. AB - Hepatic peliosis is a rare vascular disorder of the liver characterized by small cavities containing blood. It is most often asymptomatic but may give rise to portal hypertension and even fatal liver rupture. In this case a 47-year-old woman presented with abdominal pain and elevated alkaline phosphatase. An ultrasonography and additional MRI of the liver detected three lesions suspected of focal nodular hyperplasia. A core needle biopsy revealed that hepatic peliosis was the correct diagnosis. No causative factors were found and the patient was followed by consecutive MRIs. PMID- 25497608 TI - [Effect of acyclovir and steroid in a young immunocompetent male with herpes zoster myelitis]. AB - Herpes zoster myelitis is a rare condition, usually seen in aged and immunocompromised patients. Due to atypical presen-tations it can be hard to diagnose. Intraspinal lesions on magnetic resonance imaging (MRI) support the diagnosis. We present a 39-year-old otherwise healthy male with symptoms of viral meningitis and rapidly progressing symptoms of myelitis. Lumbar puncture showed increased levels of monocytes and varicella zoster virus DNA. Despite a negative MRI, based on a few previous case reports and because of lack of progress on antiviral treatment, treatment with steroids was established early, recovering the patient dramatically. This supports that a combination of antiviral treatment and steroids may be a more efficient treatment of zoster myelitis and reminds us that the diagnosis cannot be excluded by a negative MRI. PMID- 25497609 TI - [Cardiac tamponade after laparoscopic operation for a traumatic]. AB - Cardiac tamponade is a rare complication of diaphragmatic hernia repair. We report a case of a 79-year-old female, who underwent a laparoscopic procedure with mesh implantation. Tackers were used to secure the mesh to the diaphragm. Nine hours after surgery the patient died from circulatory collapse. Autopsy showed perforation of the pericardium and the right coronary artery by a tacker. A review of the literature reveals nine earlier reported cases. In three of these cases the complication resulted in death. Rapid diagnosis and intervention can decrease mortality. To avoid further incidents it is necessary to consider alternatives to tacks. PMID- 25497610 TI - [Cardiac arrest with syndrome of apparent mineralocorticoid excess]. AB - Ventricular fibrillation is an unknown complication to the syndrome of apparent mineralocorticoid excess (SAME). This case report describes a young woman admitted with hypo-kalaemia and hypertension. Concentrations of both P-renin and P-aldosterone were low and urinary steroid metabolites revealed an abnormal excretion pattern pointing to the diagnosis of SAME. Three years later the woman suffered from ventricular fibrillation due to the hypokalaemia caused by her disease. This case report demonstrates the need for increased attention on the potassium concentration in patients with SAME. PMID- 25497611 TI - [Adenicarcinoma in an ileostomy 41 years after proctocolectomy due to familial adenomatous polyposis]. AB - This casestory describes a complication 41 years after a proctocolectomy due to familial adenomatous polyposis. Due to a granuloma the patient experienced problems in bandaging his ileostomy. The granuloma was excised, and a histologic examination revealed an adenocarcinoma. A small bowel resection was performed and 30 cm of the ileum was removed along with 3 cm of surrounding peristomal tissue. The patient did not wish to move the ileostomy, and a peristomal hernia occured. The recommendation is to excise the stoma including a tube of the surrounding tissue and to move the new stoma to another location, thereby reducing the risk of stomal hernia. PMID- 25497612 TI - [Cerebral aspergillosis in an immunocompromised patient with follicular lymphoma]. AB - We present a case of central nervous system aspergillosis in an immunocompromised 69-year-old male with a history of chemotherapeutic treatment for follicular lymphoma. The patient presented with aphasia, apraxia and confusion. An MRI of the central nervous system and Aspergillus antigen in the spinal fluid was suggestive for this invasive fungal infection. Despite treatment with voriconazole the patient succumbed to the infection. A rise in rare, severe infectious complications as presented is expected due to increasing dose intensity of chemotherapy. PMID- 25497613 TI - [Dilated cardiomyopathy as part of familial dystrophia myotonica]. AB - Dilated cardiomyopathy (DCM) is a condition characterized by non-ischaemic heart failure and is often hereditary. We present a family in which the proband had DCM in isolation while several relatives presented with myotonia, hypotonia, poly hydramnion during pregnancy or a mental handicap. The disease presentation and subsequent genetic investigations were consistent with a diagnosis of dystrophia myotonica. This case presentation illustrate that DCM may be part of a systemic condition and that familial investigations may have important implications for correct diagnosis, treatment and counseling. PMID- 25497614 TI - [Febrile infection-related status epilepticus in a child after a common infection]. AB - A 13-year-old boy developed seizures and intractable status epilepticus a week after having had a sore throat. Ketogenic diet possibly had some effect. Antibodies to calmodulin dependent protein kinase II were found and could possibly suggest an immunologic aetiology. PMID- 25497615 TI - [Fistula-producing giant coronary aneurysm in a 62-year-old woman]. AB - Giant coronary aneurysms (GCA with a diameter > 20 mm) are rare with a prevalence < 0.02%. A 62-year-old woman with no history of ischaemic heart disease was admitted to hospital with acute chest pain. A coronary angiography revealed a left an-terior descendent-associated GCA. A cardiac computed tomo-g-raphy demonstrated a "snake-pit"-like fistula connecting the GCA and the pulmonary artery. Atherosclerosis, connective tissue dis-orders, and previous coronary intervention will predispose to GCA. No evidence-based treatment regimen exists, but coiling, excision or a conservative approach, as in this case, is possible strategies. PMID- 25497617 TI - [Keratitis after laser in situ keratomileusis (LASIK). A different entity and treatment management]. AB - Keratitis after laser in situ keratomileusis (LASIK) is rare and challenging as patients may present with mild symptoms and initial management differs significantly. Post-LASIK keratitis is usually due to gram-positive bacteria or opportunistic/atypical microorganisms located beneath the corneal flap. Due to relative protective interface location it is necessary to lift the corneal flap for cultures and antibiotic irrigation. The case report demonstrates that post LASIK keratitis requires prompt referral to ophthalmology department as correct initial management is pivotal for good visual outcome. PMID- 25497616 TI - [Hip pain as a paraneoplastic rheumatic syndrome in a patient with double-hit lymphoma]. AB - A 63-year-old woman consulted the Department of Rheuma-tology for hip pain. X rays were normal. No signs of arthritis. Four days after she was hospitalized with abdominal pain. CT-urography revealed three enlarged lymph nodes. A biopsy revealed a double-hit lymphoma, an aggressive B-cell lymphoma with translocation of both MYC and BCL2. After starting chemotherapy the hip pain disappeared. A brief complete remission was followed by CNS relapse and death 11 months after diagnosis. PMID- 25497618 TI - [Ileus caused by V-loc sutures]. AB - A laparoscopic bilateral inguinal hernia repair was performed on a 62-year-old man. The peritoneum was sutured on both sides laterally to medial with the V-loc unidirectional barbed suture. An end of approximately 2 cm was left on both sides. Five days later the patient returned to hospital with intestinal obstruction. Exploratory laparoscopy revealed that the two ends of the sutures had formed a string medially, and the small intestine was caught over the string, causing the obstruction. This case demonstrates the need for fast diagnosis in our patients after surgery, when introducing new surgical material. PMID- 25497619 TI - [Jejunal diverticulitis as the cause of acute abdomen]. AB - We present two patients with jejunal diverticulitis. Diverticula in jejunum and ileum are very rare, occurring with an incidence of 0.07-2% in the gastrointestinal tract. They are often associated with unspecific symptoms as intermittent abdominal pain, nausea and diarrhoea. The treatment of mild diverticular disease is intravenous fluids and antibiotics. If there is an occurrence of peritonitis as a complication of jejunal diverticulitis, laparatomy may be indicated. Both of the patients received a conservative treatment with intravenous fluids and antibiotics with good response. PMID- 25497620 TI - [Malignant peritoneal mesothelioma is a rare disease]. AB - Malignant peritoneal mesothelioma is characterized by diffuse symptoms such as bloating, abdominal pain, weight loss, anorexia, fever, diarrhoea, vomiting and ascites. The findings by radiographic imaging are unspecific and the diagnosis is therefore often first achieved by biopsy from the affected area. Although treatment with chemotherapy and cytoreductive surgery has improved the survival prognosis for the patients is poor with a median survival of 38 month. PMID- 25497621 TI - [Multiple cerebral cavernous haemangiomas in a woman with visual hallucinations]. AB - Cerebral vascular malformations is a common condition though it remains clinically silent in the vast majority of patients. Symptoms comprise seizures, headaches, focal neurological deficits and unconsciousness due to major cerebral haemor-rhage. A 31-year-old woman was referred for assessment of intermittent visual hallucinations, headache and dizziness. A magnetic resonance imaging of the brain revealed multiple supra- and infratentorial cavernous haemangiomas. The woman suffered from simple focal seizures with visual hallucinations every twenty minutes. The biggest haemangioma was surgically removed and the epileptic condition was treated with drugs. PMID- 25497622 TI - [Fatal complication of haemorrhoidal banding]. AB - Rubber band ligation (RBL) is a common procedure for treating haemorrhoids. We present a case of a previously healthy young man admitted with symptoms of pain, urinary difficulties and perineal oedema seven days after having had a RBL. The initial examination was unremarkable and the patient was discharged. Twelve hours later he was readmitted due to continued pain, but despite surgery and aggressive intensive treatment the patient deteriorated rapidly and eventually succumbed to fulminant pelvic sepsis. Sepsis is a rare but severe complication after haemorrhoid treatment. PMID- 25497623 TI - [Pigmented villonodular synovitis causing ankle pain]. AB - A rare case of diffuse pigmented villonodular synovitis is described. Because of unspecific symptoms as oedema and pain and uncertain relation with trauma the diagnosis was delayed for almost two years, until a MRI showed diffuse hypodense infiltrative lesions involving soft tissue structures around the ankle. Treatment was a radical open synovectomy of the ankle and subtalar joints and tenosynovectomy of the tendons around the ankle. PMID- 25497624 TI - [Pulmonal bacillus Calmette-Guerin infection two years after intravesical bacillus Calmette-Guerin installation]. AB - Major complications following installation of bacillus Calmette Guerin (BCG) in the bladder as treatment for early stage cancer are rare and there are only few reports of BCG isolated from patients with suspected "BCGitis". We report a case where sputum culture yielded a BCG strain identical to one used two years earlier to treat the patient's bladder cancer. Some aspects were challenging in differential diagnosis: the patient's prior history of pulmonary tuberculosis ten years earlier and a two-year interval since BCG installation. PCR analysis and culture finally provided the diagnosis disseminated BCG infection. PMID- 25497625 TI - [Severe interstitial lung disease due to treatment with infliximab and azathioprine]. AB - A 41-year-old man developed severe interstitial lung disease (ILD) after treatment with infliximab (IFX) and azathioprine (AZA). A relapse of ulcerative colitis was treated with corticosteroids (CS) and IFX as rescue therapy. Following remission AZA was given as prophylaxis. AZA was initiated the same day as the third infusion of IFX (week 6). Within a few days he developed signs of lung involvement progressing into severe ILD. A high resolution computed tomography showed subacute hypersensitive pneumonitis. He was treated with oxygen and high dose CS. After three months his state of health had returned to normal. PMID- 25497626 TI - [Early-onset epileptic encephalopathy caused by CDKL5 mutation]. AB - Two girls suffering from early-onset epileptic encephalopathy are described. Both girls had changes involving the gene CDKL5. They both had seizures in the first weeks of life and normal EEG interictally. Both developed infantile spasms and severe developmental defect. The epilepsy was difficult to treat. PMID- 25497627 TI - [Oesophageal perforation of osteosynthesis material after anterior cervical surgery]. AB - The rare, potentially life-threatening complication to anterior cervical surgery, oesophageal perforation, occurs after surgical trauma or due to erosion by migrating hardware. Symptoms are hoarseness, dysphagia, neck/throat pain, subcutaneous emphysema and fever. Imaging and endoscopic diagnosis can give false negative results. We present a case of a 74-year-old male, who was readmitted with sepsis and abscess in the operation area three weeks after anterior cervical surgery. Veillonella parvula was found in the abscess material and computed tomography confirmed the diagnosis of oesophageal perforation. PMID- 25497628 TI - [Nuchal-type fibromas in the posterior region of the neck]. AB - Nuchal-type fibroma is a benign tumour usually presenting in the posterior region of the neck. It was first described in 1988, and the largest publication includes 52 cases of nuchal-type fibroma. It can easily be confused with lipoma, but upon surgical exploration it reveals as poorly defined and difficult to dissecate. Histologically nuchal-type fibroma is a paucicellular tumour with thick, randomly arranged collagen fibres with centrally lobulated architecture. We present three cases of nuchal-type fibroma. PMID- 25497629 TI - [An almost fatal airway obstruction caused by a secretion plug in an endotracheal tube]. AB - Airway obstruction caused by a secretion plug in an endotracheal tube or a tracheostomy cannula can be a serious complication to mechanical ventilation. This case describes an event caused by a mucus plug localized to the distal part of a tracheostomy tube in a tetraplegic patient. The plug functioned as a check valve, allowing air to pass in - but not out - of the patient. A suction catheter could be passed through the airway without any resistance, and thus the airway was believed to be free. The event, which had an almost fatal outcome due to hyperinflation of the lungs, was relieved by replacement of the tracheostomy cannula. PMID- 25497630 TI - [Malignant lymphoma perforating the small intestine]. AB - A rare cause of acute abdominal pain: lymphoma making its debut by perforation of the small intestine. Lymphomas localised to the gastrointestinal tract are rare. A case is presented where the initial symptom of the disease was acute abdominal pain because of perforation of one of the lymphomas in the small intestine. The diagnostic and therapeutic options in such emergency cases are discussed. PMID- 25497631 TI - [Marjolin's ulcer in a 54-year-old skin graft]. AB - Marjolin's ulcer (MU) is a malignant degeneration of a chronic wound and spinocellular carcinoma is the most common type. MU is described as being aggressive in nature and carries a high incidence of metastases. A 71-year-old man developed spinocellular carcinoma 54 years after a primary amputation and a construction of a skin graft due to a severe foot trauma. The carcinoma was excised and a forefoot amputation was performed. PMID- 25497632 TI - [Congenite intestinal malrotation as cause of intermittent abdominal pain]. AB - Intestinal malrotation occurs during foetal development when the normal rotation and fixation of the midgut fails to take place. This condition may lead to volvulus and duodenal obstruction. It is almost exclusively a paediatric diagnosis, but it can become symptomatic much later in life. A 49-year-old woman, who had been suffering from intermittent abdominal pain for most of her adult life, was admitted to the hospital with severe abdominal pain. A computed tomography showed a displaced caecum and mesenteric whirlpool sign. She was diagnosed with intestinal malrotation and underwent a laparoscopic Ladd's procedure. PMID- 25497633 TI - [Suspected anaphylaxis by wound treatment with polyhexanide derivate wound products]. AB - Only four cases of anaphylaxis triggered by polyhexanide have been reported in the literature. We report a case of anaphylaxis in a Danish patient treated with polyhexanide derivate (Prontosan) wound products. We emphasise the importance of intramuscular injection of adrenaline as part of the treatment protocol in the initial phase of anaphylaxis and stress the importance of being aware of polyhexanide as a potential trigger of anaphylaxis. PMID- 25497634 TI - [Visual symptoms by syphilis]. AB - This case presents a 42-year-old homosexual man with weight loss, urticaria type rash, tinnitus/phonophobia, dizziness and blurred vision and scotoma on the left side. Visual acuity was affected and a left papillitis was present. The patient was tested positive for antibodies against Treponoma pallidum. This case illustrates that symptoms of the syphilis disease can come from different organ systems and cross medical specialties. We encourage clinicians to more readily think of syphilis whenever there is a sexual active patient with complaints from different parts of the body. PMID- 25497635 TI - [Pasteurella multocida septicaemia and pneumonia after chemotherapy in a patient who had no known contact with animals]. AB - Pasteurella multocida inhabits the upper respiratory tract of many animals. It can cause skin and soft tissue infections in humans, usually in association with animal bites. We present a case of a 66-year-old chemotherapy-induced immunocompromised patient with lung cancer, who was treated for pneumonia and septicaemia due to P. multocida. There was no anamnestic contact with animals, which underlines the fact that immunocompromised patients can suffer from serious systemic infections due to P. multocida - even with no known animal contact. PMID- 25497636 TI - [Brachial plexopathy after breast cancer]. AB - Neoplastic plexopathy is an unusual, but known cause of neuropathy. This is a case report of a patient, who developed brachial plexopathy years after completing treatment for breast cancer. The patient presented with pain in one arm and, subsequently, developed sensory deficits and muscle atrophy, resulting in severely impaired hand function. Repeated magnetic resonance imaging and positron emission tomography scans were necessary before the final diagnosis could be made. The case report illustrates the importance of a thorough and repeated diagnostic work-up, when metastatic cancer is a perhaps unlikely but possible cause of plexopathy. PMID- 25497637 TI - [Self-treatment with baking soda can lead to severe metabolic alkalosis]. AB - This case report describes a 66-year-old man, previously healthy besides mild hypertension. He ingested a self-made folk remedy consisting of baking soda and water against acid reflux in dosages that resulted in severe metabolic alkalosis (pH 7.8). Diagnosing and treating MA is easy and cheap, but if the condition is not treated, consequences can be severe. The challenge is to uncover patients' use of non prescription medications and folk remedies in the diagnostic process. Having this information it is possible to prevent MA in both high- and low-risk patients. PMID- 25497639 TI - [A combination of cardiac arrest and cerebral haemorrhage treated with extracorporeal membrane oxygenation]. AB - A 46-year-old, healthy woman with sudden hemiplegia and nausea suffered cardiac arrest during transport to the hospital. This was treated en route with LUCAS-2. A computed tomography ruled out cerebral haemorrhage, and an electricardiogramme showed inferior myocardial infarction. During percutaneous intervention the patient had another cardiac arrest. Despite revascularization she was very unstable and received more than 20 cardioversions of ventricular fibrillation. In the catheterization laboratory, the patient was connected to a heart lung machine (extracorporeal membrane oxygenation) while treated with LUCAS-2. After two months of hospitalization, the patient was able to walk and had minor cognitive impairment. PMID- 25497638 TI - [Spinal epidural abscesses are rare and warrant fast intervention]. AB - A spinal epidural abscess is a rare infectious disease that warrants urgent treatment. Symptoms involve a classic triad of fever, backache and neurological deficits but all the symptoms are rarely seen at the first contact. The low incidence and the non-specific symptoms can delay the diagnosis, resulting in grave neurological sequelae and death. Common risk factors are diabetes mellitus and intravenous drug abuse. Successful treatment relies on a multidisciplinary approach. We describe a case of spinal epidural abscesses in a previously healthy young man without known risk factors. PMID- 25497640 TI - [Whipple's disease in an elderly patient with a substantial weight loss and gastrointestinal symptoms]. AB - Whipple's disease is a multisystemic infection with Tropheryma whipplei often characterised by its gastrointestinal involvement. However, due to the broad spectrum of unspecific symptoms, the diagnosis is often delayed. We report a case of a 70 year-old-man, who presented with extensive weight loss and lymphadenopathy. The diagnosis of Whipple's disease was made 18 months later on a duodenal biopsy. Retrospectively, it was discovered that a mesenterial biopsy taken earlier also revealed signs of Whipple's disease. Clinicians and pathologists need to be aware of this very rare and potentially fatal disease. PMID- 25497641 TI - [New innovative glucose-controlled pump enabling glucose control in a pregnant patient with diabetes]. AB - Continuous glucose monitoring enables innovative insulin pumps to stop infusion of insulin at selected blood glucose thresholds. We present the first and successful Danish clinical case using this device, a Medtronics Veo insulin pump, in a patient with numerous cases of severe hypoglycaemia during earlier pregnancies. During this treatment insulin infusion was frequently stopped and severe hypoglycaemia prevented in the remaining part of pregnancy. PMID- 25497642 TI - [Pulmonary embolus after adder bite]. AB - The clinical course after adder bites (Vipera berus) is unpredictable. Antivenom can reduce morbidity markedly. Preventive use of low-molecular-weight heparin is not routinely recommended. We present a case report, where indication for antivenom was not found, and the patient developed pulmonary embolus. Thrombotic complications are known, but to our knowledge pulmonary embolus has not previously been described in the literature. PMID- 25497643 TI - [Patients with diagnostic challenging intestinal involvement of the endometriosis]. AB - A considerable proportion of women with endometriosis have intestinal involvement of the endometriosis. Intestinal endometriosis (IE) often results in abdominal pain and thus mimics the symptoms of other bowel diseases, including colon cancer. As a consequence, some women with IE are initially referred to general surgery and treated under suspicion of colon cancer. This case report demonstrates the diagnostic challenges and describes the key symptoms of IE. Women with key symptoms should be referred to a gynaecological department for transvaginal ultrasonography. The optimal surgical treatment for IE is laparoscopically assisted bowel resection. PMID- 25497644 TI - [Cytomegalovirus-associated haemophagocytic syndrome and acute renal failure in a patient with chronic lymphocytic leukaemia]. AB - A 60-year-old man with chronic lymphocytic leukaemia was admitted to our department with fever and hepatospleno-megaly. Laboratory findings revealed hyperferritinaemia of 40,300 microgram/l and both liver and renal dysfunction. A bone marrow biopsy showed haemophagocytosis consistent with haemophagocytic syndrome. The serology was compatible with acute Cytomegalovirus infection. The patient received therapy with ganciclovir, prednisolone and gamma globulin, and the acute renal failure was treated with haemodialysis. The patient responded well to the treatment and was discharged after a month with normal lever and renal function. PMID- 25497645 TI - [Encapsulating peritoneal sclerosis in a patient who had previously been in peritoneal dialysis]. AB - Encapsulating peritoneal sclerosis (EPS) is a rare but potentially fatal complication to long-term peritoneal dialysis (PD). We describe a case of EPS in a 58-year-old patient who had formerly had PD. The interdisciplinary approach for diagnosis and possible treatments in this condition is discussed. PMID- 25497646 TI - [Miliary tuberculosis in a patient with morbus Bechterew treated with tumour necrosis factor-alpha]. AB - Tumour necrosis factor (TNF)-alpha inhibitors are registered for treatment of several severe dermatologic, rheumatologic and gastrointestinal diseases. Due to TNF-alpha's important role in the immune system patients have increased risk of serious infections during treatment with TNF-alpha inhibitor. We here present a case of miliary tuberculosis complicated by pericardial effusion in a Danish man treated with TNF-alpha inhibitor that emphasizes the need for rapid examination of new symptoms in this patient category. PMID- 25497647 TI - [Traumatic cervical disc prolapse with severe neurological impact]. AB - A 51-year-old male drove into a ditch on his scooter. Immediately after the trauma the patient complained of neck pain and decreased ability to feel and move his extremities. An initial trauma computed tomography (CT) of the columna showed normal conditions. Because the patient had neurological deficiencies, magnetic resonance imaging of the columna was performed 12 days later, and a disc prolapse at the C3/C4 level with spinal cord compression was visible. Despite decompression the patient did not recover. Traumatic cervical disc prolapse is a rare and positionally dangerous condition, which can be present despite a CT showing normal conditions. PMID- 25497648 TI - [Fistula as cause of cyclic haematuria in a woman]. AB - We report a case of a 32-year-old female with a vesicouterine fistula (Youssef's syndrome). She had had a low segment caesarean section and subsequently developed cyclic haematuria and menorrhoea. There was a significant delay in diagnosis of the fistula because of problems with visualising the fistula. In this case the fistula was lastly diagnosed with magnetic resonance imaging (MRI), the patient was treated with hysterectomy (patient's wish) and the fistula tract was repaired succesfully. If investigation with ultrasonography, cystoscopy and computerised tomography at a highly specialised department is negative, we recommend that MRI should be performed. PMID- 25497649 TI - [Hereditary hypokaliaemic periodic paralysis in a 13-year-old boy]. AB - Hypokaliaemic periodic paralysis is a rare hereditary neuro-muscular disease caused by an error in the ion-canals in muscle cells resulting in decreased excitabiliy. It presents itself in the late childhood or teenage years with a periodic paralysis without involving respiratory and heart muscles. Our patient was a 13-year-old boy, who woke up with decreased strength in arms and legs after excessive physical activity and a high carbo-hydrate intake. Tests showed a low P potassium level. The patient had full remission of his symptoms within 24 hours. PMID- 25497650 TI - [Keratopathy versus allergic eye disease: misdiagnosis leading to keratitis]. AB - A case report of involutional ectropion associated with exposure keratopathy - which complicated to exposure keratitis due to incorrect management is presented. Upon consulting the local pharmacy the patient was wrongly given anti-allergic eye drops. Patients with involutional ectropion have high risk of dry eye disease and may rarely be complicated with keratitis. Distinguishing between exposure keratopathy and allergic eye disease is pivotal as management differs and wrong therapy may lead to serious eye disease. PMID- 25497651 TI - [Combined antithrombin deficiency and factor VLeiden in a Danish family]. AB - Factor VLeiden (FVL) and antithrombin (AT) deficiency are both known genetic risk factors for venous thromboembolism (VTE). The combination is rare and leads to significantly increased risk for VTE. In this case we present a 22-year-old woman with VTE while treated with oral contraceptives. Laboratory investigation of the patient and her relatives showed co-segregation of FVL and AT deficiency. This is the first Danish family reported with co-segregated FVL and AT deficiency, and this clarifies the importance for thorough laboratory screening of patients presenting VTE while treated with oral contraceptives. PMID- 25497652 TI - [Acute urinary retention in a young woman with Lyme borreliosis]. AB - Acute urinary retention (AUR) in females is a rare condition (annual incidence 3 7/100,000/year). In the past AUR was considered to be of psychogenic origin. Today diagnostic tools have improved and aetiologic factors for AUR are more easily diagnosed and managed. Causes of AUR can be of infectious, pharmacological, neurological, anatomical, myopathic and functional origin. We report a case of a woman aged 34 who presented with AUR caused by Lyme borreliosis. The patient fully recovered after intravenous antibiotic treatment and micturition returned to the habitual condition. PMID- 25497653 TI - [The first case of cap polyposis in Denmark]. AB - Cap polyposis (CP) is characterized by the presence of inflammatory polyps mainly involving the rectosigmoid. It primarily causes mucous to bloody diarrhoea and is often misdiagnosed initially. We report the first case in Denmark with multiple polyps in the rectosigmoid causing constipation in between periods of mucous and bloody diarrhoea. He was initially misdiagnosed as having ulcerative colitis with pseudopolyps. Due to insufficient effect of medical treatment biopsies from the polyps were obtained. They showed typical histological signs of CP. He was successfully treated by rectosigmoid resection. PMID- 25497654 TI - [A monstrous tumour in the thorax can represent a thymoma]. AB - Pulmonary infiltrates on radiological imaging are most often assumed to be a potential lung cancer, although seldom, other malignant intrathoracal tumours can appear. Knowledge of these, their growth pattern and localisation is of significance in order to reach a differential diagnosis and to plan targeted treatment. In mediastinum anterior thymoma is the most frequent form of cancer arising from the thymus epithelium. This case report describes a male patient suspected of lung cancer who happened to have malignant thymoma with atypical dissemination, which challenged the diagnostics. PMID- 25497655 TI - [Retroperitoneal benign cyst with osseous metaplasia as the cause of abdominal pain]. AB - A 27-year-old female patient with no previous medical history, presented a computed tomography displaying a calcified retroperitoneal cyst. The patient had experienced occasional abdominal pain in her right side. The tumour was found in the retroperitoneum, was non-adherent to neighbouring organs and was excised laparoscopically without postoperative complications. Histology revealed a benign, cystic mass, with calcification and osseous metaplasia in the cyst wall, and no epithelia. The material of the cyst was amorphic and necrotic. No other retroperitoneal masses alike has been described in the literature. PMID- 25497656 TI - [Stress fracture after changing to barefoot running]. AB - Barefoot running is increasing in popularity but little is known about the implications in respect to injuries. It has been proposed that barefoot running is associated with a decrease in running injuries as it represents a more natural way of running. A 50-year-old runner with a weekly running distance of 50 km presented suffering from a stress fracture of the second metatarsal after six weeks of intensive barefoot running. PMID- 25497657 TI - [Vena cava agenesia presented as incarcerated groin hernia]. AB - The case describes a 45-year-old man with a rare finding of vena cava agenesia presented as incarcerated groin hernia. From childhood the patient had developed dilatation of subcutaneous veins with establishment of aneurismal dilatation in the lower right side of the abdomen and groin. The patient was submitted with severe abdominal pain in the lower right side. The case describes the difficulties of an initially incorrect radiological diagnosis of incarcerated groin hernia and the discrepancy of the clinical findings. The case stresses the importance of a thorough evaluation of each patient. PMID- 25497658 TI - [Bacterial sacroiliitis caused by group B streptococci]. AB - A 12-year-old girl was admitted to the paediatric department due to a short history of severe pain in the right hip, inability to walk and fever, 39 degrees C. She had had no previous trauma or ongoing infection elsewhere. Examination showed a septic girl with pain of the right sacroiliac joint. Laboratory findings showed a marginally raised white blood cell count and C-reactive protein. A magnetic resonance imaging was performed and showed effusion of the right sacroiliac joint without root compression. Three days later blood cultures showed group B streptococci and the patient received intravenous antibiotic treatment for two weeks and continued with oral antibiotics for four weeks. PMID- 25497659 TI - [Twisted arteriae et venae iliaca externa after total hip arthroplasty]. AB - Vascular injuries associated with total hip arthroplasty are rare, but often lead to serious complications even in the hand of a very skilled surgeon. Fast diagnosis of vascular complication is of crucial importance for the prognosis. PMID- 25497660 TI - [Risk of nerve damage by surgery of the lateral malleolus]. AB - Fracture of the lateral malleolus is a common injury, which often requires surgery. The lateral approach is often used with a "cut straight to bone" method. In this 59-year-old woman with an ankle fracture we found a variant of the superficial peroneal nerve (SPN) crossing the operative field with great danger of laceration. A review of the literature reveals that in more than 10% of the cases significant nerve branches may be found in the operative field. This report emphasises the need for neurological exam and recommends that great care for nerve variants should be taken during surgery on and around the lateral malleolus. PMID- 25497661 TI - [Acute kidney injury secondary to the first intravenous administration of acyclovir]. AB - Acute kidney injury secondary to precipitation of acyclovir crystals in the kidneys is well known and mainly observed in the setting of dehydration or pre existing renal impairment. We describe a case of acute kidney injury secondary to intravenous administration of acyclovir in a 64-year-old female with trans-versal myelitis and no prior medical history. She developed a rapid rise in the plasma creatinine level only seven hours after the primary drug administration. Acyclovir was discontinued and a urinary flow rate was maintained at 100-200 ml/h with IV fluids. The kidney function returned to normal within five days. PMID- 25497662 TI - [Buckwheat allergy can cause live-threatening anaphylaxia]. AB - Alongside with the globalization of the Danish kitchen and the introduction of a larger number of commercial food items containing buckwheat, buckwheat allergy no longer seems to be a rare disease in Denmark. Since buckwheat allergy can cause life-threathening reactions, it is important for medical doctors to be aware of this allergy. Reliable serological tests showing specific IgE to buckwheat protein 2S albumin (Fag e2) are available in most countries. Three patients with anaphylactic reactions due to buckwheat allergy are presented. PMID- 25497663 TI - [Life-threatening appendicitis caused by Fusobacterium necrophorum]. AB - Fusobacterium necrophorum is a well-known cause of Lemierre's syndrome. Recent studies suggest a causative association between F. necrophorum and acute appendicitis. We present a case of a 15-year-old previously healthy girl who presented with acute non-perforated appendicitis, intra-abdominal abscesses and thrombosis that led to omental necrosis. This resulted in a life-threatening septic shock with the need for prolonged intensive care. We suggest that F. necrophorum identified in pus from the abdomen caused this fulminant variation of appendicitis with findings similar to those seen with Lemierre's syndrome. PMID- 25497664 TI - [Oral ulcer as primary manifestation of HIV infection in an 80-year-old man]. AB - Oral lesions such as candidiasis, Kaposi's sarcoma, hairy leukoplakia, herpes simplex infection, and ulcerative periodontitis are associated with HIV infection and may be the primary presentation in persons with undiagnosed HIV. We report a clinical case in which an 80-year-old man presented with an oral ulcer with morphological signs of immuno-suppression. The patient was perceived to be at low risk of HIV infection and thus, diagnostic HIV testing was delayed until subsequent development of Kaposi's sarcoma on the skin. PMID- 25497665 TI - [Thyroid hormone resistance may course hypotonia in infancy]. AB - Allan Herndon Dudley's syndrome (AHDS) is X-linked mental retardation and hypotonia caused by mutations in a thyroid hormone transporter gene - MCT8. The typical thyreoidea AHDS profile is elevated T3, low-normal T4 and normal or elevated thyroid stimulating hormone (TSH). Neonatal screening with TSH often does not identify AHDS in boys and therefore it is of paramount importance to screen boys who present with hypo-tonia and/or mental retardation with thyroidea profile. In the case report a four and a half month-old boy with develop-mental delay and hypotonia is described and diagnosed with AHDS. The finding of the typical thyroidea profile leads to the diagnosis which is confirmed by DNA analysis. PMID- 25497666 TI - [Development of scleroderma renal crisis in a patient with undiagnosed scleroderma]. AB - Less than 10% of the patients with systemic scleroderma develop renal crisis, i.e. acute renal failure and severe hypertension in most cases. Kidney biopsy shows hypertensive arteriolar changes. This complication was lethal until treatment with captopril was introduced in 1976. Since that time the survival of the patients has improved. If treatment is started early, further deteoriation of the kidney may be prevented. PMID- 25497667 TI - [Rare dislocation of caput humeri by proximal humerus fracture]. AB - This case report describes a patient with Neer type 6 and 4 fragmentary proximal humerus fracture. Caput humeri was situated medial of the conjoined tendon, which is rarely seen in this fracture type. The fracture was treated with hemiarthroplasty with a good result. There are various advantages and disadvantages when treating proximal humerus fractures with either plate osteosyntese or hemiarthroplasty, which has to be taken into account when choosing the treatment of this fracture type. PMID- 25497668 TI - Microbial growth within saline-filled tissue expanders. AB - BACKGROUND: Tissue expander based reconstruction is the most common restorative procedure used following mastectomy. Infection is a common complication in the post-operative period and may lead to failure of the reconstruction. Various previous studies have investigated the potential sources of infection during these procedures. The purpose of this study was to examine the fluid within the saline-filled tissue expander at time of implant exchange for the presence of microbial growth. METHODS: Twenty-five patients (39 breasts) were enrolled in the study. Fluid samples were sent for Gram stain, aerobic, anaerobic, fungal, and acid-fast bacilli (AFB) cultures. Average age was 53.1. Mean time to exchange was 7.7 months. Average follow-up was 25 months. RESULTS: None of the samples were positive for microbial growth at final culture (0/39). DISCUSSION: These results show the tissue expander fluid maintains a microbial-free environment during the expansion process, and is unlikely a significant source of contamination in cases of infection. LEVEL OF EVIDENCE: Level II, prospective cohort, therapeutic study. PMID- 25497669 TI - Divergence and codon usage bias of Betanodavirus, a neurotropic pathogen in fish. AB - Betanodavirus is a small bipartite RNA virus of global economical significance that can cause severe neurological disorders to an increasing number of marine fish species. Herein, to further the understanding of the evolution of betanodavirus, Bayesian coalescent analyses were conducted to the time-stamped entire coding sequences of their RNA polymerase and coat protein genes. Similar moderate nucleotide substitution rates were then estimated for the two genes. According to age calculations, the divergence of the two genes into the four genotypes initiated nearly simultaneously at ~700 years ago, despite the different scenarios, whereas the seven analyzed chimeric isolates might be the outcomes of a single genetic reassortment event taking place in the early 1980s in Southern Europe. Furthermore, codon usage bias analyses indicated that each gene had influences in addition to mutational bias and codon choice of betanodavirus was not completely complied with that of fish host. PMID- 25497670 TI - Reply to A. Dragutinovic, 'A reply to: The transferability of diatoms to clothing and the methods appropriate for their collection and analysis in forensic geoscience Forensic Sci. Int. 241 (2014) 127-137'. PMID- 25497671 TI - Pancreatic enzyme replacement therapy for people with cystic fibrosis (Review). PMID- 25497672 TI - RRM1 modulates mitotane activity in adrenal cancer cells interfering with its metabolization. AB - The anti-proliferative activity of mitotane (o,p'DDD) in adrenocortical cancer is mediated by its metabolites o,p'DDE and o,p'DDA. We previously demonstrated a functional link between ribonucleotide reductase M1(RRM1) expression and o,p'DDD activity, but the mechanism is unknown. In this study we assessed the impact of RRM1 on the bioavailability and cytotoxic activity of o,p'DDD, o,p'DDE and o,p'DDA in SW13 and H295R cells. In H295R cells, mitotane and its metabolites showed a similar cytotoxicity and RRM1 expression was not influenced by any drug. In SW13 cells, o,p'DDA only showed a cytotoxic activity and did not modify RRM1 expression, whereas the lack of sensitivity to o,p'DDE was associated to RRM1 gene up-modulation, as already demonstrated for o,p'DDD. RRM1 silencing in SW13 cells increased the intracellular transformation of mitotane into o,p'DDE and o,p'DDA. These data demonstrate that RRM1 gene interferes with mitotane metabolism in adrenocortical cancer cells, as a possible mechanisms of drug resistance. PMID- 25497673 TI - Catheter-related bacteremia caused by Kocuria salsicia: the first case. AB - We report the first case of catheter-related bacteremia caused by Kocuria salsicia in a patient with short bowel syndrome. The pathogen was initially identified as Kocuria varians by a Vitek 2-based assessment, but its 16S rRNA gene sequence showed 100% similarity to K. salsicia. The patient was successfully treated with vancomycin and removal of the catheter. PMID- 25497674 TI - Detection of bacteria and fungi in blood of patients with febrile neutropenia by real-time PCR with universal primers and probes. AB - Febrile neutropenia is the main treatment-related cause of mortality in cancer patients. During June 2012 to April 2014, 97 blood culture samples were collected from patients receiving chemotherapy for hematological malignancy and cancer with febrile neutropenia episodes (FNEs). The samples were examined for the presence of bacteria and fungi using real-time PCR amplification and sequencing of 16S and 18S rRNA genes. Bacteria were identified in 20 of 97 samples (20.6%) by the real time PCR assay and in 10 of 97 (10.3%) samples by blood culture. In 6 blood culture-positive samples, the real-time PCR assay detected the same type of bacteria. No fungi were detected by the real-time PCR assay or blood culture. During antibiotic therapy, all samples were negative by blood culture, but the real-time PCR assay yielded a positive result in 2 cases of 2 (100%). The bacterial DNA copy number was not well correlated with the serum C-reactive protein titer of patients with FNEs. We conclude that a real-time PCR assay could provide better detection of causative microbes' in a shorter time, and with a smaller blood sample than blood culture. Using a real-time PCR assay in combination with blood culture could improve microbiological documentation of FNEs. PMID- 25497675 TI - Water and sediment transport modeling of a large temporary river basin in Greece. AB - The objective of this research was to study the spatial distribution of runoff and sediment transport in a large Mediterranean watershed (Evrotas River Basin) consisting of temporary flow tributaries and high mountain areas and springs by focusing on the collection and use of a variety of data to constrain the model parameters and characterize hydrologic and geophysical processes at various scales. Both monthly and daily discharge data (2004-2011) and monthly sediment concentration data (2010-2011) from an extended monitoring network of 8 sites were used to calibrate and validate the Soil and Water Assessment Tool (SWAT) model. In addition flow desiccation maps showing wet and dry aquatic states obtained during a dry year were used to calibrate the simulation of low flows. Annual measurements of sediment accumulation in two reaches were used to further calibrate the sediment simulation. Model simulation of hydrology and sediment transport was in good agreement with field observations as indicated by a variety of statistical measures used to evaluate the goodness of fit. A water balance was constructed using a 12 year long (2000-2011) simulation. The average precipitation of the basin for this period was estimated to be 903 mm yr(-1). The actual evapotranspiration was 46.9% (424 mm yr(-1)), and the total water yield was 13.4% (121 mm yr(-1)). The remaining 33.4% (302 mm yr(-1)) was the amount of water that was lost through the deep groundwater of Taygetos and Parnonas Mountains to areas outside the watershed and for drinking water demands (6.3%). The results suggest that the catchment has on average significant water surplus to cover drinking water and irrigation demands. However, the situation is different during the dry years, where the majority of the reaches (85% of the river network are perennial and temporary) completely dry up as a result of the limited rainfall and the substantial water abstraction for irrigation purposes. There is a large variability in the sediment yield within the catchment with the highest annual sediment yield (3.5 t ha(-1)yr(-1)) to be generated from the western part of the watershed. The developed methodology facilitated the simulation of hydrology and sediment transport of the catchment providing consistent results and suggesting its usefulness as a tool for temporary rivers management. PMID- 25497676 TI - A field application of a personal sensor for ultrafine particle exposure in children. AB - BACKGROUND: Ultrafine particles (UFPs) have been associated with adverse health outcomes in children, but studies are often limited by surrogate estimates of exposure. Accurately characterizing children's personal exposure to UFP is difficult due to the high spatiotemporal variability of UFP and children's time activity patterns. OBJECTIVE: The objectives of this study were to conduct a field test of a personal sensor for UFP (PUFP) by measuring UFP exposure among children and assess the sensor's capabilities and limitations. METHODS: Children wore the sensor at school, during transit periods between school and home, and in their home for 2-4h on 2 consecutive days and provided feedback regarding their experience with the sensor. The PUFP sensor recorded UFP number concentration at one second intervals and recorded GPS location allowing for comparisons of UFP exposure at homes, schools, and during transit. A mixed-effects linear model was used to compare the effect of microenvironment on personal UFP measurements. RESULTS: The overall total median personal exposure to UFP was 12,900 particles/cm(3) (p/cm(3)). Median UFP exposure at homes, schools and during transit was 17,800, 11,900, and 13,600 p/cm(3), respectively. Results of the mixed-effects model found that riding in a car and walking were significantly associated with 1.36 (95% CI 1.33-1.39) and 2.51 (95% CI 2.44-2.57) times higher UFP concentrations compared to the home. CONCLUSIONS: The PUFP sensor can measure near real-time exposure to UFP with high spatiotemporal resolution. Children's exposure to UFP varies by location, with increased exposure during transit to and from school. PMID- 25497677 TI - Fate of hazardous elements in agricultural soils surrounding a coal power plant complex from Santa Catarina (Brazil). AB - Hazard element contamination coming from coal power plants is something obvious, but when this contamination is accompanied by other contamination sources, such as, urban, coal mining and farming activities the study gets complicated. This is the case of an area comprised in the southern part of Santa Catarina state (Brazil) with the largest private power plant generator. After the elemental analysis of 41 agricultural soils collected in an extensive area around the thermoelectric (from 0 to 47 km), the high presence of As, Co, Cr, Cu, Fe, Mn, Mo, Pb, Sb, Sn, Tl, V and Zn was found in some specific areas around the power plant. Nevertheless, as the NWAC (Normalized-and-Weighted Average Concentration) confirmed, only soils from one site were classified as of very high concern due to the presence of potential toxic elements. This site was located within the sedimentation basin of the power plant. The spatial distribution obtained by kriging in combination with the analysis of the data by Principal Component Analysis (PCA) revealed three important hotspots in the area according to soil uses and geographic localization: the thermoelectric, its area of influence due to volatile compound deposition, and the area comprised between two urban areas. Farming practice turn out to be an important factor too for the quantity of hazard element stored in soils. PMID- 25497678 TI - Personal exposure monitoring of PM2.5 in indoor and outdoor microenvironments. AB - Adverse health effects from exposure to air pollution are a global challenge and of widespread concern. Recent high ambient concentration episodes of air pollutants in European cities highlighted the dynamic nature of human exposure and the gaps in data and knowledge about exposure patterns. In order to support health impact assessment it is essential to develop a better understanding of individual exposure pathways in people's everyday lives by taking account of all environments in which people spend time. Here we describe the development, validation and results of an exposure method applied in a study conducted in Scotland. A low-cost particle counter based on light-scattering technology - the Dylos 1700 was used. Its performance was validated in comparison with equivalent instruments (TEOM-FDMS) at two national monitoring network sites (R(2)=0.9 at a rural background site, R(2)=0.7 at an urban background site). This validation also provided two functions to convert measured PNCs into calculated particle mass concentrations for direct comparison of concentrations with equivalent monitoring instruments and air quality limit values. This study also used contextual and time-based activity data to define six microenvironments (MEs) to assess everyday exposure of individuals to short-term PM2.5 concentrations. The Dylos was combined with a GPS receiver to track movement and exposure of individuals across the MEs. Seventeen volunteers collected 35 profiles. Profiles may have a different overall duration and structure with respect to times spent in different MEs and activities undertaken. Results indicate that due to the substantial variability across and between MEs, it is essential to measure near complete exposure pathways to allow for a comprehensive assessment of the exposure risk a person encounters on a daily basis. Taking into account the information gained through personal exposure measurements, this work demonstrates the added value of data generated by the application of low-cost monitors. PMID- 25497679 TI - A framework for rating environmental value of urban parks. AB - In this study, indicators are proposed to characterize the intrinsic environmental properties and external value of urban parks. The intrinsic properties involve both acoustic factors and non-acoustic factors, such as visual aspects and size. To assess external value, the restoration level is defined, which measures the nearby presence of a quiet, 'green' area at residential areas outside parks. The restoration levels of green areas are based on intrinsic properties and the distances of each dwelling to urban park areas. The overall environmental value of a park, the group restoration level, is defined as a logarithmic summation of the restoration levels over its surrounding residential areas. Restoration levels were determined for sixteen public parks in the city of Rotterdam and compared with survey data from questionnaires. Results show that the investigated parks display a large variation in the group restoration level levels, mainly due to differences in size and average noise levels. To validate the proposed method, survey data from questionnaires are investigated as to correlation with restoration levels. PMID- 25497680 TI - Effects of nutrient enrichment on mangrove leaf litter decomposition. AB - Nutrient enrichment of mangroves, a common phenomenon along densely populated coastlines, may negatively affect mangrove ecosystems by modifying internal carbon and nutrient cycling. The decomposition of litter exerts a strong influence on these processes and is potentially modified by eutrophication. This study describes effects of N and P enrichment on litter decomposition rate and mineralisation/immobilisation patterns. By making use of reciprocal litter transplantation experiments among fertiliser treatments, it was tested if nutrient addition primarily acts on the primary producers (i.e. changes in litter quantity and quality) or on the microbial decomposers (i.e. changes in nutrient limitation for decomposition). Measurements were done in two mangrove forests where primary production was either limited by N or by P, which had been subject to at least 5 years of experimental N and P fertilisation. Results of this study indicated that decomposers were always N-limited regardless of the limitation of the primary producers. This leads to a differential nutrient limitation between decomposers and primary producers in sites where mangrove production was P limited. In these sites, fertilisation with P caused litter quality to change, resulting in a higher decomposition rate. This study shows that direct effects of fertilisation on decomposition through an effect on decomposer nutrient availability might be non-significant, while the indirect effects through modifying litter quality might be quite substantial in mangroves. Our results show no indication that eutrophication increases decomposition without stimulating primary production. Therefore we do not expect a decline in carbon sequestration as a result of eutrophication of mangrove ecosystems. PMID- 25497681 TI - Hydrochemical evolution and groundwater flow processes in the Galilee and Eromanga basins, Great Artesian Basin, Australia: a multivariate statistical approach. AB - The Galilee and Eromanga basins are sub-basins of the Great Artesian Basin (GAB). In this study, a multivariate statistical approach (hierarchical cluster analysis, principal component analysis and factor analysis) is carried out to identify hydrochemical patterns and assess the processes that control hydrochemical evolution within key aquifers of the GAB in these basins. The results of the hydrochemical assessment are integrated into a 3D geological model (previously developed) to support the analysis of spatial patterns of hydrochemistry, and to identify the hydrochemical and hydrological processes that control hydrochemical variability. In this area of the GAB, the hydrochemical evolution of groundwater is dominated by evapotranspiration near the recharge area resulting in a dominance of the Na-Cl water types. This is shown conceptually using two selected cross-sections which represent discrete groundwater flow paths from the recharge areas to the deeper parts of the basins. With increasing distance from the recharge area, a shift towards a dominance of carbonate (e.g. Na-HCO3 water type) has been observed. The assessment of hydrochemical changes along groundwater flow paths highlights how aquifers are separated in some areas, and how mixing between groundwater from different aquifers occurs elsewhere controlled by geological structures, including between GAB aquifers and coal bearing strata of the Galilee Basin. The results of this study suggest that distinct hydrochemical differences can be observed within the previously defined Early Cretaceous-Jurassic aquifer sequence of the GAB. A revision of the two previously recognised hydrochemical sequences is being proposed, resulting in three hydrochemical sequences based on systematic differences in hydrochemistry, salinity and dominant hydrochemical processes. The integrated approach presented in this study which combines different complementary multivariate statistical techniques with a detailed assessment of the geological framework of these sedimentary basins, can be adopted in other complex multi-aquifer systems to assess hydrochemical evolution and its geological controls. PMID- 25497682 TI - Effect of biosolids-derived triclosan and triclocarban on the colonization of plant roots by arbuscular mycorrhizal fungi. AB - Arbuscular mycorrhizal fungi (AMF) form a symbiotic relationship with the majority of crop plants. AMF provide plants with nutrients (e.g., P), modulate the effect of metal and pathogen exposure, and increase tolerance to moisture stress. The benefits of AMF to plant growth make them important to the development of sustainable agriculture. The land application of biosolids is becoming an increasingly common practice in sustainable agriculture, as a source of nutrients. However, biosolids have been found to contain numerous pharmaceutical and personal care products including antimicrobial chemicals such as triclosan and triclocarban. The potential risks that these two compounds may pose to plant-AMF interactions are poorly understood. The current study investigated whether biosolids-derived triclosan and triclocarban affect the colonization of the roots of lettuce and corn plants by AMF. Plants were grown in soil amended with biosolids that contained increasing concentrations of triclosan (0 to 307 MUg/g dw) or triclocarban (0 to 304 MUg/g dw). A relationship between the concentration of triclosan or triclocarban and colonization of plants roots by AMF was not observed. The presence of biosolids did not have a significant (p>0.05) effect on percent colonization of corn roots but had a significant, positive effect (p<0.05) on lettuce roots. Biosolids-derived triclosan and triclocarban did not inhibit the colonization of crop plant roots by AMF. PMID- 25497683 TI - Improvement of balance control ability and flexibility in the elderly Tai Chi Chuan (TCC) practitioners: a systematic review and meta-analysis. AB - BACKGROUND: Falls are the main cause of accidental death in the elderly people, which is associated with balance control ability and flexibility of the older adults. The purpose of this study was to evaluate the effect of TCC on the balance control and flexibility of the older adults. METHODS: We searched the PubMed, Embase and Cochrane library with the deadline of May 15th, 2014. This meta-analysis was performed using RevMan5.0 software. The overall weighted mean difference (WMD) and its 95% confidence interval (CI) were calculated. RESULTS: A total of 7 randomized controlled trials including 1088 participants (544 TCC practitioners and 544 participants with other interventions) were considered in this meta-analysis. The pooled estimate of Get up and Go test (WMD=1.04; 95%CI: 0.67-1.41; P<0.0001) indicated that TCC significantly shorten the completion time of Get up and Go test of the older adults, indicating flexibility of older adults was improved by practicing TCC. The overall estimates of the single-leg stand test (WMD=5.33; 95%CI: 3.35-7.32; P<0.0001) and Berg (balance) test (WMD=2.86; 95%CI: 1.91-3.81; P<0.0001) indicated that TCC could significantly prolong the time of single-leg stand and improve the balance control ability of older adults. CONCLUSIONS: In conclusion, TCC practice was beneficial to improve the balance control ability and flexibility of older adults, which may be the reason of preventing falls. PMID- 25497685 TI - BOLD responses to itch in the human spinal cord. AB - Itch is an independent sensory modality and a very common symptom with manifold causes. However, the neuronal representation of itch perception in the central nervous system is not entirely understood and there is hardly any knowledge about neuronal correlates of itch in the human spinal cord. In the present study we aimed to identify itch-related neural activity in the cervical spinal cord in healthy volunteers employing high-resolution functional magnetic resonance imaging (fMRI). We studied histamine-induced itch on the radial forearm and modulated itch intensity by non-noxious cooling. To control for effects of thermal stimulation (i.e., cooling), volunteers also underwent an identical session without histamine. We studied histamine-induced itch on the radial forearm, by using a block design with alternating blocks of non-noxious cooling separated by blocks of skin temperature. Non-noxious cooling of histamine-treated skin compared to cooling of non-treated skin led to a significant increase in itch perception. On the neural level, itch was paralleled by activation in the dorsal horn of the spinal cord at the transition between spinal segment C5 and C6, ipsilateral to the side of stimulation. These results suggest that itch related neural activity can be assessed noninvasively in humans at the spinal cord. PMID- 25497684 TI - Finding imaging patterns of structural covariance via Non-Negative Matrix Factorization. AB - In this paper, we investigate the use of Non-Negative Matrix Factorization (NNMF) for the analysis of structural neuroimaging data. The goal is to identify the brain regions that co-vary across individuals in a consistent way, hence potentially being part of underlying brain networks or otherwise influenced by underlying common mechanisms such as genetics and pathologies. NNMF offers a directly data-driven way of extracting relatively localized co-varying structural regions, thereby transcending limitations of Principal Component Analysis (PCA), Independent Component Analysis (ICA) and other related methods that tend to produce dispersed components of positive and negative loadings. In particular, leveraging upon the well known ability of NNMF to produce parts-based representations of image data, we derive decompositions that partition the brain into regions that vary in consistent ways across individuals. Importantly, these decompositions achieve dimensionality reduction via highly interpretable ways and generalize well to new data as shown via split-sample experiments. We empirically validate NNMF in two data sets: i) a Diffusion Tensor (DT) mouse brain development study, and ii) a structural Magnetic Resonance (sMR) study of human brain aging. We demonstrate the ability of NNMF to produce sparse parts-based representations of the data at various resolutions. These representations seem to follow what we know about the underlying functional organization of the brain and also capture some pathological processes. Moreover, we show that these low dimensional representations favorably compare to descriptions obtained with more commonly used matrix factorization methods like PCA and ICA. PMID- 25497686 TI - BOLD fractional contribution to resting-state functional connectivity above 0.1 Hz. AB - Blood oxygen level dependent (BOLD) spontaneous signals from resting-state (RS) brains have typically been characterized by low-pass filtered timeseries at frequencies <= 0.1 Hz, and studies of these low-frequency fluctuations have contributed exceptional understanding of the baseline functions of our brain. Very recently, emerging evidence has demonstrated that spontaneous activities may persist in higher frequency bands (even up to 0.8 Hz), while presenting less variable network patterns across the scan duration. However, as an indirect measure of neuronal activity, BOLD signal results from an inherently slow hemodynamic process, which in fact might be too slow to accommodate the observed high-frequency functional connectivity (FC). To examine whether the observed high frequency spontaneous FC originates from BOLD contrast, we collected RS data as a function of echo time (TE). Here we focus on two specific resting state networks the default-mode network (DMN) and executive control network (ECN), and the major findings are fourfold: (1) we observed BOLD-like linear TE-dependence in the spontaneous activity at frequency bands up to 0.5 Hz (the maximum frequency that can be resolved with TR=1s), supporting neural relevance of the RSFC at a higher frequency range; (2) conventional models of hemodynamic response functions must be modified to support resting state BOLD contrast, especially at higher frequencies; (3) there are increased fractions of non-BOLD-like contributions to the RSFC above the conventional 0.1 Hz (non-BOLD/BOLD contrast at 0.4-0.5 Hz is ~4 times that at <0.1 Hz); and (4) the spatial patterns of RSFC are frequency dependent. Possible mechanisms underlying the present findings and technical concerns regarding RSFC above 0.1 Hz are discussed. PMID- 25497687 TI - Smokeless tobacco, sport and the heart. AB - Smokeless tobacco (snuff) is a finely ground or shredded tobacco that is sniffed through the nose or placed between the cheek and gum. Chewing tobacco is used by putting a wad of tobacco inside the cheek. Smokeless tobacco is widely used by young athletes to enhance performance because nicotine improves some aspects of physiology. However, smokeless tobacco has harmful health effects, including cardiovascular disorders, linked to nicotine physiological effects, mainly through catecholamine release. Nicotine decreases heart rate variability and the ventricular fibrillation threshold, and promotes the occurrence of various arrhythmias; it also impairs endothelial-dependent vasodilation and could therefore promote premature atherogenesis. At rest, heart rate, blood pressure, inotropism, cardiac output and myocardial oxygen consumption are increased by nicotine, leading to an imbalance between myocardial oxygen demand and supply. The same occurs at submaximal levels of exercise. These increases are accompanied by a rise in systemic resistances. At maximal exercise, heart rate, cardiac output and maximal oxygen uptake (VO2max) are unaffected by nicotine. Because endothelial dysfunction is promoted by nicotine, paradoxical coronary vasoconstriction may occur during exercise and recovery. Nicotine induces a decrease in muscular strength and impairs anaerobic performance. However, nicotine is used in sports as it diminishes anxiety, enhances concentration and agility, improves aerobic performance and favours weight control. Importantly, smokeless tobacco, similar to cigarette smoking, leads to nicotine dependence through dopaminergic pathways. Smokeless tobacco has harmful cardiovascular effects and is addictive: it fulfils all the criteria for inclusion in the World Anti-Doping Agency prohibited list as a doping product. Smokeless tobacco use in sporting activities must be discouraged. PMID- 25497689 TI - Toll-like receptor 4 enhancement of non-NMDA synaptic currents increases dentate excitability after brain injury. AB - Concussive brain injury results in neuronal degeneration, microglial activation and enhanced excitability in the hippocampal dentate gyrus, increasing the risk for epilepsy and memory dysfunction. Endogenous molecules released during injury can activate innate immune responses including toll-like receptor 4 (TLR4). Recent studies indicate that immune mediators can modulate neuronal excitability. Since non-specific agents that reduce TLR4 signaling can limit post-traumatic neuropathology, we examined whether TLR4 signaling contributes to early changes in dentate excitability after brain injury. Concussive brain injury caused a transient increase in hippocampal TLR4 expression within 4h, which peaked at 24h. Post-injury increase in TLR4 expression in the dentate gyrus was primarily neuronal and persisted for one week. Acute, in vitro treatment with TLR4 ligands caused bidirectional modulation of dentate excitability in control and brain injured rats, with a reversal in the direction of modulation after brain injury. TLR4 antagonists decreased, and agonist increased, afferent-evoked dentate excitability one week after brain injury. NMDA receptor antagonist did not occlude the ability of LPS-RS, a TLR4 antagonist, to decrease post-traumatic dentate excitability. LPS-RS failed to modulate granule cell NMDA EPSCs but decreased perforant path-evoked non-NMDA EPSC peak amplitude and charge transfer in both granule cells and mossy cells. Our findings indicate an active role for TLR4 signaling in early post-traumatic dentate hyperexcitability. The novel TLR4 modulation of non-NMDA glutamatergic currents, identified herein, could represent a general mechanism by which immune activation influences neuronal excitability in neurological disorders that recruit sterile inflammatory responses. PMID- 25497690 TI - Incentive Processing in Persistent Disruptive Behavior and Psychopathic Traits: A Functional Magnetic Resonance Imaging Study in Adolescents. AB - BACKGROUND: Children with early-onset disruptive behavior disorder (DBD), especially those with callous-unemotional traits, are at risk of developing persistent and severe adult antisocial behavior. One possible underlying mechanism for persistence is deficient reward and loss sensitivity, i.e., deficient incentive processing. However, little is known about the relation between deficient incentive processing and persistence of antisocial behavior into adulthood or its relation with callous-unemotional and other psychopathic traits. In this study, we investigate the relationship between the neural correlates of incentive processing and both DBD persistence and psychopathic traits. METHODS: In a sample of 128 adolescents (mean age 17.7) with a history of criminal offending before age 12, functional magnetic resonance imaging was performed during a monetary incentive delay task designed to assess neural responses during incentive processing. Neural activation during incentive processing was then associated with DBD persistence and psychopathic traits, measured with the Youth Psychopathic Traits Inventory. RESULTS: Compared with both healthy control subjects and youths who had desisted from DBD, persistent DBD subjects showed lower neural responses in the ventral striatum during reward outcomes and higher neural responses in the amygdala during loss outcomes. Callous-unemotional traits were related to lower neural responses in the amygdala during reward outcomes, while other psychopathic traits were not related to incentive processing. CONCLUSIONS: In the current study, aberrant incentive processing is related to persistence of childhood antisocial behavior into late adolescence and to callous-unemotional traits. This mechanism may underlie treatment resistance in a subgroup of antisocial youth and provide a target for intervention. PMID- 25497688 TI - Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways. AB - Gene multiplications or point mutations in alpha (alpha)-synuclein are associated with familial and sporadic Parkinson's disease (PD). An increase in copper (Cu) levels has been reported in the cerebrospinal fluid and blood of PD patients, while occupational exposure to Cu has been suggested to augment the risk to develop PD. We aimed to elucidate the mechanisms by which alpha-synuclein and Cu regulate dopaminergic cell death. Short-term overexpression of wild type (WT) or mutant A53T alpha-synuclein had no toxic effect in human dopaminergic cells and primary midbrain cultures, but it exerted a synergistic effect on Cu-induced cell death. Cell death induced by Cu was potentiated by overexpression of the Cu transporter protein 1 (Ctr1) and depletion of intracellular glutathione (GSH) indicating that the toxic effects of Cu are linked to alterations in its intracellular homeostasis. Using the redox sensor roGFP, we demonstrated that Cu induced oxidative stress was primarily localized in the cytosol and not in the mitochondria. However, alpha-synuclein overexpression had no effect on Cu-induced oxidative stress. WT or A53T alpha-synuclein overexpression exacerbated Cu toxicity in dopaminergic and yeast cells in the absence of alpha-synuclein aggregation. Cu increased autophagic flux and protein ubiquitination. Impairment of autophagy by overexpression of a dominant negative Atg5 form or inhibition of the ubiquitin/proteasome system (UPS) with MG132 enhanced Cu-induced cell death. However, only inhibition of the UPS stimulated the synergistic toxic effects of Cu and alpha-synuclein overexpression. Our results demonstrate that alpha synuclein stimulates Cu toxicity in dopaminergic cells independent from its aggregation via modulation of protein degradation pathways. PMID- 25497691 TI - High-Dose Testosterone Treatment Increases Serotonin Transporter Binding in Transgender People. AB - BACKGROUND: Women are two times more likely to be diagnosed with depression than men. Sex hormones modulating serotonergic transmission are proposed to partly underlie these epidemiologic findings. Here, we used the cross-sex steroid hormone treatment of transsexuals seeking sex reassignment as a model to investigate acute and chronic effects of testosterone and estradiol on serotonin reuptake transporter (SERT) binding in female-to-male and male-to-female transsexuals. METHODS: Thirty-three transsexuals underwent [(11)C]DASB positron emission tomography before start of treatment, a subset of which underwent a second scan 4 weeks and a third scan 4 months after treatment start. SERT nondisplaceable binding potential was quantified in 12 regions of interest. Treatment effects were analyzed using linear mixed models. Changes of hormone plasma levels were correlated with changes in regional SERT nondisplaceable binding potential. RESULTS: One and 4 months of androgen treatment in female-to male transsexuals increased SERT binding in amygdala, caudate, putamen, and median raphe nucleus. SERT binding increases correlated with treatment-induced increases in testosterone levels, suggesting that testosterone increases SERT expression on the cell surface. Conversely, 4 months of antiandrogen and estrogen treatment in male-to-female transsexuals led to decreases in SERT binding in insula, anterior, and mid-cingulate cortex. Increases in estradiol levels correlated negatively with decreases in regional SERT binding, indicating a protective effect of estradiol against SERT loss. CONCLUSIONS: Given the central role of the SERT in the treatment of depression and anxiety disorders, these findings may lead to new treatment modalities and expand our understanding of the mechanism of action of antidepressant treatment properties. PMID- 25497692 TI - Dopamine receptor D4 (DRD4) gene modulates the influence of informational masking on speech recognition. AB - Listeners vary substantially in their ability to recognize speech in noisy environments. Here we examined the role of genetic variation on individual differences in speech recognition in various noise backgrounds. Background noise typically varies in the levels of energetic masking (EM) and informational masking (IM) imposed on target speech. Relative to EM, release from IM is hypothesized to place greater demand on executive function to selectively attend to target speech while ignoring competing noises. Recent evidence suggests that the long allele variant in exon III of the DRD4 gene, primarily expressed in the prefrontal cortex, may be associated with enhanced selective attention to goal relevant high-priority information even in the face of interference. We investigated the extent to which this polymorphism is associated with speech recognition in IM and EM conditions. In an unscreened adult sample (Experiment 1) and a larger screened replication sample (Experiment 2), we demonstrate that individuals with the DRD4 long variant show better recognition performance in noise conditions involving significant IM, but not in EM conditions. In Experiment 2, we also obtained neuropsychological measures to assess the underlying mechanisms. Mediation analysis revealed that this listening condition specific advantage was mediated by enhanced executive attention/working memory capacity in individuals with the long allele variant. These findings suggest that DRD4 may contribute specifically to individual differences in speech recognition ability in noise conditions that place demands on executive function. PMID- 25497695 TI - IBIS-I tamoxifen update: maturity brings questions. PMID- 25497693 TI - Semantic retrieval during overt picture description: Left anterior temporal or the parietal lobe? AB - Retrieval of semantic representations is a central process during overt speech production. There is an increasing consensus that an amodal semantic 'hub' must exist that draws together modality-specific representations of concepts. Based on the distribution of atrophy and the behavioral deficit of patients with the semantic variant of fronto-temporal lobar degeneration, it has been proposed that this hub is localized within both anterior temporal lobes (ATL), and is functionally connected with verbal 'output' systems via the left ATL. An alternative view, dating from Geschwind's proposal in 1965, is that the angular gyrus (AG) is central to object-based semantic representations. In this fMRI study we examined the connectivity of the left ATL and parietal lobe (PL) with whole brain networks known to be activated during overt picture description. We decomposed each of these two brain volumes into 15 regions of interest (ROIs), using independent component analysis. A dual regression analysis was used to establish the connectivity of each ROI with whole brain-networks. An ROI within the left anterior superior temporal sulcus (antSTS) was functionally connected to other parts of the left ATL, including anterior ventromedial left temporal cortex (partially attenuated by signal loss due to susceptibility artifact), a large left dorsolateral prefrontal region (including 'classic' Broca's area), extensive bilateral sensory-motor cortices, and the length of both superior temporal gyri. The time-course of this functionally connected network was associated with picture description but not with non-semantic baseline tasks. This system has the distribution expected for the production of overt speech with appropriate semantic content, and the auditory monitoring of the overt speech output. In contrast, the only left PL ROI that showed connectivity with brain systems most strongly activated by the picture-description task, was in the superior parietal lobe (supPL). This region showed connectivity with predominantly posterior cortical regions required for the visual processing of the pictorial stimuli, with additional connectivity to the dorsal left AG and a small component of the left inferior frontal gyrus. None of the other PL ROIs that included part of the left AG were activated by Speech alone. The best interpretation of these results is that the left antSTS connects the proposed semantic hub (specifically localized to ventral anterior temporal cortex based on clinical neuropsychological studies) to posterior frontal regions and sensory-motor cortices responsible for the overt production of speech. PMID- 25497696 TI - Impact of an information campaign on delays and ambulance use in acute coronary syndrome. PMID- 25497697 TI - Internal hernia presenting as pseudomyocardial infarction. PMID- 25497694 TI - Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. AB - BACKGROUND: Four previously published randomised clinical trials have shown that tamoxifen can reduce the risk of breast cancer in healthy women at increased risk of breast cancer in the first 10 years of follow-up. We report the long-term follow-up of the IBIS-I trial, in which the participants and investigators remain largely masked to treatment allocation. METHODS: In the IBIS-I randomised controlled trial, premenopausal and postmenopausal women 35-70 years of age deemed to be at an increased risk of developing breast cancer were randomly assigned (1:1) to receive oral tamoxifen 20 mg daily or matching placebo for 5 years. Patients were randomly assigned to the two treatment groups by telephone or fax according to a block randomisation schedule (permuted block sizes of six or ten). Patients and investigators were masked to treatment assignment by use of central randomisation and coded drug supply. The primary endpoint was the occurrence of breast cancer (invasive breast cancer and ductal carcinoma in situ), analysed by intention to treat. Cox proportional hazard models were used to assess breast cancer occurrence and mortality. The trial is closed to recruitment and active treatment is completed, but long-term follow-up is ongoing. This trial is registered with controlledtrials.com, number ISRCTN91879928. FINDINGS: Between April 14, 1992, and March 30, 2001, 7154 eligible women recruited from genetics clinics and breast care clinics in eight countries were enrolled into the IBIS-I trial and were randomly allocated to the two treatment groups: 3579 to tamoxifen and 3575 to placebo. After a median follow up of 16.0 years (IQR 14.1-17.6), 601 breast cancers have been reported (251 [7.0%] in 3579 patients in the tamoxifen group vs 350 [9.8%] in 3575 women in the placebo group; hazard ratio [HR] 0.71 [95% CI 0.60-0.83], p<0.0001). The risk of developing breast cancer was similar between years 0-10 (226 [6.3%] in 3575 women in the placebo group vs 163 [4.6%] in 3579 women in the tamoxifen group; hazard ratio [HR] 0.72 [95% CI 0.59-0.88], p=0.001) and after 10 years (124 [3.8%] in 3295 women vs 88 [2.6%] in 3343, respectively; HR 0.69 [0.53 0.91], p=0.009). The greatest reduction in risk was seen in invasive oestrogen receptor-positive breast cancer (HR 0.66 [95% CI 0.54-0.81], p<0.0001) and ductal carcinoma in situ (0.65 [0.43-1.00], p=0.05), but no effect was noted for invasive oestrogen receptor-negative breast cancer (HR 1.05 [95% CI 0.71-1.57], p=0.8). INTERPRETATION: These results show that tamoxifen offers a very long period of protection after treatment cessation, and thus substantially improves the benefit-to-harm ratio of the drug for breast cancer prevention. FUNDING: Cancer Research UK (UK) and the National Health and Medical Research Council (Australia). PMID- 25497699 TI - Sexual dimorphism and age of Mediterranean salamanders. AB - We analysed sexual size dimorphism (SSD) for two Mediterranean species of the "true" salamander clade possessing distinct life histories (Salamandra algira and Mertensiella caucasica) and equilibrated the morphometric approach to individual age by using skeletochronology. For species that have a short breeding season and live at high altitudes, such as Mediterranean amphibians, the fecundity advantage hypothesis predicts female-biased SSD to maximise reproductive success. Our results showed no SSD in either species; however, morphometric data indicated a male-biased dimorphism in limb (arm and leg) dimensions in both species when compared to body size. Limb dimorphisms are likely related to the particular mating system, which involves an amplexus during spermatophore transfer. Arm length appeared sexually dimorphic during ontogeny both in viviparous S. algira and oviparous M. caucasica. A review on SSD indicated monomorphy of body size as a common lineage-specific pattern among the "true" salamander clade, but also the common presence of other traits such as sexually dimorphic limb proportions. PMID- 25497698 TI - Pulmonary embolism and heparin-induced thrombocytopenia successfully treated with tissue plasminogen activator and argatroban. PMID- 25497700 TI - Overexpression of nuclear FUS induces neuronal cell death. AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative diseases that overlap clinically, genetically, and pathologically. Dysregulation of fused in sarcoma (FUS) has been hypothesized to cause ALS and FTLD in gain-of-function and/or loss-of-function manners. However, the link between the pathogenesis of ALS/FTLD and dysfunction of FUS has not been clearly determined. In this study, we found that overexpression of FUS, but not knocking-down of endogenous FUS expression, induces death in motor neuronal NSC34 cells and primary cortical neurons via the mitochondrial apoptotic pathway, possibly independently of transactive response DNA-binding protein-43. Furthermore, we found that nuclear FUS, but not cytoplasmic FUS, is responsible for FUS-induced neuronal cell death. These observations suggest that the gain-of function of FUS in the nucleus contributes to the pathogenesis of FUS-linked neurodegenerative diseases. PMID- 25497701 TI - Peptide based diagnostics: are random-sequence peptides more useful than tiling proteome sequences? AB - Diagnostics using peptide ligands have been available for decades. However, their adoption in diagnostics has been limited, not because of poor sensitivity but in many cases due to diminished specificity. Numerous reports suggest that protein based rather than peptide-based disease detection is more specific. We examined two different approaches to peptide-based diagnostics using Coccidioides (aka Valley Fever) as the disease model. Although the pathogen was discovered more than a century ago, a highly sensitive diagnostic remains unavailable. We present a case study where two different approaches to diagnosing Valley Fever were used: first, overlapping Valley Fever epitopes representing immunodominant Coccidioides antigens were tiled using a microarray format of presynthesized peptides. Second, a set of random sequence peptides identified using a 10,000 peptide immunosignaturing microarray was compared for sensitivity and specificity. The scientific hypothesis tested was that actual epitope peptides from Coccidioides would provide sufficient sensitivity and specificity as a diagnostic. Results demonstrated that random sequence peptides exhibited higher accuracy when classifying different stages of Valley Fever infection vs. epitope peptides. The epitope peptide array did provide better performance than the existing immunodiffusion array, but when directly compared to the random sequence peptides, reported lower overall accuracy. This study suggests that there are competing aspects of antibody recognition that involve conservation of pathogen sequence and aspects of mimotope recognition and amino acid substitutions. These factors may prove critical when developing the next generation of high performance immunodiagnostics. PMID- 25497702 TI - Fluorescently labeled dengue viruses as probes to identify antigen-specific memory B cells by multiparametric flow cytometry. AB - Low frequencies of memory B cells in the peripheral blood make it challenging to measure the functional and phenotypic characteristics of this antigen experienced subset of B cells without in vitro culture. To date, reagents are lacking to measure ex vivo frequencies of dengue virus (DENV)-specific memory B cells. We wanted to explore the possibility of using fluorescently labeled DENV as probes to detect antigen-specific memory B cells in the peripheral blood of DENV immune individuals. Alexa Fluor dye-labeled DENV yielded viable virus that could be stored at -80 degrees C for long periods of time. Using a careful gating strategy and methods to decrease non-specific binding, we were able to identify a small frequency of B cells from dengue immune individuals that bound labeled DENV. Sorted DENV(+) B cells from immune, but not naive donors secreted antibodies that bound DENV after in vitro stimulation. Overall, Alexa Fluor dye-labeled DENVs are useful reagents to enable the detection and characterization of memory B cells in DENV immune individuals. PMID- 25497703 TI - TNF inhibitors directly target Th17 cells via attenuation of autonomous TNF/TNFR2 signalling in psoriasis. PMID- 25497704 TI - Fear extinction in 17 day old rats is dependent on metabotropic glutamate receptor 5 signaling. AB - We used pharmacological modulation of the mGlu5 receptor to investigate its role in the extinction of conditioned fear throughout development. In postnatal day (P) 17 rats, the positive allosteric modulator CDPPB facilitated, while the negative allosteric modulator MTEP impaired extinction. These drugs had no such effects on P24 or adult rats. These results establish a changing importance of mGlu5 in extinction of conditioned fear at distinct stages of development. PMID- 25497705 TI - Involvement of dopamine in the differences in sexual behaviour between Roman high and low avoidance rats: an intracerebral microdialysis study. AB - Outbred Roman high- (RHA) and low-avoidance (RLA) rats are selected for respectively rapid vs. poor acquisition of the active avoidance response and display different copulatory patterns when exposed to a sexually receptive female, with RHA rats showing more robust sexual motivation and better performance than RLA rats also after repeated sexual activity. Here we show that the distinct patterns of sexual behaviour of the Roman lines are correlated with differences in the activity of the dopaminergic mesolimbic system, which plays a key role in sexual motivation and copulatory performance. Thus, differential increases in the concentrations of dopamine and its main metabolite 3,4 dihydroxyphenylacetic acid, occurred in dialysates obtained from the nucleus accumbens shell of naive and sexually experienced Roman rats during the anticipatory and consummatory phases of sexual activity. These differences were particularly evident between sexually naive RHA and RLA rats and tended to diminish but still persisted between sexually experienced rats, as did the differences in sexual behaviour. Analysis of the biochemical and behavioural findings showed that, while in RHA rats sexual experience caused a shift in the changes in both the dopaminergic activity and copulation towards the first period of the sexual test, in RLA rats sexual experience increased dopaminergic activity and copulation throughout the entire test. Therefore, this study adds experimental support to the view that the different sexual patterns of the Roman lines are due, at least in part, to a more robust functional tone of the mesolimbic dopaminergic system of RHA rats. PMID- 25497706 TI - Increased risk of ischemic stroke in patients with pneumoconiosis. AB - Although past studies have confirmed that chronic dust exposure is a risk factor for cardiovascular disease, the relationship between it and cerebrovascular disease is still unclear. We aimed to determine whether pneumoconiosis is related to increased incidence of ischemic stroke in the following 5 to 11 years. We selected 1238 patients with pneumoconiosis from Taiwan's National Health Insurance database as our study cohort. After matching for age, sex and the date of ambulatory care visit, another 4952 patients without pneumoconiosis were selected as the comparison cohort. Each patient was individually followed up until the end of 2010 to track the incidence of stroke, and Cox proportional hazard regression analysis was performed to compute the relative hazard ratio of stroke. Our results showed 19.6% of pneumoconiosis patients and 15.8% of non pneumoconiosis patients developed stroke. After statistically adjusting for age, sex, and medical comorbidities, the hazard of developing stroke was 1.36 times greater for those with pneumoconiosis compared to those without. Even in those with pneumoconiosis excluding chronic obstructive pulmonary disease, the hazard of developing stroke was still 1.31 times greater than those without pneumoconiosis. Our study revealed that pneumoconiosis patients are at a higher risk of ischemic stroke, and primary prevention of stroke is particularly important in this group of patients. PMID- 25497707 TI - In vitro anti-yeast activity of chloramphenicol: A preliminary report. AB - Chloramphenicol is a bacteriostatic antimicrobial agent but its antifungal activity is not known. The present study aimed to investigate the activity of chloramphenicol against 30 representative yeasts. The antimicrobial assay of chloramphenicol (50mg/mL; 100mg/mL and 200mg/mL) was determined by the disc diffusion method using Mueller-Hinton agar against 30 representative yeast strains. Zone of inhibition was read after 48-72h incubation at 37 degrees C and results were compared with some standard antifungal agents. Most of the tested yeasts (73.3%) showed inhibition zones (5 up to 35mm) to chloramphenicol impregnated discs (200mg/mL). Three out of the four tested Candida albicans as well as Candida famata, Candida glabrata, Candida haemolonei and Cryptococcus neoformans showed no inhibition zones to chloramphenicol (200mg/mL). Caspofungin acetate (50mg/mL) inhibited 83.3% of the strains; ketoconazole (200mg/mL) 70% and metronidazole 10%. Chloramphenicol discs: 50 and 100mg/mL showed less activity (6.7% and 36.7%, respectively) compared to the 200mg discs; whereas chloramphenicol (BBL; 3MUg/mL) inhibited 13.3% of the strains. The anti-yeast activities of chloramphenicol were comparable to other known antifungal compounds. Moreover, it is cheap, has fewer side effects and its inclusions in selective fungal media such as Mycosel have to be questioned. PMID- 25497708 TI - Lycium barbarum polysaccharide improves traumatic cognition via reversing imbalance of apoptosis/regeneration in hippocampal neurons after stress. AB - AIMS: Previous studies in our laboratory have demonstrated the increased neuronal apoptosis in the hippocampus and abnormal hippocampal morphology after severe stress, which directly correlates to the pathogenesis of post-traumatic stress disorder (PTSD). This study aims to investigate the effects of Lycium barbarum polysaccharide (LBP) on intrusive memory of posttraumatic stress in rats, and to analyze the mechanism of regeneration/apoptosis balance in the hippocampal neurons. MAIN METHODS: The experimental rats received 20 inescapable electric foot shocks in an enclosed box for six times in three days. The rats were treated by intragastric administration of LBP (20mg/kg/day) for 3 days before stress in the stress plus prophylactic group, and for 28 days after stress in the stress plus therapeutic group. The emotion, intrusive memory-related behavior (freezing, open field, pain latency, spatial cognition), hippocampus cell morphology, and relation of neurogenesis and apoptosis in dental gyrus of the hippocampus were observed. The hippocampus volume was evaluated by stereology. Meanwhile, the neurogenesis and apoptosis were analyzed with 5-bromo-2'-deoxyuridine and terminal deoxylnucleotidyl transferase mediated-dUTP nick end labeling (TUNEL) method. KEY FINDINGS: The treatment of LBP in pre-stress and post-stress had obvious beneficial effect on the behaviors and neurogenesis. The stressed rats showed improvement of intrusive memory related cognition defect, alleviation of the apoptosis in the hippocampus and recovery for the neurogenesis, which was related to the hippocampus volume after LBP treatment. SIGNIFICANCE: LBP treatment might effectively improve the traumatic cognition defect induced by severe stress and be useful for the intrusive memory-related cognition recovery. PMID- 25497709 TI - Orientin alleviates cognitive deficits and oxidative stress in Abeta1-42-induced mouse model of Alzheimer's disease. AB - AIMS: beta-Amyloid (Abeta)-mediated neurotoxicity plays a critical role in the pathogenesis of Alzheimer's disease (AD), possibly including Abeta-induced mitochondrial dysfunction and oxidative stress. Previous studies have demonstrated that orientin (Ori) possesses antioxidation capabilities in vitro. Therefore, current study is to demonstrate that Ori can activate Nrf2/HO-1 signaling and alleviate apoptosis induced by Abeta1-42, and ameliorate cognitive deficits in AD mice. MAIN METHODS: AD models were made by injecting Abeta1-42 into the bilateral hippocampus of mice. The mice were randomly assigned to three groups: the normal mice and Abeta1-42-induced AD mice with saline, and Abeta1-42 induced AD mice with Ori (5mg/kg), and were injected intraperitoneally once a day for 15 days. After the Morris Water Maze (MWM) test, mice were sacrificed and brains were harvested for biochemical analysis. KEY FINDINGS: Results indicated that Ori could ameliorate cognitive deficits in AD mice. Levels of oxidative stress, indicated by production of reactive oxygen species (ROS), 3-nitrotyrosine (3-NT), 4-hydroxy-nonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), were significantly decreased after Ori treatment. In addition, the current study showed that Ori could attenuate mitochondrial dysfunction induced by Abeta1-42, and subsequently inhibited the mitochondrial apoptotic pathway. Ori induced the nuclear translocation of Nrf2, which enhanced the expression of HO-1 and activation of the redox signaling pathway. SIGNIFICANCE: Ori might alleviate cognitive deficits and oxidative stress in AD mice, which might be a potential therapeutic drug for AD. PMID- 25497710 TI - Metformin reduces the Walker-256 tumor development in obese-MSG rats via AMPK and FOXO3a. AB - AIMS: Studies have associated obesity with a wide variety of cancers. Metformin, an anti-diabetic drug, has recently received attention as a potentially useful therapeutic agent for treating cancer. Therefore, the objective of this study was to analyze the mechanisms involved in the increase in tumor development and the reduction of it by metformin in obesity using an experimental breast tumor model. MATERIAL AND METHODS: Newborn male Wistar rats were subcutaneously injected with 400mg/kg monosodium glutamate (MSG) (obese) or saline (control) at 2, 3, 4, 5 and 6 days of age. After 16 weeks, 1 * 10(7) Walker-256 tumor cells were subcutaneously injected in the right flank of the rats and concomitantly the treatment with metformin 300 mg/kg/15 days, via gavage, started. The rats were divided into 4 groups: control tumor (CT), control tumor metformin (CTM), obese MSG tumor (OT) and obese-MSG tumor metformin (OTM). On the 18th week the tumor development and metformin effect were analyzed. KEY FINDINGS: Tumor development was higher in OT rats compared with CT rats. Activation of insulin-IR-ERK1/2 pathway and an anti-apoptotic effect might be the mechanisms involved in the higher development of tumor in obesity. The effect of metformin reducing the tumor development in obese rats might involve increased mRNA expression of pRb and p27, increased activity of AMPK and FOXO3a and decreased expression of p ERK1/2 (Thr202/Tyr204) in Walker-256 tumor. SIGNIFICANCE: Our data allow us to suggest that metformin, reducing the stimulatory effect of obesity on tumor development, has a potential role in the management of cancers. PMID- 25497711 TI - CB2 receptor-mediated effects of pro-inflammatory macrophages influence survival of cardiomyocytes. AB - AIMS: The endocannabinoid system and cannabinoid receptor 2 (CB2 receptor) have been associated with modulation of inflammatory response and myocardial adaptation after ischemic injury. In order to elucidate CB2 receptor-related effects during cellular interactions, we investigated cardiomyocyte survival and macrophage function in vitro. MAIN METHODS: Murine embryonic (eCM) and adult (CM) cardiomyocytes, murine macrophages (MO), and their subtypes M1 (M1-MO) and M2 (M2 MO) were derived from wildtype- (WT) and CB2 receptor-deficient (Cnr2(-/-)) mice. Cells were cultured separately or in co-culture under normoxia or hypoxia (2% O2) and pro-inflammatory stimulation using interferon (IFN)gamma. Besides immunohistochemistry, we also measured mRNA expression (Taqman(r)) and performed FACS-analysis of cardiomyocytes. Macrophage migration was assessed using Boyden chamber assay. KEY FINDINGS: We found a significant induction of CB2 receptor mRNA and protein in murine eCM as well as M1- and M2-MO in vitro following cultivation under hypoxia or stimulation with IFNgamma. A significantly higher amount of apoptotic Cnr2(-/-)-CMs was found after incubation under hypoxia when compared to WT-CMs. We observed a significantly stronger migration potential in Cnr2(-/-)-M1-MOs towards the supernatant of apoptotic CM, than in corresponding WT-cells. Co-culture revealed a significantly higher loss of eCMs and induction of their apoptosis after cultivation with Cnr2(-/-)-M1-MOs. Production of TNF alpha in M1-MOs was dependent on CB2 receptor stimulation by anandamide. SIGNIFICANCE: Our data provide novel insights into CB2 receptor-mediated protection of cardiomyocytes during hypoxia and pro-inflammatory stimulation. We show CB2 receptor-dependent effects on migration and function of M1-MOs in interaction with cardiomyocytes, thereby influencing their survival. PMID- 25497712 TI - Pseudolaric acid B inhibits T-cell mediated immune response in vivo via p38MAPK signal cascades and PPARgamma activation. AB - AIMS: Pseudolaric acid B (PAB) has been prescribed for its potent immunomodulatory effect. However, the detail of mechanism remains to be demonstrated. The purpose of this study is to further clarify the mechanism of PAB on T-cell mediated immune response in vivo. MAIN METHODS: Investigations were carried to ascertain the pharmacological effect of PAB in a delayed-type hypersensitivity (DTH) mouse model of T-cell mediated immune response. Histological assessment was examined by hematoxylin and eosin staining. Affymetrix GeneChip(r) Mouse Genome 430 2.0 arrays were employed to evaluate the expression profile of PAB. Western blot was performed to detect p38MAPK signal cascades, including p38MAPK, ATF-2, MK2, and HSP27. Finally, TNF-alpha level was analyzed by ELISA, and Jurkat T cells were treated with PAB to determine its role on PPARgamma activation using a reporter gene assay. KEY FINDINGS: The results showed that PAB (5, 10, and 20mg/kg) could lead to a marked improvement for ear swelling and inflammatory infiltrate in DTH mice dose-dependently. According to the associated biological pathways from microarray analysis, PAB resulted in the restoration of abnormal immune-related gene expression linked to MAPK and PPAR signaling pathways. Moreover, PAB inhibited the activation of p38MAPK, ATF-2, MK2, and HSP27 significantly, as well as the production of TNF-alpha, which was reversed by GW9662, a specific antagonist for PPARgamma. In addition, treatment with PAB also increased the transcriptional activity of PPARgamma in a dose dependent manner. SIGNIFICANCE: These results provide us with novel insights into pharmacological action of PAB as a potential immunomodulator for the treatment of immune-related diseases. PMID- 25497713 TI - Cutaneous silent period recordings in demyelinating and axonal polyneuropathies. AB - OBJECTIVE: To investigate the cutaneous silent period (CSP), a spinal inhibitory reflex mainly mediated by A-delta fibres, in demyelinating and axonal polyneuropathy (PNP) and evaluate whether CSP parameters differ between patients with and without neuropathic pain. METHODS: Eighty-four patients with demyelinating PNP, 178 patients with axonal PNP and 265 controls underwent clinical examination, DN4 questionnaire, standard nerve conduction study, motor root stimulation and CSP recordings from abductor digiti minimi. We calculated the afferent conduction time of CSP (a-CSP time) with the formula: CSP latency root motor evoked potential latency. RESULTS: In the demyelinating PNP group the a-CSP time was significantly longer; in the axonal PNP group, CSP duration was shorter than the demyelinating group (p=0.010) and controls (p=0.001). CSP parameters were not different between patients with and without neuropathic pain. CONCLUSIONS: The abnormality of a-CSP time in the demyelinating PNP group suggests the crucial role of A-delta fibres in the mechanism of CSP; the shorter CSP duration in the axonal PNP group supports the strong influence of the number of axons on this parameter. Our study suggests that neuropathic pain could be related to pathophysiological mechanisms differing from mere A-delta fibre loss. SIGNIFICANCE: CSP evaluation is effective in detecting A-delta fibre dysfunction in axonal as well as demyelinating PNP. PMID- 25497714 TI - Factors associated with not receiving homecare, end-of-life homecare, or early homecare referral among cancer decedents: A population-based cohort study. AB - Publicly funded homecare has been shown to reduce acute care use and improve quality of life for those nearing end-of-life (EOL). Yet despite the known benefits of homecare, many EOL cancer patients never receive these services. We used administrative data on all cancer decedents in Ontario, Canada in 2006 to determine predictive factors of not receiving homecare, not receiving EOL homecare, and late initiation of EOL homecare. 22,262 decedents met the eligibly criteria, 25% of whom never received homecare in the last six months of life. A logistic regression found that cancer disease site, having a comorbidity (OR: 1.15, 95% CI: 1.1-1.2), region of residence, shorter cancer survival (OR: 2.09, 95% CI: 1.8-2.4), being male (OR: 1.25, 95% CI: 1.2-1.3), lower income (OR: 1.06, 95% CI: 1.03-1.08), older age (OR: 1.03, 95% CI: 1.02-1.05), and less prior emergency department use were significant factors associated with not receiving homecare (p<0.001). Individuals with hematological cancer (OR: 1.57, 95% CI: 1.3 1.8) were less likely to receive homecare in their final months. Some of these covariates also predicted not receiving EOL homecare and late referral to these services (p<0.05). The systematic differences in homecare use that we identified can help to guide strategies for improving access to these important services. PMID- 25497715 TI - Nationwide Smoking Cessation Treatment Support Program--Turkey project. AB - BACKGROUND: In 2011, Turkish Ministry of Health (MoH) initiated a nation-wide "Smoking Cessation Treatment Support Program" (SCTSP), to provide smoking cessation drugs free of charge. METHODS: SCTSP was conducted in all 81 cities of Turkey, at 228 smoking cessation clinics, and by over 400 physicians. In total, 164,733 participants took advantage of the program between January and November 2011. Varenicline (Champix((r)), Pfizer) and Bupropion (Zyban((r)), GlaxoSmithKline) were used in the program at a ratio of 0.7 and 0.3 respectively. Post-program data were obtained by phone interviews from randomly selected participants, who had completed a 1-year follow-up after enrollment in the program. FINDINGS: Quit rates were 29.6% for those given Varenicline and 25.1% for those given Bupropion. The quit rates for participants with hypertension (35.0%), diabetes mellitus (36.9%), coronary artery disease (32.1%) and cerebrovascular events (34.0%) were higher than those without. Increased age, female gender, longer duration of cessation drug use, low Fagerstrom score, the presence of hypertension, the absence of chronic obstructive pulmonary disease, and the absence of cancer were found to be associated with higher success rates. INTERPRETATION: SCTSP is the first successful report of a nation-wide community based smoking cessation intervention. The real-life quit rates obtained herein are comparable to those of clinical evidence to date. The centralization of smoking cessation clinics, standardization of treatment guidelines, application of a specific drug assignment algorithm, and provision of primary care support and follow-ups by trained physicians, appeared to be key elements for success. PMID- 25497716 TI - Elements of innovation and tradition in meat fermentation: Conflicts and synergies. AB - Fermented meats are often studied by food technologists and microbiologists with respect to their safety and quality properties. They are archetypal traditional foods, since they have originated as the products of empirical methods for meat preservation in a distant past and have evolved over many centuries towards a large assortment of varieties with strong territorial and socio-cultural connotations. Yet, an unambiguous definition of "traditional foods" is problematic and largely context-dependent, often being institutionalized and applied in a multitude of conflicting discourses by different actors. Contemporary food markets frequently rely on the seemingly oxymoronic concept of innovation-through-tradition, possibly as a manner to deal with a threatening and globalizing environment of change. The present paper focuses on the complex notion of "traditional fermented meats", following a four-dimensional hermeneutic setup (including a temporal, geographic, know-how, and meaning component). It gives an overview of elements of innovation and habits that are pertinent to meat fermentation and its technological and cultural track record. Such elements include the significance of time frames and localized production, as well as of artisan practice and the attribution of (cultural) meaning. Of particular interest is the reliance on "typical" microbial communities for fermentation. In addition, the boundaries of tradition and innovation in fermented meats are explored, with respect to what is acceptable to industry and consumers. PMID- 25497717 TI - Metabolic control via the mitochondrial protein import machinery. AB - Mitochondria have to import most of their proteins in order to fulfill a multitude of metabolic functions. Sophisticated import machineries mediate targeting and translocation of preproteins from the cytosol and subsequent sorting into their suborganellar destination. The mode of action of these machineries has been considered for long time as a static and constitutively active process. However, recent studies revealed that the mitochondrial protein import machinery is subject to intense regulatory mechanisms that include direct control of protein flux by metabolites and metabolic signalling cascades. PMID- 25497718 TI - Simultaneous orientation and thickness mapping in transmission electron microscopy. AB - In this paper we introduce an approach for simultaneous thickness and orientation mapping of crystalline samples by means of transmission electron microscopy. We show that local thickness and orientation values can be extracted from experimental dark-field (DF) image data acquired at different specimen tilts. The method has been implemented to automatically acquire the necessary data and then map thickness and crystal orientation for a given region of interest. We have applied this technique to a specimen prepared from a commercial semiconductor device, containing multiple 22 nm technology transistor structures. The performance and limitations of our method are discussed and compared to those of other techniques available. PMID- 25497719 TI - Transmission environmental scanning electron microscope with scintillation gaseous detection device. AB - A transmission environmental scanning electron microscope with use of a scintillation gaseous detection device has been implemented. This corresponds to a transmission scanning electron microscope but with addition of a gaseous environment acting both as environmental and detection medium. A commercial type of low vacuum machine has been employed together with appropriate modifications to the detection configuration. This involves controlled screening of various emitted signals in conjunction with a scintillation gaseous detection device already provided with the machine for regular surface imaging. Dark field and bright field imaging has been obtained along with other detection conditions. With a progressive series of modifications and tests, the theory and practice of a novel type of microscopy is briefly shown now ushering further significant improvements and developments in electron microscopy as a whole. PMID- 25497720 TI - Ischemic stroke subtype and presence of sleep-disordered breathing: the BASIC sleep apnea study. AB - BACKGROUND: Little is known about the prevalence of sleep-disordered breathing (SDB) across ischemic stroke subtypes. Given the important implications for SDB screening, we tested the association between SDB and ischemic stroke subtype in a population-based study. METHODS: Within the Brain Attack Surveillance in Corpus Christi Project, ischemic stroke patients were offered SDB screening with the ApneaLink Plus (n = 355). A neurologist assigned Trial of the ORG 10172 in Acute Stroke Treatment subtype (with an additional category for nonlacunar infarctions of unknown etiology) using hospital records. Unadjusted and adjusted (demographics, body mass index, National Institutes of Health Stroke Scale, diabetes, history of stroke/transient ischemic attack) logistic and linear regression models were used to test the association between subtype and SDB or apnea-hypopnea index (AHI). RESULTS: Median age was 65%, and 55% were men; 59% were Mexican American. Median time from stroke onset to SDB screen was 13 days (interquartile range [IQR] 6, 21). Overall, 215 (61%) had SDB (AHI >= 10). Median AHI was 13 (IQR 6, 27). Prevalence of SDB by subtype was cardioembolism, 66%; large-artery atherosclerosis, 57%; small-vessel occlusion, 68%; other determined, 50%; undetermined etiology, 58%; and nonlacunar stroke of unknown etiology, 63%. Ischemic stroke subtype was not associated with SDB in unadjusted (P = .72) or adjusted models (P = .91) models. Ischemic stroke subtype was not associated with AHI in unadjusted (P = .41) or adjusted models (P = .62). CONCLUSIONS: In this population-based stroke surveillance study, ischemic stroke subtype was not associated with the presence or severity of SDB. Sleep-disordered breathing is likely to be present after ischemic stroke, and the subtype should not influence decisions about SDB screening. PMID- 25497721 TI - Fibrinogen decrease after intravenous thrombolysis in ischemic stroke patients is a risk factor for intracerebral hemorrhage. AB - BACKGROUND: Intravenous thrombolysis is an effective treatment in acute stroke patients, but it increases the risk of intracerebral hemorrhages. Our aim is to establish if fibrinogen depletion increases the risk of intracerebral hemorrhage after intravenous thrombolysis for acute ischemic stroke. METHODS: In 104 ischemic stroke patients, treated with intravenous thrombolysis, we assessed the rate of intracerebral hemorrhages documented by computed tomographic scan at 24 hours and within 7 days post-treatment. Fibrinogen levels were determined at 2 hours after therapy: patients were classified as belonging to "low fibrinogen group" if levels decreased to less than 2 g/L and/or by 25% or more. Fibrinogen levels and other known hemorrhagic risk factors were studied using univariate and multivariate analyses. RESULTS: During the first 7 days, an intracerebral hemorrhage was detected in 24 patients (23.1%), and only 6 of these (5.8%) experienced symptomatic bleeding; 41 patients were included in the low fibrinogen group. Among the 24 hemorrhages, 18 occurred in the low fibrinogen group and 6 in the "normal fibrinogen group": the bleeding rate in the low fibrinogen group was significantly higher (43.9%) than that in the normal fibrinogen group (9.5%; odds ratio [OR] 7.43, P < .001). Univariate and multivariate analyses revealed that only clinical severity (OR 1.15, P < .001) and hypofibrinogenemia (OR 7.47, P < .001) were significantly associated with brain bleeding at 7 days and at 24 hours (P = .008). CONCLUSIONS: An early fibrinogen reduction seems to increase the risk of intracerebral hemorrhage after rtPA treatment in ischemic stroke. Fibrinogen assessment could be a rapid, inexpensive, and widely available tool to help the identification of patients at higher risk of bleeding. PMID- 25497722 TI - Transfer time to a high-volume center for patients with subarachnoid hemorrhage does not affect outcomes. AB - OBJECTIVES: The objective of our study was to examine patients with aneurysmal subarachnoid hemorrhage transferred and directly admitted to our institution in order to determine how transfer time affects outcomes. METHODS: A retrospective cohort study was performed of all patients undergoing treatment for aneurysmal subarachnoid hemorrhage between 2005 and 2012 at the University of Michigan. Variables, including transfer time, were tested for their independent association with the primary outcomes of symptomatic vasospasm and 12-month outcome as well as secondary outcomes of aneurysm rebleeding and 12-month mortality. RESULTS: During the study period, 263 (87.4%) patients were transferred to our institution and 38 (12.6%) were directly admitted for treatment of aneurysmal subarachnoid hemorrhage. Transfer time was not associated with the occurrence of symptomatic vasospasm, 12-month outcome, rebleeding, or 12-month mortality. Higher Hunt-Hess grade was associated with the occurrence of symptomatic vasospasm as well as with poorer 12-month outcome. CONCLUSIONS: Transfer time was not associated with the occurrence of symptomatic vasospasm, 12-month outcome, rebleeding, or 12-month mortality. We believe our data argue that protocols should emphasize early resuscitation and stabilization followed by safe transfer rather than a hyperacute transfer paradigm. However, transfer time should be minimized as much as possible so as not to delay time to definitive treatment. PMID- 25497723 TI - Family history of stroke and cardiovascular health in a national cohort. AB - BACKGROUND: We investigated the association between family history of stroke (FHS) and Life's Simple 7 (LS7), a public health metric defined by the American Heart Association. METHODS: Reasons for Geographic and Racial Differences in Stroke is a national population-based cohort of 30,239 blacks and whites, aged 45 years or older, sampled from the US population between 2003 and 2007. Data were collected by telephone, mail questionnaires, and in-home examinations. FHS was defined as any first-degree relative with stroke. Levels of the LS7 components (total cholesterol, blood pressure, fasting glucose, physical activity, diet, smoking, and body mass index) were each coded as poor (0 points), intermediate (1 point), or ideal (2 points) health. Ordinal logistic regression was used to model the data. RESULTS: Among 20,567 subjects with complete LS7 and FHS data, there were 7702 (37%) participants with an FHS. The mean age of the participants was 64 years. The mean (+/- standard deviation) overall LS7 score was lower for blacks (6.5 +/- 2.0) than that of whites (7.6 +/- 2.1). FHS was associated with poorer levels of physiological factors, particularly high blood pressure (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.07-1.19) and inversely associated with behaviors such as smoking (OR, .92; 95% CI, .85-.99). CONCLUSIONS: Our results suggest that screening for FHS can provide an opportunity for earlier detection and management of modifiable risk factors. PMID- 25497725 TI - What binds biosociality? The collective effervescence of the parent-led conference. AB - Questions of community are central to many research settings in the social sciences. Rabinow argued that, in the wake of the Human Genome Project, an increasingly important form of collectivity would be biosociality. Biosociality recognises a central role for biomedical knowledge in constructing genetic identities and producing and reproducing social relationships. Accordingly, it is often imagined as a new form of social solidarity. We draw on observations of parent-led conferences to explore the way in which biosociality is expressed at events organised around a particular genetic syndrome - 22q11 deletion syndrome. The parent-led conferences took place within the United Kingdom between 2007 and 2010 and were observed as part of a multi-sited ethnographic study. By bringing together a geographically dispersed group of people together within the same physical location, conferences offer an ideal platform to empirically examine sociality. Durkheim used the term collective effervescence to describe the collective expression of heightened emotion. We suggest that in the case of the 22q11 deletion syndrome activities discussed in this paper, collective effervescence is a mechanism through which individuals become a collective. We argue that parent-led conferences gather individuals in one location on the basis of common biological factors, but it is the shared emotional experience of being together that consolidates and renews the connection between members. PMID- 25497726 TI - Latent and manifest empiricism in Q'eqchi' Maya healing: a case study of HIV/AIDS. AB - This paper presents a case study of the traditional treatment of a Q'eqchi' Maya man in southern Belize in 2011 who is suffering from AIDS-related sickness. The purpose is to detail the empirical nature of Q'eqchi' Maya medicine, distinguishing between manifest and latent empiricism, as evidenced in the healers evolving attempts to treat the patient in the absence of knowledge of his biomedical diagnosis. The paper argues for a more complete understanding of the empirical nature of much Indigenous healing, which parallels aspects of scientific medicine, and for better collaboration among traditional healers and biomedical practitioners in strongly Indigenous areas. PMID- 25497724 TI - The alarmin IL-1alpha is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles. AB - BACKGROUND: Inflammasome-activated IL-1beta plays a major role in lung neutrophilic inflammation induced by inhaled silica. However, the exact mechanisms that contribute to the initial production of precursor IL-1beta (pro IL-1beta) are still unclear. Here, we assessed the implication of alarmins (IL 1alpha, IL-33 and HMGB1) in the lung response to silica particles and found that IL-1alpha is a master cytokine that regulates IL-1beta expression. METHODS: Pro- and mature IL-1beta as well as alarmins were assessed by ELISA, Western Blot or qRT-PCR in macrophage cultures and in mouse lung following nano- and micrometric silica exposure. Implication of these immune mediators in the establishment of lung inflammatory responses to silica was investigated in knock-out mice or after antibody blockade by evaluating pulmonary neutrophil counts, CXCR2 expression and degree of histological injury. RESULTS: We found that the early release of IL 1alpha and IL-33, but not HMGB1 in alveolar space preceded the lung expression of pro-IL-1beta and neutrophilic inflammation in silica-treated mice. In vitro, the production of pro-IL-1beta by alveolar macrophages was significantly induced by recombinant IL-1alpha but not by IL-33. Neutralization or deletion of IL-1alpha reduced IL-1beta production and neutrophil accumulation after silica in mice. Finally, IL-1alpha released by J774 macrophages after in vitro exposure to a range of micro- and nanoparticles of silica was correlated with the degree of lung inflammation induced in vivo by these particles. CONCLUSIONS: We demonstrated that in response to silica exposure, IL-1alpha is rapidly released from pre-existing stocks in alveolar macrophages and promotes subsequent lung inflammation through the stimulation of IL-1beta production. Moreover, we demonstrated that in vitro IL-1alpha release from macrophages can be used to predict the acute inflammogenic activity of silica micro- and nanoparticles. PMID- 25497727 TI - Temporal lobe proteins implicated in synaptic failure exhibit differential expression and deamidation in vascular dementia. AB - Progressive synaptic failure precedes the loss of neurons and decline in cognitive function in neurodegenerative disorders, but the specific proteins and posttranslational modifications that promote synaptic failure in vascular dementia (VaD) remain largely unknown. We therefore used an isobaric tag for relative and absolute proteomic quantitation (iTRAQ) to profile the synapse associated proteome of post-mortem human cortex from vascular dementia patients and age-matched controls. Brain tissue from VaD patients exhibited significant down-regulation of critical synaptic proteins including clathrin (0.29; p < 1.0?10(-3)) and GDI1 (0.51; p = 3.0?10(-3)), whereas SNAP25 (1.6; p = 5.5?10( 3)), bassoon (1.4; p = 1.3?10(-3)), excitatory amino acid transporter 2 (2.6; p = 9.2?10(-3)) and Ca(2+)/calmodulin dependent kinase II (1.6; p = 3.0?10(-2)) were substantially up-regulated. Our analyses further revealed divergent patterns of protein modification in the dementia patient samples, including a specific deamidation of synapsin1 predicted to compromise protein structure. Our results reveal potential molecular targets for intervention in synaptic failure and prevention of cognitive decline in VaD. PMID- 25497728 TI - BAX-induced apoptosis can be initiated through a conformational selection mechanism. AB - BAX protein plays a key role in the mitochondria-mediated apoptosis. However, it remains unclear by what mechanism BAX is triggered to initiate apoptosis. Here, we reveal the mechanism using electron spin resonance (ESR) techniques. An inactive BAX monomer was found to exhibit conformational heterogeneity and exist at equilibrium in two conformations, one of which has never been reported. We show that upon apoptotic stimulus by BH3-only peptides, BAX can be induced to convert into either a ligand-bound monomer or an oligomer through a conformational selection mechanism. The kinetics of reaction is studied by means of time-resolved ESR, allowing a direct in situ observation for the transformation of BAX from the native to the bound states. In vitro mitochondrial assays provide further discrimination between the proposed BAX states, thereby revealing a population-shift allosteric mechanism in the process. BAX's apoptotic function is shown to critically depend on excursions between different structural conformations. PMID- 25497729 TI - Free RCK arrangement in Kch, a putative escherichia coli potassium channel, as suggested by electron crystallography. AB - The ligand-gated potassium channels are stimulated by various kinds of messengers. Previous studies showed that ligand-gated potassium channels containing RCK domains (the regulator of the conductance of potassium ion) form a dimer of tetramer structure through the RCK octameric gating ring in the presence of detergent. Here, we have analyzed the structure of Kch, a channel of this type from Escherichia coli, in a lipid environment using electron crystallography. By combining information from the 3D map of the transmembrane part of the protein and docking of an atomic model of a potassium channel, we conclude that the RCK domains face the solution and that an RCK octameric gating ring arrangement does not form under our crystallization condition. Our findings may be applied to other potassium channels that have an RCK gating ring arrangement. PMID- 25497730 TI - Unique structural features in DNA polymerase IV enable efficient bypass of the N2 adduct induced by the nitrofurazone antibiotic. AB - The reduction in the efficacy of therapeutic antibiotics represents a global problem of increasing intensity and concern. Nitrofuran antibiotics act primarily through the formation of covalent adducts at the N(2) atom of the deoxyguanosine nucleotide in genomic DNA. These adducts inhibit replicative DNA polymerases (dPols), leading to the death of the prokaryote. N(2)-furfuryl-deoxyguanosine (fdG) represents a stable structural analog of the nitrofuran-induced adducts. Unlike other known dPols, DNA polymerase IV (PolIV) from E. coli can bypass the fdG adduct accurately with high catalytic efficiency. This property of PolIV is central to its role in reducing the sensitivity of E. coli toward nitrofuran antibiotics such as nitrofurazone (NFZ). We present the mechanism used by PolIV to bypass NFZ-induced adducts and thus improve viability of E. coli in the presence of NFZ. Our results can be used to develop specific inhibitors of PolIV that may potentiate the activity of nitrofuran antibiotics. PMID- 25497731 TI - Structural and functional characterization of the phosphorylation-dependent interaction between PML and SUMO1. AB - PML and several other proteins localizing in PML-nuclear bodies (PML-NB) contain phosphoSIMs (SUMO-interacting motifs), and phosphorylation of this motif plays a key role in their interaction with SUMO family proteins. We examined the role that phosphorylation plays in the binding of the phosphoSIMs of PML and Daxx to SUMO1 at the atomic level. The crystal structures of SUMO1 bound to unphosphorylated and tetraphosphorylated PML-SIM peptides indicate that three phosphoserines directly contact specific positively charged residues of SUMO1. Surprisingly, the crystal structure of SUMO1 bound to a diphosphorylated Daxx-SIM peptide indicate that the hydrophobic residues of the phosphoSIM bind in a manner similar to that seen with PML, but important differences are observed when comparing the phosphorylated residues. Together, the results provide an atomic level description of how specific acetylation patterns within different SUMO family proteins can work together with phosphorylation of phosphoSIM's regions of target proteins to regulate binding specificity. PMID- 25497732 TI - Exocytosis regulates trafficking of GABA and glycine heterotransporters in spinal cord glutamatergic synapses: a mechanism for the excessive heterotransporter induced release of glutamate in experimental amyotrophic lateral sclerosis. AB - The impact of synaptic vesicle endo-exocytosis on the trafficking of nerve terminal heterotransporters was studied by monitoring membrane expression and function of the GABA transporter-1 (GAT-1) and of type-1/2 glycine (Gly) transporters (GlyT-1/2) at spinal cord glutamatergic synaptic boutons. Experiments were performed by inducing exocytosis in wild-type (WT) mice, in amphiphysin-I knockout (Amph-I KO) mice, which show impaired endocytosis, or in mice expressing high copy number of mutant human SOD1 with a Gly93Ala substitution (SOD1(G93A)), a model of human amyotrophic lateral sclerosis showing constitutively excessive Glu exocytosis. Exposure of spinal cord synaptosomes from WT mice to a 35mM KCl pulse increased the expression of GAT-1 at glutamatergic synaptosomal membranes and enhanced the GAT-1 heterotransporter induced [(3)H]d-aspartate ([(3)H]d-Asp) release. Similar results were obtained in the case of GlyT-1/2 heterotransporters. Preventing depolarization-induced exocytosis normalized the excessive GAT-1 and GlyT-1/2 heterotransporter-induced [(3)H]d-Asp release in WT mice. Impaired endocytosis in Amph-I KO mice increased GAT-1 membrane expression and [(3)H]GABA uptake in spinal cord synaptosomes. Also the GAT-1 heterotransporter-evoked release of [(3)H]d-Asp was augmented in Amph-I KO mice. The constitutively excessive Glu exocytosis in SOD1(G93A) mice resulted in augmented GAT-1 expression at glutamatergic synaptosomal membranes and GAT-1 or GlyT-1/2 heterotransporter-mediated [(3)H]d-Asp release. Thus, endo-exocytosis regulates the trafficking of GAT-1 and GlyT-1/2 heterotransporters sited at spinal cord glutamatergic nerve terminals. As a consequence, it can be hypothesized that the excessive GAT-1 and GlyT-1/2 heterotransporter-mediated Glu release, in the spinal cord of SOD1(G93A) mice, is due to the heterotransporter over-expression at the nerve terminal membrane, promoted by the excessive Glu exocytosis. PMID- 25497733 TI - Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult onset leukodystrophy with axonal spheroids and pigmented glia (ALSP). AB - Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/- and control Csf1r+/+ mice. Six to 8-month old Csf1r+/- mice exhibit cognitive deficits, and by 9-11 months develop sensorimotor deficits and in male mice, depression and anxiety like behavior. MRIs of one year-old Csf1r+/- mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/- mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches. Furthermore, our results suggest that aberrant activation of microglia in Csf1r+/- mice may play a central role in ALSP pathology. PMID- 25497736 TI - Association between serum YKL-40 level and dysglycemia in cystic fibrosis. AB - BACKGROUND: YKL-40, a chitinase-like protein, is a biomarker for type 1 and type 2 diabetes prognosis. We hypothesized that YKL-40 protein levels are elevated in CF patients with dysglycemia. METHODS: Seventeen healthy control subjects and 66 CF patients were prospectively recruited and subjected to an oral glucose tolerance test. In all participants, fasting serum YKL-40 was compared between control and CF patients and between normal glucose-tolerant patients (NG-CF) and CF patients with dysglycemia (DG-CF). A Botnia clamp procedure was performed on a subset of patients for each group to determine the impact of acute increases of either glucose or insulin on YKL-40 concentration. RESULTS: CF patients had higher serum YKL-40 values than the controls (113 [49;288] vs. 38 [30;50] ng/ml, p<0.001). YKL-40 concentrations in CF patients were mainly increased in the DG-CF group, who had significantly higher values: 213 [93;383] vs. 67 [27;97] ng/ml in the NG-CF group, p<0.001). No significant modulation of YKL-40 concentration was observed in serum of CF (NG or DG-CF) or non-CF patients, after acute exposure to glucose or insulin. CONCLUSIONS: Higher serum YKL-40 levels in CF patients are significantly associated with dysglycemia. The increase in YKL-40 is potentially associated with an inflammatory response resulting from chronic glucose intolerance or CF disease evolution. PMID- 25497734 TI - Neutrophil elastase mediates acute pathogenesis and is a determinant of long-term behavioral recovery after traumatic injury to the immature brain. AB - While neutrophil elastase (NE), released by activated neutrophils, is a key mediator of secondary pathogenesis in adult models of brain ischemia and spinal cord injury, no studies to date have examined this protease in the context of the injured immature brain, where there is notable vulnerability resulting from inadequate antioxidant reserves and prolonged exposure to infiltrating neutrophils. We thus reasoned that NE may be a key determinant of secondary pathogenesis, and as such, adversely influence long-term neurological recovery. To address this hypothesis, wild-type (WT) and NE knockout (KO) mice were subjected to a controlled cortical impact at post-natal day 21, approximating a toddler-aged child. To determine if NE is required for neutrophil infiltration into the injured brain, and whether this protease contributes to vasogenic edema, we quantified neutrophil numbers and measured water content in the brains of each of these genotypes. While leukocyte trafficking was indistinguishable between genotypes, vasogenic edema was markedly attenuated in the NE KO. To determine if early pathogenesis is dependent on NE, indices of cell death (TUNEL and activated caspase-3) were quantified across genotypes. NE KO mice showed a reduction in these markers of cell death in the injured hippocampus, which corresponded to greater preservation of neuronal integrity as well as reduced expression of heme oxygenase-1, a marker of oxidative stress. WT mice, treated with a competitive inhibitor of NE at 2, 6 and 12h post-injury, likewise showed a reduction in cell death and oxidative stress compared to vehicle-treated controls. We next examined the long-term behavioral and structural consequences of NE deficiency. NE KO mice showed an improvement in long-term spatial memory retention and amelioration of injury-induced hyperactivity. However, volumetric and stereological analyses found comparable tissue loss in the injured cortex and hippocampus independent of genotype. Further, WT mice treated acutely with the NE inhibitor showed no long term behavioral or structural improvements. Together, these findings validate the central role of NE in both acute pathogenesis and chronic functional recovery, and support future exploration of the therapeutic window, taking into account the prolonged period of neutrophil trafficking into the injured immature brain. PMID- 25497735 TI - Long-term effects of neonatal treatment with fluoxetine on cognitive performance in Ts65Dn mice. AB - Individuals with Down syndrome (DS), a genetic condition caused by triplication of chromosome 21, are characterized by intellectual disability and are prone to develop Alzheimer's disease (AD), due to triplication of the amyloid precursor protein (APP) gene. Recent evidence in the Ts65Dn mouse model of DS shows that enhancement of serotonergic transmission with fluoxetine during the perinatal period rescues neurogenesis, dendritic pathology and behavior, indicating that cognitive impairment can be pharmacologically restored. A crucial question is whether the short-term effects of early treatments with fluoxetine disappear at adult life stages. In the current study we found that hippocampal neurogenesis, dendritic pathology and hippocampus/amygdala-dependent memory remained in their restored state when Ts65Dn mice, which had been neonatally treated with fluoxetine, reached adulthood. Additionally, we found that the increased levels of the APP-derived betaCTF peptide in adult Ts65Dn mice were normalized following neonatal treatment with fluoxetine. This effect was accompanied by restoration of endosomal abnormalities, a betaCTF-dependent feature of DS and AD. While untreated adult Ts65Dn mice had reduced hippocampal levels of the 5-HT1A receptor (5-HT1A-R) and methyl-CpG-binding protein (MeCP2), a protein that promotes 5-HT1A R transcription, in neonatally-treated mice both 5-HT1A-R and MeCP2 were normalized. In view of the crucial role of serotonin in brain development, these findings suggest that the enduring outcome of neonatal treatment with fluoxetine may be due to MeCP2-dependent restoration of the 5-HT1A-R. Taken together, results provide new hope for the therapy of DS, showing that early treatment with fluoxetine enduringly restores cognitive impairment and prevents early signs of AD-like pathology. PMID- 25497738 TI - Effect of 593C>T GPx1 SNP alone and in synergy with 47C>T SOD2 SNP on the outcome of critically ill patients. AB - During critical illness and sepsis there is severe antioxidant depletion, and this scenario raises the critical ill patient's mortality risk. Glutathione peroxidase (GPx) is one of the first endogenous antioxidant defense enzymes, and it works cooperatively with superoxide dismutase (SOD) and catalase (CAT) to detoxify free radicals from the cellular environment. Genetic studies are important to understand the complexity of human oxidative stress and how the organism responds to an extreme situation such as critically care conditions. Previous studies with a GPx1 single nucleotide polymorphism (593C>T SNP; rs1050450; protein variant in GPx1: Pro198Leu) showed 593T carriers and 593TT homozygotes present higher risk to develop different diseases. We assessed the relationship of the genotype distribution of GPx1 SNP in critically ill patients with their conditions (organ dysfunction, sepsis, and septic shock) and their outcome. We monitored 626 critically ill patients daily from the ICU (intensive care unit) admission to their discharge from hospital, or death. Our study revealed a significant association between 593TT GPx1 genotype and mortality; the mortality rate was higher in homozygous 593TT GPx1 (N=94) when compared with the group of subjects with genotypes 593CT or 593CC GPx1 (N=532) (52% vs. 38%, P=0.009; OR=1.79; 95% CI=1.13-2.85). Evaluating the subgroup of 293 ICU patients with sepsis, a pooled analysis including two genetic variants GPx1 and SOD2 (47C>T SNP, rs4880; protein variant in MnSOD: Ala-9Val) showed a significant difference in relation to progression to septic shock. The frequency of septic shock among septic patients with 593T GPx1 and 47C SOD2 alleles (N=122) was higher when compared with septic patients carrying other settings of genotypes (N=174) (78% vs. 66%; P=0.028; OR=1.81; 95% CI=1.03-3.18). Accepting the previously reported functional effects of these two SNPs on GPx1 and SOD2 gene expressions and, consequently, on GPx1 and MnSOD enzyme activities, we believe our results may be considered as an important contribution for the understanding of oxidative imbalance during the critical ill. PMID- 25497740 TI - Obama calls on Congress to fund $6.2bn emergency Ebola initiative. PMID- 25497737 TI - Structural and agonist properties of XCL2, the other member of the C-chemokine subfamily. AB - Known for its unusual metamorphic native state structure, XCL1 has been the focus of most efforts to elucidate the structural, functional, and physiological properties of chemokines in the C subfamily. By comparison, its closely related paralog XCL2 remains virtually uncharacterized. Based on the importance of the chemokine N-terminus in receptor activation, it was hypothesized that two amino acid differences in XCL2 would alter its agonist activity relative to XCL1 for their shared receptor XCR1. This present study reveals several properties of XCL2 that were unexamined until now. Structurally, XCL1 and XCL2 are very similar, exchanging between the monomeric chemokine fold and an unrelated dimeric state under physiological NaCl and temperature conditions. Ca(2+) flux, chemotaxis, and heparin binding assays showed that the monomer form of XCL2 is responsible for G protein-coupled receptor activation while the dimeric form is important for GAG binding. Despite their high structural similarity, XCL2 displays a slightly higher affinity for heparin than XCL1. Because their in vitro functional profiles are virtually identical, distinct physiological roles for XCL1 and XCL2 are probably encoded at the level of expression. PMID- 25497739 TI - Suppression of proliferation, tumorigenicity and metastasis of lung cancer cells after their transduction by interferon-beta gene in baculovirus vector. AB - BACKGROUND: Gene therapy represents an interesting alternative treatment for cancers. Interferon-beta is well known as a multifunctional cytokine that provides antiviral, antiproliferative, antiangiogenic and immunomodulating effects. For this reason introduction of this cytokine gene in baculovirus vector is seen as a rather promising tool for anticancer therapy. AIM: Investigation of biological behavior in vitro and in vivo of lung cancer cells modified by interferon-beta gene which was introduced into the cells in vitro with baculovirus vector. MATERIALS AND METHODS: Studies were performed on mouse Lewis lung carcinoma cells as the tumor model (LL cell line). Transductions of cells by recombinant baculoviruses, in vitro and in vivo analysis of tumor cell biology and immunocytochemical method have been used. RESULTS: The study of various in vitro biological parameters of LL cancer cells transduced by recombinant baculovirus with interferon gene demonstrated that the transduction of cells is accompanied by significant inhibition of their proliferation and ability to form colonies in semisolid agar. Also, transduction of LL cells with interferon gene inhibited their tumorigenicity, i.e. the ability to cause formation of tumors and metastases in lungs of mice in vivo. Anti-tumor activity of recombinant interferon is realized via high level of its local production in tumors, induced by LL carcinoma cells, transduced with recombinant interferon-beta gene. Recombinant baculovirus without interferon gene did not influence significantly on tumorigenicity and metastatic ability of lung cancer cells. CONCLUSIONS: Introduction of interferon-beta gene in Lewis lung carcinoma cells in vitro in recombinant baculovirus leads to inhibition of their proliferation potential and malignant behavior in vitro, tumorigenicity and metastatic activity in vivo. PMID- 25497741 TI - Association between interleukin-10 polymorphisms and sepsis: a meta-analysis. AB - Genetic association studies of the cytokine interleukin-10 (IL-10) and sepsis have provided inconsistent results. This work attempts to further quantitatively assess the association of three widely evaluated polymorphisms of IL-10 (-592C/A, -819C/T, -1082A/G) with sepsis susceptibility through a meta-analysis. A search of Pubmed, Web of Science and EMBASE databases was performed. Overall, the three polymorphisms have no strong association with sepsis risk. Subgroup analysis by ethnicity showed there was association between sepsis susceptibility with -592C/A in Caucasians (A vs. C: OR 0.78, 95% CI 0.62-1.00, P = 0.05; AA + CA vs. CC: OR 0.75, 95% CI 0.56-1.00, P = 0.05), and with -1082A/G in Asians (G vs. A: OR 1.41, 95% CI 1.04-1.91, P = 0.03; GG + AG vs. AA: OR 2.11, 95% CI 1.07-4.16, P = 0.03). This meta-analysis suggests that -592C/A and -1082A/G polymorphisms are associated with sepsis susceptibility in Caucasian, and Asian populations, respectively. PMID- 25497742 TI - [Rectal dexmedetomidine in rats: evaluation of sedative and mucosal effects]. AB - BACKGROUND AND OBJECTIVES: In this study, we investigated the anesthetic and mucosal effects of the rectal application of dexmedetomidine to rats. METHODS: Male Wistar albino rats weighing 250-300g were divided into four groups: Group S (n=8) was a sham group that served as a baseline for the normal basal values; Group C (n=8) consisted of rats that received the rectal application of saline alone; Group IPDex (n=8) included rats that received the intraperitoneal application of dexmedetomidine (100MUgkg(-1)); and Group RecDex (n=8) included rats that received the rectal application of dexmedetomidine (100MUgkg(-1)). For the rectal drug administration, we used 22G intravenous cannulas with the stylets removed. We administered the drugs by advancing the cannula 1cm into the rectum, and the rectal administration volume was 1mL for all the rats. The latency and anesthesia time (min) were measured. Two hours after rectal administration, 75mgkg(-1) ketamine was administered for intraperitoneal anesthesia in all the groups, followed by the removal of the rats' rectums to a distal distance of 3cm via an abdominoperineal surgical procedure. We histopathologically examined and scored the rectums. RESULTS: Anesthesia was achieved in all the rats in the Group RecDex following the administration of dexmedetomidine. The onset of anesthesia in the Group RecDex was significantly later and of a shorter duration than in the Group IPDEx (p<0.05). In the Group RecDex, the administration of dexmedetomidine induced mild-moderate losses of mucosal architecture in the colon and rectum, 2h after rectal inoculation. CONCLUSION: Although 100MUgkg(-1) dexmedetomidine administered rectally to rats achieved a significantly longer duration of anesthesia compared with the rectal administration of saline, our histopathological evaluations showed that the rectal administration of 100MUgkg( 1) dexmedetomidine led to mild-moderate damage to the mucosal structure of the rectum. PMID- 25497743 TI - [Preoperative patient education: can we improve satisfaction and reduce anxiety?]. AB - BACKGROUND AND OBJECTIVES: Patients' knowledge deficits concerning anesthesia and the anesthesiologist's role in their care may contribute to anxiety. The objective of this study was to develop anesthesia patient education materials that would help improve patient's satisfaction regarding their knowledge of the perioperative process and decrease anxiety in a community hospital with a large Spanish-speaking population. METHODS: A survey (Survey A) in English and Spanish was administered to all adult anesthesiology preoperative clinic patients during a 4-week period. The data were analyzed and then a patient education handout was developed in both English and Spanish to assist with our patients' major concerns. A second survey (Survey B) was administered that was completed after the education handout had been put into use at the clinic. The survey asked for basic demographic information and included questions on satisfaction with regard to understanding of anesthesia as well as worries regarding surgery and pain. RESULTS: In the patients who received the handout, statistically significant improvement was found in the questions that asked about satisfaction with regard to understanding of type of anesthesia, options for pain control, what patients are supposed to do on the day of surgery, and the amount of information given with regard to anesthetic plan. There was no difference in anxiety related to surgery in patients who received the educational handout compared to those patients who did not. CONCLUSIONS: Patient education handouts improved patient's satisfaction regarding their knowledge of the perioperative process but did not reduce anxiety related to surgery. PMID- 25497744 TI - [Ultrasound and nerve stimulator guided continuous femoral nerve block analgesia after total knee arthroplasty: a multicenter randomized controlled study]. AB - BACKGROUND AND OBJECTIVES: Postoperative analgesia is crucial for early functional excise after total knee arthroplasty. To investigate the clinical efficacy of ultrasound and nerve stimulator guided continuous femoral nerve block analgesia after total knee arthroplasty. METHODS: 46 patients with ASA grade I III who underwent total knee arthroplasty received postoperative analgesia from October 2012 to January 2013. In 22 patients, ultrasound and nerve stimulator guided continuous femoral nerve block were performed for analgesia (CFNB group); in 24 patients, epidural analgesia was done (PCEA group). The analgesic effects, side effects, articular recovery and complications were compared between two groups. RESULTS: At 6h and 12h after surgery, the knee pain score (VAS score) during functional tests after active exercise and after passive excise in CFNB were significantly reduced when compared with PCEA group. The amount of parecoxib used in CFNB patients was significantly reduced when compared with PCEA group. At 48h after surgery, the muscle strength grade in CFNB group was significantly higher, and the time to ambulatory activity was shorter than those in PCEA group. The incidence of nausea and vomiting in CFNB patients was significantly reduced when compared with PCEA group. CONCLUSION: Ultrasound and nerve stimulator guided continuous femoral nerve block provide better analgesia at 6h and 12h, demonstrated by RVAS and PVAS. The amount of parecoxib also reduces, the incidence of nausea and vomiting decreased, the influence on muscle strength is compromised and patients can perform ambulatory activity under this condition. PMID- 25497745 TI - [Evaluation of genotoxicity induced by repetitive administration of local anaesthetics: an experimental study in rats]. AB - BACKGROUND AND OBJECTIVE: Previous studies regarding the effects of some local anaesthetics have suggested that these agents can cause genetic damage. However, they have not been tested for genotoxicity related to repetitive administration. The aim of this study was to evaluate the genotoxic potential of local anaesthetics upon repetitive administration. METHODS: 80 male Wistar rats were divided into: group A - 16 rats intraperitoneally injected with lidocaine hydrochloride 2%; group B - 16 rats IP injected with mepivacaine 2%; group C - 16 rats intraperitoneally injected with articaine 4%; group D - 16 rats IP injected with prilocaine 3% (6.0mg/kg); group E - 8 rats subcutaneously injected with a single dose of cyclophosphamide; and group F - 8 rats intraperitoneally injected with saline. Eight rats from groups A to D received a single dose of anaesthetic on Day 1 of the experiment; the remaining rats were dosed once a day for 5 days. RESULTS: The median number of micronuclei in the local anaesthetics groups exposed for 1 or 5 days ranged from 0.00 to 1.00, in the cyclophosphamide-exposed group was 10.00, and the negative control group for 1 and 5 days was 1.00 and 0.00, respectively (p<0.0001). A significant difference in the number of micronuclei was observed between the cyclophosphamide group and all local anaesthetic groups (p=0.0001), but not between the negative control group and the local anaesthetic groups (p>0.05). CONCLUSION: No genotoxicity effect was observed upon repetitive exposure to any of the local anaesthetics evaluated. PMID- 25497746 TI - [Neurotoxic effects of levobupivacaine and fentanyl on rat spinal cord]. AB - BACKGROUND: The purpose of the study was to compare the neurotoxic effects of intrathecally administered levobupivacaine, fentanyl and their mixture on rat spinal cord. METHODS: In experiment, there were four groups with medication and a control group. Rats were injected 15MUL saline or fentanyl 0.0005MUg/15MUL, levobupivacaine 0.25%/15MUL and fentanyl 0.0005MUg+levobupivacaine 0.25%/15MUL intrathecally for four days. Hot plate test was performed to assess neurologic function after each injection at 5th, 30th and 60th min. Five days after last lumbal injection, spinal cord sections between the T5 and T6 vertebral levels were obtained for histologic analysis. A score based on subjective assessment of number of eosinophilic neurons - Red neuron - which means irreversible neuronal degeneration. They reflect the approximate number of degenerating neurons present in the affected neuroanatomic areas as follows: 1, none; 2, 1-20%; 3, 21-40%; 4, 41-60%; and 5, 61-100% dead neurons. An overall neuropathologic score was calculated for each rat by summating the pathologic scores for all spinal cord areas examined. RESULTS: In the results of HPT, comparing the control group, analgesic latency statistically prolonged for all four groups. In neuropathologic investment, the fentanyl and fentanyl+levobupivacaine groups have statistically significant high degenerative neuron counts than control and saline groups. CONCLUSIONS: These results suggest that, when administered intrathecally in rats, fentanyl and levobupivacaine behave similar for analgesic action, but fentanyl may be neurotoxic for spinal cord. There was no significant degeneration with levobupivacaine, but fentanyl group has had significant degeneration. PMID- 25497747 TI - [The effect of esmolol on corrected-QT interval, corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients taking an angiotensin-converting enzyme inhibitor]. AB - BACKGROUND AND OBJECTIVES: The importance of minimizing the exaggerated sympatho adrenergic responses and QT interval and QT interval dispersion changes that may develop due to laryngoscopy and tracheal intubation during anesthesia induction in the hypertensive patients is clear. Esmolol decreases the hemodynamic response to laryngoscopy and intubation. However, the effect of esmolol in decreasing the prolonged QT interval and QT interval dispersion as induced by laryngoscopy and intubation is controversial. We investigated the effect of esmolol on the hemodynamic, and corrected-QT interval and corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients using angiotensin converting enzyme inhibitors. METHODS: 60 ASA I-II patients, with essential hypertension using angiotensin converting enzyme inhibitors were included in the study. The esmolol group received esmolol at a bolus dose of 500mcg/kg followed by a 100mcg/kg/min infusion which continued until the 4th min after intubation. The control group received 0.9% saline similar to the esmolol group. The mean blood pressure, heart rate values and the electrocardiogram records were obtained as baseline values before the anesthesia, 5min after esmolol and saline administration, 3min after the induction and 30s, 2min and 4min after intubation. RESULTS: The corrected-QT interval was shorter in the esmolol group (p=0.012), the corrected-QT interval dispersion interval was longer in the control group (p=0.034) and the mean heart rate was higher in the control group (p=0.022) 30s after intubation. The risk of arrhythmia frequency was higher in the control group in the 4-min period following intubation (p=0.038). CONCLUSION: Endotracheal intubation was found to prolong corrected-QT interval and corrected-QT interval dispersion, and increase the heart rate during anesthesia induction with propofol in hypertensive patients using angiotensin converting enzyme inhibitors. These effects were prevented with esmolol (500mcg/kg bolus, followed by 100mcg/kg/min infusion). During induction, the blood pressure tends to decrease with esmolol where care is needed. PMID- 25497748 TI - [Changes in retinal nerve fiber layer thickness after spinal surgery in the prone position: a prospective study]. AB - BACKGROUND AND OBJECTIVES: Changes in ocular perfusion play an important role in the pathogenesis of ischemic optic neuropathy. Ocular perfusion pressure is equal to mean arterial pressure minus intraocular pressure. The aim of this study was to evaluate the changes in the intraocular pressure and the retinal nerve fiber layer thickness in patients undergoing spinal surgery in the prone position. METHODS: This prospective study included 30 patients undergoing spinal surgery. Retinal nerve fiber layer thickness were measured one day before and after the surgery by using optical coherence tomography. Intraocular pressure was measured by tonopen six times at different position and time-duration: supine position (baseline); 10min after intubation (Supine 1); 10 (Prone 1), 60 (Prone 2), 120 (Prone 3)min after prone position; and just after postoperative supine position (Supine 2). RESULTS: Our study involved 10 male and 20 female patients with the median age of 57 years. When postoperative retinal nerve fiber layer thickness measurements were compared with preoperative values, a statistically significant thinning was observed in inferior and nasal quadrants (p=0.009 and p=0.003, respectively). We observed a statistically significant intraocular pressure decrease in Supine 1 and an increase in both Prone 2 and Prone 3 when compared to the baseline. Mean arterial pressure and ocular perfusion pressure were found to be significantly lower in Prone 1, Prone 2 and Prone 3, when compared with the baseline. CONCLUSIONS: Our study has shown increase in intraocular pressure during spinal surgery in prone position. A statistically significant retinal nerve fiber layer thickness thinning was seen in inferior and nasal quadrants one day after the spinal surgery. PMID- 25497749 TI - [Effects of smoking on venous cannulation pain: a randomized prospective trial]. AB - BACKGROUND AND OBJECTIVES: It has been demonstrated that smoking increases pain perception; however the effect of smoking on perception of pain during venous cannulation is not known. The purpose of this study is to determine whether or not smoking has an effect on pain perception due to peripheral venous cannulation. METHODS: 220 patients scheduled to have elective surgery were enrolled in the study and were divided into two groups (Group S and C, n=110 for each) according to their smoking habits. Numerical rating scale was introduced to the patients and then peripheral venous cannulation at the dorsum of the hand was made with a 20G intracath. Pain perception of the patients was scored by subsequent numerical rating scale questioning. RESULTS: The demographic characteristics of the groups were identical. Numerical rating scale scores in Group S and C were 3.31+/-1.56 and 1.65+/-1.23, respectively (p<0.001). CONCLUSION: Pain perception due to peripheral venous cannulation is higher in smokers. Future studies on pain treatment should consider the smoking habits of patients. PMID- 25497750 TI - [Effects of various anesthesia maintenance on serum levels of selenium, copper, zinc, iron and antioxidant capacity]. AB - BACKGROUND AND OBJECTIVES: In this study, we aimed to investigate the effects of sevoflurane, desflurane and propofol maintenances on serum levels of selenium, copper, zinc, iron, malondialdehyde, and glutathion peroxidase measurements, and antioxidant capacity. METHODS: 60 patients scheduled for unilateral lower extremity surgery which would be performed with tourniquet under general anesthesia were divided into three groups. Blood samples were collected to determine the baseline serum levels of selenium, copper, zinc, iron, malondialdehyde and glutathion peroxidase. Anesthesia was induced using 2 2.5mgkg(-1) propofol, 1mgkg(-1) lidocaine and 0.6mgkg(-1) rocuronium. In the maintenance of anesthesia, under carrier gas of 50:50% O2:N2O 4Lmin(-1), 1 MAC sevoflorane was administered to Group S and 1 MAC desflurane to Group D; and under carrier gas of 50:50% O2:air 4Lmin(-1) 6mgkgh(-1) propofol and 1MUgkgh(-1) fentanyl infusion were administered to Group P. At postoperative blood specimens were collected again. RESULTS: It was observed that only in Group S and P, levels of MDA decreased at postoperative 48th hour; levels of glutathion peroxidase increased in comparison to the baseline values. Selenium levels decreased in Group S and Group P, zinc levels decreased in Group P, and iron levels decreased in all three groups, and copper levels did not change in any groups in the postoperative period. CONCLUSION: According to the markers of malondialdehyde and glutathion peroxidase, it was concluded that maintenance of general anesthesia using propofol and sevoflurane activated the antioxidant system against oxidative stress and using desflurane had no effects on oxidative stress and antioxidant system. PMID- 25497751 TI - [Comparison between magnesium sulfate and dexmedetomidine in controlled hypotension during functional endoscopic sinus surgery]. AB - BACKGROUND AND OBJECTIVES: It is crucial to decrease bleeding during functional endoscopic sinus surgery. Our primary goal was to investigate the effects of magnesium sulfate and dexmedetomidine used for controlled hypotension on the visibility of the surgical site. METHODS: 60 patients aged between 18 and 65 years were enrolled. In the magnesium sulfate group (Group M), patients were administered 40mg/kg magnesium sulfate in 100mL saline solution over 10min as the intravenous loading dose 10min before induction, with a subsequent 10-15mg/kg/h infusion during surgery. In the dexmedetomidine group (Group D), patients were administered 1MUg/kg dexmedetomidine in 100mL saline solution as the loading dose 10min before surgery and 0.5-1MUg/kg/h dexmedetomidine during surgery. Deliberate hypotension was defined as a mean arterial pressure of 60-70mmHg. RESULTS: Bleeding score was significantly decreased in Group D (p=0.002). Mean arterial pressure values were significantly decreased in Group D compared to that in Group M, except for the initial stage, after induction and 5min after intubation (p<0.05). The number of patients who required nitroglycerine was significantly lower in Group D (p=0.01) and surgeon satisfaction was significantly increased in the same group (p=0.001). Aldrete recovery score >=9 duration was significantly shorter in Group D (p=0.001). There was no difference between the two groups in terms of recovery room verbal numerical rating scale. CONCLUSIONS: Dexmedetomidine can provide more effective controlled hypotension and thus contribute to improved visibility of the surgical site. PMID- 25497752 TI - [Satellite glial cells in sensory ganglia: its role in pain]. AB - BACKGROUND AND OBJECTIVES: Satellite glial cells in sensory ganglia are a recent subject of research in the field of pain and a possible therapeutic target in the future. Therefore, the aim of this study was to summarize some of the important physiological and morphological characteristics of these cells and gather the most relevant scientific evidence about its possible role in the development of chronic pain. CONTENT: In the sensory ganglia, each neuronal body is surrounded by satellite glial cells forming distinct functional units. This close relationship enables bidirectional communication via a paracrine signaling between those two cell types. There is a growing body of evidence that glial satellite cells undergo structural and biochemical changes after nerve injury, which influence neuronal excitability and consequently the development and/or maintenance of pain in different animal models of chronic pain. CONCLUSIONS: Satellite glial cells are important in the establishment of physiological pain, in addition to being a potential target for the development of new pain treatments. PMID- 25497753 TI - [Postdural puncture headache after caesarean section: are preventive strategies worse than the cure?]. PMID- 25497754 TI - Real time estimation of generation, extinction and flow of muscle fibre action potentials in high density surface EMG. AB - PURPOSE: Developing a real time method to estimate generation, extinction and propagation of muscle fibre action potentials from bi-dimensional and high density surface electromyogram (EMG). METHOD: A multi-frame generalization of an optical flow technique including a source term is considered. A model describing generation, extinction and propagation of action potentials is fit to epochs of surface EMG. RESULTS: The algorithm is tested on simulations of high density surface EMG (inter-electrode distance equal to 5mm) from finite length fibres generated using a multi-layer volume conductor model. The flow and source term estimated from interference EMG reflect the anatomy of the muscle, i.e. the direction of the fibres (2 degrees of average estimation error) and the positions of innervation zone and tendons under the electrode grid (mean errors of about 1 and 2mm, respectively). The global conduction velocity of the action potentials from motor units under the detection system is also obtained from the estimated flow. The processing time is about 1 ms per channel for an epoch of EMG of duration 150 ms. CONCLUSIONS: A new real time image processing algorithm is proposed to investigate muscle anatomy and activity. Potential applications are proposed in prosthesis control, automatic detection of optimal channels for EMG index extraction and biofeedback. PMID- 25497755 TI - Physician payments under health care reform. AB - This study examines the impact of major health insurance reform on payments made in the health care sector. We study the prices of services paid to physicians in the privately insured market during the Massachusetts health care reform. The reform increased the number of insured individuals as well as introduced an online marketplace where insurers compete. We estimate that, over the reform period, physician payments increased at least 11 percentage points relative to control areas. Payment increases began around the time legislation passed the House and Senate-the period in which their was a high probability of the bill eventually becoming law. This result is consistent with fixed-duration payment contracts being negotiated in anticipation of future demand and competition. PMID- 25497756 TI - The effect of state dependent mandate laws on the labor supply decisions of young adults. AB - Prior to the Affordable Care Act, the majority of states in the U.S. had already implemented state laws that extended the age that young adults could enroll as dependents on their parent's employer-based health insurance plans. Because of the fundamental link between health insurance and employment in the U.S., such policies may effect the labor supply decisions of young adults. Although the interaction between labor supply and health insurance has been extensively studied for other subpopulations, little is known about the role of health insurance in the labor supply decisions of young adults. I use the variation from the implementation and changes in state policies that expanded dependent health insurance coverage to examine how young adults adjusted their labor supply when they were able to be covered as a dependent on their parent's plan. I find that these state mandates led to a decrease in labor supply on the intensive margin. PMID- 25497757 TI - WITHDRAWN: Immobilization of Cd in a paddy soil using moisture management and amendment. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published in , http://dx.doi.org/10.1007/S11356-014-3788-5. The duplicate article has therefore been withdrawn.The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal PMID- 25497762 TI - Mike Slater: President, BOHS 2014-2015. PMID- 25497763 TI - GPs should be allowed to provide good quality patient centred care to encourage a person centred NHS. PMID- 25497764 TI - Effect of amyloid beta-peptide on the fluidity of phosphatidylcholine membranes: Uses and limitations of diphenylhexatriene fluorescence anisotropy. AB - There is accumulating evidence that peptide-induced perturbations in the order and dynamics of cellular membranes may play a role in the neurotoxicity of amyloid beta-peptide (Abeta). Several studies have reported that Abeta decreases fluidity of membranes based on an Abeta-induced increase in the fluorescence anisotropy of diphenylhexatriene (DPH). However, the effect of Abeta on the membrane fluidity is still a subject of controversy, because other studies that employed pyrene as a fluorescent probe have shown that Abeta has the opposite effect. To reveal the reason for this discrepancy, we have examined the effect of Abeta on the fluidity of phosphatidylcholine membranes using spectroscopic methods. The fluorescence anisotropy of DPH is dramatically increased on addition of Abeta to DPH-containing phosphatidylcholine membranes. However, Abeta does not affect the Raman spectrum of the membrane, which is sensitive to the packing order of the hydrocarbon chains of lipids. We have also found that circular dichroism (CD) bands of DPH appear during incubation of DPH-containing membranes with Abeta, whereas DPH is an achiral molecule. The observed CD bands of DPH are induced by a chiral environment of Abeta but not by that of the lipids, because positive CD bands appear regardless of the d/l-chirality of phosphatidylcholine. The findings obtained from CD measurements provide evidence that DPH molecules translocate from the membrane to Abeta. The peptide-mediated extraction of DPH from the membrane may cause changes in the fluorescence anisotropy of DPH, even though Abeta does not affect the fluidity of membranes. PMID- 25497765 TI - Membrane interactions in small fast-tumbling bicelles as studied by 31P NMR. AB - Small fast-tumbling bicelles are ideal for studies of membrane interactions at molecular level; they allow analysis of lipid properties using solution-state NMR. In the present study we used 31P NMR relaxation to obtain detailed information on lipid head-group dynamics. We explored the effect of two topologically different membrane-interacting peptides on bicelles containing either dimyristoylphosphocholine (DMPC), or a mixture of DMPC and dimyristoylphosphoglycerol (DMPG), and dihexanoylphosphocholine (DHPC). KALP21 is a model transmembrane peptide, designed to span a DMPC bilayer and dynorphin B is a membrane surface active neuropeptide. KALP21 causes significant increase in bicelle size, as evidenced by both dynamic light scattering and 31P T2 relaxation measurements. The effect of dynorphin B on bicelle size is more modest, although significant effects on T2 relaxation are observed at higher temperatures. A comparison of 31P T1 values for the lipids with and without the peptides showed that dynorphin B has a greater effect on lipid head-group dynamics than KALP21, especially at elevated temperatures. From the field-dependence of T1 relaxation data, a correlation time describing the overall lipid motion was derived. Results indicate that the positively charged dynorphin B decreases the mobility of the lipid molecules--in particular for the negatively charged DMPG--while KALP21 has a more modest influence. Our results demonstrate that while a transmembrane peptide has severe effects on overall bilayer properties, the surface bound peptide has a more dramatic effect in reducing lipid head-group mobility. These observations may be of general importance for understanding peptide-membrane interactions. PMID- 25497766 TI - Efficacy and safety of rituximab in auto-immune hemolytic anemia: A meta-analysis of 21 studies. AB - OBJECTIVE: This study aims to evaluate the response to rituximab (RTX) treatment in auto-immune hemolytic anemia (AIHA) patients. METHODS: Studies were selected from MEDLINE up to March 2014. Two investigators independently extracted data on study design, patient characteristics, clinical features (AIHA type, disease duration, previous treatments), dose-schedule of rituximab, duration of treatment follow-up, and toxicities. Pooled overall response rate (ORR) and complete response (CR) rates were evaluated to determine RTX efficacy and toxicity by calculating the weighted mean proportion with fixed or random-effects models in case of heterogeneity (p<0.1 or I(2)>50%). RESULTS: Twenty-one studies encompassing 409 patients were included in the meta-analysis. The characteristics of the entire analyzed cohort reported were as follows: mean male proportion: 43%, mean age: 50 years, splenectomized patients range: 0-50%. Warm AIHA, primary AIHA and adults were mostly represented. With the random-effect model, the overall response rate (ORR) was 73% (95% CI 64-81%, 20 studies encompassing 402 patients). CR rate was 37% (95% CI 26-49%, 20 studies including 397 patients). The ORRs were close to 70% for warm AIHA (79%, 95% CI 60-90%, 11 studies, 154 patients), primary AIHA (67%, 95% CI 49-81%, 10 studies, 161 patients), and secondary AIHA (72%, 95% CI 60-82%, 8 studies, 66 patients). The ORR was 57% (95% CI 47-66%, 6 studies, 109 patients) for cold agglutinin disease (CAD). The CR rate was 42% (95% CI 27-58%, 11 studies, 154 patients) for warm AHAI, 32% (95% CI 17-51%, 11 studies, 176 patients) for primary AIHA, 46% (95% CI 30-62%, 9 studies, 87 patients) for secondary AIHA and only 21% (95% CI 6-51%, 7 studies, 118 patients) for CAD. Definitive response rates were evaluated during follow-up. CR rate was the highest within 2 to 4 months after RTX (13 studies, 203 patients, CR=70% [57-80%]). As for toxicities, 38 adverse events in 364 patients were noted (14% (95% CI 9-21%)). Sixteen events were infusion-linked side effects, mostly chills and fever, whereas twenty-two were severe. Only one opportunistic Pneumocystis jiroveci pneumonia was reported. Seventeen patients out of 364 (4.6%) died during follow-up. In univariate mixed-effect meta-regressions, ORR and CR were significantly associated with warm AIHA (p=0.002) and mean age (p<0.001), and marginally associated with disease type (p=0.06 and 0.005, respectively). CONCLUSIONS: Rituximab seems to be a safe and effective therapy for AIHA in this meta-analysis of observational studies. The authors suggest that it could be used at an earlier point in therapy, before more toxic immunosuppressive drugs, or in place of splenectomy in some cases. PMID- 25497767 TI - Immunotoxicity of washing soda in a freshwater sponge of India. AB - The natural habitat of sponge, Eunapius carteri faces an ecotoxicological threat of contamination by washing soda, a common household cleaning agent of India. Washing soda is chemically known as sodium carbonate and is reported to be toxic to aquatic organisms. Domestic effluent, drain water and various human activities in ponds and lakes have been identified as the major routes of washing soda contamination of water. Phagocytosis and generation of cytotoxic molecules are important immunological responses offered by the cells of sponges against environmental toxins and pathogens. Present study involves estimation of phagocytic response and generation of cytotoxic molecules like superoxide anion, nitric oxide and phenoloxidase in E. carteri under the environmentally realistic concentrations of washing soda. Sodium carbonate exposure resulted in a significant decrease in the phagocytic response of sponge cells under 4, 8, 16 mg/l of the toxin for 96h and all experimental concentrations of the toxin for 192h. Washing soda exposure yielded an initial increase in the generation of the superoxide anion and nitric oxide followed by a significant decrease in generation of these cytotoxic agents. Sponge cell generated a high degree of phenoloxidase activity under the experimental exposure of 2, 4, 8, 16 mg/l of sodium carbonate for 96 and 192 h. Washing soda induced alteration of phagocytic and cytotoxic responses of E. carteri was indicative to an undesirable shift in their immune status leading to the possible crises of survival and propagation of sponges in their natural habitat. PMID- 25497768 TI - Combined toxicity of cadmium and copper in Avicennia marina seedlings and the regulation of exogenous jasmonic acid. AB - Seedlings of Avicennia marina were exposed to single and combined metal treatments of cadmium (Cd) and copper (Cu) in a factorial design, and the combined toxicity of Cu and Cd was tested. The effects of the exogenous jasmonic acid (JA) on chlorophyll concentration, lipid peroxidation, Cd and Cu uptake, antioxidative capacity, endogenous JA concentration, and type-2 metallothionein gene (AmMT2) expression in seedlings of A. marina exposed to combined metal treatments were also investigated. A binary mixture of low-dose Cd (9 umolL(-1)) and high-dose Cu (900 umolL(-1)) showed toxicity to the seedlings, indicated by the significant augmentation in leaf malondialdehyde (MDA) and reduction in leaf chlorophylls. The toxicity of the combined metals was significantly alleviated by the addition of exogenous JA at 1 umolL(-1), and the chlorophyll and MDA contents were found to be restored to levels comparable to those of the control. Compare to treatment with Cd and Cu only, 1 and 10 umolL(-1) JA significantly enhanced the ascorbate peroxidase activity, and 10 umolL(-1) JA significantly decreased the uptake of Cd in A. marina leaves. The relative expression of leaf AmMT2 gene was also significantly enhanced by 1 and 10 umolL(-1) JA, which helped reduce Cd toxicity in A. marina seedlings. PMID- 25497769 TI - Silicon-mediated alleviation of Cr(VI) toxicity in wheat seedlings as evidenced by chlorophyll florescence, laser induced breakdown spectroscopy and anatomical changes. AB - Silicon (Si)-mediated alleviation of Cr(VI) toxicity was examined in wheat seedlings using an in vivo approach that involves chlorophyll fluorescence, laser induced breakdown spectroscopy (LIBS) and anatomical changes. Exposure to Cr(VI) significantly reduced the growth and photosynthetic activities (chlorophyll fluorescence) in wheat which was accompanied by remarkable accumulation of this element in tissues. However, addition of Si to the growth medium alleviated the effects of Cr(VI). The LIBS spectra were used as a fingerprint of the elemental compositions in wheat seedlings, which showed a reduction in Cr accumulation following Si addition. Nutrient element levels (Ca, Mg, K and Na) declined in wheat following the addition of Cr (VI), as recorded by LIBS and inductively coupled plasma atomic emission spectroscopy (ICAP-AES). However, addition of Si along with Cr(VI) increased the contents of nutrient elements in wheat. LIBS, ICAP-AES and AAS showed a similar distribution pattern of elements measured in wheat. Anatomical observations of leaf and root revealed that Cr(VI) affected internal structures while Si played a role in protection from toxic effects. The results showed the suitability of chlorophyll fluorescence as a parameter and appropriateness of LIBS technique and anatomical procedures to elucidate Si mediated alleviation of Cr(VI) toxicity. Furthermore, our results suggest that the measured parameters and techniques can be used non-invasively for monitoring the growth of crops under different environmental conditions. PMID- 25497770 TI - Heavy metal partitioning in sediments and bioaccumulation in commercial fish species of three major reservoirs of river Cauvery delta region, India. AB - Chemical partitioning of heavy metals (Fe, Mn, Cu, Cr, Pb, Zn, Ni) were determined in surface sediments of three reservoirs at the Delta region of Cauvery River, India. The abundance of metals in sediments varied in the following descending order: Fe, Mn, Cr, Zn, Cu, Ni, and Pb. Higher concentrations of Zn, Pb, Fe, Mn and Cu in exchangeable and carbonate fraction indicated toxicity risk to the biota. Therefore, to understand the extent of bioaccumulation, six commercial fish species were collected from the same sites and analyzed for heavy metals distribution in different organs. Among the metals found in fish samples, iron was observed in the highest concentration, followed by Zn, Pb, Cr, Mn, Cu, and Ni. Concentrations of Pb, Cr and Zn in many fish samples exceeded the permissible limits of Food and Agriculture Organization. The concentrations of Pb (17.7-31.7%), Cr (6.2-15.1%), Cu (15.2-30.5%) and Zn (30 40%) associated with exchangeable and carbonate fractions had significant positive correlation with the respective metal concentrations in fish. Among the fish species, Catla catla and Etroplus suratensis showed the highest accumulation of metals suggesting risk for human consumption. PMID- 25497771 TI - Effects of enrofloxacin, ciprofloxacin, and trimethoprim on two generations of Daphnia magna. AB - Multigenerational tests on Daphnia magna were performed exposing two subsequent generation to enrofloxacin (EFX) and its metabolite ciprofloxacin (CPX), and to trimethoprim (TMP). Mortality rate of 100% and 50% was detected in F0 at concentrations of >= 13 mgL(-1) (EFX) and 50 mgL(-1) (TMP), respectively. In F1 with respect to F0, both for growth and reproduction, a worsening trend of the response with EFX, a similar response with CPX and an attenuating trend with TMP was observed. Furthermore, the lowest EC20 for reproduction inhibition (1.3 mgL( 1)) was calculated for F1 exposed to EFX. However, other experimentations, longer and more complex, are necessary in order to confirm that EFX is more hazardous to daphnids than CPX and TMP. EC50 measured for the three assayed antibacterials were in the 6.5-37 mgL(-1) range therefore environmental unrealistic, except in case of exceptional contaminations that may occur in relation to poorly controlled wastewaters from pharmaceutical factories or excessive use of prophylactic treatments in aquaculture. PMID- 25497773 TI - Emerging themes in bacterial autophagy. AB - The role of autophagy in the control of intracellular bacterial pathogens, also known as xenophagy, is well documented. Here, we highlight recent advances in the field of xenophagy. We review the importance of bacterial targeting by ubiquitination, diacylglycerol (DAG) or proteins such as Nod1, Nod2, NDP52, p62, NBR1, optineurin, LRSAM1 and parkin in the process of xenophagy. The importance of metabolic sensors, such as mTOR and AMPK, in xenophagy induction is also discussed. We also review the in vitro and in vivo evidence that demonstrate a global role for xenophagy in the control of bacterial growth. Finally, the mechanisms evolved by bacteria to escape xenophagy are presented. PMID- 25497774 TI - Effect of chlorfenapyr on cypermethrin-resistant Culex pipiens pallens Coq mosquitoes. AB - Chlorfenapyr is a promising pyrrole insecticide with a unique mechanism of action that does not confer cross-resistance to neurotoxic insecticides. The effect of chlorfenapyr on pyrethorid-resistant Culex pipiens pallens Coq (Diptera: Culicidae) has not been fully investigated under laboratory conditions. In this study, cypermethrin-resistant C. p. pallens exhibited 376.79-fold and 395.40-fold increase in resistance to cypermethrin compared with susceptible strains after exposure for 24 and 48h, respectively. Larvae and adults were tested for susceptibility using dipping, topical, and impregnated paper methods as recommended by the WHO. No cross-resistance to chlorfenapyr was found. Increased mortality was apparent between 48 and 72h, indicating a slow rate of toxic activity. Synergism experiments with piperonyl butoxide (PBO) showed an antagonistic effect on chlorfenapyr toxicity. Mixtures of chlorfenapyr and cypermethrin could therefore provide additional benefits over either insecticide used alone. Mixtures of 5ng/ml chlorfenapyr and 500ng/ml cypermethrin exhibited a slight synergistic effect on cypermethrin-resistant mosquitoes (3.33, 6.84 and 2.34% after 24, 48 and 72h exposure, respectively. This activity was lost when the chlorfenapyr concentration was increased to 10 or 20ng/ml. Chlorfenapyr showed quite good results for pyrethroid-resistant C. p. pallens, and could improve public health by reducing the occurrence of mosquito bites and subsequently protecting against transmission of lymphatic filariasis and Japanese encephalitis. PMID- 25497772 TI - Autophagy is upregulated in brain tissues of pigeons exposed to avermectin. AB - Avermectin (AVM) is used in agriculture and veterinary medicine for the prevention of parasitic diseases; AVM is the active component of some insecticidal and nematicidal products. Residues of AVM drugs or their metabolites in livestock feces have toxic effects on non-target aquatic and terrestrial organisms. In this study, changes in the levels of autophagy related genes and ultrastructure in pigeon brain tissues after subchronic exposure to AVM for 30, 60 and 90 d were investigated. The decrease in the mRNA levels of TORC1 and TORC2 and increase in the mRNA levels of LC3, Beclin 1, Dynein, ATG5 and ATG4B and the increase in the protein levels of LC3, Beclin 1 and Dynein in a dose- and time dependent manner in the pigeon brain were observed. The number of autophagic vacuoles in the cerebrum, cerebellum and optic lobe increased significantly with the concentration of AVM and the exposure time. We found that the changes in the levels of autophagy related genes and the ultrastructure in the cerebrum were more obvious than in the cerebellum and the optic lobe. The results suggest that AVM could induce autophagy in pigeon brain tissues. The information presented in this study is helpful for understanding the mechanism of AVM-induced autophagy in birds. PMID- 25497776 TI - Antioxidant potential is correlated to omega6 / omega3 ratio and Brasfield score in cystic fibrosis children. AB - OBJECTIVES: Oxidative stress is associated with the condition of cystic fibrosis (CF), but no guidelines exist for its assessment or treatment. Our aim was to evaluate a test that measures the blood antioxidant capability in CF children. METHODS: This antioxidant capability was assessed by the Kit Radicaux Libres (KRL) test in 44 CF children (24 boys). We recorded also anthropometric measures, pulmonary function, CF severity scores, and plasma nutritional and inflammatory parameters (proteins, vitamins, erythrocyte fatty acids, and micronutrients). We performed univariate and multivariate analyses with linear regression models. RESULTS: The mean age at the first KRL assessment was 12.2 +/- 3.8 years. Factors that correlated with decreased antioxidant capacity were mostly related to the severity of pulmonary disease [ forced expiratory volume at 1 second (FEV1), acute exacerbation, and congestion. In multivariate analysis, the correlation between Brasfield score and erythrocyte antioxidant potential remained significant (beta = - 0.611, p < 0.001). Among nutritional factors, the omega6/omega3 ratio was significantly correlated to erythrocyte antioxidant potential (beta = - 1.213, p = 0.01). CONCLUSION: The blood antioxidant capability, measured by the KRL test, appears to be an interesting biomarker to evaluate oxidative stress in CF. This study suggests that the omega6/omega3 ratio should be regarded as a nutritional marker in antioxidant management in CF children. PMID- 25497775 TI - Adenosine, lidocaine and Mg2+ improves cardiac and pulmonary function, induces reversible hypotension and exerts anti-inflammatory effects in an endotoxemic porcine model. AB - INTRODUCTION: The combination of Adenosine (A), lidocaine (L) and Mg(2+) (M) (ALM) has demonstrated cardioprotective and resuscitative properties in models of cardiac arrest and hemorrhagic shock. This study evaluates whether ALM also demonstrates organ protective properties in an endotoxemic porcine model. METHODS: Pigs (37 to 42 kg) were randomized into: 1) Control (n = 8) or 2) ALM (n = 8) followed by lipopolysaccharide infusion (1 MUg ? kg(-1) ? h(-1)) for five hours. ALM treatment consisted of 1) a high dose bolus (A (0.82 mg/kg), L (1.76 mg/kg), M (0.92 mg/kg)), 2) one hour continuous infusion (A (300 MUg ? kg(-1) ? min(-1)), L (600 MUg ? kg(-1) ? min(-1)), M (336 MUg ? kg(-1) ? min(-1))) and three hours at a lower dose (A (240 ? kg(-1) ? min(-1)), L (480 MUg ? kg(-1) ? min(-1)), M (268 MUg ? kg(-1) ? min(-1))); controls received normal saline. Hemodynamic, cardiac, pulmonary, metabolic and renal functions were evaluated. RESULTS: ALM lowered mean arterial pressure (Mean value during infusion period: ALM: 47 (95% confidence interval (CI): 44 to 50) mmHg versus control: 79 (95% CI: 75 to 85) mmHg, P < 0.0001). After cessation of ALM, mean arterial pressure immediately increased (end of study: ALM: 88 (95% CI: 81 to 96) mmHg versus control: 86 (95% CI: 79 to 94) mmHg, P = 0.72). Whole body oxygen consumption was significantly reduced during ALM infusion (ALM: 205 (95% CI: 192 to 217) ml oxygen/min versus control: 231 (95% CI: 219 to 243) ml oxygen/min, P = 0.016). ALM treatment reduced pulmonary injury evaluated by PaO2/FiO2 ratio (ALM: 388 (95% CI: 349 to 427) versus control: 260 (95% CI: 221 to 299), P = 0.0005). ALM infusion led to an increase in heart rate while preserving preload recruitable stroke work. Creatinine clearance was significantly lower during ALM infusion but reversed after cessation of infusion. ALM reduced tumor necrosis factor-alpha peak levels (ALM 7121 (95% CI: 5069 to 10004) pg/ml versus control 11596 (95% CI: 9083 to 14805) pg/ml, P = 0.02). CONCLUSION: ALM infusion induces a reversible hypotensive and hypometabolic state, attenuates tumor necrosis factor-alpha levels and improves cardiac and pulmonary function, and led to a transient drop in renal function that was reversed after the treatment was stopped. PMID- 25497777 TI - Zinc status as compared to zinc intake and iron status: a case study of Iranian populations from Isfahan province. AB - The aim of this study was to estimate the zinc (Zn) and iron (Fe) status of different age groups in rural (Rooran) and suburban (Khomeini Shahr) populations in central Iran, to relate the Zn status to Zn intake from animal and plant foods, and to examine the relationship between Zn and Fe status. Blood samples from 341 subjects including preschool children (27), schoolchildren (157), women (91), and men (66) were analyzed for serum zinc (SZn), serum ferritin (SF), total C-reactive protein, and hemoglobin. Daily Zn and phytic acid (PA) intakes from major food groups were estimated using a 3-day weighed food record. The overall prevalence of Zn deficiency based on low SZn was 5.9 % in Rooran and 7.2 % in Khomeini Shahr. Anemia was higher in the village than in the suburb (33.5 % vs. 22.7 %; p = 0.04) and almost half of the anemia in Khomeini Shahr and 36 % in Rooran was associated with iron deficiency (ID) based on low SF. The PA:Zn molar ratio in the diet was 10 - 13, indicating a diet of moderate Zn bioavailability. About 18 % of the population consumed less Zn than their WHO Estimated Average Requirements. There was no association between Zn status and Fe status. The modest prevalence of Zn deficiency in the study populations can be explained by a relatively high Zn intake from animal source foods. Anemia however is a serious public health problem affecting some 30 % of the subjects, with almost half due to ID. The lower Fe status than Zn status could be due to the frequent consumption of tea and dairy products. PMID- 25497778 TI - Serum levels of some micronutrients and congenital malformations: a prospective cohort study in healthy saudi-arabian first-trimester pregnant women. AB - BACKGROUND/OBJECTIVES: Various studies have linked vitamin deficiencies in early pregnancy with birth defects. The objective of this study was to identify the relationship between micronutrient deficiency and congenital malformations (CM). SUBJECTS AND METHODS: There were 1,180 healthy, first-trimester pregnant Saudi Arabian females selected from the antenatal care clinics of two hospitals and 21 health care centers located all over the city. Their full medical history, clinical examination, anthropometry, and various laboratory analyses were completed. RESULTS: Forty-eight infants were born with CM. The serum concentrations of the analyzed nutrients (selenium, zinc, magnesium, and vitamins A, E, B12, and folic acid) were significantly lower in mothers of infants with CM compared to the mothers of infants without CM. In comparison, the serum totals of homocysteine (tHcy) levels were significantly higher among the CM group. CONCLUSION: This study highlights the association of CM with the deficiency of certain vitamins and minerals among pregnant women. PMID- 25497779 TI - Personal eating, lifestyle, and family-related behaviors correlate with fruit and vegetable consumption in adolescents living in sicily, southern Italy. AB - Lifestyle habits and parental modeling have been reported to influence adolescents? food choices, such as for fruit and vegetable consumption. The aim of this study was to investigate the association be-tween personal eating (i. e. breakfast and snacking behavior), lifestyle (sedentary and physical activity), and family-related (i. e. consuming meals with parents, family rules, and television use) habits and fruit and vegetable consumption among adolescents living in Sicily, southern Italy. A cross-sectional survey was conducted across 14 schools in urban and rural areas, including 1,135 adolescents (12 - 14 years old). Validated instruments were used to assess possible relationships between the study variables and daily fruit and vegetable consumption. Higher parental education, occupation, and rural environment were positively associated with adolescents? daily consumption of fruits and vegetables. Both types of food consumption were negatively associated with an increased frequency of between meal and out-of-home eating, and positively with having meals with parents and higher parental influence in adolescents? food choices. Television viewing habits were not related with adolescents? vegetable consumption, whereas having a television in their room and commercial advertisings were negatively associated with daily intake of fruits. Although socioeconomic and cultural status may influence fruit and vegetable consumption, personal eating and family-related behaviors may be targeted for implementing recommendations. PMID- 25497780 TI - Cardiotoxicity induced by dietary oxidized sunflower oil in rats: pro- and antioxidant effects of alpha-tocopherol. AB - This study highlighted the pro-oxidative functions of alpha-tocopherol (alphaT) on the heart antioxidant system and tissue histopathology of oxidized sunflower oil (OSO)-exposed rats.Four groups of male Wistar rats were fed with different diets: 1) control diet containing FSO (fresh sunflower oil); 2) diet containing 5 % OSO; 3) diet containing 5 % OSO, supplemented with 600 mg alphaT kg-1; and 4) diet containing 5 % OSO, supplemented with 1200 mg alphaT kg-1. The hearts were then isolated, and the antioxidant enzymatic activities were assessed. Body weight and catalase (CAT), glutathione peroxidase (GPx) activities significantly decreased in groups fed with OSO, while the lipid peroxidation (LPO) level significantly increased. Administration of OSO with alphaT (600 mg . kg-1) returned the body weight values and LPO levels to similar values as the control group. The CAT and GPx activities increased but remained significantly lower compared to the control group. In the OSO group with alphaT (1200 mg . kg-1), the CAT and GPx activities also decreased, while LPO significantly increased. Heart tissue sections obtained from the groups revealed the presence of large areas of necrosis. This study suggested that OSO induced oxidative stress and that administration of a moderate dose of alphaT restored the antioxidant balance, but that high levels of alphaT supplementation result in a pro-oxidant effect. PMID- 25497781 TI - Gender differences in the relationship between vitamin C and abdominal obesity. AB - BACKGROUND: Vitamin C is a commonly used antioxidant supplement; however, its effects on obesity and fat distribution are equivocal. We examined nationally representative data to determine whether intake of vitamin C is related to abdominal obesity. METHODS: In total, 16,414 adults (58 % women) from the 2007 - 2010 Korea National Health and Nutrition Examination Survey were included in the analysis. Vitamin C intake was calculated using 24-hour recalls and categorized into quintiles. The multivariate models in logistic regression analysis were adjusted for age, energy intake, sodium intake, smoking, alcohol consumption, physical activity, education, income, pre-existing disease conditions, survey year, and menopausal status (in women only). RESULTS: Compared with the lowest quintile (Q1) of vitamin C intake, the adjusted odds ratios of Q2, Q3, Q4, and Q5 for abdominal adiposity were 0.92, 0.86, 0.81, and 0.70, respectively, in women (p for trend = 0.0007). This association was maintained after adjusting for the confounding factors; however, we observed no association between intake of vitamin C and abdominal obesity in men. CONCLUSIONS: Vitamin C intake showed a negative association with abdominal obesity in women. Further research is warranted on the association between and the mechanism of vitamin C in abdominal obesity. PMID- 25497782 TI - Hormonal, luteal, and follicular changes during initiation of persistent corpus luteum in mares. AB - Mares with persistent CL (PCL) with no known etiology (idiopathic) were matched with mares with an interovulatory interval (IOI) of apparent physiological length, so that ovulation at the beginning of each PCL and IOI occurred during the same month (n = 6/group). Blood samples were collected daily from Days 12 to 22 (Day 0 = ovulation). Mean progesterone (P4) decreased in both groups on Days 14 and 15 and then diverged with a continued decrease in the IOI group and the beginning of constant and greater (P < 0.05) P4 concentration on each day in the PCL group. Before P4 divergence between groups, P4 in the PCL group decreased either abruptly (apparent incomplete luteolysis) or gradually. Concentration of PGFM (a metabolite of PGF2alpha) was not different between groups and reached maximum on mean Day 15 in each group. After the divergence in P4 between groups, LH and estradiol (E2) remained low in the PCL group. There was no indication that an increase in a luteotropic effect of LH in the PCL group accounted for the divergence in P4. Differences in prolactin between the groups were inconclusive. The hypothesis that secretion of PGF2alpha at the time of expected luteolysis is defective in mares with idiopathic PCL was not supported. The hypothesis that E2 concentration before expected luteolysis is greater in mares with PCL than those without PCL was not supported; however, a difference on Day 12 approached significance (P < 0.06) and tentatively indicated greater E2 in the PCL group before the beginning of luteolysis. PMID- 25497783 TI - Combined epidermal growth factor and hyaluronic acid supplementation of in vitro maturation medium and its impact on bovine oocyte proteome and competence. AB - The conditions for in vitro oocyte maturation impact on cytoplasmic and nuclear processes in the oocyte. These events are differentially influenced by the nature of the maturation inducer and the presence of intact cumulus in cumulus-oocyte complexes. Epidermal growth factor is the main growth factor promoting oocyte maturation. Also, hyaluronic acid (HA) produced by cumulus cells is known to be responsible for the correct structural and functional organization of the cumulus during oocyte maturation. Therefore, we evaluated the developmental competence of bovine oocytes matured in vitro in a maturation medium supplemented with both EGF and HA, compared to FSH and fetal bovine serum (FBS). In addition, the impact of IVM conditions on the proteomic profile of metaphase II bovine oocytes was analyzed by two-dimensional electrophoresis. Cumulus-oocyte complexes were matured in two media: (1) 10 ng/mL EGF, 15 MUg/mL HA, and 100-MUM cysteamine and (2) 0.01 UI/mL rh-FSH and 10% FBS. The percentages of first polar body and embryo production and the kinetics of embryo development and oocyte proteomic profiles were analyzed. Oocytes matured in the presence of EGF-HA showed an increase (6%, P < 0.05) in the percentage of polar body extrusion. The blastocyst rate was 3% (P < 0.05) higher in the FSH-FBS group, but no differences were found in the rate of expanded blastocyst neither in total embryo production between IVM conditions. Cleavage rate of oocytes matured with FSH-FBS was 5% higher (P < 0.05) with respect to EGF-HA-matured oocytes when evaluated 30 hours after fertilization. However, at Day 7, those inseminated oocytes that underwent division at a correct timing showed that although there are still early blastocysts in the FSH-FBS condition, EGF-HA embryos have developed completely into blastocysts. Still, the production rate of those embryos that achieved expansion was similar between both maturation conditions. On the other hand, noncleaved presumptive zygotes at Day 7 developed into the different stages with similar rates (~4%) independently of the medium condition. Modifications of IVM medium composition markedly affected protein profile of bovine oocytes in a differential manner. The proteomic approach revealed the presence of 68 spots in both treatments, 41 exclusively found in the FSH-FBS group and 64 exclusive for the EGF-HA group. Taken together, these results indicate that combined EGF-HA supplementation of in vitro maturation medium could be used to improve oocyte meiotic competence and ensure a better timing to develop into the blastocyst stage. PMID- 25497785 TI - Bradycardia and asystole during generalised interictal EEG discharges. AB - Few studies have investigated the effects of interictal epileptic discharges on the cardiac autonomic system. This study reports the case of a 37-year-old man with refractory generalised epilepsy, who recently reported an increase in frequency of nocturnal tonic-clonic seizures, not responding to treatment. During the nocturnal video study, in non-rapid eye movements sleep, we recorded 106 generalised sharp- and polyspike-waves lasting for 3 to 7 seconds, associated with bradycardia and asystole, without behavioural changes and without increase in deltoid muscle activity. The asystole had a duration of between 3 and 8 seconds. In one case, a 7 second asystole was associated with a tonic-clonic generalised seizure. A 24-hour electrocardiographic study revealed a bradycardia and a Wenckebach atrioventricular block. Heart rate analysis at the time of the interictal epileptic discharges revealed an abrupt increase in the RR interval, occurring simultaneously with the onset of interictal epileptic discharges and followed by a return to values below baseline value. A cardiac pacemaker was installed with a reduction of asystole length during the interictal epileptic discharges. Our findings indicate, for the first time, the role of interictal generalised discharges in EEG-related asystole and bradycardia. These data support the hypothesis that some patients with epilepsy may be predisposed to disturbances of the autonomic cardiac system. PMID- 25497784 TI - Modulation of lipopolysaccharide-induced neuronal response by activation of the enteric nervous system. AB - BACKGROUND: Evidence continues to mount concerning the importance of the enteric nervous system (ENS) in controlling numerous intestinal functions in addition to motility and epithelial functions. Nevertheless, little is known concerning the direct participation of the ENS in the inflammatory response of the gut during infectious or inflammatory insults. In the present study we analyzed the ENS response to bacterial lipopolysaccharide, in particular the production of a major proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha). METHODS: TNF alpha expression (measured by qPCR, quantitative Polymerase Chain Reaction) and production (measured by ELISA) were measured in human longitudinal muscle myenteric plexus (LMMP) and rat ENS primary cultures (rENSpc). They were either treated or not treated with lipopolysaccharide (LPS) in the presence or not of electrical field stimulation (EFS). Activation of extracellular signal-regulated kinase (ERK) and 5'-adenosine monophosphate-activated protein kinase (AMPK) pathways was analyzed by immunocytochemistry and Western blot analysis. Their implications were studied using specific inhibitors (U0126, mitogen-activated protein kinase kinase, MEK, inhibitor and C compound, AMPK inhibitor). We also analyzed toll-like receptor 2 (TLR2) expression and interleukin-6 (IL-6) production after LPS treatment simultaneously with EFS or TNF-alpha-neutralizing antibody. RESULTS: Treatment of human LMMP or rENSpc with LPS induced an increase in TNF-alpha production. Activation of the ENS by EFS significantly inhibited TNF alpha production. This regulation occurred at the transcriptional level. Signaling analyses showed that LPS induced activation of ERK but not AMPK, which was constitutively activated in rENSpc neurons. Both U0126 and C compound almost completely prevented LPS-induced TNF-alpha production. In the presence of LPS, EFS inhibited the ERK and AMPK pathways. In addition, we demonstrated using TNF alpha-neutralizing antibody that LPS-induced TNF-alpha production increased TLR2 expression and reduced IL-6 production. CONCLUSIONS: Our results show that LPS induced TNF-alpha production by enteric neurons through activation of the canonical ERK pathway and also in an AMPK-dependent manner. ENS activation through the inhibition of these pathways decreased TNF-alpha production, thereby modulating the inflammatory response induced by endotoxin. PMID- 25497786 TI - Secular trends in the incidence of primary hyperparathyroidism over five decades (1965-2010). AB - Introduction of automated serum calcium measurements in the 1970s resulted in a sharp rise in primary hyperparathyroidism (PHPT) incidence. However, recent investigations suggest a significant rise in PHPT incidence for unclear reasons. Our objective was to update our population-based secular trends in PHPT incidence, to determine if there has been a significant rise in PHPT incidence as suggested by others, and, if possible, to identify changes in clinical practice that might be responsible. Rochester, Minnesota, residents who met the criteria for PHPT from 2002 through 2010 were identified through the medical records linkage system of the Rochester Epidemiology Project and added to the historical cohort beginning in 1965. Incidence rates were adjusted to the 2010 US white population. Altogether, 1142 Rochester residents have been diagnosed with PHPT since 1965, including 341 in 2002-2010. Over time, two periods of increased PHPT incidence occurred, one beginning in 1974 (121.7 per 100,000 person-years) and a second peak (86.2 per 100,000 person-years) starting in 1998. The median age of PHPT subjects has increased significantly from 55 years in 1985-1997 to 60 years of age in 1998-2010 and more patients (36%) had a parathyroidectomy in 1998-2010. Although serum calcium measurement has declined since 1996, there was a progressive increase in parathyroid hormone testing between 1994 and 2008. There was also a rise in orders for bone mineral density measurements in women since 1998, which peaked in 2003-2004. A second sharp rise in PHPT incidence occurred in our community in 1998, simultaneously with the introduction of national osteoporosis screening guidelines, Medicare coverage for bone density measurement, and new medications for the treatment of osteoporosis. Case ascertainment bias from targeted PHPT screening in patients being evaluated for osteoporosis is the most likely explanation. PMID- 25497787 TI - In vitro toxicity of iron oxide nanoparticle: oxidative damages on Hep G2 cells. AB - During the past years many studies have been done highlighting the great need for a more thorough understanding of cell-iron oxide nanoparticle interactions. To improve our knowledge in this field, there is a great need for standardized protocols that would allow to comparing the cytotoxic potential of any Fe2O3-NP type with previously studied particles. Several approaches are reported that several parameters which are of great importance for Fe2O3 nanoparticle induced toxicity. Nanoparticles because of their very small size can pass through the cell membrane and can make oxidative damage in all parts of the cells such as mitochondria, membrane, DNA due to high surface area. This study focuses on acute cytotoxicity of reactive oxygen species and DNA damaging effects of mentioned nanoparticles. Results showed increase of the oxidative damage leads cells to the apoptosis, therefore reduced cell viability. It is interesting that all of the results are concentration and time dependent. PMID- 25497788 TI - Investigation by microarray analysis of effects of cigarette design characteristics on gene expression in human lung mucoepidermoid cancer cells NCI H292 exposed to cigarette smoke. AB - The effects of tobacco leaf types and the presence or absence of charcoal in the cigarette filters on gene expression were investigated using cigarette prototypes made of either flue-cured (FC) leaf or burley (BLY) leaf and Kentucky Reference 2R4F as a representative blend cigarette with cellulose acetate filters or charcoal filters. NCI-H292, human lung mucoepidermoid carcinoma cell line, was exposed to the total particulate matter (TPM) and gas/vapor phase (GVP) from each prototype for 8h and then the changes in gene expression from microarray data were analyzed. A number of genes associated with oxidative stress, inflammation, DNA damage and xenobiotic response were modified by the two fractions, TPM and GVP, from the three prototypes with cellulose acetate filters. Both TPM and GVP fractions strongly enhanced the gene expression of HMOX1, which is encoding the limiting enzyme in heme degradation and a key regulator of oxidative stress and inflammatory process. Comparing the effects of TPM and GVP fraction, TPM strongly activated Nrf2 pathway-mediated anti-oxidative stress reaction, whereas GVP caused notable DNA damage response. In comparison of FC and BLY, TPM from FC more strongly induced the expression of histone family proteins than that from BLY. GVP from FC markedly induced gene expression associated with HSP70-mediated inflammation relative to that from BLY. Charcoal included in the filter strongly reduced the effects of GVP from each cigarette on gene expression. However, charcoal did not modified the effects of TPM. As a whole, charcoal is a useful material for reducing the biological effects of GVP. PMID- 25497789 TI - Short communication: economics of sex-biased milk production. AB - In a recent data study using 2.4 million lactations of 1.5 million cows, it was reported that gestation of a female calf in the first parity increases cumulative milk production by approximately 445kg over the first 2 lactations. The reported effect in this study is large and remarkable because it has not been found before. To our knowledge, the economic implications of this or any other sex bias have not been studied. The objective of the current study was to quantify the reported influence of fetal sex across lactations by using a simulation model of a dairy herd including youngstock. Two scenarios were evaluated and compared with a scenario in which cows and heifers were exclusively bred with conventional (nonsexed) semen. In the first scenario, sexed semen was used moderately-on 30% of all heifers and 30% of the first parity cows. A second scenario was studied in which sexed semen was used intensively-on all heifers and 50% of the first-parity cows. The simulated proportion of cows giving birth to 2 consecutive heifers increased from 23% when using exclusively conventional semen up to 31 and 48% when using sexed semen moderately and intensively, respectively. The proportion of cows having 2 consecutive bulls decreased from 27% (conventional semen only) to 20 and 8% when using sexed semen moderately and intensively, respectively. When incorporating the sex bias in the simulation model, the simulated milk yield in the scenario in which sexed semen was used moderately increased by 48kg of energy-corrected milk (ECM) per cow/yr, compared with only 36kg of ECM when not incorporating the sex bias in the model. For the scenario in which sexed semen was used intensively, milk yield increased by 66 and 99kg of ECM when excluding and including the sex bias, respectively. The economic implications of the assumed sex bias were ?4.0 and ?9.9 per cow/yr, in the scenarios in which sexed semen was used moderately and intensively, respectively. PMID- 25497790 TI - Effect of increasing body condition on key regulators of fat metabolism in subcutaneous adipose tissue depot and circulation of nonlactating dairy cows. AB - In response to negative energy balance, overconditioned cows mobilize more body fat than thin cows and subsequently are prone to develop metabolic disorders. Changes in adipose tissue (AT) metabolism are barely investigated in overconditioned cows. Therefore, the objective was to investigate the effect of increasing body condition on key regulator proteins of fat metabolism in subcutaneous AT and circulation of dairy cows. Nonlactating, nonpregnant dairy cows (n=8) investigated in the current study served as a model to elucidate the changes in the course of overcondition independent from physiological changes related to gestation, parturition, and lactation. Cows were fed diets with increasing portions of concentrate during the first 6wk of the experiment until 60% were reached, which was maintained for 9wk. Biopsy samples from AT of the subcutaneous tailhead region were collected every 8wk, whereas blood was sampled monthly. Within the experimental period cows had an average BW gain of 243+/-33.3 kg. Leptin and insulin concentrations were increased until wk 12. Based on serum concentrations of glucose, insulin, and nonesterified fatty acids, the surrogate indices for insulin sensitivity were calculated. High-concentrate feeding led to decreased quantitative insulin sensitivity check index and homeostasis model assessment due to high insulin and glucose concentrations indicating decreased insulin sensitivity. Adiponectin, an adipokine-promoting insulin sensitivity, decreased in subcutaneous AT, but remained unchanged in the circulation. The high concentrate diet affected key enzymes reflecting AT metabolism such as AMP activated protein kinase and hormone-sensitive lipase, both represented as the proportion of the phosphorylated protein to total protein, as well as fatty acid synthase. The extent of phosphorylation of AMP-activated protein kinase and the protein expression of fatty acid synthase were inversely regulated throughout the experimental period, whereas the extent of phosphorylation of hormone-sensitive lipase was consistently decreasing by the high-concentrate diet. Overcondition in nonpregnant, nonlactating dairy cows changed the expression of key regulator proteins of AT metabolism and circulation accompanied by impaired insulin sensitivity, which might increase the risk for metabolic disorders. PMID- 25497791 TI - Enhanced early-life nutrition promotes hormone production and reproductive development in Holstein bulls. AB - Holstein bull calves often reach artificial insemination centers in suboptimal body condition. Early-life nutrition is reported to increase reproductive performance in beef bulls. The objective was to determine whether early-life nutrition in Holstein bulls had effects similar to those reported in beef bulls. Twenty-six Holstein bull calves were randomly allocated into 3 groups at approximately 1 wk of age to receive a low-, medium-, or high-nutrition diet, based on levels of energy and protein, from 2 to 31 wk of age. Calves were on their respective diets until 31 wk of age, after which they were all fed a medium nutrition diet. To evaluate secretion profiles and concentrations of blood hormones, a subset of bulls was subjected to intensive blood sampling every 4 wk from 11 to 31 wk of age. Testes of all bulls were measured once a month; once scrotal circumference reached 26cm, semen collection was attempted (by electroejaculation) every 2 wk to confirm puberty. Bulls were maintained until approximately 72 wk of age and then slaughtered at a local abattoir. Testes were recovered and weighed. Bulls fed the high-nutrition diet were younger at puberty (high=324.3 d, low=369.3 d) and had larger testes for the entire experimental period than bulls fed the low-nutrition diet. Bulls fed the high-nutrition diet also had an earlier and more substantial early rise in LH than those fed the low nutrition diet and had increased concentrations of insulin-like growth factor-I (IGF-I) earlier than the bulls fed the low-nutrition diet. Furthermore, we detected a temporal association between increased IGF-I concentrations and an early LH rise in bulls fed the high-nutrition diet. Therefore, we inferred that IGF-I had a role in regulating the early gonadotropin rise (in particular, LH) and thus reproductive development of Holstein bulls. Overall, these results support our hypothesis that Holstein bull calves fed a high-nutrition diet reach puberty earlier and have larger testes than those fed a low-nutrition diet, and they provide clear evidence that nutritional modulation of Holstein bull calves during early life has profound effects on reproductive development. PMID- 25497792 TI - Spoilage potential of Pseudomonas species isolated from goat milk. AB - Pseudomonas spp. are usually associated with spoilage microflora of dairy products due to their proteolytic potential. This is of particular concern for protein-based products, such as goat milk cheeses and fermented milks. Therefore, the goal of the present study was to characterize the proteolytic activity of Pseudomonas spp. isolated from goat milk. Goat milk samples (n=61) were obtained directly from bulk tanks on dairy goat farms (n=12), and subjected to a modified International Organization for Standardization (ISO) protocol to determine the number and proteolytic activity of Pseudomonas spp. Isolates (n=82) were obtained, identified by PCR, and subjected to pulsed-field gel electrophoresis with XbaI macro-restriction. Then, the isolates were subjected to PCR to detect the alkaline protease gene (apr), and phenotypic tests were performed to check proteolytic activity at 7 degrees C, 25 degrees C, and 35 degrees C. Mean Pseudomonas spp. counts ranged from 2.9 to 4.8 log cfu/mL, and proteolytic Pseudomonas spp. counts ranged from 1.9 to 4.6 log cfu/mL. All isolates were confirmed to be Pseudomonas spp., and 41 were identified as Pseudomonas fluorescens, which clustered into 5 groups sharing approximately 82% similarity. Thirty-six isolates (46.9%) were positive for the apr gene; and 57 (69.5%) isolates presented proteolytic activity at 7 degrees C, 82 (100%) at 25 degrees C, and 64 (78%) at 35 degrees C. The isolates were distributed ubiquitously in the goat farms, and no relationship among isolates was observed when the goat farms, presence of apr, pulsotypes, and proteolytic activity were taken into account. We demonstrated proteolytic activity of Pseudomonas spp. present in goat milk by phenotypic and genotypic tests and indicated their spoilage potential at distinct temperatures. Based on these findings and the ubiquity of Pseudomonas spp. in goat farm environments, proper monitoring and control of Pseudomonas spp. during production are critical. PMID- 25497793 TI - Effects of diets containing grape seed, linseed, or both on milk production traits, liver and kidney activities, and immunity of lactating dairy ewes. AB - This study aimed to evaluate the effects of the dietary inclusion of grape seed, alone or in combination with linseed, on milk production traits, immune response, and liver and kidney metabolic activity of lactating ewes. Twenty-four Sarda dairy ewes were randomly assigned to 4 dietary treatments consisting of a control diet (CON), a diet containing 300 g/d per head of grape seed (GS), a diet containing 220 g/d per head of extruded linseed (LIN), and a diet containing a mix of 300 g/d per head of grape seed and 220 g/d per head of extruded linseed (MIX). The study lasted 10 wk, with 2 wk of adaptation period and 8 wk of experimental period. Milk yield was measured and samples were collected weekly and analyzed for fat, protein, casein, lactose, pH, milk urea nitrogen, and somatic cell count. Blood samples were collected every 2 wk by jugular vein puncture and analyzed for hematological parameters, for albumin, alkaline phosphatase, bilirubin, creatinine, gamma glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, protein, blood urea nitrogen, and for anti-albumin IgG, IL-6, and lymphocyte T-helper (CD4(+)) and lymphocyte T cytotoxic (CD8(+)) cells. On d 0, 45, and 60 of the trial, lymphocyte response to phytohemagglutinin was determined in vivo on each animal by measuring skin-fold thickness (SFT) at the site of phytohemagglutinin injection. Humoral response to chicken egg albumin was stimulated by a subcutaneous injection with albumin. Dietary treatments did not affect milk yield and composition. Milk urea nitrogen and lactose were affected by diet * period. Diets did not influence hematological, kidney, and liver parameters, except for blood urea nitrogen, which decreased in LIN and increased in MIX compared with CON and GS. Dietary treatments did not alter CD4(+), CD8(+), and CD4(+)-to-CD8(+) ratio. The SFT was reduced in GS and MIX and increased in LIN compared with CON. The IgG and IL-6 were affected by diet * period. The reduction in IgG on d 60 and SFT in ewes fed GS suggests an immunomodulatory effect of this residue. The limited variation in milk and hematological and metabolic parameters suggests that GS and LIN can be included, alone or in combination, in the diet of dairy ewes without adverse effects on milk production and health status. PMID- 25497794 TI - Effects of dry period length and dietary energy source on metabolic status and hepatic gene expression of dairy cows in early lactation. AB - In a prior study, we observed that cows with a 0-d dry period had greater energy balance and lower milk production compared with cows with a 30- or 60-d dry period in early lactation. The objective of the current study was to evaluate the influence of dry period length on metabolic status and hepatic gene expression in cows fed a lipogenic or glucogenic diet in early lactation. Holstein-Friesian dairy cows (n=167) were assigned randomly to 3*2 factorial design with 3 dry period lengths (n=56, 55, and 56 for 0-, 30-, and 60-d dry, respectively) and 2 early lactation diets (n=84 and 83 for glucogenic and lipogenic diet, respectively). Cows were fed a glucogenic or lipogenic diet from 10d before the expected calving date and onward. The main ingredient for a glucogenic concentrate was corn, and the main ingredients for a lipogenic concentrate were sugar beet pulp, palm kernel, and rumen-protected palm oil. Blood was sampled weekly from 95 cows from wk 3 precalving to wk 8 postcalving. Liver samples were collected from 76 cows in wk -2, 2, and 4 relative to calving. Liver samples were analyzed for triacylglycerol concentrations and mRNA expression of 12 candidate genes. Precalving, cows with a 0-d dry period had greater plasma beta hydroxybutyrate, urea, and insulin concentrations compared with cows with a 30- or 60-d dry period. Postcalving, cows with a 0-d dry period had lower liver triacylglycerol and plasma nonesterified fatty acids concentrations (0.20, 0.32, and 0.36mmol/L for 0-, 30-, and 60-d dry period, respectively), greater plasma glucose, insulin-like growth factor-I, and insulin (24.38, 14.02, and 11.08uIU/mL for 0-, 30-, and 60-d dry period, respectively) concentrations, and lower hepatic mRNA expression of pyruvate carboxylase, compared with cows with a 30- or 60-d dry period. Plasma urea and beta-hydroxybutyrate concentrations were greater in cows fed a lipogenic diet compared with cows fed a glucogenic diet. In conclusion, cows with a 0-d dry period had an improved metabolic status in early lactation, indicated by lower plasma concentrations of nonesterified fatty acids, greater plasma concentrations of glucose, insulin-like growth factor-I, and insulin, and lower mRNA expression of pyruvate carboxylase in the liver, compared with cows with a 30- or 60-d dry period. Independent of dry period length, the glucogenic diet also improved the metabolic status compared with the lipogenic diet. PMID- 25497795 TI - Invited review: organic and conventionally produced milk-an evaluation of factors influencing milk composition. AB - Consumer perception of organic cow milk is associated with the assumption that organic milk differs from conventionally produced milk. The value associated with this difference justifies the premium retail price for organic milk. It includes the perceptions that organic dairy farming is kinder to the environment, animals, and people; that organic milk products are produced without the use of antibiotics, added hormones, synthetic chemicals, and genetic modification; and that they may have potential benefits for human health. Controlled studies investigating whether differences exist between organic and conventionally produced milk have so far been largely equivocal due principally to the complexity of the research question and the number of factors that can influence milk composition. A main complication is that farming practices and their effects differ depending on country, region, year, and season between and within organic and conventional systems. Factors influencing milk composition (e.g., diet, breed, and stage of lactation) have been studied individually, whereas interactions between multiple factors have been largely ignored. Studies that fail to consider that factors other than the farming system (organic vs. conventional) could have caused or contributed to the reported differences in milk composition make it impossible to determine whether a system-related difference exists between organic and conventional milk. Milk fatty acid composition has been a central research area when comparing organic and conventional milk largely because the milk fatty acid profile responds rapidly and is very sensitive to changes in diet. Consequently, the effect of farming practices (high input vs. low input) rather than farming system (organic vs. conventional) determines milk fatty acid profile, and similar results are seen between low-input organic and low-input conventional milks. This confounds our ability to develop an analytical method to distinguish organic from conventionally produced milk and provide product verification. Lack of research on interactions between several influential factors and differences in trial complexity and consistency between studies (e.g., sampling period, sample size, reporting of experimental conditions) complicate data interpretation and prevent us from making unequivocal conclusions. The first part of this review provides a detailed summary of individual factors known to influence milk composition. The second part presents an overview of studies that have compared organic and conventional milk and discusses their findings within the framework of the various factors presented in part one. PMID- 25497796 TI - Constraints for nutritional grouping in Wisconsin and Michigan dairy farms. AB - A survey was conducted in Wisconsin (WI) and Michigan (MI) to quantify the proportion of farms that use a single diet for all lactating cows and to better understand the reasons for current grouping strategies and the limitations to grouping for better nutritional management. A questionnaire was mailed to all WI dairy farmers with >=200 lactating cows (971 farms) and to a random sample of grade-A MI dairy farmers (800 farms) of varying herd sizes. The survey return rate was 20% in WI (196 farms) and 26% in MI (211 farms; 59 of them had >=200 lactating cows). Feeding 2 or more different diets to lactating cows was predominant: 63% in WI (124 farms, all >=200 lactating cows), 76% in MI farms with >=200 lactating cows (45 farms), and 28% in MI farms with <200 lactating cows (43 farms). Farmers feeding more than 1 diet used 1 or more of the following criteria for grouping lactating cows: stage of lactation, milk production, or body condition score. Overall for both states, 52% of the farms (211 from 407 farms) feeding more than 1 diet grouped cows according to their nutritional needs. However, a notable population of farms fed the same diet to all lactating cows: 37% in WI (72 farms), 24% in MI (14 farms) for herds of >=200 lactating cows, and 72% in MI for herds of <200 lactating cows (109 MI farms). "Desire to keep it simple" and "milk drops when cows are moved to a different group" were identified as main constraints to having more groups within a farm for nutritional purposes. Farm facilities and labor were also limiting factors to grouping in farms with herd sizes of <200 lactating cows. PMID- 25497797 TI - Genetic variation and posttranslational modification of bovine kappa-casein: effects on caseino-macropeptide release during renneting. AB - Chymosin-induced cleavage of kappa-casein (kappa-CN) occurs during the first enzymatic phase in milk coagulation during cheese manufacturing, where the hydrophilic C-terminal peptide of kappa-CN, named caseino-macropeptide (CMP), is released into the whey. The CMP peptide is known for its rather heterogeneous composition with respect to both genetic variation and multiple posttranslational modifications, including phosphorylation and O-linked glycosylation. An approach of liquid chromatography coupled with mass spectrometry was used to investigate (1) the overall protein profile and (2) the release of various forms of CMP after addition of chymosin to individual cow milk samples from 2 breeds, Danish Jersey (DJ) and Danish Holstein-Friesian (DH). The cows were selected to represent distinct homo- and heterozygous types of the kappa-CN genetic variants A, B, and E (i.e., genotypes AA, BB, AB, EE, and AE). Initially, investigation of the protein profile showed milk with kappa-CN BB exhibited the highest relative content of kappa-CN, whereas AE milk exhibited the lowest, and after 40min of renneting >90% of intact kappa-CN was hydrolyzed by chymosin in milk representing all kappa-CN genotype. By in-depth analysis of the CMP chromatographic profile, multiple CMP isoforms with 1 to 3 O-linked glycans (1-3 G) and 1 to 3 phosphate groups (1-3 P) were identified, as well as nonmodified CMP isoforms. The number of identified CMP isoforms varied to some extent between breeds (21CMP isoforms identified in DJ, 26CMP isoforms in DH) and between kappa-CN genetic variants (CMP variant A being the most heterogeneous compared with CMP B and E), as well as between individual samples within each breed. The predominant forms of glycans attached to CMP were found to be the acidic tetrasaccharide {N-acetyl-neuraminic acid alpha(2-3)galactose beta(1-3)[N-acetyl-neuraminic acid alpha(2-6)]N-acetyl galactose} or trisaccharides {N-acetyl-neuraminic acid alpha(2-3)galactose beta(1 3)N-acetyl galactose and galactose beta(1-3)[N-acetyl-neuraminic acid (alpha2 6)]N-acetyl galactose}. The CMP release was calculated to follow first-order kinetics and was determined by the measurement of CMP content during renneting. The highest rate of release for all CMP isoforms occurred from 0 to 2min after chymosin addition. Concurring results from both breeds showed that CMP variant A with 1-2 P had the highest reaction rate of CMP release, followed by CMP B 1-2 P and then by CMP E 1-2 P (only in DH). All the identified glycosylated CMP isoforms had lower reaction rates of release compared with that of nonglycosylated CMP, thus glycan modifications seemed to negatively influence the reaction rate of chymosin-induced hydrolysis of kappa-CN. PMID- 25497798 TI - Microfiltration of skim milk and modified skim milk using a 0.1-um ceramic uniform transmembrane pressure system at temperatures of 50, 55, 60, and 65 degrees C. AB - Increasing the temperature of microfiltration (MF) to >50 degrees C may allow for operation at higher fluxes and reduce the bacterial growth during MF. However, there is a concern that operating at higher temperatures could cause calcium phosphate precipitation that would lead to membrane fouling. Our objective was to determine the effect of operating a 0.1-um ceramic uniform transmembrane pressure MF unit at temperatures of 50, 55, 60, and 65 degrees C on membrane fouling and serum protein (SP) removal from skim milk with and without removal of low molecular-weight soluble milk components by ultrafiltration (UF) before MF at a flux of 54kg/m(2) per hour. For each replicate, 1,000kg of pasteurized skim milk was split into 2 batches. One batch was ultrafiltered (with diafiltration) to remove an average of 89+/-2% of the lactose and a percentage of the soluble calcium and phosphorus. The retentate from UF was diluted back to the protein concentration of skim milk, creating the diluted UF retentate (DUR). On subsequent days, both the DUR and skim milk were run on the MF unit with the flux maintained at 54kg/m(2) per hour and a concentration factor of 3* and the system run in recycle mode. The temperature of MF was increased in 5 degrees C steps from 50 to 65 degrees C, with a 1-h stabilization period after each increase. During the run, transmembrane pressure was monitored and permeate and retentate samples were taken and analyzed to determine if any changes in SP, calcium, or phosphorus passage through the membrane occurred. Increasing temperature of MF from 50 to 65 degrees C at a flux of 54kg/m(2) per hour did not produce a large increase in membrane fouling when using either skim milk or a DUR as the MF feed type as measured by changes in transmembrane pressure. Increasing the temperature to 65 degrees C only caused a slight reduction in calcium concentration in the permeate (11+/-3%) that was similar between the 2MF feed types. Increasing processing temperature reduced the percentage of SP removal by the process, but the increased temperature also caused a decrease in casein contamination in the permeate with no evidence of membrane fouling. PMID- 25497799 TI - Association between antibody status to bovine herpesvirus 1 and quality of milk in dairy herds in Poland. AB - Bovine herpesvirus 1 (BoHV1) is one of the most important pathogens of cattle; however, its effect on somatic cell count and milk components is not completely understood. The aim of the current study was to examine the effect of BoHV1 infection on quality of bovine bulk tank milk (BTM). A total of 1,790 individual blood samples collected at 28 dairy farms were used to determine the BoHV1 infection status of the herds with ELISA tests. The quality parameters of milk were evaluated by instrumental methods with BTM samples collected at monthly intervals from May 2011 to May 2012. The statistical analysis was performed to study the associations between BoHV1 herd status, quality of BTM, and herd specific parameters. The risk factors influencing bulk milk somatic cell count (BMSCC) were estimated using the multivariable mixed-effects maximum likelihood regression model. The true prevalences of BoHV1 infection at the animal and herd levels were 49.3 and 64.6%, respectively. The average BMSCC differed significantly between the herds grouped accordingly to their BoHV1 infection status. Interestingly, the highest BMSCC was observed in the vaccinated herds (240.3*10(3) cells/mL). Additionally, the BoHV1 herd status had a significant effect on the fat content of BTM. The largest herds that were investigated had a BoHV1 seroprevalence over 30%. The herd status was considerably influenced by the numbers of cows in the herds. Besides, no significant differences in total bacterial count or protein content in milk from BoHV1-infected und uninfected herds were observed. An increase in BMSCC was observed during summer compared with the winter months regardless of the BoHV1 status of the herds. In the final multivariable regression model, the main risk factors associated with BMSCC were BoHV1 herd status, the percentage of BoHV1 infected animals in a herd, the number of cows in a herd, and the season. Our study suggests that BoHV1 infection may influence BMSCC levels, which are key parameters of BTM quality and a reference for subclinical mastitis in a herd. In conclusion, BoHV1 infection may cause economic losses by decrease both of quantity and quality of milk. PMID- 25497800 TI - Temperature and relative humidity influence the ripening descriptors of Camembert type cheeses throughout ripening. AB - Ripening descriptors are the main factors that determine consumers' preferences of soft cheeses. Six descriptors were defined to represent the sensory changes in Camembert cheeses: Penicillium camemberti appearance, cheese odor and rind color, creamy underrind thickness and consistency, and core hardness. To evaluate the effects of the main process parameters on these descriptors, Camembert cheeses were ripened under different temperatures (8, 12, and 16 degrees C) and relative humidity (RH; 88, 92, and 98%). The sensory descriptors were highly dependent on the temperature and RH used throughout ripening in a ripening chamber. All sensory descriptor changes could be explained by microorganism growth, pH, carbon substrate metabolism, and cheese moisture, as well as by microbial enzymatic activities. On d 40, at 8 degrees C and 88% RH, all sensory descriptors scored the worst: the cheese was too dry, its odor and its color were similar to those of the unripe cheese, the underrind was driest, and the core was hardest. At 16 degrees C and 98% RH, the odor was strongly ammonia and the color was dark brown, and the creamy underrind represented the entire thickness of the cheese but was completely runny, descriptors indicative of an over ripened cheese. Statistical analysis showed that the best ripening conditions to achieve an optimum balance between cheese sensory qualities and marketability were 13+/-1 degrees C and 94+/ 1% RH. PMID- 25497801 TI - Technical note: a pilot study using a mouse mastitis model to study differences between bovine associated coagulase-negative staphylococci. AB - Coagulase-negative staphylococci (CNS) are a group of bacteria classified as either minor mastitis pathogens or commensal microbiota. Recent research suggests species- and even strain-related epidemiological and genetic differences within the large CNS group. The current pilot study investigated in 2 experiments whether a mouse mastitis model validated for bovine Staphylococcus aureus can be used to explore further differences between CNS species and strains. In a first dose titration experiment, a low inoculum dose of S. aureus Newbould 305 (positive control) was compared with increasing inoculum doses of a Staphylococcus chromogenes strain originating from a chronic bovine intramammary infection to a sham-inoculated mammary glands (negative control). In contrast to the high bacterial growth following inoculation with S. aureus, S. chromogenes was retrieved in very low levels at 24 h postinduction (p.i.). In a second experiment, the inflammation inflicted by 3 CNS strains was studied in mice. The host immune response induced by the S. chromogenes intramammary strain was compared with the one induced by a Staphylococcus fleurettii strain originating from cow bedding sawdust and by a S. chromogenes strain originating from a teat apex of a heifer. As expected, at 28 and 48 h p.i., low bacterial growth and local neutrophil influx in the mammary gland were induced by all CNS strains. As hypothesized, bacterial growth p.i. was the lowest for S. fleurettii compared with that induced by the 2 S. chromogenes strains, and the overall immune response established by the 3 CNS strains was less pronounced compared with the one induced by S. aureus. Proinflammatory cytokine profiling revealed that S. aureus locally induced IL-6 and IL-1beta but not TNF-alpha, whereas, overall, CNS inoculated glands lacked a strong cytokine host response but also induced IL 1beta locally. Compared with both other CNS strains, S. chromogenes from the teat apex inflicted a more variable IL-1beta response characterized by a more intense local reaction in several mice. This pilot study suggests that an intraductal mouse model can mimic bovine CNS mastitis and has potential as a complementary in vivo tool for future CNS mastitis research. Furthermore, it indicates that epidemiologically different bovine CNS species or strains induce a differential host innate immune response in the murine mammary gland. PMID- 25497802 TI - Kinetics of microbial methionine metabolism in continuous cultures administered different methionine sources. AB - The Met precursor 2-hydroxy-4-(methylthio) butanoic acid (HMB) is expected to be more extensively degraded in the rumen than its isopropyl ester (HMBi). A control and 3 isomolar treatments-0.097% dl-methionine, 0.11% HMBi (HMBi), and 0.055% HMBi plus 0.048% Met (Met + HMBi)-were dosed every 8h simultaneously with 3-times daily feeding into continuous cultures. Starting on d 9, for 6 consecutive doses, both [1-(13)C]-l-Met and [methyl-(2)H3]-l-Met replaced part of the unlabeled dl Met, [(13)C5]-dl-HMBi replaced a portion of the unlabeled dl-HMBi, and [1-(13)C] l-Met plus [(13)C5]-dl-HMBi replaced a portion of the respective unlabeled doses for the Met + HMBi treatment. After the sixth dose (d 11), unlabeled Met or HMBi provided 100% of the doses to follow elimination kinetics of the labels in HMBi, free Met, and bacterial Met compartments. The free [1-(13)C]-l-Met recycled more and was recovered in bacterial Met to a lesser extent than was the free [methyl (2)H3]-l-Met recycling and that was recovered in bacterial Met. Increasing HMBi inclusion (0, 50, and 100% substitution of the exogenously dosed Met on a molar equivalent basis) tended to increase HMBi escape from 54.7 to 71.3% for the 50 and 100% HMBi treatments, respectively. Despite HMBi substituting for and decreasing the dosage of Met, increasing HMBi increased accumulation of free Met in fermenter fluid. The HMBi (after de-esterification of the isopropyl group) presumably produces Met through the intermediate alpha-ketomethylthyiobutyrate with an aminotransferase that also has high affinity for branched-chain AA. We provide evidence that the HMBi-derived Met is likely released from bacterial cells and accumulates rather than being degraded, potentially as a result of lagging d-stereoisomer metabolism. More research is needed to evaluate racemization and metabolism of stereoisomers of HMBi, Met, and other AA in ruminal microbes. PMID- 25497803 TI - The optimal number of heifer calves to be reared as dairy replacements. AB - Dairy farmers often keep almost all their newborn heifer calves despite the high cost of rearing. By rearing all heifer calves, farmers have more security and retain flexibility to cope with the uncertainty in the availability of replacement heifers in time. This uncertainty is due to mortality or infertility during the rearing period and the variation in culling rate of lactating cows. The objective of this study is to provide insight in the economically optimal number of heifer calves to be reared as replacements. A herd-level stochastic simulation model was developed specific for this purpose with a herd of 100 dairy cows; the biological part of the model consisted of a dairy herd unit and rearing unit for replacement heifers. The dairy herd unit included variation in the number of culled dairy cows. The rearing unit incorporated variation in the number of heifers present in the herd by including uncertainty in mortality and variation in fertility. The dairy herd unit and rearing unit were linked by the number of replacement heifers and culled dairy cows. When not enough replacement heifers were available to replace culled dairy cows, the herd size was temporarily reduced, resulting in an additional cost for the empty slots. When the herd size reached 100 dairy cows, the available replacement heifers that were not needed were sold. It was assumed that no purchase of cows and calves occurred. The optimal percentage of 2-wk-old heifer calves to be retained was defined as the percentage of heifer calves that minimized the average net costs of rearing replacement heifers. In the default scenario, the optimal retention was 73% and the total net cost of rearing was estimated at ?40,939 per herd per year. This total net cost was 6.5% lower than when all heifer calves were kept. An earlier first-calving age resulted in an optimal retention of 75%, and the net costs of rearing were ?581 per herd per year lower than in the default scenario. For herds with a lower or higher culling rate of dairy cows (10 or 40% instead of 25% in the default scenario), it was optimal to retain 35 or 100% of the heifer calves per year. Herds that had a lower or higher cost of empty slots (?50 or ?120 per month instead of ?82 in the default scenario) had an optimal retention of 49 or 83% per year; the optimal retention percentage was dependent on farm and herd characteristics. For Dutch dairy farming conditions, it was not optimal to keep all heifer calves. PMID- 25497804 TI - Improving ergonomics in milking parlors: empirical findings for optimal working heights in five milking parlor types. AB - Milking postures have shifted from seated milking in tethered stalls to milking in a standing position in parlors. However, the musculoskeletal workload of dairy farmers remains high. Previous studies have shown that different working heights affect ergonomics, but they could not objectively evaluate and quantify the workload. The aim of the present study was to assess the effect of working height in different milking parlor types on the milker's workload during the task of attaching milking clusters. Computer-assisted recording and long-term analysis of movements were used to record positions of joints and body regions while performing certain tasks in terms of angular degrees of joints (ADJ) according to the neutral zero method. The 5th, 50th, and 95th percentiles described the distribution of angular degree values measured for each joint. The ADJ were evaluated according to international standards and other scientific literature on the issue to assess the muscular load. The workload was compared between 5 parlor types (auto tandem, herringbone 30 degrees , herringbone 50 degrees , parallel, and rotary) on 15 farms with 2 subjects per parlor and 1 milking period per subject. The working height was defined as a coefficient based on the milker's body height, the floor level, and the cow's udder height. The data recorded during the attachment task were analyzed using generalized linear mixed-effects models taking into account the hierarchical experimental design. The results indicated that the interaction of the cow's udder height, the milker's body height, and the parlor type had a larger effect on ergonomics than each parameter had independently. The interaction was significant in at least 1 of the 3 percentiles in 28 out of 31 ADJ. The postural differences between parlor types, however, were minor. A milking health formula was created to calculate the ideal depth of pit by considering the parlor type, the milker's height, and the mean herd udder height. This formula can be used to develop individual recommendations for future parlor construction. PMID- 25497805 TI - Feeding and lying behavior of heat-stressed early lactation cows fed low fiber diets containing roughage and nonforage fiber sources. AB - In addition to reduced nutrient intake, an environmental thermal load may directly affect milk yield in heat-stressed dairy cows. Feeding and lying behaviors of early lactation cows fed low fiber diets containing neutral detergent fiber (NDF) from roughage and nonforage fiber sources (NFFS) were investigated under summer conditions in Thailand. Immediately after calving, 30 multiparous cows (87.5% Holstein * 12.5% Sahiwal) were randomly allocated to dietary treatments for 63 d in a completely randomized design. The dietary treatments contained 25% of dry matter (DM) as dietary NDF. The control diet consisted of 13.9% roughage NDF from rice straw (RS). Two additional treatments were created by replacing 3.9% of DM with NDF from either soy hulls (SH) or cassava (Manihot esculenta Grantz) residues (CR), so that the roughage NDF content was reduced to 10%. During the experimental period, the minimum and maximum temperature-humidity indices (THI) were 86.4+/-2.5 and 91.5+/-2.7 during the day and 74.2+/-2.1 and 81.0+/-2.5 during the night, respectively, indicating conditions appropriate for induction of extreme heat stress. The duration of feeding and lying bouts decreased linearly with increasing THI. The DM intake during the day was greater for cows fed diets containing SH and CR than for those fed the diet containing NDF from RS. The number of meals during the day and night was lower, whereas meal size and meal length during the day and night were greater for cows fed diets containing SH and CR. Cows fed diets containing SH and CR lay down less frequently and longer during the day. These results suggest that under the severe heat stress during the day, early lactation cows fed the diet containing NFFS increased DM intake by increasing meal length and meal size rather than by increasing meal frequency and they spent more time lying. Cows fed diets containing NDF from SH and CR produced more 4% fat-corrected milk, lost less body weight, and had lower rectal temperatures measured at the 1530h milking. Therefore, reducing the filling effect may contribute to reducing heat load derived from the change in feeding and lying behavior. This should be considered as a factor for impairing productivity of heat-stressed early lactation cows. PMID- 25497807 TI - Within-day variation and effect of acute stress on plasma and milk cortisol in lactating goats. AB - An experiment was carried out to study the effect of acute stress on cortisol concentration in goat milk (milk cortisol; MC) and its suitability for stress assessment. Additional variables studied were plasma cortisol (PC), blood glucose (BG), and somatic cell count (SCC). Ten goats free of mastitis at 2 mo of lactation were divided into 2 groups. One group of animals was exposed to acute stress (visual and auditory, but not physical, contact with a barking dog for 3 min) immediately before the 1000 h sampling (STR), and the other group was considered as the control group, not exposed to acute stress (CON). The animals were gradually accustomed to the sampling schedule for 1 wk before the stress treatment (pre-experimental period). The variables PC, MC, BG, SCC, and milk composition (fat, lactose, whey protein, true protein, and casein) were recorded at 0600, 1000, 1130, 1400, 1800, 2200, and 0200 h. Milk variables were recorded in both glands separately. The right gland (n=10) was completely milked and the left gland (n=10) was milked to 30 mL at every sampling except at 1000 h, when complete milking was carried out on both glands. Variables were analyzed by using a linear mixed model. Both PC and MC concentrations varied throughout the day, with values being highest in the morning. Higher PC levels were recorded in the STR group immediately after treatment compared with CON (36.9 vs 16.3 ng/mL). For MC, differences between treatments were noted 1.5h after STR treatment (1.27 vs 0.25 ng/mL). Blood glucose increased immediately after treatment in STR animals, being different from CON until 1.5h after treatment sampling (101 vs. 58 mg/dL). The SCC was not increased by STR treatment, showing higher values in the morning and afternoon compared with evening and night (5.6+/-0.13 to 5.87+/-0.13 log10 SCC). The STR treatment had no significant effect on milk composition, and overall milk yield of a complete day after stress stimulus of both groups was similar (STR: 2,067+/-280 g/d; CON: 2,134+/-427 g/d). We conclude that plasma and milk cortisol concentrations in control dairy goats varied throughout the day; MC showed significant differences in the STR group if samples were taken 1.5h after the stressing stimulus, whereas PC showed significant differences in samples taken immediately after the stressing stimulus. Additionally, MC sampling has the advantage of being noninvasive compared with blood sampling. PMID- 25497806 TI - Hepatic glucocorticoid and alpha1- and beta2-adrenergic receptors in calves change during neonatal maturation and are related to energy regulation. AB - Catecholamines and glucocorticoids are involved in fetal maturation of organ systems to prepare the fetus for extrauterine life. Calves, especially when born preterm, depend on function of the adrenergic system and the glucocorticoid axis to adapt energy metabolism for the neonatal period. We tested the hypothesis that hepatic glucocorticoid and alpha1- and beta2-adrenergic receptors in neonatal calves are involved in adaptation of energy metabolism around birth and that respective binding capacities depend on stage of maturation during the neonatal period. Calves (n=7 per group) were delivered by section preterm (PT, 9d before term) or were born at term (full-term, FT; spontaneous vaginal delivery), or spontaneously born and fed colostrum for 4d (FTC). Blood samples were taken immediately after birth and before and 2h after feeding at 24h after birth (PT, FT) or on d 4 of life (FTC) to determine metabolic and endocrine changes. After slaughter at 26h after birth (PT, FT) or on d 4 of life (FTC), liver tissue was obtained to measure hepatic binding capacity of glucocorticoid and alpha1- and beta2-adrenergic receptors. Maximal binding capacity and binding affinity were calculated by saturation binding assays using [(3)H]-prazosin and [(3)H]-CGP 12177 for determination of alpha1- and beta2-adrenergic receptors, respectively, and [(3)H]-dexamethasone for determination of glucocorticoid receptor in liver. Additional liver samples were taken to measure mRNA abundance of glucocorticoid and alpha1- and beta2-adrenergic receptors, of key enzymes and factors related to hepatic lipid metabolism, and of insulin-like growth factor 1 (IGF1). Plasma concentrations of beta-hydroxybutyrate and leptin changed with time, and leptin concentrations were affected by stage of maturation. The binding capacities for hepatic glucocorticoid and beta2-adrenergic receptors as well as gene expression of IGF1 were greater in FTC than in FT and PT, and binding affinity for beta2 adrenergic receptor was lowest in PT. The binding capacity of hepatic alpha1 adrenergic receptor was greatest in FTC and greater in FT than in PT. The binding capacities of glucocorticoid and alpha1-adrenergic receptors were mainly related to variables of glucose and lipid metabolism. In conclusion, our results indicate dependence of hepatic glucocorticoid and adrenergic receptors on stage of maturation in neonatal calves and emphasize the association of alpha1-adrenergic receptor and glucocorticoid receptor with neonatal glucose and lipid metabolism. PMID- 25497808 TI - Investment appraisal of technology innovations on dairy farm electricity consumption. AB - The aim of this study was to conduct an investment appraisal for milk-cooling, water-heating, and milk-harvesting technologies on a range of farm sizes in 2 different electricity-pricing environments. This was achieved by using a model for electricity consumption on dairy farms. The model simulated the effect of 6 technology investment scenarios on the electricity consumption and electricity costs of the 3 largest electricity-consuming systems within the dairy farm (i.e., milk-cooling, water-heating, and milking machine systems). The technology investment scenarios were direct expansion milk-cooling, ice bank milk-cooling, milk precooling, solar water-heating, and variable speed drive vacuum pump milking systems. A dairy farm profitability calculator was combined with the electricity consumption model to assess the effect of each investment scenario on the total discounted net income over a 10-yr period subsequent to the investment taking place. Included in the calculation were the initial investments, which were depreciated to zero over the 10-yr period. The return on additional investment for 5 investment scenarios compared with a base scenario was computed as the investment appraisal metric. The results of this study showed that the highest return on investment figures were realized by using a direct expansion milk-cooling system with precooling of milk to 15 degrees C with water before milk entry to the storage tank, heating water with an electrical water-heating system, and using standard vacuum pump control on the milking system. Return on investment figures did not exceed the suggested hurdle rate of 10% for any of the ice bank scenarios, making the ice bank system reliant on a grant aid framework to reduce the initial capital investment and improve the return on investment. The solar water-heating and variable speed drive vacuum pump scenarios failed to produce positive return on investment figures on any of the 3 farm sizes considered on either the day and night tariff or the flat tariff, even when the technology costs were reduced by 40% in a sensitivity analysis of technology costs. PMID- 25497809 TI - Body condition score at calving affects systemic and hepatic transcriptome indicators of inflammation and nutrient metabolism in grazing dairy cows. AB - Calving body condition score (BCS) is an important determinant of early-lactation dry matter intake, milk yield, and disease incidence. The current study investigated the metabolic and molecular changes induced by the change in BCS. A group of cows of mixed age and breed were managed from the second half of the previous lactation to achieve mean group BCS (10-point scale) that were high (HBCS, 5.5; n=20), medium (MBCS, 4.5; n=18), or low (LBCS, 3.5; n=19). Blood was sampled at wk -4, -3, -2, 1, 3, 5, and 6 relative to parturition to measure biomarkers of energy balance, inflammation, and liver function. Liver was biopsied on wk 1, 3, and 5 relative to parturition, and 10 cows per BCS group were used for transcript profiling via quantitative PCR. Cows in HBCS and MBCS produced more milk and had greater concentrations of nonesterified fatty acids and beta-hydroxybutyrate postpartum than LBCS. Peak concentrations of nonesterified fatty acids and beta-hydroxybutyrate and greater hepatic triacylglycerol concentrations were recorded in HBCS at wk 3. Consistent with blood biomarkers, HBCS and MBCS had greater expression of genes associated with fatty acid oxidation (CPT1A, ACOX1), ketogenesis (HMGCS2), and hepatokines (FGF21, ANGPTL4), whereas HBCS had the lowest expression of APOB (lipoprotein transport). Greater expression during early lactation of BBOX1 in MBCS and LBCS suggested greater de novo carnitine synthesis. The greater BCS was associated with lower expression of growth hormone/insulin-like growth factor-1 signaling axis genes (GHR1A, IGF1, and IGFALS) and greater expression of gluconeogenic genes. These likely contributed to the higher milk production and greater gluconeogenesis. Despite greater serum haptoglobin around calving, cows in HBCS and MBCS had greater blood albumin. Cows in MBCS, however, had a higher albumin:globulin ratio, probably indicating a less pronounced inflammatory status and better liver function. The marked decrease in expression of NFKB1, STAT3, HP, and SAA3 coupled with the increase in ALB on wk 3 in MBCS cows were consistent with blood measures. Overall, results suggest that the greater milk production of cows with higher calving BCS is associated with a proinflammatory response without negatively affecting expression of genes related to metabolism and the growth hormone/insulin-like growth factor-1 axis. Results highlight the sensitivity of indicators of metabolic health and inflammatory state to subtle changes in calving BCS and, collectively, indicate a suboptimal health status in cows calving at either BCS 3.5 or 5.5 relative to BCS 4.5. PMID- 25497810 TI - Technical note: validation of data loggers for recording lying behavior in dairy goats. AB - Changes in standing and lying behavior are frequently used in farm animals as indictors of comfort and health. In dairy goats, these behaviors have primarily been measured using labor-intensive video and live observation methodologies. The aim of this study was to validate accelerometer-based data loggers for use in goats. Two commercial dairy goat farms in Ontario were enrolled; goats were fitted with data loggers on their rear left legs and the pens were equipped with video. Data loggers compared well with video in identifying lying and standing events on both farms (farm 1 and 2, respectively: sensitivity=99.7 and 99.8%, specificity=99.5 and 99.4%, false readings=0.43 and 0.36%). The loggers were also able to record if the goat was lying on her left or right side (farm 1 only: sensitivity=99.9%, specificity=99.3%, false readings=0.38%), but these measures were only accurate if the loggers were attached with sufficient tension to prevent logger rotation. The mature does enrolled on farm 1 spent 14.5+/-1.0h/d lying down and frequently changed lying side even within a single lying bout (24+/-5 shifts/d between left and right sides and 16+/-5 lying bouts/d). The young goats on the second farm averaged just 8.5+/-3.2h/d in lying time, and spread this time over 8+/-4 bouts/d. Data loggers accurately measured lying time and lying bouts in mature does and younger goats on both farms, and lying laterality (e.g., left and right lying sides) in mature does on farm 1. PMID- 25497811 TI - Short communication: limit feeding affects behavior patterns and feeding motivation of dairy heifers. AB - The study objective was to assess the effects of limit feeding dairy heifers on behavior patterns and feeding motivation. Ten Holstein heifers (291.6+/-39.2d of age, weighing 324.2+/-61.2kg; mean +/- SD) were exposed to each of 2 dietary treatments, in a random order, over 2 successive 26-d treatment periods (14-d adaptation period and a 12-d data collection period) using a crossover design: (1) a high-forage total mixed ration (TMR), provided ad libitum (CON) and (2) a low-forage TMR, limit-fed at 2.05% body weight (LF). Heifers were fed daily at 1100h and motivation to access a low-nutritive feedstuff (straw) was assessed using a push-door apparatus at 2 time points: 3h after feed delivery (1400h) and 21h after feed delivery (0800h). The amount of weight pushed, weight pushed as percentage of body weight, and latency to access the push door were recorded on 3 different days for each heifer at each time point on each treatment. When fed CON, heifers had greater dry matter intake (12.9 vs. 7.2kg/d), greater feeding time (209.3 vs. 82.4min/d), greater ruminating time (452.2 vs. 318.3min/d), and slower rates of intake (0.06 vs. 0.09kg of dry matter/min) than when fed LF. Heifers fed LF pushed more weight as a percentage of body weight at 3h (4.5 vs. 1.9%) and 21h (9.3 vs. 2.8%) after feed delivery. At both 3 and 21h after feed delivery, latency to access the door was shorter for the LF heifers compared with the CON heifers (65 vs. 145 s). These results indicate that, in addition to decreasing feeding time, limit feeding increases motivation of heifers to access a low-nutritive feedstuff, possibly due to lack of satiety resulting from lack of physical fill or insufficient time spent foraging. PMID- 25497812 TI - Bovine chromosomal regions affecting rheological traits in rennet-induced skim milk gels. AB - Optimizing cheese yield and quality is of central importance to cheese manufacturing. The yield is associated with the time it takes before the gel has an optimal consistency for further processing, and it is well known that gel formation differs between individual milk samples. By identifying genomic regions affecting traits related to rennet-induced gelation, the aim of this study was to identify potential candidate genes affecting these traits. Hence, rennet-induced gelation, including rennet coagulation time, gel strength, and yield stress, was measured in skim milk samples collected from 379 animals of the Swedish Red breed using low-amplitude oscillation measurements. All animals had genotypes for almost 621,000 segregating single nucleotide polymorphisms (SNP), identified using the Bovine HD SNPChip (Illumina Inc., San Diego, CA). The genome was scanned for associations, haplotypes based on SNP sets comprising highly associated SNP were inferred, and the effects of the 2 most common haplotypes within each region were analyzed using mixed models. Even though the number of animals was relatively small, a total of 21 regions were identified, with 4 regions showing association with more than one trait. A major quantitative trait locus for all traits was identified around the casein cluster explaining between 9.3 to 15.2% of the phenotypic variation of the different traits. In addition, 3 other possible candidate genes were identified; that is, UDP-N-acetyl-alpha-d galactosamine:polypeptide N-acetylgalactosaminyl-transferase 1 (GALNT1), playing a role in O-glycosylation of kappa-casein, and 2 cathepsins, CTSZ and CTSC, possibly involved in proteolysis of milk proteins. We have shown that other genes than the casein genes themselves may be involved in the regulation of gelation traits. However, additional analysis is needed to confirm these results. To our knowledge, this is the first study identifying quantitative trait loci affecting rennet-induced gelation of skim milk through a high-density genome-wide association study. PMID- 25497813 TI - Short communication: genetic parameters for fertility-related disorders in Norwegian Red. AB - Heritabilities and genetic correlations were estimated for the 4 most common fertility-related disorders in Norwegian Red: retained placenta, cystic ovaries, silent heat, and metritis. Data on 1,747,500 lactations from 780,114 cows calving from January 2001 through December 2011 were analyzed using multivariate threshold sire models to estimate variance components for the 4 disorders in the first 5 lactations. The traits were defined as binary within lactation (0=unaffected, 1=affected), and each fertility-related disorder was analyzed separately with the 5 lactations as correlated traits. The mean frequency of affected cows ranged from 0.5 to 1.7% for cystic ovaries, 0.7 to 1.1% for metritis, 1.3 to 3.4% for retained placenta, and 1.7 to 2.7% for silent heat. Posterior means (standard deviations) of heritability of liability ranged from 0.02 (0.01) to 0.12 (0.01), and were lowest for silent heat and highest for cystic ovaries. Genetic correlations across lactation within disorder were positive and moderate to high, ranging from 0.79 to 0.95 for cystic ovaries, 0.40 to 0.75 for metritis, 0.53 to 0.94 for retained placenta, and 0.39 to 0.83 for silent heat. PMID- 25497814 TI - Alterations in sheep peripheral blood mononuclear cell proliferation and cytokine release by polyunsaturated fatty acid supplementation in the diet under high ambient temperature. AB - The aim of this study was to investigate the effects of polyunsaturated fatty acid (PUFA) supplementation from different sources in the diet of dairy sheep under high ambient temperatures on ex vivo lymphocyte proliferation and inflammatory responses. The experiment was carried out during summer: 32 Comisana ewes were divided into 4 groups of 8. The FS group was supplemented with whole flaxseed, the AG group was supplemented with Ascophyllum nodosum, the FS+AG group was supplemented with a combination of flaxseed and A. nodosum. The fourth group (CON group) was a control and received a diet containing no supplement. The average maximum temperature was around 33 degrees C during wk 2 and 3, whereas the mean temperature never decreased below 26 degrees C. Following 15 d of treatment with respective diets, peripheral blood mononuclear cells (PBMC) from sheep who received a diet supplemented with A. nodosum had impaired cell proliferation responses and IL-6 production after mitogen stimulation compared with PBMC from FS+AG sheep. In addition, PBMC from AG sheep displayed impaired cell proliferation compared with cells from the CON group. The FS+AG cells produced lower levels of IL-10 than CON cells, and higher IL-6 than AG and CON cells. Results demonstrated that the supplementation with PUFA from different sources in a sheep's diet can influence their immunological responses under high ambient temperatures depending on the composition of fatty acid supplementation. In particular, synergistic effects of different PUFA from flaxseed and A. nodosum, simultaneously administrated in the sheep diet, were observed on activation of inflammation response. PMID- 25497815 TI - Genetic parameters of dairy cow energy intake and body energy status predicted using mid-infrared spectrometry of milk. AB - Energy balance (EB) and energy intake (EI) are heritable traits of economic importance. Despite this, neither trait is explicitly included in national dairy cow breeding goals due to a lack of routinely available data from which to compute reliable breeding values. Mid-infrared (MIR) spectrometry, which is performed during routine milk recording, is an accurate predictor of both EB and EI. The objective of this study was to estimate genetic parameters of EB and EI predicted using MIR spectrometry. Measured EI and EB were available for 1,102 Irish Holstein-Friesian cows based on actual feed intake and energy sink data. A subset of these data (1,270 test-day records) was used to develop equations to predict EI, EB, and daily change in body condition score (DeltaBCS) and body weight (DeltaBW) using the MIR spectrum with or without milk yield also as a predictor variable. Accuracy of cross-validation of the prediction equations was 0.75, 0.73, 0.77, and 0.70 for EI, EB, DeltaBCS, and DeltaBW, respectively. Prediction equations were applied to additional spectral data, yielding up to 94,653 records of MIR-predicted EI, EB, DeltaBCS, and DeltaBW available for variance component estimation. Variance components were estimated using repeatability animal linear mixed models. Heritabilities of MIR-predicted EI, EB, DeltaBCS, and DeltaBW were 0.20, 0.10, 0.07, and 0.06, respectively; heritability estimates of the respective measured traits were 0.35, 0.16, 0.07, and 0.08, respectively. The genetic correlation between measured and MIR-predicted EI was 0.84 and between measured and MIR-predicted EB was 0.54, indicating that selection based on MIR-predicted EI or EB would improve true EI or EB. Genetic and phenotypic associations between EI and both the milk production and body change traits were generally in agreement, regardless of whether measured EI or MIR-predicted EI was considered. Higher-yielding animals of higher body weight had greater EI. Predicted EB was negatively genetically correlated with milk yield (genetic correlation=-0.29) and positively genetically correlated with both milk fat and protein percent (genetic correlation=0.17 and 0.16, respectively). Least squares means phenotypic EI of 198 animals stratified as low, average, and high estimated breeding values for MIR-predicted EI (animal phenotypes were not included in the genetic evaluation) were 154.3, 156.0, and 163.3 MJ/d, corroborating that selection on MIR-predicted EI will, on average, result in differences in phenotypic true EI. PMID- 25497816 TI - The effect of hybrid type and dietary proportions of corn silage on the lactation performance of high-producing dairy cows. AB - We evaluated the effects of corn silage hybrids [control vs. brown midrib (BMR)] and the proportion of corn silage in rations on the performance of high-producing dairy cows. The chemical composition of the corn silages was similar except for lignin, which was higher in the control hybrid [3.09%, dry matter (DM) basis] compared with the BMR hybrid (2.19%). The 30-h in vitro neutral detergent fiber (NDF) digestibility was also higher (62.8% of NDF) in the BMR hybrid than in the control hybrid (52.2%). Twenty-seven Holstein cows were fed 1 of 3 diets comprising 62% forage and 38% concentrate (DM basis) containing 35% (DM basis) corn silage from the control hybrid (NLO), 35% of the BMR hybrid (BLO), or 50% of the BMR (BHI). Cows were fed the diets in a replicated 3*3 Latin square design with 28-d periods. Intake of DM was similar among treatments but milk production was greater for cows fed BLO (50.1kg/d) and BHI (51.1kg/d) than for NLO (47.9kg/d). Milk fat percentage was lower for cows fed BHI (3.37%) than for those fed BLO (3.55%) and NLO (3.56%) but yield of milk fat was similar among treatments. Yield and percentage of milk protein was higher for cows in BHI compared with NLO. The concentration of milk urea N was lower in cows fed BHI (14.0mg/dL) than in those fed NLO (14.7mg/dL) and intermediate for BLO (14.5mg/dL). The yield of 3.5% fat-corrected milk was higher in cows fed BLO (50.2kg/d) than in NLO (48.2kg/d) and was intermediate for BHI (49.8kg/d). The total-tract digestibility of dietary DM, organic matter, starch, and crude protein was lower for cows in NLO compared with the other treatments. The total tract digestibility of NDF was highest for BHI (54.4%), intermediate for BLO (50.9%), and lowest for NLO (43.2%). We conclude that BMR corn silage can be included in rations at moderate and high proportions of a total ration, resulting in high levels of milk production. PMID- 25497817 TI - Longitudinal study of the effects of teat condition on the risk of new intramammary infections in dairy cows. AB - Machine milking-induced alterations of teat tissue may impair local defense mechanisms and increase the risk of new intramammary infections. The objective of the current study was to assess the influence of short-term and long-term alterations of teat tissue and infectious status of the udder quarter on the risk of naturally occurring new intramammary infections, inflammatory responses, and mastitis. Short-term and long-term changes in teat condition of right udder quarters of 135 cows of a commercial dairy farm in Saxony-Anhalt, Germany, were recorded monthly for 10 mo using simple classification schemes. Quarter milk samples were collected from all examined quarters at each farm visit. Bacteriological culture results and somatic cell counts of quarter milk samples were used to determine new inflammatory responses (increase from <=100,000 cells/mL to >100,000 cells/mL between 2 samples), new infections (detection of a pathogen from a quarter that was free of the same pathogen at the preceding sampling), and new mastitis (combination of new inflammatory response and new infection). Separate Poisson mixed models for new inflammatory responses, new infections, and new mastitis caused by specific pathogens or groups of pathogens (contagious, environmental, major, minor, or any) were used to estimate risk ratios and 95% confidence intervals. Data preparation and parameter estimation were performed using the open source statistical analysis software R. We observed no effect of any variable describing teat condition on the risk of new intramammary infections, inflammatory responses, or mastitis. Intramammary infections of the same udder quarter in the preceding month did not affect risk either. PMID- 25497818 TI - The effect of digital dermatitis on hoof conformation. AB - Digital dermatitis (DD) is the most prevalent cause of lameness of infectious origin in cattle. However, little is known about the effects of DD on hoof conformation (HC) during the clinical disease. The objectives of the present study were to (1) evaluate the changes in HC observed in feet affected with clinical DD lesions and (2) investigate the temporal relationship between DD and heel horn erosion (HHE). A longitudinal study was carried out including a cohort of 644 Holstein heifers. Digital dermatitis, HC, and presence of HHE in the rear feet of each heifer were assessed during a period of 6 mo. A total of 1,979 feet evaluations were included in the data set, of which 157 corresponded to feet presenting DD lesions >20mm [mean (SD) size of 27.2 (8.2) mm]. Age, days of pregnancy, hip height, and girth circumference were also recorded at cow level. Significant HC changes were observed in DD-affected feet. Results standardized to a period of 90d of follow-up showed an increase in heel height [mean (95% CI) 3.4 (2.5, 4.4) and 2.8 (2.0, 3.7) mm] and claw angle [0.8 (0.2, 1.4) and 1.4 (0.7, 2.0) degrees] of the medial and lateral claws, respectively. In addition, an increase in depth of the interdigital cleft [3.2 (2.7, 3.7) mm] and on debris accumulation [14% (7, 21) of feet] was also observed. Feet affected with clinical DD lesions also experienced a 46% point increase in the presence of severe HHE. In the short term, HC changes returned to normal levels when clinical cure of DD was achieved after topical treatment. In conclusion, significant HC changes occur in heifers affected by clinical DD before lameness symptoms are detected. The transformation of the heel area in feet affected by DD likely promotes the creation of a local environment that favors the persistence of the disease and the occurrence of severe HHE. To avoid further hoof damage, active surveillance and early intervention to reduce HC changes are recommended to improve DD control programs. Successful restoration of HC can be achieved upon clinical cure of DD. The long-term effects in lifetime performance of the HC changes due to DD remain to be further investigated. PMID- 25497819 TI - Technical note: A portable on-chip assay system for absorbance and plasmonic detection of protein hormone in milk. AB - This paper reports a portable device and method to extract and detect protein hormone in milk samples. Recombinant protein hormone spiked into milk samples was extracted by solid-phase extraction, and detection was carried out using the plasmonic property of gold nanoislands deposited on a glass substrate. Trace levels of hormone spiked in milk were analyzed by their optical absorbance property using a microfluidic chip. We built a portable assay system using disposable lab-on-chip devices. The proposed method is able to detect spiked recombinant protein hormone in milk at concentrations as low as 5ng/mL. PMID- 25497820 TI - Effect of protein provision via milk replacer or solid feed on protein metabolism in veal calves. AB - The current study evaluated the effects of protein provision to calves fed a combination of solid feed (SF) and milk replacer (MR) at equal total N intake on urea recycling and N retention. Nitrogen balance traits and [(15)N2]urea kinetics were measured in 30 calves (23 wk of age, 180+/-3.7kg of body weight), after being exposed to the following experimental treatments for 11 wk: a low level of SF with a low N content (SF providing 12% of total N intake), a high level of SF with a low N content (SF providing 22% of total N intake), or a high level of SF with a high N content (SF providing 36% of total N intake). The SF mixture consisted of 50% concentrates, 25% corn silage, and 25% straw on a dry matter basis. Total N intake was equalized to 1.8g of N.kg of BW(-0.75).d(-1) by adjusting N intake via MR. All calves were housed individually on metabolic cages to allow for quantification of a N balance of calves for 5 d, and for the assessment of urea recycling from [(15)N2]urea kinetics. Increasing low-N SF intake at equal total N intake resulted in a shift from urinary to fecal N excretion but did not affect protein retention (0.71g of N.kg of BW(-0.75).d( 1)). Increasing low-N SF intake increased urea recycling but urea reused for anabolism remained unaffected. Total-tract neutral detergent fiber digestibility decreased (-9%) with increasing low-N SF intake, indicating reduced rumen fermentation. Increasing the N content of SF at equal total N intake resulted in decreased urea production, excretion, and return to ornithine cycle, and increased protein retention by 17%. This increase was likely related to an effect of energy availability on protein retention due to an increase in total-tract neutral detergent fiber digestion (>10%) and due to an increased energy supply via the MR. In conclusion, increasing low-N SF intake at the expense of N intake from MR, did not affect protein retention efficiency in calves. Increasing the N content of SF at equal total N intake decreased urea production, increased protein retention, and coincided with improved fiber degradation. Therefore, results suggest that low N availability in the rumen limits microbial growth and rumen fermentation in calves fed low-N SF (93g of CP/kg of DM), and this effect cannot be compensated for by recycling of urea originating from MR. PMID- 25497821 TI - Interaction between the physical form of the starter feed and straw provision on growth performance of Holstein calves. AB - Two experiments were conducted to assess the effect of physical form of a starter feed with or without straw supplementation on growth performance of Holstein calves. In experiment 1, a total of 32 calves were randomly assigned at 7 d of age to texturized starter feed (containing rolled barley, corn, and oats) without straw, texturized starter feed with chopped straw, and pelleted starter feed with chopped straw. All calves were offered 4 L of pasteurized whole milk twice daily from 7 to 35 d of age, 2 L of milk twice daily from 36 to 42 d of age, and 2 L of milk from 43 to 49 d of age. Animals were weaned at 50 d of age, and the study finished when calves were 63 d old. In experiment 2, a total of 60 calves (8 d of age) were randomly assigned to texturized starter feed (containing whole corn) without straw, pelleted starter feed without straw, and pelleted starter feed with chopped straw. All calves were offered the same milk replacer (MR; 23% crude protein and 19.5 fat) at 11% dry matter concentration, 4 L/d of MR until 14 d of age, 6 L/d of MR from 14 to 37 d, 3 L/d of MR from 38 to 44 d, and 1.5 L/d of MR from 45 to 52 d of age. The experiment finished when calves were 58 d old (1 wk after weaning). Rumen liquid pH was measured after weaning. In both studies, calves were individually housed in pens on sawdust bedding and starter feed and chopped straw were offered free choice in separate buckets. In experiment 1, starter feed and straw intake and growth did not differ among treatments. However, calves receiving straw showed a greater rumen pH compared with those not receiving straw. In experiment 2, pelleted started feed supplemented with straw fostered an increase in solid feed intake (as percentage of body weight) compared with a pelleted or texturized starter feed without straw supplementation. However, calves that received the texturized starter feed containing whole corn had rumen pH similar to those fed a pelleted starter feed with straw. Feeding a texturized starter feed containing rolled barley, corn, and oats (with or without straw provision) was not able to maintain rumen pH or promote growth and intake compared with offering a pelleted starter feed with chopped straw. However, when whole corn was used in the texturized starter feed, rumen pH was equivalent to that obtained with a pelleted starter feed and straw supplementation. PMID- 25497822 TI - Short communication: opposing effects of lactoferrin on the proliferation of fibroblasts and epithelial cells from bovine mammary gland. AB - Lactoferrin is present in several physiologic fluids, including milk and colostrum. Recently, evidence has accumulated that lactoferrin acts as a regulator of cell proliferation. Lactoferrin mRNA and protein levels in bovine mammary glands are known to markedly increase after cessation of milking. To clarify the role of bovine lactoferrin (bLF) in mammary involution and remodeling during dry periods, we investigated whether bLF affects the proliferation of cultured cells derived from bovine mammary gland and examined the mechanism underlying the proliferative response to bLF. Addition of bLF to the culture medium increased the proliferation of bovine mammary stromal fibroblasts (bMSF), but decreased that of bovine mammary epithelial cells (bMEC). Proliferation was significantly increased in the bMSF treated with bLF (100MUg/mL or greater) as compared with unstimulated cells. The maximal proliferative effect of bLF on bMSF occurred at 1,000MUg/mL, such that the proliferation of the bLF-stimulated bMSF was approximately 2.5 times that of unstimulated cells. The bLF increased the production of proliferating cell nuclear antigen and rapid phosphorylation of the p44/p42 mitogen-activated protein kinase in bMSF, but not in bMEC. The bLF induced proliferation and production of proliferating cell nuclear antigen in bMSF was suppressed by U0126, a specific inhibitor of mitogen-activated protein kinase. Furthermore, treatment with bLF for 24h decreased the mRNA levels of the 3 isoforms of transforming growth factor beta in bMSF (16-66%) but upregulated those in bMEC (122-157%). These opposite effects of bLF on the proliferation of epithelial and fibroblast cells and their expression of transforming growth factor beta may play a crucial role in bovine mammary involution and remodeling. PMID- 25497823 TI - Risk factors for subclinical and clinical ketosis and association with production parameters in dairy cows in the Netherlands. AB - Ketosis is associated with many transition cow diseases and the subclinical form has been found to be a common condition in high-producing dairy cows. The objectives of this field study in the Netherlands were (1) to determine risk factors for subclinical ketosis [SCK; 1.2-2.9mmol of beta-hydroxybutyrate (BHBA)/L of serum] and clinical ketosis (CK: >=3.0mmol of BHBA/L of serum) at 7 to 14 d in milk and (2) to assess the association of SCK and CK with production parameters at the first dairy herd improvement (DHI) testing. Twenty-three dairies were enrolled by a local veterinary practice from 2009 to 2010, and 1,715 cows were screened for ketosis by measuring serum BHBA concentrations at 7 to 14 d in milk. Overall, 47.2% of cows had SCK and 11.6% had CK. Mixed generalized logit models with a random effect of herd were used to evaluate cow level factors associated with SCK and CK. The associations of SCK and CK with milk production parameters were tested using mixed linear models with a random effect of herd. Cows at a moderate (3.25-3.75) or fat (>=4) body condition score before calving were more likely to develop SCK and CK than thin (body condition score<=3.0) cows. The risk for developing SCK was higher in parity 2 and older cows compared with heifers, whereas for CK only, parity >=3 cows had a higher risk. The quarter of the year in which a cow calved was associated with the risk for SCK and CK. For SCK quarter 1 (January-March) and quarter 2 (April-June), and for CK quarter 1, quarter 2, and quarter 3 (July-September) all increased the risk of development of the condition compared with quarter 4 (October-December). An increased yield of colostrum at first milking was associated with increasing risk for SCK and CK. Prolonged previous lactation length and dry period length were both associated with increased odds for SCK and CK. Subclinical ketosis and CK were associated with a higher milk yield, a higher milk fat percentage, and a lower milk protein percentage at first DHI test day. Overall the study reinforces previous findings that the major risk factors for both SCK and CK are increasing parity, overconditioning of animals prepartum, season of calving, and dry period length. In addition, previous lactation length and liters of colostrum have been identified as additional risk factors for the development of ketosis. PMID- 25497824 TI - Prevalence, characterization, and antimicrobial resistance of Yersinia species and Yersinia enterocolitica isolated from raw milk in farm bulk tanks. AB - The aims of this study were to investigate the prevalence and to characterize and determine the antibiotic resistance of Yersinia spp. isolates from raw milk. From September 2008 to August 2010, 446 raw milk samples were obtained from farm bulk milk tanks in Varamin, Iran. Yersinia spp. were detected in 29 (6.5%) samples, out of which 23 (79.3%), 5 (17.2%), and 1 (3.4%) were isolated from cow, sheep, and goat raw milk, respectively. The most common species isolated was Yersinia enterocolitica (65.5%), followed by Yersinia frederiksenii (31%), and Yersinia kristensenii (3.4%). Of the 19 Y. enterocolitica isolates, 14 (73.7%) were grouped into bioserotype 1A/O:9, 4 (21.1%) belonged to bioserotype 1B:O8, 1 (5.3%) belonged to bioserotype 4/O:3, and 1 isolate (biotype 1A) was not typable. All the isolates of biotypes 1B and 4harbored both the ystA and ail genes. However, all the isolates of biotype 1A were only positive for the ystB gene. The tested Yersinia spp. showed the highest percentages of resistance to tetracycline (48.3%), followed by ciprofloxacin and cephalothin (each 17.2%), ampicillin (13.8%), streptomycin (6.9%), and amoxicillin and nalidixic acid (each 3.4%). All of the tested isolates demonstrated significant sensitivity to gentamicin and chloramphenicol. Recovery of potentially pathogenic Y. enterocolitica from raw milk indicates high risks of yersiniosis associated with consumption of raw milk. PMID- 25497825 TI - Reduction of teat skin mastitis pathogen loads: differences between strains, dips, and contact times. AB - The purpose of these experiments was to (1) assess differences in mastitis pathogen strain sensitivities to teat disinfectants (teat dips), and (2) determine the optimum time for premilking teat dips to remain in contact with teat skin to reduce pathogen loads on teat skin. Two experiments were conducted using the excised teat model. In experiment 1, the differences in mastitis pathogen strain sensitivities to 4 commercially available dips (dip A: 1% H2O2; dip B: 1% chlorine dioxide; dip C: 1% iodophor; and dip D: 0.5% iodophor) were evaluated. Four strains of 11 common mastitis pathogens (Staphylococcus aureus, Streptococcus agalactiae, Mycoplasma bovis, Streptococcus dysgalactiae, Streptococcus uberis, Escherichia coli, Staphylococcus chromogenes, Staphylococcus epidermidis, Staphylococcus hyicus, Staphylococcus xylosus, and Staphylococcus haemolyticus) were tested. In experiment 2, the percentage log reduction of mastitis pathogens (Escherichia coli, Streptococcus uberis, Streptococcus dysgalactiae, Klebsiella species, Staphylococcus chromogenes, Staphylococcus haemolyticus, Staphylococcus xylosus, and Staphylococcus epidermidis) on teat skin with 3 commercially available teat dips: dip A; dip D; and dip E: 0.25% iodophor, using dip contact times of 15, 30, and 45 s, was evaluated. Experiment 1 results indicated significant differences in strain sensitivities to dips within pathogen species: Staphylococcus aureus, Staphylococcus chromogenes, and Streptococcus uberis. Species differences were also found where Mycoplasma bovis (97.9% log reduction) was the most sensitive to tested teat dips and Staphylococcus haemolyticus (71.4% log reduction) the most resistant. Experiment 2 results indicated that contact times of 30 and 45 s were equally effective in reducing recovered bacteria for dips D and E and were also significantly more effective than a 15-s contact time. No differences were seen in recovered bacteria between tested contact times after treatment with dip A. It can be concluded that different mastitis pathogen species and strains within species may possess different sensitivities to teat dips, which may have implications in selection of teat dips on dairies. Furthermore, a 30-s premilking dip contact time for iodophors and 15 s for H2O2 dips may be optimal in reducing pathogen load in the shortest amount of time. A reduction in premilking teat dip contact time may improve milking parlor efficiency. PMID- 25497826 TI - Genome-wide association study for claw disorders and trimming status in dairy cattle. AB - Performing a genome-wide association study (GWAS) might add to a better understanding of the development of claw disorders and the need for trimming. Therefore, the aim of the current study was to perform a GWAS on claw disorders and trimming status and to validate the results for claw disorders based on an independent data set. Data consisted of 20,474 cows with phenotypes for claw disorders and 50,238 cows with phenotypes for trimming status. Recorded claw disorders used in the current study were double sole (DS), interdigital hyperplasia (IH), sole hemorrhage (SH), sole ulcer (SU), white line separation (WLS), a combination of infectious claw disorders consisting of (inter-)digital dermatitis and heel erosion, and a combination of laminitis-related claw disorders (DS, SH, SU, and WLS). Of the cows with phenotypes for claw disorders, 1,771 cows were genotyped and these cow data were used for the GWAS on claw disorders. A SNP was considered significant when the false discovery rate<=0.05 and suggestive when the false discovery rate<=0.20. An independent data set of 185 genotyped bulls having at least 5 daughters with phenotypes (6,824 daughters in total) for claw disorders was used to validate significant and suggestive SNP detected based on the cow data. To analyze the trait "trimming status" (i.e., the need for claw trimming), a data set with 327 genotyped bulls having at least 5 daughters with phenotypes (18,525 daughters in total) was used. Based on the cow data, in total 10 significant and 45 suggestive SNP were detected for claw disorders. The 10 significant SNP were associated with SU, and mainly located on BTA8. The suggestive SNP were associated with DS, IH, SU, and laminitis-related claw disorders. Three of the suggestive SNP were validated in the data set of 185 bulls, and were located on BTA13, BTA14, and BTA17. For infectious claw disorders, SH, and WLS, no significant or suggestive SNP associations were detected. For trimming status, 1 significant and 1 suggestive SNP were detected, both located close to each other on BTA15. Some significant and suggestive SNP were located close to SNP detected in studies on feet and leg conformation traits. Genes with major effects could not be detected and SNP associations were spread across the genome, indicating that many SNP, each explaining a small proportion of the genetic variance, influence claw disorders. Therefore, to reduce the incidence of claw disorders by breeding, genomic selection is a promising approach. PMID- 25497827 TI - Dairy cow preference and usage of an alternative freestall design. AB - Freestall housing for dairy cows was created to reduce the amount of bedding and labor needed to keep stalls clean. However, some aspects of stall design may restrict stall usage by cows. The aim of this study was to assess dairy cow preference and usage of a conventional stall (with a neck rail and metal stall dividers) and an alternative stall design with no neck rail or stall dividers other than a wooden board protruding slightly (8cm) above the lying surface. In the no-choice phase of the study, 48 cows were randomly assigned to 8 groups (of 6 cows each); groups were alternately allocated to the 2 treatments. Each group was observed for 7 d on one treatment and then switched to the alternate treatment for 7 d. For the choice phase (also 7 d), groups in adjacent pens were merged (to form 4 groups, each with 12 cows) and cows had free access to both treatments within the merged pen. In the no-choice phase, cows spent more time standing with 4 hooves in the alternative versus conventional freestall (0.60+/ 0.06 vs. 0.05+/-0.06h/d), but stall designs had no effect on time spent lying down (13.2+/-0.4 vs. 12.9+/-0.4h/d). In the choice phase, cows spent more time lying down in the conventional freestall (9.4+/-0.8 vs. 4.1+/-0.8h/d) and more time standing with all 4 hooves in the alternative stall (0.24+/-0.03 vs. 0.02+/ 0.03h/d). These results illustrate how different stall design features can affect different types of stall use; the more open design facilitated standing fully in the stall, but the protruding partitions likely made the stall less suitable for lying. PMID- 25497828 TI - Gas release-based prescreening combined with reversed-phase HPLC quantitation for efficient selection of high-gamma-aminobutyric acid (GABA)-producing lactic acid bacteria. AB - High gamma-aminobutyric acid (GABA)-producing lactobacilli are promising for the manufacture of GABA-rich foods and to synthesize GRAS (generally recognized as safe)-grade GABA. However, common chromatography-based screening is time consuming and inefficient. In the present study, Korean kimchi was used as a model of lactic acid-based fermented foods, and a gas release-based prescreening of potential GABA producers was developed. The ability to produce GABA by potential GABA producers in de Man, Rogosa, and Sharpe medium supplemented with or without monosodium glutamate was further determined by HPLC. Based on the results, 9 isolates were regarded as high GABA producers, and were further genetically identified as Lactobacillus brevis based on the sequences of 16S rRNA gene. Gas release-based prescreening combined with reversed-phase HPLC confirmation was an efficient and cost-effective method to identify high-GABA producing LAB, which could be good candidates for probiotics. The GABA that is naturally produced by these high-GABA-producing LAB could be used as a food additive. PMID- 25497829 TI - Depressive symptomatology in severe dementia in a European sample: prevalence, associated factors and prescription rate of antidepressants. AB - BACKGROUND: Depression is a common comorbid disorder of dementia. This study explores the prevalence of and factors associated with depressive symptomatology, and antidepressant prescription rates in severe dementia across eight European countries. METHODS: In total, 414 people with severe dementia completed measures of cognition and quality of life (QoL), whilst carers completed proxy measures of activities of daily living (ADLs), depression, neuropsychiatric symptoms, QoL and comorbidity. RESULTS: Findings indicated that 30% of the sample had depression, whilst the highest and lowest prevalence of depression was reported in Germany and Finland, respectively. Lower QoL, the presence of pain and more frequent neuropsychiatric symptoms were associated with depressive symptomatology, whilst no significant relationship between impairment of ADLs, comorbidity, and depression emerged. Spain and Estonia had the highest and lowest rates of antidepressant prescribing, respectively, whilst Germany had the highest discrepancy between depressive symptomatology and prescription. CONCLUSIONS: The study highlights variations across countries in the prevalence of depressive symptomatology in severe dementia and prescription of antidepressants. Information about factors associated with depressive symptomatology may help to better identify and manage depression. PMID- 25497830 TI - Diminishing returns in next-generation sequencing (NGS) transcriptome data. AB - RNA-seq is increasingly used to study gene expression of various organisms. While it provides a great opportunity to explore genome-scale transcriptional patterns with tremendous depth, it comes with prohibitive costs. Establishing a minimal sequencing depth for required accuracy will guide cost-effective experimental design and promote the routine application of RNA-seq. To address this issue, we selected 36 RNA-seq datasets, each with more than 20 million reads from six widely-used model organisms: Saccharomyces cerevisiae, Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans, Mus musculus, and Arabidopsis thaliana, and investigated statistical correlations between the sequencing depth and the outcome accuracy. To achieve this, we randomly chose reads from each dataset, mapped them to the reference genomes, and analyzed the accuracy achieved with varying coverage. Our results indicated that as low as one million reads can provide the same sequencing accuracy in transcript abundance (r=0.99) as >30 million reads for highly-expressed genes in all six species. Because many metabolically and pathologically-relevant genes are highly expressed, our findings might be instructive for cost-effective experimental designs in NGS based research and also provide useful guidance to similar research for other organisms. PMID- 25497831 TI - Low molecular weight heparin may prevent acute lung injury induced by sepsis in rats. AB - The purpose of this study was to assess the protective effect of low molecular weight heparin (LMWH) on acute lung injury (ALI) in rats induced by sepsis. Rat ALI model was reproduced by cecal ligation and puncture (CLP). All rats were randomly divided into three groups (n=50): control group (A), ALI group (B), and LMWH-treated group (C). Group A received a sham operation and the other groups underwent CLP operation. Groups A and B accepted intraperitoneal injection (i.p.) of normal saline (NS) at a dose of 2.0 ml kg(-1) and ceftriaxone (30 mg kg(-1)), group C was intraperitoneally injected with additional LMWH (150 U kg(-1)) except saline and ceftriaxone. Blood was collected and lung tissue was harvested at the designated time points for analysis. The lung specimens were harvested for morphological studies, immunohistochemistry examination. Lung tissue edema was evaluated by tissue water content. The levels of lung tissue myeloperoxidase (MPO) were determined. Meanwhile, the nuclear factor-kappa B (NF-kappaB) activation, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) levels, high mobility group box 1 (HMGB1) and intercellular adhesion molecule-1 (ICAM-1) protein levels in the lung were studied. There was a significant difference in each index between groups A and B (P<0.05). Treatment with LMWH significantly decreased the expression of TNF-alpha, IL-1beta, HMGB1 and ICAM-1 in the lungs of ALI rats. Similarly, treatment with LMWH dramatically diminished sepsis-induced neutrophil sequestration and markedly reduced the enhanced lung permeability. In the present study, LMWH administration inhibited the nuclear translocation of NF-kappaB in the lungs. These data suggest that LMWH attenuates inflammation and ameliorates lung pathology in CLP-induced sepsis in a rat model. PMID- 25497832 TI - Three unsaturated fatty acid biosynthesis-related genes in yellow catfish Pelteobagrus fulvidraco: Molecular characterization, tissue expression and transcriptional regulation by leptin. AB - Three key genes, stearoyl-CoA desaturase-1 (SCD1), Delta6 fatty acyl desaturases (Fads2 (Delta6)) and elongase of very long-chain fatty acid 5 (ELOVL5) were firstly isolated and characterized from yellow catfish, Pelteobagrus fulvidraco. The protein sequence of yellow catfish SCD1 and Fads2 (Delta6) possessed all the characteristics of microsomal fatty acid Fads2 (Delta6), including three histidine boxes, two transmembrane regions and one N-terminal cytochrome b5 domain containing heme-binding motif. The protein sequence of yellow catfish ELOVL5 possessed characteristic features of ELOVL5, including multiple transmembrane regions, endoplasmic reticulum retention signal and a single histidine box. mRNAs of the three genes were expressed in various tissues, but their mRNA levels varied among tissues. Intraperitoneal injection of recombinant human leptin (rb-hLEP) inhibited mRNA expression of SCD1, but not Fads2 (Delta6) and ELOVL5. For the first time, our study cloned SCD1, Fads2 (Delta6) and ELOVL5 genes in Siluriformes and demonstrated their differential expression among tissues, and also differential regulation by leptin, which serves to increase our understanding on their physiological function in fish. PMID- 25497833 TI - Analysis of synonymous codon usage pattern in duck circovirus. AB - Duck circovirus (DuCV) disease causes a long-term immunosuppressive and multiple secondary infection in ducks. In this study, relative synonymous codon usage (RSCU) values, nucleotide contents and effective number of codon (ENC) values were calculated and compared among open reading frames (ORFs) of 53 DuCV genomes. The results reveal that most of the codons are ended with C and the overall bias is not remarkable in DuCV. A comparative analysis of codon contents and ENC values indicates that mutation pressure is the most significant factor responsible for the evolutional processes of codon usage bias in DuCV. However, other factors, such as composition constraints, translation selection, hydrophobicity and aromaticity should not be ignored. Finally principal component analysis (PCA) and hierarchical clustering method were performed based on RSCU. The significant difference of codon usage bias exists in DuCV-1 and DuCV-2 genotypes, but codon usage pattern of DuCV from the different epidemic areas or subtypes fails to influence the formation of codon usage bias. Analysis of the relationship of synonymous codon usage variation based on the two genotypes suggests that DuCV-2 is more conservative than DuCV-1, which may because of recombination events. Moreover, there are distinct differences in the degree of codon usage pattern evolution in different function genes, rep and cap. Therefore, the genotypes, subtypes and different functional genes also relate to the pattern of synonymous codon usage. The main objective of this study is to provide some sight into synonymous codon usage characteristics and the evolutionary relationship of DuCV. PMID- 25497834 TI - A comparative analysis of LEF-1 in odontogenic and salivary tumors. AB - LEF-1 is a nuclear transcription factor of the Wnt pathway that regulates multipotent skin stem cell differentiation. beta-Catenin is considered a transcriptional coactivator that interacts with LEF-1.This study evaluates LEF-1 in a variety of odontogenic and salivary tumors and determines the prevalence of beta-catenin coexpression. Ninety-eight salivary gland tumors and 51 odontogenic tumors were evaluated for LEF-1 and beta-catenin immunohistochemical staining. Positivity was defined as at least 2+ intensity in more than 50% of tumor cells, which required a composite score of 6 or more. LEF-1 was positive in 64% (7/11) of calcifying cystic odontogenic tumors (CCOT). Nuclear beta-catenin was present in 82% (9/11) of CCOT. Coexpression of LEF-1 and nuclear beta-catenin was noted in all LEF-1-positive CCOT. Strong and diffuse LEF-1 expression was seen in 69% (11/16) of basal cell adenocarcinomas (BCAC) and 63% (5/8) of basal cell adenomas (BA). Nuclear beta-catenin was present in 50% (4/8) of BA and 43% (6/14) of BCAC. For BA, 4 of 5 LEF-1-positive tumors showed coexpression of beta-catenin, and for BCAC, 5 of 9 LEF-1-positive tumors showed coexpression. In conclusion, this study documents for the first time the presence of LEF-1 expression and nuclear beta catenin coexpression in select basaloid salivary gland tumors and various odontogenic tumors. We demonstrate LEF-1 expression in both BA and BCAC preferentially over other salivary gland tumors suggesting some utility as a diagnostic marker. PMID- 25497835 TI - A neural circuit mechanism for regulating vocal variability during song learning in zebra finches. AB - Motor skill learning is characterized by improved performance and reduced motor variability. The neural mechanisms that couple skill level and variability, however, are not known. The zebra finch, a songbird, presents a unique opportunity to address this question because production of learned song and induction of vocal variability are instantiated in distinct circuits that converge on a motor cortex analogue controlling vocal output. To probe the interplay between learning and variability, we made intracellular recordings from neurons in this area, characterizing how their inputs from the functionally distinct pathways change throughout song development. We found that inputs that drive stereotyped song-patterns are strengthened and pruned, while inputs that induce variability remain unchanged. A simple network model showed that strengthening and pruning of action-specific connections reduces the sensitivity of motor control circuits to variable input and neural 'noise'. This identifies a simple and general mechanism for learning-related regulation of motor variability. PMID- 25497837 TI - Enhanced homology-directed human genome engineering by controlled timing of CRISPR/Cas9 delivery. AB - The CRISPR/Cas9 system is a robust genome editing technology that works in human cells, animals and plants based on the RNA-programmed DNA cleaving activity of the Cas9 enzyme. Building on previous work (Jinek et al., 2013), we show here that new genetic information can be introduced site-specifically and with high efficiency by homology-directed repair (HDR) of Cas9-induced site-specific double strand DNA breaks using timed delivery of Cas9-guide RNA ribonucleoprotein (RNP) complexes. Cas9 RNP-mediated HDR in HEK293T, human primary neonatal fibroblast and human embryonic stem cells was increased dramatically relative to experiments in unsynchronized cells, with rates of HDR up to 38% observed in HEK293T cells. Sequencing of on- and potential off-target sites showed that editing occurred with high fidelity, while cell mortality was minimized. This approach provides a simple and highly effective strategy for enhancing site-specific genome engineering in both transformed and primary human cells. PMID- 25497836 TI - Heterochromatin assembly and transcriptome repression by Set1 in coordination with a class II histone deacetylase. AB - Histone modifiers play essential roles in controlling transcription and organizing eukaryotic genomes into functional domains. Here, we show that Set1, the catalytic subunit of the highly conserved Set1C/COMPASS complex responsible for histone H3K4 methylation (H3K4me), behaves as a repressor of the transcriptome largely independent of Set1C and H3K4me in the fission yeast Schizosaccharomyces pombe. Intriguingly, while Set1 is enriched at highly expressed and repressed loci, Set1 binding levels do not generally correlate with the levels of transcription. We show that Set1 is recruited by the ATF/CREB homolog Atf1 to heterochromatic loci and promoters of stress-response genes. Moreover, we demonstrate that Set1 coordinates with the class II histone deacetylase Clr3 in heterochromatin assembly at prominent chromosomal landmarks and repression of the transcriptome that includes Tf2 retrotransposons, noncoding RNAs, and regulators of development and stress-responses. Our study delineates a molecular framework for elucidating the functional links between transcriptome control and chromatin organization. PMID- 25497838 TI - Individualized long-term outcomes in blood phenylalanine concentrations and dietary phenylalanine tolerance in 11 patients with primary phenylalanine hydroxylase (PAH) deficiency treated with Sapropterin-dihydrochloride. AB - We analyzed long-term sustainability of improved blood Phenylalanine (Phe) control and changes to dietary Phe tolerance in 11 patients (1 month to 16 years), with various forms of primary PAH deficiency (classic, moderate, severe phenylketonuria [PKU], mild hyperphenylalaninemia [HPA]), who were treated with 15-20mg/kg/d Sapropterin-dihydrochloride during a period of 13-44 months. 7/11 patients had a sustainable, significant reduction of baseline blood Phe concentrations and 6 of them also had an increase in mg/kg/day Phe tolerance. In 2 patients with mild HPA, blood Phe concentrations remained in the physiologic range even after a 22 and 36% increase in mg/kg/day Phe tolerance and an achieved Phe intake at 105% and 268% of the dietary reference intake (DRI) for protein. 2 of these responders had classic PKU. 1 patient with mild HPA who started treatment at 2 months of life, had a significant and sustainable reduction in pretreatment blood Phe concentrations, but no increase in the mg/kg/day Phe tolerance. An increase in Phe tolerance could only be demonstrated when expressing the patient's daily Phe tolerance with the DRI for protein showing an increase from 58% at baseline to 78% of normal DRI at the end of the observation. Long-term follow-up of patients with an initial response to treatment with Sapropterin is essential to determine clinically meaningful outcomes. Phenylalanine tolerance should be expressed in mg/kg/day and/or % of normal DRI to differentiate medical therapy related from physiologic growth related increase in daily Phe intake. PMID- 25497840 TI - Non surgical treatment of vestibular schwannoma. AB - INTRODUCTION AND OBJECTIVES: To evaluate the results of local control and complications in the treatment of vestibular schwannoma treated with radiation. METHODS: A retrospective study of 194 patients diagnosed with vestibular schwannoma, treated consecutively with radiation (either stereotactic radiosurgery or fractionated radiotherapy) from 1997 to 2012. We analyze the local control of tumors, as well as secondary complications to treatment with radiation. RESULTS: A total of 132 (68%) tumors 68% are grade I-II tumors of the Koos classification, 40 (19%) are grade III, and 22 (13%) are grade IV. The tumors associated with neurofibromatosis (NF2), are 3.6% (6 tumors in 4 patients). The tumor control for the overall serie is 97% at 5 years, with a median follow-up of 80.4 months. For large tumors the local control is 91% at 5 years. Free survival of chronic complications is 89% at 5 years. Additionally, 50 tumors were subjected to regular follow-up with MRI without treatment, and 28 (58%) did not experienced tumor growth. CONCLUSIONS: Radiation and follow up with MRI, are an alternative to surgery in the treatment of vestibular schwannoma, with a low level of complications inside of multidisciplinary approach. PMID- 25497839 TI - Enhanced expression of FNDC5 in human embryonic stem cell-derived neural cells along with relevant embryonic neural tissues. AB - Availability of human embryonic stem cells (hESCs) has enhanced the capability of basic and clinical research in the context of human neural differentiation. Derivation of neural progenitor (NP) cells from hESCs facilitates the process of human embryonic development through the generation of neuronal subtypes. We have recently indicated that fibronectin type III domain containing 5 protein (FNDC5) expression is required for appropriate neural differentiation of mouse embryonic stem cells (mESCs). Bioinformatics analyses have shown the presence of three isoforms for human FNDC5 mRNA. To differentiate which isoform of FNDC5 is involved in the process of human neural differentiation, we have used hESCs as an in vitro model for neural differentiation by retinoic acid (RA) induction. The hESC line, Royan H5, was differentiated into a neural lineage in defined adherent culture treated by RA and basic fibroblast growth factor (bFGF). We collected all cell types that included hESCs, rosette structures, and neural cells in an attempt to assess the expression of FNDC5 isoforms. There was a contiguous increase in all three FNDC5 isoforms during the neural differentiation process. Furthermore, the highest level of expression of the isoforms was significantly observed in neural cells compared to hESCs and the rosette structures known as neural precursor cells (NPCs). High expression levels of FNDC5 in human fetal brain and spinal cord tissues have suggested the involvement of this gene in neural tube development. Additional research is necessary to determine the major function of FDNC5 in this process. PMID- 25497841 TI - All that wheezes is not asthma! A case of cavitatory pediatric tuberculosis. PMID- 25497842 TI - Gender differences in perceptions and self-reported driving behaviors among teenagers. AB - BACKGROUND: The Centers for Disease Control reports that motor vehicle crashes (MVCs) are the leading cause of injury and death among U.S. teenagers, and disproportionately affect males. Among preventable causes of MVCs involving teenage drivers, distracted driving continues to be a serious public health problem. OBJECTIVES: To describe gender differences in teenage drivers' self perceptions of safe driving behaviors, and self-reported risk behaviors and distractions while driving. METHODS: We prospectively surveyed teenage drivers from four high schools in Pennsylvania and New Jersey. Gender comparisons were made between self-reported perceptions and self-reported driving behaviors. Descriptive statistics and chi-squared testing were used in data analyses; significance was set at p < 0.05. RESULTS: Seven hundred fifty-six high school teenage drivers completed surveys. Males (52%) and females (48%) were equally distributed; 32% of males reported that they were extremely safe drivers, whereas only 18% of females reported that they were extremely safe drivers (p < 0.001). Significantly more females (91%) compared to males (77%) reported always wearing their seatbelts (p < 0.001). Female drivers were more likely than male drivers to self-report that they always make their passengers wear a seat belt (76% vs. 63%, p < 0.001). A higher proportion of males reported using their cell phones while driving, compared to females (68% vs. 56%, p = 0.004), and 42% of males reported texting while driving, compared to 34% of females (p = 0.037). CONCLUSION: Teenage male drivers perceive themselves to be safe drivers, but report engaging in more distracted driving and risky behaviors compared to females. These results suggest that there is an opportunity for gender-specific educational and injury prevention programs for teen drivers. PMID- 25497843 TI - An alternative explanation for abnormal globe contour. PMID- 25497844 TI - Preventing suicide in the emergency department. PMID- 25497845 TI - Successful flumazenil reversal of paradoxical reaction to midazolam in a child. AB - BACKGROUND: Greater attention to and management of anxiety and pain in pediatric patients signifies a healthy evolution in the care of children in emergency departments (EDs). Interventions to address such distress may involve unanticipated adverse effects. Midazolam, a benzodiazepine commonly administered to children for anxiolysis, may precipitate paradoxical agitation and delirium, a rare but alarming effect that warrants prompt identification and treatment. CASE REPORT: The case presented is that of a 4-year-old girl who received oral midazolam and developed a paradoxical reaction, which was reversed successfully with flumazenil. This is the first such case report in an ED involving a child. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians must stay abreast of the adverse and unintended effects of the treatments provided. The literature on benzodiazepine-induced paradoxical reactions is reviewed, and flumazenil as well as other treatment options and anxiolytic alternatives are presented. PMID- 25497846 TI - Composite-180 degrees pulse-based symmetry sequences to recouple proton chemical shift anisotropy tensors under ultrafast MAS solid-state NMR spectroscopy. AB - There is considerable interest in the measurement of proton ((1)H) chemical shift anisotropy (CSA) tensors to obtain deeper insights into H-bonding interactions which find numerous applications in chemical and biological systems. However, the presence of strong (1)H/(1)H dipolar interaction makes it difficult to determine small size (1)H CSAs from the homogeneously broadened NMR spectra. Previously reported pulse sequences for (1)H CSA recoupling are prone to the effects of radio frequency field (B1) inhomogeneity. In the present work we have carried out a systematic study using both numerical and experimental approaches to evaluate gamma-encoded radio frequency (RF) pulse sequences based on R-symmetries that recouple (1)H CSA in the indirect dimension of a 2D (1)H/(1)H anisotropic/isotropic chemical shift correlation experiment under ultrafast magic angle spinning (MAS) frequencies. The spectral resolution and sensitivity can be significantly improved in both frequency dimensions of the 2D (1)H/(1)H correlation spectrum without decoupling (1)H/(1)H dipolar couplings but by using ultrafast MAS rates up to 70 kHz. We successfully demonstrate that with a reasonable RF field requirement (<200 kHz) a set of symmetry-based recoupling sequences, with a series of phase-alternating 270 degrees 0-90 degrees 180 composite-180 degrees pulses, are more robust in combating B1 inhomogeneity effects. In addition, our results show that the new pulse sequences render remarkable (1)H CSA recoupling efficiency and undistorted CSA lineshapes. Experimental results on citric acid and malonic acid comparing the efficiencies of these newly developed pulse sequences with that of previously reported CSA recoupling pulse sequences are also reported under ultrafast MAS conditions. PMID- 25497847 TI - Accelerated hyperfractionated intensity-modulated radiotherapy for recurrent/unresectable rectal cancer in patients with previous pelvic irradiation: results of a phase II study. AB - BACKGROUND: This study was conducted to investigate the local effects and toxicity of accelerated hyperfractionated intensity-modulated radiotherapy for recurrent/unresectable rectal cancer in patients with previous pelvic irradiation. METHODS: Twenty-two patients with recurrent/unresectable rectal cancer who previously received pelvic irradiation were enrolled in our single center trial between January 2007 and August 2012. Reirradiation was scheduled for up to 39 Gy in 30 fractions using intensity-modulated radiotherapy plans. The dose was delivered via a hyperfractionation schedule of 1.3 Gy twice daily. Patient follow-up was performed by clinical examination, CT/MRI, or PET/CT every 3 months for the first 2 years and every 6 months thereafter. Tumor response was evaluated 1 month after reirradiation by CT/MRI based on the RECIST criteria. Adverse events were assessed using the National Cancer Institute (NCI) common toxicity criteria (version 3.0). RESULTS: The median time from the end of the initial radiation therapy to reirradiation was 30 months (range, 18-93 months). Overall local responses were observed in 9 patients (40.9%). None of the patients achieved a complete response (CR), and 9 patients (40.9%) had a partial response (PR). Thirteen patients failed to achieve a clinical response: 12 (54.5%) presented with stable disease (SD) and 1 (4.5%) with progressive disease (PD). Among all the patients who underwent reirradiation, partial or complete symptomatic relief was achieved in 6 patients (27.3%) and 13 patients (59.1%), respectively. Grade 4 acute toxicity and treatment-related deaths were not observed. The following grade 3 acute toxicities were observed: diarrhea (2 patients, 9.1%), cystitis (1 patient, 4.5%), dermatitis (1 patient, 4.5%), and intestinal obstruction (1 patient, 4.5%). Late toxicity was infrequent. Chronic severe diarrhea, small bowel obstruction, and dysuria were observed in 2 (9.1%), 1 (4.5%) and 2 (9.1%) of the patients, respectively. CONCLUSIONS: This study showed that accelerated hyperfractionated intensity-modulated radiotherapy significantly relieved local symptoms and led to a promising local response with an acceptable toxicity profile in patients with recurrent/unresectable rectal cancer and previous pelvic irradiation. Innovative treatment regimens should be evaluated in future studies to improve the clinical outcome while avoiding excessive toxicity in patients with recurrent rectal cancer and previous pelvic irradiation. PMID- 25497848 TI - Let us do it ourselves. PMID- 25497849 TI - Cortical inhibition effect in musicians and non-musicians using P300 with and without contralateral stimulation. AB - INTRODUCTION: Musicians have more robust and efficient neural responses in the cortical and sub-cortical regions, demonstrating that musical experience benefits the processing of both non-linguistic and linguistic stimuli. OBJECTIVE: This study aimed to verify P300's latency and amplitude behavioral using contralateral stimulation in musicians and non-musicians. METHODS: This was a case-control study. Subjects were divided in two groups: musicians, comprising 30 professional musicians, and non-musicians, comprising 25 subjects without musical experience. RESULTS: The present study showed that the musicians had lower latencies and higher amplitudes than the non-musicians in the P300 without contralateral noise. For the P300 amplitude values, the difference between groups persisted, and the musicians presented significantly higher amplitude values compared with the non musicians; additionally, the analysis of the noise effect on the P300 response showed that the latency values were significantly increased in the musicians. CONCLUSION: The central auditory nervous system of musicians presents peculiar characteristics of electrophysiological responses probably due to the plasticity imposed by musical practice. PMID- 25497850 TI - Scales of degree of facial paralysis: analysis of agreement. AB - INTRODUCTION: It has become common to use scales to measure the degree of involvement of facial paralysis in phonoaudiological clinics. OBJECTIVE: To analyze the inter- and intra-rater agreement of the scales of degree of facial paralysis and to elicit point of view of the appraisers regarding their use. METHODS: Cross-sectional observational clinical study of the Chevalier and House & Brackmann scales performed by five speech therapists with clinical experience, who analyzed the facial expression of 30 adult subjects with impaired facial movements two times, with a one week interval between evaluations. The kappa analysis was employed. RESULTS: There was excellent inter-rater agreement for both scales (kappa>0.80), and on the Chevalier scale a substantial intra-rater agreement in the first assessment (kappa=0.792) and an excellent agreement in the second assessment (kappa=0.928). The House & Brackmann scale showed excellent agreement at both assessments (kappa=0.850 and 0.857). As for the appraisers' point of view, one appraiser thought prior training is necessary for the Chevalier scale and, four appraisers felt that training is important for the House & Brackmann scale. CONCLUSION: Both scales have good inter- and intra-rater agreement and most of the appraisers agree on the ease and relevance of the application of these scales. PMID- 25497851 TI - Vestibular disorders in the elderly. PMID- 25497852 TI - Cephalometric and anthropometric data of obstructive apnea in different age groups. AB - INTRODUCTION: Patients with obstructive sleep apnea syndrome usually present with changes in upper airway morphology and/or body fat distribution, which may occur throughout life and increase the severity of obstructive sleep apnea syndrome with age. OBJECTIVE: To correlate cephalometric and anthropometric measures with obstructive sleep apnea syndrome severity in different age groups. METHODS: A retrospective study of cephalometric and anthropometric measures of 102 patients with obstructive sleep apnea syndrome was analyzed. Patients were divided into three age groups (>=20 and <40 years, >=40 and <60 years, and >=60 years). Pearson's correlation was performed for these measures with the apnea-hypopnea index in the full sample, and subsequently by age group. RESULTS: The cephalometric measures MP-H (distance between the mandibular plane and the hyoid bone) and PNS-P (distance between the posterior nasal spine and the tip of the soft palate) and the neck and waist circumferences showed a statistically significant correlation with apnea-hypopnea index in both the full sample and in the >=40 and <60 years age group. These variables did not show any significant correlation with the other two age groups (<40 and >=60 years). CONCLUSION: Cephalometric measurements MP-H and PNS-P and cervical and waist circumferences correlated with obstructive sleep apnea syndrome severity in patients in the >=40 and <60 age group. PMID- 25497853 TI - Changing cycles: the necessary rupture to achieve excellence. PMID- 25497854 TI - Giant osteoma of the mandible. PMID- 25497855 TI - [Endometriosis and obstetrical complications]. AB - Approximately 5-10% of the women in the reproductive age are afflicted with endometriosis and many become pregnant after fertility treatment. Women with endometriosis seem to have an increased risk of placental complications, bleeding in pregnancy and during labour as well as possible increased risk of pre eclampsia, preterm birth and low birthweight. Large epidemiological studies are needed to clarify the magnitude of these risks in order to define the appropriate level of proactive management of pregnant women with endometriosis. PMID- 25497856 TI - [The Lazarus phenomenon]. AB - The pathophysiological mechanisms of auto resuscitation - also called the Lazarus phenomenon - are unknown, but they are thought to be related to matters such as hyperkalaemia, hyperventilation and alkalosis or increased end-expiratory pressure during assisted ventilation. The phenomenon is probably underreported and this case report of the Lazarus phenomenon in a patient with severe hyperkalaemia demonstrates the necessity of following recommendations regarding resuscitation such as allowing pauses in assisted ventilation as well as ten minutes post resuscitation monitoring before declaring the patient dead. PMID- 25497857 TI - [360-degree feedback for medical trainees]. AB - In 360-degree feedback medical colleagues and collaborators give a trainee feedback by answering a questionnaire on behaviour of the trainee. The questionnaire may contain questions answered on a scale or/and they may contain open questions. The result from 360-degree feedback is used for formative feedback and assessment. In order to secure reliability 8-15 respondents are needed. It is a matter of discussion whether the respondents should be chosen by the trainee or by a third part, and if respondents should be anonymous. The process includes a feedback session with a trained supervisor. PMID- 25497858 TI - [Obese asthma patients have poorer asthma control]. AB - Current literature indicates that asthma is more prevalent among obese individuals. In addition, studies have shown that higher body mass index (BMI), particularly BMI >= 30 kg/m2, is associated with poorer asthma control and asthma related quality of life. Furthermore, growing evidence suggests that obese patients with asthma respond less favourably to inhaled corticosteroids compared to non-obese patients. Moreover, longitudinal studies indicate that weight reduction improves asthma control. Therefore, preventing and treating obesity should be an integrated part of asthma management. PMID- 25497859 TI - [Dissection in the vertebral arteries is uncommon and may be misdiagnosed]. AB - Spontaneous dissection of a vertebral artery is uncommon, but potentially harmful and initially easily misdiagnosed as ordinary headache, neck pain or dizziness. The condition may progress with infarctions in the brainstem and cerebellar areas and ataxia, nystagmus, Horner syndrome, dysarthria, cranial nerve palsy or hemiparesis. We report an initially misdiagnosed case and remind about the clinical clues which lead to a correct diagnosis: young age, no risk factors for thromboembolism, the typical clinical findings and the presence of neck pain. PMID- 25497860 TI - [Pseudoaneurysm in the subclavian artery as a long-term complication to clavicula fracture]. AB - Post-traumatic pseudoaneurysm in the subclavian artery is a rare complication to clavicula fracture, but it seldom requires intervention, and therefore screening for pseudoaneurysms is not recommended after a relevant trauma. This case report confirms that a pseudoaneurysm can develop slowly and can manifest even several years after the primary trauma. A 79-year-old patient presented herself with a 20 * 20 cm large pulsating tumour on the left side of her neck, and a pseudoaneurysm on the subclavian artery had been diagnosed as a late complication to a clavicula fracture nine years before. This case was rare because of the late-onset aneurysm, manifesting itself by the large size and neurological symptoms. The patient was treated with stent grafting without further surgical intervention, resulting in relief from neurological symptoms and a decreasing size of the pseudoaneurysm. Antithrombotic treatment after the endovascular procedure was not recommended. PMID- 25497861 TI - [Progressive multifocal leukoencephalopathy in a patient with multiple myeloma]. AB - Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease in the central nervous system. It is caused by reactivation of John Cunningham virus and has a grave prognosis. PML occurs most frequently in HIV-patients, but can also be seen in patients with iatrogenic immunodeficiency. Here, we present a patient with multiple myeloma and cardiac amyloidosis who developed PML after receiving treatment with several chemotherapeutics. This case report underlines the importance of bearing PML in mind when immunocompromised patients develop diffuse neurological symptoms. PMID- 25497862 TI - Seasonal change in the avian hippocampus. AB - The hippocampus plays an important role in cognitive processes, including memory and spatial orientation, in birds. The hippocampus undergoes seasonal change in food-storing birds and brood parasites, there are changes in the hippocampus during breeding, and further changes occur in some species in association with migration. In food-storing birds, seasonal change in the hippocampus occurs in fall and winter when the cognitively demanding behaviour of caching and retrieving food occurs. The timing of annual change in the hippocampus of food storing birds is quite variable, however, and appears not to be under photoperiod control. A variety of factors, including cognitive performance, exercise, and stress may all influence seasonal change in the avian hippocampus. The causal processes underlying seasonal change in the avian hippocampus have not been extensively examined and the more fully described hormonal influences on the mammalian hippocampus may provide hypotheses for investigating the control of hippocampal seasonality in birds. PMID- 25497863 TI - Response to Letters to the Editors: 1. More details on the database used by the study should be provided. 2. Mediclaim Hospital Discharge System and income levels of cohort. PMID- 25497864 TI - The use of hyperosmotic saline for chondroprotection: implications for orthopaedic surgery and cartilage repair. AB - OBJECTIVE: Articular cartilage may experience iatrogenic injury during routine orthopaedic/arthroscopic procedures. This could cause chondrocyte death, leading to cartilage degeneration and posttraumatic osteoarthritis. In an in vitro cartilage injury model, chondrocyte death was reduced by increasing the osmolarity of normal saline (NS), the most commonly-used irrigation solution. Here, we studied the effect of hyperosmolar saline (HS) on chondrocyte viability and cartilage repair in an in vivo injury model. DESIGN: Cartilage injury was induced by a single scalpel cut along the patellar groove of 8 week old rats in the absence of irrigation or with either NS (300 mOsm) or HS (600 mOsm). The percentage of cell death (PCD) within the injured area was assessed using confocal microscopy. Repair from injury was evaluated by histology/immunostaining, and inflammatory response by histology, cytokine array analysis and ELISA (enzyme-linked immunosorbent assay). RESULTS: The PCD in saline-irrigated joints was increased compared to non-irrigated (NI) joints [PCD = 20.8% (95%CI; 14.5, 27.1); PCD = 9.14% (95%CI; 6.3, 11.9); P = 0.0017]. However, hyperosmotic saline reduced chondrocyte death compared to NS (PCD = 10.4% (95%CI; 8.5, 12.3) P = 0.0024). Repair score, type II collagen and aggrecan levels, and injury width, were significantly improved with hyperosmotic compared to NS. Mild synovitis and similar changes in serum cytokine profile occurred in all operated joints irrespective of experimental group. CONCLUSIONS: Hyperosmotic saline significantly reduced the chondrocyte death associated with scalpel induced injury and enhanced cartilage repair. This irrigation solution might be useful as a simple chondroprotective strategy and may also reduce unintentional cartilage injury during articular reconstructive surgery and promote integrative cartilage repair, thereby reducing the risk of posttraumatic osteoarthritis. PMID- 25497865 TI - More details on the database used in the study should be provided. PMID- 25497866 TI - Mediclaim Hospital Discharge System and income levels of cohort. PMID- 25497867 TI - Meaning of ureter dilatation during ultrasonography in infants for evaluating vesicoureteral reflux. AB - PURPOSE: To investigate the meaning of ureter dilatation during ultrasonography (US) in infants for evaluating vesicoureteral reflux (VUR). MATERIALS AND METHODS: We retrospectively reviewed abdominal US images of infants who were diagnosed with urinary tract infection (UTI group) or only hydronephrosis without UTI (control group). Hydronephrosis (graded 0-4) and ureter dilatation (present or absent) were evaluated on each side with US. Voiding cystourethrography (VCUG) within 3 months time interval with US was also reviewed and VUR was graded (0-5) on each side. Hydronephrosis, ureter dilatation, and VUR were then compared between the two groups. RESULTS: Four hundred and three infants (142 in the UTI group and 261 in the control group) were included and VCUG was performed in 129 infants (68 in UTI and 61 in control groups). VUR grades were not different between the two groups (p=0.252). Hydronephrosis grade was not related to VUR in either group (p>0.05). However, ureter dilatation had a significant relationship with VUR in the UTI group (p=0.015), even among patients with a high-grade VUR (p=0.005). Whereas, ureter dilatation was not associated with VUR in the control group (p=0.744). The relationship between ureter dilatation and VUR was different between the two groups for both all grades (p=0.014) and high-grade (p=0.004) VUR. Ureter dilatation had 66.7% sensitivity, 80.3% specificity, and 79.4% accuracy for evaluating high-grade VUR in the UTI group. CONCLUSION: Ureter dilatation on US can be a helpful finding for detecting VUR in infants with UTI, but not infants without UTI. PMID- 25497868 TI - Antiangiogenic effects of a novel synthetic curcumin analogue in pancreatic cancer. AB - Hypoxia-inducible factors (HIFs) and NF-kappaB play essential roles in cancer cell growth and metastasis by promoting angiogenesis. Heat shock protein 90 (Hsp90) serves as a regulator of HIF-1alpha and NF-kappaB protein. We hypothesized that curcumin and its analogues EF31 and UBS109 would disrupt angiogenesis in pancreatic cancer (PC) through modulation of HIF-1alpha and NF kappaB. Conditioned medium from MIA PaCa-2 or PANC-1 cells exposed to curcumin and its analogues in vitro significantly impaired angiogenesis in an egg CAM assay and blocked HUVEC tube assembly in comparison to untreated cell medium. In vivo, EF31 and UBS109 blocked the vascularization of subcutaneous matrigel plugs developed by MIA PaCa-2 in mice. Significant inhibition of VEGF, angiopoietin 1, angiopoietin 2, platelet derived growth factor, COX-2, and TGFbeta secretion was observed in PC cell lines treated with UBS109, EF31 or curcumin. Treatment with UBS109, EF31 or curcumin inhibited HSP90, NF-kappaB, and HIF-1alpha transcription in PC cell lines. UBS109 and EF31 inhibited HSP90 and HIF-1alpha expression even when elevated due to NF-kappaB (p65) overexpression. Finally, we demonstrate for the first time that curcumin analogues EF31 and UBS109 induce the downregulation of HIF-1alpha, Hsp90, COX-2 and VEGF in tumor samples from xenograft models compared to untreated xenografts. Altogether, these results suggest that UBS109 and EF31 are potent curcumin analogues with antiangiogenic activities. PMID- 25497869 TI - The cl2/dro1/ccdc80 null mice develop thyroid and ovarian neoplasias. AB - We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80(-/-) mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80(-/-) mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis. PMID- 25497871 TI - Pseudo-Hirschsprung's disease with rectal hypoganglionosis: an autopsied case of circulatory failure due to severe constipation. AB - We report a 21-year-old female patient who suddenly died of circulatory failure due to pressure from megacolon allied with pseudo-Hirschsprung's disease. Since 3 years before her death, she had exhibited the feeling of abdominal distention, which was diagnosed as constipation. However, her constipation did not respond well to the prescribed oral administration of laxatives and enemas. She was found dead at home in the morning, lying on her back. An autopsy revealed a decreased number of ganglion cells in the rectum, suggesting hypoganglionosis. In cases of intractable chronic constipation, careful investigation of the cause of such symptoms is important. PMID- 25497870 TI - alpha integrin targeting for radiosensitization of three-dimensionally grown human head and neck squamous cell carcinoma cells. AB - Integrin cell adhesion molecules play a crucial role in tumor cell resistance to radio- and chemotherapy and are therefore considered attractive targets for cancer therapy. Here, we assessed the role of beta1 integrin-interacting alpha integrin subunits in more physiological three-dimensional extracellular matrix grown head and neck squamous cell carcinoma (HNSCC) cell cultures for evaluating cytotoxic and radiosensitizing potential. alpha2, alpha3, alpha5 and alpha6 integrins, which are overexpressed in HNSCC according to Oncomine database analysis, were coprecipitated with beta1 integrin. More potently than alpha2, alpha5 or alpha6 integrin inhibition, siRNA-based alpha3 integrin targeting resulted in reduced clonogenic cell survival, induced apoptosis and enhanced radiosensitivity. These events were associated with diminished phosphorylation of Akt, Cortactin and Paxillin. Cell line-dependently, simultaneous alpha3 and beta1 integrin inhibition led to higher cytotoxicity and radiosensitization than alpha3 integrin blocking alone. Stable overexpression of wild-type and constitutively active forms of the integrin signaling mediator focal adhesion kinase (FAK) revealed FAK as a key determinant of alpha3 integrin depletion-mediated radiosensitization. Our findings show that alpha3 integrin is essentially involved in HNSCC cell radioresistance and critical for a modified cellular radiosensitivity along with beta1 integrins. PMID- 25497873 TI - Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: controversies, insights, and changing horizons. AB - The use of stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer is growing rapidly, particularly since it has become the recommended therapy for unfit patients in current European and North American guidelines. As three randomized trials comparing surgery and SABR closed prematurely because of poor accrual, clinicians are faced with a dilemma in individual patient decision-making. Radiation oncologists, in particular, should be aware of the data from comparative effectiveness studies that suggest similar survival outcomes irrespective of local treatment modality. The necessity of obtaining a pathological diagnosis, particularly in frail patients prior to treatment remains a challenge, and this topic was addressed in recent European recommendations. Awareness of the high incidence of a second primary lung cancer in survivors, as well as other competing causes of mortality, is needed. The challenges in distinguishing focal scarring from recurrence after SABR also need to be appreciated by multidisciplinary tumor boards. With a shift in focus toward patient-centered decision-making, clinicians will need to be aware of these new developments and communicate effectively with patients, to ensure that treatment decisions are reflective of patient preferences. Priorities for additional research in the area are proposed. PMID- 25497872 TI - Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy. AB - PURPOSE: To report the prognostic factors for local control in patients treated for locally advanced cervical cancer with image guided pulsed-dose rate brachytherapy. MATERIALS/METHODS: Patients treated with curative intent by a combination of external beam radiotherapy and pulsed-dose rate brachytherapy were selected. Local failure was defined as any relapse in the cervix, vagina, parametria, or uterus during follow-up. Prognostic factors were selected based on log rank tests and then analyzed with a Cox model. Dose/effect correlations were performed using the probit model. RESULTS: Two hundred and twenty-five patients treated from 2006 to 2011 were included. According to the FIGO classification, 29% were stage IB, 58% stage II, 10% stage III, and 3% stage IVA; 95% received concomitant chemotherapy. Thirty patients were considered having incomplete response or local failure. Among the selected parameters, D90 for HR-CTV, D90 for IR-CTV, the overall treatment time, the TRAK, and the HR-CTV volume appeared significantly correlated with local control in univariate analysis. In multivariate analysis, overall treatment time >55days and HR-CTV volume >30cm(3) appeared as independent. The probit analysis showed significant correlations between the D90 for both CTVs, and the probability of achieving local control (p=0.008 and 0.024). The thresholds to reach to warrant a probability of 90% of local control were 85Gy to the D90 of the HR-CTV and 75Gy to 90% of the IR-CTV (in 2Gy equivalent, alpha/beta=10). To warrant the same local control rate, the D90 HR-CTV should be significantly increased in stage III-IV tumors, in case of HR-CTV >30cm(3), excessive treatment time, or tumor width at diagnosis >5cm (97, 92, 105, and 92Gy respectively). CONCLUSIONS: Overall treatment time and HR-CTV volume were independent prognostic factors for local control. The D90 for HR and IR CTV were significantly correlated with local control, and D90 HR-CTV should be adapted to clinical criteria. PMID- 25497874 TI - Can perfusion MRI predict response to preoperative treatment in rectal cancer? AB - BACKGROUND AND PURPOSE: Dynamic contrast-enhanced MRI (DCE-MRI) provides information on perfusion and could identify good prognostic tumors. Aim of this study was to evaluate whether DCE-MRI using a novel blood pool contrast-agent can accurately predict the response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer. MATERIALS AND METHODS: Thirty patients underwent DCE-MRI before and 7-10weeks after chemoradiotherapy. Regions of interest were drawn on DCE-MRI with T2W-images as reference. DCE-MRI-based kinetic parameters (initial slope, initial peak, late slope, and AUC at 60, 90, and 120s) determined pre- and post-CRT and their Delta were compared between good (TRG1-2) and poor (TRG3-5) responders. Optimal thresholds were determined and sensitivities, specificities, positive predictive values (PPV), and negative predictive values (NPV) were calculated. RESULTS: Pre-therapy, the late slope was able to discriminate between good and poor responders (-0.05*10(-3) vs. 0.62*10(-3), p<0.001) with an AUC of 0.90, sensitivity 92%, specificity 82%, PPV 80%, and NPV 93%. Other pre-CRT parameters showed no significant differences, nor any post-CRT parameters or their Delta. CONCLUSIONS: The kinetic parameter 'late slope' derived from DCE-MRI could potentially be helpful to predict before the onset of neoadjuvant chemoradiotherapy which tumors are likely going to respond. This could allow for personalized treatment-options in rectal cancer patients. PMID- 25497875 TI - Cardiac volume effects during chemoradiotherapy for esophageal cancer (Regarding Lutkenhaus et al. Reduction in cardiac volume during chemoradiotherapy for patients with esophageal cancer). PMID- 25497876 TI - Comparison of toxicity after IMRT and 3D-conformal radiotherapy for patients with pancreatic cancer - a systematic review. AB - IMRT has been suggested to reduce treatment-related toxicity in pancreatic cancer. We attempted to identify all IMRT-studies indexed in PubMed/Medline, comparing them with recent 3D-CRT trials. The predominant treatment-related toxicities, namely nausea/vomiting, diarrhoea and late GI toxicity, are significantly reduced with IMRT while there was no apparent difference for outcome measures. PMID- 25497878 TI - Sociocultural influences on strategies to lose weight, gain weight, and increase muscles among ten cultural groups. AB - This study determined how sociocultural messages to change one's body are perceived by adolescents from different cultural groups. In total, 4904 adolescents, including Australian, Chilean, Chinese, Indo-Fijian, Indigenous Fijian, Greek, Malaysian, Chinese Malaysian, Tongans in New Zealand, and Tongans in Tonga, were surveyed about messages from family, peers, and the media to lose weight, gain weight, and increase muscles. Groups were best differentiated by family pressure to gain weight. Girls were more likely to receive the messages from multiple sociocultural sources whereas boys were more likely to receive the messages from the family. Some participants in a cultural group indicated higher, and others lower, levels of these sociocultural messages. These findings highlight the differences in sociocultural messages across cultural groups, but also that adolescents receive contrasting messages within a cultural group. These results demonstrate the difficulty in representing a particular message as being characteristic of each cultural group. PMID- 25497877 TI - Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. AB - Spinal muscular atrophy is a disorder of lower motor neurons, most commonly caused by recessive mutations in SMN1 on chromosome 5q. Cases without SMN1 mutations are subclassified according to phenotype. Spinal muscular atrophy, lower extremity-predominant, is characterized by lower limb muscle weakness and wasting, associated with reduced numbers of lumbar motor neurons and is caused by mutations in DYNC1H1, which encodes a microtubule motor protein in the dynein dynactin complex and one of its cargo adaptors, BICD2. We have now identified 32 patients with BICD2 mutations from nine different families, providing detailed insights into the clinical phenotype and natural history of BICD2 disease. BICD2 spinal muscular atrophy, lower extremity predominant most commonly presents with delayed motor milestones and ankle contractures. Additional features at presentation include arthrogryposis and congenital dislocation of the hips. In all affected individuals, weakness and wasting is lower-limb predominant, and typically involves both proximal and distal muscle groups. There is no evidence of sensory nerve involvement. Upper motor neuron signs are a prominent feature in a subset of individuals, including one family with exclusively adult-onset upper motor neuron features, consistent with a diagnosis of hereditary spastic paraplegia. In all cohort members, lower motor neuron features were static or only slowly progressive, and the majority remained ambulant throughout life. Muscle MRI in six individuals showed a common pattern of muscle involvement with fat deposition in most thigh muscles, but sparing of the adductors and semitendinosus. Muscle pathology findings were highly variable and included pseudomyopathic features, neuropathic features, and minimal change. The six causative mutations, including one not previously reported, result in amino acid changes within all three coiled-coil domains of the BICD2 protein, and include a possible 'hot spot' mutation, p.Ser107Leu present in four families. We used the recently solved crystal structure of a highly conserved region of the Drosophila orthologue of BICD2 to further-explore how the p.Glu774Gly substitution inhibits the binding of BICD2 to Rab6. Overall, the features of BICD2 spinal muscular atrophy, lower extremity predominant are consistent with a pathological process that preferentially affects lumbar lower motor neurons, with or without additional upper motor neuron involvement. Defining the phenotypic features in this, the largest BICD2 disease cohort reported to date, will facilitate focused genetic testing and filtering of next generation sequencing-derived variants in cases with similar features. PMID- 25497879 TI - Resistive and pulsatile arterial hemodynamics and cardiovascular events: the Multiethnic Study of Atherosclerosis. AB - BACKGROUND: Arterial blood pressure is dependent on interactions between the heart and arteries. Resistive and pulsatile components of arterial load can be assessed by systemic vascular resistance (SVR, a microvascular property) and the ratio of stroke volume to pulse pressure (a surrogate of total arterial compliance, TAC), respectively. The relationship between arterial function and cardiovascular events in populations without cardiovascular disease is unknown. METHODS AND RESULTS: We studied 4806 adults enrolled in the Multi-Ethnic Study of Atherosclerosis who were free of clinical cardiovascular disease at baseline. SVR and stroke volume/pulse pressure (SV/PP) were derived by sphygmomanometry and magnetic resonance imaging. The relationship between these measures of arterial function and incident cardiovascular events was assessed using Cox regression. With a mean follow-up of 7.5 years, cardiovascular events occurred in 358 participants (7.4%). There was no relationship between SVR and subsequent cardiovascular events. However, increased stroke volume/pulse pressure was associated with reduced event rate in unadjusted (hazard ratio=0.67, 95% CI=0.58 to 0.77, P<0.001) and analyses that adjusted for multiple confounders (HR=0.75; 95% CI=0.62 to 0.90; P<0.001). CONCLUSIONS: Greater total arterial compliance, manifest by higher stroke volume/pulse pressure is associated with a reduced incidence of subsequent CVE. In contrast, SVR was not independently associated with CVE in subjects free of overt cardiovascular disease at baseline. These findings support the concept that alternations in the large conduit vessels, rather than changes in microvascular resistance, are primarily related to incident cardiovascular disease. PMID- 25497880 TI - Phenotypic analysis of arrhythmogenic cardiomyopathy in the Hutterite population: role of electrocardiogram in identifying high-risk desmocollin-2 carriers. AB - BACKGROUND: The p.Gln554X mutation in desmocollin-2 (DSC2) is prevalent in ~10% of the Hutterite population. While the homozygous mutation causes severe biventricular arrhythmogenic right ventricular cardiomyopathy, the phenotypic features and prognosis of heterozygotes remain incompletely understood. METHODS AND RESULTS: Eleven homozygotes (mean age 32+/-8 years, 45% female), 28 heterozygotes (mean age 40+/-15 years, 50% female), and 22 mutation-negatives (mean age 43+/-17 years, 41% female) were examined. Diagnostic testing was performed as per the arrhythmogenic right ventricular cardiomyopathy modified Task Force Criteria. Inverted T waves in the right precordial leads on ECG were seen in all homozygotes but not in their counterparts (P<0.001). Homozygotes had higher median daily premature ventricular complex burden than did heterozygotes or mutation-negatives (1407 [IQR 1080 to 2936] versus 2 [IQR 0 to 6] versus 6 [IQR 0 to 214], P=0.0002). Ventricular tachycardia was observed in 60% of homozygotes but in none of the remaining individuals (P<0.001). On cardiac magnetic resonance imaging, homozygotes had significantly larger indexed end diastolic volumes (right ventricular: 122+/-24 versus 83+/-17 versus 83+/-12 mL/m(2), P<0.0001; left ventricular: 93+/-18 versus 76+/-13 versus 80+/-11 mL/m(2), P=0.0124) and lower ejection fraction values compared with heterozygotes and mutation-negatives (right ventricular ejection fraction: 41+/-9% versus 59+/ 9% versus 61+/-6%, P<0.0001; left ventricular ejection fraction: 53+/-8% versus 65+/-5% versus 64+/-5%, P<0.0001). Most affected individuals lacked right ventricular wall motion abnormalities. Thus, few met cardiac magnetic resonance imaging task force criteria. CONCLUSIONS: The ECG reliably identifies homozygous p.Gln554X carriers and may be useful as an initial step in the screening of high risk Hutterites. The cardiac phenotype of heterozygotes appears benign, but further prospective follow-up of their arrhythmic risk is needed. PMID- 25497882 TI - One-year follow-up of women who participated in a physiotherapy and health education program before and after obstetric fistula surgery. AB - OBJECTIVE: To investigate whether the positive impact of a program of physiotherapy and health education on the outcome of obstetric fistula surgery was maintained after 1 year. METHODS: The present follow-up analysis included 108 women who underwent obstetric fistula surgery at a center in Tanguieta, Benin, between March 2011 and March 2012, and who had received a structured program of physiotherapy and health education before and after surgery. After discharge, follow-up visits were made 3, 6, and 12 months after surgery. The Ditrovie scale was used to measure quality of life (QoL), and continence and performance of the physiotherapy exercises were assessed. RESULTS: Mean QoL score was 36.9 (range 16.0-49.0) before surgery. Overall, 84 women were followed up for 1 year. Their mean QoL score had improved significantly to 18.5 (range 10.0-47.0; P<0.001). Between hospital discharge and 1 year, the number of women with a closed fistula increased from 48 (57.1%) to 53 (63.1%) and the number with urinary stress incontinence reduced from 11 (13.1%) to 9 (10.7%). CONCLUSION: Results obtained after surgery and physiotherapy were maintained at 1 year, and QoL had improved significantly. When women are encouraged to continue exercises, improvements are also seen in residual stress incontinence. PMID- 25497881 TI - Mouse ERG K(+) channel clones reveal differences in protein trafficking and function. AB - BACKGROUND: The mouse ether-a-go-go-related gene 1a (mERG1a, mKCNH2) encodes mERG K(+) channels in mouse cardiomyocytes. The mERG channels and their human analogue, hERG channels, conduct IKr. Mutations in hERG channels reduce IKr to cause congenital long-QT syndrome type 2, mostly by decreasing surface membrane expression of trafficking-deficient channels. Three cDNA sequences were originally reported for mERG channels that differ by 1 to 4 amino acid residues (mERG-London, mERG-Waterston, and mERG-Nie). We characterized these mERG channels to test the postulation that they would differ in their protein trafficking and biophysical function, based on previous findings in long-QT syndrome type 2. METHODS AND RESULTS: The 3 mERG and hERG channels were expressed in HEK293 cells and neonatal mouse cardiomyocytes and were studied using Western blot and whole cell patch clamp. We then compared our findings with the recent sequencing results in the Welcome Trust Sanger Institute Mouse Genomes Project (WTSIMGP). CONCLUSIONS: First, the mERG-London channel with amino acid substitutions in regions of highly ordered structure is trafficking deficient and undergoes temperature-dependent and pharmacological correction of its trafficking deficiency. Second, the voltage dependence of channel gating would be different for the 3 mERG channels. Third, compared with the WTSIMGP data set, the mERG-Nie clone is likely to represent the wild-type mouse sequence and physiology. Fourth, the WTSIMGP analysis suggests that substrain-specific sequence differences in mERG are a common finding in mice. These findings with mERG channels support previous findings with hERG channel structure-function analyses in long-QT syndrome type 2, in which sequence changes in regions of highly ordered structure are likely to result in abnormal protein trafficking. PMID- 25497883 TI - Risk factors associated with abnormal glucose tolerance in the early postpartum period among Japanese women with gestational diabetes. AB - OBJECTIVE: To identify the risk factors associated with abnormal glucose tolerance (AGT) on the first postpartum oral glucose tolerance test (OGTT) among Japanese women with gestational diabetes (GDM). METHODS: In a retrospective study, data were analyzed from women with GDM who underwent their first postpartum OGTT 6-8weeks post partum at a center in Omura, Japan, between January 1, 2007, and December 31, 2011. Women with diabetes or impaired glucose tolerance were deemed to have postpartum AGT. The association between postpartum AGT and various risk factors was analyzed. RESULTS: Among 169 women who underwent a postpartum OGTT, 58 (34.3%) had AGT. The significant risk factors associated with postpartum AGT in univariate analysis were pre-pregnancy body mass index (P=0.096), 1-hour plasma glucose (P=0.006), hemoglobin A1c (P<0.001), insulinogenic index (P=0.05), an insulinogenic index of less than 0.4 (P=0.006), and insulin therapy during pregnancy (P<0.001). Independent risk factors identified by multivariate logistic regression models were insulinogenic index (odds ratio [OR] 0.10, 95% confidence interval [CI] 0.01-0.74; P=0.002), an insulinogenic index of less than 0.4 (OR 5.70, 95% CI 1.69-21.66; P=0.005), and insulin therapy during pregnancy (OR 3.43, 95% CI 1.03-12.55; P=0.044). CONCLUSION: Among Japanese women with GDM, a lower insulinogenic index and use of insulin therapy during pregnancy are associated with early postpartum AGT. PMID- 25497884 TI - Flavor preference conditioning by different sugars in sweet ageusic Trpm5 knockout mice. AB - Knockout (KO) mice missing the taste signaling protein Trpm5 have greatly attenuated sweetener preferences but develop strong preferences for glucose in 24 h tests, which is attributed to post-oral sugar conditioning. Trpm5 KO mice express mild preferences for galactose but no preferences for fructose in 24-h tests, which suggests that these sugars differ in their post-oral reinforcing effects. Here we investigated sugar-conditioned flavor preferences in Trpm5 KO and C57BL/6J wildtype (B6) mice. The mice were trained to consume a flavored (CS+, e.g. grape) 8% sugar solution and flavored (CS-, e.g., cherry) water on alternating days followed by two-bottle choice tests with CS+ vs. CS- flavors in water and with unflavored sugar vs. water. The KO mice displayed strong preferences (>80%) for the CS+ glucose and CS+ galactose but not for the CS+ fructose flavor. They also preferred glucose and galactose, but not fructose to water. In contrast, the B6 mice preferred all three CS+ flavors to the CS- flavor, and all three sugars to water. In tests with the non-metabolizable sugar alpha-methyl-d-glucopyranoside (MDG), the KO and B6 mice preferred 8% MDG to water but did not prefer the CS+ 8% MDG to CS-. However, they preferred a CS+ flavor mixed with 4% MDG over the CS- flavor. Trpm5 KO mice also preferred galactose and MDG to fructose in direct choice tests. The Trpm5 KO data indicate that glucose and, to a lesser extent, galactose and MDG have post-oral reinforcing actions that stimulate intake and preference while fructose has a much weaker effect. The CS+ flavor and sugar preferences of B6 mice may be mediated by the sweet taste and/or post-oral actions of the various sugars. Glucose, galactose, and MDG, but not fructose, are ligands for the sodium-glucose transporter 1 (SGLT1) which is implicated in post-oral sugar conditioning in B6 mice. PMID- 25497885 TI - No man is an island. A personal tribute to Bob Blanchard and ethoexperimental approaches to the study of behaviour. AB - I first met Bob Blanchard at an international conference in Paris some 40 years ago. We collaborated intensively during the late 1980s/early 1990s on the ethopharmacology of antipredator defence in wild and laboratory rats, and remained good friends until his untimely passing in November 2013. Bob will undoubtedly be remembered as one of the most influential behavioural neuroscientists of the 20th century and, with Caroline, the most eloquent advocate of ethoexperimental approaches to the study of behaviour. In this brief trip down memory lane, I describe when and where Bob and I first met and how, over a lengthy period, he directly and indirectly helped shape my own research career. His profound influence in this regard is illustrated by reference to not only our collaborative research on antipredator behaviour but also my other work on the ethopharmacology of agonistic behaviour, social conflict analgesia, anxiety, and appetite. The element common to all of this work has been ethoexperimental analysis and, for teaching me the true value of this approach, I shall always remain indebted to the big man. Literally and figuratively, Bob was most certainly larger than life. PMID- 25497886 TI - Perceiving one's body shapes empathy. AB - BACKGROUND: Empathy is a basic human ability with affective and cognitive facets and high interindividual variability. Accurately detecting one's internal body signals (interoceptive sensitivity) strongly contributes to the awareness of oneself and is known to interact with emotional and cognitive processes. This study investigated whether interoceptive sensitivity (i.e., heartbeat perception task) shapes affective and cognitive empathy. METHODS: Ninety-three participants were asked to report the valence of their feelings, as well as the degree of compassion, arousal, and distress they felt in response to pictures depicting other people in pain or in non-pain situations. Participants also had to estimate how painful the situation was. RESULTS: Main results showed that greater interoceptive sensitivity enhanced the estimated degree of pain (cognitive empathy), as well as arousal and feelings of compassion (affective empathy), in response to painful pictures. CONCLUSIONS: The accurate perception of bodily states and their representation shape both affective and cognitive empathy. This perception enables us to feel more compassion for another person and to evaluate the pain that they experience as being more intense. PMID- 25497887 TI - Immunocompetence of breeding females is sensitive to cortisol levels but not to communal rearing in the degu (Octodon degus). AB - One hypothesis largely examined in social insects is that cooperation in the context of breeding benefits individuals through decreasing the burden of immunocompetence and provide passive immunity through social contact. Similarly, communal rearing in social mammals may benefit adult female members of social groups by reducing the cost of immunocompetence, and through the transfer of immunological compounds during allonursing. Yet, these benefits may come at a cost to breeders in terms of a need to increase investment in individual immunocompetence. We examined how these potential immunocompetence costs and benefits relate to reproductive success and survival in a natural population of the communally rearing rodent, Octodon degus. We related immunocompetence (based on ratios of white blood cell counts, total and specific immunoglobulins of G isotype titers) and fecal glucocorticoid metabolite (FGC) levels of adults immunized with hemocyanin from the mollusk Concholepas concholepas to measures of sociality (group size) and communal rearing (number of breeding females). Offspring immunocompetence was quantified based on circulating levels of the same immune parameters. Neither female nor offspring immunocompetence was influenced by communal rearing or sociality. These findings did not support that communal rearing and sociality enhance the ability of females to respond to immunological challenges during lactation, or contribute to enhance offspring condition (based on immunocompetence) or early survival (i.e., to 3months of age). Instead, levels of humoral and cellular components of immunocompetence were associated with variation in glucorcorticoid levels of females. We hypothesize that this covariation is driven by physiological (life-history) adjustments needed to sustain breeding. PMID- 25497888 TI - Modeling abrupt cultural regime shifts during the Palaeolithic and Stone Age. AB - The coupled dynamics of the size and the mean cultural/technological level of a population, with positive feedback between these two variables, is modeled in the Malthusian-Boserupian framework. Bifurcation diagrams, with innovativeness or the cultureless carrying capacity as the parameter, show that abrupt transitions in the mean cultural level are possible. For example, a gradual evolutionary change toward greater innate innovativeness would produce an associated gradual increase in mean cultural level, until a threshold is crossed that triggers an abrupt cultural regime shift. Hence, the model may help explain the apparently sudden and dramatic efflorescences of Palaeolithic/Stone Age culture during the Late Pleistocene, without having to invoke major contemporaneous genetic changes in cognition. The results of statistical studies on the association between population size and toolkit diversity among ethnographic societies are also discussed. PMID- 25497889 TI - Use of experimental design to optimize a triple-potential waveform to develop a method for the determination of streptomycin and dihydrostreptomycin in pharmaceutical veterinary dosage forms by HPLC-PAD. AB - An HPLC-PAD method using a gold working electrode and a triple-potential waveform was developed for the simultaneous determination of streptomycin and dihydrostreptomycin in veterinary drugs. Glucose was used as the internal standard, and the triple-potential waveform was optimized using a factorial and a central composite design. The optimum potentials were as follows: amperometric detection, E1=-0.15V; cleaning potential, E2=+0.85V; and reactivation of the electrode surface, E3=-0.65V. For the separation of the aminoglycosides and the internal standard of glucose, a CarboPacTM PA1 anion exchange column was used together with a mobile phase consisting of a 0.070 mol L(-1) sodium hydroxide solution in the isocratic elution mode with a flow rate of 0.8 mL min(-1). The method was validated and applied to the determination of streptomycin and dihydrostreptomycin in veterinary formulations (injection, suspension and ointment) without any previous sample pretreatment, except for the ointments, for which a liquid-liquid extraction was required before HPLC-PAD analysis. The method showed adequate selectivity, with an accuracy of 98-107% and a precision of less than 3.9%. PMID- 25497890 TI - A micro-QuEChERS method coupled to GC-MS for the quantification of pesticides in specific maternal and fetal tissues. AB - The aim of this study was to establish a new QuEChERS (quick, easy, cheap, effective, rugged and safe) method coupled to gas chromatography-mass spectrometry (GC-MS) detection for the evaluation of the pesticide biodistribution in specific maternal and fetal tissues. This method was validated for the quantification of pesticides such as chlorotriazines (atrazine, simazine and propazine), their chlorinated metabolites (DIA, DEA and DACT). This new QuEChERS method was developed to facilitate extraction from small tissues such as fetal tissues (mean value: 200mg). The limits of detection, quantification, recovery, precision and accuracy were evaluated for different tissues (liver and brain) and blood. LOD and LOQ ranged between 0.34 and 3.27 ng/g and 1.04 to 9.91 ng/g, respectively. Recovery exceeded 80% for all pesticides, except DACT, with an associated RSD<15%. Precision and accuracy satisfied the criteria usually applied in the validation of bioanalytical methods. The results obtained indicate that this technique is suitable for use in studies of the biodistribution of pesticides in fetal tissues and can be used to evaluate the risk of exposure to pesticides during gestation. PMID- 25497891 TI - Ultrasound-assisted ionic liquid-based homogeneous liquid-liquid microextraction high-performance liquid chromatography for determination of tanshinones in Salvia miltiorrhiza Bge. root. AB - The ultrasound-assisted ionic liquid-based homogeneous liquid-liquid microextraction has been developed and applied to the extraction of four tanshinones, including dihydrotanshinone, tanshinone I, cryptotanshinone and tanshinone IIA in Salvia miltiorrhiza Bge. root. High performance liquid chromatography was applied to the separation and determination of the analytes. The ionic liquid was used as extraction solvent and target analytes were extracted with help of ultrasound. Then, ion-pairing agent was added into the sample solution, which resulted in the formation of water-insoluble ionic liquid in the solution. The phase separation was performed by centrifugation. The extraction, concentration and purification of target analytes were performed simultaneously. The experimental parameters, including type and volume of ionic liquid, sample amount, the size of sample particle, pH value of extraction medium, extraction temperature, extraction time, amount of ion-pairing agent and centrifuging time, were investigated and optimized. The calibration curves showed good linear relationship (r>0.9997). The limits of detection and quantification were in the range of 0.052-0.093 and 0.17-0.31 MUg mL(-1), respectively. The recoveries were between 70.45% and 94.23% with relative standard deviations lower than 5.31%. The present method is free of volatile organic solvents, and represents lower expenditures of sample, extraction time and solvent, compared with UAE and HRE. There was no obvious difference in the extraction yields of active constitutions obtained by the three extraction methods. PMID- 25497892 TI - Simultaneous determination of triamcinolone acetonide palmitate and triamcinolone acetonide in beagle dog plasma by UPLC-MS/MS and its application to a long-term pharmacokinetic study of triamcinolone acetonide palmitate lipid emulsion injection. AB - In order to investigate the pharmacokinetics of triamcinolone acetonide palmitate (TAP) which is a lipid-soluble prodrug of triamcinolone acetonide (TA), a rapid, simple, sensitive and reproducible UPLC-MS/MS method has been developed and validated for the simultaneous determination of TAP and TA in beagle dog plasma. After simple liquid-liquid extraction, the analytes and internal standard (dexamethasone, DEX) were separated on Phenomenex Luna C18 column (50 mm * 2.1mm, 1.7 MUm) using a mobile phase consisting of solvent A (acetonitrile) and solvent B (0.1% ammonia solution) at a flow rate of 0.2 ml/min with gradient elution. Acquisition of mass spectrometric data was performed in multiple reaction monitoring (MRM) mode via positive electrospray ionization using the ion transitions of m/z 673.5->397.3, 435.3->415.3 and 393.3->355.3 for TAP, TA and IS, respectively. The method was of satisfactory specificity, sensitivity, precision and accuracy over the concentration range of 1-1,000 ng/ml for TAP and 0.5-500 ng/ml for TA. The intra- and inter-day precisions for both TAP and TA were 3.2% to 18.7% and the accuracy was in the range of -8.4% to 6.8%. The mean recoveries of TAP, TA and IS were 86.7-104.7%. The method was successfully applied to a long-term pharmacokinetic study of TAP and TA after 28-day repeated intravenous administration of TAP lipid emulsion injection to beagle dogs. PMID- 25497893 TI - Qualitative and simultaneous quantitative analysis of cimetidine polymorphs by ultraviolet-visible and shortwave near-infrared diffuse reflectance spectroscopy and multivariate calibration models. AB - The object of the present study was to investigate the feasibility of applying ultraviolet-visible and shortwave near-infrared diffuse reflectance spectroscopy (UV-vis-SWNIR DRS) coupled with chemometrics in qualitative and simultaneous quantitative analysis of drug polymorphs, using cimetidine as a model drug. Three polymorphic forms (A, B and D) and a mixed crystal (M1) of cimetidine, obtained by preparation under different crystallization conditions, were characterized by microscopy, X-ray powder diffraction (XRPD) and infrared spectroscopy (IR). The discriminant models of four forms (A, B, D and M1) were established by discriminant partial least squares (PLS-DA) using different pretreated spectra. The R and RMSEP of samples in the prediction set by discriminant model with original spectra were 0.9959 and 0.1004. Among the quantitative models of binary mixtures (A and D) established by partial least squares (PLS) and least squares support vector machine (LS-SVM) with different pretreated spectra, the LS-SVM models based on original and MSC spectra had better prediction effect with a R of 1.0000 and a RMSEP of 0.0134 for form A, and a R of 1.0000 and a RMSEP of 0.0024 for form D. For ternary mixtures, the established PLS quantitative models based on normalized spectra had relatively better prediction effect for forms A, B and D with R of 0.9901, 0.9820 and 0.9794 and RMSEP of 0.0471, 0.0529 and 0.0594, respectively. This research indicated that UV-vis-SWNIR DRS can be used as a simple, rapid, nondestructive qualitative and quantitative method for the analysis of drug polymorphs. PMID- 25497894 TI - Microextraction by packed sorbent (MEPS) to analyze catecholamines in innovative biological samples. AB - A new microextraction by packed sorbent (MEPS) procedure coupled to a high performance liquid chromatographic method has been developed for quantitation of catecholamines (i.e. norepinephrine, epinephrine and dopamine) in innovative biological samples, namely dried plasma and urine spots. Analyses were carried out on a C18 reversed-phase column using a mobile phase composed of 2.5% methanol and 97.5% aqueous citrate buffer, containing octanesulfonic acid. Coulometric detection was used, setting the first analytical cell at -0.350 V and the second analytical cell at +0.400 V. Dried matrices were purified by means of a fast and feasible MEPS procedure, optimized on C18 sorbent and requiring only a small amount of biological sample. The availability of miniaturized procedures allowed satisfying specific requirements that ought to be considered during pre-treatment intended for catecholamine analysis. The extraction yield values were always higher than 85% and sensitivity was good, with a limit of quantitation of 100 pg mL(-1) for all the analytes. Satisfactory results were also obtained in terms of linearity, precision and accuracy. The method was successfully applied to dried plasma and urine spots derived from two socially diversified groups, namely psychiatric patients and poly-drug abusers, in comparison to healthy volunteers. PMID- 25497895 TI - Ultrasound-guided hematoma block for distal radial and ulnar fractures. AB - BACKGROUND: Hematoma blocks of the radius can provide excellent analgesia for simple distal radius fractures. However, the landmark-based approach can be difficult, and ultrasound guidance may improve success of the block and analgesia during reduction. There is limited literature describing the ultrasound-guided approach, and prior case descriptions have not involved comminuted fractures or concomitant ulnar styloid fractures. OBJECTIVES: This report reviews the technique of the ultrasound-guided hematoma block for distal radius fractures and introduces a second step, which can be used in the case of concomitant distal ulna fractures. DISCUSSION: The use of the ultrasound-guided hematoma block allows for direct visualization of needle advancement, as well as a simple approach to anesthetizing most distal radial and ulnar fractures. CONCLUSION: The ultrasound-guided hematoma block may be helpful in improving anesthesia of complicated distal radial and ulnar fractures, especially when landmark-based localization is difficult. PMID- 25497896 TI - Emergency medicine residents' knowledge of mechanical ventilation. AB - BACKGROUND: Although Emergency physicians frequently intubate patients, management of mechanical ventilation has not been emphasized in emergency medicine (EM) residency curricula. OBJECTIVES: The objective of this study was to quantify EM residents' education, experience, and knowledge regarding mechanical ventilation. METHODS: We developed a survey of residents' educational experiences with ventilators and an assessment tool with nine clinical questions. Correlation and regression analyses were performed to evaluate the relationship between residents' scores on the assessment instrument and their training, education, and comfort with ventilation. RESULTS: Of 312 EM residents, 218 responded (69.9%). The overall correct response rate for the assessment tool was 73.3%, standard deviation (SD) +/- 22.3. Seventy-seven percent (n = 167) of respondents reported <= 3 h of mechanical ventilation education in their residency curricula over the past year. Residents reported frequently caring for ventilated patients in the ED, as 64% (n = 139) recalled caring for >= 4 ventilated patients per month. Fifty-three percent (n = 116) of residents endorsed feeling comfortable caring for mechanically ventilated ED patients. In multiregression analysis, the only significant predictor of total test score was residents' comfort with caring for mechanically ventilated patients (F = 10.963, p = 0.001). CONCLUSIONS: EM residents report caring for mechanically ventilated patients frequently, but receive little education on mechanical ventilation. Furthermore, as residents' performance on the assessment tool is only correlated with their self-reported comfort with caring for ventilated patients, these results demonstrate an opportunity for increased educational focus on mechanical ventilation management in EM residency training. PMID- 25497897 TI - Accuracy of optic nerve sheath diameter measurement by emergency physicians using bedside ultrasound. AB - BACKGROUND: Ultrasound (US) measurement of the optic nerve sheath diameter (ONSD) has been utilized as an indirect assessment of intracranial pressure. It is usually performed by trained ultrasonographers. OBJECTIVES: To evaluate whether or not emergency physicians (EP) are capable of measuring the ONSD accurately by US. MATERIALS AND METHODS: A retrospective measurement of ONSD was conducted on computed tomography (CT) scans of the head or facial bones. These patients had undergone ocular US performed by EPs prior to CT scanning. The CT scan measurements of ONSD read by a board-certified radiologist were compared with that of the US read by a registered diagnostic medical sonographer. A difference in measurements of the ONSD >= 0.5 mm between the two modalities was considered as significant for this study. RESULTS: The ONSD measurements were performed with CT scan and compared to that of the US. Of the 61 patients studied, 36 (59%) were male and 25 (41%) were female. The average age was 56 +/- 17 years. All but 4 patients had ONSD measurements that were between 5 and 6 mm [Corrected]. Discrepancy in measurements of the ONSD between US and CT for both groups fell within our predetermined value (0.5 mm) for the majority of cases. None of the measurements were above 6 mm. The intraclass correlation coefficient was 0.9 (95% confidence interval 0.8846-0.9303). CONCLUSION: Emergency physicians were capable of accurately measuring the ONSD using bedside US. Prospective studies with a larger sample size are recommended to validate these findings. PMID- 25497899 TI - Editorial overview: Multi-protein assemblies in signaling. PMID- 25497898 TI - Lovastatin and perillyl alcohol inhibit glioma cell invasion, migration, and proliferation--impact of Ras-/Rho-prenylation. AB - Alterations in small GTPase mediated signal transduction pathways have emerged as a central step in the molecular pathogenesis of glioblastoma (GBM), the most common malignant brain tumor in adults. Farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) are derived from mevalonate, whose production is catalyzed by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Prenylation by FPP and GGPP is required for membrane insertion and oncogenic function of Ras- and Rho-proteins, within the stimulation of the Ras-Raf-MEK-ERK pathway. A straightforward prediction from HMG-CoA reductase inhibitor studies is that statins decrease FPP and GGPP levels and diminish ERK signaling ensuring less proliferation and migration of cancer cells. Perillyl alcohol (POH), a naturally occurring monoterpene inhibits prenyltransferases and is able to inhibit cancer cell growth, but the underlying mechanism is still unclear. We here report that lovastatin (LOV) and POH impair the regulation of the mevalonate- and the Ras-Raf MEK-ERK pathway in U87 and U343 glioblastoma cells. Both compounds affected the post-translational modification of H-Ras and Rac1. While LOV diminished the substrates of the transferase reaction that catalyze prenylation, POH inhibited the enzymes itself. Our data highlight the impact of isoprenoids for post translational modification of small GTPases promoting proliferation, migration and invasion capabilities in glioma cells. PMID- 25497900 TI - Analysis of spontaneous hippocampal activity allows sensitive detection of acetylcholine-mediated effects. AB - INTRODUCTION: Excitation of Acetylcholine-mediated (Ach) transmission (especially if irreversible) may pose life-threatening adverse events by increasing neuronal network activity. Unfortunately, adequate detection of this liability during early drug development is hampered, because published ex vivo electrophysiological models are very insensitive to this regard. For example, Eserine, which reversibly inhibits acetylcholinesterase (AchE) in the double digit nM range, affects electrically evoked potentials in hippocampal slices only at >=10MUM. Here, a significantly more sensitive method for detecting Ach mediated alternations is presented by analyzing spontaneous neuronal network activity in hippocampal slices. METHODS: The microelectrode array (MEA) technique with an 8*8 electrode grid was applied to analyze evoked and spontaneous extracellular field recordings in parallel from acute rat hippocampal slices. For evoked potentials, the Schaffer collateral CA3-CA1 pathway was electrically stimulated and the resulting field potential analyzed at the CA1 pyramidal layer. Spontaneous spike activity was detected as negative inflections from the 100Hz high pass filtered signal. Spike frequency was analyzed within the whole CA1 region. RESULTS: Modification of Ach-mediated neuronal transmission via carbachol, Eserine, or Diisopropylfluorophosphate (DFP) does not induce any effects on evoked field potentials at physiologically relevant concentrations. Similar to previous reports, subtle effects were detectable at very high concentrations. By contrast, spontaneous spike frequency was already increased within the expected concentration range. Eserine-induced effects can also be reversed by atropine and washout. On the contrary, effects by the irreversible AchE-blocker DFP could not be washed out. DISCUSSION: Compared to evoked field potentials, spontaneous spike activity in the hippocampal CA1 region appears to be a significantly more sensitive parameter for functional electrophysiological analysis of drug induced Ach-mediated effects. This finding may supplement existing models for detection and prediction of drug-related adverse effects like seizure liability already during early development stages. PMID- 25497902 TI - Effects of anthropogenic and demographic factors on patterns of parasitism in African small mammal communities--corrigendum. PMID- 25497901 TI - Rapid analysis of hypolipidemic drugs in a live zebrafish assay. AB - INTRODUCTION: Hyperlipidemia is the most common form of dyslipidemia, which is the key risk factor for cardiovascular disease and stroke. The development of effective and safe drug treatments for hyperlipidemia has been proven challenging. METHODS: In this study, taking advantage of the transparency of larval zebrafish, we developed a zebrafish hyperlipidemia model for drug screening and efficacy assessment. Zebrafish at 5 d.p.f (days post fertilization) were fed with 0.1% egg yolk for 48 h (hours), followed by drug treatment for 24h or 48 h. Tested drugs were administered into the zebrafish by direct soaking. Drug effect was evaluated based on quantitative analysis of Oil Red O (ORO) in zebrafish vena caudalis. RESULTS: All 5 human hypolipidemic drugs (simvastatin, lovastatin, ezetimibe, bezafibrate and hyodesoxycholic acid) showed significant hypolipidemic effects (p<0.01) in a dose-dependent manner in the zebrafish hyperlipidemia model. 'We also found a well-known Chinese tea Pu-erh tea significantly reduced lipids in this model (p<0.001 and p<0.01). DISCUSSION: Our results demonstrate that the zebrafish hyperlipidemia model developed and validated in this study could be used for in vivo hyperlipidemia studies and drug screening and for assessing hypolipidemic drugs with different mechanisms. PMID- 25497903 TI - Matrix Biology highlights. PMID- 25497904 TI - Survival and relapse free period of 2926 unselected older breast cancer patients: a FOCUS cohort study. AB - BACKGROUND: Previous studies have shown that breast cancer survival decreases with increasing age among older patients who participate in trials. However, trial participants differ from patients in the general population. Therefore, the aim of this study was to evaluate the association between age and breast cancer outcome in an unselected group of older breast cancer patients. METHODS: We included all older (65 years and older) consecutive breast cancer patients, diagnosed between 1997 and 2004 from a geographically defined area in the Netherlands. Primary outcome was relative survival and the secondary endpoint was breast cancer recurrence. These outcomes were compared between two age-categories (65-74 years and >=75 years). RESULTS: Five-year relative survival was 91.9% in patients aged 65-74 years, and 84.3% in patients aged >=75 years. This corresponded with a higher excess risk of death in patients aged >=75 years as compared to patients aged 65-74 years (multivariable relative excess risk of death: 1.73 (95% CI 1.20-2.49)). The risks of locoregional recurrence, distant recurrence and contralateral breast cancer were similar in both age-categories. CONCLUSIONS: Breast cancer survival deteriorates with increasing age among unselected older breast cancer patients. Of note, this was not accompanied by an increased risk of recurrence. This study shows that not only in relatively healthy patients who participate in a trial, but in all older breast cancer patients, outcome deteriorates with increasing age. These findings urge the need for age-specific breast cancer studies, in order to obtain evidence-based medicine in this large and heterogeneous group of patients. PMID- 25497906 TI - Letter from the editor: Combining PET with MRI. PMID- 25497907 TI - Letter from the guest editors. PMID- 25497905 TI - Estradiol regulation of hypothalamic astrocyte adenosine 5'-monophosphate activated protein kinase activity: role of hindbrain catecholamine signaling. AB - Recent work challenges the conventional notion that metabolic monitoring in the brain is the exclusive function of neurons. This study investigated the hypothesis that hypothalamic astrocytes express the ultra-sensitive energy gauge adenosine 5'-monophosphate-activated protein kinase (AMPK), and that the ovarian hormone estradiol (E) controls activation of this sensor by insulin-induced hypoglycemia (IIH). E- or oil (O)-implanted ovariectomized (OVX) rats were pretreated by caudal fourth ventricular administration of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) prior to sc insulin or vehicle injection. Individual astrocytes identified in situ by glial fibrillary acidic protein immunolabeling were laser-microdissected from the ventromedial (VMH), arcuate (ARH), and paraventricular (PVH) nuclei and the lateral hypothalamic area (LHA), and pooled within each site for Western blot analysis of AMPK and phosphoAMPK (pAMPK) protein expression. In the VMH, baseline astrocyte AMPK and pAMPK levels were respectively increased or decreased in OVX+E versus OVX+O; these profiles did not differ between E and O rats in other hypothalamic loci. In E animals, astrocyte AMPK protein was reduced [VMH] or augmented [PVH; LHA] in response to either 6-OHDA or IIH. IIH increased astrocyte pAMPK expression in each structure in vehicle-, but not 6-OHDA-pretreated E rats. Results provide novel evidence for hypothalamic astrocyte AMPK expression and hindbrain catecholamine-dependent activation of this cell-specific sensor by hypoglycemia in the presence of estrogen. Further research is needed to determine the role of astrocyte AMPK in reactivity of these glia to metabolic imbalance and contribution to restoration of neuro-metabolic stability. PMID- 25497908 TI - Early response monitoring of receptor tyrosine kinase inhibitor therapy in metastatic renal cell carcinoma using [F-18]fluorothymidine-positron emission tomography-magnetic resonance. PMID- 25497909 TI - Positron emission tomography-magnetic resonance imaging: technical review. PMID- 25497910 TI - Artifacts and diagnostic pitfalls in positron emission tomography-magnetic resonance imaging. PMID- 25497911 TI - Management and organization of positron emission tomography/magnetic resonance imaging. PMID- 25497912 TI - Positron emission tomography-magnetic resonance imaging in the evaluation of brain tumors: current status and future prospects. PMID- 25497913 TI - Heterogeneous effect of gestational weight gain on birth weight: quantile regression analysis from a population-based screening. AB - PURPOSE: Classical regression models might give an incomplete picture of the associations between predictors and outcomes. We investigated associations between gestational weight gain (GWG) and birth weight along the entire birth weight distribution with quantile regression and estimated effects of hypothetical prevention strategies. METHODS: The GWG-birth weight association was analyzed using quantile and classical regression models on data from a population based gestational diabetes screening (n = 4760) at the Szent Imre Teaching Hospital in Budapest, Hungary (2002-2005). Birth weight distributions were modeled based on hypothetical GWG changes. RESULTS: At a body mass index of 20 kg/m(2), a 1-kg difference in GWG was associated with a 14.2 g (95% confidence interval, 10.0-20.9) higher birth weight at the fifth percentile of the birth weight distribution and a 29.0 g (21.3-35.6) higher birth weight at the 95th percentile. The coefficient from linear regression was 20.7 (17.5-24.0). Estimates differed modestly between the two regressions at a body mass index of 30 kg/m(2). A population-wide 2-kg decrease in GWG would rather affect the risk of macrosomia (-1.8%) than that of low birth weight (+0.4%). In contrast, a 3-kg decrease in GWG among overweight and obese women would lower macrosomia more modestly (-0.8%). CONCLUSIONS: A population-wide lowering of GWG would lead to greater improvements in the right tail of the birth weight distribution. PMID- 25497914 TI - Liquid culture fermentation for rapid production of desiccation tolerant blastospores of Beauveria bassiana and Isaria fumosorosea strains. AB - A major constraint to the commercial use of fungal biocontrol agents is the availability of low-cost production media and processes. Previous attempts in producing Beauveria blastospores using liquid culture fermentation processes required long fermentation times (6-8days) and produced cells that had poor survival after desiccation and storage. In this study, isolates of Beauveria bassiana and Isaria fumosorosea were evaluated for blastospore yield, desiccation tolerance, storage stability, and biocontrol efficacy using fermentation media containing acid hydrolyzed casein or cottonseed flour as the nitrogen source. Cultures of B. bassiana and I. fumosorosea grown in media containing cottonseed flour produced high blastospore concentrations (>1*10(9)mL(-1)) after 3days which is comparatively less expensive nitrogen source than acid hydrolyzed casein. The resultant air-dried blastospores (<3% moisture) of all fungal isolates survived drying (61-86% viability), irrespective of the nitrogen source tested. Storage stability at 4 degrees C varied with nitrogen source and fungal strain. Air-dried blastospores of B. bassiana strains showed half-lives >14months in contrast to 9.2-13.1months for I. fumosorosea. Blastospores of B. bassiana and I. fumosorosea killed Bemisia tabaci whitefly nymphs faster and required lower concentrations compared with aerial conidia. Our findings support the use of liquid culture fermentation as a cost-effective process to rapidly produce high yields of stable and infective blastospores of either B. bassiana or I. fumosorosea. These results support further evaluation of blastospore sprayable formulations for the control of soft-bodied insects. PMID- 25497915 TI - The N-terminal repeat and the ligand binding domain A of SdrI protein is involved in hydrophobicity of S. saprophyticus. AB - Staphylococcus saprophyticus is an important cause of urinary tract infection, and its cell surface hydrophobicity may contribute to virulence by facilitating adherence of the organism to uroepithelia. S. saprophyticus expresses the surface protein SdrI, a member of the serine-aspartate repeat (SD) protein family, which has multifunctional properties. The SdrI knock out mutant has a reduced hydrophobicity index (HPI) of 25%, and expressed in the non-hydrophobic Staphylococcus carnosus strain TM300 causes hydrophobicity. Using hydrophobic interaction chromatography (HIC), we confined the hydrophobic site of SdrI to the N-terminal repeat region. S. saprophyticus strains carrying different plasmid constructs lacking either the N-terminal repeats, both B or SD-repeats were less hydrophobic than wild type and fully complemented SdrI mutant (HPI: 51%). The surface hydrophobicity and HPI of both wild type and the complemented strain were also influenced by calcium (Ca(2+)) and were reduced from 81.3% and 82.4% to 10.9% and 12.3%, respectively. This study confirms that the SdrI protein of S. saprophyticus is a crucial factor for surface hydrophobicity and also gives a first significant functional description of the N-terminal repeats, which in conjunction with the B-repeats form an optimal hydrophobic conformation. PMID- 25497916 TI - Endophytic Bacillus spp. produce antifungal lipopeptides and induce host defence gene expression in maize. AB - Endophytes are mutualistic symbionts within healthy plant tissues. In this study we isolated Bacillus spp. from seeds of several varieties of maize. Bacillus amyloliquifaciens or Bacillus subtilis were found to be present in all maize varieties examined in this study. To determine whether bacteria may produce antifungal compounds, generally lipopeptides in Bacillus spp., bacterial cultures were screened for production of lipopeptides. Lipopeptides were extracted by acid precipitation from liquid cultures of Bacillus spp. Lipopeptide extracts from Bacillus spp. isolated from Indian popcorn and yellow dent corn showed inhibitory activity against Fusarium moniliforme at 500MUg per disk. Using MALDI-TOF mass spectrometry we detected the presence of antifungal iturin A, fengycin and bacillomycin in these isolates. PCR amplification also showed the presence of genes for iturin A and fengycin. B. subtilis (SG_JW.03) isolated from Indian popcorn showed strong inhibition of Arabidopsis seed mycoflora and enhanced seedling growth. We tested for the induction of defence gene expression in the host plant after treatment of plants with B. subtilis (SG_JW.03) and its lipopeptide extract using RT-qPCR. Roots of Indian popcorn seedlings treated with a suspension of B. subtilis (SG_JW.03) showed the induction of pathogenesis related genes, including PR-1 and PR-4, which relate to plant defence against fungal pathogens. The lipopeptide extract alone did not increase the expression of these pathogenesis-related genes. Based on our study of maize endophytes, we hypothesize that, bacterial endophytes that naturally occur in many maize varieties may function to protect hosts by secreting antifungal lipopeptides that inhibit pathogens as well as inducing the up-regulation of pathogenesis-related genes of host plants (systemic acquired resistance). PMID- 25497917 TI - Epstein-Barr virus: dermatologic associations and implications: part I. Mucocutaneous manifestations of Epstein-Barr virus and nonmalignant disorders. AB - Epstein-Barr virus (EBV) is a ubiquitous virus that has been implicated in a wide range of human diseases, many of which have mucocutaneous manifestations. As a member of the herpesviridae family, EBV causes lifelong infection by establishing latency in B lymphocytes. An intact immune response is critical in preventing progression of EBV disease, and the clinical manifestations of infection are dependent on the intricate relationship between virus and host immune system. This review provides a comprehensive overview of the epidemiology, pathophysiology, and diagnostic testing in EBV infection. In part I of this continuing medical education article, the mucocutaneous manifestations of EBV infection are reviewed with an emphasis on pathophysiology and management. PMID- 25497918 TI - Epstein-Barr virus: dermatologic associations and implications: part II. Associated lymphoproliferative disorders and solid tumors. AB - Epstein-Barr virus (EBV) was the first human virus to be associated with oncogenesis. Over the past few decades, cumulative research has revealed that latent EBV infection may be implicated in the pathogenesis of a heterogeneous group of lymphoproliferative disorders and malignancies occurring in both immunocompetent and immunocompromised hosts. Many of these diseases have either primary or secondary cutaneous manifestations. Serologic studies and EBV-encoded RNA in situ hybridization stains have been used to show the association of EBV with disease; while these findings may imply a role, they do not equate with causation. In part II of this continuing medical education review, the salient features of EBV-associated lymphoproliferative disorders and solid tumors are detailed. PMID- 25497919 TI - The case for equal access to urgent dermatology appointments for Medicaid beneficiaries: when professional duty conflicts with economic reality. PMID- 25497920 TI - A unique psoriasis biologics clinic serving underprivileged patients in the United States. PMID- 25497921 TI - It's time for "keratinocyte carcinoma" to replace the term "nonmelanoma skin cancer". PMID- 25497922 TI - Pressure alopecia: clinical findings and prognosis. PMID- 25497923 TI - Smoking behavior and association of melanoma and nonmelanoma skin cancer in the Women's Health Initiative. PMID- 25497924 TI - Medicaid acceptance among pediatric dermatologists. PMID- 25497925 TI - Smartphones, photography, and security in dermatology. PMID- 25497926 TI - Mohs micrographic surgery in the treatment of trichilemmal carcinoma: the Mayo Clinic experience. PMID- 25497927 TI - Comments on "Lack of efficacy with 1064-nm neodymium:yttrium-aluminum-garnet laser for the treatment of onychomycosis: a randomized controlled trial". PMID- 25497928 TI - Regarding "The use of donated products to train residents to perform injectable cosmetic procedures". PMID- 25497929 TI - Reply: Injectable products considered "samples". PMID- 25497930 TI - Statistical comments on "Increased serum levels of interleukin 33 in patients with atopic dermatitis". PMID- 25497931 TI - Response to "Statistical comments on 'Increased serum levels of interleukin 33 in patients with atopic dermatitis'". PMID- 25497932 TI - Reply to: "Commenting on: Duration of efficacy increases with the repetition of botulinum toxin A injections in primary palmar hyperhidrosis". PMID- 25497933 TI - Commenting on: "Duration of efficacy increases with the repetition of botulinum toxin A injections in primary palmar hyperhidrosis". PMID- 25497941 TI - Getting the most from your dermatoscope. PMID- 25497942 TI - Clinical photography of nail diseases: a simple method to include all fingernails in a frame. PMID- 25497943 TI - Creating a sterile field for plantar procedures. PMID- 25497944 TI - The pulley set-back dermal suture: an easy to implement everting suture technique for wounds under tension. PMID- 25497946 TI - Facial adenocarcinoma treated with intra-arterial chemotherapy. PMID- 25497948 TI - Ulcerations within striae distensae associated with bevacizumab therapy. PMID- 25497947 TI - Resolution of urticarial vasculitis after treatment of neurocysticercosis. PMID- 25497949 TI - Psoriasis as a manifestation of HIV-related immune reconstitution inflammatory syndrome. PMID- 25497950 TI - Granulomatous rosacea manifesting after herpes simplex 2 infection: a case of Wolf's isotopic response. PMID- 25497951 TI - Large epidermal cleft formation in verrucous-keratotic malignant melanoma of the heel. PMID- 25497952 TI - Acral localized acquired cutis laxa: report of a case associated with inflammatory arthritis. PMID- 25497953 TI - Successful use of a modified Goeckerman regimen in the treatment of generalized prurigo nodularis. PMID- 25497954 TI - PsAPASH: a new syndrome associated with hidradenitis suppurativa with response to tumor necrosis factor inhibition. PMID- 25497955 TI - Synchronous Paget disease of the breast and axilla. PMID- 25497959 TI - Regulation of serum-responsive transmembrane kinase EhTMKB1-9 by an unsaturated lipid, oleic acid in protistan parasite Entamoeba histolytica. AB - Transmembrane kinases of Entamoeba histolytica are known to play a wide range of roles from virulence, phagocytosis, and proliferation to stress response. Transmembrane kinase EhTMKB1-9 is thought to be involved in early proliferative response and it was originally identified as a serum inducible gene. Ability to stimulate EhTMKB1 expression of serum starved cells resides in unsaturated fatty acids associated with albumin fraction of serum and the mechanism of stimulation follows activation of EhTMKB1-9 promoter. Gel shift assay showed the presence of proteins that bind to the specific site of EhTMKB1-9 upstream region and the concentration of these protein(s) go down on serum starvation, but level of binding protein(s) go up on serum or fatty acid replenishment. This increase in concentration of binding molecule(s) is due to new synthesis rather than activation of existing molecule(s) as a protein synthesis inhibitor blocked enhanced level of gel shifted material on replenishment. The stimulating activity resides in the fatty acyl chain, but not in the head group. Moreover, the fatty acid initiates signaling through class I PI3 kinases that result in activation of EhTMKB1-9 expression. These results suggest a novel mechanism of gene regulation in E. histolytica, and unsaturated fatty acids as potential new signaling molecules. PMID- 25497960 TI - Analysis of a compartmental model of amyloid beta production, irreversible loss and exchange in humans. AB - Amyloid beta (Abeta) peptides, and in particular Abeta42, are found in senile plaques associated with Alzheimer's disease. A compartmental model of Abeta production, exchange and irreversible loss was recently developed to explain the kinetics of isotope-labeling of Abeta peptides collected in cerebrospinal fluid (CSF) following infusion of stable isotope-labeled leucine in humans. The compartmental model allowed calculation of the rates of production, irreversible loss (or turnover) and short-term exchange of Abeta peptides. Exchange of Abeta42 was particularly pronounced in amyloid plaque-bearing participants. In the current work, we describe in much greater detail the characteristics of the compartmental model to two distinct audiences: physician-scientists and biokineticists. For physician-scientists, we describe through examples the types of questions the model can and cannot answer, as well as correct some misunderstandings of previous kinetic analyses applied to this type of isotope labeling data. For biokineticists, we perform a system identifiability analysis and a sensitivity analysis of the kinetic model to explore the global and local properties of the model. Combined, these analyses motivate simplifications from a more comprehensive physiological model to the final model that was previously presented. The analyses clearly demonstrate that the current dataset and compartmental model allow determination with confidence a single 'turnover' parameter, a single 'exchange' parameter and a single 'delay' parameter. When combined with CSF concentration data for the Abeta peptides, production rates may also be obtained. PMID- 25497961 TI - Identification of a novel glycan processing enzyme with exo-acting beta allosidase activity in the Golgi apparatus using a new platform for the synthesis of fluorescent substrates. AB - The majority of eukaryotic proteins undergo post-translational modifications (PTMs) involving the attachment of complex glycans, predominantly through N glycosylation and O-glycosylation. PTMs play important roles in virtually all cellular processes, and aberrant regulation of protein glycosylation and glycan processing has been implicated in various diseases. However, glycan processing on proteins in various cellular contexts has not been visualized. We had previously developed a quinone methide cleavage (QMC) platform for enhanced substrate design. This platform was applied here to screen for novel glycan-processing enzymes. We designed and synthesized fluorescent substrates with beta allopyranoside residues using the QMC platform. When applied in cell-based assays, the fluorescent substrates allowed rapid and clear visualization of beta allosidase activity in the Golgi apparatus of human cultured cells. The QMC platform will likely find broad applications in visualizing the activities of glycan processing enzymes in living cells and in studying PTMs. PMID- 25497962 TI - Clofazimine analogs with antileishmanial and antiplasmodial activity. AB - A set of novel riminophenazine derivatives has been synthesized and evaluated for in vitro activity against chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) strains of Plasmodium falciparum and against different species of Leishmania promastigotes. Most of the new compounds inhibited the growth of Leishmania promastigotes as well as CQ-S and CQ-R strains of P. falciparum with IC50 in submicromolar range, resulting in the best cases 1-2 orders of magnitude more potent than the parent compound clofazimine. PMID- 25497963 TI - Bioactive constituents from the green alga Caulerpa racemosa. AB - Three diterpenoids, including a pair of epimers, racemobutenolids A and B (1 and 2), and 4',5'-dehydrodiodictyonema A (3), an alpha-tocopheroid, alpha tocoxylenoxy (8), and an 28-oxostigmastane steroid, (23E)-3beta-hydroxy-stigmasta 5,23-dien-28-one (11), together with 12 known compounds, were isolated from the green alga Caulerpa racemosa. The structures of the new compounds were elucidated by detailed analysis of spectroscopic data, and by comparison with data for related known compounds. The epimers (1 and 2) are two unusual diterpenoid lactones bearing a beta-methyl-gamma-substituted butenolide moiety, and 3 and 8 represent the first naturally occurring natural products with a hematinic acid ester group and 3,5-dimethylphenoxy functionality, respectively. The enzyme inhibitory activities of the isolated compounds were evaluated in vitro against PTP1B and related PTPs (TCPTP, CDC25B, LAR, SHP-1, and SHP-2). Compounds 3, 5, 6, and 9-14 exhibited different levels of PTP1B inhibitory activities with IC50 values ranging from 2.30 to 50.02MUM. Of these compounds, 3, 9, and 11 showed the most potent inhibitory activities towards PTP1B with IC50 values of 2.30, 3.85, and 3.80MUM, respectively. More importantly, the potent PTP1B inhibitors 3, 9, and 11 also displayed high selectivity over the highly homologous TCPTP and other PTPs. Also, the neuroprotective effects of the isolates against Abeta25-35 induced cell damage in SH-SY5Y cells were investigated. Compounds 10, 11, and 14 exhibited significant neuroprotective effects against Abeta25-35-induced SH-SY5Y cell damage with 11.31-15.98% increases in cell viability at 10MUM. In addition, the cytotoxic activities of the isolated compounds were tested against the human cancer cell lines A-549 and HL-60. PMID- 25497964 TI - 4(alpha-l-rhamnosyloxy)-benzyl isothiocyanate, a bioactive phytochemical that attenuates secondary damage in an experimental model of spinal cord injury. AB - 4(alpha-l-Rhamnosyloxy)-benzyl isothiocyanate (glucomoringin isothiocyanate; GMG ITC) is released from the precursor 4(alpha-l-rhamnosyloxy)-benzyl glucosinolate (glucomoringin; GMG) by myrosinase (beta-thioglucoside glucohydrolase; E.C. 3.2.1.147) catalyzed hydrolysis. GMG is an uncommon member of the glucosinolate group as it presents a unique characteristic consisting in a second glycosidic residue within the side chain. It is a typical glucosinolate found in large amounts in the seeds of Moringa oleifera Lam., the most widely distributed plant of the Moringaceae family. GMG was purified from seed-cake of M. oleifera and was hydrolyzed by myrosinase at neutral pH in order to form the corresponding GMG ITC. This bioactive phytochemical can play a key role in counteracting the inflammatory response connected to the oxidative-related mechanisms as well as in the control of the neuronal cell death process, preserving spinal cord tissues after injury in mice. Spinal cord trauma was induced in mice by the application of vascular clips (force of 24g) for 1 min., via four-level T5-T8 after laminectomy. In particular, the purpose of this study was to investigate the dynamic changes occurring in the spinal cord after ip treatment with bioactive GMG-ITC produced 15 min before use from myrosinase-catalyzed hydrolysis of GMG (10mg/kg body weight+5 MUl Myr mouse/day). The following parameters, such as histological damage, distribution of reticular fibers in connective tissue, nuclear factor (NF)-kappaB translocation and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkappaB-alpha) degradation, expression of inducible Nitric Oxide Synthases (iNOS), as well as apoptosis, were evaluated. In conclusion, our results show a protective effect of bioactive GMG-ITC on the secondary damage, following spinal cord injury, through an antioxidant mechanism of neuroprotection. Therefore, the bioactive phytochemical GMG-ITC freshly produced before use by myrosinase-catalyzed hydrolysis of pure GMG, could prove to be useful in the treatment of spinal cord trauma. PMID- 25497965 TI - Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach. AB - Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti diabetes and obesity drugs with a safer profile. PMID- 25497966 TI - Glucose excursions and glycaemic control during Ramadan fasting in diabetic patients: insights from continuous glucose monitoring (CGM). AB - AIM: Ramadan fasting represents a major shift in meal timing and content for practicing Muslims. This study used continuous glucose monitoring (CGM) to assess changes in markers of glycaemic excursions during Ramadan fasting to investigate the short-term safety of this practice in different groups of patients with diabetes. METHODS: A total of 63 subjects (56 with diabetes, seven healthy volunteers; 39 male, 24 female) had CGM performed during, before and after Ramadan fasting. Mean CGM curves were constructed for each group for these periods that were then used to calculate indicators of glucose control and excursions. Post hoc data analyses included comparisons of different medication categories (metformin/no medication, gliptin, sulphonylurea and insulin). Medication changes during Ramadan followed American Diabetes Association guidelines. RESULT: Among patients with diabetes, there was a significant difference in mean CGM curve during Ramadan, with a slow fall during fasting hours followed by a rapid rise in glucose level after the sunset meal (iftar). The magnitude of this excursion was greatest in the insulin-treated group, followed by the sulphonylurea-treated group. Markers of control deteriorated in a small number (n=3) of patients. Overall, whether fasting or non-fasting, subjects showed no statistically significant changes in mean interstitial glucose (IG), mean amplitude of glycaemic excursion (MAGE), high and low blood glucose indices (HBGI/LBGI), and number of glucose excursions and rate of hypoglycaemia. CONCLUSION: The main change in glycaemic control with Ramadan fasting in patients with diabetes is in the pattern of excursions. Ramadan fasting caused neither overall deterioration nor improvement in the majority of patients with good baseline glucose control. PMID- 25497967 TI - Effect of phytosterols/stanols on LDL concentration and other surrogate markers of cardiovascular risk. AB - Plant sterols and stanols are well-known to reduce LDL-cholesterol (LDL-C) concentrations. It is generally accepted that supplementation with 2g/day of sterols/stanols leads to a 10% reduction in LDL. However, most of the clinical trials supporting this conclusion were of short-term duration, and the results of longer interventions are scanty. In four studies, interventions lasting>6 months were carried out and the LDL-C-lowering effects were maintained over this longer duration, although some results suggest that a reduced effect may be observed with sterols, while stanols maintain their effect. In any case, the data are too limited to be definitive. In a free-living population as well as in multiparametric interventional studies, however, the LDL-C-lowering effect has been confirmed, although to a lesser extent than in clinical studies. In the absence of data on cardiovascular morbidity and mortality, data for surrogate markers of cardiovascular risk could be considered adequate alternatives. Several studies have been conducted on this basis, but their results failed to demonstrate any favourable effects. The present report summarizes the different results obtained in long-term studies, and in those comparing the effects of sterols and stanols on lipids and other surrogate markers of cardiovascular risk. PMID- 25497968 TI - Potential risks associated with increased plasma plant-sterol levels. AB - The consumption of plant sterols is associated with a decrease in LDL cholesterol. However, it is also associated with an increase in plasma plant sterol (sitosterol, campesterol) levels that may be detrimental. Indeed, the genetic disease sitosterolaemia, which is characterized by elevated plasma levels of plant sterol, is associated with premature atherosclerosis. Yet, although plasma plant-sterol levels are recognized markers of cholesterol absorption, the relationship between such levels and atherosclerosis is not clear. Several studies have analysed the association between plasma plant-sterol levels and cardiovascular disease (CVD), but have found conflicting results. Although the largest prospective trials and genome-wide association studies suggest that high plasma levels of plant sterols are associated with increased CV risk, other studies have reported no such association and even an inverse relationship. Thus, the available data cannot confirm an increased CV risk with plant sterols, but cannot rule it out either. Only a prospective interventional trial to analyse the effects of plant-sterol-enriched food on the occurrence of CV events can exclude a potential CV risk linked with their consumption. PMID- 25497969 TI - Ndt80p is involved in L-sorbose utilization through regulating SOU1 in Candida albicans. AB - Ndt80p, a known transcriptional factor, regulates various targets involved in stress responses, filamentous growth, and virulence in Candida albicans. Potential targets of Ndt80p have been identified at the transcriptional level. The present study was conducted to identify genes regulated by Ndt80p from the protein level. We found that the levels of Ahp1p, Fma1p, Hsp21p, Rfa2p, Snz1p, Sod1p, Sou1p, Trp99p, orf19.251, orf19.1862, and orf19.5620, were affected by the null mutation of NDT80 by two-dimensional polyacrylamide gel-electrophoresis analysis. Among the 11 proteins, all but Sou1p and Rfa2p are suggested to be involved in known functions of Ndt80p. Here, we demonstrate that Ndt80p plays a role in l-sorbose utilization through regulating SOU1 in C. albicans. PMID- 25497970 TI - Increasing burden of urinary tract infections due to intrinsic colistin-resistant bacteria in hospitals in Marseille, France. AB - The emergence of multidrug-resistant (MDR) Gram-negative bacteria has become a major public health problem, eliciting renewed interest in colistin, an old antibiotic that is now routinely used to treat MDR bacterial infections. Here we investigated whether colistin use has affected the prevalence of infections due to intrinsic colistin-resistant bacteria (CRB) in university hospitals in Marseille (France) over a 5-year period. All data from patients infected by intrinsic CRB were compiled from January 2009 to December 2013. Escherichia coli infections were used for comparison. Colistin consumption data were also collected from pharmacy records from 2008 to 2013. A total of 4847 intrinsic CRB infections, including 3150 Proteus spp., 847 Morganella spp., 704 Serratia spp. and 146 Providencia spp., were collected between 2009 and 2013. During this period, the annual incidence rate of hospital-acquired CRB infections increased from 220 per 1000 patients to 230 per 1000 patients and that of community acquired CRB infections increased from 100 per 1000 patients to 140 per 1000 patients. In parallel, colistin consumption increased 2.2-fold from 2008 to 2013, mainly because of an increase in the use of colistin aerosol forms (from 50 unitary doses to 2926 unitary doses; P<10(-5)) that was significantly correlated with an increase in the number of patients positive for CRB admitted to ICUs and units of long-term care between 2009 and 2013 (r=0.91; P=0.03). The global rise in infections due to intrinsic CRB is worrying and surveillance is warranted to better characterise this intriguing epidemiological change. PMID- 25497971 TI - Human knockout research: new horizons and opportunities. AB - Although numerous approaches have been pursued to understand the function of human genes, Mendelian genetics has by far provided the most compelling and medically actionable dataset. Biallelic loss-of-function (LOF) mutations are observed in the majority of autosomal recessive Mendelian disorders, representing natural human knockouts and offering a unique opportunity to study the physiological and developmental context of these genes. The restriction of such context to 'disease' states is artificial, however, and the recent ability to survey entire human genomes for biallelic LOF mutations has revealed a surprising landscape of knockout events in 'healthy' individuals, sparking interest in their role in phenotypic diversity beyond disease causation. As I discuss in this review, the potentially wide implications of human knockout research warrant increased investment and multidisciplinary collaborations to overcome existing challenges and reap its benefits. PMID- 25497972 TI - Microbicidal activity of neutrophils is inhibited by isolates from recurrent vaginal candidiasis (RVVC) caused by Candida albicans through fungal thioredoxin reductase. AB - Vulvovaginal candidiasis (VVC) is characterized by an infection of the vulva and vagina, mainly caused by Candida albicans, a commensal microorganism that inhabits the vaginal, digestive, and respiratory mucosae. Vulvovaginal candidiasis affects approximately 75% of women, and 5% develop the recurrent form (RVVC). The aim of the present study was to evaluate whether neutrophils microbicidal response is triggered when activated with RVVC isolates caused by C. albicans. Our results showed that RVVC isolates induced neutrophil migration but significantly decrease the microbicidal activity of neutrophils, compared with VVC and ASS isolates. The microbicidal activity of neutrophils is highly dependent on the production of reactive oxygen species/reactive nitrogen species (ROS/RNS). However, this isolate induced detoxification of ROS/RNS produced by neutrophils, reflected by the high level of thiol groups and by the oxygen consumption. Therefore, RVVC isolates induced biochemical changes in the inflammatory response triggered by neutrophils, and these effects were mainly related to the detoxification of ROS/RNS through the thioredoxin reductase (TR), a key antioxidant enzyme in fungi. This might be one of the resistance mechanisms triggered by RVVC caused by C. albicans. PMID- 25497973 TI - Ectopic expression of Fas Ligand on cardiomyocytes renders cardiac allografts resistant to CD4(+) T-cell mediated rejection. AB - Fas Ligand limits inflammatory injury and permits allograft survival by inducing apoptosis of Fas-bearing lymphocytes. Previous studies have shown that the CD4(+) T-cell is both sufficient and required for murine cardiac allograft rejection. Here, utilizing a transgenic mouse that over-expresses Fas Ligand specifically on cardiomyocytes as heart donors, we sought to determine if Fas Ligand on graft parenchymal cells could resist CD4(+) T-cell mediated rejection. When transplanted into fully immunocompetent BALB/c recipients Fas Ligand transgenic hearts were acutely rejected. However, when transplanted into CD4(+) T-cell reconstituted BALB/c-rag(-/-) recipients, Fas Ligand hearts demonstrated long term survival. These results indicate that Fas Ligand over-expression on cardiomyocytes can indeed resist CD4(+) T-cell mediated cardiac rejection and suggests contact dependence between Fas Ligand expressing graft parenchymal cells and the effector CD4(+) T-cells. PMID- 25497974 TI - Thrombomodulin inhibits the activation of eosinophils and mast cells. AB - Eosinophils and mast cells play critical roles in the pathogenesis of bronchial asthma. Activation of both cells leads to the release of pro-inflammatory mediators in the airway of asthmatic patients. Recently, we have shown that inhaled thrombomodulin inhibits allergic bronchial asthma in a mouse model. In the present study, we hypothesize that thrombomodulin can inhibit the activation of eosinophils and mast cells. The effect of thrombomodulin on the activation and release of inflammatory mediators from eosinophils and mast cells was evaluated. Thrombomodulin inhibited the eotaxin-induced chemotaxis, upregulation of CD11b and degranulation of eosinophils. Treatment with thrombomodulin also significantly suppressed the degranulation and synthesis of inflammatory cytokines and chemokines in eosinophils and mast cells. Mice treated with a low dose of inhaled thrombomodulin have decreased number of eosinophils and activated mast cells and Th2 cytokines in the lungs compared to untreated mice. The results of this study suggest that thrombomodulin may modulate allergic responses by inhibiting the activation of both eosinophils and mast cells. PMID- 25497975 TI - Five functional polymorphisms of B7/CD28 co-signaling molecules alter susceptibility to colorectal cancer. AB - Polymorphisms within the 3'-untranslated region (3'-UTR) of genes have been proved to contribute to the risk of cancers. Here, we determined 16 putatively functional polymorphisms in the 3'-UTR of 11 B7/CD28 genes in 382 colorectal cancer patients and 714 healthy controls. Statistical analysis revealed that ICOS rs4404254-C-allele carriers (p=0.0014), rs1559931-A-allele carriers (p=0.0027), and rs4675379-C-allele carriers (p=0.026) were significantly fewer in patients than those in controls. B7-H4-rs13505-GG homozygotes were more prevalent in patients (p=0.03). CD80-rs7628626-GT was apparently less in the patients with lymph node metastasis (p=0.004) or in advanced stage (p=0.037). Furthermore, we found that these polymorphisms impacted the regulatory role of miR-21-3p, miR-186 5p, miR-323b-5p, miR-1207-5p, miR-1279, miR-2117, and miR-3692-3p in the expression of the B7/CD28 molecules. Our findings suggest that rs7628626, rs13505, rs4404254, rs1559931, and rs4675379, through disrupting the regulatory role of miRNAs in the expression of B7/CD28 molecules, contribute to the occurrence and progress of colorectal cancer. PMID- 25497976 TI - Simultaneous occurrence of a CD30 positive/ALK-negative high grade T-cell lymphoma and plasma cell myeloma: Report of a case. AB - Simultaneous occurrences of T-cell and B-cell neoplasms are rare, and etiological relationships between these two malignancies are poorly understood. We report the case of a 76-year-old man who presented with hypercalcemia, multiple skin nodular lesions, fatigue, episodic fever, and night sweats. PET/CT scan showed diffuse skin and subcutaneous fat plane active lesions, supra- and infra- diaphragmatic active lymph nodes, liver and spleen involvement, bone marrow infiltration, and nonspecific bilateral lung nodules. A skin biopsy showed a high grade CD30 positive/ALK-negative T-cell lymphoma. A bone marrow biopsy showed involvement by the same neoplastic cells. Additionally, a monoclonal lambda restricted plasma cell population (15% of marrow elements) was identified, which, in view of an IgA lambda spike in the serum, was consistent with plasma cell myeloma. To the best of our knowledge, this case is the first reported case of a plasma cell neoplasm associated with an aggressive CD30-positive ALK-negative systemic T-cell lymphoma with skin involvement. Reporting such cases is important as it adds to the pool of rare cases of concomitant T-cell neoplasms and plasma cell myelomas, and might help in determining an etiological relationship, if any, between these two hematological malignancies. PMID- 25497977 TI - Early T cell precursor lymphoid blast crisis of chronic myeloid leukemia - a novel transformation. PMID- 25497978 TI - Unaddressed biases in reported prevalence of continuous deep sedation until death. PMID- 25497979 TI - Covariate adjustment had similar benefits in small and large randomized controlled trials. AB - OBJECTIVES: Covariate adjustment is a standard statistical approach in the analysis of randomized controlled trials. We aimed to explore whether the benefit of covariate adjustment on statistical significance and power differed between small and large trials, where chance imbalance in prognostic factors necessarily differs. STUDY DESIGN AND SETTING: We studied two large trial data sets [Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO-I), N = 30,510 and International Stroke Trial (IST), N = 18,372] repeatedly drawing random samples (500,000 times) of sizes 300 and 5,000 per arm and simulated each primary outcome using the control arms. We empirically determined the treatment effects required to fix power at 80% for all unadjusted analyses and calculated the joint probabilities in the discordant cells when cross-classifying adjusted and unadjusted results from logistic regression models (ie, P < 0.05 vs. P >= 0.05). RESULTS: The power gained from an adjusted analysis for small and large samples was between 5% and 6%. Similar proportions of discordance were noted irrespective of the sample size in both the GUSTO-I and the IST data sets. CONCLUSION: The proportions of change in statistical significance from covariate adjustment of strongly prognostic characteristics were the same for small and large trials with similar gains in statistical power. Covariate adjustment is equally recommendable in small and large trials. PMID- 25497981 TI - Electrochemical sensors using gold submicron particles modified electrodes based on calcium complexes formed with alizarin red S for determination of Ca(2+) in isolated rat heart mitochondria. AB - A simple glassy carbon electrode (GCE) modified with gold submicron particles (AuSPs), characterized by a mean diameter of about0.15-0.20MUm has been developed. Herein, the complexation reaction of Ca(2+) with alizarin red S (ARS), in 0.1M KOH, has been followed by electrochemical methods using the modified electrode which is able to catalyze the electro-reduction of ARS. When the stoichiometry ratio of Ca(2+) and ARS is 1:2, a new reduction peak at a higher negative potential of -0.975V appeared, and the peak of ARS at -0.815V disappeared. The peak current of ARS in alkaline solution is proportional to the concentration of Ca(2+) in the range 6.0*10(-7)-1.2*10(-4)M with a limit of detection (LOD) of 5.1*10(-7)M. Furthermore, the complex site of Ca(2+) with ARS was analysized by the experimental UV-vis and infrared spectrums and those calculated electronic and vibrational spectroscopies with density functional theory (DFT). The good accordance between theoretical and experimental data confirms that chelation of calcium ion preferentially occurs at the deprotonated catechol site. Then, we implemented an electrochemical assay for the investigation of Ca(2+) in preparations of isolated rat heart mitochondria, which demonstrates the submicron particles modified electrode is a simple and rapid sensor for determining the Ca(2+) in the biological samples. PMID- 25497982 TI - A cascade signal amplification strategy for surface enhanced Raman spectroscopy detection of thrombin based on DNAzyme assistant DNA recycling and rolling circle amplification. AB - A sensitive protocol for surface enhanced Raman spectroscopy (SERS) detection of thrombin is designed with R6G-Ag NPs as a signal tag by combining DNAzyme assistant DNA recycling and rolling circle amplification (RCA). Molecular beacon (MB) as recognition probe immobilizes on the glass slides and performs the amplification procedure. After thrombin-induced structure-switching DNA hairpins of probe 1, the DNAzyme is liberated from the caged structure, which hybridizes with the MB for cleavage of the MB in the presence of cofactor Zn(2+) and initiates the DNA recycling process, leading to the cleavage of a large number of MB and the generation of numerous primers for triggering RCA reaction. The long amplified RCA product which contained hundreds of tandem-repeat sequences, which can bind with oligonucleotide functionalized Ag NPs reporters. The attached signal tags can be easily read out by SERS. Because of the cascade signal amplification, these newly designed protocols provides a sensitive SERS detection of thrombin down to the femolar level (2.3fM) with a linear range of 5 orders of magnitude (from 10(-14) to 10(-9)M) and have high selectivity toward its target protein. The proposed method is expected to be a good clinical tool for the diagnosis of a thrombotic disease. PMID- 25497980 TI - Statistical approaches to harmonize data on cognitive measures in systematic reviews are rarely reported. AB - OBJECTIVES: To identify statistical methods for harmonization, the procedures aimed at achieving the comparability of previously collected data, which could be used in the context of summary data and individual participant data meta-analysis of cognitive measures. STUDY DESIGN AND SETTING: Environmental scan methods were used to conduct two reviews to identify (1) studies that quantitatively combined data on cognition and (2) general literature on statistical methods for data harmonization. Search results were rapidly screened to identify articles of relevance. RESULTS: All 33 meta-analyses combining cognition measures either restricted their analyses to a subset of studies using a common measure or combined standardized effect sizes across studies; none reported their harmonization steps before producing summary effects. In the second scan, three general classes of statistical harmonization models were identified (1) standardization methods, (2) latent variable models, and (3) multiple imputation models; few publications compared methods. CONCLUSION: Although it is an implicit part of conducting a meta-analysis or pooled analysis, the methods used to assess inferential equivalence of complex constructs are rarely reported or discussed. Progress in this area will be supported by guidelines for the conduct and reporting of the data harmonization and integration and by evaluating and developing statistical approaches to harmonization. PMID- 25497984 TI - Enhanced electrochemical sensing of thiols based on cobalt phthalocyanine immobilized on nitrogen-doped graphene. AB - A hybrid nanocomposite based on cobalt phthalocyanine (CoPc) immobilized on nitrogen-doped graphene (N-G) (N-G/CoPc) has been developed to modify glassy carbon electrode (GCE) for the sensitive detection of thiols. The nanocomposites were characterized by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and electrochemical impedance spectroscopy (EIS). Cyclic voltammetric studies showed that cobalt phthalocyanine and nitrogen doped graphene have a synergic effect and significantly enhance the electrocatalytic activity of the modified electrode towards thiols oxidation compared with electrodes modified with solely CoPc or N-G. The electrochemical oxidation responses were studied and the reaction mechanisms were discussed. The sensors exhibited a wide linear response range from 1MUMU to 16mM and a low detection limit of 1MUMU for the determination of l-cysteine, reduced l-glutathione and 2 mercaptoethanesulfonic acid in alkaline aqueous solution. The proposed N-G/CoPc hybrids contribute to the construction of rapid, convenient and low-cost electrochemical sensors for sensitive detection of thiols. PMID- 25497983 TI - A novel GMO biosensor for rapid ultrasensitive and simultaneous detection of multiple DNA components in GMO products. AB - Since the introduction of genetically modified organisms (GMOs), there has been on-going and continuous concern and debates on the commercialization of products derived from GMOs. There is an urgent need for development of highly efficient analytical methods for rapid and high throughput screening of GMOs components, as required for appropriate labeling of GMO-derived foods, as well as for on-site inspection and import/export quarantine. In this study, we describe, for the first time, a multi-labeling based electrochemical biosensor for simultaneous detection of multiple DNA components of GMO products on the same sensing interface. Two-round signal amplification was applied by using both an exonuclease enzyme catalytic reaction and gold nanoparticle-based bio-barcode related strategies, respectively. Simultaneous multiple detections of different DNA components of GMOs were successfully achieved with satisfied sensitivity using this electrochemical biosensor. Furthermore, the robustness and effectiveness of the proposed approach was successfully demonstrated by application to various GMO products, including locally obtained and confirmed commercial GMO seeds and transgenetic plants. The proposed electrochemical biosensor demonstrated unique merits that promise to gain more interest in its use for rapid and on-site simultaneous multiple screening of different components of GMO products. PMID- 25497985 TI - Approaching near real-time biosensing: microfluidic microsphere based biosensor for real-time analyte detection. AB - In this study we describe a simple lab-on-a-chip (LOC) biosensor approach utilizing well mixed microfluidic device and a microsphere-based assay capable of performing near real-time diagnostics of clinically relevant analytes such cytokines and antibodies. We were able to overcome the adsorption kinetics reaction rate-limiting mechanism, which is diffusion-controlled in standard immunoassays, by introducing the microsphere-based assay into well-mixed yet simple microfluidic device with turbulent flow profiles in the reaction regions. The integrated microsphere-based LOC device performs dynamic detection of the analyte in minimal amount of biological specimen by continuously sampling micro liter volumes of sample per minute to detect dynamic changes in target analyte concentration. Furthermore we developed a mathematical model for the well-mixed reaction to describe the near real time detection mechanism observed in the developed LOC method. To demonstrate the specificity and sensitivity of the developed real time monitoring LOC approach, we applied the device for clinically relevant analytes: Tumor Necrosis Factor (TNF)-alpha cytokine and its clinically used inhibitor, anti-TNF-alpha antibody. Based on the reported results herein, the developed LOC device provides continuous sensitive and specific near real time monitoring method for analytes such as cytokines and antibodies, reduces reagent volumes by nearly three orders of magnitude as well as eliminates the washing steps required by standard immunoassays. PMID- 25497986 TI - Detection of Hepatitis B virus antigen from human blood: SERS immunoassay in a microfluidic system. AB - A highly sensitive immunoassay utilizing surface-enhanced Raman scattering (SERS) has been developed with a new Raman reporter and a unique SERS-active substrate incorporated into a microfluidic device. An appropriately designed Raman reporter, basic fuchsin (FC), gives strong SERS enhancement and has the ability to bind both the antibody and gold nanostructures. The fuchsin-labeled immuno-Au nanoflowers can form a sandwich structure with the antigen and the antibody immobilized on the SERS-active substrate based on Au-Ag coated GaN. Our experimental results indicate that this SERS-active substrate with its strong surface-enhancement factor, high stability and reproducibility plays a crucial role in improving the efficiency of SERS immunoassay. This SERS assay was applied to the detection of Hepatitis B virus antigen (HBsAg) in human blood plasma. A calibration curve was obtained by plotting the intensity of SERS signal of FC band at 1178cm(-1) versus the concentration of antigen. The low detection limit for Hepatitis B virus antigen was estimated to be 0.01IU/mL. The average relative standard deviation (RSD) of this method is less than 10%. This SERS immunoassay gives exact results over a broad linear range, reflecting clinically relevant HBsAg concentrations. It also exhibits high biological specificity for the detection of Hepatitis B virus antigen. PMID- 25497987 TI - A one-step electrochemiluminescence immunosensor preparation for ultrasensitive detection of carbohydrate antigen 19-9 based on multi-functionalized graphene oxide. AB - A one-step electrochemiluminescence (ECL) immunosensor for ultrasensitive detection of carbohydrate antigen 19-9 (CA19-9) was developed based on multi functionalized graphene oxide (GO), which was prepared with N-(4-aminobutyl)-N ethylisoluminol (ABEI) and CA19-9 antibody (anti-CA19-9) chemically bound to the surface of magnetic GO (nanoFe3O4@GO). ABEI and anti-CA19-9 acted as the electrochemiluminophore and the capture device for CA19-9 respectively. NanoFe3O4@GO enabled all the ABEI immobilized molecules electrochemically active due to its good conductivity, and brought multi-functionalized GO attracted on the surface of magnetic glass carbon electrode through magnetism. Thus the ECL immunosensor could be prepared through a one-step process that facilitates ultrasensitive detection of CA19-9. Under optimal conditions, the ECL intensity of the immunosensor decreased proportionally to the logarithmic concentrations of CA19-9 in the range of 0.001-5U/mL with a detection limit of 0.0005U/mL. This one step ECL immunosensor showed good performance in specificity, stability, reproducibility, regeneration and application. It opened a new avenue to apply multi-functionalized bionanomaterials in ECL immunoassay. PMID- 25497988 TI - Anti-inflammatory components of Chrysanthemum indicum flowers. AB - One new octulosonic acid derivative, chrysannol A (1), along with 17 known compounds (2-18), were isolated from Chrysanthemum indicum flowers. Their structures were determined from 1D NMR, 2D NMR, HR-ESI-MS spectral data, and comparisons with previous reports. The effects of these compounds on lipopolysaccharide (LPS)-induced nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) production by RAW 264.7 cells were investigated. Compound 8 showed the highest inhibition of NO production of 46.09% at a concentration of 10.0MUM. Compounds 7, 10, 11, and 16 inhibited TNF-alpha secretion at all concentration tested (0.4, 2.0, and 10.0MUM), with inhibition values ranging from 22.27% to 33.13%. In addition, compound 8 and 9 decrease COX-2 and iNOS protein on Western blot analysis in dose dependent manner. PMID- 25497990 TI - Estimation of the chemical-induced eye injury using a weight-of-evidence (WoE) battery of 21 artificial neural network (ANN) c-QSAR models (QSAR-21): part I: irritation potential. AB - Evaluation of potential chemical-induced eye injury through irritation and corrosion is required to ensure occupational and consumer safety for industrial, household and cosmetic ingredient chemicals. The historical method for evaluating eye irritant and corrosion potential of chemicals is the rabbit Draize test. However, the Draize test is controversial and its use is diminishing - the EU 7th Amendment to the Cosmetic Directive (76/768/EEC) and recast Regulation now bans marketing of new cosmetics having animal testing of their ingredients and requires non-animal alternative tests for safety assessments. Thus, in silico and/or in vitro tests are advocated. QSAR models for eye irritation have been reported for several small (congeneric) data sets; however, large global models have not been described. This report describes FDA/CFSAN's development of 21 ANN c-QSAR models (QSAR-21) to predict eye irritation using the ADMET Predictor program and a diverse training data set of 2928 chemicals. The 21 models had external (20% test set) and internal validation and average training/verification/test set statistics were: 88/88/85(%) sensitivity and 82/82/82(%) specificity, respectively. The new method utilized multiple artificial neural network (ANN) molecular descriptor selection functionalities to maximize the applicability domain of the battery. The eye irritation models will be used to provide information to fill the critical data gaps for the safety assessment of cosmetic ingredient chemicals. PMID- 25497989 TI - Reduced pulmonary function and increased pro-inflammatory cytokines in nanoscale carbon black-exposed workers. AB - BACKGROUND: Although major concerns exist regarding the potential consequences of human exposures to nanoscale carbon black (CB) particles, limited human toxicological data is currently available. The purpose of this study was to evaluate if nanoscale CB particles could be responsible, at least partially, for the altered lung function and inflammation observed in CB workers exposed to nanoscale CB particles. METHODS: Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), and Brunauer-Emmett-Teller were used to characterize CB. Eighty-one CB-exposed male workers and 104 non-exposed male workers were recruited. The pulmonary function test was performed and pro-inflammatory cytokines were evaluated. To further assess the deposition and pulmonary damage induced by CB nanoparticles, male BALB/c mice were exposed to CB for 6 hours per day for 7 or 14 days. The deposition of CB and the pathological changes of the lung tissue in mice were evaluated by paraffin sections and TEM. The cytokines levels in serum and lung tissue of mice were evaluated by ELISA and immunohistochemical staining (IHC). RESULTS: SEM and TEM images showed that the CB particles were 30 to 50 nm in size. In the CB workplace, the concentration of CB was 14.90 mg/m3. Among these CB particles, 50.77% were less than 0.523 micrometer, and 99.55% were less than 2.5 micrometer in aerodynamic diameter. The reduction of lung function parameters including FEV1%, FEV/FVC, MMF%, and PEF% in CB workers was observed, and the IL-1beta, IL-6, IL-8, MIP-1beta, and TNF- alpha had 2.86-, 6.85-, 1.49-, 3.35-, and 4.87-folds increase in serum of CB workers, respectively. In mice exposed to the aerosol CB, particles were deposited in the lung. The alveolar wall thickened and a large amount of inflammatory cells were observed in lung tissues after CB exposure. IL-6 and IL-8 levels were increased in both serum and lung homogenate. CONCLUSIONS: The data strongly suggests that nanoscale CB particles could be responsible for the lung function reduction and pro-inflammatory cytokines secretion in CB workers. These results, therefore, provide the first evidence of a link between human exposure to CB and long-term pulmonary effects. PMID- 25497991 TI - 90-day dietary toxicity study with esterified propoxylated glycerol (EPG) in rats. AB - The subchronic (90-day) toxicity of a "core" version of EPG was assessed in rats. Crl:CD-1(r)(ICR)BR rats (70/sex) received diets containing a constant level of 5% EPG (w/w) or adjusted to deliver 0 (control), 0.5, 1, or 2g/kg of body weight/day (g/kg bw/day). Subsets of animals from each group (20/sex) were evaluated after 30 days (interim sacrifice); the remainder after 90 days. EPG intake at all dose levels was associated with lower mean liver vitamin E levels; liver vitamin A and serum vitamin D were also lower, but less consistently. Animals given 5% EPG had higher fecal output (males) and cholesterol (males and females) without corresponding changes in serum cholesterol. Urinary pH was also mildly lower in males given 5% EPG. However, detailed evaluation of general health and assessment of blood, organs and tissues showed no evidence that EPG administration compromised the nutritional requirements of the animals, caused a state of fat soluble vitamin deficiency, or caused' toxicity to any organ system. Based on the results of this study, it was not possible to establish a no-observable-effect level (NOEL). The possible effect of EPG on vitamin levels in the absence of any clinical signs of deficiency was not considered "adverse" per se. As such, the 2g/kg and 5% EPG level were considered to represent a no-observable-adverse effect levels (NOAELs). PMID- 25497992 TI - Developmental toxicity evaluation of esterified propoxylated glycerol (EPG) administered in the diet to New Zealand white rabbits. AB - The safety of a "core" version of esterified propoxylated glycerols (EPGs) was assessed in a developmental toxicity study in New Zealand white rabbits, Hra:(NZW)SPF. Four groups each of 18 inseminated female rabbits received diets ad libitum containing concentrations of 0%, 2.5%, 5%, and 10% EPG (w/w) with 6% corn oil (w/w). No treatment-related effects were observed in any maternal toxicity parameter, including maternal body weight and weight gain, feed consumption, or clinical signs of toxicity. There were no statistically significant treatment related effects in gestational parameters, including pre- and post-implantation loss, litter size, sex ratio, fetal body weight, and crown-rump length. The incidences of fetal external, visceral, and skeletal malformations or variations were also comparable across groups. A no-observable-adverse-effect level (NOAEL) of 10% EPG (approximately 4.76 g/kg bw/day) for both maternal and developmental toxicity is proposed based on the results of this study. PMID- 25497993 TI - Toxicological assessment of kretek cigarettes: Part 2: kretek and American blended cigarettes, smoke chemistry and in vitro toxicity. AB - Two commercial kretek cigarettes typical for the Indonesian market and a reference kretek cigarette were compared to the American-blended reference cigarette 2R4F by smoke chemistry characterization and in vitro cytotoxicity and mutagenicity assessments. Despite the widely diverse designs and deliveries of the selected kretek cigarettes, their smoke composition and in vitro toxicity data present a consistent pattern when data were normalized to total particulate matter (TPM) deliveries. This confirms the applicability of the studies' conclusions to a wide range of kretek cigarette products. After normalization to TPM delivery, nicotine smoke yields of kretek cigarettes were 29-46% lower than that of the 2R4F. The yields of other nitrogenous compounds were also much lower, less than would be expected from the mere substitution of one third of the tobacco filler by clove material. Yields of light molecular weight pyrolytic compounds, notably aldehydes and hydrocarbons, were reduced, while yields of polycyclic aromatic hydrocarbons were unchanged and phenol yield was increased. The normalized in vitro toxicity was lowered accordingly, reflecting the yield reductions in gas-phase cytotoxic compounds and some particulate-phase mutagenic compounds. These results do not support a higher toxicity of the smoke of kretek cigarettes compared to American-blended cigarettes. PMID- 25497994 TI - 90-day dietary toxicity study with esterified propoxylated glycerol (EPG) in micropigs. AB - The subchronic (90-day) toxicity of esterified propoxylated glycerol (EPG) was assessed in micropigs. Animals (5/sex/group) received feed containing 5%, 10%, and 17% EPG, mixed accordingly throughout the study to deliver 1.5, 3, and 5 g/kg bw/day of EPG, respectively. Corn oil served as the vehicle control (0 g/kg bw/day). Subsets of animals were evaluated at Week 6; the remainder between Weeks 12 and 14. With the exception of liver and serum vitamin levels, statistically significant difference between control and EPG groups were seen sporadically, and with no apparent connection to treatment and/or no consistency across time intervals. EPG intakes of 3 and 5 g/kg bw/day, but not at 1.5 g/kg bw/day were associated with significantly lower serum 25-OH vitamin D levels. Serum total vitamin D levels were significantly lower across all EPG groups. There were also trends toward lower levels of liver vitamins A and E among EPG-treated animals, but the effects were less consistent. The effects on vitamin levels observed in EPG-treated animals were not accompanied by any signs of vitamin deficiency (e.g., effects on growth, clinical signs, or clinical pathology), and might have been related to the larger mass of EPG acting as a lipid "sink" during transit in the gastrointestinal tract. PMID- 25497995 TI - Revision of omalizumab dosing table for dosing every 4 instead of 2 weeks for specific ranges of bodyweight and baseline IgE. AB - The dosing level and frequency of omalizumab are guided by a dosing table based on total serum immunoglobulin E (IgE) and bodyweight. Using a validated, mathematical simulation model (based on concentration data from 8 studies), we evaluated the impact of a revised omalizumab dosing table (every 4 weeks dosing regimen) on the pharmacokinetic and pharmacodynamic profiles of free and total IgE. Safety analysis, in patients with high levels of exposure to omalizumab, was done using data from the clinical and post-marketing databases. The model accurately predicted observed omalizumab, free and total IgE concentrations. After reaching steady-state, the average increase in exposure was 10%, even for patients with the highest concentrations at the upper 97.5th percentile. Free IgE suppression slightly increased in the initial phase, and slightly reduced at the trough of the dosing cycle, but average suppression remained similar for both regimens. The safety profile of omalizumab was similar for patients receiving higher or lower doses. Thus, doubling the dose of omalizumab, in a subset of patients receiving 225-300 mg of omalizumab (every 2 weeks dosing regimen) can efficiently suppress free IgE without compromising safety or efficacy. PMID- 25497996 TI - Navigating through orphan medicinal product regulations in EU and US- similarities and differences. AB - Rare diseases as the name suggests are the diseases which occur in a very small population due to which the development of medicinal products for these diseases is sidelined as it is anticipated that the cost of development will never be recovered from the sales. It has been estimated by National Institute of Health (NIH) that globally around 7000 rare diseases are there, many of which are of genetic origin. This paper aims to analyze the basic similarities and differences between the rules and regulations put forth by regulatory agencies of US and EU for development of medicinal products for rare diseases, also called orphan medicinal products. The basic purpose was to carve out the loopholes as well as positive aspects of each of these acts and regulations so as to have a clear understanding on the subject. It was to understand that how these legal instruments have stimulated the growth of the drug products for rare diseases and what other things can be done in order to achieve a better impact. This article also provides an overview of the various incentives offered as well as challenges and hurdles faced by each of these regulatory agencies while implementing these regulations. PMID- 25497997 TI - Genotoxicity testing of esterified propoxylated glycerol (EPG). AB - Four versions of esterified propoxylated glycerols (EPGs) were evaluated for potential genotoxicity using a range of in vitro and in vivo assays. H-EPG-05 HR/SO 9:1, H-EPG-05 soyate, and H-EPG-14 soyate were non-mutagenic in reverse mutation assays (maximum concentration 1000 MUg/plate) using Salmonella typhimurium and Escherichia coli. Heated and unheated H-EPG-05 HR/SO 9:1 and EPG 05 HR/ST 45:55 were likewise non-mutagenic in reverse mutation assays in S. typhimurium strains TA98 and TA100 (maximum concentration 5000 MUg/plate). H-EPG 05 HR/SO 9:1, H-EPG-05 soyate, and H-EPG-14 soyate, were devoid of mutagenic activity in a mouse lymphoma assay in L5178Y tk +/- cells (maximum concentration 200 MUg/plate for H-EPG-05 HR/SO 9:1; 100 MUg/plate for H-EPG-05 soyate and H-EPG 14 soyate), and a chromosomal aberration test using human lymphocytes (maximum concentration 50 MUg/plate for H-EPG-05 HR/SO 9:1 and H-EPG-05 soyate; 60 MUg/plate for H-EPG-14 soyate). All assays were conducted with and without metabolic activation. Additionally, H-EPG-05 HR/SO 9:1, H-EPG-05 soyate, and H EPG-14 soyate were non-genotoxic in unscheduled DNA synthesis tests in rats (maximum dose 2000 mg/kg). Based on the results of these assays it was concluded that these versions of EPG were not genotoxic under any of the conditions of the assays performed. PMID- 25497998 TI - Assessment of the effect of esterified propoxylated glycerol (EPG) on the status of fat-soluble vitamins and select water-soluble nutrients following dietary administration to humans for 8 weeks. AB - This double-blind, randomized, controlled study assessed the effect of esterified propoxylated glycerol (EPG) on fat-soluble vitamins and select nutrients in human subjects. For 8 weeks, 139 healthy volunteers consumed a core diet providing adequate caloric and nutrient intakes. The diet included items (spread, muffins, cookies, and biscuits) providing EPG (10, 25, and 40 g/day) vs. margarine alone (control). EPG did not significantly affect circulating retinol, alpha tocopherol, or 25-OH D2, but circulating beta-carotene and phylloquinone were lower in the EPG groups, and PIVKA-II levels were higher; 25-OH D3 increased but to a lesser extent than the control. The effect might be related to EPG acting as a lipid "sink" during gastrointestinal transit. No effects were seen in secondary endpoint measures (physical exam, clinical pathology, serum folate, RBC folate, vitamin B12, zinc, iron, calcium, phosphorus, osteocalcin, RBP, intact PTH, PT, PTT, cholesterol, HDL-C, LDL-C, triglycerides). Gastrointestinal adverse events (gas with discharge; diarrhea; oily spotting; oily evacuation; oily stool; liquid stool; soft stool) were reported more frequently by subjects receiving 25 or 40 g/day of EPG. In general, the incidence and duration of these symptoms correlated directly with EPG dietary concentration. The results suggest 10 g/day of EPG was reasonably well tolerated. PMID- 25497999 TI - Article series: Safety of esterified propoxylated glycerol (EPG), a nonabsorbable fat replacer. AB - This article introduces a series of articles addressing the safety of esterified propoxylated glycerols (EPGs), a family of fat- and oil-like substances that resemble triglycerides in structure and appearance, but have been modified to prevent or limit their digestion when consumed in food. A general summary of the history, composition, metabolism, and safety of EPGs is provided. PMID- 25498000 TI - Toxicological assessment of kretek cigarettes: Part 1: background, assessment approach, and summary of findings. AB - This publication introduces a series of six other publications describing the toxicological assessment of kretek cigarettes, i.e., cigarettes characterized primarily by the use of a significant amount of cloves as an ingredient added to the tobacco. This paper presents background information on kretek cigarettes, describes the general approach of the in vitro and in vivo toxicological assessment of mainstream smoke from kretek cigarettes, presents the methodology used, and summarizes the results of the assessment program. In summary, the smoke from kretek cigarettes gives rise to the typical cigarette smoke-related effects known from American-blended cigarettes, does not reveal any novel toxicity, and exhibits an unexpected distinct attenuation of pulmonary inflammation. Based on equal amounts of smoke total particulate matter (TPM), kretek cigarettes deliver less toxicants when compared to American-blended cigarettes; when assessed in vitro, the smoke from kretek cigarettes is less cytotoxic (gas/vapor phase) and less mutagenic (TPM). When assessed in vivo, kretek cigarette smoke shows lower toxicity in the respiratory tract. When based on an equal nicotine basis, several of the toxicity endpoints in kretek cigarettes become equivalent to American blended cigarettes. The data do not indicate an increased hazard potential of kreteks compared to American-blended cigarettes. PMID- 25498001 TI - Modelling climate change impact on the spatial distribution of fresh water snails hosting trematodes in Zimbabwe. AB - BACKGROUND: Freshwater snails are intermediate hosts for a number of trematodes of which some are of medical and veterinary importance. The trematodes rely on specific species of snails to complete their life cycle; hence the ecology of the snails is a key element in transmission of the parasites. More than 200 million people are infected with schistosomes of which 95% live in sub-Saharan Africa and many more are living in areas where transmission is on-going. Human infection with the Fasciola parasite, usually considered more of veterinary concern, has recently been recognised as a human health problem. Many countries have implemented health programmes to reduce morbidity and prevalence of schistosomiasis, and control programmes to mitigate food-borne fascioliasis. As these programmes are resource demanding, baseline information on disease prevalence and distribution becomes of great importance. Such information can be made available and put into practice through maps depicting spatial distribution of the intermediate snail hosts. METHODS: A biology driven model for the freshwater snails Bulinus globosus, Biomphalaria pfeifferi and Lymnaea natalensis was used to make predictions of snail habitat suitability by including potential underlying environmental and climatic drivers. The snail observation data originated from a nationwide survey in Zimbabwe and the prediction model was parameterised with a high resolution Regional Climate Model. Georeferenced prevalence data on urinary and intestinal schistosomiasis and fascioliasis was used to calibrate the snail habitat suitability predictions to produce binary maps of snail presence and absence. RESULTS: Predicted snail habitat suitability across Zimbabwe, as well as the spatial distribution of snails, is reported for three time slices representative for present (1980-1999) and future climate (2046 2065 and 2080-2099). CONCLUSIONS: It is shown from the current study that snail habitat suitability is highly variable in Zimbabwe, with distinct high- and low- suitability areas and that temperature may be the main driving factor. It is concluded that future climate change in Zimbabwe may cause a reduced spatial distribution of suitable habitat of host snails with a probable exception of Bi. pfeifferi, the intermediate host for intestinal schistosomiasis that may increase around 2055 before declining towards 2100. PMID- 25498002 TI - Preclinical pharmacokinetic, biodistribution, imaging and therapeutic efficacy of (177)Lu-Labeled glycated bombesin analogue for gastrin-releasing peptide receptor positive prostate tumor targeting. AB - The gastrin-releasing peptide receptor (GRPR) has been shown to be overexpressed in many human tumors, including prostate, colon, gastric, breast, pancreatic, and small cell lung cancers. Because bombesin (BBS) binds to GRPR with high affinity, BBS derivatives have been labeled with various radionuclides and have been demonstrated to be successful candidates for peptide receptor radiotherapy (PRRT). The present study describes the in vitro and in vivo preclinical characteristics of (177)Lu-DOTA-Lys(glucose)-4 aminobenzoic acid-BBS7-14 ((177)Lu DOTA-gluBBN) to prepare radiolabeled candidates for the treatment of GRPR expressing prostate tumors. METHODS: (177)Lu-DOTA-gluBBN was prepared as previously published [1]. Human prostate PC-3 tumor cells were used to determine the binding (Kd) retention and efflux of (177)Lu-DOTA-gluBBN. Pharmacokinetic, imaging, and radiotherapy studies were performed in PC-3 xenografted mice. RESULTS: The Kd value of (177)Lu-DOTA-gluBBN was 0.63 nM, with a maximum binding capacity (Bmax) of 669.7 fmol/10(6) cells (4.04*10(5) GRPR/cell). During a 2-hr incubation, 90.1+/-0.4% of the cell-associated radio-peptide was internalized, and 56.3+/-7.1% of the internalized radio-peptide was externalized in vitro. High amounts of the radio-peptide were rapidly accumulated in a PC-3 tumor in vivo, and the % ID/g of the tumor was 12.42+/-2.15 1 hr p.i. The radio-peptide was quickly cleared from the blood, yielding tumor-to-blood ratios of 39.22+/-17.36 at 1 hr p.i. and 330.67+/-131.23 at 24hr p.i. In addition, (177)Lu-DOTA-gluBBN was clearly visualized in PC-3 tumors 1 hr p.i. and significantly inhibited the tumor growth (P<0.05). Treatment-related toxicity in the pancreas and kidneys was not observed, except for slight glomerulopathy. CONCLUSIONS: The pharmacokinetic, imaging, and therapy studies suggest that this (177)Lu-DOTA-gluBBN has promising characteristics for application in nuclear medicine, namely, for the diagnosis and treatment of GRPR-overexpressing prostate tumors. PMID- 25498003 TI - Development of a flow system for studying biofilm formation on medical devices with microcalorimetry. AB - Isothermal microcalorimetry (IMC) is particularly suited to the study of microbiological samples in complex or heterogeneous environments because it does not require optical clarity of the sample and can detect metabolic activity from as few as 10(4) CFU/mL cells. While the use of IMC for studying planktonic cultures is well established, in the clinical environment bacteria are most likely to be present as biofilms. Biofilm prevention and eradication present a number of challenges to designers and users of medical devices and implants, since bacteria in biofilm colonies are usually more resistant to antimicrobial agents. Analytical tools that facilitate investigation of biofilm formation are therefore extremely useful. While it is possible to study pre-prepared biofilms in closed ampoules, better correlation with in vivo behaviour can be achieved using a system in which the bacterial suspension is flowing. Here, we discuss the potential of flow microcalorimetry for studying biofilms and report the development of a simple flow system that can be housed in a microcalorimeter. The use of the flow system is demonstrated with biofilms of Staphylococcus aureus. PMID- 25498004 TI - Using enhanced-mitophagy to measure autophagic flux. AB - Macroautophagy (hereafter termed autophagy) is a cellular membrane-trafficking process that functions to deliver cytoplasmic constituents to lysosomes for degradation. Autophagy operates at basal levels to turn over damaged and misfolded proteins and it is the only process for the turnover of organelles. The process is therefore critically important for the preservation of cellular integrity and viability. Autophagy is also highly adaptable and the rate and cargoes of autophagy can be altered to bring about desired cellular responses to intracellular and environmental cues, disease states and a spectrum of pharmaceutical drugs. As a result, there is much interest in understanding the dynamics of autophagy in a variety of situations. To date, the majority of assays to monitor autophagy either measure changes in a parameter of the process at a set point in time or use markers/tracers to monitor flow of membrane-bound proteins from one point in the process to another. As such, these assays do not measure changes in endogenous cargo degradation which is the ultimate end-point of the autophagy process. We describe here an assay to measure autophagic cargo degradation by engineering cells to degrade mitochondria en masse. We show that this 'enhanced-mitophagy' assay can be used to measure differences in the rate of autophagy between different cells or in response to agents which are known to promote or inhibit autophagic flux. We consider therefore that this assay will prove to be a valuable resource for investigations in which autophagy is considered important and is believed to be modulated. PMID- 25498005 TI - The deconvolution of differential scanning calorimetry unfolding transitions. AB - This paper is a review of a process for deconvolution of unfolding thermal transitions measured by differential scanning calorimetry. The mathematical background is presented along with illustrations of how the unfolding data is processed to resolve the number of sequential transitions needed to describe an unfolding mechanism and to determine thermodynamic properties of the intermediate states. Examples of data obtained for a simple two-state unfolding of a G quadruplex DNA structure derived from the basic human telomere sequence, (TTAGGG)4TT are used to present some of the basic issues in treating the DSC data. A more complex unfolding mechanism is also presented that requires deconvolution of a multistate transition, the unfolding of a related human telomere structure, (TTAGGG)12 TT. The intent of the discussion is to show the steps in deconvolution, and to present the data at each step to help clarify how the information is derived from the various mathematical manipulations. PMID- 25498006 TI - Autophagy in zebrafish. AB - From a hitherto underappreciated phenomenon, autophagy has become one of the most intensively studied cellular processes in recent years. Its role in cellular homeostasis, development and disease is supported by a fast growing body of evidence. Surprisingly, only a small fraction of new observations regarding the physiological functions of cellular "self-digestion" comes from zebrafish, one of the most popular vertebrate model organisms. Here we review the existing information about autophagy reporter lines, genetic knock-down assays and small molecular reagents that have been tested in this system. As we argue, some of these tools have to be used carefully due to possible pleiotropic effects. However, when applied rigorously, in combination with novel mutant strains and genome editing techniques, they could also transform zebrafish into an important animal model of autophagy research. PMID- 25498007 TI - Live-cell imaging for the assessment of the dynamics of autophagosome formation: focus on early steps. AB - Autophagy is a cytosolic degradative pathway, which through a series of complicated membrane rearrangements leads to the formation of a unique double membrane vesicle, the autophagosome. The use of fluorescent proteins has allowed visualizing the autophagosome formation in live cells and in real time, almost 40 years after electron microscopy studies observed these structures for the first time. In the last decade, live-cell imaging has been extensively used to study the dynamics of autophagosome formation in cultured mammalian cells. Hereby we will discuss how the live-cell imaging studies have tried to settle the debate about the origin of the autophagosome membrane and how they have described the way different autophagy proteins coordinate in space and time in order to drive autophagosome formation. PMID- 25498008 TI - Structural characterization and gastroprotective property of a novel glucofructan from Allium ampeloprasum var. porrum. AB - A new polysaccharide with an estimated weight-average molar mass of 2.6*10(3) was isolated from Allium ampeloprasum var. porrum by hot water extraction, and purified by Sephacryl S-300 HR high-resolution chromatography. It was composed of D-fructose and D-glucose in 10:6 molar ratio, respectively. The structure of the glucofructan was investigated by chemical and spectroscopic methods, including methylation analysis, nuclear magnetic resonance, and electrospray mass spectrometry (ES-MS). The results permitted the structure of the glucofructan to be written as alpha-D-Glcp-(1->1)-beta-D-Fruf-(2->1)-{[alpha-D-Glcp-(1->6)-beta-D Fruf-(2->6)]-beta-D-Fruf-(2->1)}4-beta-D-Fruf-(2<->1)-alpha-D-Glcp. Results of the present study indicated that this new glucofructan exhibited significant gastroprotective property, using in vivo experimental models. PMID- 25498009 TI - Araf51 with improved transglycosylation activities: one engineered biocatalyst for one specific acceptor. AB - A random mutagenesis of the arabinofuranosyl hydrolase Araf51 has been run in order to have access to efficient biocatalysts for the synthesis of alkyl arabinofuranosides. The mutants were selected on their ability to catalyze the transglycosylation reaction of p-nitrophenyl alpha-L-arabinofuranoside (pNP-Araf) used as a donor and various aliphatic alcohols as acceptors. This screening strategy underlined 5 interesting clones, each one corresponding to one acceptor. They appeared to be much more efficient in the transglycosylation reaction compared to the wild type enzyme whereas no self-condensation or hydrolysis products could be detected. Moreover, the high specificity of the mutants toward the alcohols for which they have been selected validates the screening process. Sequence analysis of the mutated enzymes revealed that, despite their location far from the active site, the mutations affect significantly the kinetics properties as well as the substrate affinity of these mutants toward the alcohol acceptors in the transglycosylation reaction. PMID- 25498010 TI - The core and O-polysaccharide structure of the Caulobacter crescentus lipopolysaccharide. AB - Here we describe the analysis of the structure of the lipopolysaccharide (LPS) from Caulobacter crescentus strain JS1025, a derivative of C. crescentus CB15 NA1000 with an engineered amber mutation in rsaA, leading to the loss of the protein S-layer and gene CCNA_00471 encoding a putative GDP-L-fucose synthase. LPS was isolated using an aqueous membrane disruption method. Polysaccharide and core oligosaccharide were produced by mild acid hydrolysis and analyzed by nuclear magnetic resonance spectroscopy and chemical methods. Spectra revealed the presence of two polysaccharides, one of them, a rhamnan, could be removed using periodate oxidation. Another polymer, built from 4-amino-4-deoxy-D-rhamnose (perosamine), mannose, and 3-O-methyl-glucose, should be the O-chain of the LPS according to genetic data. The attribution of the rhamnan as a part of LPS or a separate polymer was not possible. PMID- 25498011 TI - Direct thiophenylation accompanying orthoester-cleavage of 1,2,4-O-orthoacetyl 3,6-O-(o-xylylene)glucopyranose. AB - The 3,6-O-(o-xylylene) bridge locks the conformation of glucopyranose to an axial rich form. Although the conformational lock induces complete beta-selectivity in a glycosylation reaction, the leaving group of the glycosyl donor is limited to fluorine. On the other hand, the bridge confers the furanose-preferred property to glucose, which makes synthesis of corresponding pyranosyl derivatives that equip various leaving groups difficult. This problem was solved through direct phenylthio glucosidation of 3,6-O-(o-xylylene)-1,2,4-O-orthoacetylglucose accompanying cleavage of the orthoester moiety. This paper describes the process of establishing direct thiophenylation. This process reduced the synthetic steps for the known glucopyranosyl fluoride and will expand application of conformationally locked glycosyl donors. PMID- 25498012 TI - Recent progress in the field of glycoconjugates. AB - The ubiquity of glycoconjugates in nature and their role in different biological processes, has led to the development of several methodologies to synthesize these molecules. Synthetic glycoconjugates are now used to answer a variety of glycoconjugate-related biological questions and have provided new potential vaccines against cancer, viral, and bacterial infections and new biotechnological tools. This review aims to collect and compile the recent advances in the field of glycopeptides, glycoproteins, and glycolipid synthesis and also to update the previous reviews made on this subject. Finally, by highlighting the successes and failures of past research, we hope that this review will inspire fruitful research in this important medicinal chemistry field. PMID- 25498013 TI - Characterization of the N-acetylneuraminic acid synthase (NeuB) from the psychrophilic fish pathogen Moritella viscosa. AB - Moritella viscosa is a Gram-negative psychrophilic bacterium that causes winter ulcer disease in Atlantic salmon and cod. Its genome reveals that it possesses the ability to synthesize sialic acids. Indeed, sialic acid can be isolated from the bacterium and when analyzed using HPLC-MS/MS, the presence of N acetylneuraminic acid was confirmed. Thus, the N-acetylneuraminic acid synthase NeuB from M. viscosa (MvNeuB) was recombinantly produced and characterized. The optimum pH and temperature for MvNeuB activity are 7.5 and 30 degrees C, respectively. The KM for N-acetylmannosamine and phosphoenolpyruvate is 18+/-5 and 0.8+/-0.2 mM, respectively. The kcat value (~225 min(-1)) for both N acetylmannosamine and phosphoenolpyruvate is the highest turnover number found for an enzyme in this class until the date. A calorimetric study of MvNeuB shows that the enzyme has a two-step transition peak probably reflecting the two domains these proteins consist of. MvNeuB is less stable at higher temperature and has a high catalytic activity at lower temperature compared to mesophilic counterparts. Enzymes from psychrophilic organisms are generally cold adapted meaning they can maintain adequate function near the freezing point of water. Cold adapted enzymes are catalytically more efficient at lower temperature and are more thermo-labile compared to their mesophilic counterparts. MvNeuB is a typical cold adapted enzyme and could be further explored for production of sialic acids and derivates at low temperatures. PMID- 25498014 TI - Computational study to evaluate the birefringence of uniaxially oriented film of cellulose triacetate. AB - The intrinsic birefringence of a cellulose triacetate (CTA) film is evaluated using the polarizability of the monomer model of the CTA repeating unit, which is calculated using the density functional theory (DFT). Since the CTA monomer is known to have three rotational isomers, referred to as gg, gt, and tg, the intrinsic birefringence of these isomers is evaluated separately. The calculation indicates that the monomer CTA with gg and gt structures shows a negative intrinsic birefringence, whereas the monomer unit with a tg structure shows a positive intrinsic birefringence. By using these values, a model of the uniaxially elongated CTA film is constructed with a molecular dynamics simulation, and the orientation birefringence of the film model was evaluated. The result indicates that the film has negative orientation birefringence and that its value is in good agreement with experimental results. PMID- 25498015 TI - Anomeric selectivity and influenza A virus inhibition study on methoxylated analogues of Pentagalloylglucose. AB - Anomeric selectivity in galloylation of D-glucose and D-mannose with carboxylic acid was explored under steglich conditions. Base catalyst 4 dimethylaminopyridine favored the formation of alpha-anomers, while adding an acid and carbodiimide favored the formation of beta-anomers. Steric hindrance between alpha,beta-unsaturated acid and C-2 OH stereochemistry (adjacent carbon to anomeric) influenced anomeric selectivity for both D-glucose and D-mannose. The influenza A virus inhibition activities of the synthesized compounds were evaluated in Madin-Darby canine kidney cell line using the cytopathic effect inhibition assay. All the synthetic methoxylated analogues showed more considerable activity against influenza A virus than their corresponding acids, which indicated the sugar core as key functionality for anti-viral activity. The activities of trimethoxy-cinnamic acid Pentagalloylglucose analogues, 3alpha, 3beta, 4alpha, and 4beta (IC50, 109.1 MUM, 134.4 MUM, 119.5 MUM, 111.1 MUM, respectively) were better than those of trimethoxy-benzoic acid Pentagalloylglucose analogues, 1-alphabeta and 2alpha, 2beta (IC50, 209.8 MUM, 132.9 MUM, 161.2 MUM, respectively), which suggested that the double bond in cinnamic acid Pentagalloylglucose analogues makes the major contribution for influenza A virus inhibitory activity. Notably, several anomeric mixtures showed better activities than pure alpha or beta anomer and were almost two times more effective than Ribavirin, a clinically used anti-viral drug. PMID- 25498017 TI - Relative reactivities in the O-methylation of glucomannans: the influence of stereochemistry at C-2 and the solvent effect. AB - The main hemicellulose in softwood, glucomannan (GM), structurally resembles cellulose but has quite different physical and chemical properties. In addition to branching and original acetylation, the only other difference between these two beta-1,4-linked glycans is the configuration at C-2 in approximately 80% of the sugar residues. In contrast to glucose, the 2-OH in mannose has an axial orientation. The influence of this stereochemistry on the relative reactivities of glucosyl compared to mannosyl units in methylation reactions are studied in this work. Glucomannan isolated from spruce (SGM) and commercially available konjac glucomannan (KGM) was methylated in DMSO/Li-dimsyl/MeI and water/NaOH/MeI system, respectively. In the early stage of the reaction, the glucose part of the SGM achieved slightly higher DS values than the mannose residues, but the overall relative rate constants were close to 1:1. The order of reactivities in glucose was k2>k3>k6 and k3>k2>k6 for mannose (in DMSO/Li-dimsyl/MeI). The rate constants did not remain constant, but k3 decreased when k2 increased for both epimeric sugars. In water/NaOH/MeI, the methylation of the primary 6-OH was much more pronounced with an order of reactivity of O-6>O-2>O-3 for mannose and O-2>O-6>O-3 for glucose. The results are discussed with respect to the OH-acidity and the stereoelectronic, sterical, and solvent effects. PMID- 25498016 TI - Recent developments in beta-C-glycosides: synthesis and applications. AB - In the last few years, considerable progress has been made in the synthesis of C glycosides. Despite its challenging chemistry, due to its versatility, C glycosides play a pivotal role in developing novel materials, surfactants and bioactive molecules. In this review, we present snapshots of various synthetic methodologies developed for C-glycosides in the recent years and the potential application of C-glycosides derived from beta-C-glycosidic ketones. PMID- 25498018 TI - Elucidation of differences in N-glycosylation between different molecular weight forms of recombinant CLEC-2 by LC MALDI tandem MS. AB - C-type lectin-like receptor 2 (CLEC-2) is a newly identified receptor expressed on the platelet surface. It has been reported that CLEC-2 exists as a higher molecular weight (HMW) and a lower molecular weight (LMW) form, which share the same protein core but differ in glycans. The two forms appear to have different ligand-binding abilities, indicating that the differential glycosylation of CLEC 2 possibly produces functionally distinct glycoforms. This study aimed to explore an easy method to directly elucidate the N-glycosylation difference by employing a glycoproteomics approach. The off-line coupling of nano-LC with a MALDI-QIT-TOF mass spectrometer was demonstrated to be capable of sensitive and direct elucidation of the glycosylation difference between HMW and LMW CLEC-2, simultaneously providing information about their oligosaccharide structures and the glycosylation sites. The results reveal that a specific glycosylation site, Asn 134, is differently glycosylated in the two forms, with complex types of bi antennary, tri-antennary and tetra-antennary, N-linked, fucosylated glycans identified at this site in the HMW form but not in the LMW form. The observed difference in glycosylation might provide new insights into the underlying mechanisms of biological functions of CLEC-2. Because of its simplicity and sensitivity, the method explored in this work suggests that it holds promise as a method of elucidating differences in direct N-glycosylation of target glycoprotein, even in small amount of samples. PMID- 25498019 TI - Analysis of breast cancer-associated glycosphingolipids using electrospray ionization-linear ion trap quadrupole mass spectrometry. AB - Abnormal glycosphingolipids (GSLs) are expressed in many human tumors. These tumor-associated GSLs may have important roles in tumor progression. However, they are hard to be detected because of their low concentration and the limited availability of antibodies and lectins that recognize them. Thus, mass spectrometry is an effective method to analyze GSLs with high sensitivity. Here, we use electrospray ionization-linear ion trap quadrupole mass spectrometry (ESI LTQ-MS) and liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) to determine the structure of a certain GSL in human breast cancer tissue. To obtain the breast cancer-associated GSLs, we applied relative abundance contrast of GSLs and signal-to-noise ratio (SNR) analyses. We also used alpha1,2 fucosidase and fucosyltransferases as tools in the structural analysis. Based on this analysis, we identified the ion with m/z 1184 molecular ion as fucosyl-lactoceramide (Fuc-LacCer) with a C16 fatty acid ceramide. Quantitative analysis of GSLs revealed both Fuc-LacCer and Globo-H increased in breast cancer tissues. However, these two breast cancer-associated GSLs had different roles. The results of SNR analysis suggested the abnormal Fuc-LacCer is specific to breast cancer. The GSL profiling of breast cancer cells showed fucosyltransferase 1 contributed to the biosynthesis of Globo-H and Fuc-LacCer. In conclusion, MS analysis identified an accumulation of Fuc-LacCer in breast cancer tissue. Our findings provide GSL profiles of human breast cancer and develop an MS method for the study of cancer-associated GSLs. PMID- 25498020 TI - Synthesis of mixed glycosyl disulfides/selenenylsulfides using benzyltriethylammonium tetrathiomolybdate as a sulfur transfer reagent. AB - An easy and mild method has been developed for the synthesis of mixed glycosyl disulfides/selenenylsulfides from glycosyl halides and diaryl/dialkyl dichalcogenides in the presence of benzyltriethylammonium tetrathiomolybdate [(BnEt3N)2MoS4]. The salient feature of this method is the sulfur transfer from [BnEt3N]2MoS4 to form glycosyl disulfides which with excess tetrathiomolybdate further undergo exchange reaction with other dichalcogenides in a one-pot operation. PMID- 25498021 TI - A supramolecular vesicle of camptothecin for its water dispersion and controllable releasing. AB - Camptothecin, as an antitumor drug, has shown significant antitumor activity against various cancers through the inhibition of topoisomerase I. However, its poor solubility severely limits the clinical applications. Here, we report a camptothecin supramolecular vesicle based on the host-guest interactions, which can uniformly disperse camptothecin into water and greatly enhance camptothecin aqueous solubility. The camptothecin vesicles were identified by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and dynamic light scattering (DLS). X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), UV-vis spectrum, 1H NMR and 2D NMR ROESY were further employed to study the formation mechanism of the vesicles. Furthermore, camptothecin could be controllably released when the competitive guests were added into the vesicles system. Finally, the camptothecin vesicles in aqueous solution exhibited comparable antitumor activity in vitro as natural camptothecin in DMSO to HeLa cells under the same conditions. PMID- 25498022 TI - Halogenated D-xylono-delta-lactams: synthesis and enzyme inhibition study. AB - A concise synthesis of four C-3 fluoro/chloro-D-xylono-delta-lactams 3/4 has been reported. The methodology involves Corey-Link approach with suitably protected 3 oxo-D-gluco-furanose to introduce F/Cl as well as ester/amide functionalities at C-3 of glucose. In next steps, 5,6-O-isopropylidene group was converted to the 5 azido xylosugars that on opening of 1,2-acetonide group, and intramolecular Schmidt-Boyer reaction with TFA/H2O, in one pot, afforded lactams 3/4. Conformational aspect of delta-lactams was studied by the 1H NMR spectroscopy. The halogenated delta-lactams 3/4 showed no inhibition against different glycosidase enzymes. PMID- 25498023 TI - Triterpenoid saponins from root bark of Zanha golungensis (Sapindaceae). AB - The chemical investigation of the methanolic extract from root bark of Zanha golungensis Hiern led to the isolation of five new and one known triterpenoid saponins. Their structures were elucidated by full analysis of their spectroscopic data and by partial hydrolysis. These glycosides contain zanhic acid as aglycone, a rare oleanane-type triterpenoid found in species belonging to Sapindaceae, Caryophyllaceae, Asteraceae, and Fabaceae. Two new saponins are esterified saponins by 3,3-dimethylacryloyl and 3-hydroxy-2-methyl-butanoyl residues located on the sugar part. The new compounds were named zanhasaponins D H following previous isolation of similar compounds from Zanha africana. PMID- 25498024 TI - The structure of the Morganella morganii lipopolysaccharide core region and identification of its genomic loci. AB - The core region of the lipopolysaccharide of Morganella morganii serotype O:1ab was obtained by hydrolysis of the LPS and studied by 2D NMR, ESI MS, and chemical methods. Its structure was highly homologous to those from the two major members of the same Proteeae tribe, Proteus mirabilis and Providencia alcalifaciens, and analysis of the M. morganii genome disclosed that the loci for its outer core, lipid A and Ara4N moieties are similarly conserved. PMID- 25498025 TI - Steroidal saponins obtained by biotransformation of total furostanol glycosides from Dioscorea zingiberensis with Absidia coerulea. AB - Five new steroidal saponins (1-5) were isolated from the fermentation broth of total furostanol glycosides from tubers of Dioscorea zingiberensis C.H. Wright incubated with a fungal, Absidia coerulea AS 3.3389, along with known saponins, zingiberensis new saponin (6), deltonin (7), prosapogenin A of dioscin (8), and protobioside (9), and their structures were established by NMR spectroscopy and mass spectrometry as well as by comparison with previously reported spectral data in the literatures. The induced effects in vitro on rat platelet aggregation of all compounds were evaluated. PMID- 25498026 TI - Stabilization of ribofuranose by a mineral surface. AB - The existence of the ribose moiety in biomolecules poses two problems for prebiotic chemistry. First, the exclusive presence of the furanose isomer in RNA has to be accounted for since furanose is a minor form in solution and does not exist in crystals. Second, all D-ribose polymorphs are unstable in aqueous medium so that a stabilization mechanism has to be invoked. We observed that the adsorption on mineral surfaces as amorphous silica protects the sugar from degradation processes. Moreover, this silica surface, used as realistic chert model, is able to increase significantly the proportion of ribofuranose compared to ribopyranose forms. The interaction between surface and sugar was analyzed by 13C NMR. Our results show a very significant chemical and thermal stabilization of the adsorbed sugar by a silica surface and an almost twofold increase of ribofuranose compared to ribose in solution. PMID- 25498027 TI - Synthesis of 4-amidomethyl-1-glucosyl-1,2,3-triazoles and evaluation as glycogen phosphorylase inhibitors. AB - Glycogen phosphorylase (GP) appears as a key enzyme for the control of hyperglycemia in the context of type 2 diabetes. In order to gain additional data for structure-activity studies of the inhibition of this enzyme, a series of eight GP inhibitor candidates were prepared from peracetylglucopyranosyl azide 1 by click-chemistry. The need for a N-Boc-protected propargylamine was identified in the CuAAC with azide 1 under Meldal's conditions, while Sharpless' conditions were better adapted to the CuAAC of azide 1 with propargyl bromide. Cycloaddition of Boc-propargylamine with azide 1 afforded the N-Boc precursor of a 4 aminomethyl-1-glucosyl-1,2,3-triazole which gave access to a series of eight amide and sulfonamide derivatives. After deacetylation, enzymatic studies revealed poor to moderate inhibitions toward this enzyme. The N-Boc-protected amine was the best inhibitor (IC50=620 MUM) unexpectedly slightly better than the 2-naphthylamido substituted analogue (IC50=650 MUM). PMID- 25498028 TI - Shielding effect of 'surface ion pairs' on physicochemical and bactericidal properties of N,N,N-trimethyl chitosan salts. AB - Different methodologies were employed in this study to synthesize N,N,N-trimethyl chitosan salts (TMC). TMC free of O-methylation and with partial O-methylation were obtained and characterized through 1H nuclear magnetic resonance, wide angle X-ray scattering, scanning electron microscopy coupled with X-ray energy dispersive spectroscopy, and thermogravimetric analysis. It was verified that the dialysis process allowed the removal of 'surface ion pairs' on TMC salt structure, increasing the mobility of TMC chains. The surface ion pairs considerably increased the material crystallinity, this property being independent of the used synthesis methodology. Biological tests showed that after dialysis, TMC salts free of 'surface ion pairs' kill Escherichia coli in only 6h of incubation. So, the increase in the mobility of dialyzed TMC chains allowed a strong interaction with the cell envelope and the good bactericidal activity of TMC was enhanced. PMID- 25498029 TI - Neuroimaging studies of depression, dementia, and mobility in older adults. PMID- 25498030 TI - Smoking dependence across the levels of cigarette smoking in a multiethnic sample. AB - OBJECTIVES: The Brief Wisconsin Inventory of Smoking Dependence Motives (WISDM) is a multi-dimensional smoking dependence measure that assesses primary dependence motives (PDM; e.g., core dependence marked by tolerance, craving) and secondary dependence motives (SDM; e.g., auxiliary dependence motives such as cognitive enhancement, weight control). However, the relationship between PDM, SDM, and smoking level remains unclear. Thus, we examined these scales across smoking levels in a diverse sample of smokers. METHODS: Participants were 2376 African American, Latino, and non-Hispanic White smokers recruited using an online panel research company. The sample included 297 native nondaily smokers (never smoked daily), 297 converted nondaily smoker (previously smoked daily for >=six months), 578 light daily smokers (<=10 cigarettes per day [cpd]), and 597 moderate to heavy daily smokers (>10cpd). METHODS: Results of a multinomial logistic regression showed that for each unit increase in SDM, after controlling for PDM, the odds of being a native nondaily, converted nondaily or light smoker vs. moderate to heavy smoker increased by 29% to 56% (ps<0.001). In the model, higher PDM scores were associated with lower odds of being a native nondaily, converted nondaily, or light smoker vs. a moderate to heavy daily smoker (ps<0.001). CONCLUSION: Nondaily and light smokers endorse higher secondary dependence motives relative to their primary dependence motives. Smoking cessation trials for nondaily and light smokers might address these secondary motives within the context of counseling intervention to enhance abstinence. PMID- 25498032 TI - The effect of psychological support for the relatives of intensive care unit patients on cadaveric organ donation rate. AB - We searched to see whether psychological support for relatives of intensive care unit patients helps them to donate organs of their brain-dead relatives. After receiving ethics committee permission, first-degree relatives of 200 general intensive care unit patients were enrolled in the study. The participants were divided into 2 groups randomly: an interview group (n = 100) and a control group (n = 100). Participants were asked to complete a questionnaire. Interviews with the psychologist and patients' relatives in the interview group were therapeutic in nature and were conducted according to the relatives' psychosocial needs in an unstructured format. In the control group, the psychologist and patients' relatives were not interviewed. The study utilized demographic data, the questionnaire for relatives of patients to mention their attitude on organ donation and the reasons for this choice, and the Participant Information Form to record demographic data and relatives' degree of relationship with the patient. There was no statistically significant difference between the 2 groups when compared according to sex ratio, patient age, and duration of patients' hospital stay. Whereas in the interview group, 75% agreed to allow their relatives to be organ donors, only 32% in the control group agreed (P < .0001). Of the 200 patients enrolled in the study, 93 lost their lives: 50 from the interview group and 43 from the control group. Among the relatives whose patients had lost their lives, 78% belonging to the interview group accepted to donate the organs of their patients, whereas in the control group 13.9% accepted (P < .0001). We hope that psychological support for the relatives of the potential brain-dead donor to cope with the psychological problems to be faced can improve the rate of organ donation. PMID- 25498031 TI - Mesenchymal properties of SJL mice-stem cells and their efficacy as autologous therapy in a relapsing-remitting multiple sclerosis model. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) are a multipotent population of adult stem cells, which may represent a promising therapeutic approach for neurological autoimmune diseases such as multiple sclerosis. The mouse is the most used species for obtaining and studying the characteristics of MSC and their potential as autologous transplants in pre-clinical models. However, conflicting data have been published disclosing intraspecies variations. The choice of the mouse strain and the tissue source appear, among others, as important factors in the experimental application of MSCs. METHODS: Adipose tissue-derived MSCs obtained from the SJL/JCrl mouse strain (SJL-AdMSC) have been cultured for a long time (from passage 0 up to 15) under controlled experimental conditions, and their growth rate, morphology, stromal and haematopoietic marker expression profiles and differentiation capacity towards adipocytes, osteocytes and chondrocytes have been determined. Moreover, their preclinical efficacy has been assessed by autologous transplant in relapsing-remitting experimental autoimmune encephalomielitis (RR-EAE)-induced SJL mice (a well established mice model for the study of RR-multiple sclerosis). RESULTS: We demonstrate that SJL-AdMSCs show the same fibroblastic shape, growth rate, profile of markers expression and multipotency described for MSCs in every passage evaluated (up to passage 15). Additionally, SJL-AdMSCs ameliorate the RR-EAE course, suggesting that they could modulate disease progression. Moreover, their features studied are fully comparable with the standardized Ad-MSCs obtained from the C57BL/6 mouse strain, which strengthens their use in cell therapy. CONCLUSION: SJL-AdMSCs might be a suitable source of Ad-MSCs for studies related to the properties of MSCs and their application as promising therapeutic tools in autologous transplants in experimental medicine. PMID- 25498033 TI - Satisfaction with the organ donation process of brain dead donors' families in Korea. AB - PURPOSE: The purpose of this study was to investigate the satisfaction of the families of brain dead donors with regard to donation processes as well as their emotions after the donation. METHOD: A cross-sectional survey study was performed that included 45 families of brain-dead donors in 1 hospital-based organ procurement organization (HOPO) in Korea between February 2007 and April 2011. RESULTS: Donor willingness and desire in life was the most frequent reason organs were donated (34.5%), followed by the advice of family members or friends (31.0%). Satisfaction with the organ donation processes was 4.04 of 6 points. In each category, the satisfaction with the decision of donation was the highest (4.96 points) and the satisfaction with the procedure of donation was the lowest (3.07 points); of each question, the satisfaction of "information and help on funeral arrangements was enough" and "the process of preparing the relevant documents was cumbersome" was the lowest. "Missing" the dead person and "pride" were the most common emotions experienced after organ donation (69.0% and 62.1%, respectively), followed by "grief," "family coherence," and "guilt." Religious practices were observed to be most helpful for psychological stress relief after donation, followed by spending time with family and friends. Moreover, 24.1% responded that they had not yet overcome their suffering. CONCLUSION: Because donors' own willingness is the most common reason that families choose donation, it is necessary to remind the public of the importance of organ donation through education and public relations using mass communication approaches. Additionally, because the families felt grief and guilt as well as missing their loved ones and pride regarding their dead loved ones after organ donation, continuous and systematic supports are needed to promote their psychological stability. PMID- 25498034 TI - Adenosine receptor expression in the development of renal fibrosis following ischemic injury. AB - Long-term renal allograft survival has not improved despite improvements in short term outcomes. Graft loss is characterized histologically by the development of interstitial fibrosis and tubular atrophy (IFTA). Mechanisms underlying the development of IFTA are multifactorial and include ischemia-reperfusion injury (IRI). Therapeutic options to reduce IFTA include management of immunologic causes, such as rejection, but despite these efforts IFTA can still occur and leads to the inexorable destruction of the transplanted kidney. The adenosine A2B receptor (A2BR) has recently been implicated in the development of renal fibrosis. We performed an observational study to examine the mRNA expression of the adenosine receptors after renal ischemia up to the development of renal fibrosis in a mouse model of unilateral IRI. A2BR was the only adenosine receptor that showed elevated expression following ischemia until the development of renal fibrosis 4 weeks after injury. At 2 weeks after ischemia, increased expression of the fibrotic markers transforming growth factor beta and Collagen-1alpha was observed. Expression of hypoxia inducible factor 1alpha and endothelin-1, which lie downstream of A2BR activation and have been recognized to promote renal fibrosis, were also significantly up-regulated at 2 weeks after ischemia. Expression of fibrotic markers returned to baseline by 4 weeks after ischemia, indicating resolution of injury with the concurrent development of renal fibrosis and reduced renal function. Our data suggest that A2BR may be a therapeutic target in reducing the development of renal fibrosis after ischemia. PMID- 25498035 TI - RAndomized Comparison of raDIal vs. femorAL Access for Routine Catheterization of Heart Transplant Patients (RADIAL-heart transplant study). AB - Although a transradial approach (TRA) is considered feasible in many clinical situations, no data are available in patients undergoing orthotopic heart transplantation (OHT). Our goal was to randomly compare TRA versus a transfemoral approach (TFA) in this clinical setting. This single-center, prospective, randomized trial was conducted from January to November 2006, and all OHT patients scheduled for a control coronary angiography were randomized to receive TRA or TFA. The primary endpoint was the amount of contrast used during the procedure. The participating interventional cardiologists were intermediate volume radial operators, and this was their initial experience of TRA in OHT patients. The analysis was performed according to the intention-to-treat principle. Overall, 49 patients (mean age, 55 +/- 13 years; 74% male) were included in the trial: 26 patients were assigned to TRA, and 23 were assigned to TFA. A higher amount of contrast (147 mL [range, 113-175 mL] vs 105 mL [range, 86 127 mL]; P = .009), a longer fluoroscopy time (9.2 minutes [range, 6-12 minutes] vs 3.5 minutes [range, 3-5 minutes]; P < .001), a trend toward increased number of catheters used for left ostium cannulation, and a higher crossover rate (19% vs 0%; P = .03) were associated with TRA compared with TFA. Furthermore, patients treated with TRA exhibit a shorter hospital stay (6 [range 4-8]) compared with the other group (26 [range 24-28]) (P < .001). There were no significant differences between the 2 groups regarding total procedural time, and no vascular complications were reported in either group. For these operators with their first experience of TRA in OHT patients, TFA seemed to be more efficient. PMID- 25498036 TI - Contraception in women after organ transplantation. AB - INTRODUCTION: Organ transplantation has improved the quality and length of life for many people suffering from end-stage diseases, among them women of reproductive age. Therefore, it has made pregnancy possible for those previously unable to conceive. Nevertheless, conception itself should be desired and properly timed in these specific patients to ensure the best possible perinatal outcome. OBJECTIVE: The objective of the study was to assess whether female graft recipients apply proper family planning methods and use effective contraception. METHODS: In a single-center, observational study, information was collected using a self-administered questionnaire distributed among 100 female graft recipients (post-transplant group [TG]) and 67 healthy female volunteers (control group [CG]). The survey covered data regarding present menstrual patterns, sexual activity, gynecological counseling, and contraceptive methods used. RESULTS: Female graft recipients were more sexually active after than before transplantation (87% vs 64%, P = .0001) and equally active as controls. Sexually active post-transplantation patients used contraception less frequently than sexually active controls (51.72% vs 82.76%, P < .0001). Condoms were the most frequently used method in TG, and oral contraception in CG. Oral contraception was used more rarely by counseled graft recipients than by counseled controls (3.9% vs 60.7%, P < .0001). After counseling, intrauterine device usage increased and oral contraception usage decreased in TG. Among women with chronic diseases, intrauterine device was used more often in TG (4% vs 0%), whereas oral contraception was used more often in CG (8.3% vs 50%, P < .0001). CONCLUSIONS: Despite the fact that post-transplantation women of reproductive age have many indications for highly effective contraception, only few of them actually use it. Contraceptive counseling has to be included as part of routine post transplantation care by all health professionals involved in the management of female graft recipients of reproductive age. PMID- 25498037 TI - Return to work after organ transplantation: a cross-sectional study on working ability evaluation and employment status. AB - INTRODUCTION: Organ transplantation has increased in Italy over the last decade. Thus, an increasing number of workers may face the problem of returning to work. The aim of this study was to provide an assessment of working ability of transplant recipients in comparison with their actual employment status. METHODS: This study was based on 150 patients who underwent transplantation since 1994 and who underwent periodic post-transplantation examination during 2012. Fifty patients who had undergone heart transplantation (HT), 50 liver transplantation (LT), and 50 kidney transplantation (KT) and survived at least 12 months after surgery were eligible for this study. All patients underwent the International Classification of Functioning, Disabilities and Health (ICF) questionnaire; ten questions were further applied to those who were employed at the time of the study. X(2) statistics were used to compare working ability evaluation and employment status and for internal comparison among different organ recipients. RESULTS: The employment status was as follows: 92 (61%) patients were in paid employment, 6 (4%) were students or housewives, 36 (24%) were unemployed, and 17 (11%) were retired because of invalidity benefits. According to our fitness evaluation only 4% to 10% of the patients were unfit for any job. When we excluded retired subjects, the X(2) statistics for correlated observations showed a highly significant statistical difference (P < .0001) between unemployed and unfit. As a result of the ICF questionnaire administration, there was a marked difference, although not statistically significant, in the fitness for previously performed jobs between KT and LT recipients (62% and 58%, respectively) and HT recipients (42%). DISCUSSION AND CONCLUSION: In this cross-sectional study we found a relatively high rate of unemployment as compared with the working ability evaluation by ICF questionnaire and other questions. This may be due to several factors including health status and the possibility of gaining an adequate job. The ICF questionnaire proved to be a useful framework that can be used for research but also by occupational physicians in their usual practice after specific training. PMID- 25498038 TI - Hepatocellular protein profiles after hepatic ischemia/reperfusion injury with or without octreotide preconditioning in a rabbit model. AB - Hepatic ischemic/reperfusion injury (HIRI) is a major complication of liver resection and transplantation. Octreotide, a somatostatin analogue, has been used to treat hepatic fibrosis and portal hypertension; however, its function against HIRI remains unclear. To elucidate the effect of octreotide in HIRI, we investigated the hepatocellular protein profiles in response to octreotide preconditioning in a rabbit model by using proteomic analysis. Twenty-four rabbits were divided into 3 groups: the sham operative group (control), the ischemia/reperfusion group (IR), and the ischemia/reperfusion + octreotide group (IR+Oct). They were subjected to 30 minutes of normothermic ischemia followed by 120 minutes of reperfusion by using Pringle's maneuver method. Proteomic studies were then performed to compare the protein profiles of their left liver lobe. A total of 16 differential proteins were successfully identified. These findings suggest that octreotide might exert an effect against HIRI through up-regulating the expression of the anti-injury substances, such as heat-shock proteins 70 and 27 (confirmed by using Western blot analysis); significantly raising the phosphatidylethanolamine-binding protein that alleviates IR-related apoptosis; and down-regulating mitochondrial metabolic enzymes such as NADH2 dehydrogenase and triosephosphate isomerase. PMID- 25498039 TI - Cost-effectiveness of kidney transplantation from DCD in Italy. AB - INTRODUCTION: Kidney transplantation represents the best therapeutic option for patients with end-stage renal disease (ESRD), providing the best outcomes for survival, quality of life, and cost-effectiveness. To increase kidney donations, in 2007, the Italian IRCCS Policlinico San Matteo Foundation in Pavia designed and conducted Programma Alba, a protocol for organ donation after cardiac death (DCD). This study evaluated the costs and health outcomes of DCD transplantation and in all types of transplants compared with current clinical practice. PATIENTS AND METHODS: A Markov-based model was used to assess costs and health outcomes for new ESRD patients for 2008 to 2013. A health care founder perspective was used. Data sources were the Italian National Institute of Statistics and the Lombardy Registry of Dialysis and Transplantation. A microcosting analysis was performed to calculate costs related to clinical pathways for DCD. We assessed costs, survival, quality-adjusted survival, and cost-effectiveness. FINDINGS: Changing the actual practice pattern for new patients with ESRD and increasing the availability of kidneys from DCD to 10 extra transplants per year will induce an incremental cost per quality-adjusted life-year of ?4255. Increases in transplantation to reach an extra 10% by transplant type would result in reduced costs and increased patient survival and quality of life compared with the current scenario. INTERPRETATION: Our data show that increasing DCD transplants would result in a cost-effective policy to expand the kidney donor pool compared with current ESRD treatment patterns. Italian policies should make an effort to increase transplant rates to optimize cost-effectiveness in ESRD service supply. PMID- 25498040 TI - Brain death is associated with endoplasmic reticulum stress and apoptosis in rat liver. AB - Cell death pathways initiated by stress on the endoplasmic reticulum (ER) have been implicated in a variety of common diseases, such as ischemia/reperfusion injury, diabetes, heart disease, and neurodegenerative disorders. However, the contribution of ER stress to apoptosis and liver injury after brain death is not known. In the present study, we found that brain death induces a variety of signature ER stress markers, including ER stress-specific X box-binding protein 1 and up-regulation of glucose-regulated protein 78. Furthermore, brain death causes up-regulation of C/EBP homologous protein and caspase-12. Consistent with this, terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5' triphosphate nick-end labeling assay and transmission electron microscopy confirmed apoptosis in the liver after brain death. Taken together, the present study provides strong evidence supporting the presence and importance of ER stress and response in mediating brain death-induced apoptosis and liver injury. PMID- 25498041 TI - Triptolide attenuates acute small-for-size liver graft injury in rats by inhibition of Toll-like receptor 4. AB - INTRODUCTION: The mechanism underlying small-for-size graft failure after reperfusion is still unknown. Toll-like receptor 4 (TLR4) has attracted a great deal of attention in inflammation and allograft rejection in recent years. Medicinally, triptolide has anti-inflammatory, immunosuppressive, and antineoplastic activities. In the present study, we studied the effect of triptolide on TLR4 expression in small-for-size grafts. MATERIALS AND METHODS: The potential inhibitory effect of triptolide on TLR4 messenger ribonucleic acid and protein in a mouse model of small-for-size liver graft injury was assessed. We also assessed the expression of tumor necrosis factor alpha and interleukin-6 in this model. RESULTS: The expression of hepatic TLR4 messenger ribonucleic acid and protein and downstream mediators, such as tumor necrosis factor alpha and interleukin-6, were reduced in the triptolide pretreatment groups (50 and 100 MUg) in small-for-size liver grafts. In these same triptolide pretreatment groups, edema and necrosis were reduced and the levels of alanine aminotransferase and aspartate aminotransferase were significantly decreased in these small-for-size liver grafts. CONCLUSIONS: This study showed that triptolide might inhibit TLR4 in vivo and that pretreatment with triptolide could inhibit TLR4 activation and reduce small-for-size liver graft injury. PMID- 25498042 TI - Low-flow hypothermic crystalloid perfusion is superior to cold storage during prolonged heart preservation. AB - BACKGROUND: Preservation of donor hearts for transplantation has traditionally been performed with the use of static cold storage. We have developed and tested a novel gravity-powered system of cold crystalloid perfusion for prolonged donor heart preservation. METHODS: Greyhounds were anesthetized; their hearts were arrested with cold cardioplegic solution and excised. Hearts were allocated to 12 hours of perfusion preservation (n = 6) or cold storage in ice (n = 5). Non preserved hearts (n = 5) served as a normal reference group. Perfusion hearts were perfused (20 mL/min, 8-12 degrees C) with a novel oxygenated nutrient containing preservation solution. After preservation, the recovery of the hearts was assessed in a blood-perfused working heart rig over 2 hours in terms of function, blood lactate level, myocardial adenosine triphosphate, and histology. RESULTS: After 2 hours of reperfusion, in comparison with cold storage hearts, perfused heart function curves showed superior recovery of cardiac output (P = .001), power (P = .001), and efficiency (0.046 +/- 0.01 vs 0.004 +/- 0.003 joules/mL O2, P = .034). Myocardial adenosine triphosphate content (mmol/mg protein) was reduced significantly from the normal level of 26.5 (15.9, 55.8) to 5.08 (0.50, 10.4) (P = .049) in cold storage hearts but not in perfused hearts. Over a period of 2 hours, lactate levels in the blood perfusate were significantly lower in the perfusion group than in the cold storage group (P < .05). CONCLUSIONS: Continuous hypothermic crystalloid perfusion provides myocardial preservation superior to cold storage for long-term heart preservation, with potential applicability to marginal and donation after circulatory death hearts. PMID- 25498043 TI - Heart donation after cardiac death: preliminary study on an isolated, perfused swine heart after 20 minutes of normothermic ischemia. AB - BACKGROUND: We measured the functional and metabolic status of hearts submitted to normothermic ischemia before preservation through the use of an ex vivo pig heart model to assess the feasibility of donation after cardiac death (DCD) in heart transplantation. METHODS: Ten pigs were separated into 2 groups: control (n = 6, brain-dead group) and DCD (n = 4, heart donation after cardiac death). In the control group, hearts were excised 20 minutes after the brachiocephalic trunk cross-clamping and were immediately reperfused. In DCD, hearts were excised 20 minutes after exsanguination and asphyxia, stored in the Centre de Resonance Magnetique Biologique et Medicale (CRMBM) solution for 2 hours, and then were reperfused. Cardioplegic arrest was induced with the use of 1 L of CRMBM solution (4 degrees C) and the heart was reperfused for 60 minutes through the use of an ex vivo perfusion system in Langendorff mode with normothermic autologous blood. During reperfusion, functional parameters were analyzed. Biochemical assays were performed in myocardial effluents and freeze-clamped hearts. RESULTS: No electromechanical activity was found in DCD compared with control. Creatine kinase (CK) was higher at 2 minutes of reperfusion in DCD versus control (P = .005). Adenosine triphosphate was lower in DCD versus control (P = .0019). Malondialdehyde, an oxidative stress index, was present only in DCD. The nitric oxide (NO) pathway was impaired in DCD versus control, with lower eNOS expression (P < .0001) and total nitrate concentration content (P = .04). CONCLUSIONS: We reported no cardiac functional and metabolic recovery in the DCD group after normothermic ischemia and reperfusion, which indicates that a single immersion of the cardiac graft during storage does not provide an optimal protection. New strategies in heart preservation are necessary for recruiting heart donation after cardiac death. PMID- 25498044 TI - Dopamine treatment of brain-dead Fisher rats improves renal histology but not early renal function in Lewis recipients after prolonged static cold storage. AB - BACKGROUND: Brain death (BD) and cold preservation are major risk factors for an unfavorable transplantation outcome. Although donor dopamine treatment in brain dead rats improves renal function and histology in allogeneic recipients, it remains to be assessed if this also holds true for the combinations of BD and prolonged static cold preservation. METHODS: BD was induced in F344 donor rats, which were subsequently treated with NaCl 1 mL/h (BD, n = 11), NaCl/hydroxy ethyl starch (BD-norm, n = 10), or 10 MUg/min/kg dopamine (BD-dopa, n = 10). Renal grafts were harvested 4 h after BD and transplanted into bilateral nephrectomized Lewis recipients 6 h after cold preservation in University of Wisconsin solution. Renal function was evaluated by use of serum creatinine and urea concentrations at days 0, 1, 3, 5, and 10. Ten days after transplantation, recipients were killed and the renal allografts were processed for light microscopy and immune histology. RESULTS: Serum urea concentrations at days 5 and 10 were significantly lower in recipients that received a renal graft from dopamine-treated rats; for serum creatinine, only a trend was observed at day 10. Immune histology revealed a lower degree of ED1-positive cells in the donor dopamine-treated group. Under light microscopy, Banff classification revealed significantly less intimal arteritis in these grafts (P < .05). CONCLUSIONS: Although donor dopamine treatment clearly improves renal histology in this model, the beneficial effect on early renal function was marginal. It remains to be assessed if donor dopamine treatment has a beneficial effect on renal function in long-term follow-up. PMID- 25498045 TI - Can ischemia-modified albumin be used as an objective biomarker for renal ischemic damage? An experimental study with Wistar albino rats. AB - INTRODUCTION: This study sought to evaluate the correlation of ischemia-modified albumin (IMA) with time-dependent renal ischemic injury. METHODS: We established 5 groups of 8 Wistar albino rats as follows: sham, 10 minutes of renal ischemia, 20 minutes of renal ischemia, 30 minutes of renal ischemia, and 40 minutes of renal ischemia. Renal ischemia was established by occlusion of the right renal pedicle. Blood samples were obtained after exploration of the renal pedicle in the sham group and after thoracotomy and directly from the cardiac chambers at the end of the ischemic period in the other groups. The ischemic kidneys were removed for histopathological evaluation, and the rats were killed. RESULTS: There were significant differences among the IMA levels of the 5 groups (P = .0013). Pathological examination showed that renal ischemic injury corresponded to the duration of ischemia. In the group analysis, the pathological evaluation scores were significantly different among the groups (P < .001). CONCLUSIONS: This study shows that IMA levels can be used as a nonselective biomarker for renal ischemic injury. However, further studies are needed to support our findings. PMID- 25498046 TI - Pretransplant biopsy in expanded criteria donors: do we really need it? AB - INTRODUCTION: Renal transplantation is the best treatment for end-stage renal disease, including when using expanded criteria donors (ECD) kidneys. However, these suboptimal kidneys should be evaluated rigorously to meet their usefulness. Opinions differ about the best way to evaluate them. MATERIALS AND METHODS: We retrospectively reviewed kidneys from ECD harvested by a single academic institution between January 2008 and September 2013. Needle biopsies were performed at the time of the harvest when considered relevant by the transplant team. Two pathologists where responsible for their analysis; the Remuzzi classification has been used in all cases. RESULTS: We evaluated 560 ECD kidneys. Biopsies were made in 197 (35.2%) organs, 20 of which were considered not usable and 36 good only for double transplantation. Sixty-three kidneys (11.3%) were discarded by the transplant team based on the biopsy result and clinical criteria. Donors who underwent a biopsy were older (P < .001) and had a worse glomerular filtration rate (GFR; P = .001). Comparing donors approved and rejected by the biopsy, the rejected donors were heavier (P = .003) and had a lower GFR (P = .002). Cold ischemia time was longer for the biopsy group (P < .001). Regarding graft function, the biopsy overall score correlated with the transplant outcome in the short and long term. Separately, glomeruli and interstitium scores were correlated with recipient's GFR in the earlier periods (3 months; P = .025 and .037), and the arteries and tubules correlated with GFR in the longer term (at 3 years P = .004 and .010). CONCLUSION: The decision on the usability of ECD grafts is complex. At our center, we chose a mixed approach based on donor risk. Low-risk ECD do not require biopsy. In more complex situations, especially older donors or those with a lower GFR, prompted a pretransplant biopsy. The biopsy results proved to be useful as they relate to subsequent transplant outcomes, thereby allowing us to exclude grafts whose function would most probably be less than optimal. PMID- 25498047 TI - Kidneys from standard-criteria donors with different severities of terminal acute kidney injury. AB - OBJECTIVES: High terminal serum creatinine level in a deceased donor has been reported as the second most frequent cause of refusal for kidney transplantation. A growing body of evidence has shown a comparable outcome of kidney transplantation from deceased donors with acute kidney injury (AKI). However, the influence of the severity of AKI on graft outcomes remains to be elucidated. METHODS: In this retrospective cohort study, 84 consecutive kidney transplants from 57 standard-criteria donors were classified into 4 groups by RIFLE (Risk, Injury, Failure, Loss of function, and End-stage renal disease) classification according to donor AKI severity before kidney procurement. The donor and recipient characteristics and graft outcomes were compared. RESULTS: Of 84 kidney transplants, 56, 11, 10, and 7 recipients were in the Non-AKI, Risk, Injury, and Failure groups. The mean terminal creatinine was 1.1, 1.6, 2.3, and 4.4 mg/dL in these 4 groups. However, the graft outcomes, including primary nonfunction rate, delayed graft function rate, acute rejection rate, renal function, graft survival and overall survival over the first 5 years had no statistical difference. A trend toward increasing delayed graft function rate as the severity of AKI increased was observed (Non-AKI, Risk, Injury, and Failure: 26.8%, 36.4%, 60.0%, and 57.1%, P = .099). CONCLUSIONS: Our study demonstrates that AKI before procurement does not cause adverse long-term graft outcomes. Standard-criteria donors with AKI are suitable for kidney transplantation, even with a high severity of AKI. PMID- 25498048 TI - Low incidence of coronary angiography in the evaluation process of the potential heart donor. AB - INTRODUCTION: We investigated the practice of coronary angiography (CA) on donor hearts. PATIENTS AND METHODS: Between January 1, 2000, and December 31, 2010, all reported organ donors aged <66 years were analyzed retrospectively. Donor charts were evaluated regarding a performed CA, its outcome, the timing of CA during the evaluation process, and reasons for organ refusal. The percentage of positive CA studies in organ donors aged >=45 years was also evaluated. RESULTS: Of 292 reported organ donors, 152 organ donor hearts were declined (group 1), and 140 hearts (group 2) were transplanted. Of the 152 declined hearts, 91 hearts were found not suitable for organ offer, and 61 were not successfully allocated or were refused by Eurotransplant. CA was conducted in 17 organ donors (5.8%). In 6 donors, a previous CA was reported (all had pathologic findings), and in 11 donors, a donor CA was performed, indicating 4 pathologic and 7 negative findings (54.5% of the hearts evaluated by donor CA were transplanted). No complication or delay of the donation process was reportedly related to donor CA. CONCLUSIONS: Special emphasis and implementation of recommendations for CA to be part of the evaluation of donor organs seem necessary. PMID- 25498049 TI - Performance of the ImmuKnow assay in differentiating infection and acute rejection after kidney transplantation: a meta-analysis. AB - BACKGROUND: The ImmuKnow test is an assay for determining the functional activity of immunocytes, which reflects cell-mediated immune responses in populations undergoing organ transplantation. METHODS: Electronic and manual searches were conducted to identify studies of the ImmuKnow test. After methodological quality assessment and data extraction, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were assessed, and summary receiver operating characteristic analysis was performed systematically. The extent of heterogeneity was explored. RESULTS: Six studies were identified for analysis. The pooled sensitivity, specificity, PLR, NLR, and DOR of ImmuKnow for predicting the risk of infection were 0.51 (95% confidence interval [CI], 0.45-0.57), 0.75 (95% CI, 0.71-0.78), 1.97 (95% CI, 0.91-4.26), 0.67 (95% CI, 0.38-1.19), and 3.56 (95% CI, 0.80-15.89), respectively. A DOR of 13.81 (95% CI, 0.79-240.44), with a sensitivity of 0.51 (95% CI, 0.40-0.61), a specificity of 0.90 (95% CI, 0.87-0.93), a PLR of 4.45 (95% CI, 0.91-21.74), and an NLR of 0.35 (95% CI, 0.08-1.45), was found in the analysis of the predictive value for acute rejection. The summary receiver operating characteristic curve values for ImmuKnow in distinguishing patients with infections from those with acute rejections were 0.631 +/- 0.215 and 0.986 +/- 0.015, respectively. CONCLUSIONS: Our analysis did not support the use of the ImmuKnow assay to predict or monitor the risks of infection and acute rejection in renal transplant recipients. Further studies are needed to confirm the relationships between the ImmuKnow assay and infection and acute rejection in kidney transplantation. PMID- 25498050 TI - Contrast-enhanced ultrasonography in the early period after kidney transplantation predicts long-term allograft function. AB - INTRODUCTION: Real-time contrast-enhanced sonography (CES) can assess microvascular tissue perfusion using gas-filled microbubbles. The purpose of the study was to evaluate the feasibility of early CES in predicting long-term kidney allograft function in comparison to color Doppler ultrasonography (CDUS). METHODS: We prospectively studied 68 consecutive kidney transplant recipients using CES and conventional CDUS investigation 1 week after transplantation. Transplant tissue perfusion imaging was performed by low-power imaging during intravenous administration of the sonocontrast SonoVue. Renal tissue perfusion was assessed quantitatively using flash replenishment kinetics of microbubbles to estimate renal blood flow (RBF). The obtained sonography values were correlated with clinical data 1 week up to 1 year after transplantation. RESULTS: In contrast with conventional CDUS resistive indices, RBF estimated by CES 1 week posttransplantation significantly correlated with kidney function after 1 year (r = 0.67; P < .001). Determination of RBF by CES revealed a significant correlation with donor age but not recipient age, whereas conventional CDUS resistive index was significantly correlated to recipient age (r = 0.54; P < .001) but not donor age. Furthermore RBF was associated with vascular fibrosis and intimal thickening of the engraftment biopsies. CONCLUSION: This is the first prospective study demonstrating the prognostic value of CES early after kidney transplantation. In contrast with CDUS, CES reveals information about kidney allograft perfusion independent of recipient vascular compliance. PMID- 25498051 TI - Serum microRNAs as new diagnostic biomarkers for pre- and post-kidney transplantation. AB - BACKGROUND: In the present study, we compared the expression levels of 3 microRNAs (miRNAs) between patients who had undergone kidney transplantation and healthy individuals in a search for a new diagnostic biomarker after kidney transplantation. METHODS: We used real-time quantitative polymerase chain reaction to investigate the expression levels of miR-181a, miR-483-5p, and miR 557 in the serum of 15 kidney transplantation patients before transplantation on the first, third, and seventh days after transplantation. The study was performed in the Guilin 181st Hospital between 2010 and 2012. The results of this study may assist with early diagnosis and treatment and contribute to our understanding of the pathological parameters. Receiver operating characteristic (ROC) analysis was performed to determine the area under the curve of each equation to predict evolution to rejection. RESULTS: ROC curves were performed to explore miRNAs to predict rejection occurrence after transplantation showed pre-transplantation expression levels of miR-181a to be a potential factor with a significant area under the curve (AUC = 0.985, P < .05). The expression of miR-181a before kidney transplantation was also significantly different on days 1 and 3 after kidney transplantation, the area under the curve (AUC) was, respectively, 0.980 (P < .05) and 0.830 (P < .05). Predictors on days 1, 3, and 7 show that miR-483-5p and miR-557 are also predictive factors for rejection. Predictors for miR-483-5p and miR-557 were significantly under the area ROC, respectively (AUC = 0.920, P < .05), and (AUC = 0.990, P < .005) on day 1 (AUC = 0.920, P < .05) and (AUC = 0.960, P < .005) on day 3, (AUC = 0.845, P < .05) and (AUC = 0.889, P < .05) on day 7. CONCLUSIONS: This study of miRNAs was unrelated to age, sex, histological classification, and metastasis (all P > .05). Serum miR-181a, miR-483-5p, and miR 557 could serve as circulating biomarkers for the early diagnosis of active situations of before and after kidney transplantation. PMID- 25498052 TI - Can stroke volume variation be an alternative to central venous pressure in patients undergoing kidney transplantation? AB - BACKGROUND: Stroke volume variation (SVV) is known to be a simple and less invasive hemodynamic parameter for evaluating fluid responsiveness and preload status. Central venous pressure (CVP) has been targeted to achieve an adequate level for improving the graft perfusion and long-term graft function in kidney transplantation (KT) recipients, despite the various potential complications. The aim of this study was to investigate whether SVV could substitute for CVP in guiding intravascular volume management during KT. METHODS: This retrospective study evaluated 635 patients who underwent KT because of end-stage renal disease. Hemodynamic variables including CVP and SVV were obtained before skin incision (T1), 5 minutes after iliac vein clamping (T2), and 10 minutes after renal graft reperfusion (T3). The ability of SVV to predict CVP level was investigated with receiver operating characteristic (ROC) curve analysis. RESULTS: CVPs were 6.0 +/ 2.6, 8.6 +/- 2.7, and 9.3 +/- 2.5 mm Hg, and SVVs were 6.9 +/- 3.0, 5.0 +/- 2.1, and 4.3 +/- 2.1% at T1, T2, and T3, respectively. ROC analysis showed that the discriminative power of SVV was fairly good with an area under the ROC curve of 0.70 (95% confidence interval, 0.67-0.72) for a CVP of 8 mm Hg, and that an optimal cutoff value of SVV was 6% as an alternative to CVP of 8 mm Hg during KT. CONCLUSIONS: SVV may replace CVP in the volume management of patients who have undergone KT. Our results suggest that SVV can guide volume management to improve graft perfusion at critical time points during KT. PMID- 25498053 TI - C4d immunoreactivity of intraoperative zero-hour biopsy in renal allograft. AB - C4d deposition in the peritubular capillaries is known to be correlated with antibody-mediated rejection (AMR) in renal allografts. An intraoperative zero hour biopsy during transplantation is considered an indicator to indirectly determine the status of the donor kidney. In this study, we investigated the relationship between C4d immunoreactivity of intraoperative zero-hour biopsy in renal allograft, thought to be due to donor condition, and acute rejection episodes during follow-up. We collected 147 renal transplantation cases examining intraoperative zero-hour biopsy with C4d immunohistochemical staining. All cases were from the Seoul National University Hospital between 2010 and 2011. Of the 147 cases, 24 (16.3%) showed strong C4d staining in the glomeruli, 38 (25.9%) showed weak staining, and the remainder (57.8%) showed negative staining. Nine cases (6.1%) showed positive C4d staining in the arterioles, and the remainder (93.9%) were negative. There were no significant differences between acute T-cell mediated rejection and acute AMR episodes in the renal allograft specimens during follow-up according to the glomerular or arteriolar C4d immunoreactivity of the intraoperative zero-hour biopsy specimens. PMID- 25498054 TI - Anti-angiotensin type 1 receptor antibodies associated with antibody-mediated rejection in patients without preformed HLA-donor-specific antibody. AB - INTRODUCTION: Angiotensin II is a peptide hormone involved in the renin angiotensin system (RAS). Anti-angiotensin receptor 1 (AT1R) antibodies are implicated in stimulating RAS and are suspected to have some adverse impacts on renal transplantation outcome. METHODS: From November 2009 to February 2012, 37 remaining sera from renal transplantation recipients with biopsy-proven antibody mediated rejection (AMR) (n = 6), acute cellular rejection (ACR) (n = 23), and AMR + ACR (n = 8) without preformed human leukocyte antigeon (HLA) antibodies were tested with anti-AT1R antibody assay. Forty-two control patients without rejection also were analyzed. RESULTS: The frequency of elevated anti-AT1R antibodies was higher in patients with AMR (n = 14) compared to controls (28.6% vs 4.9%, P = .03, OR = 8.0). It was also higher in patients with AMR + ACR (n=8) (37.5% vs 4.9%, P = .03, OR = 12.0). There was no difference in frequencies of elevated anti-AT1R antibody in patients with ACR. CONCLUSION: Anti-AT1R antibodies were suspected to be associated with occurrence of AMR without preformed HLA antibodies in renal transplantation. Further studies in a larger number of patients are needed. PMID- 25498055 TI - A randomized trial of everolimus and low-dose cyclosporine in renal transplantation: with or without steroids? AB - This multicenter, randomized, prospective, controlled trial (EVIDENCE study) aimed to determine short-term effects of early steroid withdrawal in renal transplant patients initially treated with everolimus, low-dose cyclosporine (CsA), and steroids. Patients were randomized to standard triple therapy with CsA, everolimus twice daily and steroids (group A), steroid-free immunosuppression (group B), or triple therapy once daily (group C). However, since patient enrollment was slower than expected, group C randomization was prematurely discontinued. The primary end point was treatment failure rate (composite end point of death, graft loss, biopsy-proven acute rejection, and loss to follow-up) between randomization and month 12. Patients evaluable for the primary end point included 139 randomized patients. According to intention-to treat analysis, 2.8% of patients in group A and 14.7% in group B experienced treatment failure (95% upper confidence limit 19.7%). As this was higher than the predefined noninferiority limit of 10%, noninferiority could not be proved. No conclusive statements can be made on noninferiority of the steroid withdrawal regimen vs the standard regimen in these patients. Additional studies with longer follow-up are required to determine the efficacy of steroid-free immunosuppression in renal transplant recipients receiving everolimus. PMID- 25498056 TI - Retrospective evaluation of the effect of mycophenolate mofetil dosage on survival of kidney grafts based on biopsy results. AB - INTRODUCTION: Plasma concentration monitoring is commonly used to adjust immunosuppressant dosage in transplant recipients, but adjustment is often based on clinical experience rather than rigorous quantitative indicators. METHODS: We examined the effect of mycophenolate mofetil (MMF) dosage on graft survival by pathologic and immunologic analysis of 88 kidney recipients who were given a postoperative immunosuppressive regimen of tacrolimus (FK506), MMF, and corticosteroids. Patients were given a conventional dosage (>=1.5 g/d; n = 40) or a reduced dosage (n = 48) of MMF owing to postoperative adverse side effects. RESULTS: The reduced-dose group included patients given low doses (<=1.0 g/d; n = 27), ultra-low doses (<=0.5 g/d; n = 15), and those who discontinued MMF (n = 6). The dose reduction group had increased acute rejection, chronic rejection, and graft dysfunction, poorer pathologic scores, and increased cell infiltration of graft tissue (CD4, CD8, CD68, and CD138 positivity) and expression of interleukin 2R and HLA-DR. Finally, hazard analysis indicated that patients given low doses and ultra-low doses of MMF had poorer long-term kidney grafts survival (hazard ratios of 1.52 and 1.78, respectively). CONCLUSIONS: These results indicate the importance of using an appropriate dosage of MMF in kidney transplant recipients. PMID- 25498057 TI - Everolimus associated with low-dose calcineurin inhibitors, an option in kidney transplant recipients of very old donors. AB - BACKGROUND: Despite potential renal and cardiovascular advantages of proliferation signal inhibitors, their de novo use in kidney transplantation (KT) from elderly donors (ED) is poorly documented. We retrospectively analyzed two consecutive cohorts of KT from ED: low-dose extended-release tacrolimus (Tac) was used from 2010 to 2012 and cyclosporine (Csa) was used from 2008 to 2010. METHODS: Associated maintenance drugs were everolimus (Eve) and steroids. Outcomes were compared between groups over a 12-month follow-up. Fifty-six patients were analyzed in the Tac-Eve group and 54 in the Csa-Eve group. RESULTS: There were no significant differences at baseline with the exception of older donors age in the Tac-Eve cohort (74 vs 71 years, P = .002). There were no deaths, primary non functions, or graft losses. Eight (14%) Tac-Eve and 15 (28%) Csa-Eve patients had delayed graft function (P = .10). Renal function was fairly stable over time (median cGFR 36-49 mL/min and 51-55 mL/min in single kidney transplantation and dual kidney transplantation patients, respectively) with no significant differences between groups at month 12. Surgical complications were infrequent and observed mostly in dual kidney transplantation recipients. Thirty nine (70%) and 30 (56%) patients remained under their initial Tac-Eve or Csa-Eve regimen, respectively. CONCLUSIONS: Induction with Thymoglobuline and maintenance with Eve and low-dose extended-release Tac and steroids is safe and effective in renal transplant from ED. PMID- 25498058 TI - Comparison of cadaveric kidney transplantation from in-center and external center donors. AB - INTRODUCTION: Renal transplantation is the best treatment modality for end-stage renal disease. We investigated the effects of donor source on renal allograft and patient survival in deceased donor transplants. METHODS: We analyzed retrospectively 190 cadaver kidney transplants performed in our center from January 2000 to December 2009. Of these, 136 kidneys were harvested in our transplantation center and 54 were from external donors. Primary outcome of graft survival was assessed with the Kaplan-Meier method and the significance of possible variables was determined with the Cox proportional hazard model. RESULTS: There was no difference between groups in the age of donor and recipient, recipient body mass index, duration of dialysis, or panel reactive antibody >30%. Twenty recipients lost their grafts (14 from external donors and 6 from internal donors). Graft survival at 1, 3, and 5 years was 99.2%, 97.3%, and 95.5% for in-center donors and 98.1%, 88.9%, and 86.2% for external donor transplants (P = .01). There was no difference in patient survival rates between the groups. Acute rejection episodes (hazard ratio [HR], 13.2; P < .001) and external hospital donor (HR, 9.3; P = .008) were independent factors associated with failure. Higher age of recipient was associated with increased patient death rate (HR, 1.2; P = .02). CONCLUSION: Graft survival of cadaveric transplants from in-center donors was better than that of transplants from external center donors. Acute rejection episodes and location of harvest were significant factors for graft survival. Further study is needed to evaluate the effects of center-level factors on allograft outcomes. PMID- 25498059 TI - Incidence and management of leukopenia/neutropenia in 233 kidney transplant patients following single dose alemtuzumab induction. AB - BACKGROUND: The purpose of this study was to determine the incidence and management strategies for post-transplant leukopenia/neutropenia in kidney recipients receiving alemtuzumab induction during the first year following transplantation. METHODS: We prospectively identified 233 adult patients who underwent kidney transplantation with alemtuzumab induction at a single institution. The incidence and severity of leukopenia (white blood cell count [WBC] <=2500/mm(3)) and neutropenia (absolute neutrophil count [ANC] <=500/mm(3)) were evaluated at 1, 3, 6, and 12 months post-transplantation. We determined any association with cytomegalovirus (CMV) infection, graft rejection, and infections requiring hospitalization. We also reviewed interventions performed, including medication adjustments, treatment with granulocyte stimulating factor, and hospitalization. RESULTS: The combined incidence of either leukopenia or neutropenia was 47.5% (n = 114/233) with an average WBC nadir of 1700 +/- 50/mm(3) at 131.0 +/- 8.5 days and an average ANC nadir of 1500 +/- 100/mm(3) at 130.4 +/- 9.6 days. No significant difference in graft rejection, CMV infection, or infections requiring hospitalization was found in the leukopenia/neutropenia group vs the normal WBC group (P = .3). The most common intervention performed for leukopenia/neutropenia group was prophylactic medication adjustment. Six patients (5.2%) required a change in >1 medication. The majority of these patients also required granulocyte stimulating factor (61.5%; 32/52), with an average of 2.5 doses given. A total of 25 patients (21.9%) required hospitalization due to leukopenia/neutropenia with an average length of stay of 6 days. CONCLUSIONS: Kidney transplant patients receiving alemtuzumab induction required significant interventions due to leukopenia/neutropenia in the first year post-transplantation. These results suggest the need for additional studies aimed at defining the optimum management strategies of leukopenia/neutropenia in this population. PMID- 25498060 TI - Alemtuzumab induction and antibody-mediated rejection in kidney transplantation. AB - BACKGROUND: Induction therapy improves graft outcomes in kidney transplant recipients (KTRs). We aimed to compare the incidences of antibody-mediated rejection (AMR) and acute cellular rejection (ACR) as well as graft and patient outcomes in KTRs who underwent induction with alemtuzumab versus rabbit antithymocyte globulin (r-ATG). METHODS: This was a single-center retrospective study involving patients who underwent kidney transplantation between January 2009 and December 2011 after receiving induction therapy with either alemtuzumab or r-ATG. Maintenance immunosuppression included tacrolimus and mycophenolate mofetil with early steroid withdrawal. Acute rejection was diagnosed using allograft biopsy. RESULTS: Among the 108 study patients, 68 received alemtuzumab and 40 got r-ATG. There was a significantly higher incidence of AMR (15% vs 2.5%; P = .008) and similar incidence of ACR (4.4% vs 10%; P = .69) for alemtuzumab versus r-ATG groups. One-year serum creatinine levels (l.68 +/- 0.8 mg/dL vs 1.79 +/- 1.8 mg/dL; P = .66) as well as graft (91.1 +/- 3.5% vs 94.5 +/- 3.8%; P = .48) and patient (93.8 +/- 3.0% vs 96.4 +/- 3.5%; P = .92) survivals were similar for the alemtuzumab versus the r-ATG groups. CONCLUSION: Our study showed a higher incidence of AMR and similar incidence of ACR in KTRs who underwent induction with alemtuzumab compared with those who received r-ATG and were maintained on tacrolimus and MMF. This was despite a lower HLA mismatch in the alemtuzumab group. One-year graft survival, patient survival, and allograft function were similar. Inadequate B-cell suppression by alemtuzumab as well as altered phenotypic and functional properties of repopulating B cells could be contributing to heightened risk of AMR in these patients. PMID- 25498061 TI - Safety of kidney transplantation using anti-HBc-positive donors. AB - BACKGROUND: Prospective studies evaluating the risk of hepatitis B virus (HBV) transmission in transplants of kidneys from hepatitis B core antibody (anti-HBc) positive/hepatitis B surface antibody (anti-HBs)-negative donors are still lacking. The objective of this study was to assess the safety of kidney transplantation with the use of anti-HBc-positive donors. METHODS: This prospective case series study included 50 kidney transplant recipients from anti HBc-positive donors with or without anti-HBs positivity. Recipients were required to test positive for anti-HBs (titers >10 mUI/mL), regardless of anti-HBc status, and negative for hepatitis B surface antigen (HBsAg). Recipient and donor data were retrieved from medical records, databases, and organ procurement organization sheets. Liver function tests were performed at progressively increasing post-transplantation intervals. Complete serologic tests for HBV were performed before transplantation, 3 and 6 months after transplantation, and annually thereafter. RESULTS: Six months after transplantation, all recipients were negative for HBsAg, HBeAg, anti-HBe, and anti-HBcIgM. No seroconversion was observed among the 20 patients who received kidneys from anti-HBc-positive/anti HBs-negative donors. No patient showed elevated liver enzymes during follow-up. CONCLUSIONS: Kidney transplantation using organs from anti-HBcIgG-positive donors (even when they are concurrently anti-HBs negative) in anti-HBs-positive recipients is a safe procedure and may be considered as a way to expand the donor pool. PMID- 25498062 TI - Dual kidney transplantation involving organs from expanded criteria donors: a review of our series and an update on current indications. AB - BACKGROUND: Our purpose was to review our kidney transplantation program based on the use of expanded criteria donors, and to determine current indications for dual kidney transplantation (DKT). In 1996, a program was initiated to transplant kidneys from donors of over 60 years performing single or dual transplantation. METHODS: In 1996, a program was initiated to transplant kidneys from donors of over 60 years performing single or dual transplantation. DKT were performed with donors >75 and donors between 60 and 74 years of age and glomerulosclerosis of >15%. The kidneys of donors between 60 and 74 years of age and with glomerulosclerosis of <15% were used for single kidney transplantation (SKT). In 2005, we started to perform SKT despite glomerulosclerosis being >15%, taking into account donor and recipient characteristics. RESULTS: From 1996 to 2004, 222 SKTs and 88 DKTs were performed. Graft survival after 1 and 4 years was, respectively, 91% and 78% for SKT and 95% and 79% for DKT. In 2005, we started to perform SKT despite glomerulosclerosis being >15%, taking into account donor and recipient characteristics. From 2005 to 2011, 328 SKT and 32 DKT were performed. During this period most kidneys used for DKT were from female donors >75 years old, weighing <65 kg, with a creatinine of >1 mg/dL and glomerulosclerosis of >15%. The recipients for DKT were mostly male, <70 years old and whose weight was >75 kg. CONCLUSION: DKT from expanded criteria donors shows good outcomes. However, in many cases SKT may fulfill the need of the recipient. The archetype for DKT is an older female weighing <65 kg and the most common recipient is an overweight male who is <70 years old. PMID- 25498063 TI - Outcomes in obese kidney transplant recipients. AB - BACKGROUND: Kidney transplantation (KT) in obese patients is controversial. The present study aimed to evaluate patient and graft survival and post transplantation complications between obese and nonobese recipients. METHODS: Patients (n = 3,054) receiving a KT from 1998 to 2008 were divided according to body mass index (BMI) into 3 groups for analysis: group I: BMI <30 kg/m(2) (nonobese); group II: >=30-34.9 kg/m(2) (class I obese); and group III: >=35 kg/m(2) (class II and III obese). RESULTS: Mean BMIs were: group I (n = 2,822): 22.6 +/- 3.3 kg/m(2); group II (n = 185): 31.9 +/- 1.3 kg/m(2); and group III (n = 47): 36.8 +/- 1.7 kg/m(2). There were no differences among the 3 groups in patient demographic variables regarding race, sex, or organ source. One-year (I, 98%; II, 98%; III, 95%) and 5-year (I, 90%; II, 92%; III, 89%) patient survival rates were similar among groups. Graft survival rates at 1 year were 96% for groups I and II and 91.5% for group III. Five-year graft survivals were: I, 81%; II, 96%; and III, 79%. The most common cause of graft loss was death, and the main cause of death was infection in all groups. Obese patients were more likely to experience wound dehiscence (I, 1.9%; II, 7.6%; III, 19.1%; P < .001), develop new-onset diabetes after transplantation (NODAT; I, 16.2%; II, 27%; III, 36%; P < .001), and have a prolonged length of hospital stay (I, 11.3 +/- 11.4 d; II, 14.5 +/- 14.3 d; III, 15.9 +/- 16.7 d; P < .001). CONCLUSIONS: Obese recipients demonstrated outcomes similar to nonobese patients regarding patient and graft survival. However, they had higher rates of prolonged length of hospital stay, wound dehiscence, and NODAT. PMID- 25498064 TI - Outcomes of paired-exchange live-donor kidney transplantation: a single-center experience. AB - INTRODUCTION: Paired-exchange kidney transplantation (PEKT) enables recipients with willing but incompatible donors to find potential matches from a larger pool of donors. It involves transportation of donor kidneys to the intended recipient with a consequent increase in the cold ischemia time (CIT). PATIENTS AND METHODS: Our single-center study compared the outcomes of PEKT versus traditional in center live-donor kidney transplants (ICKT). Retrospective chart review of adult patients who underwent PEKT and ICKT from January 2009 to February 2012 at our institution was performed. Delayed graft function, acute rejection rates, incidence of proteinuria, trends in serum creatinine, and graft and patient survival rates were compared between groups. RESULTS: Baseline demographic data were similar between the PEKT group (n = 15) and the ICKT group (n = 30) except that CIT (13.1 vs 3.8 hours; P < .001) and panel reactive antibody titers (12.6% +/- 22.9% vs 0.9% +/- 4.9%; P = .01) were significantly higher in the PEKT group. No patient developed delayed graft function. At a median follow-up of 12.4 months (range: 2-27.5 months), graft and patient survival rates were 100% in both groups. Serial creatinine levels were similar between the groups. There were no significant differences between groups in acute rejection rates (3 of 15 vs 3 of 30) and development of proteinuria posttransplantation (8 of 15 vs 22 of 30). CONCLUSIONS: Our study found similar outcomes between the PEKT and ICKT groups despite longer CIT and higher panel reactive antibody titers in the PEKT group. These findings support the current practice of PEKT with transporting of donor kidneys, with the resultant increase in the chances of living-donor kidney transplantation. PMID- 25498065 TI - HLA-identical sibling renal transplantation: influence of donor and recipient gender mismatch on long-term outcomes. AB - BACKGROUND: Long-term function of living-related kidney allograft depends on multiple variables. The aim of the present study was to assess the influence of donor and recipient gender mismatch on the short and long-term outcomes in human leukocyte antigen (HLA)-identical sibling renal transplants (SRTs) receiving induction therapy and different immunosuppressive regimens. MATERIAL AND METHODS: Twenty-nine recipients who were grafted from their HLA-identical siblings between 1994 and 2008 were divided into 2 groups (same and mismatched) according to gender of donor and recipient. The analyzed variables were age, gender, cholesterol, triglyceride, proteinuria, estimated glomerular filtration rate, weight, body mass index, and serum creatinine at 6, 12, 24, 36, 48, and 60 months, and median follow-up. Univariate and multivariate logistic regression models (when appropriate) were used to evaluate the effects of variables on allograft survival. RESULTS: The number of male donors (P = .001) and recipient age (P = .019) was significantly higher in the same gender group than in mismatched gender group; there were no relationships between remainder analyzed parameters. Multivariate regression analysis revealed that after median follow-up period of 84 months (range, 60-232) the most important potential factors to significantly influence long-term outcomes were male donor (P = .002), recipient age (P < .001), and donor age (P = .021). CONCLUSION: Our study demonstrated that male donor, and donor and recipient age affected long-term survival of HLA identical SRTs, supported with antibody induction therapy and lifetime immunosuppression. PMID- 25498066 TI - Quality of life and psychology after living-related kidney transplantation from donors and recipients in China. AB - BACKGROUND: The state of organ transplantation in general in China is experiencing transition; however, living-donor organ transplantation has gained more attention recently. We have found that because traditional Chinese ideas, few Chinese transplantation surgeons have the quality of life (QOL) and mental health of living transplantation donors and recipients as their focus in care giving. Physicians outside of China typically have a different view. This study investigated QOL and psychology characteristics in Chinese living-related kidney donors and recipients after transplantation. METHODS: Demographics, socioeconomics, transplantation processes, QOL scores, and psychosocial outcomes of 169 pairs of living-related kidney donors and recipients were analyzed using a self-made socio-demographic questionnaire, the short-form 36 health survey, and the Zung self-rating anxiety and depression scales. RESULTS: The majority of both donors (81.8%, 90/110) and recipients (83.1%, 103/124) were at secondary school or lesser education levels. Eighty-five and five tenths percent (94/110) of donors and 54.8% (68/124) of recipients were of moderate or low incomes. In addition, the donors were predominantly female (61.8%, 68/110), 6 of whom (5.5%, 6/110) stated that their transplantation had a negative impact on marriage due to kidney donation. The evaluation of the donors' QOL was not significantly different from that of the Chinese norm. The recipients' QOL was obviously improved comparing with the hemodialysis patients. There was no anxiety and depression among donors, but slightly anxious (1.6%, 2/124) and depressive (5.6%, 7/124) symptoms were found among recipients. CONCLUSION: Living-related kidney transplantation did not adversely affect the lives and psychological aspects of donors and significantly improved the QOL of recipients. Screening donors strictly, perfecting the medical care system, intensifying follow-up and social supports, and providing necessary healthy and psychological counseling should be fundamental prerequisites. PMID- 25498067 TI - A novel and personalized rehabilitation program for obese kidney transplant recipients. AB - INTRODUCTION: Physical rehabilitation programs for kidney transplant recipients are not routinely personalized to patients' physical and emotional health, which could result in a potentially limited health impact, shorter-term participation, and an overall low success rate. MATERIALS AND METHODS: We conducted an internal review board-approved randomized prospective study involving a 12-month supervised multidisciplinary rehabilitation program (GH method) initiated after kidney transplantation in obese recipients (body mass index >30). The new method incorporates 3 major components: physical exercise, behavioral interventions, and nutritional guidance. We compared 9 patients who underwent supervised rehabilitation with 8 patients who underwent standard care. Patients were followed up after the start of the intervention, and multiple assessments were performed. RESULTS: The adherence to training and follow-up was 100% in the intervention group, compared with 25% at 12 months in the control group. There was a trend for a higher glomerular filtration rate in the intervention group compared with the control group (55.5 +/- 18.6 mL/min/1.73 m(2) vs 38.8 +/- 18.9 mL/min/1.73 m(2), P = .06). The quality of life (SF-36) mean score improved more in the intervention group compared with the control group (583 +/- 13 vs 436 +/- 22, P = .008). There was a significantly higher employment rate in the intervention group, 77.7% at 12 months compared with 12.5% in the control group (P = .02). CONCLUSIONS: Our preliminary results suggest that this comprehensive approach to physical rehabilitation can improve adherence, kidney function, quality of life, and employment rate for obese patients after kidney transplantation. PMID- 25498068 TI - Negative impact of underlying non-insulin-dependent diabetes mellitus nephropathy on long-term allograft survival in kidney transplantation: a 10-year analysis from a single center. AB - INTRODUCTION: We analyzed the relationship between underlying nephropathy and long-term outcomes in kidney transplant recipients. METHODS: We retrospectively analyzed data from 678 patients who underwent kidney transplantation (KTx) between 1998 and 2011. Recipients with 13 major nephropathies were evaluated for graft and patient survival, and causes of graft loss. RESULTS: The best 10-year graft survival rates (100%) were in the patients with autosomal-dominant polycystic kidney disease, preeclampsia, Alport syndrome, and purpura nephritis. The worst rate (50.8%) was in patients with non-insulin-dependent diabetes mellitus nephropathy (NIDDMN; P = .039). Causes of graft-loss in the NIDDM patients included chronic rejection (6 cases), acute rejection (3 cases), infection (2 cases), and cardiovascular event (2 cases). Significant risk factors for graft loss were donor age (P < .01) and NIDDMN (P < .01). CONCLUSION: Underlying NIDDMN before KTx was a significant risk factor for long-term graft function. Immunologic factors and nonimmunologic factors influenced the long-term outcomes in patients with underlying NIDDMN. PMID- 25498069 TI - N-terminal pro-B-type natriuretic peptide is inversely related to bone mineral density in renal transplant recipients. AB - INTRODUCTION: Bone mineral density (BMD) was significantly lower in heart failure patients. Our aim was to evaluate the relationship between BMD and fasting serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration in renal transplant recipients. METHODS: Fasting blood samples were obtained from 69 renal transplant recipients. BMD was measured by dual energy x-ray absorptiometry in lumbar vertebrae (L2-L4). Serum NT-proBNP levels were measured by electrochemiluminescence immunoassay. RESULTS: Among the renal transplant recipients, 8 patients (11.6%) had osteoporosis and 28 (40.6%) had osteopenia; 33 had a normal BMD. Increased serum NT-proBNP (P < .001) and decreased body mass index (P = .033) and body weight (P = .010) were significantly correlated with low lumbar T-score cutoff points between groups (normal, osteopenia, and osteoporosis). Women had lower lumbar BMD than did men (P = .013). Menopause in women (P = .005), use of tacrolimus (P = .020), and use of cyclosporine (P = .046) among renal transplant recipients were associated with lower lumbar BMD. Multivariate forward stepwise linear regression analysis of the significant variables revealed that log-transformed NT-proBNP (beta, -0.545; R(2) = 0.331; P < .001), and body weight (beta, 0.273, R(2) = 0.104; P = .005) were independent predictors of lumbar BMD values among the renal transplant recipients. CONCLUSIONS: Serum NT-proBNP concentrations correlate negatively with lumbar BMD values among renal transplant recipients and may be an alternative to energy x ray absorptiometry for identifying at risk of osteoporosis in renal transplant recipients. PMID- 25498070 TI - Risk factors for BK virus infection and BK virus-associated nephropathy under the impact of intensive monitoring and pre-emptive immunosuppression reduction. AB - BACKGROUND: BK virus (BKV) nephropathy (BKVN) is an increasingly recognized cause of kidney allograft loss and is thought to be related to the newer, more potent immunosuppressive agents. However, the risk factors for different types of BKV infection under the impact of intensive monitoring and reduction of maintenance immunosuppression are not well understood. METHODS: Quantitative BKV DNA surveillance in plasma/urine and cytological testing in urine were performed regularly within the first year post-transplantation in 229 kidney recipients. Patients with BK viremia and BKVAN treated with immunosuppression reduction were monitored for BKV every 3-6 months. All the patients were followed up for a minimum of 5 years to exclude later development of BKVAN. Potential variables were compared and analyzed using logistic regression model multivariate analysis to assess and rank the BKV infection-related factors. RESULTS: Seventy-eight (34.1%) patients had decoy cells, 99 (43.2%) BK viruria, 38 (16.6%) BK viremia, and 7 (3.1%) BKVAN. Risk for decoy cells, BK viruria, and viremia, and BKVAN in univariate analyses were higher with tacrolimus (Tac) and deceased kidney donation. Multivariate analysis showed that Tac ([HR, 2.7; P = .008], [HR, 2.3; P = .016], [HR, 2.9; P = .032]) and deceased kidney donation ([HR, 2.5; P = .004], [HR, 2.6; P = .002], [HR, 2.1; P = .071]) were risk factors for BK decoy cells, BK viruria, and viremia, respectively. BKVAN was inclined to the patients with the combination of Tac and mycophenolate mofetil and longer BKV clearance time. CONCLUSIONS: Tac and deceased kidney donation are independent risk factors for BKV infection under the impact of therapeutic drug monitoring. PMID- 25498071 TI - Surgical site and early urinary tract infections in 1000 kidney transplants with antimicrobial perioperative prophylaxis. AB - Surgical site infections (SSIs) and early urinary tract infections (UTIs) are well recognized postoperative kidney transplant complications. These complications seldom lead to graft loss, although they may result in significant morbidity with prolonged hospitalization. Thus, perioperative antibiotic prophylaxis (PAP) has traditionally been used in this setting. Between April 1988 and December 2012, we identified 1000 kidney transplant recipients (33 from living donors) who underwent prophylaxis with ceftriaxone before the surgical procedure. A retrospective analysis was conducted to evaluate both the incidence rate and outcome of SSIs and UTIs. Recipients who developed SSIs were also assessed to identify risk factors and potential correlations with different immunosuppressive regimens. A total of 20 SSIs (2%) and 93 UTIs (9.3%) were observed. The most significant risk factor for SSIs was urine leak (15.38%; odds ratio [OR], 12.3; P < .0001) followed by sirolimus-based maintenance immunosuppression therapy (5%; OR, 2.97; P = .04) and induction therapy with either antithymocyte globulin or basiliximab (3.18%; OR, 3.45; P = .01). Sex was identified as the only risk factor for UTI (female vs male, 17.1% vs 4.6%; P < .0001). We believe universal ceftriaxone-based prophylaxis is useful for preventing SSIs and UTIs, considering its effectiveness and safety profile. PMID- 25498072 TI - Impact of ureteral stenting on urological complications after kidney transplantation surgery: a single-center experience. AB - BACKGROUND: Urological complications such as ureteral strictures and ureteral leakage can affect the outcome of kidney transplantation by increasing morbidity and mortality, including graft loss. Controversy still exists regarding the role of stents in renal transplantation. The aim of this study was to evaluate the role of ureteral stenting in kidney transplantation. METHODS: We performed a retrospective study on a series of 798 consecutive renal transplants performed in our center between January 1, 2004, and December 31, 2011. Ureteral stents were used in 152 cases (19.1%) of the total (stent group) and were removed 2 weeks postoperatively. Donor and recipient age, sex, type of ureteroneocystostomy, stent and non-stent patients, cold and warm ischemia time, and urological complications were analyzed. RESULTS: The overall incidence of urological complications was 7.8% (62 cases). Ureteral stenosis (3.1%) and ureteral leakage (2.4%) were the most common complications; 39.7% (25 cases) of complications were recorded in the first month after transplantation. Major urological complication rate was 3.3% in the stent group compared with 8.8% in the non-stent group (P = .04). However, stent use was associated with the increase of urinary tract infections rate in the stent group (51.3%) compared with the non-stent group (17.9%) (P = .03). CONCLUSIONS: In our study, the use of ureteral stents significantly decreased urological complications in kidney transplant recipients but increased the risk for development of urinary tract infections. PMID- 25498073 TI - Antibiotic prophylaxis at urinary catheter removal prevents urinary tract infection after kidney transplantation. AB - BACKGROUND: Urinary tract infections (UTI) are common nosocomial infections in kidney transplant recipients, with limited evidence to guide antibiotic prophylaxis at urinary catheter removal. The aim of our study was to evaluate the effect of short-term antibiotic therapy at the moment of catheter removal after kidney transplantation. METHODS: Twenty kidney transplant recipients received 250 mg of ciprofloxacin orally twice daily 1 day before and at the day of the removal of the urinary catheter and were compared with 20 kidney transplant recipients without prophylaxis. UTI was diagnosed by use of urine culture and clinical signs. RESULTS: All patients were comparable in sex, age, etiology of end-stage renal failure, immunosuppression, donor type, and initial function. After catheter removal at the 6th postoperative day, a rapid rise of UTI in kidney transplant recipients without prophylaxis (n = 12, 60%) was observed, whereas in patients with antibiotic prophylaxis the rate of UTI could be significantly reduced to 20%. Escherichia coli was the most isolated pathogen in the patients with UTI and was detected at the catheter tip in more than 50% of cases. In 2 patients (10%) after antibiotic prophylaxis, a ciprofloxacin-resistant E coli strain was detected. CONCLUSIONS: The use of antibiotic prophylaxis during urinary catheter removal is recommended to prevent UTI in kidney transplant recipients. PMID- 25498074 TI - Bladder cancer in renal allograft recipients: risk factors and outcomes. AB - BACKGROUND: Solid organ transplant recipients have an increased cancer risk owing to immunosuppression and oncogenic viral infections. We report on the incidence and types of bladder cancer in kidney transplant recipients in Ireland, describing possible additional risk factors and outcomes in these patients. METHODS: We identified kidney transplant recipients diagnosed with de novo bladder cancer between January 1, 1994, and July 31, 2012, by integrating data from the Irish National Cancer Registry and National Renal Transplant Registry. We calculated the standardized incidence ratio (SIR) and examined patient and tumor characteristics and 1-year survival rate. RESULTS: Fifteen patients were diagnosed with de novo bladder cancer during the study period, representing 0.48% of kidney transplant recipients. The SIR was 2.5 (95% CI, 1.4-4.2; P < .001). The mean interval between transplantation and diagnosis of bladder tumor was 8.6 years and mean age at time of diagnosis was 55.7 years. Sixty percent of patients were male. The tumor types were transitional cell carcinoma (9 patients), squamous cell carcinoma (3 patients), adenocarcinoma (1 patient), carcinoma in situ (1 patient), and diffuse large B-cell lymphoma (1 patient). Beside immunosuppression, risk factors associated with bladder cancer were urogenital disease (6 patients), cyclophosphamide exposure (2 patients), BK nephropathy (1 patient), analgesic nephropathy (1 patient), and extensive smoking (1 patient). Eight patients underwent radical cystectomy for invasive tumors, with resection of other pelvic organs in 7 patients. Mortality rate within the first year was 40%. CONCLUSION: Bladder cancer occurred more commonly in kidney transplant recipients with a predominance of aggressive tumors and a high mortality. In patients with preexisting risk factors such as urologic abnormalities and cyclophosphamide exposure careful assessment before transplantation and vigilant monitoring posttransplantation with a low threshold for cystoscopy may improve outcomes. PMID- 25498075 TI - Perioperative predictors for refractory hyperglycemia during the neohepatic phase of liver transplantation. AB - BACKGROUND: Hyperglycemia in the neohepatic phase of liver transplantation (LT) tends to decrease toward completion of the surgical procedure. Refractory hyperglycemia in the neohepatic phase (RH) is influenced by multiple perioperative factors and may be connected to posttransplant outcomes. We attempted to demonstrate the relationship of RH to posttransplant outcomes and to establish a predictive model for RH in living donor liver transplantation (LDLT). METHODS: Perioperative data of 211 patients who underwent LDLT from 2009 and 2012 were reviewed, including declines in the blood glucose levels during the neohepatic phase. Perioperative variables including the posttransplant model for end-stage liver disease (MELD) score until day 30 were compared between patients with normal declines in blood glucose and patients with RH. Selected variables after intergroup comparisons were examined by means of multivariate logistic regression to establish a predictive model for RH occurrence. RESULTS: The mean blood glucose decline was 22.3 +/- 31.5 mg/dL during the neohepatic phase, and 84 of 203 patients (41.4%) had no decline in blood glucose. In intergroup comparisons, preoperative factors associated with RH included sex, Child-Pugh Turcotte class, MELD score, emergency, liver enzymes, and graft-to-recipient weight ratio. During surgery, surgical time, serum lactate, and arterial pH were associated with RH. After surgery, the RH group showed slower recovery of the MELD score (15.2 versus 11.9 days) and higher MELD scores until day 10 (P < .05). After the multivariate analysis, recipient sex, emergency, surgical time (<=9 h), and the final intraoperative serum lactate level (>=5.0 mmol/L) were included in the predictive model for RH. CONCLUSIONS: RH was associated with delayed functional recovery of the liver graft in LT. Recipient sex, emergency, surgical time, and the final intraoperative serum lactate level were identified as predictors of RH. Close monitoring of intraoperative blood glucose in LDLT may be an early prognostic indicator. PMID- 25498076 TI - Efficacy and tolerability of rifaximin in combination with lactulose in end-stage liver disease patients with MELD greater than 20: a single center experience. AB - BACKGROUND: Rifaximin is a non-absorbable antibiotic which is approved for the treatment of hepatic encephalopathy (HE) in the United States. Our goal was to retrospectively assess this in patients with very advanced liver disease with our center data. METHODS: Between 2003 and 2010, we examined a total of 286 consecutive patients from our center who were on a combination of rifaximin and lactulose, who had been evaluated or listed as eligible for a liver transplant. Patients who received less than 3 months of rifaximin and lactulose were excluded. Patients who had incomplete data; specifically, a lack of MELD score upon hospital admission were excluded from this analysis. The retrospective chart review was approved by the institutional review board. RESULTS: We observed a total of 723 hospitalizations among the patients. Of the 723 hospitalizations, 218 were due to portosystemic encephalopathy (PSE), whereas 505 were due to other causes. We observed that patients with a MELD < 20 had an average of 2.5 hospitalizations per 6 month period, and that those with a MELD > 20 had an average of 1.6 hospitalizations per 6 month period for HE. At the same time, patients who had a MELD score < 20 had 3.29 hospitalizations for HE unrelated causes and those whose MELD was >20 had 3.73 hospitalizations for causes not related to HE. In this cohort 65% of all hospitalizations from HE were in patients whose MELD was < 20, and 35% of all hospitalizations were for patients with a MELD > 20. CONCLUSION: In our experience, HE related hospitalizations were lower in patients whose MELD > 20 who were on a combination of rifaximin and lactulose compared to patients with MELD < 20. In contrast, patients whose MELD > 20 had greater hospitalizations for non HE events which may be an expected result owing to the overall increased severity of their liver disease. The limitation of this study is its retrospective nature and single center experience. In conclusion, administration of rifaximin appears to significantly reduce hospitalizations from HE in patients with MELD > 20 and therefore is advocated in maintenance of remission of HE in patients with very advanced liver disease. PMID- 25498077 TI - Accuracy of urine collection methods compared to measured GFR in adults with liver disease. AB - BACKGROUND: Assessment of kidney function is necessary to stage kidney disease, dose medications, and to make decisions about organ allocation. Estimating equations that incorporate serum creatinine (SCr) are not consistently reliable. However, assessment of creatinine clearance (CrCl) using 24-hour urine collection methods is also prone to errors. The purpose of this study was to evaluate the accuracy of measured CrCl determined using shorter urine collection times compared to glomerular filtration rate measured by (125)I-iothalamate clearance ((125)I-CL) in patients with liver disease. METHODS: Adult patients with chronic liver disease were enrolled. All patients received (125)I-iothalamate and had a catheter placed for urine collection. Blood samples were collected at designated times over 8 hours to determine (125)I-CL. CrCl was determined from a 1-hour and a 4-hour urine collection and compared to (125)I-CL. RESULTS: Characteristics of the eight patients enrolled included age 52 +/- 6 years; SCr 1.2 +/- 0.4 mg/dL; and Model for End-stage Liver Disease score of 13 +/- 3. All patients were Child Pugh Class B. Mean estimates of kidney function (mean +/- SD, mL/min/1.73 m(2)) by method were 74 +/- 38 for (125)I-CL, 79 +/- 28 for the 1-hour urine collection, and 72 +/- 26 for the 4-hour urine collection. Measured CrCl did not differ significantly from (125)I-CL (P = .641 for 1-hour CrCl versus (125)I-CL, and P = 1.0 for the 4-hour CrCl versus (125)I-CL). CONCLUSION: When urine collection methods are necessary for an individualized assessment of kidney function, shorter collection times can provide accurate results and would be more feasible for the patient. PMID- 25498078 TI - Balloon aortic valvuloplasty as a bridge to liver transplantation in patients with severe aortic stenosis: a case series. AB - BACKGROUND: Patients with end-stage liver disease and severe aortic stenosis pose a significant perioperative management challenge during liver transplantation (OLT). This patient population is at risk for significant morbidity and mortality and is often denied transplantation. CASE SERIES: We describe the successful use of balloon aortic valvuloplasty as a bridging therapy to facilitate perioperative management during OLT with traditional open aortic valve replacement after recovery from OLT. CONCLUSIONS: Valvuloplasty should be considered as an option to reduce perioperative risk in this patient population. PMID- 25498080 TI - Model for End-Stage Liver Disease (MELD) score does not predict outcomes of hepatitis B-induced acute-on-chronic liver failure in transplant recipients. AB - BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe clinical entity and liver transplantation is the only definitive therapy to salvage these patients. However, the timing of liver transplant for these patients remains unclear. METHODS: Seventy-eight patients undergoing liver transplantation because of hepatitis B ACLF were retrospectively analyzed from June 2004 to December 2010. The areas under the receiver operating characteristic curve (AUC) of Model for End-Stage Liver Disease (MELD) score and Child-Turcotte-Pugh (CTP) score for the post-transplantation outcomes were calculated. RESULTS: The median age was 44 years (range, 25-64 years), serum bilirubin 418.53 MUmol/L (range, 112.90-971.40 MUmol/L), INR 3.177 (range, 1.470-9.850), and creatinine 70.84 MUmol/L (range, 12.39-844.1 MUmol/L); the median MELD score was 32 (range, 21-53) and CTP score 12 (8-15). The AUCs of MELD and CTP scores for 3-month mortality were 0.581 (95% confidence interval [CI], 0.421-0.742; sensitivity, 87.5%; specificity, 32.8%) and 0.547 (95% CI, 0.401-0.693; sensitivity, 75%; specificity, 41%), respectively. Meanwhile, there were no significant differences in hospital mortality (P = .252) or morbidity (P = .338) between the patients with MELD score >=30 and those <30. CONCLUSIONS: MELD score had no predictive ability for the outcomes of patients with hepatitis B ACLF after orthotopic liver transplantation. PMID- 25498079 TI - Everolimus-based immunosuppression in patients with hepatocellular carcinoma at high risk of recurrence after liver transplantation: a case series. AB - BACKGROUND: Liver transplantation offers the most effective treatment in patients with hepatocellular carcinoma (HCC). However, transplant patients outside the Milan criteria have a high risk of tumor recurrence, which has been linked to standard immunosuppression regimens. Everolimus is a mammalian target of rapamycin inhibitor that has been used for immunosuppression, but its effect on recurrence and survival in HCC patients with a high risk of tumor recurrence has not been examined. We compared long-term survival and cumulative recurrence in high-risk patients receiving everolimus-based immunosuppression after liver transplantation for HCC with an historic control group. METHODS: The everolimus group comprised 21 patients receiving a liver transplant at our center from February 2005 to December 2010. The control group comprised 31 patients receiving a liver transplant from May 1994 to January 2005. All patients received cyclosporine or tacrolimus as initial post-transplant immunosuppression. Patients in the everolimus group switched to everolimus 2 weeks later. RESULTS: There were no differences between the two groups in number of rejection episodes or of infectious or surgical complications. Five-year survival was 60.2% in the everolimus group and 32.3% in the control group (P = .05). Five-year cumulative recurrence rate was 61.3% in the control group and 41.3% in the everolimus group. Treatment with everolimus was identified as an independent predictor of longer survival (hazard ratio = 0.34; P = .02). CONCLUSIONS: Patients receiving liver transplantation for HCC with a high risk of tumor recurrence may well benefit from everolimus-based immunosuppression, with no added risks of rejection or other post-transplant complications. PMID- 25498081 TI - Kinetics of interleukin-6, procalcitonin, and C-reactive protein after pediatric liver transplantation. AB - In the early phase after pediatric liver transplantation (pLT) several concomitant factors may reduce the performance of established sepsis markers. To date, their clinical interpretation is hindered by a lack of information on their postoperative kinetics. To gather more information on the postoperative course and their changes in bacterial sepsis, we prospectively studied C-reactive protein (CRP), interleukin-6 (IL-6), and procalcitonin (PCT) on 9 perioperative days in 25 consecutive pLTs. After an initial postoperative peak, IL-6 and CRP levels significantly re-increased in patients with bacterial sepsis (P < .001). In contrast, PCT had very high postoperative levels; therefore severe infection was a comparatively inferior trigger for PCT elevation compared with the initial operation. The area under the receiver operating characteristic curve to diagnose postoperative sepsis for PCT was only 0.52, compared with 0.95 for IL-6 and 0.89 for CRP. None of the studied biomarkers were depressed by poor graft function. In conclusion, PCT performs poorly as a biomarker for sepsis in the early phase after pLT. With a rapid decline of initially elevated levels, IL-6 provides the best kinetics for detection of postoperative bacterial sepsis. PMID- 25498082 TI - CD152 and PD-1 down-regulation on CD8 T cells is associated with human acute liver allograft rejection. AB - PURPOSE: To investigate CD152 and PD-1 expression on T lymphocytes and the function of CD152- and PD-1-positive CD8 T cells in human acute liver allograft rejection. MATERIALS AND METHODS: Sixty-three patients undergoing liver transplantation were enrolled in this study, including 26 cases with acute allograft rejection (Gr-AR) and 37 cases with stable allograft liver function (Gr SF). The expression of CD152 and PD-1 on T lymphocytes and the expression of granzyme and perforin on CD152- and PD-1-positive CD8 T cells in peripheral blood were analyzed using flow cytometry. RESULTS: The peripheral CD4/CD8 ratio in Gr AR was significantly lower than that in Gr-SF (P < .01). The expression of CD152 and PD-1 on CD8 and CD4 T cells was significantly lower in Gr-AR than in Gr-SF (all P < .01). The expression of granzyme B and perforin was significantly higher in Gr-AR than in Gr-SF (P < .01). CONCLUSIONS: Down-regulation of the expression of negative costimulatory molecules such as CD152 and PD-1 on CD8 T cells may be associated with human acute liver allograft rejection. PMID- 25498083 TI - Sleep disturbances and quality of life in patients after living donor liver transplantation. AB - BACKGROUND: Following improvements in patient and graft survival after liver transplantation (LT), the recipients' quality of life has become an important focus of patient care. Sleep is closely related to physical and mental health; however, sleep disturbances in LT patients have not yet been evaluated. METHODS: We assessed 59 LT patients (aged >=18 years) between September 2011 and September 2012. The patients completed the restless legs syndrome (RLS), 36-item short-form health survey (SF-36), Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS) questionnaires. In addition, laboratory data were obtained and neuropsychological tests (NPT) were performed during study entry. RESULTS: Thirty-eight patients (64%) were included in the poor sleep group (PSQI >=6 or ESS >=10). The SF-36 scores were lower in the poor sleep group than in the good sleep group. Eleven patients (18%) had RLS. An NPT score >=3 indicated minimal hepatic encephalopathy (MHE3). The MHE3 group consisted of 22 patients (43%). The time after LT was shorter; serum albumin, branched chain amino acid/tyrosine molar ratio (BTR), and role limitations due to poor physical health were lower; and serum ammonia levels were higher in the MHE3 group than in the MHE0-2 group. When the poor sleep group was divided into subgroups (control, MHE, RLS, and unknown), MHE patients had high model for end-stage liver disease scores, high ammonia levels, and low BTR, whereas RLS patients showed a short time after LT. CONCLUSION: Sixty-four percent of recipients were classified as poor sleepers. SF 36 scores were lower for poor sleepers than good sleepers. RLS and MHE are major diseases that cause sleep disturbances in patients after LT. PMID- 25498084 TI - Severe veno-occlusive disease/sinusoidal obstruction syndrome after deceased donor and living-donor liver transplantation. AB - Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) occurring after liver transplantation is a relatively rare complication but it often takes a life threatening course. However, the detailed etiology and mechanism of VOD/SOS after liver transplantation (LT) remains unclear. We report two cases with rapidly progressive VOD/SOS after ABO-identical LT resistant to various therapies. In case 1, in which the patient underwent deceased-donor LT, the first episode of acute allograft rejection was triggered VOD/SOS, and the presence of donor non specific anti-HLA antibodies was confirmed. The recipient died with graft failure on day 46 after transplantation. Case 2, in which the patient underwent living donor LT from the mother, had neither rejection nor mechanical venous obstruction, but condition of the patient rapidly worsened and he died on day 13 after transplantation. This recipient's direct cross-match test for the donor's B lymphocyte was strongly positive, but that for T lymphocyte was negative. In both cases, neither stenosis of hepatic vein outflow tract nor C4d deposition in post transplantation liver biopsy specimens and autopsy specimen was found. On the other hand, in both cases, the patient was transfusion unresponsive thrombocytopenia and hyperbilirubinemia persisted postoperatively, and glycoprotein I balpha was strongly stained in the neighboring centrilobular area (zone 3), especially in the space of Disse, and platelet phagocytosis was observed in Kupffer cells and hepatocytes around zone 3 such as clinical xenotransplantation of the liver in post-transplantation liver biopsy specimens. From the viewpoint of graft injury, VOD/SOS was considered that sustained sinusoidal endothelial cells injury resulted in bleeding in the space of Disse and led to around centrilobular hemorrhagic necrosis, and the fundamental cause was damage around centrilobular area including sinusoid by acute cellular rejection, antibody-mediated rejection or ischemic reperfusion injury. The extrasinusoidal platelet activation, aggregation, and phagocytosis of platelets were some of the main reasons for VOD/SOS and transfusion-resistant thrombocytopenia. PMID- 25498085 TI - Systematic computer tomographic scans 7 days after liver transplantation surgery can lower rates of repeat-transplantation due to arterial complications. AB - Arterial complications are a major cause of graft lost after liver transplantation (LT). The aim of our study was to assess the clinical impact of systematic early postoperative injected computed tomographic (CT) scans after LT rather than its performance on demand in the event of abnormalities. Two series of consecutive transplantation patients in different periods (1997-1999, 231 patients versus 2008-2010, 250 patients) were analyzed. During the first period, an injected CT scan was only performed in the event of clinical, biological, or ultrasound abnormalities revealed by tests performed daily during the first week after surgery. During the second period, in addition to standard follow-up examination, an injected CT scan was performed systematically at approximately postoperative day 7. During the first (versus the more recent) period, both recipients (whose ages were 46 +/- 13 years versus 50 +/- 12 years; P = .004) and donors (whose ages were 42 +/- 17 versus 52 +/- 17 years; P = .0001) were younger and end-stage liver disease was more common (34% versus 12%; P = .0001), but hepatocellular carcinoma (7% vs 26%; P = .0001) and retransplantation (2% versus 7%; P = .01) were less frequent. Postoperative mortality was higher during the first period (14% versus 4%; P = .0003). The incidence of early arterial thrombosis (<1 month) was similar (1.3% versus 1.6%; P = .78), but that of arterial stenosis was higher with a systematic CT scan (1.7 versus 4.4; P = .07). As a consequence of the early detection and treatment of arterial abnormalities, the repeat LT rate due to late arterial thrombosis was nil in the second period and 2.1% (5/231) in the first period. In conclusion, a systematic CT angiogram at the end of the first postoperative week reduced retransplantation rates due to late hepatic artery thrombosis by detecting patients at risk who required specific treatment. PMID- 25498086 TI - Risk factors of cytomegalovirus infection after pediatric liver transplantation. AB - PURPOSE: Cytomegalovirus (CMV) infection is known to be the most frequently viral infection among patients after liver transplantation. This is especially true in pediatric living-donor liver transplantation because the recipients have often not been infected with CMV and postoperative primary infection with CMV frequently occurs. PATIENTS AND METHODS: Of 93 patients who underwent pediatric liver transplantation at our department, 33 patients (36.3%) were diagnosed with CMV infection using the antigenemia method (C7-HRP). Retrospective review and statistical analysis were conducted to confirm risk factors of post transplantation CMV infection. RESULT: Positive lymphocytes were diagnosed between postoperative days 8 and 111 after transplantation. Ganciclovir or foscavir were administrated to 21 patients. The other 10 patients who had one positive lymphocyte were observed and the cell disappeared on follow-up examination. We did not observe any cases of positive lymphocytes with C7-HRP in patients who received a graft from a CMV antibody-negative donor. Independent predictors associated with CMV infection in the multivariable analysis were administration of OKT3 and grafts from CMV antibody-positive donors. CONCLUSION: In CMV infection after pediatric liver transplantation, cases with CMV antibody positive donors and with OKT3 administration for acute rejection are considered high risk, and cases with CMV antibody-negative donors are considered low risk. PMID- 25498087 TI - Correlation between risk of hepatitis B virus recurrence and tissue expression of covalently closed circular DNA in living donor liver transplant recipients treated with high-dose hepatitis B immunoglobulin. AB - BACKGROUND AND AIMS: Despite the application of prophylaxis, the risk of hepatitis B virus (HBV) recurrence remains. However, actual mechanism(s) and definite risk factor(s) are obscure. The present study examined the correlation between the HBV load in liver explants and post-liver transplant (OLT) HBV recurrence. METHODS: HBV DNA was extracted from liver tissue taken from 50 living donor OLT (LDLT) patients using the QuickGene DNA Tissue Kit S (Fujifilm, Tokyo, Japan) and subjected to real-time polymerase chain reaction with the following primers: 5'-CACATGGCCTCCAAGGAGTAA-3' (forward primer) and 5' TGAGGGTCTCTCTCTTCCTCTTGT-3' (reverse primer). To prevent HBV infection, patients were treated daily with high-dose (10,000 IU) hepatitis B immunoglobulin (HBIG) for the first week after LDLT. They then received weekly doses for the next month and then monthly doses for <=1 year. If the anti-hepatitis surface antigen antibody titer was <1,000 IU/L, an antiviral agent (AVA) was added to the regimen. RESULTS: The mean (+/-SD) tissue HBV DNA and covalently closed circular DNA (cccDNA) loads were -0.8 +/- 1.2 (range, -2.9 to 2.6) and -2.3 +/- 1.1 (range, -4.6 to 0.6) log10 copies/cell, respectively. There was a significant correlation between serum and tissue HBV DNA (r = 0.65; P = .00) and cccDNA concentrations (r = 0.55; P = .00). Six patients suffered HBV recurrence and 9 required additional AVA. There was no direct correlation between HBV recurrence and tissue cccDNA concentration. However, the concentration of cccDNA was significantly greater those patients suffering recurrence and receiving AVA treatment (high-risk group). CONCLUSION: High tissue cccDNA concentrations may be a risk factor for HBV recurrence despite high-dose HBIG prophylaxis. PMID- 25498088 TI - Prophylactic use of liposomal amphotericin B in preventing fungal infections early after liver transplantation: a retrospective, single-center study. AB - In this study the authors evaluated the efficacy of prophylaxis with liposomal amphotericin B (L-AmB) in the incidence of fungal infections (FI) during the first 3 months after liver transplant (LT). The study was retrospective and accessed a 4-year period from 2008 to 2011. All patients who died in the first 48 hours after LT were excluded. Patients were divided by the risk groups for FI: Group 1, high-risk (at least 1 of the following conditions: urgent LT; serum creatinine >2 mg/dL; early acute kidney injury [AKI] after LT; retransplantation; surgical exploration early post-LT; transfused cellular blood components [>40 U]); and Group 2, low-risk patients. Group 1 patients were further separated into those who received antifungal prophylaxis with L-AmB and those who did not. Prophylaxis with L-AmB consisted of intravenous administration of L-AmB, 100 mg daily for 14 days. Four hundred ninety-two patients underwent LT; 31 died in the first 48 hours after LT. From the remaining 461 patients, 104 presented with high risk factors for FI (Group 1); of these, 66 patients received antifungal prophylaxis and 38 did not. In this group 8 FI were observed, 5 in patients without antifungal prophylaxis (P = .011). Three more FI were identified in Group 2. By logistic regression analysis, the categorical variable high-risk group was independently related to the occurrence of invasive FI (P = .006). We conclude that prophylaxis with L-AmB after LT was effective in reducing the incidence of FI. No influence on mortality was detected. PMID- 25498089 TI - Risk factors for mortality in liver transplant recipients with ESKAPE infection. AB - BACKGROUND: Although infections caused by the pathogens Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp (ESKAPE) have recently been identified as serious emerging problems in solid organ transplant, no information in liver transplant (LT) recipients is available. We sought to investigate the risk factors for associated mortality in LT recipients with ESKAPE infections. METHODS: A retrospective analysis of infection after LT was reviewed. Risk factors for mortality caused by ESKAPE infection were identified. RESULTS: Fifty three episodes of infections caused by ESKAPE were documented in 51 LT recipients. The main sites of infection were the bloodstream (49.0%), the lungs (33.3%), and the intra-abdominal/biliary tract (17.6%). The risk factors for mortality independently associated with ESKAPE infection were female sex (odds ratio [OR] = 6.6, 95% confidence interval [CI] = 1.1-40.8, P = .042), septic shock (OR = 30.1, 95% CI = 3.7-244.8, P = .001), and lymphocyte counts <300/mm(3) (OR = 20.2, 95% CI = 2.9-142.2, P = .003). CONCLUSIONS: To improve the results of LT, more effective therapeutic treatments are of paramount importance when female LT recipients with ESKAPE infection present with septic shock and decreased lymphocyte counts. PMID- 25498090 TI - Incidence and risk factors of deep vein thrombosis after liver transplantation. AB - BACKGROUND: Deep venous thrombosis (DVT) occurs in 0.1% of persons per year, affecting 15%-40% of general surgical procedures without prophylaxis. Thromboembolic prophylaxis is not commonly used after orthotopic liver transplantation (LT) owing to the risks of bleeding and coagulopathy. Cirrhosis and the association with the coagulation cascade, before and after transplantation, are not well understood. The purpose of this study was to determine the incidence of DVT and its risk factors after LT. METHODS: We retrospectively reviewed LTs performed at our center from 2005 to 2012. We identified patients with Doppler examinations showing DVT after LT, platelet count, and international normalized ratio (INR) at time of DVT, associated symptoms, DVT prophylaxis, and perioperative risk factors. We determined the incidence of DVT, the odds ratio of each preoperative risk factor, the difference in platelet count and INR between those with and without a DVT, and the weighted risk of each factor in the development of DVT with the use of logistic regression modeling. RESULTS: Of 314 patients, the incidence of DVT was 8.6% (27/314). Between those with and without DVT there was no significant difference in age, sex, platelet count, INR, infection, hepatocellular cancer, use of venous bypass, and prior surgery. There was a significant difference in mobility, 67% vs 20% (P < .0001), and the use of factor VII, 11% vs 2% (P < .05). The estimated risk for of developing DVT for patients with neither of these factors was 4%; with factor VII the risk rose to 17%; with mobility difficulty the risk rose to 23%; and with both the risk was 62%. In our entire population, there were no cases of pulmonary embolism. CONCLUSIONS: The risk of developing a DVT after LT is >=9% even with mechanical DVT prophylaxis. Consideration should be given to using both mechanical and chemical prophylaxis after LT. PMID- 25498091 TI - Anti-thymocyte gamma-globulin may prevent antibody production after heart transplantation. AB - BACKGROUND: Rabbit anti-thymocyte globulin (RATG) has been used as induction therapy in heart transplantation. RATG is polyclonal and has been postulated to have anti-humoral properties by preventing the production of circulating antibodies after heart transplant. Thus, we reviewed our patients who received RATG induction therapy and compared them with those who did not receive therapy for post-transplant de novo antibody production. METHODS: Between January 1, 2006, and January 1, 2013, we assessed 196 non-sensitized heart transplant recipients and divided them into those who received 3 to 5 days of RATG induction therapy mostly due to renal insufficiency (n = 35) versus patients who did not receive therapy (n = 161). All patients were given tacrolimus, mycophenolate mofetil, and corticosteroids. Post-transplant circulating antibodies were routinely monitored at 1, 3, 6, and 12 months after heart transplantation; 1-year and 3-year end points were assessed. RESULTS: The RATG-treated group had a significantly higher 12-month freedom from de novo antibody production compared with the patients who did not receive RATG induction (89% vs 71%, log-rank P = .043); however there was no significant difference for 12-month freedom from de novo donor-specific antibody production (91% vs 88%, log-rank P = .541). Treated rejection rates in the first-year were comparable in both groups; 3-year actuarial survival, freedom from cardiac allograft vasculopathy, and freedom from non-fatal major adverse cardiac events were also similar between both groups. CONCLUSIONS: RATG induction therapy appears to reduce the production of de novo circulating antibodies in non-sensitized patients during the first year after heart transplantation. Although there were no short-term clinical differences between groups, there were imbalances in group characteristics and relatively short follow-up, which are limitations to this study. A randomized, clinical trial with longer follow-up in a larger cohort of patients is warranted. PMID- 25498092 TI - Left ventricular assist device in patients with body mass index greater than 30 as bridge to weight loss and heart transplant candidacy. AB - INTRODUCTION: In obese patients with heart failure, weight reduction may be difficult due to physical restrictions, but may be necessary to achieve heart transplant candidacy. We report the outcomes of obese patients who underwent implantation of a left ventricular assist device (LVAD) using a pulsatile (HeartMate XVE [XVE]) or continuous flow (HeartMate II [HMII]) design and the effect on body mass index (BMI). METHODS: Of 37 patients with BMI >30 kg/m(2) who underwent LVAD implantation, 29 survived at least 30 days and were followed for weight change. In the 30-day survivors, end points of the study were continued LVAD support, heart transplant, or death. One patient underwent gastric bypass surgery and was excluded. RESULTS: In the 28 patients who met inclusion criteria, BMI was 35.6 +/- 4.4 kg/m(2) at baseline, and at follow-up was 33.1 +/- 5.5 kg/m(2) (mean BMI change -2.5 kg/m(2); P = .063), with a mean follow-up time of 301.6 +/- 255.5 days. The XVE group showed a significant BMI reduction of 3.9 kg/m(2) (P = .016 vs baseline); however, the HMII group showed 0.1 kg/m(2) increase in BMI. BMI <30 kg/m(2) at follow-up was achieved in 6 patients (21%), 5 of 19 (26%) in XVE group, and 1 of 9 (11%) in HMII group. In the 14 patients (12 XVE, 2 HMII) or 50% who received a heart transplant, the mean decrease in BMI was 4.6 kg/m(2) (P = .003). CONCLUSIONS: LVAD placement in patients with BMI >30 kg/m(2) provided significant weight loss in the pulsatile XVE group, but not in recipients of the continuous flow HMII. In patients successfully bridged to a heart transplant after LVAD insertion, mean reduction in BMI was 4.6 kg/m(2) (P = .003). LVAD implantation provides a period of hemodynamic support for obese patients with advanced heart failure, during which time opportunity may be available for weight loss. Pulsatile devices appear to be associated with greater weight loss than nonpulsatile continuous flow devices. Additional therapies may be necessary to achieve significant weight loss in recipients of the continuous flow LVAD. PMID- 25498093 TI - Endomyocardial biopsy technique for orthotopic heart transplantation and cardiac stem-cell harvesting. AB - INTRODUCTION: Orthotopic heart transplantation (OHT) is performed using the bicaval and pulmonary venous anastomoses or the standard (biatrial) anastomoses. The special considerations of endomyocardial biopsy after OHT using the bicaval technique, and after myocardial infarction for harvesting of cardiac stem cells, have not been described. METHODS: When approached via the right or left internal jugular vein, important technical considerations were ultrasound guidance for vascular access; a soft, 80-cm, 0.035-inch, J-tipped guidewire; a long (23-cm), 7 Fr sheath; and a flexible 7-Fr, 50-cm bioptome. These technical aspects were helpful to avoid disruption of the superior vena cava suture line, avoid entry into the right atrial appendage or coronary sinus, avoid right ventricular free wall perforation, and provide ready access to the right ventricular septal wall. We used the same principles and technical considerations when obtaining the cardiac stem cells after myocardial infarction in patients enrolled in the CADUCEUS trial. RESULTS: From January 2002 to December 2005, 754 biopsy procedures were performed in 179 patients after OHT with the bicaval technique, using bioptome A. There was 1 occurrence of ventricular fibrillation requiring cardioversion, and no occurrence of cardiac tamponade during the procedure. From January 2006 to September 2013, 2818 biopsy procedures were performed in 1064 patients using bioptome B. No patient developed ventricular fibrillation or cardiac tamponade during the procedure. In 2010 and 2011, 23 biopsy procedures were performed in 23 patients after acute myocardial infarction, using bioptome B. No immediate complications occurred while performing these biopsies. The late occurrence of tricuspid regurgitation was not evaluated in this study. CONCLUSIONS: Endomyocardial biopsy procedures can be safely performed after OHT with the bicaval technique and after myocardial infarction for harvesting of cardiac stem cells. Ultrasound guidance for vascular access, a long guidewire and sheath, and a flexible bioptome are important features for the safe conduct of the biopsy procedure. PMID- 25498094 TI - Incidence, risk factors, and outcomes of delayed-onset cytomegalovirus disease in a large, retrospective cohort of heart transplant recipients. AB - BACKGROUND: Delayed-onset cytomegalovirus (CMV) disease can occur among heart transplant recipients after stopping anti-CMV prophylaxis. We evaluated a large, retrospective cohort of heart transplant recipients in the United States through the use of billing data from 3 Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases (SID) to determine the epidemiology of delayed-onset CMV disease coded during hospital readmission. METHODS: We identified 2280 adult heart transplant recipients from 2004 to 2010 through the use of the California, Florida, and New York SID. Demographics, comorbidities, heart failure etiology, CMV disease, and inpatient death were identified. CMV disease was classified as early-onset (<=100 days) or delayed-onset (>100 days after transplant). Possible tissue invasion by CMV was determined through the use of codes for CMV pneumonitis, hepatitis, and gastrointestinal endoscopy. Multivariate analysis was performed with the use of Cox proportional hazards models. RESULTS: Delayed-onset CMV disease occurred in 7.5% (170/2280) and early-onset CMV disease occurred in 2.0% (45/2280) of heart transplant recipients. Risk factors for delayed-onset CMV disease included residence in a non-metropolitan locale (aHR. 1.8; 95% confidence interval [CI], 1.0-3.3) and ischemic cardiomyopathy as heart failure etiology (aHR, 1.8; 95% CI, 1.3-2.5). Inpatient death >100 days after transplant was associated with delayed-onset CMV disease with possible tissue invasion (aHR, 2.0; 95% CI, 1.1-3.8), transplant failure or rejection (aHR, 4.0; 95% CI, 2.7 5.8), and renal failure (aHR, 1.5; 95% CI, 1.1-2.0). CONCLUSIONS: Delayed-onset CMV disease is more common than early-onset CMV disease among heart transplant recipients. These results suggest that delayed-onset tissue-invasive CMV disease may be associated with an increased risk of death. PMID- 25498095 TI - Increased incidence of transfusion-related acute lung injury during orthotopic liver transplantation: a short report. AB - Intractable severe pulmonary edema during Orthotopic Liver Transplant (OLT) can be a fatal perioperative complication. We sought to characterize the incidence, timing, and related risk factors of severe pulmonary edema during OLT. We performed a retrospective observational survey of OLT cases performed between 2007 and 2011 at Miami Transplant Institute. Of all 632 OLT patients, a total of 9 patients (1.4%) had severe pulmonary edema during OLT. All these patients received blood transfusions before and after reperfusion (Packed red blood cell 8.9 +/- 2.6 units, Fresh frozen plasma 12 +/- 3.7 units, Platelets 5.4 +/- 8.6 units). Eight episodes occurred after reperfusion (89%) and 1 before reperfusion (11%). Median time interval from last blood transfusion to severe pulmonary edema was 79 min (25-257 min). In the 8 patients that developed severe pulmonary edema post reperfusion, median time interval from reperfusion to severe pulmonary edema was 34 min (15-85 min). Perioperative mortality among severe pulmonary edema cases was 11% (1 in 9). Incidence of severe pulmonary edema was 1.4% in our patient population, and this number is much higher than that reported for TRALI in other large series (0.075 to 0.12%). Despite a large dose of steroids given at reperfusion, 89% of pulmonary edema episodes occurred within 2.5 hours of reperfusion. Also, heart failure and pulmonary embolism were unlikely based on intraoperative transesophageal echocardiography findings. These results may suggest an association between TRALI and the post reperfusion syndrome during liver transplantation that warrants further investigation. PMID- 25498096 TI - Acute kidney injury after ex vivo lung perfusion (EVLP). AB - BACKGROUND: Ex vivo lung perfusion (EVLP) identifies viability for marginal organs but complicates and lengthens lung transplantation surgery. Preliminary evidence supports equivalency for EVLP-assisted versus traditional (non-EVLP) procedures regarding graft function, postoperative course, mortality, and survival. However, acute kidney injury (AKI), a common serious complication of lung transplantation, has not been assessed. We tested the hypothesis that EVLP assisted and non-EVLP lung transplantations are associated with different AKI rates. METHODS: Demographic, procedural, and renal data were gathered for 13 EVLP viable lung transplantations and a non-EVLP group matched 4:1 for single versus double, pulmonary disease, and age. AKI was defined by AKI Network (AKIN) criteria and peak creatinine rise relative to baseline (Delta%Cr) during the 1st 10 postoperative days. Chi-square was performed for AKIN and 2-tailed t test for %DeltaCr. RESULTS: Patient and procedural characteristics were similar between the groups. One non-EVLP patient required postoperative dialysis. AKI rates were also similar, as assessed by both AKIN (EVLP 7/13 (54%) vs non-EVLP 32/52 (62%); P = .61) and %DeltaCr (EVLP 91 +/- 81% vs non-EVLP 72 +/- 62%; P = .63). CONCLUSIONS: We did not observe different AKI rates between EVLP-assisted and traditional lung transplant procedures. Although 1 non-EVLP patient required dialysis, AKI rates were otherwise similar. These findings further support EVLP as a strategy to expand the organ pool and reduce concerns for high-renal risk recipients. The small sample size and retrospective design are limitations. However, our sample size is similar to other reports, and it is the first to analyze AKI after EVLP-assisted lung transplantation. Larger multicenter prospective studies are needed. PMID- 25498097 TI - Clinical usefulness of oral immunoglobulins in lung transplant recipients with norovirus gastroenteritis: a case series. AB - Viral gastroenteritis causing diarrhea is a common complication observed in lung transplant recipients. Differently from the mild and typically self-limited disease seen in immunocompetent subjects, immunocompromised patients frequently have a more severe course. Norovirus and rotavirus are among the leading causes of severe gastroenteritis in transplant recipients. Specific treatment is unavailable, although good supportive treatment can significantly reduce morbidity. Previous studies have suggested that oral immunoglobulins may be used for the treatment of acute viral gastroenteritis after solid-organ transplantation. Herein, we conducted a retrospective chart review of 12 lung transplant recipients with norovirus-induced gastroenteritis who were treated with oral immunoglobulins for 2 days. Eleven patients were successfully treated, whereas 1 subject was only mildly improved. Four patients had at least 1 recurrence. No significant adverse effects were observed. We conclude that oral immunoglobulins may be clinically useful for lung transplant recipients with norovirus-induced gastroenteritis. PMID- 25498098 TI - Risk factors for hepatotoxicity in solid organ transplants recipients being treated for tuberculosis. AB - BACKGROUND: Tuberculosis (TB) is associated with high morbidity and mortality in solid organ transplant (SOT) recipients. Also, SOT patients have a 20- to 74-fold increase in the chance of developing TB compared to the general population. Here we evaluated the incidence of hepatotoxicity in SOT recipients on treatment for TB and determined risk factors for liver toxicity in these patients. PATIENTS AND METHODS: Retrospective cohort conducted in a reference hospital for SOT in Southern Brazil. All SOT recipients who underwent TB treatment during the years 2000-2012 were considered for the study. RESULTS: A total of 69 patients were included in the study and 23 had liver toxicity (incidence 33.3%). Independent risk factors for hepatotoxicity were rifampin use at doses of >=600 mg daily (P = .016; OR 2.47; 95% CI, 1.18-5.15) and lung transplantation (P = .017; OR 2.05; 95% CI, 1.14-3.70). Kidney transplantation appeared as a protective factor (P = .036; OR 0.50; 95% CI, 0.26-0.96). Mortality was higher in the patients who had hepatotoxicity (43.5%), compared with those who did not (19.6%). CONCLUSION: In this study, the use of rifampin at doses of 600 mg daily or higher was found to be an independent risk factor for liver toxicity in SOT recipients. The importance of additional risk factors for hepatotoxicity, such as lung transplantation as well as the protective role of kidney transplantation, should be better investigated in SOT recipients being treated for TB. PMID- 25498099 TI - Glomerular diseases associated with chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation: case reports. AB - Chronic graft-versus-host disease (cGVHD) is the major complication following allogeneic stem cell transplantation (allo-SCT). Nephrotic syndrome (NS) and other types of glomerulonephritis have been proposed to be the very rare forms of renal cGVHD. From 1991 to 2011, 253 patients underwent allo-SCT at our center. We report here 4 cases (1.6%) presenting with varieties of glomerular manifestations associated with cGVHD. The first case was typical NS. The renal pathology showed membranous nephropathy (MN). The second case was also MN, but this patient also had the pathology of focal segmental glomerulosclrosis (FSGS) and acute tubular necrosis (ATN). The third case showed lupus nephritis-like glomerular lesions with a high anti-nuclear antibody (ANA) titer. The fourth case presented with rapidly progressive glomerulonephritis (RPGN)-like symptoms. The kidney histology in this case was not available. The patient responded well to immunosuppressive therapy, but NS later recurred. Therefore, overt glomerular diseases after allo SCT in Thai patients are not very rare. Monitoring urinalysis during withdrawal of immunosuppressive drugs and also during follow-up of patients with cGVHD may be considered. PMID- 25498100 TI - Short-term pharmacokinetic study of mycophenolate mofetil in neonatal swine. AB - BACKGROUND: Mycophenolate mofetil (MMF) is an effective immunosuppressive agent that has been frequently used in laboratory animals including swine; however, the pharmacokinetic properties of MMF in swine have not been studied. This short-term study was designed to evaluate the feasibility and the pharmacokinetic profiles of MMF therapy in neonatal swine. MATERIALS AND METHODS: Twelve neonatal pigs were randomized into four groups including one control and three treated groups with oral MMF administered at 0.5, 1, and 2 g/m(2)/d for 4 days, divided by 2 half-doses at 9:00 and 17:00 (except day 4 during which MMF was not administered at 17:00). Blood samples were collected at 9:00 on days 0, 2, 3 and 4 for complete blood count and hepatic/renal function examination; the trough concentration of plasma mycophenolic acid (MPA) was also determined. On days 2 and 4, blood was collected to determine the area under the curve (AUC) of plasma MPA concentration. Animal body-weight growth and manifestations of MMF side effects such as anorexia, vomiting, and diarrhea were also observed. RESULTS: MMF has no acute hepatic/renal toxicity in newborn pigs; however, less body-weight growth was observed in treated groups. In the control group, a spontaneous increase of lymphocyte count was observed; in contrast, MMF therapy with doses of 1 and 2 g/m(2)/d reduced both lymphocyte and monocyte counts of piglets. Oral MMF had high bioavailability in neonatal swine. MPA-AUC0-12h of doses 0.5, 1, and 2 g/m(2)/d was 22.00 +/- 3.32, 57.57 +/- 34.30, and 140.00 +/- 19.70 MUg * h/mL, respectively. Neither MPA trough concentration (MPA-C0), nor MPA maximum concentration (MPA-Cmax) or MPA-AUC0-6h had high correlation with MMF-dose. For surveillance of MPA exposure, MPA-C0 had significant correlation with MPA-AUC0 12h (Spearman's rho = 0.933, AUC0-12h = 17.882 * C0 + 14.479, r(2) = 0.966). CONCLUSION: To reach adequate drug exposure and to reduce dose-dependent side effects, an MMF dose of 1 g/m(2)/d is recommended to be used as an initial dose for immunosuppressive therapy in piglets, and MPA-C0 monitoring is the most practical strategy for experimental transplantation study. PMID- 25498101 TI - Evaluating the impact of gastrointestinal episodes on the health-related quality of life of solid organ transplant recipients: sensitivity to change of the SIGIT QoL questionnaire: Mypaciente-2 study. AB - A significant proportion of transplant patients undergoing immunosuppressant therapy experience gastrointestinal (GI) symptoms. The SIGIT-QoL is a brief instrument developed to measure adverse gastrointestinal effects on patients' health-related quality of life (HRQoL). The goal of this study was to analyze the psychometric properties of the SIGIT-QoL that are required for its use in clinical research and practice, especially its value for detecting changes in the impact of gastrointestinal symptoms on HRQoL of solid organ transplant (SOT) recipients. To this end, an observational, multicenter, prospective study was conducted. SOT patients aged >=18 years who had received the graft 3 to 24 months before and were experiencing gastrointestinal symptoms were evaluated at baseline, 1 to 2 weeks later, and 3 months after baseline. Sociodemographic and clinical data recorded included: age, sex, SOT type (lung, kidney, liver, or heart), acute allograft rejection, gastrointestinal etiology, Clinical Global Impressions (CGI) and Patient Global Impression (PGI) Severity of Illness (SI) and Global Improvement (GI) scores, and the SIGIT-QoL (scores range from 0 [maximum impact] to 68 [minimum disruption]). Intraclass correlation coefficients, differences between baseline and last visit (Wilcoxon test), effect size (Cohen's d), the minimal important differences (using CGI and PGI scores as anchors in General Linear Models), and the cutoff score (receiver-operating characteristic analysis) were calculated. In total, 277 SOT patients (61.4% male) were included. Mean +/- SD age was 52.69 +/- 11.65 years, time since transplantation was 12.31 +/- 6.74 months, and 22.4% experienced an acute allograft rejection. At baseline, total SIGIT-QoL mean scores (51.21 +/- 11.25) showed an impact on patients' HRQoL that was diminished 3 months later (57.40 +/- 8.38; P < .001). SIGIT-QoL test-retest reliability was adequate (intraclass correlation coefficient, 0.740-0.895). A moderate effect size (d = -0.550) was found. Moreover, a minimal important difference of 4.2 points in total scores was found (F4,223 = 16.917 [P < .001] and F4,224 = 25.138 [P < .001]). Finally, a cutoff point (55.00 points) was estimated (area under the concentration-time curve, 0.846 [95% confidence interval, 0.798-0.894], P < .001; sensitivity, 0.793; specificity, 0.713; negative likelihood ratio, 0.290; positive likelihood ratio, 2.762). We concluded that the SIGIT-QoL is a feasible (average completion time, <6.5 minutes), reliable, and valid instrument for assessing the impact of gastrointestinal symptoms on the HRQoL of SOT patients. PMID- 25498102 TI - Local cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin inhibition of rejection response is dependent on indoleamine 2,3-dioxygenase activities in the allograft. AB - A previous study showed that local gene transfer of cytotoxic T-lymphocyte associated antigen-4 immunoglobulin (CTLA4Ig) significantly prolonged the survival time of rat flap allografts. However, the underlying mechanism is not fully understood. Indoleamine 2,3-dioxygenase (IDO) is considered to be able to modulate the unresponsiveness state of allografts. In this study, we tested the expression of the CD80 molecule, IDO mRNA, and the level of the tryptophan metabolite kynurenine with or without the application of the IDO blocker 1-methyl tryptophan (1-MT) in a rat composite tissue allotransplantation model. CD80 expression could be detected in the allograft. The ration of IDO mRNA/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA and the level of kynurenine were both enhanced (46.3 +/- 8.8 versus 4.6 +/- 1.8 and 18.9 +/- 1.3 MUmol/L versus 2.1 +/- 0.2 MUmol/L separately) after adenovirus-mediated CTLA4Ig (AdCTLA4Ig) transduction. When 1-MT was applied to the AdCTLA4Ig perfusion recipients, the ration of IDO mRNA/GAPDH mRNA (5.2 +/- 2.9) and the level of kynurenine (0.8 +/- 0.5 MUmol/L) were significantly reduced. Moreover, the allograft survival time was greatly reduced when 1-MT was applied to AdCTLA4Ig perfusion recipients compared to single AdCTLA4Ig perfusion therapy recipients (7.2 days versus 13.6 days). We showed that the inhibitory effect of locally delivered CTLA4Ig is dependent on IDO activities within the allograft. PMID- 25498103 TI - Infusion of dendritic cells carrying donor lymphocytes treated with 8 methoxypsoralen and ultraviolet A light induces CD19+ IL-10+ regulatory B cells and promotes skin allograft survival. AB - PUVA-SP DCs are immature dendritic cells (imDCs) that have taken up donor splenic lymphocytes treated with 8-methoxypsoralen and ultraviolet A light (PUVA-SPs). Phagocytosis of donor PUVA-SPs does not stimulate phenotype maturation of recipient imDCs, and infusion of PUVA-SP DCs can induce CD4(+)CD25(high)Foxp3(+) regulatory T cells (Treg). However, the regulatory effect of PUVA-SP DCs on B cells is poorly understood. In this study, we compared PUVA-SP DCs with imDCs in terms of lipopolysaccharide (LPS) responsiveness and flow cytometric analysis of interleukin (IL) 10 expression in splenic CD19(+)B cells. Our results demonstrate that PUVA-SP DCs can suppress subsequent LPS-induced DC maturation and that infusion of PUVA-SP DCs, in the absence of an immunosuppressant, significantly promotes skin allograft survival. This effect was associated with up-regulation of circulating regulatory B cells exhibiting preferential IL-10 secretion. Our results suggest that effective treatments involving infusion of PUVA-SP DCs is likely related to the modulation not only of T-cell and Treg functions but also of B-cell and regulatory B-cell (Breg) functions. PMID- 25498104 TI - Features and ethical considerations associated with living kidney and liver transplantations in South Korea. AB - When the Organ Transplantation Act came into effect in 2000 in South Korea, living organ donations were legalized and the Korean Network for Organ Sharing (KONOS) had a duty to approve the application of donation. The number of living organ donors has increased and the waiting time of recipients has been steady or decreased. The Organ Transplantation Act mainly focuses on the informed consent process of donations, so unrelated directed donations are permitted unless there is a suspicion of organ trafficking. But the annual reports show that directed donations of unrelated and related donors may have an ethical concern about organ sales. The donations of family members show another ethical concern. The numbers of ABO-incompatible transplantations have steadily increased since 2008, and lineal descendants, including minors, comprised 61% of living liver donors in 2012. Addressing the unethical practices without inhibiting living organ donations is the current task in South Korea. Private agencies have actively operated the living organ donations programs. The web-based computerized organ exchange program has been cooperatively run by hospital-based organizations. The strict legal regulations that could decrease living organ donations are hard to adopt. In the current situation, the functions of the official system need to be more developed. A national organ exchange program run by KONOS could be an option which could reduce ABO-incompatible transplantations and relieve the ethical concern of organ sales in unrelated directed donations. PMID- 25498105 TI - Reassessing the Aurignacian of Slovenia: techno-economic behaviour and direct dating of osseous projectile points. AB - The Palaeolithic of southern Central Europe has a long history of archaeological research. Particularly, the presence of numerous osseous projectile points in many early Upper Palaeolithic (EUP) assemblages in this region has attracted the attention of the international research community. However, the scarcity of properly identified and well-dated Aurignacian contexts represents an obstacle for investigation of the nature and timing of the Middle to Upper Palaeolithic transition. In this context, the question of whether Neandertals made Aurignacian osseous projectile points, either on their own or as a consequence of cultural interaction with anatomically modern humans (AMH), still remains an open issue. Here we reassess the EUP record of Slovenia by evaluating the Aurignacian character of the assemblages from Potocka zijalka, Mokriska jama and Divje babe I in the light of their suggested roots in the local Mousterian. We provide a comprehensive description of the lithic industry from Potocka zijalka, which represents one of the rare EUP assemblages of southern Central Europe with a representative number of lithic artefacts to be analysed from the perspective of lithic technology and raw material economy. Our re-analysis of the Slovenian assemblages is backed by a series of 11 new ultrafiltered collagen 14C dates obtained directly on associated osseous projectile points from the studied assemblages. The Aurignacian of Potocka zijalka underlines the remarkable consistency of the Early Aurignacian with low typo-technological variability across Europe, resulting from a marked dependence on transported toolkits and raw material conservation. The new radiocarbon determinations for the Aurignacian of Slovenia appear to post-date the 34-32 ka BP (thousands of years before present) threshold for the last Neandertals in the region. Although not falsified, the hypothesis of Aurignacian bone tools in southern Central Europe as a product of late Neandertals is not supported by our re-examination of the EUP record of Slovenia. PMID- 25498106 TI - Myelomeningocele: How we can improve the assessment of the most severe form of spina bifida. AB - Myelomeningocele (MMC) is a devastating spinal cord birth defect, which results in significant life-long disabilities, impaired quality of life, and difficult medical management. The pathological progression of MMC involves failure in neural tube and vertebral arch closure at early gestational ages, followed by subsequent impairment in spinal cord and vertebral growth during fetal development. MMC is irreversible at term. Thus, prenatal therapeutic strategies that interrupt progressive pathological processes offer an appealing approach for treatment of MMC. However, a thorough understanding of pathological progression of MMC is mandatory for appropriate treatment to be rendered. This article is part of a Special Issue entitled SI: Spinal cord injury. PMID- 25498107 TI - Decoding signal processing in thalamo-hippocampal circuitry: implications for theories of memory and spatial processing. AB - A major tool in understanding how information is processed in the brain is the analysis of neuronal output at each hierarchical level through which neurophysiological signals are propagated. Since the experimental brain operation performed on Henry Gustav Molaison (known as patient H.M.) in 1953, the hippocampal formation has gained special attention, resulting in a very large number of studies investigating signals processed by the hippocampal formation. One of the main information streams to the hippocampal formation, vital for episodic memory formation, arises from thalamo-hippocampal projections, as there is extensive connectivity between these structures. This connectivity is sometimes overlooked by theories of memory formation by the brain, in favour of theories with a strong cortico-hippocampal flavour. In this review, we attempt to address some of the complexity of the signals processed within the thalamo hippocampal circuitry. To understand the signals encoded by the anterior thalamic nuclei in particular, we review key findings from electrophysiological, anatomical, behavioural and computational studies. We include recent findings elucidating the integration of different signal modalities by single thalamic neurons; we focus in particular on the propagation of two prominent signals: head directionality and theta rhythm. We conclude that thalamo-hippocampal processing provides a centrally important, substantive, and dynamic input modulating and moderating hippocampal spatial and mnemonic processing. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25498108 TI - Cervical spondylodiscitis as a rare presentation of neck pain in a systemically well patient. PMID- 25498109 TI - Novel use of carbon dioxide arteriography in renal artery pseudoaneurysm in patients with poor renal function. AB - Renal artery pseudoaneurysm (RAP) is a rare complication of partial nephrectomy, but is usually effectively managed with renal vessel embolisation. We report a particularly challenging case of a patient with chronic kidney disease (CKD) who developed a RAP following a laparoscopic heminephrectomy and was treated using superselective renal vessel coil embolisation with carbon dioxide (CO2) as the primary contrast agent for arteriographic localisation of the RAP and feeder artery. To the best our knowledge we report the first utilisation of CO2 arteriography in the definitive diagnosis and treatment of RAP following heminephrectomy in a patient with severe CKD. PMID- 25498110 TI - Lens coloboma in one eye and ectopia lentis in the other eye of a patient with Marfan syndrome. AB - We present a case of Marfan syndrome with lens coloboma in one eye and ectopia lentis in the other. A 14-year-old girl reported decreased vision in the left eye. Her visual acuity was 6/24 and counting fingers at 1 m in the right and left eyes, respectively. Her intraocular pressure was 15 mm Hg in both eyes. Evaluation of the right eye on slit lamp biomicroscopy under mydriasis revealed an inferiorly visible flattened and concave crystalline lens equator from 4 to 8 o'clock position along with notching and absence of zonules, suggestive of lens coloboma. Left eye examination revealed a superiorly subluxated lens from 3 to 9 o'clock position and posterior subcapsular cataract. The posterior segment evaluation of both eyes was normal. Her father, aunt and grandfather were of tall stature, characteristic of Marfan syndrome. On systemic evaluation, the patient was diagnosed as Marfan syndrome. After surgical correction she achieved vision of 6/6 in both eyes. PMID- 25498111 TI - Gastroparesis as the initial presentation of pulmonary adenocarcinoma. AB - Malignancy-associated gastroparesis is an under-reported entity and its diagnosis as a cause of cachexia or gastrointestinal symptoms is often missed in clinical practice. This case report highlights an unusual association of pulmonary adenocarcinoma with gastroparesis at presentation. Malignancy-associated gastroparesis should be added to the differential diagnosis in patients presenting with delayed gastric emptying of unknown aetiology and should prompt further radiological investigations. Early detection and treatment of underlying gastroparesis in patients with cancer is necessary to improve the quality of life and to avoid premature clinical deterioration due to intolerance to oral treatment. PMID- 25498113 TI - An unusual case of biliary bezoar causing small bowel obstruction in a patient with ampullary diverticulum and stapled gastroplasty. AB - Primary small bowel bezoars constitute 0.44% of small bowel obstructions (SBO). We report a case of a man with a history of gastroplasty who presented with lower abdominal pain. Initial examination revealed leucocytosis and serum lipase. CT of the abdomen/pelvis was consistent with pancreatitis, cholelithiasis and a stable, 3.8 cm, ampullary diverticulum, without obstruction of the pancreatic/common bile duct. Considering this was the patient's first episode of pancreatitis with evidence of cholelithiasis, it seemed prudent that he would benefit from cholecystectomy but not diverticulectomy. Post-cholecystectomy he represented to the hospital with biliary emesis. CT of the abdomen/pelvis revealed postsurgical changes. Owing to non-resolution of the symptoms, 48 h later a small bowel follow through was obtained that suggested partial SBO. Ultimately, the patient was taken for exploratory laparoscopy and small bowel resection, after a large intramural mass was encountered in the small bowel. Final pathology revealed a 3 cm biliary bezoar causing obstruction and stercoral ulceration. PMID- 25498114 TI - Venous thrombosis: not always in the legs. PMID- 25498112 TI - Biochemical and MRI findings of Kallmann's syndrome. AB - Kallmann's syndrome is a neuronal migration disorder characterised by anosmia/hyposmia and hypogonadotropic hypogonadism. We present a case of a 21 year-old man who was unable to sense smell since birth and who displayed non development of secondary sexual characteristics for the past 10 years. Blood investigations showed low basal levels of serum follicle stimulating hormone (FSH), serum luteinising hormone (LH) and serum testosterone. After a gonadotropin releasing hormone challenge test there was a slight increase in serum FSH and serum LH, and after a human chorionic gonadotropin (HCG) challenge test the patient's serum testosterone level increased to 34 times that of his basal level. MRI of the brain showed absence of bilateral olfactory bulbs and sulcus with an apparently normal appearing pituitary gland, and bilateral loss of distinction between the gyrus rectus and medial orbital gyrus, thus confirming the diagnosis. The patient is on treatment with injection of HCG 2000 IU deep intramuscular twice a week and is on follow-up. PMID- 25498115 TI - An unusual presentation of a ruptured degenerative fibroid in a perimenopausal woman. AB - A 55-year-old woman in a perimenopausal state presented with severe suprapubic pain and fever. Physical examination revealed a tender pelvic mass measuring 24 weeks in size. Ultrasound of the pelvis and CT scan of the abdomen and pelvis showed a 12 cm mass arising from the posterior wall of the uterus with irregular margin inferiorly, raising suspicion of a ruptured mass. The patient was treated conservatively and discharged from the hospital with regular simple analgaesia. She had an elective total hysterectomy bilateral salpingo-oophrectomy and frozen section the following week and histology revealed a benign leiomyoma with extensive necrosis. Moreover, intraoperatively, the fibroid was found to have ruptured its capsule. This case illustrates that a ruptured degeneration of uterine leiomyoma should be considered as one of the differential diagnoses for all women presenting with abdominal pain and a large fibroid mass regardless of their hormonal status or age. PMID- 25498116 TI - Atomic force microscopy analysis of IgG films at hydrophobic surfaces: a promising method to probe IgG orientations and optimize ELISA tests performance. AB - IgG films are widely used in the field of immunoassays, especially in (double) antibody-sandwich ELISA tests where capture antibodies are coated on surfaces like polystyrene or hydrophobic self-assembled monolayers (h-SAMs). It is critical to analyze-at a molecular scale and under liquid conditions-the structure of the deposited IgG film in order to quantitatively address the efficiency of the ELISA test in terms of antigen detection. In this communication, we report an atomic force microscopy (AFM) analysis evidencing a strong relationship between immunological activities of mouse monoclonal anti human interleukin-2 (IL-2) and 6 (IL-6) antibodies, thickness and roughness of the IgG monolayer adsorbed onto h-SAMs, and surface concentration of IgG molecules. Indirect information may be further obtained on antibody orientation. Collating the results obtained by AFM and those from ELISA tests leads us to conclude that antibodies like anti-IL-6 forming flat monolayers should be more efficient under ELISA detection conditions. In addition, the concentration of IgG in the coating suspension should be optimized to obtain a monolayer heavily populated by "end-on" adsorbed molecules, an orientation that is desirable for enhancing ELISA tests performance. PMID- 25498117 TI - Macular degeneration needs longer lasting treatments. PMID- 25498118 TI - Patient characteristics associated with artifacts in Spectralis optical coherence tomography imaging of the retinal nerve fiber layer in glaucoma. AB - PURPOSE: To determine patient factors and eye conditions associated with artifacts in Spectralis optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) scans. DESIGN: Retrospective cross-sectional study. METHODS: The prevalence of 12 artifact types were described in this review of 2313 eye scans from 1188 patients who underwent a complete eye examination with Spectralis OCT scanning during the period of September 2009 to July 2013. The generalized estimating equations model was used to analyze associations between increased artifact prevalence and 10 patient characteristics, which included age, sex, race, visual acuity, refractive error, astigmatism, cataract status, glaucoma staging, visual field reliability, and glaucoma diagnosis. RESULTS: A total of 1070 or 46.3% of the 2313 eye scans had at least 1 artifact. Decentration error was the most common artifact (27.8%), followed by posterior vitreous detachment artifacts (14.4%). Visual acuity of less than 20/40 (P < .0001), presence of moderate to severe cataracts (P < .0001), advanced stage of glaucoma (P < .0001), and a diagnosis of open-angle glaucoma (P = .0003) were associated with increased prevalence of artifacts. CONCLUSIONS: Clinicians should first assess scans for artifacts before making therapeutic decisions based on RNFL thickness measurements. PMID- 25498119 TI - Familial aggregation of arthritis-related diseases in seropositive and seronegative rheumatoid arthritis: a register-based case-control study in Sweden. AB - OBJECTIVES: Our objective was to estimate the risk of developing rheumatoid arthritis (RA) associated with a family history of non-RA arthritis-related diseases. This familial co-aggregation is of clinical interest since it is often encountered when assessing family history of RA specifically, but also informative on the genetic overlap between these diseases. Since anticitrullinated peptide antibodies/rheumatoid factor (RF)-positive and RF negative RA have both specific and shared genetic factors, the familial co aggregation was assessed separately for seropositive and seronegative disease. METHODS: Nested case-control study in prospectively recorded Swedish total population data. The Multi-Generation Register identified first-degree relatives. RA and arthritis-related diseases were ascertained through the nationwide patient register. RA serology was based on International Classification of Diseases tenth revision coded diagnoses, mainly reflecting RF. Familial risks were calculated using conditional logistic regression. Results were replicated using the Swedish rheumatology register. RESULTS: Familial co-aggregation was found between RA and every studied arthritis-related disease, but the magnitude varied widely, from juvenile idiopathic arthritis (JIA) (seropositive RA OR=3.98 (3.01 to 5.26); seronegative RA OR=5.70 (3.47 to 9.36)) to osteoarthritis (seropositive RA OR=1.03 (1.00 to 1.06); seronegative RA OR=1.05 (1.00 to 1.09)). The familial co aggregation pattern of non-RA arthritis-related diseases was overall similar for seropositive and seronegative RA. Among those with family history of RA, relatives' other arthritis-related diseases conferred little or no additional risk. CONCLUSIONS: Although family history of several arthritis-related diseases may be useful to predict RA (eg, lupus and JIA), others (eg, osteoarthritis and arthralgia) are less useful. Seropositive and seronegative RA had rather similar familial co-aggregation patterns with arthritis-related diseases, suggesting that the two RA subsets are similar in the genetic factors that overlap with these diseases. PMID- 25498120 TI - A circulating reservoir of pathogenic-like CD4+ T cells shares a genetic and phenotypic signature with the inflamed synovial micro-environment. AB - OBJECTIVES: Systemic immunological processes are profoundly shaped by the micro environments where antigen recognition occurs. Identifying molecular signatures distinctive of such processes is pivotal to understand pathogenic immune responses and manipulate them for therapeutic purposes. Unfortunately, direct investigation of peripheral tissues, enriched in pathogenic T cells, is often impossible or imposingly invasive in humans. Conversely, blood is easily accessible, but pathogenic signatures are diluted systemically as a result of the strict compartmentalisation of immune responses. In this work, we aimed at defining immune mediators shared between the bloodstream and the synovial micro environment, and relevant for disease activity in autoimmune arthritis. METHODS: CD4(+) T cells from blood and synovium of patients with juvenile idiopathic arthritis (JIA) were immunophenotyped by flow cytometry. The TCR repertoire of a circulating subset showing similarity with the synovium was analysed through next generation sequencing of TCR beta-chain CDR3 to confirm enrichment in synovial clonotypes. Finally, clinical relevance was established by monitoring the size of this subset in the blood of patients with JIA and rheumatoid arthritis (RA). RESULTS: We identified a small subset of circulating CD4(+) T cells replicating the phenotypical signature of lymphocytes infiltrating the inflamed synovium. These circulating pathogenic-like lymphocytes (CPLs) were enriched in synovial clonotypes and they exhibited strong production of pro-inflammatory cytokines. Importantly, CPLs were expanded in patients with JIA, who did not respond to therapy, and also correlated with disease activity in patients with RA. CONCLUSIONS: CPLs provide an accessible reservoir of pathogenic cells recirculating into the bloodstream and correlating with disease activity, to be exploited for diagnostic and research purposes. PMID- 25498121 TI - The association between exaggeration in health related science news and academic press releases: retrospective observational study. AB - OBJECTIVE: To identify the source (press releases or news) of distortions, exaggerations, or changes to the main conclusions drawn from research that could potentially influence a reader's health related behaviour. DESIGN: Retrospective quantitative content analysis. SETTING: Journal articles, press releases, and related news, with accompanying simulations. SAMPLE: Press releases (n = 462) on biomedical and health related science issued by 20 leading UK universities in 2011, alongside their associated peer reviewed research papers and news stories (n = 668). MAIN OUTCOME MEASURES: Advice to readers to change behaviour, causal statements drawn from correlational research, and inference to humans from animal research that went beyond those in the associated peer reviewed papers. RESULTS: 40% (95% confidence interval 33% to 46%) of the press releases contained exaggerated advice, 33% (26% to 40%) contained exaggerated causal claims, and 36% (28% to 46%) contained exaggerated inference to humans from animal research. When press releases contained such exaggeration, 58% (95% confidence interval 48% to 68%), 81% (70% to 93%), and 86% (77% to 95%) of news stories, respectively, contained similar exaggeration, compared with exaggeration rates of 17% (10% to 24%), 18% (9% to 27%), and 10% (0% to 19%) in news when the press releases were not exaggerated. Odds ratios for each category of analysis were 6.5 (95% confidence interval 3.5 to 12), 20 (7.6 to 51), and 56 (15 to 211). At the same time, there was little evidence that exaggeration in press releases increased the uptake of news. CONCLUSIONS: Exaggeration in news is strongly associated with exaggeration in press releases. Improving the accuracy of academic press releases could represent a key opportunity for reducing misleading health related news. PMID- 25498122 TI - Can doctors be trained in a 48 hour working week? PMID- 25498123 TI - Preventing bad reporting on health research. PMID- 25498124 TI - Most maternal deaths are caused by deterioration in unrelated medical conditions. PMID- 25498125 TI - Methylglyoxal as a new biomarker in patients with septic shock: an observational clinical study. AB - INTRODUCTION: The role of reactive carbonyl species, such as methylglyoxal (MG), has been overlooked within the context of the sepsis syndrome. The aims of this study were to assess the impact of MG formation in different inflammatory settings and to evaluate its use for early diagnosis as well as prognosis of the sepsis syndrome. METHODS: In total, 120 patients in three groups were enrolled in this observational clinical pilot study. The three groups included patients with septic shock (n = 60), postoperative controls (n = 30), and healthy volunteers (n = 30). Plasma samples from patients with septic shock were collected at sepsis onset and after 24 hours and 4, 7, 14, and 28 days. Plasma samples from postoperative controls were collected prior to surgery, immediately following the end of the surgical procedure as well as 24 hours later and from healthy volunteers once. Plasma levels of MG were determined by high-performance liquid chromatography. Additionally, plasma levels of procalcitonin, C-reactive protein, soluble CD14 subtype, and interleukin-6 were determined. RESULTS: Patients with septic shock showed significantly higher plasma levels of MG at all measured times, compared with postoperative controls. MG was found to identify patients with septic shock more effectively-area under the curve (AUC): 0.993-than procalcitonin (AUC: 0.844), C-reactive protein (AUC: 0.791), soluble CD14 subtype (AUC: 0.832), and interleukin-6 (AUC: 0.898) as assessed by receiver operating characteristic (ROC) analysis. Moreover, plasma levels of MG in non-survivors were significantly higher than in survivors (sepsis onset: *P = 0.018 for 90-day survival; **P = 0.008 for 28-day survival). Plasma levels of MG proved to be an early predictor for survival in patients with septic shock (sepsis onset: ROC-AUC 0.710 for 28-day survival; ROC-AUC 0.686 for 90-day survival). CONCLUSIONS: MG was identified as a marker for monitoring the onset, development, and remission of sepsis and was found to be more useful than routine diagnostic markers. Further studies are required to determine the extent of MG modification in sepsis and whether targeting this pathway could be therapeutically beneficial to the patient. TRIAL REGISTRATION: German Clinical Trials Register DRKS00000505. Registered 8 November 2010. PMID- 25498126 TI - Educational technologies in problem-based learning in health sciences education: a systematic review. AB - BACKGROUND: As a modern pedagogical philosophy, problem-based learning (PBL) is increasingly being recognized as a major research area in student learning and pedagogical innovation in health sciences education. A new area of research interest has been the role of emerging educational technologies in PBL. Although this field is growing, no systematic reviews of studies of the usage and effects of educational technologies in PBL in health sciences education have been conducted to date. OBJECTIVE: The aim of this paper is to review new and emerging educational technologies in problem-based curricula, with a specific focus on 3 cognate clinical disciplines: medicine, dentistry, and speech and hearing sciences. Analysis of the studies reviewed focused on the effects of educational technologies in PBL contexts while addressing the particular issue of scaffolding of student learning. METHODS: A comprehensive computerized database search of full-text articles published in English from 1996 to 2014 was carried out using 3 databases: ProQuest, Scopus, and EBSCOhost. Eligibility criteria for selection of studies for review were also determined in light of the population, intervention, comparison, and outcomes (PICO) guidelines. The population was limited to postsecondary education, specifically in dentistry, medicine, and speech and hearing sciences, in which PBL was the key educational pedagogy and curriculum design. Three types of educational technologies were identified as interventions used to support student inquiry: learning software and digital learning objects; interactive whiteboards (IWBs) and plasma screens; and learning management systems (LMSs). RESULTS: Of 470 studies, 28 were selected for analysis. Most studies examined the effects of learning software and digital learning objects (n=20) with integration of IWB (n=5) and LMS (n=3) for PBL receiving relatively less attention. The educational technologies examined in these studies were seen as potentially fit for problem-based health sciences education. Positive outcomes for student learning included providing rich, authentic problems and/or case contexts for learning; supporting student development of medical expertise through the accessing and structuring of expert knowledge and skills; making disciplinary thinking and strategies explicit; providing a platform to elicit articulation, collaboration, and reflection; and reducing perceived cognitive load. Limitations included cumbersome scenarios, infrastructure requirements, and the need for staff and student support in light of the technological demands of new affordances. CONCLUSIONS: This literature review demonstrates the generally positive effect of educational technologies in PBL. Further research into the various applications of educational technology in PBL curricula is needed to fully realize its potential to enhance problem-based approaches in health sciences education. PMID- 25498127 TI - Fracture resistance of endodontically treated roots with oval canals restored with oval and circular posts. AB - INTRODUCTION: The aim of the present study was to evaluate the effects of post space preparations with circular and oval post drills and the placement of oval and circular posts on the fracture strength of roots with oval canals. METHODS: Seventy mandibular premolars with oval root canals were decoronated. Fourteen teeth were used as a control group (group 1), and the root canals of the remaining teeth were prepared up to size #30. The root canals were filled, and the samples were randomly divided into 4 experimental groups as follows: post space preparation with circular-shaped drills (group 2), post space preparation with oval-shaped drills (group 3), circular post placement (group 4), and oval post placement (group 5). A fracture strength test was performed on each specimen, and the data were statistically evaluated using 1-way analysis of variance and Tukey post hoc tests. RESULTS: The fracture strengths of the circular posts-placed group were higher than those of the oval post-placed group (P < .001). The post space preparation using oval-shaped drills significantly decreased the fracture strength of the roots compared with the control group (P < .001). CONCLUSIONS: Within the limitations of the present study, oval posts did not provide a higher fracture resistance to endodontically treated roots with oval canals compared with circular posts. Therefore, clinicians should be aware that oval posts are similar to circular posts in terms of enhancing the fracture resistance of roots with oval canals. PMID- 25498128 TI - 3-dimensional analysis of regenerative endodontic treatment outcome. AB - INTRODUCTION: A growing body of evidence supports the regeneration potential of dental tissues after regenerative endodontic treatment (RET). Nevertheless, a standard method for the evaluation of RET outcome is lacking. The aim of this study was to develop a standardized quantitative method for RET outcome analysis based on cone-beam computed tomographic (CBCT) volumetric measurements. METHODS: Five human teeth embedded in mandibular bone samples were scanned using both an Accuitomo 170 CBCT machine (Morita, Kyoto, Japan) and a SkyScan 1174 micro computed tomographic (MUCT) system (SkyScan, Antwerp, Belgium). For subsequent clinical application, clinical data and low-dose CBCT scans (preoperatively and follow-up) from 5 immature permanent teeth treated with RET were retrieved. In vitro and clinical 3-dimensional image data sets were imported into a dedicated software tool. Two segmentation steps were applied to extract the teeth of interest from the surrounding tissue (livewire) and to separate tooth hard tissue and root canal space (level set methods). In vitro and clinical volumetric measurements were assessed separately for differences using Wilcoxon matched pairs test. Pearson correlation analysis and Bland-Altman plots were used to evaluate the relation and agreement between the segmented CBCT and MUCT volumes. RESULTS: The results showed no statistical differences and strong agreement between CBCT and MUCT volumetric measurements. Volumetric comparison of the root hard tissue showed significant hard tissue formation. (The mean volume of newly formed hard tissue was 27.9 [+/-10.5] mm(3) [P < .05]). CONCLUSIONS: Analysis of 3-dimensional data for teeth treated with RET offers valuable insights into the treatment outcome and patterns of hard tissue formation. PMID- 25498129 TI - Systemically administered anti-TNF therapy ameliorates functional outcomes after focal cerebral ischemia. AB - BACKGROUND: The innate immune system contributes to the outcome after stroke, where neuroinflammation and post-stroke systemic immune depression are central features. Tumor necrosis factor (TNF), which exists in both a transmembrane (tm) and soluble (sol) form, is known to sustain complex inflammatory responses associated with stroke. We tested the effect of systemically blocking only solTNF versus blocking both tmTNF and solTNF on infarct volume, functional outcome and inflammation in focal cerebral ischemia. METHODS: We used XPro1595 (a dominant negative inhibitor of solTNF) and etanercept (which blocks both solTNF and tmTNF) to test the effect of systemic administration on infarct volume, functional recovery and inflammation after focal cerebral ischemia in mice. Functional recovery was evaluated after one, three and five days, and infarct volumes at six hours, 24 hours and five days after ischemia. Brain inflammation, liver acute phase response (APR), spleen and blood leukocyte profiles, along with plasma microvesicle analysis, were evaluated. RESULTS: We found that both XPro1595 and etanercept significantly improved functional outcomes, altered microglial responses, and modified APR, spleen T cell and microvesicle numbers, but without affecting infarct volumes. CONCLUSIONS: Our data suggest that XPro1595 and etanercept improve functional outcome after focal cerebral ischemia by altering the peripheral immune response, changing blood and spleen cell populations and decreasing granulocyte infiltration into the brain. Blocking solTNF, using XPro1595, was just as efficient as blocking both solTNF and tmTNF using etanercept. Our findings may have implications for future treatments with anti TNF drugs in TNF-dependent diseases. PMID- 25498130 TI - Insulin degludec/insulin aspart versus biphasic insulin aspart 30 in Asian patients with type 2 diabetes inadequately controlled on basal or pre-/self-mixed insulin: a 26-week, randomised, treat-to-target trial. AB - AIMS: Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of IDeg and IAsp. This pan-Asian, 26-week trial investigated efficacy and safety of IDegAsp vs biphasic insulin aspart 30 (BIAsp 30) in Asian adults with type 2 diabetes (T2DM), inadequately controlled on once- or twice-daily (BID) basal, premixed or self-mixed insulin. METHODS: Participants (mean age 59.8 years, HbA1c 8.4%, FPG 7.9 mmol/L, BMI 25.4 kg/m(2)) were randomised 2:1 to BID IDegAsp (n=282) or BIAsp 30 (n=142) and continued existing metformin treatment. Insulins were administered with breakfast and main evening meal, titrated to a pre breakfast and pre-main evening meal self-measured plasma glucose target of 4-5 mmol/L. RESULTS: IDegAsp achieved the primary endpoint of non-inferiority to BIAsp 30 for mean change in HbA1c (estimated treatment difference [ETD] IDegAsp BIAsp 30: 0.05% points [95% CI -0.10; 0.20]). IDegAsp was superior in lowering fasting plasma glucose (FPG) (ETD -1.06 mmol/L, 95% CI -1.43; -0.70, p<0.001), and resulted in a lower final mean daily insulin dose (0.79 U/kg vs 0.99 U/kg, estimated rate ratio [RR] 0.79, 95% CI 0.73; 0.85, p<0.0001). Rates of overall confirmed and severe hypoglycaemia were similar between treatments, while rate of nocturnal confirmed hypoglycaemia was numerically (p=ns) lower with IDegAsp. During the maintenance period there was a trend (p=ns) towards lower hypoglycaemia rates for IDegAsp. CONCLUSION: In Asian adults with T2DM, IDegAsp BID effectively improves long-term glycaemic control, and compared to BIAsp 30, provides superior reductions in FPG with a lower dose, and numerically less nocturnal hypoglycaemia. PMID- 25498131 TI - Mutational analysis of paediatric patients with tuberous sclerosis complex in Korea: genotype and epilepsy. AB - To date, only a few studies have reported that, in tuberous sclerosis, TSC2 mutations are more frequently associated with infantile spasms and cognitive impairment compared to TSC1 mutations. We analyzed the mutational spectrum of patients with tuberous sclerosis in Korea and attempted to explore the associations between genotype and seizure type/outcome. We performed mutational analyses on 70 unrelated patients with clinically confirmed tuberous sclerosis by using direct DNA sequencing and/or multiplex ligation-dependent probe amplification. The patients' medical records, including epilepsy type and outcome, were reviewed retrospectively. We identified pathogenic mutations in 55 patients (79%), 25 of which were novel. There were 12 TSC1 mutations and 43 TSC2 mutations. TSC1 mutations included 8 frameshift and 4 nonsense mutations. TSC2 mutations included 12 frameshift, 10 nonsense, 6 splicing, and 6 missense mutations, as well as 4 in-frame deletions and 5 large deletions. Fifty-eight patients had epilepsy (83%), including 19 patients with a history of infantile spasms. Compared to patients with TSC1 mutations, individuals with TSC2 mutations had a significantly higher frequency of epilepsy (p<0.05) and tended to have a higher frequency of infantile spasms (37% vs 17%; p<0.3). Most of the patients with TSC2 mutations who developed infantile spasms exhibited subsequent epilepsy (13/14; 93%). However, the presence/absence of infantile spasms did not influence seizure remission or cognitive outcome. PMID- 25498132 TI - The nerve ring in cnidarians: its presence and structure in hydrozoan medusae. AB - In our previous studies of the Hydra nerve ring, we proposed the following hypothesis: "The nerve ring in the hypostome of Hydra is a central nervous system (CNS)-like neuronal structure." Related to this hypothesis, we have started to survey the nerve ring immunocytochemically using antibodies against neuropeptides throughout the whole phylum of cnidarians. In the present study, we describe nerve rings in hydrozoan medusae. We examined the medusae of five hydrozoan species belonging to three orders: Eirene sp. (order Leptomedusae), Craspedacusta sowerbyi (order Limnomedusae), Sarsia tubulosa, Turritopsis nutricula, and Cladonema radiatum (order Anthomedusae). We observed a well-developed nerve ring in all species. The nerve ring runs circumferentially around the margin of the bell. In all cases, the nerve ring was visualized by plural antibodies, suggesting that it contains different neural subpopulations. In C. radiatum, antibodies against four different neuropeptides labeled the nerve ring. We established clear (without undesirable cross-reactions) double-staining procedures with two rabbit primary antibodies. Using the double-staining method, three neural subsets visualized by three antibodies revealed completely separate neural populations. The results show that the nerve ring is a common feature in hydrozoan medusae and has a complex heterogeneous structure composed of different neural subsets. PMID- 25498133 TI - Preliminary study of anxiety symptoms, family dysfunction, and the brain-derived neurotrophic factor (BDNF) Val66Met genotype in offspring of parents with bipolar disorder. AB - Several genetic and environmental factors place youth offspring of parents with bipolar disorder (BD) at high risk for developing mood and anxiety disorders. Recent studies suggest that anxiety symptoms, even at subclinical levels, have been associated with an increased risk for developing BD. The brain-derived neurotrophic factor (BDNF) gene has been implicated in the pathophysiology of both BD and anxiety disorders. We aimed to explore whether anxiety in BD offspring was associated with the BDNF Val66Met polymorphism. 64 BD offspring (mean age: 13.73 (S.D. 3.45) M = 30, F = 34) and 51 HC (mean age: 13.68 (S.D. 2.68) M = 23, F = 28) were compared on presence of the met allele and on scores from the Multidimensional Anxiety Scale for Children (MASC). To assess family function, we used the Family Adaptability and Cohesion Evaluation Scales (FACES IV). The Baron & Kenny method was the statistical approach used to examine the moderating effects between variables. BD offspring showed higher levels of overall anxiety than did the HC group. BD offspring with the val/val genotype showed higher levels of anxiety than BD offspring with other genotypes. No significant levels of anxiety or its association with BDNF genotype were found in the HC group. BD offspring group showed significantly more family dysfunction when compared with the HC group and the family dysfunction moderated the association between the BDNF genotype and anxiety symptoms. This study demonstrated the potential interplay of three factors: BD offspring, anxiety symptoms and family dysfunction. PMID- 25498134 TI - Spouse-caregivers' quality of life in Alzheimer's disease. AB - BACKGROUND: The relationship between sexuality and quality of life (QoL) of spouse-caregivers remains unclear. We designed this study to evaluate the relationship between sexual satisfaction and spouse-caregivers' QoL, and to determine the influence of the clinical characteristics of people with dementia (PWD) on spouse-caregivers' self-reported QoL. METHODS: Using a cross-sectional design, 54 PWD and their spouse-caregivers completed the QoL in Alzheimer's Disease scale (QoL-AD), questionnaire on sexual experience and satisfaction (QSES), Mini-Mental State Examination (MMSE), Clinical Dementia Rating scale (CDR), Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia (ASPIDD), Pfeffer functional activities questionnaire (FAQ), the Cornell scale for depression in dementia (CSDD) and Zarit burden interview (ZBI). Univariate and multivariate regression analyses were conducted to identify the factors that influenced the spouse-caregivers' QoL ratings. RESULTS: We did not find a significant difference in QoL between male and female spouse-caregivers (p = 0.71). We also found that 13% of males and 48.1% of females demonstrated moderate to severe sexual dissatisfaction. However, we did not find a significant correlation between spouse-caregivers' QoL and sexual satisfaction (p = 0.41). The linear regression indicated that impaired awareness and lower QoL of PWD were significantly related to spouse-caregivers' QoL (p = 0.000). CONCLUSIONS: The spouse-caregivers' QoL is influenced by awareness of disease and PWD QoL. Our study would be helpful for the development of adequate psycho-educational approaches to increase spouse-caregivers' QoL, considering the specificities of the couples' relationship. PMID- 25498135 TI - Liver transplantation using grafts with rare metabolic disorders. AB - Metabolic diseases that involve the liver represent a heterogeneous group of disorders. Apart from the metabolic defect, the subject's liver functions may be normal. With the increasing need for organs, livers from donors with metabolic diseases other than familial amyloid polyneuropathy might be possibly used for transplantation. However, whether such livers qualify as grafts and how they might impact recipient outcome are still unanswered questions. This review of the literature summarizes current experience in the use of such grafts in the context of cadaveric, domino, and living-related liver transplantation. PMID- 25498136 TI - Toxicokinetics of permethrin biomarkers of exposure in orally exposed volunteers. AB - Permethrin is a widely used pyrethroid insecticide for which the toxicokinetics of exposure biomarkers in humans is not fully documented. The time courses of key biomarkers of permethrin exposure were thus assessed in accessible biological matrices of orally exposed volunteers. Six volunteers ingested 0.1 mg/kg body weight of permethrin (60:40 trans/cis). Blood samples were withdrawn at fixed periods over 72 h following ingestion and complete timed-urine voids were collected over 84 h post-dosing. Cis-and trans-3-(2,2-dichlorovinyl)-2,2-dimethyl cyclopropane-1-carboxylic acids (cis-and trans-DCCA) and 3-phenoxybenzoic acid (3 PBA) were quantified in samples. In plasma, peak concentrations of cis-DCCA, trans-DCCA and 3-PBA were reached about ~7 h post-dosing, and elimination appeared monophasic with a mean apparent elimination half-life (t1/2) of 6.2, 7.1 and 6.5 h, respectively. In urine, elimination rate time courses of cis-DCCA, trans-DCCA and 3-PBA evolved in parallel with plasma, with respective mean apparent elimination t1/2 of 4.5, 5.4 and 5.7 h. Over the 84 h period post treatment, 43-46% of administered molar dose were excreted in urine as trans-DCCA (molar % of trans-permethrin) and 3-PBA. Results show similarities in the different metabolite profiles and a rapid equilibrium between urine and plasma levels; data should help interpret the significance of biological measurements and optimal sampling strategies. PMID- 25498137 TI - Beware of nebulized bronchodilators. PMID- 25498138 TI - Digital tomosynthesis (DTS) for quantitative assessment of trabecular microstructure in human vertebral bone. AB - Digital tomosynthesis (DTS) provides slice images of an object using conventional radiographic methods with high in-plane resolution. The objective of this study was to explore the potential of DTS for describing microstructural, stiffness and stress distribution properties of vertebral cancellous bone. Forty vertebrae (T6, T8, T11, and L3) from 10 cadavers (63-90 years) were scanned using microCT and DTS. Anisotropy (MUCT.DA), and the specimen-average and standard deviation of trabecular bone volume fraction (BV/TV), thickness (Tb.Th), number (Tb.N) and separation (Tb.Sp) were obtained using stereology. Apparent modulus (EFEM), and the magnitude (VMExp/sigmaapp) and variability (VMCV) of trabecular stresses were calculated using microCT-based finite element modeling. Mean intercept length, line fraction deviation and fractal parameters were obtained from coronal DTS slices, then correlated with stereological and finite element parameters using linear regression models. Twenty-one DTS parameters (out of 27) correlated to BV/TV, Tb.Th, Tb.N, Tb.Sp and/or MUCT.DA (p<0.0001-p<0.05). DTS parameters increased the explained variability in EFEM and VMCV (by 9-11% and 13-19%, respectively; p<0.0001-p<0.04) over that explained by BV/TV. In conclusion, DTS has potential for quantitative assessment of cancellous bone and may be used as a modality complementary to those measuring bone mass for assessing spinal fracture risk. PMID- 25498139 TI - Analysis of grain boundary dynamics using event detection and cumulative averaging. AB - To analyze extended time series of high resolution images, we have employed automated frame-by-frame comparisons that are able to detect dynamic changes in the structure of a grain boundary in Au. Using cumulative averaging of images between events allowed high resolution measurements of the atomic relaxation in the interface with sufficient accuracy for comparison with atomistic models. Cumulative averaging was also used to observe the structural rearrangement of atomic columns at a moving step in the grain boundary. The technique of analyzing changing features in high resolution images by averaging between incidents can be used to deconvolute stochastic events that occur at random intervals and on time scales well beyond that accessible to single-shot imaging. PMID- 25498140 TI - First results on laser-induced field emission from a CNT-based nanotip. AB - We present the first demonstration of ultrafast laser-induced field emission and measurement of the energy distribution of electrons from a nanotip based on a carbon nanotube (CNT). Our experimental setup extends the studies performed on conventional tungsten or gold tips by using this new innovative tip. The carbon tip consists of concentric carbon layers in the shape of a cone, and has been previously studied as a very good candidate for cold field emission. The first laser-induced field emission from a CNT-based nanotip has been observed and we measured the energy spectrum as well as the polarization dependance of the emission. We also characterize the damage threshold of the tip, when illuminated by a high repetition rate femtosecond laser. These first results are encouraging further studies of electron emission from CNT-based carbon nanotips. PMID- 25498141 TI - The influence of Cs/Cc correction in analytical imaging and spectroscopy in scanning and transmission electron microscopy. AB - Aberration correction in scanning/transmission electron microscopy (S/TEM) owes much to the efforts of a small dedicated group of innovators. Leading that frontier has been Prof. Harald Rose. To date his leadership and dynamic personality has spearheaded our ability to leave behind many of the limitations imposed by spherical aberration (Cs) in high resolution phase contrast imaging. Following shortly behind, has been the development of chromatic aberration correction (Cc) which augments those accomplishments. In this paper we will review and summarize how the combination of Cs/Cc technology enhances our ability to conduct hyperspectral imaging and spectroscopy in today's and future computationally mediated experiments in both thin as well as realistic specimens in vacuo and during in-situ/environmental experiments. PMID- 25498142 TI - Environmental transmission electron microscopy for catalyst materials using a spherical aberration corrector. AB - Atomic resolution has been obtained using environmental transmission electron microscopy (ETEM) by installing a spherical aberration corrector (Cs-corrector) on the objective lens. Simultaneously, the technology for controlling the environment around a specimen in ETEM has advanced significantly in the past decade. Quantification methodology has recently been established for deriving relevant experimental data in catalyst materials from substantial and systematic ETEM observation at the atomic scale. With this background, this paper summarizes aspects of the evolutional microscopy technique: necessary conditions for atomic resolution in ETEM; reduction of the scattering of electrons by the medium surrounding a specimen; and an environmental cell for structural imaging of a crystalline specimen. The high spatial resolution of a Cs-corrected ETEM is demonstrated for different observation conditions. After statistical analysis combined with numerical image analysis of ETEM data is briefly described, the recent applications of the Cs-corrected ETEM to catalyst materials are reviewed. For gold nanoparticulate catalysts, the structural information on the reaction sites and adsorption sites are deduced. For Pt nanoparticulate catalysts, ETEM studies elucidate the correlation between the catalytic activity and the morphology of the nanoparticles. These studies also reveal oxidation and reduction on the topmost Pt surface layer at the atomic scale. Finally, current issues and the future perspectives of Cs-corrected ETEM are summarized, including the reproducibility of ETEM observation data, the control of environments, the critical evaluation of electron irradiation effects, the full implementation of transmission electron microscopy technology in ETEM, and the safety issues for an ETEM laboratory. PMID- 25498143 TI - Pathogenicity island-directed transfer of unlinked chromosomal virulence genes. AB - In recent decades, the notorious pathogen Staphylococcus aureus has become progressively more contagious, more virulent, and more resistant to antibiotics. This implies a rather dynamic evolutionary capability, representing a remarkable level of genomic plasticity, most probably maintained by horizontal gene transfer. Here we report that the staphylococcal pathogenicity islands have a dual role in gene transfer: they not only mediate their own transfer, but they can independently direct the transfer of unlinked chromosomal segments containing virulence genes. While transfer of the island itself requires specific helper phages, transfer of unlinked chromosomal segments does not, so potentially any pac-type phage will serve. These results reveal that SaPIs can increase the horizontal exchange of accessory genes associated with disease and may shape pathogen genomes beyond the confines of their attachment sites. PMID- 25498145 TI - PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. AB - The lysosome is the final destination for degradation of endocytic cargo, plasma membrane constituents, and intracellular components sequestered by macroautophagy. Fusion of endosomes and autophagosomes with the lysosome depends on the GTPase Rab7 and the homotypic fusion and protein sorting (HOPS) complex, but adaptor proteins that link endocytic and autophagy pathways with lysosomes are poorly characterized. Herein, we show that Pleckstrin homology domain containing protein family member 1 (PLEKHM1) directly interacts with HOPS complex and contains a LC3-interacting region (LIR) that mediates its binding to autophagosomal membranes. Depletion of PLEKHM1 blocks lysosomal degradation of endocytic (EGFR) cargo and enhances presentation of MHC class I molecules. Moreover, genetic loss of PLEKHM1 impedes autophagy flux upon mTOR inhibition and PLEKHM1 regulates clearance of protein aggregates in an autophagy- and LIR dependent manner. PLEKHM1 is thus a multivalent endocytic adaptor involved in the lysosome fusion events controlling selective and nonselective autophagy pathways. PMID- 25498144 TI - Mitochondrial ADCK3 employs an atypical protein kinase-like fold to enable coenzyme Q biosynthesis. AB - The ancient UbiB protein kinase-like family is involved in isoprenoid lipid biosynthesis and is implicated in human diseases, but demonstration of UbiB kinase activity has remained elusive for unknown reasons. Here, we quantitatively define UbiB-specific sequence motifs and reveal their positions within the crystal structure of a UbiB protein, ADCK3. We find that multiple UbiB-specific features are poised to inhibit protein kinase activity, including an N-terminal domain that occupies the typical substrate binding pocket and a unique A-rich loop that limits ATP binding by establishing an unusual selectivity for ADP. A single alanine-to-glycine mutation of this loop flips this coenzyme selectivity and enables autophosphorylation but inhibits coenzyme Q biosynthesis in vivo, demonstrating functional relevance for this unique feature. Our work provides mechanistic insight into UbiB enzyme activity and establishes a molecular foundation for further investigation of how UbiB family proteins affect diseases and diverse biological pathways. PMID- 25498146 TI - Use of refractometry as a new management tool in AI boar centers for quality assurance of extender preparations. AB - A study was performed to see if refractometry can be used as a new quality control tool for boar semen extenders. For this the refractive index and osmolality of BTS extender concentrations (EC) were recorded in 10%-steps from 50% to 150% and 200% of the correct amount. Twelve boar ejaculates were evaluated for semen quality. The refractive index for the correctly prepared extender was 4.6+/-0.0 degrees Bx, corresponded to 316+/-16mOsmkg(-1), and correlated highly with osmolality (r=0.99; P<0.001). Total sperm motility with 100% EC differed significantly from <=70% EC (P<0.001) and 200% EC (P<0.001) on day 1 (d1) and d4, respectively. The percentage of motile spermatozoa in a thermoresistance test on d2 showed a significant drop using <=70% EC (P=0.047) and >=140% EC (P=0.004). Secondary apical ridge defects were significantly higher using 50% EC (P<0.001) and >=150% EC (P=0.032) compared to 100% EC, respectively. An increased number of coiled tails were observed using <=60% EC (P<0.001). Percentages of spermatozoa with intact membranes on d2 resulted in a significant decrease using 50% EC (P<0.001) and >=150% EC (P=0.005), respectively. The mean percentage of PI negative spermatozoa with active mitochondria on d2 showed a significant difference using <=60% EC (P=0.016) and >=140% EC (P<0.001) compared to 100% EC, respectively. Boar sperm quality is affected by inexact extender preparation. The refractive-index is an indicator of osmolality and may be used to verify semen extender preparation. The sensitivity is sufficient to detect deviations from correct extender preparation before negative effects on sperm quality occur. PMID- 25498147 TI - Persistent Mullerian duct syndrome (PMDS) in the Polish free-ranged bull populations of the European bison (Bison bonasus L.). AB - This study describes the diversity of vestigial male uteri of the European bison (Eb) examined for: (1) morphology, (2) glycoprotein localization, (3) total protein and glycoprotein profiles, (4) steroid concentrations, and (5) PMDS based on the mutation of AMH and AMHR2 genes. Uteri of adult bulls (5-12 years old) were compared to a uterus of a juvenile female (6 months old). Male uterine proteins were analyzed in parallel to secretory endometrial proteins of pseudo pregnant pig (PsEND) and BSA used as profile-controls. Hematoxylin/eosin-staining revealed the diversity of male uterine morphology, including lumen size/shape, endometrial (END) gland density, luminal knob-like epithelial structures and multiple intrauterine cells proliferating within the lumen. PAS-staining revealed the presence of glycoproteins restricted to luminal epithelial cells and END glands. Heterologous total protein PAGE-profiles (20-66kDa) revealed two dominant fractions (66 and 45kDa), similar to PAS-profiles (67 and 47kDa) in male and female uterine tissues. In male uterine tissues, androstendione and progesterone, but not testosterone, estrone or estradiol concentrations were lower than in the female. Sequencing of AMH- and AMHR2-like amplicons allowed identification of these gene mutations in Eb. Our results provide novel data regarding PMDS, demonstrating the diversity of uterine morphology, glycoprotein mass/profile, steroid concentration and AMH/AMHR2 mutations in Eb bulls. PMID- 25498148 TI - Mating-related behaviour of grizzly bears inhabiting marginal habitat at the periphery of their North American range. AB - In comparison to core populations, peripheral populations have low density and recruitment, and are subject to different selective pressures, such as environmental conditions, food type and availability, predation, disease, etc., which may result in behavioural modifications to mating. We test the roam-to-mate hypothesis for a peripheral population of grizzly bears (Ursus arctos) at the northern extent of their North American range, in Canada's Arctic. If bears are roaming-to-mate, we predicted greater range size and daily displacement, and more linear movements for receptive animals during the mating period compared to post mating. In contrast to our predictions, we found that in general range size and displacement increased from mating to post-mating regardless of reproductive status. When considered across both periods, females with cubs-of-the-year had smaller range use metrics than other reproductive groups, which we attribute to a counter-strategy against sexually selected infanticide and the reduced mobility of cubs. Linearity of movements remained near zero during both periods across all groups, suggesting tortuous movements more characteristic of foraging than of mate-searching. We suggest that for this population, finding quality habitat takes precedence over mate-searching in this marginal Arctic landscape. Alternatively, a more monogamous mating system and sequestering behaviour may have obscured movement differences between the two periods. The behavioural differences in mating that we observed from what is typical of core populations may reflect local adaptation to marginal conditions and could benefit the species in the face of ongoing environmental change. PMID- 25498149 TI - Extraction of ranitidine and nizatidine with using imidazolium ionic liquids prior spectrophotometric and chromatographic detection. AB - A new extraction medium was proposed for liquid-liquid extraction of the histamine H2 receptor antagonists ranitidine (RNT) and nizatidine (NZT). The ionic liquids with low vapor pressure and favorable solvating properties for a range of compounds such as 1-butyl-3-methylimidazolium hexafluorophosphate [C4mim][PF6] and 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [C4mim][Tf2N] were tested for isolation of analytes. The extraction parameters of RNT and NZT, namely, amount of ionic liquid, pH of sample solution, shaking and centrifugation time were optimized. The isolation processes were performed with 1 mL of the ionic liquids. The extracted samples (pH values near 4) were shaken at 1750 rpm. The influence of interfering substances on the efficiency of extraction process was also studied. Methods for the histamine H2 receptor antagonists (ranitidine and nizatidine) determination after their separation using imidazolium ionic liquids by high performance liquid chromatography (HPLC) combined with UV spectrophotometry were developed. The application of ionic liquids in extraction step allows for selective isolation of analytes from aqueous matrices and their preconcentration. The above methods were applied to the determination of RNT and NZT in environmental samples (river water and wastewater after treatment). PMID- 25498150 TI - Analytical approach for the determination of steroid profile of humans by gas chromatography isotope ratio mass spectrometry aimed at distinguishing between endogenous and exogenous steroids. AB - The contamination of commonly used supplements by unknown steroids as well as their metabolites (parent compounds) become a challenge for the analytical laboratories. Although the determination of steroids profile is not trivial because of the complex matrix and low concentration of single compound, one of the most difficult current problem is to distinguish, during analytical procedure, endogenous androgens such as testosterone, dehydrotestosterone or dehydroepiandrosterone from their synthetic equivalents. The aim of this work was to develop and validate an analytical procedure for determination of the steroid profile in human urine by gas chromatography-combustion-isotope ratio mass spectrometry (GC/C/IRMS) toward distinguishing between endogenous and exogenous steroids. Beside the optimization of the experimental parameters for gas chromatography separation and mass spectrometry, attention was focused on urine sample preparation. Using an optimized sample preparation protocol it was possible to achieve better chromatographic resolutions and better sensitivity enabling the determination of 5 steroids, androsterone, etiocholanolone, testosterone, 5-androstandiol, 11-hydroxyandrdostane, pregnandiol, with the expanded uncertainty (k=2) below 10/00. This enable to evaluate the significant shift of the delta(13)C/(12)C [0/00] values for each of examined steroids (excluding ERC). The analytical protocol described in this work was successfully used for the confirmation of positive founding urine by evaluation T/E ratio after GC/C/IRMS analysis. PMID- 25498151 TI - A massive open online course (MOOC) can be used to teach physiotherapy students about spinal cord injuries: a randomised trial. AB - QUESTION: Does a massive open online course (MOOC) based around an online learning module about spinal cord injuries improve knowledge or confidence among physiotherapy students more than if physiotherapy students are left to work through the online learning module at their own pace. Which method of presenting the content leads to greater satisfaction among the students? STUDY DESIGN: Randomised controlled trial with concealed allocation and intention-to-treat analysis. PARTICIPANTS: Forty-eight physiotherapy students in Bangladesh. INTERVENTION: Participants randomised to the control group were instructed to work at their own pace over a 5-week period through a physiotherapy-specific online learning module available at www.elearnSCI.org. Experimental participants were enrolled in a 5-week MOOC. The MOOC involved completing the same online learning module but experimental participants' progress through the module was guided each week and they were provided with the opportunity to engage in online discussion through Facebook. OUTCOME MEASURES: The primary outcome was knowledge, and the secondary outcomes were perceived confidence to treat people with spinal cord injuries and satisfaction with the learning experience. RESULTS: The mean between-group difference for knowledge was 0.7 points (95% CI -1.3 to 2.6) on a 0 to 20-point scale. The equivalent results for perceived confidence and satisfaction with the learning experience were 0.4 points (95% CI -1.0 to 1.8) and 0.0 points (95% CI -1.1 to 1.2) on a 0 to 10-point scale. CONCLUSION: The MOOC was no better for students than working at their own pace through an online learning module for increasing knowledge, confidence or satisfaction. However, students in the MOOC group highlighted positive aspects of the course that were unique to their group, such as interacting with students from other countries through the MOOC Facebook group. TRIAL REGISTRATION: ACTRN12614000422628. PMID- 25498152 TI - Smooth pursuit eye movement training improves recovery from functional neglect in individuals with postacute stroke. PMID- 25498155 TI - The key role of socio-demographic and socio-environmental factors in urban malaria occurrence and control - An illustration using the city of Yaounde. AB - Cities in developing countries are experiencing an unprecedented population growth that illustrates a demographic transition and a shift towards modernization with consequences on their epidemiological profiles. However, this change is characterized by an important rural-to-urban social and cultural transfer that can bias the expected epidemiological transition; at the same time, this transfer renders the understanding of the occurrence of communicable diseases more complex than it appears. Urban malaria occurrence was modeled for the city of Yaounde in Cameroon. Retrospective interviews were conducted to describe a variety of epidemiological, social and environmental variables at the household level. Various ecological variables originating from remote sensing data were also integrated. Multivariate multilevel negative binomial analyses were developed to evaluate the distinct contributions of explanatory social and ecological variables. Spatial models based on the level of urbanity were implemented to understand the intelligence of urban malaria as characterized by those variables. The results showed an overall higher statistical importance of socio-environmental variables, particularly those describing rural origin socio cultural features in terms of non-conventional housing types and urban agriculture (UA). The spatial patterns of the urban malaria occurrences displayed a complex combination of population density gradients and socio-environmental factors, illustrating the importance of conventional urban features over rural/non-conventional features in reducing the occurrence of urban malaria. PMID- 25498154 TI - After spouses depart: emotional wellbeing among nonmigrant Mexican mothers. AB - Nonmigrant family members play a central role in facilitating Mexico-U.S. migration by maintaining families, sustaining social relationships, and overseeing household economic organization in sending communities. This study investigates changes to the emotional wellbeing of nonmigrant mothers when their partners reside in the United States. We hypothesize that partner migration affects mothers' wellbeing through three pathways: directly via the toll of spousal separation, and indirectly via changes to the economic profile of the sending household and through changes to mothers' household responsibilities. We test these relationships using data on 2813 mothers aged 18-44 in 2002 and measured in three waves (2002, 2005, 2009) of the Mexican Family Life Survey. We employ a fixed-effect estimation strategy that improves causal attribution of women's wellbeing to spousal residential location. We find evidence of increases in some forms of distress-sadness, crying, difficulty sleeping-when spouses are in the United States but no meaningful increase in depressive symptomology. Though partner emigration shifts several aspects of women's lives in sending households, changes to household resources or time allocation do not account for the moderate shifts in emotional duress associated with spousal absence. Importantly, additional tests reveal that we would observe large and significant associations between spousal migration and mothers' emotional wellbeing using a less rigorous estimation strategy, raising caution about the interpretation of cross-sectional studies evaluating wellbeing in sending homes. PMID- 25498153 TI - Dynamic recruitment of the curvature-sensitive protein ArhGAP44 to nanoscale membrane deformations limits exploratory filopodia initiation in neurons. AB - In the vertebrate central nervous system, exploratory filopodia transiently form on dendritic branches to sample the neuronal environment and initiate new trans neuronal contacts. While much is known about the molecules that control filopodia extension and subsequent maturation into functional synapses, the mechanisms that regulate initiation of these dynamic, actin-rich structures have remained elusive. Here, we find that filopodia initiation is suppressed by recruitment of ArhGAP44 to actin-patches that seed filopodia. Recruitment is mediated by binding of a membrane curvature-sensing ArhGAP44 N-BAR domain to plasma membrane sections that were deformed inward by acto-myosin mediated contractile forces. A GAP domain in ArhGAP44 triggers local Rac-GTP hydrolysis, thus reducing actin polymerization required for filopodia formation. Additionally, ArhGAP44 expression increases during neuronal development, concurrent with a decrease in the rate of filopodia formation. Together, our data reveals a local auto regulatory mechanism that limits initiation of filopodia via protein recruitment to nanoscale membrane deformations. PMID- 25498156 TI - Mechanistic study of carvacrol processing and stabilization as glassy solid solution and microcapsule. AB - Essential oils and other liquid active pharmaceutical ingredients (APIs) are frequently microencapsulated to improve shelf life, handling, and for tailoring release. A glassy solid solution (GSS), a single-phase system, where the excipient is plasticized by the API, could be an alternative formulation system. Thus this study focuses on the investigation of two formulation strategies using carvacrol as a model compound, namely a microcapsule (MC) and a glassy solid solution (GSS). Applying the solubility parameter approach, polyvinylpyrrolidone (PVP) was chosen as a suitable matrix material for a GSS system, whereas maltodextrin and sucrose served as excipients for a microcapsule (MC) system. Differential scanning calorimetry (DSC) measurements of the excipients' glass transition temperatures and the melting point of carvacrol verified plasticizing properties of carvacrol on PVP. Batch mixing processes, as preliminary experiments for future extrusion processes, were performed to prepare GSSs and MCs with various amounts of carvacrol, followed by crushing and sieving. Maximally 4.5% carvacrol was encapsulated in the carbohydrate material, whereas up to 16.3% were stabilized as GSS, which is an outstanding amount. However, grinding of the samples led to a loss of up to 30% of carvacrol. PMID- 25498157 TI - Personalised dosing: Printing a dose of one's own medicine. AB - Ink-jet printing is a versatile, precise and relatively inexpensive method of depositing small volumes of solutions with remarkable accuracy and repeatability. Although developed primarily as a technology for image reproduction, its areas of application have expanded significantly in recent years. It is particularly suited to the manufacture of low dose medicines or to short production runs and so offers a potential manufacturing solution for the paradigm of personalised medicines. This review discusses the technical and clinical aspects of ink-jet printing that must be considered in order for the technology to become widely adopted in the pharmaceutical arena and considers applications in the literature. PMID- 25498158 TI - Detection of Chlamydia trachomatis infection in patients seen at a sexually transmitted infection clinic. PMID- 25498159 TI - Primary angiomatoid melanoma as an exceptional morphologic pattern in cutaneous melanoma. A case report and review of the literature. AB - We report a case of angiomatoid melanoma on the right thigh of a 59-year-old man. The histologic growth pattern of the tumor mimicked vascular proliferation, and the cells lining the pseudovascular spaces were positive for protein S-100, HMB 45, and MITF-1. The differential diagnosis is with angiosarcoma and pseudovascular adenoid squamous cell carcinoma. The case we present is the fifth reported to date. PMID- 25498160 TI - Sarcopenia is a prognostic factor for overall survival in patients with critical limb ischemia. AB - BACKGROUND: Sarcopenia has been proposed as a prognostic factor for various diseases. Patients with critical limb ischemia (CLI) have a very poor prognosis, but sarcopenia has not been reported as a prognostic factor for CLI patients. If sarcopenia is associated with the prognosis of CLI patients, it could help select the treatment plan. Therefore, we examined whether sarcopenia is a prognostic factor for CLI patients. METHODS: We performed a retrospective study of CLI patients diagnosed with Fontaine III or IV peripheral artery disease who underwent preoperative computed tomography imaging and revascularization between January 2002 and December 2009. The presence of sarcopenia was defined as skeletal muscle area of <114.0 cm(2) for men or <89.8 cm(2) for women using transverse computed tomography scans at the third lumbar vertebra. We compared the 5-year survival rate and clinical characteristics between patients with or without sarcopenia. We also screened possible prognostic factors for overall survival using hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Of 64 eligible patients, 28 patients had sarcopenia and 36 did not. There were significant differences in age, skeletal muscle area, body mass index, and the presence of smoking, cerebrovascular disease, and hemodialysis between patients with and without sarcopenia (all P < .05). The 5-year survival rate was significantly lower in patients with sarcopenia (23.5% vs 77.5%, P = .001). Prognostic factors for overall survival were the presence of sarcopenia (HR, 3.22; 95% CI, 1.24-9.11; P = .02), requirement for hemodialysis (HR, 4.30; 95% CI, 1.60-12.2; P = .004), and postoperative complications (HR, 5.02; 95% CI, 1.90 13.7; P = .001). CONCLUSIONS: Our results suggest that sarcopenia is a prognostic factor for CLI patients. Exercise and nutritional interventions focusing on improving sarcopenia might be useful treatment options for CLI patients. PMID- 25498161 TI - Modest utility of quantitative measures in (18)F-fluorodeoxyglucose positron emission tomography scanning for the diagnosis of aortic prosthetic graft infection. AB - BACKGROUND: The clinical dilemma in suspected aortic graft infection (AGI) is how to noninvasively obtain a reliable proof of infection. In addition to confirming the presence of infection, obtaining information regarding the extent of infection to select a proper strategy for reoperation is also necessary. Therefore, developing a more reliable noninvasive physiologic approach to detect infected prostheses is required. (18)F-fluorodeoxyglucose positron emission tomography scanning ((18)F-FDG PET) has been suggested to have a pivotal role in the detection of AGI. In this study, we assessed the contribution of two (semi) quantitative parameters-maximal standardized uptake value (SUVmax) and tissue-to background ratio (TBR)-and of two visual parameters-fluorodeoxyglucose (FDG) distribution patterns and visual grading scale-in the final confirmation of the diagnosis of AGI. METHODS: Patients with a central aortic prosthetic graft and symptoms clinically suggestive of AGI were gathered from a prospectively maintained database. Included were those who underwent (18)F-FDG PET scanning combined with computed tomography angiography and in whom periprosthetic samples were taken at some stage in the diagnostic process. AGI was considered proven in case of a positive culture and compared with a group with negative cultures. Positive predictive values (PPVs) and negative predictive values (NPVs) were calculated. Receiver operating characteristics curves were used to assess the ability of SUVmax and TBR to identify the presence and absence of AGI (ie, accuracy). RESULTS: In 37 of 77 patients with suspected AGI, (18)FDG-PET and perigraft material for culturing was obtained. The tissue culture was positive in 21 of these 37 patients (56.7%). Mean +/- standard deviation SUVmax for proven infection was 8.1 +/- 3.7 (range, 3.6-18.5) and TBR was 5.9 +/- 2.7 (range, 1.7 13.0). The area under the curve for SUVmax was 0.78 (95% confidence interval, 0.63-0.93). A cutoff value of 8 yielded a PPV of 80% and a NPV of 54%. The area under the curve for TBR was 0.70 (95% confidence interval, 0.52-0.87). A cutoff value of 6 yielded a PPV of 73% and NPV of 52%. The PPVs for the visual grading scale and (18)F-FDG distribution patterns were 75% and 61%, respectively; the NPVs were 77% and 67%, respectively. CONCLUSIONS: Our study, performed in a small sample of patients suspected of AGI, showed that the diagnostic abilities of quantitative and visual (18)F-FDG PET parameters are modest. PMID- 25498162 TI - Embolization treatment of pseudoaneurysms originating from the external carotid artery. AB - OBJECTIVE: The purpose of this study was to review a single-institution contemporary experience with embolization treatment of pseudoaneurysms (PAs) from the external carotid artery (ECA). METHODS: From December 2000 to June 2014, PAs in the head and neck of 17 patients underwent embolization treatment and were retrospectively evaluated. All were treated with obliteration of the feeding artery or the PA by detachable coils or fibered coils, or both. Clinical follow up was a mean of 91.9 months (range, 4-173 months) and was performed for all patients. Therapeutic outcomes were determined by evaluating the postprocedural image and clinical outcome of symptoms and signs. RESULTS: The 17 consecutive patients with head and neck PAs who underwent coils embolization treatment consisted of 14 male patients (82.3%) and three female patients (17.7%). The average age was 37.5 years (range, 16-57 years). The most common symptom and sign was a pulsatile mass, seen in 15 of 17 patients, and other symptoms included pain (three patients) or bleeding (four patients). Digital substraction angiography revealed that the PAs originated from the ECA in 3 patients and others originated from the branches of the ECA, including the superficial temporal artery in 6 patients, internal maxillary artery in 4, superior thyroid artery in 2, and the facial artery and posterior auricular artery in 1. Seventeen coils embolizations for occlusion of the parent artery were performed in 14 patients with a transarterial approach and in three by direct percutaneous puncture. All patients remained symptom free, and no procedure-related complications occurred. CONCLUSIONS: Embolization treatment of PAs from the ECA is a useful alternative to standard surgical repair. This modality avoids the necessity for surgical exposure of the face and of the neck with its inherent morbidity. PMID- 25498163 TI - Changes in quantity, spending, and nutritional characteristics of adult, adolescent and child urban corner store purchases after an environmental intervention. AB - OBJECTIVES: The purpose of this study was to assess one-year changes in corner store purchases (nutritional characteristics, amount spent) of children, adolescents, and adults in a low-income urban environment before and after implementing an environmental intervention to increase the availability of healthier products. METHODS: Corner store owners were provided tools (trainings, signage, refrigeration) to increase the promotion and availability of several healthy foods. Based on the degree of support provided, stores were classified as "basic" or "high-intensity" intervention stores. Data on purchases and their nutrient content were gathered (n = 8671 at baseline, n = 5949 at follow-up) through customer purchase assessment interviews and direct observation outside of 192 corner stores in Philadelphia from March 2011 to August 2012. RESULTS: At baseline, shoppers spent $2.81 +/- 3.52 for 643 +/- 1065 kcal. Energy, select nutrients, and the total amount spent did not significantly change in the overall sample from baseline to follow-up. Similarly, there was no effect on energy and nutrient content when comparing changes over time between basic and high intensity stores. CONCLUSIONS: There were no significant changes in the energy or nutrient content of corner store purchases one year after implementation of environmental changes to increase the availability of healthier products. PMID- 25498164 TI - Autoxidated linolenic acid inhibits aflatoxin biosynthesis in Aspergillus flavus via oxylipin species. AB - Aflatoxins produced by Aspergillus species are among the most toxic and carcinogenic compounds in nature. Although it has been known for a long time that seeds with high oil content are more susceptible to aflatoxin contamination, the role of fatty acids in aflatoxin biosynthesis remains controversial. Here we demonstrate in A. flavus that both the saturated stearic acid (C18:0) and the polyunsaturated linolenic acid (C18:3) promoted aflatoxin production, while C18:3, but not C18:0, inhibited aflatoxin biosynthesis after exposure to air for several hours. Further experiments showed that autoxidated C18:3 promoted mycelial growth, sporulation, and kojic acid production, but inhibited the expression of genes in the AF biosynthetic gene cluster. Mass spectrometry analyses of autoxidated C18:3 fractions that were able to inhibit aflatoxin biosynthesis led to the identification of multiple oxylipin species. These results may help to clarify the role of fatty acids in aflatoxin biosynthesis, and may explain why controversial results have been obtained for fatty acids in the past. PMID- 25498165 TI - Ultimate mimicry: methamphetamine-induced pseudovasculitis. PMID- 25498166 TI - Secondary kwashiorkor: a rare complication of gastric bypass surgery. PMID- 25498167 TI - Quality improvement process in a sickle cell infusion center. AB - BACKGROUND: The American Pain Society recommends that individuals experiencing sickle cell crisis receive parenteral pain medication within 30 minutes of assessment. We examined factors affecting achievement of this standard at the Johns Hopkins Sickle Cell Infusion Center. METHODS: Baseline patient care time intervals and data on variables affecting the ability to achieve the American Pain Society goal were measured. Time to first parenteral opiate administration was modeled using simple and multivariable linear regression. RESULTS: Mean time from initial assessment to first dose was initially 41 minutes. Increased nurse to patient ratio decreased time to first dose. CONCLUSIONS: Of the factors associated with improved times to first dose, only nurse to patient ratio is amenable to process change, suggesting it as a potential target for future interventions. PMID- 25498168 TI - Senile cardiac amyloidosis: an undervalued cause of heart failure. PMID- 25498169 TI - Angiosarcoma of the bladder following prostate radiotherapy. PMID- 25498170 TI - [In Process Citation]. PMID- 25498171 TI - ["Cardiac packages" for garden gnomes]. AB - Garden gnomes tend to be obese, to smoke and to be physically inactive. Further, they are often socioeconomically deprived which adversely influences the risk and prognosis of cardiovascular disease. It is likely that garden gnomes will not benefit from the "cardiac packages", describing how Danish patients supposed to suffer from cardiovascular disease are entitled to timely and structured assessment in outpatient departments. This paper suggests that cardiovascular assessment and rehabilitation of garden gnomes must address their sociocultural needs (such as targeted dietary counselling). This is probably best achieved by special outreach clinics. PMID- 25498172 TI - [The magic bubbles of champagne]. AB - The effervescence of champagne is due to 4.8 l of CO2-gas dissolved at a pressure of five bars. The velocity of an uncontrolled cork (60 km/h) may cause serious eye injuries. The fizz of champagne is mediated by carbonic anhydrase IV located in the membrane of sour-sensing cells. The association between alcohol intake, cardiovascular disease and all-cause mortality follows a J-shaped curve with the nadir at consumption levels of one drink/day. Polyphenols present in champagne increase spatial working memory in aged rodents and induce a neuroprotective effect against oxidative neuronal injury. PMID- 25498173 TI - [Difficulties in the IT solutions of the Danish health-care system]. AB - INTRODUCTION: The IT solutions of the Danish health-care system have been under criticism. Especially the time spent on login. We examined if the daily recommended pelvic floor muscle training could be achieved during login. METHODS: Login time was measured on five laptops used in daily care in a hospital. Time to conduct pelvic floor training was measured in six volunteers. RESULTS: Median login time/day was 77 minutes and four seconds, and median time to complete exercises was 35 minutes and 14 seconds. CONCULSION: The hypothesis was verified, and further studies to optimize time spent on login are recommended. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25498174 TI - [One in five surgeons do not wash hands after visiting a toilet - an ethnographic field study]. AB - INTRODUCTION: Non-compliance with regard to hand hygiene is a major problem in the health-care system especially among surgeons and anaesthetists. The purpose of this study was to examine the hand hygiene routines after toilet visits among participants attending an international surgical congress. METHODS: An observational study was conducted at the American College of Surgeons (ACS) Clinical Congress 2012 and at the American Medical Writers Association (AMWA) Congress 2012 as comparison. The study was performed as an ethnographic field study. A standardized observational matrix was developed for observing whether hand washing (as a surrogate measure of hand hygiene) was performed after toilet visits by observers. Frequencies were compared using Fisher's exact test. RESULTS: A total of 100 persons were observed (80% males). Of the 50 males observed at the ACS meeting, ten males did not use hand hygiene in relation to toilet visits (20%), while only one person at the AMWA meeting out of the 50 observed did not use hand hygiene (2%), p = 0.008. At both congresses only males did not use hand hygiene in relation to toilet visits. CONCLUSION: One in five surgeons did not wash hands after visiting a toilet. Even though the observed surgeons were not observed in an operating theatre or in a setting that required a distinct degree of hand hygiene, it does reveal a worrying behaviour. It is not known whether this was a conscious act, the result of business, or if it was due to lack of knowledge about the effects of hand hygiene on bacterial transmission. FUNDING: not relevant. TRIAL REGISTRATION: This study was neither registered at the National Committee of Health Research nor at Clinical Trials since it did not meet the requirements of registration. PMID- 25498175 TI - [Classification of duties in surgical wards]. AB - INTRODUCTION: Night duties in surgical wards can be demanding physically and mentally. Staffing the emergency room, performing emergency operations and taking care of the admitted patients are only few of surgeons' tasks during these busy duties. Night duties can have different effects on the following day/days tasks, limiting some of the leisure activities and maybe life quality. Literature search, however, shows few studies about the subject. The aim of this study was twofold: to study the effects of night duties on the general health of surgeons and to classify duties according to these effects. METHODS: Retrospective study based on modified Short Form Survey (SF)-12. Questionnaire forms were sent to all surgeons in the surgical department at Hvidovre Hospital. RESULTS: The questionnaire forms were sent to 64 surgeons and 38 answered (59.4%). The highest response rate was in the residents group (71.9%: 23/32), senior residents group (70%: 7/10) and the lowest rate in consultants group (36.4%: 8/22). CONCLUSION: Night duties have no significant effect on surgeons' general health. There is a trend, however, that these duties have an effect on hard physical and/or mental activities in the following day especially for female surgeons. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25498176 TI - [Sengeredning]. PMID- 25498177 TI - [Standard ballpoint pens disappear from the coats with a half-life of nine days]. AB - Ballpoint pens are important tools for the daily work of the physicians. However, a practical challenge seems to be that they disappear just when one needs them most. We call this the ballpoint pen paradox. We have studied the fate of 60 ballpoint pens in an outpatient clinical setting. Five physicians, five nurses and five medical secretaries were equipped with four barcode-tagged ballpoint pens. During follow-ups, we systematically searched the participants' coat and the department for the barcode-tagged ballpoint pens. We illustrated the migration of the ballpoint pens using a diagram and tested fit of linear and exponential trend line. The ballpoint pens displayed a tremendous migration in the department. Disappearance from the coat was exponentially with a half-life of 9 days - only 23% were left after 18 days. Disappearance from the department was linear with a 3% loss per day - only 42% were left after 18 days. Ballpoint pens have a high migration and turnover rate. The fate is unknown for a great amount of ballpoint pens. They are treated carelessly, which finally results in waste of time and resources. It may be that the ballpoint pen paradox can be diminished by phasing out ballpoint pens of low quality. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25498179 TI - [Cinnamon rolls are not associated with admission for toxic or alcoholic hepatitis in a Danish liver referral centre]. AB - INTRODUCTION: Cinnamon contains cumarin, which may be toxic to the liver. EU regulations standardardize the amount of cinnamon in pastry including cinnamon rolls. The aim of the study was to investigate if cinnamon intake from pastry was associated with toxic or alcoholic hepatitis. RESULTS: We registered 58 patients with toxic hepatitis, 38 (66%) women and 20 (34%) men with a median age of 51 (range: 32-80) and 53 (range: 18-78) years, respectively. A total of 22 patients had primarily cholestasis and 36 had hepatitis biochemically. The duration of toxic liver disease from admission to normalization of liver enzymes was similar in the two groups (3.5 +/- 3.5 vs 3.6 +/- 3.5 months). Toxic hepatitis was most often caused by drugs e.g. NSAID (n = 15; 26%), antibiotics (n = 9; 16%), alternative medicine (n = 7; 12%) and Antabuse (n = 5; 9%). We registered eight patients admitted with severe alcoholic hepatitis, five men and three women, median age of 60 (range: 34-67) years. Alcoholic hepatitis was associated with high alcohol intake. None of the patients with toxic or alcoholic hepatitis reported of excessive intake of cinnamon rolls and there was no evidence of cinnamon added to alcohol of alternative medicine products. CONCLUSION: Intake of cinnamon from cinnamon rolls is not associated with admission for toxic or alcoholic hepatitis. However, for the diagnosis of toxic liver diseases including alcohol it is very important to have patient information regarding any new drugs, alternative medicine and alcohol intake. Further, other causes of liver diseases should be excluded. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25498178 TI - [Infectious disease doctors also contract travellers' diarrhoea]. AB - INTRODUCTION: Acute infectious diarrhoea is common in travellers. The aim of this study was to examine the incidence of travellers' diarrhoea in a group of Danish doctors and to identify exposures that may confer protective benefits. METHODS: A total of 19 Danish infectious disease doctors, pediatricians and clinical microbiologists received a questionnaire regarding symptoms of infectious diarrhoea after a journey to Myanmar. The association between exposure and outcome was calculated as a relative risk. RESULTS: The occurence of travellers' diarrhoea was independent of medical specialty and age. Doxycycline prophylaxis was a significant protective factor and high intake of yogurt seemed also to confer protection, albeit not significantly. No protective benefits were found from avoidance of ice cubes, raw salad or the use of hand sanitizer. Self medication with antibiotics was associated with female sex, high age, previous travel experience, employment in the eastern part of Denmark and medical specialty other than infectious diseases, although not significant. DISCUSSION: Infectious disease doctors have a similar incidence of travellers' diarrhoea as others. Only a few intended to use common travel advice regarding food and drinks and no effect was shown. The reduced risk conferred by yogurt can be caused by the effect of live probiotics on diarrhoea pathogenesis. The reasons why the use of antibiotics was associated with sex, employment region and medical specialty are unaccounted for and should be interpreted with caution because of lack of statistical significance. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 25498180 TI - [Love bite on the neck resulted in an embolic stroke]. AB - A 35-year-old woman experienced sudden onset of right-sided weakness due to a left middle cerebral artery stroke 12 hours after she had obtained a love bite on the left side of her neck. Duplex ultrasonography showed a near-occlusion of the left internal carotid artery (ICA) and CT angiography revealed a mural thrombus at the same location. This case report shows that love bites on the neck are a rare cause of embolic stroke. The most likely aetiology is embolization of thrombus material from a local intimal lesion of the ICA. PMID- 25498181 TI - [Recurrent periods of respiratory tract infections in a 22-year-old]. AB - A 22-year-old male with recurrent periods of coughing and nasal discharge was unable to work and cooperate. A bronchoscopy revealed high amounts of leucocytes and no eosinofils, acute inflammation and > 105/ml Streptococcus pneumoniae susceptible to penicillin. The symptoms relapsed after penicillin and at the age of 24 the patient was CT-scanned which revealed bilateral sinusitis, mastoiditis and bronchiectasis. Treatment with azithromycin and a weight loss programme (from 156 kg) improved the health of the patient, who was an orangutan. This highlights the benefit of cooperation between medical doctors and veterinarians. PMID- 25498182 TI - [Mnemonics are useful memory tools in modern medicine]. AB - Mnemonics are useful memory tools in medical school and during clinical work. They serve to learn, consolidate or recall information. Different types of mnemonics exist. The most commonly used are acronyms or alphabetical types (e.g. RICE in case of soft tissue injury or ABC in acute situations), though other types such as visual mnemonics or the method of loci are possibly more effective. Memory techniques work because they apply other routes to remembering than traditional learning. They often link information to well-known knowledge and sometimes they appeal to humour or feelings. PMID- 25498183 TI - [How to make a budget for fund applications]. AB - There has been an enhanced focus on the use of foundation grants in the past year. This article gives an example on how to make a budget for fund applications. PMID- 25498184 TI - [Spontaneous bilateral quadriceps tendon rupture in obese patient medicated with statin]. AB - Bilateral quadriceps tendon rupture (BQTR) is a rare diagnosis only reported in about 100 cases in international literature, and is often associated with medical diseases, trauma or certain medications. We present a 64-year-old man with spontaneous BQTR, diagnosed and treated at our hospital. His risk factors were obesity (BMI = 30.95 kg/m2), statin use, and recreational tennis at time of injury. The diagnosis of BQTR is difficult and is often missed initially. There is also emerging thoughts that the use of statins may be a risk factor for BQTR. The evidence, however, is scarce. PMID- 25498185 TI - [Active surveillance is a useful strategy in the management of patients with low risk prostate cancer]. AB - Radical prostatectomy has in randomised settings failed to demonstrate a survival difference in patients with low-risk prostate cancer when tested against an observational strategy. Active surveillance has been introduced in order to reduce overtreatment by distinguishing between cancers with a biological potential, and truly indolent cancers best left untreated. Preliminary results from large prospective active surveillance cohorts are promising; however, uncertainties persist concerning optimal patient selection and follow-up, as well as the long-term safety. PMID- 25498186 TI - [Congenital trans-mesenteric hernia with incarceration in a five-year-old boy]. AB - This is a case report of a five-year-old boy, presenting with abdominal pain and signs of gastrointestinal emergency imitating appendicitis. Diagnostic laparoscopy revealed an incarcerated internal hernia involving 50 cm of ischaemic small bowel. Bowel resection and primary anastomosis was performed. The post operative outcome was uneventful. We wish to shed light on a seldom but important differential diagnosis to appendicitis in children, and raise attention to internal hernias in patients presenting with acute abdomen, whether it is due to congenital defects or a post-operative complication. PMID- 25498187 TI - [Endoscopic ultrasound-guided coeliac plexus neurolysis to reduce pain in patients with pancreatic cancer]. AB - Pain is among the most common symptoms in patients with pancreatic cancer and up to 80% require analgesics, most often as opioids. Unfortunately the analgesic effect is frequently insufficient, and increasing doses are required, resulting in unpleasant side effects. Endoscopic ultrasound-guided neurolysis is a well established method to alleviate or reduce pain due to pancreatic cancer with a documented effect in 80% of patients. The aim of this review is to draw attention to endoscopic ultrasound-guided neurolysis and to discuss its potential which may not be fully utilized. PMID- 25498188 TI - [Pasteurella multocida meningitis secondary to functional endoscopic sinus surgery]. AB - Functional endoscopic sinus surgery (FESS) is a common, surgical procedure in Danish ear-nose-throat departments. Surgery is often performed as an outpatient procedure. Major complications are rare, however, they may develop after the patient has been discharged. This is a case report of Pasteurella multocida meningitis secondary to FESS in a 54-year-old male. PMID- 25498189 TI - [Pulmonary cystic disease may be a rare complication to recurrent respiratory human papilloma virus infection]. AB - A 19-year-old woman with a history of juvenile laryngeal papillomatosis (JLP), treated since childhood with multiple resections, was admitted with symptoms of pneumonia. A chest X-ray and CAT-scan revealed multiple lung cysts and a bronchoalveolar lavage detected human papilloma virus 11. The patient responded well to antibiotics. A body plethysmography showed small lung volumes and low diffusion capacity for carbon monoxide, but normal volume diffusion capacity divided by alveolar volume. Pulmonary cystic disease should be considered when patients with JLP have symptoms of pneumonia. PMID- 25498190 TI - [Challenges for health-care professionals in the treatment of ethnic minorities with type 2 diabetes]. AB - This literature review describes health-care professionals' perspective on roles and approaches in encounters with ethnic minorities with type 2 diabetes, including perceived barriers and potentials. They shift between roles in encounters with ethnic minority patients and they consider language and cultural barriers to have an impact on roles, communication as well as time consumption. They emphasise the importance of patient-centeredness and insight into patients' cultural background; however, they report lack of competences to provide good quality in diabetes care to ethnic minority patients. PMID- 25498191 TI - Meta-analysis of the effects of statins on perioperative outcomes in vascular and endovascular surgery. AB - BACKGROUND: Compelling evidence from large randomized trials demonstrates the salutary effects of statins on primary and secondary protection from adverse cardiovascular events in high-risk populations. Our objective was to investigate the role of perioperative statin therapy in noncardiac vascular and endovascular surgery. METHODS: Electronic information sources were systematically searched to identify studies comparing outcomes after noncardiac surgical or endovascular arterial reconstruction in patients who were and were not taking statin in the perioperative or peri-interventional period. The Cochrane Collaboration's tool and the Newcastle-Ottawa scale were used to assess the methodologic quality and risk of bias of the selected studies. Random-effects models were applied to calculate pooled outcome data. RESULTS: Four randomized controlled trials and 20 observational cohort or case-control studies were selected for analysis. The randomized studies enrolled 675 patients, and the observational studies enrolled 22,861 patients. Statin therapy was associated with a significantly lower risk of all-cause mortality (odds ratio [OR], 0.54; 95% CI, [CI], 0.38-0.78), myocardial infarction (OR, 0.62; 95% CI, 0.45-0.87), stroke (OR, 0.51; 95% CI, 0.39-0.67), and the composite of myocardial infarction, stroke, and death (OR, 0.45; 95% CI, 0.29-0.70). No significant differences in cardiovascular mortality (OR, 0.82; 95% CI, 0.41-1.63) and the incidence of kidney injury (OR, 0.90; 95% CI, 0.58-1.39) between the groups were identified. CONCLUSIONS: Our analysis demonstrated that statin therapy is beneficial in improving operative and interventional outcomes and should be considered as part of the optimization strategy for prevention of adverse cardiovascular and cerebrovascular events and death. PMID- 25498192 TI - Altered microRNA expression in stenoses of native arteriovenous fistulas in hemodialysis patients. AB - OBJECTIVE: Arteriovenous fistula (AVF) disfunction is largely due to venous stenosis characterized by a marked amount of intima-media hyperplasia. However, the molecular mechanisms are currently poorly understood. MicroRNAs (miRNAs), small noncoding RNAs that are post-transcriptional regulators of gene expression, could provide insights into a mechanism for the differential expression of genes in stenotic AVFs. METHODS: A microarray study was done to detect differences in miRNA levels between stenotic AVF (n = 8) and controls (n = 4). Real-time quantitative reverse-transcription polymerase chain reaction assays with 12 stenotic AVF veins and eight control veins from predialytic patients were used for verification. Putative gene targets were retrieved from miRNA target prediction databases. Networks from the target gene set were created and examined. Western blotting and immunohistochemical staining were performed to confirm the bioinformatic findings. RESULTS: A microarray study identified 33 miRNAs with markedly different expression levels between stenotic AVFs and control veins. Among them, nine miRNAs were upregulated and 24 miRNAs were downregulated in the stenotic AVFs. Real-time reverse-transcription polymerase chain reaction confirmed statistically consistent expression of six selected miRNAs with microarray analysis. The predicted miRNA target genes differentially expressed in stenotic AVF based on databases were identified. The mitogen activated protein kinase signaling pathway might be regulated by miRNAs according to bioinformatic analyses and further confirmed by Western blotting and immunohistochemical staining. CONCLUSIONS: Our genome-wide approach identified several differentially expressed miRNAs in stenotic AVFs. This study also suggested that the mitogen-activated protein kinase signaling pathway might play a role in the pathogenesis of stenotic AVF. PMID- 25498193 TI - Outcome of the FUSION vascular graft for above-knee femoropopliteal bypass. AB - OBJECTIVE: Although endovascular procedures have become popular for the treatment of patients with femoropopliteal occlusive disease, open surgical bypass is still required in a significant proportion of patients. Saphenous vein is the conduit of choice, but prosthetic bypass grafts are often necessary. The Peripheral Bypass Grafting: Prospective Evaluation of FUSION Vascular Graft for Above Knee Targets (PERFECTION) trial was performed to assess the clinical outcome of the FUSION vascular graft (Maquet Cardiovascular, Wayne, NJ), a novel bilayer prosthetic graft with an external expanded polytetrafluoroethylene inner layer and an outer knit polyester layer. METHODS: Eligible study patients included those requiring prosthetic femoral-to-above-knee popliteal bypass for claudication, rest pain, or localized tissue loss without wet gangrene. During a 30-month period ending in March 2012, 117 patients were enrolled in the PERFECTION trial and underwent bypass with FUSION vascular grafts at 10 European investigational sites. Patients were followed up with duplex ultrasound imaging and ankle-brachial indices performed at 30 days, 6 months, and 12 months. The primary efficacy end point was 12-month primary patency of the study graft, assessable in 102 patients. Safety end points included all-cause mortality, major adverse events, amputation, and graft reinterventions. RESULTS: The 67 male (57.3%) and 50 female (42.7%) patients averaged 67.8 +/- 8.9 years in age and were implanted with 6-mm (25 [21.4%]), 7-mm (26 [22.2%]), or 8-mm (66 [56.4%]) FUSION grafts. The 30-day primary graft patency was 95.3%, with five graft occlusions in the perioperative period. The 12-month primary rate was 85.6%, and the secondary patency rate was 93.2%. Ankle-brachial indices increased from a mean of 0.53 +/- 0.20 preoperatively to 0.97 +/- 0.16 at 30 days and 0.91 +/- 0.22 at 12 months. There were no major amputations through 12 months of follow up, 15 patients (12.8%) had graft reinterventions, one patient (0.9%) developed a graft infection, and five patients (4.3%) died of unrelated causes. CONCLUSIONS: The findings of the prospective, multicenter PERFECTION study confirm clinical utility of the FUSION vascular graft through 12 months of follow-up. Patency rates equal or exceed those reported with other nonbioactive vascular grafts. These observations suggest that the FUSION graft is a useful alterative to standard expanded polytetrafluoroethylene grafts and should be considered as an option in patients requiring prosthetic femoral-to-above-knee popliteal arterial reconstruction. PMID- 25498194 TI - Targeting sterol metabolism for the development of antileishmanials. AB - Membrane sterol profiles differ between humans and Leishmania parasites, and the sterol pathway has been investigated for potential therapeutic targets. Recently, mutants of the C14alpha-sterol demethylase in Leishmania major were found to have several major alterations such as increased membrane fluidity, hypersensitivity to heat stress, and severe reduction of virulence. PMID- 25498195 TI - Can one hear the shape of a population history? AB - Reconstructing past population size from present day genetic data is a major goal of population genetics. Recent empirical studies infer population size history using coalescent-based models applied to a small number of individuals. Here we provide tight bounds on the amount of exact coalescence time data needed to recover the population size history of a single, panmictic population at a certain level of accuracy. In practice, coalescence times are estimated from sequence data and so our lower bounds should be taken as rather conservative. PMID- 25498196 TI - Feasibility and efficacy of simultaneous integrated boost intensity-modulated radiation therapy in patients with limited-disease small cell lung cancer. AB - PURPOSE: To evaluate the feasibility and efficacy of simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) in patients with limited disease small-cell lung cancer (LD-SCLC). METHODS: Patients with LD-SCLC were treated with SIB-IMRT within 1 week after completion of 2 cycles of induction chemotherapy. Then 2-4 cycles of adjuvant chemotherapy were administered within 1 week after SIB-IMRT. Irradiation was given accelerated hyper-fractionated with the prescribed dose 57Gy at 1.9Gy twice daily to the gross tumor volume (GTV) , 51Gy at 1.7Gy twice daily to the clinical tumor volume (CTV) and 45Gy at 1.5Gy twice daily to the planning target volume (PTV). The chemotherapy regimen consisted of platinum plus etoposide. Prophylactic cranial radiation (25Gy in 10 fractions) was administered to patients who got complete response (CR) or near complete response (nCR). The primary endpoint of this study was the frequency of grade 3 or higher acute non-hematologic treatment-related toxicities. Secondary end points included objective response, overall survival (OS), progression-free survival (PFS), locoregional recurrence-free survival (LRFS). RESULTS: A cohort of 35 patients were enrolled in the study, the biological equivalent dose (BED) of the GTV in the SIB-IMRT was 59.16Gy. Grade 1, 2, and 3 esophagitis were observed in 11 (31%), 12 (34%), and 6 (17%) patients, respectively; Grade 1 and 2 pneumonitis were observed in 8 (23%) and 4 (11%) patients, respectively. The median OS and PFS of the whole group were 37.7 months and 29.3 months, respectively. The 1- and 2-year OS was 94.1% and 68.5%, respectively. The 1- and 2-year PFS was 76.8% and 40.7%, respectively. The 1- and 2-year LRFS was 87.7% and 73.8%, respectively. CONCLUSIONS: SIB-IMRT was feasible and well-tolerated in patients with LD-SCLC, and worth further evaluating in a large prospective clinical trial. PMID- 25498197 TI - Advances in multifunctional glycosylated nanomaterials: preparation and applications in glycoscience. AB - Applications of glycosylated nanomaterials have gained considerable attention in recent years due to their unique structural properties and compatibility in biological systems. In this review, glyco-nanoparticles (glyco-NPs) are defined as compounds that contain a nano-sized metallic core, are composed of noble metals, magnetic elements, or binary inorganic nanoparticles, and that exhibit carbohydrate ligands on the surface in three dimensional polyvalent displays similar to the glycocalyx structures on cell membranes. Nanomaterials decorated with suitable biological recognition ligands have yielded novel hybrid nanobiomaterials with synergistic functions, especially in biomedical applications. This review focuses on strategies for building various types of glyco-NPs and highlights their potential in targeted drug delivery and molecular imaging as well as their uses in bioassays and biosensors. The most recent examples of glyco-NPs as vaccine candidates and probes for assaying enzymes with bond-forming activities are also discussed. PMID- 25498198 TI - Heparin nanoparticles for beta amyloid binding and mitigation of beta amyloid associated cytotoxicity. AB - Accumulation of beta amyloid (Abeta) in the brain is believed to play a key role in the pathology of Alzheimer's disease. Glycosaminoglycans on surface of neuronal cells can serve as nucleation sites to promote plaque formation on cell surface. To mimic this process, magnetic nanoparticles coated with heparin have been synthesized. The heparin nanoparticles were demonstrated to bind with Abeta through a variety of techniques including enzyme-linked immunosorbent assay, gel electrophoresis, and thioflavin T assay. The nanoparticle exhibited little toxicity to neuronal cells and at the same time can effectively protect them from Abeta induced cytotoxicity. These results suggest that heparin nanoparticles can be a very useful tool for Abeta studies. PMID- 25498199 TI - Synthesis and characterisation of glucose-functional glycopolymers and gold nanoparticles: study of their potential interactions with ovine red blood cells. AB - Carbohydrate-protein interactions can assist with the targeting of polymer- and nano-delivery systems. However, some potential protein targets are not specific to a single cell type, resulting in reductions in their efficacy due to undesirable non-specific cellular interactions. The glucose transporter 1 (GLUT 1) is expressed to different extents on most cells in the vasculature, including human red blood cells and on cancerous tissue. Glycosylated nanomaterials bearing glucose (or related) carbohydrates, therefore, could potentially undergo unwanted interactions with these transporters, which may compromise the nanomaterial function or lead to cell agglutination, for example. Here, RAFT polymerisation is employed to obtain well-defined glucose-functional glycopolymers as well as glycosylated gold nanoparticles. Agglutination and binding assays did not reveal any significant binding to ovine red blood cells, nor any haemolysis. These data suggest that gluco-functional nanomaterials are compatible with blood, and their lack of undesirable interactions highlights their potential for delivery and imaging applications. PMID- 25498201 TI - Multivalent glycocyclopeptides: toward nano-sized glycostructures. AB - Cyclopeptides have recently emerged as attractive molecular scaffolds for the multivalent presentation of carbohydrates in a well-defined constrained spatial orientation. This mini-review describes the last advances on the synthesis and the biological applications of these particular structures, going from low molecular weight glycoclusters to fully synthetic nano-sized glycodendrimers. PMID- 25498200 TI - Polysaccharide-based nanocomposites and their applications. AB - Polysaccharide nanocomposites have become increasingly important materials over the past decade. Polysaccharides offer a green alternative to synthetic polymers in the preparation of soft nanomaterials. They have also been used in composites with hard nanomaterials, such as metal nanoparticles and carbon-based nanomaterials. This mini review describes methods for polysaccharide nanocomposite preparation and reviews the various types and diverse applications for these novel materials. PMID- 25498202 TI - Galactose grafting on poly(epsilon-caprolactone) substrates for tissue engineering: a preliminary study. AB - The grafting of galactose units onto poly(epsilon-caprolactone) (PCL) substrates by a wet chemistry two-step procedure is proposed. Even though a reduction of hardness from 0.58-0.31 GPa to 0.12-0.05 GPa is achieved, the chemical functionalization does not negatively affect the tensile modulus (332.2+/-31.3 MPa and 328.5+/-34.7 MPa for unmodified and surface-modified PCL, respectively) and strength (15.1+/-1.3 MPa and 14.8+/-1.5 MPa as assessed before and after the surface modification, respectively), as well as the mechanical behaviour evaluated through small punch test. XPS and enzyme-linked lectin assay (ELLA) demonstrate the presence, and also the correct exposition of the saccharidic epitope on PCL substrates. The introduction of carbohydrate moieties on the PCL surfaces clearly enhances the hydrophilicity of the substrate, as the water contact angle decreases from 82.1+/-5.8 degrees to 62.1+/-4.2 degrees . Furthermore, preliminary biological analysis shows human mesenchymal stem cell viability over time and an improvement of cell adhesion and spreading. PMID- 25498203 TI - Related structures of the O-polysaccharides of Cronobacter dublinensis G3983 and G3977 containing 3-(N-acetyl-L-alanyl)amino-3,6-dideoxy-D-galactose. AB - Cronobacter spp. are emerging opportunistic human pathogens linked with life threatening infections predominantly in neonates. O-Antigen (O-polysaccharide) is highly variable and plays an important role in virulence and niche adaptation. In this work, short-chain O-polysaccharides consisting on the average of 2-3 repeating units were obtained by mild acid or mild alkaline degradation of the lipopolysaccharides of C. dublinensis G3983 and G3977 and studied by composition analysis, Smith degradation, and (1)H and (13)C NMR spectroscopy. The following structures of the O-polysaccharides were established: [Formula: see text] where R indicates H in strain G3983 or alpha-D-Glcp in strain G3977, d-Fuc3NAlaAc indicates 3-(N-acetyl-L-alanyl)amino-3,6-dideoxy-D-galactose. Both strains share the O-antigen gene cluster, which is identical to that of C. dublinensis O1 (Foodborne Pathog. Dis.2013, 10, 343-352). The assigned gene functions are in agreement with the O-antigen structure of C. dublinensis G3983, and the side chain glucosylation of the O-antigen of C. dublinensis G3977 is evidently encoded elsewhere in the genome. PMID- 25498204 TI - Usefulness of a rotation-revolution mixer for mixing powder-liquid reline material. AB - PURPOSE: The purpose of this study was to evaluate the distribution of bubbles, degree of mixing, flowability and mechanical strength of powder-liquid reline material by manually and with a rotation-revolution (planetary) mixer, and to determine the usefulness of a rotation-revolution mixer for this application. METHODS: Powder-liquid reline material (Mild Rebaron, GC, Tokyo, Japan) was mixed with a powder to liquid ratio of 1:0.62 according to the manufacturer's instruction. Two methods were used to mix it: mixed by manually ("manual-mixing") and automatically with a rotation-revolution mixer (Super Rakuneru Fine, GC, Tokyo, Japan; "automatic-mixing"). Disc-shaped specimens, 30 mm in diameter and 1.0mm in thickness, were used to observe the distribution of bubbles in at 10* magnifications. Flowability tests were carried out according to the JIS T6521 for denture base hard reline materials. A three point bending test was carried out by a universal testing machine. Elastic modulus and flexural stress at the proportional limit were calculated. RESULTS: A median of 4 bubbles and inhomogeneous were observed in manual-mixed specimens. However, no bubbles and homogeneous were observed in automatic-mixed specimens. Flowability was within the JIS range in all mixing conditions and did not differ significantly across conditions. The elastic modulus was the same for manual-mixed and automatic-mixed specimens. On the other hand, the flexural stress at the proportional limit differed significantly between manual-mixed and automatic-mixed specimens. CONCLUSION: The results confirm that rotation-revolution mixer is useful for mixing powder-liquid reline material. Automatic-mixing may be recommended for clinical practice. PMID- 25498205 TI - Dry mouth: a critical topic for older adult patients. AB - PURPOSE: Diminished salivary flow, or dry mouth impacts the oral health of many older adults, dentate and edentulous. As a result typical oral conditions can prove more challenging to both the patient's comfort and home care and the treatment selected by the clinician. This paper will review issues of dry mouth from a clinical and symptomatic perspective and will include the condition's causes, treatment and prevention. STUDY SELECTION: We performed a review of PubMed using the words: older adults, dry mouth, xerostomia, radiation-induced xerostomia, and salivary gland hypofunction. We selected 90 articles with a clinical application perspective. RESULTS: When it comes to treatment of dry mouth conditions, either objective or subjective, there are no easy answers as to the best course of action for a specific individual. While most of the cited studies have examined the most difficult cases of dry mouth (e.g., Sjogren's syndrome, and that seen during and post head and neck cancer treatments), there are many older adults who demonstrate dry mouth from the use of multiple medications. This paper presents a summary of the etiology, diagnosis, prevention, and pharmacological and non-pharmacological treatment of dry mouth (salivary hypofunction and xerostomia in older adults). CONCLUSIONS: It is important to understand the causes of dry mouth and to educate our patients. Starting a prevention program as early as possible considering the most practical, cost effective and efficient treatments with the best risk-benefit ratio will help to diminish dry mouth symptoms and sequelae. PMID- 25498206 TI - Landscape influence on spatial patterns of meningeal worm and liver fluke infection in white-tailed deer. AB - Parasites that primarily infect white-tailed deer (Odocoileus virginianus), such as liver flukes (Fascioloides magna) and meningeal worm (Parelaphostrongylus tenuis), can cause morbidity and mortality when incidentally infecting moose (Alces alces). Ecological factors are expected to influence spatial variation in infection risk by affecting the survival of free-living life stages outside the host and the abundance of intermediate gastropod hosts. Here, we investigate how ecology influenced the fine-scale distribution of these parasites in deer in Voyageurs National Park, Minnesota. Deer pellet groups (N = 295) were sampled for the presence of P. tenuis larvae and F. magna eggs. We found that deer were significantly more likely to be infected with P. tenuis in habitats with less upland deciduous forest and more upland mixed conifer forest and shrub, a pattern that mirrored microhabitat differences in gastropod abundances. Deer were also more likely to be infected with F. magna in areas with more marshland, specifically rooted-floating aquatic marshes (RFAMs). The environment played a larger role than deer density in determining spatial patterns of infection for both parasites, highlighting the importance of considering ecological factors on all stages of a parasite's life cycle in order to understand its occurrence within the definitive host. PMID- 25498207 TI - Molecular deformation mechanisms of the wood cell wall material. AB - Wood is a biological material with outstanding mechanical properties resulting from its hierarchical structure across different scales. Although earlier work has shown that the cellular structure of wood is a key factor that renders it excellent mechanical properties at light weight, the mechanical properties of the wood cell wall material itself still needs to be understood comprehensively. The wood cell wall material features a fiber reinforced composite structure, where cellulose fibrils act as stiff fibers, and hemicellulose and lignin molecules act as soft matrix. The angle between the fiber direction and the loading direction has been found to be the key factor controlling the mechanical properties. However, how the interactions between theses constitutive molecules contribute to the overall properties is still unclear, although the shearing between fibers has been proposed as a primary deformation mechanism. Here we report a molecular model of the wood cell wall material with atomistic resolution, used to assess the mechanical behavior under shear loading in order to understand the deformation mechanisms at the molecular level. The model includes an explicit description of cellulose crystals, hemicellulose, as well as lignin molecules arranged in a layered nanocomposite. The results obtained using this model show that the wood cell wall material under shear loading deforms in an elastic and then plastic manner. The plastic regime can be divided into two parts according to the different deformation mechanisms: yielding of the matrix and sliding of matrix along the cellulose surface. Our molecular dynamics study provides insights of the mechanical behavior of wood cell wall material at the molecular level, and paves a way for the multi-scale understanding of the mechanical properties of wood. PMID- 25498208 TI - Adverse events following vaccination with an inactivated, Vero cell culture derived Japanese encephalitis vaccine in the United States, 2009-2012. AB - BACKGROUND: In March 2009, the U.S. Food and Drug Administration licensed an inactivated, Vero cell culture-derived Japanese encephalitis vaccine (JE-VC [Ixiaro]) for use in adults. The vaccine was licensed based on clinical trial safety data in 3558 JE-VC recipients. It is essential to monitor post-licensure surveillance data to evaluate the safety of JE-VC because rare adverse events may not be detected until the vaccine is administered to a larger population. METHODS: We reviewed adverse events reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) for adults (>=17 years) who received JE-VC from May 2009 through April 2012. Adverse event reporting rates were calculated using 275,848 JE-VC doses distributed. RESULTS: Over the 3 year period, 42 adverse events following vaccination with JE-VC were reported to VAERS for an overall reporting rate of 15.2 adverse events per 100,000 doses distributed. Of the 42 total reports, 5 (12%) were classified as serious for a reporting rate of 1.8 per 100,000 doses distributed; there were no deaths. Hypersensitivity reactions (N=12) were the most commonly reported type of adverse event, with a rate of 4.4 per 100,000 doses distributed; no cases of anaphylaxis were reported. Three adverse events of the central nervous system were reported (one case of encephalitis and two seizures) for a rate of 1.1 per 100,000; all occurred after receipt of JE-VC with other vaccines. CONCLUSIONS: These post-marketing surveillance data suggest a good safety profile for JE-VC consistent with findings from pre-licensure clinical trials. Post-licensure safety data should continue to be monitored for any evidence of rare serious or neurologic adverse events. PMID- 25498209 TI - Preparation of pure, high titer, pseudoinfectious Flavivirus particles by hollow fiber tangential flow filtration and anion exchange chromatography. AB - Purification of enveloped viruses such as live flavivirus vaccine candidates poses a challenge as one must retain viral infectivity to preserve immunogenicity. Here we describe a laboratory-scale purification procedure for two replication defective (single-cycle) flavivirus variants for use in a pre clinical setting. The two step purification scheme based on hollow fiber tangential flow filtration (TFF) followed by anion exchange chromatography using convective interaction media (CIM((r))) monoliths results in a ~60% recovery of infectious virus titer and can be used to prepare nearly homogenous, highly purified vaccine viruses with titers as high as 1*10(9) focus forming units per mL. Flavivirus virions prepared by this method are 2 and 3 orders of magnitude more pure with respect to dsDNA and BHK host cell proteins, respectively, as compared to the raw feed stream. PMID- 25498210 TI - Virus-specific T cells as correlate of (cross-)protective immunity against influenza. AB - Since inactivated influenza vaccines mainly confer protective immunity by inducing strain-specific antibodies to the viral hemagglutinin, these vaccines only afford protection against infection with antigenically matching influenza virus strains. Due to the continuous emergence of antigenic drift variants of seasonal influenza viruses and the inevitable future emergence of pandemic influenza viruses, there is considerable interest in the development of influenza vaccines that induce broader protective immunity. It has long been recognized that influenza virus-specific CD8(+) T cells directed to epitopes located in the relatively conserved internal proteins can cross-react with various subtypes of influenza A virus. This implies that these CD8(+) T cells, induced by prior influenza virus infections or vaccinations, could afford heterosubtypic immunity. Furthermore, influenza virus-specific CD4(+) T cells have been shown to be important in protection from infection, either via direct cytotoxic effects or indirectly by providing help to B cells and CD8(+) T cells. In the present paper, we review the induction of virus-specific T cell responses by influenza virus infection and the role of virus-specific CD4(+) and CD8(+) T cells in viral clearance and conferring protection from subsequent infections with homologous or heterologous influenza virus strains. Furthermore, we discuss vector-based vaccination strategies that aim at the induction of a cross-reactive virus specific T cell response. PMID- 25498212 TI - Bovine adenovirus-3 as a vaccine delivery vehicle. AB - The use of vaccines is an effective and relatively inexpensive means of controlling infectious diseases, which cause heavy economic losses to the livestock industry through animal loss, decreased productivity, treatment expenses and decreased carcass quality. However, some vaccines produced by conventional means are imperfect in many respects including virulence, safety and efficacy. Moreover, there are no vaccines for some animal diseases. Although genetic engineering has provided new ways of producing effective vaccines, the cost of production for veterinary use is a critical criterion for selecting the method of production and delivery of vaccines. The cost effective production and intrinsic ability to enter cells has made adenovirus vectors a highly efficient tool for delivery of vaccine antigens. Moreover, adenoviruses induce both humoral and cellular immune responses to expressed vaccine antigens. Since nonhuman adenoviruses are species specific, the development of animal specific adenoviruses as vaccine delivery vectors is being evaluated. This review summarizes the work related to the development of bovine adenovirus-3 as a vaccine delivery vehicle in animals, particularly cattle. PMID- 25498211 TI - Brucella abortus S19 and RB51 vaccine immunogenicity test: Evaluation of three mice (BALB/c, Swiss and CD-1) and two challenge strains (544 and 2308). AB - The aim of the present study was to evaluate the use of different mouse strains (BALB/c, Swiss and CD-1) and different challenge strains (Brucella abortus 544 and 2308) in the study of B. abortus vaccine (S19 and RB51) immunogenicity test in the murine model. No significant difference in B. abortus vaccine potency assay was found with the use of B. abortus 544 or B. abortus 2308 as challenge strain. Results of variance analysis showed an interaction between treatment and mouse strain; therefore these parameters could not be compared separately. When CD-1 groups were compared, those vaccinated showed significantly lower counts than non-vaccinated ones (P<0.05), independently of the vaccine received (S19 or RB51). Similar results were observed on BALB/c groups. However, in Swiss mouse groups, S19 was more protective than RB51 (P<0.05), which showed protection when compared to the non-vaccinated group (P<0.05). In summary, data from the present study showed that CD-1, BALB/c and Swiss mice strains, as well as both challenge strains, B. abortus strains 544 and 2308, can be used in immunogenicity tests of S19 and RB51 vaccines. PMID- 25498213 TI - How cardiomyocyte excitation, calcium release and contraction become altered with age. AB - Cardiovascular disease is the main cause of death globally, accounting for over 17 million deaths each year. As the incidence of cardiovascular disease rises markedly with age, the overall risk of cardiovascular disease is expected to increase dramatically with the aging of the population such that by 2030 it could account for over 23 million deaths per year. It is therefore vitally important to understand how the heart remodels in response to normal aging for at least two reasons: i) to understand why the aged heart is increasingly susceptible to disease; and ii) since it may be possible to modify treatment of disease in older adults if the underlying substrate upon which the disease first develops is fully understood. It is well known that age modulates cardiac function at the level of the individual cardiomyocyte. Generally, in males, aging reduces cell shortening, which is associated with a decrease in the amplitude of the systolic Ca(2+) transient. This may arise due to a decrease in peak L-type Ca(2+) current. Sarcoplasmic reticulum (SR) Ca(2+) load appears to be maintained during normal aging but evidence suggests that SR function is disrupted, such that the rate of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA)-mediated Ca(2+) removal is reduced and the properties of SR Ca(2+) release in terms of Ca(2+) sparks are altered. Interestingly, Ca(2+) handling is modulated by age to a lesser degree in females. Here we review how cellular contraction is altered as a result of the aging process by considering expression levels and functional properties of key proteins involved in controlling intracellular Ca(2+). We consider how changes in both electrical properties and intracellular Ca(2+) handling may interact to modulate cardiomyocyte contraction. We also reflect on why cardiovascular risk may differ between the sexes by highlighting sex-specific variation in the age associated remodeling process. This article is part of a Special Issue entitled CV Aging. PMID- 25498214 TI - 2-Deoxy adenosine triphosphate improves contraction in human end-stage heart failure. AB - We are developing a novel treatment for heart failure by increasing myocardial 2 deoxy-ATP (dATP). Our studies in rodent models have shown that substitution of dATP for adenosine triphosphate (ATP) as the energy substrate in vitro or elevation of dATP in vivo increases myocardial contraction and that small increases in the native dATP pool of heart muscle are sufficient to improve cardiac function. Here we report, for the first time, the effect of dATP on human adult cardiac muscle contraction. We measured the contractile properties of chemically-demembranated multicellular ventricular wall preparations and isolated myofibrils from human subjects with end-stage heart failure. Isometric force was increased at both saturating and physiologic Ca(2+) concentrations with dATP compared to ATP. This resulted in an increase in the Ca(2+) sensitivity of force (pCa50) by 0.06 pCa units. The rate of force redevelopment (ktr) in demembranated wall muscle was also increased, as was the rate of contractile activation (kACT) in isolated myofibrils, indicating increased cross-bridge binding and cycling compared with ATP in failing human myocardium. These data suggest that dATP could increase dP/dT and end systolic pressure in failing human myocardium. Importantly, even though the magnitude and rate of force development were increased, there was no increase in the time to 50% and 90% myofibril relaxation. These data, along with our previous studies in rodent models, show the promise of elevating myocardial dATP to enhance contraction and restore cardiac pump function. These data also support further pre-clinical evaluation of this new approach for treating heart failure. PMID- 25498215 TI - First-Line and Sequential Use of Pazopanib Followed by Mammalian Target of Rapamycin Inhibitor Therapy Among Patients With Advanced Renal Cell Carcinoma in a US Community Oncology Setting. AB - BACKGROUND: Clinical trials have demonstrated that pazopanib prolongs progression free survival (PFS), with an acceptable safety profile, for patients with advanced renal cell carcinoma (aRCC). The efficacy of second-line mammalian target of rapamycin (mTOR) inhibitors in pazopanib-treated patients has also been evaluated in clinical trials; however, few studies have evaluated first-line pazopanib or second-line mTOR inhibitors in real-world settings. The present study evaluated the outcomes of first-line pazopanib, and pazopanib followed by mTOR inhibitors, in a community oncology setting. PATIENTS AND METHODS: The present study was a retrospective analysis of eligible patients in US Oncology's iKnowMed electronic health records database who had been treated for aRCC from November 1, 2009 to August 31, 2012. The patients received first-line therapy with pazopanib (cohort 1), followed by second-line therapy with either everolimus or temsirolimus (cohort 2). The key outcomes included overall survival (OS), PFS, adverse events (AEs), treatment patterns, and healthcare resource use. RESULTS: The median OS in cohort 1 (n = 177) was 22 months, and the median PFS was 8.5 months. The most common AEs were fatigue (56%), diarrhea (52%), vomiting (44%), and nausea (40%). The median persistence was 151 days with pazopanib. The median OS in cohort 2 (n = 35) was 16 months; the median PFS was 5.7 months. The most common AEs were fatigue (51%) and nausea (34%). The median persistence was 93 days with everolimus and 49 days with temsirolimus. CONCLUSION: The outcomes for the patients treated with first-line pazopanib in the community setting were consistent with those reported by previous prospective and retrospective studies. Although the second-line cohort was small, the results of mTOR inhibitors after pazopanib were also consistent with those of previous observations. PMID- 25498216 TI - Prediction of drug gene associations via ontological profile similarity with application to drug repositioning. AB - The amount of biomedical literature has been increasing rapidly during the last decade. Text mining techniques can harness this large-scale data, shed light onto complex drug mechanisms, and extract relation information that can support computational polypharmacology. In this work, we introduce a fully corpus-based and unsupervised method which utilizes the MEDLINE indexed titles and abstracts to infer drug gene associations and assist drug repositioning. The method measures the Pointwise Mutual Information (PMI) between biomedical terms derived from the Gene Ontology and the Medical Subject Headings. Based on the PMI scores, drug and gene profiles are generated and candidate drug gene associations are inferred when computing the relatedness of their profiles. Results show that an Area Under the Curve (AUC) of up to 0.88 can be achieved. The method can successfully identify direct drug gene associations with high precision and prioritize them. Validation shows that the statistically derived profiles from literature perform as good as manually curated profiles. In addition, we examine the potential application of our approach towards drug repositioning. For all FDA approved drugs repositioned over the last 5 years, we generate profiles from publications before 2009 and show that new indications rank high in the profiles. In summary, literature mined profiles can accurately predict drug gene associations and provide insights onto potential repositioning cases. PMID- 25498217 TI - Downregulation of TES by hypermethylation in glioblastoma reduces cell apoptosis and predicts poor clinical outcome. AB - BACKGROUND: Gliomas are the most common human brain tumors. Glioblastoma, also known as glioblastoma multiform (GBM), is the most aggressive, malignant, and lethal glioma. The investigation of prognostic and diagnostic molecular biomarkers in glioma patients to provide direction on clinical practice is urgent. Recent studies demonstrated that abnormal DNA methylation states play a key role in the pathogenesis of this kind of tumor. In this study, we want to identify a novel biomarker related to glioma initiation and find the role of the glioma-related gene. METHODS: We performed a methylation-specific microarray on the promoter region to identify methylation gene(s) that may affect outcome of GBM patients. Normal and GBM tissues were collected from Tiantan Hospital. Genomic DNA was extracted from these tissues and analyzed with a DNA promoter methylation microarray. Testis derived transcript (TES) protein expression was analyzed by immunohistochemistry in paraffin-embedded patient tissues. Western blotting was used to detect TES protein expression in the GBM cell line U251 with or without 5-aza-dC treatment. Cell apoptosis was evaluated by flow cytometry analysis using Annexin V/PI staining. RESULTS: We found that the TES promoter was hypermethylated in GBM compared to normal brain tissues under DNA promoter methylation microarray analysis. The GBM patients with TES hypermethylation had a short overall survival (P <0.05, log-rank test). Among GBM samples, reduced TES protein level was detected in 33 (89.2%) of 37 tumor tissues by immunohistochemical staining. Down regulation of TES was also correlated with worse patient outcome (P <0.05, log-rank test). Treatment on the GBM cell line U251 with 5-aza-dC can greatly increase TES expression, confirming the hypermethylation of TES promoter in GBM. Up-regulation of TES prompts U251 apoptosis significantly. This study demonstrated that both TES promoter hypermethylation and down-regulated protein expression significantly correlated with worse patient outcome. Treatment on the GBM cell line (U251) with 5-aza-dC can highly release TES expression resulting in significant apoptosis in these cells. CONCLUSIONS: Our findings suggest that the TES gene is a novel tumor suppressor gene and might represent a valuable prognostic marker for glioblastoma, indicating a potential target for future GBM therapy. PMID- 25498220 TI - Towards effective adjuvant treatment for urothelial cancer. PMID- 25498219 TI - Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial. AB - BACKGROUND: Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment. METHODS: We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (>=18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374. FINDINGS: We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths. INTERPRETATION: Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater. FUNDING: Italian Sarcoma Group. PMID- 25498221 TI - The role of the ventral dentate gyrus in anxiety-based behaviors. AB - Dorsoventral lesion studies of the hippocampus (HPP) indicate that the dorsal axis is important for spatial processing and the ventral axis is important in anxiety and olfactory processes. There is some evidence that ventral CA3 and ventral CA1 subregions are important for cued retrieval in fear conditioning, which supports a ventral-anxiety relationship. However, the role of the ventral dentate gyrus (DG) in anxiety-based behaviors is less understood. Therefore, we used elevated plus and open field mazes to investigate the role of the ventral DG in the ability to modify behavior in potentially dangerous conditions and to clarify a few previous reports that ventral HPP lesions may induce hyperactivity. Rats with ventral DG lesions spent significantly more time in the open arms of the elevated plus maze and inner zone of the open field test than did controls and rats with dorsal DG lesions. Locomotor measures indicate that all rats traveled at similar rates in enclosed arms, as well as in open arms of the elevated plus maze and all groups traveled at similar rates in the open field test, which indicates that differences in exploration were not likely due to hyperactivity. The present study findings indicate that the ventral DG plays an important role in anxiety-based behaviors, such as preference for safer environments and the ability to modify exploratory behavior when in potentially dangerous environments and that the dorsal DG is not importantly involved in anxiety. PMID- 25498218 TI - Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. AB - BACKGROUND: Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS: This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS: From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7.0 years (IQR 5.2-8.7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0.78, 95% CI 0.56-1.08; p=0.13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0.54, 95% CI 0.4-0.73, p<0.0001), with 5 year progression-free survival of 47.6% (95% CI 38.8-55.9) in the immediate treatment group and 31.8% (24.2-39.6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION: Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING: Lilly, Canadian Cancer Society Research. PMID- 25498222 TI - REM sleep rescues learning from interference. AB - Classical human memory studies investigating the acquisition of temporally-linked events have found that the memories for two events will interfere with each other and cause forgetting (i.e., interference; Wixted, 2004). Importantly, sleep helps consolidate memories and protect them from subsequent interference (Ellenbogen, Hulbert, Stickgold, Dinges, & Thompson-Schill, 2006). We asked whether sleep can also repair memories that have already been damaged by interference. Using a perceptual learning paradigm, we induced interference either before or after a consolidation period. We varied brain states during consolidation by comparing active wake, quiet wake, and naps with either non-rapid eye movement sleep (NREM), or both NREM and REM sleep. When interference occurred after consolidation, sleep and wake both produced learning. However, interference prior to consolidation impaired memory, with retroactive interference showing more disruption than proactive interference. Sleep rescued learning damaged by interference. Critically, only naps that contained REM sleep were able to rescue learning that was highly disrupted by retroactive interference. Furthermore, the magnitude of rescued learning was correlated with the amount of REM sleep. We demonstrate the first evidence of a process by which the brain can rescue and consolidate memories damaged by interference, and that this process requires REM sleep. We explain these results within a theoretical model that considers how interference during encoding interacts with consolidation processes to predict which memories are retained or lost. PMID- 25498223 TI - Tea polyphenols alleviate motor impairments, dopaminergic neuronal injury, and cerebral alpha-synuclein aggregation in MPTP-intoxicated parkinsonian monkeys. AB - Tea polyphenols (TPs) are bioactive flavanol-related catechins that have been shown to protect dopaminergic (DAergic) neurons against neurotoxin-induced injury in mouse Parkinson's disease (PD) models. However, the neuroprotective efficacy of TP has not been investigated in nonhuman PD primates, which can more accurately model the neuropathology and motor impairments of human PD patients. Here, we show that oral administration of TP alleviates motor impairments and DAergic neuronal injury in the substantia nigra in N-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-intoxicated PD monkeys, indicating an association between protection against motor deficits and preservation of DAergic neurons. We also show a significant inhibition of MPTP-induced accumulation of neurotoxic alpha-synuclein (alpha-syn) oligomers in the striatum and other brain regions, which may contribute to the neuroprotection and improved motor function conferred by TP. The association between reduced alpha-syn oligomerization and neuroprotection was confirmed in cultured DAergic cells. The most abundant and bioactive TP in the mixture used in vivo, (-)-epigallocatechin-3-gallate, reduced intracellular levels of alpha-syn oligomers in neurons treated with alpha-syn oligomers, 1-methyl-4-phenylpyridiniumion, or both, accompanied by increased cell viability. The present study provides the first evidence that TP can alleviate motor impairments, DAergic neuronal injury, and alpha-syn aggregation in nonhuman primates. PMID- 25498224 TI - Gating of hippocampal output by beta-adrenergic receptor activation in the pilocarpine model of epilepsy. AB - Norepinephrine acting via beta-adrenergic receptors (beta-ARs) plays an important role in hippocampal plasticity including the subiculum which is the principal target of CA1 pyramidal cells and which controls information transfer from the hippocampus to other brain regions including the neighboring presubiculum and the entorhinal cortex (EC). Subicular pyramidal cells are classified as regular- (RS) and burst-spiking (BS) cells. Activation of beta-ARs at CA1-subiculum synapses induces long-term potentiation (LTP) in burst- but not in RS cells (Wojtowicz et al., 2010). To elucidate seizure-associated disturbances in the norepinephrine dependent modulation of hippocampal output, we investigated the functional consequences of the beta-AR-dependent synaptic plasticity at CA1-subiculum synapses for the transfer of hippocampal output to the parahippocampal region in the pilocarpine model of temporal lobe epilepsy. Using single-cell and multi channel field recordings in slices, we studied beta-AR-mediated changes in the functional connectivity between CA1, the subiculum and its target-structures. We confirm that application of the beta-adrenergic agonist isoproterenol induces LTP in subicular BS- but not RS cells. Due to the distinct spatial distribution of RS and BS cells in the proximo-to-distal axis of the subiculum, in field recordings, LTP was significantly stronger in the distal than in the proximal subiculum. In pilocarpine-treated animals, beta-AR-mediated LTP was strongly reduced in the distal subiculum. The attenuated LTP was associated with a disturbed polysynaptic transmission from the CA1, via the subiculum to the presubiculum, but with a preserved transmission to the medial EC. Our findings suggest that synaptic plasticity may influence target-related information flow and that such regulation is disturbed in pilocarpine-treated epileptic rats. PMID- 25498225 TI - Effect of prenatal exposure to LPS combined with pre- and post-natal high-fat diet on hippocampus in rat offspring. AB - OBJECTIVE: Prenatal exposure to lipopolysaccharide (LPS) or high-fat diet (HFD) results in hippocampal impairment and cognitive deficits in offspring rats. What is not clear is how prenatal exposure to LPS combined with pre- and post-natal HFD would affect the hippocampus in offspring rats. METHODS: 32 pregnant rats were randomly divided into four groups, including control group; LPS group (pregnant rats were injected with LPS 0.4 mg/kg intraperitoneally on the 8th, 10th and 12th day of pregnancy); HFD group (maternal rats had HFD during pregnancy and the lactation period, and their pups also had HFD up to the third month of life); LPS+HFD group (rats were exposed to the identical experimental scheme with LPS group and HFD group). The serum IL-6 and TNF-alpha concentration was measured in three-month-old offspring rats in all groups. Hippocampal morphology and expressions of glial fibrillary acidic protein (GFAP), Tau and synaptophysin (SYP) in offspring rats were measured. RESULTS: Serum IL-6 and TNF alpha concentration in the HFD group increased significantly compared with the control group, LPS group and LPS+HFD group. Compared with the control group and the LPS+HFD group, cells in the LPS and HFD groups were smaller and arranged in disorder, and cell membrane was not complete, nucleoli and nuclear heterochromatin stained darkly with hematoxylin. GFAP and Tau expression in the hippocampus of the LPS and HFD groups increased significantly compared with the control group and LPS+HFD group. SYP expression in the LPS and HFD groups decreased significantly compared with the control group and HFD group, increased in the LPS+HFD group. CONCLUSION: Prenatal exposure to LPS combined with pre- and post-natal HFD result in a protective effect on the hippocampus in offspring rats, and it might be a benefit from the predictive adaptive response to prenatal inflammation. PMID- 25498226 TI - PET/MRI in lung cancer. PMID- 25498227 TI - Positron emission tomography/magnetic resonance imaging of the breast. PMID- 25498228 TI - Whole-body positron emission tomography-magnetic resonance in breast cancer. PMID- 25498229 TI - Potential role of positron emission tomography/magnetic resonance imaging in gastrointestinal and abdominal malignancies: preliminary experience. PMID- 25498230 TI - Positron emission tomography-magnetic resonance imaging in oncologic diseases of the male and female pelvis. PMID- 25498231 TI - Magnetic resonance/positron emission tomography (MR/PET) oncologic applications: bone and soft tissue sarcoma. PMID- 25498232 TI - Clinical applications of pediatric positron emission tomography-magnetic resonance imaging. PMID- 25498234 TI - Nicotinic alteration of decision-making. AB - Addiction to nicotine is characterized by impulses, urges and lack of self control towards cigarettes. A key element in the process of addiction is the development of habits oriented towards nicotine consumption that surpass flexible systems as a consequence of a gradual adaptation to chronic drug exposure. However, the long-term effects of nicotine on brain circuits also induce wide changes in decision-making processes, affecting behaviors unrelated to cigarettes. This review aims at providing an update on the implications of nicotine on general decision-making processes, with an emphasis on impulsivity and risk-taking. As impulsivity is a rather ambiguous behavioral trait, we build on economic and normative theories to better characterize these nicotine-induced alterations in decision-making. Nonetheless, experimental data are sparse and often contradictory. We will discuss how the latest findings on the neurobiological basis of choice behavior may help disentangling these issues. We focus on the role of nicotine acetylcholine receptors and their different subunits, and on the spatio-temporal dynamics (i.e. diversity of the neural circuits, short- and long-term effects) of both endogenous acetylcholine and nicotine action. Finally, we try to link these neurobiological results with neuro computational models of attention, valuation and action, and of the role of acetylcholine in these decision processes. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25498233 TI - Natural genetic variability of the neuronal nicotinic acetylcholine receptor subunit genes in mice: Consequences and confounds. AB - Recent human genetic studies have identified genetic variants in multiple nicotinic acetylcholine receptor (nAChR) subunit genes that are associated with risk for nicotine dependence and other smoking-related measures. Genetic variability also exists in the nAChR subunit genes in mice. Most studies on mouse nAChR subunit gene variability to date have focused on Chrna4, the gene that encodes the alpha4 nAChR subunit and Chrna7, the gene that encodes the alpha7 nAChR subunit. However, genetic variability exists for all nAChR genes in mice. In this review, we will describe what is known about nAChR subunit gene polymorphisms in mice and how it relates to variability in nAChR expression and function in brain. The relationship between nAChR genetic variability in mice and the effects of nicotine on several behavioral and physiological measures also will be discussed. In addition, an overview of the contribution of other genetic variation to nicotine sensitivity in mice will be provided. Finally, the potential for natural genetic variability to confound and/or modify the results of studies that utilize genetically engineered mice will be considered. As an example of the ability of a natural genetic variant to modify the effect of an engineered mutation, data will be presented that demonstrate that the effect of Chrna5 deletion on oral nicotine intake is dependent upon naturally occurring variant alleles of Chrna4. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25498235 TI - Design, syntheses and evaluation of 4-oxo-5-cyano thiouracils as SecA inhibitors. AB - Protein translocation is essential for bacterial survival and the most important translocation mechanism is the secretion (Sec) pathway in which SecA is a central core driving force. Thus targeting SecA is a promising strategy for developing novel antibacterial therapeutics. Herein, we report the syntheses and evaluation of a series of nearly 60 4-oxo-5-cyano thiouracil derivatives based upon our previously reported core pyrimidine structure. Introduction of polar group such as -N3 and linker groups such as -CH2-O- enhanced the potency several fold. Apart from being potential antibacterial agents, these inhibitors can be indispensable tools for biologists to probe the mechanism of protein translocation via the SecA machinery in bacteria. PMID- 25498236 TI - Impact of maternal malnutrition during the periconceptional period on mammalian preimplantation embryo development. AB - During episodes of undernutrition and overnutrition the mammalian preimplantation embryo undergoes molecular and metabolic adaptations to cope with nutrient deficits or excesses. Maternal adaptations also take place to keep a nutritional microenvironment favorable for oocyte development and embryo formation. This maternal-embryo communication takes place via several nutritional mediators. Although adaptive responses to malnutrition by both the mother and the embryo may ensure blastocyst formation, the resultant quality of the embryo can be compromised, leading to early pregnancy failure. Still, studies have shown that, although early embryonic mortality can be induced during malnutrition, the preimplantation embryo possesses an enormous plasticity that allows it to implant and achieve a full-term pregnancy under nutritional stress, even in extreme cases of malnutrition. This developmental strategy, however, may come with a price, as shown by the adverse developmental programming induced by even subtle nutritional challenges exerted exclusively during folliculogenesis and the preimplantation period, resulting in offspring with a higher risk of developing deleterious phenotypes in adulthood. Overall, current evidence indicates that malnutrition during the periconceptional period can induce cellular and molecular alterations in preimplantation embryos with repercussions for fertility and postnatal health. PMID- 25498237 TI - Differential gene expression and immunolocalization of platelet-derived growth factors and their receptors in caprine ovaries. AB - This study evaluated the messenger RNA (mRNA) expression and immunolocalization of all members of the platelet-derived growth factor (PDGF) family in caprine ovaries by quantitative PCR and immunohistochemistry, respectively. Detectable levels of PDGF-A mRNA were not observed in primordial follicles. Higher levels of PDGF-B mRNA were observed in primary follicles than in primordial follicles (P < 0.05). PDGF-D mRNA levels were higher in secondary follicles than in the other preantral follicle categories (P < 0.05). PDGF-B mRNA expression was higher than PDGF-C mRNA expression in primary follicles (P < 0.05). In antral follicles, PDGF A mRNA expression was higher in cumulus-oocyte complexes (COCs) from small antral follicles than in those from large antral follicles and their respective granulosa/theca (GT) cells (P < 0.05). Furthermore, in COCs from small and large antral follicles, PDGF-A mRNA expression was higher than that of the other PDGF isoforms (P < 0.05). The mRNA levels of PDGF-B and PDGF-D and PDGFR-alpha and PDGFR-beta were higher in GT cells from large antral follicles than in GT cells from small antral follicles and in their respective COCs (P < 0.05). In COCs and GT cells from small antral follicles, the mRNA levels of PDGFR-alpha were higher than those of PDGFR-beta (P < 0.05). All proteins were observed in the cytoplasm of oocytes from all follicular categories. In granulosa cells, all PDGFs and PDGFR-beta were detected from starting at the secondary stage, and in theca cells, all proteins, except PDGF-C, were detected starting at the antral stage. In conclusion, PDGF and its receptors are differentially expressed in the oocytes and ovarian cells according to the stage of follicular development, suggesting their role in the regulation of folliculogenesis in goats. PMID- 25498239 TI - Calcium carbonate as a possible dosimeter for high irradiation doses. AB - The aim of this work is to analyze the interactions of 5MeV electron beam radiation and a 290MeV/u Carbon beam with calcium carbonate (powder) at 298K and at different irradiation doses, for the potential use of calcium carbonate as a high-dose dosimeter. The irradiation doses with the electron beam were from 0.015 to 9MGy, and with Carbon beam from 1.5kGy to 8kGy. High-energy radiation induces the formation of free radicals in solid calcium carbonate that can be detected and measured by electron paramagnetic resonance (EPR). An increase of the EPR response for some of the free radicals produced in the sample was observed as a function of the irradiation dose. These measurements are reproducible; the preparation of the sample is simple and inexpensive; and the signal is stable for several months. The response curves show that the dosimeter tends to saturate at 10MGy. Based on these properties, we propose this chemical compound as a high dose dosimeter, mainly for electron irradiation. PMID- 25498238 TI - Inhibition of multidrug transporter in tumor endothelial cells enhances antiangiogenic effects of low-dose metronomic paclitaxel. AB - Tumor angiogenesis plays an important role in tumor progression and metastasis. Tumor endothelial cells (TECs) are a therapeutic target of antiangiogenic chemotherapy that was recently developed and is currently being investigated in the clinic with promising results. Low-dose chemotherapy, which is the long-term administration of relatively low doses of chemotherapeutic agents, has been proposed for targeting tumor angiogenesis in various types of cancers. Although the efficacy of low-dose chemotherapy has been confirmed in several clinical models, some studies show insufficient therapeutic effect for malignant cancers. As a possible mechanism of the treatment failure, it has been considered that tumor cells may acquire resistance to this therapy. However, drug resistance by TECs may also be due to another mechanism for resistance of tumor cells to low dose chemotherapy. We reported elsewhere that TECs were resistant to the anticancer drug paclitaxel, which is a mitotic inhibitor, concomitant with P glycoprotein up-regulation. Verapamil, a P-glycoprotein inhibitor, abrogated TEC resistance in vitro. Herein, we demonstrated that verapamil coadministration enhanced the effects of low-dose paclitaxel concomitant with inhibiting tumor angiogenesis in a preclinical in vivo mouse melanoma xenograft model. Furthermore, verapamil coadministration reduced lung metastasis. These results suggest that inhibiting P-glycoprotein in TECs may be a novel strategy for low dose chemotherapy targeting TECs. PMID- 25498241 TI - The complex impact of five years of stress related to life-threatening events on pregnancy outcomes: a preliminary retrospective study. AB - OBJECTIVE: To study the impact of chronic, life-threatening stressors in the form of daily missile attacks, for five consecutive years, on pregnancy outcomes. METHOD: Charts of deliveries from two neighboring towns in the south of Israel, covering the years 2000 and 2003-2008, were reviewed retrospectively. One city had been exposed to missile attacks, while the other was not. For each year, 100 charts were chosen at random. RESULTS: Significant association was found between exposure to stress and frequency of pregnancy complications (P=0.047) and premature membrane rupture (P=0.029). A more detailed analysis, based on dividing the stressful years into three distinct periods: early (2003-2004), intermediate (2005-2006) and late (2007-2008), revealed that preterm deliveries were significantly more frequent (P=0.044) during the intermediate period, as was premature membrane rupture during the late period (P=0.014). CONCLUSION: Exposure to chronic life-threatening stress resulted in more pregnancy complications and in particular more premature membrane ruptures. The impact was most significant during the middle period of the 5-year-exposure to the stressor. Hence it seems that factors of duration and habituation may play a role in the impact of chronic, life-threatening stressors on pregnancy. PMID- 25498242 TI - Comparative neuropsychiatry: white matter abnormalities in children and adolescents with schizophrenia, bipolar affective disorder, and obsessive compulsive disorder. AB - BACKGROUND: There is considerable evidence that white matter abnormalities play a key role in the pathogenesis of a number of major psychiatric disorders, including schizophrenia, bipolar affective disorder, and obsessive-compulsive disorder. Few studies, however, have compared white matter abnormalities early in the course of the illness. METHODS: A total of 102 children and adolescents participated in the study, including 43 with early-onset schizophrenia, 13 with early-onset bipolar affective disorder, 17 with obsessive-compulsive disorder, and 29 healthy controls. Diffusion tensor imaging scans were obtained on all children and the images were assessed for the presence of non-spatially overlapping regions of white matter differences, a novel algorithm known as the pothole approach. RESULTS: Patients with early-onset schizophrenia and early onset bipolar affective disorder had a significantly greater number of white matter potholes compared to controls, but the total number of potholes did not differ between the two groups. The volumes of the potholes were significantly larger in patients with early-onset bipolar affective disorder compared to the early-onset schizophrenia group. Children and adolescents with obsessive compulsive disorder showed no differences in the total number of white matter potholes compared to controls. CONCLUSIONS: White matter abnormalities in early onset schizophrenia and bipolar affective disorder are more global in nature, whereas children and adolescents with obsessive-compulsive disorder do not show widespread differences in FA. PMID- 25498240 TI - Influence of birth cohort on age of onset cluster analysis in bipolar I disorder. AB - PURPOSE: Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database. METHODS: The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared. RESULTS: There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups. CONCLUSION: These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research. PMID- 25498243 TI - Efficacy of EGFR tyrosine kinase inhibitors in patients with EGFR-mutated non small cell lung cancer except both exon 19 deletion and exon 21 L858R: a retrospective analysis in Korea. AB - BACKGROUND: NSCLC can be defined by various molecular criteria, especially by the type of EGFR mutations present. Besides two major EGFR mutations, other rare or complex types have not been fully described. We performed this study to investigate the clinical significance and efficacy of EGFR-TKIs in NSCLC patients with rare or complex EGFR mutations. METHODS: We retrospectively reviewed data for consecutive patients with advanced NSCLC. Subjects with wild type EGFR, EGFR del-19 alone, or EGFR L858R alone were excluded. A rare mutation was defined as any mutation other than del-19 or L858R in exon 21 and a complex mutation was defined as two or more different mutations co-existing within the same tumor sample. RESULTS: A total of 1738 patients underwent EGFR genotyping. Among them, 88 (5.1%) had rare or complex mutations and 54 were treated with TKIs. Thirty three patients had single rare mutations and 21 had complex mutations. The response was evaluated in 50 patients. Partial response was achieved in 11 (20.4%) patients, and stable disease was achieved in 20 (37.0%) patients. The median progression-free survival was 2.6 months (95% CI; 0.0-5.4 months) at a median follow-up duration of 381.0 days (range; 10-1307 days). The median overall survival was 12.7 months (95% CI; 7.2-18.2 months). CONCLUSIONS: These results suggest that rare or complex EGFR mutations confer inferior response and survival to the EGFR-TKI treatment compared to common mutations. Further studies using larger numbers of patients are needed to determine better subclassifications for these patients. PMID- 25498244 TI - On the use of Legionella/Rickettsia chimeras to investigate the structure and regulation of Rickettsia effector RalF. AB - A convenient strategy to interrogate the biology of regulatory proteins is to replace individual domains by an equivalent domain from a related protein of the same species or from an ortholog of another species. It is generally assumed that the overall properties of the native protein are retained in the chimera, and that functional differences reflect only the specific determinants contained in the swapped domains. Here we used this strategy to circumvent the difficulty in obtaining crystals of Rickettsia prowazekii RalF, a bacterial protein that functions as a guanine nucleotide exchange factor for eukaryotic Arf GTPases. A RalF homolog is encoded by Legionella pneumophila, in which a C-terminal capping domain auto-inhibits the catalytic Sec7 domain and localizes the protein to the Legionella-containing vacuole. The crystal structures of domain-swapped chimeras were determined and used to construct a model of Legionella RalF with a RMSD of less than 1A with the crystal structure, which validated the use of this approach to build a model of Rickettsia RalF. In the Rickettsia RalF model, sequence differences in the capping domain that target it to specific membranes are accommodated by a shift of the entire domain with respect to the Sec7 domain. However, local sequence changes also give rise to an artifactual salt bridge in one of the chimeras, which likely explains why this chimera is recalcitrant to activation. These findings highlight the structural plasticity whereby chimeras can be engineered, but also underline that unpredictable differences can modify their biochemical responses. PMID- 25498245 TI - Reduced ex vivo stimulated IL-6 response in infants randomized to fish oil from 9 to 18 months, especially among PPARG2 and COX2 wild types. AB - We investigated whether n-3 LCPUFA affected immune function in late infancy and explored effect-modification by single nucleotide polymorphisms (SNPs) and links to intestinal microbiota. Infants (n=105) were randomized to fish oil (FO, 1.2g/d n-3 LCPUFA) or sunflower oil (SO)-supplements from age 9-18 months. Immune function was assessed by ex vivo cytokine production in stimulated blood and plasma immunoglobulin E (IgE). We genotyped functional SNPs in PPARG2 and COX2 and analyzed fecal microbiota by 16S-rRNA terminal restriction fragment length polymorphism. FO compared to SO reduced Lactobacillus paracasei-stimulated IL-6 at 18 months (P=0.03, n=104). This effect was most pronounced among infants wild type for PPARG2-Pro12Ala and/or COX2-T8473C (P<0.05). Predominant bacterial fragments were associated with 18 months IgE in all infants (P=0.004) (bp100) and with IL-6 production among infants weaned before 9 months (P=0.047) (bp102). Thus, FO reduced IL-6 in a genotype-modified manner. The microbiota was partly linked to IL-6 and IgE, not directly to FO. PMID- 25498246 TI - Cell words: modelling the visual appearance of cells in histopathology images. AB - Detection and classification of cells in histological images is a challenging task because of the large intra-class variation in the visual appearance of various types of biological cells. In this paper, we propose a discriminative dictionary learning paradigm, termed as Cell Words, for modelling the visual appearance of cells which includes colour, shape, texture and context in a unified manner. The proposed framework is capable of distinguishing mitotic cells from non-mitotic cells (apoptotic, necrotic, epithelial) in breast histology images with high accuracy. PMID- 25498247 TI - Threat of attacks of Ixodes ricinus ticks (Ixodida: Ixodidae) and Lyme borreliosis within urban heat islands in south-western Poland. AB - BACKGROUND: The increased incidence of Lyme disease in Europe necessitates permanent monitoring of the occurrence and activity of its vector. Therefore, in this study, we have investigated the presence and seasonal activity of Ixodes ricinus ticks in various habitats of a large industrial region in south-western Poland in correlation with environmental factors present in urban heat islands. Additionally, the risk of borreliosis in this part of Poland has been assessed. METHODS: The investigations were carried out at two-week intervals between April and October 2001 and 2002. Ticks were collected from four localities in Upper Silesia, i.e. in a city park (CH), on the outskirts of two large cities (KO, MI), and in a forest (KL). We analysed the impact of temperature and humidity measured during the collection period in the I. ricinus habitats, the climatic conditions prevailing in the study area, and the degree of environmental contamination on the abundance and activity of these ticks in the respective sites. The degree of borreliosis risk in the region was determined on the basis of the results of research on the prevalence of Borrelia burgdorferi s.l. in ticks and reports from sanitary-epidemiological stations. RESULTS: In total, 2061 I. ricinus ticks, including 606 nymphs and 1455 adults, were collected in the study area. The number and activity of the ticks varied during the collection in the different sites. In the urban locality CH, tick abundance was the lowest (455 throughout the investigation period), and the seasonal activity of females was unimodal and persisted for as long as 4 months. In the suburban localities KO and MI, tick abundance was higher (485 and 481 specimens, respectively) and the activity of females was unimodal. The highest abundance (640 ticks) and a bimodal pattern of female activity were reported from the forest locality KL. In all the localities, the activity of nymphs was unimodal. Humidity was found to be a factor influencing I. ricinus abundance and activity, whereas temperature did not affect their number and behaviour significantly. The climate parameters within the urban heat islands noted during the investigations contributed to dispersal of dust and gas pollutants. The analysis of the data reveals that there is a risk of borreliosis in the entire study area; however, it is higher in the urban localities than in the suburban sites. CONCLUSIONS: Environmental conditions (habitat, climate, and dust and gas pollution) prevailing within urban heat islands may exert an impact on tick abundance and activity and the prevalence of Lyme disease in the study area. The greatest effect of the environmental factors on ticks was found in the city park, where the risk of human infection with B. burgdorferi s.l. spirochetes is the highest as well. PMID- 25498248 TI - Mossbauer spectroscopy of Fe/S proteins. AB - Iron-sulfur (Fe/S) clusters are structurally and functionally diverse cofactors that are found in all domains of life. (57)Fe Mossbauer spectroscopy is a technique that provides information about the chemical nature of all chemically distinct Fe species contained in a sample, such as Fe oxidation and spin state, nuclearity of a cluster with more than one metal ion, electron spin ground state of the cluster, and delocalization properties in mixed-valent clusters. Moreover, the technique allows for quantitation of all Fe species, when it is used in conjunction with electron paramagnetic resonance (EPR) spectroscopy and analytical methods. (57)Fe-Mossbauer spectroscopy played a pivotal role in unraveling the electronic structures of the "well-established" [2Fe-2S](2+/+), [3Fe-4S](1+/0), and [4Fe-4S](3+/2+/1+/0) clusters and -more-recently- was used to characterize novel Fe/S clustsers, including the [4Fe-3S] cluster of the O2 tolerant hydrogenase from Aquifex aeolicus and the 3Fe-cluster intermediate observed during the reaction of lipoyl synthase, a member of the radical SAM enzyme superfamily. PMID- 25498249 TI - Role of dynamin in elongated cell migration in a 3D matrix. AB - The use of 3-dimensional (3D) collagen gels has yielded new insights into the migratory behaviour of cancer cells. While the large GTPase dynamin has emerged as an important regulator of cancer cell migration and invasion under 2D conditions, its role in 3D migration is unclear. We have used a potent dynamin modulator, a bis-tyrphostin derivative, Ryngo(r) 1-23, to investigate the role of dynamin in 3D migration in 3 different cell lines. The compound specifically inhibits persistent, elongated 3D migration in U87MG and SMA-560 cells. Treated U87MG cells adopt a rounded morphology that is not due to apoptosis, loss of matrix metalloprotease activity or inhibition of clathrin-mediated endocytosis. Given that Ryngo 1-23 is known to regulate dynamin oligomerisation and actin dynamics at the leading edge, we analysed actin filament distribution. Ryngo 1-23 induced a switch in actin filament organization in 3D cultures resulting in the generation of multiple short actin-rich microspikes. Correlated with the change in actin filament distribution, cells displayed reduced collagen gel contraction. Since acto-myosin force transmission to the extra-cellular matrix underpins persistent, elongated migration, our results suggest that Ryngo 1-23 modulates this process in 3D migration via dynamin-mediated regulation of acto-myosin force transmission to the extra-cellular matrix. PMID- 25498251 TI - Investigation of ATP6V1B1 and ATP6V0A4 genes causing hereditary hearing loss associated with distal renal tubular acidosis in Iranian families. AB - BACKGROUND: Hearing defects are the most common sensory disorders, affecting 1 out of every 500 newborns. ATP6V1B mutations are associated with early sensorineural hearing loss, whereas ATP6V0A4 mutations are classically associated with either late-onset sensorineural hearing loss or normal hearing. ATP6V1B1 and ATP6V0A4 genetic mutations cause recessive forms of distal renal tubular acidosis. METHOD: Ten unrelated deaf Iranian families with distal renal tubular acidosis were referred to the Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran. All exons of the ATP6V1B1 and ATP6V0A4 genes were sequenced in affected family members. RESULTS: We identified a previously reported ATP6V1B1 frameshift mutation (P385fsX441) in two families and a nucleotide substitution in exon 10 (P346R) in three families. In addition, one patient was homozygous for a novel nucleotide substitution in exon 3. CONCLUSION: ATP6V1B1 genetic mutations were detected in more than half of the families studied. Mutations in this gene therefore seem to be the most common causative factors in hearing loss associated with distal renal tubular acidosis in these families. PMID- 25498252 TI - Effect of a 2-tier rapid response system on patient outcome and staff satisfaction. AB - BACKGROUND: Rapid response systems (RRS) have been recommended as a strategy to prevent and treat deterioration in acute care patients. Questions regarding the most effective characteristics of RRS and strategies for implementing these systems remain. AIMS: The aims of this study were to (i) describe the structures and processes used to implement a 2-tier RRS, (ii) determine the comparative prevalence of deteriorating patients and incidence of unplanned intensive care unit (ICU) admission and cardiac arrest prior to and after implementation of the RRS, and (iii) determine clinician satisfaction with the RRS. METHOD: A quasi experimental pre-test, post-test design was used to assess patient related outcomes and clinician satisfaction prior to and after implementation of a 2-tier RRS in a tertiary metropolitan hospital. Primary components of the RRS included an ICU Outreach Nurse and a Rapid Response Team. Prevalence of deteriorating patients was assessed through a point prevalence assessment and chart audit. Incidence of unplanned admission to ICU and cardiac arrests were accessed from routine hospital databases. Clinician satisfaction was measured through surveys. RESULTS: Prevalence of patients who met medical emergency call criteria without current treatment reduced from 3% prior to RRS implementation to 1% after implementation; a similar reduction from 9% to 3% was identified on chart review. The number of unplanned admissions to ICU increased slightly from 17.4/month prior to RRS implementation to 18.1/month after implementation (p=0.45) while cardiac arrests reduced slightly from 7.5/month to 5.6/month (p=0.22) but neither of these changes were statistically significant. Staff satisfaction with the RRS was generally high. CONCLUSION: The 2-tier RRS was accessed by staff to assist with care of deteriorating patients in a large, tertiary hospital. High levels of satisfaction have been reported by clinical staff. PMID- 25498253 TI - Quality of pharmacy-specific Medical Subject Headings (MeSH) assignment in pharmacy journals indexed in MEDLINE. AB - BACKGROUND: The Medical Subject Headings (MeSH) is the National Library of Medicine (NLM) controlled vocabulary for indexing articles. Inaccuracies in the MeSH thesaurus have been reported for several areas including pharmacy. OBJECTIVES: To assess the quality of pharmacy-specific MeSH assignment to articles indexed in pharmacy journals. METHODS: The 10 journals containing the highest number of articles published in 2012 indexed under the MeSH 'Pharmacists' were identified. All articles published over a 5-year period (2008-2012) in the 10 previously selected journals were retrieved from PubMed. MeSH terms used to index these articles were extracted and pharmacy-specific MeSH terms were identified. The frequency of use of pharmacy-specific MeSH terms was calculated across journals. RESULTS: A total of 6989 articles were retrieved from the 10 pharmacy journals, of which 328 (4.7%) were articles not fully indexed and therefore did not contain any MeSH terms assigned. Among the 6661 articles fully indexed, the mean number of MeSH terms was 10.1 (SD = 4.0), being 1.0 (SD = 1.3) considered as Major MeSH. Both values significantly varied across journals. The mean number of pharmacy-specific MeSH terms per article was 0.9 (SD = 1.2). A total of 3490 (52.4%) of the 6661 articles were indexed in pharmacy journals without a single pharmacy-specific MeSH. Of the total 67193 MeSH terms assigned to articles, on average 10.5% (SD = 13.9) were pharmacy-specific MeSH. A statistically significant different pattern of pharmacy-specific MeSH assignment was identified across journals (Kruskal-Wallis P < 0.001). CONCLUSIONS: The quality of assignment of the existing pharmacy-specific MeSH terms to articles indexed in pharmacy journals can be improved to further enhance evidence gathering in pharmacy. Over half of the articles published in the top-10 journals publishing pharmacy literature were indexed without a single pharmacy-specific MeSH. PMID- 25498255 TI - An introduction from the co-chairs of the WMS Practice Guidelines Committee. PMID- 25498256 TI - Wilderness Medical Society practice guidelines for spine immobilization in the austere environment: 2014 update. AB - In an effort to produce best practice guidelines for spine immobilization in the austere environment, the Wilderness Medical Society convened an expert panel charged with the development of evidence-based guidelines for management of the injured or potentially injured spine in an austere (dangerous or compromised) environment. Recommendations are made regarding several parameters related to spinal immobilization. These recommendations are graded on the basis of the quality of supporting evidence and balance between the benefits and risks or burdens for each parameter according to the methodology stipulated by the American College of Chest Physicians. A treatment algorithm based on the guidelines is presented. This is an updated version of original WMS Practice Guidelines for Spine Immobilization in the Austere Environment published in Wilderness & Environmental Medicine 2013;24(3):241-252. PMID- 25498254 TI - Diesel exhaust particle exposure in vitro impacts T lymphocyte phenotype and function. AB - BACKGROUND: Diesel exhaust particles (DEP) are major constituents of ambient air pollution and their adverse health effect is an area of intensive investigations. With respect to the immune system, DEP have attracted significant research attention as a factor that could influence allergic diseases interfering with cytokine production and chemokine expression. With this exception, scant data are available on the impact of DEP on lymphocyte homeostasis. Here, the effects of nanoparticles from Euro 4 (E4) and Euro 5 (E5) light duty diesel engines on the phenotype and function of T lymphocytes from healthy donors were evaluated. METHODS: T lymphocytes were isolated from peripheral blood obtained from healthy volunteers and subsequently stimulated with different concentration (from 0.15 to 60 MUg/ml) and at different time points (from 24 h to 9 days) of either E4 or E5 particles. Immunological parameters, including apoptosis, autophagy, proliferation levels, mitochondrial function, expression of activation markers and cytokine production were evaluated by cellular and molecular analyses. RESULTS: DEP exposure caused a pronounced autophagic-lysosomal blockade, thus interfering with a key mechanism involved in the maintaining of T cell homeostasis. Moreover, DEP decreased mitochondrial membrane potential but, unexpectedly, this effect did not result in changes of the apoptosis and/or necrosis levels, as well as of intracellular content of adenosine triphosphate (ATP). Finally, a down-regulation of the expression of the alpha chain of the interleukin (IL)-2 receptor (i.e., the CD25 molecule) as well as an abnormal Th1 cytokine expression profile (i.e., a decrease of IL-2 and interferon (IFN)-gamma production) were observed after DEP exposure. No differences between the two compounds were detected in all studied parameters. CONCLUSIONS: Overall, our data identify functional and phenotypic T lymphocyte parameters as relevant targets for DEP cytotoxicity, whose impairment could be detrimental, at least in the long run, for human health, favouring the development or the progression of diseases such as autoimmunity and cancer. PMID- 25498257 TI - Wilderness Medical Society practice guidelines for basic wound management in the austere environment: 2014 update. AB - In an effort to produce best-practice guidelines for wound management in the austere environment, the Wilderness Medical Society convened an expert panel charged with the development of evidence-based guidelines for the management of wounds sustained in an austere (dangerous or compromised) environment. Recommendations are made about several parameters related to wound management. These recommendations are graded based on the quality of supporting evidence and the balance between the benefits and risks or burdens for each parameter according to the methodology stipulated by the American College of Chest Physicians. This is an updated version of the original guidelines published in Wilderness & Environmental Medicine 2014;25(3):295-310. PMID- 25498258 TI - Wilderness Medical Society practice guidelines for the use of epinephrine in outdoor education and wilderness settings: 2014 update. AB - The Epinephrine Roundtable took place on July 27, 2008, during the 25th Annual Meeting of the Wilderness Medical Society (WMS) in Snowmass, CO. The WMS convened this roundtable to explore areas of consensus and uncertainty in the field treatment of anaphylaxis. Panelists were selected on the basis of their relevant academic or professional experience. There is a paucity of data that address the treatment of anaphylaxis in the wilderness. Anaphylaxis is a rare disease, with a sudden onset and drastic course that does not lend itself to study in randomized, controlled trials. Therefore, the panel endorsed the following position based on the limited available evidence and review of published articles, as well as expert consensus. The position represents the consensus of the panelists and is endorsed by the WMS. In 2014, the authors reviewed relevant articles published since the Epinephrine Roundtable. The following is an updated version of the original guidelines published in Wilderness & Environmental Medicine 2010;21(4):185-187. PMID- 25498259 TI - Wilderness Medical Society practice guidelines for treatment of eye injuries and illnesses in the wilderness: 2014 update. AB - A panel convened to develop an evidence-based set of guidelines for the recognition and treatment of eye injuries and illnesses that may occur in the wilderness. These guidelines are meant to serve as a tool to help wilderness providers accurately identify and subsequently treat or evacuate for a variety of ophthalmologic complaints. Recommendations are graded on the basis of the quality of their supporting evidence and the balance between risks and benefits according to criteria developed by the American College of Chest Physicians. This is an updated version of the original guidelines published in Wilderness & Environmental Medicine 2012;23(4):325-336. PMID- 25498260 TI - Wilderness Medical Society practice guidelines for treatment of exercise associated hyponatremia: 2014 update. AB - Exercise-associated hyponatremia (EAH) is defined by a serum or plasma sodium concentration below the normal reference range of 135 mmol/L that occurs during or up to 24 hours after prolonged physical activity. It is reported to occur in individual physical activities or during organized endurance events conducted in austere environments in which medical care is limited and often not available, and patient evacuation to definitive care is often greatly delayed. Rapid recognition and appropriate treatment are essential in the severe form to ensure a positive outcome. Failure in this regard is a recognized cause of event-related fatality. In an effort to produce best practice guidelines for EAH in the austere environment, the Wilderness Medical Society convened an expert panel. The panel was charged with the development of evidence-based guidelines for management of EAH. Recommendations are made regarding the situations when sodium concentration can be assessed in the field and when these values are not known. These recommendations are graded on the basis of the quality of supporting evidence and balance between the benefits and risks/burdens for each parameter according to the methodology stipulated by the American College of Chest Physicians. This is an updated version of the original WMS Practice Guidelines for Treatment of Exercise-Associated Hyponatremia published in Wilderness & Environmental Medicine 2013;24(3):228-240. PMID- 25498261 TI - Wilderness Medical Society practice guidelines for the prevention and treatment of acute altitude illness: 2014 update. AB - To provide guidance to clinicians about best practices, the Wilderness Medical Society convened an expert panel to develop evidence-based guidelines for prevention and treatment of acute mountain sickness, high altitude cerebral edema, and high altitude pulmonary edema. These guidelines present the main prophylactic and therapeutic modalities for each disorder and provide recommendations about their role in disease management. Recommendations are graded based on the quality of supporting evidence and balance between the benefits and risks/burdens according to criteria put forth by the American College of Chest Physicians. The guidelines also provide suggested approaches to prevention and management of each disorder that incorporate these recommendations. This is an updated version of the original WMS Consensus Guidelines for the Prevention and Treatment of Acute Altitude Illness published in Wilderness & Environmental Medicine 2010;21(2):146-155. PMID- 25498262 TI - Wilderness Medical Society practice guidelines for the prevention and treatment of frostbite: 2014 update. AB - The Wilderness Medical Society convened an expert panel to develop a set of evidence-based guidelines for the prevention and treatment of frostbite. We present a review of pertinent pathophysiology. We then discuss primary and secondary prevention measures and therapeutic management. Recommendations are made regarding each treatment and its role in management. These recommendations are graded on the basis of the quality of supporting evidence and balance between the benefits and risks or burdens for each modality according to methodology stipulated by the American College of Chest Physicians. This is an updated version of the original guidelines published in Wilderness & Environmental Medicine 2011;22(2):156-166. PMID- 25498263 TI - Wilderness Medical Society practice guidelines for the prevention and treatment of heat-related illness: 2014 update. AB - The Wilderness Medical Society (WMS) convened an expert panel to develop a set of evidence-based guidelines for the recognition, prevention, and treatment of heat illness. We present a review of the classifications, pathophysiology, and evidence-based guidelines for planning and preventive measures as well as best practice recommendations for both field and hospital-based therapeutic management of heat illness. These recommendations are graded on the basis of the quality of supporting evidence, and balance between the benefits and risks or burdens for each modality. This is an updated version of the original WMS Practice Guidelines for the Prevention and Treatment of Heat-Related Illness published in Wilderness & Environmental Medicine 2013;24(4):351-361. PMID- 25498264 TI - Wilderness Medical Society practice guidelines for the out-of-hospital evaluation and treatment of accidental hypothermia: 2014 update. AB - To provide guidance to clinicians, the Wilderness Medical Society (WMS) convened an expert panel to develop evidence-based guidelines for the out-of-hospital evaluation and treatment of victims of accidental hypothermia. The guidelines present the main diagnostic and therapeutic modalities and provide recommendations for the management of hypothermic patients. The panel graded the recommendations based on the quality of supporting evidence and the balance between benefits and risks/burdens according the criteria published by the American College of Chest Physicians. The guidelines also provide suggested general approaches to the evaluation and treatment of accidental hypothermia that incorporate specific recommendations. This is an updated version of the original Wilderness Medical Society Practice Guidelines for the Out-of-Hospital Evaluation and Treatment of Accidental Hypothermia published in Wilderness & Environmental Medicine 2014;25(4):425-445. PMID- 25498265 TI - Wilderness Medical Society practice guidelines for the prevention and treatment of lightning injuries: 2014 update. AB - To provide guidance to clinicians about best practices, the Wilderness Medical Society (WMS) convened an expert panel to develop evidence-based guidelines for the treatment and prevention of lightning injuries. These guidelines include a review of the epidemiology of lightning and recommendations for the prevention of lightning strikes, along with treatment recommendations organized by organ system. Recommendations are graded on the basis of the quality of supporting evidence according to criteria put forth by the American College of Chest Physicians. This is an updated version of the original WMS Practice Guidelines for Prevention and Treatment of Lightning Injuries published in Wilderness & Environmental Medicine 2012;23(3):260-269. PMID- 25498266 TI - Wilderness Medical Society practice guidelines for the treatment of acute pain in remote environments: 2014 update. AB - The Wilderness Medical Society convened an expert panel to develop evidence-based guidelines for the management of pain in austere environments. Recommendations are graded on the basis of the quality of supporting evidence as defined by criteria put forth by the American College of Chest Physicians. This is an updated version of the original WMS Practice Guidelines for the Treatment of Acute Pain in Remote Environments published in Wilderness & Environmental Medicine 2014;25(1):41-49. PMID- 25498267 TI - Re: Randomized controlled trial to compare the safety and efficacy of Tamsulosin, Solifenacin, and combination of both in treatment of double-j stent-related lower urinary symptoms. PMID- 25498268 TI - Beyond the frontiers. PMID- 25498269 TI - Tubularized incised plate urethroplasty for hypospadias reoperation: a review and meta-analysis. AB - PURPOSE: Tubularized Incised Plate (TIP) urethroplasty is a technique for urethral reconstruction of hypospadias although there are some controversies for its use in recurrent cases. The aim of this study was to review the results of TIP technique in various studies and the usage of different flaps for covering the repair site. MATERIAL AND METHODS: Extensive Search was performed for articles published between 1994 and 2013 in common electronic databases. The overall TIP complication rates were estimated by a fixed effects model meta analysis. RESULTS: 17 articles of hypospadia repair using the TIP method were reviewed. All studies performed surgery and repair on the basis of the Snodgrass's method; however, some introduced modifications to the method. The prevalence of complications in repeated TIP surgery was 11.1 to 33.3% and the most prevalent complication in different studies was fistula. Based on the meta analysis, the overall estimation of complications was 21.8% (95% CI: 18.3 to 25.5). CONCLUSION: Most studies performed the incision of the urethral plate to create a supportive coverage upon neourethra, and confirmed its success. We recommend further investigation on using different flaps in well-designed randomized controlled trials to choose the best surgical method for repairing recurrent hypospadias. PMID- 25498270 TI - Parameters of two-dimensional perineal ultrasonography for evaluation of urinary incontinence after Radical Prostatectomy. AB - INTRODUCTION: Urinary incontinence remains a major concern for patients undergoing radical prostatectomy. Its prevalence can reach 20% in the late postoperative period. MATERIALS AND METHODS: This clinical study investigated the differences of a dynamic evaluation of the urethra and pelvic floor contraction using perineal ultrasound in men without prostate surgery and in men submitted to radical prostatectomy with and without stress urinary incontinence. Ninety two male patients were included, which 70% of them underwent radical prostatectomy (RP) for more than one year. Thirty one men with clinically post prostatectomy incontinence were compared by two-dimensional (2D) perineal ultrasound to 34 patients without post prostatectomy incontinence and to 27 men without surgery in two centers in Brazil. RESULTS: Our results showed that the continent group presented the urethral angle at rest significantly lower than the prostate group (p = 0.0002). We also observed that the incontinent group showed the displacement of the anterior bladder neck during contraction significantly lower than the continent group (p = 0.008). CONCLUSIONS: We found that the continent group presented the urethral angle at rest significantly lower than the prostate group. The incontinent group also showed the anterior bladder neck displacement during contraction significantly lower than the continent group. It was more evident when the severe incontinent group and the continent group were compared. PMID- 25498271 TI - How many cores should be taken in a repeat biopsy on patients in whom atypical small acinar proliferation has been identified in an initial transrectal prostate biopsy? AB - OBJECTIVE: To compare cancer detection rates according to the number of biopsy cores in patients on whom a repeat prostate biopsy was performed for atypical small acinar proliferation (ASAP). MATERIALS AND METHODS: The data of 4950 consecutive patients on whom prostate biopsies were performed were assessed retrospectively. A total of 107 patients were identified as having ASAP following an initial prostate biopsy, and they were included in the study. A six-core prostate biopsy (PBx) was performed on 15 of the 107 patients, 12 PBx on 32 patients, and 20 PBx on 60 patients. Cancer detection rates were compared according to the number of biopsy cores. The localization of the cancer foci was also evaluated. RESULTS: The cancer detection rates in patients on whom 6 PBx, 12 PBx, and 20 PBx were performed were 20% (3/15), 31% (10/32), and 58% (35/60), respectively, and a statistically significant difference was found (p = 0.005). When cancer detection rates in patients with total prostate specific antigen (PSA) < 10ng/mL, PSA density >= 0.15, normal digital rectal examination, and prostate volume >= 55mL were compared according to the number of biopsy cores, a significant difference was identified (p = 0.02, 0.03, 0.006, and 0.04, respectively). Seventy-five percent of the foci where cancer was detected were at the same and/or adjacent sites as the ASAP foci in the initial biopsy, and 54% were identified in contralateral biopsies in which ASAP foci were present. CONCLUSION: As the biopsy core number increases, the cancer detection rate increases significantly in patients on whom a repeat biopsy is performed due to ASAP. The highest cancer rate is found in 20-core repeat biopsies performed equally from all foci. PMID- 25498272 TI - Prostate volume predicts high grade prostate cancer both in digital rectal examination negative (ct1c) and positive (>=ct2) patients. AB - INTRODUCTION: We aimed to assess the relationship between prostate volume (PV) and high grade prostate carcinoma (HGPCa) in patients with benign and suspicious digital rectal examination (DRE) in our prostate biopsy cohort. MATERIALS AND METHODS: Between 2009-2012, 759 consecutive initial transrectal systematic 12 cores prostate biopsies were included. PVs were calculated with transrectal ultrasound. Only prostate adenocarcinomas (PCa) were included into the study. For standardization, patients with missing data, and who have been exposed to any form of hormonal or radiation therapy were excluded. Patients were categorized with DRE (negative or positive) and Gleason sum [<7: low grade PCa(LGPCa), >=7: HGPCa]. RESULTS: Median PV was significantly lower in patients with HGPCa. There was a significantly increased risk of HGPCa with PV according to all groups in univariate logistic regression (LR). The significant relationship continued in multivariate LR with PSA and age. From the ROC curve analyses, again a significantly statistical concordance was found between the detection of HGPCa and PV (AUC:0.63, p<0.001), as well as between HGPCa and tPSA (AUC:0.73, p<0.001). tPSA and PV were also significantly concordant with HGPCa both in DRE negative and positive patients. CONCLUSIONS: There is a significant relationship between HGPCa and decreasing PV. The continued significant relationship both in DRE negative and positive patients reinforces this relation. PMID- 25498273 TI - Impact of trait anxiety on psychological well-being in men with prostate cancer. AB - OBJECTIVE: The aim of the present study was to determine state anxiety following radical treatment for localized prostate cancer (PCa), and the impact of trait anxiety on psychological well-being in affected patients. MATERIAL AND METHODS: The present study was a cross-sectional survey of 70 men with localized PCa performed between February 2012 and July 2012. Of those, 21, 24, and 25 patients were treated by radical retropubic prostatectomy (RRP), permanent prostate brachytherapy (PPB), and external beam radiotherapy (EBRT), respectively. State anxiety, trait anxiety, and general health were assessed using the State-Trait Anxiety Inventory and 8 Items Short Form Health Survey (SF-8). RESULTS: The rate of very high and high state anxiety in patients who received RRP was 47.6%, while that in patients who received PPB and EBRT was 40.0% and 37.5%, respectively. In contrast, the rate of very high and high trait anxiety in the RRP group was much lower (23.7%). Trait anxiety showed a high correlation with state anxiety and the mental health component summary of SF-8 (correlation coefficient=0.715, -0.504). CONCLUSIONS: Trait anxiety was associated with the degree of state anxiety regarding treatments for PCa, followed by change in state anxiety, which might have effects on psychological well-being. Information regarding state anxiety as a consequence of treatments and trait anxiety measurement tool are important considerations for treatment decision-making in newly diagnosed PCa patients. PMID- 25498274 TI - Identifying unrecognized collecting system entry and the integrity of repair during open partial nephrectomy: comparison of two techniques. AB - PURPOSE: To compare retrograde dye injection through an externalized ureteral catheter with direct needle injection of dye into proximal ureter for identification of unrecognized collecting system disruption and integrity of subsequent repair during open partial nephrectomy. MATERIALS AND METHODS: We retrospectively reviewed the records of 259 consecutive patients who underwent open partial nephrectomy. Externalized ureteral catheters were placed preoperatively in 110 patients (Group 1); needle injection of methylene blue directly into proximal ureter was used in 120 patients (Group 2). No assessment of the collecting system was performed in 29 patients (Group 3). We compared intraoperative parameters, tumor characteristics, collecting system entry and incidence of urine leaks among the three groups. RESULTS: The mean tumor diameter was 3.1 cm in Group 1, 3.6cm in Group 2, and 3.8 cm in Group 3 (p = 0.04); mean EBL 320cc, 351 cc and 376cc (p = 0.5); mean operative time 193.5 minutes, 221 minutes and 290 minutes (p < 0.001). Collecting system entry was recognized in 63%, 76% and 38% of cases in Groups 1, 2 and 3 respectively. (p = 0.07). Postoperative urine leaks requiring some form of management occurred in 11 patients from group 1 and 6 from group 2. (p = 0.2). No patient in Group 3 developed a urinary leak. CONCLUSIONS: Identification of unrecognized collecting system disruption as well as postoperative urine leak rate in patients undergoing partial nephrectomy were not influenced by the intraoperative technique of identifying unrecognized collecting system entry. Postoperative urine leaks are uncommon despite recognized collecting system disruption in the majority of patients. PMID- 25498275 TI - Micro RNA expression and prognosis in low-grade non-invasive urothelial carcinoma. AB - PURPOSE: To analyze a possible correlation between a miRNA expression profile and important prognostic factors for pTa urothelial carcinomas (UC), including tumor size, multiplicity and episodes of recurrence. MATERIALS AND METHODS: Thirty low grade non-invasive pTa bladder UC from patients submitted to transurethral resection were studied, in a mean follow-up of 17.7 months. As controls, we used normal bladder tissue from five patients submitted to retropubic prostatectomy to treat benign prostatic hyperplasia. Extraction, cDNA and amplification were performed for 14 miRNAs (miR-100, -10a, -21, -205, -let7c, -143, -145, -221, 223, -15a, -16, -199a and -452) using specific kits, and RNU-43 and -48 were used as endogenous controls. Statistical tests were used to compare tumor size, multiplicity and episodes of recurrence with miRNAs expression profiles. RESULTS: There was a marginal correlation between multiplicity and miR-let7c over expression. For all others miRNA no correlation between their expression and prognostic factors was found. CONCLUSION: We did not find differences for miRNAs expression profiles associated with prognostic factors in tumor group studied. The majority of miRNAs are down-regulated, except mir-10a, over-expressed in most of cases, seeming to have increased levels as tumor with more unfavorable prognostic factors. More studies are needed in order to find a miRNA profile able to provide prognosis in pTa UC to be used in clinical practice. PMID- 25498276 TI - Comparison of pneumatic, ultrasonic and combination lithotripters in percutaneous nephrolithotripsy. AB - PURPOSE: We aimed to compare the outcomes of pneumatic (PL), ultrasonic (UL) and combined (PL/UL) lithotripsy performed in percutaneous lithotripsy (PNL) according to success rates and stone clearence. MATERIALS AND METHODS: The medical records of 512 patients treated with PNL between April 2010 and April 2013 were evaluated. Postoperative stone analysis revealed as calcium oxalate in 408 of these patients. The operation notes of 355 patients recorded in detail with complete parameters were reviewed. According to stone disintegration method, patients were divided into three groups: PL only in Group I, UL only in Group II, and UL/PL combination in Group III. Number of patients was 155, 110 and 90, respectively. RESULTS: Fluoroscopy screening time was significantly shorter in group II, and III compared to group I (p<0.001). The failure rates were 13.5% (21 patients) for group I, 3.6% (4 patients) for group II, and 3.3% (3 patients) for group III. There was a significant statistical difference in favor of group II and III by means of success (p=0.023). Group II and III had larger FSA, and this was statistically significant (p=0.032). Stone disintegration time (SDT) was 64.0 +/- 41.92 minutes for group I, 49.5 +/- 34.63 for group II, and 37.7 +/- 16.89 for group III. Group III has a statistically significant shorter SDT (p=0.011). CONCLUSIONS: We concluded that, in cases with high stone burden, where faster and efficient lithotripsy is needed, combined ultrasonic / pneumatic lithotripter may be the ideal choice and in suitable cases ultrasonic lithotripter usage provides important advantages to the surgeon. PMID- 25498278 TI - Differences in urodynamic voiding variables recorded by conventional cystometry and ambulatory monitoring in symptomatic women. AB - OBJECTIVES: To determine whether there are differences in pressure and flow measurements between conventional cystometry (CONV) and ambulatory urodynamic monitoring (AMB) in women with overactive bladder syndrome and urinary incontinence. MATERIALS AND METHODS: Retrospective study which included female subjects who underwent both CONV (with saline filling medium) and AMB, separated by less than 24 months, not using medication active on the lower urinary tract and without history of prior pelvic surgery. Both tests were carried out in compliance with the International Continence Society standards. The paired Student's t test was used to compare continuous variables. Bland-Altman statistics were used to assess the agreement of each variable between both studies. RESULTS: Thirty women with a median (range) age of 50 (14 - 73) years met the inclusion criteria. AMB was carried out at a mean (SD) of 11 (6) months after CONV. Measurements of pves and pabd at the end of filling, and Qmax were significantly higher from AMB recordings. There were no differences in pdet at the end of filling, pdetQmax or pdetmax during voiding, nor significant difference in Vvoid. CONCLUSIONS: We provide previously undocumented comparative voiding data between CONV and AMB for patients who most commonly require both investigations. Our findings show higher values of Qmax but similar values of pdetQmax measured by AMB which may partly reflect an overall lower catheter caliber, physiological filling but perhaps also more 'normal' voiding conditions. PMID- 25498277 TI - Surgical management of adrenal cysts: a single-institution experience. AB - OBJECTIVE: To analyze surgical methods and evaluate treatment efficacy and safety for managing adrenal cystic lesions. MATERIALS AND METHODS: All patients presenting with adrenal lesions of the West China Hospital were reviewed retrospectively from January 2003 to April 2013 and 47 were diagnosed as adrenal cysts. Basic information, clinical history, physical examination, laboratory investigations, abdominal ultrasound and enhanced computed tomography were detailed noted. Cysts with different surgical management were analyzed and surgery option, operative time, postoperative complications and after-surgery hospital stay were all noted. The final diagnosis was judged by histopathology. Patients were followed from 3 month to 10 years. RESULTS: All the 47 patients with a mean age of 43.8 years were managed by surgical intervention. Compared laparoscopic technology with open technology, the laparoscopic has the advantage of a shorter operation time, shorter hospital stay after surgery and enhanced cosmesis. The histopathologic result was: 23 (50%) were endothelial cysts and 16 (35%) were pseudocysts. One patient had evidence to recurrence at the followed-up stage. CONCLUSION: Adrenal cysts are rare and with the development of imaging techniques many of these are diagnosed incidentally. CT has advantages in detecting the cysts with haemorrhage, intracystic debris, calcification and mixed adrenal mass. Minimally invasive surgery offers equivalent efficacy to traditional open procedures, while providing a shorter operation time, shorter convalescence and improved cosmesis. Patients after surgical resection should be followed up closely especially if functional cysts and histopathology of cystic tumor are present. PMID- 25498279 TI - Epididymitis in patients with anorectal malformations: a cause for urologic concern. AB - INTRODUCTION: Epididymitis in patients with anorectal malformation (ARM) represents a unique problem because unlike the general population, an underlying urinary tract problem is frequently identified. We review our experience with epididymitis in ARM population with an emphasis on examining urologic outcomes. MATERIALS AND METHODS: We performed a retrospective review of male patients with ARM cared for from 1980 to 2010. Clinical and pathologic variables recorded included age at presentation, recurrence, associated urologic anomalies, incidence of ureteral fusion with mesonephric ductal structures, glomerular filtration rate and urodynamic parameters. RESULTS: Twenty-six patients were identified with documented episodes of epididymitis. Renal injury was noted in five patients (19%), all of whom were diagnosed with neurogenic bladder (NGB) several years after anorectoplasty. NGB was found in ten patients (38%) in our series. Ectopic insertion of ureter into a mesonephric ductal structure was discovered in five patients (19%). Twelve patients (46%) had recurrent episodes of epididymitis, with seven of these patients (58%) being diagnosed with NGB. Two patients in the pubertal group presented with a history of epididymitis and complained of ejaculatory pain. CONCLUSION: Epididymitis in a patient with ARM warrants a comprehensive urologic investigation, particularly in recurrent episodes. Attempts at surgical intervention (e.g. vasectomy) should be avoided until functional assessment of the urinary tract has occurred. Failure to recognize this association may lead to potentially avoidable complications and morbidity. Long term urological follow up of these patients is warranted to identify at risk patients and minimize renal deterioration. PMID- 25498280 TI - Alpha adrenergic receptors in renal pelvis and calyces: can rat models be used? AB - We aimed, in this study, to determine the distribution of alpha-1 AR subtypes in rat and human pelvis and calyces, and to evaluate, by comparing these two species, the possibility of rats to be used as models for humans. Twenty patients with renal carcinoma were included into the study. The patients underwent radical nephrectomy for renal cell carcinoma (RCC). After nephrectomy, specimens were evaluated and excisional biopsies from healthy pelvis and calyces tissues were performed. When pathology confirmed the non-invasion of RCC, specimen was included into the study. A total of 7 adult Wistar Albino (250-300 g) female rats were used in this study. Specimens included renal pelvis and calyces. All specimens were evaluated under light microscope histopathologically. The concentrations of the receptor densities did not differ between the two groups. With the demonstration of the alpha receptors in rat kidneys and calyces, many receptor-based studies concerning both humans and rats can take place. Novel medication targeting these subtypes -in this matter alpha1A and alpha1D for renal pelvis and calyces- may be helpful for expulsive therapy and/or pain relief. With the demonstration of similar receptor densities between human and rat tissues, rat model may be useful for alpha-receptor trials for renal pelvis and calyces. PMID- 25498281 TI - Intravenous misplacement of nephrostomy tube following percutaneous nephrolithotomy: Three new cases and review of seven cases in the literature. AB - PURPOSE: We investigated the characteristics and management of patients with intravenous misplacement of a nephrostomy tube. MATERIALS AND METHODS: Between July 2007 and July 2013, 4148 patients with urolithiasis underwent percutaneous nephrolithotomy (PCNL) in our hospital. Intravenous misplacement of a nephrostomy tube occurred in two of these patients. Another patient with intravenous misplacement of a nephrostomy tube, who underwent PCNL in another hospital, was transferred to our hospital. The data of the three patients were retrospectively analyzed. RESULTS: The incidence of intravenous misplacement of a nephrostomy tube following PCNL was 0.5% (2/4148) at our hospital. A solitary kidney was present in one of the three patients. The tip of tube was located into the inferior vena cava (IVC) in two patients and into the renal vein in one patient. All three patients were successfully managed with strict bed rest, intravenous antibiotics and one-step (one patient) or two-step (two patients) tube withdrawal under close monitoring. None of the patients underwent antithrombotic therapy. The original operations were performed successfully under close observation in two patients and changed to another operation in one patient. All patients were discharged uneventfully. CONCLUSIONS: The incidence of intravenous misplacement of a nephrostomy tube following PCNL is 0.5% at our hospital. Intravenous nephrostomy tube misplacement is an uncommon complication of PCNL. A solitary kidney may render patients susceptible to this complication. Most patients may be managed conservatively with strict bed rest, intravenous antibiotics and one-step or two-step tube withdrawal under close monitoring. PMID- 25498282 TI - Two-handed assisted laparoscopic surgery: Evaluation in an animal model. AB - PURPOSES: To evaluate in an animal model the feasibility of a novel concept of hand-assisted surgery consisting of inserting two hands into the abdomen instead of one. The chosen procedure was retroperitoneal lymph node dissection (L-RPLND) that was performed in five pigs. SURGICAL TECHNIQUE: A Pfannestiel and a transverse epigastric incisions were made through which both hands were introduced. The scope was inserted through the umbilicus. The colon was moved medially and the dissection was performed as in open surgery using short conventional surgical instruments. COMMENTS: The surgery was fulfilled easily and safely in quite a similar way as in open surgery. Two-handed laparoscopy may be indicated in cases that still today require an open approach as apparently makes the operation easier and significantly shortens the surgery time. However, new opinions and trials are required. PMID- 25498283 TI - Urological surgery in epidermolysis bullosa: tactical planning for surgery and anesthesia. AB - Epidermolysis bullosa (EB) is characterized by extreme fragility of the skin and mucosae. Anesthetic and surgical techniques have to be adapted to those children and routine practice may not be adequate. Urological problems are relatively common, but surgical techniques adapted to those children have not been well debated and only low evidence is available to this moment. Herein we discuss the specifics of anesthetic and surgical techniques chosen to treat a six year old EB male presenting with symptomatic phimosis. PMID- 25498284 TI - Optimizing penile length in patients undergoing partial penectomy for penile cancer: novel application of the ventral phalloplasty oncoplastic technique. AB - The ventral phalloplasty (VP) has been well described in modern day penile prosthesis surgery. The main objectives of this maneuver are to increase perceived length and patient satisfaction and to counteract the natural 1-2 cm average loss in length when performing implantation of an inflatable penile prosthesis. Similarly, this video represents a new adaptation for partial penectomy patients. One can only hope that the addition of the VP for partial penectomy patients with good erectile function will increase their quality of life. The patient in this video is a 56-year-old male who presented with a 4.0x3.5x1.0 cm, pathologic stage T2 squamous cell carcinoma of the glans penis. After partial penectomy with VP and inguinal lymph node dissection, pathological specimen revealed negative margins, 3/5 right superficial nodes and 1/5 left superficial nodes positive for malignancy. The patient has been recommended post operative systemic chemotherapy (with external beam radiotherapy) based on the multiple node positivity and presence of extranodal extension. The patient's pre operative penile length was 9.5 cm, and after partial penectomy with VP, penile length is 7 cm. PMID- 25498285 TI - Extracorporeal transient distal penile corporoglanular shunt in early ischemic priapism treatment. AB - PURPOSE: Ischemic priapism, which is a compartment syndrome, needs urgent treatment in order to nourish corpora cavernosa. As the first step, the aspiration of blood and/or the irrigation of the cavernosal bodies are performed to prevent fibrotic activity and secure erectile capability. While performing aspiration and irrigation, there are some risks of the procedure in which most refrained one is cardiovascular side effects of adrenergic agonists. We aimed to evaluate extracorporeal transient distal penile corporoglanular shunt technique in place of aspiration/ irrigation techniques for early ischemic priapism treatment. MATERIALS AND METHODS: In this transient shunt technique, a sterile closed system blood collection set (BD Vacutainer, Cat. No.: 367282; NJ, USA), which has two 21G needles, was used. The length of the needle and tubing was 19 mm. (0.75 inch) and 178 mm. (7 inches), respectively. This blood collection set was designed to be used not only for blood collection but can also be used for short term infusions (maximum 2 hours). RESULTS: Ten patients out of fifteen with early ischemic priapism were successfully treated with this transient shunt technique. The permanent detumescence achieved in the first 10 minutes in nine out of fifteen patients.No additional procedure needed after the disappearance of rigidity in successfully treated patients. The permanent detumescence achieved in the first 10 minutes in nine out of fifteen patients. CONCLUSIONS: We demonstrated that this extracorporeal transient shunt technique gets some advantages over aspiration and irrigation in early ischemic priapism treatment. Our results indicate thatthe presented technique to be offered for the patients with an ischemic priapism episode of no more than 7 hours. PMID- 25498286 TI - Active surveillance of renal masses: an analysis of growth kinetics and clinical outcomes stratified by radiological characteristics at diagnosis. AB - AIMS: To determine the growth rate of renal masses (RMs) under active surveillance (AS), and to describe the clinical outcome of AS patients. MATERIALS AND METHODS: We conducted a retrospective review of an AS database to obtain demographics, radiological and pathologic characteristics and RM size of patients. RMs were followed at 6-12 month intervals for >=1 year with computed tomography (CT), magnetic resonance imaging (MRI), or renal ultrasound. Kaplan Meier analysis determined the annual likelihood of intervention. RMs were divided into 3 radiographic subcategories (solid, cystic, and angiomyolipoma). A linear regression model determined RM growth rates. RESULTS: 131 RMs in 114 patients were included. Median age, Charlson Comorbidity Index score and mean follow-up were 69.1 years, 4.0 and 4.2+/-2.6 years, respectively. Maximal tumor diameter (MTD) at diagnosis was 2.1 +/- 1.3 cm. 49 RMs exhibited negative or zero net growth. Mean MTD growth rate for all RMs was 0.72+/-3.2 (95% CI: 0.16-1.28) mm/year. When stratified by MTD at diagnosis, mean RM growth rates were 0.84, 0.84, 0.44, 0.74 and 0.71 mm/year for RMs <=1 cm, 1-<=2cm, 2-<= 3cm, 3-<= 4cm and >=4cm, respectively (p<=0.01). The 5 and 10-year freedom from intervention rates were 93.1% and 88.5%, respectively. There was a single case of suspected metastases, but no deaths related to kidney cancer. CONCLUSIONS: RMs under AS grew slowly, and had a low incidence of requiring surgical intervention and progression. Solid enhancing masses grew slowly, and were more likely to trigger intervention. AS should be considered for selected patients with small RMs. PMID- 25498287 TI - Effects of increased anterior-posterior voluntary sway frequency on mechanical and perceived postural stability. AB - Despite a substantial number of studies, the interaction between mechanical indicators of stability and perception of instability remains unclear. The purpose of this study was to determine the effect of sway frequency and verbal restraint on mechanical and perceived postural stability. Fourteen participants underwent a series of standing voluntary anterior-posterior swaying trials at three frequencies (20, 40, and 60bpm) and two levels of restraint (non restraint and verbally restraint to swaying at the ankle). Repeated measures ANOVA tests revealed greater mechanical stability defined though the margin of stability, and greater horizontal ground reaction forces, while the center of pressure excursions remained unchanged with increasing frequency. Furthermore, ground reaction forces were greater in the non-restraint condition. Moreover, a tendency toward greater perceived instability with increasing voluntary sway frequency was observed. Our results indicate that variations in sway frequency and verbal restraint resulted in noticeable alterations in mechanical indicators of stability, with no clear effect on perceived instability. PMID- 25498288 TI - In-shoe multi-segment foot kinematics of children during the propulsive phase of walking and running. AB - Certain styles of children's shoes reduce 1st metatarsophalangeal joint (MTPJ) and midfoot motion during propulsion of walking. However, no studies have investigated if the splinting effect of shoes on children's 1st MTPJ and midfoot motion occurs during running. This study investigated the effect of sports shoes on multi-segment foot kinematics of children during propulsion of walking and running. Twenty children walked and ran at a self-selected velocity while barefoot and shod in a random order. Reflective markers were used to quantify sagittal plane motion of the 1st MTPJ and three-dimensional motion of the midfoot and ankle. Gait velocity increased during shod walking and running and was considered a covariate in the statistical analysis. Shoes reduced 1st MTPJ motion during propulsion of walking from 36.0 degrees to 10.7 degrees and during running from 31.5 degrees to 12.6 degrees . Midfoot sagittal plane motion during propulsion reduced from 22.5 degrees to 6.2 degrees during walking and from 27.4 degrees to 9.6 degrees during running. Sagittal plane ankle motion during propulsion increased during shod running from 26.7 degrees to 34.1 degrees . During propulsion of walking and running, children's sports shoes have a splinting effect on 1st MTPJ and midfoot motion which is partially compensated by an increase in ankle plantarflexion during running. PMID- 25498290 TI - Modulation of motor variability related to experimental muscle pain during elbow flexion contractions. AB - Experimental muscle pain typically reorganizes the motor control. The pain effects may decrease when the three-dimensional force components are voluntarily adjusted, but it is not known if this could have negative consequences on other structures of the motor system. The present study assessed the effects of acute pain on the force variability during sustained elbow flexion when controlling task-related (one-dimensional) and all (three-dimensional) contraction force components via visual feedback. Experimental muscle pain was induced by bolus injection of hypertonic saline into m. biceps brachii, and isotonic saline was used as control. Twelve subjects performed sustained elbow flexion at different levels of the maximal voluntary contraction (5-30% MVC) before, during, and after the injections. Three-dimensional force components were measured simultaneously with surface electromyography (EMG) from elbow flexors and auxiliary muscles. Results showed that force variability was increased during pain compared to baseline for contractions using one-dimensional feedback (P<.05), but no significant differences were found for three-dimensional feedback. During painful contractions (1) EMG activity from m. trapezius was increased during contractions using both one-dimensional and three-dimensional feedback (P<.05), and (2) the complexity of EMG from m. triceps brachii and m. deltoid was higher for the three dimensional feedback (P<.05). In conclusion, the three-dimensional feedback reduced the pain-related functional distortion at the cost of a more complex control of synergistic muscles. PMID- 25498289 TI - The relative contribution of ankle moment and trailing limb angle to propulsive force during gait. AB - A major factor for increasing walking speed is the ability to increase propulsive force. Although propulsive force has been shown to be related to ankle moment and trailing limb angle, the relative contribution of each factor to propulsive force has never been determined. The primary purpose of this study was to quantify the relative contribution of ankle moment and trailing limb angle to propulsive force for able-bodied individuals walking at different speeds. Twenty able-bodied individuals walked at their self-selected and 120% of self-selected walking speed on the treadmill. Kinematic data were collected using an 8-camera motion-capture system. A model describing the relationship between ankle moment, trailing limb angle and propulsive force was obtained through quasi-static analysis. Our main findings were that ankle moment and trailing limb angle each contributes linearly to propulsive force, and that the change in trailing limb angle contributes almost as twice as much as the change in ankle moment to the increase in propulsive force during speed modulation for able-bodied individuals. Able-bodied individuals preferentially modulate trailing limb angle more than ankle moment to increase propulsive force. Future work will determine if this control strategy can be applied to individuals poststroke. PMID- 25498291 TI - Effects of atrazine on the proliferation and cytotoxicity of murine lymphocytes with the use of carboxyfluorescein succinimidyl ester-based flow cytometric approaches. AB - Atrazine (ATZ) is one of the most commonly applied herbicides worldwide. ATZ has been associated with adverse effects on the immune system; however, the mechanism of its immunotoxicity has not been completely elucidated. In this study, the immunotoxic effects of ATZ on murine splenic lymphocytes and magnetic bead enriched NK cells were investigated in vitro with the use of carboxyfluorescein succinimidyl ester (CFDA-SE)-based flow cytometric approaches. Proliferation responses, NK cell activity, and T-cell early activation were determined with CFDA-SE loading, CFDA-SE/propidium iodide (PI) staining, and CD69+ expression, respectively. Cell apoptosis/cycle, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were evaluated using PI, 2',7' dichlorodihydrofluorescein diacetate, and rhodamine 123, respectively. The intracellular expressions of apoptosis-related Bcl-2 and caspase-3 were analyzed through intracellular staining and flow cytometry. Results showed that proliferation and NK cell activity were suppressed by ATZ treatment. Such suppression might be associated with the cell apoptosis induced by increased ROS and declined MMP. The underlying mechanism might be the induced caspase-3 expression and decreased Bcl-2 expression. ATZ could elicit immunotoxic effects on murine lymphocytes; its presence in the environment might compromise immune function in organisms. The flow cytometric methods presented in this study should be further investigated in immunotoxicology. PMID- 25498292 TI - Acetogenic mixotrophy: novel options for yield improvement in biofuels and biochemicals production. AB - Mass yields of biofuels and chemicals from sugar fermentations are limited by the decarboxylation reactions involved in Embden-Meyerhof-Parnas (EMP) glycolysis. This paper reviews one route to recapture evolved CO2 using the Wood-Ljungdahl carbon fixation pathway (WLP) in a process called anaerobic, non-photosynthetic (ANP) mixotrophic fermentation. In ANP mixotrophic fermentation, the two molecules of CO2 and eight electrons produced from glycolysis are used by the WLP to generate three molecules of acetyl-CoA from glucose, rather than the two molecules that are produced by typical fermentation processes. In this review, we define the bounds of ANP mixotrophy, calculate the potential metabolic advantages, and discuss the viability in a number of host organisms. Additionally, we highlight recent accomplishments in the field, including the recent discovery of electron bifurcation in acetogens, and close with recommendations to realize mixotrophic biofuel and biochemical production. PMID- 25498293 TI - Expression patterns of CD66a and CD117 in the mouse submandibular gland. AB - The epithelial tissue of the salivary gland consists of the acinar and ductal parts, the latter of which is further divided into the intercalated, striated and excretory duct segments and is the residential site for salivary stem/progenitor cells. In the present study, the expression patterns of two cell surface molecules, CD66a and CD117, were investigated in the adult mouse submandibular glands (SMG) by immunofluorescence microscopy. Combinations of the two molecules differentially marked several types of SMG epithelial cells, including acinar cells (CD66a-intense, CD117-negative), intercalated duct cells (CD66a-intense, CD117-positive), a subset of the striated and excretory duct cells (CD66a-weak, CD117-positive). Most of the CD117-positive ductal cells were negative for cytokeratin 5 and overlapped with the NKCC1-expressing cells. The CD117- and keratin 5-positive cells resided only in the excretory duct were suggested to correspond to the recently identified salivary stem cells. CD66a and CD117 may be useful markers to isolate several cell types consisting of SMG epithelium and to analyze their molecular and cellular nature. Our data also suggest that CD117 expressing epithelial cells of the gland include at least two distinct populations of the stem/progenitor cells. PMID- 25498294 TI - Evolution of the microstructure and mechanical properties during fabrication of mini-tubes from a biomedical beta-titanium alloy. AB - The processing of Ti-25Nb-3Mo-3Zr-2Sn tubes with outside diameters of 5.6-8.0 mm and wall-thicknesses of 0.7-1.0 mm were investigated in order to study the evolution of microstructure and mechanical properties and their impact on the processing of the tubes. The annealed small tubes with single beta phase microstructures exhibit double yielding during tensile tests. The onset of martensitic phase transformation was observed to occur after the lowest point of the strain hardening. Cold rolling also activates the formation of the stress induced martensitic alpha" phase. Its volume fraction increased with increasing epsilon. The rate of strain hardening and the modulus of the tubes are related to the stress induced transformation of the beta phase to the alpha" phase. The stress induced alpha" slightly improves the yield strength of the tubes at low levels of strain. However, larger strains result in grain growth during annealing, which diminishes the mechanical properties. PMID- 25498295 TI - Fatigue properties of magnesium alloy AZ91 processed by severe plastic deformation. AB - Fatigue properties of cast AZ91 magnesium alloy processed by severe plastic deformation were investigated and compared with the properties of the initial cast state. The severe plastic deformation was carried out by equal channel angular pressing (ECAP). The ECAP treatment resulted in a bimodal structure. The bimodality consists in a coexistence of fine grained areas with higher content of Mg17Al12 particles and areas exhibiting larger grains and lower density of Mg17Al12 particles. Improvement of the basic mechanical properties of AZ91 (yield stress, tensile strength and ductility) by ECAP was significant. Also the improvement of the fatigue life in the low-cycle fatigue region was substantial. However the improvement of the fatigue strength in the high-cycle fatigue region was found to be negligible. The endurance limit based on 10(7) cycles for the cast alloy was 80 MPa and for the alloy processed by ECAP 85 MPa. The cyclic plastic response in both states was qualitatively similar; initial softening was followed by a long cyclic hardening. Fatigue cracks in cast alloy initiate in cyclic slip bands which were formed in areas of solid solution. In the case of severe plastic deformed material with bimodal structure two substantially different mechanisms of crack initiation were observed. Crack initiation in slip bands was a preferred process in the areas with large grains whereas the grain boundaries cracking was a characteristic mechanism in the fine grained regions. PMID- 25498297 TI - Influence of the mineral staggering on the elastic properties of the mineralized collagen fibril in lamellar bone. AB - In this work, a three-dimensional finite element model of the staggered distribution of the mineral within the mineralized collagen fibril has been developed to characterize the lamellar bone elastic behavior at the sub-micro length scale. Minerals have been assumed to be embedded in a collagen matrix, and different degrees of mineralization have been considered allowing the growth of platelet-shaped minerals both in the axial and the transverse directions of the fibril, through the variation of the lateral space between platelets. We provide numerical values and trends for all the elastic constants of the mineralized collagen fibril as a function of the volume fraction of mineral. In our results, we verify the high influence of the mineral overlapping on the mechanical response of the fibril and we highlight that the lateral distance between crystals is relevant to the mechanical behavior of the fibril and not only the mineral overlapping in the axial direction. PMID- 25498296 TI - Importance of age on the dynamic mechanical behavior of intertubular and peritubular dentin. AB - An experimental evaluation of human coronal dentin was performed using nanoscopic dynamic mechanical analysis (nanoDMA). The primary objectives were to quantify any unique changes in mechanical behavior of intertubular and peritubular dentin with age, and to evaluate the microstructure and mechanical behavior of the mineral deposited within the lumens. Specimens of coronal dentin were evaluated by nanoDMA using single indents and in scanning mode via scanning probe microscopy. Results showed that there were no significant differences in the storage modulus or complex modulus between the two age groups (18-25 versus 54-83 yrs) for either the intertubular or peritubular tissue. However, there were significant differences in the dampening behavior between the young and old dentin, as represented in the loss modulus and tandelta responses. For both the intertubular and peritubular components, the capacity for dampening was significantly lower in the old group. Scanning based nanoDMA showed that the tubules of old dentin exhibit a gradient in elastic behavior, with decrease in elastic modulus from the cuff to the center of tubules filled with newly deposited mineral. PMID- 25498298 TI - Effect of adsorption time on the adhesion strength between salivary pellicle and human tooth enamel. AB - Salivary pellicle is a biofilm that is formed by the selective adsorption of salivary proteins. Almost all the functions of the salivary pellicle (lubricating properties, anti-caries properties, etc.) are closely associated with its adhesion strength to tooth surface. The objective of this study was to investigate the effect of adsorption time on the adhesion strength between salivary pellicle and human tooth enamel, aiming to understand what act as the determinant of the interfacial adhesion. In this study, human tooth enamel samples were immersed in human whole saliva in vitro to obtain a salivary pellicle on the surface of enamel. Immersion treatments lasting up to 1, 3, 10 and 60 min were conducted, respectively. Nano-scratch tests were conducted on the surface of enamel after different adsorption times. The wettability of enamel surface was measured through water contact angle. Results showed that the shear energy between salivary pellicle and enamel surface increased exponentially with the adsorption time. The adhesion force between salivary pellicle and bare enamel surface was more than twice that between salivary pellicle and salivary pellicle. It was found that both the wettability and zeta potential of enamel increased obviously after 1 min saliva-adsorption treatment, and then they almost kept stable as the adsorption time further increased. In summary, the adhesion strength between initial salivary pellicle and enamel surface was much higher than that between initial salivary pellicle and outer salivary pellicle. It seemed that electrostatic interaction contributed to the adhesion between the initial salivary pellicle and enamel surface, but not to the adhesion between the initial and outer salivary pellicle. The results would be helpful to extend the understanding of the adhesion mechanism of salivary pellicle and then to develop new artificial saliva and dental restorative materials. PMID- 25498299 TI - Response to research letter in relation to paper by Bongaerts et al., a clinical screening score for diabetic polyneuropathy: KORA F4 and AusDiab studies (a single question screening test for the detection of diabetic peripheral neuropathy). PMID- 25498300 TI - Healthcare utilization and costs in diabetes relative to the clinical spectrum of painful diabetic peripheral neuropathy. AB - AIMS: Diabetic peripheral neuropathy (DPN) accompanied by painful symptoms is known as painful DPN (pDPN). This study characterized healthcare resource utilization and costs in patients with DPN, pDPN, and severe pDPN relative to diabetes only. METHODS: Four adult cohorts were identified from the Humedica database: type 2 diabetes without DPN (n=288,328); DPN (n=35,050); pDPN (DPN subjects with a pain score >=1 on a 0-10 numeric rating scale; n=3449); and severe pDPN (pain scores 7-10; n=1824). Resource utilization and costs for 12 months post-diagnosis were compared for diabetes relative to the other cohorts. RESULTS: Demographic characteristics were different across cohorts. Relative to diabetes alone, DPN, pDPN, and severe pDPN were characterized by significantly higher proportions of patients with resource utilization for all resource categories (all P<0.0001); the highest resource use generally observed for severe pDPN. Total annual direct medical costs were $6632 for diabetes only, with costs for DPN ($12,492), pDPN ($27,931), and severe pDPN ($30,755) significantly higher (all P<0.0001); outpatient costs were consistently the primary driver of total costs. CONCLUSIONS: Patients with DPN, pDPN, and severe pDPN had significantly greater healthcare resource utilization and costs than patients with diabetes only, with the highest burden associated with severe pDPN. PMID- 25498301 TI - Research letter in relation to paper by Bongaerts et al., a clinical screening score for diabetic polyneuropathy: KORA F4 and AusDiab studies. PMID- 25498302 TI - Comparison of a multispectral vision system and a colorimeter for the assessment of meat color. AB - The color assessment ability of a multispectral vision system is investigated by a comparison study with color measurements from a traditional colorimeter. The experiment involves fresh and processed meat samples. Meat is a complex material; heterogeneous with varying scattering and reflectance properties, so several factors can influence the instrumental assessment of meat color. In order to assess whether two methods are equivalent, the variation due to these factors must be taken into account. A statistical analysis was conducted and showed that on a calibration sheet the two instruments are equally capable of measuring color. Moreover the vision system provides a more color rich assessment of fresh meat samples with a glossier surface, than the colorimeter. Careful studies of the different sources of variation enable an assessment of the order of magnitude of the variability between methods accounting for other sources of variation leading to the conclusion that color assessment using a multispectral vision system is superior to traditional colorimeter assessments. PMID- 25498304 TI - AKT1 gene amplification as a biomarker of treatment response in ovarian cancer: mounting evidence of a therapeutic target. PMID- 25498303 TI - Alkali dilution of blood samples for high throughput ICP-MS analysis-comparison with acid digestion. AB - OBJECTIVES: The direct dilution of blood with alkali has been introduced as an alternative to acid digestion for improvement of the analytical productivity when measuring trace elements using inductively coupled plasma mass spectrometry (ICP MS). This study compared these two sample preparation methods for the ICP-MS determination of multiple elements in human blood and serum. METHODS: Aliquots (0.2 or 0.5 mL) of human whole blood and serum samples, including reference samples (whole blood and serum), were subjected to alkali dilution (ammonia solution) or acid digestion (nitric acid). The samples were then analysed for their concentrations of Li, B, Mg, P, S, K, Ca, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Rb, Sr, Mo, Cd, Sb, Cs, Ba, Pb and U with a quadrupole ICP-MS instrument equipped with a collision/reaction cell. RESULTS: Analysis of the reference materials showed that the alkali dilution and acid digestion methods provided equally good agreement with the reference values for Mg, Mn, Co, Ni, Cu, Zn, As, Se, Rb, Mo, Cd, Sb and Pb. The alkali dilution method generally gave better agreement with the reference values for Li, B, P, S, K, Cr and U, whereas acid digestion gave better agreement for Ca, Fe, Sr and Cs. Strong associations (R(2)>0.90) between the two methods were obtained for the concentrations of Li, B, Mn, Co, Cu, As, Se, Rb, Sr, Mo, Cd, Cs and Pb in the collected human whole blood and for Li, B, Mg, P, S, K, Fe, Co, Cu, Zn, As, Se, Rb, Sr, Sb and Cs in the collected serum. CONCLUSIONS: The results suggest that the alkali dilution method is suitable for the determination of Li, B, Mn, Co, Cu, Zn, As, Se, Rb and Sr in whole blood and serum; Mo, Cd and Pb in whole blood; and Sb in serum by ICP MS. Acid digestion is preferred for Fe and for low concentrations of Cs. PMID- 25498305 TI - Association between vitamin D deficiency and mortality in critically ill adult patients: a meta-analysis of cohort studies. AB - INTRODUCTION: Vitamin D deficiency is common in critically ill patients, and was reported to be associated with adverse outcomes. However, the effect of vitamin D deficiency on mortality in critically ill patients remains unclear. METHODS: We searched PubMed and EMBASE from the inception to July 2014 for cohort studies to assess the effect of vitamin D deficiency on the incidence of mortality in critically ill patients. Mortality-specific odds ratio (OR) with 95% confidence interval (CI) were pooled with a random- or fixed-effect models when appropriate. RESULTS: Seven cohort studies with a total of 4,204 participants including 1,679 cases of vitamin D deficiency were included in this meta-analysis. Vitamin D deficiency was significantly associated with an increased hospital mortality (OR 1.76; 95% CI, 1.38 to 2.24; P < 0.001), with very low heterogeneity (I (2) = 2.3%; P = 0.402). The finding of increased hospital mortality in critically ill adult patients was consistently found in every stratum of our subgroup analyses. CONCLUSIONS: This meta-analysis suggests that vitamin D deficiency is associated with increased incidence of hospital mortality in critically ill adult patients. PMID- 25498306 TI - Reversal of doxorubicin resistance in breast cancer by mitochondria-targeted pH responsive micelles. AB - Chemotherapy is an important approach for clinical cancer treatment. However, the success of chemotherapy is usually hindered by the occurrence of intrinsic or acquired multidrug resistance of cancer cells. Herein, we reported an effective approach to overcome doxorubicin (DOX) resistance in MCF-7/ADR breast cancer using DOX-loaded pH-responsive micelles. The micelles were prepared from a pH responsive diblock copolymer, poly(ethylene glycol)-block-poly(2 (diisopropylamino)ethyl methacrylate) (PEG-b-PDPA), and a vitamin E derivate (D alpha-tocopheryl polyethylene glycol 1000 succinate, TPGS) (denoted as PDPA/TPGS micelles). At neutral pH of 7.4, DOX was loaded into the hydrophobic core of PDPA/TPGS micelles via a film sonication method. After cellular uptake, the DOX payload was released in early endosomes by acidic pH-triggered micelle dissociation. Meanwhile, the TPGS component synergistically improved the cytotoxicity of DOX by targeting mitochondrial organelles and reducing the mitochondrial transmembrane potential. In vitro cell culture experiments using DOX-resistant MCF-7/ADR cells demonstrated that PDPA/TPGS micelles reduced the IC50 of DOX by a sixfold magnitude. In vivo animal studies showed that DOX-loaded PDPA/TPGS micelles (PDPA/TPGS@DOX) inhibited tumor growth more efficiently than free DOX in a nude mouse model bearing orthotopic MCF-7/ADR tumor. All these results imply that the mitochondria-targeted pH-responsive PDPA/TPGS micelles have significant potential for efficiently combating DOX resistance in breast cancer cells. PMID- 25498308 TI - Motivations for contributing to health-related articles on Wikipedia: an interview study. AB - BACKGROUND: Wikipedia is one of the most accessed sources of health information online. The current English-language Wikipedia contains more than 28,000 articles pertaining to health. OBJECTIVE: The aim was to characterize individuals' motivations for contributing to health content on the English-language Wikipedia. METHODS: A set of health-related articles were randomly selected and recent contributors invited to complete an online questionnaire and follow-up interview (by Skype, by email, or face-to-face). Interviews were transcribed and analyzed using thematic analysis and a realist grounded theory approach. RESULTS: A total of 32 Wikipedians (31 men) completed the questionnaire and 17 were interviewed. Those completing the questionnaire had a mean age of 39 (range 12-59) years; 16 had a postgraduate qualification, 10 had or were currently studying for an undergraduate qualification, 3 had no more than secondary education, and 3 were still in secondary education. In all, 15 were currently working in a health related field (primarily clinicians). The median period for which they have been an active editing Wikipedia was 3-5 years. Of this group, 12 were in the United States, 6 were in the United Kingdom, 4 were in Canada, and the remainder from another 8 countries. Two-thirds spoke more than 1 language and 90% (29/32) were also active contributors in domains other than health. Wikipedians in this study were identified as health professionals, professionals with specific health interests, students, and individuals with health problems. Based on the interviews, their motivations for editing health-related content were summarized in 5 strongly interrelated categories: education (learning about subjects by editing articles), help (wanting to improve and maintain Wikipedia), responsibility (responsibility, often a professional responsibility, to provide good quality health information to readers), fulfillment (editing Wikipedia as a fun, relaxing, engaging, and rewarding activity), and positive attitude to Wikipedia (belief in the value of Wikipedia). An additional factor, hostility (from other contributors), was identified that negatively affected Wikipedians' motivations. CONCLUSIONS: Contributions to Wikipedia's health-related content in this study were made by both health specialists and laypeople of varying editorial skills. Their motivations for contributing stem from an inherent drive based on values, standards, and beliefs. It became apparent that the community who most actively monitor and edit health-related articles is very small. Although some contributors correspond to a model of "knowledge philanthropists," others were focused on maintaining articles (improving spelling and grammar, organization, and handling vandalism). There is a need for more people to be involved in Wikipedia's health-related content. PMID- 25498307 TI - Respiratory-swallow training in patients with head and neck cancer. AB - OBJECTIVE: To test a novel intervention to train swallowing to occur in the midexpiratory to low expiratory phase of quiet breathing to improve swallowing safety and efficiency. DESIGN: Safety and efficacy nonrandomized controlled trial with 1-month follow-up. SETTING: Ambulatory clinics. PARTICIPANTS: Patients (N=30) with head and neck cancer (HNC) and chronic dysphagia completed the intervention. Fifteen of these patients participated in a 1-month follow-up visit. INTERVENTIONS: Training protocol based on hierarchy of motor skill acquisition to encourage autonomous and optimal respiratory-swallowing coordination. Visual feedback of respiratory phase and volume for swallowing initiation was provided by nasal airflow and rib cage/abdomen signals. MAIN OUTCOME MEASURES: Respiratory-swallow phase pattern, Modified Barium Swallow Impairment Profile (MBSImP) scores, Penetration-Aspiration Scale (PAS) scores, and MD Anderson Dysphagia Inventory scores. RESULTS: Using visual feedback, patients were trained to initiate swallows during the midexpiratory phase of quiet breathing and continue to expire after swallowing. This optimal phase patterning increased significantly after treatment (P<.0001). Changes in respiratory-swallowing coordination were associated with improvements in 3 MBSImP component scores: laryngeal vestibular closure (P=.0004), tongue base retraction (P<.0001), and pharyngeal residue (P=.01). Significant improvements were also seen in PAS scores (P<.0001). Relative to pretreatment values, patients participating in 1-month follow-up had increased optimal phase patterning (P<.0001), improved laryngeal vestibular closure (P=.01), tongue base retraction (P=.003), and pharyngeal residue (P=.006) MBSImP scores and improved PAS scores (P<.0001). CONCLUSIONS: Improvements in respiratory-swallowing coordination can be trained using a systematic protocol and respiratory phase-lung volume-related biofeedback in patients with HNC and chronic dysphagia, with favorable effects on airway protection and bolus clearance. PMID- 25498309 TI - Insights into the early evolution of animal calcium signaling machinery: a unicellular point of view. AB - The basic principles of Ca(2+) regulation emerged early in prokaryotes. Ca(2+) signaling acquired more extensive and varied functions when life evolved into multicellular eukaryotes with intracellular organelles. Animals, fungi and plants display differences in the mechanisms that control cytosolic Ca(2+) concentrations. The aim of this review is to examine recent findings from comparative genomics of Ca(2+) signaling molecules in close unicellular relatives of animals and in common unicellular ancestors of animals and fungi. Also discussed are the evolution and origins of the sperm-specific CatSper channel complex, cation/Ca(2+) exchangers and four-domain voltage-gated Ca(2+) channels. Newly identified evolutionary evidence suggests that the distinct Ca(2+) signaling machineries in animals, plants and fungi likely originated from an ancient Ca(2+) signaling machinery prior to early eukaryotic radiation. PMID- 25498311 TI - Reforming private drug coverage in Canada: inefficient drug benefit design and the barriers to change in unionized settings. AB - Prescription drugs are the highest single cost component for employees' benefits packages in Canada. While industry literature considers cost-containment for prescription drug costs to be a priority for insurers and employers, the implementation of cost-containment measures for private drug plans in Canada remains more of a myth than a reality. Through 18 semi-structured phone interviews conducted with experts from private sector companies, unions, insurers and plan advisors, this study explores the reasons behind this incapacity to implement cost-containment measures by examining how private sector employers negotiate drug benefit design in unionized settings. Respondents were asked questions on how employee benefits are negotiated; the relationships between the players who influence drug benefit design; the role of these players' strategies in influencing plan design; the broad system that underpins drug benefit design; and the potential for a universal pharmacare program in Canada. The study shows that there is consensus about the need to educate employees and employers, more collaboration and data-sharing between these two sets of players, and for external intervention from government to help transform established norms in terms of private drug plan design. PMID- 25498312 TI - Non-epileptic myoclonic attacks in infancy: three cases. AB - Since the first cases of abnormal paroxystic movements in normal infants were described, the importance of accurate characterization of this medical condition has been increasingly confirmed in the literature. Non-epileptic attacks mimic epileptic paroxysms in clinical presentation, but they have a typically benign course and are unresponsive to pharmacological treatment. An evident feature of the syndrome is its extreme variability in clinical manifestation. Here, we describe three normal infants with two similar forms of non-epileptic paroxysms. Electroclinical manifestations and profile of evolution were investigated. Ictal video-EEG polygraphic recordings were obtained for each patient. The increasing number of such reported clinical cases in the literature may contribute to high quality systematic reviews and the development of useful guidelines in the future. The clinical heterogeneity of non-epileptic attacks, together with the relative rarity of the condition, may make differential diagnosis with epileptic attacks very challenging. [Published with video sequences]. PMID- 25498310 TI - Quinolinic acid toxicity on oligodendroglial cells: relevance for multiple sclerosis and therapeutic strategies. AB - The excitotoxin quinolinic acid, a by-product of the kynurenine pathway, is known to be involved in several neurological diseases including multiple sclerosis (MS). Quinolinic acid levels are elevated in experimental autoimmune encephalomyelitis rodents, the widely used animal model of MS. Our group has also found pathophysiological concentrations of quinolinic acid in MS patients. This led us to investigate the effect of quinolinic acid on oligodendrocytes; the main cell type targeted by the autoimmune response in MS. We have examined the kynurenine pathway (KP) profile of two oligodendrocyte cell lines and show that these cells have a limited threshold to catabolize exogenous quinolinic acid. We further propose and demonstrate two strategies to limit quinolinic acid gliotoxicity: 1) by neutralizing quinolinic acid's effects with anti-quinolinic acid monoclonal antibodies and 2) directly inhibiting quinolinic acid production from activated monocytic cells using specific KP enzyme inhibitors. The outcome of this study provides a new insight into therapeutic strategies for limiting quinolinic acid-induced neurodegeneration, especially in neurological disorders that target oligodendrocytes, such as MS. PMID- 25498314 TI - The binding, transport and fate of aluminium in biological cells. AB - Aluminium is the most abundant metal in the Earth's crust and yet, paradoxically, it has no known biological function. Aluminium is biochemically reactive, it is simply that it is not required for any essential process in extant biota. There is evidence neither of element-specific nor evolutionarily conserved aluminium biochemistry. This means that there are no ligands or chaperones which are specific to its transport, there are no transporters or channels to selectively facilitate its passage across membranes, there are no intracellular storage proteins to aid its cellular homeostasis and there are no pathways which evolved to enable the metabolism and excretion of aluminium. Of course, aluminium is found in every compartment of every cell of every organism, from virus through to Man. Herein we have investigated each of the 'silent' pathways and metabolic events which together constitute a form of aluminium homeostasis in biota, identifying and evaluating as far as is possible what is known and, equally importantly, what is unknown about its uptake, transport, storage and excretion. PMID- 25498315 TI - Spontaneous aberrant right subclavian arterio-oesophageal fistula in a previously healthy child. AB - An aberrant right subclavian artery arising from a left aortic arch is the most frequently described congenital aortic arch anomaly, occurring in 0.5 to 2.3% of the general population. Despite the retro-oesophageal course of the aberrant subclavian artery, an arterio-oesophageal fistula is an uncommon finding, only previously reported as a very rare complication in critically ill patients with oesophageal instrumentation or foreign body ingestion. We describe a unique case of a spontaneous aberrant right subclavian arterio-oesophageal fistula without an inciting event in a 17-month-child. PMID- 25498313 TI - Pioglitazone restores phagocyte mitochondrial oxidants and bactericidal capacity in chronic granulomatous disease. AB - BACKGROUND: Deficient production of reactive oxygen species (ROS) by the phagocyte nicotinamide adenine dinucleotide (NADPH) oxidase in patients with chronic granulomatous disease (CGD) results in susceptibility to certain pathogens secondary to impaired oxidative killing and mobilization of other phagocyte defenses. Peroxisome proliferator-activated receptor (PPAR) gamma agonists, including pioglitazone, approved for type 2 diabetes therapy alter cellular metabolism and can heighten ROS production. It was hypothesized that pioglitazone treatment of gp91(phox-/-) mice, a murine model of human CGD, would enhance phagocyte oxidant production and killing of Staphylococcus aureus, a significant pathogen in patients with this disorder. OBJECTIVES: We sought to determine whether pioglitazone treatment of gp91(phox-/-) mice enhanced phagocyte oxidant production and host defense. METHODS: Wild-type and gp91(phox-/-) mice were treated with the PPARgamma agonist pioglitazone, and phagocyte ROS and killing of S aureus were investigated. RESULTS: As demonstrated by 3 different ROS-sensing probes, short-term treatment of gp91(phox-/-) mice with pioglitazone enhanced stimulated ROS production in neutrophils and monocytes from blood and neutrophils and inflammatory macrophages recruited to tissues. Mitochondria were identified as the source of ROS. Findings were replicated in human monocytes from patients with CGD after ex vivo pioglitazone treatment. Importantly, although mitochondrial (mt)ROS were deficient in gp91(phox-/-) phagocytes, their restoration with treatment significantly enabled killing of S aureus both ex vivo and in vivo. CONCLUSIONS: Together, the data support the hypothesis that signaling from the NADPH oxidase under normal circumstances governs phagocyte mtROS production and that such signaling is lacking in the absence of a functioning phagocyte oxidase. PPARgamma agonism appears to bypass the need for the NADPH oxidase for enhanced mtROS production and partially restores host defense in CGD. PMID- 25498316 TI - Assessing somatic symptom burden: a psychometric comparison of the patient health questionnaire-15 (PHQ-15) and the somatic symptom scale-8 (SSS-8). AB - OBJECTIVE: The Patient Health Questionnaire-15 (PHQ-15) is a frequently used questionnaire to assess somatic symptom burden. Recently, the Somatic Symptom Scale-8 (SSS-8) has been published as a short version of the PHQ-15. This study examines whether the instruments' psychometric properties and estimates of symptom burden are comparable. METHODS: Psychosomatic outpatients (N=131) completed the PHQ-15, the SSS-8 and other questionnaires (PHQ-9, GAD-7, WI-7, SF 12). Item characteristics and measures of reliability, validity, and symptom severity were determined and compared. RESULTS: The reliabilities of the PHQ-15 and SSS-8 were alpha=0.80 and alpha=0.76, respectively and both scales were highly correlated (r=0.83). The item characteristics were comparable. Both instruments showed the same pattern of correlations with measures of depression, anxiety, health anxiety and health-related quality of life (r=0.32 to 0.61). On both scales a 1-point increase was associated with a 3% increase in health care use. The percentile distributions of the PHQ-15 and the SSS-8 were similar. Using the same thresholds for somatic symptom severity (5, 10, and 15 points), both instruments identified nearly identical subgroups of patients with respect to health related quality of life. CONCLUSION: The PHQ-15 and the SSS-8 showed similar reliability and validity but the comparability of severity classifications needs further evaluation in other populations. Until then we recommend the use of the previously established thresholds. Overall, the SSS-8 performed well as a short version of the PHQ-15 which makes it preferable for assessment in time restricted settings. PMID- 25498317 TI - A Breathlessness Catastrophizing Scale for chronic obstructive pulmonary disease. AB - OBJECTIVE: Catastrophizing about breathlessness may be related to disability in patients with chronic obstructive pulmonary disease (COPD), but assessment options are limited. This study reports the initial validation of a 13-item Breathlessness Catastrophizing Scale (BCS). METHOD: Pulmonary rehabilitation inpatients completed spirometric, functional performance and questionnaire assessments at admission (N=242) and discharge (n=186). RESULTS: The BCS comprised a unifactorial scale that demonstrated excellent internal consistency (Cronbach's alpha=.96) and correlated with measures of anxiety sensitivity, depression, and self-efficacy, but not with performance on walk and stair climbing tests. BCS scores improved robustly with rehabilitation, approaching a medium effect size (d=.43), and demonstrated a modest association with enhanced performance in a stair-climbing test of exercise tolerance. CONCLUSION: The BCS is a reliable measure of catastrophizing in severe COPD that has good convergent validity and sensitivity to change. Its association with functional performance requires further investigation. However, it appears that a high level of catastrophizing about breathlessness is not a barrier to functional improvement with inpatient pulmonary rehabilitation. PMID- 25498318 TI - The role of insomnia in the treatment of chronic fatigue. AB - BACKGROUND: The definition of Chronic Fatigue Syndrome (CFS) overlaps with definitions of insomnia, but there is limited knowledge about the role of insomnia in the treatment of chronic fatigue. AIMS: To test if improvement of insomnia during treatment of chronic fatigue was associated with improved outcomes on 1) fatigue and 2) cortisol recovery span during a standardized stress exposure. METHODS: Patients (n = 122) with chronic fatigue received a 3.5-week inpatient return-to-work rehabilitation program based on Acceptance and Commitment Therapy, and had been on paid sick leave>8 weeks due their condition. A physician and a psychologist examined the patients, assessed medication use, and SCID-I diagnoses. Patients completed self-report questionnaires measuring fatigue, pain, depression, anxiety, and insomnia before and after treatment. A subgroup (n = 25) also completed the Trier Social Stress Test for Groups (TSST-G) before and after treatment. Seven cortisol samples were collected during each test and cortisol spans for the TSST-G were calculated. RESULTS: A hierarchical regression analysis in nine steps showed that insomnia improvement predicted improvement in fatigue, independently of age, gender, improvement in pain intensity, depression and anxiety. A second hierarchical regression analysis showed that improvement in insomnia significantly predicted the cortisol recovery span after the TSST-G independently of improvement in fatigue. CONCLUSION: Improvement in insomnia severity had a significant impact on both improvement in fatigue and the ability to recover from a stressful situation. Insomnia severity may be a maintaining factor in chronic fatigue and specifically targeting this in treatment could increase treatment response. PMID- 25498319 TI - Adverse life events and health: a population study in Hong Kong. AB - OBJECTIVE: Although the effects of adverse life events on mental health have been well documented in the literature, there has never been a population based study that investigated systematically the association between history of adverse life events and physical health (objective and subjective) in adults. METHOD: Cross sectional, face-to-face household population based survey of adults (18+) in Hong Kong (N=1147). Participants were asked if they had a diagnosis of six health conditions including hypertension, heart disease, arthritis, diabetes, eyesight degeneration, and hearing loss. They were also asked if they had experienced five adverse life events including death of a partner or spouse, abuse, natural disaster, life threatening illness or injury, and family disruption. Interviews also included the Short-Form 12 Health Survey (SFHS-12) and the short version of the Centre for Epidemiologic Studies Depression Scale (CES-D). RESULTS: Overall, results indicate that specific adverse life events may be associated with specific health conditions. However, all tested life events were associated with subjective physical and mental health. Death of partner or parent and life threatening illness or injury were found to have the strongest association with physical health problems. A dose-response relationship between adverse life events and physical health in general was evident but more so for heart disease and eyesight degeneration. CONCLUSION: Considering the high prevalence of traumatic events and how common the conditions associated with such events are in the general population, screening for adverse life events as part of comprehensive assessment will allow a deeper understanding of patients' needs. PMID- 25498320 TI - Dermatomyositis and myastenia gravis: An uncommon association with therapeutic implications. AB - The association of dermatomyositis with myasthenia gravis (MG) is uncommon, having been reported so far in only 26 cases. We report the case of a 69 year-old man diagnosed with MG two years ago and currently treated with piridostigmyne. The patient developed acute proximal weakness, shoulder pain and elevated creatine-kinase (CK). He also developed generalized facial erythema and Gottron's papules. Laboratory tests showed positive antinuclear and anti-Mi2 antibodies. Further analysis confirmed CK levels above 1000 U/l. The clinical management of the patient and the therapeutic implications derived from the coexistence of both entities are discusssed. PMID- 25498321 TI - Incidental entry of a colonoscope into the scrotum: not a mystery but a missed history. PMID- 25498322 TI - Pharmaceutical properties of supramolecular assembly of co-loaded cardanol/triazole-halloysite systems. AB - Halloysite nanotubes were explored as drug carrier for cardanol, which is considered as a promising natural anticancer active species. To this aim, besides the pristine nanoclay, a chemical modification of the nanocarrier was performed by attaching triazolium salts with different hydrophobicity at the outer surface of the hollow nanotubes. The interaction between cardanol and nanotubes was highlighted in solution by HPLC. This method proved the loading of the drug into the nanotubes. The solid dried complexes formed by pristine and modified halloysite with the cardanol were characterized by IR spectroscopy, thermogravimetric analysis as well as water contact angle to evidence the structure, thermal properties and wettability of the obtained materials. The kinetics of cardanol release as well as cell viability experiments provided promising results that put forward a new strategy for potential applications of cardanol as active antiproliferative molecule and clay nanotubes as drug carrier. PMID- 25498323 TI - The significance of hand dominance in hip osteoarthritis. AB - OBJECTIVES: Hip arthroplasty registries, encompassing all-cause end-stage hip degeneration, have shown that slightly more right hip replacements are performed than left. Given that greater than 85% of individuals are right-handed, we sought to investigate the association between side of hand dominance and side of hip osteoarthritis. METHODS: This Level III observational study evaluated exclusively end-stage osteoarthritis of the hip, using 3 independent centres totalling 386 consecutive arthroplasty patients. Logistic regression was used as a statistical model. RESULTS: In total, 322 patients with hip osteoarthritis were included in the final analysis, including 146 (45.5%) women and 176 (54.5%) men, with a mean age of 68.1 years (SD = 9.5 years). There were 133 (41.2%) right, 73 (22.6%) left, and 116 (35.9%) bilateral hips where the contralateral side had been previously replaced. The proportion of individuals requiring unilateral hip arthroplasty on their dominant side was 67.4%. CONCLUSIONS: In the development of hip osteoarthritis, one is significantly more likely to require hip arthroplasty on their dominant side than in the contralateral hip. Assessment of hand dominance identifies cerebral laterality as a contributing factor in predisposing one's dominant side to hip osteoarthritis. PMID- 25498324 TI - Specific antibody deficiency with normal immunoglobulin concentration in children with recurrent respiratory infections. AB - BACKGROUND: Response to polysaccharide antigens is a test to evaluate the immunological competence of children with recurrent respiratory infections (RRI) of unknown cause and no other immune system abnormality. In order to detect specific antibody deficiency (SAD), a group of children with RRI without other immunodeficiency were prospectively studied. METHODS: We included 20 children (12 male), age range 3-14 years, with six or more annual episodes of respiratory infections (RI); one or more monthly episodes of RI during the winter months; or three or more annual episodes of lower RI. The children were immunised with 23 valent polysaccharide anti-pneumococcal vaccine, and ELISA was used to measure anti-polysaccharide IgG antibody levels for 10 pneumococcal serotypes at baseline (T0), and 45 days (T1) and one year post-immunisation (T2). Post-immunisation response above 1.3 MUg/ml for more than 50% of the serotypes was considered normal for children 2-5 years, and for more than 70% of the serotypes in children older than 5 years. RESULTS: At T1 19/20 children showed a normal response for their age, and only one patient showed a deficient response, suggestive of classic moderate SAD. At T2, 8/20 patients showed deficient responses, suggestive of impaired persistence of specific antibodies. There was a noteworthy association between deficient response and asthma and allergic rhinitis. CONCLUSIONS: We propose first ruling out local or systemic causes, then performing serum immunoglobulin IgM, IgG, IgA, IgE and IgG subclass levels, and finally measuring response to polysaccharide pneumococcal antigens for detection of SAD. PMID- 25498326 TI - NHS should adopt new ways of working, such as joint ventures and collaboratives with private providers, Dalton report says. PMID- 25498325 TI - Ebola virus vaccine trials: the ethical mandate for a therapeutic safety net. PMID- 25498328 TI - New multiplex PCR method for the simultaneous diagnosis of the three known species of equine tapeworm. AB - Although several techniques exist for the detection of equine tapeworms in serum and feces, the differential diagnosis of tapeworm infection is usually based on postmortem findings and the morphological identification of eggs in feces. In this study, a multiplex polymerase chain reaction (PCR)-based method for the simultaneuos detection of Anoplocephala magna, Anoplocephala perfoliata and Anoplocephaloides mamillana has been developed and validated. The method simultaneously amplifies hypervariable SSUrRNA gene regions in the three tapeworm species in a single reaction using three pairs of primers, which exclusively amplify the internal transcribed spacer 2 (ITS-2) in each target gene. The method was tested on three types of sample: (a) 1/10, 1/100, 1/500, 1/1000, 1/2000 and 1/5000 dilutions of 70 ng of genomic DNA of the three tapeworm species, (b) DNA extracted from negative aliquots of sediments of negative control fecal samples spiked with 500, 200, 100, 50 and 10 eggs (only for A. magna and A. perfoliata; no A. mamillana eggs available) and (c) DNA extracted from 80, 50, 40, 30, 10 and 1 egg per 2 MUl of PCR reaction mix (only for A. magna and A. perfoliata; no A. mamillana eggs available). No amplification was observed against the DNA of Gasterophilus intestinalis, Parascaris equorum and Strongylus vulgaris. The multiplex PCR method emerged as specific for the three tapeworms and was able to identify as few as 50 eggs per fecal sample and as little as 0.7 ng of control genomic DNA obtained from the three species. The method proposed is able to differentiate infections caused by the two most frequent species A. magna or A. perfoliata when the eggs are present in feces and is also able to detect mixed infections by the three cestode species. PMID- 25498329 TI - Do we really rely on fast for decision-making in the management of blunt abdominal trauma? AB - INTRODUCTION: The Focused Assessment with Sonography in Trauma examination (FAST) is currently taught and recommended in the ATLS((r)), often as an addendum to the primary survey for patients with blunt abdominal trauma. Although it is non invasive and rapidly performed at bedside, the utility of FAST in blunt abdominal trauma has been questioned. We designed this study to examine our hypothesis that FAST is not an efficacious screening tool for identifying intra-abdominal injuries. METHODS: We performed a retrospective chart review of all patients with confirmatory diagnosis of blunt abdominal injuries with CT and/or laparotomy for a period of 1.5 years (from 7/2009 to 11/2010). FAST was performed by ED residents and considered positive when free intra-abdominal fluid was visualized. Abdominal CT, or exploratory laparotomy findings were used as confirmation of intra-abdominal injury. RESULTS: A total of 1671 blunt trauma patients were admitted to and evaluated in the Emergency Department during a 11/2 year period and 146 patients were confirmed intra-abdominal injuries by CT and/or laparotomy. Intraoperative findings include injuries to the liver, spleen, kidneys, and bowels. In 114 hemodynamically stable patients, FAST was positive in 25 patients, with a sensitivity of 22%. In 32 hemodynamically unstable patients, FAST was positive in 9 patients, with a sensitivity of 28%. A free peritoneal fluid and splenic injury are associated with a positive FAST on univariate analysis, and are the independent predictors for a positive FAST on multiple logistic regression. CONCLUSION: FAST has a very low sensitivity in detecting blunt intraabdominal injury. In hemodynamically stable patients, a negative FAST without a CT may result in missed intra-abdominal injuries. In hemodynamically unstable blunt trauma patients, with clear physical findings on examination, the decision for exploratory laparotomy should not be distracted by a negative FAST. PMID- 25498327 TI - Anisakid nematodes in beaked redfish (Sebastes mentella) from three fishing grounds in the North Atlantic, with special notes on distribution in the fish musculature. AB - Parasitic anisakid nematodes commonly occur in the musculature and visceral organs of many fish species from the North Atlantic. In this respect, the presence of the third stage larvae of Anisakis spp. in the fish musculature may pose a potential consumer hazard due to the parasite's ability to cause anisakidosis. Thus, knowledge on the occurrence and distribution of these potentially zoonotic parasites in the commercially important North Atlantic fish species is crucial in order to evaluate and consequently prevent human infections. In the present study, 300 Sebastes mentella from three North Atlantic fishing grounds (Northern North Sea: Tampen; Barents Sea: off Bear Island; Irminger Sea: off SE Greenland) were examined for anisakid nematodes, with emphasis on occurrence and distribution in the musculature. Overall larval prevalence and mean intensity were significantly higher in redfish from Tampen (94%; 13.5+/-20.0) and Bear Island (94%; 14.5+/-19.4) than in fish from SE Greenland (75%; 6.0+/-5.8; p<0.01). The same trend was observed for larval infection in the musculature showing prevalence and mean intensities of 79%, 73%, and 55%, and 5.9+/-6.6, 5.8+/-6.5, and 3.2+/-2.4, in the musculature of redfish from Tampen, Bear Island, and Greenland, respectively. Conventional microscopy and rDNA ITS-gene sequencing of various subsamples of muscle-dwelling nematode larvae of redfish from every catching locality revealed the presence of two anisakid species; Anisakis simplex sensu stricto and the non-zoonotic Hysterothylacium aduncum. Since the larvae of H. aduncum typically occur in or on the viscera of fish, our findings of two specimens in the belly flaps of redfish were unusual. Additionally, more than 92% of the muscle-dwelling larvae occurred in the belly flaps, i.e. the hypaxial part of the musculature surrounding the visceral organs on either fish side. Thus, trimming the fillets of beaked redfish by removal of most of the belly flaps would significantly reduce the probability of anisakid nematode larvae to be present in the final product. PMID- 25498330 TI - Activity of bone cement loaded with daptomycin alone or in combination with gentamicin or PEG600 against Staphylococcus epidermidis biofilms. AB - Daptomycin is a promising candidate for local treatment of bone infection due to its activity against multi-resistant staphylococci. We investigated the activity of antibiotic-loaded PMMA against Staphylococcus epidermidis biofilms using an ultra-sensitive method bacterial heat detection method (microcalorimetry). PMMA cylinders loaded with daptomycin alone or in combination with gentamicin or PEG600, vancomycin and gentamicin were incubated with S. epidermidis-RP62A in tryptic soy broth (TSB) for 72 h. Cylinders were thereafter washed and transferred in microcalorimetry ampoules pre-filled with TSB. Bacterial heat production, proportional to the quantity of biofilm on the PMMA, was measured by isothermal microcalorimetry at 37 degrees C. Heat detection time was considered time to reach 20 MUW. Experiments were performed in duplicate. The heat detection time was 5.7-7.0 h for PMMA without antibiotics. When loaded with 5% of daptomycin, vancomycin or gentamicin, detection times were 5.6-16.4 h, 16.8-35.7 h and 4.7-6.2 h, respectively. No heat was detected when 5% gentamicin or 0.5% PEG600 was added to the daptomycin-loaded PMMA. The study showed that vancomycin was superior to daptomycin and gentamicin in inhbiting staphylococcal adherence in vitro. However, PMMA loaded with daptomycin combined with gentamicin or PEG600 completely inhibited S. epidermidis-biofilm formation. PMMA loaded with these combinations may represent effective strategies for local treatment in the presence of multi-resistant staphylococci. PMID- 25498331 TI - Making the most of injury surveillance data: using narrative text to identify exposure information in case-control studies. AB - INTRODUCTION: Free-text fields in injury surveillance databases can provide detailed information beyond routinely coded data. Additional data, such as exposures and covariates can be identified from narrative text and used to conduct case-control studies. METHODS: To illustrate this, we developed a text search algorithm to identify helmet status (worn, not worn, use unknown) in the U.S. National Electronic Injury Surveillance System (NEISS) narratives for bicycling and other sports injuries from 2005 to 2011. We calculated adjusted odds ratios (ORs) for head injury associated with helmet use, with non-head injuries representing controls. For bicycling, we validated ORs against published estimates. ORs were calculated for other sports and we examined factors associated with helmet reporting. RESULTS: Of 105,614 bicycling injury narratives reviewed, 14.1% contained sufficient helmet information for use in the case control study. The adjusted ORs for head injuries associated with helmet-wearing were smaller than, but directionally consistent, with previously published estimates (e.g., 1999 Cochrane Review). ORs illustrated a protective effect of helmets for other sports as well (less than 1). CONCLUSIONS: This exploratory analysis illustrates the potential utility of relatively simple text-search algorithms to identify additional variables in surveillance data. Limitations of this study include possible selection bias and the inability to identify individuals with multiple injuries. A similar approach can be applied to study other injuries, conditions, risks, or protective factors. This approach may serve as an efficient method to extend the utility of injury surveillance data to conduct epidemiological research. PMID- 25498332 TI - Synchrotron based planar imaging and digital tomosynthesis of breast and biopsy phantoms using a CMOS active pixel sensor. AB - The SYRMEP (SYnchrotron Radiation for MEdical Physics) beamline at Elettra is performing the first mammography study on human patients using free-space propagation phase contrast imaging. The stricter spatial resolution requirements of this method currently force the use of conventional films or specialized computed radiography (CR) systems. This also prevents the implementation of three dimensional (3D) approaches. This paper explores the use of an X-ray detector based on complementary metal-oxide-semiconductor (CMOS) active pixel sensor (APS) technology as a possible alternative, for acquisitions both in planar and tomosynthesis geometry. Results indicate higher quality of the images acquired with the synchrotron set-up in both geometries. This improvement can be partly ascribed to the use of parallel, collimated and monochromatic synchrotron radiation (resulting in scatter rejection, no penumbra-induced blurring and optimized X-ray energy), and partly to phase contrast effects. Even though the pixel size of the used detector is still too large - and thus suboptimal - for free-space propagation phase contrast imaging, a degree of phase-induced edge enhancement can clearly be observed in the images. PMID- 25498333 TI - Role of induction chemotherapy for N3 head and neck squamous cell carcinoma. AB - OBJECTIVE: The treatment of head and neck squamous cell carcinoma (HNSCC) with N3 (>6cm) lymph nodes remains difficult, and the best treatment strategy has not been elucidated. The aim of this study was to evaluate the outcomes of various treatment modalities. METHODS: Sixty-nine patients with HNSCC and N3 neck disease treated with definitive therapy in our institute between 1987 and 2013 were included in the analysis. We compared the clinical outcomes of radiotherapy (RT) alone, chemoradiotherapy (CRT) and surgery with or without induction chemotherapy (ICT). RESULTS: The overall survival (OS) at three years for the patients with N3 neck disease was 41%. The three-year OS rates of patients treated with definitive surgery and definitive CRT were 41% and 48%, respectively. There were no significant differences between these two treatments (P=0.82). The OS of patients who received ICT followed by definitive therapy was significantly better than that of patients who did not (P<0.001). The most common recurrence pattern was distant metastases. The rate of distant metastases was 61% of all treatment failures (20/33). CONCLUSION: The high rate of distant metastases in patients with N3 neck disease suggests that prevention of distant metastases can improve survival. Based on this study, we consider that ICT may play an important role in the treatment of N3 neck disease. PMID- 25498334 TI - Haplotyping strategy highlights the specificity of FTO gene association with polycystic ovary syndrome in Tunisian women population. AB - The FTO (fat mass and obesity associated) gene was associated with different metabolic disorders in populations from different origins but with great difference between African and non-African populations. North-African populations combine many genetic backgrounds, among which African, Berber and Caucasian components, which makes North-Africans a good model for studying the genetic association of FTO. In the present investigation we explored the association of FTO gene with polycystic ovary syndrome (PCOS) in a population from Tunisia (n=278). Single nucleotide polymorphisms (SNPs) used in this study were previously associated in non-African populations: rs8050136 (A/C), rs9939609 (A/T), rs9930506 (G/A), or in both African and non-African populations: rs8057044 (A/G). Genotyping was performed by allelic discrimination method on StepOne real time PCR system or KASPar technology. Linkage disequilibrium (LD) pattern was assessed by HAPLOVIEW and reconstruction of haplotypes was performed by PHASE, while statistical analyses were performed using StatView and GoldenHelix programs. Among the 13 haplotypes in the population, three (h1, h7 and h13) were strongly associated with PCOS notably h13 (P<0.0001, OR95%CI=0.040 [0.005-0.294]) while SNPs display weaker association. Moreover the LD pattern in FTO in the Tunisian population (r(2) index) was intermediary between those of Caucasian and Africans. This highlights the need for studying the genetics of complex disorders in the North-African populations taking into-account the haplotype structure of candidate loci more than SNPs taken alone. PMID- 25498335 TI - Priming with a double-stranded DNA virus alters Brassica rapa seed architecture and facilitates a defense response. AB - BACKGROUND: Abiotic and biotic stresses alter genome stability and physiology of plants. Under some stressful situations, a state of stress tolerance can be passed on to the offspring rendering them more suitable to stressful events than their parents. In plants, the exploration of transgenerational response has remained exclusive to model species, such as Arabidopsis thaliana. Here, we expand transgenerational research to include Brassica rapa, a close relative to economically important plant canola (Brassica napus), as it is exposed to the biotic stress of a double-stranded DNA virus Cauliflower mosaic virus (CaMV). RESULTS: Parent plants exposed to a low dose of 50ng purified CaMV virions just prior to the bolting stage produced significantly larger seeds than mock inoculated and healthy treatments. The progeny from these large seeds displayed resistance to the pathogen stress applied in the parental generation. Differences in defense pathways involving fatty acids, and primary and secondary metabolites were detected by de novo transcriptome sequencing of CaMV challenged progeny exhibiting different levels of resistance. CONCLUSIONS: Our study highlights biological and cellular processes that may be linked to the growth and yield of economically important B. rapa, in a transgenerational manner. Although much remains unknown as to the mechanisms behind transgenerational inheritance, our work shows a disease resistance response that persists for several weeks and is associated with an increase in seed size. Evidence suggests that a number of changes involved in the persistent stress adaption are reflected in the transcriptome. The results from this study demonstrate that treating B. rapa with dsDNA virus within a critical time frame and with a specified amount of infectious pathogen produces economically important agricultural plants with superior coping strategies for growing in unfavorable conditions. PMID- 25498336 TI - Cloning of porcine GPIHBP1 gene and its tissue expression pattern and genetic effect on adipose traits. AB - Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism and is transported by glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) from the interstitial spaces to the capillary lumen. Here, we cloned a cDNA and the genomic locus of the porcine GPIHBP1 gene, and investigated its tissue expression pattern and its genetic effects on adipose traits. Porcine GPIHBP1 exhibits a four-exon/three-intron structure, including a 543bp open reading frame that encodes 180 amino acids. The porcine GPIHBP1 protein shows 49% 65% homology and shares the major conserved structural domains of GPIHBP1 proteins in other mammals. Porcine GPIHBP1 mRNA levels were high in the adipose tissue, muscle and lung, and higher mRNA levels were observed in sows compared to boars in adipose tissues of the inner and outer layers of subcutaneous fat, abdominal fat, and suet fat. The mRNA expression pattern of porcine GPIHBP1 and LPL genes was similar in most tissues except for the lung. Thirty six single nucleotide polymorphisms (SNPs) were found in the porcine GPIHBP1 gene. Association analyses showed that the g.-255G>C and g.-626T>G SNPs are associated with intramuscular fat content, and that the g.-1557T>C and g.-1948G>A SNPs are associated with back fat thickness. In conclusion, porcine GPIHBP1 mRNA is abundantly expressed in the adipose tissue, muscle and lung, and gender affects GPIHBP1 mRNA expression levels; furthermore, four GPIHBP1 SNPs are genetic factors affecting adipose traits. PMID- 25498337 TI - Carriage niches and molecular epidemiology of Staphylococcus lugdunensis and methicillin-resistant S. lugdunensis among patients undergoing long-term renal replacement therapy. AB - We collected nasal, axilla, and groin swabs from 252 adult patients from 2 nephrology centers in Hong Kong. Staphylococcus lugdunensis carriage was detected in 51.6% patients (groin, 39.3%; axilla, 19.8%; nose, 17.9%). The carriage rates of methicillin-sensitive S. lugdunensis and methicillin-resistant S. lugdunensis (MRSL) were 46.0% and 8.3%, respectively. Independent risk factors for S. lugdunensis carriage included male sex (odds ratio [OR], 4.4), hemodialysis (OR, 2.2), and aged 18-50years (OR, 2.4). The isolates belonged to 10 pulsotype clusters (n=129) and 8 singletons (n=8). All MRSL and most gentamicin- and tetracycline-resistant strains were found in a predominating sequence type 3 clone, designated HKU1, which accounted for 51.8% of all colonizing S. lugdunensis strains. The 21 MRSL isolates had SCCmec type V (n=18), type IV (n=2), and type I (n=1). The finding highlights the potential for dissemination of multidrug resistance through successful S. lugdunensis clones. PMID- 25498338 TI - Double-layered closure of chronic oroantral fistulas using a palatal rotational flap and suturing of the sinus membrane perforation: is it a successful technique? AB - PURPOSE: Chronic oroantral fistulas (OAFs) are a challenging problem in oral and maxillofacial surgery, and the treatment success rate of OAFs is as low as 67%. Thus, the double-layered closure has been described. The purpose of this study was to evaluate the simplicity and effectiveness of using a palatal rotational flap and suturing of the sinus membrane perforation as a new technique for double layered closure. MATERIALS AND METHODS: A prospective case series study was performed in patients who had chronic OAFs and were treated at Al-Zahraa Hospital from 2010 to 2013. The following demographic and clinical data were collected: age, gender, location of defect, size, etiology, signs and symptoms, postoperative healing, and complications. Under local anesthesia, fistulectomy and sinus irrigation were performed to control sinusitis. Under general anesthesia, the oral side of the fistulous tract was sutured with a purse suture. A palatal flap was reflected and sutured to the buccal tissue. RESULTS: Twelve patients 19 to 51 years old were enrolled in this study. All patients tolerated the surgical procedures; all surgical wounds healed uneventfully without recurrence. CONCLUSION: Double-layered closure of OAFs is a straightforward, convenient, and successful technique that provides stable, strong, and double sealed closure of chronic OAFs. PMID- 25498339 TI - Biology wars: the eukaryotes strike back. AB - It is increasingly clear that eukaryotes have acquired bacterial DNA and function through horizontal gene transfer (HGT). In this issue of Cell Host & Microbe, Chou et al. (2014) and Metcalf et al. (2014) report multiple HGTs of bacterial tae and lysozyme genes, respectively, to diverse eukaryotic and archaeal hosts that may complement their response to bacteria. PMID- 25498341 TI - Using fat to turbo-charge intracellular parasite growth. AB - Early during infection, the malaria parasite invades liver cells and undergoes robust replication, generating thousands of new parasites within days. In this issue of Cell Host & Microbe, Itoe et al. (2014) show that parasite replication in the liver depends on the synthesis of host bulk phospholipids, which are incorporated into the expanding parasite and surrounding vacuolar membranes. PMID- 25498340 TI - Pathogens' exploitation of the intestinal food web. AB - Competition for nutrients is a key factor controlling pathogen colonization within the gastrointestinal tract. In this issue, Ferreyra et al. (2014) and Curtis et al. (2014) show that diverse enteric pathogens can exploit a metabolic byproduct from the commensal microbiota, succinate, to enhance their own virulence expression and proliferation. PMID- 25498342 TI - Co-opting the cell-cycle machinery for plant immunity. AB - Plant effector-triggered immunity is a robust cellular defense response activated by a family of intracellular receptors. In this issue of Cell Host & Microbe, Wang et al. (2014) show that receptor-activated defense pathways utilize several core cell-cycle regulatory components to induce resistance and programmed cell death against pathogens. PMID- 25498343 TI - The gut commensal Bacteroides thetaiotaomicron exacerbates enteric infection through modification of the metabolic landscape. AB - The enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes severe diarrhea, but the influence of the gut microbiota on EHEC infection is largely unknown. A predominant member of the microbiota, Bacteroides thetaiotaomicron (Bt), is resident at EHEC attachment sites. We show that Bt enhances EHEC virulence gene expression through the transcription factor Cra, which is functionally sensitive to sugar concentrations. This enhanced virulence accompanies increased formation of attaching and effacing (AE) lesions requisite for EHEC colonization. Infection with Citrobacter rodentium, a natural mouse pathogen homologous to EHEC, in Bt-reconstituted mice results in increased gut permeability along with exacerbated host pathology and mortality compared to mice deplete of microflora. Bt modifies the metabolite environment at infection sites, increasing metabolites involved in gluconeogenesis, with stark increases in succinate, which can be sensed by Cra. Our findings suggest that microbiota composition affects disease outcome and may explain links between microbiota composition and disease susceptibility. PMID- 25498347 TI - A novel approach to the theory of homogeneous and heterogeneous nucleation. AB - A new approach to the theory of nucleation, formulated relatively recently by Ruckenstein, Narsimhan, and Nowakowski (see Refs. [7-16]) and developed further by Ruckenstein and other colleagues, is presented. In contrast to the classical nucleation theory, which is based on calculating the free energy of formation of a cluster of the new phase as a function of its size on the basis of macroscopic thermodynamics, the proposed theory uses the kinetic theory of fluids to calculate the condensation (W(+)) and dissociation (W(-)) rates on and from the surface of the cluster, respectively. The dissociation rate of a monomer from a cluster is evaluated from the average time spent by a surface monomer in the potential well as obtained from the solution of the Fokker-Planck equation in the phase space of position and momentum for liquid-to-solid transition and the phase space of energy for vapor-to-liquid transition. The condensation rates are calculated using traditional expressions. The knowledge of those two rates allows one to calculate the size of the critical cluster from the equality W(+)=W(-) as well as the rate of nucleation. The developed microscopic approach allows one to avoid the controversial application of classical thermodynamics to the description of nuclei which contain a few molecules. The new theory was applied to a number of cases, such as the liquid-to-solid and vapor-to-liquid phase transitions, binary nucleation, heterogeneous nucleation, nucleation on soluble particles and protein folding. The theory predicts higher nucleation rates at high saturation ratios (small critical clusters) than the classical nucleation theory for both solid-to-liquid as well as vapor-to-liquid transitions. As expected, at low saturation ratios for which the size of the critical cluster is large, the results of the new theory are consistent with those of the classical one. The present approach was combined with the density functional theory to account for the density profile in the cluster. This approach was also applied to protein folding, viewed as the evolution of a cluster of native residues of spherical shape within a protein molecule, which could explain protein folding/unfolding and their dependence on temperature. PMID- 25498346 TI - Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Berberine, extracted from Coptis Root and Phellodendron Chinese, has been frequently used for the adjuvant treatment of type 2 diabetes mellitus, hyperlipidemia, and hypertension in China. Safety and efficacy studies in terms of evidence-based medical practice have become more prevalent in application to Chinese Herbal Medicine. It is necessary to assess the efficacy and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipidemia and hypertension by conducting a systematic review and meta-analysis of available clinical data. MATERIALS AND METHODS: We searched the English databases PubMed, ScienceDirect, Cochrane library, EMbase, etc., and Chinese databases including China biomedical literature database (CBM), Chinese Technology Journal Full-text Database, Chinese journal full text database (CNKI), and Wanfang digital periodical full text database. Relevant studies were selected based on the inclusion and exclusion criteria. Meta-analysis was performed with RevMan5.0 software after data extraction and the quality of studies assessment. RESULTS: Twenty-seven randomized controlled clinical trials were included with 2569 patients. There are seven subgroups in our meta-analysis: berberine versus placebo or berberine with intensive lifestyle intervention versus intensive lifestyle intervention alone; berberine combined with oral hypoglycemic versus hypoglycemic alone; berberine versus oral hypoglycemic; berberine combined with oral lipid lowering drugs versus lipid lowering drugs alone; berberine versus oral lipid lowering drugs; berberine combined with oral hypotensor versus hypotensive medications; berberine versus oral hypotensive medications. In the treatment of type 2 diabetes mellitus, we found that berberine with lifestyle intervention tended to lower the level of FPG, PPG and HbA1c than lifestyle intervention alone or placebo; the same as berberine combined with oral hypoglycaemics to the same hypoglycaemics; but there was no statistical significance between berberine and oral hypoglycaemics. As for the treatment of hyperlipidemia, berberine with lifestyle intervention was better than lifestyle intervention, berberine with oral lipid lowering drugs was better than lipid lowering drugs alone in reducing the level of TC and LDL-C, and raising the level of HDL-C. In the comparative study between berberine and oral lipid lowering drugs, there was no statistical significance in reducing the level of TC and LDL C, but berberine shows better effect in lowering the level of TG and raising the level of HDL-C. In the treatment of hypertension, berberine with lifestyle intervention tended to lower the level of blood pressure more than the lifestyle intervention alone or placebo did; The same occurred when berberine combined with oral hypotensor was compared to the same hypotensor. Notably, no serious adverse reaction was reported in the 27 experiments. CONCLUSION: This study indicates that berberine has comparable therapeutic effect on type 2 DM, hyperlipidemia and hypertension with no serious side effect. Considering the relatively low cost compared with other first-line medicine and treatment, berberine might be a good alternative for low socioeconomic status patients to treat type 2 DM, hyperlipidemia, hypertension over long time period. Due to overall limited quality of the included studies, the therapeutic benefit of berberine can be substantiated to a limited degree. Better methodological quality, large controlled trials using standardized preparation are expected to further quantify the therapeutic effect of berberine. PMID- 25498345 TI - Host cell phosphatidylcholine is a key mediator of malaria parasite survival during liver stage infection. AB - During invasion, Plasmodium, the causative agent of malaria, wraps itself in a parasitophorous vacuole membrane (PVM), which constitutes a critical interface between the parasite and its host cell. Within hepatocytes, each Plasmodium sporozoite generates thousands of new parasites, creating high demand for lipids to support this replication and enlarge the PVM. Here, a global analysis of the total lipid repertoire of Plasmodium-infected hepatocytes reveals an enrichment of neutral lipids and the major membrane phospholipid, phosphatidylcholine (PC). While infection is unaffected in mice deficient in key enzymes involved in neutral lipid synthesis and lipolysis, ablation of rate-limiting enzymes in hepatic PC biosynthetic pathways significantly decreases parasite numbers. Host PC is taken up by both P. berghei and P. falciparum and is necessary for correct localization of parasite proteins to the PVM, which is essential for parasite survival. Thus, Plasmodium relies on the abundance of these lipids within hepatocytes to support infection. PMID- 25498344 TI - Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. AB - Clostridium difficile is a leading cause of antibiotic-associated diarrhea. The mechanisms underlying C. difficile expansion after microbiota disturbance are just emerging. We assessed the gene expression profile of C. difficile within the intestine of gnotobiotic mice to identify genes regulated in response to either dietary or microbiota compositional changes. In the presence of the gut symbiont Bacteroides thetaiotaomicron, C. difficile induces a pathway that metabolizes the microbiota fermentation end-product succinate to butyrate. The low concentration of succinate present in the microbiota of conventional mice is transiently elevated upon antibiotic treatment or chemically induced intestinal motility disturbance, and C. difficile exploits this succinate spike to expand in the perturbed intestine. A C. difficile mutant compromised in succinate utilization is at a competitive disadvantage during these perturbations. Understanding the metabolic mechanisms involved in microbiota-C. difficile interactions may help to identify approaches for the treatment and prevention of C. difficile-associated diseases. PMID- 25498348 TI - In vivo and in vitro observations of polyhydroxybutyrate granules formed by Dinoroseobacter sp. JL 1447. AB - Polyhydroxybutyrate (PHB) granules formed by a marine aerobic anoxygenic phototrophic bacterial strain Dinoroseobacter sp. JL 1447 were detected using transmission electron microscopy and atomic force microscopy. When Dinoroseobacter sp. JL 1447 was inoculated into a medium with glucose as the sole carbon source, the formation of PHB granules occurred and accumulated with incubation time, reaching their maximum in the stationary phase cultures. PHB granules, formed in the cytoplasm at the cell poles or future cell poles, were remobilized and used by the cells in late stationary complex cultures. When PHB granules formed, cell length elongated from 0.5 to 1.5 MUm and spherical protrusions appeared on the cell surface. The French press method was used to break the cells and isolate the PHB granules. The freshly prepared and intact PHB granules were spherical with a soft, smooth outer envelope without visible substructures. Upon treating PHB granules with sodium dodecyl sulfate, the envelope was destroyed and nearly parted from the granules, and uniform, spherical structures with a central pore appeared on the granule surface. PMID- 25498349 TI - k-Carrageenan/poly vinyl pyrollidone/polyethylene glycol/silver nanoparticles film for biomedical application. AB - Biopolymer composite film containing k-carrageenan (KC), polyvinyl pyrrolidone (PVP), and polyethylene glycol (PEG) was formulated by dissolving KC and PVP in water containing PEG. Silver nanoparticles (AgNPs), was produced by Honeybee and added to solution. Finally, all solutions were poured onto dishes and dried overnight at 40 degrees C to form the final films. Tensile strength (TS) and elongation (E %) is evaluated. The water contact angle is inspected. Thermal properties (TGA) and swelling behavior for water were considered. Fungal activity is also examined. Morphology of all films was also explored using scanning electron microscope. AgNPs induced significant hydrophilicity to KC-PVP-PEG film with contact angle of 41.6 and 34.7 for KC-PVP-PEG-AgNPs. Films with AgNPs exhibited higher thermal stability and strength properties than other films without. Films with AgNPs explore lower swelling behavior than other films without. Both SEM and EDX proved the deposition of AgNPs on the surface of films. Films with AgNPs showed higher activity against pathogenic fungi compared with the chemical fungicide; fluconazole. PMID- 25498350 TI - Metabolic compensations in mitochondria isolated from the heart, liver, kidney, brain and white muscle in the southern catfish (Silurus meridionalis) by seasonal acclimation. AB - In order to examine the effects of seasonal acclimation on mitochondrial metabolic functions and test tissue-specific pattern of the metabolic compensation within individuals of the southern catfish (Silurus meridionalis Chen), rates of mitochondrial respiration and activities of cytochrome c oxidase (COX) in the heart, liver, kidney, brain and white muscle of this fish in the summer-acclimatized group (153.20+/-1.66 g) and winter-acclimatized group (177.71+/-3.04 g) were measured at seven assay temperatures (7.5, 12.5, 17.5, 22.5, 27.5, 32.5 and 37.5 degrees C), respectively. The results show that compensatory adjustments in state III respiratory rate and COX activity occur significantly in the heart, kidney and liver, but do not in the brain and white muscle, which suggest that the metabolic compensation of this fish in response to seasonal acclimation exhibits a tissue-specific pattern. The cold acclimation increases mitochondrial oxidative capacities in the heart, kidney and liver concomitantly with reducing their upper thermal limits of mitochondrial functions at acute warming and the thermal tolerance shifts in the same tissue-specific pattern as the metabolic compensation. When combining the effects of seasonal acclimation on mitochondrial oxidative capacity and organ mass, the metabolic compensation demonstrates an organ-specific pattern with four categories: over compensation in the heart, complete compensation in the kidney, partial compensation in the liver and no compensation in the brain. The organ-specific pattern of metabolic compensation might be a trade-off strategy of the performance adjustments in the seasonal acclimation for this fish to maximize its fitness. PMID- 25498351 TI - Activation of AMP-activated protein kinase in response to temperature elevation shows seasonal variation in the zebra mussel, Dreissena polymorpha. AB - Global climate change is affecting ectothermic species, and a variety of studies are needed on thermal tolerances, especially from cellular and physiological perspectives. This study utilized AMP-activated protein kinase (AMPK), a key regulator of cellular energy levels, to examine the effects of high water temperatures on zebra mussel (Dreissena polymorpha) physiology. During heating, AMPK activity increased as water temperature increased to a point, and maximum AMPK activity was detected at high, but sublethal, water temperatures. This pattern varied with season, suggesting that cellular mechanisms of seasonal thermal acclimatization affect basic metabolic processes during sublethal heat stress. There was a greater seasonal variation in the water temperature at which maximum AMPK activity was measured than in lethal water temperature. Furthermore, baseline AMPK activity varied significantly across seasons, most likely reflecting altered metabolic states during times of growth and reproduction. In addition, when summer-collected mussels were lab-acclimated to winter and spring water temperatures, patterns of heat stress mirrored those of field-collected animals. These data suggest that water temperature is the main driver of the seasonal variation in physiology. This study concluded that AMPK activity, which reflects changes in energy supply and demand during heat stress, can serve as a sensitive and early indicator of temperature stress in mussels. PMID- 25498352 TI - Effect of long-after glow phosphorescent pigment on reproductive parameters and ovarian maturation in the yellowtail damselfish, Chrysiptera parasema. AB - Photoperiod is considered the most important factor that entrains animal rhythms, including the reproductive cycle. The present study tested differences in sex maturation and sex steroid hormones of yellowtail damselfish (Chrysiptera parasema) exposed to a white fluorescent bulb (12L:12D and 14L:10D) or long afterglow phosphorescent pigment (LumiNova sheet) for 4 months. At the end of the experiment, in the phosphorescent group, mRNA expressions of gonadotropin hormones [(GTHs, including gonadotropin (GTH) alpha and luteinizing hormone (LH) beta)], estrogen receptor (ER), and vitellogenin were significantly higher than in the photoperiod groups (12L:12D and 14L:10D), and these results are consistent with those of Western blotting for protein expression. Furthermore, in the phosphorescent group, plasma FSH, LH, and estradiol-17beta (E2) levels were significantly higher than in the photoperiod groups. However, plasma melatonin levels were significantly lower than in the photoperiod groups. Because LumiNova sheets continue to emit green light (520 nm) for approximately 2h after sunset, the extended light conditions probably contributed to reproductive ability in the experimental fish. In conclusion, long-afterglow phosphorescent pigment can be used for energy-efficient aquaculture to regulate the reproduction of fish, although its effect needs to be evaluated in other species. PMID- 25498353 TI - Three-dimensional vascular imaging of proliferative diabetic retinopathy by Doppler optical coherence tomography. AB - PURPOSE: To evaluate the 3-dimensional architecture of neovascularization in proliferative diabetic retinopathy using Doppler optical coherence tomography (OCT). DESIGN: Prospective, nonrandomized clinical trial. METHODS: Seventeen eyes of 14 patients with proliferative diabetic retinopathy were prospectively studied. Prototype Doppler OCT was used to evaluate the 3-dimensional vascular architecture at vitreoretinal adhesions. RESULTS: Proliferative membranes were detected in all eyes with proliferative diabetic retinopathy by standard OCT images. Doppler OCT images detected blood flow by neovascularization of the disc in 12 eyes and neovascularization elsewhere in 11 eyes. Doppler OCT images showed the 3-dimensional extent of new vessels at various stages of neovascularization, and the extent of new vessels could be clearly confirmed at vitreoretinal adhesions. CONCLUSIONS: Doppler OCT is useful for the detection and evaluation of the 3-dimensional vascular structure of neovascularization, and can assist in the noninvasive assessment of proliferative diabetic retinopathy. PMID- 25498354 TI - Diagnostic capability of peripapillary retinal thickness in glaucoma using 3D volume scans. AB - PURPOSE: To determine the diagnostic capability of spectral-domain optical coherence tomography (SD OCT) peripapillary retinal thickness (RT) measurements from 3-dimensional (3D) volume scans for primary open-angle glaucoma (POAG). DESIGN: Cross-sectional study. METHODS: setting: Institutional. study population: 156 patients (89 POAG and 67 normal subjects). observation procedures: One eye of each subject was included. SD OCT peripapillary RT values from 3D volume scans were calculated for 4 quadrants of 3 different sized annuli. Peripapillary retinal nerve fiber layer (RNFL) thickness values were also determined. main outcome measures: Area under the receiver operating characteristic curve (AUROC) values, sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios. RESULTS: The top 5 RT AUROCs for all glaucoma patients and for a subset of early glaucoma patients were for the inferior quadrant of outer circumpapillary annulus of circular grid (OCA) 1 (0.959, 0.939), inferior quadrant of OCA2 (0.945, 0.921), superior quadrant of OCA1 (0.890, 0.811), inferior quadrant of OCA3 (0.887, 0.854), and superior quadrant of OCA2 (0.879, 0.807). Smaller RT annuli OCA1 and OCA2 consistently showed better diagnostic performance than the larger RT annulus OCA3. For both RNFL and RT measurements, best AUROC values were found for inferior RT OCA1 and OCA2, followed by inferior and overall RNFL thickness. CONCLUSION: Peripapillary RT measurements from 3D volume scans showed excellent diagnostic performance for detecting both glaucoma and early glaucoma patients. Peripapillary RT values have the same or better diagnostic capability compared to peripapillary RNFL thickness measurements, while also having fewer algorithm errors. PMID- 25498356 TI - Long-term result of maintenance treatment with tacrolimus ointment in chronic ocular graft-versus-host disease. AB - PURPOSE: To investigate the efficacy and safety of long-term maintenance treatment with tacrolimus ointment in chronic ocular graft-vs-host disease (GVHD) with ocular surface inflammation. DESIGN: A retrospective interventional consecutive case series. METHOD: Long-term maintenance treatment (>=6 months) with topical 0.02% tacrolimus ointment was applied to patients with chronic ocular GVHD with ocular surface inflammation (at least grade 2 inflammatory score). We evaluated the inflammatory score, steroid score and steroid use period of total duration, and numbers of inflammatory aggravations before and after tacrolimus treatment. The clinical outcomes were assessed by symptom score, ocular surface staining, Schirmer I test, tear break-up time (TBUT), and classification of chronic GVHD conjunctivitis at the initial and final examinations. RESULTS: Thirteen patients (24 eyes) were treated with tacrolimus ointment for up to 20 months (average 12.2 months). The ocular surface inflammatory score decreased from 2.8 to 0.6 (P = .001) within 2-8 weeks after starting tacrolimus ointment treatment. The numbers of inflammatory aggravation and the need for steroid treatment also decreased after initiating tacrolimus treatment. At the final follow-up, all patients reported improvement in clinical outcomes, compared to initial findings. Except for blurred vision or mild burning sensation, there were no reported side effects. CONCLUSION: Considering the chronic course of GVHD, long-term maintenance treatment with tacrolimus ointment could be useful and safe to locally treat ocular surface inflammation in chronic ocular GVHD. PMID- 25498355 TI - Quality of life in adults with strabismus. AB - PURPOSE: To assess relative quality of life in patients with strabismus. DESIGN: Retrospective cohort study. METHODS: The 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) was performed in 42 strabismic adults over the age of 50 years at a single institution. Subscale scores were compared with those of patients with other ocular diseases, including diabetic retinopathy, age related macular degeneration (AMD), glaucoma, cataract, cytomegalovirus (CMV) retinitis, and low vision. RESULTS: Median visual acuity was 20/20 (range 20/12.5 20/50), and 34 patients (81%) reported diplopia. Strabismic patients performed the same or worse on nearly all vision-related subscales than did patients with diabetic retinopathy, age-related macular degeneration, glaucoma, cataract, and CMV retinitis. Additionally, strabismic patients reported significantly worse ocular pain than all comparison groups before any surgery was performed. CONCLUSIONS: Strabismus impacts quality of life through both functional and psychosocial factors. Physicians treating strabismic patients should recognize these quality-of-life issues and address them accordingly. PMID- 25498357 TI - Comparison of lamina cribrosa thickness in normal tension glaucoma patients with unilateral visual field defect. AB - PURPOSE: To compare the lamina cribrosa thickness, measured by swept-source optical coherence tomography (SS OCT), between each eye of normal tension glaucoma (NTG) patients with unilateral visual field (VF) defect and to investigate the correlation between lamina cribrosa thickness and VF loss. DESIGN: Prospective, cross-sectional study. METHODS: Optic nerve heads were scanned using SS OCT, and laminar thickness was measured on mid-superior, central, and mid-inferior regions of vertical midline of the optic disc. The inter-eye differences of lamina cribrosa thickness in NTG patients with unilateral VF defect and the intra-eye difference of lamina cribrosa thickness in VF-affected eyes were analyzed using the paired t test. We evaluated the correlation between lamina cribrosa thickness and mean deviation, measured using standard automated perimetry, in NTG patients. RESULTS: This study included 102 eyes in 51 NTG patients with unilateral VF defect and 47 eyes in 47 normal subjects without glaucomatous change in either eye. The mean lamina cribrosa thickness of normal fellow eyes was thicker than VF-affected eyes in NTG patients (P < .001), but thinner than normal subject eyes (P < .001). Within VF-affected eyes, lamina cribrosa thickness of regions correlated with visual field defect was thinner than horizontally contralateral locations (P < .001). The mean deviation was statistically correlated with inter-eye difference of lamina cribrosa thickness in NTG patients (n = 51; r(2) = 0.12; P = .01). CONCLUSIONS: The lamina cribrosa was thinner in VF-unaffected eyes of NTG patients than in normal subject eyes, in VF-affected eyes than in normal fellow eyes of NTG patients, and in regions correlated with visual field loss than in horizontally contralateral ones in VF-affected eyes. PMID- 25498358 TI - Clinical outcome of deep-seated atypical lipomatous tumor of the extremities with median-term follow-up study. AB - AIMS: There is no consensus on the best surgical treatment for deep-seated atypical lipomatous tumor (ALT) of the extremities; furthermore, the appropriate duration for follow-up observation remains unclear. We investigated clinical and functional median-term outcomes in the primary operations for ALT of the extremities in order to find its best treatment methods and observation periods. METHODS: From 1996 to 2009, we diagnosed 41 patients with deep-seated ALT of the extremities. Wide resection was performed on 11 patients and marginal resection was performed on 30 patients. The minimum follow-up was 5 years (median, 8.5; range, 5-17.4). Patients were evaluated for their local recurrence, dedifferentiation, and post-operative function using the ISOLS/MSTS scoring system. RESULTS: Recurrence and dedifferentiation rates were both 0% for the wide resection group, while the rates were 23% (7/30) and 3% (1/30) for the marginal resection group, respectively. Median duration before recurrence was 7.2 years (range, 4.0-14.2). Local recurrence-free survival rate was significantly higher in the wide resection group (P = 0.013). In the marginal resection group, 10% (3/30) of the cases showed residual tumor. The localization of these tumors was all intermuscular. The ISOLS/MSTS scores were 98% (range, 90-100) for wide resection and 99% (range, 93-100) for marginal resection, with no statistical difference (P = 0.694). No ALT-related deaths occurred during the observation period. CONCLUSIONS: In addition to long-term (at least 8 years) of continuous observation, a wide resection is necessary in order to prevent recurrence, dedifferentiation, and residual tumor. PMID- 25498359 TI - Sarcopenia is associated with toxicity in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer. AB - BACKGROUND: Patients with potentially curative oesophago-gastric cancer typically undergo neo-adjuvant chemotherapy prior to surgery. The majority of anti-cancer drugs have a narrow therapeutic index. The aim of this study was to determine if features of body composition, assessed using computed tomography (CT) scans, may be predictive of dose-limiting toxicity (DLT) in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer. The influence of sarcopenia and DLT on overall survival was also evaluated. METHODS: 89 Patients having potentially curative oesophago-gastric cancer surgery were studied. Patients studied had histologically confirmed oesophago-gastric cancer with no evidence of distant metastasis on pre-operative staging. CT scan was performed in all cases at diagnosis. DLT was defined as toxicity leading to postponement of treatment, a drug dose reduction or definitive interruption of drug administration. RESULTS: DLT occurred in 37 out of 89 patients (41.6%) undergoing chemotherapy. Sarcopenia (odds ratio, 2.95; 95% confidence interval, 1.23-7.09; p = 0.015) was associated with DLT on multivariate analysis. Median overall survival for patients who were sarcopenic was 569 days (IQ range: 357-1230 days) vs. 1013 days (IQ range: 496 1318 days) for patients who were not sarcopenic (p = 0.04). There was no significant difference in overall survival in patients who experienced DLT compared with those that did not (p = 0.665). CONCLUSIONS: Sarcopenia is a significant predictor of DLT in oesophago-gastric cancer patients undergoing neo adjuvant chemotherapy. These results raise the potential for use of assessment of skeletal muscle mass using CT scans to predict toxicity and individualize chemotherapy dosing. PMID- 25498361 TI - Gender regimes in health systems. PMID- 25498360 TI - Gender bias in clinical research, pharmaceutical marketing, and the prescription of drugs. AB - This thesis is part of the studies of gender bias in health which together with the paradigm of evidence-based medicine shares the empirical assumption that there are inaccuracies in medical practice, in addition to a lack of rigour and transparency. It worked with the distinction between the concepts of sex and gender and between the concepts of sex-related differences and gender inequalities, in terms of applying a gender perspective in the study design and the subsequent analysis. This PhD review presents the research process conducted in Spain, which can provide an example for future research. Study I described a review of 58 clinical trials (CTs) of etoricoxib to assess its compliance with the Recommendations of Evaluation of Gender Differences in the Clinical Evaluation of Drugs. In Study II, key informants from professions related to different areas in drug development and pharmacovigilance held a working meeting to reach a consensus document on recommendations for the study and evaluation of gender differences in CTs in Spain. In Study III, the websites of the eight best selling hormone replacement therapy drugs in Spain on Google first page of results were analysed. In Study IV, a logistic regression analysis was performed to compare analgesic prescription by sex in regions with a higher or lower Gender Development Index (GDI) than the Spanish average. Gender biases identified in this thesis limited the legitimacy of medicine, which is not based on the best possible evidence. The results also demonstrate the existence of inequalities between men and women that are not due merely to biological differences, but are gender inequalities stemming from the social differences that exist between both sexes. PMID- 25498362 TI - Critical friends: A way to develop preceptor competence? AB - Preceptorship entails for nurses to create a supportive learning and working climate where students or newcomers are given opportunities to develop professional competence. However, being a skilled and experienced nurse does not automatically turn the professional into a skilled educator as teaching of a subject is a whole different story. Preceptors need to continuously and critically reflect on their practices in order to facilitate the development of professional pedagogical competence. Critical friends are colleagues with comparable educational background evaluating the work of each other. The relationship should rely on friendship and mutual trust, adding new dimensions to the reflective process. Being engaged in a critical friendship allows the "friends" to become aware of their own shortcomings which can then be reflected on in relation to clinical as well as pedagogical practices. Being and having a critical friend might be one promising way forward for preceptors to develop pedagogical and professional competence. PMID- 25498363 TI - Effect of body weight on spinal loads in various activities: a personalized biomechanical modeling approach. AB - Epidemiological studies are divided over the causative role of body weight (BW) in low back pain. Biomechanical modeling is a valuable approach to examine the effect of changes in BW on spinal loads and risk of back pain. Changes in BW have not been properly simulated by previous models as associated alterations in model inputs on the musculature and moment arm of gravity loads have been neglected. A detailed, multi-joint, scalable model of the thoracolumbar spine is used to study the effect of BW (varying at five levels, i.e., 51, 68, 85, 102, and 119 kg) on the L5-S1 spinal loads during various static symmetric activities while scaling moment arms and physiological cross-sectional areas of muscles using in vivo imaging data. The L5-S1 loads substantially increased with BW especially in flexed postures. As BW increased from 51 to 119 kg, the L5-S1 compression increased in flexed postures by ~80-147% with no load in hands and by ~46-52% in load holding tasks. In obese individuals with body mass index>30 kg/m(2) spinal loads further increased by up to 15% as lever arms for gravity loading at the waistline (T12 through L5) increased by 2 cm (for BW=102 kg) and 4 cm (for BW=119 kg). With changes in BW, spinal loads would have moderately altered (<17%) had identical muscle parameters been considered. Since scaling muscle parameters demands additional efforts in modeling, one could opt for simulation of alterations only in BW while using some averaged musculature values. PMID- 25498364 TI - Muscle coordination of support, progression and balance during stair ambulation. AB - Stair ambulation is more physically demanding than level walking because it requires the lower-limb muscles to generate greater net joint moments. Although lower-limb joint kinematics and kinetics during stair ambulation have been extensively studied, relatively little is known about how the lower-limb muscles accelerate the whole-body center of mass (COM) during stair ascent and descent. The aim of the current study was to evaluate differences in muscle contributions to COM accelerations between level walking and stair ambulation in 15 healthy adults. Three-dimensional quantitative gait analysis and musculoskeletal modeling were used to calculate the contributions of the individual lower-limb muscles to the vertical, fore-aft and mediolateral accelerations of the COM (support, progression, and balance, respectively) during level walking, stair ascent and stair descent. Muscles that contribute most significantly to the acceleration of the COM during level walking (hip, knee, and ankle extensors) also dominate during stair ambulation, but with noticeable differences in coordination. In stair ascent, gluteus maximus accelerates the body forward during the first half of stance and soleus accelerates the body backward during the second half of stance, opposite to the functions displayed by these muscles in level walking. In stair descent, vasti generates backward and medial accelerations of the COM during the second half of stance, whereas it contributes minimally during this period in level walking. Gluteus medius performs similarly in controlling mediolateral balance during level walking and stair ambulation. Differences in lower-limb muscular coordination exist between stair ambulation and level walking, and our results have implications for interventions aimed at preventing stair-related falls. PMID- 25498365 TI - Inertial control as novel technique for in vitro gait simulations. AB - In vitro gait simulations are a preferential platform to study new intervention techniques or surgical procedures as they allow studying the isolated effect of surgical interventions. Commonly, simulations are performed by applying pre defined setpoints for the kinetics and kinematics on all degrees of freedom (DOFs) of the cadaveric specimen. This however limits the applicability of the experiment to simulations for which pre-defined kinematics and kinetics can be measured in vivo. In this study we introduce inertial control as a new methodology for gait simulations that omits the need for pre-defined setpoints for the externally applied vertical ground reaction force (vGRF) and therefore allows the effect of interventions to be reflected upon it. Gait simulations of stance (1 s) were performed in 10 cadaveric specimens under three clinically relevant conditions: native ankle, total ankle prosthesis (TAP) and total ankle prosthesis plus triple arthrodesis (TAP+TA). In the native ankle, simulated vGRF was compared against the vGRF measured in vivo in 15 healthy volunteers and high correlations were found (R(2)=0.956, slope of regression line S=1.004). In TAP and TAP+TA, vGRF changed, therefore confirming the sensitivity of the method to kinematic constrains imposed with surgery. Inertial control can replicate in vivo kinetic conditions and allows investigating the isolated effect of surgical interventions on kinematic as well as kinetics. PMID- 25498367 TI - Relationships between tissue composition and viscoelastic properties in human trabecular bone. AB - Trabecular bone is a metabolically active tissue with a high surface to volume ratio. It exhibits viscoelastic properties that may change during aging. Changes in bone properties due to altered metabolism are sensitively revealed in trabecular bone. However, the relationships between material composition and viscoelastic properties of bone, and their changes during aging have not yet been elucidated. In this study, trabecular bone samples from the femoral neck of male cadavers (n=21) aged 17-82 years were collected and the tissue level composition and its associations with the tissue viscoelastic properties were evaluated by using Raman microspectroscopy and nanoindentation, respectively. For composition, collagen content, mineralization, carbonate substitution and mineral crystallinity were evaluated. The calculated mechanical properties included reduced modulus (Er), hardness (H) and the creep parameters (E1, E2, eta1and eta2), as obtained by fitting the experimental data to the Burgers model. The results indicated that the creep parameters, E1, E2, eta1and eta2, were linearly correlated with mineral crystallinity (r=0.769-0.924, p<0.001). Creep time constant (eta2/E2) tended to increase with crystallinity (r=0.422, p=0.057). With age, the mineralization decreased (r=-0.587, p=0.005) while the carbonate substitution increased (r=0.728, p<0.001). Age showed no significant associations with nanoindentation parameters. The present findings suggest that, at the tissue level, the viscoelastic properties of trabecular bone are related to the changes in characteristics of bone mineral. This association may be independent of human age. PMID- 25498366 TI - Fracture healing in mice lacking Pten in osteoblasts: a micro-computed tomography image-based analysis of the mechanical properties of the femur. AB - In the United States, approximately eight million osseous fractures are reported annually, of which 5-10% fail to create a bony union. Osteoblast-specific deletion of the gene Pten in mice has been found to stimulate bone growth and accelerate fracture healing. Healing rates at four weeks increased in femurs from Pten osteoblast conditional knock-out mice (Pten-CKO) compared to wild-type mice (WT) of the same genetic strain as measured by an increase in mechanical stiffness and failure load in four-point bending tests. Preceding mechanical testing, each femur was imaged using a Skyscan 1172 micro-computed tomography (MUCT) scanner (Skyscan, Kontich, Belgium). The present study used uCT image based analysis to test the hypothesis that the increased femoral fracture force and stiffness in Pten-CKO were due to greater section properties with the same effective material properties as that of the WT. The second moment of area and section modulus were computed in ImageJ 1.46 (National Institutes of Health) and used to predict the effective flexural modulus and the stress at failure for fourteen pairs of intact and callus WT and twelve pairs of intact and callus Pten CKO femurs. For callus and intact femurs, the failure stress and tissue mineral density of the Pten-CKO and WT were not different; however, the section properties of the Pten-CKO were more than twice as large 28 days post-fracture. It was therefore concluded, when the gene Pten was conditionally knocked-out in osteoblasts, the resulting increased bending stiffness and force to fracture were due to increased section properties. PMID- 25498368 TI - High frequency circular translation pin-on-disk method for accelerated wear testing of ultrahigh molecular weight polyethylene as a bearing material in total hip arthroplasty. AB - The temporal change of the direction of sliding relative to the ultrahigh molecular weight polyethylene (UHMWPE) component of prosthetic joints is known to be of crucial importance with respect to wear. One complete revolution of the resultant friction vector is commonly called a wear cycle. It was hypothesized that in order to accelerate the wear test, the cycle frequency may be substantially increased if the circumference of the slide track is reduced in proportion, and still the wear mechanisms remain realistic and no overheating takes place. This requires an additional slow motion mechanism with which the lubrication of the contact is maintained and wear particles are conveyed away from the contact. A three-station, dual motion high frequency circular translation pin-on-disk (HF-CTPOD) device with a relative cycle frequency of 25.3 Hz and an average sliding velocity of 27.4 mm/s was designed. The pins circularly translated at high frequency (1.0 mm per cycle, 24.8 Hz, clockwise), and the disks at low frequency (31.4mm per cycle, 0.5 Hz, counter-clockwise). In a 22 million cycle (10 day) test, the wear rate of conventional gamma-sterilized UHMWPE pins against polished CoCr disks in diluted serum was 1.8 mg per 24 h, which was six times higher than that in the established 1 Hz CTPOD device. The wear mechanisms were similar. Burnishing of the pin was the predominant feature. No overheating took place. With the dual motion HF-CTPOD method, the wear testing of UHMWPE as a bearing material in total hip arthroplasty can be substantially accelerated without concerns of the validity of the wear simulation. PMID- 25498369 TI - Examining the feasibility of applying principal component analysis to detecting localized changes in mechanical properties. AB - Ultrasound elastography is being increasingly used to diagnose musculoskeletal pathologies. This technique measures strain distributions within the muscle tissue, which can be used to calculate local tissue stiffness. However, inaccuracies in the model assumptions, as well as operator variability during imaging, can cause significant error in the resulting stiffness measurements. Principal component analysis (PCA) offers a means to better account for the physiological differences and inter-operator error between subjects. In this study we explore the feasibility of using PCA to detect contusion injury in skeletal muscle. We used finite element analysis to simulate quasi-static transverse compressions of both healthy and injured biceps brachii muscles. Injuries were modeled as circular regions with dissimilar mechanical properties. The compression magnitude and direction, as well as the muscle material properties, were varied to account for user error and inter-muscle differences, respectively. Image noise was added to the resulting displacement maps to simulate measurement error. PCA was performed on the displacement images of the healthy muscle. The resulting principal components were compared against the displacement maps from injured muscle to identify local changes in mechanical properties. The results indicate that changes in mechanical properties of +/-5% can be detected for regions as small as +/-5% of the muscle depth. However, detection accuracy was greatly affected by image noise. We show that PCA of displacement images is a feasible tool for detecting and quantifying localized changes in mechanical properties. Additional work is needed before this technique can be applied to images generated using ultrasound elastography. PMID- 25498370 TI - Identification of a hemodynamic parameter for assessing treatment outcome of EDAS in Moyamoya disease. AB - This work is a novel attempt to incorporate computational fluid dynamics (CFD) techniques in the analysis of hemodynamic parameters of Moyamoya disease (MMD). Highly prevalent in Asian countries, MMD is characterised by progressive occlusion of the intracranial Internal Carotid Arteries (ICA). We intend to identify a reliable hemodynamic parameter that can be used to gauge treatment outcome. This will aid surgeons in the perioperative management of MMD patients. We carried out CFD analysis on eight patients (5 female, 3 male) with MMD treated by EDAS (encephalo-duro-arterio-synangiosis) between 2011 and 2012. All the eight patients presented with haemorrhage, with subsequent 4-12 month follow-up done using Magnetic Resonance Angiography (MRA) to capture auto-remodelling. We calculated percentage change in flow rate and pressure drop indicator (RhoDI) across the Left and Right ICA. Pressure drop indicator (PDI) is defined as the difference of pressure reduction within the carotid arteries, measured at post-op and follow up, using patient specific inflow rates. The measured percentage flow change and pressure reduction showed an increase at follow up for improved patients (characterised by angiography according to the method of Matsushima), who did not develop any complications after surgery. The inverse was observed in patients who were clinically classified as no change and retrogressed (according to the method of Matsushima) cases post-operation. This elucidates that our findings have instituted a new parameter that may well play a critical role as an assistive clinical decision making tool in MMD. PMID- 25498372 TI - Human-induced eutrophication maintains high parasite prevalence in breeding threespine stickleback populations. AB - Anthropogenic activities are having profound impacts on species interactions, with further consequences for populations and communities. We investigated the influence that anthropogenic eutrophication has on the prevalence of the parasitic tapeworm Schistocephalus solidus in threespine stickleback Gasterosteus aculeatus populations. We caught stickleback from four areas along the coast of Finland, and within each area from one undisturbed and one eutrophied habitat. We found the prevalence of the parasite to be lower in the eutrophied habitats at the start of the breeding season, probably because of fewer piscivorous birds that transmit the parasite. However, while the prevalence of the parasite declined across the season in the undisturbed habitat, it did less so in eutrophied habitats. We discuss different processes that could be behind the differences, such as lower predation rate on infected fish, higher food availability and less dispersal in eutrophied habitats. We found no effect of eutrophication on the proportion of infected stickleback that entered reproductive condition. Together with earlier findings, this suggests that eutrophication increases the proportion of infected stickleback that reproduce. This could promote the evolution of less parasite resistant populations, with potential consequences for the viability of the interacting parties of the host parasite system. PMID- 25498371 TI - Minocycline ameliorates cognitive impairment induced by whole-brain irradiation: an animal study. AB - BACKGROUND: It has been long recognized that cranial irradiation used for the treatment of primary and metastatic brain tumor often causes neurological side effects such as intellectual impairment, memory loss and dementia, especially in children patients. Our previous study has demonstrated that whole-brain irradiation (WBI) can cause cognitive decline in rats. Minocycline is an antibiotic that has shown neuroprotective properties in a variety of experimental models of neurological diseases. However, whether minocycline can ameliorate cognitive impairment induced by ionizing radiation (IR) has not been tested. Thus this study aimed to demonstrate the potential implication of minocycline in the treatment of WBI-induced cognitive deficits by using a rat model. METHODS: Sprague Dawley rats were cranial irradiated with electron beams delivered by a linear accelerator with a single dose of 20 Gy. Minocycline was administered via oral gavages directly into the stomach before and after irradiation. The open field test was used to assess the anxiety level of rats. The Morris water maze (MWM) was used to assess the spatial learning and memory of rats. The level of apoptosis in hippocampal neurons was measured using immunohistochemistry for caspase-3 and relative markers for mature neurons (NeuN) or for newborn neurons (Doublecortin (DCX)). Neurogenesis was determined by BrdU incorporation method. RESULTS: Neither WBI nor minocycline affected the locomotor activity and anxiety level of rats. However, compared with the sham-irradiated controls, WBI caused a significant loss of learning and memory manifest as longer latency to reach the hidden platform in the MWM task. Minocycline intervention significantly improved the memory retention of irradiated rats. Although minocycline did not rescue neurogenesis deficit caused by WBI 2 months post-IR, it did significantly decreased WBI-induced apoptosis in the DCX positive neurons, thereby resulting in less newborn neuron depletion 12 h after irradiation. CONCLUSIONS: Minocycline significantly inhibits WBI-induced neuron apoptosis, leading to less newborn neurons loss shortly after irradiation. In the long run, minocycline improves the cognitive performance of rats post WBI. The results indicate a potential clinical implication of minocycline as an effective adjunct in radiotherapy for brain tumor patients. PMID- 25498373 TI - Cost-effectiveness Analysis Comparing Apixaban and Acenocoumarol in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation in Spain. AB - INTRODUCTION AND OBJECTIVES: Cost-effectiveness analysis of apixaban (5 mg twice daily) vs acenocoumarol (5mg/day) in the prevention of stroke in patients with nonvalvular atrial fibrillation in Spain. METHODS: Markov model covering the patient's entire lifespan with 10 health states. Data on the efficacy and safety of the drugs were provided by the ARISTOTLE trial. Warfarin and acenocoumarol were assumed to have therapeutic equivalence. PERSPECTIVES: The Spanish National Health System and society. Information on the cost of the drugs, complications, and the management of the disease was obtained from Spanish sources. RESULTS: In a cohort of 1000 patients with nonvalvular atrial fibrillation, administration of apixaban rather than acenocoumarol would avoid 18 strokes, 71 hemorrhages (28 intracranial or major), 2 myocardial infarctions, 1 systemic embolism, and 23 related deaths. Apixaban would prolong life (by 0.187 years) and result in more quality-adjusted life years (by 0.194 years) per patient. With apixaban, the incremental costs for the Spanish National Health System and for society would be ? 2,488 and ? 1,826 per patient, respectively. Consequently, the costs per life year gained would be ? 13,305 and ? 9,765 and the costs per quality-adjusted life year gained would be ? 12,825 and ? 9,412 for the Spanish National Health System and for society, respectively. The stability of the baseline case was confirmed by sensitivity analyses. CONCLUSIONS: According to this analysis, apixaban may be cost-effective in the prevention of stroke in patients with nonvalvular atrial fibrillation compared with acenocoumarol. PMID- 25498374 TI - Normal discrimination of spatial frequency and contrast across visual hemifields in left-onset Parkinson's disease: evidence against perceptual hemifield biases. AB - Individuals with Parkinson's disease (PD) with symptom onset on the left side of the body (LPD) show a mild type of left-sided visuospatial neglect, whereas those with right-onset (RPD) generally do not. The functional mechanisms underlying these observations are unknown. Two hypotheses are that the representation of left-space in LPD is either compressed or reduced in salience. We tested these hypotheses psychophysically. Participants were 31 non-demented adults with PD (15 LPD, 16 RPD) and 17 normal control adults (NC). The spatial compression hypothesis was tested by showing two sinusoidal gratings, side by side. One grating's spatial frequency (SF) was varied across trials, following a staircase procedure, whereas the comparison grating was held at a constant SF. While fixating on a central target, participants estimated the point at which they perceived the two gratings to be equal in SF. The reduced salience hypothesis was tested in a similar way, but by manipulating the contrast of the test grating rather than its SF. There were no significant differences between groups in the degree of bias across hemifields for SF discrimination or for contrast discrimination. Results did not support either the spatial compression hypothesis or the reduced salience hypothesis. Instead, they suggest that at this perceptual level, LPD do not have a systematically biased way of representing space in the left hemifield that differs from healthy individuals, nor do they perceive stimuli on the left as less salient than stimuli on the right. Neglect-like syndrome in LPD instead presumably arises from dysfunction of higher-order attention. PMID- 25498376 TI - Introduction: Mineral bone disorder is a key player in chronic kidney disease. PMID- 25498375 TI - Sex-specific immune modulation of primary hypertension. AB - It is well known that the onset of essential hypertension occurs earlier in men than women. Numerous studies have shown sex differences in the vasculature, kidney and sympathetic nervous system contribute to this sex difference in the development of hypertension. The immune system also contributes to the development of hypertension; however, sex differences in immune system modulation of blood pressure (BP) and the development of hypertension has only recently begun to be explored. Here we review findings on the effect of one's sex on the immune system and specifically how these effects impact BP and the development of primary hypertension. We also propose a hypothesis for why mechanisms underlying inflammation-induced hypertension are sex-specific. These studies underscore the value of and need for studying both sexes in the basic science exploration of the pathophysiology of hypertension as well as other diseases. PMID- 25498377 TI - The role of klotho on vascular calcification and endothelial function in chronic kidney disease. AB - Recent insights into novel roles of klotho in vascular biology make this primarily kidney-derived protein a possible candidate to form a link between chronic kidney disease and cardiovascular morbidity and mortality. Typical features of vascular dysfunction or structural abnormalities in the arterial wall are exacerbated in klotho-deficient states. Reported klotho functions include inhibition of local phosphate transport in vascular cells, phenotypic switches of vascular cellular elements into bone-forming cells, attenuation of matrix mineralization and calcification, and also preservation of endothelial functional properties and viability. To a large extent these insights rely on animal models of kidney or cardiovascular diseases. In this review the current state of knowledge on these issues is summarized, and we aim to provide a possible new perspective on cardiovascular disease in chronic kidney disease. PMID- 25498378 TI - New insights into the FGF23-Klotho axis. AB - Abnormal mineral metabolism is a hallmark in patients with advanced chronic kidney disease (CKD). Hyperphosphatemia, and the homeostatic mechanisms controlling phosphate metabolism, have received particular attention over the past decade. The phosphate-regulating hormone fibroblast growth factor-23 (FGF23) was discovered through studies of rare hypophosphatemic disorders, whereas Klotho, which subsequently turned out to be a co-receptor for FGF23, was identified in a mouse model showing hyperphosphatemia and multiple aging-like traits. The FGF23-Klotho endocrine axis is a pivotal regulator of mineral metabolism. In CKD, early onset of Klotho deficiency contributes to renal FGF23 resistance and a maladaptive increase in circulating FGF23. FGF23 is an early biomarker of renal injury and increased FGF23 predicts adverse clinical outcomes, in particular cardiovascular disease. A paradigm of FGF23 excess and Klotho deficiency is proposed, in which FGF23 preferentially stimulates left ventricular hypertrophy, and loss of Klotho augments fibrosis, endothelial dysfunction, and vascular calcification. The clinical benefit of FGF23 and Klotho measurements remain uncertain, nevertheless, the FGF23-Klotho axis is a solid candidate for a novel diagnostic and therapeutic target in CKD. PMID- 25498380 TI - When, how, and why a bone biopsy should be performed in patients with chronic kidney disease. AB - In chronic kidney disease the excessive production of parathyroid hormone increases the bone resorption rate and leads to histologic bone signs of secondary hyperparathyroidism. However, in other situations, the initial increase in parathyroid hormone and bone remodeling may be slowed down excessively by a multitude of factors including age, ethnic origin, sex, and treatments such as vitamin D, calcium salts, calcimimetics, steroids, and so forth, leading to low bone turnover or adynamic bone disease. Both high and low bone turnover diseases actually are observed equally in chronic kidney disease patients treated by dialysis, and all types of renal osteodystrophy are associated with an increased risk of skeletal fractures, reduced quality of life, and poor clinical outcomes. Unfortunately, the diagnosis of these bone abnormalities cannot be obtained correctly by current clinical, biochemical, and imaging methods. Therefore, bone biopsy has been, and still remains, the gold standard analysis for assessing the exact type of renal osteodystrophy. It is also the unique way to assess the mechanisms of action, safety, and efficacy of new bone-targeting therapies. PMID- 25498379 TI - News on biomarkers in CKD-MBD. AB - The increased awareness of the potential role played by mineral and bone disorder in the appearance of cardiovascular disease in renal patients has produced research efforts aimed at discovering possible pathogenic links. Accordingly, the diagnostic significance of the classic bone markers of mineral disorders and of the new markers in the setting of chronic kidney disease-mineral and bone disorders (CKD-MBD) needs to be re-evaluated along with increasing information. In this article we include classic markers of bone metabolism and some of the noncollagenous bone proteins that are gaining experimental and clinical significance in CKD-MBD. Among classic markers of secondary hyperparathyroidism and of renal osteodystrophy, we analyzed parathyroid hormone, alkaline phosphatase, tartrate-resistant acid phosphatase, and bone collagen-derived peptides. We underlined, for each, the relevance of parent proteins (peptides or isoforms) that affect assay methods and, eventually, the diagnostic or prognostic significance. Also, we considered their relationship with cardiovascular mortality. Among the numerous noncollagenous bone proteins, we examined matrix Gla protein (MGP), osteocalcin (OC), osteoprotegerin, and the small integrin binding ligand N-linked glycoprotein family. For MGP and OC we report the relevant involvement with the process of calcification (MGP) and with glucose and energy metabolism (OC). Both of these proteins require vitamin K to become active and this is a specific problem in renal patients who frequently are deficient of this vitamin. Finally, recent acquisitions on the fascinating family of the small integrin-binding ligand N-linked glycoprotein proteins are recapitulated briefly to underline their potential clinical interest and their complex involvement with all aspects of CKD-MBD. Their diagnostic role in clinical practice awaits further studies. PMID- 25498381 TI - Adynamic bone disease: from bone to vessels in chronic kidney disease. AB - Adynamic bone disease (ABD) is a well-recognized clinical entity in the complex chronic kidney disease (CKD)-mineral and bone disorder. Although the combination of low intact parathyroid hormone (PTH) and low bone alkaline phosphatase levels may be suggestive of ABD, the gold standard for precise diagnosis is histomorphometric analysis of tetracycline double-labeled bone biopsies. ABD essentially is characterized by low bone turnover, low bone volume, normal mineralization, and markedly decreased cellularity with minimal or no fibrosis. ABD is increasing in prevalence relative to other forms of renal osteodystrophy, and is becoming the most frequent type of bone lesion in some series. ABD develops in situations with reduced osteoanabolic stimulation caused by oversuppression of PTH, multifactorial skeletal resistance to PTH actions in uremia, and/or dysregulation of Wnt signaling. All may contribute not only to bone disease but also to the early vascular calcification processes observed in CKD. Various risk factors have been linked to ABD, including calcium loading, ageing, diabetes, hypogonadism, parathyroidectomy, peritoneal dialysis, and antiresorptive therapies, among others. The relationship between low PTH level, ABD, increased risk fracture, and vascular calcifications may at least partially explain the association of ABD with increased mortality rates. To achieve optimal bone and cardiovascular health, attention should be focused not only on classic control of secondary hyperparathyroidism but also on prevention of ABD, especially in the steadily growing proportions of diabetic, white, and elderly patients. Overcoming the insufficient osteoanabolic stimulation in ABD is the ultimate treatment goal. PMID- 25498382 TI - Calcific uremic arteriolopathy: a call for action. AB - Calciphylaxis (calcific uremic arteriolopathy [CUA]) is a threatening disease that increasingly is acknowledged as a challenging condition at the interface of nephrology, dermatology, and cardiology. The primary CUA diagnosis is determined most often in nephrology care units because the vast majority of affected cases are detected in patients with advanced or end-stage renal disease. The typical clinical cascade starts with severe pain in initially often inconspicuous skin areas, which might progress to deep tissue ulcerations. Ulcer development is a severe complication with particularly high morbidity and mortality. Unfortunately, there has been a certain stagnancy regarding the slow progress in our understanding of how and why CUA develops. In addition, several important open issues regarding therapy have not been addressed successfully yet. Therefore, the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) scientific working group Chronic Kidney Disease-Mineral and Bone Disorders (CKD-MBD) has accepted the challenge and has initiated a call for action by defining calciphylaxis as one of the outstanding research targets for the upcoming years. PMID- 25498383 TI - Calcium-sensing receptor activation in chronic kidney disease: effects beyond parathyroid hormone control. AB - Secondary hyperparathyroidism (SHPT) is an important complication of advanced chronic kidney disease (CKD). Cinacalcet, an allosteric modulator of the calcium sensing receptor (CaSR) expressed in parathyroid glands, is the only calcimimetic approved to treat SHPT in patients on dialysis. By enhancing CaSR sensitivity for plasma extracellular calcium (Ca(2+)0), cinacalcet reduces serum parathyroid hormone, Ca(2+)0, and serum inorganic phosphorous concentrations, allowing better control of SHPT and CKD-mineral and bone disorders. Of interest, the CaSR also is expressed in a variety of tissues where its activation regulates diverse cellular processes, including secretion, apoptosis, and proliferation. Thus, the existence of potential off-target effects of cinacalcet cannot be neglected. This review summarizes our current knowledge concerning the potential role(s) of the CaSR expressed in various tissues in CKD-related disorders, independently of parathyroid hormone control. PMID- 25498384 TI - The uses and abuses of Vitamin D compounds in chronic kidney disease-mineral bone disease (CKD-MBD). AB - Vitamin D is of paramount importance to skeletal development, integrity and health. Vitamin D homeostatis is typically deranged in a number of chronic conditions, of which chronic kidney disease is one of the most important. The use of vitamin D based therapy to target secondary hyperparathyroidism is now several decades old, and there is a large body of clinical practice, experience, guidelines and research to underpin this. However, there are many unknowns, of significant clinical relevance. Amongst which is what "species" of vitamin D we should be using, in what patient, and, under what conditions. Sadly, there has been a real dearth of randomised controlled trials, and trials with outputs of clinical relevance, which means our clinical practice has not developed and refined adequately ove the last 4 decades. This article will discuss the vexed but critical questions of which vitamin D therapies might suit which kidney patients, and will high-light the many important clinical questions which urgently require answering. PMID- 25498385 TI - Guanfacine enhances cardiac acetylcholine release with little effect on norepinephrine release in anesthetized rabbits. AB - An alpha2A-adrenergic agonist guanfacine improves autonomic imbalance in attention-deficit hyperactivity disorder, suggesting that it may be useful to correct autonomic imbalance in chronic heart failure (CHF) patients. To investigate the effects of guanfacine on cardiac autonomic nerve activities, a microdialysis technique was applied to anesthetized rabbit heart. Acetylcholine (ACh) and norepinephrine (NE) concentrations in atrial dialysates were measured as indices of cardiac autonomic nerve activities. Guanfacine at a dose of 100 MUg/kg significantly decreased heart rate and increased dialysate ACh concentration without decreasing sympathetic NE release. Guanfacine may be useful for vagal activation therapy in CHF patients. PMID- 25498386 TI - Experimental validation of plant peroxisomal targeting prediction algorithms by systematic comparison of in vivo import efficiency and in vitro PTS1 binding affinity. AB - Most peroxisomal matrix proteins possess a C-terminal targeting signal type 1 (PTS1). Accurate prediction of functional PTS1 sequences and their relative strength by computational methods is essential for determination of peroxisomal proteomes in silico but has proved challenging due to high levels of sequence variability of non-canonical targeting signals, particularly in higher plants, and low levels of availability of experimentally validated non-canonical examples. In this study, in silico predictions were compared with in vivo targeting analyses and in vitro thermodynamic binding of mutated variants within the context of one model targeting sequence. There was broad agreement between the methods for entire PTS1 domains and position-specific single amino acid residues, including residues upstream of the PTS1 tripeptide. The hierarchy Leu>Met>Ile>Val at the C-terminal position was determined for all methods but both experimental approaches suggest that Tyr is underweighted in the prediction algorithm due to the absence of this residue in the positive training dataset. A combination of methods better defines the score range that discriminates a functional PTS1. In vitro binding to the PEX5 receptor could discriminate among strong targeting signals while in vivo targeting assays were more sensitive, allowing detection of weak functional import signals that were below the limit of detection in the binding assay. Together, the data provide a comprehensive assessment of the factors driving PTS1 efficacy and provide a framework for the more quantitative assessment of the protein import pathway in higher plants. PMID- 25498387 TI - Human apurinic/apyrimidinic endonuclease 1 (APE1) has 3' RNA phosphatase and 3' exoribonuclease activities. AB - Apurinic/apyrimidinic endonuclease 1 (APE1) is the predominant mammalian enzyme in DNA base excision repair pathway that cleaves the DNA backbone immediately 5' to abasic sites. In addition to its abasic endonuclease activity, APE1 has 3' phosphatase and 3'-5' exonuclease activities against DNA. We recently identified APE1 as an endoribonuclease that preferentially cleaves at UA, UG, and CA sites in single-stranded regions of RNAs and can regulate c-myc mRNA level and half life in cells. APE1 can also endonucleolytically cleave abasic single-stranded RNA. Here, we show for the first time that the human APE1 has 3' RNA phosphatase and 3' exoribonuclease activities. Using three distinct RNA substrates, we show that APE1, but not RNase A, can remove the phosphoryl group from the 3' end of RNA decay products. Studies using various site-directed APE1 mutant proteins (H309N, H309S, D283N, N68A, D210N, Y171F, D308A, F266A, and D70A) suggest that the 3' RNA phosphatase activity shares the same active center as its other known nuclease activities. A number of APE1 variants previously identified in the human population, including the most common D148E variant, have greater than 80% reduction in the 3' RNA phosphatase activity. APE1 can remove a ribonucleotide from the 3' overhang of RNA decay product, but its 3'-5' exoribonuclease activity against unstructured poly(A), poly(C), and poly(U) RNAs is relatively weak. This study further underscores the significance of understanding the role of APE1 in RNA metabolism in vivo. PMID- 25498388 TI - Computational de novo design of a self-assembling peptide with predefined structure. AB - Protein and peptide self-assembly is a powerful design principle for engineering of new biomolecules. More sophisticated biomaterials could be built if both the structure of the overall assembly and that of the self-assembling building block could be controlled. To approach this problem, we developed a computational design protocol to enable de novo design of self-assembling peptides with predefined structure. The protocol was used to design a peptide building block with a betaalphabeta fold that self-assembles into fibrillar structures. The peptide associates into a double beta-sheet structure with tightly packed alpha helices decorating the exterior of the fibrils. Using circular dichroism, Fourier transform infrared spectroscopy, electron microscopy and X-ray fiber diffraction, we demonstrate that the peptide adopts the designed conformation. The results demonstrate that computational protein design can be used to engineer protein and peptide assemblies with predefined three-dimensional structures, which can serve as scaffolds for the development of functional biomaterials. Rationally designed proteins and peptides could also be used to investigate the subtle energetic and entropic tradeoffs in natural self-assembly processes and the relation between assembly structure and assembly mechanism. We demonstrate that the de novo designed peptide self-assembles with a mechanism that is more complicated than expected, in a process where small changes in solution conditions can lead to significant differences in assembly properties and conformation. These results highlight that formation of structured protein/peptide assemblies is often dependent on the formation of weak but highly precise intermolecular interactions. PMID- 25498389 TI - Lead-DBS: a toolbox for deep brain stimulation electrode localizations and visualizations. AB - To determine placement of electrodes after deep brain stimulation (DBS) surgery, a novel toolbox that facilitates both reconstruction of the lead electrode trajectory and the contact placement is introduced. Using the toolbox, electrode placement can be reconstructed and visualized based on the electrode-induced artifacts on post-operative magnetic resonance (MR) or computed tomography (CT) images. Correct electrode placement is essential for efficacious treatment with DBS. Post-operative knowledge about the placement of DBS electrode contacts and trajectories is a promising tool for clinical evaluation of DBS effects and adverse effects. It may help clinicians in identifying the best stimulation contacts based on anatomical target areas and may even shorten test stimulation protocols in the future. Fifty patients that underwent DBS surgery were analyzed in this study. After normalizing the post-operative MR/CT volumes into standard Montreal Neurological Institute (MNI)-stereotactic space, electrode leads (n=104) were detected by a novel algorithm that iteratively thresholds each axial slice and isolates the centroids of the electrode artifacts within the MR/CT-images (MR only n=32, CT only n=10, MR and CT n=8). Two patients received four, the others received two quadripolar DBS leads bilaterally, summing up to a total of 120 lead localizations. In a second reconstruction step, electrode contacts along the lead trajectories were reconstructed by using templates of electrode tips that had been manually created beforehand. Reconstructions that were made by the algorithm were finally compared to manual surveys of contact localizations. The algorithm was able to robustly accomplish lead reconstructions in an automated manner in 98% of electrodes and contact reconstructions in 69% of electrodes. Using additional subsequent manual refinement of the reconstructed contact positions, 118 of 120 electrode lead and contact reconstructions could be localized using the toolbox. Taken together, the toolbox presented here allows for a precise and fast reconstruction of DBS contacts by proposing a semi-automated procedure. Reconstruction results can be directly exported to two- and three-dimensional views that show the relationship between DBS contacts and anatomical target regions. The toolbox is made available to the public in form of an open-source MATLAB repository. PMID- 25498390 TI - Improved statistical evaluation of group differences in connectomes by screening filtering strategy with application to study maturation of brain connections between childhood and adolescence. AB - Detecting local differences between groups of connectomes is a great challenge in neuroimaging, because the large number of tests that have to be performed and the impact on multiplicity correction. Any available information should be exploited to increase the power of detecting true between-group effects. We present an adaptive strategy that exploits the data structure and the prior information concerning positive dependence between nodes and connections, without relying on strong assumptions. As a first step, we decompose the brain network, i.e., the connectome, into subnetworks and we apply a screening at the subnetwork level. The subnetworks are defined either according to prior knowledge or by applying a data driven algorithm. Given the results of the screening step, a filtering is performed to seek real differences at the node/connection level. The proposed strategy could be used to strongly control either the family-wise error rate or the false discovery rate. We show by means of different simulations the benefit of the proposed strategy, and we present a real application of comparing connectomes of preschool children and adolescents. PMID- 25498391 TI - Visual attention in preterm born adults: specifically impaired attentional sub mechanisms that link with altered intrinsic brain networks in a compensation-like mode. AB - Although pronounced and lasting deficits in selective attention have been observed for preterm born individuals it is unknown which specific attentional sub-mechanisms are affected and how they relate to brain networks. We used the computationally specified 'Theory of Visual Attention' together with whole- and partial-report paradigms to compare attentional sub-mechanisms of pre- (n=33) and full-term (n=32) born adults. Resting-state fMRI was used to evaluate both between-group differences and inter-individual variance in changed functional connectivity of intrinsic brain networks relevant for visual attention. In preterm born adults, we found specific impairments of visual short-term memory (vSTM) storage capacity while other sub-mechanisms such as processing speed or attentional weighting were unchanged. Furthermore, changed functional connectivity was found in unimodal visual and supramodal attention-related intrinsic networks. Among preterm born adults, the individual pattern of changed connectivity in occipital and parietal cortices was systematically associated with vSTM in such a way that the more distinct the connectivity differences, the better the preterm adults' storage capacity. These findings provide first evidence for selectively changed attentional sub-mechanisms in preterm born adults and their relation to altered intrinsic brain networks. In particular, data suggest that cortical changes in intrinsic functional connectivity may compensate adverse developmental consequences of prematurity on visual short-term storage capacity. PMID- 25498392 TI - Polymicrobial synergy and dysbiosis in inflammatory disease. AB - Uncontrolled inflammation of the periodontal area may arise when complex microbial communities transition from a commensal to a pathogenic entity. Communication among constituent species leads to polymicrobial synergy between metabolically compatible organisms that acquire functional specialization within the developing community. Keystone pathogens, even at low abundance, elevate community virulence, and the resulting dysbiotic community targets specific aspects of host immunity to further disable immune surveillance while promoting an overall inflammatory response. Inflammophilic organisms benefit from proteinaceous substrates derived from inflammatory tissue breakdown. Inflammation and dysbiosis reinforce each other, and the escalating environmental changes further select for a pathobiotic community. We have synthesized the polymicrobial synergy and dysbiotic components of the process into a new model for inflammatory diseases. PMID- 25498393 TI - Incidence rate of fluoroquinolone-resistant gram-negative rod bacteremia among allogeneic hematopoietic cell transplantation patients during an era of levofloxacin prophylaxis. AB - There are concerns that emerging resistance to fluoroquinolones (FQ) may be leading to increasing rates of gram-negative rod (GNR) bacteremia in hematopoietic cell transplant (HCT) recipients. We set out to describe time trends in the incidence rates of GNR bacteremia and FQ-resistant GNR bacteremia in HCT recipients during an era of levofloxacin prophylaxis. We conducted a longitudinal retrospective study of adults undergoing allogeneic HCT between 2003 and 2012 at the Seattle Cancer Care Alliance (SCCA). Annual trends in the incidence rates of GNR bacteremia and FQ-resistant GNR bacteremia through 100 days after transplantation were assessed using Poisson regression. Cox proportional hazards regression was used to compare 30-day mortality between patients with FQ-resistant and those with FQ-sensitive GNR bacteremia. Of the 2306 patients included in this cohort, 280 (12.1%) had GNR bacteremia. The incidence rates of GNR bacteremia and FQ-resistant GNR bacteremia increased from 2003 to 2009 and decreased afterwards; however, the overall annual trends were not significant (incidence rate ratio [IRR], 1.01; 95% confidence interval [CI], .98 to 1.05; IRR, 1.01; 95% CI, .95 to 1.08, respectively). FQ-resistant GNR bacteremia was associated with increased mortality compared with FQ-sensitive GNR bacteremia, even after adjustment for underlying disease severity, conditioning regimen, and age at transplantation (hazard ratio, 2.11; 95% CI, 1.06 to 4.23). On average, rates of FQ-resistant GNR bacteremia have not significantly changed over 10 years of FQ prophylaxis, although FQ-resistant GNR bacteremia is associated with increased mortality compared with FQ-sensitive GNR bacteremia. PMID- 25498395 TI - Letter from the editor: Can I have my popcorn and eat it too? PMID- 25498394 TI - Inhibition of DOR prevents remifentanil induced postoperative hyperalgesia through regulating the trafficking and function of spinal NMDA receptors in vivo and in vitro. AB - BACKGROUND: Several studies have demonstrated that intraoperative remifentanil infusions have been associated with opioid-induced hyperalgesia (OIH). Activation of delta opioid receptor (DOR) and augmentation of N-methyl-d-aspartate (NMDA) receptor expression and function may play an important role in the development of OIH. The aim of this study was to investigate whether DOR inhibition could prevent remifentanil-induced hyperalgesia via regulating spinal NMDA receptor expression and function in vivo and in vitro. METHODS: A rat model of remifentanil-induced postoperative hyperalgesia was performed with the DOR agonist deltorphin-deltorphin II or the DOR antagonist naltrindole injected intrathecally 10 min before remifentanil infusion. Mechanical and thermal hyperalgesia were measured at -24h, 2, 6, 24 and 48 h after remifentanil infusion. Western blot was applied to detect the membrane and total expression of DOR and NMDA receptor subunits (NR1, NR2A and NR2B) in spinal cord L4-L6 segments. In addition, whole-cell patch-clamp recording was used to investigate the effect of DOR inhibition on NMDA receptor-induced current in spinal cord slices in vitro. RESULTS: We found that membrane trafficking of DOR, NR1 and NR2B subunits in the spinal cord increased after remifentanil administration and surgery. The DOR antagonist naltrindole could attenuate mechanical and thermal hyperalgesia without affecting baseline nociceptive threshold, reduce membrane expression of DOR and decrease the membrane and total expressions of NR1 and NR2B subunits. Furthermore, the amplitude and the frequency of NMDA receptor-induced current were significantly increased by remifentanil incubation in neurons of the dorsal horn, which was reversed by the application of naltrindole. CONCLUSION: The above results indicate that inhibition of DOR could significantly inhibit remifentanil-induced hyperalgesia via modulating the total protein level, membrane trafficking and function of NMDA receptors in the dorsal horn of spinal cord, suggesting that naltrindole could be a potential anti-hyperalgesic agent for treating OIH. PMID- 25498396 TI - Letter from the guest editor: Interstitial lung disease. PMID- 25498397 TI - Case of the season: usual interstitial pneumonia with dendriform pulmonary ossification. PMID- 25498398 TI - The idiopathic interstitial pneumonias: histology and imaging. PMID- 25498399 TI - Diffuse smoking-related lung disease: emphysema and interstitial lung disease. PMID- 25498400 TI - Imaging of cystic lung disease. PMID- 25498401 TI - An overview of collagen vascular disease-associated interstitial lung disease. PMID- 25498402 TI - Occupational lung disease. PMID- 25498403 TI - Sarcoidosis: overview of pulmonary manifestations and imaging. PMID- 25498404 TI - Visuo-tactile interactions are dependent on the predictive value of the visual stimulus. AB - In this study we aimed to explore the predictive link between visual stimuli moving towards the body and the tactile consequences that follow. More specifically, we tested if information derived from an approaching visual stimulus in the region directly surrounding the body (the peripersonal space) could be used to make judgments about the location and time of impending tactile contact. We used moving arm stimuli, displayed on a computer screen, which appeared to travel either towards the face (middle of the left/right cheek) or slightly away from the subject's face. This stimulus was followed by tactile stimulation of the left/right cheek. The time lag between the visual stimulus and tactile stimulation was also manipulated to simulate tactile contact at a time that was either consistent or inconsistent with the speed of the approaching hand. Reaction time information indicated that faster responses were produced when the arm moved towards the hemispace in which the tactile stimulation was delivered and was insensitive to whether the arm was moving towards the cheek or slightly away from the cheek. Furthermore, response times were fastest when the tactile stimulation arrived at the moment that was consistent with the speed of the moving arm. The effects disappeared when the arm appeared to be retracting from the subject's face. These results suggest the existence of a predictive mechanism that exploits the visual information derived from objects moving towards the body for making judgments about the time and location of impending tactile contact. PMID- 25498405 TI - The neural basis of social risky decision making in females with major depressive disorder. AB - Recent evidence indicates that Major Depressive Disorder (MDD) may be associated with reduced tendency of committing noncompliant actions during social decision making even when the risk of being punished is low. The neural underpinnings of this behavioral pattern are unknown, although it likely relates to compromised functioning of the lateral prefrontal-striatal/limbic networks implicated in executive control, emotion regulation and risk/value-based instrumental behaviors. We employed a modified trust game (TG) that provided explicit information on the risk levels of cheating behaviors being detected and punished. Behavioral and neuro-image data were acquired and analyzed from 14 first-episode female MDD patients and 15 age- and gender-matched controls performing the role of trustee in the TG. Relative to controls, MDD patients exhibited less behavioral switching to making cheating choices under low risk, and reduced activity in the dorsal putamen, anterior insula and dorsolateral prefrontal cortex (DLPFC) during making low-risk cheating versus benevolent choices, with limited evidence indicating abnormal bilateral inferior frontal gyrus activities of patients when making high-risk cheating versus benevolent choices. Patients' left dorsal putamen/anterior insular signals correlated positively with their frequency of low-risk cheating. MDD patients' symptom severity correlated positively with their signals in the lateral prefrontal networks during decision making. A psycho-physiological interaction analysis provided tentative evidence for the recruitment of IFG-striatal/limbic circuitry among the control participants, but greater frontopolar-striatal/limbic connectivity among the MDD patients, during low-risk decision-making. We propose that making risky social decisions based on the balancing of self-gain and other's welfare relies on the functioning of the integrated lateral prefrontal-striatal/limbic networks, which are less efficient and dysregulated among MDD patients compared with controls, impacting negatively on the patients' social capacity and highlighting a key therapeutic target for MDD. PMID- 25498406 TI - The interaction of process and domain in prefrontal cortex during inductive reasoning. AB - Inductive reasoning is an everyday process that allows us to make sense of the world by creating rules from a series of instances. Consistent with accounts of process-based fractionations of the prefrontal cortex (PFC) along the left-right axis, inductive reasoning has been reliably localized to left PFC. However, these results may be confounded by the task domain, which is typically verbal. Indeed, some studies show that right PFC activation is seen with spatial tasks. This study used fMRI to examine the effects of process and domain on the brain regions recruited during a novel pattern discovery task. Twenty healthy young adult participants were asked to discover the rule underlying the presentation of a series of letters in varied spatial locations. The rules were either verbal (pertaining to a single semantic category) or spatial (geometric figures). Bilateral ventrolateral PFC activations were seen for the spatial domain, while the verbal domain showed only left ventrolateral PFC. A conjunction analysis revealed that the two domains recruited a common region of left ventrolateral PFC. The data support a central role of left PFC in inductive reasoning. Importantly, they also suggest that both process and domain shape the localization of reasoning in the brain. PMID- 25498407 TI - Multisensory interactions in the depth plane in front and rear space: a review. AB - In this review, we evaluate the neurophysiological, neuropsychological, and psychophysical evidence relevant to the claim that multisensory information is processed differently depending on the region of space in which it happens to be presented. We discuss how the majority of studies of multisensory interactions in the depth plane that have been conducted to date have focused on visuotactile and audiotactile interactions in frontal peripersonal space and underline the importance of such multisensory interactions in defining peripersonal space. Based on our review of studies of multisensory interactions in depth, we question the extent to which peri- and extra-personal space (both frontal and rear) are characterized by differences in multisensory interactions (as evidenced by multisensory stimuli producing a different behavioral outcome as compared to unisensory stimulation). In addition to providing an overview of studies of multisensory interactions in different regions of space, our goal in writing this review has been to demonstrate that the various kinds of multisensory interactions that have been documented may follow very similar organizing principles. Multisensory interactions in depth that involve tactile stimuli are constrained by the fact that such stimuli typically need to contact the skin surface. Therefore, depth-related preferences of multisensory interactions involving touch can largely be explained in terms of their spatial alignment in depth and their alignment with the body. As yet, no such depth-related asymmetry has been observed in the case of audiovisual interactions. We therefore suggest that the spatial boundary of peripersonal space and the enhanced audiotactile and visuotactile interactions that occur in peripersonal space can be explained in terms of the particular spatial alignment of stimuli from different modalities with the body and that they likely reflect the result of prior multisensory experience. PMID- 25498408 TI - Correlation between nutritional markers and appetite self-assessments in hemodialysis patients. AB - OBJECTIVE: Protein-energy malnutrition is among the comorbidities that most strongly affect the prognosis of patients with chronic kidney disease. Anorexia, defined as a loss of desire to eat, is one cause of such malnutrition. Tools that evaluate appetite and the correlation between appetite and nutritional parameters require further study. To evaluate the appetite status in patients from 2 hemodialysis clinics in Fortaleza, Brazil and the correlations between appetite (evaluated in the past week and in the past 4 weeks) and demographic, laboratory, and nutritional parameters. METHODS: This was a cross-sectional study of patients aged >=18 years who had undergone dialysis for >3 months. Appetite was evaluated using the first 3 questions of the Appetite and Diet Assessment Tool (ADAT) questionnaire, which evaluate the appetite status during the past week as well as 1 question from the Kidney Disease and Quality of LifeTM Short Form that assesses appetite in the past 4 weeks. The patients were divided into 3 groups according to the degree of appetite: group 1: very good and good appetite (ADAT) or not and somewhat (Kidney Disease and Quality of LifeTM Short Form); group 2: fair or moderately; and group 3: poor and very poor, or very much and extremely. The nutritional parameters evaluated were body mass index (BMI), serum albumin, Geriatric Nutritional Risk Index (GNRI) and lean body mass index (lean mass in kilogram per square meter) as obtained by multifrequency bioelectrical impedance analysis. Patients with a BMI <23 kg/m(2), albumin <4 g/dL, GNRI <98, and lean body mass index below the lowest quartile were considered malnourished. The associations between appetite and nutritional variables were tested using Fisher exact test and by comparing the means of the variables in the 3 groups using the analysis of variance and Kruskal-Wallis tests. RESULTS: A total of 136 patients were included in the study with a mean age of 50.9 years and a median time on dialysis of 45 months; 57% of the patients were male. Regarding the first question on the ADAT questionnaire, 36% of patients exhibited anorexia in the past week. Furthermore, 28.7% of the population reported a lack of appetite in the last month. Moreover, 34.3% of the patients were considered malnourished according to BMI, 34.1% according to albumin, and 31.6% according to GNRI. Among the studied variables, the mean values of the following variables were different between groups 1, 2, and 3: hemoglobin (P = .0186), creatinine (P = .0392), albumin (P = .0065), GNRI (P = .0274), and lean BMI (P = .0274). CONCLUSIONS: The prevalence of a lack of appetite in hemodialysis patients in both the past week and the past month was high in the present study. The questionnaire evaluating appetite in the last 4 weeks could be used as a malnutrition screening tool in hemodialysis patients as suggested by the correlation of decreased appetite in the last month with variables that assess nutritional status such as albumin, lean body mass index, and GNRI. PMID- 25498409 TI - The theory-of-mind network in support of action verb comprehension: evidence from an fMRI study. AB - The theory-of-mind (ToM) network refers to a specific group of brain regions implicated in the thinking of people's mental states. It remains unclear how this network contributes to verb comprehension. In the present study, we compared brain activations evoked by verbs that refer to social actions, private actions, and nonhuman events. All classic regions of the ToM network, including the posterior superior temporal sulcus (pSTS) whose activation during word comprehension is typically interpreted as the processing of motion properties, showed stronger activations to social action verbs than the others. These findings indicate that the ToM network is involved in the processing of social/mental knowledge of verb meanings. Furthermore, the activation of the pSTS during word comprehension mainly reflects the processing of social/mental properties but not that of biological-motion properties. PMID- 25498410 TI - The relationship between chief complaint and comparable sign in patients with spinal pain: An exploratory study. AB - Many musculoskeletal management philosophies advocate the exploration of the relationship between the patient's chief complaint (CC) and the physical examination findings that reproduce/reduce/change that CC. Geoffrey Maitland developed the concept "comparable sign(s) (CS), which are physical examination findings related to the CC(s) that are reproduced during an examination/treatment. These include observed abnormalities of movement, postures or motor control, abnormal responses to movement, static deformities, and abnormal joint assessment findings. There are no studies that have explored the potential clinical relationships between the patient's CC and a CS, thus this exploratory study evaluated the associations, outcomes, and prevalence of the findings. This cohort study involved 112 subjects age 54.3 years (SD = 13.4 years), with neck (25.9%) or low back pain (74.1%) who were treated with physiotherapy for an average of 42 days. Data analysis revealed 88.4% identified a CC at baseline. There was a moderate statistical association between CC and the active physiological finding of a CS (r = 0.36), and small-moderate associations between all examination phases (r = 0.25-0.37). There were no statistical differences in pain and disability outcomes for those with and without a CC or CS; however, baseline pain levels were higher for those without CC (p = 0.04). Further, rate of recovery was lower in those without a CS during passive physiological examination. The results would suggest that there may be content validity to the concept of CS but further research with larger samples sizes is required to explore the extent of the validity is warranted. PMID- 25498411 TI - Photocatalytic H2 evolution from NADH with carbon quantum dots/Pt and 2-phenyl-4 (1-naphthyl)quinolinium ion. AB - Carbon quantum dots (CQDs) were simply blended with platinum salts (K2PtCl4 and K2PtCl6) and converted into a hydrogen-evolution co-catalyst in situ, wherein Pt salts were dispersed on the surface of CQDs under photoirradiation of an aqueous solution of NADH (an electron and proton source) and 2-phenyl-4-(1 naphthyl)quinolinium ion (QuPh(+)-NA) employed as an organic photocatalyst. The co-catalyst (CQDs/Pt) exhibits similar catalytic reactivity in H2 evolution as that of pure Pt nanoparticles (PtNPs) although the Pt amount of CQDs/Pt was only 1/200 that of PtNPs previously reported. CQDs were able to capture the Pt salt acting as Pt supports. Meanwhile, CQDs act as electron reservoir, playing an important role to enhance electron transfer from QuPh(+)-NA to the Pt salt, which was confirmed by kinetic studies, XPS and HRTEM. PMID- 25498412 TI - Obituary: Elizabeth Colbourn. PMID- 25498413 TI - Animal personality and state-behaviour feedbacks: a review and guide for empiricists. AB - An exciting area in behavioural ecology focuses on understanding why animals exhibit consistent among-individual differences in behaviour (animal personalities). Animal personality has been proposed to emerge as an adaptation to individual differences in state variables, leading to the question of why individuals differ consistently in state. Recent theory emphasizes the role that positive feedbacks between state and behaviour can play in producing consistent among-individual covariance between state and behaviour, hence state-dependent personality. We review the role of feedbacks in recent models of adaptive personalities, and provide guidelines for empirical testing of model assumptions and predictions. We discuss the importance of the mediating effects of ecology on these feedbacks, and provide a roadmap for including state-behaviour feedbacks in behavioural ecology research. PMID- 25498414 TI - Dopamine D3 receptor agonists as pharmacological tools. AB - Dysregulation of the dopaminergic innervation in the central nervous system plays a key role in different neurological disorders like Parkinson's disease, restless legs syndrome, schizophrenia etc. Although dopamine D3 receptors have been recognized as an important target in these diseases, their full pharmacological properties need further investigations. With focus on dopamine D3 receptor full agonists, this review has divided the ergoline and non-ergoline ligands in dissimilar chemical subclasses describing their pharmacodynamic properties on different related receptors, on species differences and their functional properties on different signaling mechanism. This is combined with a short description of structure-activity relationships for each class. Therefore, this overview should support the rational choice for the optimal compound selection based on affinity, selectivity and efficacy data in biochemical and pharmacological studies. PMID- 25498415 TI - Cross-sex hormone treatment in male-to-female transsexual persons reduces serum brain-derived neurotrophic factor (BDNF). AB - Serum levels of brain-derived neurotrophic factor (BDNF) are reduced in male-to female transsexual persons (MtF) compared to male controls. It was hypothesized before that this might reflect either an involvement of BDNF in a biomechanism of transsexualism or to be the result of persistent social stress due to the condition. Here, we demonstrate that 12 month of cross-sex hormone treatment reduces serum BDNF levels in male-to-female transsexual persons independent of anthropometric measures. Participants were acquired through the European Network for the Investigation of Gender Incongruence (ENIGI). Reduced serum BDNF in MtF thus seems to be a result of hormonal treatment rather than a consequence or risk factor of transsexualism. PMID- 25498416 TI - Elevation of brain allopregnanolone rather than 5-HT release by short term, low dose fluoxetine treatment prevents the estrous cycle-linked increase in stress sensitivity in female rats. AB - Withdrawal from long-term dosing with exogenous progesterone precipitates increased anxiety-linked changes in behavior in animal models due to the abrupt decrease in brain concentration of allopregnanolone (ALLO), a neuroactive metabolite of progesterone. We show that a withdrawal-like effect also occurs during the late diestrus phase (LD) of the natural ovarian cycle in rats, when plasma progesterone and ALLO are declining but estrogen secretion maintains a stable low level. This effect at LD was prevented by short-term treatment with low dose fluoxetine. During LD, but not at other stages of the estrous cycle, exposure to anxiogenic stress induced by whole body vibration at 4 Hz for 5 min evoked a significant decrease in tail flick latency (stress-induced hyperalgesia) and a decrease in the number of Fos-positive neurons present in the periaqueductal gray (PAG). The threshold to evoke fear-like behaviors in response to electrical stimulation of the dorsal PAG was lower in the LD phase, indicating an increase in the intrinsic excitability of the PAG circuitry. All these effects were blocked by short-term administration of fluoxetine (2 * 1.75 mg kg(-1) i.p.) during LD. This dosage increased the whole brain concentration of ALLO, as determined using gas chromatography-mass spectrometry, but was without effect on the extracellular concentration of 5-HT in the dorsal PAG, as measured by microdialysis. We suggest that fluoxetine-induced rise in brain ALLO concentration during LD offsets the sharp physiological decline, thus removing the trigger for the development of anxiogenic withdrawal effects. PMID- 25498418 TI - [Abortions have actually increased in France in 2013]. PMID- 25498417 TI - Effects of methylphenidate and MDMA on appraisal of erotic stimuli and intimate relationships. AB - Methylphenidate mainly enhances dopamine neurotransmission whereas 3,4 methylenedioxymethamphetamine (MDMA, "ecstasy") mainly enhances serotonin neurotransmission. However, both drugs also induce a weaker increase of cerebral noradrenaline exerting sympathomimetic properties. Dopaminergic psychostimulants are reported to increase sexual drive, while serotonergic drugs typically impair sexual arousal and functions. Additionally, serotonin has also been shown to modulate cognitive perception of romantic relationships. Whether methylphenidate or MDMA alter sexual arousal or cognitive appraisal of intimate relationships is not known. Thus, we evaluated effects of methylphenidate (40 mg) and MDMA (75 mg) on subjective sexual arousal by viewing erotic pictures and on perception of romantic relationships of unknown couples in a double-blind, randomized, placebo controlled, crossover study in 30 healthy adults. Methylphenidate, but not MDMA, increased ratings of sexual arousal for explicit sexual stimuli. The participants also sought to increase the presentation time of implicit sexual stimuli by button press after methylphenidate treatment compared with placebo. Plasma levels of testosterone, estrogen, and progesterone were not associated with sexual arousal ratings. Neither MDMA nor methylphenidate altered appraisal of romantic relationships of others. The findings indicate that pharmacological stimulation of dopaminergic but not of serotonergic neurotransmission enhances sexual drive. Whether sexual perception is altered in subjects misusing methylphenidate e.g., for cognitive enhancement or as treatment for attention deficit hyperactivity disorder is of high interest and warrants further investigation. PMID- 25498419 TI - Stressor-induced proteome alterations in zebrafish: a meta-analysis of response patterns. AB - Proteomics approaches are being increasingly applied in ecotoxicology on the premise that the identification of specific protein expression changes in response to a particular chemical would allow elucidation of the underlying molecular pathways leading to an adverse effect. This in turn is expected to promote the development of focused testing strategies for specific groups of toxicants. Although both gel-based and gel-free global characterization techniques provide limited proteome coverage, the conclusions regarding the cellular processes affected are still being drawn based on the few changes detected. To investigate how specific the detected responses are, we analyzed a set of studies that characterized proteome alterations induced by various physiological, chemical and biological stressors in zebrafish, a popular model organism. Our analysis highlights several proteins and protein groups, including heat shock and oxidative stress defense proteins, energy metabolism enzymes and cytoskeletal proteins, to be most frequently identified as responding to diverse stressors. In contrast, other potentially more specifically responding protein groups are detected much less frequently. Thus, zebrafish proteome responses to stress reported by different studies appear to depend mostly on the level of stress rather than on the specific stressor itself. This suggests that the most broadly used current proteomics technologies do not provide sufficient proteome coverage to allow in-depth investigation of specific mechanisms of toxicant action. We suggest that the results of any differential proteomics experiment performed with zebrafish should be interpreted keeping in mind the list of the most frequent responders that we have identified. Similar reservations should apply to any other species where proteome responses are analyzed by global proteomics methods. Careful consideration of the reliability and significance of observed changes is necessary in order not to over-interpret the experimental results and to prevent the proliferation of false positive linkages between the chemical and the cellular functions it perturbs. We further discuss the implications of the identified "top lists" of frequently responding proteins and protein families, and suggest further directions for proteomics research in ecotoxicology. Apart from improving the proteome coverage, further research should focus on defining the significance of the observed stress response patterns for organism phenotypes and on searching for common upstream regulators that can be targeted by specific assays. PMID- 25498420 TI - Parental exposure to environmental concentrations of diuron leads to aneuploidy in embryos of the Pacific oyster, as evidenced by fluorescent in situ hybridization. AB - Changes in normal chromosome numbers (i.e. aneuploidy) due to abnormal chromosome segregation may arise either spontaneously or as a result of chemical/radiation exposure, particularly during cell division. Coastal ecosystems are continuously subjected to various contaminants originating from urban, industrial and agricultural activities. Genotoxicity is common to several families of major environmental pollutants, including pesticides, which therefore represent a potential important environmental hazard for marine organisms. A previous study demonstrated the vertical transmission of DNA damage by subjecting oyster genitors to short-term exposure to the herbicide diuron at environmental concentrations during gametogenesis. In this paper, Fluorescent in situ hybridization (FISH) was used to further characterize diuron-induced DNA damage at the chromosomal level. rDNA genes (5S and 18-5.8-28S), previously mapped onto Crassostrea gigas chromosomes 4, 5 and 10, were used as probes on the interphase nuclei of embryo preparations. Our results conclusively show higher aneuploidy (hypo- or hyperdiploidy) level in embryos from diuron-exposed genitors, with damage to the three studied chromosomal regions. This study suggests that sexually developing oysters are vulnerable to diuron exposure, incurring a negative impact on reproductive success and oyster recruitment. PMID- 25498421 TI - New tensor/sensor technologies. PMID- 25498422 TI - Trochleoplasty - simple or tricky? PMID- 25498423 TI - BASK presidency: the last 2 years. PMID- 25498424 TI - "Arthroscopic washout of the knee: a procedure in decline" by Stefan Lazic et al. PMID- 25498425 TI - I would like to thank Mr. Tice for his analysis. PMID- 25498426 TI - Functional imaging of olfaction by CBV fMRI in monkeys: insight into the role of olfactory bulb in habituation. AB - Cerebral blood volume (CBV) fMRI with superparamagnetic iron oxide nanoparticles (USPIO) as contrast agent was used to investigate the odorant-induced olfaction in anesthetized rhesus monkeys. fMRI data were acquired in 24 axial slices covering the entire brain, with isoamyl-acetate as the odor stimulant. For each experiment, multiple fMRI measurements were made during a 1- or 2-h period, with each measurement consisting of a baseline period, a stimulation period, and a recovery period. Three different stimulation paradigms with a stimulation period of 1 min, 2 min, or 8 min, respectively, were used to study the olfactory responses in the olfactory bulb (OB). Odorant-induced CBV increases were observed in the OB of each individual monkey. The spatial and temporal activation patterns were reproducible within and between animals. The sensitivity of CBV fMRI in OB was comparable with the sensitivities reported in previous animal fMRI studies. The CBV responses during the 1-min, 2-min, or 8-min odor stimulation period were relatively stable, and did not show attenuation. The amplitudes of CBV response to the repeated stimuli during the 1- or 2-h period were also stable. The stable CBV response in the OB to both continuous and repeated odor stimuli suggests that the OB may not play a major role in olfactory habituation. The technical approach described in this report can enable more extensive fMRI studies of olfactory processing in OB of both humans and non-human primates. PMID- 25498427 TI - One diffusion acquisition and different white matter models: how does microstructure change in human early development based on WMTI and NODDI? AB - White matter microstructural changes during the first three years of healthy brain development are characterized using two different models developed for limited clinical diffusion data: White Matter Tract Integrity (WMTI) metrics from Diffusional Kurtosis Imaging (DKI) and Neurite Orientation Dispersion and Density Imaging (NODDI). Both models reveal a non-linear increase in intra-axonal water fraction and in tortuosity of the extra-axonal space as a function of age, in the genu and splenium of the corpus callosum and the posterior limb of the internal capsule. The changes are consistent with expected behavior related to myelination and asynchrony of fiber development. The intra- and extracellular axial diffusivities as estimated with WMTI do not change appreciably in normal brain development. The quantitative differences in parameter estimates between models are examined and explained in the light of each model's assumptions and consequent biases, as highlighted in simulations. Finally, we discuss the feasibility of a model with fewer assumptions. PMID- 25498428 TI - Tracking slow modulations in synaptic gain using dynamic causal modelling: validation in epilepsy. AB - In this work we propose a proof of principle that dynamic causal modelling can identify plausible mechanisms at the synaptic level underlying brain state changes over a timescale of seconds. As a benchmark example for validation we used intracranial electroencephalographic signals in a human subject. These data were used to infer the (effective connectivity) architecture of synaptic connections among neural populations assumed to generate seizure activity. Dynamic causal modelling allowed us to quantify empirical changes in spectral activity in terms of a trajectory in parameter space - identifying key synaptic parameters or connections that cause observed signals. Using recordings from three seizures in one patient, we considered a network of two sources (within and just outside the putative ictal zone). Bayesian model selection was used to identify the intrinsic (within-source) and extrinsic (between-source) connectivity. Having established the underlying architecture, we were able to track the evolution of key connectivity parameters (e.g., inhibitory connections to superficial pyramidal cells) and test specific hypotheses about the synaptic mechanisms involved in ictogenesis. Our key finding was that intrinsic synaptic changes were sufficient to explain seizure onset, where these changes showed dissociable time courses over several seconds. Crucially, these changes spoke to an increase in the sensitivity of principal cells to intrinsic inhibitory afferents and a transient loss of excitatory-inhibitory balance. PMID- 25498429 TI - The impact of gradient strength on in vivo diffusion MRI estimates of axon diameter. AB - Diffusion magnetic resonance imaging (MRI) methods for axon diameter mapping benefit from higher maximum gradient strengths than are currently available on commercial human scanners. Using a dedicated high-gradient 3T human MRI scanner with a maximum gradient strength of 300 mT/m, we systematically studied the effect of gradient strength on in vivo axon diameter and density estimates in the human corpus callosum. Pulsed gradient spin echo experiments were performed in a single scan session lasting approximately 2h on each of three human subjects. The data were then divided into subsets with maximum gradient strengths of 77, 145, 212, and 293 mT/m and diffusion times encompassing short (16 and 25 ms) and long (60 and 94 ms) diffusion time regimes. A three-compartment model of intra-axonal diffusion, extra-axonal diffusion, and free diffusion in cerebrospinal fluid was fitted to the data using a Markov chain Monte Carlo approach. For the acquisition parameters, model, and fitting routine used in our study, it was found that higher maximum gradient strengths decreased the mean axon diameter estimates by two to three fold and decreased the uncertainty in axon diameter estimates by more than half across the corpus callosum. The exclusive use of longer diffusion times resulted in axon diameter estimates that were up to two times larger than those obtained with shorter diffusion times. Axon diameter and density maps appeared less noisy and showed improved contrast between different regions of the corpus callosum with higher maximum gradient strength. Known differences in axon diameter and density between the genu, body, and splenium of the corpus callosum were preserved and became more reproducible at higher maximum gradient strengths. Our results suggest that an optimal q-space sampling scheme for estimating in vivo axon diameters should incorporate the highest possible gradient strength. The improvement in axon diameter and density estimates that we demonstrate from increasing maximum gradient strength will inform protocol development and encourage the adoption of higher maximum gradient strengths for use in commercial human scanners. PMID- 25498431 TI - Another reason for easier right nasal intubation than for left nasal intubation. PMID- 25498430 TI - Head motion during MRI acquisition reduces gray matter volume and thickness estimates. AB - Imaging biomarkers derived from magnetic resonance imaging (MRI) data are used to quantify normal development, disease, and the effects of disease-modifying therapies. However, motion during image acquisition introduces image artifacts that, in turn, affect derived markers. A systematic effect can be problematic since factors of interest like age, disease, and treatment are often correlated with both a structural change and the amount of head motion in the scanner, confounding the ability to distinguish biology from artifact. Here we evaluate the effect of head motion during image acquisition on morphometric estimates of structures in the human brain using several popular image analysis software packages (FreeSurfer 5.3, VBM8 SPM, and FSL Siena 5.0.7). Within-session repeated T1-weighted MRIs were collected on 12 healthy volunteers while performing different motion tasks, including two still scans. We show that volume and thickness estimates of the cortical gray matter are biased by head motion with an average apparent volume loss of roughly 0.7%/mm/min of subject motion. Effects vary across regions and remain significant after excluding scans that fail a rigorous quality check. In view of these results, the interpretation of reported morphometric effects of movement disorders or other conditions with increased motion tendency may need to be revisited: effects may be overestimated when not controlling for head motion. Furthermore, drug studies with hypnotic, sedative, tranquilizing, or neuromuscular-blocking substances may contain spurious "effects" of reduced atrophy or brain growth simply because they affect motion distinct from true effects of the disease or therapeutic process. PMID- 25498434 TI - From the local to the global: fifty years of historical research on tuberculosis. PMID- 25498435 TI - The strength of a loosely defined movement: eugenics and medicine in imperial Russia. AB - This essay examines the 'infiltration' of eugenics into Russian medical discourse during the formation of the eugenics movement in western Europe and North America in 1900-17. It describes the efforts of two Russian physicians, the bacteriologist and hygienist Nikolai Gamaleia (1859-1949) and the psychiatrist Tikhon Iudin (1879-1949), to introduce eugenics to the Russian medical community, analysing in detail what attracted these representatives of two different medical specialties to eugenic ideas, ideals, and policies advocated by their western colleagues. On the basis of a close examination of the similarities and differences in Gamaleia's and Iudin's attitudes to eugenics, the essay argues that lack of cohesiveness gave the early eugenics movement a unique strength. The loose mix of widely varying ideas, ideals, methods, policies, activities and proposals covered by the umbrella of eugenics offered to a variety of educated professionals in Russia and elsewhere the possibility of choosing, adopting and adapting particular elements to their own national, professional, institutional and disciplinary contexts, interests and agendas. PMID- 25498432 TI - Comparative study on Toxoplasma infection between Malaysian and Myanmar pregnant women. AB - BACKGROUND: Toxoplasma gondii, an obligate intracellular protozoan parasite, causes a disease called toxoplasmosis which can sometimes be acquired congenitally by a newborn from an infected mother. This study aimed to determine the seroprevalence of Toxoplasma infection and its associated risks among 219 and 215 pregnant women from Malaysia and Myanmar, respectively. METHODS: Anti Toxoplasma IgG and IgM antibodies were screened by using standard commercial ELISA kits. The socio-demographic, obstetrics and risk factors associated with Toxoplasma infection data were compared between the two countries. RESULTS: The overall prevalence of Toxoplasma infection in Malaysian pregnant women (42.47%; 95% CI = 36.11-49.09) was significantly higher (p < 0.05) than Myanmar pregnant women (30.70%; 95% CI = 27.92-37.16). By univariate analysis, this study identified that age group, education, parity, awareness on toxoplasmosis and consumption of undercooked meat were significantly associated (p < 0.05) with Toxoplasma seropositive Malaysian pregnant women but none of these factors associated with Toxoplasma seropositive Myanmar pregnant women. In comparison using univariate analysis between the two countries, it was found that Toxoplasma seropositive Malaysian pregnant women was associated with aged 30 years and above, secondary or lower-secondary level of education, the third trimester of pregnancy, having one child or more, lacking awareness of toxoplasmosis, absence of bad obstetrics history, having no history of close contact with cats or soil, living on a farm and also consumption of undercooked meat, unpasterized milk or untreated water. Avidity measurement was used to confirm the stages of Toxoplasma infection in pregnant women who were positive for both IgG and IgM antibodies and found all were infected in the past. CONCLUSION: From our study, Toxoplasma screening and its risk measurement in pregnant women is firmly recommended for monitoring purposes and assisting proper management, including diagnosis and treatment during antenatal period. Also, it is necessary to initiate preventive measures for Toxoplasma infection among reproductive-age women in general and seronegative pregnant women in particular. Avidity measurement should be incorporated in Toxoplasma routine screening, especially with the availability of a single serum sample to assist in the diagnosis. PMID- 25498436 TI - Bolshevik disease and Stalinist terror: on the historical casuistry of artificial pneumothorax. AB - From its initial development by Carlo Forlanini at the end of the nineteenth century until the advent of antibiotics in the 1940s, artificial pneumothorax was one of the most widely used treatments for pulmonary tuberculosis. However, there were strongly held reservations about this therapy because of its risks and side effects. In the Soviet Union under Stalin, such uncertainties became instruments of political denunciation. The leading Soviet pulmonary physician Volf S. Kholtsman (1886-1941) was alleged to have used the so-called 'aristocratic therapy' of artificial pneumothorax to kill prominent Bolsheviks. Drawing on documents from Stalin's personal Secretariat, this historical study of the pneumothorax scandal contributes to the cultural history of tuberculosis, showing how it was instrumentalised for political purposes. PMID- 25498437 TI - World trade in medicinal plants from Spanish America, 1717-1815. AB - This article outlines the history of the commerce in medicinal plants and plant based remedies from the Spanish American territories in the eighteenth century. It maps the routes used to transport the plants from Spanish America to Europe and, along the arteries of European commerce, colonialism and proselytism, into societies across the Americas, Asia and Africa. Inquiring into the causes of the global 'spread' of American remedies, it argues that medicinal plants like ipecacuanha, guaiacum, sarsaparilla, jalap root and cinchona moved with relative ease into Parisian medicine chests, Moroccan court pharmacies and Manila dispensaries alike, because of their 'exotic' charisma, the force of centuries old medical habits, and the increasingly measurable effectiveness of many of these plants by the late eighteenth century. Ultimately and primarily, however, it was because the disease environments of these widely separated places, their medical systems and materia medica had long become entangled by the eighteenth century. PMID- 25498438 TI - "You have no good blood in your body". Oral communication in sixteenth-century physicians' medical practice. AB - In his personal notebooks, the little known Bohemian physician Georg Handsch (1529-c. 1578) recorded, among other things, hundreds of vernacular phrases and expressions he and other physicians used in their oral interaction with patients and families. Based primarily on this extraordinary source, this paper traces the terms, concepts and images to which sixteenth-century physicians resorted when they explained the nature of a patient's disease and justified their treatment. At the bedside and in the consultation room, Handsch and his fellow physicians attributed most diseases to a local accumulation of impure, putrid or otherwise pathological humours. The latter were commonly said to result, in turn, from an insufficient concoction and assimilation of food and drink in the stomach and the liver or from an obstruction of the humoral flow inside the body and across its borders. By contrast, other notions and explanatory models, which had a prominent place in contemporary learned medical writing, hardly played a role at all in the physicians' oral communication. Specific disease terms were rarely used, a mere imbalance of the four natural humours in the body was almost never inculpated, and the patient's personal life-style and other non-naturals did not attract much attention either. These striking differences between the ways in which physicians explained the patients' diseases in their daily practice and the explanatory models we find in contemporary textbooks, are attributed, above all, to the physicians' precarious situation in the early modern medical marketplace. Since dissatisfied patients were quick to turn to another healer, physicians had to explain the disease and justify their treatment in a manner that was comprehensible to ordinary lay people and in line with their expectations and beliefs, which, at the time, revolved almost entirely around notions of impurity and evacuation. PMID- 25498439 TI - On the borders: surgeons and their activities in the Venetian State (1540-1640). AB - Through the biographies of a dynasty of practitioners who were active in some of the mountainous villages of the Venetian Terraferma the article brings to light unknown aspects of the professional world of surgeons. Their activities were profoundly influenced by the economic and geographic peculiarities of the territory where they lived and worked. Provincial towns and their territories offered professional opportunities both to licensed and to non-university trained practitioners. However, it was generally in small villages, especially those situated in border areas and part of the main commercial networks, that surgeons preferred to establish their practices, thus supplementing the medical services supplied by the town. Normally their knowledge was largely empirical and was transmitted from father to son. The apprenticeship-based training does not appear alternative to the academic education typical of learned practitioners: much evidence points to the existence of 'scientific autodidacts', self-taught practitioners who possessed and read medical texts or had attended academic courses, even if only in part. Practising surgery in this area was a highly mobile activity, stretching from the village to the neighbouring valleys, and even to areas outside the boundaries of the city and across the border of the Venetian state. Surgeons, furthermore, were able to transfer their skills and knowledge across a range of different occupations such as shoemakers, leather workers and tailors, a fact that confirms their close ties with the local artisan milieu. PMID- 25498440 TI - Getting it right? Lessons from the interwar years on pulmonary tuberculosis control in England and Wales. AB - This paper examines morbidity and mortality patterns in interwar England and Wales, using previously under-explored primary archival source materials. These materials help us understand not only what local authorities could and did do, but also the reasons for the marked variations in the ability of different authorities to manage the problem. We identify where and why there were problems and also how and why some authorities were more successful than others in dealing with the disease. Wealth was not an issue. We find a combination of pro-active preventative measures was significant. PMID- 25498447 TI - Social media trends in medical history: tweets as sources in the history of contemporary science. PMID- 25498448 TI - Some comments on 'Social media trends in medical history'. PMID- 25498451 TI - Hypoxic exosomes promote angiogenesis. AB - In this issue of Blood, Umezu et al identified that exosomal miR-135b plays a critical role in mediating multiple myeloma (MM) cell-to-endothelial cell communication under chronic hypoxia. PMID- 25498452 TI - Platelets: balancing the septic triad. AB - In this issue of Blood, de Stoppelaar et al further unravel the relevance of platelets in a mouse model of pneumonia-derived sepsis by illustrating how platelets dynamically modulate infection and the inflammatory response. PMID- 25498453 TI - GVHD prophylaxis made safe, easy, and inexpensive. AB - In this issue of Blood, Kanakry and coworkers report on the use of posttransplant cyclophosphamide (Cy) as sole immunoprophylaxis against graft-versus-host disease (GVHD) in HLA-matched related or unrelated allogeneic hematopoietic stem cell transplant (HSCT). PMID- 25498454 TI - Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. PMID- 25498455 TI - Ibrutinib-naive chronic lymphocytic leukemia lacks Bruton tyrosine kinase mutations associated with treatment resistance. PMID- 25498456 TI - Acute megakaryocytic leukemia is associated with worse outcomes than other types of acute myeloid leukemia. PMID- 25498457 TI - A qualitative and quantitative high-throughput assay for screening of gluconate high-yield strains by Aspergillus niger. AB - A novel two-step high-throughput strategy was developed for screening of gluconate high-yield strains by Aspergillus niger. The first step was fast qualitative assay according to the indicator color change, the second step was quantitative assay according to the absorbance of chelate formed with Cu(2+) at 810nm. The accuracy of high-throughput assay was comparable to that of high performance liquid chromatography (HPLC). The correlation coefficient between CuSO4 assay and HPLC assays was exceeding 0.99 by statistical analysis. As a result, 3 high-yield mutants were screened out from 1000 viable single colonies, the mutants II-2-A1, IV-7-C6, and V-11-C5 were further validated in 5L of bioreactor. The average production rates were 15.5%, 32.8%, and 12.1% higher than that of the parental strain, respectively. PMID- 25498458 TI - Arthroscopic-assisted latissimus dorsi tendon transfer for irreparable posterosuperior cuff tears. AB - PURPOSE: To evaluate, in a multicenter, prospective study, the clinical, magnetic resonance imaging (MRI), and radiologic results of arthroscopic-assisted latissimus dorsi (LD) tendon transfer for irreparable posterosuperior rotator cuff tears; and to assess the influence of perioperative data on clinical results. METHODS: Fifty-five patients with irreparable tears of at least the supraspinatus and infraspinatus tendons were managed with arthroscopic-assisted LD tendon transfer and reviewed clinically, with standardized radiographs and MRI, after a mean of 29 months. Outcome measures included the Constant score and the Subjective Shoulder Value. The osteoarthritic stage and acromiohumeral distance were measured on standardized radiographs, and the transferred tendon aspect was evaluated on MRI. RESULTS: Thirty patients had already undergone 1 or more previous surgical procedures. The mean Subjective Shoulder Value increased from 26% preoperatively to 71% postoperatively. The Constant score improved from 37 preoperatively to 65.4 postoperatively. The pain score increased from 1.7 preoperatively to 12.6 postoperatively; the activity score, from 6.4 to 13.8; active forward flexion, from 134 degrees to 157 degrees ; active abduction, from 67 degrees to 92.5 degrees ; active external rotation, from 29 degrees to 41.5 degrees ; and abduction strength, from 1.4 kg to 4.8 kg. The only statistically significant factor negatively influencing the Constant score was previous surgery. Four patients had a ruptured LD tendon on MRI follow-up at 1 year. There was no statistical difference between preoperative and final follow-up acromiohumeral distance. There was no increase in osteoarthritic stage. CONCLUSIONS: Arthroscopic-assisted LD tendon transfer improves shoulder pain and function in patients with irreparable posterosuperior cuff tears, with similar clinical and radiologic results compared with results of published series using open techniques. Patients with a history of surgery had lower Constant scores compared with non-previously operated patients. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25498459 TI - Non-communicable diseases (NCDs) in developing countries: a symposium report. AB - In recent years, non-communicable diseases (NCDs) have globally shown increasing impact on health status in populations with disproportionately higher rates in developing countries. NCDs are the leading cause of mortality worldwide and a serious public health threat to developing countries. Recognizing the importance and urgency of the issue, a one-day symposium was organized on NCDs in Developing Countries by the CIHLMU Center for International Health, Ludwig-Maximilians Universitat, Munich on 22nd March 2014. The objective of the symposium was to understand the current situation of different NCDs public health programs and the current trends in NCDs research and policy, promote exchange of ideas, encourage scientific debate and foster networking, partnerships and opportunities among experts from different clinical, research, and policy fields. The symposium was attended by more than seventy participants representing scientists, physicians, academics and students from several institutes in Germany and abroad. Seven key note presentations were made at the symposium by experts from Germany, UK, France, Bangladesh and Vietnam. This paper highlights the presentations and discussions during the symposium on different aspects of NCDs in developing countries. The symposium elucidated the dynamics of NCDs in developing countries and invited the participants to learn about evidence-based practices and policies for prevention and management of major NCDs and to debate the way forward. PMID- 25498460 TI - Retinal hemorrhages: what are we talking about? PMID- 25498461 TI - Grading system for retinal hemorrhages in abusive head trauma: clinical description and reliability study. AB - PURPOSE: There is currently no universally accepted grading system for describing retinal hemorrhages (RH) in abusive head trauma (AHT). The purpose of this study was to devise and evaluate a novel grading system and descriptive nomenclature for RH in AHT for clinical and research purposes. METHODS: A traumatic hemorrhagic retinopathy (THR) grading system was developed for assessing and quantitatively analyzing retinal findings in abusive head trauma. The criteria for the THR grade included the extent, spread, and morphology of RH. Extent was classified as region 1 (posterior pole) or region 2 (peripheral). Spread, based on number of retinal hemorrhages, was classified as mild (10 or fewer RH), moderate (more than 10 RH) and severe (more than half of involved regions covered by RH). Morphology was classified by its intraretinal or extraretinal involvement. Two independent graders calculated the THR grade from RetCam images of 38 eyes of 19 patients <3 years of age with retinal hemorrhages associated with head injury. Grading was performed on two separate occasions. Intra- and interobserver reliability was assessed with Spearman correlation coefficient (r) and intraclass correlation coefficient (ICC). RESULTS: There was a high level of intraobserver agreement across both assessments (97% agreement [Spearman r = 0.997; P < 0.0001] and 100% agreement [Spearman r = 1.0; P < 0.0000]). Intraclass correlation (ICC, 0.995; 95% CI, 0.991-0.997; P < 0.0001) confirmed a very high level of agreement overall. CONCLUSIONS: The traumatic hemorrhagic retinopathy grading system demonstrated excellent intraobserver and interobserver reliability. The nomenclature is easily understood and may be useful in medical records and medicolegal reports. PMID- 25498462 TI - Combining rectus muscle recessions with a central tenectomy to treat large-angle horizontal strabismus. AB - PURPOSE: To report the effectiveness of incorporating a central tenectomy on the recessed rectus muscles when treating large-angle horizontal deviations. METHODS: Patients undergoing recession and central tenectomy from March 2010 to January 2013 were prospectively enrolled. The procedure entails making two longitudinal incisions, each 4 mm, on the muscle adjacent to sutures made during the recession procedure. With recession complete and muscle sutured to the sclera, the central flap (with approximately one-third of the insertion width) is excised. The following variables were analyzed: expected correction (according to surgical dose tables), achieved correction (preoperative deviation minus postoperative deviation), and tenectomy effect (achieved correction minus expected correction). RESULTS: A total of 16 horizontal rectus muscles of 16 eyes of 12 patients were included, 8 with exotropia and 4 with esotropia. No cases of significant limitation in duction in the field of the recessed muscle occurred. In all patients, the median achieved corrections at distance (55(Delta)) and at near (53.5(Delta)) were significantly higher than the median expected corrections (45(Delta) for both distance and near [P = 0.002]). The postoperative deviations at distance and near were lower in the unilateral surgery group (n = 8; statistically significant only for near deviation). The tenectomy effects in the esotropia group for both distance and near were more pronounced than those of the exotropia group (although not statistically significant). CONCLUSIONS: In our patients central tenectomy of the recessed rectus muscles increased the effect of recession procedures without limiting ductions. There were possible greater effects in esotropia patients and recession-resection procedures. PMID- 25498463 TI - The effectiveness of the Spot Vision Screener in detecting amblyopia risk factors. AB - PURPOSE: To evaluate the updated Spot Vision Screener (PediaVision, Welch Allyn, Skaneateles Falls, NY) in detecting amblyopia risk factors using 2013 guidelines of American Association for Pediatric Ophthalmology and Strabismus (AAPOS). METHODS: In this prospective study, patients seen from June 2012 to November 2013 were tested with the Spot prior to examination by a pediatric ophthalmologist who was masked to test results. The following data were analyzed: age, subject testability, examination findings, and systemic and ocular pathology. Children were divided into three age groups to determine gold standard results according to the AAPOS guidelines. RESULTS: A total of 444 children (average age, 72 months) were included. Compared to the ophthalmologist's examination, the Spot sensitivity was 87.7% and the specificity was 75.9% in detecting amblyopia risk factors. Sensitivity did not differ significantly between age groups, although the positive predictive value improved in the older age groups. CONCLUSIONS: In our study cohort, the Spot provided good specificity and sensitivity in detecting amblyopia risk factors according 2013 AAPOS criteria, with minor improvements with updated versions. PMID- 25498464 TI - Using spectral-domain optical coherence tomography to detect optic neuropathy in patients with craniosynostosis. AB - BACKGROUND: Detecting and monitoring optic neuropathy in patients with craniosynostosis is a clinical challenge due to limited cooperation, and subjective measures of visual function. The purpose of this study was to appraise the correlation of peripapillary retinal nerve fiber layer (RNFL) thickness measured by spectral-domain ocular coherence tomography (SD-OCT) with indication of optic neuropathy based on fundus examination. METHODS: The medical records of all patients with craniosynostosis presenting for ophthalmic evaluation during 2013 were retrospectively reviewed. The following data were abstracted from the record: diagnosis, historical evidence of elevated intracranial pressure, current ophthalmic evaluation and visual field results, and current peripapillary RNFL thickness. RESULTS: A total of 54 patients were included (mean age, 10.6 years [range, 2.4-33.8 years]). Thirteen (24%) had evidence of optic neuropathy based on current fundus examination. Of these, 10 (77%) demonstrated either peripapillary RNFL elevation and papilledema or depression with optic atrophy. Sensitivity for detecting optic atrophy was 88%; for papilledema, 60%; and for either form of optic neuropathy, 77%. Specificity was 94%, 90%, and 83%, respectively. Kappa agreement was substantial for optic atrophy (kappa = 0.73) and moderate for papilledema (kappa = 0.39) and for either form of optic neuropathy (kappa = 0.54). Logistic regression indicated that peripapillary RNFL thickness was predictive of optic neuropathy (P < 0.001). Multivariable analysis demonstrated that RNFL thickness measurements were more sensitive at detecting optic neuropathy than visual field testing (likelihood ratio = 10.02; P = 0.002). Sensitivity and specificity of logMAR visual acuity in detecting optic neuropathy were 15% and 95%, respectively. CONCLUSIONS: Peripapillary RNFL thickness measured by SD-OCT provides adjunctive evidence for identifying optic neuropathy in patients with craniosynostosis and appears more sensitive at detecting optic atrophy than papilledema. PMID- 25498465 TI - Unilateral strabismus surgery in patients with exotropia results in postoperative lateral incomitance. AB - PURPOSE: To determine whether unilateral strabismus surgery creates lateral incomitance in patients with exotropia. METHODS: Patients >7 years of age with intermittent or constant exotropia who underwent unilateral horizontal rectus muscle surgery between December 2009 and January 2012 were prospectively evaluated. Prism and alternate cover testing was performed with distance fixation in primary position, right gaze, and left gaze after 1 hour of monocular occlusion. Measurements were obtained within 1 month prior to surgery, within 1 week after surgery, and >3 months after surgery. The surgical procedure varied according to the surgeon's discretion. The change in deviation induced by strabismus surgery in lateral gaze was expressed as a percentage of the change in deviation induced in primary position. RESULTS: A total of 12 patients met inclusion criteria. Of the 11 patients with postoperative examinations within 1 week after surgery, 10 (91%) had greater surgical effect with gaze toward the operated eye (P = 0.007). All 9 patients with >3 months' follow-up had greater surgical effect with gaze toward the operated eye (P = 0.003). On average, the surgical effect in gaze toward the operated eye was 120% of that achieved in primary position; in gaze away from the operated eye, 75% (P < 0.001). Three patients had diplopia in lateral gaze toward the operated eye that remained >6 months after surgery. CONCLUSIONS: Unilateral strabismus surgery induces lateral incomitance that may cause diplopia >6 months after surgery in patients with exotropia. This should be considered when planning strabismus surgery and counseling patients. PMID- 25498466 TI - Disparity-driven vs blur-driven models of accommodation and convergence in binocular vision and intermittent strabismus. AB - PURPOSE: To propose an alternative and practical model to conceptualize clinical patterns of concomitant intermittent strabismus, heterophoria, and convergence and accommodation anomalies. METHODS: Despite identical ratios, there can be a disparity- or blur-biased "style" in three hypothetical scenarios: normal; high ratio of accommodative convergence to accommodation (AC/A) and low ratio of convergence accommodation to convergence (CA/C); low AC/A and high CA/C. We calculated disparity bias indices (DBI) to reflect these biases and provide early objective data from small illustrative clinical groups that fit these styles. RESULTS: Normal adults (n = 56) and children (n = 24) showed disparity bias (adult DBI 0.43 [95% CI, 0.50-0.36], child DBI 0.20 [95% CI, 0.31-0.07]; P = 0.001). Accommodative esotropia (n = 3) showed less disparity-bias (DBI 0.03). In the high AC/A-low CA/C scenario, early presbyopia (n = 22) showed mean DBI of 0.17 (95% CI, 0.28-0.06), compared to DBI of -0.31 in convergence excess esotropia (n=8). In the low AC/A-high CA/C scenario near exotropia (n = 17) showed mean DBI of 0.27. DBI ranged between 1.25 and -1.67. CONCLUSIONS: Establishing disparity or blur bias adds to AC/A and CA/C ratios to explain clinical patterns. Excessive bias or inflexibility in near-cue use increases risk of clinical problems. PMID- 25498467 TI - Clinical characteristics and surgical approach to visually significant persistent pupillary membranes. AB - BACKGROUND: Infants with hyperplastic persistent pupillary membranes (PPM) may be at risk for deprivation amblyopia due to obstructions of the visual axis. We describe the long-term visual and anatomic outcomes of a surgical technique for their removal. METHODS: The medical records of consecutive patients <3 years of age who underwent surgical removal of PPMs between December 1998 and May 2012 were retrospectively reviewed. Each PPM was judged to be visually significant based on poor visual acuity, poor retinoscopic reflex, or inability to visualize the fundus. The surgical technique included injection of a viscoelastic agent beneath the pupillary strands to bow them anteriorly, careful peeling of residual adherent strands from the anterior lens capsule, and lysis of the strands at the pupillary margin with intraocular scissors. Pre- and postoperative visual and anatomic results were recorded. RESULTS: This case series included 10 eyes of 6 patients: PPMs were bilateral in 4 patients and unilateral in 2. The patient age at time of surgery ranged from 2.5 months to 2.5 years (mean, 14 months). Mean postoperative follow-up was 5.3 years (range, 2.5-8 years). All patients had successful clearance of the visual axis and good visual acuity. No intraoperative complications occurred. CONCLUSIONS: All patients in this series had excellent visual and structural outcomes, with no significant complications. The technique described here may be considered for patients with visually significant PPMs to improve visual function and pupil appearance. PMID- 25498468 TI - Reply: To PMID 24924279. PMID- 25498469 TI - Wheat bran extract alters colonic fermentation and microbial composition, but does not affect faecal water toxicity: a randomised controlled trial in healthy subjects. AB - Wheat bran extract (WBE), containing arabinoxylan-oligosaccharides that are potential prebiotic substrates, has been shown to modify bacterial colonic fermentation in human subjects and to beneficially affect the development of colorectal cancer (CRC) in rats. However, it is unclear whether these changes in fermentation are able to reduce the risk of developing CRC in humans. The aim of the present study was to evaluate the effects of WBE on the markers of CRC risk in healthy volunteers, and to correlate these effects with colonic fermentation. A total of twenty healthy subjects were enrolled in a double-blind, cross-over, randomised, controlled trial in which the subjects ingested WBE (10 g/d) or placebo (maltodextrin, 10 g/d) for 3 weeks, separated by a 3-week washout period. At the end of each study period, colonic handling of NH3 was evaluated using the biomarker lactose[15N, 15N']ureide, colonic fermentation was characterised through a metabolomics approach, and the predominant microbial composition was analysed using denaturing gradient gel electrophoresis. As markers of CRC risk, faecal water genotoxicity was determined using the comet assay and faecal water cytotoxicity using a colorimetric cell viability assay. Intake of WBE induced a shift from urinary to faecal 15N excretion, indicating a stimulation of colonic bacterial activity and/or growth. Microbial analysis revealed a selective stimulation of Bifidobacterium adolescentis. In addition, WBE altered the colonic fermentation pattern and significantly reduced colonic protein fermentation compared with the run-in period. However, faecal water cytotoxicity and genotoxicity were not affected. Although intake of WBE clearly affected colonic fermentation and changed the composition of the microbiota, these changes were not associated with the changes in the markers of CRC risk. PMID- 25498470 TI - Characterization of Alternaria strains from Argentinean blueberry, tomato, walnut and wheat. AB - Alternaria species have the ability to produce a variety of secondary metabolite, which plays important roles in food safety. Argentina is the second largest exporter of fresh and processed food products to Europe, however, few studies on Alternaria mycotoxins and other bioactive secondary metabolites have been carried out on Argentinean cereals, fruit and vegetables. Knowing the full chemical potential and the distribution of Alternaria spp. on crops, it is necessary to establish a toxicological risk assessment for food products for human consumption. In the present study, 87 Alternaria strains from different substrates (tomato, wheat, blueberries and walnuts) were characterized according to morphology and metabolite production. Aggressive dereplication (accurate mass, isotopic patterns and lists of all described compounds from Alternaria) was used for high-throughput evaluation of the chemical potential. Four strains belonged to the Alternaria infectoria sp.-grp., 6 to the Alternaria arborescens sp.-grp., 6 showed a sporulation pattern similar to that of "M" according to Simmons, 1 to that of Alternaria vaccinii, and the remaining 70 constituted a diverse group belonging to morphological groups "G" and "H". The cluster analysis yielded 16 almost identical dendrograms and grouped the Alternaria strains into four clusters and 11 singletons and outlier groups. The chemical analysis showed that AOH and AME were the most common metabolites produced, followed by TEN, ALXs and TeA. The A. infectoria sp.-grp. had no metabolites in common with the rest of the strains. Several secondary metabolites isolated from large-spored Alternaria species or other fungal genera were detected, such as dehydrocurvularin, pyrenochaetic acid and alternarienonic acid. The strains isolated from tomato produced lower amounts of metabolites than strains from blueberries, walnut and wheat, although individual strains from tomato produced the highest amount of some metabolites. The A. infectoria sp.-grp. was unique to cereals, whereas strains classified as belonging to the A. arborescens sp.-grp or having sporulation pattern "M" were only isolated from tomatoes. Otherwise, no clear association between substrate and identity could be found. The analyses in the study show that at least 75% of the Argentinean strains are able to produce potential mycotoxins. PMID- 25498471 TI - Efficacy of low-temperature high hydrostatic pressure processing in inactivating Vibrio parahaemolyticus in culture suspension and oyster homogenate. AB - Culture suspensions of five clinical and five environmental Vibrio parahaemolyticus strains in 2% NaCl solution were subjected to high pressure processing (HPP) under various conditions (200-300MPa for 5 and 10 min at 1.5-20 degrees C) to study differences in pressure resistance among the strains. The most pressure-resistant and pressure-sensitive strains were selected to investigate the effects of low temperatures (15, 5 and 1.5 degrees C) on HPP (200 or 250MPa for 5 min) to inactivate V. parahaemolyticus in sterile oyster homogenates. Inactivation of V. parahaemolyticus cells in culture suspensions and oyster homogenates was greatly enhanced by lowering the processing temperature from 15 to 5 or 1.5 degrees C. A treatment of oyster homogenates at 250MPa for 5 min at 5 degrees C decreased the populations of V. parahaemolyticus by 6.2logCFU/g for strains 10290 and 100311Y11 and by >7.4logCFU/g for strain 10292. Decreasing the processing temperature of the same treatment to 1.5 degrees C reduced all the V. parahaemolyticus strains inoculated to oyster homogenates to non-detectable (<10CFU/g) levels. Factors including pressure level, processing temperature and time all need to be considered for developing effective HPP for eliminating pathogens from foods. Further studies are needed to validate the efficacy of the HPP (250MPa for 5 min at 1.5 degrees C) in inactivating V. parahaemolyticus cells in whole oysters. PMID- 25498472 TI - Optimization of fermentation parameters to study the behavior of selected lactic cultures on soy solid state fermentation. AB - The use of solid fermentation substrate (SSF) has been appreciated by the demand for natural and healthy products. Lactic acid bacteria and bifidobacteria play a leading role in the production of novel functional foods and their behavior is practically unknown in these systems. Soy is an excellent substrate for the production of functional foods for their low cost and nutritional value. The aim of this work was to optimize different parameters involved in solid state fermentation (SSF) using selected lactic cultures to improve soybean substrate as a possible strategy for the elaboration of new soy food with enhanced functional and nutritional properties. Soy flour and selected lactic cultures were used under different conditions to optimize the soy SSF. The measured responses were bacterial growth, free amino acids and beta-glucosidase activity, which were analyzed by applying response surface methodology. Based on the proposed statistical model, different fermentation conditions were raised by varying the moisture content (50-80%) of the soy substrate and temperature of incubation (31 43 degrees C). The effect of inoculum amount was also investigated. These studies demonstrated the ability of selected strains (Lactobacillus paracasei subsp. paracasei and Bifidobacterium longum) to grow with strain-dependent behavior on the SSF system. beta-Glucosidase activity was evident in both strains and L. paracasei subsp. paracasei was able to increase the free amino acids at the end of fermentation under assayed conditions. The used statistical model has allowed the optimization of fermentation parameters on soy SSF by selected lactic strains. Besides, the possibility to work with lower initial bacterial amounts to obtain results with significant technological impact was demonstrated. PMID- 25498473 TI - No change in survival after cardiac arrest in 2007 and 2012 at a hospital in Denmark. PMID- 25498474 TI - Fertilization failure after IVF in 304 couples--a case-control study on predictors and long-term prognosis. AB - OBJECTIVES: To identify predictors of total fertilization failure (TFF) and thereby optimize the primary allocation of patients with no well-defined male factor to either IVF or intracytoplasmatic sperm injection (ICSI). Further, to evaluate the long-term fertility prognosis of couples experiencing TFF. STUDY DESIGN: A retrospective case-control study including 304 couples with TFF and 304 controls with fertilization after IVF during a 10-year period from year 2000 2010. The controls were the patients with minimum one fertilized oocyte just prior to the cases. Multiple logistic regression analysis was used to evaluate the predictors of TFF. RESULTS: The multiple regression analysis identified the following independent predictors of TFF: female smoking, adjusted odds ratio (AOR) 1.7 (95% CI 1.1-2.3), non-tubal factor AOR 2.2 (95% CI 1.5-3.4), progressive motile spermatozoa after preparation * 10(6)/ml (Log2 scale) AOR 1.4 (95% CI 1.2-1.6). For every oocyte, decreasing from four to one oocytes, the risk of TFF increased with AOR 2.0 (95% CI: 1.5-2.9) and from seven to four oocytes with AOR 1.2 (95%CI: 1.0-1.3), respectively. In case of more than seven oocytes the risk of TFF did not vary significantly by the number of oocytes. Female age, BMI, duration of infertility, earlier natural or IUI conceptions were not predictors of TFF. After a minimum of 30 months of follow-up from the index cycle, 50% of the TFF patients succeeded in a live childbirth compared with 70% of the controls. Only thirty five percent of the total number of births in the TFF patients was after ICSI. CONCLUSION: The risk of TFF is associated with the number of available oocytes for fertilization, female smoking, non-tubal factor infertility and an apparently minor sperm factor. However, anticipated predictors like advanced female age, duration of infertility and earlier conceptions proved not to have any predictive value. Couples experiencing TFF have a significantly reduced overall long-term chance of live birth compared with controls. PMID- 25498475 TI - Abdominal obesity can induce both systemic and follicular fluid oxidative stress independent from polycystic ovary syndrome. AB - OBJECTIVE: The abdominal form of obesity is prevalent in women with polycystic ovary syndrome (PCOS). Visceral fat accumulation seems to play an important role in etiology of PCOS. In this cross-sectional study we evaluated the association of oxidative stress (OS) induced with PCOS and abdominal obesity in serum and follicular fluid (FF) of infertile women. STUDY DESIGN: A total of 80 women younger than 37 years old undergoing an IVF program were studied in the same period of time from September 2012 to October 2013. Blood serum and FF obtained from 40 women with PCOS (diagnosed by the Rotterdam 2004 criteria) and 40 women without PCOS undergoing IVF were evaluated for two OS markers: lipid peroxide (LPO) and total antioxidant capacity (TAC), after puncture. The patients were divided into 4 groups on the basis of presence of PCOS and waist-to-hip ratio (WHR) or abdominal obesity (OA). RESULTS: Healthy and PCOS women with abdominal obesity had significantly higher amounts of LPO in the serum and FF as compared with women without abdominal obesity. LPO concentration in FF was significantly lower than in serum and corroborates the hypothesis that the germinal cells have a potent antioxidant mechanism. We also found that LPO concentration in the PCOS group associated with AO had an increasing trend vs. those AO patients without PCOS but this difference was not significant, so the increase in LPO level was approximately independent of PCOS. Based on our results, the association and interaction between PCOS and AO can lead to TAC concentration reduction in patients. CONCLUSIONS: Abdominal obesity can induce local and systemic oxidative stress in PCOS and non-PCOS patients. We suggest that PCOS-induced disorders are likely to be exacerbated in the presence of abdominal obesity. PMID- 25498476 TI - Medicare's use of cost-effectiveness analysis for prevention (but not for treatment). AB - CONTEXT: Medicare currently pays for 23 preventive services in its benefits package, the majority of which were added since 2005. In the past decade, the program has transformed from one essentially administering treatment claims, to one increasingly focused on health promotion and maintenance. What is largely unappreciated is the role cost-effectiveness analysis has played in the coverage of preventive services. METHODS: We review the role of cost-effectiveness analysis in Medicare coverage of preventive services and contrast it to the lack of such consideration in the coverage of treatments. FINDINGS: While not considered for coverage of treatment, cost-effectiveness analysis played a role in the coverage of nine preventive services, and was evaluated in a number of instances when the service was not added. Pneumococcal vaccine, the first preventive service added to the benefit (1981), followed a Congressionally requested cost-effectiveness analysis, which showed it to be cost-saving. More recently, the Centers for Medicare and Medicaid Services (CMS) reviewed cost effectiveness evidence when covering preventive services such as HIV screening (2010) and screening and behavioral counseling for alcohol misuse (2011) (studies reported cost-effectiveness ratios of $55,440 per QALY, and $1755 per QALY, respectively). CONCLUSIONS: Cost-effectiveness analysis has played a longstanding role in informing the addition of preventive services to Medicare. It offers Medicare officials information they can use to help ensure health gains are achieved at reasonable cost. However, limiting cost-effectiveness evidence to prevention and not treatment is inconsistent and potentially inefficient. PMID- 25498477 TI - Critical transitions in chronic disease: transferring concepts from ecology to systems medicine. AB - Ecosystems and biological systems are known to be inherently complex and to exhibit nonlinear dynamics. Diseases such as microbiome dysregulation or depression can be seen as complex systems as well and were shown to exhibit patterns of nonlinearity in their response to perturbations. These nonlinearities can be revealed by a sudden shift in system states, for instance from health to disease. The identification and characterization of early warning signals which could predict upcoming critical transitions is of primordial interest as prevention of disease onset is a major aim in health care. In this review, we focus on recent evidence for critical transitions in diseases and discuss the potential of such studies for therapeutic applications. PMID- 25498478 TI - Recent progress on DNA based walkers. AB - DNA based synthetic molecular walkers are reminiscent of biological protein motors. They are powered by hybridization with fuel strands, environment induced conformational transitions, and covalent chemistry of oligonucleotides. Recent developments in experimental techniques enable direct observation of individual walkers with high temporal and spatial resolution. The functionalities of state of-the-art DNA walker systems can thus be analyzed for various applications. Herein we review recent progress on DNA walker principles and characterization methods, and evaluate various aspects of their functions for future applications. PMID- 25498479 TI - Non-random distribution of 17 Y-chromosome STR loci in different areas of Sardinia. AB - Allele frequencies of 17 Y-chromosome short tandem repeat (STR) loci, included in the AmpFlSTR(r) Y-FilerTM amplification kit, were analyzed for the first time in different samplings (N=268) from Sardinia, Italy. Samples were collected from three isolated populations (N=139) and three open populations (N=129). A total of 230 unique haplotypes were detected; the observed haplotype diversity and discrimination capacity were 0.998 and 0.858, respectively. The data presented confirm that Sardinian population is well differentiated from other Italian and Mediterranean populations. Although regarded as a homogeneous population, substantial heterogeneity was detected when Sardinian isolated villages or microareas were analyzed. Our results highlights the importance of building a Sardinia-own database, organized by small areas, as a powerful tool for both forensic applications and population genetics studies. PMID- 25498480 TI - Open Bankart repair for revision of failed prior stabilization: outcome analysis at a mean of more than 10 years. AB - BACKGROUND: The purpose of this study was to analyze the outcome of open Bankart repair for failed stabilization surgery at a mean follow-up of >10 years. MATERIALS AND METHODS: Thirty patients underwent revision open Bankart repair by a single surgeon for failed prior stabilization surgery, with a standard technique and postoperative rehabilitation. All patients were referred by other surgeons. Evaluation was by an independent examiner, at a mean follow-up of 10.2 years. Evaluation included a history, physical examination for range of motion, outcome scores, recurrence, return to athletics, and radiographic examination. RESULTS: All cases had persistent Bankart and Hill-Sachs lesions. Failures included 14 patients with a failed single arthroscopic Bankart repair; 1 patient with 2 failed arthroscopic Bankart repairs; 1 patient with an arthroscopic failure and an open Bankart repair; 7 patients with failed open Bankart repairs; and 1 patient with a failed open Bankart repair, then a failed arthroscopic attempt. Two patients had had thermal capsulorrhaphy; 2 others had staple capsulorrhaphy, 1 with an open capsular shift and 1 after a failed arthroscopic Bankart repair, an open Bankart repair, and then a coracoid transfer. All arthroscopic Bankart repairs had anchors placed medial and superior on the glenoid neck. Mean motion loss compared with the normal contralateral side was as follows: elevation 1.15 degrees , abduction 4.2 degrees , external rotation at the side 3.2 degrees , external rotation in abduction 5.1 degrees , and internal rotation 0.6 vertebral levels (NS). No patient had an apprehension sign, pain, or instability. Of 23 who played sports, 22 resumed after. Outcomes scores were as follows: American Shoulder and Elbow Surgeons, 89.44; Rowe, 86.67; Western Ontario Shoulder Instability Index, 476.26. On radiographic examination, there were 13 normal radiographs and 7 with mild, 2 with moderate, and 0 with severe arthritic changes. CONCLUSION: The open Bankart repair offers a reliable, consistently successful option for revision of failed stabilizations. PMID- 25498482 TI - Developmental alterations of the C. elegans male anal depressor morphology and function require sex-specific cell autonomous and cell non-autonomous interactions. AB - We studied the Caenorhabditis elegans anal depressor development in larval males and hermaphrodites to address how a differentiated cell sex-specifically changes its morphology prior to adulthood. In both sexes, the larval anal depressor muscle is used for defecation behavior. However in the adult males, the muscle's sarcomere is reorganized to facilitate copulation. To address when the changes occur in the anal depressor, we used YFP:actin to monitor, and mutant analysis, laser-ablation and transgenic feminization to perturb the cell's morphological dynamics. In L1 and L2 stage larva, the muscle of both sexes has similar sarcomere morphology, but the hermaphrodite sex-determination system promotes more growth. The male anal depressor begins to change in the L3 stage, first by retracting its muscle arm from the neurons of the defecation circuit. Then the muscle's ventral region develops a slit that demarcates an anterior and posterior domain. This demarcation is not dependent on the anal depressor's intrinsic genetic sex, but is influenced by extrinsic interactions with the developing male sex muscles. However, subsequent changes are dependent on the cell's sex. In the L4 stage, the anterior domain first disassembles the dorsal-ventral sarcomere region and develops filopodia that elongates anteriorly towards the spicule muscles. Later, the posterior domain dissembles the remnants of its sarcomere, but still retains a vestigial attachment to the ventral body wall. Finally, the anterior domain attaches to the sex muscles, and then reassembles an anterior posteriorly oriented sarcomere. Our work identifies key steps in the dimorphic re sculpting of the anal depressor that are regulated by genetic sex and by cell cell signaling. PMID- 25498481 TI - Super-resolution imaging in live cells. AB - Over the last twenty years super-resolution fluorescence microscopy has gone from proof-of-concept experiments to commercial systems being available in many labs, improving the resolution achievable by up to a factor of 10 or more. There are three major approaches to super-resolution, stimulated emission depletion microscopy, structured illumination microscopy, and localisation microscopy, which have all produced stunning images of cellular structures. A major current challenge is optimising performance of each technique so that the same sort of data can be routinely taken in live cells. There are several major challenges, particularly phototoxicity and the speed with which images of whole cells, or groups of cells, can be acquired. In this review we discuss the various approaches which can be successfully used in live cells, the tradeoffs in resolution, speed, and ease of implementation which one must make for each approach, and the quality of results that one might expect from each technique. PMID- 25498483 TI - Altered AMP deaminase activity may extend postmortem glycolysis. AB - Postmortem energy metabolism drives hydrogen accumulation in muscle and results in a fairly constant ultimate pH. Extended glycolysis results in adverse pork quality and may be possible with greater adenonucleotide availability postmortem. We hypothesized that slowing adenonucleotide removal by reducing AMP deaminase activity would extend glycolysis and lower the ultimate pH of muscle. Longissimus muscle samples were incorporated into an in vitro system that mimics postmortem glycolysis with or without pentostatin, an AMP deaminase inhibitor. Pentostatin lowered ultimate pH and increased lactate and glucose 6-phosphate with time. Based on these results and that AMPK gamma3(R200Q) mutated pigs (RN-) produce low ultimate pH pork, we hypothesized AMP deaminase abundance and activity would be lower in RN- muscle than wild-type. RN- muscle contained lower AMP deaminase abundance and activity. These data show that altering adenonucleotide availability postmortem can extend postmortem pH decline and suggest that AMP deaminase activity may, in part, contribute to the low ultimate pH observed in RN pork. PMID- 25498485 TI - Higher energy efficient homes are associated with increased risk of doctor diagnosed asthma in a UK subpopulation. AB - INTRODUCTION: The United Kingdom (UK) has one of the highest prevalence of asthma in the world, which represents a significant economic and societal burden. Reduced ventilation resulting from increased energy efficiency measures acts as a modifier for mould contamination and risk of allergic diseases. To our knowledge no previous study has combined detailed asset management property and health data together to assess the impact of household energy efficiency (using the UK Government's Standard Assessment Procedure) on asthma outcomes in an adult population residing in social housing. METHODS: Postal questionnaires were sent to 3867 social housing properties to collect demographic, health and environmental information on all occupants. Detailed property data, residency periods, indices of multiple deprivation (IMD) and household energy efficiency ratings were also investigated. Logistic regression was used to calculate odds ratios and confidence intervals while allowing for clustering of individuals coming from the same location. RESULTS: Eighteen percent of our target social housing population were recruited into our study. Adults had a mean age of 59 (SD+/-17.3) years and there was a higher percentage of female (59%) and single occupancy (58%) respondents. Housing demographic characteristics were representative of the target homes. A unit increase in household Standard Assessment Procedure (SAP) rating was associated with a 2% increased risk of current asthma, with the greatest risk in homes with SAP >71. We assessed exposure to mould and found that the presence of a mouldy/musty odour was associated with a two-fold increased risk of asthma (OR 2.2 95%; CI 1.3-3.8). A unit increase in SAP led to a 4-5% reduction in the risk of visible mould growth and a mouldy/musty odour. DISCUSSION: In contrast to previous research, we report that residing in energy efficient homes may increase the risk of adult asthma. We report that mould contamination increased the risk of asthma, which is in agreement with existing knowledge. Exposure to mould contamination could not fully explain the association between increased energy efficiency and asthma. Our findings may be explained by increased energy efficiency combined with the provision of inadequate heating, ventilation, and increased concentrations of other biological, chemical and physical contaminants. This is likely to be modified by a complex interaction between occupant behaviours and changes to the built environment. Our findings may also be confounded by our response rate, demographic and behavioural differences between those residing in low versus high energy efficient homes, and use of self-reported exposures and outcomes. CONCLUSION: Energy efficiency may increase the risk of current adult asthma in a population residing in social housing. This association was not significantly modified by the presence of visible mould growth, although further research is needed to investigate the interaction between other demographic and housing characteristic risk factors, especially the impact of fuel poverty on indoor exposures and health outcomes. STUDY IMPLICATIONS: A multidisciplinary approach is required to assess the interaction between energy efficiency measures and fuel poverty behaviours on health outcomes prior to the delivery of physical interventions aimed at improving the built environment. Policy incentives are required to address fuel poverty issues alongside measures to achieve SAP ratings of 71 or greater, which must be delivered with the provision of adequate heating and ventilation strategies to minimise indoor dampness. Changes in the built environment without changes in behaviour of domicile residents may lead to negative health outcomes. PMID- 25498484 TI - Mechanism of action of tranexamic acid in bleeding trauma patients: an exploratory analysis of data from the CRASH-2 trial. AB - INTRODUCTION: To investigate the mechanism of action of tranexamic acid (TXA) in bleeding trauma patients, we examined the timing of its effect on mortality. We hypothesised that if TXA reduces mortality by decreasing blood loss, its effect should be greatest on the day of the injury when bleeding is most profuse. However, if TXA reduces mortality via an anti-inflammatory mechanism its effect should be greater over the subsequent days. METHODS: Exploratory analysis, including per-protocol analyses, of data from the CRASH-2 trial, a randomised placebo controlled trial of the effect of TXA on mortality in 20,211 trauma patients with, or at risk of, significant bleeding. We examined hazard ratios (HR) and 95% confidence intervals for all-cause mortality, deaths due to bleeding and non-bleeding deaths, according to the day since injury. The CRASH-2 trial is registered as ISRCTN86750102 and ClinicalTrials.gov NCT00375258. RESULTS: The effect of TXA on mortality is greatest for deaths occurring on the day of the injury (HR all-cause mortality = 0.83, 0.73 to 0.93). This survival benefit is only evident in patients in whom treatment is initiated within 3 hours of their injury (HR <= 3 hours = 0.78, 0.68 to 0.90; HR > 3 hours = 1.02, 0.76 to 1.36). Initiation of TXA treatment within 3 hours of injury reduced the hazard of death due to bleeding on the day of the injury by 28% (HR = 0.72, 0.60 to 0.86). TXA treatment initiated beyond 3 hours of injury appeared to increase the hazard of death due to bleeding, although the estimates were imprecise. CONCLUSIONS: Early administration of tranexamic acid appears to reduce mortality primarily by preventing exsanguination on the day of the injury. PMID- 25498486 TI - Investigations on microstructural changes in pH responsive mixed micelles of Triton X-100 and bile salt. AB - Aqueous solution behaviour of a nonionic surfactant Triton X-100 is investigated in the presence of two bile salts namely sodium deoxycholate (NaDC) and sodium cholate (NaC) at different pH, temperatures and in the presence of sodium chloride and the resultant structural changes to accordingly formed mixed micelles were analyzed by using cloud point (CP), viscosity and scattering techniques. Both the bile salts increased the CP and showed a corresponding decrease in viscosity and apparent hydrodynamic diameter (Dh), which can further be subsided with the progressive addition of sodium chloride and an increase in temperature. Interestingly, in the presence of bile salt below pH ~5, CP decreased with corresponding increase in viscosity, while a reversed trend was observed above pH~8. Small angle neutron scattering data reveal that nearly spherical mixed micelles were formed in the presence of bile salt which grow and transform to prolate ellipsoidal ones at pH~3. These morphological changes are facilitated by the protonation of carboxylic acid group of bile salt and deeper penetration of bile acid molecules into TX-100 micelles at lower pH. Proposed molecular interactions are extremely informative to understand more about these biologically important compounds playing a crucial role in digestion processes. PMID- 25498487 TI - Modification of carbon derived from Sargassum sp. by lanthanum for enhanced adsorption of fluoride. AB - Excessive fluoride in water causes serious environmental issues and adverse impacts on human health. In this study, an innovative lanthanum-modified carbon (LMC) adsorbent rooted in Sargassum sp. was developed for fluoride removal. Excellent removal efficiency was observed over a wide pH range of 3-9. Almost 90% of fluoride adsorption occurred within the first 1h; the equilibrium was established within 4h. The maximum adsorption capacity of LMC could reach 94.34 mg/g at neutral pH, much higher than many commercial adsorbents. Although the presence of such competitive anions as SiO3(2-), SO4(2-), HCO3(-), PO4(3-) and AsO3(-) had certain interference on fluoride uptake, it was noticed that there was no significant impact in the presence of humic acid. Furthermore, according to the instrumental analysis, the fluoride removal was majorly controlled by outer-sphere complex adsorption, while electrostatic attraction and ion exchange mechanisms could also be observed in the fluoride adsorption process. The findings from this study suggest that our adsorbent may have a great potential in industrial applications. PMID- 25498488 TI - Pouch adenomas in Familial Adenomatous Polyposis after restorative proctocolectomy. AB - INTRODUCTION: Australian Clinical Practice Guidelines suggest six to twelve monthly endoscopic pouch surveillance in patients after restorative proctocolectomy for Familial Adenomatous Polyposis (FAP). There are several reports of adenomas and carcinomas forming within the ileum, ileal pouch mucosa or residual rectal mucosa. A retrospective clinical study was performed to audit pouch endoscopic surveillance at a large Sydney tertiary referral Hospital. The aim was to evaluate adenoma development after restorative proctocolectomy for FAP and the adherence rate to published clinical guidelines. METHODS: Thirty-nine patients who had restorative proctocolectomy for FAP from 1985 to 2011 were identified. Demographic data, details of surgery, original histopathology and details of follow-up pouch endoscopy and pathology findings were obtained. RESULTS: Of the thirty-nine patients, twenty-seven patients were included in this study. Adenomas were found in twelve of 27 (44%) patients. Mean time to first polyp formation was 88 months and median time was 72 months (range 18-249 months). All polyps were either tubular or tubulovillous in histology. One polyp had high grade dysplasia. The remainder had mild or moderate dysplasia. Polyps were excised either endo-anally or during pouchoscopy. None of the five patients who had a hand-sewn ileal pouch-anal anastomosis (IPAA) developed polyps on follow-up, compared with 12 of the 22 (55%) with a double stapled anastomosis (fishers exact test; p=0.047 (two-tailed)). Of those who developed pouch adenomas, eight (67%) developed further pouch adenomas on follow-up. CONCLUSIONS: This study supports guidelines recommending lifelong pouch surveillance after restorative proctocolectomy for FAP. Those who develop pouch adenomas may be at greater risk of developing further adenomas. Residual rectal mucosa at the pouch anal anastomosis should be carefully examined. PMID- 25498489 TI - Increased collagen maturity with sildenafil citrate: experimental high risk colonic anastomosis model. AB - BACKGROUND: Inadequate healing and high anastomosis leak rates at rectal anastomosis may be due to lack of supportive serosal layer and technical difficulty of low anterior resections. Positive effects of sildenafil on wound healing were observed. The aim of this study was to simulate rectal anastomosis as a technical insufficient anastomosis and investigate the effects of sildenafil on anastomosis healing. METHODS: Colonic anastomoses were carried out in 64 rats and randomized into four groups, CA-S, complete anastomoses without sildenafil (10 mg/kg for 5 days); CA+S, complete anastomoses with sildenafil; IA-S, incomplete anastomoses without sildenafil; IA+S, incomplete anastomoses with sildenafil. Half of the rats in every group were sacrificed on post-operative day (POD) 3, half of them sacrificed on POD 7. Tissues from the anastomoses were used for functional, histochemical, biochemical investigations. RESULTS: Sildenafil treatment resulted in increased bursting pressures in IA+S on POD 7 (p=0.010). Collagen maturity was higher in IA+S on POD 3 and POD 7, CA+S on POD 7 (p=0.010; p=0.010; p<0.007). Collagen content was higher in IA+S on POD 7 (p<0.001). Glutathione, hydroxyproline levels were similar. Malondialdehyde levels were lower in IA+S on POD 3 (p<0.001). Epithelization score was higher in IA+S on POD 7 (p=0.007). Inflammation score was higher in CA-S group on POD 3 and POD 7 (p<0.001; p<0.001). Neutrophil score was lower in CA+S on POD 3 (p=0.005). CONCLUSION: An increase in collagen content, maturity, and epithelization, a decrease in neutrophil infiltration, oxidative stress and better mechanical strength were observed with the administration of sildenafil. PMID- 25498490 TI - Endoscopic snare papillectomy: a single institutional experience of a standardized technique. A retrospective cohort study. AB - BACKGROUND: Indications for endoscopic snare papillectomy (ESP) remain controversial. Main concerns with ESP are related to the incomplete removal of the lesion, high recurrence rates and inadequate oncological resection. Aim of the study is to report short and long term outcomes after endoscopic papillectomy in a single institutional series with strict inclusion criteria and a standardized technique. METHODS: Patients with ampullary tumors who underwent endoscopic papillectomy over a 5 year period were reviewed. Inclusion criteria for endoscopic resection were: tumor diameter less than 3 cm, no endoscopic evidence of malignancy, absence of infiltration of biliary and pancreatic duct at pre-operative ERCP and tumor confined to the submucosa at EUS. An en-block resection was attempted in all cases, followed by a pancreatic stent insertion whenever possible. RESULTS: Twenty-seven patients (10 female, mean age 68 y) have been identified. Ampullectomy was successfully performed in all the cases. En bloc resection was completed in 24 patients (88.8%), while 3 patients had a piecemeal resection. A pancreatic stent was successfully placed in all the patients. Five patients experienced complications, including bleeding (2 cases, 7.4%) and acute pancreatitis (3 cases, 11.1%). There was no procedure-related mortality. Histology revealed a poor prognosis in two patients, which were subsequently treated by duodenopancreatectomy. Over a long-term follow-up (median 18 months), one patient developed local recurrence, which was successfully treated with further endoscopic resection. Overall curative resection rate was 92.6%. CONCLUSIONS: Endoscopic ampullectomy allows resection of benign tumors and in situ carcinoma. Strict indications and a proper standardized technique seem to be key factors in order to achieve excellent short and long-term results. PMID- 25498491 TI - Open incisional hernia repair with a self-gripping retromuscular Parietex mesh: a retrospective cohort study. AB - INTRODUCTION: The Rives-Stoppa and component separation technique are considered to be favourable techniques in the treatment of complex incisional hernias. However, mesh-related complications like chronic pain are still a common problem after mesh repair. As a result, a new self-gripping mesh to omit suture fixation has been developed. This study aimed to evaluate the safety and feasibility of the ParietexTM Progrip self-gripping mesh in retromuscular position for the treatment of incisional hernias. METHODS: Patients with incisional hernia who underwent repair between June 2012 and June 2014, using a self-gripping mesh in retromuscular position, were included in the study. All patients visited the outpatient clinic to identify postoperative complications and early recurrence. RESULTS: A total of 28 consecutive patients with a median age of 48 years were included in the study. Twenty-two patients (79%) were diagnosed with an incisional hernia, of whom nine (32%) had a recurrence. Six patients (21%) had an incisional hernia combined with another abdominal wall hernia. The median follow up was 12 weeks (IQR: 8-20 weeks). Twenty-three patients (82%) did not report any pain at their final outpatient clinic visit; two patients (7%) reported mild abdominal pain, and three patients (11%) had moderate abdominal pain. None of the 28 patients developed a recurrence during follow-up. CONCLUSION: This is the first study concerning the use of a ParietexTM Progrip mesh placed in retromuscular position. The study shows that it is a safe and feasible prosthesis in incisional hernias repair, as short-term recurrence did not occur and adverse events were limited. PMID- 25498492 TI - Evaluation of the relation between interstitial cells of cajal (CD117) and serotonin receptor (5HT-3A) with postfundoplication dysphagia. AB - OBJECTIVE: The aim of the present study is to investigate the effect of Nissen fundoplication to the pacemaker cells of an intestinal system and the serotonin receptors on an ICC membrane. METHODS: Sixteen adult male rats were taken into study. Rats were divided in to the following two groups. Nissen fundoplication was performed to study group (Group 1) and no surgical procedures were applied to control group (group 2). The rats who were subjected to surgery and the rats without surgery were sacrificed on to postoperative 14 days. Specimens for the pathologic analysis were obtained from upper esophagus (group A) and esophagogastric junction (EGJ) (group B). Distribution of ICC and 5HT-3A were evaluated separately. RESULTS: There was a significant difference (p=0.01, p=0.02, respectively) regarding number of cells stained with CD117 between the group 1B-2B and group 2A-2B. Also there was a significant difference between (p=0.01, p=0.01 respectively) number of cells stained with 5HT-3A in groups 1A-1B and 2A-2B. However, no correlation was detected between group 1B-2B for 5HT-3A. CONCLUSION: A reduction in the number of ICC was observed in esophagogastric junctions of the fundoplication group but 5HT-3A distribution did not show a significant difference. A decrease in the number of ICC may be effective at postfundoplication dysphagia. PMID- 25498493 TI - Performing sleeve gastrectomy. PMID- 25498494 TI - Publication of surgeon specific outcome data: a review of implementation, controversies and the potential impact on surgical training. AB - Government-mandated publication of named surgeon-specific outcome data (SSD) has recently been introduced across nine surgical speciality areas in England. This move is the first time that such national data has been released in any country, and it promises to provide a significant advancement in health service transparency. Data is derived from nine preexisting national surgical audit databases. However, eight of these were not originally designed for this purpose, and there is considerable controversy surrounding data quality, risk adjustment, patient use and interpretation, and surgeons' subsequent case selection. Concerns also surround the degree to which these results truly reflect the individual consultant, or the wider hospital team and accompanying resources. The potential impact on surgical training has largely been overlooked. This paper investigated the background to SSD publication and controversies surrounding this, the potential impact on surgical training and the response to these concerns from medical and surgical leaders. As SSD collection continues to be refined, the most appropriate outcomes measurements need to be established, and risk adjustment requires ongoing improvement and validation. Prospective evaluation of changes in surgical training should be undertaken, as any degradation of will have both short and long-term consequences for patients and surgeons alike. It is important that the literature supporting the safety of supervised trainee practice is also promoted in order to counterbalance any potential concerns that might detract from trainee operating opportunities. Finally, it is important that outcomes data is communicated to patients in the most meaningful way in order to facilitate their understanding and interpretation given the complexities of the data and analysis involved. PMID- 25498495 TI - Gentamicin-containing collagen implant reduces sternal wound complications after cardiac surgery: a retrospective analysis. AB - INTRODUCTION: The majority of evidence for use of gentamicin-containing collagen implants (GCCI) demonstrates a positive impact on infection prophylaxis despite the equivocal results of a recently published large-scale study. The primary aim of the study was to evaluate the impact of prophylactic use of GCCI on SWI following cardiac surgery in a routine clinical setting. A secondary aim was to identify the risk factors for SWI among the patient cohort. METHODS: A consecutive series of patients who had undergone sternotomy were analysed on a retrospective basis. Patient characteristics, risk factors and procedure-related variables were analysed for Group I (superficial sternal wound infection [SSWI]) and Group II (deep sternal wound infection [DSWI]) in relation to patients with complete wound healing. RESULTS: A total of 1118 patients met the inclusion criteria. The bivariate analysis demonstrated that the SSWI rate was significantly reduced by 43% in the GCCI group vs. standard treatment. Multivariate analysis demonstrated that addition of GCCI to standard treatment reduced the DSWI rate by 59% vs. standard treatment alone. Arterial hypertension, permanent/persistent atrial fibrillation and chest revision were identified as new risk factors for SSWI and pulmonary hypertension and chest revision were identified as new risk factors for DSWI. DISCUSSION: This study confirms the positive results with GCCI seen in the majority of published studies in cardiac surgery. CONCLUSION: In routine clinical practice the addition of GCCI to standard infection prophylaxis reduces the risk of both SSWI and DSWI in high risk patients undergoing cardiac surgery. PMID- 25498496 TI - Predictive value of abnormally raised serum bilirubin in acute appendicitis: a cohort study. AB - Appendicitis is a common clinical diagnosis aided by biochemical, haematological and radiological investigations. The role of some investigations, such as bilirubin, is controversial but could indicate complicated appendicitis. Accurate diagnosis enables prioritisation of patients on operating lists and a possible reduction in unnecessary investigations. METHODS: This is a retrospective cohort study of 1347 patients who underwent appendicectomy. Statistical analysis of serum bilirubin levels was performed according to histological classification of appendicitis. RESULTS: Mean serum bilirubin levels; perforated/gangrenous appendicitis 20.5 mg/L (SD 12.6), inflamed appendicitis mean 17.5 mg/L (SD CI 11.1), normal appendix mean 12.6 mg/L (7.0). Kruskal-Wallis indicated bilirubin levels were significantly different (H=128.87, df=4, p<.001) between histological groups, and a post hoc analysis with Bonferroni adjustment showed perforated/gangrenous to be significantly higher than all other groups (p<.001). Binary logistic regression combining White Cell Count (WCC) level, C-Reactive Protein (CRP) and Bilirubin levels gave a sensitivity and specificity of .69 with AUROC=.766 (std error .015) for gangrenous/perforated. Assessment according to clinical relevance showed only 30.4% of patients with an abnormally raised bilirubin had gangrenous/perforated appendicitis. CONCLUSIONS: Serum bilirubin does not independently predict perforation/gangrenous appendicitis. Statistical analysis showed differences in mean bilirubin between histological groups however this did not relate to clinical significance as bilirubin levels were still within normal clinical limits. Diagnosis of complicated appendicitis should be made on clinical grounds, with utilization of biochemical/haematological investigations, but there should not be independent reliance on investigations such as bilirubin. PMID- 25498497 TI - Patterns, risks and outcomes of urethral recurrence after radical cystectomy for urothelial cancer; over 20 year single center experience. AB - PURPOSE: To evaluate the factors affecting urethral recurrence after radical cystectomy for bladder cancer and relationship between urinary diversion type and urethral recurrence rates. PATIENTS AND METHODS: In our 504 radical cystectomy series, 287 male patients whose final pathological were urothelial carcinoma were included in the study. The relationship between urethral recurrence and pathological stage, grade, lymph node involvement and diversion type was researched in addition to risk factors for urethral recurrence. RESULTS: A Total of 287 patients. Orthotopic continent urinary diversion (OCD) and ileal conduit (IC) was performed after radical cystectomy in 141 (49.1%) and 146 (50.9%) patients respectively. Urethral recurrence was observed in 11 (3.8%) patients and urethral recurrence rates in OCD and IC groups were 1.4% and 6.2% (p=0.034). Pathological stages of recurrent patients were 2 pT1, 1 pT2 and 8 pT4 respectively (p<0.001). Urethral recurrence was significantly lower in OCD group when compared to IC group (p=0.036). When all parameters were analyzed using Cox multivariate regression analysis, the most important factor that affects urethral recurrence was pathological T stage (p<0.001). Risk factors for urethral recurrence were present in 92 patients. Urethral recurrence rates in patients with and without risk factors were 8.69% and 1.53% (p<0.01). CONCLUSIONS: In this study, pathological stage was found to be the most important factor affecting urethral recurrence and prostatic stromal invasion was an important prognostic factor in these cases. Although risk factors for urethral recurrence were similar in both groups, urethral recurrence rates were significantly lower in OCD group when compared to IC group. PMID- 25498498 TI - Laparoscopic appendicectomy in obese is associated with improvements in clinical outcome: systematic review. AB - BACKGROUND: Obese patients with general surgical emergencies provide unique challenges to the emergency surgical teams. Acute appendicitis is the most common adult acute surgical emergency encountered in practice. This systematic review evaluates the role of laparoscopic appendicectomy in obese by comparing the outcomes of laparoscopic appendicectomy in obese versus non-obese and the laparoscopic versus open appendicectomy in obese patients. METHODS: Relevant comparative studies were identified from the Cochrane Central Register of Controlled Trials, MEDLINE, Embase and PubMed (1990-2013). Primary outcomes evaluated were mortality, overall morbidity and duration of surgery. Secondary outcomes evaluated were superficial (superficial wound infection) and deep surgical site infection (intra-abdominal abscesses), conversion to open surgery, and cost of the procedure. RESULTS: Seven retrospective cohort studies and one prospective randomized controlled trial met the inclusion criteria. There was no statistically significant difference in the primary and secondary outcomes between the obese and non-obese patients undergoing laparoscopic appendicectomy. Laparoscopic appendicectomy in obese patients is associated with reduced mortality (risk ratio [RR]: 0.19 (95% CI 0.12-0.30), reduced overall morbidity (RR: 0.49 (95% CI: 0.47-0.51)), reduced superficial wound infections (RR: 0.27 (95% CI 0.21-0.35)), shorter operating times and post-operative length of hospital stay, compared to open appendicectomy. Methodological quality of the included studies is low. CONCLUSION: Laparoscopic appendicectomy appears to be a safer alternative approach to open surgery in obese adult patents. There is no significant difference in the outcomes between the obese and non-obese patients undergoing laparoscopic appendicectomy. PMID- 25498499 TI - The SPIRIT 2013 statement--defining standard protocol items for trials. PMID- 25498500 TI - Effective internalization of U251-MG-secreted exosomes into cancer cells and characterization of their lipid components. AB - Exosomes, the natural vehicles of various biological molecules, have been examined in several research fields including drug delivery. Although understanding of the biological functions of exosomes has increased, how exosomes are transported between cells remains unclear. We hypothesized that cell tropism is important for effective exosomal intercellular communication and that parental cells regulate exosome movement by modulating constituent exosomal molecules. Herein, we demonstrated the strong translocation of glioblastoma-derived exosomes (U251exo) into their parental (U251) cells, breast cancer (MDA-MB-231) cells, and fibrosarcoma (HT-1080). Furthermore, disruption of proteins of U251exo by enzymatic treatment did not affect their uptake. Therefore, we focused on lipid molecules of U251exo with the expectation that they are crucial for effective incorporation of U251exo by cancer cells. Phosphatidylethanolamine was identified as a unique lipid component of U251-MG cell-derived extracellular vesicles. From these results, valuable insight is provided into the targeting of U251exo to cancer cells, which will help to develop a cancer-targeted drug delivery system. PMID- 25498501 TI - The glucosylceramide synthase inhibitor PDMP sensitizes pancreatic cancer cells to MEK/ERK inhibitor AZD-6244. AB - Here we show that d,l-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), a glycosphingolipid biosynthesis inhibitor, increases the sensitivity of pancreatic cancer cells to the novel MEK-ERK inhibitor AZD-6244. AZD-6244 and PDMP co-administration induced massive pancreatic cancer cell death and apoptosis, more potently than either drug alone. We discovered that AZD-6244 induced ceramide production in pancreatic cancer cells, yet the excess ceramide was metabolically removed in the long-term (24-48h). PDMP facilitated AZD-6244 induced ceramide production, and ceramide level remained elevated up to 48h. Meanwhile, exogenously-added cell-permeable short chain ceramide (C2) similarly sensitized AZD-6244's activity, the two caused substantial pancreatic cancer cell death and apoptosis. At the molecular level, PDMP and AZD-6244 co-treatment inactivated ERK1/2 and AKT-mTOR signalings simultaneously in pancreatic cancer cells, while either agent alone only affected one signaling. In summary, PDMP significantly increased the sensitivity of AZD-6244 in pancreatic cancer cells. This appears to involve a sustained ceramide production as well as concurrent block of ERK and AKT-mTOR signalings. PMID- 25498502 TI - Genetic knockout and pharmacologic inhibition of NCX2 cause natriuresis and hypercalciuria. AB - The Na(+)/Ca(2+) exchanger (NCX) is a bidirectional transporter that is controlled by membrane potential and transmembrane gradients of Na(+) and Ca(2+). Although two isoforms of NCX1 and NCX2 are coexpressed on the basolateral membrane of the distal nephron, the functional significance of these isoforms is not entirely clear. Therefore, we used NCX1- and NCX2-heterozygote knockout mice (KO) and their double KO, as well as isoform-selective NCX inhibitors, to determine the roles of NCX isoforms in urine formation and electrolyte excretion in mice. NCX inhibitors, particularly NCX2-sensitive inhibitors, caused a dose dependent natriuresis and in a higher dose, moreover, hypercalciuria. Consistently, NCX1-KO possessed normal renal function similar to wild-type mice (WT), whereas NCX2-KO and double KO exhibited moderate natriuresis and hypercalciuria. Notably, renal responses to YM-244769 were equivalently observed in NCX1-KO and WT, but disappeared in NCX2-KO and double KO. Thus, functional inhibition of NCX2 initially causes natriuresis, and further inhibition of NCX2 produces hypercalciuria, suggesting that the functional significance of NCX2 lies in Na(+) and Ca(2+) reabsorption of the kidney. PMID- 25498503 TI - Tissue factor pathway inhibitor-2 is critical in zebrafish cardiogenesis. AB - Human tissue factor pathway inhibitor-2 (Tfpi-2) is an extracellular matrix associated Kunitz-type serine proteinase inhibitor and plays an important role in various cellular processes. We have previously shown that zebrafish Tfpi-2 (zTfpi 2) mainly expressed in the brain and heart of zebrafish, and it is involved in the development of central nervous system. Here, we identified zTfpi-2 as an evolutionarily conserved protein essential for zebrafish heart development, as embryos depleted of zTfpi-2 failed to undergo cardiogenesis. Changes of cardiogenic markers, vmhc, amhc and bmp4, confirmed zTfpi-2 knockdown caused cardiac defects, including retrenched ventricle, enlarged atrium and malformation of atrioventricular boundary. The sarcomeric organization was also disrupted by embryonic depletion of zTfpi-2, thus establishing the functional role of zTfpi-2 in cardiac contractility. In addition, hematopoietic defects were detected in the zTfpi-2-deficiency embryos. Importantly, injection of ztfpi-2 mRNA attenuated those cardiac and hematopoietic defects. Taken together, this study demonstrated a critical role of zTfpi-2 during embryonic cardiac development, as well as an important regulator of hematopoiesis. PMID- 25498504 TI - Neuronal pentraxin 1 expression is regulated by hypoxia inducible factor-1alpha. AB - Neuronal pentraxins (NPs) are belong to sub family of long pentraxin proteins consist of neuronal pentraxin 1 (NP1), neuronal pentraxin 2 (NP2), and neuronal pentraxin receptor (NPR). Enhanced expression of NP1 in hypoxic conditions has shown to induce cell death in neuronal cells, however, the underlying mechanism of NP1 regulation by hypoxia remains elusive. To demonstrate that, we have cloned human NP1 gene promoter upstream of the luciferase gene and the activity of NP1 promoter was studied using HEK cell lines. Within the promoter region of the human NP1 gene, we identified six putative hypoxia inducible factor (HIF) responsive elements. By luciferase reporter assays we determined that the hypoxia inducible factor responsive element is located between -332 to -215 positions relative to the translation start site are essential for transcriptional activation of NP1 under hypoxic conditions. To further confirm the activity is solely due to hypoxia, we transiently transfected green fluorescent protein (EGFP) under transcriptional control of five copies of a hypoxia response element (HRE). The intensity of GFP was recorded at normal and hypoxic conditions. Taken together, our results demonstrate that NP1 gene is a target of as a hypoxia inducible factor and it regulate NP1 expression by binding to hypoxia responsive elements (HREs) in its promoter region. PMID- 25498505 TI - Cdc6 localizes to S- and G2-phase centrosomes in a cell cycle-dependent manner. AB - The Cdc6 protein has been primarily investigated as a component of the pre replicative complex for the initiation of chromosome replication, which contributes to maintenance of chromosomal integrity. Here, we show that Cdc6 localized to the centrosomes during S and G2 phases of the cell cycle. The centrosomal localization was mediated by Cdc6 amino acid residues 311-366, which are conserved within other Cdc6 homologues and contains a putative nuclear export signal. Deletions or substitutions of the amino acid residues did not allow the proteins to localize to centrosomes. In contrast, DsRed tag fused to the amino acid residues localized to centrosomes. These results indicated that a centrosome localization signal is contained within amino acid residues 311-366. The cell cycle-dependent centrosomal localization of Cdc6 in S and G2 phases suggest a novel function of Cdc6 in centrosomes. PMID- 25498506 TI - PDGFB hypomethylation is a favourable prognostic biomarker in primary myelofibrosis. AB - Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterised by the clonal proliferation of the haematopoietic precursors together with the progressive development of bone marrow fibrosis. This stromal alteration is an important clinical issue and specific prognostic markers are not currently available. In bone marrow biopsies from 58 PMF patients, we explored the methylation pattern of genes encoding cytokines involved in the stromal reaction, namely platelet-derived growth factor-beta (PDGFB), transforming growth factor beta (TGFB) and basic fibroblast growth factor (FGF2). We also evaluated the methylation profile of the Long Interspersed Nucleotide Element 1 (LINE-1). PDGFB, FGF2 and LINE-1, but not TGFB, were significantly differently methylated in PMF compared to controls. Significantly, PDGFB hypomethylation (<16%) was correlated with a favourable PMF prognosis (grade of marrow fibrosis, p=0.03; International Prognostic Scoring Systems p=0.01 and Dynamic International Prognostic Scoring Systems, p=0.02). Although the basis of the association of PDGFB hypomethylation with favourable prognosis remains to be clarified, we speculate that hypomethylation in PMF could represent the effect of acquired somatic mutations in genes involved in epigenetic regulation of the genome. PMID- 25498507 TI - Optimal time-points for minimal residual disease monitoring change on the basis of the method used in patients with acute myeloid leukemia who underwent allogeneic stem cell transplantation: a comparison between multiparameter flow cytometry and Wilms' tumor 1 expression. AB - Minimal residual disease (MRD) of 30 adult AML patients was monitored by multiparameter flow cytometry (MFC) and WT1 expression before and after allogeneic stem cell transplantation (allo-SCT). Diagnostic performance of pre transplant MRD measured by MFC was higher than that obtained by WT1 expression. Comparable results were displayed at day +30 post-transplant, while better values by WT1 compared to MFC were found at day +90. Positive MRD by MFC predicted a shorter disease free survival (DFS) before and 1 month after transplant (p=0.006 and p=0.005), while only high WT1 levels at 1 month from the transplant significantly impacted on DFS (p=0.010). Our results support the idea that MRD monitoring by MFC should be suggested before and 30 days after the transplant, while WT1 expression should be preferred after this procedure. The assessment of MRD at day +30 from allo-SCT is recommended as post transplant check-point for the predictive role displayed, independently of the method used. PMID- 25498508 TI - Pilot study of erlotinib in patients with acute myeloid leukemia. AB - We conducted a pilot study to investigate clinical efficacy of tyrosine kinase inhibitor erlotinib in the treatment of acute myeloid leukemia (AML). A total of 11 patients with de novo AML were treated, including 2 with relapsed and/or refractory disease and 9 older patients with previously untreated AML. Patients with high baseline leukocyte count were excluded. Erlotinib was given orally at 150 mg per day continuously in 28-day cycles. The treatment was tolerated well, and no toxicities were observed. An initial reduction in circulating blasts, followed by disease progression, was observed in 2 patients. Nine other patients did not demonstrate any response in blood or bone marrow. Baseline and post-cycle 1 flow-cytometry were performed on bone marrow blasts to investigate signs of differentiation. No immunophenotypic changes suggestive of differentiation were observed. This pilot study did not demonstrate response to standard doses of erlotinib in patients with AML. PMID- 25498510 TI - Knowledge of the diagnostic algorithm for pulmonary embolism in primary care. AB - BACKGROUND: Diagnostic algorithms for pulmonary embolism (PE) have been validated in patients attending hospital emergency departments. However, general practitioners (GPs) are often the professionals of first resort for the majority of non-critical cases of PE. AIM: To evaluate the knowledge of the diagnostic algorithm for PE among GPs in France. DESIGN AND SETTING: Questionnaire-based survey of GPs with a private practice. METHOD: All GPs in the study area were sent a questionnaire including several questions on the diagnosis of PE and two clinical cases scenario with suspected PE. Factors associated with knowledge of the diagnostic algorithm were analysed by univariate and multivariate analyses. RESULTS: Five-hundred and eight questionnaires were distributed and 155 (30.5%) were available for analysis. Only 55% of the GPs did know about clinical scores for the assessment of clinical probability of PE and 42% of the GPs were aware that clinical probability is needed to interpret the result of D-dimer testing. Forty GPs (26%) gave valid responses to both clinical cases, 54 GPs (35%) had one valid case out of the two and 61 (39%) gave invalid responses to both clinical cases. Participation in specific training on PE was significantly associated with valid responses to the two clinical cases in multivariate analysis (p<0.017). CONCLUSION: The majority of GPs were unaware of the diagnostic algorithm for PE. Clinical probability was rarely assessed and knowledge about D-dimers was poor. Specific training on PE and greater awareness of clinical probability scores may promote knowledge of PE algorithm diagnosis. PMID- 25498511 TI - A European Emergency Card for adrenal insufficiency can save lives. PMID- 25498509 TI - Retinal antigen-specific regulatory T cells protect against spontaneous and induced autoimmunity and require local dendritic cells. AB - BACKGROUND: We previously reported that the peripheral regulatory T cells (pTregs) generated 'on-demand' in the retina were crucial to retinal immune privilege, and in vitro analysis of retinal dendritic cells (DC) showed they possessed antigen presenting cell (APC) activity that promoted development of the Tregs and effector T cells (Teffs). Here, we expanded these findings by examining whether locally generated, locally acting pTregs were protective against spontaneous autoimmunity and autoimmunity mediated by interphotoreceptor retinoid binding protein (IRBP). We also examined the APC capacity of retinal DC in vivo. METHODS: Transgenic (Tg) mice expressing diphtheria toxin receptor (DTR) and/or green fluorescent protein (GFP) under control of the endogenous FoxP3 promoter (GFP only in FG mice, GFP and DTR in FDG mice) or the CD11c promoter (GFP and DTR in CDG mice) were used in conjunction with Tg mice expressing beta-galactosidase (betagal) as retinal neo-self antigen and betagal-specific TCR Tg mice (BG2). Retinal T cell responses were assayed by flow cytometry and retinal autoimmune disease assessed by histological examination. RESULTS: Local depletion of the Tregs enhanced actively induced experimental autoimmune uveoretinitis to the highly expressed retinal self-antigen IRBP in FDG mice and spontaneous autoimmunity in betagal-FDG-BG2 mice, but not in mice lacking autoreactive T cells or their target antigen in the retina. The presence of retinal betagal downregulated the generation of antigen-specific Teffs and pTregs within the retina in response to local betagal challenge. Retinal DC depletion prevented generation of Tregs and Teffs within retina after betagal injection. Microglia remaining after DC depletion did not make up for loss of DC-dependent antigen presentation. CONCLUSIONS: Our results suggest that local retinal Tregs protect against spontaneous organ-specific autoimmunity and that T cell responses within the retina require the presence of local DC. PMID- 25498512 TI - Gene transfer of high-mobility group box 1 box-A domain in a rat acute liver failure model. AB - BACKGROUND: High-mobility group box 1 (HMGB1) has recently been identified as an important mediator of various kinds of acute and chronic inflammation. The protein encoded by the box-A domain of the HMGB1 gene is known to act as a competitive inhibitor of HMGB1. In this study, we investigated whether box-A gene transfer results in box-A protein production in rats and assessed therapeutic efficacy in vivo using an acute liver failure (ALF) model. MATERIALS AND METHODS: Three types of adenovirus vectors were constructed-a wild type and two mutants and a mutant vector was then selected based on the secretion from HeLa cells. The secreted protein was subjected to a tumor necrosis factor (TNF) production inhibition test in vitro. The vector was injected via the portal vein in healthy Wistar rats to confirm box-A protein production in the liver. The vector was then injected via the portal vein in rats with ALF. RESULTS: Western blot analysis showed enhanced expression of box-A protein in HeLa cells transfected with one of the mutant vectors. The culture supernatant from HeLa cells transfected with the vector inhibited TNF-alpha production from macrophages. Expression of box-A protein was confirmed in the transfected liver at 72 h after transfection. Transfected rats showed decreased hepatic enzymes, plasma HMGB1, and hepatic TNF alpha messenger RNA levels, and histologic findings and survival were significantly improved. CONCLUSIONS: HMGB1 box-A gene transfer results in box-A protein production in the liver and appears to have a beneficial effect on ALF in rats. PMID- 25498513 TI - Serum miR-195 is a diagnostic and prognostic marker for osteosarcoma. AB - BACKGROUND: MicroRNAs have been proved to be successful diagnostic and prognostic markers in several cancers, including osteosarcoma. miR-195, as a tumor suppressor, has been reported to suppress osteosarcoma cell invasion and migration in vitro. However, its clinical value is still unclear. The aim of this study was to determine the expression pattern of miR-195 in osteosarcoma patients and to investigate its associations with tumor progression and prognosis. METHODS: miR-195 levels in sera from 166 osteosarcoma patients and 60 healthy controls were detected by real-time quantitative reverse transcription polymerase chain reaction. Then, the association of serum miR-195 level with clinicopathologic factors or survival of osteosarcoma patients was further evaluated. RESULTS: miR-195 levels in sera from osteosarcoma patients were significantly lower than those in healthy controls (P < 0.001). Importantly, miR 195 could efficiently screen osteosarcoma patients from healthy controls (area under receiver operating characteristic curve = 0.892). Additionally, low miR-195 expression was more frequently occurred in osteosarcoma patients with advanced clinical stage (P = 0.002) and positive distant metastasis (P = 0.008). Univariate survival analysis revealed that osteosarcoma patients with low miR-195 expression had significantly shorter overall survival and disease-free survival than those with high miR-195 expression (both P < 0.001). Multivariate analysis further determined that low miR-195 expression was an independent and significant prognostic factor to predict poor overall survival (P = 0.002) and disease-free survival (P = 0.01). CONCLUSIONS: Decreased expression of miR-195 in serum may be a novel biomarker for screening osteosarcoma and can predict poor prognosis. Detection of serum miR-195 expression may have potential applications for the diagnosis, prognosis, and treatment of osteosarcoma. PMID- 25498514 TI - Antitumor activity of paclitaxel is significantly enhanced by a novel proapoptotic agent in non-small cell lung cancer. AB - BACKGROUND: Newer targeted agents are increasingly used in combination chemotherapy regimens with enhanced survival and improved toxicity profile. Taxols, such as paclitaxel, independently potentiate tumor destruction via apoptosis and are used as first line therapy in patients with advanced non-small cell lung cancer (NSCLC). Procaspase-3-activating compound-1 (PAC-1) is a novel proapoptotic agent that directly activates procaspase-3 (PC-3) to caspase-3, leading to apoptosis in human lung adenocarcinoma cells. Hence, we sought to evaluate the antitumor effects of paclitaxel in combination with PAC-1. METHODS: Human NSCLC cell lines (A-549 and H-322m) were incubated in the presence of PAC-1 and paclitaxel. Tumor cell viability was determined by a tetrazolium-based colorimetric assay (MTT assay). Western blot and flow cytometric analysis were performed to evaluate expression of PC-3 and the proportion of apoptotic cells, respectively. A xenograft murine model of NSCLC was used to study the in vivo antitumor effects of PAC-1. RESULTS: PAC-1 significantly reduced the inhibitory concentration 50% of paclitaxel from 35.3 to 0.33 nM in A-549 and 8.2 to 1.16 nM in H-322m cell lines. Similarly, the apoptotic activity significantly increased to 85.38% and 70.36% in A-549 and H322m, respectively. Significantly enhanced conversion of PC-3 to caspase-3 was observed with PAC-1 paclitaxel combination (P < 0.05). Mice treated with a drug combination demonstrated 60% reduced tumor growth rate compared with those of controls (P < 0.05). CONCLUSIONS: PAC-1 significantly enhances the antitumor activity of paclitaxel against NSCLC. The activation of PC-3 and thus the apoptotic pathway is a potential strategy in the treatment of human lung cancer. PMID- 25498516 TI - A comparison of continuous video-EEG monitoring and 30-minute EEG in an ICU. AB - AIM: To determine whether there is added benefit in detecting electrographic abnormalities from 16-24 hours of continuous video-EEG in adult medical/surgical ICU patients, compared to a 30-minute EEG. METHODS: This was a prospectively enroled non-randomized study of 130 consecutive ICU patients for whom EEG was requested. For 117 patients, a 30-minute EEG was requested for altered mental state and/or suspected seizures; 83 patients continued with continuous video-EEG for 16-24 hours and 34 patients had only the 30-minute EEG. For 13 patients with prior seizures, continuous video-EEG was requested and was carried out for 16-24 hours. We gathered EEG data prospectively, and reviewed the medical records retrospectively to assess the impact of continuous video-EEG. RESULTS: A total of 83 continuous video-EEG recordings were performed for 16-24 hours beyond 30 minutes of routine EEG. All were slow, and 34% showed epileptiform findings in the first 30 minutes, including 2% with seizures. Over 16-24 hours, 14% developed new or additional epileptiform abnormalities, including 6% with seizures. In 8%, treatment was changed based on continuous video-EEG. Among the 34 EEGs limited to 30 minutes, almost all were slow and 18% showed epileptiform activity, including 3% with seizures. Among the 13 patients with known seizures, continuous video-EEG was slow in all and 69% had epileptiform abnormalities in the first 30 minutes, including 31% with seizures. An additional 8% developed epileptiform abnormalities over 16-24 hours. In 46%, treatment was changed based on continuous video-EEG. CONCLUSION: This study indicates that if continuous video-EEG is not available, a 30-minute EEG in the ICU has a substantial diagnostic yield and will lead to the detection of the majority of epileptiform abnormalities. In a small percentage of patients, continuous video-EEG will lead to the detection of additional epileptiform abnormalities. In a sub-population, with a history of seizures prior to the initiation of EEG recording, the benefits of continuous video-EEG in monitoring seizure activity and influencing treatment may be greater. PMID- 25498515 TI - Personal health record reach in the Veterans Health Administration: a cross sectional analysis. AB - BACKGROUND: My HealtheVet (MHV) is the personal health record and patient portal developed by the United States Veterans Health Administration (VA). While millions of American veterans have registered for MHV, little is known about how a patient's health status may affect adoption and use of the personal health record. OBJECTIVE: Our aim was to characterize the reach of the VA personal health record by clinical condition. METHODS: This was a cross-sectional analysis of all veterans nationwide with at least one inpatient admission or two outpatient visits between April 2010 and March 2012. We compared adoption (registration, authentication, opt-in to use secure messaging) and use (prescription refill and secure messaging) of MHV in April 2012 across 18 specific clinical conditions prevalent in and of high priority to the VA. We calculated predicted probabilities of adoption by condition using multivariable logistic regression models adjusting for sociodemographics, comorbidities, and clustering of patients within facilities. RESULTS: Among 6,012,875 veterans, 6.20% were women, 61.45% were Caucasian, and 26.31% resided in rural areas. The mean age was 63.3 years. Nationwide, 18.64% had registered for MHV, 11.06% refilled prescriptions via MHV, and 1.91% used secure messaging with their clinical providers. Results from the multivariable regression suggest that patients with HIV, hyperlipidemia, and spinal cord injury had the highest predicted probabilities of adoption, whereas those with schizophrenia/schizoaffective disorder, alcohol or drug abuse, and stroke had the lowest. Variation was observed across diagnoses in actual (unadjusted) adoption and use, with registration rates ranging from 29.19% of patients with traumatic brain injury to 14.18% of those with schizophrenia/schizoaffective disorder. Some of the variation in actual reach can be explained by facility-level differences in MHV adoption and by differences in patients' sociodemographic characteristics (eg, age, race, income) by diagnosis. CONCLUSIONS: In this phase of early adoption, opportunities are being missed for those with specific medical conditions that require intensive treatment and self-management, which could be greatly supported by functions of a tethered personal health record. PMID- 25498518 TI - The effects of diet and arginine treatment on serum metabolites and selected hormones during the estrous cycle in sheep. AB - The aim of this study was to determine the effects of diet and arginine (Arg) treatment on serum concentrations of selected metabolites and metabolic and reproductive hormones in nonpregnant ewes. Sixty days before the onset of estrus (Day 0), Rambouillet ewes were randomly assigned to one of three dietary groups: maintenance control (C; N = 16; 100% National Research Council requirements), overfed (O; N = 16; 2 * C), or underfed (U; N = 16, 0.6 * C) to achieve and maintain three different body conditions during their estrous cycle(s). At Day 0, ewes from each nutritional group were randomly assigned to receive one of two treatments: saline (Sal) or Arg (L-Arg-HCl; 155 MUmol Arg per kg of body weight [BW]; intravenous), which was administered three times per day for 21 or 26 days. Blood samples were collected on Days 0, 6, 10, 12, 16, 21, and 26 of Sal or Arg treatment for evaluation of Arg, nitric oxide metabolite, cholesterol, glucose, insulin, insulin-like growth factor 1, leptin, and progesterone. For a time response trial, blood samples were collected at 0, 1, 2, 4, and 7 hours after Sal or Arg treatment at the mid-luteal phase to determine serum Arg concentrations. During the 11-week study, C maintained body weight, O gained 9.6 +/- 0.7 kg, and U lost 13.9 +/- 0.1 kg. Overall, serum concentrations of Arg, glucose, insulin, insulin-like growth factor 1, leptin, and progesterone were greater (P < 0.05) in O ewes than C and/or U ewes and were not affected by Arg treatment. Serum Arg concentration increased at 1 and 2 hours and decreased to basal level at 4 and 7 hours after Arg treatment. These data reinforce the importance of diet in regulation of metabolic and endocrine functions, and demonstrated that the dose and duration of Arg treatment used in this study does not alter serum metabolites or hormones in nonpregnant ewes of various nutritional planes. PMID- 25498517 TI - Upgraded heart failure therapy leads to an improved outcome of dilated cardiomyopathy in infants and toddlers. AB - OBJECTIVE: Dilated cardiomyopathy is a leading cause of cardiac death in children. Approximately 30% of children die or need cardiac transplantation in the first year after establishing the diagnosis. New strategies are needed to improve the outcome in this high-risk patient population. METHOD AND RESULTS: We present our experience in 38 patients below the age of three years, who were diagnosed with dilated cardiomyopathy and who were treated at our institution between 2006 and 2012. The treatment strategy involved institution of beta blockers and angiotensin-converting enzyme inhibitors as soon as feasible. In selected cases, pulmonary artery banding or intracoronary autologous bone marrow derived cell therapy was performed. The median age at presentation was six months (range 1-26 months). The median follow-up age was 16 months (range 2-80 months). Kaplan-Meier analysis of survival after dilated cardiomyopathy diagnosis revealed a one-year survival of 97% and a five-year survival of 86%. The rate of freedom from death or heart transplantation was 82% at one year and 69% at five years. Surviving patients who were free of transplantation, at the follow-up at 25 months (3-80 months), showed a significant improvement in left ventricular ejection fraction (from 19+/-11 to 46+/-16%) and left ventricular end-diastolic diameter (z-score from 4.6+/-2.4 to 1.4+/-1.6). In addition, the levels of B-type natriuretic peptide improved significantly (from 3330+/-3840 to 171+/-825 pg/ml). CONCLUSION: Our data suggest that the clinical approach described here may result in a markedly improved medium-term outcome in young children with dilated cardiomyopathy. Further studies are required to evaluate whether these approaches reduce end-points such as transplantation or death. PMID- 25498519 TI - Characteristics of estrous cycles in gilts treated with gonadotropins after estrus or treatment with a progestogen. AB - A combination of eCG (400 IU) and hCG (200 IU) (P.G. 600; Merck Animal Health, Summit, NJ, USA) stimulates puberty in gilts, but variation in the estrual response exists among farms. We hypothesized that some of the variability is a consequence of gilts that have commenced cycling being inadvertently treated. The objective of experiment 1 was to determine the effect of intramuscular (im) P.G. 600 on estrous cycles in sexually mature gilts. Gilts in treatment 1 (n = 16) received P.G. 600 at the onset of daily boar exposure. Gilts in treatments 2 to 5 (n = 16 per treatment) were allowed to express a natural first estrus and were then treated with P.G. 600 during the first estrous cycle as follows: treatment 2 at Day 6, treatment 3 at Day 12, and treatment 4 at Day 18 of the estrous cycle. Treatment 5 gilts received no P.G. 600. The proportion of gilts displaying a normal estrous cycle (18-24 days) was greater (P < 0.05) for treatments 4 (100%) and 5 (100%) compared with treatments 1 (73.3%) and 3 (60%), with treatment 2 having a value (87.5%) that was not different from the other groups. For treatment 3, 33% of gilts displayed an increased interestrus interval that averaged 32.5 days. Concentrations of progesterone remained elevated 20 days after the onset of first estrus in treatment 3 gilts, which supports the concept that P.G. 600 administered at Day 12 of the estrous cycle induced follicular growth, ovulation, and formation of CL that functioned for approximately 15 days, increasing the length of the estrous cycle. It is common for swine producers to have groups of replacement gilts that include both cycling and prepubertal animals, or individuals, the cycling status of which is unknown. The objective of experiment 2 was to evaluate a system using a combination of a progestogen (Matrix; Merck Animal Health) and P.G. 600 to synchronize estrus in replacement gilts. Crossbred gilts, assumed to be a mix of cycling and prepubertal females, were allocated to one of four treatments (n = 12 per treatment): treatment 1, Matrix (15 mg/day) fed for 14 days and im P.G. 600 24 hours after the last feeding of Matrix; treatment 2, Matrix for 7 days and P.G. 600; treatment 3, P.G. 600 only; and treatment 4, im water only. The percentage of gilts in estrus within 7 days after im treatment was the greatest (P < 0.02) and days to estrus the least (P < 0.05) for gilts receiving Matrix for 14 days and P.G. 600 (treatment 1, 91.7% and 5.4 +/- 1.9 days; treatment 2, 50% and 9.2 +/- 2.0 days; treatment 3, 33% and 13.8 +/- 2.1 days; and treatment 4, 50% and 9.1 +/- 1.9 days). The results of these experiments suggest that P.G. 600 administered to gilts that have already obtained puberty may cause abnormal estrous cycles and demonstrate to swine producers the need to correctly classify replacement gilts as prepubertal or cycling before administering the product. The use of Matrix and P.G. 600 in combination has potential as an effective strategy for synchronizing estrus in a mix of prepubertal and mature, cycling gilts. PMID- 25498520 TI - Contact- and contact-free wear between various resin composites. AB - OBJECTIVE: Nowadays direct and indirect resin composites are frequently applied to build up the occlusion when extensive tooth wear took place. To achieve long lasting restorations it is essential to obtain knowledge about their interactions due to occlusal contacts. Therefore, the two- and three-body wear between frequently used direct and indirect resin composites was investigated. MATERIALS AND METHODS: The two- and three-body wear of three direct resin composites and three indirect resin composites, with Clearfil AP-X, Filtek Z250, and Filtek Supreme XT as antagonists, were measured, using the ACTA wear device. The wear rates were determined and the surfaces were evaluated with SEM. RESULTS: The most remarkable outcome was that the two-body wear rate of the different composites opposing the Z250 wheel were significantly higher. Furthermore, it was shown that the three-body wear rate was independent on the antagonist and in general higher than the two-body wear rate. CONCLUSIONS: To reduce abrasion of the opposing resin composite surface the resin composite fillers should consist of a softer glass, e.g. barium glass or in case of a harder filler the size should be reduced to nano-size. PMID- 25498521 TI - Methacrylate bonding to zirconia by in situ silica nanoparticle surface deposition. AB - OBJECTIVE: This study introduces an innovative method to enhance adhesion of methacrylate-based cements to yttria-stabilized zirconia (Y-TZP) by means of a silica-nanoparticle deposition process. METHODS: Two alkoxide organic precursors, tetraethyl-orthosilicate (TEOS) and zirconium tert-butoxide (ZTB) were diluted in hexane at different concentrations in order to obtain several experimental materials to enhance deposition of a SiO(x) reactive layer to Y-TZP. This deposition was attained via sintering alkoxide precursors directly on pre sintered zirconia (infiltration method-INF) or application on the surface of fully sintered zirconia (coating method-COA). Untreated specimens and a commercial tribochemical silica coating were also tested as controls and all the treated Y-TZP specimens were analyzed using SEM-EDX. Specimens were bonded using silane, adhesive and dual-cure luting cement and submitted to shear bond strength test after different water storage periods (24 h, 3-, 6- and 12-months). RESULTS: SEM-EDX revealed Y-TZP surface covered by silica nanoclusters. The morphology of silica-covered Y-TZP surfaces was influenced by sintering method, employed to deposit nanoclusters. High bond strength (MPa) was observed when using COA method; highest TEOS percentage achieved the greatest bond strengths to Y-TZP surface (36.7+/-6.3 at 24 h). However, bonds stability was dependent on ZTB presence (32.9+/-9.7 at 3 months; 32.3+/-7.1 at 6 months). Regarding INF method, the highest and more stable resin-zirconia bond strength was attained when using experimental solutions containing TEOS and no ZTB. Both sintering methods tested in this study were able to achieve a bonding performance similar to that of classic tribochemical strategies. SIGNIFICANCE: This study demonstrates that it is possible to achieve a reliable and long-lasting bonding between yttria stabilized zirconia ceramic and methacrylate-based cements when using this novel, simple, and cost-effective bonding approach. PMID- 25498522 TI - Cytotoxicity and terminal differentiation of human oral keratinocyte by indium ions from a silver-palladium-gold-indium dental alloy. AB - OBJECTIVE: Dental alloys containing indium (In) have been used in dental restoration for two decades; however, no study has investigated the biological effects of In ions, which may be released in the oral cavity, on human oral keratinocytes. The objective of the present study was to investigate the biological effects of In ions on human oral keratinocyte after confirming their release from a silver-palladium-gold-indium (Ag-Pd-Au-In) dental alloy. METHODS: As a corrosion assay, a static immersion tests were performed by detecting the released ions in the corrosion solution from the Ag-Pd-Au-In dental alloy using inductively coupled plasma atomic emission spectroscopy. The cytotoxicity and biological effects of In ions were then studied with In compounds in three human oral keratinocyte cell lines: immortalized human oral keratinocyte (IHOK), HSC-2, and SCC-15. RESULTS: Higher concentrations of In and Cu ions were detected in Ag Pd-Au-In (P<0.05) than in Ag-Pd-Au, and AgCl deposition occurred on the surface of Ag-Pd-Au-In after a 7-day corrosion test due to its low corrosion resistance. At high concentrations, In ions induced cytotoxicity; however, at low concentrations (~0.8In(3+)mM), terminal differentiation was observed in human oral keratinocytes. Intracellular ROS was revealed to be a key component of In induced terminal differentiation. SIGNIFICANCE: In ions were released from dental alloys containing In, and high concentrations of In ions resulted in cytotoxicity, whereas low concentrations induced the terminal differentiation of human oral keratinocytes via increased intracellular ROS. Therefore, dental alloys containing In must be biologically evaluated for their safe use. PMID- 25498523 TI - The difference on the osteogenic differentiation between periodontal ligament stem cells and bone marrow mesenchymal stem cells under inflammatory microenviroments. AB - Periodontitis is a major cause of tooth loss in adults and periodontal ligament stem cells (PDLSCs) is the most favorable candidate for the reconstruction of tissues destroyed by periodontal diseases. However, pathological alterations caused by inflammatory insults might impact the regenerative capacities of these cells. Bone-marrow-derived human mesenchymal stem cells (hBMSCs) would accelerate alveolar bone regeneration by transplantation, compared to PDLSCs. Therefore, a better understanding of the osteogenic differentiation between PDLSCs and BMSCs in inflammatory microenviroments is therefore warranted. In this study, human PDLSCs were investigated for their stem cell characteristics via analysis of cell surface marker expression, colony forming unit efficiency, osteogenic differentiation and adipogenic differentiation, and compared to BMSCs. To determine the impact of both inflammation and the NF-kappabeta signal pathway on osteogenic differentiation, cells were challenged with TNF-alpha under osteogenic induction conditions and investigated for mineralization, alkaline phosphatase (ALP) activity, cell proliferation and relative genes expression. Results showed that PDLSCs exhibit weaker mineralization and ALP activity compared to BMSCs. TNF alpha inhibited genes expression of osteogenic differentiation in PDLSCs, while, it stimulates gene expressions (BSP and Runx2) in BMSCs. Enhanced NF-kappabeta activity in PDLSCs decreases expression of Runx2 but it does not impede the osteogenic differentiation of BMSCs. Taken together, these results may suggest that the BMSCs owned the stronger immunomodulation in local microenvironment via anti-inflammatory functions, compared to PDLSCs. PMID- 25498524 TI - CXCR3 ligands in disease and therapy. AB - Chemokines, binding their various G protein-coupled receptors, lead the way for leukocytes in health and inflammation. Yet chemokine receptor expression is not limited to leukocytes. Accordingly, chemokines are remarkably pleiotropic molecules involved in a range of physiological as well as pathological processes. For example, the CXCR3 chemokine receptor is expressed on activated T lymphocytes, dendritic cells and natural killer cells, but also fibroblasts and smooth muscle, epithelial and endothelial cells. In men, these cells express either CXCR3A, its splice variant CXCR3B or a balanced combination of both. The CXCR3 ligands, activating both receptor variants, include CXCL4, CXCL4L1, CXCL9, CXCL10 and CXCL11. Upon CXCR3A activation these ELR-negative CXC chemokines mediate chemotactic and proliferative responses, for example in leukocytes. In contrast, CXCR3B induces anti-proliferative and anti-migratory effects, as exemplified by angiostatic effects on endothelial cells. Taken together, the unusual and versatile characteristics of CXCR3 and its ligands form the basis for their pertinent involvement in a myriad of diseases. In this review, we discuss the presence and function of all CXCR3 ligands in various malignant, angiogenic, infectious, inflammatory and other disorders. By extension, we have also elaborated on the potential therapeutic applicability of CXCR3 ligand administration or blockade, as well as their additional value as predictive or prognostic biomarkers. This review illustrates the multifunctional, intriguing character of the various CXCR3-binding chemokines. PMID- 25498525 TI - IFN-beta and multiple sclerosis: cross-talking of immune cells and integration of immunoregulatory networks. AB - Multiple sclerosis (MS) is characterized by autoimmune inflammation affecting the central nervous system and subsequent neurodegeneration. Historically, damage was thought to be mediated exclusively by auto-antigen-activated pro-inflammatory T cells. However, more recently, we are gaining increasing knowledge on the pathogenic role played in MS by B cells, dendritic cells and monocytes. IFN-beta therapy was one the first approved therapy for MS for its ability to reduce relapse rate and MRI lesion activity and to significantly decrease risk of disability progression. IFN-beta-mediated mechanisms of action, even if not completely understood, mainly rely on its multifaceted pleiotropic effects resulting in sustained anti-inflammatory properties directed toward almost every immune cell type. Here, we will discuss in detail literature data characterizing the pathogenic activity of the different immune cell subsets involved in MS pathogenesis and how IFN-beta therapy regulates their function by modulating bystander responses. We believe that the effectiveness of this drug in MS treatment, even if in use for a long time, can unveil new insights on this disease and still teach a lesson to researchers in the MS field. PMID- 25498526 TI - [Chorea: a rare manifestation of Takayasu's arteritis]. AB - The case of a girl with recurring chorea and a Takayasu's arteritis diagnosis is reported. This clinical manifestation has been reported in only one patient with this vasculitis in the pediatric group. PMID- 25498527 TI - [Twiddler's syndrome in a patient with obsessive-compulsive disorder treated with deep brain stimulation]. AB - Twiddler's syndrome is a rare complication associated with implantable electrical stimulation devices. First described in a patient with a pacemaker, it is a known complication in the field of cardiology. However, it is not so recognised in the world of neurosurgery, in which it has been described in relation to deep brain stimulation (DBS) devices. Characterised by manipulating either consciously or unconsciously the generator of such devices, which causes it to rotate on itself, the syndrome causes the coiling of the wiring of these systems and can lead to their rupture or the displacement of intracranial electrodes. We describe a case of twiddler's syndrome in a patient treated with DBS for obsessive-compulsive disorder, in which clinical deterioration presented after a good initial response. Control radiographs revealed rotation of the wiring system and displacement of the intracranial electrodes. PMID- 25498528 TI - [Facial paralysis surgery. Current concepts]. AB - Facial palsy is a relatively common condition, from which most cases recover spontaneously. However, each year, there are 127,000 new cases of irreversible facial paralysis. This condition causes aesthetic, functional and psychologically devastating effects in the patients who suffer it. Various reconstructive techniques have been described, but there is no consensus regarding their indication. While these techniques provide results that are not perfect, many of them give a very good aesthetic and functional result, promoting the psychological, social and labour reintegration of these patients. The aim of this article is to describe the indications for which each technique is used, their results and the ideal time when each one should be applied. PMID- 25498529 TI - Clinical features and impact of empirical therapy in cirrhotic adults with community-onset bacteremia. AB - OBJECTIVES: The objectives were to investigate the clinical characteristics of community-onset bacteremia in cirrhotic adults visiting the emergency department (ED), as well as the clinical impact of empirical antibiotics on their outcome. METHODS: Cirrhotic adults with community-onset bacteremia who visited the ED from January 2005 to December 2009 were included retrospectively. Clinical data and outcome were collected from the medical chart. The in vitro susceptibility was measured by the broth microdilution method. RESULTS: Of the 246 bacteremic episodes in cirrhotic patients, the major sources of bacteremia included intraabdominal infections (111, 45.1%), primary bacteremia (43, 17.5%), urinary tract infection (39, 15.9%), and soft tissue infection (22, 8.9%). Of the 258 bacteremic pathogens identified, Escherichia coli (83 isolates, 33.7%) and Klebsiella pneumoniae (61, 23.6%) were the most common microorganisms. In the multivariate analysis, delayed appropriate antibiotic therapy (>72 hours; odds ratio [OR], 4.29; P=.003), serum creatinine greater than 1.5 mg/dL at the ED (OR, 3.12; P=.005), severe sepsis (OR, 3.61; P=.01), Pittsburgh bacteremia score of at least 4 (OR, 2.66; P=.04), bacteremia due to pneumonia (OR, 5.44; P=.02), and a comorbidity of diabetes mellitus (OR, 3.54; P=.004) were independently associated with the 28-day mortality. CONCLUSIONS: Focusing on cirrhotic adults with community-onset bacteremia, we emphasized that the cirrhosis severity is one of the critical factors when choosing empirical antimicrobial therapy and that the strategy of empirical therapy is warranted for cirrhotic adults with severe decompensation (Child's C group). For critically ill patients, especially in those with Child's C group, only piperacillin/tazobactam, ertapenem, or imipenem treatment was warranted because of susceptibility rate of greater than 90%. PMID- 25498530 TI - Improved door-to-needle times and neurologic outcomes when IV tissue plasminogen activator is administered by emergency physicians with advanced neuroscience training. AB - BACKGROUND: The neurologic emergency department (neuro ED) at our medical center is staffed by emergency medicine physicians who have specialized neuroscience training and give intravenous (IV) tissue plasminogen activator (tPA) independently for acute ischemic stroke patients. Door-to-needle (DTN) times, discharge location, and discharge National Institute of Health Stroke Scale (NIHSS) scores were studied between the neuro ED and main emergency department (ED) with the hypothesis that all measures would be better in the neuro ED group. METHODS: This is a retrospective study evaluating DTN time, discharge outcomes, and discharge location in acute stroke patients who received IV tPA at our comprehensive stroke center. These outcome measures were compared between patients who were evaluated and treated in our neuro ED to those treated in our main ED. RESULTS: From 2012 to 2014, 67 acute stroke patients received IV tPA in our ED. Thirty-five patients were evaluated in the neuro ED, and 32, in the main ED. Average DTN times were significantly faster in the neuro ED at 35 minutes, compared to main ED DTN times of 83 minutes. Discharge NIHSS score was significantly lower, and more patients were discharged to home in the neuro ED group compared to the main ED group. CONCLUSIONS: Trained neuro ED physicians can safely give IV tPA independently for stroke patients with improved DTN times, lower discharge NIHSS, and higher likelihood of being discharged to home compared to the main ED physicians who used teleneurology consultation. This suggests utility in training emergency medicine physicians to administer tPA independently based on clinical practice guidelines. PMID- 25498531 TI - Pulmonary embolism in 2014--the mosaic seems completing. PMID- 25498532 TI - Acute respiratory distress syndrome in a young soccer player: search obturator internus primary pyomyositis. A reverse Lemierre syndrome. PMID- 25498533 TI - A rare cause of acute abdomen for which broad-spectrum antibiotics should be initiated in emergency service: typhlitis. PMID- 25498534 TI - Comparison of refractive assessment by wavefront aberrometry, autorefraction, and subjective refraction. AB - PURPOSE: To compare refractive assessment results obtained with an aberrometer, an autorefractor, and manual subjective refraction (SR) in a healthy population with optimal visual potential. METHODS: Sixty adults aged 18-59 years with visual acuity of 20/25 or better, no media opacity, and no known corneal or retinal abnormalities were recruited during the course of routine eye examination. Refractive error in both eyes of each patient was assessed by 3 methods: manual SR, a Nidek 530-A autorefractor (AR), and a Nidek OPD-II Scan wavefront aberrometer (OPD). The order of testing was randomized. One technician collected all OPD and AR measurements, and 1 optometrist performed manual SR. Refractive measurements were converted from spherocylindrical prescriptions to power vectors and compared between methods by 2-factor repeated measures and Bland-Altman analysis. RESULTS: Analysis of the power vectors followed by a log transformation showed no significant difference in refractive results between AR, OPD, and SR (P=.63). Bland-Altman analysis identified mean differences (95% CI of limits of agreement) of -0.06 (-0.67 to 0.55) for OPD vs SR, 0.001 (-0.522 to 0.524) for AR vs SR, and 0.06 (-0.541 to 0.662) for AR vs OPD. CONCLUSION: Agreement between all refractive assessments was comparable to previously reported agreement between repeated measures of SR. Agreement between AR and SR was slightly stronger than between OPD and SR. Although both the OPD and AR results, in general, showed a high level of agreement with SR, results beyond +/-0.50D (5.8% for AR, 10% for OPD) would discourage prescribing spectacles directly from either instrument. PMID- 25498535 TI - [Cross-hand replantation in bilateral upper limb amputation: An anatomical emergency]. AB - Bilateral amputations of upper limbs are excessively rare clinical situations. We report an exceptional clinical case of bilateral amputation of upper limbs at different levels: destruction of the right hand and left transhumeral amputation in a patient after an attempted suicide on train lines. This special situation led us to perform a cross-hand replantation of the left hand to the right forearm. Only 4 other similar cases have been published in the literature. Once the surgical indication had been formulated collectively, and taking into account all the ethical issues surrounding such a decision, we had to solve the issue of inverting anatomical structures in emergency. We have provided a detailed description of our surgical technique. The aim was to save at least one organ used for grasping. The result obtained is presented and reviewed. PMID- 25498536 TI - Licensed indication for risperidone in dementia. PMID- 25498538 TI - A third of NHS contracts awarded since health act have gone to private sector, BMJ investigation shows. PMID- 25498537 TI - The protective effect of 18beta-Glycyrrhetinic acid against UV irradiation induced photoaging in mice. AB - It has been confirmed that repeated exposure of skin to ultraviolet (UV) radiation results in cutaneous oxidative stress and inflammation, which act in concert to cause premature skin aging, well known as photoaging. 18beta Glycyrrhetinic acid (GA), widely used to treat various tissue inflammations, is the main active component of licorice root, and has also been shown to possess favorable anti-oxidative property and modulating immunity function. In the present study, we investigated the potential protective effect of GA on UV induced skin photoaging in a mouse model. During the experimental period of ten consecutive weeks, the dorsal depilated skin of mice was treated with topical GA for 2 hours prior to UV irradiation. The results showed that GA pretreatment significantly alleviated the macroscopic and histopathological damages in mice skin caused by UV. Meanwhile, the data also indicated that GA markedly up regulated the activities of the antioxidant enzymes (SOD, GSH-Px), and increased the content of skin collagen, while obviously decreased malonaldehyde level and inhibited high expressions of matrix metalloproteinase-1 (MMP-1) and -3 (MMP-3), as well as down-regulated the expression of inflammatory cytokines such as IL-6, TNF-alpha and IL-10. Taken together, these findings amply demonstrate that GA observably attenuates UV-induced skin photoaging mainly by virtue of its antioxidative and anti-inflammatory properties, as well as regulating the abnormal expression of MMP-1 and MMP-3. PMID- 25498539 TI - Fifteen-year experience with carotid artery stenting (from the carotid artery stenting-registry of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte). AB - To date only sparse data are available on trends and changes in indications, patient's characteristics, and clinical outcome of patients undergoing carotid artery stenting (CAS) in clinical practice. From February 1996 to December 2010, 6,116 CAS procedures were performed in 5,976 patients at 36 hospitals within the prospective, multicenter CAS registry of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte. Median age of patients was 71 years, 71.6% were men; a symptomatic stenosis was treated in 50.3% and an embolic protection device (EPD) was used in 82.5% of the patients. The overall hospital mortality or stroke rate was 3.1%. Stroke or in-hospital death occurred in 4.0% in symptomatic patients and in 2.2% in asymptomatic patients. In a logistic regression model, independent predictors of in-hospital death or stroke were heart failure (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.22 to 3.36, p = 0.006), symptomatic stenosis (OR 1.52, 95% CI 1.05 to 2.18, p = 0.03), and age (OR per 10 years 1.46, 95% CI 1.17 to 1.81, p <0.001). The use of an EPD was significantly associated with a lower rate of death or stroke in the registry (OR 0.45, 95% CI 0.26 to 0.78, p = 0.004). From 1996 to 2010, mean age of patients increased by 4.1 years (p <0.001), the proportion of male patients decreased from 82.4% to 70.2% (p = 0.07), the proportion of symptomatic stenoses decreased (84.6% to 24.7%, p <0.001), and the use of EPDs increased from 1.4% to 97.2% (p <0.001). Comparing 2 periods from 1996 to 2003 and 2004 to 2010, a numeric decrease in the in-hospital stroke or death rate was seen in symptomatic (4.7% vs 3.5%, p = 0.11), and in asymptomatic patients (2.9% vs 2.1%, p = 0.27) undergoing CAS, which did not reach statistical significance. In conclusion, the proportion of symptomatic carotid artery stenoses decreased significantly; EPDs established as a standard tool and a numeric decrease of in-hospital stroke or death was seen in asymptomatic and symptomatic patients undergoing CAS in clinical practice over the last 15 years. PMID- 25498540 TI - Different Angiotensin-converting enzyme inhibitors and the associations with overall and cause-specific mortalities in patients with hypertension. AB - BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors have been widely used in the treatment of hypertension, but the comparative effectiveness in reducing mortality among different drugs is seldom reported. METHODS: We identified hypertensive patients who started captopril, enalapril, lisinopril, fosinopril, perindopril, ramipril, or imidapril therapy from Taiwan's National Health Insurance database between 1 January 2004 and 31 December 2009. Overall and cause specific mortalities were ascertained through a linkage to Taiwan's National Death Registry. Patients were followed from the initiation of ACE inhibitors to death, disenrollment, or study termination (31 December 2010). A Cox proportional hazard regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI), using ramipril as the reference group. RESULTS: A total of 989,489 hypertensive patients were included, with a mean follow-up ranging from 3.5 years for imidapril to 4.5 years for enalapril. Captopril initiators had the highest overall mortality rate (117.8 per 1,000,000 person-days) as compared to other ACE inhibitors (54.3-79.4 per 1,000,000 person-days). Patients who started captopril therapy had a significantly increased risk of overall mortality (HR: 1.28, 95% CI: 1.24-1.31) when compared with ramipril. Enalapril (HR: 1.08, 95% CI: 1.05-1.11) and fosinopril (HR: 1.08, 95% CI: 1.05-1.12) were also associated with a modestly increased risk. No difference in mortality was found for lisinopril, perindopril, and imidapril, as compared with ramipril. CONCLUSIONS: There are differences in the mortality risk associated with different ACE inhibitors. However, potential residual confounding effects might still exist. PMID- 25498541 TI - Teleost soluble CSF-1R modulates cytokine profiles at an inflammatory site, and inhibits neutrophil chemotaxis, phagocytosis, and bacterial killing. AB - Soluble colony stimulating factor-1 receptor (sCSF-1R) is a novel bony fish protein that contributes to the regulation of macrophage proliferation. We recently showed that this soluble receptor is highly upregulated by teleost macrophages in the presence of apoptotic cells. Further, recombinant sCSF-1R inhibited leukocyte infiltration into a challenge site in vivo. Herein, we characterized the mechanisms underlying these changes as a platform to better understand the evolutionary origins of the CSF-1 immune-regulatory axis and inflammation control in teleosts. Using an in vivo model of self-resolving peritonitis, we show that sCSF-1R downregulates chemokine expression and inhibits neutrophil chemotaxis. Soluble CSF-1R also inhibited gene expression of several pro-inflammatory cytokines and promoted the expression of an anti-inflammatory mediator, IL-10. Finally, the phenotype of infiltrating neutrophils changed significantly in the presence of sCSF-1R. Both a reduced capacity for phagocytosis and pathogen killing were observed. Overall, our results implicate sCSF-1R as an important regulator of neutrophil responses in teleosts. It remains unclear whether this represents an inflammation regulatory factor that is unique to this animal group or one that may be evolutionarily conserved and continues to contribute to the regulation of antimicrobial processes at inflammatory sites in higher vertebrates. PMID- 25498542 TI - Activation of eNOS in endothelial cells exposed to ionizing radiation involves components of the DNA damage response pathway. AB - In this study, the involvement of ataxia telangiectasia mutated (ATM) kinase and heat shock protein 90 (HSP90) in endothelial nitric oxide synthase (eNOS) activation was investigated in X-irradiated bovine aortic endothelial cells. The activity of nitric oxide synthase (NOS) and the phosphorylation of serine 1179 of eNOS (eNOS-Ser1179) were significantly increased in irradiated cells. The radiation-induced increases in NOS activity and eNOS-Ser1179 phosphorylation levels were significantly reduced by treatment with either an ATM inhibitor (Ku 60019) or an HSP90 inhibitor (geldanamycin). Geldanamycin was furthermore found to suppress the radiation-induced phosphorylation of ATM-Ser1181. Our results indicate that the radiation-induced eNOS activation in bovine aortic endothelial cells is regulated by ATM and HSP90. PMID- 25498543 TI - Altered microRNAs expression profiling in mice with diabetic neuropathic pain. AB - Neuropathic pain is one of the most common chronic complications of diabetes mellitus, one hallmark of which is tactile allodynia. However, the molecular mechanisms underlying tactile allodynia are not well understood. It has been demonstrated that microRNAs (miRNAs) are essential regulators of gene expression in the nervous system where they contribute to neuronal plasticity. Thus, in this study, we investigated the differentially expressed microRNAs in the lumbar spinal dorsal horn of streptozotocin (STZ)-induced diabetic neuropathic pain (DNP) mice and vehicle controls. Results from miRNA microarrays showed that 42 miRNAs were significantly altered in DNP spinal cord tissue (P<0.05, fold change: ? 2) compared with control sample. Among them, 21 miRNAs were significantly up regulated while the other 21 down-regulated. Further validation by quantitative real-time polymerase chain reaction (qRT-PCR) indicated that the 2 significant differentially expressed candidate miRNAs (miR-184-5p and miR-190a-5p) in DNP tissue showed the same changes as in the microarray analysis. The bioinformatics analysis revealed that some of the differentially expressed miRNAs after DNP were potential regulators of some inflammation associated with genes that are known to be involved in the pathogenesis of DNP. These findings suggest that aberrant expression of miRNAs may contribute to the pathogenesis of DNP and are potential targets for therapeutic interventions following DNP. PMID- 25498544 TI - Oral collagen-derived dipeptides, prolyl-hydroxyproline and hydroxyprolyl glycine, ameliorate skin barrier dysfunction and alter gene expression profiles in the skin. AB - Oral supplementation with collagen hydrolysate (CH) has been shown to improve the condition of the skin in humans and experimental animals. Several hydroxyproline containing oligo-peptides were previously detected in human peripheral blood after the ingestion of CH, and the two dipeptides, prolyl-hydroxyproline (PO) and hydroxyprolyl-glycine (OG), have been proposed to have beneficial effects on human health. When HR-1 hairless mice were fed a HR-AD diet, which lacked magnesium and zinc, transepidermal water loss (TEWL) increased and water content of stratum corneum decreased. In the present study, we investigated the effects of dietary PO and OG on skin barrier dysfunction in HR-1 hairless mice. Mice were fed a HR-AD diet with or without PO (0.15%) and OG (0.15%) for 35 consecutive days. The administration of PO and OG significantly decreased TEWL, and significantly increased water content of stratum corneum. A DNA microarray analysis of the dorsal skin revealed differences in gene expression between the group administered PO and OG and the control group. We also identified muscle related Gene Ontology as a result of analyzing the up-regulated genes. These results suggested that the administration of PO and OG improved skin barrier dysfunction and altered muscle-related gene expression. PMID- 25498545 TI - Betaine is a positive regulator of mitochondrial respiration. AB - Betaine protects cells from environmental stress and serves as a methyl donor in several biochemical pathways. It reduces cardiovascular disease risk and protects liver cells from alcoholic liver damage and nonalcoholic steatohepatitis. Its pretreatment can rescue cells exposed to toxins such as rotenone, chloroform, and LiCl. Furthermore, it has been suggested that betaine can suppress cancer cell growth in vivo and in vitro. Mitochondrial electron transport chain (ETC) complexes generate the mitochondrial membrane potential, which is essential to produce cellular energy, ATP. Reduced mitochondrial respiration and energy status have been found in many human pathological conditions including aging, cancer, and neurodegenerative disease. In this study we investigated whether betaine directly targets mitochondria. We show that betaine treatment leads to an upregulation of mitochondrial respiration and cytochrome c oxidase activity in H2.35 cells, the proposed rate limiting enzyme of ETC in vivo. Following treatment, the mitochondrial membrane potential was increased and cellular energy levels were elevated. We propose that the anti-proliferative effects of betaine on cancer cells might be due to enhanced mitochondrial function contributing to a reversal of the Warburg effect. PMID- 25498546 TI - Genetic variants of vitamin D receptor and susceptibility to ischemic stroke. AB - Vitamin D receptor (VDR) is a potential candidate for cardiovascular disease. To date the genetic association of VDR with ischemic stroke has not been explored. In the present study we aimed to evaluate the association between VDR gene variants and ischemic stroke in Asian Indian population. Overall, 557 subjects were investigated that included 313 ischemic stroke patients and 244 control subjects. Four single nucleotide polymorphisms of the VDR gene termed as Fok I, Apa I, Taq I and Bsm I were genotyped by using PCR-RFLP method. The genotype distribution of Bsm I polymorphism was found to deviate from the Hardy-Weinberg equilibrium in control subjects, and hence excluded from the study. Apa I and Taq I polymorphisms were not found to be associated with ischemic stroke. However, presence of ff genotype of Fok I was found to confer 2.97-fold risk of ischemic stroke (95% CI=1.16-7.63, P=0.02) as compared to FF genotype. This association was found to be independent of various demographic and important biochemical covariates including age, gender, smoking, alcohol intake, BMI, and serum glucose, lipid profile, insulin and HOMA-IR, 25-hydroxyvitamin D and plasma NOx levels [OR=2.27, 95% CI=1.25-4.09, P=0.01]. However, adjustment for lipid metabolites attenuated the genetic association [OR=1.68, 95% CI=0.75-3.78, P=0.21]. Fok I polymorphism was also found to be associated with total cholesterol levels; ff genotype carriers were found to have significantly higher cholesterol levels (203.56 +/- 30.50mg/dl) as compared to FF carriers (177.38 +/- 47.90 mg/dl) (P=0.04). On stratification by gender the genetic association between Fok I polymorphism and ischemic stroke remained significant in females only (OR=2.28, 95% CI=1.15-4.53, P=0.02). This genetic association was also found to attenuate on adjustment with lipid variables. In the present study we could associate the only known functional polymorphism of VDR i.e., Fok I, with ischemic stroke in a gender specific manner. Adjustment with lipid variables was found to attenuate this association indicating that impaired lipid metabolism may be the underlying mechanism of action of this polymorphism which leads to an increase in the risk of ischemic stroke. Further larger scale validations in other population are warranted in other population. PMID- 25498547 TI - Reconstructing the chemical diversity of labdane-type diterpene biosynthesis in yeast. AB - Terpenes are a large class of natural products, many of which are used in cosmetics, pharmaceuticals, or biofuels. However, terpene's industrial application is frequently hindered by limited availability of natural sources or low yields of chemical synthesis. In this report, we developed a modular platform based on standardized and exchangeable parts to reproduce and potentially expand the diversity of terpene structures in Saccharomyces cerevisiae. By combining different module-specific parts, we exploited the substrate promiscuity of class I diterpene synthases to produce an array of labdane-type scaffolds. These were subsequently modified by a scaffold decoration module consisting of a mutant library of a promiscuous cytochrome P450 to afford a range of hydroxylated diterpenes. Further P450 protein engineering yielded dedicated and efficient catalysts for specific products. Terpenes produced include precursors of pharmacologically important compounds, molecules that are difficult to obtain from natural sources, or new natural products. The approach described here provides a platform on which additional gene mining, combinatorial biosynthesis, and protein engineering efforts can be integrated to sustainably explore the terpene chemical space. PMID- 25498548 TI - Value of lifestyle intervention to prevent diabetes and sequelae. AB - BACKGROUND: The Community Preventive Services Task Force recommends combined diet and physical activity promotion programs for people at increased risk of type 2 diabetes, as evidence continues to show that intensive lifestyle interventions are effective for overweight individuals with prediabetes. PURPOSE: To illustrate the potential clinical and economic benefits of treating prediabetes with lifestyle intervention to prevent or delay onset of type 2 diabetes and sequelae. METHODS: This 2014 analysis used a Markov model to simulate disease onset, medical expenditures, economic outcomes, mortality, and quality of life for a nationally representative sample with prediabetes from the 2003-2010 National Health and Nutrition Examination Survey. Modeled scenarios used 10-year follow-up results from the lifestyle arm of the Diabetes Prevention Program and Outcomes Study versus simulated natural history of disease. RESULTS: Over 10 years, estimated average cumulative gross economic benefits of treating patients who met diabetes screening criteria recommended by the ADA ($26,800) or USPSTF ($24,700) exceeded average benefits from treating the entire prediabetes population ($17,800). Estimated cumulative, gross medical savings for these three populations averaged $10,400, $11,200, and $6,300, respectively. Published estimates suggest that opportunistic screening for prediabetes is inexpensive, and lifestyle intervention similar to the Diabetes Prevention Program can be achieved for <=$2,300 over 10 years. CONCLUSIONS: Lifestyle intervention among people with prediabetes produces long-term societal benefits that exceed anticipated intervention costs, especially among prediabetes patients that meet the ADA and USPSTF screening guidelines. PMID- 25498549 TI - Sociodemographic factors and the risk of developing cardiovascular disease in Bangladesh. AB - BACKGROUND: Sociodemographic determinants of predicted 10-year risk for stroke or myocardial infarction are vital to identify patients who are at increased risk. Although some risk factors of predicted cardiovascular disease (CVD) risk are documented, further exploration is necessary considering various socioeconomic and demographic factors. PURPOSE: To examine risk factors for stroke or myocardial infarction according to 10-year prediction, among hypertensive patients and by sociodemographic risk differences, using a nationally representative survey. METHODS: Data were obtained from the 2011 Bangladesh Demographic Health Survey and analyzed in March and July 2014. The analyses were based on responses from 1,620 hypertensive individuals. WHO guidelines for predicting 10-year risk of stroke or myocardial infarction were applied to categorize risk of CVD into low, medium, or high strata. RESULTS: A total of 21.8% of hypertensive adults were at high risk for CVD. An adjusted ordinal logistic regression model showed that a female- versus male-headed household (AOR=1.85); an urban versus rural residence (AOR=1.32); being overweight/obese versus underweight (AOR=1.80); and being aged 55-69 years (AOR=1.95) or >=70 years (AOR=2.87) versus 35-54 years were significantly associated with higher CVD risk. A regional difference in distribution of CVD risk strata was observed. CONCLUSIONS: Living in a female-headed household, having an urban residence, being overweight/obese, old age, and regional variations are factors associated with higher risk of CVD among hypertensive patients. PMID- 25498551 TI - Annual healthcare spending attributable to cigarette smoking: an update. AB - BACKGROUND: Fifty years after the first Surgeon General's report, tobacco use remains the nation's leading preventable cause of death and disease, despite declines in adult cigarette smoking prevalence. Smoking-attributable healthcare spending is an important part of overall smoking-attributable costs in the U.S. PURPOSE: To update annual smoking-attributable healthcare spending in the U.S. and provide smoking-attributable healthcare spending estimates by payer (e.g., Medicare, Medicaid, private insurance) or type of medical services. METHODS: Analyses used data from the 2006-2010 Medical Expenditure Panel Survey linked to the 2004-2009 National Health Interview Survey. Estimates from two-part models were combined to predict the share of annual healthcare spending that could be attributable to cigarette smoking. The analysis was conducted in 2013. RESULTS: By 2010, 8.7% (95% CI=6.8%, 11.2%) of annual healthcare spending in the U.S. could be attributed to cigarette smoking, amounting to as much as $170 billion per year. More than 60% of the attributable spending was paid by public programs, including Medicare, other federally sponsored programs, or Medicaid. CONCLUSIONS: These findings indicate that comprehensive tobacco control programs and policies are still needed to continue progress toward ending the tobacco epidemic in the U.S. 50 years after the release of the first Surgeon General's report on smoking and health. PMID- 25498552 TI - Feasibility of metal-organic nanotubes [Cu3(MU3-O)(MU-OH)(triazolate)2]+-coated fibers for solid-phase microextraction of polychlorinated biphenyls in water samples. AB - Metal-organic nanotubes (MONTs), a novel class of hybrid materials, have attracted considerable attention because of their uniform and fixed internal diameters, impressive topological structures, and versatile applications. However, to the best of our knowledge, no studies on MONTs coating fabrication for solid-phase microextraction are yet available. The aim of this work is to investigate the feasibility of using [Cu3(MU3-O)(MU-OH)(triazolate)2]+ as a solid phase microextraction coating material to enrich trace levels of polychlorinated biphenyls in water samples. The novel [Cu3(MU3-O)(MU-OH)(triazolate)2]+-coated fibers achieved large enhancement factors (396-1343), low limits of detection (3.9-21.7 pg L-1), and wide linearity (0.1-500 ng L-1) for detecting polychlorinated biphenyls. Relative standard deviations obtained ranged from 2.12 to 7.22%, and spiked PCBs recoveries (spiking concentrations of 1 and 5 ng L-1) in four environmental water samples ranged from 71.3 to 104%. These findings indicate that [Cu3(MU3-O)(MU-OH)(triazolate)2]+ as a solid-phase microextraction coating material is an excellent alternative for the rapid and sensitive analysis of trace levels of polychlorinated biphenyls in the environment. PMID- 25498550 TI - A cost-effectiveness analysis of the first federally funded antismoking campaign. AB - BACKGROUND: In 2012, CDC launched the first federally funded national mass media antismoking campaign. The Tips From Former Smokers (Tips) campaign resulted in a 12% relative increase in population-level quit attempts. PURPOSE: Cost effectiveness analysis was conducted in 2013 to evaluate Tips from a funding agency's perspective. METHODS: Estimates of sustained cessations; premature deaths averted; undiscounted life years (LYs) saved; and quality-adjusted life years (QALYs) gained by Tips were estimated. RESULTS: Tips saved about 179,099 QALYs and prevented 17,109 premature deaths in the U.S. With the campaign cost of roughly $48 million, Tips spent approximately $480 per quitter, $2,819 per premature death averted, $393 per LY saved, and $268 per QALY gained. CONCLUSIONS: Tips was not only successful at reducing smoking-attributable morbidity and mortality but also was a highly cost-effective mass media intervention. PMID- 25498553 TI - Linear isotherm determination from linear gradient elution experiments. AB - A procedure to estimate equilibrium adsorption parameters as a function of the modifier concentration in linear gradient elution chromatography is proposed and its reliability is investigated by comparison with experimental data. Over the past decades, analytical solutions of the so-called equilibrium model under linear gradient elution conditions were derived assuming that proteins and modifier molecules access the same fraction of the pore size distribution of the porous particles. The present approach developed in this work accounts for the size exclusion effect resulting in different exclusions for proteins and modifier. A new analytical solution was derived by applying perturbation theory for differential equations, and the 1st-order approximated solution is presented in this work. Eventually, a turnkey and reliable procedure to efficiently estimate isotherm parameters as a function of modifier concentration from linear gradient elution experiments is proposed. PMID- 25498554 TI - Limit of detection studies for application to natural product identification using high performance liquid chromatography coupled to nuclear magnetic resonance spectroscopy. AB - In the pursuit of new natural products, the demand to rapidly identify compounds present, in ever decreasing amounts, in complex crude extracts has become a limiting factor. Despite improvements in HPLC-NMR hardware and pulse sequences, no extensive limit of detection (LOD) investigations have been reported for the acquisition of 2D NMR spectroscopic experiments acquired through HPLC-NMR. In this study the LOD for five key 1D and 2D NMR spectroscopic experiments have been established, using two reference compounds, including the on-flow (WET 1D proton), stop-flow (WET1D proton), gCOSY, HSQCAD and gHMBCAD NMR experiments. The LOD for all of the NMR experiments were within the range of 700ng to 1mg for the set of fixed experimental parameters implemented. For principle components in a complex multi-component mixture, this would allow for in situ compound identification. HPLC-NMR analysis was employed to investigate the principle components present in a marine brown alga crude extract, Cystophora subfarcinata. PMID- 25498555 TI - Evaluation of two sub-2 MUm stationary phases, core-shell and totally porous monodisperse, in the second dimension of on-line comprehensive two dimensional liquid chromatography, a case study: separation of milk peptides after expiration date. AB - Milk is a rich source of bioactive peptides of great interest for their healthy properties. These peptides are usually encrypted in the sequences of proteins and are released after time dependent proteolysis as very complex hydrolysates. In order to separate and identify the bioactive sequences, we developed an on-line comprehensive two dimensional liquid chromatography approach using the high performance combined with the ultra high performance conditions. A microbore reversed phase (C18 silica, 5 MUm) column was employed in first dimension, while, in second dimension, two different UHPLC columns, packed with C18 silica, were tested: a new column based on monodisperse sub-2 MUm fully porous particles with high surface area (50 mm * 3.0 mm, 1.9 MUm d.p., from Supelco), and a column based on sub-2 MUm core-shell particles (50 mm * 3.0 mm, 1.7MUm d.p, from Phenomenex((r))). Both set-ups were compared, showing high peak capacity values with respect to a high efficiency monodimensional method, maintaining the same analysis time. Satisfactory selectivity was obtained through the use of different pH between the two dimension, while a very fast continuous shifted gradient in second dimension ensured a good employment of the 2D separation space. PMID- 25498556 TI - Nanostructured porous polymer monolithic columns for capillary liquid chromatography of peptides. AB - The macroporous structure of poly(styrene-co-divinylbenzene) monolithic capillary columns has been optimized for the gradient separation of peptides. To exploit monolithic supports with porosity exceeding 70%, the thermodynamic properties of the polymerization mixture were carefully tailored to yield homogeneous monolithic materials featuring macropore and polymer microglobule sizes in the range of 50-200 nm. The effects of (i) initiator content, (ii) composition of porogenic mixture, comprising tetrahydrofuran and 1-decanol, (iii) percentage of divinylbenzene crosslinker, and (iv) monomers to porogen ratio on the morphology was investigated. The resulting column structures were investigated using scanning electron microscopy and the prepared monolithic columns were tested for the separation of a tryptic digest of cytochrome c while applying a fixed flow rate and gradient time. To obtain a better understanding of the effects of macropore and microglobule size, and structure homogeneity on the separation performance in gradient elution, both in terms of peak capacity and gradient plate height, separations were also carried out at different flow rates while maintaining a constant gradient steepness. Furthermore, performance limits were determined applying ultra-high pressure conditions up to the maximum system pressure of 80 MPa. The potential of monolithic nanostructured columns is demonstrated for the separation of tryptic digests of cytochrome c and bovine serum albumin. PMID- 25498557 TI - Perfusive ion-exchange chromatographic materials with high capacity. AB - In this work, novel macro-porous chromatographic stationary phases, combining low mass transfer resistance and high binding capacity, were thoroughly characterized in terms of porosity, HETP, resolution and binding capacity. These new stationary phases exhibited better performance compared to commercially available materials, i.e. Poros 50HS and Fractogel EMD SO3 (M). With the technique of reactive gelation under shear, it is possible to produce particles with pores from 100 nm to several microns, in which part of the flow can go through. This way, the mass transport inside the particles is significantly increased with perfusive flow faction values between 0.02 and 0.01. Despite the low pore surface area resulting from the large pore size, high binding capacity is obtained by functionalizing the pore surface with charged polymeric brushes resulting in a binding capacity in the range from 25 to 140 mg/mL col. This, together with the high mass transfer, gives excellent resolution performance and dynamic binding capacity compared to other commercial materials even at high flow rates. PMID- 25498558 TI - A novel cation exchange polymer as a reversed-dispersive solid phase extraction sorbent for the rapid determination of rhodamine B residue in chili powder and chili oil. AB - This paper presents a new analytical method for the determination of rhodamine B (RB) residue in chili powder and chili oil based on a novel reversed-dispersive solid phase extraction (r-dSPE) and ultra high performance liquid chromatography high resolution mass spectrometry (UHPLC-HRMS). Chili powder and chili oil samples were first extracted with acetonitrile/water (1:1, v/v) and acetonitrile, respectively. Then, RB from the extract was adsorbed to the polymer cation exchange (PCX) sorbent with the characteristics of ion exchange and reversed phase retention. Subsequently, the analyte in PCX sorbent was eluted with ammonium hydroxide/methanol (1:99, v/v) through a simple unit device equipped with 1 mL syringe and 0.22 MUm nylon syringe filter. All of the samples were analyzed by UHPLC-HRMS/MS on a Waters Acquity BEH C18 column with 0.1% formic acid and 4 mM ammonium formate in water/acetonitrile as the mobile phase with gradient elution. The matrix effect, recovery, and repeatability, within laboratory reproducibility, and the LODs and LOQs of the r-dSPE cleanup method were investigated. The method showed a good linearity (R2 > 0.999) in the ranges of 0.01-1 MUg/L and 1-100 MUg/L for the analyte. The LODs of RB for chili powder and chili oil samples were 0.5 MUg/kg. The average recoveries of RB from the samples spiked at four different concentrations (2, 20, 500 and 5000 MUg/kg) were in a range from 76.7 to 104.9%. Results showed that the proposed method was simple, fast, economical and effective for the determination of RB in chili powder and chili oil. Considering the excellent sorptive performance of PCX for RB, further work should be done to evaluate the usefulness of the PCX in r-dSPE for the clean-up and analyses of other trace-level alkaline contaminants. PMID- 25498559 TI - Fish contamination by polychlorobiphenyls: the mass spectrometric ortho effect in a new and easy gas chromatography-mass spectrometry method for the analysis of the seven indicators. The case of Bluefin Tuna. AB - A simple instrumental procedure was developed to carry out the not simple analysis of PCBs in fish samples. PCBs with the same degree of chlorination (the isomers) are expected to be totally indistinguishable among them by all existing detectors and by all existing mass spectrometers, and there is no apparent solution in those frequent cases where two isomers chromatographically coelute. Generally such coelutions are solved by means of multidimensional GC, but it is a complex technique impractical for most laboratories. The present research focuses on the seven important "indicator PCBs" by using the mass spectrometer in an innovative way. The "mass spectrometric ortho effect" was usefully exploited in addressing coelutions between isomers. Other new important observations on mass spectra were decisive in solving the apparent problem arising from coelutions between higher chlorinated PCBs with the lower chlorinated ones when low resolution MS is used. With the proposed procedure, the seven indicators are analyzed in a simple way and with a degree of accuracy never observed with the conventional gas chromatography. The method was applied to some Bluefin Tuna fish samples of big size suspected to have not negligible levels of PCBs due to the high position of this species in the food chain. The supposition was partly confirmed. On the basis of the results here obtained, the recently introduced EU Regulation on six of the seven indicators shows one critical point: in the present paper, an amendment to the Regulation is proposed. A number of important validation measures are reported. PMID- 25498560 TI - Efficiency of an automatic dehydrated carrier for the vitrification of human embryos derived from three pronuclei fertilized zygotes. AB - The efficiency of a new vitrification technique using embryos obtained after abnormal fertilization was assesed. A total of 100 embryos were vitrified, 48 with the automatic dehydrated carrier (ADC) technique and 52 with cryotop. The survival rates in ADC and cryotop groups were similar (85.4% versus 92.3%). The loss rates of 10.4% for the ADC group and 1.9% for the cryotop group were not significantly different. The intact rate was significantly lower in the ADC group (26.8% versus 64.6%; P = 0.001). After 48 h of culture, blastocyst formation rates in the ADC and cryotop groups were 14.6% and 25.0%, respectively, which were not significantly different. In conclusion, the practicability of ADC vitrification was demonstrated. The study has some limitations, which necessitates further work. PMID- 25498561 TI - Abortion legislation: exploring perspectives of general practitioners and obstetrics and gynaecology clinicians. AB - Abortion legislation remains a contentious topic in the UK, which receives much attention from politicians, clinicians and professional bodies alike. In this study, the perspectives of general practitioners and obstetrics and gynaecology clinicians on the Abortion Act 1967 was explored. To this end, a short electronic questionnaire was distributed to all 211 GP and obstetrics and gynaecology clinicians affiliated with the University of Cambridge School of Clinical Medicine. Of the 100 anonymous responses collected, a significant majority felt that abortion law in Northern Ireland should be changed in line with the rest of the UK. The respondents' votes, however, were either opposed to or divided over any other changes to the Abortion Act, including altering the 24 week time limit, clarifying the legal definition of fetal abnormalities, introducing abortion purely on the woman's request, and modifying the requirement for two clinicians to approve any request for abortion. These perspectives were not entirely aligned with the recommendations of the Royal College of Obstetricians and Gynaecologists and the House of Commons Science and Technology Committee, or with current medical evidence and demographic data. PMID- 25498562 TI - Periodontal status among patients with diabetes in Nuuk, Greenland. AB - BACKGROUND: Diabetes is becoming more common in the Greenlandic population. Patients with diabetes are more prone to periodontal disease. Periodontal status may have an effect on metabolic control. OBJECTIVE: The aim of this study was to estimate the prevalence of periodontitis amongst patients with diabetes in Nuuk, Greenland, and secondly, to observe if dental care was associated with improved periodontal status and metabolic control. STUDY DESIGN: Observational cross sectional study and a pilot study of a dental care intervention. METHODS: Sixty two Greenlandic patients with diabetes were included in the study. Data were collected from the Electronic Medical Records (EMR), in addition to a telephone interview. Patients were offered 3 dental examinations with a 3-month interval. The dental examinations consisted of a full-mouth assessment of number of remaining teeth and assessment of periodontal status. Patients received scaling and root planing, together with information and instructions on oral hygiene. Information on glycated haemoglobin (HbA(1C)) values was collected from the EMR at each dental examination. RESULTS: In this study, 21.0% (13/62) of patients with diabetes had periodontitis. About 42% had less than 20 teeth. The association between diabetes and periodontitis was known by 20 out of the 62 patients. Over half of the patients had been to a dental examination within the last year. The prevalence of periodontitis decreased significantly from 21.0 to 0% (p<0.001) after 3 dental examinations. No change in HbA(1C) levels was observed (p=0.440). CONCLUSION: Periodontitis was common among patients with diabetes in Nuuk. Dental health status based on Periodontal Screening Index (PSI) and bleeding on probing (BOP) seemed to improve after dental health care, indicating a need for increased awareness among patients and health care professionals. HbA(1C) levels were not improved among the patients. PMID- 25498563 TI - Immunological consequences of stress-related proteins--cytosolic tryparedoxin peroxidase and chaperonin TCP20--identified in splenic amastigotes of Leishmania donovani as Th1 stimulatory, in experimental visceral leishmaniasis. AB - In earlier studies, proteomic characterization of splenic amastigote fractions from clinical isolates of Leishmania donovani, exhibiting significant cellular responses in cured Leishmania subjects, led to the identification of cytosolic tryparedoxin peroxidase (LdcTryP) and chaperonin-TCP20 (LdTCP20) as Th1 stimulatory proteins. Both the proteins, particularly LdTCP20 for the first time, were successfully cloned, overexpressed, purified and were found to be localized in the cytosol of purified splenic amastigotes. When evaluated against lymphocytes of cured Leishmania-infected hamsters, the purified recombinant proteins (rLdcTryP and rLdTCP20) induced their proliferations as well as nitric oxide production. Similarly, these proteins also generated Th1-type cytokines (IFN-gamma/IL-12) from stimulated PBMCs of cured/endemic Leishmania patients. Further, vaccination with rLdcTryP elicited noticeable delayed-type hypersensitivity response and offered considerably good prophylactic efficacy (~78% inhibition) against L. donovani challenge in hamsters, which was well supported by the increased mRNA expression of Th1 and Th2 cytokines. However, animals vaccinated with rLdTCP20 exhibited comparatively lesser prophylactic efficacy (~55%) with inferior immunological response. The results indicate the potentiality of rLdcTryP protein, between the two, as a suitable anti-leishmanial vaccine. Since, rLdTCP20 is also an important target, for optimization, further attempts towards determination of immunodominant regions for designing fusion peptides may be taken up. PMID- 25498564 TI - Doxepin and diphenhydramine increased non-rapid eye movement sleep through blockade of histamine H1 receptors. AB - Histaminergic neurons have been reported to play an important role in the regulation of sleep-wake behavior through the histamine H1 receptor (R, H1R). First generation H1R antagonists, such as doxepin and diphenhydramine, produce drowsiness in humans, and are occasionally used to treat insomnia. However, if H1R antagonists function via physically blocking the H1R remains unclear. In the current study, we used H1R knockout (KO) mice to investigate if the sleep promoting effects of doxepin and diphenhydramine are dependent on blockade of the H1R. When doxepin was administered, non-rapid eye movement (NREM) sleep in wild type (WT) mice increased for 4h, with an increase in the numbers of NREM sleep bouts of 256-512 s and 512-1024 s. These effects were not observed in the H1R KO mice. Furthermore, diphenhydramine increased NREM sleep for 6h in WT, and not in the H1R KO mice after the injection. These results indicate that both doxepin at 15 mg/kg and diphenhydramine at 10 mg/kg induce NREM sleep through blockade of H1R. PMID- 25498566 TI - Large mucinous neoplasm of the appendix mimicking adnexal mass in a postmenopausal woman. AB - INTRODUCTION: Appendiceal tumors are rare, late-diagnosed neoplasms that may not be differentiated from adnexal masses even by advanced imaging methods and other diagnostic procedures. They may be asymptomatic and remain undiagnosed until surgery. PRESENTATION OF CASE: We report a case of 81-year-old postmenopausal woman presented with abdominal pain. A magnetic resonance imaging revealed right adnexal mass. Laparotomy was performed and detected a 12cm*9cm mucinous tumoral mass arising in the appendix. An appendectomy and a right hemicolectomy with ileo transverse anastomosis were performed. Histopathological examination was revealed appendiceal mucinous neoplasm with low malignancy potential. DISCUSSION: Gastrointestinal tumors such as appendiceal tumors can mimicking adnexal mass. Therefore, appendiceal tumor kept in mind in a patient with diagnosed adnexal mass, especially patient had non-specific clinical symptoms, laboratory and radiologic findings. CONCLUSION: Gastrointestinal tumors such as appendiceal tumors kept in mind in a patient with diagnosed adnexal mass. PMID- 25498565 TI - Impact of treatment planning and delivery factors on gastrointestinal toxicity: an analysis of data from the RADAR prostate radiotherapy trial. AB - BACKGROUND: To assess the impact of incremental modifications of treatment planning and delivery technique, as well as patient anatomical factors, on late gastrointestinal toxicity using data from the TROG 03.04 RADAR prostate radiotherapy trial. METHODS: The RADAR trial accrued 813 external beam radiotherapy participants during 2003-2008 from 23 centres. Following review and archive to a query-able database, digital treatment plans and data describing treatment technique for 754 patients were available for analysis. Treatment demographics, together with anatomical features, were assessed using uni- and multivariate regression models against late gastrointestinal toxicity at 18-, 36- and 54-month follow-up. Regression analyses were reviewed in the context of dose volume data for the rectum and anal canal. RESULTS: A multivariate analysis at 36 month follow-up shows that patients planned using a more rigorous dose calculation algorithm (DCA) was associated with a lower risk of stool frequency (OR: 0.435, CI: 0.242-0.783, corrected p = 0.04). Patients using laxative as a method of bowel preparation had higher risk of having increased stool frequency compared to patients with no dietary intervention (OR: 3.639, CI: 1.502-8.818, corrected p = 0.04). Despite higher risks of toxicities, the anorectum, anal canal and rectum dose-volume histograms (DVH) indicate patients using laxative had unremarkably different planned dose distributions. Patients planned with a more rigorous DCA had lower median DVH values between EQD23 = 15 Gy and EQD23 = 35 Gy. Planning target volume (PTV), conformity index, rectal width and prescription dose were not significant when adjusted for false discovery rate. Number of beams, beam energy, treatment beam definition, positioning orientation, rectum-PTV separation, rectal length and mean cross sectional area did not affect the risk of toxicities. CONCLUSIONS: The RADAR study dataset has allowed an assessment of technical modifications on gastrointestinal toxicity. A number of interesting associations were subsequently found and some factors, previously hypothesised to influence toxicity, did not demonstrate any significant impact. We recommend trial registries be encouraged to record technical modifications introduced during the trial in order for more powerful evidence to be gathered regarding the impact of the interventions. PMID- 25498567 TI - Colonic perforation by a large gallstone: A rare case report. AB - INTRODUCTION: Herein we present the case of an 86-year-old woman with gallstone perforation of the sigmoid colon. PRESENTATION OF CASE: An 86-year-old woman with known cholelithiasis presented to our office with one week of abdominal pain and nausea. X-rays taken at presentation demonstrated pneumobilia, and CT scan showed a 3.5cm gallstone in the sigmoid colon. Medical management was unsuccessful in passing the stone, and a colonoscopy on day 4 was unsuccessful in incorporating the stone. Subsequent clinical deterioration prompted a laparotomy, where a perforation was discovered. A Hartmann's procedure was performed and the patient recovered after a complicated post-operative course. DISCUSSION: Gallstone ileus is an uncommon, but medically important, cause of bowel obstruction. This presentation is considered a surgical emergency and thus prompt identification and removal is essential. Obstructions tend to occur in either the stomach or along the various segments of the small intestine but have been reported in the colon as well. CONCLUSION: In cases of gallstones that manage to pass into the large intestine, it is prudent to attempt conservative measures for passage. Failure to do so should raise suspicion of a possible stricture, either benign or malignant, preventing its evacuation. Earlier surgical intervention should be considered in these cases. PMID- 25498568 TI - A genomic algorithm for the molecular classification of common renal cortical neoplasms: development and validation. AB - PURPOSE: Accurate discrimination of benign oncocytoma and malignant renal cell carcinoma is useful for planning appropriate treatment strategies for patients with renal masses. Classification of renal neoplasms solely based on histopathology can be challenging, especially the distinction between chromophobe renal cell carcinoma and oncocytoma. In this study we develop and validate an algorithm based on genomic alterations for the classification of common renal neoplasms. MATERIALS AND METHODS: Using TCGA renal cell carcinoma copy number profiles and the published literature, a classification algorithm was developed and scoring criteria were established for the presence of each genomic marker. As validation, 191 surgically resected formalin fixed paraffin embedded renal neoplasms were blindly submitted to targeted array comparative genomic hybridization and classified according to the algorithm. CCND1 rearrangement was assessed by fluorescence in situ hybridization. RESULTS: The optimal classification algorithm comprised 15 genomic markers, and involved loss of VHL, 3p21 and 8p, and chromosomes 1, 2, 6, 10 and 17, and gain of 5qter, 16p, 17q and 20q, and chromosomes 3, 7 and 12. On histological rereview (leading to the exclusion of 3 specimens) and using histology as the gold standard, 58 of 62 (93%) clear cell, 51 of 56 (91%) papillary and 33 of 34 (97%) chromophobe renal cell carcinomas were classified correctly. Of the 36 oncocytoma specimens 33 were classified as oncocytoma (17 by array comparative genomic hybridization and 10 by array comparative genomic hybridization plus fluorescence in situ hybridization) or benign (6). Overall 93% diagnostic sensitivity and 97% specificity were achieved. CONCLUSIONS: In a clinical diagnostic setting the implementation of genome based molecular classification could serve as an ancillary assay to assist in the histological classification of common renal neoplasms. PMID- 25498569 TI - Impact of county rurality and urologist density on urological cancer mortality in illinois. AB - PURPOSE: The urology work force is contracting at a time when service demand is increasing due to demographic changes, especially in rural areas. We investigated the impact of rural status and urologist density on kidney and renal pelvis, bladder and prostate cancer mortality at the county level in Illinois. MATERIALS AND METHODS: We stratified the 102 Illinois counties by 2003 RUCCs as urban (36, RUCCs 1 to 3) and rural (66, RUCCs 4 to 9). Area Health Resource Files were used for county demographic data and urologist density. County level age adjusted mortality rates from 1990 to 2010 were derived from National Center for Health Statistics data using SEER*Stat. We examined the associations of urological cancer mortality rates with rural status and urologist density. RESULTS: Average urologist density significantly differed between rural and urban counties (1.9 vs 3.4/100,000 population, p < 0.01). The kidney and renal pelvis cancer mortality rate in rural counties was higher than in urban counties while that of prostate cancer was lower (4.9 vs 4.3 and 28.7 vs 32.2/100,000 population, respectively, each p < 0.01). Urologist density correlated with the mortality rate of kidney and renal pelvis cancer (Pearson coefficient -0.33, p < 0.01) but not with the bladder or prostate cancer mortality rate. Multiple regression analysis revealed that rurality and lower urologist density (p = 0.01 and < 0.05) were significantly associated with higher kidney and renal pelvis cancer mortality. CONCLUSIONS: Rural residence and low urologist density were associated with increased kidney and renal pelvis cancer mortality on the county level in Illinois. Further expansion and testing of evidence-based telemedicine is warranted because remote technical consultation is now technologically feasible, effective, inexpensive and satisfactory to patients. PMID- 25498570 TI - External validation of the CAPRA-S score to predict biochemical recurrence, metastasis and mortality after radical prostatectomy in a European cohort. AB - PURPOSE: The CAPRA-S score predicts prostate cancer recurrence based on pathological information from radical prostatectomy. To our knowledge CAPRA-S has never been externally validated in a European cohort. We independently validated CAPRA-S in a single institution European database. MATERIALS AND METHODS: The study cohort comprised 14,532 patients treated with radical prostatectomy between January 1992 and August 2012. Prediction of biochemical recurrence, metastasis and cancer specific mortality by CAPRA-S was assessed by Kaplan-Meier analysis and the c-index. CAPRA-S performance to predict biochemical recurrence was evaluated by calibration plot and decision curve analysis. RESULTS: Median followup was 50.8 months (IQR 25.0-96.0). Biochemical recurrence developed in 20.3% of men at a median of 21.2 months (IQR 7.7-44.9). When stratifying patients by CAPRA-S risk group, estimated 5-year biochemical recurrence-free survival was 91.4%, 70.4% and 29.3% in the low, intermediate and high risk groups, respectively. The CAPRA-S c-index to predict biochemical recurrence, metastasis and cancer specific mortality was 0.80, 0.85 and 0.88, respectively. Metastasis developed in 417 men and 196 men died of prostate cancer. CONCLUSIONS: The CAPRA S score was accurate when applied in a European study cohort. It predicted biochemical recurrence, metastasis and cancer specific mortality after radical prostatectomy with a c-index of greater than 0.80. The score can be valuable in regard to decision making for adjuvant therapy. PMID- 25498571 TI - Intracompartmental pressure as a predictor of intratesticular blood flow: a rat model. AB - PURPOSE: We identified an intratesticular pressure at which vascular flow would cease in a testicular compartment syndrome model, defining a critical vascular stop flow pressure. MATERIALS AND METHODS: A total of 52 male Sprague Dawley(r) rats were used for the study. The testicle of each rat was delivered from the scrotum and size measurements were taken. An intracompartment pressure monitor needle was inserted into the testis to record basal intratesticular pressure. The monitor needle remained in the testicle for the duration of the procedure. Vascular flow within the testis was measured using a variable frequency linear ultrasound transducer with color flow and pulse wave Doppler modalities. Saline was infused through the compartment monitor in 5 mm Hg increments via a pressure infusion pump. Following each 5 mm Hg increase intratesticular vascular blood flow and velocities were recorded using color flow and pulse wave, respectively. Data collection proceeded until color flow images indicated a complete absence of flow within the testis. RESULTS: Using a paired t-test (p <0.0001), mean color flow stop flow pressure was 52.17 mm Hg (95% CI 49.57-54.77) and pulse wave stop flow pressure was 36.34 mm Hg (95% CI 33.90-38.77). Regression analysis of pulse wave vs color flow showed a slope of 0.6960 +/- 0.09112, a y-intercept of 0.02427 +/- 4.824 and an x-intercept of -0.03486. CONCLUSIONS: This is the first known study to characterize a stop flow pressure within the testicular parenchyma resulting from an increased intracompartmental pressure. Due to probe sensitivity limitations, color flow appears to provide the most precise mean pressure of occlusion of 52.17 mm Hg. PMID- 25498572 TI - Calcium phosphate stone morphology can reliably predict distal renal tubular acidosis. AB - PURPOSE: Calcium stones represent 85% to 90% of all urinary calculi, including various crystalline compositions and etiological conditions. Calcium phosphate accounts for 10% to 15% of cases. These stones are mainly related to 3 groups of risk factors, including calcium or phosphate metabolism disturbance, renal acidification defects and urinary tract infection. Identifying the stone etiology often requires extensive metabolic evaluation. We assessed whether stone analysis including morphological typing in addition to stone composition could be a valuable help for diagnosis. MATERIALS AND METHODS: Of 60,564 stones analyzed by morphological examination and infrared spectroscopy at our laboratory 6,439 (10.6%) were mainly composed of carbapatite. Of these stone 1,093 patients were included in study who had an available etiological diagnosis and stones containing at least 70% of calcium phosphate without struvite. RESULTS: Of the 1,093 calcium phosphate stones 12.8% showed a peculiar morphology termed IVa2, characterized by a smooth aspect and a glazed brown-yellow appearance with tiny cracks. IVa2 morphology was observed in 96.1% of stones associated with inherited distal renal tubular acidosis. In contrast, the other stones of similar composition but different morphology were related to distal renal tubular acidosis in only 3.9% of cases. In addition, IVa2 stones were found in 65% of calcium phosphate stone formers associated with Sjogren syndrome and in 35% of calcium phosphate stones in patients with medullary sponge kidney. These 2 conditions are related to a mild to moderate distal acidification defect. CONCLUSIONS: Identifying IVa2 stone morphology is clinically relevant because it should prompt clinicians to search for complete or incomplete distal acidosis and initiate specific therapy to decrease recurrence. PMID- 25498573 TI - Prophylactic pelvic lymph node dissection in patients with penile cancer. AB - PURPOSE: Pelvic lymph node involvement in penile cancer carries a poor prognosis. Therefore, there is controversy about the curative role of pelvic lymph node dissection. We analyzed the characteristics of tumor positive inguinal regions predictive for pelvic lymph node involvement in patients prophylactically treated with pelvic lymph node dissection. MATERIALS AND METHODS: All chemonaive consecutive cases treated with prophylactic pelvic lymph node dissection at our institution since 2001 were included in analysis. A generalized estimating equation model was used to predict pelvic node involvement based on inguinal characteristics. Disease specific survival was calculated with the Kaplan-Meier method. RESULTS: Included in study were 79 chemotherapy naive patients without preoperative evidence of pelvic disease who were treated with prophylactic pelvic lymph node dissection. Pelvic nodes were positive in 24% of the patients. Inguinal extranodal extension, or 2 or more tumor positive nodes were predictive of tumor positive pelvic nodes. The 5-year disease specific survival rate in patients with pelvic involvement was 17%. CONCLUSIONS: Inguinal extranodal extension, or 2 or more inguinal tumor positive lymph nodes are predictive of pelvic tumor positivity in patients without evidence of pelvic involvement. However, disease specific survival remains poor in patients with pelvic node involvement who are treated with surgery only. PMID- 25498574 TI - Patient and tumor characteristics can predict nondiagnostic renal mass biopsy findings. AB - PURPOSE: Identification of patient and tumor characteristics associated with nondiagnostic biopsies is necessary to improve prebiopsy counseling and patient selection. MATERIALS AND METHODS: We reviewed the clinical records and prebiopsy imaging of all patients treated with percutaneous biopsy for a renal mass 7 cm or less. Univariate and multivariate logistic regression models were constructed to examine the association between biopsy outcome and clinical/radiographic features. RESULTS: A total of 565 biopsies of renal tumors 7 cm or less in 525 patients were included in the study. There was no significant difference in age, body mass index, Charlson comorbidity score or gender between the patient cohorts with diagnostic and nondiagnostic biopsy. In 83 of 565 patients (14.7%) overall and in 72 of the 413 (17.4%) with a mass of 4 cm or less the biopsy findings were nondiagnostic. Overall 14.7% of masses were cystic and 85.3% were solid with a median tumor size of 2.75 cm (IQR 2.05-4.25). Independent predictors of nondiagnostic biopsy included cystic features, enhancement less than 20 HU, left tumor, tumor diameter and skin-to-tumor distance. The nondiagnostic rate of repeat biopsies was 20.8%, which did not statistically differ from the nondiagnostic rate at the initial renal mass biopsy attempt. Radiologist or pathologist experience was not associated with the biopsy nondiagnostic rate. In 7 of 565 patients (1.2%) hospital admission was required for adverse events after biopsy. CONCLUSIONS: Nondiagnostic renal mass biopsies are more common in cystic, nonenhancing, small masses when patients have a skin-to-tumor distance of 13 cm or greater. Excluding patients with these criteria decreased the nondiagnostic rate from 14.7% to 8.7%. PMID- 25498575 TI - Antenatal diagnosis of agenesis of the corpus callosum. AB - AIM: To estimate the diagnostic performance of ultrasound in detecting agenesis of the corpus callosum (ACC). MATERIALS AND METHODS: A retrospective review was performed of 1722 in utero MRI examinations. All cases were identified in which the fetus had been referred from ultrasonography with a diagnosis of ACC and those in which ACC was given as a diagnosis on the in utero MRI study. The MRI was assumed to provide the correct diagnosis of ACC and descriptive statistics of diagnostic accuracy for ultrasound were calculated. RESULTS: Of the 1722 ultrasound examinations performed, 121 had a diagnosis of ACC and approximately 50% were confirmed at MRI. Forty-two fetuses with ACC not suspected at ultrasonography were also identified at MRI. Ultrasonography had a positive predictive value of 47% (95% CI: 38-56%) and a negative predictive value of 97% (95% CI: 96-98%) for detecting ACC. CONCLUSION: Ultrasound is poor in diagnosing ACC and in utero MRI should be performed if there is any suspicion on antenatal ultrasonography. PMID- 25498577 TI - The 2014 BJA/PGA special issue: a selection of six educational reviews. PMID- 25498578 TI - Intracranial haemorrhage: therapeutic interventions and anaesthetic management. AB - Intracranial haemorrhage (ICH) is a devastating cause of stroke. Although the total incidence of ICH has remained stable worldwide, the proportion associated with the use of anticoagulant medications is increasing. Innovative interventions developed to improve patient outcomes often require peri-procedure anaesthetic management. This non-systematic review examines the pathophysiology of ICH at a clinical level, reports on novel therapeutic interventions, many of which are currently in clinical trials, and reviews the current published recommendations for the management of patients with ICH. PMID- 25498576 TI - Immunity to Cryptococcus neoformans and C. gattii during cryptococcosis. AB - The vast majority of infection with cryptococcal species occurs with Cryptococcus neoformans in the severely immunocompromised. A significant exception to this is the infections of those with apparently normal immune systems by Cryptococcus gattii. Susceptibility to cryptococcosis can be broadly categorised as a defect in adaptive immune responses, especially in T cell immunity. However, innate immune cells such as macrophages play a key role and are likely the primary effector cell in the killing and ultimate clearance of cryptococcal infection. In this review we discuss the current state of our understanding of how the immune system responds to cryptococcal infection in health and disease, with reference to the work communicated at the 9th International Conference on Cryptococcus and Cryptococcosis (ICCC9). We have focussed on cell mediated responses, particularly early in infection, but with the aim of presenting a broad overview of our understanding of immunity to cryptococcal infection, highlighting some recent advances and offering some perspectives on future directions. PMID- 25498579 TI - Perioperative use of oxygen: variabilities across age. AB - Enormous interest has emerged in the perioperative use of high concentrations of inspired oxygen in an attempt to increase tissue oxygenation and thereby improve postoperative outcome. An extensive debate has arisen regarding the risk/benefit ratio of oxygen therapy, with some researchers advocating the benefits of perioperative hyperoxia, particularly with regard to surgical site infection, whereas others emphasize its detrimental consequences on multiple organs, particularly the lungs and the brain. As one aspect of this debate, there is increased awareness of effects of reactive oxygen metabolites, a feature that contributes to the complexity of achieving consensus regarding optimum oxygen concentration in the perioperative period. Many reviews have discussed the pros and cons in the use of perioperative oxygen supplementation, but the potential importance of age-related factors in hyperoxia has not been addressed. The present narrative review provides a comprehensive overview of the physiological mechanisms and clinical outcomes across the age range from neonates to the elderly. Risks greatly outweigh the benefits of hyperoxia both in the very young, where growth and development are the hallmarks, and in the elderly, where ageing increases sensitivity to oxidative stress. Conversely, in middle age, benefits of short-term administration of perioperative oxygen therapy exceed potential adverse change effects, and thus, oxygen supplementation can be considered an important therapy to improve anaesthesia management. PMID- 25498580 TI - Role of the massive transfusion protocol in the management of haemorrhagic shock. AB - The concept of rapid delivery of multiple blood products to the bedside of a massively haemorrhaging patient seems to be a logical approach to the management of the massively bleeding patient. However, controversy exists in the use of fixed blood component ratios. Assessing the extent of the coagulopathy through point-of-care testing might provide patients with product administration as needed, and avoid excessive transfusion and its associated complications. PMID- 25498581 TI - Monitoring and delivery of sedation. AB - Sedation for medical procedures is provided in a variety of clinical settings by medical personnel with differing levels of education and training. Although generally a safe practice, there is a degree of morbidity and mortality associated with sedation practice. Monitoring standards continue to be refined by professional societies with the goal of improving care. The depth of sedation should be monitored with clinical criteria. Processed electroencephalographic monitors currently do not contribute significantly to sedation care. Monitoring ventilation using pulse oximetry should be abandoned for more direct methods, such as capnography-transcutaneous carbon dioxide, respiratory acoustical and thoracic impedance monitoring could also play a role. Propofol has become widely utilized for sedation, although there are concerns about its margin of safety and synergistic interactions with other agents. Dexmedetomidine and propofol/ketamine also have utility. Patient-controlled sedation pumps and target-controlled infusion devices have been developed to improve patient care and satisfaction. A computer-assisted propofol sedation device to be used by non-anaesthesiologists has been approved in the USA by the Food and Drug Administration. More computer assisted sedation delivery devices are likely to be developed, but their clinical utility is unclear. PMID- 25498582 TI - Challenges in paediatric procedural sedation: political, economic, and clinical aspects. AB - Paediatric sedation has expanded in volume and demand over the past decade. In parallel with the increasing demand for and delivery of sedation by multi specialty providers, conflicting political agendas have surfaced. With a limited selection of sedatives and few new sedatives to market over the past decade, some providers utilize agents that formerly were considered exclusive for administration by anaesthesiologists. This review highlights the important contributions to paediatric sedation over the past century. Considerations include the barriers and politics that impede progress and also future advances and contributions that may lie ahead. PMID- 25498583 TI - Anaesthetic management of the patient with acute ischaemic stroke. AB - Anaesthetic management of the acute stroke patient demands consideration of the penumbra as the central focus. Recent studies have shown that patients who receive general anaesthesia for endovascular therapy for acute ischaemic stroke have worse outcomes than those who receive local anaesthesia. Although baseline condition of the patients in these studies differed, we should heed the warnings evident in the results. 'Time is brain': therapy should be quickly provided. Arterial pressure should be monitored carefully upon induction, avoiding a drastic reduction, and allowing for a reduction in arterial pressure upon recanalization. Keeping these factors in mind, anaesthetic technique (general, monitored anaesthesia care, or local) must be selected considering the individual patient's risks and benefits. Unfortunately, there are no proven neuroprotective strategies to date for use in acute ischaemic stroke. PMID- 25498591 TI - Altered regional loading patterns on articular cartilage following meniscectomy are not fully restored by autograft meniscal transplantation. AB - OBJECTIVE: To quantify the changes in regional dynamic loading patterns on tibial articular cartilage during simulated walking following medial meniscectomy and meniscal transplantation. METHODS: Seven fresh frozen human cadaveric knees were tested under multidirectional loads mimicking the activity of walking, while the contact stresses on the tibial plateau were synchronously recorded using an electronic sensor. Each knee was tested for three conditions: intact meniscus, medial meniscectomy, and meniscal transplantation. The loading profiles at different locations were assessed and common loading patterns were identified at different sites of the tibial plateau using an established numerical algorithm. RESULTS: Three regional patterns were found on the tibial plateau of intact knees. Following medial meniscectomy, the area of the first pattern which was located at the posterior aspect of the medial plateau was significantly reduced, while the magnitude of peak load was significantly increased by 120%. The second pattern which was located at the central-posterior aspects of the lateral plateau shifted anteriorly and laterally without changing its magnitude. The third pattern in the cartilage-to-cartilage contact region of the medial plateau was absent following meniscectomy. Meniscal transplantation largely restored the first pattern, but it did not restore the other two patterns. CONCLUSION: There are site-dependent changes in regional loading patterns on both the medial and lateral tibial plateau following medial meniscectomy. Even when a meniscal autograft is used where the geometry and material properties are kept constant, the only region in which the loading pattern is restored is at posterior aspect of the medial plateau. PMID- 25498590 TI - The chemokine receptor CCR5 plays a role in post-traumatic cartilage loss in mice, but does not affect synovium and bone. AB - OBJECTIVE: C-C chemokine receptor type 5 (CCR5) has been implicated in rheumatoid arthritis and several inflammatory diseases, where its blockade resulted in reduced joint destruction. However, its role in modulating cartilage and bone changes in post-traumatic osteoarthritis (OA) has not yet been investigated. In this study, we investigated changes in articular cartilage, synovium and bone in a post-traumatic OA model using CCR5-deficient (CCR5(-/-)) mice. METHOD: Destabilization of the medial meniscus (DMM) was performed on the right knee of 10-week old CCR5(-/-) and C57BL/6J wild-type (WT) mice to induce post-traumatic OA. The contralateral left knee served as sham-operated control. Knee joints were analyzed at 4-, 8- and 12-weeks after surgery to evaluate cartilage degeneration and synovitis by histology, and bone changes via micro-CT. RESULTS: Our findings showed that CCR5(-/-) mice exhibited significantly less cartilage degeneration than WT mice at 8- and 12-weeks post-surgery. CCR5(-/-) mice showed some altered bone parameters 18- and 22-weeks of age, but body size and weight were not affected. The effect of CCR5-ablation was insignificant at all time points post surgery for synovitis and for bone parameters such as bone volume/total volume, connectivity density index (CDI), structure model index (SMI), subchondral bone plate thickness, and trabecular bone number, thickness and spacing. CONCLUSION: These findings suggest that CCR5(-/-) mice developed less cartilage degeneration, which may indicate a potential protective role of CCR5-ablation in cartilage homeostasis. There were no differences in bone or synovial response to surgery suggesting that CCR5 functions primarily in cartilage during the development of post-traumatic OA. PMID- 25498592 TI - Time-related increase in urinary testosterone levels and stable semen analysis parameters after bariatric surgery in men. AB - The aim of this prospective cohort study was to determine the time-course in androgen and semen parameters in men after weight loss associated with bariatric surgery. Six men aged 18-40 years, meeting National Institutes of Health bariatric surgery guidelines, were followed between 2005 and 2008. Study visits took place at baseline, then 1, 3, 6 and 12 months after surgery. All men underwent Roux-en-y gastric bypass (RYGB). At each visit, biometric, questionnaire, serum, and urinary specimens and seman analysis were collected. Urinary integrated total testosterone levels increased significantly (P < 0.0001) by 3 months after surgery, and remained elevated throughout the study. Circulating testosterone levels were also higher at 1 and 6 months after surgery, compared with baseline. Serum sex hormone-binding globulin levels were significantly elevated at all time points after surgery (P < 0.01 to P = 0.02). After RYGB surgery, no significant changes occurred in urinary oestrogen metabolites (oestrone 3-glucuronide), serum oestradiol levels, serial semen parameters or male sexual function by questionnaire. A threshold of weight loss is necessary to improve male reproductive function by reversing male hypogonadism, manifested as increased testosterone levels. Further serial semen analyses showed normal ranges for most parameters despite massive weight loss. PMID- 25498593 TI - Hysteroscopic outpatient metroplasty to expand dysmorphic uteri (HOME-DU technique): a pilot study. AB - The new classification system of uterine anomalies from the European Society of Human Reproduction and Embryology and the European Society for Gynaecological Endoscopy defines T-shaped and tubular-shaped infantilis uteri as 'dysmorphic'. Such malformations have been proven to be associated with poor reproductive performance. A prospective observational study was conducted with 30 infertile women with dysmorphic uterus who underwent the novel Hysteroscopic Outpatient Metroplasty to Expand Dysmorphic Uteri (HOME-DU ) technique. Incisions are made on the uterine walls with a 5 Fr bipolar electrode. The procedure was conducted in outpatients under conscious sedation, using a 5-mm office hysteroscope. The technique was successful in all cases without complications. A net increase of uterine volume was found, as measured at hysteroscopy and three-dimensional transvaginal ultrasound (P < 0.001). Uterine morphology improved in all patients but one. At mean follow-up of 15 months, clinical pregnancy rate was 57% and term delivery rate 65%. These early data support HOME-DU as safe and effective in expanding the volume and normalizing the appearance of the uterine cavity of dysmorphic uteri. Although the cohort was small, pregnancy and live births outcomes were favourable in this poor-prognosis group, implying desirable benefits, which should be compared with other techniques. PMID- 25498594 TI - Dehydroepiandrosterone administration before IVF in poor responders: a prospective cohort study. AB - The use of dehydroepiandrosterone (DHEA) may improve ovarian stimulation outcomes in women of advanced reproductive age and could reduce embryo aneuploidy. In this prospective study, 48 women diagnosed with poor ovarian response received DHEA supplementation for at least 12 weeks. These women were compared with a group of poor responders (n = 113) who did not receive supplementation. During the study period, patients taking day 2 FSH and oestradiol were measured monthly before and after treatment. Stimulation characteristics, stimulation outcome and clinical outcome (clinical pregnancy and live birth rates) were reported. Evaluation of anti-Mullerian hormone (AMH) was carried out before initiation of treatment and immediately before the subsequent stimulation. Supplementation with DHEA for at least 12 weeks resulted in a modest, but statistically significant, increase in AMH levels and decrease in baseline FSH (P < 0.001 and P = 0.007, respectively). Administration of DHEA had no effect on any of the stimulation parameters nor was there any difference in clinical pregnancy rates and live birth rates between the two groups. Supplementation with DHEA significantly affects women with poor prognosis undergoing ovarian stimulation for IVF. Patients should be counselled about the uncertain effectiveness, potential side-effects and cost of this treatment. PMID- 25498595 TI - The effect of human follicular fluid on bovine oocyte developmental competence and embryo quality. AB - In this study, the hypothesis that embryo development during routine IVF procedures is determined by the pre-ovulatory follicular fluid composition was tested. Follicular fluid from women with obesity ('obese') and a 'positive' or 'negative' IVF outcome was added during the in-vitro maturation of bovine oocytes. 'Negative' and 'obese' follicular fluid reduced bovine embryo development, compared with laboratory control embryo development (P < 0.05 or P < 0.1). The addition of follicular fluid also altered bovine blastocyst gene expression. Furthermore, LDHA and PPARGC1B gene expression differed between follicular fluid groups. Data suggest that pre-ovulatory follicular fluid can potentially affect oocyte developmental competence and embryo quality. Furthermore, the bovine model may be used as a screening tool. PMID- 25498596 TI - Should IVF be used as first-line treatment or as a last resort? A debate presented at the 2013 Canadian Fertility and Andrology Society meeting. AB - Infertility outcomes can be influenced by many factors. Although a number of treatments are offered, deciding which one to use first is a controversial topic. Although IVF may have superior efficacy in achieving a live birth with a reasonable safety profile, the availability of cheaper and less invasive treatments preclude its absolute use. For this reason, certain patient groups with 'good-prognosis' infertility are traditionally treated with less invasive treatments first. 'Good-prognosis' infertility may include unexplained infertility, mild male factor infertility, stage I or II endometriosis, unilateral tubal blockage and diminished ovarian reserve. Here, evidence behind the use of IVF as a first-line treatment is compared with its use as a last resort option in women with 'good-prognosis' infertility. PMID- 25498597 TI - The effect of childhood cancer therapy on ovarian reserve and pubertal development. AB - The effects of childhood cancer therapy on ovarian reserve tests and on pubertal development within 5 years were compared with a control group. The study group was composed of 41 patients who underwent chemotherapy during pre-menarche (subgroup A; n = 15) and after menarche (subgroup B; n = 26); the control group was composed of 44 patients admitted with non-cancer related diseases (in total n = 85). Mean total ovarian volume and total antral follicle counts on ultrasound examination were significantly lower in the study group compared with the control group (3.5 +/- 2.3 versus 5.2 +/- 2.4 ml; P = 0.001; and 3.4 +/- 3.3 versus 8.6 +/- 3.5; P < 0.001, respectively). Mean FSH level was significantly higher in the study group (13.5 +/- 16.2 versus 7.3 +/- 2.7 mIU/ml; P = 0.017). Anti-Mullerian hormone levels in subgroup A were significantly higher than in subgroup B (1.8 +/ 0.1 versus 1.5 +/- 0.08 pg/dl; P = 0.034). In conclusion ovarian volume, antral follicle count and FSH can be used for evaluating the harmful effect of cancer chemotherapy on ovarian follicles. Post-menarche, Anti-Mullerian values reveal that ovarian follicles are more sensitive to the devastating effects of cytotoxic treatment. PMID- 25498598 TI - Animal memory: A review of delayed matching-to-sample data. AB - We performed a meta-analysis of over 90 data sets from delayed matching-to-sample (DMTS) studies with 25 species (birds, mammals, and bees). In DMTS, a sample stimulus is first presented and then removed. After a delay, two (or more) comparison stimuli are presented, and the subject is rewarded for choosing the one matching the sample. We used data on performance vs. delay length to estimate two parameters informative of working memory abilities: the maximum performance possible with no delay (comparison stimuli presented as soon as the sample is removed), and the rate of performance decay as the delay is lengthened (related to memory span). We conclude that there is little evidence that zero-delay performance varies between these species. There is evidence that pigeons do not perform as well as mammals at longer delay intervals. Pigeons, however, are the only extensively studied bird, and we cannot exclude that other birds may be able to bridge as long a delay as mammals. Extensive training may improve memory, although the data are open to other interpretations. Overall, DMTS studies suggest memory spans ranging from a few seconds to several minutes. We suggest that observations of animals exhibiting much longer memory spans (days to months) can be explained in terms of specialized memory systems that deal with specific, biologically significant information, such as food caches. Events that do not trigger these systems, on the other hand, appear to be remembered for only a short time. This article is part of a Special Issue entitled: In Honor of Jerry Hogan. PMID- 25498599 TI - Computational investigation of inhibitory mechanism of flavonoids as bovine serum albumin anti-glycation agents. AB - BACKGROUND: Glycation of serum albumin and its consequence products were considered as an important factor in drug distribution and diabetic complications, therefore finding the glycation inhibitors and their inhibitory mechanisms became a valuable field of study. In this work, bovine serum albumin (BSA) became a subject as a model protein for analyzing the inhibitory mechanism of flavonoids, known as natural BSA glycation inhibitors in the early stage of glycation. METHODS: Firstly, for theoretical study, the three-dimensional model of BSA structure was generated by homology modeling and refined through molecular dynamic simulation. Secondly, several validation methods (statistical assessment methods and also neural network methods) by simultaneous docking study were employed for insurance about accuracy of our simulation. Then docking studies were performed for visualizing the relation between flavonoids' binding sites and BSA glycation sites besides, the correlation analyzes between calculated binding energy and reported experimental inhibitory IC50 values of the flavonoids set, was considered to explore their molecular inhibitory mechanism. RESULTS: The quality assessment methods and simultaneous docking studies on interaction of quercetin (as the most studied flavonoids) with BSA and Human serum albumin (HAS), confirm the accuracy of simulation and the second stage of docking results which were in close agreement with experimental observations, suggest that the potential residues in flavonoids binding sites (which were place neighbor of tryptophan 212 within 5A) cannot be considered as one of glycation sites. CONCLUSIONS: Based on the results, flavonoids don't participate in inhibitory interference mechanism, and also, the differentiation between complexes of flavonoids with BSA and HSA could destroy the speculation of using them as an exchangeable model protein in study of serum albumin and flavonoids interactions. PMID- 25498600 TI - Yawning, acute stressors, and arousal reduction in Nazca booby adults and nestlings. AB - Yawning is a familiar and phylogenetically widespread phenomenon, but no consensus exists regarding its functional significance. We tested the hypothesis that yawning communicates to others a transition from a state of physiological and/or psychological arousal (for example, due to action of a stressor) to a more relaxed state. This arousal reduction hypothesis predicts little yawning during arousal and more yawning (above baseline) during and after down-regulation of arousal. Experimental capture-restraint tests with wild adult Nazca boobies (Sula granti), a seabird, increased yawning frequency after release from restraint, but yawning was almost absent during tests. Natural maltreatment by non-parental adults also increased yawning by nestlings, but only after the maltreatment ended and the adult left. CORT (corticosterone) was a logical a priori element of the stress response affecting the stressor-yawning relationship under the arousal reduction hypothesis, and cannot be excluded as such for adults in capture restraint tests but is apparently unimportant for nestlings being maltreated by adults. The arousal reduction hypothesis unites formerly disparate results on yawning: its socially contagious nature in some taxa, its clear pharmacological connection to the stress response, and its temporal linkage to transitions in arousal between consciousness and sleep. PMID- 25498601 TI - The origins and significance of coastal resource use in Africa and Western Eurasia. AB - The systematic exploitation of marine foods by terrestrial mammals lacking aquatic morphologies is rare. Widespread ethnographic and archaeological evidence from many areas of the world shows that modern humans living on coastlines often ratchet up the use of marine foods and develop social and technological characteristics unusual to hunter-gatherers and more consistent with small scale food producing societies. Consistent use of marine resources often is associated with reduced mobility, larger group size, population packing, smaller territories, complex technologies, increased economic and social differentiation, and more intense and wide-ranging gifting and exchange. The commitment to temporally and spatially predictable and dense coastal foods stimulates investment in boundary defense resulting in inter-group conflict as predicted by theory and documented by ethnography. Inter-group conflict provides an ideal context for the proliferation of intra-group cooperative behaviors beneficial to the group but not to the altruist (Bowles, 2009). The origins of this coastal adaptation marks a transformative point for the hominin lineage in Africa since all previous adaptive systems were likely characterized by highly mobile, low density, egalitarian populations with large territories and little boundary defense. It is important to separate occasional uses of marine foods, present among several primate species, from systematic and committed coastal adaptations. This paper provides a critical review of where and when systematic use of coastal resources and coastal adaptations appeared in the Old World by a comparison of the records from Africa and Europe. It is found that during the Middle Stone Age in South Africa there is evidence that true coastal adaptations developed while there is, so far, a lack of evidence for even the lowest levels of systematic coastal resource use by Neanderthals in Europe. Differences in preservation, sample size, and productivity between these regions do not explain the pattern. PMID- 25498602 TI - Preparation and characterization of a novel pH-response dietary fiber: chitosan coated konjac glucomannan. AB - The purpose of this study was to prepare a kind of novel pH-response dietary fiber from chitosan-coated konjac glucomannan (KGM) powders (KGM/Chitosan or K/C powders) by a physical grind method. The K/C powders were selectively soluble in aqueous solutions of different pH. Meanwhile, the coated chitosan could largely decrease the viscosity of KGM in neutral condition, which is the main limitation for KGM application in food industry. Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), swelling ability and rheological measurements were utilized to characterize the performance of K/C powders. K/C powders exhibited much higher viscosity and swelling ability in acidic condition than in neutral condition. Therefore, this study will extend the application of KGM in food industry and in other pH-specific applications as well. PMID- 25498603 TI - Graft copolymerization of ethyl acrylate onto tamarind kernel powder, and evaluation of its biodegradability. AB - In the present study, tamarind kernel powder and ethyl acrylate were reacted by free radical polymerization to synthesize a grafted copolymer soluble in water. The grafted copolymer was analyzed by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR); FTIR showed a shift of the vibration of R-CO-OR' from 1258 cm(-1) to 1253 cm(-1). This shift appeared because of the grafting copolymerization. Films were prepared to study the mechanical properties and the biodegradation of this material. The mechanical properties of the grafted copolymer were found to lie between those of the parent polymers, suitable for disposable products. The new grafted copolymer manifested a steady process of biodegradation under incubation with the bacterial strain Alicycliphilus sp. BQ1; this was proved by scanning electron microscopy (SEM) and near infrared spectroscopy (NIR). PMID- 25498604 TI - Extraction of hemicelluloses from fiberized spruce wood. AB - A novel mechanical pre-treatment method was used to separate the wood chips into fiber bundles in order to extract high molecular weight wood polymers. The mechanical pre-treatment involved chip compression in a conical plug-screw followed by defibration in a fiberizer. The fiberized wood was treated with hot water at various combinations of time and temperature in order to analyze the extraction yield of hemicelluloses at different conditions. Nearly 6 mg/g wood of galactoglucomannan was obtained at 90 degrees C/120 min which was about three times more than what could be extracted from wood chips. The extracted carbohydrates had molecular weight ranging up to 60 kDa. About 10% of each of the extracted material had a molecular weight above 30 kDa. The extraction liquor could also be reused for consecutive extractions with successive increase in the extraction yield of hemicelluloses. PMID- 25498605 TI - In vitro release of theophylline from starch-based matrices prepared via high hydrostatic pressure treatment and autoclaving. AB - Recent works have demonstrated that release behavior of bioactive compounds varies with the nature of the matrix regarding its chemical composition, morphology and surface properties. Starch matrices varying in amylose content (maize, sorghum, Hylon VII) or pure amylopectin ones (waxy maize, amaranth starch), containing theophylline (10 mg, 50 mg/0.5 g of starch), were obtained via high hydrostatic pressure treatment (650 MPa/9 min) and autoclaving (120 degrees C/20 min). Both the treatment used and drug dose affected the theophylline release profiles from the matrices studied. The profiles of amylopectin starch matrices satisfactorily fitted with selected mathematical models, indicating a controlled theophylline release. The principal component analysis confirmed substantial differences in drug release between the amylose and amylopectin matrices. The differences in matrix morphology, internal surface area and porosity (mesopore diameter, cumulative pore volume) between the matrices studied were found to be key factors affecting the theophylline dissolution. PMID- 25498606 TI - Gold nanoparticles in the engineering of antibacterial and anticoagulant surfaces. AB - Simultaneous antibacterial and anticoagulant surfaces have been prepared by immobilization of engineered gold nanoparticles onto different kinds of surfaces. The gold nanoparticle core is surrounded by a hemocompatible, anticoagulant polysaccharide, 6-O chitosan sulfate, which serves as reduction and stabilizing agent for the generation of gold nanoparticles in a microwave mediated reaction. The particle suspension shows anticoagulant activity, which is investigated by aPTT and PT testing on citrated blood samples of three patients suffering from congenital or acquired bleeding disorders. The amount of nanoparticles deposited on the surfaces is quantified by a quartz crystal microbalance with dissipation unit. All gold containing surfaces exhibit excellent antimicrobial properties against the chosen model organism, Escherichia coli MG 1655 [R1-16]. Moreover, blood plasma coagulation times of the surfaces are increased after deposition of the engineered nanoparticles as demonstrated by QCM-D. PMID- 25498607 TI - A biocompatible calcium salt of hyaluronic acid grafted with polyacrylic acid. AB - We have synthesized hyaluronic acid (HA) grafted with polyacrylic acid (PAA) via controlled radical polymerization (CRP) in aqueous media. The grafted HA (HA-g PAA) showed slow degradation by hyaluronidase compared with unmodified HA as a result of the steric hindrance produced by grafted PAA, and PAA was detached by hydrolysis and enzymatic degradation by lipase. It formed an insoluble salt immediately after mixing with Ca(2+) by the binding between grafted PAA and Ca(2+). Both HA-g-PAA and its salt showed good biocompatibility, especially to mesothelial cells in vitro. Finally, they were administered into mice subcutaneously and intraperitoneally. The residue of the material was observed 7 days after subcutaneous administration, while the material was almost cleared from the peritoneum 7 days after intraperitoneal administration with or without Ca(2+). HA-g-PAA is expected to be applicable to medical uses such as drug delivery in the peritoneum and for materials preventing peritoneal adhesion. PMID- 25498608 TI - Preparation, characterization and in vitro digestibility of gellan and chitosan gellan microgels. AB - Gellan microgels with potential application in delivery systems were obtained by physically cross-linked gellan gum. The microgels were produced by atomization followed by ionotropic gelation using CaCl2 (gellan/Ca) or KCl (gellan/K) as hardening agent and part of them were coated with chitosan in order to improve their resistance to gastric digestion. Size distribution, morphology and zeta potential of microgels were evaluated before and after in vitro digestion process. The long term stability was also evaluated. Spherical microparticles were obtained at gellan concentration above 0.6% w/w, showing average size among 70-120 MUm. Most of the coated and uncoated microgels showed stability in aqueous media, except the uncoated gellan/K microgel. The in vitro digestion evaluation showed that all particles maintained their size and shape after the gastric digestion step. However, the enteric digestion caused disintegration of microgels indicating their potential application for enteric delivery systems. The chitosan coated microgels showed lower degree of fragmentation when compared to the uncoated microgels, indicating that the coating process enable a better control of microgels releasing properties during the enteric digestion. PMID- 25498609 TI - Anti-diabetic effect mediated by Ramulus mori polysaccharides. AB - Diabetes mellitus is a complicated metabolic disease, whose pathogenesis is related to apoptosis within pancreatic tissue. In this study, the potential therapeutic benefits of Ramulus mori polysaccharides (RMP) on streptozotocin (STZ)-induced diabetic mice were evaluated. Our experiments indicated that RMP lowered hyperglycemia and increased insulin levels in diabetic mice. Histopathological examination revealed that RMP contributed to the reduction of STZ-lesioned pancreatic cells. In addition, the serum level of HbA1c was decreased. RMP treatment also showed increased Bcl-2 expression and reduced Bax protein level in pancreatic tissue. Furthermore, intrapancreatic expressions of p JNK, p-p38 and cleaved-caspase-3 were down-regulated by RMP treatment. Collectively, the findings demonstrate that RMP exerts the pronounced hypoglycemic effect via regulation of the intrapancreatic JNK/p38 pathway to protect against STZ-induced apoptosis in pancreatic tissue, eventually ameliorating metabolic function in the pancreas. PMID- 25498610 TI - Mechanism of Au(III) reduction by chitosan: comprehensive study with 13C and 1H NMR analysis of chitosan degradation products. AB - The mechanism of Au(III) reduction by chitosan has been proposed on the basis of comprehensive study of kinetics of Au(III) reduction and chitosan chain degradation using UV-vis spectroscopy and viscosimetry, and identification of reaction products using colloid titration and (13)C, (1)H NMR spectroscopy. We have shown that formation of gold nanoparticles in H[AuCl4]/chitosan solutions starts with hydrolysis of chitosan catalyzed by Au(III). The products of chitosan hydrolysis rather than chitosan itself act as the main reducing species. According to (13)C and (1)H NMR spectroscopy data, chitosan/Au(0) composites contain chitosan with reduced molecular weight and acetylation degree, whereas water-soluble by-products consist of chitosan oligomers with higher acetylation degree, derivatives of glucosamine acids, and formate ion. Chitosan degradation has significantly contributed to the decrease of its efficiency as a gold nanoparticles stabilizer. The gold particle size increased from 6.9 nm to 16.2 nm, when Au(III)/chitosan molar ratio changed from 1:80 to 1:10. PMID- 25498611 TI - Starch/rosin complexes for improving the interaction of mineral filler particles with cellulosic fibers. AB - On the basis of inclusion complex formation of starch with small guest molecules, the concept of filler modification for papermaking by calcium-ion-induced deposition of starch/rosin complexes in the presence of filer particles was demonstrated. The rosin amount of 3% (on the basis of the dry weight of starch) induced effective starch deposition. Due to the cellulose-bondable nature of starch/rosin complexes, filler modification resulted in improved interaction of precipitated calcium carbonate particles with cellulosic fibers, leading to reduced negative impact of filler addition on paper strength. The efficiency of alkyl ketene dimer emulsion as an internal sizing agent for cellulosic paper was also improved as a result of filler modification. The concept demonstrated in this study may provide a useful alternative to the improvement of the use of mineral fillers in the paper industry. PMID- 25498612 TI - Starch and cellulose nanocrystals together into thermoplastic starch bionanocomposites. AB - In the present work, thermoplastic maize starch based bionanocomposites were prepared as transparent films, plasticized with 35% of glycerol and reinforced with both waxy starch (WSNC) and cellulose nanocrystals (CNC), previously extracted by acidic hydrolysis. The influence of the nanofiller content was evaluated at 1 wt.%, 2.5 wt.% and 5 wt.% of WSNC. The effect of adding the two different nanoparticles at 1 wt.% was also investigated. As determined by tensile measurements, mechanical properties were improved at any composition of WSNC. Water vapour permeance values maintained constant, whereas barrier properties to oxygen reduced in a 70%, indicating the effectiveness of hydrogen bonding at the interphase. The use of CNC or CNC and WSNC upgraded mechanical results, but no significant differences in barrier properties were obtained. A homogeneous distribution of the nanofillers was demonstrated by atomic force microscopy, and a shift of the two relaxation peaks to higher temperatures was detected by dynamic mechanical analysis. PMID- 25498613 TI - Hypoglycemic and hypolipidemic properties of polysaccharides from Enterobacter cloacae Z0206 in KKAy mice. AB - The water-soluble polysaccharides (EPS) were isolated from culture broth of Enterobacter cloacae Z0206, and the hypoglycemic and hypolipidemic effects of EPS were investigated. In this study, KKAy mice were gavaged once daily with either distilled water or EPS (200 mg/kg body weight) for 6 weeks. Results showed that EPS possessed significant hypoglycemic effects. Improved oral glucose tolerance, reduced serum insulin levels as well as decreased serum triglycerides (TG), cholesterol (TC) and low density lipoprotein cholesterol (LDL-c) were observed after treatment with EPS. Furthermore, EPS upregulated the expression of glucokinase (GK), HSL (Hormone Sensitive Lipase), adipose triglyceride lipase (ATGL), carnitine palmitoyl transferase 1-alpha (CPT1-alpha), glucose transporter 2 (Glut2), adenosine monophosphate activated protein kinase (AMPK) and silent information regulator 1 (Sirt1), but downregulated the gene expression of glucose 6-phosphatase (G6P) and fatty acid synthase (FAS) in the liver. These results suggest that EPS exhibits hypoglycemic and hypolipidemic effects possibly through regulating AMPK- and SirT1-mediated effects on carbohydrate and lipid metabolism. PMID- 25498614 TI - Preparation and characterization of regenerated cellulose from ionic liquid using different methods. AB - In this study, regenerated cellulose was prepared from ionic liquid 1-butyl-3 methylimidazolium acetate ([Bmim]Ac) solution using anti-solvent compressed CO2 of different pressures. And other anti-solvents like water, ethanol and acetonitrile were also employed to regenerate cellulose to provide comparisons. The two-dimensional nuclear magnetic resonance (2D NMR), namely heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond coherence (HMBC), and attenuated total reflectance Fourier transform infrared spectroscopy (ATR FTIR) indicated that carboxylate zwitterions [Bmim(+)-COO(-)] formed through the chemical reactions between CO2 and [Bmim]Ac. Besides, FTIR, wide-angle X-ray diffraction (XRD), thermal gravimetric analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to provided structure characterization of native and regenerated cellulose using different anti-solvents. The results show that the crystallinity of cellulose decreases during the dissolution and regeneration process. And a crystal transformation of cellulose I to cellulose II was verified. The stability of the regenerated cellulose is lower than that of native cellulose. A higher compressed CO2 pressure results in a smoother surface, a thicker shape and a more homogeneous texture of regenerated cellulose. PMID- 25498615 TI - Isolation and characterization of a hyperbranched proteoglycan from Ganoderma lucidum for anti-diabetes. AB - Presently, an efficient protein tyrosine phosphatase 1B (PTP1B) inhibitor, named FYGL-n, was isolated from Ganoderma Lucidum and characterized for its structure and bioactivity. Structure and chain conformation of FYGL-n based on both chemical and spectroscopic analysis showed that FYGL-n was a hyperbranched heteropolysaccharide bonded with protein via both serine and threonine residues by O-type glycoside, and showed a sphere observed by AFM. Specifically, monosaccharide composition indicated that FYGL-n consisted of D-arabinose, D galactose, L-rhamnose and D-glucose in a mole ratio of 0.08:0.21:0.24:0.47, with a molecular mass of 72.9 kDa. The analysis of amino acids in FYGL-n indicated that there were 16 common amino acids, among which aspartic acid, glycine, serine, alanine, glutamic acid and threonine were the dominant components. Also it was demonstrated that FYGL-n could inhibit the PTP1B activity on a competitive mechanism in vitro. PMID- 25498616 TI - Structural analyses and immunomodulatory properties of fructo-oligosaccharides from onion (Allium cepa). AB - Onion (Allium cepa) is an immune-boosting food rich in fructans. The major aim of this study is to characterize and investigate the immunomodulatory properties of onion fructo-oligosaccharides (FOS). FOS was isolated from onion bulbs by hot 80% ethanol extraction (yield: ~4.5 g/100 g fw) followed by gel permeation chromatography. NMR of onion FOS revealed unusual beta-D-Glc terminal residue at the non-reducing end. TLC and ESI-MS analyses showed that onion FOS ranged from trisaccharides to hexasaccharides. Onion FOS (50 MUg/mL) significantly increased (~3-fold) the proliferation of mouse splenocytes/thymocytes vs. control. Further, onion FOS enhanced (~2.5-fold) the production of nitric oxide by peritoneal exudates cells (PECs) from Wistar rats; intracellular free radicals production and phagocytic activity of isolated murine PECs were also augmented. Our structural and in vitro results indicate that onion FOS comprising of tri- to hexasaccharide units belongs to inulin-type fructans, and possess immunostimulatory activities towards murine lymphocytes and macrophages. PMID- 25498617 TI - Modified chitosan for the collection of reactive blue 4, arsenic and mercury from aqueous media. AB - In the present investigation a series of modified chitosan as adsorbents were synthesized free radically at 70 degrees C using acryloylated chitosan (AC chitosan) as macromer, 2-acrylamido-2-methyl-1-propansulfonic acid (AMPS), 2 (diethylamino) ethylmethacrylate (DAEMA) as co-monomers and N,N'-methylene bisacrylamide (N-MBA) as a crosslinker for using as adsorbents in effluent remediation. Their structures ((1)H and (13)C NMR), thermal stability (TG/DTG), surface morphology (SEM), reactive blue 4 (RB4), toxic metals such as arsenic (AsO(2-)) and mercury (Hg(2+)) uptake, swellability and reusability were evaluated. The adsorption of RB4 (701 mg/g), and the uptake of AsO(2-) (551 mg/g) and Hg(2+) (455 mg/g) showed Langmuir isotherm behavior with pseudo-first-order kinetics. The diffusion of water, RB4, AsO(2-) and Hg(2+) into the matrix followed non-Fickian mechanism. The evaluated changes in Gibbs free energy (DeltaG degrees ), entropy (DeltaS degrees ) and enthalpy (DeltaH degrees ) for adsorption indicated that the process was exothermic. PMID- 25498618 TI - Choline chloride/urea as an effective plasticizer for production of cellulose films. AB - Recently, choline chloride/urea (ChCl/urea), a typical deep eutectic solvent (DES), has been found to possess various applications in organic synthesis, electrochemistry, and nanomaterial preparation. Herein we reported the first attempt to plasticize regenerated cellulose film (RCF) using ChCl/urea as an effective plasticizer. Meanwhile, RCFs plasticized with glycerol and sorbitol were also prepared for comparison. The plasticized RCFs were investigated by Fourier transform infrared (FT-IR) spectroscopy, wide-angle X-ray diffraction (XRD), atomic force microscopy (AFM), and mechanical testing. Transparent and soft RCFs could be successfully prepared in the presence of ChCl/urea, and high elongation at break (34.88%) suggested a significant plasticizing efficiency. No new crystal and phase separation occurred to ChCl/urea plasticized RCFs. The thermal stability of ChCl/urea plasticized RCF was lowered. These results indicated that ChCl/urea was an effective plasticizer for producing cellulose films. PMID- 25498619 TI - Development of alginate microspheres as nystatin carriers for oral mucosa drug delivery. AB - To develop more effective antifungal mucoadhesive systems for the treatment of oral candidiasis, three types of microspheres, alginate (AM1), chitosan coated (CCM) and hydrogel (AM2) containing nystatin (Nys) were successfully elaborated by emulsification/internal gelation method. Physicochemical properties of microspheres resulted in 85-135 MUm mean sizes, spherical shaped with narrow distribution. Optimal encapsulation efficiency and negative zeta potentials were observed. AM2 showed a consistent decrease in viscosity with increasing shear rate (Herschel-Bulkley). Optimal mucoadhesive properties and swelling behaviour where evidenced. Nys release from AM1 and CCM followed a concentration gradient pattern, contrary AM2 followed a complex release mechanism. All systems exhibited a marked fungicidal activity against Candida albicans strains. In vivo studies demonstrated that Nys was not found in systemic circulation assuring the safety of the treatment. Nys amounts retained in the mucosa were more than enough to ensure an effective fungicidal action without tissue damage. Based on the obtained results, AM2 could be proposed as the vehicle with the best properties for the buccal vehiculization of Nys. PMID- 25498620 TI - Electron beam irradiation of maltodextrin and cinnamyl alcohol mixtures: influence of glycerol on cross-linking. AB - The influence of glycerol on the electron beam-induced changes in maltodextrins cinnamyl alcohol (CA) blends is examined with respect to its influence on the degree of chain scission, grafting, and cross-linking. The study is relevant to radiation-induced polysaccharide modification, specifically in the perspective of using blended starch as a thermoplastic material, where glycerol is commonly used as a plasticizer. In the absence of CA, glycerol protects maltodextrin from chromophore formation onto the main chain, but also induces more chain scission. The presence of CA provides efficient radiation-protection against scission. Glycerol is shown to affect the interaction between maltodextrin and CA, most likely in the form of an inclusion complex when glycerol is absent. The global behavior under radiation is therefore governed by the physical interactions between the blend constituents rather than on the role of glycerol role as a plasticizer, or as an OH radical scavenger. PMID- 25498621 TI - Silver nanowire-functionalized cotton fabric. AB - In this study, general functionalization of cotton fabric by loading silver nanowires (AgNWs) on cotton surface is reported. Initially, AgNWs were synthesized by a polyol process and then were conformal coated onto individual cotton fibers through a simple "dip and dry" process. SEM images revealed a thin and uniform AgNWs coating on the cotton microfibers which was supported by a surface chemical analysis by EDX. The average electrical surface resistivity of the fabric coated with conductive network of AgNWs was measured to be 27.4 Omega/sq. Incubating the modified fabric with either Escherichia coli or Staphylococcus aureus demonstrated that the fabric had substantial antimicrobial capacity against both Gram-positive and Gram-negative bacteria (100% microbial death). The fabric also showed excellent UV-blocking ability with the UV protection factor of 113.14. The fluorosilane coated AgNWs-loaded fabric displayed stable superhydrophobicity with CA and SHA values of 156.2 degrees +/ 3.2 degrees and 7 degrees , respectively. PMID- 25498622 TI - Characterization and antioxidant activity of beta-carotene loaded chitosan-graft poly(lactide) nanomicelles. AB - beta-Carotene (beta-C) is a well-established natural antioxidant agent, but its poor water-solubility, low chemical stability and low bioavailability limit its application in food, pharmaceuticals and cosmetics industries. Thus it is critical to develop an efficient method to improve the water solubility and stability of beta-C. In this research, amphiphilic chitosan-graft-poly (lactide) (CS-g-PLA) copolymer was synthesized via a homogeneous ring-opening polymerization (ROP) in ionic liquid. The obtained CS-g-PLA copolymer was able to self-assemble into about 14 nm micelles in water at low concentration, and beta-C loaded micelles (beta-C/M) had low beta-C degradation after 15 days. The antioxidant properties of the beta-C/M were investigated by the 2, 2-diphenyl-1 picrylhydrazyl (DPPH) method and ferric reducing antioxidant power (FRAP) method, respectively. Significantly improved antioxidant activity was observed for beta C/M in compare with free beta-C. The aqueous dispersion of beta-C/M has potential to be applied in the field of functional food and cosmetics. PMID- 25498623 TI - Plasticized chitosan/polyolefin films produced by extrusion. AB - Plasticized chitosan and polyethylene blends were produced through a single-pass extrusion process. Using a twin-screw extruder, chitosan plasticization was achieved in the presence of an acetic acid solution and glycerol, and directly mixed with metallocene polyethylene, mPE, to produce a masterbatch. Different dilutions of the masterbatch (2, 5 and 10 wt% of plasticized chitosan), in the presence of ethylene vinyl acetate, EVA, were subsequently achieved in single screw film extrusion. Very small plasticized chitosan domains (number average diameter <5 MUm) were visible in the polymeric matrix. The resulting films presented a brown color and increasing haze with chitosan plasticized content. Mechanical properties of the mPE films were affected by the presence of plasticized chitosan, but improvement was observed as a result of some compatibility between mPE and chitosan in the presence of EVA. Finally the incorporation of plasticized chitosan affected mPE water vapor permeability while oxygen permeability remained constant. PMID- 25498624 TI - Extraction optimization and biological properties of a polysaccharide isolated from Gleoestereum incarnatum. AB - Extraction was optimized of polysaccharides from Gleoestereum incarnatum (GIP). The three parameters, extraction temperature, extraction time and the ratio of water to raw material, were optimized using the Box-Behnken design. As a result, the optimal extraction conditions were: extraction temperature 87.5 degrees C, extraction time 1 h and the ratio of water to raw material of 39.7 mL/g, where the highest yield of polysaccharide (13.18%) was obtained. GIP-II was the main fraction purified form GIP. GIP-II was composed of galactose, glucose, xylose, and mannose, with glucose was the predominant monosaccharide. GIP-II exhibited strong scavenging activities against DPPH and hydroxyl radials in vitro, as well as a strong inhibitory effect on the growth of HepG2 cells. The overall findings indicated that GIP-II is worthy of further exploration for its potential applications in antitumor drugs or health foods. PMID- 25498625 TI - The interplay of alpha-amylase and amyloglucosidase activities on the digestion of starch in in vitro enzymic systems. AB - In vitro hydrolysis assays are a key tool in understanding differences in rate and extent of digestion of starchy foods. They offer a greater degree of simplicity and flexibility than dynamic in vitro models or in vivo experiments for quantifiable, mechanistic exploration of starch digestion. In the present work the influence of alpha-amylase and amyloglucosidase activities on the digestion of maize and potato starch granules was measured using both glucose and reducing sugar assays. Data were analysed through initial rates of digestion, and by 1st order kinetics, utilising logarithm of slope (LOS) plots. The rate and extent of starch digestion was dependent on the activities of both enzymes and the type of starch used. Potato required more enzyme than maize to achieve logarithmic reaction curves, and complete digestion. The results allow targeted design of starch digestion experiments through a thorough understanding of the contributions of alpha-amylase and amyloglucosidase to digestion rates. PMID- 25498626 TI - Synthesis and characterization of amphiphilic photocleavable polymers based on dextran and substituted-E-caprolactone. AB - In this study, we synthesized photocleavable amphiphilic block copolymers containing photodegradable linkers, 5-hydroxy-2-nitrobenzyl alcohol, as junction points between hydrophilic dextran (or maltodextrin) and hydrophobic poly(4 substituted-E-caprolactone) chains, by using a combination of ring-opening polymerization and nucleophilic substitution reactions. When the polymer solutions were exposed to ultraviolet (UV) irradiation, major structural and morphological changes were observed in the particles. The copolymers were biodegradable and biocompatible, and they can self-assemble into spherical photoresponsive micelles. Fluorescence emission measurements indicated the release of Nile red, a hydrophobic dye, encapsulated by the Dex-ONB-PXCL micelles, in response to irradiation caused by the disruption of the micelles. Light-triggered bursts were observed for indomethacin (IMC)-loaded Dex-ONB-PXCL micelles during the first 5 h. The nanoparticles were associated with nonsignificant toxicity at concentrations of less than 100 MUg mL(-1). The confocal microscopy and flow cytometry results showed that the uptake of DOX loaded micelles by HeLa cells was slightly less than that of free DOX, and it was predominantly retained in the cytoplasm. PMID- 25498627 TI - A low-toxic artificial fluorescent glycoprotein can serve as an efficient cytoplasmic labeling in living cell. AB - To maintain the virtue of good optical property and discard the dross of conventional fluorescent staining dyes, we provide a strategy for designing new fluorescent scaffolds. In this study, a novel fluorescent labeling glycoprotein (chitosan-poly-L-cysteine, CPC) was synthesized through graft copolymerization. CPC gives emission peak at 465-470 nm when excited at 386 nm. The submicro-scale CPC microspheres could be localized and persisted specifically in the cytoplasm of living cells, with strong blue fluorescence. Moreover, CPC was highly resistant to photo bleaching, the fluorescence was remained stable for up to 72 h as the cells grew and developed. The glycoprotein CPC was bio-compatible and in zero grade cytotoxicity as quantified by MTT assay. The fluorescent labeling process with our newly designed glycoprotein CPC is exceptionally efficient. PMID- 25498628 TI - Optimization on conditions of Lycium barbarum polysaccharides liposome by RSM and its effects on the peritoneal macrophages function. AB - The purpose of this study was to optimize the preparation conditions of Lycium barbarum polysaccharides liposome (LBPL) by response surface methodology (RSM) and to investigate the effect of LBPL activating function of peritoneal macrophages. LBPL was prepared using the reverse-phase evaporation method. The optimal preparation conditions of LBPL by RSM were as follows: the ratio of lipid to drug (w/w) of 25:1, the ultrasound time of 14 min and the ratio of soybean phospholipids to cholesterol (w/w) of 2.4:1. Under these conditions, the experimental encapsulation efficiency of LBPL was 86.37+/-0.63%, which was close to the predicted value. These indicated that LBPL with high entrapping efficiency and small particle size could be prepared by the reverse-phase evaporation method, which is applied easily. Furthermore, macrophages are the key players in the innate immune system. LBPL could effectively enhance peritoneal macrophages phagocytosis and resulted in inducing NO (nitric oxide) production in mouse peritoneal macrophages. PMID- 25498629 TI - Synthesis, characterisation and microbial utilisation of amorphous polysugars from lactose. AB - The melt polymerisations of glucose, galactose, xylose and fucose with citric acid, and mixtures of sugars therein are reported. Characterisation of the citric acid catalysed reaction products indicated similar degrees of branched polymerisation but differences in the overall molecular weight of the polymers produced. The dairy by-product lactose could not be polymerised in a similar fashion but was shown to be readily hydrolysed using microwave radiation and a polymer generated from the melt condensation of the resultant glucose and galactose monosaccharides. A preliminary assessment of the bifido-bacterial utilisation of the lactose-derived polymerised products demonstrated a significantly different growth profile compared to commercially utilised galactooligosaccharides (GOS). PMID- 25498630 TI - Flexible conductive polypyrrole nanocomposite membranes based on bacterial cellulose with amphiphobicity. AB - Flexible conductive polypyrrole nanocomposite membranes based on bacterial cellulose (BC) with amphiphobicity have been successfully prepared through in situ chemical synthesis and then infiltrated with polysiloxane solution. The results suggested that polypyrrole (PPy) nanoparticles deposited on the surface of BC formed a continuous core-shell structure by taking along the BC template. After modification with polysiloxane, the surface characteristics of the conductive BC membranes changed from highly hydrophilic to hydrophobic. The AFM images revealed that the roughness of samples after polysiloxane treatment increased along with the increase of pyrrole concentration. The contact angles (CAs) data revealed that the highest water contact angle and highest oil contact angle are 160.3 degrees and 136.7 degrees , respectively. The conductivity of the amphiphobic membranes with excellent flexibility reached 0.32 S/cm and demonstrated a good electromagnetic shielding effectiveness with an SE of 15 dB which could be applied in electromagnetic shielding materials with self-cleaning properties. It opened a new field of potential applications of BC materials. PMID- 25498631 TI - Simulation of the effect of hydrogen bonds on water activity of glucose and dextran using the Veytsman model. AB - Carbohydrates exhibit either van der Waals and ionic interactions or strong hydrogen bonding interactions. The prominence and large number of hydrogen bonds results in major contributions to phase behavior. A thermodynamic framework that accounts for hydrogen bonding interactions is therefore necessary. We have developed an extension of the thermodynamic model based on the Veytsman association theory to predict the contribution of hydrogen bonds to the behavior of glucose-water and dextran-water systems and we have calculated the free energy of mixing and its derivative leading to chemical potential and water activity. We compared our calculations with experimental data of water activity for glucose and dextran and found excellent agreement far superior to the Flory-Huggins theory. The validation of our calculations using experimental data demonstrated the validity of the Veytsman model in properly accounting for the hydrogen bonding interactions and successfully predicting water activity of glucose and dextran. Our calculations of the concentration of hydrogen bonds using the Veytsman model were instrumental in our ability to explain the difference between glucose and dextran and the role that hydrogen bonds play in contributing to these differences. The miscibility predictions showed that the Veytsman model is also able to correctly describe the phase behavior of glucose and dextran. PMID- 25498632 TI - Synthesis and characterization of multi-active site grafting starch copolymer initiated by KMnO4 and HIO4/H2SO4 systems. AB - A novel initiator system containing KMO4, HIO4, and H2SO4 for synthesizing grafting starch copolymers is reported. In this system, KMnO4 was used to oxidize the primary hydroxyl group to aldehyde group of glucose in the starch, and the formed aldehyde group reacted with Mn(4+), Mn(3+) to afford starch free radical. At the same time HIO4 perform as the oxidant to open the C2C3 bond of glucose ring in starch to form two more aldehyde groups, and then two more free radicals are generated. As a result one glucose unit could provide ultimately three active sites for starch grafting reaction. Graft copolymers with a higher grafting ratio and grafting efficiency could be obtained by using the composite initiation system than the KMnO4/H2SO4 initiation system. The grafting of polyacrylamide onto the corn starch backbone was confirmed by viscometry, elemental analysis, infrared spectroscopy, nuclear magnetic resonance, X-ray diffraction and scanning electron microscopy. PMID- 25498633 TI - Bifidogenic characteristic and protective effect of saba starch on survival of Lactobacillus plantarum CIF17AN2 during vacuum-drying and storage. AB - Resistant starch (RS) from unripe saba banana (Musa sapientum (Linn)) (Kluai Hin) exhibited high resistance to gastric acid and intestinal amylases. Its bifidogenic effect under competition of human fecal microflora was determined in the simulated proximal region of human colon. In addition, saba RS effectively protected Lactobacillus plantarum CIF17AN2 during drying process. The maximum survival of 85.81% was achieved under vacuum drying operated at 37 degrees C when saba RS was added. The addition of saba RS to formulate a synbiotic product was able to retain high viability of the vacuum-dried L. plantarum during 8-week storage at ambient temperature. This is because saba RS can stabilize the moisture content of the synbiotic product. In contrast, the dramatic increase of moisture content in the vacuum-dried L. plantarum without saba RS led to significant decrease in cell survival. Moreover, saba RS could potentially protect the vacuum-dried L. plantarum from gastric acid and bile exposures. PMID- 25498634 TI - Establishing whether the structural feature controlling the mechanical properties of starch films is molecular or crystalline. AB - The effects of molecular and crystalline structures on the tensile mechanical properties of thermoplastic starch (TPS) films from waxy, normal, and high amylose maize were investigated. Starch structural variations were obtained through extrusion and hydrothermal treatment (HTT). The molecular and crystalline structures were characterized using size-exclusion chromatography and X-ray diffractometry, respectively. TPS from high-amylose maize showed higher elongation at break and tensile strength than those from normal maize and waxy maize starches when processed with 40% plasticizer. Within the same amylose content, the mechanical properties were not affected by amylopectin molecular size or the crystallinity of TPS prior to HTT. This lack of correlation between the molecular size, crystallinity and mechanical properties may be due to the dominant effect of the plasticizer on the mechanical properties. Further crystallization of normal maize TPS by HTT increased the tensile strength and Young's modulus, while decreasing the elongation at break. The results suggest that the crystallinity from the remaining ungelatinized starch granules has less significant effect on the mechanical properties than that resulting from starch recrystallization, possibly due to a stronger network from leached-out amylose surrounding the remaining starch granules. PMID- 25498635 TI - Cationic starch (Q-TAC) pre-treatment of cotton fabric: influence on dyeing with reactive dye. AB - Reactive dyes require high concentrations of an electrolyte to improve dye-fiber interaction, leading to the discharge of harmful effluent. One approach to reduce this unsafe release is treatment of the cotton fabric with cationic chemical reagents. This paper reports on the treatment of cotton fabric with cationic starch (Q-TAC), a commercial product, by batchwise method and pad batch method for the first time prior to reactive dyeing process. Furthermore,three commercial reactive dyes, based on monochloro triazine, vinyl sulfone and monochlorotriazine + vinyl sulfonechemistry, was applied on the cotton fabrics by continuous (pad dry-cure) method. The treated cotton fabric by batchwise method produced 70% higher color yield (K/S) and 20% enhanced dye fixation (%F) than the untreated cotton fabric. X-ray photoelectron spectrometer (XPS) analysis revealed the presence of N1s peaks in the treated cotton fabrics. The crystallinity of treated cotton fabrics was reduced in comparison to untreated cotton fabric as revealed by wide angle X-ray diffraction (WAXD) measurements. Field Emission Scanning Electron Microscopy (FE-SEM) showed that the surface of treated cotton fabrics was rougher than untreated cotton fabric due to the deposition of cationic starch. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectrum confirmed the existence of quaternary ammonium groups, N(+)(CH3)3, in the treated cotton fabrics. The analysis of color fastness tests demonstrated good to excellent ratings for treated cotton fabrics. In this way, cationic starch treatment of cotton fabric before reactive dyeing process has been proven potentially a more environmentally sustainable method than conventional dyeing method. PMID- 25498636 TI - Physical characterisation of high amylose maize starch and acylated high amylose maize starches. AB - The particle size, water sorption properties and molecular mobility of high amylose maize starch (HAMS) and high amylose maize starch acylated with acetate (HAMSA), propionate (HAMSP) and butyrate (HAMSB) were investigated. Acylation increased the mean particle size (D(4,3)) and lowered the specific gravity (G) of the starch granules with an inverse relationship between the length of the fatty acid chain and particle size. Acylation of HAMS with fatty acids lowered the monolayer moisture content with the trend being HAMSBTCN>ACN with corresponding order of decreased Mw but increased crystallinity. The CNs' diameters were on the nanometre scale, with lengths of ECN>TCN>ACN. For CN-films, TCN and ACN fibrils were stretched and parallel to each other due to surface charges. For CN-GM films, both components interacted strongly with each other, resulting in changes of crystallinity, specific surface area, fibril diameter and contact angle compared with CN films. The composite films had good thermal, optical and mechanical properties; the last ones are apparently better than similar films reported in the literature. This is the first systematic study of different tunicate CN-GM nanocomposite films and the first ever for spruce GM. PMID- 25498638 TI - Phase separation behavior of egg yolk suspensions after anionic polysaccharides addition. AB - The objectives of this study were to understand the interactions between three anionic polysaccharides (gum arabic, xanthan gum and iota-carrageenan) and egg yolk at pH 3, 5, 6, 8, 10 and possible phase separation behavior. Zeta potential of egg yolk was not affected by gum arabic addition while it became more negative at pH 5 after xanthan gum and iota-carrageenan addition. The particle size of iota-carrageenan yolk suspension was considerably higher than the other polysaccharide yolk suspensions at pH below 6 but was dramatically decreased at alkaline pH. Most polysaccharide yolk suspensions formed either a biphasic or a monophasic system, whereas three distinct phases were observed for xanthan gum yolk suspension at pH 6. Protein profile analysis of the lipid-rich cream phase obtained from xanthan gum added yolk showed similarities to apoproteins from low density lipoproteins (LDL) of egg yolk. Microscopy analysis indicated the co presence of xanthan gum and LDL in the creamy phase, within a network formed by xanthan gum. It was suggested that electrostatic and hydrophobic interactions between the egg yolk and xanthan gum as well as xanthan gum's rheological properties could be responsible for the unique phase separation observed in the study. The findings of this study can form the basis for future studies to develop a new method to separate LDL from egg yolk. PMID- 25498639 TI - Hyperbranched phosphoramidate-hyaluronan hybrid: a reduction-sensitive injectable hydrogel for controlled protein release. AB - In the study, an injectable hybrid hydrogel (HPPAE-HA) was fabricated by in situ polymerization between acrylated hyperbranched polyphosphoramidate (HPPAE-AC) and thiolated hyaluronan (HA-SH) via Michael-addition reaction. Gelation times ranged from 4 to 360 min, depending on the stoichiometric ratio of HA-SH to HPPAE-AC, HA concentration and solution pH. In addition, due to the readily oxidation of thiol groups, the HPPAE-HA hydrogel bears disulfide bond. The DTT triggered disulfide bond cleavage and the subsequent cross-linking between thiol and abundant acryloyl groups presented in HPPAE-HA hydrogel contribute to the controlled release of bovine serum albumin (BSA) from the hydrogels. The burst release of BSA from HPPAE-HA hydrogel decreased from 23.7 to 4.0% during the first 3 h, and the 80% cumulative release of BSA was retarded for 12 h to nearly 96 h in 10 mM DTT. The facile synthesis of Michael-additional, disulfide containing HPPAE-HA hydrogel may enable further development of hydrogel matrices potentially suitable for tissue engineering and drug delivery applications. PMID- 25498640 TI - Self-assembly and chiroptical property of poly(N-acryloyl-L-amino acid) grafted celluloses synthesized by RAFT polymerization. AB - Three amphiphilic poly(N-acryloyl-L-amino acid) grafted celluloses were prepared by RAFT polymerization of N-acryloyl-L-amino acid, where amino acid is alanine, proline or glutamic acid, onto cellulose backbones. The chemical structure and solution properties of the brush copolymers were characterized with FTIR, NMR and wide angle X-ray diffraction (WAXD). The thermal stability of the brush copolymers was estimated by thermal gravimetric analysis (TGA). Circular dichroism (CD) and specific rotation measurements confirmed that these grafted celluloses had characteristic chiroptical properties. The amphiphilic brush copolymers self-assembled into micelles in the aqueous solution as confirmed by transmission electron microscopy (TEM) and dynamic light scattering (DLS) analyses. The micellar aggregates showed a tunable pH-responsive property and disaggregated to form unimolecular micelles at higher pH in diluted solutions. The brush copolymers have potential applications in controlled drug release and high-performance liquid chromatography, and so forth. PMID- 25498641 TI - Iron oxide/cassava starch-supported Ziegler-Natta catalysts for in situ ethylene polymerization. AB - Iron oxide nanoparticles were used as supporters for in situ polymerization to produce polymer nanocomposites with well-dispersed fillers in polymer matrix. Iron oxide could be sustained as colloidal solutions by cassava starch to produce a good dispersion of iron oxide in the matrix. New supports based on iron oxide/cassava starch or cassava starch for Ziegler-Natta catalysts were utilized as heterogeneous supporters for partially hydrolyzed triethylaluminum. Then, TiCl4 was immobilized on the supports as catalysts for polymerization of ethylene. High-density polyethylene (HDPE) composites were obtained by the synthesized catalysts. A good dispersion of iron oxide/cassava starch particles was observed in the synthesized polymer matrix promoting to good mechanical properties of HDPE. PMID- 25498643 TI - Synthesis and characterization of PEPO grafted carboxymethyl guar and carboxymethyl tamarind as new thermo-associating polymers. AB - New thermo associating polymers were designed and synthesized by grafting amino terminated poly(ethylene oxide-co-propylene oxide) (PEPO) onto carboxymethyl guar (CMG) and carboxymethyl tamarind (CMT). The grafting was performed by coupling reaction between NH2 groups of PEPO and COOH groups of CMG and CMT using water soluble EDC/NHS as coupling agents. The grafting efficiency and the temperature of thermo-association, T(assoc) in the copolymer were studied by NMR spectroscopy. The graft copolymers, CMG-g-PEPO and CMT-g-PEPO exhibited interesting thermo-associating behavior which was evidenced by the detailed rheological and fluorescence measurements. The visco-elastic properties (storage modulus, G'; loss modulus, G") of the copolymer solutions were investigated using oscillatory shear experiments. The influence of salt and surfactant on the T(assoc) was also studied by rheology, where the phenomenon of "Salting out" and "Salting in" was observed for salt and surfactant, respectively, which can give an easy access to tunable properties of these copolymers. These thermo associating polymers with biodegradable nature of CMG and CMT can have potential applications as smart injectables in controlled release technology and as thickeners in cosmetics and pharmaceutical formulations. PMID- 25498642 TI - Preparation of novel curdlan nanoparticles for intracellular siRNA delivery. AB - RNA interference (RNAi) down-regulates gene expression post-transcriptionally, which is a therapeutically significant phenomenon that could potentially reduce the level of disease related proteins that are undruggable by conventional small molecular approaches. However, clinical application of small interference RNAs (siRNAs) requires design of potent siRNA sequences and development of safe and efficient delivery systems. To create a biocompatible siRNA delivery agent, we chemically modified natural polysaccharide curdlan in a regioselective manner to introduce amino group in the glucose units. The resulting 6-amino-curdlan (6AC) is water soluble and forms nanoparticles upon complexing with siRNAs. The novel curdlan-based nanoparticles efficiently delivered siRNAs to human cancer cells and mouse primary cells, and reduced 70-90% of target mRNA level. Moreover, 6AC nanoparticles delivered siRNA targeting eGFP to mouse embryonic stem (mES) cells stably expressing eGFP, and produced substantial reductions of GFP protein level. The novel curdlan-based nanoparticle is a promising vehicle for delivery of short RNAs to knock down endogenous mRNAs. PMID- 25498644 TI - The anti-DHAV activities of Astragalus polysaccharide and its sulfate compared with those of BSRPS and its sulfate. AB - This paper studied the anti-duck hepatitis A virus (DHAV) activities of Astragalus polysaccharide (APS) and its sulfate (sAPS) compared with those of Bush Sophora Root polysaccharide (BSRPS) and its sulfate (sBSRPS). The antiviral activities of APS and sAPS were measured by MTT and real-time PCR methods, in vitro. In vivo experiment, the mortality rate and the evaluation indexes of hepatic injury, peroxidative injury and immune level were measured. Just like the condition of BSRPS and sBSRPS, the anti-DHAV activities of sAPS were stronger than those of APS, both in vitro and in vivo. It indicated sulfated modification could enhance the antiviral ability of polysaccharide. But unlike the antiviral effects of BSPRS and sBSRPS in vivo, APS and sAPS did not reduce the mortality rates as their abilities of scavenging free radicals and alleviating the hepatic injuries were weaker than those of BSRPS and sBSRPS. And they even did not enhance the immune levels. PMID- 25498645 TI - Enhanced formability and mechanical performance of wood hydrolysate films through reductive amination chain extension. AB - An O-acetyl-4-O-methylglucuronoxylan-rich wood hydrolysate (WH), generated by the hydrothermal treatment of hardwood, was chain extended using di- and tri functionalized amino chain extenders through reductive amination. Chain extension was achieved via facile one- or two-step syntheses. The carbohydrate chain extension efficiency, molecular weights, and branching patterns were determined through a combination of SEC, 1HNMR, FTIR and elemental analysis. The mild reaction conditions enabled an increase in the molecular weight while preserving the initial structures of the hemicelluloses. The chain extension strategy developed in this study was demonstrated to significantly improve the formability and mechanical performance of WH films, allowing for the water-casting production of coherent films with higher ratios of WH-70-85% (w/w)-and reducing the need for co-components. Chain-extended WHs produced stronger and more ductile films than corresponding formulations prepared from unmodified WH. Films made from ethylenediamine chain-extended WH mixed with 30% (w/w) carboxymethyl cellulose showed a tensile strength of 62 MPa and a strain-to-failure of 3.3%. Additionally, chain-extended WHs produced films with an oxygen permeability as low as 0.2 cm(3) MUm m(-2) day(-1) kPa(-1) at 50% RH. PMID- 25498646 TI - Monitoring of cellulose depolymerization in 1-ethyl-3-methylimidazolium acetate by shear and elongational rheology. AB - The thermal stability of cellulose in the ionic liquid (IL) 1-ethyl-3 methylimidazolium acetate, [emim]OAc was investigated. For this purpose, Eucalyptus urugrandis prehydrolysis kraft pulp was first dissolved in [emim]OAc by means of a vertical kneader and then stored at three different temperatures to study the time-depended behavior of the cellulose-[emim]OAc system. Cellulose depolymerization was assessed by characterizing the precipitated cellulose and the rheological behavior of the cellulose-[emim]OAc solutions. The results show decreases in the weight average molecular mass and in the shear viscosity at temperatures exceeding 60 degrees C, which can be related to progressing degradation of cellulose in the IL upon storage at elevated temperature. The changes in behavior of the solutions under extensional stresses also attest the gradual depolymerization of cellulose. The degradation has been analyzed using appropriate kinetic models. Propyl gallate appeared to be an efficient stabilizer of the cellulose-[emim]OAc system during the dissolution step even though the mechanism has not been fully understood yet. PMID- 25498647 TI - An experimental design approach to the chemical characterisation of pectin polysaccharides extracted from Cucumis melo Inodorus. AB - Extracted pectins have been utilised in a number of applications in both the food and pharmaceutical industries where they are generally used as gelling agents, thickeners and stabilisers, although a number of pectins have been shown to be bioactive. These functional properties will depend upon extraction conditions. A statistical experimental design approach was used to study the effects of extraction conditions pH, time and temperature on pectins extracted from Cucumis melo Inodorus. The results show that the chemical composition is very sensitive to these conditions and that this has a great influence on for example the degree of branching. Higher temperatures, lower pHs and longer extraction times lead to a loss of the more acid labile arabinofuranose residues present on the pectin side chain. The fitting of regression equations relating yield and composition to extraction conditions can therefore lead to tailor-made pectins for specific properties and/or applications. PMID- 25498648 TI - Chemical structure of the arabinogalactan protein from gum ghatti and its interaction with bovine serum albumin. AB - Exudate gums, because of their beneficial properties, have been significant items of international trade in various industries for centuries. This manuscript sets out to gain insight into the fine structural details of an arabinogalactan protein (AGP) of gum ghatti (Anogeissus latifolia gum). The presence of a highly branched 554 kDa AGP having 1,6-linked Galp, 1,2-linked Manp, 1,3-linked Araf and 1,4-linked GlcpA main chain, substituted at O-4,6 of 1,2-linked Manp, and O-3/O 3,4 of 1,6-linked Galp residues by Araf, Arap and Galp units was revealed by chemical, chromatographic, ESMS, and NMR analyses. In particular, ESMS analysis of per acetylated oligomeric fragments derived from AGP by Smith degradation followed by acetylation was described as a commanding tool for providing critical structural information on a spectrum of glycerol tagged oligosaccharides. In addition, formation of an electrostatically driven complex between the isolated AGP and bovine serum albumin resulting in changes in the microenvironment around the tryptophan residues of BSA was established. A moderate radical scavenging activity comparable with those of standard antioxidants was observed from the AGP fraction (~94% at 1 mg/mL) that could be valuable in foods or pharmaceutical products as alternatives to synthetic antioxidants. PMID- 25498649 TI - beta-Cyclodextrin and calix[4]arene-25,26,27,28-tetrol capped carbon dots for selective and sensitive detection of fluoride. AB - In this work we have designed a novel system based on carbon dots prepared from chitosan gel capped with beta-cyclodextrin and calix[4]arene-25,26,27,28-tetrol for sensitive and selective detection of fluoride ions in aqueous media. Fluorescent carbon dots prepared from chitosan gel when capped with beta cyclodextrin and calix[4]arene-25,26,27,28-tetrol results in quenching of its fluorescence intensity. Introduction of F(-) ions to carbon dots capped with beta cyclodextrin and calix[4]arene-25,26,27,28-tetrol system results in enhancement and restoration of fluorescence intensity leading to detection of F(-) ion. Minimum detection limit was determined to be ~6.6 MUM. The detection is selective as with other halide ions i.e. Cl(-), Br(-) and I(-) and hydroxyl ion (OH(-)), there is observed decrease of fluorescence intensity. A possible mechanism to justify the observation is also discussed in the paper. PMID- 25498650 TI - Ionic starch-based hydrogels for the prevention of nonspecific protein adsorption. AB - Non-fouling materials bind water molecules via either hydrogen bonding or ionic solvation to form a hydration layer which is responsible for their resistance to protein adsorption. Three ionic starch-based polymers, namely a cationic starch (C-Starch), an anionic starch (A-Starch) and a zwitterionic starch (Z-Starch), were synthesized via etherification reactions to incorporate both hydrogen bonding and ionic solvation hydration groups into one molecule. Further, C-, A- and Z-Starch hydrogels were prepared via chemical crosslinking. The non-fouling properties of these hydrogels were tested with different proteins in solutions with different ionic strengths. The C-Starch hydrogel had low protein resistance at all ionic strengths; the A-Starch hydrogel resisted protein adsorption at ionic strengths of more than 10mM; and the Z-Starch hydrogel resisted protein adsorption at all ionic strengths. In addition, the A- and Z-Starch hydrogels both resisted cell adhesion. This work provides a new path for developing non fouling materials using the integration of polysaccharides with anionic or zwitterionic moieties to regulate the protein resistance of materials. PMID- 25498651 TI - Characterization of new natural cellulosic fiber from Cissus quadrangularis stem. AB - Polymer composite has contributed tremendously for energy efficient technologies in automotive and aero industries. Environmental and health concerns related to the carcinogenic nature of artificial fiber in polymer composite needs a retrofit. Eco friendly natural cellulosic fiber extract from the stem of Cissus quadrangularis plant is extensively characterized to consider as a viable alternative for man-made hazardous fibers. Anatomical study, chemical analysis, physical analysis, FTIR, XRD, SEM analysis and thermo gravimetric analysis were done to establish the certainty of using them as reinforcement fiber. Its light weight and the presence of high cellulose content (82.73%) with very little wax (0.18%) provide high specific strength and good bonding properties in composite manufacturing. The flaky honeycomb outer surface revealed through electron microscopy contributes for high modulus in CQ stem fiber and thermo gravimetric analysis ensures thermal stability up to 270 degrees C, which is within the polymerization process temperature. PMID- 25498652 TI - Heparin derivatives for the targeting of multiple activities in the inflammatory response. AB - An attractive strategy for ameliorating symptoms arising from the multi-faceted processes of excessive and/or continual inflammation would be to identify compounds able to interfere with multiple effectors of inflammation. The well tolerated pharmaceutical, heparin, is capable of acting through several proteins in the inflammatory cascade, but its use is prevented by strong anticoagulant activity. Derivatives of heparin involving the periodate cleavage of 2,3 vicinal diols in non-sulfated uronate residues (glycol-split) and replacement of N sulphamido- with N-acetamido- groups in glucosamine residues, capable of inhibiting neutrophil elastase activity in vitro, while exhibiting attenuated anticoagulant properties, have been identified and characterised. These also interact with two other important modulators of the inflammatory response, IL-8 and TNF-alpha. It is therefore feasible in principle to modulate several activities, while minimising anticoagulant side effects, providing a platform from which improved anti-inflammatory agents might be developed. PMID- 25498653 TI - Facile fabrication of hierarchical cellulose nanospicules via hydrolytic hydrogenation. AB - A new spicule-like cellulose nanostructure is prepared from electrospun cellulose nanofibers using a one-pot bifunctional catalysis strategy namely hydrolytic hydrogenation. The electrospun cellulose nanofibers or cellulose film was treated in presence of catalyst consisting of an alkali and a metal to produce celluloses with structures like nanospicules, nanoflowers or nanorods, respectively. This work highlights the promising combination of electrospinning and hydrolysis/hydrogenation for facile production of hierarchical cellulose nanostructures such as nanospicules and nanorods. PMID- 25498654 TI - Fabrication of cellulose self-assemblies and high-strength ordered cellulose films. AB - Based on the formation of cellulose hydrogels in NaOH/urea aqueous solvent media, cellulose self-assembly precursor is acquired. It is proved that the water uptake capability of the cellulose hydrogels depends highly on the cross-link degree (CLD) of cellulose. With varying CLD and concentration of cellulose, a variety of morphologies of cellulose self-assemblies, including sheets with perfect morphology, high-aspect-ratio fibers, and disorganized segments and network, are formed through evaporation. Furthermore, cellulose films are fabricated by diecasting and evaporating the cellulose hydrogels, resulting in a 3D-ordered structure of closely stacking of cellulose sheets. The mechanical test indicates both tensile strength and flexibility of the cellulose films are greatly improved, which is attributed to the formation of the orderly stacking of cellulose sheets. The study is expected to lay an important foundation on the preparation of ordered and high-strength cellulose materials. PMID- 25498656 TI - Construction of selenium nanoparticles/beta-glucan composites for enhancement of the antitumor activity. AB - We report on a green procedure for the stabilization of selenium nanoparticles (SeNPs) by a naturally occurring beta-glucan with triple helical conformation known as Lentinan (t-LNT) in water after denaturing into single chains (s-LNT) at 140 degrees C. The results demonstrated that the s-LNT can interact with SeNPs through Se-O-H interaction. Transmission electron microscopy (TEM), energy dispersive X-ray (EDX) spectra, UV/vis, X-ray diffraction (XRD) and dynamic light scattering (DLS) showed that s-LNT coated SeNPs to form a stable nano-composite Se/s-LNT, leading to good dispersion of SeNPs. Especially, the as-prepared Se/s LNT composite in the solution could remain homogeneous and translucent for 30 days without any precipitates. Different size distribution of SeNPs was prepared by simply controlling the concentrations of selenite sodium and the corresponding reducing agent ascorbic acid. The size effect of SeNPs on anti-tumor activity was revealed that the SeNPs with more evenly particle size distribution show the higher anticancer activity. PMID- 25498655 TI - Study on Dendrobium officinale O-acetyl-glucomannan (Dendronan(r)): part II. Fine structures of O-acetylated residues. AB - Main objective of this study was to investigate the detailed structural information about O-acetylated sugar residues in Dendronan((r)). A water solution (2%, w/w) of Dendronan((r)) was treated with endo-beta-mannanase to produce oligosaccharides rich in O-acetylated sugar residues. The oligosaccharides were partly recovered by ethanol precipitation (70%, w/w). The recovered sample (designated Hydrolyzed Dendrobium officinale Polysaccharide, HDOP) had a yield of 24.7% based on the dry weight of Dendronan((r)) and was highly O-acetylated. A D2O solution of HDOP (6%, w/w) generated strong signals in (1)H, (13)C, 2D (1)H (1)H COSY, 2D (1)H-(1)H TOCSY, 2D (1)H-(1)H NOESY, 2D (1)H-(13)C HMQC, and 2D (1)H-(13)C HMBC NMR spectra. Results of NMR analyses showed that the majority of O-acetylated mannoses were mono-substituted with acetyl groups at O-2 or O-3 position. There were small amounts of mannose residues with di-O-acetyl substitution at both O-2 and O-3 positions. Minor levels of mannoses with 6-O acetyl, 2,6-di-O-acetyl, and 3,6-di-O-acetyl substitutions were also identified. Much information about sugar residue sequence was extracted from 2D (1)H-(13)C HMBC and 2D (1)H-(1)H NOESY spectra. (1)J(C-H) coupling constants of major sugar residues were obtained. Evidences for the existence of branches or O-acetylated glucoses in HDOP were not found. The major structure of Dendronan((r)) is shown as follows: [Formula: see text] M: beta-D-mannopyranose; G: beta-D-glucopyranose; a: O-acetyl group. PMID- 25498657 TI - Cellulose nanocrystals' production in near theoretical yields by 1-butyl-3 methylimidazolium hydrogen sulfate ([Bmim]HSO4)-mediated hydrolysis. AB - We report on near theoretical yield production of cellulose I nanocrystals (CNCs) using a two-step hydrolysis with the mildly acidic ionic liquid (IL) 1-butyl-3 methylimidazolium hydrogen sulfate ([Bmim]HSO4) in aqueous solution from common cellulosic sources. Two successive Taguchi experimental plans were performed to evaluate the impact of selected reaction parameters (T, t, H2O:IL ratio) and their interactions on the CNCs' yield from bleached softwood kraft pulp (SWP), bleached hardwood kraft pulp (HWP) and microcrystalline cellulose (MCC). With these experimental plans, the molar yield for extraction of nanocrystals was optimized to near theoretical levels, reaching 57.7+/-3.0%, 57.0+/-2.0%, and 75.6+/-3.0%, for SWP, HWP and MCC, respectively. The reaction yields corresponded to a relative crystalline region recovery of 84.1+/-5.3%, 71.7+/-1.3%, 76.0+/ 2.0% from SWP, HWP and MCC, respectively. The collected nanocrystals exhibited high aspect ratios (36-43), negligible sulfur content (0.02-0.21%) and high solvent dispersibility in comparison to those obtained with the traditional sulfuric acid method. Additionally these near theoretical yields were achieved for mild reaction conditions with the combined severity factor of 2 and 3 for MCC and pulp, respectively. Overall this two-stage IL-mediated preparation of nanocrystals combines the advantages of achieving high product quality, high reaction yields and mild conditions. PMID- 25498658 TI - Antioxidant activity of polysaccharides produced by Hirsutella sp. and relation with their chemical characteristics. AB - Extracellular polysaccharide (EPS) and intracellular polysaccharide (IPS) were produced in a mycelial liquid culture of the Hirsutella sp. liquid fermentation. The polysaccharides were precipitated with 50% ethanol (EPS-1, IPS-1), 65% ethanol (EPS-2, IPS-2) and 80% ethanol (EPS-3, IPS-3). The polysaccharide fragments precipitated in lower ethanol percentages had a lower neutral sugar content and a larger molecular weight. EPS-1, EPS-2, IPS-1 and IPS-2 were composed of glucose (Glu), galactose (Gal) and mannose (Man). Galactose was not detected in EPS-3 and IPS-3. Evaluated by the 1/IC50 values of hydroxyl radical scavenging activity, the polysaccharides with higher protein content, lower neutral sugar content and molecular weight about 10-20 kDa were found to have better radical scavenging activity. Significant correlations demonstrated that the antioxidant effect of the polysaccharides was influenced by monosaccharide composition (mannose, r=0.942; glucose, r=-0.905). PMID- 25498659 TI - Physicochemical assessment of dextran-g-poly (E-caprolactone) micellar nanoaggregates as drug nanocarriers. AB - Self-assembling polymers in aqueous solution have attracted significant attention with recent research efforts focused on the development of new strategies to design devices useful in the field of controlled drug delivery. In this context, amphiphilic copolymers having specific structural features and self-assembling behaviors in aqueous media that would enable controlled drug release over longer time periods. In this work, we report on the synthesis and characterization of a Poly (E-caprolactone)-grafted Dextran copolymer and its use in the preparation of micellar nanoaggregates. The characterization and study of the morphology, topography, size distribution and stability of micellar nanoaggregates by Transmission Electron Microscopy (TEM), Atomic Force Microscopy (AFM), Dynamic Light Scattering (DLS) and Zeta Potential (zeta), respectively, were carried out. Spherical-shaped morphologies and an average size of approximately 83 nm, for drug-free nanoaggregates, were observed. In addition, Zeta Potential studies showed that drug-free nanoaggregates are more stable than drug-loaded structures measured in a phosphate buffer (pH 7.2) medium. UV-vis spectrophotometry of both the drug entrapment efficiency (EE%) and in vitro drug release behavior were assessed. The EE% was determined to be 78% (w/w), and a combination of diffusion and eroding polymer matrix mechanisms for drug release were established. Finally, these results indicate that Dx-g-PCL micellar nanoaggregates are suitable for use as a potential nanocarrier having both biodegradable and biocompatible properties. PMID- 25498660 TI - Preparation, characterization, and antimicrobial activity of chitin nanofibrils reinforced carrageenan nanocomposite films. AB - Present study illustrates the preparation of chitin nanofibrils (CNF) reinforced carrageenan nanocomposite films by the solution-casting technique. CNF was prepared by acid hydrolysis of chitin, followed by high speed homogenization and sonication. FTIR result demonstrated that the chemical structure of chitin had not changed after acid hydrolysis. However, the crystalinity of CNF was found to be higher than chitin. The crystallite size of chitin and CNF was 4.73 and 6.27 nm, respectively. The char content at 600 degrees C of chitin (19.2%) was lower than the CNF (25%). The carrageenan/CNF composite films were smooth and flexible and the CNF was dispersed uniformly in the carrageenan polymer matrix. The tensile strength and modulus of carrageenan film were increased significantly (p<0.05) after CNF reinforcement with up to 5 wt%, however, elongation at break, water vapor permeability, and transparency decreased slightly. Carrageenan/CNF nanocomposite films showed strong antibacterial activity against a Gram-positive food-borne pathogen, Listeria monocytogenes. PMID- 25498661 TI - Sulfated heterorhamnans from the green seaweed Gayralia oxysperma: partial depolymerization, chemical structure and antitumor activity. AB - Sulfated heterorhamnans produced by Gayralia oxysperma were utilized for the preparation of two homogeneous and highly sulfated Smith-degraded products (M(w) of 109 and 251 kDa), which were constituted principally by 3-linked alpha-L rhamnosyl units 2- or 4-sulfate and 2-linked alpha-L-rhamnosyl units 4- or 3,4 sulfate, in different percentages. The homogeneous products and the crude extracts containing the sulfated heterorhamnans showed cytotoxic effect against U87MG cells. These sulfated polysaccharides induced an increase in the number of cells in G1 phase with concomitant increase of the mRNA levels of p53 and p21. The presence of 2-linked disulfated rhamnose residues together with the molecular weight could be important factors to be correlated with the inhibitory effect on human glioblastoma cells. PMID- 25498662 TI - Physicochemical properties of corn stalk after treatment using steam explosion coupled with acid or alkali. AB - The aim of this study was to evaluate comparatively the effects of different pretreatments including steam explosion, acid, and alkali, alone or in combination, on the structural properties and thermal stability of corn stalk. All of the treated treatments decreased the contents of hemicellulose and lignin and thereby increased the content of cellulose in corn stalks. But the combined treatments with alkali and steam explosion under 0.4-0.6 MPa were better as compared with other treatments based on the removals of hemicellulose and lignin, and about 71.58-79.59% of hemicellulose and 64.32-71.83% of lignin were removed. Treatment with steam explosion coupled with acid or alkali changed the bonding distribution and surface morphology and increased the crystallinity and thermal stability of corn stalks, and the degradation temperature reached over 350 degrees C. These results suggest that steam explosion coupled with alkali is a better method for the depolymerization of corn stalk polymer. PMID- 25498663 TI - Carboxymethylation of Cassia angustifolia seed gum: synthesis and rheological study. AB - The seeds of Cassia angustifolia are a rich source of galactomannan gum. The seed gums possess a wide variety of industrial applications. To utilize C. angustifolia seed gum for broader industrial applications, the carboxymethyl Cassia angustifolia seed gum (CM-CAG) was synthesized. The gum was etherified with sodium monochloroacetate (SMCA) in a methanol-water system in presence of alkali (NaOH) at different reaction conditions. The variables studied includes alkali concentration, SMCA concentration, methanol:water ratio, liquor:gum ratio, reaction temperature and time. The extent of carboxymethylation was determined as degree of substitution (DS). The optimum conditions for preparing CM-CAG (DS=0.474) comprised 0.100 mol of NaOH, 0.05 mol of SMCA, 80% of methanol:water ratio (as % methanol) and liquor:gum ratio (v/w) of 10:1 at 75 degrees C for 60 min using 0.03 mol (as AGU) of CAG. Rheological studies showed CM-CAG to exhibit non-Newtonian pseudoplastic behaviour, relatively high viscosity, cold water solubility and solution stability. PMID- 25498664 TI - Physicochemical characterization of exopolysaccharides produced by Lactobacillus rhamnosus on various carbon sources. AB - The impact of five carbohydrate sources (glucose, maltose, galactose, sucrose, and lactose) on the chemical composition, structure, morphology, and physicochemical properties, as well as, viscosity of exopolysaccharides (EPSs) produced by Lactobacillus rhamnosus E/N was investigated. GLC-MS analysis and 2DNMR spectroscopy showed that the EPSs had the same primary structure independently of the carbon source used in the growth medium. The following EPS composition was elucidated: four rhamnose, two glucose, and one galactose residue with a pyruvate substituent. Molecular masses (M(w)) were determined by gel permeation chromatography, which revealed differences in M(w) distribution. EPS Gal, EPS-Suc, and EPS-Lac showed heterogenic fractions of a high and low molecular weight, while EPS-Mal and EPS-Glc contained only a high-molecular weight fraction. AFM microscopy revealed morphological differences in chain length, thickness, and branching. Differences in the Mw ratio and thickness of the polymer chain were correlated with high viscosity of EPS solutions. Our results indicate that a single bacterial strain, depending on the carbon source in the medium, can produce EPSs of different rheological properties. PMID- 25498665 TI - Development of liposomal Ganoderma lucidum polysaccharide: formulation optimization and evaluation of its immunological activity. AB - The aim of this study was to investigate the optimizing preparation conditions of Ganoderma lucidum polysaccharide liposome (GLPL) with response surface methodology (RSM) and the immunological enhancement activity of GLPL. The immunological enhancement activity of GLPL on splenocyte proliferation was measured. The optimum formulation of GLPL, in which the ratio of soybean phospholipid to cholesterol(w/w) of 11:1, the ratio of soybean phospholipid to tween-80 (w/w) of 10.5:1 and ultrasonic time(min) of 11, had higher entrapment efficiency (EE) of 71.43+/-0.49% with spherical shape and uniform sizes. In addition, GLPL could significantly promote splenocyte proliferation singly or synergistically with PHA and LPS. That indicated that the immunological enhancement of Ganoderma lucidum polysaccharide (GLP) was significantly enhanced after encapsulation with the liposome. PMID- 25498666 TI - Production of bacterial cellulose using different carbon sources and culture media. AB - In this work, the effects of carbon sources and culture media on the production and structural properties of bacterial cellulose (BC) have been studied. BC nanofibers were synthesized using Gluconacetobacter xylinus strain PTCC 1734. Media used were Hestrin-Schramm (H), Yamanaka (Y), and Zhou (Z). Five different carbon sources, namely date syrup, glucose, mannitol, sucrose, and food-grade sucrose were used in these media. All the produced BC pellicles were characterized in terms of dry weight production, biomass yield, thermal stability, crystallinity and morphology by thermogravimetric analysis (TGA), x ray diffraction (XRD), and field emission scanning electron microscopy (FE-SEM). The obtained results showed that mannitol lead to the highest yield, followed by sucrose. The highest production efficiency of mannitol might be due to the nitrogen source, which plays an important role. The maximum improvement on the thermal stability of the composites was achieved when mannitol was used in H medium. In addition, the crystallinity was higher in BC formed in H medium compared to other media. FE-SEM micrographs illustrated that the BC pellicles, synthesized in the culture media H and Z, were stable, unlike those in medium Y that were unstable. The micrographs of BC produced in media containing mannitol and sucrose provided evidence of the strong interfacial adhesion between the BC fibers without noticeable aggregates. PMID- 25498667 TI - Glycerophosphate-based chitosan thermosensitive hydrogels and their biomedical applications. AB - Chitosan is non-toxic, biocompatible and biodegradable polysaccharide composed of glucosamine and derived by deacetylation of chitin. Chitosan thermosensitive hydrogel has been developed to form a gel in situ, precluding the need for surgical implantation. In this review, the recent advances in chitosan thermosensitive hydrogels based on different glycerophosphate are summarized. The hydrogel is prepared with chitosan and beta-glycerophosphate or alphabeta glycerophosphate which is liquid at room temperature and transits into gel as temperature increases. The gelation mechanism may involve multiple interactions between chitosan, glycerophosphate, and water. The solution behavior, rheological and physicochemical properties, and gelation process of the hydrogel are affected not only by the molecule weight, deacetylation degree, and concentration of chitosan, but also by the kind and concentration of glycerophosphate. The properties and the three-dimensional networks of the hydrogel offer them wide applications in biomedical field including local drug delivery and tissue engineering. PMID- 25498668 TI - Carboxymethylagarose-AuNPs generated through green route for selective detection of Hg2+ in aqueous medium with a blue shift. AB - We report here a facile, rapid, cost-effective method via a green route for the selective detection of Hg(2+) in aqueous media. In this study carboxymethylagarose (CMA) is used to generate gold nanoparticles and subsequently to act as a stabilizer for the CMA-functionalized gold nanoparticles (CMA-AuNPs). The resulting CMA-AuNPs was characterized by UV-visible, X-ray diffraction, transmission electron microscopy (TEM), dynamic light scattering (DLS), atomic force microscopy (AFM) and zeta potential measurements. Zeta potential value (~ -73 mv) of CMA-AuNPs in the aqueous medium shows its higher stability. When CMA-AuNPs were exposed to an aqueous Hg(2+), a blue shift for its localized surface plasmon resonance absorbance (LSPR) band is observed along with significant colour change of the solution. The probe enables to detect Hg(2+) in the range of 0.01-100 ppm even in spiked lake water samples. This study offers a sustainable and eco-friendly route for selective detection of Hg(2+) in aqueous solution and may find potential application towards water purification. PMID- 25498669 TI - Characterization of an adhesive molecule from Bacillus megaterium ADE-0-1. AB - An adhesive exopolysaccharide (EPS), from a biofilm forming marine strain ADE-0 1, identified as Bacillus megaterium using conventional microbiological test and 16S rDNA analysis, contained 75% carbohydrate, 17% uronic acid and 0.00125% pyruvate on dry weight basis as per colorimetric determinations and found anionic in nature by ion exchange chromatography. Paper chromatographic and HPLC analysis of EPS hydrolysate indicated presence of arabinose, glucose, mannose, galacturonic acid and glucuronic acid. Its molecular weight was 0.5*10(6) Da, by gel permeation chromatography. FT-IR spectroscopic analysis of EPS revealed presence of hydroxyl and carboxyl groups particularly. EPS exhibited an adhesive nature and could glue wood, metals and acrylic plastic. Using this EPS adhesive (10% w/v), maximum lap shear strength observed was 6.12 MPa at pH 7 and 50 degrees C (curing temperature) for wood to wood specimen as compared to 6.54 MPa obtained with fevicol (48 to 50% w/v). PMID- 25498670 TI - Amorphous nanodrugs prepared by complexation with polysaccharides: carrageenan versus dextran sulfate. AB - Amorphous nanodrugs prepared by electrostatic complexation of drug molecules with oppositely charged polysaccharides represent a promising bioavailability enhancement strategy for poorly-soluble drugs owed to their high supersaturation generation capability and simple preparation. Using ciprofloxacin (CIP) as the model drug, we investigated the effects of using dextran sulfate (DXT) or carrageenan (CGN) on the (1) preparation efficiency, (2) physical characteristics, (3) supersaturation generation, (4) antimicrobial activity, and (5) cytotoxicity of the amorphous drug-polysaccharide nanoparticle complex (nanoplex) produced. Owing to the higher charge density and chain flexibility of DXT, coupled with the greater hydrophobicity of CGN, the CIP-DXT nanoplex exhibited superior preparation efficiency and larger size than the CIP-CGN nanoplex. Whereas the low solubility and high gelation tendency of CGN resulted in superior supersaturation generation capability for the CIP-DXT nanoplex. The non-cytotoxicity, antimicrobial activity, colloidal, and amorphous state stability were established for both nanoplexes, making them an ideal supersaturated drug delivery system. PMID- 25498671 TI - Hydrothermal effect and mechanical stress properties of carboxymethylcellulose based hydrogel food packaging. AB - The PVP-CMC hydrogel film is biodegradable, transparent, flexible, hygroscopic and breathable material which can be used as a food packaging material. The hygroscopic character of CMC and PVP plays a big role in the changing of their mechanical properties where load carrying capacity is one of important criteria for packaging materials. This paper reports about the hydrothermal effect on the mechanical and viscoelastic properties of neat CMC, and PVP-CMC (20:80) hydrogel films under the conditions of combined multiple stress factors such as temperature, time, load, frequency and humidity. The dry films were studied by transient and dynamic oscillatory experiments using dynamic mechanical analyser combined with relative humidity chamber (DMA-RH). The mechanical properties of PVP-CMC hydrogel film at room temperature (25 degrees C), in the range of 0 30%RH remain steady. The 20 wt% of PVP in PVP-CMC hydrogel increases the stiffness of CMC from 2940 to 3260 MPa at 25 degrees C and 10%RH. PMID- 25498672 TI - Selective and recyclable depolymerization of cellulose to levulinic acid catalyzed by acidic ionic liquid. AB - Cellulose depolymerization to levulinic acid (LA) was catalyzed by acidic ionic liquids (ILs) selectively and recyclably under hydrothermal conditions. The effects of reaction temperature, time, water amount and cellulose intake were investigated. Dilution effect becomes more pronounced at lower cellulose intake, dramatically improving the yield of LA to 86.1%. A kinetic model has been developed based on experimental data, whereby a good fit was obtained and kinetic parameters were derived. The relationships between IL structure, polymeric structure and depolymerization efficiency were established, shedding light on the in-depth catalytic mechanism of IL, inclusive of acidity and hydrogen bonding ability. The LA product can be readily separated through extraction by methyl isobutyl ketone (MIBK) and IL can be reused over five cycles without loss of activity. This environmentally friendly methodology can be applied to selective production of LA from versatile biomass feedstocks, including cellulose and derivatives, glucose, fructose and HMF. PMID- 25498674 TI - The hygroscopic power of amorphous cellulose: a modeling study. AB - The relationship between cellulose and water was studied by building dense amorphous cellulose models and subjecting them to increasing moisture contents. When starting from completely dry cellulose, the first diffused water molecules were essentially individualized and hydrogen bonded exclusively to the O6 and O2 hydroxyl groups of cellulose. Upon continued hydration increase, the hydroxyl at O3 and then the acetal oxygens of cellulose also started to attract the upcoming water molecules, which were no longer isolated. They progressively became aggregated, first into clusters and then at high hydration content, into continuous capillary channels. A benefit of this study was to allow predicting a number of physical parameters of amorphous cellulose and their variation under hydration. With some parameters, the calculated values matched rather well the experimental literature determinations. This was the case for the hydration dependence of Tg, the stereoselectivity of the cellulose oxygen atoms for water molecules, together with the diffusion coefficients of water into cellulose. An estimate of the hygro-expansion of amorphous cellulose was provided. PMID- 25498673 TI - Thiolated nanocarriers for oral delivery of hydrophilic macromolecular drugs. AB - It was the aim of this study to investigate the effect of unmodified as well as thiolated anionic poly(acrylic acid) (PAA) and cationic chitosan (CS) utilized in free-soluble form and as nanoparticulate system on the absorption of the hydrophilic compound FD4 across intestinal epithelial cell layer with and without a mucus layer. Modifications of these polymers were achieved by conjugation with cysteine to PAA (PAA-Cys) and thioglycolic acid to CS (CS-TGA). Particles were prepared via ionic gelation and characterized based on their amount of thiol groups, particle size and zeta potential. Effects on the cell layer concerning absorption enhancement, transepithelial electrical resistance (TEER) and cytotoxicity were investigated. Permeation enhancement was evaluated with respect to in vitro transport of FD4 across Caco-2 cells, while mucoadhesion was indirectly examined in terms of adsorption behaviour when cells were covered with a mucus layer. Lyophilized particles displayed around 1000 MUmol/g of free thiol groups, particle sizes of less than 300 nm and a zeta potential of 18 mV (CS-TGA) and -14 mV (PAA-Cys). Cytotoxicity studies confirmed that all polymer samples were used at nontoxic concentrations (0.5% m/v). Permeation studies revealed that all thiolated formulations had pronounced effects on the paracellular permeability of mucus-free Caco-2 layers and enhanced the permeation of FD4 3.0- to 5.3-fold. Moreover, polymers administered as particles showed a higher permeation enhancement than their corresponding solutions. However, the absorption-enhancing effect of each thiolated formulation was significantly (p<0.05) reduced when cells were covered with mucus layer. In addition, all formulations were able to decrease the TEER of the cell layer significantly (p<0.05). Therefore, both thiolated polymers as nanoparticulate delivery systems represent a promising tool for the oral administration of hydrophilic macromolecules. PMID- 25498675 TI - Manipulation the behavior of supramolecular hydrogels of alpha-cyclodextrin/star like block copolymer/carbon-based nanomaterials. AB - A new supramolecular hydrogel self-assembled between alpha-cyclodextrin (alpha CD) and a star-like block copolymer AE73 was prepared. The cooperation effect of complexation of poly-(ethylene oxide) (PEO) segments with alpha-CD and the hydrophobic interaction between poly-(propylene oxide) (PPO) blocks resulted in the formation of the supramolecular hydrogel with a strong macromolecular network. Then two kinds of carbon materials (graphene and graphene oxide) were successfully incorporated into the above alpha-CD/AE73 hydrogel to further enhance the mechanical properties. The native hydrogel, as well as hybrid hydrogels, have been thoroughly characterized by using various microscopic techniques, including transmission electron microscopy (TEM), field emission scanning electron microscopy (FE-SEM), Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), thermogravimetric analysis (TGA). Our main purpose is to ascertain whether the properties of the obtained gels depend on these architectures. Interestingly, the phase behavior, the morphology and the mechanical strength of the native hydrogel can be successfully modulated by incorporating graphene and graphene oxide. Taking into account that both PEO/PPO copolymers and alpha-CD seem to be biocompatible, these gels can be promising for biomedical applications. PMID- 25498676 TI - Characterization and antioxidant activities of the polysaccharides from mycelium of Phellinus pini and culture medium. AB - Two polysaccharides isolated and purified from the mycelium (PPM) and its culture medium (PPE) of Phellinus pini using gel filtration were subjected to composition analysis and valuated for the antioxidant activity. The average molecular weights of PPM and PPE were approximately 22.0 and 38.0 kDa, respectively. PPM and PPE were both neutral heteropolysaccharides consisting of mannose, galactose, and glucose with molecular ratios of 2.99:1.00:0.34 and 38.40:1.00:1.76, respectively. In vitro antioxidant assay, PPM and PPE could scavenge 1,1-diphenyl 2-picrylhydrazyl (DPPH) radical and hydroxyl radical, chelate ferrous ion and reduce ferric ion. The antioxidant activities of PPM were stronger than those of PPE, suggesting that PPM has significant potential as a natural antioxidant agent. PMID- 25498677 TI - Effects of heat moisture treatment on the physicochemical properties of starch nanoparticles. AB - In this study, the effect of heat moisture treatment (HMT) on the properties of waxy maize starch nanoparticles (SNPs) was investigated. The SNPs were adjusted to 20% and 30% moisture levels and heated at 90 degrees C and 110 degrees C for 4 h. Transmission electron microscopy, X-ray diffractometry, differential scanning calorimetry, and Fourier transform infrared spectroscopy were used to characterize the morphology and crystal structure of the SNPs after HMT. The research found that the morphology of SNPs did not change significantly, keeping nanoscale size. When the SNPs were subjected to HMT at 110 degrees C and 30% moisture content, the crystalline structures changed from B-type to A-type, and the crystallinity of the SNPs increased significantly. HMT significantly increased the onset temperature, peak temperature, final temperature, and enthalpy value of the SNPs. As the HMT temperature and SNP moisture content increased, the hydrogen bonds between the starch molecular chains in the SNPs became stronger. PMID- 25498678 TI - Self-assembled nanoparticles of acetylated cashew gum: characterization and evaluation as potential drug carrier. AB - Acetylated cashew gum (ACG) was synthesized and self-assembled nanoparticles were obtained through the dialysis of an organic solution (DMSO) against a non-solvent (water). The ACG was characterized by infrared spectroscopy. The degree of substitution was 2.8 as determined by NMR spectroscopy. The physicochemical properties of the self-assembled nanoparticles in aqueous media were characterized by DLS, SEM and fluorescence spectroscopy. The mean diameter of the self-assembled nanoparticles obtained was 179 nm and the critical aggregation concentration (CAC) in water was 2.1*10(-3) g/L. Indomethacin (IND) was used as a hydrophobic model drug and was incorporated into the hydrophobized polysaccharide. Both loaded and unloaded nanoparticles were found to be spherical with diameters in the ranges of 70-170 nm and 108-314 nm (determined by SEM), respectively. Controlled drug release was observed for up to 72 h. PMID- 25498679 TI - Effects of surface functionalized graphene oxide on the behavior of sodium alginate. AB - The aim of this study was to improve the miscibility between fillers and polymer through modifying the face of graphene oxide (GO). In order to compare the effects of GO and modified graphene oxide (MGO) to sodium alginate (SA), sodium alginate/graphene oxide (SA/GO-n) and sodium alginate/modified graphene oxide (SA/MGO-n) biocomposite films were prepared, then the interaction between nanofillers and matrix was evaluated. The structure, morphologies and properties of biocomposites were characterized by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), thermal gravimetric analysis (TGA), Ultraviolet-visible (UV-vis), scanning electron microscopy (SEM) and mechanical tests. The results revealed that strong interactions existed between GO (MGO) and SA. Compared with neat SA film, the maximum level of Young's moduli (E), tensile strength (sigma(b)) and elongation at break (E(b)) of the SA/MGO biocomposites improved by 37.8%, 68.4% and 44.9%, while that of the SA/GO biocomposites improved by 19.6%, 44% and 36.5%. PMID- 25498680 TI - Augmented digestion of lignocellulose by steam explosion, acid and alkaline pretreatment methods: a review. AB - Lignocellulosic materials can be explored as one of the sustainable substrates for bioethanol production through microbial intervention as they are abundant, cheap and renewable. But at the same time, their recalcitrant structure makes the conversion process more cumbersome owing to their chemical composition which adversely affects the efficiency of bioethanol production. Therefore, the technical approaches to overcome recalcitrance of biomass feedstock has been developed to remove the barriers with the help of pretreatment methods which make cellulose more accessible to the hydrolytic enzymes, secreted by the microorganisms, for its conversion to glucose. Pretreatment of lignocellulosic biomass in cost effective manner is a major challenge to bioethanol technology research and development. Hence, in this review, we have discussed various aspects of three commonly used pretreatment methods, viz., steam explosion, acid and alkaline, applied on various lignocellulosic biomasses to augment their digestibility alongwith the challenges associated with their processing. PMID- 25498681 TI - Effect of extraction methods on property and bioactivity of water-soluble polysaccharides from Amomum villosum. AB - In the present study, effect of different extraction methods on property and bioactivity of water-soluble polysaccharides (WSP) from the seeds of Amomum villosum were investigated. Firstly, four different extraction methods were used to extract WSP, which include hot water extraction (HWE), ultrasonic-assisted extraction (UAE), microwave-assisted extraction (MAE) and enzyme-assisted extraction (EAE). As a result, four WSP samples, WSP(H), WSP(U), WSP(M) and WSP(E) were acquired. Then, the difference of four WSP samples in yield, characterization and antioxidant activities in vitro were further compared. Experimental results showed that the four WSP samples had the same monosaccharide composition, but mere difference in the content; they all had typical IR spectra characteristic of polysaccharides. WSP(U) contained the highest contents of uronic acid and sulfate. The yield of WSP(U) was the highest and its antioxidant activity was the best. These results suggested that ultrasonic-assisted extraction was the best extraction method for WSP. PMID- 25498682 TI - Nonionic gelation agents prepared from hydroxypropyl guar gum. AB - Nonionic gels were prepared from hydroxypropyl guar gum (HPG) with different molar substitution degrees by crosslinking with ethylene glycol diglycidyl ether (EGDE). FTIR and solid-state NMR spectroscopy revealed that the crosslinking degree of HPG gels increased with the amount of EGDE used during the reaction; this result was also confirmed by the water mobility in the swollen gels. Rheological characterization revealed behaviors typical of true gels, and their viscoelastic behaviors strongly depended on the crosslinking degree. The HPG gels absorbed buffers, aqueous saline, and water, and the absorption was not affected by the ionic strength or pH of the solution. In addition, HPG gels with high crosslinking degrees and molar substitution degrees exhibited gelation ability toward protic organic solvents such as methanol, ethanol, and 1-propanol. These HPG gels may find application as gelation agents for many industrial uses. PMID- 25498683 TI - Pyrolytic and kinetic characteristics of Platycodon grandiflorum peel and its cellulose extract. AB - The pyrolytic and kinetic characteristics of a biomass waste material, namely Platycodon grandiflorum A. DC (P. G.) peel and its cellulose extract were studied at heating rates of 10, 30 and 50 degrees C/min under a nitrogen flow atmosphere. The most probable mechanism function and activation energy pre exponential factors were calculated by using the Popescu, FWO and KAS methods. The three stages appeared during pyrolysis include: moisture evaporation, primary devolatilization and residual decomposition. Significant differences in the average activation energy, thermal stability, final residuals and reaction rates of the P. G. peel and its cellulose extract were observed. Stage II of the P. G. peel and its cellulose extract could be described by the function Avrami-Erofeev [-ln(1-alpha)](3) and the function chemical reaction (1-alpha)(-0.5), respectively. The average activation energy of P. G. peel and its cellulose extract were 157 and 196 kJ/mol, respectively. Kinetic compensation effects of the pre-exponential factors and activation energy were also observed. PMID- 25498684 TI - Effect of ultrasonic treatment on the degradation and inhibition cancer cell lines of polysaccharides from Porphyra yezoensis. AB - The exposure of polysaccharides solutions to high-energy ultrasound produces a permanent reduction in viscosity and change in activity. However, the exact mechanism which occurs in the process is still not clear. In this work, degradation of polysaccharides from Porphyra yezoensis (PP) was indirectly and directly judged by intrinsic viscosity and high performance gel permeation chromatography. The degradation process was established with dynamics and affirmed by theoretical derivation. Inhibition of cancer cell lines (SGC-7901, 95D) was also investigated by assays of tetrazolium colorimetric. The intrinsic viscosity of the degraded PP decreased exponentially with increase in ultrasonic time, and theoretical derivation was established and confirmed well. The distribution and new fraction of degraded polysaccharides was found. Ultrasound degraded preferentially large PP molecules and cleavage took place roughly at the centre of the molecules. During ultrasound degradation the molecular weight distribution was narrowed. The inhibition activities of SGC7901 with ultrasound degraded polysaccharides were increased. PMID- 25498685 TI - Fabrication of porous zeolite/chitosan monoliths and their applications for drug release and metal ions adsorption. AB - Ordered porous zeolite/chitosan (Zel/Chi) monoliths were prepared by a unidirectional freeze-drying method, and their properties and structures were characterized by various instrumental methods. The metal ion adsorption and the drug release performance of the porous Zel/Chi monoliths were also studied. The release rate of cefalexin from drug-loaded Zel/Chi monoliths depended on the composition and porous structure of the monoliths. The metal ion adsorption capacity of the Zel/Chi monoliths was related to the concentration of the metal ions, the adsorption time and the Zel/Chi ratio. An experimentally maximum adsorption of 89 mg/g was achieved for Cu(2+) ions. The Zel/Chi monoliths with adsorbed Cu(2+) ions effectively catalyzed the reduction of 4-nitrophenol to 4 aminophenol and had good recyclability. They were easily recovered by simply removing them from the reaction system and rinsing them with water. PMID- 25498686 TI - Dissolution of cellulose in 1-allyl-3-methylimizodalium carboxylates at room temperature: a structure-property relationship study. AB - The development of highly efficient cellulose solvents is imperative to the effective utilization of cellulose. In this work, ionic liquids (ILs) with the same 1-allyl-3-methylimidazolium cation ([Amim](+)) but different carboxylate anions, such as formate ([HCOO](-)), acetate ([CH3COO](-)), propionate ([CH3CH2COO](-)), butyrate ([CH3CH2CH2COO](-)), glycollate ([HOCH2COO](-)), lactate ([CH3CHOHCOO](-)) and benzoate ([C6H5COO](-)) were synthesized, and their thermal properties and viscosities were determined. Then these ILs were used to investigate the effect of anion structure on solubility of cellulose in the ILs. It was shown that the viscosity and cellulose solubility depended strongly on the anion structure of the ILs. For example, at 30 degrees C solubility of cellulose in [Amim][CH3CH2COO] was as high as 19.0%, whereas cellulose was not soluble in [Amim][HOCH2COO], [Amim][CH3CHOHCOO] and [Amim][C6H5COO]. In addition, solvatochromic UV/vis probe and (13)C NMR measurements were performed to demonstrate dissolution mechanism of cellulose in the ILs. The results suggested that although cations of the ILs have un-negligible contribution to the highly efficient dissolution of cellulose, hydrogen bonding interactions of anions of the ILs with cellulose is predominant. PMID- 25498687 TI - Aerobic oxidation of starch catalyzed by isopolyoxovanadate Na4Co(H2O)6V10O28. AB - The partial oxidation of starch was achieved in the presence of oxygen with Na4Co(H2O)6V10O28.18H2O (abbreviated as CoV10) as catalyst. The oxidation degree of starch was determined by FT-IR, XRD and SEM measurements, which indicated that the aerobic oxidation of starch was promoted by oxidative catalyst CoV10. The application of CoV10 could give a high oxidation degree (DO) of 1.35 COOH/100 GU and 2.07 CO/100 GU with 86 wt.% yield of solid starch under mild reaction conditions (pH=6; reaction time, 8 h; temperature, 50 degrees C; catalyst amount, 8 mg, when 1.5 g starch was used as substrate; atmospheric pressure). Among some vanadium compounds, CoV10 exhibited 4-fold activity higher than orthovanadate due to its coordination effect of cobalt and V10O28. Meanwhile, CoV10 could be recycled for six times with only a slight decrease in activity. Thus, CoV10/O2 is one of the most efficient systems for partial oxidation of starch reported so far. PMID- 25498688 TI - Chemical alterations of pine wood saccharides during heat sterilisation. AB - Alterations in saccharides during heat sterilisation of pine wood (Pinus sylvestris L.) were investigated. The mass loss, extractives, lignin, cellulose, holocellulose and hemicelluloses were determined. Changes in saccharides were evaluated by the determination of monosaccharides in wood, size exclusion chromatography (SEC) as well as Fourier transform infrared (FTIR) spectroscopy. During heat sterilisation of pine wood the slight mass loss, an increase in extractives and a decrease in lignin and polysaccharides were observed. Hemicelluloses are degraded approximately twice as fast as cellulose. The degree of polymerisation of cellulose decreases approximately by 10% and it increases in holocellulose (by approx. 8%) as a result of a faster degradation of shorter hemicellulose chains. FTIR spectroscopy shows that sterilisation results in the deacetylation of cellulose and the formation of new carbonyl groups, an increase in the total crystallinity index (TCI) and a decrease in the lateral order index (LOI) and the hydrogen-bond intensity (HBI). PMID- 25498689 TI - Pectin/lysozyme bilayers layer-by-layer deposited cellulose nanofibrous mats for antibacterial application. AB - Positively charged lysozyme (LZ) and negatively charged pectin, were alternately deposited on the surface of the cellulose nanofibrous mats by layer-by-layer (LBL) self-assembly technique. Scanning electron microscopy images showed that the nanofibers were orderly and compactly arrayed after LBL. Besides, as the number of LZ/pectin bilayers increased, the average diameter of nanofibers increased. LZ has assembled on the cellulose mats successfully, which was confirmed by X-ray photoelectron spectroscopy analysis. Thermal gravimetric analysis results showed that the thermal properties of LZ/pectin films coated mats was better than that of the unmodified cellulose mats. Importantly, the results of the bacterial inhibition test for LBL structured mats and cellulose mats indicated that the nanofibrous mats coated by 10.5 LZ/pectin bilayers (with LZ on the outmost layer) possessed the strongest inhibitory effect against both Escherichia coli and Staphylococcus aureus. PMID- 25498690 TI - One-step degradation of cellulose to 5-hydroxymethylfurfural in ionic liquid under mild conditions. AB - One-step conversion of cellulose to HMF (5-hydroxymethylfurfural) has been achieved by using metal chlorides (CrCl3, CuCl2, SnCl4, WCl6) in [BMIM]Cl. The effects of temperature, reaction time, amount of catalysts, and the purity of [BMIM]Cl on the performance have been studied and discussed in detail. More than 63% yield of HMF and 80% yield of TRS (total reducing sugar) were obtained in [BMIM]Cl with CrCl3 at 120 degrees C under atmospheric pressure. Filter paper and cotton were also used as a source for cellulose degradation to HMF, but only a moderate yield of HMF was obtained (40% for filter paper and 12% for cotton). The reutilization of this system was examined and the reaction mechanism was also discussed. PMID- 25498691 TI - Homogeneous ring opening graft polymerization of E-caprolactone onto xylan in dual polar aprotic solvents. AB - Homogeneous ring-opening graft polymerization (ROGP) of E-caprolactone (E-CL) onto xylan was investigated in dual polar aprotic solvents, N,N dimethylformamide/lithium chloride (DMF/LiCl), N,N-dimethylacetamide/LiCl (DMAc/LiCl), and 1-methyl-2-pyrrolidinone/LiCl (NMP/LiCl). The effects of reaction solvents, temperature, and the molar ratio of E-CL to anhydroxylose units (AXU) on the degree of substitution (DS) of xylan-graft-poly(E caprolactone) (xylan-g-PCL) copolymers and the degree of polymerization (DP) of the attached PCL side chains were investigated. FT-IR and NMR analyses provided the evidence of the occurrence of ROGP reaction. The thermal stability of xylan increased upon ROGP reaction due to the increased length of PCL side chains. With the increased attachment of PCL side chains, the tensile strength and Young's modulus of the films decreased, whereas the elongation at break increased. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) observations provided the evidences of the increased film properties due to the attachment of PCL side chains. PMID- 25498692 TI - Solid state NMR and IR characterization of wood polymer structure in relation to tree provenance. AB - (13)C nuclear magnetic resonance and mid-infrared spectroscopies were used for characterizing changes in the chemical structure of wood polymers (cellulose, hemicellulose and lignin) in relation to the tree growth location. Samples of three provenances in Europe (Finland, Poland and Italy) were selected for studies. The requirement was to use untreated solid wood samples to minimize any manipulation to the nanostructure of native wood. The results confirm that the chemical and physical properties of samples belonging to the same wood species (Picea abies Karst.) differ due to the origin. Both FT-IR and dynamic NMR spectroscopies were able to correctly discriminate samples originating from three different provenances in Europe. Such methods might be very useful for both, research and understanding of wood microstructure and its variability due to the growth conditions. PMID- 25498693 TI - Incorporation of chitosan in biomimetic gelatin/chondroitin-6-sulfate/hyaluronan cryogel for cartilage tissue engineering. AB - We prepare an elastic macroporous gelatin/chondoitin-6-sulfate/hyaluronan (GCH) cryogel scaffold mimic the composition of cartilage extracellular matrix for cartilage tissue engineering. By incorporating chitosan in the cryogel to replace 20% gelatin, a GCH-chitosan cryogel was also synthesized and compared with GCH cryogel for scaffold mechanical properties and chondrocytes response. The GCH chitosan cryogel has larger pores, higher ultimate strain (stress) and elastic modulus, and lower stress relaxation percentage than the GCH cryogel. Both cryogels show a highly elastic property with a loss tangent around 0.1, but chitosan incorporation increases the storage modulus (elasticity). Chondrocytes proliferate and redifferentiate in cryogels; chitosan diminishes cell proliferation but up-regulates glycosaminoglycans (GAGs) and type II collagen (COL II) secretion. Implantation of a chondrocytes/GCH-chitosan cryogel construct in a full-thickness articular cartilage defect regenerates cartilage with positive stainings for GAGs and COL II and an elastic modulus similar to the native cartilage. PMID- 25498694 TI - A method for top down preparation of chitosan nanoparticles and nanofibers. AB - A method of top down preparation of chitosan nanoparticles and nanofibers is proposed. Chitin nanofibrils (chitin NFs) were prepared using ultrasonic assisted method from crab shells with an average diameter of 5 nm and the length less than 3 MUm as analyzed by atomic force microscopy and transmission electron microscopy. These chitin nanofibers were used as the precursor material for the preparation of chitosan nanoparticles and nanofibers. The degree of deacetylation of these prepared chitosan nanostructures were found to be approximately 98%. In addition these chitosan nanostructures showed amorphous crystallinity. Transmission electron microscopic studies revealed that chitosan nanoparticles were roughly spherical in nature and had diameters less than 300 nm. These larger particles formed through self-assembly of much smaller 25 nm particles as evidenced by the TEM imaging. The diameter and the length of the chitosan nanofibers were found to be less than 100 nm and 3 MUm respectively. It is envisaged that due to the cavitation effect, the deacetylated chitin nanofibers were broken down to small pieces to form seed particles. These seed particles can then be self-assembled to form larger chitosan nanoparticles. PMID- 25498695 TI - Components interactions controlling starch-kaolinite composite films properties. AB - In order to relate the primary filler-matrix interactions to the macroscopic properties of starch-kaolinite composite material, these interactions are monitored through homo- or hetero-coagulation experiments involving both components. Turbidity measurement and Infrared spectra confirm the extreme weakness of the interactions. The addition of calcium cations shows that these weak interactions between starch and kaolinite are due to the combination of the electrostatic repulsion and hydrogen bonds formation between this two negatively charge components. Some possible relationships between the starch-kaolinite interactions and starch-kaolinite composite films properties are proposed. PMID- 25498696 TI - Interphase vs confinement in starch-clay bionanocomposites. AB - Starch-clay bionanocomposites containing 1-10% of natural montmorillonite were elaborated by melt processing in the presence of water. A complex macromolecular dynamics behavior was observed: depending on the clay content, an increase of the glass transition temperature and/or the presence of two overlapped alpha relaxation peaks were detected. Thanks to a model allowing the prediction of the average interparticle distance, and its comparison with the average size of starch macromolecules, it was possible to associate these phenomena to different populations of macromolecules. In particular, it seems that for high clay content (10%), the slowdown of segmental relaxation due to confinement of the starch macromolecules between the clay tactoids is the predominant phenomenon. While for lower clay contents (3-5%), a significant modification of chain relaxation seems to occur, due to the formation of an interphase by the starch macromolecules in the vicinity of clay nanoparticles coexisting with the bulk polymer. PMID- 25498697 TI - D-glucans from edible mushrooms: a review on the extraction, purification and chemical characterization approaches. AB - D-Glucans from edible mushrooms present diversified chemical structures. The most common type consists of a backbone of beta-D-glucose (1->3)-linked frequently branched at O-6 by beta-D-glucose residues as side chains. However it is possible to distinguish alpha-, beta- and mixed D-glucans. Further discrimination could be made on the basis of glycosidic bond position in a pyranoid ring, distribution of specific glycosidic bonds along the chain, branching and molecular weight. The present manuscript reviews the processes of extraction, purification and chemical characterization of D-glucans, such as NMR studies, methylation analysis, Smith degradation, and some other methodologies employed in carbohydrate chemistry characterization. In addition, these polysaccharides are important because they can provide many therapeutic benefits related to their biological activity in animals and humans, either immunostimulatory activity, inhibiting tumor growth, as well as exerting antinociceptive and anti-inflammatory action, among others, which are usually attached to their structure, molecular weight and degree of branching. PMID- 25498698 TI - Imino-chitosan biopolymeric films. Obtaining, self-assembling, surface and antimicrobial properties. AB - The paper reports the preparation of twelve imino-chitosan biopolymer films by acid condensation of the amino groups of chitosan with various aldehydes, in aqueous medium, followed by slow water removal. FTIR spectroscopy has shown drastic conformation changes of chitosan macromolecular chains-from a stiff coil to a straight one, while wide angle X-ray diffraction evidenced a layered morphology of the biopolymer films. Contact angle and surface free energy determination indicated a higher biocompatibility of the new biopolymers as compared to the chitosan parent, while the microbiological screening demonstrated their self-defense properties against common and virulent pathogen agents. It was concluded that the reversibility of imine forming promotes the self-assembling of imino-chitosan biopolymer films into a lamellar morphology and, on the other hand, the slow release of the antimicrobial aldehyde in the microbiological culture. The obtained results demonstrate that chitosan polyamine is a challenging workbench to functional biodynamic materials. PMID- 25498699 TI - Green synthesis of biocompatible carboxylic curdlan-capped gold nanoparticles and its interaction with protein. AB - This study demonstrates a facile, green strategy for the preparation of gold nanoparticles (AuNPs) from chloroauric acid (HAuCl4) using carboxylic curdlan (Cc) as both reducing and stabilizing agent. The as-prepared AuNPs are characterized by UV-vis spectroscopy, high resolution transmission electron microscopy, X-ray diffraction, energy dispersive X-ray spectrometry and Fourier transform infrared spectroscopy. The results indicated that the particle size of the AuNPs changes with variations in the reaction time and concentrations of Cc and HAuCl4. The spherical AuNPs are well dispersed, exhibiting high stability even after six months storage. The carboxylic groups (COO(-)) in the Cc molecules tend to adsorb and stabilize the surface of the AuNPs. The interaction between BSA and the Cc-capped AuNPs was investigated using fluorescence and circular dichroism spectroscopies. The results indicated that the BSA molecules adsorb on the surface of the AuNPs, without significant change in its helical structure even after conjugation with the AuNPs. PMID- 25498700 TI - Alkali-treated konjac glucomannan film as a novel wound dressing. AB - To investigate the potential medical application of konjac glucomannan (KGM), we treated KGM film with potassium hydroxide (KOH) or calcium hydroxide (Ca(OH)2), and evaluated its use as a wound dressing. The Ca(OH)2-treated KGM (Ca(OH)2-KGM) film exhibited more favorable properties of swelling, tensile strength, and elongation compared with the KOH-treated KGM (KOH-KGM) film, and also had a suitable water vapor transmission rate. Results from in vitro 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay further indicated the biocompatibility of the Ca(OH)2-KGM film with L929 fibroblast cells and HaCaT keratinocyte cells. The Ca(OH)2-KGM film inhibited the absorption and activation of platelets, and effectively promoted wound contractility in vivo, particularly at an early healing stage. Histological examination revealed considerably collagen secretion and advanced development of granulation tissue and epithelial coverage by Days 7 and 14 postsurgery in wounds treated with Ca(OH)2-KGM film. Our study results indicate the potential use of alkali-treated KGM film as a novel wound dressing. PMID- 25498701 TI - Preparation, characterization and bioactivities of derivatives of an exopolysaccharide from Lachnum. AB - An exopolysaccharide, obtained previously LEP-2b from Lachnum YM405, was phosphated and sulfated successfully. The derivatives named PLEP-2b and SLEP-2b, respectively, and their respective degree of substitution were 0.174 and 0.431. Phosphate groups -PO3H2 substituted at C-6 of 1,4-beta-D-mannopyranose, C-5 of 2,6-beta-d-1-OMe-mannofuranoside, C-3 of 1,6-beta-D-galactopyranose, C-2 of 1 beta-D-glucopyranose, and C-6 of 1,2-alpha-D-rhampyranose, while sulfate groups SO3H were mainly at C-6 of 1,4-beta-D-Manp, C-6 of 1-beta-D-Glcp and C-6 of 1,2 alpha-D-Rhap. Compared with LEP-2b, the scavenging effects of the derivatives, on hydroxyl radical and superoxide anion were significantly increased after the modifications, except for reducing power. Meanwhile, phosphorylated and sulfated modifications remarkably strengthened the inhibiting effect of LEP-2b on the proliferation of CT-26 murine colon carcinoma, Lewis lung carcinoma and human hepatocellular carcinoma HepG2 cells. The derivatives significantly enhanced the antioxidant and antitumor activities in vitro. Compared with sulfation, phosphorylation improved the inhibitory effect more contraposingly on some specific tumor cells. PMID- 25498702 TI - Polysaccharide-based aerogel microspheres for oral drug delivery. AB - Polysaccharide-based aerogels in the form of microspheres were investigated as carriers of poorly water soluble drugs for oral administration. These bio-based carriers may combine the biocompatibility of polysaccharides and the enhanced drug loading capacity of dry aerogels. Aerogel microspheres from starch, pectin and alginate were loaded with ketoprofen (anti-inflammatory drug) and benzoic acid (used in the management of urea cycle disorders) via supercritical CO2 assisted adsorption. Amount of drug loaded depended on the aerogel matrix structure and composition and reached values up to 1.0*10(-3) and 1.7*10(-3) g/m(2) for ketoprofen and benzoic acid in starch microspheres. After impregnation, drugs were in the amorphous state in the aerogel microspheres. Release behavior was evaluated in different pH media (pH 1.2 and 6.8). Controlled drug release from pectin and alginate aerogel microspheres fitted Gallagher Corrigan release model (R(2)>0.99 in both cases), with different relative contribution of erosion and diffusion mechanisms depending on the matrix composition. Release from starch aerogel microspheres was driven by dissolution, fitting the first-order kinetics due to the rigid starch aerogel structure, and showed different release rate constant (k1) depending on the drug (0.075 and 0.160 min(-1) for ketoprofen and benzoic acid, respectively). Overall, the results point out the possibilities of tuning drug loading and release by carefully choosing the polysaccharide used to prepare the aerogels. PMID- 25498703 TI - Structural analysis of galactoarabinan from duckweed. AB - A highly branched galactoarabinan named DAG1 (Mw~4.0*10(4) Da) was purified from Lemna aequinoctialis 6000 via 70% (v/v) ethanol extraction, followed by size exclusion chromatography on Bio-Gel P2 and Superdex 75. Methylation analysis showed that DAG1 consisted of t-Araf, (1->5)-Araf, (1->2,5)-Araf, (1->3)-Galp, and (1->3,6)-Galp in a relative proportion of approximately 6:4:3:3:3, suggesting an arabinogalactan/galactoarabinan polysacchairde. With the aid of arabinan degrading enzymes, the structure of DAG1 repeating unit was further characterized by ELISA with specific monoclonal antibodies and Yariv reagent assay. Analyses indicated that the proposed repeating unit of DAG1 had a backbone composed of seven alpha-(1->5)-L-arabinofuranose residues where branching occurred at O-2 with either terminal arabinoses or arabinogalactan side chain. The arabinogalactan side chain was composed of six beta-(1->3)-D-galactopyranose residues, half of which were ramified at O-6 with terminal arabinoses and the last galactose was terminated with arabinose. PMID- 25498704 TI - Facile preparation of silver nanoparticles immobilized on chitin nanofiber surfaces to endow antifungal activities. AB - Silver nanoparticles were prepared on chitin nanofiber surfaces by UV light reduction of silver ions. The chitin nanofibers could be efficient substrates to immobilize silver nanoparticles with stable dispersion states. The dispersion and the nanocomposite film with acrylic resin showed characteristic absorption property in the visible light region due to the effect of the silver nanoparticles. Silver nanoparticles endowed strong antifungal activity to chitin nanofibers. PMID- 25498705 TI - Homogeneous tritylation of cellulose in 1-allyl-3-methylimidazolium chloride and subsequent acetylation: the influence of base. AB - Homogeneous tritylation of cellulose in 1-allyl-3-methylimidazolium chloride (AmimCl) ionic liquid with triphenylmethy chloride as regents, pyridine or 1 butylimidazole (BIM) as base was investigated, and subsequent acetylation of the 6-O-functionalized products was further studied. The structure of products was analyzed by FTIR and (13)C NMR spectroscopy and base influences on the structure were discussed as well. The solution with pyridine as base underwent heterogeneous-homogeneous-heterogeneous process and the obtained trityl cellulose (TC) had organized structure with trityl group located completely at C-6 position of cellulose with maximum DS(trityl) of nearly 1. In the case of BIM as base, the solution was homogeneous for the whole reaction, but the highest DS(trityl) was about 0.22, with trityl group located not only at position 6 but also partially at position 2. Subsequent acetylation of the TC led to products with a preferred functionalization of the unprotected secondary OH-groups. PMID- 25498706 TI - Mechanical and optical characterization of gelled matrices during storage. AB - The effect of composition and storage time on the rheological and optical attributes of multi-component gels containing locust bean gum (LBG), low acyl (LAG) and high acyl (HAG) gellan gums, was determined using three-component mixture design. The generalized Maxwell model was used to fit experimental rheological data. Mechanical and relaxation spectra of gelled systems were determined by the type of gellan gum used, except LBG alone which behaved as a diluted gum dispersion. Storage time dependence of the gels was analyzed using the rubber elasticity theory and to determine changes in network mesh size the equivalent network approach was applied. Destabilization kinetic was obtained from light scattering results; increasing LAG content improved the long-term stability of the matrices. Almost every formulation exhibited an increment in both moduli during the first 10 days remaining practically constant thereafter or until they broke (binary mixtures with LBG); gels with HAG/LBG mixtures were the least stable. PMID- 25498707 TI - Polysaccharides from the green seaweed Codium decorticatum. Structure and cell wall distribution. AB - The cell wall polysaccharides from Codium decorticatum and their assembly were studied and these results were compared with those obtained previously for this genus. The water soluble polysaccharides are: (i) Pyruvylated and sulfated 3- and 6-linked beta-D-galactans with sulfate mainly on C-4 and also on C-6. Pyruvate ketals are linked to O-3 and O-4 of terminal beta-D-galactose or O-4 and O-6 of 3 linked beta-D-galactose. (ii) Sulfated 3-linked beta-L-arabinans substituted on C 2 or C-2 and C-4 predominantly with sulfate, but also with single stubs of arabinose, and (iii) 4-linked beta-D-mannans with a low degree of sulfation on C 2. The whole polysaccharide system comprises 6.9% of sulfated polysaccharides and 32.9% of fibrillar polysaccharides, mostly insoluble mannans. By in situ localization it was possible to detect two similar fibrillar layers separated by a zone rich in charged polymers. Besides, arabinogalactan proteins co-localized with the fibrillar components. PMID- 25498708 TI - Physicochemical properties of dehydrated potato parenchyma cells with ungelatinized and gelatinized starches. AB - Potato parenchyma cells were characterized to identify the function of intact parenchyma cell walls on their physicochemical properties. Parenchyma cells were separated using pectinase from raw and cooked potatoes (R-Cell and G-Cell, respectively), and investigated with respect to their morphology, chemical composition, starch leaching and swelling power, gelatinization, and pasting property. Potato flour (RPF) and potato granule (PGL) prepared in laboratory were used as controls of R-Cell and G-Cell, respectively. Protein and ash were lost during parenchyma cell isolation. Ungelatinized and gelatinized starches within parenchyma cells were tightly wrapped by intact parenchyma cell walls. Compared to their controls, the parenchyma cell walls prevented starch leaching from R Cell and G-Cell. R-Cell exhibited the reduced swelling powers and pasting viscosities, while the opposite patterns were observed for G-Cell. R-Cell revealed the increased gelatinization temperatures than native potato starch. Overall, potato parenchyma cells may expand the industrial availability of dehydrated potato products. PMID- 25498709 TI - Physicochemical properties of complex rhamnogalacturonan I from gelatinous cell walls of flax fibers. AB - The physicochemical properties of flax fiber cell wall rhamnogalacturonan I (RG I) and its fragments, obtained after galactanase treatment (fraction G1), were characterized. RG-I retains its hydrodynamic volume after its molecular weight decreases by approximately half, as revealed by SEC. Two techniques, DLS and NMR, with different principles of diffusion experiment were used to establish the reasons for this property of RG-I. Three possible types of particles were revealed by DLS depending on the concentration of the RG-I and G1 solutions (2 2.5, 15-20, and 150-200 nm). It was determined by BPP-LED experiments that the backbone of the RG-I was 1.3-1.9-fold more mobile than the side chains. The obtained data suggest a novel type of pectin spatial organization-the formation of RG-I associates with the backbone at the periphery and the interaction between the side chains to form a core zone. PMID- 25498710 TI - Changes in the microstructure and properties of aspen chemithermomechanical pulp fibres during recycling. AB - The effects of recycling on the microstructure and properties of bleached aspen chemithermomechanical pulp (CTMP) fibres were systematically investigated. The low-temperature nitrogen adsorption and atomic force microscopy results showed that a substantial amount of large pores and most of the very small pores in the fibre wall closed and the fibre surface became less coarse and porous during recycling. The partial cocrystallisation of cellulose microfibrils took place, as reflected in the increment of the cellulose crystallinity and the width of the crystallite in the 0 0 2 lattice plane. These irreversible structural changes caused significant hornification of the recycled fibres, leading to the loss of swelling and bonding capability. The decrease of the tensile index, burst index, and tear index further demonstrated the deterioration of the fibre properties. However, the single-fibre strength considerably increased after recycling, which was mainly due to the enlarged cellulose aggregates in the fibre wall. PMID- 25498711 TI - The gelation of oil using ethyl cellulose. AB - The characterization of the thermo-gelation mechanism and properties of ethyl cellulose/canola oil oleogels was performed using rheology and thermal analysis. Thermal analysis detected no evidence for thermal transitions contributed to secondary conformational changes, suggesting a gelation mechanism that does not involve secondary ordered structure formation. Rheological analysis demonstrated a relationship between the polymer molecular weight and the final gel strength, the cross-over behavior as well as the gel point temperature. Increasing polymer molecular weight led to an increase in final gel strength, the modulus at cross over, and the gel point temperature. Cooling/heating rates affect gel modulus only for the low molecular weight samples. A decrease in gel strength with increasing cooling rate was detected. The cross-over temperature was not affected by the cooling/heating rates. Cooling rate also affected the gelation setting time where slow cooling rates produced a stable gel faster. PMID- 25498712 TI - A polysaccharide from Polygonatum sibiricum attenuates amyloid-beta-induced neurotoxicity in PC12 cells. AB - One of the pathological hallmarks of Alzheimer's disease (AD) is the progressive accumulation of beta-amyloid (Abeta) in the form of senile plaques, and Abeta induced neurotoxicity has been identified as a major cause of the onset of AD. In this study, we investigated the protective effects of a polysaccharide (PS-WNP) from Polygonatum sibiricum against the Abeta(25-35)-induced neurotoxicity in PC12 cells and explored the underlying mechanism. The results showed that pretreatment with PS-WNP significantly attenuated cell death and the elevated Bax/Bcl-2 ratio evoked by Abeta(25-35), and subsequently inhibited mitochondrial dysfunction and cytochrome c release into the cytosol. Moreover, PS-WNP significantly inhibited Abeta(25-35) induced caspase-3 activation and enhanced the protein levels of phosphorylated Akt (p-Akt) in PC12 cells. Additionally, pretreatment with the PI3K inhibitor (LY294002) completely abolished the protective effects of PS-WNP against Abeta(25-35)-induced neuronal cell apoptosis. These observations unambiguously suggested that the protective effect of PS-WNP against Abeta(25-35) induced apoptosis in PC12 cells was associated with the enhancement of PI3K/Akt signaling pathway. PMID- 25498713 TI - Contact time- and pH-dependent adhesion and cohesion of low molecular weight chitosan coated surfaces. AB - Low molecular weight chitosan (LMW chitosan, ~5 kDa) potentially has many desirable biomedical applications such as anti-microbial, anti-tumor, and anti diabetes. Unlike high molecular weight chitosan, LMW chitosan is easily dissolvable in aqueous solutions even at neutral and basic pH, but its dissolution mechanism is not well understood. Here, we measured adhesion and cohesion of molecularly thin LMW chitosan films in aqueous solutions in different buffer pHs (from 3.0 to 8.5) using a surface forces apparatus (SFA). Interestingly, significantly lower adhesion force was measured for LMW chitosan films compared to the high molecular weight chitosan (~150 kDa) films. Not only the strength of adhesion is lower, but also the critical contact time where adhesion starts to increase with contact time is longer. The results from both the SFA and atomic force microscopy (AFM) indicate that, in physiological and basic conditions, the low cohesion of LMW chitosan due to the stiffness of the chain which cause strong electrostatic correlation energy penalty when they are aggregated. Here, we propose the reduction in cohesion for shorter chitosan (LMW chitosan) as an explanation of its high solubility of LMW chitosan in physiological pHs. PMID- 25498714 TI - Optimization of ultrasound-assisted compound enzymatic extraction and characterization of polysaccharides from blackcurrant. AB - In the present study, an efficient procedure for ultrasound-assisted compound enzymatic extraction of polysaccharides from blackcurrant fruits was investigated using response surface methodology (RSM). The Box-Behnken design was applied to optimize the effects of enzyme concentration (X1), pH (X2) and ultrasonic time (X3). The statistical analysis indicated that the independent variables (X1) and the quadratic terms (X1(2) and X3(2)) had significant effects on the yield of blackcurrant polysaccharides (BCP). The optimal conditions were: enzyme concentration 1.575%, pH 5.3, and ultrasonic time 25.6 min. The experimental yield of BCP was 14.28+/-0.06%, which was closely matched with the predicted yield of 14.31%. After preliminary purification, BCP I was obtained and characterized by GC, HPLC, and IR. BCP I comprised rhamnose, arabinose, xylose, mannose, glucose, and galactose in a molar ratio of 1.818:1.362:0.377:0.501:1.581:1.722 and its molecular weight was 8146 kDa. BCP I showed notable alpha-amylase inhibitory activity. PMID- 25498715 TI - Quantification of xylooligomers in hot water wood extract by 1H-13C heteronuclear single quantum coherence NMR. AB - A new method that employs 2D-HSQCNMRwasdeveloped to determine xylooligomer concentrations in the hot water extracts of Paulownia elongata, aspen, sugar maple, southern hardwood mixture, and willow woodchips. Equations for computing oligomer concentrations calculation were developed based on HSQC corresponding resonance integrals of xylooligomer C1H1 and monomeric sugar standard curves. The degree of polymerization (DP) of xylooligomers in the hot water extract was computed by equation obtained from a series of xylooligomer standard solutions with DPs that ranged from 2 to 6. Another group of hot water wood extract that is served as a control group was hydrolyzed by 4% sulfuric acid at 121 degrees C for 60 min in order to convert all xylooligomer into xylose. As 2D-HSQC resonance response is different for acetylated xylo-units, as compared with non-acetylated units, proton NMR was used to calibrate the acetylated xylooligomer concentration. Xylooligomer concentrations determined from HSQC compared fairly well with data after hydrolysis. PMID- 25498716 TI - Trapping by amylose of the aliphatic chain grafted onto chlorogenic acid: importance of the graft position. AB - 5-Caffeoylquinic acid (chlorogenic acid), is classified in acid-phenols family and as polyphenolic compounds it possesses antioxidant activity. The oxydative modification of chlorogenic acid in foods may lead to alteration of their qualities; to counteract these degradation effects, molecular encapsulation was used to protect chlorogenic acid. Amylose can interact strongly with a number of small molecules, including lipids. In order to enable chlorogenic acid complexation by amylose, a C16 aliphatic chain was previously grafted onto the cycle of quinic acid. This work showed that for the two lipophilic derivatives of chlorogenic acid: hexadecyl chlorogenate obtained by alkylation and 3-O-palmitoyl chlorogenic acid obtained by acylation; only the 3-O-palmitoyl chlorogenic acid complexed amylose. The chlorogenic acid derivatives were studied by X-ray diffraction, differential scanning calorimetry and NMR to elucidate the interaction. By comparing the results with previous work on the complexation of amylose by 4-O-palmitoyl chlorogenic acid, the importance of the aliphatic chain position on the cycle of the quinic acid is clearly highlighted. A study in molecular modeling helped to understand the difference in behavior relative to amylose of these three derivatives of chlorogenic acid. PMID- 25498718 TI - Assessment of antiproliferative activity of pectic substances obtained by different extraction methods from rapeseed cake on cancer cell lines. AB - In this work the antiproliferative activity of pectic substances obtained by different extraction methods from defatted rapeseed cake was assessed on cancer cell lines. The process consisted of sequential treatment with alkalized water (pH~8), EDTA (0.01 M), alkaline protease (Alkalase 2.4L) and a commercial pectinase preparation (Viscozyme L or Pectinex Ultra SP-L). Pectic extracts identification was performed using spectroscopy and chromatography techniques. FT IR and HPLC-IR results suggest that the neutral pectic extracts produced would be arabinogalactans and beta-galactans. All the pectic substances extracted (acid and neutral) from RSC exhibited antiproliferative activity, being more effective on MCF-7 cells than Caco-2. The most effective pectic extract was obtained by Alkalase 2.4 L which killed over 80% of MCF-7 cells and 60% of Caco-2 cells. At less than 10 mg/mL pectic extracts enriched in neutral sugars also exhibited antiproliferative activity (50 and 40%, respectively), which was superior to the modified citric pectins activity at the same concentration for the breast cancer cell line (61.6% for MCF-7 and 49.9% for Caco-2 cells). These results show that the antiproliferative activity depends on both the type of pectin (acid or neutral) and the extraction procedure. PMID- 25498717 TI - Ultrasonic enhance acid hydrolysis selectivity of cellulose with HCl-FeCl3 as catalyst. AB - The effect of ultrasonic pretreatment coupled with HCl-FeCl3 catalyst was evaluated to hydrolyze cellulose amorphous regions. The ultrasonic pretreatment leads to cavitation that affects the morphology and microstructure of fibers, enhancing the accessibility of chemical reagent to the loosened amorphous regions of cellulose. In this work, Fourier transform infrared spectroscopy (FTIR) was used to identify characteristic absorption bands of the constituents and the crystallinity was evaluated by the X-ray diffraction (XRD) technique. The results indicated that appropriate ultrasonic pretreatment assisted with FeCl3 can enhance the acid hydrolysis of amorphous regions of cellulose, thus improving the crystallinity of the remaining hydrocellulose. It was observed that sonication samples that were pretreated for 300 W and 20 min followed by acid hydrolysis had maximum of 78.9% crystallinity. The crystallinity was 9.2% higher than samples that were not subjected to ultrasound. In addition, the average fines length decreased from 49 MUm to 37 MUm. PMID- 25498719 TI - Mucoadhesive electrospun chitosan-based nanofibre mats for dental caries prevention. AB - The mucoadhesive electrospun nanofibre mats were developed using chitosan (CS) and thiolated chitosan (CS-SH) as mucoadhesive polymers. Garcinia mangostana (GM) extract was incorporated into nanofibre mats. The antibacterial activity in the single and combined agents was evaluated against dental caries pathogens. The morphology of mats was observed using SEM. The mats were evaluated for GM extract amount, mucoadhesion, in vitro release, antibacterial activity and cytotoxicity. The mucoadhesion and antibacterial activity were determined in healthy human volunteers. The prepared mats were in nanoscale with good physical and mucoadhesive properties. The CS-SH caused the higher mucoadhesion. All mats rapidly released active substances, which had the synergistic antibacterial activity. In addition, the reduction of bacteria and good mucoadhesion in the oral cavity occurred without cytotoxicity. The results suggest that mats have the potential to be mucoadhesive dosage forms to maintain oral hygiene by reducing the bacterial growth that causes the dental caries. PMID- 25498721 TI - Revealing the structures of cellulose nanofiber bundles obtained by mechanical nanofibrillation via TEM observation. AB - To reveal the structures of cellulose naonfiber bundles extracted from lignocellulosic pulps and prepared by mechanical nanofibrillation methods, the samples were systematically investigated by transmission electron microscopy (TEM) observation. First, high magnification and high resolution TEM images were obtained starting from one end of the bundles. The imaging position was then carefully shifted along the length of the bundles until the other end was reached. Finally, a series of TEM images were integrated through image processing and analyzed. The cellulose nanofiber bundles displayed ribbon-like structures, which were organized with parallel aligned cellulose nanofibers 2-5 nm in width. The length of the bundles was >11 MUm. The bundles were interconnected with other nanofibers and nanofiber bundles, forming entangled, web-like networks in suspension. Evidence demonstrating the existence of twisted bundle morphologies was also presented. PMID- 25498720 TI - Electrospun aligned poly(propylene carbonate) microfibers with chitosan nanofibers as tissue engineering scaffolds. AB - In this study, parallel-aligned poly(propylene carbonate) (PPC) microfibers with a fiber diameter of 1.48+/-0.42 MUm were prepared by electrospinning and modified by oxygen plasma treatment. Next, chitosan nanofibers with a fiber diameter size of 278+/-98 nm were introduced into the PPC fiber mats by freeze drying. Morphological analyses showed that the PPC scaffolds treated with 0.05 mg/ml chitosan solution provided the best micro and nanofiber structure with abundant chitosan nanofibers but without the formation of films. Surface chemical properties were analyzed by X-ray photoelectron spectroscopy (XPS). The initial water contact angle of the scaffolds decreased from 122.3+/-0.4 degrees for neat PPC scaffolds to 53.8+/-1.6 degrees for scaffolds with plasma treatment and chitosan nanofibers. The mechanical properties of the scaffolds were affected by plasma treatment with Young's modulus experiencing a reduction of 63%. Meanwhile, Young's modulus experienced a 26% improvement after the introduction of chitosan nanofibers. Fibroblast cells were cultured on the scaffolds to study the effects of both the plasma treatment and the introduction of chitosan nanofibers on cell adhesion, proliferation, and morphology. The scaffolds with PPC microfibers and chitosan nanofibers showed a superior cell response in terms of cell attachment, cell proliferation, and cell-scaffold interactions over the other scaffolds. PMID- 25498722 TI - Creep behavior of starch-based nanocomposite films with cellulose nanofibrils. AB - Nanocomposite films were successfully prepared by incorporating cellulose nanofibrils (CNFs) from sugar beet pulp into plasticized starch (PS) at CNFs concentration of 5-20%. The storage (G') and loss (G") moduli, creep and creep recovery behavior of these films were studied. The creep behavior of these films at long time frame was studied using time-temperature superposition (TTS). The CNFs were uniformly distributed within these films up to 15% of CNFs. The PS-only and the PS/CNFs nanocomposite films exhibited dominant elastic behavior. The incorporation of CNFs increased both the G' and G". The CNFs improved the creep resistance and reduced the creep recovery rate of the PS/CNFs nanocomposite films. TTS method was successfully used to predict the creep behavior of these films at longer time frame. Power law and Burgers model were capable (R(2)>0.98) of fitting experimental G' versus angular frequency and creep strain versus time data, respectively. PMID- 25498723 TI - Inulin crystal initiation via a glucose-fructose cross-link of adjacent polymer chains: atomic force microscopy and static molecular modelling. AB - Semi-crystalline microparticles of inulin (MPI) have clinical utility as potent human vaccine adjuvants but their relevant surface structure and crystal assembly remain undefined. We show inulin crystal surfaces to resemble multi-layered, discoid radial spherulites resulting from very rapid formation of complex tertiary structures, implying directed crystal initiation. Physical and in silico molecular modelling of unit cells confirm steric feasibility of initiation by hydrogen-bonded cross-linking of terminal glucose to a fructose of another chain, mimicking bonding in sucrose crystals. A strong, chelate-like dual H-bond is proposed to compel the known antiparallel alignment of inulin chains. Such cross linking would require one extra fructose per chain in the native inulin crystal, as observed. Completion of five H-bonded internal ring-domains would 'lock in' each new 6-fructose structural unit of each antiparallel helix pair to create a new isoform. All known properties of inulin isoforms follow readily from these concepts. PMID- 25498724 TI - Modification of chitosan with monomethyl fumaric acid in an ionic liquid solution. AB - Antibacterial and antioxidant monomethyl fumaric acid (MFA) was selected to modify chitosan, using aqueous solution of an ionic liquid as a homogeneous and green reaction media. The chemical structures of resulting polymers were systematically characterized by (1)H NMR, diffusion ordered spectroscopy, solid (13)C NMR and wide-angle X-ray diffraction. The results show that two kinds of MFA modified chitosan materials with totally different chemical structures have been synthesized. One product was a MF-chitosan salt composed of chitosan cation and MFA anion, which was obtained with the mediation of 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide. The other one synthesized with the mediation of EDC was a MF-chitosan amide in which MFA and chitosan are covalently attached. Solubility of chitosan has been improved, and MF-chitosan salt can be readily dissolved in water. The antioxidant activity has been enhanced with the introduction of MFA, irrespective of the chemical structure. PMID- 25498725 TI - A comparative study of the neutral and acidic polysaccharides from Allium macrostemon Bunge. AB - Neutral and acidic polysaccharides, named AMP40N and AMP40S respectively, were isolated and purified from the dried bulbs of Allium macrostemon Bunge. Both of them showed a single and symmetrically sharp peak, indicating they were homogeneous polysaccharides. Molecular weights of AMP40N and AMP40S were determined to be 18.2 and 105.1 kDa, respectively. AMP40N was composed of arabinose and glucose, while AMP40S was composed of rhamnose, arabinose, glucose and galactose and a certain amount of uronic acid. FT-IR, periodic acid oxidation, Smith degradation, methylation and GC-MS analysis revealed that non reducing terminal and ->2,6)-Glc-(1-> existed in AMP40N and AMP40S. The glycosidic linkage of arabinose in AMP40N was ->2)-Ara-(1->, whereas it was Ara (1-> in AMP40S. AMP40S had (1->2)-linked l-rhamnose residue. Both AMP40N and AMP40S exhibited strong anti-tumor potential against human gastric carcinoma cells BGC-823, in particular, AMP40S presented significantly higher inhibitory rate of 85.94% than AMP40N of 52.63%. PMID- 25498726 TI - Effect of structure and viscosity of the components on some properties of starch rich hybrid blends. AB - Glycerol-plasticized cornstarch and poly(lactic acid) (PLA) were melt-blended alone and at a constant 70:30 (m/m) composition, in the present of an organoclay. The effect of increasing contents of the organoclay on extruded and compression molded samples was evaluated by X-ray diffraction (XRD), capillary rheometry, thermogravimetric analysis (TGA), scanning electron microscopy (SEM), and tensile tests. XRD and shear viscosity results obtained for the hybrid components (TPS/organoclay and PLA/organoclay) were correlated with the hybrid blends properties. XRD and TGA results suggested that the organoclay was similarly dispersed within both phases. SEM images revealed improved adhesion between the phases. Shear viscosities results indicated improved compatibilization as the organoclay content was increased. Some of the extruded materials were also submitted to injection molding, and characterized by SEM and by tensile tests. For the extruded and compression-molded samples, improved mechanical properties were obtained for the samples with higher contents of the organoclay. For the injection-molded samples, the mechanical properties seemed to be dependent on the organoclay dispersion. PMID- 25498727 TI - Enhancing antibacterium and strength of cellulosic paper by coating triclosan loaded nanofibrillated cellulose (NFC). AB - The nanofibrillated cellulose (NFC) was used as substrates to carry triclosan (TCS), which was then applied as a coating agent for impacting antibacterial property to paper while also improving its strength. The TCS-loaded NFC material was further characterized. UV-vis spectra results showed that a characteristic absorption band at 282 nm was observed, which was attributed to triclosan, confirming its successful loading onto NFC. The antibacterial activity tests indicated that the coated paper exhibited excellent antibacterial activity against Escherichia coli, and the growth inhibition of bacteria (GIB) increased as the loading amount of triclosan coated on paper increased. The GIB can reach 98.7% when the 0.023 g TCS-loaded NFC was coated on paper. Meanwhile, the tensile and tear index of the coated paper increased by 18.0% and 26.4%, respectively compared to the blank paper. Therefore, the triclosan-loaded paper could be potentially used in the medical field. PMID- 25498728 TI - Structure of Arabidopsis leaf starch is markedly altered following nocturnal degradation. AB - Little is known about the thermal properties and internal molecular structure of transitory starch. In this study, granule morphology, thermal properties, and the cluster structure of Arabidopsis leaf starch at beginning and end of the light period were explored. The structural properties of building blocks and clusters were evaluated by using diverse chromatographic techniques. On the granular level, starch from end of day had larger granule size, thinner crystalline lamellae thickness, lower free surface energy of crystals, and lower tendency to retrograde than that from end of night. On the molecular level, the starch had lower amylose content, larger cluster size, and higher number of blocks per cluster at the end of day than at end of night. It is concluded that the core of the granules contains a more permanent molecular and less-ordered physical structure different from the transitory layers laid down around the core at daytime. PMID- 25498729 TI - Acetylation of bleached Kraft pulp: effect of xylan content on properties of acetylated compounds. AB - Bleached Kraft pulp (BKP) from Eucalyptus globulus and cotton xylan blends (CXB) was acetylated. The effects of xylan content on cellulose acetylation and the properties of the acetylated material were studied. An increase in xylan content caused a slight decrease in the degree of substitution (2.98 to 2.68 for CXB; 2.93 to 2.84 for BKP). Thermal analysis showed that the melting temperature also decreases from 268.0 to 188.8 degrees C for CXB and from 221.4 to 212.8 degrees C for BKP. Moreover, the solubility decreased due to the partial dissolution of acetylated xylans. The presence of xylans during Kraft pulp acetylation does not have a significant negative effect on the physical properties of the acetylated material, but the decrease in melting temperature was beneficial for the application of acetylated polymer as a natural internal plasticizer. This is considered to be an important argument for BKP utilization in the cellulose acetate manufacturing process. PMID- 25498730 TI - Purification and structural characterization of Chinese yam polysaccharide and its activities. AB - Purification and structural characterization of Chinese yam polysaccharide were investigated and its activities were analyzed. Results indicated that a single component polysaccharide with a molecular weight of 16,619 Da was obtained after hot water extraction with sequential sevage deproteinization, HSCCC and Sephadex G-100 size-exclusion chromatography. The FTIR analysis showed that it had characteristic absorptive peaks and contained uronic acid. The methylation and GC MS analysis showed that it comprised of glucose and galactose with a molar ratio of 1.52:1, and that it mainly contained 1,3-linked-glc, 1-linked-gal and 1,6 linked-gal glycosidic bonds. (1)H NMR and (13)C NMR spectra analysis showed that there were two alpha-configurations and one beta-configuration, and that beta-1,3 glucose, alpha-1-galactose, alpha-1,6-galactose might exist in the structure of the purified polysaccharide. The determination of the antioxidative activity showed that it could scavenge hydroxyl and superoxide radicals. The purified polysaccharide displayed a certain inhibitory activity against Escherichia coli, with a MIC of 2.5 mg/mL. PMID- 25498731 TI - New emulsifying and cryoprotective exopolysaccharide from Antarctic Pseudomonas sp. ID1. AB - Pseudomonas sp. ID1 is a cold-adapted bacterium isolated from a marine sediment sample collected from South Shetland Islands (Antarctica) that is noted for the highly mucous appearance of its colonies. In this work, we have characterized an exopolysaccharide (EPS) produced by this strain, which is mainly composed of glucose, galactose and fucose, and has a molecular mass higher than 2*10(6) Da. We have also studied its potential biotechnological applications as an emulsifier and cryoprotectant agent. The EPS emulsifying activity against different food and cosmetic oils was much higher than commercial gums such as xanthan gum and arabic gum, and surfarctants such as Span 20. It formed highly stable emulsions against the cosmetic oil cetiol V, exhibiting pseudoplastic flow behavior, low thixotrophy and yield stress. The EPS of Pseudomonas sp. ID1 conferred significant cryoprotection for the strain itself as well as for other bacteria, including Escherichia coli, suggesting a universal cryoprotectant role. The cryoprotective activity of the EPS showed a clear dose-response relation at -20 degrees C and -80 degrees C and was significantly higher than that observed for the membrane stabilizer fetal bovine serum (FBS). These properties make the EPS of Pseudomonas sp. ID1 a promising alternative to commercial polysaccharides as an emulsifier and cryoprotectant agent for food, pharmaceutical and cosmetic industries. PMID- 25498733 TI - Clinical trials for multiple system atrophy. PMID- 25498732 TI - Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. AB - BACKGROUND: Multiple system atrophy is a complex neurodegenerative disorder for which no effective treatment exists. We aimed to assess the effect of rasagiline on symptoms and progression of the parkinsonian variant of multiple system atrophy. METHODS: We did this randomised, double-blind, placebo-controlled trial between Dec 15, 2009, and Oct 20, 2011, at 40 academic sites specialised in the care of patients with multiple systemic atrophy across 12 countries. Eligible participants aged 30 years or older with possible or probable parkinsonian variant multiple system atrophy were randomly assigned (1:1), via computer generated block randomisation (block size of four), to receive either rasagiline 1 mg per day or placebo. Randomisation was stratified by study centre. The investigators, study funder, and personnel involved in patient assessment, monitoring, analysis and data management were masked to group assignment. The primary endpoint was change from baseline to study end in total Unified Multiple System Atrophy Rating Scale (UMSARS) score (parts I and II). Analysis was by modified intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00977665. FINDINGS: We randomly assigned 174 participants to the rasagiline group (n=84) or the placebo group (n=90); 21 (25%) patients in the rasagiline group and 15 (17%) in the placebo group withdrew from the study early. At week 48, patients in the rasagiline group had progressed by an adjusted mean of 7.2 (SE 1.2) total UMSARS units versus 7.8 (1.1) units in those in the placebo group. This treatment difference of -0.60 (95% CI -3.68 to 2.47; p=0.70) was not significant. 68 (81%) patients in the rasagiline group and 67 (74%) patients in the placebo group reported adverse events, and we recorded serious adverse events in 29 (35%) versus 23 (26%) patients. The most common adverse events in the rasagiline group were dizziness (n=10 [12%]), peripheral oedema (n=9 [11%]), urinary tract infections (n=9 [11%]), and orthostatic hypotension (n=8 [10%]). INTERPRETATION: In this population of patients with the parkinsonian variant of multiple system atrophy, treatment with rasagiline 1 mg per day did not show a significant benefit as assessed by UMSARS. The study confirms the sensitivity of clinical outcomes for multiple system atrophy to detect clinically significant decline, even in individuals with early disease. FUNDING: Teva Pharmaceutical Industries and H Lundbeck A/S. PMID- 25498734 TI - Validity of the modified Charlson Comorbidity Index as predictor of short-term outcome in older stroke patients. AB - The modified Charlson Comorbidity Index (MCCI) has been proposed as a tool for adjusting the outcomes of stroke for comorbidity, but its validity in such a context has been evaluated in only a few studies and needs to be further explored, especially in elderly patients. We aimed to retrospectively assess the validity of the MCCI as a predictor of the short-term outcomes in a cohort of 297 patients with first-ever ischemic stroke, older than 60 years, and managed according to a clinical pathway. The poor outcome (PO) at 1 month, defined as a modified Rankin Scale score of 3-6, was the primary end point. Furthermore, a new comorbidity index has been developed, specific to our cohort, according to the same statistical approach used for the original CCI. The MCCI showed a positive association with PO (odds ratio [OR] 1.62; 95% confidence interval [CI] .98-2.68) and mortality (hazard ratio [HR] 1.85; 95% CI .94-3.61), not statistically significant and totally dependent on its association with the severity of neurologic impairment at onset. The new comorbidity index showed, as expected, a significant association with the PO and mortality with higher point estimates of OR (2.74; 95% CI 1.64-4.59) and HR (2.73; 95% CI 1.51-4.94), but this association was also dependent on stroke severity and premorbid disability. Our results do not support the validity of the MCCI as a predictor of the short-term outcomes in elderly stroke patients nor could we develop a more valid index from the available data. This suggests the need for development of disease- and age specific indexes, possibly according to a prospective design. In any case, initial stroke severity, a strong predictor of outcome, is associated with the degree of comorbidity. PMID- 25498735 TI - Do billing codes accurately capture intravenous tissue plasminogen activator treatment rates? Justified concern for clinical performance measures based on billing code assignment. AB - BACKGROUND: International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes are commonly used to determine US national stroke volume and intravenous (IV) tissue plasminogen activator (tPA) treatment rates; however, this method is often criticized because of assumed poor validity and reliability of coding assignment. We sought to understand the validity of IV tPA ICD-9-CM code assignments within a comprehensive stroke center in the southeastern United States. METHODS: Confirmed stroke registry IV tPA cases were retrieved from 2009 to 2011; tPA drip and ship cases were eliminated from the analysis. Retained clinical data included admission National Institutes of Health Stroke Scale (NIHSS) scores, hemorrhagic transformation, diffusion positive magnetic resonance imaging (MRI) results, and discharge modified Rankin Scale (mRS) score. RESULTS: A total of 247 IV tPA cases were assembled, of which 78% were appropriately assigned the IV tPA billing code. ICD-9 code 434.91 (cerebral artery occlusion with infarct) was used for 72% of the sample, 434.11 (cerebral emboli with infarct) was used for 9% of cases, and 433.11 (carotid occlusion with infarct) was assigned to 2% of cases. Interestingly, 435 (transient cerebral ischemia) was assigned to 2% (n = 7) with all of these cases having NIHSS score more than 2 at time of treatment, diffusion MRI documentation of infarction in 29%, and 43% having a discharge mRS score more than 2. CONCLUSIONS: Our findings support the concern that billing codes may significantly underestimate actual IV tPA treatment volume in the United States and suggest the need for regular audit of billing codes by Stroke Center leaders, with provision of feedback and education to coders, aimed at improving code assignment. PMID- 25498736 TI - The impact of uric acid on long-term mortality in patients with asymptomatic carotid atherosclerotic disease. AB - BACKGROUND: Serum uric acid (SUA) has been discussed to be related to cardiovascular (CV) disease and outcome. We investigated whether levels of SUA predict long-term mortality in neurologically asymptomatic patients with carotid atherosclerotic disease. METHODS: We prospectively studied 959 consecutive patients with carotid atherosclerosis as evaluated by duplex Doppler sonography for all-cause and CV death, respectively. RESULTS: During a median follow-up time of 6.3 years (interquartile range [IQR], 5.4-7.1 years), 246 deaths (25.7%), including 160 CV deaths (16.7%), were recorded. Median baseline SUA levels were 5.9 mg/dL (IQR, 5.0-7.0 mg/dL). SUA was significantly associated with all-cause death and CV death. Adjusted hazard ratios (HRs) for an increase of 1 mg/dL of SUA levels were 1.12 (95% confidence interval [CI], 1.04-1.21; P = .003) and 1.20 (95% CI, 1.11-1.30; P < .001) for all-cause and CV death, respectively. Quartiles of SUA levels showed a significant association with CV mortality (log-rank P = .002). For CV death, adjusted HRs for quartiles of increasing SUA levels were 1.45 (95% CI, .87-2.43), 1.44 (95% CI, .85-2.46), and 2.26 (95% CI, 1.36-3.76; P < .01), compared with the lowest quartile, respectively. Patients with baseline carotid stenosis of more than 50% and/or increased levels of SUA (>=median) had an approximately 2-fold increase in risk of (CV) death, compared with patients with carotid narrowing of less than 50% and/or SUA levels less than the median (P < .001). CONCLUSIONS: Levels of SUA represent independent predictors for CV mortality in a cohort of patients with asymptomatic carotid atherosclerosis. PMID- 25498737 TI - Prospective evaluation of blood coagulability and effect of treatment in patients with stroke using rotational thromboelastometry. AB - BACKGROUND: Stroke is the second largest cause of death worldwide. Abnormalities in hemostasis play an important role in the pathophysiology of ischemic stroke (IS). These hemostatic defects can be detected using rotational thromboelastometry (ROTEM) as a global method of measuring coagulation. This study assessed the effects of IS on blood hypercoagulability using ROTEM method, before and subsequent to therapeutic interventions. METHODS: In a prospective observational cohort study, whole blood coagulation using ROTEM, along with full blood count and standard coagulation tests, were compared between patients with IS and an age-matched control group of healthy volunteers. Further assessment took place at 2-4 hours and at 24 hours in the stroke group after therapy to assess the effects of therapeutic intervention. RESULTS: Seventy-two patients with IS were age-matched to 71 healthy subjects. Clotting time (CT) INTEM (P = .01) and maximum clot firmness (MCF) INTEM (P = .02) were significantly different between stroke patients at baseline and healthy subjects, but this difference disappeared when controlled for by smoking status. There was no association between ROTEM parameters and time from stroke symptom onset or stroke severity as reflected in The National Institute of Health Stroke Scale score. Significant but small changes in the values of MCF-EXTEM, clot formation time (CFT) EXTEM, and alpha-EXTEM CT were observed after therapeutic intervention (thrombolysis or aspirin treatment). CONCLUSIONS: ROTEM testing does not seem to detect a hypercoagulable state in patients with IS. Nonetheless, some ROTEM parameters had a small change after antiplatelet therapy or thrombolysis. PMID- 25498738 TI - Methodology of the Stroke Self-Management Rehabilitation Trial: an international, multisite pilot trial. AB - RATIONALE: Stroke is a major cause of long-term adult disability with many survivors living in the community relying on family members for on-going support. However, reports of inadequate understanding of rehabilitation techniques are common. A self-management DVD-based observational learning tool may help improve functional outcomes for survivors of stroke and reduce caregivers' burden. AIMS: This article describes the methodology of the stroke self-management rehabilitation trial. The overall aim of this pilot trial is to assess the feasibility and preliminary efficacy of a DVD-based intervention for improving functional outcomes of survivors of stroke 2 months postrandomization to inform the design of a full-scale randomized clinical trial. DESIGN: Recruitment of a minimum of 20 survivors of stroke and their informal caregivers (where available) in each of the participating centers will occur across multiple international sites. After baseline assessments, participants will be randomly assigned to an intervention or standard care group. The intervention comprises a structured DVD observation and practice schedule over 8 weeks. All participants will complete follow-up assessments. STUDY OUTCOMES: The outcome measures will include a global shift in the Rankin Scale scores and dichotomized scores, changes in quality of life, general health, depression, and caregiver burden at 2 months postrandomization. A qualitative analysis of the effects of the intervention will also be undertaken. DISCUSSION: The results of the pilot study will provide knowledge of whether observational learning techniques delivered via DVD can effectively improve recovery after stroke and reduce caregiver burden. PMID- 25498739 TI - Combined exposure to hypercapnia and hypoxia provides its maximum neuroprotective effect during focal ischemic injury in the brain. AB - BACKGROUND: In the present research, we compared the neuroprotective efficiency of combined and isolated exposure to hypoxia and hypercapnia preceding focal cerebral ischemic injury in rats. The study was conducted to verify the hypothesis of a possible increase in normobaric hypoxia (NbH; 90 mm Hg) efficiency when combined with permissive hypercapnia (PH; 50 mm Hg). METHODS: The rats from the test groups were subjected to a 15-fold exposure to NbH (90 mm Hg) and/or PH (50 mm Hg). After the 15th exposure, cerebral ischemic injury was induced by photochemical thrombosis. Seventy-two hours later, neurologic deficit was determined on the Neurological Severity Score scale and by the rotarod test, and the volume of cerebral infarction was measured after focal photochemical thrombosis. RESULTS: The neurologic deficit decreased most efficiently in rats that underwent PH and hypercapnic hypoxia (HH) exposure, whereas NbH had no impact on the neurologic status of the animals. On the contrary, motor coordination disturbances were minimal during exposure to hypoxia and HH. All respiratory interventions reduced the cerebral ischemic infarction volume in rats. The smallest infarction volumes were registered in the area of photochemical thrombosis in rats from the hypercapnic-hypoxic impact group, whereas exposure to NbH or PH did not show any cross difference. CONCLUSIONS: The impact of PH has greater neuroprotective potential compared with NbH. Thus, we can assume that hypercapnia is a predominant factor in providing neuroprotection in combination with hypoxia. PMID- 25498741 TI - Nurses as scapegoats in Ebola virus disease response. PMID- 25498740 TI - Developmental level and psychopathology: comparing children with developmental delays to chronological and mental age matched controls. AB - Children with developmental delays (DD) are at heightened risk for developing clinically significant behavioral and emotional difficulties as compared to children with typical development (TD). However, nearly all studies comparing psychopathology in youth with DD employ TD control groups of the same chronological age (CA). It is unclear, then, whether the heightened symptomology found in age-matched children with DD is beyond what would be expected given their developmental level. The present study assessed rates of behavior problems and mental disorder in 35 children with DD at age 9 years. These were compared with rates from 35 children with TD matched for CA at age 9 and also earlier rates for these same children at age 6, when matched for mental age (MA). Children with DD had significantly more behavior problems in 7 of the 17 scales of the CBCL when compared to TD children matched for CA, and 6 of 17 scales when compared to the MA-matched group. Rates of meeting DSM-IV criteria for a psychiatric disorder were significantly higher in the DD group than both the CA- and MA-matched TD groups for three and four, respectively, of the seven diagnoses examined. Descriptively, the mean ratings for all variables assessed were higher for the DD group than both TD comparison groups, with the exception of the Anxious/Depressed scale of the CBCL. These findings validate the heightened risk for clinically significant behavior problems and mental disorders in youth with DD above and beyond their developmental functioning. PMID- 25498742 TI - The impact of abdominal massage administered to intubated and enterally fed patients on the development of ventilator-associated pneumonia: a randomized controlled study. AB - BACKGROUND: Enteral nutrition is one of the major risk factors for ventilator associated pneumonia. Abdominal massage is assumed to prevent the development of ventilator-associated pneumonia by reducing residual gastric volume. OBJECTIVES: To identify the effect of abdominal massage administered to critically ill patients with mechanical ventilation and continuous enteral feeding on the development of ventilator-associated pneumonia. DESIGN: A randomized controlled design was used in this study. SETTING: This study was performed in a critical care unit of a university hospital in Turkey. PARTICIPANTS: The sample of the study consisted of a total of 32 patients, selected randomly to receive abdominal massage (n=16) and a control group (n=16). The stratified randomization was used in this study. Patients were stratified according to age and gender. METHODS: A fifteen-minute abdominal massage was administered to the patients in the intervention group twice daily. No intervention was administered to the patients in the control group. RESULTS: At the end of monitoring days a reduction, compared to the control patients, was identified. The amount of gastric residual volume and abdominal circumference measurement of the patients in the intervention group had decreased. This reduction was found to be significant in the statistical analysis (p<0.05). Also, although not reaching the statistical significance level, ventilator-associated pneumonia decreased in the intervention group with a ratio of 6.3% compared to the control group (31.3%) (p>0.05). CONCLUSION: This study revealed that abdominal massage administered to intubated and enterally fed patients reduced gastric residual volume and abdominal distension. In addition, a decrease in the ratio of ventilator-associated pneumonia was determined. PMID- 25498743 TI - Learning with sublexical information from emerging reading vocabularies in exceptionally early and normal reading development. AB - Predictions from theories of the processes of word reading acquisition have rarely been tested against evidence from exceptionally early readers. The theories of Ehri, Share, and Byrne, and an alternative, Knowledge Sources theory, were so tested. The former three theories postulate that full development of context-free letter sounds and awareness of phonemes are required for normal acquisition, while the claim of the alternative is that with or without such, children can use sublexical information from their emerging reading vocabularies to acquire word reading. Results from two independent samples of children aged 3 5, and 5 years, with mean word reading levels of 7 and 9 years respectively, showed underdevelopment of their context-free letter sounds and phoneme awareness, relative to their word reading levels and normal comparison samples. Despite such underdevelopment, these exceptional readers engaged in a form of phonological recoding that enabled pseudoword reading, at the level of older-age normal controls matched on word reading level. Moreover, in the 5-year-old sample further experiments showed that, relative to normal controls, they had a bias toward use of sublexical information from their reading vocabularies for phonological recoding of heterophonic pseudowords with irregular consistent spelling, and were superior in accessing word meanings independently of phonology, although only if the readers were without exposure to explicit phonics. The three theories were less satisfactory than the alternative theory in accounting for the learning of the exceptionally early readers. PMID- 25498744 TI - What is the link between synaesthesia and sound symbolism? AB - Sound symbolism is a property of certain words which have a direct link between their phonological form and their semantic meaning. In certain instances, sound symbolism can allow non-native speakers to understand the meanings of etymologically unfamiliar foreign words, although the mechanisms driving this are not well understood. We examined whether sound symbolism might be mediated by the same types of cross-modal processes that typify synaesthetic experiences. Synaesthesia is an inherited condition in which sensory or cognitive stimuli (e.g., sounds, words) cause additional, unusual cross-modal percepts (e.g., sounds trigger colours, words trigger tastes). Synaesthesia may be an exaggeration of normal cross-modal processing, and if so, there may be a link between synaesthesia and the type of cross-modality inherent in sound symbolism. To test this we predicted that synaesthetes would have superior understanding of unfamiliar (sound symbolic) foreign words. In our study, 19 grapheme-colour synaesthetes and 57 non-synaesthete controls were presented with 400 adjectives from 10 unfamiliar languages and were asked to guess the meaning of each word in a two-alternative forced-choice task. Both groups showed superior understanding compared to chance levels, but synaesthetes significantly outperformed controls. This heightened ability suggests that sound symbolism may rely on the types of cross-modal integration that drive synaesthetes' unusual experiences. It also suggests that synaesthesia endows or co-occurs with heightened multi-modal skills, and that this can arise in domains unrelated to the specific form of synaesthesia. PMID- 25498745 TI - Why loose rings can be tight: the role of learned object knowledge in the development of Korean spatial fit terms. AB - The Korean fit distinction has been at the center of a debate about whether language can influence spatial concepts. Most research on this issue has largely assumed that the concepts that support Korean fit terms are signaled by innate abstract visual cues (e.g., relative motion of objects), while linguistic studies in Korean suggest that fit terms are object-specific. To examine this issue, Korean-speaking three- to six year-old children and adults were asked to describe spatial scenes, which varied in object type/relations and visual cues for fit. Both groups relied on the prototypical relation between pairs of objects (e.g., rings tend to fit tightly on fingers) in selecting tight-fit terms, and this dependence increased with age. In contrast to Whorfian and Conceptual tuning accounts (Bowerman & Choi, 2003; Hespos & Spelke, 2004), these results suggest that Korean fit concepts are not entirely innate or abstract. PMID- 25498746 TI - Infants' representations of others' goals: representing approach over avoidance. AB - Goals fall into two broad types--approach and avoidance. Research on infants' early goal understanding has focused only on approach goals, usually assuming that infants will encode an ambiguous display where an actor picks one object over another as the actor wanting to approach the former rather than avoid the latter. We investigated infants' understanding of approach and avoidance separately by presenting 7-month-olds with a hand either consistently approaching, or consistently avoiding, an object. Infants dishabituated to a disruption of the consistent approach pattern, but not of the consistent avoidance pattern. In the second experiment, we show that 14-month-olds, who have a richer understanding of goals, still do not dishabituate when a hand first reaches to and picks up an object it has consistently avoided before. A third experiment found that 7-month-olds successfully dishabituated to the first motion of a previously stationary object when all the objects moved on their own with no hand present, ruling out several low-level interpretations of infants' failure to dishabituate to the violations of the avoidance pattern in Experiments 1 and 2. We conclude that infants do not represent avoidance from the same type of evidence they can use to represent approach. PMID- 25498747 TI - Cross-linguistic gestures reflect typological universals: a subject-initial, verb final bias in speakers of diverse languages. AB - In communicating events by gesture, participants create codes that recapitulate the patterns of word order in the world's vocal languages (Gibson et al., 2013; Goldin-Meadow, So, Ozyurek, & Mylander, 2008; Hall, Mayberry, & Ferreria, 2013; Hall, Ferreira, & Mayberry, 2014; Langus & Nespor, 2010; and others). Participants most often convey simple transitive events using gestures in the order Subject-Object-Verb (SOV), the most common word order in human languages. When there is a possibility of confusion between subject and object, participants use the order Subject-Verb-Object (SVO). This overall pattern has been explained by positing an underlying cognitive preference for subject-initial, verb-final orders, with the verb-medial order SVO order emerging to facilitate robust communication in a noisy channel (Gibson et al., 2013). However, whether the subject-initial and verb-final biases are innate or the result of languages that the participants already know has been unclear, because participants in previous studies all spoke either SVO or SOV languages, which could induce a subject initial, verb-late bias. Furthermore, the exact manner in which known languages influence gestural orders has been unclear. In this paper we demonstrate that there is a subject-initial and verb-final gesturing bias cross-linguistically by comparing gestures of speakers of SVO languages English and Russian to those of speakers of VSO languages Irish and Tagalog. The findings show that subject initial and verb-final order emerges even in speakers of verb-initial languages, and that interference from these languages takes the form of occasionally gesturing in VSO order, without an additional bias toward other orders. The results provides further support for the idea that improvised gesture is a window into the pressures shaping language formation, independently of the languages that participants already know. PMID- 25498748 TI - Emphasizing the only character: emphasis, attention and contrast. AB - In conversations, pragmatic information such as emphasis is important for identifying the speaker's/writer's intention. The present research examines the cognitive processes involved in emphasis processing. Participants read short discourses that introduced one or two character(s), with the character being emphasized or non-emphasized in subsequent texts. Eye movements showed that: (1) early processing of the emphasized word was facilitated, which may have been due to increased attention allocation, whereas (2) late integration of the emphasized character was inhibited when the discourse involved only this character. These results indicate that it is necessary to include other characters as contrastive characters to facilitate the integration of an emphasized character, and support the existence of a relationship between Emphasis and Contrast computation. Taken together, our findings indicate that both attention allocation and contrast computation are involved in emphasis processing, and support the incremental nature of sentence processing and the importance of contrast in discourse comprehension. PMID- 25498749 TI - Eye movements reveal memory processes during similarity- and rule-based decision making. AB - Recent research suggests that when people retrieve information from memory they tend to fixate on the location where the information had appeared during encoding. We used this phenomenon to investigate if different information is activated in memory when people use a rule- versus a similarity-based decision strategy. In two studies, participants first memorized multiple pieces of information about various job candidates (exemplars). In subsequent test trials they judged the suitability of new candidates that varied in their similarity to the previously learned exemplars. Results show that when using similarity, but not when using a rule, participants fixated longer on the previous location of exemplars that resembled the new candidates than on the location of dissimilar exemplars. This suggests that people using similarity retrieve previously learned exemplars, whereas people using a rule do not. The study illustrates that eye movements can provide new insights into the memory processes underlying decision making. PMID- 25498750 TI - Animal cell substrates for the production of biologicals: An introduction to WHO documents. PMID- 25498751 TI - Development of an intravenous immunoglobulin with improved safety and functional activity. AB - The development and properties of a liquid intravenous immunoglobulin (Gammaplex((r))), of high purity, stability and functional activity, is described. Virus and TSE reduction by specific steps in the process were evaluated by spiking studies using small-scale models. The removal of procoagulant activity was determined using immunochemical and functional activity assays. Neutralisation and opsonic activity were used to demonstrate the functional activity of the IgG. The final low pH formulated product was stable at room temperature and was of high purity and functional activity. Three dedicated virus inactivation steps, i.e. solvent detergent, low pH and virus filtration, were shown to be effective. When combined with the B + I ethanol precipitation step, this gave a total reduction of >21 to >24 log for the enveloped and >10 to >13 log for the non-enveloped viruses tested. Several steps in the process were shown to contribute to TSE removal using scrapie. Potential procoagulant activity including Factor XI/XIa, was reduced to very low/undetectable levels in the final product. A new high purity liquid IVIG product has been developed, of high purity and good functional activity and stability. The process includes various steps for the removal of pathogens and procoagulant activity. PMID- 25498752 TI - ADAMTS13 content and VWF multimer and triplet structure in commercially available VWF/FVIII concentrates. AB - ADAMTS13 is a metalloproteinase that cleaves von Willebrand factor (VWF) into smaller multimers in vivo. This cleavage creates both the typical multimeric size distribution and the characteristic triplet band distribution of VWF. Here we analysed ADAMTS13 content, VWF multimeric size distribution and VWF triplet structure in five commercial VWF/factor VIII (FVIII) concentrates. The relative distribution of ADAMTS13 activity values corresponded well to the ADAMTS13 antigen values for all examined concentrates except Haemate HS(r), which had markedly higher ADAMTS13 antigen/activity ratio, with Fanhdi(r) and Haemate HS(r) displaying the most intense ADAMTS13 signal. Interestingly, ADAMTS13 levels did not correlate with the high molecular weight multimer content of the concentrates, but did correlate with VWF triplet distribution. Densitometric quantification showed that Wilate(r), Immunate(r) and Willfact(r) displayed human plasma-like VWF triplet distribution, whereas Fanhdi(r) and Haemate HS(r) showed enhanced content of the faster migrating triplet band, which corresponded well to their higher ADAMTS13 content. In summary, Immunate(r), Willfact(r) and Wilate(r) had lower levels of ADAMTS13 antigen and activity and exhibited a plasma-like VWF triplet structure. Fanhdi(r) and Haemate HS(r) had higher ADAMTS13 content and an altered triplet structure. The possible impact of these observations on function and clinical efficacy of VWF/FVIII concentrates is discussed. PMID- 25498753 TI - Tribute to Jonna Barry. PMID- 25498754 TI - Reply to: Is drinking to thirst a prudent guideline to avoid hyponatremia? PMID- 25498755 TI - A novel mutation in lamin a/c causing familial dilated cardiomyopathy associated with sudden cardiac death. AB - BACKGROUND: Dilated cardiomyopathy (DCM), a cardiac heterogeneous pathology characterized by left ventricular or biventricular dilatation, is a leading cause of heart failure and heart transplantation. The genetic origin of DCM remains unknown in most cases, but >50 genes have been associated with DCM. We sought to identify the genetic implication and perform a genetic analysis in a Spanish family affected by DCM and sudden cardiac death. METHODS AND RESULTS: Clinical assessment and genetic screening were performed in the index case as well as family members. Of all relatives clinically assessed, nine patients showed clinical symptoms related to the pathology. Genetic screening identified 20 family members who carried a novel mutation in LMNA (c.871 G>A, p.E291K). Family segregation analysis indicated that all clinically affected patients carried this novel mutation. Clinical assessment of genetic carriers showed that electrical dysfunction was present previous to mechanical and structural abnormalities. CONCLUSIONS: Our results report a novel pathogenic mutation associated with DCM, supporting the benefits of comprehensive genetic studies of families affected by this pathology. PMID- 25498756 TI - Nicotinamide phosphoribosyltransferase/pre-B-cell colony enhancing factor/visfatin plasma levels and clinical outcome in patients with dilated cardiomyopathy. AB - BACKGROUND: Nicotinamide phosphoribosyltransferase (Nampt) is an enzyme involved in nicotinamide adenine dinucleotide biosynthesis. Nampt functions as gatekeeper of energy status and survival in cardiac myocytes in animal models of ischemia reperfusion and might regulate inflammatory processes. Therefore, we performed for the 1st time a clinical study to determine the effects of Nampt on cardiac function in patients with nonischemic dilated (DCM) and inflammatory (DCMi) cardiomyopathy. METHODS AND RESULTS: A total of 113 patients were enrolled in the study and classified into control (n = 25), DCM (n = 38), and DCMi (n = 50) groups. Cardiac functional and inflammatory parameters as well as plasma Nampt and cardiac mRNA and protein Nampt expression were determined at baseline and follow-up after 6 months. Patients with DCM (1.04 +/- 0.8 ng/mL; P < .001) and DCMi (1.07 +/- 0.7 ng/mL; P < .001) showed significantly increased Nampt plasma concentrations at baseline compared with the control group (0.57 +/- 0.5 ng/mL). Patients with higher Nampt concentrations in both heart failure groups showed significant better improvement of cardiac functional parameters (correlation between Nampt plasma levels and the change of left ventricular ejection fraction after 6 months: DCM: r = 0.698, P < .001; DCMi: r = 0.503, P < .001). Moreover, cardiac inflammation did not influence Nampt expression, and Nampt concentrations did not modulate cardiac inflammation in DCMi. A multivariate linear regression model revealed high plasma Nampt expression to contribute to better improvement of cardiac function in patients of both heart failure groups. Moreover, heart failure patients with high plasma Nampt levels showed suppressed cardiac TNF alpha and IL-6 mRNA expression after 6 months' follow-up as well as lower B-type natriuretic peptide levels compared with heart failure patients with low Nampt plasma concentrations. CONCLUSIONS: High Nampt expression in patients with nonischemic DCM and DCMi is associated with a favorable outcome and improvement in functional status. PMID- 25498757 TI - Heart failure is a major contributor to hospital readmission penalties. AB - BACKGROUND: The Hospital Readmissions Reduction Program provides incentives to hospitals to reduce early readmissions for heart failure (HF), acute myocardial infarction (AMI), and pneumonia (PNE). METHODS AND RESULTS: To examine the contribution of each diagnosis to readmissions penalty size, data were obtained from the Center for Medicare and Medicaid Services, American Hospital Association, and United States Census Bureau including number of cases; readmissions payment adjustment factor (values <1 indicate a penalty for excess readmissions), excess readmission ratio (ERR, or ratio of adjusted predicted readmission based on comorbidities, frailty, and individual patient demographics to expected probability of readmission at an average hospital) for each diagnosis, hospital teaching status, bed number, and zip code socioeconomic status. Of 2,228 hospitals with >=25 cases per diagnosis, 1,636 received a penalty. Univariate correlation coefficients between penalty and ERR were -0.66, 0.61, and -0.43 for HF, PNE, and AMI, respectively (all P < .001). Correlation between ERRs was greatest for PNE and HF (0.30; P < .001) and weakest for PNE and AMI (0.12; P < .001). In regression analyses, the HF ERR explained the most variance in the penalty (R(2) range 0.21-0.44). CONCLUSION: HF ERR, not the number of cases, was related to penalty magnitude. These findings have implications for the design of hospital-based quality initiatives regarding readmissions. PMID- 25498758 TI - Solitary liver lesions in children: interobserver agreement and accuracy of MRI diagnosis. AB - PURPOSE: The purpose of the study was to evaluate interobserver agreement (IOA) and accuracy of magnetic resonance imaging (MRI) diagnosis of pediatric solitary liver lesions (PSLLs). METHODS: Fifty consecutive MRIs performed for PSLLs were reviewed to assess IOA and agreement between consensus imaging diagnosis and final diagnosis indicating accuracy using kappa statistics. RESULTS: In 39/50 cases, the MRI diagnosis given by two readers matched with substantial IOA (kappa=0.7294). There was moderate agreement (kappa=0.60784) between consensus imaging diagnosis and the final diagnosis in 10 cases with available pathology. CONCLUSION: Based on the limited available pathology and follow-up, we found that most PSLLs can be noninvasively characterized and accurately diagnosed using MRI. PMID- 25498759 TI - DNA barcoding: complementing morphological identification of mosquito species in Singapore. AB - BACKGROUND: Taxonomy that utilizes morphological characteristics has been the gold standard method to identify mosquito species. However, morphological identification is challenging when the expertise is limited and external characters are damaged because of improper specimen handling. Therefore, we explored the applicability of mitochondrial cytochrome C oxidase subunit 1 (COI) gene-based DNA barcoding as an alternative tool to identify mosquito species. In the present study, we compared the morphological identification of mosquito specimens with their differentiation based on COI barcode, in order to establish a more reliable identification system for mosquito species found in Singapore. METHODS: We analysed 128 adult mosquito specimens, belonging to 45 species of 13 genera. Phylogenetic trees were constructed for Aedes, Anopheles, Culex and other genera of mosquitoes and the distinctive clustering of different species was compared with their taxonomic identity. RESULTS: The COI-based DNA barcoding achieved a 100% success rate in identifying the mosquito species. We also report COI barcode sequences of 16 mosquito species which were not available previously in sequence databases. CONCLUSIONS: Our study utilised for the first time DNA barcoding to identify mosquito species in Singapore. COI-based DNA barcoding is a useful tool to complement taxonomy-based identification of mosquito species. PMID- 25498760 TI - A potential role for regulatory T-cells in the amelioration of DSS induced colitis by dietary non-digestible polysaccharides. AB - Inflammatory bowel diseases (IBD) including ulcerative colitis (UC) and Crohn's disease (CD) are chronic relapsing inflammatory disorders of the gastrointestinal tract. The interaction between a disturbed microbial composition, the intestinal mucosal barrier and the mucosal immune system plays an important role in IBD and its chronicity. It has been indicated that due to the altered microbial composition the balance between T regulatory cells (Treg) and T helper cells (Th) 17 is disturbed, leading to an inflammatory state. The present study shows that oral intake of a specific multi fibre mix (MF), designed to match the fibre content of a healthy diet, counteracts IBD-like intestinal inflammation and weight loss in dextran sodium sulphate treated mice. This reduction in inflammation might be brought about, at least in part, by the MF-induced decrease in inflammatory cytokines, increase in IL-10 and the relative increase in Treg cells in the mesenteric lymph nodes (MLN). Moreover, the Treg percentage in the MLN correlates with the percentage of tolerogenic lamina propria derived CD103+RALDH+dendritic cells in the MLN, suggesting that these play a role in the observed effects. In children with CD exclusive enteral nutrition (EEN) is a widely used safe and effective therapy. Optimizing enteral nutritional concepts with the tested fibre mix, know to modulate the gut microbiota composition, SCFA production and inflammatory status (as indicated by the present study) could possibly further improve efficacy in inducing remission. PMID- 25498761 TI - What the Agency for Healthcare Research and Quality forgets to tell Americans about how to protect their sexual and reproductive health. PMID- 25498762 TI - Psychological intimate partner violence and sexual risk behavior: examining the role of distinct posttraumatic stress disorder symptoms in the partner violence sexual risk link. AB - BACKGROUND: Research has examined how physical and sexual intimate partner violence (IPV) victimization increases sexual risk behavior, yet research is lacking on 1) the effect of psychological IPV on sexual risk behavior and 2) factors through which psychological IPV may be linked to sexual risk behavior. METHODS: The current study examined the relationship between psychological IPV and sexual risk behavior controlling for other forms of IPV (i.e., physical and sexual) in a sample of 186 human immunodeficiency virus (HIV)-negative community women currently experiencing IPV. Further, this study examined the potential mediating effects of four posttraumatic stress disorder (PTSD) symptom severity clusters (i.e., re-experiencing, avoidance, numbing, and hyperarousal) on this relationship. FINDINGS: Results revealed that greater severity of psychological IPV was uniquely and directly related to greater sexual risk behavior. Additionally, of the four PTSD symptom severity clusters, only avoidance symptom severity mediated the relationship between psychological IPV and sexual risk behavior. CONCLUSION: Implications for addressing psychological IPV and PTSD to improve women's sexual health outcomes are discussed. PMID- 25498764 TI - Disparities in vaccinations and cancer screening among U.S.- and foreign-born Arab and European American non-Hispanic White women. AB - BACKGROUND: Disparities in vaccinations and cancer screening exist when comparing foreign-born and U.S.-born women collectively and disaggregated by race and ethnicity. The purpose of this study was to estimate and compare the age-adjusted prevalence of not receiving a flu or pneumonia vaccine, clinical breast examination, mammogram or Pap smear among U.S.- and foreign-born White women by region of birth and examine associations while controlling for potential confounders. METHODS: We pooled 12 years of National Health Interview Survey data (n = 117,893). To approximate an "Arab-American" ethnicity, we identified 15 "Arab" countries from the Middle East region that comprise the Arab Nations. Data was requested from the National Center for Health Statistics Research Data Center. We used the chi(2) statistic to compare descriptive statistics and odds ratios (ORs) with 95% CIs were used for inferential statistics. FINDINGS: Compared to U.S.-born, foreign-born Whites from the Arab Nations had higher estimates of not receiving recommended vaccinations and cancer screenings. In crude and adjusted analyses, foreign-born Arab-American women were less likely to report receiving a flu vaccine (OR, 0.34; 95% CI, 0.21-0.58), pneumonia vaccine (OR, 0.14; 95% CI, 0.06-0.32), Pap smear (OR, 0.13; 95% CI, 0.05-0.31), or clinical breast examination (OR, 0.16; 95% CI, 0.07-0.37) compared with U.S.-born White women. There were no differences for mammography. CONCLUSIONS: This national study examining uptake of flu and pneumonia vaccines and preventive cancer screenings suggests that estimates are lower for foreign-born Arab American women compared with U.S.-born White women. Future studies should collect qualitative data that assess the cultural context surrounding prevention and screening behaviors among Arab-American women. PMID- 25498765 TI - Improvement of the chemical content prediction of a model powder system by reducing multiple scattering using polarized light spectroscopy. AB - Near-infrared spectroscopy (NIRS) is a powerful non-destructive analytical method used to analyze major compounds in bulk materials and products and requiring no sample preparation. It is widely used in routine analysis and also in line in industries, in vivo with biomedical applications, or in field for agricultural and environmental applications. However, highly scattering samples subvert Beer Lambert law's linear relationship between spectral absorbance and the concentration. Instead of spectral pre-processing, which is commonly used by NIR spectroscopists to mitigate the scattering effect, we put forward an optical method, i.e., coupling polarized light with NIR spectrometry, to free spectra from scattering effect. This should allow us to retrieve linear and steady conditions for spectral analysis. When tested in visible-NIR (Vis-NIR) range (400 800 nm) on model media, mixtures of scattering and absorbing particles, the setup provided significant improvements in absorber concentration estimation precision as well as in the quality and robustness of the calibration model. PMID- 25498763 TI - Demographic characteristics associated with homelessness and risk among female and male veterans accessing VHA outpatient care. AB - BACKGROUND: This study explored demographic influences on veterans' reports of homelessness or imminent risk of homelessness with a particular focus on gender. METHODS: We analyzed data for a cohort of veterans who responded to the U.S. Department of Veterans Affairs (VA), Veterans Health Administration (VHA) universal screener for homelessness and risk during a 3-month period. Multinomial mixed effects models-stratified by gender-predicted veterans' reports of homelessness or risk based on age, race, marital status, and receipt of VA compensation. FINDINGS: The proportion of positive screens-homelessness or risk was 2.7% for females and 1.7% for males. Women more likely to report being at risk of homelessness were aged 35 to 54 years, Black, and unmarried; those more likely to experience homelessness were Black and unmarried. Among male veterans, the greatest predictors of both homelessness and risk were Black race and unmarried status. Among both genders, receiving VA disability compensation was associated with lesser odds of being homeless or at risk. CONCLUSIONS: The findings describe the current population of veterans using VHA health care services who may benefit from homelessness prevention or intervention services, identify racial differences in housing stability, and distinguish subpopulations who may be in particular need of intervention. Interventions to address these needs are described. PMID- 25498766 TI - Human serotonin transporter availability predicts fear conditioning. AB - Serotonin facilitates fear learning in animals. We therefore predicted that individual differences in the capacity to regulate serotonergic transmission in the human neural fear circuit would be inversely related to fear conditioning. The capacity to regulate serotonergic transmission was indexed by serotonin transporter availability measured with [(11)C]-DASB positron emission tomography. Results indicate that lower serotonin transporter availability in the amygdala, insula and dorsal anterior cingulate cortex predicts enhanced conditioned autonomic fear responses. Our finding supports serotonergic modulation of fear conditioning in humans and may aid in understanding susceptibility for developing anxiety conditions such as post-traumatic stress disorder. PMID- 25498767 TI - [Is there a place for surgical management in stage IIIA N2 non-small cell lung cancer?]. AB - INTRODUCTION: Non-small cell lung cancer (NSCLC) remains a major health problem, with a 5-year overall survival of 25%. Surgical management of stage IIIA NSCLC is still controversial. We conduct a systematic analysis of the different management strategies for stage IIIA-N2 NSCLC. METHODS: We analyzed randomized control trials published between January 1990 to December 2013, comparing induction chemotherapy followed by surgery vs. surgery alone, and those comparing induction chemo or radiotherapy followed by surgery vs. induction chemotherapy followed by radiotherapy for stage IIIA-N2 NSCLC. RESULTS: A 16% significant increase in overall survival was found in favor of induction chemotherapy followed by surgery vs. surgery alone. However, there was no significant difference in overall survival between induction chemo- or radiotherapy followed by surgery and induction chemotherapy followed by radiotherapy. CONCLUSION: Current scientific data do not permit the exclusion of surgery as an option in the management of stage IIIA-N2 NSCLC. PMID- 25498768 TI - [Which factors influence inclusion of thoracic cancer patients in clinical trials?]. PMID- 25498769 TI - Adapting to the health impacts of climate change in a sustainable manner. AB - The climate is changing and this poses significant threats to human health. Climate change is one of the greatest challenges facing Pacific Island countries and territories due to their unique geophysical features, and their social, economic and cultural characteristics. The Pacific region also faces challenges with widely dispersed populations, limited resources and fragmented health systems. Over the past few years, there has been a substantial increase in international aid for health activities aimed at adapting to the threats of climate change. This funding needs to be used strategically to ensure an effective approach to reducing the health risk from climate change. Respecting the principles of development effectiveness will result in more effective and sustainable adaptation, in particular, 1) processes should be owned and driven by local communities, 2) investments should be aligned with existing national priorities and policies, and 3) existing systems must not be ignored, but rather expanded upon and reinforced. PMID- 25498770 TI - Toward a functional definition of a "rare disease" for regulatory authorities and funding agencies. AB - BACKGROUND: The designation of a disease as "rare" is associated with some substantial benefits for companies involved in new drug development, including expedited review by regulatory authorities and relaxed criteria for reimbursement. How "rare disease" is defined therefore has major financial implications, both for pharmaceutical companies and for insurers or public drug reimbursement programs. All existing definitions are based, somewhat arbitrarily, on disease incidence or prevalence. OBJECTIVES: What is proposed here is a functional definition of rare based on an assessment of the feasibility of measuring the efficacy of a new treatment in conventional randomized controlled trials, to inform regulatory authorities and funding agencies charged with assessing new therapies being considered for public funding. METHODS: It involves a five-step process, involving significant negotiations between patient advocacy groups, pharmaceutical companies, physicians, and public drug reimbursement programs, designed to establish the feasibility of carrying out a randomized controlled trial with sufficient statistical power to show a clinically significant treatment effect. RESULTS AND CONCLUSIONS: The steps are as follows: 1) identification of a specific disease, including appropriate genetic definition; 2) identification of clinically relevant outcomes to evaluate efficacy; 3) establishment of the inherent variability of measurements of clinically relevant outcomes; 4) calculation of the sample size required to assess the efficacy of a new treatment with acceptable statistical power; and 5) estimation of the difficulty of recruiting an adequate sample size given the estimated prevalence or incidence of the disorder in the population and the inclusion criteria to be used. PMID- 25498771 TI - Mapping from the Health Assessment Questionnaire to the EQ-5D: the impact of different algorithms on cost-effectiveness results. AB - BACKGROUND: Many algorithms exist for converting the Health Assessment Questionnaire (HAQ) score to utility in rheumatoid arthritis (RA). Different algorithms convert the same HAQ score to different utility values, and could therefore lead to different cost-effectiveness results. OBJECTIVE: To investigate the impact of different mapping algorithms within the same cost-effectiveness model. METHODS: We rebuilt an existing economic model that had previously been used for estimating the cost-effectiveness of second-line biologics in RA. We reviewed the literature to identify algorithms that converted the HAQ score to utility and incorporated them into the model. We compared the cost-effectiveness results using different algorithms, exploring the reasons behind the different results and the potential effect on reimbursement decisions. RESULTS: We identified 24 different algorithms that estimated utility on the basis of the HAQ score, age, sex, and pain. The incremental cost-effectiveness ratio for rituximab versus disease-modifying antirheumatic drugs varied between L18,407/quality adjusted life-year and L32,039/quality-adjusted life-year, which we speculate could have changed the recommendations made by the National Institute for Health and Care Excellence. CONCLUSIONS: Using different algorithms to convert the HAQ score to utility affects the cost-effectiveness of second-line biologics for the treatment of RA. Using different algorithms in economic modeling for RA could lead health technology assessment bodies to make different reimbursement decisions. PMID- 25498772 TI - Optimizing the position and use of omalizumab for severe persistent allergic asthma using cost-effectiveness analysis. AB - BACKGROUND: There has been some controversy on whether the costs of omalizumab outweigh its benefits for severe persistent allergic asthma. OBJECTIVES: This study aimed to resolve the uncertainties and limitations of previous analyses and establish the cost-effectiveness of omalizumab under the list price and Patient Access Scheme (PAS) discounted price for the UK National Health Service. METHODS: A decision-analytic model was developed to evaluate the long-term cost effectiveness of omalizumab under the perspective of the National Health Service. Outcomes were expressed as quality-adjusted life-years (QALYs). Patient subgroups were defined post hoc on the basis of data collected in clinical trials: previous hospitalization, on maintenance oral corticosteroids, and three or more previous exacerbations. RESULTS: The incremental cost-effectiveness ratio varied from L30,109 to L57,557 per QALY gained depending on the population considered using the PAS price; incremental cost-effectiveness ratios were over a third higher using the list price. Omalizumab is likely to be cost-effective at the threshold of L30,000 per QALY gained in the severe subgroups if the improvement in health related quality of life from omalizumab is mapped from an asthma-specific measure to the EuroQol five-dimensional questionnaire (vs. the EuroQol five-dimensional questionnaire directly collected from patients) or asthma mortality refers to death after hospitalization from asthma (vs. asthma-mortality risk in the community). CONCLUSIONS: Although the cost-effectiveness of omalizumab is more favorable under the PAS price, it represents good value for money only in severe subgroups and under optimistic assumptions regarding asthma mortality and improvement in health-related quality of life. For these reasons, omalizumab should be carefully targeted to ensure value for money. PMID- 25498774 TI - Cost-effectiveness of telaprevir in patients with genotype 1 hepatitis C in Australia. AB - BACKGROUND: Protease inhibitors such as telaprevir (Incivo) are reimbursed in Australia for the treatment of patients with genotype 1 hepatitis C virus (HCV) infection in combination with pegylated interferon and ribavirin (PR). OBJECTIVES: To assess the cost-effectiveness of telaprevir plus PR compared with PR alone in 1) previously untreated patients and 2) patients who had received treatment with PR earlier. METHODS: Sustained virological response rates and average treatment durations of telaprevir and PR (given with or without telaprevir) were taken from the telaprevir ADVANCE and REALIZE clinical trials but were modified to take account of differences in prescribing rules between the trials and Australian clinical practice. The probability of transitioning between Markov disease states was based on data from the Australian Kirby Institute where possible and supplemented using data from the published literature. Utility values obtained from the EuroQol five-dimensional questionnaire data collected in the ADVANCE and REALIZE trials were used to represent the utility during HCV treatment. Utility values for Markov health states were taken from the published literature. Unit costs (2014 AU $) were taken from Australian sources. RESULTS: In treatment-naive patients, the discounted cost per life-years gained was AU $37,706 and the discounted cost per quality-adjusted life-year was AU $19,283. In treatment-experienced patients, the discounted cost per life-year gained was AU $23,855 and the discounted cost per quality-adjusted life-year was AU $14,948. CONCLUSION: Telaprevir plus PR in the Australian setting is cost-effective when compared with PR alone in patients infected with genotype 1 HCV. PMID- 25498773 TI - Economic evaluation of a cluster randomized trial of interventions to improve health workers' practice in diagnosing and treating uncomplicated malaria in Cameroon. AB - BACKGROUND: Malaria rapid diagnostic tests (RDTs) are a valid alternative to malaria testing with microscopy and are recommended for the testing of febrile patients before prescribing an antimalarial. There is a need for interventions to support the uptake of RDTs by health workers. OBJECTIVE: To evaluate the cost effectiveness of introducing RDTs with basic or enhanced training in health facilities in which microscopy was available, compared with current practice. METHODS: A three-arm cluster randomized trial was conducted in 46 facilities in central and northwest Cameroon. Basic training had a practical session on RDTs and lectures on malaria treatment guidelines. Enhanced training included small group activities designed to change health workers' practice and reduce the consumption of antimalarials among test-negative patients. The primary outcome was the proportion of febrile patients correctly treated: febrile patients should be tested for malaria, artemisinin combination therapy should be prescribed for confirmed cases, and no antimalarial should be prescribed for patients who are test-negative. Individual patient data were obtained from facility records and an exit survey. Costs were estimated from a societal perspective using project reports and patient exit data. The analysis used bivariate multilevel modeling and adjusted for imbalance in baseline covariates. RESULTS: Incremental cost per febrile patient correctly treated was $8.40 for the basic arm and $3.71 for the enhanced arm. On scale-up, it was estimated that RDTs with enhanced training would save $0.75 per additional febrile patient correctly treated. CONCLUSIONS: Introducing RDTs with enhanced training was more cost-effective than RDTs with basic training when each was compared with current practice. PMID- 25498775 TI - Cost-effectiveness of three adjunct cellular/tissue-derived products used in the management of chronic venous leg ulcers. AB - OBJECTIVES: Determine the cost-effectiveness of three topically applied cellular/tissue-derived products (CTPs) used as adjunct therapies to standard care in the management of venous leg ulcers (VLUs). METHODS: A three-state Markov model derived from the medical literature was developed to estimate the comparative cost-effectiveness of three CTPs in relation to VLU standard care. CTPs evaluated in the study included extracellular matrix (ECM), human skin equivalent (HSE), and living skin equivalent (LSE). The three Markov states included unhealed, healed, and death. A 1-year time horizon was used to determine the number of ulcer-free weeks and the expected costs of therapies. The payer perspective was taken in the analysis and only the direct costs of care were considered. Sensitivity analyses were performed to gauge model parameter uncertainty. RESULTS: The expected costs for standard care, ECM, HSE, and LSE VLU therapy were $6,132, $6,732, $10,638, and $11,237, while the expected outcomes were 24, 31, 29, and 27 ulcer-free weeks, respectively. ECM was economically dominant among the three CTPs. In the base case of ECM versus standard care, the incremental cost-effectiveness ratio for ECM therapy was $86 per ulcer-free week. Sensitivity analysis did not alter ECM dominance. Clinic visits and home health utilization exhibited the greatest influence on cost. CONCLUSIONS: ECM is the most cost-effective CTP when used in the management of VLUs as an adjunct to standard care. These findings suggest that VLU standard care therapy with ECM can yield potential cost savings and produce better outcomes than do other CTPs. PMID- 25498776 TI - Conceptual model and economic experiments to explain nonpersistence and enable mechanism designs fostering behavioral change. AB - BACKGROUND: Medical nonpersistence is a worldwide problem of striking magnitude. Although many fields of studies including epidemiology, sociology, and psychology try to identify determinants for medical nonpersistence, comprehensive research to explain medical nonpersistence from an economics perspective is rather scarce. OBJECTIVES: The aim of the study was to develop a conceptual framework that augments standard economic choice theory with psychological concepts of behavioral economics to understand how patients' preferences for discontinuing with therapy arise over the course of the medical treatment. The availability of such a framework allows the targeted design of mechanisms for intervention strategies. METHODS: Our conceptual framework models the patient as an active economic agent who evaluates the benefits and costs for continuing with therapy. We argue that a combination of loss aversion and mental accounting operations explains why patients discontinue with therapy at a specific point in time. We designed a randomized laboratory economic experiment with a student subject pool to investigate the behavioral predictions. RESULTS: Subjects continue with therapy as long as experienced utility losses have to be compensated. As soon as previous losses are evened out, subjects perceive the marginal benefit of persistence lower than in the beginning of the treatment. Consequently, subjects start to discontinue with therapy. CONCLUSIONS: Our results highlight that concepts of behavioral economics capture the dynamic structure of medical nonpersistence better than does standard economic choice theory. We recommend that behavioral economics should be a mandatory part of the development of possible intervention strategies aimed at improving patients' compliance and persistence behavior. PMID- 25498777 TI - Validation of the Patient Perception of Intensity of Urgency Scale in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia. AB - OBJECTIVE: To assess the reliability and validity of scores derived from the Patient Perception of Intensity of Urgency Scale (PPIUS) in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). METHODS: A post hoc analysis of the phase II Solifenacin and Tamsulosin in Males with Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia trial (NCT00510406), a 12-week clinical trial in men with LUTS associated with BPH, assessed the measurement properties of six PPIUS-derived scores: mean score; maximum urgency score; total urgency and frequency score (TUFS; average sum of urgency scores over 3 days); and numbers of urgency episodes, urgency episodes of grade 3 or 4, and urgency incontinence episodes. Test-retest reliability, presence of floor/ceiling effects, responsiveness to change, known-group validity, and concurrent validity were assessed for each score. RESULTS: A total of 901 patients had at least one valid PPIUS assessment after baseline. TUFS demonstrated good test-retest reliability (intraclass correlation coefficient >0.8), discriminated between groups defined based on International Prostate Symptom Score storage score severity (known-groups validity), had high concurrent validity, and had high responsiveness to change (Guyatt's responsiveness statistic 0.88), with an absence of floor or ceiling effects. The psychometric properties of other PPIUS-derived scores were not as consistently robust and showed either low-to-moderate responsiveness, presence of a floor or ceiling effect, or low-to-moderate test-retest reliability. CONCLUSIONS: This study shows that the PPIUS is reliable and valid in patients with LUTS associated with BPH. TUFS provided the best combination of psychometric properties of the six scores derived from the PPIUS and appeared to be an appropriate measure of urgency and frequency. PMID- 25498778 TI - Parents' willingness to pay for biologic treatments in juvenile idiopathic arthritis. AB - BACKGROUND: Biologic therapies are considered the standard of care for children with the most severe forms of juvenile idiopathic arthritis (JIA). Inconsistent and inadequate drug coverage, however, prevents many children from receiving timely and equitable access to the best treatment. OBJECTIVE: The objective of this study was to evaluate parents' willingness to pay (WTP) for biologic and nonbiologic disease-modifying antirheumatic drugs (DMARDs) used to treat JIA. METHODS: Utility weights from a discrete choice experiment were used to estimate the WTP for treatment characteristics including child-reported pain, participation in daily activities, side effects, days missed from school, drug treatment, and cost. Conditional logit regression was used to estimate utilities for each attribute level, and expected compensating variation was used to estimate the WTP. Bootstrapping was used to generate 95% confidence intervals for all WTP estimates. RESULTS: Parents had the highest marginal WTP for improved participation in daily activities and pain relief followed by the elimination of side effects of treatment. Parents were willing to pay $2080 (95% confidence interval $698-$4065) more for biologic DMARDs than for nonbiologic DMARDs if the biologic DMARD was more effective. CONCLUSIONS: Parents' WTP indicates their preference for treatments that reduce pain and improve daily functioning without side effects by estimating the monetary equivalent of utility for drug treatments in JIA. In addition to evidence of safety and efficacy, assessments of parents' preferences provide a broader perspective to decision makers by helping them understand the aspects of drug treatments in JIA that are most valued by families. PMID- 25498779 TI - Valuations of genetic test information for treatable conditions: the case of colorectal cancer screening. AB - BACKGROUND: The value of the information that genetic testing services provide can be questioned for insurance-based health systems. The results of genetic tests oftentimes may not lead to well-defined clinical interventions; however, Lynch syndrome, a genetic mutation for which carriers are at an increased risk for colorectal cancer, can be identified through genetic testing, and meaningful health interventions are available via increased colonoscopic surveillance. Valuations of test information for such conditions ought to account for the full impact of interventions and contingent outcomes. OBJECTIVES: To conduct a discrete-choice experiment to elicit individuals' preferences for genetic test information. METHODS: A Web-enabled discrete-choice experiment survey was administered to a representative sample of US residents aged 50 years and older. In addition to specifying expenditures on colonoscopies, respondents were asked to make a series of nine selections between two hypothetical genetic tests or a no-test option under the premise that a relative had Lynch syndrome. The hypothetical genetic tests were defined by the probability of developing colorectal cancer, the probability of a false-negative test result, privacy of the result, and out-of-pocket cost. A model specification identifying necessary interactions was derived from assumptions of risk behavior and the decision context and was estimated using random-parameters logit. RESULTS: A total of 650 respondents were contacted, and 385 completed the survey. The monetary equivalent of test information was approximately $1800. Expenditures on colonoscopies to reduce mortality risks affected valuations. Respondents with lower income or who reported being employed significantly valued genetic tests more. CONCLUSION: Genetic testing may confer benefits through the impact of subsequent interventions on private individuals. PMID- 25498780 TI - US valuation of health outcomes measured using the PROMIS-29. AB - OBJECTIVES: Health valuation studies enhance economic evaluations of treatments by estimating the value of health-related quality of life (HRQOL). The Patient Reported Outcomes Measurement Information System (PROMIS) includes a 29-item short-form HRQOL measure, the PROMIS-29. METHODS: To value PROMIS-29 responses on a quality-adjusted life-year scale, we conducted a national survey (N = 7557) using quota sampling based on the US 2010 Census. Based on 541 paired comparisons with over 350 responses each, pair-specific probabilities were incorporated into a weighted least-squared estimator. RESULTS: All losses in HRQOL influenced choice; however, respondents valued losses in physical function, anxiety, depression, sleep, and pain more than those in fatigue and social functioning. CONCLUSIONS: This article introduces a novel approach to valuing HRQOL for economic evaluations using paired comparisons and provides a tool to translate PROMIS-29 responses into quality-adjusted life-years. PMID- 25498781 TI - Capitalizing on prescribing pattern variation to compare medications for type 2 diabetes. AB - BACKGROUND: Clinical trials often compare hypoglycemic medications on the basis of glycemic control but do not examine long-term outcomes (e.g., mortality). This study demonstrates an alternative approach to lengthening clinical trials to assess these long-term outcomes. OBJECTIVE: To use observational quasi experimental methods using instrumental variables (IVs) to compare the effect of two hypoglycemic medications, sulfonylureas (SUs) and thiazolidinediones (TZDs), on long-term outcomes. METHODS: This study used administrative data from the Veterans Health Administration and Medicare from 2000 to 2010. The study population included US veterans dually enrolled in Medicare who received a prescription for metformin and then initiated SUs or TZDs. Patients could either continue on or discontinue metformin after the initiation of the second agent. Treatment was defined as starting either a SU or a TZD. Local variations in SU prescribing rates were used as instruments in IV models to control for selection bias. Survival models predicted all-cause mortality, ambulatory care sensitive condition hospitalizations, and stroke or heart attack (acute myocardial infarction). RESULTS: Starting on SUs compared to TZDs significantly increased the likelihood of experiencing mortality and ACSC hospitalization. The estimated hazard ratio for the effect of starting on SUs compared to TZDs was 1.50 (95% confidence interval [CI] 1.09-2.09) for all-cause mortality, 1.68 (95% CI 1.31 2.15) for ambulatory care sensitive condition hospitalization, and 1.15 (95% CI 0.80-1.66) for acute myocardial infarction or stroke. CONCLUSIONS: Our findings suggest increased risk of major adverse events associated with SUs as a second line agent. Quasi-experimental IV methods may be an important alternative to lengthening clinical trials to assess long-term outcomes. PMID- 25498783 TI - Does convenience matter in health care delivery? A systematic review of convenience-based aspects of process utility. AB - OBJECTIVES: To systematically review the existing literature on the value associated with convenience in health care delivery, independent of health outcomes, and to try to estimate the likely magnitude of any value found. METHODS: A systematic search was conducted for previously published studies that reported preferences for convenience-related aspects of health care delivery in a manner that was consistent with either cost-utility analysis or cost-benefit analysis. Data were analyzed in terms of the methodologies used, the aspects of convenience considered, and the values reported. RESULTS: Literature searches generated 4715 records. Following a review of abstracts or full-text articles, 27 were selected for inclusion. Twenty-six studies reported some evidence of convenience-related process utility, in the form of either a positive utility or a positive willingness to pay. The aspects of convenience valued most often were mode of administration (n = 11) and location of treatment (n = 6). The most common valuation methodology was a discrete-choice experiment containing a cost component (n = 15). CONCLUSIONS: A preference for convenience-related process utility exists, independent of health outcomes. Given the diverse methodologies used to calculate it, and the range of aspects being valued, however, it is difficult to assess how large such a preference might be, or how it may be effectively incorporated into an economic evaluation. Increased consistency in reporting these preferences is required to assess these issues more accurately. PMID- 25498782 TI - Predicting adherence to medications using health psychology theories: a systematic review of 20 years of empirical research. AB - OBJECTIVES: This review sought to identify the empirical evidence for the application of models from sociocognitive theory, self-regulation theory, and social support theory at predicting patient adherence to medications. METHODS: A systematic review of the published literature (1990-2010) using MEDLINE, EMBASE, Cochrane Library, CINAHL, and PsychINFO identified studies examining the application of health psychology theory to adherence to medication in adult patients. Two independent reviewers extracted data on medication, indication, study population, adherence measure, theory, model, survey instruments, and results. Heterogeneity in theoretical model specification and empirical investigation precluded a meta-analysis of data. RESULTS: Of 1756 unique records, 67 articles were included (sociocognitive = 35, self-regulation = 21, social support = 11). Adherence was most commonly measured by self-report (50 of 67). Synthesis of studies highlighted the significance (P <= 0.05) of self-efficacy (17 of 19), perceived barriers (11 of 17), perceived susceptibility (3 of 6), necessity beliefs (8 of 9), and medication concerns (7 of 8). CONCLUSIONS: The results of this review provide a foundation for the development of theory-led adherence-enhancing interventions that could promote sustainable behavior change in clinical practice. PMID- 25498784 TI - Evolution of drug reimbursement in Canada: the Pan-Canadian Pharmaceutical Alliance for new drugs. AB - Canada has a unique system of public drug coverage and reimbursement characterized by a centralized review agency that makes funding recommendations along with decentralized authority for delivering health care across 10 provinces and three territories. There has been a significant increase in price negotiation for new pharmaceuticals in the past 10 years, first by individual provinces and now through a collective price negotiation process called the "Pan-Canadian Pharmaceutical Alliance." As of February 2014, the Pan-Canadian Pharmaceutical Alliance has already completed 32 negotiations despite still being in a formative stage; it is anticipated that a formal process will be developed in the coming year. In this article, we describe the evolution of price negotiation in Canada and identify several opportunities for improvement of the current process, including the incorporation of economic considerations into price negotiation. PMID- 25498785 TI - Performance of the UKPDS outcomes model for prediction of myocardial infarction and stroke in the ADDITION-Europe trial cohort: does the ADDITION validation add up? PMID- 25498787 TI - Self-affirmation facilitates cardiovascular recovery following interpersonal evaluation. AB - Self-affirmation is known to reduce defensive psychological responses to ego threats. The current experiment tested the hypothesis that self-affirmation reduces physiological responses to a form of ego threat-interpersonal evaluation. Participants wrote an essay and received either neutral or insulting evaluative feedback about their essay, ostensibly from another participant. Then participants wrote about a core personal value (self-affirmation) or about a less important value (no self-affirmation). Lastly, participants played a competitive reaction time game that permitted them to blast their purported evaluator with noise. Noise blasts did not vary across conditions, but mean arterial blood pressure increased in response to being evaluated and returned to baseline more quickly following self-affirmation. Further, insulting (versus neutral) evaluative feedback caused a greater increase in heart rate, except among those who self-affirmed following the evaluation manipulation. These results suggest that self-affirmation facilitates the return to baseline cardiovascular activity following interpersonal evaluation. PMID- 25498786 TI - Diet and glycaemia: the markers and their meaning. A report of the Unilever Nutrition Workshop. AB - Consumption of carbohydrate-containing foods leads to transient postprandial rises in blood glucose concentrations that vary between food types. Higher postprandial glycaemic exposures have particularly been implicated in the development of chronic cardiometabolic diseases. Reducing such diet-related exposures may be beneficial not only for diabetic patients but also for the general population. A variety of markers have been used to track different aspects of glycaemic exposures, with most of the relevant knowledge derived from diabetic patients. The assessment of glycaemic exposures among the non-diabetic population may require other, more sensitive markers. The present report summarises key messages of presentations and related discussions from a workshop organised by Unilever intended to consider currently applied markers of glycaemic exposure. The particular focus of the meeting was to identify the potential applicability of glycaemic exposure markers for studying dietary effects in the non-diabetic population. Workshop participants concluded that markers of glycaemic exposures are sparsely used in intervention studies among non-diabetic populations. Continuous glucose monitoring remains the optimal approach to directly assess glycaemic exposure. Markers of glycaemic exposure such as glycated Hb, fructosamine, glycated albumin, 1,5-anhydroglucitol and advanced glycation end products can be preferred dependent on the aspect of interest (period of exposure and glucose variability). For all the markers of glycaemia, the responsiveness to interventions will probably be smaller among the non diabetic than among the diabetic population. Further validation and acceptance of existing glycaemic exposure markers applied among the non-diabetic population would aid food innovation and better design of dietary interventions targeting glycaemic exposure. PMID- 25498788 TI - The role of inhibitory mechanisms in the regulation of facial expressiveness during pain. AB - Although it is assumed that inhibitory control plays a role in regulating the degree of facial expressiveness, so far the specific type of inhibitory mechanism involved has not been identified. The present study was designed to investigate the association between different types of inhibitory mechanisms and the degree of facial expressiveness. Facial expressiveness during experimental pain was assessed using the Facial Action Coding System and facial electromyography (criterion variables). Different aspects of inhibitory functioning (Antisaccade task, Stroop task, questionnaire) were used as predictor variables. The degree of facial expressiveness was significantly predicted by the performance in the Antisaccade, but not the Stroop task or the questionnaire. The higher the ability was to inhibit saccadic eye movements, the lower was the degree of facial expressiveness. This data suggests that the degree of facial expressiveness is not regulated by inhibitory control in general, but specifically depends on inhibitory mechanisms regulating automatic motor responses. PMID- 25498790 TI - Neuropeptide Y may mediate psychological stress and enhance TH2 inflammatory response in asthma. PMID- 25498789 TI - Integrating phenotypic small-molecule profiling and human genetics: the next phase in drug discovery. AB - Over the past decade, tremendous progress in high-throughput small molecule screening methods has facilitated the rapid expansion of phenotype-based data. Parallel advances in genomic characterization methods have complemented these efforts by providing a growing list of annotated cell line features. Together, these developments have paved the way for feature-based identification of novel, exploitable cellular dependencies, subsequently expanding our therapeutic toolkit in cancer and other diseases. Here, we provide an overview of the evolution of phenotypic small-molecule profiling and discuss the most significant and recent profiling and analytical efforts, their impact on the field, and their clinical ramifications. We additionally provide a perspective for future developments in phenotypic profiling efforts guided by genomic science. PMID- 25498791 TI - The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells. AB - BACKGROUND: Mast cells (MCs) are hematopoietic cells that mature in tissues and are involved in allergy, immunity, and inflammation by secreting multiple mediators. The natural flavone luteolin has anti-inflammatory actions and inhibits human mast cells (MCs). OBJECTIVE: We sought to investigate the ability of luteolin and its novel structural analog 3',4',5,7-tetramethoxyluteolin (methlut) to inhibit human MC mediator expression and release in vitro and in vivo. METHODS: Human LAD2 cells and umbilical primary human cord blood-derived cultured mast cells were stimulated with substance P (SP) or IgE/anti-IgE with or without preincubation with luteolin, methlut, or cromolyn (1-100 MUmol/L) for 2 or 24 hours, after which mediator secretion was measured. The effect of the compounds on MC intracellular calcium levels and nuclear factor kappaB activation was also investigated. Pretreatment with methlut was also studied in mice passively sensitized with dinitrophenol-human serum albumin and challenged intradermally. RESULTS: Methlut is a more potent inhibitor than luteolin or cromolyn for beta-hexosaminidase and histamine secretion from LAD2 cells stimulated by either SP or IgE/anti-IgE, but only methlut and luteolin significantly inhibit preformed TNF secretion. Methlut is also a more potent inhibitor than luteolin of de novo-synthesized TNF from LAD2 cells and of CCL2 from human cord blood-derived cultured MCs. This mechanism of action for methlut might be due to its ability to inhibit intracellular calcium level increases, as well as nuclear factor kappaB induction, at both the transcriptional and translational levels in LAD2 cells stimulated by SP without affecting cell viability. Intraperitoneal treatment with methlut significantly decreases skin vascular permeability of Evans blue dye in mice passively sensitized to dinitrophenol-human serum albumin and challenged intradermally. CONCLUSION: Methlut is a promising MC inhibitor for the treatment of allergic and inflammatory conditions. PMID- 25498792 TI - The inhibition of activated hepatic stellate cells proliferation by arctigenin through G0/G1 phase cell cycle arrest: persistent p27(Kip1) induction by interfering with PI3K/Akt/FOXO3a signaling pathway. AB - Proliferation of hepatic stellate cells (HSCs) is vital for the development of fibrosis during liver injury. In this study, we describe that arctigenin (ATG), a major bioactive component of Fructus Arctii, exhibited selective cytotoxic activity via inhibiting platelet-derived growth factor-BB (PDGF-BB)-activated HSCs proliferation and arrested cell cycle at G0/G1 phase, which could not be observed in normal human hepatocytes in vitro. The cyclin-dependent kinase (CDK) 4/6 activities could be strongly inhibited by ATG through down-regulation of cyclin D1 and CDK4/6 expression in early G1 phase arrest. In the ATG-treated HSCs, the expression level of p27(Kip1) and the formation of CDK2-p27(Kip1) complex were also increased. p27(Kip1) silencing significantly attenuated the effect of ATG, including cell cycle arrest and suppression of proliferation in activated HSCs. We also found that ATG suppressed PDGF-BB-induced phosphorylation of Akt and its downstream transcription factor Forkhead box O 3a (FOXO3a), decreased binding of FOXO3a to 14-3-3 protein, and stimulated nuclear translocation of FOXO3a in activated HSCs. Furthermore, knockdown of FOXO3a expression by FOXO3a siRNA attenuated ATG-induced up-regulation of p27(Kip1) in activated HSCs. All the above findings suggested that ATG could increase the levels of p27(Kip1) protein through inhibition of Akt and improvement of FOXO3a activity, in turn inhibited the CDK2 kinase activity, and eventually caused an overall inhibition of HSCs proliferation. PMID- 25498794 TI - Swimming reduces the severity of physical and psychological dependence and voluntary morphine consumption in morphine dependent rats. AB - Previous studies have indicated that voluntary exercise decreases the severity of the anxiogenic-like behaviors in both morphine-dependent and withdrawn rats. This study examined the effects of regular swimming exercise during the development of dependency and spontaneous morphine withdrawal on the anxiety-depression profile and voluntary morphine consumption in morphine dependent rats. The rats were chronically treated with bi-daily doses (10 mg/kg, at 12h intervals) of morphine over a period of 14 days. The exercising rats were allowed to swim (45 min/d, five days per a week, for 14 or 21 days) during the development of morphine dependence and withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice paradigm in animal models of craving. The results showed that withdrawal signs were decreased in swimmer morphine dependent rats than sedentary rats (P<0.05). Also, the swimmer morphine-dependent and withdrawn rats exhibited an increase in EPM open arm time and entries (P<0.05), higher levels of sucrose preference (P<0.001) than sedentary rats. Voluntary consumption of oral morphine was less in the swimmer morphine-withdrawn rats than the sedentary groups during four periods of the intake of drug (P<0.01). We conclude that regular swimming exercise reduces the severity of morphine dependence and voluntary morphine consumption with reducing anxiety and depression in morphine-dependent and withdrawn rats. Thus, swimming exercise may be a potential method to ameliorate some of the deleterious behavioral consequences of morphine dependence. PMID- 25498793 TI - The involvement of the TRPA1 receptor in a mouse model of sympathetically maintained neuropathic pain. AB - Sympathetic fibres maintain some forms of neuropathic pain, but the underlying mechanisms are poorly understood. Therefore, this study investigated the possible involvement of transient receptor potential ankyrin 1 (TRPA1) and the role of the sympathetic nervous system (involved in sympathetically maintained neuropathic pain) in a model of neuropathic pain induced by sciatic nerve chronic constriction injury (CCI) in mice. Systemic injection of the selective TRPA1 antagonist HC-030031 reversed the mechanical and cold allodynia that was induced by sciatic nerve chronic constriction injury (CCI). Nerve injury also sensitised mice to nociception, which was induced by the intraplantar injection of a low dose of the TRPA1 agonist allyl isothiocyanate without changing TRPA1 immunoreactivity in the injected paw. Furthermore, chemical sympathectomy produced by guanethidine largely prevented CCI-induced mechanical and cold allodynia. CCI also induced a norepinephrine-triggered nociception that was inhibited by an alpha-adrenoceptor antagonist, norepinephrine transporter block and monoamine oxidase inhibition. Finally, the peripheral injection of HC-030031 also largely reduced CCI-induced norepinephrine nociception and mechanical or cold allodynia. Taken together, the present findings reveal a critical role of TRPA1 in mechanical and cold hypersensitivity and norepinephrine hypersensitivity following nerve injury. Finally, our results suggest that TRPA1 antagonism may be useful to treat patients who present sympathetically maintained neuropathic pain. PMID- 25498795 TI - Incidence, risk factors and outcomes of new-onset atrial fibrillation in patients with sepsis: a systematic review. AB - INTRODUCTION: Critically ill patients with sepsis are prone to develop cardiac dysrhythmias, most commonly atrial fibrillation (AF). Systemic inflammation, circulating stress hormones, autonomic dysfunction, and volume shifts are all possible triggers for AF in this setting. We conducted a systematic review to describe the incidence, risk factors and outcomes of new-onset AF in patients with sepsis. METHODS: MEDLINE, EMBASE and Web Of Science were searched for studies reporting the incidence of new-onset AF, atrial flutter or supraventricular tachycardia in patients with sepsis admitted to an intensive care unit, excluding studies that primarily focused on postcardiotomy patients. Studies were assessed for methodological quality using the GRADE system. Risk factors were considered to have a high level of evidence if they were reported in >= 2 studies using multivariable analyses at a P value <0.05. Subsequently, the strength of association was classified as strong, moderate or weak, based on the reported odds ratios. RESULTS: Eleven studies were included. Overall quality was low to moderate. The weighted mean incidence of new-onset AF was 8% (range 0 to 14%), 10% (4 to 23%) and 23% (6 to 46%) in critically ill patients with sepsis, severe sepsis and septic shock, respectively. Independent risk factors with a high level of evidence included advanced age (weak strength of association), white race (moderate association), presence of a respiratory tract infection (weak association), organ failure (moderate association), and pulmonary artery catheter use (moderate association). Protective factors were a history of diabetes mellitus (weak association) and the presence of a urinary tract infection (weak association). New-onset AF was associated with increased short term mortality in five studies (crude relative effect estimates ranging from 1.96 to 3.32; adjusted effects 1.07 to 3.28). Three studies reported a significantly increased length of stay in the ICU (weighted mean difference 9 days, range 5 to 13 days), whereas an increased risk of ischemic stroke was reported in the single study that looked at this outcome. CONCLUSIONS: New-onset AF is a common consequence of sepsis and is independently associated with poor outcome. Early risk stratification of patients may allow for pharmacological interventions to prevent this complication. PMID- 25498796 TI - Letter to the Editor regarding Analysis of Changing Paradigms of Management in 179 Patients with Spinal Tuberculosis During a 12-Year Period and Proposal of a New Management Algorithm. PMID- 25498797 TI - Impact of a Vascular Neurosurgery Simulation-Based Course on Cognitive Knowledge and Technical Skills in European Neurosurgical Trainees. AB - OBJECTIVE: To assess microsurgical and diagnostic cerebral angiography modules and their corresponding objective assessment scales as educational tools for European neurosurgical residents at the European Association of Neurosurgical Societies Resident Vascular Neurosurgery course, which was held in Prague, Czech Republic, on September 2013. Microsurgical skills and cerebral angiography are fundamental skills in vascular neurosurgery. There is a need to develop a simulation-based curriculum focusing on these skills for neurosurgical trainees worldwide. METHODS: The course consisted of 2 modules: microanastomosis and diagnostic cerebral angiography. In addition to an initial screening survey, each module was divided into 3 components: 1) a before didactic cognitive knowledge and technical skills testing, 2) a didactic lecture, and 3) an after didactic cognitive knowledge and technical skills testing. We compared the trainees' cognitive and technical scores from the before and after testing phases. Wilcoxon sum rank test was used to test statistical significance. RESULTS: The knowledge test median scores increased from 63% and 68% to 80% and 88% (P < 0.01) on the microanastomosis and cerebral angiography modules, respectively. The practical hands-on simulation assessment median scores increased from 42% and 50% to 50.5% and 68% (P < 0.01) on the microanastomosis and cerebral angiography modules, respectively. CONCLUSIONS: Our course suggests that a simulation-based vascular neurosurgery curriculum is feasible and may enhance resident knowledge and technical proficiency. PMID- 25498798 TI - Surgery of olfactory groove meningiomas: when in Rome, do as the Romans do? PMID- 25498799 TI - The Awe of the Dura Mater During the Ages "Noli me tangere". PMID- 25498800 TI - Novel bilayer wound dressing composed of silicone rubber with particular micropores enhanced wound re-epithelialization and contraction. AB - Wound dressing is critical important for cutaneous wound healing. However, the application of current products is limited due to poor mechanical property, unsuitable water vapor transmission rate (WVTR), poor anti-infective property or poor biocompatibility, etc. In the present study, a microporous silicone rubber membrane bilayer (SRM-B) composed of two layers with different pore sizes was prepared. The physical properties, the influences of pore structure on the bacterial penetration, the cell adhesion and proliferation were studied. Lastly, the effects of the SRM-B on the healing of a mouse full-thickness wound were examined. The data showed that the small pore upper layer of SRM-B could effectively prevent the bacterial invasion, as well as properly keep the water vapor transmission rate; the large pore lower layer of SRM-B could promote the cell adhesion and proliferation. The in vivo results showed that SRM-B could significantly enhance wound re-epithelialization and contraction, which accelerated the wound healing. Our data suggested that the SRM-B, with different particular pore sizes, could serve as a kind of promising wound dressing. PMID- 25498801 TI - Graphene oxide as a chemosensitizer: diverted autophagic flux, enhanced nuclear import, elevated necrosis and improved antitumor effects. AB - Graphene oxide (GO) is a nanomaterial that provokes autophagy in CT26 colon cancer cells and confers antitumor effects. Here we demonstrated that both GO and the chemotherapy drug cisplatin (CDDP) induced autophagy but elicited low degrees of CT26 cell death. Strikingly, GO combined with CDDP (GO/CDDP) potentiated the CT26 cell killing via necrosis. GO/CDDP not only elicited autophagy, but induced the nuclear import of CDDP and the autophagy marker LC3. The nuclear LC3 did not co-localize with p62 or Lamp-2, neither did blocking autolysosome formation significantly hinder the nuclear import of LC3/CDDP and necrosis, indicating that autophagosome and autolysosome formation was dispensable. Conversely, suppressing phagophore formation and importin-alpha/beta significantly alleviated the nuclear import of LC3/CDDP and necrosis. These data suggested that GO/CDDP diverted the LC3 flux in the early phase of autophagy, resulting in LC3 trafficking towards the nucleus in an importin-alpha/beta-dependent manner, which concurred with the CDDP nuclear import and necrosis. Intratumoral injection of GO/CDDP into mice bearing CT26 colon tumors potentiated immune cell infiltration and promoted cell death, autophagy and HMGB1 release, thereby synergistically augmenting the antitumor effects. Altogether, we unveiled a mechanism concerning how nanomaterials chemosensitize cancer cells and demonstrated the potentials of GO as a chemosensitizer. PMID- 25498802 TI - Effects of graphene oxide on the development of offspring mice in lactation period. AB - The potential toxicity of graphene oxide (GO) has attracted much attention with numerous promising biomedical applications in recent years. However, information about GO on the development of filial animals is rare. In this work, we studied the potential developmental toxicity of GO when they entered the body of maternal mice and their offspring by oral exposure with two doses. The results showed that the increase of body weight, body length and tail length of the filial mice received GO at 0.5 mg mL(-1) (about 0.8 mg each mouse) every day in the lactation period was significantly retarded comparing with the control group. The anatomy and histology results revealed the delayed developments of offspring in high dosage group. We also evaluated the possible toxicological mechanism caused by GO and found that the length of the intestinal villus of the filial mice received high concentration GO were decreased significantly compared with the control group. It can be concluded that GO showed many negative effects on the development of mice in the lactation period. These findings can be significant for the development of graphene materials-based drug delivery system and other biomedical applications in the future. PMID- 25498803 TI - DJ-1 as a human oncogene and potential therapeutic target. AB - DJ-1 is a cancer- and Parkinson's disease-associated protein that participates in different intracellular signaling pathways to protect cells from toxic stresses. DJ-1 expression, oxidation, localization, and phosphorylation are often altered in human tumors, and DJ-1 has been implicated in various aspects of transformation, including uncontrolled proliferation, invasion, metastasis, and resistance to chemotherapy and apoptosis. Despite the strong relationship between DJ-1 and cancer, which made it a particularly attractive therapeutic target for cancer treatment, the detailed mechanisms of how this oncogene coordinates altered signaling with cell survival remains elusive. In this commentary, we discuss the role of DJ-1 in transformation, highlight some of the significant aspects of and prospects for therapeutically targeting the DJ-1 signaling in cancer, and describe what the future may hold. PMID- 25498804 TI - A meta-analysis of child physical abuse prevalence in China. AB - This study estimated the prevalence of child physical abuse in China, compared Chinese prevalence with international and Asian estimates, and ascertained whether some differences in sample characteristics and methodological factors (e.g., time prevalence, definitional or regional difference) help explain variations in Chinese rates. Based on a meta-analysis of 47 studies found in English- and Chinese-language peer-reviewed journals that involved general populations of students or residents reporting child physical abuse prior to age 18, the life time prevalence of any child physical abuse in China was estimated at 36.6% (95% CI: 30.4-42.7), which was significantly higher than either the international or the Asian estimate in Stoltenborgh et al.'s (2013) study. Chinese prevalence was estimated at 43.1% (95% CI: 36.6-52.5) for minor physical abuse, 26.6% (95% CI: 21.4-31.8) for severe physical abuse, and 7.8% (95% CI: 5.0 10.5) for very severe physical abuse. Subgroup analysis found a significant difference between lifetime and 12-month or less prevalence only for minor physical abuse. The prevalence of any and minor child physical abuse in mainland China was significantly higher than that in non-mainland China. The mainland and non-mainland difference was significant even controlling for definitional and methodological factors as well as sample characteristics. The findings suggested the need to develop educational programs to promote non-violent parenting particularly in mainland China. PMID- 25498805 TI - Intracranial pseudoaneurysm after intracranial pressure monitor placement. AB - Traumatic intracranial pseudoaneurysms are a rare but severe complication following arterial injury. Pseudoaneurysm formation can occur secondary to blunt or penetrating trauma or iatrogenic injury. We report a case of traumatic pseudoaneurysm secondary to placement of an intracranial pressure (ICP) monitor. A 27-year-old man was involved in a motorcycle accident resulting in multiple intracranial hemorrhages. The patient underwent craniectomy and placement of an ICP monitor. 17 days later he developed dilation of his left pupil, with imaging demonstrating a new hemorrhage in the vicinity of the previous ICP monitor. A cerebral angiogram confirmed a left-sided distal M4 pseudoaneurysm which was treated by n-butyl cyanoacrylate embolization. Intracranial pseudoaneurysm formation following neurosurgical procedures is uncommon. Delayed intracranial hemorrhage in a region of prior intracranial manipulation, even following a procedure as 'routine' as placement of an ICP monitor, should raise the suspicion for this rare but potentially lethal complication. PMID- 25498806 TI - Just a drop of cement: a case of cervical spine bone aneurysmal cyst successfully treated by percutaneous injection of a small amount of polymethyl-methacrylate cement. AB - Aneurysmal bone cyst (ABC) is a benign hemorrhagic tumor, commonly revealed by local pain. The best treatment for this lesion is still controversial. We report the case of a patient with chronic neck pain revealing an ABC of the third cervical vertebra. After percutaneous injection of a small amount of polymethyl methacrylate bone cement, the patient experienced significant clinical and radiological improvement. PMID- 25498807 TI - Pseudozyma spp catheter-associated blood stream infection, an emerging pathogen and brief literature review. AB - Pseudozyma spp are amorphic yeasts. They are commonly plant pathogens, but rarely cause invasive fungal disease in humans. Only three cases of central venous catheter (CVC)-associated blood stream infections due to this organism have been reported in the literature. Main underlying risk factors for Pseudozyma spp infection are bowel surgery, CVC and total parenteral nutrition. We present a rare case of Pseudozyma spp catheter-associated blood stream infection that was successfully treated with antifungal therapy and removal of CVC. It is important to recognise and differentiate this species from other yeasts as it may require the use of amphotericin B or voriconazole instead of fluconazole, to which the organism is variably resistant. PMID- 25498808 TI - Psoriatic erythroderma-induced septicaemia causing Janeway lesions. PMID- 25498809 TI - Golden 'S' sign. PMID- 25498810 TI - Squamous carcinoma arising in a parotid Warthin's tumour. AB - Warthin's tumour is the second most common benign neoplasm to affect the salivary glands. It virtually affects the sole parotid gland. A sudden increase in a tumour's size is usually due to a malignant transformation of the tumour. The transformation of the lymphoid stroma into malignant lymphoma is relatively common, while an epithelial malignancy is extremely rare. In this paper, the authors present a case of squamous cell carcinoma arising in Warthin's tumour. The patient underwent enucleoresection of the tumour. Intraoperative frozen section revealed the presence of a cystic component associated with the squamous cell carcinoma areas. In consideration of the result of the intraoperative consultation, the surgeons decided to enlarge the previous resection by removal of a 30*25 mm cuff from the surrounding parotid tissue. Close follow-up was carried out and 12 months after surgery there was no evidence of recurrence or metastatic neoplasm. PMID- 25498811 TI - Ethylenediaminium di(4-nitrophenolate): a third order NLO material for optical limiting applications. AB - Single crystals of ethylenediaminium di(4-nitrophenolate) [EDA4NP] were grown by slow evaporation solution growth technique using ethanol as solvent at constant temperature. It crystallizes in monoclinic centrosymmetric space group C2/c with cell dimension a=11.326A, b=7.264A, c=20.036A; beta=93.55 degrees . Fourier Transform Infra Red (FT-IR) spectrum was recorded to identify various functional groups present in EDA4NP. Nuclear Magnetic Resonance (NMR) spectral studies were performed to confirm the functional groups. Thermogravimetric analysis and differential thermal analysis showed that the compound melts at 142.9 degrees C. The material possesses a wide optical transparency window in the visible and near IR region (500-1200nm). The nonlinear refractive index, nonlinear absorption coefficient and third-order nonlinear susceptibility of EDA4NP were estimated to be n2=5.46*10(-8)cm(2)W(-1), beta=0.65*10(-3)cmW(-1) and chi((3))=2.96*10(-6)esu respectively. The limiting behavior observed with the sample is attributed mainly to nonlinear refraction. PMID- 25498812 TI - Comparative studies on removal of Erythrosine using ZnS and AgOH nanoparticles loaded on activated carbon as adsorbents: Kinetic and isotherm studies of adsorption. AB - Erythrosine adsorption (Er) onto ZnS and AgOH nanoparticle-loaded activated carbon (ZnS-NP-AC and AgOH-NP-AC) was studied and results were compared. Subsequent preparation were fully analyzed by different approach such as BET to obtain knowledge about surface area, pore volume, while FT-IR analysis give comprehensive information about functional group the dependency of removal percentage to adsorbent mass, initial Er concentration and contact time were investigated and optimum conditions for pH, adsorbent dosage, Er concentration and contact time was set as be 3.2, 0.016g, 20mg/L and 16min and 3.2, 0.015g, 19mg/L and 2min for ZnS-NP-AC and AgOH-NP-AC, respectively. The equilibrium data correspond to adsorption strongly follow Langmuir model by ZnS-NP-AC and Freundlich model for AgOH-NP-AC. High adsorption capacity for of 55.86-57.80mgg( 1) and 67.11-89.69mgg(-1) for ZnS-NP-AC and AgOH-NP-AC, respectively. The result of present study confirm the applicability of small amount of these adsorbent (<0.02g) for efficient removal of Er (>95%) in short reasonable time (20min). PMID- 25498813 TI - Synthesis, structure, crystal growth and characterization of a novel semiorganic nonlinear optical l-proline lithium bromide monohydrate single crystal. AB - l-Proline lithium bromide monohydrate (LPLBM), a promising semiorganic nonlinear optical material, was synthesized and single crystals of LPLBM were grown from solution by slow evaporation technique. Single crystal X-ray structure solution reveals that the grown crystal belongs to monoclinic system with space group P21. Presence of various functional groups was identified by FT-IR and FT-Raman spectral analyses. UV-Vis-NIR spectroscopic study shows that the LPLBM crystal possesses 90% of transmittance in the range of 250-1100nm. Vickers microhardness values, the dielectric constant and dielectric loss of the LPLBM crystal were reported. Elemental analysis by energy dispersive X-ray analysis shows the presence of carbon, nitrogen, oxygen and bromine. The surface morphology of the crystal was investigated using scanning electron microscopic study. The thermal stability of the LPLBM crystal was studied from TGA and DSC analysis. Second harmonic generation efficiency of the LPLBM crystal measured by Kurtz and Perry powder technique using Nd:YAG laser is about 0.3 times that of urea. PMID- 25498814 TI - Prediction and characterization of halogen bonds involving formamidine and its derivatives. AB - Ab initio calculations have been carried out for the complexes of formamidine (FA) and some representative halogenated molecules XY (X=Cl, Br, and I; Y=F, CCH, CF3, CN, and NC). The FA-(Z) complex combines with the halogenated molecule through a halogen bond, while the FA-(E) complex is stabilized jointly by both a halogen bond and a X?H interaction. The FA-(E) complex is more stable than the FA (Z) counterpart, with the interaction energy of -3.4 to -23.4kcal/mol, indicating that FA is a good electron donor in halogen bonding. The methyl substituent particularly one at the imino nitrogen atom of FA has an enhancing effect on the strength of halogen bond. The similar effect is found for the phenyl and pyridyl substituents, depending on the FA conformation and substitution position of pyridyl. The stability of stronger halogen bonding is mainly attributed to electrostatic and polarization energies, which is different from the weak one with an electrostatic nature. PMID- 25498816 TI - Structure of collagen adsorbed on a model implant surface resolved by polarization modulation infrared reflection-absorption spectroscopy. AB - The polarization modulation infrared reflection-absorption spectra of collagen adsorbed on a titania surface and quantum chemical calculations are used to describe components of the amide I mode to the protein structure at a sub molecular level. In this study, imino acid rich and poor fragments, representing the entire collagen molecule, are taken into account. The amide I mode of the collagen triple helix is composed of three absorption bands which involve: (i) (~1690cm(-1)) the CO stretching modes at unhydrated groups, (ii) (1655-1673cm( 1)) the CO stretching at carbonyl groups at imino acids and glycine forming intramolecular hydrogen bonds with H atoms at both NH2 and, unusual for proteins, CH2 groups at glycine at a neighbouring chain and (iii) (~1640cm(-1)) the CO stretching at carbonyl groups forming hydrogen bonds between two, often charged, amino acids as well as hydrogen bonds to water along the entire helix. The IR spectrum of films prepared from diluted solutions (c<50MUgml(-1)) corresponds to solution spectra indicating that native collagen molecules interact with water adsorbed on the titania surface. In films prepared from solutions (c?50MUgml(-1)) collagen multilayers are formed. The amide I mode is blue-shifted by 18cm(-1), indicating that intramolecular hydrogen bonds at imino acid rich fragments are weakened. Simultaneous red-shift of the amide A mode implies that the strength of hydrogen bonds at the imino acid poor fragments increases. Theoretically predicted distortion of the collagen structure upon adsorption on the titania surface is experimentally confirmed. PMID- 25498815 TI - Molecular vibrational investigation [FT-IR, FT-Raman, UV-Visible and NMR] on Bis(thiourea) Nickel chloride using HF and DFT calculations. AB - In the present research work, the FT-IR, FT-Raman spectra of the Bis(thiourea) Nickel chloride (BTNC) were recorded and analyzed. The observed fundamental frequencies in finger print and functional group regions were assigned according to their uniqueness region. The computational calculations were carried out by HF and DFT (B3LYP and B3PW91) methods with 6-31++G(d,p) and 6-311++G(d,p) basis sets and the corresponding results were tabulated. The present organo-metallic compound was made up of covalent and coordination covalent bonds. The modified vibrational pattern of the complex molecule associated with ligand group was analyzed. Furthermore, the (13)C NMR and (1)H NMR spectral data were calculated by using the gauge independent atomic orbital (GIAO) method with B3LYP/6 311++G(d,p) basis set and their spectra were simulated and the chemical shifts linked to TMS were compared. A investigation on the electronic and optical properties; absorption wavelengths, excitation energy, dipole moment and frontier molecular orbital energies were carried out. The kubo gap of the present compound was calculated related to HOMO and LUMO energies which confirm the occurring of charge transformation between the base and ligand. Besides frontier molecular orbitals (FMO), molecular electrostatic potential (MEP) was performed. The NLO properties related to Polarizability and hyperpolarizability based on the finite field approach were also discussed. PMID- 25498817 TI - Spectroscopic study on the interaction of Abeta42 with di(picolyl)amine derivatives and the toxicity to SH-S5Y5 cells. AB - In order to confirm the neurotoxicity of bifunctional chelators containing hydrophobic groups and metal chelating moiety, the interaction of di(picolyl)amine (dpa) derivatives toward Abeta42 peptide was investigated. Fluorescence titration reveals that a hydrophobic chelator (such as BODIPY) shows high binding affinity to amyloid Abeta42. Circular dichroism (CD) spectra confirm that the hydrophobic bifunctional chelator can decrease alpha-helix fraction and increase the beta-sheet fraction of amyloid Abeta42. In particular, experimental results indicate that a bifunctional chelator can assemble with Cu(II)-Abeta42 forming chelator-Cu(II)-Abeta42 nanospheres, which are toxic to SH-S5Y5 cells. The hydrophobic interaction between the chelator and the amyloid peptide (Abeta42) has great contribution to the formation of neurotoxic chelator-Cu(II) Abeta42 nanospheres. This work gives a general guide to the development of low cytotoxic inhibitors of Abeta42 aggregation. PMID- 25498818 TI - Identification of allanite (Ce, Ca, Y)2(Al, Fe(3+))3(SiO4)3OH found in marble from Chillagoe, Queensland using Raman spectroscopy. AB - Samples of marble from Chillagoe, North Queensland have been analyzed using scanning electron microscopy (SEM) with energy dispersive X-ray spectroscopy (EDS) and Raman spectroscopy. Chemical analyses provide evidence for the presence of minerals other than limestone and calcite in the marble, including silicate minerals. Some of these analyses correspond to silicate minerals. The Raman spectra of these crystals were obtained and the Raman spectrum corresponds to that of allanite from the Arizona State University data base (RRUFF) data base. The combination of SEM with EDS and Raman spectroscopy enables the characterization of the mineral allanite in the Chillagoe marble. PMID- 25498819 TI - Adsorption of N-(1-(2-bromophenyl)-2-(2-nitrophenyl)ethyl)-4 methylbenzenesulfonamide on silver nanoparticles: SERS investigation. AB - SERS provides essential data regarding the interaction of molecules in drugs with DNA. In the present study silver nanoparticles were synthesized using a solution combustion method with urea as fuel. The prepared silver nanoparticles are rod like structure. Surface-enhanced Raman scattering (SERS) of N-(1-2-bromophenyl)-2 (2-nitrophenyl)ethyl)-4-methylbenzenesulfonamide (BrS) adsorbed on the silver nanoparticle was studied. The nRs and Raman spectral analysis reveal that the BrS adsorbed tilted orientation on the silver surface. Vibrational modes of nRs along with HF calculations are also performed to study the HOMO and LUMO behavior and vibrational features of BrS. PMID- 25498820 TI - Effect of pyrolytic temperature on the properties of TiO2/ITO films for hydrogen sensing. AB - Titanium dioxide (TiO2) thin films were prepared on ITO (222) coated glass substrates by spray pyrolysis technique. The influence of substrate temperature on the orientation, phase, vibrational bands and band gap energy of TiO2 films were discussed. The X-ray diffraction patterns of the films revealed preferentially oriented (101) TiO2 anatase phase at the substrate temperature of 300 degrees C and 350 degrees C. Fourier transform infrared spectra of the films showed the significant sharpening of absorption band at ~645cm(-1) with increase in substrate temperature, which clearly indicates the formation of anatase phase dependent on substrate temperature. Fourier Raman Spectra of the films showed the significant presence of long range order anatase TiO2 phase. The optical measurements of the film prepared at different substrate temperatures revealed the direct band gap of 3.15-3.63eV and indirect band gap of 3.48-3.73eV, characteristic of TiO2 anatase phase. To understand the enhancement of sensing performances of TiO2 films with substrate temperature, the gas sensing mechanism of the films towards 400sccm of hydrogen at room temperature was studied and discussed. PMID- 25498821 TI - Novel pyrazoline-based selective fluorescent probe for the detection of hydrazine. AB - A novel pyrazoline-based fluorescent probe, 2-[4-(3,5-diphenyl-4,5-dihydro pyrazol-1-yl)-benzylidene]-malononitrile, with a simple structure and low detection limit (6.16*10(-6)M) for the detection of hydrazine is designed and synthesized. The probe responds selectively to hydrazine over other molecules with marked fluorescence enhancement. The probe can detect hydrazine effectively at pH 5.0-9.0 with a special emission wavelength at 520nm. Moreover, the probe can be used to detect hydrazine from variety of natural source water. PMID- 25498822 TI - Vibrational spectroscopic and DFT calculation studies of 2-amino-7-bromo-5-oxo [1]benzopyrano [2,3-b]pyridine-3 carbonitrile. AB - The vibrational spectra of 2-amino-7-bromo-5-oxo-[1]benzopyrano [2,3-b]pyridine-3 carbonitrile were recorded using fourier transform-infrared and fourier transform Raman spectrometer. The optimized structural parameters, vibrational frequencies, Mulliken atomic charge distribution, frontier molecular orbitals, thermodynamic properties, temperature dependence of thermodynamic parameters, first order hyperpolarizability and natural bond orbital calculations of the molecule were performed using the Gaussian 09 program. The vibrational frequencies were assigned on the basis of potential energy distribution calculation using the VEDA 4.0 program. The calculated first order hyperpolarizability of ABOBPC molecule was obtained as 6.908*10(-30) issue, which was 10.5 times greater than urea. The nonlinear optical activity of the molecule was also confirmed by the frontier molecular orbitals and natural bond orbital analysis. The frontier molecular orbitals analysis shows that the lower energy gap of the molecule, which leads to the higher value of first order hyperpolarizability. The natural bond orbital analysis indicates that the nonlinear optical activity of the molecule arises due to the pi->pi(*) transitions. The Mulliken atomic charge distribution confirms the presence of intramolecular charge transfer within the molecule. The reactive site of the molecule was predicted from the molecular electrostatic potential contour map. The values of thermo dynamic parameters were increasing with increasing temperature. PMID- 25498823 TI - Binuclear ruthenium(III) bis(thiosemicarbazone) complexes: synthesis, spectral, electrochemical studies and catalytic oxidation of alcohol. AB - A new series of binuclear ruthenium(III) thiosemicarbazone complexes of general formula [(EPh3)2(X)2Ru-L-Ru(X)2(EPh3)2] (where E=P or As; X=Cl or Br; L=NS chelating bis(thiosemicarbazone ligands) has been synthesized and characterized by analytical and spectral (FT-IR, UV-Vis and EPR). IR spectra show that the thiosemicarbazones behave as monoanionic bidentate ligands coordinating through the azomethine nitrogen and thiolate sulphur. The electronic spectra of the complexes indicate that the presence of d-d and intense LMCT transitions in the visible region. The complexes are paramagnetic (low spin d(5)) in nature and all the complexes show rhombic distortion around the ruthenium ion with three different 'g' values (gx?gy?gz) at 77K. All the complexes are redox active and exhibit an irreversible metal centered redox processes (Ru(III)-Ru(III)/Ru(IV) Ru(IV); Ru(III)-Ru(III)/Ru(II)-Ru(II)) within the potential range of 0.38-0.86V and -0.39 to -0.66 V respectively, versus Ag/AgCl. Further, the catalytic efficiency of one of the complexes [Ru2Cl2(AsPh3)4(L1)] (4) has been investigated in the case of oxidation of primary and secondary alcohols into their corresponding aldehydes and ketones in the presence of N-methylmorpholine-N oxide(NMO) as co-oxidant. The formation of high valent Ru(V)O species is proposed as catalytic intermediate for the catalytic cycle. PMID- 25498824 TI - Synthesis, structural and spectral analysis of 1-(pyrazin-2-yl) piperidin-2-ol by density functional theory. AB - The organic compound 1-(pyrazin-2-yl) piperidin-2-ol (abbreviated as PPOL) has been synthesized and characterized by IR, Raman, (1)H NMR and UV-Vis spectroscopy. The Fourier-transform Raman (3500-50cm(-1)) and infrared spectra (4000-400cm(-1)) were recorded in the solid state and interpreted by comparison with theoretical spectra derived from density functional theory (DFT) calculations. The optimized geometry, frequency and intensity of the vibrational bands of the compound was obtained by the density functional theory using 6 31G(d,p) basis set. In the optimized geometry results shows that geometry parameters are good agreement with XRD values. Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. In calculation of electronic absorption spectra, TD-DFT calculations were carried out in the both gas and solution phases. (1)H NMR chemical shifts were calculated by using the gauge invariant atomic orbital (GIAO) method. (1)H NMR analysis is evident for O-H?O intermolecular interaction of the title molecule. The thermodynamic properties of the title compound have been calculated at different temperatures and the results reveal that the standard heat capacities (Cp,m), standard entropies (Sm) and standard enthalpy changes (Hm) increase with rise in temperature. In addition, HOMO and LUMO energies and the first-order hyperpolarizability have been computed. PMID- 25498825 TI - Structural study, NCA, FT-IR, FT-Raman spectral investigations, NBO analysis, thermodynamic functions of N-acetyl-l-phenylalanine. AB - The FT-IR and FT-Raman spectra of N-acetyl-l-phenylalanine were recorded and analyzed. Natural bond orbital analysis has been carried out for various intramolecular interactions that are responsible for the stabilization of the molecule. HOMO-LUMO energy gap has been computed with the help of density functional theory. The statistical thermodynamic functions (heat capacity, entropy, vibrational partition function and Gibbs energy) were obtained for the range of temperature 100-1000K. The polarizability, first hyperpolarizability, anisotropy polarizability invariant has been computed using quantum chemical calculations. The infrared and Raman spectra were also predicted from the calculated intensities. Comparison of the experimental and theoretical spectra values provides important information about the ability of the computational method to describe the vibrational modes. PMID- 25498826 TI - A new solid phase microextraction method using organic ligand in micropipette tip syringe system packed with modified carbon cloth for preconcentration of cadmium in drinking water and blood samples of kidney failure patients. AB - A simple and efficient miniaturized solid phase microextraction (M-SPMUE) in a syringe system was developed for preconcentration of cadmium (Cd) in environmental and biological samples, followed by flame atomic absorption technique. The syringe system contains the micropipette tip packed with activated carbon cloth, coated with modified magnetic nanoparticles of iron oxide Triton X114 (ACC-NPs). Scanning electron microscopy and energy dispersive spectroscopy used for characterization of the size, morphology and elemental composition of ACC-NPs. The sample solution treated with a complexing reagent 8-hydroxyqunilone (8-HQ), and drawn into the syringe, filled with ACC-MNPs and dispensed manually for 2-10 drawing/discharging cycles. The analyte retained on ACC-NPs in micropipette tip-syringe system were then eluted with different volume of 1.5molL(-1) HCl by 1-5 drawing/discharging cycles. The syringe system directly couple with FAAS for analysis. The influence of different variables on the extraction efficiency of Cd, including adsorbent dosage, pH, sample volume, eluent volume and drawing/discharging cycles of syringe system were optimized. At optimized extraction conditions, the method showed good linearity in the range of 5-250MUgL(-1), with a limit of detection 0.15MUgL(-1). Repeatability of the extraction (%RSD) was <5%, n=5. The validity and accuracy of the method was checked by the certified reference materials. The proposed method was successfully applied for the determination of Cd in different drinking water and biological samples of kidney failure patients and healthy controls. PMID- 25498827 TI - FT-IR, FT-Raman, UV-visible, and NMR spectroscopy and vibrational properties of the labdane-type diterpene 13-epi-sclareol. AB - In this work, FT-IR, FT-Raman, UV-Visible and NMR spectroscopies and density functional theory (DFT) calculations were employed to study the structural and vibrational properties of the labdane-type diterpene 13-epi-sclareol using the hybrid B3LYP method together with the 6-31G(*) basis set. Three stable structures with minimum energy found on the potential energy curves (PES) were optimized, and the corresponding molecular electrostatic potentials, atomic charges, bond orders, stabilization energies and topological properties were computed at the same approximation level. The complete assignment of the bands observed in the vibrational spectrum of 13-epi-sclareol was performed taking into account the internal symmetry coordinates for the three structures using the scaled quantum mechanical force field (SQMFF) methodology at the same level of theory. In addition, the force constants were calculated and compared with those reported in the literature for similar compounds. The predicted vibrational spectrum and the calculated (1)H NMR and (13)C NMR chemical shifts are in good agreement with the corresponding experimental results. The theoretical UV-Vis spectra for the most stable structure of 13-epi-sclareol demonstrate a better correlation with the corresponding experimental spectrum. The study of the three conformers by means of the theory of atoms in molecules (AIM) revealed different H bond interactions and a strong dependence of the interactions on the distance between the involved atoms. Furthermore, the natural bond orbital (NBO) calculations showed the characteristics of the electronic delocalization for the two six-membered rings with chair conformations. PMID- 25498828 TI - Preliminary results using a newly developed projection method to visualize vascular anatomy prior to DIEP flap breast reconstruction. AB - INTRODUCTION: In a deep inferior epigastric perforator (DIEP) flap breast reconstruction, computed tomography angiography (CTA) is currently considered as the gold standard in preoperative imaging for this procedure. Unidirectional Doppler ultrasound (US) is frequently used; however, this method does not distinguish the main axial vessels from perforator arteries at the height of the fascia, it has a limited penetration depth, and it cannot assess the branching patterns of the deep inferior arteries. A new method and system were developed, which consisted of a video projector preoperatively displaying the location and intramuscular course of the artery perforators and subcutaneous branching on the patient's abdomen. METHOD: All patients (n=9) underwent a standard protocol: a preoperative CTA was performed and the DIEPs were localized using a unidirectional Doppler probe. In addition, a three-dimensional (3D) reconstruction of the perforator locations based on CTA was projected on the abdomen of the patients. All projected perforator locations were assessed using a unidirectional Doppler probe. The intraoperative results were collected for comparison. RESULTS: A total of 88 locations were marked with the use of unidirectional Doppler and a total of 100 perforators were projected (p=0.38). In 98 out of 100 projected perforator locations, a Doppler signal was audible. The intraoperative results demonstrate that 19 out of 34 transplanted perforators were correctly identified with unidirectional Doppler (56.9%+/-31.4%), where the projection method properly revealed 29 locations (84.3%+/-25.8%) (p=0.030). CONCLUSION: The projection method is not only capable of providing more information and identifying more perforators used for transplantation than unidirectional Doppler probing but also more accurate in pointing out the corresponding perforator found intraoperatively. PMID- 25498829 TI - The impact of comorbidity upon determinants of outcome in patients with lung cancer. AB - BACKGROUND: Survival from lung cancer remains poor in Scotland, UK. It is believed that comorbidity may play an important role in this. The goal of this study was to determine the value of a novel comorbidity scoring system (SCSS) and to compare it with the already established Charlson Comorbidity Index and the modified Glasgow Prognostic Score (mGPS). We also wished to explore the relationship between comorbidity, mGPS and Performance Status (PS). In addition we investigated a number of standard prognostic markers and demographics. This study aimed to determine which of these factors most accurately predicted survival. METHODS: Between 2005 and 2008 all newly diagnosed lung cancer patients coming through the Multi-Disciplinary Teams (MDTs) in four Scottish Centres were included in the study. Patient demographics, World Health Organization/Eastern Cooperative Oncology Group performance status, clinico-pathological features, mGPS, comorbidity and proposed primary treatment modality were recorded. Univariate survival analysis was carried out using Kaplan-Meier method and the log rank test. RESULTS: This large unselected population based cohort study of lung cancer patients has demonstrated that a number of important factors have significant impact in terms of survival. It has gone further by showing that the factors which influence survival are different, depending upon the stage of cancer at diagnosis and the potential treatment strategy. The novel comorbidity scoring system, the SCSS, has compared very favourably with the more established CCI. CONCLUSION: This study has identified that a variety of factors are independent prognostic determinants of outcome in lung cancer. There appear to be clear differences between the early and late stage groups. PMID- 25498831 TI - Activated fibronectin-secretory phenotype of mesenchymal stromal cells in pre fibrotic myeloproliferative neoplasms. AB - We characterized bone marrow stromal cells (BMSC) from patients with pre-fibrotic myeloproliferative neoplasms (MPN). MPN-BMSC showed decreased capacity to stimulate the proliferation of colony-forming units of normal hematopoietic stem and progenitor cells and displayed increased matrix remodelling (in particular fibronectin deposition) compared to control BMSC. This finding was confirmed in pre-fibrotic MPN bone marrow biopsies in a tissue microarray (n = 34), which stained positive for fibronectin in the absence of reticulin as a standard myelofibrosis marker. Fibronectin expression correlated significantly with reduced haemoglobin levels in MPN-patients (p = 0.007; R2 = 0.42). Our data show significant cell-intrinsic alterations in MPN-MSC and suggest that Fibronectin expression might be applicable as a biomarker for the identification of early myelofibrotic transformation in reticulin-negative MPN. PMID- 25498830 TI - Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia. AB - We report on a serum autoantibody associated with cerebellar ataxia. Immunohistochemical studies of sera from four patients referred for autoantibody testing revealed binding of high-titer (up to 1:5,000) IgG antibodies, mainly IgG1, to the molecular layer, Purkinje cell layer, and white matter on mouse, rat, porcine, and monkey cerebellum sections. The antibody bound to PC somata, dendrites, and axons, resulting in a binding pattern similar to that reported for anti-Ca/anti-ARHGAP26, but did not react with recombinant ARHGAP26. Extensive control studies were performed to rule out a broad panel of previously described paraneoplastic and non-paraneoplastic anti-neural autoantibodies. The characteristic binding pattern as well as double staining experiments suggested inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) as the target antigen. Verification of the antigen included specific neutralization of the tissue reaction following preadsorption with ITPR1 (but not ARHGAP26) and a dot-blot assay with purified ITPR1 protein. By contrast, anti-ARHGAP26-positive sera did not bind to ITPR1. In a parallel approach, a combination of histoimmunoprecipitation and mass spectrometry also identified ITPR1 as the target antigen. Finally, a recombinant cell-based immunofluorescence assay using HEK293 cells expressing ITPR1 and ARHGAP26, respectively, confirmed the identification of ITPR1. Mutations of ITPR1 have previously been implicated in spinocerebellar ataxia with and without cognitive decline. Our findings suggest a role of autoimmunity against ITPR1 in the pathogenesis of autoimmune cerebellitis and extend the panel of diagnostic markers for this disease. PMID- 25498832 TI - Unilateral fusion of a supernumerary tooth to a maxillary permanent lateral incisor: a report of a rare case. AB - A supernumerary tooth is an additional entity to the normal series of teeth that may occur in isolation or may be fused to a normal counterpart. Diagnosis and delineation of an accurate treatment plan in cases involving supernumerary teeth are often a challenge. This report describes a case of unilateral fusion of a supernumerary tooth to a maxillary permanent lateral incisor in which a conservative approach was used to reach a favorable outcome. PMID- 25498833 TI - Enriched trimethylation of lysine 4 of histone H3 of WDR63 enhanced osteogenic differentiation potentials of stem cells from apical papilla. AB - INTRODUCTION: Dental tissue-derived mesenchymal stem cells (MSCs) are a reliable cell source for dental tissue regeneration. However, the molecular mechanisms underlying their directed differentiation remain unclear, thus limiting their use. Trimethylation of lysine 4 of histone H3 (H3K4Me3) correlates with gene activation and osteogenic differentiation. We used stem cells from apical papilla (SCAPs) to investigate the effects of genomic changes in H3K4Me3 modification at gene promoter regions on MSC osteogenic differentiation. METHODS: ChIP-on-chip assays were applied to compare the H3K4Me3 profiles at gene promoter regions of undifferentiated and differentiated SCAPs. Alkaline phosphatase activity assay, alizarin red staining, quantitative analysis of calcium, the expressions of osteogenesis-related genes, and transplantation in nude mice were used to investigate the osteogenic differentiation potentials of SCAPs. RESULTS: In differentiated SCAPs, 119 gene promoters exhibited >2-fold increases of H3K4Me3; in contrast, the promoter regions of 21 genes exhibited >2-fold decreases of H3K4Me3. On the basis of enriched H3K4Me3 and up-regulated gene expression on the osteogenic differentiation of SCAPs, WDR63 may be a potential regulator for mediating SCAP osteogenic differentiation. Through gain-of-function and loss-of function studies, we discovered that WDR63 enhances alkaline phosphatase activity, mineralization, and the expression of BSP, OSX, and RUNX2 in vitro. In addition, transplant experiments in nude mice confirmed that SCAP osteogenesis is triggered by activated WDR63. CONCLUSIONS: These results indicate that WDR63 is a positive enhancer for SCAP osteogenic differentiation and suggest that activation of WDR63 signaling might improve tissue regeneration mediated by MSCs of dental origin. PMID- 25498834 TI - Periapical and endodontic status scale based on periapical bone lesions and endodontic treatment quality evaluation using cone-beam computed tomography. AB - INTRODUCTION: The purpose of this study was to present a new periapical and endodontic status scale (PESS) that is based on the complex periapical index (COPI), which was designed for the identification and classification of periapical bone lesions in cases of apical periodontitis, and the endodontically treated tooth index, which was designed for endodontic treatment quality evaluation by means of cone-beam computed tomographic (CBCT) analysis. METHODS: Periapical and endodontic status parameters were selected from the already known indexes and scientific literature for radiologic evaluation. Radiographic images (CBCT imaging, digital orthopantomography [DOR], and digital periapical radiography) from 55 patients were analyzed. All parameters were evaluated on CBCT, DOR, and digital periapical radiographic images by 2 external observers. The statistical analysis was performed with software SPSS version 19.0 (SPSS Inc, Chicago, IL). Chi-square tests were used to compare frequencies of qualitative variables. The level of significance was set at P <= .05. RESULTS: Overall intraobserver and interobserver agreements were very good and good, respectively. CBCT analysis found more lesions and lesions of bigger dimension (P < .001). CBCT imaging was also superior in locating lesions in the apical part on the side compared with DOR and in the diagnosis of cortical bone destruction compared with both methods (P < .001). Through CBCT analysis, more root canals and more canals associated with lesions were found. The most informative and reproducible periapical and endodontic status parameters were selected, and a new PESS was proposed. CONCLUSIONS: The classification proposed in the present study seems to be reproducible and objective and adds helpful information with respect to the existing indexes. Future studies need to be conducted to validate PESS. PMID- 25498835 TI - Social media and mobile apps for health promotion in Australian Indigenous populations: scoping review. AB - BACKGROUND: Health promotion organizations are increasingly embracing social media technologies to engage end users in a more interactive way and to widely disseminate their messages with the aim of improving health outcomes. However, such technologies are still in their early stages of development and, thus, evidence of their efficacy is limited. OBJECTIVE: The study aimed to provide a current overview of the evidence surrounding consumer-use social media and mobile software apps for health promotion interventions, with a particular focus on the Australian context and on health promotion targeted toward an Indigenous audience. Specifically, our research questions were: (1) What is the peer reviewed evidence of benefit for social media and mobile technologies used in health promotion, intervention, self-management, and health service delivery, with regard to smoking cessation, sexual health, and otitis media? and (2) What social media and mobile software have been used in Indigenous-focused health promotion interventions in Australia with respect to smoking cessation, sexual health, or otitis media, and what is the evidence of their effectiveness and benefit? METHODS: We conducted a scoping study of peer-reviewed evidence for the effectiveness of social media and mobile technologies in health promotion (globally) with respect to smoking cessation, sexual health, and otitis media. A scoping review was also conducted for Australian uses of social media to reach Indigenous Australians and mobile apps produced by Australian health bodies, again with respect to these three areas. RESULTS: The review identified 17 intervention studies and seven systematic reviews that met inclusion criteria, which showed limited evidence of benefit from these interventions. We also found five Australian projects with significant social media health components targeting the Indigenous Australian population for health promotion purposes, and four mobile software apps that met inclusion criteria. No evidence of benefit was found for these projects. CONCLUSIONS: Although social media technologies have the unique capacity to reach Indigenous Australians as well as other underserved populations because of their wide and instant disseminability, evidence of their capacity to do so is limited. Current interventions are neither evidence-based nor widely adopted. Health promotion organizations need to gain a more thorough understanding of their technologies, who engages with them, why they engage with them, and how, in order to be able to create successful social media projects. PMID- 25498836 TI - Prediction of the thickness of the compensator filter in radiation therapy using computational intelligence. AB - In this study, artificial neural networks (ANNs) and adaptive neuro-fuzzy inference system (ANFIS) are investigated to predict the thickness of the compensator filter in radiation therapy. In the proposed models, the input parameters are field size (S), off-axis distance, and relative dose (D/D0), and the output is the thickness of the compensator. The obtained results show that the proposed ANN and ANFIS models are useful, reliable, and cheap tools to predict the thickness of the compensator filter in intensity-modulated radiation therapy. PMID- 25498837 TI - A planning study investigating dual-gated volumetric arc stereotactic treatment of primary renal cell carcinoma. AB - This is a planning study investigating the dosimetric advantages of gated volumetric-modulated arc therapy (VMAT) to the end-exhale and end-inhale breathing phases for patients undergoing stereotactic treatment of primary renal cell carcinoma. VMAT plans were developed from the end-inhale (VMATinh) and the end-exhale (VMATexh) phases of the breathing cycle as well as a VMAT plan and 3 dimensional conformal radiation therapy plan based on an internal target volume (ITV) (VMATitv). An additional VMAT plan was created by giving the respective gated VMAT plan a 50% weighting and summing the inhale and exhale plans together to create a summed gated plan. Dose to organs at risk (OARs) as well as comparison of intermediate and low-dose conformity was evaluated. There was no difference in the volume of healthy tissue receiving the prescribed dose for the planned target volume (PTV) (CI100%) for all the VMAT plans; however, the mean volume of healthy tissue receiving 50% of the prescribed dose for the PTV (CI50%) values were 4.7 (+/- 0.2), 4.6 (+/- 0.2), and 4.7 (+/- 0.6) for the VMATitv, VMATinh, and VMATexh plans, respectively. The VMAT plans based on the exhale and inhale breathing phases showed a 4.8% and 2.4% reduction in dose to 30cm(3) of the small bowel, respectively, compared with that of the ITV-based VMAT plan. The summed gated VMAT plans showed a 6.2% reduction in dose to 30cm(3) of the small bowel compared with that of the VMAT plans based on the ITV. Additionally, when compared with the inhale and the exhale VMAT plans, a 4% and 1.5%, respectively, reduction was observed. Gating VMAT was able to reduce the amount of prescribed, intermediate, and integral dose to healthy tissue when compared with VMAT plans based on an ITV. When summing the inhale and exhale plans together, dose to healthy tissue and OARs was optimized. However, gating VMAT plans would take longer to treat and is a factor that needs to be considered. PMID- 25498838 TI - Spine stereotactic body radiation therapy plans: Achieving dose coverage, conformity, and dose falloff. AB - We report our experience of establishing planning objectives to achieve dose coverage, conformity, and dose falloff for spine stereotactic body radiation therapy (SBRT) plans. Patients with spine lesions were treated using SBRT in our institution since September 2009. Since September 2011, we established the following planning objectives for our SBRT spine plans in addition to the cord dose constraints: (1) dose coverage-prescription dose (PD) to cover at least 95% planning target volume (PTV) and 90% PD to cover at least 99% PTV; (2) conformity index (CI)-ratio of prescription isodose volume (PIV) to the PTV < 1.2; (3) dose falloff-ratio of 50% PIV to the PTV (R(50%)); (4) and maximum dose in percentage of PD at 2 cm from PTV in any direction (D(2cm)) to follow Radiation Therapy Oncology Group (RTOG) 0915. We have retrospectively reviewed 66 separate spine lesions treated between September 2009 and December 2012 (31 treated before September 2011 [group 1] and 35 treated after [group 2]). The chi(2) test was used to examine the difference in parameters between groups. The PTV V(100% PD) >= 95% objective was met in 29.0% of group 1 vs 91.4% of group 2 (p < 0.01) plans. The PTV V(90% PD) >= 99% objective was met in 38.7% of group 1 vs 88.6% of group 2 (p < 0.01) plans. Overall, 4 plans in group 1 had CI > 1.2 vs none in group 2 (p = 0.04). For D(2cm), 48.3% plans yielded a minor violation of the objectives and 16.1% a major violation for group 1, whereas 17.1% exhibited a minor violation and 2.9% a major violation for group 2 (p < 0.01). Spine SBRT plans can be improved on dose coverage, conformity, and dose falloff employing a combination of RTOG spine and lung SBRT protocol planning objectives. PMID- 25498839 TI - Unusual cause of aborted sudden cardiac death in a teen athlete: homozygosity for the 4G allele of the plasminogen activase inhibitor type 1 gene. AB - Common aetiologies of sudden cardiac death in children include coronary anomalies, channelopathies, and cardiomyopathies. Less frequently, hypercoagulable states cause sudden arrest. We report an unusual case of aborted sudden cardiac death in a teenager, ultimately found to have homozygosity for the 4G allele of the plasminogen activase inhibitor type 1 gene. PMID- 25498840 TI - Treatment of thoracic or lumbar spinal tuberculosis complicated by resultant listhesis at the involved segment. PMID- 25498842 TI - Decreased expression of IL-27 and its correlation with Th1 and Th17 cells in progressive multiple sclerosis. AB - Progressive multiple sclerosis (MS) is an immune-mediated demyelinating disease in which both imbalanced T helper (Th) subsets and aberrant cytokine profiles have been found. Interleukin-27 (IL-27), a cytokine with pro-inflammatory and anti-inflammatory effects, plays pleiotropic roles in immunomodulation. In the present study, plasma levels of IL-27, interferon-gamma (IFN-gamma), IL-17 and frequencies of peripheral Th1, Th17 cells were determined by enzyme-linked immunosorbent assay (ELISA) and flow cytometry in 45 progressive MS and 25 healthy controls. mRNA expression levels of IL-27, IFN-gamma, T-bet, IL-17 and RAR-related orphan receptor gamma t (RORgammat) in peripheral blood mononuclear cells (PBMCs) were also quantified by real-time polymerase chain reaction. Plasma and mRNA levels of IL-27 in progressive MS patients were significantly lower than those in healthy controls, while plasma concentrations of IL-17, frequencies of circulating Th17, and mRNA expression levels of IL-17 as well as RORgammat were all increased remarkably compared with healthy controls. No statistical significance was observed in IFN-gamma and T-bet mRNA expression or plasma IFN gamma levels between progressive MS patients and healthy controls. Moreover, plasma levels of IL-27 were found to be negatively correlated to the percentages of circulating Th17 or plasma IL-17 concentrations in patients with progressive MS. Our data showed that progressive MS patients had decreased plasma and mRNA expression levels of IL-27, suggesting that it might be involved in the pathophysiological process of MS. PMID- 25498841 TI - Emerging therapeutic targets in bladder cancer. AB - Treatment of muscle invasive urothelial bladder carcinoma (BCa) remains a major challenge. Comprehensive genomic profiling of tumors and identification of driver mutations may reveal new therapeutic targets. This manuscript discusses relevant molecular drivers of the malignant phenotype and agents with therapeutic potential in BCa. Small molecule pan-FGFR inhibitors have shown encouraging efficacy and safety results especially among patients with activating FGFR mutations or translocations. mTOR inhibitors for patients with TSC1 mutations and concomitant targeting of PI3K and MEK represent strategies to block PI3K/AKT/mTOR pathway. Encouraging preclinical results with ado-trastuzumab emtansine (T-DM1) exemplifies a new potential treatment for HER2-positive BCa along with innovative bispecific antibodies. Inhibitors of cell cycle regulators (aurora kinase, polo like kinase 1, and cyclin-dependent kinase 4) are being investigated in combination with chemotherapy. Early results of clinical studies with anti-CTLA4 and anti-PDL1 are propelling immune modulating drugs to the forefront of emerging treatments for BCa. Collectively, these novel therapeutic targets and treatment strategies hold promise to improve the outcome of patients afflicted with this malignancy. PMID- 25498843 TI - Convexity subarachnoid hemorrhage in ischemic stroke. AB - OBJECTIVE: To report three cases of convexity subarachnoid hemorrhage (cSAH) after acute ischemic stroke and review the relevant literature. BACKGROUND: cSAH is an unusual presentation and the association with acute ischemic stroke has only infrequently been reported. DESIGN AND METHODS: Case series with retrospective review of the clinical presentation and neuroimaging features of patients who presented with cSAH and acute ischemic stroke. RESULTS: We describe three cases of cSAH who presented with ipsilateral acute ischemic stroke. Two patients had ipsilateral ICA stenosis, with one patient developing cSAH after ICA stenting. The third patient developed cSAH in setting of small distal cortical ischemic lesions with normal cranial vasculature. None of these patients had evidence for cerebral amyloid angiopathy on magnetic resonance imaging-gradient echo (MRI-GRE) sequence. All our patients remained clinically stable with limited neurological deficit at the time of discharge. CONCLUSION: We report three more cases linking cSAH with ischemic strokes. All of our patients had good outcome with minimal neurological deficit. cSAH should remain in differential diagnosis and early complication of acute ischemic stroke. PMID- 25498844 TI - Relationship between ADAMTS13 activity, von Willebrand factor antigen levels and platelet function in the early and late phases after TIA or ischaemic stroke. AB - BACKGROUND: Reduced ADAMTS13 activity is seen in thrombotic thrombocytopenic purpura (TTP), and may lead to accumulation of prothrombotic ultra-large von Willebrand factor (ULVWF) multimers in vivo. ADAMTS13 activity and its relationship with VWF antigen (VWF:Ag) levels and platelet function in 'non-TTP related' TIA or ischaemic stroke has not been comprehensively studied. METHODS: In this prospective pilot observational analytical case-control study, ADAMTS13 activity and VWF:Ag levels were quantified in platelet poor plasma in 53 patients in the early phase (<= 4 weeks) and 34 of these patients in the late phase (>= 3 months) after TIA or ischaemic stroke on aspirin. Data were compared with those from 22 controls not on aspirin. The impact of ADAMTS13 on platelet function in whole blood was quantified by measuring Collagen-ADP (C-ADP) and Collagen Epinephrine closure times on a platelet function analyser (PFA-100((r))). RESULTS: Median ADAMTS13 activity was significantly reduced in the early phase (71.96% vs. 95.5%, P <0.01) but not in the late phase after TIA or stroke compared with controls (86.3% vs. 95.5%, P=0.19). There was a significant inverse relationship between ADAMTS13 activity and VWF:Ag levels in the early phase (r= 0.31; P=0.024), but not in the late phase after TIA or stroke (P=0.74). There was a positive correlation between ADAMTS13 activity and C-ADP closure times in early phase patients only, likely mediated via VWF:Ag levels. DISCUSSION: ADAMTS13 activity is reduced and VWF:Ag expression is increased within 4 weeks of TIA or ischaemic stroke onset, and can promote enhanced platelet adhesion and aggregation in response to stimulation with collagen and ADP via VWF-mediated pathways. These data improve our understanding of the dynamic haemostatic and thrombotic profiles of ischaemic cerebrovascular disease (CVD) patients, and are important in view of the potential future role that ADAMTS13 may have to play as an anti-thrombotic agent in CVD. PMID- 25498845 TI - Delayed dysosmia and dysgeusia after thalamic infarction. PMID- 25498846 TI - Is malaria control better with both treated nets and spraying? PMID- 25498847 TI - Efficacy of indoor residual spraying with dichlorodiphenyltrichloroethane against malaria in Gambian communities with high usage of long-lasting insecticidal mosquito nets: a cluster-randomised controlled trial. AB - BACKGROUND: Although many malaria control programmes in sub-Saharan Africa use indoor residual spraying with long-lasting insecticidal nets (LLINs), the two studies assessing the benefit of the combination of these two interventions gave conflicting results. We aimed to assess whether the addition of indoor residual spraying to LLINs provided a significantly different level of protection against clinical malaria in children or against house entry by vector mosquitoes. METHODS: In this two-arm cluster, randomised, controlled efficacy trial we randomly allocated clusters of Gambian villages using a computerised algorithm to LLINs alone (n=35) or indoor residual spraying with dichlorodiphenyltrichloroethane plus LLINs (n=35). In each cluster, 65-213 children, aged 6 months to 14 years, were surveyed at the start of the 2010 transmission season and followed in 2010 and 2011 by passive case detection for clinical malaria. Exposure to parasite transmission was assessed by collection of vector mosquitoes with both light and exit traps indoors. Primary endpoints were the incidence of clinical malaria assessed by passive case detection and number of Anopheles gambiae sensu lato mosquitoes collected per light trap per night. Intervention teams had no role in data collection and the data collection teams were not informed of the spray status of villages. The trial is registered at the ISRCTN registry, number ISRCTN01738840. FINDINGS: LLIN coverage in 2011 was 3510 (93%) of 3777 children in the indoor residual spraying plus LLIN group and 3622 (95.5%) of 3791 in the LLIN group. In 2010, 7845 children were enrolled, 7829 completed passive case detection, and 7697 (98%) had complete clinical and covariate data. In 2011, 7009 children remained in the study, 648 more were enrolled, 7657 completed passive case detection, and 7545 (98.5%) had complete data. Indoor residual spraying coverage per cluster was more than 80% for both years in the indoor residual spraying plus LLIN group. Incidence of clinical malaria was 0.047 per child-month at risk in the LLIN group and 0.044 per child month at risk in the indoor residual spraying plus LLIN group in 2010, and 0.032 per child-month at risk in the LLIN group and 0.034 per child-month at risk in the indoor residual spraying plus LLIN group in 2011. The incident rate ratio was 1.08 (95% CI 0.80-1.46) controlling for confounders and cluster by mixed-effect negative binomial regression on all malaria attacks for both years. No significant difference was recorded in the density of vector mosquitoes caught in light traps in houses over the two transmission seasons; the mean number of A gambiae sensu lato mosquitoes per trap per night was 6.7 (4.0-10.1) in the LLIN group and 4.5 (2.4-7.4) in the indoor residual spraying plus LLIN group (p=0.281 in the random-effects linear regression model). INTERPRETATION: We identified no significant difference in clinical malaria or vector density between study groups. In this area with high LLIN coverage, moderate seasonal transmission, and susceptible vectors, indoor residual spraying did not provide additional benefit. FUNDING: UK Medical Research Council. PMID- 25498848 TI - Visual and auditory socio-cognitive perception in unilateral temporal lobe epilepsy in children and adolescents: a prospective controlled study. AB - AIM: A high rate of abnormal social behavioural traits or perceptual deficits is observed in children with unilateral temporal lobe epilepsy. In the present study, perception of auditory and visual social signals, carried by faces and voices, was evaluated in children or adolescents with temporal lobe epilepsy. METHODS: We prospectively investigated a sample of 62 children with focal non idiopathic epilepsy early in the course of the disorder. The present analysis included 39 children with a confirmed diagnosis of temporal lobe epilepsy. Control participants (72), distributed across 10 age groups, served as a control group. Our socio-perceptual evaluation protocol comprised three socio-visual tasks (face identity, facial emotion and gaze direction recognition), two socio auditory tasks (voice identity and emotional prosody recognition), and three control tasks (lip reading, geometrical pattern and linguistic intonation recognition). All 39 patients also benefited from a neuropsychological examination. RESULTS: As a group, children with temporal lobe epilepsy performed at a significantly lower level compared to the control group with regards to recognition of facial identity, direction of eye gaze, and emotional facial expressions. We found no relationship between the type of visual deficit and age at first seizure, duration of epilepsy, or the epilepsy-affected cerebral hemisphere. Deficits in socio-perceptual tasks could be found independently of the presence of deficits in visual or auditory episodic memory, visual non-facial pattern processing (control tasks), or speech perception. A normal FSIQ did not exempt some of the patients from an underlying deficit in some of the socio perceptual tasks. CONCLUSION: Temporal lobe epilepsy not only impairs development of emotion recognition, but can also impair development of perception of other socio-perceptual signals in children with or without intellectual deficiency. Prospective studies need to be designed to evaluate the results of appropriate re education programs in children presenting with deficits in social cue processing. PMID- 25498850 TI - Milk-alkali-induced pancreatitis in a chronically hypocalcemic patient with DiGeorge syndrome. AB - BACKGROUND: Pancreatitis is a common diagnosis in the emergency department (ED), and milk-alkali syndrome (MAS) is an uncommon etiology for pancreatitis. MAS is caused by increased calcium and alkali ingestion, causing hypercalcemia accompanied by metabolic alkalosis and renal failure. Once considered rare, MAS is an increasingly common cause of hypercalcemia. Awareness of the resurgence of this syndrome is important for emergency physicians when recalling the causes of renal failure and pancreatitis. We present a case of pancreatitis and acute renal failure (ARF) in a chronically hypocalcemic DiGeorge syndrome patient, resulting from hypercalcemia secondary to excessive ingestion of calcium carbonate tablets. CASE REPORT: A patient with DiGeorge syndrome and chronic abdominal pain due to gastroesophageal reflux disease (GERD) presented to our ED for severe abdominal pain. He reported nausea and vomiting, as well as epigastric pain that seemed worse than his typical pain. Laboratory evaluation revealed pancreatitis and ARF, although the patient had no prior history of these conditions. Upon further questioning, his mother divulged that the patient had been taking large quantities of calcium carbonate tablets for his worsening GERD symptoms. The patient was admitted to the intensive care unit where his pancreatitis and ARF eventually resolved as his calcium levels returned to his baseline. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: MAS is a relatively uncommon diagnosis, but can lead to serious sequelae such as pancreatitis and ARF. Questioning the patient about calcium ingestion is an important facet to the diagnosis and work up of pancreatitis and ARF. Recognition of this etiology can improve patient outcomes and prevent recurrences. PMID- 25498851 TI - The C-MAC(r) video laryngoscope is superior to the direct laryngoscope for the rescue of failed first-attempt intubations in the emergency department. AB - OBJECTIVE: To compare the effectiveness of the C-MAC(r) video laryngoscope (CMAC) to the direct laryngoscope (DL) when used to rescue a failed first attempt intubation in the emergency department (ED). METHODS: Data were prospectively collected on all patients intubated in an academic ED center over a five-year period from February 1, 2009 to January 31, 2014 when both the CMAC and the DL were available. Following each intubation the operator completed a continuous quality improvement (CQI) form documenting patient, operator and intubation characteristics. All orotracheal intubations attempted by emergency physicians (EPs) on adult patients with a failed first intubation attempt, and in which the CMAC or the DL was used for the second attempt, were included. The primary outcome was successful intubation on the second attempt using either the CMAC or the DL. A multivariate logistic regression analysis was performed to adjust for potential confounders. RESULTS: During the five-year study period, there were 460 adult orotracheal intubation attempts by EPs which were not successful on the first attempt. In 398 (86.5%) of these cases the same operator performed the second attempt. The CMAC was utilized for the second attempt in 141 cases and was successful in 116 (82.3%; 95% CI 75.0%-88.2%) and the DL was utilized in 94 cases and was successful in 58 (61.7%; 95% CI 51.1%-71.5%). In a multivariate logistic regression analysis the CMAC was associated with an increased odds (adjusted OR 3.5; 95% CI 1.9-6.7) of a second attempt success compared to the DL. CONCLUSIONS: After a failed first intubation attempt in the ED, regardless of the initial device used, the CMAC was more successful than the DL when used for the second attempt. This suggests that the CMAC is the preferred rescue device after an initial intubation attempt in the ED fails. PMID- 25498852 TI - Usefulness of (1,3) beta-D-glucan detection in bronchoalveolar lavage samples in Pneumocystis pneumonia and Pneumocystis pulmonary colonization. AB - OBJECTIVE OF THE STUDY: Recent data demonstrate the usefulness of (1,3) beta-d glucan (BG) detection in serum samples to distinguish patients developing Pneumocystis pneumonia and patients who are colonized by the fungus. In contrast, data of BG detection in bronchoalveolar lavage (BAL) samples from these patient populations are still rare. PATIENTS: In this context, we determined BG levels in BAL samples from 11 Pneumocystis pneumonia (PCP) patients, 10 colonized patients, and 24 Pneumocystis-uninfected patients. MATERIALS AND METHODS: BG levels were determined on each BAL sample using the Fungitell((r)) kit (Associates of Cape Cod, Inc., Cape Cod, MA, USA) according to the manufacturer's instructions applied to serum sample examination. RESULTS: The BG levels in BAL samples from the PCP patient group (mean value 20 588 pg/mL) were significantly higher than those in the colonized patient group (mean value 105 pg/mL) (P=0.0001, Mann Whitney test) and than those in the Pneumocystis-uninfected patient group (mean value 74 pg/mL) (P<0.0001, Mann-Whitney test). The BG levels in BAL samples from the colonized patient group did not differ significantly from those in the Pneumocystis-uninfected patients group (P=0.21). CONCLUSION: The results suggest that measurements of BAL BG levels may facilitate the differential diagnosis of PCP and pulmonary colonization with Pneumocystis. PMID- 25498849 TI - Diverse novel mesorhizobia nodulate New Zealand native Sophora species. AB - Forty eight rhizobial isolates from New Zealand (NZ) native Sophora spp. growing in natural ecosystems were characterised. Thirty eight isolates across five groups showed greatest similarity to Mesorhizobium ciceri LMG 14989(T) with respect to their 16S rRNA and concatenated recA, glnll and rpoB sequences. Seven isolates had a 16S rRNA sequence identical to M. amorphae ATCC 19665(T) but showed greatest similarity to M. septentrionale LMG 23930(T) on their concatenated recA, glnll and rpoB sequences. All isolates grouped closely together for their nifH, nodA and nodC sequences, clearly separate from all other rhizobia in the GenBank database. None of the type strains closest to the Sophora isolates based on 16S rRNA sequence similarity nodulated Sophora microphylla but they all nodulated their original host. Twenty one Sophora isolates selected from the different 16S rRNA groupings produced N2-fixing nodules on three Sophora spp. but none nodulated any host of the type strains for the related species. DNA hybridisations indicated that these isolates belong to novel Mesorhizobium spp. that nodulate NZ native Sophora species. PMID- 25498853 TI - [Trends and clinical need of ethical principles]. PMID- 25498854 TI - Assessment of anti-diabetic activity of an ethnopharmacological plant Nerium oleander through alloxan induced diabetes in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Nerium oleander L. (syn. Nerium indicum Mill. and Nerium odorum Aiton.) is used for its anti-diabetic properties in Pakistan, Algeria, Morocco and is also recognized in Ayurveda. The present study was undertaken to investigate the anti-diabetic capacity of a standardized hydromethanolic extract of Nerium oleander in alloxan induced diabetes in mice. MATERIALS AND METHODS: Nerium oleander leaf extract (NOLE) was orally administered at 50 and 200mg/kg body weight (BW) dose to alloxanized mice (blood glucose >200mg/dl). After 20 consecutive days of treatment, various diabetic parameters were studied and compared with untreated mice. Furthermore, gas chromatography-mass spectrometry (GC-MS) and high performance liquid chromatography (HPLC) analysis was employed to reveal the phytochemical composition of the plant extract. RESULTS: NOLE demonstrated antihyperglycaemic activity by reducing 73.79% blood glucose level after 20 days of treatment. Oral glucose tolerance test (OGTT) revealed increase in glucose tolerance as evident by 65.72% decrease in blood glucose in 3h post treatment. Percentage decrease in different liver marker enzymes were significant along with decrease in triglyceride and cholesterol levels, displaying potent antihyperlipidemic activity. Peroxidase and catalase activity in liver, kidney and skeletal muscle were significantly restored besides marked reduction in lipid peroxidation and normalization of hepatic glycogen level in the NOLE treated alloxanized mice. Different bioactive phytocompounds with potent anti-diabetic activity were identified by GC-MS and HPLC analysis. CONCLUSION: The present investigation revealed that Nerium oleander possess potent anti-diabetic activity as claimed in different ethnopharmacological practices. PMID- 25498856 TI - Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: a systematic review and meta-analysis of observational studies. AB - This study is a critical analysis of the association between selective serotonin reuptake inhibitors (SSRIs) exposure during pregnancy and autism spectrum disorder (ASD) risk in children. Electronic databases were searched for observational studies published from January 1946 to June 2014 related to the association between SSRI exposure during pregnancy and ASD in children. Studies relevant to the association between SSRI exposure during pregnancy and ASD in children were extracted and compiled for meta-analysis evaluation. Ninety-five citations were identified and seven observational studies were included. Four case-control studies were eligible for the meta-analysis and two cohort studies were narratively reviewed. The pooled crude and adjusted odds ratios of the case control studies were 2.13 (95% CI 1.66-2.73) and 1.81 (95% CI 1.47-2.24) respectively. Low heterogeneity was observed between studies. The two population based cohort studies, utilizing the same Denmark data set, have conflicting results. The findings of this meta-analysis and narrative review support an increased risk of ASD in children of mothers exposed to SSRIs during pregnancy; however, the causality remains to be confirmed. PMID- 25498857 TI - Electrical stimulation of the medial forebrain bundle in pre-clinical studies of psychiatric disorders. AB - Modulating neuronal activity by electrical stimulation has expanded from the realm of motor indications into the field of psychiatric disorders in the past 10 years. The medial forebrain bundle (MFB), with a seminal role in motor, reward orientated and affect regulation behaviors, and its afferent and efferent loci, have been targeted in several DBS trials in patients with psychiatric disorders. However, little is known about the consequences of modulating the MFB in affective disorders. The paper reviews the relevant pre-clinical literature investigating electrical stimulation of regions associated with the MFB in the context of several models of psychiatric disorders, in particular depression. The clinical data is promising but limited, and pre-clinical studies are essential for improved understanding of the anatomy, the connectivity, and the consequences of stimulation of the MFB and regions associated with the neurocircuitry of psychiatric disorders. Current data suggests that the MFB is at a "privileged" position on this circuitry and its stimulation can simultaneously modulate activity at other key sites, such as the nucleus accumbens, the ventromedial prefrontal cortex or the ventral tegmental area. Future experimental work will need to shed light on the anti-depressive mechanisms of MFB stimulation in order to optimize clinical interventions. PMID- 25498855 TI - Quality of Life and Cost of Care at the End of Life: The Role of Advance Directives. AB - CONTEXT: Advance directives (ADs) are expected to improve patients' end-of-life outcomes, but retrospective analyses, surrogate recall of patients' preferences, and selection bias have hampered efforts to determine ADs' effects on patient outcomes. OBJECTIVES: The aim was to examine associations among ADs, quality of life, and estimated costs of care in the week before death. METHODS: We used prospective data from interviews of 336 patients with advanced cancer and their caregivers and analyzed patient baseline interview and caregiver and provider post-mortem evaluation data from the Coping with Cancer study. Cost estimates were from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample and published Medicare payment rates and cost estimates. Outcomes were quality of life (range 0-10) and estimated costs of care received in the week before death. Because patient end-of-life care preferences influence both AD completion and care use, analyses were stratified by preferences regarding heroic end-of-life measures (everything possible to remain alive). RESULTS: Most patients did not want heroic measures (76%). Do-not-resuscitate (DNR) orders were associated with higher quality of life (beta = 0.75, standard error = 0.30, P = 0.01) across the entire sample. There were no statistically significant relationships between DNR orders and outcomes among patients when we stratified by patient preference or between living wills/durable powers of attorney and outcomes in any of the patient groups. CONCLUSION: The associations between DNR orders and better quality of life in the week before death indicate that documenting preferences against resuscitation in medical orders may be beneficial to many patients. PMID- 25498858 TI - The vestibular-basal ganglia connection: balancing motor control. AB - Connections between the vestibular system and the basal ganglia have been sporadically studied over the last century. Electrophysiological studies of field potentials in animals have shown that most areas of the striatum respond to electrical vestibular stimulation while human studies isolated responses to vestibular stimulation to the putamen of the striatum. Protein studies have shown inconsistent results regarding changes in receptor levels of a number of receptor types. Recent tracer studies identified a pathway between the vestibular nucleus and the striatum via the thalamus, completely bypassing the cortex. Vestibular sensory input is represented in the part of the striatum - the dorsolateral striatum - where fibres from the sensorimotor areas terminate. It is therefore possible that vestibular signals are used together with other sensorimotor inputs in the striatum for body and limb control. The combination of electrophysiological results, changes in protein levels and tracer studies have led to the idea that the dorsolateral striatum is likely to be the main input area for vestibular signals in the basal ganglia and these will have an influence on motor control. This may have clinical implications in the treatment of basal ganglia disorders and other movement disorders. PMID- 25498859 TI - Effects of donepezil on hERG potassium channels. AB - Donepezil is a potent, selective inhibitor of acetylcholinesterase, which is used for the treatment of Alzheimer's disease. Whole-cell patch-clamp technique and Western blot analyses were used to study the effects of donepezil on the human ether-a-go-go-related gene (hERG) channel. Donepezil inhibited the tail current of the hERG in a concentration-dependent manner with an IC50 of 1.3 MUM. The metabolites of donepezil, 6-ODD and 5-ODD, inhibited the hERG currents in a similar concentration-dependent manner; the IC50 values were 1.0 and 1.5 MUM, respectively. A fast drug perfusion system demonstrated that donepezil interacted with both the open and inactivated states of the hERG. A fast application of donepezil during the tail currents inhibited the open state of the hERG in a concentration-dependent manner with an IC50 of 2.7 MUM. Kinetic analysis of donepezil in an open state of the hERG yielded blocking and unblocking rate constants of 0.54 uM(-1)s(-1) and 1.82 s(-1), respectively. The block of the hERG by donepezil was voltage-dependent with a steep increase across the voltage range of channel activation. Donepezil caused a reduction in the hERG channel protein trafficking to the plasma membrane at low concentration, but decreased the channel protein expression at higher concentrations. These results suggest that donepezil inhibited the hERG at a supratherapeutic concentration, and that it did so by preferentially binding to the activated (open and/or inactivated) states of the channels and by inhibiting the trafficking and expression of the hERG channel protein in the plasma membrane. PMID- 25498860 TI - Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene that is characterized by progressive action tremor, gait ataxia, and cognitive decline. Recent studies of mitochondrial dysfunction in FXTAS have suggested that iron dysregulation may be one component of disease pathogenesis. We tested the hypothesis that iron dysregulation is part of the pathogenic process in FXTAS. We analyzed postmortem choroid plexus from FXTAS and control subjects, and found that in FXTAS iron accumulated in the stroma, transferrin levels were decreased in the epithelial cells, and transferrin receptor 1 distribution was shifted from the basolateral membrane (control) to a predominantly intracellular location (FXTAS). In addition, ferroportin and ceruloplasmin were markedly decreased within the epithelial cells. These alterations have implications not only for understanding the pathophysiology of FXTAS, but also for the development of new clinical treatments that may incorporate selective iron chelation. PMID- 25498861 TI - Cloning, expression, and purification of cold inducible RNA-binding protein and its neuroprotective mechanism of action. AB - BACKGROUND: Cold-inducible RNA-binding protein (CIRP) is induced in response to hypothermia, where it exerts neuroprotective effects. Our preliminary studies revealed that it inhibits H2O2-induced apoptosis in rat neurons. In the current study, we report effective expression and purification approaches for the synthesis of CIRP, and assess its potential protective effects against oxidative stress. METHODS: CIRP-encoding was expressed using the prokaryotic expression system pGEX-4T-1, and SP-Sepharose and Sephacryl S-200 columns were used to purify rCIRP. To mimic ischemia/reperfusion injury-associated oxidative stress, neuro2a cells (N2a) were pre-treated with rCIRP for 2h, followed by hydrogen peroxide (H2O2 60 MUmol/ml) for 24h. Cell viability was then quantified using an MTT assay. In addition, western blotting was performed to measure the cell cycle related signal transduction pathways. RESULTS: N2a cells exhibited decreased viability following H2O2 treatment, whereas rCIRP significantly improved viability following H2O2 treatment. CIRP also accelerated cell cycle progression from S to G2/M phase in cultured mouse neuroblastoma cells. In addition, CIRP increased levels of p-ERK and p-Akt, and also re-activated the cell cycle-related protein cyclin D1 and c-Myc. These results suggest that CIRP activated the Akt and ERK signal transduction pathways in N2a cells. CONCLUSIONS: Our findings suggest that CIRP could exert protective effects against oxidative stress, and that it might be a novel neuroprotective agent. PMID- 25498863 TI - The esthetic preference of Chinese typefaces--an event-related potential study. AB - Emotional stimuli such as pictures, logos, geometric shapes, etc can evoke human esthetic preference from previous neuroesthetic studies. Chinese characters can be considered as emotional stimuli as they have an important property: typeface. Intuitively, the emotional meaning of Chinese characters can cause esthetic preference. However, whether a typeface can cause esthetic preference or not from an empirical perspective is still unknown. To address this issue, participants' event-related potential (ERP) waves are recorded while they are presented a series of Chinese characters in different typefaces. Participants are asked to distinguish specific target from the others. Afterwards, from the Chinese characters presented in this task, participants are asked individually to select the characters they like the most and dislike the most. By recording the ERP responses (a response of implicit preference to Chinese characters themselves) during the experiment to different typefaces of Chinese characters, we find a significant difference between disliked and all characters in the frontal-central area in the 200-300 ms window after the stimulus' onset. In the 400-600 ms window, after the stimulus' onset, a significant bias for disliked characters emerges in frontal, central, parietal and occipital areas. Our results suggest that people could make a rapid, implicit esthetic preference for the typefaces of Chinese characters. PMID- 25498864 TI - The modulatory action of harmane on serotonergic neurotransmission in rat brain. AB - The naturally occurring beta-carboline, harmane, has been implicated in various physiological and psychological conditions. Some of these effects are attributed to its interaction with monoaminergic systems. Previous literature indicates that certain beta-carbolines including harmane modulate central monoamine levels partly through monoamine oxidase (MAO) inhibition. However, this is not always the case and thus additional mechanisms may be involved. This study set to assess the potential modulatory role of harmane on the basal or K(+) stimulated release of preloaded radiolabelled noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in rat brain cortex in vitro in the presence of the MAO inhibitor pargyline. Harmane displayed an overt elevation in K(+) -evoked [(3)H]5-HT release; whilst little and no effect was reported with [(3)H]DA and [(3)H]NA respectively. The effect of harmane on [(3)H]5-HT efflux was partially compensated in K(+)-free medium. Further analyses demonstrated that removal of Ca(2+) ions and addition of 1.2mM EGTA did not alter the action of harmane on [(3)H]5-HT release from rat brain cortex. The precise mechanism of action however remains unclear but is unlikely to reflect an involvement of MAO inhibition. The current finding aids our understanding on the modulatory action of harmane on monoamine levels and could potentially be of therapeutic use in psychiatric conditions such as depression and anxiety. PMID- 25498865 TI - Estrogen receptor KO mice study on rapid modulation of spines and long-term depression in the hippocampus. AB - Rapid modulation of hippocampal synaptic plasticity through synaptic estrogen receptors is an essential topic. We analyzed estradiol-induced modulation of CA1 dendritic spines using adult male ERalphaKO and ERbetaKO mice. A 2h treatment of estradiol particularly increased the density of middle-head spines (diameter 0.3 0.4 um) in wild type mouse hippocampal slices. The enhancement of spinogenesis was completely suppressed by MAP kinase inhibitor. Estradiol-induced increase in middle-head spines was observed in ERbetaKO mice (which express ERalpha), but not in ERalphaKO, indicating that ERalpha is necessary for the spinogenesis. Direct observation of the dynamic estradiol-induced enhancing effect on rapid spinogenesis was performed using time-lapse imaging of spines in hippocampal live slices from yellow fluorescent protein expressed mice. Both appearance and disappearance of spines occurred, and the number of newly appeared spines was significantly greater than that of disappeared spines, resulting in the net increase of the spine density within 2h. As another type of synaptic modulation, we observed that estradiol rapidly enhanced N-methyl-D-aspartate (NMDA)-induced long-term depression (LTD) in CA1 of the wild type mouse hippocampus. In contrast, estradiol did not enhance NMDA-LTD in ERalphaKO mice, indicating the involvement of ERalpha in the estrogen signaling. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25498866 TI - Development of therapeutics for treatment of Ebola virus infection. AB - Ebola virus infection can cause Ebola virus disease (EVD). Patients usually show severe symptoms, and the fatality rate can reach up to 90%. No licensed medicine is available. In this review, development of therapeutics for treatment of Ebola virus infection and EVD will be discussed. PMID- 25498867 TI - Genetic tuning of avian influenza A (H7N9) virus promotes viral fitness within different species. AB - Since their emergence in eastern China, novel influenza A (H7N9) viruses have been continuously circulating in poultry and causing human infections and death. We have proposed a "genetic tuning" mechanism for the genesis and evolution of the novel H7N9 virus during interspecies transmission. PMID- 25498868 TI - Severe fever with thrombocytopenia syndrome and its pathogen SFTSV. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever in East Asia with case fatality up to 50%. SFTS is caused by SFTSV, a tick borne bunyavirus. In endemic area in China 1%-3% population was infected with SFTSV, but age is critical risk factor for hospitalization and death of SFTS patients. PMID- 25498869 TI - Characterization of symptomatic hip impingement in butterfly ice hockey goalies. AB - PURPOSE: This study aimed to characterize the radiographic deformity observed in a consecutive series of butterfly goalies with symptomatic mechanical hip pain and to use computer-based software analysis to identify the location of impingement and terminal range of motion. We also compared these analyses to a matched group of positional hockey players with symptomatic femoroacetabular impingement (FAI). METHODS: A consecutive series of 68 hips in 44 butterfly-style hockey goalies and a matched group of 34 hips in 26 positional hockey players who underwent arthroscopic correction for symptomatic FAI were retrospectively analyzed. Each patient underwent preoperative anteroposterior (AP) and modified Dunn lateral radiographs and computed tomography (CT) of the affected hips. Common FAI measurements were assessed on plain radiographs. Patient-specific, CT based 3-dimensional (3D) models of the hip joint were developed, and the femoral version, alpha angles at each radial clock face position, and femoral head coverage were calculated. Maximum hip flexion, abduction, internal rotation in 90 degrees flexion (IRF), flexion/adduction/internal rotation (FADIR), and butterfly position were determined, and the areas of bony collision were defined. RESULTS: Butterfly goalies had an elevated mean alpha angle on both AP (61.3 degrees ) and lateral radiographs (63.4 degrees ) and a diminished beta angle (26.0 degrees ). The mean lateral center-edge angle (LCEA) measured 27.3 degrees and acetabular inclination was 6.1 degrees . A crossover sign was present in 59% of the hips. The maximum alpha angle on the radial reformatted computed tomographic scan was significantly higher among the butterfly goalies (80.9 degrees v 68.6 degrees ; P < .0001) and was located in a more lateral position (1:00 o'clock v. 1:45 o'clock; P < .0001) compared with positional players. CONCLUSIONS: Symptomatic butterfly hockey goalies have a high prevalence of FAI, characterized by a unique femoral cam-type deformity and noted by an elevated alpha angle and loss of offset, which is greater in magnitude and more lateral when compared with that in positional hockey players. Associated acetabular dysplasia is also common among hockey goalies. LEVEL OF EVIDENCE: Level IV, prognostic case series. PMID- 25498870 TI - Arthroscopic suprapectoral and open subpectoral biceps tenodesis: a comparison of restoration of length-tension and mechanical strength between techniques. AB - PURPOSE: This study aimed to (1) evaluate the ex vivo restoration of the long head biceps length-tension for both arthroscopic suprapectoral biceps tenodesis (ASPBT) and open subpectoral biceps tenodesis (OSPBT) techniques and (2) assess how location in the proximal humerus affects pullout strength for tenodesis using an interference screw implant. METHODS: Eighteen matched cadaveric shoulders were randomized to OSPBT or ASPBT groups (9 each). Tenodesis was performed using clinical techniques. Preoperatively, a metallic bead was placed in the biceps tendon and a fluoroscopic image was obtained. Postoperatively, an image was obtained to evaluate the location of the tenodesis and the metallic bead and determine tensioning. Biomechanical load-to-failure testing was then performed. RESULTS: The ASPBT technique resulted in an average of 2.15 +/- 0.62 cm of biceps overtensioning compared with 0.78 +/- 0.35 cm (P < .001) in the OSPBT group. The average load to failure in the ASPBT group was 138.8 +/- 29.1 N compared with 197 +/- 38.6 N (P = .002) in the OSPBT group. Failure caused by implant pullout was significantly more frequent in the ASPBT group (7 of 9) than in the OSPBT group (1 of 9). CONCLUSIONS: The described ASPBT technique using an interference screw implant has the tendency to overtension the biceps and has a significantly decreased ultimate load to failure compared with an open subpectoral technique in matched cadaveric specimens. CLINICAL RELEVANCE: This study shows differences in the biomechanical properties of OSPBT and ASPBT. Modification of currently published ASPBT techniques may be necessary to improve restoration of the physiological length-tension relationship of the biceps. Clinical studies may need to clarify if the lower ultimate load to failure for the ASPBT technique is clinically significant. PMID- 25498871 TI - Long-term results of abrasion arthroplasty for full-thickness cartilage lesions of the medial femoral condyle. AB - PURPOSE: To evaluate the long-term functional results of arthroscopic abrasion arthroplasty for the treatment of full-thickness cartilage lesions of the medial femoral condyle. METHODS: Between 1990 and 1996, 75 consecutive patients with isolated chondral lesions of the medial femoral condyle were treated with arthroscopic chondral abrasion. A retrospective analysis of the clinical results of this cohort was performed. The patients were evaluated according to the Knee Society Score questionnaire preoperatively, at 10 years postoperatively, and at final long-term follow-up at a mean of 20 years. At final follow-up, they were also assessed according to the Western Ontario and McMaster Universities Osteoarthritis Index. Patients were divided according to the lesion size and by age, and the Kaplan-Meier survivorship function (with second operation taken as an endpoint) for the various groups was calculated. RESULTS: At a mean of final follow-up of 20 years (range, 16.94 to 23.94 years), a positive functional outcome (Knee Society Score >=70 points or no reoperation) was recorded in 67.9% of the patients. Twenty-year survivorship in this cohort was 71.4% (95% confidence interval, 0.5690 to 0.8590). The survivorship was 89.5% for patients younger than 50 years and 55.7% for patients aged 50 years or older. The functional results for patients with lesions smaller than 4 cm(2) were significantly better than those for patients with lesions of 4 cm(2) or greater (P = .031). There were no statistical differences between patients with and without associated lesions at the time of surgery. CONCLUSIONS: Our hypothesis that there would be survivorship greater than 86% was disproved. However, arthroscopic abrasion arthroplasty can be a valid treatment for medial femoral condylar full-thickness defects of the knee, even in the long-term, particularly for younger patients and those with smaller lesions. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25498872 TI - A matched-pair controlled study of microfracture of the hip with average 2-year follow-up: do full-thickness chondral defects portend an inferior prognosis in hip arthroscopy? AB - PURPOSE: This study compared 2-year clinical outcomes in hip arthroscopy patients treated with microfracture to a matched control group without full-thickness chondral damage. METHODS: During the study period between June 2008 and July 2011, data were collected on all patients treated with hip arthroscopy who underwent microfracture. All patients were assessed pre- and postoperatively with 4 patient-reported outcome (PRO) measures. Pain was estimated on the visual analog scale (VAS), and satisfaction was measured on a scale from 0 to 10. A matched-pair group of patients who did not undergo microfracture was selected in a 1:2 ratio. Matching criteria were age within 5 years, sex, surgical procedures, and radiographic findings. RESULTS: Average follow-up for the study was 26.66 months (17.29 to 48.89 months). Forty-nine hips were included in the microfracture group and 98 hips were in entered in the nonmicrofracture group, with no significant difference in PRO scores preoperatively between the groups. Both groups had statistically significant postoperative improvement in all scores, and the average amount of change from preoperative to postoperative scores between the 2 groups was not statistically significantly different for any of the PRO scores. Most importantly, there was no statistically significant difference in postoperative PRO scores between the microfracture and control groups. Patient satisfaction was 6.9 for the microfracture group and 7.84 for the nonmicrofracture group, which was statistically significant (P < .05). When comparing patients who received acetabular microfracture to those who received femoral microfracture, both groups had similar preoperative and postoperative PRO scores, with no significant difference in the magnitude of change (delta) at final follow-up. CONCLUSIONS: Our study found that patients undergoing microfracture during hip arthroscopy did not show a statistically significant difference in PRO scores when compared with a matched-pair control group at an average of 2 years of follow-up. Both groups showed significant improvement in all PRO scores. LEVEL OF EVIDENCE: Level III, matched case-control study. PMID- 25498873 TI - Patient-centered outcomes after hip arthroscopy for femoroacetabular impingement and labral tears are not different in patients with normal, high, or low femoral version. AB - PURPOSE: The purpose of this study was to determine whether outcomes after hip arthroscopy were different based on femoral version. METHODS: The inclusion criteria were diagnosis of femoroacetabular impingement (FAI) based on clinical examination and/or imaging findings and preoperative measurement of femoral version by magnetic resonance imaging. For this study, the definition of FAI was a positive impingement sign, a positive flexion-abduction-external rotation examination finding, or radiographic signs of impingement. A query of a prospective data registry identified 180 patients who matched the inclusion and exclusion criteria. Group 1 had version of less than 5 degrees (n = 48), group 2 had version of 5 degrees to 15 degrees (n = 84), and group 3 had version greater than 15 degrees (n = 48). The mean age of the patients was 35 years (range, 18 to 61 years). RESULTS: On radiographic examination, the mean alpha angle for all patients' injured hips was 63 degrees (range, 42 degrees to 88 degrees ). The mean center-edge angle was 30 degrees (range, 20 degrees to 43 degrees ), and mean femoral version was 9.9 degrees (range, -16 degrees to 29 degrees ). There was no significant difference in age, alpha angle, or center edge angle among the 3 version groups. A significant difference in psoas release procedures (psoas impingement) was seen with increasing femoral version. The mean follow-up period was 30 months (range, 18 to 47 months). Patient-reported functional outcomes were not statistically different among the groups. CONCLUSIONS: Patient-reported functional outcomes after hip arthroscopy for labral tears and FAI were not different based on femoral version in this population. Although some differences were observed regarding intraoperative findings, these also did not result in differences in patient outcomes reported at a mean follow-up of 2 years. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25498874 TI - Diagnostic glenohumeral arthroscopy fails to fully evaluate the biceps-labral complex. AB - PURPOSE: The purpose of this study was to define the limits of diagnostic glenohumeral arthroscopy and determine the prevalence and frequency of hidden extra-articular "bicipital tunnel" lesions among chronically symptomatic patients. METHODS: Eight fresh-frozen cadaveric specimens underwent diagnostic glenohumeral arthroscopy with percutaneous tagging of the long head of the biceps tendon (LHBT) during maximal tendon excursion. The percentage of visualized LHBT was calculated relative to the distal margin of subscapularis tendon and the proximal margin of the pectoralis major tendon. Then, a retrospective review of 277 patients who underwent subdeltoid transfer of the LHBT to the conjoint tendon were retrospectively analyzed for lesions of the biceps-labral complex. Lesions were categorized by anatomic location (inside, junctional, or bicipital tunnel). Inside lesions were labral tears. Junctional lesions were LHBT tears visualized during glenohumeral arthroscopy. Bicipital tunnel lesions were extra-articular lesions hidden from view during standard glenohumeral arthroscopy. RESULTS: Seventy-eight percent of LHBT were visualized relative to the distal margin of the subscapularis tendon and only 55% relative to the proximal margin of the pectoralis major tendon. No portion of the LHBT inferior to the subscapularis tendon was visualized. Forty-seven percent of patients had hidden bicipital tunnel lesions. Scarring was most common and accounted for 48% of all such lesions. Thirty-seven percent of patients had multiple lesion locations. Forty five percent of patients with junctional lesions also had hidden bicipital tunnel lesions. The only offending lesion was in the bicipital tunnel for 18% of patients. CONCLUSIONS: Diagnostic glenohumeral arthroscopy fails to fully evaluate the biceps-labral complex because it visualizes only 55% of the LHBT relative to the proximal margin of the pectoralis major tendon and did not identify extra-articular bicipital tunnel lesions present in 47% of chronically symptomatic patients. LEVEL OF EVIDENCE: Level IV, therapeutic case series and cadaveric study. PMID- 25498862 TI - Pathways of polyunsaturated fatty acid utilization: implications for brain function in neuropsychiatric health and disease. AB - Essential polyunsaturated fatty acids (PUFAs) have profound effects on brain development and function. Abnormalities of PUFA status have been implicated in neuropsychiatric diseases such as major depression, bipolar disorder, schizophrenia, Alzheimer's disease, and attention deficit hyperactivity disorder. Pathophysiologic mechanisms could involve not only suboptimal PUFA intake, but also metabolic and genetic abnormalities, defective hepatic metabolism, and problems with diffusion and transport. This article provides an overview of physiologic factors regulating PUFA utilization, highlighting their relevance to neuropsychiatric disease. PMID- 25498875 TI - Posterior shoulder instability: does glenoid retroversion predict recurrence and contralateral instability? AB - PURPOSE: To determine whether glenoid retroversion is a predictor of posterior shoulder instability, contralateral instability, or recurrent instability in patients with traumatic, contact-related posterior shoulder instability. METHODS: Patients who underwent shoulder stabilization by 2 senior orthopaedic sport surgeons were identified retrospectively. Patients with a connective tissue disorder, multidirectional instability, or non-trauma-induced pathology were excluded. Patients with a glenoid lesion involving greater than 25% of the glenoid or an engaging humeral lesion were also excluded. Thus patients with a traumatic injury and a magnetic resonance imaging scan available for review were included. Magnetic resonance imaging scans were reviewed, and glenoid version was measured using the glenoid vault method. Charts were reviewed for epidemiologic data, recurrent instability requiring reoperation, evidence of glenoid/humeral bone lesions, and contralateral shoulder instability requiring surgery. Both recurrence and contralateral injury were defined based on having repeat surgery. RESULTS: We identified 143 patients who met the inclusion criteria. Twenty-eight patients had posterior instability, whereas 115 patients had anterior instability. Patients with posterior instability had significantly more glenoid retroversion than patients with anterior instability (-15.4 degrees +/- 5.14 degrees v -12.1 degrees +/- 6.9 degrees ; P < .016). Patients with retroversion of more than -16 degrees showed a higher incidence of contralateral injuries (P < .036). However, no difference in postsurgical recurrent instability was noted. CONCLUSIONS: Our data show that patients with posterior instability have a higher incidence of having a retroverted glenoid. Patients with increased retroversion showed increased posterior contralateral instability. Furthermore, patients with posterior instability and no humeral bone lesions may be more likely to incur contralateral injuries than those with humeral lesions. These data suggest that glenoid version and concomitant injury patterns may be used to help physicians counsel patients on their future risks of contralateral injury. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25498877 TI - Adsorption and stabilizing effects of highly-charged latex nanoparticles in dispersions of weakly-charged silica colloids. AB - An experimental study was undertaken to determine the effectiveness of using highly-charged nanoparticles as stabilizers for colloidal dispersions. The specific systems used here involved cationic (amidine) and anionic (sulfate) polystyrene latex nanoparticles with an approximate diameter of 20 nm and silica microparticles of diameter 1.0 MUm, and experiments were conducted at the isoelectric point of the silica. It was found that while both types of nanoparticles adsorbed to the silica microparticles and increased the zeta potential to values where stability was expected, long term stability was not achieved, even at bulk nanoparticle concentrations as high as 0.5 vol.%. It is theorized that the incomplete coverage of the microparticles by the nanoparticles (i.e., surface coverage never exceeded 50%) allowed either direct contact between bare patches of the underlying microparticles or, alternatively, for nanoparticles adsorbed on one microparticle to bridge to bare spots on a neighboring microparticle. PMID- 25498876 TI - Interoceptive ability and body awareness in autism spectrum disorder. AB - Autism spectrum disorder (ASD) has been associated with various sensory atypicalities across multiple domains. Interoception, the ability to detect and attend to internal bodily sensations, has been found to moderate the experience of body ownership, a known difference in ASD that may affect social function. However, interoception has not been empirically examined in ASD. In the current study, 45 children (21 with ASD and 24 controls) ages 8 to 17 years completed a heartbeat perception paradigm as a measure of interoceptive ability. A subset of these children also completed the rubber hand illusion task, a multisensory paradigm probing the malleability of perceived body ownership. Although the heartbeat perception paradigm yielded comparable interoceptive awareness (IA) overall across both groups, children with ASD were superior at mentally tracking their heartbeats over longer intervals, suggesting increased sustained attention to internal cues in ASD. In addition, IA was negatively correlated with rubber hand illusion susceptibility in both groups, supporting a previously demonstrated inverse relationship between internal awareness and one's ability to incorporate external stimuli into one's perception of self. We propose a trade-off between attention to internal cues and attention to external cues, whereby attentional resources are disproportionately allocated to internal, rather than external, sensory cues in ASD. PMID- 25498878 TI - Controllable synthesis of concave cubic gold core-shell nanoparticles for plasmon enhanced photon harvesting. AB - Well-defined core-shell nanoparticles (NPs) containing concave cubic Au cores and TiO2 shells (CA@T) were synthesized in colloidal suspension. These CA@T NPs exhibit Localized Surface Plasmon Resonance (LSPR) absorption in the NIR region, which provides a unique property for utilizing the low energy range of the solar spectrum. In order to evaluate the plasmonic enhancement effect, a variety of CA@T NPs were incorporated into working electrodes of dye-sensitized solar cells (DSSCs). By adjusting the shell thickness of CA@T NPs, the plasmonic property can be tuned to achieve maximum photovoltaic improvement. Furthermore, the DSSC cells fabricated with the CA@T NPs exhibit a remarkably plasmonic assisted conversion efficiency enhancement (23.3%), compared to that (14.8%) of the reference cells assembled with spherical Au@TiO2 core-shell (SA@T) NPs under similar conditions. Various characterizations reveal that this performance improvement is attributed to the much stronger electromagnetic field generated at the hot spots of CA@T NPs, resulting in significantly higher light harvesting and more efficient charge separation. This study also provides new insights into maximizing the plasmonic enhancement, offering great potential in other applications including light matter interaction, photocatalytic energy conversion and new-generation solar cells. PMID- 25498879 TI - Association of polymorphisms in drug transporter genes (SLCO1B1 and SLC10A1) and anti-tuberculosis drug-induced hepatotoxicity in a Chinese cohort. AB - This study investigated the association between genetic variants in two hepatic uptake transporter genes (SLCO1B1 and SLC10A1) and the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH) in a Chinese cohort. The frequencies and distributions of single nucleotide polymorphisms (SNPs) and haplotypes of these genes were compared among 89 incident ATDH cases and 356 matched ATDH-free controls using a multivariate conditional logistic regression analysis. After correction for potential confounding factors, significant differences were found in polymorphism of rs4149014 under an addictive model (P = 0.008) and a recessive model (P = 0.016). The result of haplotype analysis suggested that patients carrying at least one SLCO1B1*15 haplotype had a higher risk of ATDH (odds ratio (OR) = 1.74, 95% confidence intervals (CI): 1.04-2.90, P = 0.034) in comparison with those carrying SLCO1B1*1a or SLCO1B1*1b haplotypes. These findings indicate that genetic variants of SLCO1B1 are associated with the development of ATDH in Chinese population. PMID- 25498881 TI - The current state of hepatopancreatobiliary fellowship experience in North America. AB - AIM: The face of hepatopancreatobiliary (HPB) training has changed over the past decade. The growth of focused HPB fellowships, which are vetted with a rigorous accreditation process through the Fellowship Council (FC), has established them as an attractive mode of training in HPB surgery. This study looks at the volumes of HPB cases performed during these fellowships in North America. METHODS: After approval by the FC research committee, data from all HPB fellowships that had 3 years worth of complete fellow case log data were tabulated and reported (n = 12). For 2-year fellowships, the fellow logs were tabulated at the completion of both years. Those programs that had transplant experience (n = 9) were reported. RESULTS: Data for the current fellows' case numbers show that graduating fellows have a median of 26 biliary cases, 19 major liver cases (hemilivers), 28 other liver cases, 40 pancreaticoduodenectomies,18 distal pancreatectomies, and 9 other pancreas cases. The programs that provided transplantation experience had 10 cases for each fellow. CONCLUSION: This study validates that FC-accredited HPB fellowships have a robust exposure to complex HPB surgery. Fellows completing these fellowships should be well versed in the management and surgical treatment of HPB patients. PMID- 25498880 TI - Estimation of mortality risk for vascular operations by trainees vs attending surgeons. AB - OBJECTIVE: The development of the ability to estimate patient mortality preoperatively in surgical trainees has not been well studied. DESIGN: Prospective comparative study in which the expected perioperative mortality risk and the maximum tolerable mortality at which operation would still be offered were estimated by the operating surgeons immediately before planned vascular procedures. SETTING: University vascular surgery teaching service. PARTICIPANTS: Predicted and maximum allowable mortality risks were compared between trainees and attending surgeons, with the mortality calculated using the Veterans Administration Surgical Quality Improvement Program (VASQIP) as a reference. RESULTS: Surveys were performed before 379 procedures over a 10-month period. The median expected mortality risk predicted by trainees (2%; interquartile range [IQR]: 1%-5%) was higher than the risk predicted by attending surgeons (1%; IQR: 0.8%-3%) (p < 0.01). The median expected mortality risk calculated by VASQIP (0.8%; IQR: 0.4%-1.7%) was less than that estimated by trainees by a median of 0.3% (IQR: 0.2%-3.2%) or and that by attending surgeons by 0.3% (IQR: 0.2-1.3%) (p < 0.01). The median maximum tolerable mortality risk predicted by trainees (10%; IQR: 5%-27.5%) was equal to the risk predicted by attending surgeons (10%; IQR: 5%-17.5%). The perioperative mortality calculated by VASQIP exceeded the maximum tolerable mortality offered by trainees or attending surgeons in 1% of cases each. Discrepancies between expected mortality and maximum tolerable mortality for trainees and attending surgeons were greater for younger (postgraduate year 1 or 2) trainees (0.8%; IQR: 0-3.0%) than for more senior (postgraduate year 4 or 5) trainees (0.4%; IQR: 0.1%-2.0%). CONCLUSION: Surgeons in training overestimated the perioperative mortality risk of operations and were willing to tolerate a greater mortality risk compared with attending surgeons. Both trainee and attending surgeons tended to overestimate the perioperative mortality risk compared with that calculated by VASQIP. PMID- 25498882 TI - Establishing a conceptual framework for handoffs using communication theory. AB - BACKGROUND: A significant consequence of the 2003 Accreditation Council for Graduate Medical Education duty hour restrictions has been the dramatic increase in patient care handoffs. Ineffective handoffs have been identified as the third most common cause of medical error. However, research into health care handoffs lacks a unifying foundational structure. We sought to identify a conceptual framework that could be used to critically analyze handoffs. METHODS: A scholarly review focusing on communication theory as a possible conceptual framework for handoffs was conducted. A PubMed search of published handoff research was also performed, and the literature was analyzed and matched to the most relevant theory for health care handoff models. RESULTS: The Shannon-Weaver Linear Model of Communication was identified as the most appropriate conceptual framework for health care handoffs. The Linear Model describes communication as a linear process. A source encodes a message into a signal, the signal is sent through a channel, and the signal is decoded back into a message at the destination, all in the presence of internal and external noise. The Linear Model identifies 3 separate instances in handoff communication where error occurs: the transmitter (message encoding), channel, and receiver (signal decoding). CONCLUSIONS: The Linear Model of Communication is a suitable conceptual framework for handoff research and provides a structured approach for describing handoff variables. We propose the Linear Model should be used as a foundation for further research into interventions to improve health care handoffs. PMID- 25498883 TI - A 4-task skills examination for residents for the assessment of technical ability in hand trauma surgery. AB - OBJECTIVES: The aim of this study was to evaluate a 4-task skills examination model for surgical trainees as a method of assessment of the different technical skills essential in hand trauma surgery. DESIGN: Using established validation methodology, construct validity was assessed by comparing the performance of 2 groups of residents in surgery (group A: residents with any formation in microsurgery and hand surgery and group B: residents with specific formation in hand or microsurgery or both). PARTICIPANTS AND SETTING: Overall, 19 residents in surgery with different degree of formation in hand and microsurgery participated in the study. All the residents performed 4 tasks on synthetic models consecutively: task 1-Z-plasty, task 2-metacarpal fracture fixation, task 3 tendon repair, and task 4-end-to-end anastomosis. The running order was awarded in a random drawing and 4 independent observers scored each resident. RESULTS: There was a significant difference in performance in the overall score between groups A and B and particularly for tasks 1 and 4. All participants felt the 4 tasks were good models to learn the procedure and recommended this approach to younger residents. CONCLUSION: This approach was based on a 4-tasks examination is the first model of evaluation of the different technical skills required for hand trauma surgery for residents. The results show a good differentiation between residents that have microsurgical and hand formation and those who do not have. This easy model can be easily integrated in the curriculum of residents, who want to specialize in hand surgery. PMID- 25498884 TI - A novel approach for needs assessment to build global orthopedic surgical capacity in a low-income country. AB - OBJECTIVE: Visiting surgical teams are a vital aspect of capacity-building continuing medical education (CME) in low-income countries like Haiti. Imperfect understanding of the genuine needs of local surgeons limit CME initiatives. Previous paper-based needs assessment efforts have been unsuccessful because of low response rates. We explored using an electronic audience response system (ARS) during a Haitian CME conference to improve the response rates and better assess needs. METHODS: Data were prospectively collected using an ARS from 78 conference participants (57 Haitian and 21 foreign) about current and desired knowledge of 7 topic and 8 skill areas using a 5-point Likert scale presented in English and in French. The response rates using ARS vs a similar paper survey were compared using a 2-sample test of proportions. The current and desired knowledge levels were compared using paired t tests. Analysis of variance and post hoc unpaired t tests were used to compare between demographic groups. RESULTS: The response rates were significantly greater for ARS vs a paper survey (87.7 vs 63.2%, p = 0.002). The 4 areas of least self-confidence for Haitians were pelvic and articular injury, joint dislocation, and osteomyelitis. The 4 skills of least self-confidence for Haitians were arthroscopy, open reduction and internal fixation-plate, external fixation, and fasciotomy. Haitians desired improvements in knowledge and management of articular, diaphyseal, and pelvic injury, joint dislocation, and osteomyelitis to a greater extent than foreigners (p < 0.05). Participants who previously attended the conference on open fractures felt more knowledgeable about open fractures as a topic (p < 0.05), but not in its management. CONCLUSIONS: We are the first to show that an ARS improves response rates to allow for better characterization of surgeon needs in the developing world. We also demonstrate the importance of skill building paired with topic area teaching. Lastly, we show how a CME conference is an effective tool to build surgical capacity and increase confidence level. PMID- 25498885 TI - Genetic and environmental influences on obsessive-compulsive behaviour across development: a longitudinal twin study. AB - BACKGROUND: Little is known about the factors influencing the stability of obsessive-compulsive behaviour (OCB) from childhood to adolescence. The current study aimed to investigate: (1) the stability of paediatric OCB over a 12-year period; (2) the extent to which genetic and environmental factors influence stability; and (3) the extent to which these influences are stable or dynamic across development. METHOD: The sample included 14 743 twins from a population based study. Parental ratings of severity of OCB were collected at ages 4, 7, 9 and 16 years. RESULTS: OCB was found to be moderately stable over time. The genetic influence on OCB at each age was moderate, with significant effects also of non-shared environment. Genetic factors exerted a substantial influence on OCB persistence, explaining 59-80% of the stability over time. The results indicated genetic continuity, whereby genetic influences at each age continue to affect the expression of OCB at subsequent ages. However, we also found evidence for genetic attenuation in that genetic influences at one age decline in their influence over time, and genetic innovation whereby new genes 'come on line' at each age. Non shared environment influenced stability of OCB to a lesser extent and effects were largely unique to each age and displayed negligible influences on OCB at later time points. CONCLUSIONS: OCB appears to be moderately stable across development, and stability is largely driven by genetic factors. However, the genetic effects are not entirely constant, but rather the genetic influence on OCB appears to be a developmentally dynamic process. PMID- 25498886 TI - microRNA-137 functions as a tumor suppressor in human non-small cell lung cancer by targeting SLC22A18. AB - Our previous study demonstrated that the overexpression of solute carrier family 22 member 18 (SLC22A18) in human non-small cell lung cancer (NSCLC) tissues might be associated with tumor progression and patients' prognosis. The aim of this study was to investigate the molecular mechanisms underlying its roles in NSCLC. As a result, bioinformatics analysis and luciferase reporter assay showed that microRNA (miRNA)-137 directly targeted SLC22A18 in NSCLC cells. Then, functional studies indicated that the ectopic expression of miR-137 significantly inhibited NSCLC cell proliferation, invasion and migration by targeting SLC22A18. More importantly, the decreased expression of miR-137 in clinical NSCLC tissues was correlated with advanced TNM stage, positive metastasis and poor prognosis of patients with this malignancy. In conclusion, these findings offer the convincing evidence that the roles of SLC22A18 in NSCLC progression may be partially caused by the regulatory effects of miR-137, which may function as a tumor suppressor. Our clinical data further indicated that miR-137 may be an independent favorable prognostic factor in NSCLC patients. PMID- 25498888 TI - Every contact is an opportunity to promote healthy lifestyles. PMID- 25498887 TI - The effect of tumor volume and its change on survival in stage III non-small cell lung cancer treated with definitive concurrent chemoradiotherapy. AB - BACKGROUND: To investigate a prognostic role of gross tumor volume (GTV) changes on survival outcomes following concurrent chemoradiotherapy (CCRT) in stage III non-small-cell lung cancer (NSCLC) patients. METHODS: We enrolled 191 patients with stage III NSCLC from 2001 to 2009 undergoing definitive CCRT. The GTV of 157 patients was delineated at the planning CT prior to CCRT and with a follow-up CT 1 month after CCRT. We assessed the volumetric parameters of pre-treatment GTV (GTVpre) post-treatment GTV (GTVpost), and volume reduction ratio of GTV (VRR). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and locoregional progression-free survival (LRPFS). The best cut-off value was defined as that which exhibited the maximum difference between the two groups. RESULTS: The median follow-up duration was 52.7 months in surviving patients. Median survival, 3-year OS, PFS and LRPFS rates were 25.5 months, 36.4%, 23.0%, and 45.0%, respectively. The selected cut off values were 50 cm(3) for GTVpre, 20 cm(3) for GTVpost, and 50% for VRR. The smaller GTVpre and GTVpost values were associated with better OS (p<0.001 and p=0.015) and PFS (p=0.001 and p=0.004), respectively, upon univariate analysis. The higher VRR of > 50% was associated with a trend toward poorer OS (p=0.004) and PFS (p=0.054). Upon multivariate analysis, smaller GTVpre indicated significantly improved OS (p=0.001), PFS (p=0.013) and LRPFS (p=0.002), while smaller GTVpost was marginally significant for PFS (p=0.086). Higher VRR was associated with a trend toward poorer OS (p=0.075). CONCLUSIONS: In patients with stage III NSCLC undergoing definitive CCRT, GTVpre was an independent prognostic factor of survival. Notably, improved outcome was not correlated with higher VRR after short-term follow-up with CT alone. PMID- 25498889 TI - Reproducible extracellular vesicle size and concentration determination with tunable resistive pulse sensing. AB - INTRODUCTION: The size of extracellular vesicles (EVs) can be determined with a tunable resistive pulse sensor (TRPS). Because the sensing pore diameter varies from pore to pore, the minimum detectable diameter also varies. The aim of this study is to determine and improve the reproducibility of TRPS measurements. METHODS: Experiments were performed with the qNano system (Izon) using beads and a standard urine vesicle sample. With a combination of voltage and stretch that yields a high blockade height, we investigate whether the minimum detected diameter is more reproducible when we configure the instrument targeting (a) fixed stretch and voltage, or (b) fixed blockade height. RESULTS: Daily measurements with a fixed stretch and voltage (n=102) on a standard urine sample show a minimum detected vesicle diameter of 128+/-19 nm [mean+/-standard deviation; coefficient of variation (CV) 14.8%]. The vesicle concentration was 2.4.109+/-3.8.109 vesicles/mL (range 1.4.108-1.8.1010). When we compared setting a fixed stretch and voltage to setting a fixed blockade height on 3 different pores, we found a minimum detected vesicle diameter of 118 nm (CV 15.5%, stretch), and 123 nm (CV 4.5%, blockade height). The detected vesicle concentration was 3.2-8.2.108 vesicles/mL with fixed stretch and 6.4-7.8.108 vesicles/mL with fixed blockade height. Summary/conclusion: Pore-to-pore variability is the cause of the variation in minimum detected size when setting a fixed stretch and voltage. The reproducibility of the minimum detectable diameter is much improved by setting a fixed blockade height. PMID- 25498890 TI - Neuroprotective effect of ginsenoside-Rg1 on cerebral ischemia/reperfusion injury in rats by downregulating protease-activated receptor-1 expression. AB - AIMS: Ginsenoside-Rg1 (G-Rg1), a saponin that is a primary component of ginseng, is very useful and important in traditional Chinese medicine for stroke. The objective of this study was to explore the mechanisms underlying the neuroprotective effect of G-Rg1 on focal cerebral ischemia/reperfusion. MAIN METHODS: Focal cerebral ischemia was induced by middle cerebral artery occlusion. Neurological examinations were performed by using Longa's 5-point scale. The brain infarct volume was determined by the 2,3,5-triphenyltetrazolium chloride staining. The permeability of the blood-brain barrier (BBB) was evaluated by Evans blue dye. Western blot and quantitative RT-PCR were used to assess protease activated receptor-1 (PAR-1) expression. KEY FINDINGS: After G-Rg1 treatment, there was a significant decrease in the neurobehavioral function score compared with normal saline (NS) treatment after ischemia/reperfusion (P<0.05). G-Rg1 significantly reduced the infarct volume compared with NS treatment after ischemia/reperfusion (P<0.001). The permeability of the BBB was significantly decreased in the G-Rg1 group compared with the NS group (P<0.05 or P<0.01). Western blot and quantitative real time RT-PCR indicated that G-Rg1 administration down-regulated the expression of PAR-1 in the ischemic hemisphere compared with NS administration (P<0.01 and P<0.05, respectively). The level of PAR-1 expression strongly correlated with BBB permeability in both the G-Rg1- and NS-treated rats (r=0.856 and r=0.908, respectively, P<0.01). SIGNIFICANCE: G-Rg1 may ameliorate the neurological injury, the brain infarct volume and the BBB permeability induced by focal cerebral ischemia in rats and its neuroprotective mechanism is related to the down-regulation of PAR-1 expression. PMID- 25498891 TI - Toll-like receptor 4 inhibition reduces vascular inflammation in spontaneously hypertensive rats. AB - AIMS: Hypertension is associated with increased levels of circulating cytokines and recent studies have shown that innate immunity contributes to hypertension. The mechanisms which hypertension stimulates immune response remain unclear, but may involve formation of neo-antigens that activate the immune system. Toll like receptor 4 (TLR4) is an innate immune receptor that binds a wide spectrum of exogenous (lipopolysaccharide) and endogenous ligands. TLR4 signaling leads to activation of nuclear factor kappa B (NFkappaB) and transcription of genes involved in inflammatory response. We previously demonstrated that TLR4 blockade reduces blood pressure and the augmented vascular contractility in spontaneously hypertensive rats (SHR). Here we hypothesized that inhibition of TLR4 ameliorates the vascular inflammatory process by a NFkappaB signaling pathway. MAIN METHODS: SHR and Wistar rats were treated with anti-TLR4 antibody (1MUg/day) or unspecific IgG for 15days (i.p.). KEY FINDINGS: Anti-TLR4 treatment decreased production of reactive oxygen species and expression of IL-6 cytokine in mesenteric resistance arteries from SHR, when compared with IgG-treated SHR. Anti-TLR4 treatment also abolished the increased vascular reactivity to noradrenaline observed in IgG treated SHR, as described before, and inhibition of NFkappaB decreased noradrenaline responses only in IgG-treated SHR. Mesenteric arteries from SHR treated with anti-TLR4 displayed decreased expression of MyD88, but not TRIF, key molecules in TLR4 signaling. Phosphorylation of p38 and NF-kappaB p65 were decreased in arteries from anti-TLR4-treated SHR versus IgG-treated SHR. SIGNIFICANCE: Together, these results suggest that TLR4 is a key player in hypertension and vascular inflammatory process by a NFkappaB signaling pathway. PMID- 25498892 TI - Omega-3 fatty acids prevent the ketamine-induced increase in acetylcholinesterase activity in an animal model of schizophrenia. AB - AIMS: Schizophrenia is a debilitating neurodevelopmental disorder that is associated with dysfunction in the cholinergic system. Early prevention is a target of treatment to improve long-term outcomes. Therefore, we evaluated the preventive effects of omega-3 fatty acids on AChE activity in the prefrontal cortex, hippocampus and striatum in an animal model of schizophrenia. MAIN METHODS: Young Wistar rats (30 days old) were initially treated with omega-3 fatty acids or vehicle alone. Animals received ketamine to induce an animal model of schizophrenia or saline plus omega-3 fatty acids or vehicle alone for 7 consecutive days beginning on day 15. A total of 22 days elapsed between the treatment and intervention. Animals were sacrificed, and brain structures were dissected to evaluate AChE activity and gene expression. KEY FINDINGS: Our results demonstrate that ketamine increased AChE activity in these three structures, and omega-3 fatty acids plus ketamine showed lower values for the studied parameters, which indicate a partial preventive mechanism of omega-3 fatty acid supplementation. We observed no effect on AChE expression. Together, these results indicate that omega-3 fatty acid supplementation effectively reduced AChE activity in an animal model of schizophrenia in all studied structures. In conclusion, the present study provides evidence that ketamine and omega-3 fatty acids affect the cholinergic system, and this effect may be associated with the physiopathology of schizophrenia. Further studies are required to investigate the mechanisms that are associated with this effect. PMID- 25498893 TI - Effects of extremely low frequency electromagnetic field (ELF-EMF) on catalase, cytochrome P450 and nitric oxide synthase in erythro-leukemic cells. AB - AIMS: Extremely low frequency electromagnetic fields (ELF-EMFs) are widely employed in electrical appliances and different equipment such as television sets, mobile phones, computers and microwaves. The molecular mechanism through which ELF-EMFs can influence cellular behavior is still unclear. A hypothesis is that ELF-EMFs could interfere with chemical reactions involving free radical production. Under physiologic conditions, cells maintain redox balance through production of ROS/RNS and antioxidant molecules. The altered balance between ROS generation and elimination plays a critical role in a variety of pathologic conditions including neurodegenerative diseases, aging and cancer. Actually, there is a disagreement as to whether there is a causal or coincidental relationship between ELF-EMF exposure and leukemia development. Increased ROS levels have been observed in several hematopoietic malignancies including acute and chronic myeloid leukemias. MAIN METHODS: In our study, the effect of ELF-EMF exposure on catalase, cytochrome P450 and inducible nitric oxide synthase activity and their expression by Western blot analysis in myelogenous leukemia cell line K562 was evaluated. KEY FINDINGS: A significant modulation of iNOS, CAT and Cyt P450 protein expression was recorded as a result of ELF-EMF exposure in both phorbol 12-myristate 13-acetate (PMA)-stimulated and non-stimulated cell lines. Modulation in kinetic parameters of CAT, CYP-450 and iNOS enzymes in response to ELF-EMF indicates an interaction between the ELF-EMF and the enzymological system. SIGNIFICANCE: These new insights might be important in establishing a mechanistic framework at the molecular level within which the possible effects of ELF-EMF on health can be understood. PMID- 25498894 TI - Contribution of the renin-angiotensin system in chronic foot-shock induced hypertension in rats. AB - AIMS: Chronic foot shock has been demonstrated to induce hypertension. The present study was designed to explore whether the renin-angiotensin system (RAS) plays a role in this process and the possible mechanisms involved in chronic-foot shock-induced hypertension. MAIN METHODS: Male Sprague-Dawley rats were subjected to a two-week foot shock with or without an angiotensin II (Ang II) type 1 receptor blocker (ARB, candesartan) or an angiotensin I converting enzyme inhibitor (ACEI, captopril). The expression of RAS components in the central nervous and circulatory systems was examined. Antioxidant levels in the plasma were monitored. KEY FINDINGS: Two-week foot shock significantly increased systolic blood pressure (SBP). Angiotensinogen, angiotensin I converting enzyme (ACE)-1, ACE-2, angiotensin type 1a and type 1b receptors, and vasopressin (VAP) mRNA expression in the cerebral cortex and hypothalamus were increased along with the concentration of renin and Ang II in the plasma; these changes were accompanied by decreased glutathione peroxidase activity and increased lipid peroxidation levels and plasma corticosterone concentrations. Both candesartan and captopril suppressed not only the increases in SBP but also the increases in VAP expression in the hypothalamus and RAS components in the central nervous system and the circulatory system. The decreases in antioxidant levels and the increases in lipid peroxidation and corticosterone levels were also partially reversed by candesartan or captopril treatment. SIGNIFICANCE: Chronic foot shock increases expression of the main RAS components, which play an important role in the development of high blood pressure through increased VAP levels, oxidative stress levels and stress hormone levels. PMID- 25498895 TI - Antiepileptogenic, antioxidant and genotoxic evaluation of rosmarinic acid and its metabolite caffeic acid in mice. AB - AIMS: Antioxidant compounds have been extensively investigated as a pharmacological alternatives to prevent epileptogenesis. Rosmarinic acid (RA) and caffeic acid (CA) are compounds with antioxidant properties, and RA has been shown to inhibit GABA transaminase activity (in vitro). Our aim was to evaluate the effect of RA and CA on seizures induced by pentylenotetrazole (PTZ) using the kindling model in mice. MAIN METHODS: Male CF-1 mice were treated once every three days during 16days with RA (1, 2 or 4mg/kg; i.p.), or CA (1, 4 or 8mg/kg; i.p.), or positive controls diazepam (1mg/kg; i.p.) or vigabatrin (600mg/kg; p.o.), 30min before PTZ administration (50mg/kg; s.c.). After the last treatment, animals were sacrificed and the cortex was collected to evaluate free radicals (determined by 2',7'-dichlorofluorescein diacetate probe), superoxide dismutase (SOD) and genotoxic activity (Alkaline Comet Assay). KEY FINDINGS: Rosmarinic acid 2mg/kg increased latency and decreased percentage of seizures, only on the 4th day of observation. The other tested doses of RA and CA did not show any effect. Rosmarinic acid 1mg/kg, CA 4mg/kg and CA 8mg/kg decreased free radicals, but no dose altered the levels of enzyme SOD. In the comet assay, RA 4mg/kg and CA 4mg/kg reduced the DNA damage index. SIGNIFICANCE: Some doses of rosmarinic acid and CA tested showed neuroprotective action against oxidative and DNA damage produced in the kindling epilepsy model, although they did not produce antiepileptogenic effect in vivo. PMID- 25498896 TI - The role of Pyruvate Dehydrogenase Complex in cardiovascular diseases. AB - The regulation of mammalian myocardial carbohydrate metabolism is complex; many factors such as arterial substrate and hormone levels, coronary flow, inotropic state and the nutritional status of the tissue play a role in regulating mammalian myocardial carbohydrate metabolism. The Pyruvate Dehydrogenase Complex (PDHc), a mitochondrial matrix multienzyme complex, plays an important role in energy homeostasis in the heart by providing the link between glycolysis and the tricarboxylic acid (TCA) cycle. In TCA cycle, PDHc catalyzes the conversion of pyruvate into acetyl-CoA. This review determines that there is altered cardiac glucose in various pathophysiological states consequently causing PDC to be altered. This review further summarizes evidence for the metabolism mechanism of the heart under normal and pathological conditions including ischemia, diabetes, hypertrophy and heart failure. PMID- 25498897 TI - Nuclear factor (NF)-kappaB p65 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta. AB - AIMS: Nuclear factor (NF)-kappaB signaling pathway contributes to the pathogenesis of lung fibrosis. However, the expression and roles of NF-kappaB p65 subunit in fibroblasts under fibrotic conditions have not been studied. We checked the expression of p65 in lung tissue and fibroblasts from bleomycin (BLM) challenged mice and investigated the roles of p65 in human lung fibroblast differentiation during transforming growth factor beta (TGF-beta) challenge. MAIN METHODS: A murine model of BLM-induced lung fibrosis and in vitro cultures of lung fibroblast from human and mouse were used to study the expression and role of p65 during fibrogenesis. The si-RNA knockdown strategy was used to check the mechanism of TGF-beta induced p65 expression and roles of p65 during fibroblast differentiation. KEY FINDINGS: We found that the expression of p65 was significantly increased in lung tissue, fibrotic foci and fibroblast from BLM challenged mice. In vitro, TGF-beta stimulated p65 expression, nuclear translocation and cell differentiation in human lung fibroblast; knockdown smad3 expression inhibited TGF-beta-induced p65 expression and differentiation in human lung fibroblast. Additionally, knockdown the expression of p65 suppressed TGF beta-induced differentiation and p65 translocation to nuclei in human lung fibroblast. SIGNIFICANCE: These data suggested that p65 expression is up regulated in lung fibroblast during differentiation through TGF-beta/smad3 pathway and synergistically regulates TGF-beta induced differentiation of lung fibroblasts. PMID- 25498898 TI - The adrenal medulla, not CB1 receptors, mediates the inhibitory effect of acute transverse aortic constriction on the neurogenic vasopressor response. PMID- 25498899 TI - Identification of mitochondrial deficits and melatonin targets in liver of septic mice by high-resolution respirometry. AB - AIMS: Previous data showed that melatonin maintains liver mitochondrial homeostasis during sepsis, but neither the mechanisms underlying mitochondrial dysfunction nor the target of melatonin are known. MAIN METHODS: Here, we analyzed mitochondrial respiration in isolated mouse liver mitochondria with different substrate combinations (glutamate/malate, glutamate/malate/sucinate or succinate/rotenone) to identify mitochondrial defects and melatonin targets during sepsis. Other bioenergetic parameters including a + a3, b, and c + c1 content, mitochondrial mass, and mitochondrial supercomplexes formation were analyzed. Mitochondrial function was assessed during experimental sepsis induced by cecal ligation and puncture (CLP) in livers of 3 mo. C57BL/6 mice at early and late phases of sepsis, i.e., at 8 and 24 h after sepsis induction. KEY FINDINGS: Septic mice showed mitochondrial injury with a decrease in state 3, respiratory control rate, mitochondrial mass, and cytochrome b and c + c1 content, which was prevented by melatonin treatment. Mitochondrial dysfunction in sepsis was mainly linked to complex I damage, because complex II was far less impaired. These mitochondria preserved the respiratory supramolecular organization, maintaining their electron transport system capacity. SIGNIFICANCE: This work strengthens the use of substrate combinations to identify specific respiratory defects and selective melatonin actions in septic mitochondria. Targeting mitochondrial complex I should be a main therapeutical approach in the treatment of sepsis, whereas the use of melatonin should be considered in the therapy of clinical sepsis. PMID- 25498900 TI - The rise of moral cognition. AB - The field of moral cognition has grown rapidly in recent years thanks in no small part to Cognition. Consistent with its interdisciplinary tradition, Cognition encouraged the growth of this field by supporting empirical research conducted by philosophers as well as research native to neighboring fields such as social psychology, evolutionary game theory, and behavioral economics. This research has been exceptionally diverse both in its content and methodology. I argue that this is because morality is unified at the functional level, but not at the cognitive level, much as vehicles are unified by shared function rather than shared mechanics. Research in moral cognition, then, has progressed by explaining the phenomena that we identify as "moral" (for high-level functional reasons) in terms of diverse cognitive components that are not specific to morality. In light of this, research on moral cognition may continue to flourish, not as the identification and characterization of distinctive moral processes, but as a testing ground for theories of high-level, integrative cognitive function. PMID- 25498901 TI - Independent studies needed before expanding flu vaccination. PMID- 25498903 TI - Effects of hyperbaric oxygen on nitric oxide generation in humans. AB - BACKGROUND: Hyperbaric oxygen (HBO2) has been suggested to affect nitric oxide (NO) generation in humans. Specific NO synthases (NOSs) use L-arginine and molecular oxygen to produce NO but this signaling radical may also be formed by serial reduction of the inorganic anions nitrate and nitrite. Interestingly, commensal facultative anaerobic bacteria in the oral cavity are necessary for the first step to reduce nitrate to nitrite. The nitrate-nitrite-NO pathway is greatly potentiated by hypoxia and low pH in contrast to classical NOS-dependent NO generation. We investigated the effects of HBO2 on NO generation in healthy subjects including orally and nasally exhaled NO, plasma and salivary nitrate and nitrite as well as plasma cGMP and plasma citrulline/arginine ratio. In addition, we also conducted in-vitro experiments in order to investigate the effects of hyperoxia on nitrate/nitrite metabolism and NO generation by oral bacteria. METHODS: Two separate HBO2 experiments were performed. In a cross-over experiment (EXP1) subjects breathed air at 130 kPa (control) or oxygen at 250 kPa for 100 minutes and parameters were measured before and after exposure. In experiment 2 (EXP 2) measurements were performed also during HBO2 at 250 kPa for 110 minutes. RESULTS: HBO2 acutely reduced orally and nasally exhaled NO by 30% and 16%, respectively. There was a marked decrease in salivary nitrite/nitrate ratio during and after HBO2, indicating a reduced bacterial conversion of nitrate to nitrite and NO. This was supported by in vitro experiments with oral bacteria showing that hyperoxia inhibited bacterial nitrate and nitrite reduction leading to reduced NO generation. Plasma nitrate was unaffected by HBO2 while plasma nitrite was reduced during HBO2 treatment. In contrast, plasma cGMP increased during HBO2 as did citrulline/arginine ratio after treatment and control. CONCLUSION: HBO2-exposure in humans affects NO generation in the airways and systemically differently. These data suggest that the individual NOSs as well as the nitrate-nitrite-NO pathway do not respond in a similar way to HBO2. PMID- 25498902 TI - Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine. AB - Inappropriate activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is common in cancer and has many cellular consequences including elevated endoplasmic reticulum (ER) stress. Cells employ autophagy as a critical compensatory survival mechanism during ER stress. This study utilised drug induced ER stress through nelfinavir in order to examine ER stress tolerance in cell lines with hyper-active mTORC1 signalling. Our initial findings in wild type cells showed nelfinavir inhibited mTORC1 signalling and upregulated autophagy, as determined by decreased rpS6 and S6K1 phosphorylation, and SQTSM1 protein expression, respectively. Contrastingly, cells with hyper-active mTORC1 displayed basally elevated levels of ER stress which was greatly exaggerated following nelfinavir treatment, seen through increased CHOP mRNA and XBP1 splicing. To further enhance the effects of nelfinavir, we introduced chloroquine as an autophagy inhibitor. Combination of nelfinavir and chloroquine significantly increased ER stress and caused selective cell death in multiple cell line models with hyper-active mTORC1, whilst control cells with normalised mTORC1 signalling tolerated treatment. By comparing chloroquine to other autophagy inhibitors, we uncovered that selective toxicity invoked by chloroquine was independent of autophagy inhibition yet entrapment of chloroquine to acidified lysosomal/endosomal compartments was necessary for cytotoxicity. Our research demonstrates that combination of nelfinavir and chloroquine has therapeutic potential for treatment of mTORC1-driven tumours. PMID- 25498904 TI - Usefulness and applicability of infectious disease control measures in air travel: a review. AB - BACKGROUND: Air travel has opened up opportunities for world transportation, but has also increased infectious disease transmission and public health risks. To control disease spread, airlines and governments are able to implement control measures in air travel. This study inventories experiences and applicability of infectious disease control measures. METHODS: A literature search was performed in PubMed, including studies between 1990 and 2013. Search terms included air travel terms and intervention terms. Interventions were scored according outcome, required resources, preparation, passenger inconvenience and passenger compliance. RESULTS: Provision of information to travelers, isolation, health monitoring, hygiene measures and vector control reportedly prevent disease spread and are well applicable. Contact tracing can be supportive in controlling disease spread but depend on disease characteristics. Exit and entry screening, quarantine and travel restrictions are unlikely to be very effective in preventing disease spread, while implementation requires extensive resources or travel implications. CONCLUSIONS: Control measures should focus on providing information towards travelers, isolation, health monitoring and hygiene measures. Appropriateness of measures depends on disease characteristics, and the required resources. As most studies analyze one type of measure in a particular situation, further research comparing the effectiveness of measures is recommended. PMID- 25498905 TI - Hematopoietic stem cell transplantation in children with refractory cytopenia of childhood: single-center experience using high-dose cytarabine containing myeloablative and aplastic anemia oriented reduced-intensity conditioning regimens. AB - Refractory cytopenia of childhood (RCC) is the most common subtype of myelodysplastic syndrome in children, and the clinical course of RCC is heterogeneous. A certain proportion of RCC patients need allogeneic hematopoietic stem cell transplantation (HSCT); however, data on HSCT outcomes are not abundant, and the optimal intensity of a preparative conditioning regimen remains uncertain. In this study, we evaluated the outcomes of HSCT in 24 patients with RCC. Eleven patients received myeloablative conditioning (MAC) consisting of high dose cytarabine, cyclophosphamide, and either total body irradiation (TBI) or busulfan. Nine patients (38%) received a reduced-intensity conditioning (RIC) regimen; of these, 7 received low-dose TBI and cyclophosphamide (200 mg/kg) with or without antithymocyte globulin or fludarabine, and 2 patients received low dose TBI, fludarabine, and melphalan (140 mg/m(2)). The remaining 4 patients had disease progression before HSCT and received the MAC regimen. With a median follow-up of 91 months (range, 6 to 263), the probability of overall survival at 5 years was 81.1% (95% CI, 57.0 to 92.5). The 5-year overall survival for the 15 patients who received MAC was 73.3% (95% CI, 43.6 to 89.1), and all 9 patients with RIC are alive without any events. Further study is needed to evaluate the efficacy of RIC for children with RCC with an expectation for reduction of late effects such as growth retardation and infertility. PMID- 25498906 TI - Comparison of cord blood transplantation with unrelated bone marrow transplantation in patients older than fifty years. AB - We retrospectively compared the transplantation outcomes for patients 50 years or older who received umbilical cord blood transplantation (UCBT) with those who received unrelated bone marrow transplantation (UBMT) for hematologic malignancies. A total of 1377 patients who underwent transplantation between 2000 and 2009 were included: 516 received 8/8 HLA allele-matched UBMT, 295 received 7/8 HLA allele-matched UBMT, and 566 received 4/6 to 6/6 HLA-matched UCBT. Adjusted overall survival (OS) was significantly lower in those who underwent UCBT than those who underwent 8/8 HLA-matched UBMT but was similar to that of 7/8 HLA-matched UBMT (the 2-year OS after 8/8 HLA-matched UBMT, 7/8 HLA-matched UBMT, and UCBT were 49% [95% confidence interval (CI), 45% to 55%], 38% [95% CI, 32% to 45%], and 39% [95% CI, 34% to 43%], respectively). However, adjusted OS was similar between 8/8 HLA-matched UBMT and UCBT receiving >=.84 * 10(5) CD34(+) cells/kg among those with acute myeloid leukemia and those with acute lymphoblastic leukemia (the 2-year OS was 49% [95% CI, 43% to 55%], and 49% [95% CI, 41% to 58%], respectively). These data suggest that UCB is a reasonable alternative donor/stem cell source for elderly patients with similar outcomes compared with UBM from 8/8 HLA-matched unrelated donors when the graft containing >=.84 * 10(5) CD34(+) cells/kg is available. PMID- 25498907 TI - High-throughput transcriptome analysis of barley (Hordeum vulgare) exposed to excessive boron. AB - Boron (B) is an essential micronutrient for optimum plant growth. However, above certain threshold B is toxic and causes yield loss in agricultural lands. While a number of studies were conducted to understand B tolerance mechanism, a transcriptome-wide approach for B tolerant barley is performed here for the first time. A high-throughput RNA-Seq (cDNA) sequencing technology (Illumina) was used with barley (Hordeum vulgare), yielding 208 million clean reads. In total, 256,874 unigenes were generated and assigned to known peptide databases: Gene Ontology (GO) (99,043), Swiss-Prot (38,266), Clusters of Orthologous Groups (COG) (26,250), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) (36,860), as determined by BLASTx search. According to the digital gene expression (DGE) analyses, 16% and 17% of the transcripts were found to be differentially regulated in root and leaf tissues, respectively. Most of them were involved in cell wall, stress response, membrane, protein kinase and transporter mechanisms. Some of the genes detected as highly expressed in root tissue are phospholipases, predicted divalent heavy-metal cation transporters, formin-like proteins and calmodulin/Ca(2+)-binding proteins. In addition, chitin-binding lectin precursor, ubiquitin carboxyl-terminal hydrolase, and serine/threonine-protein kinase AFC2 genes were indicated to be highly regulated in leaf tissue upon excess B treatment. Some pathways, such as the Ca(2+)-calmodulin system, are activated in response to B toxicity. The differential regulation of 10 transcripts was confirmed by qRT-PCR, revealing the tissue-specific responses against B toxicity and their putative function in B-tolerance mechanisms. PMID- 25498908 TI - Hamster SRD5A3 lacks steroid 5alpha-reductase activity in vitro. AB - According to current knowledge, two steroid 5alpha-reductases, designated type 1 (SRD5A1) and type 2 (SRD5A2), are present in all species examined to date. These isozymes play a central role in steroid hormone physiology by catalyzing the reduction of 3-keto-4-ene-steroids into more active 5alpha-reduced derivatives, including the conversion of testosterone (T) to dihydrotestosterone (DHT). A third 5alpha-reductase (SRD5A3, -type 3), which is overexpressed in hormone refractory prostate cancer cells, has been identified; however, its enzymatic characteristics are practically unknown. Here, we isolated a cDNA encoding hamster Srd5a3 (hSrd5a3) and performed functional metabolic assays to investigate its biochemical properties. The cloned cDNA encodes a 330 amino acid protein that is 87% identical to the homologous protein in mice and 78% to that in humans. However, hSrd5a3 exhibits low sequence homology with its counterparts hSrd5a1 (19%) and hSrd5a2 (17%). A fusion protein consisting of hSrd5a3 and green fluorescent protein provided evidence for cytoplasmic localization in transfected mammalian cells. Real-time PCR analysis revealed that, Srd5a3 mRNA was present in nearly all hamster tissues, with high expression in the cerebellum, Harderian gland and testis. Functional assays expressing hSrd5a3 cDNA in HEK-293 cells revealed that this isozyme is unable to reduce T into DHT. Further expression assays confirmed that similar to testosterone, progesterone, androstenedione and corticosterone are not reduced by hSrd5a3 or human SRD5A3. Together, these results indicate that hSrd5a3 lacks the catalytic activity to transform 3-keto-4 ene-compounds; therefore 5alpha-reductase type 3 may not be involved in 5alpha reduction of steroids. PMID- 25498910 TI - Loss of DGKepsilon induces endothelial cell activation and death independently of complement activation. AB - Atypical hemolytic uremic syndrome (aHUS) is classically described to result from a dysregulation of the complement alternative pathway, leading to glomerular endothelial cell (EC) damage and thrombosis. However, recent findings in families with aHUS of mutations in the DGKE gene, which is not an integral component of the complement cascade, led us to consider other pathophysiologic mechanisms for this disease. Here, we demonstrate that loss of DGKepsilon expression/activity in EC induces an increase in ICAM-1 and tissue factor expression through the upregulation of p38-MAPK-mediated signals, thus highlighting a proinflammatory and prothrombotic phenotype of DGKepsilon-deficient ECs. More interestingly, DGKE silencing also increases EC apoptosis and impairs EC migration and angiogenesis in vitro, suggesting that DGKE loss-of-function mutations impair EC repair and angiogenesis in vivo. Conversely, DGKE knockdown moderately decreases the expression of the complement inhibitory protein MCP on quiescent EC, but does not induce complement deposition on their surface in vitro. Collectively, our data strongly suggest that in DGKE-associated aHUS patients, thrombotic microangiopathy results from impaired EC proliferation and angiogenesis rather than complement-mediated EC lesions. Our study expands the current knowledge of aHUS mechanisms and has implications for the treatment of patients with isolated DGKE mutations. PMID- 25498909 TI - Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII specific T- and B-cell responses. AB - Expansion of human regulatory T cells (Tregs) for clinical applications offers great promise for the treatment of undesirable immune responses in autoimmunity, transplantation, allergy, and antidrug antibody responses, including inhibitor responses in hemophilia A patients. However, polyclonal Tregs are nonspecific and therefore could potentially cause global immunosuppression. To avoid this undesirable outcome, the generation of antigen-specific Tregs would be advantageous. Herein, we report the production and properties of engineered antigen-specific Tregs, created by transduction of a recombinant T-cell receptor obtained from a hemophilia A subject's T-cell clone, into expanded human FoxP3(+) Tregs. Such engineered factor VIII (FVIII)-specific Tregs efficiently suppressed the proliferation and cytokine production of FVIII-specific T-effector cells. Moreover, studies with an HLA-transgenic, FVIII-deficient mouse model demonstrated that antibody production from FVIII-primed spleen cells in vitro were profoundly inhibited in the presence of these FVIII-specific Tregs, suggesting potential utility to treat anti-FVIII inhibitory antibody formation in hemophilia A patients. PMID- 25498911 TI - Fcgamma-receptor-mediated trogocytosis impacts mAb-based therapies: historical precedence and recent developments. AB - A specialized form of trogocytosis occurs when Fcgamma receptors on acceptor cells take up and internalize donor cell-associated immune complexes composed of specific monoclonal antibodies (mAbs) bound to target antigens on donor cells. This trogocytosis reaction, an example of antigenic modulation, has been described in recent clinical correlative studies and in vitro investigations for several mAbs used in cancer immunotherapy, including rituximab and ofatumumab. We discuss the impact of Fcgamma-receptor-mediated trogocytosis on the efficacy of cancer immunotherapy and other mAb-based therapies. PMID- 25498912 TI - ST3Gal-4 is the primary sialyltransferase regulating the synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes. AB - The precise glycosyltransferase enzymes that mediate selectin-ligand biosynthesis in human leukocytes are unknown. This knowledge is important because selectin mediated cell tethering and rolling is a critical component of both normal immune response and various vascular disorders. We evaluated the role of 3 alpha(2,3)sialyltransferases, ST3Gal-3, -4, and -6, which act on the type II N Acetyllactosamine structure (Galbeta1,4GlcNAc) to create sialyl Lewis-X (sLe(X)) and related sialofucosylated glycans on human leukocytes of myeloid lineage. These genes were either silenced using lentiviral short hairpin RNA (shRNA) or functionally ablated using the clustered regularly interspaced short palindromic repeat/Cas9 technology. The results show that ST3Gal-4, but not ST3Gal-3 or -6, is the major sialyltransferase regulating the biosynthesis of E-, P-, and L selectin ligands in humans. Reduction in ST3Gal-4 activity lowered cell-surface HECA-452 epitope expression by 75% to 95%. Glycomics profiling of knockouts demonstrate an almost complete loss of the sLe(X) epitope on both leukocyte N- and O-glycans. In cell-adhesion studies, ST3Gal-4 knockdown/knockout cells displayed 90% to 100% reduction in tethering and rolling density on all selectins. ST3Gal-4 silencing in neutrophils derived from human CD34(+) hematopoietic stem cells also resulted in 80% to 90% reduction in cell adhesion to all selectins. Overall, a single sialyltransferase regulates selectin-ligand biosynthesis in human leukocytes, unlike mice where multiple enzymes contribute to this function. PMID- 25498914 TI - Contraception and sexual health in obese women. AB - As the proportion of women with obesity increases worldwide, understanding the influence of body weight on sexual behavior, fertility, and contraceptive effectiveness is critical for health-care professionals and patients. Although many have theorized that obese women are different from normal-weight women regarding sexual health and behavior, current evidence for the most part disproves this. The exception is in adolescents where body image may play a role in riskier behavior, placing them at a greater risk of an unintended pregnancy. Given that most modern contraceptives were not originally evaluated in obese women, understanding how weight affects contraceptive pharmacokinetics and efficacy should be a focus of ongoing research. Evidence is reassuring that most modern contraceptive methods are safe and effective in obese women. This paper reviews what is known about sexual and contraceptive behavior, as well as the effectiveness and pharmacokinetics of modern contraceptives, for overweight and obese women. PMID- 25498915 TI - Effects of asymmetrical stance and movement on body rotation in pushing. AB - Pushing objects in the presence of body asymmetries could increase the risk of back injury. Furthermore, when the object is heavy, it could exacerbate the effects induced by asymmetrical posture. We investigated how the use of asymmetrical posture and/or upper extremity movement affect vertical torque (Tz) and center of pressure (COP) displacement during pushing. Ten healthy volunteers were instructed to push objects of three different weights using two hands (symmetrical hand use) or one hand (asymmetrical hand use) while standing in symmetrical or asymmetrical foot-positions. The peak values of Tz and COP displacement in the medial-lateral direction (COPML) were analyzed. In cases of isolated asymmetry, changes in the Tz were mainly linked with effects of hand-use whereas effects of foot-position dominated changes in the COPML displacement. In cases of a combined asymmetry, the magnitudes of both Tz and COPML were additive when asymmetrical hand-use and foot-position induced the rotation of the lower and upper body in the same direction or subtractive when asymmetries resulted in the rotation of the body segments in the opposite directions. Moreover, larger Tz and COP displacements were seen when pushing the heavy weight. The results point out the importance of using Tz and COPML to describe the isolated or combined effects of asymmetrical upper extremity movement and asymmetrical posture on body rotation during pushing. Furthermore, it suggests that a proper combination of unilateral arm movement and foot placements could help to reduce body rotation even when pushing heavy objects. PMID- 25498916 TI - Effects of vision and lumbar posture on trunk neuromuscular control. AB - The goal of this study was to determine the effects of vision and lumbar posture on trunk neuromuscular control. Torso perturbations were applied with a pushing device while the subjects were restrained at the pelvis in a kneeling-seated position. Torso kinematics and the muscle activity of the lumbar part of the M. Longissimus were recorded for 14 healthy subjects. Four conditions were included: a flexion, extension and neutral lumbar posture with eyes closed and the neutral posture with eyes open. Frequency response functions of the admittance and reflexes showed that there was no significant difference between the eyes open and eyes closed conditions, thereby confirming that vision does not play a role in the stabilization of the trunk during small-amplitude trunk perturbations. In contrast, manipulating posture did lead to significant differences. In particular, the flexed condition led to a lower admittance and lower reflex contribution compared to the neutral condition. Furthermore, the muscle pre activation (prior to the onset of the perturbation) was significantly lower in the flexed posture compared to neutral. This confirms that flexing the lumbar spine increases the passive tissue stiffness and decreases the contribution of reflex activity to trunk control. PMID- 25498917 TI - Chronic SO2 inhalation above environmental standard impairs neuronal behavior and represses glutamate receptor gene expression and memory-related kinase activation via neuroinflammation in rats. AB - Sulfur dioxide (SO2), as a ubiquitous air pollutant implicated in the genesis of pulmonary disease, is now being considered to be involved in neurotoxicity and increased risk for hospitalization of brain disorders. However, comparatively little is known about the impact of chronically SO2 inhalation on neuronal function. In the present study, by exposing male Wistar rats to SO2 at 3.50 and 7.00 mg/m(3) (approximately 1225 and 2450 ppb, 4.08-8.16 (24h average concentration) times higher than the EPA standard for environmental air concentrations) or filtered air for 90 days, we investigated the impact of chronic SO2 inhalation on performance in Morris water maze, and probed the accompanying neurobiological effects, including activity-regulated cytoskeletal associated gene (Arc) and glutamate receptor gene expression, memory-related kinase level and inflammatory cytokine release in the hippocampus. Here, we found that SO2 exposure reduced the number of target zone crossings and time spent in the target quadrant during the test session in the spatial memory retention of the Morris water maze. Following the neuro-functional abnormality, we detected that SO2 inhalation reduced the expression of Arc and glutamate receptor subunits (GluR1, GluR2, NR1, NR2A, and NR2B) with a concentration-dependent property in comparison to controls. Additionally, the expression of memory kinases was attenuated statistically in the animals receiving the higher concentration, including protein kinase A (PKA), protein kinase C (PKC) and calcium/calmodulin dependent protein kinaseIIalpha (CaMKIIalpha). And the inflammatory cytokine release was increased in rats exposed to SO2. Taken together, our results suggest that long-term exposure to SO2 air pollution at concentrations above the environmental standard in rats impaired spatial learning and memory, and indicate a close link between the neurobiological changes highlighted in the brain and the behavioral disturbances. PMID- 25498918 TI - Concepts and pitfalls in measuring and interpreting attributable fractions, prevented fractions, and causation probabilities. AB - Measures of causal attribution and preventive potential appear deceptively simple to define, yet have many subtle variations and are subject to numerous pitfalls in conceptualization, interpretation, and application. This article reviews basic concepts, measures, and problems to serve as an introduction to more detailed literature. Allowing for validity and generalization (projection) issues, epidemiologic attribution measures can serve as useful policy inputs for contrasting expected caseloads or survival times under different well-defined interventions. Nonetheless, their application in these settings requires attention to effects of the interventions besides those on the study outcome. Their use as estimates of etiologic attribution requires assumptions beyond the usual validity and statistical assumptions; these further assumptions will usually have little support or plausibility when the mechanisms of action are unknown. PMID- 25498913 TI - Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma. AB - We studied the global microRNA (miRNA) expression in diffuse large B-cell lymphoma (DLBCL; n = 79), Burkitt lymphoma (BL; n = 36), primary mediastinal B cell lymphoma (PMBL; n = 12), B-cell lines (n = 11), and normal subsets of naive B cells, centroblasts (CBs), and peripheral blood B cells along with their corresponding gene expression profiles (GEPs). The normal B-cell subsets have well-defined miRNA signatures. The CB miRNA signature was significantly associated with germinal center B-cell (GCB)-DLBCL compared with activated B-cell (ABC)-DLBCL (P = .002). We identified a 27-miRNA signature that included v-myc avian myelomatosis viral oncogene homolog (MYC) targets and enabled the differentiation of BL from DLBCL, a distinction comparable with the "gold standard" GEP-defined diagnosis. Distinct miRNA signatures were identified for DLBCL subgroups, including GCB-DLBCL, activated B-cell (ABC)-DLBCL, and PMBL. Interestingly, most of the unclassifiable-DLBCL by GEP showed a strong similarity to the ABC-DLBCL by miRNA expression profiling. Consistent results for BL and DLBCL subgroup classification were observed in formalin-fixed, paraffin-embedded tissue, making such tests practical for clinical use. We also identified predictive miRNA biomarker signatures in DLBCL, including high expression of miR 155, which is significantly associated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment failure. This finding was further supported by the observation that high expression of miR-155 sensitizes cells to v-akt murine thymoma viral oncogene homolog-1 inhibitors in vitro, suggesting a novel treatment option for resistant DLBCL. PMID- 25498919 TI - Utilizing online tools to increase volunteer ombudsmen presence in long-term care. AB - In this descriptive study, former and current volunteer ombudsmen (n = 65) completed an online survey and Chi-square analyses were used to determine group differences in order to examine the impact of internet-based communication on the recruitment and retention of volunteer long-term care ombudsmen. The results showed that the program's shift to internet-based recruitment and communication methods helped increase the number of volunteers by 50% and contributed to a positive shift in role perception and satisfaction. Consequently, the proliferation of internet and social media usage permits greater volunteer management opportunities than previously were available. These tools also allow for consistency of message, extended training opportunities, and recourse to resources at need which permit ombudsmen volunteers to identify more readily with the role of resident advocate and receive greater performance satisfaction as it relates to that role. PMID- 25498920 TI - Medial frontal gyrus alterations in schizophrenia: relationship with duration of illness and executive dysfunction. AB - Executive functioning is consistently impaired in schizophrenia, and it has been associated with reduced gray matter volume in prefrontal areas. Abnormalities in prefrontal brain regions have also been related to the illness duration. The aim of the study was to investigate the effect of executive functioning decline and chronicity in prefrontal regions of patients with schizophrenia. Participants comprised 33 schizophrenic patients, 18 with duration of illness (DoI) shorter than 10 years and 15 with duration of illness longer than 10 years. In addition, 24 healthy controls served as a comparison group. Participants performed the Wisconsin Card Sorting Test (WCST) and underwent structural magnetic resonance imaging. Patients with longer DoI showed significant reduction of gray matter volume in the left medial frontal gyrus compared with healthy controls. Moreover, there was a trend for greater gray matter volume decrease in patients with a longer illness duration compared with patients with shorter illness duration. There was no interaction between the volume of the left medial frontal gyrus performance on the WCST. The present study supports the hypothesis that medial frontal gyrus alterations in schizophrenia are sensitive to duration of illness. These alterations were not associated with executive functioning. PMID- 25498921 TI - Oral Candida colonization in oral cancer patients and its relationship with traditional risk factors of oral cancer: a matched case-control study. AB - OBJECTIVES: Candida, an opportunistic fungal pathogen, has been implicated in oral and oesophageal cancers. This study aimed to examine oral Candida carriage in 52 oral cancer patients and 104 age-, gender- and denture status-matched oral cancer-free subjects. MATERIAL AND METHODS: We assessed general health, smoking and alcohol drinking habits, use of alcohol-containing mouthwash and periodontal status (community periodontal index of treatment needs). Yeasts were isolated using oral rinse technique and genetically identified via Real-Time PCR-High resolution melting curve analysis of conserved ribosomal DNA. Conditional and binary logistic regressions were used to identify explanatory variables that are risk factors for oral cancer. RESULTS AND CONCLUSION: The frequencies of oral yeasts' presence and high oral colonization were significantly higher in oral cancer than non-oral cancer patients (p=001; p=0.033, respectively). No significant difference in the isolation profile of Candida species was found between the two groups, except C. parapsilosis was more frequent in non-oral cancer group. Differences were noticed in the incidence of C. albicans strains where significantly more C. albicans genotype-A was isolated from cancer patients and significantly more C. albicans genotype-B isolated from non-cancer patients. Multiple regression analyses showed significant association with cancer observed for alcohol drinking (OR=4.253; 95% CI=1.351, 13.386), Candida presence (OR=3.242; 95% CI=1.505, 6.984) and high oral colonization (OR=3.587; 95% CI=1.153, 11.162). These results indicate that there is a significant association between oral cancer occurrence and Candida oral colonization and that the observed genotypic diversity of C. albicans strains may play a role in oral carcinogenesis. PMID- 25498922 TI - Clinical characteristics of multiple primary carcinomas of the oral cavity. AB - OBJECTIVES: This study aimed to clarify the clinical characteristics of multiple primary carcinomas of the oral cavity. MATERIALS AND METHODS: We retrospectively reviewed the cases of 1015 patients who were treated during follow up for oral cancer at Tokyo Medical and Dental University between March 2001 and December 2012. We compared the clinical characteristics of 961 patients who developed single primary oral squamous cell carcinoma (SCC) during follow up and 54 patients who subsequently developed multiple primary carcinomas in the oral cavity. RESULTS: Mean age at first diagnosis was significantly higher in patients with multiple primary carcinomas than single primary carcinoma. Multiple primary carcinomas showed a female predilection, were most prevalent in the gingiva, and tended to show earlier tumor and nodal stages than single primary carcinoma. The local recurrence rate was higher for multiple primary carcinomas than single primary carcinoma, and it increased with the number of multiple primary occurrences. The disease-specific survival rate at 10 years for patients with single primary carcinoma was 85.3% and that for patients with multiple primary carcinomas was 79.6%. The cumulative incidence rate for metachronous second multiple primary carcinomas after the onset of first carcinoma at 10 years was 8.0%. The recurrence of multiple primary carcinomas did not decrease the survival rate. CONCLUSION: Differences were found in the clinical characteristics between patients with single oral SCC and those with multiple primary oral carcinomas. Early diagnosis and treatment as well as close long-term follow up are needed for patients with multiple primary oral carcinomas. PMID- 25498923 TI - Biopsy-verified bronchiolitis obliterans and other noninfectious lung pathologies after allogeneic hematopoietic stem cell transplantation. AB - Bronchiolitis obliterans (BO) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Lung biopsy is the gold standard for diagnosis. This study describes the course of BO and assesses the congruity between biopsy-verified BO and a modified version of the National Institutes of Health's consensus criteria for BO syndrome (BOS) based exclusively on noninvasive measures. We included 44 patients transplanted between 2000 and 2010 who underwent lung biopsy for suspected BO. Of those, 23 were diagnosed with BO and 21 presented other noninfectious pulmonary pathologies, such as cryptogenic organizing pneumonia, diffuse alveolar damage, interstitial pneumonia, and nonspecific interstitial fibrosis. Compared with patients with other noninfectious pulmonary pathologies, BO patients had significantly lower values of forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity, and maximal mid-expiratory flow throughout follow-up, but there was no difference in the change in pulmonary function from the time of lung biopsy. The BO diagnosis was not associated with poorer overall survival. Fifty-two percent of patients with biopsy-verified BO and 24% of patients with other noninfectious pulmonary pathology fulfilled the BOS criteria. Pathological BO diagnosis was not superior to BOS criteria in predicting decrease in pulmonary function beyond the time of biopsy. A lung biopsy may provide a characterization of pathological patterns that can extend our knowledge on the pathophysiology of HSCT-related lung diseases. PMID- 25498925 TI - What is the point of Science & Justice? PMID- 25498924 TI - Increased bacterial infections after transfusion of leukoreduced non-irradiated blood products in recipients of allogeneic stem cell transplants after reduced intensity conditioning. AB - Blood components transfused to hematopoietic stem cell transplant (HSCT) recipients are irradiated to prevent transfusion-associated graft-versus-host disease (TA-GVHD). The effect of transfusing non-irradiated blood products in HSCT outcome, including incidence of transplant complications, bacterial infections, acute and chronic GVHD presentation, and characteristics, has not been documented. Clinical records as well as blood bank and electronic databases of HSCT patients grafted after reduced-intensity conditioning who received irradiated versus non-irradiated blood products, after blood irradiation became unavailable at our center, were scrutinized for transplant outcome, clinical evolution, engraftment characteristics including days to neutrophil and platelet recovery, acute and chronic GVHD, rate and type of infections, and additional transplant-related comorbidities. All transfused blood products were leukoreduced. A total of 156 HSCT recipients was studied, 73 received irradiated and 83 non-irradiated blood components. Bacterial infections were significantly more frequent in patients transfused with non-irradiated blood products, P = .04. Clinically relevant increased rates of fever and neutropenia and mucositis were also documented in these patients. No cases of TA-GVHD occurred. Classical GVHD developed in 37 patients (50.7%) who received irradiated blood products and 36 (43.9%) who received non-irradiated blood products, P = .42. Acute GVHD developed in 28 patients (38.4%) in the blood-irradiated and 33 patients (39.8%) in the non irradiation group, P = .87. The 2-year GVHD-free survival rate was 40% in the irradiated versus 40.6% in the non-irradiation group, P = .071. Increased bacterial infections were found in HSCT recipients transfused with non-irradiated blood products, which ideally must always be irradiated. PMID- 25498926 TI - Likelihood ratio methods for forensic comparison of evaporated gasoline residues. AB - In the investigation of arson, evidence connecting a suspect to the fire scene may be obtained by comparing the composition of ignitable liquid residues found at the crime scene to ignitable liquids found in possession of the suspect. Interpreting the result of such a comparison is hampered by processes at the crime scene that result in evaporation, matrix interference, and microbial degradation of the ignitable liquid. Most commonly, gasoline is used as a fire accelerant in arson. In the current scientific literature on gasoline comparison, classification studies are reported for unevaporated and evaporated gasoline residues. In these studies the goal is to discriminate between samples of several sources of gasoline, based on a chemical analysis. While in classification studies the focus is on discrimination of gasolines, for forensic purposes a likelihood ratio approach is more relevant. In this work, a first step is made towards the ultimate goal of obtaining numerical values for the strength of evidence for the inference of identity of source in gasoline comparisons. Three likelihood ratio methods are presented for the comparison of evaporated gasoline residues (up to 75% weight loss under laboratory conditions). Two methods based on distance functions and one multivariate method were developed. The performance of the three methods is characterized by rates of misleading evidence, an analysis of the calibration and an information theoretical analysis. The three methods show strong improvement of discrimination as compared with a completely uninformative method. The two distance functions perform better than the multivariate method, in terms of discrimination and rates of misleading evidence. PMID- 25498927 TI - The ignitability of petrol vapours and potential for vapour phase explosion by use of TASER(r) law enforcement electronic control device. AB - An experimental study was made of the potential of the TASER-X26TM law enforcement electronic control device to ignite petrol vapours if used by an officer to incapacitate a person soaked in petrol, or within a flammable atmosphere containing petrol vapour. Bench scale tests have shown that a wooden mannequin with pig skin covering the chest was a suitable representation of a human target. Full scale tests using the mannequin have shown that the arc from a TASER-X26TM is capable of igniting petrol/air vapours on a petrol-soaked person. Further tests in a 1/5 scale and a full scale compartment have shown that if a TASER is used within a compartment, a petrol vapour explosion (deflagration) may be achieved. It is evident from this research that if used in a flammable vapour rich environment, the device could prove fatal not only to the target but the TASER(r) operator as well. PMID- 25498928 TI - Cannabinoids determination in oral fluid by SPME-GC/MS and UHPLC-MS/MS and its application on suspected drivers. AB - The confirmation of Delta9-tetrahydrocannabinol (THC) in oral fluid (OF) is an important issue for assessing Driving Under the Influence of Drugs (DUID). The aim of this research was to develop a highly sensitive method with minimal sample pre-treatment suitable for the analysis of small OF volumes (100 MUL) for the confirmation of cannabinoids in DUID cases. Two methods were compared for the confirmation of THC in residual OF samples, obtained from a preliminary on-site screening with commercial devices. An ultra high performance LC-MS (UHPLC-MS/MS) method and an SPME-GC/MS method were hence developed. 100 MUL of the residual mixture OF/preservative buffer or neat OF was simply added to 10 MUL of THC-D3 (1 MUg/mL) and submitted to the two different analyses: A - direct injection of 10 MUL in UHPLC-MS/MS in positive electrospray ionisation (ESI) mode and B - sampling for 30 min with SPME (100 MUm polydimethylsiloxane or PDMS fibre) and direct injection by desorption of the fibre in the GC injection port. The lowest limit of detection (LLOD) of THC was 2 ng/mL in UHPLC-MS/MS and 0.5 ng/mL in SPME GC/MS. In addition, cannabidiol (CBD) and cannabinol (CBN) could be detected in GC/MS equipment at 2 ng/mL, whilst in UHPLC-MS/MS the LLOD was 20 ng/mL. Both methods were applied to 70 samples coming from roadside tests. By SPME-GC/MS analysis, THC was confirmed in 42 samples, whilst CBD was detected in 21 of them, along with CBN in 14 samples. THC concentrations ranged from traces below the lowest limit of quantification or LLOQ (2 ng/mL) up to 690 ng/mL. PMID- 25498929 TI - Analysis of the fluorescence of body fluids on different surfaces and times. AB - The use of screening techniques, such as an alternative light source (ALS), is important for finding biological evidence at a crime scene. The objective of this study was to evaluate whether biological fluid (blood, semen, saliva, and urine) deposited on different surfaces changes as a function of the age of the sample. Stains were illuminated with a MegamaxxTM ALS System and photographed with a Canon EOS UtilityTM camera. Adobe PhotoshopTM was utilized to prepare photographs for analysis, and then ImageJTM was used to record the brightness values of pixels in the images. Data were submitted to analysis of variance using a generalized linear mixed model with two fixed effects (surface and fluid). Time was treated as a random effect (through repeated measures) with a first-order autoregressive covariance structure. Means of significant effects were compared by the Tukey test. The fluorescence of the analyzed biological material varied depending on the age of the sample. Fluorescence was lower when the samples were moist. Fluorescence remained constant when the sample was dry, up to the maximum period analyzed (60 days), independent of the substrate on which the fluid was deposited, showing the novelty of this study. Therefore, the forensic expert can detect biological fluids at the crime scene using an ALS even several days after a crime has occurred. PMID- 25498930 TI - The application of visible wavelength reflectance hyperspectral imaging for the detection and identification of blood stains. AB - Current methods of detection and identification of blood stains rely largely on visual examination followed by presumptive tests such as Kastle-Meyer, Leuco malachite green or luminol. Although these tests are useful, they can produce false positives and can also have a negative impact on subsequent DNA tests. A novel application of visible wavelength reflectance hyperspectral imaging has been used for the detection and positive identification of blood stains in a non contact and non destructive manner on a range of coloured substrates. The identification of blood staining was based on the unique visible absorption spectrum of haemoglobin between 400 and 500 nm. Images illustrating successful discrimination of blood stains from nine red substances are included. It has also been possible to distinguish between blood and approximately 40 other reddish stains. The technique was also successfully used to detect latent blood stains deposited on white filter paper at dilutions of up to 1 in 512 folds and on red tissue at dilutions of up to 1 in 32 folds. Finally, in a blind trial, the method successfully detected and identified a total of 9 blood stains on a red T-shirt. PMID- 25498931 TI - Bodies in sequestered and non-sequestered aquatic environments: a comparative taphonomic study using decompositional scoring system. AB - The study of decomposition by using accumulated degree days (ADDs) has been suggested not only in terrestrial decay but also for water-related deaths. Previous studies have demonstrated that the accumulation of thermal energy as a function of the post-mortem submersion interval (PMSI) can be derived from a descriptive decompositional scoring system (DSS). In order to verify how useful can the total aquatic decomposition score (TADS) for ADD prediction be, a comparative taphonomic study has been performed between two series of bodies: 16 corpses found floating in shallower waters with a presumptive PMSI from 3 to 118 days and exposed to water temperatures (Tw) between 10.5 and 20.3 degrees C approximately equating from a minimum of 46 to 1.392 ADD; 52 bodies, all victims of a single shipwreck, found in sequestered environments and subjected to constant Tw of 4 degrees C for 210 days approximately equating to 840 ADD. The two series of bodies have revealed different stages of decay and a large DSS variability. In most of bodies, freshly formed adipocere was able to delay the appearance of later decompositional stages explaining why most of the bodies were in relatively good condition. Although promising, the accuracy of the TADS model can be affected by adipocere and animal activity. The TADS model suffers of the same limitations for ADD calculations as they can give a false perception of accuracy due to the complexity of integrating all changing factors affecting human decay in sequestered and non-sequestered marine environments (currents, animal activity, water temperatures, depth of submersion). PMID- 25498932 TI - Estimation of legal age using calcification stages of third molars in living individuals. AB - The increased number of adolescents and young adults with unknown or inaccurately given date of birth is a current issue in justice and legal medicine. The objective of this study was to determine the extent to which third molar calcification stages assessed on panoramic X-rays could be useful as additional criteria for forensic age estimation in living individuals, focusing on the legally important ages 17 and 18. In a retrospective multi-center study, the developmental stage of each individual's third molar was analyzed using Demirjian's scale in 2360 cases. Additionally, sex, age and ancestry were assessed. Individuals with the lowest calcification stage of all present molars in stage H were >=18 years with a likelihood of >=99.05% in the female (n=388), and >=99.24% in the male (n=482) population. The lowest calcification stage of all present third molars proved to be useful as an additional reliable criterion for the determination of an age >=18 years. PMID- 25498933 TI - Transfer of fibres on the hands of living subjects and their persistence during hand washing. AB - Textile fibres were transferred to the hands of ten living subjects and their persistence was determined after hand washing. Average number of fibres transferred was 300 +/- 133 (female 288 +/- 92, male 311 +/- 163) per 100 cm(2) hand area in the 100 experiments. However the number of fibres transferred was not gender dependent but individual dependent. The hand texture of subjects was compared with the number of fibres transferred but the relationship was not observed. The number of fibres transferred varied significantly for the 10 repeated experiments performed under the same conditions for the same subject. The subjects were then asked to wash their hands with water. One test group washed their hands with standing water, and the other with running tap water. Afterwards, the number of fibres remaining on the test subjects' hands were investigated. Migration of the fibres on the surface of the observed hands did occur but total loss of transferred fibre after hand washing did not occur. The average number of fibres remaining per 100 cm(2) hand area was 14 +/- 10 (range=3 72) for hand washing with standing water, and 10 +/- 12 (range=0-79) for washing with running tap water. The results of this study show the possibility of finding fibres on the hands of a person involved in a criminal case even after hand washing before fibre collection. PMID- 25498934 TI - Direct and non-destructive proof of authenticity for the 2nd generation of Brazilian real banknotes via easy ambient sonic spray ionization mass spectrometry. AB - Using a desorption/ionization technique, easy ambient sonic-spray ionization coupled to mass spectrometry (EASI-MS), documents related to the 2nd generation of Brazilian Real currency (R$) were screened in the positive ion mode for authenticity based on chemical profiles obtained directly from the banknote surface. Characteristic profiles were observed for authentic, seized suspect counterfeit and counterfeited homemade banknotes from inkjet and laserjet printers. The chemicals in the authentic banknotes' surface were detected via a few minor sets of ions, namely from the plasticizers bis(2-ethylhexyl)phthalate (DEHP) and dibutyl phthalate (DBP), most likely related to the official offset printing process, and other common quaternary ammonium cations, presenting a similar chemical profile to 1st-generation R$. The seized suspect counterfeit banknotes, however, displayed abundant diagnostic ions in the m/z 400-800 range due to the presence of oligomers. High-accuracy FT-ICR MS analysis enabled molecular formula assignment for each ion. The ions were separated by 44 m/z, which enabled their characterization as Surfynol(r) 4XX (S4XX, XX=40, 65, and 85), wherein increasing XX values indicate increasing amounts of ethoxylation on a backbone of 2,4,7,9-tetramethyl-5-decyne-4,7-diol (Surfynol(r) 104). Sodiated triethylene glycol monobutyl ether (TBG) of m/z 229 (C10H22O4Na) was also identified in the seized counterfeit banknotes via EASI(+) FT-ICR MS. Surfynol(r) and TBG are constituents of inks used for inkjet printing. PMID- 25498935 TI - Scientific analysis and historical aspects as tools in the legal investigation of paintings: a case study in Brazil. AB - The faker makes use of several strategies to give credibility to his work, as for example by copying artist's style or by using artificial aging techniques. The characterization of artistic materials, such as pigments, binding media and supports through chemical and/or physico-chemical analysis, coupled with art historical information is essential to establish the non-authenticity of works of art. This paper presents a contribution in a legal case regarding paintings attributed to important Brazilian and European artists such as Candido Portinari, Juan Gris, Camille Pissarro, and Umberto Boccioni, among others. In the investigation, modern synthetic painting materials were identified in all the ground layers of the suspected paintings. The use of diverse instrumental analytical techniques such as Fourier transform infrared spectroscopy, polarized light microscopy and pyrolysis-gas chromatography/mass spectrometry enabled this characterization. The results demonstrated the presence of titanium dioxide, calcium carbonate and kaolin as inorganic components of the paints, and polyvinyl acetate copolymerized with vinyl versatates or diisobutylphtalate as binding media in the ground layers of the paintings. The results obtained, along with art historical information and art technological studies, were very important in the judicial process, due to the possibility to use titanium dioxide and polyvinyl acetate copolymerized with vinyl versatates as chronological markers. PMID- 25498936 TI - A forensic science perspective on the role of images in crime investigation and reconstruction. AB - This article presents a global vision of images in forensic science. The proliferation of perspectives on the use of images throughout criminal investigations and the increasing demand for research on this topic seem to demand a forensic science-based analysis. In this study, the definitions of and concepts related to material traces are revisited and applied to images, and a structured approach is used to persuade the scientific community to extend and improve the use of images as traces in criminal investigations. Current research efforts focus on technical issues and evidence assessment. This article provides a sound foundation for rationalising and explaining the processes involved in the production of clues from trace images. For example, the mechanisms through which these visual traces become clues of presence or action are described. An extensive literature review of forensic image analysis emphasises the existing guidelines and knowledge available for answering investigative questions (who, what, where, when and how). However, complementary developments are still necessary to demystify many aspects of image analysis in forensic science, including how to review and select images or use them to reconstruct an event or assist intelligence efforts. The hypothetico-deductive reasoning pathway used to discover unknown elements of an event or crime can also help scientists understand the underlying processes involved in their decision making. An analysis of a single image in an investigative or probative context is used to demonstrate the highly informative potential of images as traces and/or clues. Research efforts should be directed toward formalising the extraction and combination of clues from images. An appropriate methodology is key to expanding the use of images in forensic science. PMID- 25498937 TI - The ParaDNA(r) Screening System - a case study in bringing forensic R&D to market. AB - The creation of new technologies and their application to forensic science is key to the field's development. Rapid DNA profiling is one such area of research which has grown in response to a desire from enforcement authorities for in-house forensic DNA processing and rapid access to forensic genetic intelligence. However, introducing novel technologies into the forensics market must be carefully monitored and controlled as the success or failure of any technology ultimately has long standing implications for victims, suspects, and also to Police and forensic practitioners. This article outlines the research, development, validation and implementation of the ParaDNA(r) Screening System as a case study in taking forensic research and development to market. PMID- 25498938 TI - Choice of population database for forensic DNA profile analysis. AB - When evaluating the weight of evidence (WoE) for an individual to be a contributor to a DNA sample, an allele frequency database is required. The allele frequencies are needed to inform about genotype probabilities for unknown contributors of DNA to the sample. Typically databases are available from several populations, and a common practice is to evaluate the WoE using each available database for each unknown contributor. Often the most conservative WoE (most favourable to the defence) is the one reported to the court. However the number of human populations that could be considered is essentially unlimited and the number of contributors to a sample can be large, making it impractical to perform every possible WoE calculation, particularly for complex crime scene profiles. We propose instead the use of only the database that best matches the ancestry of the queried contributor, together with a substantial FST adjustment. To investigate the degree of conservativeness of this approach, we performed extensive simulations of one- and two-contributor crime scene profiles, in the latter case with, and without, the profile of the second contributor available for the analysis. The genotypes were simulated using five population databases, which were also available for the analysis, and evaluations of WoE using our heuristic rule were compared with several alternative calculations using different databases. Using FST=0.03, we found that our heuristic gave WoE more favourable to the defence than alternative calculations in well over 99% of the comparisons we considered; on average the difference in WoE was just under 0.2 bans (orders of magnitude) per locus. The degree of conservativeness of the heuristic rule can be adjusted through the FST value. We propose the use of this heuristic for DNA profile WoE calculations, due to its ease of implementation, and efficient use of the evidence while allowing a flexible degree of conservativeness. PMID- 25498939 TI - Expanding forensic science through forensic intelligence. AB - Research and Development ('R&D') in forensic science currently focuses on innovative technologies improving the efficiency of existing forensic processes, from the detection of marks and traces at the scene, to their presentation in Court. R&D approached from this perspective provides no response to doubts raised by recent criminological studies, which question the effective contribution of forensic science to crime reduction, and to policing in general. Traces (i.e. forensic case data), as remnants of criminal activity are collected and used in various forms of crime monitoring and investigation. The aforementioned doubts therefore need to be addressed by expressing how information is conveyed by traces in these processes. Modelling from this standpoint expands the scope of forensic science and provides new R&D opportunities. Twelve propositions for R&D are stated in order to pave the way. PMID- 25498940 TI - Assessing evidence and testing appropriate hypotheses. AB - It is crucial to identify the most appropriate hypotheses if one is to apply probabilistic reasoning to evaluate and properly understand the impact of evidence. Subtle changes to the choice of a prosecution hypothesis can result in drastically different posterior probabilities to a defence hypothesis from the same evidence. To illustrate the problem we consider a real case in which probabilistic arguments assumed that the prosecution hypothesis "both babies were murdered" was the appropriate alternative to the defence hypothesis "both babies died of Sudden Infant Death Syndrome (SIDS)". Since it would have been sufficient for the prosecution to establish just one murder, a more appropriate alternative hypothesis was "at least one baby was murdered". Based on the same assumptions used by one of the probability experts who examined the case, the prior odds in favour of the defence hypothesis over the double murder hypothesis are 30 to 1. However, the prior odds in favour of the defence hypothesis over the alternative 'at least one murder' hypothesis are only 5 to 2. Assuming that the medical and other evidence has a likelihood ratio of 5 in favour of the prosecution hypothesis results in very different conclusions about the posterior probability of the defence hypothesis. PMID- 25498941 TI - Accreditation - straight belt or life jacket? Presentation to Forensic Science Society Conference November 2013. PMID- 25498942 TI - Regarding Champod, editorial: "Research focused mainly on bias will paralyse forensic science". PMID- 25498943 TI - Letter to editor in response to editorial by Risinger et al. PMID- 25498944 TI - Letter to the editor. PMID- 25498945 TI - Cystatin C and body surface area are major determinants of the ratio of N terminal pro-brain natriuretic peptide to brain natriuretic peptide levels in children. AB - BACKGROUND: Production of N-terminal pro-brain natriuretic peptide (NT) and BNP is equimolar. Although NT clearance occurs only in the kidneys, BNP clearance occurs in the kidneys and other organs. This study tested the hypothesis that NT/BNP ratio in children may be independently related to cystatin C (CysC), a glomerular filtration rate marker, when diastolic function and age/body size are taken into consideration. METHODS: The study included 430 children (5.3+/-4.9 years) with heart disease who had undergone cardiac catheterization and simultaneous BNP, NT, and CysC measurements. Pulmonary capillary wedge pressure (PCWP) was used as a ventricular diastolic stretch marker. Variables showing skewed distribution were transformed into a common logarithm. RESULTS: Univariate regression revealed that logNT/BNP was affected by PCWP (r=-0.12) and logCysC (r=0.57). When age and the log of body surface area (BSA) were added to the stepwise regression, age was not adopted because of multicollinearity to logBSA, but PCWP (beta=-0.10), logCysC (beta=0.22), and logBSA (beta=-0.66) were independent factors of logNT/BNP. CONCLUSIONS: Renal dysfunction independently increased NT/BNP, whereas high BSA decreased it and is the greatest determinant of NT/BNP. The observation that high PCWP decreased NT/BNP may suggest that worsening heart failure slows BNP clearance from other organs, a compensatory pathway of heart failure. These factors need to be considered when assessing BNP and NT. PMID- 25498947 TI - Implicit interactions between number and space in digit-color synesthesia. AB - In digit-color synesthesia, a variant of grapheme-color synesthesia, digits trigger an additional color percept. Recent work on number processing in synesthesia suggests that colors can implicitly elicit numerical representations in digit-color synesthetes implying that synesthesia is bidirectional. Furthermore, morphometric investigations revealed structural differences in the parietal cortex of grapheme-color synesthetes, i.e., in the brain region where interactions between number and space occur in non-synesthetic subjects. Based upon these previous findings, we here examined whether implicitly evoked numerical representations interact with spatial representations in synesthesia in such a way that even a non-numerical, visuo-spatial task (here: line bisection) is modulated, i.e., whether synesthetes exhibit a systematic bisection bias for colored lines. Thirteen digit-color synesthetes were asked to bisect two sets of lines which were colored in their individual synesthetic colors associated with a small or a large digit, respectively. For all colored line stimuli combined, digit-color synesthetes showed--like control subjects (n = 13, matched for age, gender, IQ and handedness)--a pseudo-neglect when bisecting colored lines. Measuring the color-induced change of the bisection bias (i.e., comparing the biases when bisecting lines colored according to a small number vs those lines corresponding to a large number) revealed that only digit-color synesthetes were significantly influenced by line color. The results provide further evidence for the bidirectional nature of synesthesia and support the concept of a mental number line. In addition, they extend previous reports on bidirectionality in synesthesia by showing that even non-numerical, visuo-spatial performance can be modulated by implicit bidirectional processes. PMID- 25498946 TI - Leishmania braziliensis replication protein A subunit 1: molecular modelling, protein expression and analysis of its affinity for both DNA and RNA. AB - BACKGROUND: Replication factor A (RPA) is a single-strand DNA binding protein involved in DNA replication, recombination and repair processes. It is composed by the subunits RPA-1, RPA-2 and RPA-3; the major DNA-binding activity resides in the subunit 1 of the heterotrimeric RPA complex. In yeast and higher eukaryotes, besides the three basic structural DNA-binding domains, the RPA-1 subunit contains an N-terminal region involved in protein-protein interactions with a fourth DNA-binding domain. Remarkably, the N-terminal extension is absent in the RPA-1 of the pathogenic protozoan Leishmania (Leishmania) amazonensis; however, the protein maintains its ability to bind ssDNA. In a recent work, we identify Leishmania (Viannia) braziliensis RPA-1 by its specific binding to the untranslated regions of the HSP70 mRNAs, suggesting that this protein might be also an RNA-binding protein. METHODS: Both rLbRPA-1 purified by His-tag affinity chromatography as well as the in vitro transcribed L. braziliensis 3' HSP70-II UTR were used to perform pull down assays to asses nucleic acid binding properties. Also, homology modeling was carried out to construct the LbRPA-1 tridimensional structure to search relevant amino acid residues to bind nucleic acids. RESULTS: In this work, after obtaining the recombinant L. braziliensis RPA 1 protein under native conditions, competitive and non-competitive pull-down assays confirmed the single-stranded DNA binding activity of this protein and demonstrated its interaction with the 3' UTR from the HSP70-II mRNA. As expected, this protein exhibits a high affinity for ssDNA, but we have found that RPA-1 interacts also with RNA. Additionally, we carried out a structural analysis of L. braziliensis RPA-1 protein using the X-ray diffraction structure of Ustilago maydis homologous protein as a template. Our results indicate that, in spite of the evolutionary divergence between both organisms, the structure of these two RPA-1 proteins seems to be highly conserved. CONCLUSION: The LbRPA-1 protein is a ssDNA binding protein, but also it shows affinity in vitro for the HSP70 mRNA; this finding supports a possible in vivo role in the HSP70 mRNA metabolism. On the other hand, the three dimensional model of Leishmania RPA-1 serves as a starting point for both functional analysis and its exploration as a chemotherapeutic target to combat leishmaniasis. PMID- 25498948 TI - Retrofibular osteochondroma with peroneal tendon subluxation. AB - Osteochondroma of the bone can cause a range of complications involving tendons, joints and neurovascular structures. Distal fibular osteochondroma and non traumatic peroneal tendon subluxation are both rare. In this case report, we describe an unusual case of distal retrofibular osteochondroma in a 36-year old male causing peroneal tendon subluxation. He presented with pain and instability around his ankle, but with no history of trauma. He successfully underwent osteochondroma excision, peroneal groove deepening and a Brostrom-Gould type reconstruction for the lateral ankle ligament insufficiency. Complete resolution of the symptoms of instability and subluxation was noted upon 6-month follow up. PMID- 25498949 TI - Testosterone supplementation and cardiovascular risk. PMID- 25498950 TI - Development of artificial empathy. AB - We have been advocating cognitive developmental robotics to obtain new insight into the development of human cognitive functions by utilizing synthetic and constructive approaches. Among the different emotional functions, empathy is difficult to model, but essential for robots to be social agents in our society. In my previous review on artificial empathy (Asada, 2014b), I proposed a conceptual model for empathy development beginning with emotional contagion to envy/schadenfreude along with self/other differentiation. In this article, the focus is on two aspects of this developmental process, emotional contagion in relation to motor mimicry, and cognitive/affective aspects of the empathy. It begins with a summary of the previous review (Asada, 2014b) and an introduction to affective developmental robotics as a part of cognitive developmental robotics focusing on the affective aspects. This is followed by a review and discussion on several approaches for two focused aspects of affective developmental robotics. Finally, future issues involved in the development of a more authentic form of artificial empathy are discussed. PMID- 25498951 TI - The deaf utilize phonological representations in visually presented verbal memory tasks. AB - The phonological abilities of congenitally deaf individuals are inferior to those of people who can hear. However, deaf individuals can acquire spoken languages by utilizing orthography and lip-reading. The present study used functional magnetic resonance imaging (fMRI) to show that deaf individuals utilize phonological representations via a mnemonic process. We compared the brain activation of deaf and hearing participants while they memorized serially visually presented Japanese kana letters (Kana), finger alphabets (Finger), and Arabic letters (Arabic). Hearing participants did not know which finger alphabets corresponded to which language sounds, whereas deaf participants did. All of the participants understood the correspondence between Kana and their language sounds. None of the participants knew the correspondence between Arabic and their language sounds, so this condition was used as a baseline. We found that the left superior temporal gyrus (STG) was activated by phonological representations in the deaf group when memorizing both Kana and Finger. Additionally, the brain areas associated with phonological representations for Finger in the deaf group were the same as the areas for Kana in the hearing group. Overall, despite the fact that they are superior in visual information processing, deaf individuals utilize phonological rather than visual representations in visually presented verbal memory. PMID- 25498952 TI - Effects of riluzole on respiratory rhythm generation in the brainstem-spinal cord preparation from newborn rat. AB - The persistent sodium channel is an important pacemaker component in rhythm generation. In the present study, we examined the effects of a persistent sodium channel blocker, riluzole on pre-inspiratory (Pre-I) and inspiratory neurons in the rostral medulla as well as on 4th cervical ventral root (C4)-inspiratory activity in brainstem-spinal cord preparations. Preparations were isolated from postnatal day 0-3 Wistar rats and were superfused with artificial cerebrospinal fluid, equilibrated with 95% O2 and 5% CO2, pH 7.4, at 25-26 degrees C. The C4 inspiratory burst rate decreased in a dose-dependent manner (50-200 MUM) after 15 min application of riluzole. Riluzole caused a strong reduction in the drive potential of Pre-I neurons but not of inspiratory neurons. After washout, C4 inspiratory burst gradually changed into an episodic pattern, in which one burst consisted of 3-9 short separate bursts. Riluzole also depressed the induction of repetitive firing induced by depolarizing stimulation. Under voltage clamp conditions, riluzole suppressed the negative-slope component of Pre-I neurons. Riluzole also depressed the intrinsic burst generation of Pre-I neurons in low calcium and high magnesium solution. Our findings indicate that the burst generation of Pre-I neurons is more sensitive than inspiratory burst generation to riluzole and thus suggested that persistent sodium channels have an important role in the burst generation of Pre-I neurons and are involved in the primary respiratory rhythm generation. PMID- 25498953 TI - The cortical motor system of the marmoset monkey (Callithrix jacchus). AB - Precise descriptions of the anatomical pathways that link different areas of the cerebral cortex are essential to the understanding of the sensorimotor and association processes that underlie human actions, and their impairment in pathological situations. Many years of research in macaque monkeys have critically shaped how we currently think about cortical motor function in humans. However, it is important to obtain additional understanding about the homologies between cortical areas in human and various non-human primates, and in particular how evolutionary changes in connectivity within specific neural circuits impact on the capacity for different behaviors. Current research has converged on the New World marmoset monkey as an important animal model for cortical function and dysfunction, emphasizing advantages unique to this species. However, the motor repertoire of the marmoset differs from that of the macaque in many ways, including the capacity for skilled use of the hands. Here, we review current knowledge about the cortical frontal areas in marmosets, which are key to the generation and control of motor behaviors, with focus on comparative analyses. We note significant parallels with the macaque monkey, as well as a few potentially important differences, which suggest future directions for work involving architectonic and functional analyses. PMID- 25498954 TI - Reply to letter 'Surprising results in an article in press from your journal'. PMID- 25498955 TI - Stump lengthening procedure with modular endoprostheses - the better alternative to disarticulations of the hip joint? AB - We report outcomes of 28 patients after stump-lengthening procedures (SLPs) with modular tumor endoprostheses following high-thigh amputation and hip disarticulation over 11years. Mean follow up was 41.3months (range 7.4 to 133.6months). Mean Musculoskeletal Tumour Society Score was 56% (n=11); ten out of eleven patients alive used an exoprosthesis regularly. Complications occurred in 15 patients with infection being most common. In 2 cases, the prostheses had to be explanted. Our data suggest that SLP facilitates post-operative rehabilitation and prosthesis usage. Modular endoprostheses for stump-lengthening allow optimization of remnant soft-tissue envelope, reducing the risk of stump perforation. PMID- 25498956 TI - Evaluation of Patient Specific Instruments. To measure is to know! PMID- 25498957 TI - Fully automated decomposition of Raman spectra into individual Pearson's type VII distributions applied to biological and biomedical samples. AB - Rapid technological advances have made the acquisition of large numbers of spectra not only feasible, but also routine. As a result, a significant research effort is focused on semi-automated and fully automated spectral processing techniques. However, the need to provide initial estimates of the number of peaks, their band shapes, and the initial parameters of these bands presents an obstacle to the full automation of peak fitting and its incorporation into fully automated spectral-preprocessing workflows. Moreover, the sensitivity of peak-fit routines to initial parameter settings and the resultant variations in solution quality further impede user-free operation. We have developed a technique to perform fully automated peak fitting on fully automated preconditioned spectra specifically, baseline-corrected and smoothed spectra that are free of cosmic-ray induced spikes. Briefly, the tallest peak in a spectrum is located and a Gaussian peak-fit is performed. The fitted peak is then subtracted from the spectrum, and the procedure is repeated until the entire spectrum has been processed. In second and third passes, all the peaks in the spectrum are fitted concurrently, but are fitted to a Pearson Type VII model using the parameters for the model established in the prior pass. The technique is applied to a synthetic spectrum with several peaks, some of which have substantial overlap, to test the ability of the method to recover the correct number of peaks, their true shape, and their appropriate parameters. Finally the method is tested on measured Raman spectra collected from human embryonic stem cells and samples of red blood cells. PMID- 25498958 TI - Involvement of low- and middle-income countries in randomized controlled trial publications in oncology. AB - BACKGROUND: We describe trends in participation by investigators from low- and middle-income countries (LMCs) in publications describing oncology randomized control trials (RCTs) over a decade. METHODS: We used Medline to identify RCTs published in English from 1998 to 2008 evaluating treatment in lung, breast, colorectal, stomach and liver cancers. Data on author affiliations, authorship roles, trial characteristics, funding and interventions were extracted from each article. Countries were stratified as low-, middle- or high-income using World Bank data. Interventions were categorized as requiring basic, limited, enhanced or maximal resources as per the Breast Health Global Initiative classification. Logistic regression was used to identify factors associated with authorship by investigators from LMCs. RESULTS: 454 publications were identified. Proportion of articles with at least one LMC author increased over time from 20% in 1998 to 29% in 2008 (p = 0.01), but almost all LMC authors were from middle-income countries. Proportion of articles with at least one LMC author was higher among articles that explicitly reported recruitment in at least one LMC vs those that did not (76% vs 13%). Among 87 articles (19%) that involved authors from LMCs, 17% had LMC authors as first or corresponding authors, and 67% evaluated interventions requiring enhanced or maximal resources. Factors associated with LMC authorship included industry funding (OR = 3.54, p = 0.0001), placebo comparator arm (OR = 2.57, p = 0.02) and palliative intent treatment (OR = 4.00, p = 0.0003). CONCLUSION: An increasing number of publications describing oncology RCTs involve authors from LMC countries but primarily in non-leadership roles in industry funded trials. PMID- 25498959 TI - Dietary effects on human gut microbiome diversity. AB - The human gut harbours diverse and abundant microbes, forming a complex ecological system that interacts with host and environmental factors. In this article, we summarise recent advances in microbiome studies across both Western and non-Western populations, either in cross-sectional or longitudinal surveys, and over various age groups, revealing a considerable diversity and variability in the human gut microbiome. Of all the exogenous factors affecting gut microbiome, a long-term diet appears to have the largest effect to date. Recent research on the effects of dietary interventions has shown that the gut microbiome can change dramatically with diet; however, the gut microbiome is generally resilient, and short-term dietary intervention is not typically successful in treating obesity and malnutrition. Understanding the dynamics of the gut microbiome under different conditions will help us diagnose and treat many diseases that are now known to be associated with microbial communities. PMID- 25498960 TI - Pulmonary function outcomes for assessing cystic fibrosis care. AB - BACKGROUND: Assessing cystic fibrosis (CF) patient quality of care requires the choice of an appropriate outcome measure. We looked systematically and in detail at pulmonary function outcomes that potentially reflect clinical practice patterns. METHODS: Epidemiologic Study of Cystic Fibrosis data were used to evaluate six potential outcome variables (2002 best FVC, FEV(1), and FEF(25-75) and rate of decline for each from 2000 to 2002). We ranked CF care sites by outcome measure and then assessed any association with practice patterns and follow-up pulmonary function. RESULTS: Sites ranked in the top quartile had more frequent monitoring, treatment of exacerbations, and use of chronic therapies and oral corticosteroids. The follow-up rate of pulmonary function decline was not predicted by site ranking. CONCLUSIONS: Different pulmonary function outcomes associate slightly differently with practice patterns, although annual FEV(1) is at least as good as any other measure. Current site ranking only moderately predicts future ranking. PMID- 25498961 TI - Daily successive changes in reproductive gene expression and neuronal activation in the brains of pubertal female mice. AB - Puberty is governed by the secretion of gonadotropin releasing hormone (GnRH), but the roles and identities of upstream neuropeptides that control and time puberty remain poorly understood. Indeed, how various reproductive neural gene systems change before and during puberty, and in relation to one another, is not well-characterized. We detailed the daily pubertal profile (from postnatal day [PND] 15 to PND 30) of neural Kiss1 (encoding kisspeptin), Kiss1r (kisspeptin receptor), Tac2 (neurokinin B), and Rfrp (RFRP-3, mammalian GnIH) gene expression and day-to-day c-fos induction in each of these cell types in developing female mice. Kiss1 expression in the AVPV/PeN increased substantially over the pubertal transition, reaching adult levels around vaginal opening (PND 27.5), a pubertal marker. However, AVPV/PeN Kiss1 neurons were not highly activated, as measured by c-fos co-expression, at any pubertal age. In the ARC, Kiss1 and Tac2 cell numbers showed moderate increases across the pubertal period, and neuronal activation of Tac2/Kiss1 cells was moderately elevated at all pubertal ages. Additionally, Kiss1r expression specifically in GnRH neurons was already maximal by PND 15 and did not change with puberty. Conversely, both Rfrp expression and Rfrp/c-fos co expression in the DMN decreased markedly in the early pre-pubertal stage. This robust decrease of the inhibitory RFRP-3 population may diminish inhibition of GnRH neurons during early puberty. Collectively, our data identify the precise timing of important developmental changes - and in some cases, lack thereof - in gene expression and neuronal activation of key reproductive neuropeptides during puberty, with several changes occurring well before vaginal opening. PMID- 25498962 TI - Mature adipocyte proteome reveals differentially altered protein abundances between lean, overweight and morbidly obese human subjects. AB - Overweight (OW) and obese individuals are considered to be graded parts of the scale having increasing weight as a common feature. They may not, however, be part of the same continuum and may differ metabolically. In this study we applied an untargeted proteomic approach to compare protein abundances in mature adipocytes derived from the subcutaneous adipose tissue of overweight and morbidly obese female subjects to those of lean age matched controls. Mature adipocytes were isolated from liposuction samples of abdominal subcutaneous adipose tissue collected from both lean (L; n = 7, 23.3 +/- 0.4 kg/m(2); mean BMI +/- SD), overweight (OW; n = 8, 27.9 +/- 0.6 kg/m(2); mean BMI +/- SD) and morbidly obese (MOB; n = 7, 44.8 +/- 3.8 kg/m(2); mean BMI +/- SD) individuals. Total protein extracts were then compared by two-dimensional difference in gel electrophoresis (2D DIGE). One hundred and ten differentially expressed protein spots (i.e., fitting the statistical criteria ANOVA test, p < 0.05; fold-change >=1.5) were detected, and of these, 89 were identified by MALDI-TOF mass spectrometry. Of these, 66 protein spots were common to both groups whereas 23 were unique to the MOB group. Significant differences were evident in the abundances of key proteins involved in glucose and lipid metabolism, energy regulation, cytoskeletal structure and redox control signaling pathways. Differences in the abundance of some chaperones were also evident. The differentially abundant proteins were investigated using Ingenuity Pathway Analysis (IPA) to establish their associations with known biological functions. The network identified in the OW group with the highest score relates to-: cell to-cell signaling and interaction; in contrast, in the MOB group the major interacting pathways are associated with lipid metabolism, small molecule biochemistry and cancer. The differences in abundance of the differentially regulated proteins were validated by immunoblotting. These findings provide insights into metabolic differences in OW and MOB individuals. PMID- 25498964 TI - Eco-evolutionary dynamics in an urbanizing planet. AB - A great challenge for ecology in the coming decades is to understand the role humans play in eco-evolutionary dynamics. If, as emerging evidence shows, rapid evolutionary change affects ecosystem functioning and stability, current rapid environmental change and its evolutionary effects might have significant implications for ecological and human wellbeing on a relatively short time scale. Humans are major selective agents with potential for unprecedented evolutionary consequences for Earth's ecosystems, especially as cities expand rapidly. In this review, I identify emerging hypotheses on how urbanization drives eco evolutionary dynamics. Studying how human-driven micro-evolutionary changes interact with ecological processes offers us the chance to advance our understanding of eco-evolutionary feedbacks and will provide new insights for maintaining biodiversity and ecosystem function over the long term. PMID- 25498963 TI - Toying with fate: Redirecting the differentiation of adrenocortical progenitor cells into gonadal-like tissue. AB - Cell fate decisions are integral to zonation and remodeling of the adrenal cortex. Animal models exhibiting ectopic differentiation of gonadal-like cells in the adrenal cortex can shed light on the molecular mechanisms regulating steroidogenic cell fate. In one such model, prepubertal gonadectomy (GDX) of mice triggers the formation of adrenocortical neoplasms that resemble luteinized ovarian stroma. Transcriptomic analysis and genome-wide DNA methylation mapping have identified genetic and epigenetic markers of GDX-induced adrenocortical neoplasia. Members of the GATA transcription factor family have emerged as key regulators of cell fate in this model. Expression of Gata4 is pivotal for the accumulation of gonadal-like cells in the adrenal glands of gonadectomized mice, whereas expression of Gata6 limits the spontaneous and GDX-induced differentiation of gonadal-like cells in the adrenal cortex. Additionally, Gata6 is essential for proper development of the adrenal X-zone, a layer analogous to the fetal zone of the human adrenal cortex. The relevance of these observations to developmental signaling pathways in the adrenal cortex, to other animal models of altered adrenocortical cell fate, and to human diseases is discussed. PMID- 25498965 TI - Urinary markers of nucleic acid oxidation and cancer in type 2 diabetes. AB - AIMS/HYPOTHESIS: We investigated whether urinary markers of nucleic acid oxidation are associated with an increased risk of cancer in type 2 diabetes patients. METHODS: Urine samples from 1381 newly diagnosed diabetes patients were assayed for the oxidatively modified guanine nucleosides 8-oxo-7,8-dihydro-2' deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo). Cox proportional hazards regression was used to examine the relationship between the urinary markers and cancer incidence. RESULTS: The crude analyses showed an association between overall cancer and urinary excretion of the RNA oxidation marker 8-oxoGuo (unadjusted hazard ratio for cancer per natural log increase in 8 oxoGuo 1.35 [95% CI, 1.01-1.81]), however, in the adjusted analyses, no significant associations between 8-oxodG or 8-oxoGuo and overall cancer were found. For site-specific cancers 8-oxodG was associated with breast cancer in the crude analyses (unadjusted hazard ratio for breast cancer per natural log increase in 8-oxodG was 2.37 [95% CI, 1.07-5.26]), although the association was attenuated in the adjusted analyses (sex- and age-adjusted hazard ratio 2.15 [95% CI, 0.92-5.02] and multivariate adjusted hazard ratio1.98 [95% CI, 0.95-4.10]). CONCLUSIONS: Urinary excretion of the nucleic acid oxidation markers 8-oxodG and 8-oxoGuo at the time of diagnosis was not associated with cancer overall in type 2 diabetes patients. For site-specific cancers, risk elevations were seen for breast cancer (8-oxodG). These findings should be examined in future and larger studies. PMID- 25498966 TI - A novel role for 12/15-lipoxygenase in regulating autophagy. AB - 12/15-Lipoxygenase (LOX) enzymatically generates oxidized phospholipids in monocytes and macrophages. Herein, we show that cells deficient in 12/15-LOX contain defective mitochondria and numerous cytoplasmic vacuoles containing electron dense material, indicating defects in autophagy or membrane processing, However, both LC3 expression and lipidation were normal both basally and on chloroquine treatment. A LOX-derived oxidized phospholipid, 12 hydroxyeicosatetraenoic acid-phosphatidylethanolamine (12-HETE-PE) was found to be a preferred substrate for yeast Atg8 lipidation, versus native PE, while both native and oxidized PE were effective substrates for LC3 lipidation. Last, phospholipidomics demonstrated altered levels of several phospholipid classes. Thus, we show that oxidized phospholipids generated by 12/15-LOX can act as substrates for key proteins required for effective autophagy and that cells deficient in this enzyme show evidence of autophagic dysfunction. The data functionally link phospholipid oxidation with autophagy for the first time. PMID- 25498967 TI - The role of the catecholic and the electrophilic moieties of caffeic acid in Nrf2/Keap1 pathway activation in ovarian carcinoma cell lines. AB - In recent years, numerous studies have demonstrated the health benefits of polyphenols. A major portion of polyphenols in western diet are derived from coffee, which is one of the most consumed beverages in the world. It has been shown that many polyphenols gain their beneficial properties (e.g. cancer prevention) through the activation of the Nrf2/Keap1 pathway as well as their direct antioxidant activity. However, activation of Nrf2 in cancer cells might lead to resistance towards therapy through induction of phase II enzymes. In the present work we hypothesize that caffeic acid (CA), a coffee polyphenol, might act as an electrophile in addition to its nucleophilic properties and is capable of inducing the Nrf2/EpRE pathway in cancer cells. The results indicate that CA induces Nrf2 translocation into the nucleus and consequently its transcription. It has been demonstrated that generated hydrogen peroxide is involved in the induction process. It has also been found that this process is induced predominantly via the double bond in CA (Michael acceptor). However, surprisingly the presence of both nucleophilic and electrophilic moieties in CA resulted in a synergetic activation of Nrf2 and phase II enzymes. We also found that CA possesses a dual activity, although inducing GSTP1 and GSR, it inhibiting their enzymatic activity. In conclusion, the mechanism of induction of Nrf2 pathway and phase II enzymes by CA has been elucidated. The electrophilic moiety in CA is essential for the oxidation of the Keap1 protein. It should be noted that while the nucleophilic moiety (the catechol/quinone moiety) can provide scavenging ability, it cannot contribute directly to Nrf2 induction. It was found that this process may be induced by H2O2 produced by the catechol group. On the whole, it appears that CA might play a major role in the cancer cells by enhancing their resistance to treatment. PMID- 25498968 TI - Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications. AB - The cytochrome P450 mixed function oxidase enzymes play a major role in the metabolism of important endogenous substrates as well as in the biotransformation of xenobiotics. The liver P450 system is the most active in metabolism of exogenous substrates. This review briefly describes the liver P450 (CYP) mixed function oxidase system with respect to its enzymatic components and functions. Electron transfer by the NADPH-P450 oxidoreductase is required for reduction of the heme of P450, necessary for binding of molecular oxygen. Binding of substrates to P450 produce substrate binding spectra. The P450 catalytic cycle is complex and rate-limiting steps are not clear. Many types of chemical reactions can be catalyzed by P450 enzymes, making this family among the most diverse catalysts known. There are multiple forms of P450s arranged into families based on structural homology. The major drug metabolizing CYPs are discussed with respect to typical substrates, inducers and inhibitors and their polymorphic forms. The composition of CYPs in humans varies considerably among individuals because of sex and age differences, the influence of diet, liver disease, presence of potential inducers and/or inhibitors. Because of such factors and CYP polymorphisms, and overlapping drug specificity, there is a large variability in the content and composition of P450 enzymes among individuals. This can result in large variations in drug metabolism by humans and often can contribute to drug drug interactions and adverse drug reactions. Because of many of the above factors, especially CYP polymorphisms, there has been much interest in personalized medicine especially with respect to which CYPs and which of their polymorphic forms are present in order to attempt to determine what drug therapy and what dosage would reflect the best therapeutic strategy in treating individual patients. PMID- 25498969 TI - Hydroxylation index of omeprazole in relation to CYP2C19 polymorphism and sex in a healthy Iranian population. AB - BACKGROUND: Polymorphism of CYP2C19 gene is one of the important factors in pharmacokinetics of CYP2C19 substrates. Omeprazole is a proton pump inhibitor which is mainly metabolized by cytochrome P450 2C19 (CYP2C19). The aim of present study was to assess omeprazole hydroxylation index as a measure of CYP2C19 activity considering new variant allele (CYP2C19*17) in Iranian population and also to see if this activity is sex dependent. METHODS: One hundred and eighty healthy unrelated Iranian individuals attended in this study. Blood samples for genotyping and phenotyping were collected 3 hours after administration of 20 mg omeprazole orally. Genotyping of 2C19 variant alleles *2, *3 and *17 was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and semi-nested PCR methods. Plasma concentrations of omeprazole and hydroxyomeprazole were determined by high performance liquid chromatography (HPLC) technique and hydxroxylation index (HI) (omeprazole/ hydroxyomeprazole) was calculated. RESULTS: The CYP2C19*17 was the most common variant allele in the studied population (21.6%). Genotype frequencies of CYP2C19*17*17, *1*17, and *2*17 were 5.5%, 28.8% and 3.3% respectively. The lowest and the highest median omeprazole HI was observed in *17*17 and *2*2 genotypes respectively (0.36 vs. 13.09). The median HI of omeprazole in subjects homozygous for CYP2C19*1 was 2.16-fold higher than individuals homozygous for CYP2C19*17 (P < 0.001) and the median HI of CYP2C19*1*17 genotype was 1.98-fold higher than CYP2C19 *17*17 subjects (P < 0.001). However, subjects with CYP2C19*2*17 (median HI: 1.74) and CYP2C19*1*2 (median HI: 1.98) genotypes and also CYP2C19*1*17 (median HI: 0.71) and CYP2C19*1*1 (mean HI: 0.78) did not show any significantly different enzyme activity. In addition, no statistically significant difference was found between women and men in distribution of CYP2C19 genotypes. Furthermore, the hydroxylation index of Omeprazole was not different between women and men in the studied population. CONCLUSION: Our data point out the importance of CYP2C19*2 and CYP2C19*17 variant alleles in metabolism of omeprazole and therefore CYP2C19 activity. Regarding the high frequency of CYP2C19*17 in Iranian population, the importance of this new variant allele in metabolism of CYP2C19 substrates shall be considered. PMID- 25498971 TI - Imaging S1P1 activation in vivo. AB - Sphingosine-1-phosphate receptor 1 (S1P1) is a G protein-coupled receptor that is activated by the sphingolipid ligand sphingosine-1-phosphate (S1P). S1P1 is widely expressed across tissues and, when activated, has broad functions in the immune, vascular and nervous systems. In several diseases in which inflammation plays a critical role, S1P1 activation has been found to be involved in pathogenesis. However, the details of S1P1 activation in vivo under different physiologic conditions are not well understood. Here we describe how a new in vivo methodology to identify S1P1 activation has helped increase understanding of the manner in which this signaling molecule functions both in homeostasis and during inflammation. PMID- 25498970 TI - Effect of a fever control protocol-based strategy on ventilator-associated pneumonia in severely brain-injured patients. AB - INTRODUCTION: Fever is associated with a poor outcome in severely brain-injured patients, and its control is one of the therapies used in this condition. But, fever suppression may promote infection, and severely brain-injured patients are frequently exposed to infectious diseases, particularly ventilator-associated pneumonia (VAP). Therefore, we designed a study to explore the role of a fever control protocol in VAP development during neuro-intensive care. METHODS: An observational study was performed on severely brain-injured patients hospitalized in a university ICU. The primary goal was to assess whether fever control was a risk factor for VAP in a prospective cohort in which a fever control protocol was applied and in a historical control group. Moreover, the density of VAP incidence was compared between the two groups. The statistical analysis was based on a competing risk model multivariate analysis. RESULTS: The study included 189 brain injured patients (intervention group, n = 98, and historical control group, n = 91). The use of a fever control protocol was an independent risk factor for VAP (hazard ratio 2.73, 95% confidence interval (1.38, 5.38; P = 0.005)). There was a significant increase in the incidence of VAP in patients treated with a fever control protocol (26.1 versus 12.5 VAP cases per 1000 days of mechanical ventilation). In cases in which a fever control protocol was applied for > 3 days, we observed a higher rate of VAP in comparison with the rate among patients treated for <= 3 days. CONCLUSIONS: Fever control in brain-injured patients was a major risk factor for VAP occurrence, particularly when applied for > 3 days. PMID- 25498972 TI - Collateral sensitivity to cold stress and differential BCL-2 family expression in new daunomycin-resistant lymphoblastoid cell lines. AB - The acquisition of a multidrug-resistant (MDR) phenotype by tumor cells is one of the main causes of chemotherapy failure in cancer, and, usually, is due to the increased expression of P-glycoprotein (MDR-1, P-gp, ABCB1), a pump that expels chemotherapeutics from the cell and/or regulates apoptosis. Thus, it is fundamental to find drugs or stress stimuli with a capacity to induce apoptosis in such cells and to identify the mechanisms involved. We address this matter in human cells and establish new daunomycin (DNM)-resistant cell lines (IM-9R) by exposing the parental lymphoblastic cells (IM-9) to increasing doses of the anti neoplastic drug, daunomycin. The resistance level of IM-9R cell lines, MDR-1 expression and functionality, collateral sensitivity and Bcl-2 and caspases protein expression are analyzed. As a result, we show for the first time that, unlike the parental cells, human lymphoblastic resistant cells exhibit collateral sensitivity to cold stress, confirming that this phenomenon is not exclusive to murine leukemic cells, but a broader one associated with the acquisition of drug resistance. Furthermore, the new resistant cell lines undergo a significant increase in active caspase-3 and -9 levels and drastic changes in Bcl-2 family protein expression during the process of MDR phenotype acquisition. PMID- 25498978 TI - New approaches to cardiovascular surgery. AB - Modern treatment of cardiovascular disease requires a patient-centered approach. With several technological advances, the options for treatment must be carefully weighed and novel approaches tested for safety and efficacy. In this article, we outline some of the new approaches available to cardiothoracic surgeons for the treatment of cardiovascular diseases, including off-pump coronary artery bypass grafting, transcatheter valve replacement, and hybrid and robotic technology. We discuss current evidence and controversies and highlight the challenges that we face in training surgeons in an environment of ever-evolving surgical techniques. PMID- 25498973 TI - The type 2 diabetes associated rs7903146 T allele within TCF7L2 is significantly under-represented in Hereditary Multiple Exostoses: insights into pathogenesis. AB - Hereditary Multiple Exostoses (HME) is an autosomal-dominant disorder characterized by benign cartilage tumors (exostoses) forming near the growth plates, leading to severe health problems. EXT1 and EXT2 are the two genes known to harbor heterozygous loss-of-function mutations that account for the vast majority of the primary genetic component of HME. However, patients present with wide clinical heterogeneity, suggesting that modifier genes play a role in determining severity. Our previous work has pointed to an imbalance of beta catenin signaling being involved in the pathogenesis of osteochondroma formation. TCF7L2 is one of the key 'gate-keeper' TCF family members for Wnt/beta-catenin signaling pathway, and TCF7L2 and EXT2 are among the earliest associated loci reported in genome wide appraisals of type 2 diabetes (T2D). Thus we investigated if the key T allele of single nucleotide polymorphism (SNP) rs7903146 within the TCF7L2 locus, which is strongly over-represented among T2D cases, was also associated with HME. We leveraged genotype data available from ongoing GWAS efforts from genomics and orthopedic centers in the US, Canada and Italy. Collectively 213 cases and 1890 controls were analyzed and, surprisingly, the T allele was in fact significantly under-represented in the HME patient group [P = 0.009; odds ratio = 0.737 (95% C.I. 0.587-0.926)]; in addition, the direction of effect was consistent within each individual cohort. Immunohistochemical analyses revealed that TCF7L2 is differentially expressed and distributed in normal human growth plate zones, and exhibits substantial variability in human exostoses in terms of staining intensity and distribution. In summary, the data indicate that there is a putative genetic connection between TCF7L2 and EXT in the context of HME. Given this observation, we suggest that these loci could possibly modulate shared pathways, in particular with respect to beta-catenin, and their respective variants interplay to influence HME pathogenesis as well as T2D. PMID- 25498979 TI - Lack of transplacental transmission of Bartonella bovis. AB - Transplacental transmission of Bartonella spp. has been reported for rodents, but not for cats and has never been investigated in cattle. The objective of this study was to assess vertical transmission of Bartonella in cattle. Fifty-six cow calf pairs were tested before (cows) and after (calves) caesarean section for Bartonella bacteremia and/or serology, and the cotyledons were checked for gross lesions and presence of the bacteria. None of the 29 (52%) bacteremic cows gave birth to bacteremic calves, and all calves were seronegative at birth. Neither placentitis nor vasculitis were observed in all collected cotyledons. Bartonella bovis was not detected in placental cotyledons. Therefore, transplacental transmission of B. bovis and multiplication of the bacteria in the placenta do not seem likely. The lack of transplacental transmission may be associated with the particular structure of the placenta in ruminants or to a poor affinity/agressiveness of B. bovis for this tissue. PMID- 25498980 TI - Therapeutic potential of group III metabotropic glutamate receptor ligands in pain. AB - Metabotropic glutamate receptors (mGluRs) modulate neurotransmission all along the pain neuraxis. While the involvement of group I and group II mGluRs in pain is well documented, information has only just started to emerge concerning the role and contribution of group III mGluRs subtypes to pain modulation. Recent data suggest that these receptors reduce symptoms in animal models of chronic pain, as well as regulate neurotransmission at different levels of ascending and descending pain pathway, suggesting that group III mGluRs may be interesting therapeutic targets for the development of analgesics. PMID- 25498981 TI - NMDA receptor subunit mutations in neurodevelopmental disorders. AB - N-Methyl-D-aspartate receptors (NMDARs) are glutamate-gated cation channels that are expressed throughout the brain and play essential role in brain functioning. Diversity of the subunits and of their spatio-temporal expression imparts distinct functional properties for the particular NMDAR in a particular brain region and developmental stage. Mutations in NMDARs may have pathological consequences and actually lead to various neurological disorders. Recent human genetic studies as highlighted here show the existence of multiple alterations in NMDARs subunits genes in several usual and common brain diseases, such as intellectual disability, autism spectrum disorders (ASD), or epilepsy. Relation of a particular mutation to the corresponding alteration of NMDARs function may provide an avenue to the targeted therapy for the pharmacological treatment of the disorders. PMID- 25498983 TI - Neurophysiological traces of the reader's geographical perspective associated with the deictic verbs of motion to go and to come. AB - This ERP study explores how participants activate their own geographical perspective, while reading sentences describing a motion (to come or to go), or a static spatial relation (to be) referred either to the participant's current location or a distant place. The ERPs recorded at the place names revealed that, compared to "distant places", "close places" enhanced ERP's components, associated with motivational relevance, in the context of the deictic verbs of motion to come and to go, but not in the context of the static verb to be. Also, in the context of the verbs of motion source estimation showed that "close places" elicited more activity than "distant places" in the medial temporal cortex (around the parahippocampal gyrus), suggesting projection of the reader's self-relevant information, or retrieval of geographical episodic memories. Finally, sentences describing motions congruent with the self-perspective (e.g. "going to distant place") elicited less activation than sentences incongruent with the self-perspective (e.g. "coming to distant place") in the right fronto polar cortex and in the posterior cingulate cortex, regions generally associated with the other's perspective or with self/other perspective conflict. These findings provide information on the brain processes underlying readers' perspective taking, guided by the deictic verbs of motion. PMID- 25498982 TI - Frequency-band signatures of visual responses to naturalistic input in ferret primary visual cortex during free viewing. AB - Neuronal firing responses in visual cortex reflect the statistics of visual input and emerge from the interaction with endogenous network dynamics. Artificial visual stimuli presented to animals in which the network dynamics were constrained by anesthetic agents or trained behavioral tasks have provided fundamental understanding of how individual neurons in primary visual cortex respond to input. In contrast, very little is known about the mesoscale network dynamics and their relationship to microscopic spiking activity in the awake animal during free viewing of naturalistic visual input. To address this gap in knowledge, we recorded local field potential (LFP) and multiunit activity (MUA) simultaneously in all layers of primary visual cortex (V1) of awake, freely viewing ferrets presented with naturalistic visual input (nature movie clips). We found that naturalistic visual stimuli modulated the entire oscillation spectrum; low frequency oscillations were mostly suppressed whereas higher frequency oscillations were enhanced. In average across all cortical layers, stimulus induced change in delta and alpha power negatively correlated with the MUA responses, whereas sensory-evoked increases in gamma power positively correlated with MUA responses. The time-course of the band-limited power in these frequency bands provided evidence for a model in which naturalistic visual input switched V1 between two distinct, endogenously present activity states defined by the power of low (delta, alpha) and high (gamma) frequency oscillatory activity. Therefore, the two mesoscale activity states delineated in this study may define the degree of engagement of the circuit with the processing of sensory input. PMID- 25498984 TI - Synaptic plasticity and experimental autoimmune encephalomyelitis: implications for multiple sclerosis. AB - Structural and functional neuronal plasticity could play a crucial role during the course of multiple sclerosis (MS). The immune system and the central nervous system (CNS) strictly interact in physiologic conditions and during inflammation to modulate neuroplasticity and in particular the ability of the synapses to undergo long-term changes in the efficacy of synaptic transmission, such as long term potentiation (LTP). During MS, neuro-inflammation might deeply influence the ability of neuronal networks to express physiologic plasticity, reducing the plastic reserve of the brain, with a negative impact on symptoms progression and cognitive performances. In this manuscript we review the evidence on synaptic plasticity alterations in experimental autoimmune encephalomyelitis (EAE), the most diffuse and widely utilized experimental model of MS, together with their potential underlying mechanisms and clinical relevance. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25498985 TI - Actin dynamics and the evolution of the memory trace. AB - The goal of this essay is to link the regulation of actin dynamics to the idea that the synaptic changes that support long-term potentiation and memory evolve in temporally overlapping stages-generation, stabilization, and consolidation. Different cellular/molecular processes operate at each stage to change the spine cytoarchitecture and, in doing so, alter its function. Calcium-dependent processes that degrade the actin cytoskeleton network promote a rapid insertion of AMPA receptors into the post synaptic density, which increases a spine's capacity to express a potentiated response to glutamate. Other post-translation events then begin to stabilize and expand the actin cytoskeleton by increasing the filament actin content of the spine and reorganizing it to be resistant to depolymerizing events. Disrupting actin polymerization during this stabilization period is a terminal event-the actin cytoskeleton shrinks and potentiated synapses de-potentiate and memories are lost. Late-arriving, new proteins may consolidate changes in the actin cytoskeleton. However, to do so requires a stabilized actin cytoskeleton. The now enlarged spine has properties that enable it to capture other newly transcribed mRNAs or their protein products and thus enable the synaptic changes that support LTP and memory to be consolidated and maintained. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25498986 TI - Conceptual transitions in methods of skull-photo superimposition that impact the reliability of identification: a review. AB - Establishing identification during skull-photo superimposition relies on correlating the salient morphological features of an unidentified skull with those of a face-image of a suspected dead individual using image overlay processes. Technical progression in the process of overlay has included the incorporation of video cameras, image-mixing devices and software that enables real-time vision-mixing. Conceptual transitions occur in the superimposition methods that involve 'life-size' images, that achieve orientation of the skull to the posture of the face in the photograph and that assess the extent of match. A recent report on the reliability of identification using the superimposition method adopted the currently prevalent methods and suggested an increased rate of failures when skulls were compared with related and unrelated face images. The reported reduction in the reliability of the superimposition method prompted a review of the transition in the concepts that are involved in skull-photo superimposition. The prevalent popular methods for visualizing the superimposed images at less than 'life-size', overlaying skull-face images by relying on the cranial and facial landmarks in the frontal plane when orienting the skull for matching and evaluating the match on a morphological basis by relying on mix-mode alone are the major departures in the methodology that may have reduced the identification reliability. The need to reassess the reliability of the method that incorporates the concepts which have been considered appropriate by the practitioners is stressed. PMID- 25498987 TI - CaMKII inhibition with KN93 attenuates endothelin and serotonin receptor-mediated vasoconstriction and prevents subarachnoid hemorrhage-induced deficits in sensorimotor function. AB - BACKGROUND: It has been suggested that transcriptional upregulation of cerebral artery contractile endothelin (ETB) and 5-hydroxytryptamine (5-HT1B) receptors play an important role in the development of late cerebral ischemia and increased vasoconstriction after subarachnoid hemorrhage (SAH). We tested the hypothesis that inhibition of calcium calmodulin-dependent protein kinase II (CaMKII) may reduce cerebral vasoconstriction mediated by endothelin and serotonin receptors and improve neurological outcome after experimental SAH. METHODS: SAH was induced in adult rats by injection of 250 MUL autologous blood into the basal cisterns. The CaMKII activity in cerebral vessels was studied by Western blot and immunohistochemistry. The vasomotor responses of middle cerebral and basilar arteries were measured in a sensitive myograph system. The functional outcome was examined by the rotating pole test 2 and 3 days after SAH. RESULTS: SAH induced a rapid early increase in phosphorylated CaMKII protein at 1 h that was attenuated by cisternal administration of the CaMKII inhibitor KN93 (0.501 MUg/kg) 45 min prior and immediately after SAH as evaluated by Western blot. Application of KN93 at 1 h and every 12 h post-SAH significantly reduced vascular CaMKII immunoreactivity at 72 h. In addition, contractile responses of cerebral arteries to endothelin-1 (ET-1) and 5-hydroxycarboxamide (5-CT) were increased at this time-point. KN93 treatment significantly attenuated the contraction induced by ET 1 and 5-CT. Importantly, treatment with the CaMKII inhibitor prevented SAH induced deficits in neurological function, as evaluated by the rotating pole test, and similar sensorimotor scores were seen in sham-operated animals. CONCLUSIONS: The present study has shown that SAH is associated with increased contractile responses to ET-1 and 5-CT in cerebral arteries and enhanced early activation of CaMKII. Treatment with the CaMKII inhibitor KN93 attenuated the contractile responses and prevented impaired sensorimotor function after SAH. PMID- 25498988 TI - Evaluation of a community diabetes initiative: Integrating diabetes care. AB - AIMS: To evaluate the impact of a community diabetes initiative, aiming to improve the efficiency of type 2 diabetes (T2DM) care within the Cardiff and Vale Health Board. METHODS: In 2012, a community diabetes initiative was introduced in Cardiff and Vale. Ten National Health Service (NHS) consultant diabetologists and three nurse specialists supported 69 general practices in this region. Here we evaluate the impact of this initiative by assessing the number and quality of secondary care diabetes clinic referrals before (2011-2012) and after implementation (2013-2014). Referrals pre and post initiative were audited against Cardiff and Vale T2DM referral guidelines in two 6-month periods. RESULTS: In the 6-months prior to the initiative, 108 referrals were received, 78 of which were in line with local guidance. Approximately one year after embarking on the diabetes initiative (2013-2014) there was a 31% reduction (p<0.01) in the total number of T2DM clinic referrals and a 57% reduction (p<0.01) in referrals outside the guidelines. A decrease in referrals was not seen in the practice noted not to engage with the initiative. CONCLUSIONS: The community diabetes initiative intervention has significantly improved the appropriateness of T2DM referrals from GP practices engaged with the initiative. As a result we advocate a move towards integrated diabetes care within the community. PMID- 25498989 TI - Analysis of stress relaxation in temporization materials in dentistry. AB - OBJECTIVE: Although temporization is intended as an interim step, complexity of individual treatment situations may demand medium to longer term use of temporary appliances in clinical practice. The durability and integrity of these restorations for continued use to meet the treatment demands is therefore an important clinical problem. The goal of this study was to evaluate the short to medium term stability of these materials under controlled loading to study their stress relaxation behavior. METHODS: Acrylic resins (poly(methyl) and poly(ethyl) methacrylate) and bis-acryl composite resins were tested in vitro in this study. The stress decay data with time (under an applied constant strain) due to internal strain caused by molecular relaxation were systematically analyzed using important parameters derived from stress changes with time. RESULTS AND SIGNIFICANCE: The results showed significant differences in the stress relaxation behavior between different materials which may have significant bearing on their durability in medium to longer term interim clinical applications. Poly(ethyl) methacrylate (PEMA) resins subjected to applied constant strain over a period of time showed large time dependent decay of applied stress, indicating very high internal molecular relaxation effects, relative to those of poly(methyl) methacrylate (PMMA) and bis-acryl composites. The results showed that PMMA and composite resins were superior in their ability to maintain constant strain without excessive dissipation of applied stress than PEMA resin. This suggests that internal strain caused by molecular relaxation events may lead to excessive dimensional instability in PEMA. PMID- 25498990 TI - Molecular genetics of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia. AB - According to the 2008 World Health Organization classification, chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia are rare diseases. The remarkable progress in our understanding of the molecular genetics of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms has made it clear that there are some specific genetic abnormalities in these 3 rare diseases. At the same time, there is considerable overlap among these disorders at the molecular level. The various combinations of genetic abnormalities indicate a multi-step pathogenesis, which likely contributes to the marked clinical heterogeneity of these disorders. This review focuses on the current knowledge and challenges related to the molecular pathogenesis of chronic neutrophilic leukemia, chronic myelomonocytic leukemia and atypical chronic myeloid leukemia and relationships between molecular findings, clinical features and prognosis. PMID- 25498991 TI - Lactoferrin induced neuronal differentiation: A boon for brain tumours. AB - The cumulative treatments of bovine lactoferrin (bLf) and iron saturated lactoferrin (Fe-bLf) in the neuroblastoma cells showed neuronal differentiating actions evident with the expression of specific differentiating markers, beta tubulin III and neurofilaments. The protein treatments also showed lowered endogenous survivin that is responsible for cell proliferation and the miRNA 584 and miRNA214-3p, required for differentiation. Further, bLf adopted the PI3K signalling predominantly, while Fe-bLf involved both the PI3K and ERK signalling for inducing differentiation. In conclusion, this is the first study to report the neuronal differentiating effects of milk proteins and future studies are warranted for clinical application. PMID- 25498992 TI - Use of home telemonitoring to support multidisciplinary care of heart failure patients in Finland: randomized controlled trial. AB - BACKGROUND: Heart failure (HF) patients suffer from frequent and repeated hospitalizations, causing a substantial economic burden on society. Hospitalizations can be reduced considerably by better compliance with self-care. Home telemonitoring has the potential to boost patients' compliance with self care, although the results are still contradictory. OBJECTIVE: A randomized controlled trial was conducted in order to study whether the multidisciplinary care of heart failure patients promoted with telemonitoring leads to decreased HF related hospitalization. METHODS: HF patients were eligible whose left ventricular ejection fraction was lower than 35%, NYHA functional class >=2, and who needed regular follow-up. Patients in the telemonitoring group (n=47) measured their body weight, blood pressure, and pulse and answered symptom related questions on a weekly basis, reporting their values to the heart failure nurse using a mobile phone app. The heart failure nurse followed the status of patients weekly and if necessary contacted the patient. The primary outcome was the number of HF-related hospital days. Control patients (n=47) received multidisciplinary treatment according to standard practices. Patients' clinical status, use of health care resources, adherence, and user experience from the patients' and the health care professionals' perspective were studied. RESULTS: Adherence, calculated as a proportion of weekly submitted self-measurements, was close to 90%. No difference was found in the number of HF-related hospital days (incidence rate ratio [IRR]=0.812, P=.351), which was the primary outcome. The intervention group used more health care resources: they paid an increased number of visits to the nurse (IRR=1.73, P<.001), spent more time at the nurse reception (mean difference of 48.7 minutes, P<.001), and there was a greater number of telephone contacts between the nurse and intervention patients (IRR=3.82, P<.001 for nurse-induced contacts and IRR=1.63, P=.049 for patient-induced contacts). There were no statistically significant differences in patients' clinical health status or in their self-care behavior. The technology received excellent feedback from the patient and professional side with a high adherence rate throughout the study. CONCLUSIONS: Home telemonitoring did not reduce the number of patients' HF related hospital days and did not improve the patients' clinical condition. Patients in the telemonitoring group contacted the Cardiology Outpatient Clinic more frequently, and on this way increased the use of health care resources. TRIAL REGISTRATION: Clinicaltrials.gov NCT01759368; http://clinicaltrials.gov/show/NCT01759368 (Archived by WebCite at http://www.webcitation.org/6UFxiCk8Z). PMID- 25498993 TI - Selective partial middle turbinectomy to minimize postoperative obstruction following Lester Jones tube placement. AB - PURPOSE: Conjunctivodacryocystorhinostomy (CDCR) with the insertion of a Jones tube is a surgical procedure used to relieve epiphora caused by upper lacrimal system dysfunction from extensive proximal canalicular obstruction, canalicular stenosis, or canalicular flaccidity. Jones tube obstruction, which is the second most frequent complication of CDCR with tube placement, can result from tube placement against the anterior end of the middle turbinate. In this study, we describe our results in 5 patients who underwent anterosuperior partial middle turbinectomy to prevent obstruction. METHODS: A retrospective analysis was performed on 5 patients who underwent selective anterosuperior partial middle turbinectomy to prevent Jones tube obstruction. Three of these patients developed Jones tube obstruction due to contact between a previously placed Jones tube and the anterosuperior aspect of the adjacent middle turbinate. Two other patients had observed contact between the Jones tube and middle turbinate at initial Jones tube placement and underwent anterosuperior partial middle turbinectomy to prevent development of obstruction. Patency of the Jones tube was assessed symptomatically and by nasal endoscopy at the latest follow-up. RESULTS: All 5 patients displayed a patent Jones tube after a mean follow-up of 29.6 months without complications. Longer-term complications associated with CDCR with Jones tube placement, including continuous epiphora, dacrocystitis, and poor patient satisfaction, were not observed. CONCLUSIONS: Selective anterosuperior partial middle turbinectomy may prevent or relieve Jones tube obstruction, provide increased room along the lateral nasal wall along which to place the Jones tube, and decrease the need for further surgeries arising from tube blockage. PMID- 25498994 TI - Dysphagia, hoarseness, and globus in a postoperative patient. AB - Sore throat, hoarseness, and dysphagia are known and recognized postoperative complications of laryngeal mask airway use during operative procedures. The patient's symptoms, present immediately after surgery, are thought related to airway manipulation. Airway foreign bodies, although low on the differential, can cause similar symptoms. We present a case of a single patient who presented to a tertiary care center after an elective outpatient procedure with postoperative sore throat, hoarseness, and dysphagia. A foreign body was found lodged in the patient's hypopharynx. The differential diagnosis of sore throat, hoarseness, and dysphagia in the postoperative patient is explored in further detail. PMID- 25498995 TI - Associations between biomarkers of renal function with cerebral microbleeds in hypertensive patients. AB - BACKGROUND: Cerebral microbleeds (CMBs) have been observed in the elderly and have been regarded as a manifestation of small vessel disease (SVD). Cerebral and glomerular SVD may have a common source of pathogenesis because these organs are closely connected through anatomic and hemodynamic similarities. The purpose of this study was to clarify the associations between kidney biomarker levels and CMBs in hypertensive patients. METHODS: The presence and number of CMBs were assessed on susceptibility-weighted imaging. We calculated the urinary albumin/creatinine ratio (UACR) from morning spot urine and the estimated glomerular filtration rate (eGFR) in serum samples. Serum cystatin C (CysC) was measured with an automated particle-enhanced turbidimetric immunoassay. RESULTS: UACR and CysC levels were higher in the patients with CMBs than those without, and the eGFR was lower in the patients with CMBs than those without. A logistic regression analysis indicates that eGFR and UACR were independently associated with the prevalence of deep or infratentorial CMBs. The odds ratio (OR) (95% confidence interval (CI)) of eGFR and UACR was 1.95 (1.37-3.27) and 2.25 (1.66 4.46), respectively. CysC was independently associated with CMBs in both deep or infratentorial and lobar locations. The ORs (95% CI) were 2.59 (1.57-6.22) and 1.57 (1.15-4.85), respectively. Furthermore, CysC exhibited fair diagnostic value for CMBs, with an area under the curve of 0.80. CONCLUSIONS: Kidney biomarker levels are associated with the presence of CMB in hypertensive patients without a history of transient ischemic attack (TIA) or stroke, independent of conventional risk factors, and CysC was a better marker for CMBs than eGFR and UACR. PMID- 25498996 TI - Heme Oxygenase Improves Renal Function by Potentiating Podocyte-Associated Proteins in Nomega-Nitro-l-Arginine-Methyl Ester (l-NAME)-Induced Hypertension. AB - BACKGROUND: Although heme-oxygenase (HO) is cytoprotective, its effects on podocyte regulators like podocalyxin, podocin, CD2-associated protein (CD2AP) in renal dysfunction in N (omega)-nitro-l-arginine-methyl ester (l-NAME) hypertension are largely unclear. METHODS: Hypertension was induced in normotensive Sprague Dawley rats by administering l-NAME for 4 weeks. Enzyme immunoassay, enzyme-linked immunosorbent, histology/morphology, spectrophotometry, and western immunoblotting were used. HO was enhanced with heme-arginate (HA) or inhibited with chromium mesoporphyrin (CrMP). RESULTS: Treatment with heme-arginate reduced several renal histo-pathological lesions including renal arteriolar thickening, glomerular abnormalities, tubular cast, tubular atrophy/fibrosis, and mononuclear cell infiltration in l-NAME hypertensive rats. Similarly, HA abated the elevated levels of renal extracellular matrix/profibrotic proteins like collagen and fibronectin that deplete nephrin, a fundamental transmembrane protein that forms the scaffoldings of the podocyte slit diaphragm permitting small ions to filter, but not massive excretion of proteins, hence proteinuria. Correspondingly, HA enhanced the aberrant expression of nephrin alongside other important regulators of podocyte like podocalyxin, podocin, and CD2AP, and improved renal function by reducing albuminuria/proteinuria, while increasing creatinine clearance. The renoprotection by HA were accompanied by significant reduction of inflammatory/oxidative mediators including nuclear factor-kappaB, macrophage inflammatory protein-1-alpha, macrophage chemoattractant protein-1, tumor necrosis factor-alpha, interleukin (IL)-6, IL1beta, 8-isoprostane, endothelin-1, and aldosterone. These were associated with increased levels of adiponectin, HO 1, HO activity, cyclic guanosine monophosphate, and atrial natriuretic peptide (ANP), whereas the HO inhibitor, CrMP annulled the renoprotection and exacerbated renal dysfunction. CONCLUSIONS: HA improves renal function by attenuating histopathological lesions, suppressing inflammatory/oxidative mediators, abating profibrotic/extracellular matrix proteins, and reducing albuminuria/proteinuria, while concomitantly potentiating the HO-adiponectin-ANP axis, enhancing nephrin, podocin, podocalyxin, CD2AP and increasing creatinine clearance. Our study underscores the benefit of potentiating the HO-adiponectin-ANP against nephropathy. PMID- 25498997 TI - Elevated Homocysteine Levels Are Associated With the Metabolic Syndrome and Cardiovascular Events in Hypertensive Patients. AB - BACKGROUND: Hyperhomocysteinemia and the metabolic syndrome are established cardiovascular risk factors and are frequently associated with hypertension. The relationship of plasma homocysteine (Hcy) with the metabolic syndrome and insulin resistance, however, is debated and studies in hypertensive patients are limited. In this study, we have investigated the association of Hcy with the metabolic syndrome and cerebro- cardiovascular events in hypertension. METHODS: In 562 essential hypertensive patients who underwent accurate assessment of fasting and postload glucose metabolism, insulin sensitivity, and renal function, we measured plasma levels of Hcy, vitamin B12, folate, and fibrinogen and assessed the prevalence of the metabolic syndrome and of coronary heart and cerebrovascular disease (CVD). RESULTS: Patients with the metabolic syndrome had significantly higher plasma Hcy levels. After correction for covariates, increasing Hcy levels were associated with an increasing prevalence of the metabolic syndrome, coronary heart disease, and CVD. Plasma Hcy was directly correlated with age, waist circumference, fasting glucose, triglyceride, uric acid, and fibrinogen levels, and homeostatic model assessment index and inversely with creatinine clearance and high-density lipoprotein cholesterol, vitamin B12, and folate levels. Logistic regression analysis showed an independent association of Hcy levels with age, male gender, vitamin B12 and folate levels, and the metabolic syndrome. Logistic regression indicated also an independent association of Hcy with cerebro cardiovascular disease that was independent of the metabolic syndrome. CONCLUSIONS: Elevated plasma Hcy is associated with the metabolic syndrome in hypertensive patients. Prevalence of events increases with increasing plasma Hcy levels suggesting a contribution of Hcy to cerebro-cardiovascular diseases in these patients. PMID- 25498999 TI - Plasma Renin Activity and Resting Heart Rate in a Population of Community Dwelling Japanese: The Tanushimaru Study. AB - BACKGROUND: Heart rate is a strong predictor of mortality and development of obesity and diabetes. The renin-angiotensin-aldosterone system plays an important role in blood pressure control and volume homeostasis. Although many studies have indicated the association between aldosterone and hypertension or insulin resistance, epidemiological evidence of the association of heart rate with plasma renin activity (PRA) remains scant. Therefore, we investigated whether heart rate is associated with PRA. METHODS: A total of 1,943 subjects were enrolled, who underwent a health examination in Tanushimaru in 2009. Plasma renin and aldosterone concentrations were measured by radioimmunoassay. PRA and the homeostasis model assessment (HOMA) were used by natural-log transformed. Resting heart rate was measured using electrocardiography. RESULTS: We divided the subjects into four groups by heart rate (<60/min, 60-69/min, 70-79/min, >=80/ min), and analyzed an association between PRA and heart rate by analysis of covariance after adjustments for age and sex. The adjusted mean PRA and HOMA index showed a significant trend (P < 0.01) as higher heart rate, although there was no significant trend between aldosterone and heart rate (P = 0.26). In multiple linear regression analysis adjusted for age, sex, systolic blood pressure, HOMA index, and hypertensive medication, PRA was positively and strongly associated with elevated heart rate (P < 0.01). CONCLUSIONS: This epidemiological study demonstrated that PRA, but not aldosterone, is significantly and positively associated with higher resting heart rate in a general population. PMID- 25498998 TI - Reducing racial and ethnic disparities in hypertension prevention and control: what will it take to translate research into practice and policy? AB - INTRODUCTION: Despite available, effective therapies, racial and ethnic disparities in care and outcomes of hypertension persist. Several interventions have been tested to reduce disparities; however, their translation into practice and policy is hampered by knowledge gaps and limited collaboration among stakeholders. METHODS: We characterized factors influencing disparities in blood pressure (BP) control by levels of an ecological model. We then conducted a literature search using PubMed, Scopus, and CINAHL databases to identify interventions targeted toward reducing disparities in BP control, categorized them by the levels of the model at which they were primarily targeted, and summarized the evidence regarding their effectiveness. RESULTS: We identified 39 interventions and several state and national policy initiatives targeted toward reducing racial and ethnic disparities in BP control, 5 of which are ongoing. Most had patient populations that were majority African-American. Of completed interventions, 27 demonstrated some improvement in BP control or related process measures, and 7 did not; of the 6 studies examining disparities, 3 reduced, 2 increased, and 1 had no effect on disparities. CONCLUSIONS: Several effective interventions exist to improve BP in racial and ethnic minorities; however, evidence that they reduce disparities is limited, and many groups are understudied. To strengthen the evidence and translate it into practice and policy, we recommend rigorous evaluation of pragmatic, sustainable, multilevel interventions; institutional support for training implementation researchers and creating broad partnerships among payers, patients, providers, researchers, policymakers, and community-based organizations; and balance and alignment in the priorities and incentives of each stakeholder group. PMID- 25499001 TI - The specifical inhibition of the expression of integrin alpha5/beta1 probably enhances the treatment effects and improves the prognosis of epithelial ovarian cancer. AB - Due to subtle symptoms and the absence of effective early screening methods, most of epithelial ovarian cancer patients are diagnosed in the late stage, when current treatment strategies are not so satisfactory. To date, ovarian cancer is still the leading cause of gynecological malignancy deaths in women. The formation of massive ascites is one of the important characteristics of epithelial ovarian carcinoma in the late stage. Cancer cells, existing in ascites in the form of spheroids, play an important role in metastasis and recurrence of the malignancy. Alpha5/beta1 integrin has been found to participate in the formation of epithelial ovarian cancer multicellular spheroids in vitro. But if we want to choose alpha5- and beta1-integrin subunits as treatment targets, we must specifically block the two subunits in cancer cells, because these two subunits are very important for the physiological activities in normal cells. Based on the knowledge mentioned above, we present hypotheses that we can inhibit specifically the expression of alpha5/beta1 integrin in cancer cells with the help of complementary replication defective adenovirus. As a result, the formation of cancer cells spheroids in ascites might be interfered with and the treatment effects and prognosis of epithelial ovarian cancer might be improved. PMID- 25499000 TI - [Detection of the IS2404 insertion sequence and ketoreductase produced by Mycobacterium ulcerans in the aquatic Heteroptera in the health districts of Dabou and Tiassale in Cote d'Ivoire]. AB - Buruli ulcer (BU) disease, caused by Mycobacterium ulcerans, is a major public health problem in Cote d'Ivoire. Until now, the mode of BU transmission was unknown, but recent studies implicate aquatic Heteroptera in the chain of transmission. This study was launched in Cote d'Ivoire to search for specific genetic markers for M. ulcerans in these bugs, including the insertion sequence IS2404 and ketoreductase (Kr), both involved in the synthesis of mycolactone, a toxin produced by these mycobacteria. Samples of aquatic Heteroptera were collected monthly with deep nets from ponds near villages in the health districts of Dabou and Tiassale. After identification and enumeration of the bugs, batches of the same taxon underwent real-time PCR to search for the IS2404 target and Kr. Saliva of 69 specimens of Diplonychus sp randomly selected in the samples was also analyzed by PCR. In all, 283 single-taxon batches were created. Thus, PCR identified 26 batches belonging to the families of Belostomatidae, Naucoridae, Corixidae, Ranatridae, and Nepidae as positive for both targets. The IS2404 insertion sequence and Kr were present in 6 of the 69 samples analyzed in the saliva of Diplonychus sp. These aquatic Heteroptera suspected of infection by M. ulcerans might release it into the environment because of their ability to fly. They might thus be the source of human contamination. PMID- 25499002 TI - A putative role for telocytes in placental barrier impairment during preeclampsia. AB - Preeclampsia (PE) is a major health problem occurring in pregnant women and the principal cause of maternal morbidity and perinatal mortality. It is characterized by alteration of the extravilli trophoblast cell migration toward the endometrial spiral arteries with a concomitant reduction in maternal blood flow in the placenta. This result in a state of ischemia-hypoxia which triggers an oxidative stress stage with production of reactive oxygen species. A cascade of cellular and molecular events leads then to endothelial dysfunction, transduction pathway signal disruption and induction of apoptosis and necrosis mechanisms and therefore a significant reduction in the amount of nutrients required for normal fetal development. Placental anchoring chorionic and stem villi present a skeleton of myofibroblasts arranged in parallel disposition to its longitudinal axis. The intraplacental blood volume is controlled by the contraction/relaxation of these myofibroblasts, promoting the delivery of nutrients and metabolites to the fetus. Recently, a new mesodermal originated cell type has been described in the villous stroma, the so named "telocytes". These cells are strategically located between the smooth muscle cells of the blood vessel wall and the myofibroblasts, and it is reasonable to hypothesize that they may play a pacemaker role, as in the intestine. This study provide new information supporting the notion that the occurrence of oxidative stress in PE is not only related to endothelial dysfunction and apoptosis of the trophoblast cells, but also involves telocytes and its putative role in the regulation of fetal blood flow and the intra-placental blood volume. Some ideas aimed at dilucidating the relationship between placental failure and the behavior of telocytes in pathological organs in adulthood, are also discussed. PMID- 25499004 TI - Decisions about medication use and cancer screening across age groups in the United States. AB - OBJECTIVE: To describe decision process and quality for common cancer screening and medication decisions by age group. METHODS: We included 2941 respondents to a national Internet survey who made at least one decision about colorectal, breast, and prostate cancer screening, blood pressure or cholesterol medications. Respondents were queried about decision processes. RESULTS: Across the five decisions considered, decision process scores were similar (and generally low) across age groups for medication and cancer screening, indicating that all groups had poor involvement in medical decision making. Overall knowledge scores were low across age groups, with elderly (75+) having slightly higher knowledge about medications vs. younger respondents. Elderly respondents reported similar goals and concerns when making decisions, though placed greater importance of having peace of mind from a normal result for cancer screening vs. younger respondents. CONCLUSION: Across age groups, respondents reported poor decision processes about common medications and cancer screening, despite little evidence of benefit for some interventions (cancer screening, cholesterol lowering medicines in low risk elderly) and possibility of harm in the elderly. PRACTICE IMPLICATIONS: Particular care should be taken to help patients understand both benefit and risk of screening tests and routine medications. PMID- 25499003 TI - Medical student socio-demographic characteristics and attitudes toward patient centered care: do race, socioeconomic status and gender matter? A report from the Medical Student CHANGES study. AB - OBJECTIVE: To determine whether attitudes toward patient-centered care differed by socio-demographic characteristics (race, gender, socioeconomic status) among a cohort of 3191 first year Black and White medical students attending a stratified random sample of US medical schools. METHODS: This study used baseline data from Medical Student CHANGES, a large national longitudinal cohort study of medical students. Multiple logistic regression was used to assess the association of race, gender and SES with attitudes toward patient-centered care. RESULTS: Female gender and low SES were significant predictors of positive attitudes toward patient-centered care. Age was also a significant predictor of positive attitudes toward patient-centered care such that students older than the average age of US medical students had more positive attitudes. Black versus white race was not associated with attitudes toward patient-centered care. CONCLUSIONS: New medical students' attitudes toward patient-centered care may shape their response to curricula and the quality and style of care that they provide as physicians. Some students may be predisposed to attitudes that lead to both greater receptivity to curricula and the provision of higher-quality, more patient-centered care. PRACTICE IMPLICATIONS: Medical school curricula with targeted messages about the benefits and value of patient-centered care, framed in ways that are consistent with the beliefs and world-view of medical students and the recruitment of a socioeconomically diverse sample of students into medical schools are vital for improved care. PMID- 25499005 TI - Patients' reports of barriers to expressing concerns during cancer consultations. AB - OBJECTIVE: To identify cancer patients' most influential barriers to expressing concerns during cancer consultations in a new manner by examining patients' reports of perceived barriers and perceived occurrence of barriers in consultations. METHODS: Two online focus groups (N=16) and an online survey (N=236) were conducted among cancer patients and cancer survivors. The online focus groups and survey were used to examine two elements of patients' barriers, i.e., patients' reports of perceived barriers and perceived occurrence of barriers in consultations. Composite scores of these two elements were calculated to determine influential barriers. RESULTS: Results showed that the most influential barriers were related to providers' behavior (e.g., providers do not explicitly invite patients to express concerns) and the environment where the consultation takes place (e.g., perceived lack of time). CONCLUSION: The results of this study indicate that influential barriers to expressing concerns are barriers that patients cannot overcome themselves (i.e., they are related to providers' behavior or the environment of the consultation). A collaborative approach between researchers, providers and policy makers is needed to overcome these barriers. PRACTICE IMPLICATIONS: The results of this study can be used to develop strategies to overcome barriers to patients expressing concerns. PMID- 25499006 TI - Emergency Resuscitation of Patients Enrolled in the US Diaspirin Cross-linked Hemoglobin (DCLHb) Clinical Efficacy Trial. AB - INTRODUCTION: Optimal emergent management of traumatic hemorrhagic shock patients requires a better understanding of treatment provided in the prehospital/Emergency Medical Services (EMS) and emergency department (ED) settings. Hypothesis/Problem Described in this research are the initial clinical status, airway management, fluid and blood infusions, and time course of severely injured hemorrhagic shock patients in the EMS and ED settings from the diaspirin cross-linked hemoglobin (DCLHb) clinical trial. METHODS: Data were analyzed from 17 US trauma centers gathered during a randomized, controlled, single-blinded efficacy trial of a hemoglobin solution (DCLHb) as add-on therapy versus standard therapy. RESULTS: Among the 98 randomized patients, the mean EMS Glasgow Coma Scale (GCS) was 10.6 (SD = 5.0), the mean EMS revised trauma score (RTS) was 6.3 (SD = 1.9), and the mean injury severity score (ISS) was 31 (SD = 17). Upon arrival to the ED, the GCS was 20% lower (7.8 (SD = 5.3) vs 9.7 (SD = 6.3)) and the RTS was 12% lower (5.3 (SD = 2.0) vs 6.0 (SD = 2.1)) than EMS values in blunt trauma patients (P < .001). By ED disposition, 80% of patients (78/98) were intubated. Rapid sequence intubation (RSI) was utilized in 77% (60/78), most often utilizing succinylcholine (65%) and midazolam (50%). The mean crystalloid volume infused was 4.2 L (SD = 3.4 L), 80% of which was infused within the ED. Emergency department blood transfusion occurred in 62% of patients, with an average transfused volume of 1.2 L (SD = 2.0 L). Blunt trauma patients received 2.1 times more total fluids (7.4 L vs 3.5 L, < .001) and 2.4 times more blood (2.4 L vs 1.0 L, P < .001). The mean time of patients taken from injury site to operating room (OR) was 113 minutes (SD = 87 minutes). Twenty-one (30%) of the 70 patients taken to the OR from the ED were sent within 60 minutes of the estimated injury time. Penetrating trauma patients were taken to the OR 52% sooner than blunt trauma patients (72 minutes vs 149 minutes, P < .001). CONCLUSION: Both GCS and RTS decreased prior to ED arrival in blunt trauma patients. Intubation was performed using RSI, and crystalloid infusion of three times the estimated blood loss volume (L) and blood transfusion of the estimated blood loss volume (L) were provided in the EMS and ED settings. Surgical intervention for these trauma patients most often occurred more than one hour from the time of injury. Penetrating trauma patients received surgical intervention more rapidly than those with a blunt trauma mechanism. PMID- 25499007 TI - Meniere's disease and the DVLA. PMID- 25499008 TI - Association between ACVR2A and early-onset preeclampsia: replication study in a Northeastern Brazilian population. AB - INTRODUCTION: Preeclampsia is a complex and heterogeneous disease with increased risk of maternal mortality, especially for earlier gestational onset. There is a great inconsistency regarding the genetics of preeclampsia across the literature. The gene Activin A receptor, type IIA (ACVR2A), was reported as associated to preeclampsia in Australian/New Zealand and Norwegian populations. The goal of this study was to validate this genetic association in a Brazilian population. METHODS: We performed a case-control study using 693 controls and 613 cases (443 preeclampsia, 64 eclampsia and 106 HELLP syndrome), from a Northeastern Brazilian population. Five single nucleotide polymorphisms (SNPs) in ACVR2A were tested for association through multiple logistic regression models. RESULTS: There was no statistical association with preeclampsia (per se), eclampsia or HELLP. However, by grouping preeclampsia in accordance to the gestational age at delivery, SNPs rs1424954 (OR = 1.86; 95% CI, 1.25-2.78; p = 0.002) and rs1014064 (OR = 1.77; 95% CI, 1.21-2.60; p = 0.004) were significantly associated with early onset preeclampsia (gestational age <= 34 weeks). The risk haplotype had a frequency of 0.468 in early preeclampsia compared to 0.316 in controls (p = 0.0008 and permuted p = 0.002). DISCUSSION: Activin A receptors are important in decidualization, trophoblast invasion and placentation processes during pregnancy. The gene ACVR2A was associated with the more severe early onset preeclampsia. This finding supports the hypothesis of different pathogenic mechanisms contributing to the early- and late-onset preeclampsia. PMID- 25499009 TI - 2-Methoxyestradiol regulates VEGFR-2 and sFlt-1 expression in human placenta. AB - INTRODUCTION: 2-Methoxyestradiol (2-ME), a metabolite of estradiol, has been identified as an initiator of cytotrophoblast transformation to an invasive phenotype, with low levels implicated with the onset of preeclampsia. Here, we investigated the effects of 2-ME on VEGFR-2, sFlt-1 and HIF1alpha expression in human placenta. METHODS: First trimester human placental villous explants were maintained at 3% and 20% O2. Samples were treated with 0.5 MUM 2-ME with or without 1 mM DMOG or 0.2 mM CoCl2 for 17 h. Western and qPCR analyses were performed for VEGFR-2, sFlt-1 and HIF1alpha expression levels. sFlt-1 specific ELISA was also performed on conditioned explant media. RESULTS: Placental explants maintained at 3% O2 revealed decreased protein and transcript levels of VEGFR-2 with increased sFlt-1 and HIF1alpha. Overnight treatment with 0.5 MUM 2 ME rescued altered expression levels of VEGFR-2, sFlt-1 and HIF1alpha. 2-ME also decreased levels of sFlt-1 in conditioned explant media. While 2-ME treatment rescued decreased levels of VEGFR-2 in DMOG and CoCl2-treated explants, no effect was observed for sFlt-1 levels. Furthermore, 2-ME was observed to further exacerbate elevated HIF1alpha levels by DMOG and CoCl2. DISCUSSION: 2-ME rescues altered levels of VEGFR-2, sFlt-1 and HIF1alpha in hypoxic placental explants, suggesting potential therapeutic measures for the treatment of preeclampsia. However, the unaltered sFlt-1 levels and enhanced HIF1alpha levels by 2-ME in DMOG and CoCl2 treated explants suggests 2-ME also elicits its effects through HIF1alpha-independent pathways. PMID- 25499010 TI - Highly purified mycobacterial phosphatidylinositol mannosides drive cell-mediated responses and activate NKT cells in cattle. AB - Mycobacterial lipids play an important role in the modulation of the immune response upon contact with the host. Using novel methods, we have isolated highly purified phosphatidylinositol mannoside (PIM) molecules (phosphatidylinositol dimannoside [PIM2], acylphosphatidylinositol dimannoside [AcPIM2], diacyl phosphatidylinositol dimannoside [Ac2PIM2], acylphosphatidylinositol hexamannoside [AcPIM6], and diacylphosphatidylinositol hexamannoside [Ac2PIM6]) from virulent Mycobacterium tuberculosis to assess their potential to stimulate peripheral blood mononuclear cell (PBMC) responses in Mycobacterium bovis infected cattle. Of these molecules, one (AcPIM6) induced significant levels of gamma interferon (IFN-gamma) in bovine PBMCs. Three PIM molecules (AcPIM6, Ac2PIM2, and Ac2PIM6) were shown to drive significant proliferation in bovine PBMCs. AcPIM6 was subsequently used to phenotype the proliferating cells by flow cytometry. This analysis demonstrated that AcPIM6 was predominantly recognized by CD3(+) CD335(+) NKT cells. In conclusion, we have identified PIM lipid molecules that interact with bovine lymphocyte populations, and these lipids may be useful as future subunit vaccines or diagnostic reagents. Further, these data demonstrate, for the first time, lipid-specific NKT activation in cattle. PMID- 25499011 TI - Open-label trial of immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults >= 50 years of age in Mexico. AB - This open-label multicenter clinical trial conducted in Mexico assessed the immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine (PCV13) in adults >= 50 years of age not previously vaccinated with the 23-valent pneumococcal polysaccharide vaccine (PPSV23). The PCV13 elicited a robust immune response in this study population, as reflected by the magnitude of fold rises in functional antibody levels measured by serotype-specific opsonophagocytic activity (OPA) assays before and 1 month after vaccination. Although the prevaccination OPA geometric mean titers (GMTs) for the majority of the serotypes were significantly lower in the 50- to 64-year age group than those in the >= 65 year age group, the postvaccination immune responses were generally similar. The overall immune responses were higher for the majority of the serotypes in the Mexican study population than those in similar adult study populations who received the PCV13 in Europe and the United States. PCV13 was well tolerated, and there were no vaccine-related serious adverse events. In conclusion, PCV13 is safe and immunogenic when administered to adults >= 50 years of age in Mexico and has the potential to protect against vaccine-type pneumococcal disease. (This study has been registered at ClinicalTrials.gov under registration no. NCT01432262.). PMID- 25499012 TI - High rates of associated morbidity and mortality justify flu vaccination. PMID- 25499013 TI - Routine cell salvage during elective caesarean section: a pilot randomised trial. PMID- 25499014 TI - Fractures of the pubic rami and sacrum identified after delivery. PMID- 25499015 TI - Intracranial pressure monitoring and caesarean section in a patient with von Hippel-Lindau disease and symptomatic cerebellar haemangioblastomas. AB - Von Hippel-Lindau disease is a rare genetic disorder which gives rise to a range of tumours including central nervous system haemangioblastomas. We report a case of caesarean section in a patient with symptomatic cerebellar haemangioblastomas associated with von Hippel-Lindau disease. An intracranial pressure monitor was inserted before surgery, which enabled intracranial pressure to be monitored throughout. The anaesthetic implications of von Hippel-Lindau disease are discussed and clinical options explored. PMID- 25499016 TI - The effect of intra-abdominal pressure on sensory block level of single-shot spinal anesthesia for cesarean section: an observational study. AB - BACKGROUND: Increased intra-abdominal pressure in pregnancy is thought to affect intrathecal drug spread. However this assumption remains largely untested. The aim of this prospective study was to evaluate the association between intra abdominal pressure and maximum sensory block level in parturients receiving spinal anesthesia for cesarean section. METHODS: Parturients having elective cesarean section with single-shot spinal anesthesia using hyperbaric bupivacaine 12.5mg were included. Intra-abdominal pressure was measured via a bladder catheter after establishing a T4 sensory block and at the end of surgery in the supine position with 10 degrees left lateral tilt. We recorded demographic data, descriptive characteristics of pregnancy, self-reported weight gain and weight of the newborn. As secondary outcomes, we evaluated onset of sensory block, maximum sensory block, motor block, number of hypotensive episodes, fluid and ephedrine requirements, time to first analgesic request, time to one-point recovery of motor block and side effects. RESULTS: The median value of the maximum sensory block level was T2 in 117 parturients. Median [interquartile range] pre-incision and postoperative intra-abdominal pressure were 13 [11-16] and 9 [6-10]mmHg respectively. No association was observed between maximum sensory block level and pre-incision intra-abdominal pressure (P=0.83). Weight was associated with pre incision intra-abdominal pressure with an estimated odds ratio of 1.04 per kg (99.4% CI: 1.00-1.08). There was a moderate correlation between pre-incision and postoperative intra-abdominal pressure with a Spearman correlation coefficient of 0.67 (99.5% CI: 0.5-0.79). There was no association between pre-incision intra abdominal pressure and secondary outcomes. CONCLUSIONS: In parturients, intra abdominal pressure was not associated with spinal block spread, block onset time, recovery or side effects. PMID- 25499017 TI - Surgical resection of renal carcinoma with right atrial extension associated with an unnoticed large atrial septal defect. PMID- 25499018 TI - Optimal experimental design for nano-particle atom-counting from high-resolution STEM images. AB - In the present paper, the principles of detection theory are used to quantify the probability of error for atom-counting from high resolution scanning transmission electron microscopy (HR STEM) images. Binary and multiple hypothesis testing have been investigated in order to determine the limits to the precision with which the number of atoms in a projected atomic column can be estimated. The probability of error has been calculated when using STEM images, scattering cross sections or peak intensities as a criterion to count atoms. Based on this analysis, we conclude that scattering cross-sections perform almost equally well as images and perform better than peak intensities. Furthermore, the optimal STEM detector design can be derived for atom-counting using the expression for the probability of error. We show that for very thin objects LAADF is optimal and that for thicker objects the optimal inner detector angle increases. PMID- 25499019 TI - Thermal magnetic field noise: electron optics and decoherence. AB - Thermal magnetic field noise from magnetic and non-magnetic conductive parts close to the electron beam recently has been identified as a reason for decoherence in high-resolution transmission electron microscopy (TEM). Here, we report about new experimental results from measurements for a layered structure of magnetic and non-magnetic materials. For a simplified version of this setup and other situations we derive semi-analytical models in order to predict the strength, bandwidth and spatial correlation of the noise fields. The results of the simulations are finally compared to previous and new experimental data in a quantitative manner. PMID- 25499020 TI - Pulmonary drug delivery systems for tuberculosis treatment. AB - Tuberculosis (TB) remains a major global health problem as it is the second leading cause of death from an infectious disease worldwide, after the human immunodeficiency virus (HIV). Conventional treatments fail either because of poor patient compliance to the drug regimen or due to the emergence of multidrug resistant tuberculosis. The aim of this review is to give an update on the information available on tuberculosis, its pathogenesis and current antitubercular chemotherapies. Direct lung delivery of anti-TB drugs using pulmonary delivery systems is then reviewed since it appears as an interesting strategy to improve first and second line drugs. A particular focus is place on research performed on inhalable dry powder formulations of antitubercular drugs to target alveolar macrophages where the bacteria develop. Numerous studies show that anti-TB drugs can be incorporated into liposomes, microparticles or nanoparticles which can be delivered as dry powders to the deep lungs for instantaneous, targeted and/or controlled release. Treatments of infected animals show a significant reduction of the number of viable bacteria as well as a decrease in tissue damage. These new formulations appear as interesting alternatives to deliver directly drugs to the lungs and favor efficient TB treatment. PMID- 25499021 TI - Exopolysaccharides from Cyanobacterium aponinum from the Blue Lagoon in Iceland increase IL-10 secretion by human dendritic cells and their ability to reduce the IL-17+RORgammat+/IL-10+FoxP3+ ratio in CD4+ T cells. AB - Regular bathing in the Blue Lagoon in Iceland has beneficial effects on psoriasis. Cyanobacterium aponinum is a dominating member of the Blue Lagoon's microbial ecosystem. The aim of the study was to determine whether exopolysaccharides (EPSs) secreted by C. aponinum (EPS-Ca) had immunomodulatory effects in vitro. Human monocyte-derived dendritic cells (DCs) were matured in the absence or presence of EPS-Ca and the effects were determined by measuring the secretion of cytokines by ELISA and the expression of surface molecules by flow cytometry. DCs matured with EPS-Ca at 100 MUg/ml secreted higher levels of IL-10 than untreated DCs. Subsequently, DCs matured in the presence or absence of EPS-Ca were co-cultured with allogeneic CD4(+) T cells and their effects on T cell activation analysed by measuring expression of intracellular and surface molecules and cytokine secretion. Supernatant from allogeneic T cells co-cultured with EPS-Ca-exposed DCs had raised levels of IL-10 compared with control. A reduced frequency of IL-17(+)RORgammat(+) T cells was observed when co-cultured with EPS-Ca-exposed DCs and a tendency towards increased frequency of FoxP3(+)IL 10(+) T cells, resulting in a lower IL-17(+)RORgammat(+)/FoxP3(+)IL-10(+) ratio. The study shows that EPSs secreted by C. aponinum stimulate DCs to produce vast amounts of the immunosuppressive cytokine IL-10. These DCs induce differentiation of allogeneic CD4(+) T cells with an increased Treg but decreased Th17 phenotype. These data suggest that EPSs from C. aponinum may play a role in the beneficial clinical effect on psoriasis following bathing in the Blue Lagoon. PMID- 25499022 TI - Ceftriaxone prevents and reverses behavioral and neuronal deficits in an MPTP induced animal model of Parkinson's disease dementia. AB - Glutamatergic hyperactivity plays an important role in the pathophysiology of Parkinson's disease (PD). Ceftriaxone increases expression of glutamate transporter 1 (GLT-1) and affords neuroprotection. This study was aimed at clarifying whether ceftriaxone prevented, or reversed, behavioral and neuronal deficits in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were injected daily with either ceftriaxone starting 5 days before or 3 days after MPTP lesioning (day 0) or saline and underwent a bar test on days 1-7, a T-maze test on days 9-11, and an object recognition test on days 12-14, then the brains were taken for histological evaluation on day 15. Dopaminergic degeneration in the substantia nigra pars compacta and striatum was observed on days 3 and 15. Motor dysfunction in the bar test was observed on day 1, but disappeared by day 7. In addition, lesioning resulted in deficits in working memory in the T-maze test and in object recognition in the object recognition task, but these were not observed in rats treated pre- or post lesioning with ceftriaxone. Lesioning also caused neurodegeneration in the hippocampal CA1 area and induced glutamatergic hyperactivity in the subthalamic nucleus, and both changes were suppressed by ceftriaxone. Increased GLT-1 expression and its co-localization with astrocytes were observed in the striatum and hippocampus in the ceftriaxone-treated animals. To our knowledge, this is the first study showing a relationship between ceftriaxone-induced GLT-1 expression, neuroprotection, and improved cognition in a PD rat model. Ceftriaxone may have clinical potential for the prevention and treatment of dementia associated with PD. PMID- 25499023 TI - Drug-coated balloon for peripheral arterial disease in the United States: a safe and effective landing zone. PMID- 25499024 TI - Overview of the 2014 Food and Drug Administration Circulatory System Devices Panel meeting regarding the Lutonix(r) drug coated balloon. AB - The Lutonix(r) drug coated balloon (DCB) is a combination device composed of a standard percutaneous angioplasty balloon coated with paclitaxel. Depending on the balloon size, a dose density of 2MUg/mm(2) yields a variable total dose raging from 1.5mg to 3.8mg. This drug coated balloon aims to provide improved patency rates in patients with symptomatic femoropopliteal de novo or restenotic atherosclerotic disease. On June 12, 2014, the Food and Drug Administration's (FDA) Circulatory System Devices Panel reviewed the Lutonix DCB premarket approval application (PMA). This PMA application was primarily based on data from the pivotal randomized, controlled and multicenter clinical trial, which compared the Lutonix DCB with PTA. This summary aims to describe the discussions and recommendations made by the advisory panel during the meeting. Based on the Panel's recommendations, it is possible that the FDA will approve this device. PMID- 25499025 TI - Molecular mechanisms governing Arabidopsis iron uptake. AB - Plants are the principal source of dietary iron (Fe) for most of Earth's population and Fe deficiency can lead to major health problems. Developing strategies to improve plant Fe content is a challenge because Fe is essential and toxic and therefore regulating Fe uptake is crucial for plant survival. Acquiring soil Fe relies on complex regulatory events that occur in root epidermal cells. We review recent advances in elucidating many aspects of the regulation of Fe acquisition. These include the expanding protein network involved in FER-LIKE IRON DEFICIENCY INDUCED TRANSCRIPTION FACTOR (FIT)-dependent gene regulation and novel findings on the intracellular trafficking of the Fe transporter IRON REGULATED TRANSPORTER 1 (IRT1). We outline future challenges and propose strategies, such as exploiting natural variation, to further expand our knowledge. PMID- 25499026 TI - Comparative Analysis of Registered Nurses' and Nursing Students' Attitudes and Use of Nonpharmacologic Methods of Pain Management. AB - Despite the benefits that nonpharmacologic methods of pain management have to offer, nurses cite barriers that inhibit their use in practice. The purpose of this research study was to compare the perceptions of prelicensed student nurses (SNs) and registered nurses (RNs) toward nonpharmacologic methods of pain management. A sample size of 64 students and 49 RNs was recruited. Each participant completed a questionnaire about their use and perceptions nonpharmacologic pain control methods. Sixty-nine percent of RNs reported a stronger belief that nonpharmacologic methods gave relief to their patients compared with 59% of SNs (p = .028). Seventy-five percent of student nurses felt they had adequate education about nonpharmacologic pain modalities compared with 51% of RN who felt less than adequately educated (p = .016). These findings highlight the need for education about nonpharmacologic approaches to pain management. Applications of these findings may decrease barriers to the use of nonpharmacologic methods of pain management. PMID- 25499028 TI - Internal medicine resident training and provision of diabetes quality of care indicators. AB - OBJECTIVE: Existing research is inconsistent on whether clinical experience is associated with improved management of type 2 diabetes mellitus. We sought to determine whether meeting diabetes quality indicators improves as general internal medicine physicians progress from first to last year of residency. METHODS: We performed a chart abstraction of electronic health records data covering the period from September 2008 to August 2011. In all, 352 patient records were abstracted and linked to year of resident provider. Type 2 diabetes quality indicators included glycated hemoglobin (A1C), low-density lipoprotein, diastolic and systolic blood pressure control, obtaining urine microalbumin or prescription for angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and documented foot and eye examinations. Chi-square tests and logistic regression analysis were used to determine whether year of residency was associated with quality of care indices before and after adjusting for patient age, gender, race, body mass index and cigarette smoking. RESULTS: Urine microalbumin was the most often met indicator (76.9%), and the least often met indicator was documented eye examination (37.4%). Results of adjusted analysis indicated that the odds of A1C, low-density lipoprotein control, obtaining urine microalbumin and documented eye and foot examinations were greater among patients of second- and third-year residents compared with those of first-year residents (odds ratios range, 1.26-5.12). Urine microalbumin was the indicator most often in optimal control and least often met indicators were eye and foot examinations. CONCLUSIONS: We observed improvement in quality of diabetes care throughout residency. However, the low prevalence of several quality indicators indicates a need for additional training and quality improvement. PMID- 25499027 TI - Chronic alcohol consumption enhances iNKT cell maturation and activation. AB - Alcohol consumption exhibits diverse effects on different types of immune cells. NKT cells are a unique T cell population and play important immunoregulatory roles in different types of immune responses. The effects of chronic alcohol consumption on NKT cells remain to be elucidated. Using a mouse model of chronic alcohol consumption, we found that alcohol increases the percentage of NKT cells, especially iNKT cells in the thymus and liver, but not in the spleen or blood. Alcohol consumption decreases the percentage of NK1.1(-) iNKT cells in the total iNKT cell population in all of the tissues and organs examined. In the thymus, alcohol consumption increases the number of NK1.1(+)CD44(hi) mature iNKT cells but does not alter the number of NK1.1(-) immature iNKT cells. A BrdU incorporation assay shows that alcohol consumption increases the proliferation of thymic NK1.1(-) iNKT cells, especially the NK1.1(-)CD44(lo) Stage I iNKT cells. The percentage of NKG2A(+) iNKT cells increases in all of the tissues and organs examined; whereas CXCR3(+) iNKT cells only increases in the thymus of alcohol consuming mice. Chronic alcohol consumption increases the percentage of IFN-gamma producing iNKT cells and increases the blood concentration of IFN-gamma and IL-12 after in vivo alpha-galactosylceramide (alphaGalCer) stimulation. Consistent with the increased cytokine production, the in vivo activation of iNKT cells also enhances the activation of dendritic cells (DC) and NK, B, and T cells in the alcohol-consuming mice. Taken together the data indicate that chronic alcohol consumption enhances iNKT cell maturation and activation, which favors the Th1 immune response. PMID- 25499029 TI - MR microscopy for noninvasive detection of water distribution during soaking and cooking in the common bean. AB - Magnetic resonance microscopy (MRM) was used to study water distribution and mobility in common bean (Phaseolus vulgaris) seed during soaking at room temperature (20 degrees C) and during the cooking of presoaked and dry bean seed in near-boiling water (98 degrees C). Two complementary MRI methods were used to determine the total water uptake into the seed: the T2-weighted 3D RARE method, which yielded an increased signal from regions of highly mobile (bulk) water and a suppressed signal from regions of poorly mobile (bound) water; and the 3D SPI method, which yielded an increased signal from regions of water restricted in motion and a suppressed signal from the bulk water regions owing to the short repetition time of the method. Based on these results, it can be concluded that during soaking water enters the bean through the micropyle, migrating below the seed coat. The raphe and hypocotyl are hydrated first, while the cotyledon tissue is hydrated next. It was also observed that the imbibition rate increases with an increasing soaking temperature. PMID- 25499030 TI - Antipyretic analgesic drugs have different mechanisms for regulation of the expression of inducible nitric oxide synthase in hepatocytes and macrophages. AB - Antipyretic analgesic drugs (including non-steroidal anti-inflammatory drugs) inhibit cyclooxygenase-2 and inducible nitric oxide synthase (iNOS), resulting in decreases of the proinflammatory mediators prostaglandin E2 and nitric oxide (NO), respectively. Both mediators are regulated by nuclear factor-kappa B (NF kappaB), a key transcription factor in inflammation. Few reports have compared the efficacy and potency of anti-inflammatory drugs as NO inhibitors. In our study, we examined the effects of four popular antipyretic analgesic drugs on NO production induced in hepatocytes and macrophages. Mouse RAW264.7 macrophages treated with bacterial lipopolysaccharide showed the highest efficacy with regard to NO production; aspirin, loxoprofen, ibuprofen, and acetaminophen dose dependently suppressed NO induction. Ibuprofen showed the highest potency in suppressing the induced production of NO. In rat hepatocytes, all the drugs inhibited interleukin 1beta-induced NO production and ibuprofen and loxoprofen inhibited NO induction effectively. Unexpectedly, the potency of NO suppression of each drug in hepatocytes did not always correlate with that observed in RAW264.7 cells. Microarray analyses of mRNA expression in hepatocytes revealed that the effects of the four antipyretic analgesic drugs modulated the NF-kappaB signaling pathway in a similar manner to the regulation of the expression of genes associated with inflammation, including the iNOS gene. However, the affected signal-transducing molecules in the NF-kappaB pathway were different for each drug. Therefore, antipyretic analgesic drugs may decrease NO production by modulating the NF-kappaB pathway in different ways, which could confer different efficacies and potencies with regard to their anti-inflammatory effects. PMID- 25499032 TI - The novel white spot syndrome virus-induced gene, PmERP15, encodes an ER stress responsive protein in black tiger shrimp, Penaeus monodon. AB - By microarray screening, we identified a white spot syndrome virus (WSSV) strongly induced novel gene in gills of Penaeus monodon. The gene, PmERP15, encodes a putative transmembrane protein of 15 kDa, which only showed some degree of similarity (54-59%) to several unknown insect proteins, but had no hits to shrimp proteins. RT-PCR showed that PmERP15 was highly expressed in the hemocytes, heart and lymphoid organs, and that WSSV-induced strong expression of PmERP15 was evident in all tissues examined. Western blot analysis likewise showed that WSSV strongly up-regulated PmERP15 protein levels. In WSSV-infected hemocytes, immunofluorescence staining showed that PmERP15 protein was colocalized with an ER enzyme, protein disulfide isomerase, and in Sf9 insect cells, PmERP15-EGFP fusion protein colocalized with ER -TrackerTM Red dye as well. GRP78, an ER stress marker, was found to be up-regulated in WSSV-infected P. monodon, and both PmERP15 and GRP78 were up-regulated in shrimp injected with ER stress inducers tunicamycin and dithiothreitol. Silencing experiments showed that although PmERP15 dsRNA-injected shrimp succumbed to WSSV infection more rapidly, the WSSV copy number had no significant changes. These results suggest that PmERP15 is an ER stress-induced, ER resident protein, and its induction in WSSV-infected shrimp is caused by the ER stress triggered by WSSV infection. Furthermore, although PmERP15 has no role in WSSV multiplication, its presence is essential for the survival of WSSV-infected shrimp. PMID- 25499031 TI - Obesity induced rapid melanoma progression is reversed by orlistat treatment and dietary intervention: role of adipokines. AB - Obesity, owing to adiposity, is associated with increased risk and development of various cancers, and linked to their rapid growth as well as progression. Although a few studies have attempted to understand the relationship between obesity and melanoma, the consequences of controlling body weight by reducing adiposity on cancer progression is not well understood. By employing animal models of obesity, we report that controlling obesity either by orlistat treatment or by restricting caloric intake significantly slows down melanoma progression. The diminished tumor progression was correlated with decreased fat mass (adiposity) in obese mice. Obesity associated factors contributing to tumor progression were decreased in the experimental groups compared to respective controls. In tumors, protein levels of fatty acid synthase (FASN), caveolin (Cav) 1 and pAkt, which are tumor promoting molecules implicated in melanoma growth under obese state, were decreased. In addition, increased necrosis and reduction in angiogenesis as well as proliferative markers PCNA and cyclin D1 were observed in tumors of the orlistat treated and/or calorically restricted obese mice. We observed that growth of melanoma cells cultured in conditioned medium (CM) from orlistat-treated adipocytes was reduced. Adipokines (leptin and resistin), via activating Akt and modulation of FASN as well as Cav-1 respectively, enhanced melanoma cell growth and proliferation. Together, we demonstrate that controlling body weight reduces adipose mass thereby diminishing melanoma progression. Therefore, strategic means of controlling obesity by reduced caloric diet or with antiobesity drugs treatment may render obesity-promoted tumor progression in check and prolong survival of patients. PMID- 25499033 TI - The serpin superfamily in channel catfish: identification, phylogenetic analysis and expression profiling in mucosal tissues after bacterial infections. AB - The superfamily of serine protease inhibitors (serpins) are broadly distributed in all kingdoms of life. Serpins play critical roles in an array of fundamental biological processes. In this study, we identified a complete set of 25 serpin genes from channel catfish genome by comprehensive data mining of existing genomic resources. Phylogenetic analysis verified their identities and supported the classification of serpins into six families as in mammals. Extensive comparative genomic analyses suggested that most serpins were conserved among vertebrates, while some were lineage-specific. Analysis of serpin gene expression in mucosal tissues after bacterial infections indicated that serpin genes were regulated in a tissue-specific and time-dependent manner. Distinct expression patterns between infections of the two pathogens were observed, indicating that much more rapid host responses of serpin expression were initiated after ESC infection than after columnaris infection. These studies set the foundation for future studies of host-pathogen interactions. PMID- 25499034 TI - Molecular cloning, expression, purification and characterization of vitellogenin in scallop Patinopecten yessoensis with special emphasis on its antibacterial activity. AB - Vitellogenin (Vg), the major precursor of the egg-yolk proteins, has been found to play an immune role in fish and protochordate amphioxus, however, no study on the immune function of Vg in invertebrates has ever been studied before. In this study, the complete cDNA of Vg was identified from the scallop Patinopecten yessoensis (termed PyVg). The cDNA contained an open reading frame (ORF) of 6888 bp, encoding a polypeptide of 2295 amino acid protein, which had an N-terminal signal peptide followed by the mature Vg. The mature Vg had the domains Vitellogenin_N, domain of unknown function 1943 (DUF1943) and von Willebrand factor type D domain (VWD) as well as the consensus cleavage site (R-X-R/K-R) and conserved motif (KTIGNAG). Tissue distribution assay revealed that PyVg transcripts were predominantly present in the ovary and hepatopancreas, and its expression profile in ovary well reflected the annual cycle of vitellogenesis. Interestingly, bacterial challenge caused a significant change in PyVg expression, hinting an involvement of PyVg in the acute phase response in P. yessoensis. Consistently, recombinant DUF1943 and VWD domains both could interact with LTA and LPS on bacterial wall, and purified native PyVg displayed a broad spectrum antibacterial activity against both Gram-negative (Escherichia coli and Vibrio anguillarum) and Gram-positive bacteria (Staphylococcus aureus). Overall, these data indicate that Vg is a pattern recognition molecule with bacterial growth-inhibiting activity in the scallop. PMID- 25499036 TI - Right hemisphere advantage in statistical learning: evidence from a probabilistic sequence learning task. AB - BACKGROUND: Picking up statistical regularities of patterns from the environment is essential for predictive and adaptive behavior. One of the most important challenges is to understand how statistical learning occurs and how the acquired information consolidates and stabilizes in the brain. Evidence suggests that the prefrontal cortex (PFC) has a critical role in these processes; the division of labor between hemispheres, however, is less characterized. OBJECTIVE/HYPOTHESIS: The aim of the present study was to directly investigate the causal role of the right and left PFC in statistical learning and its consolidation. METHODS: Healthy, young adults were trained on a probabilistic sequence learning task. Anodal transcranial direct current stimulation (tDCS) over the right or left dorsolateral PFC (DLPFC) was applied during the training in order to modify learning-related cortical plasticity in the targeted brain regions by increasing neural excitability. Performance was tested during and immediately after the stimulation, 2-h and 24-h later. RESULTS: We found that the anodal tDCS over the right DLPFC led to enhanced learning performance both after the 2-h and 24-h retention periods, suggesting the causal role of this area in statistical learning. In contrast, we did not find any effect of left DLPFC stimulation on learning. CONCLUSIONS: These results highlight the role of the right fronto striatal network in statistical learning and its consolidation. PMID- 25499035 TI - Effects of subcallosal cingulate deep brain stimulation on negative self-bias in patients with treatment-resistant depression. AB - BACKGROUND: The cognitive neuropsychological model states that antidepressant treatment alters emotional biases early in treatment, and after this initial change in emotional processing, environmental and social interactions allow for long-term/sustained changes in mood and behavior. OBJECTIVE: Changes in negative self-bias after chronic subcallosal cingulate (SCC) deep brain stimulation (DBS) were investigated with the hypothesis that treatment would lead to changes in emotional biases followed by changes in symptom severity. METHODS: Patients (N = 7) with treatment-resistant depression were assessed at three time points: pre treatment; after one month stimulation; and after six months stimulation. The P1, P2, P3, and LPP (late positive potential) components of the event-related potential elicited by positive and negative trait adjectives were recorded in both a self-referential task and a general emotion recognition task. RESULTS: Results indicate that DBS reduced automatic attentional bias toward negative words early in treatment, as indexed by the P1 component, and controlled processing of negative words later in treatment, as indexed by the P3 component. Reduction in negative words endorsed as self-descriptive after six months DBS was associated with reduced depression severity after six months DBS. Change in emotional processing may be restricted to the self-referential task. CONCLUSIONS: Together, these results suggest that the cognitive neuropsychological model, developed to explain the time-course of monoamine antidepressant treatment, may also be used as a framework to interpret the antidepressant effects of SCC DBS. PMID- 25499038 TI - Cystic microfilarial infestation of the liver: a rare presentation. AB - Cystic liver lesions in an adult may occur for a variety of reasons, most of which are benign in nature. Infiltrating benign lesions in the liver parenchyma may pose a clinical challenge in diagnosis and management. In the case presented herein, a cystic lesion adjacent to the gall bladder and involving the liver parenchyma had to be differentiated from gall bladder carcinoma, which is quite common in India. Parasitic infestation of the liver is an extremely rare presentation and may pose a significant challenge in its diagnosis and management. This case highlights an infrequent presentation and the challenges in the clinical approach and subsequent management. PMID- 25499037 TI - Montage matters: the influence of transcranial alternating current stimulation on human physiological tremor. AB - BACKGROUND: Classically, studies adopting non-invasive transcranial electrical stimulation have placed greater importance on the position of the primary "stimulating" electrode than the secondary "reference" electrode. However, recent current density modeling suggests that ascribing a neutral role to the reference electrode may prove an inappropriate oversimplification. HYPOTHESIS: We set out to test the hypothesis that the behavioral effects of transcranial electrical stimulation are critically dependent on the position of the return ("reference") electrode. METHODS: We examined the effect of transcranial alternating current stimulation (sinusoidal waveform with no direct current offset at a peak-to-peak amplitude of 2000 MUA and a frequency matched to each participant's peak tremor frequency) on physiological tremor in a group of healthy volunteers (N = 12). We implemented a sham-controlled experimental protocol where the position of the stimulating electrode remained fixed, overlying primary motor cortex, whilst the position of the return electrode varied between two cephalic (fronto-orbital and contralateral primary motor cortex) and two extracephalic (ipsilateral and contralateral shoulder) locations. We additionally controlled for the role of phosphenes in influencing motor output by assessing the response of tremor to photic stimulation, through self-reported phosphene ratings. RESULTS: Altering only the position of the return electrode had a profound behavioral effect: only the montage with extracephalic return contralateral to the primary stimulating electrode significantly entrained physiological tremor (15.9% +/- 6.1% increase in phase stability, 1 S.E.M.). Photic stimulation also entrained tremor (11.7% +/ 5.1% increase in phase stability). Furthermore, the effects of electrical stimulation are distinct from those produced from direct phosphene induction, in that the latter were only seen with the fronto-orbital montage that did not affect the tremor. CONCLUSION: The behavioral effects of transcranial alternating current stimulation appear to be critically dependent on the position of the reference electrode, highlighting the importance of electrode montage when designing experimental and therapeutic protocols. PMID- 25499040 TI - Incidence and risk factors of linezolid-induced lactic acidosis. AB - BACKGROUND: The use of linezolid has increased with the emergence of multidrug resistant bacteria. Serum lactic acidosis has been reported as a serious side effect of linezolid use, therefore we evaluated the incidence and characteristics of linezolid-related lactic acidosis. METHODS: Patients admitted to an 860-bed university hospital were enrolled. The patients were divided into two groups, those who used linezolid and those who used teicoplanin (control group). The study was conducted by review of the medical charts. RESULTS: Seventy-two patients were included in the linezolid group. The control group comprised 72 patients matched to those in the linezolid group for age and indication for antibiotic use. Lactic acidosis occurred in five cases (6.8%) in the linezolid group. None of the patients who used teicoplanin developed lactic acidosis, which was a comparable result. The median change in anion gap in the linezolid group was -0.8 mmol/l (interquartile range (IQR) -3.55 to 1.28 mmol/l), which was significantly higher than in the teicoplanin group, 0.05 mmol/l (IQR -1.75 to 2.3 mmol/l) (p=0.026). The number of increased anion gap events in patients who used linezolid for more than 6 weeks was higher than in the group who used linezolid for less than 6 weeks (p=0.0014). However, no statistically significant difference was observed according to age, estimated glomerular filtration rate, or diabetes. CONCLUSIONS: Linezolid showed an association with treatment-related lactic acidosis. A longer duration of linezolid use (>6 weeks) was one of the risk factors for metabolic acidosis. We suggest checking serum lactate concentrations regularly, especially in those on long-term use. PMID- 25499041 TI - Impact of HIV-1, HIV-2, and HIV-1+2 dual infection on the outcome of tuberculosis. AB - BACKGROUND: HIV-1 infection has been shown to impact the outcome of patients with tuberculosis (TB), but data regarding the impact of HIV-2 on TB outcomes are limited. The aim of this study was to assess the impact of HIV types on mortality among TB patients in Guinea-Bissau and to examine the predictive ability of the TBscoreII, a clinical score used to assess disease severity. METHODS: In a prospective follow-up study, we examined the prevalence of HIV-1, HIV-2, and HIV 1+2 co-infection in TB patients in Guinea-Bissau, and the impact on outcomes at 12 months of follow-up. We included all adult TB patients in an observational TB cohort at the Bandim Health Project (BHP) in Guinea-Bissau between 2003 and 2013 and assessed survival status at 12 months after the start of treatment. RESULTS: A total 1312 patients were included; 499 (38%) were female (male/female ratio 1.6). Three hundred and seventy-nine patients were HIV-infected: 241 had HIV-1, 93 had HIV-2, and 45 were HIV-1+2 dual infected. The HIV type-associated risk of TB was 6-fold higher for HIV-1, 7-fold higher for HIV-1+2 dual infection, and 2 fold higher for HIV-2 compared with the HIV-uninfected. Of the patients included, 144 (11%) died, 62 (12%) among females and 82 (9%) among males (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.64-1.30; p=0.596). Compared to male patients, female patients were younger (1 year younger, 95% CI 0.5-2; p=0.04), reported a longer duration of symptoms (14 days longer, 95% CI 4-25; p=0.003), and had a higher TBscoreII (0.5 points more, 95% CI 0.3-0.7; p<0.001). More females than males were HIV-infected (36% vs. 25%; p<0.001) and more females had a body mass index (BMI) <15 kg/m(2) (11% vs. 6%; p<0.001) and a mid upper arm circumference (MUAC) <200 mm (13% vs. 7%; p < 0.001). HIV infection increased the mortality risk, with HIV-1 infection displaying the highest HR (5.0, 95% CI 3.5 7.1), followed by HIV-1+2 (HR 4.2, 95% CI 2.2-7.8) and HIV-2 (HR 2.1, 95% CI 1.2 3.8). A TBscoreII >=4 was associated with increased mortality (HR 2.2, 95% CI 1.5 3.1). Significantly increased HRs were found for signs of wasting; a BMI <18 kg/m(2) was associated with a HR of 1.8 (95% CI 1.3-2.6) and a MUAC <220 mm with a HR of 3.8 (95% CI 2.7-5.2). CONCLUSION: The HIV type-associated risk of TB was much higher for HIV-1 patients and higher but less so for HIV-2 patients, compared with the HIV-uninfected. Clinical severity at presentation was also higher for HIV-infected patients, although less so for HIV-2-infected patients, and all HIV-infected patients had a poorer outcome than the uninfected; mortality was 4-5-fold higher for HIV-1 and dually infected patients and two-fold higher for HIV-2-infected patients. These differences between HIV types did not disappear after adjusting for CD4 count. PMID- 25499039 TI - Prognosis of neonatal tetanus in the modern management era: an observational study in 107 Vietnamese infants. AB - OBJECTIVES: Most data regarding the prognosis in neonatal tetanus originate from regions where limited resources have historically impeded management. It is not known whether recent improvements in critical care facilities in many low- and middle-income countries have affected indicators of a poor prognosis in neonatal tetanus. We aimed to determine the factors associated with worse outcomes in a Vietnamese hospital with neonatal intensive care facilities. METHODS: Data were collected from 107 cases of neonatal tetanus. Clinical features on admission were analyzed against mortality and a combined endpoint of 'death or prolonged hospital stay'. RESULTS: Multivariable analysis showed that only younger age (odds ratio (OR) for mortality 0.69, 95% confidence interval (CI) 0.48-0.98) and lower weight (OR for mortality 0.06, 95% CI 0.01-0.54) were significantly associated with both the combined endpoint and death. A shorter period of onset (OR 0.94, 95% CI 0.88-0.99), raised white cell count (OR 1.17, 95% CI 1.02-1.35), and time between first symptom and admission (OR 3.77, 95% CI 1.14-12.51) were also indicators of mortality. CONCLUSIONS: Risk factors for a poor outcome in neonatal tetanus in a setting with critical care facilities include younger age, lower weight, delay in admission, and leukocytosis. PMID- 25499042 TI - Exploring HIV infection and susceptibility to measles among older children and adults in Malawi: a facility-based study. AB - BACKGROUND: HIV infection increases measles susceptibility in infants, but little is known about this relationship among older children and adults. We conducted a facility-based study to explore whether HIV status and/or CD4 count were associated with either measles seroprotection and/or measles antibody concentration. METHODS: A convenience sample was recruited comprising HIV infected patients presenting for follow-up care, and HIV-uninfected individuals presenting for HIV testing at Chiradzulu District Hospital, Malawi, from January to September 2012. We recorded age, sex, and reported measles vaccination and infection history. Blood samples were taken to determine the CD4 count and measles antibody concentration. RESULTS: One thousand nine hundred and thirty five participants were recruited (1434 HIV-infected and 501 HIV-uninfected). The majority of adults and approximately half the children were seroprotected against measles, with lower odds among HIV-infected children (adjusted odds ratio 0.27, 95% confidence interval 0.10-0.69; p=0.006), but not adults. Among HIV-infected participants, neither CD4 count (p=0.16) nor time on antiretroviral therapy (p=0.25) were associated with measles antibody concentration, while older age (p<0.001) and female sex (p<0.001) were independently associated with this measure. CONCLUSIONS: We found no evidence that HIV infection contributes to the risk of measles infection among adults, but HIV-infected children (including at ages older than previously reported), were less likely to be seroprotected in this sample. PMID- 25499043 TI - Salinomycin exerts anticancer effects on human breast carcinoma MCF-7 cancer stem cells via modulation of Hedgehog signaling. AB - Breast cancer tissue contains a small population of cells that have the ability to self-renew, these cells are known as breast cancer stem cells (BCSCs). The Hedgehog signal transduction pathway plays a central role in stem cell development, its aberrant activation has been shown to contribute to the development of breast cancer, making this pathway an attractive therapeutic target. Salinomycin (Sal) is a novel identified cancer stem cells (CSCs) killer, however, the molecular basis for its anticancer effects is not yet clear. In the current study, Sal's ability to modulate the activity of key elements in the Hedgehog pathway was examined in the human breast cancer cell line MCF-7, as well as in a subpopulation of cancer stem cells identified within this cancer cell line. We show here that Sal inhibits proliferation, invasion, and migration while also inducing apoptosis in MCF-7 cells. Interestingly, in a subpopulation of MCF 7 cells with the CD44(+)/CD24(-) markers and high ALDH1 levels indicative of BCSCs, modulators of Hedgehog signaling Smo and Gli1 were significantly down regulated upon treatment with Sal. These results demonstrate that Sal also inhibits proliferation and induces apoptosis of BCSCs, further establishing it as therapeutically relevant in the context of breast cancers and also indicating that modulation of Hedgehog signaling is one potential mechanism by which it exerts these anticancer effects. PMID- 25499044 TI - Negative symptoms and functioning during the first year after a recent onset of schizophrenia and 8 years later. AB - BACKGROUND: Understanding the longitudinal course of negative symptoms, especially in relationship to functioning, in the early phase of schizophrenia is crucial to developing intervention approaches. The course of negative symptoms and daily functioning was examined over a 1-year period following a recent onset of schizophrenia and at an 8-year follow-up point. METHODS: The study included 149 recent-onset schizophrenia patients who had a mean age of 23.7 (SD=4.4)years and mean education of 12.9 (SD=2.2)years. Negative symptom (BPRS and SANS) and functional outcome (SCORS) assessments were conducted frequently by trained raters. RESULTS: After antipsychotic medication stabilization, negative symptoms during the first outpatient year were moderately stable (BPRS ICC=0.64 and SANS ICC=0.66). Despite this overall moderate stability, 24% of patients experienced at least one period of negative symptoms exacerbation. Furthermore, entry level of negative symptoms was significantly associated with poor social functioning (r=-.34, p<.01) and work/school functioning (r=-.25, p<.05) at 12months, and with negative symptoms at the 8-year follow-up (r=.29, p<.05). DISCUSSION: Early negative symptoms are fairly stable during the first outpatient year, are predictors of daily functioning at 12months, and predict negative symptoms 8years later. Despite the high levels of stability, negative symptoms did fluctuate in a subsample of patients. These findings suggest that negative symptoms may be an important early course target for intervention aimed at promoting recovery. PMID- 25499045 TI - Metacognitive and social cognition approaches to understanding the impact of schizophrenia on social quality of life. AB - While some studies view metacognition and social cognition as representing the same phenomenon, others suggest that they represent distinctive sets of abilities that are related to different outcomes. The current study used a cross-sectional design that includes samples of persons with schizophrenia (N=39) and healthy individuals (N=60) to further explore the distinction between social cognition and metacognition and their associations with social quality of life. The Face Emotion Identification Task (FEIT), Faux-Pas Task, Indiana Psychiatric Illness Interview (IPII), Metacognition Assessment Scale - Abbreviated (MAS-A), and Social Quality of Life Scale were administrated to all participants. Correlations, t-tests and regressions were conducted. Results showed that persons with schizophrenia performed more poorly on all measures than healthy controls. Social cognition and metacognition measures were related for the combined total sample, but only a few associations were found among both sub-samples. A diagnosis of schizophrenia and metacognitive capacity, but not social cognition, predicted social quality of life. Self-reflectivity had a negative relationship to social quality of life while understanding of others' minds had a positive relation to social quality of life. The current study provides evidence that many with schizophrenia experience deficits in both social cognition and metacognition and that those deficits may be distinct and have different kinds of relationships with social quality of life. Clinical implications include the need to emphasize narrative aspects of psychotherapy in order to promote metacognition. PMID- 25499046 TI - Trauma and recent life events in individuals at ultra high risk for psychosis: review and meta-analysis. AB - BACKGROUND: Childhood trauma and recent life-events have been related to psychotic disorders. The aim of the present study was to examine whether childhood trauma and recent life-events are significantly more prevalent in patients at Ultra High Risk (UHR) of developing a psychotic disorder compared to healthy controls. METHOD: A search of PsychInfo and Embase was conducted, relevant papers were reviewed, and three random-effects meta-analyses were performed. One meta-analysis assessed the prevalence rate of childhood trauma in UHR subjects and two meta-analyses were conducted to compare UHR subjects and healthy control subjects on the experience of childhood trauma and recent life events. RESULTS: We found 12 studies on the prevalence of (childhood) trauma in UHR populations and 4 studies on recent life-events in UHR populations. We performed a meta-analysis on 6 studies (of which trauma prevalence rates were available) on childhood trauma in UHR populations, yielding a mean prevalence rate of 86.8% (95% CI 77%-93%). Childhood trauma was significantly more prevalent in UHR subjects compared to healthy control groups (Random effects Hedges' g=1.09; Z=4.60, p<.001). In contrast to our hypothesis, life-event rates were significantly lower in UHR subjects compared to healthy controls (Random effects Hedges' g=-0.53; Z=-2.36, p<.02). CONCLUSIONS: Our meta-analytic results illustrate that childhood trauma is highly prevalent among UHR subjects and that childhood trauma is related to UHR status. These results are in line with studies on childhood trauma in psychotic populations. In contrast to studies on recent life-events in psychotic populations, our results show that recent life-events are not associated with UHR status. PMID- 25499047 TI - Population genetic structure and Wolbachia infection in an endangered butterfly, Zizina emelina (Lepidoptera, Lycaenidae), in Japan. AB - Zizina emelina (de l'Orza) is listed on Japan's Red Data List as an endangered species because of loss of its principal food plant and habitat. We compared parts of the mitochondrial and nuclear genes of this species to investigate the level of genetic differentiation among the 14 extant populations. We also examined infection of the butterfly with the bacterium Wolbachia to clarify the bacterium's effects on the host population's genetic structure. Mitochondrial and nuclear DNA analyses revealed that haplotype composition differed significantly among most of the populations, and the fixation index F ST was positively correlated with geographic distance. In addition, we found three strains of Wolbachia, one of which was a male killer; these strains were prevalent in several populations. There was linkage between some host mitochondrial haplotypes and the three Wolbachia strains, although no significant differences were found in a comparison of host mitochondrial genetic diversity with nuclear genetic diversity in Wolbachia-infected or -uninfected populations. These genetic analyses and Wolbachia infection findings show that Z. emelina has little migratory activity and that little gene flow occurs among the current populations. PMID- 25499048 TI - Development of a standardized method for contouring the larynx and its substructures. AB - OBJECTIVES: Limiting radiation dose to the larynx can diminish effects of laryngeal dysfunction. However, no clear guidelines exist for defining the larynx and its substructures consistently on cross-sectional imaging. This study presents computed tomography (CT)- and magnetic resonance imaging (MRI)-based guidelines for contouring laryngeal organs-at-risk (OARs). MATERIALS AND METHODS: Standardized guidelines for delineating laryngeal OARs were devised and used to delineate on CT and MRI for head-and-neck cancer patients. Volumetric comparisons were performed to evaluate consistency and reproducibility of guideline-based contours. RESULTS: For the initial 5 patients the mean CT and MRI based larynx volume did not differ significantly between imaging modalities; 34.39 +/- 9.85 vs. 35.01 +/- 9.47 (p = .09). There was no statistical difference between the CT based mean laryngeal volume in the subsequent 44 patients compared to the initial 5 patients outlined on CT and the MRI scan (p = 0.53 and 0.62). The OAR volume for laryngeal substructures were not statistically different among patients or between imaging modalities. Once established, the guidelines were easy to follow. CONCLUSION: The guidelines developed provide a precise method for delineating laryngeal OARs. These guidelines need to be validated and clinical significance of outlining laryngeal substructures and dose-volume constraints should be investigated before routine implementation in clinic practice. PMID- 25499049 TI - Toxicity of sediment-bound pollutants in the Seine estuary, France, using a Eurytemora affinis larval bioassay. AB - Coastal urbanisation exposes surrounding estuarine environments to urban-related contaminants such as polycyclic aromatic hydrocarbons (PAHs), polychlorobiphenyls (PCBs) and pesticide mixtures. Hydrophobic contaminants can adsorb on estuarine sediments. They can subsequently be released on a massive scale in the aquatic environment due to artificial or natural phenomena (e.g. dredging, tides), thereby threatening living organisms. The contamination of sediment is a significant ecological issue in the Seine estuary, France. However, few relevant methods have been developed to assess sediment toxicity and its ecological impacts in a cost-effective way. In this context, we aimed to assess the toxicity of natural sediments from the Seine estuary on the development of the calanoid copepod Eurytemora affinis using a previously developed larval bioassay. This assay involves direct exposure of nauplii to elutriates of sediments for six days. Sediments were collected along the Seine estuary from six polluted sites and one reference site. Pollutants in this estuary included PAHs, PCBs and OCPs (organochlorine pesticides). Nauplius survival was significantly more affected by exposure to all contaminated sediment elutriates, than by exposure to sediment from Yville-sur-Seine (the reference site), whereas nauplius growth was significantly reduced after exposure to contaminated sediment elutriates from four of the six contaminated sites. We identified two distinct site clusters, one including both the sand-rich and the least polluted sediments (Oissel, Quillebeuf sur-Seine, Caudebec-en-Caux) and the other including both the clay- and silt rich, and the most polluted sediments (La Bouille, Poses, Pont de Normandie). As expected, survival was significantly more impacted after exposure to elutriates from the second cluster than from the first. This work enables (i) assessment of the toxicity of natural sediments in the Seine estuary and (ii) validation of the larval bioassay previously developed using sorbed sediment with model molecules. PMID- 25499050 TI - Characteristics of concentration-inhibition curves of individual chemicals and applicability of the concentration addition model for mixture toxicity prediction. AB - The concentration addition (CA) model has been widely applied to predict mixture toxicity. However, its applicability is difficult to evaluate due to the complexity of interactions among substances. Considering that the concentration response curve (CRC) of each component of the mixture is closely related to the prediction of mixture toxicity, mathematical treatments were used to derive a characteristic index kECx (k was the slope of the tangent line of a CRC at concentration ECx). The implication is that the CA model would be applicable for predicting the mixture toxicity only when chemical components have similar kECx in the whole or part of the concentration range. For five selected chemicals whose toxicity was detected using luminescent bacteria, sodium dodecyl benzene sulfonate (SDBS) showed much higher kECx values than the others and its existence in the binary mixtures brought about overestimation of the mixture toxicity with the CA model. The higher the mass ratio of SDBS in a multi-mixture was, the more the toxicity prediction deviated from measurements. By applying the method proposed in this study to analyze some published data, it is confirmed that some components having significantly different kECx values from the other components could explain the large deviation of the mixture toxicity predicted by the CA model. PMID- 25499051 TI - Earthworm populations of highly metal-contaminated soils restored by fly ash aided phytostabilisation. AB - Highly metal contaminated soils found in the North of France are the result of intense industrial past. These soils are now unfit for the cultivation of agricultural products for human consumption. Solutions have to be found to improve the quality of these soils, and especially to reduce the availability of trace elements (TEs). Phytostabilisation and ash-aided phytostabilisation applied since 2000 to an experimental site located near a former metallurgical site (Metaleurop-Nord) was shown previously as efficacious in reducing TEs mobility in soils. The aim of the study was to check whether this ten years trial had influenced earthworm communities. This experimental site was compared to plots located in the surroundings and differing by the use of soils. Main results are that: (1) whatever the use of soils, earthworm communities are composed of few species with moderate abundance in comparison with communities found in similar habitats outside the TEs-contaminated area, (2) the highest abundance and specific richness (4-5 species) were observed in afforested plots with various tree species, (3) ash amendments in afforested plots did not increase the species richness and modified the communities favoring anecic worms but disfavoring epigeic ones. These findings raised the questions of when and how to perform the addition of ashes firstly, to avoid negative effects on soil fauna and secondly, to keep positive effects on metal immobilization. PMID- 25499052 TI - Effect of selenium foliar spray on physiological and biochemical processes and chemical constituents of wheat under drought stress. AB - Selenium (Se) is considered an essential micronutrient for humans, animals and plants due to its physiological and antioxidative properties. The positive role of Se in attenuation of drastic effects of various environmental stresses in plants is, however, still unclear and need to be explored. The present study aimed at investigating the physiological and biochemical changes induced by Se foliar spray to improve the drought tolerance potential of wheat. Additionally, we also examined the effect of supplemental Se on uptake of nutrients using detection by ICP-OES. Foliar Se application significantly lowered osmotic potential (13%) that markedly improved turgor by 63%, enhanced transpiration rate (60%), improved accumulation of total soluble sugars (33%) and free amino acids (118%) and activity of antioxidant system which ultimately increased the grain yield by 24%. Supplemental Se also significantly increased Se contents (5.77ugg( 1)DW) and improved Fe (91%) and Na (16%) uptake, whereas it reduced Zn accumulation by 54% and did not affect Ca contents. The results supported our hypothesis that supplemental Se influences nutrients uptake and wheat yield through maintenance of turgor and gas exchange characteristics and enhancement in antioxidant system activity. PMID- 25499053 TI - CeO2 nanoparticles induce no changes in phenanthrene toxicity to the soil organisms Porcellionides pruinosus and Folsomia candida. AB - Cerium oxide nanoparticles (CeO2 NPs) are used as diesel fuel additives to catalyze oxidation. Phenanthrene is a major component of diesel exhaust particles and one of the most common pollutants in the environment. This study aimed at determining the effect of CeO2 NPs on the toxicity of phenanthrene in Lufa 2.2 standard soil for the isopod Porcellionides pruinosus and the springtail Folsomia candida. Toxicity tests were performed in the presence of CeO2 concentrations of 10, 100 or 1000mg Ce/kg dry soil and compared with results in the absence of CeO2 NPs. CeO2 NPs had no adverse effects on isopod survival and growth or springtail survival and reproduction. For the isopods, LC50s for the effect of phenanthrene ranged from 110 to 143mg/kg dry soil, and EC50s from 17.6 to 31.6mg/kg dry soil. For the springtails, LC50s ranged between 61.5 and 88.3mg/kg dry soil and EC50s from 52.2 to 76.7mg/kg dry soil. From this study it may be concluded that CeO2 NPs have a low toxicity and do not affect toxicity of phenanthrene to isopods and springtails. PMID- 25499054 TI - Major factors influencing cadmium uptake from the soil into wheat plants. AB - At present, soil quality standards for agriculture have not been improved for many years and are applied uniformly for a diverse variety of crops and different soil types, not fully considering the effects of soil properties on cadmium (Cd) uptake via soil-plant transfer. In this study, the characteristics of Cd transfer from soil to eight wheat varieties were investigated, and the results showed that Xiaoyan 22 was moderately sensitive to Cd. Upon growing Xiaoyan 22 in 18 different Chinese soils, we studied the major controlling factors of Cd transfer and constructed a bioaccumulation prediction model from the soil properties. The results showed that pH was the most important factor contributing to Cd uptake. After calibration for the eight wheat varieties, a continuous soil threshold model for wheat was derived for the species sensitive distribution based on food safety standards. PMID- 25499055 TI - Modelling the effect of fluctuating herbicide concentrations on algae growth. AB - Herbicide concentrations fluctuate widely in watercourses after crop applications and rain events. The level of concentrations in pulses can exceed the water chronic quality criteria. In the present study, we proposed modelling the effects of successive pulse exposure on algae. The deterministic model proposed is based on two parameters: (i) the typical growth rate of the algae, obtained by monitoring growth rates of several successive batch cultures in growth media, characterizing both the growth of the control and during the recovery periods; (ii) the growth rate of the algae exposed to pulses, determined from a dose response curve obtained with a standard toxicity test. We focused on the herbicide isoproturon and on the freshwater alga Scenedesmus vacuolatus, and we validated the model prediction based on effect measured during five sequential pulse exposures in laboratory. The comparison between the laboratory and the modelled effects illustrated that the results yielded were consistent, making the model suitable for effect prediction of the herbicide photosystem II inhibitor isoproturon on the alga S. vacuolatus. More generally, modelling showed that both pulse duration and level of concentration play a crucial role. The application of the model to a real case demonstrated that both the highest peaks and the low peaks with a long duration affect principally the cell density inhibition of the alga S. vacuolatus. It is therefore essential to detect these characteristic pulses when monitoring of herbicide concentrations are conducted in rivers. PMID- 25499056 TI - The impact of value-directed remembering on the own-race bias. AB - Learners demonstrate superior recognition of faces of their own race or ethnicity, compared to faces of other races or ethnicities; a finding termed the own-race bias. Accounts of the own-race bias differ on whether the effect reflects acquired expertise with own-race faces or enhanced motivation to individuate own-race faces. Learners have previously been motivated to demonstrate increased recall for highly important items through a value-based paradigm, in which item importance is designated using high (vs. low) point values. Learners receive point values by correctly recalling the corresponding items at test, and are given the goal of achieving a high total point score. In two experiments we examined whether a value-based paradigm can motivate learners to differentiate between other-race faces, reducing or eliminating the own-race bias. In Experiment 1, participants studied own- and other-race faces paired with high or low point values. High point values (12-point) indicated that face was highly important to learn, whereas low point values (1-point) indicated that face was less important to learn. Participants demonstrated increased recognition for high-value own-race (but not other-race) faces, suggesting that motivation alone is not enough to reduce the own-race bias. In Experiment 2, we examined whether participants could use value to enhance recognition when permitted to self-pace their study. Recognition did not differ between high-value own- and other-race faces, reducing the own-race bias. Such data suggest that motivation can influence the own-race bias when participants can control encoding. PMID- 25499057 TI - Highly reflective reasoners show no signs of belief inhibition. AB - The processes underlying individual differences in reasoning performance are not entirely understood. What do people who do well on reasoning tasks where beliefs and logic conflict do differently from other people? Because abundant evidence shows that even poorer reasoners detect these conflicts, it has been suggested that individual differences in reasoning performance arise from inhibition failures later in the reasoning process. The present paper argues that a minority of highly skilled reasoners may deviate from this general reasoning process from an early stage. Two studies investigated signs of belief inhibition using a lexical access paradigm (Study 1) and a negative priming paradigm (Study 2). Study 1 showed that while other people exhibited signs of belief inhibition following a belief-logic conflict, people with the highest disposition for cognitive reflection did not. In Study 2, this finding was replicated and similar results were also obtained when comparing groups with higher and lower general cognitive ability. Two possible explanations are discussed. The reasoners with a highly reflective cognitive style or high general cognitive ability may have engaged and inhibited belief processing but if so, they may have been exceptionally efficient at recovering from it, wherefore no belief inhibition effects were found. An alternative account is that these reasoners started Type 2 processing directly, without first engaging in and then inhibiting belief-based processing. Under either explanation, the results indicate that individual differences in reasoning may partly arise from differences that occur early in the reasoning process. PMID- 25499059 TI - [Viral etiology of acute childhood respiratory infections in Bangui, Central African Republic]. PMID- 25499058 TI - Prevalence, Determinants, and Clinical Significance of Masked Hypertension in a Population-Based Sample of African Americans: The Jackson Heart Study. AB - BACKGROUND: The disproportionate rates of cardiovascular disease in African Americans may, in part, be due to suboptimal assessment of blood pressure (BP) with clinic BP measurements alone. To date, however, the prevalence of masked hypertension in African Americans has not been fully delineated. The purpose of this study was to evaluate masked hypertension prevalence in a large population based sample of African Americans and examine its determinants and association with indices of target organ damage (TOD). METHODS: Clinic and 24-hour ambulatory BP monitoring were conducted in 972 African Americans enrolled in the Jackson Heart Study. Common carotid artery intima-media thickness, left ventricular mass index, and the urinary albumin:creatinine excretion ratio were evaluated as indices of TOD. RESULTS: Masked hypertension prevalence was 25.9% in the overall sample and 34.4% in participants with normal clinic BP. All indices of TOD were significantly higher in masked hypertensives compared to sustained normotensives and were similar between masked hypertensives and sustained hypertensives. Male gender, smoking, diabetes, and antihypertensive medication use were independent determinants of masked hypertension in multivariate analyses. CONCLUSIONS: In this population-based cohort of African Americans, approximately one-third of participants with presumably normal clinic BP had masked hypertension when BP was assessed in their daily environment. Masked hypertension was accompanied by a greater degree of TOD in this cohort. PMID- 25499060 TI - Evaluation of co-solvent fraction, pressure and temperature effects in analytical and preparative supercritical fluid chromatography. AB - A chemometric approach is used for studying the combined effect of temperature, pressure and co-solvent fraction in analytical and preparative supercritical fluid chromatography (SFC). More specifically, by utilizing design of experiments coupled with careful measurements of the experimental conditions the interaction between pressure, temperature and co-solvent fraction was studied with respect to productivity, selectivity and retention in chiral SFC. A tris-(3,5 dimethylphenyl) carbamoyl cellulose stationary phase with carbon dioxide/methanol as mobile phase and the two racemic analytes trans-stilbene oxide (TSO) and 1,1' bi-2-naphthol (BINOL) were investigated. It was found for the investigated model system that the co-solvent fraction and pressure were the parameters that most affected the retention factors and that the co-solvent fraction and column temperature were most important for controlling the selectivity. The productivity in the preparative mode of SFC was most influenced by the co-solvent fraction and temperature. Both high co-solvent fraction and temperature gave maximum productivity in the studied design space. PMID- 25499061 TI - Comprehensive analytical strategy for biomonitoring of pesticides in urine by liquid chromatography-orbitrap high resolution masss pectrometry. AB - In this study we propose an analytical strategy that combines a target approach for the quantitative analysis of contemporary pesticide metabolites with a comprehensive post-target screening for the identification of biomarkers of exposure to environmental contaminants in urine using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). The quantitative method for the target analysis of 29 urinary metabolites of organophosphate (OP) insecticides, synthetic pyrethroids, herbicides and fungicides was validated after a previous statistical optimization of the main factors governing the ion source ionization and a fragmentation study using the high energy collision dissociation (HCD) cell. The full scan accurate mass data were acquired with a resolving power of 50,000 FWHM (scan speed, 2 Hz), in both ESI+ and ESI- modes, and with and without HCD-fragmentation. The method - LOQ was lower than 3.2 MUg L 1 for the majority of the analytes. For post-target screening a customized theoretical database was built, for the identification of 60 metabolites including pesticides, PAHs, phenols, and other metabolites of environmental pollutants. For identification purposes, accurate exact mass with less than 5 ppm, and diagnostic ions including isotopes and/or fragments were used. The analytical strategy was applied to 20 urine sample collected from children living in Valencia Region. Eleven target metabolites were detected with concentrations ranging from 1.18 to 131 MUg L-1. Likewise, several compounds were tentatively identified in the post-target analysis belonging to the families of phthalates, phenols and parabenes. The proposed strategy is suitable for the determination of target pesticide biomarkers in urine in the framework of biomonitoring studies, and appropriate for the identification of other non-target metabolites. PMID- 25499062 TI - Savings from switching to bevacizumab for retinal disorders are underestimated. PMID- 25499063 TI - Probe-based confocal laser endomicroscopy in the pancreatic duct provides direct visualization of ductal structures and aids in clinical management. AB - BACKGROUND: Confocal endomicroscopy provides real-time evaluation of various sites and has been used to provide detailed endomicroscopic imaging of the biliary tree. We aimed to evaluate the feasibility and utility of probe-based confocal laser endomicroscopy of the pancreatic duct as compared to cytologic and histologic results in patients with indeterminate pancreatic duct strictures. METHODS: Retrospective data on patients with indeterminate pancreatic strictures undergoing endoscopic retrograde cholangiopancreatography (ERCP) and confocal endomicroscopy were collected from two tertiary care centres. Real-time confocal endomicroscopy images were obtained during ERCP and immediate interpretation according to the Miami Classification was performed. RESULTS: 18 patients underwent confocal endomicroscopy for evaluation of pancreatic strictures from July 2011 to December 2012. Mean pancreatic duct size was 4.2mm (range 2.2-8mm). Eight cases were interpreted as benign, 4 as malignant, 4 suggestive of intraductal papillary mucinous neoplasms, and 2 appeared normal. Cytology/histopathology for 15/16 cases showed similar results to confocal endomicroscopy interpretation. Kappa coefficient of agreement between cyto/histopathology and confocal endomicroscopy was 0.8 (p=0.0001). Pancreatic confocal endomicroscopy changed management in four patients, changing the type of surgery from total pancreatectomy to whipple. CONCLUSIONS: Confocal endomicroscopy is effective in assisting with diagnosis of indeterminate pancreatic duct strictures as well as mapping of abnormal pancreatic ducts prior to surgery. PMID- 25499064 TI - Impact of social media on gastroenterologists in the United States. PMID- 25499065 TI - The role of parent psychological flexibility in relation to adolescent chronic pain: further instrument development. AB - Parental responses to their child's pain are associated with the young person's functioning. Psychological flexibility--defined as the capacity to persist with or change behavior, depending on one's values and the current situation, while recognizing cognitive and noncognitive influences on behavior--may provide a basis for further investigating the role of these responses. The Parent Psychological Flexibility Questionnaire (PPFQ) is a promising but preliminary measure of this construct. Parents of 332 young people with pain (301 mothers, 99 fathers, 68 dyads) completed the PPFQ during appointments in a pediatric pain clinic. Initial item screening eliminated 6 of the 31 items. Mothers' and fathers' data were then subjected to separate principal components analyses with oblique rotation, resulting in a 4-factor solution including 17 items, with subscales suggesting Values-Based Action, Pain Acceptance, Emotional Acceptance, and Pain Willingness. The PPFQ correlated significantly with adolescent-rated pain acceptance, functional disability, and depression. Differences were observed between mothers' and fathers' PPFQ scores, in particular, those related to school absence and fears of physical injury. The 17-item PPFQ appears reasonable for research and clinical use and may potentially identify areas for intervention with parents of young people with chronic pain. PERSPECTIVE: Parent psychological flexibility, as measured by the PPFQ, appears relevant to functioning, depression, and pain acceptance in adolescents with chronic pain. This model may help tie parental responses to adolescent distress and disability and may help clarify the development and maintenance of disability within the context of chronic pain. PMID- 25499066 TI - Toxicological assessment of multi-walled carbon nanotubes on A549 human lung epithelial cells. AB - An in vitro model resembling the respiratory epithelium was used to investigate the biological response to laboratory-made pristine and functionalised multi walled carbon nanotubes (pMWCNT and MWCNT-COOH). Cell uptake was analysed by MWCNT-COOH, FITC labelled and the effect of internalisation was evaluated on the endocytic apparatus, mitochondrial compartment and DNA integrity. In the dose range 12.5-100MUgml(-1), cytotoxicity and ROS generation were assayed, evaluating the role of iron (the catalyst used in MWCNTs synthesis). We observed a correlation between MWCNTs uptake and lysosomal dysfunction and an inverse relationship between these two parameters and cell viability (P<0.01). In particular, pristine-MWCNT caused a time- and dose-dependent ROS increase and higher levels of lipid hydroperoxides compared to the controls. Mitochondrial impairment was observed. Conversely to the functionalised MWCNT, higher micronuclei (MNi) frequency was detected in mono- and binucleate pMWCNT-treated cells, underlining an aneugenic effect due to mechanical damage. Based on the physical and chemical features of MWCNTs, several toxicological pathways could be activated in respiratory epithelium upon their inhalation. The biological impacts of nano-needles were imputable to their efficient and very fast uptake and to the resulting mechanical damages in cell compartments. Lysosomal dysfunction was able to trigger further toxic effects. PMID- 25499067 TI - Diosmin induces genotoxicity and apoptosis in DU145 prostate cancer cell line. AB - Plant-derived dietary polyphenolic compounds, such as flavonoids, with cancer cell-specific pro-apoptotic activity and chemopreventive potential are thought to be promising anticancer agents. In the present study, we were interested in determining if flavonoid-induced genotoxicity may also provoke cancer cell death. Cyto- and genotoxicity of three selected flavonoid glycosides (naringin, diosmin and hesperidin) in DU145 prostate cancer cell line were investigated. Flavonoid glycosides decreased cancer cell number and proliferative activity in a different manner. Flavonoid glycosides induced oxidative stress: intracellular total ROS and superoxide production were augmented after flavonoid treatment. Flavonoid glycosides stimulated DNA double strand breaks (DSBs) and micronuclei production. Diosmin was found the most potent genotoxic agent in DU145 cells, which, in turn, resulted in its pro-apoptotic activity. The more robust recruitment of 53BP1 was correlated with lower DNA and chromosomal damage after naringin and hesperidin treatment compared with diosmin treatment. Flavonoid glycosides were also found to be DNA hypomethylating agents with an ability to modulate cancer cell epigenome leading to changes in the gene expression patterns. Taken together, diosmin, a dietary flavonoid glycoside, was found active against DU145 cells by promoting genotoxic events and a concomitant apoptotic cell death. Thus, a comprehensive analysis of biological activity of diosmin against cancer cells both in vitro and in vivo deserves further investigation. PMID- 25499072 TI - Participation in ball sports may represent a prehabilitation strategy to prevent future stress fractures and promote bone health in young athletes. AB - Sports participation has many benefits for the young athlete, including improved bone health. However, a subset of athletes may attain suboptimal bone health and be at increased risk for stress fractures. This risk is greater for female than for male athletes. In healthy children, high-impact physical activity has been shown to improve bone health during growth and development. We offer our perspective on the importance of promoting high-impact, multidirectional loading activities, including ball sports, as a method of enhancing bone quality and fracture prevention based on collective research. Ball sports have been associated with greater bone mineral density and enhanced bone geometric properties compared with participation in repetitive, low-impact sports such as distance running or nonimpact sports such as swimming. Runners and infantry who participated in ball sports during childhood were at decreased risk of future stress fractures. Gender-specific differences, including the coexistence of female athlete triad, may negate the benefits of previous ball sports on fracture prevention. Ball sports involve multidirectional loading with high ground reaction forces that may result in stiffer and more fracture-resistant bones. Encouraging young athletes to participate in ball sports may optimize bone health in the setting of adequate nutrition and in female athletes, eumenorrhea. Future research to determine timing, frequency, and type of loading activity could result in a primary prevention program for stress fracture injuries and improved life-long bone health. PMID- 25499068 TI - Immune-related conditions and acute leukemia in children with Down syndrome: a Children's Oncology Group report. AB - BACKGROUND: Children with Down syndrome have unique immune profiles and increased leukemia susceptibility. METHODS: Mothers of 158 children with Down syndrome diagnosed with acute leukemia at 0 to 19 years in 1997 to 2002 and 173 children with Down syndrome but no leukemia were interviewed. Associations were evaluated via multivariable unconditional logistic regression. RESULTS: No associations were detected for asthma, eczema, allergies, or hypothyroidism. Diabetes mellitus associated with leukemia (OR = 9.23; 95% confidence interval 2.33-36.59); however, most instances occurred concurrent with or after the leukemia diagnosis. CONCLUSIONS AND IMPACT: Children with Down syndrome who develop leukemia have increased diabetes risk, likely due to treatment and underlying susceptibility factors. PMID- 25499073 TI - Measuring the burden of treatment. PMID- 25499074 TI - Identification of seizure onset zone and preictal state based on characteristics of high frequency oscillations. AB - OBJECTIVE: We investigate the relevance of high frequency oscillations (HFO) for biomarkers of epileptogenic tissue and indicators of preictal state before complex partial seizures in humans. METHODS: We introduce a novel automated HFO detection method based on the amplitude and features of the HFO events. We examined intracranial recordings from 33 patients and compared HFO rates and characteristics between channels within and outside the seizure onset zone (SOZ). We analyzed changes of HFO activity from interictal to preictal and to ictal periods. RESULTS: The average HFO rate is higher for SOZ channels compared to non SOZ channels during all periods. Amplitudes and durations of HFO are higher for events within the SOZ in all periods compared to non-SOZ events, while their frequency is lower. All analyzed HFO features increase for the ictal period. CONCLUSIONS: HFO may occur in all channels but their rate is significantly higher within SOZ and HFO characteristics differ from HFO outside the SOZ, but the effect size of difference is small. SIGNIFICANCE: The present results show that based on accumulated dataset it is possible to distinguish HFO features different for SOZ and non-SOZ channels, and to show changes in HFO characteristics during the transition from interictal to preictal and to ictal periods. PMID- 25499075 TI - Complete genome sequence of Lactobacillus helveticus H9, a probiotic strain originated from kurut. AB - Lactobacillus helveticus H9 is a probiotic strain that is able to produce antihypertensive peptides during milk fermentation. Its genome has a circular 1.87Mb chromosome. Comparative genomic analysis revealed that the component of proteinases, peptide transport systems and peptidases in L. helveticus appeared to be strain-specific. Such information may help us to understand how the proteolytic system is related to its probiotic properties. PMID- 25499076 TI - N-glycoprofiling analysis in a simple glycoprotein model: a comparison between recombinant and pituitary glycosylated human prolactin. AB - Human prolactin (hPRL) is a polypeptide hormone occurring in the non-glycosylated (NG-hPRL) and glycosylated (G-hPRL) forms, with MM of approximately 23 and 25kDa, respectively. It has a single, partially occupied N-glycosylation site located at Asn-31, which makes it a particularly simple and interesting model for glycosylation studies. The bioactivity of G-hPRL is lower than that of NG-hPRL (by ca. 4-fold) and its physiological function is not clear. However, carbohydrate moieties generally play important roles in the biosynthesis, secretion, biological activity, and plasma survival of glycohormones and can vary depending on the host cell. The main objective of this study was to determine the N-glycan structures present in native, pituitary G-hPRL and compare them with those present in the recombinant hormone. To obtain recombinant G-hPRL, genetically modified Chinese hamster ovary cells (CHO), adapted to growth in suspension, were treated with cycloheximide, thus increasing the glycosylation site occupancy from 5.5% to 38.3%, thereby facilitating G-hPRL purification. CHO cell-derived G-hPRL (CHO-G-hPRL) was compared to pituitary G-hPRL (pit-G-hPRL) especially with regard to N-glycoprofiling. Among the main differences found in the pituitary sample were an extremely low presence of sialylated (1.7%) and a high percentage of sulfated (74.0%) and of fucosylated (90.5%) glycans. A ~6-fold lower in vitro bioactivity and a higher clearance rate in mice were also found for pit-G-hPRL versus CHO-G-hPRL. N-Glycan profiling proved to be a useful and accurate methodology also for MM and carbohydrate content determination for the two G-hPRL preparations, in good agreement with the values obtained directly via MALDI-TOF-MS. PMID- 25499077 TI - Benzoate-induced stress enhances xylitol yield in aerobic fed-batch culture of Candida mogii TISTR 5892. AB - Production of the natural sweetener xylitol from xylose via the yeast Candida mogii TISTR 5892 was compared with and without the growth inhibitor sodium benzoate in the culture medium. Sodium benzoate proved to be an uncompetitive inhibitor in relatively poorly oxygenated shake flask aerobic cultures. In a better controlled aerobic environment of a bioreactor, the role of sodium benzoate could equally well be described as competitive, uncompetitive or noncompetitive inhibitor of growth. In intermittent fed-batch fermentations under highly aerobic conditions, the presence of sodium benzoate at 0.15gL(-1) clearly enhanced the xylitol titer relative to the control culture without the sodium benzoate. The final xylitol concentration and the average xylitol yield on xylose were nearly 50gL(-1) and 0.57gg(-1), respectively, in the presence of sodium benzoate. Both these values were substantially higher than reported for the same fermentation under microaerobic conditions. Therefore, a fed-batch aerobic fermentation in the presence of sodium benzoate is promising for xylitol production using C. mogii. PMID- 25499078 TI - Dosimetric comparison of two arc-based stereotactic body radiotherapy techniques for early-stage lung cancer. AB - To compare the dosimetric and delivery characteristics of two arc-based stereotactic body radiotherapy (SBRT) techniques for early-stage lung cancer treatment. SBRT treatment plans for lung tumors of different sizes and locations were designed using a single-isocenter multisegment dynamic conformal arc technique (SiMs-arc) and a volumetric modulated arc therapy technique (RapidArc) for 5 representative patients treated previously with lung SBRT. The SiMs-arc plans were generated with the isocenter located in the geometric center of patient's axial plane (which allows for collision-free gantry rotation around the patient) and 6 contiguous 60 degrees arc segments spanning from 1 degrees to 359 degrees . 2 RapidArc plans, one using the same arc geometry as the SiMs-arc and the other using typical partial arcs (210 degrees ) with the isocenter inside planning target volume (PTV), were generated for each corresponding SiMs-arc plan. All plans were generated using the Varian Eclipse treatment planning system (V10.0) and were normalized with PTV V100 to 95%. PTV coverage, dose to organs at risk, and total monitor units (MUs) were then compared and analyzed. For PTV coverage, the RapidArc plans generally produced higher PTV D99 (by 1.0% to 3.3%) and higher minimum dose (by 2.7% to 12.7%), better PTV conformality index (by 1% to 8%), and less volume of 50% dose outside 2cm from PTV (by 0 to 20.8cm(3)) than the corresponding SiMs-arc plans. For normal tissues, no significant dose differences were observed for the lungs, trachea, chest wall, and heart; RapidArc using partial arcs produced lowest maximum dose to spinal cord. For dose delivery, the RapidArc plans typically required 50% to 90% more MUs than SiMs-arc plans to deliver the same prescribed dose. The additional intensity modulation afforded by variable gantry speed and dose rate and by overlapping arcs enabled RapidArc plans to produce dosimetrically improved plans for lung SBRT, but required more MUs (by a factor > 1.5) to deliver. The dosimetric improvements, most notably in PTV minimum dose and in dose conformality for irregularly shaped PTVs, may outweigh the increased MUs in using RapidArc. For small and peripherally located tumors, SiMs-arc produces comparable dosimetric quality and could be more efficient in both treatment planning and dose delivery. PMID- 25499079 TI - Pancreatic cancer stem cells: new insight into a stubborn disease. AB - Resistance to conventional therapy and early distant metastasis contribute to the unsatisfactory prognosis of patients with pancreatic cancer. The concept of cancer stem cells (CSCs) brings new insights into cancer biology and therapy. Many studies have confirmed the important role of these stem cells in carcinogenesis and the development of hematopoietic and solid cancers. Recent studies have shown that CSCs regulate aggressive behavior, recurrence, and drug resistance in pancreatic cancer. Here, we review recent advances in pancreatic cancer stem cells (PCSCs) research. Particular attention is paid to the regulation mechanisms of pancreatic cancer stem cell functions, such as stemness related signaling pathways, microRNAs, the epithelial-mesenchymal transition (EMT), and the tumor microenvironment, and the development of novel PCSCs targeted therapy. We seek to further understand PCSCs and explore potential therapeutic targets for pancreatic cancer. PMID- 25499080 TI - Mutations of p53 and KRAS activate NF-kappaB to promote chemoresistance and tumorigenesis via dysregulation of cell cycle and suppression of apoptosis in lung cancer cells. AB - Although mutations of p53 and KRAS and activation of NF-kappaB signaling have been highly associated with chemoresistance and tumorigenesis of lung cancer, the interactive mechanisms between two of p53, KRAS, and NF-kappaB are elusive. In the present study, we first observed that blocking of NF-kappaB function in KRAS mutant A549 cell line with an IkappaBalpha mutant (IkappaBalphaM) inhibited cell cycle progression, anti-apoptosis, chemoresistance, and tumorigenesis. Silencing of p53 or KRAS in A549 or H358 cells either enhanced or attenuated the resistance of cells to cisplatin and taxol through promotion or suppression of the NF-kappaB p65 nuclear translocation. Introduction of a wild type p53 into p53 null lung cancer cell lines H1299 and H358 inhibited NF-kappaB activity, leading to the enhanced response to chemotherapeutic drugs. Delivery of a mutant p53 or KRAS-V12 into A549/IkappaBalphaM or H1299/p53Wt cells increased cell cycle progression, anti-apoptosis, chemoresistance, and tumorigenesis due to the accumulated nuclear localization of NF-kappaB p65, while treatment of H1299/p53Wt/KRAS-V12 with NF kappaB inhibitor PS1145 diminished these effects. Thus, we conclude that p53 deficiency and KRAS mutation activate the NF-kappaB signaling to control chemoresistance and tumorigenesis, and that the status of p53 and KRAS may be considered for the targeted therapy against NF-kappaB in lung cancer patients. PMID- 25499081 TI - RNA over-editing of BLCAP contributes to hepatocarcinogenesis identified by whole genome and transcriptome sequencing. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, although the treatment of this disease has changed little in recent decades because most of the genetic events that initiate this disease remain unknown. To better understand HCC pathogenesis at the molecular level and to uncover novel tumor-initiating events, we integrated RNA-seq and DNA-seq data derived from two pairs of HCC tissues. We found that BLCAP is novel editing gene in HCC and has over-editing expression in 40.1% HCCs compared to adjacent liver tissues. We then used RNA interference and gene transfection to assess the roles of BLCAP RNA editing in tumor proliferation. Our results showed that compared to the wild-type BLCAP gene, the RNA-edited BLCAP gene may stably promote cell proliferation (including cell growth, colony formation in vitro, and tumorigenicity in vivo) by enhancing the phosphorylation of AKT, mTOR, and MDM2 and inhibiting the phosphorylation of TP53. Our current results suggest that the RNA over-editing of BLCAP gene may serve as a novel potential driver in advanced HCC through activating AKT/mTOR signal pathway. PMID- 25499082 TI - Deubiquitinase OTUD5 mediates the sequential activation of PDCD5 and p53 in response to genotoxic stress. AB - Programmed cell death 5 (PDCD5) positively regulates p53-mediated apoptosis and rapidly accumulates upon DNA damage. However, the underlying mechanism of PDCD5 upregulation during the DNA damage response remains unknown. Here, we found that OTU deubiquitinase 5 (OTUD5) was bound to PDCD5 in response to etoposide treatment and increased the stability of PDCD5 by mediating deubiquitination of PDCD5 at Lys-97/98. Overexpression of OTUD5 efficiently enhanced the activation of both PDCD5 and p53. Conversely, PDCD5 knockdown greatly attenuated the effect of OTUD5 on p53 activation. In addition, when OTUD5 was depleted, PDCD5 failed to facilitate p53 activation, demonstrating an essential role for the PDCD5-OTUD5 network in p53 activation. Importantly, we found that OTUD5-dependent PDCD5 stabilization was required for sequential activation of p53 in response to genotoxic stress. The sequential activation of PDCD5 and p53 was abrogated by knockdown of OTUD5. Finally, impairment of the genotoxic stress response upon PDCD5 ablation was substantially rescued by reintroducing PDCD5(WT) but not PDCD5(E94D) (defective for OTUD5 interaction) or PDCD5(E16D) (defective for p53 interaction). Together, our findings have uncovered an apoptotic signaling cascade linking PDCD5, OTUD5, and p53 during genotoxic stress responses. PMID- 25499084 TI - Short-term effects of backpack carriage on plantar pressure and gait in schoolchildren. AB - PURPOSE: To assess the effects of backpack carriage on plantar pressure distributions and spatio-temporal gait parameters among children. PARTICIPANTS: Two hundred-eighteen schoolchildren, aged 6-13, and attending primary and secondary schools in the city of Cagliari (Italy). METHODS: Participants were tested at school, during regular days. A pressure plate and wearable inertial sensors were used to measure plantar pressures and spatio-temporal parameters of gait. Measures were obtained during both quiet standing and walking, and both with and without a backpack. The latter contained those items a child had on the testing day. RESULTS: Participants carried a mean mass in their backpacks of 5.2 kg, and more than half had a backpack/body mass ratio higher than 15%. While spatio-temporal gait parameters were not affected by backpack carriage, significant increases (up to 25%) in plantar pressures were found during both static standing and walking, especially in the forefoot. CONCLUSION: Under realistic conditions, the impact of backpack carriage was more evident on foot ground interaction than on gait features. However, long-term consequences of altered plantar pressure need to be assessed in future work, considering the actual durations typically spent carrying school items. PMID- 25499083 TI - Phlebovirus and Leishmania detection in sandflies from eastern Thrace and northern Cyprus. AB - BACKGROUND: Phlebotomine sandflies are vectors of several pathogens with significant impact for public health. This study was conducted to investigate and characterize phlebovirus and Leishmania infections in vector sandflies collected in the eastern Thrace region in Turkey and Northern Cyprus, where previous data indicate activity of these agents. METHODS: Field sampling of sandflies was performed at 4 locations in Edirne and Tekirdag provinces of eastern Thrace and at 17 locations in Lefkosa, Girne, Magosa and Guzelyurt provinces of northern Cyprus. In sandfly pools, phlebovirus RNA and Leishmania DNA were screened via a generic polymerase chain reaction (PCR) and kinetoplast minicircle PCR, respectively. Selected sandfly specimens unsuitable for pathogen detection were identified to species level. Cytochrome oxidase 1 gene region was used for DNA barcoding of selected specimens and pathogen positive pools. Positive amplicons were cloned and characterized by sequencing. RESULTS: A total of 2690 sandflies, collected from Eastern Thrace (15.4%) and Northern Cyprus (84.6%) were evaluated. Morphological examination of 780 specimens from Cyprus exhibited Phlebotomus perfiliewi sensu lato (72.6%), Phlebotomus tobbi (19.7%), Phlebotomus papatasi (2.8%), Laroussius sp. (1.6%) and Sergentomyia azizi (1.6%), Sergentomyia sp. (0.9%), Sergentomyia minuta (0.5%) and Phleobotomus jacusieli (0.1%) species. Pathogen screening was performed in 1910 specimens distributed in 195 pools. In eight pools of P.tobbi sandflies collected in Cyprus, Leishmania infantum DNA was demonstrated. Toscana virus (TOSV) genotype A sequences were identified in two pools of P. perfiliewi s.l. and one pool of P.tobbi sandflies from Cyprus. Co infection of TOSV and Leishmania infantum was characterized in a P.tobbi pool. Sequences belonging to novel phleboviruses are revealed in three P. perfiliewi s.l. pools. One sequence, provisionally named Edirne virus, identified in Edirne province in eastern Thrace, demonstrated the highest rate of genomic similarity to Adria and Salehabad viruses. Furthermore, Girne 1 and Girne 2 viruses, identified in Girne province, revealed similarities to TOSV and Sandfly Fever Sicilian virus and related strains, respectively. CONCLUSIONS: Activity of TOSV genotype A strains in Cyprus and co-infection of sandfly vectors with L. infantum was documented for the first time. Novel phlebovirus strains of unknown medical significance was identified in sampling regions. PMID- 25499085 TI - Comparison of Fourier and wavelet analysis for fatigue assessment during repetitive dynamic exertion. AB - The comparative ability of the Fourier transform (FFT) and discrete wavelet transform (DWT) algorithms in assessing muscle fatigue during sub-maximal repetitive dynamic exertion was investigated in this study. Surface electromyography data recorded from the upper trapezius muscle during forty minutes of repetitive upper extremity exertion performed by 10 male participants were used in the analysis. Multi-model regression analysis was performed to study the trend in the power values of the different frequency bands estimated using the FFT and DWT algorithms. Less variability and higher statistical significance was observed for the power value trend computed using the DWT algorithm compared to the FFT algorithm. The regression models provided a better fit for the power values estimated under more fatigued condition compared to the less fatigued condition. The lower frequency bands of 23-46 Hz and 46-93 Hz exhibited the expected and consistent power trend independent of the algorithm (DWT or FFT) used. For the exertions tested in this study, a cubic or curvilinear model explained the fatigue development process with a higher precision than the linear models. PMID- 25499086 TI - The effect of individual factors on health behaviors among college students: the mediating effects of eHealth literacy. AB - BACKGROUND: College students' health behavior is a topic that deserves attention. Individual factors and eHealth literacy may affect an individual's health behaviors. The integrative model of eHealth use (IMeHU) provides a parsimonious account of the connections among the digital divide, health care disparities, and the unequal distribution and use of communication technologies. However, few studies have explored the associations among individual factors, eHealth literacy, and health behaviors, and IMeHU has not been empirically investigated. OBJECTIVE: This study examines the associations among individual factors, eHealth literacy, and health behaviors using IMeHU. METHODS: The Health Behavior Scale is a 12-item instrument developed to measure college students' eating, exercise, and sleep behaviors. The eHealth Literacy Scale is a 12-item instrument designed to measure college students' functional, interactive, and critical eHealth literacy. A nationally representative sample of 525 valid college students in Taiwan was surveyed. A questionnaire was administered to collect background information about participants' health status, degree of health concern, major, and the frequency with which they engaged in health-related discussions. This study used Amos 6.0 to conduct a confirmatory factor analysis to identify the best measurement models for the eHealth Literacy Scale and the Health Behavior Scale. We then conducted a multiple regression analysis to examine the associations among individual factors, eHealth literacy, and health behaviors. Additionally, causal steps approach was used to explore indirect (mediating) effects and Sobel tests were used to test the significance of the mediating effects. RESULTS: The study found that perceptions of better health status (t520=2.14-6.12, P<.001-.03) and greater concern for health (t520=2.58-6.95, P<.001-.003) influenced college students' development of 3 dimensions of eHealth literacy and adoption of healthy eating, exercise, and sleep behaviors. Moreover, eHealth literacy played an intermediary role in the association between individual factors and health behaviors (Sobel test=2.09-2.72, P<.001-.03). Specifically, higher levels of critical eHealth literacy promoted students' health status and their practice of multiple positive health behaviors, including eating, exercise, and sleep behaviors. CONCLUSIONS: Because this study showed that eHealth literacy mediates the association between individual factors and health behaviors, schools should aim to enhance students' eHealth literacy and promote their health behaviors to help them achieve high levels of critical eHealth literacy. Although some of the study's hypotheses were not supported in this study, the factors that influence health behaviors are complex and interdependent. Therefore, a follow-up study should be conducted to further explore how these factors influence one another. PMID- 25499088 TI - Concentrations of anti-Mullerian hormone in the domestic cat. Relation with spay or neuter status and serum estradiol. AB - Female cats with unknown history can be diagnosed as spayed or intact with a GnRH stimulation test or an LH test independent of the stage in the estrous cycle. However, although most females are correctly diagnosed with the LH test, the sensitivity and specificity are not 100%. The GnRH-stimulation test, although reliable, requires an injection of buserelin 2 hours before the blood sample is collected. Granulosa cells are the only cell type that produces anti-Mullerian hormone (AMH) in females, whereas Sertoli cells produce AMH in males. Anti Mullerian hormone has been linked to spay status in dogs and cats and to ovarian and testicular pathology and fertility in different species. Our aim was to evaluate serum AMH concentrations in spayed female cats and in intact female cats of known age and reproductive stage (inactive ovaries or luteal phase). In addition, our aim was to compare serum AMH concentrations in intact and neutered male cats. We analyzed serum AMH concentrations in 15 spayed and 16 intact females and in 15 intact and 12 neutered male cats. Serum AMH was below the lowest standard point (<0.14 ng/mL) in all spayed females and neutered males, ranged between 1.3 and 19.0 ng/mL in the intact females and between 4.8 and 81.3 ng/mL in intact males. Thus, the AMH test had 100% sensitivity and specificity to diagnose the presence or absence of ovaries and testes in this study. In addition, in contrast to serum estradiol, serum AMH was not affected by buserelin stimulation (P = 0.459). Serum AMH was not correlated with serum estradiol before (rs = -0.188, P = 0.519) or after (rs = 0.335, P = 0.242) buserelin stimulation in the intact females. Four 6-month-old intact cats (two females and two males) had the highest AMH concentrations which in the females might represent a prepubertal peak previously described in other species and in males is likely due to high concentrations before puberty. In conclusion, we found that the AMH Gen II ELISA is reliable for diagnosing spay and neuter status of cats and that the domestic cat might be an interesting model for studies on AMH dynamics. PMID- 25499087 TI - Novel mutations support a role for Profilin 1 in the pathogenesis of ALS. AB - Mutations in the gene encoding profilin 1 (PFN1) have recently been shown to cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. We sequenced the PFN1 gene in a cohort of ALS patients (n = 485) and detected 2 novel variants (A20T and Q139L), as well as 4 cases with the previously identified E117G rare variant (~ 1.2%). A case-control meta-analysis of all published E117G ALS+/- frontotemporal dementia cases including those identified in this report was significant p = 0.001, odds ratio = 3.26 (95% confidence interval, 1.6-6.7), demonstrating this variant to be a susceptibility allele. Postmortem tissue from available patients displayed classic TAR DNA-binding protein 43 pathology. In both transient transfections and in fibroblasts from a patient with the A20T change, we showed that this novel PFN1 mutation causes protein aggregation and the formation of insoluble high molecular weight species which is a hallmark of ALS pathology. Our findings show that PFN1 is a rare cause of ALS and adds further weight to the underlying genetic heterogeneity of this disease. PMID- 25499089 TI - Post-thawing quality and incubation resilience of cryopreserved ram spermatozoa are affected by antioxidant supplementation and choice of extender. AB - The performance of cryopreserved semen in ovine artificial insemination still needs improvement. Some antioxidants have been tested, with variable success. We cryopreserved semen from Churra rams using TES-Tris-fructose with 4% glycerol and 10% egg yolk (EY) or 3.5% soybean lecithin (SL), with 1 mM of reduced glutathione (GSH), Trolox, crocin, or cysteamine. Samples were analyzed after thawing and incubation (6 hours, 38 degrees C) for motility (computer-assisted sperm analysis [CASA]), viability, acrosomal integrity, apoptosis, mitochondrial activity, chromatin status, and lipoperoxidation (malondialdehyde production). Interactions (antioxidant/extender/incubation) were significant for most variables. Extenders yielded similar results, although SL depressed mitochondrial activity and linearity (P < 0.001), it improved motility (P < 0.05), DNA fragmentation (P < 0.05), and acrosomal damage (P < 0.001). The control, GSH, and Trolox showed greater viability with SL (P < 0.01). Cysteamine depressed motility (0 hours: 51.6 +/- 2.0% vs. 32.3 +/- 4.3%; 6 hours: no motility vs. 32.5 +/- 1.9%; P < 0.001), but improved viability when using EY (P = 0.004). Crocin increased acrosomal damage (P = 0.022) but improved linearity-related parameters after thawing (P = 0.014). Trolox considerably reduced malondialdehyde production in both extenders (8.6 +/- 0.4 nmol per 10(8) cells vs. 14.2 +/- 0.3 in EY and 20 +/- 0.6 in SL; P < 0.001). Interestingly, thiol antioxidants (cysteamine and GSH) increased DNA fragmentation (percentage of DNA fragmentation index), whereas crocin reduced it (P < 0.05). Interactions between extender and antioxidant must be taken into account for improving sperm cryopreservation. Soybean lecithin seems to be a suitable replacement for EY, but its effect on mitochondria must be investigated. Trolox and crocin might be useful for ram semen freezing. PMID- 25499091 TI - Part II--Management of pediatric post-traumatic headaches. AB - BACKGROUND: Post-traumatic headache is one of the most common symptoms occurring after mild traumatic brain injury in children. METHODS: This is an expert opinion based two-part review on pediatric post-traumatic headaches. In part II, we focus on the medical management of post-traumatic headaches. There are no randomized controlled trials evaluating the efficacy of therapies specifically for pediatric post-traumatic headaches. Thus, the algorithm we propose has been extrapolated from the primary headache literature and small noncontrolled trials of post traumatic headache. RESULTS: Most post-traumatic headaches are migraine or tension type, and standard medications for these headache types are used. A multifaceted approach is needed to address all the possible causes of headache and any comorbid conditions that may delay recovery or alter treatment choices. For acute treatment, nonsteroidal anti-inflammatories can be used. If the headaches have migrainous features and nonsteroidal anti-inflammatories are not effective, triptans may be beneficial. Opioids are not indicated. Medication overuse should be avoided. For preventive treatments, some reports indicate that amitriptyline, gabapentin, or topiramate may be beneficial. Amitriptyline is a good choice because it can be used to treat both migraine and tension-type headaches. Nerve blocks, nutraceuticals (e.g. melatonin), and behavioral therapies may also be useful, and lifestyle factors, especially adequate sleep hygiene and strategies to cope with anxiety, should be emphasized. CONCLUSIONS: Improved treatment of acute post-traumatic headache may reduce the likelihood of developing chronic headaches, which can be especially problematic to effectively manage and can be functionally debilitating. PMID- 25499090 TI - Evolution and gene capture in ancient endogenous retroviruses - insights from the crocodilian genomes. AB - BACKGROUND: Crocodilians are thought to be hosts to a diverse and divergent complement of endogenous retroviruses (ERVs) but a comprehensive investigation is yet to be performed. The recent sequencing of three crocodilian genomes provides an opportunity for a more detailed and accurate representation of the ERV diversity that is present in these species. Here we investigate the diversity, distribution and evolution of ERVs from the genomes of three key crocodilian species, and outline the key processes driving crocodilian ERV proliferation and evolution. RESULTS: ERVs and ERV related sequences make up less than 2% of crocodilian genomes. We recovered and described 45 ERV groups within the three crocodilian genomes, many of which are species specific. We have also revealed a new class of ERV, ERV4, which appears to be common to crocodilians and turtles, and currently has no characterised exogenous counterpart. For the first time, we formally describe the characteristics of this ERV class and its classification relative to other recognised ERV and retroviral classes. This class shares some sequence similarity and sequence characteristics with ERV3, although it is phylogenetically distinct from the other ERV classes. We have also identified two instances of gene capture by crocodilian ERVs, one of which, the capture of a host KIT-ligand mRNA has occurred without the loss of an ERV domain. CONCLUSIONS: This study indicates that crocodilian ERVs comprise a wide variety of lineages, many of which appear to reflect ancient infections. In particular, ERV4 appears to have a limited host range, with current data suggesting that it is confined to crocodilians and some lineages of turtles. Also of interest are two ERV groups that demonstrate evidence of host gene capture. This study provides a framework to facilitate further studies into non-mammalian vertebrates and highlights the need for further studies into such species. PMID- 25499092 TI - A review of episodic and chronic pediatric headaches of brief duration. AB - BACKGROUND: Headaches that last less than an hour in duration are uncommon, except for atypical migraine, and without a practitioner's appropriate knowledge, may result in misdiagnosis. Although most of these headaches are classified as primary headache syndromes, some have secondary etiologies such as structural lesions. METHODS: This pediatric-specific review updates these headache syndromes. Included are atypical migraine, the trigeminal autonomic cephalgias, idiopathic stabbing headache, cranial neuralgias, occipital neuralgia, thunderclap headache, nummular headache, the red ear syndrome, and the numb tongue syndrome. CONCLUSION: Knowledge of the clinical characteristics of these headache patterns in children allows physicians to quickly establish the headache diagnosis and develop the optimal treatment plan. PMID- 25499093 TI - Pilot validation of the tuberous sclerosis-associated neuropsychiatric disorders (TAND) checklist. AB - BACKGROUND: Tuberous sclerosis complex is a multisystem disorder that includes a range of tuberous sclerosis-associated neuropsychiatric disorders (TAND). The lifetime prevalence rates of TAND are very high; yet surveys suggest that the majority of individuals with tuberous sclerosis never receive appropriate assessment or treatment for TAND. To aid systematic enquiry, a TAND Checklist was developed. Here, we performed pilot validation of the TAND Checklist. METHOD: Mixed methods were used across two stages. In stage 1, we gathered feedback on the Checklist from tuberous sclerosis "expert professionals" and "expert parents and caregivers." The aim was to examine face and content validity. Stage 2 involved the administration of the refined TAND Checklist to 20 parents of individuals with tuberous sclerosis concurrently with four widely used validated rating scales, to examine external validity and obtain qualitative feedback on face-to-face administration of the TAND Checklist. RESULTS: Twenty professionals and 62 parents and caregivers from 28 countries participated in the pilot. The TAND Checklist demonstrated good face and content validity with high overall mean and median scores. Qualitative analysis highlighted concerns about the likely use of the TAND Checklist, suggesting that family members and individuals with tuberous sclerosis should drive usage. Stage 2 results showed moderate-to-very good external validity across TAND domain and key subdomains. Internal consistency of domains and subdomains was acceptable to very good. Ninety-three percent of all participants (93%) reported four or more lifetime TAND behavioral difficulties. CONCLUSION: The pilot validation suggested that the TAND Checklist could provide a useful screening tool in clinical settings. PMID- 25499094 TI - [Thyroid surgery applicable in developing countries]. AB - Thyroid surgery in developing countries is performed by general surgeons with limited diagnostic and therapeutic resources. The aim of this review is to describe the indications for and appropriate type of surgery according to the diseases observed. Endemic goiter (grade 1 and 2) usually regresses with iodine therapy. Surgery is indicated only for its complications: mechanical, neoplastic, or related to hyperthyroidism. The choice of operation depends on the specific disease and also on the likelihood that thyroxine will be continuously available for the patient's lifetime. Total thyroidectomy should be avoided whenever possible if thyroxine supplies are unreliable. Hemithyroidectomy and subtotal thyroidectomy are the techniques that should be used in priority. PMID- 25499095 TI - Fasting serum CGRP levels are related to calcium concentrations, but cannot be elevated by short-term calcium/vitamin D supplementation. AB - Calcitonin gene-related peptide (CGRP) is an important cardioprotective neuropeptide. Few studies have shown that calcium supplementation may increase CGRP levels transiently. However, the relationship between CGRP and calcium is poorly known. This study was to explore the correlation between serum calcium and CGRP in coronary artery disease (CAD), and observe whether short-term calcium/vitamin D supplementation would increase fasting serum CGRP. A randomized, placebo-controlled and double-blind clinical trial, and a supplementary study for further analysis of the correlations were conducted. The results showed that the correlation between serum calcium and CGRP was positive in CAD without myocardial infarction (MI) (r = 0.487, P = 0.029), but negative in acute and healing MI (r = -0.382, P = 0.003). Moreover, we found a positive correlation between lg (amino-terminal pro-B-type natriuretic peptide, NT-proBNP) and CGRP (r = 0.312, P = 0.027), but a negative correlation between lg (NT proBNP) and serum calcium (r = -0.316, P = 0.025) in acute and healing MI. As to the clinical trial, participants subjected to CAD but without evolving or acute MI, together with blood calcium <= 2.4 mmol/L, were randomized into three groups. Among the groups of placebo, caltrate (600 mg elemental calcium; 125 IU vitamin D3, per tablet) 1 tablet/d and caltrate 2 tablets/d, there were no significant differences in baseline characteristics. After short-term (5 days) treatments, the results indicated that the effect of grouping was not statistically significant (P = 0.915). In conclusion, the correlations between serum calcium and CGRP in different types of CAD are inconsistent, and the main reason may be associated with elevated natriuretic peptides after acute MI. Further, our study shows that short-term calcium/vitamin D supplementation cannot significantly increase fasting serum CGRP levels. PMID- 25499097 TI - Clinical trials: what a waste. PMID- 25499096 TI - Early high protein intake is associated with low mortality and energy overfeeding with high mortality in non-septic mechanically ventilated critically ill patients. AB - INTRODUCTION: Early protein and energy feeding in critically ill patients is heavily debated and early protein feeding hardly studied. METHODS: A prospective database with mixed medical-surgical critically ill patients with prolonged mechanical ventilation (>72 hours) and measured energy expenditure was used in this study. Logistic regression analysis was used to analyse the relation between admission day-4 protein intake group (with cutoffs 0.8, 1.0, and 1.2 g/kg), energy overfeeding (ratio energy intake/measured energy expenditure > 1.1), and admission diagnosis of sepsis with hospital mortality after adjustment for APACHE II (Acute Physiology and Chronic Health Evaluation II) score. RESULTS: A total of 843 patients were included. Of these, 117 had sepsis. Of the 736 non-septic patients 307 were overfed. Mean day-4 protein intake was 1.0 g/kg pre-admission weight per day and hospital mortality was 36%. In the total cohort, day-4 protein intake group (odds ratio (OR) 0.85; 95% confidence interval (CI) 0.73 to 0.99; P = 0.047), energy overfeeding (OR 1.62; 95%CI 1.07 to 2.44; P = 0.022), and sepsis (OR 1.77; 95%CI 1.18 to 2.65; P = 0.005) were independent risk factors for mortality besides APACHE II score. In patients with sepsis or energy overfeeding, day-4 protein intake was not associated with mortality. For non-septic, non overfed patients (n = 419), mortality decreased with higher protein intake group: 37% for < 0.8 g/kg, 35% for 0.8 to 1.0 g/kg, 27% for 1.0 to 1.2 g/kg, and 19% for >= 1.2 g/kg (P = 0.033). For these, a protein intake level of >= 1.2 g/kg was significantly associated with lower mortality (OR 0.42, 95%CI 0.21 to 0.83, P = 0.013). CONCLUSIONS: In non-septic critically ill patients, early high protein intake was associated with lower mortality and early energy overfeeding with higher mortality. In septic patients early high protein intake had no beneficial effect on mortality. PMID- 25499098 TI - Integration of community home based care programmes within national primary health care revitalisation strategies in Ethiopia, Malawi, South-Africa and Zambia: a comparative assessment. AB - BACKGROUND: In 2008, the WHO facilitated the primary health care (PHC) revitalisation agenda. The purpose was to strengthen African health systems in order to address communicable and non-communicable diseases. Our aim was to assess the position of civil society-led community home based care programmes (CHBC), which serve the needs of patients with HIV, within this agenda. We examined how their roles and place in health systems evolved, and the prospects for these programmes in national policies and strategies to revitalise PHC, as new health care demands arise. METHODS: The study was conducted in Ethiopia, Malawi, South Africa and Zambia and used an historical, comparative research design. We used purposive sampling in the selection of countries and case studies of CHBC programmes. Qualitative methods included semi-structured interviews, focus group discussions, service observation and community mapping exercises. Quantitative methods included questionnaire surveys. RESULTS: The capacity of PHC services increased rapidly in the mid-to-late 2000s via CHBC programme facilitation of community mobilisation and participation in primary care services and the exceptional investments for HIV/AIDS. CHBC programmes diversified their services in response to the changing health and social care needs of patients on lifelong anti-retroviral therapy and there is a general trend to extend service delivery beyond HIV-infected patients. We observed similarities in the way the governments of South Africa, Malawi and Zambia are integrating CHBC programmes into PHC by making PHC facilities the focal point for management and state-paid community health workers responsible for the supervision of community-based activities. Contextual differences were found between Ethiopia, South Africa, Malawi and Zambia, whereby the policy direction of the latter two countries is to have in place structures and mechanisms that actively connect health and social welfare interventions from governmental and non-governmental actors. CONCLUSIONS: Countries may differ in the means to integrate and co-ordinate government and civil society agencies but the net result is expanded PHC capacity. In a context of changing health care demands, CHBC programmes are a vital mechanism for the delivery of primary health and social welfare services. PMID- 25499099 TI - Novel single nucleotide polymorphism in CYP2C9 is associated with changes in warfarin clearance and CYP2C9 expression levels in African Americans. AB - Warfarin is a widely used anticoagulant whose active S-enantiomer is primarily metabolized by the CYP2C9 enzyme. The CYP2C9*2 and CYP2C9*3 alleles are associated with lower warfarin dose requirement and decreased enzyme activity. In contrast, we previously identified a novel single-nucleotide polymorphism (SNP) (rs7089580A > T) in CYP2C9 that is associated with higher warfarin dose requirement in African Americans (AAs). In this study, we examine the effect of rs7089580 on warfarin pharmacokinetics and CYP2C9 expression in 63 AA patients and 32 AA liver tissues, respectively. We found oral clearance of S-warfarin to be higher among carriers of the minor rs7089580 allele (T) compared with wild type homozygotes (3.73 +/- 1.46 vs 2.95 +/- 1.39 mL/min; P = 0.04). CYP2C9 messenger RNA expression in liver tissue was also higher among A/T and T/T genotypes compared with A/A (P < 0.02). Our findings indicate that rs7089580 is associated with higher S-warfarin clearance and CYP2C9 expression and may help explain the higher dose requirement of warfarin in AAs. Furthermore, rs7089580 is in complete linkage disequilibrium with the promoter SNP rs12251841 in AAs, which may provide a biologically plausible explanation for the observed effect on CYP2C9 expression levels. Given the many clinically relevant substrates of CYP2C9, identifying polymorphisms that affect expression levels and metabolism across ethnicities is essential for individualization of doses with a narrow therapeutic index. PMID- 25499100 TI - Signal molecule changes in the gills and lungs of the African lungfish Protopterus annectens, during the maintenance and arousal phases of aestivation. AB - African lungfishes are obligate air breathers, with reduced gills and pulmonary breathing throughout their life. During the dry season they aestivate on land, with the collapse of secondary lamellae of their gills and the establishment of an exclusive aerial ventilation through the vascularization and expansion of their lungs. To date, the mechanisms underlining the respiratory organ remodeling in aestivating lungfishes are unknown. This study aimed to identify key switch components of the stress-induced signal transduction networks implicated in both rapid and medium-long term remodeling of the gills and lungs of the African lungfish Protopterus annectens during aestivation. Through immunofluorescence microscopy and Western blotting, the localization and the expression of nitric oxide synthase (NOS), Akt, Hsp-90 and HIF-1alpha were evaluated in both gills and lungs exposed to three experimental conditions: freshwater (FW), 6 months of experimentally induced aestivation (6mAe), and 6 days after arousal from 6 months of aestivation (6mAe6d). After 6mAe, the expression of NOS (p-eNOS antibody), Akt (p-Akt antibody), and Hsp-90 decreased in the gills, while NOS and Hsp-90 expression increased with Akt remained unchanged in the lungs. Upon 6mAe6d, NOS, Akt and Hsp-90 expression in the gills returned to the respective FW values. In the lungs of the aroused fish, NOS and Akt decreased to their respective FW levels, while Hsp-90 expression was enhanced with respect to aestivation. In both respiratory organs, the qualitative and quantitative patterns of HIF-1alpha expression correlated inversely to those of NOS. Overall, our findings suggest that the molecular components of the NOS/NO system changed in a tissue-specific manner in parallel with organ readjustment in the gills and lungs of P. annectens during aestivation and arousal. PMID- 25499102 TI - Cardiac mMCP-4+ mast cell expansion and elevation of IL-6, and CCR1/3 and CXCR2 signaling chemokines in an adjuvant-free mouse model of tree nut allergy. AB - BACKGROUND: Nut allergy is a growing and potentially fatal public health problem. We have previously reported a novel mouse model of near-fatal hazelnut (HN) allergy that involves transdermal sensitization followed by oral elicitation of allergic reactions. Here we studied the cardiac mast cell and cardiac tissue responses during oral nut induced allergic reaction in this mouse model. METHODS: Groups of mice were sensitized with HN and specific and total IgE were measured by ELISA. Oral allergic reaction was quantified by rectal thermometry and plasma mouse mast cell protease (mMCP)-1 by ELISA. Cardiovascular functions were determined by a non-invasive tail cuff method. Mucosal mast cells (MMC) and intestinal connective tissue MC (CTMC) were studied by immunohistochemistry (IHC) for mMCP-1 and mMCP-4 protein expression respectively. Cardiac MC were studied by toluidine blue (TB) as well as by the above IHC methods. Cytokines and chemokines in the tissues were quantified by a multiplex protein array method. RESULTS: Oral allergen challenge (OAC) of transdermal sensitized mice results in hypothermia, hypotension, tachycardia and rapid elevation of circulating mMCP-1. The IHC analysis of small intestine found significant expansion of mMCP-1+ MMCs and mMCP 4+ CTMCs. The TB analysis of cardiac tissues showed degranulation of majority of cardiac MCs. The IHC analysis of cardiac tissues showed very little mMCP-1 expression, but marked mMCP-4 expression. Furthermore, repeated OAC resulted in significant expansion of mMCP-4+ cardiac MCs in both the pericardium and the myocardium. Protein array analysis revealed significant elevation of cardiac IL-6 and CCR1/3 and CXCR2 signaling chemokines upon oral elicitation compared to sensitization alone. CONCLUSION: These results demonstrate that: (i) besides the intestine, cardiac mast cells and the cardiac tissue respond during oral nut induced allergic reaction; and (ii) repeated oral elicitation of reaction is associated with cardiac mMCP-4+ mast cell expansion and elevation of cardiac IL 6, and CCR1/3 and CXCR2 signaling chemokines. PMID- 25499103 TI - Light-induced oxidation and isomerization of all-trans-beta-cryptoxanthin in a model system. AB - The oxidation and isomerization of all-trans-beta-cryptoxanthin as affected by iodine-catalysed illumination and non-iodine-catalysed illumination were studied. Seven cis-isomers and two oxidation products were separated by HPLC method using a C30 column. The identification and structural elucidation of the compounds were determined by HPLC-DAD-APCI-MS. Five compounds were identified in details for the first time, namely, beta-beta-carotene-3-one, 5,6-epoxy-beta-beta-carotene-3-one, 13,15-di-cis-, 9,13-di-cis- and 9,9'-di-cis-beta-cryptoxanthin. Sum of 13- and 13'-cis-beta-cryptoxanthin was the major cis-isomer of beta-cryptoxanthin formed, accounting for 59.0% and 30.6%, respectively. The formation of di-cis isomers may prefer in the present of iodine. 13,15-di-cis-beta-cryptoxanthin was the major di cis-isomer of the iodine-catalysed photo-isomerization. PMID- 25499104 TI - Polyethyleneimine anchored copper(II) complexes: synthesis, characterization, in vitro DNA binding studies and cytotoxicity studies. AB - The water soluble polyethyleneimine-copper(II) complexes, [Cu(phen)(L tyr)BPEI]ClO4 (where phen=1,10-phenanthroline, L-tyr=L-tyrosine and BPEI=branched polyethyleneimine) with various degree of copper(II) complex units in the polymer chain were synthesized and characterized by elemental analysis and electronic, FT IR, EPR spectroscopic techniques. The binding of these complexes with CT-DNA was studied using UV-visible absorption titration, thermal denaturation, emission, circular dichroism spectroscopy and cyclic voltammetric methods. The changes observed in the physicochemcial properties indicated that the binding between the polymer-copper complexes and DNA was mostly through electrostatic mode of binding. Among these complexes, the polymer-copper(II) complex with the highest degrees of copper(II) complex units (higher degrees of coordination) showed higher binding constant than those with lower copper(II) complex units (lower degrees of coordination) complexes. The complex with the highest number of metal centre bound strongly due to the cooperative binding effect. Therefore, anticancer study was carried out using this complex. The cytotoxic activity for this complex on MCF-7 breast cancer cell line was determined adopting MTT assay, acridine orange/ethidium bromide (AO/EB) staining and comet assay techniques, which revealed that the cells were committed to specific mode of cell death either apoptosis or necrosis. PMID- 25499101 TI - Circadian rhythms, alcohol and gut interactions. AB - The circadian clock establishes rhythms throughout the body with an approximately 24 hour period that affect expression of hundreds of genes. Epidemiological data reveal chronic circadian misalignment, common in our society, significantly increases the risk for a myriad of diseases, including cardiovascular disease, diabetes, cancer, infertility and gastrointestinal disease. Disruption of intestinal barrier function, also known as gut leakiness, is especially important in alcoholic liver disease (ALD). Several studies have shown that alcohol causes ALD in only a 20-30% subset of alcoholics. Thus, a better understanding is needed of why only a subset of alcoholics develops ALD. Compelling evidence shows that increased gut leakiness to microbial products and especially LPS play a critical role in the pathogenesis of ALD. Clock and other circadian clock genes have been shown to regulate lipid transport, motility and other gut functions. We hypothesized that one possible mechanism for alcohol-induced intestinal hyperpermeability is through disruption of central or peripheral (intestinal) circadian regulation. In support of this hypothesis, our recent data shows that disruption of circadian rhythms makes the gut more susceptible to injury. Our in vitro data show that alcohol stimulates increased Clock and Per2 circadian clock proteins and that siRNA knockdown of these proteins prevents alcohol-induced permeability. We also show that intestinal Cyp2e1-mediated oxidative stress is required for alcohol-induced upregulation of Clock and Per2 and intestinal hyperpermeability. Our mouse model of chronic alcohol feeding shows that circadian disruption through genetics (in Clock(?19) mice) or environmental disruption by weekly 12h phase shifting results in gut leakiness alone and exacerbates alcohol-induced gut leakiness and liver pathology. Our data in human alcoholics show they exhibit abnormal melatonin profiles characteristic of circadian disruption. Taken together our data support circadian mechanisms for alcohol-induced gut leakiness that could provide new therapeutic targets for ALD. PMID- 25499105 TI - Evaluation of an interactive science publishing tool: toward enabling three dimensional analysis of medical images. AB - RATIONALE AND OBJECTIVES: Higher resolution medical imaging platforms are rapidly emerging, but there is a challenge in applying these tools in a clinically meaningful way. The purpose of the current study was to evaluate a novel three dimensional (3D) software imaging environment, known as interactive science publishing (ISP), in appraising 3D computed tomography images and to compare this approach with traditional planar (2D) imaging in a series of lung cancer cases. MATERIALS AND METHODS: Twenty-four physician volunteers at different levels of training across multiple specialties were recruited to evaluate eight lung cancer related clinical vignettes. The volunteers were asked to compare the performance of traditional 2D versus the ISP 3D imaging in assessing different visualization environments for diagnostic and measurement processes and to further evaluate the ISP tool in terms of general satisfaction, usability, and probable applicability. RESULTS: Volunteers were satisfied with both imaging methods; however, the 3D environment had significantly higher ratings. Measurement performance was comparable using both traditional 2D and 3D image evaluation. Physicians not trained in 2D measurement approaches versus those with such training demonstrated better performance with ISP and preferred working in the ISP environment. CONCLUSIONS: Recent postgraduates with only modest self-administered training performed equally well on 3D and 2D cases. This suggests that the 3D environment has no reduction in accuracy over the conventional 2D approach, while providing the advantage of a digital environment for cross-disciplinary interaction for shared problem solving. Exploration of more effective, efficient, self-directed training could potentially result in further improvement in image evaluation proficiency and potentially decrease training costs. PMID- 25499106 TI - [20 years guidelines and evidence based medicine in Germany: has evidence based medicine arrived in health care?]. PMID- 25499107 TI - [Reflections on 20 years of clinical practice guideline programmes in Germany: what is their impact?]. AB - Following a recommendation of the National Advisory Council for the Concerted Action in Health Care, the Association of the Scientific Medical Societies (AWMF) have promoted, supported and coordinated the development of clinical practice guidelines in Germany since 1995. The allocation of the responsibility for guideline development in the scientific societies corresponded to the principle of subsidiarity, in contrast to other countries counting on government-organised guideline programmes. To fulfil internationally consented criteria of high quality guidelines, a quality improvement system was established relying on frequent assessments of the current state. Today, high-quality clinical practice guidelines developed by the scientific societies organised under the umbrella of the AWMF are an indispensable tool for various initiatives to improve healthcare in the German healthcare system. The next challenging goal is to establish a theory-driven framework allowing for a systematic implementation and evaluation of guidelines in Germany on the basis of existing approaches. However, success in this endeavour will require further research and funding. PMID- 25499108 TI - [Experiences with synopses of clinical guidelines using the example of synopses for Disease Management Programmes (DMP)]. AB - Guideline synopses, i.e. the systematic synthesis of clinical practice guidelines, are used as a basis for Disease Management Programmes (DMPs) in Germany. One of the responsibilities of the German Institute for Quality and Efficiency in Health Care (IQWiG) is the preparation of guideline synopses for DMPs. The article describes the experiences with this methodology. METHODS: For the preparation of guideline synopses, a systematic search for evidence-based guidelines is conducted, and their recommendations are extracted and synthesised. In parallel, the quality of the guidelines is assessed using the AGREE instrument. The need for updating or supplementing a DMP is justified by means of the Grade of Recommendation (GoR) or, alternatively, the Level of Evidence (LoE). EXPERIENCES: Since 2006 IQWiG has synthesised recommendations from 256 evidence based guidelines in 12 guideline synopses for DMPs. The results are then used by the Federal Joint Committee (G-BA) to update DMPs. Using the example of the 12 synopses, several analyses were conducted. It was determined that a search for guidelines in guideline databases is sufficient and that a search in bibliographic databases can be dispensed with. Furthermore, the analyses showed that a large proportion of recommendations in evidence-based guidelines are not clearly linked to a GoR or LoE. If GoR and LoE are provided, only about 42% of recommendations with a strong GoR also refer to a strong LoE. It was also shown that only 21 % of the analysed guideline providers supplied information on the handling of unpublished data. With consistent average to high values, the assessment of the methodological quality across all of the prepared synopses allows for the conclusion of a basically acceptable guideline quality, but with a need for improvement. OUTLOOK: A guideline synopsis is an established tool for identifying health care standards as a basis for developing and updating DMPs. Further methodological development, particularly in collaboration with guideline providers, appears to be reasonable. It should be examined whether guideline synopses are suitable not only for guideline and DMP development, but also for other health care issues. PMID- 25499109 TI - [Methods of patient involvement in the development of guidelines - a systematic review]. AB - BACKGROUND: Involving patients or patient-representatives in the development of guidelines is widely recommended. The expected benefits of patient involvement include an increase in the relevance and acceptability of the guidelines. So far there has been no systematic review of patient involvement in the development process of the German AMWF S3 and nursing guidelines and no description of the recommendations made by guideline-developing organisations and the scientific literature concerning the methods of patient involvement. METHOD: A systematic search was performed (July 2013) to identify AWMF S3 and nursing guidelines, manuals for guideline development, and scientific literature on methods of patient involvement. The following data were extracted: the methods of patient involvement from the guidelines, and all recommendations on a successful patient involvement from the manuals of guideline development and from the scientific literature. RESULTS: A total of 124 AWMF S3 and 18 nursing guidelines, six manuals of guideline development and ten scientific publications were included. Patient representatives were involved in the development process in 71 out of 142 guidelines (n=63 AWMF S3 and n=8 nursing guidelines). The manuals for guideline development included recommendations for a global involvement of patient representatives and recommendations for specific stages of the development process. In the scientific publications, active and early involvement has been identified as a key element to a successful involvement of patient representatives. DISCUSSION: In the German AMWF and nursing guidelines, patient involvement is currently not an established standard. This could be improved by including mandatory rules for patient involvement in the manuals for guideline development. More research is needed on the effects of patient involvement on the content and applicability of guidelines. PMID- 25499110 TI - [Effectiveness of quality assurance programmes for inpatient care in Germany: a literature review]. AB - BACKGROUND: Over the past decades, a large number of measures for quality management and quality assurance (QM/QA) of healthcare were established in the German healthcare system. Considering the resources required, it has been repeatedly demanded that such quality programmes be checked for their effectiveness. In this context, the present paper describes the results of a systematic literature review to evaluate German QM/QA programmes in the inpatient sector. METHODS: A systematic literature search was conducted in the electronic databases Medline, Cochrane Library and topic-related institution websites. In addition, hand searches were conducted, and the search engine Google Scholar was used. For Germany, no time limit was placed on the literature search. Evaluation studies were only selected if they included a comparison group without or at the beginning of a QM/QA programme and measured the effects on outcomes, process or structure of inpatient care. The methodological quality of the eligible studies was assessed and summarised. RESULTS: Out of 3,065 hits, 18 publications were included in the literature review. In Germany, no causal relationships between QM/QA programmes and a relevant benefit for improved quality of care for patients in the hospital sector could be detected in any study. Results were inconsistent or insufficiently reliable without demonstrating a clear positive or negative impact of the analysed programmes on the quality of care. Overall, the quality of the included studies was low. CONCLUSION: No acceptable scientific studies for the German healthcare system could be detected that provided proof for a patient related effectiveness or ineffectiveness of the established quality programmes. Due to the insufficient evidence and despite the challenges faced when conducting convincing evaluation studies in the field of QM/QA, established methods of the evaluation research should be applied and extended. PMID- 25499111 TI - [Involvement of patient representatives in clinical practice guideline development: a qualitative study]. AB - BACKGROUND: The involvement of patient representatives in the development process of clinical practice guidelines is accepted as an international standard. However, there is no consensus on the optimal methods to be used. We explored how patient advocates experienced their role while being actively involved in guideline development. METHODS: From November 2012 to January 2013 problem centred interviews were conducted with eleven patient representatives from Germany who were involved in evidence-based guideline development. The interviews were analysed using the methods of Grounded Theory. RESULTS: Three main categories were derived which patient representatives perceived as the most important prerequisites for active participation in guideline development groups: knowledge, endorsement and adopting the role. Knowledge combined with an explicit clarification of the role of the patient representative seems to have a positive impact on the adoption of the specific role in a guideline developing group. CONCLUSION: Our study indicates how active involvement of patient representatives in guideline development processes can be optimised. Initially, the role of the patient representative should be explicitly clarified; and courses offering methodological support should be provided. The informative value of the study is limited by the small number of interviews. Therefore, further studies are needed. PMID- 25499112 TI - [Adopted in patient care, but not yet familiar]. PMID- 25499113 TI - [A new label or more quality?: Organization and responsibilities of the Institute for Quality Assurance and Transparency in Healthcare]. PMID- 25499114 TI - When Choosing Wisely meets clinical practice guidelines. AB - The American Board of Internal Medicine (ABIM) Foundation launched the Choosing Wisely campaign in 2012 and until today convinced more than 50 US specialist societies to develop lists of interventions that may not improve people's health but are potentially harmful. We suggest combining these new efforts with the already existing efforts in clinical practice guideline development. Existing clinical practice guidelines facilitate a more participatory and evidence-based approach to the development of top 5 lists. In return, adding top 5 lists (for overuse and underuse) to existing clinical practice guidelines nicely addresses a neglected dimension to clinical practice guideline development, namely explicit information on which Do or Don't do recommendations are frequently disregarded in practice. PMID- 25499115 TI - Ebola - contradictions between knowledge and communication. PMID- 25499116 TI - Why Evidence Based Approaches are urgently needed in Africa. PMID- 25499117 TI - [Medical school admission test at the University of Goettingen - which applicants will benefit?]. AB - Medical schools in Germany may select 60% of the student applicants through their own admission tests. The influence of the school-leaving examination grades (EGs) in each of the procedural steps is controversial. At Goettingen Medical School, we combine a structured interview and a communicative skills assessment. We analysed how many applicants succeeded in our admission test, compared to a model which only takes EGs into account. Admission scores were transferred into SPSS 21. Sociodemographic data were submitted by the Stiftung Hochschulstart. Besides descriptive statistics, we used Pearson-correlation and means comparisons (t test, analysis of variance). 221 applicants (EGs 1.0-1.9) were invited in the winter semester 2013/14 and 222 applicants (EGs 1.1-1.8) in the summer semester 2014. The proportion of women was 68% (winter) and 74% (summer). Sixteen and 37 applicants had a medical vocational training and performed slightly better. The analysis showed that our test was gender neutral. EGs did not correlate with interviews or skills assessment. Despite a two-fold impact of EGs, 26 (winter) and 44 (summer) of the overall 181 applicants had EGs of 1.4 -1.9, which would have been too low for admission otherwise. If EGs were only considered once, 40 (winter) and 59 (summer) applicants would have succeeded. PMID- 25499118 TI - [Doctoral thesis projects for medical students? Retrospective estimation of the fraction of successfully completed medical doctoral thesis projects at Witten/Herdecke University]. AB - BACKGROUND: The German "Dr med" plays a specific role in doctoral thesis settings since students may start the underlying doctoral project during their studies at medical school. If a Medical Faculty principally encourages this approach, then it should support the students in performing the respective projects as efficiently as possible. Consequently, it must be ensured that students are able to implement and complete a doctoral project in parallel to their studies. As a characteristic efficiency feature of these "Dr med" initiatives, the proportion of doctoral projects successfully completed shortly after graduating from medical school is proposed and illustrated. METHODS: The proposed characteristic can be estimated by the time period between the state examination (date of completion of the qualifying medical examination) and the doctoral examination. Completion of the doctoral project "during their medical studies" was then characterised by a doctoral examination no later than 12 months after the qualifying medical state examination. To illustrate the estimation and interpretation of this characteristic, it was retrospectively estimated on the basis of the full sample of all doctorates successfully completed between July 2009 and June 2012 at the Department of Human Medicine at the Faculty of Health of the University of Witten/Herdecke. RESULTS: During the period of investigation defined, a total number of 56 doctoral examinations were documented, 30 % of which were completed within 12 months after the qualifying medical state examination (95% confidence interval 19 to 44 %). The median duration between state and doctoral examination was 27 months. The proportion of doctoral projects completed parallel to the medical studies increased during the investigation period from 14 % in the first year (July 2009 till June 2010) to 40 % in the third year (July 2011 till June 2012). CONCLUSION: Only about a third of all "Dr med" projects at the Witten/Herdecke Faculty of Health were completed during or close to the qualifying medical studies. This proportion, however, increased after the introduction of a curriculum on research methodology and practice in 2010; prospective longitudinal studies will have to clarify whether this is causal or mere chronological coincidence. In summary, the proposed method for determining the process efficiency of a medical faculty's "Dr med" programme has proven to be both feasible and informative. PMID- 25499119 TI - Soluble urokinase-type plasminogen activator receptor (suPAR) as new biomarker of the prosthetic joint infection: correlation with inflammatory cytokines. AB - Post-operative prosthetic joint infection (PJI) is the most common cause of failure of total joint arthroplasty, requiring revision surgery, but a gold standard for the diagnosis and the treatment of PIJ is still lacking. PJI is mainly due to Gram-positive bacteria, in particular, Staphylococcus Aureus, and more rarely by Gram-negative bacteria such as Pseudomonas. This study aimed to examine the diagnostic value of SuPAR in post-operative PJI, in order to explore the possible application of this new biomarker in the early diagnosis of PJI. The level of SuPAR has been measured in PJI patients and healthy controls, correlated with canonical inflammatory markers, such as C-reactive protein, IL-6, IL-1 and TNFalpha and the chemokine CCL2. Serum suPAR displayed a strongly significative increase in PJI patients compared to not infected controls, and a significative positive correlation with C-reactive protein, IL-6, IL-1 and TNFalpha and the chemokine CCL2. Also serum CCL2 showed statistically significative increase in PJI patients, and it displayed a strong positive correlation with serum suPAR. This study provides a clear indication of the diagnostic potential of suPAR, in association to routine inflammatory parameters such as CRP, in the diagnosis of PJI. PMID- 25499120 TI - 1H NMR-derived serum metabolomics of leukoplakia and squamous cell carcinoma. AB - BACKGROUND: Oral cancer (OC) is the sixth commonest cancer worldwide with alarming mortality. If identified at an early stage, the survival rate would be improved. METHODS: We appraised the feasibility of using (1)H nuclear magnetic resonance ((1)H NMR) based metabolomics in the identification of signature metabolites in serum from patients suffering with oral leukoplakia (OLK, n=100), oral squamous cell carcinoma (OSCC, n=100), and healthy control (HC, n=75). (1)H NMR derived data were processed by principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) to reveal discriminating metabolites among these groups. Receiver operating characteristic (ROC) curve evaluation was also executed. RESULTS: NMR-derived serum metabolomics reveals eight differentially expressed biomarkers. Among them four biomarkers (glutamine, propionate, acetone, and choline) were able to accurately (ROC; 0.97) segregate 93.5% of OC cases equated to HC with substantial sensitivity and specificity. Similarly, four biomarkers (glutamine, acetone, acetate, and choline) were able to precisely (ROC; 0.96) discriminate, 92.4% of OLK cases from OSCC with considerable sensitivity and specificity. (1)H NMR-based metabolic fingerprint obtained for oral cancer is remarkable, even for OLK stage. CONCLUSION: There is a systemic metabolic response to initial stage of cancer, which carries immense possibility for early appraisal. PMID- 25499122 TI - Pharmacists in primary care. PMID- 25499121 TI - Pegylated arginine deiminase synergistically increases the cytotoxicity of gemcitabine in human pancreatic cancer. AB - BACKGROUND: Pancreatic ductal adenocarcinoma has proven to be one of the most chemo-resistant among all solid organ malignancies. Several mechanisms of resistance have been described, though few reports of strategies to overcome this chemo-resistance have been successful in restoring sensitivity to the primary chemotherapy (gemcitabine) and enter the clinical treatment arena. METHODS: We examined the ability of cellular arginine depletion through treatment with PEG ADI to alter in vitro and in vivo cytotoxicity of gemcitabine. The effect on levels of key regulators of gemcitabine efficacy (e.g. RRM2, hENT1, and dCK) were examined. RESULTS: Combination of PEG-ADI and gemcitabine substantially increases growth arrest, leading to increased tumor response in vivo. PEG-ADI is a strong inhibitor of the gemcitabine-induced overexpression of ribonucleotide reductase subunit M2 (RRM2) levels both in vivo and in vitro, which is associated with gemcitabine resistance. This mechanism is through the abrogation of the gemcitabine-mediated inhibitory effect on E2F-1 function, a transcriptional repressor of RRM2. CONCLUSION: The ability to alter gemcitabine resistance in a targeted manner by inducing metabolic stress holds great promise in the treatment of advanced pancreatic cancer. PMID- 25499123 TI - Incidence and mortality of tuberculosis before and after initiation of antiretroviral therapy: an HIV cohort study in India. AB - INTRODUCTION: India has the highest burden of tuberculosis (TB) in the world, but the epidemiology of HIV-associated TB is not well known. METHODS: We describe the incidence and the mortality of TB from HIV diagnosis to antiretroviral therapy (ART) initiation (pre-ART group) and after ART initiation (on-ART group) in an HIV cohort study in Anantapur, India. Multivariable analysis of factors associated with TB was performed using competing risk regression and restricted cubic spline methods. RESULTS: A total of 4590 patients and 3133 person-years (py) of follow-up were included in the pre-ART group, and 3784 patients and 4756 py were included in the on-ART group. In the pre-ART group, the incidence of TB was high during the first month after HIV diagnosis and dropped nearly four times soon after. In the on-ART group, the incidence of TB increased after ART initiation reaching a peak in the third month. The probability of having TB within 30 months was 22.3% (95% confidence interval [CI], 21.1-23.6) in the pre ART group and 17.8% (95% CI, 16.3-19.3) in the on-ART group. In a multivariable analysis, women had a lower risk of TB in both groups. Poor socio-economical conditions were associated with an increased risk of TB in the pre-ART group, but not in the group on-ART. While the association between low CD4 counts and TB was strong in the pre-ART group, this association was weaker in the on-ART group, and the highest risk of TB was seen in those patients with CD4 counts around 110 cells/mm3. The cumulative incidence of mortality at 12 months in patients with TB was 29.6% (95% CI, 26.9-32.6) in pre-ART TB and 34.9% (95% CI, 31-39.1) in on-ART TB. Half deaths before ART initiation and two thirds of deaths after ART initiation occurred in patients with TB. CONCLUSIONS: The high incidence and mortality of TB seen in this study underscore the urgent need to improve the prevention and diagnosis of HIV-associated TB in India. We found substantial differences between TB before and after ART initiation. PMID- 25499124 TI - Neuraminidase mutations conferring resistance to laninamivir lead to faster drug binding and dissociation. AB - The neuraminidase (NA) inhibitors oseltamivir and zanamivir are administered twice daily for 5days for treatment of influenza. Laninamivir is a 7-methoxy derivative of zanamivir, but a single dose is effective when taken as the laninamivir octanoate prodrug. We show here in IC50 kinetics assays and a solid phase reactivation assay that compared to zanamivir laninamivir also demonstrates slow binding to but slower dissociation from multiple wild type NAs. A D197E mutation in an influenza B and an E119G in an N9 neuraminidase which confer 15- and 150-fold resistance to laninamivir result in faster binding and dissociation. Despite similar IC50s our assays demonstrate more rapid dissociation of laninamivir from clade 1 compared to 2 H5N1 NAs. PMID- 25499127 TI - The early days of the multi channel cochlear implant: efforts and achievement in France. AB - On September 10th 2013, the clinical medical research Lasker award winners were rewarded for their work on multichannel cochlear implant. It has been my pleasure to see that such a major topic had caught the attention of the Members of the Jury for this prestigious award. That is why I accepted an invitation to participate in a special issue of Hearing Research devoted to the three winners. Here I highlight four scientific contributions made by the French team in late 1970s and early 1980s to modern multichannel cochlear implant development. 1) Chouard and MacLeod plotted an approximate frequency map of the whole length of the human cochlea, including its "hidden face" corresponding to speech frequencies. Moreover MacLeod suggested a sequential display of electrical stimulation as a function of each electrode, a precursor to today's electrodogram and interleaved stimulation. 2) Chouard performed total cochlear implantation in a deaf adult male with 8 electrically independent electrodes that were evenly distributed along the cochlea. 3) Chouard and MacLeod described in a patent detailed sound signal processing for a functional multichannel cochlear implant and reported speech discrimination without help of lip reading in some totally deafened patients. 4) Chouard experimentally demonstrated in the guinea pig the advantage of early cochlear implantation in treating profound neonatal deafness. This article is part of a Special Issue entitled . PMID- 25499125 TI - Anti-cytomegalovirus activity of the anthraquinone atanyl blue PRL. AB - Human cytomegalovirus (CMV) causes significant disease in immunocompromised patients and serious birth defects if acquired in utero. Available CMV antivirals target the viral DNA polymerase, have significant toxicities, and suffer from resistance. New drugs targeting different pathways would be beneficial. The anthraquinone emodin is proposed to inhibit herpes simplex virus by blocking the viral nuclease. Emodin and related anthraquinones are also reported to inhibit CMV. In the present study, emodin reduced CMV infectious yield with an EC50 of 4.9MUM but was cytotoxic at concentrations only twofold higher. Related anthraquinones acid blue 40 and alizarin violet R inhibited CMV at only high concentrations (238-265MUM) that were also cytotoxic. However, atanyl blue PRL inhibited infectious yield of CMV with an EC50 of 6.3MUM, significantly below its 50% cytotoxic concentration of 216MUM. Atanyl blue PRL reduced CMV infectivity and inhibited spread. When added up to 1h after infection, it dramatically reduced CMV immediate early protein expression and blocked viral DNA synthesis. However, it had no antiviral activity when added 24h after infection. Interestingly, atanyl blue PRL inhibited nuclease activities of purified CMV UL98 protein with IC50 of 4.5 and 9.3MUM. These results indicate that atanyl blue PRL targets very early post-entry events in CMV replication and suggest it may act through inhibition of UL98, making it a novel CMV inhibitor. This compound may provide valuable insights into molecular events that occur at the earliest times post-infection and serve as a lead structure for antiviral development. PMID- 25499128 TI - Interferon-gamma expression and infectivity of Toxoplasma infected tissues in experimentally infected sheep in comparison with pigs. AB - Livestock animals are a potential risk for transmission of toxoplasmosis to humans. Sheep and pigs still remain an important source because their meat is often eaten undercooked which has been regarded as a major route of infection in many countries. Moreover, porcine tissues are processed in many food products. In the current study, the IFN-gamma (T-helper 1 cells), IL-4 (Th2 cells) and IL-10 mRNA (Treg cells) expression by blood mononuclear cells, and the serum antibody response against Toxoplasma gondii total lysate antigen, recombinant T. gondii GRA1, rGRA7, rMIC3 and rEC2, a chimeric antigen composed of MIC2, MIC3 and SAG1, was studied in sheep the first two months after a T. gondii infection and compared with these responses in pigs. At the end of this period, the parasite distribution in heart, brain and two skeletal muscles in sheep was compared with this in pigs. Whereas the parasite distribution was similar in sheep and pigs, the antibody response differed considerably. In sheep, antibodies appeared against all tested T. gondii antigens, but mainly against rGRA7, rMIC3234307 and TLA whereas in pigs only rGRA7-specific antibodies could be demonstrated. Also, the cytokine response differed. Both in sheep and pigs an IFN-gamma response occurred which seemed to be a slightly more pronounced in sheep. In sheep, also IL-10 and IL-4 mRNA expression showed an increase, but later than IFN-gamma and with more variation. However, in pigs no such increase was seen. As concerning diagnosis, results indicate that serum antibodies against GRA7 in live sheep and pigs and heart tissue for bioassay and qPCR in slaughtered animals are the best targets to demonstrate presence of T. gondii infection. PMID- 25499129 TI - Impact of plasma Lp-PLA2 activity on the progression of aortic stenosis: the PROGRESSA study. AB - OBJECTIVES: The purpose of this prospective study was to examine the relationship between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and the progression rate of aortic stenosis (AS). BACKGROUND: We recently reported that Lp-PLA2 is highly expressed in stenotic aortic valves where it may contribute to the mineralization of valvular interstitial cells. METHODS: Patients with AS were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study. AS progression rate was assessed by annualized increase in peak aortic jet velocity (Vpeak), mean gradient (MG), and aortic valve area index (AVAi). Circulating Lp-PLA2 activity was measured and dichotomized based on the median value. RESULTS: Of 183 patients included in this subanalysis of the PROGRESSA study, 70% were men and the mean age was 66 +/- 13 years. Over the 2.5 +/- 1.4 years of follow up, the AS progression rate tended to be higher in patients with high versus low Lp-PLA2 activity (annualized Vpeak = 0.17 +/- 0.23 m/s vs. 0.12 +/- 0.18 m/s; p = 0.14). There was a significant interaction (p < 0.05) between baseline AS severity and Lp-PLA2 activity with respect to impact on AS progression rate. In patients with mild AS (i.e., Vpeak <3 m/s; n = 123), increased Lp-PLA2 activity was associated with a significantly faster AS progression rate (Vpeak 0.16 +/- 0.18 m/s vs. 0.09 +/- 0.14 m/s; p = 0.01) but not in patients with moderate or severe AS (p = 0.99). After adjustment for other risk factors, increased Lp-PLA2 activity remained independently associated with faster AS progression rate (p = 0.005) in the former subset. CONCLUSIONS: There was no significant association between plasma Lp-PLA2 activity or mass and stenosis progression in the whole cohort. However, increased Lp-PLA2 activity was associated with a faster stenosis progression rate in the subset of patients with mild AS. These findings provide an impetus for the elaboration of a randomized trial targeting Lp-PLA2 activity in patients with early stages of calcific aortic valve disease. PMID- 25499130 TI - Regurgitant volume informs rate of progressive cardiac dysfunction in asymptomatic patients with chronic aortic or mitral regurgitation. AB - OBJECTIVES: This study hypothesized that regurgitation severity, as determined by using the regurgitant volume index, would better delineate differential cardiac dysfunction in asymptomatic patients with moderate to severe aortic regurgitation (AR) and mitral regurgitation (MR). BACKGROUND: Frequent surveillance echocardiography is considered appropriate in asymptomatic patients with moderate to severe AR and MR. However, the evidence to support this practice and to define the appropriate frequency is limited. METHODS: This was an observational cohort study of consecutive patients with moderate to severe asymptomatic AR or MR who underwent exercise echocardiography. Our cohort included 130 patients with moderate to severe asymptomatic MR and 130 patients with moderate to severe asymptomatic AR who were matched according to age and regurgitant volume index. All patients underwent yearly echocardiographic follow-up studies. Regurgitation severity was determined according to regurgitant volume index, with a level >=30 ml/m(2) considered a marker of severe regurgitation. RESULTS: During follow-up, regardless of etiology, patients with severe regurgitation demonstrated increasing left ventricular volume indexes (4.2 +/- 1.5 ml/m(2) per year; p = 0.01) and decreasing left ventricular ejection fractions (1.3 +/- 0.4% per year; p = 0.002). In patients with moderate regurgitation, left ventricular volumes and ejection fractions did not significantly change. In addition, patients with severe regurgitation experienced a similar drop in contractility (end-systolic pressure/end-systolic volume ratio and single-beat pre-load recruitable stroke work) during follow-up independent of regurgitation etiology. Contractility parameters did not change in patients with moderate regurgitation. CONCLUSIONS: These asymptomatic patients with moderate AR or MR had stable cardiac function during 3 years of follow-up; thus, frequent echocardiography without a change in clinical status may not be necessary. In the setting of severe regurgitation, further cardiac deterioration occurred at a similar rate and manner irrespective of whether the dysfunction was related to AR or MR. PMID- 25499131 TI - Native T1 in discrimination of acute and convalescent stages in patients with clinical diagnosis of myocarditis: a proposed diagnostic algorithm using CMR. AB - OBJECTIVES: This study investigated whether T1 mapping by cardiac magnetic resonance (CMR) reflects the clinical evolution of disease in myocarditis and supports its diagnosis independently of the disease stages. BACKGROUND: Acute viral myocarditis is characterized by a range of intracellular changes due to viral replication and extracellular spill of debris within days of viral infection. Convalescence may be characterized by a chronic low-grade inflammation leading to ventricular remodelling, but also a complete resolution of myocardial changes. METHODS: Patients with clinical diagnosis of viral myocarditis (N = 165) underwent routine clinical CMR protocol (1.5- and 3.0-T) for assessment of cardiac function and structure, and tissue characterization with T2-weighted imaging and late gadolinium enhancement. T1 mapping was obtained in a mid ventricular short-axis slice before and >20 min after administration of 0.2 mmol/kg of gadobutrol. RESULTS: Compared with control subjects (n = 40), T1 indexes were increased in patients with myocarditis. Patients with acute symptoms (n = 61) had higher values of T1 indexes compared with patients in clinical convalescence (n = 67). Native T1 is an independent discriminator between health and disease, as well as a discriminator between acute and convalescent stage of the disease. Native T1- was superior to T2-weighted imaging and late gadolinium enhancement with high diagnostic accuracy and positive and negative predictive values. Using pre-defined cutoff values for normal ranges, we demonstrated that acute myocarditis can be independently identified by native T1 of >5 SD above the mean of normal range, whereas convalescence is best defined by either abnormal native T1 (>2 SD) or presence of late gadolinium enhancement. We prospectively tested a new diagnostic algorithm in an independent dataset of patients with clinical diagnosis of myocarditis and achieved similar diagnostic performance. CONCLUSIONS: The new diagnostic algorithm using native T1 can reliably discriminate between health and disease and determine the clinical disease stage in patients with a clinical diagnosis of myocarditis. PMID- 25499132 TI - 11C-Pittsburgh B PET imaging in cardiac amyloidosis. AB - OBJECTIVES: This study sought to investigate the efficacy of (11)C-Pittsburgh B (PiB) positron emission tomography (PET)/computed tomography (CT) in the diagnosis of cardiac amyloidosis. BACKGROUND: The PiB compound has been promising for detection of amyloid deposits in the brain. METHODS: A total of 22 consecutive patients were enrolled in this prospective pilot study of monoclonal gammopathy patients with suspected cardiac amyloidosis. The study consisted of a series of (11)C-PiB PET/CT, echocardiography, cardiac magnetic resonance, and endomyocardial biopsy within a 1-month period. In addition, 10 normal subjects were recruited to determine the most optimal cut-off value for a positive (11)C PiB PET/CT scan. RESULTS: Among the 22 patients, 15 patients were diagnosed as cardiac amyloidosis by endomyocardial biopsy and 5 patients had undergone chemotherapy previously before the (11)C-PiB PET/CT. There were no differences in echocardiographic parameters between patients with versus without cardiac amyloidosis, except for a marginal difference in the left ventricular end diastolic dimension (median 41.0 mm [range 33.0 to 49.0 mm] vs. 50.0 mm [range 38.0 to 55.0 mm], p = 0.066). (11)C-PiB PET/CT was positive in 13 of 15 biopsy proven cardiac amyloidosis patients, whereas none of the patients without cardiac amyloidosis demonstrated positive (11)C-PiB PET/CT scan results. The maximal myocardium-to-blood cavity ratio was significantly different between patients with versus without cardiac amyloidosis (median 3.9 [range 1.7 to 19.9] vs. 1.0 [range 0.8 to 1.2], p < 0.001). In association with the significant difference of (11)C-PiB uptake in the myocardium between the chemotherapy naive versus the previous chemotherapy group (median 10.4 [range 1.7 to 19.9] vs. 2.3 [range 1.7 to 3.8], p = 0.014), all except 1 patient among the 5 previously treated patients had responded to chemotherapy by serum free light chain assay results at the time of (11)C-PiB PET/CT scan. CONCLUSIONS: (11)C-PiB PET/CT may be valuable for the diagnosis of cardiac amyloidosis noninvasively. Whether (11)C-PiB PET/CT may be a good surrogate marker of active light chain deposition in the myocardium warrants further investigation in a larger number of patients. PMID- 25499134 TI - Tako-Tsubo Cardiomyopathy: A Heart Stressed Out of Energy? PMID- 25499133 TI - Macrophages and intravascular OCT bright spots: a quantitative study. AB - OBJECTIVES: This study hypothesized that bright spots in intravascular optical coherence tomography (IVOCT) images may originate by colocalization of plaque materials of differing indexes of refraction. To quantitatively identify bright spots, we developed an algorithm that accounts for factors including tissue depth, distance from light source, and signal-to-noise ratio. We used this algorithm to perform a bright spot analysis of IVOCT images and compared these results with histological examination of matching tissue sections. BACKGROUND: Bright spots are thought to represent macrophages in IVOCT images, and studies of alternative etiologies have not been reported. METHODS: Fresh human coronary arteries (n = 14 from 10 hearts) were imaged with IVOCT in a mock catheterization laboratory and then processed for histological analysis. The quantitative bright spot algorithm was applied to all images. RESULTS: Results are reported for 1,599 IVOCT images co-registered with histology. Macrophages alone were responsible for only 23% of the bright spot-positive regions, although they were present in 57% of bright spot-positive regions (as determined by histology). Additional etiologies for bright spots included cellular fibrous tissue (8%), interfaces between calcium and fibrous tissue (10%), calcium and lipids (5%), and fibrous cap and lipid pool (3%). Additionally, we showed that large pools of macrophages in CD68(+) histology sections corresponded to dark regions in comparative IVOCT images; this is due to the fact that a pool of lipid-rich macrophages will have the same index of refraction as a pool of lipid and thus will not cause bright spots. CONCLUSIONS: Bright spots in IVOCT images were correlated with a variety of plaque components that cause sharp changes in the index of refraction. Algorithms that incorporate these correlations may be developed to improve the identification of some types of vulnerable plaque and allow standardization of IVOCT image interpretation. PMID- 25499135 TI - Serum albumin binding analysis and toxicological screening of novel chroman-2,4 diones as oral anticoagulants. AB - Two chroman-2,4-dione derivatives, namely 2a and 2f, were tested as in vivo anticoagulants by seven days of continuous per os application to adult male Wistar rats in a concentration of 20 mg/kg of body weight. Derivatives were selected from a group of six previously intraperitoneally applied compounds on the basis of presenting remarkable activity in a concentration of 2 mg/kg of body weight. The derivatives 2a and 2f are VKORC1 inhibitors, and comparison of the absorption spectra, association, and dissociation constants suggested that the compounds will be bound to serum albumin in the same manner as warfarin is, leading to transfer towards the molecular target VKORC1. After oral administration, the compounds proved to be anticoagulants comparable with warfarin, inasmuch as the measured prothrombin times for 2a and 2f were 56.63 and 60.08 s, respectively. The INR values of 2a and 2f ranged from 2.6 to 2.8, recommending them as useful therapeutics in the treatment of patients suffering from thromboembolic events and atrial fibrillation. The high percentage of binding and high binding affinity of 2a and 2f towards serum albumin reduced the risk of induced internal bleeding. Several kinds of toxicity studies were performed to investigate whether or not 2a and 2f can cause pathological changes in the liver, kidneys, and DNA. The catalytic activity of serum enzymes, concentration and catalytic activity of liver and kidney oxidative stress markers and enzymes, respectively, as well as the observed hepatic and renal morphological changes indicated that the compounds in relation to warfarin induced irrelevant hepatic toxicity, no increment of necrosis, and inconsiderable oxidative damage in the liver and kidneys. Estimation of DNA damage using the comet assay confirmed that 2a and 2f caused no clinically significant genotoxicity. The higher activity and lower toxicity of 2f recommended this compound as a better drug candidate than 2a. PMID- 25499136 TI - PARP-1 inhibitor sensitizes arsenic trioxide in hepatocellular carcinoma cells via abrogation of G2/M checkpoint and suppression of DNA damage repair. AB - Arsenic trioxide (ATO) is successfully used to treat hematological malignancies. However, the clinical application of the agent in solid tumors is largely limited by its dose-dependent toxicity which results from the high intrinsic resistance of the cancer cells. In this study, we firstly identified a series of sensitization effects of 4AN, a PARP-1 inhibitor, on human hepatocellular carcinoma cell line HepG2 to ATO treatment. We showed that treatment of HepG2 cells with 4AN promoted ATO-induced cell death in a synergistic manner. The ATO sensitization by 4AN was associated with its effect on abrogation of ATO-induced G2/M checkpoint which impairs DNA damage repair and promotes cell apoptosis. Further analysis demonstrated that the ATO-induced G2/M checkpoint was closely related to a decrease in cyclin B1, a key G2/M mediator; whereas 4AN up-regulated the expression of cyclin B1 in ATO-treated cells, which may be at least partly responsible for its effect on abrogation of ATO-induced G2/M checkpoint. This was further supported by the result showing that down-regulation of cyclin B1 using siRNA could restore the G2/M checkpoint in cells co-treated with ATO and 4AN, thereby improving DNA damage repair and decreasing apoptosis. Our study indicates that the abrogation of G2/M checkpoint and the suppression of DNA damage repair contribute to ATO-sensitization by PARP-1 inhibitor in HepG2 cells, which provides a novel insight into the chemo-sensitization mechanism of PARP-1 inhibitor. PMID- 25499137 TI - Nymphayol increases glucose-stimulated insulin secretion by RIN-5F cells and GLUT4-mediated insulin sensitization in type 2 diabetic rat liver. AB - Nymphaea stellata (Willd.) has been used in traditional medicine for centuries to treat several illnesses, including diabetes. However, scientific evidence supporting its mechanism of action is lacking. Here, we showed that an N. stellata flower chloroform extract (NSFCExt) has significant plasma glucose lowering ability. Furthermore, an active compound was identified and purified by column chromatography, and the structure of this compound, nymphayol, was determined by X-ray crystallographic analysis. Nymphayol was tested for its effects on insulin secretion by RIN-5F cells cultured in low or high glucose medium; we found that nymphayol treatment improved glucose-stimulated insulin secretion in vitro. Additionally, insulin sensitization and glucose uptake were increased in L6 myotubes. Nymphayol was administered to type 2 diabetic male Wistar rats at several doses (5, 10 or 20 mg/kg/day) for 45 days. After nymphayol administration, the plasma glucose concentration was significantly (p?0.05) lower (60.33%) than in control diabetic rats, and the plasma insulin level increased in a dose-dependent manner. In addition, the cellular insulin response was analyzed in type 2 diabetic rats; oral administration of nymphayol increased IRS1 phosphorylation and GLUT4 protein expression in liver and muscle. Nymphayol significantly (p?0.05) restored the levels of HbA1c, hepatic glycogen and hepatic glucose-metabolizing enzyme (hexokinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1, 6-bisphosphatase, glycogen synthase and glycogen phosphorylase) activity in diabetic rats. The administration of glibenclamide, a reference drug (600 MUg/kg), also produced a significant (p?0.05) reduction in blood glucose in STZ-nicotinamide induced diabetic rats. The results suggest that nymphayol may be a useful therapy for diabetes because it stimulates insulin secretion and promotes glucose absorption. PMID- 25499138 TI - Evaluation of tributyltin toxicity in Chinese rare minnow larvae by abnormal behavior, energy metabolism and endoplasmic reticulum stress. AB - Tributyltin (TBT) is a ubiquitous contaminant in aquatic environment, but the detailed mechanisms underlying the toxicity of TBT have not been fully understood. In this study, the effects of TBT on behavior, energy metabolism and endoplasmic reticulum (ER) stress were investigated by using Chinese rare minnow larvae. Fish larvae were exposed at sublethal concentrations of TBT (100, 400 and 800 ng/L) for 7 days. Compared with the control, energy metabolic parameters (RNA/DNA ratio, Na(+)-K(+)-ATPase) were significantly inhibited in fish exposed at highest concentration (800 ng/L), as well as abnormal behaviors observed. Moreover, we found that the PERK (PKR-like ER kinase)-eIF2alpha (eukaryotic translation initiation factor 2alpha) pathway, as the main branch was activated by TBT exposure in fish larvae. In short, TBT-induced physiological, biochemical and molecular responses in fish larvae were reflected in parameters measured in this study, which suggest that these biomarkers could be used as potential indicators for monitoring organotin compounds present in aquatic environment. PMID- 25499139 TI - Right ventricular remodeling in idiopathic pulmonary arterial hypertension: adaptive versus maladaptive morphology. AB - BACKGROUND: Although increased pulmonary pressure is caused by changes in the pulmonary vasculature, prognosis in idiopathic pulmonary arterial hypertension (IPAH) is strongly associated with right ventricular (RV) function. The aim of this study was to describe the best RV adaptive remodeling pattern to increased afterload in IPAH. METHODS: In 60 consecutive patients with IPAH, RV morphologic and functional features were evaluated by echocardiography and cardiac magnetic resonance imaging. To address the question of the best RV adaptation pattern, we divided the study population into two groups by the median value of RV mass/volume ratio (0.46) because this parameter allows the distinction between RV eccentric (<=0.46) and concentric hypertrophy (>0.46). The two groups were compared for RV remodeling and systolic function parameters, World Health Organization class, pulmonary hemodynamics, and 6-minute walk test. RESULTS: Despite similar pulmonary vascular resistance, mean pulmonary pressure, and compliance, patients with eccentric hypertrophy had advanced World Health Organization class and worse 6-minute walk test, hemodynamics, RV remodeling, and systolic function parameters compared with patients with concentric hypertrophy. The group with concentric hypertrophy had higher RV to pulmonary arterial coupling compared with the group with eccentric hypertrophy (1.24 +/- 0.26 vs 0.83 +/- 0.33, p = 0.0001), indicating higher RV efficiency. A significant correlation was found between pulmonary vascular resistance and RV to pulmonary arterial coupling (r = -0.55, r(2) = 0.31, p = 0.0001), with patients with RV mass/volume ratio > 0.46 at the higher part of the scatterplot, confirming more adequate RV function. CONCLUSIONS: Concentric hypertrophy might represent a more favorable RV adaptive remodeling pattern to increased afterload in IPAH because it is associated with more suitable systolic function and mechanical efficiency. PMID- 25499142 TI - The structure and short-term stability of the emotional disorders: a dimensional approach. AB - BACKGROUND: Factor-analytic studies have found that depressive, bipolar, post traumatic, obsessive-compulsive, and anxiety disorders - jointly referred to as the emotional disorders - form an internalizing spectrum that includes distress and fear subfactors. However, placement of some disorders is uncertain. Also, prior research analysed dichotomous interview-based diagnoses or dimensional self report measures. We investigated this structure using a third-generation measure the Interview for Mood and Anxiety Symptoms (IMAS) - that combines strengths of a clinical interview with dimensional assessment. METHOD: The interview was administered to 385 students and 288 psychiatric out-patients. Participants were reinterviewed 2 months later. RESULTS: Exploratory and confirmatory factor analyses identified three factors: distress (depression, generalized anxiety, post-traumatic stress, irritability, and panic syndrome); fear (social anxiety, agoraphobia, specific phobia, and obsessive-compulsive); and bipolar (mania and obsessive-compulsive). The structure was consistent over time and across samples, except that panic and agoraphobia had higher factor loadings in patients. Longitudinal analyses revealed high temporal stability of the factors (test retest r = 0.72 to 0.87), but also substantial disorder-specific stability. CONCLUSIONS: This investigation - which bridges diagnostic and self-report studies - found three subfactors of internalizing psychopathology. It provided support for a new subfactor, clarified the placement of obsessive-compulsive and bipolar disorders, and demonstrated that this model generalizes across populations. The accumulating research suggests the need to recognize formally the close links among the emotional disorders, as well as empirical clusters within this spectrum. The IMAS demonstrated strong psychometric properties and can be useful for various research and clinical applications by providing dimensional, interview-based assessment of the emotional disorders. PMID- 25499140 TI - Heart transplantation using allografts from older donors: Multicenter study results. AB - BACKGROUND: The lengthy waiting time for heart transplantation is associated with high mortality. To increase the number of donors, new strategies have emerged, including the use of hearts from donors >=50 years old. However, this practice remains controversial. The aim of this study was to evaluate outcomes of patients receiving heart transplants from older donors. METHODS: We retrospectively analyzed 2,102 consecutive heart transplants in 8 Spanish hospitals from 1998 to 2010. Acute and overall mortality were compared in patients with grafts from donors >=50 years old versus grafts from younger donors. RESULTS: There were 1,758 (84%) transplanted grafts from donors < 50 years old (Group I) and 344 (16%) from donors >=50 years old (Group II). Group I had more male donors than Group II (71% vs. 57%, p = 0.0001). The incidence of cardiovascular risk factors was higher in older donors. There were no differences in acute mortality or acute rejection episodes between the 2 groups. Global mortality was higher in Group II (rate ratio, 1.40; 95% confidence interval, 1.18-1.67; p = 0.001) than in Group I. After adjusting for donor cause of death, donor smoking history, recipient age, induction therapy, and cyclosporine therapy, the differences lost significance. Group II had a higher incidence of coronary allograft vasculopathy at 5 years (rate ratio, 1.67; 95% confidence interval, 1.22-2.27; p = 0.001). CONCLUSIONS: There were no differences in acute and overall mortality after adjusting for confounding factors. However, there was a midterm increased risk of coronary allograft vasculopathy with the use of older donors. Careful selection of recipients and close monitoring of coronary allograft vasculopathy are warranted in these patients. PMID- 25499141 TI - Bronchiolitis obliterans syndrome is not specific for bronchiolitis obliterans in pediatric lung transplant. AB - BACKGROUND: Bronchiolitis obliterans (BO) is the leading cause of mortality beyond the first year after pediatric lung transplant, but the performance of an open lung biopsy is often required for diagnosis. Bronchiolitis obliterans syndrome (BOS) is a clinical diagnosis based on spirometric data that is the accepted standard for staging chronic allograft dysfunction. METHODS: We determined the sensitivity, specificity, and positive and negative predictive values of BOS for predicting BO in children. A chart review was conducted on 139 open lung biopsies and 43 lung explants performed at our center from 1990 through June 2010 in pediatric recipients of lung transplants. Results were excluded from analysis if insufficient data existed to calculate a stable BOS stage before biopsy/explant. RESULTS: The criteria for inclusion in the study were met by 67 open lung biopsies and 31 lung explants. The sensitivity, specificity, positive predictive value, and negative predictive value of BOS for predicting BO were 91.0%, 25.8%, 72.6%, and 57.1%. CONCLUSIONS: We found that early declines in lung function are sensitive, but not specific, for BO. The low specificity of BOS for identifying BO illustrates the challenge facing clinicians in determining the etiology of pulmonary decline after lung transplant. PMID- 25499143 TI - Bhopal's legacy: three decades on and residents are still being poisoned. PMID- 25499144 TI - Professionalization of anesthesiologists and critical care specialists in humanitarian action: a nationwide poll among italian residents. AB - BACKGROUND: Over the last decades, humanitarian crises have seen a sharp upward trend. Regrettably, physicians involved in humanitarian action have often demonstrated incomplete preparation for these compelling events which have proved to be quite different from their daily work. Responders to these crises have included an unpredictable mix of beginner-level, mid-level, and expert-level providers. The quality of care has varied considerably. The international humanitarian community, in responding to international calls for improved accountability, transparency, coordination, and a registry of professionalized international responders, has recently launched a call for further professionalization within the humanitarian assistance sector, especially among academic-affiliated education and training programs. As anesthetists have been involved traditionally in medical relief operations, and recent disasters have seen a massive engagement of young physicians, the authors conducted, as a first step, a poll among residents in Anesthesia and Critical Care Medicine in Italy to evaluate their interest in participating in competency-based humanitarian assistance education and in training incorporated early in residencies. METHODS: The Directors of all the 39 accredited anesthesia/critical care training programs in Italy were contacted and asked to submit a questionnaire to their residents regarding the objectives of the poll study. After acceptance to participate, residents were enrolled and asked to complete a web-based poll. RESULTS: A total of 29 (74%) of the initial training programs participated in the poll. Out of the 1,362 questionnaires mailed to residents, 924 (68%) were fully completed and returned. Only 63(6.8%) of the respondents voiced prior participation in humanitarian missions, but up to 690 (74.7%) stated they were interested in participating in future humanitarian deployments during their residency that carried over into their professional careers. Countrywide, 896 (97%) favored prior preparation for residents before participating in humanitarian missions, while the need for a specific, formal, professionalization process of the entire humanitarian aid sector was supported by 889 (96.2%). CONCLUSIONS: In Italy, the majority of anesthesia/critical care residents, through a formal poll study, affirmed interest in participating in humanitarian assistance missions and believe that further professionalization within the humanitarian aid sector is required. These results have implications for residency training programs worldwide. PMID- 25499145 TI - Boosting pitch encoding with audiovisual interactions in congenital amusia. AB - The combination of information across senses can enhance perception, as revealed for example by decreased reaction times or improved stimulus detection. Interestingly, these facilitatory effects have been shown to be maximal when responses to unisensory modalities are weak. The present study investigated whether audiovisual facilitation can be observed in congenital amusia, a music specific disorder primarily ascribed to impairments of pitch processing. Amusic individuals and their matched controls performed two tasks. In Task 1, they were required to detect auditory, visual, or audiovisual stimuli as rapidly as possible. In Task 2, they were required to detect as accurately and as rapidly as possible a pitch change within an otherwise monotonic 5-tone sequence that was presented either only auditorily (A condition), or simultaneously with a temporally congruent, but otherwise uninformative visual stimulus (AV condition). Results of Task 1 showed that amusics exhibit typical auditory and visual detection, and typical audiovisual integration capacities: both amusics and controls exhibited shorter response times for audiovisual stimuli than for either auditory stimuli or visual stimuli. Results of Task 2 revealed that both groups benefited from simultaneous uninformative visual stimuli to detect pitch changes: accuracy was higher and response times shorter in the AV condition than in the A condition. The audiovisual improvements of response times were observed for different pitch interval sizes depending on the group. These results suggest that both typical listeners and amusic individuals can benefit from multisensory integration to improve their pitch processing abilities and that this benefit varies as a function of task difficulty. These findings constitute the first step towards the perspective to exploit multisensory paradigms to reduce pitch-related deficits in congenital amusia, notably by suggesting that audiovisual paradigms are effective in an appropriate range of unimodal performance. PMID- 25499146 TI - Maintaining a cautious state of mind during a recognition test: a large-scale fMRI study. AB - Decision criterion is an important factor in recognition memory, determining the amount of evidence required to judge an item as previously encountered. For a typical recognition memory test involving the prior study of a set of items, a conservative criterion establishes a higher standard of evidence for recognition and designates fewer items as previously studied. In contrast, a liberal criterion establishes a lower standard of evidence and designates more items as previously studied. Therefore, the hit rate and the correct rejection rate on a recognition memory test can be affected by both the memory strength of the studied items and the criterion used to make that judgment. Yet most neuroimaging studies of the successful retrieval effect (a contrast between hits and correct rejections) fail to measure or consider decision criterion. The goal of the current fMRI study with ninety-five participants was to directly manipulate decision criteria on two tests of recognition memory by varying the likelihood of an item's prior occurrence. Our results indicate that regions of the lateral prefrontal and parietal cortex associated with successful retrieval are significantly more active when using conservative criteria than liberal criteria. Furthermore, our results reveal that activity in these regions associated with successful retrieval can be accounted for by individual differences in the conservativeness of the decision criterion above and beyond any differences in memory strength. These results expound on the role of cognitive control in recognition memory and the neural mechanisms that mediate this processing. PMID- 25499147 TI - An optimal glucose feeding strategy integrated with step-wise regulation of the dissolved oxygen level improves N-acetylglucosamine production in recombinant Bacillus subtilis. AB - In our previous work, a recombinant Bacillus subtilis strain for the microbial production of N-acetylglucosamine (GlcNAc) was constructed through modular pathway engineering. In this study, to enhance GlcNAc production, glucose feeding approaches and dissolved oxygen (DO) control methods in fed-batch culture were systematically investigated. We first studied the effects of different glucose feeding strategies, including exponential fed-batch culture, pulse fed-batch culture, constant rate fed-batch culture, and glucose control (5 g/L, 10 g/L, 15 g/L) fed-batch culture, on cell growth and GlcNAc synthesis. We found that GlcNAc production in glucose control (5 g/L) fed-batch culture reached 26.58 g/L, which was 3.10 times that in batch culture. Next, the effect of DO level (20%, 30%, 40%, and 50%) on GlcNAc production was investigated, and a step-wise DO control strategy (0-7 h, 30%; 7-15 h, 50%; 15-50 h, 40%; 50-72 h, 30%) was introduced. With the optimal glucose and DO control strategy, GlcNAc production reached 35.77 g/L, which was 4.17 times the production in batch culture without DO control. PMID- 25499148 TI - Current progress and future prospect of microalgal biomass harvest using various flocculation technologies. AB - Microalgae have been extensively studied for the production of various valuable products. Application of microalgae for the production of renewable energy has also received increasing attention in recent years. However, high cost of microalgal biomass harvesting is one of the bottlenecks for commercialization of microalgae-based industrial processes. Considering harvesting efficiency, operation economics and technological feasibility, flocculation is a superior method to harvest microalgae from mass culture. In this article, the latest progress of various microalgal cell harvesting methods via flocculation is reviewed with the emphasis on the current progress and prospect in environmentally friendly bio-based flocculation. Harvesting microalgae through bio-based flocculation is a promising component of the low-cost microalgal biomass production technology. PMID- 25499149 TI - Prophylactic Cranial Irradiation for Patients With Locally Advanced Non-Small Cell Lung Cancer at High Risk for Brain Metastases. AB - BACKGROUND: Although there is no proven survival benefit of prophylactic cranial irradiation (PCI) for patients with locally advanced (LA) non-small-cell lung cancer (NSCLC), some speculate that PCI might be helpful for certain subpopulations at higher risk of brain metastases (< 60 years, adenocarcinoma, or stage IIIB). In this study we evaluated the effect of PCI on survival among these high-risk LA-NSCLC patients on a national scale. MATERIALS AND METHODS: Using the Surveillance, Epidemiology, and End Results database, we included all adult patients with primary stage III NSCLC, diagnosed from 1988 to 1997 (years during which PCI was recorded) with follow-up until 2008. The Kaplan-Meier estimator, log-rank test, and Cox proportional hazard regression were used to evaluate the survival effect of PCI. Sequential landmark analysis excluding patients from 1 to 6 months after diagnosis was used to account for immortal time bias. RESULTS: A total of 17,852 patients were included in the analysis, among whom 326 (1.8%) received PCI. Patients younger than 60 years and those with adenocarcinoma were significantly more likely to receive PCI. After adjustment for available covariates, there was no statistically significant survival difference between PCI and non-PCI patients (hazard ratio, 1.04; 95% confidence interval, 0.93 1.16). Similar results were found in all subgroup analyses of high-risk patients. Sequential landmark analysis suggested a potential survival detriment associated with PCI when analyzing only patients who survived at least 3 months after diagnosis. CONCLUSION: Our population-based analysis suggested no overall survival benefit of PCI for LA-NSCLC patients, even among a group of patients who were at higher risk for brain metastases. PMID- 25499150 TI - Genetic and epigenetic pathways in myelodysplastic syndromes: A brief overview. AB - Myelodysplastic syndromes (MDS) are a highly heterogenous group of hematopoietic tumors, mainly due to variable clinical features and diverse set of cytogenetic, molecular genetic and epigenetic lesions. The major clinical features of MDS are ineffective hematopoiesis, peripheral cytopenias, and an increased risk of transformation to acute myeloid leukemias, which in turn is most likely determined by specific genetic abnormalities and other presenting hematologic features. The risk of developing MDS is relatively higher in some genetic syndromes such as Fanconi anemia and receipt of chemotherapy and radiation treatment. In recent years a significant progress has occurred and a vast literatures has become available including the spectrum of cytogenetic abnormalities, gene mutations relating to RNA splicing machinery, epigenetic regulation of gene expression and signaling pathways associated with MDS pathogenesis, which have provided opportunities to understand the molecular mechanisms as well as employ targeted therapeutic approaches to treat MDS. The cytogenetic abnormalities detected in MDS varies from a single abnormality to complex karyotype not easily amenable to conventional cytogenetic analysis. In such cases, array based high resolution genomic analysis detected abnormalities, which are diagnostic as well as prognostic. The most common driver gene mutations detected in patients with MDS include RNA splicing (SF3B1,SRSF2,U2F1,ZRSR2), DNA methylation (TET2,DNMT3A,IDH1/IDH2), chromatin modification (ASXL1,EZH2), transcription regulation (RUNX1,BCOR) and DNA repair control p53. A small subset of MDS arise due to deregulation of RAS pathway, mainly due to NRAS/KRAS/NF1 mutations. Identification of these mutations and pathways have provided opportunities for oncologists to target these patients with specific therapies. Several drugs which either target the spliceosome, oncogenic RAS signaling, or hypomethylating agents have been employed to successfully treat MDS patients. PMID- 25499151 TI - Epilepsy Foundation's "#DareTo" campaign. PMID- 25499152 TI - Commissural reconnection: a possible reason for failure of corpus callosotomy in refractory epilepsy. PMID- 25499153 TI - Outpatient education reduces emergency room use by patients with epilepsy. AB - Epilepsy is a costly diagnosis, with emergency room (ER) visits and hospital admissions comprising a large portion of total direct cost. An educational intervention to decrease the number of ER visits was implemented on outpatients with epilepsy, using educational handouts and DVD. The number of ER visits declined significantly in the four months following intervention compared with the preceding four months. This finding supports patient education as a valuable tool to reduce ER use, which may, in turn, cut down on health-care cost. PMID- 25499154 TI - The benefits of antiepileptic drug (AED) blood level monitoring to complement clinical management of people with epilepsy. AB - INTRODUCTION: Some argue that there is no evidence to support the use of antiepileptic drug (AED) blood level monitoring when treating people with epilepsy (PWE). This paper identifies how AED monitoring can be invaluable in such treatment. SPECIFIC EXAMPLES: (i) Compliance: Antiepileptic drug blood levels often confirm noncompliance rather than adequate seizure control, confirming subtherapeutic levels in PWE attending hospitals due to seizures. Routine monitoring of AED levels may prevent breakthrough seizures by identifying noncompliance and instituting heightened compliance measures before experiencing breakthrough seizures without modifying dosages. For PWE attending hospitals due to seizures, loading with the AED shown to be subtherapeutic may be all that is required. (ii) Cluster seizures and status epilepticus: When using long-acting AEDs to complement benzodiazepines, blood level monitoring confirms that an adequate dosage was given and, if not, a further bolus can be administered with further monitoring. This is particularly useful when using rectal administration of AEDs. (iii) Polypharmacy: Polypharmacy provokes drug interactions in which case AED monitoring helps in differentiating adequate dosing, offending AED with toxicity and free level measuring benefits when total levels are unhelpful. (iv) Generic substitution: Generic AEDs can fluctuate considerably from a parent compound, and even a parent compound, sourced from an alternative supplier, may have altered bioavailability for which blood level monitoring is very useful. CONCLUSIONS: While therapeutic blood level monitoring is not a substitute for good clinical judgment, it offers a valuable adjunct to patient care. PMID- 25499155 TI - Inter- and intraobserver agreement of seizure behavior scoring in the amygdala kindled rat. AB - INTRODUCTION: The Racine scale is a 5-point seizure behavior scoring paradigm used in the amygdala kindled rat. Though this scale has been applied widely in experimental epilepsy research, studies of reproducibility are rare. The aim of the current study was, therefore, to assess its interobserver variability and intraobserver variability. MATERIAL AND METHODS: A video database set was acquired in the course of amygdala kindling of 67 Wistar rats. Six blinded observers received scoring instructions and then viewed a set of 15 random videos (session #1). Next, each observer scored 379 to 1048 additional videos (session #2) and finally scored the same set of 15 videos again (session #3). Scores included the occurrence of seizures (yes or no), the total seizure time (start of stimulus until the absence of seizure behavior), and the highest Racine stage. Interobserver variability and intraobserver variability were assessed in and between sessions #1 and #3 using a 2-way mixed intraclass correlation or Cohen's kappa depending on the variable. RESULTS: Interobserver agreement in session #1 was 0.664 for seizure occurrence, 0.861 for total seizure time, and 0.797 for the highest Racine stage. In session #3, interobserver agreement on seizure occurrence declined to 0.492, total seizure time declined to 0.625, and agreement for the highest Racine stage was 0.725. Interobserver agreement was scored insufficiently on focal R2 seizures in both sessions (0.287 and 0.182). Intraobserver agreement reached >0.80 agreement for seizure occurrence, highest seizure score, and total seizure time in 3 out of 4 observers. Racine's scale stage 2 seizure scores were only 0.135 in one observer but 0.650, 0.810, and 0.635 in the other observers. DISCUSSION AND CONCLUSION: Overall, interobserver agreement and intraobserver agreement in scoring with Racine's scale were adequate. However, because interobserver agreement declined after a period of individually scoring videos, we suggest periodic repetition of the standardized instruction in the course of evaluating videos in order to ensure reproducible results. PMID- 25499156 TI - Preservation of absolute pitch after right amygdalohippocampectomy for a pianist with TLE. AB - Absolute pitch (AP) ability is a rare musical phenomenon. In the literature, it has been suggested that the relative specialization for pitch processing is in the right temporal lobe in the non-AP population. Since the anatomic basis for absolute pitch is not fully understood and cases of temporal lobe epilepsy of AP possessors are extremely rare, applicability of resection as a treatment of epilepsy in this particular area should be evaluated with caution. In the present study, we examined an AP possessor who suffered from medically refractory temporal lobe epilepsy and underwent right selective amygdalohippocampectomy (SAH). The SAH procedure clearly avoided disturbing important structures for AP, inasmuch as postsurgically she preserved her AP ability and was seizure-free. She did well post-operatively in the test of pure sine wave tones with short reaction time, which could be identified as "true" absolute pitch. PMID- 25499157 TI - Parent-rated emotional-behavioral and executive functioning in childhood epilepsy. AB - The present study examined clinical and demographic risk factors associated with parent-rated emotional-behavioral and executive functioning in children and adolescents with epilepsy. The medical records of 152 children and adolescents with epilepsy referred for neuropsychological evaluation were reviewed. Results indicated that the sample displayed significantly elevated symptoms across the emotional-behavioral and executive domains assessed. Executive functioning and behavioral symptoms had the highest rates of clinically elevated scores, with lowest rates of elevated scores in internalizing and externalizing emotional problems. Only 34% of those participants with clinically significant emotional behavioral or executive functioning difficulties had a history of psychological or counseling services, highlighting the underserved mental health needs of this population. In regard to clinical factors, the majority of seizure-related variables were not associated with emotional-behavioral or executive functioning. However, the frequency of seizures (i.e., seizure status) was associated with behavioral regulation aspects of executive functioning, and the age at evaluation was associated with externalizing problems and behavioral symptoms. Family psychiatric history (with the exception of ADHD) was associated with all domains of executive and emotional-behavioral functioning. In summary, emotional behavioral and executive functioning difficulties frequently co-occur with seizures in childhood epilepsy, with both seizure-related and demographic factors contributing to the presentation of such neurobehavioral comorbidities. The present findings provide treatment providers of childhood epilepsy with important information to assist in better identifying children and adolescents who may be at risk for neurobehavioral comorbidities and may benefit from intervention. PMID- 25499158 TI - Sudden unexpected death in epilepsy (SUDEP): what do patients think? AB - OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is a major cause of mortality in epilepsy. Despite its devastating consequences, SUDEP appears to be poorly discussed with patients by health professionals. The risk of causing psychological distress to the patient is highlighted as a reason for not discussing SUDEP. However, no studies have assessed the adult patients' views on this important question. We conducted this cross-sectional study to evaluate the awareness and perspectives on SUDEP among adult patients with epilepsy. METHODS: One hundred five consecutive adult patients with epilepsy, referred to the Epilepsy Clinic of a tertiary hospital between October 2012 and November 2013, were surveyed to ascertain their views and understanding of SUDEP. The data were analyzed using logistic regression to explore the association between patients' awareness of SUDEP and characteristics such as age, gender, duration of epilepsy, level of education, and employment. RESULTS: Awareness of SUDEP among adult patients with epilepsy was poor (14.3%). However, the vast majority (89.5%) wished to be informed about SUDEP, and 59% requested detailed information. The treating neurologist was considered to be the most appropriate source of SUDEP information by 85.6% of patients. Multivariable analysis of the data showed no association between characteristics of patients (age, gender, duration of epilepsy, level of education, and employment) and their awareness of SUDEP or desire to get SUDEP-related information. CONCLUSIONS: Our study suggests that the majority of adult patients wish to be informed about SUDEP. This is in contrast to the general reluctance of medical professionals to inform all patients routinely about this condition. PMID- 25499159 TI - Theoretical considerations on Koubeissi et al. PMID- 25499160 TI - Cognitive development in females with PCDH19 gene-related epilepsy. AB - Mutations in the PCDH19 gene are now recognized to cause epilepsy in females and are claiming increasing interest in the scientific world. Clinical features and seizure semiology have been described as heterogeneous. Intellectual disability might be present, ranging from mild to severe; behavioral and psychiatric problems are a common feature of the disorder, including aggressiveness, depressed mood, and psychotic traits. The purpose of our study was to describe the cognitive development in 11 girls with a de novo mutation in PCDH19 and early onset epilepsy. Six patients had average mental development or mild intellectual disability regardless of persistence of seizures in clusters. Five patients presented moderate or severe intellectual disability and autistic features. In younger patients, we found that despite an average developmental quotient, they all presented a delay of expressive language acquisition and lower scores at follow-up testing completed at older ages, underlining that subtle dysfunctions might be present. Larger cohort and long-term follow-up might be useful in defining cognitive features and in improving the care of patients with PCDH19. PMID- 25499161 TI - Hypothesis: Astrocytes in the central medial amygdala may be implicated in sudden unexpected death in epilepsy by melanocortinergic signaling. PMID- 25499162 TI - A prospective long-term study of external trigeminal nerve stimulation for drug resistant epilepsy. AB - BACKGROUND: External trigeminal nerve stimulation (eTNS) is an emerging noninvasive therapy for drug-resistant epilepsy (DRE). We report the long-term safety and efficacy of eTNS after completion of a phase II randomized controlled clinical trial for drug-resistant epilepsy. METHODS: This was a prospective open label long-term study. Subjects who completed the phase II randomized controlled trial of eTNS for DRE were offered long-term follow-up for 1year. Subjects who were originally randomized to control settings were crossed over to effective device parameters (30s on, 30s off, pulse duration of 250s, frequency of 120Hz). Efficacy was assessed using last observation carried forward or parametric imputation methods for missing data points. Outcomes included change in median seizure frequency, RRATIO, and 50% responder rate. RESULTS: Thirty-five of 50 subjects from the acute double-blind randomized controlled study continued in the long-term study. External trigeminal nerve stimulation was well tolerated. No serious device-related adverse events occurred through 12months of long-term treatment. At six and twelve months, the median seizure frequency for the original treatment group decreased by -2.39 seizures per month at 6 months ( 27.4%) and -3.03 seizures per month at 12 months (-34.8%), respectively, from the initial baseline (p<0.05, signed-rank test). The 50% responder rates at three, six, and twelve months were 36.8% for the treatment group and 30.6% for all subjects. CONCLUSION: The results provide long-term evidence that external trigeminal nerve stimulation is a safe and promising long-term treatment for drug resistant epilepsy. PMID- 25499163 TI - Atorvastatin prevents development of kindling by modulating hippocampal levels of dopamine, glutamate, and GABA in mice. AB - PURPOSE: Atorvastatin (ATV) is widely used for the treatment of dyslipidemias. Recent evidence has shown that ATV has protection effects against seizures. However, the effect of ATV on certain neurotransmitter and oxidative stress markers associated with seizures had not been reported. Therefore, the present study aimed to evaluate the effects of ATV on oxidative stress markers on whole brain and GABA, glutamate, and dopamine levels in the hippocampus of PTZ-kindled mice. Additionally, effects of ATV on animal models of seizures, anxiety, and depression were also assessed. MATERIALS AND METHODS: Swiss albino mice were given ATV (20, 40, and 80mg/kg/p.o.) in an acute study. On the seventh day, animals were subjected to various neurological and neurobehavioral tests, viz, increasing current electroshock (ICES) test, pentylenetetrazole (PTZ)-induced seizures, Elevated Plus Maze (EPM), and Forced Swim Test (FST). For the development of kindling, a subconvulsant dose of PTZ, i.e., 25mg/kg, i.p., was administered every other day, and ATV in all the three doses was administered daily. Seizure score was continuously monitored until the development of kindling. Thiobarbituric acid reacting species (TBARS), glutathione, dopamine, GABA, and glutamate levels were also assessed in the brain tissues of mice. RESULTS: The results showed that in the ICES test, ATV 80mg/kg increased the seizure threshold to hind limb extension (HLE), and a complete protection against HLE was observed when ATV 80mg/kg was combined with a subanticonvulsant dose of phenytoin. Atorvastatin in all the tested doses suppressed the development of kindling, reduced lipid peroxidation, and increased glutathione levels. All doses of ATV maintained the normal levels of glutamate, GABA, and dopamine in kindled mice. CONCLUSION: Atorvastatin possesses anticonvulsant activity against electroconvulsions. It was found to suppress the development of PTZ kindling, presumably altering the redox status and hippocampal levels of dopamine, glutamate, and GABA. PMID- 25499164 TI - Social competence among well-functioning adolescents with epilepsy. AB - PURPOSE: The aims of the study were to measure the social competence of well functioning adolescents with epilepsy and compare it with that of their healthy peers as well as to analyze the effects of epilepsy-related variables on the social competence. METHODS: Ninety well-functioning adolescents with epilepsy 12 19years of age were compared with healthy controls using the Achenbach Youth Self Report Questionnaire measures of social competence. Within the group with epilepsy, the impact of duration of epilepsy, etiology, seizure frequency, seizure type, and antiepileptic drugs (AEDs) (monotherapy or polytherapy) on the above measures was also determined. RESULTS: Twenty-five (27.8%) adolescents with epilepsy obtained Total Competence T scores in the clinical range, as opposed to only two (3.3%) of the healthy adolescents. There were statistically significant differences in the Activity and Social subscales and Total Competence T score between the group with epilepsy and the control group (p<0.05). Comparing T scores for epilepsy-related variables in the group with epilepsy, we found that there were statistically significant differences in all the social competence subscales regarding the seizure control and seizure types. No significant differences were obtained for other epilepsy-related variables: duration of epilepsy, onset of epilepsy, etiology, and AEDs. CONCLUSION: Our results indicate that adolescents with epilepsy are less active in clubs, socialize less with their friends, and have a poorer school performance compared with their healthy peers. This study shows that adolescents with epilepsy are at an increased risk of having difficulties in social competence. PMID- 25499166 TI - Enhancing patient blood management: a long-term FOCUS. PMID- 25499165 TI - Liberal versus restrictive blood transfusion strategy: 3-year survival and cause of death results from the FOCUS randomised controlled trial. AB - BACKGROUND: Blood transfusion might affect long-term mortality by changing immune function and thus potentially increasing the risk of subsequent infections and cancer recurrence. Compared with a restrictive transfusion strategy, a more liberal strategy could reduce cardiac complications by lowering myocardial damage, thereby reducing future deaths from cardiovascular disease. We aimed to establish the effect of a liberal transfusion strategy on long-term survival compared with a restrictive transfusion strategy. METHODS: In the randomised controlled FOCUS trial, adult patients aged 50 years and older, with a history of or risk factors for cardiovascular disease, and with postoperative haemoglobin concentrations lower than 100 g/L within 3 days of surgery to repair a hip fracture, were eligible for enrolment. Patients were recruited from 47 participating hospitals in the USA and Canada, and eligible participants were randomly allocated in a 1:1 ratio by a central telephone system to either liberal transfusion in which they received blood transfusion to maintain haemoglobin level at 100 g/L or higher, or restrictive transfusion in which they received blood transfusion when haemoglobin level was lower than 80 g/L or if they had symptoms of anaemia. In this study, we analysed the long-term mortality of patients assigned to the two transfusion strategies, which was a secondary outcome of the FOCUS trial. Long-term mortality was established by linking the study participants to national death registries in the USA and Canada. Treatment assignment was not masked, but investigators who ascertained mortality and cause of death were masked to group assignment. Analyses were by intention to treat. The FOCUS trial is registered with ClinicalTrials.gov, number NCT00071032. FINDINGS: Between July 19, 2004, and Feb 28, 2009, 2016 patients were enrolled and randomly assigned to the two treatment groups: 1007 to the liberal transfusion strategy and 1009 to the restrictive transfusion strategy. The median duration of follow-up was 3.1 years (IQR 2.4-4.1 years), during which 841 (42%) patients died. Long-term mortality did not differ significantly between the liberal transfusion strategy (432 deaths) and the restrictive transfusion strategy (409 deaths) (hazard ratio 1.09 [95% CI 0.95-1.25]; p=0.21). INTERPRETATION: Liberal blood transfusion did not affect mortality compared with a restrictive transfusion strategy in a high-risk group of elderly patients with underlying cardiovascular disease or risk factors. The underlying causes of death did not differ between the trial groups. These findings do not support hypotheses that blood transfusion leads to long-term immunosuppression that is severe enough to affect long-term mortality rate by more than 20-25% or cause of death. FUNDING: National Heart, Lung, and Blood Institute. PMID- 25499167 TI - Whole-population vision screening in children aged 4-5 years to detect amblyopia. AB - Amblyopia is a neurodevelopmental disorder that affects at least 2% of most populations and can lead to permanently reduced vision if not detected and treated within a specific period in childhood. Whole-population screening of children younger than 5 years is applied in many countries. The substantial diversity in existing programmes reflects their heterogeneous implementation in the absence of the complete evidence base that is now a pre-requisite for instituting screening. The functional importance of amblyopia at an individual level is unclear as data are scarce, but in view of the high prevalence the population-level effect might be notable. Screening of all children aged 4-5 years (eg, at school entry) confers most benefit and addresses inequity in access to timely treatment. Screening at younger ages is associated with increased risk of false-positive results, and at older ages with poor outcomes for children with moderate to severe amblyopia. We suggest that the real-life adverse effects of amblyopia should be characterised and screening and diagnosis should be standardised. PMID- 25499168 TI - Kinematic difference between various geometric centers and contact points for tri condylar bi-surface knee system. AB - The purpose of the study was to analyze the motion of contact points (CPs), lowest points (LPs), and component facet centers of tri-condylar implants. In vivo knee kinematics was assessed for 43 knees implanted with a multi-radii femoral component during deep knee bend activity, using a model fitting approach. Both LPs had the similar positions to the corresponding geometric centers of the femoral component, and the LP and geometric center angles represented the same component rotation angle defined by Grood and Suntay. Antero-posterior translation of both CPs was significantly overestimated, compared to LPs, and the CP angle showed significant differences from other rotation angles. In conclusion LPs seemed better to evaluate kinematics than CPs because polyethylene congruity had considerable effects on CP analysis. PMID- 25499169 TI - Answer to Letter to the Editor, concerning: Functional and Radiographic Short Term Outcome Evaluation of the Visionaire System(r), a Patient Matched Instrumentation System for Total Knee Arthroplasty. PMID- 25499170 TI - When is it safe for patients to drive after right total hip arthroplasty? AB - Old studies recommend 6weeks post-operative before patients can return to driving safely. This is a prospective study assessing brake reaction time (BRT) after THA. 38 patients underwent a pre-operative, 2, 4 and 6weeks post-operative BRT test. General linear repeated measurement was used. The mean pre-operative reaction time was 0.635+/-0.160seconds SD and 2-week was 0.576+/-0.137seconds SD (P=0.029); 33 patients (87%) were able to reach their baseline time by 2weeks. The remaining five patients (13%) reached their baseline at the 4-week post operative. No differences were found with respect to age, gender, and the use of assistive devices. With new techniques in THA, most of patients return to normal times within the 2-week. PMID- 25499171 TI - The Effect of Dislocation Type (Crowe Types I-IV) on Pelvic Development in Developmental Dysplasia of the Hip: A Radiologic Study of Anatomy. AB - Classification of hip pathology in developmental dysplasia of the hip (DDH) helps in appropriate placement of implants during total hip arthroplasty. We examined preoperative unilateral and bilateral pelvic radiographs of 57 patients (114 hips) undergoing total hip arthroplasty because of DDH. Both sides of the pelvis were visually separated into 3 areas for comparison. When area ratios of hips with Crowe types II, III, and IV DDH were compared with ratios for healthy hips, values in hips with DDH were significantly low for the iliac wings, significantly high for the acetabular regions, and significantly low for the ischial area. Using a line crossing the healthy hip's teardrop and parallel to a line joining the distal sacroiliac joints is useful for calculating limb-length discrepancy. PMID- 25499172 TI - Above knee amputation following total knee arthroplasty: when enough is enough. AB - In some cases, above knee amputation (AKA) for a chronically infected total knee arthroplasty is the only option. The purpose of this study was to assess patient satisfaction following AKA and to identify factors which may be indicative of successful outcome following AKA. A review was performed of 7 patients who underwent an AKA for a recurrent peri-prosthetic knee infection. Patient satisfaction was gauged through a modified questionnaire. All patients were satisfied with their AKA and 6 of 7 stated that they would have chosen an amputation earlier. Greater than 6 attempts at limb-salvage and failed gastrocnemius flap were identified by expert opinion as possible poor prognostic factors. Despite poor function, patients with chronically infected TKAs are satisfied following an AKA. PMID- 25499173 TI - Survival outcome assessed according to tumor burden and progression patterns in patients with epidermal growth factor receptor mutant lung adenocarcinoma undergoing epidermal growth factor receptor tyrosine kinase inhibitor therapy. AB - BACKGROUND: Mutations in the epidermal growth factor receptor (EGFR) have been associated with a marked therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small-cell lung cancer (NSCLC). However, the clinical predictors of the survival benefit of EGFR-TKI therapy for NSCLC with EGFR-activating mutations have not been well elucidated. Therefore, the present study evaluated the clinical predictors of survival outcome in patients with EGFR mutant NSCLC who had been treated with EGFR-TKIs. MATERIAL AND METHODS: The data from 224 patients with EGFR-mutant lung adenocarcinoma treated with EGFR-TKIs were retrospectively reviewed. The treatment outcomes were evaluated according to the clinical factors, number of metastasis sites, and progression patterns. RESULTS: The clinical factors associated with reduced progression-free survival (PFS) and overall survival (OS) on univariate analysis were Eastern Cooperative Oncology Group (ECOG) performance status (PS) >= 2, intra- and extrathoracic metastasis, extrathoracic metastasis, a high number of metastatic sites, metastasis to the liver or adrenal gland at baseline, and rapid progression at the diagnosis of progressive disease (PD). On multivariate analysis, the factors that remained significantly associated with a shorter PFS were ECOG PS >= 2 (odds ratio [OR], 2.189; 95% confidence interval [CI], 1.374-3.437; P < .001) and rapid tumor progression at PD (OR, 1.800; 95% CI, 1.059-3.058; P = .030). CONCLUSION: Thus, the tumor burden, expressed as the number of metastatic sites at EGFR-TKI treatment, and rapid tumor progression at PD were predictive of inferior survival in patients with lung adenocarcinoma with activating EGFR mutations. PMID- 25499174 TI - RBF-network based sparse signal recovery algorithm for compressed sensing reconstruction. AB - The approach of applying a cascaded network consisting of radial basis function nodes and least square error minimization block to Compressed Sensing for recovery of sparse signals is analyzed in this paper to improve the computation time and convergence of an existing ANN based recovery algorithm. The proposed radial basis function-least square error projection cascade network for sparse signal Recovery (RASR) utilizes the smoothed L0 norm optimization, L2 least square error projection and feedback network model to improve the signal recovery performance over the existing CSIANN algorithm. The use of ANN architecture in the recovery algorithm gives a marginal reduction in computational time compared to an existing L0 relaxation based algorithm SL0. The simulation results and experimental evaluation of the algorithm performance are presented here. PMID- 25499175 TI - Association of Toll like receptor Asp299Gly with rheumatoid arthritis risk: a systematic review of case-control studies and meta-analysis. AB - OBJECTIVE: Rheumatoid arthritis (RA) is thought to be triggered by various genetic and environmental factors. Few human epidemiologic studies demonstrated that single nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes are associated with RA. We aimed to evaluate the effects of TLR polymorphisms on the risk of RA pathogenesis by using a meta-analysis approach. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a systematic search and meta-analysis of the literature was conducted. We screened the medical literature based on keywords search in MEDLINE and EMBASE 'Toll-like receptor', 'polymorphism', and rheumatoid arthritis. Meta analyses were performed under the random-effects model by using: (1) recessive, (2) homozygous, (3) dominant, (4) codominant and allele contrast models. RESULTS: A total of 3086 cases and 3756 controls in nine studies were included in the meta analysis. Association between TLR4 Asp299Gly and RA risk was marginally significant [OR = 0.856 (95% CI, 0.716-1.022); P = 0.086] in the homozygous model. AA and GG homozygote genotypes tended to be significant protective factors against RA risk. CONCLUSION: Our overall analyses indicated that TLR4 Asp299Gly polymorphism might contribute to RA pathogenesis. PMID- 25499176 TI - Predictors of early death in patients with acute pulmonary embolism. AB - AIM: We aimed to determine the predictors of early death in the course of acute pulmonary embolism (APE). MATERIALS AND METHODS: We included 206 patients who had been admitted to our hospital between January 2011 and April 2013 with the diagnosis of APE. We derived a new model including corrected QT interval dispersion (QTcd) and P wave dispersion (Pd), echocardiographic findings, laboratory markers, and blood cell count indices to predict early death in patients with APE. RESULTS: Thirty patients (14.5%) died; 176 patients (85.5%) lived after diagnosis of APE. Logistic regression (LR) analysis found that troponin I (odds ratio [OR], 1.084 [95% confidence interval {CI}, 1.009-1.165]), creatinine (OR, 4.153 [95% CI, 1.375-12.541]), mean platelet volume (OR, 1.991 [95% CI, 1.230-3.223]), neutrophil to lymphocyte ratio (NLR) (OR, 1.079 [95% CI, 1.005-1.160]), QTcd (OR, 1.084 [95% CI, 1.043-1.127]), Pd (OR, 1.049 [95% CI, 1.004-1.096]) were associated with early death in APE. New LR model (area under the curve [AUC], 0.970) performed better than the simplified pulmonary embolism severity index (sPESI) score (AUC, 0.859) in predicting early death in APE (P=.021). The predictivity of the sPESI score significantly improved after its single combination with creatinine, QTcd, or troponin I. When the combined model was constructed together with these 6 independent variables and sPESI score, stepwise LR model automatically excluded Pd and NLR, and the AUC from the rest of the combined model was 0.976, which is significantly different from the AUC of sPESI (0.859) (P=.0031). CONCLUSIONS: Creatinine, troponin I, and QTcd significantly improves sPESI score. A new model with troponin I, creatinine, mean platelet volume, NLR, QTcd, and Pd seems to have greater prognostic power than the sPESI scoring system. PMID- 25499177 TI - Recent advances in food biopeptides: production, biological functionalities and therapeutic applications. AB - The growing momentum of several common life-style diseases such as myocardial infarction, cardiovascular disorders, stroke, hypertension, diabetes, and atherosclerosis has become a serious global concern. Recent developments in the field of proteomics offering promising solutions to solving such health problems stimulates the uses of biopeptides as one of the therapeutic agents to alleviate disease-related risk factors. Functional peptides are typically produced from protein via enzymatic hydrolysis under in vitro or in vivo conditions using different kinds of proteolytic enzymes. An array of biological activities, including antioxidative, antihypertensive, antidiabetic and immunomodulating has been ascribed to different types of biopeptides derived from various food sources. In fact, biopeptides are nutritionally and functionally important for regulating some physiological functions in the body; however, these are yet to be extensively addressed with regard to their production through advance strategies, mechanisms of action and multiple biological functionalities. This review mainly focuses on recent biotechnological advances that are being made in the field of production in addition to covering the mode of action and biological activities, medicinal health functions and therapeutic applications of biopeptides. State-of the-art strategies that can ameliorate the efficacy, bioavailability, and functionality of biopeptides along with their future prospects are likewise discussed. PMID- 25499178 TI - Polymer nanotechnology based approaches in mucosal vaccine delivery: challenges and opportunities. AB - Mucosal sites serve as the main portal for the entry of pathogens and thus immunization through mucosal routes can greatly improve the immunity. Researchers are continuously exploring the vaccination strategies to engender protective mucosal immune responses. Unearthing of mucosal adjuvants, that are safe and effective, is enhancing the magnitude and quality of the protective immune response. Use of nanotechnology based polymeric nanocarrier systems which encapsulate vaccine components for protection of sensitive payload, incorporate mucosal adjuvants to maximize the immune responses and target the mucosal immune system is a key strategy to improve the effectiveness of mucosal vaccines. These advances promise to accelerate the development and testing of new mucosal vaccines against many human diseases. This review focuses on the need for the development of nanocarrier based mucosal vaccines with emphases on the polymeric nanoparticles, their clinical status and future perspectives. This review focuses on the need and new insights for the development of nanoarchitecture governed mucosal vaccination with emphases on the various polymeric nanoparticles, their clinical status and future perspectives. PMID- 25499179 TI - Achromobacter bacteraemia outbreak in a paediatric onco-haematology department related to strain with high surviving ability in contaminated disinfectant atomizers. AB - BACKGROUND: Achromobacter spp. are Gram-negative bacilli from aqueous environments, occasionally involved in bacteraemia in immunocompromised hosts and in outbreaks. AIM: We describe the characteristics of an achromobacter bacteraemia outbreak in a paediatric onco-haematology department. METHODS: Throughout a one-year period, 16 blood cultures from seven patients were positive for Achromobacter sp. All patients were immunocompromised, febrile, and central venous catheter (CVC) holders. A microbiological study was performed in patients' rooms, completed with an analysis of the disinfectant atomizers (didecyl diammonium chloride 0.25%, Surfanios, DMA). In total, 41 clinical and environmental strains were analysed by enterobacterial repetitive intergenic consensus (ERIC) polymerase chain reaction (PCR), repetitive PCR, and random amplified polymorphic DNA (RAPD)-PCR, and pulsed-field gel electrophoresis (PFGE). The bactericidal activity of DMA was studied on two Achromobacter sp. representative strains and one Pseudomonas aeruginosa reference strain, comparing biofilm and planktonic growth models. FINDINGS: The seven patients, including two severe cases, were successfully treated by systemic antimicrobial therapy and/or catheter removal. The 25 environmental isolates were recovered with the following chronology: hospital filtered tap water, disinfectant atomizers, and patients' rooms. All environmental, patient, and atomizer strains had identical PCR and PFGE patterns. The disinfectant susceptibility assay revealed that the strain isolated from the atomizers had high survival abilities in biofilm conditions and remained resistant to DMA after short contact periods. CONCLUSION: The use of disinfectant atomizers associated with the survival of Achromobacter in the atomizer pipes may explain the contamination and colonization of the CVC. Control measures (non-atomizer containers and use of sterile water) allowed the eradication of the source and the outbreak control. PMID- 25499181 TI - An approach to bioassessment of water quality using diversity measures based on species accumulative curves. AB - Traditional community-based bioassessment is time-consuming because they rely on full species-abundance data of a community. To improve bioassessment efficiency, the feasibility of the diversity measures based on species accumulative curves for bioassessment of water quality status was studied based on a dataset of microperiphyton fauna. The results showed that: (1) the species accumulative curves well fitted the Michaelis-Menten equation; (2) the beta- and gamma diversity, as well as the number of samples to 50% of the maximum species number (Michaelis-Menten constant K), can be statistically estimated based on the formulation; (3) the rarefied alpha-diversity represented a significant negative correlation with the changes in the nutrient NH4-N; and (4) the estimated beta diversity and the K constant were significantly positively related to the concentration of NH4-N. The results suggest that the diversity measures based on species accumulative curves might be used as a potential bioindicator of water quality in marine ecosystems. PMID- 25499180 TI - A metabolomic investigation of the effects of metal pollution in oysters Crassostrea hongkongensis. AB - Metal pollution has been of great concern in the estuaries in Southern China. In this study, metabolic differences between oysters Crassostrea hongkongensis from clean and metal-polluted sites were characterized using NMR-based metabolomics. We collected oyster samples from one clean (Jiuzhen) and two metal polluted sites (Baijiao and Fugong). The metal concentrations in oyster gills indicated that both the Baijiao and Fugong sites were severely polluted by several metals, including Cr, Ni, Cu, Zn, Ag, Cd and Pb. In particular, Cu and Zn were the major contaminants from the Baijiao and Fugong sites. Compared with those oysters from the clean site (JZ), metal pollution in BJ and FG induced disturbances in osmotic regulation and energy metabolism via different metabolic pathways, as indicated by different metabolic biomarkers. This study demonstrates that NMR-based metabolomics is a useful tool for characterizing metabolic responses induced by metal pollution. PMID- 25499182 TI - Nutrient removal in a closed silvofishery system using three mangrove species (Avicennia germinans, Laguncularia racemosa, and Rhizophora mangle). AB - The removal of ammonium (NH4(+)), nitrite (NO2(-)), nitrate (NO3(-)), and phosphate (PO4(-3)) in a closed silvofishery system was examined using three mangrove species (i.e., Avicennia germinans, Laguncularia racemosa, and Rhizophora mangle). Specifically, six closed tanks were installed for this experiment with a population of 60 Dormitator latifrons fishes per tank. We planted 40 seedlings in each of three experimental tanks separated by species, while the remaining tanks were used as control. During 15 weeks, nutrient concentrations among the three mangrove systems presented no significant differences (P>0.05). However, nutrient removal variability was minimum during the last 2-5 weeks. Mangroves presented an average efficiency of 63% for the removal of NH4(+) and NO2(-). Contrary, the average removal potential of NO3(-) and PO4(-3) was 50%. Results from this study suggest that the three mangrove species could be used in a closed silvofishery systems for the biological removal of NH4(+), NO2(-), NO3(-), and PO4(-3). PMID- 25499183 TI - Response of a seagrass fish assemblage to improved wastewater treatment. AB - We compared the structure of a seagrass fish assemblage near a sewage outlet before and after improvements to wastewater treatment. To determine whether responses by the fish assemblage were due to changes in water quality or to other factors, comparisons were made with the structure of a fish assemblage from a nearby site unaffected by sewage effluent. Total species richness, density and biomass of fish, decreased at both sites over the 30-year period. An increase in mean trophic level near the sewage outlet following improvements in water quality indicated that wastewater treatment had another important effect. This result is consistent with the reductions in food webs supporting pelagic and benthic fishes that typically accompany decreases in nutrient inputs. Although improvements to wastewater treatment explained much of the variation in the structure of the fish assemblage at PC, our results also suggest that fishing and climate change, at both sites. PMID- 25499184 TI - The effects of oil pollution on Antarctic benthic diatom communities over 5 years. AB - Although considered pristine, Antarctica has not been impervious to hydrocarbon pollution. Antarctica's history is peppered with oil spills and numerous abandoned waste disposal sites. Both spill events and constant leakages contribute to previous and current sources of pollution into marine sediments. Here we compare the response of the benthic diatom communities over 5 years to exposure to a commonly used standard synthetic lubricant oil, an alternative lubricant marketed as more biodegradable, in comparison to a control treatment. Community composition varied significantly over time and between treatments with some high variability within contaminated treatments suggesting community stress. Both lubricants showed evidence of significant effects on community composition after 5 years even though total petroleum hydrocarbon reduction reached approximately 80% over this time period. It appears that even after 5 years toxicity remains high for both the standard and biodegradable lubricants revealing the temporal scale at which pollutants persist in Antarctica. PMID- 25499185 TI - Occurrence of carbapenemase-producing bacteria in coastal recreational waters. AB - The spread of carbapenemase-producing Gram-negative rods is an emerging global problem. Although most infections due to carbapenemase producers are limited to healthcare institutions, reports of the occurrence of clinically relevant carbapenemase producers in sewage and polluted rivers are increasingly frequent. Polluted rivers flowing to oceans may contaminate coastal waters with multidrug resistant bacteria, potentially threatening the safety of recreational activities in these locations. Here we assessed the occurrence of carbapenemase producers in water from touristic beaches located in Rio de Janeiro, Brazil, showing distinct pollution patterns. The presence of enterobacteria was noted, including the predominantly environmental genus Kluyvera spp., producing either Klebsiella pneumoniae carbapenemase (KPC) or Guyana extended-spectrum (GES)-type carbapenemases and often associated with quinolone resistance determinants. An Aeromonas sp. harbouring blaKPC and qnrS was also observed. These findings strengthen the role of aquatic matrices as reservoirs and vectors of clinically relevant antimicrobial-resistant bacteria, with potential to favour the spread of these resistance threats throughout the community. PMID- 25499186 TI - High rate of levofloxacin resistance in a background of clarithromycin- and metronidazole-resistant Helicobacter pylori in Vietnam. AB - Antimicrobial resistance in Helicobacter pylori has increased worldwide and has become a major cause of treatment failure in many countries, including Vietnam. It is advisable to perform an antibiogram to provide optimal regimens for H. pylori eradication. This study evaluated the rate of antibiotic resistance to the four commonly used antibiotics against H. pylori at a tertiary care hospital in Central Vietnam and analysed point mutations in genes related to clarithromycin (CLA) and levofloxacin (LFX) resistance. A total of 92 H. pylori strains from gastric biopsy specimens were tested; 42.4% were resistant to CLA (primary, 34.2%; secondary, 73.7%), 41.3% to LFX (primary, 35.6%; secondary, 63.2%), 76.1% to metronidazole (MTZ) and 1.1% to amoxicillin. Multidrug resistance was observed in 56.5% (primary, 50.7%; secondary, 78.9%) of isolates (P<0.05). The rate of resistance to LFX was significantly higher in females than males (P<0.05). Most of the CLA- and LFX-resistant strains harboured resistance-associated mutations, with common positions at A2143G and T2182C in the 23S rRNA gene and at Asn-87 or Asp-91 in GyrA. Minimum inhibitory concentrations (MICs) increased in strains carrying quadruple mutations in their 23S rRNA gene and in strains with Asn-87 GyrA mutation (P<0.05). One high-level LFX-resistant strain (MIC=32mg/L) had new mutations with a combination of N87A, A88N and V65I. High resistance rates to CLA, MTZ and LFX discourage standard and LFX-based triple therapies as first-line treatment in Vietnam. PMID- 25499187 TI - Comparison of the effects of albumin and crystalloid on mortality in adult patients with severe sepsis and septic shock: a meta-analysis of randomized clinical trials. AB - INTRODUCTION: The aim of this study was to examine whether albumin reduced mortality when employed for the resuscitation of adult patients with severe sepsis and septic shock compared with crystalloid by meta-analysis. METHODS: We searched for and gathered data from MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials and Web of Science databases. Studies were eligible if they compared the effects of albumin versus crystalloid therapy on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Disagreements were resolved by discussion with other two reviewers until a consensus was achieved. Data including mortality, sample size of the patients with severe sepsis, sample size of the patients with septic shock and resuscitation endpoints were extracted. Data were analyzed by the methods recommended by the Cochrane Collaboration Review Manager 4.2 software. RESULTS: A total of 5,534 records were identified through the initial search. Five studies compared albumin with crystalloid. In total, 3,658 severe sepsis and 2,180 septic shock patients were included in the meta-analysis. The heterogeneity was determined to be non-significant (P = 0.86, I(2) = 0%). Compared with crystalloid, a trend toward reduced 90-day mortality was observed in severe sepsis patients resuscitated with albumin (odds ratio (OR) 0.88; 95% CI, 0.76 to 1.01; P = 0.08). However, the use of albumin for resuscitation significantly decreased 90-day mortality in septic shock patients (OR 0.81; 95% CI, 0.67 to 0.97; P = 0.03). Compared with saline, the use of albumin for resuscitation slightly improved outcome in severe sepsis patients (OR 0.81; 95% CI, 0.64 to 1.08; P = 0.09). CONCLUSIONS: In this meta-analysis, a trend toward reduced 90 day mortality was observed in severe sepsis patients resuscitated with albumin compared with crystalloid and saline. Moreover, the 90-day mortality of patients with septic shock decreased significantly. PMID- 25499188 TI - Persistence of West Nile virus. AB - West Nile virus (WNV) is a widespread global pathogen that results in significant morbidity and mortality. Data from animal models provide evidence of persistent renal and neurological infection from WNV; however, the possibility of persistent infection in humans and long-term neurological and renal outcomes related to viral persistence remain largely unknown. In this paper, we provide a review of the literature related to persistent infection in parallel with the findings from cohorts of patients with a history of WNV infection. The next steps for enhancing our understanding of WNV as a persistent pathogen are discussed. PMID- 25499189 TI - Epithelial cell ADAM17 activation by Helicobacter pylori: role of ADAM17 C terminus and Threonine-735 phosphorylation. AB - Helicobacter pylori transactivates the epidermal growth factor receptor (EGFR) on gastric epithelial cells via a signalling cascade involving a disintegrin and metalloprotease 17 (ADAM17) cleavage of membrane bound heparin binding-epidermal growth factor (HB-EGF). The effects of H. pylori on ADAM17 C-terminus in epithelial cells have been examined. Total cellular ADAM17 and surface expression of ADAM17 were significantly increased by H. pylori in AGS gastric epithelial cells. These changes were associated with ADAM17 C-terminal phosphorylation at T375 and S791. AGS cells lacking the ADAM17 C-terminal domain induced significantly attenuated cleavage of HB-EGF and were also unable to upregulate HB EGF and EGFR transcripts to the same extent as cells expressing full length ADAM17. In mitotic unstimulated AGS and ADAM17 over-expressing AGS cells, ADAM17 was highly T735 phosphorylated indicating ADAM17 T735 phosphorylation is modified during the cell cycle. In conclusion, H. pylori induced ADAM17 C-terminal T735 and/or S791 phosphorylation in gastric epithelial cells are likely to be an important trigger inducing ADAM17 activation and shedding of HB-EGF leading to EGFR transactivation. ADAM17 over-expression in gastric cancer represents a potential target for therapeutic intervention. PMID- 25499190 TI - Investigating attention in complex visual search. AB - How we attend to and search for objects in the real world is influenced by a host of low-level and higher-level factors whose interactions are poorly understood. The vast majority of studies approach this issue by experimentally controlling one or two factors in isolation, often under conditions with limited ecological validity. We present a comprehensive regression framework, together with a matlab implemented toolbox, which allows concurrent factors influencing saccade targeting to be more clearly distinguished. Based on the idea of gaze selection as a point process, the framework allows each putative factor to be modeled as a covariate in a generalized linear model, and its significance to be evaluated with model-based hypothesis testing. We apply this framework to visual search for faces as an example and demonstrate its power in detecting effects of eccentricity, inversion, task congruency, emotional expression, and serial fixation order on the targeting of gaze. Among other things, we find evidence for multiple goal-related and goal-independent processes that operate with distinct visuotopy and time course. PMID- 25499191 TI - Spatially variant noise estimation in MRI: a homomorphic approach. AB - The reliable estimation of noise characteristics in MRI is a task of great importance due to the influence of noise features in extensively used post processing algorithms. Many methods have been proposed in the literature to retrieve noise features from the magnitude signal. However, most of them assume a stationary noise model, i.e., the features of noise do not vary with the position inside the image. This assumption does not hold when modern scanning techniques are considered, e.g., in the case of parallel reconstruction and intensity correction. Therefore, new noise estimators must be found to cope with non stationary noise. Some methods have been recently proposed in the literature. However, they require multiple acquisitions or extra information which is usually not available (biophysical models, sensitivity of coils). In this work we overcome this drawback by proposing a new method that can accurately estimate the non-stationary parameters of noise from just a single magnitude image. In the derivation, we considered the noise to follow a non-stationary Rician distribution, since it is the most common model in real acquisitions (e.g., SENSE reconstruction), though it can be easily generalized to other models. The proposed approach makes use of a homomorphic separation of the spatially variant noise in two terms: a stationary noise term and one low frequency signal that correspond to the x-dependent variance of noise. The non-stationary variance of noise is then estimated by a low pass filtering with a Rician bias correction. Results in real and synthetic experiments evidence the better performance and the lowest error variance of the proposed methodology when compared to the state-of the-art methods. PMID- 25499192 TI - Using PubMed search strings for efficient retrieval of manual therapy research literature. AB - OBJECTIVE: The aim of this study was to construct PubMed search strings that could efficiently retrieve studies on manual therapy (MT), especially for time constrained clinicians. METHODS: Our experts chose 11 Medical Subject Heading terms describing MT along with 84 additional potential terms. For each term that was able to retrieve more than 100 abstracts, we systematically extracted a sample of abstracts from which we estimated the proportion of studies potentially relevant to MT. We then constructed 2 search strings: 1 narrow (threshold of pertinent articles >=40%) and 1 expanded (including all terms for which a proportion had been calculated). We tested these search strings against articles on 2 conditions relevant to MT (thoracic and temporomandibular pain). We calculated the number of abstracts needed to read (NNR) to identify 1 potentially pertinent article in the context of these conditions. Finally, we evaluated the efficiency of the proposed PubMed search strings to identify relevant articles included in a systematic review on spinal manipulative therapy for chronic low back pain. RESULTS: Fifty-five search terms were able to extract more than 100 citations. The NNR to find 1 potentially pertinent article using the narrow string was 1.2 for thoracic pain and 1.3 for temporomandibular pain, and the NNR for the expanded string was 1.9 and 1.6, respectively. The narrow search strategy retrieved all the randomized controlled trials included in the systematic review selected for comparison. CONCLUSION: The proposed PubMed search strings may help health care professionals locate potentially pertinent articles and review a large number of MT studies efficiently to better implement evidence-based practice. PMID- 25499193 TI - A comparison of lumbopelvic motion patterns and erector spinae behavior between asymptomatic subjects and patients with recurrent low back pain during pain-free periods. AB - OBJECTIVES: The purpose of this study was to determine the patterns of lumbopelvic motion and erector spinae (ES) activity during trunk flexion extension movements and to compare these patterns between patients with recurrent low back pain (LBP) in their pain-free periods and matched asymptomatic subjects. METHODS: Thirty subjects participated (15 patients with disc herniation and recurrent LBP in their pain-free periods and 15 asymptomatic control subjects). A 3-dimensional videophotogrammetric system and surface electromyography (EMG) were used to record the angular displacements of the lumbar spine and hip in the sagittal plane and the EMG activity of the ES during standardized trunk flexion extension cycles. Variables were maximum ranges of spine and hip flexion; percentages of maximum lumbar and hip flexion at the start and end of ES relaxation; average percentages of EMG activity during flexion, relaxation, and extension; and flexion-extension ratio of myoelectrical activity. RESULTS: Recurrent LBP patients during their pain-free period showed significantly greater ES activation both in flexion and extension, with a higher flexion-extension ratio than controls. Maximum ranges of lumbar and hip flexion showed no differences between controls and patients, although patients spent less time with their lumbar spine maximally flexed. CONCLUSIONS: This study showed that reduced maximum ranges of motion and absence of ES flexion-relaxation phenomenon were not useful to identify LBP patients in the absence of acute pain. However, these patients showed subtle alterations of their lumbopelvic motion and ES activity patterns, which may have important clinical implications. PMID- 25499194 TI - The first reported case of central venous catheter-related fungemia caused by Cryptococcus liquefaciens. AB - We describe a case of central venous catheter-related fungemia caused by Cryptococcus liquefaciens, a non-neoformans and non-gattii Cryptococcus, in a non HIV patient. A 71-year-old man with diffuse large B-cell lymphoma receiving antineoplastic chemotherapy was febrile approximately 30 weeks after central venous port insertion, and C. liquefaciens was isolated from all three performed blood cultures as well as a central venous catheter tip culture. In vitro antifungal susceptibility tests showed that this yeast isolate was susceptible to low concentrations of amphotericin B, fluconazole, itraconazole and voriconazole yet was resistant to 5-fluorocytosine (MIC: >64 MUg/ml), unlike Cryptococcus neoformans. Treatment of the patient with oral and intravenous voriconazole was effective and consistent with the susceptibility tests. Although non-neoformans and non-gattii Cryptococcus spp. are considered non-pathogenic environmental yeast, they may rarely be the causative agents of serious infections in humans, as in the present case. PMID- 25499195 TI - A newly developed kit for the measurement of urinary liver-type fatty acid binding protein as a biomarker for acute kidney injury in patients with critical care. AB - In recent years, it has been reported that the urinary level of Liver-type fatty acid-binding protein (L-FABP) serves as a useful biomarker for diagnosing acute kidney injury (AKI) or sepsis complicated by AKI. However, because the urinary level of L-FABP is currently measured by enzyme-linked immunosorbent assay (ELISA), several days may elapse before the results of the measurement become available. We have newly developed a simplified kit, the Dip-test, for measuring the urinary level of L-FABP. The Dip-test was measured at 80 measurement points (22 points in noninfectious disease, 13 points in SIRS, 20 points in infectious disease, and 25 points in sepsis) in 20 patients. The urinary L-FABP levels as determined by ELISA in relation to the results of the Dip-test were as follows: 10.10 +/- 12.85 ng/ml in patients with a negative Dip-test ([-] group), 41.93 +/- 50.51 ng/ml in patients with a +/- test ([+/-] group), 70.36 +/- 73.70 ng/ml in patients with a positive test ([+] group), 1048.96 +/- 2117.68 ng/ml in patients with a 2 + test ([2+] group), and 23,571.55 +/- 21,737.45 ng/ml in patients with a 3 + test ([3+] group). The following tendency was noted: the stronger the positive Dip-test reaction, the higher the urinary L-FABP level. Multigroup comparison revealed a significant differences in the urinary L-FABP levels between the Dip-test (-) group and each of the other groups. In this study, the usefulness of the Dip-test, our newly developed simplified kit for measuring the urinary L-FABP level, is suggested. PMID- 25499196 TI - INEQUITY ISSUES AND MOTHERS' PREGNANCY, DELIVERY AND EARLY-AGE SURVIVAL EXPERIENCES IN ENDE DISTRICT, INDONESIA. AB - Indonesia's infant mortality rates are among the highest in South-East Asia, and there are substantial variations between its sub-national regions. This qualitative study aims to explore early mortality-related health service provision and gender inequity issues based on mothers' pregnancy, delivery and early-age survival experience in Ende district, Nusa Tenggara Timur province. Thirty-two mothers aged 18-45 years with at least one birth in the previous five years were interviewed in depth in May 2013. The results show most mothers have little knowledge about the danger signs for a child's illness. Mothers with early age deaths generally did not know the cause of death. Very few mothers had received adequate information on maternal and child health during their antenatal and postnatal visits to the health facility. Some mothers expressed a preference for using a traditional birth attendant, because of their ready availability and the more extensive range of support services they provide, compared with local midwives. Unprofessional attitudes displayed by midwives were reported by several mothers. As elsewhere in Indonesia, the power of health decision-making lies with the husband. Policies aimed at elevating mothers' roles in health care decision making are discussed as measures that would help to improve early-age survival outcomes. Widening the public health insurance distribution, especially among poorer mothers, and equalizing the geographical distribution of midwives and health facilities are recommended to tackle geographical inequities and to increase early-age survival in Ende district. PMID- 25499197 TI - Detection of genomic loci associated with environmental variables using generalized linear mixed models. AB - We tested the use of Generalized Linear Mixed Models to detect associations between genetic loci and environmental variables, taking into account the population structure of sampled individuals. We used a simulation approach to generate datasets under demographically and selectively explicit models. These datasets were used to analyze and optimize GLMM capacity to detect the association between markers and selective coefficients as environmental data in terms of false and true positive rates. Different sampling strategies were tested, maximizing the number of populations sampled, sites sampled per population, or individuals sampled per site, and the effect of different selective intensities on the efficiency of the method was determined. Finally, we apply these models to an Arabidopsis thaliana SNP dataset from different accessions, looking for loci associated with spring minimal temperature. We identified 25 regions that exhibit unusual correlations with the climatic variable and contain genes with functions related to temperature stress. PMID- 25499198 TI - Neutrophil CD64 serves as a sensitive and reliable biomarker for the diagnosis of bacterial infection in hematological disorders. PMID- 25499199 TI - Performance of pro-adrenomedullin for identifying adverse outcomes in community acquired pneumonia. AB - BACKGROUND: We sought to evaluate the usefulness of biomarkers-procalcitonin (PCT), C-reactive protein (CRP) and proadrenomedullin (pro-ADM)-combined with prognostic scales (PSI, CURB-65 and SCAP score) for identifying adverse outcomes in patients with community-acquired pneumonia (CAP) attending at an Emergency Department (ED). METHODS: Prospective observational study in a teaching hospital among patients with CAP. In addition to collecting data for the prognostic scales, samples were taken at the ED for assessing PCT, CRP and pro-ADM levels. We compared the prognostic accuracy of these biomarkers with severity scores to predict pneumonia related complications, using the area under the receiver operating characteristics curves (AUC), which evaluates how well the model discriminate between patients who had a pneumonia related complication or not. RESULTS: A total of 491 patients with CAP were enrolled, 256 being admitted to the hospital and 235 treated as outpatients. Admitted patients had higher biomarker levels than outpatients (p < 0.001). The SCAP score and pro-ADM level had the best AUCs for predicting pneumonia related complications (0.83 and 0.84, respectively). Considering SCAP score plus pro-ADM level, the AUC increased significantly to 0.88. SCAP score class 0 or 1 with a pro-ADM level <0.5 ng/mL was the best indicator for selecting patients for outpatient care. CONCLUSIONS: A new risk score combining SCAP score with pro-ADM level is useful to classify severity risk in CAP patients and hence supporting decision-making on hospital admission. PMID- 25499200 TI - Cellular microRNA-miR-548g-3p modulates the replication of dengue virus. AB - OBJECTIVE: It has been well recognized that microRNA plays a role in the host pathogen interaction network. The significance of microRNA in the regulation of dengue virus (DENV) replication, however, remains unknown. The objective of our study was to determine the biological function of miR-548g-3p in modulating the replication of dengue virus. METHODS: Here we report that employment of a microRNA target search algorithm to analyze the 5' untranslated region (5'UTR) consensus sequences of DENV (DENV serotypes 1-4) led to a discovery that miR-548g 3p directly targets the stem loop A promoter element within the 5'UTR, a region essential for DENV replication. Real-time PCR was used to measure the expression levels of miR-548g-3p under DENV infection. We performed overexpression and inhibition assays to test the role of miR-548g-3p on DENV replication. The protein and mRNA levels of interferon were measured by ELISA and real-time PCR respectively. RESULT: We found that overexpression of miR-548g-3p suppressed multiplication of DENV 1, 2, 3 and 4, and that miR-548g-3p was also found to interfere with DENV translation, thereby suppressing the expression of viral proteins. CONCLUSION: Our results suggest that miR-548g-3p directly regulates DENV replication and warrant further study to investigate the feasibility of microRNA-based anti-DENV approaches. PMID- 25499201 TI - Nongated vs electrocardiography-gated CT imaging of blunt aortic root rupture in a trauma patient. AB - An 18-year-old male, involved in a car accident, underwent a non-gated contrast enhanced CT with apparently no evidence of significant abnormalities of the thoracic aorta. The later onset of aortic valve regurgitation prompted a prospectively ECG-triggered high-pitch spiral acquisition using a dual-source CT system which showed a tear with a huge pseudoaneurysm of the aortic root. The patient underwent successful urgent conservative surgical repair. CT is the primary screening modality for aortic injuries. Cardiac motion artifacts may hamper sensitivity at the root/ascending aorta level when a non ECG-gated technique is used, thus masking a potentially life-threatening condition. ECG gated-CT should be mandatorily performed in patients with a high suspicion for an aortic root trauma thus allowing timely repair and avoiding a catastrophic event. PMID- 25499202 TI - Coronary vasospasm in CT angiography procedure. PMID- 25499203 TI - Anal carcinoma - Survival and recurrence in a large cohort of patients treated according to Nordic guidelines. AB - OBJECTIVE: To evaluate treatment outcome in a large population-based cohort of patients with anal cancer treated according to Nordic guidelines. MATERIAL: Clinical data were collected on 1266 patients with anal squamous cell carcinoma diagnosed from 2000 to 2007 in Sweden, Norway and Denmark. 886 of the patients received radiotherapy 54-64Gy with or without chemotherapy (5-fluorouracil plus cisplatin or mitomycin) according to different protocols, stratified by tumor stage. RESULTS: High age, male gender, large primary tumor, lymph node metastases, distant metastases, poor performance status, and non-inclusion into a protocol were all independent factors associated with worse outcome. Among patients treated according to any of the protocols, the 3-year recurrence-free survival ranged from 63% to 76%, with locoregional recurrences in 17% and distant metastases in 11% of patients. The highest rate of inguinal recurrence (11%) was seen in patients with small primary tumors, treated without inguinal irradiation. CONCLUSIONS: Good treatment efficacy was obtained with Nordic, widely implemented, guidelines for treatment of anal cancer. Inguinal prophylactic irradiation should be recommended also for small primary tumors. PMID- 25499204 TI - [Analysis of the question-answer activity of a hospital pharmacy. Example of the handling of drug interactions]. AB - INTRODUCTION: The medical care of patients generates questions among healthcare professionals. Some will necessitate an advanced research. The hospital pharmacist is at the interface between prescribers, caregivers and the medicines and is requested to answer these requests. Studies conducted in other countries showed that this question-answer activity represents a significant amount of time in daily work. In France, this topic was poorly explored. The objective of our work was to study the volume and the type of questions, the clinical situations, the time required, the medicines implicated and the sources of information used. MATERIALS AND METHODS: A prospective study was conducted in the pharmacy of a university hospital. All the requests answered by the pharmaceutical team, which needed a specific research, analysis and writing of an answer were collected. RESULTS: A hundred and one questions were analyzed, originating from doctors or medicals interns. Almost half concerned drug interactions, and among them, almost a fourth were not mentioned in the Summary of Product Characteristics of the medicines involved. A pharmaceutical advice was provided in 91.5% of the cases. Time dedicated to the research varied between less than 30 minutes and more than 8 hours. DISCUSSION AND CONCLUSION: This study illustrates the question-answer activity of a hospital pharmacy, which is currently not taken into account as an indicator of pharmaceutical activity. A large part concerns analysis and management of drug interactions and requires a significant amount of pharmaceutical time. PMID- 25499206 TI - Insight to leptin's function. PMID- 25499205 TI - Dosimetric analysis of the brachial plexus among patients with breast cancer treated with post-mastectomy radiotherapy to the ipsilateral supraclavicular area: report of 3 cases of radiation-induced brachial plexus neuropathy. AB - BACKGROUND: The purpose of this study was to evaluate the brachial plexus (BP) dose of postmastectomy radiotherapy (PMRT) to the ipsilateral supraclavicular (ISCL) area, and report the characteristics of radiation-induced brachial plexus neuropathy (RIBPN). METHODS: The BP dose of 31 patients who received adjuvant PMRT to the ISCL area and chest wall using three-dimensional conformal radiotherapy (3DCRT) and the records of 3 patients with RIBPN were retrospectively analyzed based on the standardized Radiation Therapy Oncology Group-endorsed guidelines. The total dose to the ISCL area and chest wall was 50 Gy in 25 fractions. RESULTS: Patients with a higher number of removed lymph nodes (RLNs) had a higher risk of RIBPN (hazard ratio [HR]: 1.189, 95% confidence interval [CI]: 1.005-1.406, p = 0.044). In 31 patients treated with 3DCRT, the mean dose to the BP without irradiation to the ISCL area was significantly less than that with irradiation to the ISCL area (0.97 +/- 0.20 vs. 44.39 +/- 4.13 Gy, t = 136.75, p <0.001). In the 3DCRT plans with irradiation to the ISCL area and chest wall, the maximum dose to the BP was negatively correlated with age (r = 0.40, p = 0.026), body mass index (BMI) (r = -0.44, p = 0.014), and body weight (r = -0.45, p = 0.011). Symptoms of the 3 patients with RIBPN occurred 37-65 months after radiotherapy, and included progressive upper extremity numbness, pain, and motor disturbance. After treatment, 1 patient was stable, and the other 2 patients' symptoms worsened. CONCLUSIONS: The incidence of RIBPN was higher in patients with a higher number of RLNs after PMRT. The dose to the BP is primarily from irradiation of the ISCL area, and is higher in slim and young patients. Prevention should be the main focus of managing RIBPN, and the BP should be considered an organ-at-risk when designing a radiotherapy plan for the ISCL area. PMID- 25499207 TI - Is neck pain associated with worse health-related quality of life 6 months later? A population-based cohort study. AB - BACKGROUND CONTEXT: Current evidence suggests that neck pain is negatively associated with health-related quality of life (HRQoL). However, these studies are cross-sectional and do not inform the association between neck pain and future HRQoL. PURPOSE: The purpose of this study was to investigate the association between increasing grades of neck pain severity and HRQoL 6 months later. In addition, this longitudinal study examines the crude association between the course of neck pain and HRQoL. STUDY DESIGN: This is a population based cohort study. PATIENT SAMPLE: Eleven hundred randomly sampled Saskatchewan adults were included. OUTCOME MEASURES: Outcome measures were the mental component summary (MCS) and physical component summary (PCS) of the Short-Form-36 (SF-36) questionnaire. METHODS: We formed a cohort of 1,100 randomly sampled Saskatchewan adults in September 1995. We used the Chronic Pain Questionnaire to measure neck pain and its related disability. The SF-36 questionnaire was used to measure physical and mental HRQoL 6 months later. Multivariable linear regression was used to measure the association between graded neck pain and HRQoL while controlling for confounding. Analysis of variance and t tests were used to measure the crude association among four possible courses of neck pain and HRQoL at 6 months. The neck pain trajectories over 6 months were no or mild neck pain, improving neck pain, worsening neck pain, and persistent neck pain. Finally, analysis of variance was used to examine changes in baseline to 6-month PCS and MCS scores among the four neck pain trajectory groups. RESULTS: The 6-month follow-up rate was 74.9%. We found an exposure-response relationship between neck pain and physical HRQoL after adjusting for age, education, arthritis, low back pain, and depressive symptomatology. Compared with participants without neck pain at baseline, those with mild (beta=-1.53, 95% confidence interval [CI]=-2.83, 0.24), intense (beta=-3.60, 95% CI=-5.76, -1.44), or disabling (beta=-8.55, 95% CI=-11.68, -5.42) neck pain had worse physical HRQoL 6 months later. We did not find an association between neck pain and mental HRQoL. A worsening course of neck pain and persistent neck pain were associated with worse physical HRQoL. CONCLUSIONS: We found that neck pain was negatively associated with physical but not mental HRQoL. Our analysis suggests that neck pain may be a contributor of future poor physical HRQoL in the population. Raising awareness of the possible future impact of neck pain on physical HRQoL is important for health-care providers and policy makers with respect to the management of neck pain in populations. PMID- 25499208 TI - Comparison of the lumbar disc herniation patients randomized in SPORT to 6,846 discectomy patients from NSQIP: demographics, perioperative variables, and complications correlate well. AB - BACKGROUND CONTEXT: The Spine Patient Outcomes Research Trial (SPORT) is a highly referenced clinical trial that randomized patients with lumbar pathology to receive surgery or continued conservative treatment. PURPOSE: The purpose of this study was to compare the SPORT lumbar disc herniation cohort and an analogous cohort from the National Surgical Quality Improvement Program (NSQIP) database. STUDY DESIGN/SETTING: This is a retrospective cohort study comparing a national database population to a randomized clinical trial. PATIENT SAMPLE: Elective lumbar discectomies from NSQIP between 2010 and 2012 were used. OUTCOME MEASURES: Demographics were compared between the randomized SPORT cohorts (surgical and nonoperative) and NSQIP. Perioperative factors and complications were then compared between SPORT discectomy patients and NSQIP. METHODS: Using current procedural terminology and International Classification of Diseases, ninth revision codes, all elective lumbar discectomies from NSQIP between 2010 and 2012 were identified. Where possible based on the published data and variables available in each cohort, the two populations were compared. RESULTS: A total of 6,846 NSQIP discectomy patients were compared with the randomized SPORT surgical and nonoperative cohorts. Demographic comparisons showed that NSQIP patients were older (average age 48.2+/-14.5 years [mean+/-standard deviation] vs. 41.7+/-11.8 and 43.0+/-11.3 years, respectively [p<.001]) and had higher body mass index (29.6+/-6.2 kg/m(2) vs. 27.8+/-5.6 and 28.2+/-5.4 kg/m(2), respectively [p<.001]). No statistical differences existed for gender or race. Smoking status was not different between the SPORT nonoperative group and NSQIP but was higher in NSQIP compared with SPORT surgical patients (p=.020 by 7%). Comparisons of perioperative factors and complications between the SPORT surgical cohort and NSQIP showed no statistical difference in average operative time, length of stay, deep wound infections, wound dehiscence, total wound complications, or blood transfusions. Spine Patient Outcomes Research Trial superficial wound infection rates were higher than NSQIP (p=.029 by 1.4%). As expected, SPORT 1-year reoperation rates were higher than NSQIP 30-day rates (7% vs. 2%, p<.001). CONCLUSIONS: Spine Patient Outcomes Research Trial lumbar disc herniation results are similar to those from a large national patient sample. Even statistically significant differences would be considered clinically similar. These findings support the generalizability of the SPORT lumbar disc herniation results. PMID- 25499209 TI - Relationship between rat retinal degeneration and potassium channel KCNQ5 expression. AB - KCNQ5/Kv7.5 is a low-threshold non-inactivating voltage-gated potassium channel preferentially targeted to excitatory endings in brain neurons. The M-type current is mediated by KCNQ5 channel subunits in monkey retinal pigment epithelium cells and in brain neurons. This study was undertaken to analyze KCNQ5 expression and the interaction signals of KCNQ5 with other proteins in normal rat retina and during photoreceptor degeneration. The KCNQ5 expression pattern was studied by immunocytochemistry and Western blot in normal rat retinas (Sprague Dawley, SD) and P23H-1 rats as a retinitis pigmentosa model. The physical interactions of KCNQ5 with calmodulin (CaM), vesicular glutamate transporter 1 (VGluT1) and glial fibrillary acidic protein (GFAP) were analyzed by in situ proximity ligation assays and were supported by calcium recording. KCNQ5 expression was found in the plexiform layers, ganglion cell layer and basal membrane of the retinal pigment epithelium. The physical interactions among KCNQ5 and CaM, VGluT1 and GFAP changed with age and during retinal degeneration. The maximal level of KCNQ5/CaM interaction was found when photoreceptors had almost completely disappeared; the KCNQ5/VGluT1 interaction signal decreased and the KCNQ5/GFAP interaction increased in the inner retina, while degeneration progressed. The basal calcium levels in the astrocytes and neurons of P23H-1 were higher than in the control SD retinas. This study demonstrates that KCNQ5 is present in the rat retina where its activity may be moderated by CaM. Retinal degeneration progression in P23H-1 rats can be followed by an interaction between KCNQ5 with CaM in an in situ system. The relationship between KCNQ5 and VGluT1 or GFAP needs to be more cautiously interpreted. PMID- 25499210 TI - Isolation of microvascular endothelial cells from cadaveric corneal limbus. AB - Limbal microvascular endothelial cells (L-MVEC) contribute to formation of the corneal-limbal stem cell niche and to neovascularization of diseased and injuries corneas. Nevertheless, despite these important roles in corneal health and disease, few attempts have been made to isolate L-MVEC with the view to studying their biology in vitro. We therefore explored the feasibility of generating primary cultures of L-MVEC from cadaveric human tissue. We commenced our study by evaluating growth conditions (MesenCult-XF system) that have been previously found to be associated with expression of the endothelial cell surface marker thrombomodulin/CD141, in crude cultures established from collagenase-digests of limbal stroma. The potential presence of L-MVEC in these cultures was examined by flow cytometry using a more specific marker for vascular endothelial cells, CD31/PECAM-1. These studies demonstrated that the presence of CD141 in crude cultures established using the MesenCult-XF system is unrelated to L-MVEC. Thus we subsequently explored the use of magnetic assisted cell sorting (MACS) for CD31 as a tool for generating cultures of L-MVEC, in conjunction with more traditional endothelial cell growth conditions. These conditions consisted of gelatin-coated tissue culture plastic and MCDB-131 medium supplemented with foetal bovine serum (10% v/v), D-glucose (10 mg/mL), epidermal growth factor (10 ng/mL), heparin (50 MUg/mL), hydrocortisone (1 MUg/mL) and basic fibroblast growth factor (10 ng/mL). Our studies revealed that use of endothelial growth conditions are insufficient to generate significant numbers of L-MVEC in primary cultures established from cadaveric corneal stroma. Nevertheless, through use of positive-MACS selection for CD31 we were able to routinely observe L-MVEC in cultures derived from collagenase-digests of limbal stroma. The presence of L MVEC in these cultures was confirmed by immunostaining for von Willebrand factor (vWF) and by ingestion of acetylated low-density lipoprotein. Moreover, the vWF(+) cells formed aligned cell-to-cell 'trains' when grown on GeltrexTM. The purity of L-MVEC cultures was found to be unrelated to tissue donor age (32-80 years) or duration in eye bank corneal preservation medium prior to use (3-10 days in Optisol) (using multiple regression test). Optimal purity of L-MVEC cultures was achieved through use of two rounds of positive-MACS selection for CD31 (mean +/- s.e.m, 65.0 +/- 20.8%; p < 0.05). We propose that human L-MVEC cultures generated through these techniques, in conjunction with other cell types, will provide a useful tool for exploring the mechanisms of blood vessel cell growth in vitro. PMID- 25499211 TI - Role of portal haemodynamic parameters in prediction of oesophageal varices in cirrhotic patients. AB - BACKGROUND AND STUDY AIMS: Screening all cirrhotic patients by endoscopy for detection of varices is not cost-effective as the number of patients increases by time and half of them still would not have developed varices 10years after being diagnosed with cirrhosis. Therefore, this study aimed to evaluate hepatic haemodynamic Doppler parameters in predicting the presence of oesophageal varices (OVs) in cirrhotic patients for better selection of those actually needed for screening endoscopy. PATIENTS AND METHODS: Eighty-one patients with liver cirrhosis, 32 females and 49 males, with a mean age of 50.7+/-11.7years were recruited for the study. They included 61 patients with OVs and 20 patients without varices. The diagnosis of liver cirrhosis was based on clinical history, examination, and investigations. Liver function and kidney function tests and complete blood count (CBC) were performed for all patients. All patients underwent abdominal ultrasound (US), upper endoscopy, and hepatic Doppler US examination. RESULTS: The portal vein velocity (PVV) and liver vascular index (LVI) showed statistically significantly lower values in patients with OVs than those without OVs (p value=0.02 and 0.000, respectively). The congestion index (CI) of the portal vein, the portal hypertension index (PHI), and the splenoportal index (SPI) showed statistically significantly higher values in patients with OVs than those without OVs (p value=0.006, 0.001, and 0.001, respectively). CI and SPI were the best parameters that could predict the presence of OVs with high sensitivity, specificity, and diagnostic accuracy when cutoff values were set at >0.069 and 3.57, respectively (area under the curve=0.864 and 0.894, respectively). CONCLUSIONS: The CI of the portal vein and SPI are good predictors for the presence of OVs in cirrhotic patients, and could be used noninvasively to decrease the burden on the upper endoscopy unit by proper selection of those who are candidates for screening endoscopy. PMID- 25499212 TI - Incidence and predictors of rebleeding after band ligation of oesophageal varices. AB - BACKGROUND AND STUDY AIMS: Variceal bleeding is a severe complication in patients with portal hypertension. Early rebleeding occurs frequently in the first few weeks after band ligation, and the mortality associated with each bleeding episode ranges from 30% to 50%. Our aims were to study the rate of early rebleeding oesophageal varices after band ligation in the Sohag University Hospital, Egypt, and to assess different clinical, biochemical, ultrasonographic, and endoscopic parameters that may predict the risk factors of rebleeding. PATIENTS AND METHODS: In the period from December 2011 to December 2012, we performed endoscopic variceal ligation (EVL) for 146 cirrhotic patients (105 male and 41 female) with a mean age of 51.77+/-10.47years; the patients were divided into rebleeding and non-rebleeding groups. Complete history taking, clinical examination, laboratory investigations, abdominal ultrasound (US), and upper gastrointestinal (GI) endoscopy were performed for all patients. RESULTS: The incidence of early rebleeding after EVL was 20.54%, and it was significantly associated with male gender (p=0.013), older age (p=0.009), infection with spontaneous bacterial peritonitis (SBP) (p<0.0007), reduced liver size (p=0.017), a coarser echo pattern (p=0.03), the presence of hepatic focal lesions (p<0.001), splenomegaly (p=0.02), the presence of portosystemic collaterals (p=0.006), a low haemoglobin (HB) level (p<0.0001), prothrombin concentration (p=0.017), high aspartate aminotransferase (AST) level (p=0.01), Child-Pugh B and C (p=0.02, 0.003), large oesophageal varices F3 in the two endoscopies (p=0.002; p<0.0001), varices extending to the superior third Ls (p<0.001), and the presence of massive red colour signs (RC+++) (p<0.0001). By multivariate analysis, SBP and low HB level were found to be independent predictors of rebleeding. CONCLUSION: The following conclusions were drawn from this study: (1) The incidence of rebleeding after EVL in our centre is about 20%. (2) Early rebleeding after EVL is affected by many clinical, laboratory, ultrasonographic, and endoscopic parameters. The most prominent of them are SBP, splenomegaly, the presence of collaterals, anaemia, more decompensated cirrhosis, and the presence of large varices with red signs. (3) SBP and low HB level were found to be independent predictors of rebleeding. PMID- 25499214 TI - Notch3/Jagged1 circuitry reinforces notch signaling and sustains T-ALL. AB - Deregulated Notch signaling has been extensively linked to T-cell acute lymphoblastic leukemia (T-ALL). Here, we show a direct relationship between Notch3 receptor and Jagged1 ligand in human cell lines and in a mouse model of T ALL. We provide evidence that Notch-specific ligand Jagged1 is a new Notch3 signaling target gene. This essential event justifies an aberrant Notch3/Jagged1 cis-expression inside the same cell. Moreover, we demonstrate in Notch3-IC overexpressing T lymphoma cells that Jagged1 undergoes a raft-associated constitutive processing. The proteolytic cleavage allows the Jagged1 intracellular domain to empower Notch signaling activity and to increase the transcriptional activation of Jagged1 itself (autocrine effect). On the other hand, the release of the soluble Jagged1 extracellular domain has a positive impact on activating Notch signaling in adjacent cells (paracrine effect), finally giving rise to a Notch3/Jagged1 auto-sustaining loop that supports the survival, proliferation, and invasion of lymphoma cells and contributes to the development and progression of Notch-dependent T-ALL. These observations are also supported by a study conducted on a cohort of patients in which Jagged1 expression is associated to adverse prognosis. PMID- 25499215 TI - Frequent disruption of chromodomain helicase DNA-binding protein 8 (CHD8) and functionally associated chromatin regulators in prostate cancer. AB - Abnormal expression and function of chromatin regulators results in the altered chromatin structure seen in cancer. The chromatin regulator CTCF, its cofactor CHD8, and antagonistic paralogue BORIS have wide-ranging effects on gene regulation. Their concurrent expression and regulation was examined in benign, localized, and metastatic prostate cancer (PCa) arrays with extended follow-up using an automated quantitative imaging system, VECTRA. Epithelial staining was quantified and compared against a range of clinicopathologic variables. CHD8 expression was decreased in HGPIN, localized, and metastatic PCa compared to benign (P < .001). CHD8 promoter hypermethylation, assessed by Quantitative Pyrosequencing, occurred in over 45% of primary cancers in this population as well as the TGCA database. Treatment of cell lines with the demethylating agent 5 Aza-2'-deoxycytidine reinduced expression. An interesting dichotomy for CHD8 was observed within primary cancers, with higher nuclear protein expression associated with adverse clinical outcomes including extracapsular extension (P = .007), presence of metastases (P = .025) and worse PSA-recurrence free survival (P = .048). CHD8 outperformed Gleason score and predicted biochemical failure within intermediate grade prostate cancers. The BORIS/CTCF expression ratio increased in localized (P = .03) and metastatic PCa (P = .006) and was associated with higher Gleason score (P = .02), increased tumor volume (P = .02) and positive margins (P = .04). Per cell heterogeneity of expression revealed all protein expression to be more heterogeneous in cancerous tissue (both P < .001), especially high grade (P < .01). In the first detailed analysis in cancer, a marked loss of CHD8 expression and increased BORIS/CTCF ratio indicate frequent disruption of CTCF and its effector genes in PCa. PMID- 25499213 TI - In vivo Mn-enhanced MRI for early tumor detection and growth rate analysis in a mouse medulloblastoma model. AB - Mouse models have increased our understanding of the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor that often forms in the cerebellum. A major goal of ongoing research is to better understand the early stages of tumorigenesis and to establish the genetic and environmental changes that underlie MB initiation and growth. However, studies of MB progression in mouse models are difficult due to the heterogeneity of tumor onset times and growth patterns and the lack of clinical symptoms at early stages. Magnetic resonance imaging (MRI) is critical for noninvasive, longitudinal, three dimensional (3D) brain tumor imaging in the clinic but is limited in resolution and sensitivity for imaging early MBs in mice. In this study, high-resolution (100 MUm in 2 hours) and high-throughput (150 MUm in 15 minutes) manganese enhanced MRI (MEMRI) protocols were optimized for early detection and monitoring of MBs in a Patched-1 (Ptch1) conditional knockout (CKO) model. The high tissue contrast obtained with MEMRI revealed detailed cerebellar morphology and enabled detection of MBs over a wide range of stages including pretumoral lesions as early as 2 to 3 weeks postnatal with volumes close to 0.1 mm(3). Furthermore, longitudinal MEMRI allowed noninvasive monitoring of tumors and demonstrated that lesions within and between individuals have different tumorigenic potentials. 3D volumetric studies allowed quantitative analysis of MB tumor morphology and growth rates in individual Ptch1-CKO mice. These results show that MEMRI provides a powerful method for early in vivo detection and longitudinal imaging of MB progression in the mouse brain. PMID- 25499216 TI - Harnessing the p53-PUMA axis to overcome DNA damage resistance in renal cell carcinoma. AB - Resistance to DNA damage-induced apoptosis is a hallmark of cancer and a major cause of treatment failure and lethal disease outcome. A tumor entity that is largely resistant to DNA-damaging therapies including chemo- or radiotherapy is renal cell carcinoma (RCC). This study was designed to explore the underlying molecular mechanisms of DNA damage resistance in RCC to develop strategies to resensitize tumor cells to DNA damage-induced apoptosis. Here, we show that apoptosis-resistant RCC cells have a disconnect between activation of p53 and upregulation of the downstream proapoptotic protein p53 upregulated modulator of apoptosis (PUMA). We demonstrate that this disconnect is not caused by gene specific repression through CCCTC-binding factor (CTCF) but instead by aberrant chromatin compaction. Treatment with an HDAC inhibitor was found to effectively reactivate PUMA expression on the mRNA and protein level and to revert resistance to DNA damage-induced cell death. Ectopic expression of PUMA was found to resensitize a panel of RCC cell lines to four different DNA-damaging agents tested. Remarkably, all RCC cell lines analyzed were wild-type for p53, and a knockdown was likewise able to sensitize RCC cells to acute genotoxic stress. Taken together, our results indicate that DNA damage resistance in RCC is reversible, involves the p53-PUMA axis, and is potentially targetable to improve the oncological outcomes of RCC patients. PMID- 25499217 TI - Regulation of Mcl-1 expression in context to bone marrow stromal microenvironment in chronic lymphocytic leukemia. AB - A growing body of evidence suggests that the resistance of CLL cells to apoptosis is partly mediated through the interactions between leukemia cells and adjacent stromal cells residing in the lymphatic tissue or bone marrow microenvironment. Mcl-1, an anti-apoptotic protein that is associated with failure to treatment is up-regulated in CLL lymphocytes after interaction with microenvironment. However, the regulation of its expression in context to microenvironment is unclear. We evaluated and compared changes in Mcl-1 in CLL B-cells in suspension culture and when co-cultured on stromal cells. The blockade of apoptosis in co-cultured CLL cells is associated with diminution in caspase-3 and PARP cleavage and is not dependent on cytogenetic profile or prognostic factors of the disease. Stroma derived resistance to apoptosis is associated with a cascade of transcriptional events such as increase in levels of total RNA Pol II and its phosphorylation at Ser2 and Ser5, increase in the rate of global RNA synthesis, and amplification of Mcl-1 transcript levels. The latter is associated with increase in Mcl-1 protein level without an impact on the levels of Bcl-2 and Bcl-xL. Post-translational modifications of protein kinases show increased phosphorylation of Akt at Ser473, Erk at Thr202/Tyr204 and Gsk-3beta at Ser9 and augmentation of total Mcl-1 accumulation along with phosphorylation at Ser159/Thr163 sites. Collectively, stroma-induced apoptosis resistance is mediated through signaling proteins that regulate transcriptional and translational expression and post-translational modification of Mcl-1 in CLL cells in context to bone marrow stromal microenvironment. PMID- 25499218 TI - Suppression of invasion and metastasis of triple-negative breast cancer lines by pharmacological or genetic inhibition of slug activity. AB - Most triple-negative breast cancers (TNBCs) exhibit gene expression patterns associated with epithelial-to-mesenchymal transition (EMT), a feature that correlates with a propensity for metastatic spread. Overexpression of the EMT regulator Slug is detected in basal and mesenchymal-type TNBCs and is associated with reduced E-cadherin expression and aggressive disease. The effects of Slug depend, in part, on the interaction of its N-terminal SNAG repressor domain with the chromatin-modifying protein lysine demethylase 1 (LSD1); thus, we investigated whether tranylcypromine [also known as trans-2 phenylcyclopropylamine hydrochloride (PCPA) or Parnate], an inhibitor of LSD1 that blocks its interaction with Slug, suppresses the migration, invasion, and metastatic spread of TNBC cell lines. We show here that PCPA treatment induces the expression of E-cadherin and other epithelial markers and markedly suppresses migration and invasion of TNBC cell lines MDA-MB-231 and BT-549. These effects were phenocopied by Slug or LSD1 silencing. In two models of orthotopic breast cancer, PCPA treatment reduced local tumor growth and the number of lung metastases. In mice injected directly in the blood circulation with MDA-MB-231 cells, PCPA treatment or Slug silencing markedly inhibited bone metastases but had no effect on lung infiltration. Thus, blocking Slug activity may suppress the metastatic spread of TNBC and, perhaps, specifically inhibit homing/colonization to the bone. PMID- 25499219 TI - The transcriptional repressor ZBTB4 regulates EZH2 through a MicroRNA-ZBTB4 specificity protein signaling axis. AB - ZBTB4 is a transcriptional repressor and examination of publically-available microarray data sets demonstrated an inverse relationship in the prognostic value and expression of ZBTB4 and the histone methyltransferase EZH2 in tumors from breast cancer patients. The possibility of functional interactions between EZH2 and ZBTB4 was investigated in breast cancer cells and the results showed that EZH2 is directly suppressed by ZBTB4 which in turn is regulated (suppressed) by miR-106b and other paralogues from the miR-17-92, miR-106b-25 and miR-106a-363 clusters that are highly expressed in breast and other tumors. ZBTB4 also acts a suppressor of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4, and RNA interference studies show that Sp proteins are required for EZH2 expression. The prediction analysis results from breast cancer patient array data sets confirm an association of Sp1-dependent EZH2 gene signature with decreased survival of breast cancer patients. Disruption of oncogenic miR-ZBTB4 signaling axis by anticancer agent such as betulinic acid that induce down-regulation of Sp proteins in breast cancer cells resulted in inhibition of tumor growth and colonization of breast cancer cells in a mouse model. Thus, EZH2 is reciprocally regulated by a novel signaling network consisting of Sp proteins, oncogenic miRs and ZBTB4, and modulation of this gene network is a novel therapeutic approach for treatment of breast cancer and possibly other cancers. PMID- 25499220 TI - Elevated estrogen receptor-alpha in VHL-deficient condition induces microtubule organizing center amplification via disruption of BRCA1/Rad51 interaction. AB - Since loss of VHL is frequently detected early phase genetic event in human renal cell carcinoma, pVHL is assumed to be indispensable for suppression of tumor initiation step. However, induction of HIF-1alpha, target of pVHL E3 ligase, is more adequate to angiogenesis step after tumor mass formation. Concerning this, it has been reported that pVHL is involved in centrosome location during metaphase and regulates ER-alpha signaling. Here, we provide the evidences that pVHL-mediated ER-alpha suppression is critical for microtubule organizing center (MTOC) maintaining and elevated ER-alpha promotes MTOC amplification through disruption of BRCA1-Rad51 interaction. In fact, numerous MTOC in VHL- or BRCA1 deficient cells are reduced by Fulvestrant, inhibitor of ER-alpha expression as well as antagonist. In addition, we reveal that activation of ER signaling can increase gamma-tubulin, core factor of TuRC and render the resistance to Taxol. Thus, Fulvestrant but not Tamoxifen, antagonist against ER-alpha, can restore the Taxol sensitivity in VHL- or BRCA1-deficient cells. Our results suggest that pVHL mediated ER-alpha suppression is important for regulation of MTOC as well as drug resistance. PMID- 25499221 TI - KIF20A-mediated RNA granule transport system promotes the invasiveness of pancreatic cancer cells. AB - Pancreatic cancers are aggressive because they are highly invasive and highly metastatic; moreover, effective treatments for aggressive pancreatic cancers are lacking. Here, we report that the motor kinesin protein KIF20A promoted the motility and invasiveness of pancreatic cancer cells through transporting the RNA binding protein IGF2BP3 and IGF2BP3-bound transcripts toward cell protrusions along microtubules. We previously reported that IGF2BP3 and its target transcripts are assembled into cytoplasmic stress granules of pancreatic cancer cells, and that IGF2BP3 promotes the motility and invasiveness of pancreatic cancer cells through regulation of localized translation of IGF2BP3-bound transcripts in cell protrusions. We show that knockdown of KIF20A inhibited accumulation of IGF2BP3-containing stress granules in cell protrusions and suppressed local protein expression from specific IGF2BP3-bound transcripts, ARF6 and ARHGEF4, in the protrusions. Our results provide insight into the link between regulation of KIF20A-mediated trafficking of IGF2BP3-containing stress granules and modulation of the motility and invasiveness in pancreatic cancers. PMID- 25499222 TI - Hypoxia-inducible lncRNA-AK058003 promotes gastric cancer metastasis by targeting gamma-synuclein. AB - Hypoxia has been implicated as a crucial microenvironmental factor that induces cancer metastasis. We previously reported that hypoxia could promote gastric cancer (GC) metastasis, but the underlying mechanisms are not clear. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of carcinogenesis that act on multiple pathways. However, whether lncRNAs are involved in hypoxia-induced GC metastasis remains unknown. In this study, we investigated the differentially expressed lncRNAs resulting from hypoxia-induced GC and normoxia conditions using microarrays and validated our results through real-time quantitative polymerase chain reaction. We found an lncRNA, AK058003, that is upregulated by hypoxia. AK058003 is frequently upregulated in GC samples and promotes GC migration and invasion in vivo and in vitro. Furthermore, AK058003 can mediate the metastasis of hypoxia-induced GC cells. Next, we identified gamma-synuclein (SNCG), which is a metastasis-related gene regulated by AK058003. In addition, we found that the expression of SNCG is positively correlated with that of AK058003 in the clinical GC samples used in our study. Furthermore, we found that the SNCG gene CpG island methylation was significantly increased in GC cells depleted of AK058003. Intriguingly, SNCG expression is also increased by hypoxia, and SNCG upregulation by AK058003 mediates hypoxia-induced GC cell metastasis. These results advance our understanding of the role of lncRNA AK058003 as a regulator of hypoxia signaling, and this newly identified hypoxia/lncRNA-AK058003/SNCG pathway may help in the development of new therapeutics. PMID- 25499223 TI - TSH signaling overcomes B-RafV600E-induced senescence in papillary thyroid carcinogenesis through regulation of DUSP6. AB - B-RafV600E oncogene mutation occurs most commonly in papillary thyroid carcinoma (PTC) and is associated with tumor initiation. However, a genetic modification by B-RafV600E in thyrocytes results in oncogene-induced senescence (OIS). In the present study, we explored the factors involved in the senescence overcome program in PTC. First of all, we observed down-regulation of p-extracellular signal-regulated kinases 1/2 and up-regulation of dual specific phosphatase 6 (DUSP6) in the PTC with B-RafV600E mutation. DUSP6 overexpression in vitro induced extracellular signal-regulated kinases 1/2 dephosphorylation and inhibited B-RafV600E-induced senescence in thyrocytes. Although DUSP6 protein was degraded by B-RafV600E-induced reactive oxygen species (ROS), thyroid-stimulating hormone (TSH) stabilized DUSP6 protein by increasing Mn superoxide dismutase expression and inhibited B-RafV600E-induced senescence. Although serum TSH was not increased, its receptor was markedly upregulated in PTC with B-RafV600E. Furthermore, TSH together with DUSP6 reactivated Ras signaling, resulted in activation of Ras/AKT/glycogen synthase kinase 3beta, and stabilized c-Myc protein by inhibiting its degradation. These observations led us to conclude that increased TSH signaling overcomes OIS and is essential for B-RafV600E-induced papillary thyroid carcinogenesis. PMID- 25499224 TI - A novel RNA in situ hybridization assay for the long noncoding RNA SChLAP1 predicts poor clinical outcome after radical prostatectomy in clinically localized prostate cancer. AB - Long noncoding RNAs (lncRNAs) are an emerging class of oncogenic molecules implicated in a diverse range of human malignancies. We recently identified SChLAP1 as a novel lncRNA that demonstrates outlier expression in a subset of prostate cancers, promotes tumor cell invasion and metastasis, and associates with lethal disease. Based on these findings, we sought to develop an RNA in situ hybridization (ISH) assay for SChLAP1 to 1) investigate the spectrum of SChLAP1 expression from benign prostatic tissue to metastatic castration-resistant prostate cancer and 2) to determine whether SChLAP1 expression by ISH is associated with outcome after radical prostatectomy in patients with clinically localized disease. The results from our current study demonstrate that SChLAP1 expression increases with prostate cancer progression, and high SChLAP1 expression by ISH is associated with poor outcome after radical prostatectomy in patients with clinically localized prostate cancer by both univariate (hazard ratio = 2.343, P = .005) and multivariate (hazard ratio = 1.99, P = .032) Cox regression analyses. This study highlights a potential clinical utility for SChLAP1 ISH as a novel tissue-based biomarker assay for outcome prognostication after radical prostatectomy. PMID- 25499225 TI - Trichomonas vaginalis among women raped in Antananarivo, 2005-2011. AB - Rape is a forensic emergency due to the possibility of sexually transmitted infections, including HIV/AIDS. Moreover, an upsurge is currently underway. The objective of this study was to determine the incidence of Trichomonas vaginalis in women undergoing tests at the Microbiology Unit of the Joseph Ravoahangy Andrianavalona Antananarivo Hospital after being raped. This retrospective descriptive study covers the 7-year period from 2005 to 2011 and reports the results of direct examination of the vaginal discharge after vulvar smears from rape patients. We studied the age of patients and the results of these direct smear examinations that tested for T. vaginalis. In our study, the number of women with T. vaginalis increased markedly with age. The mean age of the patients was 13.7 years (range: 2 to 41 years). Among the 232 rape victims tested, only 26 were positive for it (11.20%); trichomoniasis was thus rare among these women. T. vaginalis is a common cause of vaginitis in women and one of the most common infections transmitted by sexual assault. In children, the presence of T. vaginalis in vaginal sample is a strong indicator of sexual abuse. Other sexually transmitted infections can be transmitted during sexual abuse. PMID- 25499226 TI - CuO nanoparticles incorporated in hierarchical MFI zeolite as highly active electrocatalyst for non-enzymatic glucose sensing. AB - A hierarchical MFI zeolite, with typical micro/meso bimodal pore structures, was prepared by desilication method. CuO nanoparticles (NPs) were incorporated into the hierarchical MFI zeolite by impregnation method. CuO/hierarchical zeolite composites were characterized by X-ray diffraction, transmission electron microscopy and nitrogen sorption. It is shown that the CuO nanoparticles are mostly dispersed in the mesopores with remaining of the crystallinity and morphology of the host zeolite. CuO nanoparticles located in hierarchical zeolite exhibit the excellent electrocatalytic performances to oxidation of glucose in alkaline media. The electrocatalytic activity enhances with increasing the loading content of CuO from 5% to 15%. The composites were fabricated for nonenzyme glucose sensing. Under the optimal conditions, the sensor shows a wide linear range from 5*10(-7) to 1.84*10(-2) M with a low detection limit of 3.7*10( 7) M. The sensor also exhibits good repeatability, long-term stability as well as high selectivity against interfering species. PMID- 25499227 TI - Framework effect of amphiphilic polyesters on their molecular movement and protein adsorption-resistance properties. AB - Surface chemical characteristics of biomedical polymers, which are determined by the migration and rearrangement of polymeric chains, play an important role in the protein adsorption. In this work, the relationship between the architectures of amphiphilic polyesters and their protein adsorption resistance was investigated. Three poly (E-caprolactone)s containing sulfobetaines (PCL-b-PDEAS) segments with linear, four arms and six arms star-shaped architectures were synthesized with the combination of ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP). The structures of the amphiphiles were confirmed by (1)H NMR and FTIR. Water contact angles (WCA) and X-ray photoelectron spectroscopy (XPS) were used to study the surface properties of the amphiphilic copolymer films. The water contact angles were decreased due to the surface migration of hydrophilic segments. Transmission electron microscopy (TEM) displayed the occurrence of microphase separation phenomena for PCL-b-PDEAS above glass transition temperature (Tg). The results showed that the hydrophilic segments in the copolymers would migrate to the surface of the films, which resulted in the surface more hydrophilic to resist protein adsorption. The adsorption of both fibrinogen (Fg) and bovine serum albumin (BSA) were studied. The results showed that protein adsorption was depended on not only the hydrophilic chain migration but also the shape of proteins. PMID- 25499228 TI - A new strategy for synthesizing AgInS2 quantum dots emitting brightly in near infrared window for in vivo imaging. AB - A new strategy for fabricating water-dispersible AgInS2 quantum dots (QDs) with bright near-infrared (NIR) emission is demonstrated. A type of multidentate polymer (MDP) was synthesized and utilized as a compact capping ligand for the AgInS2 QDs. Using silver nitrate, indium acetate and sulfur-hydrazine hydrate complex as the precursors, MDP-capping AgInS2 QDs were synthesized in aqueous solution at room temperature. Characterization indicates that the MDP-capping AgInS2 QDs are highly photoluminescent in NIR window and possess good photostability. Also, the QDs are stable in different media and have low cytotoxicity. Nude mice photoluminescence imaging shows that the MDP-capping AgInS2 QDs can be well applied to in vivo imaging. These readily prepared NIR fluorescent nanocrystals have huge potential for biomedical applications. PMID- 25499229 TI - Vitamin D receptor polymorphism in chronic kidney disease patients with complicated cardiovascular disease. AB - Several studies indicate a relationship between vitamin D and cardiovascular disease. Pleiotropic actions of vitamin D and its analogs are mediated by vitamin D receptor (VDR). VDRs have been identified in almost all tissues, including vascular smooth muscle cells, cardiomyocytes, and endothelial cells. The FokI and BsmI polymorphisms of the VDR gene are regarded as strong markers of disturbed vitamin D signaling pathway. Studies investigating the relationship between VDR genotypes and left ventricular hypertrophy revealed a highly significant association with the BsmI Bb heterozygous genotype. There are conflicting data on the action of vitamin D in left ventricular hypertrophy. Experimental as well as observational studies and small clinical trials have suggested that vitamin D administration may favorably influence left ventricular hypertrophy, whereas large randomized clinical trials have shown negative results. However, a beneficial effect on the left atrial volume index and the duration of hospitalization were observed in patients treated with vitamin D analogs. Larger clinical trials with robust clinical end points are needed to confirm that vitamin D is effective in preventing cardiovascular disease in chronic kidney disease patients and in general population. PMID- 25499230 TI - Recent topics on podocytes and aldosterone. AB - Podocyte injury is a major cause of proteinuria, a core component of chronic kidney disease. We reported that podocyte impairment underlied the early glomerulopathy in animal models of lifestyle-related diseases, such as hypertension and metabolic syndrome. Accumulating evidence suggests that overactivation of the aldosterone-mineralocorticoid receptor (MR) system has harmful effects on podocytes. We found that MR signaling was enhanced in such lifestyle-related diseases with podocyte injury and proteinuria, which were ameliorated by MR antagonist. Subsequent studies revealed that plasma aldosterone concentrations are not always increased in proteinuric conditions with renal MR activation, and the mechanisms of MR overactivation remained elusive. We recently identified a novel mechanism of Rac1-mediated podocyte impairment using RhoGDIalpha knockout mice; Rac1 potentiates the activity of MR in a ligand independent manner, thereby accelerating podocyte injury. We demonstrated that the Rac1-MR pathway contributes to the ligand-independent aberrant MR activation in salt-sensitive hypertension and renal injury models. The importance of the RhoGDIalpha-Rac1-MR pathway in human glomerular disease is underscored by the findings that mutations in RhoGDIalphagene cause nephrotic syndrome. Our results provide evidence that the Rac1-MR signal cascade as a novel therapeutic target for chronic kidney disease. PMID- 25499231 TI - Mitochondrial DNA based identification of forensically important Indian flesh flies (Diptera: Sarcophagidae). AB - An absolutely vital prerequisite in the forensic entomology cases is the estimation of post mortem interval (PMI). Due to similar morphological look, identification of the flesh fly fauna associated with the corpse is very difficult for nontaxonomists and needs professional hand to be dealt with. So, to simplify the identification process the application of 465 bp fragment of COI gene for differentiation of ten forensically significant species of flesh flies is demonstrated in this paper. Percentage nucleotide composition, genetic divergence and substitution rate were calculated by using the Maximum likelihood method. Phylogenetic analysis was done by Neighbour-joining tree constructed by using Tamura-3-parameter given in the MEGA5 software. The results show the robustness of COI gene as diagnostic marker, since its nucleotide variability enables dependable distinction to be drawn between species. PMID- 25499232 TI - Enforced expression of E47 has differential effects on Lmo2-induced T-cell leukemias. AB - LIM domain only-2 (LMO2) overexpression in T cells induces leukemia but the molecular mechanism remains to be elucidated. In hematopoietic stem and progenitor cells, Lmo2 is part of a protein complex comprised of class II basic helix loop helix proteins, Tal1and Lyl1. The latter transcription factors heterodimerize with E2A proteins like E47 and Heb to bind E boxes. LMO2 and TAL1 or LYL1 cooperate to induce T-ALL in mouse models, and are concordantly expressed in human T-ALL. Furthermore, LMO2 cooperates with the loss of E2A suggesting that LMO2 functions by creating a deficiency of E2A. In this study, we tested this hypothesis in Lmo2-induced T-ALL cell lines. We transduced these lines with an E47/estrogen receptor fusion construct that could be forced to homodimerize with 4-hydroxytamoxifen. We discovered that forced homodimerization induced growth arrest in 2 of the 4 lines tested. The lines sensitive to E47 homodimerization accumulated in G1 and had reduced S phase entry. We analyzed the transcriptome of a resistant and a sensitive line to discern the E47 targets responsible for the cellular effects. Our results suggest that E47 has diverse effects in T-ALL but that functional deficiency of E47 is not a universal feature of Lmo2-induced T ALL. PMID- 25499233 TI - Severe infusion-related reactions are uncommon in rituximab-treated CLL patients in clinical practice: results from a Swedish national observational study. AB - There have been concerns about serious infusion-related adverse drug reactions (ADR) with rituximab in chronic lymphocytic leukemia (CLL). We therefore conducted an observational trial in which CLL patients planned for rituximab containing therapy were eligible. Ninety-six patients from 19 centers were enrolled. The most common regimen was rituximab, fludarabine and cyclophosphamide. Fifty-six patients experienced ADR during rituximab infusion. Reactions >= grade 3 occurred in five patients and no cases of tumor lysis syndrome were recorded. Despite a high number of circulating tumor cells few severe ADR were noted. Thus, rituximab-containing regimens can be considered safe for CLL patients in general practice. PMID- 25499234 TI - Chemotherapy dose in obese AML patients: to cap or not to cap? PMID- 25499235 TI - A review of the synthesis of alpha-carbolines. AB - Since the first reported synthesis of an alpha-carboline almost a century ago, there has been a steady interest in the development of strategies towards this unique heterocyclic motif. This interest can mainly be attributed to a range of biological activity displayed by the alpha-carboline natural products including cytotoxicity, anticancer properties or CNS activity. Numerous studies have led to the development of a number of alternative methods to prepare simple alpha carbolines as well as a range of synthetic alpha-carboline derived compounds. PMID- 25499236 TI - Effects of 5alpha-dihydrotestosterone on expression of genes related to steroidogenesis and spermatogenesis during the sex determination and differentiation periods of the pejerrey, Odontesthes bonariensis. AB - Sex steroid hormones are important players in the control of sex differentiation by regulating gonadal development in teleosts. Although estrogens are clearly associated with the ovarian differentiation in teleosts, the effects of androgens on early gonadal development are still a matter of debate. Traditionally, 11 ketotestosterone (11-KT) is considered the major androgen in fish; however, 5alpha-dihydrotestosterone (5alpha-DHT), the most potent androgen in tetrapods, was recently found in fish testis and plasma, but its physiological role is still unknown. In this context, the expression of genes associated with steroidogenesis and spermatogenesis, body growth and sex differentiation were assessed in Odontesthes bonariensis larvae fed with food supplemented with two doses of 5alpha-DHT (0.1 and 10MUg/g of food) from hatching to 6weeks of age. At the lowest dose, 5alpha-DHT treated larvae showed an estrogenic gene expression pattern, with low hsd11b2 and high cyp19a1a and er2 expression levels with no differences in sex ratio. At the highest dose, 5alpha-DHT produced a male-shifted sex ratio and the larvae exhibited a gene expression profile characteristic of an advancement of spermatogenesis, with inhibition of amh and stimulation of ndrg3. No differences were observed in somatic growth. These results suggest that in this species, 5alpha-DHT could have a role on sex differentiation and its effects can differ according to the dose. PMID- 25499237 TI - Maternal dietary protein supplement confers long-term sex-specific beneficial consequences of obesity resistance and glucose tolerance to the offspring in Brandt's voles. AB - Maternal under- or over-nutrition not only alters neonatal body mass but also increases the risk of metabolic disorders in adulthood. Little is known about how maternal dietary protein affects offspring fitness in wild rodents. The present study was conducted to test the hypothesis that maternal dietary protein supplement has a long-term beneficial effect on offspring fitness in Brandt's vole (Lasiopodomys brandtii), a herbivorous rodent model. The vole dams were fed either a control (18% protein) or high-protein (36% protein) diet throughout pregnancy and lactation. After weaning, all offspring received a control diet till 14 weeks old. Energetic parameters, serum leptin concentration and glucose tolerance were measured. The adult offspring were fed high-fat diet for 8 weeks, and body weight and food intake were measured. No difference was observed in litter size, litter mass or pup mass before weaning. Maternal protein supplement increased body mass and the mass of reproductive organ but decreased digestibility and fat deposition and alleviated HFD-induced obesity especially in the males. Glucose tolerance was elevated in the offspring from maternal protein supplement, especially in the females. The accelerated growth may be associated with high serum leptin concentration at weaning, a state of leptin resistance, and the low digestibility may predispose obesity resistance especially in male offspring from maternal high-protein diet. These data demonstrate that maternal protein supplement confers the long-term sex-specific beneficial consequences of accelerated growth and improved obesity resistance and glucose tolerance of their offspring. PMID- 25499238 TI - Variation in quantity and composition of cuticular hydrocarbons in the scorpion Buthus occitanus (Buthidae) in response to acute exposure to desiccation stress. AB - Scorpions exhibit some of the lowest recorded water loss rates among terrestrial arthropods. Evaporative water loss to the surrounding environment occurs mainly through the integument, and thus its resistance to water loss has paramount significance for the ability of scorpions to tolerate extremely dry habitats. Cuticular hydrocarbons (HCs) deposited on the outer epicuticle play an important role in determining cuticular waterproofing, and seasonal variation in both cuticular HC quantity and composition has been shown to correlate with water loss rates. Precursor incorporation rates into cuticle HCs have been observed to be extremely low in scorpions compared with insects. We therefore used adult male Buthus occitanus (Buthidae) in order to test HC profile plasticity during acute exposure to 14 d and 28 d of experimental desiccation. Cuticular HC profile of hydrated scorpions was similar to that reported for several other scorpion species, consisting of similar fractions of n-alkanes and branched alkanes, with no evidence for unsaturation. Most abundant of the n-alkanes were n-heptacosane (C27; 19+/-2% of total HCs), n-nonacosane (C29; 16+/-1%) and n-hentriacontane (C31; 11+/-1%). Exposure to desiccation stress resulted in a significant increase in the total amount of extracted HCs, and in the relative abundance of branched alkanes at the expense of n-alkanes. Together with an increase in HC chain lengths, these changes mimic previously-reported seasonal variation among freshly collected specimens. This indicates that scorpions respond to water shortage by regulating the properties of their passive integumental barrier to water loss. PMID- 25499239 TI - Early life mortality and height in Indian states. AB - Height is a marker for health, cognitive ability and economic productivity. Recent research on the determinants of height suggests that postneonatal mortality predicts height because it is a measure of the early life disease environment to which a cohort is exposed. This article advances the literature on the determinants of height by examining the role of early life mortality, including neonatal mortality, in India, a large developing country with a very short population. It uses state level variation in neonatal mortality, postneonatal mortality, and pre-adult mortality to predict the heights of adults born between 1970 and 1983, and neonatal and postneonatal mortality to predict the heights of children born between 1995 and 2005. In contrast to what is found in the literature on developed countries, I find that state level variation in neonatal mortality is a strong predictor of adult and child heights. This may be due to state level variation in, and overall poor levels of, pre-natal nutrition in India. PMID- 25499240 TI - Integrated biomarker responses of the invasive species Corbicula fluminea in relation to environmental abiotic conditions: a potential indicator of the likelihood of clam's summer mortality syndrome. AB - The aim of this study was to investigate the variation of several biomarkers in wild populations of Corbicula fluminea in relation to abiotic condition changes to identify environmental factors associated with increased stress in this species potentially leading to massive mortality events. The study was carried out from July to October in the freshwater tidal areas of the estuaries of Minho and Lima Rivers (NW Iberian Peninsula). Monthly, 7 biomarkers (biotransformation, energy production, anti-oxidant defenses and lipid peroxidation damages) were determined in C. fluminea and 17 abiotic parameters were determined in water or sediments in 4 sampling sites: M1, M2 and M3 in Minho (up=> downstream); and L in Lima estuaries. The results of biomarkers were integrated using the Integrated Biomarker Response (IBR), Index and also analysed in relation to environmental parameters by Redundancy Analysis (RDA). Overall, the findings of the present study indicate that July and August are particularly stressful months for the studied C. fluminea populations, especially at downstream sites; the increase of nutrients and ammonium water concentrations, water temperature and conductivity are major contributors for this increased stress; the biomarkers indicated that in July/August C. fluminea is exposed to oxidative stress inducers, environmental chemical contaminants biotransformed by esterases and glutathione S-transferase enzymes, and that organisms need additional energy to cope with the chemical and/or thermally-induced stress. The findings of the present study stress the importance of biomonitoring the health condition of C. fluminea because it may allow determining the likelihood of summer/post summer mortality syndrome in this species. PMID- 25499241 TI - Chronic hypercapnic incubation increases relative organ growth and reduces blood pressure of embryonic American alligator (Alligator mississippiensis). AB - Reptilian nests can experience natural hypoxic and hypercapnic conditions. We incubated alligator eggs at a female-only producing temperature (30 degrees C) in three conditions: 21% O2/0.04% CO2, 21% O2/3.5% CO2 and 21% O2/7% CO2. Alligator embryos chronically incubated in high CO2 were markedly hypotensive (blood pressure reduced by 46%) and had relatively (mass-specific) enlarged hearts (dry mass increased by 20%), lungs (dry mass increased by 17%), and kidneys (dry mass increased by 14%). This study is the first to chronically incubate reptilian eggs in hypercapnia and suggests that high CO2 alters the cardiovascular phenotype of alligator embryos (low blood pressure, relatively enlarged hearts), as well as the relative size of the organs primarily responsible for acid base balance, lungs and kidneys. The lungs and kidneys are largely non-functional during embryonic development, and the embryonic phenotype of increased relative mass may be a predictive-adaptation to metabolic or respiratory acidosis, such as during exercise or high respiratory CO2. This study demonstrates that phenotypic plasticity of alligator embryos incubated in high CO2 may result in either preferential organ growth, or maintenance of organ growth with reduced somatic growth. PMID- 25499242 TI - Adaptations of a deep sea scavenger: high ammonia tolerance and active NH4+ excretion by the Pacific hagfish (Eptatretus stoutii). AB - The Pacific hagfish (Eptatretus stoutii) has an exceptional ability to both withstand and recover from exposure to high external ammonia (HEA). This tolerance is likely due to the feeding behavior of this scavenger, which feeds on intermittent food falls of carrion (e.g. fish, large marine mammals) during which time it may be exposed to high concentrations of total ammonia (T(Amm)=NH3+NH4(+)) while burrowed inside the decomposing carcass. Here we exposed hagfish to 20 mmol L(-1) T(Amm) for periods of up to 48 h and then let animals recover in ammonia-free seawater. During the 48 h HEA exposure period, plasma T(Amm) increased 100-fold to over 5000 MUmol L(-1) while ammonia excretion (J(amm)) was transiently inhibited. This increase in plasma T(Amm) resulted from NH3 influx down massive inwardly directed DeltaP(NH3) gradients, which also led to a short-lived metabolic alkalosis. Plasma [T(Amm)] stabilized after 24-48 h, possibly through a reduction in NH3 permeability across the body surface, which lowered NH3 influx. Ammonia balance was subsequently maintained through the re establishment of J(amm) against an inwardly directed DeltaP(NH3). Calculations of the Nernst potential for ammonia strongly indicated that J(amm) was also taking place against a large inwardly directed NH4(+) electrochemical gradient. Recovery from HEA in ammonia-free water was characterized by a large ammonia washout, and the restoration of plasma TAmm concentrations to near control concentrations. Ammonia clearance was also accompanied by a residual metabolic acidosis, which likely offset the ammonia-induced metabolic alkalosis seen in the early stages of HEA exposure. We conclude that restoration of J(amm) by the Pacific hagfish during ammonia exposure likely involves secondary active transport of NH4(+), possibly mediated by Na(+)/NH4(+) (H(+)) exchange. PMID- 25499243 TI - Health care worker quarantine for Ebola: to eradicate the virus or alleviate fear? PMID- 25499244 TI - Health-related quality of life in women and men with type 2 diabetes: a comparison across treatment groups. AB - AIM: This study compares health-related quality of life (HRQL) in patients with type 2 diabetes (T2DM) across treatment groups and explores gender differences. METHODS: Four regional surveys (KORA, CARLA, SHIP, DHS) and a national survey (GNHIES98) were pooled at individual level. HRQL was assessed with the SF-12/ 36v1. Linear regression models were used to assess the effect of T2DM by treatment type (no medication; oral; oral/insulin combination; insulin) on the physical (PCS-12) and mental summary score (MCS-12) and the SF-6D, controlling for age, sex, study and covariates. We also performed an explanatory analysis of single items. RESULTS: PCS-12 scores and treatment type were associated (P-value 0.006), with lowest values for insulin treatment (-4.44 vs. oral; -4.41 vs. combination). MCS-12 scores were associated with treatment type and gender (P value <0.012), with lower scores for women undergoing oral (-4.25 vs. men) and combination treatment (-6.99 vs. men). Similar results were observed for SF-6D utilities and single items, related to mental health, social functioning, vitality and role limitation (emotional). Comorbidities were predictors of lower PCS-12 and SF-6D scores. CONCLUSIONS: T2DM treatment impacts differently on physical and mental HRQL and on women and men. Further studies of gender-specific perceptions of T2DM treatment regimens are needed. PMID- 25499245 TI - The value of ultrasonography in the diagnosis of appendicitis. AB - INTRODUCTION: Ultrasonography is a commonly used investigation in the UK for patients with right iliac fossa pain where the diagnosis of appendicitis is unclear. The published sensitivity and specificity of ultrasonography is higher than the results observed by clinicians in every day practice. The aim of this study was to elucidate the real-world value of ultrasonography in the diagnosis of appendicitis, and its impact on negative appendicectomy rates (NAR). METHODS: A retrospective multicentre audit was conducted at three UK hospitals over a twelve month period in 2012. RESULTS: 573 patients underwent ultrasonography prior to appendicectomy. The appendix was not visualised in 45% of scans. The sensitivity and specificity of ultrasonography for the diagnosis of appendicitis was 51.8% and 81.4%. The mean NAR was 26.7%, or 18.3% after a positive ultrasound scan. CONCLUSION: In clinical practice at UK centres, ultrasonography commonly does not visualise the appendix, and has a low sensitivity for appendicitis. To reduce the NAR, management options include a return to observation and serial examination, increased use of CT or a commitment to improving the performance of ultrasonography. PMID- 25499246 TI - Electroless reduction of silver chloride precipitates for the preparation of highly sensitive substrates for surface-enhanced infrared absorption (SEIRA) measurements. AB - To prepare silver nanoparticles (AgNPs) on infrared-transmitting crystal for surface-enhanced infrared absorption (SEIRA) measurements, a new strategy is proposed and demonstrated using electroless reduction of preformed silver chloride (AgCl) particles. Silver chloride precipitates were formed using an additive of polyvinyl pyrrolidone (PVP) to vary the size and shape of the precipitates. After settling on germanium substrates, the preformed particles of AgCl were reduced electrolessly and spontaneously coagulated to AgNPs. The resulting AgNPs showed a multilayer structure, but the AgNPs were isolated, as shown by the lack of absorption-band distortion in the SEIRA measurements. Hence, the sensitivity and analyte-loading capacity for SEIRA measurements are improved significantly. To optimize the chemical deposition and electroless reduction method, we examined several parameters, including the concentrations of reagents during AgCl precipitation and the reaction time required in the deposition reduction steps. We used para-nitrobenzoic acid (pNBA) to probe the intensity of the SEIRA effect for the prepared substrates. To better correlate the SEIRA performances with each variable, we examined the prepared substrates using a scanning electron microscope and SEIRA. The results indicate that two major morphologies of AgNPs are observed: nanoparticles and nanorods. The distributions of nanorods we observed were related to the procedures used to prepare the substrates. Based on SEIRA signals, we observed enhancement factors approaching three orders of magnitude compared to conventional transmission measurement. Also, based on the morphologies, the large signals were mainly caused by the formation of multilayers of non-percolated AgNPs. PMID- 25499248 TI - Two regression methods for estimation of a two-parameter Weibull distribution for reliability of dental materials. AB - OBJECTIVES: Comparison of estimation of the two-parameter Weibull distribution by two least squares (LS) methods with interchanged axes. Investigation of the influence of plotting positions and sample size. Derivation of 95% confidence intervals (95%CI) for Weibull parameters applicable in the context of LS estimation. Preparation of a free available Excel template for computation of point estimates and 95%CI for Weibull modulus (m) and characteristic strength (s). METHODS: Monte Carlo simulation covering a wide range of Weibull parameters and sample sizes. Mathematical derivation of formulae for computation of 95%CI according to a Menon-type approach for both m and s. Empirical proof that the practically observed coverage agrees with the nominal one of 95%. RESULTS: Relative and absolute performance of LS estimators depended on sample size, plotting positions and parameter to be estimated. For most situations they outperformed the corresponding Maximum Likelihood (ML) estimator in terms of bias, while precision was almost the same. Naive Wald-type 95%CI based on standard errors of LS regression coefficients did not reach targeted coverage. An easy-to-apply alternative based on asymptotic standard errors (Menon 95%CI) resulted in excellent coverage. CONCLUSION: Accuracy of the LS methods for Weibull modulus and characteristic strength essentially depend on plotting position and sample size. Large sample sizes (n>=30) support a credible Weibull parameters estimation. An important complement of the point estimates of Weibull parameters is provided by the Menon 95%CI. A free available Excel template considerably facilitating computation of point and interval estimates of Weibull parameters is provided. PMID- 25499247 TI - Molecular level evaluation on HEMA interaction with a collagen model. AB - OBJECTIVE: 2-Hydroxyethylmethacrylate (HEMA) diffuses in wet dentin and promotes adhesion during dentin priming and bonding. We have investigated the molecular level interaction between HEMA and a collagen model by using saturation transfer difference (STD) NMR. METHODS: The binding of HEMA to collagen was preliminarily investigated by suspending demineralized human dentin powders in a 4mM HEMA solution for 1h and measuring the decrease in the HEMA concentration on a spectrophotometer. The molecular level interaction of HEMA with atelocollagen, which was used as a collagen model, was investigated by STD-NMR spectroscopy. RESULTS: The HEMA concentration in the suspension did not change, indicating that HEMA did not bind to dentin collagen. This was confirmed by STD-NMR; when the atelocollagen resonance was saturated, no saturation was propagated to HEMA and no STD signals were detected. SIGNIFICANCE: The HEMA protons were not near the atelocollagen surface, indicating HEMA did not interact with atelocollagen. The collagen fibrils may be surrounded by water molecules in dentin/bond interfaces, which prevent the direct HEMA binding interaction. PMID- 25499249 TI - Optical behavior of dental zirconia and dentin analyzed by Kubelka-Munk theory. AB - OBJECTIVES: To use the Kubelka-Munk theory to evaluate the scattering (S), absorption (K) and transmittance (T) of non-colored and colored dental zirconia systems and human (HD) and bovine (BD) dentins. METHODS: Two zirconia systems were used: ZC- ZirCAD (Ivoclar Vivadent) and LV-LAVA (3M ESPE). Specimens from each ceramic system were divided into 3 groups (n=5): ZC1 and LV1 (non-colored); ZC2 and LV2 colored to shade A1, and ZC3 and LV3 colored to shade A3. Five human and bovine anterior teeth were flattened and polished through 1200 grit SiC paper to expose the superficial buccal dentin. All samples were prepared to a final thickness of 0.5 mm. Diffuse reflectance was measured against white and black backgrounds, using a spectroradiometer in a viewing booth with D65 illuminant and d/0 degrees geometry. S and K coefficients and T were calculated using Kubelka Munk's equations. Data was statistically analyzed using Kruskal-Wallis, Mann Whitney tests, and VAF coefficient. RESULTS: Spectral distributions of S, K and T were wavelength dependent. The spectral behavior of S and T was similar to HD (VAF>=96.80), even though they were statistically different (p<=0.05). The spectral behavior of K was also similar to HD, except for LV1 (VAF=38.62), yet all ceramics were statistically different from HD (p<=0.05). HD and BD showed similar values of S and T (p>0.05). SIGNIFICANCE: The dental professional should consider the optical behavior differences between the zirconia systems evaluated and the human dentin to achieve optimal esthetics in restorative dentistry. PMID- 25499250 TI - A rare cause of appendicular syndrome. PMID- 25499251 TI - [Hereditary angioedema: treatment and educational therapeutic program]. AB - Hereditary angioedema (HAE) is a chronic disease with unpredictable and severe acute attacks that are potentially life threatening. The treatment of HAE has two main objectives: treat acute attacks and limit their occurrence in the short term and long term. The acute treatment should be administered as soon as possible for better efficiency and patient safety. Self-administration should be encouraged for greater patient autonomy and safety (reducing delay to receive treatment injection). Long-term prophylaxis treatments should be set up to limit acute attacks occurrences and finally improve patients' quality of life and safety. Short-term prophylaxis treatments are required and should be thoroughly applied in case of exposure to known potential triggers (surgery, dental care...). CREAK protocols are available. The HAE National Educational Therapeutic Program "Educreak" is in place to allow the patient and his close family or partners to acquire skills for greater autonomy in day to day disease management. PMID- 25499252 TI - [Use of a standard format to describe the activity of hospital-based palliative care team: a lever for improving end of life care]. AB - INTRODUCTION: Early integrated palliative care is recommended in patients with incurable disease. Despite their development, hospital-based palliative care teams (PCT) are introduced late in the course of standard oncology care. The objective of this study is to describe the activity of an academic hospital-based PCT, using a standard format, which integrates indicators of early introduction and quality of end of life care, thus allowing a systematic analysis of its practice. METHODS: The annual activity of the PCT is described from 2007 to 2012. Data are collected for each patient prospectively by the team: reasons for referral and activities of PCT, performance status and chemotherapy at the time of first referral, visit to emergency and admission to ICU. RESULTS: The number of patients referred to the PCT increased from 337 patients in 2007 to 539 in 2012, among whom 90% were cancer patients, 84% at metastatic stage. Relief of symptoms was the most frequent reason for referral. In 2012, 280 (64%) patients were receiving chemotherapy and 41% had a PS<=2 at the time of first referral. Half patients died each year (270 in 2012); 17% of these received chemotherapy in their last 14 days of life, 3% visited emergency room twice and 13% were admitted in ICU, once during their last month of life, 48% died in hospice or at home. CONCLUSION: The use of a standard format to describe the activity of hospital based PCTs, the timing of their introduction and the quality of care is feasible. The generalization of this format for monitoring to assess the curative medicine interface/palliative could be a lever for improving the integration of palliative care. PMID- 25499253 TI - [Authors' response to the letter on the article: "Wine: good for all cardiovascular diseases?"]. PMID- 25499255 TI - Overexpression of brachyury contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma. AB - AIMS: Brachyury overexpression has been reported in various human malignant neoplasms, but its expression and function in hepatocellular carcinoma progression and metastasis remains unknown. The present study aimed to evaluate the critical role of Brachyury in HCC metastasis. METHODS: The expression of Brachyury in human HCC (SMMC7721, HepG2, FHCC98, and Hep3B) and control cell lines was analyzed using quantitative reverse-transcriptase polymerase chain reaction and immunoflourence methods. Cancerous tissues collected from patients with HCC (n = 112) were analyzed using immunohistochemical method; a microarray analysis of HCC tissues was performed to explore the clinicopathological variables of HCC. The migratory and invasive capacities of Brachyury-SMMC7721 and Brachyury-HepG2 transfected cells were evaluated using in vitro scratch wound healing and Matrigel invasion assays, respectively. Further, six-week-old male BALB/c nude mice (n = 10) model was used in vivo assay. RESULTS: Elevated expression of Brachyury was detected in HCCs (62.5%) compared with that in adjacent nontumorous tissues. Clinicopathological analysis revealed a close correlation of Brachyury expression with distant metastasis and poor prognosis of HCC. Overexpression of Brachyury promoted epithelial-mesenchymal transition (EMT) and metastasis of HCC cells in vitro and in vivo. Brachyury overexpression enhanced Akt activation by inhibiting phosphatase and tensin homolog (PTEN), which led to subsequent stabilization of Snail, a critical EMT mediator. CONCLUSION: The study findings suggest that elevated Brachyury facilitates HCC metastasis by promoting EMT via PTEN/Akt/Snail-dependent pathway. Brachyury plays a pivotal role in HCC metastasis and may serve as a novel prognostic biomarker and therapeutic target. PMID- 25499256 TI - Arsenic exposure, hyperuricemia, and gout in US adults. AB - BACKGROUND: There is very limited information on the association between arsenic and serum uric acid levels or gout. The aim of this study was to investigate the association of arsenic with hyperuricemia and gout in US adults. METHODS: A cross sectional study was conducted in 5632 adults aged 20years or older from the National Health and Nutrition Examination Survey (NHANES) 2003-2010 with determinations of serum uric acid and urine total arsenic and dimethylarsinate (DMA). Hyperuricemia was defined as serum uric acid higher than 7.0mg/dL for men and 6.0mg/dL for women. Gout was defined based on self-reported physician diagnosis and medication use. RESULTS: After adjustment for sociodemographic factors, comorbidities and arsenobetaine levels, the increase in the geometric means of serum uric acid associated with one interquartile range increase in total arsenic and DMA levels was 3% (95% CI 2-5) and 3% (2-5), respectively, in men and 1% (0-3) and 2% (0-4), respectively, in women. In men, the adjusted odds ratio for hyperuricemia comparing the highest to lowest quartiles of total arsenic was 1.84 (95% CI, 1.26-2.68) and for DMA it was 1.41 (95% CI, 1.01-1.96). The corresponding odds ratios in women were 1.26 (0.77, 2.07) and 1.49 (0.96, 2.31), respectively. The odds ratio for gout comparing the highest to lowest tertiles was 5.46 (95% CI, 1.70-17.6) for total arsenic and 1.98 (0.64-6.15) for DMA among women older than 40years old. Urine arsenic was not associated with gout in men. CONCLUSION: Low level arsenic exposures may be associated with the risk of hyperuricemia in men and with the prevalence of gout in women. Prospective research focusing on establishing the direction of the relationship among arsenic, hyperuricemia, and gout is needed. PMID- 25499257 TI - Regulatory T cells and TGF-beta1 in clinically localized renal cell carcinoma: Comparison with age-matched healthy controls. AB - PURPOSE: We investigated the proportion of regulatory T cells (Treg cells) in the peripheral blood (PB) and among tumor-infiltrating lymphocytes (TILs) of patients with renal cell carcinoma (RCC) compared with age-matched healthy controls (HCs). We also assessed the presence of several immunomodulatory cytokines in these patients. METHODS: The proportion of Treg cells in the PB of 59 patients with clinically localized RCC and 65 HCs, as well as the prevalence of Treg cells among TILs and lymphocytes in normal kidney tissue, were evaluated by flow cytometry using specific monoclonal antibodies recognizing CD4(+), CD25(+), and Foxp3(+) markers. In addition, the levels of transforming growth factor (TGF) beta1, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma were determined using standard enzyme-linked immunosorbent assay. RESULTS: There was no difference between the mean percentage of Treg cells in the PB of patients with RCC and HCs (P = 0.148). However, the proportion of Treg cells showed a significant positive correlation with tumor size (r = 0.295, P = 0.029), with the percentage of PB Treg cells significantly higher in patients with RCC with large tumors (>=7 cm) than in HCs (4.6 +/- 5.8% vs. 1.9 +/- 2.6%, P = 0.023). There was no statistically significant difference in the percentage of Treg cells among TILs and lymphocytes in normal kidney tissue (P = 0.629). The mean TGF-beta1 level in patients with RCC was statistically significantly higher than in HCs (P<0.001). CONCLUSIONS: In this study, we provide evidence for an increased proportion of Treg cells in the PB of clinically localized patients with RCC with substantial tumor burden and a higher level of TGF-beta1 compared with age matched HCs. PMID- 25499258 TI - Preoperative predictors of malignancy and unfavorable pathology for clinical T1a tumors treated with partial nephrectomy: a multi-institutional analysis. AB - PURPOSE: To determine preoperative predictors associated with renal cell carcinoma (RCC) and unfavorable pathology in small renal masses treated with partial nephrectomy (PN). MATERIALS AND METHODS: PN records from 5 centers were retrospectively queried for patients with a clinically localized single tumor <4 cm on imaging (clinical T1a). Between 2007 and 2013, 1,009 patients met the inclusion criteria. Unfavorable pathology was defined as any grade III or IV RCC or tumors upstaged to pathologic T3a disease. Logistic regression models were used to determine preoperative characteristics associated with RCC and with unfavorable pathology. RESULTS: A total of 771 (76.4%) patients were found to have RCC and 198 (19.6%) had unfavorable pathology. On multivariate, bootstrap adjusted logistic regression analysis, factors associated with the presence of malignancy were imaging tumor size >= 3 cm (odds ratio [OR] = 1.46; P = 0.040), male sex (OR = 1.88; P<0.0001), and nephrometry score >= 8 (OR = 1.64; P = 0.005). These same factors were independently associated with risk of unfavorable pathology: size >= 3 cm (OR = 1.46; P = 0.021), male sex (OR = 2.35; P<0.0001), and nephrometry score >= 8 (OR = 1.49; P = 0.015). The c statistic was 0.62 for the predicting malignancy and 0.63 for unfavorable pathology. CONCLUSIONS: In this multi-institutional cohort, male sex, imaging tumor size >= 3 cm, and nephrometry score >= 8 were predictors of RCC and adverse pathology following PN. These factors may assist in risk stratification and selective renal mass biopsy before decision making. Further studies are necessary to validate these findings. PMID- 25499259 TI - Uterine sarcomas and parasitic myomas after laparoscopic hysterectomy with power morcellation. AB - OBJECTIVE: The purpose of this study was to describe the incidence and risk factors for uterine sarcomas and parasitic myomas at the time of power morcellation. STUDY DESIGN: We performed a retrospective review of 3523 women who underwent laparoscopic hysterectomy from 2001-2012. Univariate analyses were used for the morcellation cases to identify potential risk factors. Multivariable logistic regression was performed. RESULTS: Nine hundred forty-one patients underwent power morcellation at the time of hysterectomy; 10 of 941 patients (1.1%) were diagnosed subsequently with uterine sarcomas or parasitic myomas. The overall incidence of uterine sarcoma was 6 of 941 (0.6%), with a median age of 47 years (range, 41-52 years). There was no association among any of the factors analyzed and uterine sarcoma. Three of 6 patients had sarcoma diagnosed on initial pathologic evaluation of the morcellated specimen; 3 patients had delayed diagnosis of sarcoma with benign disease at the time of the initial procedure (median time to second evaluation, 6 years). For parasitic myomas (n=4), the median age was 35 years (range, 32-40 years), and the median time to second evaluation was 5 years. On multivariate analysis, age<40 years (odds ratio, 26; 95% confidence interval, 2.7015-261.9; P<=.01) was associated with higher risk of the development of parasitic myomas. CONCLUSION: Uterine sarcoma was found in 0.6% of patients who underwent power morcellation but was not found to be associated significantly with any preoperative factors. All 6 cases were noted to have apparent fibroid tumors as an indication for their hysterectomy. Age<40 years was a risk factor for parasitic myomas after power morcellation. Patients should be counseled about these complications before power morcellation. PMID- 25499260 TI - Incidence of cervical precancers among HIV-seropositive women. AB - OBJECTIVE: The objective of the study was to estimate the impact of human immunodeficiency virus (HIV) infection on the incidence of high-grade cervical intraepithelial neoplasia (CIN). STUDY DESIGN: HIV-seropositive and comparison seronegative women enrolled in a prospective US cohort study were followed up with semiannual Papanicolaou testing, with colposcopy for any abnormality. Histology results were retrieved to identify CIN3+ (CIN3, adenocarcinoma in situ, and cancer) and CIN2+ (CIN2 and CIN3+). Annual detection rates were calculated and risks compared using a Cox analysis. Median follow-up (interquartile range) was 11.0 (5.4-17.2) years for HIV-seronegative and 9.9 (2.5-16.0) for HIV seropositive women. RESULTS: CIN3+ was diagnosed in 139 HIV-seropositive (5%) and 19 HIV-seronegative women (2%) (P<.0001), with CIN2+ in 316 (12%) and 34 (4%) (P<.0001). The annual CIN3+ detection rate was 0.6 per 100 person-years in HIV seropositive women and 0.2 per 100 person-years in seronegative women (P<.0001). The CIN3+ detection rate fell after the first 2 years of study, from 0.9 per 100 person-years among HIV-seropositive women to 0.4 per 100 person-years during subsequent follow-up (P<.0001). CIN2+ incidence among these women fell similarly with time, from 2.5 per 100 person-years during the first 2 years after enrollment to 0.9 per 100 person-years subsequently (P<.0001). In Cox analyses controlling for age, the hazard ratio for HIV-seropositive women with CD4 counts less than 200/cmm compared with HIV-seronegative women was 8.1 (95% confidence interval, 4.8-13.8) for CIN3+ and 9.3 (95% confidence interval, 6.3-13.7) for CIN2+ (P<.0001). CONCLUSION: Although HIV-seropositive women have more CIN3+ than HIV-seronegative women, CIN3+ is uncommon and becomes even less frequent after the initiation of regular cervical screening. PMID- 25499261 TI - Robotic-assisted laparoscopic removal of cesarean scar ectopic and hysterotomy revision. AB - A 38-year-old gravida 6 para 2042 woman presented in consultation regarding management of a uterine defect, or "niche," following resolution of a cesarean scar ectopic pregnancy. She had 3 prior losses, followed by in vitro fertilization that resulted in 2 healthy births, both delivered by cesarean. A third in vitro embryo transfer resulted in the cesarean scar ectopic. After consideration of treatment options, she underwent multiple-dose parenteral methotrexate with eventual termination of the ectopic. Magnetic resonance imaging demonstrated a uterine defect, suspected to contain residual pregnancy tissue. Questions considered in her consultation included whether the defect should be repaired and, if so, from a hysteroscopic or laparoscopic approach, as well as her risk of intrauterine scarring, when, or if, it would be safe to pursue another pregnancy, and her subsequent risk of uterine rupture. Literature review regarding cesarean niche was helpful, but did not seem to completely inform this particular clinical scenario. She elected to proceed with robotic-assisted laparoscopic repair. The vesicovaginal space was opened to expose the defect. Dilute vasopressin was injected circumferentially around the defect to help minimize the use of electrosurgery in opening the hysterotomy. Scar overlying the defect was resected and pregnancy tissue removed. The hysterotomy was closed with delayed-absorbable barbed suture, extrapolating technique from laparoscopic myomectomy. The first layer was imbricated with a second, similar to a 2-layer closure in cesarean delivery. Follow-up magnetic resonance imaging revealed resolution of the defect. After several failed attempts at repeat in vitro fertilization, spontaneous pregnancy was achieved 18 months postoperatively. The pregnancy was uncomplicated and she underwent scheduled cesarean delivery of a healthy neonate at 37 weeks' gestation. The lower uterine segment was thick and developed, with no evidence of a dehiscence. PMID- 25499262 TI - Laparoscopic sacrocolpopexy: demonstration of a nerve-sparing technique. AB - Laparoscopic sacrocolpopexy is a well-established technique to treat apical vaginal prolapse. De novo micturition disorders, pelvic pain, and defecation disorders have been reported and may be due to intraoperative compromise of the superior hypogastric plexus. The video demonstrates our technique for nerve sparing laparoscopic sacrocolpopexy. The patient is a 62-year-old woman with symptomatic stage III posthysterectomy vaginal vault prolapse. Key steps of the procedure are opening the peritoneum at the level of the promontory, identification of the fibers of the superior hypogastric plexus, deep anterior and posterior dissection with attachment of the mesh to the vagina, displacement of the nerve fibers to the left side during suturing of the mesh to the longitudinal ligament, and complete peritonealization. This technique of the identification and protection of relevant nerve structures appears to be reproducible and can be considered by surgeons who perform laparoscopic sacrocolpopexy. PMID- 25499263 TI - Prenatal head growth and child neuropsychological development at age 14 months. AB - OBJECTIVE: We sought to assess the association between prenatal head growth and child neuropsychological development in the general population. STUDY DESIGN: We evaluated 2104 children at the age of 14 months from a population-based birth cohort in Spain. Head circumference (HC) was measured by ultrasound examinations at weeks 12, 20, and 34 of gestation and by a nurse at birth. Head growth was assessed using conditional SD scores between weeks 12-20 and 20-34. Trained psychologists assessed neuropsychological functioning using the Bayley Scales of Infant Development. Head size measurements at birth were transformed into a 3 category variable: microcephalic (<10th percentile), normocephalic (>=10th and <90th percentile), and macrocephalic (>=90th percentile) based on the cohort distribution. P values<.05 were considered statistically significant. RESULTS: No overall associations were observed between HC or head growth and mental and psychomotor scores. In particular, no associations were found between HC at birth and mental scores (coefficient, 0.04; 95% confidence interval, -0.02 to 0.09) and between interval head growth (20-34 weeks) and mental scores (0.31; 95% confidence interval, -0.36 to 0.99). Upon stratification by microcephalic, normocephalic, or macrocephalic head size, results were imprecise, although there were some significant associations in the microcephalic and macrocephalic groups. Adjustment by various child and maternal cofactors did not affect results. The minimum sample size required for present study was 883 patients (beta=2, alpha=0.05, power=0.80). CONCLUSION: Overall prenatal and perinatal HC was not associated with 14-month-old neuropsychological development. Findings suggest HC growth during uterine life among healthy infants may not be an important marker of early-life neurodevelopment but may be marginally useful with specific populations. PMID- 25499264 TI - The role of N-glycans of HIV-1 gp41 in virus infectivity and susceptibility to the suppressive effects of carbohydrate-binding agents. AB - BACKGROUND: Carbohydrate-binding agents (CBAs) are potent antiretroviral compounds that target the N-glycans on the HIV-1 envelope glycoproteins. The development of phenotypic resistance to CBAs by the virus is accompanied by the deletion of multiple N-linked glycans of the surface envelope glycoprotein gp120. Recently, also an N-glycan on the transmembrane envelope glycoprotein gp41 was shown to be deleted during CBA resistance development. RESULTS: We generated HIV 1 mutants lacking gp41 N-glycans and determined the influence of these glycan deletions on the viral phenotype (infectivity, CD4 binding, envelope glycoprotein incorporation in the viral particle and on the transfected cell, virus capture by DC-SIGN(+) cells and transmission of DC-SIGN-captured virions to CD4(+) T lymphocytes) and on the phenotypic susceptibility of HIV-1 to a selection of CBAs. It was shown that some gp41 N-glycans are crucial for the infectivity of the virus. In particular, lack of an intact N616 glycosylation site was shown to result in the loss of viral infectivity of several (i.e. the X4-tropic IIIB and NL4.3 strains, and the X4/R5-tropic HE strain), but not all (i.e. the R5-tropic ADA strain) studied HIV-1 strains. In accordance, we found that the gp120 levels in the envelope of N616Q mutant gp41 strains NL4.3, IIIB and HE were severely decreased. In contrast, N616Q gp41 mutant HIV-1ADA contained gp120 levels similar to the gp120 levels in WT HIV-1ADA virus. Concomitantly deleting multiple gp41 N glycans was often highly detrimental for viral infectivity. Using surface plasmon resonance technology we showed that CBAs have a pronounced affinity for both gp120 and gp41. However, the antiviral activity of CBAs is not dependent on the concomitant presence of all gp41 glycans. Single gp41 glycan deletions had no marked effects on CBA susceptibility, whereas some combinations of two to three gp41 glycan-deletions had a minor effect on CBA activity. CONCLUSIONS: We revealed the importance of some gp41 N-linked glycans, in particular the N616 glycan which was shown to be absolutely indispensable for the infectivity potential of several virus strains. In addition, we demonstrated that the deletion of up to three gp41 N-linked glycans only slightly affected CBA susceptibility. PMID- 25499265 TI - Involvement of aberrant miR-139/Jun feedback loop in human gastric cancer. AB - Accumulating evidence indicates that some miRNAs could form feedback loops with their targets to fine-tune tissue homeostasis, while disruption of these loops constitutes an essential step towards human tumorigenesis. In this study, we report the identification of a novel negative feedback loop formed between miR 139 and its oncogenic target Jun. In this loop, miR-139 could inhibit Jun expression by targeting a conserved site on its 3'-UTR, whereas Jun could induce miR-139 expression in a dose dependent manner through a distant upstream regulatory element. Interestingly, aberration in this loop was found in human gastric cancer, where miR-139 was down-regulated and inversely correlated with Jun expression. Further functional analysis showed that restored expression of miR-139 in gastric cancer cells significantly induces apoptosis, and inhibits cell migration and proliferation as well as tumour growth through targeting Jun. Thus, our data strongly suggests a role of aberrant miR-139/Jun negative feedback loop in the development of human gastric cancer and miR-139 as a potential therapeutic target for gastric cancer. Given that miR-139 and Jun are deregulated in many cancers, our findings here might have broader implication in other types of human cancers. PMID- 25499266 TI - SAP97 blocks the RXR ER retention signal of NMDA receptor subunit GluN1-3 through its SH3 domain. AB - SAP97 is directly involved in exporting NMDA receptors with a specific subunit composition from the endoplasmic reticulum (ER). Characterization of the interactions between SAP97 and an NMDA receptor splice variant, GluN1-3, and of the effects on forward trafficking revealed that an ER-level interaction blocked the RXR ER-retention motif in the GluN1-3 cytoplasmic C-terminus in the context of both reporter molecules and full-length receptors. Binding of SAP97 to the PDZ binding domain of GluN1-3 was required, but the blockade of ER-retention was mediated by the SH3-GuK domains coupled with the action of the N-terminus of SAP97. While other domains of SAP97 were involved in forward trafficking of GluN1 3 out of the ER, the SH3 domain was necessary and sufficient to block the ER retention. This is the first direct evidence for the masking of ER-retention signals by PDZ domain-containing proteins, and provides detailed underlying mechanistic requirements. Such a mechanism could be central to modulating the ER exit of receptors into local, non-conventional or conventional, secretory pathways in neurons. PMID- 25499267 TI - Kcnip1 a Ca2+-dependent transcriptional repressor regulates the size of the neural plate in Xenopus. AB - In amphibian embryos, our previous work has demonstrated that calcium transients occurring in the dorsal ectoderm at the onset of gastrulation are necessary and sufficient to engage the ectodermal cells into a neural fate by inducing neural specific genes. Some of these genes are direct targets of calcium. Here we search for a direct transcriptional mechanism by which calcium signals are acting. The only known mechanism responsible for a direct action of calcium on gene transcription involves an EF-hand Ca2+ binding protein which belongs to a group of four proteins (Kcnip1 to 4). Kcnip protein can act in a Ca2+-dependent manner as a transcriptional repressor by binding to a specific DNA sequence, the Downstream Regulatory Element (DRE) site. In Xenopus, among the four kcnips, we show that only kcnip1 is timely and spatially present in the presumptive neural territories and is able to bind DRE sites in a Ca2+-dependent manner. The loss of function of kcnip1 results in the expansion of the neural plate through an increased proliferation of neural progenitors. Later on, this leads to an impairment in the development of anterior neural structures. We propose that, in the embryo, at the onset of neurogenesis Kcnip1 is the Ca2+-dependent transcriptional repressor that controls the size of the neural plate. This article is part of a Special Issue entitled: 13th European Symposium on Calcium. PMID- 25499269 TI - The Endotrol tracheal tube using McGrath can be a viable alternative to laryngoscope intubation. PMID- 25499270 TI - Positive perceptions on safety and satisfaction during a patient-centered timeout before peripheral nerve blockade. AB - OBJECTIVES: To determine the psychometric outcomes of patients participating in an extensive patient-centered verification process before receiving sedation for regional anesthesia. DESIGN: Survey. SETTING: Perioperative areas of university affiliated hospital. PATIENTS: Two hundred eligible patients scheduled for elective orthopedic surgery undergoing peripheral nerve blockade. INTERVENTIONS: Postoperative survey evaluating patient perception, experience, and satisfaction with the anesthetic timeout before regional anesthesia. MEASUREMENTS: Measures using numeric rating scales were obtained on patient perceptions of safety, confidence in anesthesia provider, anxiety, and positive sentiments during participation in block timeout. These variables were analyzed using logistic regression models to correlate with reported pain and satisfaction perioperatively. MAIN RESULTS: One hundred seventy-five patients (93% enrollment) completed the study. More than 90% of patients reported agreeing strongly to feeling safe, confident, relaxed, and positive about their participation in the block timeout. These sentiments are associated with less reported perioperative pain and higher overall satisfaction. CONCLUSIONS: Patient perceptions of confidence and safety in regional anesthesia providers were enhanced by a preprocedural timeout process. These positive attitudes are associated with a superior perioperative experience and patient satisfaction. PMID- 25499272 TI - Extra L2bn for NHS will mean 30,000 more staff, MPs hear. PMID- 25499271 TI - Myoclonus in patient on fluoxetine after receiving fentanyl and low-dose methylene blue during sentinel lymph node biopsy. AB - Serotonin released in the nerve synapses is cleared through reuptake into presynaptic neurons and metabolism with monoamine oxidase (MAO). Therapy with selective serotonin reuptake inhibitors (SSRIs) or MAO inhibitors increases serotonin concentration in the synaptic cleft and may result in serotonin syndrome (SS). Our patient undergoing sentinel lymph node biopsy was on fluoxetine (SSRI) and intraoperatively developed SS after receiving fentanyl (200 MUg) and methylene blue (MAO inhibitor), 7 mg subcutaneously into the scalp. Initial presentation was several episodes of generalized muscle activity, which was later diagnosed as lower extremity myoclonus consistent with SS. Upon awakening, the patient showed no evidence of encephalopathy, and the clonus was less intense. The patient was discharge home the next day. Our case suggests the possibility that even a small dose of methylene blue, when administered simultaneously with other serotoninergic medications, may be associated with serotonin toxicity. PMID- 25499273 TI - Patients who showed paradoxical increase in HbA1c levels after intensification of diabetes treatment. AB - OBJECTIVES: When diabetes treatment is started, added, or changed (intensification of treatment) in patients with poor glycemic control, GA (glycated albumin) decreases within a few weeks, while HbA1c increases in some patients, resulting in a discrepancy between changes in GA and HbA1c. In the present study, we investigated the pathophysiology of such discrepancies. DESIGN AND METHODS: Four diabetic patients with poor glycemic control in whom GA showed a decrease while HbA1c showed an increase at a few weeks after intensification of treatment, resulting in a discrepancy between the time course of HbA1c and that of GA, were studied. RESULTS: In all patients HbA1c increased during the course before intensification of treatment; GA measured in two patients before the intensification of treatment also increased. After the intensification of treatment, GA decreased in all patients. On the other hand, HbA1c increased even after the intensification of treatment, but it decreased later in these patients. CONCLUSIONS: In patients in whom HbA1c increased in spite of a decrease in GA after the intensification of diabetes treatment, glycemic control got worsened before the intensification of treatment. In such patients, therapeutic effect may be misinterpreted if glycemic control is evaluated by HbA1c, and thus it is preferable to evaluate glycemic control by fasting plasma glucose, GA and fructosamine in such situations. PMID- 25499274 TI - NICE guidance on dabrafenib for treating unresectable or metastatic BRAF V600 mutation-positive melanoma. PMID- 25499268 TI - The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel. AB - The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) type 2 (IP3R2) is an intracellular Ca2+-release channel located on the endoplasmic reticulum (ER). IP3R2 is characterized by a high sensitivity to both IP3 and ATP and is biphasically regulated by Ca2+. Furthermore, IP3R2 is modulated by various protein kinases. In addition to its regulation by protein kinase A, IP3R2 forms a complex with adenylate cyclase 6 and is directly regulated by cAMP. Finally, in the ER, IP3R2 is less mobile than the other IP3R isoforms, while its functional properties appear dominant in heterotetramers. These properties make the IP3R2 a Ca2+ channel with exquisite properties for setting up intracellular Ca2+ signals with unique characteristics. IP3R2 plays a crucial role in the function of secretory cell types (e.g. pancreatic acinar cells, hepatocytes, salivary gland, eccrine sweat gland). In cardiac myocytes, the role of IP3R2 appears more complex, because, together with IP3R1, it is needed for normal cardiogenesis, while its aberrant activity is implicated in cardiac hypertrophy and arrhythmias. Most importantly, its high sensitivity to IP3 makes IP3R2 a target for anti apoptotic proteins (e.g. Bcl-2) in B-cell cancers. Disrupting IP3R/Bcl-2 interaction therefore leads in those cells to increased Ca2+ release and apoptosis. Intriguingly, IP3R2 is not only implicated in apoptosis but also in the induction of senescence, another tumour-suppressive mechanism. These results were the first to unravel the physiological and pathophysiological role of IP3R2 and we anticipate that further progress will soon be made in understanding the function of IP3R2 in various tissues and organs. PMID- 25499275 TI - Carcinogenicity of fluoro-edenite, silicon carbide fibres and whiskers, and carbon nanotubes. PMID- 25499284 TI - WHO Framework Convention on Tobacco Control conference. PMID- 25499285 TI - CRC risk knowledge does not affect screening compliance. PMID- 25499286 TI - Adjuvant trastuzumab improves survival in early breast cancer. PMID- 25499287 TI - PSA test not recommended by Canadian Task Force. PMID- 25499288 TI - FOLFOXIRI and bevacizumab in metastatic colorectal cancer. PMID- 25499289 TI - Late detection of lung cancer. PMID- 25499290 TI - US hospitals object to changes in Genentech drug distribution. PMID- 25499291 TI - Australian HPV vaccination programme yields results. PMID- 25499292 TI - Combination boosts survival for metastatic melanoma. PMID- 25499293 TI - CIN excision and preterm birth risk. PMID- 25499294 TI - Prostate cancer services vary in England and Wales. PMID- 25499295 TI - Radiotherapy for testicular cancer increases gastric cancer risk. PMID- 25499296 TI - Development of three full-length infectious cDNA clones of distinct brassica yellows virus genotypes for agrobacterium-mediated inoculation. AB - Brassica yellows virus is a newly identified species in the genus of Polerovirus within the family Luteoviridae. Brassica yellows virus (BrYV) is prevalently distributed throughout Mainland China and South Korea, is an important virus infecting cruciferous crops. Based on six BrYV genomic sequences of isolates from oilseed rape, rutabaga, radish, and cabbage, three genotypes, BrYV-A, BrYV-B, and BrYV-C, exist, which mainly differ in the 5' terminal half of the genome. BrYV is an aphid-transmitted and phloem-limited virus. The use of infectious cDNA clones is an alternative means of infecting plants that allows reverse genetic studies to be performed. In this study, full-length cDNA clones of BrYV-A, recombinant BrYV5B3A, and BrYV-C were constructed under control of the cauliflower mosaic virus 35S promoter. An agrobacterium-mediated inoculation system of Nicotiana benthamiana was developed using these cDNA clones. Three days after infiltration with full-length BrYV cDNA clones, necrotic symptoms were observed in the inoculated leaves of N. benthamiana; however, no obvious symptoms appeared in the upper leaves. Reverse transcription-PCR (RT-PCR) and western blot detection of samples from the upper leaves showed that the maximum infection efficiency of BrYVs could reach 100%. The infectivity of the BrYV-A, BrYV-5B3A, and BrYV-C cDNA clones was further confirmed by northern hybridization. The system developed here will be useful for further studies of BrYV, such as host range, pathogenicity, viral gene functions, and plant-virus-vector interactions, and especially for discerning the differences among the three genotypes. PMID- 25499297 TI - Genetic variability of VP6, VP7, VP4, and NSP4 genes of porcine rotavirus group H detected in Brazil. AB - Rotaviruses (RV) are a common cause of viral gastroenteritis in humans and animals. Despite the seven groups/species of RV (A-G), recently it was proposed the creation of a new RV group/specie H (RVH) based on VP6 sequence analysis. In this study we determined the VP6, VP7, VP4, and NSP4 nucleotide and deduced amino acid sequences of 6 (BR59-BR64) RVH-positive stool specimens obtained from piglets with diarrhea in Mato Grosso do Sul, Central-West region of Brazil in 2012, using RT-PCR assay. Based on the high sequence identities (>99%) of the VP6, VP4, VP7, and NSP4 genes among 5 of the studied fecal specimens (BR59-BR63), they are considered the same local rotavirus strain denominated RVH/BRA-1. In contrast, once that the fecal sample BR64 showed a relatively high difference (81.6% nt identity and 83.4% aa identity) in the VP7 sequence when compared to the other 5 specimens it was named RVH/BRA-2 strain. Comparative phylogenetic analysis showed that the 6 RVH strains do not cluster together with any available sequences of members of the established RV groups (RVA-RVG), however, seem to be related to RVB and RVG. These results confirm the presence of RVH in Brazil, demonstrate their genetic diversity, and provide new data that will assist in understanding the viral phylogeny and epidemiology, as well as the explanation of patterns of viral evolution and biological properties of RVH. PMID- 25499298 TI - Analysis of genetic divergence among strains of porcine rotavirus C, with focus on VP4 and VP7 genotypes in Japan. AB - Porcine rotavirus C (RVC) has been often detected in sporadic cases or outbreaks of diarrhoea in suckling and weaned pigs. Surveillance studies of RVCs have demonstrated high prevalence in the United States, and Japan, and some other countries. To date, the zoonotic impact and pathogenicity of RVCs are not well understood, and only a few complete sequences of RVCs are available. The aim of this study was to perform sequence and phylogenetic analyses for the VP4 and VP7 genes of the 22 porcine RVCs identified in Japan from 2002 to 2010. The genetic classification of the VP4 genes of the 22 porcine RVCs revealed the presence of six clusters including one cluster each from human and bovine RVCs with a cut-off value of 80%. In addition, VP7 genes of the 22 porcine RVCs were grouped into four of the seven known clusters on the basis of cut-off values of 85% at the nucleotide level reported previously. The data presented here demonstrate that multiple porcine RVC strains with distinctive genotypes based on a combination of the VP4 and VP7 genes are widely distributed and circulated among farms throughout Japan. According to establishment of dual genetic classification for VP4 and VP7 genotypes of porcine RVCs, furthermore, we discovered a possible event of gene reassortment between different rotavirus strains from the same farm. Our findings should advance the understanding of the evolution and pathogenicity of RVCs. PMID- 25499299 TI - Cysteine residues of the porcine reproductive and respiratory syndrome virus ORF5a protein are not essential for virus viability. AB - ORF5a protein was recently identified as a novel structural protein in porcine reproductive and respiratory syndrome virus (PRRSV). The ORF5a protein possesses two cysteines at positions 29 and 30 that are highly conserved among type 2 PRRSV. In this study, the significance of the ORF5a protein cysteine residues on virus replication was determined based on a type 2 PRRSV cDNA clone (pAJXM). Each cysteine was substituted by serine or glycine and the mutations were introduced into pAJXM. We found that the replacement of cysteine to glycine at position 30 was lethal for virus viability, but all serine mutant clones produced infectious progeny viruses. This data indicated that cysteine residues in the ORF5a protein were not essential for replication of type 2 PRRSV. The bimolecular fluorescence complementation (BiFC) and Co-immunoprecipitation (Co-IP) assay were used to study ORF5a protein interacted with other enveloped proteins. These results showed that ORF5a protein interacted non-covalently with itself and interacted with GP4 and 2b protein. The replacement of cysteine to glycine at position 30 affected the ORF5a protein interacted non-covalently with itself, which may account for the lethal phenotype of mutants carrying substitution of cysteine to glycine at position 30. PMID- 25499300 TI - Extended use of percutaneous edge-to-edge mitral valve repair beyond EVEREST (Endovascular Valve Edge-to-Edge Repair) criteria: 30-day and 12-month clinical and echocardiographic outcomes from the GRASP (Getting Reduction of Mitral Insufficiency by Percutaneous Clip Implantation) registry. AB - OBJECTIVES: This study sought to compare, in high-risk patients with 3+ to 4+ mitral regurgitation (MR) dichotomized by baseline echocardiographic features, acute, 30-day, and 12-month outcomes following percutaneous mitral valve repair using the MitraClip. BACKGROUND: The feasibility and mid-term outcomes after MitraClip implantation in patients with echocardiographic features different from the EVEREST (Endovascular Valve Edge-to-Edge Repair) I and II trials have been scarcely studied. METHODS: Clinical and echocardiographic outcomes through 12 month follow-up of consecutive patients who underwent MitraClip implantation were obtained from an ongoing prospective registry. Two different groups, divided according to baseline echocardiographic criteria (investigational group [EVERESTOFF] and control group [EVERESTON]), were compared. RESULTS: Seventy eight patients were included in EVERESTOFF and 93 patients in EVERESTON groups. Important and comparable acute reductions in MR and no clip-related complications were revealed. The primary safety endpoint at 30 days was comparable between groups (2.6% vs. 6.5%, respectively, p = 0.204); in addition, MR reduction was mostly sustained, whereas equivalent improvement in New York Heart Association functional class were demonstrated. Kaplan-Meier freedom from death, surgery for mitral valve dysfunction, or grade >=3+ MR at 12 months was demonstrated in 71.4% and 76.2%, respectively, in the EVERESTOFF and EVERESTON groups (log rank p = 0.378). Significant improvements in ejection fraction and reduction in left ventricle volumes were demonstrated in both groups over time, but the baseline between-group differences were sustained. CONCLUSIONS: MitraClip implantation in patients with expanded baseline echocardiographic features, compared with the control group, was associated with similar rates of safety and efficacy through 12-month follow-up. Further validation of our findings is warranted. PMID- 25499301 TI - The impact of extreme-risk cases on hospitals' risk-adjusted percutaneous coronary intervention mortality ratings. AB - OBJECTIVES: The goal of this study was to examine the calibration of a validated risk-adjustment model in very high-risk percutaneous coronary intervention (PCI) cases and assess whether sites' case mix affects their performance ratings. BACKGROUND: There are concerns that treating PCI patients with particularly high risk features such as cardiogenic shock or prior cardiac arrest may adversely impact hospital performance ratings. However, there is little investigation on the validity of these concerns. METHODS: We examined 624,286 PCI procedures from 1,168 sites that participated in the CathPCI Registry in 2010. Procedural risk was estimated using the recently published Version 4 National Cardiovascular Data Registry (NCDR) PCI risk-adjusted mortality (RAM) model. We calculated observed/expected mortality using several risk classification methods, and simulated hospital performance after combining their highest risk cases over 2 years into a single year. RESULTS: In 2010, crude in-hospital PCI mortality was 1.4%. The NCDR model was generally well calibrated among high risk, however there was slight overprediction of risk in extreme cases. Hospitals treating the highest overall expected risk PCI patients or those treating the top 20% of high risk cases had lower (better) RAM ratings than centers treating lower-risk cases (1.25% vs. 1.51%). The observed/expected ratio for top-risk quintile versus low risk quintile was 0.91 (0.87 to 0.96) versus 1.10 (1.03 to 1.17). Combining all the high-risk patients over a 2-year period into a single year also did not negatively impact the site's RAM ratings. CONCLUSIONS: Evaluation of a contemporary sample of PCI cases across the United States showed no evidence that treating high-risk PCI cases adversely affects hospital RAM rates. PMID- 25499302 TI - Comparison of sirolimus-eluting stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery: 7-year follow-up of a randomized trial. AB - OBJECTIVES: The aim of this analysis was to assess the 7-year long-term safety and effectiveness of a randomized comparison of percutaneous coronary intervention (PCI) with sirolimus-eluting stents (SES) versus minimally invasive direct coronary artery bypass (MIDCAB) surgery for the treatment of isolated proximal left anterior descending lesions. BACKGROUND: Long-term follow-up data comparing PCI by SES and MIDCAB surgery for isolated proximal left anterior descending lesions are sparse. METHODS: Patients were randomized either to PCI with SES (n = 65) or MIDCAB (n = 65). Follow-up data were obtained after 7 years with respect to the primary composite endpoint of death, myocardial infarction, and target vessel revascularization. Angina was assessed by the Canadian Cardiovascular Society classification and quality of life with Short Form 36 and MacNew quality of life questionnaires. RESULTS: Follow-up was conducted in 129 patients at a median time of 7.3 years (interquartile range: 5.7, 8.3). There were no significant differences in the incidence of the primary composite endpoint between groups (22% PCI vs. 12% MIDCAB; p = 0.17) or the endpoints death (14% vs. 17%; p = 0.81) and myocardial infarction (6% vs. 9%, p = 0.74). However, the target vessel revascularization rate was higher in the PCI group (20% vs. 1.5%; p < 0.001). Clinical symptoms and quality of life improved significantly from baseline with both interventions and were similar in magnitude between groups. CONCLUSIONS: At 7-year follow-up, PCI by SES and MIDCAB in isolated proximal left anterior descending lesions yielded similar long-term outcomes regarding the primary composite clinical endpoint and quality of life. Target vessel revascularization was more frequent in the PCI group. (MIDCAB Versus DES in Proximal LAD Lesions; NCT00299429). PMID- 25499303 TI - The public reporting risk of performing high-risk procedures: perception or reality? PMID- 25499304 TI - Endovascular repair of ruptured pseudoaneurysm of left internal mammary graft following redo aortic valve replacement and coronary artery bypass grafting. PMID- 25499306 TI - In-scaffold restenosis in a previous left main bifurcation lesion treated with bioresorbable scaffold v-stenting. PMID- 25499307 TI - Optical coherence tomography assessment of late intra-scaffold dissection: a new challenge of bioresorbable scaffolds. PMID- 25499305 TI - Randomized controlled study of excimer laser atherectomy for treatment of femoropopliteal in-stent restenosis: initial results from the EXCITE ISR trial (EXCImer Laser Randomized Controlled Study for Treatment of FemoropopliTEal In Stent Restenosis). AB - OBJECTIVES: The purpose of this study was to evaluate the safety and efficacy of excimer laser atherectomy (ELA) with adjunctive percutaneous transluminal angioplasty (PTA) versus PTA alone for treating patients with chronic peripheral artery disease with femoropopliteal bare nitinol in-stent restenosis (ISR). BACKGROUND: Femoropopliteal stenting has shown superiority to PTA for lifestyle limiting claudication and critical limb ischemia, although treating post-stenting artery reobstruction, or ISR, remains challenging. METHODS: The multicenter, prospective, randomized, controlled EXCITE ISR (EXCImer Laser Randomized Controlled Study for Treatment of FemoropopliTEal In-Stent Restenosis) trial was conducted across 40 U.S. centers. Patients with Rutherford Class 1 to 4 and lesions of target lesion length >=4 cm, vessel diameter 5 to 7 mm were enrolled and randomly divided into ELA + PTA and PTA groups by a 2:1 ratio. The primary efficacy endpoint was target lesion revascularization (TLR) at 6-month follow up. The primary safety endpoint was major adverse event (death, amputation, or TLR) at 30 days post-procedure. RESULTS: Study enrollment was stopped at 250 patients due to early efficacy demonstrated at a prospectively-specified interim analysis. A total of 169 ELA + PTA subjects (62.7% male; mean age 68.5 +/- 9.8 years) and 81 PTA patients (61.7% male; mean age 67.8 +/- 10.3 years) were enrolled. Mean lesion length was 19.6 +/- 12.0 cm versus 19.3 +/- 11.9 cm, and 30.5% versus 36.8% of patients exhibited total occlusion. ELA + PTA subjects demonstrated superior procedural success (93.5% vs. 82.7%; p = 0.01) with significantly fewer procedural complications. ELA + PTA and PTA subject 6-month freedom from TLR was 73.5% versus 51.8% (p < 0.005), and 30-day major adverse event rates were 5.8% versus 20.5% (p < 0.001), respectively. ELA + PTA was associated with a 52% reduction in TLR (hazard ratio: 0.48; 95% confidence interval: 0.31 to 0.74). CONCLUSIONS: The EXCITE ISR trial is the first large, prospective, randomized study to demonstrate superiority of ELA + PTA versus PTA alone for treating femoropopliteal ISR. (Randomized Study of Laser and Balloon Angioplasty Versus Balloon Angioplasty to Treat Peripheral In-stent Restenosis [EXCITE ISR]; NCT01330628). PMID- 25499308 TI - The transcription factor Forkhead Box P3 gene variants affect idiopathic recurrent pregnancy loss. AB - INTRODUCTION: Forkhead Box P3 (FOXP3) is an essential transcription factor for the induction and development of Tregs. It plays an important role in regulation and suppression of immune responses. We tested whether FOXP3 gene variants are associated with idiopathic recurrent miscarriages (IRM). METHODS: We included 200 women with at least three unexplained spontaneous abortions before twentieth week of gestation and 300 healthy parous women. The detection of genetic variants of rs2232365, and rs5902434 SNPs were carried-out by using polymerase chain reaction (PCR) with sequence-specific primers, while rs3761548 and rs2294021 SNPs were genotyped by PCR followed by RFLP analysis. The logistic odds ratios (ORs) of idiopathic RM risk were estimated with a 95% confidence interval (CI) after maternal age adjustment. Multifactor dimension reduction (MDR) analysis was used to evaluate the potential SNP ~ SNP interactions. RESULTS: Single marker analysis revealed an increased risk ranged from almost 3-fold-2-fold for rs2232365, rs3761548, rs5902434 and rs2294021 SNPs in IRM cases. The mutant haplotype carriers of rs2232365, rs3761548, rs5902434 and rs2294021 SNPs showed an increased risk of 2.5-fold for IRM cases. Linkage disequilibrium analysis revealed moderate LD between rs2232365, rs3761548, rs5902434 and rs2294021 SNPs. The MDR analysis revealed 6-fold increased risk for IRM cases in four factor models of rs2232365, rs3761548, rs5902434 and rs2294021 SNPs. The maximum testing accuracy, highest cross validation consistency and greater significance was observed in four SNP model. DISCUSSION: These results suggest that variants of FOXP3 SNPs namely; rs2232365, rs3761548, rs5902434 and rs2294021 may be associated with idiopathic RM. PMID- 25499309 TI - Telomeres are shorter in placentas from pregnancies with uncontrolled diabetes. AB - INTRODUCTION: The intrauterine environment, including the placenta, is influenced by a variety of factors, among which is diabetes during pregnancy. These factors can affect lifetime morbidity. Senescence is a state of cellular metabolic arrest, known to be correlated with age-related diseases and is usually accompanied by short telomeres. This study evaluated telomere characteristics in placentas and in cord blood from term pregnancies complicated by uncontrolled diabetes mellitus. METHODS: Placental biopsies and cord blood were collected from 16 pregnancies with poorly controlled diabetes and from 16 healthy controls. Senescence-associated heterochromatin foci (SAHF) and senescence-associated beta galactosidase (SAbeta-Gal) staining were evaluated. Apoptosis was evaluated using tunel staining. Telomere length and aggregate formation were assessed in placentas and in cord blood using Q-FISH. RESULTS: Increased SAHF (19.28% +/- 7.93 vs. 7.78% +/- 5.31, P < 0.001) and SAbeta-Gal (7.1% +/- 1.32 vs. 0.8% +/- 0.41, P < 0.001), but not apoptosis were present in placentas from diabetic pregnancies compared to controls. Higher percentage of trophoblasts with short telomeres (24.42% +/- 12.6 vs. 4.92% +/- 6.4, P = 0.013) and noticeably more aggregate formation (2.75% +/- 1.14 vs. 0.62% +/- 0.87, P < 0.001) were observed in diabetic placentas compared to controls. These differences were not observed in cord blood samples. DISCUSSION: Poorly controlled diabetes is related to increased senescence and shorter telomeres in placentas. Those findings may partially explain increased long-term, related morbidity. PMID- 25499311 TI - The importance of cultural factors in the distribution of medicinal plant knowledge: a case study in four Basque regions. AB - ETHNOBOTANICAL RELEVANCE: Previous research suggests that the use of medicinal plants by a given group is mainly driven by biological variables such as the chemical composition or the ecological distribution of plants. However, other studies highlight the importance of cultural aspects such as the curative meaning given to a plant, beliefs, religion or the historical context. Such aspects could play an important role in the use, diffusion or even in the effectiveness of a plant remedy. MATERIALS AND METHODS: Fieldwork consisted of 233 orally consented semi-structured interviews with 178 informants about medicinal uses of plants. Interviews were conducted in four historically and geographycally delimited regions of Alava and Biscay with similar environmental conditions but different sociolinguistic backgrounds: two regions were Basque- and two Spanish-speaking. Data were structured in use-reports. A Between Class Analysis was conducted to assess the intercultural and intracultural variability of medicinal plants knowledge. RESULTS: The results show the existence of four clearly different medicinal ethnofloras. While the four ethnofloras share remedies widely distributed through the territory, each of them also includes remedies that are only shared among closely related communities. The ecological availability and chemical composition of the plants may explain why there are widely used plant remedies. On the contrary, the distribution of the locally shared remedies matches up with the cultural heterogeneity of the territory, so cultural factors, such as, language, social networks or the meaning response of the plants seem to explain the use of many traditional plant remedies. In Addition, we also found that Basque speaking territories show higher knowledge levels than Spanish speaking territories. In this sense, the development and reinforcement of Basque identity by Basque nationalism seems to have contributed to maintain the traditional knowledge in the Basque speaking regions. CONCLUSIONS: Despite the fact that pharmacological effectiveness and ecological availability are usually considered as the main variables that shape the traditional use of medicinal plants, our results suggest that cultural factors can be at least as important as ecological and chemical factors. In fact, differences in language, in the cultural meaning of the plants, in the context related to cultural identities, and in social networks seem to play a fundamental role in the use and diffusion and maintenance or erosion of traditional knowledge about medicinal plants in the study area. PMID- 25499310 TI - Strongyloides stercoralis infection in marmosets: replication of complicated and uncomplicated human disease and parasite biology. AB - BACKGROUND: Strongyloides stercoralis can undergo an alternative autoinfective life cycle in the host, which, in some individuals can lead to a lethal infection. However, due to a number of factors, such as, the majority of those infected are from low-income backgrounds and the limitation in experimental models for studying human S. stercoralis, strongyloidiasis remains neglected. Improved knowledge of animal models that are susceptible to this parasite is needed in order to investigate the immunological mechanisms involved during infection and in particular to further understand the natural history of the autoinfective cycle. METHODS: Callithrix penicillata were inoculated subcutaneously with 100 (n = 2), 300 (n = 4) or 500 (n = 9) third-stage infective larvae (L3i) of S. stercoralis of human origin. Three marmosets received smaller inocula (i.e., one received 100 and two received 300 L3i) to ensure a greater capacity to withstand the infection after immunosuppression, which was triggered by administration of dexamethasone during early patency. Qualitative faecal analyses began at 7 days post-infection (DPI), and semi-quantitative tests were also performed for the dexamethasone-treated primates and the three matched controls. During the necropsies, specimens of S. stercoralis were recovered and tissue fragments were processed for histopathology. RESULTS: The mean prepatency and patency periods were 16.1 +/- 3.0 and 161.1 +/- 72.2 DPI, respectively. The marmosets typically tolerated the infection well, but immunosuppressed individuals exhibited higher numbers of larvae in the faeces and progressive clinical deterioration with late disseminated infection. In these cases, the number of females recovered was significantly higher than the number of inoculated L3i. Large quantities of larvae were observed migrating through the host tissues, and histopathology revealed pulmonary and intestinal injuries consistent with those observed in human strongyloidiasis. CONCLUSIONS: Both complicated and uncomplicated strongyloidiasis occur in C. penicillata that is described as a susceptible small non-human primate model for S. stercoralis. This host permits the maintenance of a human strain of the parasite in the laboratory and can be useful for experimental investigations of strongyloidiasis. In parallel, we discuss data related to the autoinfective cycle that provides new insights into the biology of S. stercoralis. PMID- 25499312 TI - The effects of modified sini decoction on liver injury and regeneration in acute liver failure induced by D-galactosamine in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Modified sini decoction (MSND) is a well-known traditional Chinese medical formula that has been used to treat cardiovascular and liver diseases for many years. We investigated the effects of MSND on acute liver failure and identified the possible mechanisms of these effects. MATERIAL AND METHODS: Acute liver failure was induced by intraperitoneal injection of d galactosamine (d-GalN) into specific pathogen-free male Wistar rats. Next, the rats were treated with Stronger Neo-Minophagen C and MSND via gavage. Biochemical parameters, histological changes in the liver, the survival of rats and the mRNA levels of toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-kappaB), high mobility group box 1 (HMGB1) caspase-3 and proliferating cell nuclear antigen (PCNA) were analyzed. RESULTS: MSND prolonged the survival times of the acute liver failure rats. The biochemical parameters were improved, and necrosis in the liver tissues was reduced by both Stronger Neo-Minophagen C (SNMC) and MSND, but MSND induced greater effects. The mRNA expressions of HMGB1, TLR4, NF-kappaB, and Caspase-3 were remarkably decreased, and the expression of PCNA was remarkably increased by SNMC and MSND, and the effects of MSND were greater. CONCLUSIONS: MSND protected the liver and increased the survival rate of acute liver failure rats. These effects were likely mediated by the inhibitions of the inflammatory reaction and apoptosis and the promotion of liver tissue regeneration. PMID- 25499313 TI - Cross-generational trans fat intake facilitates mania-like behavior: oxidative and molecular markers in brain cortex. AB - Since that fast food consumption have raised concerns about people's health, we evaluated the influence of trans fat consumption on behavioral, biochemical and molecular changes in the brain-cortex of second generation rats exposed to a model of mania. Two successive generations of female rats were supplemented with soybean oil (SO, rich in n-6 FA, control group), fish oil (FO, rich in n-3 FA) and hydrogenated vegetable fat (HVF, rich in trans FA) from pregnancy, lactation to adulthood, when male rats from 2nd generation received amphetamine (AMPH-4 mg/kg-i.p., once a day, for 14 days) treatment. AMPH increased locomotor index in all animals, which was higher in the HVF group. While the FO group showed increased n-3 polyunsaturated fatty acid (PUFA) incorporation and reduced n-6/n-3 PUFA ratio, HVF allowed trans fatty acid (TFA) incorporation and increased n-6/n 3 PUFA ratio in the brain-cortex. In fact, the FO group showed minor AMPH-induced hyperactivity, decreased reactive species (RS) generation per se, causing no changes in protein carbonyl (PC) levels and dopamine transporter (DAT). FO supplementation showed molecular changes, since proBDNF was increased per se and reduced by AMPH, decreasing the brain-derived neurotrophic factor (BDNF) level following drug treatment. Conversely, HVF was related to increased hyperactivity, higher PC level per se and higher AMPH-induced PC level, reflecting on DAT, whose levels were decreased per se as well as in AMPH-treated groups. In addition, while HVF increased BDNF-mRNA per se, AMPH reduced this value, acting on BDNF, whose level was lower in the same AMPH-treated experimental group. ProBDNF level was influenced by HVF supplementation, but it was not sufficient to modify BDNF level. These findings reinforce that prolonged consumption of trans fat allows TFA incorporation in the cortex, facilitating hyperactive behavior, oxidative damages and molecular changes. Our study is a warning about cross-generational consumption of processed food, since high trans fat may facilitate the development of neuropsychiatric conditions, including bipolar disorder (BD). PMID- 25499314 TI - Transplantation of fetal ventral mesencephalic progenitor cells overexpressing high molecular weight fibroblast growth factor 2 isoforms in 6-hydroxydopamine lesioned rats. AB - Fibroblast growth factor-2 (FGF-2) is a potent neurotrophic factor promoting survival of dopaminergic (DA) neurons in vitro and in vivo. FGF-2 is expressed in different isoforms representing distinct translation products from a single mRNA. For this study, we focused on the high molecular weight (HMW) isoform, which, after non-viral plasmid-based overexpression in embryonic day 12 (E12) rat ventral mesencephalon (VM)-derived cells, revealed increased numbers of tyrosine hydroxylase-positive (TH(+)) cells in a 'colayer' cell culture model. To determine the therapeutic potential of VM cells producing FGF-2-HMW as their 'own' neurotrophic factor, we transplanted cell suspensions obtained from such in vitro modified and differentiated cell cultures into the 6-hydroxydopamine (6 OHDA) hemiparkinsonian rat model. Animals, having received either non-transfected cells, empty-control transfected, or FGF-2-HMW-plasmid transfected cells, were analyzed in two different transplantation paradigms each using 172,000 or 520,000 cells, respectively. The behavioral performances in the amphetamine- and apomorphine-induced rotational test as well as in the cylinder test were evaluated for up to thirteen weeks post transplantation (postTX). Finally, the integration of the grafted cells into the host striatum was analyzed by immunohistochemical measurements. Those analyses revealed improvements of behavioral deficits in all five groups receiving DA neuron grafts, except for amphetamine-induced rotation of the FGF-2-HMW small graft group. Altogether, genetic modification with the FGF-2-HMW-plasmid did not further improve functional recovery compared to the control groups and had no influence on either the number of surviving DA neurons or on the density of outgrowing TH(+) fibers. PMID- 25499315 TI - Cortical surface area and cortical thickness in the precuneus of adult humans. AB - The precuneus has received considerable attention in the last decade, because of its cognitive functions, its role as a central node of the brain networks, and its involvement in neurodegenerative processes. Paleoneurological studies suggested that form changes in the deep parietal areas represent a major character associated with the origin of the modern human brain morphology. A recent neuroanatomical survey based on shape analysis suggests that the proportions of the precuneus are also a determinant source of overall brain geometrical differences among adult individuals, influencing the brain spatial organization. Here, we evaluate the variation of cortical thickness and cortical surface area of the precuneus in a sample of adult humans, and their relation with geometry and cognition. Precuneal thickness and surface area are not correlated. There is a marked individual variation. The right precuneus is thinner and larger than the left one, but there are relevant fluctuating asymmetries, with only a modest correlation between the hemispheres. Males have a thicker cortex but differences in cortical area are not significant between sexes. The surface area of the precuneus shows a positive allometry with the brain surface area, although the correlation is modest. The dilation/contraction of the precuneus, described as a major factor of variability within adult humans, is associated with absolute increase/decrease of its surface, but not with variation in thickness. Precuneal thickness, precuneal surface area and precuneal morphology are not correlated with psychological factors such as intelligence, working memory, attention control, and processing speed, stressing further possible roles of this area in supporting default mode functions. Beyond gross morphology, the processes underlying the large phenotypic variation of the precuneus must be further investigated through specific cellular analyses, aimed at considering differences in cellular size, density, composition, and structural covariance compared to other brain areas. PMID- 25499316 TI - NADPH oxidase 2-dependent oxidative stress, mitochondrial damage and apoptosis in the ventral cochlear nucleus of D-galactose-induced aging rats. AB - Aging has been associated with oxidative stress and the accumulation of mitochondrial DNA (mtDNA) mutation. The previous study has established a mimetic rat model of aging using D-galactose (D-gal) and revealed that chronic injection of D-gal can increase NADPH oxidase (NOX)-dependent oxidative stress, mitochondrial damage and apoptosis in the peripheral auditory system. However, the effects of NOXs in the central auditory system (CAS) were still obscure. The current study was designed to investigate potential causative mechanisms of central presbycusis by using the D-gal-induced aging rats. We found that the levels of H2O2 and the expression of NADPH oxidase 2 (NOX2) and its corresponding subunits P22(phox), P47(phox) and P67(phox) were greatly increased in the ventral cochlear nucleus (VCN) of D-gal-treated rats as compared with controls. And, the levels of a typical biomarker of oxidative stress, 8-hydroxy-2-deoxyguanosine (8 OHdG), and the accumulation of mtDNA common deletion (CD) were also increased in the VCN of D-gal-treated rats as compared with controls. Moreover, the damage of mitochondrial ultrastructure, a decline in ATP levels, the loss of mitochondrial membrane potential (MMP), an increase in the amount of cytochrome c (cyt c) translocated to the cytoplasm and caspase-3 activation were observed in the VCN induced by D-gal. In addition, we also found that the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end-labeling (TUNEL)-positive cells in the VCN were increased in D-gal-treated rats. Taken together, these findings suggest that NOX2-dependent oxidative stress may contribute to mitochondrial damage and activate a caspase-3-dependent apoptosis pathway in the CAS during aging. This study also provides new insights into the development of presbycusis. PMID- 25499317 TI - Effects of endogenous melatonin on glutamate and GABA rhythms in the striatum of unilateral 6-hydroxydopamine-lesioned rats. AB - We have previously reported a time-dependent increase in melatonin (MLT) and decrease in dopamine (DA) in striatal dialysate 3 weeks after unilateral 6 hydroxydopamine (6-OHDA) lesioning in the rat substantia nigra pars compacta (SNc) and medial forebrain bundle (MFB). This study aimed to investigate dynamic and circadian variations in DA, MLT, glutamate (Glu) and gamma-aminobutyric acid (GABA) in striatal dialysates in the same 6-OHDA animal model. These neurotransmitters were determined using high-performance liquid chromatography (HPLC). Three weeks following 6-OHDA lesioning, there was a significant increase in extracellular Glu (156%) and decrease in GABA (15%) and DA (85%) in the lesioned striatum. These changes continued over time. Concomitantly, MLT was increased by 107% in the lesioned striatal dialysates after 4 weeks, and continued to increase gradually over time. Six weeks post-treatment, levels of MLT secretion at 12 time points were higher, and the peak time of MLT secretion was earlier, in 6-OHDA-lesioned rats compared with vehicle-treated rats. In addition, significant variations in extracellular levels of Glu and GABA between day and night were observed in vehicle-treated rat striatum. However, no circadian variations were observed in the striatum of unilateral 6-OHDA-lesioned rats. Six weeks post-treatment, MLT levels correlated well with Glu and GABA levels at corresponding time-points in the striatum ipsilateral to the injected side in both groups, and increased MLT levels also correlated well with changes in Glu and GABA in the striatum in 6-OHDA-lesioned rats. These data suggest that 6-OHDA lesioning affects the endogenous productions of DA, MLT, Glu and GABA, and changes the MLT secretion pattern. Augmented striatal MLT levels and advanced MLT secretion pattern caused by unilateral intracerebral injection of 6-OHDA may influence the variations in Glu and GABA between day and night. PMID- 25499318 TI - Intra-visceral insular cortex 2-arachidonoylglycerol, but not N arachidonoylethanolamide, suppresses acute nausea-induced conditioned gaping in rats. AB - The visceral insular cortex (VIC) has previously been shown to play a critical role during acute nausea-induced conditioned gaping in rats. Specifically, localized administration of the conventional anti-emetic, ondansetron or the synthetic cannabinoid, HU210, interferes with the establishment of conditioned gaping, likely by reducing the effects of an illness-inducing treatment. However the precise role of the VIC in endocannabinoid-suppression of nausea remains unknown; thus we investigated the potential of localized intra-VIC endocannabinoid administration to interfere with acute nausea-induced conditioned gaping behavior in male Sprague-Dawley rats. Animals received an intraoral infusion of saccharin (0.1%) followed by intra-VIC exogenous N arachidonoylethanolamide (AEA; 0.4, 4 MUg) or 2-arachidonoylglycerol (2-AG; 0.5, 1 MUg), and were subsequently injected with nausea-inducing LiCl (0.15M) 15 min later. Bilateral intra-VIC infusions of 2-AG (1 MUg, but not 0.5 MUg) dose dependently suppressed conditioned gaping, whereas exogenous AEA was without effect. Interestingly, 2-AG reduced conditioned gaping despite additional pretreatment with the selective cannabinoid receptor type 1 (CB1) antagonist, AM 251; however, concomitant pretreatment with the cyclooxygenase inhibitor, indomethacin (0.5 MUg), blocked the suppressive effects of intra-VIC 2-AG. These findings suggest that the modulatory role of the endocannabinoid system during nausea is driven largely by the endocannabinoid, 2-AG, and that its anti-nausea effects may be partly independent of CB1-receptor signaling through metabolic products of the endocannabinoid system. PMID- 25499319 TI - Statins and non-cardiac surgery: clarifying the discussion. PMID- 25499320 TI - Is left ventricular hypertrabeculation/noncompaction in athletes benign? PMID- 25499321 TI - Cardioprotective effect of isoflurane anesthesia from Takotsubo syndrome and its implications. PMID- 25499322 TI - Role of hypocalcemia in identification of 22q11 deletion syndrome among patients with congenital heart defects. PMID- 25499323 TI - Programmed death-1 (PD-1): a novel mechanism for understanding the acute immune deregulation in ST-segment elevation myocardial infarction. PMID- 25499324 TI - One-year outcome of biolimus eluting stent with biodegradable polymer in all comers: the Italian Nobori Stent Prospective Registry. AB - OBJECTIVES: INSPIRE-1 (Italian Nobori Stent ProspectIve REgistry-1) was designed and conducted to assess clinical performance of Nobori biolimus A9-eluting stent (BES) implantation in an unrestricted "real-world" cohort of patients. METHODS: Unrestricted consecutive high-risk patients treated with BES with biodegradable polymer (Nobori, Terumo, Tokyo, Japan) between February 2008 and July 2012 were prospectively enrolled in an independent multicenter registry and divided in two groups: complex and non complex lesions. RESULTS: 1066 patients (1589 lesions) treated with Nobori BES were analyzed. The majority of patients (57%) were treated for at least one complex lesion and presented a high-risk clinical profile (previous CABG 17.6%, diabetes mellitus 33.1%, chronic kidney disease 14.3%). Angiographic success rate was achieved in 96.2% cases. At 1 year, the primary endpoint, (composite of cardiac death, myocardial infarction, and clinically driven target vessel revascularization), occurred in 39 (4.0%) patients, and was higher in the complex lesions (5.2% vs. 2.5%, P = 0.032). Target lesion failure (TLF, secondary endpoint) occurred in 45 (4.6%) patients, and was more frequent in the complex lesions group (6.2% vs. 2.7%, P = 0.011), mainly due to a higher incidence of any target lesion revascularization (4.8% vs. 2.7%; P = 0.095). Definite and probable stent thrombosis (ST) rate was 0.6% and 0.5% respectively, with no difference between groups. CONCLUSIONS: In unrestricted daily practice, BESs were implanted predominantly in high risk patients with complex lesions. Despite this, the Nobori BES was associated with a relatively low rate of primary endpoint and TLF, with a higher risk in patients with complex lesions. PMID- 25499325 TI - Long-term prognostic value of late gadolinium enhancement in a cohort of patients with nonischemic dilated cardiomyopathy. PMID- 25499326 TI - Natural course of isolated spontaneous coronary artery dissection in Marfan syndrome. PMID- 25499327 TI - Timing of intervention and outcome in non-ST-elevation acute coronary syndromes: there is risk on both sides of the curve. PMID- 25499328 TI - Recurrence of takotsubo cardiomyopathy with different ballooning patterns. PMID- 25499329 TI - Life threatening severe hyperkalemia presenting typical electrocardiographic changes--rapid recovery following medical, temporary pacing, and hemodialysis treatments. PMID- 25499330 TI - N-Acetylcysteine (NAC) inhibits renal nitrite and nitrate reabsorption in healthy subjects and in patients undergoing cardiac surgery: risk of nitric oxide (NO) bioavailability loss by NAC? PMID- 25499331 TI - Prevalence and length of hospital stay in patients with aortic valve disease is lower amongst South Asians. PMID- 25499332 TI - Renal denervation: one potential therapeutic target for comorbid diabetes mellitus and worsening heart failure. PMID- 25499333 TI - Reply to the letter regarding the article "Growth differentiation factor-15 in Takotsubo cardiomyopathy: diagnostic and prognostic value". PMID- 25499334 TI - Nlrp3 plays no role in acute cardiac infarction due to low cardiac expression. PMID- 25499335 TI - Mechanisms explaining the late "catch-up" phenomenon after sirolimus-eluting stent implantation. PMID- 25499336 TI - Matrix metalloproteinases 2 and 9 as diagnostic tools in Chagas cardiomyopathy. PMID- 25499337 TI - The impact of medical malpractice litigation on cardiovascular practice in the US and China. PMID- 25499338 TI - Subcutaneous implantable-defibrillator is better to be a "collaborator" rather than a "replacement". PMID- 25499339 TI - Timing of coronary artery bypass graft surgery for acute myocardial infarction patients: a meta-analysis. PMID- 25499340 TI - Widened QRS interval and left ventricular systolic depression after propafenone and promazine exposure. PMID- 25499341 TI - Acute hemodynamic response of infused fasudil in patients with pulmonary arterial hypertension: a randomized, controlled, crossover study. AB - BACKGROUND: The Rho-kinase pathway has been shown to be involved in the pathogenesis of PAH. As yet, however, the acute effects of the Rho-kinase inhibitor fasudil have not been compared with established pulmonary selective vasodilators in patients with PAH. We compared the acute effects of intravenous fasudil with inhaled iloprost in patients with pulmonary arterial hypertension (PAH). METHODS: Using a crossover design, 50 patients with PAH (idiopathic PAH, PAH associated with repaired left-to-right cardiac shunts, or connective tissue disease) were randomized to iloprost inhalation (5 MUg) and intravenous fasudil (30 mg over 30 min). Hemodynamic data were collected at baseline and during acute drug exposure. RESULTS: Comparable decreases were observed in mean pulmonary artery pressure (-4.6 +/- 4.3 mmHg vs. -4.8 +/- 4.2 mmHg) and pulmonary vascular resistance (-3.0 +/- 3.0 Wood U vs. -2.2 +/- 2.7 Wood U) with fasudil infusion and iloprost inhalation, respectively, during acute challenge. However, fasudil infusion resulted in a more pronounced increase in mean cardiac output and mixed venous oxygen saturation compared with iloprost inhalation (13.7 +/- 17.1% vs. 6.9 +/- 15.0%; p=0.044 and 4.5 +/- 5.3% vs. 2.7 +/- 8.2%; p=0.044, respectively). Whereas inhaled iloprost resulted in a non-significant increase in mean systemic arterial oxygen saturation (0.8 +/- 3.6%), infused fasudil resulted in a non significant reduction (-0.6 +/- 1.1%). CONCLUSION: Infused fasudil improved pulmonary hemodynamics in patients with PAH without significant toxicity. PMID- 25499342 TI - The impact of age on fractional flow reserve-guided percutaneous coronary intervention: a FAME (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) trial substudy. AB - BACKGROUND: Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) improved outcomes compared with an angiography-guided strategy in patients with multivessel coronary artery disease (CAD). However, the effect of age on FFR has not been well-studied. We aimed to evaluate the impact of age on the favorable results of routine FFR-guided PCI for multivessel CAD. METHODS: We compared 1 year outcomes between FFR-guided PCI and angiography-guided PCI in the 512 patients enrolled in the FAME study <65 years old compared to the 493 patients >= 65 years old. We also evaluated the effect of age on the FFR result of varying degrees of visually estimated coronary stenosis. RESULTS: The 1-year rate of death, myocardial infarction or repeat revascularization in the angiography-guided group tended to be higher than in the FFR-guided group for both those patients <65 (17.2% vs. 12.0%, P = 0.098) and those >= 65 years old (19.7% vs. 14.3%, P = 0.111) with no significant interaction based on age (P = 0.920). Older patients had higher FFR in vessels with 50% to 70% stenosis (0.83 +/- 0.11 vs. 0.80 +/- 0.13, P = 0.028) and in vessels with 71% to 90% stenosis (0.69 +/- 0.15 vs. 0.65 +/- 0.16, P = 0.002). The proportion of functionally significant lesions (FFR <= 0.80) in vessels with 71% to 90% stenosis was significantly lower in elderly compared to younger patients (75.3% vs. 84.1%, P = 0.013). CONCLUSIONS: FFR-guided PCI is beneficial regardless of age, however, older patients have fewer functionally significant lesions, despite a similar angiographic appearance. PMID- 25499343 TI - Acetylation: a potential "regulating valve" of cardiac energy metabolism during atrial fibrillation. PMID- 25499344 TI - Expression profile of long non-coding RNAs in a mouse model of cardiac hypertrophy. PMID- 25499345 TI - Analysis of endomyocardial biopsies in suspected myocarditis--diagnostic value of left versus right ventricular biopsy. PMID- 25499346 TI - MitraClip in CRT non-responders with severe mitral regurgitation. AB - BACKGROUND: Severe mitral regurgitation (MR) >= 3+ and left ventricular dyssynchrony in heart failure patients are markers of CRT non response. The MitraClip (MC) implantation is a therapy for MR >= 3+ in patients with high surgical risk of mitral valve reconstruction. METHODS AND RESULTS: We investigated 42 patients with CRT and MR >= 3+ who received an MC device at our center. One and two year mortality rates were compared with the predicted mortality by Seattle Heart Failure Model (SHFM) and meta-analysis global group in chronic heart failure (MAGGIC), using the baseline characteristics of patients at the time of MC implantation. The median time interval between CRT and MC implantation was 20.1 (4.5-43.3) months. In 19 patients we observed a functional regurgitation with normal leaflets and in 23 patients a degenerative mechanism for mitral regurgitation. There was no change in mean QRS duration by biventricular pacing or MC implantation. The use of MC led to significant reductions in: median N-terminal pro-brain natriuretic peptide (NT-proBNP) level (pg/ml) from 3923 to 2636 (p = 0.02), tricuspid regurgitation pressure gradient (TRPG) from 43 to 35 mmHg (p = 0.019) and in left ventricular end-diastolic volume (LVEDV) by MC (p = 0.008). At the 2 year follow-up interval the all-cause mortality was 25%. CONCLUSION: MC implantation leads to an improvement of NT proBNP level, TRPG and LVEDV in both functional and degenerative MR but does not influence QRS duration. Two year all-cause mortality was 25% and did not differ significantly from that predicted by SHFM and MAGGIC. PMID- 25499347 TI - Sitagliptin and the risk of hospitalization for heart failure: a population-based study. AB - BACKGROUND: Saxagliptin was associated with an increased risk of hospitalization for heart failure (HHF) in diabetic patients with high cardiovascular risk. This study assessed the risk of HHF during an exposure to sitagliptin in general diabetic patients. METHODS: In Taiwan National Health Insurance research database, a study of the beneficiaries aged >= 45 years with diabetes treated with or without sitagliptin between March 2009 and July 2011 was conducted. Patients treated with sitagliptin were matched to patients never exposed to a dipeptidyl peptidase-4 (DPP-4) inhibitor by the propensity score methodology. The outcome measures were the first and the total number of HHF, and mortality for heart failure or all causes. RESULTS: A total of 8288 matched pairs of patients were analyzed. During a median of 1.5 years, the first event of HHF occurred in 339 patients with sitagliptin and 275 patients never exposed to a DPP-4 inhibitor (hazard ratio: 1.21, 95% confidence interval: 1.04-1.42, P = 0.017); all-cause mortality was similar (hazard ratio: 0.87, 95% confidence interval: 0.74-1.03, P = 0.109). The risk for HHF was proportional to exposure (hazard ratio: 1.09, 95% confidence interval: 1.06-1.11, P < 0.001 for every 10% increase in adherence to sitagliptin). Overall, there were 935 events of HHF, in which the association between the number of HHF and the adherence to sitagliptin was linear. The greatest total number of HHF occurred in the patients with the highest adherence. CONCLUSIONS: The use of sitagliptin was associated with a higher risk of HHF but no excessive risk for mortality was observed. PMID- 25499348 TI - Gender-related differences in risk of cardiovascular morbidity and all-cause mortality in patients hospitalized with incident atrial fibrillation without concomitant diseases: a nationwide cohort study of 9519 patients. AB - BACKGROUND: Previous studies of patients with "lone" and "idiopathic" atrial fibrillation (AF) have provided conflicting evidence concerning the development, management and prognosis of this condition. METHODS: In this nation-wide, retrospective, cohort study, we studied patients diagnosed with incidental AF recorded in national Swedish registries between 1995 and 2008. Controls were matched for age, sex and calendar year of the diagnosis of AF in patients. All subjects were free of any in-hospital diagnosis from 1987 and until patients were diagnosed with AF and also free of any diagnosis within one year from the time of inclusion. Follow-up continued until 2009. We identified 9519 patients (31% women) and 12,468 matched controls. RESULTS: Relative risks (RR) versus controls for stroke or transient ischemic attack (TIA) in women were 19.6, 4.4, 3.4 and 2.5 in the age categories <55, 55-64, 65-74 and 75-85, years respectively. Corresponding figures for men were 3.4, 2.5, 1.7 and 1.9. RR for heart failure were 6.6, 6.6, 6.3 and 3.8 in women and 7.8, 4.6, 4.9 and 2.9 in men. All RR were statistically significant with p < 0.01. RR for myocardial infarction and all cause mortality were statistically significantly increased only in the two oldest age categories in women and 65-74 years in men. CONCLUSIONS: Patients with AF and no co-morbidities at inclusion had at least a doubled risk of stroke or TIA and a tripled risk of heart failure, through all age categories, as compared to controls. Women were at higher RR of stroke or TIA than men. PMID- 25499349 TI - Overexpression of JAZF1 protected ApoE-deficient mice from atherosclerosis by inhibiting hepatic cholesterol synthesis via CREB-dependent mechanisms. AB - Genome wide association studies have suggested an association of Juxtaposed with another zinc finger gene 1(JAZF1) with type 2 diabetes mellitus (T2DM). As an inhibitor of the TAK1/TR4 signaling pathway, JAZF1 has been shown to be involved in gluconeogenesis, lipid metabolism and insulin sensitivity. However, its role in insulin resistance and atherosclerosis in vivo remains unknown. The present study was designed to investigate in vivo the impact of JAZF1 on insulin resistance-associated dyslipidemia and atherosclerosis. Adenovirus-mediated JAZF1 overexpression was used to characterize the role of JAZF1 in the regulation of lipid metabolism and the development of atherosclerosis in normal chow- or HFD fed ApoE KO mice. Insulin sensitivity was examined by EHC. Cholesterol de novo synthesis was measured by intraperitoneal [1-(14)C] acetate injection and atherosclerotic plaques were quantified by histological analysis. A dual luciferase reporter assay was used to assess the ability of JAZF1 to regulate HMGCR transcriptional activity. JAZF1 overexpression improved HFD-induced hepatic insulin resistance in C57BL/6J mice. In HFD-fed ApoE KO mice, JAZF1 overexpression decreased serum cholesterol levels and hepatic cholesterol synthesis by inhibiting CREB-dependent HMGCR promoter transcriptional activity. Analysis of atherosclerotic lesion showed that JAZF1 overexpression had significantly reduced aortic and aortic sinus en face and cross-sectional plaque areas in HFD-fed ApoE KO mice. These data provide the first evidence for an important role of JAZF1 in increasing hepatic insulin sensitivity and preventing atherosclerosis. PMID- 25499350 TI - Heart failure patients with B1-adrenoreceptor polymorphisms have augmented carvedilol response as detected by cardiac I123-MIBG scintigraphy. PMID- 25499351 TI - The Austrian transcatheter aortic valve implantation (TAVI) Registry--3 years' data. PMID- 25499352 TI - Thromboembolic risk in the initiation, switch and interruption/re-initiation of oral anticoagulants: do newcomers improve outcomes? Insights from a meta-analysis of RCTs. PMID- 25499353 TI - Spontaneous baroreflex sensitivity measured early after acute myocardial infarction is an independent predictor of cardiovascular mortality: results from a 12-year follow-up study. PMID- 25499354 TI - Adrift while swimming and Takotsubo syndrome: the vagotonia connection. PMID- 25499355 TI - Cardiac medication during pregnancy, data from the ROPAC. AB - BACKGROUND: Data on pharmacological management during pregnancy are scarce. The aim of this study was to describe the type and frequency of cardiac medication used in pregnancy in patients with cardiovascular disease and to assess the relationship between medication use and fetal outcome. METHODS AND RESULTS: Between 2007 and 2011 sixty hospitals in 28 countries enrolled 1321 pregnant women. All patients had structural heart disease (congenital 66%, valvular 25% or cardiomyopathy 7% or ischemic 2%). Medication was used by 424 patients (32%) at some time during pregnancy: 22% used beta-blockers, 8% antiplatelet agents, 7% diuretics, 2.8% ACE inhibitors and 0.5% statins. Compared to those who did not take medication, patients taking medication were older, more likely to be parous, have valvular heart disease and were less often in sinus rhythm. The odds ratio of fetal adverse events in users versus non-users of medication was 2.6 (95% CI 2.0-3.4) and after adjustment for cardiac and obstetric parameter was 2.0 (95% CI 1.4-2.7). Babies of patients treated with beta-blockers had a significantly lower adjusted birth weight (3140 versus 3240 g, p = 0.002). The highest rate of fetal malformation was found in patients taking ACE inhibitors (8%). CONCLUSION: One third of pregnant women with heart disease used cardiac medication during their pregnancy, which was associated with an increased rate of adverse fetal events. Birth weight was significantly lower in children of patients taking beta blockers. A randomized trial is needed to distinguish the effects of the medication from the effects of the underlying maternal cardiac condition. PMID- 25499356 TI - Statin treatment is associated with improved prognosis in patients with AF related stroke. AB - BACKGROUND/OBJECTIVES: The most recent ACC/AHA guidelines recommend high intensity statin therapy in ischemic stroke patients of presumably atherosclerotic origin. On the contrary, there is no specific recommendation for the use of statin in patients with non-atherosclerotic stroke, e.g. strokes related to atrial fibrillation (AF). We investigated whether statin treatment in patients with AF-related stroke is associated with improved survival and reduced risk for stroke recurrence and future cardiovascular events. METHODS: All consecutive patients registered in the Athens Stroke Registry with AF-related stroke and no history of coronary artery disease nor clinically manifest peripheral artery disease were included in the analysis and categorized in two groups depending on whether statin was prescribed at discharge. The primary outcome was overall mortality; the secondary outcomes were stroke recurrence and a composite cardiovascular endpoint comprising of recurrent stroke, myocardial infarction, aortic aneurysm rupture or sudden cardiac death during the 5-year follow-up. RESULTS: Among 1602 stroke patients, 404 (25.2%) with AF-related stroke were included in the analysis, of whom 102 (25.2%) were discharged on statin. On multivariate Cox-proportional-hazards model, statin treatment was independently associated with a lower mortality (hazard-ratio (HR): 0.49, 95%CI:0.26-0.92) and lower risk for the composite cardiovascular endpoint during the median 22 months follow-up (HR: 0.44, 95%CI:0.22-0.88), but not with stroke recurrence (HR: 0.47, 95%CI:0.22-1.01, p: 0.053). CONCLUSIONS: In this long-term registry of patients with AF-related stroke, statin treatment was associated with improved survival and reduced risk for future cardiovascular events. PMID- 25499357 TI - QT interval is not prolonged in patients with eating disorders. PMID- 25499358 TI - Long term followup of aortic root size after repair of tetralogy of Fallot. PMID- 25499359 TI - Is recurrent pericarditis a risk for constrictive evolution? PMID- 25499360 TI - Response to letter by Tsikas et al. PMID- 25499361 TI - Acute myocardial infarction and mortality in patients with systemic lupus erythematosus: the role of inflammatory cells and of Kounis syndrome. PMID- 25499362 TI - mTOR mediates the cross-talk of macrophage polarization and autophagy in atherosclerosis. PMID- 25499363 TI - Surgical treatment following transcatheter intervention in an adult patient with supravalvar mitral ring, large patent ductus arteriosus and severe pulmonary hypertension. PMID- 25499364 TI - Myocarditis and takotsubo syndrome: are they mutually exclusive? PMID- 25499365 TI - Reduction of C-reactive protein is not associated with reduced cardiovascular risk and mortality in patients treated with statins. A meta-analysis of 22 randomized trials. AB - BACKGROUND: The association between C-reactive protein (CRP) levels and risk of cardiovascular (CV) events has been reported in several studies. However, it is unclear whether a reduction in CRP is associated with a reduction in risk of clinical events. Therefore we sought to investigate, in a meta-regression analysis of randomized studies enrolling patients treated by statins, whether changes in CRP are associated with changes in risk of CV events or overall survival. METHODS: Randomized trials enrolling patients treated by statins, reporting CRP at baseline and at end of follow-up, CV events [myocardial infarction (MI) and stroke], CV and all-cause mortality were selected. RESULTS: Twenty-two trials enrolling 54,213 participants were included in the analysis. Meta-analysis showed that active treatment significantly reduced risk of all cause death by 8%, myocardial infarction by 11%, stroke by 10.3% and the composite outcome (including CV death, MI and stroke) by 8%, whereas risks of CV mortality was not significantly reduced. Meta-regression analysis revealed that reduction in CRP levels was significantly associated only with the reduction of MI, whereas no relationship was identified between changes in CRP and risk of stroke, CV and all-cause mortality, and the composite outcome. CONCLUSIONS: These findings demonstrate that statin-induced changes in CRP do not correlate with major CV events apart from the risk of MI nor with overall survival in high-risk patients. These data suggest that although CRP may be a surrogate marker for coronary risk, it should not be used for predicting the effectiveness of statin therapy. PMID- 25499366 TI - Plateletcrit: a novel prognostic marker for acute coronary syndrome. PMID- 25499367 TI - Cardiac rupture in a patient with Takotsubo syndrome triggered by acute myocardial infarction: two messages. PMID- 25499368 TI - Neurogenic stunned myocardium vs. Takotsubo syndrome: we should stop making a distinction. PMID- 25499369 TI - Myocardial infarction, Takotsubo syndrome, or myocardial infarction/Takotsubo syndrome? PMID- 25499370 TI - Valve disease and hypotension hospital admissions peaked at physiologically equivalent temperature 0-5 degrees C in Germany in 2009-2011. PMID- 25499371 TI - Renal function largely influences Galectin-3 prognostic value in heart failure. AB - BACKGROUND: Galectin-3 (Gal-3) has been associated with cardiac remodeling and heart failure (HF) prognosis. Renal function is also a well known HF prognostic indicator. The link between renal insufficiency, HF, and Gal-3 is not completely elucidated. METHODS AND RESULTS: We explored the association between Gal-3 and renal function in a cohort of 876 consecutive ambulatory patients with HF (mean age: 68 years; mean left ventricular ejection fraction [LVEF]: 36%), 52.2% had HF etiology of ischemic heart disease. Circulating Gal-3 was highly correlated with estimated glomerular filtration rate (eGFR), calculated with either the chronic kidney disease-epidemiology (CKD-EPI) equation (r = -0.64) or the CKD-EPI cystatin-C equation (r = -0.59) and with Cystatin-C levels (r = 0.70), after adjusting for age, sex, New York Heart Association (NYHA) functional class, LVEF, and HF etiology (all p<0.001). Patients were stratified by CKD-EPI-eGFR (ml/min/1.73 m(2)), as follows: >= 60 (n = 218), 30 to 59 (n = 434), and <30 (n = 224). In these strata, Gal-3 significantly increased (median [IQR]: 12.3 [10.4 15.6]; 16.1 [13-19.8]; and 24.5 [20-33.8] ng/ml, respectively; trend p < 0.001). This was independent of NYHA functional class (I-II and III-IV) and LVEF (<45% and >= 45%). Gal-3 was associated with mortality in univariate analyses, but after adjusting for CKD-EPI-eGFR, the hazard ratios were 1.10 (95% CI: 0.89-1.34, p = 0.39) for all cause death, and 0.90 (95% CI: 0.68-1.21, p = 0.50) for cardiovascular death. Similar results were obtained with eGFRs calculated with the CKD-EPI-cystatin-C equation. CONCLUSION: Circulating Gal-3 was highly associated with renal function in outpatients with HF. The value of Gal-3 for HF prognosis declined after adjusting for renal function. PMID- 25499372 TI - Mechanisms of maintained exercise capacity in adults with repaired tetralogy of Fallot. AB - BACKGROUND: The mechanisms whereby cardiac output is augmented with exercise in adult repaired tetralogy of Fallot (TOF) are poorly characterised. METHODS: 16 repaired TOF patients (25 +/- 7 years of age) and 8 age and sex matched controls (25 +/- 4 years of age) underwent cardiopulmonary exercise testing and then real time cardiac MRI (1.5 T) at rest and whilst exercising within the scanner, aiming for 30% heart rate reserve (Level 1) and 60% heart rate reserve (Level 2), using a custom-built MRI compatible foot pedal device. RESULTS: At rest, TOF patients had severely dilated RVs (indexed RV end-diastolic volume: 149 +/- 37 mL/m(2)), moderate-severe PR (regurgitant fraction 35 +/- 12%), normal RV fractional area change (FAC) (52 +/- 7%) and very mildly impaired exercise capacity (83 +/- 15% of predicted maximal work rate). Heart rate and RV FAC increased significantly in TOF patients (75 +/- 10 vs 123 +/- 17 beats per minute, p<0.001; 44 +/- 7 vs 51 +/- 10%, p=0.025), and similarly in control subjects (70 +/- 11 vs 127 +/- 12 beats per minute, p<0.001; 49 +/- 7 vs 61 +/- 9%, p=0.003), when rest was compared to Level 2. PR fraction decreased significantly but only modestly, from rest to Level 2 in TOF patients (37 +/- 15 to 31 +/- 15%, p=0.002). Pulmonary artery net forward flow was maintained and did not significantly increase from rest to Level 2 in TOF patients (70 +/- 19 vs 69 +/- 12 mL/beat, p=0.854) or controls (93 +/- 9 vs 95 +/- 21 mL/beat, p=0.648). CONCLUSIONS: During exercise in repaired TOF subjects with dilated RV and free PR, increased total RV output per minute was facilitated by an increase in heart rate, an increase in RV FAC and a decrease in PR fraction. PMID- 25499374 TI - Tako tsubo cardiomyopathy in respiratory stress syndrome in amyotrophic lateral sclerosis. PMID- 25499373 TI - Comparison of new point-of-care troponin assay with high sensitivity troponin in diagnosing myocardial infarction. AB - OBJECTIVES: The aim of this study is to compare a new improved point of care cardiac troponin assay (new POC-cTnI) with 1. its predecessor (old POC-cTnI) and 2. a high sensitivity assay (hs-cTnI) for the diagnosis of acute myocardial infarction (AMI) and for major adverse cardiac events (MACE) by 30 days. METHODS: This is a single centre observational study, set in Christchurch Hospital, New Zealand. Patients presenting to the emergency department with non-traumatic chest pain underwent blood sampling at 0 h and 2h post presentation for analysis with the 3 cTnI assays for the outcome of AMI and for analysis using an accelerated diagnostic protocol (ADP-normal 2h troponins, normal electrocardiograms and Thrombolysis In Myocardial Infarction (TIMI) score of 0 or <= 1) for 30 day MACE. RESULTS: Of 962 patients, 220 (22.9%) had AMI. Old POC-cTnI was least sensitive at 70.0% (65.4-73.9%) by 2h (p<0.001). New POC-cTnI, sensitivity 93.6% (89.9 96.2%) had similar sensitivity to hs-cTnI, sensitivity 95.0% (91.5-97.3%) (p = 0.508). There were 231 (24.0%) patients with 30 day MACE. When used as part of the ADP, all assays had 100% (98.0-100%) sensitivity using TIMI = 0. Sensitivities of new POC-cTnI ADP, 98.3% (95.4-99.4%), old POC-cTnI, 96.5% (93.2 98.4%) and hs-cTnI, 98.7% (96.0-99.7%) were similar (p = 0.063-0.375) using TIMI <= 1. CONCLUSIONS: A new POC-cTnI has improved sensitivity for AMI and MACE compared with its predecessor and comparable sensitivity to a high sensitivity assay. Now that sensitivities of the POC assay are improved, the new assay may be a useful alternative to central laboratory assays when rapid turn-around times are not possible. PMID- 25499375 TI - Seven-year clinical follow-up of a Chinese homozygous familial hypercholesterolemia child with premature xanthomas and coronary artery disease- a need for early diagnosis and aggressive treatment. PMID- 25499377 TI - Prevalence of Takotsubo syndrome in men and premenopausal women. PMID- 25499376 TI - High platelet reactivity is associated with vascular function in patients after percutaneous coronary intervention receiving clopidogrel. AB - BACKGROUND: In the present study, we evaluated the association of platelet reactivity with vascular function in patients after percutaneous coronary intervention receiving clopidogrel treatment. METHODS: We enrolled 150 patients with stable CAD receiving clopidogrel regimen (75 mg/d), 1 month after percutaneous coronary intervention. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as an index of arterial wave reflections. High on treatment platelet reactivity (HPR) was evaluated using VerifyNow Assay. VerifyNow reports its results in P2Y12 reaction units (PRU), and the diagnostic cutoff value is 230 PRU. Patients were evaluated prospectively up to 24 months. The primary end point was a composite of death from cardiovascular causes, nonfatal major cardiovascular events and hospitalization for cardiovascular causes. RESULTS: There was no difference in the basic clinical and demographic characteristics between subjects with HPR and non-HPR. Subjects with high on treatment platelet reactivity and PRU>230 had significantly increased PWV (8.81 +/- 2.25 m/s vs. 7.69 +/- 1.95 m/s, p = 0.001) and AIx (25.27 +/- 8.67% vs. 20.87 +/- 10.57%, p = 0.04) compared to subjects with PRU<=230. PWV was also associated with PRU (r = 0.23, p = 0.02). HPR was associated with significantly increased risk of primary end point [HR = 5.38, 95%CI:(1.15, 26.04), p = 0.03]. CONCLUSIONS: Increased platelet reactivity is associated with impaired arterial stiffness in patients after percutaneous coronary intervention receiving clopidogrel treatment, highlighting another clinical factor implicated in individual platelet response to antiplatelet therapy. Moreover, increased platelet reactivity is associated with adverse outcome in these patients. PMID- 25499378 TI - A novel wearable vest for tracking pulmonary congestion in acutely decompensated heart failure. PMID- 25499379 TI - Factors associated with multimorbidity and its link with poor blood pressure control among 223,286 hypertensive patients. AB - Multimorbidity has become the norm worldwide as populations age. It remains, however, infrequently researched. This study evaluated factors associated with multimorbidity in a predominantly Chinese hypertensive population. We included all adult patients prescribed their first antihypertensive agents in the entire public sector in Hong Kong from a validated database. Multimorbidity was defined as having one or more medical conditions (cardiovascular diseases; respiratory diseases; diabetes or impaired fasting glucose; renal disease) in addition to hypertension. We studied the prevalence of multimorbidity and performed multinomial regression analyses to evaluate factors independently associated with multimorbidity. 223,286 hypertensive patients (average age of 59.9 years, SD 17.6) were included. The prevalence of having 0, 1 and >= 2 additional conditions was 59.6%, 32.8% and 7.5%, respectively. The most common conditions were cardiovascular disease (24.2%) and diabetes (23.0%), followed by respiratory disorders (14.6%) and renal disease (10.9%). Older age (>50 years), male sex, lower household income, receipt of social security allowance and suboptimal blood pressure control (>140 mmHg or >90 mmHg; >130 mmHg or >80 mmHg for diabetes patients; AOR = 3.38-4.49) were significantly associated with multimorbidity. There exists a synergistic effect among these variables as older (>= 70 years), male patients receiving security allowance had substantially higher prevalence of multimorbidity (19.9% vs 7.5% among all patients). Multimorbidity is very common in hypertensive patients and its prevalence increased markedly with the presence of risk factors identified in this study. Hypertensive patients with multimorbidities should receive more meticulous clinical care as their blood pressure control tends to be poorer. PMID- 25499380 TI - Real-life use of the polypill components (ASA+ACEI+statins) after an acute coronary syndrome and long-term mortality. PMID- 25499381 TI - Marked attenuation of the electrocardiogram QRS complexes in a patient with pheochromocytoma and Takotsubo syndrome. PMID- 25499382 TI - Reasons why patients suffering from chronic heart failure at very high risk for death survive. AB - BACKGROUND: An accurate prognostic stratification is essential for optimizing the clinical management and treatment decision-making of patients with chronic heart failure (HF). Among the best available models, we used the Cardiac and Comorbid Conditions HF (3C-HF) Score, to predict all-cause mortality in patients with CHF. METHODS: we selected and characterized the subgroup of patients at very high risk with the worst mid-term prognosis belonging to the highest decile of 3C-HF score with the aim to assess predictors of survival in subjects with an expected probability of 1-year mortality near to 45%. METHODS AND RESULTS: We recruited 1777 consecutive chronic HF patients at 3 Italian Cardiology Units. Median age was 76 +/- 10 years, 43% were female, and 32% had preserved ejection fraction. Subjects belonging to the highest decile of 3C-HF score were 246 (13.8% of total population). During a median follow-up of 21 [12-40] months, 110 of these patients (45%) survived and 136 (55%) died. The variables that contributed to survival prediction emerged by Cox regression multivariate analysis were the lower degree of renal dysfunction and higher body mass index. CONCLUSIONS: The prognostic stratification of chronic HF patients allows in daily practice to select patients at different risk for death and identify prognosticators of survival in outliers at very high risk of death. The reasons why these patients outlive the matching part of subjects who expectedly die are related to the maintenance of a satisfactory renal function and body mass index. PMID- 25499383 TI - Efficacy and safety of eplerenone in the management of mild to moderate arterial hypertension: systematic review and meta-analysis. AB - BACKGROUND: The role of eplerenone in arterial hypertension has been investigated only in small studies. To systematically assess the efficacy and tolerability of eplerenone in patients with mild to moderate arterial hypertension, we did a meta analysis of controlled randomized trials. METHODS: We performed an electronic literature search of Medline, Pubmed, Scopus and Cochrane databases for studies published up to March 31, 2014. Randomized studies comparing eplerenone with placebo or other antihypertensive drugs for net reduction of systolic and diastolic blood pressures (SBP; DBP) from baseline and for incidence of adverse events were considered. Weighted mean differences (WMD) and odds ratios with 95% confidence interval were calculated for continuous and dichotomous data, respectively. RESULTS: A total of 11 trials and 3566 patients were overall included. Compared to placebo, eplerenone significantly reduced either SBP [WMD 8.07, 95% CI -8.17 to -7.96 mm Hg, p < 0.00001] and DBP [WMD -4.08, -4.15 to 4.01 mm Hg, p < 0.00001]. In the overall comparison, reduction of both SBP and DBP with eplerenone was greater than other antihypertensive agents (WMD for SBP 1.50 mm Hg, p < 0.0001; WMD for DBP -0.54 mm Hg, p < 0.00001); this was essentially driven by a greater anti-hypertensive action vs enalapril and losartan for SBP and vs losartan for DBP. Rates of any adverse event were significantly higher with eplerenone than placebo (odds ratio 1.37, 95% CI 1.1 to 1.71; p = 0.005), whereas the occurrence of serious adverse events and hyperkalemia was similar. There was no difference between eplerenone and other antihypertensives in the frequency of any or serious adverse events, whereas hyperkalemia was more common with eplerenone (odds ratio 2.36, 95% CI 1.00 to 5.57; p = 0.05). CONCLUSION: This study-level meta-analysis provides a robust evidence that eplerenone has a reassuring safety profile and is effective in lowering blood pressure in patients with mild-to-moderate hypertension; this effect is at least comparable to that of other anti-hypertensive agents (PROSPERO Registration No. CRD42014010071). PMID- 25499384 TI - Major adverse maternal cardiovascular-related events in those with aortopathies. What should we expect? AB - Major adverse maternal cardiovascular-related events (MAMCRE) in aortopathy patients undergoing pregnancy are poorly defined. The aim was to assess for MAMCRE in pregnant patients with aortopathy or aortic enlargement in conotruncal defects (CTD), and determine if there are differences between groups. We conducted a single-center retrospective review of pregnant women (2000-2013) with hereditary vascular disease (HVD: BAV, COA), heritable fibrillinopathies (HF: MFS, EDS, LDS, FTAAS), and CTD with aortic dilatation (TOF, d-TGA, DORV). MAMCRE included: aortic dissection/surgery, therapeutic abortion, change in mode of delivery, and aortic growth > 0.5 cm within 1 year. We identified 73 patients/97 pregnancies (39/50 HVD, 15/20 HF, and 19/27 CTD). There were 14 MAMCRE (14%); 85% (n = 12) occurred in HV and HF patients and was associated with higher baseline cross-sectional-to-height (CSA/Ht) ratio (6.6 [Symbol: see text] 2.5 vs. 5.1 [Symbol: see text] 1.3, p = 0.005). There was more aortic surgery in the HF (vs. HV) (RR 3.9, p = 0.12). Only 2 MAMCRE (aortic growth) occurred in CTD. Overall and emergent C-section was higher than the general population (52% vs. 29%, p < 0.001 and 16% vs. 3%, p < 0.001) as was postpartum hemorrhage (PPH) (6% vs. 1.5%, p < 0.001). We describe the largest series of pregnant women with aortopathy and found a substantial incidence of MAMCRE, which was associated with higher pre pregnancy CSA/Ht ratio. Rates of C-section and PPH were higher than the general population. Our data suggest that larger, multi-center studies are needed to define risks that predict MAMCRE/obstetric events in women with aortopathies, allowing optimal medical care during pregnancy. PMID- 25499385 TI - 3,3'-Diindolylmethane improves myocardial energy metabolism imbalance induced by pressure overload via AMPKalpha in mice. PMID- 25499387 TI - The link between increased carotid intima media thickness and cardiovascular risk: how strong and in which patient subgroup is it? PMID- 25499386 TI - Meta-analysis of coronary computed tomography angiography versus standard of care strategy for the evaluation of low risk chest pain: are randomized controlled trials and cohort studies showing the same evidence? AB - BACKGROUND: Randomized control trials (RCTs) have established the use of Coronary Computed Tomography Angiography (CCTA) for the evaluation of low to intermediate risk patients presenting with acute chest pain to the emergency department (ED). However, concerns remain regarding the downstream resource utilization and the clinical impact of such strategy. METHODS: We performed a meta-analysis of existing studies to compare CCTA to the standard of care (SOC) strategies in the low to intermediate risk chest pain patients. We abstracted the reported incidence of acute coronary syndromes (ACS), the total number of invasive coronary angiography (ICA) and subsequent revascularization procedures, the rates of hospital readmissions and repeat ED visits. We stratified the results according to the type of the studies (randomized or not) and used random effect analysis for the studied outcomes. RESULTS: Four RCTs and 3 case-control studies with 3306 patients undergoing CCTA and 2752 assigned to SOC were included in the analysis. Following the index visit, we observed a significant reduction in the risk of ACS (RR: 0.26, 95% CI, 0.08 to 0.87; p = 0.03) and in the rates of repeat ED visits (RR: 0.58, 95% CI: 0.36 to 0.94; p = 0.03). In addition, a trend toward less hospital readmission (p = 0.07) was noted. There was no difference in ICA (p = 0.99) but an increase in revascularization procedures (RR: 1.46, 95% CI: 1.09 to 1.94; p = 0.01). CONCLUSION: CCTA use in the ED for the triage of low to intermediate risk patients reduces the risk of future ACS and subsequent ED visits for chest pain. PMID- 25499388 TI - Serum phosphorus level is related to degree of clinical response to up-titration of heart failure pharmacotherapy. AB - Serum phosphorus abnormalities may pose a risk on the cardiovascular system. In heart failure (HF) phosphorus homeostatic mechanisms are altered and may be modified by modern HF therapy. The impact of therapy optimization on phosphorus abnormalities and related outcome remains unknown. In 722 patients with HF subjected to treatment up-titration we analyzed the prevalence of serum phosphorus abnormalities and their relation to HF severity on top of optimal treatment, and we assessed adjusted risk of phosphorus abnormalities at different stages of HF. We analyzed predictors of hypo- and hyperphosphatemia and relation to prognosis. Hypophosphatemia was associated with better response to therapy, was more prevalent in milder HF, and the association was independent of age, sex, BMI, etiology of HF, kidney function and the use of diuretics. Hypophosphatemic patients lost more phosphorus into urine. They had also less catabolic profile. Patients with hyperphosphatemia on top of optimal therapy responded worse to treatment. Hyperphosphatemia was more prevalent in advanced HF, but the effect was attenuated after adjustment for potential confounders. Clinical and biochemical profiles of hyperphosphatemics suggested domination of catabolism. Neither hypophosphatemia nor hyperphosphatemia modifies the outcome Serum phosphorus abnormalities are related to HF severity on top of optimal therapy. Hypophosphatemia occurring on HF up-titration therapy likely has a multifactorial pathophysiology comprising of urinary phosphorus wasting and refeeding effects. Hyperphosphatemia is linked to the catabolic profile but the effect of renal impairment can't be ruled out. The prognostic impact of serum phosphorus abnormalities remain to be established. PMID- 25499389 TI - Racial differences in mortality in patients with advanced systolic heart failure: potential role of right ventricular ejection fraction. AB - In Beta-Blocker Evaluation of Survival Trial (BEST) bucindolol significantly reduced mortality among Caucasians with systolic heart failure (HF) but not among African Americans. Whether this differential effect can be explained by racial differences in baseline characteristics has not been previously examined. Of the 2708 BEST participants, 627 were African Americans. Because African Americans were more likely to be younger and women, we used age-sex-adjusted hazard ratios (HR) and 95% confidence intervals (CI) to estimate their outcomes (vs. Caucasians). A step-wise multivariable-adjusted model using 24 baseline characteristics was used to identify variables associated with between-race outcome differences and propensity-matching was used to determine independence of associations. Age-sex-adjusted HR for all-cause mortality for African Americans during 2 years of mean follow-up was 1.27. African Americans were more likely to have lower right ventricular ejection fraction. African Americans had no association with mortality among propensity-matched patients. The higher risk of death among African Americans in BEST may in part be due to their lower RVEF which may in part explain the lack of response to bucindolol among these patients. Future studies need to examine the role of low RVEF on the effect of beta-blockers in patients with systolic HF. PMID- 25499390 TI - "Pulmonary valve replacement diminishes the presence of restrictive physiology and reduces atrial volumes": a prospective study in Tetralogy of Fallot patients. AB - Pulmonary valve replacement (PVR) reduces right ventricular (RV) volumes in the setting of long-term pulmonary regurgitation after Tetralogy of Fallot (ToF) repair; however, little is known of its effect on RV diastolic function. Right atrial volumes may reflect the burden of RV diastolic dysfunction. The objective of this paper is to evaluate the clinical, echocardiographic, biochemical and cardiac magnetic resonance (CMR) variables, focusing particularly on right atrial response and right ventricular diastolic function prior to and after elective PVR in adult patients with ToF. This prospective study was conducted from January 2009 to April 2013 in consecutive patients > 18 years of age who had undergone ToF repair in childhood and were accepted for elective PVR. Twenty patients (mean age: 35 years; 70% men) agreed to enter the study. PVR was performed with a bioporcine prosthesis. Concomitant RV reduction was performed in all cases when technically possible. Pulmonary end-diastolic forward flow (EDFF) decreased significantly from 5.4 ml/m(2) to 0.3 ml/m(2) (p < 0.00001), and right atrial four-chamber echocardiographic measurements and volumes by 25% (p = 0.0024): mean indexed diastolic/systolic atrial volumes prior to surgery were 43 ml/m(2) (SD+/ 4.6)/63 ml/m(2) (SD+/-5.5), and dropped to 33 ml/m(2) (SD+/-3)/46 ml/m(2) (SD+/ 2.55) post-surgery. All patients presented right ventricular diastolic and systolic volume reductions, with a mean volume reduction of 35% (p < 0.00001). Right ventricular diastolic dysfunction was common in a population of severely dilated RV patients long term after ToF repair. Right ventricular diastolic parameters improved as did right atrial volumes in keeping with the known reduction in RV volumes, after PVR. PMID- 25499391 TI - Short-term inhibition of DPP-4 enhances endothelial regeneration after acute arterial injury via enhanced recruitment of circulating progenitor cells. AB - BACKGROUND: Endothelial injuries regularly occur in atherosclerosis and during interventional therapies of the arterial occlusive disease. Disturbances in the endothelial integrity can lead to insufficient blood supply and bear the risk of thrombus formation and acute vascular occlusion. At present, effective therapeutics to restore endothelial integrity are barely available. We analyzed the effect of pharmacological DPP-4-inhibition by Sitagliptin on endogenous progenitor cell-based endothelial regeneration via the SDF-1alpha/CXCR4-axis after acute endothelial damage in a mouse model of carotid injury. METHODS AND RESULTS: Induction of a defined endothelial injury was performed in the carotid artery of C57Bl/6 mice which led to a local upregulation of SDF-1alpha expression. Animals were treated with placebo, Sitagliptin or Sitagliptin+AMD3100. Using mass spectrometry we could prove that Sitagliptin prevented cleavage of the chemokine SDF-1alpha. Accordingly, increased SDF-1alpha concentrations enhanced recruitment of systemically applied and endogenous circulating CXCR4+ progenitor cells to the site of vascular injury followed by a significantly accelerated reendothelialization as compared to placebo-treated animals. Improved endothelial recovery, as well as recruitment of circulating CXCR4+ progenitor cells (CD133+, Flk1+), was reversed by CXCR4-antagonization through AMD3100. In addition, short-term Sitagliptin treatment did not significantly promote neointimal or medial hyperplasia. CONCLUSION: Sitagliptin can accelerate endothelial regeneration after acute endothelial injury. DPP-4 inhibitors prevent degradation of the chemokine SDF-1alpha and thus improve the recruitment of regenerative circulating CXCR4+ progenitor cells which mediate local endothelial cell proliferation without adversely affecting vessel wall architecture. PMID- 25499392 TI - Impact of percutaneous pulmonary valve implantation for right ventricular outflow tract dysfunction on exercise recovery kinetics. AB - The recovery of cardiopulmonary variables from peak exercise in patients with pulmonary stenosis (PS) or regurgitation (PR) is delayed, but the impact of treating PS or PR on exercise recovery kinetics is unknown. 43 patients (median age 14 years) with PS (n = 23) or PR (n = 20) after repair of congenital heart disease underwent successful percutaneous pulmonary valve implantation (PPVI). Cardiopulmonary exercise tests (CPET) were performed both before and within 1 month after PPVI. Apart from peak oxygen uptake (VO2), the constant decay of VO2, CO2 output (VCO2), minute ventilation (VE), and heart rate (HR) and oxygen pulse were calculated for the first minute of recovery as the first-degree slope of a single linear relation. PPVI led to a significant improvement in NYHA functional class in the PS and PR groups (p<0.001 and p=0.0015, respectively). On CPET, peak VO2 improved post-PPVI only in the PS (25.6 +/- 6.2 vs. 27.8 +/- 7.9 ml/kg/min; p = 0.01) but not PR group (29.0 +/- 9.8 vs. 28.6 +/- 8.9 ml/kg/min; p = 0.6). However, VO2 slope improved in the PS (0.40 +/- 0.23 vs. 0.65 +/- 0.27, p < 0.001) as well as in the PR group (0.56 +/- 0.37 vs. 0.67 +/- 0.37, p = 0.003) as did VCO2 slope (0.39 +/- 0.2 vs. 0.55 +/- 0.24, p = 0.002 and 0.42 +/- 0.33 vs. 0.53 +/- 0.35, p = 0.02: for the PS and PR groups, respectively). The VE and HR slopes did not change after PPVI. Despite the lack of improvement in exercise capacity in the PR group, treatment of PS and PR by PPVI induces significant and similar improvements in the ability of recovering from maximal exercise in the 2 groups. PMID- 25499393 TI - Determinants of improved one-year survival in non-ST-segment elevation myocardial infarction patients: insights from the French FAST-MI program over 15 years. AB - BACKGROUND: Improved early outcome in non-ST elevation myocardial infarction (NSTEMI) patients has been mainly attributed to a broader use of invasive strategies. Little is known about the impact of other changes in early management. METHODS: We aimed to assess 15-year trends in one-year mortality and their determinants in NSTEMI patients. We used data from 4 one-month French registries, conducted 5 years apart from 1995 to 2010 including 3903 NSTEMI patients admitted to intensive care units. RESULTS: From 1995 to 2010, no major change was observed in patient characteristics, while therapeutic management evolved considerably. Early use of antiplatelet agents, beta-blockers, ACE inhibitors and statins increased over time (P < 0.001); use of newer anticoagulants (low-molecular-weight heparin, bivalirudin or fondaparinux) increased from 40.8% in 2000 to 78.9% in 2010 (P < 0.001); percutaneous coronary intervention (PCI)<= 3 days of admission rose from 7.6% to 48.1% (P < 0.001). One year death decreased from 20% to 9.8% (HR adjusted for baseline parameters, 2010 vs. 1995 = 0.47, 95% CI: 0.35-0.62). Early PCI (HR = 0.67; 95% CI: 0.49-0.90), use of newer anticoagulants (HR = 0.62; 95% CI: 0.48-0.78) and early use of evidence based medical therapy (HR = 0.54; 95% CI: 0.40-0.72) were predictors of improved one year-survival. CONCLUSIONS: One-year mortality of NSTEMI patients decreased by 50% in the past 15years. Our data support current guidelines recommending early invasive strategies and use of newer anticoagulants for NSTEMI, and also show a strong positive association between early use of appropriate medical therapies and one-year survival, suggesting that these medications should be used from the start. PMID- 25499394 TI - PET/CT and MR imaging biomarker of lipid-rich plaques using [64Cu]-labeled scavenger receptor (CD68-Fc). AB - Continued uptake of modified low-density lipoproteins (LDL) by the scavenger receptor, CD68, of activated macrophages is a crucial process in the development of atherosclerotic plaques and leads to the formation of foam cells. Eight-weeks old male Apolipoprotein E-deficient (ApoE(-/-)) mice (n = 6) were fed a high-fat diet for 12 weeks. C57BL/6J wildtype (WT) mice served as controls (n = 6). Positron emission tomography (PET) with an acquisition time of 1800 s (NanoPET/CT scanner; Mediso, Hungary & Bioscan, USA) was carried out 24h after intravenous tail vein administration of 50 ul (64)Cu-CD68-Fc (~20-30 ug labeled protein/mouse containing approximately 10-12 MBq (64)Cu-CD68-Fc per mouse). Three days after PET/CT, all mice received an intravenous administration of 0.2 mmol/kg body weight of a gadolinium-based elastin-binding contrast agent to assess plaque burden and vessel wall remodeling. Two hours after injection, mice were imaged in a 3T clinical MR scanner (Philips Healthcare, Best, NL) using a dedicated single loop surface coil (23 mm). Enhanced (64)Cu-CD68-Fc uptake was found in the aortic arches of ApoE(-/-) compared to WT mice (ApoE(-/-) mice:10.5 +/- 1.5 Bq/cm(3) vs. WT mice: 2.1 +/- 0.3 Bq/cm(3); P = 0.002). Higher gadolinium-based elastin binding contrast agent uptake was also detected in the aortic arch of ApoE(-/-) compared to WT mice using R(1) maps (R(1) = 1.47 +/- 0.06 s(-1) vs. 0.92 +/- 0.05 s(-1); P <0.001). Radiolabeled scavenger receptor ((64)Cu-CD68-Fc) may help to target foam cell rich plaques with high content of oxidized LDL. This novel imaging biomarker tool may have potential to identify unstable plaques and for risk stratification. PMID- 25499395 TI - Proton pump inhibitor use represents an independent risk factor for myocardial infarction. AB - BACKGROUND: There is substantial debate regarding the development of acute coronary syndrome in patients using proton pump inhibitors (PPIs) combined with clopidogrel. However, data remain limited to address the effect of PPIs alone on the subsequent risk of myocardial infarction (MI). We aimed to explore the subsequent risk of MI in PPI users who had no previous history of MI. METHODS: The records of inpatients and outpatients with PPI prescriptions were retrieved from the Taiwan National Health Insurance Research Database between 2000 and 2009. We conducted two different study designs, the first using propensity score (PS)-matching analyses and the second using case-crossover analyses. The risk of developing MI for PPI users was analyzed in the PS-matched study. The association between risk of MI and prior PPI exposure was further validated in the case crossover study. RESULTS: In the PS-matched study, we included 126,367 PPI users and 126,367 PS-matched PPI non-users. After 120 days of follow-up, PPI use was associated with a 1.58-fold greater risk of MI (adjusted hazard ratio [HR] = 1.58, 95% confidence interval [CI] = 1.11 to 2.25). In the case-crossover study, adjusted odds ratios of PPI for MI risk were 4.61 (95% CI = 1.76 to 12.07) for the 7-day window and 3.47 (95% CI = 1.76 to 6.83) for the 14-day window. CONCLUSIONS: Use of PPIs may be independently associated with an increased risk of MI. However, the benefits of PPIs may greatly outweigh the risks of adverse cardiovascular effects, with number needed to harm of 4357. PMID- 25499396 TI - Resveratrol attenuated homocysteine-induced apoptosis of rat ventricular myocytes. PMID- 25499397 TI - Implantable cardiac defibrillator among adults with transposition of the great arteries and atrial switch operation: case series and review of literature. AB - BACKGROUND: The experience with the implantable cardiac defibrillator (ICD) in patients with transposition of the great arteries (TGA) and history of atrial switch surgery remains limited. METHODS: Retrospective evaluation aiming to assess characteristics and outcomes of consecutive TGA patients with history of atrial switch surgery implanted with an ICD between January 2005 and June 2012 in four French centers. RESULTS: Of the 12 patients (median 34 years [28, 40]; 67% male), 4 patients (33%) were implanted for secondary prevention after symptomatic documented sustained ventricular tachycardia or sudden cardiac arrest. ICDs were implanted for primary prevention in 8 patients (67%), including cardiac resynchronization in 3 patients; severe systemic ventricle dysfunction was present in all cases (median ejection fraction 27% [20, 40]). Overall, one patient died during the ICD implantation secondary to refractory cardiac arrest after defibrillation testing. Over a median follow-up of 19 months [10, 106], 6 patients out of 11 (54%) experienced worsening of congestive heart failure, including 5 who were eventually transplanted. Overall, 3 patients (27%) experienced significant ICD-related complications, whereas only one patient (primary prevention indication) developed appropriate ICD therapy (successful anti-tachycardia pacing without shock). Half of the patients presented with at least one episode of sustained (>= 5 min) atrial arrhythmia during follow-up. CONCLUSIONS: Our findings underline the key role of progressive heart failure in dictating outcomes among TGA patients with prior atrial switch repair. Our results also underline the need of better risk-stratification for sudden cardiac death in those patients. PMID- 25499398 TI - Cognitive performance and the course of depressive symptoms over 7 years of follow-up: the SMART-MR study. AB - BACKGROUND: Depressive symptoms and cognitive impairment often co-occur, but their interactive relationship is complex and the direction of causation is still a topic of research. We examined the influence of cognitive performance on the course of depressive symptoms during 7 years of follow-up in patients with vascular disease. METHOD: Within the SMART-MR study, 736 patients (mean age 62 +/ 10 years) had neuropsychological assessment on four cognitive domains at baseline [memory (MEM), working memory (WMEM), executive functioning (EXEC), and information processing speed (SPEED)]. Depressive symptoms were assessed with the Patient Health Questionnaire-9 (PHQ-9) at baseline and every 6 months during 7 years of follow-up. Generalized Estimating Equation (GEE) models were used to assess the association between cognitive performance with depressive symptoms at multiple time points during follow-up. Interaction terms between the respective cognitive domains and time was included to examine if the course of depressive symptoms differed according to baseline cognitive performance. RESULTS: The GEE analyses showed no significant interactions between the respective cognitive domains and time indicating no different course of depressive symptoms according to baseline cognitive performance. Lower MEM, EXEC or SPEED, but not WMEM performance, was significantly associated with more depressive symptoms during follow-up per z score decrease: MEM [B = 0.70, 95% confidence interval (CI) 0.35 1.05]; EXEC (B = 0.88, 95% CI 0.41-1.36), and SPEED (B = 0.57, 95% CI 0.21-0.92). CONCLUSIONS: Poorer cognitive performance on the domains MEM, EXEC and SPEED, but not WMEM, was associated with higher levels of depressive symptoms over 7 years of follow-up, but not with a different course of depressive symptoms over time. PMID- 25499399 TI - Increasing fluid intake and reducing dehydration risk in older people living in long-term care: a systematic review. AB - OBJECTIVE: To assess the efficacy of interventions and environmental factors on increasing fluid intake or reducing dehydration risk in older people living in long-term care facilities. DESIGN: Systematic review of intervention and observational studies. DATA SOURCES: Thirteen electronic databases were searched from inception until September 2013 in all languages. References of included papers and reviews were checked. ELIGIBILITY CRITERIA: Intervention and observational studies investigating modifiable factors to increase fluid intake and/or reduce dehydration risk in older people (>=65 years) living in long-term care facilities who could drink orally. REVIEW METHODS: Two reviewers independently screened, selected, abstracted data, and assessed risk of bias from included studies; narrative synthesis was performed. RESULTS: A total of 4328 titles and abstracts were identified, 325 full-text articles were obtained and 23 were included in the review. Nineteen intervention and 4 observational studies from 7 countries investigated factors at the resident, institutional, or policy level. Overall, the studies were at high risk of bias due to selection and attrition bias and lack of valid outcome measures of fluid intake and dehydration assessment. Reported findings from 6 of the 9 intervention studies investigating the effect of multicomponent strategies on fluid intake or dehydration described a positive effect. Components included greater choice and availability of beverages, increased staff awareness, and increased staff assistance with drinking and toileting. Implementation of the US Resident Assessment Instrument reduced dehydration prevalence from 3% to 1%, P = .01. Two smaller studies reported positive effects: one on fluid intake in 9 men with Alzheimer disease using high-contrast red cups, the other involved supplementing 13 mildly dehydrated residents with oral hydration solution over 5 days to reduce dehydration. Modifications to the dining environment, advice to residents, presentation of beverages, and mode of delivery (straw vs beaker; prethickened drinks vs those thickened at the bedside) were inconclusive. Two large observational studies with good internal validity investigated effects of ownership; in Canada, for-profit ownership was associated with increased hospital admissions for dehydration; no difference was seen in dehydration prevalence between US for-profit and not-for-profit homes, although chain facilities were associated with lower odds of dehydration. This US study did not suggest any effect of staffing levels on dehydration prevalence. CONCLUSIONS: A wide range of interventions and exposures were identified, but the efficacy of many strategies remains unproven due to the high risk of bias present in many studies. Reducing dehydration prevalence in long-term care facilities is likely to require multiple strategies involving policymakers, management, and care staff, but these require further investigation using more robust study methodologies. The review protocol was registered with the International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42012003100). PMID- 25499400 TI - Herlyn-Werner-Wunderlich syndrome: a very rare urogenital anomaly in a teenage girl. AB - BACKGROUND: Herlyn-Werner-Wunderlich (HWW) syndrome is an uncommon variant of Mullerian duct anomalies, consisting of uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis. It usually presents in a post-pubertal adolescent or adult woman in whom hematometrocolpos produces a pronounced mass effect and pain on the side of the obstructed hemivagina. CASE REPORT: We report the case of a 13-year-old girl who presented to the emergency radiology department with sudden onset of severe pain at the right lower quadrant of the abdomen; imaging confirmed the diagnosis of HWW syndrome. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: When unilateral renal agenesis and uterus didelphys coexist, the first thing that the physician should remember is to confirm or refute the presence of a blind vagina for diagnosis of HWW syndrome. PMID- 25499401 TI - Severe hyponatremia associated with thiazide diuretic use. AB - BACKGROUND: Thiazide diuretics are commonly used as first-line antihypertensive agents. Hyponatremia is a reported, though uncommon, complication of thiazide use. Although the exact mechanism of thiazide-induced hyponatremia (TIH) is unclear, it can be a significant cause of morbidity and mortality. CASE REPORT: We report a 69-year-old man with generalized weakness beginning 2 weeks after starting hydrochlorothiazide (HCTZ). Evaluation revealed a serum sodium level of 120 mmol/L. The patient was admitted and successfully treated with free water restriction and discontinuation of the HCTZ. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Hyponatremia is an uncommon complication of thiazide diuretic use, which frequently presents with nonspecific symptoms. Identification of TIH is crucial to prevent its potentially life-threatening complications. PMID- 25499402 TI - Surviving malignant hypertrophic cardiomyopathy with all major complications in a single patient. PMID- 25499403 TI - Contradictory effects of hypercholesterolemia and diabetes mellitus on the progression of abdominal aortic aneurysm. PMID- 25499404 TI - Usefulness of measuring both body mass index and waist circumference for the estimation of visceral adiposity and related cardiometabolic risk profile (from the INSPIRE ME IAA study). AB - Despite its well-documented relation with visceral adiposity (VAT) and cardiometabolic risk (CMR), whether waist circumference (WC) should be measured in addition to body mass index (BMI) remains debated. This study tested the relevance of adding WC to BMI for the estimation of VAT and CMR. In the International Study of Prediction of Intra-abdominal Adiposity and Its Relationship with Cardiometabolic Risk/Intra-abdominal Adiposity, 297 physicians recruited 4,504 patients (29 countries). Both BMI and WC were measured, whereas VAT and liver fat were assessed by computed tomography. A composite CMR score was calculated. From the 4,109 patients included in the present analyses (20 <= BMI < 40 kg/m(2), 47% women), about 30% displayed discordant values for WC and BMI quintiles, despite a strong correlation between the 2 anthropometric variables (r = 0.87 and r = 0.84 for men and women, respectively, p <0.001). Within each single BMI unit, VAT and WC showed substantial variability between subjects (mean difference between 90th and 10th percentiles: 175 cm(2)/16 cm and 137 cm(2)/18 cm for VAT/WC in men and women, respectively). Within each BMI category, increasing gender-specific WC tertiles were associated with significantly higher VAT, liver fat, and with a more adverse CMR profile. In conclusion, this large international cardiometabolic study highlights the frequent discordance between BMI and WC, driven by the substantial variability in VAT for a given BMI. Within each BMI category, WC was cross-sectionally associated with VAT, liver fat, and CMR factors. Thus, WC allows a further refinement of the CMR related to any given BMI. PMID- 25499405 TI - The Brief Fatigue Inventory is reliable and valid for the burn patient cohort. AB - OBJECTIVE: After burn, patients are at risk of fatigue which may influence negatively their capacity to participate in activity, rehabilitation and other treatments. Fatigue may stem from the wound healing and systemic responses to burn which drive a hypermetabolic state that may persist for months. However, an established method is not available for objectively measuring fatigue after burns. The Brief Fatigue Inventory (BFI) was hypothesised to be an appropriate option for assessments following severe burn. The primary aim of the study was to establish if the BFI was reliable and valid in a burn patient sample. METHODS: Adult patients admitted between 2009 and 2013 to Royal Perth Hospital Burn Center were included. Patients completed the BFI and Burns Specific Health Scale Brief (BSHS-B) in tandem at one, three, six and 12 months after burn. Reliability was assessed using Cronbach's alpha; construct validity using factor analysis and multi-variable regression of BFI; and, criterion validity with longitudinal regression of BFI with BSHS-B. RESULTS: The sample (n=587) had a median TBSA of 3% (range=<1-75%). The BFI demonstrated excellent reliability (alpha>0.90). The factor analysis confirmed a single-domain construct, centred around the first scale item. Good correlation between BFI and BSHS-B scores (p<0.001) on longitudinal analysis confirmed criterion validity. There was a significant difference in fatigue scores between minor and major burn patients and a significant association of fatigue levels over time with TBSA. CONCLUSION: The BFI is a reliable and valid tool for fatigue measurement in patients during the first 12 months after burn. PMID- 25499406 TI - Cost-effective outpatient burn-care for minor burns. PMID- 25499407 TI - ICG angiography predicts burn scarring within 48 h of injury in a porcine vertical progression burn model. AB - The current standard of care in determining the need to excise and graft a burn remains with the burn surgeon, whose clinical judgment is often variable. Prior work suggests that minimally invasive perfusion technologies are useful in burn prognostication. Here we test the predictive capabilities of Laser Doppler Imaging (LDI) and indocyanine green dye (ICG) angiography in the prediction of burn scarring 28 days after injury using a previously validated porcine burn model that shows vertical progression injury. Twelve female Yorkshire swine were burned using a 2.5 * 2.5 cm metal bar at variable temperature and application times to create distinct burn depths. Six animals (48 injuries total) each were analyzed with LDI or ICG angiography at 1, 24, 48, and 72 h following injury. A linear regression was then performed correlating perfusion measurements against wound contraction at 28 days after injury. ICG angiography showed a peak linear correlate (r(2)) of .63 (95% CI .34 to .92) at 48 h after burn. This was significantly different from the LDI linear regression (p < .05), which was measured at r(2) of .20 (95% CI .02 to .39). ICG angiography linear regression was superior to LDI at all timepoints. Findings suggest that ICG angiography may have significant potential in the prediction of long-term burn outcomes. PMID- 25499412 TI - Ultrasound-guided percutaneous dilatational tracheostomy: stated advantages are just the tip of the iceberg. PMID- 25499413 TI - Combination of Acute Physiology and Chronic Health Evaluation II score, early lactate area, and N-terminal prohormone of brain natriuretic peptide levels as a predictor of mortality in geriatric patients with septic shock. AB - BACKGROUND: Given the high mortality rates in elderly patients with septic shock, the early recognition of patients at greatest risk of death is crucial for the implementation of early intervention strategies. Serum lactate and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels are often elevated in elderly patients with septic shock and are therefore important biomarkers of metabolic and cardiac dysfunction. We hypothesized that a risk stratification system that incorporates the Acute Physiology and Chronic Health Evaluation (APACHE) II score and lactate and NT-proBNP biomarkers would better predict mortality in geriatric patients with septic shock than the APACHE II score alone. METHODS: A single-center prospective study was conducted from January 2012 to December 2013 in a 30-bed intensive care unit of a triservice hospital. The lactate area score was defined as the sum of the area under the curve of serial lactate levels measured during the 24 hours following admission divided by 24. The NT-proBNP score was assigned based on NT-proBNP levels measured at admission. The combined score was calculated by adding the lactate area and NT-proBNP scores to the APACHE II score. Multivariate logistic regression analyses and receiver operating characteristic curves were used to evaluate which variables and scoring systems served as the best predictors of mortality in elderly septic patients. RESULTS: A total of 115 patients with septic shock were included in the study. The overall 28-day mortality rate was 67.0%. When compared to survivors, nonsurvivors had significantly higher lactate area scores, NT-proBNP scores, APACHE II scores, and combined scores. In the multivariate regression model, the combined score, lactate area score, and mechanical ventilation were independent risk factors associated with death. Receiver operating characteristic curves indicated that the combined score had significantly greater predictive power when compared to the APACHE II score or the NT-proBNP score (P < .05). CONCLUSIONS: A combined score that incorporates the APACHE II score with early lactate area and NT-proBNP levels is a useful method for risk stratification in geriatric patients with septic shock. PMID- 25499414 TI - Sonographic patterns of lung consolidation in mechanically ventilated patients with and without ventilator-associated pneumonia: a prospective cohort study. AB - PURPOSE: Thoracic ultrasound (TUS) has been successfully used in the diagnosis of community-acquired pneumonia. Little is known about its diagnostic potential in ventilator-associated pneumonia (VAP). The purpose of this study was to systematically describe the morphology and temporal changes of sonographic patterns in mechanically ventilated patients and to evaluate the diagnostic performance characteristics of TUS-based VAP diagnoses. MATERIALS AND METHODS: Patients who were placed on invasive ventilation for reasons other than pneumonia and who were considered at risk for the development of VAP received daily TUS examinations while being closely monitored for the development of pneumonia. RESULTS: Fifty-seven patients were studied. The incidence of VAP was 21.1%. Sonographic patterns of reduced or absent lung aeration were found in 64.2% of examinations. The sonographic pattern of lung consolidation with either dynamic or static air bronchograms was 100% sensitive and 60% specific for VAP in those patients who developed clinical signs and symptoms compatible with pneumonia. The pretest and posttest probabilities were 0.38 and 0.6, respectively. CONCLUSIONS: Sonographic patterns of abnormal aeration are frequently observed in mechanically ventilated patients. If sonographic lung consolidation with either static or dynamic air bronchograms is absent, VAP is highly unlikely. The presence of these sonographic patterns in patients with signs and symptoms suggestive of pneumonia significantly increases the probability of VAP. PMID- 25499415 TI - A two-site survey of clinicians to identify practices and preferences of intensive care unit transfers to general medical wards. AB - INTRODUCTION: The transfer of patients from the intensive care unit (ICU) to the general medical ward is high risk for adverse events and health care provider dissatisfaction. We aimed to identify perceived practices, and what information is important to communicate during an ICU transfer. METHODS: This study used a self-administered questionnaire that surveyed physicians in 2 different hospitals. These physicians provide care in either the ICU or the general medical ward. Responses were evaluated with Likert scales and frequencies. RESULTS: A total of 121 physicians (54% response rate) completed the survey. Current practice most often includes written chart and telephone communication. Most providers (63.3%) believed that the current process is inadequate. Surprises are common (79% of respondents); and reported adverse events include medication errors (60.4%), aspiration (49.5%), and decreased level of consciousness requiring intervention (44.6%). The use of an ICU transfer tool is one potential mechanism of improving this process of care, and providers reported several items that may be useful. CONCLUSION: Providers reported the current process of transferring patients from the ICU to the general medical ward as inadequate. We highlight data that physicians feel is important to communicate at the time of transfer. PMID- 25499416 TI - A risk prediction model for mortality in the moribund general surgical patient. AB - INTRODUCTION: Surgeons struggle to counsel families on the role of surgery and likelihood of survival in the moribund patient. We sought to develop a risk prediction model for postoperative inpatient death for the moribund surgical candidate. MATERIALS AND METHODS: Using 2007-2012 American College of Surgeons National Surgical Quality Improvement Program data, we identified American Society of Anesthesiologists class 5 (moribund) patients. The sample was randomly divided into development and validation cohorts. In the development cohort, preoperative patient characteristics were evaluated. The primary outcome measure was in-hospital mortality. Factors significant in univariate analysis were entered into a multivariable model; points were assigned based on beta coefficients. A scoring system was generated to predict inpatient mortality. Models were developed separately for operations performed within and after 24 hours of admission, and tested on the validation cohort. RESULTS: A total of 3120 patients were included. In-hospital mortality was 50.6%. In multivariable analysis, patient characteristics associated with in-hospital mortality were age, functional status, recent dialysis, recent myocardial infarction, ventilator dependence, body mass index, and procedure type. The scoring system generated from this model accurately predicted in-hospital mortality for patients undergoing surgery within and after 24 hours. CONCLUSION: A simple risk prediction model using readily available preoperative patient characteristics accurately predicts postoperative mortality in the moribund surgical patient. This scoring system can assist in decision making. PMID- 25499417 TI - Defining an ideal technique for percutaneous dilatational tracheostomy--is real time ultrasound guidance the final piece of the puzzle? PMID- 25499418 TI - Ultrasound-guided percutaneous dilatational tracheostomy: going deep into the sea. PMID- 25499419 TI - Just ask: hospice familiarity in Asian and Hispanic adults. AB - CONTEXT: Previous research documents the under-utilization of hospice services by minority ethnic groups, but less data exist for Asian and Hispanic Americans. It is unclear whether these low utilization rates are a result of attitudinal or information barriers, or both. OBJECTIVES: To examine self-reported familiarity and attitudes toward hospice among Asian and Hispanic groups in ethnically diverse Queens County, NY. METHODS: We surveyed diverse adults during health fairs, at senior centers, and church programs directed at ethnic populations. Respondents completed surveys in their preferred language: Spanish, Chinese (Mandarin), and Korean. Analysis of variance was used to compare continuous variables among language groups; Fisher's exact test compared categorical variables. RESULTS: A total of 604 community adults were surveyed: 99 Chinese, 349 Korean, 156 Spanish. Respondents were mostly female, average age 53 years. Familiarity with hospice varied significantly among the groups (P < 0.001) and was lower in the Hispanic (16%) and higher in the Chinese (45%) and Korean (56%) groups. Personal experiences with hospice were low (8-16%) in all groups. A majority (75-94%) responded they would share hospice information with loved ones, but the Hispanic group was significantly less likely to do so compared with Chinese and Korean Americans. Between 74 and 95% reported willingness to receive future information about hospice, but the Korean group was significantly less likely to want information. CONCLUSION: When surveyed in their preferred language, Asian and Hispanic adults reported variable levels of familiarity with hospice services. Most responded positively to receiving future information and would tell friends and family members about hospice. PMID- 25499420 TI - Independent validation of the modified prognosis palliative care study predictor models in three palliative care settings. AB - CONTEXT: Accurate prognostic information in palliative care settings is needed for patients to make decisions and set goals and priorities. The Prognosis Palliative Care Study (PiPS) predictor models were presented in 2011, but have not yet been fully validated by other research teams. OBJECTIVES: The primary aim of this study is to examine the accuracy and to validate the modified PiPS (using physician-proxy ratings of mental status instead of patient interviews) in three palliative care settings, namely palliative care units, hospital-based palliative care teams, and home-based palliative care services. METHODS: This multicenter prospective cohort study was conducted in 58 palliative care services including 16 palliative care units, 19 hospital-based palliative care teams, and 23 home based palliative care services in Japan from September 2012 through April 2014. RESULTS: A total of 2426 subjects were recruited. For reasons including lack of followup and missing variables (primarily blood examination data), we obtained analyzable data from 2212 and 1257 patients for the modified PiPS-A and PiPS-B, respectively. In all palliative care settings, both the modified PiPS-A and PiPS B identified three risk groups with different survival rates (P<0.001). The absolute agreement ranged from 56% to 60% in the PiPS-A model and 60% to 62% in the PiPS-B model. CONCLUSION: The modified PiPS was successfully validated and can be useful in palliative care units, hospital-based palliative care teams, and home-based palliative care services. PMID- 25499422 TI - Re: The Sidney ProjectTM. PMID- 25499423 TI - The questionable practice of hospice flipping to improve inpatient mortality. PMID- 25499424 TI - Identification of IgG-K type macroprolactin found in the serum of an 8-year-old girl. PMID- 25499421 TI - Frequency and factors associated with unexpected death in an acute palliative care unit: expect the unexpected. AB - CONTEXT: Few studies have examined the frequency of unexpected death and its associated factors in a palliative care setting. OBJECTIVES: To determine the frequency of unexpected death in two acute palliative care units (APCUs); to compare the frequency of signs of impending death between expected and unexpected deaths; and to determine the predictors associated with unexpected death. METHODS: In this prospective, longitudinal, observational study, consecutive patients admitted to two APCUs were enrolled and physical signs of impending death were documented twice daily until discharge or death. Physicians were asked to complete a survey within 24 hours of APCU death. The death was considered unexpected if the physician answered "yes" to the question "Were you surprised by the timing of the death?" RESULTS: In total, 193 of 203 after-death assessments (95%) were collected for analysis. Nineteen of 193 patients died unexpectedly (10%). Signs of impending death, including non-reactive pupils, inability to close eyelids, decreased response to verbal stimuli, drooping of nasolabial folds, peripheral cyanosis, pulselessness of the radial artery, and respiration with mandibular movement, were documented more frequently in expected deaths than unexpected deaths (P < 0.05). Longer disease duration was associated with unexpected death (33 months vs. 12 months, P = 0.009). CONCLUSION: Unexpected death occurred in an unexpectedly high proportion of patients in the APCU setting and was associated with fewer signs of impending death. Our findings highlight the need for palliative care teams to be prepared for the unexpected. PMID- 25499426 TI - Association between chemokine (C-C motif) ligand 2 gene -2518 A/G polymorphism and pancreatitis risk: a meta-analysis. AB - OBJECTIVE: Many studies have focused on the relationship between chemokine (C-C motif) ligand 2 gene (CCL2) -2518 A/G polymorphism and pancreatitis risk, but the results remain inconsistent. Thus, a meta-analysis was carried out to derive a more precise estimation of the association between CCL2 -2518 A/G polymorphism and pancreatitis risk. METHODS: Relevant publications were searched in several widely used databases and six studies were included in the meta-analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between CCL2 -2518 A/G polymorphism and pancreatitis risk. RESULTS: Significant associations between CCL2 -2518 A/G polymorphism and pancreatitis risk were observed in both overall meta-analysis (OR = 0.62, 95% CI = 0.43-0.89 for AA versus AG + GG; OR = 0.71, 95% CI = 0.51 0.98 for A allele versus G allele), and acute pancreatitis subgroup (OR = 0.56, 95% CI = 0.31-0.99 for AA versus AG + GG), especially severe acute pancreatitis subgroup when compared with controls (OR = 0.48, 95% CI = 0.24-0.97 for AG versus GG; OR = 0.35, 95% CI = 0.18-0.70 for AA + AG versus GG). However, no significant pancreatitis risk variation was detected for all genetic models in the severe acute pancreatitis versus mild acute pancreatitis subgroup and the subgroup analysis based on ethnicity. CONCLUSIONS: The CCL2 -2518 A/G polymorphism probably associates with pancreatitis risk, especially severe acute pancreatitis risk when compared with controls, with the G allele acting as a risk factor. PMID- 25499425 TI - Selecting models for a respiratory protection program: what can we learn from the scientific literature? AB - BACKGROUND: An unbiased source of comparable respirator performance data would be helpful in setting up a hospital respiratory protection program. METHODS: The scientific literature was examined to assess the extent to which performance data (respirator fit, comfort and usability) from N95 filtering facepiece respirator (FFR) models are available to assist with FFR model selection and procurement decisions. RESULTS: Ten studies were identified that met the search criteria for fit, whereas 5 studies met the criteria for comfort and usability. CONCLUSION: Analysis of these studies indicated that it is difficult to directly use the scientific literature to inform the FFR selection process because of differences in study populations, methodologies, and other factors. Although there does not appear to be a single best fitting FFR, studies demonstrate that fit testing programs can be designed to successfully fit nearly all workers with existing products. Comfort and usability are difficult to quantify. Among the studies found, no significant differences were noted. PMID- 25499427 TI - Analysis of a parent-initiated social media campaign for Hirschsprung's disease. AB - BACKGROUND: Social media can be particularly useful for patients or families affected by rare conditions by allowing individuals to form online communities across the world. OBJECTIVE: Our aim in this study was to conduct a descriptive and quantitative analysis of the use of a social media community for Hirschsprung's Disease (HD). METHODS: In July 2011, a mother of a child with HD launched the "Shit Happens" campaign. The campaign uses social media (blogs, Twitter, and Facebook) to engage other families affected by HD. Internet analytics including Google Analytics and Facebook Insights were used to evaluate the reach and responsiveness of this campaign. RESULTS: On the day the HD campaign was launched, 387 people viewed the blog "Roo's Journey". Blog views have now exceeded 5400 views from 37 countries. The Facebook page extends to 46 countries, has an average post reach of 298 users, 1414 "likes", and an overall reach of 131,032 users. The campaign has 135 Twitter followers and 344 tweets at the time of writing. The most common question posted on the Facebook page is related to treatment for extreme diaper rash. Responsiveness assessment demonstrated that within 2 hours of posting, a question could receive 143 views and 20 responses, increasing to 30 responses after 5 hours. CONCLUSIONS: Social media networks are well suited to discussion, support, and advocacy for health related conditions and can be especially important in connecting families affected by rare conditions. The HD campaign demonstrates the reach and responsiveness of a community that primarily relies on social media to connect families affected by HD. Although responsive, this community is currently lacking consistent access to evidence-based guidance for their common concerns. We will explore innovative consumer-researcher partnerships to offer a solution in future research. PMID- 25499428 TI - The bioimpedance phase angle predicts low muscle strength, impaired quality of life, and increased mortality in old patients with cancer. AB - OBJECTIVES: We investigated the impact of low phase angle (PhA) values on muscle strength, quality of life, symptom severity, and 1-year mortality in older cancer patients. DESIGN: Prospective study with 1-year follow-up. PARTICIPANTS: Cancer patients aged >60 years. METHODS: PhA was derived from whole body impedance analysis. The fifth percentile of age-, sex-, and body mass index-stratified reference values were used as cut-off. Quality of life was determined with the European Organization of Research and Treatment in Cancer questionnaire, reflecting both several function scales and symptom severity. Muscle strength was assessed by hand grip strength, knee extension strength, and peak expiratory flow. RESULTS: 433 cancer patients, aged 60-95 years, were recruited. Patients with low PhA (n = 197) exhibited decreased muscle strength compared with patients with normal PhA (hand grip strength: 22 +/- 8.6 vs 28.9 +/- 8.9 kg, knee extension strength: 20.8 +/- 11.8 vs 28.1 +/- 14.9 kg, and peak expiratory flow: 301.1 +/- 118 vs 401.7 +/- 142.6 L/min, P < .001). Physical function, global health status, and role function from the European Organization of Research and Treatment in Cancer questionnaire were reduced, and most symptoms (fatigue, anorexia, pain, and dyspnea) increased in patients with low PhA (P < .001). In a risk-factor adjusted regression analysis, PhA emerged as independent predictor of physical function (beta:-0.538, P = .023), hand grip strength (beta:-4.684, P < .0001), knee extension strength (beta:-4.548, P = .035), and peak expiratory flow (beta:-66.836, P < .0001). Low PhA moreover predicted 1-year mortality in the Cox proportional hazards regression model, whereas grip strength was no longer significant. CONCLUSIONS: PhA below the fifth reference percentile is highly predictive of decreased muscle strength, impaired quality of life, and increased mortality in old patients with cancer and should be evaluated in routine assessment. PMID- 25499429 TI - Depression, frailty, and all-cause mortality: a cohort study of men older than 75 years. AB - BACKGROUND: Depression is associated with increased mortality, but it is unclear if this relationship is truly causal. OBJECTIVES: To determine the relative mortality associated with past and current depression, taking into account the effect of frailty. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal cohort study of 2565 men aged 75 years or over living in metropolitan Perth, Western Australia, who completed the third wave of assessments of the Health In Men Study throughout 2008. MAIN OUTCOME AND MEASURES: All-cause mortality data were derived from Australian death records up to June 17, 2013. History of past depression and age of onset of symptoms were obtained from direct questioning and from electronic health record linkage. Diagnosis of current major depressive symptoms followed Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision guidelines. We considered that participants were frail if they showed evidence of impairment in 3 or more of the 5 domains on the fatigue, resistance, ambulation, illnesses, and loss of weight (FRAIL) scale. Other measured factors included age, education, living arrangements, smoking and alcohol history, and physical activity. RESULTS: 558 participants died during mean period of follow-up of 4.2 +/- 1.1 years. The annual death rate per thousand was 50 for men without depression, 52 for men with past depression, and 201 for men with major depressive symptoms at baseline. The crude mortality hazard was 4.26 (95% confidence interval = 2.98, 6.09) for men with depression at baseline compared with never depressed men, and 1.79 (95% confidence interval = 1.21, 2.62) after adjustment for frailty. Further decline in mortality hazard was observed after adjustment for other measured factors. CONCLUSIONS: Current, but not past, depression is associated with increased mortality, and this excess mortality is strongly associated with frailty. Interventions designed to decrease depression-related mortality in later life may need to focus on ameliorating frailty in addition to treating depression. PMID- 25499430 TI - Antitumor platinum(II) complexes of N-cyclobutyl-1R,2R-diaminocyclohexane with dicarboxylates as leaving groups. AB - Four platinum(II) complexes of N-cyclobutyl-1R,2R-diaminocyclohexane with different bidentate dicarboxylates (1 oxalate, 2 malonate, 3 1,1 cyclobutanedicarboxylate and 4 3-hydroxy-1,1-cyclobutanedicarboxylate) as leaving groups were synthesized and characterized by elemental analyses, IR and (1)HNMR spectra together with ESI-MS spectroscopy. All complexes showed considerable cytotoxicity against the tested four human tumor cell lines including A549, HCT 116, HepG-2 and MCF-7. Especially, complex 4 showed good cytotoxicity against A549 (IC50=3.5MUM) and HCT-116 (IC50=0.9MUM) cancer cell lines. Moreover, complex 3 is the most effective agent among the tested compounds against MCF-7 cell line (IC50=1.1MUM). The DNA binding behavior of both complexes 3 and 4, studied by agarose gel electrophoresis, revealed that they bound to DNA in almost the same way as cisplatin. PMID- 25499431 TI - Investigating the binding interactions of the anti-Alzheimer's drug donepezil with CYP3A4 and P-glycoprotein. AB - The anti-Alzheimer's agent donepezil is known to bind to the hepatic enzyme CYP3A4, but its relationship with the efflux transporter P-glycoprotein (P-gp) is not as well elucidated. We conducted in vitro inhibition studies of donepezil using human recombinant CYP3A4 and P-gp. These studies show that donepezil is a weak inhibitor of CYP3A4 (IC50=54.68+/-1.00MUM) whereas the reference agent ketoconazole exhibited potent inhibition (CYP3A4 IC50=0.20+/-0.01MUM). P-gp inhibition studies indicate that donepezil exhibits better inhibition relative to CYP3A4 (P-gp EC50=34.85+/-4.63MUM) although it was less potent compared to ketoconazole (P-gp EC50=9.74+/-1.23MUM). At higher concentrations, donepezil exhibited significant inhibition of CYP3A4 (69%, 84% and 87% inhibition at 100, 250 and 500MUM, respectively). This indicates its potential to cause drug-drug interactions with other CYP3A4 substrates upon co-administration; however, this scenario is unlikely in vivo due to the low therapeutic concentrations of donepezil. Similarly, donepezil co-administration with P-gp substrates or inhibitors is unlikely to result in beneficial or adverse drug interactions. The molecular docking studies show that the 5,6-dimethoxyindan-1-one moiety of donepezil was oriented closer to the heme center in CYP3A4 whereas in the P-gp binding site, the protonated benzylpiperidine pharmacophore of donepezil played a major role in its binding ability. Energy parameters indicate that donepezil complex with both CYP3A4 and P-gp was less stable (CDOCKER energies=-15.05 and 4.91kcal/mol, respectively) compared to the ketoconazole-CYP3A4 and P-gp complex (CDOCKER energies=-41.89 and -20.03kcal/mol, respectively). PMID- 25499432 TI - Development of photo-controllable hydrogen sulfide donor applicable in live cells. AB - Hydrogen sulfide (H2S) has multiple physiological roles, for example, in vasodilation and inflammation. It is a highly reactive gas under ambient conditions, so controllable H2S donors are required for studying its biological functions. Here, we describe the design, synthesis and application of a H2S donor (SPD-2) that utilizes xanthone photochemistry to control H2S release. H2S generation from SPD-2 was completely dependent on UVA-irradiation (325-385nm), as confirmed by methylene blue assay and by the use of a H2S-selective fluorescent probe. SPD-2 was confirmed to provide controlled H2S delivery in live cells, and should be suitable for various biological applications. PMID- 25499433 TI - The fungal natural product (1S,3S)-austrocortirubin induces DNA damage in HCT116 cells via a mechanism unique from other DNA damaging agents. AB - Screening a series of natural product-based tetrahydroanthraquinones led to the identification of a novel molecule, (1S,3S)-austrocortirubin (2), which acts via inducing DNA damage. Compound 2 has a GI50 of 3MUM against HCT116 and induces apoptosis. Mechanism of action studies indicate that it causes significant DNA damage during G0/G1, S, and G2 cell cycle phases. Cells are stopped at the G2/M phase checkpoint, and do not reach mitosis due to large amounts of DNA damage. Thus, compound 2 exhibits a unique mechanism of action, one that is distinct from doxorubicin, despite the high degree of structural homology between these two quinone-based structures. PMID- 25499434 TI - Synthesis and biological evaluation of (-)-6-O-desmethylcryptopleurine and analogs. AB - (-)-Cryptopleurine 1 is one of the most potent anti-proliferative member of the phenanthroquinolizidine class of alkaloids. We report here the synthesis of (-)-6 O-desmethylcryptopleurine (-)-2 and (-)-6-O-desmethyl-(15R)-hydroxycryptopleurine (-)-4 in their enantiomerically enriched form through a convergent synthetic route, where the chirality is introduced by the use of commercially available (R) methyl piperidine-2-carboxylate hydrochloride 17. Anti-proliferative activities of these compounds were evaluated on a panel of four cancer cell lines, revealing that compounds (-)-2 and (-)-4 are potent cytotoxic compared to cryptopleurine. PMID- 25499435 TI - Prophylactic treatment of asthma by an ozone scavenger in a mouse model. AB - Our hypothesis that inflammation in asthma involves production of ozone by white blood cells and that ozone could be an inflammatory mediator suggests that scavengers of reactive oxygen species (ROS), for example, electron-rich olefins, could serve for prophylactic treatment of asthma. Olefins could provide chemical protection against either exogenous or endogenous ozone and other ROS. BALB/c mice pretreated by inhalation of d-limonene before an ovalbumin challenge exhibited significant attenuation of the allergic asthma symptoms. Diminution of the inflammatory process was evident by reduced levels of aldehydes, reduced counts of neutrophils in the BAL fluid and by histological tests. A surprising systemic effect was observed by decreased levels of aldehydes in the spleen, suggesting that the examination of tissues and organs that are remote from the inflammation foci could provide valuable information on the distribution of the oxidative stress and may serve as guide for targeted treatment. PMID- 25499436 TI - New N-aryl-N'-(3-(substituted)phenyl)-N'-methylguanidines as leads to potential PET radioligands for imaging the open NMDA receptor. AB - An expansive set of N-aryl-N'-(3-(substituted)phenyl)-N'-methylguanidines was prepared in a search for new leads to prospective PET ligands for imaging of the open channel of the N-methyl-d-aspartate (NMDA) receptor in vivo. The N-aryl rings and their substituents were varied, whereas the N-methyl group was maintained as a site for potential labeling with the positron-emitter, carbon-11 (t1/2=20.4min). At micromolar concentration, over half of the prepared compounds strongly inhibited the binding of [(3)H]TCP to its binding site in the open NMDA receptor in vitro. Four ligands displayed affinities that are similar or superior to those of the promising SPECT radioligand ([(123)I]CNS1261). The 3' dimethylamino (19; Ki 36.7nM), 3'-trifluoromethyl (20; Ki 18.3nM) and 3' methylthio (2; Ki 39.8nM) derivatives of N-1-naphthyl-N'-(phenyl)-N' methylguanidine were identified as especially attractive leads for PET radioligand development. PMID- 25499437 TI - Design, synthesis and in vitro antikinetoplastid evaluation of N-acylated putrescine, spermidine and spermine derivatives. AB - A structure-activity relationship study on polyamine derivatives led to the synthesis and the determination of antikinetoplastid activity of 17 compounds. Among them, a spermidine derivative (compound 13) was specifically active in vitro against Leishmania donovani axenic amastigotes (IC50 at 5.4MUM; Selectivity Index >18.5) and a spermine derivative (compound 28) specifically active against Trypanosoma brucei gambiense (IC50 at 1.9MUM; Selectivity Index >52). PMID- 25499438 TI - Identification of N-{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-l leucine (NTRC-808), a novel nonpeptide chemotype selective for the neurotensin receptor type 2. AB - Compounds acting via the GPCR neurotensin receptor type 2 (NTS2) display analgesic effects in relevant animal models. Using a pharmacophore model based on known NT receptor nonpeptide compounds, we screened commercial databases to identify compounds that might possess activity at NTS2 receptor sites. Modification of our screening hit to include structural features known to be recognized by NTS1 and NTS2, led to the identification of the novel NTS2 selective nonpeptide, N-{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2 yl]carbonyl}-l-leucine (9). This compound is a potent partial agonist in the FLIPR assay with a profile of activity similar to that of the reference NTS2 analgesic nonpeptide levocabastine (5). PMID- 25499439 TI - Comparison of response evaluation criteria in solid tumours and Choi criteria for response evaluation in patients with advanced soft tissue sarcoma treated with trabectedin: a retrospective analysis. AB - BACKGROUND: To assess the additional value of density measurement using contrast enhancement sequences (Choi assessment) in a real-life cohort of adult soft tissue sarcoma patients treated with trabectedin. METHODS: Eligibility criteria included adults (age ?18) treated between 01/2007 and 12/2011, with at least two trabectedin cycles after failure or intolerance to doxorubicin/ifosfamide. Baseline and first computed tomography (CT)-scans were centrally reviewed by an experienced radiologist. RESULTS: The retrospective cohort consists of 134 (73 female) patients treated with trabectedin 1.5 mg/m(2) given as a 24-h infusion every 3 weeks. Patients received a median of five trabectedin cycles (range: 2 33) and the main cause of discontinuation was progressive disease (PD) (n = 105, 78.4%). Response Evaluation Criteria in Solid Tumours (RECIST) assessment was feasible in 128 (95.5%) patients, with Choi assessment performed in 92 (68.7%) patients, generally due to inadequate sequences or exclusive lung metastases. Concordance between both methods was fair (Kappa = 0.290). We identified five patients with false PD (i.e. PD according to RECIST but stable disease/partial response as per Choi). Univariate analysis did not identify any predictive factors for false PD. Median overall survival (OS) of patients with PD as per RECIST but stable disease/partial response (SD/PR) according to Choi was better than for patients with PD according to both RECIST and Choi (14 months versus 8 months; p = 0.052). CONCLUSIONS: Choi assessment may identify patients with false PD who achieved improved efficacy outcomes, suggesting that trabectedin may delay tumour progression even in the case of non-dimensional response. Dual size and tumour density assessment may be more suitable to evaluate responses to trabectedin in sarcoma patients as well as to improve the decision-making strategies for the continuation of trabectedin therapy. PMID- 25499440 TI - Burden of cardiovascular morbidity and mortality following humanitarian emergencies: a systematic literature review. AB - BACKGROUND: The global burden of cardiovascular mortality is increasing, as is the number of large-scale humanitarian emergencies. The interaction between these phenomena is not well understood. This review aims to clarify the relationship between humanitarian emergencies and cardiovascular morbidity and mortality. METHODS: With assistance from a research librarian, electronic databases (PubMed, Scopus, CINAHL, and Global Health) were searched in January 2014. Findings were supplemented by reviewing citations of included trials. Observational studies reporting the effect of natural disasters and conflict events on cardiovascular morbidity and mortality in adults since 1997 were included. Studies without a comparison group were not included. Double-data extraction was utilized to abstract information on acute coronary syndrome (ACS), acute decompensated heart failure (ADHF), and sudden cardiac death (SCD). Review Manager 5.0 (Version 5.2, The Nordic Cochrane Centre; Copenhagen Denmark,) was used to create figures for qualitative synthesis. RESULTS: The search retrieved 1,697 unique records; 24 studies were included (17 studies of natural disasters and seven studies of conflict). These studies involved 14,583 cardiac events. All studies utilized retrospective designs: four were population-based, 15 were single-center, and five were multicenter studies. Twenty-three studies utilized historical controls in the primary analysis, and one utilized primarily geographical controls. DISCUSSION: Conflicts are associated with an increase in long-term morbidity from ACS; the short-term effects of conflict vary by study. Natural disasters exhibit heterogeneous effects, including increased occurrence of ACS, ADHF, and SCD. CONCLUSIONS: In certain settings, humanitarian emergencies are associated with increased cardiac morbidity and mortality that may persist for years following the event. Humanitarian aid organizations should consider morbidity from noncommunicable disease when planning relief and recuperation projects. PMID- 25499441 TI - Mangiferin inhibits endoplasmic reticulum stress-associated thioredoxin interacting protein/NLRP3 inflammasome activation with regulation of AMPK in endothelial cells. AB - BACKGROUND: Endothelial dysfunction is tightly associated with cardiovascular complications in diabetic patients. This study aims to investigate the effects of mangiferin on the regulation of endothelial homeostasis under endoplasmic reticulum stress (ER stress) conditions. RESULTS: High glucose (25 mmol/L) exposure induced ER stress and promoted ROS production in endothelial cells. Mangiferin effectively inhibited ER stress-associated oxidative stress by attenuating IRE1alpha phosphorylation and reducing ROS production. In response to ER stress, thioredoxin-interacting protein (TXNIP) expression increased, followed by NLRP3 inflammasome activation and increased IL-1beta secretion. Mangiferin treatment attenuated the expressions of TXNIP and NLRP3 and reduced IL-1beta and IL-6 production, demonstrating its inhibitory effects on TXNIP/NLRP3 inflammasome activation. NLRP3 inflammasome activation is responsible for mitochondrial cell death. Mangiferin restored the loss of the mitochondrial membrane potential (Deltapsim) and inhibited caspase-3 activity, and thereby protected cells from high glucose-induced apoptosis. Moreover, mangiferin inhibited ET-1 secretion and restored the loss of NO production when cells were exposed to high glucose. Mangiferin enhanced AMPK phosphorylation and AMPK inhibitor compound C diminished its beneficial effects, indicating the potential role of AMPK in its action. CONCLUSION: Our work showed the beneficial effects of mangiferin on the improvement of endothelial homeostasis and elucidated the molecular pathway through which mangiferin ameliorated endothelial dysfunction by inhibition of ER stress-associated TXNIP/NLRP3 inflammasome activation in endothelial cells. SIGNIFICANCE: These findings demonstrated the beneficial effects of mangiferin on the regulation of endothelial homeostasis and indicated its potential application in the management of diabetic cardiovascular complications. PMID- 25499442 TI - Systems approaches in integrative cardiac biology: illustrations from cardiac heterocellular signalling studies. AB - Understanding the complexity of cardiac physiology requires system-level studies of multiple cardiac cell types. Frequently, however, the end result of published research lacks the detail of the collaborative and integrative experimental design process, and the underlying conceptual framework. We review the recent progress in systems modelling and omics analysis of the heterocellular heart environment through complementary forward and inverse approaches, illustrating these conceptual and experimental frameworks with case studies from our own research program. The forward approach begins by collecting curated information from the niche cardiac biology literature, and connecting the dots to form mechanistic network models that generate testable system-level predictions. The inverse approach starts from the vast pool of public omics data in recent cardiac biological research, and applies bioinformatics analysis to produce novel candidates for further investigation. We also discuss the possibility of combining these two approaches into a hybrid framework, together with the benefits and challenges. These interdisciplinary research frameworks illustrate the interplay between computational models, omics analysis, and wet lab experiments, which holds the key to making real progress in improving human cardiac wellbeing. PMID- 25499443 TI - Breast cancer anti-estrogen resistance 3 inhibits transforming growth factor beta/Smad signaling and associates with favorable breast cancer disease outcomes. AB - INTRODUCTION: This study helps to define the implications of breast cancer anti estrogen resistance 3 (BCAR3) in breast cancer and extends the current understanding of its molecular mechanism of action. BCAR3 has been shown to promote cell proliferation, migration and attachment to extracellular matrix components. However, in a cohort of metastatic breast cancer patients who received tamoxifen treatment, high BCAR3 mRNA levels were associated with favorable progression-free survival outcome. These results suggest that, besides its established roles, BCAR3 may have additional mechanisms of action that regulate breast cancer aggressive phenotype. In this study, we investigated whether BCAR3 is a novel antagonist of the canonical transforming growth factor beta (TGFbeta) pathway, which induces potent migration and invasion responses in breast cancer cells. METHODS: We surveyed functional genomics databases for correlations between BCAR3 expression and disease outcomes of breast cancer patients. We also studied how BCAR3 could regulate the TGFbeta/Smad signaling axis using Western blot analysis, coimmunoprecipitation and luciferase assays. In addition, we examined whether BCAR3 could modulate TGFbeta-induced cell migration and invasion by using an automated imaging system and a confocal microscopy imaging-based matrix degradation assay, respectively. RESULTS: Relatively low levels of BCAR3 expression in primary breast tumors correlate with poor distant metastasis-free survival and relapse-free survival outcomes. We also found a strong correlation between the loss of heterozygosity at BCAR3 gene alleles and lymph node invasion in human breast cancer, further suggesting a role for BCAR3 in preventing disease progression. In addition, we found BCAR3 to inhibit Smad activation, Smad-mediated gene transcription, Smad-dependent cell migration and matrix digestion in breast cancer cells. Furthermore, we found BCAR3 to be downregulated by TGFbeta through proteasome degradation, thus defining a novel positive feedback loop mechanism downstream of the TGFbeta/Smad signaling pathway. CONCLUSION: BCAR3 is considered to be associated with aggressive breast cancer phenotypes. However, our results indicate that BCAR3 acts as a putative suppressor of breast cancer progression by inhibiting the prometastatic TGFbeta/Smad signaling pathway in invasive breast tumors. These data provide new insights into BCAR3's molecular mechanism of action and highlight BCAR3 as a novel TGFbeta/Smad antagonist in breast cancer. PMID- 25499444 TI - New evidence of heterogeneity in social anxiety disorder: defining two qualitatively different personality profiles taking into account clinical, environmental and genetic factors. AB - PURPOSE: To study qualitatively different subgroups of social anxiety disorder (SAD) based on harm avoidance (HA) and novelty seeking (NS) dimensions. METHOD: One hundred and forty-two university students with SAD (SCID-DSM-IV) were included in the study. The temperament dimensions HA and NS from the Cloninger's Temperament and Character Inventory were subjected to cluster analysis to identify meaningful subgroups. The identified subgroups were compared for sociodemographics, SAD severity, substance use, history of suicide and self-harm attempts, early life events, and two serotonin transporter gene polymorphisms (5 HTTLPR and STin2.VNTR). RESULTS: Two subgroups of SAD were identified by cluster analysis: a larger (61% of the sample) inhibited subgroup of subjects with "high HA/low-NS", and a smaller (39%) atypical impulsive subgroup with high-moderate HA and NS. The two groups did not differ in social anxiety severity, but did differ in history of lifetime impulsive-related-problems. History of suicide attempts and self-harm were as twice as frequent in the impulsive subgroup. Significant differences were observed in the pattern of substance misuse. Whereas subjects in the inhibited subgroup showed a greater use of alcohol (P=0.002), subjects in the impulsive subgroup showed a greater use of substances with a high-sensation seeking profile (P<0.001). The STin2.VNTR genotype frequency showed an inverse distribution between subgroups (P=0.005). CONCLUSIONS: Our study provides further evidence for the presence of qualitatively different SAD subgroups and the propensity of a subset of people with SAD to exhibit impulsive, high-risk behaviors. PMID- 25499445 TI - High-resolution structure of a new Tn antigen-binding lectin from Vatairea macrocarpa and a comparative analysis of Tn-binding legume lectins. AB - Plant lectins have been studied as histological markers and promising antineoplastic molecules for a long time, and structural characterization of different lectins bound to specific cancer epitopes has been carried out successfully. The crystal structures of Vatairea macrocarpa (VML) seed lectin in complex with GalNAc-alpha-O-Ser (Tn antigen) and GalNAc have been determined at the resolution of 1.4A and 1.7A, respectively. Molecular docking analysis of this new structure and other Tn-binding legume lectins to O-mucin fragments differently decorated with this antigen provides a comparative binding profile among these proteins, stressing that subtle alterations that may not influence monosaccharide binding can, nonetheless, directly impact the ability of these lectins to recognize naturally occurring antigens. In addition to the specific biological effects of VML, the structural and binding similarities between it and other lectins commonly used as histological markers (e.g., VVLB4 and SBA) strongly suggest VML as a candidate tool for cancer research. PMID- 25499446 TI - The recombinant prepro region of TvCP4 is an inhibitor of cathepsin L-like cysteine proteinases of Trichomonas vaginalis that inhibits trichomonal haemolysis. AB - Trichomonas vaginalis expresses multiple proteinases, mainly of the cysteine type (CPs). A cathepsin L-like 34kDa CP, designated TvCP4, is synthesized as a 305 amino-acid precursor protein. TvCP4 contains the prepro fragment and the catalytic triad that is typical of the papain-like CP family of clan CA. The aim of this work was to determine the function of the recombinant TvCP4 prepro region (ppTvCP4r) as a specific inhibitor of CPs. We cloned, expressed, and purified the recombinant TvCP4 prepro region. The conformation of the purified and refolded ppTvCP4r polypeptide was verified by circular dichroism spectroscopy and fluorescence emission spectra. The inhibitory effect of ppTvCP4r was tested on protease-resistant extracts from T. vaginalis using fluorogenic substrates for cathepsin L and legumain CPs. In 1-D zymograms, the inhibitory effect of ppTvCP4r on trichomonad CP proteolytic activity was observed in the ~97, 65, 39, and 30 kDa regions. By using 2-D zymograms and mass spectrometry, several of the CPs inhibited by ppTvCP4r were identified. A clear reduction in the proteolytic activity of several cathepsin L-like protein spots (TvCP2, TvCP4, TvCP4-like, and TvCP39) was observed compared with the control zymogram. Moreover, pretreatment of live parasites with ppTvCP4r inhibited trichomonal haemolysis in a concentration dependent manner. These results confirm that the recombinant ppTvCP4 is a specific inhibitor of the proteolytic activity of cathepsin L-like T. vaginalis CPs that is useful for inhibiting virulence properties depending on clan CA papain-like CPs. PMID- 25499447 TI - TIPE2 protein negatively regulates HBV-specific CD8+ T lymphocyte functions in humans. AB - Cytotoxic T cell-mediated killing of virus-infected hepatocytes is an important pathogenic process of hepatitis B. However, its underlying molecular mechanisms are not fully understood. TNFAIP8L2 (TIPE2) is a newly described anti inflammatory protein that is essential for maintaining immune homeostasis. In this study, we found that the protein levels of TIPE2 in PBMCs of hepatitis B patients were significantly reduced and negatively correlated with the sera values of aminotransferases. Importantly, TIPE2 protein was downregulated preferentially in cytotoxic CD8(+) T cells, not CD4(+) helper T cells. The CD8(+) T cells with low TIPE2 expression were more activated and produced higher levels of perforin, granzyme B, and IFN-gamma. As a result, their cytolytic activity was markedly enhanced. Interestingly, HBc18-27 peptide stimulation could reduce TIPE2 expression in PBMCs. These results indicate that TIPE2 plays an important role in regulating HBV-specific CD8(+) T cell functions in patients with hepatitis B. PMID- 25499448 TI - Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. AB - Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), patients who fail R-CHOP have a dismal outcome. Thus, optimization of front-line therapy, as well as the development of more effective salvage strategies, remains an important objective. Advances in molecular genetics have vastly improved our understanding of the biological diversity of DLBCL and have led to the discovery of key oncogenic pathways. In addition to the major molecular designations of germinal center B-cell and activated B-cell subtypes, next-generation sequencing technologies have unveiled the remarkable complexity of DLBCL and identified unique molecular targets that may be differentially exploited for therapeutic benefit. These findings have translated into a growing list of promising novel agents. Moving forward, it is of paramount importance to recognize the heterogeneity of DLBCL and to investigate these targeted agents within patient populations who are most likely to benefit. It will be necessary to prioritize drugs that affect key driver pathways and to combine them rationally to optimize their benefit. Improved prognostication and the availability of predictive biomarkers will be crucial to allow for the possibility of individualized risk-adapted therapy. PMID- 25499449 TI - Transformed follicular non-Hodgkin lymphoma. AB - Histologic transformation of follicular lymphoma to an aggressive non-Hodgkin lymphoma is a critical biologic event with profound implications on the natural history of this otherwise indolent disease. Recent insights into the genetic and epigenetic basis of transformation have been described, with the recognition of pivotal events governing the initiation and persistence of tumor evolution. Outcomes of patients with transformed lymphoma have historically been poor; however, several studies in the rituximab era suggest that survival may be more favorable than previously recognized. This review highlights our current understanding of transformed follicular lymphoma biology and pathogenesis, current treatment, and future directions. PMID- 25499450 TI - Primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma: do they require a unique therapeutic approach? AB - Primary mediastinal B-cell lymphoma (PMBL) is a subtype of diffuse large B-cell lymphoma (DLBCL) that is putatively derived from a thymic B cell. Accounting for up to 10% of cases of DLBCL, this subtype predominantly affects women in the third and fourth decades of life. Its clinical and molecular characteristics are distinct from other subtypes of DLBCL and, in fact, closely resemble those of nodular sclerosing Hodgkin lymphoma (NSHL). Recently, mediastinal lymphomas with features intermediate between PMBL and NSHL, called mediastinal gray-zone lymphomas, have been described. The optimal management of PMBL is controversial, and most standard approaches include a combination of immunochemotherapy and mediastinal radiation. Recently, the recognition that mediastinal radiation is associated with significant long-term toxicities has led to the development of novel approaches for PMBL that have shown excellent efficacy and challenge the need for routine mediastinal radiation. PMID- 25499451 TI - Mantle cell lymphoma: evolving management strategies. AB - Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin's lymphoma that generally affects older individuals and continues to have one of the worst outcomes of all the lymphomas. Over the last decade, there has been a widespread adoption of cytarabine-based therapy in younger patients, and the incorporation of rituximab into chemotherapeutic regimens has become an evidence based standard of care. However MCL remains a largely incurable disease, and following relapse, it can be a challenge to manage. Although it is possible to define prognosis reliably, there are, as yet, no clear diagnostic or response adjusted parameters that can help to guide therapeutic decisions. However, there are a number of highly active targeted therapies that are moving into the clinic that are set to transform the therapeutic paradigm for this disease in the very near future. This review will explore the molecular pathogenesis of MCL and the current and evolving therapeutic strategies for this disease. PMID- 25499452 TI - Introduction to a clinical review series on aggressive B-cell lymphoma. PMID- 25499453 TI - How I treat classical Hodgkin lymphoma in patients infected with human immunodeficiency virus. AB - HIV-associated classical Hodgkin lymphoma (HIV-cHL) is an important complication of HIV disease in the era of effective combination antiretroviral therapy (cART). Generally, newly diagnosed HIV-cHL should be managed with curative intent. With modern HIV therapeutics, HIV-cHL treatment outcomes are largely comparable to those of the background population with cHL (non-HIV-cHL). To achieve these outcomes, particular attention must be given to managing HIV. This management includes understanding HIV as a comorbid condition with a spectrum of impact that is unique to each patient. Meticulous attention to drug-drug interactions is required to avoid toxicity and pharmacokinetic effects that can undermine cure. Relapsed and refractory HIV-cHL poses additional therapeutic challenges. The standard management in this setting should also be based on that for non-HIV-cHL, and includes the use of salvage chemotherapy followed by autologous stem cell transplant in chemosensitive disease. The role of allogeneic hematopoietic stem cell transplant is less clear but may be useful in select cases. Newer agents with activity in cHL are being tested as part of primary and salvage therapy and are also highly relevant for HIV-cHL. PMID- 25499454 TI - The second transferrin receptor regulates red blood cell production in mice. AB - Transferrin receptor 2 (TFR2) contributes to hepcidin regulation in the liver and associates with erythropoietin receptor in erythroid cells. Nevertheless, TFR2 mutations cause iron overload (hemochromatosis type 3) without overt erythroid abnormalities. To clarify TFR2 erythroid function, we generated a mouse lacking Tfr2 exclusively in the bone marrow (Tfr2(BMKO)). Tfr2(BMKO) mice have normal iron parameters, reduced hepcidin levels, higher hemoglobin and red blood cell counts, and lower mean corpuscular volume than normal control mice, a phenotype that becomes more evident in iron deficiency. In Tfr2(BMKO) mice, the proportion of nucleated erythroid cells in the bone marrow is higher and the apoptosis lower than in controls, irrespective of comparable erythropoietin levels. Induction of moderate iron deficiency increases erythroblasts number, reduces apoptosis, and enhances erythropoietin (Epo) levels in controls, but not in Tfr2(BMKO) mice. Epo target genes such as Bcl-xL and Epor are highly expressed in the spleen and in isolated erythroblasts from Tfr2(BMKO) mice. Low hepcidin expression in Tfr2(BMKO) is accounted for by erythroid expansion and production of the erythroid regulator erythroferrone. We suggest that Tfr2 is a component of a novel iron-sensing mechanism that adjusts erythrocyte production according to iron availability, likely by modulating the erythroblast Epo sensitivity. PMID- 25499456 TI - Addressing gender inequality and intimate partner violence as critical barriers to an effective HIV response in sub-Saharan Africa. AB - INTRODUCTION: In Africa, women and girls represent 57% of people living with HIV, with gender inequality and violence being an important structural determinant of their vulnerability. This commentary draws out lessons for a more effective combination response to the HIV epidemic from three papers recently published in JIAS. DISCUSSION: Hatcher and colleagues present qualitative data from women attending ante-natal clinics in Johannesburg, describing how HIV diagnosis during pregnancy and subsequent partner disclosure are common triggers for violence within relationships. The authors describe the challenges women face in adhering to medication or using services. Kyegombe and colleagues present a secondary analysis of a randomized controlled trial in Uganda of SASA! - a community violence prevention programme. Along with promising community impacts on physical partner violence, significantly lower levels of sexual concurrency, condom use and HIV testing were reported by men in intervention communities. Remme and her colleagues present a systematic review of evidence on the costs and cost effectiveness of gender-responsive HIV interventions. The review identified an ever-growing evidence base, but a paucity of accompanying economic analyses, making it difficult to assess the costs or value for money of gender-focused programmes. CONCLUSIONS: There is a need to continue to accumulate evidence on the effectiveness and costs of different approaches to addressing gender inequality and violence as part of a combination HIV response. A clearer HIV specific and broader synergistic vision of financing and programming needs to be developed, to ensure that the potential synergies between HIV-specific and broader gender-focused development investments can be used to best effect to address vulnerability of women and girls to both violence and HIV. PMID- 25499457 TI - Foreword: Immune dysregulation and pediatric gastrointestinal disorders. PMID- 25499455 TI - Type II NKT-TFH cells against Gaucher lipids regulate B-cell immunity and inflammation. AB - Chronic inflammation including B-cell activation is commonly observed in both inherited (Gaucher disease [GD]) and acquired disorders of lipid metabolism. However, the cellular mechanisms underlying B-cell activation in these settings remain to be elucidated. Here, we report that beta-glucosylceramide 22:0 (betaGL1 22) and glucosylsphingosine (LGL1), 2 major sphingolipids accumulated in GD, can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Human betaGL1-22- and LGL1-reactive CD1d tetramer positive T cells have a distinct T-cell receptor usage and genomic and cytokine profiles compared with the classical type I NKT cells. In contrast to type I NKT cells, betaGL1-22- and LGL1-specific NKT cells constitutively express T follicular helper (TFH) phenotype. Injection of these lipids leads to an increase in respective lipid-specific type II NKT cells in vivo and downstream induction of germinal center B cells, hypergammaglobulinemia, and production of antilipid antibodies. Human betaGL1-22- and LGL1-specific NKT cells can provide efficient cognate help to B cells in vitro. Frequency of LGL1-specific T cells in GD mouse models and patients correlates with disease activity and therapeutic response. Our studies identify a novel type II NKT-mediated pathway for glucosphingolipid mediated dysregulation of humoral immunity and increased risk of B-cell malignancy observed in metabolic lipid disorders. PMID- 25499458 TI - Celiac disease: an immune dysregulation syndrome. AB - Celiac disease is a chronic immune-mediated condition that develops in genetically predisposed individuals. It is characterized by the presence of circulating auto-antibodies in addition to an enteropathy and at times, other extra-intestinal manifestations triggered by exposure to the gliadin fraction of gluten, a family of proteins found in wheat, barley, and rye. There seems to be a rise in reported adverse reactions to gluten, an entity currently termed non celiac gluten (or perhaps more accurately, wheat) sensitivity, where neither the enteropathy nor the auto-antibodies are present. Celiac disease has protean extra intestinal manifestations, and an accurate diagnosis should be sought in people suffering from seemingly unrelated complaints, such as fatigue, anorexia, delayed puberty, short stature, decreased bone density, unusual skin rashes, unexplained iron deficiency, and infertility. The presence of an enteropathy, in conjunction with the positive serology, is considered the diagnostic gold standard for making the diagnosis of celiac disease. It is important to stress that the elimination of gluten, even in asymptomatic patients, brings about health benefits, particularly in relation to bone health, as well as a decrease in the incidence of small bowel malignancy, especially lymphoma. Better understanding of the pathophysiology of celiac disease and the molecular mechanisms involved in antigen recognition and processing has provided the impetus for the development of pharmacologic agents that might block the recognition of gluten and its conversion to a toxic antigenic target. Inhibition of tight junction dysregulation could also prevent or minimize the damage triggered by gluten. Work on genetically modified wheat cultivars has progressed, and the possibility of a vaccine to block the immune mediated trigger is being actively investigated. Education and guidance by a knowledgeable nutritionist or registered dietitian can go a long way in minimizing the stress and facilitating the acceptance of the diet and the life-style changes that it represents. PMID- 25499459 TI - Inflammatory bowel disease: the classic gastrointestinal autoimmune disease. AB - Inflammatory bowel disease (IBD) is an idiopathic disease thought to be caused by a dysregulated immune response to host intestinal microflora. The role of genetic factors is indicated by familial clustering of cases and higher incidence in monozygotic twins. An interaction between genetic and environmental factors is thought to play a role in the pathogenesis of these disorders. Changes in diet, antibiotic use and intestinal colonization have likely contributed to increased prevalence of inflammatory bowel disease in the past century. Environmental factors or infections are thought to alter the barrier function of the epithelium, leading to loss of immune tolerance to intestinal antigens. This loss of tolerance activates dendritic cells, triggering their transport to mesenteric lymph nodes, where they promote differentiation of naive T cells to TH-1, TH-2, TH-17 cells or T regulatory cells. Production of proinflammatory cytokines and chemokines then follows. Circulating effector and regulatory cells enter the intestine through a highly selective mechanism that involves interaction with the vascular endothelium, diapedesis through the vessel wall and migration to the lamina propria. There are several genes implicated in IBD. Mutations in certain genes can cause defective down regulation of the innate immune response, ineffective clearance of intracellular bacteria and proliferation of both luminal and mucosal-adherent commensal bacteria. IBD is a chronic relapsing inflammatory condition that is immune mediated. Results from research in animal models, human genetics, basic science and clinical trials provide evidence that it is heterogeneous, characterized by various genetic abnormalities, leading to a dysregulated and overly aggressive T cell response to commensal enteric bacteria. Different genetic abnormalities can be characterized as causing defects in mucosal barrier function, immunoregulation or bacterial clearance. Advances in our understanding of the interplay between components of innate and adaptive immune response will be central to future progress. PMID- 25499460 TI - Eosinophilic esophagitis: an autoimmune esophageal disorder. AB - Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal inflammatory disease associated with esophageal dysfunction resulting from severe inflammation. The incidence and prevalence of EoE have been increasing in the past decade; however, the reason for this increase is unclear. There is a chronic inflammatory infiltrate that is present in EoE which promotes inflammation, symptoms, and dysfunction. In addition to eosinophils, interleukin (IL)-5 expressing T cells, B cells, eotaxin-3, IL-13, and IgE-bearing mast cells are present in EoE and are thought to contribute to the disease process. Eosinophils are pro-inflammatory and modulate multiple aspects of the immune response. Eosinophils produce a wide range of inflammatory cytokines, chemokines, granulocyte-monocyte colony-stimulating factors, and tumor necrosis factors. Once activated, eosinophils release granule components, which are toxic to a variety of tissues. Transforming growth factor beta1 is a pro-fibrotic molecule produced by epithelial and inflammatory cells, is overexpressed in EoE, and plays a role in esophageal remodeling. Fibrous remodeling in EoE could be associated with symptoms of dysphagia and may explain and predict future esophageal strictures and dysmotility. EoE is a complex disease involving multiple activation pathways, a large number of cells, and various inflammatory molecules. It, along with other atopic disease, is becoming increasingly prevalent and has an important genetic load and may represent as an immunological tolerance disorder of the GI tract. PMID- 25499461 TI - [Plasmapheresis in hypertriglyceridemic acute pancreatitis]. PMID- 25499462 TI - AKT and MET signalling mediates antiapoptotic radioresistance in head neck cancer cell lines. AB - OBJECTIVES: Induction of apoptosis is a major mechanism of radiosensitivity in different types of cancer. In contrast, EGFR/PI3K/AKT signalling and recently the presence of so-called cancer stem cells are discussed as reasons for radioresistance. MATERIALS AND METHODS: The study investigates mechanisms of apoptosis, key oncogenes of the PI3K/AKT pathway and the presence of cancer cells with stem cell properties during irradiation in two cell lines (PCI-9A, and PCI 15) of head and neck squamous cell carcinoma. WST-1-tests, qRT-PCR, western blots and FACS analysis were performed for analysis. RESULTS: The two cell lines presented different degrees of cell death upon irradiation. The radiosensitive cell line PCI-9A showed increased apoptosis after irradiation measured by expressed cleaved caspases 3 and 7 while the radioresistant cell line PCI-15 upregulated antiapoptotic Survivin and BCL2A1 mRNA. Besides, increased PI3K/AKT- and ERK1/2-signalling was associated with radioresistance accompanied by loss of PTEN function through phosphorylation on S380. Blockade of pAKT increased radiation-induced cell death, and moreover, led to an upregulation of pMET in the radioresistant cell line. The percentage of ALDH-positive tumour cells was markedly decreased after irradiation in the radiosensitive cell line. CONCLUSIONS: Functional apoptosis is mandatory for sensitivity to irradiation in head neck cancer cells. Upregulation of the AKT-pathway seems to be one reason for poor radioresponse. Activated MET may also predict radioresistance, possibly through ERK1/2 signalling. Moreover MET may indicate the presence of cancer stem cells facilitating radioresistance as shown by increased ALDH expression. PMID- 25499463 TI - Evolution of adolescent mental health in a rapidly changing socioeconomic environment: a review of mental health studies in adolescents in India over last 10 years. AB - BACKGROUND: Significant changes in the economic, familial and social support aspects in India have occurred in recent times, making it an interesting naturalistic setting to observe the effects of a dynamic socioeconomic environment on behavioral and emotional disorders in adolescents. OBJECTIVE: This systematic review attempts to synthesize and evaluate the available evidence on mental health disorders and interventions in adolescents in India in last 10 years as well as identify conceptual trends and methodological lacunae in these studies. METHOD: A systematic search of electronic databases was performed in March 2014 and 27 school and community based studies evaluating behavioral problems, psychiatric morbidity, stress, suicide-related behaviors, depression, anxiety, aggression, self concept in adolescents in India were reviewed. CONCLUSION: There is a wide variation in the reported prevalence of psychiatric morbidity and behavioral problems in Indian adolescents. Some of the risk and protective factors are similar to those identified by other International studies in this age group. These include female gender, academic difficulties, parental fights, strained familial relationships, school absenteeism, school dropout and other school related factors. However, there are certain variables that appear to be context specific and need further investigation. These are mother's working status, studying in Government institutions or belonging to a nuclear family as risk factors and praying as a coping skill, parental involvement as a protective factor for psychiatric disorders. The suspected upward trend in the psychiatric morbidity in this age group needs more studies to be established. PMID- 25499464 TI - Influence of small ruminant lentivirus infection on cheese yield in goats. AB - Three-year cohort study was carried out to investigate the influence of small ruminant lentivirus (SRLV) infection on cheese yield in goats. For this purpose records of milk yield, milk composition and cheese yield were collected in a dairy goat herd. Cheese yield was recorded as the amount of fresh cheese obtained from 1 kg milk. All goats were serologically tested for SRLV infection twice a year. The analysis included 247 records in total (71 for seropositive and 176 from seronegative individuals) and was carried out with the use of the four-level hierarchical linear model (alpha = 0.05). SRLV infection proved to be a statistically significant independent factor reducing cheese yield (P = 0.013)- when other covariates were held constant cheese yield was reduced by 4.6 g per each 1 kg milk in an infected goat compared with an uninfected goat. Other statistically significant covariates positively associated with cheese yield were protein contents, fat contents and the 3rd stage of lactation (P < 0.001 for all). PMID- 25499465 TI - Understanding the mechanism of ultrasound on the synthesis of cellulose/Cu(OH)2/CuO hybrids. AB - Understanding the mechanism of ultrasound from metal hydroxide to oxides via an ultrasound irradiation method is of great importance for broadening and improving their synthesis and industrial applications. The purpose of this article was to explore the mechanism of ultrasound on the synthesis of cellulose/Cu(OH)2/CuO hybrids. The influences of various reaction parameters including the volume of H2O2, heating method, pulse mode of ultrasound irradiation, sonication time, and power density on the cellulose/Cu(OH)2/CuO hybrids were investigated in detail by means of X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray spectra (EDS), thermogravimetric analysis (TGA), and derivative thermogravimetry (DTG). The experimental results indicated that all the parameters have effects on the cellulose/Cu(OH)2/CuO hybrids, power density had an effect on the phase transformation of Cu(OH)2 to CuO, and the addition of H2O2 played an important role in the shape of cellulose hybrids, which provided an indirect evidence on the H2O2-induced oxidation route for the transformation process from Cu(OH)2 to CuO during the ultrasound irradiation process. These results maybe direct the synthesis and potential applications of cellulose hybrids in the near future. PMID- 25499466 TI - High-intensity ultrasonication as a way to prepare graphene/amorphous iron oxyhydroxide hybrid electrode with high capacity in lithium battery. AB - The preparation of graphene/iron oxyhydroxide hybrid electrode material with very homogeneous distribution and close contact of graphene and amorphous iron oxyhydroxide nanoparticles has been achieved by using high-intensity ultrasonication. Due to the negative charge of the graphene surface, iron ions are attracted toward the surface of dispersed graphene, according to the zeta potential measurements. The anchoring of the FeO(OH) particles to the graphene layers has been revealed by using mainly TEM, XPS and EPR. TEM observations show that the size of the iron oxide particles is about 4 nm. The ultrasonication treatment is the key parameter to achieve small particle size in these graphene/iron oxyhydroxide hybrid materials. The electrochemical behavior of composite graphene/amorphous iron oxyhydroxide prepared by using high-intensity ultrasonication is outstanding in terms of gravimetric capacity and cycling stability, particularly when metallic foam is used as both the substrate and current collector. The XRD-amorphous character of iron oxyhydroxide in the hybrid electrode material and the small particle size contribute to achieve the improved electrochemical performance. PMID- 25499468 TI - Immediate rather than delayed memory impairment in older adults with latent toxoplasmosis. AB - The neurotropic parasite Toxoplasma gondii infects one third of the world population, but its effect on memory remains ambiguous. To examine a potential relationship of the infection with immediate and delayed memory, a population based study was conducted in 4485 participants of the Third National Health and Nutrition Examination Survey aged 60years and older. Serum anti-Toxoplasma IgG antibodies were measured by enzyme immune assay and verbal memory was assessed using the Mini-Mental State Examination and the East Boston Memory Test. The prevalence of latent toxoplasmosis was 41%; in one way analysis of variance, anti Toxoplasma IgG antibody levels significantly differed across tertiles for immediate (P=0.006) but not delayed memory scores (P=0.22). In multinomial logistic regression adjusting for covariates, Toxoplasma seropositivity was associated with lower immediate memory performance (OR: 0.65, 95% CI: 0.44, 0.97 for medium tertile and OR: 0.61, 95% CI: 0.37, 0.98 for highest tertile in reference to the lowest tertile), especially in non-Hispanic Whites (OR: 0.56, 95% CI: 0.36, 0.88 for medium tertile and OR: 0.51, 95% CI: 0.30, 0.87 for highest tertile in reference to the lowest tertile). However, no relationship with delayed memory was observed. In conclusion, latent toxoplasmosis is widespread in older adults and may primarily affect immediate rather than delayed memory, particularly in White Americans. PMID- 25499467 TI - Analysis of TGF-beta1 and TGF-beta3 as regulators of encephalitogenic Th17 cells: Implications for multiple sclerosis. AB - The phenotype of the CD4(+) T cells that mediate the CNS pathology in multiple sclerosis is still unclear, and yet a vital question for developing therapies. One of the conundrums is the role of TGF-beta in the development of encephalitogenic Th17 cells. In the present study, TGF-beta1 and TGF-beta3 were directly compared in their capacity to promote the differentiation of myelin specific Th17 cells that could induce experimental autoimmune encephalomyelitis (EAE). Myelin-specific CD4(+) T cell receptor transgenic cells differentiated with antigen in the presence of IL-6+TGF-beta1 or IL-6+TGF-beta3 generated T cells that produced robust amounts of IL-17, but were incapable of inducing EAE when transferred into mice. Further analysis of these non-encephalitogenic Th17 cells found that they expressed lower amounts of GM-CSF or IL-23R, both molecules necessary for encephalitogenicity. Thus, TGF-beta, irrespective of isoform, negatively regulates the differentiation of encephalitogenic Th17 cells. PMID- 25499469 TI - Onset of maternal psychiatric disorders after the birth of a child with intellectual disability: a retrospective cohort study. AB - Mothers of a child with intellectual disability (ID) have more psychiatric disorders after the birth of their child than other mothers. However, it is unclear if this is because they have more psychiatric disorders before the birth or if the increase is related to the burden of caring for the child. We aimed to calculate the rate of new psychiatric disorders in mothers after the birth of their eldest child with ID born between 1983 and 2005 and to compare these with rates in women with a child with no ID or autism spectrum disorder (ASD) born during the same period. By linking data from Western Australian population-based registries, we selected women with no psychiatric history who survived the birth of their live-born child (N = 277,559) and compared rates of psychiatric disorders for women with a child with ID and women without a child with or ASD. Negative binomial regression with STATA 12 was used for all analyses. Mothers of children with mild-moderate ID of unknown cause had around two to three and a half times the rate of psychiatric disorders of mothers of children without ID or ASD. Mothers of children with Down syndrome and no pre-existing psychiatric disorder showed resilience and had no impairments in their mental health. Interventions and services are needed for mothers of other children with ID to improve their mental health. Further research is implicated to explore the mental health of mothers of children with ID and a pre-existing psychiatric disorder. PMID- 25499470 TI - Seizure states identification in experimental epilepsy using gabor atom analysis. AB - BACKGROUND: Epileptic seizures evolve through several states, and in the process the brain signals may change dramatically. Signals from different states share similar features, making it difficult to distinguish them from a time series; the goal of this work is to build a classifier capable of identifying seizure states based on time-frequency features taken from short signal segments. METHODS: There are different amounts of frequency components within each Time-Frequency window for each seizure state, referred to as the Gabor atom density. Taking short signal segments from the different states and decomposing them into their atoms, the present paper suggests that is possible to identify each seizure state based on the Gabor atom density. The brain signals used in this work were taken form a database of intracranial recorded seizures from the Kindling model. RESULTS: The findings suggest that short signal segments have enough information to be used to derive a classifier able to identify the seizure states with reasonable confidence, particularly when used with seizures from the same subject. Achieving average sensitivity values between 0.82 and 0.97, and area under the curve values between 0.5 and 0.9. CONCLUSIONS: The experimental results suggest that seizure states can be revealed by the Gabor atom density; and combining this feature with the epoch's energy produces an improved classifier. These results are comparable with the recently published on state identification. In addition, considering that the order of seizure states is unlikely to change, these results are promising for automatic seizure state classification. PMID- 25499472 TI - Biocompatibility and in vivo osteogenic capability of novel bone tissue engineering scaffold A-W-MGC/CS. AB - BACKGROUND: This study aims to investigate the biocompatibility and in vivo osteogenic capability of the novel bone tissue engineering scaffold apatite wollastonite-magnetic glass ceramic/chitosan (A-W-MGC/CS). METHODS: Rabbit bone marrow stromal cells (BMSCs) were transfected with adenovirus-human bone morphogenetic protein-2-green fluorescent protein (Ad-hBMP2-GFP). The transfected BMSCs were then inoculated onto the scaffold material A-W-MGC/CS to construct tissue-engineered bone. The attachment and proliferation of BMSCs were observed by scanning electron microscopy (SEM) and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) detection, respectively. Rabbit models of bone defects were established and divided into three groups. Experimental group 1 was implanted with prepared tissue-engineered bone. Experimental group 2 was implanted with A-W-MGC/CS without transfected BMSCs. The blank group was injected with transfected BMSCs, without implantation of any scaffold. In the 12th week after surgery, the repair of bone defect was observed by X-ray examination, and histological observations of the area of bone defect were performed. RESULTS: A-W MGC/CS resulted in good BMSC attachment and had no obvious effects on cell proliferation. In experimental group 1, good repair of bone defect was observed, and the scaffold material degraded completely. In experimental group 2, new bone was formed, but its quality was poor. In the blank group, there was mainly filling of fibrous connective tissues with no observable bone defect repair. CONCLUSION: A-W-MGC/CS possesses good biocompatibility and in vivo osteogenic capability for bone defect repair. PMID- 25499473 TI - Development of decellularized aortic valvular conduit coated by heparin-SDF 1alpha multilayer. AB - BACKGROUND: Decellularization can reduce the immune response to aortic valve allograft tissue, but the thrombogenicity and in vivo remolding of these grafts remain controversial. The aim of the present study was to modify the surface of decellularized valvular conduits with heparin-stromal cell-derived factor-1alpha (SDF-1alpha) polyelectrolyte multilayer film and to test the thrombogenicity and biocompatibility in vitro and recellularization in vivo. METHODS: The donor aortic valvular conduits were decellularized with a combination of different detergents and were coated with heparin and SDF-1alpha alternately to form a polyelectrolyte multilayer. Platelet adhesion and lactate dehydrogenase assay were used to evaluate the antiplatelet property. The adhesion, growth, and migration of bone marrow stem cells (BMSCs) to the scaffolds were assessed. For in vivo studies, the grafts were anastomosed to the infrarenal aorta, without or with heparin and SDF-1alpha multilayer. Functional assessment was performed by Doppler echography and micro-computed tomography at 2-week and 4-week time points after implantation. Explanted grafts were examined histologically and by immunohistochemistry. RESULTS: In vitro studies demonstrated that the heparin-SDF 1alpha multilayer film improved hemocompatibility with respect to a substantial reduction of platelet adhesion. BMSCs also achieved better adhesion, proliferation, and migration on the modified graft. For in vivo studies, the grafts in both groups remained patent after 4 weeks, but it was demonstrated that the modified decellularized grafts had better self-endothelialization and recruitment of endothelial progenitor cells. CONCLUSIONS: These results indicate that heparin-SDF-1alpha multilayer film can be used to cover the decellularized aortic valvular graft to decrease platelet adhesion while precipitating regeneration of the decellularized aortic valve allograft in vivo. PMID- 25499471 TI - Safety of noninvasive brain stimulation in children and adolescents. AB - BACKGROUND: Noninvasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) and transcranial current stimulation (tCS) have the potential to mitigate a variety of symptoms associated with neurological and psychiatric conditions, including stroke, cerebral palsy, autism, depression, and Tourette syndrome. While the safety of these modalities has been established in adults, there is a paucity of research assessing the safety of NIBS among children. OBJECTIVE: To examine the existing literature regarding the safety of NIBS techniques in children and adolescents with neurologic and neuropsychiatric disorders. METHODS: An electronic search was performed on online databases for studies using NIBS in individuals less than 18 years of age. Non-English publications, diagnostic studies, electroconvulsive therapy, single/dual pulse TMS studies, and reviews were excluded. Adverse events reported in the studies were carefully examined and synthesized to understand the safety and tolerability of NIBS among children and adolescents. RESULTS: The data from 48 studies involving more than 513 children/adolescents (2.5-17.8 years of age) indicate that the side effects of NIBS were, in general, mild and transient [TMS: headache (11.5%), scalp discomfort (2.5%), twitching (1.2%), mood changes (1.2%), fatigue (0.9%), tinnitus (0.6%); tCS: tingling (11.5%), itching (5.8%), redness (4.7%), scalp discomfort (3.1%)] with relatively few serious adverse events. CONCLUSION: Our findings indicate that both repetitive TMS and tCS are safe modalities in children and adolescents with various neurological conditions, especially when safety guidelines are followed. The incidence of adverse events appears to be similar to that observed in adults; however, further studies with longer treatment and follow-up periods are needed to better understand the benefits and tolerance of long-term use of NIBS in children. PMID- 25499474 TI - Comparison of outcomes after heart replacement therapy in patients over 65 years old. AB - BACKGROUND: There are currently no well-defined, evidence-based guidelines for management of end-stage heart failure in patients over 65, and the decisions to use mechanical circulatory support with left ventricular assist device (LVAD), either as a bridge to transplantation or destination therapy, or isolated heart transplantation (HTx) remain controversial. We aimed to compare the outcomes after the implementation of three heart replacement strategies in this high-risk population. METHODS: We conducted a retrospective cohort study of all patients between the ages of 65 and 72 receiving a continuous-flow LVAD as bridge to transplantation or destination therapy or isolated HTx at our center between 2005 and 2012. The patients were stratified according to treatment strategy into three groups: group D (destination LVAD, n = 23), group B (bridge to transplantation LVAD, n = 43), and group H (HTx alone, n = 47). The primary outcomes of interest were survival to discharge and 2-year overall survival. RESULTS: The patients in group D were significantly older, had a higher prevalence of ischemic cardiomyopathy, and had a higher pulmonary vascular resistance than did patients in groups B or H. There were no significant differences between groups in survival to discharge (87% D vs 83.7% B vs 87.2% H, p = 0.88) or 2-year overall survival (75.7% D vs 68.7% B vs 80.9% H, log-rank p = 0.47). The incidence rates of readmission were 1.1 events/patient.year in group D and 0.5 events/patient.year in group H. CONCLUSIONS: There was no significant difference in perioperative, short-term, and medium-term survival between the treatment groups. However, the LVAD patients had a higher incidence of readmission. Larger trials are needed to refine differences in long-term survival, quality of life, and resource utilization for elderly patients requiring heart replacement therapy. PMID- 25499475 TI - Long-term outcomes after surgical resection of pulmonary metastases from colorectal cancer. AB - BACKGROUND: Surgical resection has been widely performed on patients with pulmonary metastases from colorectal cancer with favorable outcomes. However, there are currently no standard surgical indications for pulmonary metastases. METHODS: We reviewed 94 patients who underwent complete resection of pulmonary metastases from colorectal cancer between November 1991 and April 2013. The cumulative survival rate after pulmonary metastasectomy was calculated, and prognostic factors for long-term survival were analyzed. RESULTS: There were 60 men and 34 women, and their median age was 66 years. The 5-year survival rate was 45.5% after pulmonary metastasectomy. The 5-year survival of patients with colon and rectal cancers was 62.4% and 33.8%, respectively (p = 0.030), and the 5-year survival of those with normal and high carcinoembryonic antigen (CEA) levels before pulmonary resection was 57.0% and 30.9%, respectively (p = 0.038). Multivariate analysis revealed the preoperative CEA level was an independent prognostic factor. Recurrence was identified in 65 of the 94 patients (69.1%) after pulmonary metastasectomy, and the patients who underwent surgical resection for recurrent lesions in the liver or lungs, or both, had better survival than those who received other treatments or palliative care. CONCLUSIONS: Surgical resection offers a chance to prolong survival in colorectal cancer patients with resectable pulmonary metastases. Owing to the high recurrence rate, careful postoperative follow-up for early detection is recommended, and even for recurrence, surgical resection should be considered for better survival if the lesions are limited to the liver or lungs, or both. PMID- 25499476 TI - Leaving a mobilized thoracic esophagus in situ when incurable cancer is discovered intraoperatively. AB - BACKGROUND: Occasionally incurable cancer is encountered after completion of the thoracic (first) phase of a three-phase esophagectomy. The outcome of aborting the operation at this stage, leaving the mobilized thoracic esophagus in situ, is unknown. METHODS: A multicenter retrospective analysis was performed of patients in whom a completely mobilized thoracic esophagus was left in situ when incurable disease was discovered intraoperatively. The occurrence of esophageal necrosis or perforation, mortality, and all other adverse events were recorded and graded by severity. RESULTS: Some 18 patients were included. The median admission time was 9 days. All patients had resumed oral intake at discharge, except for 1 patient who was fed through a nasojejunal tube. After the operation, the median overall survival was 2.9 months. Postoperatively, 7 patients (39%) experienced major surgical adverse events, and 11 patients (61%) had no or only minor adverse events. Major adverse events were associated with the patient's death in 6 patients (33%), within 5 to 34 days postoperatively. Esophageal perforation or ischemia developed in 4 patients (22%) and 1 patient (6%), respectively. No predictive factors could be identified. CONCLUSIONS: Leaving a completely mobilized thoracic esophagus in situ when incurable cancer was discovered intraoperatively was a successful strategy in more than half of the patients. However, one third experienced major adverse events leading to mortality. PMID- 25499477 TI - Improved early survival with a nonsternotomy approach for continuous-flow left ventricular assist device replacement. AB - BACKGROUND: Even in the modern era of continuous-flow left ventricular assist devices (CF LVADs), device replacement may be required. Nonsternotomy (NS) approaches are being used more commonly for replacement procedures. Outcomes after this less invasive approach compared with those after a reoperative sternotomy (RS) have not been extensively studied. Furthermore, the clinical impact of concurrent cardiac procedures during device replacement has not been examined. METHODS: From 2005 to 2013, all consecutive implantable LVAD procedures were reviewed, and those using CF devices as both the initial and replacement device were identified. These CF LVAD replacement procedures were divided into those using an RS and those using an NS approach. Periprocedural morbidity and mortality were compared between the groups. RESULTS: A total of 42 CF LVAD replacements were performed in 39 patients, with 20 using an RS approach and 22 using an NS approach. Eleven of the 20 replacement procedures performed by RS included a concurrent cardiac procedure. Relative to the RS cohort, the NS approach was associated with shorter cardiopulmonary bypass time, reduced length of mechanical ventilation, decreased transfusion requirements, less inotropic support, decreased incidence of right ventricular (RV) dysfunction, and shorter intensive care unit (ICU) and overall hospital stays. An NS approach was also associated with improved 30- and 90-day survival (100% versus 79.0% in the RS group; p = 0.048). RS replacement procedures appeared to be associated with increased morbidity, regardless of whether they included concurrent cardiac procedures. CONCLUSIONS: Patients who did not require an RS approach and who underwent CF LVAD replacement through an NS approach had improved survival and reduced morbidity compared with those who required an RS. PMID- 25499479 TI - Coronary artery surgery versus percutaneous coronary intervention in octogenarians: long-term results. AB - BACKGROUND: The aim of this study was to compare 7-year rates of all-cause death, cardiac death, myocardial infarction, target vessel revascularization, and stroke in a large cohort of octogenarians with left main coronary artery or multivessel disease, treated with coronary artery bypass grafting or percutaneous coronary intervention. METHODS: Two propensity score-matched cohorts of patients undergoing revascularization procedures at regional public and private centers of Emilia-Romagna, Italy, from July 2002 to December 2008 were used to compare long term outcomes of percutaneous coronary intervention (947 patients) and coronary artery bypass grafting (441 patients). RESULTS: There were no significant differences between groups in 30-day mortality. In the follow-up the overall and the matched percutaneous coronary intervention population experienced significantly worse outcomes in terms of cardiac mortality, myocardial infarction, and target vessel revascularization. No difference was found for stroke between treatment groups. Percutaneous coronary intervention was an independent predictor of increased death at long-term follow-up. The subgroups in which coronary artery bypass grafting reduced more clearly the risk of death were age 80 to 85 years, previous myocardial infarction, history of cardiac heart failure, chronic renal failure, peripheral vascular disease, and patients with three-vessel disease associated with the left main coronary artery. CONCLUSIONS: In this real-world setting, surgical coronary revascularization remains the standard of care for patients with left main or multivessel disease. The long term outcomes of current percutaneous coronary intervention technology in octogenarians are yet to be determined with adequately powered prospective randomized studies. PMID- 25499478 TI - Preoperative continuation of aspirin therapy may improve perioperative saphenous venous graft patency after off-pump coronary artery bypass grafting. AB - BACKGROUND: There is limited information about the effect of preoperative continuation of aspirin therapy on perioperative graft patency in patients undergoing off-pump coronary artery bypass (OPCAB). We sought to evaluate the effect of preoperative continuation of aspirin therapy on perioperative graft patency after OPCAB. METHODS: Using retrospectively collected data from 582 consecutive patients undergoing first-time isolated OPCAB by a single surgeon at Fuwai Hospital from October 2009 through September 2012, we evaluated the association between aspirin (100 mg daily) preceding OPCAB and the risk of adverse in-hospital postoperative events. The primary outcomes were in-hospital mortality and graft patency. The secondary outcome measures were hemorrhage related outcomes (reexploration rate, blood transfusions, perioperative drainage loss). RESULTS: There was no death in the postoperative hospitalization period. Patients receiving preoperative continuation of aspirin therapy (n = 400) had significantly higher postoperative saphenous venous graft patency than did those not receiving preoperative aspirin [98.2% vs 96.1%, p = 0.02]. Multivariate analysis indicated that preoperative discontinuation of aspirin therapy significantly increased the risk of occlusion of saphenous venous graft (odds ratio, 2.193; 95% confidence interval, 1.023 to 4.701, p = 0.043). No significant differences between the two groups were observed in perioperative bleeding risks, including chest tube drainage, blood product transfusion, and reoperation for bleeding. CONCLUSIONS: This study indicates that preoperative continuation of aspirin therapy may improve perioperative saphenous vein graft patency after OPCAB without increasing the risk of perioperative bleeding. PMID- 25499480 TI - Defining the role of adjuvant chemotherapy after lobectomy for typical bronchopulmonary carcinoid tumors. AB - BACKGROUND: Treatment guidelines for typical bronchopulmonary carcinoid tumors recommend observation alone after resection of stage I-IIIA disease, but there are limited data related to the use of adjuvant chemotherapy in the setting of nodal metastases found at operation. METHODS: Patients in the National Cancer Data Base (NDCB) who underwent lobectomy for typical carcinoid and had metastatic nodal disease were stratified by the use of adjuvant chemotherapy. Baseline characteristics and outcomes were compared between groups. Next, patients were propensity matched using a 3:1 nearest-neighbor algorithm, and adjusted outcomes were compared. Finally, long-term survival was evaluated using the Kaplan-Meier method with comparisons based on the log-rank test. RESULTS: Overall, 4,612 patients were identified, among whom 629 (13.6%) had positive lymph nodes at the time of operation. Of them, adjuvant chemotherapy was used in 37 patients (5.9%). There were no baseline differences between patients who did and those who did not receive adjuvant chemotherapy. Patients treated with chemotherapy demonstrated a survival disadvantage at 5 years (69.7% versus 81.9%; p = 0.042). After propensity matching, all baseline characteristics between groups were highly similar. There remained a trend toward inferior 5-year survival for patients who received adjuvant chemotherapy, although the difference no longer met statistical significance (69.7% versus 80.9%; p = 0.096). CONCLUSIONS: Adjuvant chemotherapy is not associated with improved survival among patients who undergo lobectomy for typical carcinoids and nodal metastases. These data support current treatment guidelines. PMID- 25499481 TI - VATS lobectomy has better perioperative outcomes than open lobectomy: CALGB 31001, an ancillary analysis of CALGB 140202 (Alliance). AB - BACKGROUND: The short-term superiority of video-assisted thoracoscopic surgery lobectomy compared with open lobectomy for early-stage lung cancer has been suggested by single-institution studies. Lack of equipoise limits the feasibility of a randomized study to confirm this. The hypothesis of this study (CALGB 31001) was that VATS lobectomy results in shorter length of hospital stay and fewer complications compared with open lobectomy in stages I and II non-small cell lung cancer in a multi-institutional setting. METHODS: Five hundred nineteen patients whose tumors had been collected as part of CALGB 140202 (lung cancer tissue bank) were eligible. Propensity-scoring using age, race, sex, performance status, comorbidities, histology, tumor stage, and size as independent variables was used to create a 1:1 matched group of 175 pairs of patients. McNemar's test for binary variables and Wilcoxon signed-rank test for continuous variables were used to assess differences in length of hospital stay, complications, and discharge dispositions between the groups. Comparison of disease-free and overall survival between the two approaches was done using the log-rank test. Probability values of less than 0.05 were considered significant. RESULTS: The matched data on length of hospital stay, complications, and discharge dispositions significantly favored the video-assisted thoracoscopic surgery group. There was no statistically significant difference in survival between the two approaches. CONCLUSIONS: This multi-institutional study supports the assertion that thoracoscopic lobectomy results in shorter hospital length of stay, fewer perioperative complications, and greater likelihood of independent home discharge compared with open lobectomy for early-stage lung cancer. Survival was comparable between the two groups. PMID- 25499482 TI - Intraaortic counterpulsation during cardiopulmonary bypass impairs distal organ perfusion. AB - BACKGROUND: Recent studies have focused on the use of fixed-rate intraaortic balloon pumping (IABP) during cardiopulmonary bypass (CPB) to achieve pulsatile flow. Because application of an IABP catheter may represent a functional obstruction within the descending aorta, we explored the effect of IABP-pulsed CPB-perfusion with special attention to perfusion above and below the IABP balloon. METHODS: Sixteen animals received an IABP catheter that remained turned off position (NP group, n = 8) or was switched to an automatic mode of 80 beats/min during CPB (PP group, n = 8). Flow-data and pressure-data were obtained above and below the IABP balloon. Tissue perfusion was evaluated by microspheres. RESULTS: IABP-pulsed CPB-perfusion, as assessed at 30 minutes on CPB, increased proximal mean aortic pressure (p < 0.05) and carotid artery blood flow (p < 0.001), but decreased distal mean aortic pressure (p < 0.001). The decrease of distal mean aortic pressure in the PP group was associated with a 75 % decrease (p < 0.001) of renal tissue perfusion. During nonpulsed perfusion the respective variables remained essentially unchanged compared with pre-CPB levels. CONCLUSIONS: Using IABP as a surrogate to achieve pulsatile perfusion during CPB contributes significantly to lowered aortic pressure in the distal portion of aorta and impaired tissue perfusion of the kidneys. The results are focusing on effects that may contribute to organ dysfunction and acute kidney injury. Consequently, assessment of perfusion pressure distal to the balloon should be addressed whenever IABP is used during CPB. PMID- 25499483 TI - Blood conservation in extracorporeal membrane oxygenation for acute respiratory distress syndrome. AB - BACKGROUND: Extracorporeal membrane oxygenation support (ECMO) typically requires multiple blood transfusions and is associated with frequent bleeding complications. Blood transfusions are known to increase morbidity and mortality in critically ill patients, which may extend to patients receiving ECMO. Aiming to reduce transfusion requirements, we implemented a blood conservation protocol in adults with severe acute respiratory distress syndrome (ARDS) receiving ECMO. METHODS: This was a retrospective study of adults receiving ECMO for ARDS after initiation of a blood conservation protocol that included a transfusion trigger of hemoglobin of less than 7.0 g/dL, use of low-dose anticoagulation targeting an activated partial thromboplastin time of 40 to 60 seconds, and autotransfusion of circuit blood during decannulation. The primary objective was to evaluate transfusion requirements during ECMO support. Clinical outcomes included survival, neurologic function, renal function, bleeding, and thrombotic complications. RESULTS: The analysis included 38 patients; of these, 24 (63.2%) received a transfusion while receiving ECMO. Median hemoglobin was 8.29 g/dL. A median of 1.0 units (range, 250 to 300 mL) was transfused during ECMO support over a median duration of 9.0 days, equivalent to 0.11 U/d (range, 27.5 to 33.3 mL/d). The median activated partial thromboplastin time was 46.5 seconds. Bleeding occurred in 10 patients (26.3%); severe bleeding occurred in 2 patients (5.3%). Twenty-eight patients (73.7%) survived to hospital discharge. CONCLUSIONS: Implementation of a blood conservation protocol in adults receiving ECMO for ARDS resulted in lower transfusion requirements and bleeding complications than previously reported in the literature and was associated with comparable survival and organ recovery. PMID- 25499484 TI - Effects of seasonal climatic variability on several toxic contaminants in urban lakes: Implications for the impacts of climate change. AB - Climate change is supposed to have influences on water quality and ecosystem. However, only few studies have assessed the effect of climate change on environmental toxic contaminants in urban lakes. In this research, response of several toxic contaminants in twelve urban lakes in Beijing, China, to the seasonal variations in climatic factors was studied. Fluorides, volatile phenols, arsenic, selenium, and other water quality parameters were analyzed monthly from 2009 to 2012. Multivariate statistical methods including principle component analysis, cluster analysis, and multiple regression analysis were performed to study the relationship between contaminants and climatic factors including temperature, precipitation, wind speed, and sunshine duration. Fluoride and arsenic concentrations in most urban lakes exhibited a significant positive correlation with temperature/precipitation, which is mainly caused by rainfall induced diffuse pollution. A negative correlation was observed between volatile phenols and temperature/precipitation, and this could be explained by their enhanced volatilization and biodegradation rates caused by higher temperature. Selenium did not show a significant response to climatic factor variations, which was attributed to low selenium contents in the lakes and soils. Moreover, the response degrees of contaminants to climatic variations differ among lakes with different contamination levels. On average, temperature/precipitation contributed to 8%, 15%, and 12% of the variations in volatile phenols, arsenic, and fluorides, respectively. Beijing is undergoing increased temperature and heavy rainfall frequency during the past five decades. This study suggests that water quality related to fluoride and arsenic concentrations of most urban lakes in Beijing is becoming worse under this climate change trend. PMID- 25499485 TI - Preparation of cross-linked magnetic chitosan with quaternary ammonium and its application for Cr(VI) and P(V) removal. AB - Pollutants that exist in anionic species are issues of concern in water treatment. Compared to cationic pollutants, the removal of anionic pollutants by adsorption is more difficult because most adsorbents carry predominantly negative charges in neutral and alkaline environments. In this study, a cross-linked chitosan derivative with quaternary ammonium and magnetic properties (QM chitosan) was prepared and employed to remove chromium (VI) and phosphorus (V) (Cr(VI) and P(V)) from aqueous environments. The QM-chitosan was characterized by Fourier transform infrared spectrometry (FT-IR), thermogravimetric analysis (TGA), energy dispersive X-ray (SEM-EDX) and zeta potential. Batch experiments show that QM-chitosan can effectively remove Cr(VI) and P(V), and the main mechanism was believed to be electrostatic interaction. A pseudo second-order model was fitted to describe the kinetic processes of Cr(VI) and P(V) removal. The adsorption isotherms of both Cr(VI) and P(V) on the QM-chitosan were well fitted by the Langmuir isotherm equation. The saturated adsorption capacity of P(V) (2.783 mmol/g) was found to be higher than that of Cr(VI) (2.323 mmol/g), resulting from the size of the H(2)PO(4)(-) ions being smaller than that of the HCrO(4)(-) ions. However, the theoretical calculation and experimental results showed that QM-chitosan had a stronger affinity for Cr(VI) than P(V). The adsorption-desorption of the QM-chitosan was evaluated, and high regeneration rates were demonstrated. PMID- 25499486 TI - Formation pathways of brominated products from benzophenone-4 chlorination in the presence of bromide ions. AB - The brominated products, formed in chlorination treatment of benzophenone-4 in the presence of bromide ions, were identified, and the formation pathways were proposed. Under disinfection conditions, benzophenone-4 would undertake electrophilic substitution generating mono- or di-halogenated products, which would be oxidized to esters and further hydrolyzed to phenol derivatives. The generated catechol intermediate would be transformed into furan-like heterocyclic product. The product species were pH-dependent, while benzophenone-4 elimination was chlorine dose-dependent. When the chlorination treatment was performed on ambient water spiked with benzophenone-4 and bromide ions, most of brominated byproducts could be detected, and the acute toxicity significantly increased as well. PMID- 25499487 TI - Influence of the inherent properties of drinking water treatment residuals on their phosphorus adsorption capacities. AB - Batch experiments were conducted to investigate the phosphorus (P) adsorption and desorption on five drinking water treatment residuals (WTRs) collected from different regions in China. The physical and chemical characteristics of the five WTRs were determined. Combined with rotated principal component analysis, multiple regression analysis was used to analyze the relationship between the inherent properties of the WTRs and their P adsorption capacities. The results showed that the maximum P adsorption capacities of the five WTRs calculated using the Langmuir isotherm ranged from 4.17 to 8.20mg/g at a pH of 7 and further increased with a decrease in pH. The statistical analysis revealed that a factor related to Al and 200 mmol/L oxalate-extractable Al (Alox) accounted for 36.5% of the variations in the P adsorption. A similar portion (28.5%) was attributed to an integrated factor related to the pH, Fe, 200 mmol/L oxalate-extractable Fe (Feox), surface area and organic matter (OM) of the WTRs. However, factors related to other properties (Ca, P and 5 mmol/L oxalate-extractable Fe and Al) were rejected. In addition, the quantity of P desorption was limited and had a significant negative correlation with the (Feox+Alox) of the WTRs (p<0.05). Overall, WTRs with high contents of Alox, Feox and OM as well as large surface areas were proposed to be the best choice for P adsorption in practical applications. PMID- 25499488 TI - Radiation induced decomposition of a refractory cefathiamidine intermediate. AB - Diisopropylthiourea (DPT), an intermediate of a widely used cephalosporin, has been found to be one of the most refractory components in cephalosporin synthesis wastewater. This compound cannot be completely removed by conventional biological processes due to its antimicrobial property. Ionizing radiation has been applied in the decomposition of refractory pollutants in recent years and has proved effective. Therefore, the decomposition of DPT by gamma-irradiation was studied. The compound was irradiated at the dose of 150-2000 Gy before a change of concentration and UV absorption of the solutions was detected. Furthermore, the decomposition kinetics and radiation yield (G-value) of DPT was investigated. The results of radiation experiments on DPT-containing aqueous showed that the DPT can be effectively degraded by gamma-radiation. DPT concentration decreased with increasing absorbed doses. G-values of radiolytic decomposition for DPT (20 mg/L) were 1.04 and 0.47 for absorbed doses of 150 and 2000 Gy, respectively. The initial concentration and pH of the solutions affected the degradation. As the concentration of substrate increased, the decomposition was reduced. The decrease of removal rate and radiation efficacy under alkaline condition suggested that lower pH values benefit the gamma-induced degradation. UV absorption from 190 to 250 nm decreased after radiation while that from 250 to 300 nm increased, indicating the formation of by-products. PMID- 25499489 TI - Characterization of aerosol optical properties, chemical composition and mixing states in the winter season in Shanghai, China. AB - Physical and chemical properties of ambient aerosols at the single particle level were studied in Shanghai from December 22 to 28, 2009. A Cavity-Ring-Down Aerosol Extinction Spectrometer (CRD-AES) and a nephelometer were deployed to measure aerosol light extinction and scattering properties, respectively. An Aerosol Time of-Flight Mass Spectrometer (ATOFMS) was used to detect single particle sizes and chemical composition. Seven particle types were detected. Air parcels arrived at the sampling site from the vicinity of Shanghai until mid-day of December 25, when they started to originate from North China. The aerosol extinction, scattering, and absorption coefficients all dropped sharply when this cold, clean air arrived. Aerosol particles changed from a highly aged type before this meteorological shift to a relatively fresh type afterwards. The aerosol optical properties were dependent on the wind direction. Aerosols with high extinction coefficient and scattering Angstrom exponent (SAE) were observed when the wind blew from the west and northwest, indicating that they were predominantly fine particles. Nitrate and ammonium correlated most strongly with the change in aerosol optical properties. In the elemental carbon/organic carbon (ECOC) particle type, the diurnal trends of single scattering albedo (SSA) and elemental carbon (EC) signal intensity had a negative correlation. We also found a negative correlation (r=-0.87) between high mass-OC particle number fraction and the SSA in a relatively clean period, suggesting that particulate aromatic components might play an important role in light absorption in urban areas. PMID- 25499490 TI - Knudsen cell and smog chamber study of the heterogeneous uptake of sulfur dioxide on Chinese mineral dust. AB - The heterogeneous uptake processes of sulfur dioxide on two types of Chinese mineral dust (Inner Mongolia desert dust and Xinjiang sierozem) were investigated using both Knudsen cell and smog chamber system. The temperature dependence of the uptake coefficients was studied over a range from 253 to 313 K using the Knudsen cell reactor, the initial uptake coefficients decreased with the increasing of temperature for these two mineral dust samples, whereas the steady state uptake coefficients of the Xinjiang sierozem increased with the temperature increasing, and these temperature dependence functions were obtained for the first time. In the smog chamber experiments at room temperature, the steady state uptake coefficients of SO2 decreased evidently with the increasing of sulfur dioxide initial concentration from 1.72 * 1012 to 6.15 * 1012 mol/cm3. Humid air had effect on the steady state uptake coefficients of SO2onto Inner Mongolia desert dust. Consequences about the understanding of the uptake processes onto mineral dust samples and the environmental implication were also discussed. PMID- 25499491 TI - Experimental study on filtration and continuous regeneration of a particulate filter system for heavy-duty diesel engines. AB - This study investigated the filtration and continuous regeneration of a particulate filter system on an engine test bench, consisting of a diesel oxidation catalyst (DOC) and a catalyzed diesel particulate filter (CDPF). Both the DOC and the CDPF led to a high conversion of NO to NO2 for continuous regeneration. The filtration efficiency on solid particle number (SPN) was close to 100%. The post-CDPF particles were mainly in accumulation mode. The downstream SPN was sensitively influenced by the variation of the soot loading. This phenomenon provides a method for determining the balance point temperature by measuring the trend of SPN concentration. PMID- 25499492 TI - Combination of heterogeneous Fenton-like reaction and photocatalysis using Co TiO2nanocatalyst for activation of KHSO5 with visible light irradiation at ambient conditions. AB - A novel coupled system using Co-TiO2was successfully designed which combined two different heterogeneous advanced oxidation processes, sulfate radical based Fenton-like reaction (SR-Fenton) and visible light photocatalysis (Vis-Photo), for degradation of organic contaminants. The synergistic effect of SR-Fenton and Vis-Photo was observed through comparative tests of 50mg/L Rhodamine B (RhB) degradation and TOC removal. The Rhodamine B degradation rate and TOC removal were 100% and 68.1% using the SR-Fenton/Vis-Photo combined process under ambient conditions, respectively. Moreover, based on XRD, XPS and UV-DRS characterization, it can be deduced that tricobalt tetroxide located on the surface of the catalyst is the SR-Fenton active site, and cobalt ion implanted in the TiO2lattice is the reason for the visible light photocatalytic activity of Co TiO2. Finally, the effects of the calcination temperature and cobalt concentration on the synergistic performance were also investigated and a possible mechanism for the synergistic system was proposed. This coupled system exhibited excellent catalytic stability and reusability, and almost no dissolution of Co2+ was found. PMID- 25499493 TI - Atmospheric sulfur hexafluoride in-situ measurements at the Shangdianzi regional background station in China. AB - We present in-situ measurements of atmospheric sulfur hexafluoride (SF6) conducted by an automated gas chromatograph-electron capture detector system and a gas chromatography/mass spectrometry system at a regional background site, Shangdianzi, in China, from June 2009 to May 2011, using the System for Observation of Greenhouse gases in Europe and Asia and Advanced Global Atmospheric Gases Experiment (AGAGE) techniques. The mean background and polluted mixing ratios for SF6 during the study period were 7.22 * 10-12 (mol/mol, hereinafter) and 8.66 * 10-12, respectively. The averaged SF6 background mixing ratios at Shangdianzi were consistent with those obtained at other AGAGE stations located at similar latitudes (Trinidad Head and Mace Head), but larger than AGAGE stations in the Southern Hemisphere (Cape Grim and Cape Matatula). SF6 background mixing ratios increased rapidly during our study period, with a positive growth rate at 0.30 * 10-12 year-1. The peak to peak amplitude of the seasonal cycle for SF6 background conditions was 0.07 * 10-12, while the seasonal fluctuation of polluted conditions was 2.16 * 10-12. During the study period, peak values of SF6 mixing ratios occurred in autumn when local surface horizontal winds originated from W/WSW/SW/SWS/S sectors, while lower levels of SF6 mixing ratios appeared as winds originated from N/NNE/NE/ENE/E sectors. PMID- 25499494 TI - Direct radiative forcing of urban aerosols over Pretoria (25.75 degrees S, 28.28 degrees E) using AERONET Sunphotometer data: first scientific results and environmental impact. AB - The present study uses the data collected from Cimel Sunphotometer of Aerosol Robotic Network (AERONET) for the period from January to December, 2012 over an urban site, Pretoria (PTR; 25.75 degrees S, 28.28 degrees E, 1449 m above sea level), South Africa. We found that monthly mean aerosol optical depth (AOD, tau(a)) exhibits two maxima that occurred in summer (February) and winter (August) having values of 0.36 +/- 0.19 and 0.25 +/- 0.14, respectively, high-to moderate values in spring and thereafter, decreases from autumn with a minima in early winter (June) 0.12 +/- 0.07. The Angstrom exponents (alpha440-870) likewise, have its peak in summer (January) 1.70 +/- 0.21 and lowest in early winter (June) 1.38 +/- 0.26, while the columnar water vapor (CWV) followed AOD pattern with high values (summer) at the beginning of the year (February, 2.10 +/ 0.37 cm) and low values (winter) in the middle of the year (July, 0.66 +/- 0.21 cm). The volume size distribution (VSD) in the fine-mode is higher in the summer and spring seasons, whereas in the coarse mode the VSD is higher in the winter and lower in the summer due to the hygroscopic growth of aerosol particles. The single scattering albedo (SSA) ranged from 0.85 to 0.96 at 440 nm over PTR for the entire study period. The averaged aerosol radiative forcing (ARF) computed using SBDART model at the top of the atmosphere (TOA) was -8.78 +/- 3.1 W/m2, while at the surface it was -25.69 +/- 8.1 W/m2 leading to an atmospheric forcing of +16.91 +/- 6.8 W/m2, indicating significant heating of the atmosphere with a mean of 0.47K/day. PMID- 25499495 TI - Chemical characteristics and source apportionment of atmospheric particles during heating period in Harbin, China. AB - Atmospheric particles (total suspended particles (TSPs); particulate matter (PM) with particle size below 10 MUm, PM10; particulate matter with particle size below 2.5 MUm, PM(2.5)) were collected and analyzed during heating and non heating periods in Harbin. The sources of PM10 and PM(2.5) were identified by the chemical mass balance (CMB) receptor model. Results indicated that PM(2.5)/TSP was the most prevalent and PM(2.5) was the main component of PM(10), while the presence of PM(10-100) was relatively weak. SO(4)(2-) and NO(3)(-) concentrations were more significant than other ions during the heating period. As compared with the non-heating period, Mn, Ni, Pb, S, Si, Ti, Zn, As, Ba, Cd, Cr, Fe and K were relatively higher during the heating period. In particular, Mn, Ni, S, Si, Ti, Zn and As in PM(2.5) were obviously higher during the heating period. Organic carbon (OC) in the heating period was 2-5 times higher than in the non-heating period. Elemental carbon (EC) did not change much. OC/EC ratios were 8-11 during the heating period, which was much higher than in other Chinese cities (OC/EC: 4-6). Results from the CMB indicated that 11 pollution sources were identified, of which traffic, coal combustion, secondary sulfate, secondary nitrate, and secondary organic carbon made the greatest contribution. Before the heating period, dust and petrochemical industry made a larger contribution. In the heating period, coal combustion and secondary sulfate were higher. After the heating period, dust and petrochemical industry were higher. Some hazardous components in PM(2.5) were higher than in PM(10), because PM(2.5) has a higher ability to absorb toxic substances. Thus PM(2.5) pollution is more significant regarding human health effects in the heating period. PMID- 25499496 TI - Microbial community structures in an integrated two-phase anaerobic bioreactor fed by fruit vegetable wastes and wheat straw. AB - The microbial community structures in an integrated two-phase anaerobic reactor (ITPAR) were investigated by 16S rDNA clone library technology. The 75L reactor was designed with a 25L rotating acidogenic unit at the top and a 50L conventional upflow methanogenic unit at the bottom, with a recirculation connected to the two units. The reactor had been operated for 21 stages to co digest fruit/vegetable wastes and wheat straw, which showed a very good biogas production and decomposition of cellulosic materials. The results showed that many kinds of cellulose and glycan decomposition bacteria related with Bacteroidales, Clostridiales and Syntrophobacterales were dominated in the reactor, with more bacteria community diversities in the acidogenic unit. The methanogens were mostly related with Methanosaeta, Methanosarcina, Methanoculleus, Methanospirillum and Methanobacterium; the predominating genus Methanosaeta, accounting for 40.5%, 54.2%, 73.6% and 78.7% in four samples from top to bottom, indicated a major methanogenesis pathway by acetoclastic methanogenesis in the methanogenic unit. The beta diversity indexes illustrated a more similar distribution of bacterial communities than that of methanogens between acidogenic unit and methanogenic unit. The differentiation of methanogenic community composition in two phases, as well as pH values and volatile fatty acid (VFA) concentrations confirmed the phase separation of the ITPAR. Overall, the results of this study demonstrated that the special designing of ITPAR maintained a sufficient number of methanogens, more diverse communities and stronger syntrophic associations among microorganisms, which made two phase anaerobic digestion of cellulosic materials more efficient. PMID- 25499497 TI - Persistent pollutants and the patchiness of urban green areas as drivers of genetic richness in the epiphytic moss Leptodon smithii. AB - We determined genetic variation and metal and polycyclic aromatic hydrocarbon concentrations in Leptodon smithii moss collected in holm oak stands at cities, outskirts and remote areas of Campania and Tuscany (Italy) to investigate if anthropogenic pressure (pollutant emissions and land use change) affects moss genetic richness. In both regions, metal and polycyclic aromatic hydrocarbon concentrations reflected the trend urban>outskirts>remote areas, excepting Tuscany remote site. In both regions, the moss gene diversity increased from urban to remote areas. The findings suggest the extent and the fragmentation of urban green areas, as drivers of moss genetic richness. PMID- 25499498 TI - Enhanced removal of ethylbenzene from gas streams in biotrickling filters by Tween-20 and Zn(II). AB - The effects of Tween-20 and Zn(II) on ethylbenzene removal were evaluated using two biotrickling filters (BTFs), BTF1 and BTF2. Only BTF1 was fed with Tween-20 and Zn(II). Results show that ethylbenzene removal decreased from 94% to 69% for BTF1 and from 74% to 54% for BTF2 with increased organic loading from 64.8 to 189.0 g ethylbenzene/(m3.hr) at EBRT of 40 sec. The effect of EBRT (60-15 sec) at a constant ethylbenzene inlet concentration was more significant than that of EBRT (30-10 sec) at a constant organic loading. Biomass accumulation rate within packing media was reduced significantly. PMID- 25499499 TI - Enhanced efficiency of cadmium removal by Boehmeria nivea (L.) Gaud. in the presence of exogenous citric and oxalic acids. AB - Boehmeria nivea (L.) Gaud. is a potential candidate for the remediation of Cd contaminated sites. The present investigation aims to explore Cd tolerance threshold and to quickly identify the role of exogenous organic acids in Cd uptake and abiotic metal stress damage. Elevated Cd levels (0-10mg/L) resulted in an obvious rise in Cd accumulation, ranging from 268.0 to 374.4 in root and 25.2 to 41.2mg/kg dry weight in shoot, respectively. Citric acid at 1.5 mmol/L significantly facilitated Cd uptake by 26.7% in root and by 1-fold in shoot, respectively. Cd translocation efficiency from root to shoot was improved by a maximum of 66.4% under 3 mmol/L of oxalic acid. Citric acid exhibited more prominent mitigating effect than oxalic acid due to its stronger ligand affinity for chelating with metal and avoiding the toxicity injury of free Cd ions more efficiently. The present work provides a potential strategy for efficient Cd remediation with B. nivea. PMID- 25499500 TI - Comparative sorption and desorption behaviors of PFHxS and PFOS on sequentially extracted humic substances. AB - The sorption and desorption behaviors of two perfluoroalkane sulfonates (PFSAs), including perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) on two humic acids (HAs) and humin (HM), which were extracted from a peat soil, were investigated. The sorption kinetics and isotherms showed that the sorption of PFOS on the humic substances (HSs) was much higher than PFHxS. For the same PFSA compound, the sorption on HSs followed the order of HM>HA2>HA1. These suggest that hydrophobic interaction plays a key role in the sorption of PFSAs on HSs. The sorption capacities of PFSAs on HSs were significantly related to their aliphaticity, but negatively correlated to aromatic carbons, indicating the importance of aliphatic groups in the sorption of PFSAs. Compared to PFOS, PFHxS displayed distinct desorption hysteresis, probably due to irreversible pore deformation after sorption of PFHxS. The sorption of the two PFSAs on HSs decreased with an increase in pH in the solution. This is ascribed to the electrostatic interaction and hydrogen bonding at lower pH. Hydrophobic interaction might also be stronger at lower pH due to the aggregation of HSs. PMID- 25499501 TI - Inhibitory effects of nisin-coated multi-walled carbon nanotube sheet on biofilm formation from Bacillus anthracis spores. AB - Multi-walled carbon nanotube (MWCNT) sheet was fabricated from a drawable MWCNT forest and then deposited on poly(methyl methacrylate) film. The film was further coated with a natural antimicrobial peptide nisin. We studied the effects of nisin coating on the attachment of Bacillus anthracis spores, the germination of attached spores, and the subsequent biofilm formation from attached spores. It was found that the strong adsorptivity and the super hydrophobicity of MWCNTs provided an ideal platform for nisin coating. Nisin coating on MWCNT sheets decreased surface hydrophobicity, reduced spore attachment, and reduced the germination of attached spores by 3.5 fold, and further inhibited the subsequent biofilm formation by 94.6% compared to that on uncoated MWCNT sheet. Nisin also changed the morphology of vegetative cells in the formed biofilm. The results of this study demonstrated that the anti-adhesion and antimicrobial effect of nisin in combination with the physical properties of carbon nanotubes had the potential in producing effective anti-biofilm formation surfaces. PMID- 25499502 TI - A comparative study and evaluation of sulfamethoxazole adsorption onto organo montmorillonites. AB - Three organo-montmorillonites were prepared using surfactants, and their adsorption behaviors toward sulfamethoxazole (SMX) were investigated. The surfactants used were cetyltrimethyl ammonium bromide (CTMAB), 3-(N,N dimethylhexadecylammonio) propane sulfonate (HDAPS) and 1,3 bis(hexadecyldimethylammonio)-propane dibromide (BHDAP). The properties of the organo-montmorillonites were characterized by X-ray diffraction, scanning electron microscopy and N2 adsorption-desorption isotherm measurements. Results showed that the interlayer spacing of montmorillonite was increased and the surface area as well as the morphology were changed. Batch adsorption experiments showed that the surfactant loading amount had a great effect on the adsorption of SMX. The adsorption process was pH dependent and the maximum adsorption capacity was obtained at pH3 for HDAPS-Mt, while CTMAB-Mt and BHDAP-Mt showed a high removal efficiency at 3-11. The adsorption capacity increased with the initial SMX concentration and contact time but decreased with increasing solution ionic strength. Kinetic data were best described by the pseudo second-order model. Equilibrium data were best represented by the Langmuir model, and the Freundlich constant (n) indicated a favorable adsorption process. The maximum adsorption capacity of SMX was 235.29 mg/g for CTMAB-Mt, 155.28 mg/g for HDAPS-Mt and 242.72 mg/g for BHDAP-Mt. Thermodynamic parameters were calculated to evaluate the spontaneity and endothermic or exothermic nature. The adsorption mechanism was found to be dominated by electrostatic interaction, while hydrophobic interaction played a secondary role. PMID- 25499503 TI - Removal of formaldehyde over Mn(x)Ce(1)-(x)O(2) catalysts: thermal catalytic oxidation versus ozone catalytic oxidation. AB - Mn(x)Ce(1)-(x)O(2) (x: 0.3-0.9) prepared by Pechini method was used as a catalyst for the thermal catalytic oxidation of formaldehyde (HCHO). At x=0.3 and 0.5, most of the manganese was incorporated in the fluorite structure of CeO(2) to form a solid solution. The catalytic activity was best at x=0.5, at which the temperature of 100% removal rate is the lowest (270 degrees C). The temperature for 100% removal of HCHO oxidation is reduced by approximately 40 degrees C by loading 5wt.% CuO(x) into Mn(0.5)Ce(0.5)O(2). With ozone catalytic oxidation, HCHO (61 ppm) in gas stream was completely oxidized by adding 506 ppm O3over Mn(0.5)Ce(0.5)O(2) catalyst with a GHSV (gas hourly space velocity) of 10,000 hr 1 at 25 degrees C. The effect of the molar ratio of O(3) to HCHO was also investigated. As O(3)/HCHO ratio was increased from 3 to 8, the removal efficiency of HCHO was increased from 83.3% to 100%. With O(3)/HCHO ratio of 8, the mineralization efficiency of HCHO to CO(2) was 86.1%. At 25 degrees C, the p type oxide semiconductor (Mn(0.5)Ce(0.5)O(2)) exhibited an excellent ozone decomposition efficiency of 99.2%, which significantly exceeded that of n-type oxide semiconductors such as TiO(2), which had a low ozone decomposition efficiency (9.81%). At a GHSV of 10,000 hr-1, [O(3)]/[HCHO]=3 and temperature of 25 degrees C, a high HCHO removal efficiency (>= 81.2%) was maintained throughout the durability test of 80 hr, indicating the long-term stability of the catalyst for HCHO removal. PMID- 25499504 TI - Humic acid transport in saturated porous media: influence of flow velocity and influent concentration. AB - Understanding the transport of humic acids (HAs) in porous media can provide important and practical evidence needed for accurate prediction of organic/inorganic contaminant transport in different environmental media and interfaces. A series of column transport experiments was conducted to evaluate the transport of HA in different porous media at different flow velocities and influent HA concentrations. Low flow velocity and influent concentration were found to favor the adsorption and deposition of HA onto sand grains packed into columns and to give higher equilibrium distribution coefficients and deposition rate coefficients, which resulted in an increased fraction of HA being retained in columns. Consequently, retardation factors were increased and the transport of HA through the columns was delayed. These results suggest that the transport of HA in porous media is primarily controlled by the attachment of HA to the solid matrix. Accordingly, this attachment should be considered in studies of HA behavior in porous media. PMID- 25499505 TI - Salinity influence on soil microbial respiration rate of wetland in the Yangtze River estuary through changing microbial community. AB - Estuarine wetland, where freshwater mixes with salt water, comprises different regions (rivers and marine ecosystems) with significantly varying tidal salinities. Two sampling areas, ZXS and JS, were selected to investigate the effect of tidal salinity on soil respiration (SR). ZXS and JS were located in Zhongxia Shoal and Jiangyanan Shoal of Jiuduansha Wetland respectively, with similar elevation and plant species, but significantly different in salinity. The results showed that with almost identical plant biomass, the SR and soil microbial respiration (SMR) of the tidal wetland with lower salinity (JS) were significantly higher than those of the tidal wetland with higher salinity (ZXS) (p<0.05). However, unlike SMR and SR, the difference in the soil microbial biomass (SMB) was not significant (p>0.05) with the SMB of ZXS a little higher than that of JS. The higher SMR and SR of JS may be closely connected to the soil microbial community structures and amount of dominant bacteria. Abundant beta- and gamma-Proteobacteria and Actinobacteria in JS soil, which have strong heterotrophic metabolic capabilities, could be the main reason for higher SMR and SR, whereas a high number of epsilon-Proteobacteria in ZXS, some of which have carbon fixation ability, could be responsible for relatively lower carbon output. Path analysis indicated that soil salinity had the maximum negative total influencing coefficient with SMR among the various soil physical and chemical factors, suggesting that higher soil salinity, restricting highly heterotrophic bacteria, is the principle reason for lower SMR and SR in the ZXS. PMID- 25499506 TI - Comments on "Adsorption of 2-mercaptobenzothiazole from aqueous solution by organo-bentonite" by P. Jing, M.H. Hou, P. Zhao, X.Y. Tang, H.F. Wan. PMID- 25499507 TI - Reply to comments on "Adsorption of 2-mercaptobenzothiazole from aqueous solution by organo-bentonite" by Yuhshan Ho. PMID- 25499508 TI - A polymorphic marker associated with non-syndromic cleft lip with or without cleft palate in a population in Heilongjiang Province, northern China. AB - OBJECTIVE: To further assess the roles of the ABCA4 (ATP-binding cassette, sub family A, member 4) gene in NSCL/P, we investigated two tag SNPs in ABCA4 (rs481931 and rs560426) in a northern Chinese Han population where the prevalence of NSCL/P is high. MATERIALS AND METHODS: The two SNPs were examined for association with NSCL/P in 344 patients and 324 healthy controls. Peripheral blood samples were acquired at study enrollment, and DNA samples were extracted. SNPs were genotyped using a mini-sequencing (SNAPSHOT) method. RESULTS: We observed a significant correlation between the ABCA4 SNP rs560426 and NSCL/P (p=0.0041) but no evidence of association between rs481931 and NSCL/P. The G/G genotype at the rs560426 SNP in ABCA4 gene had an odd ratios of 2.39 (95%CI: 1.38 4.14, p=0.0041) compared with the A/A genotype, and a similar significance was noted in the CL/P subgroup (ORA/G=1.60, 95%CI: 1.09-2.34, ORG/G=2.96, 95%CI: 1.63 5.37 and ORG/G+A/G=1.80, 95%CI: 1.25-2.60, p=0.0007). CONCLUSIONS: Our study provides further evidence regarding the roles of genetic markers in ABCA4 in NSCL/P development in this northern Chinese Han population. G allele of rs560426 may be a risk factor for developing NSCL/P. PMID- 25499509 TI - Diverticular Disease and Vascular Diseases: A Shared Responsiveness to Injury Is Likely to Be the Underlying Mechanism. PMID- 25499510 TI - Arg-265: a critical residue of L.donovani cytosolic SHMT in maintaining the binding of THF and catalysis. AB - Serine hydroxymethyltransferase belongs to the class of pyridoxal-5-phosphate enzymes along with aspartate aminotransferase. To explore the function of residue(s) involved in binding of the carboxylate group of Tetrahydrofolic acid (THF) to L. donovani cytosolic serine hydroxymethyltransferase (LdcSHMT), the gene was cloned in pET-28(a) vector, overexpressed and purified to homogeneity. With the help of docking results of THF to the active site of protein, the key residues involved in interaction were identified. In an attempt to unravel the function of Arg265 residue involved in binding of the carboxylate group of THF, Arg-265 was mutated to Ala by site-directed mutagenesis. The Arg265Ala-LdcSHMT showed increased Km value (threefold) and decreased kcat/Km value (threefold) for H4-folate as compared with wild type enzyme. The wild and mutant enzymes exhibited similar Km and kcat/Km values for L-allo-threonine. Unlike the wild type enzyme, mutant failed to form characteristic quinonoid intermediate and was unable to carry out the exchange of alpha-proton from glycine in the presence of Tetrahydrofolate. These results suggested that Arg265 residue is required for the binding of Tetrahydrofolate and may be the base that abstracts alpha-proton from glycine, leading to formation of quinonoid intermediate in cytosolic SHMT of L. donovani. PMID- 25499511 TI - Triclosan and triclosan-loaded liposomal nanoparticles in the treatment of acute experimental toxoplasmosis. AB - Efficacy of triclosan (TS) and TS-loaded liposomes against the virulent strain of Toxoplasma gondii (T. gondii) was evaluated. Swiss albino mice were intraperitoneally infected with 10(4) tachyzoites of RH HXGPRT(-) strain of T. gondii, then were orally treated with 150 mg/kg TS or 100 mg/kg TS liposomes twice daily for 4 days. Mice mortality, peritoneal and liver parasite burdens, viability, infectivity and ultrastructural changes of peritoneal tachyzoites of infected treated mice were studied, in comparison with those of infected non treated controls. Drug safety was biochemically assessed by measuring liver enzymes and thyroxin. Both TS and TS liposomes induced significant reduction in mice mortality, parasite burden, viability and infectivity of tachyzoites harvested from infected treated mice. Scanning electron microscopy of treated tachyzoites showed distorted shapes, reduced sizes, irregularities, surface protrusions, erosions and peeling besides apical region distortion. Transmission electron microscopy showed that treated tachyzoites were intracellularly distorted, had cytoplasmic vacuolation, discontinuous plasma membranes, nuclear abnormalities and disrupted internal structures. Besides, in TS liposomes-treated subgroup, most tachyzoites were seen intracellularly with complete disintegration of the parasite plasma and nuclear membranes, with complete destruction of the internal structures. Biochemical safety of TS and TS liposomes was proven. Accordingly, TS can be considered as a promising alternative to the standard therapy for treating acute murine toxoplasmosis. Liposomal formulation of TS enhanced its efficacy and allowed its use in a lower dose. PMID- 25499512 TI - Effect of the treatment with Achyrocline satureioides (free and nanocapsules essential oil) and diminazene aceturate on hematological and biochemical parameters in rats infected by Trypanosoma evansi. AB - This study aimed to verify the effect of the treatment with A. satureioides essential oil (free and nanoencapsulated forms) and diminazene aceturate on hematological and biochemical variables in rats infected by Trypanosoma evansi. The 56 rats were divided into seven groups with eight rats each. Groups A, C and D were composed by uninfected animals, and groups B, E, F and G were formed by infected rats with T. evansi. Rats from groups A and B were used as negative and positive control, respectively. Rats from the groups C and E were treated with A. satureioides essential oil, and groups D and F were treated with A. satureioides nanoencapsulated essential oil. Groups C, D, E and F received one dose of oil (1.5 mL kg(-1)) during five consecutive days orally. Group G was treated with diminazene aceturate (D.A.) in therapeutic dose (3.5 mg kg(-1)) in an only dose. The blood samples were collected on day 5 PI for analyses of hematological (erythrocytes and leukocytes count, hemoglobin concentration, hematocrit, mean corpuscular and mean corpuscular hemoglobin concentration) and biochemical (glucose, triglycerides, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, urea and creatinine) variables. A. satureioides administered was able to maintain low parasitemia, mainly the nanoencapsulated form, on 5 days post infection. On the infected animals with T. evansi treated with A. satureioides essential oil (free and nanocapsules) the number of total leucocytes, lymphocytes and monocytes present was similar to uninfected rats, and different from infected and not-treated animals (leukocytosis). Treatment with A. satureioides in free form elevated levels of ALT and AST, demonstrating liver damage; however, treatment with nanoencapsulated form did not cause elevation of these enzymes. Finally, treatments inhibited the increase in creatinine levels caused by infection for T. evansi. In summary, the nanoencapsulated form showed better activity on the trypanosome; it did not cause liver toxicity and prevented renal damage. PMID- 25499513 TI - A putative role for inosine 5' monophosphate dehydrogenase (IMPDH) in Leishmania amazonensis programmed cell death. AB - Leishmania amazonensis undergoes apoptosis-like programmed cell death (PCD) under heat shock conditions. We identified a potential role for inosine 5' monophosphate dehydrogenase (IMPDH) in L. amazonensis PCD. Trypanosomatids do not have a "de novo" purine synthesis pathway, relying on the salvage pathway for survival. IMPDH, a key enzyme in the purine nucleotide pathway, is related to cell growth and apoptosis. Since guanine nucleotide depletion triggers cell cycle arrest and apoptosis in several organisms we analyzed the correlation between IMPDH and apoptosis-like death in L. amazonensis. The L. amazonensis IMPDH inhibition effect on PCD was evaluated through gene expression analysis, mitochondrial depolarization and detection of Annexin-V labeled parasites. We demonstrated a down-regulation of impdh expression under heat shock treatment, which mimics the natural mammalian host infection. Also, IMPDH inhibitors ribavirin and mycophenolic acid (MPA) prevented cell growth and generated an apoptosis-like phenotype in sub-populations of L. amazonensis promastigotes. Our results are in accordance with previous results showing that a subpopulation of parasites undergoes apoptosis-like cell death in the nutrient poor environment of the vector gut. Here, we suggest the involvement of purine metabolism in previously observed apoptosis-like cell death during Leishmania infection. PMID- 25499514 TI - [Epidemiology of upper gastrointestinal bleeding in Gabon]. AB - The department of internal medicine of the military hospital of Gabon managed 92 cases of upper gastrointestinal bleeding from April 2009 to November 2011. The frequency of these hemorrhages in the department was 8.2%; they occurred most often in adults aged 30-40 years and 50-60 years, and mainly men (74%). Erosive ulcerative lesions (65.2%) were the leading causes of hemorrhage, followed by esophageal varices (15.2%). These results underline the importance of preventive measures for the control of this bleeding. PMID- 25499515 TI - Asymmetry in upper blepharoplasty: a retrospective evaluation study of 365 bilateral upper blepharoplasties conducted between January 2004 and December 2013. AB - BACKGROUND: This study was undertaken to evaluate dermatochalasis, eyebrow position, and (a)symmetry in both sides in patients before and after bipolar coagulation-assisted orbital (BICO) septo-blepharoplasty, so as to carry out further investigation if these aforementioned aspects improve, persist, or even worsen after this procedure. METHODS: The preoperative and postoperative photographs of 365 patients were evaluated for the (asymmetry in) degree of skin surplus, eyebrow height, and eyelid fissure height (EFH). The degree of skin surplus was scored using a five-point grading scale (0 = no, 1 = minimal, 2 = moderate, 3 = evident, and 4 = severe skin surplus). For eyebrow height and EFH, respectively, the distance was measured between the lower bound of the eyebrow and the center of the pupil and between the upper and lower lash line. RESULTS: On both the right and left upper eyelids, the skin surplus was significantly lesser postoperatively than preoperatively (p = 0.000). Furthermore, the asymmetry in skin surplus between the right and left upper eyelid was significantly lesser postoperatively (p = 0.000). The eyebrow height was significantly lower on both the right and left sides postoperatively than preoperatively (p = 0.000). EFH was significantly higher postoperatively than preoperatively in both the right and left eyes (p = 0.000). Therefore, the asymmetry in EFH between the right and left eyes was significantly lesser postoperatively (p = 0.000). CONCLUSIONS: A significant decrease in skin surplus and eyebrow height and a significant increase in EFH were observed in patients after BICO septo-blepharoplasty. However, a significant reduction in (the prevalence of) asymmetry in skin surplus and EFH was observed after the procedure. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25499516 TI - Utility and safety of commercially available injection laryngoplasty materials in a rabbit model. AB - OBJECTIVE: To demonstrate foreign body and chronic inflammatory reaction of commercially available injection materials using the rabbit vocal fold paralysis model. STUDY DESIGN: Animal study. METHODS: The left recurrent laryngeal nerve was identified and divided at the tracheoesophageal groove. Amounts (100 MUL) of phosphate-buffered saline (PBS), polyacrylamide hydrogel (Aquamid; Ferrosan A/S, Soborg, Denmark), calcium hydroxyapatite (Radiesse; BioForm Medical Inc., San Mateo, CA), or hyaluronic acid derivative (Rofilan; Rofil Medical International, Breda, Netherlands) were injected into the left vocalis muscle. Six months later, the larynx was harvested. Hematoxylin/eosin and Masson trichrome staining were performed to compare inflammatory and foreign body reactions, granuloma development, and relative vocal fold areas among groups. RESULTS: Compared with the PBS (control) group, the Aquamid, Radiesse, and Rofilan groups exhibited only mild chronic inflammatory reactions that did not significantly differ among groups, or from controls (P > 0.05). However, the Aquamid and Radiesse groups exhibited moderate foreign body reactions that were significantly greater than those of controls (P < 0.05). No foreign body granuloma formed in any group. All test groups exhibited significant increases in vocal fold areas at 6 months (P < 0.05). CONCLUSIONS: Although commercially available injection materials induced more foreign body reactions than a control injection of PBS, no foreign body granuloma developed and the augmented vocal fold area was maintained until 6 months after injection. PMID- 25499517 TI - Dysphonia in nursing home and assisted living residents: prevalence and association with frailty. AB - OBJECTIVE: Previous studies of geriatric dysphonia prevalence have been limited to ambulatory outpatient and senior communities. Our goal was to identify prevalence of dysphonia in nursing home residents and assisted living residents and search for correlations between indices of dysphonia and indices of frailty. STUDY DESIGN: Prospective epidemiological survey. METHODS: Residents of a vertically integrated senior care organization who were 65 or older and able to understand and complete the questionnaire were recruited to complete the voice handicap index 10 (VHI-10) to assess for dysphonia (VHI-10 > 10 = dysphonia) and Vulnerable Elders Survey 13 (VES-13), a validated instrument to assess for frailty (VES > 3 = frailty). RESULTS: A total of 119 residents were surveyed. Thirty-three percent of nursing home residents, and 25% of assisted living residents reported dysphonia with 29% of all respondents reporting dysphonia. The mean VHI-10 was 7.4, the median was 5, and the interquartile range was 2-12.5. There was a significant relationship between VHI-10 and VES-13 score (P = 0.029). There were no statistically significant relationships between frailty, age, or type of living and dysphonia or VHI-10. CONCLUSION: There is a high prevalence of voice dysfunction in assisted living and nursing home residents. The correlation between VHI-10 and VES-13 suggests that voice declines as frailty increases. PMID- 25499518 TI - Design of a clinical vocal loading test with long-time measurement of voice. AB - OBJECTIVES: The aim of this study was to design a clinical vocal loading task (VLT) and to track vocal loading and recovery in voice-healthy subjects. STUDY DESIGN: Pilot study. METHODS: Voice-healthy subjects (six female, five male) took part in a controlled VLT in the voice clinic. The VLT was designed to induce vocal fatigue. The subjects read aloud while making themselves heard through ambient speech-babble aired at 85 dB sound pressure level (SPL). Reading was terminated by the subjects when or if they felt any discomfort from the throat. The subjects wore a voice accumulator and filled out a voice activity questionnaire 1 day preceding and for 2 days following the VLT. Expert panels assessed vocal quality and laryngeal physiology from recordings. RESULTS: The subjects endured the VLT for 3-30 minutes. All subjects perceived vocal loading in the VLT. All subjects raised the fundamental frequency and SPL of their speech during the VLT. No match was shown between assessment of voice quality and laryngeal physiology. The subjects showed phonation quotients of 64-82% in the task. Measurements of phonation threshold pressure (PTP) were unstable and were not used. Self-perceived vocal loading receded after 24 hours. CONCLUSIONS: An authentic vocal load was simulated through the chosen method. Onset and recovery from self-perceived vocal loading was traceable through the voice activity questionnaire. The range of endurance in the VLT was an unexpected finding, indicating the complexity of vocal loading. PMID- 25499519 TI - Effects of implant stiffness, shape, and medialization depth on the acoustic outcomes of medialization laryngoplasty. AB - OBJECTIVE: Medialization laryngoplasty is commonly used to treat glottic insufficiency. In this study, we investigated the effects of implant stiffness (Young modulus), medialization depth, and implant medial surface shape on acoustic outcomes. STUDY DESIGN: Basic science study using ex vivo laryngeal phonation model. METHODS: In an ex vivo human larynx phonation model, bilateral medialization laryngoplasties were performed with implants of varying stiffness, medial surface shape (rectangular, divergent, and convergent), and varying depths of medialization. The subglottal pressure, the flow rate, and the outside sound were measured as the implant parameters were varied. RESULTS: Medialization through the use of implants generally improved the harmonic-to-noise ratio (HNR) and the number of harmonics excited in the outside sound spectra. The degree of acoustic improvement depended on the implant insertion depth, stiffness, and to a lesser degree implant shape. Varying implant insertion depth led to large variations in phonation for stiff implants, but had much smaller effects for soft implants. CONCLUSIONS: Implants with stiffness comparable to vocal folds provided more consistent improvement in acoustic outcomes across different implant conditions. Further investigations are required to better understand the underlying mechanisms. PMID- 25499520 TI - Homeostasis of hyaluronic acid in normal and scarred vocal folds. AB - OBJECTIVES/HYPOTHESIS: Vocal fold scarring is one of the most challenging laryngeal disorders to treat. Hyaluronic acid (HA) is the main component of lamina propria, and it plays an important role in proper vocal fold vibration and is also thought to be important in fetal wound healing without scarring. Although several animal models of vocal fold scarring have been reported, little is known about the way in which HA is maintained in vocal folds. The purpose of this study was to clarify the homeostasis of HA by examining the expression of hyaluronan synthase (Has) and hyaluronidase (Hyal), which produce and digest HA, respectively. STUDY DESIGN: Experimental prospective animal study. METHODS: Vocal fold stripping was performed on 38 Sprague-Dawley rats. Vocal fold tissue was collected at five time points (3 days-2 months). Expression of HA was examined by immunohistochemistry, and messenger RNA (mRNA) expression of Has and Hyal was examined by real-time polymerase chain reaction and in-situ hybridization. RESULTS: In scarred vocal folds, expression of Has1 and Has2 increased at day 3 together with expression of HA and returned to normal at 2 weeks. At 2 months, Has3 and Hyal3 mRNA showed higher expressions than normal. CONCLUSIONS: Expression patterns of Has and Hyal genes differed between normal, acute-scarred, and chronic-scarred vocal folds, indicating the distinct roles of each enzyme in maintaining HA. Continuous upregulation of Has genes in the acute phase may be necessary to achieve scarless healing of vocal folds. PMID- 25499521 TI - Teachers' voice disorders and loss of work ability: a case-control study. AB - BACKGROUND: Teachers constitute a profession with a high occurrence of voice disorders due to the occupation's intense vocal demands and unfavorable work environment. PURPOSE: To identify the association between voice disorders and work ability among teachers from public schools in Sao Paulo, Brazil. METHODS: This is a case-control study. The case group comprised teachers with voice disorder complaints, vocal quality deviations in speech pathology evaluations, and vocal fold lesions according to an evaluation by an otorhinolaryngologist. The control group was randomly selected from the same schools as those in the case group. Both groups answered the following questionnaires: sociodemographic, lifestyles, working conditions, work organization, conditions of vocal production teacher (CVP-T), and Work Ability Index (WAI). The analysis used the chi-square association test and univariate and multivariate regression models. RESULTS: The analyses of both groups showed comparable populations with no significant differences in the demographic and control variables. The groups differed, as expected, in vocal symptoms. Analyzing associations with the WAI, there was an association between decreased work ability and voice disorder (P < 0.001). This association remained in multivariate analyses where decreased (OR = 9.5, P = 0.001) and moderate (OR = 6.7, P < 0.001) work ability were also associated with voice disorders. Analyzing the ability to work, age, and acoustics; decreased (OR = 12.2, P < 0.001) and moderate (OR = 7.7, P < 0.001) work ability, age 50-65 years (OR = 3.7, P = 0.006) and poor acoustics (OR = 2.7, P = 0.007) were factors associated with voice disorders. CONCLUSIONS: The occurrence of voice disorders is significantly associated with work ability, which may eventually compromise teachers' ability to continue working. PMID- 25499522 TI - Formants frequency and dispersion in relation to the length and projection of the upper and lower jaws. AB - OBJECTIVE: Investigate the association between formants frequencies and length and sagittal projection of the maxilla and mandible. STUDY DESIGN: Cross sectional study. METHOD: A total of 47 consecutive patients were recruited. Craniofacial measures included; maxillary length (ANS-PNS), mandibular length (Co Gn), relationship between maxilla and mandible in the sagittal plane (ANB), the sagittal projection of the maxilla (SNA), and mandible (SNB). Subjects were asked to phonate vowels /a/, /i/, /o/, and /u/. Measurements were made in real-time and formant frequencies across F1, F2, F3, and F4 were determined. RESULTS: There was a significant negative association between the length of the maxilla and F4 for all the vowels, and a significant negative association between the length of the mandible and F4 for vowels /o/ and /u/. The length of maxilla and mandible also negatively associated with F3 for vowels /a/, /i/, /o/, and vowels /i/, /o/, and /u/ respectively. For the first two formants, the negative association was less pronounced. CONCLUSION: There was a significant negative association between the formant frequencies F3, F4, and the length of the mandible and maxilla for vowels /a/, /i/, /o/, and /u/. PMID- 25499523 TI - Vocal tract discomfort symptoms in patients with different voice disorders. AB - OBJECTIVE: To analyze the symptoms of vocal tract discomfort in patients with different voice disorders. STUDY DESIGN: This study was descriptive, observational, and cross-sectional. METHODS: A total of 210 subjects with vocal complaints and prior medical assessment were divided into five groups according to diagnosis: no laryngeal lesion, lesion to membranous portion, voice disorder of neurological origin, incomplete glottal closure without organic or neurologic cause, and voice disorder secondary to gastroesophageal reflux. All participants responded to the vocal tract discomfort scale at the time of assessment. RESULTS: Patients had a mean of 4.01 +/- 0.70 symptoms, with sore throat being the most commonly reported. Compared with patients in other groups, patients with lesions in the membranous portion of the vocal folds and those with voice disorder due to gastroesophageal reflux showed an increased number of symptoms. Voice disorders of reflux were shown to result in a higher frequency of sore throat and lump in the throat than in those with neurological etiology. The intensity of the lump in the throat was higher in patients with reflux than in patients with neurologic voice disorders. CONCLUSION: There was a difference between the number, frequency, and intensity of symptoms of vocal tract discomfort based on the type of voice disorder. PMID- 25499524 TI - Discriminant capacity of acoustic, perceptual, and vocal self: the effects of vocal demands. AB - OBJECTIVES: To analyze the discrimination ability of acoustic, auditory parameters, and perception of vocal effort during professional and social voice use, and the correlations of these parameters with the vocal demands. STUDY DESIGN: Longitudinal study. METHODS: Seventy-three subjects participated in the study: 31 females aged from 28 to 65 years (G1; professional voice users) and 42 females aged from 31 to 59 years (G2, social voice users; ). All the subjects were subjected to acoustic voice analysis including F0 median, semiamplitude interquartile, quantile 99.5%, and skewness; first F0 derivate mean, standard deviation (SD), and skewness; intensity skewness; spectral slope mean, SD, and skewness; long-term average spectrum-frequency SD, perceptual parameters (GRBASI scale), and self-perception of vocal effort, before and after 2 hours and 30 minutes of voice use. Statistical analyses were completed via multivariate discriminant analysis and canonical correlation analysis. RESULTS: Discriminant analysis of acoustic, perceptual, and self-rating variables and analysis of the grouped parameters did not differentiate the samples before and after vocal use. Higher levels of canonical correlation were found for the professional voice group after voice use, with a correlation between perceptual analysis and acoustic measures. CONCLUSIONS: The current measures could not discriminate the differences of the type of vocal demands, professional or social. PMID- 25499525 TI - The effects of emotional expression on vibrato. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to investigate the effect of emotional expression on several acoustic measures of vibrato, including its rate, extent, and steadiness. We hypothesized that singing a passage with emotional content would influence these variables. STUDY DESIGN: This study used a within subjects, repeated-measures design. Singer performance under different conditions was analyzed. METHODS: Ten graduate student singers (eight women, two men) completed a series of tasks including sustained sung vowels at several pitch and loudness levels, an assigned song that was judged to have relatively neutral emotion, and a personal selection that included passages of intense emotion. Vowel tokens were extracted from the recordings and averaged for each task. Dependent measures included the mean fundamental frequency (F0), mean intensity, frequency modulation (FM) rate, FM extent, and measures of FM rate and extent variability. RESULTS: The FM rate and extent were higher and the modulation variability was lower for the more emotional song than for the sustained vowels. Mean F0 and intensity were higher for the emotional song than for the neutral song. CONCLUSIONS: Singing an emotional passage influences acoustic features of vibrato when compared with isolated, sustained vowels. The wider dynamic and pitch ranges for emotional passages only partly explain vibrato differences between emotional and neutral singing. PMID- 25499526 TI - Objective dysphonia measures in the program Praat: smoothed cepstral peak prominence and acoustic voice quality index. AB - PURPOSE: A version of the "smoothed cepstral peak prominence" (i.e., CPPS) has recently been implemented in the program Praat. The present study therefore estimated the correspondence between the original CPPS from the program SpeechTool and Praat's version of the CPPS. Because the CPPS is the main factor in the multivariate Acoustic Voice Quality Index (AVQI), this study also investigated the proportional relationship between the AVQI with the original and the second version of the CPPS. STUDY DESIGN: Comparative cohort study. METHODS: Clinical recordings of sustained vowel phonation and continuous speech from 289 subjects with various voice disorders were analyzed with the two versions of the CPPS and the AVQI. Pearson correlation coefficients and coefficients of determination were calculated between both CPPS-methods and between both AVQI methods. RESULTS: Quasi-perfect correlations and coefficients of determination approaching hundred percent were found. CONCLUSIONS: The findings of this study demonstrate that the outcomes of the two CPPS-methods and the two AVQI-methods are highly comparable, increasing the clinical feasibility of both methods as measures of dysphonia severity. PMID- 25499527 TI - Virulence gene profiling and antibiotic resistance pattern of Indian isolates of Pasteurella multocida of small ruminant origin. AB - Pasteurellosis in small ruminants affects the livelihood of small and marginal farmers of India. The present study was undertaken to understand the trends in gene carriage and antibiotic resistance pattern of Pasteurella multocida isolates recovered from small ruminants over a period of 10 years in India. A total of 88 P. multocida isolates of small ruminant origin were subjected to virulence gene profiling for 19 genes by PCR and antibiogram study employing 17 different antibiotics. Virulence genes like exbB, exbD, tonB, oma87, sodA, sodC, nanB and plpB (100% prevalence) and ptfA and hsf-2 (>90% prevalence) were found to be uniformly distributed among isolates. Unexpectedly, a very high prevalence (95.45%) of pfhA gene was observed in the present study. Dermonecrotoxin gene (toxA) was observed in 48.9% of isolates with highest occurrence among serotype A isolates and interestingly, one of each isolate of serotype B and F were found to carry this gene. Antimicrobial susceptibility testing revealed 17.04% isolates to be multidrug resistant. Amongst all the antibiotics tested, most of the P. multocida isolates were found to be susceptible to enrofloxacin and chloramphenicol. This study highlights novel epidemiological information on frequency and occurrence of virulence genes among Indian isolates from small ruminants. PMID- 25499528 TI - Exploring experienced nurses' attitudes, views and expectations of new graduate nurses: a critical review. AB - OBJECTIVES: This critical review evaluates the existing primary research literature to identify experienced registered nurses' attitudes, views and expectations of graduate nurses which may create a barrier for optimal graduate nurse performance. DESIGN/DATA SOURCES: Relevant primary studies were identified by searching online databases using a wide variety of appropriate keyword combinations. Online databases including Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, PsycINFO and Google Scholar were comprehensively searched for relevant research. The selected studies were subjected to a rigorous critical appraisal to evaluate the studies and to determine if the findings were applicable to practice. REVIEW METHODS: A manual method of thematic analysis was conducted to highlight explicit and implicit themes from the reviewed studies. Themes were grouped and continually reduced until only essential themes remain. Themes and subthemes emerged which were then compared and contrasted to analyse results. The four major themes identified include nursing skills, inadequate preparation during academic program, attitudes and ward culture and concerns with confidence. Subthemes were identified within these categories. RESULTS: Findings indicate experienced registered nurses discussed themes including 'nursing skills', 'inadequate preparation during academic program', 'attitudes and ward culture' and 'concerns with confidence'. Concerns were raised including the value of traditional training versus tertiary education programs, coping with unprofessional behaviour and inadequate preparation for practice. DISCUSSION AND IMPLICATIONS FOR PRACTICE: Further research is required to fully address management of the theory-practice gap, as well as the attitudes of experienced registered nurses educated in traditional programs versus those in tertiary education programs. Nurse managers should be aware of the possible occurrence of unprofessional behaviour, and increased workplace training regarding lateral violence would assist in raising awareness regarding negative and unacceptable behaviour. PMID- 25499529 TI - Emotional intelligence education in pre-registration nursing programmes: an integrative review. AB - OBJECTIVE: To investigate the state of knowledge on emotional intelligence (EI) education in pre-registration nursing programmes. DESIGN: Integrative literature review. DATA SOURCES: CINAHL, Medline, Scopus, ERIC, and Web of Knowledge electronic databases were searched for abstracts published in English between 1992-2014. REVIEW METHODS: Data extraction and constant comparative analysis of 17 articles. RESULTS: Three categories were identified: Constructs of emotional intelligence; emotional intelligence curricula components; and strategies for emotional intelligence education. CONCLUSIONS: A wide range of emotional intelligence constructs were found, with a predominance of trait-based constructs. A variety of strategies to enhance students' emotional intelligence skills were identified, but limited curricula components and frameworks reported in the literature. An ability-based model for curricula and learning and teaching approaches is recommended. PMID- 25499530 TI - Do octogenarians still have a high risk of adverse outcomes after carotid endarterectomy in the era of a super-aged society? A single-center study in Japan. AB - BACKGROUND: The aim of this study was to evaluate the safety and feasibility of carotid endarterectomy (CEA) in Japanese octogenarians. METHODS: This study prospectively included 157 consecutive CEA procedures in 145 patients treated at Fukuoka University Hospital between May 2008 and April 2013. Clinical and radiologic findings were obtained from the medical records and by telephone interview. Major events and outcomes were compared between patients 80 years of age or older (octogenarians) and those less than 79 years of age (nonoctogenarians). RESULTS: The rate of major adverse events (major stroke, myocardial infarction, or death) in the perioperative period was 1.2%. Follow-up data were available for 142 patients (97.9%). Only 1 case (.7%) of ipsilateral stroke occurred during the follow-up period. Thirteen patients died of causes other than stroke. The estimated 1-, 3-, and 5-year overall survival rates were 98.5%, 96.9%, and 93.1%, respectively. Nineteen (13.4%) of the patients were octogenarians. There were no significant differences in baseline characteristics between octogenarians and nonoctogenarians, except for age. In octogenarians, there were no major adverse events during the perioperative period and no cases of stroke or stroke-related death during the follow-up period. The estimated 1-, 3-, and 5-year overall survival rates in octogenarians were 92.9%, 92.9%, and 61.9%, respectively. There was no significant difference in overall survival between octogenarians and nonoctogenarians (P = .371). CONCLUSIONS: The results of this study suggest that CEA can be safely performed in Japanese octogenarians. Midterm outcomes were relatively good, but long-term outcomes require further study. PMID- 25499531 TI - Predictors of infarct growth after endovascular therapy for acute ischemic stroke. AB - BACKGROUND: Intra-arterial (IA) thrombectomy for acute ischemic stroke has an excellent recanalization rate but variable outcomes. The core infarct also grows at a variable rate despite recanalization. We aim to study the factors that are associated with infarct growth after IA therapy. METHODS: We reviewed the hyperacute ischemic stroke imaging database at Cleveland Clinic for those undergoing endovascular thrombectomy of anterior circulation from 2009 to 2012. Patients with both pretreatment and follow-up magnetic resonance imaging were included. Seventy-six patients were stratified into quartiles by infarct volume growth from initial to follow-up diffusion-weighted imaging (DWI) measure by a region of interest demarcation. RESULTS: The median infarct growth of each quartile was .6 cm(3) (no-growth group), 13.8, 37, and 160.2 cm(3) (large-growth group). Pretreatment stroke severity was comparable among groups. Compared with the no-growth group, the large-growth group had larger initial infarct defined by computed tomography (CT) Alberta Stroke Program Early CT score (median 10 versus 8, P = .032) and DWI volume (mean 13.8 versus 29.2 cm(3), P = .034), lack of full collateral vessels on CT angiography (36.8% versus 0%, P = .003), and a lower recanalization rate (thrombolysis in cerebral infarction >=2b, P = .044). The increase in infarct growth is associated with decrease in favorable outcomes defined by a modified Rankin Scale score of 0-2 at 30 days: 57.9%, 42.1%, 21.1%, and 5.3%, respectively (P < .001). DWI reversal was observed in 11 of 76 patients, translating to 82% favorable outcome. CONCLUSIONS: Infarct evolution after endovascular thrombectomy is associated with an outcome. DWI reversal or no growth translated to a favorable outcome. Small initial ischemic core, good collateral support, and better recanalization grades predict the smaller infarct growth and favorable outcome after endovascular thrombectomy. PMID- 25499533 TI - Glycosomal membrane proteins and lipids from Leishmania mexicana. AB - Constituents of the glycosomal membrane from Leishmania mexicana should play a critical role in the coordination of metabolic processes occurring in the cytosol and those compartmentalized within glycosomes. We have made an inventory of glycosomal membrane-associated proteins using approaches specific for enriching both integral and peripheral membrane proteins. Surprisingly, 70% of the proteins were recovered in the hydrophobic fraction of membranes solubilized with Triton X 114, while 20% were present in the soluble fraction obtained upon treatment with Na2CO3. 14 major polypeptides, ranging in molecular weight from 65 to 16 kDa, were found to be associated with the membrane, nine of them behaving as integral membrane proteins. Assessment of their topology in the membrane indicated that the polypeptides of 56, 50, 46 and 32 kDa have no domains exposed to the cytosol. The 50 kDa protein is the most abundant one of the glycosomal membrane, where it is peripherically located at the matrix face. The major phospholipids of glycosomal membranes are phosphatidyl-ethanolamine, phosphatidyl-choline and phosphatidyl-serine, with smaller proportions of sphingomyelin and phosphatidyl inositol. The sterols found were of 5-dehydroepisterol, ergosta-5,7,24(24(1)) trien-3beta-ol, and also their precursors, consistent with the notion that these organelles are involved in de novo biosynthesis of sterols in trypanosomatids. PMID- 25499532 TI - Understanding the molecular manipulation of DCAF1 by the lentiviral accessory proteins Vpr and Vpx. AB - Vpr and Vpx are primate lentivirus proteins that manipulate the cellular CRL4 ubiquitin ligase complex. While Vpr is common to all primate lentiviruses, Vpx is only encoded by HIV-2 and a limited range of SIVs. Although Vpr and Vpx share a high degree of homology they are known to induce markedly different effects in host cell biology through the recruitment of different substrates to CRL4. Here we explore the interaction of HIV-1 Vpr and SIVmac Vpx with the CRL4 substrate receptor DCAF1. Through mutational analysis of DCAF1 we demonstrate that although Vpr and Vpx share a highly similar DCAF1-binding motif, they interact with a different set of residues in DCAF1. In addition, we show that Vpx recruits SAMHD1 through a protein-protein interface that includes interactions of SAMHD1 with both Vpx and DCAF1, as was first suggested in crystallography data by (Schwefel, D., Groom, H.C.T., Boucherit, V.C., Christodoulou, E., Walker, P.A., Stoye, J.P., Bishop, K.N., Taylor, I.A., 2014. Structural basis of lentiviral subversion of a cellular protein degradation pathway., Nature, 505, 234-238). PMID- 25499534 TI - Prediction of clinical outcome in glioblastoma using a biologically relevant nine microRNA signature. AB - BACKGROUND: Glioblastoma is the most aggressive primary brain tumor, and is associated with a very poor prognosis. In this study we investigated the potential of microRNA expression profiles to predict survival in this challenging disease. METHODS: MicroRNA and mRNA expression data from glioblastoma (n = 475) and grade II and III glioma (n = 178) were accessed from The Cancer Genome Atlas. LASSO regression models were used to identify a prognostic microRNA signature. Functionally relevant targets of microRNAs were determined using microRNA target prediction, experimental validation and correlation of microRNA and mRNA expression data. RESULTS: A 9-microRNA prognostic signature was identified which stratified patients into risk groups strongly associated with survival (p = 2.26e 09), significant in all glioblastoma subtypes except the non-G-CIMP proneural group. The statistical significance of the microRNA signature was higher than MGMT methylation in temozolomide treated tumors. The 9-microRNA risk score was validated in an independent dataset (p = 4.50e-02) and also stratified patients into high- and low-risk groups in lower grade glioma (p = 5.20e-03). The majority of the 9 microRNAs have been previously linked to glioblastoma biology or treatment response. Integration of the expression patterns of predicted microRNA targets revealed a number of relevant microRNA/target pairs, which were validated in cell lines. CONCLUSIONS: We have identified a novel, biologically relevant microRNA signature that stratifies high- and low-risk patients in glioblastoma. MicroRNA/mRNA interactions identified within the signature point to novel regulatory networks. This is the first study to formulate a survival risk score for glioblastoma which consists of microRNAs associated with glioblastoma biology and/or treatment response, indicating a functionally relevant signature. PMID- 25499535 TI - The transitional association between beta-amyloid pathology and regional brain atrophy. AB - INTRODUCTION: Alzheimer's disease (AD) is characterized by the accumulation of beta-amyloid (Abeta) associated with brain atrophy and cognitive decline. The functional form to model the association between Abeta and regional brain atrophy has not been well defined. To determine the relationship between Abeta and atrophy, we compared the performance of the usual dichotomization of cerebrospinal fluid (CSF) Abeta to identify subjects as Abeta+ and Abeta- with a trilinear spline model of CSF Abeta. METHODS: One hundred and eighty-three subjects with mild cognitive impairment and 108 cognitively normal controls with baseline CSF Abeta and up to 4 years of longitudinal magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative were analyzed using mixed-effects regression. Piecewise-linear splines were used to evaluate the nonlinear nature of the association between CSF Abeta and regional atrophy and to identify points of acceleration of atrophy with respect to Abeta. Several parameterizations of CSF Abeta were compared using likelihood ratio tests and the Akaike information criterion. Periods of acceleration of atrophy in which subjects transition from CSF Abeta negativity to CSF Abeta positivity were estimated from the spline models and tested for significance. RESULTS: Spline models resulted in better fits for many temporal and parietal regions compared with the dichotomous models. The trilinear model showed that periods of acceleration of atrophy varied greatly by region with early changes seen in the insula, amygdala, precuneus, hippocampus, and other temporal regions, occurring before the clinical threshold for CSF Abeta positivity. DISCUSSION: The use of piecewise-linear splines provides an improved model of the nonlinear association between CSF Abeta and regional atrophy in regions implicated in the progression of AD. The important biological finding of this work is that some brain regions show periods of accelerated volume loss well before the CSF Abeta42 threshold. This implies that signs of brain atrophy develop before the current conventional definition of "preclinical AD". PMID- 25499538 TI - Failure analysis in the identification of synergies between cleaning monitoring methods. AB - BACKGROUND: The 4 monitoring methods used to manage the quality assurance of cleaning outcomes within health care settings are visual inspection, microbial recovery, fluorescent marker assessment, and rapid ATP bioluminometry. These methods each generate different types of information, presenting a challenge to the successful integration of monitoring results. A systematic approach to safety and quality control can be used to interrogate the known qualities of cleaning monitoring methods and provide a prospective management tool for infection control professionals. We investigated the use of failure mode and effects analysis (FMEA) for measuring failure risk arising through each cleaning monitoring method. METHODS: FMEA uses existing data in a structured risk assessment tool that identifies weaknesses in products or processes. Our FMEA approach used the literature and a small experienced team to construct a series of analyses to investigate the cleaning monitoring methods in a way that minimized identified failure risks. RESULTS: FMEA applied to each of the cleaning monitoring methods revealed failure modes for each. The combined use of cleaning monitoring methods in sequence is preferable to their use in isolation. CONCLUSIONS: When these 4 cleaning monitoring methods are used in combination in a logical sequence, the failure modes noted for any 1 can be complemented by the strengths of the alternatives, thereby circumventing the risk of failure of any individual cleaning monitoring method. PMID- 25499536 TI - A randomized noninferiority trial of condensed protocols for genetic risk disclosure of Alzheimer's disease. AB - INTRODUCTION: Conventional multisession genetic counseling is currently recommended when disclosing apolipoprotein E (APOE) genotype for the risk of Alzheimer's disease (AD) in cognitively normal individuals. The objective of this study was to evaluate the safety of brief disclosure protocols for disclosing APOE genotype for the risk of AD. METHODS: A randomized, multicenter noninferiority trial was conducted at four sites. Participants were asymptomatic adults having a first-degree relative with AD. A standard disclosure protocol by genetic counselors (SP-GC) was compared with condensed protocols, with disclosures by genetic counselors (CP-GC) and by physicians (CP-MD). Preplanned co-primary outcomes were anxiety and depression scales 12 months after disclosure. RESULTS: Three hundred and forty-three adults (mean age 58.3, range 33-86 years, 71% female, 23% African American) were randomly assigned to the SP GC protocol (n = 115), CP-GC protocol (n = 116), or CP-MD protocol (n = 112). Mean postdisclosure scores on all outcomes were well below cut-offs for clinical concern across protocols. Comparing CP-GC with SP-GC, the 97.5% upper confidence limits at 12 months after disclosure on co-primary outcomes of anxiety and depression ranged from a difference of 1.2 to 2.0 in means (all P < .001 on noninferiority tests), establishing noninferiority for condensed protocols. Results were similar between European Americans and African Americans. CONCLUSIONS: These data support the safety of condensed protocols for APOE disclosure for those free of severe anxiety or depression who are actively seeking such information. PMID- 25499537 TI - The triggering receptor expressed on myeloid cells 2 (TREM2) is associated with enhanced inflammation, neuropathological lesions and increased risk for Alzheimer's dementia. AB - INTRODUCTION: The objective of this study was to elucidate the relationship between the triggering receptor expressed on myeloid cells 2 (TREM2) risk variant, neuropathological lesions, alterations in gene and protein expression, and the severity of neuroinflammation. METHODS: The genetic association study of the R47 H TREM2 variant with Alzheimer's disease (AD), neuropathology, and changes in TREM2 and TYRO protein tyrosine kinase-binding protein (TYROBP) gene and protein expression, and neuroinflammatory markers. RESULTS: The TREM2 variant is associated with: (i) AD (odds ratio: 4.76; P = .014); (ii) increased density of amyloid plaques and neurofibrillary tangles in multiple brain regions; (iii) increased TREM2 (P = .041) and TYROBP (P = .006) gene expression; (iv) decreased TREM2 protein levels (P = .016); and (v) upregulation of proinflammatory cytokines (regulated on activation, normal T cell expressed and secreted [RANTES] and interferon [IFN] gamma) (P = .003) and nominal downregulation of protective markers (alpha2-macroglobulin, interleukin 4 or IL-4, and ApoA1) (P = .018). DISCUSSION: These findings link the TREM2 missense mutation with specific molecular abnormalities and increases in neuropathological lesions in the human brain. PMID- 25499539 TI - Communication in a Human biomonitoring study: Focus group work, public engagement and lessons learnt in 17 European countries. AB - A communication strategy was developed by The Consortium to Perform Human Biomonitoring on a European Scale (COPHES), as part of its objectives to develop a framework and protocols to enable the collection of comparable human biomonitoring data throughout Europe. The framework and protocols were tested in the pilot study DEMOCOPHES (Demonstration of a study to Coordinate and Perform Human biomonitoring on a European Scale). The aims of the communication strategy were to raise awareness of human biomonitoring, encourage participation in the study and to communicate the study results and their public health significance. It identified the audiences and key messages, documented the procedure for dissemination of results and was updated as the project progressed. A communication plan listed the tools and materials such as press releases, flyers, recruitment letters and information leaflets required for each audience with a time frame for releasing them. Public insight research was used to evaluate the recruitment material, and the feedback was used to improve the documents. Dissemination of results was coordinated in a step by step approach by the participating countries within DEMOCOPHES, taking into account specific national messages according to the needs of each country. Participants received individual results, unless they refused to be informed, along with guidance on what the results meant. The aggregate results and policy recommendations were then communicated to the general public and stakeholders, followed by dissemination at European level. Several lessons were learnt that may assist other future human biomonitoring studies. Recruitment took longer than anticipated and so social scientists, to help with community engagement, should be part of the research team from the start. As a European study, involving multiple countries, additional considerations were needed for the numerous organisations, different languages, cultures, policies and priorities. Therefore, communication documents should be seen as templates with essential information clearly indicated and the option for each country to tailor the material to reflect these differences. Future studies should consider setting up multidisciplinary networks of medical professionals and communication experts, and holding training workshops to discuss the interpretation of results and risk communication. Publicity and wide dissemination of the results helped to raise awareness of human biomonitoring to the general public, policy makers and other key stakeholders. Effective and timely communication, at all stages of a study, is essential if the potential of human biomonitoring research to improve public health is to be realised. PMID- 25499540 TI - Are anti-HIV IgAs good guys or bad guys? AB - An estimated 90% of all HIV transmissions occur mucosally. Immunoglobulin A (IgA) molecules are important components of mucosal fluids. In a vaccine efficacy study, in which virosomes displaying HIV gp41 antigens protected most rhesus monkeys (RMs) against simian-human immunodeficiency virus (SHIV), protection correlated with vaginal IgA capable of blocking HIV transcytosis in vitro. Furthermore, vaginal IgG exhibiting virus neutralization and/or antibody dependent cellular cytotoxicity (ADCC) correlated with prevention of systemic infection. In contrast, plasma IgG had neither neutralizing nor ADCC activity. More recently, a passive mucosal immunization study provided the first direct proof that dimeric IgAs (dIgAs) can prevent SHIV acquisition in RMs challenged mucosally. This study compared dimeric IgA1 (dIgA1), dIgA2, or IgG1 versions of a human neutralizing monoclonal antibody (nmAb) targeting a conserved HIV Env epitope. While the nmAb neutralization profiles were identical in vitro, dIgA1 was significantly more protective in vivo than dIgA2. Protection was linked to a new mechanism: virion capture. Protection also correlated with inhibition of transcytosis of cell-free virus in vitro. While both of these primate model studies demonstrated protective effects of mucosal IgAs, the RV144 clinical trial identified plasma IgA responses to HIV Env as risk factors for increased HIV acquisition. In a secondary analysis of RV144, plasma IgA decreased the in vitro ADCC activity of vaccine-induced, Env-specific IgG with the same epitope specificity. Here we review the current literature regarding the potential of IgA - systemic as well as mucosal - in modulating virus acquisition and address the question whether anti-HIV IgA responses could help or harm the host. PMID- 25499542 TI - Endoplasmic reticulum stress inhibition is a valid therapeutic strategy in vitrifying oocytes. AB - The aim of this study is to determine the link between oocyte cryopreservation and endoplasmic reticulum (ER) stress; whether ER stress inhibition improves the efficiency of oocyte vitrification is also explored. Oocytes from mice were exposure to tauroursodeoxycholic acid (TUDCA, an ER stress inhibitor) or TM (tunicamycin, an ER stress inducer) with or without vitrification. The expressions of X-box binding protein-1 (XBP-1) protein and caspase-12 protein, viability of vitrified-warmed oocytes, and their subsequent embryo competence were measured. The levels of XBP-1 protein and caspase-12 protein expression in vitrified-warmed oocytes were significantly higher than those of fresh control oocytes. TUDCA improved the viability of vitrified-warmed oocytes and their subsequent embryo competence. Mouse oocyte cryopreservation is associated with ER stress, and ER stress inhibition improves the efficiency of oocyte vitrification. PMID- 25499541 TI - Wnt3a expression is associated with epithelial-mesenchymal transition and promotes colon cancer progression. AB - INTRODUCTION: Epithelial-mesenchymal transition (EMT) contributes to the progression and metastasis of cancer cells and is associated with a more invasive phenotype of cancer. The Wnt/beta-catenin signaling pathway is one of the major pathways involved in EMT regulation. Many studies provide evidence that beta catenin, the key regulator of the canonical Wnt signaling pathway, is important in regulating EMT in cancer. However, the roles of Wnt3a, the representative canonical Wnt ligand, in EMT and colon cancer progression have not yet been fully explored. METHODS: The expression levels of Wnt3a and EMT-associated proteins (E cadherin, vimentin, and beta-catenin) were assessed by immunohistochemistry in human colon cancer tissues to evaluate the clinicopathological significance of Wnt3a, as well as the correlation between Wnt3a and EMT. We then upregulated Wnt3a expression in HCT116 colon cancer cells, established a nude mouse xenograft model, detected the expression of EMT and Wnt/beta-catenin signaling-associated proteins, and observed invasion and clone-initiating abilities. RESULTS: In 203 human colon cancer tissue samples, Wnt3a protein overexpression was related to colon cancer histological differentiation (P = 0.004), clinical stage (P = 0.008), presence of metastasis and recurrence (P = 0.036), and survival time (P = 0.007) of colon cancer patients. Wnt3a expression was notably concomitant with EMT immunohistochemical features, such as reduced expression of the epithelial marker E-cadherin (P = 0.012), increased expression of the mesenchymal marker vimentin (P = 0.002), and cytoplasmic distribution of beta-catenin (P = 0.021). Results of in vitro and in vivo experiments showed that Wnt3a overexpression could alter cell morphology, regulate EMT-associated protein expression, and enhance clone-initiation and invasion. Dkk1 (antagonist of Wnt/beta-catenin signaling) could also partially reverse the expression of EMT-associated proteins in Wnt3a-overexpressing cells. CONCLUSIONS: Wnt3a expression was associated with EMT and promoted colon cancer progression. The EMT-inducing effect was partially due to the stimulative effect of Wnt3a on the Wnt/beta-catenin pathway. PMID- 25499544 TI - Governments must do more to address interpersonal violence. PMID- 25499543 TI - Effect of neonatal vitamin A supplementation on mortality in infants in Tanzania (Neovita): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Supplementation of vitamin A in children aged 6-59 months improves child survival and is implemented as global policy. Studies of the efficacy of supplementation of infants in the neonatal period have inconsistent results. We aimed to assess the efficacy of oral supplementation with vitamin A given to infants in the first 3 days of life to reduce mortality between supplementation and 180 days (6 months). METHODS: We did an individually randomised, double blind, placebo-controlled trial of infants born in the Morogoro and Dar es Salaam regions of Tanzania. Women were identified during antenatal clinic visits or in the labour wards of public health facilities in Dar es Salaam. In Kilombero, Ulanga, and Kilosa districts, women were seen at home as part of the health and demographic surveillance system. Newborn infants were eligible for randomisation if they were able to feed orally and if the family intended to stay in the study area for at least 6 months. We randomly assigned infants to receive one dose of 50,000 IU of vitamin A or placebo in the first 3 days after birth. Infants were randomly assigned in blocks of 20, and investigators, participants' families, and data analysis teams were masked to treatment assignment. We assessed infants on day 1 and day 3 after dosing, as well as at 1, 3, 6, and 12 months after birth. The primary endpoint was mortality at 6 months, assessed by field interviews. The primary analysis included only children who were not lost to follow-up. This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), number ACTRN12610000636055. FINDINGS: Between Aug 26, 2010, and March 3, 2013, 31,999 newborn babies were randomly assigned to receive vitamin A (n=15,995) or placebo (n=16,004; 15,428 and 15,464 included in analysis of mortality at 6 months, respectively). We did not find any evidence for a beneficial effect of vitamin A supplementation on mortality in infants at 6 months (26 deaths per 1000 livebirths in vitamin A vs 24 deaths per 1000 livebirths in placebo group; risk ratio 1.10, 95% CI 0.95-1.26; p=0.193). There was no evidence of a differential effect for vitamin A supplementation on mortality by sex; risk ratio for mortality at 6 months for boys was 1.08 (0.90 1.29) and for girls was 1.12 (0.91-1.39). There was also no evidence of adverse effects of supplementation within 3 days of dosing. INTERPRETATION: Neonatal vitamin A supplementation did not result in any immediate adverse events, but had no beneficial effect on survival in infants in Tanzania. These results strengthen the evidence against a global policy recommendation for neonatal vitamin A supplementation. FUNDING: Bill & Melinda Gates Foundation to WHO. PMID- 25499545 TI - Effect of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Results of randomised controlled trials of newborn (age 1-3 days) vitamin A supplementation have been inconclusive. The WHO is coordinating three large randomised trials in Ghana, India, and Tanzania (Neovita trials). We present the findings of the Neovita trial in Ghana. METHODS: This study was a population-based, individually randomised, double-blind, placebo-controlled trial in the Brong Ahafo region of Ghana. The trial participants were infants aged at least 2 h, identified at home or facilities on the day of birth or in the next 2 days, able to feed orally, and likely to stay in the study area for at least 6 months. They were randomly assigned (ratio 1:1) to receive either one oral dose of vitamin A (50,000 IU) or placebo immediately after recruitment. The research team and parents of the infants were masked to treatment assignment. Follow-up home visits were undertaken every 4 weeks, when data were recorded for deaths, facility use, and care seeking. The primary outcome was post-supplementation mortality to 6 months of age. Analysis was by intention to treat. Potential adverse events were recorded at 1 and 3 days after supplementation. This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR)CTRN12610000582055. FINDINGS: We assessed 26,414 livebirths for eligibility between Aug 16, 2010, and Nov 7, 2011. We recruited 22,955 newborn infants, with 11,474 randomly assigned to receive vitamin A and 11,481 to receive placebo. Loss to follow-up was low with vital status at 6 months of age reported for 22,698 (98.9%) infants. We recorded 278 post-supplementation deaths to 6 months of age in the vitamin A group (mortality risk 24.5 in 1000 supplemented infants) and 248 deaths in the placebo group (mortality risk 21.8 per 1000 supplemented infants), relative risk (RR) 1.12 (95% CI 0.95-1.33; p=0.183) and risk difference (RD) 2.66 (95% CI -1.25 to 6.57; p=0.18). Adverse events within 3 days of supplementation did not differ by trial group. 122 infants died in the first 3 days after supplementation; 70 (0.6%) in the vitamin A and 52 (0.5%) in the placebo group (risk ratio [RR] 1.35, 95% CI 0.94-1.93, p=0.102). 53 infants were reported to have a bulging fontanelle; 32 (0.3%) in the vitamin A group and 21 (0.2%) in the placebo group (RR 1.53, 0.88-2.62, p=0.130). INTERPRETATION: The results of this trial do not support inclusion of newborn vitamin A supplementation as a child survival strategy in Ghana. FUNDING: Bill & Melinda Gates Foundation grant to the WHO. PMID- 25499546 TI - Efficacy of early neonatal supplementation with vitamin A to reduce mortality in infancy in Haryana, India (Neovita): a randomised, double-blind, placebo controlled trial. AB - BACKGROUND: Vitamin A supplementation in children aged 6 months to 5 years has been shown to reduce mortality. The efficacy of neonatal supplementation with vitamin A to reduce mortality in the first 6 months of life is plausible but not established. We aimed to assess the efficacy of neonatal oral supplementation with vitamin A to reduce mortality between supplementation and 6 months of age. METHODS: We undertook an individually randomised, double-blind, placebo controlled trial in Haryana, India. We identified pregnant women through a surveillance programme undertaken every 3 months of all female residents in two districts of Haryana, India, aged 15-49 years, and screened every identified livebirth. Eligible participants were neonates whose parents consented to participate, were likely to stay in the study area until at least 6 months of age, and were able to feed orally at the time of enrolment. Participants were randomly assigned to receive oral capsules containing vitamin A (retinol palmitate 50,000 IU plus vitamin E 9.5-12.6 IU) or placebo (vitamin E 9.5-12.6 IU) within 72 h of birth. Randomisation was in blocks of 20 according to a randomisation list prepared by a statistician not otherwise involved with the trial. Investigators, participants' families, and the data analysis team were masked to treatment allocation. The primary outcome was mortality between supplementation and 6 months of age. Analysis included all participants assigned to study groups. This trial is registered with ClinicalTrials.gov, number NCT01138449, and the Indian Council of Medical Research Clinical Trial Registry, number CTRI/2010/091/000220. FINDINGS: Between June 24, 2010, and July 1, 2012 we screened 47,777 neonates and randomly assigned 44,984 to receive vitamin A (22,493) or placebo (22,491). Between supplementation and 6 months of age, 656 infants died in the vitamin A group compared with 726 in the placebo group (29.2 per 1000 vs 32.3 per 1000; difference -3.1 per 1000, 95% CI -6.3 to 0.1; risk ratio 0.90, 95% CI 0.81 to 1.00). We noted no significant interactions between the intervention effect and sex on mortality at 6 months (p=0.409). Supplementation with 50,000 IU vitamin A within the first 72 h of life was generally safe and well tolerated, with the exception of a small excess risk of transient bulging fontanelle (205 cases in the vitamin A group confirmed by physician vs 80 cases in the placebo group, risk ratio 2.56 [95% CI 1.98-3.32]). INTERPRETATION: The findings of this study, done in a population in which vitamin A deficiency is a moderate public health problem, are consistent with a modest reduction in mortality between supplementation and 6 months of age. These findings must be viewed together with similar trials in other populations to enable determination of appropriate public health policy. FUNDING: Bill & Melinda Gates Foundation to WHO. PMID- 25499547 TI - Neonatal vitamin A supplementation: time to move on. PMID- 25499548 TI - Short- and long-term effects of a physical activity counselling programme in COPD: a randomized controlled trial. AB - BACKGROUND: We were interested in the effects of a physical activity (PA) counselling programme in three groups of COPD patients from general practice (primary care), outpatient clinic (secondary care) and pulmonary rehabilitation (PR). METHODS: In this randomized controlled trial 155 COPD patients, 102 males, median (IQR) age 62 (54-69) y, FEV1predicted 60 (40-75) % were assigned to a 12 weeks' physical activity counselling programme or usual care. Physical activity (pedometer (Yamax SW200) and metabolic equivalents), exercise capacity (6-min walking distance) and quality of life (Chronic Respiratory Questionnaire and Clinical COPD Questionnaire) were assessed at baseline, after three and 15 months. RESULTS: A significant difference between the counselling and usual care group in daily steps (803 steps, p = 0.001) and daily physical activity (2214 steps + equivalents, p = 0.001)) from 0 to 3 months was found in the total group, as well as in the outpatient (1816 steps, 2616 steps + equivalents, both p = 0.007) and PR (758 steps, 2151 steps + equivalents, both p = 0.03) subgroups. From 0 to 15 months no differences were found in physical activity. However, when patients with baseline physical activity>10,000 steps per day (n = 8), who are already sufficiently active, were excluded, a significant long-term effect of the counselling programme on daily physical activity existed in the total group (p = 0.02). Differences in exercise capacity and quality of life were found only from 0 to 3 months, in the outpatient subgroup. CONCLUSION: Our PA counselling programme effectively enhances PA level in COPD patients after three months. Sedentary patients at baseline still benefit after 15 months. ClinicalTrials.gov: registration number NCT00614796. PMID- 25499549 TI - Non-selective and selective enrichment media for the recovery of Clostridium difficile from chopped beef. AB - Clostridium difficile exists within the intestines of animals and in meat products. Enrichment of C. difficile in an appropriate medium is necessary for the detection of C. difficile in meat products. Non-selective media (brain heart infusion medium [TBHI] and cooked meat medium containing sodium taurocholate [TCM]) and selective media (cycloserine-cefoxitin-fructose medium [TCCFB] and C. difficile moxalactam-norfloxacin medium containing antibiotics and sodium taurocholate [TCDMN]) can be used to enrich C. difficile. This study aimed to evaluate non-selective and selective enrichment media for the recovery of C. difficile from beef specimens. The efficiency of the enrichment media was investigated on the basis of the recovery frequency of C. difficile from beef specimens inoculated with C. difficile. The beef specimens were inherently contaminated with bacteria (around 10(4)CFUg(-1)), and further inoculated with C. difficile (around 10(0)CFUg(-1)). The antibiotics in TCCFB and TCDMN adversely affected C. difficile growth. The bacteria inherent to these specimens exhibited resistance to antibiotics and grew during the enrichment of C. difficile inoculated chopped beef in TCCFB and TCDMN, which hindered the recovery of C. difficile. The frequency of recovery of C. difficile from beef specimens in TCM was higher than that from any other enrichment medium. PMID- 25499550 TI - Traffic pollution is associated with early childhood aeroallergen sensitization. AB - BACKGROUND: No large, prospective, epidemiologic study has investigated the association between diesel exhaust particle (DEP) exposure and early aeroallergen sensitization and allergic rhinitis (AR) at 4 years of age. OBJECTIVE: To determine how exposure to traffic exhaust during infancy is associated with aeroallergen sensitization and AR at 4 years of age and the predictive utility of the wheal area at 1 to 3 years of age on AR at 4 years of age. METHODS: Infants born to aeroallergen sensitized parents were evaluated annually with skin prick tests to 15 aeroallergens with measurement of wheal areas. At 4 years of age, AR was defined as at least one positive aeroallergen skin prick test result and the presence of sneezing and a runny nose without a cold or flu. Infant (DEP) exposure was estimated using data from 27 air sampling monitors and a land use regression model. RESULTS: Complete data were available for 634 children at 4 years of age. Prevalence of AR increased annually from 6.9% to 21.9%. A positive trend was observed for high DEP exposure and aeroallergen sensitization at 2 and 3 years of age (odds ratio, 1.40; 95% confidence interval, 0.97-2.0) and (odds ratio, 1.35; 95% confidence interval, 0.98-1.85) but not with AR. At 2 years of age, every 1-mm(2) increase in the wheal area of timothy and Alternaria significantly increased the odds of AR at 4 years of age. At 3 years of age, every 1-mm(2) increase in the wheal area of fescue, dog, and Penicillium significantly increased the odds of AR at 4 years of age. CONCLUSION: DEP exposure enhances the risk of early aeroallergen sensitization. Aeroallergen wheal area at 2 and 3 years of age is associated with AR at 4 years of age. PMID- 25499551 TI - Inhibition of bacterial mevalonate diphosphate decarboxylase by eriochrome compounds. AB - Mevalonate diphosphate decarboxylase (MDD; EC 4.1.1.33) catalyzes the irreversible decarboxylation of mevalonate diphosphate in the mevalonate pathway to form isopentenyl diphosphate, which is a precursor in the biosynthesis of many essential polyisoprenoid natural products, including sterols. In low G/C Gram positive bacteria, which utilize the mevalonate pathway, MDD is required for cell viability and thus is a potential target for development of antibiotic drugs. To identify potential inhibitors of the enzyme, the National Cancer Institute's Mechanistic Diversity Set library of compounds was screened for inhibitors of Staphylococcus epidermidis MDD. From this screen, the compound Eriochrome Black A (EBA), an azo dye, was found to inhibit the enzyme with an IC50 value<5MUM. Molecular docking of EBA into a crystal structure of S. epidermidis MDD suggested binding at the active site. EBA, along with the related Eriochrome B and T compounds, was evaluated for its ability to not only inhibit enzymatic activity but to inhibit bacterial growth as well. These compounds exhibited competitive inhibition towards the substrate mevalonate diphosphate, with Ki values ranging from 0.6 to 2.7MUM. Non-competitive inhibition was observed versus ATP indicating binding of the inhibitor in the mevalonate diphosphate binding site, consistent with molecular docking predictions. Fluorescence quenching analyses also supported active site binding of EBA. These eriochrome compounds are effective at inhibiting S. epidermidis cell growth on both solid media and in liquid culture (MIC50 from 31 to 350MUM) raising the possibility that they could be developed into antibiotic leads targeting pathogenic low-G/C Gram-positive cocci. PMID- 25499552 TI - Detection of hepatocellular carcinoma in transgenic mice by Gd-DTPA- and rhodamine 123-conjugated human serum albumin nanoparticles in T1 magnetic resonance imaging. AB - Nanoparticle (NP)-based contrast agents that enable high resolution anatomic T1 weighted magnetic resonance imaging (MRI) offer the prospect of improving differential diagnosis of liver tumors such as hepatocellular carcinoma (HCC). In the present study, we investigated the possibility of employing novel non-toxic human serum albumin nanoparticles conjugated with Gd-DTPA and rhodamine 123 (Gd Rho-HSA-NPs) for the detection of HCC by T1-weighted MRI. In addition, the influence of surface coating of the NPs with poloxamine 908, which alters the absorptive behavior of NPs and changes their distribution between the liver and tumor was examined. MRI of transgenic mice with endogenously formed HCCs following intravenous injection of Gd-Rho-HSA-NPs revealed a strong negative contrast of the tumors. Contrasting of the HCCs by NP-enhanced MRI required less Gd as compared to gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid enhanced MRI, which currently provides the most sensitive detection of HCC in patients. Immunohistochemical analyses revealed that the Gd-Rho-HSA-NPs were localized to macrophages, which were - similar to HCC in patients - fewer in number in HCC as compared to the liver tissue, which is in agreement with the negative contrasting of HCC in Gd-Rho-HSA-NP-enhanced MRI. Poloxamine-coated NPs showed lower accumulation in the tumor macrophages and caused a longer lasting enhancement of the MRI signal. These data indicate that Gd-Rho-HSA-NPs enable sensitive detection of HCC by T1-weighted MRI in mice with endogenous HCC through their uptake by macrophages. Poloxamine coating of the NPs delayed the tumor localization of the NPs. PMID- 25499553 TI - A rapid drug release system with a NIR light-activated molecular switch for dual modality photothermal/antibiotic treatments of subcutaneous abscesses. AB - Eradicating subcutaneous bacterial infections remains a significant challenge. This work reports an injectable system of hollow microspheres (HMs) that can rapidly produce localized heat activated by near-infrared (NIR) light and control the release of an antibiotic via a "molecular switch" in their polymer shells, as a combination strategy for treating subcutaneous abscesses. The HMs have a shell of poly(d,l-lactic-co-glycolic acid) (PLGA) and an aqueous core that is comprised of vancomycin (Van) and polypyrrole nanoparticles (PPy NPs), which are photothermal agents. Experimental results demonstrate that the micro-HMs ensure efficiently the spatial stabilization of their encapsulated Van and PPy NPs at the injection site in mice with subcutaneous abscesses. Without NIR irradiation, the HMs elute a negligible drug concentration, but release substantially more when exposed to NIR light, suggesting that this system is suitable as a photothermally-responsive drug delivery system. The combination of photothermally induced hyperthermia and antibiotic therapy with HMs increases cytotoxicity for bacteria in abscesses, to an extent that is greater than the sum of the two treatments alone, demonstrating a synergistic effect. This treatment platform may find other clinical applications, especially for localized hyperthermia-based cancer therapy. PMID- 25499554 TI - An assessment of the ability of the obstruction-scaling model to estimate solute diffusion coefficients in hydrogels. AB - The ability to estimate the diffusion coefficient of a solute within hydrogels has important application in the design and analysis of hydrogels used in drug delivery, tissue engineering, and regenerative medicine. A number of mathematical models have been derived for this purpose; however, they often rely on fitted parameters and so have limited predictive capability. Herein we assess the ability of the obstruction-scaling model to provide reasonable estimates of solute diffusion coefficients within hydrogels, as well as the assumption that a hydrogel can be represented as an entangled polymer solution of an equivalent concentration. Fluorescein isothiocyanate dextran solutes were loaded into sodium alginate solutions as well as hydrogels of different polymer volume fractions formed from photoinitiated cross-linking of methacrylate sodium alginate. The tracer diffusion coefficients of these solutes were measured using fluorescence recovery after photobleaching (FRAP). The measured diffusion coefficients were then compared to the values predicted by the obstruction-scaling model. The model predictions were within +/-15% of the measured values, suggesting that the model can provide useful estimates of solute diffusion coefficients within hydrogels and solutions. Moreover, solutes diffusing in both sodium alginate solutions and hydrogels were demonstrated to experience the same degree of solute mobility restriction given the same effective polymer concentration, supporting the assumption that a hydrogel can be represented as an entangled polymer solution of equivalent concentration. PMID- 25499555 TI - A polymeric conjugate foreignizing tumor cells for targeted immunotherapy in vivo. AB - Antigen-specific CD8(+) cytotoxic T lymphocytes (CTLs) are key elements of immunological rejection in transplantation as well as cancer immunotherapy. Most tumors, however, are not immunologically rejected because they have self antigens, which are not recognized as the foreigner by CTLs. In this study, we hypothesized that "foreignizing" tumor cells by delivering non-self foreign antigens into the tumors would result in rejection by foreign antigen-reactive CTLs. As the model system to foreignize the tumors, we prepared a polymeric conjugate consisting of hyaluronic acid as the CD44(+) tumor-targeting ligand and ovalbumin (OVA) as a foreign antigen. When the conjugate was treated with CD44(high) TC-1 tumor cells, it was effectively taken up and allowed for displaying of antigenic OVA257-264 peptide at MHC class I on the surface of the cells. In addition, the conjugate was effectively accumulated into tumor tissue after its systemic administration to mice which are immunized with a vaccine for a vaccinia virus expressing OVA to generate OVA257-264 specific CTLs, resulting in substantial inhibition of tumor growth. Overall, these results suggest that the polymeric conjugates bearing foreign antigens may be innovative and promising cancer immunotherapeutic agents by foreignizing tumor cells, leading to immunological rejection. PMID- 25499556 TI - Clinical situations that lead to misinterpretation of indirect biochemical indexes in liver diseases. PMID- 25499557 TI - Resolution enhancement in second-derivative spectra. AB - Derivative spectroscopy is a powerful tool for the resolution enhancement in infrared, near-infrared, Raman, ultraviolet-visible, nuclear magnetic resonance, electron paramagnetic resonance, and fluorescence spectroscopy. Despite its great significance in analytical chemistry, not all aspects of the applications of this method have been explored as yet. This is the first systematic study of the parameters that influence the resolution enhancement in the second derivative spectra. The derivative spectra were calculated with the Savitzky-Golay method with different window size (5, 15, 25) and polynomial order (2, 4). The results obtained in this work show that the resolution enhancement in the second derivative spectra strongly depends on the data spacing in the original spectra, window size, polynomial order, and peak profile. As shown, the resolution enhancement is related to variations in the width of the peaks upon the differentiation. The present study reveals that in order to maximize the separation of the peaks in the second derivative spectra, the original spectra should be recorded at high resolution and differentiated using a small window size and high polynomial order. However, working with the real spectra one has to compromise between the noise reduction and optimization of the resolution enhancement in the second derivative spectra. PMID- 25499558 TI - Ear pain, vesicular rash, and facial palsy. PMID- 25499559 TI - The influence of differential response and other factors on parent perceptions of child protection involvement. AB - As Child Protective Services (CPS) agencies examine how to produce better outcomes with the families they serve, child welfare literature has increasingly focused on the perspectives, emotional responses, and engagement of CPS-involved parents or other primary caregivers. Despite this encouraging trend, the construct of engagement is ill-defined and our understanding of precursors to and factors affecting parent engagement is limited. This article extends the literature by presenting a conceptual framework for examining engagement and associating the identified constructs with parent outcomes. Using data from a survey of parents who were randomly assigned to receive either an assessment response (AR) or investigation response (IR) in two states' Differential Response CPS systems, a factor analysis on 12 commonly assessed emotional responses reported by parents indicated that parents responded with three primary emotions: positive affect, worry, or anger and that these responses varied by their receipt of AR or IR. Further, the results of multivariate analyses indicate that pathway assignment (AR or IR), parents' assessments of the quality of the casework they received, and other parent or household factors contribute to differences observed on the three emotional response factors identified. PMID- 25499560 TI - Commentary on a study of the prevalence of mental disorders by Breslau et al. PMID- 25499561 TI - Yin and yang surfaces: an evolutionary perspective. AB - A search of the Chinese medicine literature reveals several conflicting explanations of the division of the body into yin and yang surfaces. This paper attempts to clarify this basic concept and reconcile the differing descriptions of it through an exploration of material from other disciplines. A remarkable similarity exists between the surfaces on the human body that are defined by the pathways of the yin and yang meridians and those that have evolved from the ventral and the dorsal aspects of early vertebrate structure. Many of the evolutionary changes described have parallels in our embryological development and are evident in the underlying anatomy of our limbs. The degree of convergence between the two descriptions strongly supports the definition of the yin and yang surfaces as those traversed by the yin and yang meridians. It also goes a long way towards reconciling the conflicting definitions found in the literature. Finding a solution to this question of yin and yang surfaces that is based on anatomy and evolutionary theories has several advantages. It can throw light on differences in the clinical effects of points on the yin and yang meridians and enable the identification of anomalies in the pathways of the main meridian network. PMID- 25499562 TI - Primo vascular system in human umbilical cord and placenta. AB - The primo vascular system (PVS) has been observed in various animals such as mice, rats, rabbits, dogs, swine, and cow, but not in humans. In this work, we report on the observation of a human PVS on both the epithelial fascia and inside the blood vessels of the umbilical cord (UC). The main morphological characteristics of the primo vessels (PVs) and primo nodes (PNs) from the human UC were in agreement with those of the PVS in various animal organs, including the thicknesses and the transparency of the PVs, the sizes of the PNs, the broken line arrangement of the rod-shaped nuclei, the sparse distribution of nuclei, and the presence of hollow lumens in the central inner parts of the PNs. It was rather surprising that the human PV was not thicker than the PVs from small animals. The difference between the PVS and blood/lymph vessels was confirmed using immunofluorescence staining of von Willebrand factor, CD31, LYVE-1, and D2 40. The positive expression of the PVS to proliferating cell nuclear antigen, a cell-proliferation marker, was consistent with the recent finding of very small embryonic-like stem cells in the PVS of mice. PMID- 25499563 TI - Effective isolation of primo vessels in lymph using sound- and ultrasonic-wave stimulation. AB - The effects of stimulation with sound and ultrasonic waves of a specific bandwidth on the microdissection of primo vessels in lymphatic vessels of rabbit were investigated. The primo vessels stained with alcian-blue dye injected in the lymph nodes were definitely visualized and more easily isolated by sound-wave vibration and ultrasonic stimulation applied to rabbits at various frequencies and intensities. With sound wave at 7 Hz and ultrasonic waves at 2 MHz, the probability of detecting the primo vessels was improved to 90%; however, without wave stimulation the probability of discovering primo vessels was about 50% only. Sound and ultrasonic waves at specific frequency bands should be effective for microdissection of the primo vessels in the abdominal lymph of rabbit. We suggest that oscillation of the primo vessels by sound and ultrasonic waves may be useful to visualize specific primo structure, and wave vibration can be a very supportive process for observation and isolation of the primo vessels of rabbits. PMID- 25499564 TI - Numerical analysis of the change in skin color due to ecchymosis and petechiae generated by cupping: a pilot study. AB - Cupping is one of the various treatment methods used in traditional oriental medicine. Cupping is also used as a diagnostic method and it may cause skin hyperpigmentation. Quantitative measurements and analysis of changes in skin color due to cupping are critical. The purpose of this study is to suggest an optical technique to visualize and identify changes in skin color due to cupping. We suggest the following analysis methods: digital color spaces [red, green, and blue (RGB) and L*a*b], the Erythema Index (E.I.), and the Melanin Index (M.I.). For experiments, we selected and stimulated 10 acupoints at 80 kilopascals (kPa) per minute. The RGB and L*a*b color spaces were observed to be decreased (p < 0.05) after cupping. The E.I. and M.I. were observed to be increased significantly (p < 0.05) after cupping. To assess various changes in skin color, we observed the changes for 72 hours. We also obtained the color changes by using the recovery pattern during the recovery period (p < 0.01). We propose that this method can be useful for visual identification and as a way to improve the identification of skin color changes. PMID- 25499565 TI - Nausea control by needling at acupuncture point Neiguan (PC6) during an intraoral impression-taking procedure. AB - The objective of this study was to evaluate the effectiveness of acupuncture point PC6 (Neiguan) in controlling nausea during intraoral impression taking. This study was conducted in Piracicaba, Sao Paulo, Brazil. The sample consisted of 33 adult volunteers with nausea, who were randomly divided into control and study groups, and treated with nonpenetrating sham acupuncture and real acupuncture, respectively, at acupoint PC6. The two groups had two maxillary impressions taken, one prior to acupuncture and the other after acupuncture. The nausea assessment was made using the visual analog scale, Gagging Severity Index (GSI), and Gagging Prevention Index. Volunteers' expectation that nausea would be reduced through acupuncture was also assessed. For statistical analysis, we used the t test and the Spearman correlation (p < 0.05). When assessed by Gagging Severity Index/Gagging Prevention Index, nausea was reduced in the real acupuncture group (p < 0.01). In the visual analog scale assessment, similar reductions of nausea were noted in both groups (p > 0.05). No correlation existed between the expected and the actual reductions in nausea. Our results indicate that acupoint PC6 was effective for controlling nausea during the maxillary impression-taking procedure. Patients' expectation did not influence the results. PMID- 25499566 TI - Gender and measuring-position differences in the radial pulse of healthy individuals. AB - In this research, radial pulse differences according to gender and measuring positions in healthy individuals were investigated in an objective manner. A total of 372 healthy volunteers (189 males and 183 females) participated in this study. The radial pulse was measured at six different measuring positions using a multistep tonometry system. The pulse data were compared between males and females and between different measuring positions. Compared to the pulses in females, those in males were deeper and slower, with a longer diastolic proportion and a shorter systolic proportion. Amplitude of the radial pulse increased as it went distal. The pulse was deepest at the Cheock position and shallowest at the Gwan position. Compared to the right pulse, the radial augmentation index was higher and the main peak angle was larger in case of the left pulse. The results of this research show that the radial pulses in healthy individuals differ significantly according to gender and measuring positions. PMID- 25499567 TI - Use of the Layer Analysis Method of the Yellow Emperor's Inner Classic in modern society. AB - This article introduces the Layer Analysis Method of the Yellow Emperor's Inner Classic text to revive its use in modern acupuncture and medicine. This is a crucial concept, especially for the diagnosis and treatment of diseases by acupuncture. First, the rise and decline of this method is explored. Second, the differentiation of this method is described by symptoms, the affected organs, and the stage of the disease. Third, the treatment method is summarized into four categories: (1) equipment, (2) technique, (3) acupoint, and (4) pathology. The resemblance of the Layer Analysis Method to modern clinical applications is worth examining. The sinew layer is especially fascinating with its similarity to the Anatomy Trains' track. The skin, vessel, muscle, and bone layers have their respective resemblances to their counterparts in modern medicine. The holism concept of traditional Chinese medicine (TCM) is demonstrated throughout the Layer Analysis Method theory. In addition, the Layer Analysis Method of the Yellow Emperor's Inner Classic should be reconsidered and complemented by channel collateral pattern differentiation for acupuncturists to achieve better clinical results. Future research on acupuncture should consider this theory with the channel-collateral pattern differentiation theory. PMID- 25499568 TI - Visualization of the primo vascular system afloat in a lymph duct. AB - Because of the potential roles of the primo vascular system (PVS) in cancer metastasis, immune function, and regeneration, understanding the molecular biology of the PVS is desirable. The current state of PVS research is comparable to that of lymph research prior to the advent of Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1). There is very little knowledge of the molecular biology of the PVS due to difficulties in identifying and isolating primo endothelial cells. Present investigations rely on the morphology and the use of differential staining procedures to identify the PVS within tissues, making detailed molecular studies all but impossible. To overcome such difficulties, one may emulate the explosive development of lymph molecular biology. For this purpose, there is a need for a reliable method to obtain PVS specimens to initiate the molecular investigation. One of the most reliable methods is to detect the primo vessels and primo nodes afloat in the lymph flow. The protocols for observation of the PVS in the large lymph ducts in the abdominal cavity and the thoracic cavity were reported earlier. These methods require a laparectomy and skillful techniques. In this work, we present a protocol to identify and harvest PVS specimens from the lymph ducts connecting the inguinal and the axillary nodes, which are located entirely in the skin. Thus, the PVS specimen is more easily obtainable. This method is a stepping-stone toward development of a system to monitor migration of cancer cells in metastasis from a breast tumor to the axillary nodes, where cancer cells use the PVS as a survival rope in hostile lymph flow. PMID- 25499569 TI - Field evaluation of a novel synthetic odour blend and of the synergistic role of carbon dioxide for sampling host-seeking Aedes albopictus adults in Rome, Italy. AB - BACKGROUND: Despite the expanding worldwide distribution of Aedes albopictus and its increasing relevance as arboviral vector, current methods to collect adult specimens are not optimal. Improved approaches are thus needed to monitor their density and pathogen infections, and to establish baseline data for control interventions. A widely used device is the BG-Sentinel (BG-trap) which mostly targets host-seeking females attracted by release of CO2 and/or a synthetic odour blend (the BG lure). We compared the attractiveness of this blend to that of the Mbita (MB5) lure, a new synthetic blend of proven efficiency in attracting Afrotropical malaria vectors, and evaluated the additional effect of CO2 to the two odour baits. FINDINGS: We carried out 6x6 Latin square experiments in two Ae. albopictus-infested areas in Rome, baiting the BG-traps as follows: CO2, BG lure, MB5 lure, BG lure + CO2, MB5 lure + CO2, no bait. CO2 was derived from yeast fermented sugar. Overall, 949 females and 816 males were collected. Baited traps collected significantly more females than unbaited ones. Traps baited with either lures in combination with CO2 were more effective than those baited with CO2 alone. No significant differences were observed in female captures between traps baited with any of the two lures, nor between the two lures, independently from the addition of CO2. The use of BG lure + CO2 significantly increased males catches compared to unbaited traps. CONCLUSIONS: The results suggest a broad significance of the MB5 lure for sampling medically important mosquito species and highlight the high efficacy of the combination of lures + CO2 for female Ae. albopictus and of BG lure + CO2 for males, leading to consider CO2 as an essential additional cue for the sampling of this species. PMID- 25499570 TI - Lateral habenula as a link between dopaminergic and serotonergic systems contributes to depressive symptoms in Parkinson's disease. AB - Degeneration of substantia nigra dopaminergic neurons is a key pathological change of Parkinson's disease (PD), and its motor consequences have been widely recognized. Recently, mood disorders associated with PD have begun to attract a great deal of interest, however, their pathogenesis remains unclear. PD is associated with not only degenerative changes in dopaminergic neurons in the substantia nigra but also changes in serotonergic neurons in the raphe nuclei. The abnormalities in central 5-hydroxytryptamine (5-HT) neurotransmission are thought to play a key role in the pathogenesis of depression. The lateral habenula (LHb) is closely related to the substantia nigra and raphe nuclei, and its hyperactivity is closely related to the pathogenesis of depression. In this study, we screened rats with depressive-like behaviors from PD model animals and found that cytochrome c oxidase activity in the LHb of these rats was twice that seen in the control rats. In the forced swim test, LHb lesions caused a decrease in depressive-like behavior of PD rats as indexed by decreased immobility times and increased climbing times. Additionally, LHb lesions caused an enhance in 5-HT levels in the raphe nuclei. These results suggest that LHb lesions may improve depressive-like behavior in PD rats by increasing 5-HT levels in the raphe nuclei. Thus, LHb contributes to the depressive-like behavior in PD rats via mediating the effects of dopaminergic neurons in the substantia nigra on serotonergic neurons in the raphe nuclei. PMID- 25499571 TI - Montelukast in paediatric asthma: where we are now and what still needs to be done? AB - Leukotriene receptor antagonists were introduced as an entirely new concept in asthma therapy, which indeed they are. However, although an intellectually new concept, they have largely disappointed in clinical practice. A small minority of school age asthmatics may respond better to these medications as against inhaled corticosteroids as prophylactic therapy. In children not responding to low dose inhaled corticosteroids, the best add-on therapy is salmeterol, but a small number respond better to Montelukast. In pre-school wheeze, intermittent Montelukast may be an effective strategy in some children who wheeze just with viral colds, but the clinical trial data are controversial. Pre-schoolers with multiple trigger wheeze are probably best treated with inhaled corticosteroids. What is clear is that clinically, a higher proportion of children are prescribed Montelukast than would be predicted from the lterature to respond to the medication. No biomarker to predict response to Montelukast has reached clinical practice, so N of 1 clinical trials should be performed. It is important not to leave children on Montelukast if there is no convincing response to this treatment. PMID- 25499572 TI - Chest wall mini-symposium. PMID- 25499573 TI - Getting to grips with 'dysfunctional breathing'. AB - Dysfunctional breathing (DB) is common, frequently unrecognised and responsible for a substantial burden of morbidity. Previously lack of clarity in the use of the term and the use of multiple terms to describe the same condition has hampered our understanding. DB can be defined as an alteration in the normal biomechanical patterns of breathing that result in intermittent or chronic symptoms. It can be subdivided into thoracic and extra thoracic forms. Thoracic DB is characterised by breathing patterns involving relatively inefficient, excessive upper chest wall activity with or without accessory muscle activity. This is frequently associated with increased residual volume, frequent sighing and an irregular pattern of respiratory effort. It may be accompanied by true hyperventilation in the minority of subjects. Extra thoracic forms include paradoxical vocal cord dysfunction and the increasingly recognised supra-glottic 'laryngomalacia' commonly seen in young sportsmen and women. While the two forms would appear to be two discreet entities they often share common factors in aetiology and respond to similar interventions. Hence both forms are considered in this review which aims to generate a more coherent approach to understanding, diagnosing and treating these conditions. PMID- 25499574 TI - Cortical morphology and early adverse birth events in men with first-episode psychosis. AB - BACKGROUND: Reduced cortical gray-matter volume is commonly observed in patients with psychosis. Cortical volume is a composite measure that includes surface area, thickness and gyrification. These three indices show distinct maturational patterns and may be differentially affected by early adverse events. The study goal was to determine the impact of two distinct obstetrical complications (OCs) on cortical morphology. METHOD: A detailed birth history and MRI scans were obtained for 36 patients with first-episode psychosis and 16 healthy volunteers. RESULTS: Perinatal hypoxia and slow fetal growth were associated with cortical volume (Cohen's d = 0.76 and d = 0.89, respectively) in patients. However, the pattern of associations differed across the three components of cortical volume. Both hypoxia and fetal growth were associated with cortical surface area (d = 0.88 and d = 0.72, respectively), neither of these two OCs was related to cortical thickness, and hypoxia but not fetal growth was associated with gyrification (d = 0.85). No significant associations were found within the control sample. CONCLUSIONS: Cortical dysmorphology was associated with OCs. The use of a global measure of cortical morphology or a global measure of OCs obscured important relationships between these measures. Gyrification is complete before 2 years and its strong relationship with hypoxia suggests an early disruption to brain development. Cortical thickness matures later and, consistent with previous research, we found no association between thickness and OCs. Finally, cortical surface area is largely complete by puberty and the present results suggest that events during childhood do not fully compensate for the effects of early disruptive events. PMID- 25499575 TI - Circulating biologically active oxidized phospholipids show on-going and increased oxidative stress in older male mice. AB - BACKGROUND: The biologically active phospholipids Platelet-activating Factor (PAF) and oxidatively truncated phospholipids from chemical oxidation are increased in the circulation of rats subject to the oxidant stress of chronic ethanol ingestion. Potentially, circulating inflammatory and apoptotic phospholipids correlate to physiologic oxidative stress. RESULTS: PAF and the common oxidatively truncated and biologically active phospholipid azelaoyl phosphatidylcholine (Az-PC) were significantly increased in the plasma of older mice, and in male mice. PAF and Az-PC are very rapidly cleared from the circulation, which was unaffected by age or sex. Platelets exposed to Az-PC display phosphatidylserine on their surface, and occlusive platelet carotid arterial thrombosis is enhanced by aging. CONCLUSION: Biologically active phospholipids vary in the circulation, with the highest levels being found in older, male mice. Turnover of PAF and the biologically active Az-PC are rapid and are invariant with age and sex, so increased production accounts for the increased concentration and flux of both lipids. Platelets are exposed to plasma Az-PC that depolarizes their mitochondria to increase pro-thrombotic phosphatidylserine expression, and occlusive platelet thrombosis is enhanced in aged mice. SIGNIFICANCE: Oxidatively modified phospholipids are increased in the circulation during common, mild oxidant stresses of aging, or in male compared to female animals. Turnover of these biologically active phospholipids by rapid transport into liver and kidney is unchanged, so circulating levels reflect continuously increased production. PMID- 25499577 TI - A man with generalised lymphadenopathy. PMID- 25499576 TI - Insights into the role of oxidative stress in the pathology of Friedreich ataxia using peroxidation resistant polyunsaturated fatty acids. AB - Friedreich ataxia is an autosomal recessive, inherited neuro- and cardio degenerative disorder characterized by progressive ataxia of all four limbs, dysarthria, areflexia, sensory loss, skeletal deformities, and hypertrophic cardiomyopathy. Most disease alleles have a trinucleotide repeat expansion in the first intron of the FXN gene, which decreases expression of the encoded protein frataxin. Frataxin is involved in iron-sulfur-cluster (ISC) assembly in the mitochondrial matrix, and decreased frataxin is associated with ISC-enzyme and mitochondrial dysfunction, mitochondrial iron accumulation, and increased oxidative stress. To assess the role of oxidative stress in lipid peroxidation in Friedreich ataxia we used the novel approach of treating Friedreich ataxia cell models with polyunsaturated fatty acids (PUFAs) deuterated at bis-allylic sites. In ROS-driven oxidation of PUFAs, the rate-limiting step is hydrogen abstraction from a bis-allylic site; isotopic reinforcement (deuteration) of bis-allylic sites slows down their peroxidation. We show that linoleic and alpha-linolenic acids deuterated at the peroxidation-prone bis-allylic positions actively rescue oxidative-stress-challenged Friedreich ataxia cells. The protective effect of the deuterated PUFAs is additive in our models with the protective effect of the CoQ10 analog idebenone, which is thought to decrease the production of free radicals. Moreover, the administration of deuterated PUFAs resulted in decreased lipid peroxidation as measured by the fluorescence of the fatty acid analog C11 BODIPY (581/591) probe. Our results are consistent with a role for lipid peroxidation in Friedreich ataxia pathology, and suggest that the novel approach of oral delivery of isotope-reinforced PUFAs may have therapeutic potential in Friedreich ataxia and other disorders involving oxidative stress and lipid peroxidation. PMID- 25499578 TI - Factors contributing to the effectiveness of physical activity counselling in primary care: a realist systematic review. AB - OBJECTIVE: Physical activity (PA) counselling in primary care increases PA but is not consistently practiced. This study examined factors that optimise the delivery and impact of PA counselling. METHODS: A realist systematic review based on the PRECEDE-PROCEED model and RAMESES principles was conducted to identify essential components of PA counselling. MEDLINE, EMBASE, Cochrane Library, PsycINFO, and Physical Education Index were searched from 2000 to 2013 for studies that evaluated family practice PA counselling. RESULTS: Of 1546 articles identified, 10 were eligible for review (3 systematic reviews, 5 randomised controlled trials, 2 observational studies). Counselling provided by clinicians or counsellors alone that explored motivation increased self-reported PA at least 12 months following intervention. Multiple sessions may sustain increased PA beyond 12 months. CONCLUSION: Given the paucity of eligible studies and limited detail reported about interventions, further research is needed to establish the optimal design and delivery of PA counselling. Research and planning should consider predisposing, reinforcing and enabling design features identified in these studies. PRACTICE IMPLICATIONS: Since research shows that PA counselling promotes PA but is not widely practiced, primary care providers will require training and tools to operationalize PA counselling. PMID- 25499580 TI - The site frequency spectrum of dispensable genes. AB - The differences between DNA-sequences within a population are the basis to infer the ancestral relationship of the individuals. Within the classical infinitely many sites model, it is possible to estimate the mutation rate based on the site frequency spectrum, which is comprised by the numbers C1,...,Cn-1 where n is the sample size and Cs is the number of site mutations (Single Nucleotide Polymorphisms, SNPs) which are seen in s genomes. Classical results can be used to compare the observed site frequency spectrum with its neutral expectation, E[Cs]=theta2/s, where theta2 is the scaled site mutation rate. In this paper, we will relax the assumption of the infinitely many sites model that all individuals only carry homologous genetic material. Especially, it is today well-known that bacterial genomes have the ability to gain and lose genes, such that every single genome is a mosaic of genes, and genes are present and absent in a random fashion, giving rise to the dispensable genome. While this presence and absence has been modeled under neutral evolution within the infinitely many genes model in Baumdicker et al. (2010), we link presence and absence of genes with the numbers of site mutations seen within each gene. In this work we derive a formula for the expectation of the joint gene and site frequency spectrum, denoted by Gk,s, the number of mutated sites occurring in exactly s gene sequences, while the corresponding gene is present in exactly k individuals. We show that standard estimators of theta2 for dispensable genes are biased and that the site frequency spectrum for dispensable genes differs from the classical result. PMID- 25499579 TI - The motivational basis of cognitive determinants of addictive behaviors. AB - If a person expects that (a) drinking alcohol or using another addictive substance will enhance positive affect or reduce negative affect, and (b) there is a strong likelihood that these desirable consequences will occur if the substance is used, that person is likely to form a goal of using the substance. The theoretical framework presented here predicts that when that happens, the person will have a current concern for using the substance, with the person thereby sensitized to environmental stimuli related to procuring and using the substance. One indication of the sensitization is selective attention to substance-related stimuli, which is correlated with urges to use and actual use of the substance. Accordingly, interventions have been developed for helping substance users to overcome substance-related attentional bias. The results are promising for reducing both the attentional bias and the substance use. Finally, we discuss other cognitive-modification and motivational techniques that have been evaluated with promising results. PMID- 25499583 TI - Down-sizing of neuronal network activity and density of presynaptic terminals by pathological acidosis are efficiently prevented by Diminazene Aceturate. AB - Local acidosis is associated with neuro-inflammation and can have significant effects in several neurological disorders, including multiple sclerosis, brain ischemia, spinal cord injury and epilepsy. Despite local acidosis has been implicated in numerous pathological functions, very little is known about the modulatory effects of pathological acidosis on the activity of neuronal networks and on synaptic structural properties. Using non-invasive MRI spectroscopy we revealed protracted extracellular acidosis in the CNS of Experimental Autoimmune Encephalomyelitis (EAE) affected mice. By multi-unit recording in cortical neurons, we established that acidosis affects network activity, down-sizing firing and bursting behaviors as well as amplitudes. Furthermore, a protracted acidosis reduced the number of presynaptic terminals, while it did not affect the postsynaptic compartment. Application of the diarylamidine Diminazene Aceturate (DA) during acidosis significantly reverted both the loss of neuronal firing and bursting and the reduction of presynaptic terminals. Finally, in vivo DA delivery ameliorated the clinical disease course of EAE mice, reducing demyelination and axonal damage. DA is known to block acid-sensing ion channels (ASICs), which are proton-gated, voltage-insensitive, Na(+) permeable channels principally expressed by peripheral and central nervous system neurons. Our data suggest that ASICs activation during acidosis modulates network electrical activity and exacerbates neuro-degeneration in EAE mice. Therefore pharmacological modulation of ASICs in neuroinflammatory diseases could represent a new promising strategy for future therapies aimed at neuro-protection. PMID- 25499584 TI - [Combined hamartoma of the retina and retinal pigment epithelium. Anti-VEGF treatment of the associated choroidal neovascular membranes]. AB - CASE REPORT: A 58 year-old female was diagnosed with a juxtapapillary combined hamartoma of the retina and retinal pigment epithelium (CHR-RPE) in her left eye 14 years ago. Her visual acuity in that eye was 20/20. Recently, she came to our department with a sudden visual loss and metamorphopsis in her left eye. After performing funduscopy, angiography and OCT, she was diagnosed with choroidal neovascular membrane (CNVM) at lesion border, and started on antiangiogenic therapy. DISCUSSION: CHR-RPE, despite being a benign condition, may become complicated with severe visual impairment. Antiangiogenic therapy provides a good alternative to photodynamic therapy or laser photocoagulation for treatment of CNVM, avoiding adding iatrogenesis from these treatment to the complications associated with this pathology. PMID- 25499585 TI - Rectal perforation with an intrauterine device: a case report. AB - A 27-year-old woman presented for routine examination 1 year after intrauterine device (IUD) placement; strings were not visualized. The device was found to be penetrating through the rectal mucosa. It was removed easily through the rectum during an examination under anesthesia. Perforated IUDs with rectal involvement require thoughtful surgical planning to optimize outcomes. PMID- 25499586 TI - Effectiveness of in vitro fertilization in women with previous tubal sterilization. AB - OBJECTIVE: The objective was to determine the effectiveness of in vitro fertilization (IVF) on live-delivery rates in women who had previously undergone tubal sterilization. STUDY DESIGN: We examined first IVF live deliveries for women aged 20-44 years at their first embryo transfer (ET) with history of hospital admission for tubal sterilization in Western Australia (WA). The ET cycles (n=178) were ascertained over the period of 1996 to 2010 using WA hospital records. A control group of subfertile women matched by age was randomly selected (n=178). We used Kaplan-Meier curves and life-table analysis to evaluate the cumulative live-delivery rates. RESULTS: An overall cumulative live-delivery rate in women who had undergone previous tubal sterilization (31%) was comparable to that of subfertile controls (34%) within the first 24 months. Younger women (aged 20-34 years) with previous sterilization (34%) were slightly more likely to deliver an IVF live baby than older women (aged 35-39 and 40-44 years) (33% and 22%, respectively), although this difference was not statistically significant (p=.449). CONCLUSION: Women who desire fertility after a tubal sterilization procedure and undergo IVF have rates of pregnancy similar to age-matched subfertile IVF control patients. IMPLICATIONS: In vitro fertilization success in women who had undergone previous tubal sterilization is similar to that of the subfertile controls and thus does not depend on past fertility. Age is the most important predictive factor in achieving pregnancy. PMID- 25499587 TI - Intracesarean insertion of the Copper T380A versus 6 weeks postcesarean: a randomized clinical trial. AB - OBJECTIVES: To compare rates of Copper T380A intrauterine device (IUD) utilization and satisfaction with immediate versus delayed IUD insertion after cesarean delivery in Kampala, Uganda. METHODS: This study was a randomized clinical trial of women undergoing cesarean section who desired an IUD in Kampala, Uganda. Participants were randomly assigned to IUD insertion at the time of cesarean delivery or 6weeks afterward. The primary outcome was IUD utilization at 6months after delivery. RESULTS: Among 68 women who underwent randomization, an IUD was inserted in 100% (34/34) of the women in the immediate insertion group and in 53% (18/34) in the delayed group. IUD use at 6 months was higher in the immediate insertion group (93% vs. 50% after delayed insertion; p<.0001). Infection and expulsion were rare and did not differ between groups. When we pooled both groups and looked at IUD users compared to nonusers, 91% (39/43) of IUD users were satisfied or very satisfied with their contraceptive method compared to 44% (11/25) of nonusers (p<.0001). Women who chose not to be in the study or had the IUD removed often did so because of perceived husband or community disapproval. CONCLUSION: The 6-month utilization of an IUD after immediate insertion was significantly higher than after delayed insertion without increased complications. Contraceptive satisfaction was significantly higher among IUD users than nonusers. Community and husband attitudes influence IUD utilization and continuation in Kampala, Uganda. IMPLICATIONS: This work is important because it shows the safety and efficacy of providing IUDs during cesarean section in a setting where access to any healthcare, including contraception, can be extremely limited outside of childbearing and the consequences of an unintended, closely spaced pregnancy after a cesarean section can be life threatening. PMID- 25499588 TI - Barriers to and enablers of contraceptive use among adolescent females and their interest in an emergency department based intervention. AB - OBJECTIVE: Over 15 million adolescents, many at high risk for pregnancy, use emergency departments (EDs) in the United States annually, but little is known regarding reasons for failure to use contraceptives in this population. The purpose of this study was to identify the barriers to and enablers of contraceptive use among adolescent females using the ED and determine their interest in an ED-based pregnancy prevention intervention. STUDY DESIGN: We conducted semistructured, open-ended interviews with females in an urban ED. Eligible females were 14-19 years old, sexually active, presenting for reproductive health complaints and at risk for pregnancy, defined as nonuse of effective (per the World Health Organization) contraception. Interviews were recorded, transcribed and coded based on thematic analysis. Enrollment continued until no new themes emerged. A modified Health Belief Model guided the organization of the data. RESULTS: Participants (n=14) were predominantly Hispanic (93%), insured (93%) and in a sexual relationship (86%). The primary barrier to contraceptive use was perceived health risk, including effects on menstruation, weight and future fertility. Other barriers consisted of mistrust in contraceptives, ambivalent pregnancy intentions, uncertainty about the future, partner's desire for pregnancy and limited access to contraceptives. Enablers of past contraceptive use included the presence of a school-based health clinic and clear plans for the future. All participants were receptive to ED-based pregnancy prevention interventions. CONCLUSIONS: The identified barriers and enablers influencing hormonal contraceptive use can be used to inform the design of future ED-based adolescent pregnancy prevention interventions. IMPLICATIONS: Adolescents who visit the emergency department (ED) identify contraceptive side effects, mistrust in contraceptives, limited access, pregnancy ambivalence and partner pregnancy desires as barriers to hormonal contraception use. They expressed interest in an ED-based intervention to prevent adolescent pregnancy; such an intervention could target these themes to maximize effectiveness. PMID- 25499589 TI - Adjunct mifepristone for cervical preparation prior to dilation and evacuation: a randomized trial. AB - OBJECTIVE: The objective was to investigate mifepristone as a potential adjunct to cervical preparation for surgical abortion after 19 weeks of gestation, with the aim of improving procedure access, convenience and comfort. METHODS: This is a site-stratified, block-randomized, noninferiority trial of 50 women undergoing surgical abortion between 19 and 23 6/7 weeks of gestation randomized to receive either one set of osmotic dilators plus mifepristone the day prior to procedure (mifepristone group) or two sets of osmotic dilators (placed 18-24 h apart) in the 2 days prior to procedure (control group). All subjects received preprocedure misoprostol. Primary outcome was procedure time. Secondary outcomes included preoperative cervical dilation, ease of procedure, and side effects and pain experienced by subjects. RESULTS: Mean gestational age was similar between groups (20 weeks); more nulliparous subjects were randomized to the mifepristone group (46% vs. 12%, p=.009). Mean procedure times were similar: mifepristone group 11:52 (SD 5:29) vs. control group 10:56 (SD 5:08); difference in means -56s, with confidence interval (95% CI -4:09 to +2:16) not exceeding the 5-min difference we a priori defined as clinically significant. Preprocedure cervical dilation did not differ and was >3cm for the majority of subjects in both groups. There was no difference (p=.6) in ease of procedure reported by providers. Preoperative (postmisoprostol) pain and postoperative pain levels were greater with mifepristone (p = 0.02 and p= 0.04 respectively). Overall subject experience was not different (p=0.80), with most reporting a "better than expected" experience. CONCLUSIONS: Mifepristone with one set of osmotic dilators and misoprostol did not result in longer procedure times or less cervical dilation than serial (two sets) of osmotic dilators and misoprostol, and has the potential to improve access to second trimester abortion without compromising safety. IMPLICATIONS: Use of mifepristone for cervical preparation before surgical abortion after 19 weeks allows for fewer visits and fewer osmotic dilators without compromising cervical dilation or increasing procedure time. PMID- 25499590 TI - Grief after second-trimester termination for fetal anomaly: a qualitative study. AB - OBJECTIVES: We aimed to qualitatively evaluate factors that contribute to and alleviate grief associated with termination of a pregnancy for a fetal anomaly and how that grief changes over time. STUDY DESIGN: We conducted a longitudinal qualitative study of decision satisfaction, grief and coping among women undergoing termination (dilation and evacuation or induction termination) for fetal anomalies and other complications. We conducted three post-procedure interviews at 1-3 weeks, 3 months and 1 year. We used a generative thematic approach to analyze themes related to grief using NVivo software program. RESULTS: Of the 19 women in the overall study, 13 women's interviews were eligible for analysis of the grief experience. Eleven women completed all three interviews, and two completed only the first interview. Themes that contributed to grief include self-blame for the diagnosis, guilt around the termination decision, social isolation related to discomfort with abortion and grief triggered by reminders of pregnancy. Social support and time are mechanisms that serve to alleviate grief. CONCLUSIONS: Pregnancy termination in this context is experienced as a significant loss similar to other types of pregnancy loss and is also associated with real and perceived stigma. Women choosing termination for fetal anomalies may benefit from tailored counseling that includes dispelling misconceptions about cause of the anomaly. In addition, efforts to decrease abortion stigma and increase social support may improve women's experiences and lessen their grief response. IMPLICATIONS: The nature and course of grief after second-trimester termination for fetal anomaly are, as of yet, poorly understood. With improved understanding of how women grieve over time, clinicians can better recognize the significance of their patients' suffering and offer tools to direct their grief toward positive coping. PMID- 25499591 TI - Astragalus polysaccharides repress myocardial lipotoxicity in a PPARalpha dependent manner in vitro and in vivo in mice. AB - BACKGROUND: The role of peroxisome proliferator-activated receptor alpha (PPARalpha) in the development of myocardial lipotoxicity is widely observed in diabetic disorders. Thus, we investigated if treatment of Astragalus polysaccharides modulates lipotoxic cardiomyopathy both in vivo and in vitro through PPARalpha mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: The effects of Astragalus polysaccharides (APS) on PPARalpha target gene expression and protein levels were tested in vitro and in vivo, including in mice with PPARalpha cardiac restricted overexpression [myosin heavy chain (MHC)-PPARalpha] and in H9c2 embryonic rat cardiomyocytes with or without PPARalpha agonist. Echocardiographic studies, analyses of myocardial triglyceride and cardiac fuel utilization analyses were also performed in MHC-PPARalpha mice. Treatment with APS prevented myocardial triglyceride accumulation and cardiac dysfunction in the MHC-PPARalpha mice, with the normalization of energy metabolic derangements in hearts including reduced free fatty acids utilization and increased glucose uptake. Consistently, both in the MHC-PPARalpha hearts and H9c2 cardiomyocytes with PPARalpha agonist, the activation of PPARalpha gene regulatory pathway involved in FFA-oxidation was down-regulated by APS treatment, while the suppression of PPARalpha target genes involved in glucose uptake and oxidation was normalized by APS administration. CONCLUSIONS: Therapy with APS could prevent the development of lipotoxic cardiomyopathy through a mechanism mainly dependent on the cardiac PPARalpha mediated regulatory pathways. PMID- 25499592 TI - A Low-Intensity Mobile Health Intervention With and Without Health Counseling for Persons With Type 2 Diabetes, Part 1: Baseline and Short-Term Results From a Randomized Controlled Trial in the Norwegian Part of RENEWING HEALTH. AB - BACKGROUND: Self-management support for people with type 2 diabetes is essential in diabetes care. Thus, mobile health technology with or without low-intensity theory-based health counseling could become an important tool for promoting self management. OBJECTIVES: The aim was to evaluate whether the introduction of technology-supported self-management using the Few Touch Application (FTA) diabetes diary with or without health counseling improved glycated hemoglobin (HbA1c) levels, self-management, behavioral change, and health-related quality of life, and to describe the sociodemographic, clinical, and lifestyle characteristics of the participants after 4 months. METHODS: A 3-armed randomized controlled trial was conducted in Norway during 2011-2013. In the 2 intervention groups, participants were given a mobile phone for 1 year, which provided access to the FTA diary, a self-help tool that recorded 5 elements: blood glucose, food habits, physical activity, personal goal setting, and a look-up system for diabetes information. One of the intervention groups was also offered theory based health counseling with a specialist diabetes nurse by telephone for 4 months from baseline. Both intervention groups and the control group were provided usual care according to the national guidelines. Adults with type 2 diabetes and HbA1c >=7.1% were included (N=151). There were 3 assessment points: baseline, 4 months, and 1 year. We report the short-term findings after 4 months. HbA1c was the primary outcome and the secondary outcomes were self-management (Health Education Impact Questionnaire, heiQ), behavioral change (diet and physical activity), and health-related quality of life (SF-36 questionnaire). The data were analyzed using univariate methods (ANOVA), multivariate linear, and logistic regression. RESULTS: Data were analyzed from 124 individuals (attrition rate was 18%). The groups were well balanced at baseline. There were no differences in HbA1c between groups after 4 months, but there was a decline in all groups. There were changes in self-management measured using the health service navigation item in the heiQ, with improvements in the FTA group compared to the control group (P=.01) and in the FTA with health counseling group compared with both other groups (P=.04). This may indicate an improvement in the ability of patients to communicate health needs to their health care providers. Furthermore, the FTA group reported higher scores for skill and technique acquisition at relieving symptoms compared to the control group (P=.02). There were no significant changes in any of the domains of the SF-36. CONCLUSIONS: The primary outcome, HbA1c, did not differ between groups after 4 months. Both of the intervention groups had significantly better scores than the control group for health service navigation and the FTA group also exhibited improved skill and technique acquisition. PMID- 25499593 TI - Anaortic OPCAB for high-risk patients. PMID- 25499594 TI - Right-to-left interatrial shunt secondary to right hemidiaphragmatic paralysis: an unusual scenario for urgent percutaneous closure of patent foramen ovale. AB - A 66 year-old female presented with a refractory hypoxaemia in association with an isolated paralysis of the right hemidiaphragm. Transoesophageal echocardiography (TEE) with both colour Doppler and bubble test demonstrated a significant patent foramen ovale (PFO)-mediated right-to-left shunt (RTLS) without an increased interatrial pressure gradient. The PFO was urgently closed by deployment of an AMPLATZER((r)) occluder device, resulting in complete recovery of the arterial oxygen saturation and patient's symptoms. As noted on TEE, the RTLS was due to redirection of blood flow from the inferior vena cava directly through the PFO secondary to distortion of the cardiac anatomy by right hemidiaphragmatic paralysis. PMID- 25499595 TI - The merger of Regulatory Peptides and Peptides. PMID- 25499596 TI - MRI-guided breast biopsy: outcomes and effect on patient management. AB - INTRODUCTION: The purpose of this study was to correlate the pathology results of MRI-guided breast biopsies at our institution with MRI findings and patient clinical history characteristics. The effect of MRI-guided breast biopsies on surgical management in patients with a new diagnosis of breast cancer was also assessed. PATIENTS AND METHODS: In this Health Insurance Portability and Accountability Act-compliant study we retrospectively reviewed all MRI-guided breast biopsies performed from March 2006 to May 2012. Clinical history, MRI features, and pathology outcomes were reviewed. In patients who underwent breast MRI to evaluate extent of disease, any change in surgical management resulting from the MRI-guided biopsy was recorded. Statistical analysis included binary logistic regression and independent Student t test. RESULTS: Two-hundred fifteen lesions in 168 patients were included, of which 23 (10.7%) were malignant, 43 (20%) were high-risk, and 149 (69.3%) were benign. No clinical characteristic was associated with malignancy in our cohort. MRI features associated with malignancy were: larger size (mean 2.6 cm vs. 1.3 cm; P = .046), washout kinetics (18% malignancy rate; P = .02), and marked background parenchymal enhancement (40% malignancy rate; P < .001-.03). Nineteen (28%) of the 67 patients with a new diagnosis of breast cancer who underwent MRI-guided breast biopsy had a change in surgical management based on the biopsy result. CONCLUSION: Malignancy rate was associated with lesion size, washout kinetics, and marked background enhancement of the breast parenchyma but was not associated with any clinical history characteristics. Preoperative MRI-guided breast biopsies changed surgical management in 28% of women with a new diagnosis of breast cancer. PMID- 25499597 TI - Symptomatic breast cancer diagnosis and multimodal management in women aged 40 to 50 years; consequences of current mammographic screening programs. AB - INTRODUCTION: Consensus exists that screening mammography is appropriate for women aged 50 to 69 years. However, the effectiveness of such screening for women aged 40 to 50 years is still questioned. The aim of our study was to analyze breast cancer management in the 40- to 50-year age group. We also wished to determine the proportion of patients with a significant family history and whether this was associated with more advanced disease. PATIENTS AND METHODS: All female patients with primary breast cancer diagnosed between 40 and 50 years of age were included over a 4-year period. The database of the National Breast Cancer Research Institute was interrogated, and a chart and radiology review carried out to obtain relevant details of clinical presentation, family history, radiological findings, and treatments undertaken. RESULTS: Three hundred thirty four patients were diagnosed in this cohort during the study period. Twenty-two percent of those diagnosed had a family history of breast cancer with 1.8% having a genetically confirmed predisposition to breast cancer. A significant proportion of patients presented with advanced disease, with 50% of patients having nodal involvement and 3% who presented with distant metastases. The overall rate of mastectomy was 47%, with minimal variation between the surgeons who performed the surgeries. More than half of the patients in our analysis underwent axillary clearance (51%). CONCLUSION: Our results indicate that a large proportion of patients in the 40- to 50-year age group presented with advanced disease and required aggressive surgical and adjuvant treatment. The presence of a family history did not identify a subgroup with more advanced disease at presentation. PMID- 25499598 TI - Sleep-disordered breathing, sleep duration, and childhood overweight: a longitudinal cohort study. AB - OBJECTIVES: To examine independent associations between sleep-disordered breathing (SDB), sleep duration from birth through 6.75 years, and body mass index (BMI) through 15 years of age in a population-based cohort. STUDY DESIGN: The Avon Longitudinal Study of Parents and Children collected parent questionnaire data on child sleep duration and SDB symptoms from birth through 6.75 years and child BMI from the Avon Longitudinal Study of Parents and Children research clinics (n = 1899). For SDB, logistic regression models-minimal, confounder, and confounder + sleep duration adjusted-examined associations with BMI at 7, 10, and 15 years of age. For short sleep duration (<=10th percentile), comparable SDB-adjusted models examined associations with BMI at 15 years of age. RESULTS: Children with the worst SDB symptoms vs asymptomatic children, had increased odds of overweight at 7 (OR = 2.08, 95% CI = 1.04-4.17), 10 (OR = 1.79, 95% CI = 1.02-3.16), and 15 years of age (OR = 2.25, 95% CI = 1.27-3.97) in models adjusted for sleep duration. Similarly, short sleep duration at ~5-6 years was associated with overweight at 15 years, independent of SDB. Children with short sleep duration at 4.75 years were more likely to be overweight at 15 years in minimally (OR = 2.21, 95% CI = 1.52-3.20), confounder (OR = 1.99, 95% CI = 1.34-2.96), and SDB-adjusted (OR = 2.04, 95% CI = 1.36-3.04) models. CONCLUSIONS: Both SDB and short sleep duration significantly and independently increase children's odds of becoming overweight. Findings underscore the potential importance of early identification and remediation of SDB, along with insufficient sleep, as strategies for reducing childhood obesity. PMID- 25499599 TI - Health related quality of life improvement in breast cancer patients: secondary outcome from a simple blinded, randomised clinical trial. AB - OBJECTIVE: To determine the effectiveness of an early physiotherapy intervention for the prevention of secondary lymphoedema on health-related quality of life in women who also received an education program after breast cancer surgery. METHODS: One hundred and fifty three women diagnosed with unilateral breast cancer (stage I-II) treated with breast surgery, which included axillary lymph node dissection, from Hospital Principe de Asturias, Alcala de Henares, Madrid (Spain) were randomly assigned into two groups. Subjects in early physiotherapy group (n = 76) received a physiotherapy intervention combined with a therapeutic education program; women in the control group (n = 77) received only the therapeutic education program. Both interventions were delivered by two different physiotherapists of Physiotherapy in Women's Health Research Group at Physiotherapy Department of Alcala University. Health related quality of life was measured with EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires in 5 assessments: after surgery just before group interventions started (A1), after the 3-week group interventions finished (A2); and a follow-up period in 3 (A3), 6 (A4) and 12 (A5) months after surgical intervention. RESULTS: Greater change in quality of life was observed for early physiotherapy group arm compared to control group, although no strong statistical evidence was found (p > .05) for most of the dimensions except for physical function and social function areas (p < .003). CONCLUSIONS: The control group with therapeutic education program reported a clear improvement in the perception of quality of life. Adding early physiotherapy to the therapeutic education program did not show statistically significant changes in the global score or in most of the dimensions, but showed an improvement in the physical and social dimensions. PMID- 25499602 TI - Content validity of the NCCN-FACT ovarian symptom index-18 (NFOSI-18). AB - OBJECTIVE: This study examined the content validity of the NCCN-FACT Ovarian Symptom Index-18 (NFOSI-18), an advanced ovarian cancer symptom index comprised of symptoms perceived as most important by clinical experts and women with advanced ovarian cancer. METHODS: Eighteen women with advanced ovarian cancer completed the NFOSI-18 and participated in cognitive interviews to assess: (a) the understandability of the NFOSI-18; and (b) the things patients have in mind when responding to the item, "I am bothered by side effects of treatment;" and (c) the interpretation patients place on items relating to fatigue and lack of energy. Interviews were recorded and transcribed for qualitative analysis. RESULTS: All but 2 (89%) participants indicated that each item was clear and understandable and the same proportion (89%) stated they were "very confident" or "confident" about providing accurate answers to all but one item. When responding to the item, "I am bothered by side effects of treatment," fatigue, nausea, and neuropathy constituted the most frequently mentioned concerns. Among the participants who were asked, eight participants responded that "fatigue" and "lack of energy" were the same concept and nine responded they were different. Participants associated "fatigue" with tiredness and associated "lack of energy" with the inability to perform daily tasks and activities. CONCLUSIONS: The findings support the content validity of the NFOSI-18. Item revisions, deletions or additions do not appear warranted. Future research can address the reliability and validity of the NFOSI-18 in clinical research. PMID- 25499600 TI - A Hierarchical Factor Model of Executive Functions in Adolescents: Evidence of Gene-Environment Interplay. AB - Executive functions (EF) are a complex set of neurodevelopmental, higher-ordered processes that are especially salient during adolescence. Disruptions to these processes are predictive of psychiatric problems in later adolescence and adulthood. The objectives of the current study were to characterize the latent structure of EF using bifactor analysis and to investigate the independent and interactive effects of genes and environments on EF during adolescence. Using a representative young adolescent sample, we tested the interaction of a polymorphism in the serotonin transporter gene (5-HTTLPR) and parental supervision for EF through hierarchical linear regression. To account for the possibility of a hierarchical factor structure for EF, a bifactor analysis was conducted on the eight subtests of the Delis-Kaplan Executive Functions System (D KEFS). The bifactor analysis revealed the presence of a general EF construct and three EF subdomains (i.e., conceptual flexibility, inhibition, and fluency). A significant 5-HTTLPR by parental supervision interaction was found for conceptual flexibility, but not for general EF, fluency or inhibition. Specifically, youth with the L/L genotype had significantly lower conceptual flexibility scores compared to youth with S/S or S/L genotypes given low levels of parental supervision. Our findings indicate that adolescents with the L/L genotype were especially vulnerable to poor parental supervision on EF. This vulnerability may be amenable to preventive interventions. PMID- 25499601 TI - Hormone metabolism pathway genes and mammographic density change after quitting estrogen and progestin combined hormone therapy in the California Teachers Study. AB - INTRODUCTION: Mammographic density (MD) is a strong biomarker of breast cancer risk. MD increases after women start estrogen plus progestin therapy (EPT) and decreases after women quit EPT. A large interindividual variation in EPT associated MD change has been observed, but few studies have investigated genetic predictors of the EPT-associated MD change. Here, we evaluate the association between polymorphisms in hormone metabolism pathway genes and MD changes when women quit EPT. METHODS: We collected mammograms before and after women quit EPT and genotyped 405 tagging single nucleotide polymorphisms (SNPs) in 30 hormone metabolism pathway genes in 284 non-Hispanic white participants of the California Teachers Study (CTS). Participants were ages 49 to 71 years at time of mammography taken after quitting EPT. We assessed percent MD using a computer assisted method. MD change was calculated by subtracting MD of an 'off-EPT' mammogram from MD of an 'on-EPT' (that is baseline) mammogram. Linear regression analysis was used to investigate the SNP-MD change association, adjusting for the baseline 'on-EPT' MD, age and BMI at time of baseline mammogram, and time interval and BMI change between the two mammograms. An overall pathway and gene level summary was obtained using the adaptive rank truncated product (ARTP) test. We calculated 'P values adjusted for correlated tests (P(ACT))' to account for multiple testing within a gene. RESULTS: The strongest associations were observed for rs7489119 in SLCO1B1, and rs5933863 in ARSC. SLCO1B1 and ARSC are involved in excretion and activation of estrogen metabolites of EPT, respectively. MD change after quitting was 4.2% smaller per minor allele of rs7489119 (P = 0.0008; P(ACT) = 0.018) and 1.9% larger per minor allele of rs5933863 (P = 0.013; P(ACT) = 0.025). These individual SNP associations did not reach statistical significance when we further used Bonferroni correction to consider the number of tested genes. The pathway level summary ARTP P value was not statistically significant. CONCLUSIONS: Data from this longitudinal study of EPT quitters suggest that genetic variation in two hormone metabolism pathway genes, SLCO1B1 and ARSC, may be associated with change in MD after women stop using EPT. Larger longitudinal studies are needed to confirm our findings. PMID- 25499603 TI - Metformin and the risk of endometrial cancer: a population-based cohort study. AB - OBJECTIVE: While some observational studies have suggested a protective effect of metformin on incident cancer, concerns about potential bias remain. We compared the incidence of endometrial cancer in metformin versus sulfonylurea initiators. Research design and methods We conducted a retrospective cohort analysis using US healthcare claims (MarketScan(r)), 2000-2011. We identified new users of metformin versus sulfonylureas with no prior cancer diagnoses and followed them until a diagnosis of endometrial cancer, hysterectomy, treatment change, or disenrollment. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards, using an as-treated analytic approach. Stabilized inverse probability of treatment weights were used to adjust for potential confounding at baseline. RESULTS: Of 541,128 eligible women, 456,838 (84%) initiated metformin and 84,290 (16%) initiated sulfonylurea. The treatment groups differed at baseline in terms of age and recent diagnosis codes for diabetes, polycystic ovarian syndrome, and endometrial hyperplasia. Over a median follow-up of 1.2 (IQR 0.4-2.3) years and a total of 2,030,914 person-years, 729 women developed endometrial cancer. Metformin initiation was associated with a lower risk of endometrial cancer in the unadjusted analysis (HR 0.81, 95% CI 0.67 0.97). However, after balancing baseline covariates across groups, metformin was not associated with a reduced risk of endometrial cancer (HR 1.09, 95% CI 0.88 1.35). This finding was consistent across multiple sensitivity analyses and subgroup analyses in diabetic patients and relevant age groups. CONCLUSIONS: In this population-based cohort of >500,000 women, initiating metformin compared with sulfonylureas was not associated with a reduced risk of developing endometrial cancer. PMID- 25499604 TI - 1H-MRS of the anterior cingulate cortex in childhood and adolescent obsessive compulsive disorder: a case-control study. AB - Abnormal glutamate concentrations in the anterior cingulate cortex (ACC) have been identified in children and adults with obsessive-compulsive disorder (OCD). The purpose of the present study was to measure in vivo (1)H-MRS neurometabolite concentrations in the ACC of children and adolescents with OCD, in order to identify metabolite abnormalities compared to healthy controls and to assess their relationship with clinical variables. 3T proton-magnetic resonance spectroscopy was used to probe ACC biochemistry in 47 paediatric and adolescent OCD patients (11-18 years old) compared to 31 healthy subjects of similar age, sex and estimated intellectual quotient. There were no significant differences in the concentration of glutamate plus glutamine (Glx) adjusted for CSF between OCD patients and healthy controls [F1,74=0.00; P=0.943], but there were significant differences in the concentration of Glx adjusted for CSF in paediatric and adolescent OCD patients according to duration of illness (less than or more than 24 months) [F2,73=3.95; P=0.024]. In addition, we found significantly lower levels of myo-inositol adjusted for CSF in the ACC [F1,74=5.686; P=0.02] in patients compared with controls. The present findings do not confirm the hypothesis of differences in Glx concentrations in the ACC between children and adolescents with OCD and healthy controls; however, the observation of differences in the Glx concentration in children and adolescent OCD patients depending on the duration of illness is of interest. PMID- 25499605 TI - Pharmacogenetic predictor of extrapyramidal symptoms induced by antipsychotics: multilocus interaction in the mTOR pathway. AB - Antipsychotic (AP) treatment-emergent extrapyramidal symptoms (EPS) are acute adverse reactions of APs. The aim of the present study is to analyze gene-gene interactions in nine genes related to the mTOR pathway, in order to develop genetic predictors of the appearance of EPS. 243 subjects (78 presenting EPS: 165 not) from three cohorts participated in the present study: Cohort 1, patients treated with risperidone, (n=114); Cohort 2, patients treated with APs other than risperidone (n=102); Cohort 3, AP-naive patients with first-episode psychosis treated with risperidone, paliperidone or amisulpride, n=27. We analyzed gene gene interactions by multifactor dimensionality reduction assay (MDR). In Cohort 1, we identified a four-way interaction, including the rs1130214 (AKT1), rs456998 (FCHSD1), rs7211818 (Raptor) and rs1053639 (DDIT4), that correctly predicted 97 of the 114 patients (85% accuracy). We validated the predictive power of the four way interaction in Cohort 2 and in Cohort 3 with 86% and 88% accuracy respectively. We develop and validate a powerful pharmacogenetic predictor of AP induced EPS. For the first time, the mTOR pathway has been related to EPS susceptibility and AP response. However, validation in larger and independent populations will be necessary for optimal generalization. PMID- 25499606 TI - Enzymatic characterization of ELOVL1, a key enzyme in very long-chain fatty acid synthesis. AB - X-linked adrenoleukodystrophy (X-ALD) is a neurometabolic disease that is caused by mutations in the ABCD1 gene. ABCD1 protein deficiency impairs peroxisomal very long-chain fatty acid (VLCFA) degradation resulting in increased cytosolic VLCFA CoA levels, which are further elongated by the VLCFA-specific elongase, ELOVL1. In adulthood, X-ALD most commonly manifests as a gradually progressive myelopathy (adrenomyeloneuropathy; AMN) without any curative or disease modifying treatments. We recently showed that bezafibrate reduces VLCFA accumulation in X ALD fibroblasts by inhibiting ELOVL1. Although, in a clinical trial, bezafibrate was unable to lower VLCFA levels in plasma or lymphocytes in X-ALD patients, inhibition of ELOVL1 remains an attractive therapeutic option. In this study, we investigated the kinetic characteristics of ELOVL1 using X-ALD fibroblasts and microsomal fractions from ELOVL1 over-expressing HEK293 cell lines and analyzed the inhibition kinetics of a series of fibrates. Our data show that the CoA esters of bezafibrate and gemfibrozil reduce chain elongation by specifically inhibiting ELOVL1. These fibrates can therefore serve as lead compounds for the development of more potent and more specific inhibitors for ELOVL1. PMID- 25499607 TI - GM1 and GD1a gangliosides modulate toxic and inflammatory effects of E. coli lipopolysaccharide by preventing TLR4 translocation into lipid rafts. AB - Exogenous gangliosides are known to inhibit the effects of Escherichia coli lipopolysaccharide (LPS) in different cells exhibiting anti-inflammatory and immunosuppressive activities. The mechanisms underlying ganglioside action are not fully understood. Because LPS recognition and receptor complex formation occur in lipid rafts, and gangliosides play a key role in their maintenance, we hypothesize that protective effects of exogenous gangliosides would depend on inhibition of LPS signaling via prevention of TLR4 translocation into lipid rafts. The effect of GM1 and GD1a gangliosides on LPS-induced toxic and inflammatory reactions in PC12 cells, and in epithelial cells isolated from the frog urinary bladder, was studied. In PC12 cells, GD1a and GM1 significantly reduced the effect of LPS on the decrease of cell survival and on stimulation of reactive oxygen species production. In epithelial cells, gangliosides decreased LPS-stimulated iNOS expression, NO, and PGE2 production. Subcellular fractionation, in combination with immunoblotting, showed that pretreatment of cells with GM1, GD1a, or methyl-beta-cyclodextrin, completely eliminated the effect of LPS on translocation of TLR4 into lipid rafts. The results are consistent with the hypothesis that ganglioside-induced prevention of TLR4 translocation into lipid rafts could be a mechanism of protection against LPS in various cells. PMID- 25499608 TI - [Mesenteric paraganglioma mimicking an ovarian neoplasm]. PMID- 25499609 TI - [Bowel preparation for colonoscopy. Any significant progress on the horizon?]. AB - Colonoscopy is the method of choice for colorectal cancer screening. To be effective, screening colonoscopy must have high quality standards. The key element is the quality of the preparation. However, up to 20% of patients are inadequately prepared and, at present, anterograde washing is the least tolerated part of the procedure. In the choice of preparation, safety is a prerequisite and efficacy is a priority. Tolerance is a secondary but nevertheless influential factor in the quality of preparation and has consequently been the primary focus of many recent studies. In the last few years, a rapidly increasing number of studies have evaluated new drugs, dosages and adjuvant therapies to improve efficacy and tolerability. These studies have collaterally shown that inadequate preparation and lack of adherence to the prescribed regimen can be partially predicted, making it essential to identify this patient subgroup and invest the necessary effort in their instruction. New individualized and flexible approaches are expected for the different clinical scenarios. The search for the ideal colonoscopy preparation, which would be tolerable, safe and above all effective, remains open. PMID- 25499611 TI - Electrically-induced muscle fatigue affects feedforward mechanisms of control. AB - OBJECTIVE: To investigate the effects of focal muscle fatigue induced by electromyostimulation (EMS) on Anticipatory Postural Adjustments (APAs) during arm flexions performed at maximal velocity. METHODS: Fifteen healthy subjects performed self-paced arm flexions at maximal velocity before and after the completion of fatiguing electromyostimulation programs involving the medial and anterior deltoids and aiming to degrade movement peak acceleration. APA timing and magnitude were measured using surface electromyography. RESULTS: Following muscle fatigue, despite a lower mechanical disturbance evidenced by significant decreased peak accelerations (-12%, p<.001), APAs remained unchanged as compared to control trials (p>.11 for all analyses). CONCLUSION: The fatigue signals evoked by externally-generated contractions seem to be gated by the Central Nervous System and result in postural strategy changes which aim to increase the postural safety margin. SIGNIFICANCE: EMS is widely used in rehabilitation and training programs for its neuromuscular function-related benefits. However and from a motor control viewpoint, the present results show that the use of EMS can lead to acute inaccuracies in predictive motor control. We propose that clinicians should investigate the chronic and global effects of EMS on motor control. PMID- 25499610 TI - Cortical activation and inter-hemispheric sensorimotor coherence in individuals with arm dystonia due to childhood stroke. AB - OBJECTIVE: Dystonia is a disabling motor disorder often without effective therapies. To better understand the genesis of dystonia after childhood stroke, we analyzed electroencephalographic (EEG) recordings in this population. METHODS: Resting spectral power of EEG signals over bilateral sensorimotor cortices (Powrest), resting inter-hemispheric sensorimotor coherence (Cohrest), and task related changes in power (TRPow) and coherence (TRCoh) during wrist extension were analyzed in individuals with dystonia (age 20+/-3years) and healthy volunteers (age 17+/-5years). RESULTS: Ipsilesional TRPow decrease was significantly lower in patients than controls during the more affected wrist task. Force deficits of the affected wrist correlated with reduced alpha TRPow decrease on the ipsilesional and not the contralesional hemisphere. Cohrest was significantly lower in patients than controls, and correlated with more severe dystonia and poorer hand function. Powrest and TRCoh were similar between groups. CONCLUSIONS: The association between weakness and cortical activation during wrist extension highlights the importance of ipsilesional sensorimotor activation on function. Reduction of Cohrest in patients reflects a loss of inter hemispheric connectivity that may result from structural changes and neuroplasticity, potentially contributing to the development of dystonia. SIGNIFICANCE: Cortical and motor dysfunction are correlated in patients with childhood stroke and may in part explain the genesis of dystonia. PMID- 25499612 TI - Dynamic changes of interictal post-spike slow waves toward seizure onset in focal cortical dysplasia type II. AB - OBJECTIVE: A post-spike slow wave (PSS) as part of a spike and slow wave is presumably related to inhibition of epileptic activity. In this study, we evaluated dynamic changes of PSS power toward seizure onset in patients with focal cortical dysplasia (FCD) type II. METHODS: We collected data from 10 pediatric patients with FCD type II, who underwent invasive monitoring with subdural grids. The PSS were averaged based on spike-triggering in 30s epochs during both interictal and preictal periods. We quantitatively measured and compared PSS power and distribution between interictal and preictal periods, both within and outside the seizure onset zone (SOZ). RESULTS: PSS power was significantly higher in all areas during preictal period compared with interictal period. During preictal period, PSS power within SOZ was significantly higher than outside SOZ. From interictal to preictal period, the number of electrodes with high power PSS significantly increased within SOZ and decreased outside SOZ. CONCLUSIONS: Toward seizure onset, PSS power increased in all areas, predominantly within SOZ, and became confined into SOZ in a subset of FCD type II patients. SIGNIFICANCE: Preictal PSS power increase and confinement into SOZ accompany transition to seizures. PMID- 25499613 TI - Somatosensory and motor evoked potentials as biomarkers for post-operative neurological status. AB - SEPs and MEPs (EPs) are often used as surrogates for postoperative clinical endpoints of muscle strength and sensory status, as these true endpoints are not available during surgery. EPs as surrogate endpoints were evaluated using a three step framework (Analytical Validation, Qualification, Utilization) recently proposed by the Institute of Medicine (USA). EP performance on Analytical Validation may surpass that of some other biomarkers used in medicine (tumor size, cardiac troponin). Qualification of EP surrogates was evaluated with guidelines for causation proposed by A.B. Hill, which supported causal links between surgical events and EP changes and revised estimates of EP diagnostic test performance for three illustrative studies. Qualification was also addressed with a 3*2 contingency analysis which demonstrated decreased deficit proportions for EP declines which recovered after surgeon intervention. Utilization of EP surrogates will depend on surgical procedure and alert criteria. EPs are often used as surrogate endpoints to avoid new postoperative deficits. Although not fully validated, their continued use as surrogates during surgical procedures with the potential for significant morbidity is justified by their potential to help avoid injury and the absence of "second best options." PMID- 25499614 TI - Heat-induced changes in the properties of modified skim milks with different casein to whey protein ratios. AB - The heat-induced changes in pH, Ca activity and viscosity after heating at 90 degrees C for 10 min of five modified skim milks were studied as a function of the initial pH of the milks at 25 degrees C. The milks had (i) different ratios of casein : whey protein (0.03, 1.74, 3.97, 5.27 and 7.25), (ii) the same total solids concentration (9% w/w) and (iii) prior to the adjustment of the pH, similar values of pH (6.67-6.74), concentration of serum calcium, and calcium activity, suggesting that the sera have similar mineral composition. The total protein concentrations of the milks differ (2.8-4.0%, w/w). The pH decrease in situ upon heating from 25-90 degrees C was similar for all the modified skim milks with the same starting pH, suggesting that the pH changes to milk on heating were primarily mediated by the initial mineral composition of the serum and were unaffected by the casein : whey protein ratio or the total protein content of the milk. The heat-induced changes in pH and calcium activity were largely reversible on cooling. The two milks with the lowest ratios of casein to whey protein gelled on heating to 90 degrees C for 10 min and cooling to 25 degrees C when the pH was adjusted to pH = 6.2 prior to heating. The viscosities of all other milks with casein to whey protein ratio of 3.97, 5.27 and 7.25 and/or pH >=6.7 prior to heating did not change significantly. The effect of casein : whey protein ratio and the pH are the dominant factors in controlling the susceptibility to thickening of the milks on heating in this study. PMID- 25499615 TI - TickBot: a novel robotic device for controlling tick populations in the natural environment. AB - A semi-autonomous 4-wheeled robot (TickBot) was fitted with a denim cloth treated with an acaricide (permethrinTM) and tested for its ability to control ticks in a tick-infested natural environment in Portsmouth, Virginia. The robot's sensors detect a magnetic field signal from a guide wire encased in 80m polyethylene tubing, enabling the robot to follow the trails, open areas and other terrain where the tubing was located. To attract ticks to the treated area, CO2 was distributed through the same tubing, fitted with evenly spaced pores and flow control valves, which permitted uniform CO2 distribution. Tests were done to determine the optimum frequency for TickBot to traverse the wire-guided treatment site as well as the duration of operation that could be accomplished on a single battery charge. Prior to treatment, dragging was done to determine the natural abundance of ticks in the test site. Controls were done without CO2 and without permethrin. TickBot proved highly effective in reducing the overall tick densities to nearly zero with the treatment that included both carbon dioxide pretreatment and the permethrin treated cloth. Following a 60min traverse of the treatment areas, adult tick numbers, almost entirely Amblyomma americanum, was reduced to zero within 1h and remained at or near zero for 24h. Treatments without CO2 also showed reduction of ticks to near zero within 1h, but the populations were no different than the control sections at 4h. This study demonstrates the efficacy of TickBot as a tick control device to significantly reduce the risk of tick bites and disease transmission to humans and companion animals visiting a previously tick-infested natural environment. Continued deployment of TickBot for additional days or weeks can assure a relatively tick safe environment for enjoyment by the public. PMID- 25499616 TI - Fencing and mowing as effective methods for reducing tick abundance on very small, infested plots. AB - The tick Ixodes ricinus (L.) transmits a large variety of pathogens to humans and is therefore a matter of concern for public health. Different strategies for reducing the risk of tick bite, and thus of infection, have been developed and vary according to the kind of exposure (occupational, recreational, peridomestic). The present study (carried out in an endemic region for both Lyme borreliosis and tick-borne encephalitis) aimed to assess the efficacy of two simple and cheap interventions for reducing I. ricinus abundance around residential properties surrounded by wooded areas. The immediate impact of exclosures (host-targeted control methods) and mowing (vegetation management) on very small surfaces (<1ha) were evaluated both alone and in combination. Results suggest that fencing (even if applied on very small surfaces), by preventing the entrance of tick reproductive hosts, can decrease the abundance of parasites in a short time, and that mowing can contribute to reach the goal. This control method could be of great value in small portions of heavily infested areas that have to be kept tick-free to reduce the risk of peridomestic exposure or to permit their recreational use (e.g. picnic areas within natural parks). Benefits appear even greater when considering that these interventions are environmental safe, cheap, technically simple and effective even in close proximity to heavy infested woodlands. PMID- 25499617 TI - Blunted neuroendocrine stress reactivity in young women with eating disorders. AB - OBJECTIVE: Stress is known to influence risk and progression of eating disorders (EDs). However, studies investigating physiological and psychological stress responses under laboratory conditions in patients with Anorexia nervosa or Bulimia nervosa are scarce and often produce conflicting findings. We therefore aimed to compare the neuroendocrine and affective stress response in ED inpatients and healthy controls. METHODS: Twenty-eight female inpatients with Anorexia or Bulimia nervosa and 26 healthy women were exposed to the Trier Social Stress Test (TSST). Salivary cortisol and alpha-amylase (sAA) levels were assessed before as well as repeatedly after stress exposure, while heart rate and heart rate variability were determined before and during the TSST. Negative affective state was assessed at baseline and post-TSST. RESULTS: Compared to healthy controls, ED patients showed blunted cortisol stress responses combined with overall attenuated sAA levels. The latter was reflected in generally enhanced parasympathetic activity indicated by lower heart rate and stronger high frequency heart rate variability throughout the TSST. Although patients reported more negative affect overall, they did not differ in their affective stress response. CONCLUSIONS: In summary, patients suffering from eating disorders show a blunted HPA axis reactivity to stress exposure and a generally reduced sympathetic/exaggerated parasympathetic nervous system activity. This combination may contribute to elevated health risks seen in eating disorder patients, such as enhanced inflammatory activity, and thus provide insight into the underlying stress-related mechanisms. PMID- 25499618 TI - Development and validation of an Infertility Stigma Scale for Chinese women. AB - OBJECTIVE: To develop and validate a scale of stigma for infertile Chinese women. METHOD(S): Infertile women admitted to the Xiangya Hospital, the Second Xiangya Hospital, and the Third Xiangya Hospital of Central South University for treatment were approached to participate in this study. The Infertility Stigma Scale (ISS) development involved: [1] item generation based on literature, interview (experts/patients: N=5/N=20) and related scale; [2] pre-test questionnaire formation with both experts' ratings (N=9) and infertile women's feedbacks (N=30); [3] the component structure assessed by principal components analysis with varimax rotation (N=334); [4] convergent validity assessed with Social Support Rating scale, Self-Esteem scale, Family APGAR Index (N=334); and [5] reliability identified by internal consistency Cronbach's alpha (N=334), split-half reliability (N=334), test-retest reliability (N=20). RESULT(S): This study yielded a 27-item ISS with 4 factors (self-devaluation, social withdrawal, public stigma, and family stigma). Exploratory factor analysis indicated that these 4 factors accounted for 58.17% of total variances. The Cronbach's alpha, split-half coefficient and test-retest correlation coefficient for the whole scale was 0.94, 0.90, and 0.91, respectively. The associations of the ISS with other measures suggested good convergent validity. The Content Validity Index (CVI) was 0.92. CONCLUSION(S): The ISS appears to be a reliable and valid measure to assess levels of stigma experienced by infertile Chinese women. It may be a useful tool to help identify infertile women at greater risks of distress. PMID- 25499619 TI - The impact of chronic stress burden of 520-d isolation and confinement on the physiological response to subsequent acute stress challenge. AB - Collective evidence indicates that previous exposure to stressful condition might be able to induce changes in brain structure, HPA axis activity and related neurotransmission, and accordingly affect physiological responses to subsequent challenges. During long-term spaceflight, space travelers have to live under the condition of isolation and confinement in the spacecraft for a long period. It is still largely unknown if this kind of chronic stress burden can induce any long lasting changes. To address this question, following 520-d isolation and confinement simulating a flight to Mars, the participants and a matched control group were exposed to an acute stress challenge called parabolic flight. Brain cortical activity, HPA axis activity, and sympathetic adrenal-medullary system response were monitored by EEG signal, cortisol secretion, and catecholamine production, respectively. We observed enhanced EEG signals, elevated cortisol levels and increased adrenaline productions. A group effect on cortisol output was revealed showing higher cortisol peak levels in the Mars520 group as compared to the control group, suggesting that HPA axis was to a certain extent more activated in the subjects who had chronic stress experience. PMID- 25499620 TI - Tissue plasminogen activator modulates emotion in a social context. AB - Tissue plasminogen activator (tPA) is known to play physiologically and pathologically crucial roles in the central nervous system. However, it is still obscure whether it affects social behavior. We investigated social behavior and neuronal activation after social stimulation in tPA knockout (KO) mice. In a resident-intruder test, the latency to the first contact was significantly delayed in tPA KO mice compared with that in tPA heterogenic (Het) mice. However, tPA KO mice spent significantly more time undertaking active behavior than tPA Het mice did. In a sociability test, tPA KO mice significantly spent more time and walked a greater distance in the chamber containing an empty cage than tPA Het mice. Furthermore, tPA KO mice approached an empty cage more frequently than tPA Het mice did. In a social novelty test, there was no difference in the duration spent sniffing a stimulator mouse between genotypes. However, tPA KO mice approached even a familiar mouse more frequently than tPA Het mice did. tPA KO mice spent similar durations in a chamber containing a familiar mouse and that containing an unfamiliar mouse, and tPA KO mice walked a significantly greater distance in the former chamber than tPA Het mice did. Furthermore, at the cingulate and prelimbic cortices, the number of cFos-positive cells was significantly increased in tPA KO mice compared with that in tPA Het mice after social stimulation. Our results suggest that tPA modulates emotion in a social context through the function of the prefrontal cortex. PMID- 25499621 TI - Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. AB - miRNA (miR) 34a has been shown to modulate critical gene transcripts involved in tumorigenesis, but its role in tumor-mediated immunosuppression is largely unknown. PD-L1 plays an important role in immune responses, however, presently its transcriptional regulatory mechanisms are not well understood. In the present study, we analyzed the expression of PD-L1 and miR-34a in 44 acute myeloid leukemia (AML) samples, and observed an inverse correlation between PD-L1 and miR 34a expression. Overexpression of miR-34a in HL-60 and Kasumi-1 cells blocked PD L1 expression, and reduced PD-L1 surface expression. Using luciferase reporter assay and mutagenesis, we identified miR-34a as a putative binder of the PD-L1 3'UTR. Surface expression of PD-L1 induced by chemotherapeutic agents could also be reversed by miR-34a; furthermore, PD-L1 specific T cell apoptosis was reduced as well following miR-34a transfection. We also found that there is a positive feedback between PD-L1 expression and AKT activation. Our data suggest that miR 34a can regulate PD-L1 expression by targeting PD-L1 mRNA, and our present findings shed new light on the complex regulation of PD-L1 in human tumors, and on miR-34a in cancer immuno-based therapy. PMID- 25499622 TI - Cost-effectiveness analysis of rotavirus vaccination among Libyan children using a simple economic model. AB - BACKGROUND: Rotavirus infection is a major cause of childhood diarrhea in Libya. The objective of this study is to evaluate the cost-effectiveness of rotavirus vaccination in that country. METHODS: We used a published decision tree model that has been adapted to the Libyan situation to analyze a birth cohort of 160,000 children. The evaluation of diarrhea events in three public hospitals helped to estimate the rotavirus burden. The economic analysis was done from two perspectives: health care provider and societal. Univariate sensitivity analyses were conducted to assess uncertainty in some values of the variables selected. RESULTS: The three hospitals received 545 diarrhea patients aged<=5 with 311 (57%) rotavirus positive test results during a 9-month period. The societal cost for treatment of a case of rotavirus diarrhea was estimated at US$ 661/event. The incremental cost-effectiveness ratio with a vaccine price of US$ 27 per course was US$ 8,972 per quality-adjusted life year gained from the health care perspective. From a societal perspective, the analysis shows cost savings of around US$ 16 per child. CONCLUSION: The model shows that rotavirus vaccination could be economically a very attractive intervention in Libya. PMID- 25499623 TI - Treatment response of cutaneous mantle cell lymphoma to ibrutinib and radiotherapy. PMID- 25499624 TI - Real-life experience of a brief arsenic trioxide-based consolidation chemotherapy in the management of acute promyelocytic leukemia: favorable outcomes with limited anthracycline exposure and shorter consolidation therapy. AB - BACKGROUND: Anthracyclines have activity against acute promyelocytic leukemia (APL) but can cause cardiac toxicity and secondary malignancy. The all-trans retinoic acid (ATRA)-arsenic trioxide (ATO) combination is an effective noncytotoxic approach for APL. However, its efficacy against high-risk APL (white blood cell count > 10,000/MUL) has not been documented. Also, it requires >= 8 months to complete therapy. PATIENTS AND METHODS: We report a retrospective analysis of 63 patients with APL given one cycle of ATO-based consolidation chemotherapy. RESULTS: The 5-year overall survival, event-free survival, and leukemia-free survival was 93% (95% confidence interval [CI], 82%-97%), 89% (95% CI, 77%-95%), and 92% (95% CI, 80%-97%), respectively. CONCLUSION: These data have confirmed that an abbreviated ATO-based chemotherapy regimen is an effective consolidation therapy for APL, including high-risk APL, and can be completed within 4 months. PMID- 25499626 TI - Rhythmomimetic drug delivery. PMID- 25499625 TI - Talocalcaneal coalition combined with flatfoot in children: diagnosis and treatment: a review. AB - Talocalcaneal coalition often leads to a flatfoot deformity in children. Previous reports have uncovered many aspects of tarsal coalition and flatfoot respectively, including the etiology, clinical presentation, and diagnostic imaging, as well as treatment. However, the optimum surgical procedure for talocalcaneal coalition combined with flatfoot has not been definitively determined. The nonconformity of treatment options is due to our incomplete knowledge of biomechanics, diagnosis, and indication of treatment for talocalcaneal coalition with flatfoot. The objectives of this review are to provide an overview of the current knowledge about etiology, biomechanics, classification, diagnosis, and treatment options for talocalcaneal coalitions with flatfoot and highlight its therapies in children. PMID- 25499627 TI - Transvenous extraction profile of Riata leads: procedural outcomes and technical complexity of mechanical removal. AB - BACKGROUND: Riata (RT) and Sprint Fidelis (SF) leads were recalled by the United States Food and Drug Administration because of an increased rate of failure mainly due to conductor fracture or insulation abrasion. According to lead design and type of failure, extraction complexity may be different, potentially affecting procedural outcomes and indications. OBJECTIVE: The purpose of this study was to assess the extraction profile of RT leads with and without cable externalization in comparison to SF leads. METHODS: From January 1997 to April 2014, all consecutive RT and SF leads extracted transvenously were analyzed. Among 661 consecutive patients with 705 ventricular implantable cardioverter defibrillator (ICD) leads extracted, 194 patients with 134 RT leads (RT group) and 61 SF leads (SF group) were identified. Removal indications often were infective (64%), and extracted leads had a prevalence of dual-coil design (89%). Baseline patients and lead characteristics were comparable between groups. RESULTS: Success rate was high in both groups (97.8% RT vs 100% SF) without major complications. Mechanical dilation was comparable between groups, but RT leads often required larger sheaths (11.7 +/- 1.4 vs 11.3 +/- 1.4), a more frequent crossover to the internal transjugular approach (14% vs 3%), and a longer procedural time (23 +/- 33 minutes vs 12 +/- 16 minutes). Implantation time (odds ratio 4.84, 95% confidence interval 1.05-22.2, P = .042) and RT leads (odds ratio 1.04, 95% confidence interval 1.02-1.06, P <.001) were independent predictors of the internal transjugular approach. CONCLUSION: Extraction of RT leads is feasible and effective. However, extraction of RT leads is more complex than that of SF leads. Lack of coil backfilling and cable externalization in RT group may account for these differences. PMID- 25499628 TI - Neonatal ECG screening: opinions and facts. PMID- 25499629 TI - [Waste management from dental care in the health districts of Dakar, Senegal]. AB - Management of medical waste is becoming an increasing public health concerns, especially as these waste treatment methods can themselves create both health and environmental risks. The objective of the study was to evaluate the management of waste from dental care in Dakar. A cross-sectional, descriptive study of dental services in Dakar, based on a questionnaire was used to determine the knowledge and attitudes of dentists on the management of dental waste. All practitioners stated that their offices had waste bins, 81.2% using plastic bags; 73.2% reported that the bins were washed and disinfected an average of once a day. Only 7.2% of the offices or facilities had an autoclave, and 5.8% an incinerator. Three quarters of the respondents did not know how to dispose of contaminated waste and none of them had conducted a study to estimate the quantity of their departmental waste. The management of waste from dental care is not structured in Senegal nor in most developing countries. Moreover, the gaps and ineffectiveness of legislation result in major threats to public health and the environment. The government should focus, among other things, on stakeholder awareness and training, by providing facilities with the resources necessary to contribute to sustainable development through the management of dental waste. PMID- 25499630 TI - Radiation oncology: introduction. PMID- 25499631 TI - Immunotherapy and radiation. AB - Radiation therapy and immunotherapy are both well-established treatments for malignant disease. Radiotherapy has long been utilized for purposes of providing local tumor control, and the recent success with novel immunomodulatory agents has brought immunotherapy into the forefront of clinical practice for the treatment of many tumor types. Although radiotherapy has traditionally been thought to mediate tumor regression through direct cytotoxic effects, it is now known that radiation also alters the local tumor microenvironment with effects on both the local and systemic anti-tumor immune response. There is growing evidence that the rational integration of the immunomodulatory effects of radiotherapy with the expanding armamentarium of clinically approved immunotherapeutics can yield potent anti-tumor responses exceeding the benefit of either therapy alone. Here we summarize current approaches to the combination of immunotherapy with radiation therapy. PMID- 25499632 TI - Hyperthermia, radiation and chemotherapy: the role of heat in multidisciplinary cancer care. AB - The compelling biologic basis for combining hyperthermia with modern cancer therapies including radiation and chemotherapy was first appreciated nearly half a century ago. Hyperthermia complements radiation as conditions contributing to radio-resistance generally enhance sensitivity to heat and sensitizing effects occur through increased perfusion/tumor oxygenation and alteration of cellular death pathways. Chemosensitization with hyperthermia is dependent on the particular mechanism of effect for each agent with synergistic effects noted for several commonly used agents. Clinically, randomized trials have demonstrated benefit including survival with the addition of hyperthermia to radiation or chemotherapy in treatment of a wide range of malignancies. Improvements in treatment delivery techniques, streamlined logistics, and greater understanding of the relationship of thermal dosimetry to treatment outcomes continue to facilitate wider clinical implementation. Evolving applications include thermal enhancement of immunotherapy, targeted drug delivery and application of principals of thermal biology towards integration of thermal ablation into multimodality oncologic care. PMID- 25499633 TI - Altered fractionation schedules in radiation treatment: a review. AB - Conventionally fractionated radiotherapy is delivered in 1.8- to 2.0-Gy fractions. With increases in understanding of radiation and tumor biology, various alterations of radiotherapy schedules have been tested in clinical trials and are now regarded by some as standard treatment options. Hyperfractionation is delivered through a greater number of smaller treatment doses. Accelerated fractionation decreases the amount of time over which radiotherapy is delivered typically by increasing the number of treatments per day. Hypofractionation decreases the number of fractions delivered by increasing daily treatment doses. Furthermore, many of these schedules have been tested with concurrent chemotherapy regimens. In this review, we summarize the major clinical studies that have been conducted on altered fractionation in various disease sites. PMID- 25499634 TI - Palliative radiotherapy: current status and future directions. AB - For nearly 100 years, palliative radiotherapy has been a time-efficient, effective treatment for patients with metastatic or advanced cancer in any area where local tumors are causing symptoms. Short courses including a single fraction of radiotherapy may be effective for symptom relief with minimal side effects and maximization of convenience for patient and family. With recent advances in imaging, surgery, and other local therapies as well as systemic cancer therapies, palliative radiotherapy has been used frequently in patients who may not yet have symptoms of advanced or metastatic cancer. In this setting, more prolonged radiotherapy courses and advanced radiotherapy techniques including intensity-modulated radiotherapy (IMRT) or stereotactic radiotherapy (SRT) may be useful in obtaining local control and durable palliative responses. This review will explore the use of radiotherapy across the spectrum of patients with advanced and metastatic cancer and delineate an updated, rational approach for the use of palliative radiotherapy that incorporates symptoms, prognosis, and other factors into the delivery of palliative radiotherapy. PMID- 25499635 TI - Symptom management during the radiation oncology treatment course: a practical guide for the oncology clinician. AB - Symptom management during radiation therapy is critical to providing high-quality care for patients receiving treatment. Symptoms are varied and dependent on the site irradiated. Common symptoms associated with radiation therapy include dermatitis, xerostomia, mucositis, and pneumonitis. Treatment strategies include prevention, anticipation, and development of clinical practice enabling rapid identification and management of emerging symptoms. Understanding the spectrum of symptomatology affecting irradiated patients is integral to improved quality of life and treatment efficacy. PMID- 25499636 TI - Stereotactic body radiotherapy. AB - Extracranial stereotactic body radiotherapy (SBRT) has been developed and refined over the last 25 years as a means to precisely deliver ablative doses of hypofractionated radiotherapy to small targets located outside of the cranial vault. SBRT has armed the radiation oncologist with a therapeutic approach that allows for intensification of both dose delivered and fractionation regimen employed. As a consequence, tumor control rates have improved to levels that previously have been associated only with surgical resection. Several prospective phase I and II studies have evaluated the use of SBRT for non-small cell lung cancer (NSCLC), liver tumors, and spinal metastases. This article will give an overview of SBRT and evidence for its use in the most common sites of disease for which it is employed today. PMID- 25499637 TI - The role of surgery and ablative radiotherapy in oligometastatic breast cancer. AB - The ability to deliver precise focused radiation, combined with improved surgical techniques, has led to multiple reports of long-term survivors in patients with oligometastatic breast cancer. The removal or ablation of known metastases, often present after systemic therapy regimens has the potential to be paradigm shifting rendering many patients without evidence of disease. However, the utility of these therapies has not been proven in phase III studies. Additionally, patient selection for metastasis-directed therapies is based on clinical criteria, with many patients not benefiting from these therapies. Refinements of radiation techniques are continuing, and discoveries are uncovering the biology of breast cancer in the oligometastatic state among patients. Integrated into ongoing studies, and those in development, they have the potential to alter standard management strategies in oligometastatic patients. PMID- 25499638 TI - Current management of locally advanced head and neck cancer: the combination of chemotherapy with locoregional treatments. AB - This review will discuss the evolution of the role of chemotherapy in the treatment of locally advanced head and neck cancer (HNC), over the last few decades. Studies were identified by searching PubMed electronic databases. Surgery followed by radiotherapy (RT) or definitive RT are potentially curative approaches for locally advanced HNC. While chemotherapy itself is not curative, it can improve cure rates when given as an adjunct to RT. The benefit of combining chemotherapy with RT is related to the timing of the chemotherapy. Several prospective randomized trials have demonstrated that concurrent delivery of chemotherapy and RT (CRT) is the most promising approach, given that locoregional recurrence is the leading pattern of failure for patients with locally advanced HNC. Induction chemotherapy before CRT has not been shown to be superior to CRT alone and the added toxicity may negatively impact the compliance with CRT. Sequential chemotherapy administration, in the form of induction chemotherapy followed by RT or CRT, has been successful as a strategy for organ preservation in patients with potentially resectable laryngeal and hypopharyngeal cancer. Systemic chemotherapy delivered concurrently with RT is used as a standard treatment for locally advanced HNC. PMID- 25499639 TI - Special cases for proton beam radiotherapy: re-irradiation, lymphoma, and breast cancer. AB - The dose distributions that can be achieved with protons are usually superior to those of conventional photon external-beam radiation. There are special cases where proton therapy may offer a substantial potential benefit compared to photon treatments where toxicity concerns dominate. Re-irradiation may theoretically be made safer with proton therapy due to lower cumulative lifetime doses to sensitive tissues, such as the spinal cord. Proton therapy has been used in a limited number of patients with rectal, pancreatic, esophageal, and lung cancers. Chordomas and soft tissue sarcomas require particularly high radiation doses, posing additional challenges for re-irradiation. Lymphoma is another special case where proton therapy may be advantageous. Late toxicities from even relatively low radiation doses, including cardiac complications and second cancers, are of concern in lymphoma patients with high cure rates and long life expectancies. Proton therapy has begun to be used for consolidation after chemotherapy in patients with Hodgkin and non-Hodgkin lymphoma. Breast cancer is another emerging area of proton therapy development and use. Proton therapy may offer advantages compared to other techniques in the setting of breast boosts, accelerated partial breast irradiation, and post-mastectomy radiotherapy. In these settings, proton therapy may decrease toxicity associated with breast radiotherapy. As techniques are refined in proton therapy, we may be able to improve the therapeutic ratio by maintaining the benefits of radiotherapy while better minimizing the risks. PMID- 25499641 TI - Modern brachytherapy. AB - Brachytherapy consists of placing radioactive sources within, or directly adjacent to a tumor, and is a means of delivering highly targeted and conformal radiation. While its history dates back to the origins of the field, in recent years brachytherapy treatment paradigms have been evolving considerably. This has been driven primarily by advancements in imaging, which allow for precise placement of sources and applicators under image guidance, and volume-based optimization to ensure adequate tumor coverage while sparing adjacent normal tissue. There has been a shift towards high-dose-rate (HDR) brachytherapy for many of the disease sites treated with brachytherapy. Simultaneously, with increasingly conformal treatment, there has been a shift towards utilization of higher doses per fraction, over fewer fractions, for specific disease sites where hypofractionation is believed to confer a radiobiological benefit. Here we review recent data and trends for those disease sites and conditions that are commonly treated with brachytherapy, including prostate, gynecologic, breast, head and neck, and skin cancers and salvage of recurrent disease. PMID- 25499640 TI - Photodynamic therapy for lung cancer and malignant pleural mesothelioma. AB - Photodynamic therapy (PDT) is a form of non-ionizing radiation therapy that uses a drug, called a photosensitizer, combined with light to produce singlet oxygen ((1)O2) that can exert anti-cancer activity through apoptotic, necrotic, or autophagic tumor cell death. PDT is increasingly being used to treat thoracic malignancies. For early-stage non-small cell lung cancer (NSCLC), PDT is primarily employed as an endobronchial therapy to definitively treat endobronchial or roentgenographically occult tumors. Similarly, patients with multiple primary lung cancers may be definitively treated with PDT. For advanced or metastatic NSCLC and small cell lung cancer (SCLC), PDT is primarily employed to palliate symptoms from obstructing endobronchial lesions causing airway compromise or hemoptysis. PDT can be used in advanced NSCLC to attempt to increase operability or to reduce the extent of operation intervention required, and selectively to treat pleural dissemination intraoperatively following macroscopically complete surgical resection. Intraoperative PDT can be safely combined with macroscopically complete surgical resection and other treatment modalities for malignant pleural mesothelioma (MPM) to improve local control and prolong survival. This report reviews the mechanism of and rationale for using PDT to treat thoracic malignancies, details prospective and major retrospectives studies of PDT to treat NSCLC, SCLC, and MPM, and describes improvements in and future roles and directions of PDT. PMID- 25499642 TI - Altering the response to radiation: sensitizers and protectors. AB - A number of agents are used clinically to enhance the efficacy of radiotherapy today, many of which are cytotoxic chemotherapies. Agents that enhance radiation induced tumor cell killing or protect normal tissues from the deleterious effects of ionizing radiation are collectively termed radiation modifiers. A significant effort in radiobiological research is geared towards describing and testing radiation modifiers with the intent of enhancing the therapeutic effects of radiation while minimizing normal tissue toxicity. In this review, we discuss the characteristics of these agents, the testing required to translate these agents into clinical trials, and highlight some challenges in these efforts. PMID- 25499643 TI - Cancer "causation" by infections--individual contributions and synergistic networks. AB - The search for infectious agents playing a role in human carcinogenesis and their identification remain important issues. This could provide clues for a broader spectrum of cancers preventable by vaccination and accessible to specific therapeutic regimens. Yet, the various ways of interacting among different factors functioning synergistically and their different modes of affecting individual cells should bring to question the validity of the term "causation". It also should put a word of caution into all attempts to summarize criteria for "causality" of infectious agents in cancer development. At least in the opinion of these authors, we would be much better off avoiding these terms, replacing "causal factor" by "risk factor" and grading them according to their contribution to an individual's cancer risk. PMID- 25499644 TI - A 60-year-old male with synchronous acute myeloid leukemia and metastatic adenocarcinoma of the pancreas. PMID- 25499646 TI - Insulin signaling pathway in the oriental fruit fly: The role of insulin receptor substrate in ovarian development. AB - Insulin signaling pathways have integral roles in regulating organ growth and body size of insects. Here, we identified and characterized six insulin signaling pathway components-InR, IRS, PI3K92E, PI3K21B, Akt, and PDK-from Bactrocera dorsalis. Quantitative real-time polymerase chain reaction was used to establish gene expression profiles for the insulin signaling pathway components for different developmental stages and tissues, and in response to 20-hydroxyecdysone (20E) and starvation. IRS, PI3K92E, and PI3K21B were highly expressed in the head, while InR, Akt, and PDK were most abundant in Malpighian tubules. Both IRS and PI3K92E were highly expressed during the larval-pupal and pupal-adult transition, while the remaining four genes were highly expressed only during the pupal-adult transition. Following initial exposure to 20E, the expression levels of most genes were significantly decreased. However, the expression levels of IRS, PI3K92E, and PI3K21B were significantly increased at 8 and 12h post treatment compared with the control. Moreover, we found that most insulin signaling pathway genes in B. dorsalis were up-regulated in response to starvation, but decreased when re-fed. On the contrary, transcript levels of PI3K21B decreased significantly during starvation. Furthermore, injection of IRS dsRNA into adult females significantly reduced IRS transcript levels. Suppression of IRS expression inhibited ovarian development, and the average ovary size was reduced by 33% compared with the control. This study provides new insight into the roles of insulin signaling pathway components in B. dorsalis, and demonstrates an important role for IRS in ovarian development. PMID- 25499647 TI - Eliciting older people's preferences for exercise programs: a best-worst scaling choice experiment. AB - QUESTION: What relative value do older people with a previous fall or mobility related disability attach to different attributes of exercise? DESIGN: Prospective, best-worst scaling study. PARTICIPANTS: Two hundred and twenty community-dwelling people, aged 60 years or older, who presented with a previous fall or mobility-related disability. METHODS: Online or face-to-face questionnaire. OUTCOME MEASURES: Utility values for different exercise attributes and levels. The utility levels were calculated by asking participants to select the attribute that they considered to be the best (ie, they were most likely to want to participate in programs with this attribute) and worst (ie, least likely to want to participate). The attributes included were: exercise type; time spent on exercise per day; frequency; transport type; travel time; out-of-pocket costs; reduction in the chance of falling; and improvement in the ability to undertake tasks inside and outside of home. RESULTS: The attributes of exercise programs with the highest utility values were: home-based exercise and no need to use transport, followed by an improvement of 60% in the ability to do daily tasks at home, no costs, and decreasing the chances of falling to 0%. The attributes with the lowest utility were travel time of 30 minutes or more and out-of-pocket costs of AUD50 per session. CONCLUSION: The type of exercise, travel time and costs are more highly valued by older people than the health benefits. These findings suggest that physical activity engagement strategies need to go beyond education about health benefits and focus on improving accessibility to exercise programs. Exercise that can be undertaken at or close to home without any cost is most likely to be taken up by older people with past falls and/or mobility-related disability. PMID- 25499648 TI - Kinesio Taping does not decrease swelling in acute, lateral ankle sprain of athletes: a randomised trial. AB - QUESTION: Does Kinesio Taping reduce swelling in athletes who have suffered an acute, lateral ankle sprain? DESIGN: Randomised controlled trial with concealed allocation, intention-to-treat analysis and blinded assessment. PARTICIPANTS: Thirty-six athletes who participated regularly in one of seven different sports modalities and suffered an acute ankle sprain. INTERVENTION: The experimental group received Kinesio Taping application for 3 days, which was designed to treat swelling. The control group received an inert Kinesio Taping application. OUTCOME MEASURES: For the comparison between groups, the swelling was measured via volumetry, perimetry, relative volumetry and two analyses of the difference in volume and perimetry between ankles of each participant. Data were collected immediately after the 3 days of intervention and at follow-up, which was 15 days post intervention. RESULTS: At 3 days after intervention, there were no differences between groups for swelling in volumetry (MD -2 ml, 95% CI -28 to 32); perimetry (MD 0.2 cm, 95% CI -0.6 to 1.0); relative volumetry (MD 0.0 cm, 95% CI -0.1 to 0.1); and the other analyses. At day 15 follow-up, there were no significant between-group differences in outcomes. CONCLUSION: The application of Kinesio Taping, with the aim of stimulating the lymphatic system, is ineffective in decreasing acute swelling after an ankle sprain in athletes. TRIAL REGISTRATION: Brazilian Registry of Clinical Trials, RBR-32sctf. PMID- 25499650 TI - Tai Chi improves balance and prevents falls in people with Parkinson's disease. PMID- 25499651 TI - Does correcting myths about the flu vaccine work? An experimental evaluation of the effects of corrective information. AB - Seasonal influenza is responsible for thousands of deaths and billions of dollars of medical costs per year in the United States, but influenza vaccination coverage remains substantially below public health targets. One possible obstacle to greater immunization rates is the false belief that it is possible to contract the flu from the flu vaccine. A nationally representative survey experiment was conducted to assess the extent of this flu vaccine misperception. We find that a substantial portion of the public (43%) believes that the flu vaccine can give you the flu. We also evaluate how an intervention designed to address this concern affects belief in the myth, concerns about flu vaccine safety, and future intent to vaccinate. Corrective information adapted from the Centers for Disease Control and Prevention (CDC) website significantly reduced belief in the myth that the flu vaccine can give you the flu as well as concerns about its safety. However, the correction also significantly reduced intent to vaccinate among respondents with high levels of concern about vaccine side effects--a response that was not observed among those with low levels of concern. This result, which is consistent with previous research on misperceptions about the MMR vaccine, suggests that correcting myths about vaccines may not be an effective approach to promoting immunization. PMID- 25499652 TI - Metabolic engineering of Enterobacter cloacae for high-yield production of enantiopure (2R,3R)-2,3-butanediol from lignocellulose-derived sugars. AB - Biotechnological production of biofuels is restricted by toxicity of the products such as ethanol and butanol. As its low toxicity to microbes, 2,3-butanediol (2,3 BD), a fuel and platform bio-chemical, could be a promising alternative for biofuel production from renewable bioresources. In addition, no bacterial strains have been reported to produce enantiopure 2,3-BD using lignocellulosic hydrolysates. In this study, Enterobacter cloacae strain SDM was systematically and metabolically engineered to construct an efficient biocatalyst for production of the fuel and enantiopure bio-chemical-(2R,3R)-2,3-BD. First, the various (2R,3R)-2,3-BD dehydrogenase encoding genes were expressed in a meso-2,3-BD dehydrogenase encoding gene disrupted E. cloacae strain under native promoter Pb of the 2,3-BD biosynthetic gene cluster of E. cloacae. Then, carbon catabolite repression was eliminated via inactivation of the glucose transporter encoding gene ptsG and overexpression of a galactose permease encoding gene galP. The resultant strain could utilize glucose and xylose simultaneously. To improve the efficiency of (2R,3R)-2,3-BD production, the byproduct-producing genes (ldh and frdA) were knocked out, thereby enhancing the yield of (2R,3R)-2,3-BD by 16.5% in 500-mL Erlenmeyer flasks. By using fed-batch fermentation in a 5-L bioreactor, 152.0 g/L (2R,3R)-2,3-BD (purity>97.5%) was produced within 44 h with a specific productivity of 3.5 g/[Lh] and a yield of 97.7% from a mixture of glucose and xylose, two major carbohydrate components in lignocellulosic hydrolysates. In addition, when a lignocellulosic hydrolysate was used as the substrate, 119.4 g/L (2R,3R)-2,3-BD (purity>96.0%) was produced within 51 h with a productivity of 2.3g/[Lh] and a yield of 95.0%. These results show that the highest records have been acquired for enantiopure (2R,3R)-2,3-BD production by a native or engineered strain from biomass-derived sugars. In addition to producing the 2,3-BD, our systematic approach might also be used in the production of other important chemicals by using lignocellulose-derived sugars. PMID- 25499653 TI - Evaluation of new superficially porous particles with carbon core and nanodiamond polymer shell for proteins characterization. AB - A new superficially porous material possessing a carbon core and nanodiamond polymer shell and pore size of 180A was evaluated for the analysis of large proteins. Because the stationary phase on this new support contains a certain amount of protonated amino groups within the shell structure, the resulting retention mechanism is most probably a mix between reversed phase and anion exchange. However, under the applied conditions (0.1-0.5% TFA in the mobile phase), it seemed that the main retention mechanism for proteins was hydrophobic interaction with the C18 alkylchains on this carbon based material. In this study, we demonstrated that there was no need to increase mobile phase temperature, as the peak capacity was not modified considerably between 30 and 80 degrees C for model proteins. Thus, the risk of thermal on-column degradation or denaturation of large proteins is not relevant. Another important difference compared to silica-based materials is that this carbon-based column requires larger amount of TFA, comprised between 0.2 and 0.5%. Finally, it is important to mention that selectivity between closely related proteins (oxidized, native and reduced forms of Interferon alpha-2A variants) could be changed mostly through mobile phase temperature. PMID- 25499654 TI - Stabilities of neutral and basic esters of bendamustine in plasma compared to the parent compound: kinetic investigations by HPLC. AB - Esters of the cytostatic bendamustine (1), previously demonstrated to be much more potent than the parent compound as antiproliferative agents in vitro, were investigated for stability in buffer and plasma, as well as against porcine liver esterase in the presence of different amounts of albumin using a validated RP HPLC method with fluorescence detection. The hydrolysis of the nitrogen mustard moiety was retarded (for 1: approximately 130 vs. 11 min) in the presence of plasma proteins. For the derivatives, both cleavage of ester and nitrogen mustard moieties were analyzed. Enzymatic hydrolysis was very fast in the case of 2 pyrrolidino-, 2-piperidino- and 2-(4-methylpiperazino)-ethyl esters, whereas methyl, ethyl, morpholinoethyl and branched 2-pyrrolidinoethyl esters were considerably more stable (half-lives between 41 and 116 min, compared to <5 min). Inhibition by physostigmine indicated unspecific cholinesterases to be involved in the rapid ester cleavage. Due to lower protein content and higher enzymatic activity in murine compared to human plasma, reduced stability of all investigated esters in mouse plasma (t1/2<2 min) has to be taken into account with respect to the design of animal studies. PMID- 25499655 TI - Determination of beta-caryophyllene skin permeation/retention from crude copaiba oil (Copaifera multijuga Hayne) and respective oil-based nanoemulsion using a novel HS-GC/MS method. AB - Copaiba oil is largely used in the Amazonian region for the treatment of inflammation, and recent studies demonstrated that one of the major components of the oil, beta-caryophyllene (CAR), is a potent anti-inflammatory. The nanoemulsification of this oleoresin, which has unctuous character, converts it in a more acceptable hydrophilic formulation and may improve CAR penetration through the skin due to the small droplet size and the high contact surface afforded by the nanoemulsions. This paper describes the validation of a novel, sensitive, practical and solvent free method that uses gas chromatography in headspace mode coupled with mass spectrometry to evaluate the skin permeation/retention of CAR from the crude copaiba oil and its nanoemulsion. Our results show that the bioanalytic method was fully validated, demonstrating linearity (r(2)>0.99), specificity (no peaks co-eluting with CAR retention time), precision (RSD<15%) and accuracy (recovery>90%) within the accepted parameters and that the copaiba oil nanoemulsion presented a better skin penetration compared to the crude oil, with CAR achieving the most profound layer of the skin, the dermis. PMID- 25499656 TI - Changes in longitudinal myocardial deformation during acute cardiac rejection: the clinical role of two-dimensional speckle-tracking echocardiography. AB - BACKGROUND: Diagnosing and monitoring acute cellular rejection (ACR) is a major objective in the surveillance of heart-transplanted patients. The aim of this study was to evaluate the value of global longitudinal strain (GLS), measured by two-dimensional speckle-tracking echocardiography, as a noninvasive tool for graft function monitoring in relation to ACR. METHODS: The study population consisted of all heart-transplanted patients who underwent biopsy and corresponding echocardiography at one institution from 2011 to 2013 (n = 64). ACR was classified according to the International Society of Heart and Lung Transplantation (0R-3R). Changes in graft function were serially evaluated before, during, and in the resolving period after ACR. RESULTS: No sign of rejection was seen in 268 biopsies (52.7%), minimal rejection (1R) in 202 biopsies (39.7%), and moderate rejection (2R) in 39 biopsies (7.7%); no patients had severe (3R) rejection. A significant difference in GLS was observed comparing the groups with 0R (-15.5%; 95% confidence interval, -16.2% to -14.2%), 1R ( 15.3%; 95% confidence interval, -16.0% to -14.6%), and 2R (-13.8%; 95% confidence interval, -14.6% to -12.9%) rejection (P < .0001). GLS remained significantly reduced in the 2R group despite the exclusion of patients with impaired systolic function (ejection fraction < 50%), allograft vasculopathy, and late rejection (>2 years) after transplantation. In the serial assessment, GLS was decreasing significantly at the time of moderate 2R rejection and improved significantly in the resolving period. The traditional diastolic Doppler parameters, E-wave deceleration time and isovolumetric relaxation time, were unaffected by rejections, whereas the E/A and E/e' ratios were significantly higher in the 2R group (P = .004 and P = .01) compared with the 0R and 1R groups. CONCLUSIONS: GLS is significantly reduced during moderate (2R) ACR and improves significantly in the resolving period. The present results provide encouraging evidence to consider the routine use of GLS as a marker of graft function involvement during ACR. PMID- 25499657 TI - Ileal ulcers not responding to infliximab therapy: think about intestinal ganglioneuromatosis. PMID- 25499658 TI - Caring for people with dementia in residential aged care: successes with a composite person-centered care model featuring Montessori-based activities. AB - Person-centered models of dementia care commonly merge aspects of existing models with additional influences from published and unpublished evidence and existing government policy. This study reports on the development and evaluation of one such composite model of person-centered dementia care, the ABLE model. The model was based on building the capacity and ability of residents living with dementia, using environmental changes, staff education and organizational and community engagement. Montessori principles were also used. The evaluation of the model employed mixed methods. Significant behavior changes were evident among residents of the dementia care Unit after the model was introduced, as were reductions in anti-psychotic and sedative medication. Staff reported increased knowledge about meeting the needs of people with dementia, and experienced organizational culture change that supported the ABLE model of care. Families were very satisfied with the changes. PMID- 25499659 TI - Ultrasensitive immunochromatographic assay for the simultaneous detection of five chemicals in drinking water. AB - In this paper, we describe the development of a multicomponent lateral-flow assay based on an antibody-antigen reaction for the rapid and simultaneous detection of trace contaminants in water, including a heavy metal, algal toxin, antibiotic, hormone, and pesticide. The representative analytes chosen for the study were lead (Pb(II), microcystin-leucine-arginine (MC-LR), chloramphenicol (CAP), testosterone (T), and chlorothalonil (CTN). Five different antigens were immobilized separately in five test lines on a nitrocellulose membrane. The monoclonal antibodies specifically recognized the corresponding antigens, and there was no cross-reactivity between the antibodies in the detection assay. Samples or standards containing the five analytes were preincubated with the freeze-dried colloidal-gold-labeled monoclonal antibody conjugates to improve the sensitivity of the assay. The results were obtained within 20min with a paper based sensor. The cut-off values for the strip test were 4ng/mL for Pb(II), 1ng/mL for MC-LR, 0.1ng/mL for CAP, 5ng/mL for T, and 5ng/mL for CTN. The assay was evaluated using spiked water samples, and the accuracy and reproducibility of the results were good. In summary, this lateral-flow device provides an effective and rapid method for the onsite detection of multiple contaminants in water samples, with no treatment or devices required. PMID- 25499660 TI - Au nanoparticle/graphene nanocomposite as a platform for the sensitive detection of NADH in human urine. AB - Here we report on a facile, rapid, sensitive, selective and highly stable electrochemical sensing platform for beta-nicotinamide adenine dinucleotide (NADH) based on uncapped Au nanoparticle/reduced graphene oxide (rGO) nanocomposites without the aid of any redox mediators and enzymes. The Au nanoparticle/rGO composite sensing platform was directly formed on a glassy carbon electrode through an in situ electrochemical reduction of GO and Au(3+) with a 100% usage of the precursors. The as-prepared Au nanoparticle/rGO composites demonstrated excellent direct electrocatalytic oxidation toward NADH, providing a large electrochemical active surface area as well as a favorable environment for electron transfer from NADH to the electrode via the enhanced mobility of charge carriers. The Au nanoparticle/rGO composites offered a ~2.3 times higher electrocatalytic current density with a negative shift of 112mV, in comparison to Au nanoparticles. The sensor developed in this study displayed a high sensitivity of 0.916uA/uMcm(2) and a wide linear range of from 50nM to 500uM with a limit of detection of 1.13nM (S/N=3). The interferences from the common interferents such as glutathione, glucose, ascorbic acid and quanine were negligible. The prepared sensor was further tested for the determination of NADH in human urine samples, showing the Au nanoparticle/rGO nanocomposites simultaneously formed by one-step electrochemical reduction have promising biomedical applications. PMID- 25499661 TI - A review: fabrications, detections and applications of peptide nucleic acids (PNAs) microarray. AB - Peptide nucleic acid (PNA) is a mimic of DNA that shows a high chemical stability and can survive the enzymatic degradation of nucleases and proteases. The superior binding properties of PNA enable the formation of PNA/DNA or PNA/RNA duplex with excellent thermal stability and unique ionic strength effect. The introduction of microarray makes it possible to achieve accurate, high throughput parallel analysis of DNA or RNA with a highly integrated and low reagents consuming device. This powerful tool expands the applications of PNA in genotyping based on single nucleotide polymorphism (SNP) detection, the monitoring of disease-related miRNA expression and pathogen detection. This review paper discusses the fabrications of PNA microarrays through in situ synthesis strategy or spotting method by automatic devices, the various detection methods for the microarray-based hybridization and the current applications of PNA microarrays. PMID- 25499662 TI - Fabrication of DNA, o-phenylenediamine, and gold nanoparticle bioimprinted polymer electrochemical sensor for the determination of dopamine. AB - A simple methodology was used to develop a novel molecularly bioimprinted polymer (MBIP) sensor for the determination of dopamine. The bioimprinted film was prepared by electrochemical entrapment of ds-DNA and Au nanoparticles in the o phenylenediamine network via one-step electropolymerization on the surface of the modified pencil graphite electrode. The integration of ds-DNA with molecularly imprinted polymer sensors allowed the preparation of novel analytical tools with more selectivity for the determination of dopamine in complex matrices. The fabrication process of the proposed MBIP sensor was evaluated by atomic force microscopy, cyclic voltammetry, and electrochemical impedance spectroscopy. The proposed sensor showed good selectivity for dopamine, compared to the conventional electrochemical methods and the chemicals with high similarity to dopamine. Also, it had a comparable sensitivity, stability, repeatability and reproducibility. Differential pulse voltammetry was applied as a sensitive analytical method for the determination of dopamine and a good linear relationship between dopamine concentration and peak current was obtained within the range of 20-7000nM with a detection limit of 6nM. Furthermore, it was successfully applied for determination of dopamine in biological samples. PMID- 25499663 TI - Sources of innovation: an assessment of intellectual property. AB - An analysis of US Food and Drug Administration (FDA)-approved new molecular entities (NMEs) reveals dynamism in terms of new innovation. An assessment of the first patent for each drug shows that the pharmaceutical industry, particularly large, established companies in North America, tend to dominate the field. Over the past 10-15 years, European and Asian organizations have begun to close the gap. A dynamic inventive environment in drug discovery is suggested by the fact that NMEs for biologics or awarded to biotechnology companies often have inventors from the pharmaceutical and academic sectors. Whereas inventors continue to found biotechnology companies at a steady rate, recent trends suggest these inventors more often come from the private sector. PMID- 25499664 TI - Investigational new treatments for Clostridium difficile infection. AB - Significant progress has been made by industry and academia in the past two years to address the medical threats posed by Clostridium difficile infection. These developments provide an excellent example of how patient need has driven a surge of innovation in drug discovery. Indeed, only two drugs were approved for the infection in the past 30 years but there are 13 treatment candidates in clinical trials today. What makes the latter number even more remarkable is the diversity in the strategies represented (antibiotics, microbiota supplements, vaccines, antibiotic quenchers and passive immunization). In this review, we provide a snapshot of the current stage of these breakthroughs and argue that there is still room for further innovation in treating C. difficile infection. PMID- 25499665 TI - Active-learning strategies in computer-assisted drug discovery. AB - High-throughput compound screening is time and resource consuming, and considerable effort is invested into screening compound libraries, profiling, and selecting the most promising candidates for further testing. Active-learning methods assist the selection process by focusing on areas of chemical space that have the greatest chance of success while considering structural novelty. The core feature of these algorithms is their ability to adapt the structure-activity landscapes through feedback. Instead of full-deck screening, only focused subsets of compounds are tested, and the experimental readout is used to refine molecule selection for subsequent screening cycles. Once implemented, these techniques have the potential to reduce costs and save precious materials. Here, we provide a comprehensive overview of the various computational active-learning approaches and outline their potential for drug discovery. PMID- 25499666 TI - Pharmacokinetic properties and tolerability of low-dose SoluMatrix diclofenac. AB - PURPOSE: This study compared the pharmacokinetic properties and safety profile of low-dose (18- and 35-mg) diclofenac capsules manufactured using SoluMatrix Fine Particle Technology (Trademark of iCeutica Inc. (Philadelphia, Pennsylvania), and the technology is licensed to Iroko Pharmaceuticals, LLC (Philadelphia, Pennsylvania) for exclusive use in NSAIDs), which produces submicron-sized drug particles with enhanced dissolution properties, to those of diclofenac potassium immediate-release (IR) 50-mg tablets. METHODS: This Phase 1, single-center, randomized, open-label, single-dose crossover study was conducted in 40 healthy volunteers. Subjects received, in randomized order, SoluMatrix diclofenac 18- or 35-mg capsules in the fasting condition, SoluMatrix diclofenac 35-mg capsules under fed conditions, and diclofenac potassium IR 50-mg tablets under fasting and fed conditions. Pharmacokinetic parameters (T(max), C(max), AUC(0-t), AUC(0 infinity)) were calculated from the concentrations of diclofenac in the plasma. Absorption, food effect, and dose proportionality were determined using a mixed model ANOVA for C(max), AUC(0-t), AUC(0-infinity). Tolerability was assessed by recording adverse events, physical examination findings, vital sign measurements: clinical laboratory test results. FINDINGS: Overall, 35 healthy volunteers aged 18 to 52 years completed the study. The mean age of the subjects was 33.4 years, and approximately half were men (47.5%). Median T(max) values were similar between the low-dose SoluMatrix diclofenac 35-mg capsules and the diclofenac potassium IR 50-mg tablets (both, ~1.0 hour). The mean maximum plasma concentration (C(max)) after the administration of low-dose SoluMatrix diclofenac 35-mg capsules was 26% lower than that with diclofenac potassium IR 50-mg tablets under fasting conditions (868.72 vs 1194.21 ng/mL). The administration of low dose SoluMatrix diclofenac 35-mg capsules was associated with a 23% lower overall systemic exposure compared with that of diclofenac potassium IR 50-mg tablets under fasting conditions. Food decreased the rate but not the overall extent of absorption of SoluMatrix diclofenac. No serious AEs and no clinically significant abnormalities in physical examination findings, including vital sign measurements, or clinical laboratory test results, were noted during this study. IMPLICATIONS: The pharmacokinetic properties of low-dose SoluMatrix diclofenac capsules in the healthy volunteers in this study suggest rapid diclofenac absorption as measured by T(max). Low-dose SoluMatrix diclofenac capsules represent a potential option for the management of acute and osteoarthritis related pain. PMID- 25499667 TI - Effect of aortic infrarenal clamping and unclamping on intraocular pressure during abdominal aortic aneurysm repair. PMID- 25499668 TI - Assessing effect of obesity on acute kidney injury following cardiac surgery with cardiopulmonary bypass. PMID- 25499669 TI - Moderate-to-large increases in perioperative serum sodium concentration associated with adverse neurologic events after continuous flow left ventricular assist device implantation. AB - OBJECTIVE: It was hypothesized that preoperative hyponatremia is associated with increased 30-day mortality after left ventricular assist device placement, and that large increases in sodium concentration are associated with adverse neurologic events and 30-day mortality. DESIGN: Data were collected retrospectively on all patients having continuous flow left ventricular assist device implantation between January 1, 2009 and March 31, 2013. Preoperative variables, operative variables, and perioperative sodium concentrations were recorded. Both 30-day mortality and 72-hour adverse neurologic events (stroke or seizure) were recorded as primary outcome variables. Preoperative sodium and Delta sodium (postoperative sodium-preoperative sodium) were analyzed as tests for 30-day mortality and adverse neurologic events using receiver operating characteristic curves. Both crude and adjusted logistic regression analyses were used to estimate odds ratios for the outcome variables. SETTING: Tertiary care academic medical center. PARTICIPANTS: Patients having durable continuous flow left ventricular assist device placement. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 88 patients, 30-day mortality was 14% (12 of 88) and the rate of perioperative stroke or seizure was 9% (8 of 88). There were 3 strokes and 5 tonic-clonic seizures. Preoperative sodium was a poor discriminative test for 30 day mortality and stroke or seizure (AUC=0.47 and 0.57, respectively). Delta sodium was a poor discriminative test for 30-day mortality, but a fair discriminative test for stroke or seizure (AUC=0.55 and 0.78, respectively). Delta sodium was a good discriminative test for seizure alone (AUC=0.82) and a fair discriminative test for stroke alone (AUC=0.70). It also increased the odds of stroke or seizure significantly, even when adjusting for possible confounders. CONCLUSIONS: Moderate-to-large increases in sodium concentration during left ventricular assist device placement appear to be associated with adverse postoperative neurologic events. Preoperative hyponatremia has no relationship with 30-day mortality or adverse perioperative neurologic events. PMID- 25499670 TI - Myocardial infarction in older than 75 years: An increasing population. CASTUO Study. AB - OBJECTIVES: Elderly patients with acute myocardial infarction constitute a population that is not adequately represented in clinical trials or medical registries. Our objective was to compare the clinical characteristics, treatments administered and mortality among patients younger and older than 75 years. MATERIAL AND METHODS: Observational retrospective study of patients hospitalized for acute myocardial infarction in the decade 2000-2009. Multivariate models were constructed to determine hospital and late mortality (median, 4.6 years; IQR 25 75: 2.1-7.3). RESULTS: We included 2,177 patients (995 men [79%]), with a mean age of 70.8 years (SD, 12.6). A total of 917 (42.0%) of the patients were 75 years of age or older. When compared with the patients younger than 75 years, the older patients had a greater prevalence of diabetes (38.3% vs. 32.5%; P<.002), chronic obstructive pulmonary disease (15.6% vs. 11.2%; P<.002), stroke (14.3% vs. 7.3%; P<.001), chronic renal failure (11.0% vs. 3.9%; P<.001), atrial fibrillation (15.9% vs. 6.9%; P<.001), heart failure (28.0% vs. 23.4%; P<.008). The older patients were treated with fewer beta-blockers (55.9% vs. 71.2%; P<.001), statins (44.3% vs. 62.3%; P<.001), coronary angiographies (17.9% vs. 48.5%; P<.001) and angioplasties (10.8% vs. 29.1%; P<.001). The patients older than 75 years had lower survival (mortality, 44.5% vs. 18.9%; HR 1.89; 95% CI 1.57-2.29). The use of beta-blockers (HR, 0.74; 95% CI 0.62-0.89), statins (HR 0.73; 95% CI 0.58-0.91) and angioplasty (HR, 0.42; 95% CI 0.30-0.57) was inversely correlated with mortality. CONCLUSIONS: Patients older than 75 years with acute myocardial infarction had lower survival and were treated with fewer beta-blockers, statins and angioplasty, indications that are associated with lower mortality. PMID- 25499671 TI - Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model. AB - BACKGROUND: Different patterns of drug resistance are observed in treated and therapy naive HIV-1 infected populations. Especially the NRTI-related M184I/V variants, which are among the most frequently encountered mutations in treated patients, are underrepresented in the antiretroviral naive population. M184I/V mutations are known to have a profound effect on viral replication and tend to revert over time in the new host. However it is debated whether a diminished transmission efficacy of HIV variants with a reduced replication capacity can also contribute to the observed discrepancy in genotypic patterns. As dendritic cells (DCs) play a pivotal role in HIV-1 transmission, we used a model containing primary human Langerhans cells (LCs) and DCs to compare the transmission efficacy M184 variants (HIV-M184V/I/T) to HIV wild type (HIV-WT). As control, we used HIV harboring the NNRTI mutation K103N (HIV-K103N) which has a minor effect on replication and is found at a similar prevalence in treated and untreated individuals. RESULTS: In comparison to HIV-WT, the HIV-M184 variants were less efficiently transmitted to CCR5(+) Jurkat T cells by both LCs and DCs. The transmission rate of HIV-K103N was slightly reduced to HIV-WT in LCs and even higher than HIV-WT in DCs. Replication experiments in CCR5(+) Jurkat T cells revealed no apparent differences in replication capacity between the mutant viruses and HIV-WT. However, viral replication in LCs and DCs was in concordance with the transmission results; replication by the HIV-M184 variants was lower than replication by HIV-WT, and the level of replication of HIV-K103N was intermediate for LCs and higher than HIV-WT for DCs. CONCLUSIONS: Our data demonstrate that drug resistant M184-variants display a reduced replication capacity in LCs and DCs which directly impairs their transmission efficacy. As such, diminished transmission efficacy may contribute to the lower prevalence of drug resistant variants in therapy naive individuals. PMID- 25499672 TI - Sleep complaints and metabolic syndrome in an elderly population: the Three-City Study. AB - OBJECTIVES: To assess whether sleep complaints (rather than clinically defined sleep disturbances) were associated with the metabolic syndrome (MetS) and each of its components in an elderly population. METHODS: Cross-sectional analyses of data from the French Three City Study, a large multicenter cohort of elderly community-dwellers. PARTICIPANTS: 6,354 participants (56.4% women, median age 73; range: 65-97 years). MEASUREMENTS: Frequency of insomnia complaints (difficulty in initiating sleep, difficulty in maintaining sleep [DMS], and early morning awakening) and excessive daytime sleepiness (EDS) were self-reported. MetS was assessed using National Cholesterol Education program Adult Treatment Panel III criteria. RESULTS: A total of 977 participants had MetS. After adjustment for a large range of potential confounders, we report an association between the number of insomnia complaints and MetS. Among insomnia complaints only DMS was consistently associated with MetS (OR: 1.23, 95% CI: 1.06 to 1.43). Our results showed that EDS independently increased the risk of MetS (OR: 1.46, 95% CI: 1.18 to 1.81 for "frequently"; OR: 1.99, 95% CI: 1.49 to 1.67 for "often"). The EDS MetS association was independent of past-history of cardiovascular disease, insomnia complaints, and obesity and loud snoring. CONCLUSION: We report significant independent associations between frequent sleep complaints (EDS and to a lesser extent DMS) and MetS in the elderly with potential implications in terms of management and cardiovascular prevention in general geriatric practice. Prospective studies are required to clarify the direction of the association between sleep complaints and MetS. PMID- 25499673 TI - Does an outreaching stepped care program reduce depressive symptoms in community dwelling older adults? A randomized implementation trial. AB - OBJECTIVES: To examine the effects of an outreaching stepped care intervention program (Lust for Life) compared with usual care on depressive symptoms in older adults living in the community. DESIGN: Randomized clinical implementation trial. SETTING: 18 general practices and a home care organization in the Netherlands. PARTICIPANTS: 263 community-dwelling 65+-year-olds with depressive symptoms according to the Patient Health Questionnaire-9 (PHQ-9). INTERVENTION: After three months of watchful waiting, participants could sequentially choose between the following evidence-based interventions: 1) guided self-help or an exercise program, 2) problem solving treatment or life review, and 3) a referral to their general practitioner. MEASUREMENTS: The outcome measure was depression severity (PHQ-9), measured every three months over 2 years. RESULTS: After the provision of the stepped care program, a significant short-term positive effect on depressive symptoms was found in the first three months after implementation, in which average PHQ-9 scores dropped from 9.34 (SE: 0.61, 95% CI: 8.14-10.5) to 7.83 (SE: 0.51, 95% CI: 6.84-8.81). CONCLUSIONS: The Lust for Life program has a promising potential to relieve depressive symptoms of older adults in primary care in the short term. Providing one single clinical intervention in accordance with participants' choices instead of stepped care could be sufficient. PMID- 25499674 TI - White Matter Microstructural Integrity Is Associated with Executive Function and Processing Speed in Older Adults with Coronary Artery Disease. AB - OBJECTIVE: Coronary artery disease (CAD) is associated with an increased risk of cognitive decline. Although cerebral white matter (WM) damage predicts cognitive function in CAD, conventional neuroimaging measures only partially explain the effect of CAD on cognition. The purpose of this study was to determine if WM microstructural integrity and CAD using diffusion tensor imaging (DTI) correlates with cognitive function in older adults with CAD. METHODS: Forty-nine CAD patients (66 +/- 7 years old, 86% male) underwent neurocognitive assessments using the cognitive battery recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network for the study of vascular cognitive impairment. Composite scores for each cognitive domain were calculated. Microstructural integrity in normal-appearing WM was quantified as fractional anisotropy (FA) using DTI in nine bilateral and two interhemispheric WM tracts from the Johns Hopkins University WM Tractography Atlas. Linear regression models examined associations between FA and cognitive performance, controlling for age, sex, and education, with correction for multiple comparisons using a false discovery rate of 5%. RESULTS: Executive function was most significantly associated with FA in the left parahippocampal cingulum (beta = 0.471, t = 3.381, df = 44, p = 0.002) and left inferior fronto-occipital fasciculus (beta = 0.430, t = 2.984, df = 44, p = 0.005). FA was not associated with memory in any of the WM tracts examined. CONCLUSION: These results suggest that WM microstructural integrity may be an important neural correlate of executive function even in cognitively intact CAD patients. This study suggests WM damage may be relevant to subtle cognitive decline in a population that may have early neural risk for dementia. PMID- 25499676 TI - Three-dimensional cultures of trophoblast stem cells autonomously develop vascular-like spaces lined by trophoblast giant cells. AB - The maternal blood space in the mouse placenta is lined not by endothelial cells but rather by various subtypes of trophoblast giant cells (TGCs), defined by their location and different patterns of gene expression. While TGCs invade the spiral arteries to displace the maternal endothelium, the rest of the vascular space is created de novo but the mechanisms are not well understood. We cultured mouse trophoblast stem (TS) cells in suspension and found that they readily form spheroids (trophospheres). Compared to cells grown in monolayer, differentiating trophospheres showed accelerated expression of TGC-specific genes. Morphological and gene expression studies showed that cavities form within the trophospheres that are primarily lined by Prl3d1/Pl1alpha-positive cells analogous to parietal TGCs (P-TGCs) which line the maternal venous blood within the placenta. Lumen formation in trophospheres and in vivo was associated with cell polarization including CD34 sialomucin deposition on the apical side and cytoskeletal rearrangement. While P-TGCs preferentially formed in trophospheres at atmospheric oxygen levels (19%), decreasing oxygen to 3% shifted differentiation towards Ctsq positive sinusoidal and/or channel TGCs. These studies show that trophoblast cells have the intrinsic ability to form vascular channels in ways analogous to endothelial cells. The trophosphere system will be valuable for assessing mechanisms that regulate specification of different TGC subtypes and their morphogenesis into vascular spaces. PMID- 25499675 TI - p16(INK4a) expression in retinoblastoma: a marker of differentiation grade. AB - BACKGROUND: The tumor suppressor protein p16(INK4a) has been extensively studied in many tumors with very different results, ranging from its loss to its clear overexpression, which may be associated with degree of tumor differentiation and prognosis. However, its expression remains unclear in human retinoblastoma (RB), a common malignant tumor of retina in childhood. The aim of this study was to explore the expression pattern of p16(INK4a) in RB, and the correlation between p16(INK4a) expression and histopathological features of RB. METHODS: Sixty-five cases of RB were retrospectively analyzed. Paraffin-embedded blocks were retrieved from the archives of ocular pathology department at Zhongshan Ophthalmic Center of Sun Yat-sen University, China. Serial sections were cut and subjected to hematoxylin and eosin staining. Immunohistochemical staining was further done with antibodies p16(INK4a), CRX and Ki67. The correlation of p16 (INK4a) expression with CRX and Ki67 and clinicopathological features of RB were analyzed. RESULTS: RB tumor histologically consists of various differentiation components including undifferentiated (UD) cells, Homer-Wright rosettes (HWR) or Flexner-Winterstein rosettes (FWR) and fleurettes characteristic of photoreceptor differentiation or Retinocytoma (RC). p16(INK4a) expression was negative in both fleurette region and the residual retinal tissue adjacent to the tumor, weakly to moderately positive in FWR, strongly positive in both HWR and UD region. However, CRX had the reverse expression patterns in comparison with p16(INK4a). It was strongly positive in photoreceptor cells within the residual retina and fleurettes, but weakly to moderately positive in UD area. Together with Ki67 staining, high p16(INK4a) expression was associated with poor histological differentiation of RB tumors, which had higher risk features with the optic nerve invasion and uveal invasion. CONCLUSIONS: p16(INK4a) expression increased with the decreasing level of cell differentiation of RBs. RB tumors extensively expressing p16(INK4a) tended to have higher risk features with poor prognosis. This study suggested that p16(INK4a) would be a valuable molecular marker of RB to distinguish its histological phenotypes and to serve as a predictor of its prognosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_180. PMID- 25499678 TI - Gross trunnion failure after primary total hip arthroplasty. AB - Unfavorable outcomes from trunnion fretting and corrosion damage have been reported in the literature, gross failures of tapers in primary total hip arthroplasties have been less frequently reported. We report on 5 patients, who presented with gross trunnion failures of modular metal-on-polyethylene or ceramic-on-polyethylene bearings from 5 implant manufacturers, all necessitating revision surgery. None of these patients had an antecedent history of trauma, and the majority presented with pain or instability. No common factor was identified that may be predictive of these type of failures. Since there were 5 different stem designs, this suggests that it may be a rare generic phenomenon occurring with multiple designs. Currently, further investigations are necessary, including retrieval analysis, to identify risk factors that may predispose to such failures. PMID- 25499677 TI - Total hip arthroplasty with a non-modular conical stem and transverse subtrochanteric osteotomy in treatment of high dislocated hips. AB - Conventional stems may be unsuitable for hypoplastic femurs associated with severe dysplasia, meanwhile, custom-made or modular stems in total hip arthroplasty are often complex and expensive. This series included 21 Crowe type IV dysplastic hips in which a non-modular cementless conical stem was implanted with transverse subtrochanteric femoral osteotomy. Follow up averaged 40months. Twenty hips survived with mean Harris hip score improved from 52 to 90. One hip failed for stem loosening. The average leg lengthening was 3.8cm with transient sciatic nerve palsy occurring in three hips. Femoral offset averaged 3.3cm postoperatively. The non-modular conical stem not only obviated the complexities, high medical cost and potential risk at the neck-stem interface associated with stem modularity, but also simplified surgical technique. PMID- 25499679 TI - Strength and Functional Improvement Using Pneumatic Brace with Extension Assist for End-Stage Knee Osteoarthritis: A Prospective, Randomized trial. AB - Pneumatic unloader bracing with extension assists have been proposed as a non operative modality that may delay the need for knee surgery by reducing pain and improving function. This prospective, randomized trial evaluated 52 patients who had knee osteoarthritis for changes in: (1) muscle strength; (2) objective functional improvements; (3); subjective functional improvements; (4) pain; (5) quality of life; and (6) conversion to total knee arthroplasty (TKA) compared to standard of care. Patient outcomes were evaluated at a minimum 3 months. Braced patient's demonstrated significant improvements in muscle strength, several functional tests, and patient reported outcomes when compared to the matched cohort. These results are encouraging and suggest that this device may represent a promising alternative to standard treatment methods for knee osteoarthritis. PMID- 25499680 TI - Galectin-13/PP-13 expression in term placentas of gestational diabetes mellitus pregnancies. AB - INTRODUCTION: Gestational diabetes mellitus (GDM) is an increasing harm in pregnancy. Inflammatory processes in the placenta seem to have an influence on pathogenesis besides known factors like maternal BMI. Galectin-13 (gal-13) is an immunoregulatory protein, which is suspected to play a role in development of GDM in the placenta. METHODS: A total of 40 placentas were obtained from women treated for gestational diabetes mellitus. Placental tissue for control group was obtained from 40 women with normal pregnancy. We investigated the protein expression of gal-13 in term placentas with immunohistochemistry and immunofluorescence. Immunohistochemical staining was analyzed with the semi quantified IRS score. Gal-13 serum levels were performed with ELISA on a total of 20 probes from women with GDM and healthy control pregnancies in the third trimester. RESULTS: Gal-13 was found in syncytiotrophoblast, in nuclei of syncytiotrophoblast and trophoblast cells as well in extravillous trophoblast cells of normal placentas. In GDM placentas, gal-13 expression was significantly decreased in all of these examined cell types (syncytiotrophoblast p = 0.003, nuclei of syncytiotrophoblast p = 0.007; extravillous trophoblast cells p = 0.001). The ELISA showed a significant lower gal-13 serum level in blood from pregnant women with GDM in comparison to healthy controls. DISCUSSION: As gal-13 with its anti-inflammatory functions plays a role in regulation of maternal immune system, a lack of gal-13 may contribute to an imbalance in inflammation processes in the placenta during pregnancy and therefore influences development of GDM. PMID- 25499681 TI - Placental miR-106a~363 cluster is dysregulated in preeclamptic placenta. AB - Preeclampsia (PE) is the leading cause of maternal and perinatal mortality and morbidity. MicroRNAs are strongly implicated in the pathogenesis of this syndrome. In current study, we performed a microarray assay to explore miRNA expression profile in the placenta, and found 11 upregulated and 7 downregulated miRNAs in preeclampsia. miR-363, plus other 5 member of miR-106a~363 cluster was further examined and validated. These findings would facilitate further investigation of aberrant expression of miRNAs in the pathology of preeclampsia. PMID- 25499682 TI - Monochorionic placentas with proximate umbilical cord insertions: definition, prevalence and angio-architecture. AB - INTRODUCTION: Not much is known on the definition, occurrence and characteristics of proximate umbilical cord insertions (PCI) in monochorionic (MC) placentas. The purpose of this study was to establish a reference range for the distance between cord insertions and to evaluate the prevalence and angio-architecture of MC placentas with PCI. METHODS: All MC placentas not treated with laser surgery were included in this study. The reference range of distance between cord insertions was created using the standard methodology proposed by Royston and Wright. We defined PCI as a cord insertion distance below the 5th centile. RESULTS AND DISCUSSION: A total of 369 MC placentas were analyzed during this study period. The 5th centile was calculated by the equation: 0.027 * gestational age (weeks) +2.91 (cm), and ranged from 3.3 to 4 cm throughout gestation. Accordingly, 18 of the 369 (5%) MC placentas fulfilled the definition criteria for PCI. PCI occurred frequently in MC monoamniotic placentas (53%, 9/17) but were rare in MC diamniotic placentas (3%, 9/352). The prevalence of arterio-arterial and veno venous anastomoses in MC placentas with and without PCI was respectively 100% versus 80% (P = .12) and 56% versus 26% (P = .01). PCI may be representative of later splitting of inner cell mass. CONCLUSION: The threshold for PCI (5th centile) is approximately 4 cm throughout gestation. PCI are rare in MC diamniotic placentas, but are quite common in MC monoamniotic placentas. MC placentas with PCI are characterized by higher rates of superficial AA and/or VV anastomoses. PMID- 25499683 TI - Hyperscanning neuroimaging technique to reveal the "two-in-one" system in social interactions. AB - Using a technique for measuring brain activity simultaneously from two people, known as hyperscanning, we can calculate inter-brain neural effects that appear only in interactions between individuals. Hyperscanning studies using fMRI are advantageous in that they can precisely determine the region(s) involved in inter brain effects. However, it is almost impossible to record inter-brain effects in daily life. By contrast, hyperscanning EEG studies have high temporal resolution and could be used to capture moment-to-moment interactions. In addition, EEG instrumentation is portable and easy to wear, offering the opportunity to record inter-brain effects during daily-life interactions. However, the disadvantage of this approach is that it is difficult to localize the epicenter of the inter brain effect. fNIRS has better temporal resolution and portability than fMRI, but has limited spatial resolution and a limited ability to record deep brain structures. Future studies should employ hyperscanning EEG-fMRI, because this approach combines the high temporal resolution of EEG with the high spatial resolution of fMRI. Hyperscanning EEG-fMRI allows us to use inter-brain effects as neuromarkers of the properties of social interactions in daily life. We also wish to emphasize the need to develop a mathematical model explaining how two brains can exhibit synchronized activity. PMID- 25499684 TI - Measurement of chemical leaching potential of sulfate from landfill disposed sulfate containing wastes. AB - A number of sulfate-containing wastes are disposed in municipal solid wastes (MSW) landfills including residues from coal, wood, and MSW combustion, and construction and demolition (C&D) waste. Under anaerobic conditions that dominate landfills, the sulfate can be reduced to hydrogen sulfide which is problematic for several reasons including its low odor threshold, toxicity, and corrosive nature. The overall objective of this study was to evaluate existing protocols for the quantification of total leachable sulfate from solid samples and to compare their effectiveness and efficiency with a new protocol described in this study. Methods compared include two existing acid extraction protocols commonly used in the U.S., a pH neutral protocol that requires multiple changes of the leaching solution, and a new acid extraction method. The new acid extraction method was shown to be simple and effective to measure the leaching potential of sulfate from a range of landfill disposed sulfate-containing wastes. However, the acid extraction methods do not distinguish between sulfate and other forms of sulfur and are thus most useful when sulfate is the only form of sulfur present. PMID- 25499685 TI - Neurophysiological handover from MMN to P3a in first-episode and recurrent major depression. AB - BACKGROUND: Mismatch negativity (MMN) and P3a components are sequential and co occur. MMN represents the pre-attentive index of deviance detection and P3a represents the attention orienting response. Major depressive disorder (MDD) is characterized by impaired pre-attentive information processing. To assess whether impaired pre-attentive information processing can lead to an impairment of subsequent orienting process as the neurophysiological transmission spreads from MMN to P3a in MDD. METHODS: MMN/P3a was obtained during a two-tone auditory paradigm with 8% duration deviants in 45 first-episode major depression subjects (F-MD), 40 recurrent major depression subjects (R-MD), and 46 healthy controls (HC). RESULTS: Compared with HC, F-MD and R-MD had lower MMN amplitudes and no differences were found between F-MD and R-MD. Notably, R-MD had lower P3a amplitudes and longer P3a latencies compared to HC, while F-MD had no differences. Interestingly, no correlations were found between the severity of depression and the deficits of MMN amplitude. The deficits of P3a amplitude, however, were negatively correlated with the severity of depression in F-MD and R MD. Furthermore, the P3a amplitude deficits were positively correlated with the number of episodes in R-MD. LIMITATIONS: Patients were on antidepressant medication. CONCLUSIONS: The recurrence of depressive episodes can lead to impaired pre-attentive information processing, causing an impairment of subsequent orienting process as the neurophysiological transmission from MMN to P3a. It further suggests that the impaired processing indexed by MMN amplitude may be a stable trait biomarker for the appearance of depression, while P3a amplitude can be used a potential biomarker for recurrence. PMID- 25499686 TI - Anxiety comorbidity in bipolar spectrum disorders: the mediational role of perfectionism in prospective depressive symptoms. AB - BACKGROUND: Bipolar spectrum disorders (BSDs) are highly comorbid with anxiety, which is associated with an extended duration and exacerbation of depressive symptoms. Unfortunately, the underlying mechanisms are not known. This study examined the role of maladaptive cognitive styles in the co-occurrence of BSDs and anxiety disorders and prediction of depressive symptoms. METHODS: Participants included 141 young adults (69.6% female, mean age=20.24, SD=2.11), in one of three groups: a BSD group (bipolar II, cyclothymia, n=48), a comorbid BSD/anxiety group (n=50), and a demographically-matched healthy control group (n=43), who were followed prospectively. Participants completed the Cognitive Style Questionnaire (CSQ), Depressive Experiences Questionnaire (DEQ), Dysfunctional Attitudes Scale (DAS), Sociotropy Autonomy Scale (SAS), Halberstadt Mania Inventory (HMI) and Beck Depression Inventory (BDI) at the initial assessment. One year later, participants completed the BDI and HMI again to assess severity of depressive and hypomanic/manic symptoms. RESULTS: A multivariate analysis of co-variance (MANCOVA) revealed significant differences between the three groups on their DAS Perfectionism, DEQ Dependency, DEQ Self Criticism, CSQ Negative, SAS Autonomy, and Time 2 BDI scores, with the BSD/anxiety group scoring higher than the BSD only group on all measures except the CSQ. Preacher and Hayes' (2008) bootstrapping method was used to test for mediational effects of the significant cognitive style measures on depressive symptoms at follow-up. The 95% confidence intervals for the indirect effect of group on follow-up depressive symptoms through DAS Perfectionism did not include zero, indicating the presence of a significant mediating relationship for perfectionism. LIMITATIONS: This study only used two waves of data; three waves of data would allow one to investigate the full causal effect of one variable on another. Further, a comorbid anxiety diagnosis consisted of any anxiety disorder. Further research should separate groups by their specific anxiety diagnoses; this could afford a more complete understanding of the effect of types of anxiety on prospective depressive symptoms. CONCLUSIONS: After taking into account initial levels of depressive and hypomanic/manic symptoms, we found that those with BSD/anxiety comorbidity experienced more severe depressive symptoms, but not more severe hypomanic/manic symptoms. Further, their more severe prospective depressive symptoms are explained by a perfectionistic cognitive style. PMID- 25499687 TI - Exercise training in adults with Pompe disease: the effects on pain, fatigue, and functioning. AB - OBJECTIVE: To assess if a 12-week exercise intervention to improve aerobic fitness, muscle strength, and core stability also had an impact on fatigue, pain, activity, and participation in adults with Pompe disease, an inherited neuromuscular disorder. DESIGN: Open-label trial. Change was assessed by the chi square test and Wilcoxon signed-rank test. SETTING: Physiotherapy practices. PARTICIPANTS: Mildly affected adult patients with Pompe disease who were not dependent on ventilators and/or walking devices and were receiving enzyme replacement therapy. INTERVENTION: Patients participated in a 12-week exercise program, which included 36 sessions of standardized aerobic, resistance, and core stability exercises. MAIN OUTCOME MEASURES: Before and after the training program we evaluated fatigue (Fatigue Severity Scale), pain (yes/no), motor function (Quantitative Muscle Function Test, Rasch-built Pompe-specific Activity Scale), amount of physical activity (activity monitor), and health status (Medical Outcomes Study 36-Item Short-Form Health Survey). RESULTS: Of the 25 patients enrolled, 23 completed the program. At the end of the program, levels of fatigue (median, 5.33 to 4.78, P=.01) and pain (56.5% to 21.7%, P=.04) improved. The quality of motor function and the amount of physical activity patients engaged in did not change. Changes in pain and fatigue were not related to improvements in aerobic fitness or muscle strength. CONCLUSIONS: This study in mildly affected adult patients with Pompe disease suggests that a combined training program aiming to increase aerobic fitness, muscle strength, and core stability also leads to improvements in fatigue and pain. PMID- 25499688 TI - Effectiveness of functional electrical stimulation on walking speed, functional walking category, and clinically meaningful changes for people with multiple sclerosis. AB - OBJECTIVE: To determine the effectiveness of functional electrical stimulation (FES) on drop foot in patients with multiple sclerosis (MS), using data from standard clinical practice. DESIGN: Case series with a consecutive sample of FES users collected between 2008 and 2013. SETTING: Specialist FES center at a district general hospital. PARTICIPANTS: Patients with MS who have drop foot (N=187) (117 women, 70 men; mean age, 55y [range, 27-80y]; mean duration since diagnosis, 11.7y [range, 1-56y]). A total of 166 patients were still using FES after 20 weeks, with 153 patients completing the follow-up measures. INTERVENTIONS: FES of the common peroneal nerve (178 unilateral, 9 bilateral FES users). MAIN OUTCOME MEASURES: Clinically meaningful changes (ie, >.05m/s and >0.1m/s) and functional walking category derived from 10-m walking speed. RESULTS: An increase in walking speed was found to be highly significant (P<.001), both initially where a minimum clinically meaningful change was observed (.07m/s) and after 20 weeks with a substantial clinically meaningful change (.11m/s). After 20 weeks, treatment responders displayed a 27% average improvement in their walking speed. No significant training effect was found. Overall functional walking category was maintained or improved in 95% of treatment responders. CONCLUSIONS: FES of the dorsiflexors is a well-accepted intervention that enables clinically meaningful changes in walking speed, leading to a preserved or an increased functional walking category. PMID- 25499689 TI - Do we need more nucleos(t)ide analogs for the treatment of chronic hepatitis B? PMID- 25499690 TI - Calculation of inelastic scattering processes of relativistic electrons in oriented crystals. AB - The inelastic scattering of electrons in oriented crystals has been used to determine the positions of atoms within a crystal, to obtain site-dependent electron energy loss spectra and, more recently, to obtain an energy loss signal corresponding to the circular dichroism in X-ray absorption spectroscopy. The theoretical approaches currently used for the description of these processes are based on the nonrelativistic Schrodinger equation. Nowadays many experiments, however, are conducted with incident energies of 200 or 300 keV. Therefore it is indispensable to use a relativistic description for such processes based on the Dirac equation. Using the Coulomb gauge it is shown, that the fully relativistic cross sections for plane wave scattering are given by the modulus square of a sum of two terms: one describing the electrostatic interactions similar to the nonrelativistic theory plus one additional term describing the interaction of the specimen with the magnetic field produced by the incident electron. In crystals both terms can interfere leading to large deviations from nonrelativistic theory. PMID- 25499691 TI - Sublethal exposure to azamethiphos causes neurotoxicity, altered energy allocation and high mortality during simulated live transport in American lobster. AB - In the Bay of Fundy, New Brunswick, sea lice outbreaks in caged salmon are treated with pesticides including Salmosan((r)), applied as bath treatments and then released into the surrounding seawater. The effect of chronic exposure to low concentrations of this pesticide on neighboring lobster populations is a concern. Adult male lobsters were exposed to 61 ngL(-1) of azamethiphos (a.i. in Salmosan((r)) formulation) continuously for 10 days. In addition to the direct effects of pesticide exposure, effects on the ability to cope with shipping conditions and the persistence of the effects after a 24h depuration period in clean seawater were assessed. Indicators of stress and hypoxia (serum total proteins, hemocyanin and lactate), oxidative damage (protein carbonyls in gills and serum) and altered energy allocation (hepatosomatic and gonadosomatic indices, hepatopancreas lipids) were assessed in addition to neurotoxicity (chlolinesterase activity in muscle). Directly after exposure, azamethiphos treated lobsters had inhibition of muscle cholinesterase, reduced gonadosomatic index and enhanced hepatosomatic index and hepatopancreas lipid content. All these responses persisted after 24-h depuration, increasing the risk of cumulative impacts with further exposure to chemical or non-chemical stressors. In both control and treated lobsters exposed to simulated shipment conditions, concentrations of protein and lactate in serum, and protein carbonyls in gills increased. However, mortality rate was higher in azamethiphos-treated lobsters (33 +/- 14%) than in controls (2.6 +/- 4%). Shipment and azamethiphos had cumulative impacts on serum proteins. Both direct effects on neurological function and energy allocation and indirect effect on ability to cope with shipping stress could have significant impacts on lobster population and/or fisheries. PMID- 25499692 TI - Laparoscopic surgery for radiation enteritis. AB - BACKGROUND: The aim of this study was to determine the safety and feasibility of laparoscopic surgery for radiation enteritis-induced intestinal stenosis requiring ileocecal resection. METHODS: Clinical records of radiation enteritis patients that underwent laparoscopic ileocecal resection and ileo-ascending colonic side-to-side anastomosis in a single center from January 2012-February 2014 were retrospectively analyzed. Thirty patients were identified and matched by abdominal adhesion grade, age, gender, primary malignancy distribution, previous abdominal surgery history, and body mass index to 30 patients that underwent open surgery for the same procedure from August 2009-December 2011. General information, operative findings, and short-term outcomes were compared between the two groups. RESULTS: The conversion rate of laparoscopic surgery was 23.3%. The length of skin incision in the laparoscopic group was significantly shorter than that of the open surgery group (6.8 cm versus 15.8 cm, P = 0.001). Laparoscopic surgery significantly decreased recovery time to total enteral nutrition (10.3 d versus 15.6 d, P = 0.037); however, postoperative hospital stay was not significantly different between the two groups (28.2 d versus 32.4 d, P = 0.924). Intraoperative blood loss (125 mL versus 189 mL, P = 0.000) and operation time (138 min versus 171 min, P = 0.003) were significantly improved in the laparoscopic group compared with those in the open surgery group. Laparoscopic surgery did not significantly decrease postoperative morbidity but did decrease the pleural effusion rate. CONCLUSIONS: Laparoscopic surgery is feasible for treatment of radiation enteritis-induced intestinal stenosis with a relatively low conversion rate. Laparoscopic surgery is as safe as open surgery and is superior to open surgery with decreased skin incision length, operation time, intraoperative blood loss, and postoperative recovery time to total enteral nutrition. PMID- 25499693 TI - Bacterial diguanylate cyclases: structure, function and mechanism in exopolysaccharide biofilm development. AB - The ubiquitous bacterial cyclic di-guanosine monophosphate (c-di-GMP) emerges as an important messenger for the control of many bacterial cellular functions including virulence, motility, bioluminescence, cellulose biosynthesis, adhesion, secretion, community behaviour, biofilm formation and cell differentiation. The synthesis of this cyclic nucleotide arises from external stimuli on various signalling domains within the N-terminal region of a dimeric diguanylate cyclase. This initiates the condensation of two molecules of guanosine triphosphate juxtaposed to each other within the C-terminal region of the enzyme. The biofilm from pathogenic microbes is highly resistant to antimicrobial agents suggesting that diguanylate cyclase and its product - c-di-GMP - are key biomedical targets for the inhibition of biofilm development. Furthermore the formation and long term stability of the aerobic granule, a superior biofilm for biological wastewater treatment, can be controlled by stimulation of c-di-GMP. Any modulation of the synthetic pathways for c-di-GMP is clearly advantageous in terms of medical, industrial and/or environmental bioremediation implications. This review discusses the structure and reaction of individual diguanylate cyclase enzymes with a focus on new directions in c-di-GMP research. Specific attention is made on the molecular mechanisms that control bacterial exopolysaccharide biofilm formation and aerobic granules. PMID- 25499695 TI - The influence of body mass index on survival in breast cancer patients. AB - INTRODUCTION: More than half of breast cancer survivors (BCSs) are obese at diagnosis and experience approximately 50% to 96% of weight gain during treatment that could physically affect their survival. The aim of the study was to evaluate the influence of body mass index (BMI) on physical, anthropometric, and physiological parameters in BCSs. PATIENTS AND METHODS: A cross-sectional study was conducted with 147 BCSs. Health-related fitness, anthropometric measures, cardiovascular state, and cancer-related fatigue (CRF) were assessed for our analysis and 3 groups were formed. RESULTS: Tests of force handgrip (affected side: F = 3.44; P < .05; nonaffected side: F = 3.067; P < .05), functional capacity (F = 3.239; P = .043), and endurance of trunk flexors (*2 = 8.264; P = .016) were significantly lower in obese BCSs compared with the normal-weight group, whereas systolic (F = 5.839; P = .004) and diastolic blood pressure (F = 8.794; P < .001), waist circumference (F = 85.81; P < .001), and arm circumference at 10 cm (affected side: F = 23.530; P < .001; nonaffected side: F = 17.095; P < .001) and 5 cm (affected side: F = 21.751; P < .001; nonaffected side: F = 22.490; P < .001) were significantly greater in BCSs with higher BMI compared with other groups. No significant differences were observed between groups regarding lower limb endurance, resting heart rate or CRF. CONCLUSION: This study demonstrated the influence of obesity on health-related fitness, anthropometric measures, and cardiovascular state. PMID- 25499694 TI - Socioeconomic and racial disparities in the selection of chest wall boost radiation therapy in californian women after mastectomy. AB - To better elucidate the socioeconomic and racial differences in women who received postmastectomy radiation therapy with or without a chest wall boost, the records from 4747 women included in the California Cancer Registry were reviewed. Poor and Hispanic women were more likely to receive a chest wall boost than were more affluent and non-Hispanic women. INTRODUCTION: Healthcare disparities in breast cancer treatment have been well documented. We investigated the socioeconomic status (SES) and racial factors in women with locally advanced breast cancer from the California Cancer Registry who had received postmastectomy radiation therapy (PMRT) with or without a chest wall boost (CWB). PATIENTS AND METHODS: The records of 4747 women with invasive breast cancer, diagnosed from 2005 to 2009, who had undergone PMRT, were reviewed and stratified by treatment with (n = 2686 [57%]) or without (n = 2061 [43%]) a CWB. Various patient demographic and biologic factors were analyzed using univariate and multivariate analysis. RESULTS: Receipt of a CWB was associated with race/ethnicity (P < .001), SES (P < .001), tumor size (P = .038), tumor grade (P = .033), human epidermal growth factor 2 (HER2) status (P = .015), American Joint Committee on Cancer stage (P = .001), number of nodes examined (P = .001), and number of positive nodes (P = .037) on univariate analysis. After controlling for confounding factors, race/ethnicity and SES remained independently predictive of a CWB. Hispanic women were more likely to receive a CWB than Asian (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.60-0.90), black (HR, 0.63; 95% CI, 0.48-0.83), or white (HR, 0.81; 95% CI, 0.69-0.95) women. Also, women of low SES were more likely to receive a CWB than women of high SES (HR, 0.74; 95% CI, 0.64 0.86). CONCLUSION: We found that poor and Hispanic women were more commonly treated with a CWB than were more affluent and non-Hispanic women with a similar cancer stage, cancer biology, and treatment paradigm. PMID- 25499696 TI - The complete mitochondrial DNA of Tegillarca granosa and comparative mitogenomic analyses of three Arcidae species. AB - To better understand the characteristics and the evolutionary dynamics of mt genomes in Arcidae, the complete mitochondrial genome of Tegillarca granosa was firstly determined and compared with other two Arcidae species (Scapharca broughtonii and Scapharca kagoshimensis). The complete mitochondrial genome of T. granosa was 31,589 bp in length, including 12 protein-coding genes, 2 rRNA genes and 23 tRNA genes, and a major non-coding region. Three tandem repeat fragments were identified in the major non-coding region and the tandem repeat motifs of these fragments can be folded into stem-loop structures. The mitochondrial genome of the three species has several common features such as the AT content, the arrangement of the protein-coding genes, the codon usage of the protein-coding genes and AT/GC skew. However, a high level of variability is presented in the size of the genome, the number of tRNA genes and the length of non-coding sequences in the three mitogenomes. According to the phylogenetic analyses, these mitogenome-level characters are correlated with their phylogenetic relationships. It is the absence of the duplicated tRNAs and large non-coding sequences that are responsible for the length divergence of mitogenomes between T. granosa and other two Arcidae species. The phylogenetic analyses were conducted based on 12 partitioned protein genes, which support the relationship at the family level: (((Pectinidae+Ostreidae)+Mytilidae)+Arcidae). PMID- 25499697 TI - Molecular characterization and developmental expression of vitellogenin in the oriental river prawn Macrobrachium nipponense and the effects of RNA interference and eyestalk ablation on ovarian maturation. AB - Vitellogenin (Vg) is the precursor of yolk protein, which functions as a nutritive resource that is important for embryonic growth and gonad development. In this study, the cDNA encoding the Vg gene from the oriental river prawn Macrobrachium nipponense was cloned using expressed sequence tag (EST) analysis and the rapid amplification of cDNA ends (RACE) approach. The transcript encoded 2536 amino acids with an estimated molecular mass of 286.810 kDa. Quantitative real-time PCR indicated high expression of Mn-Vg in the female ovary, hemocytes, and hepatopancreas. As ovaries developed, the expression level of Mn-Vg increased in both the hepatopancreas and ovary. In the hepatopancreas, the expression level rose more slowly at the early stage of vitellogenesis and reached the peak more rapidly compared to the expression pattern in ovary. The observed changes in Mn Vg expression level at different development stages suggest the role of nutrient source in embryonic and larval development. Eyestalk ablation caused the Mn-Vg expression level to increase significantly compared to eyestalk-intact groups during the ovary development stages. Ablation accelerated ovary maturation by removing hormone inhibition of Mn-Vg in the hepatopancreas and ovary. In adult females, Mn-Vg dsRNA injection resulted in decreased expression of Mn-Vg in both the hepatopancreas and ovary, and two injection treatment dramatically delayed ovary maturation. Vg RNA interference down-regulated the vitellogenin receptor (VgR) expression level in the ovary, which illustrates the close relationship between Vg and VgR in the process of vitellogenesis. PMID- 25499698 TI - The complete mitochondrial genome and its remarkable secondary structure for a stonefly Acroneuria hainana Wu (Insecta: Plecoptera, Perlidae). AB - The Plecoptera (stoneflies) is a hemimetabolous order of insects, whose larvae are usually used as indicators for fresh water biomonitoring. Herein, we describe the complete mitochondrial (mt) genome of a stonefly species, namely Acroneuria hainana Wu belonging to the family Perlidae. This mt genome contains 13 PCGs, 22 tRNA-coding genes and 2 rRNA-coding genes that are conserved in most insect mt genomes, and it also has the identical gene order with the insect ancestral gene order. However, there are three special initiation codons of ND1, ND5 and COI in PCGs: TTG, GTG and CGA, coding for L, V and R, respectively. Additionally, the 899-bp control region, with 73.30% A+T content, has two long repeated sequences which are found at the 3'-end closing to the tRNA(Ile) gene. Both of them can be folded into a stem-loop structure, whose adjacent upstream and downstream sequences can be also folded into stem-loop structures. It is presumed that the four special structures in series could be associated with the D-loop replication. It might be able to adjust the replication speed of two replicate directions. PMID- 25499699 TI - Exploring the role of conventionality in children's interpretation of ironic remarks. AB - Irony comprehension in seven- and eight-year-old children with typically developing language skills was explored under the framework of the graded salience hypothesis. Target ironic remarks, either conventional or novel/situation-specific, were presented following brief story contexts. Children's responses to comprehension questions were used to determine their understanding of the components of irony: speaker meaning, speaker attitude, and speaker intent. It was hypothesized that conventional remarks would be easier to comprehend than novel/situation-specific remarks because they are more likely to be familiar to the children. Results indicated that children demonstrated better comprehension of speaker meaning for conventional remarks than for novel/situation-specific remarks but no significant differences were found for inferring speaker attitude or speaker intent. PMID- 25499701 TI - US provides immunity from legal claims related to three Ebola vaccines. PMID- 25499700 TI - The colonization of pyrethroid resistant strain from wild Anopheles sinensis, the major Asian malaria vector. AB - BACKGROUND: Anopheles sinensis is one of the most important malaria vectors in Asian countries. The rapid spread of insecticide resistance has become a major obstacle for insecticide-based strategies for vector control. Therefore, it is necessary to prepare an insecticide-resistant strain of An. sinensis to further understand the insecticide resistance mechanisms in this species to facilitate genetic approaches to targeting the insecticide-resistant population of this important malaria vector. METHODS: An. sinensis mosquitoes were collected from regions where pyrethroid resistance had been reported. The mosquitoes were subjected to continuous pyrethroid selection after species confirmation, and the forced copulation method was used to increase the mating rate. In addition, the knockdown-resistance (kdr) mutation frequencies of each generation of An. sinensis were measured; and the metabolic enzyme activities of cytochrome P450 monoxygenases (P450s) and glutathione S-transferases (GSTs) were detected. RESULTS: The identification of field-captured An. sinensis was confirmed by both morphological and molecular methods. The population of An. sinensis exhibited stable resistance to pyrethroid after continuous generations of pyrethroid selection in the laboratory with high kdr mutation frequencies; and elevated levels of both P450s and GSTs were significantly found in field selected populations comparing with the laboratory susceptible strain. So far, the colonised strain has reached its eleventh generation and culturing well in the laboratory. CONCLUSIONS: We colonised a pyrethroid-resistant population of An. sinensis in the laboratory, which provides a fundamental model for genetic studies of this important malaria vector. PMID- 25499702 TI - Autologous human plasma in stem cell culture and cryopreservation in the creation of a tissue-engineered vascular graft. AB - OBJECTIVE: Previous work demonstrated the effectiveness of autologous adipose derived stem cells (ASCs) as endothelial cell (EC) substitutes in vascular tissue engineering. We further this work toward clinical translation by evaluating ASC function after (1) replacement of fetal bovine serum (FBS) with autologous human plasma (HP) in culture and (2) cryopreservation. METHODS: Human ASCs and plasma, isolated from periumbilical fat and peripheral blood, respectively, were collected from the same donors. ASCs were differentiated in endothelial growth medium supplemented with FBS (2%) vs HP (2%). Proliferation was measured by growth curves and MTT assay. Endothelial differentiation was measured by quantitative polymerase chain reaction, assessment of acetylated low-density lipoprotein uptake, and cord formation after plating on Matrigel (BD Biosciences, San Jose, Calif). Similar studies were conducted before and after cryopreservation of ASCs and included assessment of cell retention on the luminal surface of a vascular graft. RESULTS: ASCs expanded in HP-supplemented medium showed (1) similar proliferation to FBS-cultured ASCs, (2) consistent differentiation toward an EC lineage (increases in CD31, von Willebrand factor, and CD144 message; acetylated low-density lipoprotein uptake; and cord formation on Matrigel), and (3) retention on the luminal surface after seeding and subsequent flow conditioning. Cryopreservation did not significantly alter ASC viability, proliferation, acquisition of endothelial characteristics, or retention after seeding onto a vascular graft. CONCLUSIONS: This study suggests that (1) replacement of FBS with autologous HP--a step necessary for the translation of this technology into human use--does not significantly impair proliferation or endothelial differentiation of ASCs used as EC substitutes and (2) ASCs are tolerant to cryopreservation in terms of maintaining EC characteristics and retention on a vascular graft. PMID- 25499703 TI - Management and outcomes of dialysis access-associated steal syndrome. AB - OBJECTIVE: Dialysis access-associated steal syndrome (DASS) complicates arteriovenous access surgery. We describe a 10-year experience with the surgical management of DASS. METHODS: DASS operations were retrospectively reviewed from July 2003 to July 2013 from a single academic institution. Demographics, symptoms, surgical details, and outcomes were collected. RESULTS: A total of 201 patients had 218 episodes of DASS. Mean age was 65 years, and 62% were women. DASS was caused by 175 arteriovenous fistulas (80%), 41 upper extremity prosthetic grafts (19%), and two thigh grafts (1%); 87% were brachial artery based. A portion (22%) were referred for DASS from outside practices. All patients had grade 2 (48%) or grade 3 (52%) DASS; 92% (185) were available for follow-up, with a median time to first follow-up of 23 days. Surgical procedures included ligation (73), distal revascularization with interval ligation (DRIL) (59), revision using distal inflow (RUDI) (21), banding (38), proximalization of arterial inflow (12), and distal radial artery ligation (13). There were no differences in preoperative comorbidities between treatment groups. The 30-day complications included continued steal, thrombosis, bleeding, infection, and mortality. Ligation and DRIL were performed most often for grade 3 steal. Ligation and banding were performed most acutely (median time to intervention after access creation of 39 and 24 days vs DRIL and RUDI at 97 and 100 days). Fistula preservation was 0% for ligation, 100% for DRIL, 95% for RUDI, and 89% for banding (P < .01). Improvement of symptoms ranged from 75% (banding) to 98% (DRIL) (P = .005). Women were less likely to have DRIL but more likely to have ligation (P = .001). Complications were highest in the banding (49%) and RUDI (37%) groups. Average mortality was 3.5%, with no significant differences among groups. During the study period, 3287 access procedures were performed, and access volume steadily increased (2003-2008, 1312 access creations; 2008-2013, 1975). Percentage of fistulas (79% vs 86%), incidence of steal (4% vs 6%), and percentage of DRILs (25% vs 28%) were consistent across the two study periods. CONCLUSIONS: DRIL and ligation were performed in patients with the most severe symptoms. Compared with ligation, DRIL has equal symptom resolution, no increase in complications, and fistula preservation. Compared with banding, DRIL resulted in superior fistula preservation and fewer complications. DRIL should be considered the preferred procedure for management of DASS in patients with a functioning autologous fistula who can tolerate a major operation. PMID- 25499704 TI - Transradial approach for percutaneous intervention of malfunctioning arteriovenous accesses. AB - OBJECTIVE: Interventions on arteriovenous (AV) access are typically performed with a direct puncture into the fistula. An alternative is the transradial approach (TRA), which offers the advantage of visualizing both the arterial and venous limbs as well as any juxta-anastomotic stenosis, all through one access. METHODS: From September 2010 to 2013, 511 fistulograms were performed on 322 patients, 55 of which were TRA procedures in 40 patients (50% male; mean age, 60.4 +/- 16.5 years). Of these, 37 of 40 accesses (92.5%) were AV fistulas, and 54 of 55 interventions (98%) were performed for stenotic lesion(s). There were 37 initial interventions, 13 secondary inventions, and five diagnostic fistulograms through the TRA. Stenotic lesions were juxta-anastomotic in 28, venous in 11, or both in 11. Mean follow-up was 14.3 months in 37 of 40 patients. Outcomes included technical and clinical success, complications, functional patency, and flow rate changes. RESULTS: All TRA punctures were successful, with no radial artery thromboses or hand ischemia. Technical success was 88% (44 of 50). Functional patency rates were 88.5% (23 of 26), 84.2% (16 of 19), and 83% (10 of 12) at 1, 6, and 12 months, respectively. The complication rate was 1.8% (one of 55), consisting of AV fistula rupture after angioplasty. The average flow rate in the 20 juxta-anastomotic stenosis increased from 637 mL/min to 1094 mL/min (P = .01) after the procedure. CONCLUSIONS: The TRA is a practical option with functional patency rates that are comparable to traditional approaches when intervening on a malfunctioning dialysis access in the appropriately selected patient. No hand ischemia was noted. This approach may be particularly attractive for treatment of juxta-anastomotic stenoses in a variety of AV accesses and offers unique practical advantages for the maintenance of AV accesses. PMID- 25499705 TI - Comparison of popliteal artery aneurysm therapies. AB - OBJECTIVE: Surgical treatment of popliteal artery aneurysms (PAAs) has advanced over time. Constant development of new endovascular techniques has converted these into the most attractive methods available today. However, results for each endovascular procedure are still limited, and available data have emerged from studies examining only a small number of cases. The present retrospective review was designed to examine early and late results for PAA treatment and to identify possible factors associated with graft patency. METHODS: This was a retrospective review of all PAAs treated from January 1993 to December 2013. Symptomatic and asymptomatic PAAs >2 cm treated using open surgery or an endovascular procedure were included. Kaplan-Meier curves and the Breslow test were used to analyze data. RESULTS: A total of 171 aneurysms were treated in 142 men (mean age, 69.3 years); of these, 53.3% were asymptomatic and 18.7% presented as acute ischemia. Saphenous vein was used for bypass in 57.9% of the patients, expanded polytetrafluoroethylene (ePTFE) in 23.4%, and a stent graft in 18.7%. In the open surgical group, a popliteal-popliteal bypass was performed in 37.4% and a distal anastomosis to a tibial vessel was required in 14.4%. Good runoff (two to three vessels) was present in 69%. Perioperative mortality (30 days) was 1.8%. Of eight early occlusions recorded, five (2.9%) underwent reoperations. Major amputations were needed in five patients (all with previous acute ischemia). Median follow-up for the entire cohort was 49 months (range, 1-228 months). Primary and secondary patency rates at 24, 36, and 60 months were 76.3% and 89.5%, 73.4% and 87.4%, and 68.3% and 80.9%, respectively. Popliteal-popliteal bypasses showed better primary patency at 24 months when saphenous vein was used vs ePTFE (94.9% vs 79%; P = .04); however, similar patency rates were recorded for short ePTFE bypasses and stent grafts (79% vs 79.7%). On multivariate analysis, only poor runoff emerged as an independent factor for worse primary patency (hazard ratio, 3.5; 95% confidence interval, 1.7-7.2; P = .001). CONCLUSIONS: The open repair of PAA offers good long-term results, especially in asymptomatic patients, those undergoing elective surgery, and those showing good runoff. Given the also good midterm outcomes of endovascular treatment, this may be a feasible option in selected patients. PMID- 25499706 TI - Fenestrated endovascular repair of abdominal aortic aneurysms is associated with increased morbidity but comparable mortality with infrarenal endovascular aneurysm repair. AB - OBJECTIVE: A recent prospective study found that fenestrated endovascular abdominal aortic aneurysm (AAA) repair (FEVAR) was safe and effective in appropriately selected patients at experienced centers. As this new technology is disseminated to the community, it will be important to understand how this technology compares with standard endovascular AAA repair (EVAR). The goal of this study was to compare the outcomes of FEVAR vs EVAR of AAAs. METHODS: The American College of Surgeons-National Surgical Quality Improvement Program database from 2005 to 2012 was queried for AAAs (International Classification of Diseases, Ninth Revision code 441.4). Patients were stratified according to procedure (FEVAR vs EVAR). A bivariate analysis was done to assess preoperative and intraoperative risk factors for postoperative outcomes. Thirty-day postoperative mortality and complication rates were described for each procedure type. Multivariable logistic regression was performed to assess the association between the type of procedure and the risk of postoperative complications. RESULTS: A total of 458 patients underwent FEVAR and 19,060 patients underwent EVAR for AAA. Patients undergoing FEVAR were older (P = .02) and less likely to have a bleeding disorder (P = .046). Otherwise, the incidence of comorbidities in both groups was similar. FEVAR was associated with increased median operative time (156 vs 137 minutes; P < .001), and average postoperative length of stay (3.3 vs 2.8 days; P = .03). There was a statistically significant increase in overall complications (23.6% vs 14.3%; P < .001) and postoperative transfusions (15.3% vs 6.1%, P < .001) and trends toward increased cardiac complications (2.2% vs 1.3%; P = .09) and the need for dialysis (1.5% vs 0.8%; P = .08) in the FEVAR group. Mortality (2.4% vs 1.5%; P = .12) was not statistically different. On multivariable analysis, FEVAR remained independently associated with the need for postoperative transfusions when operative time was <75th percentile (adjusted odds ratio, 1.72; 95% confidence interval, 1.09-2.72; P = .02) as well as when operative time was >75th percentile for respective procedures (adjusted odds ratio, 5.33; 95% confidence interval, 3.55-8.00; P < .001). CONCLUSIONS: Patients undergoing FEVAR are more likely than patients undergoing EVAR to receive blood transfusions postoperatively and are more likely to sustain postoperative complications. Although mortality was similar, trends toward increased cardiac and renal complications may suggest the need for judicious dissemination of this new technology. Future research with larger number of FEVAR cases will be necessary to determine if these associations remain. PMID- 25499707 TI - Discussion. PMID- 25499708 TI - Abdominal compartment syndrome associated with endovascular and open repair of ruptured abdominal aortic aneurysms. AB - BACKGROUND: Abdominal compartment syndrome (ACS) is a known complication of ruptured abdominal aortic aneurysm (rAAA) repair and can occur with either endovascular (EVAR) or open repair. We hypothesize that the underlying mechanism for the development of ACS may differ for patients treated with EVAR or open operation. METHODS: All patients who presented with rAAA at a tertiary care medical center between January 2005 and December 2010 were included in the study. Demographic factors, type of repair (open vs EVAR), development of ACS, intraoperative and postoperative fluid requirements, estimated blood loss, length of stay, and morbidity and mortality were recorded. Student t-test and Fisher exact test were performed. A P value < .05 was considered significant. RESULTS: Seventy-three patients, 62 men and 11 women with an average age of 70.5 years, were treated for rAAA. Forty-four (60%) underwent open repair; 29 (40%) had EVAR. Overall mortality was 42% (31 of 73), with mortality being 31% (9 of 29) in EVAR and 48% (21 of 44) in open repair. ACS developed in 21 patients (29%), more frequently in open repair than in EVAR (15 of 44 [34%] vs 6 of 29 [21%]; P = NS). Mortality was higher in patients who developed ACS compared with those without ACS (13 of 21 [62%] vs 17 of 52 [33%]; P = .022). This finding was especially pronounced in the EVAR group, in which mortality in patients with ACS was 83% (5 of 6) compared with 17% (4 of 23) without ACS (P = .005). Intraoperative fluid requirements were significantly higher in EVAR patients who developed ACS compared with those without ACS, including packed red blood cells (5600 mL vs 1100 mL; P < .0001), total blood products (9300 mL vs 1500 mL; P < .001), crystalloid (11,200 mL vs 4500 mL; P < .001), and estimated blood loss (5000 mL vs 660 mL; P = .006). In patients treated with open repair, there were no significant differences in intraoperative fluid requirements between those who developed ACS and those without ACS. However, patients who developed ACS after open repair required significantly more crystalloid on the first and second postoperative days (first postoperative day, 8300 mL vs 5600 mL [P = .01]; second postoperative day, 6500 mL vs 3800 mL [P = .004]). CONCLUSIONS: This study demonstrates that the development of ACS after repair of rAAA is associated with increased mortality, especially in EVAR-treated patients. The higher intraoperative blood and blood product requirements associated with ACS in EVAR patients suggest that one potential cause of early ACS is continued hemorrhage from lumbar and inferior mesenteric vessels through the ruptured aneurysm sac. Hence, open ligation of such vessels should be considered in patients developing early ACS after EVAR for rAAA. PMID- 25499709 TI - Age and disease-related geometric and structural remodeling of the carotid artery. AB - BACKGROUND: Carotid artery geometry has been suggested as a risk factor for atherosclerotic carotid artery disease (ACD). Although normal aging and development of disease can both lead to geometric changes in the artery, whether geometric changes in a given artery actually predispose to disease or are just a consequence of remodeling during aging is unclear. We investigated carotid artery geometric changes with aging to identify geometric features associated with the presence of ACD. METHODS: Carotid artery geometry was quantified by measuring carotid artery diameter, tortuosity, and bifurcation angle using three dimensional reconstructions of thin-section computed tomography angiography scans in 15 healthy individuals (average age, 43 +/- 18 years; range, 15-64 years). The same geometric features were measured in 17 patients (68 +/- 10 years old) with unilateral ACD. Geometric features associated with presence of ACD were determined by using the nondiseased contralateral carotid artery as an intrinsic control. Elastin-stained carotid arteries were analyzed to assess age-related structural changes in 12 deceased individuals. RESULTS: Increases were noted in bulb diameter (0.64 mm), bifurcation angle (10 degrees ), and tortuosity of the common carotid (CCA; 0.03) and internal carotid arteries (ICA; 0.04) for every decade of life. Density and continuity of circumferential and longitudinal elastin in the CCA and ICA decreased with age. Compared with normal carotid arteries, those with ACD demonstrated larger bulb diameters (P = .001) but smaller bifurcation angles (P = .001). CCA tortuosity (P = .038) increased in ACD arteries compared with normal carotid arteries, but ICA tortuosity was decreased (P = .026). CONCLUSIONS: With increasing age, bulb diameter, tortuosity, and bifurcation angle increases in carotid arteries. These geometric changes may be related to degradation and fragmentation of intramural elastin. Arteries with atherosclerotic occlusive disease demonstrate decreased ICA tortuosity and smaller bifurcation angles compared with nondiseased carotid arteries. PMID- 25499710 TI - Discussion. PMID- 25499711 TI - Preoperative frailty Risk Analysis Index to stratify patients undergoing carotid endarterectomy. AB - OBJECTIVE: Rapid and objective preoperative assessment of patients undergoing carotid endarterectomy (CEA) remains problematic. Preoperative variables correlate with increased morbidity and mortality, yet no easily implemented tool exists to stratify patients. We determined the relationship between our fully implemented frailty-based bedside Risk Analysis Index (RAI) and complications after CEA. METHODS: Patients undergoing CEA in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database from 2005 to 2011 were included. Variables of frailty RAI were matched to preoperative NSQIP variables, and outcomes including stroke, mortality, myocardial infarction (MI), and length of stay were analyzed. We further analyzed patients who were symptomatic and asymptomatic before CEA. RESULTS: With use of the NSQIP database, 44,832 patients undergoing CEA were analyzed (17,696 [39.5%] symptomatic; 27,136 [60.5%] asymptomatic). Increasing frailty RAI score correlated with increasing stroke, death, and MI (P < .0001) as well as with length of stay. RAI demonstrated increasing risk of stroke and death on the basis of risk stratification (low risk [0-10], 2.1%; high risk [>10], 5.0%). Among patients undergoing CEA, 88% scored low (<10) on the RAI. In symptomatic patients, the risk of stroke and death for patients with a score of <=10 is 2.9%, whereas if the RAI score is 11 to 15, it is 5.0%; 16 to 20, 6.9%; and >21, 8.6%. In asymptomatic patients, the risk of stroke and death for patients with a score of <=10 is 1.6%, whereas if the RAI score is 11 to 15, it is 2.9%; 16 to 20, 5.2%; and >21, 6.2%. CONCLUSIONS: Frailty is a predictor of increased stroke, mortality, MI, and length of stay after CEA. An easily implemented RAI holds the potential to identify a limited subset of patients who are at higher risk for postoperative complications and may not benefit from CEA. PMID- 25499712 TI - The effect of acute kidney injury after revascularization on the development of chronic kidney disease and mortality in patients with chronic limb ischemia. AB - OBJECTIVE: This study examined the effect of perioperative acute kidney injury (AKI) on long-term kidney dysfunction and death after lower extremity revascularization. Perioperative AKI is commonly seen in the form of mild rises of serum creatinine after major cardiovascular surgeries. Its effect on long-term survival and development of chronic kidney disease (CKD) is well established in cardiac surgery patients. However, there are no data on the effect of AKI on long term outcomes after revascularization for lower limb ischemia. METHODS: We retrospectively reviewed the patients with peripheral arterial occlusive diseases who underwent endovascular or surgical revascularization of the lower extremities from 2001 through 2010. All demographic and clinical information have been maintained prospectively by the surgeon and followed up by the research team. Perioperative AKI was defined as rises of >=0.3 mg/dL in serum creatinine from the values measured preoperatively. The primary end points were development of CKD (estimated glomerular filtration rate <60 mL/min) and all-cause mortality. Univariate and multivariate analyses were performed to examine relevant associations. RESULTS: Within the study period, 717 patients underwent 875 procedures. Mean follow-up was 42 +/- 14 months. AKI developed in 86 patients after the index procedure. Overall prevalence of CKD diagnosed postoperatively was 14.9%. Overall mortality reported within the follow-up period was 55.9%. Perioperative AKI was a significant predictor of CKD (area under the curve, 0.84 +/- 0.13) and all cause mortality (area under the curve, 0.82 +/- 0.12). CONCLUSIONS: Perioperative AKI is associated with an increased occurrence of CKD and a higher mortality rate after revascularization procedures of the lower extremities. PMID- 25499713 TI - Intravascular ultrasound is a critical tool for accurate endograft sizing in the management of blunt thoracic aortic injury. AB - BACKGROUND: Accurate measurement of true aortic luminal diameter (ALD) is critical for endograft sizing in endovascular treatment of blunt thoracic aortic injury (BTAI), but ALD is dynamic and changes with respect to patients' hemodynamic status. This study aimed to characterize how ALD at the time of diagnosis of BTAI compares with ALD at the time of endovascular repair and later at follow-up. METHODS: This is an Institutional Review Board-approved, single institution retrospective analysis of prospectively obtained data. Patients were included who presented between July 2007 and December 2012 with computed tomography angiography (CTA)-diagnosed BTAI; who underwent thoracic endovascular aortic repair (TEVAR); and who underwent preoperative CTA, intraoperative intravascular ultrasound (IVUS), and postimplantation CTA. Comparison measurements of the ALD were made among CTA and IVUS images at the level of the left subclavian artery (LSCA) and between initial CTA and postimplantation CTA at 10, 15, and 20 cm distal to the LSCA. Theoretical endograft sizes were determined and compared for each ALD at the LSCA. RESULTS: Twenty-two patients were included in the analysis. Mean age was 38 +/- 14 years (range, 17-61 years), with 82% men and mean Injury Severity Score of 43 +/- 11 (range, 24-66). Mean time from emergency department admission to initial CTA was -1.2 +/- 5 hours (range, -13 to 11.5 hours; negative time implies imaging at an outside facility before admission). Mean time from initial CTA to IVUS was 1.2 +/- 1.4 days (range, 2.5 hours-5.7 days) and from IVUS to postimplantation CTA 33 +/- 45 days (range, 17 hours-169 days). Overall, ALD measured by IVUS was significantly larger than that by initial CTA (Delta2.5 +/- 3.1 mm; P < .05). ALD was also larger at 10, 15, and 20 cm distal to the LSCA in comparing the postimplantation CTA with the initial CTA (Delta2.4, 2.0, and 2.0 mm, respectively; all P < .05). More than half the devices would be sized differently with ALD measured by IVUS at the time of TEVAR vs initial CTA. CONCLUSIONS: The ALD of patients with BTAI is significantly larger when it is measured by IVUS at the time of TEVAR compared with at the time of initial CTA. This difference in ALD may translate to undersizing of endografts used in TEVAR for BTAI. IVUS at the time of TEVAR provides a more accurate measurement of the actual ALD and should be used for endograft sizing for patients with BTAI. PMID- 25499714 TI - The effect of chronic renal insufficiency by use of glomerular filtration rate versus serum creatinine level on late clinical outcome of carotid endarterectomy. AB - BACKGROUND: Several studies have reported mixed results after carotid endarterectomy (CEA) in patients with chronic renal insufficiency (CRI), and we previously reported the perioperative outcome in patients with CRI by use of serum creatinine (Cr) level and glomerular filtration rate (GFR). However, only a few of these studies used GFR by the Modification of Diet in Renal Disease equation in their analysis of long-term outcome. METHODS: During the study period, 1000 CEAs (926 patients) were analyzed; 940 of these CEAs had Cr levels and 925 had GFR data. Patients were classified into normal (GFR >=60 mL/min/1.73 m(2) or Cr <1.5 mg/dL), moderate CRI (GFR >=30-59 or Cr >=1.5-2.9), and severe CRI (GFR <30 or Cr >=3). RESULTS: At a mean follow-up of 34.5 months and a median of 34 months (range, 1-53 months), combined stroke and death rates for Cr levels (867 patients) were 9%, 18%, and 44% for Cr <1.5, >=1.5 to 2.9, and >=3 (P = .0001) in contrast to 8%, 14%, and 26% for GFR (854 patients) of >60, >=30 to 59, and <30, respectively (P = .0003). Combined stroke and death rates for asymptomatic patients were 8%, 17%, and 44% (P = .0001) for patients with Cr levels of <1.5, >=1.5 to 2.9, and >=3, respectively, vs 7%, 13%, and 24% for a GFR of >=60, >=30 to 59, and <30 (P = .0063). By Kaplan-Meier analysis, stroke free survival rates at 1 year, 2 years, and 3 years were 97%, 94%, and 92% for Cr <1.5; 92%, 85%, and 81% for Cr >=1.5 to 2.9; and 56%, 56%, and 56% for Cr >=3 (P < .0001); vs 98%, 95%, and 93% for a GFR >=60; 93%, 90%, and 86% for a GFR of >=30 to 59; and 86%, 77%, and 73% for a GFR <30 (P < .0001). These rates for asymptomatic patients at 1 year, 2 years, and 3 years were 97%, 95%, and 93% for Cr <1.5; 94%, 87%, and 82% for Cr >=1.5 to 2.9; and 56%, 56%, and 56% for Cr >=3 (P < .0001); vs 98%, 95%, and 94% for a GFR >=60; 95%, 91%, and 86% for a GFR of >=30 to 59; and 84%, 80%, and 75% for a GFR <30 (P = .0026). A univariate regression analysis for asymptomatic patients showed that the hazard ratio (HR) of stroke and death was 6.5 (P = .0003) for a Cr >=3 and 3.1 for a GFR <30 (P = .0089). A multivariate analysis showed that Cr >=3 had an HR of stroke and death of 4.7 (P = .008), and GFR <30 had an HR of 2.2 (P = .097). CONCLUSIONS: Patients with severe CRI had higher rates of combined stroke/death. Therefore, CEA for these patients (particularly in asymptomatic patients) must be considered with caution. PMID- 25499715 TI - Limb salvage after vascular reconstruction followed by tissue transfer during the Global War on Terror. AB - BACKGROUND: Combat extremity wounds are complex and frequently require an immediate vascular reconstruction in the operational environment followed by delayed tissue coverage at a stateside medical treatment facility. The purpose of this study was to evaluate limb salvage outcomes after combat-related vascular reconstruction that subsequently required delayed soft tissue coverage during the Global War on Terror. METHODS: Patients who incurred a war-related extremity injury necessitating an immediate vascular intervention followed by definitive limb reconstruction requiring flap coverage from combat injuries were reviewed. Patient demographics, types of vascular and extremity injuries, and surgical interventions were examined. Outcomes included limb salvage, primary and secondary graft patency, flap outcomes, and complications. Differences between upper extremities (UEs) and lower extremities (LEs) were compared. RESULTS: From 2003 to 2012, 27 patients were treated for combat-related extremity injuries with an immediate vascular reconstruction followed by delayed tissue coverage. Fifteen LEs and 12 UEs were treated. The mean age was 24 years. An explosion was the cause in 77% of patients, with a mean Injury Severity Score (ISS) of 19. An autogenous vein bypass was the most common reconstruction performed in 20 patients (74%). Other vascular repairs included a primary repair, a patch angioplasty with bovine pericardium, and a bypass with use of a prosthetic graft. Eight patients (30%) had a concomitant venous injury, and 23 (85%) had a bone fracture. Thirty flaps were performed at a mean of 33 days from the original injury. Pedicle flaps were used in 24 limbs and free tissue flaps in six limbs. Muscle, fasciocutaneous, bone, and composite flaps were used for tissue coverage. At a mean follow-up of 16 months, primary patency rates of all arterial reconstructions were 66% in the UE and 53% in the LE (P = .69). Secondary patency rates were 100% in the UE and 86% in the LE (P = .48). The overall limb salvage rate was 81%. Limb salvage rates were 66% in the LE and 100% in the UE (P = .04). Three amputated lower limbs (60%) had inline flow to the foot. The flap success rate was 96%. Reasons for amputation included arterial thrombosis, flap failure, persistent soft tissue infection, osteomyelitis, and debilitating peripheral nerve injuries with associated chronic pain. CONCLUSIONS: Immediate vascular repair followed by delayed tissue coverage can be performed with a high (>80%) limb salvage rate after combat trauma. Limb salvage rates were higher in the UE despite equivocally high arterial patency rates. Wounded warriors can expect limb salvage by use of this international algorithm. PMID- 25499716 TI - Carotid plaque morphometric assessment with three-dimensional ultrasound imaging. AB - OBJECTIVE: As investigations into nonsurgical treatment for atherosclerosis expand, the measurement of plaque regression and progression has become an important end point to evaluate. Measurements of three-dimensional (3D) plaque volume are more reliable and sensitive to change than are traditional estimates of stenosis severity or cross-sectional area. 3D ultrasound (3D US) imaging may allow monitoring of plaque volume changes but has not been used routinely due to the cumbersome motorized units required to drive transducers. We investigated the variability, reliability, and the least amount of change detectable by 1D plaque measures, as well as 2D and 3D measures of plaque morphometry, that can be applied in a clinical environment. METHODS: 3D US imaging was obtained in 10 patients with carotid stenosis. The lumen and outer wall boundaries were outlined in serial cross-sectional images 1 mm apart. Three observers manually segmented vessel wall volumes (VWVs), and the segmentation was repeated again 4 weeks later. This allowed measurement of interobserver and intraobserver variability of 6 pairs of observations. We measured Bland-Altman statistics, intraclass correlation coefficients, coefficient of variability, and the minimum detectable plaque change for each morphometric measure. RESULTS: The mean VWV of carotid lesions in the study was 1276.8 mm(3) (range, 620.6-1956.3 mm(3)). Bland-Altman plots demonstrated low interobserver and intraobserver variability. The interobserver variability of volume measurements as a function of mean volume was 14.8% and interobserver variability was 8.9%. Reliability was 87% as quantified by the interclass correlation and was 95% by the intraclass correlation. The least detectable change in VWV was 12.9% for interobserver variability and 4.5% for intraobserver variability for the three observers. CONCLUSIONS: Carotid plaque diameter measurements from B-mode images have high variability. Plaque burden, as estimated by VWV, can be measured reliably with a 3D US technique using a clinical scanner. The volumetric change, with 95% confidence, that must be observed to establish that a plaque has undergone growth or regression is ~12.9% for different observers and 4.5% for the same observer performing the follow-up study. PMID- 25499718 TI - Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice. AB - The key mechanism for acetaminophen hepatotoxicity is cytochrome P450 (CYP) dependent formation of N-acetyl-p-benzoquinone imine, a potent electrophile that forms protein adducts. Previous studies revealed the fundamental role of glutathione, which binds to and detoxifies N-acetyl-p-benzoquinone imine. Glutathione is synthesized from cysteine in the liver, and N-acetylcysteine is used as a sole antidote for acetaminophen poisoning. Here, we evaluated the potential roles of transsulfuration enzymes essential for cysteine biosynthesis, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CTH), in acetaminophen hepatotoxicity using hemizygous (Cbs(+/-) or Cth(+/-)) and homozygous (Cth(-/-)) knockout mice. At 4 h after intraperitoneal acetaminophen injection, serum alanine aminotransferase levels were highly elevated in Cth(-/-) mice at 150 mg/kg dose, and also in Cbs(+/-) or Cth(+/-) mice at 250 mg/kg dose, which was associated with characteristic centrilobular hepatocyte oncosis. Hepatic glutathione was depleted while serum malondialdehyde accumulated in acetaminophen-injected Cth(-/-) mice but not wild-type mice, although glutamate cysteine ligase (composed of catalytic [GCLC] and modifier [GCLM] subunits) became more activated in the livers of Cth(-/-) mice with lower Km values for Cys and Glu. Proteome analysis using fluorescent two-dimensional difference gel electrophoresis revealed 47 differentially expressed proteins after injection of 150 mg acetaminophen/kg into Cth(-/-) mice; the profiles were similar to 1000 mg acetaminophen/kg-treated wild-type mice. The prevalence of Cbs or Cth hemizygosity is estimated to be 1:200-300 population; therefore, the deletion or polymorphism of either transsulfuration gene may underlie idiosyncratic acetaminophen vulnerability along with the differences in Cyp, Gclc, and Gclm gene activities. PMID- 25499717 TI - Children's health in Latin America: the influence of environmental exposures. AB - BACKGROUND: Chronic diseases are increasing among children in Latin America. OBJECTIVE AND METHODS: To examine environmental risk factors for chronic disease in Latin American children and to develop a strategic initiative for control of these exposures, the World Health Organization (WHO) including the Pan American Health Organization (PAHO), the Collegium Ramazzini, and Latin American scientists reviewed regional and relevant global data. RESULTS: Industrial development and urbanization are proceeding rapidly in Latin America, and environmental pollution has become widespread. Environmental threats to children's health include traditional hazards such as indoor air pollution and drinking-water contamination; the newer hazards of urban air pollution; toxic chemicals such as lead, asbestos, mercury, arsenic, and pesticides; hazardous and electronic waste; and climate change. The mix of traditional and modern hazards varies greatly across and within countries reflecting industrialization, urbanization, and socioeconomic forces. CONCLUSIONS: To control environmental threats to children's health in Latin America, WHO, including PAHO, will focus on the most highly prevalent and serious hazards-indoor and outdoor air pollution, water pollution, and toxic chemicals. Strategies for controlling these hazards include developing tracking data on regional trends in children's environmental health (CEH), building a network of Collaborating Centres, promoting biomedical research in CEH, building regional capacity, supporting development of evidence based prevention policies, studying the economic costs of chronic diseases in children, and developing platforms for dialogue with relevant stakeholders. PMID- 25499719 TI - Placental angiogenic and hormonal factors are affected by thyroid hormones in rats. AB - The objective of the present study was to evaluate the effect of the thyroid hormones in the gene transcription and immunohistochemical expression of hormonal and angiogenic factors in the placenta of rats. Seventy-two adult female rats were divided equally into propylthiouracil (PTU)-treated, thyroxine (T4)-treated, and control groups. The animals were sacrificed at 10, 14, and 19 days of gestation. We evaluated the immunohistochemical expression of VEGF and its receptor Flk-1. The gene transcription of VEGF, Flk-1, PGF, sFlt1, PL-1, and rPlf was evaluated in placental discs by real-time RT-PCR. The data were analyzed using a Student-Newman-Keuls (SNK) test. At day 10, T4-treated rats presented increased VEGF and PGF gene expression, while PTU-treated rats showed increased rPlf gene expression. Both groups showed reduced Flk-1 and PL-1 gene expression at day 10. At day 14, PTU-treated rats showed reduced VEGF, PGF, and rPlf gene expression. PTU-treated group showed reduced VEGF immunostaining in the placental labyrinth at 14 and 19 days of gestation but it showed increased VEGF immunostaining in the spongiotrophoblast layer at day 14. PTU-treated rats showed increased Flk-1 expression at 14 days of gestation. At days 14 and 19, T4-treated group showed increased PL-1 gene expression and reduced VEGF immunostaining. T4 treated rats also showed reduced Flk-1 and sFlt-1 expression at day 19. Both groups showed increased rPlf gene expression at day 19. In conclusion, rats treated with PTU and T4 have differential effects on the expression of factors involved in placental angiogenic and hormonal activity, and these effects are dependent on the gestational period. PMID- 25499720 TI - Loss of lamin A but not lamin C expression in epithelial ovarian cancer cells is associated with metastasis and poor prognosis. AB - OBJECTIVE: To elucidate the different roles of lamin A and lamin C in the metastasis of epithelial ovarian cancer (EOC) by examining their expression in EOC tissues and cell lines and their correlations with clinicopathological features. METHODS: The expression of lamin A and lamin C was assessed in ovarian tissues from 61 EOC patients and 13 normal, 14 benign controls, respectively, using immunohistochemistry. Two pairs of EOC cell lines: HO-8910, HO-8910PM, SKOV 3 and SKOV-3ip were also examined to see the differential expression patterns of lamin A and lamin C. RESULTS: Lamin A expression was significantly lower in EOC tissues than that in normal and benign ovarian tissues (p<0.05), while lamin C expression was not. Lamin A expression level was closely associated with pathological grades, clinical stages, peritoneal metastasis and lymph node metastasis (all p<0.05). The progression-free survival rate of the EOC patients with low lamin A expression level was remarkably lower than that of the EOC patients with high expression level (p<0.05). Lamin A detected by PCR, Western Blot and immunocytochemistry also showed a significantly lower expression level in HO-8910PM than that in HO-8910 (p<0.05), but not for lamin C. There was no difference between SKOV-3 and SKOV-3ip cells. CONCLUSIONS: The results suggested that loss of lamin A but not lamin C expression in EOC was related to metastasis and poor prognosis. Lamin A may play a critical role in the metastasis of EOC. PMID- 25499721 TI - Environmental exposures, breast development and cancer risk: Through the looking glass of breast cancer prevention. AB - This review summarizes the report entitled: Breast Cancer and the Environment: Prioritizing Prevention, highlights research gaps and the importance of focusing on early life exposures for breast development and breast cancer risk. PMID- 25499723 TI - Impact of diabetes on early postoperative outcomes after total elbow arthroplasty. AB - BACKGROUND: Diabetes is known to be associated with poorer perioperative outcomes after hip, knee, and shoulder arthroplasty. This study is the first, to our knowledge, to examine the association between diabetes and in-hospital complications, length of stay, non-homebound discharge, transfusion risk, and total charges after total elbow arthroplasty (TEA). METHODS: By use of International Classification of Diseases, Ninth Revision codes, epidemiologic as well as patient and hospital demographic data for all patients undergoing TEA were extracted from the Nationwide Inpatient Sample from 2007 through 2011. We found 13,698 patients who underwent TEA and subsequently separated them into 2 cohorts, those patients with (16.5%) and without (83.5%) diabetes. Specific outcome measures between the diabetic and nondiabetic cohorts were compared through bivariate and multivariate analyses. RESULTS: Diabetic patients had significantly longer lengths of stay, increased rates of needing a transfusion perioperatively, and higher rates of a number of complications after TEA compared with the nondiabetic group. Significant differences in demographic factors in diabetic patients compared with nondiabetic patients included age, gender, insurance type, and geography. Diabetes was an independent predictor of both prolonged hospital stay and non-homebound discharge after TEA. DISCUSSION: Diabetic patients have significantly higher rates of several perioperative complications, and diabetes is an independent risk factor for prolonged hospital stay, as well as increased risk of non-homebound discharge. Future studies need to further investigate this relationship between diabetes and poorer TEA outcomes. PMID- 25499722 TI - The mammary gland is a sensitive pubertal target in CD-1 and C57Bl/6 mice following perinatal perfluorooctanoic acid (PFOA) exposure. AB - Perfluorooctanoic acid (PFOA) is a developmental toxicant in mice, with varied strain outcomes depending on dose and period of exposure. The impact of PFOA on female mouse pubertal development at low doses (<=1mg/kg) has yet to be determined. Therefore, female offspring from CD-1 and C57Bl/6 dams exposed to PFOA, creating serum concentrations similar to humans, were examined for pubertal onset, including mammary gland development. Pups demonstrated a shorter PFOA elimination half-life than that reported for adult mice. Prenatal exposure to PFOA caused significant mammary developmental delays in female offspring in both strains. Delays started during puberty and persisted into young adulthood; severity was dose-dependent. Also an evaluation of female serum hormone levels and pubertal timing onset revealed no effects of PFOA compared to controls in either strain. These data suggest that the mammary gland is more sensitive to early low level PFOA exposures compared to other pubertal endpoints, regardless of strain. PMID- 25499724 TI - [Diagrams to interpret and solve physiopathological events triggered after severe traumatic brain injury]. PMID- 25499725 TI - Predictors of mortality and poor functional outcome in severe spontaneous intracerebral hemorrhage: a prospective observational study. AB - OBJECTIVE: To analyze mortality and functional outcome in patients with severe spontaneous intracerebral hemorrhage (ICH), and identify the clinical characteristics, radiological findings and therapeutic procedures predictive of mortality in the Intensive Care Unit (ICU) and during hospitalization, as well as of poor functional results at 6 months. DESIGN: A prospective, observational study was carried out. SETTING: Neurocritical Care Unit of a university hospital. PATIENTS: Patients diagnosed with ICH were included over a period of 23 months. VARIABLES OF INTEREST: Demographic characteristics, cardiovascular risk factors, regular medication, laboratory test parameters, cranial CT findings, therapeutic procedures and outcome data. INTERVENTION: None. RESULTS: A total of 186 patients with ICH met the inclusion criteria. Surgery to evacuate ICH was performed in 25.8% of the patients. The mortality rate was 46.7%. The modified Rankin score at 6 months was 5 (RI: 4.6). Multivariate Cox regression analysis showed the presence of diabetes, prior anticoagulation, as well as APACHE II severity and the type of bleeding on the cranial CT scan to be predictors of mortality and poor functional outcomes. On the other hand, neurosurgical procedures and intracranial pressure (ICP) monitoring were associated with better outcomes. CONCLUSION: The presence of comorbidities such as diabetes, or previous anticoagulation, as well as the CT findings were associated to poorer outcomes. In contrast, ICP monitoring and early neurosurgery were predictive of longer survival and better functional outcomes. PMID- 25499726 TI - Research on choleretic effect of menthol, menthone, pluegone, isomenthone, and limonene in DanShu capsule. AB - Danshu capsule (DSC) is a medicinal compound in traditional Chinese medicine (TCM). It is commonly used for the treatment of acute & chronic cholecystitis as well as choleithiasis. To study its choleretic effect, healthy rats were randomly divided into DSC high (DSCH, 900mg/kg), medium (DSCM, 450mg/kg), and low (DSCL, 225mg/kg) group, Xiaoyan Lidan tablet (XYLDT, 750mg/kg), and saline group. The bile was collected for 1h after 20-minute stabilization as the base level, and at 1h, 2h, 3h, and 4h after drug administration, respectively. Bile volume, total cholesterol, and total bile acid were measured at each time point. The results revealed that DSC significantly stimulated bile secretion, decreased total cholesterol level and increased total bile acid level. Therefore, it had choleretic effects. To identify the active components contributing to its choleretic effects, five major constituents which are menthol (39.33mg/kg), menthone (18.02mg/kg), isomenthone (8.18mg/kg), pluegone (3.31mg/kg), and limonene (4.39mg/kg) were tested on our rat model. The results showed that menthol and limonene could promote bile secretion when compared to DSC treatment (p > 0.05); Menthol, menthol and limonene could significantly decrease total cholesterol level (p<0.05 or p<0.01) as well as increase total bile acid level (p<0.05 or p<0.01); Isomenthone, as a isomer of menthone, existed slightly choleretic effects; Pluegone had no obvious role in bile acid efflux. These findings indicated that the choleretic effects of DSC may be attributed mainly to its three major constituents: menthol, menthone and limonene. PMID- 25499727 TI - Down-regulation of carboxylesterases 1 and 2 plays an important role in prodrug metabolism in immunological liver injury rats. AB - Liver plays a central role in xenobiotics metabolism, thus affecting the in vivo disposition and therapeutic effects of drugs. Carboxylesterases (CESs), with the main isoforms CES1 and CES2, are important in the metabolism of ester-type prodrugs. However, influences of immunological liver injury on the activity of CES remain undefined. In the present study, we demonstrated treatment with lipopolysaccharide (LPS) suppressed the activities of CES1 and CES2. The decreased activities of CES1 and CES2 were preliminarily assessed by the hydrolysis assay for their common substrate p-nitrophenyl acetate (PNPA) with rat hepatic microsomal enzyme. Subsequently, RT-PCR results showed that the levels of CES1 mRNA and mRNA of CES2 (AB010635) and CES2 (AY034877) in the model group were significantly lower than those of the normal control group (P<0.05). Western blot results showed that the expressions of CES1 and CES2 proteins were decreased (P<0.05). To further clarify the effects of LPS on the metabolic activities of CESs, pharmacokinetic studies were performed in rats by utilizing imidapril and irinotecan (CPT-11) as the specific substrates for CES1 and CES2, respectively. After treatment with LPS, AUC0-infinity and Cmax of imidaprilat were decreased from 2084.86+/-340.66ng.h(-1).mL(-1) and 234.66+/-68.85ng.mL(-1) to 983.87+/ 315.34ng.h(-1).mL(-1) and 113.1+/-19.69ng.mL(-1) (P<0.05), respectively. Moreover, AUC0-infinity and Cmax of SN-38 were decreased from 8100+/-918.6ng.h( 1).mL(-1) and 144.67+/-20.28ng.mL(-1) to 3270+/-500.5ng.h(-1).mL(-1) and 56.19+/ 10.38ng.mL(-1) (P<0.05), respectively. In summary, immunological liver injury remarkably attenuated the expressions and metabolic activities of CES1 and CES2, which may be associated with the regulatory effects of cytokines under inflammation. PMID- 25499728 TI - Suppression of Th2 immune responses by the sulfated polysaccharide from Porphyra haitanensis in tropomyosin-sensitized mice. AB - The sulfated polysaccharide from Porphyra was hypothesized to exhibit immunoregulatory, anti-tumor and anti-inflammatory activity, but its anti allergic activity is not fully understood. Therefore, the aim of this study was to isolate sulfated polysaccharide from Porphyra haitanensis (PHPS) and investigate its anti-allergic potential using a tropomyosin (TM)-induced mouse allergy model. Intraperitoneal injection of PHPS suppressed the allergic reaction by modulating serum IgE, IgG1 and IgG2a levels in mice. In particular, when PHPS was injected prior to the first immunization with TM, the IgE level decreased by 34.2% compared with the control (PBS) group. Oral therapeutic administration of PHPS to TM-sensitized mice decreased histamine release and repaired the pathology in the jejunum of the small intestine. In vitro, the mRNA expressions of the TM induced Th2 cytokines (interleukin-4 (IL-4), IL-5 and IL-13) in splenic lymphocytes were reduced by PHPS; however, the expression of Th1 and regulatory cytokines (interferon gamma (IFN-gamma) and IL-10) were up-regulated in PHPS treated splenic lymphocytes. In the splenic lymphocyte supernatant, the IL-4, IL 13 and IFN-gamma levels were also regulated by PHPS. Moreover, PHPS induced IFN gamma secretion via the Jun N-terminal kinase (JNK) and Janus kinase 2 (JAK2) signaling pathways. Therefore, these results suggest that PHPS suppresses the TM induced allergic reaction, possibly by modulating the imbalance of the Th1/Th2 immune response. PMID- 25499729 TI - Immunomodulatory effect of diethylcarbamazine citrate plus filarial excretory secretory product on rat hepatocarcinogenesis. AB - Diethylcarbamazine citrate (DEC) had a significance in anti-filarial chemotherapy, while excretory-secretory product (ES) is released from adult filarial females. The target of the current study was to examine the immunomodulatory effect of DEC, Setaria equina ES or a combination of them on rat hepatocellular carcinoma (HCC) induced by diethylnitrosamine (DEN). In vitro effect of combined DEC and ES or ES alone on lipopolysaccharide (LPS)-stimulated rat peripheral blood mononuclear cells (PBMCs) was tested through IFN-gamma assay in culture supernatants. In addition, single or repeated doses of DEC, ES or DEC+ES have been applied in white albino rats to test the effect on HCC. Levels of IFN-gamma and anti-ES IgG antibodies in rat serum were assayed using ELISA. Hemolytic complement activity (CH50) was determined in serum while the concentration of nitric oxide (NO) was assayed in liver tissue. The infiltration of NK cells as well as the expression of MHC Iproliferating cell nuclear antigen (PCNA), inducible NO synthase (iNOS), Bcl2 and p53 were determined using immunohistochemistry. There was a dose-dependent increase in IFN-gamma after in vitro exposure to DEC+ES. Repeated ES doses increased NO concentration (p<0.05) and expression of iNOS but reduced CH50 (p<0.001), while repeated DEC+ES doses could increase anti-ES IgG (p<0.01), IFN-gamma level (p<0.05) and NK cell infiltration. The same treatments could also reduce the expression of MHC I expression, PCNA, Bcl2 and p53. This study has shown immunomodulatory and protective effects of DEC+ES repeated doses on rat HCC. PMID- 25499730 TI - Drug-related deaths and the sales of needles through pharmacies. AB - BACKGROUND: Providing needles to people who inject drugs is a well-proven public health response to the transmission of HIV and other blood borne viruses. Despite over a quarter of a century of research, new concerns about potential unintended negative consequences of needle distribution continue to emerge. Specifically, a claim was recently made that the introduction of pharmacy sales of needles was followed by an increase in overdoses in pharmacy parking lots. If true, this would have serious implications for the design of needle access programs, particularly those involving pharmacy sales of needles. METHODS: We examine spatial relationships between drug-related deaths and pharmacies in Los Angeles County (population 9.8 million) before and after the 2007 enactment of a California law allowing pharmacy sales of needles without a prescription. Seven thousand and forty-nine drugs related deaths occurred in Los Angeles county from 2000 to 2009 inclusive. Four thousand two hundred and seventy-five of these deaths could be geocoded, and were found to be clustered at the census tract level. RESULTS: We used three methods to examine spatial relationships between overdose death locations and pharmacy locations for two years on either side of the enactment of the pharmacy sales law, and found no statistically significant changes. Among the 711 geocodable deaths occurring in the two years following the change in law, no death was found to occur within 50m of a pharmacy which sold needles. CONCLUSION: These results are consistent with prior studies which suggest pharmacy sales of needles improve access to needles without causing increased harms to the surrounding community. PMID- 25499731 TI - Predictors of changes in daily alcohol consumption in the aftermath of military deployment. AB - BACKGROUND: Several studies have documented factors related to increase in alcohol consumption in the context of stressful experiences. However, little is known about predictors of different courses of alcohol use in this context. This study aims to investigate diverse predictors and correlates of increase and decrease of average daily alcohol consumption (aDAC) in the aftermath of military deployment taking into account a variety of potentially relevant factors. METHODS: N=358 soldiers were examined before (T1) and 12 months after return from deployment (T2) using standardized interviews. Change in aDAC was categorized into decreased (n=72), stable (n=215) and increased (n=71) aDAC. RESULTS: Overall, aDAC did not change significantly between T1 and T2 (median change=0.0 g, inter quartile range=11.3g). Compared to stable aDAC, increase was characterized by a lower proportion of high-educated individuals (OR: 0.3 (0.1 0.7), p=0.008), lower rank (marginally significant: OR: 2.0 (1.0-4.1), p=0.050), and less acceptance (trend: MR: 0.97 (0.93-1.00), p=0.053). Correlates of increased aDAC were less social support (MR: 0.84 (0.71-0.99), p=0.043), more sleeping problems (MR: 1.15 (1.00-1.31), p=0.045) and more negative post-event cognitions following deployment (MR: 2.32 (1.28-4.21), p=0.006). Decrease in aDAC was predicted by lower PTSD symptom severity before deployment (MR: 0.34 (0.16 0.72), p=0.005) and less childhood emotional neglect (marginally significant: MR: 0.78 (0.60-1.00), p=0.050). CONCLUSIONS: Increase and decrease in alcohol use after stressful experiences might have differential risk factors and correlates. Findings might stimulate future research that could result in improved measures to prevent increases as well as in interventions that could foster decreases in alcohol consumption in the context of stressful experiences. PMID- 25499732 TI - Drunkenness and its association with health risk behaviors among adolescents and young adults in three Asian cities: Hanoi, Shanghai, Taipei. AB - PURPOSE: To assess the prevalence of drunkenness among adolescents in Hanoi, Shanghai, and Taipei and explore the association between heavy drinking and other health risk behaviors. METHODS: The data are drawn from the Three-city Collaborative Study of Adolescent Health, conducted in Hanoi, Shanghai, and Taipei in 2006. A sample of 17,016 adolescents and young adults, aged 15-24 years, was selected by multistage sampling. Descriptive analysis was used to estimate the proportion of drunkenness and other health risk behaviors. Multivariate logistic regression was used to investigate relationships between drunkenness and risky health behaviors. RESULTS: The proportions of the sample getting drunk during the past month were 6.36%, 4.53%, and 8.47% in Hanoi, Shanghai, and Taipei, respectively. More males than females reported drunkenness in all three cities, with the difference highest in Hanoi (11.08% vs. 1.14%) and lowest in Taipei (9.69% vs. 7.18%). Different levels of relationship between drunkenness and health risk behaviors, such as anxiety, suicidal ideation, smoking, gambling, fighting, drinking and driving, and having sexual intercourse, were found across the three cities; an exception was nonuse of contraception. CONCLUSION: Drunkenness was positively associated with many health risk behaviors. It may serve as an indicator of other risky behaviors. Interventions to reduce drinking and drunkenness may contribute considerably to the prevention of other risk behaviors and to adolescent safety and well-being. PMID- 25499733 TI - Porous bead-on-string poly(lactic acid) fibrous membranes for air filtration. AB - Porous bead-on-string poly(lactic acid) (PLA) nanofibrous membranes (NMs) were fabricated by electrospinning, and the formation mechanism of the membranes was determined in this study. The PLA fibrous morphology, including the fiber diameter, bead size, number of beads, and surface structure of the beads, could be closely controlled by regulating the solvent compositions and the concentrations of the PLA solutions. The filtration performance, which was evaluated by measuring the penetration of sodium chloride (NaCl) aerosol particles with an average diameter of 260nm, indicated that the filtration efficiency and pressure drop for the resultant PLA membranes could be manipulated by modifying the morphology of the fibers. Moderate bead size and quantity contribute to the low pressure drop, and small fiber diameters and nanopores on the beads were conducive to high filtration efficiency. Furthermore, the NM formed from a 5 wt% solution and a solvent mixture containing dichloromethane (DCM)/N,N-dimethylacetamide (DMAC) in a 10/1 ratio of PLA by weight exhibited excellent filtration efficiency (99.997%) and a low pressure drop (165.3 Pa), which are promising characteristics for the membranes' application as filters for respiratory protection, indoor air purification, and other filtration applications. PMID- 25499734 TI - Myeloid cells and the microenvironment, microorganisms and metabolism. PMID- 25499736 TI - Nurses' use of mobile devices to access information in health care environments in australia: a survey of undergraduate students. AB - BACKGROUND: The growth of digital technology has created challenges for safe and appropriate use of mobile or portable devices during work-integrated learning (WIL) in health care environments. Personal and professional use of technology has outpaced the development of policy or codes of practice for guiding its use at the workplace. There is a perceived risk that portable devices may distract from provision of patient or client care if used by health professionals or students during employment or WIL. OBJECTIVE: This study aimed to identify differences in behavior of undergraduate nurses in accessing information, using a portable or mobile device, when undertaking WIL compared to other non-work situations. METHODS: A validated online survey was administered to students while on placement in a range of health care settings in two Australian states. RESULTS: There were 84 respondents, with 56% (n=47) reporting access to a mobile or portable device. Differences in use of a mobile device away from, compared with during WIL, were observed for non-work related activities such as messaging (P<.001), social networking (P<.001), shopping on the Internet (P=.01), conducting personal business online (P=.01), and checking or sending non-work related texts or emails to co-workers (P=.04). Study-related activities were conducted more regularly away from the workplace and included accessing University sites for information (P=.03) and checking or sending study-related text messages or emails to friends or co-workers (P=.01). Students continued to access nursing, medical, professional development, and study-related information away from the workplace. CONCLUSIONS: Undergraduate nurses limit their access to non-work or non-patient centered information while undertaking WIL. Work-related mobile learning is being undertaken, in situ, by the next generation of nurses who expect easy access to mobile or portable devices at the workplace, to ensure safe and competent care is delivered to their patients. PMID- 25499735 TI - Protecting the mitochondrial powerhouse. AB - Mitochondria are the oxygen-consuming power plants of cells. They provide a critical milieu for the synthesis of many essential molecules and allow for highly efficient energy production through oxidative phosphorylation. The use of oxygen is, however, a double-edged sword that on the one hand supplies ATP for cellular survival, and on the other leads to the formation of damaging reactive oxygen species (ROS). Different quality control pathways maintain mitochondria function including mitochondrial DNA (mtDNA) replication and repair, fusion fission dynamics, free radical scavenging, and mitophagy. Further, failure of these pathways may lead to human disease. We review these pathways and propose a strategy towards a treatment for these often untreatable disorders. PMID- 25499737 TI - Post-disaster stressful life events and WTC-related posttraumatic stress, depressive symptoms, and overall functioning among responders to the World Trade Center disaster. AB - BACKGROUND: The current study examined contributions of post-disaster stressful life events in relation to the maintenance of WTC-related posttraumatic stress, depressive symptoms, and overall functioning among rescue, recovery, and clean-up workers who responded to the September 11, 2001 World Trade Center (WTC) terrorist attacks. METHODS: Participants were 18,896 WTC responders, including 8466 police officers and 10,430 non-traditional responders (85.8% male; 86.4% Caucasian; M(age) = 39.5, SD = 8.8) participating in the WTC Health Program who completed an initial examination between July, 2002 and April, 2010 and who were reassessed, on average, 2.5 years later. RESULTS: Path analyses were conducted to evaluate contributions of life events to the maintenance of WTC-related posttraumatic stress, depressive symptoms, and overall functioning. These analyses were stratified by police and non-traditional responder groups and adjusted for age, sex, time from 9/11 to initial visit, WTC exposures (three WTC contextual exposures: co-worker, friend, or a relative died in the disaster; co worker, friend, or a relative injured in the disaster; and responder was exposed to the dust cloud on 9/11), and interval from initial to first follow-up visit. In both groups, WTC-related posttraumatic stress, depressive symptoms, and overall functioning were stable over the follow-up period. WTC exposures were related to these three outcomes at the initial assessment. WTC-related posttraumatic stress, depressive symptoms, and overall functioning, at the initial assessment each predicted the occurrence of post-disaster stressful life events, as measured by Disaster Supplement of the Diagnostic Interview Schedule. Post-disaster stressful life events, in turn, were associated with subsequent mental health, indicating partial mediation of the stability of observed mental health. CONCLUSIONS: The present findings suggest a dynamic interplay between exposure, post-disaster stressful life events, and WTC-related posttraumatic stress, depressive symptoms, and overall functioning among WTC disaster responders. PMID- 25499738 TI - Response to letter from Khan et al. PMID- 25499739 TI - The adenosine A2A receptor antagonist, istradefylline enhances the anti parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets. AB - The adenosine A2A receptor antagonist, istradefylline, enhances anti-parkinsonian activity in patients with advanced Parkinson's disease (PD) already treated with combinations of L-DOPA and dopamine agonist drugs but who are still exhibiting prolonged 'OFF' periods. In contrast, the effects of istradefylline on motor function when administered in combination with low dose dopamine agonist therapy in early PD are unknown. We now investigate whether istradefylline administered with a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide enhances anti-parkinsonian activity in the 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. Both ropinirole (0.01-0.1mg/kg p.o.) and pergolide (0.003-0.1mg/kg p.o.) administered alone produced dose dependent increases in locomotor activity, a reduction in motor disability. Threshold doses of ropinirole (0.025-0.075mg/kg p.o.) and pergolide (0.01-0.075mg/kg p.o.) were then selected that in individual animals caused a small but non-significant anti-parkinsonian effect. Administration of istradefylline (10mg/kg p.o.) alone resulted in a decrease in motor disability and increase in 'ON' time but dyskinesia was not observed. Combined administration of pergolide or ropinirole with istradefylline resulted in an increase in the reversal of motor disability and increase in 'ON' time compared to that produced by either treatment alone but dyskinesia was still not observed. These results show that istradefylline is effective in improving motor function when combined with low dose dopamine agonist treatment. In early PD, this may avoid dose escalation or allow a reduction in dopamine agonist dosage without a loss of efficacy and prevent dopaminergic side-effects from becoming treatment limiting. PMID- 25499740 TI - Margaret McCartney: The Care Quality Commission is not fit for purpose. PMID- 25499741 TI - Bond strength and bioactivity of Zn-doped dental adhesives promoted by load cycling. AB - The purpose of this study was to evaluate if mechanical loading influences bioactivity and bond strength at the resin-dentin interface after bonding with Zn doped etch-and-rinse adhesives. Dentin surfaces were subjected to demineralization by 37% phosphoric acid (PA) or 0.5 M ethylenediaminetetraacetic acid (EDTA). Single bond (SB) adhesive-3M ESPE-SB+ZnO particles 20 wt% and SB+ZnCl2 2 wt% were applied on treated dentin to create the groups PA+SB, SB+ZnO, SB+ZnCl2, EDTA+SB, EDTA+ZnO, and EDTA+ZnCl2. Bonded interfaces were stored in simulated body fluid for 24 h and tested or submitted to mechanical loading. Microtensile bond strength (MTBS) was assessed. Debonded dentin surfaces were studied by high-resolution scanning electron microscopy. Remineralization of the bonded interfaces was assessed by atomic force microscope imaging/nanoindentation, Raman spectroscopy/cluster analysis, and Masson's trichrome staining. Load cycling (LC) produced reduction in MTBS in all PA+SB, and no change was encountered in EDTA+SB specimens, regardless of zinc doping. LC increased the mineralization and crystallographic maturity at the interface; a higher effect was noticed when using ZnO. Trichrome staining reflected a narrow demineralized dentin matrix after loading of dentin surfaces that were treated with SB-doped adhesives. This correlates with an increase in mineral platforms or plate-like multilayered crystals in PA or EDTA-treated dentin surfaces, respectively. PMID- 25499742 TI - Novel probiotics and prebiotics: road to the market. AB - Novel probiotics and prebiotics designed to manipulate the gut microbiota for improving health outcomes are in demand as the importance of the gut microbiota in human health is revealed. The regulations governing introduction of novel probiotics and prebiotics vary by geographical region. Novel foods and foods with health claims fall under specific regulations in several countries. The paper reviews the main requirements of the regulations in the EU, USA, Canada and Japan. We propose a number of areas that need to be addressed in any safety assessment of novel probiotics and prebiotics. These include publication of the genomic sequence, antibiotic resistance profiling, selection of appropriate in vivo model, toxicological studies (including toxin production) and definition of target population. PMID- 25499744 TI - Cultivation of microalgal Chlorella for biomass and lipid production using wastewater as nutrient resource. AB - Using wastewater for microalgal cultures is beneficial for minimizing the use of freshwater, reducing the cost of nutrient addition, removing nitrogen and phosphorus from wastewater and producing microalgal biomass as bioresources for biofuel or high-value by-products. There are three main sources of wastewater, municipal (domestic), agricultural and industrial wastewater, which contain a variety of ingredients. Some components in the wastewater, such as nitrogen and phosphorus, are useful ingredients for microalgal cultures. In this review, the effects on the biomass and lipid production of microalgal Chlorella cultures using different kinds of wastewater were summarized. The use of the nutrients resource in wastewater for microalgal cultures was also reviewed. The effect of ammonium in wastewater on microalgal Chlorella growth was intensively discussed. In the end, limitations of wastewater-based of microalgal culture were commented in this review article. PMID- 25499743 TI - Extracellular matrix protein 1 regulates cell proliferation and trastuzumab resistance through activation of epidermal growth factor signaling. AB - INTRODUCTION: Extracellular matrix protein 1 (ECM1) is a secreted glycoprotein with putative functions in cell proliferation, angiogenesis and differentiation. Expression of ECM1 in several types of carcinoma suggests that it may promote tumor development. In this study, we investigated the role of ECM1 in oncogenic cell signaling in breast cancer, and potential mechanisms for its effects. METHODS: In order to find out the functional role of ECM1, we used the recombinant human ECM1 and viral transduction systems which stably regulated the expression level of ECM1. We examined the effect of ECM1 on cell proliferation and cell signaling in vitro and in vivo. Moreover, tissues and sera of patients with breast cancer were used to confirm the effect of ECM1. RESULTS: ECM1 protein was increased in trastuzumab-resistant (TR) cells, in association with trastuzumab resistance and cell proliferation. Through physical interaction with epidermal growth factor receptor (EGFR), ECM1 potentiated the phosphorylation of EGFR and extracellular signal-regulated kinase upon EGF treatment. Moreover, ECM1 induced galectin-3 cleavage through upregulation of matrix metalloproteinase 9 not only improved mucin 1 expression, but also increased EGFR and human epidermal growth factor receptor 3 protein stability as a secondary signaling. CONCLUSIONS: ECM1 has important roles in both cancer development and trastuzumab resistance in breast cancer through activation of EGFR signaling. PMID- 25499745 TI - Biological butanol production from microalgae-based biodiesel residues by Clostridium acetobutylicum. AB - This study conducted batch experiments to evaluate the potential of butanol production from microalgae biodiesel residues by Clostridium acetobutylicum. The results indicated that with 90 g/L of glucose as the sole substrate the highest butanol yield of 0.2 g/g-glucose was found, but the addition of butyrate significantly enhanced the butanol yield. The highest butanol yield of 0.4 g/g glucose was found with 60 g/L of glucose and 18 g/L of butyrate. Using microalgae biodiesel residues as substrate, C. acetobutylicum produced 3.86 g/L of butanol and achieved butanol yield of 0.13 g/g-carbohydrate via ABE fermentation, but the results indicated that approximately one third of carbohydrate was not utilized by C. acetobutylicum. Biological butanol production from microalgae biodiesel residues can be possible, but further research on fermentation strategies are required to improve production yield. PMID- 25499746 TI - Effects of selenium on proliferation, interleukin-2 production and selenoprotein mRNA expression of normal and dexamethasone-treated porcine splenocytes. AB - Porcine splenocytes were isolated in vitro, treated with different levels of dexamethasone (DEX), and stimulated by concanavalin A. Further, the normal (non DEX-supplemented) or DEX-treated (0.01 umol/L) splenocytes were incubated with 0, 0.5, 2, and 5 umol/L Na2SeO3. The splenocyte proliferation, IL-2 production, intracellular glutathione peroxidase 1 (GPx1) mRNA level and activity and thioredoxin reductase 1 mRNA level were measured. The results showed that addition of 0.5 or 2 umol/L Na2SeO3 significantly promoted normal and DEX-treated splenocyte proliferation, IL-2 production and GPx1 mRNA expression and activity (P < 0.05), respectively. The maximum effect was observed in DEX-treated splenocytes with 0.5 umol/L Na2SeO3. Thus, our results show that the immune state modulation of Se is stronger in DEX-treated splenocytes than normal splenocytes. The mechanism underlying this effect may be increased in GPx1 expression induced by Se. Our results explain the controversy of varying reports on the immune state modulation induced by Se. PMID- 25499748 TI - Seasonal changes in the neuroendocrine system: introduction to the special issue. PMID- 25499747 TI - Food restriction during pregnancy in rabbits: effects on hormones and metabolites involved in energy homeostasis and metabolic programming. AB - This study examined the effects of food restriction during rabbit pregnancy on hormones and metabolites involved in energy homeostasis and metabolic programming. Pregnant does were assigned to four groups: the control group was fed a standard ration while the others received a restricted amount of food (30% restriction) during early (0-9 days), mid (9-18 days), and late (19-28 days) pregnancy. The pregnancy induced a coordinated range of adaptations to fulfil energy requirements of both mother and foetus, such as hyperleptinaemia and hyperinsulinaemia, reduced insulin sensitivity, increased cortisol and non esterified fatty acid. Food restriction altered leptin, insulin, T3, non esterified fatty acids and glucose concentrations depending on the gestational phase in which it was applied. Collectively, present data confirm that the endocrinology of pregnancy and the adaptive responses to energy deficit make the rabbit an ideal model for studying nutritional-related disorders and foetal programming of metabolic disease. PMID- 25499749 TI - The microbiota is important for IL-17A expression and neutrophil infiltration in lesional skin of Flg(ft/ft) mice. PMID- 25499750 TI - Pichia anomala, a new species of yeast-like endosymbionts and its variation in small brown planthopper (Laodelphax striatellus). AB - Yeast-like symbionts (YLS) are endosymbionts that promote the growth of delphacid planthoppers (Hemiptera: Delphacidae), some of which are pests on cultivated rice. Identification and characterization of YLS growth can be helpful for pest control, because it has been demonstrated that there is a variety of YLS in rice planthopper and they affected the planthopper's growth and virulence to plant hosts. So, elucidation of the species of YLS in planthopper is crucial for exploiting a new way to control planthopper. In this study, a new isolated of YLS was obtained from the small brown planthopper, Laodelphax striatellus, which was cultured in vitro, simultaneously identified as Pichia anomala based on its phylogenetic analysis. In order to confirm the existence of P. anomala in the L. striatellus body, we used the denaturing gradient gel electrophoresis (DGGE) to identify the YLS and obtain the specific bands for P. anomala. The quantification and localization of P. anomala in L. striatellus samples were determined by fluorescent in situ hybridization (FISH) using genus-specific 18S rDNA targeted probe. The result confirmed that a certain number of P. anomala exist in L. striatellus's abdomen. Subsequently, the variation and copy number of P. anomala in different L. striatellus instars was measured by using absolute quantitative real-time PCR (qPCR), the results indicated that the new isolated strain was closely related to the developmental process of L. striatellus. PMID- 25499751 TI - Production and application of a rare disaccharide using sucrose phosphorylase from Leuconostoc mesenteroides. AB - Sucrose phosphorylase (SPase) from Leuconostoc mesenteroides exhibited activity towards eight ketohexoses, which behaved as D-glucosyl acceptors, and alpha-D glucose-1-phosphate (G1P), which behaved as a donor. All eight of these ketohexoses were subsequently transformed into the corresponding d-glucosyl ketohexoses. Of the eight ketohexoses evaluated in the current study, d-allulose behaved as the best substrate for SPase, and the resulting d-glucosyl-d alluloside product was found to be a non-reducing sugar with a specific optical rotation of [alpha]D(20) + 74.36 degrees . D-Glucosyl-D-alluloside was identified as alpha-D-glucopyranosyl-(1->2)-beta-D-allulofuranoside by NMR analysis. D Glucosyl-D-alluloside exhibited an inhibitory activity towards an invertase from yeast with a Km value of 50 mM, where it behaved as a competitive inhibitor with a Ki value of 9.2 mM. D-Glucosyl-D-alluloside was also successfully produced from sucrose using SPase and D-tagatose 3-epimerase. This process also allowed for the production of G1P from sucrose and d-allulose from D-fructose, which suggested that this method could be used to prepare d-glucosyl-d-alluloside without the need for expensive reagents such as G1P and d-allulose. PMID- 25499752 TI - Analyses of chicken sialyltransferases related to N-glycosylation. AB - Proteins exogenously expressed and deposited in the egg whites of transgenic chickens did not contain terminal sialic acid in their N-glycan. Since this sugar is important for the biological stability of therapeutic proteins, we examined chicken sialyltransferases (STs). Based on homologies in DNA sequences, we cloned and expressed several chicken STs, which appeared to be involved in N glycosylation in mammals, in 293FT cells. Enzymatic activity was detected with ST3Gal3, ST3Gal6 and ST6Gal1 using galactose-beta1,4-N-acetylglucosamine (Galbeta1,4GlcNAc) as an acceptor. Using Golgi fractions from the cell-free extracts of chicken organs, alpha2,3- and/or alpha2,6-ST activities were detected in the liver and kidney, but were absent in the oviduct cells in which egg-white proteins were produced. This result suggested that the lack of ST activities in oviduct cells mainly caused the lack of sialic acid in the N-glycan of proteins exogenously expressed and deposited in egg white. PMID- 25499753 TI - Factors influencing secondary non-response to botulinum toxin type A injections in cervical dystonia. AB - BACKGROUND: The development of secondary non-response (SNR) to botulinum neurotoxin type-A (BoNT-A) is considered a key issue in the management of cervical dystonia (CD). This case-controlled study was performed to systematically identify factors influencing SNR during BoNT-A therapy. METHODS: This was a retrospective, international, non-interventional study of CD patients. Patients with SNR were matched with up to three responder patients (control) on the basis of duration of therapy and number of injection cycles. Factors influencing the development of SNR were screened using a univariate logistic regression model and confirmed using a multivariate conditional logistic regression model. RESULTS: 216 patients were enrolled, and 201 (SNR = 52; responder = 149) were matched and subdivided into blocks (doublets, triplets or quadruplets). At baseline, a significantly higher proportion of SNR patients had received previous or concomitant therapies (p = 0.038) and surgery for CD (p = 0.007) compared with controls. Although disease severity at onset was similar between groups, a significantly higher proportion of SNR patients experienced severe CD at the time of SNR compared with controls at the last documented visit. Multivariate analyses identified five factors that were significantly associated in predicting SNR (odds ratio [OR] > 1 indicated higher chances for being SNR): previous surgical procedure for CD (OR 9.8, p = 0.013), previous BoNT-A related severe adverse event (AE) (OR 5.6 p = 0.027), physical therapy (OR 4.6, p = 0.028), neuroleptic use (OR 3.3, p = 0.019) and average BoNT-A dose (OR 2.7, p = 0.010). CONCLUSIONS: These findings suggest that SNR may not reflect true pharmacological resistance to BoNT-A therapy, but may be related to underlying disease severity. PMID- 25499754 TI - Diagnostic trap in relation to an intranasal tumour. PMID- 25499755 TI - [Melioidosis: a sporadic or an emerging disease in Colombia?]. PMID- 25499756 TI - Relationship between leptin and blood pressure in patients with multiple system atrophy. PMID- 25499757 TI - Clinical and radiological characteristics of 17 Chinese patients with pathology confirmed tumefactive demyelinating diseases: follow-up study. AB - Tumefactive demyelinating disease is a rare inflammatory demyelinating disease (IDD) of the central nervous system (CNS). The literature lacks a clear and consistent description of the clinical and radiological spectrum of this disorder, and few Chinese cases have been studied. Here we report 17 Chinese patients, with pathology confirmed CNS IDD, who had distinct clinical and imaging features from those in previous reports. Median age at onset was 47 years, with a female to male ratio of 1.1:1. Multifocal lesions were present in nine cases (53%) on their pre-biopsy magnetic resonance imagings (MRIs), with locations predominantly involving periventricular white matter (41%), subcortical white matter (41%), juxtacortical regions (41%), and cortical gray matter (35%). Moderate to severe perilesional edema and/or mass effect were present in 35% of cases. A variety of enhancement patterns were observed; most were heterogeneous, including ring-like, patchy, venular-like, nodular, punctate, and diffuse in a decreased frequency. Perilesional restriction on diffusion-weighted images (DWI) were evident in 70% cases. Clinical course prior to biopsy was a first neurological event in 82% cases. During a median follow-up of 4.1 years, 76% of cases remained as isolated demyelinating syndrome, and 70% experienced a total or near-total recovery regardless of whether they received immunotherapy. Further studies are needed, especially concerning series with pathological confirmation and long-term follow-up information. PMID- 25499758 TI - Tumefactive demyelination following in vitro fertilization (IVF). AB - Tumefactive demyelination (TD) is a solitary cerebral demyelinating lesion clinically and radiologically mimicking brain tumors. It can occur in isolation or may be rarely associated with other demyelinating diseases. The underlying pathogenic mechanisms are unknown. We present the first report of TD following in vitro fertilization (IVF) in a 36-year-old healthy woman who developed subacute right hemiparesis shortly after a scheduled IVF cycle. Evaluation revealed left hemispheric space-occupying lesion pathologically diagnosed as TD. Treatment with intravenous methylprednisolone promptly resulted in a clinical and radiological improvement maintained thereafter. This report confirms and expands the spectrum of inflammatory demyelinating conditions associated with IVF and suggests possible hormonal influence in the development of TD. PMID- 25499759 TI - Loss of PRDM11 promotes MYC-driven lymphomagenesis. AB - The PR-domain (PRDM) family of genes encodes transcriptional regulators, several of which are deregulated in cancer. By using a functional screening approach, we sought to identify novel tumor suppressors among the PRDMs. Here we demonstrate oncogenic collaboration between depletion of the previously uncharacterized PR domain family member Prdm11 and overexpression of MYC. Overexpression of PRDM11 inhibits proliferation and induces apoptosis. Prdm11 knockout mice are viable, and loss of Prdm11 accelerates MYC-driven lymphomagenesis in the Eu-Myc mouse model. Moreover, we show that patients with PRDM11-deficient diffuse large B-cell lymphomas (DLBCLs) have poorer overall survival and belong to the nongerminal center B-cell-like subtype. Mechanistically, genome-wide mapping of PRDM11 binding sites coupled with transcriptome sequencing in human DLBCL cells evidenced that PRDM11 associates with transcriptional start sites of target genes and regulates important oncogenes such as FOS and JUN. Hence, we characterize PRDM11 as a putative novel tumor suppressor that controls the expression of key oncogenes, and we add new mechanistic insight into B-cell lymphomagenesis. PMID- 25499760 TI - Janus kinase inhibition by ruxolitinib extends dasatinib- and dexamethasone induced remissions in a mouse model of Ph+ ALL. AB - Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is initiated and driven by the oncogenic fusion protein BCR-ABL, a constitutively active tyrosine kinase. Despite major advances in the treatment of this highly aggressive disease with potent inhibitors of the BCR-ABL kinase such as dasatinib, patients in remission frequently relapse due to persistent minimal residual disease possibly supported, at least in part, by salutary cytokine driven signaling within the hematopoietic microenvironment. Using a mouse model of Ph+ ALL that accurately mimics the genetics, clinical behavior, and therapeutic response of the human disease, we show that a combination of 2 agents approved by the US Food and Drug Administration (dasatinib and ruxolitinib, which inhibit BCR-ABL and Janus kinases, respectively), significantly extends survival by targeting parallel signaling pathways. Although the BCR-ABL kinase cancels the cytokine requirement of immature leukemic B cells, dasatinib therapy restores cytokine dependency and sensitizes leukemic cells to ruxolitinib. As predicted, ruxolitinib alone had no significant antileukemic effect in this model, but it prevented relapse when administered with dasatinib. The combination of dasatinib, ruxolitinib, and the corticosteroid dexamethasone yielded more durable remissions, in some cases after completion of therapy, avoiding the potential toxicity of other cytotoxic chemotherapeutic agents. PMID- 25499761 TI - The hidden genomic landscape of acute myeloid leukemia: subclonal structure revealed by undetected mutations. AB - The analyses carried out using 2 different bioinformatics pipelines (SomaticSniper and MuTect) on the same set of genomic data from 133 acute myeloid leukemia (AML) patients, sequenced inside the Cancer Genome Atlas project, gave discrepant results. We subsequently tested these 2 variant-calling pipelines on 20 leukemia samples from our series (19 primary AMLs and 1 secondary AML). By validating many of the predicted somatic variants (variant allele frequencies ranging from 100% to 5%), we observed significantly different calling efficiencies. In particular, despite relatively high specificity, sensitivity was poor in both pipelines resulting in a high rate of false negatives. Our findings raise the possibility that landscapes of AML genomes might be more complex than previously reported and characterized by the presence of hundreds of genes mutated at low variant allele frequency, suggesting that the application of genome sequencing to the clinic requires a careful and critical evaluation. We think that improvements in technology and workflow standardization, through the generation of clear experimental and bioinformatics guidelines, are fundamental to translate the use of next-generation sequencing from research to the clinic and to transform genomic information into better diagnosis and outcomes for the patient. PMID- 25499763 TI - CMV promotes recipient T-cell immunity following reduced-intensity T-cell depleted HSCT, significantly modulating chimerism status. AB - Cytomegalovirus (CMV) remains a significant cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). Clinical risk varies according to a number of factors, including recipient/donor CMV serostatus. Current dogma suggests risk is greatest in seropositive recipient (R+)/seronegative donor (D-) transplants and is exacerbated by T-cell depletion. We hypothesized that in the setting of reduced-intensity T-cell-depleted conditioning, recipient-derived CMV specific T cells escaping deletion may contribute significantly to CMV-specific immunity and might therefore also influence chimerism status. We evaluated 105 recipients of alemtuzumab-based reduced-intensity HSCT and collated details on CMV infection episodes and T-cell chimerism. We used CMV-specific HLA multimers to enumerate CMV-specific T-cell numbers and select cells to assess chimerism status in a subset of R+/D- and R+/seropositive donor patients. We show that in R+/D- patients, CMV-specific T cells are exclusively of recipient origin, can protect against recurrent CMV infections, and significantly influence the chimerism status toward recipients. The major findings were replicated in a separate validation cohort. T-cell depletion in the R+/D- setting may actually, therefore, foster more rapid reconstitution of protective antiviral immunity by reducing graft-vs-host directed alloreactivity and the associated elimination of the recipient T-cell compartment. Finally, conversion to donor chimerism after donor lymphocytes is associated with clinically occult transition to donor derived immunity. PMID- 25499762 TI - Bone marrow skeletal stem/progenitor cell defects in dyskeratosis congenita and telomere biology disorders. AB - Dyskeratosis congenita (DC) is an inherited multisystem disorder, characterized by oral leukoplakia, nail dystrophy, and abnormal skin pigmentation, as well as high rates of bone marrow (BM) failure, solid tumors, and other medical problems such as osteopenia. DC and telomere biology disorders (collectively referred to as TBD here) are caused by germline mutations in telomere biology genes leading to very short telomeres and limited proliferative potential of hematopoietic stem cells. We found that skeletal stem cells (SSCs) within the BM stromal cell population (BMSCs, also known as BM-derived mesenchymal stem cells), may contribute to the hematologic phenotype. TBD-BMSCs exhibited reduced clonogenicity, spontaneous differentiation into adipocytes and fibrotic cells, and increased senescence in vitro. Upon in vivo transplantation into mice, TBD BMSCs failed to form bone or support hematopoiesis, unlike normal BMSCs. TERC reduction (a TBD-associated gene) in normal BMSCs by small interfering TERC-RNA (siTERC-RNA) recapitulated the TBD-BMSC phenotype by reducing proliferation and secondary colony-forming efficiency, and by accelerating senescence in vitro. Microarray profiles of control and siTERC-BMSCs showed decreased hematopoietic factors at the messenger RNA level and decreased secretion of factors at the protein level. These findings are consistent with defects in SSCs/BMSCs contributing to BM failure in TBD. PMID- 25499764 TI - Depletion of poly(A)-specific ribonuclease (PARN) inhibits proliferation of human gastric cancer cells by blocking cell cycle progression. AB - Regulation of mRNA decay plays a crucial role in the post-transcriptional control of cell growth, survival, differentiation, death and senescence. Deadenylation is a rate-limiting step in the silence and degradation of the bulk of highly regulated mRNAs. However, the physiological functions of various deadenylases have not been fully deciphered. In this research, we found that poly(A)-specific ribonuclease (PARN) was upregulated in gastric tumor tissues and gastric cancer cell lines MKN28 and AGS. The cellular function of PARN was investigated by stably knocking down the endogenous PARN in the MKN28 and AGS cells. Our results showed that PARN-depletion significantly inhibited the proliferation of the two types of gastric cancer cells and promoted cell death, but did not significantly affect cell motility and invasion. The depletion of PARN arrested the gastric cancer cells at the G0/G1 phase by upregulating the expression levels of p53 and p21 but not p27. The mRNA stability of p53 was unaffected by PARN-knockdown in both types of cells. A significant stabilizing effect of PARN-depletion on p21 mRNA was observed in the AGS cells but not in the MKN28 cells. We further showed that the p21 3'-UTR triggered the action of PARN in the AGS cells. The dissimilar observations between the MKN28 and AGS cells as well as various stress conditions suggested that the action of PARN strongly relied on protein expression profiles of the cells, which led to heterogeneity in the stability of PARN-targeted mRNAs. PMID- 25499766 TI - Bacterial community structures as a diagnostic tool for watershed quality assessment. AB - The analysis of bacterial community structures can be considered a promising instrument when assessing the quality and health of a body of water. Here, the representation of a new biological approach to studying such pollutant-based impact on freshwater sediments is explored. To test our hypothesis, sediment samples of Phragmites australis (common reed)-associated rhizosphere were collected at sites affected by different types and levels of pollution, all located in Zhangye, Gansu Province, China. The analyzed bacterial community structures showed a varying pattern according to the presence, characteristics and level of contaminants. Results of the study showed that bacterial community structures could be effectively used as diagnostic tools to map watershed quality status. PMID- 25499765 TI - Prostaglandin F2alpha receptor (FP) signaling regulates Bmp signaling and promotes chondrocyte differentiation. AB - Prostaglandins are a group of lipid signaling molecules involved in various physiological processes. In addition, prostaglandins have been implicated in the development and progression of diseases including cancer, cardiovascular disease, and arthritis. Prostaglandins exert their effects through the activation of specific G protein-coupled receptors (GPCRs). In this report, we examined the role of prostaglandin F2alpha receptor (FP) signaling as a regulator of chondrocyte differentiation. We found that FP expression was dramatically induced during the differentiation of chondrocytes and was up-regulated in cartilages. Forced expression of FP in ATDC5 chondrogenic cell line resulted in the increased expression of differentiation-related genes and increased synthesis of the extracellular matrix (ECM) regardless of the presence of insulin. Similarly, PGF2alpha treatment induced the expression of chondrogenic marker genes. In contrast, knockdown of endogenous FP expression suppressed the expression of chondrocyte marker genes and ECM synthesis. Organ culture of cartilage rudiments revealed that PGF2alpha induces chondrocyte hypertrophy. Additionally, FP overexpression increased the levels of Bmp-6, phospho-Smad1/5, and Bmpr1a, while knockdown of FP reduced expression of those genes. These results demonstrate that up-regulation of FP expression plays an important role in chondrocyte differentiation and modulates Bmp signaling. PMID- 25499767 TI - Paraspinal muscle changes of unilateral multilevel minimally invasive transforaminal interbody fusion. AB - PURPOSE: We attempted to identify changes in back muscle atrophy occurring in multilevel minimally invasive transforaminal interbody fusion (MITLIF) and the impact of these changes on clinical outcomes. METHODS: This study was conducted on 92 patients who underwent unilateral MITLIF between 2006 and 2013, had been tracked with a follow-up for at least 1 year, and had been assessed by pre- and postoperative computed tomography (CT). For the clinical evaluation, a pre- and postoperative visualized analog scale (VAS) of the back and legs, and Oswestry Disability Index (ODI) were measured. CT was used for the evaluation of back muscle atrophy and a cross-sectional area (CSA) of the multifidus was measured at the level below a fused segment, excluding metal artifacts. RESULTS: There was no significant difference in the reduction of CSA between groups with one-, two-, or three-plus-segment fusion. In addition, no statistically significant differences were found in the pre- and postoperative VAS of the back, VAS of the legs, and ODI between the three groups. The reduction of CSA showed a statistically significant positive correlation with preoperative VAS of the back (p = 0.025, r = 0.562). On the other hand, no significant difference was found in VAS of the leg (p = 0.437, r = 0.082) and ODI (p = 0.106, r = 0.017). CONCLUSION: When performing unilateral multilevel MITLIF, significant difference was not found in the atrophy of the multifidus according to the number of fused segments. The clinical outcomes also showed no significant difference. Therefore, unilateral MITLIF can be considered to be an effective surgical method to minimize lumbar muscle damage, even at multiple levels. PMID- 25499768 TI - Clinical and pathological features of melanoma in europeans living on the Western costa del sol in southern Spain. AB - OBJECTIVE: To compare clinical and pathological features of melanoma in Spanish patients with those of patients from Central or Northern Europe living in the health district of Costa del Sol Occidental in southern Spain. METHODS: We conducted a descriptive cross-sectional study of all cases of primary cutaneous melanoma histologically confirmed between 2005 and 2011 in the health care district covered by Hospital Costa del Sol in Marbella. We analyzed clinical and pathological features and performed a descriptive analysis of the 2 populations, in addition to univariate analysis with place of birth (Spain vs Central or Northern Europe) as the independent variable. RESULTS: Compared with Spaniards, patients from Central or Northern Europe were 10 years older at the time of melanoma diagnosis (66.2 vs 56.2 years, P<.001), had lighter skin (types I or II) (90.3% vs 67.1%, P<.001), and greater recreational sun exposure (93.7% vs 66.2%, P<.001). In addition, multiple melanomas (17.6% vs 4.4%, P=.001), nonmelanoma skin cancer (47.2% vs 15.7%, P<.001), and a family history of melanoma (9.5% vs 2.3%, P=.01) were more common in these patients. Central and Northern Europeans also had a higher overall frequency of melanoma on the trunk (46.3% vs 38.7%) and melanoma in situ (54.7% vs 41.8%, P=.03). CONCLUSION: Differences in melanoma presentation between Spanish patients and patients from Central or Northern Europe appear to be linked to phenotypic and lifestyle factors. A better understanding of these differences will help to tailor melanoma prevention and follow-up programs for multicultural populations, such as those on Spain's Costa del Sol. PMID- 25499769 TI - Emergency medicine resident crisis resource management ability: a simulation based longitudinal study. AB - BACKGROUND: Simulation has been identified as a means of assessing resident physicians' mastery of technical skills, but there is a lack of evidence for its utility in longitudinal assessments of residents' non-technical clinical abilities. We evaluated the growth of crisis resource management (CRM) skills in the simulation setting using a validated tool, the Ottawa Crisis Resource Management Global Rating Scale (Ottawa GRS). We hypothesized that the Ottawa GRS would reflect progressive growth of CRM ability throughout residency. METHODS: Forty-five emergency medicine residents were tracked with annual simulation assessments between 2006 and 2011. We used mixed-methods repeated-measures regression analyses to evaluate elements of the Ottawa GRS by level of training to predict performance growth throughout a 3-year residency. RESULTS: Ottawa GRS scores increased over time, and the domains of leadership, problem solving, and resource utilization, in particular, were predictive of overall performance. There was a significant gain in all Ottawa GRS components between postgraduate years 1 and 2, but no significant difference in GRS performance between years 2 and 3. CONCLUSIONS: In summary, CRM skills are progressive abilities, and simulation is a useful modality for tracking their development. Modification of this tool may be needed to assess advanced learners' gains in performance. PMID- 25499770 TI - [Monitoring pregnancy of women with a previous cesarean delivery: qualitative aspects and prognostic implications]. AB - OBJECTIVES: To assess the quality of prenatal monitoring of pregnant women with a previous cesarean delivery and determine the maternal and neonatal prognosis in an African setting. PATIENTS AND METHODS: This prospective, descriptive, and analytical study took place at Roi Baudouin Health Center in Dakar (Senegal) and examined the records of women giving birth from November 1, 2009 to August 31, 2010. It included all women admitted for delivery at 22 weeks of gestation or more, with at least one previous cesarean, and a prenatal consultation record booklet. Women with uterine scars from a gynecological intervention were excluded. The study included a qualitative analysis of the record booklets and an interview of patients. RESULTS: Women with previous cesareans accounted for 12.5% of all women giving birth during the study period. The average age of the women in our study was 28 years, their mean parity was 3, and their mean number of prenatal examinations 3 (range: 1 to 5). Most prenatal care was provided by midwives (95.1%). The clinical characteristics were rarely completed. Not all women had undergone the laboratory tests required, and fewer than half (40.7%) had had a third-trimester ultrasound. In all, 109 (28.1%) had been referred to the hospital as an appropriate structure for their delivery. Complications of labor were observed in 28.3% of the cases. In 73% of these cases, women had repeat cesareans; 26% had vaginal deliveries. The performance of the recommended prenatal check-up was significantly correlated to how early prenatal care began (p = 0.001) and the level of the structure providing prenatal care (p = 0.027). CONCLUSION: Reducing maternal and fetal morbidity and mortality due to uterine scars requires that women be made aware of the relevant issues and that healthcare providers refer them appropriately and early. PMID- 25499771 TI - In double trouble for eating pathology? An experimental study on the combined role of perfectionism and body dissatisfaction. AB - BACKGROUND AND OBJECTIVES: A number of correlational studies suggest that the combined presence of perfectionism and body dissatisfaction creates elevated risk for the development of eating disorder pathology. The aim of this study was to examine the causal role of this combination of risk factors for eating pathology. METHOD: We conducted an experimental study in a sample of female college students (N = 47). Specifically, we performed an experimental manipulation of perfectionism and examined whether this manipulation would interact with body dissatisfaction to predict eating disorder symptoms. RESULTS: We found that the effect of the experimental manipulation was moderated by body dissatisfaction, such that women in the perfectionism condition and scoring high on body dissatisfaction exhibited the highest levels of eating disorder symptoms. LIMITATIONS: The sample was rather small (resulting in limited statistical power) and the participants were predominantly healthy and well-adjusted women, which may limit the generalizability and interpretation of our findings. CONCLUSIONS: The results suggest that the combination of perfectionism and body dissatisfaction is particularly detrimental and predictive of risk for eating disorder symptoms. PMID- 25499772 TI - Rumination and implicit avoidance following bereavement: an approach avoidance task investigation. AB - BACKGROUND AND OBJECTIVES: Rumination, a risk factor in adjustment to bereavement, has often been considered a confrontation process. However, building on research on worry in generalized anxiety disorder (GAD) and rumination in post traumatic stress disorder (PTSD), researchers recently developed the Rumination as Avoidance Hypothesis (RAH), which states that rumination after bereavement serves to avoid the reality of the loss. In the present study, RAH was tested by investigating if rumination is associated with implicit loss avoidance. METHODS: An Approach Avoidance Task (AAT) was used to assess automatic behavior tendencies. Using a joystick, 71 persons who recently lost a first-degree relative (90.1% women), pulled stimuli toward themselves or pushed them away from themselves. Stimuli represented the loss (picture deceased + loss word), were loss-related but ambiguous (picture deceased + neutral word; picture stranger + loss word), or were non-loss-related (picture stranger + neutral word; puzzle picture + X's). RESULTS: Participants who ruminated more were relatively faster in pushing loss stimuli away from themselves and slower in pulling loss stimuli towards themselves, implying more rumination was associated with stronger implicit loss avoidance. Effects were maintained after controlling for depressive or post-traumatic stress symptom levels, but not when controlling for prolonged grief symptom levels. LIMITATIONS: Conjugally bereaved women were overrepresented in the sample, which limits generalizability of results. The study was correlational, precluding causal inferences. CONCLUSIONS: In line with RAH, rumination was positively associated with loss avoidance. This may indicate that the application of exposure-based techniques can reduce rumination and loss related psychopathology. PMID- 25499775 TI - Essure hysteroscopic sterilization versus interval laparoscopic bilateral tubal ligation: a comparative effectiveness review. AB - A comparative effectiveness analysis was performed to examine the risks and benefits of laparoscopic bilateral tubal ligation compared with hysteroscopic sterilization using the Essure Permanent Birth Control System (Bayer HealthCare AG, Whippany, NJ). Existing evidence shows that both LBTL and Essure are safe and effective methods of female sterilization. Both have high rates of efficacy and low rates of complications although when complications do occur, those related to the Essure procedure are more likely to be minor in nature. The analysis was limited by the restricted number of studies involving head-to-head comparisons of the 2 approaches. PMID- 25499773 TI - The NHLBI-sponsored Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR): a new paradigm for rigorous, accurate, and reproducible evaluation of putative infarct-sparing interventions in mice, rabbits, and pigs. AB - RATIONALE: Despite 4 decades of intense effort and substantial financial investment, the cardioprotection field has failed to deliver a single drug that effectively reduces myocardial infarct size in patients. A major reason is insufficient rigor and reproducibility in preclinical studies. OBJECTIVE: To develop a multicenter, randomized, controlled, clinical trial-like infrastructure to conduct rigorous and reproducible preclinical evaluation of cardioprotective therapies. METHODS AND RESULTS: With support from the National Heart, Lung, and Blood Institute, we established the Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR), based on the principles of randomization, investigator blinding, a priori sample size determination and exclusion criteria, appropriate statistical analyses, and assessment of reproducibility. To validate CAESAR, we tested the ability of ischemic preconditioning to reduce infarct size in 3 species (at 2 sites/species): mice (n=22-25 per group), rabbits (n=11-12 per group), and pigs (n=13 per group). During this validation phase, (1) we established protocols that gave similar results between centers and confirmed that ischemic preconditioning significantly reduced infarct size in all species and (2) we successfully established a multicenter structure to support CAESAR's operations, including 2 surgical centers for each species, a Pathology Core (to assess infarct size), a Biomarker Core (to measure plasma cardiac troponin levels), and a Data Coordinating Center-all with the oversight of an external Protocol Review and Monitoring Committee. CONCLUSIONS: CAESAR is operational, generates reproducible results, can detect cardioprotection, and provides a mechanism for assessing potential infarct-sparing therapies with a level of rigor analogous to multicenter, randomized, controlled clinical trials. This is a revolutionary new approach to cardioprotection. Importantly, we provide state-of the-art, detailed protocols ("CAESAR protocols") for measuring infarct size in mice, rabbits, and pigs in a manner that is rigorous, accurate, and reproducible. PMID- 25499774 TI - Prevention of lymphoceles using FloSeal and CoSeal after laparoscopic lymphadenectomy in patients with gynecologic malignancies. AB - INTRODUCTION: Pelvic +/- para-aortic lymphadenectomy (LAE) is an essential element of staging and treatment of different gynecologic malignancies. However, LAE can induce asymptomatic and symptomatic pelvic lymphoceles (LCs) in a considerable percentage of patients. Therapy of symptomatic LCs may cause additional morbidity. The best strategy to reduce the rate of LCs has not established yet. MATERIALS AND METHODS: Between January 2011 and May 2012, transperitoneal laparoscopic pelvic +/- para-aortic LAE was performed at the Department of Gynecology at Charite University Hospital Berlin in 238 patients with cervical, endometrial, ovarian, or groin-positive vulvar cancer. The application of FloSeal (Baxter, Deerfield, IL) and CoSeal (Baxter) was used in 25 patients (group A) as an alternative to routine pelvic drainage after LAE. A case control comparison was performed on 25 patients (group B) with bilateral drainage after complete LAE. The primary objective of this pilot study was to evaluate the feasibility and safety of the method. As a secondary objective, we evaluated the incidence of LCs and symptomatic LCs in both groups. The detection of LCs was performed during oncologic follow-up by sonography, computed tomographic imaging, or magnetic resonance imaging. MEASUREMENTS AND MAIN RESULTS: Pelvic (n = 50) or pelvic + para-aortic (n = 42) LAE was performed in 44 patients with cervical, 2 with endometrial, 1 with ovarian, and 2 with groin-positive vulvar cancer, respectively. In group B (n = 25), systematic bilateral pelvic drainage was placed after finishing LAE, whereas in group A (n = 25) LAE areas were sealed with 5 mL FloSeal on each side and sprayed with CoSeal afterward without placing drains. In 14 of 50 patients (28%), LCs were detected. In a subgroup of patients with cervical cancer (88% of the cohort), symptomatic LCs occurred in 11% in group A and 18% in group B. Operative revision of symptomatic LCs was necessary in 5% and 18% in groups A and B, respectively (p = .66). Mean Hospital stay was significant shorter in group A (6 days) versus B (8 days) (p = .027). CONCLUSION: The results of this case-controlled pilot study indicate that the application of FloSeal and CoSeal after transperitoneal LAE is feasible and safe, may reduce hospital stay, and may potentially decrease the rate of symptomatic LCs in patients with gynecologic malignancies. PMID- 25499776 TI - Robotic single-port hysterectomy, adnexectomy, and lymphadenectomy in endometrial cancer. AB - STUDY OBJECTIVE: To report the feasibility of performing robotic single-port surgery including pelvic lymphadenectomy in endometrial cancer. DESIGN: Canadian Task Force III. PATIENT: A 49-year-old, multiparous patient diagnosed with well differentiated Federation Internationale de Gynecologie et d'Obstetrique stage I endometrioid adenocarcinoma. SETTING: The patient underwent robotic single-port peritoneal washing, total hysterectomy, bilateral adnexectomy, and pelvic lymphadenectomy. The procedure was performed using the da Vinci Si Surgical System (Intuitive Surgical, Sunnyvale, CA) through a single 2.5-cm umbilical incision. We used a 5-lumen port for single-site instruments, a 3-dimensional high-definition 8.5-mm endoscope, a 5-mm accessory port, and insufflation channel. Monopolar cautery and a bipolar Maryland dissector were used for lymphadenectomy. Vaginal cuff closure was performed using a needle driver and Maryland dissector with V-lock suture. Near the end of the surgery, the 5-mm assistant port was changed with a 10-mm-sized port. Then, a dissected lymph node in an endobag and a needle used in vaginal cuff closure were removed through the 10-mm port. INTERVENTIONS: Total hysterectomy and bilateral adnexectomy with pelvic lymphadenectomy were performed using robotic single-site platform. MEASUREMENTS AND MAIN RESULTS: The total operative time was 206 minutes. The total vaginal cuff closure time was 22 minutes, and lymphadenectomy took 48 minutes. The estimated blood loss was 100 mL; no intraoperative and postoperative complications occurred. The total number of excised lymph nodes was 11. CONCLUSION: Robotic single-port pelvic lymphadenectomy is feasible. Further studies should be performed to assess the benefits of this procedure. PMID- 25499790 TI - Nephroprotection of plantamajoside in rats treated with cadmium. AB - Cadmium (Cd), an environmental and industrial pollutant, generates free radicals responsible for oxidative stress. Cd can also lead to various renal toxic damage such as the proximal tubules and glomerulus dysfunction. Plantamajoside (PMS), a major compound of Plantago asiatica (PA), was reported to have the antioxidant effects. In this study, we investigated the protective effects of PMS on Cd induced renal damage in the NRK-52E cell and rat kidney tissue. Cd exposure increased the ROS generation, lipid peroxidation, serum biochemical values of renal damage, and mRNA and protein expressions of KIM-1 in vitro and in vivo. The significant reduction in glutathione (GSH)/glutathione disulfide (GSSG) ratio and activities of antioxidant enzymes were also observed in the rats treated with Cd. PMS significantly decreased the ROS generation and lipid peroxidation, thus enhancing GSH/GSSG ratio, antioxidant enzyme activities in the cells and rats, and improved histochemical appearances, indicating that PMS has protective activities against Cd-induced renal injury. PMID- 25499791 TI - Interaction between blood selenium concentration and a levels of oxidative stress and antioxidative capacity in healthy children. AB - The study aimed at defining the relationship between blood selenium concentration (Se-B) and levels of oxidative stress and antioxidative capacity in healthy children. The studies were conducted on 337 children (mean age: 8.53+/-1.92 years). The groups of individuals with Se-B <1st quartile (group I, Se B<70MUg/L), with Se-B fitting the range of 1st quartile and median (group II, Se B: 70-76.9MUg/L), with Se-B between the median and 3rd quartile (group III, Se-B: 77-83.9MUg/L) and those with Se-B above the 3rd quartile (group IV, Se B>=84MUg/L) were distinguished. Level of oxidative stress was defined using determination of urine malonyldialdehyde concentration (MDA) and urine 8-hydroxy 2-deoxyguanosine concentration (8-OHdg). Urine total antioxidant status (TAS) was determined. In group IV TAS was significantly higher than in groups I-III. A positive correlation was detected between Se-B and TAS. In healthy children an appropriately high Se-B seems to ensure higher total antioxidative status. PMID- 25499792 TI - Toxicity and translocation of graphene oxide in Arabidopsis thaliana. AB - We investigated the possible safety property and translocation of graphene oxide (GO) in the range of MUg/L in Arabidopsis. GO exposure did not obviously influence germination, seed development, shoot and root development of seedlings, and flowering time. Meanwhile, GO exposure could not induce severe H2O2 production, increase in malondialdehyde content, formation of oxidative stress, and altered activities of antioxidant enzymes. Moreover, GO exposure did not change expression patterns of examined genes required for germination, photomorphogenesis, root development, and transition from vegetative to reproductive development. In the seedling, we did not observe severe GO accumulation in mesophyll and parenchyma cells of leaf or stem, and in sieve element in leaf, stem, or root. In contrast, we observed the severe GO accumulation in root hair and root parenchyma cells. Our results provide the physiological basis for safety property of GO at the examined concentrations in Arabidopsis plants. Furthermore, our data imply that although GO was absorbed by Arabidopsis plants through root hairs, plants might still have strong ability to be against GO translocation into stem or leaves. In addition, we found that cotyledon might serve as an important site for GO distribution during the early development. PMID- 25499793 TI - Guilty until proven innocent?--the Assumption of Care of a baby at birth. AB - BACKGROUND: This paper provides an overview of the history of child protection, the associated law and the 2008 amendments to the Child and Young Persons (Care and Protection) Act 1998 in relation to the Assumption of Care at birth practice. OBJECTIVE: To explore the current practice of an Assumption of Care (AOC) where a newborn baby is removed from his/her mother at the time of birth, particularly focussing on the impact of the AOC on midwives. DISCUSSION: Assumption of Care practices in NSW raise significant issues for midwives in relation to the midwifery codes of ethics and conduct and importantly, to their ability to work in ways that honour a "woman-centred care" philosophy. When midwives are exposed to conflict between workplace and personal or professional values such as the practice of AOC cognitive dissonance can occur. CONCLUSIONS: Further research is required to understand the impact of current Assumption of Care. Broader research to not only look at effect on the midwife but also on other health professionals involved and the women who personally experience the removal of their baby at the time of birth. Consideration must also be given to ways of working with vulnerable families to enhance the acceptability and efficacy of maternity services and with associated agencies will decrease the need for Assumption of Care at birth. PMID- 25499794 TI - Gabaergic control of anxiety-like behavior, but not food intake, induced by ghrelin in the intermediate medial mesopallium of the neonatal chick. AB - Ghrelin (Grh) is an endogenous ligand of the growth hormone secretagogue receptor. In neonatal chicks, central Ghr induces anxiogenic-like behavior but strongly inhibits food intake. The intermediate medial mesopallium (IMM) of the chick forebrain has been identified to be a site of the memory formation, and the modulation of the GABAA receptors that are present here modifies the expression of behavior. Thus, the GABAergic system may constitute a central pathway for Ghr action in regulating the processes of food intake and stress-related behaviors. Therefore, we investigated if the effect of systemic administration of bicuculline (GABAA receptor antagonist) and diazepam (benzodiazepine receptor agonist) on the anxiety in an Open Field test and inhibition in food intake induced by Grh (30pmol) when injected into IMM, were mediated by GABAergic transmission. In Open Field test, bicuculline was able to block the anxiogenic like behavior induced by Ghr, whereas diazepam did not produce it. However, the co-administration of bicuculline or diazepam plus Ghr did not show any change in food intake at 30, 60 and 120min after injection compared to Ghr alone. Our results indicate for the first time that Ghr, injected into the forebrain IMM area, induces an anxiogenic-like behavior, which was blocked by bicuculline but not diazepam, thus suggesting that Ghr plays an important role in the response pattern to acute stressor, involving the possible participation of the GABAergic system. Nevertheless, as neither drug affected the hypophagia induced by intra IMM Ghr, this suggests that it may be mediated by different mechanisms. PMID- 25499795 TI - PM2.5 opened a door to public participation addressing environmental challenges in China. AB - China has long been regarded as a centralized society where the public has little influence on decision-making. Such a top-down management scheme is perceived as a major obstacle to address complicated environment issues. The recent public campaign in China to urge creation of a nationwide PM2.5 monitoring network and mitigation plan provides an unprecedented case of how the public participated and influenced policy-making in a centralized society. This paper reviews key incidents in the campaign chronologically. Here we identify information technology, public awareness of air quality's health impacts and the fact air quality affects everyone as public goods as the major factors promoting public participation. This case demonstrates that public participation can happen in a centralized, top-down society such as China. Continued environmental deterioration may stimulate similar campaigns for other issues. We anticipate this essay to be a starting point for more studies on how environmental issues stimulate incremental social change by making people involved in decision-making process, especially in societies where they are rarely able to do so. PMID- 25499796 TI - Lehr's fields of campaniform sensilla in beetles (Coleoptera): functional morphology. III. Modification of elytral mobility or shape in flying beetles. AB - Some flying beetles have peculiar functional properties of their elytra, if compared with the vast majority of beetles. A "typical" beetle covers its pterothorax and the abdomen from above with closed elytra and links closed elytra together along the sutural edges. In the open state during flight, the sutural edges diverge much more than by 90 degrees . Several beetles of unrelated taxa spread wings through lateral incisions on the elytra and turn the elytron during opening about 10-12 degrees (Cetoniini, Scarabaeus, Gymnopleurus) or elevate their elytra without partition (Sisyphus, Tragocerus). The number of campaniform sensilla in their elytral sensory field is diminished in comparison with beetles of closely related taxa lacking that incision. Elytra are very short in rove beetles and in long-horn beetles Necydalini. The abundance of sensilla in brachyelytrous long-horn beetles Necydalini does not decrease in comparison with macroelytrous Cerambycinae. Strong reduction of the sensory field was found in brachyelytrous Staphylinidae. Lastly, there are beetles lacking the linkage of the elytra down the sutural edge (stenoelytry). Effects of stenoelytry were also not uniform: Oedemera and flying Meloidae have the normal amount of sensilla with respect to their body size, whereas the sensory field in the stenoelytrous Eulosia bombyliformis is 5-6 times less than in chafers of the same size but with normally linking broad elytra. PMID- 25499797 TI - Birth cohort appeared to confound effect estimates of guideline changes on statin utilization. AB - OBJECTIVES: To investigate how birth cohorts can confound population-based intervention effect estimates. STUDY DESIGN AND SETTING: Interrupted time series design was applied to study the prevalence of statin use in Dutch diabetes patients over the period 1998-2011. Effects of guideline changes on the outcome were estimated using a Poisson regression model with and without the birth cohort dimension modeled through random intercepts. RESULTS: Both models estimated a stronger increase in prevalence of statin use after influential studies were published in 2003 for patients aged below 50 and above 70 years. The model that controlled for birth cohort also estimated an effect for patients aged 50-70 years from 2003 onward. The magnitude of the intervention effect for patients aged above 70 years when we controlled for birth cohort was reduced from 0.078 [95% confidence interval (CI): 0.065, 0.091] to 0.027 (95% CI: 0.013, 0.041). Similarly, for patients aged below 50 years, the estimated guideline effect was reduced from 0.070 (95% CI: 0.048, 0.092) to 0.055 (95% CI: 0.035, 0.075). CONCLUSION: In this case study, the birth cohort dimension appeared to confound population-level effect estimates of guideline changes on prevalence of statin use in patients with diabetes. PMID- 25499798 TI - Comparative flight morphology in queens of invasive and native Patagonian bumblebees (Hymenoptera: Bombus). AB - Since its introduction in Chile, the European Bombus terrestris L. (Hymenoptera: Apidae) has progressively reduced the abundance of the native Patagonian bumblebee, Bombus dahlbomii Guerin. Because an important cause of successful invasion of a species may depend on a potentially advantageous phenotype, we studied morphologies related to flight performance (flight muscle ratio (FMR), wing loading (WL), excess power index (EPI, which integrates FMR and WL) and wing aspect ratio (AR)) in the queens of the two species. Previous empirical studies showed that greater FMR, AR and EPI, and lower WL increase flight performance. In the Patagonian Chilean fjord where the study was carried out, B. dahlbomii was 40% heavier than B. terrestris, a difference theoretically allowing the queens of the native species to take off with heavier loads, despite the fact that the two species have virtually identical FMRs. However, FMR negatively depended on body mass at the intra-specific level. The total wing area was 35% greater in B. dahlbomii, but the difference in forewing length was only of 16%. Once taken into account the effect of body size, WL, was significantly lower in B. terrestris. AR increased with body mass and did not differ between species. EPI was weakly but significantly higher in B. terrestris. Experiments formally linking such parameters with flight performance may help to explain the observed quick and wide spread of this alien species in Patagonia in the last few years. PMID- 25499799 TI - Neuroprotective and neurorestorative activities of a novel iron chelator-brain selective monoamine oxidase-A/monoamine oxidase-B inhibitor in animal models of Parkinson's disease and aging. AB - Recently, we have designed and synthesized a novel multipotent, brain-permeable iron-chelating drug, VAR10303 (VAR), possessing both propargyl and monoamine oxidase (MAO) inhibitory moieties. The present study was undertaken to determine the multiple pharmacological activities of VAR in neurodegenerative preclinical models. We demonstrate that VAR affords iron chelating/iron-induced lipid peroxidation inhibitory potency and brain selective MAO-A and MAO-B inhibitory effects, with only limited tyramine-cardiovascular potentiation of blood pressure. The results show that in 6-hydroxydopamine rat (neuroprotection) and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse (neurorescue) Parkinson's disease models, VAR significantly attenuated the loss of striatal dopamine levels, markedly reduced dopamine turnover, and increased tyrosine-hydroxylase levels. Furthermore, chronic systemic treatment of aged rats with VAR improved cognitive behavior deficits and enhanced the expression levels of neurotrophic factors (e.g., brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, and nerve growth factor), Bcl-2 family members and synaptic plasticity in the hippocampus. Our study indicates that the multitarget compound VAR exerted neuroprotective and neurorestorative effects in animal models of Parkinson's disease and aging, further suggesting that a drug that can regulate multiple brain targets could be an ideal treatment-strategy for age-associated neurodegenerative disorders. PMID- 25499800 TI - Metabolic pathway compartmentalization: an underappreciated opportunity? AB - For eukaryotic cells to function properly, they divide their intracellular space in subcellular compartments, each harboring specific metabolic activities. In recent years, it has become increasingly clear that compartmentalization of metabolic pathways is a prerequisite for certain cellular functions. This has for instance been documented for cellular migration, which relies on subcellular localization of glycolysis or mitochondrial respiration in a cell type-dependent manner. Although exciting, this field is still in its infancy, partly due to the limited availability of methods to study the directionality of metabolic pathways and to visualize metabolic processes in distinct cellular compartments. Nonetheless, advances in this field may offer opportunities for innovative strategies to target deregulated compartmentalized metabolism in disease. PMID- 25499801 TI - The use of mitochondrial and nuclear sequences in prospecting for cryptic species in Tabascotrema verai (Digenea: Cryptogonimidae), a parasite of Petenia splendida (Cichlidae) in Middle America. AB - In this study, we used sequences of mitochondrial and nuclear markers to test the hypothesis that Tabascotrema verai Lamothe-Argumedo and Pineda-Lopez, 1990, a parasite of the cichlid Petenia splendida Gunther, 1862 in Middle America, represents a single species, following a molecular prospecting approach. One hundred and five individuals of T. verai were collected from the intestine of 43 specimens of P. splendida in eight localities of Mexico, Belize and Guatemala. A portion (n=53) of the collected specimens was used for molecular studies, whereas the remaining individuals were processed for morphological studies. Fifty-three partial sequences of the cytochrome c oxidase subunit I (cox1) gene were obtained. In addition, 36 sequences of the ITS (internal transcribed spacers 1, 5.8S rRNA gene, and ITS2) and of the 28S rRNA gene were generated from most of the specimens that showed nucleotide variation with the cox1 gene. A haplotype network obtained from cox1 sequences revealed three independent groups (haplogroups 1, 2, and 3). Independent phylogenetic analyses performed with maximum likelihood and Bayesian inference of cox1, ITS and the 28S rRNA gene recovered three genetically-distinct and reciprocally-monophyletic groups, corresponding with the 3 haplogroups obtained in the haplotype network. Values of genetic divergence between clades for cox1 sequences ranged between 8.3% and 11.9%, while for ITS and the 28S rRNA gene, these ranged from 0.08% to 1.2% and from 0.3% to 0.4%, respectively. Morphological observations, and measurements of 23 characters of 44 mounted individuals, showed that no morphological differences exist between individuals from the eight collecting sites, and that the ranges of most morphological traits overlap. Our results suggest that the digenean T. verai represents a complex of cryptic species; the haplotype network, phylogenetic analyses, and genetic differences, along with the morphological stasis recorded here support this notion. Finally, the three recovered lineages showed neither geographical association nor correlation with drainage basins. PMID- 25499802 TI - Z-100, extracted from Mycobacterium tuberculosis strain Aoyama B, promotes TNF alpha production via nucleotide-binding oligomerization domain containing 2 (Nod2)-dependent NF-kappaB activation in RAW264.7 cells. AB - Macrophages are a major component of the innate immune system, and the cytokines they secrete are involved in antitumor responses. Z-100 is obtained from hot water extract of human-type Mycobacterium tuberculosis strain Aoyama B and activates the innate immune response. However, while Z-100 is known to modulate macrophage activity, the mechanism behind this modulation is not fully understood. We evaluated the effects of Z-100 on the murine macrophage cell line RAW264.7. Tumor necrosis factor-alpha (TNF-alpha) production from RAW264.7 cells was strongly induced by Z-100 and interferon-gamma (IFN-gamma) stimulation but only weakly induced by Z-100 alone. Quantitative gene expression analysis showed that nucleotide-binding oligomerization domain containing 2 (Nod2) expression was up-regulated by IFN-gamma treatment in RAW264.7 cells while Z-100-induced TNF alpha production was attenuated by Nod2 gene silencing. Further, componential analysis demonstrated that muramic acid and amino acids distinctive of muramyl dipeptide (MDP) were contained within Z-100 and Z-100Fr I, the low-molecular weight fraction containing components <3 kDa in size. In addition, Z-100Fr I enhanced TNF-alpha production in RAW264.7 cells and promoted NOD2-dependent nuclear factor-kappa B (NF-kappaB) activation in murine NOD2-expressing SEAP reporter HEK293 (HEK-Blue-mNOD2) cells. Taken together, these results suggest that Z-100 contains MDP-like molecules and augments NF-kappaB signaling via the direct activation of Nod2 in macrophages, which might be one mechanism driving the innate immune responses induced by Z-100 in cancer immunotherapy. PMID- 25499803 TI - Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression. AB - BACKGROUND: Immunogenetic evidence indicates that cytotoxic T lymphocytes (CTLs) specific for the weak CTL antigen HBZ limit HTLV-1 proviral load in vivo, whereas there is no clear relationship between the proviral load and the frequency of CTLs specific for the immunodominant antigen Tax. In vivo, circulating HTLV-1 infected cells express HBZ mRNA in contrast, Tax expression is typically low or undetectable. To elucidate the virus-suppressing potential of CTLs targeting HBZ, we compared the ability of HBZ- and Tax-specific CTLs to lyse naturally-infected cells, by co-incubating HBZ- and Tax-specific CTL clones with primary CD4(+) T cells from HLA-matched HTLV-1-infected donors. We quantified lysis of infected cells, and tested whether specific virus-induced host cell surface molecules determine the susceptibility of infected cells to CTL-mediated lysis. RESULTS: Primary infected cells upregulated HLA-A*02, ICAM-1, Fas and TRAIL-R1/2 in concert with Tax expression, forming efficient targets for both HTLV-1-specific CTLs and CTLs specific for an unrelated virus. We detected expression of HBZ mRNA (spliced isoform) in both Tax-expressing and non-expressing infected cells, and the HBZ26-34 epitope was processed and presented by cells transfected with an HBZ expression plasmid. However, when coincubated with primary cells, a high-avidity HBZ-specific CTL clone killed significantly fewer infected cells than were killed by a Tax-specific CTL clone. Finally, incubation with Tax- or HBZ-specific CTLs resulted in a significant decrease in the frequency of cells expressing high levels of HLA-A*02. CONCLUSIONS: HTLV-1 gene expression in primary CD4(+) T cells non-specifically increases susceptibility to CTL lysis. Despite the presence of HBZ spliced-isoform mRNA, HBZ epitope presentation by primary cells is significantly less efficient than that of Tax. PMID- 25499805 TI - Complete genome sequence of the actinobacterium Streptomyces glaucescens GLA.O (DSM 40922) consisting of a linear chromosome and one linear plasmid. AB - Here we report the complete and finished genome sequence of Streptomyces glaucescens GLA.O (DSM 40922), a natural producer of the alpha-glucosidase inhibitor acarbose, which is used in the treatment of type-2 diabetes mellitus. The genome of S. glaucescens GLA.O consists of two replicons, the chromosome with a size of 7,453,200bp and a G+C content of 73.0% as well as a plasmid named pSglau1 with a size of 170,574bp and a G+C content of 69.06%. PMID- 25499804 TI - Difference in distribution profiles between CD163+ tumor-associated macrophages and S100+ dendritic cells in thymic epithelial tumors. AB - BACKGROUND: In a number of human malignancies, tumor-associated macrophages (TAMs) are closely involved in tumor progression. On the other hand, dendritic cells (DCs) that infiltrate tumor tissues are involved in tumor suppression. However, there have been very few reports on the distribution profiles of TAMs and DCs in thymic epithelial tumors. We examined the difference in the distribution profiles between TAMs and DCs in thymoma and thymic carcinoma. METHODS: We examined 69 samples of surgically resected thymic epithelial tumors, namely, 16 thymic carcinomas and 53 thymomas, in which we immunohistochemically evaluated the presence of TAMs using CD68 and CD163 as markers and DCs using S100 as the marker in tumor tissue samples in comparison with normal thymic tissues. RESULTS: The percentage of samples with a large number of CD68+ TAMs was not significantly different between thymic carcinoma and thymoma (7/16 versus 16/53, p = 0.904). However, the percentage of sample with a large number of CD163+ TAMs was significantly higher in thymic carcinoma than in thymoma (15/16 versus 34/53, p = 0.024). In contrast, the percentage of samples with a large number of S100+ DCs was significantly lower in thymic carcinoma than in thymoma (2/16 versus 23/53, p = 0.021). CONCLUSIONS: To the best of our knowledge, we are the first to show a high percentage of CD163+ TAMs and a low percentage of S100+ DCs in thymic carcinoma samples, and our findings may provide an idea for future targeted therapeutic strategies for thymic carcinoma using antibodies that inhibit monocyte differentiation to TAMs, thereby skewing TAMs differentiation toward DCs. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_215. PMID- 25499806 TI - Synthesis and fungistatic activity of aryl aldoxime derivatives. AB - OBJECTIVE: The antifungal activity of 13 arylaldoxime ester and ether derivatives was tested against 4 dermatophytes Trichophyton mentagrophytes (TM), Microsporum canis (MC); M. cookei, and M. gypseum. MATERIALS AND METHODS: Structures of all new compounds prepared from aryl aldehydes were established by spectral means. The tests were performed on the Sabouraud Dextrose Agar (SDA) substrate. The sensitivity of the dermatophyte strains towards oxime derivatives was established by determining MIC and MFC values. RESULTS: The tested compounds showed a moderate fungicidal activity reaching 100% inhibition rate at 1% concentration. The activity against M. canis of 4 derivatives was higher than the activity of a reference drug clotrimazole. CONCLUSION: A novel group of biologically active compounds was introduced. Simple aldoxime derivatives can be developed into a new class of antifungals. PMID- 25499807 TI - [Qualitative fungal composition of services at risk of nosocomial infections at Aristide Le Dantec Hospital (Dakar)]. AB - INTRODUCTION: In hospitals, the quality control of the air is a key element. Indeed airborne fungi constitute a real danger for patients hospitalized in wards at risk of nosocomial infections especially when they are immunocompromised. OBJECTIVES: The objective was to determine the qualitative fungal flora composition of wards at risk of nosocomial infections at Le Dantec teaching hospital. MATERIALS AND METHODS: Between April and May 2013, 73 samples were collected from 45 compartments within seven services at risk of nosocomial infection at Aristide Le Dantec teaching Hospital (Dakar). Samples were made once by sedimentation method and the percentage of positive cultures was 100%. The most represented species were Cladosporium spp. (91.1%), Aspergillus spp. (86.6%), Penicillium spp. 71.1% and Candida spp. (57.7%). Candida albicans and Aspergillus fumigatus were isolated respectively at 15.5% and 11.1%. Wards have been classified according to the number of species isolated; 11 species in pediatric oncology, 10 species in pediatric surgery/neonatal and intensive care, nine species for oncology, eight species in general surgery and dermatology, and four species in internal medicine. CONCLUSION: This study shows that fungi causing nosocomial infections are present in hospital and their monitoring should be included in the program of Nosocomial Infections Prevention Committees (CLIN). PMID- 25499808 TI - Evaluation of methods to detect CALR mutations in myeloproliferative neoplasms. AB - The recent discovery of somatically acquired CALR mutations in a substantial proportion of patients with myeloproliferative neoplasms has provided a new marker of clonal disease, advancing both diagnosis and prognosis in these previously difficult to characterise disorders. The mutations, which can be challenging to detect on a routine basis, are heterogeneous insertions/deletions (indels) in exon 9 with mutant allele burden that vary substantially between patients. We evaluated four genetic screening methods for their ability to detect a series of different CALR mutations; Sanger sequencing, fragment analysis PCR, high resolution melt (HRM) and targeted next generation sequencing (NGS). The limit of detection (LoD) of each assay was tested using serial dilution series made with DNA from CALR positive sample DNA and a cell line, MARIMO, found to carry a heterozygous 61 nucleotide CALR deletion. All methods were capable of detecting each mutation; HRM and fragment analysis PCR were better at detecting low mutation levels compared to Sanger sequencing but targeted NGS had the lowest LoD at a 1% mutation burden. PMID- 25499809 TI - Anesthetic management of parturients with pre-existing paraplegia or tetraplegia: a case series. AB - With improvements in management and rehabilitation, more women with spinal cord injury are conceiving children. Physiologic manifestations of spinal cord injury can complicate anesthetic management during labor and delivery. Patients who delivered at Mayo Clinic, Rochester, Minnesota between January 1, 2001 and May 31, 2012 with a history of traumatic spinal cord injury were identified via electronic record search of all parturients. Eight patients undergoing nine deliveries were identified. Six deliveries (67%) among five patients (63%) involved a trial of labor. Among these deliveries, three (50%) occurred vaginally, all with successful epidural analgesia. Trial of labor failed in the remaining three patients, and required cesarean delivery facilitated via epidural (n=1), spinal (n=1) and general anesthesia (n=1). Three patients (33%) underwent scheduled cesarean delivery via epidural (n=1), spinal (n=1), and general anesthesia (n=1). Four patients having five deliveries had a history of autonomic hyperreflexia before pregnancy. One patient had symptoms during pregnancy, two patients had episodes during labor and delivery, and three patients described symptoms in the immediate postpartum period. These symptoms were not reported by any patient without a history of autonomic hyperreflexia. Neuraxial labor analgesia may have a higher failure rate in patients with spinal cord injury, possibly related to the presence of Harrington rods. Postpartum exacerbations of autonomic hyperreflexia are common in patients with a history of the disorder. PMID- 25499810 TI - Care of the clinician after an adverse event. AB - The past two decades has seen a growing understanding that health care leads to harm in a large number of patients. With this insight has come an understanding that clinicians who care for patients who are harmed experience an understandable and predictable emotional response. After an adverse event, medical care givers may experience a wide range of symptoms including anger, guilt, shame, fear, loneliness, frustration and decreased job satisfaction. These may be accompanied by physical signs of fatigue, sleep disturbances, concentration difficulties, tachycardia and hypertension. These clinicians have been referred to as the "second victims." While many clinicians recover relatively quickly from an adverse event, for some this syndrome can last for weeks, months or indefinitely. Some have even contemplated or completed suicide. Being involved in an adverse event or error may also negatively impact the quality of care the clinician subsequently provides, either because of acute emotional distraction or chronic burnout. This can lead to additional errors and a vicious cycle of error, burnout and error. Health care systems have a moral responsibility to care for second victims. Care might be as simple as asking, "Are you OK?" and acknowledging the normal human emotional response to adverse events. Some centers have developed formal peer support programs in which clinicians are trained to act as peer supporter for emotional recovery after adverse events. Finally, more formal emotional support systems might be needed by some clinicians, including employee assistance programs, hospital clergy or psychological and psychiatric services. PMID- 25499811 TI - The value of surveys in obstetric anaesthesia. AB - BACKGROUND: The Obstetric Anaesthetists' Association (OAA) has facilitated national surveys in obstetric anaesthesia since 1998. We wanted to examine trends in OAA-approved surveys since this time. METHODS: OAA-approved surveys performed between January 1998 and December 2012 were examined for the year they were carried out, the format (postal or electronic), the target group and the response rate. We determined whether each survey was presented or published. For each survey published as a substantive paper, we identified the number of times the publication had been cited. We also surveyed lead obstetric anaesthetists and expert witnesses practising in obstetric anaesthesia on the perceived usefulness of OAA-approved surveys. RESULTS: One hundred and thirty-five surveys approved by the OAA were carried out between 1998 and 2012. Response rates have fallen over the years, reaching a current plateau of 65%. Response rates varied with the target group. Seventy-eight percent of surveys were presented and 83% were published in some form. For surveys published as substantive papers (n=34, 25%), the median [IQR (range)] number of citations was 6 [3-11 (0-36)] per publication. Our survey of lead obstetric anaesthetists had a response rate of 62%. Those who replied rated OAA surveys a median [IQR (range)] of 6 [5-7 (1-9)] on a 0-10 scale of usefulness to their clinical practice. CONCLUSIONS: Response rates to OAA approved surveys have declined but remain acceptable despite an increase in the number of surveys performed. Most surveys were presented or published in some form. PMID- 25499812 TI - Anaesthetic management of a parturient with uncorrected tetralogy of Fallot undergoing caesarean section. PMID- 25499813 TI - Anesthetic technique for cesarean delivery and neonatal acid-base status: a retrospective database analysis. AB - INTRODUCTION: A previous meta-analysis reported lower umbilical artery pH with spinal anesthesia for cesarean delivery compared to general or epidural anesthesia. Ephedrine was used in the majority of studies. The objective of this study was to evaluate the effect of anesthetic technique on neonatal acid-base status now that phenylephrine has replaced ephedrine in our institution. METHODS: We retrospectively reviewed our database to identify patients who underwent cesarean delivery and had umbilical artery pH available. We decided a priori to test separately cases where cesarean delivery was performed emergently (category I and II) or non-emergently (category III and IV). Multivariable models were constructed to detect significant predictors of lower umbilical artery pH. RESULTS: One thousand sixty-four cases were included (647 emergent, 417 non emergent). In emergent cesarean delivery, anesthesia type was a significant predictor of lower umbilical artery pH (P <0.0001) with the pairwise comparisons showing lower neonatal umbilical artery pH [mean (95% CI)] with general anesthesia [7.16 (7.13, 7.19)] compared with spinal anesthesia [7.24 (7.22, 7.25)] and epidural anesthesia [7.23 (7.21, 7.24)], with no difference between spinal and epidural anesthesia. When excluding cases where general anesthesia was chosen due to insufficient time to place a neuraxial block or dose an existing epidural catheter, anesthesia type was not a predictor of lower umbilical artery pH. Anesthetic technique was not a predictor of lower umbilical artery pH in non emergent cases. CONCLUSIONS: Spinal anesthesia was not associated with lower umbilical artery pH compared to other types of anesthesia. This might be due to the use of phenylephrine in our practice. PMID- 25499814 TI - High-dose alcohol induces reactive oxygen species-mediated apoptosis via PKC beta/p66Shc in mouse primary cardiomyocytes. AB - Cardiac dysfunction caused by excessive alcohol consumption is a specific disease, alcoholic cardiomyopathy (ACM). High-dose alcohol has been found to induce oxidation stress and apoptosis in cardiomyocytes, but the signaling link between alcohol-induced oxidation stress and apoptosis in cardiomyocytes remains to be elucidated. To address the issue, we exposed primary cardiomyocytes from neonatal mouse hearts to high doses of alcohol (50mM, 100mM, and 200 mM). We found that alcohol induced dose-dependent phosphorylation of p66shc, and reactive oxygen species (ROS) production increased in parallel with phosphorylation levels of p66shc. Exposure to alcohol also led to loss of mitochondrial membrane potential and cytochrome c release. Depletion of p66Shc and inhibition of protein kinase C-beta (PKC-beta) successfully reversed all the effects and suppressed alcohol-induced apoptosis in cardiomyocytes. Collectively, our study provides a molecular basis for signaling transduction of alcohol-induced oxidation stress and apoptosis of cardiomyocytes, which may facilitate the prevention and treatment of ACM. PMID- 25499815 TI - Alterations of urinary metabolite profile in model diabetic nephropathy. AB - Countering the diabetes pandemic and consequent complications, such as nephropathy, will require better understanding of disease mechanisms and development of new diagnostic methods. Animal models can be versatile tools in studies of diabetic renal disease when model pathology is relevant to human diabetic nephropathy (DN). Diabetic models using endothelial nitric oxide synthase (eNOS) knock-out mice develop major renal lesions characteristic of human disease. However, it is unknown whether they can also reproduce changes in urinary metabolites found in human DN. We employed Type 1 and Type 2 diabetic mouse models of DN, i.e. STZ-eNOS(-/-) C57BLKS and eNOS(-/-) C57BLKS db/db, with the goal of determining changes in urinary metabolite profile using proton nuclear magnetic resonance (NMR). Six urinary metabolites with significantly lower levels in diabetic compared to control mice have been identified. Specifically, major changes were found in metabolites from tricarboxylic acid (TCA) cycle and aromatic amino acid catabolism including 3-indoxyl sulfate, cis aconitate, 2-oxoisocaproate, N-phenyl-acetylglycine, 4-hydroxyphenyl acetate, and hippurate. Levels of 4-hydroxyphenyl acetic acid and hippuric acid showed the strongest reverse correlation to albumin-to-creatinine ratio (ACR), which is an indicator of renal damage. Importantly, similar changes in urinary hydroxyphenyl acetate and hippurate were previously reported in human renal disease. We demonstrated that STZ-eNOS(-/-) C57BLKS and eNOS(-/-) C57BLKS db/db mouse models can recapitulate changes in urinary metabolome found in human DN and therefore can be useful new tools in metabolomic studies relevant to human pathology. PMID- 25499817 TI - Porcine parvovirus infection induces apoptosis in PK-15 cells through activation of p53 and mitochondria-mediated pathway. AB - Porcine parvovirus (PPV) infection has been reported to induce the cytopathic effects (CPE) in some special host cells and contribute the occurrence of porcine parvovirus disease, but the molecular mechanisms underlying PPV-induced CPE are not clear. In this study, we investigated the morphological and molecular changes of porcine kidney cell line (PK-15 cells) infected with PPV. The results showed that PPV infection inhibited the viability of PK-15 cells in a time and concentration dependent manner. PPV infection induced typical apoptotic features including chromatin condensation, apoptotic body formation, nuclear fragmentation, and Annexin V-binding activity. Further studies showed that Bax was increased and translocated to mitochondria, whereas Bcl-2 was decreased in PPV-infected cells, which caused mitochondrial outer-membrane permeabilization, resulting in the release of mitochondrial cytochrome c, followed by caspase-9 and caspase-3 activation. However, the expression of Fas and Fas ligand (FasL) did not appear significant changes in the process of PPV-induced apoptosis. Moreover, PPV infection activated p53 signaling, which was involved in the activation of apoptotic signaling induced by PPV infection via regulation of Bax and Bcl-2. Taken together, our results demonstrated that PPV infection induced apoptosis in PK-15 cells through activation of p53 and mitochondria-mediated apoptosis pathway. This study may contribute to shed light on the molecular pathogenesis of PPV infection. PMID- 25499816 TI - Role of reactive oxygen species in arsenic-induced transformation of human lung bronchial epithelial (BEAS-2B) cells. AB - Arsenic is an environmental carcinogen, its mechanisms of carcinogenesis remain to be investigated. Reactive oxygen species (ROS) are considered to be important. A previous study (Carpenter et al., 2011) has measured ROS level in human lung bronchial epithelial (BEAS-2B) cells and arsenic-transformed BEAS-2B cells and found that ROS levels were higher in transformed cells than that in parent normal cells. Based on these observations, the authors concluded that cell transformation induced by arsenic is mediated by increased cellular levels of ROS. This conclusion is problematic because this study only measured the basal ROS levels in transformed and parent cells and did not investigate the role of ROS in the process of arsenic-induced cell transformation. The levels of ROS in arsenic-transformed cells represent the result and not the cause of cell transformation. Thus question concerning whether ROS are important in arsenic induced cell transformation remains to be answered. In the present study, we used expressions of catalase (antioxidant against H2O2) and superoxide dismutase 2 (SOD2, antioxidant against O2(-)) to decrease ROS level and investigated their role in the process of arsenic-induced cell transformation. Our results show that inhibition of ROS by antioxidant enzymes decreased arsenic-induced cell transformation, demonstrating that ROS are important in this process. We have also shown that in arsenic-transformed cells, ROS generation was lower and levels of antioxidants are higher than those in parent cells, in a disagreement with the previous report. The present study has also shown that the arsenic-transformed cells acquired apoptosis resistance. The inhibition of catalase to increase ROS level restored apoptosis capability of arsenic-transformed BEAS-2B cells, further showing that ROS levels are low in these cells. The apoptosis resistance due to the low ROS levels may increase cells proliferation, providing a favorable environment for tumorigenesis of arsenic-transformed cells. PMID- 25499818 TI - Nuciferine restores potassium oxonate-induced hyperuricemia and kidney inflammation in mice. AB - Nuciferine, a major aporphine alkaloid of the leaves of Nelumbo nucifera, was found to decrease serum urate levels and improved kidney function, as well as inhibited system and renal interleukin-1beta (IL-1beta) secretion in potassium oxonate-induced hyperuricemic mice. Furthermore, nuciferine reversed expression alteration of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette, subfamily G, membrane 2 (ABCG2), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1), and organic cation/carnitine transporters 1/2 (OCTN1/2) in hyperuricemic mice. More importantly, nuciferine suppressed renal activation of Toll-like receptor 4/myeloid differentiation factor 88/NF-kappaB (TLR4/MyD88/NF-kappaB) signaling and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome to reduce serum and renal IL-1beta levels in hyperuricemic mice with renal inflammation reduction. The anti inflammatroy effect of nuciferine was also confirmed in human proximal renal tubular epithelial cells (HK-2 cells) incubated with 4mg/dl uric acid for 24h. This study firstly reported the anti-hyperuricemic and anti-inflammatory effects of nuciferine by regulating renal organic ion transporters and inflammatory signaling in hyperuricemia. These results suggest that a dietary supplement of nuciferine rich in lotus leaf may be potential for the prevention and treatment of hyperuricemia with kidney inflammation. PMID- 25499819 TI - Glucocorticoids decrease Treg cell numbers in lungs of allergic mice. AB - Glucocorticoids have been the hallmark anti-inflammatory drug used to treat asthma. It has been shown that glucocorticoids ameliorate asthma by increasing numbers and activity of Tregs, in contrast recent data show that glucocorticoid might have an opposite effect on Treg cells from normal mice. Since Tregs are target cells that act on the resolution of asthma, the aim of this study was to elucidate the effect of glucocorticoid treatment on lung Tregs in mouse models of asthma. Allergen challenged mice were treated with either oral dexamethasone or nebulized budesonide. Broncoalveolar lavage and airway hyperresponsiveness were evaluated after allergenic challenge. Lung, thymic and lymph node cells were phenotyped on Treg through flow cytometry. Lung cytokine secretion was detected by ELISA. Although dexamethasone inhibited airway inflammation and hyperresponsiveness, improving resolution, we have found that both dexamethasone and budesonide induce a reduction of Treg numbers on lungs and lymphoid organs of allergen challenged mice. The reduction of lung Treg levels was independent of mice strain or type of allergen challenge. Our study also indicates that both glucocorticoids do not increase Treg activity through production of IL-10. Glucocorticoid systemic or localized treatment induced thymic atrophy. Taken together, our results demonstrate that glucocorticoids decrease Treg numbers and activity in different asthma mouse models, probably by reducing thymic production of T cells. Therefore, it is possible that glucocorticoids do not have beneficial effects on lung populations of Treg cells from asthmatic patients. PMID- 25499821 TI - Do we map remembrances to the left/back and expectations to the right/front of a mental timeline? Space-time congruency effects with retrospective and prospective verbs. AB - Recent experimental studies have shown that people code time in terms of a mental timeline which typically runs from left to right or from back to front. Determining the cognitive function of this mental timeline for language processing, however, is still an unsettled issue. Whereas the studies of Ulrich and Maienborn (2010) and Ulrich et al. (2012) argue against an automatic activation of the mental timeline for the interpretation of tense and temporal adverbials at sentence level, Sell and Kaschak (2011) observe an automatic activation for the processing of past- and future-related sentences in small stories. The present paper reports the results of three experiments which examine the processing of sentences with retrospective and prospective verbs (e.g., to remember, to regret vs. to expect, to announce) in present tense, which locate a second, embedded event in the past or the future. When temporal information was task-relevant, a space-time congruency effect emerged (Experiment 1). This suggests that the mental timeline is not only linked to overtly deictic linguistic material but may also be construed in a more intricate way through the compositional construction of sentence meaning. The congruency effect disappeared, however, when temporal information was task-irrelevant (Experiments 2 and 3), suggesting that the mental timeline is not functionally involved in the cognitive processing of these especially demanding two-event sentences. The results of the present study support the conclusion that the relevant factor driving an automatic activation of the mental timeline is not the number of linguistically expressed events, but might rather be the number of sentential units. PMID- 25499820 TI - The past, present and future in scaffold-based tendon treatments. AB - Tendon injuries represent a significant clinical burden on healthcare systems worldwide. As the human population ages and the life expectancy increases, tendon injuries will become more prevalent, especially among young individuals with long life ahead of them. Advancements in engineering, chemistry and biology have made available an array of three-dimensional scaffold-based intervention strategies, natural or synthetic in origin. Further, functionalisation strategies, based on biophysical, biochemical and biological cues, offer control over cellular functions; localisation and sustained release of therapeutics/biologics; and the ability to positively interact with the host to promote repair and regeneration. Herein, we critically discuss current therapies and emerging technologies that aim to transform tendon treatments in the years to come. PMID- 25499822 TI - Reply to: Relationship between leptin and blood pressure in patients with multiple system atrophy. PMID- 25499823 TI - Use of DALYs in economic analyses on interventions for infectious diseases: a systematic review. AB - A systematic literature review was performed on full economic evaluations of infectious disease interventions using disability-adjusted life years (DALY) as outcome measure. The search was limited to the period between 1994 and September 2011 and conducted in Medline, SciSearch and EMBASE databases. We included 154 studies, mostly targeting HIV/AIDS and malaria with most conducted for African countries (40%) and <10% in high-income countries. Third-payer perspective was applied in 29% of the studies, 25% used the societal perspective and 12% used both. Only 16% of the studies took indirect effects (i.e. herd immunity) of interventions into account. Intervention, direct healthcare and indirect non healthcare costs were taken into account in respectively 100%, 81% and 36% of the studies. The majority of the studies followed the Global Burden of Disease method for DALY estimations, but most studies deviated from WHO cost-effectiveness guidelines. Better adherence to freely accessible guidelines will improve generalizability between full economic evaluations. PMID- 25499824 TI - Seroprevalence and risk factors associated with exposure of water buffalo (Bubalus bubalis) to Neospora caninum in northeast Thailand. AB - Water buffalo are important draft animals for agriculture in resource-restricted areas worldwide. Water buffalo were shown to be experimentally susceptible to infection with Neospora caninum, potentially affected by neosporosis, and naturally exposed to the parasite in Asia. Although enzootic to Thailand, the distribution of N. caninum among Thai water buffalo is unclear. The objectives of this study were to determine the seroprevalence of N. caninum among water buffalo of northeast Thailand and to identify risk factors associated with their exposure to N. caninum. Sera from 628 water buffalo from 288 farms were tested with an indirect fluorescent antibody test (IFAT). A total of 57 samples from 48 herds contained antibodies to N. caninum, indicating overall seroprevalence of 9.1% and 16.7% among individual animals and herds, respectively. The overall seroprevalence was highest in provinces located in the Khorat Basin in the southern part of the region tested. Host age was also associated with seroprevalence, with the greatest seroprevalence (16.1%) among buffalo over 10 years of age, followed by 5-10 years of age (13.4%), 3-5 years (9.2%), and less than 3 years (1.2%). These results collectively suggested that horizontal transmission from canine definitive hosts was an important route of water buffalo exposure to N. caninum. These results also verified the importance of risk factor analysis for effective bovine neosporosis control strategies at the local level. PMID- 25499825 TI - Occurrence of novel and rare subtype families of Cryptosporidium in bamboo rats (Rhizomys sinensis) in China. AB - This report is the first to describe Cryptosporidium infection in bamboo rats (Rhizomys sinensis). Ninety-two fresh fecal specimens were collected from a pet market in Ya'an City, China. One Cryptosporidium isolate from an asymptomatic host and two isolates from separate hosts with diarrhea were obtained by using Sheather's sucrose flotation technique and modified acid-fast staining. The Cryptosporidium spp. were genotyped by nested PCR and nucleotide sequencing of the small subunit rRNA (SSU rRNA), 70-kDa heat shock protein (HSP70), oocyst wall protein (COWP), and actin genes: isolates were identified as Cryptosporidium parvum with minor nucleotide differences at all four loci. Further subtyping was performed by PCR amplification and DNA sequence analysis of the 60-kDa glycoprotein (gp60) gene: two subtype families were detected, including a novel C. parvum subtype IIpA9 and a rare subtype IIoA13G1 (only reported in diarrheal patients of Sweden). Our results suggest that the bamboo rat is a reservoir host of C. parvum. Significantly, we discovered that the rare C. parvum subtype family IIo is also a zoonotic subtype and confirmed C. parvum subtype IIpA9 as a novel subtype family. PMID- 25499826 TI - The glycoprotein TRP36 of Ehrlichia sp. UFMG-EV and related cattle pathogen Ehrlichia sp. UFMT-BV evolved from a highly variable clade of E. canis under adaptive diversifying selection. AB - BACKGROUND: A new species of Ehrlichia, phylogenetically distant from E. ruminantium, was found in 2010 infecting cattle in Canada. In 2012 and 2013, we reported the in vitro propagation, molecular and ultrastructural characterization of Ehrlichia sp. UFMG-EV (E. mineirensis), a new species of Ehrlichia isolated from the haemolymph of Brazilian Rhipicephalus (Boophilus) microplus ticks. A new organism, named Ehrlichia sp. UFMT-BV, closely related to Ehrlichia sp. UFMG-EV, was recently described in Brazil and after experimental infection it was shown to be pathogenic for cattle. This new emerging clade of cattle Ehrlichia pathogens is closely related to E. canis. The major immunogenic Tandem Repeat Protein (TRP36; also known as gp36) is extensively used to characterize the genetic diversity of E. canis. Homologs of TRP36 were found in both Ehrlichia sp. UFMG-EV and Ehrlichia sp. UFMT-BV. FINDINGS: Herein, we characterized the evolution of this new Ehrlichia clade using TRP36 sequences. Our working hypothesis is that Ehrlichia sp. UFMG-EV and related microorganisms evolved from a highly variable E. canis clade. In support of our hypothesis we found that Ehrlichia sp. UFMG-EV and Ehrlichia sp. UFMT-BV TRP36 evolved from a highly divergent and variable clade within E. canis and this clade evolved under episodic diversifying selection with a high proportion of sites under positive selection. CONCLUSION: Our results suggest that Ehrlichia sp. UFMG-EV and Ehrlichia sp. UFMT-BV evolved from a variable clade within E. canis. PMID- 25499827 TI - Diffusion of palliative care in nursing homes: lessons from the culture change movement. AB - CONTEXT: Studies have found that nursing homes (NHs) that rely heavily on Medicaid funding are less likely to implement innovative approaches to care, such as palliative care (PC) or resident-centered approaches commonly referred to as "culture change" (CC). However, a nationally representative survey we previously conducted found that some high Medicaid facilities have implemented these innovative approaches. OBJECTIVES: The purpose of this study was to identify the factors that enable some high Medicaid NHs to implement innovative approaches to care. METHODS: We conducted telephone interviews with 16 NH administrators in four categories of facilities: 1) low PC and low CC, 2) low PC and high CC, 3) high PC and low CC, and 4) high PC and high CC. Interviews explored strategies used to overcome barriers to implementation and the resources needed for implementation. RESULTS: We had expected to find differences between low and high NHs but instead found differences in NHs' experiences with CC and PC. Since the time of our national survey in 2009-2010, most previously low CC NHs had implemented at least some CC practices; however, we did not find similar changes around PC. Administrators reported numerous ways in which they had received information and assistance from outside entities for implementing CC. This was not the case for PC where administrators reported relying exclusively and heavily on hospices for both their residents' PC needs and information related to PC. CONCLUSION: PC advocates could learn much from the CC model in which advocates have used multipronged efforts to institute reform. PMID- 25499828 TI - Compared perspectives of Arab patients in Palestine and Israel on the role of complementary medicine in cancer care. AB - CONTEXT: Complementary medicine (CM) is extensively used by patients with cancer across the Middle East. OBJECTIVES: We aimed to compare the perspectives of two Arab populations residing in diverse socioeconomic-cultural settings in Palestine and Israel regarding the role of CM in supportive cancer care. METHODS: A 27-item questionnaire was constructed and administered to a convenience sample of Arab patients receiving cancer care in four oncology centers in northern Israel and Palestine. RESULTS: Each of the two groups had 324 respondents and was equally distributed by age and marital status. Compared with the Israeli-Arab group, Palestinian participants reported significantly higher CM use for cancer-related outcomes (63.5% vs. 39.6%, P < 0.001), which included more herbal use (97.6% vs. 87.9%, P = 0.001) and significantly lower use of dietary supplements, acupuncture, mind-body and manual therapies, and homeopathy. Most respondents in both groups stated that they would consult CM providers if CM was integrated in oncology departments. Related to this theoretical integrative scenario, Palestinian respondents expressed fewer expectations from their oncologists to actively participate in building their CM treatment plan. Treatment expectations in both groups focused on improving quality of life (QOL), whereas Palestinian respondents had fewer expectations for CM to improve fatigue, emotional concerns, sleep, and daily functioning. CONCLUSION: Arab patients with cancer from Palestine and Israel highly support CM integration within their oncology institutions aiming to improve QOL. Nevertheless, respondents differed in their perceived model of CM integration, its treatment objectives, and their oncologists' role in CM integration. PMID- 25499830 TI - Mass flu vaccination of healthcare workers: not to be sniffed at. PMID- 25499831 TI - Optical coherence tomographic image of dynamic left main coronary artery compression caused by intramural haematoma due to spontaneous coronary artery dissection - degloved artery managed with bioresorbable vascular scaffold. PMID- 25499832 TI - "Heart Team" decision making in elderly patients with symptomatic aortic valve stenosis who underwent AVR or TAVI - a look behind the curtain. Results of the prospective TAVI Calculation of Costs Trial (TCCT). AB - AIMS: Little is known about how "Heart Team" treatment decisions among patients suitable for either surgical aortic valve replacement (AVR) or transcatheter aortic valve implantation (TAVI) are made under routine conditions. METHODS AND RESULTS: The "Heart Team" decision-making process was analysed with respect to124 patients of a non-randomised prospective clinical trial that included patients aged >=75 years: 41 patients underwent AVR and 83 underwent TAVI. By use of the non-parametric classification and regression tree (CART) methodology, 21 baseline parameters were tested to reconstruct the decision process retrospectively. Next, multivariate logistic and Cox regression models were fitted to evaluate the decision and outcome relevance (two-year survival) of the parameters as identified in the CART procedure. For patients with a baseline EuroSCORE I >=13.48%, no further cut-off points were identified and the majority of these patients underwent TAVI. Among patients with a baseline EuroSCORE I <13.48%, age and left ventricular ejection fraction (LVEF) were identified as further relevant decision parameters. The decision relevance of EuroSCORE I (p=0.003), age (p=0.024) and LVEF (p=0.047) were confirmed by multivariate analysis; however, outcome relevance can be confirmed for EuroSCORE I (p=0.015) only, while treatment decision (TAVI or AVR) was not a significant predictor of mortality (p=0.655). CONCLUSIONS: Despite or even because of the systematic risk selection according to EuroSCORE I values, we observed two-year survival rates of about 75% regardless of whether the patient received TAVI or AVR, suggesting that the decisions made by the "Heart Team" were appropriate. PMID- 25499829 TI - Alcohol disrupts sleep homeostasis. AB - Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired sleep homeostasis. In conclusion, we suggest that alcohol may disrupt sleep homeostasis to cause sleep disruptions. PMID- 25499833 TI - Bioresorbable everolimus-eluting vascular scaffold for the treatment of chronic total occlusions: CTO-ABSORB pilot study. AB - AIMS: We sought to assess the safety and performance of the Absorb everolimus eluting bioresorbable vascular scaffold (BVS) in percutaneous chronic total occlusion (CTO) revascularisation guided by intracoronary imaging. The feasibility of using the BVS in CTO lesions is unknown. METHODS AND RESULTS: Thirty-five consecutive true CTO lesions (EuroCTO Club definition) were included in this prospective registry. After mandatory predilatation and IVUS analysis, all target lesions were treated with BVS and no other stents were deployed. Optical coherence tomography (OCT) was performed after BVS implantation. Multislice computed tomography (MSCT) was performed at baseline and at six to eight months. The mean age was 60.7+/-9.7 years; 80% were male; 20% were diabetic; 37% had a previous PCI. The most frequently treated vessel was the RCA (46%). According to the Japanese-CTO (J-CTO) complexity score, most lesions were classified as intermediate (49%) or difficult-very difficult (26%); 34% were moderate-severely calcified. Most cases (86%) were treated with an anterograde strategy, 60% by radial or biradial approach. In 71% a cutting balloon was used. The total scaffold length implanted per lesion was 52.5+/-22.9 mm. All scaffolds were successfully delivered and deployed. Post-dilatation was undertaken in 63%. By OCT, final minimum scaffold area and lumen stenosis were 7.1+/-1.5 mm2 and 11.7+/-6.6%, without areas of significant strut malapposition. At complete six month follow-up, no major adverse events were observed. MSCT identified two cases of scaffold reocclusion. CONCLUSIONS: BVS for CTO recanalisation demonstrates excellent feasibility and safety as well as midterm efficacy. Appropriate lesion preparation is key to aiding adequate expansion of these scaffolds in this setting. PMID- 25499834 TI - Heart-rate adjustment of transcatheter haemodynamics improves the prognostic evaluation of paravalvular regurgitation after transcatheter aortic valve implantation. AB - AIMS: Paravalvular aortic regurgitation (PVAR) after balloon-expandable transcatheter aortic valve implantation (TAVI) remains difficult to quantify, and the utility of the AR index (ARi) to create a composite aortic insufficiency (CAI) score was an important advance. Heart rate (HR) influences the ARi but the clinical relevance of this phenomenon remains poorly appreciated. We sought to validate a new composite heart-rate-adjusted haemodynamic-echocardiographic aortic insufficiency (CHAI) score in the prognostic evaluation of PVAR after balloon-expandable TAVI. METHODS AND RESULTS: The severity of PVAR was assessed immediately post TAVI by transoesophageal echocardiography (TOE) with simultaneous assessment of transcatheter haemodynamics. A total of 303 patients were studied. The CHAI score, incorporating the HR-adjusted diastolic-delta (HRA DD, the difference between left ventricular and aortic diastolic pressures/HR*80), had a greater discriminatory value for one-year mortality than both PVAR by TOE (p=0.0018) and the previously proposed CAI score, based on the ARi without HR adjustment (p=0.0029). The CHAI score also better stratified percentage increases in left ventricular systolic chamber dimensions at one month and serum natriuretic peptide levels at one to three months. CONCLUSIONS: Prognostication of PVAR in the intermediate range of echocardiographic severity remains unreliable and is greatly enhanced by the integration of heart-rate adjusted transcatheter haemodynamics. PMID- 25499835 TI - Optimal septum alignment of the Figulla Flex occluder to the atrial septum in patients with secundum atrial septal defects. AB - AIMS: To investigate the implantation safety, anatomic performance and septal alignment of the Occlutech Figulla Flex occluder (FFO) device, an atrial septal defect (ASD) closure device with specific left-sided deployment characteristics and right-sided septal alignment properties. METHODS AND RESULTS: Between January 2011 and December 2013 we prospectively collected the change of orientation of the device to the septum during the release process and the feasibility of implantation of the FFO in 122 patients. The mean age was 10.7 years (+/-10.2), weight 32.9 kg (+/-20.3), and height 129.4 cm (+/-30). Devices used were 9 (n=13), 10.5 (n=16), 12 (n=16), 15 (n=39), 18 (n=17), 21 (n=8), 24 (n=5), 27 (n=7) and 30 mm (n=3) in size. No additional implantation techniques were required. Before release, the mean angles of the left and right-sided discs were 29.2 degrees (+/-9.9 degrees ) and 43.4 degrees (+/-9.2 degrees ) to the body axis, and 18.7 degrees (+/-8.7 degrees ) and 27.0 degrees (+/-10 degrees ) immediately thereafter. Thus, there was only a slight change in orientation of the left-sided (10.6 degrees +/-7.5 degrees ) and right-sided (16.3 degrees +/ 7.9 degrees ) discs. CONCLUSIONS: The design of this occluder system results in an ideal septum alignment which increases its feasibility as well as patient safety during implantation. PMID- 25499836 TI - Beyond the early stages: insights from the ASSURE registry on bioresorbable vascular scaffolds. AB - AIMS: Bioresorbable vascular scaffolds (BVS) have been available on the European market since November 2011. The ASSURE registry aims to investigate the safety and efficacy of the Absorb everolimus-eluting bioresorbable vascular scaffold in a real-world setting. METHODS AND RESULTS: Patients with de novo coronary artery disease were consecutively enrolled at six German centres in this prospective registry. Outcomes were procedural success, cardiovascular death, myocardial infarction, and ischaemia-driven target lesion revascularisation (TLR). Angiographic parameters were assessed quantitatively and visual estimates of lesion dimensions were studied. One hundred and eighty-three patients were treated. In 128 (64.7%) lesions a complex ACC/AHA morphology was present. Procedural success was achieved in all patients. Acute gain was 1.54+/-0.51 mm, resulting in a final minimal lumen diameter (MLD), which met the baseline reference vessel diameter (RVD), although visual estimates overrated the RVD by 0.5+/-0.5 mm. Up to 12 months, one patient (0.5%) had died from gastrointestinal bleeding, three (1.7%) non-target vessel myocardial infarctions occurred, and five (2.8%) TLR had become necessary because of restenosis. CONCLUSIONS: One-year results suggest that bioresorbable vascular scaffolds for de novo coronary artery disease are associated with favourable clinical and functional outcomes in routine clinical practice despite a visually overestimated RVD. PMID- 25499837 TI - Modeling the response of ON and OFF retinal bipolar cells during electric stimulation. AB - Retinal implants allowing blind people suffering from diseases like retinitis pigmentosa and macular degeneration to regain rudimentary vision are struggling with several obstacles. One of the main problems during external electric stimulation is the co-activation of the ON and OFF pathways which results in mutual impairment. In this study the response of ON and OFF cone retinal bipolar cells during extracellular electric stimulation from the subretinal space was examined. To gain deeper insight into the behavior of these cells sustained L type and transient T-type calcium channels were integrated in the synaptic terminals of reconstructed 3D morphologies of ON and OFF cone bipolar cells. Intracellular calcium concentration in the synaptic regions of the model neurons was investigated as well since calcium influx is a crucial parameter for cell-to cell activity between bipolar cells and retinal ganglion cells. It was shown that monophasic stimulation results in significant different calcium concentrations in the synaptic terminals of ON and OFF bipolar cells. Intracellular calcium increased to values up to fourfold higher in the OFF bipolar model neuron in comparison to the ON bipolar cell. Furthermore, geometric properties strongly influence the activation of bipolar cells. Monophasic, biphasic, single and repetitive pulses with similar lengths, amplitudes and polarities were applied to the two model neurons. PMID- 25499838 TI - Rapid scene categorization: role of spatial frequency order, accumulation mode and luminance contrast. AB - Visual analysis follows a default, predominantly coarse-to-fine processing sequence. Low spatial frequencies (LSF) are processed more rapidly than high spatial frequencies (HSF), allowing an initial coarse parsing of visual input, prior to analysis of finer information. Our study investigated the influence of spatial frequency processing order, accumulation mode (i.e. how spatial frequency information is received as an input by the visual system, throughout processing), and differences in luminance contrast between spatial frequencies on rapid scene categorization. In Experiment 1, we used sequences composed of six filtered scenes, assembled from LSF to HSF (coarse-to-fine) or from HSF to LSF (fine-to coarse) to test the effects of spatial frequency order. Spatial frequencies were either successive or additive within sequences to test the effects of spatial frequency accumulation mode. Results showed that participants categorized coarse to-fine sequences more rapidly than fine-to-coarse sequences, irrespective of spatial frequency accumulation in the sequences. In Experiment 2, we investigated the extent to which differences in luminance contrast rather than in spatial frequency account for the advantage of coarse-to-fine over fine-to-coarse processing. Results showed that both spatial frequencies and luminance contrast account for a predominant coarse-to-fine processing, but that the coarse-to-fine advantage stems mainly from differences in spatial frequencies. Our study cautions against the use of contrast normalization in studies investigating spatial frequency processing. We argue that this type of experimental manipulation can impair the intrinsic properties of a visual stimulus. As the visual system relies on these to enable recognition, bias may be induced in strategies of visual analysis. PMID- 25499840 TI - Load transfer at the distal ulna following simulated distal radius fracture malalignment. AB - PURPOSE: To measure the effects of distal radius malalignment on loading at the distal ulna. METHODS: Using an adjustable mechanism to simulate angulated and translated malalignments, clinically relevant distal radius deformities were simulated in a cadaveric model. A custom-built load cell was inserted just proximal to the native ulna head to measure the resultant force and torque in the distal ulna. Loads were measured before and after transecting the triangular fibrocartilage complex (TFCC). RESULTS: There was an increase in distal ulna load and torque with increasing dorsal translation and angulation. Combined conditions of angulation and translation increased force and torque in the distal ulna to a greater extent than with either condition in isolation. Transecting the TFCC resulted in a reduction in distal ulna load and torque. CONCLUSIONS: A progressive increase in load at the distal ulna was observed with increasing severity of malalignment, which may be an important contributor to residual ulnar wrist pain and dysfunction. However, no clear-cut threshold of malalignment of a dorsally angulated and translated distal radius fracture was identified. These observations suggest that radius deformities cause articular incongruity, which increases TFCC tension and distal radioulnar joint load. Cutting of the TFCC decreased distal ulna loading, likely by releasing the articular constraining effect of the TFCC on the distal radioulnar joint, allowing the radius to rotate more freely with respect to the ulna. CLINICAL RELEVANCE: Anatomical reduction of a distal radius fracture minimizes the forces in the distal ulna and may reduce residual ulnar wrist pain and dysfunction. PMID- 25499839 TI - Accuracy and reproducibility of right ventricular quantification in patients with pressure and volume overload using single-beat three-dimensional echocardiography. AB - BACKGROUND: The right ventricle is a complex structure that is challenging to quantify by two-dimensional (2D) echocardiography. Unlike disk summation three dimensional (3D) echocardiography (3DE), single-beat 3DE can acquire large volumes at high volume rates in one cardiac cycle, avoiding stitching artifacts or long breath-holds. The aim of this study was to assess the accuracy and test retest reproducibility of single-beat 3DE for quantifying right ventricular (RV) volumes in adult populations of acquired RV pressure or volume overload, namely, pulmonary hypertension (PH) and carcinoid heart disease, respectively. Three dimensional and 2D echocardiographic indices were also compared for identifying RV dysfunction in PH. METHODS: A prospective cross-sectional study was performed in 100 individuals who underwent 2D echocardiography, 3DE, and cardiac magnetic resonance imaging: 49 patients with PH, 20 with carcinoid heart disease, 11 with metastatic carcinoid tumors without cardiac involvement, and 20 healthy volunteers. Two operators performed test-retest acquisition and postprocessing for inter- and intraobserver reproducibility in 20 subjects. RESULTS: RV single beat 3DE was attainable in 96% of cases, with mean volume rates of 32 to 45 volumes/sec. Bland-Altman analysis of all subjects (presented as mean bias +/- 95% limits of agreement) revealed good agreement for end-diastolic volume (-2.3 +/- 27.4 mL) and end-systolic volume (5.2 +/- 19.0 mL) measured by 3DE and cardiac magnetic resonance imaging, with a tendency to underestimate stroke volume (-7.5 +/- 23.6 mL) and ejection fraction (-4.6 +/- 13.8%) by 3DE. Subgroup analysis demonstrated a greater bias for volumetric underestimation, particularly in healthy volunteers (end-diastolic volume, -11.9 +/- 18.0 mL; stroke volume, 11.2 +/- 20.2 mL). Receiver operating characteristic curve analysis showed that 3DE-derived ejection fraction was significantly superior to 2D echocardiographic parameters for identifying RV dysfunction in PH (sensitivity, 94%; specificity, 88%; area under the curve, 0.95; P = .031). There was significant interobserver test-retest bias for RV volume underestimation (end-diastolic volume, -12.5 +/- 28.1 mL; stroke volume, -10.6 +/- 23.2 mL). CONCLUSIONS: Single-beat 3DE is feasible and clinically applicable for volumetric quantification in acquired RV pressure or volume overload. It has improved limits of agreement compared with previous disk summation 3D echocardiographic studies and has incremental value over standard 2D echocardiographic measures for identifying RV dysfunction. Despite the ability to obtain and postprocess a full-volume 3D echocardiographic RV data set, the quality of the raw data did influence the accuracy of the data obtained. The technique performs better with dilated rather than nondilated RV cavities, with a learning curve that might affect the test-retest reproducibility for serial RV studies. PMID- 25499841 TI - Scapholunate ligament insufficiency. PMID- 25499842 TI - Topical hemostatic agents and their role in upper extremity surgery. PMID- 25499843 TI - Functional outcomes of replantation following radiocarpal amputation. AB - PURPOSE: To assess the long-term functional and clinical outcomes of patients who have undergone replantation after radiocarpal amputation. METHODS: We performed a retrospective review of radiocarpal joint amputations at a level 1 trauma center over a 13-year period. Medical records of patients treated with replantation were queried for injury data, operative reports, complications, and clinical progress. Patients who met inclusion criteria were contacted for long-term follow-up. We measured total active motion of each digit, strength (grip and pinch), and 2 point discrimination. Functional outcomes were assessed with Disabilities of Arm, Shoulder, and Hand score, Mayo Wrist Score, Patient-Rated Wrist Evaluation, and Michigan Hand Questionnaire. Descriptive statistics were calculated, including frequencies for categorical variables and means and ranges for continuous variables. RESULTS: Six patients met the inclusion criteria. The mean age was 36 years (range, 26-50 y). Five patients were available at a mean follow-up of 3.9 years (range, 1.0-6.9 y). Compared with the contralateral uninjured extremity, total active motion of the hand was 38% (range, 26% to 59%) and grip strength was 9% (range, 0% to 18%). Neither tip nor key pinch was present. Mean 2-point discrimination was 10.6 mm (range, 8-12 mm). All mean outcome scores indicated moderate disability, including Disabilities of Arm, Shoulder, and Hand (76; range, 45-82), Mayo Wrist Score (23; range, 5-50), Patient-Rated Wrist Evaluation (86; range, 56-98), and Michigan Hand Questionnaire (27; range, 15-55). Two patients were able to return to work and 3 were permanently disabled. All patients were satisfied with the hand function. CONCLUSIONS: Successful replantation for a radiocarpal joint amputation is associated with major restriction of motion, decreased strength, and moderate disability on functional outcome assessments. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25499844 TI - Nail bed injury. PMID- 25499845 TI - Management of radial head fracture with elbow dislocation. PMID- 25499846 TI - [Percutaneous ablation of hepatocellular carcinoma in older patients in clinical practice]. AB - INTRODUCTION: A high percentage of older patients with early-stage hepatocellular carcinoma (HCC) are potential candidates for percutaneous ablation. MATERIAL AND METHODS: We prospectively assessed data from patients older than 70 years with HCC. We determined their demographic and clinical characteristics, the treatment provided and the response, complications and survival among those treated with radiofrequency ablation (RFA) and/or percutaneous ethanol injection (PEI). RESULTS: Of 194 patients with HCC, 84 were older than 70 years (43.3%). The mean age was 76.8 +/- 4.5 years. Seventy-five percent were male and 91.7% had cirrhosis. Cancer was initially identified by a surveillance program in 61.9%. According to the Barcelona Clinic Liver Cancer staging system, 60.7% were classified as having early stage cancer (0-A), 19% as stage B, 12% as stage C, and 8.3% as stage D. Potentially curative initial treatment was provided in 38.2% (surgical resection in 4.8%, PEI in 22.6%, RFA in 4.8%, PEI+RFA in 6%), transarterial chemoembolization in 20.2%, and sorafenib in 3.6%. Twenty-five percent of patients were not treatment candidates and 13% refused the recommended treatment. The median follow-up after percutaneous ablation was 23 months (IQR 14.2-40.6). The mean number of sessions was 3.5 +/- 2.2 for PEI and 1.8 +/- 1.6 for RFA. The complications rate per session was 4%. Remission was achieved in 35.7%. The overall median survival was 45.7 months (95% CI 20.8-70.6). CONCLUSIONS: Almost half of the patients with HCC in our sample were elderly and more than half were diagnosed at an early stage. Percutaneous ablation was performed in one-third of the sample, achieving remission in 37.5%. There were few complications. Therefore, these patients should be assessed for percutaneous ablation. PMID- 25499847 TI - Recurrent cecocolic intussusception in a young woman. PMID- 25499848 TI - [Gastric vascular lesions in cirrhosis: gastropathy and antral vascular ectasia]. AB - Portal hypertensive gastropathy (GHP) is a complication of portal hypertension usually associated with liver cirrhosis. The pathogenesis is unclear but the presence of portal hypertension is an essential factor for its development. GHP may be asymptomatic or present as gastrointestinal bleeding or iron deficiency anemia. Endoscopic lesions vary from a mosaic pattern to diffuse red spots; the most common location is the fundus. Treatment is indicated when there is acute or chronic bleeding, as secondary prophylaxis. There is insufficient evidence to recommend primary prophylaxis in patients who have never bled. Drugs that decrease portal pressure, such as non-cardioselective beta-blockers, and/or endoscopic ablative treatments, such as argon-beam coagulation, may be used. The role of transarterial intrahepatic portosystemic shunt) or bypass surgery has been insufficiently analyzed. Antral vascular ectasia (EVA) is a rare entity in liver cirrhosis, whose pathophysiology is still unknown. Clinical presentation is similar to that of GHP and endoscopy usually shows red spots in the antrum. Biopsy is often required to differentiate EVA from GHP. There is no effective medical therapy, so endoscopic ablative therapy and, in severe cases, antrectomy are recommended. PMID- 25499849 TI - Singlet-oxygen-derived products from linoleate activate Nrf2 signaling in skin cells. AB - Linoleates are required for normal mammalian health and development, but they are also prone to oxidation, resulting in biologically active metabolites such as hydroxyoctadecadienoic acids (HODEs). To investigate the biological activity of 9 EZ-HODE, 10-EZ-HODE, 12-ZE-HODE, and 13-ZE-HODE, the metabolites of singlet oxygen-derived products from linoleates, we assessed adaptive cytoprotection in HaCaT skin cells. Treating HaCaT cells with sublethal concentrations of 10-EZ HODE and 12-ZE-HODE, which are singlet-oxygen-mediated specific oxidation metabolites of linoleates, but not 9-EZ-HODE and 13-ZE-HODE, caused resistance to hydrogen peroxide-induced oxidative damage. Microarray analysis of HaCaT cells revealed that 10-EZ-HODE and 12-ZE-HODE induced cellular antioxidant genes that are responsive to nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), such as heme oxygenase-1 and glutathione synthesis enzymes. Although 10-EZ-HODE and 12-ZE HODE did not induce Nrf2 mRNA, treatment with these metabolites increased the intranuclear expression of Nrf2. These results suggest that 10-EZ-HODE and 12-ZE HODE initiate adaptive responses that reduce the damage caused by oxidative stress. PMID- 25499850 TI - Asymmetric dimethylarginine exacerbates Abeta-induced toxicity and oxidative stress in human cell and Caenorhabditis elegans models of Alzheimer disease. AB - Growing evidence suggests a strong association between cardiovascular risk factors and incidence of Alzheimer disease (AD). Asymmetric dimethylarginine (ADMA), the endogenous nitric oxide synthase inhibitor, has been identified as an independent cardiovascular risk factor and is also increased in plasma of patients with AD. However, whether ADMA is involved in the pathogenesis of AD is unknown. In this study, we found that ADMA content was increased in a transgenic Caenorhabditis elegans beta-amyloid (Abeta) overexpression model, strain CL2006, and in human SH-SY5Y cells overexpressing the Swedish mutant form of human Abeta precursor protein (APPsw). Moreover, ADMA treatment exacerbated Abeta-induced paralysis and oxidative stress in CL2006 worms and further elevated oxidative stress and Abeta secretion in APPsw cells. Knockdown of type 1 protein arginine N methyltransferase to reduce ADMA production failed to show a protective effect against Abeta toxicity, but resulted in more paralysis in CL2006 worms as well as increased oxidative stress and Abeta secretion in APPsw cells. However, overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) to promote ADMA degradation significantly attenuated oxidative stress and Abeta secretion in APPsw cells. Collectively, our data support the hypothesis that elevated ADMA contributes to the pathogenesis of AD. Our findings suggest that strategies to increase DDAH1 activity in neuronal cells may be a novel approach to attenuating AD development. PMID- 25499851 TI - MnSOD overexpression confers cisplatin resistance in lung adenocarcinoma via the NF-kappaB/Snail/Bcl-2 pathway. AB - Manganese superoxide dismutase (MnSOD) has been shown to be associated with doxorubicin resistance in gastric cancer cells, but the underlying mechanism of MnSOD in drug resistance remains unclear. A recent study indicated that NF-kappaB activation by MnSOD promoted tumor malignancy in lung adenocarcinoma. Therefore, we hypothesized that MnSOD-mediated NF-kappaB activation might confer cisplatin resistance in lung adenocarcinoma via the NF-kappaB/Bcl-2/Snail pathway. Here, the inhibition concentration of cisplatin with 50% cell viability (IC50) was positively correlated with MnSOD expression and its activity in a panel of lung adenocarcinoma cells. The IC50 value was markedly increased and decreased by MnSOD overexpression and knockdown, respectively, in lung cancer cells. Mechanistically, an increase in Bcl-2 by MnSOD-mediated NF-kappaB activation confers greater cisplatin resistance than cIAP2, Bcl-xL, Mcl-1, and Snail. MnSOD mediated cisplatin resistance can be overcome by a Bcl-2 antagonist (ABT-199) or IKKbeta inhibitor (curcumin) in cells and xenograft tumors. MnSOD expression was positively correlated with nuclear p65 protein and Bcl-2 mRNA expression in tumors from patients with lung adenocarcinomas. A retrospective study indicated that it was more common for MnSOD-positive, nuclear p65-positive, or high Bcl-2 mRNA tumors to have an unfavorable response to cisplatin-based chemotherapy than their counterparts. Therefore, we suggest that ABT-199 or curcumin may be potentially useful to improve tumor regression and chemotherapeutic response in patients with MnSOD/Bcl-2-positive tumors. PMID- 25499852 TI - Long-term use of angiotensin II receptor antagonists and calcium-channel antagonists in Algerian hypertensive patients: effects on metabolic and oxidative parameters. AB - The effects of calcium antagonists (amlodipine) and angiotensin II receptor antagonists (telmisartan) on lipid profile and oxidative markers were investigated in Algerian hypertensive patients. At the beginning and after 1 year of antihypertensive therapy, blood samples are collected for determination of biochemical parameters (glucose, cholesterol, triglycerides, urea, creatinine) and oxidative markers (malondialdehyde, carbonyl proteins, nitric oxide, superoxide anion, vitamin C, glutathione, catalase, superoxide dismutase). The results of this study indicate that telmisartan and amlodipine are effective antihypertensive agents in the treatment of hypertension because a significant reduction in systolic and diastolic blood pressure was observed in all hypertensive patients after 1 year of treatment. Our results show also that telmisartan and amlodipine treatments counteracted hypertension-dependent lipid abnormalities and oxidative stress. Telmisartan treatment appears to be more efficient than amlodipine treatment. In addition, telmisartan, which reversed all lipid and redox changes associated with hypertension, should be prescribed, especially in hypertensive patients with hypertriglyceridemia and with severe oxidative stress. PMID- 25499853 TI - N-glycosylation-negative catalase: a useful tool for exploring the role of hydrogen peroxide in the endoplasmic reticulum. AB - Disulfide bond formation during protein folding of nascent proteins is associated with the generation of H2O2 in the endoplasmic reticulum (ER). Approaches to quantifying H2O2 directly within the ER failed because of the oxidative environment in the ER lumen, and ER-specific catalase expression to detoxify high H2O2 concentrations resulted in an inactive protein owing to N-glycosylation. Therefore, the N-glycosylation motifs at asparagine-244 and -439 of the human catalase protein were deleted by site-directed mutagenesis. The ER-targeted expression of these variants revealed that the deletion of the N-glycosylation motif only at asparagine-244 (N244) was associated with the maintenance of full enzymatic activity in the ER. Expression of catalase N244 in the ER (ER-Catalase N244) was ER-specific and protected the cells significantly against exogenously added H2O2. With the expression of ER-Catalase N244, a highly effective H2O2 inactivation within the ER was achieved for the first time. Catalase has a high H2O2-inactivation capacity without the need of reducing cofactors, which might interfere with the ER redox homeostasis, and is not involved in protein folding. With these characteristics ER-Catalase N244 is an ideal tool to explore the impact of ER-generated H2O2 on the generation of disulfide bonds or to study the induction of ER-stress pathways through protein folding overload and accumulation of H2O2. PMID- 25499855 TI - IgE responses in mouse and man and the persistence of IgE memory. AB - Rapid and robust recall or 'memory' responses are an essential feature of adaptive immunity. They constitute a defense against reinfection by pathogens, yet arguably do more harm than good in allergic disease. Immunoglobulin (Ig)E antibodies mediate the allergic reaction characterized by immediate hypersensitivity, a manifestation of IgE memory. The origin of IgE memory remains obscure, mainly due to the low proportion of IgE-expressing B cells in the total B cell population. The recent development of ultrasensitive methods for tracking these cells in vivo has overcome this obstacle, and their use has revealed unexpected pathways to IgE memory in the mouse. Here, we review these findings and consider their bearing on our understanding of IgE memory and allergic disease in man. PMID- 25499854 TI - Protein thiyl radical reactions and product formation: a kinetic simulation. AB - Protein thiyl radicals are important intermediates generated in redox processes of thiols and disulfides. Thiyl radicals efficiently react with glutathione and ascorbate, and the common notion is that these reactions serve to eliminate thiyl radicals before they can enter potentially hazardous processes. However, over the past years increasing evidence has been provided for rather efficient intramolecular hydrogen transfer processes of thiyl radicals in proteins and peptides. Based on rate constants published for these processes, we have performed kinetic simulations of protein thiyl radical reactivity. Our simulations suggest that protein thiyl radicals enter intramolecular hydrogen transfer reactions to a significant extent even under physiologic conditions, i.e., in the presence of 30 uM oxygen, 1 mM ascorbate, and 10 mM glutathione. At lower concentrations of ascorbate and glutathione, frequently observed when tissue is exposed to oxidative stress, the extent of irreversible protein thiyl radical-dependent protein modification increases. PMID- 25499856 TI - Stromal infrastructure of the lymph node and coordination of immunity. AB - The initiation of adaptive immune responses depends upon the careful maneuvering of lymphocytes and antigen into and within strategically placed lymph nodes (LNs). Non-hematopoietic stromal cells form the cellular infrastructure that directs this process. Once regarded as merely structural features of lymphoid tissues, these cells are now appreciated as essential regulators of immune cell trafficking, fluid flow, and LN homeostasis. Recent advances in the identification and in vivo targeting of specific stromal populations have resulted in striking new insights to the function of stromal cells and reveal a level of complexity previously unrealized. We discuss here recent discoveries that highlight the pivotal role that stromal cells play in orchestrating immune cell homeostasis and adaptive immunity. PMID- 25499858 TI - [1924-2014: "les Annales de pathologie", a 90-years "young" journal!]. PMID- 25499859 TI - [Gestational trophoblastic disease]. AB - Gestational trophoblastic disease encompresses a group of interrelated diseases, following a pregnancy after a variable period of time. Hydatiform mole corresponds to premalignant disorders composed of villi with excess of paternal genetic material, with a malignant potential more important for complete mole than partial mole. Gestational trophoblastic neoplasia includes invasive mole, choriocarcinoma, placental site trophoblatic tumor and epithelioid trophoblastic tumor. Their histological diagnosis may be problematic on curettage material and needs to be correlated to serum hCG level and radiological findings. The use of chemotherapy has dramatically improved the prognosis of these lesions. All patients with this rare disease need to be registered in the national service for gestational trophoblastic disease (http://www.mole-chorio.com), which coordinates their management at the national level. PMID- 25499861 TI - [Primary hepatic angiosarcoma: A retrospective analysis of eight cases]. AB - Angiosarcoma is a malignant tumor of vascular endothelial cell origin. Primary hepatic angiosarcoma is rare, most often associated with chronic exposure to toxic substances. The diagnosis of angiosarcoma is based on histological examination. Presenting symptoms are nonspecific, including abdominal pain, impaired general condition and fever. Primary hepatic angiosarcoma is a fast growing tumor and the diagnosis is usually made at an advanced stage of the disease. The prognosis is poor. Surgical resection is recommended as the curative choice in localized forms, highlighting the key role of screening programs of occupational medicine that may help to diagnose tumors at an earlier, localized stage. Radiotherapy and chemotherapy are considered to have a limited efficacy. Here, we report a series of eight cases of primary hepatic angiosarcoma diagnosed at the University Hospital of Besancon between 2001 and 2012. Clinical, radiological, histological and therapeutic characteristics of the patients are described and analyzed. PMID- 25499860 TI - [Renal tumors: The International Society of Urologic Pathology (ISUP) 2012 consensus conference recommendations]. AB - During the last 30 years many advances have been made in kidney tumor pathology. In 1981, 9 entities were recognized in the WHO Classification. In the latest classification of 2004, 50 different types have been recognized. Additional tumor entities have been described since and a wide variety of prognostic parameters have been investigated with variable success; however, much attention has centered upon the importance of features relating to both stage and grade. The International Society of Urological Pathology (ISUP) recommends after consensus conferences the development of reporting guidelines, which have been adopted worldwide ISUP undertook to review all aspects of the pathology of adult renal malignancy through an international consensus conference to be held in 2012. As in the past, participation in this consensus conference was restricted to acknowledged experts in the field. PMID- 25499862 TI - [A rapidly progressive orbital tumor in a seven-year-old girl revealing a primitive systemic vasculitis]. AB - Orbital tumor lesions in pediatric population encompass a wide range of pathological processes, which are very different in etiology and prognosis. They usually require an emergency in histological diagnosis because of their quick growth. Beside malignant and benign tumors, the inflammatory pseudo-tumors group included dysimmune orbital involvement secondary to systemic vasculitis such as granulomatosis with polyangiitis (ex-Wegener's granulomatosis). We report the case of a seven-year-old girl suffering from a severe primitive ANCA vasculitis, revealed by an orbital mass. PMID- 25499863 TI - [Broncho-pulmonary aspiration of brain and cartilage tissue in a context of gasping]. AB - Evidence of post-mortem breath movements are rarely reported. We present two cases of broncho-pulmonary aspiration of brain and cartilage tissue following two fatal suicidal gunshots to the head. We also discuss the physiopathological implications for the agony. PMID- 25499864 TI - [Cerebellar gangliocytoma in an 11-year-old child]. AB - Cerebellar gangliocytoma can correspond to Lhermitte-Duclos disease, a benign hamartomatous malformation encountered in young adults. It can also be a part of gangliogliomas/gangliocytomas family, which usually encompasses temporal pediatric neoplasms associated with longstanding seizures. We report a case of a young 11-year-old patient who presented with a gangliocytoma of the cerebellum revealed by neurologic manifestations (headache, dyspraxia, equilibrium and gait disturbances). Diagnosis was made on surgical material. Tumour was characterized by dysplastic mature ganglion cells, perivascular lymphocytic infiltrates and no glial neoplastic component. By immunohistochemistry, ganglion cells expressed neurofilaments, MAP2 protein, synaptophysin, chromogranin A and S100 protein. BRAF V600E mutation was absent. Clinical characteristics, radiology, histopathology of the two main diagnoses are discussed. PMID- 25499865 TI - [A rare tumor of the cerebellopontine angle]. PMID- 25499866 TI - [An unusual appendix lesion]. PMID- 25499867 TI - Healthy cookery lessons still affect eating habits six months later, Australian study finds. PMID- 25499868 TI - Advances in our structural understanding of orphan nuclear receptors. AB - Nuclear receptors (NRs) are key players in the regulation of gene expression, coordinating protein assemblies upon their surfaces. NRs are regulated by ligand binding, which remodels the interaction surfaces and subsequently influences macromolecular complex formation. Structural biology has been instrumental in the discovery of some of these ligands, but there are still orphan NRs (ONRs) whose bona fide ligands have yet to be identified. Over the past decade, fundamental structural and functional breakthroughs have led to a deeper understanding of ONR actions and their multidomain organization. Here, we summarize the structural advances in ONRs with implications for the therapeutic treatment of diseases such as metabolic syndrome and cancer. PMID- 25499869 TI - NHS could save over L40m a year if women breast fed for longer. PMID- 25499870 TI - Healing of the Achilles tendon in rabbits--evaluation by magnetic resonance imaging and histopathology. AB - BACKGROUND: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) could provide valuable findings for tendon regeneration. A non-invasive image method that can effectively evaluate the quality of the scar tissue has not yet been employed. METHODS: Thirteen New Zealand rabbits were divided into two groups: group 1--non-treated control (n = 4); group 2--surgical intervention (n = 9). The central portion of the Achilles tendon was resected, and after 30 days, DCE-MRI was performed. Contrast enhancement methods were applied using the region of interest (ROI) technique. In the medium third of the Achilles tendon, the intra substantial signal intensity and the presence of hyper-intense intra-tendon focus points and of signal heterogeneity were evaluated. Antero-posterior and transversal diameters of the tendon were measured. The Achilles tendon was removed and dissected free from other tissues. Sections from the central part of the tendon were stained for histological analysis. RESULTS: The difference between the contrast enhancement curves of the control and surgical groups (p < 0.0001) was observed. The surgical group had an intense contrast enhancement in the contrast sequences, enlargement of the diameter and intra-substantial signal intensity alteration, with hyper-signal focus points and widening of the tendon sheath, which presented irregular contours and intense contrast enhancement. On histology, the Achilles tendon presented diffuse widening of the tendon sheath and wedge-shaped areas with scarring tissue rich in disordered collagen fibres. These findings were related to alteration in the intra-substantial signal intensity, with hyper-signal focus points in the DCE-MRI. CONCLUSIONS: MRI with perfusion could be a useful technique for evaluating tissue and fibrous scarring in tendons. PMID- 25499871 TI - Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. AB - AIM: In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, apixaban compared with warfarin reduced the risk of stroke, major bleed, and death in patients with atrial fibrillation. In this ancillary study, we evaluated clinical consequences of major bleeds, as well as management and treatment effects of warfarin vs. apixaban. METHODS AND RESULTS: Major International Society on Thrombosis and Haemostasis bleeding was defined as overt bleeding accompanied by a decrease in haemoglobin (Hb) of >=2 g/dL or transfusion of >=2 units of packed red cells, occurring at a critical site or resulting in death. Time to event [death, ischaemic stroke, or myocardial infarction (MI)] was evaluated by Cox regression models. The excess risk associated with bleeding was evaluated by separate time-dependent indicators for intracranial (ICH) and non-intracranial haemorrhage. Major bleeding occurred in 848 individuals (4.7%), of whom 126 (14.9%) died within 30 days. Of 176 patients with an ICH, 76 (43.2%) died, and of the 695 patients with major non-ICH, 64 (9.2%) died within 30 days of the bleeding. The risk of death, ischaemic stroke, or MI was increased roughly 12-fold after a major non-ICH bleeding event within 30 days. Corresponding risk of death following an ICH was markedly increased, with HR 121.5 (95% CI 91.3-161.8) as was stroke or MI with HR 21.95 (95% CI 9.88 48.81), respectively. Among patients with major bleeds, 20.8% received vitamin K and/or related medications (fresh frozen plasma, coagulation factors, factor VIIa) to stop bleeding within 3 days, and 37% received blood transfusion. There was no interaction between apixaban and warfarin and major bleeding on the risk of death, stroke, or MI. CONCLUSION: Major bleeding was associated with substantially increased risk of death, ischaemic stroke, or MI, especially following ICH, and this risk was similarly elevated regardless of treatment with apixaban or warfarin. These results underscore the importance of preventing bleeding in anti-coagulated patients. ClinicalTrials.gov Identifier: NCT00412984. PMID- 25499872 TI - A Mobile Health Intervention for Self-Management and Lifestyle Change for Persons With Type 2 Diabetes, Part 2: One-Year Results From the Norwegian Randomized Controlled Trial RENEWING HEALTH. AB - BACKGROUND: Self-management is crucial in the daily management of type 2 diabetes. It has been suggested that mHealth may be an important method for enhancing self-management when delivered in combination with health counseling. OBJECTIVE: The objective of this study was to test whether the use of a mobile phone-based self-management system used for 1 year, with or without telephone health counseling by a diabetes specialist nurse for the first 4 months, could improve glycated hemoglobin A1c (HbA1c) level, self-management, and health related quality of life compared with usual care. METHODS: We conducted a 3-arm prospective randomized controlled trial involving 2 intervention groups and 1 control group. Eligible participants were persons with type 2 diabetes with an HbA1c level >=7.1% (>=54.1 mmol/mol) and aged >=18 years. Both intervention groups received the mobile phone-based self-management system Few Touch Application (FTA). The FTA consisted of a blood glucose-measuring system with automatic wireless data transfer, diet manual, physical activity registration, and management of personal goals, all recorded and operated using a diabetes diary app on the mobile phone. In addition, one intervention group received health counseling based on behavior change theory and delivered by a diabetes specialist nurse for the first 4 months after randomization. All groups received usual care by their general practitioner. The primary outcome was HbA1c level. Secondary outcomes were self-management (heiQ), health-related quality of life (SF-36), depressive symptoms (CES-D), and lifestyle changes (dietary habits and physical activity). Data were analyzed using univariate methods (t test, ANOVA) and multivariate linear and logistic regression. RESULTS: A total of 151 participants were randomized: 51 to the FTA group, 50 to the FTA-health counseling (FTA-HC) group, and 50 to the control group. Follow-up data after 1 year were available for 120 participants (79%). HbA1c level decreased in all groups, but did not differ between groups after 1 year. The mean change in the heiQ domain skills and technique acquisition was significantly greater in the FTA HC group after adjusting for age, gender, and education (P=.04). Other secondary outcomes did not differ between groups after 1 year. In the FTA group, 39% were substantial users of the app; 34% of the FTA-HC group were substantial users. Those aged >=63 years used the app more than their younger counterparts did (OR 2.7; 95% CI 1.02-7.12; P=.045). CONCLUSIONS: The change in HbA1c level did not differ between groups after the 1-year intervention. Secondary outcomes did not differ between groups except for an increase in the self-management domain of skill and technique acquisition in the FTA-HC group. Older participants used the app more than the younger participants did. PMID- 25499873 TI - Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). AB - BACKGROUND: Temporary interruption of oral anticoagulation for procedures is often required, and some propose using bridging anticoagulation. However, the use and outcomes of bridging during oral anticoagulation interruptions in clinical practice are unknown. METHODS AND RESULTS: The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry is a prospective, observational registry study of US outpatients with atrial fibrillation. We recorded incident temporary interruptions of oral anticoagulation for a procedure, including the use and type of bridging therapy. Outcomes included multivariable-adjusted rates of myocardial infarction, stroke or systemic embolism, major bleeding, cause-specific hospitalization, and death within 30 days. Of 7372 patients treated with oral anticoagulation, 2803 overall interruption events occurred in 2200 patients (30%) at a median follow-up of 2 years. Bridging anticoagulants were used in 24% (n=665), predominantly low molecular-weight heparin (73%, n=487) and unfractionated heparin (15%, n=97). Bridged patients were more likely to have had prior cerebrovascular events (22% versus 15%; P=0.0003) and mechanical valve replacements (9.6% versus 2.4%; P<0.0001); however, there was no difference in CHA2DS2-VASc scores (scores >= 2 in 94% versus 95%; P=0.5). Bleeding events were more common in bridged than nonbridged patients (5.0% versus 1.3%; adjusted odds ratio, 3.84; P<0.0001). The incidence of myocardial infarction, stroke or systemic embolism, major bleeding, hospitalization, or death within 30 days was also significantly higher in patients receiving bridging (13% versus 6.3%; adjusted odds ratio, 1.94; P=0.0001). CONCLUSIONS: Bridging anticoagulation is used in one quarter of anticoagulation interruptions and is associated with higher risk for bleeding and adverse events. These data do not support the use of routine bridging, and additional data are needed to identify best practices concerning anticoagulation interruptions. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01165710. PMID- 25499874 TI - A bridge too far? Findings of bridging anticoagulation use and outcomes in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT AF). PMID- 25499876 TI - "I do not exist"-Cotard syndrome in insular cortex atrophy. PMID- 25499877 TI - The synthesis of UDP-selective fluorescent probe and its imaging application in living cells. AB - A perylene-based probe was developed for uridine diphosphate (UDP) sensing and cell imaging. The probe presented about 4-fold fluorescence enhancement in the presence or absence of 100equiv UDP. The selectivity toward UDP over other phosphor-containing anions was observed. The selective UDP sensing was speculated to be related to the binding affinities of Zn(2+) ions in sensor with the uridine and phosphate moieties of UDP. Furthermore, this probe was also applied to image of UDP in living cells. PMID- 25499878 TI - Isotope chemistry; a useful tool in the drug discovery arsenal. AB - As Medicinal Chemists are responsible for the synthesis and optimization of compounds, they often provide intermediates for use by isotope chemistry. Nevertheless, there is generally an incomplete understanding of the critical factors involved in the labeling of compounds. The remit of an Isotope Chemistry group varies from company to company, but often includes the synthesis of compounds labeled with radioisotopes, especially H-3 and C-14 and occasionally I 125, and stable isotopes, especially H-2, C-13, and N-15. Often the remit will also include the synthesis of drug metabolites. The methods used to prepare radiolabeled compounds by Isotope Chemists have been reviewed relatively recently. However, the organization and utilization of Isotope Chemistry has not been discussed recently and will be reviewed herein. PMID- 25499879 TI - Synthesis and biological evaluation of novel marine-derived indole-based 1,2,4 oxadiazoles derivatives as multifunctional neuroprotective agents. AB - Phidianidines (1), isolated from the marine opisthobranch mollusk Phidiana militaris, present the first example of natural products possessing an 1,2,4 oxadiazole ring system and show various bioactivities. However, the structure activity relationship study related to 1 has not been reported yet. As our ongoing effect toward marine-derived potential neuroprotective agents, a series of phidianidine-based derivatives have been synthesized and evaluated for neuroprotective effects against amyloid-beta25-35 (Abeta25-35)-, hydrogenperoxide (H2O2)-, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells. The bioassay results indicated that some of analogs, especially 2q and 2r, exhibited good in vitro neuroprotective effects in the above three screening models. The preliminary SAR study indicated that substituent groups introduced to the benzene ring play a crucial role in their bioactivity. In particular, the linear alkoxy group at 4-position favors the neuroprotective activity, while a bulky group could lead the activity decrease or loss. These findings could provide an alternative strategy for the development of novel indole-based 1,2,4 oxadiazole derivatives for the treatment of Alzheimer's disease. PMID- 25499880 TI - Identification of a highly potent and selective CB2 agonist, RQ-00202730, for the treatment of irritable bowel syndrome. AB - Herein we report the identification of a highly potent and selective CB2 agonist, RQ-00202730 (40), obtained by lead optimization of the benzimidazole scaffold. Compound 40 showed strong agonistic activity with an EC50 of 19nM and excellent selectivity (>1300-fold) over the CB1 receptor. Compound 40 displayed a dose dependent analgesic effect on TNBS-induced visceral hypersensitivity in rats by oral administration (ED50 0.66mg/kg at 2.5h after oral administration). In addition, 40 did not show a significant effect on body temperature in rats after oral administration at 300mg/kg. These findings suggest that highly selective CB2 agonists will be effective agents for IBS therapy. PMID- 25499881 TI - Ionic liquid catalyzed synthesis of 2-(indole-3-yl)-thiochroman-4-ones and their novel antifungal activities. AB - 2-(Indole-3-yl)-thiochroman-4-ones were synthesized via ionic liquid and tested for in vitro antifungal activity. The contribution of ionic liquid to Michael addition reaction is significant. Structures of all compounds are elucidated by (1)H NMR, (13)C NMR and HRMS. Most of these compounds showed better antifungal activity than fluconazole. The results suggest that 2-(indole-3-yl)-thiochroman-4 ones would be efficient antifungal agents. PMID- 25499882 TI - New ent-kauranes from the fruits of Annona glabra and their inhibitory nitric oxide production in LPS-stimulated RAW264.7 macrophages. AB - Three new ent-kaurane diterpenoids, 7beta,16alpha,17-trihydroxy-ent-kauran-19-oic acid (1), 7beta,17-dihydroxy-16alpha-ent-kauran-19-oic acid 19-O-beta-d glucopyranoside ester (2), 7beta,17-dihydroxy-ent-kaur-15-en-19-oic acid 19-O beta-d-glucopyranoside ester (3) along with five known compounds, paniculoside IV (4), 16alpha,17-dihydroxy-ent-kaurane (5), 16beta,17-dihydroxy-ent-kaurane (6), 16beta,17-dihydroxy-ent-kauran-19-al (7), and 16beta,17-dihydroxy-ent-kauran-19 oic acid (8) were isolated from the fruits of Annona glabra. Their chemical structures were elucidated by physical and chemical methods. All compounds were evaluated for inhibitory activity against nitric oxide (NO) production in LPS stimulated RAW 264.7 macrophages. As the results, compound 3 showed potent inhibitory LPS-stimulated NO production in RAW 264.7 macrophages with the IC50 value of 0.01+/-0.01MUM; compounds 1 and 7 showed significant inhibitory NO production with the IC50 values of 0.39+/-0.12MUM and 0.32+/-0.04MUM, respectively. PMID- 25499883 TI - Novel heterocyclic scaffolds of GW4064 as farnesoid X receptor agonists. AB - The farnesoid X receptor (FXR) may play a crucial role in a number of metabolic diseases and, as such, could potentially serve as a target for the development of therapeutics as a treatment for those diseases. Previous work has described GW4064 as an FXR agonist with an interesting activity profile. This manuscript will describe the synthesis of novel analogs of GW4064 and the activity profile of those analogs. PMID- 25499884 TI - Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells. AB - A major risk factor for ovarian cancer is germline mutations of BRCA1/2. It has been found that (80%) of cellular models with acquired platinum or taxane resistance display an inverse resistance relationship, that is collateral sensitivity to the other agent. We used a clinically relevant comparative selection strategy to develop novel chemoresistant cell lines which aim to investigate the mechanisms of resistance that arise from different exposures of carboplatin and taxol on cells having BRCA1 function (UPN251) or dysfunction (OVCAR8). Resistance to carboplatin and taxol developed quicker and more stably in UPN251 (BRCA1-wildtype) compared to OVCAR8 (BRCA1-methylated). Alternating carboplatin and taxol treatment delayed but did not prevent resistance development when compared to single-agent administration. Interestingly, the sequence of drug exposure influenced the resistance mechanism produced. UPN251 6CALT (carboplatin first) and UPN251-6TALT (taxol first) have different profiles of cross resistance. UPN251-6CALT displays significant resistance to CuSO4 (2.3 fold, p=0.004) while UPN251-6TALT shows significant sensitivity to oxaliplatin (0.6-fold, p=0.01). P-glycoprotein is the main mechanism of taxol resistance found in the UPN251 taxane-resistant sublines. UPN251 cells increase cellular glutathione levels (3.0-fold, p=0.02) in response to carboplatin treatment. However, increased glutathione is not maintained in the carboplatin-resistant sublines. UPN251-7C and UPN251-6CALT are low-level resistant to CuSO4 suggesting alterations in copper metabolism. However, none of the UPN251 sublines have alterations in the protein expression of ATP7A or CTR1. The protein expression of BRCA1 and MRP2 is unchanged in the UPN251 sublines. The UPN251 sublines remain sensitive to parp inhibitors veliparib and CEP8983 suggesting that these agents are candidates for the treatment of platinum/taxane resistant ovarian cancer patients. PMID- 25499886 TI - Affective symptoms and the overactive bladder - a systematic review. AB - BACKGROUND: Overactive bladder syndrome (OAB) is characterised by urgency symptoms, with or without urgency incontinence, usually with frequency and nocturia. Although literature suggest an association between OAB, depression and anxiety, no systematic review has been presented. OBJECTIVE: Systematically review the literature on the association of affective conditions with OAB. METHODS: Systematic review according to the PRISMA guidelines. This review is registered in the PROSPERO register (CRD4201400664). RESULTS: Forty-three articles were included, describing more than 80,000 subjects. Depression and OAB were positively associated in 26 studies, anxiety and OAB in 6 studies. Longitudinal studies reported: a) OAB subjects who developed depression/anxiety or b) depressed/anxious subjects developing OAB, or c) both. The quality of evidence in studies reporting an association between the co-occurrence of OAB and depression was rated level 3 in accordance with the GRADE framework. Evidence reporting on the co-occurrence of anxiety and OAB was rated GRADE level 2. Longitudinal associations between new onset of OAB in depressive subjects was GRADE level 2. Evidence reporting association of OAB with anxiety in longitudinal studies was of GRADE level 1. CONCLUSION: To our knowledge, this systematic review is the first to give a comprehensive qualitative overview on the association between OAB and affective symptoms. Many evaluated studies failed to note longitudinal changes and lacked evidence of causality. Still, results revealed an association between OAB and affective symptoms and there is evidence for new onset of OAB in depressive subjects, but further research is necessary to examine the strength of the effect. PMID- 25499885 TI - Phosphorylation and cellular function of the human Rpa2 N-terminus in the budding yeast Saccharomyces cerevisiae. AB - Maintenance of genome integrity is critical for proper cell growth. This occurs through accurate DNA replication and repair of DNA lesions. A key factor involved in both DNA replication and the DNA damage response is the heterotrimeric single stranded DNA (ssDNA) binding complex Replication Protein A (RPA). Although the RPA complex appears to be structurally conserved throughout eukaryotes, the primary amino acid sequence of each subunit can vary considerably. Examination of sequence differences along with the functional interchangeability of orthologous RPA subunits or regions could provide insight into important regions and their functions. This might also allow for study in simpler systems. We determined that substitution of yeast Replication Factor A (RFA) with human RPA does not support yeast cell viability. Exchange of a single yeast RFA subunit with the corresponding human RPA subunit does not function due to lack of inter-species subunit interactions. Substitution of yeast Rfa2 with domains/regions of human Rpa2 important for Rpa2 function (i.e., the N-terminus and the loop 3-4 region) supports viability in yeast cells, and hybrid proteins containing human Rpa2 N terminal phospho-mutations result in similar DNA damage phenotypes to analogous yeast Rfa2 N-terminal phospho-mutants. Finally, the human Rpa2 N-terminus (NT) fused to yeast Rfa2 is phosphorylated in a manner similar to human Rpa2 in human cells, indicating that conserved kinases recognize the human domain in yeast. The implication is that budding yeast represents a potential model system for studying not only human Rpa2 N-terminal phosphorylation, but also phosphorylation of Rpa2 N-termini from other eukaryotic organisms. PMID- 25499887 TI - Indirect associations of combat exposure with post-deployment physical symptoms in U.S. soldiers: roles of post-traumatic stress disorder, depression and insomnia. AB - OBJECTIVE: To characterize the indirect associations of combat exposure with post deployment physical symptoms through shared associations with post-traumatic stress disorder (PTSD), depression and insomnia symptoms. METHODS: Surveys were administered to a sample of U.S. soldiers (N = 587) three months after a 15-month deployment to Iraq. A multiple indirect effects model was used to characterize direct and indirect associations between combat exposure and physical symptoms. RESULTS: Despite a zero-order correlation between combat exposure and physical symptoms, the multiple indirect effects analysis did not provide evidence of a direct association between these variables. Evidence for a significant indirect association of combat exposure and physical symptoms was observed through PTSD, depression, and insomnia symptoms. In fact, 92% of the total effect of combat exposure on physical symptoms scores was indirect. These findings were evident even after adjusting for the physical injury and relevant demographics. CONCLUSION: This is the first empirical study to suggest that PTSD, depression and insomnia collectively and independently contribute to the association between combat exposure and post-deployment physical symptoms. Limitations, future research directions, and potential policy implications are discussed. PMID- 25499889 TI - Cons outweigh pros of preventive aspirin in women, study finds. PMID- 25499888 TI - Bone marrow stromal antigen 2 expressed in cancer cells promotes mammary tumor growth and metastasis. AB - INTRODUCTION: Several innate immunity genes are overexpressed in human cancers and their roles remain controversial. Bone marrow stromal antigen 2 (BST-2) is one such gene whose role in cancer is not clear. BST-2 is a unique innate immunity gene with both antiviral and pro-tumor functions and therefore can serve as a paradigm for understanding the roles of other innate immunity genes in cancers. METHODS: Meta-analysis of tumors from breast cancer patients obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets were evaluated for levels of BST-2 expression and for tumor aggressiveness. In vivo, we examined the effect of knockdown of BST-2 in two different murine carcinoma cells on tumor growth, metastasis, and survival. In vitro, we assessed the effect of carcinoma cell BST-2 knockdown and/or overexpression on adhesion, anchorage-independent growth, migration, and invasion. RESULTS: BST-2 in breast tumors and mammary cancer cells is a strong predictor of tumor size, tumor aggressiveness, and host survival. In humans, BST 2 mRNA is elevated in metastatic and invasive breast tumors. In mice, orthotopic implantation of mammary tumor cells lacking BST-2 increased tumor latency, decreased primary tumor growth, reduced metastases to distal organs, and prolonged host survival. Furthermore, we found that the cellular basis for the role of BST-2 in promoting tumorigenesis include BST-2-directed enhancement in cancer cell adhesion, anchorage-independency, migration, and invasion. CONCLUSIONS: BST-2 contributes to the emergence of neoplasia and malignant progression of breast cancer. Thus, BST-2 may (1) serve as a biomarker for aggressive breast cancers, and (2) be a novel target for breast cancer therapeutics. PMID- 25499891 TI - Synthesis and characterization of zinc oxide-neem oil-chitosan bionanocomposite for food packaging application. AB - Nano zinc oxide at different concentrations (0.1, 0.3 and 0.5%) and neem essential oil were incorporated into the chitosan polymer by solution cast method to enhance the properties of the bionanocomposite film. The functional groups, crystalline particle size, thermal stability and morphology were determined using FTIR, XRD, TGA and SEM, respectively. The results showed that 0.5% nano zinc oxide incorporated composite film have improved tensile strength, elongation, film thickness, film transparency and decreased water solubility, swelling and barrier properties due to the presence of neem oil and nano zinc oxide in the polymer matrix. Further antibacterial activity by well diffusion assay method was followed against Escherichia coli which were found to have good inhibition effect. In addition to this food quality application were carried against carrot and compared with the commercial film. PMID- 25499892 TI - Catalytic synthesis of sulfated polysaccharides I: Characterization of chemical structure. AB - In the present study, sulfated derivatives of Artemisia sphaerocephala polysaccharide (SASP) with high degree of substitution (DS) were synthesized by using 4-dimethylaminopyridine (DMAP)/dimethylcyclohexylcarbodiimide (DCC) as catalyst in homogeneous conditions. It was found that DMAP/DCC showed marked improvement in DS of sulfated samples. Compared to sulfated derivatives without catalyst, the DS of SASP increased from 0.91 to 1.28 with an increment in dosage of DMAP from 0 to 10 mg. The influence of DMAP/DCC on the DS of sulfated derivatives was depended on the content of DMAP. The effect of DMAP might be due to its strong coordination to the hydroxy group. The results of FT-IR and X-ray photoelectron spectroscopy (XPS) indicated that SO3- group (S6+, binding energy of 172.3 eV) was widely present in sulfated polysaccharide molecules. 13C NMR results indicated that C-6 substitution was predominant for sulfated polysaccharide when compared with other positions. In the sulfation reaction, a sharp decrease in MW was observed. DMAP/DCC was an effective catalyst system in sulfated modification of polysaccharide. PMID- 25499893 TI - Antioxidant and anti-inflammatory activities of porphyran isolated from discolored nori (Porphyra yezoensis). AB - We found that discolored waste nori with no commercial value, contains much higher level of porphyran than normal nori that is a sheeted food stuff prepared from P. yezoensis used in sushi. Chemical analyses revealed that mean molecular mass of the porphyran prepared from discolored nori (dc-porphyran) was much lower than that of the porphyran from normal nori (n-porphyran). Dc-porphyran showed slightly greater scavenging activity toward superoxide anion and hydroxyl radical than n-porphyran. Dc-porphyran inhibited nitric oxide (NO) production in LPS stimulated RAW264.7 cells through preventing the expression of inducible NO synthase, whereas no such activity was observed in n-porphyran. Since acid hydrolyzed n-porphyran showed the inhibitory activity on NO production from LPS stimulated RAW264.7 cells, the molecular size of porphyran was suggested to be a critical factor for the activity. Dc-porphyran was separated into 4 fractions (F1 F4) on DEAE-chromatography, and F1 showed the highest inhibitory effect on NO production from LPS-stimulated RAW264.7 cells. Our results indicate that discolored waste nori is useful as a source of porphyran with even better bioactivities than porphyran from normal nori. PMID- 25499894 TI - Response of anaerobic granular sludge to single-wall carbon nanotube exposure. AB - Rapid development and application of nanotechnology have introduced various nanopaticles, such as single-walled carbon nanotubes (SWCNTs), whose negative effects on aquatic organisms and cultured cells have been reported, into anaerobic wastewater treatment systems. In this study, the response of methanogenic sludge exposed to SWCNTs in anaerobic digestion process was investigated. Results show that SWCNTs, at a concentration up to 1000 mg/L, had no significant impact on the maximum methane yield. In contrast, they induced much faster substrate utilization and methane production rates. Scanning electron microscopy examination shows that more extracellular polymeric substances (EPS) were excreted from the anaerobic sludge and closely interacted with SWCNTs. Such an interaction prevented nanoparticles from piercing into cells, and thus reduced their cytotoxicity. In the compact anaerobic granule structure, SWCNTs exposure enhanced the electrical conductance of the sludge, which might promote direct interspecies electron transfer among anaerobic fermentative bacteria and methanogens in the anaerobic digestion process. Our results provide useful information to understand the response of anaerobic microorganisms to CNTs in complex environmental matrix. PMID- 25499895 TI - The effects of CO2 addition along a pH gradient on wastewater microalgal photo physiology, biomass production and nutrient removal. AB - Carbon limitation in domestic wastewater high rate algal ponds is thought to constrain microalgal photo-physiology and productivity, particularly in summer. This paper investigates the effects of CO2 addition along a pH gradient on the performance of wastewater microalgae in high rate algal mesocosms. Performance was measured in terms of light absorption, electron transport rate, photosynthetic efficiency, biomass production and nutrient removal efficiency. Light absorption by the microalgae increased by up to 128% with increasing CO2 supply, while a reduction in the package effect meant that there was less internal self-shading thereby increasing the efficiency of light absorption. CO2 augmentation increased the maximum rate of both electron transport and photosynthesis by up to 256%. This led to increased biomass, with the highest yield occurring at the highest dissolved inorganic carbon/lowest pH combination tested (pH 6.5), with a doubling of chlorophyll-a (Chl-a) biomass while total microalgal biovolume increased by 660% in Micractinium bornhemiense and by 260% in Pediastrum boryanum dominated cultures. Increased microalgal biomass did not off-set the reduction in ammonia volatilisation in the control and overall nutrient removal was lower with CO2 than without. Microalgal nutrient removal efficiency decreased as pH decreased and may have been related to decreased Chl-a per cell. This experiment demonstrated that CO2 augmentation increased microalgal biomass in two distinct communities, however, care must be taken when interpreting results from standard biomass measurements with respect to CO2 augmentation. PMID- 25499896 TI - Autism in Brazil: a systematic review of family challenges and coping strategies. AB - OBJECTIVE: To describe the challenges faced by families caring for children with autism spectrum disorder (ASD) in Brazil and the coping strategies employed. SOURCES: Systematic review of articles published until September of 2013, without language restrictions, using quality appraisal (AMSTAR and CASP/Oxford instruments). SUMMARY OF THE FINDINGS: The literature shows parental emotional overload as one of the main challenges faced by families, especially mothers. The main stressors were diagnostic postponement, difficulty dealing with the diagnosis and associated symptoms, and poor access to health services and social support. The predominant coping strategies found included information exchange between affected families and integrated healthcare network for patient and family support. CONCLUSION: ASD exerts strong influence on family dynamics, resulting in caregiver overload, especially in mothers. The Brazilian Unified Health System needs to provide comprehensive, continuous, and coordinated care to strengthen the patient-family dyad and promote the full development and societal inclusion of children with ASD. PMID- 25499897 TI - Zoothamnium duplicatum infestation of cultured horseshoe crabs (Limulus polyphemus). AB - An outbreak of the sessile peritrich Zoothamnium duplicatum in a pilot, commercial-scale Limulus polyphemus hatchery resulted in the loss of ~96% (40,000) second/third instar larvae over a 61day period. peritrich growth was heavy, leading to mechanical obstruction of the gills and physical damage. The peritrichs were controlled without resultant loss of juvenile crabs by administering 10ppm chlorine in freshwater for 1h and the addition of aquarium grade sand; a medium into which the crabs could burrow and facilitate cleaning of the carapace. Peritrich identity was confirmed from a partial SSU rDNA contiguous sequence of 1343bp (99.7% similarity to Z. duplicatum). PMID- 25499898 TI - Perceptions and experiences of epilepsy among patients from black ethnic groups in South London. AB - OBJECTIVE: The National Institute of Clinical Excellence suggested black ethnic minorities with epilepsy have different cultural, communicative and health-care needs. However, little is known about these despite increasing migration of black African and Caribbean people to Europe. This study aims to explore perceptions and experiences of epilepsy among black African and Caribbean people in South London. METHODS: Semi-structured interviews were undertaken with 11 participants, to examine their beliefs and perceptions of living with epilepsy. Interviews were recorded, transcribed, codes generated and thematic analysis undertaken. RESULTS: African participants described supernatural causes for epilepsy and experienced considerable stigma whereas Caribbean participants described epilepsy as a 'normal illness'. However, both African and Caribbean participants experienced social restrictions arising from their epilepsy. CONCLUSIONS: The findings of higher levels of perceived stigma and social restriction seen in African participants may be a continuation of beliefs reported in participants' country of origin. There is also evidence that views regarding epilepsy transition through generations vary depending on place of birth. Practical Implications Health-care professionals need to be aware of and engage with the particular beliefs and concerns of black African and Caribbean people to achieve equity in health outcomes. PMID- 25499899 TI - Comparative analysis of targeted metabolomics: dominance-based rough set approach versus orthogonal partial least square-discriminant analysis. AB - BACKGROUND: Metabolomics is an emerging field that includes ascertaining a metabolic profile from a combination of small molecules, and which has health applications. Metabolomic methods are currently applied to discover diagnostic biomarkers and to identify pathophysiological pathways involved in pathology. However, metabolomic data are complex and are usually analyzed by statistical methods. Although the methods have been widely described, most have not been either standardized or validated. Data analysis is the foundation of a robust methodology, so new mathematical methods need to be developed to assess and complement current methods. We therefore applied, for the first time, the dominance-based rough set approach (DRSA) to metabolomics data; we also assessed the complementarity of this method with standard statistical methods. Some attributes were transformed in a way allowing us to discover global and local monotonic relationships between condition and decision attributes. We used previously published metabolomics data (18 variables) for amyotrophic lateral sclerosis (ALS) and non-ALS patients. RESULTS: Principal Component Analysis (PCA) and Orthogonal Partial Least Square-Discriminant Analysis (OPLS-DA) allowed satisfactory discrimination (72.7%) between ALS and non-ALS patients. Some discriminant metabolites were identified: acetate, acetone, pyruvate and glutamine. The concentrations of acetate and pyruvate were also identified by univariate analysis as significantly different between ALS and non-ALS patients. DRSA correctly classified 68.7% of the cases and established rules involving some of the metabolites highlighted by OPLS-DA (acetate and acetone). Some rules identified potential biomarkers not revealed by OPLS-DA (beta-hydroxybutyrate). We also found a large number of common discriminating metabolites after Bayesian confirmation measures, particularly acetate, pyruvate, acetone and ascorbate, consistent with the pathophysiological pathways involved in ALS. CONCLUSION: DRSA provides a complementary method for improving the predictive performance of the multivariate data analysis usually used in metabolomics. This method could help in the identification of metabolites involved in disease pathogenesis. Interestingly, these different strategies mostly identified the same metabolites as being discriminant. The selection of strong decision rules with high value of Bayesian confirmation provides useful information about relevant condition decision relationships not otherwise revealed in metabolomics data. PMID- 25499900 TI - [Epidemiological and clinical characteristics of anogenital dermatoses in the department of dermatology-venereology in Cotonou, Benin]. AB - OBJECTIVE: The aim of this study was to document the epidemiological and clinical characteristics of anogenital dermatoses (AGDs) in Cotonou, Benin. METHOD: This retrospective, descriptive study, conducted in the Department of Dermatology Venereology at the National University Hospital of Cotonou, examined medical records of admissions and outpatient consultations for the 5-year period 2005 2009 and included the records of all patients with a clinical diagnosis of AGD. RESULTS: The prevalence of AGD in our series was 2.6% and the prevalence of sexually transmitted AGDs (STIs) was 1.3%. The sex ratio (M:F) was 2.5, and the patients' average age was 31.1 years. AGDs were classified as infectious (77%), inflammatory (12.6%), non-infectious tumors (3.7%), physiological (2.1%), psychodermatoses (2.1%), non-infectious ulcers (1.6%), and dyschromia (1%). STIs accounted for 44% of the AGDs: condyloma (65.5%), genital herpes (19%), urethritis (8.3%), and chancroids (4.8%). The primary sites in men were the foreskin, the groin, the scrotum, and the glans, and in women, the labia majora, the groin, the labia minora, and the anal cleft. CONCLUSION: AGDs were relatively rare in hospital consultations in Cotonou. They were mainly infectious (viral or fungal), and nearly half were STIs. PMID- 25499901 TI - Continuous tissue glucose monitoring correlates with measurement of intermittent capillary glucose in patients with distributive shock. AB - BACKGROUND: Intermittent glycemic measurements in patients admitted to the intensive care unit (ICU) can result in episodes of severe hypoglycemia or in a poor control of glycemia range. We designed a study to assess accuracy and reliability of continuous monitoring of tissue glucose for patients with distributive shock. METHODS: Consecutive patients admitted to the ICU with a diagnosis of distributive shock and the need of insulin infusion for glycemic control were included in the study. These patients were implanted a Continuous Glucose Control Monitoring System (CGMS) with the sensor inserted subcutaneously into the abdominal wall. CGMS values were recorded every 5min. Capillary glucose (CG) was monitored for adjusting insulin perfusion according to the ICU protocol. Correlation between both methods was assessed. RESULTS: A total of 11,673 CGMS and 348 CG values were recorded. In five patients, CGMS failed to detect tissue glucose. A glucose value <3.33mmol/l (<60mg/dl) was observed in 3.6% of CGMS and in 0.29% CG values. 295 pairs of measurements were included in the statistical analysis for correlation assessment. The intraclass correlation coefficient was 0.706. The Pearson correlation coefficient was 0.71 (p<0.0001, 95% CI 0.65-0.76). The mean of differences between both measurement methods was 0.22mmol/l (3.98mg/dl) (95% CI 0.66-7.31). CONCLUSIONS: When the Continuous Glucose Control Monitoring System (CGMS) is able to obtain data (75% of the patients), there is correlation between the values obtained by this method and capillary blood glucose in patients with distributive shock. CGMS can detect more episodes of glycemic excursions outside the normal range than intermittent capillary glucose monitoring. Variables that may impair glucose metabolism and peripheral soft tissues perfusion could impair CGMS measurements. PMID- 25499902 TI - [Fulminant myocarditis associated to influenza A]. PMID- 25499903 TI - [Neurogenic pulmonary edema and cardiogenic shock secondary to acute multiple sclerosis exacerbation]. PMID- 25499904 TI - [Epidemiological characteristics of out-of-hospital cardiorespiratory arrest recorded by the 061 emergencies system (SAMU) in the Balearic Islands (Spain), 2009-2012]. AB - OBJECTIVE: To describe the epidemiology of out-of-hospital cardiorespiratory arrest (OHCA) and identify factors associated with recovery of spontaneous circulation (ROSC). DESIGN: Observational study of OHCA registered on a continuous basis in the Emergency Medical Services (EMS) database during 2009 2012. SETTING: The islands of Mallorca, Ibiza, Menorca and Formentera (Balearic Islands, Spain). PATIENTS: OHCA in patients >= 18 years of age. The main variables were: Patient sex, age, probable cause, place of arrest, bystander, witnessed, basic life support (BLS), shockable rhythm, intervention time, semi automatic defibrillator (AED), duration of cardiopulmonary arrest (CA), and ROSC. Independent variables were defined according to the Utstein protocol, and the dependent variable was defined as ROSC. RESULTS: The EMS treated 1170 OHCAs (28/100,000 persons-year). We included 1130 CA. The mean age was 61.4 years (73.4% males). Most CA (72.3%) were of cardiac etiology, and 84.7% were witnessed. A total of 840 (74.3%) received BLS and 400 (47.6%) did so before arrival of the EMS (45 by bystander relatives). AED was available in 330 cases CA (29.2%) (96 with shockable rhythm). The interval between emergency call and BLS and between emergency call and advanced life support was 8.4 and 15.8min, respectively. Shockable rhythm was monitored in 257 CAs (22.7%). ROSC occurred in 261 (23.1%). Factors associated with ROSC were age, shockable rhythm, BLS before EMS arrival, and CA duration less than 30min. CONCLUSION: The incidence rate of the OHCA is low. The proportion of patients receiving BLS from relatives was low. Age, shockable rhythm and BSL before EMS arrival were associated with ROSC. PMID- 25499905 TI - [Acute spinal cord injury after severe electrical trauma]. PMID- 25499908 TI - Concomitant diabetes mellitus and heart failure. AB - The prevalence of patients with concomitant diabetes mellitus (DM) and heart failure (HF) is growing exponentially. Patients with HF and DM show specific metabolic, neurohormonal, and structural heart abnormalities, which potentially contribute to worse HF outcomes than seen in patients without comorbid DM. Subgroup analysis of recent trials suggest that patients with HF and DM may respond differently to standard therapy, and data are emerging on the possible increase in the risk of hospitalizations for HF in patients with DM treated with specific class of antidiabetic agents, pointing to the need of developing specific medications to be tested in dedicated future studies to address the unique metabolic and hemodynamic alterations seen in these patients. PMID- 25499909 TI - [Obesity in Oviedo: Prevalence and time trends from 1992 to 2012]. PMID- 25499910 TI - [Advances and challenges in the fight against childhood cancer]. PMID- 25499911 TI - [Intravenous lidocaine for post-mastectomy pain treatment: randomized, blind, placebo controlled clinical trial]. AB - BACKGROUND AND OBJECTIVE: Postoperative pain treatment in mastectomy remains a major challenge despite the multimodal approach. The aim of this study was to investigate the analgesic effect of intravenous lidocaine in patients undergoing mastectomy, as well as the postoperative consumption of opioids. METHODS: After approval by the Human Research Ethics Committee of the Instituto de Medicina Integral Prof. Fernando Figueira in Recife, Pernambuco, a randomized, blind, controlled trial was conducted with intravenous lidocaine at a dose of 3 mg/kg infused over one hour in 45 women undergoing mastectomy under general anesthesia. One patient from placebo group was RESULTS: Groups were similar in age, body mass index, type of surgery, and postoperative need for opioids. Two of 22 patients in lidocaine group and three of 22 patients in placebo group requested opioid (p=0.50). Pain on awakening was identified in 4/22 of lidocaine group and 5/22 of placebo group (p=0.50); in the post-anesthetic recovery room in 14/22 and 12/22 (p=0.37) of lidocaine and placebo groups, respectively. Pain evaluation 24hours after surgery showed that 2/22 and 3/22 patients (p=0.50) of lidocaine and placebo groups, respectively, complained of pain. CONCLUSION: Intravenous lidocaine at a dose of 3 mg/kg administered over a period of an hour during mastectomy did not promote additional analgesia compared to placebo in the first 24hours, and has not decreased opioid consumption. However, a beneficial effect of intravenous lidocaine in selected and/or other therapeutic regimens patients can not be ruled out. PMID- 25499912 TI - Which kind of frontal mandibulotomy is the smartest? A biomechanical study. AB - PURPOSE: Retrospective clinical evaluation and biomechanical tests were performed to compare the primary stability and the rate of pseudarthrosis formation after irradiation for two types of mandibular split osteotomies: the stairstep osteotomy (SSO) and the straight-line osteotomy (SLO). METHODS: The postoperative occurrence of pseudarthrosis was retrospectively analysed in 46 non-consecutive clinical cases of SSO and SLO between 2003 and 2013. Biomechanical tests were performed on 12 standardised synthetic mandibles (Synbone) to compare the SSO and SLO approaches. Two 2.0 mm monocortical miniplates (Medartis) were used for osteosynthesis. The artificial mandible specimens were loaded to 300 N on the Mandibulator test bench while interfragmentary motion was measured using the PONTOS optical measurement device. RESULTS: The retrospective clinical analysis showed a rate of pseudarthrosis of 19% in the SLO group versus only 5% in the SSO group (p = 0.17). In the biomechanical investigation, the average interfragmentary movement was 14.3 +/- 7.70 for the SLO group and 4.57 +/- 2.33 for the SSO group under a maximum load of 300 N, resulting in a statistically significant difference between the two approaches (p = 0.014). CONCLUSION: To minimise the rate of postoperative pseudarthrosis formation, SSO is superior to SLO for mandibular split procedures, because SSO provides greater resistance to vertical loads and allows less interfragmentary movement. LEVEL OF EVIDENCE: 2C (Outcomes research). PMID- 25499913 TI - AMBRA1 interplay with cullin E3 ubiquitin ligases regulates autophagy dynamics. AB - Autophagy maintains cellular homeostasis by degrading harmful or unnecessary intracellular components. How the autophagy response is induced rapidly and transiently remains largely unknown. We report that the E3 ubiquitin ligases Cullin-5 and Cullin-4 regulate the onset and termination of autophagy, respectively, by dynamically interacting with AMBRA1, a regulator of autophagy. Under normal conditions, Cullin-4 binding to AMBRA1 limits its protein abundance. Autophagy stimuli promote AMBRA1 stabilization by causing ULK1-dependent Cullin-4 release. Notably, Cullin-4/AMBRA1 dissociation is transient, and the re established interaction triggers AMBRA1 degradation, terminating the autophagy response. Moreover, Cullin-4 inhibits the interaction between AMBRA1 and another Cullin E3 ligase. Indeed, upon Cullin-4 dissociation, AMBRA1 binds and inhibits Cullin-5, thus promoting the accumulation of the mTOR inhibitor DEPTOR. Through DEPTOR stabilization, AMBRA1 establishes a feedback loop that ensures the rapid onset of autophagy by enhancing mTOR inactivation. Our findings show that Cullin mediated degradation of autophagy regulators temporally controls the autophagy response. PMID- 25499915 TI - Does participation in a physical activity program impact upon the feet of overweight and obese children? AB - OBJECTIVES: To investigate the effect of a weight-bearing physical activity program on foot structure and plantar pressures generated by overweight/obese children. DESIGN: Descriptive study. METHODS: Measurements were collected for a sample of children participating in an obesity treatment trial (mean+/-SD 8.5+/ 1.1 y, 29.4% boys, 2.63+/-0.61 body mass index z-score). Children were randomised to physical activity (physical activity; n=24) and no physical activity (no physical activity; n=10) groups. Foot structure was characterised using anthropometry, an emed((r)) AT-4 system quantified pressure distributions and Actigraph accelerometers objectively measured physical activity. RESULTS: After 6 months there was a significant decrease in body mass index z-score (physical activity: p=0.002, no physical activity: p<0.001), an increase in foot length (physical activity: p<0.001, no physical activity: p<0.001) and foot height (physical activity: p<0.001, no physical activity: p=0.008), although no change in physical activity. Pressure-time integrals increased after 6 months (lateral midfoot; physical activity: p=0.036, medial forefoot; physical activity: p=0.002, no physical activity: p=0.013, middle forefoot; physical activity: p=0.044, lateral forefoot; physical activity: p=0.043) but there were no between-group differences in plantar pressures after the physical activity program. CONCLUSIONS: Although changes to foot structure and function in overweight/obese children could not be attributed to participating in the physical activity program, their developing feet may still be at risk of pain and discomfort due to higher plantar pressures and pressure-time integrals. Further research investigating ways to reduce plantar pressures generated by overweight/obese children while they are physically active is warranted. PMID- 25499914 TI - An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. AB - Cellular senescence suppresses cancer by halting the growth of premalignant cells, yet the accumulation of senescent cells is thought to drive age-related pathology through a senescence-associated secretory phenotype (SASP), the function of which is unclear. To understand the physiological role(s) of the complex senescent phenotype, we generated a mouse model in which senescent cells can be visualized and eliminated in living animals. We show that senescent fibroblasts and endothelial cells appear very early in response to a cutaneous wound, where they accelerate wound closure by inducing myofibroblast differentiation through the secretion of platelet-derived growth factor AA (PDGF AA). In two mouse models, topical treatment of senescence-free wounds with recombinant PDGF-AA rescued the delayed wound closure and lack of myofibroblast differentiation. These findings define a beneficial role for the SASP in tissue repair and help to explain why the SASP evolved. PMID- 25499917 TI - Polyethylene glycol (PEG)-dendron phospholipids as innovative constructs for the preparation of super stealth liposomes for anticancer therapy. AB - Pegylation of nanoparticles has been widely implemented in the field of drug delivery to prevent macrophage clearance and increase drug accumulation at a target site. However, the shielding effect of polyethylene glycol (PEG) is usually incomplete and transient, due to loss of nanoparticle integrity upon systemic injection. Here, we have synthesized unique PEG-dendron-phospholipid constructs that form super stealth liposomes (SSLs). A beta-glutamic acid dendron anchor was used to attach a PEG chain to several distearoyl phosphoethanolamine lipids, thereby differing from conventional stealth liposomes where a PEG chain is attached to a single phospholipid. This composition was shown to increase liposomal stability, prolong the circulation half-life, improve the biodistribution profile and enhance the anticancer potency of a drug payload (doxorubicin hydrochloride). PMID- 25499918 TI - A novel antitumour strategy using bidirectional autophagic vesicles accumulation via initiative induction and the terminal restraint of autophagic flux. AB - Autophagy is a lysosomal degradation pathway that protects cancer cells from multiple endogenous and extraneous stresses, particularly during the pathogenesis of cancer. An autophagic balance exists in the tumour microenvironment. Appropriate disturbance to this balance may have therapeutic potential. Here, we report a novel antitumour strategy based on an autophagic catastrophic vacuolisation effect in tumour cells. We achieved this effect via initiative induction and the terminal restraint of autophagic flux. The TAT-Beclin 1 peptide (T-B) was constructed for the initiative induction of autophagic flux, whereas hydroxychloroquine (HCQ)-loaded liposomes (HCQ-Lip) were constructed for terminal restraint. We demonstrate that T-B, a new CPP tandem autophagy inducing peptide, effectively activates the autophagy signal at the early stage of the autophagy pathway. HCQ deacidified the lysosome during the final stage of autophagy. We combined T-B and HCQ-Lip to induce autophagic catastrophic vacuolisation and death in several tumour cell lines based on the idea of "broadening sources of income and reducing expenditure". The co-treated group exhibited at least a 1.86 fold greater and up to 5.66-fold greater cytotoxic effect in vitro. In addition, this strategy showed at least a 2.0-fold tumour inhibitory effect compared to the other groups in vivo. Therefore, this bidirectional accumulation of autophagic vesicles exhibited potential efficacy for tumour treatment. PMID- 25499919 TI - Peptides as skin penetration enhancers: mechanisms of action. AB - Skin penetrating peptides (SPPs) have garnered wide attention in recent years and emerged as a simple and effective noninvasive strategy for macromolecule delivery into the skin. Although SPPs have demonstrated their potential in enhancing skin delivery, they are still evolving as a new class of skin penetration enhancers. Detailed studies elucidating their mechanisms of action are still lacking. Using five SPPs (SPACE peptide, TD-1, polyarginine, a dermis-localizing peptide and a skin penetrating linear peptide) and a model hydrophobic macromolecule (Cyclosporine A, CsA), herein we provide a mechanistic understanding of SPPs. To evaluate the mechanism and safety of SPPs, their effects on skin lipids, proteins and keratinocyte cells were evaluated. Three SPPs (SPACE, Polyarginine and TD-1) significantly enhanced CsA penetration into the skin. SPPs did not alter the skin lipid barrier as measured by skin resistance, transepidermal water loss (TEWL) and Fourier transform infrared (FTIR) spectroscopic analysis. In contrast, SPPs interacted with skin proteins and induced changes in skin protein secondary structures (alpha-helices, beta-sheet, random coils and turns), as evaluated by FTIR analysis and confirmed by in-silico docking. SPPs enhanced CsA skin penetration, via a transcellular pathway, enhancing its partitioning into keratin rich corneocytes through concurrent binding of SPP with keratin and CsA. Interaction between SPP and keratin best correlated with measured CsA skin transport. Many SPPs appeared to be safe as shown by negligible effect on skin integrity, nominal skin irritation potential and cytotoxicity. Among the peptides tested, SPACE peptide was found to be least toxic to keratinocytes, and among the most effective at delivering CsA into the skin. PMID- 25499920 TI - A comprehensive analysis of treatment outcomes in patients with pemphigus vulgaris treated with rituximab. AB - Approximately 500 treatment recalcitrant pemphigus vulgaris patients have been treated with rituximab. They were treated according to the lymphoma protocol (N=224) or rheumatoid arthritis protocol (RAP) (N=209) patients. Others were treated with modifications or combinations of the two. The mean duration of follow-up with the lymphoma protocol was 28.9months and 21.9 in the rheumatoid arthritis protocol. The majority of the patients received corticosteroids and immunosuppressive therapy before, during, and after rituximab therapy. A clinical remission on therapy was observed in 90%-95% of patients within less than six weeks. A complete resolution occurred within three to four months. A small percentage of patients were able to stay in clinical remission without the need for additional systemic therapy. The incidence of relapse was at least 50%. The number of patients who required additional rituximab was 60% to 90%. A majority of patients in clinical remission post-rituximab therapy, were still on CS and ISA, albeit at lower doses. Serious adverse events were reported in a mean of five patients (range 2-9), the most important was infection and frequently resulting in septicemia. The mortality rate related to rituximab was a mean of 2 patients (range 1-3). Hence, the preliminary conclusions that can be drawn are that rituximab is an excellent agent to induce early remission. The protocols that were used were not ideal for producing a prolonged and sustained remission without additional therapy. The advantages and specificity of targeting B-cells demonstrate that rituximab is one of the best biological agents, currently available for treating recalcitrant pemphigus. Its further use is encouraged. Future research needs to focus on modifying, improving and possibly adding additional agents, so that prolonged and sustained remissions can be obtained by its use. PMID- 25499921 TI - Galectin-8 predicts postoperative recurrence of patients with localized T1 clear cell renal cell carcinoma. AB - BACKGROUND: Galectin-8 (Gal-8), belonging to a family of the "tandem repeat"-type galectins that contain 2 carbohydrate recognition domains, serves to retain cell surface residency and signaling of glycoproteins including cytokine and growth factor receptors, and thereby promoting development and progression of various malignancies. This study aims to evaluate the effect of Gal-8 expression on postoperative recurrence of patients with localized pathologic T1 (pT1) clear cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: In this retrospective study, we enrolled 244 patients (122 in group A and 122 in group B) with localized pT1 ccRCC undergoing nephrectomy at a single institution. Specimens from patients were collected from January 2003 to December 2008. Median follow-up was 71 months (range: 12-120 mo) in group A and 70 months (range: 12-119 mo) in group B. Overall, 14 patients experienced recurrence in group A (n = 122) and 22 patients had recurrence in group B (n = 122). Gal-8 expression was assessed by immunohistochemistry in clinical specimens. Kaplan-Meier method with log-rank test was performed to compare survival curves. Cox regression models were used to evaluate the prognostic values of variables on recurrence-free survival. Concordance index was calculated to assess prognostic accuracy. RESULTS: In both groups, patients with high expression of Gal-8 were significantly inclined to have high rates of necrosis. High Gal-8 expression indicated early recurrence of patients with localized pT1 ccRCC. Gal-8 expression was determined to be an independent adverse prognostic indicator for recurrence. The accuracy of The Mayo Clinic Stage, Size, Grade, and Necrosis score and University of Los Angeles Integrated Staging System prognostic models was improved when Gal-8 expression was added. CONCLUSIONS: Gal-8 expression is a potential independent unfavorable prognostic indicator for postoperative recurrence of patients with localized pT1 ccRCC. PMID- 25499922 TI - MK2206 potentiates cisplatin-induced cytotoxicity and apoptosis through an interaction of inactivated Akt signaling pathway. AB - OBJECTIVES: To improve conventional chemotherapeutic efficacy, it is important to detect new molecular markers for chemosensitivity and possible accelerating cell killing mechanisms. In this study, we investigated how MK2206, an allosteric Akt inhibitor, enhances the cisplatin (CDDP)-induced cytotoxicity and apoptosis in urothelial cancer cells. MATERIALS AND METHODS: We examined bladder cancer cell lines for the expression of phospho(p)-Akt and its downstream targets by Western blot. The potential antitumor effects were analyzed by MTT assay in vitro and by subcutaneous xenograft models in vivo. The cell invasion was examined by transwell invasion assay, and the activities of the Akt signaling pathway and expression of apoptosis-related proteins were measured by Western blot. RESULTS: The expression of p-Akt and its downstream targets was increased in invasive bladder cancer cell lines vs. in noninvasive bladder cancer cell lines. MK2206 (500 nM) inhibited cell invasion in UMUC3 cell line and significantly increased the susceptibility of bladder cancer cell lines to CDDP. When used in combination with CDDP, MK2206 (500 nM) enhanced CDDP-induced cytotoxicity and apoptosis, with suppressed expression of p-Akt and its downstream targets. In vivo MK2206 combined with CDDP effectively suppressed tumor growth in subcutaneous xenograft models. CONCLUSIONS: These results suggest that concomitant use of MK2206 could promote the CDDP-induced cytotoxicity and apoptosis in urothelial cancer cell lines through the inhibited expression of the Akt pathway. This combined treatment may provide a new therapeutic option to enhance chemosensitivity in bladder cancer. PMID- 25499924 TI - Early signs show that 2014-15 flu season may be severe, CDC warns. PMID- 25499923 TI - TLR4- and TLR9-dependent effects on cytokines, cell viability, and invasion in human bladder cancer cells. AB - OBJECTIVES: Adjuvant immunotherapy of bladder cancer by instillation of bacillus Calmette-Guerin (BCG) is highly recommended within certain groups of non-muscle invasive stages but only partially effective. Toll-like receptors (TLRs) TLR4 and TLR9 likely mediate BCG effects by triggering innate systemic immune cell responses. In addition, TLR4 and TLR9 expressed in bladder cancer cells may contribute to the outcome of BCG treatment. Here, we studied the expression and function of TLR4 and TLR9 in human bladder cancer cell lines. METHODS: TLR4 and TLR9 messenger RNA and protein levels were determined by real-time reverse transcription polymerase chain reaction and Western blot. Selected cell lines were analyzed with respect to cytokine induction, proliferation, and cell invasion after addition of BCG, TLR4-specific agonist lipopolysaccharide (LPS), or TLR9 agonist (CpG-oligodeoxynucleotide [ODN]). RESULTS: TLR4 and TLR9 were expressed quite heterogeneously in human bladder cancer cells. BCG caused induction of interleukin (IL)-6 or IL-8 in BFTC905 and T24 cells as representatives for TLR4-/TLR9-expressing cells. The study aimed to dissect TLR4- and TLR9-mediated effects. For functional analysis of TLR4 with LPS, we selected T24 and BFTC905 cells with high and undetectable TLR4 levels, respectively. For TLR9 analysis with CpG-ODN, we selected UMUC3 and RT112 cells with high and low TLR9 levels, respectively. Addition of LPS caused significant induction of TNFalpha and IL-6 messenger RNA in T24 cells but not in BFTC905 cells. Addition of CpG-ODN induced interferon beta (INFbeta), IL-8, tumor necrosis factor alpha (TNFalpha) and the angiogenic factors vascular endothelial growth factor-A and placental growth factor in UMUC3 cells; whereas in RT112 cells, induction of IL-8 and TNFalpha was noticed. Interestingly, addition of CpG-ODN significantly reduced cell viability and increased cell invasion in UMUC3 and RT112 cells. CONCLUSIONS: Our findings demonstrate that bladder cancer cell lines express functional TLR4 and TLR9 with possible effects on cancer progression and outcome of BCG-based immunotherapy. PMID- 25499925 TI - Long-term outcome of sirolimus-eluting and zotarolimus-eluting coronary stent implantation in patients with and without diabetes mellitus (a Danish organization for randomized trials on clinical outcome III substudy). AB - We compared 5-year clinical outcomes in diabetic and nondiabetic patients treated with Endeavor zotarolimus-eluting stents (ZESs; Endeavor Sprint, Medtronic, Santa Rosa, California) or Cypher sirolimus-eluting stents (SESs; Cordis, Johnson & Johnson, Warren, New Jersey) coronary implantation. We randomized 2,332 patients to either ZESs (n = 1,162, n = 169 diabetic patients) or SESs (n = 1,170, n = 168 diabetic patients) stratified according to presence or absence of diabetes mellitus. End points included major adverse cardiac event (MACE), a composite of cardiac death, myocardial infarction, target vessel revascularization (TVR), and definite stent thrombosis. Among diabetic patients, MACE occurred more frequently in patients treated with ZESs than SESs (48 [28.4%] vs 31 [18.5%]; odds ratio [OR] 1.75, 95% confidence interval [CI] 1.05 to 2.93, p = 0.032) because of a higher rate of TVR (32 [18.9%] vs 14 [8.3%]; OR 2.57, 95% CI 1.32 to 5.02, p = 0.006). Among nondiabetic patients, ZES and SES had similar MACE rates at 5-year follow-up but SES was associated with a significantly higher risk of definite stent thrombosis (10 [1.0%] vs 23 [2.3%]; OR 0.43, 95% CI 0.20 to 0.91, p = 0.028). Moreover, during the last 4 years, ZES had fewer MACE, TVR, and stent thrombosis events among nondiabetic patients. In conclusion, SES remains superior to ZES in patients with diabetes throughout the 5-year follow-up, however, among nondiabetic patients, SES demonstrated a highly dynamic performance with favorable initial results followed by a late catch-up that included an overall higher risk of stent thrombosis. PMID- 25499926 TI - Relation of metabolic syndrome with long-term mortality in acute and stable coronary disease. AB - Past studies examining the effects of the metabolic syndrome (MS) on prognosis in postangiography patients were limited in size or were controversial in results. The aim of the study was to examine the association of the MS and the risk for long-term mortality in a large cohort of patients undergoing coronary angiography for various clinical indications. Medical history, physical examination, and laboratory values were used to diagnose patients with the MS. Cox regression models were used to analyze the effect of MS on long-term all-cause mortality. We prospectively recruited 3,525 consecutive patients with a mean age of 66 +/- 22 years (range 24 to 97) and 72% men. Thirty percent of the cohort had MS. Patients with MS were more likely to have advanced coronary artery disease and acute coronary syndrome (p <0.001). Patients with MS had more abnormalities in their metabolic and inflammatory biomarkers regardless of their clinical presentation. A total of 495 deaths occurred during a mean follow-up period of 1,614 +/- 709 days (median 1,780, interquartile range 1,030 to 2,178). MS was associated with an increased risk of death in the general cohort (hazard ratio [HR] 1.27, 95% confidence interval [CI] 1.01 to 1.56, p = 0.02). MS had a significant effect on mortality in stable patients (HR 1.55, 95% CI 1.1 to 2.18, p = 0.01), whereas it did not have a significant effect on mortality in patients with acute coronary syndrome (HR 1.11, 95% CI 0.86 to 1.44, p = 0.42). In conclusion, MS is associated with increased mortality in postangiography patients. Its adverse outcome is mainly seen in patients with stable angina. PMID- 25499927 TI - Opportunities and challenges in Improving Access to Psychological Therapies for people with Severe Mental Illness (IAPT-SMI): evaluating the first operational year of the South London and Maudsley (SLaM) demonstration site for psychosis. AB - Despite its demonstrated clinical and economic effectiveness, access to Cognitive Behavioural Therapy for psychosis (CBTp) in routine practice remains low. The UK National Health Service (NHS England) Improving Access to Psychological Therapies for people with Severe Mental Illness (IAPT-SMI) initiative aims to address this problem. We report 14-month outcomes for our psychosis demonstration site. Primary and secondary care and self-referrals were screened to check the suitability of the service for the person. Psychotic symptoms, distress, service use, functioning and satisfaction were measured before and after therapy, by trained assessors. User-defined wellbeing and goal-attainment were rated sessionally. Access to CBTp increased almost threefold (2011/12 accepted referrals/year n = 106; 2012/13, n = 300). The IAPT-SMI assessment protocol proved feasible and acceptable to service users, with paired primary outcomes for 97% of closed cases. Therapy completion (>=5 sessions) was high (83%) irrespective of ethnicity, age and gender. Preliminary pre-post outcomes showed clinical improvement and reduced service use, with medium/high effect sizes. User rated satisfaction was high. We conclude that individual psychological interventions for people with psychosis can be successfully delivered in routine services using an IAPT approach. High completion rates for paired outcomes demonstrate good user experience, clinical improvement, and potential future cost savings. PMID- 25499928 TI - New antitumor 6-chloropurine nucleosides inducing apoptosis and G2/M cell cycle arrest. AB - Treating cancer has been challenging for decades, following countless approaches and attempts. Nucleosides, alone or as part of nucleotides, are vital elements of living systems and have shown pharmacological effects, e.g. as antibiotic or antiviral agents. We investigated the antitumor potential on human melanoma, lung and ovarian carcinomas, and on colon adenocarcinoma of a new series of purine nucleosides based on a 6-chloropurine or a 2-acetamido-6-chloropurine scaffold linked to perbenzylated hexosyl (glucosyl, galactosyl and mannosyl) residues. All compounds were tested in a sulforhodamine B (SRB) assay for their cytotoxicity and provided micromolar GI50 values with order of magnitude comparable to structurally similar chemotherapeutics, namely 2-chloro-2'-deoxyadenosine (cladribine). Furthermore, the induction of apoptosis was established and cell cycle analysis was accomplished demonstrating a G2/M cell cycle arrest. PMID- 25499929 TI - Synthesis and structure-activity relationships of pyridinyl-1H-1,2,3 triazolyldihydroisoxazoles as potent inhibitors of tubulin polymerization. AB - Three series of compounds; pyridinyl-1H-1,2,3-triazoles, pyridinyl-1H-1,2,3 triazolylisoxazoles and pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles with TMP moiety were designed, synthesized and screened for their anti-cancer and anti tubulin properties. By sequentially designing three series of compounds comprising of dihydroisoxazole in the linker, a small substituent like chlorine on one side (R(1)) and aromatic group (R) on the pyridine ring, we have optimized the anti-cancer as well as anti-tubulin activity. Pyridinyl-1H-1,2,3 triazolyldihydroisoxazoles 28b and 28c were found to be potent anti-cancer agents against all the cell lines tested with a concomitant accumulation of cells in the G2/M phase of the cell cycle. Molecular modeling suggests that the trimethoxyphenyl ring in 28b and 28c occupies the cholchicine binding domain of beta-tubulin, whereas, the dihydroisoxazole extends towards the interface of alpha,beta-tubulin. PMID- 25499930 TI - Synthesis, anticancer activity and effects on cell cycle profile and apoptosis of novel thieno[2,3-d]pyrimidine and thieno[3,2-e] triazolo[4,3-c]pyrimidine derivatives. AB - Motivated by the widely reported anticancer activity of thieno[2,3-d]pyrimidines a series of 24 new 2-substitutedhexahydrocycloocta[4,5] thieno[2,3-d]pyrimidines with different substituents at C-4 position and hexahydrocycloocta[4,5]thieno[3,2 e]-1,2,4-triazolo[4,3-c]pyrimidines were synthesized. The anticancer activity of 17 compounds were evaluated by National Cancer Institute (USA) using a two stage process utilizing 59 different human tumor cell lines representing leukemia, melanoma, cancers of lung, colon, central nervous system (CNS), ovary, kidney, prostate as well as breast. Compound 9c showed broad spectrum potent anticancer activity in nano molar to micro molar range against 56 human tumor cell lines with GI50 less than 10 MUM ranging from 0.495 to 5.57 MUM, also it is worth mentioning that compound 9c had the marked highest selectivity against the two cell lines T-47D and MDA-MB-468 belonging to breast cancer with GI50 = 0.495 and 0.568 MUM respectively, and its effect was further studied on cell cycle progression and induction of apoptosis in the MDA-MB-468 cell line. Results showed that compound 9c induced cell cycle arrest at G2/M phase and also, showed accumulation of cells in pre-G1 phase which may result from, degradation or fragmentation of the genetic materials indicating a possible role of apoptosis in compound 9c-induced cancer cell death and cytotoxicity and verifying this compound as promising selective anticancer lead. Compound 6c was selective against K-562, SR and MOLT-4 cell lines belonging to leukemia showing growth inhibition percentages 86.38, 65.76 and 60.40 at a single dose test, at the same time it showed lethal activity against HOP-92 representing non-small cell lung cancer. Interestingly, leukemia SR, CNS cancer SNB-75 and renal cancer UO-31 cell lines proved to be sensitive to compound 6d with growth inhibition percentages 52.86, 50.94 and 53.99 respectively. Additionally, compound 6d demonstrated lethal activity to HOP-92 belonging non-small cell lung cancer. PMID- 25499931 TI - 'Erratum to "Comparing predictive drug nephrotoxicity biomarkers in kidney 3-D primary organoid culture and immortalized cell lines" [Biomaterials 33 (2012) 4712-4721]'. PMID- 25499932 TI - 'Erratum to "Micro-patterned cell-sheets fabricated with stamping-force controlled micro-contact printing" [Biomaterials 35 (2014) 9802-10]'. PMID- 25499933 TI - From the editor: drugs, genes, and lipoproteins. PMID- 25499934 TI - JCL roundtable: lipid-lowering drugs in those older than 75 years of age. AB - Using drugs in the elderly requires some special considerations; however, there is no question that our older patients benefit tremendously from the use of agents that prevent and/or control many of the risk factors for vascular disease that are most prevalent in the latter years of life. Recently, the American College of Cardiology and the American Heart Association issued guidelines for the management of blood cholesterol elevations. For the first time, little specific guidance was given for the age group older than 75 years of age. The rationale given for this approach was primarily that the data from randomized trials comparing drug therapy to treatment with placebos were inadequate for such recommendations. There was also concern regarding safety in this group. This Roundtable will consider this lack of recommendations in a broader context than statin trials. PMID- 25499935 TI - The doctor's dilemma: challenges in the diagnosis and care of homozygous familial hypercholesterolemia. PMID- 25499936 TI - Lipoprotein(a) mass: a massively misunderstood metric. AB - The importance of lipoprotein (a)-Lp(a)-as a cardiovascular (CV) risk marker has been underscored by recent findings that CV risk is directly related to baseline Lp(a) levels, even in well-treated patients. Although there is currently little that can be done pharmacologically to lower Lp(a) levels, knowledge of its serum concentration is important in overall risk assessment. This review focuses on 1 aspect of Lp(a) that is rarely discussed directly: how to express its levels in serum. There is considerable confusion on this point, and a fuller understanding of what the concentration units mean will help improve study-to-study comparisons and thereby advance our understanding of the pathobiology of this lipoprotein particle. As discussed here, the term Lp(a) mass refers to the entire mass of the particle: lipids, proteins, and carbohydrates combined. At present, there are no commercially available assays that are completely insensitive to the variability in particle mass, which arises not only from differences in apo(a) isoform mass but also from variations in lipid mass. Because lipoprotein "particle number" (molar concentration) has been found to be superior to component-based metrics (ie, low-density lipoprotein particle vs cholesterol concentrations) for CV disease risk prediction, the development of a mass-insensitive Lp(a) assay should be a high priority. PMID- 25499937 TI - Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. AB - BACKGROUND: Statin intolerance has been a major limitation in the use of statins, especially at higher doses. New effective treatments are needed for lowering low density lipoprotein cholesterol (LDL-C) in patients who cannot tolerate daily statin doses. OBJECTIVE: ODYSSEY ALTERNATIVE (NCT01709513) evaluates efficacy and safety of alirocumab, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody, in patients with well-documented statin intolerance and moderate to very high cardiovascular risk. METHODS: This is a phase 3, multicenter, randomized, double-blind, double-dummy study in statin-intolerant patients. Intolerance was defined as inability to take at least 2 different statins because of muscle-related adverse events (AEs), 1 at the lowest approved starting dose. Patients first received single-blind subcutaneous and oral placebo for 4 weeks, and were withdrawn if they developed muscle-related AEs after the placebo treatment. Continuing patients were randomized (2:2:1 ratio) to alirocumab 75 mg self-administered via single 1 mL prefilled pen every 2 weeks or ezetimibe 10 mg/day or atorvastatin 20 mg/day (statin rechallenge), for 24 weeks. Alirocumab dose was increased to 150 mg every 2 weeks (also 1 mL) at week 12 depending on week 8 LDL-C level. The primary endpoint is percent change in LDL-C from baseline to week 24 by intent-to-treat analysis. Muscle-related AEs were assessed by spontaneous patient reports and clinic queries. RESULTS: A total of 314 patients have been randomized. CONCLUSIONS: This is the first and only study of a new class of LDL-C-lowering agents in patients selected with a rigorously documented intolerance to statins, using a placebo run-in and statin control arm. PMID- 25499938 TI - Age- and sex-related difference in lipid profiles of patients hospitalized with acute myocardial infarction in East China. AB - BACKGROUND: It was not understood whether age- and sex-related differences were apparent in lipid profiles among acute myocardial infarction (AMI) patients in China. OBJECTIVES: To investigate lipid abnormalities in such AMI patients. METHODS: A retrospective analysis of 1213 patients hospitalized with a first AMI between May 2007 and July 2011. RESULTS: Our data indicated that, compared with the elderly, the nonelderly tended to have higher low-density lipoprotein cholesterol (LDL), total cholesterol (TC), and non-high-density lipoprotein cholesterol (N-HDL) for both males and females. There was significant difference in LDL among various age groups (P < .001): LDL levels in the 50-59 and 60-69 year age groups were higher than those in 70-79 and 80-89 year age groups. Compared with males, females tended to have higher LDL in both the 50-59 and 60 69 year age groups. There was no difference in HDL among various age groups for female AMI patients, but there was significance for males. Compared with males, females had higher HDL in 40-49, 50-59, 60-69, and 70-79 year age groups, respectively. Among various age groups, there was significant difference in triglycerides (TG) for male AMI patients, but no difference in TG for females. The levels of TG were higher in 40-49, 50-59, and 60-69 year age groups than those in 70-79, 80-89, and >=90 year age groups, respectively, for males. Isolated low HDL (low HDL + normal LDL + normal TG) was the most common type of combined dyslipidemia for male elderly (31.4%), male nonelderly (22.9%), and female elderly (19.2%) patients. CONCLUSION: We concluded that there was age- and sex-related difference in lipid profiles among AMI patients, with more prevalent dyslipidemia in the nonelderly than the elderly. Perimenopausal women were prone to higher LDL, and low HDL was prevalent among AMI patients in East China. PMID- 25499939 TI - Effects of Xuezhikang in patients with dyslipidemia: a multicenter, randomized, placebo-controlled study. AB - BACKGROUND: Xuezhikang (XZK) is an extract of fermented red yeast rice that has lipid-lowering properties. OBJECTIVE: To evaluate the effects of XZK on lipids in subjects with dyslipidemia but no coronary heart disease. METHODS: A total of 116 adults with baseline non-high-density lipoprotein cholesterol (non-HDL-C) levels of approximately 208 mg/dL and low-density lipoprotein cholesterol (LDL-C) levels of approximately 175 mg/dL were randomized to either placebo or XZK 1200 or 2400 mg daily and treated for 12 weeks. RESULTS: A majority of the patients were white (53.4%) or Asian (37.1%). Daily XZK 1200 mg and 2400 mg for 4 to 12 weeks resulted in statistically significant (P < .001) and clinically meaningful decreases in non-HDL-C (~24% reduction) and LDL-C (~27% reduction) compared with placebo. XZK treatment at either dose enabled approximately 50% of subjects to reduce their LDL-C levels by >= 30%. Doubling the XZK daily dose from 1200 to 2400 mg at treatment week 8 caused an additional 4.6% reduction in LDL-C. Significant benefits were also observed across secondary efficacy variables, including total cholesterol (TC), apolipoprotein B (Apo B), triglycerides, HDL-C, the TC/HDL-C ratio, and the Apo B/Apo A-I ratio, at treatment week 8 or 12. XZK was safe and well tolerated. Safety and tolerability profiles were similar across treatment groups. Most adverse events were gastrointestinal. No subject experienced myopathy or markedly elevated liver transaminases or creatine kinase. CONCLUSION: Xuezhikang significantly reduced non-HDL-C and LDL-C, and was well tolerated. Further, longer-term studies in more diverse patient populations are needed to corroborate these findings. PMID- 25499941 TI - Inverse association of legume consumption and dyslipidemia: Isfahan Healthy Heart Program. AB - BACKGROUND: Dietary intervention for improving serum lipids emphasizes on dietary fiber, plant protein, and flavonoids. This study was performed to examine whether regular legume consumption could alter serum lipids level and prevalence of dyslipidemia. MATERIALS AND METHODS: This cross-sectional study was performed among 9660 randomly selected Iranian adults in 3 districts in the central part of Iran, using data collected in the Isfahan Healthy Heart Program in 2007. Dietary behavior including frequency of legume consumption was assessed by 48-item food frequency questionnaire. Fasting serum lipids were measured by standard enzymatic methods. We applied analysis covariance test to compare adjusted mean of serum lipids across legume consumption quartile and logistic regression test was used to determine odds ratio 95% confidence interval of dyslipidemia based on legume consumption in unadjusted and 4-adjusted models. RESULTS: Adjusted mean triglyceride significantly reduced and high-density lipoprotein cholesterol (HDL C) enhanced by increasing legume consumption (P = .04). The frequency of legume consumption associated with occurrence of all kinds of dyslipidemia except for hypercholesterolemia, especially for those who had consumed legume more than 1 time per day in adjusted models (hypertriglyceridemia: 0.82 [0.68-0.98]; high low density lipoprotein [LDL-C]: 0.76 [0.60-0.97], and low HDL-C: 0.81 [0.71-0.92]). CONCLUSION: We found an inverse dose-response association between the frequency of legume consumption and the risk of hypertriglyceridemia, high LDL-C, and low HDL-C. Therefore it is suggested that increasing legume intake may be an important part of a dietary approach for primary prevention of cardiovascular disease. PMID- 25499942 TI - The Risk-Benefit Paradigm vs the Causal Exposure Paradigm: LDL as a primary cause of vascular disease. AB - All current guidelines use the 10-year risk of a cardiovascular event to select subjects for statin primary preventive therapy. Benefit from therapy is stated to be determined by risk with the result that statin primary preventive therapy is initiated only when the risk of a cardiovascular event over the next decade exceeds a specified level. Thus all current guidelines are based primarily on the Risk-Benefit paradigm of primary prevention. The recent American Heart Association/American College of Cardiology guidelines differ from others in basing selection for statin therapy virtually exclusively on risk except for those few subjects with markedly elevated levels of low-density lipoprotein cholesterol (LDL-C). The Causal Exposure paradigm differs from the Risk-Benefit paradigm in that the objective of therapy is to prevent the anatomic disease within arterial walls that produces cardiovascular risk. Moreover, the anatomic disease and, therefore, the cardiovascular risk, is a function of the injurious action of the causal factors of vascular disease, such as blood pressure and LDL, on the arterial wall over long periods. In this article, we explain the strengths and weaknesses of both paradigms to provide a more secure framework to compare the strengths and weaknesses in the different cholesterol guidelines with particular emphasis on the evidence that the cardiovascular risk and the benefit from statin therapy is related to the level of LDL. PMID- 25499940 TI - Plasma triglycerides predict incident albuminuria and progression of coronary artery calcification in adults with type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes Study. AB - BACKGROUND: Coronary artery disease and diabetic nephropathy, which are thought to share pathogenic mechanisms, remain the most common causes of mortality in type 1 diabetes (T1D). Data from basic and clinical studies indicate that hypertriglyceridemia plays an important role in the pathogenesis of vascular complications, but the role of triglycerides (TG) in the normal range remains unresolved in T1D. OBJECTIVE: We hypothesized that fasting TG would independently predict cardiorenal disease in adults with T1D and normal-to-low levels of TG. METHODS: Subjects (N = 652) were 19 to 56 years old at baseline and reexamined 6 years later. Urinary albumin excretion was measured, and categorized as microalbuminuria or greater. Progression of coronary artery calcification (CACp), measured using electron beam computed tomography, was defined as a change in the square root transformed CAC volume >=2.5. The association of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, non-HDL-C, natural log triglyceride (lnTG), ln(TG/HDL-C) ratio with CACp and incident albuminuria were examined in logistic regression. The models were adjusted for age, sex, T1D duration, hemoglobin A1c, systolic blood pressure, diastolic blood pressure, blood pressure medications, statins, and smoking status. Integrated discrimination index and net reclassification improvement were used to examine prediction performance. RESULTS: Incident albuminuria was independently associated with CACp. lnTG independently predicted both incident albuminuria (odds ratio: 1.53, 1.02-2.30, P = .04) and CACp (1.41, 1.11-1.80, P = .006). The addition of lnTG to ABC risk factors (HbA1c, systolic blood pressure, diastolic blood pressure, and LDL-C) moderately improved discrimination and reclassification of CACp and incident albuminuria. CONCLUSION: In adults with T1D, fasting TG independently predicted cardiorenal disease over 6 years and improved reclassification of risk by conventional risk factors. PMID- 25499943 TI - Liver histology during Mipomersen therapy for severe hypercholesterolemia. AB - BACKGROUND: Mipomersen is an antisense oligonucleotide that inhibits apolipoprotein B synthesis and lowers plasma low-density lipoprotein cholesterol even in the absence of low-density lipoprotein receptor function, presumably from inhibition of hepatic production of triglyceride-rich very low-density lipoprotein particles. By virtue of this mechanism, mipomersen therapy commonly results in the development of hepatic steatosis. Because this is frequently accompanied by alanine aminotransferase elevations, concern has arisen that mipomersen could promote the development of steatohepatitis, which could in turn lead to fibrosis and cirrhosis over time. OBJECTIVE: The objective of this study was to assess the liver biopsy findings in patients treated with mipomersen. METHODS: We describe 7 patients who underwent liver biopsy during the mipomersen clinical development programs. Liver biopsies were reviewed by a single, blinded pathologist. RESULTS: The histopathological features were characterized by simple steatosis, without significant inflammation or fibrosis. CONCLUSION: These findings suggest that hepatic steatosis resulting from mipomersen is distinct from nonalcoholic steatohepatitis. PMID- 25499944 TI - Purified palmitoleic acid for the reduction of high-sensitivity C-reactive protein and serum lipids: a double-blinded, randomized, placebo controlled study. AB - BACKGROUND: Purified palmitoleic acid (16-1; omega-7) has shown lipid-lowering and anti-inflammatory benefits in open label, epidemiologic, and animal studies. OBJECTIVE: Our objective was to perform the first randomized controlled trial of purified palmitoleic acid supplementation in humans. METHODS: Adults with dyslipidemia and evidence of mild systemic inflammation (high-sensitivity C reactive protein [hs-CRP] between 2 and 5 mg/L) were randomly allocated to receive either 220.5 mg of cis-palmitoleic acid (n = 30) or an identical capsule with placebo (1000 mg of medium chain triglycerides, n = 30) once per day for 30 days. Participants were asked to maintain their current diet. Serum lipids and hs CRP were drawn at baseline and study completion. RESULTS: At 30 days, there were significant mean (95% confidence interval [CI]) reductions in CRP (-1.9 [-2.3 to 1.4] mg/L), triglyceride (-30.2 [-40.2 to -25.3] mg/dL), and low-density lipoprotein (LDL) (-8.9 [-12.0 to -5.8] mg/dL), and a significant increase in high-density lipoprotein (HDL) (2.4 [1.5, 3.3] mg/dL) in the intervention group compared with control. These changes equated to 44%, 15%, and 8% reductions in CRP, triglyceride, and LDL respectively, and a 5% increase in HDL compared with control. CONCLUSIONS: Purified palmitoleic acid may be useful in the treatment of hypertriglyceridemia with the beneficial added effects of decreasing LDL and hs CRP and raising HDL. Further study is needed to elucidate mechanisms and establish appropriate human doses. PMID- 25499945 TI - The role of common variants of ABCB1 and CYP7A1 genes in serum lipid levels and lipid-lowering efficacy of statin treatment: a meta-analysis. AB - BACKGROUND: The relation between the ABCB1 and CYP7A1 genes and serum lipid levels and lipid-lowering efficacy of statin treatment is inconsistent. OBJECTIVE: The purpose of this meta-analysis was to explore the associations between the ABCB1 and CYP7A1 genes and serum lipid levels and lipid-lowering efficacy of statin treatment. METHODS: MEDLINE, EMBASE, and the Cochrane Library databases were searched systematically for studies of associations between relevant single nucleotide polymorphisms C3435 T (ABCB1), G2677 A/T (ABCB1), and A-204C (CYP7A1) and serum lipid levels or statin treatment. Associations were assessed in pooled data by calculating mean difference with 95% confidence intervals. RESULTS: Seventeen studies with 4890 patients were included in this meta-analysis. The "AA" group at A-204C (CYP7A1) had lower serum total cholesterol (TC) levels than "AC + CC" group. The "AA" group at A-204C (CYP7A1) had greater reduction in low-density lipoprotein cholesterol (LDL-C) with statin treatment than "AC + CC" group. The "GG" group at G2677 A/T (ABCB1) had less reduction in TC and LDL-C with statin treatment than "non-GG" group. CONCLUSIONS: The A-204C (CYP7A1) polymorphism was associated with the level of TC and the lipid-lowering efficacy of statin treatment in the level of LDL-C. The G2677 A/T (ABCB1) polymorphism was associated with the lipid-lowering efficacy of statin treatment in the levels of LDL-C and TC. PMID- 25499947 TI - Familial chylomicronemia syndrome and response to medium-chain triglyceride therapy in an infant with novel mutations in GPIHBP1. AB - BACKGROUND: Severe hypertriglyceridemia predisposes to attacks of acute pancreatitis, a serious condition complicated by multiorgan failure, pancreatic necrosis, and mortality rates up to 20% in adults and 6.5% in children. OVERVIEW: We describe an infant who suffered from an episode of acute pancreatitis from severe hypertriglyceridemia. Two major challenges complicate the case: identifying the etiology of severe hypertriglyceridemia and finding an efficacious treatment. A thorough history, physical examination, and laboratory workup failed to identify a clear etiology, prompting a genetic workup that identified compound heterozygous mutations in the glycosylphosphatidylinositol anchored high-density lipoprotein-binding protein 1 (GPIHBP1) gene. This patient's hypertriglyceridemia responded to an infant formula rich in medium chain triglycerides (MCTs), and she remained free of pancreatitis 6 months later. CONCLUSIONS: This case highlights the need to pursue a genetic evaluation in the absence of secondary causes of severe hypertriglyceridemia in infants. Patients with mutations in GPIHBP1 fail to respond to currently available lipid-lowering agents so dietary management-specifically, an extremely low-fat diet and supplementation with MCT-remains the cornerstone of therapy. Treatment in infants should focus on dietary measures rather than pharmacologic agents. PMID- 25499946 TI - Extreme hypertriglyceridemia managed with insulin. AB - Extreme hypertriglyceridemia can lead to acute pancreatitis and rapid lowering of serum triglycerides (TG) is necessary for preventing such life-threatening complications. However, there is no established consensus on the acute management of extreme hypertriglyceridemia. We retrospectively reviewed 10 cases of extreme hypertriglyceridemia with mean serum TG on presentation of 101.5 +/- 23.4 mmol/L (8982 +/- 2070 mg/dL) managed with insulin. Serum TG decreased by 87 +/- 4% in 24 hours in those patients managed with intravenous insulin and fasting and 40 +/- 8.4% in those managed with intravenous insulin alone (P = .0003). The clinical course was uncomplicated in all except 1 patient who subsequently developed a pancreatic pseudocyst. Thus, combination of intravenous insulin with fasting appears to be an effective, simple, and safe treatment strategy in immediate management of extreme hypertriglyceridemia. PMID- 25499948 TI - Marked hypertriglyceridemia in a woman receiving metoprolol succinate. AB - beta-blockers are commonly used therapies after acute myocardial infarction and in the management of congestive heart failure and hypertension. We report a case of a middle-aged woman with a history of mild hypertension who was placed on metoprolol succinate. Before initiation of the beta-blocker, her triglyceride level was in the borderline-high range (150-199 mg/dL). On treatment, her triglyceride levels exceeded 1000 mg/dL. She developed fatigue and mild abdominal discomfort but without biochemical evidence of pancreatitis. After discontinuation of metoprolol succinate, her triglyceride levels receded. This case illustrates an uncommon side effect with a very commonly used therapy in clinical practice. Clinicians should closely evaluate medications and/or other therapies in patients presenting with new-onset hypertriglyceridemia especially when levels are sufficiently elevated to pose increased risk of pancreatitis. PMID- 25499949 TI - Variance in niacin response in individuals with elevated lipoprotein(a). PMID- 25499950 TI - Reply: To PMID 25110227. PMID- 25499951 TI - Risk-directed therapy and research in neuroblastoma. PMID- 25499952 TI - Usefulness of the contact force sensing catheter to assess the areas of myocardial scar in patients with ventricular tachycardia. PMID- 25499953 TI - The genetic background of left ventricular hypertrabeculation / noncompaction remains vague. PMID- 25499954 TI - Early prognostic evaluation after mild therapeutic hypothermia in sudden cardiac arrest survivors. PMID- 25499955 TI - Prognostic value of exercise-induced left ventricular systolic dysfunction in hypertensive patients without coronary artery disease. AB - INTRODUCTION AND OBJECTIVES: We sought to assess the prognostic value of exercise induced left ventricular systolic dysfunction in hypertensive patients with normal resting echocardiography and absence of coronary artery disease. METHODS: From our database of patients referred for treadmill exercise echocardiography, we identified 93 hypertensive patients with preserved resting left ventricular ejection fraction (>= 50%), no evidence of structural heart disease, and absence of coronary artery disease on angiography. Overall, 39 patients developed exercise-induced left ventricular systolic dysfunction (defined as a decrease in left ventricular ejection fraction below 50% at peak exercise) and 54 exhibited a normal left ventricular ejection fraction response to exercise. The mean follow up was 6.1 (3.7) years. End points were all-cause mortality, cardiac death, heart failure, and the composite event of cardiac death or heart failure. RESULTS: Patients who developed exercise-induced left ventricular systolic dysfunction were at higher risk of death from any cause (hazard ratio=3.4; 95% confidence interval, 1.1-10.3), cardiac death (hazard ratio=5.6; 95%CI, 1.1-29.4), heart failure (hazard ratio=8.9; 95% confidence interval, 1.8-44.2), and the composite end point (hazard ratio=5.7; 95% confidence interval, 1.7-19.0). In the multivariate analysis, exercise-induced left ventricular systolic dysfunction remained an independent predictor of both heart failure (hazard ratio=6.9; 95% CI, 1.3-37.4) and the composite event of cardiac death or heart failure (hazard ratio=4.5; 95% confidence interval, 1.2-16.0). CONCLUSIONS: In hypertensive patients with preserved resting left ventricular ejection fraction and absence of coronary artery disease, exercise-induced left ventricular systolic dysfunction is a strong predictor of cardiac events and may represent early hypertensive heart disease. PMID- 25499956 TI - DODAB:monoolein liposomes containing Candida albicans cell wall surface proteins: a novel adjuvant and delivery system. AB - We describe the preparation and characterization of DODAB:MO-based liposomes and demonstrate their adjuvant potential and use in antigen delivery. Liposomes loaded with Candida albicans proteins assembled as stable negatively charged spherical nanoparticles with a mean size of 280 nm. High adsorption efficiency (91.0 +/- 9.0%) is attained with high lipid concentrations. The nanoparticles were non-toxic, avidly taken up by macrophage cells and accumulated in membrane rich regions with an internalization time of 20 min. Immunized mice displayed strong humoral and cell-mediated immune responses, producing antibodies (IgGs) against specific cell wall proteins, Cht3p and Xog1p. DODAB:MO-based liposomes loaded with C. albicans proteins have an excellent immunogenic potential and can be explored for the development of an immunoprotective strategy against Candida infections. PMID- 25499958 TI - A Spatiotemporal Profile of In Vivo Cerebral Blood Flow Changes Following Intranasal Oxytocin in Humans. AB - BACKGROUND: Animal and human studies highlight the role of oxytocin in social cognition and behavior and the potential of intranasal oxytocin (IN-OT) to treat social impairment in individuals with neuropsychiatric disorders such as autism. However, extensive efforts to evaluate the central actions and therapeutic efficacy of IN-OT may be marred by the absence of data regarding its temporal dynamics and sites of action in the living human brain. METHODS: In a placebo controlled study, we used arterial spin labeling to measure IN-OT-induced changes in resting regional cerebral blood flow (rCBF) in 32 healthy men. Volunteers were blinded regarding the nature of the compound they received. The rCBF data were acquired 15 min before and up to 78 min after onset of treatment onset (40 IU of IN-OT or placebo). The data were analyzed using mass univariate and multivariate pattern recognition techniques. RESULTS: We obtained robust evidence delineating an oxytocinergic network comprising regions expected to express oxytocin receptors, based on histologic evidence, and including core regions of the brain circuitry underpinning social cognition and emotion processing. Pattern recognition on rCBF maps indicated that IN-OT-induced changes were sustained over the entire posttreatment observation interval (25-78 min) and consistent with a pharmacodynamic profile showing a peak response at 39-51 min. CONCLUSIONS: Our study provides the first visualization and quantification of IN-OT-induced changes in rCBF in the living human brain unaffected by cognitive, affective, or social manipulations. Our findings can inform theoretical and mechanistic models regarding IN-OT effects on typical and atypical social behavior and guide future experiments (e.g., regarding the timing of experimental manipulations). PMID- 25499957 TI - The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex. AB - Psychostimulants are highly effective in the treatment of attention deficit/hyperactivity disorder. The clinical efficacy of these drugs is strongly linked to their ability to improve cognition dependent on the prefrontal cortex (PFC) and extended frontostriatal circuit. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine alpha2 and dopamine D1 receptors. In contrast, while the striatum is a critical participant in PFC dependent cognition, where examined, psychostimulant action within the striatum is not sufficient to enhance cognition. At doses that moderately exceed the clinical range, psychostimulants appear to improve PFC-dependent attentional processes at the expense of other PFC-dependent processes (e.g., working memory, response inhibition). This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic alpha2 versus alpha1 receptors. Collectively, this evidence indicates that at low, clinically relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation. PMID- 25499959 TI - Identification of a novel gene fusion (BMX-ARHGAP) in gastric cardia adenocarcinoma. AB - BACKGROUND: Gastric cardia adenocarcinoma (GCA) is one of the major causes of cancer related mortality worldwide. We aim to provide new understanding in the pathogenesis of GCA through investigations on gene expression alterations. METHODS: We preformed RNA-Seq for one pair of GCA and matched non-tumor tissues. Differentially expressed genes (DEGs) and fusion genes were acquired. PCR and gel analysis in additional 14 pairs of samples were performed to validate the chimeric transcripts. RESULTS: 1590 up-regulated and 709 down-regulated genes were detected. Functional analysis revealed that these DEGs were significantly overrepresented in gene ontology items of cell cycle, tumor invasion and proliferation. Moreover, we firstly discovered 3 fusion genes in GCA, including BMX-ARHGAP, LRP5- LITAF and CBX3-C15orf57. The chimeric transcript BMX-ARHGAP was validated and recurrently occurred in 4/15 independent tumor tissues. CONCLUSIONS: Our results may provide new understanding of GCA and biomarkers for further therapeutic studies. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_218. PMID- 25499960 TI - Frequential versus spatial colour textons for breast TMA classification. AB - Advances in digital pathology are generating huge volumes of whole slide (WSI) and tissue microarray images (TMA) which are providing new insights into the causes of cancer. The challenge is to extract and process effectively all the information in order to characterize all the heterogeneous tissue-derived data. This study aims to identify an optimal set of features that best separates different classes in breast TMA. These classes are: stroma, adipose tissue, benign and benign anomalous structures and ductal and lobular carcinomas. To this end, we propose an exhaustive assessment on the utility of textons and colour for automatic classification of breast TMA. Frequential and spatial texton maps from eight different colour models were extracted and compared. Then, in a novel way, the TMA is characterized by the 1st and 2nd order Haralick statistical descriptors obtained from the texton maps with a total of 241 * 8 features for each original RGB image. Subsequently, a feature selection process is performed to remove redundant information and therefore to reduce the dimensionality of the feature vector. Three methods were evaluated: linear discriminant analysis, correlation and sequential forward search. Finally, an extended bank of classifiers composed of six techniques was compared, but only three of them could significantly improve accuracy rates: Fisher, Bagging Trees and AdaBoost. Our results reveal that the combination of different colour models applied to spatial texton maps provides the most efficient representation of the breast TMA. Specifically, we found that the best colour model combination is Hb, Luv and SCT for all classifiers and the classifier that performs best for all colour model combinations is the AdaBoost. On a database comprising 628 TMA images, classification yields an accuracy of 98.1% and a precision of 96.2% with a total of 316 features on spatial textons maps. PMID- 25499961 TI - A manifold learning method to detect respiratory signal from liver ultrasound images. AB - Respiratory gating has been widely applied for respiratory correction or compensation in image acquisition and image-guided interventions. A novel image based method is proposed to extract respiratory signal directly from 2D ultrasound liver images. The proposed method utilizes a typical manifold learning method, based on local tangent space alignment based technique, to detect principal respiratory motion from a sequence of ultrasound images. This technique assumes all the images lying on a low-dimensional manifold embedding into the high-dimensional image space, constructs an approximate tangent space of each point to represent its local geometry on the manifold, and then aligns the local tangent spaces to form the global coordinate system, where the respiratory signal is extracted. The experimental results show that the proposed method can detect relatively accurate respiratory signal with high correlation coefficient (0.9775) with respect to the ground-truth signal by tracking external markers, and achieve satisfactory computing performance (2.3s for an image sequence of 256 frames). The proposed method is also used to create breathing-corrected 3D ultrasound images to demonstrate its potential application values. PMID- 25499962 TI - Surgical site infection after primary surgery for epithelial ovarian cancer: predictors and impact on survival. AB - OBJECTIVE: Surgical site infection (SSI) following epithelial ovarian cancer (EOC) primary surgery (PS) occurs in 10-15% of women. Perioperative factors associated with SSI and impact of SSI on survival were determined. METHODS: EOC cases that underwent PS from 1/2/2003 to 12/30/2011 were retrospectively reviewed. SSIs were defined according to ACS NSQIP. Logistic regression models were fit to identify factors associated with SSI. Cox proportional hazards models were utilized to evaluate the association of patient and perioperative characteristics with overall survival (OS) and disease-free survival (DFS). RESULTS: Among 888 cases, 96 (10.8%) developed SSI: 32 superficial, 2 deep, and 62 organ/space. Factors independently associated with superficial SSI were increasing BMI (odds ratio 1.41 [95% confidence interval, 1.12, 1.76] per 5kg/m(2)), increasing operative time (1.24 [1.02, 1.50] per hour), and advanced stage (III/IV) (10.22 [1.37, 76.20]). Factors independently associated with organ/space SSI were history of gastroesophageal reflux disease (2.13 [1.23, 3.71]), surgical complexity (intermediate 3.11 [1.02, 9.49]; high 8.07 [2.60, 25.09]; referent: low), and residual disease (RD) (measureable <=1cm 1.77 [0.96, 3.27]; suboptimal >1cm (3.36 [1.48, 7.61]; referent: microscopic). Occurrence of superficial (hazard ratio 1.69 [1.12, 2.57]) or organ/space (1.46 [1.07, 2.00]) SSI was independently associated with worse OS. SSI occurrence was not independently associated with DFS. CONCLUSIONS: SSI after PS is associated with decreased OS. Most risk factors for SSI are not modifiable. Alternative measures to lower rates of SSIs are needed as this may improve OS. Preoperative identification of SSI risk factors may assist in risk-assessment and operative planning. PMID- 25499963 TI - Entrenching environmental obligation in marine regulation. AB - The institutional frameworks addressing issues in connection with the marine commons agreed by States are set out in the 1982 UN Convention on the Law of the Sea, which is the basis of the European Union's common fisheries policy. Despite a substantial body of environmental legislation, provisions concerning the protection of ecosystems and bioversity have not been incorporated into any international measure or EU to control fishing, leading to ecosystem degradation. Regulation should impose the responsibility for rectifying damage to fish stocks and ecosystems as a result of fishing activity on the fishing industry. PMID- 25499964 TI - Distributions and sources of petroleum, aliphatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs) in surface sediments from Bohai Bay and its adjacent river, China. AB - Surface sediment samples from Bohai Bay and its adjacent river, China, were analyzed for aliphatic hydrocarbon, PAHs and biomarkers in order to determine the distribution, composition and source of organic matter in a coastal environment. Results suggested that the input of organic matter from anthropogenic activities has a more significant influence on its distribution than that from natural processes. Petroleum contamination, mainly from offshore oil exploration and discharge of pollutants from rivers, was the main source of n-alkanes. PAHs were mostly of pyrogenic origin; while some sites in Yellow River Estuary were derived mainly from the petrogenic sources. The toxic assessment suggested that the PAHs in surface sediments will not cause immediately adverse biological effects in sediments from Bohai Bay and its adjacent river, China. PMID- 25499965 TI - Responses of estuarine nematodes to an increase in nutrient supply: an in situ continuous addition experiment. AB - An experiment was carried out on an estuarine mudflat to assess impacts of inorganic nutrients used to fertilize sugar-cane fields on the surrounding aquatic ecosystem, through changes in the nematode community structure. During 118 days, nine quadrats each 4m(2) were sampled six times after the beginning of fertilizer addition. The fertilizer was introduced weekly in six areas, at two different concentrations (low and high doses), and three areas were used as control. The introduction of nutrients modified key nematode community descriptors. In general, the nematodes were negatively affected over the study period. However, Comesa, Metachromadora, Metalinhomoeus, Spirinia and Terschellingia were considered tolerant, and other genera showed different degrees of sensitivity. Nutrient input also affect the availability and quality of food, changing the nematode trophic structure. The use of inorganic fertilizer should be evaluated with care because of the potential for damage to biological communities of coastal aquatic systems. PMID- 25499966 TI - Trace elements and ingested plastic debris in wintering dovekies (Alle alle). AB - We provide the first report on winter concentrations of 32 trace metals from dovekies (Alle alle), a small, Arctic seabird that has a seasonal shift in diet from small zooplankton in the breeding season to larger zooplankton and small fish in the non-breeding season. Concentrations of selected trace elements, as well as stable carbon (delta(13)C) and nitrogen (delta(15)N) isotope concentrations for a sample of 25 dovekies, were similar between adult males and females, and there was evidence that dovekies feeding at higher trophic levels had higher hepatic Hg. We also found plastic debris in nine of 65 (14%) gizzards examined. Our study helps provide a more complete picture of the foraging ecology and contaminant profile of dovekies, an important species in Arctic marine food webs. PMID- 25499967 TI - Assessment of the European flounder responses to chemical stress in the English Channel, considering biomarkers and life history traits. AB - A multi-biomarker approach was developed to evaluate responses of European flounder (Platichthys flesus) in three contrasted estuaries over the English Channel: the Canche (pristine site), Tamar (heavy metals and PAHs contamination) and Seine (heavily pollution with a complex cocktail of contaminants). The condition factor and several biomarkers of the immune system, antioxidant enzymes, energetic metabolism and detoxification processes were investigated in young-of-the-year (0+) and one-year-old (1+) flounder. Results underlined the difference between the pristine site and the Seine estuary which showed a lower condition factor, a modulation of the immune system, a higher Cytochrome C oxidase activity, and an up-regulation of BHMT expression. The moderate biomarker responses in the Tamar fish could be linked to the specific contamination context of this estuary. Flounder life history traits were analyzed by otolith microchemistry, in order to depict how the fish use their habitat and thus respond to chemical stress in estuaries. PMID- 25499968 TI - Nursing students' perspectives of the health and healthcare issues of Australian Indigenous people. AB - BACKGROUND: Indigenous people are the most disadvantaged population within Australia with living conditions comparable to developing countries. The Bachelor of Nursing programme at the University of Western Sydney has embedded Indigenous health into the undergraduate teaching programme, with an expectation that students develop an awareness of Indigenous health and healthcare issues. AIM: To gain insight into students' perceptions of Indigenous people and whether the course learning and teaching strategies implemented improved students' learning outcomes and attitude towards Indigenous people and Indigenous health in Australia. DESIGN: A mixed methods prospective survey design was chosen. METHODS: Students enrolled in the Indigenous health subject in 2013 were invited to complete pre- and post-subject surveys that contained closed- and open-ended questions. Students' socio-demographic data was collected at baseline, but the 'Attitude Toward Indigenous Australians' (ATIA) scale, and the 3-item Knowledge, Interest and Confidence to nursing Australian Indigenous peoples scale were administered at both pre- and post-subject surveys. RESULTS: 502 students completed the baseline survey and 249 students completed the follow-up survey. There was a statistically significant attitudinal change towards Indigenous Australians, measured by the ATIA scale, and participants' knowledge, intent to work with Indigenous Australians and confidence in caring for them increased significantly at follow-up. Based on the participants' responses to open-ended questions, four key themes emerged: a) understanding Indigenous history, culture and healthcare; b) development of cultural competence; c) enhanced respect for Indigenous Australians' culture and traditional practices; and d) enhanced awareness of the inherent disadvantages for Indigenous Australians in education and healthcare. There were no statistically significant socio-demographic group differences among those who commented on key themes. CONCLUSION: Addressing health inequalities for Indigenous Australians is paramount. Nurses need cultural awareness and sensitivity to deliver culturally appropriate healthcare in Australia. PMID- 25499969 TI - Late presentation of X-linked dyskeratosis congenita with a missense mutation in codon 350 of the dyskerin protein. PMID- 25499970 TI - Hispidulin inhibits proliferation and enhances chemosensitivity of gallbladder cancer cells by targeting HIF-1alpha. AB - Gallbladder cancer (GBC) is an aggressive malignancy of the bile duct, which is associated with a low (5-year) survival and poor prognosis. The transcription factor HIF-1alpha is implicated in the angiogenesis, cell survival, epithelial mesenchymal transition (EMT) and invasiveness of GBC. In this study, we have investigated the role of HIF-1alpha in the pathobilogy of GBC and effect of hispidulin on the molecular events controlled by this transcription factor. We observed that hispidulin caused induction of apoptosis, blockade of growth and cell cycle progression in GBC cells. Our results have demonstrated for the first time that hispidulin-exerted anti-tumor effect involved the suppression of HIF 1alpha signaling. Hispidulin was found to repress the expression of HIF-1alpha protein dose-dependently without affecting the HIF-1alpha mRNA expression. In addition, the inhibition of HIF-1alpha protein synthesis was revealed to be mediated through the activation of AMPK signaling. Hispidulin also sensitized the tumor cells to Gemcitabine and 5-Fluoroucil by down-regulating HIF-1alpha/P-gp signaling. Given the low cost and exceedingly safe profile, hispidulin appears to be a promising and novel chemosensitizer for GBC treatment. PMID- 25499971 TI - Lysophospholipid receptors in drug discovery. AB - Lysophospholipids (LPs), including lysophosphatidic acid (LPA), sphingosine 1 phospate (S1P), lysophosphatidylinositol (LPI), and lysophosphatidylserine (LysoPS), are bioactive lipids that transduce signals through their specific cell surface G protein-coupled receptors, LPA1-6, S1P1-5, LPI1, and LysoPS1-3, respectively. These LPs and their receptors have been implicated in both physiological and pathophysiological processes such as autoimmune diseases, neurodegenerative diseases, fibrosis, pain, cancer, inflammation, metabolic syndrome, bone formation, fertility, organismal development, and other effects on most organ systems. Advances in the LP receptor field have enabled the development of novel small molecules targeting LP receptors for several diseases. Most notably, fingolimod (FTY720, Gilenya, Novartis), an S1P receptor modulator, became the first FDA-approved medicine as an orally bioavailable drug for treating relapsing forms of multiple sclerosis. This success is currently being followed by multiple, mechanistically related compounds targeting S1P receptor subtypes, which are in various stages of clinical development. In addition, an LPA1 antagonist, BMS-986020 (Bristol-Myers Squibb), is in Phase 2 clinical development for treating idiopathic pulmonary fibrosis, as a distinct compound, SAR100842 (Sanofi) for the treatment of systemic sclerosis and related fibrotic diseases. This review summarizes the current state of drug discovery in the LP receptor field. PMID- 25499972 TI - BCL-2 family protein, BAD is down-regulated in breast cancer and inhibits cell invasion. AB - We have previously demonstrated that the anti-apoptotic protein BAD is expressed in normal human breast tissue and shown that BAD inhibits expression of cyclin D1 to delay cell-cycle progression in breast cancer cells. Herein, expression of proteins in breast tissues was studied by immunohistochemistry and results were analyzed statistically to obtain semi-quantitative data. Biochemical and functional changes in BAD-overexpressing MCF7 breast cancer cells were evaluated using PCR, reporter assays, western blotting, ELISA and extracellular matrix invasion assays. Compared to normal tissues, Grade II breast cancers expressed low total/phosphorylated forms of BAD in both cytoplasmic and nuclear compartments. BAD overexpression decreased the expression of beta-catenin, Sp1, and phosphorylation of STATs. BAD inhibited Ras/MEK/ERK and JNK signaling pathways, without affecting the p38 signaling pathway. Expression of the metastasis-related proteins, MMP10, VEGF, SNAIL, CXCR4, E-cadherin and TlMP2 was regulated by BAD with concomitant inhibition of extracellular matrix invasion. Inhibition of BAD by siRNA increased invasion and Akt/p-Akt levels. Clinical data and the results herein suggest that in addition to the effect on apoptosis, BAD conveys anti-metastatic effects and is a valuable prognostic marker in breast cancer. PMID- 25499973 TI - sRAGE, inflammation, and risk of atrial fibrillation: results from the Atherosclerosis Risk in Communities (ARIC) Study. AB - OBJECTIVE: Advanced glycation end products (AGEs) may cause inflammation by binding to their cellular receptors (RAGE). Soluble RAGE (sRAGE) acts as a decoy receptor for AGEs and may prevent inflammation. Chronic low-grade inflammation is a risk factor for cardiovascular disease, including atrial fibrillation (AF). METHODS: We studied 1,068 participants in a subsample of the Atherosclerosis Risk in Communities (ARIC) Study who had baseline measurements of sRAGE (mean age 56, 60% female, 21% Black). Inflammation was assessed using measurements of high sensitivity C-reactive protein (hsCRP), fibrinogen, gamma-glutamyl transferase (GGT) and white blood cell (WBC) count. AF events were identified using ECG data, hospitalization discharge codes, and linkage to the National Death Index. RESULTS: Compared to the highest quartile (>1272.4 pg/mL), the lowest quartile of sRAGE (<714 pg/mL) was associated with higher baseline levels of inflammation (hsCRP >=3 mg/L: OR=2.21 [95% CI 1.41-3.49], fibrinogen >=400 mg/dL: OR=4.31 [95% CI 1.50-12.41], GGT >=36 U/L in women and >=61 U/L in men: OR=5.22 [95% CI 2.66 10.22], WBC >6.2*109/L: OR=2.38 [95% CI 1.52-3.72]). sRAGE was not prospectively associated with 6-year change in inflammatory markers (hsCRP or GGT). There was no significant association of sRAGE and risk of AF (HR 1.49 [95% CI: 0.80-2.78] for the 1st vs. 4th quartile of sRAGE). CONCLUSIONS: sRAGE was strongly inversely associated with markers of inflammation at baseline, but not prospectively. sRAGE was not significantly associated with incident AF. This supports a role for sRAGE in attenuating current inflammation, but it remains unclear whether sRAGE plays a role in the development of AF. PMID- 25499974 TI - RhoA GTPase-induced ocular hypertension in a rodent model is associated with increased fibrogenic activity in the trabecular meshwork. AB - Ocular hypertension arising from increased resistance to aqueous humor (AH) outflow through the trabecular meshwork is a primary risk factor for open-angle glaucoma, a leading cause of blindness. Ongoing efforts have found little about the molecular and cellular bases of increased resistance to AH outflow through the trabecular meshwork in ocular hypertension patients. To test the hypothesis that dysregulated Rho GTPase signaling and a resulting fibrotic activity within the trabecular meshwork may result in ocular hypertension, we investigated the effects of expressing a constitutively active RhoA GTPase (RhoAV14) in the AH outflow pathway in Sprague-Dawley rats by using lentiviral vector-based gene delivery. Rats expressing RhoAV14 in the iridocorneal angle exhibited a significantly elevated intraocular pressure. Elevated intraocular pressure in the RhoAV14-expressing rats was associated with fibrotic trabecular meshwork and increased levels of F-actin, phosphorylated myosin light chain, alpha-smooth muscle actin, collagen-1A, and total collagen in the trabecular AH outflow pathway. Most of these changes were ameliorated by topical application of Rho kinase inhibitor. Human autopsy eyes from patients with glaucoma exhibited significant increases in levels of collagen-1A and total collagen in the trabecular AH outflow pathway. Collectively, these observations indicate that increased fibrogenic activity because of dysregulated RhoA GTPase activity in the trabecular AH outflow pathway increases intraocular pressure in a Rho kinase dependent manner. PMID- 25499976 TI - Design and Usage of the HeartCycle Education and Coaching Program for Patients With Heart Failure. AB - BACKGROUND: Heart failure (HF) is common, and it is associated with high rates of hospital readmission and mortality. It is generally assumed that appropriate self care can improve outcomes in patients with HF, but patient adherence to many self care behaviors is poor. OBJECTIVE: The objective of our study was to develop and test an intervention to increase self-care in patients with HF using a novel, online, automated education and coaching program. METHODS: The online automated program was developed using a well-established, face-to-face, home-based cardiac rehabilitation approach. Education is tailored to the behaviors and knowledge of the individual patient, and the system supports patients in adopting self-care behaviors. Patients are guided through a goal-setting process that they conduct at their own pace through the support of the system, and they record their progress in an electronic diary such that the system can provide appropriate feedback. Only in challenging situations do HF nurses intervene to offer help. The program was evaluated in the HeartCycle study, a multicenter, observational trial with randomized components in which researchers investigated the ability of a third-generation telehealth system to enhance the management of patients with HF who had a recent (<60 days) admission to the hospital for symptoms or signs of HF (either new onset or recurrent) or were outpatients with persistent New York Heart Association (NYHA) functional class III/IV symptoms despite treatment with diuretic agents. The patients were enrolled from January 2012 through February 2013 at 3 hospital sites within the United Kingdom, Germany, and Spain. RESULTS: Of 123 patients enrolled (mean age 66 years (SD 12), 66% NYHA III, 79% men), 50 patients (41%) reported that they were not physically active, 56 patients (46%) did not follow a low-salt diet, 6 patients (5%) did not restrict their fluid intake, and 6 patients (5%) did not take their medication as prescribed. About 80% of the patients who started the coaching program for physical activity and low-salt diet became adherent by achieving their personal goals for 2 consecutive weeks. After becoming adherent, 61% continued physical activity coaching, but only 36% continued low-salt diet coaching. CONCLUSIONS: The HeartCycle education and coaching program helped most nonadherent patients with HF to adopt recommended self-care behaviors. Automated coaching worked well for most patients who started the coaching program, and many patients who achieved their goals continued to use the program. For many patients who did not engage in the automated coaching program, their choice was appropriate rather than a failure of the program. PMID- 25499975 TI - DEAD-box protein p68 is regulated by beta-catenin/transcription factor 4 to maintain a positive feedback loop in control of breast cancer progression. AB - INTRODUCTION: Nuclear accumulation of beta-catenin is important for cancer development and it is found to overlap with p68 (DDX5) immunoreactivity in most breast cancers, as indicated by both clinical investigations and studies in cell lines. In this study, we aim to investigate the regulation of p68 gene expression through beta-catenin/transcription factor 4 (TCF4) signaling in breast cancer. METHODS: Formalin-fixed paraffin-embedded sections derived from normal human breast and breast cancer samples were used for immunohistochemical analysis. Protein and mRNA expressions were determined by immunoblotting and quantitative RT-PCR respectively. Promoter activity of p68 was checked using luciferase assay. Occupancy of several factors on the p68 promoter was evaluated using chromatin immunoprecipitation. Finally, a syngeneic mouse model of breast cancer was used to assess physiological significance. RESULTS: We demonstrated that beta-catenin can directly induce transcription of p68 promoter or indirectly through regulation of c-Myc in both human and mouse breast cancer cells. Moreover, by chromatin immunoprecipitation assay, we have found that both beta-catenin and TCF4 occupy the endogenous p68 promoter, which is further enhanced by Wnt signaling. Furthermore, we have also established a positive feedback regulation for the expression of TCF4 by p68. To the best of our knowledge, this is the first report on beta-catenin/TCF4-mediated p68 gene regulation, which plays an important role in epithelial to mesenchymal transition, as shown in vitro in breast cancer cell lines and in vivo in an animal breast tumour model. CONCLUSIONS: Our findings indicate that Wnt/beta-catenin signaling plays an important role in breast cancer progression through p68 upregulation. PMID- 25499977 TI - Structural perspective of ARHI mediated inhibition of STAT3 signaling: an insight into the inactive to active transition of ARHI and its interaction with STAT3 and importinbeta. AB - ARHI, a putative tumor suppressor protein with unique 32 amino acid extension in the N-terminal region, differs from oncogenes Ras and Rap, negatively regulates STAT3 signaling and inhibits the migration of ovarian cancer cells. ARHI associates directly with STAT3, also forms complex with importinbeta, and prevents formation of RanGTPase-importinbeta complex, which is essential for transporting STAT3 into the nucleus. Hence, the structural aspects pertaining to ARHI mediated inhibition of STAT3 translocation can provide hints on the regulation of STAT3 signaling mechanism. Accordingly, in the present study, the structure of ARHI was predicted and its transition from inactive to active state studied using MD simulations and free energy landscape analysis. The transition of ARHI is marked by the movement of switch I region towards gamma-phosphate of GTP, in addition, the hydrophobic interaction between N-terminal helix and switch II region of ARHI accounts for its low intrinsic GTPase activity. Further, the protein-protein interaction studies reveal that the residues of N-terminal helix, effector domain, P-loop and G box motif of ARHI actively form polar and non-polar interaction with NTD of STAT3 and make them compact thereby rendering STAT3 inaccessible for Ran-importinbeta mediated translocation. On the other hand, ARHI competes with RanGTPase and interacts with importinbeta via basic-acidic patch interaction, which leads to inhibition of STAT3 translocation. The interacting residues involved for this structural mechanism would be instrumental in designing inhibitors for STAT3, which mimics ARHI thereby leading to the suppression of cancer cell growth. PMID- 25499978 TI - Molecular mechanisms of hepatic apoptosis regulated by nuclear factors. AB - Apoptosis is a prominent characteristic in the pathogenesis of liver disease. The mechanism of hepatic apoptosis is not well understood. Hepatic apoptosis alters relative levels of nuclear factors such as Foxa2, NF-kappaB, C/EBPbeta, and p53. Regulation of nuclear factors modulates the degree of hepatic apoptosis and the progression of liver disease. Nuclear factors have distinctive mechanisms to mediate hepatic apoptosis. The modification of nuclear factors is a novel therapeutic strategy for liver disease as demonstrated by pre-clinical models and clinical trials. PMID- 25499979 TI - Type III TGFbeta receptor and Src direct hyaluronan-mediated invasive cell motility. AB - During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types which contribute to the coronary vessels. This process requires epithelial to mesenchymal transition (EMT) and directed cellular invasion. The Type III Transforming Growth Factor-beta Receptor (TGFbetaR3) is required for epicardial cell invasion and coronary vessel development. Using primary epicardial cells derived from Tgfbr3(+/+) and Tgfbr3( /-) mouse embryos, high-molecular weight hyaluronan (HMWHA) stimulated cellular invasion and filamentous (f-actin) polymerization are detected in Tgfbr3(+/+) cells, but not in Tgfbr3(-/-) cells. Furthermore, HMWHA-stimulated cellular invasion and f-actin polymerization in Tgfbr3(+/+) epicardial cells are dependent on Src kinase. Src activation in HMWHA-stimulated Tgfbr3(-/-) epicardial cells is not detected in response to HMWHA. RhoA and Rac1 also fail to activate in response to HMWHA in Tgfbr3(-/-) cells. These events coincide with defective f actin formation and deficient cellular invasion. Finally, a T841A activating substitution in TGFbetaR3 drives ligand-independent Src activation. Collectively, these data define a TGFbetaR3-Src-RhoA/Rac1 pathway that is essential for hyaluronan-directed cell invasion in epicardial cells. PMID- 25499980 TI - Leptin inhibits the Na(+)/K(+) ATPase in Caco-2 cells via PKC and p38MAPK. AB - We demonstrated previously an inhibitory effect of luminal leptin on glucose absorption in differentiated Caco-2 cells. Since this process is dependent on the Na(+) gradient established by the Na(+)/K(+)ATPase this work was undertaken to investigate if the ATPase is one of the hormone's targets. Fully differentiated Caco-2 cells were incubated with 10nM luminal leptin and the activity of the Na(+)/K(+) ATPase was assayed by measuring the amount of inorganic phosphate liberated. To elucidate the signaling pathway involved, the suspected mediators, namely PKC, p38MAPK, ERK and PI3K, were inhibited with specific pharmacological inhibitors and their implication was confirmed by determining changes in the protein expression of their active phosphorylated forms by Western blot analysis. Leptin reduced significantly the activity of the Na(+)/K(+) ATPase, by activating p38MAPK via inhibition of PKC, an upstream inhibitor of the kinase. ERK and PI3K are modulators of the pump and are not along the pathway activated by leptin but cross talk with it at the level of p38MAPK. PMID- 25499981 TI - Role of enhanced vector transmission of a new West Nile virus strain in an outbreak of equine disease in Australia in 2011. AB - BACKGROUND: In 2011, a variant of West Nile virus Kunjin strain (WNVKUN) caused an unprecedented epidemic of neurological disease in horses in southeast Australia, resulting in almost 1,000 cases and a 9% fatality rate. We investigated whether increased fitness of the virus in the primary vector, Culex annulirostris, and another potential vector, Culex australicus, contributed to the widespread nature of the outbreak. METHODS: Mosquitoes were exposed to infectious blood meals containing either the virus strain responsible for the outbreak, designated WNVKUN2011, or WNVKUN2009, a strain of low virulence that is typical of historical strains of this virus. WNVKUN infection in mosquito samples was detected using a fixed cell culture enzyme immunoassay and a WNVKUN- specific monoclonal antibody. Probit analysis was used to determine mosquito susceptibility to infection. Infection, dissemination and transmission rates for selected days post-exposure were compared using Fisher's exact test. Virus titers in bodies and saliva expectorates were compared using t-tests. RESULTS: There were few significant differences between the two virus strains in the susceptibility of Cx. annulirostris to infection, the kinetics of virus replication and the ability of this mosquito species to transmit either strain. Both strains were transmitted by Cx. annulirostris for the first time on day 5 post-exposure. The highest transmission rates (proportion of mosquitoes with virus detected in saliva) observed were 68% for WNVKUN2011 on day 12 and 72% for WNVKUN2009 on day 14. On days 12 and 14 post-exposure, significantly more WNVKUN2011 than WNVKUN2009 was expectorated by infected mosquitoes. Infection, dissemination and transmission rates of the two strains were not significantly different in Culex australicus. However, transmission rates and the amount of virus expectorated were significantly lower in Cx. australicus than Cx. annulirostris. CONCLUSIONS: The higher amount of WNVKUN2011 expectorated by infected mosquitoes may be an indication that this virus strain is transmitted more efficiently by Cx. annulirostris compared to other WNVKUN strains. Combined with other factors, such as a convergence of abundant mosquito and wading bird populations, and mammalian and avian feeding behaviour by Cx. annulirostris, this may have contributed to the scale of the 2011 equine epidemic. PMID- 25499982 TI - A brief form of the Perceived Social Support Questionnaire (F-SozU) was developed, validated, and standardized. AB - OBJECTIVES: Development of a brief instrument (F-SozU K-6) for the measurement of perceived social support in epidemiologic contexts by shortening a well established German questionnaire (F-SozU K-14). STUDY DESIGN AND SETTING: The development of the F-SozU K-6 consisted of two phases; phase 1: the F-SozU K-14 was presented to a general population sample representative for the Federal Republic of Germany (N = 2,007; age: 14-92 years). Six items for the short form were selected based on the maximization of coefficient alpha. Phase 2: the new short form (F-SozU K-6) was evaluated and standardized in an independent second population survey (N = 2,508, age: 14-92 years). RESULTS: The F-SozU K-6 showed very good reliability and excellent model fit indices for the one-dimensional factorial structure of the scale. Furthermore, strict measurement invariance was detected allowing unbiased comparison of means and correlation coefficients and path coefficients between both sexes across the full lifespan from adolescence (14-92 years). Well-established associations of perceived social support with depression and somatic symptoms could be replicated using the short form. CONCLUSION: The F-SozU K-6 presents a reliable, valid, and economical instrument to assess perceived social support and can thus be effectively applied within the frameworks of clinical epidemiologic studies or related areas. PMID- 25499984 TI - Learning curve effects can be investigated with the randomized registry trial. PMID- 25499985 TI - Validity of the EuroQol-5 dimensions as a measure of recovery after pulmonary resection. AB - BACKGROUND: Surgical innovations advocated to improve patient recovery are often costly. Economic evaluation requires preference-based measures that reflect the construct of patient recovery. We investigated the responsiveness and construct validity of the EuroQol-5 dimensions (EQ-5D) as a measure of postoperative recovery after planned pulmonary resection for suspected malignant tumors. METHODS: Patients undergoing pulmonary resection completed the EQ-5D questionnaire and visual analog scales (VAS) for pain and fatigue at baseline (preoperatively) and at 1 and 3 mo postoperatively. Responsiveness and construct validity (discriminant and convergent) were investigated by testing a priori hypotheses. RESULTS: Fifty-five patients were analyzed (45% male, 62 +/- 12 y, 29% video-assisted). There was no significant difference between median EQ-5D scores obtained at baseline (0.83 [interquartile range {IQR 0.80-1}]) compared to scores at 1 mo (0.83 [0.80-1], P = 0.86) and 3 mo after surgery (1 [0.83-1]; P = 0.09). At 1 mo after surgery, EQ-5D scores were significantly lower in patients undergoing thoracotomy versus video-assisted surgery (0.82 [IQR 0.77-0.89] versus 1 [0.83-1], P = 0.003), but there were no significant differences between patients >= 70-y old versus younger (0.95 [IQR 0.82-1] versus 0.83 [0.77-1], P = 0.09) or between patients with versus without complications (0.82 [IQR 0.79-0.95] versus 0.83 [0.80-1], P = 0.10). There was a low but significant correlation between EQ-5D and VAS scores of pain and fatigue (Rho -0.30 to -0.47, P <= 0.01). CONCLUSIONS: Despite evidence of convergent validity, the EQ-5D was not sensitive to the hypothesized trajectory of postoperative recovery and showed limited discriminant validity. This study suggests that the EQ-5D may not be appropriate to value recovery after lung resection. PMID- 25499986 TI - Synthesis, reactions and biological activities of furochromones: a review. AB - Furochromone derivatives are important synthetic targets which showed a myriad of interesting biological activities. Ammi visnaga (Umbelliferae) is the most famous source of these derivatives, which has been used in folk medicine for millennia targeting different ailments. Since the isolation of furochromone derivatives, different synthetic methodologies were developed for their preparation. Despite the recent interesting findings on this class of compounds, the chemical literatures lack a comprehensive summary on the synthetic methodologies and biological activities of furochromone derivatives. This review highlights recent advances in furochromones chemistry by discussing different synthetic procedures developed for the preparation of naturally occurring derivatives as well as other unique derivatives which showed promising biological activities. It also sheds light on the most common reactions of furochromone derivatives and the utilization of these derivatives as the blocks for many biologically active compounds. PMID- 25499983 TI - A reanalysis of cluster randomized trials showed interrupted time-series studies were valuable in health system evaluation. AB - OBJECTIVES: There is often substantial uncertainty about the impacts of health system and policy interventions. Despite that, randomized controlled trials (RCTs) are uncommon in this field, partly because experiments can be difficult to carry out. An alternative method for impact evaluation is the interrupted time series (ITS) design. Little is known, however, about how results from the two methods compare. Our aim was to explore whether ITS studies yield results that differ from those of randomized trials. STUDY DESIGN AND SETTING: We conducted single-arm ITS analyses (segmented regression) based on data from the intervention arm of cluster randomized trials (C-RCTs), that is, discarding control arm data. Secondarily, we included the control group data in the analyses, by subtracting control group data points from intervention group data points, thereby constructing a time series representing the difference between the intervention and control groups. We compared the results from the single-arm and controlled ITS analyses with results based on conventional aggregated analyses of trial data. RESULTS: The findings were largely concordant, yielding effect estimates with overlapping 95% confidence intervals (CI) across different analytical methods. However, our analyses revealed the importance of a concurrent control group and of taking baseline and follow-up trends into account in the analysis of C-RCTs. CONCLUSION: The ITS design is valuable for evaluation of health systems interventions, both when RCTs are not feasible and in the analysis and interpretation of data from C-RCTs. PMID- 25499987 TI - Imidazothiazole and related heterocyclic systems. Synthesis, chemical and biological properties. AB - Fused heterobicyclic systems have gained much importance in the field of medicinal chemistry because of their broad spectrum of physiological activities. Among the heterocyclic rings containing bridgehead nitrogen atom, imidazothiazoles derivatives are especially attractive because of their different biological activities. Since many imidazothiazoles derivatives are effective for treating several diseases, is interesting to analyze the behavior of some isosteric related heterocycles, such as pirrolothiazoles, imidazothiadiazoles and imidazotriazoles. In this context, this review summarizes the current knowledge about the syntheses and biological behavior of these families of heterocycles. Traditional synthetic methodologies as well as alternative synthetic procedures are described. Among these last methodologies, the use of multicomponent reaction, novel and efficient coupling reagents, and environmental friendly strategies, like microwave assistance and solvent-free condition in ionic liquids are also summarized. This review includes the biological assessments, docking research and studies of mechanism of action performed in order to obtain the compounds leading to the development of new drugs. PMID- 25499989 TI - Multiple-Band Imaging Provides Better Value Than White-light Endoscopy in Detection of Dysplasia in Patients With Barrett's Esophagus. AB - BACKGROUND & AIMS: Surveillance of patients with Barrett's esophagus usually is performed with standard white-light endoscopy (SDWLE) and the collection of 4 biopsy specimens (every 1-2 cm of the metaplastic segment), based on Seattle protocol. New endoscopic techniques are used routinely, but have been validated based only on low-grade evidence. We aimed to validate the use of high-definition magnifying endoscopy with multiple-band imaging (HDMEMBI) with a targeted biopsy collection for the detection of dysplasia, using SDWLE with quadrant biopsy collection as the reference. METHODS: In a cross-over study, patients with suspected or histologically verified BE (without known neoplasia) seen at a tertiary referral high-volume endoscopy center in Sweden, from November 2009 through November 2012, were assigned randomly to undergo HDMEMBI (n = 63) or SDWLE (n = 47) as the initial procedure, followed by the other procedure in 1 to 4 months. The primary end point was the total number of subjects found to have low-grade dysplasia or high-grade dysplasia (HGD) by each technique. Secondary end points included the number of biopsy specimens taken and the duration of each procedure. RESULTS: There was no significant difference between groups in diagnostic yield for low-grade dysplasia (14 in HDMEMBI vs. 13 in SDWLE) or HGD. Four HGDs were found: 3 using HDMEMBI and 1 using SDWLE. Significantly fewer biopsy specimens were collected during the HDMEMBI procedure (P < .001). The diagnostic yield for the detection of dysplasia per biopsy specimen collected therefore was significantly higher for HDMEMBI than SDWLE (0.25 vs. 0.07; P = .018). There was no significant difference in the duration of procedures. CONCLUSIONS: There is no significant difference in the detection of dysplastic lesions using HDMEMBI with targeted collection of biopsy specimens vs SDWLE with 4-quadrant biopsy specimen collection. However, HDMEMBI requires the collection of significantly fewer biopsy specimens, providing better value for health care providers. ClinicalTrials.gov number: NCT01694511. PMID- 25499988 TI - Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents. AB - A hybrid pharmacophore approach was adopted to design and synthesize new series of isatin-pyridine hybrids. All the newly prepared hybrids (5a-o, 8 and 11a-d) were in vitro evaluated for their anti-proliferative activity against three human cancer cell lines, namely HepG2 hepatocellular carcinoma, A549 lung cancer and MCF-7 breast cancer. Compound 8 emerged as the most active member against HepG2 cell line (IC50 = 2.5 +/- 0.39 MUM), with 2.7-fold increased activity than the reference drug, doxorubicin (IC50 = 6.9 +/- 2.05 MUM). Whilst, compound 11c was found to be the most potent counterpart against A549 and MCF-7 cell lines with IC50 values of 10.8 +/- 1.15 and 6.3 +/- 0.79, respectively. The weightiness of the utilization of non-cleavable linker, as the chalcone linker, and simplification of the first group, was explored via the SAR study. Furthermore, a QSAR model was built to explore the structural requirements controlling the cytotoxic activities. Notably, the predicted activities by the QSAR model were very close to those experimentally observed, hinting that this model could be safely applied for prediction of more efficacious hits comprising the same skeletal framework. Finally, a theoretical kinetic study was established to predict the ADME of the active hybrids. PMID- 25499990 TI - Reply: To PMID 24321208. PMID- 25499991 TI - Association between baseline impedance values and response proton pump inhibitors in patients with heartburn. AB - BACKGROUND & AIMS: Esophageal impedance measurements have been proposed to indicate the status of the esophageal mucosa, and might be used to study the roles of the impaired mucosal integrity and increased acid sensitivity in patients with heartburn. We compared baseline impedance levels among patients with heartburn who did and did not respond to proton pump inhibitor (PPI) therapy, along with the pathophysiological characteristics of functional heartburn (FH). METHODS: In a case-control study, we collected data from January to December 2013 on patients with heartburn and normal findings from endoscopy who were not receiving PPI therapy and underwent impedance pH testing at hospitals in Italy. Patients with negative test results were placed on an 8-week course of PPI therapy (84 patients received esomeprazole and 36 patients received pantoprazole). Patients with more than 50% symptom improvement were classified as FH/PPI responders and patients with less than 50% symptom improvement were classified as FH/PPI nonresponders. Patients with hypersensitive esophagus and healthy volunteers served as controls. In all patients and controls, we measured acid exposure time, number of reflux events, baseline impedance, and swallow induced peristaltic wave indices. RESULTS: FH/PPI responders had higher acid exposure times, numbers of reflux events, and acid refluxes compared with FH/PPI nonresponders (P < .05). Patients with hypersensitive esophagus had mean acid exposure times and numbers of reflux events similar to those of FH/PPI responders. Baseline impedance levels were lower in FH/PPI responders and patients with hypersensitive esophagus, compared with FH/PPI nonresponders and healthy volunteers (P < .001). Swallow-induced peristaltic wave indices were similar between FH/PPI responders and patients with hypersensitive esophagus. CONCLUSIONS: Patients with FH who respond to PPI therapy have impedance pH features similar to those of patients with hypersensitive esophagus. Baseline impedance measurements might allow for identification of patients who respond to PPIs but would be classified as having FH based on conventional impedance-pH measurements. PMID- 25499992 TI - Reply: To PMID 24161347. PMID- 25499993 TI - Reply: To PMID 25445770. PMID- 25499994 TI - Reply: To PMID 25158926. PMID- 25499995 TI - Reply: To PMID 24407107. PMID- 25499996 TI - Appendiceal mucocele: a diagnosis to keep in mind when encountering a retrovesical lesion. PMID- 25499997 TI - Crosstalk between bone niche and immune system: osteoimmunology signaling as a potential target for cancer treatment. AB - There is a well recognized link between the bone and the immune system and in recent years there has been a major effort to elucidate the multiple functions of the molecules expressed in both bone and immune cells. Several molecules that were initially identified and studied in the immune system have been shown to have essential functions also in the bone. An interdisciplinary field embracing immune and bone biology has been brought together and called "osteoimmunology". The co-regulation of the skeletal and immune systems strikingly exemplifies the extreme complexity of such an interaction. Their interdependency must be considered in designing therapeutic approaches for either of the two systems. In other words, it is necessary to think of the osteoimmune system as a complex physiological unit. Denosumab was originally introduced to specifically target bone resorption, but it is now under evaluation for its effect on the long term immune response. Similarly, our current and still growing knowledge of the intimate link between the immune system and bone will be beneficial for the safety of drugs targeting either of these integrated systems. Given the large number of molecules exerting functions on both the skeletal and immune systems, osteoimmunological understanding is becoming increasingly important. Both bone and immune systems are frequently disrupted in cancer; and they may be crucial in regulating tumor growth and progression. Some therapies - such as bisphosphonates and receptor activator of NF-kappaB ligand (RANKL) targeted drugs - that aim at reducing pathologic osteolysis in cancer may interact with the immune system, thus providing potential favorable effects on survival. PMID- 25499998 TI - Metallic taste in cancer patients treated with chemotherapy. AB - BACKGROUND: Metallic taste is a taste alteration frequently reported by cancer patients treated with chemotherapy. Attention to this side effect of chemotherapy is limited. This review addresses the definition, assessment methods, prevalence, duration, etiology, and management strategies of metallic taste in chemotherapy treated cancer patients. METHODS: Literature search for metallic taste and chemotherapy was performed in PubMed up to September 2014, resulting in 184 articles of which 13 articles fulfilled the inclusion criteria: English publications addressing metallic taste in cancer patients treated with FDA approved chemotherapy. An additional search in Google Scholar, in related articles of both search engines, and subsequent in the reference lists, resulted in 13 additional articles included in this review. Cancer patient forums were visited to explore management strategies. FINDINGS: Prevalence of metallic taste ranged from 9.7% to 78% among patients with various cancers, chemotherapy treatments, and treatment phases. No studies have been performed to investigate the influence of metallic taste on dietary intake, body weight, and quality of life. Several management strategies can be recommended for cancer patients: using plastic utensils, eating cold or frozen foods, adding strong herbs, spices, sweetener or acid to foods, eating sweet and sour foods, using 'miracle fruit' supplements, and rinsing with chelating agents. INTERPRETATION: Although metallic taste is a frequent side effect of chemotherapy and a much discussed topic on cancer patient forums, literature regarding metallic taste among chemotherapy treated cancer patients is scarce. More awareness for this side effect can improve the support for these patients. PMID- 25499999 TI - Ethnicity and emergency presentation of colon cancer. PMID- 25500000 TI - Mechanisms of resistance to BCR-ABL TKIs and the therapeutic strategies: A review. AB - BCR-ABL caused by the translocation of t(9,22) with elevated tyrosine-kinase activity could induce leukemia in mice, which established BCR-ABL as the molecular pathogenic event in CML (Chronic myeloid leukemia). In recent years, a variety of tyrosine kinase inhibitors (TKIs) targeting at BCR-ABL specifically and effectively have been developed, which has fundamentally promoted the treatment of CML. However, the efficacy of TKIs was limited by its resistance induced by the development of kinase domain mutations and other mechanisms illustrated. In this review, we summarized BCR-ABL inhibitors approved by Food and Drug Administration (FAD), with the same concerns focus on the resistant mechanisms of BCR-ABL inhibitors and therapeutic resistant strategies. PMID- 25500001 TI - [Physical performance of older adults living in rural areas at sea level and at high altitude in Peru]. AB - INTRODUCTION: Living at high altitudes requires the inhabitants to adapt biologically and socially to the environment. The objective of this study was to determine the difference in physical performance (PP) in rural populations at sea level and at high altitude. MATERIAL AND METHODS: A cross-sectional study was conducted in rural communities in Ancash, Peru, located at 3.345 meters above sea level (m.a.s.l.) and also in communities located in coastal areas at 6m.a.s.l. PP was measured by the Short Physical Performance Battery (SPPB) and other associated factors. Adjusted prevalence ratios (aPR) were calculated. RESULTS: A total of 130 older adults were assessed in the high altitude communities and 129 on the coast. The median age was 71.4 years, and 55.6% were female. Low physical performance (SPPB <= 6) was 10.0% at high altitude and 19.4% on the coast (p<0.05). Factors associated with low physical performance were residing at the coast (aPR: 2.10, 95% CI 1.02 to 4.33), self-reported poor health (aPR: 2.48, 95% CI 1.21 -5.08), hypertension (aPR: 1.73, 95% CI 1.01 to 2.98), and age (aPR: 1.04, 95% CI 1.01 to 1.07), while being a farmer (aPR: 0.49, 95% CI 0.25 to 0.97), and being independent (aPR: 0.37, 95% CI 0,20-, 072) were found to be protective factors. It was also found that the inhabitants of the coast have a mean of 0.86 points lower total SPPB than the high altitude ones (p=0.004). CONCLUSIONS: There is an association between altitude of residence and PP in older adults. The prevalence of a low PP in older adults in rural areas at sea level is twice as high compared to those living in high altitude rural communities. PMID- 25500002 TI - [Discoveries and techniques that have contributed to improving the treatment of pancreatic diseases]. AB - Due to its retroperitoneal location, the pancreas has historically been a mysterious organ that is difficult to examine and which complicates treatment. The discovery of anesthesia and asepsis in the mid-19th century allowed laparotomic diagnosis, which was previously only possible at autopsy. The expectations of surgery were improved by the detection of blood groups, vitamin K synthesis, and the development of intensive care units. In addition, high levels of presurgical diagnosis and an unquestionable improvement of its results were enabled by advances in laboratory methods (serum quantification of amylase and lipase, tumoral markers, genetics, and techniques for measuring exocrine pancreatic function), imaging and endoscopic modalities, and fine tuning of surgical techniques. In this article, we review the history of the main milestones that have allowed progress in all these aspects. PMID- 25500003 TI - [Recurrent contralateral epiploic appendagitis]. PMID- 25500004 TI - Implications of white striping and wooden breast abnormalities on quality traits of raw and marinated chicken meat. AB - One of the consequences of intense genetic selection for growth of poultry is the recent appearance of abnormalities in chicken breast muscles, such as white striping (characterised by superficial white striations) and wooden breast (characterised by pale and bulged areas with substantial hardness). The aim of this study was to evaluate the quality traits of chicken fillets affected by white striping and wooden breast abnormalities. In two replications, 192 fillets were divided into the following four classes: normal (n=48; absence of any visual defects), white striping (n=48, presence of white striations), wooden breast (n=48; diffusely presence of hardened areas) and white striping/wooden breast (n=48; fillets affected by both abnormalities). Morphology, raw meat texture and technological properties were assessed in both unprocessed (pH, colour, drip loss, cooking loss and cooked meat shear force) and marinated meat (marinade uptake, purge loss, cooking loss and cooked meat shear force). Fillets affected by white striping, wooden breast or both abnormalities exhibited higher breast weights compared with normal fillets (305.5, 298.7, 318.3 and 244.7 g, respectively; P<0.001). Wooden breast, either alone or in combination with white striping, was associated with a significant (P<0.001) increase of fillet thickness in the caudal area and raw meat hardness compared with both normal and the white striping abnormality, for which there was no difference. Overall, the occurrence of the individual and combined white striping and wooden breast abnormalities resulted in substantial reduction in the quality of breast meat, although these abnormalities are associated with distinct characteristics. Wooden breast fillets showed lower marinade uptake and higher cooking losses than white striped fillets for both unprocessed and marinated meats. On the other hand, white-striped fillets showed a moderate decline in marinade and cooking yield. Fillets affected by both abnormalities had the highest (P<0.001) ultimate pH values. In contrast, the effects on colour of raw and cooked meat, drip loss, purge loss and cooked meat shear force were negligible or relatively low and of little practical importance. Thus, the presence of white striping and wooden breast abnormalities impair not only breast meat appearance but also the quality of both raw and marinated meats mainly by reducing water holding/binding abilities. PMID- 25500005 TI - Evaluation of the effect of short-term treatment with the integrase inhibitor raltegravir (Isentress) on the course of progressive feline leukemia virus infection. AB - Cats persistently infected with the gammaretrovirus feline leukemia virus (FeLV) are at risk to die within months to years from FeLV-associated disease, such as immunosuppression, anemia or lymphoma/leukemia. The integrase inhibitor raltegravir has been demonstrated to reduce FeLV replication in vitro. The aim of the present study was to investigate raltegravir in vivo for its safety and efficacy to suppress FeLV replication. The safety was tested in three naive specified pathogen-free (SPF) cats during a 15 weeks treatment period (initially 20mg then 40mg orally b.i.d.). No adverse effects were noted. The efficacy was tested in seven persistently FeLV-infected SPF cats attained from 18 cats experimentally exposed to FeLV-A/Glasgow-1. The seven cats were treated during nine weeks (40mg then 80mg b.i.d.). Raltegravir was well tolerated even at the higher dose. A significant decrease in plasma viral RNA loads (~5*) was found; however, after treatment termination a rebound effect was observed. Only one cat developed anti-FeLV antibodies and viral RNA loads remained decreased after treatment termination. Of note, one of the untreated FeLV-A infected cats developed fatal FeLV-C associated anemia within 5 weeks of FeLV-A infection. Moreover, progressive FeLV infection was associated with significantly lower enFeLV loads prior to infection supporting that FeLV susceptibility may be related to the genetic background of the cat. Overall, our data demonstrate the ability of raltegravir to reduce viral replication also in vivo. However, no complete control of viremia was achieved. Further investigations are needed to find an optimized treatment against FeLV. (250 words). PMID- 25500006 TI - Small molecule chemical probes of microRNA function. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that control protein expression. Aberrant miRNA expression has been linked to various human diseases, and thus miRNAs have been explored as diagnostic markers and therapeutic targets. Although it is challenging to target RNA with small molecules in general, there have been successful campaigns that have identified small molecule modulators of miRNA function by targeting various pathways. For example, small molecules that modulate transcription and target nuclease processing sites in miRNA precursors have been identified. Herein, we describe challenges in developing chemical probes that target miRNAs and highlight aspects of miRNA cellular biology elucidated by using small molecule chemical probes. We expect that this area will expand dramatically in the near future as progress is made in understanding small molecule recognition of RNA. PMID- 25500007 TI - Q192R polymorphism of paraoxonase 1 gene associated with insulin resistance in Mexican children. AB - BACKGROUND AND AIMS: The SNP rs662 in the paraoxonase 1 gene (PON1 Q192R) has been associated with obesity, dyslipidemia and cardiovascular risk. In this study, DNA samples of 117 children aged 6 to 12 years from San Luis Potosi, Mexico were genotyped for Q192R polymorphism of the PON1 gene. METHODS: Genotypic frequencies were determined by allelic discrimination assay by real-time PCR using TaqMan fluorogenic probes. Anthropometry, lipid profile, glucose and insulin were analyzed by genotype. RESULTS: The distribution of allele frequency in the population was Q = 65 and R = 35 following the Hardy Weinberg equilibrium (chi(2) = 3.15, p = 0.076). The Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) index showed statistically significant differences among QQ/QR/RR genotypes (p = 0.032). The odds ratio for the carriers of the RR genotype was associated with HOMA-IR corresponding to the 95(th) percentile or higher for Mexican children based on sex and age (OR = 4.68; 95% confidence intervals, 1.23-17.8; p = 0.016). When the absolute mean of HOMAR-IR was set as the cutoff, an increased odds was observed (OR = 6.52; 95% confidence intervals, 1.68-25.3; p = 0.008). CONCLUSIONS: According to our results, PON1 Q192R polymorphism is a risk marker for insulin resistance, a pathological factor involved in the development of metabolic syndrome. PMID- 25500008 TI - Mitofilin: Key factor in diabetic cardiomyopathy? PMID- 25500009 TI - New disease allele and de novo mutation indicate mutational vulnerability of titin exon 343 in hereditary myopathy with early respiratory failure. AB - We report two patients of Chinese ancestry with hereditary myopathy with early respiratory failure, one sporadic with atypical onset as rigid spine syndrome, the other familial with 10 years' history of hyperCKemia. Muscle biopsy was either nonspecific or typical with cytoplasmic bodies and rimmed vacuoles. Despite the phenotypic variety, both patients showed fatty infiltration of semitendinosus on muscle magnetic resonance imaging. Genetic analysis of case 1 disclosed de novo heterozygous missense mutations in the 119th fibronectin 3 domain of titin [c.90272C>T, p.P30091L]. Haplotype analysis of case 2 revealed a heterozygous missense mutation [c.90211T>C, p.C30071R] on a new disease allele incompatible with the British common haplotype. These findings suggest that hereditary myopathy with early respiratory failure is a worldwide distributed disorder and indicate the mutational vulnerability of TTN exon 343 in which de novo mutations could occur on different haplotype backgrounds. PMID- 25500010 TI - Upper limb module in non-ambulant patients with spinal muscular atrophy: 12 month changes. AB - Recent studies have suggested that in non-ambulant patients affected by spinal muscular atrophy the Upper Limb Module can increase the range of activities assessed by the Hammersmith Functional Motor Scale Expanded. The aim of this study was to establish 12-month changes in the Upper Limb Module in a cohort of non-ambulant spinal muscular atrophy patients and their correlation with changes on the Hammersmith Functional Motor Scale Expanded. The Upper Limb Module scores ranged between 0 and 17 (mean 10.23, SD 4.81) at baseline and between 1 and 17 at 12 months (mean 10.27, SD 4.74). The Hammersmith Functional Motor Scale Expanded scores ranged between 0 and 34 (mean 12.43, SD 9.13) at baseline and between 0 and 34 at 12 months (mean 12.08, SD 9.21). The correlation betweeen the two scales was 0.65 at baseline and 0.72 on the 12 month changes. Our results confirm that the Upper Limb Module can capture functional changes in non-ambulant spinal muscular atrophy patients not otherwise captured by the other scale and that the combination of the two measures allows to capture changes in different subgroups of patients in whom baseline scores and functional changes may be influenced by several variables such as age. PMID- 25500011 TI - Hip flexion weakness is associated with impaired mobility in oculopharyngeal muscular dystrophy: a retrospective study with implications for trial design. AB - Oculopharyngeal muscular dystrophy (OPMD) is a rare myopathy for which validated outcome measures are lacking, posing a barrier to clinical trials. Our goal was to identify factors associated with impaired mobility in OPMD in order to guide development of surrogate endpoints in future clinical trials. One hundred forty four individuals with OPMD were included in this retrospective, single-center study. We made novel use of parametric time-to-event analysis to model age at initial use of assistive device for ambulation. We hypothesized that limb weakness and other markers of disease severity are associated with earlier use of assistive devices. 23.6% of individuals (34/144) progressed to use of assistive devices (mean age 66.0 +/- 9.6 y). Earlier age at assistive device was associated with hip flexion Medical Research Council grade <=3 (p <0.0001), earlier disease onset (p <0.0001), and lack of blepharoptosis surgery (p = 0.011). Markers of dysphagia severity were not associated with earlier progression to assistive devices. Our study is the first to show a statistical association between hip flexion weakness and impaired mobility in OPMD, indicating that hip flexion strength could be explored as a surrogate endpoint for use in clinical trials. Since severity of disease features may be discordant within individuals, composite outcome measures are warranted. PMID- 25500012 TI - Motor unit loss estimation by the multipoint incremental MUNE method in children with spinal muscular atrophy--a preliminary study. AB - Quantitative EMG reflects denervation of muscles after lower motor neuron degeneration in spinal muscular atrophy (SMA) but does not reflect actual motor unit loss. The aim of our study was to assess the value of the multipoint incremental motor unit number estimation (MUNE) method in the modification by Shefner in estimating motor unit loss in SMA. The number of motor units, the mean amplitude of an average surface-detected single motor unit potential (SMUP), and the amplitude of compound motor action potentials (CMAP) were estimated in 14 children with SMA in the abductor pollicis brevis (ABP). Significant differences in MUNE values and SMUP and CMAP amplitude were found between the SMA and control groups (P < 0.0001). MUNE values correlated with Hammersmith Functional Motor Scale (HFMS) scores (P < 0.05). Increased SMUP amplitude values correlated with decreased HFMS scores (P < 0.05). The study confirms that MUNE method in the modification by Shefner is a useful tool reflecting motor unit loss in SMA, and it is easy to perform and well tolerated. MUNE and SMUP amplitude seemed to be sensitive parameters reflecting motor dysfunction in SMA but a longitudinal study in a larger number of subjects is needed. PMID- 25500013 TI - Congenital myasthenic syndrome caused by mutations in DPAGT. AB - Congenital myasthenic syndromes with prominent limb girdle involvement are an important differential diagnosis for congenital myopathies because of the therapeutic considerations. We present a case where accurate diagnosis was delayed for many years. Fluctuations of weakness were misinterpreted as effects of alternative treatments. Weakness was generalised, most prominently in the arms. Fatigability was more prominent in less affected muscles revealed by a positive Simpson test. Stimulation single fibre electromyography confirmed the suspected neuromuscular transmission defect. The marked response to pyridostigmine and cognitive impairment pointed to a myasthenic syndrome due to impaired glycosylation. Two mutations in trans were found in DPAGT1, the gene coding for dolichyl-phosphate N-acetylglucosaminephosphotransferase, one novel, the other previously reported in a rare form of congenital disorder of glycosylation. Gene expression studies revealed that both mutations reduce DPAGT1 expression. Phenotypic features not previously described for DPAGT1 CMS included restricted ocular abduction and long finger flexor contractures. PMID- 25500015 TI - Cytomegalovirus: a culprit or protector in multiple sclerosis? AB - Multiple sclerosis (MS) is a chronic disabling autoimmune disease of the central nervous system (CNS). Cytomegalovirus (CMV), a beta herpes virus, may have a detrimental or beneficial role in MS pathology. Accumulating evidence indicates that CMV contributes to MS disease via interplay of different mechanisms such as molecular mimicry, bystander activation, and epitope spreading. The activation and expansion of a specific T cell subset, CD4(+)CD28(null) T cells, via CMV infection could also contribute to MS pathology. Various additional observations also indicate a protective effect of CMV on autoimmune diseases. CMV immune evasion may mitigate the autoimmune reactions and proinflammatory milieu that contribute to MS. PMID- 25500014 TI - Mitochondria: diversity in the regulation of the NLRP3 inflammasome. AB - Recent studies have identified new roles for mitochondria in the regulation of autoinflammatory processes. Emerging data suggests that the release of danger signals from mitochondria in response to stress and infection promotes the formation of the inflammatory signaling platform known as inflammasomes. Activation of inflammasomes by damaged mitochondria results in caspase-1 dependent secretion of the inflammatory cytokines interleukin-1beta (IL-1beta) and IL-18, and an inflammatory form of cell death referred to as pyroptosis. Here, we review recently described mechanisms that have been proposed to be involved in mitochondria-mediated regulation of inflammasome activation and inflammation. In addition, we highlight how aberrant regulation of mitochondria induced inflammasome activation centrally contributes to the inflammatory process that is responsible for obesity and associated metabolic diseases. PMID- 25500017 TI - Genetic analysis of maintenance of pEC156, a naturally occurring Escherichia coli plasmid that carries genes of the EcoVIII restriction-modification system. AB - In the present study the role of the mechanisms responsible for maintenance of a natural plasmid pEC156, that carries genes of the EcoVIII restriction modification system was investigated. Analysis of this plasmid's genetic content revealed the presence of genetic determinants suggesting two such mechanisms. The first of them relies on site specific recombination utilizing the Xer/cer molecular machinery, while the second involves a restriction-modification system as an addiction module. Our analysis indicated that three factors affect the maintenance of pEC156: (i) a cis-acting cer site involved in resolution of plasmid multimers, (ii) a gene coding for EcoVIII endonuclease, and (iii) plasmid copy number control. The lowest stability was observed with pEC156 derivatives deprived of the cer site. Decreased stability of pEC156 derivatives was also observed in E.coli strains deficient in genes coding for proteins involved in plasmid multimer resolution (XerC, XerD, ArgR and PepA). A similar effect, but to a much lesser extent was observed for the pEC156 derivative without a functional gene coding for EcoVIII endonuclease. Our results indicate that the presence of the cer site is more important for pEC156 stable maintenance than the presence of a functional gene coding for EcoVIII endonuclease. In our work we also tested maintenance of pEC156 possessing a ColE1-type replicon in bacteria belonging to Enterobacteriaceae family. We have found that pEC156 was most stably maintained in Enterobacter cloacae and Klebsiella oxytoca representing coli-type enterobacteria. We have found that in all enterobacteria tested pEC156 derivatives deficient in the cer site were significantly less stably maintained than cer(+) variants. PMID- 25500016 TI - Isolation of a novel plasmid from Couchioplanes caeruleus and construction of two plasmid vectors for gene expression in Actinoplanes missouriensis. AB - To date, no plasmid vector has been developed for the rare actinomycete Actinoplanes missouriensis. Moreover, no small circular plasmid has been reported to exist in the genus Actinoplanes. Here, a novel plasmid, designated pCAZ1, was isolated from Couchioplanes caeruleus subsp. azureus via screening for small circular plasmids in Actinoplanes (57 strains) and Couchioplanes (2 strains). Nucleotide sequencing revealed that pCAZ1 is a 5845-bp circular molecule with a G + C content of 67.5%. The pCAZ1 copy number was estimated at 30 per chromosome. pCAZ1 contains seven putative open reading frames, one of which encodes a protein containing three motifs conserved among plasmid-encoded replication proteins that are involved in the rolling-circle mechanism of replication. Detection of single stranded DNA intermediates in C. caeruleus confirmed that pCAZ1 replicates by this mechanism. The ColE1 origin from pBluescript SK(+) and the oriT sequence with the apramycin resistance gene aac(3)IV from pIJ773 were inserted together into pCAZ1, to construct the Escherichia coli-A. missouriensis shuttle vectors, pCAM1 and pCAM2, in which the foreign DNA fragment was inserted into pCAZ1 in opposite directions. pCAM1 and pCAM2 were successfully transferred to A. missouriensis through the E. coli-mediated conjugative transfer system. The copy numbers of pCAM1 and pCAM2 in A. missouriensis were estimated to be one and four per chromosome, respectively. Thus, these vectors can be used as effective genetic tools for homologous and heterologous gene expression studies in A. missouriensis. PMID- 25500018 TI - Synergy of lipopolysaccharide and resiquimod on type I interferon, pro inflammatory cytokine, Th1 and Th2 response in chicken peripheral blood mononuclear cells. AB - Toll-like receptors (TLRs) recognize conserved molecular structures of invading pathogens and initiate an immune response to curtail the infection prior to the development of more powerful and specific adaptive immunity. Understanding the interactions between different TLRs in terms of immune response genes is a pre requisite for using various TLR agonists alone or in combination as adjuvants or as stand-alone agents against various diseases. Lipopolysaccharide (LPS) and resiquimod (R-848) are TLR agonists that are recognized by TLR4 and TLR7, respectively. In this study, the effect of LPS and/or R-848 on chicken peripheral blood mononuclear cells (PBMCs) was investigated. LPS and R-848 synergistically up-regulated the transcripts of interferon-beta (IFN-beta), IFN-gamma, IL-4 and IL-1beta as compared to the individual response (P<0.05). The results indicate that these agonists synergistically interact and enhance type-I IFN, pro inflammatory cytokine as well as Th1 and Th2 responses in chicken PBMCs, suggesting their potential as an adjuvant candidate to be used in combination with various poultry vaccines. PMID- 25500019 TI - Reliability of the modified Paediatric Evaluation of Disability Inventory, Dutch version (PEDI-NL) for children with cerebral palsy and cerebral visual impairment. AB - PURPOSE: The aims of this study were to adapt the Paediatric Evaluation of Disability Inventory, Dutch version (PEDI-NL) for children with cerebral visual impairment (CVI) and cerebral palsy (CP) and determine test-retest and inter respondent reliability. METHOD: The Delphi method was used to gain consensus among twenty-one health experts familiar with CVI. Test-retest and inter respondent reliability were assessed for parents and caregivers of 75 children (aged 50-144 months) with CP and CVI. The percentage identical scores of item scores were computed, as well as the interclass coefficients (ICC) and Cronbach's alphas of scale scores over the domains self-care, mobility, and social function. RESULTS: All experts agreed on the adaptation of the PEDI-NL for children with CVI. On item score, for the Functional Skills scale, mean percentage identical scores variations for test-retest reliability were 73-79 with Caregiver Assistance scale 73-81, and for inter-respondent reliability 21-76 with Caregiver Assistance scale 40-43. For all scales over all domains ICCs exceeded 0.87. For the domains self-care, mobility, and social function, the Functional Skills scale and the Caregiver Assistance scale have Cronbach's alpha above 0.88. CONCLUSION: The adapted PEDI-NL for children with CP and CVI is reliable and comparable to the original PEDI-NL. PMID- 25500020 TI - Micro-electrophoresis: a noninvasive method of sperm selection based on membrane charge. AB - OBJECTIVE: To develop a technique with the potential of isolating genetically fit sperm for assisted reproductive technology (ART) treatment without compromising its structural or functional competence. DESIGN: Observational study. SETTING: University hospital. PATIENT(S): Fifty patients undergoing infertility diagnosis and 88 couples undergoing ART treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Under an electric field, the percentage of positively charged sperm (PCS), negatively charged sperm (NCS), and neutrally charged sperm was determined for each ejaculate before and after density gradient centrifugation (DGC), and evaluated for sperm DNA damage, histone retention, and couples' ART outcomes. Subsequently, PCS, NCS, and neutrally charged sperm were selected using an intracytoplasmic sperm injection needle and directly analyzed for DNA damage. RESULT(S): There was a reduction in the NCS population (95.10% +/- 0.94% vs. 54.48% +/- 2.39%) and an increase in the PCS population (4.28% +/- 0.58% vs. 42.52% +/- 2.36%) after DGC. The DNA damage was inversely proportional to %NCS (r(2) = -0.242) and directly proportional to the %PCS (r(2) = 0.206). When sperm were picked according to their charge and directly analyzed, sperm DNA damage was lower in the NCS population (3.9% +/- 1.5%) compared with control (17.3% +/- 3.2%) and %PCS populations (27.8% +/- 6.0%). The %NCS was positively associated with fertilization rate (r(2) = 0.469) and blastocyst development (r(2) = 0.308) and inversely associated with embryo arrest (r(2) = -0.253). Implantation rate and clinical pregnancies were higher in patient groups with increased NCS. CONCLUSION(S): Selection of NCS through micro-electrophoresis has the potential to isolate sperm relatively free of DNA damage to be used in ART. PMID- 25500021 TI - What is the "ovarian reserve"? PMID- 25500022 TI - Iron overload-modulated nuclear factor kappa-B activation in human endometrial stromal cells as a mechanism postulated in endometriosis pathogenesis. AB - OBJECTIVE: To evaluate the effect of iron overload on nuclear factor kappa-B (NF kappaB) activation in human endometrial stromal cells (ESCs). DESIGN: Experimental study. SETTING: University hospital research laboratory. PATIENT(S): Ten healthy women. INTERVENTION(S): Isolated ESCs from endometrial biopsies were incubated with 50 MUM FeSO(4) or vehicle. The NF-kappaB inhibitor [5-(p fluorophenyl)-2-ureido] thiophene-3-carboxamide (TPCA-1), which inhibits IKKbeta, the kinase of IkappaBalpha (inhibitory protein of NF-kappaB), was used to prevent iron overload-stimulated NF-kappaB changes in ESCs. MAIN OUTCOME MEASURE(S): NF kappaB activation was assessed by p65:DNA-binding activity immunodetection assay. IkappaBalpha, p65, and intercellular adhesion molecule (ICAM)-1 proteins expression was evaluated by Western blots. ESC soluble ICAM (sICAM)-1 secretion was measured by ELISA using conditioned medium. RESULT(S): Iron overload increased p65:DNA-binding activity and decreased IkappaBalpha and p65 cytoplasmic expression in ESCs after 30 minutes of incubation as compared with the basal condition. ESC ICAM-1 expression and sICAM-1 secretion were higher after 24 hours of iron overload treatment than in the absence of treatment. TPCA-1 prevented the iron overload-induced increase of p65:DNA binding and IkappaBalpha degradation. CONCLUSION(S): Iron overload activates IKKbeta in ESCs, stimulating the NF-kappaB pathway and increasing ICAM-1 expression and sICAM-1 secretion. These results suggest that iron overload induces a proendometriotic phenotype on healthy ESCs, which could participate in endometriosis pathogenesis and development. PMID- 25500023 TI - Ovulation induction: once bitten, twice shy? PMID- 25500024 TI - JAAD dermoscopy case of the month series. PMID- 25500025 TI - Dermoscopy of pigmented variant of acral Spitz nevus. PMID- 25500026 TI - Desmoplastic trichoepithelioma and melanocytic nevus: dermoscopic and reflectance confocal microscopy presentation of a rare collision tumor. PMID- 25500027 TI - When a clinical-dermoscopic correlation is warranted. PMID- 25500028 TI - Dermoscopy in near-full facial transplantation. PMID- 25500029 TI - Pitfalls in the dermoscopic diagnosis of amelanotic melanoma. PMID- 25500030 TI - The dermoscopic variability of dermatofibromas. PMID- 25500031 TI - A pearly papule with arborizing vessels. PMID- 25500032 TI - Regressive scalp lesions: dermoscopic and confocal clues. PMID- 25500033 TI - Dermoscopic pattern in facial trichilemmomas: red iris-like structure. PMID- 25500034 TI - Dermoscopy of hypertrophic lupus erythematosus and differentiation from squamous cell carcinoma. PMID- 25500035 TI - A dermoscopic clue for scurvy. PMID- 25500036 TI - Dermoscopic diagnosis of hair breakage caused by styling procedures in patients of African descent. PMID- 25500037 TI - Comedo-like openings in dermoscopy: an essential diagnostic clue for lichen sclerosus, even in children. PMID- 25500038 TI - Bar code-like hair: dermoscopic marker of tinea capitis and tinea of the eyebrow. PMID- 25500039 TI - In vivo characterization of solitary angiokeratoma by reflectance confocal microscopy and high definition optical coherence tomography. PMID- 25500040 TI - Cutaneous metastasis of renal carcinoma. PMID- 25500041 TI - Dermoscopy of clear cell acanthoma. PMID- 25500042 TI - Extragenital lichen sclerosus: clinical, dermoscopic, confocal microscopy and histologic correlations. PMID- 25500043 TI - Seborrheic keratosis-like melanoma. PMID- 25500044 TI - Melanoma hidden in a hemangioma. PMID- 25500045 TI - Dermoscopy of circumscribed juvenile pityriasis rubra pilaris. PMID- 25500046 TI - Furuncular myiasis: dermoscopic features using a cross-polarized device without contact. PMID- 25500047 TI - Orange color: a dermoscopic clue for the diagnosis of granulomatous skin diseases. PMID- 25500048 TI - Streaks in pigmented squamous cell carcinoma in situ. PMID- 25500049 TI - Regression of seborrheic keratosis in a dermoscopic follow-up series. PMID- 25500050 TI - Dermoscopy "clears" out the diagnosis: an erythematous nodule in a psoriatic patient. PMID- 25500051 TI - A case of pigmented penile intraepithelial neoplasia: dermoscopic and clinicohistopathologic analysis. PMID- 25500052 TI - Dermoscopic "setting sun" pattern of juvenile xanthogranuloma. PMID- 25500053 TI - Collembola vs head lice: a puzzling case solved by videodermoscopy. PMID- 25500054 TI - From actinic keratosis to squamous cell carcinoma: evidence of morphologic and biologic progression. PMID- 25500055 TI - Extracranial carotid artery aneurysm: optimal treatment approach. PMID- 25500056 TI - Assessment of plasma anti-elastin antibodies for use as a diagnostic aid for chronic progressive lymphoedema in Belgian Draught Horses. AB - Diagnosis of chronic progressive lymphoedema (CPL) in draught horses, including the Belgian Draught Horse, is mainly based on clinical evaluation of typical lower limb lesions. A deficient perilymphatic elastic support, caused by a pathological elastin degradation in skin and subcutis, has been suggested as a contributing factor for CPL. Elastin degradation products induce the generation of anti-elastin Ab (AEAb), detectable in horse serum by ELISA. For a clinically healthy group of draught horses, a significantly lower average AEAb-level than 3 clinically affected groups (mild, moderate and severe symptoms) was demonstrated previously. To improve CPL-diagnosis, we evaluated the AEAb-ELISA as an in vitro diagnostic aid in individual horses. Test reproducibility was assessed, performing assays independently in 2 laboratories on a total of 345 horses. Possible factors associated with AEAb-levels (age, gender, pregnancy, test lab and date of blood collection) were analyzed using a mixed statistical model. Results were reproducible in both laboratories. AEAb-levels in moderately and severely affected horses were significantly higher than in healthy horses. Nevertheless, this was only demonstrated in barren mares, and, there was a very large overlap between the clinical groups. Consequently, even when a high AEAb cut-off was handled to obtain a reasonable specificity of 90%, a very low sensitivity (21%) of AEAb for CPL-diagnosis was obtained. Results on the present sample demonstrate that the described ELISA procedure is of no use as a diagnostic test for CPL in individual horses. PMID- 25500057 TI - A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. AB - PURPOSE: MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. EXPERIMENTAL DESIGN: This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in patients with RAS- or BRAF-mutant non-small cell lung, ovarian, or pancreatic cancer. RESULTS: Of note, 113 patients were enrolled, 66 and 47 in dose-escalation and -expansion parts, respectively. MTD was established as buparlisib 70 mg + trametinib 1.5 mg daily [5/15, 33% patients with dose-limiting toxicities (DLT)] and recommended phase II dose (RP2D) buparlisib 60 mg + trametinib 1.5 mg daily (1/10, 10% patients with DLTs). DLTs included stomatitis (8/103, 8%), diarrhea, dysphagia, and creatine kinase (CK) increase (2/103, 2% each). Treatment-related grade 3/4 adverse events (AEs) occurred in 73 patients (65%); mainly CK increase, stomatitis, AST/ALT (aspartate aminotransferase/alanine aminotransferase) increase, and rash. For all (21) patients with ovarian cancer, overall response rate was 29% [1 complete response, 5 partial responses (PR)], disease control rate 76%, and median progression-free survival was 7 months. Minimal activity was observed in patients with non-small cell lung cancer (1/17 PR) and pancreatic cancer (best overall response was SD). Relative to historical data, buparlisib exposure increased and trametinib exposure slightly increased with the combination. CONCLUSIONS: At RP2D, buparlisib 60 mg + trametinib 1.5 mg daily shows promising antitumor activity for patients with KRAS-mutant ovarian cancer. Long-term tolerability of the combination at RP2D is challenging, due to frequent dose interruptions and reductions for toxicity. PMID- 25500059 TI - Brain development in ADHD. AB - Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with underlying brain anatomical and functional measures, as well as familial/genetic factors that are major foci of neuropsychiatric research. Advances in imaging technology have shown structural and functional brain differences between individuals with and without ADHD. Longitudinal studies have enabled the elucidation of differences in developmental course. Studies comparing persisting and remitting cases of ADHD are particularly promising. Therapeutic doses of psychostimulants normalize many measures of brain anatomy and function. PMID- 25500058 TI - Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program. AB - PURPOSE: Inhibitors of PARP, an enzyme involved in base excision repair, have demonstrated single-agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here, we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan. EXPERIMENTAL DESIGN: Talazoparib was tested in vitro in combination with temozolomide (0.3-1,000 MUmol/L) or topotecan (0.03-100 nmol/L) and in vivo at a dose of 0.1 mg/kg administered twice daily for 5 days combined with temozolomide (30 mg/kg/daily x 5; combination A) or 0.25 mg/kg administered twice daily for 5 days combined with temozolomide (12 mg/kg/daily x 5; combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment. RESULTS: In vitro talazoparib potentiated the toxicity of temozolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30-50-fold). There was less potentiation for topotecan. In vivo, talazoparib potentiated the toxicity of temozolomide, and combination A and combination B represent the MTDs when combined with low-dose or high-dose talazoparib, respectively. Both combinations demonstrated significant synergism against 5 of 10 Ewing sarcoma xenografts. The combination demonstrated modest activity against most other xenograft models. Pharmacodynamic studies showed a treatment-induced complete loss of PARP only in tumor models sensitive to either talazoparib alone or talazoparib plus temozolomide. CONCLUSIONS: The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation. PMID- 25500060 TI - Environmental consequences of uranium atmospheric releases from fuel cycle facility: II. The atmospheric deposition of uranium and thorium on plants. AB - Uranium and thorium isotopes were measured in cypress leaves, wheat grains and lettuce taken in the surroundings of the uranium conversion facility of Malvesi (South of France). The comparison of activity levels and activity ratios (namely (238)U/(232)Th and (230)Th/(232)Th) in plants with those in aerosols taken at this site and plants taken far from it shows that aerosols emitted by the nuclear site (uranium releases in the atmosphere by stacks and (230)Th-rich particles emitted from artificial ponds collecting radioactive waste mud) accounts for the high activities recorded in the plant samples close to the site. The atmospheric deposition process onto the plants appears to be the dominant process in plant contamination. Dry deposition velocities of airborne uranium and thorium were measured as 4.6 * 10(-3) and 5.0 * 10(-3) m s(-1), respectively. PMID- 25500061 TI - Effective half-lives of 137Cs from persimmon tree tissue parts in Japan after Fukushima Dai-ichi Nuclear Power Plant accident. AB - To estimate the radiocesium decreasing rates from persimmon trees during a period of about 3 y following the accident at Tokyo Electric Power Company's Fukushima Dai-ichi Nuclear Power Plant (FDNPP), we conducted measurements of tree tissue parts collected in 2011-2013. The sampling was carried out in Chiba, 220 km south of FDNPP; radioactive fallouts discharged from FDNPP had mainly been observed in March-April 2011 on the sampling site. We measured (137)Cs concentrations in the tree tissue parts, i.e., fruits (flesh, skin and seeds), leaves and newly emerged branches, and then the effective half-lives (T(eff)) of (137)Cs were calculated. Leaf samples were classified into two types by sampling months according to the growing stages, that is, immature (April-May) and mature (June-November) leaves. All these parts showed exponential declines in (137)Cs concentration with good adjusted contribution ratios of higher than ca. 0.7. The calculated T(eff) values from all tissue parts were similar with the average of 229 d (range: 216-243 d). From these results, we concluded that each tree tissue was representative for the calculation of Teff. For comparison to these observation results, open source food monitoring data from 2011 to 2013 including (137)Cs data for persimmon fruits collected in Fukushima Prefecture were used to calculate T(eff) for persimmon trees. Values of Teff were obtained for persimmon fruits grown in each local government area in Fukushima Prefecture and they ranged from 303 to 475 d. PMID- 25500062 TI - Potential radiological impact of the phosphate industry on wildlife. AB - The activities of the phosphate industry may lead to enhanced levels of naturally occurring radioactivity in terrestrial and aquatic ecosystems. We performed a preliminary environmental risk assessment (ERA) of environmental contamination resulting from the activities of 5 phosphate fertiliser plants (located in Belgium, Spain, Syria, Egypt, Brazil), a phosphate-mine and a phosphate-export platform in a harbour (both located in Syria). These sites were selected because of the availability of information on concentrations of naturally occurring radionuclides in the surrounding environments. Assessments were generally performed considering highest environmental concentrations reported in the studies. The ERICA Tool, operating in a Tier 2 assessment mode, was used to predict radiation dose rates and associated risk to the selected reference organisms using the ERICA default parameter setting. Reference organisms were those assigned as default by the ERICA Tool. Potential impact is expressed as a best estimate risk quotient (RQ) based on a radiation screening value of 10 MUGy h(-1). If RQ <= 1, the environment is considered unlikely to be at risk and further radiological assessment is not deemed necessary. Except for one of the cases assessed, the best estimate RQ exceeded 1 for at least one of the reference organisms. Internal exposure covered for 90-100 % of the total dose. (226)Ra or (210)Po were generally the highest contributors to the dose. The aquatic ecosystems in the vicinity of the phosphate fertiliser plants in Tessenderlo (Belgium), Huelva (Spain), Goias (Brazil) and the terrestrial environment around the phosphate mine in Palmyra (Syria) are the ecosystems predicted to be potentially most at risk. PMID- 25500063 TI - Presence of radionuclides in sludge from conventional drinking water treatment plants. A review. AB - The analysis of sludge samples generated during water treatment processes show that different radioisotopes of uranium, thorium and radium, among others can accumulate in that kind of samples, even the good removal rates obtained in the aqueous phase (by comparison of influent and effluent water concentrations). Inconsequence, drinking water treatment plants are included in the group of Naturally Occurring Radioactive Material (NORM) industries. The accumulation of radionuclides can be a serious problem especially when this sludge is going to be reused, so more exhaustive information is required to prevent the possible radiological impact of these samples in the environment and also on the people. The main aim of this review is to outline the current situation regarding the different studies reported in the literature up to date focused on the analysis of the radiological content of these sludge samples from drinking water treatment plants. In this sense, special attention is given to the recent approaches for their determination. Another important aim is to discuss about the final disposal of these samples and in this regard, sludge reuse (including for example direct agricultural application or also as building materials) are together with landfilling the main reported strategies. PMID- 25500064 TI - Exposure of a herbivorous fish to 134Cs and 137Cs from the riverbed following the Fukushima disaster. AB - Ayu Plecoglossus altivelis, a herbivorous fish, is an important fishery resource and key component of the foodweb in many Japanese streams. Radionuclide contamination of this species is likely transferred to higher trophic levels, include humans, in the food chain. After the Fukushima accident in March 2011, ayu were exposed to highly contaminated silt while feeding on algae attached to the riverbed stones. To understand the route by which herbivorous fish are exposed to radionuclides, the activity concentrations of sum of (134)Cs and (137)Cs (radiocesium) were analyzed in riverbed samples (algae and silt) and in the internal organs and the muscle of ayu in five river systems in the Fukushima Prefecture between summer 2011 and autumn 2013. Although there was a positive correlation between the radiocesium activity concentrations in the muscle and the internal organs of ayu, the median activity concentration in the muscle was much lower than those in the internal organs. The activity concentrations of radiocesium in the riverbed samples and the internal organs and the muscle of ayu were correlated with contamination levels in soil samples taken from the watershed upstream of the sample sites. The results of the generalized linear mixed models suggest that the activity concentrations in both the internal organs and the muscle of ayu declined over time. Additionally, the activity concentrations in the internal organs were correlated with those in the riverbed samples that were collected around the same time as the ayu. The activity concentrations in the muscle were correlated with ayu body size. Our results suggest that ayu ingest (134)Cs and (137)Cs while grazing silt and algae from the riverbed, and a part of the (134)Cs and (137)Cs is assimilated into the muscle of the fish. PMID- 25500066 TI - [Magnet ingestions in children: a French multicenter study]. AB - Digestive complications related to the ingestion of magnetic foreign bodies in children are increasing, especially in Asia and North America. In France, several case reports have been reported since 2008. We conducted a retrospective multicentric study to evaluate the frequency of ingestion of magnet foreign bodies and to describe the complicated cases that have occurred in France over the last 5 years. We report 40 cases of which 60% were multiple magnet ingestions. Eighty-eight percent of the children of the group who had swallowed multiple magnets needed interventional management by endoscopy (33%) or surgery (58%). Only two children (12.5%) of the group who swallowed one magnet required removal. This problem is not uncommon in France (2% of the 1132 foreign bodies investigated in the Toulouse center over 5 years), which justifies clear information for healthcare professionals and caregivers in order to avoid potential intestinal complications. We suggest interventional management or very close monitoring in the cases of multiple magnet ingestion. Meanwhile, in the majority of confirmed cases of simple magnet ingestions, we propose home monitoring. PMID- 25500067 TI - [Testicular mass in a teenager: a case report of embryonic carcinoma discovered late]. AB - Testicular cancer is a rare disease in adolescents but is the leading cause of solid cancer in 15- to 30-year-old men. We report a clinical case of a 16-year old who presented to the pediatric emergency unit with a testicular mass that had been enlarging for several months and the diagnosis turned out to be multimetastatic testicular cancer. However, early diagnosis largely determines the prognosis of this disease. A literature review enabled us to update the prognostic factors, the reasons for diagnostic delay, and current screening practices for this disease. There are currently no formal guidelines in France. PMID- 25500068 TI - Synthesis and biological activities of vitamin D3 derivatives with cyanoalkyl side chain at C-2 position. AB - We synthesized and evaluated novel vitamin D3 derivatives with cyanoalkyl side chain at C-2 position on the basis of our previous research for 2alpha side chain which bears nitrogen atom-containing functional group. Through a study of X-ray co-crystal structures of human VDR and compound 3, we demonstrated that the 2alpha alkyl side chain in compound 3 shows a novel interaction in the complex of hVDR-LBD and ligand. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25500070 TI - Different vitamin D receptor agonists exhibit differential effects on endothelial function and aortic gene expression in 5/6 nephrectomized rats. AB - Endothelial dysfunction, common in chronic kidney disease (CKD), significantly increases cardiovascular disease risk in CKD patients. This study investigates whether different vitamin D receptor agonists exhibit different effects on endothelial function and on aortic gene expression in an animal CKD model. The 5/6 nephrectomized (NX) rat was treated with or without alfacalcidol (0.02, 0.04 and 0.08MUg/kg), paricalcitol (0.04 and 0.08MUg/kg), or VS-105 (0.004, 0.01 and 0.16MUg/kg). All three compounds at the test doses suppressed serum parathyroid hormone effectively. Alfacalcidol at 0.08MUg/kg raised serum calcium significantly. Endothelial function was assessed by pre-contracting thoracic aortic rings with phenylephrine, followed by treatment with acetylcholine or sodium nitroprusside. Uremia significantly affected endothelial-dependent aortic relaxation, which was improved by all three compounds in a dose-dependent manner with alfacalcidol and paricalcitol exhibiting a lesser effect. DNA microarray analysis of aorta samples revealed that uremia impacted the expression of numerous aortic genes, many of which were normalized by the vitamin D analogs. Real-time RT-PCR analysis confirmed that selected genes such as Abra, Apoa4, Fabp2, Hsd17b2, and Hspa1b affected by uremia were normalized by the vitamin D analogs with alfacalcidol exhibiting less of an effect. These results demonstrate that different vitamin D analogs exhibit different effects on endothelial function and aortic gene expression in 5/6 NX rats. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25500069 TI - Promiscuity and diversity in 3-ketosteroid reductases. AB - Many steroid hormones contain a Delta(4)-3-ketosteroid functionality that undergoes sequential reduction by 5alpha- or 5beta- steroid reductases to produce 5alpha- or 5beta-dihydrosteroids; and a subsequent 3-keto-reduction to produce a series of isomeric tetrahydrosteroids. Apart from steroid 5alpha-reductase all the remaining enzymes involved in the two step reduction process in humans belong to the aldo-keto reductase (AKR) superfamily. The enzymes involved in 3 ketosteroid reduction are AKR1C1-AKR1C4. These enzymes are promiscuous and also catalyze 20-keto- and 17-keto-steroid reduction. Interest in these reactions exist since they regulate steroid hormone metabolism in the liver, and in steroid target tissues, they may regulate steroid hormone receptor occupancy. In addition many of the dihydrosteroids are not biologically inert. The same enzymes are also involved in the metabolism of synthetic steroids e.g., hormone replacement therapeutics, contraceptive agents and inhaled glucocorticoids, and may regulate drug efficacy at their cognate receptors. This article reviews these reactions and the structural basis for substrate diversity in AKR1C1-AKR1C4, ketosteroid reductases. This article is part of a Special Issue entitled 'Steroid/Sterol signaling'. PMID- 25500071 TI - Rapid suppression of 7-dehydrocholesterol reductase activity in keratinocytes by vitamin D. AB - 7-Dehydrocholesterol (7DHC) serves as the sterol substrate for both cholesterol and vitamin D3 (cholecalciferol) synthesis. The pivotal enzyme in these two pathways is 7-dehydrocholesterol reductase (DHCR7), which converts 7DHC to cholesterol. Treatment of adult human epidermal keratinocytes (HEKa) with 10MUM cholecalciferol resulted in a rapid decrease in DHCR7 activity (19% of control activity at 2h). This loss of activity was observed only in HEKa cells, a primary cell line cultured from normal human skin, and not in an immortalized skin cell line (HaCaT cells) nor in two hepatoma cell lines. The decrease in DHCR7 activity was not due to direct inhibition or to dephosphorylation of the enzyme, and enzyme protein levels were not decreased. 25-Hydroxyvitamin D3 had a lesser effect on DHCR7 activity, while 1alpha,25-dihydroxyvitamin D3 had no effect on DHCR7, indicating that the vitamin D receptor is not involved. Treatment with cholecalciferol did not lead to the accumulation of 7-dehydrocholesterol, and a 50% decrease in lanosterol synthesis in these cells suggests that cholecalciferol down-regulates the entire cholesterolgenic pathway. As vitamin D has been reported to be an inhibitor of hedgehog (Hh) signaling through Smo, we tested the effect of cyclopamine, an established inhibitor of the Hh pathway, on DHCR7 activity. Cyclopamine (10MUM) also rapidly decreased DHCR7 activity (50% of control activity at 3h), suggesting that vitamin D3 may modulate DHCR7 activity and cholesterol/vitamin D3 synthesis by inhibiting hedgehog signaling. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25500072 TI - Are low ultraviolet B and vitamin D associated with higher incidence of multiple myeloma? AB - BACKGROUND: The purpose of this study was to determine whether an inverse association exists between latitude, solar ultraviolet B (UVB) irradiance, and incidence rates of multiple myeloma.Methods Associations of latitude and UVB irradiance with age-standardized incidence rates of multiple myeloma were analyzed for 175 countries while controlling for sex-specific obesity prevalence, cigarette consumption, and alcohol consumption using multiple linear regression.Results Incidence rates of multiple myeloma were greater at higher latitudes (R(2) for latitude for males=0.31, p<0.0001; females R(2)=0.27, p<0.0001). In regression models for males (R(2)=0.62, p<0.0001) and females (R(2)=0.51, p<0.0001), UVB irradiance was independently inversely associated with incidence rates.Conclusions Age-adjusted incidence rates of multiple myeloma were higher in countries with lower solar UVB irradiance. Further investigation is warranted in individuals of the association of prediagnostic serum 25(OH)D with risk. PMID- 25500073 TI - Personalized in vitro cancer modeling - fantasy or reality? AB - With greater technological advancements and understanding of pathophysiology, "personalized medicine" has become a more realistic goal. In the field of cancer, personalized medicine is the ultimate objective, as each cancer is unique and each tumor is heterogeneous. For many decades, researchers have relied upon studying the histopathology of tumors in the hope that it would provide clues to understanding the pathophysiology of cancer. Current preclinical research relies heavily upon two-dimensional culture models. However, these models have had limited success in recreating the complex interactions between cancer cells and the stroma environment in vivo. Thus, there is increasing impetus to shift to three-dimensional models, which more accurately reflect this phenomenon. With a more accurate in vitro tumor model, drug sensitivity can be tested to determine the best treatment option based on the tumor characteristics. Many methods have been developed to create tumor models or "tumoroids," each with its advantages and limitations. One significant problem faced is the replication of angiogenesis that is characteristic of tumors in vivo. Nonetheless, if three-dimensional models could be standardized and implemented as a preclinical research tool for therapeutic testing, we would be taking a step towards making personalized cancer medicine a reality. PMID- 25500074 TI - Pazopanib, a Receptor Tyrosine Kinase Inhibitor, Suppresses Tumor Growth through Angiogenesis in Dedifferentiated Liposarcoma Xenograft Models. AB - INTRODUCTION: The rarity of dedifferentiated liposarcoma (DDLPS) and the lack of experimental DDLPS models limit the development of novel therapeutic strategies. Pazopanib (PAZ) is a tyrosine kinase inhibitor that is approved for the treatment of non-adipocytic advanced soft tissue sarcoma. The activity of this agent has not yet been properly explored in preclinical liposarcoma models nor in a randomized phase SH clinical trial in this entity. The aim of the present study was to investigate whether PAZ had antitumor activity in DDLPS models in vivo. MATERIAL AND METHODS: We established two patient-derived DDLPS xenograft models (UZLX-STS3 and UZLX-STS5) through implantation of tumor material from sarcoma patients in athymic nude NMRI mice. An animal model of the SW872 liposarcoma cell line was also used. To investigate the efficacy of PAZ in vivo, mice bearing tumors were treated for 2 weeks with sterile water, doxorubicin (1.2 mg/kg, intraperitoneally, twice per week), PAZ [40 mg/kg, orally (p.o.), twice per day], or PAZ plus doxorubicin (same schedules as for single treatments). RESULTS: Patient-derived xenografts retained the histologic and molecular features of DDLPS. PAZ significantly delayed tumor growth by decreasing proliferation and inhibited angiogenesis in all models tested. Combining the angiogenesis inhibitor with an anthracycline did not show superior efficacy. CONCLUSION: These results suggest that PAZ has potential antitumor activity in DDLPS primarily through antiangiogenic effects and therefore should be explored in clinical trials. PMID- 25500076 TI - Advanced 3D-Sonographic Imaging as a Precise Technique to Evaluate Tumor Volume. AB - Determination of tumor volume in subcutaneously inoculated xenograft models is a standard procedure for clinical and preclinical evaluation of tumor response to treatment. Practitioners frequently use a hands-on caliper method in conjunction with a simplified formula to assess tumor volume. Non-invasive and more precise techniques as investigation by MR or (MU)CT exist but come with various adverse effects in terms of radiation, complex setup or elevated cost of investigations. Therefore, we propose an advanced three-dimensional sonographic imaging technique to determine small tumor volumes in xenografts with high precision and minimized observer variability. We present a study on xenograft carcinoma tumors from which volumes and shapes were calculated with the standard caliper method as well as with a clinically available three-dimensional ultrasound scanner and subsequent processing software. Statistical analysis reveals the suitability of this non invasive approach for the purpose of a quick and precise calculation of tumor volume in small rodents. PMID- 25500075 TI - MicroRNA Profiling of Laser-Microdissected Hepatocellular Carcinoma Reveals an Oncogenic Phenotype of the Tumor Capsule. AB - Several microRNAs (miRNAs) are associated with the molecular pathogenesis of hepatocellular carcinoma (HCC). However, previous studies analyzing the dysregulation of miRNAs in HCC show heterogeneous results. We hypothesized that part of this heterogeneity might be attributable to variations of miRNA expression deriving from the HCC capsule or the fibrotic septa within the peritumoral tissue used as controls. Tissue from surgically resected hepatitis C associated HCC from six well-matched patients was microdissected using laser microdissection and pressure catapulting technique. Four distinct histologic compartments were isolated: tumor parenchyma (TP), fibrous capsule of the tumor (TC), tumor-adjacent liver parenchyma (LP), and cirrhotic septa of the tumor adjacent liver (LC). MiRNA expression profiling analysis of 1105 mature miRNAs and precursors was performed using miRNA microarray. Principal component analysis and consecutive pairwise supervised comparisons demonstrated distinct patterns of expressed miRNAs not only for TP versus LP (e.g., intratumoral down-regulation of miR-214, miR-199a, miR-146a, and miR-125a; P< .05) but also for TC versus LC (including down-regulation within TC of miR-126, miR-99a/100, miR-26a, and miR 125b; P< .05). The tumor capsule therefore demonstrates a tumor-like phenotype with down-regulation of well-known tumor-suppressive miRNAs. Variations of co analyzed fibrotic tissue within the tumor or in controls may have profound influence on miRNA expression analyses in HCC. Several miRNAs, which are proposed to be HCC specific, may indeed be rather associated to the tumor capsule. As miRNAs evolve to be important biomarkers in liver tumors, the presented data have important translational implications on diagnostics and treatment in patients with HCC. PMID- 25500077 TI - The importance of reference gene analysis of formalin-fixed, paraffin-embedded samples from sarcoma patients - an often underestimated problem. AB - OBJECTIVE: Reverse transcription quantitative real-time polymerase chain reaction is efficient for quantification of gene expression, but the choice of reference genes is of paramount importance as it is essential for correct interpretation of data. This is complicated by the fact that the materials often available are routinely collected formalin-fixed, paraffin-embedded (FFPE) samples in which the mRNA is known to be highly degraded. The purpose of this study was to investigate 22 potential reference genes in sarcoma FFPE samples and to study the variation in expression level within different samples taken from the same tumor and between different histologic types. METHODS: Twenty-nine patients treated for sarcoma were enrolled. The samples encompassed 82 (FFPE) specimens. Extraction of total RNA from 7-MUm FFPE sections was performed using a fully automated, bead base RNA isolation procedure, and 22 potential reference genes were analyzed by reverse transcription quantitative real-time polymerase chain reaction. The stability of the genes was analyzed by RealTime Statminer. The intrasamples variation and the interclass correlation coefficients were calculated. The linear regression model was used to calculate the degradation of the mRNA over time. RESULTS: The quality of RNA was sufficient for analysis in 84% of the samples. Recommended reference genes differed with histologic types. However, PPIA, SF3A1, and MRPL19 were stably expressed regardless of the histologic type included. The variation in ?Cq value for samples from the same patients was similar to the variation between patients. It was possible to compensate for the time-dependent degradation of the mRNA when normalization was made using the selected reference genes. CONCLUSION: PPIA, SF3A1, and MRPL19 are suitable reference genes for normalization in gene expression studies of FFPE samples from sarcoma regardless of the histology. PMID- 25500078 TI - New Approach for Interpreting Changes in Circulating Tumour Cells (CTC) for Evaluation of Treatment Effect in Metastatic Breast Cancer. AB - AIM: Attempts have been made to use CTC values for interpretation of treatment response and to guide change of chemotherapy by using a static cut-off of 5 CTC to stratify patients in favourable or unfavourable responders. We propose a new approach to interpret treatment effect using significant changes in CTC values (SCV-limits(1)) as grouping parameter for responders and non-responders to chemotherapy among metastatic breast cancer (mBC) patients. METHOD: CTC were analysed using the CellSearch System in blood from 47 mBC patients before the start of new chemotherapy and before the third cycle of therapy. The new and old approach to interpret changes in CTC values were compared in relation to progression free survival (PFS). RESULTS: The new approach using significant CTC change (P = .032) and the old approach using static cut-off (P > .001) correlated significantly with PFS using a cohort of 47 patients. CONCLUSION: We propose a new approach to interpret significant changes between baseline and follow-up CTC values as a tool for assessing treatment effect in mBC. Our approach stratified patients in new risk groups that were stratified significantly with respect to PFS. More patients are needed to balance the size of the risk groups for better comparison to the existing approach based on a 5 CTC cut-off. PMID- 25500079 TI - Sequential Salinomycin Treatment Results in Resistance Formation through Clonal Selection of Epithelial-Like Tumor Cells. AB - Acquiring therapy resistance is one of the major obstacles in the treatment of patients with cancer. The discovery of the cancer stem cell (CSC)-specific drug salinomycin raised hope for improved treatment options by targeting therapy refractory CSCs and mesenchymal cancer cells. However, the occurrence of an acquired salinomycin resistance in tumor cells remains elusive. To study the formation of salinomycin resistance, mesenchymal breast cancer cells were sequentially treated with salinomycin in an in vitro cell culture assay, and the resulting differences in gene expression and salinomycin susceptibility were analyzed. We demonstrated that long-term salinomycin treatment of mesenchymal cancer cells resulted in salinomycin-resistant cells with elevated levels of epithelial markers, such as E-cadherin and miR-200c, a decreased migratory capability, and a higher susceptibility to the classic chemotherapeutic drug doxorubicin. The formation of salinomycin resistance through the acquisition of epithelial traits was further validated by inducing mesenchymal-epithelial transition through an overexpression of miR-200c. The transition from a mesenchymal to a more epithelial-like phenotype of salinomycin-treated tumor cells was moreover confirmed in vivo, using syngeneic and, for the first time, transgenic mouse tumor models. These results suggest that the acquisition of salinomycin resistance through the clonal selection of epithelial-like cancer cells could become exploited for improved cancer therapies by antagonizing the tumor-progressive effects of epithelial-mesenchymal transition. PMID- 25500080 TI - Prognosis of Glioblastoma With Oligodendroglioma Component is Associated With the IDH1 Mutation and MGMT Methylation Status. AB - Glioblastoma (GBM) with oligodendroglioma component (GBMO) is a newly described GBM subtype in the 2007 World Health Organization classification. However, its biological and genetic characteristics are largely unknown. We investigated the clinicopathological and molecular features of 34 GBMOs and compared the survival rate of these patients with those of patients with astrocytoma, oligodendroglioma, anaplastic oligoastrocytoma (AOA), and conventional GBMs in our hospital. GBMO could be divided into two groups based on the presence of an IDH1 mutation. The IDH1 mutation was more frequently found in secondary GBMO, which had lower frequencies of EGFR amplification but higher MGMT methylation than the wild type IDH1 group, and patients with mutant IDH1 GBMO were on average younger than those with wild-type IDH1. Therefore, GBMO is a clinically and molecularly heterogeneous subtype, largely belonging to a proneural and classical subtype of GBM. The survival rate of GBMO patients itself was worse than that of AOA patients but not significantly better than that of conventional GBM patients. GBMO survival was independent of the dominant histopathological subtype i.e., astrocyte-dominant or oligodendroglioma -dominant, but it was significantly associated with the IDH1 mutation and MGMT methylation status. Therefore, GBMO should be regarded as a separate entity from AOA and must be classified as a subtype of GBM. However, further study is needed to determine whether it is a pathologic variant or a pattern of GBM because GBMO has a similar prognosis to conventional GBMs. PMID- 25500081 TI - Quantification of rare cancer cells in patients with gastrointestinal cancer by nanostructured substrate. AB - Detecting the cancer cells in the peripheral blood, i.e. circulating tumor cell (CTC), have been considered as the "liquid biopsy" and become a particular area of focus. A deep insight into CTC provides a potential alternative method for early diagnosis of solid tumor. Previous studies showed that CTC counts could be regarded as an indicator in tumor diagnosis, predicting clinical outcomes and monitoring treatment responses. In this report, we utilize our facile and efficient CTC detection device made of hydroxyapatite/chitosan (HA/CTS) for rare cancer cells isolation and enumeration in clinical use. A biocompatible and surface roughness controllable nanofilm was deposited onto a glass slide to achieve enhanced topographic interactions with nanoscale cellular surface components, anti-EpCAM (epithelial cell adhesion molecule, EpCAM) were then coated onto the surface of nanosubstrate for specific capture of CTCs. This device performed a considerable and stable capture yields. We evaluated the relationship performance between serial CTC changes and the changes of tumor volume/serum tumor marker in gastrointestinal cancer patients undergoing anti cancer treatments. The present study results showed that changes in the number of CTC were associated with tumor burden and progression. Enumeration of CTCs in cancer patients may predict clinical response. Longitudinal monitoring of individual patients during the therapeutic process showed a close correlation between CTC quantity and clinical response to anti-cancer therapy. Effectively capture of this device is capable of CTCs isolation and quantification for monitoring of cancer and predicting treatment response. PMID- 25500082 TI - Prognostic significance of decreased expression of six large common fragile site genes in oropharyngeal squamous cell carcinomas. AB - Common fragile sites (CFSs) are large regions with profound genomic instability that often span extremely large genes a number of which have been found to be important tumor suppressors. RNA sequencing previously revealed that there was a group of six large CFS genes which frequently had decreased expression in oropharyngeal squamous cell carcinomas (OPSCCs) and real-time reverse transcriptase polymerase chain reaction experiments validated that these six large CFS genes (PARK2, DLG2, NBEA, CTNNA3, DMD, and FHIT) had decreased expression in most of the tumor samples. In this study, we investigated whether the decreased expression of these genes has any clinical significance in OPSCCs. We analyzed the six CFS large genes in 45 OPSCC patients and found that 27 (60%) of the OPSCC tumors had decreased expression of these six genes. When we correlated the expression of these six genes to each patient's clinical records, for 11 patients who had tumor recurrence, 10 of them had decreased expression of almost all 6 genes. When we divided the patients into two groups, one group with decreased expression of the six genes and the other group with either slight changes or increased expression of the six genes, we found that there is significant difference in the incidence of tumor recurrence between these two groups by Kaplan-Meier plot analysis (P < .05). Our results demonstrated that those OPSCC tumors with decreased expression of this select group of six large CFS genes were much more likely to be associated with tumor recurrence and these genes are potential prognostic markers for predicting tumor recurrence in OPSCC. PMID- 25500083 TI - High prevalence of human cytomegalovirus in brain metastases of patients with primary breast and colorectal cancers. AB - BACKGROUND: Brain metastases (BMs) develop by largely unknown mechanisms and cause major morbidity and mortality in patients with solid tumors. Human cytomegalovirus (HCMV) is frequently detected in tumor tissue from patients with different cancers. Here, we aimed to determine the prevalence and potential prognostic role of HCMV in BMs. METHODS: We obtained archived samples of BMs from 41 patients with breast cancer and 37 with colorectal cancer and paired primary tumor tissues from 13 and 12 patients in each respective group. In addition, primary breast cancer tissues from 15 patients were included. HCMV proteins were detected with an immunohistochemical technique and Western blot. HCMV nucleic acids were detected with TaqMan polymerase chain reaction (PCR) assay. RESULTS: HCMV proteins were abundantly expressed in 99% of BM specimens, and in 12 of 13 (92%) paired primary breast cancer specimens. All 12 paired colon cancer samples were positive for HCMV proteins. Protein staining was mainly confined to neoplastic cells. Western blot analysis detected an HCMV-IE reactive protein in 53% of breast cancer specimens, and PCR detected the presence of HCMV DNA and transcripts in 92% and 80% of samples, respectively. Patients with high-level expression of HCMV-IE proteins in their tumors had a shorter time to tumor progression and shorter overall survival. CONCLUSIONS: The prevalence of HCMV proteins and nucleic acids is very high in primary and metastatic tumors and may drive the development of metastatic brain tumors; therefore, this virus may represent a potential therapeutic target in metastatic cancer. PMID- 25500084 TI - The effect of Bortezomib and Rapamycin on Telomerase Activity in Mantle Cell Lymphoma. AB - Mantle cell lymphoma (MCL) is a hematological malignancy with unfavorable prognosis. Novel therapeutic approaches for treating the disease are aimed at the mechanisms regulating growth signals, cellular proliferation, and survival pathways of the malignant clones. Bortezomib (Brt), a proteasome inhibitor with pleiotropic activities was shown to be active in MCL and is currently implemented in therapeutic combinations for this disease. Telomerase activity is essential for survival of malignant cells and as such is considered a valid therapeutic target. This study evaluated the effects of bortezomib on telomerase activity and its regulation in MCL cells in vitro and ex vivo. Our study shows that bortezomib exerts a cytotoxic effect in a dose dependent manner in two MCL cell lines, with differential sensitivity. While the IC50 for HBL-2 cells ranged between 2.5 ng/ml to 1.5 ng/ml during 24-72 h respectively, the IC50 for the NCEB cells was twice. Bortezomib differentially inhibited telomerase activity (TA): in HBL-2 cells there was a decline of 20%-55% during 24-72 h respectively. However in NCEB cells the decline was much smaller, and did not exceed 25%. Inhibition of telomerase activity is shown to be operated by two separate mechanisms: reduction of the hTERT mRNA expression (controlled by the binding of transcription factors) and reduction in phosphorylation of the catalytic subunit of hTERT by its kinases, AKT and PKCalpha. A decrease in telomerase activity was demonstrated also in mononuclear cells, isolated from three MCL patients following incubation of the cells in the presence of bortezomib for 24-72 h. In one patient the decrease in TA ranged between 17%-37% respectively, in the second patient between 63%-76% and in the third patient between 70-100% for 24-72 h respectively. The current study indicates that a combination of bortezomib and rapamycin, (an m-Tor pathway inhibitor used in MCL treatment) induced synergistic inhibition of telomerase activity. In HBL-2 cells, the combined treatment of bortezomib and rapamycin decreased TA by 80% compared to the expected value (40%) and for NCEB cells a similar trend was observed. In contrast, there was neither additive nor synergistic effect of this combination on cell proliferation. In the light of the crucial role of telomerase in cancer cells, it was important to characterize the possible relations between telomerase and bortezomib and to distinguish the biochemical mechanisms of its regulation and its interactions with other signal transduction inhibitors such as rapamycin. The results of this work encourage the in vivo examination of the therapeutic potential of the combination of bortezomib and rapamycin in Mantle Cell Lymphoma patients. PMID- 25500085 TI - Microvesicles as a Biomarker for Tumor Progression versus Treatment Effect in Radiation/Temozolomide-Treated Glioblastoma Patients. AB - The standard of care for glioblastoma (GB) is surgery followed by concurrent radiation therapy (RT) and temozolomide (TMZ) and then adjuvant TMZ. This regime is associated with increased survival but also increased occurrence of equivocal imaging findings, e.g., tumor progression (TP) versus treatment effect (TE), which is also referred to as pseudoprogression (PsP). Equivocal findings make decisions regarding further treatment difficult and often delayed. Because none of the current imaging assays have proven sensitive and specific for differentiation of TP versus TE/PsP, we investigated whether blood-derived microvesicles (MVs) would be a relevant assay. METHODS: 2.8 ml of citrated blood was collected from patients with GB at the time of their RT simulation, at the end of chemoradiation therapy (CRT), and multiple times following treatment. MVs were collected following multiple centrifugations (300g, 2500g, and 15,000g). The pellet from the final spin was analyzed using flow cytometry. A diameter of approximately 300 nm or greater and Pacific Blue-labeled Annexin V positivity were used to identify the MVs reported herein. RESULTS: We analyzed 19 blood samples from 11 patients with GB. MV counts in the patients with stable disease or TE/PsP were significantly lower than patients who developed TP (P = .014). CONCLUSION: These preliminary data suggest that blood analysis for MVs from GB patients receiving CRT may be useful to distinguish TE/PsP from TP. MVs may add clarity to standard imaging for decision making in patients with equivocal imaging findings. PMID- 25500086 TI - Noninvasive characterization of locally advanced breast cancer using textural analysis of quantitative ultrasound parametric images. AB - PURPOSE: The identification of tumor pathologic characteristics is an important part of breast cancer diagnosis, prognosis, and treatment planning but currently requires biopsy as its standard. Here, we investigated a noninvasive quantitative ultrasound method for the characterization of breast tumors in terms of their histologic grade, which can be used with clinical diagnostic ultrasound data. METHODS: Tumors of 57 locally advanced breast cancer patients were analyzed as part of this study. Seven quantitative ultrasound parameters were determined from each tumor region from the radiofrequency data, including mid-band fit, spectral slope, 0-MHz intercept, scatterer spacing, attenuation coefficient estimate, average scatterer diameter, and average acoustic concentration. Parametric maps were generated corresponding to the region of interest, from which four textural features, including contrast, energy, homogeneity, and correlation, were determined as further tumor characterization parameters. Data were examined on the basis of tumor subtypes based on histologic grade (grade I versus grade II to III). RESULTS: Linear discriminant analysis of the means of the parametric maps resulted in classification accuracy of 79%. On the other hand, the linear combination of the texture features of the parametric maps resulted in classification accuracy of 82%. Finally, when both the means and textures of the parametric maps were combined, the best classification accuracy was obtained (86%). CONCLUSIONS: Textural characteristics of quantitative ultrasound spectral parametric maps provided discriminant information about different types of breast tumors. The use of texture features significantly improved the results of ultrasonic tumor characterization compared to conventional mean values. Thus, this study suggests that texture-based quantitative ultrasound analysis of in vivo breast tumors can provide complementary diagnostic information about tumor histologic characteristics. PMID- 25500087 TI - Evaluating treatment response using DW-MRI and DCE-MRI in trastuzumab responsive and resistant HER2-overexpressing human breast cancer xenografts. AB - We report longitudinal diffusion-weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced (DCE)-MRI (7 T) studies designed to identify functional changes, prior to volume changes, in trastuzumab-sensitive and resistant HER2+ breast cancer xenografts. Athymic mice (N = 33) were subcutaneously implanted with trastuzumab-sensitive (BT474) or trastuzumab-resistant (HR6) breast cancer cells. Tumor-bearing animals were distributed into four groups: BT474 treated and control, HR6 treated and control. DW- and DCE-MRI were conducted at baseline, day 1, and day 4; trastuzumab (10 mg/kg) or saline was administered at baseline and day 3. Animals were sacrificed on day 4 and tumors resected for histology. Voxel based DW- and DCE-MRI analyses were performed to generate parametric maps of ADC, K(trans), and ve. On day 1, no differences in tumor size were observed between any of the groups. On day 4, significant differences in tumor size were observed between treated vs. control BT474, treated BT474 vs. treated HR6, and treated vs. control HR6 (P < .0001). On day 1, ve was significantly higher in the BT474 treated group compared to BT474 control (P = .002) and HR6 treated (P = .004). On day 4, ve and K(trans) were significantly higher in the treated BT474 tumors compared to BT474 controls (P = .0007, P = .02, respectively). A significant decrease in Ki67 staining reinforced response in the BT474 treated group compared to BT474 controls (P = .02). This work demonstrated that quantitative MRI biomarkers have the sensitivity to differentiate treatment response in HER2+ tumors prior to changes in tumor size. PMID- 25500088 TI - Fatty Acid binding protein 7 is a molecular marker in adenoid cystic carcinoma of the salivary glands: implications for clinical significance. AB - Adenoid cystic carcinoma (ACC) is an aggressive malignant neoplasm of the salivary glands. Its diagnosis is difficult due to overlapping features with other salivary tumors. Gene expression analysis may complement traditional diagnostic methods. We searched gene expression patterns in the Gene Expression Omnibus (GEO) database and in our tumor and normal samples. The biologic and prognostic potential of the identified genes was analyzed. The GEO data set of primary xenografted ACCs revealed that expression of five genes, engrailed homeobox 1 (EN1), fatty acid binding protein 7 (FABP7), hemoglobin epsilon 1, MYB, and versican (VCAN), was dramatically increased. mRNA expression of EN1, FABP7, MYB, and VCAN distinguished our sporadic ACCs from normal tissues and benign tumors. FABP7 expression appeared to be regulated differently from EN1 and MYB and was crossly correlated with poor prognosis in our ACC cohort. Immunohistochemistry showed that FABP7 protein was predominantly expressed in the nucleus of myoepithelial cells of both tubular and cribriform subtypes. In contrast, in the solid subtype, which is often associated with a lower survival rate, FABP7 protein was uniformly expressed in cancerous cells. One case with cribriform architecture and the highest level of FABP7 mRNA showed strong FABP7 staining in both duct-type epithelial and myoepithelial cells, suggesting that diffuse expression of FABP7 protein might be related to aggressive tumor behavior and poor prognosis. We propose FABP7 as a novel biomarker in ACC. The molecule may be useful in diagnosis and for identifying more effective therapies targeting this protein or upstream molecules that regulate it. PMID- 25500089 TI - Effective strategy of the combination of high-intensity focused ultrasound and transarterial chemoembolization for improving outcome of unresectable and metastatic hepatoblastoma: a retrospective cohort study. AB - The combination of high-intensity focused ultrasound (HIFU) and transarterial chemoembolization (TACE) has been experimentally performed in a variety of malignant tumors, and its validity has not yet been evaluated for hepatoblastoma (HB). We evaluated the disease-response rate, resection rate, and toxicity in children with unresectable or metastatic HB (stage III and stage IV HB) after sequential treatment with TACE plus HIFU in a controlled clinical trial. The 35 patients with unresectable or metastatic HB were nonrandomly assigned to HIFU ablation (n = 12) or C5V chemotherapy (n = 23). The rates of complete resection, tumor response, and treatment toxicity were evaluated for both regimens. Nine patients who received C5V and 10 patients who received TACE plus HIFU became operable (P = .02). The 3-year event-free survival and overall survival rates were 43.03% and 56.68% in the C5V group and 38.57% and 57.86% in the TACE plus HIFU group, respectively. Acute grade 3 or 4 adverse events, including neutropenia, thrombocytopenia, and anemia, were more frequent in patients treated with C5V therapy than in patients receiving TACE plus HIFU. HIFU ablation achieved a higher rate of complete resection and a lower rate of severe complications compared with C5V treatment in children with advanced HB (Chinese Clinical Trials Registry No. ChiCTR-PRCH-08000182). PMID- 25500090 TI - Suitability of surgical tumor tissues, biopsy, or cytology samples for epidermal growth factor receptor mutation testing in non-small cell lung carcinoma based on chinese population. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) mutation status is crucial in treatment selection for non-small cell lung cancer (NSCLC) patients; however, the detection materials' availability remains challenging in clinical practice. In this study, we collected surgical resection tissues, lymph node biopsy, and cytological samples for EGFR mutation testing and investigated the associations between gene mutation and clinical characteristics. METHODS: Two hundred and seventy-six NSCLC adenocarcinoma specimens were collected, and highly sensitive amplification refractory mutation system method was implemented for EGFR mutation detection, with clinicopathologic characteristics involved in the final analysis. RESULTS: In the total of 276 samples, 96% (265/276) of tumors obtained evaluable EGFR mutation status, the frequency of mutation was 55.8% (148/265) in all specimens, and three different type samples shared a comparable successful testing rate: 97.4% (38/39) in surgical tumor tissues, 100% (108/108) in lymph node biopsy samples, and 92.2% (119/129) in cytological samples. EGFR mutation was significantly associated with sex, smoking history, lymph node metastasis status (N stage), primary tumor size, testing tissues origin, and sample type (P < .05). Multivariate analysis reconfirmed that smoking history and primary tumor size shared significant correlation with EGFR mutation after adjustment. CONCLUSIONS: Both lymph node biopsy and cytological samples were suitable surrogates for EGFR mutation detection in NSCLC compared with tumor tissues, gene status should be detected widely considering the high EGFR mutation rate, and nonsmoking history together with smaller primary tumor size was an independent indicator of EGFR mutation status. PMID- 25500091 TI - SIX2 Effects on Wilms Tumor Biology. AB - Wilms tumor (WT) blastema retains gene expression profiles characteristic of the multipotent nephron progenitor pool, or cap mesenchyme (CM), in the developing kidney. As a result, WT blastema and the CM are believed to represent contextual analogues of one another. Sine oculis homeobox 2 (SIX2) is a transcription factor expressed specifically in the CM, provides a critical mechanism for CM self renewal, and remains persistently active in WT blastema, although its purpose in this childhood malignancy remains unclear. We hypothesized that SIX2, analogous to its function in development, confers a survival pathway to blastema, the putative WT stem cell. To test its functional significance in WT biology, wild type SIX2 was overexpressed in the human WT cell line, WiT49. After validating this model, SIX2 effects on anchorage-independent growth, proliferation, invasiveness, canonical WNT pathway signaling, and gene expression of specific WNT pathway participants were evaluated. Relative to controls, WiT49 cells overexpressing SIX2 showed significantly enhanced anchorage-independent growth and early-passage proliferation representing surrogates of cell survival. Interestingly, overexpression of SIX2 generally repressed TCF/LEF-dependent canonical WNT signaling, which activates and coordinates both differentiation and stem pathways, but significantly heightened canonical WNT signaling through the survivin promoter, a mechanism that exclusively maintains the stem state. In summary, when overexpressed in a human WT cell line, SIX2 enhances cell survival and appears to shift the balance in WNT/beta-catenin signaling away from a differentiation path and toward a stem cell survival path. PMID- 25500092 TI - Increased Anticancer Efficacy of Intravesical Mitomycin C Therapy when Combined with a PCNA Targeting Peptide. AB - Non-muscle-invasive bladder cancers (NMIBCs) are tumors confined to the mucosa or the mucosa/submucosa. An important challenge in treatment of NMIBC is both high recurrence and high progression rates. Consequently, more efficacious intravesical treatment regimes are in demand. Inhibition of the cell's DNA repair systems is a new promising strategy to improve cancer therapy, and proliferating cell nuclear antigen (PCNA) is a new promising target. PCNA is an essential scaffold protein in multiple cellular processes including DNA replication and repair. More than 200 proteins, many involved in stress responses, interact with PCNA through the AlkB homologue 2 PCNA-interacting motif (APIM), including several proteins directly or indirectly involved in repair of DNA interstrand crosslinks (ICLs). In this study, we targeted PCNA with a novel peptide drug containing the APIM sequence, ATX-101, to inhibit repair of the DNA damage introduced by the chemotherapeutics. A bladder cancer cell panel and two different orthotopic models of bladder cancer in rats, the AY-27 implantation model and the dietary BBN induction model, were applied. ATX-101 increased the anticancer efficacy of the ICL-inducing drug mitomycin C (MMC), as well as bleomycin and gemcitabine in all bladder cancer cell lines tested. Furthermore, we found that ATX-101 given intravesically in combination with MMC penetrated the bladder wall and further reduced the tumor growth in both the slow growing endogenously induced and the rapidly growing transplanted tumors. These results suggest that ATX-101 has the potential to improve the efficacy of current MMC treatment in NMIBC. PMID- 25500093 TI - Development and impact of computerised decision support systems for clinical management of depression: A systematic review. AB - One of the proposals for improving clinical practice is to introduce computerised decision support systems (CDSS) and integrate these with electronic medical records. Accordingly, this study sought to systematically review evidence on the effectiveness of CDSS in the management of depression. A search was performed in Medline, EMBASE and PsycInfo, in order to do this. The quality of quantitative studies was assessed using the SIGN method, and qualitative studies using the CASPe checklist. Seven studies were identified (3 randomised clinical trials, 3 non-randomised trials, and one qualitative study). The CDSS assessed incorporated content drawn from guidelines and other evidence-based products. In general, the CDSS had a positive impact on different aspects, such as the screening and diagnosis, treatment, improvement in depressive symptoms and quality of life, and referral of patients. The use of CDSS could thus serve to optimise care of depression in various scenarios by providing recommendations based on the best evidence available and facilitating decision-making in clinical practice. PMID- 25500094 TI - Intrinsic and extrinsic control of expression of the immunoregulatory molecule PD L1 in epithelial cells and squamous cell carcinoma. AB - Recent clinical results for PD-1 blockade therapy have demonstrated durable tumor control with minimal immune-related adverse effects. PD-L1 is induced in non lymphoid tissue cells and tumor cells, in addition to tissue-recruiting immune cells, under inflammatory conditions triggered by several cytokines, especially IFN-gamma, and exogenous stimuli delivered by pathogen-associated molecular patterns. Receptor-mediated signaling molecules that affect the cell cycle, proliferation, apoptosis, and survival (including NF-kappaB, MAPK, PI3K, mTOR, and JAK/STAT) are involved in PD-L1 induction. PD-L1 expression in tumor cells is also triggered by the signals described above, but in some instances, intrinsic cell alteration associated with carcinogenesis contributes to PD-L1 induction. The tumor suppressor genes PTEN and Lkb1 and epithelial-mesenchymal transition related molecules are also involved in the regulation of PD-L1 expression. Notably, squamous cell carcinoma of the head and neck (SCCHN) often exhibits both host immunosuppression and cytogenetic alternations of tumor cells. Precise understanding of how PD-L1 expression is controlled will allow the development of effective approaches to PD-1 blockade therapy for patients with SCCHN. PMID- 25500095 TI - miR-494 represses HOXA10 expression and inhibits cell proliferation in oral cancer. AB - OBJECTIVES: miR-494 was identified as a candidate of the most significantly underexpressed microRNAs (miRNAs) in our oral cancer screen. The aim of this study was to validate whether miR-494 has a functional role in oral cancer. METHODS: Quantitative miRNA analyses were performed on oral tumor RNA and oral cancer cell lines. HOXA10 was selected for further analysis based on bioinformatics analysis of miR-494 targets and a previous report of overexpression of HOXA10 in oral cancer. Transient transfection of miRNA-mimic and inhibitor were performed in SCC-25 (tongue), CAL 27 (tongue), and FaDu (pharynx) cancer cells and regulation of HOXA10 by miR-494 was investigated. Dual luciferase assay was used to verify the interaction between miR-494 and HOXA10 in reporter cells. The effect of miR-494 on cell proliferation was examined. RESULTS: Our data showed that miR-494 was underexpressed whereas HOXA10 was overexpressed in oral cancer compared to normal tissues. An inverse correlation between miR-494 and HOXA10 was observed in the human tissues (p<0.05). Transient transfection of miR-494 in all cancer cell lines significantly reduced the expression of HOXA10 mRNA. The luciferase reporter that contains the 3'UTR of HOXA10 showed a significantly reduced luciferase activity by miR-494 indicating a direct interaction between HOXA10 and miR-494. Significant reduction in cell proliferation was demonstrated in tongue cancer cells transfected with miR-494. CONCLUSION: miR-494 repressed the expression of HOXA10 and also reduced the proliferation of oral cancer cells. These data give more evidence of the role of miR-494 as a tumor suppressor miRNA in oral cancer. PMID- 25500096 TI - Chlamydia trachomatis infection: possible cofactor for oropharyngeal cancer development? PMID- 25500098 TI - Modulation of particle size and molecular interactions by sonoprecipitation method for enhancing dissolution rate of poorly water-soluble drug. AB - Aim of present work was to originally elucidate the roles of ultrasonication method for modulating the size and molecular interactions in controlling release of poorly water-soluble drug. Curcumin was chosen as a model drug. Three types of polymers were investigated as carriers for preparation of polymeric nanoparticles under various ultrasonication conditions and polymer-drug ratios. Changes in drug crystallinity, particle size, and molecular interactions which would be factors enhancing drug dissolution rate were evaluated. Amorphous form of curcumin, size reduction of nanoparticles and interaction between drug and polymer in formulations were attributed to improved drug dissolution rate. Particle size was strongly affected by polymer type, polymer-drug ratio and ultrasonication conditions. Interestingly, control of those factors caused differences in molecular interactions of the hydroxyl groups and then, highly affected particle size of the nanoparticles. It was obvious that there was a reciprocal influence between the drug-polymer interactions and particle size of the nanoparticles. This relation could be modulated by polymers and ultrasonication processes for enhancing drug dissolution rate. PMID- 25500097 TI - MyPreventiveCare: implementation and dissemination of an interactive preventive health record in three practice-based research networks serving disadvantaged patients--a randomized cluster trial. AB - BACKGROUND: Evidence-based preventive services for early detection of cancer and other health conditions offer profound health benefits, yet Americans receive only half of indicated services. Policy initiatives promote the adoption of information technologies to engage patients in care. We developed a theory-driven interactive preventive health record (IPHR) to engage patients in health promotion. The model defines five levels of functionality: (1) collecting patient information, (2) integrating with electronic health records (EHRs), (3) translating information into lay language, (4) providing individualized, guideline-based clinical recommendations, and (5) facilitating patient action. It is hypothesized that personal health records (PHRs) with these higher levels of functionality will inform and activate patients in ways that simpler PHRs cannot. However, realizing this vision requires both technological advances and effective implementation based upon clinician and practice engagement. METHODS/DESIGN: We are starting a two-phase, mixed-method trial to evaluate whether the IPHR is scalable across a large number of practices and how its uptake differs for minority and disadvantaged patients. In phase 1, 40 practices from three practice based research networks will be randomized to add IPHR functionality to their PHR versus continue to use their existing PHR. Throughout the study, we will engage intervention practices to locally tailor IPHR content and learn how to integrate new functions into their practice workflow. In phase 2, the IPHR to all nonintervention practices to observe whether the IPHR can be implemented more broadly (Scalability). Phase 1 will feature an implementation assessment in intervention practices, based on the RE-AIM model, to measure Reach (creation of IPHR accounts by patients), Adoption (practice decision to use the IPHR), Implementation (consistency, fidelity, barriers, and facilitators of use), and Maintenance (sustained use). The incremental effect of the IPHR on receipt of cancer screening tests and shared decision-making compared to traditional PHRs will assess Effectiveness. In phase 2, we will assess similar outcomes as phase 1 except for effectiveness. DISCUSSION: This study will yield information about the effectiveness of new health information technologies designed to actively engage patients in their care as well as information about how to effectively implement and disseminate PHRs by engaging clinicians. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02138448. PMID- 25500099 TI - Valve-sparing root reimplantation and leaflet repair in a bicuspid aortic valve: comparison with the 3-cusp David procedure. AB - OBJECTIVE: Valve-sparing root reimplantation (VSRR) in tricuspid aortic valve (TAV) patients is well established, but in bicuspid aortic valve (BAV) patients, it has been less widely adopted. We assessed whether valve type affects midterm outcomes with VSRR. METHODS: A retrospective review was performed of 186 patients who underwent an aortic valve-sparing root reimplantation operation between 2004 and 2013. Of these, 129 patients underwent elective VSRR with the David V technique. Outcomes were compared in this cohort by valve type: TAV (n = 89) versus BAV (n = 40). RESULTS: Demographics were similar in the 2 groups. BAV patients had a higher degree of aortic insufficiency (AI) at presentation (P < .05), and an enlarged preoperative annulus (30 +/- 4 vs 28 +/- 6 mm, P = .06). All BAV patients required primary leaflet repair (6% in the TAV group; P < .01). Postoperative mortality (0), stroke (0% vs 1%), and pacemaker requirement (0% vs 5%) were similar. Postoperative freedom from AI grade >=2+ was 100% in the entire cohort, and transvalvular gradients were similar. At follow-up, a 1-year echocardiogram showed higher peak and mean transvalvular gradients in the BAV group (P < .01). One TAV group patient died from an unknown cause. The 5-year actuarial freedom from aortic valve reoperation was 100% versus 97% +/- 3% (P = .6). Three patients in the entire cohort have had AI grade >2+ on follow-up (n = 1 in the BAV group; n = 2 in the TAV group). CONCLUSIONS: Even though BAV patients present with higher AI grade and require concomitant primary valve repair, the VSRR David V technique offers excellent midterm outcomes with both the BAV and TAV valve types. PMID- 25500100 TI - Analysis of longitudinal quality-of-life data in high-risk operable patients with lung cancer: results from the ACOSOG Z4032 (Alliance) multicenter randomized trial. AB - BACKGROUND: Prior studies have suggested that low baseline quality-of-life (QOL) scores predict worse survival in patients undergoing lung cancer surgery. However, these studies involved average-risk patients undergoing lobectomy. We report QOL results from a multicenter trial, American College of Surgeons Oncology Group Z4032, which randomized high-risk operable patients to sublobar resection (SR), or SR with brachytherapy, and included longitudinal QOL assessments. METHODS: Global QOL, using the 36-item Short-Form Health Survey (SF36), and the dyspnea score from the University of California, San Diego Shortness of Breath Questionnaire (SOBQ) scale, was measured at baseline, 3, 12, and 24 months. SF36 physical component summary (PCS) and mental component summary (MCS) scores were standardized and adjusted for age and gender normals, with scores <50 indicating below-average health status. SOBQ scores were transformed to a 0-100 (poor-excellent) scale. Aims were to: (1) determine the impact of baseline scores on recurrence-free survival, overall survival, and 30-day adverse events (AEs); and (2) identify subgroups (surgical approach, resection type. tumor location, tumor size, respiratory function) with a >= 10-point decline or improvement in QOL after SR. RESULTS: Two hundred twelve eligible patients were included. There were no significant differences in baseline QOL scores between arms. Median baseline PCS, MCS, and SOBQ scores were 42.7, 51.1, and 70.8, respectively. There were no differences in grade-3+ AEs, overall survival, or recurrence-free survival in patients with baseline scores <= median versus > median values, except for a significantly worse overall survival for patients with baseline SOBQ scores <= median value. There were no significant differences between the study arms in percentage change of QOL scores from baseline to 3, 12, or 24 months. Further comparison combining the 2 arms demonstrated a higher percentage of patients with a >= 10-point decline in SOBQ scores with segmentectomy compared with wedge resection (40.5% vs 21.9%, P = .03) at 12 months, with thoracotomy versus video-assisted thoracic surgery (VATS) (38.8% vs 20.4%, P = .03) at 12 months, and T1b versus T1a tumors (46.9% vs 23.5%, P = .020) at 24 months. A >= 10-point improvement in PCS score was seen at 3 months with VATS versus thoracotomy (16.5% vs 3.6%, P = .02). CONCLUSIONS: In high-risk operable patients, poor baseline QOL scores were not predictive for worse overall or recurrence-free survival, or for higher risk for AEs following SR. VATS was associated with improvement in physical function at 3 months, and improved dyspnea scores at 12 months, lending support for the preferential use of VATS when SR is undertaken. PMID- 25500101 TI - Acute type B aortic dissection complicated by visceral ischemia. AB - OBJECTIVE: Acute type B aortic dissection (ABAD) can lead to visceral malperfusion, a potentially life-threatening complication. The purpose of this study was to investigate the presentation, management, and outcomes of ABAD patients with visceral ischemia who are enrolled in the International Registry of Acute Aortic Dissection. METHODS: Patients with ABAD enrolled in the registry between 1996 and 2013 were identified and stratified based on presence of visceral ischemia at admission. Demographics, medical history, imaging results, management, and outcomes were compared for patients with versus without visceral ischemia. RESULTS: A total of 1456 ABAD patients were identified, of which 104 (7.1%) presented with visceral ischemia. Preoperative limb ischemia (28% vs 7%, P < .001) and acute renal failure (41% vs 14%, P < .001) were more common among patients with visceral ischemia. Endovascular treatment and surgery were offered to 49% and 30% of the visceral ischemia cohort, respectively; remaining patients were managed conservatively. The in-hospital mortality was 30.8% for patients with visceral ischemia and 9.1% for those without visceral ischemia (odds ratio [OR] 4.44; 95% confidence interval [CI], 2.8-7.0, P < .0001). Mortality rates were similar after surgical and endovascular management of visceral ischemia (25.8% and 25.5%, respectively, P = not significant). Among the visceral ischemia group, medical management was a predictor of mortality in multivariate analysis (OR, 5.91; 95% CI, 1.2-31.0; P = .036). CONCLUSIONS: Patients with ABAD complicated by visceral ischemia have a high risk of mortality. We observed similar outcomes for patients treated by endovascular management versus surgery, whereas medical management was an independent predictor of mortality. Early diagnosis and intervention for visceral ischemia seems to be crucial. PMID- 25500103 TI - Aortic root translocation (Nikaidoh procedure): Intermediate follow-up and impact of conduit type. AB - OBJECTIVE: Aortic root translocation is a promising surgical option for repair of transposition of the great arteries, ventricular septal defect, and pulmonary stenosis. There are little data on the outcomes of this procedure, with no long term follow-up available. We reviewed our experience with aortic root translocation and the impact of the type of right ventricular outflow tract reconstruction. METHODS: The demographic, procedural, and outcome data were obtained for 32 patients who underwent aortic root translocation from 1997 to 2013 at Boston Children's Hospital. Patients were grouped on the basis of right ventricular outflow tract reconstruction with a valved conduit or a nonvalved anastomosis of the pulmonary artery bifurcation to the right ventricular outflow tract with anterior patch augmentation (transannular patch). RESULTS: The median age was 7.5 months (16 days to 42 years). Twenty-six patients had valved conduits, and 6 patients had transannular patches. There were no significant differences between groups in baseline and operative characteristics. There was 1 early death (transannular patch group). There were no late deaths during a median follow-up of 20.8 months (1 month to 16.5 years). No patients developed late left ventricular outflow tract obstruction. Transcatheter reintervention was required in 14 patients, 9 with valved conduits (34.6%) and 1 with transannular patch (20%, P > .99). Six patients (19.4%) required reoperation, all with a valved conduit (P = .34). CONCLUSIONS: Aortic root translocation can be done with low early and late mortality. There was preserved aortic valve function and no left ventricular outflow tract obstruction at late follow-up. The use of a transannular patch had early outcomes comparable to valved conduits, with a trend for fewer late reoperations. PMID- 25500104 TI - New procedures, new complications, and new strategies to deal with them. PMID- 25500105 TI - Valve-sparing root reimplantation and bicuspid aortic valve repair: optimism and realism. PMID- 25500106 TI - Operating Room Within the Neonatal Intensive Care Unit--Experience of a Medical Center in Taiwan. AB - BACKGROUND: Most neonates who reside in the neonatal intensive care unit (NICU) and require surgery are transferred to the operating room (OR) or undergo bedside surgery. However, critically ill neonates who are transferred often encounter the risk of complications. An OR in our NICU was therefore launched in 2009. This study was to appraise the surgeries performed in the NICU OR and compare results with the traditional main OR outside the NICU. METHODS: This was a retrospective study in the NICU of a tertiary center. Retrospective chart review was conducted for all neonates who underwent surgical procedures in the NICU OR and the main OR. The information regarding baseline characteristics, surgical procedures and duration, ventilator use, hypothermia, hyperglycemia, instrument dislocations, surgically related infection or complications, and outcomes was obtained. RESULTS: There were a total of 65 patients in this study, 37 in the NCIU OR group and 28 in the main OR group. The presurgical mean airway pressure and the fraction of inspired oxygen (FiO2) were comparable between the two groups, but the postsurgical FiO2 was significantly lower in the NICU OR group (31.0%) than in the main OR group (40.9%; p = 0.027). Furthermore, the NICU OR group required a significantly shorter preoperation waiting time (34.4 minutes vs. 63.6 minutes, p = 0.001) and had a lower incidence of hypothermia than the main OR group (8.1% vs. 39.3%, p = 0.008). However, surgically related complications were similar between groups. CONCLUSION: The OR within the NICU may reduce the risk of complications during transportation and provide continuity of care to critically ill neonates. It also decreases the disturbance to other NICU patients during operation. PMID- 25500108 TI - Secular change in cardiorespiratory fitness and body composition of women: the Aerobics Center Longitudinal Study. AB - OBJECTIVE: To investigate secular change of cardiorespiratory fitness (CRF) and body composition during 35 years in a large sample of women enrolled in the Aerobics Center Longitudinal Study. PATIENTS AND METHODS: A cross-sectional analysis of baseline fitness data collected during preventive medical examination of 13,037 women aged 20 to 64 years evaluated at the Cooper Clinic in Dallas, Texas, from January 1, 1970, through December 30, 2004, who underwent a body composition assessment and a maximal treadmill exercise test. Women were stratified by examination year (5 years for each group) and age. Analysis of covariance was used to ascertain secular change of CRF and body composition. RESULTS: Adjusted CRF levels, as indicated by maximal metabolic equivalent or relative maximum oxygen consumption, among women in the cohort increased significantly during a 35-year period for both age groups (P<.001). The greatest change occurred during the 1970s to 1980s, with a small decrease in 2000 through 2004 in both age groups. Adjusted body mass index increased 9.05% during the past 35 years (P<.001), but adjusted percentage of body fat was significantly higher in 1980 through 1984 than in the other groups (P<.001). CONCLUSIONS: In a large cohort of women, the mean CRF has improved during the past 35 years, with a slight decrease in 2000 through 2004. From 1980 through 2004, the increase in body weight was mainly attributable to the increase in fat-free mass. PMID- 25500109 TI - Modifiable factors associated with copeptin concentration: a general population cohort. AB - BACKGROUND: Vasopressin plays an important role in maintaining volume homeostasis. However, recent studies suggest that vasopressin also may play a detrimental role in the progression of chronic kidney disease. It therefore is of interest to identify factors that influence vasopressin concentration, particularly modifiable ones. STUDY DESIGN: Cross-sectional analyses. SETTING & PARTICIPANTS: Data used are from participants in a large general-population cohort study (Prevention of Renal and Vascular Endstage Disease [PREVEND]). Patients with a missing copeptin value (n=888), nonfasting blood sample (n=495), missing or assumed incorrect 24-hour urine collection (n=388), or heart failure (n=20) were excluded, leaving 6,801 participants for analysis. FACTOR: Identification of lifestyle- and diet-related factors that are associated with copeptin concentration. OUTCOMES: Copeptin concentration as surrogate for vasopressin. MEASUREMENTS: Copeptin was measured by an immunoluminometric assay as a surrogate for vasopressin. Associations were assessed in uni- and multivariable linear regression analyses. RESULTS: Median copeptin concentration was 4.7 (IQR, 2.9-7.6) pmol/L. When copeptin was studied as a dependent variable, the final stepwise backward model revealed associations with higher copeptin concentrations for lower 24-hour urine volume (P < 0.001), higher sodium excretion (P < 0.001), higher systolic blood pressure (P < 0.001), current smoking (P < 0.001), higher alcohol use (P < 0.001), higher urea excretion (P = 0.003), lower potassium excretion (P = 0.002), use of glucose-lowering drugs (P = 0.02), higher body mass index (P < 0.001), and higher plasma glucose level (P < 0.001). No associations with copeptin concentration were found for C-reactive protein or use of diuretics or nondiuretic antihypertensives. LIMITATIONS: The cross-sectional study design does not allow firm conclusions on cause-effect relationships. CONCLUSIONS: Important lifestyle- and diet-related factors associated with copeptin concentration are current smoking, alcohol use, protein and potassium intake, and particularly fluid and sodium intake. These data form a rationale to investigate whether intervening on these factors results in a lower vasopressin concentration with concomitant beneficial renal effects. PMID- 25500110 TI - Metastatic cutaneous Crohn's disease in a child. PMID- 25500107 TI - Neuroendocrine regulation of maternal behavior. AB - The expression of maternal behavior in mammals is regulated by the developmental and experiential events over a female's lifetime. In this review the relationships between the endocrine and neural systems that play key roles in these developmental and experiential processes that affect both the establishment and maintenance of maternal care are presented. The involvement of the hormones estrogen, progesterone, and lactogens are discussed in the context of ligand, receptor, and gene activity in rodents and to a lesser extent in higher mammals. The roles of neuroendocrine factors, including oxytocin, vasopressin, classical neurotransmitters, and other neural gene products that regulate aspects of maternal care are set forth, and the interactions of hormones with central nervous system mediators of maternal behavior are discussed. The impact of prior developmental factors, including epigenetic events, and maternal experience on subsequent maternal care are assessed over the course of the female's lifespan. It is proposed that common neuroendocrine mechanisms underlie the regulation of maternal care in mammals. PMID- 25500112 TI - Are "armchair socialists" still sitting? Cross sectional study of political affiliation and physical activity. AB - OBJECTIVE: To examine the validity of the concept of left wing "armchair socialists" and whether they sit more and move less than their right wing and centrist counterparts. DESIGN: Secondary analysis of Eurobarometer data from 32 European countries. SETTING: The study emanated from the authors' sit-stand desks (rather than from their armchairs). PARTICIPANTS: Total of 29,193 European adults, of whom 1985 were left wing, 1902 right wing, 17,657 political centrists, and 7649 politically uncommitted. MAIN OUTCOME MEASURES: Self-reported political affiliation, physical activity, and total daily sitting time. METHODS: Linear models were used to examine the relation between physical activity, sitting time, and reported political affiliation. RESULTS: The findings refute the existence of an "armchair socialist"; people at the extremes of both ends of the political spectrum were more physically active, with the right wing reporting 62.2 more weekly minutes of physical activity (95% confidence interval 23.9 to 100.5), and the left wing 57.8 more minutes (20.6 to 95.1) than those in the political centre. People with right wing political affiliations reported 12.8 minutes less time sitting a day (3.8 to 21.9) than the centrists. It is those sitting in the middle (politically) that are moving less, and possibly sitting more, both on the fence and elsewhere, making them a defined at-risk group. CONCLUSIONS: There is little evidence to support the notion of armchair socialists, as they are more active than the mainstream in the political centre. Encouraging centrists to adopt stronger political views may be an innovative approach to increasing their physical activity, potentially benefiting population health. PMID- 25500114 TI - Healer, dealer, heart stealer: portrayals of the doctor in popular music. PMID- 25500113 TI - The Darwin Awards: sex differences in idiotic behaviour. AB - Sex differences in risk seeking behaviour, emergency hospital admissions, and mortality are well documented. However, little is known about sex differences in idiotic risk taking behaviour. This paper reviews the data on winners of the Darwin Award over a 20 year period (1995-2014). Winners of the Darwin Award must eliminate themselves from the gene pool in such an idiotic manner that their action ensures one less idiot will survive. This paper reports a marked sex difference in Darwin Award winners: males are significantly more likely to receive the award than females (P<0.0001). We discuss some of the reasons for this difference. PMID- 25500115 TI - The King Canute GP appointment system. PMID- 25500111 TI - Spreading depression transiently disrupts myelin via interferon-gamma signaling. AB - Multiple sclerosis and migraine with aura are clinically correlated and both show imaging changes suggestive of myelin disruption. Furthermore, cortical myelin loss in the cuprizone animal model of multiple sclerosis enhances susceptibility to spreading depression, the likely underlying cause of migraine with aura. Since multiple sclerosis pathology involves inflammatory T cell lymphocyte production of interferon-gamma and a resulting increase in oxidative stress, we tested the hypothesis that spreading depression disrupts myelin through similar signaling pathways. Rat hippocampal slice cultures were initially used to explore myelin loss in spreading depression, since they contain T cells, and allow for controlled tissue microenvironment. These experiments were then translated to the in vivo condition in neocortex. Spreading depression in slice cultures induced significant loss of myelin integrity and myelin basic protein one day later, with gradual recovery by seven days. Myelin basic protein loss was abrogated by T cell depletion, neutralization of interferon-gamma, and pharmacological inhibition of neutral sphingomyelinase-2. Conversely, one day after exposure to interferon gamma, significant reductions in spreading depression threshold, increases in oxidative stress, and reduced levels of glutathione, an endogenous neutral sphingomyelinase-2 inhibitor, emerged. Similarly, spreading depression triggered significant T cell accumulation, sphingomyelinase activation, increased oxidative stress, and reduction of gray and white matter myelin in vivo. Myelin disruption is involved in spreading depression, thereby providing pathophysiological links between multiple sclerosis and migraine with aura. Myelin disruption may promote spreading depression by enhancing aberrant excitability. Thus, preservation of myelin integrity may provide novel therapeutic targets for migraine with aura. PMID- 25500116 TI - An exploration of the basis for patient complaints about the oldness of magazines in practice waiting rooms: cohort study. AB - OBJECTIVE: To explore the basis for patient complaints about the oldness of most magazines in practice waiting rooms. DESIGN: Cohort study. SETTING: Waiting room of a general practice in Auckland, New Zealand. PARTICIPANTS: 87 magazines stacked into three mixed piles and placed in the waiting room: this included non gossipy magazines (Time magazine, the Economist, Australian Women's Weekly, National Geographic, BBC History) and gossipy ones (not identified for fear of litigation). Gossipy was defined as having five or more photographs of celebrities on the front cover and most gossipy as having up to 10 such images. INTERVENTIONS: The magazines were marked with a unique number on the back cover, placed in three piles in the waiting room, and monitored twice weekly. MAIN OUTCOME MEASURES: Disappearance of magazines less than 2 months old versus magazines 3-12 months old, the overall rate of loss of magazines, and the rate of loss of gossipy versus non-gossipy magazines. RESULTS: 47 of the 82 magazines with a visible date on the front cover were aged less than 2 months. 28 of these 47 (60%) magazines and 10 of the 35 (29%) older magazines disappeared (P=0.002). After 31 days, 41 of the 87 (47%, 95% confidence interval 37% to 58%) magazines had disappeared. None of the 19 non-gossipy magazines (the Economist and Time magazine) had disappeared compared with 26 of the 27 (96%) gossipy magazines (P<0.001). All 15 of the most gossipy magazines and none of the non-gossipy magazines [corrected] had disappeared by 31 days. The study was terminated at this point. CONCLUSIONS: General practice waiting rooms contain mainly old magazines. This phenomenon relates to the disappearance of the magazines rather than to the supply of old ones. Gossipy magazines were more likely to disappear than non-gossipy ones. On the grounds of cost we advise practices to supply old copies of non-gossipy magazines. A waiting room science curriculum is urgently needed. PMID- 25500117 TI - Elderly benzodiazepine users at increased risk of activity limitations: influence of chronicity, indications, and duration of action--the three-city cohort. AB - OBJECTIVE: To examine the cross-sectional and longitudinal associations between benzodiazepine use and daily activity limitations, according to drug indications and duration of action. DESIGN: Prospective cohort study. SETTING: Population based three-city study. PARTICIPANTS: 6,600 participants aged 65 years and over included between 1999 and 2001 and followed after 2, 4, and 7 years. MEASUREMENTS: Benzodiazepine users were separated into hypnotic, short-acting anxiolytic, and long-acting anxiolytic users and compared with non users. Three outcomes were examined assessing restrictions in mobility, instrumental activities of daily living (IADLs) and social participation. RESULTS: In multivariate simple or mixed logistic models adjusted for sociodemographic variables, impairments and comorbidity, and for anxiety, insomnia, and depression, hypnotic benzodiazepines were moderately associated with mobility limitation prevalence and IADL limitation incidence. Short-acting and long-acting anxiolytics were associated with IADL limitation prevalence and with mobility limitation prevalence and incidence and long-acting anxiolytics were also associated with IADL limitation incidence. Chronic benzodiazepines users were at a marked risk of developing restrictions for the three outcomes; odds ratio: 1.71 (95% CI: 1.23-2.39) for mobility, 1.54 (95% CI: 1.14-2.10) for IADL, and 1.74 (95% CI: 1.23-2.47) for participation limitations. CONCLUSIONS: Benzodiazepine users are at increased risk of activity limitations regardless of the duration of action or indication. Chronic use of benzodiazepines should be avoided in order to extend disability-free survival. PMID- 25500118 TI - Development of a brief validated geriatric depression screening tool: the SLU "AM SAD". AB - OBJECTIVES: Combining five commonly observed symptoms of late-life depression to develop a short depression screening tool with similar sensitivity and specificity as the conventional, more time-consuming tools. METHODS: We developed the St. Louis University AM SAD (Appetite, Mood, Sleep, Activity, and thoughts of Death) questionnaire. The frequency of each symptom in the prior 2 weeks is quantified as 0, 1, or 2. Patients 65 years or older from our clinics were administered the AM SAD, the Geriatric Depression Scale (GDS-15), the Montgomery Asberg Depression Rating Scale (MADRS), and the St. Louis University Mental Status Exam (SLUMS). RESULTS: 100 patients were selected. AM SAD correlation with GDS was 0.72 and MADRS 0.80. AM SAD yielded a sensitivity and specificity of 79% and 62% against diagnosis of depression; of 88% and 62% with GDS-15; and 92% and 71% with MADRS. CONCLUSIONS: The AM SAD can be reliably used as a short depression screening tool in patients with a SLUMS score of 20 or higher. PMID- 25500119 TI - Comparative study of clinical and neuropsychological characteristics between early-, late and very-late-onset schizophrenia-spectrum disorders. AB - OBJECTIVE: To compare the clinical and neurocognitive profile of early-onset (EOP, <40 years), late-onset (LOP, 40-59 years) and very-late-onset (VLOP, >=60 years) psychosis. DESIGN: Cross-sectional observational study. SETTING: Secondary, tertiary, and community mental health care. PARTICIPANTS: Patients with a DSM-IV diagnosis of non-affective psychotic disorder were included from two complementary studies (GROUP and PSITE) on genetic and environmental risk factors of psychosis in the Netherlands and Belgium. MEASUREMENTS: Main outcome measures were the severity of positive and negative symptoms, quality of life, and age-corrected scores on measures of general intelligence, verbal memory, attention, and executive function. One-year follow-up data were used to validate diagnoses and exclude participants with possible or probable dementia. RESULTS: 286 EOP (85%), 24 LOP (7%) and 28 VLOP (8%) participated. VLOP patients reported significantly more positive symptoms than EOP patients. Age-at-onset groups had similar age-corrected scores on IQ, verbal memory, attention and executive functions. A significantly better performance was found in VLOP compared with LOP on the CAMCOG total score, though scores were still within the normal range. After controlling for possible confounding, however, VLOP differed significantly on an attention accuracy task compared with LOP patients. Re-entering data for probable dementia patients (N = 4) did change the results regarding cognition outcomes. CONCLUSIONS: VLOP patients show more positive symptoms but do not appear to differ on neuropsychological tests from EOP and LOP when age is controlled for. This questions the idea that VLOP is the expression of underlying neurodegeneration. PMID- 25500120 TI - Anxiety symptoms in amnestic mild cognitive impairment are associated with medial temporal atrophy and predict conversion to Alzheimer disease. AB - OBJECTIVE: To test the hypothesis that anxiety in amnestic mild cognitive impairment (aMCI) increases rates of conversion to Alzheimer disease (AD) and to identify potential neural mechanisms underlying such an association. METHODS: Participants (N = 376) with aMCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were studied over a median period of 36 months. A Cox proportional-hazards model was used to assess the association between anxiety severity ratings on the Neuropsychiatric Inventory Questionnaire and AD risk. Other variables were depression, memory loss, and MRI-derived AD-related regions of interest (ROIs), including hippocampal, amygdalar, entorhinal cortical (EC) volumes, and EC thickness, In addition, a linear regression model was used to determine the effect of anxiety in aMCI on rates of atrophy within ROIs. RESULTS: Anxiety severity increased rate of aMCI conversion to AD, after controlling for depression and cognitive decline. The association between anxiety and AD remained significant even with inclusion of ROI baseline values or atrophy rates as explanatory variables. Further, anxiety status predicted greater rates of decrease in EC volume. An association between anxiety and EC thickness missed significance. CONCLUSION: Anxiety symptoms in aMCI predict conversion to AD, over and beyond the effects of depression, memory loss, or atrophy within AD neuroimaging biomarkers. These findings, together with the greater EC atrophy rate predicted by anxiety, are compatible with the hypothesis that anxiety is not a prodromal noncognitive feature of AD but may accelerate decline toward AD through direct or indirect effects on EC. PMID- 25500123 TI - Expression of xenobiotic transporters in the human renal proximal tubule cell line RPTEC/TERT1. AB - The kidney is a major target for drug-induced injury, primarily due the fact that it transports a wide variety of chemical entities into and out of the tubular lumen. Here, we investigated the expression of the main xenobiotic transporters in the human renal proximal tubule cell line RPTEC/TERT1 at an mRNA and/or protein level. RPTEC/TERT1 cells expressed OCT2, OCT3, OCTN2, MATE1, MATE2, OAT1, OAT3 and OAT4. The functionality of the OCTs was demonstrated by directional transport of the fluorescent dye 4-Di-1-ASP. In addition, P-glycoprotein activity in RPTEC/TERT1 cells was verified by fluorescent dye retention in presence of various P-glycoprotein inhibitors. In comparison to proliferating cells, contact inhibited RPTEC/TERT1 cells expressed increased mRNA levels of several ABC transporter family members and were less sensitive to cyclosporine A. We conclude that differentiated RPTEC/TERT1 cells are well suited for utilisation in xenobiotic transport and pharmacokinetic studies. PMID- 25500121 TI - Paradox-breaking RAF inhibitors that also target SRC are effective in drug resistant BRAF mutant melanoma. AB - BRAF and MEK inhibitors are effective in BRAF mutant melanoma, but most patients eventually relapse with acquired resistance, and others present intrinsic resistance to these drugs. Resistance is often mediated by pathway reactivation through receptor tyrosine kinase (RTK)/SRC-family kinase (SFK) signaling or mutant NRAS, which drive paradoxical reactivation of the pathway. We describe pan RAF inhibitors (CCT196969, CCT241161) that also inhibit SFKs. These compounds do not drive paradoxical pathway activation and inhibit MEK/ERK in BRAF and NRAS mutant melanoma. They inhibit melanoma cells and patient-derived xenografts that are resistant to BRAF and BRAF/MEK inhibitors. Thus, paradox-breaking pan-RAF inhibitors that also inhibit SFKs could provide first-line treatment for BRAF and NRAS mutant melanomas and second-line treatment for patients who develop resistance. PMID- 25500122 TI - Conformation of the human immunoglobulin G2 hinge imparts superagonistic properties to immunostimulatory anticancer antibodies. AB - Monoclonal antibody (mAb) drugs that stimulate antitumor immunity are transforming cancer treatment but require optimization for maximum clinical impact. Here, we show that, unlike other immunoglobulin isotypes, human IgG2 (h2) imparts FcgammaR-independent agonistic activity to immune-stimulatory mAbs such as anti-CD40, -4-1BB, and -CD28. Activity is provided by a subfraction of h2, h2B, that is structurally constrained due its unique arrangement of hinge region disulfide bonds. Agonistic activity can be transferred from h2 to h1 by swapping their hinge and CH1 domains, and substitution of key hinge and CH1 cysteines generates homogenous h2 variants with distinct agonistic properties. This provides the exciting opportunity to engineer clinical reagents with defined therapeutic activity regardless of FcgammaR expression levels in the local microenvironment. PMID- 25500124 TI - The aryl hydrocarbon receptor-mediated and genotoxic effects of fractionated extract of standard reference diesel exhaust particle material in pulmonary, liver and prostate cells. AB - Diesel exhaust particles (DEP) and the associated complex mixtures of organic pollutants, such as polycyclic aromatic hydrocarbons (PAHs), or their derivatives, have been suggested to exert deleterious effects on human health. We used a set of defined cellular models representing liver, lung and prostate tissues, in order to compare non-genotoxic and genotoxic effects of crude and fractionated extract of a standard reference DEP material - SRM 1650b. We focused on the aryl hydrocarbon receptor (AhR)-mediated activity, modulation of cell proliferation, formation of DNA adducts, oxidative DNA damage, and induction of DNA damage responses, including evaluation of apoptosis, and phosphorylation of p53 tumor suppressor and checkpoint kinases (Chk). Both PAHs and the polar aromatic compounds contributed to the AhR-mediated activity of DEP-associated organic pollutants. The principal identified AhR agonists included benzo[k]fluoranthene, indeno[1,2,3-c,d]pyrene, chrysene and several non-priority PAHs, including benzochrysenes and methylated PAHs. In contrast to PAHs, polar compounds contributed more significantly to overall formation of DNA adducts associated with phosphorylation of p53, Chk1 or Chk2, and partly with apoptosis. Therefore, more attention should be paid to identification of DEP-associated polar organic compounds, contributing to the AhR activation and cytotoxic/genotoxic effects of complex airborne mixtures of organic contaminants produced by diesel engines. PMID- 25500126 TI - Cytotoxicity of monensin, narasin and salinomycin and their interaction with silybin in HepG2, LMH and L6 cell cultures. AB - The cytotoxic effect of monensin, narasin and salinomycin followed by their co action with silybin in the cell line cultures of human hepatoma (HepG2), chicken hepatoma (LMH) or rat myoblasts (L6) have been investigated. The effective concentration of the studied ionophoric polyethers has been assessed within two biochemical endpoints: mitochondrial activity (MTT assay) and membrane integrity (LDH assay) after 24h incubation of each compound and farther, the cytotoxicity influenced in course of their interaction with silybin was determined. The most affected endpoints were found for inhibition of mitochondrial activity of the hepatoma cell lines and their viability depended on concentration of the ionophoric polyether, as well as on the cell line tested. The rat myoblasts were more sensitive target for cellular membrane damage when compared to inhibition of mitochondrial activity. An interaction between the ionophoric polyethers and silybin resulted a considerable cytotoxicity decrease within all studied cell lines; the combination index (CI) showed differences of interaction mode and dependence on cell culture, concentration of silybin, as well as the assay used. The obtained results are of interest in respect to recent findings on applicability of salinomycin and monensin for human therapy. PMID- 25500125 TI - In vitro re-expression of the aryl hydrocarbon receptor (Ahr) in cultured Ahr deficient mouse antral follicles partially restores the phenotype to that of cultured wild-type mouse follicles. AB - BACKGROUND: The aryl hydrocarbon receptor (AHR) mediates the toxic effects of various endocrine disrupting chemicals. In female mice, global deletion of the Ahr (AhrKO) results in slow growth of ovarian antral follicles. No studies, however, have examined whether injection of the Ahr restores the phenotypes of cultured AhrKO ovarian antral follicles to wild-type levels. METHODS: We developed a system to construct a recombinant adenovirus containing the Ahr to re express the Ahr in AhrKO granulosa cells and whole antral follicles. We then compared follicle growth and levels of factors in the AHR signaling pathway (Ahr, Ahrr, Cyp1a1, and Cyp1b1) in wild-type, AhrKO, and Ahr re-expressed follicles. Further, we compared the response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in wild-type, AhrKO, and Ahr re-expressed follicles. RESULTS: Ahr injection into AhrKO follicles partially restored their growth pattern to wild-type levels. Further, Ahr re-expressed follicles had significantly higher levels of Ahr, Ahrr, Cyp1a1, and Cyp1b1 compared to wild-type follicles. Upon TCDD treatment, only Cyp1a1 levels were significantly higher in Ahr re-expressed follicles compared to the levels in wild-type follicles. CONCLUSION: Our system of re-expression of the Ahr partially restores follicle growth and transcript levels of factors in the AHR signaling pathway to wild-type levels. PMID- 25500127 TI - Short commentary to "Human in vivo database now on ACuteTox home page" [Toxicol. In Vitro 27 (2013) 2350-2351]. PMID- 25500128 TI - Anti Mullerian Hormone (AMH) level and expression in mural and cumulus cells in relation to age. AB - BACKGROUND: Serum AMH is declining with age and is highly associated with ovarian follicular reserve and disordered folliculogenesis. However, the precise role of AMH in the process of human follicular aging has still to be determined. AIM: This study investigates AMH level in the follicular fluid (FF) and mRNA expression pattern in cumulus and mural granulosa cells of human ovarian follicles in relation to age. METHODS: We conducted a prospective study. Sixty eight women undergoing In vitro fertilization (IVF) treatment were enrolled in the study. We obtained FF, mural and cumulus granulosa cells from large preovulatory follicles (17-20 mm) of 21-35 years old women (n = 40) and 40-45 years old women (n = 28) during oocyte pickup. RESULTS: Higher level of AMH mRNA expression in cumulus cells was observed in the older age group compared to the younger (P <0.01). In accordance with AMH mRNA expression results, FF AMH protein levels were significantly higher in the older group than in the younger group (4.7 +/- 1.1 ng?ml and 2.3 +/- 0.2 ng?ml respectively, p < 0.002). CONCLUSIONS: AMH is highly expressed and secreted from cumulus GCs of advanced age patients. This remarkable correlation between AMH mRNA levels in cumulus cells in respect to age suggests that AMH may be involved in follicular aging process. PMID- 25500129 TI - The impact of a stage tailored intervention on alcohol use trajectories among those who do not intend to change. AB - BACKGROUND: Persons not intending to change are an important target population for public health efforts. The aim of this study was to investigate whether subgroups characterized by different trajectories of alcohol use frequency and quantity among persons with unhealthy drinking but no intention to change benefitted differently from a stage tailored intervention. METHODS: This study was part of a randomized controlled trial among job-seekers. The participants of the intervention group (n=413) received feedback letters tailored to their motivational stage. The control group (n=414) received minimal assessment only. Among all participants, 629 (76.1%) did not intend to change alcohol use and constitute the study sample (60.7% men; mean age=29.7 years, SD=10.8). 3-, 6-, and 15-month follow-ups were conducted. Growth mixture modeling was applied to identify classes representing the heterogeneity in the development of alcohol use frequency and quantity and the influence of the intervention on different trajectories. RESULTS: Four classes were identified: a class of persons who achieved abstinence (2%), a class with low-frequent drinking with declining quantity (35%), a class with high-frequent drinking with low but slightly increasing quantity (30%), and a class with constant heavy episodic drinking (33%). Although non-significant, there was a tendency of different intervention effects for different classes. CONCLUSIONS: A sample of persons not intending to change unhealthy alcohol use was composed of subgroups characterized by different trajectories of alcohol use quantity and frequency. Trends towards beneficial intervention effects on motivation and drinking outcomes were not significant, possibly due to low power. PMID- 25500130 TI - The role of general parenting and cannabis-specific parenting practices in adolescent cannabis and other illicit drug use. AB - AIMS: To investigate general and cannabis-specific parenting practices in relation to adolescent cannabis and other illicit drug use. METHODS: Data were derived from the Dutch National School Survey on Substance Use among students (N=3209; aged 12-16 years) and one of their parents in 2011. RESULTS: Logistic regression analyses revealed that 1) parental cannabis use was significantly related to more adolescent lifetime and recent cannabis use, and 2) restrictive cannabis-specific parental rules were associated with less adolescent recent cannabis and lifetime use of other illicit drugs, even when controlled for sociodemographic factors, general parenting, adolescent tobacco use, and tobacco specific parenting. In addition, no significant interaction was observed between parental cannabis use and cannabis-specific rules in their relation to adolescent cannabis and other illicit drug use, indicating that cannabis rules are evenly associated with adolescent drug use for families with and without parental cannabis experience. CONCLUSIONS: In addition to general parenting practices, restrictive cannabis-specific rules are related to lower adolescent cannabis and other illicit drug rates. Parents who ever used cannabis have children with a higher prevalence of cannabis use. However, their restrictive cannabis-specific rules are equally related to a lower chance of adolescent cannabis use. PMID- 25500131 TI - Viability of 3h grown bacterial micro-colonies after direct Raman identification. AB - Clinical diagnostics in routine microbiology still mostly relies on bacterial growth, a time-consuming process that prevents test results to be used directly as key decision-making elements for therapeutic decisions. There is some evidence that Raman micro-spectroscopy provides clinically relevant information from a limited amount of bacterial cells, thus holding the promise of reduced growth times and accelerated result delivery. Indeed, bacterial identification at the species level directly from micro-colonies at an early time of growth (6h) directly on their growth medium has been demonstrated. However, such analysis is suspected to be partly destructive and could prevent the further growth of the colony needed for other tests, e.g. antibiotic susceptibility testing (AST). In the present study, we evaluated the effect of the powerful laser excitation used for Raman identification on micro-colonies probed after very short growth times. We show here, using envelope integrity markers (Syto 9 and Propidium Iodide) directly on ultra-small micro-colonies of a few tens of Escherichia coli and Staphylococcus epidermidis cells (3h growth time), that only the cells that are directly impacted by the laser lose their membrane integrity. Growth kinetics experiments show that the non-probed surrounding cells are sometimes also affected but that the micro-colonies keep their ability to grow, resulting in normal aspect and size of colonies after 15h of growth. Thus, Raman spectroscopy could be used for very early (<3h) identification of grown micro-organisms without impairing further antibiotics susceptibility characterization steps. PMID- 25500132 TI - The small gastroenterology practice: how to survive in a changing world. Perspectives of a practicing clinician. PMID- 25500133 TI - Current state of brachytherapy teaching in Canada: a national survey of radiation oncologists, residents, and fellows. AB - PURPOSE: The objective of the present study was to determine perceptions and barriers concerning brachytherapy (BT) teaching in Canada to guide the development of a BT credentialing process. METHODS AND MATERIALS: In May 2013, an electronic survey was sent to all radiation oncologists, program directors, residents, and fellows in Canada. Questions were asked regarding demographics, practice patterns, teaching methods and assessment, curriculum content, perceptions on resident education, and barriers to resident teaching. RESULTS: One hundred twenty-one staff radiation oncologists and 32 residents responded to the survey. Only 54% of respondents stated that their center had defined specific written objectives with respect to knowledge, skills, and attitudes required for a resident to be competent in BT. The main barriers to BT teaching were stated as being the lack of Royal College guidance (55%), heavy clinical workload (49%), lack of time (37%), and the fact that too much emphasis is placed on passing examinations (32%). Ninety-seven percent of respondents felt that it was important or very important that some elements of BT be included in the mainstream radiation oncology curriculum. Eighty percent of respondents were in agreement with the development of a formal credentialing process by the Royal College of Physicians and Surgeons of Canada, which would lead to separate certification in BT. CONCLUSIONS: The results of this study show the importance of developing specific BT curriculum and emphasize the need for a credentialing process. PMID- 25500134 TI - Identifying a role for human biomonitoring in incidents involving hazardous materials. AB - Human biological monitoring (HBM) is an established method for chemical exposure characterization. Over the past few years HBM complemented environmental modelling and measurement strategies in several large scale chemical incidents in Belgium and Germany. These applications showed biomarkers to persist in body fluids, allowing sample collection to start in the aftermath of the incident. In addition, integration of exposure over time and from different routes and sources of exposure were reflected in HBM results. Especially adducts to hemoglobin were used to study exposures of workers and of the general population in retrospect. HBM results confirmed the exposure, sometimes pointing to a-typical sources and routes of exposure, not foreseen in incident scenarios. As a next step in Belgium, Germany and The Netherlands guidelines were prepared to support a role for HBM in the response to chemical incidents. Current practices indicate that the interpretation of HBM outcome can still be improved, using refined sample collection strategies and reverse dose calculations to facilitate the use of available exposure standards in the interpretation of HBM results. Exchange of knowledge and experience as well as sharing technical resources will further strengthen the role of HBM in the response to public health incidents and disasters. PMID- 25500135 TI - Desktop analysis of potential impacts of visitor use: a case study for the highest park in the Southern Hemisphere. AB - Nature-based tourism and recreation activities have a range of environmental impacts, but most protected area agencies have limited capacity to assess them. To prioritise where and what impacts to monitor and manage, we conducted a desktop assessment using Geographical Information Systems (GIS) by combining recreation ecology research with data on visitor usage and key environmental features for a popular protected area used for mountaineering and trekking, Aconcagua Provincial Park (2400-6962 m a.s.l.) in the Andes of Argentina. First, we integrated visitor data from permits with environmental data using GIS. We then identified key impact indicators for different activities based on the recreation ecology literature. Finally, we integrated this data to identify likely ecological impacts based on the types of activities, amount of use and altitudinal zones. Visitors only used 2% of the Park, but use was concentrated in areas of high conservation value including in alpine meadows and glacier lakes. Impacts on water resources were likely to be concentrated in campsites from the intermediate to the nival/glacial zones of the Park while impacts on terrestrial biodiversity were likely to be more severe in the low and intermediate alpine zones (2400-3800 m a.s.l.). These results highlight how visitor data can be used to identify priority areas for on-ground assessment of impacts in key locations. Improvements to the management of visitors in this Park involves more effective ways of dealing with water extraction and human waste in high altitude campsites and the impacts of hikers and pack animals in the low and intermediate alpine zones. PMID- 25500136 TI - Adding fuel to the fire? Revegetation influences wildfire size and intensity. AB - The regrowth of woody vegetation in cleared landscapes (i.e. revegetation) has the potential to dramatically alter the spatial characteristics of vegetation and fuels, which will potentially alter fire characteristics. Understanding how revegetation alters fire size and intensity will be critical in determining the social and environmental value of revegetation. We used simulation modelling to examine (i) whether increasing native woody vegetation extent across landscapes cleared for pasture (i.e. revegetation) affects fire size and median fireline intensity and (ii) whether fuel load in the pasture matrix, the initial extent of land clearing and weather conditions during a fire alter the direction and/or magnitude of the relationships between revegetation and fire size or intensity. Simulations revealed that fire size and intensity were altered by increasing woody vegetation extent, though the direction of change was dependent upon landscape context. Increased woody vegetation extent led to (i) increased fire size in landscapes with low pasture fuel load (2 t ha(-1)) regardless of the extent of land clearing, (ii) decreased fire size in highly cleared landscapes with moderate (4.5 t ha(-1)) and high (7 t ha(-1)) pasture fuel load, and (iii) little change to fire size in landscapes subjected to low levels of clearing when pasture fuel load was moderate or high. Similar patterns were observed for fireline intensity. The magnitude of change in fire size and intensity was greatest under extreme fire weather conditions. Revegetation rarely increased median fireline intensity beyond suppressible levels (i.e. 4000 kW m(-1)), with fire weather and pasture fuel load being the main determinants of suppression potential. Our findings show that the response of fire size and intensity to revegetation will depend on landscape scale pasture management. PMID- 25500137 TI - Groundwater nitrogen processing in Northern Gulf of Mexico restored marshes. AB - Groundwater nitrogen processing was examined in a restored black needlerush (Juncus roemerianus) marsh to assess its potential for removing land-derived nitrogen pollution. Two restoration designs, one initially planted at 50% cover (half density plots) and the other one at 100% cover (full density plots), were compared with non-vegetated controls. The introduction via groundwater of a NO3( ) solution with a conservative tracer (Br(-)) and labeled isotopically ((15)N) allowed calculation of nitrogen removal in the plots following two methods. The first method used changes in the ratio [NOx]:[Br(-)] as the groundwater plume traveled through the plot, and the second method relied on balancing (15)N input with (15)N export. Both methods showed ~97% of the N from the simulated groundwater plume was removed (i.e. not delivered to the open waters of the adjacent estuary) in vegetated plots and ~86% was removed in non-vegetated controls. The most dominant routes of N removal from the introduced solution were N2 production and assimilation into macrophyte biomass, which were similar in magnitude for the vegetated plots, whereas N2 production dominated in the unvegetated plots. The majority of N removed from the introduced solution occurred in the first 30 cm the solution traveled in the vegetated treatments. In addition, ambient porewater concentrations of dissolved inorganic nitrogen (DIN) were similar between full and half density plots, but lower than the non vegetated control (~8.5* and 7.5*), suggesting full and half density plots removed more DIN than non-vegetated plots. These results suggest that restoring marshes by planting 50% of the area may be a more cost-effective restoration design in terms of mitigating land-derived nutrient pollution than planting 100% of the area since it requires less effort and cost while removing similar quantities of N. PMID- 25500138 TI - Chronic fatigue syndrome and non-celiac gluten sensitivity. Association or cause? PMID- 25500139 TI - Policies to promote healthy portion sizes for children. AB - People of all ages are increasingly consuming larger portions of food. Governments worldwide are involved in the regulation of many aspects of the food supply; however, policies and programs related to serving sizes for children vary or are not clearly communicated. This paper reviews U.S. federal and state government recommendations, policies, and laws related to serving size for children and suggests directions for future policy objectives and outstanding research needed to support the enactment of laws based on the best science. Specifically, this paper reviews federal dietary recommendations and requirements for nutrition programs, packaged food labels and restaurant menus; state regulation of retail environments and child care settings; food companies' self regulatory options; and directions for future research and policy initiatives. The paper concludes that there are many opportunities for government to revise its policies and programs to better support healthy portion sizes for children and create a more transparent information environment to assist caretakers to do the same. PMID- 25500140 TI - Psychotropic Drugs in Dermatology. PMID- 25500141 TI - Role of long-chain acyl-CoA synthetase 4 in formation of polyunsaturated lipid species in hepatic stellate cells. AB - Hepatic stellate cell (HSC) activation is a critical step in the development of chronic liver disease. We previously observed that the levels of triacylglycerol (TAG) species containing long polyunsaturated fatty acids (PUFAs) are increased in in vitro activated HSCs. Here we investigated the cause and consequences of the rise in PUFA-TAGs by profiling enzymes involved in PUFA incorporation. We report that acyl CoA synthetase (ACSL) type 4, which has a preference for PUFAs, is the only upregulated ACSL family member in activated HSCs. Inhibition of the activity of ACSL4 by siRNA-mediated knockdown or addition of rosiglitazone specifically inhibited the incorporation of deuterated arachidonic acid (AA-d8) into TAG in HSCs. In agreement with this, ACSL4 was found to be partially localized around lipid droplets (LDs) in HSCs. Inhibition of ACSL4 also prevented the large increase in PUFA-TAGs in HSCs upon activation and to a lesser extent the increase of arachidonate-containing phosphatidylcholine species. Inhibition of ACSL4 by rosiglitazone was associated with an inhibition of HSC activation and prostaglandin secretion. Our combined data show that upregulation of ACSL4 is responsible for the increase in PUFA-TAG species during activation of HSCs, which may serve to protect cells against a shortage of PUFAs required for eicosanoid secretion. PMID- 25500143 TI - Interleukin-33 ameliorates ischemic brain injury in experimental stroke through promoting Th2 response and suppressing Th17 response. AB - Ischemic stroke causes brain injury with activation of an inflammatory response that can contribute to clinical impairment. As a novel cytokine of the interleukin-1 (IL-1) family, IL-33 has been suggested to be involved in regulating pathophysiology and inflammatory responses in the central nervous system (CNS). However, the role and underlying mechanisms of IL-33 in ischemic stroke remain poorly understood. Here, adult male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) for stroke induction. The MCAO procedure resulted in the enhanced Th1 and Th17 immune responses from 6h after transient cerebral ischemia/reperfusion even up to day 3. Meanwhile, the protein and mRNA level of IL-33 expression was significantly decreased at 6h and 72 h, but not at 24h after MCAO. Moreover, recombinant mouse IL-33 administration substantially attenuated ischemic brain damage and neurological deficit at 24h and 72 h, but not at 6h after MCAO. Interestingly, the reduced CNS inflammation in IL-33 treated MCAO mice may be at least partly due to an induced immuno-shift of Th cells from Th1 to Th2 response and suppressing Th17 immune response. These findings demonstrate that IL-33 can play a protective role after MCAO and may be a new target for therapy of ischemic stroke. PMID- 25500142 TI - Early hyperactivity in lateral entorhinal cortex is associated with elevated levels of AbetaPP metabolites in the Tg2576 mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder which is the most common cause of dementia in the elderly today. One of the earliest symptoms of AD is olfactory dysfunction. The present study investigated the effects of amyloid beta precursor protein (AbetaPP) metabolites, including amyloid-beta (Abeta) and AbetaPP C-terminal fragments (CTF), on olfactory processing in the lateral entorhinal cortex (LEC) using the Tg2576 mouse model of human AbetaPP over expression. The entorhinal cortex is an early target of AD related neuropathology, and the LEC plays an important role in fine odor discrimination and memory. Cohorts of transgenic and age-matched wild-type (WT) mice at 3, 6, and 16months of age (MO) were anesthetized and acute, single-unit electrophysiology was performed in the LEC. Results showed that Tg2576 exhibited early LEC hyperactivity at 3 and 6MO compared to WT mice in both local field potential and single-unit spontaneous activity. However, LEC single-unit odor responses and odor receptive fields showed no detectable difference compared to WT at any age. Finally, the very early emergence of olfactory system hyper excitability corresponded not to detectable Abeta deposition in the olfactory system, but rather to high levels of intracellular AbetaPP-CTF and soluble Abeta in the anterior piriform cortex (aPCX), a major afferent input to the LEC, by 3MO. The present results add to the growing evidence of AbetaPP-related hyper excitability, and further implicate both soluble Abeta and non-Abeta AbetaPP metabolites in its early emergence. PMID- 25500144 TI - A CCRK-EZH2 epigenetic circuitry drives hepatocarcinogenesis and associates with tumor recurrence and poor survival of patients. AB - BACKGROUND & AIMS: Aberrant chromatin modification is a key feature of hepatocellular carcinoma (HCC), which is characterized by strong sexual dimorphism. Both enhancer of zeste homolog 2 (EZH2) and cell cycle-related kinase (CCRK) contribute to hepatocarcinogenesis, yet whether the two oncogenic factors have functional crosstalk is unknown. METHODS: Cellular proliferation and tumorigenicity upon transgenic expression and RNA interference were determined by colony formation and soft agar assays, xenograft, orthotopic and diethylnitrosamine-induced HCC models. Gene regulation was assessed by chromatin immunoprecipitation, site-directed mutagenesis, luciferase reporter, co immunoprecipitation and expression analyses. Protein levels in clinical specimens were correlated with clinicopathological parameters and patient survival rates. RESULTS: Ectopic CCRK expression in immortalized human liver cells increased EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) to stimulate proliferation and tumor formation. Conversely, knockdown of CCRK reduced EZH2/H3K27me3 levels and decreased HCC cell growth, which could be rescued by EZH2 over-expression. Mechanistically, GSK-3beta phosphorylation by CCRK activated a beta catenin/TCF/E2F1/EZH2 transcriptional feedback loop to epigenetically enhance androgen receptor (AR) signaling. Simultaneously, the phosphorylation of AKT/EZH2 by CCRK facilitated the co-occupancy of CCRK promoter by EZH2-AR and its subsequent transcriptional activation, thus forming a self-reinforcing circuitry. Lentiviral-mediated knockdown of CCRK, which abrogated the phosphorylation transcriptional network, prevented diethylnitrosamine-induced tumorigenicity. More importantly, the hyperactivation of the CCRK-EZH2 circuitry in human HCCs correlated with tumor recurrence and poor survival. CONCLUSIONS: These findings uncover an epigenetic vicious cycle in hepatocarcinogenesis that operates through reciprocal regulation of CCRK and EZH2, providing novel therapeutic strategy for HCC. PMID- 25500145 TI - Sporadic extra abdominal wall desmoid-type fibromatosis: surgical resection can be safely limited to a minority of patients. AB - BACKGROUND: To analyse the natural history of extra-abdominal wall desmoid-type fibromatosis (DF) and compare outcome in patients who underwent initial surgery with those who did not. PATIENTS AND METHODS: All consecutive patients affected by primary sporadic extra-abdominal wall DF observed between January 1992 and December 2012 were included. Patients were divided into surgical (SG) or non surgical groups (NSG) according to initial treatment. Relapse free survival was calculated for SG, and crude cumulative incidence (CCI) of switching to surgery or other treatments for NSG. RESULTS: 216 patients were identified, 94 in SG (43%), 122 in NSG (57%). A shift towards a more systematic use of a conservative approach (78% of all comers) was observed in the latter years (2006-2012), although a small proportion of patients (28%) had been offered the conservative strategy even in the early period (1992-2005). Median follow-up (FU) was 49 mo. (interquartile (IQ), 20-89 mo.), 76 months for SG and 39 months for NSG. 5-year relapse-free survival (RFS) for SG was 80% (95% confidence interval (CI), 72 89%). For the NSG, 5-year CCI of switching to surgery was 5% (95% CI: 1.7%, 14%), and 51% to other treatments (95% CI: 41%, 65%). 27 (20%) NSG patients underwent spontaneous regression. CONCLUSION: A non-surgical approach to extra-abdominal wall DF allowed surgery to be avoided in the majority of patients. This approach can be safely proposed and surgery offered as an option in selected cases. PMID- 25500146 TI - Mortality within 30 days following systemic anti-cancer therapy, a review of all cases over a 4 year period in a tertiary cancer centre. AB - BACKGROUND: The national confidential enquiry into patient outcomes and death (NCEPOD) set important benchmarks in assessing the quality of care received by patients dying within 30 days of systemic anticancer therapy (SACT). Monthly morbidity and mortality audits conducted to recommendations in the NCEPOD were commenced at the Christie NHS Foundation Trust in 2009, specifically to assess and improve patient outcomes. METHODS: We evaluated the outcomes of patients who died within 30 days of SACT over a 4 year period 2009-2013. We collated audit findings to determine the number of treatment related deaths, clinical characteristics of patients, causes of death and quality of care received. We examined the benefit of the audit in decreasing 30 day mortality during the 4 years and considered factors that may be associated with an increased risk of SACT related death. RESULTS: A total of 31,183 patients were treated at the Christie from 2009 to 2013. Of these 4% died within 30 days of SACT. Death was treatment related in 11%. The decision to treat with SACT was appropriate in 87% of but there was room for improvement in care in 24%. Mortality decreased over the 4 years. Possible factors associated with 30 day mortality post SACT included performance status ?2, presence of comorbidities, treatment type and treatment setting. CONCLUSIONS: We demonstrated that our audit process is feasible and robust. Further areas of research to determine predictive scores for patient treatment selection and improve outcomes were highlighted and are ongoing. PMID- 25500147 TI - [Knowledge, attitudes and practices related to venous thromboembolism prophylaxis in hospitalists in Lome (Togo)]. AB - The purpose of this study was to assess the knowledge and practices related to the prevention of venous thromboembolism (VTE) in medical settings in Lome (Togo). Hospitalists in Lome are relatively well aware of the risk of VTE in patients. They report risk factors for VTE as the primary indications for thromboprophylaxis. Few physicians cited acute medical conditions among these indications. PMID- 25500148 TI - Clinical and laboratory measures associated with health-related quality of life in individuals with chronic ankle instability. AB - OBJECTIVE: To identify clinician and laboratory-oriented measures of function capable of explaining health-related quality of life in individuals with chronic ankle instability. DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: Forty physically active individuals with chronic ankle instability attended a single testing session. MAIN OUTCOME MEASURES: Participants completed health related quality of life, postural control, strength, sensory, and mechanical assessments. Health-related quality of life assessments included the Short Form 12 Physical and Mental Summary Components, Disablement in the Physically Active Scale, Fear-Avoidance Beliefs Questionnaire, and the Foot and Ankle Ability Measure. RESULTS: A combination of mechanical and functional impairments accounted for 18-35% of the variance associated with health-related quality of life related to physical function and fear. Although physical impairments accounted for 7% of the variance associated with mental health-related quality of life, the overall model was associated with a weak effect size. CONCLUSION: Measures of postural control, dorsiflexion range of motion, plantar cutaneous sensation, and ankle arthrometry contributed to a significant proportion of the variance associated with health-related quality of life in those with chronic ankle instability. Other variables should be examined to address mental components of health-related quality of life. PMID- 25500149 TI - Monocyte chemoatractant protein-1: a potential biomarker of renal lesion and its relation with oxidative status in sickle cell disease. AB - BACKGROUND: The aim of this study was to evaluate the monocyte chemoatractant protein-1 (MCP-1) as a novel biomarker of renal lesion in sickle cell disease (SCD) and correlate it with oxidative stress. METHODS: This is a prospective study with SCD patients followed at a tertiary center in Brazil. Urine samples were collected to dosage of protein, MCP-1, malondialdehyde (MDA) and urinary creatinine. Patients taking hydroxyurea (SSHU) were compared to those not taking the drug (SS). Patients' data were also compared to a control group of 15 healthy blood donors. RESULTS: MCP-1 dosage was increased in SCD patients (Control: 42.12+/-27.6; SSHU: 168.2+/-90.1 and SS: 231.4+/-123.7 p<0.0001). SS patients presented higher levels of MCP-1 in comparison to SSHU group (SSHU: 168.2+/-90.10 and SS: 231.4+/-123.7; p=0.023). The same results were observed for MDA (Control: 2:29+/-1:13; SSHU: 5.60+/-2.39 and SS: 7.23+/-2.64, p<0.0001) and NO (control: 2.25+/-1.9; SSHU: 56.54+/-9.1 and SS: 39.1+/-9.02, p<0.0001). A positive correlation was obtained between MCP-1 and MDA (r=0.34, p=0.01); albuminuria (r=0.5, p=0.03); NO (r=0.39, p=0.005). CONCLUSION: The outcomes of the study suggest that MCP-1 is a predictive biomarker of renal lesion that can also reflect damage caused by oxidative stress present in SCD. PMID- 25500150 TI - Re-demonstration without remediation--a missed opportunity? A national survey of internal medicine clerkship directors. AB - BACKGROUND: Many different components factor into the final grade assigned for the internal medicine clerkship. Failure of one or more of these requires consideration of remedial measures. PURPOSE: To determine which assessment components are used to assign students a passing grade for the clerkship and what remediation measures are required when students do not pass a component. METHODS: A national cross-sectional survey of Clerkship Directors in Internal Medicine (CDIM) institutional members was conducted in April 2011. The survey included sections on remediation, grading practices, and demographics. The authors analyzed responses using descriptive and comparative statistics. RESULTS: Response rate was 73% (86/113). Medicine clerkships required students to pass the following components: clinical evaluations 83 (97%), NBME subject exam 76 (88%), written assignments 40 (46%), OSCE 35 (41%), in-house written exam 23 (27%), and mini-CEX 19 (22%). When students failed a component of the clerkship for the first time, 55 schools (64%) simply allowed students to make up the component, while only 16 (18%) allowed a simple make-up for a second failure. Additional ward time was required by 24 schools (28%) for a first-time failure of one component of the clerkship and by 49 (57%) for a second failure. The presence or absence of true remedial measures in a school was not associated with clerkship director academic rank, grading scheme, or percent of students who failed the clerkship in the previous year. CONCLUSIONS: Most schools required passing clinical evaluations and NBME subject exam components to pass the medicine clerkship, but there was variability in other requirements. Most schools allowed students to simply re-take the component for a first-time failure. This study raises the question of whether true remediation is being undertaken before students are asked to re-demonstrate competence in a failed area of the clerkship to be ready for the subinternship level. PMID- 25500151 TI - Diversity in medical education: the Indian Paradox. PMID- 25500152 TI - A Phase II Multicenter Trial With Rivaroxaban in the Treatment of Livedoid Vasculopathy Assessing Pain on a Visual Analog Scale. AB - BACKGROUND: Livedoid vasculopathy is an orphan skin disease characterized by recurrent thrombosis of the cutaneous microcirculation. It manifests itself almost exclusively in the ankles, the back of the feet, and the distal part of the lower legs. Because of the vascular occlusion, patients suffer from intense local ischemic pain. Incidence of livedoid vasculopathy is estimated to be around 1:100,000. There are currently no approved treatments for livedoid vasculopathy, making off-label therapy the only option. In Europe, thromboprophylactic treatment with low-molecular-weight heparins has become widely accepted. OBJECTIVE: The aim of this trial is the statistical verification of the therapeutic effects of the anticoagulant rivaroxaban in patients suffering from livedoid vasculopathy. METHODS: We performed a therapeutic phase IIa trial designed as a prospective, one-armed, multicenter, interventional series of cases with a calculated sample size of 20 patients. The primary outcome is the assessment of local pain on the visual analog scale (VAS) as an intraindividual difference of 2 values between baseline and 12 weeks. RESULTS: Enrollment started in December 2012 and was still open at the date of submission. The study is expected to finish in November 2014. CONCLUSIONS: Livedoid vasculopathy is associated with increased thrombophilia in the cutaneous microcirculation and the continuous use of anticoagulants helps improve the symptoms. The causes of cutaneous infarctions are heterogenous, but ultimately follow the known mechanisms of the coagulation cascade. Rivaroxaban affects the coagulation cascade and inhibits the factor Xa-dependent conversion of prothrombin to thrombin, thereby considerably reducing the risk of thrombosis. TRIAL REGISTRATION: Trial Registration EudraCT Number: 2012-000108-13-DE; https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012 000108-13 (Archived by WebCite at http://www.webcitation.org/6UCktWVCA); German Clinical Trials Register (DRKS): DRKS00004652; https://drks-neu.uniklinik freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00004652 (Archived by WebCite at http://www.webcitation.org/6UCIAKyCS). PMID- 25500153 TI - Fibrinogen nitrotyrosination after ischemic stroke impairs thrombolysis and promotes neuronal death. AB - Ischemic stroke is an acute vascular event that compromises neuronal viability, and identification of the pathophysiological mechanisms is critical for its correct management. Ischemia produces increased nitric oxide synthesis to recover blood flow but also induces a free radical burst. Nitric oxide and superoxide anion react to generate peroxynitrite that nitrates tyrosines. We found that fibrinogen nitrotyrosination was detected in plasma after the initiation of ischemic stroke in human patients. Electron microscopy and protein intrinsic fluorescence showed that in vitro nitrotyrosination of fibrinogen affected its structure. Thromboelastography showed that initially fibrinogen nitrotyrosination retarded clot formation but later made the clot more resistant to fibrinolysis. This result was independent of any effect on thrombin production. Immunofluorescence analysis of affected human brain areas also showed that both fibrinogen and nitrotyrosinated fibrinogen spread into the brain parenchyma after ischemic stroke. Therefore, we assayed the toxicity of fibrinogen and nitrotyrosinated fibrinogen in a human neuroblastoma cell line. For that purpose we measured the activity of caspase-3, a key enzyme in the apoptotic pathway, and cell survival. We found that nitrotyrosinated fibrinogen induced higher activation of caspase 3. Accordingly, cell survival assays showed a more neurotoxic effect of nitrotyrosinated fibrinogen at all concentrations tested. In summary, nitrotyrosinated fibrinogen would be of pathophysiological interest in ischemic stroke due to both its impact on hemostasis - it impairs thrombolysis, the main target in stroke treatments - and its neurotoxicity that would contribute to the death of the brain tissue surrounding the infarcted area. PMID- 25500155 TI - Land cover/land use change and impacts on environment in South Asia. PMID- 25500154 TI - Evaluation of host and viral factors associated with severe dengue based on the 2009 WHO classification. AB - BACKGROUND: Dengue fever (DF) is the most prevalent arthropod-borne viral disease affecting humans. The World Health Organization (WHO) proposed a revised classification in 2009 to enable the more effective identification of cases of severe dengue (SD). This was designed primarily as a clinical tool, but it also enables cases of SD to be differentiated into three specific subcategories (severe vascular leakage, severe bleeding, and severe organ dysfunction). However, no study has addressed whether this classification has advantage in estimating factors associated with the progression of disease severity or dengue pathogenesis. We evaluate in a dengue outbreak associated risk factors that could contribute to the development of SD according to the 2009 WHO classification. METHODS: A prospective cross-sectional study was performed during an epidemic of dengue in 2009 in Chiapas, Mexico. Data were analyzed for host and viral factors associated with dengue cases, using the 1997 and 2009 WHO classifications. The cost-benefit ratio (CBR) was also estimated. RESULTS: The sensitivity in the 1997 WHO classification for determining SD was 75%, and the specificity was 97.7%. For the 2009 scheme, these were 100% and 81.1%, respectively. The 2009 classification showed a higher benefit (537%) with a lower cost (10.2%) than the 1997 WHO scheme. A secondary antibody response was strongly associated with SD. Early viral load was higher in cases of SD than in those with DF. Logistic regression analysis identified predictive SD factors (secondary infection, disease phase, viral load) within the 2009 classification. However, within the 1997 scheme it was not possible to differentiate risk factors between DF and dengue hemorrhagic fever or dengue shock syndrome. The critical clinical stage for determining SD progression was the transition from fever to defervescence in which plasma leakage can occur. CONCLUSIONS: The clinical phenotype of SD is influenced by the host (secondary response) and viral factors (viral load). The 2009 WHO classification showed greater sensitivity to identify SD in real time. Timely identification of SD enables accurate early decisions, allowing proper management of health resources for the benefit of patients at risk for SD. This is possible based on the 2009 WHO classification. PMID- 25500156 TI - NASA Land Cover and Land Use Change (LCLUC): an interdisciplinary research program. AB - Understanding Land Cover/Land Use Change (LCLUC) in diverse regions of the world and at varied spatial scales is one of the important challenges in global change research. In this article, we provide a brief overview of the NASA LCLUC program, its focus areas, and the importance of satellite remote sensing observations in LCLUC research including future directions. The LCLUC Program was designed to be a cross-cutting theme within NASA's Earth Science program. The program aims to develop and use remote sensing technologies to improve understanding of human interactions with the environment. Since 1997, the NASA LCLUC program has supported nearly 280 research projects on diverse topics such as forest loss and carbon, urban expansion, land abandonment, wetland loss, agricultural land use change and land use change in mountain systems. The NASA LCLUC program emphasizes studies where land-use changes are rapid or where there are significant regional or global LCLUC implications. Over a period of years, the LCLUC program has contributed to large regional science programs such as Land Biosphere-Atmosphere (LBA), the Northern Eurasia Earth Science Partnership Initiative (NEESPI), and the Monsoon Area Integrated Regional Study (MAIRS). The primary emphasis of the program will remain on using remote sensing datasets for LCLUC research. The program will continue to emphasize integration of physical and social sciences to address regional to global scale issues of LCLUC for the benefit of society. PMID- 25500158 TI - Maternal high-fat diet feeding during pregnancy and lactation augments lung inflammation and remodeling in the offspring. AB - Accumulating evidence suggests that maternal obesity increases the risk of their offspring developing noncommunicable diseases later in life, but the potential mechanisms, especially those resulting in abnormal respiratory conditions, are not thoroughly understood. Here, we used maternal high-fat diet (HFD) feeding during premating, pregnancy, and lactation to investigate the effect of maternal HFD on offspring lung development. Offspring birth weight and body weight and composition were measured. Serum leptin levels were measured by ELISA. Hematoxylin-eosin (H&E) and Masson's staining were used in paraffin-embedded lung sections. Levels of transfer growth factor-beta (TGF-beta) and alpha-smooth muscle actin (alpha-SMA) were examined by immunohistochemistry and western blot, respectively. Maternal HFD feeding during pregnancy and lactation lead to higher birth weight, final body weight, fat accumulation and hyperleptinemia in offspring. Maternal HFD feeding aggravated lung inflammatory response in the offspring, resulting in inflammatory cell infiltration and collagen deposition potentially via the enhanced expression of TGF-beta and alpha-SMA in the offspring. PMID- 25500159 TI - Presence of anti-Ro/SSA antibody may be associated with anti-aquaporin-4 antibody positivity in neuromyelitis optica spectrum disorder. AB - BACKGROUND: Neuromyelitis optica (NMO) is often associated with systemic autoimmune diseases or serological markers of non-organ-specific autoimmunity, and has been most frequently associated with Sjogren's syndrome and anti-Ro/SSA antibody (SSA-Ab) positivity in Asian populations. OBJECTIVE: We evaluated the clinical significance of anti-Ro/SSA antibody positivity in patients with NMO spectrum disorder (NMOSD). METHODS: We retrospectively collected data from 106 consecutive patients with NMOSD and reviewed clinical features and laboratory findings. All patients underwent tests for SSA-Ab and anti-aquaporin-4 antibody (AQP4-Ab) using cell-based indirect immunofluorescence assays. RESULTS: Among 106 patients, 20 (18.9%) were positive for SSA-Ab. Of 48 AQP4-Ab-positive patients, 18 (37.5%) had SSA-Ab. AQP4-Ab seropositivity was 90.0% in patients positive for SSA-Ab, and 32.6% in patients without SSA-Ab (p<0.001). Presence of SSA-Ab was associated with systemic autoimmune diseases, including Sjogren's syndrome (p<0.001) and systemic lupus erythematosus (p=0.003), and with the presence of non-organ-specific autoantibodies such as anti-nuclear antibody and anti-dsDNA antibody in patients with NMOSD, but was not associated with annualized relapse rate or final Expanded Disability Status Scale score independent of AQP4-Ab positivity. CONCLUSION: We found that the presence of SSA-Ab was highly associated with seropositivity for AQP4-Ab in patients with NMOSD. PMID- 25500157 TI - Transmembrane helix straightening and buckling underlies activation of mechanosensitive and thermosensitive K(2P) channels. AB - Mechanical and thermal activation of ion channels is central to touch, thermosensation, and pain. The TRAAK/TREK K(2P) potassium channel subfamily produces background currents that alter neuronal excitability in response to pressure, temperature, signaling lipids, and anesthetics. How such diverse stimuli control channel function is unclear. Here we report structures of K(2P)4.1 (TRAAK) bearing C-type gate-activating mutations that reveal a tilting and straightening of the M4 inner transmembrane helix and a buckling of the M2 transmembrane helix. These conformational changes move M4 in a direction opposite to that in classical potassium channel activation mechanisms and open a passage lateral to the pore that faces the lipid bilayer inner leaflet. Together, our findings uncover a unique aspect of K(2P) modulation, indicate a means for how the K(2P) C-terminal cytoplasmic domain affects the C-type gate which lies ~40A away, and suggest how lipids and bilayer inner leaflet deformations may gate the channel. PMID- 25500160 TI - Objectively measured physical activity in Finnish employees: a cross-sectional study. AB - OBJECTIVES: To objectively measure the amount of intensity-specific physical activity by gender and age with respect to body mass index (BMI) during workdays and days off among Finnish employees. DESIGN: A cross-sectional study. SETTING: Primary care occupational healthcare units. PARTICIPANTS: A sample of 9554 Finnish employees (4221 men and 5333 women; age range 18-65 years; BMI range 18.5 40 kg/m(2)) who participated in health assessments related to occupational health promotion. MAIN OUTCOME MEASUREMENTS: The amount of moderate-to-vigorous (MVPA) and vigorous (VPA) physical activity (>=3 and >=6 metabolic equivalents, respectively) was assessed by estimating the minute-to-minute oxygen consumption from the recorded beat-to-beat R-R interval data. The estimation method used heart rate, respiration rate and on/off response information from R-R interval data calibrated by age, gender, height, weight and self-reported physical activity class. The proportion of participants fulfilling the aerobic physical activity recommendation of >=150 min/week was calculated on the basis of >=10 min bouts, by multiplying the VPA minutes by 2. RESULTS: Both MVPA and VPA were higher among men and during days off, and decreased with increasing age and BMI (p<0.001 for all). Similar results were observed when the probability of having a bout of MVPA or VPA lasting continuously for >=10 min per measurement day was studied. The total amount of VPA was low among overweight (mean <=2.6 min/day), obese (mean <=0.6 min/day) and all women in the age group 51-65 years (mean <=2.5 min/day) during both types of days. The proportion of participants fulfilling the aerobic physical activity recommendation was highest for normal weight men (65%; 95% CI 62% to 67%) and lowest for obese women (10%; 95% CI 8% to 12%). CONCLUSIONS: Objectively measured physical activity is higher among men and during days off, and decreases with increasing age and BMI. The amount of VPA is very low among obese, overweight and older women. PMID- 25500161 TI - Radiologists' perspectives about evidence-based medicine and their clinical practice: a semistructured interview study. AB - OBJECTIVES: To describe radiologist's attitudes and perspectives on evidence based medicine (EBM) and their practice. DESIGN: Face-to-face semistructured interviews, thematic analysis. SETTING: 24 institutions across six Australian states and New Zealand. Transcripts were imported into HyperRESEARCH software and thematically analysed. PARTICIPANTS: 25 radiologists. RESULTS: Six themes were identified: legitimising decisions (validated justification, prioritising patient preferences, reinforcing protocols), optimising outcomes (ensuring patient safety, maximising efficiency), availability of access (requiring immediacy, inadequacy of evidence, time constraints, proximity of peer networks, grasping information dispersion), over-riding pragmatism (perceptibly applicability, preserving the art of medicine, technical demands), limited confidence (conceptual obscurity, reputation-based trust, demands constant practice, suspicion and cynicism), and competing powers (hierarchical conflict, prevailing commercial interests). CONCLUSIONS: Radiologists believe EBM can support clinical decision-making for optimal patient outcomes and service efficiency but feel limited in their capacities to assimilate and apply EBM in practice. Improving access to evidence, providing ongoing education and training supplemented with practical tools for appraising evidence; and developing evidence-based guidelines and protocols may enhance feasibility and promote the confidence and skills among radiologists in applying EBM in radiology practice for better patient care. PMID- 25500162 TI - Opposite trends in the consumption of manufactured and roll-your-own cigarettes in Spain (1991-2020). AB - OBJECTIVE: The aim of this study is to describe trends in the consumption of manufactured and roll-your-own cigarettes between 1991 and 2012 in Spain, and to project these trends up to 2020. METHODS: We estimated daily consumption per capita during 1991-2012 using data on sales of manufactured cigarettes (20-packs) and rolling tobacco (kg) from the Tobacco Market Commission, and using data of the Spanish adult population from the National Statistics Institute. We considered different weights (0.5, 0.8 and 1 g) to compute the number of rolled cigarettes per capita. We computed the annual per cent of change and assessed possible changes in trends using joinpoint regression, and projected the consumption up to 2020 using Bayesian methods. RESULTS: Daily consumption per capita of manufactured cigarettes decreased on average by 3.0% per year in 1991 2012, from 7.6 to 3.8 units, with three trend changes. However, daily consumption per capita of roll-your-own cigarettes increased on average by 14.1% per year, from 0.07 to 0.92 units of 0.5 g, with unchanged trends. Together, daily consumption per capita decreased between 2.9% and 2.5%, depending on the weight of the roll-your-own cigarettes. Projections up to 2020 indicate a decrease of manufactured cigarettes (1.75 units per capita) but an increase of roll-your-own cigarettes (1.25 units per capita). CONCLUSIONS: While the consumption per capita of manufactured cigarettes has decreased in the past years in Spain, the consumption of roll-your-own cigarettes has increased at an annual rate around 14% over the past years. Whereas a net decrease in cigarette consumption is expected in the future, use of roll-your-own cigarettes will continue to increase. PMID- 25500163 TI - Interdisciplinary promises versus practices in medicine: the decoupled experiences of social sciences and humanities scholars. AB - This paper explores social scientists' and humanities (SSH) scholars' integration within the academic medical research environment. Three questions guided our investigation: Do SSH scholars adapt to the medical research environment? How do they navigate their career within a culture that may be inconsistent with their own? What strategies do they use to gain legitimacy? The study builds on three concepts: decoupling, doxa, and epistemic habitus. Twenty-nine semi-structured interviews were conducted with SSH scholars working in 11 faculties of medicine across Canada. Participants were selected through purposeful and snowball sampling. The data were analyzed by thematic content analysis. For most of our participants, moving into medicine has been a challenging experience, as their research practices and views of academic excellence collided with those of medicine. In order to achieve some level of legitimacy more than half of our participants altered their research practices. This resulted in a dissonance between their internalized appreciation of academic excellence and their new, altered, research practices. Only six participants experienced no form of challenge or dissonance after moving into medicine, while three decided to break with their social science and humanities past and make the medical research community their new home. We conclude that the work environment for SSH scholars in faculties of medicine does not deliver on the promise of inclusiveness made by calls for interdisciplinarity in Canadian health research. PMID- 25500164 TI - Inequalities in social capital and health between people with and without disabilities. AB - The poor mental and physical health of people with disabilities has been well documented and there is evidence to suggest that inequalities in health between people with and without disabilities may be at least partly explained by the socioeconomic disadvantage (e.g. low education, unemployment) experienced by people with disabilities. Although there are fewer studies documenting inequalities in social capital, the evidence suggests that people with disabilities are also disadvantaged in this regard. We drew on Bourdieu's conceptualisation of social capital as the resources that flow to individuals from their membership of social networks. Using data from the General Social Survey 2010 of 15,028 adults living in private dwellings across non-remote areas of Australia, we measured social capital across three domains: informal networks (contact with family and friends); formal networks (group membership and contacts in influential organisations) and social support (financial, practical and emotional). We compared levels of social capital and self-rated health for people with and without disabilities and for people with different types of impairments (sensory and speech, physical, psychological and intellectual). Further, we assessed whether differences in levels of social capital contributed to inequalities in health between people with and without disabilities. We found that people with disabilities were worse off than people without disabilities in regard to informal and formal networks, social support and self-rated health status, and that inequalities were greatest for people with intellectual and psychological impairments. Differences in social capital did not explain the association between disability and health. These findings underscore the importance of developing social policies which promote the inclusion of people with disabilities, according to the varying needs of people with different impairments types. Given the changing policy environment, ongoing monitoring of the living circumstances of people with disabilities, including disaggregation of data by impairment type, is critical. PMID- 25500166 TI - Sympathetic activation and ventricular arrhythmias: new insights from surface electrogram recordings. PMID- 25500165 TI - Thoracic Spinal Cord Stimulation for Heart Failure as a Restorative Treatment (SCS HEART study): first-in-man experience. AB - BACKGROUND: Preclinical studies suggest that neuromodulation with thoracic spinal cord stimulation (SCS) improves left ventricular (LV) function and remodeling in systolic heart failure (HF). OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of a SCS system for the treatment of systolic HF. METHODS: We performed a prospective, multicenter pilot trial in patients with New York Heart Association (NYHA) class III HF, left ventricular ejection fraction (LVEF) 20%-35%, and implanted defibrillator device who were prescribed stable optimal medical therapy. Dual thoracic SCS leads were used at the T1-T3 level. The device was programmed to provide SCS for 24 hours per day (50 Hz at pulse width 200 MUs). RESULTS: We enrolled 22 patients from 5 centers:17 patients underwent implantation of a SCS device and 4 patients who did not fulfill the study criteria served as nontreated controls. No deaths or device-device interactions were noted during the 6-month period in the 17 SCS-treated patients. Fifteen of 17 completed the efficacy endpoint assessments: composite score improved by 4.2 +/- 1.3, and 11 patients (73%) showed improvement in >=4 of 6 efficacy parameters. There was significant improvement in NYHA class (3.0 vs 2.1, P = .002; 13/17 improved); Minnesota Living with Heart Failure Questionnaire (42 +/- 26 vs 27 +/- 22, P = .026; 12/17 improved); peak maximum oxygen consumption (14.6 +/- 3.3 vs 16.5 +/- 3.9 mL/kg/min, P = .013; 10/15 improved); LVEF (25% +/- 6% vs 37% +/- 8%, P<.001; 14/16 improved); and LV end-systolic volume (174 +/- 57 vs 137 +/- 37 mL, P = .002; 11/16 improved) but not in N-terminal prohormone brain natriuretic peptide. No such improvements were observed in the 4 nontreated patients. CONCLUSION: The results of this first-in-human trial suggest that high thoracic SCS is safe and feasible and potentially can improve symptoms, functional status, and LV function and remodeling in patients with severe, symptomatic systolic HF. PMID- 25500167 TI - Bridging the gap between the neurocognitive lab and the addiction clinic. AB - In the past decennium there has been an enormous increase in new insights in cognitive mechanisms of addiction and their neural substrates. These candidate neurocognitive mechanisms, particularly those associated with "drive" and "control" aspects of addiction, are clearly involved in substance use problems but do not yet provide a full explanation. The neurocognitive mechanisms addressed in the present perspective are attentional bias, reward processing (both drive aspects) and error-processing and cognitive control (both control aspects). The time has come to transfer these recent insights more consistently to clinical practice by studying their relevance for diagnosis and treatment in patient samples. The present perspective echoes the development of recent initiatives such as the RDoC system to integrate developments in neuroscience into clinical practice. The aim of this article is to open new vistas for addiction diagnosis and treatment and to discuss why and how these neurocognitive aspects of addictive behavior can be used in clinical practice. In addition, present problematic issues and a future research agenda are provided. PMID- 25500168 TI - Both hemorrhagic and ischemic stroke following high doses of cannabis consumption. PMID- 25500169 TI - All-encomPASsing regulation of beta-cells: PAS domain proteins in beta-cell dysfunction and diabetes. AB - As a sensory micro-organ, pancreatic beta-cells continually respond to nutritional signals and neuroendocrine input from other glucoregulatory organs. This sensory ability is essential for normal beta-cell function and systemic glucose homeostasis. Period circadian protein (Per)-aryl hydrocarbon receptor nuclear translocator protein (Arnt)-single-minded protein (Sim) (PAS) domain proteins have a conserved role as sensory proteins, critical in adaptation to changes in voltage, oxygen potential, and xenobiotics. Within beta-cells, PAS domain proteins such as hypoxia inducible factor 1alpha (Hif1alpha), Arnt, PAS kinase, Bmal1, and Clock respond to disparate stimuli, but act in concert to maintain proper beta-cell function. Elucidating the function of these factors in islets offers a unique insight into the sensing capacity of beta-cells, the consequences of impaired sensory function, and the potential to develop novel therapeutic targets for preserving beta-cell function in diabetes. PMID- 25500170 TI - The use of genetic engineering techniques to improve the lipid composition in meat, milk and fish products: a review. AB - The health-promoting properties of dietary long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) for humans are well-known. Products of animal-origin enriched with n-3 LCPUFAs can be a good example of functional food, that is food that besides traditionally understood nutritional value may have a beneficial influence on the metabolism and health of consumers, thus reducing the risk of various lifestyle diseases such as atherosclerosis and coronary artery disease. The traditional method of enriching meat, milk or eggs with n-3 LCPUFA is the manipulation of the composition of animal diets. Huge progress in the development of genetic engineering techniques, for example transgenesis, has enabled the generation of many kinds of genetically modified animals. In recent years, one of the aims of animal transgenesis has been the modification of the lipid composition of meat and milk in order to improve the dietetic value of animal origin products. This article reviews and discusses the data in the literature concerning studies where techniques of genetic engineering were used to create animal-origin products modified to contain health-promoting lipids. These studies are still at the laboratory stage, but their results have demonstrated that the transgenesis of pigs, cows, goats and fishes can be used in the future as efficient methods of production of healthy animal-origin food of high dietetic value. However, due to high costs and a low level of public acceptance, the introduction of this technology to commercial animal production and markets seems to be a distant prospect. PMID- 25500171 TI - [Prescription drug consumption recovery following the co-payment change: Evidence from a regional health service]. AB - OBJECTIVES: In the past few decades, increasing pharmaceutical expenditures in Spain and other western countries led to the adoption of reforms in order to reduce this trend. The aim of our study was to analyze if reforms concerning the pharmaceutical reimbursement scheme in Spain have been associated with changes in the volume and trend of pharmaceutical consumption. DESIGN: Retrospective observational study. SETTING: Region of Murcia. Prescription drug in primary care and external consultations. PARTICIPANTS: Records of prescribed medicines between January 1, 2008 and December 31, 2013. METHOD: Segmented regression analysis of interrupted time-series of prescription drug consumption. RESULTS: Dispensing of all five therapeutic classes fell immediately after co-payment changes. The segmented regression model suggested that per patient drug consumption in pensioners may have decreased by about 6.76% (95% CI; -8.66% to -5.19%) in the twelve months after the reform, compared with the absence of such a policy. Furthermore the slope of the series of consumption increased from 6.08 (P<.001) to 12.17 (P<.019). CONCLUSIONS: The implementation of copayment policies could be associated with a significant decrease in the level of prescribed drug use in Murcia Region, but this effect seems to have been only temporary in the five therapeutic groups analyzed, since almost simultaneously there has been an increase in the growth trend. PMID- 25500172 TI - Recommendations regarding the development of combined enterotoxigenic Eschericha coli and Shigella vaccines for infants. AB - PATH hosted a workshop on October 14 and 15, 2013 in Washington, DC to solicit expert opinions on the potential merits and challenges of developing combined enterotoxigenic Escherichia coli (ETEC) and Shigella vaccine products to benefit children in developing countries. This article summarizes the key issues raised during the workshop and provides an analysis of the recommendations regarding the strategic, clinical and regulatory, and manufacturing considerations for the development of a combined enteric vaccine, which aim to guide future vaccine development efforts and donor investment strategies in this area. Notwithstanding the potential technical, legal, financial, and other constraints that would be faced in developing a combined ETEC/Shigella vaccine, it is clear that this is the preferred approach over standalone products. There are many advantages to a combined vaccine, such as the potential cost-effectiveness and easier logistics of introducing a combined vaccine instead of two standalone vaccines in low resource, endemic countries. PMID- 25500173 TI - Safety of quadrivalent human papillomavirus vaccine (Gardasil) in pregnancy: adverse events among non-manufacturer reports in the Vaccine Adverse Event Reporting System, 2006-2013. AB - BACKGROUND: In 2006, quadrivalent human papillomavirus (HPV4; Gardasil, Merck & Co., Inc.) vaccine was licensed in the US for use in females aged 9-26 years. HPV4 is not recommended during pregnancy; however, inadvertent administration during pregnancy may occur. OBJECTIVES: To evaluate and summarize reports to the Vaccine Adverse Event Reporting System (VAERS) in pregnant women who received HPV4 vaccine and assess for potentially concerning adverse events among non manufacturer reports. METHODS: We searched the VAERS database for non manufacturer reports of adverse events (AEs) in pregnant women who received HPV4 vaccine from 6/1/2006 to 12/31/2013. We conducted clinical review of reports and available medical records. RESULTS: We found 147 reports after HPV4 vaccine administered to pregnant women. The most frequent pregnancy-specific AE was spontaneous abortion in 15 (10.2%) reports, followed by elective terminations in 6 (4.1%). Maternal fever was the most frequent non-pregnancy-specific AE in 3 reports. Two reports of major birth defects were received. No maternal deaths were noted. One hundred-three (70.1%) reports did not describe an AE. CONCLUSIONS: This review of VAERS non-manufacturer reports following vaccination with HPV4 in pregnancy did not find any unexpected patterns in maternal or fetal outcomes. PMID- 25500174 TI - Differential protein expression in chicken spermatozoa before and after freezing thawing treatment. AB - The biological characteristics of rooster sperm that has undergone freezing treatment remain elusive. This study analyzed the change in sperm proteins after freezing-thawing treatment by using a proteomic approach. Semen from three 36-wk old L2 strain Taiwan country chickens were used. A qualifying ejaculate containing more than 80% motility and volume 200MUL was used for cryopreservation. The proteomic analysis explored 55 protein spots that differed significantly before and after freezing-thawing treatment (P<0.05). Among the 55 protein spots, expression levels of 19 proteins decreased after treatment. Forty five differentially expressed protein spots were identified and belong to 33 proteins. Results of gene ontology analysis revealed that most differentially expressed proteins were involved in molecular function of the cellular metabolism process (28%) and cellular carbohydrate metabolism process (15%), and were associated with molecular function of oxidoreductase activity (19%) and protein binding (18%). The differentially expressed proteins before and after freezing thawing treatment, including fructose-bisphosphate aldolase C, triosephosphate isomerase, aconitate hydratase, tubulin and outer dense-fiber protein, are associated with sperm energy metabolism and flagellum structure. In conclusion, freezing-thawing treatment significantly affects the expression of proteins related to sperm metabolism and structure in chicken spermatozoa. The differing levels of these proteins could be valuable for further enhancing the fertility of frozen-thawed chicken spermatozoa. PMID- 25500175 TI - Effects of angiotensin II, atrial natriuretic peptide and endothelin-1 on proliferation and steroidogenic output of bovine granulosa cells cultured in a chemically defined system. AB - The role of local factors in the modulation of granulosa cell (GC) proliferation and differentiation is well described in the literature. The present work used a long-term bovine GC culture, in chemically defined medium without gonadotropins, to study the effects of angiotensin II (Ang II), atrial natriuretic peptide (ANP) and endothelin-1 (EDN1) on the steroidogenesis and cellular proliferation. Small follicles (3-5mm in diameter) from ovaries obtained in the slaughterhouse were selected according to their vascularization and follicular fluid color in order to isolate GC. Granulosa cells were plated at a density of 5*10(4)cells/well in supplemented alpha-MEM containing 3 levels (0, 10(-8)M and 10(-7)M) of Ang II, ANP, and EDN1 for up to 96h. Proliferation was evaluated by tritiated thymidine incorporation. The results showed that Ang II, ANP, and EDN1 modulate the steroidogenic output and proliferation index of GCs depending on the dose and time of culture. The selected vasoactive peptides increased androstenedione (A4) consumption in parallel with increased estradiol (E2). Although the peptides also promoted a significant increase in pregnenolone (P5) and progesterone (P4) production, the E2:P4 ratio was maintained at a high at most of the tested doses. Taken together, our in vitro data suggest that these vasoactive factors may have a direct effect on physiological follicular deviation, favoring dominance of the selected follicle. PMID- 25500176 TI - Light-driven hydrogen production from Photosystem I-catalyst hybrids. AB - Solar energy conversion of water into environmentally clean fuels, such as hydrogen, offers one of the best long-term solutions for meeting future global energy needs. In photosynthesis, high quantum yield charge separation is achieved by a series of rapid, photoinitiated electron transfer steps that take place in proteins called reaction centers (RCs). Of current interest are new strategies that couple RC photochemistry to the direct synthesis of energy-rich molecules, offering opportunities to more directly tune the products of photosynthesis and potentially to increase solar energy conversion capacity. Innovative designs link RC photochemistry with synthetic molecular catalysts to create earth abundant biohybrid complexes that use light to rapidly produce hydrogen from water. PMID- 25500177 TI - Sensitivity of envelope following responses to vowel polarity. AB - Envelope following responses (EFRs) elicited by stimuli of opposite polarities are often averaged due to their insensitivity to polarity when elicited by amplitude modulated tones. A recent report illustrates that individuals exhibit varying degrees of polarity-sensitive differences in EFR amplitude when elicited by vowel stimuli (Aiken and Purcell, 2013). The aims of the current study were to evaluate the incidence and degree of polarity-sensitive differences in EFRs recorded in a large group of individuals, and to examine potential factors influencing the polarity-sensitive nature of EFRs. In Experiment I of the present study, we evaluated the incidence and degree of polarity-sensitive differences in EFR amplitude in a group of 39 participants. EFRs were elicited by opposite polarities of the vowel /epsilon/ in a natural /hVd/ context presented at 80 dB SPL. Nearly 30% of the participants with detectable responses (n = 24) showed a difference of greater than ~39 nV in EFR response amplitude between the two polarities, that was unexplained by variations in noise estimates. In Experiment II, we evaluated the effect of vowel, frequency of harmonics and presence of the first harmonic (h1) on the polarity sensitivity of EFRs in 20 participants with normal hearing. For vowels /u/, /a/ and /i/, EFRs were elicited by two simultaneously presented carriers representing the first formant (resolved harmonics), and the second and higher formants (unresolved harmonics). Individual but simultaneous EFRs were elicited by the formant carriers by separating the fundamental frequency in the two carriers by 8 Hz. Vowels were presented as part of a naturally produced, but modified sequence /susa?i/, at an overall level of 65 dB SPL. To evaluate the effect of h1 on polarity sensitivity of EFRs, EFRs were elicited by the same vowels without h1 in an identical sequence. A repeated measures analysis of variance indicated a significant effect of polarity on EFR amplitudes for the vowel /u/ and a near-significant effect for /i/, when h1 was present. EFRs elicited by unresolved harmonics and resolved harmonics without h1 demonstrated no significant differences in amplitude due to polarity. The results suggest that h1 contributes to the polarity sensitivity of EFRs elicited by low frequency F1 carriers. However, it is unlikely that this is only due to the influence of a polarity-sensitive frequency-following response to the fine structure at h1. Removing h1 by filtering also decreased the asymmetry of the vowel envelope, especially for those with low first formant frequencies. A measure called the envelope asymmetry index was computed to evaluate the relationship between stimulus envelope asymmetry above and below the baseline, and polarity-sensitive differences in EFR amplitude. A significant positive correlation between envelope asymmetry index and absolute amplitude differences in EFR due to polarity suggests that one of the causes contributing to the polarity sensitivity of EFRs could be the asymmetry in stimulus envelope. This stimulus characteristic, however, explains only a fraction of the variability observed and there may be other factors that contribute to individual differences in polarity sensitivity of the EFR to naturally produced vowel stimuli. PMID- 25500178 TI - Getting a decent (but sparse) signal to the brain for users of cochlear implants. AB - The challenge in getting a decent signal to the brain for users of cochlear implants (CIs) is described. A breakthrough occurred in 1989 that later enabled most users to understand conversational speech with their restored hearing alone. Subsequent developments included stimulation in addition to that provided with a unilateral CI, either with electrical stimulation on both sides or with acoustic stimulation in combination with a unilateral CI, the latter for persons with residual hearing at low frequencies in either or both ears. Both types of adjunctive stimulation produced further improvements in performance for substantial fractions of patients. Today, the CI and related hearing prostheses are the standard of care for profoundly deaf persons and ever-increasing indications are now allowing persons with less severe losses to benefit from these marvelous technologies. The steps in achieving the present levels of performance are traced, and some possibilities for further improvements are mentioned. This article is part of a Special Issue entitled . PMID- 25500179 TI - The ribosome as a missing link in the evolution of life. AB - Many steps in the evolution of cellular life are still mysterious. We suggest that the ribosome may represent one important missing link between compositional (or metabolism-first), RNA-world (or genes-first) and cellular (last universal common ancestor) approaches to the evolution of cells. We present evidence that the entire set of transfer RNAs for all twenty amino acids are encoded in both the 16S and 23S rRNAs of Escherichia coli K12; that nucleotide sequences that could encode key fragments of ribosomal proteins, polymerases, ligases, synthetases, and phosphatases are to be found in each of the six possible reading frames of the 16S and 23S rRNAs; and that every sequence of bases in rRNA has information encoding more than one of these functions in addition to acting as a structural component of the ribosome. Ribosomal RNA, in short, is not just a structural scaffold for proteins, but the vestigial remnant of a primordial genome that may have encoded a self-organizing, self-replicating, auto-catalytic intermediary between macromolecules and cellular life. PMID- 25500180 TI - Communities in the iron superoxide dismutase amino acid network. AB - Amino acid networks (AANs) analysis is a new way to reveal the relationship between protein structure and function. We constructed six different types of AANs based on iron superoxide dismutase (Fe-SOD) three-dimensional structure information. These Fe-SOD AANs have clear community structures when they were modularized by different methods. Especially, detected communities are related to Fe-SOD secondary structures. Regular structures show better correlations with detected communities than irregular structures, and loops weaken these correlations, which suggest that secondary structure is the unit element in Fe SOD folding process. In addition, a comparative analysis of mesophilic and thermophilic Fe-SOD AANs' communities revealed that thermostable Fe-SOD AANs had more highly associated community structures than mesophilic one. Thermophilic Fe SOD AANs also had more high similarity between communities and secondary structures than mesophilic Fe-SOD AANs. The communities in Fe-SOD AANs show that dense interactions in modules can help to stabilize thermophilic Fe-SOD. PMID- 25500181 TI - Clinical guidelines for IVF with PGD for HLA matching. AB - Preimplantation genetic diagnosis (PGD) for human leukocyte antigen (HLA) typing is an established procedure for conceiving a child who may donate cord blood or haematopoietic stem cells for transplantation to save an ill sibling. Haematopoietic stem cell transplantation (HSCT) from related matched donors improves overall survival compared with unrelated or non-matched donors. Since HSCT from related matched-donors is unavailable for 70% of patients, IVF for PGD HLA is a relevant clinical option. Recent success of HSCT after PGD-HLA, and excellent health and family support of the children born, suggests that debate over this kind of 'designer baby' and 'gift of life' should subside. Discussions about IVF for PGD-HLA should be held with families when a related matched-donor is unavailable, when HSCT can wait at least 9-12 months, within weeks of diagnosis irrespective of prognosis, and when the mother is of reproductive age. Related half-matched egg donors may also be considered. National and international collaborations should be established, and couples choosing this modality should be referred to experienced IVF and PGD centres. Clinical guidelines will improve physician and patient awareness of IVF for PGD-HLA and its role in advancing the clinical care of children in need of HSCT. PMID- 25500182 TI - Evaluation of respiratory syncytial virus (RSV) direct antigen detection assays for use in point-of-care testing. AB - RSV infections cause lower respiratory tract infections and result in surges in physician's office, emergency department visits and hospitalizations, especially in infants and toddlers. Point-of-care (POC) testing reduces healthcare costs and permits informed decisions on treatment, however, optimal POC assays must be sensitive, easy to perform and provide rapid results. A prospective study tested 230 patient nasopharyngeal specimens using 4 RSV direct antigen detection assays (Directigen, Quickvue, Sofia and Veritor) and RT-PCR. A RSV dilution study was also performed to evaluate sensitivity. RSV fluorescent antibody testing in 46/230 patients was also evaluated. Sensitivity values obtained for the Sofia, Veritor, Directigen and Quickvue assays (%) were 85, 72.5, 70 and 57.5, respectively. Fluorescent result interpretation may account for Sofia's enhanced sensitivity. Specificity (%) was 97-100 among assays. Sensitivity data were confirmed in the dilution studies. Fluorescent antibody testing demonstrated 64% sensitivity compared with RT-PCR. Objective result reporting, walk away testing and high sensitivity make the Sofia a valuable choice for POC testing. Veritor's sensitivity may also render it acceptable in POC. Lack of objective results by Directigen and the poor sensitivity observed by Quickvue may preclude their value in diagnostic testing. PMID- 25500184 TI - Cognitive science contributions to decision science. AB - This article briefly reviews the history and interplay between decision theory, behavioral decision-making research, and cognitive psychology. The review reveals the increasingly important impact that psychology and cognitive science have on decision science. One of the main contributions of cognitive science to decision science is the development of dynamic models that describe the cognitive processes that underlay the evolution of preferences during deliberation phase of making a decision. PMID- 25500185 TI - A structured annotation frame for the transposable phages: a new proposed family "Saltoviridae" within the Caudovirales. AB - Enterobacteriophage Mu is the best studied and paradigm member of the transposable phages. Mu-encoded proteins have been annotated in detail in UniProtKB and linked to a controlled vocabulary describing the various steps involved in the phage lytic and lysogenic cycles. Transposable phages are ubiquitous temperate bacterial viruses with a dsDNA linear genome. Twenty-six of them, that infect alpha, beta and gamma-proteobacteria, have been sequenced. Their conserved properties are described. Based on these characteristics, we propose a reorganization of the Caudovirales, to allow for the inclusion of a "Saltoviridae" family and two newly proposed subfamilies, the "Myosaltovirinae" and "Siphosaltovirinae". The latter could temporarily be included in the existing Myoviridae and Siphoviridae families. PMID- 25500183 TI - Rapid and generic identification of influenza A and other respiratory viruses with mass spectrometry. AB - The rapid identification of existing and emerging respiratory viruses is crucial in combating outbreaks and epidemics. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a rapid and reliable identification method in bacterial diagnostics, but has not been used in virological diagnostics. Mass spectrometry systems have been investigated for the identification of respiratory viruses. However, sample preparation methods were laborious and time-consuming. In this study, a reliable and rapid sample preparation method was developed allowing identification of cultured respiratory viruses. Tenfold serial dilutions of ten cultures influenza A strains, mixed samples of influenza A virus with human metapneumovirus or respiratory syncytial virus, and reconstituted clinical samples were treated with the developed sample preparation method. Subsequently, peptides were subjected to MALDI-TOF MS and liquid chromatography tandem mass spectrometry (LC-MS/MS). The influenza A strains were identified to the subtype level within 3h with MALDI-TOF MS and 6h with LC-MS/MS, excluding the culturing time. The sensitivity of LC-MS/MS was higher compared to MALDI-TOF MS. In addition, LC-MS/MS was able to discriminate between two viruses in mixed samples and was able to identify virus from reconstituted clinical samples. The development of an improved and rapid sample preparation method allowed generic and rapid identification of cultured respiratory viruses by mass spectrometry. PMID- 25500186 TI - An electrical cause of stridor: pediatric vagal nerve stimulators. AB - Vagal nerve stimulators (VNS) are surgically implantable medical devices which are approved by the food and drug administration (FDA) for treatment of medically refractory epilepsy in children. Two children with seizures disorders presented to the pediatric otolaryngology clinic with complaints of stridor and sleep apnea following implantation of VNS devices. Both children were evaluated with flexible laryngoscopy, direct laryngoscopy and bronchoscopy. The children were noted to have contraction of their vocal folds and supraglottis and the settings of their VNS were adjusted until no further contractions were noted. Each child had resolution of their symptoms following adjustment. PMID- 25500187 TI - Out of sight, but still in mind: electrocortical correlates of attentional capture in spider phobia as revealed by a 'dot probe' paradigm. AB - The current investigation focused on attentional processes in spider phobia. Twenty phobics and 20 controls performed a dot-probe task while event-related potentials were recorded. In each trial they viewed a picture pair (a spider or a generally disgust eliciting picture that was paired with a neutral picture) for either 100 or 1500 ms. After the offset a visual probe (a dot) was presented either at the previous position of the emotionally relevant or the neutral slide and participants were asked to indicate with a button press whether the dot had been presented on the left or the right side of the screen. Results revealed a modulation of the centro-parietal P300 (340-500 ms after picture onset). Amplitudes were higher when the dot replaced a spider than when it replaced a neutral picture. This was phobia-specific, as it was only present in phobics and did not appear in response to disgust pictures. Moreover, the modulation could only be shown for short presentation times. The results are interpreted to reflect motivated attention in spider phobia, if disorder-relevant and neutral pictures are shown simultaneously. As the modulation of the P300 was found after picture offset, attentional allocation seems to be persist after the phobic object is no longer present. PMID- 25500188 TI - Quantifying uncertainty in radiotherapy demand at the local and national level using the Malthus model. AB - The Malthus programme produces a model for the local and national level of radiotherapy demand for use by commissioners and radiotherapy service leads in England. The accuracy of simulation is dependent on the population cancer incidence, stage distribution and clinical decision data used by the model. In order to quantify uncertainty in the model, a global sensitivity analysis of the Malthus model was undertaken. As predicted, key decision points in the model relating to stage distribution and indications for surgical or non-surgical initial management of disease were observed to yield the strongest effect on simulated radiotherapy demand. The proportion of non-small cell lung cancer patients presenting with stage IIIB/IV disease had the largest effect on fraction burden in the four most common cancer types treated with radiotherapy, where a 1% change in stage IIIb/IV disease yielded a 1.3% change in fraction burden for lung cancer patients. A 1% change in mastectomy rate yielded a 0.37% change in fraction burden for breast cancer patients. The model is also highly sensitive to changes in the radiotherapy indications in colon and gastric cancer. Broadly, the findings of the sensitivity analysis mirror those previously published by other groups. Sensitivity analysis of the local-level population and cancer incidence data revealed that the cancer registration rate in the 50-64 year female population had the highest effect on simulation results. The analysis reveals where additional effort should be undertaken to provide accurate estimates of important parameters used in radiotherapy demand models. PMID- 25500189 TI - The burden and determinants of self-reported acute gastrointestinal illness in an Indigenous Batwa Pygmy population in southwestern Uganda. AB - Acute gastrointestinal illness (AGI) is an important public health priority worldwide. Few studies have captured the burden of AGI in developing countries, and even fewer have focused on Indigenous populations. This study aimed to estimate the incidence and determinants of AGI within a Batwa Pygmy Indigenous population in southwestern Uganda. A retrospective cross-sectional survey was conducted in January 2013 via a census of 10 Batwa communities (n = 583 participants). The AGI case definition included any self-reported symptoms of diarrhoea or vomiting in the past 2 weeks. The 14-day prevalence of AGI was 6.17% [95% confidence interval (CI) 4.2-8.1], corresponding to an annual incidence rate of 1.66 (95% CI 1.1-2.2) episodes of AGI per person-year. AGI prevalence was greatest in children aged <3 years (11.3%). A multivariable mixed-effects logistic regression model controlling for clustering at the community level indicated that exposure to goats [odds ratio (OR) 2.6, 95% CI 1.0-6.8], being a child aged <3 years (OR 4.8, 95% CI 1.2-18.9), and being a child, adolescent or senior Batwa in the higher median of wealth (OR 7.0, 95% CI 3.9-9.2) were significantly associated with having AGI. This research represents the first Indigenous community-census level study of AGI in Uganda, and highlights the substantial burden of AGI within this population. PMID- 25500190 TI - Identification and functional characterization of FGLamide-related allatostatin receptor in Rhodnius prolixus. AB - FGLamide-related ASTs (FGLa/ASTs) are a family of brain/gut peptides with numerous physiological roles, including inhibition of juvenile hormone (JH) biosynthesis by the corpora allata and inhibition of visceral muscle contraction. FGLa/ASTs mediate their effects by binding to a rhodopsin-like G-protein coupled receptor that is evolutionarily related to the vertebrate galanin receptor. Here we determine the cDNA sequence encoding FGLa/AST receptor (FGLa/AST-R) from the Chagas disease vector, Rhodnius prolixus (Rhopr-FGLa/AST-R), determine its spatial expression pattern using quantitative PCR and functionally characterize the receptor using a heterologous assay. Our expression analysis indicates that Rhopr-FGLa/AST-R is highly expressed in the central nervous system. The receptor is also expressed in various peripheral tissues including the dorsal vessel, midgut, hindgut and reproductive tissues of both males and females, suggesting a role in processes associated with feeding and reproduction. The possible involvement of Rhopr-FGLa/ASTs in the inhibition of JH biosynthesis is also implicated due to presence of the receptor transcript in the R. prolixus corpora cardiaca/corpora allata complex. The functional assay showed that various Rhopr FGLa/ASTs activate the receptor, with EC50 values for the response in the nanomolar range. Moreover, Rhopr-FGLa/AST-R can couple with Gq alpha subunits and cause an increase in intracellular calcium concentration. Lastly, we tested various FGLa/AST analogs in our heterologous assay. These compounds also activated the receptor and thus have the potential to serve as insect growth regulators and aid in pest control. PMID- 25500191 TI - PLEKHM1 regulates Salmonella-containing vacuole biogenesis and infection. AB - The host endolysosomal compartment is often manipulated by intracellular bacterial pathogens. Salmonella (Salmonella enterica serovar Typhimurium) secrete numerous effector proteins, including SifA, through a specialized type III secretion system to hijack the host endosomal system and generate the Salmonella containing vacuole (SCV). To form this replicative niche, Salmonella targets the Rab7 GTPase to recruit host membranes through largely unknown mechanisms. We show that Pleckstrin homology domain-containing protein family member 1 (PLEKHM1), a lysosomal adaptor, is targeted by Salmonella through direct interaction with SifA. By binding the PLEKHM1 PH2 domain, Salmonella utilize a complex containing PLEKHM1, Rab7, and the HOPS tethering complex to mobilize phagolysosomal membranes to the SCV. Depletion of PLEKHM1 causes a profound defect in SCV morphology with multiple bacteria accumulating in enlarged structures and significantly dampens Salmonella proliferation in multiple cell types and mice. Thus, PLEKHM1 provides a critical interface between pathogenic infection and the host endolysosomal system. PMID- 25500192 TI - Community behavior and spatial regulation within a bacterial microcolony in deep tissue sites serves to protect against host attack. AB - Bacterial pathogens express virulence-specific transcriptional programs that allow tissue colonization. Although phenotypic variation has been noted in the context of antibiotic exposure, no direct evidence exists for heterogeneity in virulence-specific transcriptional programs within tissues. In a mouse model of Yersinia pseudotuberculosis infection, we show that at least three subpopulations of bacteria develop within a single tissue site in response to distinct host signals. Bacteria growing on the exterior of spleen microcolonies responded to soluble signals and induced the nitric oxide (NO)-detoxifying gene, hmp. Hmp effectively eliminated NO diffusion and protected the interior bacterial population from exposure to NO-derived inducing signals. A third subpopulation, constituting the most peripherally localized bacteria, directly contacted neutrophils and transcriptionally upregulated a virulence factor. These studies demonstrate that growth within tissues results in transcriptional specialization within a single focus of microbial replication, facilitating directed pathogen counterattack against the host response. PMID- 25500193 TI - Early prediction of delayed cerebral ischemia in subarachnoid hemorrhage based on quantitative EEG: A prospective study in adults. AB - OBJECTIVES: Delayed cerebral infarction (DCI) has a significant impact on mortality and morbidity of patients with subarachnoid hemorrhage (SAH). The aim of this study was to define quantitative EEG (qEEG) parameters for the early and reliable prediction of DCI and compare the validity and time course of qEEG to standard procedures. METHODS: 12 consecutive unselected SAH patients (8 female, mean age 52 years, Hunt-and-Hess grade I-IV) were prospectively examined. Continuous six channel EEG monitoring was started within 48 h after admission (mean duration 5.2 days; range: 2-12 days). All raw and unselected EEG signal underwent automated artifact rejection, Short Time Fast Fourier Transformation and a detrending procedure in order to analyze regional spectral power changes in different frequency bands. According to clinical standards, transcranial Doppler sonography (TCD) was performed at least on alternate days and repeat cerebral computer tomography (CCT) as needed. RESULTS: 6 patients (50%) developed vasospasm/DCI. Decrease of ?40% in power persisting over ?5h in the alpha band and ?6h in the theta band marked the optimal cut-off to detect DCI (sensitivity 89%, specificity 77% for alpha). EEG changes preceded detection of vasospasm/DCI in standard procedures by 2.3d ays. Changes in the beta and delta band as well as in the alpha/delta ratio demonstrated lower correlation with imminent DCI. CONCLUSIONS: Focal reduction in alpha power may represent a valid, observer independent, non-invasive and continuous marker for vasospasm/DCI in SAH patients. SIGNIFICANCE: qEEG indicates imminent ischemia earlier than established diagnostic tools, such as TCD. PMID- 25500194 TI - National evaluation of obesity screening and treatment among veterans with and without mental health disorders. AB - OBJECTIVE: The objective was to determine whether obesity screening and weight management program participation and outcomes are equitable for individuals with serious mental illness (SMI) and depressive disorder (DD) compared to those without SMI/DD in Veterans Health Administration (VHA), the largest integrated US health system, which requires obesity screening and offers weight management to all in need. METHODS: We used chart-reviewed, clinical and administrative VHA data from fiscal years 2010-2012 to estimate obesity screening and participation in the VHA's weight management program (MOVE!) across groups. Six- and 12-month weight changes in MOVE! participants were estimated using linear mixed models adjusted for confounders. RESULTS: Compared to individuals without SMI/DD, individuals with SMI or DD were less frequently screened for obesity (94%-94.7% vs. 95.7%) but had greater participation in MOVE! (10.1%-10.4% vs. 7.4%). MOVE! participants with SMI or DD lost approximately 1 lb less at 6 months. At 12 months, average weight loss for individuals with SMI or neither SMI/DD was comparable (-3.5 and -3.3 lb, respectively), but individuals with DD lost less weight (mean=-2.7 lb). CONCLUSIONS: Disparities in obesity screening and treatment outcomes across mental health diagnosis groups were modest. However, participation in MOVE! was low for every group, which limits population impact. PMID- 25500195 TI - Synthesis and evaluation of glyco-coated liposomes as drug carriers for active targeting in drug delivery systems. AB - Novel sugar-conjugated cholesterols, beta-Gal-, alpha-Man-, beta-Man-, alpha-Fuc , and beta-Man-6P-S-beta-Ala-Chol, were synthesized and incorporated into liposomes. In vitro experiments using the glyco-coated liposomes showed that the glyco-coated liposomes are efficiently taken up by cells expressing carbohydrate binding receptors selectively. Glyco-coated liposomes are promising candidates for drug delivery vehicles. PMID- 25500196 TI - Simultaneous pressure-volume measurements using optical sensors and MRI for left ventricle function assessment during animal experiment. AB - Simultaneous pressure and volume measurements enable the extraction of valuable parameters for left ventricle function assessment. Cardiac MR has proven to be the most accurate method for volume estimation. Nonetheless, measuring pressure simultaneously during MRI acquisitions remains a challenge given the magnetic nature of the widely used pressure transducers. In this study we show the feasibility of simultaneous in vivo pressure-volume acquisitions with MRI using optical pressure sensors. Pressure-volume loops were calculated while inducing three inotropic states in a sheep and functional indices were extracted, using single beat loops, to characterize systolic and diastolic performance. Functional indices evolved as expected in response to positive inotropic stimuli. The end systolic elastance, representing the contractility index, the diastolic myocardium compliance, and the cardiac work efficiency all increased when inducing inotropic state enhancement. The association of MRI and optical pressure sensors within the left ventricle successfully enabled pressure-volume loop analysis after having respective data simultaneously recorded during the experimentation without the need to move the animal between each inotropic state. PMID- 25500197 TI - The New York Bight 25 years later: use impairments and policy challenges. AB - This paper reexamines policies and outcomes concerning the NY Bight Restoration Plan, and the NY-NJ Harbor Estuary Program (NYNJHEP) precipitated by washups of marine debris and medical wastes in the New York Bight some 25-years ago. Findings indicate progress has been made but further work is necessary. Extensive beach closures have not occurred since 1987-88, although localized closings occur annually from pathogens. Objectives of "0" beach closures may not be feasible for some beaches, not to exceed 5% closures may be more achievable. Pathogen and DO data show further reductions of the last 10-20% will be more challenging and costly, suggesting "hot spots" be a focus for further remediation. Marine debris show increasing trends on beaches; presence of balloons, plastic bags, syringes and personal hygiene items found annually is another concern. Future challenges are on two fronts, upstream (harbor estuary based)-toxics, nutrient/organic loads, and atmospheric (bight based)-toxics, metals. PMID- 25500199 TI - How can research lead to change in practice? PMID- 25500198 TI - The interleukin-15 system suppresses T cell-mediated autoimmunity by regulating negative selection and nT(H)17 cell homeostasis in the thymus. AB - The interleukin-15 (IL-15) system is important for regulating both innate and adaptive immune responses, however, its role in autoimmune disease remained unclear. Here we found that Il15(-/-) and Il15ra(-/-) mice spontaneously developed late-onset autoimmune phenotypes. CD4(+) T cells of the knockout mice showed elevated autoreactivity as demonstrated by the induction of lymphocyte infiltration in the lacrimal and salivary glands when transferred into nude mice. The antigen-presenting cells in the thymic medullary regions expressed IL-15 and IL-15Ralpha, whose deficiency resulted in insufficient negative selection and elevated number of natural IL-17A-producing CD4(+) thymocytes. These findings reveal previously unknown functions of the IL-15 system in thymocyte development, and thus a new layer of regulation in T cell-mediated autoimmunity. PMID- 25500200 TI - Primary rectal linitis: a rare clinical condition. AB - Rectal linitis is a rare tumor with a poor prognosis that may be seen as a primary tumor or in association with gastric linitis plastica. In this article we describe the morphological appearance on CT and magnetic resonance imaging, which is typical. We also discuss the oncologic management, which is not well defined, including the potential value of neo-adjuvant treatment. PMID- 25500201 TI - A prevention program for multiple health-compromising behaviors in adolescence: baseline results from a cluster randomized controlled trial. AB - OBJECTIVE: To describe the design and present the baseline findings of the evaluation study of 'Paesaggi di Prevenzione', a school-based prevention program tackling smoking, alcohol misuse, dietary risks, and physical inactivity in 12- to 14-year-olds. METHODS: The program was implemented from January 2011 to April 2012 in Emilia-Romagna, Italy, and comprised classroom activities and school-wide policies. A two-arm cluster randomized controlled trial was designed. Schools were the units of randomization and were matched by socioeconomic status, size, and type. RESULTS: Data from 4700 middle school students and 2952 high school students were collected anonymously from October to December 2010. Past-30-day smoking prevalence was 1.9% among middle school students and 20.8% among high school students. Past-30-day prevalence of alcohol intoxication was 2.2% among middle school students and 11.4% among high school students. A total of 39.7% of middle school students and 48.0% of high school students drank sugar-sweetened beverages four or more times per week; 7.5% of middle school students and 7.1% of high school students had intense physical activity every day. CONCLUSIONS: This study seems adequately powered and baseline variables appear evenly distributed between study groups. Findings are in line with those of the WHO Health Behaviour in School-Aged Children study. PMID- 25500203 TI - KLF2 exerts antifibrotic and vasoprotective effects in cirrhotic rat livers: behind the molecular mechanisms of statins. AB - OBJECTIVE: In the liver, the transcription factor, Kruppel-like factor 2 (KLF2), is induced early during progression of cirrhosis to lessen the development of vascular dysfunction; nevertheless, its endogenous expression results insufficient to attenuate establishment of portal hypertension and aggravation of cirrhosis. Herein, we aimed to explore the effects and the underlying mechanisms of hepatic KLF2 overexpression in in vitro and in vivo models of liver cirrhosis. DESIGN: Activation phenotype was evaluated in human and rat cirrhotic hepatic stellate cells (HSC) treated with the pharmacological inductor of KLF2 simvastatin, with adenovirus codifying for this transcription factor (Ad-KLF2), or vehicle, in presence/absence of inhibitors of KLF2. Possible paracrine interactions between parenchymal and non-parenchymal cells overexpressing KLF2 were studied. Effects of in vivo hepatic KLF2 overexpression on liver fibrosis and systemic and hepatic haemodynamics were assessed in cirrhotic rats. RESULTS: KLF2 upregulation profoundly ameliorated HSC phenotype (reduced alpha-smooth muscle actin, procollagen I and oxidative stress) partly via the activation of the nuclear factor (NF)-E2-related factor 2 (Nrf2). Coculture experiments showed that improvement in HSC phenotype paracrinally ameliorated liver sinusoidal endothelial cells probably through a vascular endothelial growth factor-mediated mechanism. No paracrine interactions between hepatocytes and HSC were observed. Cirrhotic rats treated with simvastatin or Ad-KLF2 showed hepatic upregulation in the KLF2-Nrf2 pathway, deactivation of HSC and prominent reduction in liver fibrosis. Hepatic KLF2 overexpression was associated with lower portal pressure ( 15%) due to both attenuations in the increased portal blood flow and hepatic vascular resistance, together with a significant improvement in hepatic endothelial dysfunction. CONCLUSIONS: Exogenous hepatic KLF2 upregulation improves liver fibrosis, endothelial dysfunction and portal hypertension in cirrhosis. PMID- 25500202 TI - Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. AB - OBJECTIVE: The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide 1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults. DESIGN: To investigate whether propionate promotes PYY and GLP 1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults. RESULTS: Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group. CONCLUSIONS: These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans. TRIAL REGISTRATION NUMBER: NCT00750438. PMID- 25500205 TI - Marivirga lumbricoides sp. nov., a marine bacterium isolated from the South China Sea. AB - A novel, aerobic, heterotrophic, orange-pigmented, Gram-staining-negative, rod shaped, gliding bacterial strain, designated JLT2000(T), was isolated from surface water of the South China Sea. The strain was oxidase- and catalase positive. The major cellular fatty acids of strain JLT2000 T: were C12 : 0, iso C15 : 1 G, iso-C15 : 0, iso-C17 : 0 3-OH, summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0 and C18 : 0. MK-7 was the major respiratory quinone and the major polar lipids were phosphatidylcholine and phosphatidylethanolamine. The genomic DNA G+C content of strain JLT2000(T) was 37.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain JLT2000(T) formed a branch within the genus Marivirga, but was clearly separated from the two established species of this genus, Marivirga tractuosa and Marivirga sericea. The 16S rRNA gene sequence similarity of strain JLT2000(T) with the type strains of these two species was 95.8 % and 96.1 %, respectively. Strain JLT2000(T) had a shorter cell length and wider growth range in different temperatures and salinities than those of Marivirga tractuosa NBRC 15989(T) and Marivirga sericea NBRC 15983(T). In addition, strain JLT2000(T) could utilize more carbon sources and hydrolyse more polymers than Marivirga tractuosa NBRC 15989(T) and Marivirga sericea NBRC 15983(T). Based on this polyphasic analysis, strain JLT2000(T) represents a novel species of the genus Marivirga, for which the name Marivirga lumbricoides sp. nov. is proposed. The type strain is JLT2000(T) ( = JCM 18012(T) = CGMCC 1.10832(T)). PMID- 25500206 TI - Etiology of angiogenesis inhibition-related hypertension. AB - Angiogenesis inhibition, targeting vascular endothelial growth factor (VEGF) or its receptors, is an established treatment for solid tumors. A common side effect of this treatment is the development of sometimes severe hypertension. This hypertension is associated with a decrease in nitric oxide production, activation of the endothelin-signaling pathway and renin suppression. The mechanism underlying activation of the endothelin-signaling pathway is not fully understood. Both activation of endothelial cells and disinhibition of the VEGF induced suppression of endothelin production by endothelial cells may be involved. The development of hypertension can be a reason to discontinue the angiogenesis inhibitor, thereby compromising anticancer treatment, but possibly is also a biomarker for a favorable antitumor response. PMID- 25500207 TI - Corrigendum to "A multiphase analysis of partitioning and hazard index characteristics of siloxanes in biosolids" [Ecotoxicol. Environ. Saf. 102 (2014) 79-83]. PMID- 25500208 TI - Immune-metabolic profiling of anorexic patients reveals an anti-oxidant and anti inflammatory phenotype. AB - CONTEXT: Anorexia nervosa (AN) is an excessive form of calorie restriction (CR) associated with pathological weight loss and alterations of the immune system. However, AN patients seem to be protected from common viral infections. OBJECTIVES: To investigate the metabolic and molecular adaptations induced by sustained extreme CR in the peripheral blood mononuclear cells (PBMCs) of patients with restrictive alimentary AN. DESIGN: Inflammatory cytokines and adipokines were measured in 15 young (age range, 15-24 years) AN female patients and 20 age-matched healthy controls. Isolated PBMCs were immunophenotyped by flow cytometry, and glycolysis and mitochondrial respiration were determined by measuring the extracellular acidification and oxygen consumption rate. Stress resistance to H2O2 and the antioxidant transcriptional profile of PBMCs and human fibroblasts incubated with sera from AN patients were also determined. RESULTS: Compared with controls, AN patients (BMI, 15.9+/-0.4 kg/m(2)) had significantly fewer leucocytes, lymphocytes and NK cells, lower serum concentrations of leptin, IGF-1 and sTNFR1, and higher levels of adiponectin, sCD40L and sICAM-1 (p<0.05). IL-1beta, TNFalpha, and IL-6 produced by PBMC cultured with autologous serum for 48 h were significantly lower in AN patients than in controls (p<0.01). Moreover, glycolysis and mitochondrial respiration were lower, and the antioxidant transcriptional profile was higher in the PBMCs of AN patients. Fibroblasts cultured in serum from AN patients showed a 24% increase in resistance to H2O2 damage. CONCLUSIONS: Extreme CR in AN patients is associated with a reduction in several immune cell populations, but with higher antioxidant potential, stress resistance and an anti-inflammatory status. PMID- 25500210 TI - Re: Untreated dentofacial deformity: in defence of Luis Suarez. PMID- 25500204 TI - Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections. AB - BACKGROUND AND AIMS: Peripancreatic fat necrosis occurs frequently in necrotising pancreatitis. Distinguishing markers from mediators of severe acute pancreatitis (SAP) is important since targeting mediators may improve outcomes. We evaluated potential agents in human pancreatic necrotic collections (NCs), pseudocysts (PCs) and pancreatic cystic neoplasms and used pancreatic acini, peripheral blood mononuclear cells (PBMC) and an acute pancreatitis (AP) model to determine SAP mediators. METHODS: We measured acinar and PBMC injury induced by agents increased in NCs and PCs. Outcomes of caerulein pancreatitis were studied in lean rats coadministered interleukin (IL)-1beta and keratinocyte chemoattractant/growth-regulated oncogene, triolein alone or with the lipase inhibitor orlistat. RESULTS: NCs had higher fatty acids, IL-8 and IL-1beta versus other fluids. Lipolysis of unsaturated triglyceride and resulting unsaturated fatty acids (UFA) oleic and linoleic acids induced necro-apoptosis at less than half the concentration in NCs but other agents did not do so at more than two times these concentrations. Cytokine coadministration resulted in higher pancreatic and lung inflammation than caerulein alone, but only triolein coadministration caused peripancreatic fat stranding, higher cytokines, UFAs, multisystem organ failure (MSOF) and mortality in 97% animals, which were prevented by orlistat. CONCLUSIONS: UFAs, IL-1beta and IL-8 are elevated in NCs. However, UFAs generated via peripancreatic fat lipolysis causes worse inflammation and MSOF, converting mild AP to SAP. PMID- 25500211 TI - Effect of nitric oxide on VnfA, a transcriptional activator of VFe-nitrogenase in Azotobacter vinelandii. AB - The transcriptional activator, VnfA, is necessary for the expression of the structural genes encoding vanadium-dependent nitrogenase in Azotobacter vinelandii. We have previously reported that VnfA harbours a Fe-S cluster as a prosthetic group, presumably a 3Fe-4S type, which is vital for the transcriptionally active VnfA. A plausible effector molecule is a reactive oxygen species (ROS), which disassembles the Fe-S cluster switching the active VnfA to become fully inactive. This finding prompted us to investigate the effect of nitric oxide (NO), another physiologically important radical species on the VnfA activity. Unlike ROS, the VnfA activity was moderately inhibited and converged to 70% of the maximum by NO irrespective of its concentration. The Fe-S cluster of VnfA was found to react with NO to form a dinitrosyl-iron complex, either in the dimeric or monomeric form, dependent on the relative stoichiometry of NO to the Fe-S cluster. The VnfA species harbouring the dinitrosyl-iron complexes in each form exhibited 50% ATPase activity compared to the active VnfA. The findings of this study would open an argument about a biological effect of NO on nitrogenase in light of its transcriptional regulatory system. PMID- 25500212 TI - Elephantiasis nostras verrucosa occurring in voluntary shut-in ("hikikomori"). PMID- 25500213 TI - Murine cysticercosis model: influence of the infection time and the time of treatment on the cysticidal efficacy of albendazole and praziquantel. AB - In the search of new alternatives for neurocysticercosis treatment, Taenia crassiceps ORF strain cysticerci have been used instead of T. solium for in vitro studies. Up to date, the main criteria for the use of the murine cysticercosis model for drug efficacy evaluation have not been assessed. The aim of the present study was to evaluate the influence of two of the main variables related to the in vivo efficacy: the length of drug treatment and the starting time of treatment after experimental infection, using albendazole (ABZ) and praziquantel (PZQ) as test drugs. Additionally, the relationship between the number of cysts and the parasite weight was assessed. For the study, female BALB/c mice were experimentally infected with T. crassiceps cysts. Three different post-infection periods (10, 20 and 30 days) and three different lengths of treatment with ABZ or PZQ (10, 20 and 30 days) were selected. The efficacy of each treatment was evaluated by comparison with a control group. Our results show that for in vivo efficacy studies, the best time to start the drug treatment is 10 days post infection and that a minimum of 20 days of treatment is required when ABZ or PZQ are used as positive control. Moreover, in this model the parasite weight can be used as a rapid tool to measure the in vivo drug activity. PMID- 25500214 TI - Modulation of endogenous Cysteine Protease Inhibitor (ICP) 1 expression in Entamoeba histolytica affects amoebic adhesion to Extracellular Matrix proteins. AB - Entamoeba histolytica is an enteric tissue-invading protozoan parasite that causes amoebic colitis and occasionally liver abscess in humans. During tissue invasion, amoebic adhesion to host components is an important event for host cell death leading to successful invasion and infection. Among amoebic virulence factors, Gal/GalNAc lectin is known to be major adhesion factor to host cells. In this study, we investigated the role of amoebic secreted CP (Cysteine Proteases) in amoebic adhesion to extracellular matrix (ECM) protein using CP inhibitor and E. histolytica strains in which the endogenous inhibitor of cysteine protease (ICP) 1 gene was overexpressed (ICP1(+)) or repressed by antisense small RNA mediated gene silencing (ICP1(-)). We found that pretreatment of wild-type amoebae with CP inhibitor E64, or thiol-group modifiers such as diamide and N Ethylmaleimide resulted in a significant decrease in adhesion to laminin and collagen ECM proteins. Furthermore, ICP1(+) strain, with a reduction of secreted CP activity, exhibited reduced ability by 40% to adhere to laminin. In contrast, ICP1(-) strain, with a 1.9-fold increase of secreted CP activity, showed a two fold increase in amoebic adherence to laminin compared to the control strain. In addition, total amount of secreted CP5 was decreased in ICP1(+) amoeba. Conversely, total amount of secreted CP1 and mature-form CP5 were increased in ICP1(-) amoeba. We also found that ICP1 was secreted into extracellular milieu. These results suggest that secreted CP activity by E. histolytica may be an important factor affecting adhesion to host proteins, and regulation of CP secretion by ICP plays a major role in pathogenesis. This study provides insight into the CP-mediated tissue pathogenesis in amoeba-invaded lesions during human amoebiasis. PMID- 25500216 TI - A tool to assess sex-gender when selecting health research projects. AB - OBJECTIVE: To validate the questionnaire "Gender Perspective in Health Research" (GPIHR) to assess the inclusion of gender perspective in research projects. DESIGN: Validation study in two stages. Feasibility was analysed in the first, and reliability, internal consistence and validity in the second. WHERE: Aragon Institute of Health Science, Aragon, Spain. PARTICIPANTS: GPIHR was applied to 118 research projects funded in national and international competitive tenders from 2003 to 2012. MAIN MEASUREMENTS: Analysis of inter- and intra-observer reliability with Kappa index and internal consistency with Cronbach's alpha. Content validity analysed through literature review and construct validity with an exploratory factor analysis. RESULTS: Validated GPIHR has 10 questions: 3 in the introduction, 1 for objectives, 3 for methodology and 3 for research purpose. Average time of application was 13min Inter-observer reliability (Kappa) varied between 0.35 and 0.94 and intra-observer between 0.40 and 0.94. Theoretical construct is supported in the literature. Factor analysis identifies three levels of GP inclusion: "difference by sex", "gender sensitive" and "feminist research" with an internal consistency of 0.64, 0.87 and 0.81, respectively, which explain 74.78% of variance. CONCLUSIONS: GPIHR questionnaire is a valid tool to assess GP and useful for those researchers who would like to include GP in their projects. PMID- 25500215 TI - Development of droplet digital PCR for the detection of Babesia microti and Babesia duncani. AB - Babesia spp. are obligate protozoan parasites of red blood cells. Transmission to humans occurs through bites from infected ticks or blood transfusion. Infections with B. microti account for the majority of the reported cases of human babesiosis in the USA. A lower incidence is caused by the more recently described species B. duncani. The current gold standard for detection of Babesia is microscopic examination of blood smears. Recent PCR-based assays, including real time PCR, have been developed for B. microti. On the other hand, molecular assays that detect and distinguish between B. microti and B. duncani infections are lacking. Closely related species of Babesia can be differentiated due to sequence variation within the internal transcribed spacer (ITS) regions of nuclear ribosomal RNAs. In the present study, we targeted the ITS regions of B. microti and B. duncani to develop sensitive and species-specific droplet digital PCR (ddPCR) assays. The assays were shown to discriminate B. microti from B. duncani and resulted in limits of detection of ~10 gene copies. Moreover, ddPCR for these species were useful in DNA extracted from blood of experimentally infected hamsters, detecting infections of low parasitemia that were negative by microscopic examination. In summary, we have developed sensitive and specific quantitative ddPCR assays for the detection of B. microti and B. duncani in blood. Our methods could be used as sensitive approaches to monitor the progression of parasitemia in rodent models of infection as well as serve as suitable molecular tests in blood screening. PMID- 25500217 TI - [Prevalence of performing and prescribing physical exercise in patients diagnosed with anxiety and depression]. AB - OBJECTIVE: To estimate the prevalence of physical exercise practice in patients diagnosed with anxiety and/or depression. DESIGN: Cross-sectional, observational study. LOCATION: Sabugo and la Magdalena primary care centers in Aviles. PARTICIPANTS: Patients aged 18 to 75 years diagnosed with anxiety and/or depression, consumers of psychoactive drugs in the three months previous to the realization of the study. We selected 376 patients by simple random sampling stratified by health center, making them a telephone survey. MAIN MEASUREMENTS: Age, sex, physical exercise realization, type and duration of exercise, diagnosis of anxiety and/or depression, exercise prescription, prescriber health personnel and use of psychotropic medication. RESULTS: 294 participants (78.19% of selected) with a mean age of 55.33 years (55.32+/-12.53 SD) and 78.2% were female. 60.9% were diagnosed with anxiety, 59.5% with depression and 20.4% both diagnoses. 62.9% used antidepressants, benzodiazepines 76.9% and 39.79% both treatments. 58.5% (95%CI: 52.70-64.31) performed exercise of which 44.77% did it 3-5 times/week. The mean duration was 1.24h each time (95%CI: 0.53-1.96). The physical exercise was prescribed to the 59.18% (95%CI: 53.39-64.97); 90.23% by the family physician, 63.22% primary care nurse, 17.24% psychiatrist and 5.17% psychologist. The adherence to the prescription was 59.77% (95%CI: 52.20-67.34). CONCLUSIONS: The percentage of anxious and/or depressed patients who practiced exercise is similar to the general population but should be higher. The exercise prescription by health personnel is insufficient. PMID- 25500219 TI - Differential acute effects of sleep on spontaneous and stimulated production of tumor necrosis factor in men. AB - Tumor necrosis factor (TNF) is considered a key molecule in the regulation of sleep in health and disease. Conversely, sleep compared to sleep deprivation can modulate TNF release, but overall results are conflicting. In this study we focused on the influence of sleep on spontaneous, i.e., unstimulated TNF production, which might be involved in sleep regulation under normal non infectious conditions, and on lipopolysaccharide (LPS)-stimulated TNF production, which reflects the capacity of the immune system to respond to a pathogen. To this end, we monitored 10 healthy men during a regular sleep-wake cycle and during 24h of wakefulness while blood was sampled repeatedly to analyze circulating TNF levels in serum as well as intracellular TNF production in monocytes spontaneously and after stimulation with LPS employing whole blood cell cultures. In addition we assessed numbers of monocyte subsets and levels of various hormones in blood. In comparison with nocturnal wakefulness, sleep acutely decreased serum TNF levels, with no parallel decrease in spontaneous monocytic TNF production, but was associated with a striking nighttime increase in the percentage of TNF producing monocytes after stimulation with LPS. The following day circulating TNF showed a reverse pattern with higher levels after regular sleep than after the nocturnal vigil. The mechanisms mediating the differential effects of sleep on circulating TNF (acutely decreased) vs. stimulated monocytic TNF production (acutely increased) remain unclear, although explorative correlational analyses pointed to a regulatory involvement of cortisol, norepinephrine and prolactin. The acute enhancing effect of sleep on LPS stimulated monocytic TNF production adds to the notion that nocturnal sleep favors immune defense to a microbial challenge. PMID- 25500220 TI - Rationale and study protocol for 'Switch-off 4 Healthy Minds' (S4HM): a cluster randomized controlled trial to reduce recreational screen time in adolescents. AB - INTRODUCTION: Excessive recreational screen time (i.e., screen use for entertainment) is a global public health issue associated with adverse mental and physical health outcomes. Considering the growing popularity of screen-based recreation in adolescents, there is a need to identify effective strategies for reducing screen time among adolescents. The aim of this paper is to report the rationale and study protocol for the 'Switch-off 4 Healthy Minds' (S4HM) study, an intervention designed to reduce recreational screen time among adolescents. METHODS: The S4HM intervention will be evaluated using a cluster randomized controlled trial in eight secondary schools (N=322 students) in New South Wales, Australia. The 6-month multi-component intervention will encourage adolescents to manage their recreational screen time using a range of evidence-based strategies. The intervention is grounded in Self-Determination Theory (SDT) and includes the following components: an interactive seminar for students, eHealth messaging, behavioral contract and parental newsletters. All outcomes will be assessed at baseline and at 6-months (i.e., immediate post-test). The primary outcome is recreational screen time measured by the Adolescent Sedentary Activity Questionnaire (ASAQ). Secondary outcomes include: self-reported psychological well-being, psychological distress, global physical self-concept, resilience, pathological video gaming and aggression, and objectively measured physical activity (accelerometry) and body mass index (BMI). Hypothesized mediators of behavior change will also be explored. DISCUSSION: The S4HM study will involve the evaluation of an innovative, theory-driven, multi-component intervention that targets students and their parents and is designed to reduce recreational screen time in adolescents. The intervention has been designed for scalability and dissemination across Australian secondary schools. PMID- 25500218 TI - Age-related increases in basal ganglia glutamate are associated with TNF, reduced motivation and decreased psychomotor speed during IFN-alpha treatment: Preliminary findings. AB - Inflammation-induced alterations in central nervous system (CNS) metabolism have focused on glutamate. At excessive concentrations, glutamate is toxic to glia and neurons, and inflammatory cytokines have been shown to influence glutamate turnover by blocking glutamate reuptake and increasing glutamate release. Increased glutamate has also been found in depression, a disorder associated with increased inflammation. Data by our group have shown increased glutamate as measured by magnetic resonance spectroscopy (MRS) in basal ganglia and dorsal anterior cingulate cortex of patients administered the inflammatory cytokine interferon (IFN)-alpha. Given data that increasing age is associated with an exaggerated CNS inflammatory response, we examined whether older age (>55years) would be associated with a greater IFN-alpha-induced increase in CNS glutamate. Using a longitudinal design, 31 patients with hepatitis C virus (HCV) underwent MRS, blood sampling for inflammatory markers, and behavioral assessments before (Visit 1) and after 4weeks (Visit 2) of either IFN-alpha (n=17) or no treatment (n=14). Older patients treated with IFN-alpha exhibited a significantly greater increase in glutamate from Visit 1 to Visit 2 as reflected by the glutamate/creatine ratio (Glu/Cr) in left basal ganglia compared to older controls and younger IFN-alpha-treated and untreated subjects. In addition, increased Glu/Cr in older but not younger IFN-alpha-treated and untreated patients was associated with increased tumor necrosis factor, reduced motivation as measured by the Multidimensional Fatigue Inventory and increased choice movement time on the Cambridge Neuropsychological Test Automated Battery. Taken together, these preliminary data support the notion that older age may interact with inflammation to exaggerate the effects of inflammatory stimuli on CNS glutamate and behavior. PMID- 25500221 TI - Balance between exocytosis and endocytosis determines the efficacy of sterol targeting antibiotics. AB - Antifungals targeting membrane ergosterol are longstanding, yet indispensable drugs in clinical use. However, the mechanisms by which the cellular membrane domains recognized by these antibiotics are generated remain largely unknown. Here, we demonstrate that the balance between endocytosis and exocytosis in membrane trafficking is a critical factor in the action of sterol-targeting antibiotics. When fission yeast cells were treated with manumycin A, cellular binding and the action of the antifungals filipin, amphotericin B, and theonellamides, all of which are ergosterol-binders, were abolished. Additionally, manumycin A treatment attenuated Cdc42 activity and inhibited exocytosis, while endocytosis was only moderately suppressed. Similar defects in membrane trafficking could be reproduced by heat shock and genetic perturbation, which also abolished the action of the antibiotics. We propose that exocytosis and endocytosis respectively supply and internalize the specific plasma membrane domains recognized by sterol-targeting antibiotics. PMID- 25500223 TI - IgGA: a "cross-isotype" engineered human Fc antibody domain that displays both IgG-like and IgA-like effector functions. AB - All clinically approved antibodies are of the IgG isotype and mediate the clearance of target cells via binding to Fcgamma receptors and complement (C1q). Even though IgA can elicit powerful cytotoxic action via FcalphaRI receptor binding, IgA antibodies have not been amenable to therapeutic development. Here, we report the engineering of a "cross-isotype" antibody, IgGA, which combines the effector functions of both IgG and IgA. IgGA binds to FcalphaRI with an affinity comparable to that of IgA, and to the activating Fcgamma receptors, FcgammaRI and FcgammaRIIa, with high affinity, and displays increased binding to C1q compared to IgG. Unlike trastuzumab-IgG, trastuzumab-IgGA potently activates both neutrophils and macrophages to kill Her2(+) cancer cells. Furthermore, IgGA mediates greater complement-dependent cytotoxicity than IgG1 or IgA antibodies. The multitude of IgGA effector functions could be important for therapeutic purposes and highlights the concept of engineering antibodies that combine effector functions from multiple antibody isotypes. PMID- 25500224 TI - Two separable mechanisms are responsible for mental stress effects on high frequency heart rate variability: an intra-individual approach in a healthy and a diabetic sample. AB - Central withdrawal of parasympathetic cardiac control and increased respiratory frequency represent two important determinants of reduced respiratory-related heart rate variability (HRV). However, studies are missing to disentangle their relative contribution during mental stress. Healthy subjects (n=10) and type 2 diabetic patients (n=8), the latter with evidence of cardiac autonomic neuropathy, participated in this study. Using an intra-individual approach, high frequency (hf) HRV was assessed for spontaneous (during rest and mental stress) and paced breathing (0.15, 0.2, 0.25, 0.3, 0.35, 0.4 and 0.45 Hz; randomized sequence). Mental stress was induced by a challenging reaction time task. Effects of respiratory frequency on hf HRV were individually predicted by paced breathing data. Mental stress decreased hf HRV (p<.001), and increased respiratory frequency (p=.01). Individual prediction of hf HRV by stress respiratory frequency resulted in lower values (p=.02) than observed during rest, indicating that respiratory stress effects were sufficient to reduce hf HRV. However, observed hf HRV values during stress were even lower (p<.001). These results indicate that hf HRV reductions during stress can only partly be explained by concomitant respiratory frequency changes. This effect is detectable in healthy subjects and in patients with evidence of diabetic cardiac autonomic neuropathy. PMID- 25500222 TI - Identification of an allosteric small-molecule inhibitor selective for the inducible form of heat shock protein 70. AB - Inducible Hsp70 (Hsp70i) is overexpressed in a wide spectrum of human tumors, and its expression correlates with metastasis, poor outcomes, and resistance to chemotherapy in patients. Identification of small-molecule inhibitors selective for Hsp70i could provide new therapeutic tools for cancer treatment. In this work, we used fluorescence-linked enzyme chemoproteomic strategy (FLECS) to identify HS-72, an allosteric inhibitor selective for Hsp70i. HS-72 displays the hallmarks of Hsp70 inhibition in cells, promoting substrate protein degradation and growth inhibition. Importantly, HS-72 is selective for Hsp70i over the closely related constitutively active Hsc70. Studies with purified protein show HS-72 acts as an allosteric inhibitor, reducing ATP affinity. In vivo HS-72 is well-tolerated, showing bioavailability and efficacy, inhibiting tumor growth and promoting survival in a HER2+ model of breast cancer. The HS-72 scaffold is amenable to resynthesis and iteration, suggesting an ideal starting point for a new generation of anticancer therapeutics targeting Hsp70i. PMID- 25500225 TI - This issue marks a new initiative for the International Journal of Psychophysiology. Introduction. PMID- 25500226 TI - Relevance of Roux-en-Y gastric bypass volumetry using 3-dimensional gastric computed tomography with gas to predict weight loss at 1 year. AB - BACKGROUND: Causes of Roux-en-Y gastric bypass (RYGB) failures are still controversial. Literature data suggest that gastric pouch or gastrojejunal anastomosis distentions over time could be a key factor. Making the hypothesis that progressive distention of RYGB volumes is 1 of the main factors of weight loss failure, the aim of our study was to evaluate bypass volumes changes using repeated 3-dimensional gastric computed tomography with gas and the possible negative correlation with weight loss results at 1 year. METHODS: Thirty-nine patients eligible for RYGB were prospectively included. Gastric bypass volumes were assessed at 3 and 12 months postsurgery performing 3-dimensional gastric computed tomography with gas and weight loss outcomes were recorded during the first postoperative year. RESULTS: There was no loss to follow up. Mean % excess body mass index lost (%EBMIL) at 1 year was 66.7%. Seven patients (17.9%) did not reach Reinhold criteria and were considered as RYGB failures. We found no linear correlation between the 1 year %EBMIL and mean values of the gastric pouch (r=.01; P=.94), and the neo stomach (r=.09 ; P=.57) at 3 months. Revisional surgery was correlated negatively with %EBMIL at 1 year. CONCLUSION: Weight loss at 1 year does not seem to be correlated to RYGB volume changes. Behavioral factors probably play a major role in weight loss failure. PMID- 25500227 TI - Procedural results and safety of common interventional procedures in congenital heart disease: initial report from the National Cardiovascular Data Registry. AB - BACKGROUND: The National Cardiovascular Data Registry (NCDR) launched the IMPACT (Improving Pediatric and Adult Congenital Treatment) Registry in 2010. By 2013, its patient enrollment exceeded that of other current and historical congenital catheterization registries. OBJECTIVES: This study sought to describe procedural results and safety of 6 common congenital interventions performed in patients enrolled during the IMPACT Registry's initial periods. METHODS: With specified exclusions, we compiled registry data from patients enrolled in the IMPACT Registry from January 2011 through March 2013 who underwent 1 of the following isolated procedures: device closure of atrial septal defect (ASD); device closure of patent ductus arteriosus (PDA); pulmonary valvuloplasty; aortic valvuloplasty; coarctation of the aorta angioplasty and stenting; and pulmonary artery stenting. Patient data, procedural data and results, and adverse events (AEs) were reviewed and described. RESULTS: In 4,152 catheterizations, 1 isolated procedure was reported. There were 1,286 single-ASD procedures, 1,375 PDA procedures, 270 "typical" pulmonary valve procedures, 305 aortic valve procedures, 671 aortic procedures, and 245 pulmonary artery procedures. The reported procedure was performed in >95% of catheterizations. Stated outcomes were accomplished in >98% of ASD and PDA procedures, but less commonly in the others, with coarctation angioplasty procedures being the least successful (51%). Reported major AE rates ranged from 0% to 3.3%; total AE rates ranged from 5.3% to 24.3%. CONCLUSIONS: Contemporary community practice, procedural outcomes, and safety for 6 common congenital interventional procedures are reported. These benchmarks may be compared with individual center results and historical single-center and multicenter results. PMID- 25500228 TI - The impact of IMPACT: a game changer for congenital cardiology. PMID- 25500230 TI - Pulmonary vein isolation for atrial fibrillation: forever young. PMID- 25500229 TI - Comparison of radiofrequency catheter ablation of drivers and circumferential pulmonary vein isolation in atrial fibrillation: a noninferiority randomized multicenter RADAR-AF trial. AB - BACKGROUND: Empiric circumferential pulmonary vein isolation (CPVI) has become the therapy of choice for drug-refractory atrial fibrillation (AF). Although results are suboptimal, it is unknown whether mechanistically-based strategies targeting AF drivers are superior. OBJECTIVES: This study sought to determine the efficacy and safety of localized high-frequency source ablation (HFSA) compared with CPVI in patients with drug-refractory AF. METHODS: This prospective, multicenter, single-blinded study of 232 patients (age 53 +/- 10 years, 186 males) randomized those with paroxysmal AF (n = 115) to CPVI or HFSA-only (noninferiority design) and those with persistent AF (n = 117) to CPVI or a combined ablation approach (CPVI + HFSA, superiority design). The primary endpoint was freedom from AF at 6 months post-first ablation procedure. Secondary endpoints included freedom from atrial tachyarrhythmias (AT) at 6 and 12 months, periprocedural complications, overall adverse events, and quality of life. RESULTS: In paroxysmal AF, HFSA failed to achieve noninferiority at 6 months after a single procedure but, after redo procedures, was noninferior to CPVI at 12 months for freedom from AF and AF/AT. Serious adverse events were significantly reduced in the HFSA group versus CPVI patients (p = 0.02). In persistent AF, there were no significant differences between treatment groups for primary and secondary endpoints, but CPVI + HFSA trended toward more serious adverse events. CONCLUSIONS: In paroxysmal AF, HFSA failed to achieve noninferiority at 6 months but was noninferior to CPVI at 1 year in achieving freedom of AF/AT and a lower incidence of severe adverse events. In persistent AF, CPVI + HFSA offered no incremental value. (Radiofrequency Ablation of Drivers of Atrial Fibrillation [RADAR-AF]; NCT00674401). PMID- 25500231 TI - Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a nationwide observational cohort study. AB - BACKGROUND: The balance between stroke reduction and increased bleeding associated with antithrombotic therapy among patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is controversial. OBJECTIVES: This study assessed the risk associated with CKD in individual CHA2DS2-VASc (Congestive heart failure; Hypertension; Age >=75 years; Diabetes mellitus; previous Stroke, transient ischemic attack, or thromboembolism; Vascular disease; Age 65 to 74 years; Sex category) strata and the net clinical benefit of warfarin in patients with AF and CKD in a nationwide cohort. METHODS: By individual-level linkage of nationwide Danish registries, we identified all patients discharged with nonvalvular AF from 1997 to 2011. The stroke risk associated with non-end-stage CKD and end-stage CKD (e.g., patients on renal replacement therapy [RRT]) was estimated using Cox regression analyses. The net clinical benefit of warfarin was assessed using 4 endpoints: a composite endpoint of death/hospitalization from stroke/bleeding; a composite endpoint of fatal stroke/fatal bleeding; cardiovascular death; and all-cause death. RESULTS: From nonvalvular AF patients (n = 154,259), we identified 11,128 patients (7.2%) with non-end-stage CKD and 1,728 (1.1%) receiving RRT. In all CHA2DS2-VASc risk groups, RRT was independently associated with a higher risk of stroke/thromboembolism, from a 5.5 fold higher risk in patients with CHA2DS2-VASc score = 0 to a 1.6-fold higher risk in patients with CHA2DS2-VASc score >=2. In patients receiving RRT with CHA2DS2-VASc score >=2, warfarin was associated with lower risk of all-cause death (hazard ratio [HR]: 0.85, 95% confidence interval [CI]: 0.72 to 0.99). In non-end-stage CKD patients with CHA2DS2-VASc score >=2, warfarin was associated with a lower risk of a composite outcome of fatal stroke/fatal bleeding (HR: 0.71, 95% CI: 0.57 to 0.88), a lower risk of cardiovascular death (HR: 0.80, 95% CI: 0.74 to 0.88), and a lower risk of all-cause death (HR: 0.64, 95% CI: 0.60 to 0.69). CONCLUSIONS: CKD is associated with a higher risk of stroke/thromboembolism across stroke risk strata in AF patients. High-risk CKD patients (CHA2DS2-VASc >=2) with AF benefit from warfarin treatment for stroke prevention. PMID- 25500232 TI - Chronic anticoagulation in chronic kidney disease. PMID- 25500234 TI - Cardiovascular disease in Asian Americans: unmasking heterogeneity. PMID- 25500233 TI - Cardiovascular disease mortality in Asian Americans. AB - BACKGROUND: Asian Americans are a rapidly growing racial/ethnic group in the United States. Our current understanding of Asian-American cardiovascular disease mortality patterns is distorted by the aggregation of distinct subgroups. OBJECTIVES: The purpose of the study was to examine heart disease and stroke mortality rates in Asian-American subgroups to determine racial/ethnic differences in cardiovascular disease mortality within the United States. METHODS: We examined heart disease and stroke mortality rates for the 6 largest Asian-American subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, and Vietnamese) from 2003 to 2010. U.S. death records were used to identify race/ethnicity and cause of death by International Classification of Diseases 10th revision coding. Using both U.S. Census data and death record data, standardized mortality ratios (SMRs), relative SMRs (rSMRs), and proportional mortality ratios were calculated for each sex and ethnic group relative to non Hispanic whites (NHWs). RESULTS: In this study, 10,442,034 death records were examined. Whereas NHW men and women had the highest overall mortality rates, Asian Indian men and women and Filipino men had greater proportionate mortality burden from ischemic heart disease. The proportionate mortality burden of hypertensive heart disease and cerebrovascular disease, especially hemorrhagic stroke, was higher in every Asian-American subgroup compared with NHWs. CONCLUSIONS: The heterogeneity in cardiovascular disease mortality patterns among diverse Asian-American subgroups calls attention to the need for more research to help direct more specific treatment and prevention efforts, in particular with hypertension and stroke, to reduce health disparities for this growing population. PMID- 25500235 TI - Targeted next-generation sequencing identifies pathogenic variants in familial congenital heart disease. AB - BACKGROUND: Many genes have been implicated in the development of congenital heart disease (CHD). Next-generation sequencing offers opportunities for genetic testing but is often complicated by logistic and interpretative hurdles. OBJECTIVES: This study sought to apply next-generation sequencing technology to CHD families with multiple affected members using a purpose-designed gene panel to assess diagnostic potential for future clinical applications. METHODS: We designed a targeted next-generation sequencing gene panel for 57 genes previously implicated in CHD. Probands were screened in 16 families with strong CHD histories and in 15 control subjects. Variants affecting protein-coding regions were classified in silico using prediction programs and filtered according to predicted mode of inheritance, minor allele frequencies, and presence in databases such as dbSNP (Single Nucleotide Polymorphism Database) and ESP (Exome Sequencing Project). Disease segregation studies were conducted in variants identified in CHD cases predicted to be deleterious and with minor allele frequencies <0.1%. RESULTS: Thirteen potential disease-causing variants were identified in 9 families. Of these, 5 variants segregated with disease phenotype, revealing a likely molecular diagnosis in 31% of this cohort. Significant increases in the number of "indels, nonsense, and splice" variants, as well as variants classified as "probably damaging" were identified in CHD cases but not in control subjects. Also, there was a significant increase in the total number of "rare" and "low" frequency variants (minor allele frequencies <0.05) in the CHD cases. CONCLUSIONS: When multiple relatives are affected by CHD, a gene panel based approach may identify its cause in up to 31% of families. Identifying causal variants has implications for clinical care and future family planning. PMID- 25500236 TI - Next-generation sequencing in congenital heart disease: do new brooms sweep clean? PMID- 25500238 TI - In search of the vulnerable plaque: is there any light at the end of the catheter? PMID- 25500237 TI - Near-infrared spectroscopy predicts cardiovascular outcome in patients with coronary artery disease. AB - BACKGROUND: Near-infrared spectroscopy (NIRS) is capable of identifying lipid core-containing plaques, which can subsequently be quantified as a lipid core burden index (LCBI). Currently, no data are available on the long-term prognostic value of NIRS in patients with coronary artery disease (CAD). OBJECTIVES: This study sought to determine the long-term prognostic value of intracoronary NIRS as assessed in a nonculprit vessel in patients with CAD. METHODS: In this prospective, observational study, NIRS imaging was performed in a nonculprit coronary artery in 203 patients referred for angiography due to stable angina pectoris (SAP) or acute coronary syndrome (ACS). The primary endpoint was the composite of all-cause mortality, nonfatal ACS, stroke, and unplanned coronary revascularization. RESULTS: The 1-year cumulative incidence of the primary endpoint was 10.4%. Cumulative 1-year rates in patients with an LCBI equal to and above the median (43.0) versus those with LCBI values below the median were 16.7% versus 4.0% (adjusted hazard ratio: 4.04; 95% confidence interval: 1.33 to 12.29; p = 0.01). The relation between LCBI and the primary endpoint was similar in SAP and ACS patients (p value for heterogeneity = 0.14). Similar differences between high and low LCBI were observed in pre-specified secondary endpoints. CONCLUSION: CAD patients with an LCBI equal to or above the median of 43.0, as assessed by NIRS in a nonculprit coronary artery, had a 4-fold risk of adverse cardiovascular events during 1-year follow-up. This observation warrants confirmation by larger studies with extended follow-up. (The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis - Intravascular Ultrasound Study [AtheroRemoIVUS]; NCT01789411). PMID- 25500239 TI - Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. AB - Triglycerides represent 1 component of a heterogeneous pool of triglyceride-rich lipoproteins (TGRLs). The reliance on triglycerides or TGRLs as cardiovascular disease (CVD) risk biomarkers prompted investigations into therapies that lower plasma triglycerides as a means to reduce CVD events. Genetic studies identified TGRL components and pathways involved in their synthesis and metabolism. We advocate that only a subset of genetic mechanisms regulating TGRLs contribute to the risk of CVD events. This "omic" approach recently resulted in new targets for reducing CVD events. PMID- 25500240 TI - Current status of bioresorbable scaffolds in the treatment of coronary artery disease. AB - State-of-the-art drug-eluting metal stents are the gold standard for interventional treatment of coronary artery disease. Although they overcome some disadvantages and limitations of plain balloon angioplasty and bare-metal stents, some limitations apply, most notably a chronic local inflammatory reaction due to permanent implantation of a foreign body, restriction of vascular vasomotion due to a metal cage, and the risk of late and very late stent thrombosis. The development of biodegradable scaffolds is a new approach that attempts to circumvent these drawbacks. These devices provide short-term scaffolding of the vessel and then dissolve, which should theoretically circumvent the side effects of metal drug-eluting stents. Various types of these bioresorbable scaffolds are currently under clinical evaluation. This review discusses different concepts of bioresorbable scaffolds with respect to material, design, and drug elution and presents the most recent evidence. PMID- 25500241 TI - Valuing our oath more than our politics. PMID- 25500242 TI - Why early career cardiologists should establish a professional home. PMID- 25500243 TI - Transcatheter valve replacement in patients with severe mitral valve disease and annular calcification. PMID- 25500244 TI - Effectiveness of antitachycardia pacing for recurrent ventricular tachycardia in ARVC. PMID- 25500245 TI - Reply: Effectiveness of antitachycardia pacing for recurrent ventricular tachycardia in ARVC. PMID- 25500246 TI - Obstructive sleep apnea and hypertrophic cardiomyopathy: obiter dictum or more? PMID- 25500247 TI - Reply: Obstructive sleep apnea and hypertrophic cardiomyopathy: obiter dictum or more? PMID- 25500248 TI - Phenotypic and molecular characterization of nosocomial K. pneumoniae isolates by ribotyping. AB - PURPOSE: To characterize clinical isolates of Klebsiella pneumoniae by phenotypic and genotypic methods. MATERIAL/METHODS: Over a 12-month period, 52 isolates of K. pneumoniae were isolated. Of these 52 isolates, 7 were isolated over a period of 21 days from a suspected outbreak in the Neonatal Intensive Care Unit (NICU) and 45 from sporadic cases occurring in different wards of hospital were analysed. RESULTS: The prevalence of K. pneumoniae isolates was 4% (52/1295). Quinolones, aztreonam and amikacin showed the greatest efficacy showing >85% sensitivity. Of the 52 isolates of K. pneumoniae, 8 (15.4%) isolates were positive for ESBL-production. Among the ESBL-producing K. pneumoniae, two out of 8 (25%) and 6 out of 8 (75%) were positive for (bla)SHV and (bla)CTX-M genes respectively. Ribotyping identified 30 distinct ribogroups among 52 isolates evaluated. Seven NICU outbreak isolates were divided into 2 ribotypes, as many as 6 belonged to one ribotype while one isolate which was isolated a week later was of a different ribotype, indicating the termination of the outbreak in the NICU. The outbreak in the NICU thus, was shown to have been caused by a single clone. CONCLUSIONS: A high discriminatory power, ease of interpretation coupled with excellent reproducibility and stability make ribotyping a very useful technique for investigating the molecular epidemiology of nosocomial infections caused by K. pneumoniae. A regular surveillance of hospital associated infections including monitoring antibiotic sensitivity pattern of K. pneumoniae, ESBL-production and molecular characterization is mandatory to control the spread of multidrug resistant and ESBL-producing K. pneumoniae and for epidemiological purposes especially in outbreak situations. PMID- 25500249 TI - The relationship between HLA-G and viral loads in non-responder HCV-infected patients after combined therapy with IFN-alpha2alpha and ribavirin. AB - Hepatitis C disease is a virus mediated infection causing major health problem worldwide. Conversions of immune surveillance play an important role in response to virus clearance. Immune modulating molecules such as HLA-G and IL-10 that convert immune response toward Th2 may play a role to inhibit response from combined therapy with IFN-alpha2alpha and ribavirin. The objective of this study was to investigate the expression of HLA-G and IL-10 in responder and non responder HCV positive patients. In this study, characteristics of the virus and 48 responder and non-responder patients in response to the combined therapy with IFN-alpha2alpha and ribavirin were analyzed. The expression levels of HLA-G and IL-10 were conducted using real-time PCR. Also, soluble HLA-G in both groups of patients and healthy individuals were determined by enzyme-linked immunosorbent assay. According to the obtained data, HCV 1a was the predominant genotype in responder and non-responder patients. Expression levels of HLA-G and IL-10 in non responder group was significantly more than responder and control groups (P<0.001). Additionally, expression levels of HLA-G and IL-10 were remarkably higher compared to healthy individuals at the beginning of treatment. Soluble HLA G in non-responder patients was noticeably increased in comparison to responder patients after treatment (P<0.05). These findings suggest that elevation of HLA-G and IL-10 in HCV infected patients may play an important role in response to combined therapy with IFN-alpha2alpha and ribavirin. PMID- 25500250 TI - HLA-G and susceptibility to develop celiac disease. AB - The Human Leukocyte Antigen-G has immunomodulatory function and its expression has been associated with several diseases. In our study we analyzed HLA-G polymorphisms in order to evaluate their possible association with susceptibility to celiac disease development. A total of 420 celiac patients and 509 controls were genotyped for HLA-G polymorphisms. We sequenced 800bp upstream the ATG codon (5' upstream regulatory region) and the whole 3' untranslated region of the HLA-G gene, whereas the DeltaC deletion at exon 3 was detected by RFLP-PCR. Five polymorphisms (namely -477 C>G, -369 C>A, 14bp del/ins, 3187 A>G, 3196 C>G) and one haplotype (TCGGTACGAAITCCCGAG) were significantly more frequent in celiac patients than controls and associated with increased disease susceptibility. The 14bp I/I, 3187 G/G, 3196 G/G genotypes and TCGGTACGAAITCCCGAG haplotype, were still significantly associated with increased disease susceptibility (and in addition also the 3003 C/C genotype) when the analysis was restricted to patients and controls presenting the DQ2.5 or DQ8 HLA-DQ celiac disease risk haplotypes. Our findings indicate an association between HLA-G gene polymorphisms and susceptibility to celiac disease development, suggesting that HLA-G molecule is possibly involved in the pathogenesis of the disease. PMID- 25500251 TI - Seven novel HLA alleles reflect different mechanisms involved in the evolution of HLA diversity: description of the new alleles and review of the literature. AB - The human leukocyte antigen (HLA) loci are among the most polymorphic genes in the human genome. The diversity of these genes is thought to be generated by different mechanisms including point mutation, gene conversion and crossing-over. During routine HLA typing, we discovered seven novel HLA alleles which were probably generated by different evolutionary mechanisms. HLA-B*41:21, HLA DQB1*02:10 and HLA-DQA1*01:12 likely emerged from the common alleles of their groups by point mutations, all of which caused non-synonymous amino acid substitutions. In contrast, a deletion of one nucleotide leading to a frame shift with subsequent generation of a stop codon is responsible for the appearance of a null allele, HLA-A*01:123N. Whereas HLA-B*35:231 and HLA-B*53:31 were probably products of intralocus gene conversion between HLA-B alleles, HLA-C*07:294 presumably evolved by interlocus gene conversion between an HLA-C and an HLA-B allele. Our analysis of these novel alleles illustrates the different mechanisms which may have contributed to the evolution of HLA polymorphism. PMID- 25500254 TI - Association of IL-17A and IL-17F polymorphisms with gastric cancer risk in Asians: a meta-analysis. AB - Increasing number of studies focused on the association of IL-17A rs2275913 and IL-17F rs763780 polymorphisms with gastric cancer (GC) risk. However, the results were inconsistent. To elucidate the exact association, we performed the present meta-analysis. Databases including PubMed, Web of knowledge and Chinese National Knowledge Infrastructure (CNKI) were systematically searched for potentially eligible literatures. Odds ratios (OR) and their 95% confidence interval (CI) were used to evaluate the strength of association. Eight studies for IL-17A rs2275913 (3345 cases and 4427 controls) and five studies for IL-17F rs763780 (1784 cases and 2592 controls) were finally included. The results indicated that individuals with AA genotype of IL-17A rs2275913 polymorphism were associated with increased GC risk compared with wild-type GG (OR=1.61, 95% CI=1.17-2.23, P=0.004); A allele was significantly associated with increased GC risk compared with G allele (OR=1.22, 95% CI=1.06-1.41, P=0.007). IL-17F rs763780 polymorphism was also significantly associated with increased GC risk (CC vs. CT: OR=1.40, 95% CI=1.04-1.88, P=0.025; CT vs. TT: OR=1.35, 95% CI=1.16-1.58, P<0.001; C allele vs. T allele: OR=1.30, 95% CI=1.15-1.47, P<0.001). In summary, IL-17A rs2275913 A/G polymorphism and IL-17F rs763780 C/T polymorphism might be associated with increased GC risk in Asians. Further large-scale studies are still required to confirm the results of this meta-analysis. PMID- 25500253 TI - Chemokine receptor V Delta32 deletion in multiple sclerosis patients in Csongrad County in Hungary and the North-Bacska region in Serbia. AB - The roles of chemokine receptor V (CCR5) and its polymorphism, rs333 in multiple sclerosis (MS) are controversial. We investigated the receptor and its deletion in a large MS (428) and a numerous control (831) population in Csongrad County (Hungary) and North-Bacska (Serbia). Taqman probes firstly were used for the allele discrimination. There was no significant difference in genotype (OR=1.092, 95% CI=0.807-1.478, p=0.568 for wt/wt (wt=wild type allele) vs wt/Delta32, Delta32/Delta32 (Delta32=Delta32 base pair deletion allele)) or allele frequency (OR=0.914, 95% CI=0.692-1.207, p=0.525). Neither the deletion nor the wt allele affected the Expanded Disability Status Scale score or the age at onset. Our results indicate no association between the CCR5 Delta32 allele and MS. PMID- 25500252 TI - Association between DRD2/ANKK1 TaqIA polymorphism and common illicit drug dependence: evidence from a meta-analysis. AB - BACKGROUND: Growing evidence indicated conflicting results about the dopamine receptor D2 (DRD2)/kinase domain containing 1 gene (ANKK1) TaqIA single nucleotide polymorphism (rs1800497) and common illicit drug dependence risk including stimulants, opioid and marijuana. We conducted a meta-analysis to evaluate the association between the polymorphism and common illicit drug dependence risk. METHOD: A total of 25 available studies (26 subgroups) testing the association between the polymorphism and common illicit drug dependence were examined through Oct 2013. Pooled odds ratios (ORs) and 95% confidence intervals (CI) were estimated using fixed- and random-effects models when appropriate. Heterogeneity and publication bias were evaluated. RESULTS: We found the DRD2/ANKK1 TaqIA polymorphism was significantly associated with increased risk of opioid dependence under homozygote, dominant, and recessive genetic model, respectively (homozygote: OR=1.546, 95%CI=1.279-1.87; dominant: OR=1.265, 95%CI=1.055-1.516; recessive: OR=1.409, 95%CI=1.182-1.680). Subgroup analyses were similar to the results of the total population by ethnicity and quality score. Besides, we also found that Caucasian and low-quality studies were major sources of heterogeneity for opioid dependence. We failed to find any significant association between the polymorphism and stimulants or marijuana neither in total population nor subgroup analyses under any genetic model. CONCLUSIONS: The current meta-analysis suggested that DRD2/ANKK1 TaqIA polymorphism might be associated with opioid dependence risk, but not associated with stimulants or marijuana dependence. PMID- 25500255 TI - The elevated expression of Th17-related cytokines and receptors is associated with skin lesion severity in early systemic sclerosis. AB - OBJECTIVE: The objective was to survey the expression and localization of Th17 related cytokines and their correlation with skin lesion severity in early systemic sclerosis (SSc). METHODS: The mRNA expression was detected by real-time quantitative polymerase chain reaction (RT-qPCR) from 21 SSc patients and 12 healthy controls (HC). The protein expression was examined by immunohistochemistry (IHC) and Western blotting. RESULTS: The RT-qPCR analysis showed a significantly higher expression of IL-17A, IL-21, IL-22, IL-26, IL-17RA, IL-21R, and IL-22R1 mRNA; consistently, the IHC analysis showed an over expression of IL-17RA, IL-21R and IL-22R1 and the Western blotting analysis showed an over-expression of IL-17A, IL-21, IL-21R and IL-22R1 in early SSc skin lesions. The mRNA levels of IL-21 were higher in diffuse cutaneous than limited cutaneous SSc lesions. The mRNA expression of IL-26, IL-22, IL-22R1, mRNA and protein expression of IL-17A, IL-21, IL-21R were positively correlated with the modified Rodnan skin score of SSc. In addition, the mRNA levels of ICAM-1 were positively correlated with IL-17A/IL-17RA, and VEGFA and IL-4 were both positively correlated with IL-21/IL-21R, while TGF-beta were moderately negatively correlated with IL-22/IL-22R1. CONCLUSIONS: Th17 cytokines contribute to progression in early SSc skin lesions. IL-21/IL-21R could act as potential biomarkers presenting early SSc skin lesions severity. PMID- 25500256 TI - TNF-alpha-308G>A polymorphism and the risk of familial CAD in a Pakistani population. AB - A case-control and trio-families study was performed to establish a potential association between TNF-alpha gene promoter SNPs at -308 and -238, and occurrence of CAD in a Pakistani population. In the first phase, 150 patients and 150 controls were enrolled in the case-control association study. In the second phase, heritability of susceptible alleles was investigated from 88 trio-families with CAD affected offspring. Biochemical analysis of lipids and hs-CRP was carried out spectrophotometrically, while serum TNF-alpha concentrations were determined by enzyme-linked immunosorbent assay. Genotyping of the TNF-alpha SNPs were determined by PCR-RFLP method. Elevated serum TNF-alpha and hs-CRP were observed from CAD vs. controls (P<0.0001; for both). The evaluation of TNF-alpha 308G>A polymorphism in case-control study revealed that the said SNP was significantly associated with the increased risk of CAD. The findings demonstrated a significant link between the TNF-alpha variant allele A at -308 and CAD (P=0.0035), whereas the -238 SNP was not associated with the disease. Haplotype A-G of the TNF-alpha gene at -308G>A and -238G>A showed higher frequency in the patient group compared with controls (P<0.05). Moreover, data showed preferential transmission of the disease susceptible allele A at TNF-alpha 308 from parent to affected offspring in a trio-family study (P<0.0001). The current research leads to conclusion that the TNF-alpha-308G>A polymorphism is associated with CAD in the study population. Furthermore, for the first time, we showed that the TNF-alpha-308A allele was significantly associated with the familial CAD in our high risk population. PMID- 25500257 TI - Association between interleukin 1 receptor antagonist gene 86-bp VNTR polymorphism and sepsis: a meta-analysis. AB - OBJECTIVE: Many studies have focused on the relationship between interleukin 1 receptor antagonist (IL1RN) gene 86-bp VNTR polymorphism and sepsis, but the results remain inconsistent. Thus, a meta-analysis was carried out to derive a more precise estimation of the association between IL1RN 86-bp VNTR polymorphism and risk of sepsis and sepsis-related mortality. METHODS: Relevant publications were searched in several widely used databases and six eligible studies were included in the meta-analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between IL1RN 86-bp VNTR polymorphism and risk of sepsis and sepsis-related mortality. RESULTS: Significant associations between IL1RN 86-bp VNTR polymorphism and sepsis risk were observed in both overall meta-analysis for L2 versus 22 (OR=0.75, 95% CI=0.59-0.94) and severe sepsis subgroup for LL+L2 versus 22 (OR=0.67, 95% CI=0.47-0.93). L stands for long alleles containing three to six repeats; 2 stands for short allele containing two repeats. However, no significant sepsis mortality variation was detected for all genetic models. CONCLUSIONS: According to the results of our meta-analysis, the IL1RN 86-bp VNTR polymorphism probably associates with sepsis risk but not with sepsis-related mortality. PMID- 25500258 TI - TRAF1/C5 rs10818488 polymorphism is not a genetic risk factor for acquired aplastic anemia in a Chinese population. AB - The tumor necrosis factor receptor-associated factor 1/complement C5 (TRAF1/C5) genes have been suggested as two candidate genes for conferring susceptibility to autoimmunity and inflammation. The aim of the present study was to investigate the association of single nucleotide polymorphisms (SNP) of TRAF1/C5 genes with the risk for aplastic anemia (AA). In this case-control study, the genotyping of TRAF1/C5 rs10818488 polymorphism was detected by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The frequencies of AA, AG and GG genotypes, and A and G alleles were 21.9%, 52.4%, 25.7%, 48.1% and 51.9%, respectively, in AA patients. There was no significant differences in terms of genotype and allele distributions between AA patients and healthy controls (P=0.687 and 0.955, respectively). Similar results were found between the two groups when stratified by the disease severity including very severe AA (vSAA), SAA and non-SAA (NSAA). Our results indicated that TRAF1/C5 rs10818488 polymorphism might not contribute to susceptibility to AA in a Chinese population. PMID- 25500259 TI - MALT1 induced immune response is governed by miR-2909 RNomics. AB - The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) has been widely recognized to play crucial role in lymphocyte activation, development and the generation of lymphomas through the modulation of innate and adaptive immune responses. Our results reported here provide evidence for the first time to support the view that MALT1 exerts its effect upon immune response involving genes coding for retinoic acid-inducible gene 1 (RIG1); interferon-beta (IFN beta); apo-lipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G); IFN-gamma; chemokine (C-C motif) ligand 5 (CCL5) and interleukin-17 (IL-17) through the initiation of cellular miR-2909 RNomics. This ensures sustained expression of specificity protein 1 (SP1)-dependent regulation of genes that in-turn governs MALT1 induced immune response. Based upon these results, a mechanistic-pathway is proposed that links the epigenomic-interplay between MALT1 and miR-2909. PMID- 25500261 TI - Recessive mutations in COL25A1 are a cause of congenital cranial dysinnervation disorder. AB - Abnormal ocular motility is a common clinical feature in congenital cranial dysinnervation disorder (CCDD). To date, eight genes related to neuronal development have been associated with different CCDD phenotypes. By using linkage analysis, candidate gene screening, and exome sequencing, we identified three mutations in collagen, type XXV, alpha 1 (COL25A1) in individuals with autosomal recessive inheritance of CCDD ophthalmic phenotypes. These mutations affected either stability or levels of the protein. We further detected altered levels of sAPP (neuronal protein involved in axon guidance and synaptogenesis) and TUBB3 (encoded by TUBB3, which is mutated in CFEOM3) as a result of null mutations in COL25A1. Our data suggest that lack of COL25A1 might interfere with molecular pathways involved in oculomotor neuron development, leading to CCDD phenotypes. PMID- 25500262 TI - Low rate loading-induced convection enhances net transport into the intervertebral disc in vivo. AB - BACKGROUND CONTEXT: The intervertebral disc primarily relies on trans-endplate diffusion for the uptake of nutrients and the clearance of byproducts. In degenerative discs, diffusion is often diminished by endplate sclerosis and reduced proteoglycan content. Mechanical loading-induced convection has the potential to augment diffusion and enhance net transport into the disc. The ability of convection to augment disc transport is controversial and has not been demonstrated in vivo. PURPOSE: To determine if loading-induced convection can enhance small molecule transport into the intervertebral disc in vivo. STUDY DESIGN: Net transport was quantified via postcontrast enhanced magnetic resonance imaging (MRI) into the discs of the New Zealand white rabbit lumbar spine subjected to in vivo cyclic low rate loading. METHODS: Animals were administered the MRI contrast agent gadodiamide intravenously and subjected to in vivo low rate loading (0.5 Hz, 200 N) via a custom external loading apparatus for either 2.5, 5, 10, 15, or 20 minutes. Animals were then euthanized and the lumbar spines imaged using postcontrast enhanced MRI. The T1 constants in the nucleus, annulus, and cartilage endplates were quantified as a measure of gadodiamide transport into the loaded discs compared with the adjacent unloaded discs. Microcomputed tomography was used to quantify subchondral bone density. RESULTS: Low rate loading caused the rapid uptake and clearance of gadodiamide in the nucleus compared with unloaded discs, which exhibited a slower rate of uptake. Relative to unloaded discs, low rate loading caused a maximum increase in transport into the nucleus of 16.8% after 5 minutes of loading. Low rate loading increased the concentration of gadodiamide in the cartilage endplates at each time point compared with unloaded levels. CONCLUSIONS: Results from this study indicate that forced convection accelerated small molecule uptake and clearance in the disc induced by low rate mechanical loading. Low rate loading may, therefore, be therapeutic to the disc as it may enhance the nutrient uptake and waste product clearance. PMID- 25500263 TI - Spinal cord herniation after resection of cervical spinal neurofibroma with a unique presentation. AB - BACKGROUND CONTEXT: Spinal cord herniation (SCH) is a very rare condition. It was first reported in the lumbar spine in 1974. Thereafter, cases were reported in the thoracic and cervical spine occurring either spontaneously or after vertebral fracture, nerve root avulsion, and trauma surgery. PURPOSE: There is only one recorded case of SCH after tumor surgery. In this article, we reported the second case. STUDY DESIGN: We described the original surgical procedure, the clinical presentation, the operative repair, and the postoperative course. METHODS: No funding was required for this case report. RESULTS: The patient was a 56-years old man, who presented with SCH 5 years after subtotal excision of a cervical neurofibroma. He presented with right upper monoparesis. CONCLUSIONS: To our knowledge, this presentation has not been reported previously in literature. PMID- 25500264 TI - Effect of neighbourhood motorization rates on walking levels. AB - BACKGROUND: Motorized traffic may discourage people walking. This study analyses the influence of motorization on pedestrian mobility in the neighbourhoods of a European city, controlling for environmental, sociodemographic, mobility and road safety characteristics of the neighbourhood in which each trip was made. METHODS: Cross-sectional ecological study using the 38 neighbourhoods of Barcelona as the unit of analysis. Mobility information was obtained from the 2006 Daily Mobility Survey. Walking rates were calculated for 32.343 men and women who made walking trips, per 1000 men and women who made trips in the 38 neighbourhoods. Data were aggregated to calculate the total number of motorized trips made in each neighbourhood. beta coefficients and their confidence intervals were calculated using Poisson regression, in order to study the relationship between walking and motorization, in the different tertiles of motorization and adjusting for contextual factors and their corresponding interactions with motorization. RESULTS: Levels of motorization in the neighbourhood negatively influence walking, even when environmental variables of the neighbourhood are considered. In men we observe a gradient whereby walking rates fall as motorization rises (beta = -0.248; P < 0.001 and beta = -0.363; P < 0.001 in the second and third quartiles of motorization, respectively). In the case of women we find that only high levels of motorization have a negative influence on the rates of women who walk. (beta = -0.256; P < 0.001). CONCLUSION: Motorized traffic discourages people walking. Motorization is a modifiable environment-related factor which should be taken into account when designing policies to promote safe active travel. PMID- 25500260 TI - Meta-analysis of correlated traits via summary statistics from GWASs with an application in hypertension. AB - Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple-even distinct-traits. Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 * 10(-8)) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 * 10(-7)) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes. PMID- 25500265 TI - Tuberculosis among migrant populations in the European Union and the European Economic Area. AB - BACKGROUND: Although tuberculosis (TB) incidence has been decreasing in the European Union/European Economic Area (EU/EEA) in the last decades, specific subgroups of the population, such as migrants, remain at high risk of TB. This study is based on the report 'Key Infectious Diseases in Migrant Populations in the EU/EEA' commissioned by The European Centre for Disease Prevention and Control. METHODS: We collected, critically appraised and summarized the available evidence on the TB burden in migrants in the EU/EEA. Data were collected through: (i) a comprehensive literature review; (ii) analysis of data from The European Surveillance System (TESSy) and (iii) evidence provided by TB experts during an infectious disease workshop in 2012. RESULTS: In 2010, of the 73,996 TB cases notified in the EU/EEA, 25% were of foreign origin. The overall decrease of TB cases observed in recent years has not been reflected in migrant populations. Foreign-born people with TB exhibit different socioeconomic and clinical characteristics than native sufferers. CONCLUSION: This is one of the first studies to use multiple data sources, including the largest available European database on infectious disease notifications, to assess the burden and provide a comprehensive description and analysis of specific TB features in migrants in the EU/EEA. Strengthened information about health determinants and factors for migrants' vulnerability is needed to plan, implement and evaluate targeted TB care and control interventions for migrants in the EU/EEA. PMID- 25500266 TI - The rate-determining steps of aldo-keto reductases (AKRs), a study on human steroid 5beta-reductase (AKR1D1). AB - Aldo-keto reductases (AKRs) are an expanding family of NAD(P)(H)-dependent oxidoreductases that catalyze the reduction of either carbonyl groups or alpha,beta-unsaturated ketones on a variety of endogenous and exogenous substrates. The enzymes catalyze a sequential ordered bi-bi kinetic mechanism, in which cofactor is bound first and released last. Using human steroid 5beta reductase (AKR1D1) as a representative enzyme, the influence of substrate structure on the rate-limiting steps of AKR catalysis has been previously determined. The rate of the chemistry step was found to differ by two orders of magnitude when different steroid substrates were used in single turnover experiments with AKR1D1. This difference was reflected in multiple turnover experiments. C17-C21 steroid substrates exhibited a fast chemistry step followed by slow product release as suggested by "burst" phase kinetics. By contrast, C27 steroids have a slower chemical step that determines the rate of the reaction and "burst-phase" kinetics are no longer observed. Here we present single turnover kinetic experiments and find that they support the existence of two different binding poses for fast substrates due to their biphasic nature. We also re interpret the loss of "burst-phase" kinetics in the multiple turnover experiments as due to long range effects of the steroid side-chain interacting with distal parts of the steroid pocket to perturb the reaction trajectory for hydride transfer and thus reduce kcat. The ability of steroid structure and hence binding pose to influence rate determination in steroid transforming AKRs is discussed as a general phenomenon. PMID- 25500267 TI - Mechanism-based inactivation of cytochrome P450 2B6 by isoimperatorin. AB - Isoimperatorin (IIMP), a 6,7-furanocoumarin derivative, occurs in many common medicinal herbs. Human exposure to IIMP mainly results from intake of fruits, foods and medicinal herbs. We examined the irreversible inhibitory effect of IIMP on cytochrome P450 2B6. IIMP was found to cause time-dependent inhibition of CYP2B6. In addition, the loss of CYP2B6 activity occurred in a NAPDH- and concentration-dependent manner. About 60% of activity of CYP2B6 was suppressed after its incubation with IIMP at 25 MUM for 9 min. Enzyme kinetic studies were performed, kinact for IIMP was found to be 0.071 min(-1), and KI was 17.1 MUM, respectively. Glutathione and catalase/superoxide dismutase showed little protective effects on CYP2B6 against the inactivation by IIMP. S-Mephenytoin, a substrate of CYP2B6, mildly prevented the enzyme from the inactivation induced by IIMP. The estimated partition ratio of the inactivation was approximately 211. Additionally, a gamma-ketoenal intermediate was identified in microsomal incubations with IIMP. CYPs 2B6, 2D6, and 1A2 were the major enzymes responsible for the metabolic activation of IIMP. In conclusion, IIMP is a mechanism-based inactivator of CYP2B6. The formation of gamma-ketoenal intermediate may be responsible for the enzyme inactivation. PMID- 25500268 TI - An alkaline phosphatase transport mechanism in the pathogenesis of Alzheimer's disease and neurodegeneration. AB - Systemic inflammation is associated with loss of blood-brain barrier integrity and neuroinflammation that lead to the exacerbation of neurodegenerative diseases. It is also associated specifically with the characteristic amyloid-beta and tau pathologies of Alzheimer's disease. We have previously proposed an immunosurveillance mechanism for epithelial barriers involving negative feedback regulated alkaline phosphatase transcytosis as an acute phase anti-inflammatory response that hangs in the balance between the resolution and the progression of inflammation. We now extend this model to endothelial barriers, particularly the blood-brain barrier, and present a literature-supported mechanistic explanation for Alzheimer's disease pathology with this system at its foundation. In this mechanism, a switch in the role of alkaline phosphatase from its baseline duties to a stopgap anti-inflammatory function results in the loss of alkaline phosphatase from cell membranes into circulation, thereby decreasing blood-brain barrier integrity and functionality. This occurs with impairment of both amyloid beta efflux and tau dephosphorylating activity in the brain as alkaline phosphatase is replenished at the barrier by receptor-mediated transport. We suggest systemic alkaline phosphatase administration as a potential therapy for the resolution of inflammation and the prevention of Alzheimer's disease pathology as well as that of other inflammation-related neurodegenerative diseases. PMID- 25500269 TI - Novel adducts from the reaction of 1-chloro-3-buten-2-one with 2'-deoxyguanosine. Structural characterization and potential as tools to investigate 1,3-butadiene carcinogenicity. AB - 1-Chloro-3-buten-2-one (CBO) is a potential reactive metabolite of 1,3-butadiene (BD), a carcinogenic air pollutant. To develop tools that may help investigate the role of CBO in BD carcinogenicity and to develop biomarkers that can be used to assess BD exposure, the reaction of CBO with 2'-deoxyguanosine (dG) under in vitro physiological conditions (pH 7.4, 37 degrees C) was investigated and the products (designated as CG-1, CG-2, CG-3, CG-4, CG-5, and CG-6 based on their retention times on HPLC) were characterized by MS and NMR spectroscopy. The structures of CG-1, CG-2, CG-3, and CG-4 were 1,N2-(3-hydroxy-3 hydroxymethylpropan-1,3-diyl)-2'-deoxyguanosine, N7-(4-chloro-3-oxobutyl)-2' deoxyguanosine, N7,8-(3-hydroxy-3-chloromethylpropan-1,3-diyl)guanine and N2-(4 chloro-3-oxobutyl)-2'-deoxyguanosine, respectively. CG-5 and CG-6, a pair of diastereomers, were characterized as 1,N2-(3-hydroxy-3-chloromethylpropan-1,3 diyl)-2'-deoxyguanosine. CG-1 was stable under in vitro physiological conditions, whereas CG-2, CG-3, CG-4, and CG-5/6 were unstable and exhibited the half-lives at <1.0, 4.8+/-0.1, 6.7+/-0.3, and 2.7+/-0.1 h, respectively. CG-2 decomposed primarily via a retro-Michael reaction to produce dG and CBO, with only a small fraction of CG-2 degrading to CG-3. Decomposition of CG-4 proceeded via a cyclization reaction and/or replacement of the chlorine atom by a hydroxyl group to form 1,N2-(1-hydroxy-1-hydroxymethylpropan-1,3-diyl)-2'-deoxyguanosine (CG 4D1) and N(2)-(4-hydroxy-3-oxobutyl)-2'-deoxyguanosine (CG-4D2), whereas decomposition of CG-5/6 yielded CG-1. Collectively, the newly characterized CBO adducts could be used to investigate the role of CBO in the mechanism of BD carcinogenicity and could also be used to develop biomarkers for BD exposure. PMID- 25500270 TI - Searching for the mechanism of signalling by plant photoreceptor cryptochrome. AB - Even though the plant photoreceptors cryptochromes were discovered more than 20 years ago, the mechanism through which they transduce light signals to their partner molecules such as COP1 (Constitutive Photomorphogenic 1) or SPA1 (Suppressor of Phytochrome A) still remains to be established. We propose that a negative charge induced by light in the vicinity of the flavin chromophore initiates cryptochrome 1 signalling. This negative charge might expel the protein bound ATP from the binding pocket, thereby pushing off the C-terminus that covers the ATP pocket in the dark state of the protein. This conformational change should allow for phosphorylation of previously inaccessible amino acids. A partially phosphorylated 'ESSSSGRR-VPE' fragment of the C-terminus could mimic the sequence of the transcription factor HY5 that is essential for binding to the negative regulator of photomorphogenesis COP1. HY5 release through competition for the COP1 binding site could represent the long-sought connection between light activation of cryptochrome and modulation of photomorphogenesis. PMID- 25500271 TI - Storage lipid synthesis is necessary for autophagy induced by nitrogen starvation. AB - Nitrogen starvation is a universal stimulus of autophagy. At present, little is known about the relationship between carbon metabolism and autophagy under nitrogen starvation. Here, we show that yeast cells continue to consume glucose and downregulate fermentation under nitrogen starvation. Storage lipid production is increased, with concurrent proliferation of lipid droplets. Furthermore, we provide evidence that triacylglycerol synthesis is crucial for autophagosome biogenesis. It is involved in a step downstream of PAS (phagophore assembly site) scaffold assembly, and upstream of the recruitment of Atg1, Atg14, Atg5 and Atg8. Finally, we demonstrate that lipid droplets transiently interact with Atg8 containing membranes. Our study reveals a novel connection linking neutral lipid metabolism, lipid droplets and autophagy. PMID- 25500272 TI - miRNAs as targets for cancer treatment: therapeutics design and delivery. Preface. PMID- 25500273 TI - Wound healing in urology. AB - Wound healing is a dynamic and complex phenomenon of replacing devitalized tissues in the body. Urethral healing takes place in four phases namely inflammation, proliferation, maturation and remodelling, similar to dermal healing. However, the duration of each phase of wound healing in urology is extended for a longer period when compared to that of dermatology. An ideal wound dressing material removes exudate, creates a moist environment, offers protection from foreign substances and promotes tissue regeneration. A single wound dressing material shall not be sufficient to treat all kinds of wounds as each wound is distinct. This review includes the recent attempts to explore the hidden potential of growth factors, stem cells, siRNA, miRNA and drugs for promoting wound healing in urology. The review also discusses the different technologies used in hospitals to treat wounds in urology, which make use of innovative biomaterials synthesised in regenerative medicines like hydrogels, hydrocolloids, foams, films etc., incorporated with growth factors, drug molecules or nanoparticles. These include surgical zippers, laser tissue welding, negative pressure wound therapy, and hyperbaric oxygen treatment. PMID- 25500274 TI - Gillian Leng: Pet hate is fixed opinions. PMID- 25500275 TI - Risk ranking of pathogens in ready-to-eat unprocessed foods of non-animal origin (FoNAO) in the EU: initial evaluation using outbreak data (2007-2011). AB - Foods of non-animal origin (FoNAO) are consumed in a variety of forms, being a major component of almost all meals. These food types have the potential to be associated with large outbreaks as seen in 2011 associated with VTEC O104. In order to identify and rank specific food/pathogen combinations most often linked to human cases originating from FoNAO in the EU, a semi-quantitative model was developed using seven criteria: strength of associations between food and pathogen based on the foodborne outbreak data from EU Zoonoses Monitoring (2007 2011), incidence of illness, burden of disease, dose-response relationship, consumption, prevalence of contamination and pathogen growth potential during shelf life. The top ranking food/pathogen combination was Salmonella spp. and leafy greens eaten raw followed by (in equal rank) Salmonella spp. and bulb and stem vegetables, Salmonella spp. and tomatoes, Salmonella spp. and melons, and pathogenic Escherichia coli and fresh pods, legumes or grains. Despite the inherent assumptions and limitations, this risk model is considered a tool for risk managers, as it allows ranking of food/pathogen combinations most often linked to foodborne human cases originating from FoNAO in the EU. Efforts to collect additional data even in the absence of reported outbreaks as well as to enhance the quality of the EU-specific data, which was used as input for all the model criteria, will allow the improvement of the model outputs. Furthermore, it is recommended that harmonised terminology be applied to the categorisation of foods collected for different reasons, e.g. monitoring, surveillance, outbreak investigation and consumption. In addition, to assist future microbiological risk assessments, consideration should be given to the collection of additional information on how food has been processed, stored and prepared as part of the above data collection exercises. PMID- 25500276 TI - Dynamic determination of kinetic parameters, computer simulation, and probabilistic analysis of growth of Clostridium perfringens in cooked beef during cooling. AB - The objective of this research was to develop a new one-step methodology that uses a dynamic approach to directly construct a tertiary model for prediction of the growth of Clostridium perfringens in cooked beef. This methodology was based on simultaneous numerical analysis and optimization of both primary and secondary models using multiple dynamic growth curves obtained under different conditions. Once the models were constructed, the bootstrap method was used to calculate the 95% confidence intervals of kinetic parameters, and a Monte Carlo simulation method was developed to validate the models using the growth curves not previously used in model development. The results showed that the kinetic parameters obtained from this study accurately matched the common characteristics of C. perfringens, with the optimum temperature being 45.3 degrees C. The results also showed that the predicted growth curves matched accurately with experimental observations used in validation. The mean of residuals of the predictions is 0.02logCFU/g, with a standard deviation of only 0.23logCFU/g. For relative growths <1logCFU/g, the residuals of predictions are <0.4logCFU/g. Overall, 74% of the residuals of predictions are <0.2logCFU/g, 7.7% are >0.4logCFU/g, while only 1.5% are >0.8logCFU/g. In addition, the dynamic model also accurately predicted four isothermal growth curves arbitrarily chosen from the literature. Finally, the Monte Carlo simulation was used to provide the probability of >1 and 2logCFU/g relative growths at the end of cooling. The results of this study will provide a new and accurate tool to the food industry and regulatory agencies to assess the safety of cooked beef in the event of cooling deviation. PMID- 25500277 TI - Cinnamon bark oil and its components inhibit biofilm formation and toxin production. AB - The long-term usage of antibiotics has resulted in the evolution of multidrug resistant bacteria, and pathogenic biofilms contribute to reduced susceptibility to antibiotics. In this study, 83 essential oils were initially screened for biofilm inhibition against Pseudomonas aeruginosa. Cinnamon bark oil and its main constituent cinnamaldehyde at 0.05% (v/v) markedly inhibited P. aeruginosa biofilm formation. Furthermore, cinnamon bark oil and eugenol decreased the production of pyocyanin and 2-heptyl-3-hydroxy-4(1H)-quinolone, the swarming motility, and the hemolytic activity of P. aeruginosa. Also, cinnamon bark oil, cinnamaldehyde, and eugenol at 0.01% (v/v) significantly decreased biofilm formation of enterohemorrhagic Escherichia coli O157:H7 (EHEC). Transcriptional analysis showed that cinnamon bark oil down-regulated curli genes and Shiga-like toxin gene stx2 in EHEC. In addition, biodegradable poly(lactic-co-glycolic acid) film incorporating biofilm inhibitors was fabricated and shown to provide efficient biofilm control on solid surfaces. This is the first report that cinnamon bark oil and its components, cinnamaldehyde and eugenol, reduce the production of pyocyanin and PQS, the swarming motility, and the hemolytic activity of P. aeruginosa, and inhibit EHEC biofilm formation. PMID- 25500278 TI - Growth rate and TRI5 gene expression profiles of Fusarium equiseti strains isolated from Spanish cereals cultivated on wheat and barley media at different environmental conditions. AB - Fusarium equiseti is a toxigenic species that often contaminates cereal crops from diverse climatic regions such as Northern and Southern Europe. Previous results suggested the existence of two distinct populations within this species with differences in toxin profile which largely corresponded to North and South Europe (Spain). In this work, growth rate profiles of 4 F. equiseti strains isolated from different cereals and distinct Spanish regions were determined on wheat and barley based media at a range of temperatures (15, 20, 25, 30, 35 and 40 degrees C) and water potential regimens (-0.7, -2.8, -7.0, and -9.8MPa, corresponding to 0.99, 0.98, 0.95 and 0.93 aw values). Growth was observed at all temperatures except at 40 degrees C, and at all the solute potential values except at -9.8MPa when combined with 15 degrees C. Optimal growth was observed at 20-30 degrees C and -0.7/-2.8MPa. The effect of these factors on trichothecene biosynthesis was examined on a F. equiseti strain using a newly developed real time RT-PCR protocol to quantify TRI5 gene expression at 15, 25 and 35 degrees C and -0.7, -2.8, -7.0 and -9.8MPa on wheat and barley based media. Induction of TRI5 expression was detected between 25 and 35 degrees C and -0.7 and -2.8MPa, with maximum values at 35 degrees C and -2.8MPa being higher in barley than in wheat medium. These results appeared to be consistent with a population well adapted to the present climatic conditions and predicted scenarios for Southern Europe and suggested some differences depending on the cereal considered. These are also discussed in relation to other Fusarium species co-occurring in cereals grown in this region and to their significance for prediction and control strategies of toxigenic risk in future scenarios of climate change for this region. PMID- 25500279 TI - [The "Spanish flu" pandemic of 1918-1919 in La Reunion (Indian Ocean)]. AB - Brought in by the ship Madonna, which was taking local survivors of World War I back to Reunion, the 1918 Spanish flu pandemic reached the island in March 1919 and lasted for three months. The controversies between doctors and between doctors and the colonial administrators, officials' desertion of their posts, and food shortages together caused a major panic. The epidemic appears to have ravaged people under the age of 40 and the most disadvantaged neighborhoods, at a period when the economy was already in the doldrums and the population had been declining since the late 19th century. Estimates indicate 2000 deaths in the capital of Saint-Denis, among a population of 25,000 inhabitants, and 7 to 20,000 deaths on the island as a whole, representing 4-11% of the population - far more than the 949 local soldiers killed on the battlefields of Europe. According to legend, salvation came from the sky as a small cyclone on May 11, 1919: it lasted an hour, swept away the "miasmas" and washed the island clean of all its impurities. PMID- 25500280 TI - The secondary contact zone of phylogenetic lineages of the Philaenus spumarius (Hemiptera: Aphrophoridae): an example of incomplete allopatric speciation. AB - Previous studies on the phylogeography of the meadow spittlebug Philaenus spumarius (L.) (Hemiptera: Aphrophoridae) suggest the existence of a contact zone of its main phylogenetic lineages along mountain chains in Europe and western Asia. This study presents a detailed examination of the population genetics of P. spumarius within the Carpathian Mountains. The main objective was to determine whether the populations inhabiting that area consist of individuals belonging to different genetic units and whether the observed pattern could be an example of secondary contact zone which formed after incomplete allopatric speciation. Specimens from six transects across the Carpathian arc were examined. The mitochondrial phylogeography of the meadow spittlebug in the examined area clearly shows that individuals from both main clades meet and mix there. Representatives of all three main EF1-alpha clades were also found. The present distribution of the main clades with a zone of overlap along the mountain ranges may suggest that these phylogenetic lineages form a young hybrid zone. Moreover, a limited number of individuals were shown to possess heteroplasmic mitochondrial DNA, which gives additional support to intraspecific hybridization. P. spumarius could be used in future work as an excellent model species in investigating population genetics, intraspecific hybridization, and speciation in progress. PMID- 25500281 TI - Pain management in cancer patients using a mobile app: study design of a randomized controlled trial. AB - BACKGROUND: Despite the availability of effective medications and clinical guidelines for pain management, pain control is suboptimal in a sizeable proportion of patients with cancer pain. The National Comprehensive Cancer Network guidelines recommend a comprehensive and multimodal approach for management of cancer pain. We developed a mobile phone application, ePAL, based on clinical guidelines to empower patients for cancer pain management by prompting regular pain assessments and coaching for self-management. OBJECTIVE: The objective of this study is to evaluate the effect of a multidimensional mobile phone-based pain management application, ePAL, on controlling cancer pain and improving quality of life in patients with cancer pain being treated at an academic palliative care clinic. METHODS: The study will be implemented as a 2 arm randomized controlled trial with 110 adult patients with CP who own a mobile phone over a follow-up period of two months. Participants will be randomized to either the intervention group receiving ePAL and usual care or to a control group receiving only usual care. The brief pain inventory will be used to assess our primary outcome which is pain intensity. We will also evaluate the effect of the intervention on secondary outcomes which include the effect of the intervention on hospital utilization for pain crisis, quality of life, adherence to analgesic medications, barriers to pain control, anxiety and patient engagement. Instruments that will be used in evaluating secondary outcomes include the Brief Pain Inventory, Morisky Medication Adherence Scale, Barriers Questionnaire-II, Functional Assessment of Cancer Therapy-General, Edmonton Symptom Assessment System, Generalized Anxiety Disorder 7-item scale, and the Functional Assessment of Chronic Illness Therapy-Fatigue. The intention-to-treat approach will be used to evaluate outcomes. Our primary outcome, pain intensity, measured longitudinally over eight weeks, will be assessed by mixed model repeated analysis. Effect sizes will be calculated as mean group differences with standard deviations. RESULTS: The study is still in progress. We hope to have results by the end of 2015. CONCLUSIONS: The multidimensional approach to pain management implemented on a mobile phone application could lead to significant improvements in patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02069743; https://clinicaltrials.gov/ct2/show/NCT02069743 (Archived by WebCite at http://www.webcitation.org/6Qb65XGGA). PMID- 25500282 TI - Ultra-small lipid nanoparticles promote the penetration of coenzyme Q10 in skin cells and counteract oxidative stress. AB - UV irradiation leads to the formation of reactive oxygen species (ROS). An imbalance between the antioxidant system and ROS can lead to cell damage, premature skin aging or skin cancer. To counteract these processes, antioxidants such as coenzyme Q10 (CoQ10) are contained in many cosmetics. To improve and optimize cell/tissue penetration properties of the lipophilic CoQ10, ultra-small lipid nanoparticles (usNLC) were developed. The antioxidant effectiveness of CoQ10-loaded usNLC compared to conventional nanocarriers was investigated in the human keratinocyte cell line HaCaT. Using confocal laser scanning microscopy investigations of the carriers additionally loaded with nile red showed a clear uptake into cells and their distribution within the cytoplasm. By use of the XTT cell viability test, CoQ10 concentrations of 10-50 MUg/ml were shown to be non toxic, and the antioxidant potential of 10 MUg/ml CoQ10 loaded usNLC in the HaCaT cells was analyzed via electron paramagnetic resonance spectroscopy after cellular exposure to UVA (1J/cm(2)) and UVB (18 mJ/cm(2)) irradiation. In comparison with the CoQ10-loaded conventional carriers, usNLC-CoQ10 demonstrated the strongest reduction of the radical formation; reaching up to 23% compared to control cells without nanocarrier treatment. Therefore, usNLC-CoQ10 are very suitable to increase the antioxidant potential of skin. PMID- 25500283 TI - Stealth anti-CD4 conjugated immunoliposomes with dual antiretroviral drugs- modern Trojan horses to combat HIV. AB - Highly active antiretroviral therapy (HAART) is the currently employed therapeutic intervention against AIDS where a drug combination is used to reduce the viral load. The present work envisages the development of a stealth anti-CD4 conjugated immunoliposomes containing two anti-retroviral drugs (nevirapine and saquinavir) that can selectively home into HIV infected cells through the CD4 receptor. The nanocarrier was characterized using transmission electron microscopy, FTIR, differential scanning calorimetry, particle size and zeta potential. The cell uptake was also evaluated qualitatively using confocal microscopy and quantitatively by flow cytometry. The drug to lipid composition was optimized for maximum encapsulation of the two drugs. Both drugs were found to localize in different regions of the liposome. The release of the reverse transcriptase inhibitor was dominant during the early phases of the release while in the later phases, the protease inhibitor is the major constituent released. The drugs delivered via anti-CD4 conjugated immunoliposomes inhibited viral proliferation at a significantly lower concentration as compared to free drugs. In vitro studies of nevirapine to saquinavir combination at a ratio of 6.2:5 and a concentration as low as 5 ng/mL efficiently blocked viral proliferation suggesting that co-delivery of anti-retroviral drugs holds a greater promise for efficient management of HIV-1 infection. PMID- 25500284 TI - Long-term outcomes of laparoscopic sleeve gastrectomy as a primary bariatric procedure. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has been established as a reliable bariatric procedure, but questions have emerged regarding its long-term results. Our aim is to report the long-term outcomes of LSG as a primary bariatric procedure. METHODS: Retrospective analysis of patients submitted to LSG between 2005 and 2007 in our institution. Long-term outcomes at 5 years were analyzed in terms of body mass index (BMI), excess weight loss (EWL) and co morbidities resolution. Surgical success was defined as %EWL>50%. Also, we compared long-term results according to preoperative BMI, using Mann-Whitney test. RESULTS: A total of 161 LSG were analyzed, and 114 patients (70.8%) were women. The median age was 36 years old (range 16-65), median preoperative BMI was 34.9 kg/m(2) (interquartile range [IQR], 33.3-37.5). A total of 112 patients (70%) completed 5 years of follow-up. At the fifth year, median BMI and %EWL was 28.5 kg/m(2) (IQR: 25.8-31.9) and 62.9% (IQR: 45.3-89.6), respectively, with a surgical success of 73.2% of followed patients. According to preoperative BMI, surgical success was achieved in 80% of patients with BMI<35 kg/m(2), 75% of BMI 35-40 kg/m(2), and 52.6% of BMI>40 kg/m(2), with significant lower %EWL in patients with BMI>40 kg/m(2) (P = .001 and .004). Dyslipidemia and insulin resistance resolution was 80.7% and 84.7%, respectively. A total of 26.7% of patients reported new-onset gastroesophageal reflux symptoms at 5 years. CONCLUSION: LSG as a primary procedure is a reliable surgery. We observed positive long-term outcomes of %EWL and co-morbidities resolution. In our series, best results are seen in patients with preoperative BMI<40 kg/m(2). PMID- 25500286 TI - Directed evolution of the substrate specificity of dialkylglycine decarboxylase. AB - Dialkylglycine decarboxylase (DGD) is an unusual pyridoxal phosphate dependent enzyme that catalyzes decarboxylation in the first and transamination in the second half-reaction of its ping-pong catalytic cycle. Directed evolution was employed to alter the substrate specificity of DGD from 2-aminoisobutyrate (AIB) to 1-aminocyclohexane-1-carboxylate (AC6C). Four rounds of directed evolution led to the identification of several mutants, with clones in the final rounds containing five persistent mutations. The best clones show ~2.5-fold decrease in KM and ~2-fold increase in kcat, giving a modest ~5-fold increase in catalytic efficiency for AC6C. Additional rounds of directed evolution did not improve catalytic activity toward AC6C. Only one (S306F) of the five persistent mutations is close to the active site. S306F was observed in all 33 clones except one, and the mutation is shown to stabilize the enzyme toward denaturation. The other four persistent mutations are near the surface of the enzyme. The S306F mutation and the distal mutations all have significant effects on the kinetic parameters for AIB and AC6C. Molecular dynamics simulations suggest that the mutations alter the conformational landscape of the enzyme, favoring a more open active site conformation that facilitates the reactivity of the larger substrate. We speculate that the small increases in kcat/KM for AC6C are due to two constraints. The first is the mechanistic requirement for catalyzing oxidative decarboxylation via a concerted decarboxylation/proton transfer transition state. The second is that DGD must catalyze transamination at the same active site in the second half-reaction of the ping-pong catalytic cycle. PMID- 25500287 TI - Apples with apples, and the history of risk models. PMID- 25500288 TI - Cardiac strangulation following epicardial pacemaker implantation: a rare pediatric complication. AB - OBJECTIVES: The aim of our study was 2-fold: to determine the incidence of cardiac strangulation (CS) and to develop a clinical pathway to aid in the diagnosis and prognosis of CS. In <2 years, 2 cases of CS occurred in our institution, which caused much alarm and led to the study's objectives. METHODS: All patients who underwent implantation of an epicardial pacemaker from January 1992 to March 2012 were included. There were no exclusion criteria. Health records were used to locate all subjects and gather all retrospective data. Prospectively, subjects without a chest radiograph from the previous 2 years were approached for imaging. RESULTS: This study included 86 patients retrospectively, and 84 patients prospectively. There was a 2.3% incidence, and a 1.2% mortality, related to CS. A pattern of posterior looping of the ventricular lead was seen in radiographs of both CS-diagnosed patients. Five variables were significantly associated with an outcome of CS (P = .0153). CONCLUSIONS: Our data indicate that the 2 cases of CS were not caused by a lack of follow-up but by a lack of consistent imaging for diagnosis. This conclusion is supported by the 8 cases of CS found in the English-language literature. If the patient is age <=6 months at the time of implantation, particular attention should be given to the placement of leads and follow-up. PMID- 25500289 TI - Who really needs an "elephant trunk"? PMID- 25500290 TI - Successful recovery from respiratory failure by external distraction sternoplasty in a patient with Jeune syndrome. PMID- 25500291 TI - Erythropoietin activates the phosporylated cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein pathway and attenuates delayed paraplegia after ischemia-reperfusion injury. AB - OBJECTIVE: Paraplegia remains a devastating complication of complex aortic surgery. Erythropoietin (EPO) has been shown to prevent paraplegia after ischemia reperfusion, but the protective mechanism remains poorly described in the spinal cord. We hypothesized that EPO induces the CREB (cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein) pathway and neurotrophin production in the murine spinal cord, attenuating functional and cellular injury. METHODS: Adult male mice were subjected to 4 minutes of spinal cord ischemia via an aortic and left subclavian cross-clamp. Experimental groups included EPO treatment 4 hours before incision (n = 7), ischemic control (n = 7), and shams (n = 4). Hind-limb function was assessed using the Basso motor score for 48 hours after reperfusion. Spinal cords were harvested and analyzed for neuronal viability using histology and staining with a fluorescein derivative. Expression of phosphorylated (p)AKT (a serine/threonine-specific kinase), pCREB, B-cell lymphoma 2, and brain-derived neurotrophic factor were determined using immunoblotting. RESULTS: By 36 hours of reperfusion, EPO significantly preserved hind-limb function after ischemia-reperfusion injury (P < .01). Histology demonstrated preserved cytoarchitecture in the EPO treatment group. Cords treated with EPO expressed significant increases in pAKT (P = .021) and pCREB (P = .038). Treatment with EPO induced expression of both of the neurotrophins, B-cell lymphoma 2, and brain-derived neurotrophic factor, beginning at 12 hours. CONCLUSIONS: Erythropoietin-mediated induction of the CREB pathway and production of neurotrophins is associated with improved neurologic function and increased neuronal viability following spinal cord ischemia reperfusion. Further elucidation of EPO-derived neuroprotection will allow for expansion of adjunct mechanisms for spinal cord protection in high-risk thoracoabdominal aortic intervention. PMID- 25500292 TI - The conundrum of coronary revascularization: stent or bypass. PMID- 25500295 TI - An unusual cause of acute kidney injury due to oxalate nephropathy in systemic scleroderma. AB - Oxalate nephropathy is an uncommon cause of acute kidney injury. Far rarer is its association with scleroderma, with only one other published case report in the literature. We report a case of a 75-year-old African-American female with a history of systemic scleroderma manifested by chronic pseudo-obstruction and small intestinal bacterial overgrowth (SIBO) treated with rifaximin, who presented with acute kidney injury with normal blood pressure. A renal biopsy demonstrated extensive acute tubular injury with numerous intratubular birefringent crystals, consistent with oxalate nephropathy. We hypothesize that her recent treatment with rifaximin for SIBO and decreased intestinal transit time in pseudo-obstruction may have significantly increased intestinal oxalate absorption, leading to acute kidney injury. Oxalate nephropathy should be considered in the differential diagnosis of acute kidney injury in scleroderma with normotension, and subsequent evaluation should be focused on bowel function to include alterations in gut flora due to antibiotic administration. PMID- 25500294 TI - Molecular characterization of a new mosaic Simian Immunodeficiency Virus in a naturally infected tantalus monkey (Chlorocebus tantalus) from Cameroon: a challenge to the virus-host co-evolution of SIVagm in African green monkeys. AB - African green monkeys (AGMs) represent the most widely distributed non-human primates species in Africa. SIVagm naturally infects four of the 6 AGMs species at high prevalence in a species-specific manner. To date, only limited information is available on molecular characteristics of SIVagm infecting Chlorocebus tantalus. Here, we characterized the full-length genome of a virus infecting a naturally infected captive C. tantalus from Cameroon by amplifying and sequencing sub-genomic PCR fragments. The isolate (SIVagmTAN-CM545) is 9923bp long and contained all canonical genes of a functional SIV. SIVagmTAN-CM545 showed a mosaic structure, with gag, pol, nef and accessory genes closely related to SIVagmSAB infecting Chlorocebus sabaeus monkeys from west Africa, and the env gene, closely related to SIVagmTAN infecting tantalus monkeys from Central Africa. Thus SIVagmTAN-CM545 is SIVagmSAB/SIVagmTAN recombinant. These unexpected findings suggest that the evolution of SIVagm is more complex than previously thought and warrant further studies. PMID- 25500296 TI - Evaluating time in therapeutic range for hemodialysis patients taking warfarin. AB - Warfarin is frequently used in the hemodialysis (HD) population for atrial fibrillation (AF) and venous thromboembolism (VTE); however, there is insufficient evidence to support this practice. Given that HD patients have 3 - 10 times the risk for both stroke and bleeding than the general population, anticoagulation in these patients is controversial. Time in therapeutic range (TTR) is accepted as a surrogate outcome of clinical effectiveness and safety of warfarin. The primary objective of this study was to evaluate TTR in an HD population. A 6-year retrospective chart review was performed in 46 HD patients on warfarin (target international normaized ratio (INR)=2-3). One year of patient data was collected, which included weekly INRs, demographics and clinical outcomes. TTR was calculated using the Rosendaal and fraction of INRs in range methods. The mean TTR using the Rosendaal and fraction of INRs in range method was 49.2+/-14.6% and 44.2+/-13.5%, respectively. Patients were 3 times more likely to be below target than above it, suggesting they were more often at risk of inadequate efficacy rather than toxicity. There were 9 serious bleeding and 9 thrombotic events; these occurred in patients with a TTR<60%. For the 9 serious bleeding events, the median INR on the day of the event was 2.1 (IQR 1.81-2.75). In conclusion, this HD unit is not meeting the TTR goal established in the literature and patients are often subtherapeutic. Further studies to investigate ways to improve TTR are warranted. Ultimately, a prospective study evaluating the safety and efficacy of warfarin in HD patients is needed. PMID- 25500297 TI - Acute symptomatic hyponatremia in a flight attendant. AB - Acute symptomatic hyponatremia after thiazide diuretic initiation is a medical emergency. Here we describe the case of a flight attendant who developed acute hyponatremia during a flight and the potential risk factors for developing this condition. A 57-year-old flight attendant with history of essential hypertension was recently started on a thiazide diuretic. As she did routinely when working, she increased her water intake during a flight from London to Mexico City. She complained of nausea and headache during the flight. Upon arrival, she developed severe disorientation and presented to the hospital emergency room (ER) with a Glasgow scale of 12, hypoxia, and a generalized tonic clonic seizure. Her laboratory results on arrival were consistent with severe hyponatremia (serum Na 116 mEql/L) and severe cerebral edema by CT scan. She was treated with hypertonic saline, with complete resolution of the neurologic symptoms. We describe high water intake and hypoxia related to decreased partial pressure of oxygen in the cabin as the two main risk factors for thiazide-induced acute hyponatremia in this case. PMID- 25500298 TI - Temperature in and around the scapholunate ligament during radiofrequency shrinkage: a cadaver study. AB - PURPOSE: To investigate whether applied radiofrequency energy (RFE) for shrinkage of the scapholunate interosseus ligament reaches temperatures required for ligament shrinkage while leaving adjacent structures unaffected. METHODS: Standard wrist arthroscopy was performed on 7 pairs of cadaveric limbs with continuous saline irrigation and gravity-assisted outflow through an 18-gauge needle. We subjected 14 scapholunate ligaments to treatment with monopolar (n = 7) or bipolar (n = 7) RFE for ligament shrinkage. Temperature was recorded simultaneously inside the dorsal part of the scapholunate interosseus ligament at a depth of 0.9 +/- 0.1 mm and at 6 other sites in and around the wrist because thermal shrinkage starts at 60 degrees C to 65 degrees C. RESULTS: We observed an increase in temperature corresponding to the time of energy application. The highest measured peak temperatures at the scapholunate ligament were 43 degrees C (monopolar) and 32 degrees C (bipolar). Mean temperatures at 30 seconds of application were 29 degrees C +/- 7 degrees C (monopolar) and 28 degrees C +/- 3 degrees C (bipolar). CONCLUSIONS: Temperatures sufficiently high to induce ligament shrinkage were not reached with either monopolar or bipolar RFE. We did not monitor temperature levels responsible for damage on adjacent cartilage or immediately adjacent capsular tissue in this setting. CLINICAL RELEVANCE: This study suggests that RFE for capsular shrinkage in the wrist is safe but ineffective. PMID- 25500299 TI - [Proposal of a five MIRU-VNTR panel to screen clinical isolates of Mycobacterium tuberculosis in Mexico]. AB - INTRODUCTION: Tuberculosis is a public health problem across Mexico. This paper aims to select a panel, with a minimum number of repetitive elements (MIRU-VNTR) for genotypic characterization of Mycobacterium tuberculosis (M. tuberculosis) clinical isolates. METHOD: In this study, a full panel of 24 MIRU-VNTR loci was used to discriminate 65 clinical isolates of M. tuberculosis from three different geographical regions of Mexico. Those loci with the highest discriminatory power were subsequently selected. RESULTS: The panel, including five loci, was obtained by selecting the highest values of allelic diversity among the genotypes obtained. The dendrogram, generated by the panel MIRU-VNTR 5, showed a high discriminatory power with 65 unique genotype profiles and formed clusters according to the geographical region of origin. CONCLUSIONS: The panel MIRU-VNTR 5 can be useful for characterizing clinical isolates of M. tuberculosis in Mexico. PMID- 25500300 TI - Hancornia speciosa Gomes (Apocynaceae) as a potential anti-diabetic drug. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Hancornia speciosa Gomes are traditionally used to treat diabetes in Brazil. The aim of the study is to evaluate the potential anti-diabetic effect of Hancornia speciosa extract and derived fractions. MATERIALS AND METHODS: The ethanolic extract from Hancornia speciosa leaves and chromatographic fractions thereof were evaluated on alpha glucosidase assay, on hyperglycemic effect and glucose uptake. The chemical composition of the extract and its most active fraction was investigated by ESI LC-MS. RESULTS: The ethanolic extract and derived fractions inhibited alpha glucosidase in vitro. However, only the crude extract and the dichloromethane fraction inhibited the hyperglycemic effect induced by starch or glucose. Both the extract and dichloromethane fraction were also able to increase glucose uptake in adipocytes. Bornesitol, quinic acid, and chorogenic acid were identified in the extract, along with flavonoid glycosides, whereas the dichloromethane fraction is majorly composed by esters of lupeol and/or alpha/beta-amirin. CONCLUSIONS: Hancornia speciosa has a potential anti-diabetic effect through a mechanism dependent on inhibition of alpha-glucosidase and increase on glucose uptake. These results give support to the use on traditional medicine of this medicinal plant. PMID- 25500302 TI - Effects of extracts of leaves from Sparattosperma leucanthum on hyperuricemia and gouty arthritis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The species Sparattosperma leucanthum (Vell.) K. Schum is used in Brazilian folk medicine to treat rheumatism, throat ulcers, stomatitis, syphilis, bladder stones and as blood cleanser. The aim of this study was to evaluate the potential, in vitro and in vivo, of the extracts of leaves from Sparattosperma leucanthum to treat hyperuricemia and inflammation in the gouty arthritis model. MATERIALS AND METHODS: Ethyl acetate extract (SLE), methanolic extract (SLM) and aqueous extract (SLW) were evaluated in vitro on XO inhibitory activity and in vivo in an experimental model with oxonate-induced hyperuricemia in mice which was used to evaluate anti-hyperuricemic activity and liver xanthine oxidase (XOD) inhibition. Anti-inflammatory activity was also investigated on MSU crystal-induced paw edema model. RESULTS: Sparattosperma leucanthum crude extracts showed expressive results on urate-lowering activity in blood. SLW at the dose of 125 mg/kg has proved to be active in reducing hyperuricemia and was capable to inhibit the hepatic xanthine oxidase enzyme (XOD). SLM showed anti-hyperuricemic activity on all doses tested; however, this extract showed activity on the XOD only at the dose of 500 mg/kg. SLE, at the three evaluated doses, has proved to be active in reducing hyperuricemia in vivo and was able to inhibit XO activity in vitro at the concentration of 100 ug/mL. This extract was also able to inhibit XOD activity in vivo at the doses of 250 mg/kg and 500 mg/kg. SLE (125 and 250 mg/kg) and SLW (500 mg/kg) showed significant anti-inflammatory activity on monosodium urate crystal-induced paw edema model. CONCLUSIONS: The ethyl acetate, methanolic and aqueous extracts of Sparattosperma leucanthum showed significant results on evaluated models and therefore may be important agents for the treatment of gouty arthritis and hyperuricemia. PMID- 25500301 TI - Supplementation with Pfaffia glomerata (Sprengel) Pedersen does not affect androgenic-anabolic parameters in male rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Paffia spp (Amaranthacea) has a widespread use of in Brazil as a possible hormonal supplement and a substitute of Panax ginseng, although information on its reproductive effects is missing. AIM OF THE STUDY: To evaluated possible anabolic-androgenic or anti-androgenic effects of Pfaffia glomerata (PG) extract using intact eight-months-old male rats and pre-pubertal castrated rats. MATERIALS AND METHODS: Three different dose levels of PG (8.5, 30 and 85 mg/kg/day) were administered to eight-months-old rats for 28 days or to castrated males for 7 days (Hershberger assay). In the experiment with intact animals, 24h fecal samples were collected for quantification of fecal metabolites of androgens throughout treatment. At the end of the treatment period, animals were euthanized for evaluation of serum testosterone, reproductive organ weights, number of spermatids per testis, diameter of seminiferous tubules and cross sectional area of soleus muscle fibers. In the Hershberber assay, androgenic or anti-androgenic effects were evaluated by the weights of androgen-dependent tissues: ventral prostate, seminal vesicle, glans penis and levator ani muscle/bulbocavernosus muscle. RESULTS: No effects were observed in the concentrations of fecal metabolites of androgens monitored during the treatment of intact eight-months-old rats. Moreover, at the end of treatment, no changes were seen in any of the investigated parameters. In the Hershberger assay, the PG extract did not induce androgenic or anti-androgenic effects at the dose levels tested. Significant effects were only observed in animals treated with testosterone and testosterone plus flutamide, which were used as positive controls for androgenicity and anti-androgenicity, respectively. CONCLUSIONS: At the dose levels tested, PG extract does not induce anabolic-androgenic or anti androgenic effects in rats. PMID- 25500303 TI - N-acetylcysteine as a potential strategy to attenuate the oxidative stress induced by uremic serum in the vascular system. AB - AIMS: Chronic kidney disease (CKD) progression is accompanied by systemic oxidative stress, which contributes to an increase in the risk of cardiovascular diseases (CVDs). N-acetylcysteine (NAC) is among the most studied antioxidants, but its therapeutic benefits in CKD-associated CVDs remain controversial. Here, we investigated whether NAC could inhibit the oxidative stress induced by uremia in vitro and in vivo. MAIN METHODS: Endothelial and smooth muscle cells were challenged with human uremic or non-uremic sera, and the effects of a pre treatment with 2mM NAC were evaluated. Reactive oxygen species (ROS) production, protein oxidation and total glutathione/glutathione disulfide (tGSH/GSSG) ratios were measured. Five-sixths nephrectomized or sham-operated rats were orally treated (in the drinking water) with 60 mg/kg/day NAC or not treated for 53 days. Plasma cysteine/cystine reduction potential Eh(Cyss/2Cys) was determined as a novel marker of the systemic oxidative stress. KEY FINDINGS: NAC inhibited all the determined oxidative stress parameters, likely by increasing the tGSH/GSSG ratio, in both cell lines exposed to uremic serum. Orally administered NAC attenuated the systemic oxidative stress in uremic rats. SIGNIFICANCE: The present results indicate that NAC, by preventing GSH depletion in vascular cells exposed to uremic serum and by attenuating the systemic oxidative stress during CKD progression, emerges as a potential strategy to prevent the oxidative stress induced by uremic toxicity in the vascular system. PMID- 25500304 TI - Aerobic exercise training as therapy for cardiac and cancer cachexia. AB - Aerobic exercise training (AET) induces several skeletal muscle changes, improving aerobic exercise capacity and health. Conversely, to the positive effects of AET, the cachexia syndrome is characterized by skeletal muscle wasting. Cachexia is a multifactorial disorderassociated with other chronic diseases such as heart failure and cancer. In these diseases, an overactivation of ubiquitin-proteasome and autophagy systems associated with a reduction in protein synthesis culminates in severe skeletal muscle wasting and, in the last instance, patient's death. In contrast, AET may recycle and enhance many protein expression and enzyme activities, counteracting metabolism impairment and muscle atrophy. Therefore, the aim of the current review was to discuss the supposed therapeutic effects of AET on skeletal muscle wasting in both cardiac and cancer cachexia. PMID- 25500293 TI - Predicting recurrent mitral regurgitation after mitral valve repair for severe ischemic mitral regurgitation. AB - OBJECTIVES: The Cardiothoracic Surgical Trials Network recently reported no difference in the primary end point of left ventricular end-systolic volume index at 1 year postsurgery in patients randomized to repair (n = 126) or replacement (n = 125) for severe ischemic mitral regurgitation. However, patients undergoing repair experienced significantly more recurrent mitral regurgitation than patients undergoing replacement (32.6% vs 2.3%). We examined whether baseline echocardiographic and clinical characteristics could identify those who will develop moderate/severe recurrent mitral regurgitation or die. METHODS: Our analysis includes 116 patients who were randomized to and received mitral valve repair. Logistic regression was used to estimate a model-based probability of recurrence or death from baseline factors. Receiver operating characteristic curves were constructed from these estimated probabilities to determine classification cut-points maximizing accuracy of prediction based on sensitivity and specificity. RESULTS: Of the 116 patients, 6 received a replacement before leaving the operating room; all other patients had mild or less mitral regurgitation on intraoperative echocardiogram after repair. During the 2-year follow-up period, 76 patients developed moderate/severe mitral regurgitation or died (53 mitral regurgitation recurrences, 13 mitral regurgitation recurrences and death, and 10 deaths). The mechanism for recurrent mitral regurgitation was largely mitral valve leaflet tethering. Our model (including age, body mass index, sex, race, effective regurgitant orifice area, basal aneurysm/dyskinesis, New York Heart Association class, history of coronary artery bypass grafting, percutaneous coronary intervention, or ventricular arrhythmias) yielded an area under the receiver operating characteristic curve of 0.82. CONCLUSIONS: The model demonstrated good discrimination in identifying patients who will survive 2 years without recurrent mitral regurgitation after mitral valve repair. Although our results require validation, they offer a clinically relevant risk score for selection of surgical candidates for this procedure. PMID- 25500305 TI - Celebrating the ACIP at 50. PMID- 25500306 TI - Antigenic and genetic comparison of foot-and-mouth disease virus serotype O Indian vaccine strain, O/IND/R2/75 against currently circulating viruses. AB - Foot-and-mouth disease (FMD) virus serotype O is the most common cause of FMD outbreaks in India and three of the six lineages that have been described are most frequently detected, namely Ind2001, PanAsia and PanAsia 2. We report the full capsid sequence of 21 serotype O viruses isolated from India between 2002 and 2012. All these viruses belong to the Middle East-South Asia (ME-SA) topotype. The serological cross-reactivity of a bovine post-vaccination serum pool raised against the current Indian vaccine strain, O/IND/R2/75,was tested by virus neutralisation test with the 23 Indian field isolates, revealing a good match between the vaccine and the field isolates. The cross reactivity of the O/IND/R2/75 vaccine with 19 field isolates from other countries (mainly from Asia and Africa) revealed a good match to 79% of the viruses indicating that the vaccine strain is broadly cross-reactive and could be used to control FMD in other countries. Comparison of the capsid sequences of the serologically non matching isolates with the vaccine strain sequence identified substitutions in neutralising antigenic sites 1 and 2, which could explain the observed serological differences. PMID- 25500307 TI - Zinc supplementation fails to increase the immunogenicity of oral poliovirus vaccine: a randomized controlled trial. AB - BACKGROUND: Polio eradication remains a challenge in Pakistan and the causes for the failure to eradicate poliomyelitis are complex. Undernutrition and micronutrient deficiencies, especially zinc deficiency, are major public health problems in Pakistan and could potentially affect the response to enteric vaccines, including oral poliovirus vaccine (OPV). OBJECTIVE: To assess the impact of zinc supplementation among infants on immune response to oral poliovirus vaccine (OPV). METHODS: A double-blind, randomized placebo-controlled trial was conducted in newborns (aged 0-14 days). Subjects were assigned to either receive 10mg of zinc or placebo supplementation daily for 18 weeks. Both groups received OPV doses at birth, at 6 weeks, 10 weeks and 14 weeks. Data was collected on prior immunization status, diarrheal episodes, breastfeeding practices and anthropometric measurements at recruitment and at 6 and 18 weeks. Blood samples were similarly collected to determine the antibody response to OPV and for micronutrient analysis. Logistic regression was used to determine the relationship between seroconversion and zinc status. RESULTS: Overall, 404 subjects were recruited. At recruitment, seropositivity was already high for poliovirus (PV) serotype 1 (zinc: 91.1%; control: 90.5%) and PV2 (90.0%; 92.7%), with lower estimates for PV3 (70.0%; 64.8%). By week 18, the proportion of subjects with measured zinc levels in the normal range (i.e. >=60 MUg/dL) was significantly greater in the intervention group compared to the control group (71.9%; 27.4%; p<0.001). No significant difference in seroconversion was demonstrated between the groups for PV1, PV2, or PV3. CONCLUSIONS: There was no effect of zinc supplementation on OPV immunogenicity. These conclusions were confirmed when restricting the analysis to those with measured higher zinc levels. PMID- 25500308 TI - Evaluation of adaptive immune responses and heterologous protection induced by inactivated bluetongue virus vaccines. AB - Eradication of bluetongue virus is possible, as has been shown in several European countries. New serotypes have emerged, however, for which there are no specific commercial vaccines. This study addressed whether heterologous vaccines would help protect against 2 serotypes. Thirty-seven sheep were randomly allocated to 7 groups of 5 or 6 animals. Four groups were vaccinated with commercial vaccines against BTV strains 2, 4, and 9. A fifth positive control group was given a vaccine against BTV-8. The other 2 groups were unvaccinated controls. Sheep were then challenged by subcutaneous injection of either BTV-16 (2 groups) or BTV-8 (5 groups). Taken together, 24/25 sheep from the 4 experimental groups developed detectable antibodies against the vaccinated viruses. Furthermore, sheep that received heterologous vaccines showed significantly reduced viraemia and clinical scores for BTV-16 when compared to unvaccinated controls. Reductions in clinical signs and viraemia among heterologously vaccinated sheep were not as common after challenge with BTV-8. This study shows that heterologous protection can occur, but that it is difficult to predict if partial or complete protection will be achieved following inactivated-BTV vaccination. PMID- 25500309 TI - Exposing hidden truncation-related errors in acute stroke perfusion imaging. AB - BACKGROUND AND PURPOSE: The durations of acute ischemic stroke patients' CT or MR perfusion scans may be too short to fully sample the passage of the injected contrast agent through the brain. We tested the potential magnitude of hidden errors related to the truncation of data by short perfusion scans. MATERIALS AND METHODS: Fifty-seven patients with acute ischemic stroke underwent perfusion MR imaging within 12 hours of symptom onset, using a relatively long scan duration (110 seconds). Shorter scan durations (39.5-108.5 seconds) were simulated by progressively deleting the last-acquired images. CBV, CBF, MTT, and time to response function maximum (Tmax) were measured within DWI-identified acute infarcts, with commonly used postprocessing algorithms. All measurements except Tmax were normalized by dividing by the contralateral hemisphere values. The effects of the scan duration on these hemodynamic measurements and on the volumes of lesions with Tmax of >6 seconds were tested using regression. RESULTS: Decreasing scan duration from 110 seconds to 40 seconds falsely reduced perfusion estimates by 47.6%-64.2% of normal for CBV, 1.96%-4.10% for CBF, 133%-205% for MTT, and 6.2-8.0 seconds for Tmax, depending on the postprocessing method. This truncation falsely reduced estimated Tmax lesion volume by 71.5 or 93.8 mL, depending on the deconvolution method. "Lesion reversal" (ie, change from above normal to apparently normal, or from >6 seconds to <=6 seconds for the time to response function maximum) with increasing truncation occurred in 37%-46% of lesions for CBV, 2%-4% for CBF, 28%-54% for MTT, and 42%-44% for Tmax, depending on the postprocessing method. CONCLUSIONS: Hidden truncation-related errors in perfusion images may be large enough to alter patient management or affect outcomes of clinical trials. PMID- 25500310 TI - Artery length sensitivity in patient-specific cerebral aneurysm simulations. AB - BACKGROUND AND PURPOSE: The reconstruction of aneurysm geometry is a main factor affecting the accuracy of hemodynamics simulations in patient-specific aneurysms. We analyzed the effects of the inlet artery length on intra-aneurysmal flow estimations by using 10 ophthalmic aneurysm models. MATERIALS AND METHODS: We successively truncated the inlet artery of each model, first at the cavernous segment and second at the clinoid segment. For each aneurysm, we obtained 3 models with different artery lengths: the originally segmented geometry with the longest available inlet from scans and 2 others with successively shorter artery lengths. We analyzed the velocity, wall shear stress, and the oscillatory shear index inside the aneurysm and compared the 2 truncations with the original model. RESULTS: We found that eliminating 1 arterial turn resulted in root mean square errors of <18% with no visual differences for the contours of the flow parameters in 8 of the 10 models. In contrast, truncating at the second turn led to root mean square errors between 18% and 32%, with consistently large errors for wall shear stress and the oscillatory shear index in 5 of the 10 models and visual differences for the contours of the flow parameters. For 3 other models, the largest errors were between 43% and 55%, with large visual differences in the contour plots. CONCLUSIONS: Excluding 2 arterial turns from the inlet artery length of the ophthalmic aneurysm resulted in large quantitative differences in the calculated velocity, wall shear stress, and oscillatory shear index distributions, which could lead to erroneous conclusions if used clinically. PMID- 25500311 TI - Altered microstructure in temporal lobe epilepsy: a diffusional kurtosis imaging study. AB - BACKGROUND AND PURPOSE: Temporal lobe epilepsy is associated with regional abnormalities in tissue microstructure, as demonstrated by DTI. However, the full extent of these abnormalities has not yet been defined because DTI conveys only a fraction of the information potentially accessible with diffusion MR imaging. In this study, we assessed the added value of diffusional kurtosis imaging, an extension of DTI, to evaluate microstructural abnormalities in patients with temporal lobe epilepsy. MATERIALS AND METHODS: Thirty-two patients with left temporal lobe epilepsy and 36 matched healthy subjects underwent diffusion MR imaging. To evaluate abnormalities in patients, we performed voxelwise analyses, assessing DTI-derived mean diffusivity, fractional anisotropy, and diffusional kurtosis imaging-derived mean diffusional kurtosis, as well as diffusional kurtosis imaging and DTI-derived axial and radial components, comparing patients with controls. RESULTS: We replicated findings from previous studies demonstrating a reduction in fractional anisotropy and an increase in mean diffusivity preferentially affecting, but not restricted to, the temporal lobe ipsilateral to seizure onset. We also noted a pronounced pattern of diffusional kurtosis imaging abnormalities in gray and white matter tissues, often extending into regions that were not detected as abnormal by DTI measures. CONCLUSIONS: Diffusional kurtosis is a sensitive and complementary measure of microstructural compromise in patients with temporal lobe epilepsy. It provides additional information regarding the anatomic distribution and degree of damage in this condition. Diffusional kurtosis imaging may be used as a biomarker for disease severity, clinical phenotypes, and treatment monitoring in epilepsy. PMID- 25500312 TI - Dynamic contrast-enhanced perfusion processing for neuroradiologists: model dependent analysis may not be necessary for determining recurrent high-grade glioma versus treatment effect. AB - BACKGROUND AND PURPOSE: Dynamic contrast-enhanced perfusion MR imaging has proved useful in determining whether a contrast-enhancing lesion is secondary to recurrent glial tumor or is treatment-related. In this article, we explore the best method for dynamic contrast-enhanced data analysis. MATERIALS AND METHODS: We retrospectively reviewed 24 patients who met the following conditions: 1) had at least an initial treatment of a glioma, 2) underwent a half-dose contrast agent (0.05-mmol/kg) diagnostic-quality dynamic contrast-enhanced perfusion study for an enhancing lesion, and 3) had a diagnosis by pathology within 30 days of imaging. The dynamic contrast-enhanced data were processed by using model dependent analysis (nordicICE) using a 2-compartment model and model-independent signal intensity with time. Multiple methods of determining the vascular input function and numerous perfusion parameters were tested in comparison with a pathologic diagnosis. RESULTS: The best accuracy (88%) with good correlation compared with pathology (P = .005) was obtained by using a novel, model independent signal-intensity measurement derived from a brief integration beginning after the initial washout and by using the vascular input function from the superior sagittal sinus for normalization. Modeled parameters, such as mean endothelial transfer constant > 0.05 minutes(-1), correlated (P = .002) but did not reach a diagnostic accuracy equivalent to the model-independent parameter. CONCLUSIONS: A novel model-independent dynamic contrast-enhanced analysis method showed diagnostic equivalency to more complex model-dependent methods. Having a brief integration after the first pass of contrast may diminish the effects of partial volume macroscopic vessels and slow progressive enhancement characteristic of necrosis. The simple modeling is technique- and observer dependent but is less time-consuming. PMID- 25500313 TI - Prediction of infarction and reperfusion in stroke by flow- and volume-weighted collateral signal in MR angiography. AB - BACKGROUND AND PURPOSE: In proximal anterior circulation occlusive strokes, collateral flow is essential for good outcome. Collateralized vessel intensity in TOF- and contrast-enhanced MRA is variable due to different acquisition methods. Our purpose was to quantify collateral supply by using flow-weighted signal in TOF-MRA and blood volume-weighted signal in contrast-enhanced MRA to determine each predictive contribution to tissue infarction and reperfusion. MATERIALS AND METHODS: Consecutively (2009-2013), 44 stroke patients with acute proximal anterior circulation occlusion met the inclusion criteria with TOF- and contrast enhanced MRA and penumbral imaging. Collateralized vessels in the ischemic hemisphere were assessed by TOF- and contrast-enhanced MRA using 2 methods: 1) visual 3-point collateral scoring, and 2) collateral signal quantification by an arterial atlas-based collateral index. Collateral measures were tested by receiver operating characteristic curve and logistic regression against 2 imaging end points of tissue-outcome: final infarct volume and percentage of penumbra saved. RESULTS: Visual collateral scores on contrast-enhanced MRA but not TOF were significantly higher in patients with good outcome. Visual collateral scoring on contrast-enhanced MRA was the best rater-based discriminator for final infarct volume < 90 mL (area under the curve, 0.81; P < .01) and percentage of penumbra saved >50% (area under the curve, 0.67; P = .04). Atlas-based collateral index of contrast-enhanced MRA was the overall best independent discriminator for final infarct volume of <90 mL (area under the curve, 0.94; P < .01). Atlas-based collateral index combining the signal of TOF- and contrast-enhanced MRA was the overall best discriminator for effective reperfusion (percentage of penumbra saved >50%; area under the curve, 0.89; P < .001). CONCLUSIONS: Visual scoring of contrast-enhanced but not TOF-MRA is a reliable predictor of infarct outcome in stroke patients with proximal arterial occlusion. By atlas-based collateral assessment, TOF- and contrast-enhanced MRA both contain predictive signal information for penumbral reperfusion. This could improve risk stratification in further studies. PMID- 25500314 TI - Identification of minimal hepatic encephalopathy in patients with cirrhosis based on white matter imaging and Bayesian data mining. AB - BACKGROUND AND PURPOSE: White matter abnormalities have been demonstrated to play an important role in minimal hepatic encephalopathy. In this study, we aimed to evaluate whether WM diffusion tensor imaging can be used to identify minimal hepatic encephalopathy among patients with cirrhosis. MATERIALS AND METHODS: Our study included 65 patients with cirrhosis with covert hepatic encephalopathy (29 with minimal hepatic encephalopathy and 36 without hepatic encephalopathy). Participants underwent DTI, from which we generated mean diffusivity and fractional anisotropy maps. We used a Bayesian machine-learning technique, called Graphical-Model-based Multivariate Analysis, to determine WM regions that characterize group differences. To further test the clinical significance of these potential biomarkers, we performed Cox regression analysis to assess the potential of these WM regions in predicting survival. RESULTS: In mean diffusivity or fractional anisotropy maps, 2 spatially distributed WM regions (predominantly located in the bilateral frontal lobes, corpus callosum, and parietal lobes) were consistently identified as differentiating minimal hepatic encephalopathy from no hepatic encephalopathy and yielded 75.4%-81.5% and 83.1% 92.3% classification accuracy, respectively. We were able to follow 55 of 65 patients (median = 18 months), and 15 of these patients eventually died of liver related causes. Survival analysis indicated that mean diffusivity and fractional anisotropy values in WM regions were predictive of survival, in addition to the Child-Pugh score. CONCLUSIONS: Our findings indicate that WM DTI can provide useful biomarkers differentiating minimal hepatic encephalopathy from no hepatic encephalopathy, which would be helpful for minimal hepatic encephalopathy detection and subsequent treatment. PMID- 25500315 TI - The Computational Fluid Dynamics Rupture Challenge 2013-Phase I: prediction of rupture status in intracranial aneurysms. AB - BACKGROUND AND PURPOSE: Rupture risk assessment for intracranial aneurysms remains challenging, and risk factors, including wall shear stress, are discussed controversially. The primary purpose of the presented challenge was to determine how consistently aneurysm rupture status and rupture site could be identified on the basis of computational fluid dynamics. MATERIALS AND METHODS: Two geometrically similar MCA aneurysms were selected, 1 ruptured, 1 unruptured. Participating computational fluid dynamics groups were blinded as to which case was ruptured. Participants were provided with digitally segmented lumen geometries and, for this phase of the challenge, were free to choose their own flow rates, blood rheologies, and so forth. Participants were asked to report which case had ruptured and the likely site of rupture. In parallel, lumen geometries were provided to a group of neurosurgeons for their predictions of rupture status and site. RESULTS: Of 26 participating computational fluid dynamics groups, 21 (81%) correctly identified the ruptured case. Although the known rupture site was associated with low and oscillatory wall shear stress, most groups identified other sites, some of which also experienced low and oscillatory shear. Of the 43 participating neurosurgeons, 39 (91%) identified the ruptured case. None correctly identified the rupture site. CONCLUSIONS: Geometric or hemodynamic considerations favor identification of rupture status; however, retrospective identification of the rupture site remains a challenge for both engineers and clinicians. A more precise understanding of the hemodynamic factors involved in aneurysm wall pathology is likely required for computational fluid dynamics to add value to current clinical decision-making regarding rupture risk. PMID- 25500316 TI - Vaccines to prevent tuberculosis infection rather than disease: Physiological and immunological aspects. AB - There is increasing enthusiasm and optimism that a vaccine could be developed that prevents infection rather than disease. In this article I discuss the fact that despite this optimism nothing has been produced so far that seems to have this capability, and moreover even the borderline between when infection ends and disease begins has not even been defined. To be effective such a vaccine, or at least the immunity it would generate, would have to work within the confines of the pulmonary physiological systems, which are complex. To date much of the emphasis here has turned away from T cell mediated immunity and towards establishing specific antibodies in the lungs. Here, I argue that with the exception of a possible exclusionary function, most claims of a protective role of antibody are completely over-blown. Finally, even if we had a potential "anti infection" vaccine, how would we test and validate it? PMID- 25500317 TI - Per cent of patients with chronic migraine who responded per onabotulinumtoxinA treatment cycle: PREEMPT. AB - OBJECTIVE: The approved use of onabotulinumtoxinA for prophylaxis of headaches in patients with chronic migraine (CM) involves treatment every 12 weeks. It is currently unknown whether patients who fail to respond to the first onabotulinumtoxinA treatment cycle will respond to subsequent treatment cycles. To help inform decisions about treating non-responders, we examined the probability of treatment cycle 1 non-responders responding in cycle 2, and cycle 1 and 2 non-responders responding in cycle 3. METHODS: Pooled PREEMPT data (two studies: a 24-week, 2-cycle, double-blind, randomised (1:1), placebo-controlled, parallel-group phase, followed by a 32-week, 3-cycle, open-label phase) evaluated onabotulinumtoxinA (155-195 U) for prophylaxis of headaches in persons with CM (>=15 days/month with headache >=4 h/day). End points of interest included the proportion of study patients who first achieved a >=50% reduction in headache days, moderate/severe headache days, total cumulative hours of headache on headache days, or a >=5-point improvement in Headache Impact Test (HIT)-6. For treatment cycle 1, all eligible participants were included. For subsequent cycles, responders in a previous cycle were no longer considered first responders. RESULTS: Among onabotulinumtoxinA-treated patients (n=688) 49.3% had a >=50% reduction in headache-day frequency during treatment cycle 1, with 11.3% and 10.3% of patients first responding during cycles 2 and 3, respectively. 54.2%, 11.6% and 7.4% of patients first responded with a >=50% reduction in cumulative hours of headache, and 56.3%, 14.5% and 7.7% of patients first responded with a >=5-point improvement in total HIT-6 during treatment cycles 1, 2 and 3, respectively. CONCLUSIONS: A meaningful proportion of patients with CM treated with onabotulinumtoxinA who did not respond to the first treatment cycle responded in the second and third cycles of treatment. TRIAL REGISTRATION NUMBER: NCT00156910, NCT00168428. PMID- 25500318 TI - Subscales of the vestibular activities and participation questionnaire could be applied across cultures. AB - OBJECTIVES: The objective of this study was to assess the objectivity, cross cultural validity, and convergent validity of the Vestibular Activities and Participation (VAP) questionnaire among four countries, Germany, United States, Jordan, and Saudi Arabia. STUDY DESIGN AND SETTING: This was a cross-sectional study conducted in four specialized outpatient dizziness clinics in Germany, United States, Jordan, and Saudi Arabia. RESULTS: A total of 453 participants were included in the study. The Rasch analysis revealed two separate subscales. Subscale 1 items included focusing attention, lying down, standing, bending, lifting and carrying objects, and sports. Subscale 2 items included walking long distances, climbing, running, moving around within buildings other than home, using transportation, and driving. The Pearson product-moment correlation between the Dizziness Handicap Inventory and the summary score of the VAP subscale 1 was 0.66 and was 0.64 for subscale 2. CONCLUSION: Owing to its shortness and intercultural adaptability, the new two-scale version of the VAP questionnaire lends itself to clinical practice and research across countries to estimate the effect of vertigo and dizziness on activity limitation and participation restrictions. Psychometrically sound summary scores can be calculated. More extended versions of the VAP can be used for comprehensive clinical assessment where summary scores are not needed or a more detailed documentation is warranted. PMID- 25500320 TI - Rational-emotive and cognitive-behavior therapy (REBT/CBT) versus pharmacotherapy versus REBT/CBT plus pharmacotherapy in the treatment of major depressive disorder in youth; a randomized clinical trial. AB - Major depressive disorder is a highly prevalent and debilitating condition in youth, so developing efficient treatments is a priority for mental health professionals. Psychotherapy (i.e., cognitive behavioral therapy/CBT), pharmacotherapy (i.e., SSRI medication), and their combination have been shown to be effective in treating youth depression; however, the results are still mixed and there are few studies engaging multi-level analyses (i.e., subjective, cognitive, and biological). Therefore, the aims of this randomized control study (RCT) were both theoretical - integrating psychological and biological markers of depression in a multi-level outcome analysis - and practical - testing the generalizability of previous results on depressed Romanian youth population. Eighty-eight (N=88) depressed Romanian youths were randomly allocated to one of the three treatment arms: group Rational Emotive Behavior Therapy (REBT)/CBT (i.e., a form of CBT), pharmacotherapy (i.e., sertraline), and group REBT/CBT plus pharmacotherapy. The results showed that all outcomes (i.e., subjective, cognitive, and biological) significantly change from pre to post-treatment under all treatment conditions at a similar rate and there were no significant differences among conditions at post-test. In case of categorical analysis of the clinical response rate, we found a non-significant trend favoring group REBT/CBT therapy. Results of analyses concerning outcome interrelations are discussed. PMID- 25500319 TI - Association between polymorphisms in genes involved in lipid metabolism and immunological status in chronically HIV-infected patients. AB - Several studies have reported associations between lipid parameters and clinical progression of HIV infection. We performed a cross-sectional study including 468 antiretroviral-treated HIV-infected patients to investigate the impact of 13 polymorphisms of 9 genes affecting lipid metabolism and CD4 and CD8-T cell levels. Polymorphisms were identified in genes selected for their role in the development of atherogenic dyslipidemia, defined as triglycerides ?1.7mmol/L and high-density lipoprotein cholesterol (HDLc) <1.02 in women or 1.28mmol/L in men. Lipid and lipoprotein parameters were determined in all participants, as well as CD4 and CD8 T-cell counts. ANOVA was performed to compare the mean values of lipid and CD4 and CD8 T-cell count data. A Bonferroni correction for multiple comparisons was applied. 468 patients were included, 148 of them had a diagnosis of atherogenic dyslipidemia. The polymorphism rs3135506 in APOA5 was associated with a 9% increase in triglycerides (p=0.002), 10% and 21% decrease in HDLc (p=0.005), and CD4 T-cell count (p=0.024), respectively. APOA5 rs662799, was associated with a 19% increase in CD8 T-cell count (p=0.002). Carriers of LPL rs328 in the dyslipidemic group presented 11% higher levels of HDLc (p=0.015) and 14% higher levels of CD4 cells (p=0.038). In conclusion, polymorphisms in genes associated to the development of atherogenic dyslipidemia, especially variants in APOA5 gene (rs3135506 and rs662799), can influence the circulating CD4 T-cell levels in chronically HIV-infected patients. These data support previous reports on the effect of lipid metabolism on immunologic parameters in HIV+ individuals on antiretroviral therapy. PMID- 25500321 TI - The reductions in monetary cost and gains in productivity with methadone maintenance treatment: one year follow-up. AB - While methadone maintenance treatment (MMT) is beneficial for heroin dependence, there is little information regarding the reductions in monetary cost and gains in productivity following MMT. The aim of this study was to evaluate the changes in the monetary cost of heroin addiction and productivity after one year of MMT. Twenty-nine participants from an MMT clinic were included. The monetary cost, productivity, quality of life (QOL) and mental health status were assessed at both baseline and one year follow-up. The average annual total cost was approximately US$26,485 (1.43 GDP per capita in 2010) at baseline, and decreased by 59.3% to US$10,784 (0.58 GDP) at follow-up. The mean number of months of unemployment dropped from 6.03 to 2.79, the mean income increased to exceed the basic salary, but only reached 45.3% of the national average monthly earnings. The participants' mental health improved, but their QOL scores did not increase significantly. After one year of MMT, the monetary cost of heroin addiction fell, both the productivity and mental health of the participants' improved, but limited gains were seen with regard to their QOL. PMID- 25500322 TI - Brain derived neurotrophic factor (BDNF) polymorphism moderates the interactive effect of 5-HTTLPR polymorphism and childhood abuse on diagnoses of major depression in women. PMID- 25500323 TI - Deliberate self-harm and the nexus of violence, victimization, and mental health problems in the United States. AB - Deliberate self-harm (DSH) is associated with diverse psychiatric diagnoses and broad psychopathology but less is known about its association with other forms of interpersonal violence and crime. Using the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), the current study examined linkages between not only DSH and mental health and substance abuse comorbidity, but also childhood abuse, lifetime victimization, and a variety of violent behaviors. We identified a prevalence of 2.91% for DSH and found that DSH is associated with generalized and severe psychopathology, wide-ranging substance abuse, and adverse childhood experiences. Contrary to other studies, we found significant racial and ethnic differences in DSH. African-American, Latinos, and Asians, were substantially less likely than Whites to report DSH. Our hypothesis that DSH would be associated with a variety of violent behaviors including robbery, intimate partner violence, forced sex, cruelty to animals, and use of a weapon was supported even after adjusting for an array of covariates. We extend previous research on DSH by examining its prevalence in one the largest comorbidity surveys ever conducted and show that DSH is associated with multiple forms of violent behavior toward others, including animals. PMID- 25500324 TI - Rationale and enrollment results for a partially randomized patient preference trial to compare continuation rates of short-acting and long-acting reversible contraception. AB - OBJECTIVES: Most published contraceptive continuation rates have scientific limitations and cannot be compared; this is particularly true for dissimilar contraceptives. This study uses a new approach to determine if high continuation rates of long-acting reversible contraception (LARC) and protection from unintended pregnancy are observable in a population not self-selecting to use LARC. STUDY DESIGN: We are conducting a partially randomized patient preference trial (PRPPT) to compare continuation rates of short-acting reversible contraception (SARC) and LARC. Only women seeking SARC were invited to participate. Participants chose to be in the preference cohort (self-selected method use) or opted to be randomized to SARC or LARC; only those in the randomized cohort received free product. We compared participant characteristics, reasons for not trying LARC previously and the contraceptive choices that were made. RESULTS: We enrolled 917 eligible women; 57% chose to be in the preference cohort and 43% opted for the randomized trial. The preference and randomized cohorts were similar on most factors. However, the randomized cohort was more likely than the preference cohort to be uninsured (48% versus 36%, respectively) and to cite cost as a reason for not trying LARC previously (50% versus 10%) (p<.01 for both comparisons). In the preference cohort, fear of pain/injury/side effects/health risks were the predominant reasons (cited by over 25%) for not trying LARC previously (p<.01 in comparison to randomized cohort). CONCLUSIONS: Enrollment was successful and the process created different cohorts to compare contraceptive continuation rates and unintended pregnancy in this ongoing trial. The choices participants made were associated with numerous factors; lack of insurance was associated with participation in the randomized trial. IMPLICATIONS: This PRPPT will provide new estimates of contraceptive continuation rates, such that any benefits of LARC will be more easily attributable to the technology and not the user. Combined with measuring level of satisfaction with LARC, the results will help project the potential role and benefits of expanding voluntary use of LARC. PMID- 25500325 TI - A sensitive biosensor for the fluorescence detection of the acetylcholinesterase reaction system based on carbon dots. AB - The carbon dots (C-dots) with high fluorescence quantum yield were prepared using hydrothermal method. C-dots have been adopted as probes for the fluorescence turn off detection of H2O2 based on the special sensibility for the hydroxyl radical. And then the biosensors for the detection of substrate and enzymes activities were established in the acetylcholinesterase reaction system, which were related to the production of H2O2. Specifically, the proposed fluorescent biosensor was successfully applied to detect the concentration of choline (in the range from 0.025 to 50 MUM) and acetylcholine (in the range from 0.050 to 50 MUM), and the activity of choline oxidase (in the range from 1 to 75 U/L) and acetylcholinesterase (1 to 80 U/L). These results showed a sensitive, universal, nontoxic and eco-friendly detecting technique has been developed. PMID- 25500326 TI - Binding of glutathione and melatonin to human serum albumin: a comparative study. AB - Binding of glutathione and melatonin to human serum albumin (HSA) has been studied using isothermal titration calorimetry (ITC) in combination with UV-vis absorption spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, and circular dichroism (CD) spectroscopy. Thermodynamic investigations reveal that glutathione/melatonin binds to HSA is driven by favorable enthalpy and unfavorable entropy, and the major driving forces are hydrogen bond and van der Waals force. For glutathione, the interaction is characterized by a high number of binding sites, which suggests that binding occurs by a surface adsorption mechanism that leads to coating of the protein surface. For melatonin, one molecule of melatonin combines with one molecule of HSA and no more melatonin binding to HSA occurs at concentration ranges used in this study. The UV-vis absorption, FT-IR, and CD spectroscopy suggest that glutathione and melatonin may induce conformational and microenvironmental changes of HSA. PMID- 25500327 TI - Role of balloon-assisted cholangioscopy in a multiethnic cohort to assess complex biliary disease (with videos). AB - BACKGROUND: Cholangioscopy is used to diagnose and treat various biliary lesions. Balloon-assisted cholangioscopy (BAC) has mostly been reported in Asian patients with large bile ducts. OBJECTIVE: To assess the feasibility and accuracy of performing BAC in complex biliary diseases in Australian patients. DESIGN: Prospective observational study. SETTING: A single Australian tertiary referral hospital. PATIENTS: Fifty-nine consecutive patients (55 non-Asian ethnicity). INTERVENTIONS: BAC using ultrathin endoscopes. MAIN OUTCOME MEASUREMENTS: Procedural success rates, diagnostic accuracy, and adverse event rates. RESULTS: Fifty-nine patients underwent 76 BAC procedures for indeterminate biliary lesions, ampullary adenomas, and difficult stone disease. The technical success rate was 93%. The median bile duct diameter was 7 mm (range, 2-20). Of 34 indeterminate biliary strictures, 22 appeared benign and 12 malignant on BAC appearance alone. All benign-appearing strictures were confirmed benign, whereas 9 of 12 malignant-appearing strictures were confirmed malignant by biopsy sampling or follow-up (sensitivity 100% [95% CI, 66%-100%], specificity 88% [95% CI, 69%-97%], positive predictive value 75% [95% CI, 42%-93%], negative predictive value 100% [95% CI, 82%-100%]). BAC appearance correctly diagnosed indeterminate masses as benign (4/4) or malignant (3/3). Eight patients were assessed for bile duct extension of ampullary adenomas and 5 of 6 had biliary stones cleared directly or with holmium laser lithotripsy. Adequate histopathologic specimens were obtained from 31 of 39 (79%) attempted biopsy specimens. The adverse event rate was 8%. LIMITATIONS: A single-center, single endoscopist experience. CONCLUSIONS: In a largely non-Asian cohort with smaller bile ducts, BAC can be performed with high success and acceptable adverse event rates. BAC is particularly useful in differentiating benign from malignant indeterminate biliary lesions. PMID- 25500328 TI - Novel risk stratification for recurrence after endoscopic resection of advanced colorectal adenoma. AB - BACKGROUND: Advanced colorectal adenoma (ACA) refers to adenomas with the following predictive characteristics: >=1 cm in diameter, and/or villous component, and/or high-grade dysplasia. ACA has high risk of transforming to colorectal cancer, and the recurrence rate is relatively high. OBJECTIVE: To assess the outcomes of patients with ACA undergoing endoscopic resection and to identify risk factors for local recurrence and development of metachronous advanced neoplasm. DESIGN: Retrospective cohort study. SETTING: Tertiary care medical center. PATIENTS: From 2005 to 2011, the records of 3625 patients who underwent colonoscopic polypectomy at Seoul National University Hospital were retrospectively reviewed. Patients with synchronous colorectal cancers, inflammatory bowel disease, previous colorectal resection, loss to follow-up, and incomplete resection were excluded. INTERVENTION: Endoscopic resection for ACA. MAIN OUTCOME MEASUREMENTS: Local recurrence and metachronous advanced neoplasm. RESULTS: The study included 917 patients with 1206 ACAs. The median duration of follow-up was 28.5 months (interquartile range, 12.8-51.7). Independent risk factors for local recurrence included ACA with 2 or more predictive characteristics (adjusted hazard ratio [HR], 2.46; 95% confidence interval [CI], 1.11-5.48; P = .027) and piecemeal resection (adjusted HR, 6.96; 95% CI, 1.58 30.71; P = .010). Independent risk factors for metachronous advanced neoplasm were male gender (adjusted HR, 1.65; 95% CI, 1.02-2.65; P = .041), >=3 adenomas (adjusted HR, 2.56; 95% CI, 1.72-3.82; P < .001), and >=3 ACAs (adjusted HR, 1.44; 95% CI, 1.01-2.06; P = .045). LIMITATIONS: Retrospective design. CONCLUSION: ACAs with 2 or more predictive characteristics recurred locally at a higher rate than ACAs with 1 predictive characteristic. These results suggest that patients who are found to have ACAs with 2 or more predictive factors at index colonoscopy are at higher risk for local recurrence, and follow-up colonoscopy should be performed sooner. PMID- 25500330 TI - Hepaticogastrostomy or choledochoduodenostomy for distal malignant biliary obstruction after failed ERCP: is there any difference? AB - BACKGROUND: EUS-guided biliary drainage (BD) is an evolving alternative technique for patients with malignant biliary obstruction for which ERCP failed. OBJECTIVE: To compare the outcomes of 2 nonanatomic EUS-guided BD routes: hepaticogastrostomy (HPG) and choledochoduodenostomy (CD). DESIGN: Prospective, randomized trial. SETTING: Tertiary endoscopic referral center. PATIENTS: Forty nine patients with unresectable distal malignant biliary obstruction and failed ERCP were included. The HPG group had 25 patients and the CD group had 24 patients. INTERVENTIONS: EUS-guided HPG or CD. In all procedures, a biliary puncture with a 19-gauge needle followed by cholangiography, wire advancement, track dilation, and self-expandable metal stent deployment were performed. MAIN OUTCOME MEASUREMENTS: Technical and clinical success, quality of life, adverse events, and survival. RESULTS: The technical success rate was 96% for HPG and 91% for CD. The clinical success rate was 91% for HPG and 77% for CD. The mean procedural time was 47.8 minutes for HPG and 48.8 minutes for CD. The mean scores of quality of life were similar during follow-up. The overall adverse event rate was 16.3% (20% for the HPG group and 12.5% for the CD group). One patient with a bile leak required percutaneous biloma drainage. There was no statistical difference between the 2 techniques and no difference with regard to survival time between the 2 groups. LIMITATIONS: Single-center study. CONCLUSION: HPG and CD techniques are similar in efficacy and safety. Both HPG and CD seem valid alternative options for BD in patients with distal malignant biliary obstruction after failed ERCP. PMID- 25500331 TI - Comment on "household effectiveness vs. laboratory efficacy of point-of-use chlorination". PMID- 25500329 TI - Volatile organic compounds in bile for early diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis: a pilot study. AB - BACKGROUND: The diagnosis of cholangiocarcinoma (CCA) in patients with primary sclerosing cholangitis (PSC) is particularly difficult. The role of volatile organic compounds (VOCs) for diagnosis of CCA in patients with PSC is not known. OBJECTIVE: Our aim was to identify potential VOCs in the headspaces (gas above the sample) in bile that may predict CCA in patients with PSC. DESIGN: Prospective cross-sectional study. SETTING: Referral center. PATIENTS: A total of 32 patients undergoing ERCP for PSC and for CCA complicating PSC. INTERVENTIONS: ERCP, bile aspiration. MAIN OUTCOME MEASUREMENTS: Selected ion flow tube mass spectrometry was used to analyze the concentration of 22 prevalent VOCs in bile samples. Logistic regression analysis was performed to build a predictive model for diagnosis of CCA. RESULTS: Levels of several compounds (ethanol, acrylonitrile, acetonitrile, acetaldehyde, benzene, carbon disulfide, dimethyl sulfide, 2-propranolol) were significantly different in patients with CCA complicating PSC compared with those having PSC (P < .05). By using receiver operating characteristic curve analysis, we developed a model for the diagnosis of CCA adjusted for age and sex based on VOC levels of acrylonitrile, 3-methyl hexane, and benzene. The model (2.3239*log [acrylonitrile] + 0.9871*log [3-methyl hexane] + 0.8448*log [benzene]) < -0.12 identified the patients with CCA (area under the curve [AUC] = 0.89), with 90.5% sensitivity and 72.7% specificity (P = .02). LIMITATIONS: Sample size. CONCLUSION: The measurement of VOCs in biliary fluid may be useful to diagnose CCA in patients with PSC. A larger study with a longitudinal study design is required to confirm our pilot observations to diagnose CCA early in patients with PSC. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01565460.). PMID- 25500332 TI - Propriospinal myoclonus: The spectrum of clinical and neurophysiological phenotypes. AB - Propriospinal myoclonus (PSM) is a rare type of spinal myoclonus characterized by muscle jerks that usually start in the midthoracic segments and then slowly propagate up and down into the spinal cord, resulting in repetitive and irregular jerky flexion, or extension of the trunk, neck, knees and hips. PSM can be symptomatic, but up to 80% of reported cases appear idiopathic. PSM tends to occur especially while the subject is lying down. PSM at sleep onset was first described by experts in sleep medicine. The original electrophysiological features included fixed pattern of muscle activations, slow spinal cord conduction (5-15 m/s), electromyographic burst duration less than 1000 ms, synchronous activation of agonist and antagonist muscles and no involvement of facial muscles. PSM has been reported to be a functional (psychogenic) movement disorder in a number of cohorts. The differential diagnosis between idiopathic PSM and the functional forms is not always straightforward. A consistent polymyographically documented muscle activation pattern may be supportive but by no means sufficient and additional neurophysiological investigations are required. PSM should be differentiated from other movement disorders involving the abdomen and trunk, or occurring at sleep-wake transition. This article offers a comprehensive overview of the spectrum of PSM phenotypes. PMID- 25500333 TI - Renal lesions in patients with type 2 diabetes: a puzzle waiting to be solved. PMID- 25500334 TI - Hyaluronic acid-modified multiwalled carbon nanotubes for targeted delivery of doxorubicin into cancer cells. AB - Development of novel drug carriers for targeted cancer therapy with high efficiency and specificity is of paramount importance and has been one of the major topics in current nanomedicine. Here we report a general approach to using multifunctional multiwalled carbon nanotubes (MWCNTs) as a platform to encapsulate an anticancer drug doxorubicin (DOX) for targeted cancer therapy. In this approach, polyethyleneimine (PEI)-modified MWCNTs were covalently conjugated with fluorescein isothiocyanate (FI) and hyaluronic acid (HA). The formed MWCNT/PEI-FI-HA conjugates were characterized via different techniques and were used as a new carrier system to encapsulate the anticancer drug doxorubicin for targeted delivery to cancer cells overexpressing CD44 receptors. We show that the formed MWCNT/PEI-FI-HA/DOX complexes with a drug loading percentage of 72% are water soluble and stable. In vitro release studies show that the drug release rate under an acidic condition (pH 5.8, tumor cell microenvironment) is higher than that under physiological condition (pH 7.4). Cell viability assay demonstrates that the carrier material has good biocompatibility in the tested concentration range, and the MWCNT/PEI-FI-HA/DOX complexes can specifically target cancer cells overexpressing CD44 receptors and exert growth inhibition effect to the cancer cells. The developed HA-modified MWCNTs hold a great promise to be used as an efficient anticancer drug carrier for tumor-targeted chemotherapy. PMID- 25500336 TI - Rho-kinase regulates human platelet activation induced by thromboxane A2 independently of p38 MAP kinase. AB - We have previously demonstrated that ristocetin, an activator of GPIb/IX/V, induces the release of soluble CD40 ligand (sCD40L) via thromboxane A2 production in human platelets. It has been shown that thromboxane A2 induces the activation of Rho-kinase, a downstream effector of Rho, in human platelets. In the present study, we investigated the exact roles of Rho-kinase in thromboxane A2-induced platelet activation. We found that U46619, a thromboxane receptor (TP) agonist, induced the phosphorylation of cofilin, a target of Rho-kinase signaling, and that the cofilin phosphorylation by U46619 was suppressed by Y27632 or fasudil, specific inhibitors of Rho-kinase. Y27632 and fasudil markedly decreased large platelet aggregate formation by U46619. The release of sCD40L and secretion of platelet-derived growth factor (PDGF)-AB stimulated by U46619 were inhibited by Y27632 and fasudil. SB203580, a specific inhibitor of p38 mitogen-activated protein (MAP) kinase, reduced the sCD40L release and PDGF-AB secretion. Y27632 and fasudil failed to affect the phosphorylation of p38 MAP kinase whereas SB203580 had little effect on the phosphorylation of cofilin induced by U46619. In conclusion, our results strongly suggest that Rho-kinase regulates thromboxane A2-induced human platelet activation independently of p38 MAP kinase. PMID- 25500335 TI - A genome-wide association study of saturated, mono- and polyunsaturated red blood cell fatty acids in the Framingham Heart Offspring Study. AB - Most genome-wide association studies have explored relationships between genetic variants and plasma phospholipid fatty acid proportions, but few have examined apparent genetic influences on the membrane fatty acid profile of red blood cells (RBC). Using RBC fatty acid data from the Framingham Offspring Study, we analyzed over 2.5 million single nucleotide polymorphisms (SNPs) for association with 14 RBC fatty acids identifying 191 different SNPs associated with at least 1 fatty acid. Significant associations (p<1*10(-8)) were located within five distinct 1MB regions. Of particular interest were novel associations between (1) arachidonic acid and PCOLCE2 (regulates apoA-I maturation and modulates apoA-I levels), and (2) oleic and linoleic acid and LPCAT3 (mediates the transfer of fatty acids between glycerolipids). We also replicated previously identified strong associations between SNPs in the FADS (chromosome 11) and ELOVL (chromosome 6) regions. Multiple SNPs explained 8-14% of the variation in 3 high abundance (>11%) fatty acids, but only 1-3% in 4 low abundance (<3%) fatty acids, with the notable exception of dihomo-gamma linolenic acid with 53% of variance explained by SNPs. Further studies are needed to determine the extent to which variations in these genes influence tissue fatty acid content and pathways modulated by fatty acids. PMID- 25500338 TI - Preparedness for emerging infectious diseases: pathways from anticipation to action. AB - Emerging and re-emerging infectious disease (EID) events can have devastating human, animal and environmental health impacts. The emergence of EIDs has been associated with interconnected economic, social and environmental changes. Understanding these changes is crucial for EID preparedness and subsequent prevention and control of EID events. The aim of this review is to describe tools currently available for identification, prioritization and investigation of EIDs impacting human and animal health, and how these might be integrated into a systematic approach for directing EID preparedness. Environmental scanning, foresight programmes, horizon scanning and surveillance are used to collect and assess information for rapidly responding to EIDs and to anticipate drivers of emergence for mitigating future EID impacts. Prioritization of EIDs - using transparent and repeatable methods - based on disease impacts and the importance of those impacts to decision-makers can then be used for more efficient resource allocation for prevention and control. Risk assessment and simulation modelling methods assess the likelihood of EIDs occurring, define impact and identify mitigation strategies. Each of these tools has a role to play individually; however, we propose integration of these tools into a framework that enhances the development of tactical and strategic plans for emerging risk preparedness. PMID- 25500337 TI - Docosahexaenoic acid (DHA) supplementation in pregnancy differentially modulates arachidonic acid and DHA status across FADS genotypes in pregnancy. AB - Some FADS alleles are associated with lower DHA and ARA status assessed by the relative amount of arachidonic acid (ARA) and docosahexaenoic acid (DHA) in plasma and red blood cell (RBC) phospholipids (PL). We determined two FADS single nucleotide polymorphisms (SNPs) in a cohort of pregnant women and examined the relationship of FADS1rs174533 and FADS2rs174575 to DHA and ARA status before and after supplementation with 600mg per day of DHA. The 205 pregnant women studied were randomly assigned to placebo (mixed soy and corn oil) (n=96) or 600mg algal DHA (n=109) in 3 capsules per day for the last two trimesters of pregnancy. Women homozygous for the minor allele of FADS1rs174533 (but not FADS2rs174575) had lower DHA and ARA status at baseline. At delivery, minor allele homozygotes of FADS1rs174533 in the placebo group had lower RBC-DHA compared to major-allele carriers (P=0.031), while in the DHA-supplemented group, all genotypes had higher DHA status compared to baseline (P=0.001) and status did not differ by genotype (P=0.941). Surprisingly, DHA but not the placebo decreased ARA status of minor allele homozygotes of both FADS SNPs but not major allele homozygotes at delivery. Any physiological effects of changing the DHA to ARA ratio by increasing DHA intake appears to be greater in minor allele homozygotes of some FADS SNPs. PMID- 25500339 TI - The "global surgeon": is it time for modifications in the American surgical training paradigm? AB - OBJECTIVE: "Global surgery" is becoming an increasingly popular concept not only for new trainees, but also for established surgeons. The need to provide surgical care in low-resource settings is laudable, but the American surgical training system currently does not impart the breadth of skills required to provide quality care. We propose one possible model for a surgical fellowship program that provides those trainees who desire to practice in these settings a comprehensive experience that encompasses not only broad technical skills but also the opportunity to engage in policy and programmatic development and implementation. METHODS: This is a descriptive commentary based on personal experience and a review of the literature. RESULTS: The proposed model is 2 years long, and can either be done after general surgery training as an additional "global surgery" fellowship or as part of a 3 + 2 general surgery + global surgery system. It would incorporate training in general surgery as well as orthopedics, urology, obstetrics & gynecology, neurosurgery, plastics & reconstructive surgery, as well as dedicated time for health systems training. Incorporating such training in a low-resource setting would be a requirement of such a program, in order to obtain field experience. CONCLUSIONS: Global surgery is a key word these days in attracting young trainees to academic surgical residency programs, yet they are subsequently inadequately trained to provide the required surgical services in these low-resource settings. Dedicated programmatic changes are required to allow those who choose to practice in these settings to obtain the full breadth of training needed to become safe, competent surgeons in such environments. PMID- 25500340 TI - Molecular classification of amyotrophic lateral sclerosis by unsupervised clustering of gene expression in motor cortex. AB - Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disease, caused by the loss of motor neurons in the brain and spinal cord. Although 10% of ALS cases are familial (FALS), the majority are sporadic (SALS) and probably associated to a multifactorial etiology. Currently there is no cure or prevention for ALS. A prerequisite to formulating therapeutic strategies is gaining understanding of its etio-pathogenic mechanisms. In this study we analyzed whole-genome expression profiles of 41 motor cortex samples of control (10) and sporadic ALS (31) patients. Unsupervised hierarchical clustering was able to separate control from SALS patients. In addition, SALS patients were subdivided in two different groups that were associated to different deregulated pathways and genes, some of which were previously associated to familiar ALS. These experiments are the first to highlight the genomic heterogeneity of sporadic ALS and reveal new clues to its pathogenesis and potential therapeutic targets. PMID- 25500341 TI - National trends in incidence and outcomes of acute pancreatitis among type 2 diabetics and non-diabetics in Spain (2001-2011). AB - BACKGROUND: Diabetes is often observed in patients with acute pancreatitis (AP). Our aim was to compare trends in the clinical epidemiology and outcomes of AP in diabetic and non-diabetic patients in Spain. METHODS: We conducted a retrospective observational study. We identified all patients who had a diagnosis of AP using national hospital discharge data (2001-2011). The incidence of discharges of patients with AP was calculated, stratified by diabetes status. We calculated length of stay and in-hospital mortality (IHM). We applied joinpoint log-linear regression to identify the years in which changes in tendency occurred in the diagnosis of AP. The multivariate analysis was adjusted for age, sex, year and Charlson comorbidity index (CCI). RESULTS: The total number of subjects who had a diagnosis of AP was 282,349. Of them, 42,009 (14.9%) had type 2 diabetes. The annual percentage of change in the incidence of AP for the whole period was 4.90% for those suffering from type 2 diabetes and almost null (0.1%) for those without this disease. Among hospitalized patients with type 2 diabetes and acute pancreatitis, those with a CCI equal to or greater than three had 5.53 times more probability of dying in the hospital than those with a CCI of zero. The corresponding OR for the non-diabetic group was 6.50 (95%CI 6.15-6.87). Suffering from type 2 diabetes was significantly associated with a lower risk of dying in the hospital with a diagnosis of AP (OR 0.82; 95% CI 0.78-0.86). CONCLUSIONS: In Spain, time trend analyses suggest that the incidence of AP is increasing more among those with prevalent type 2 diabetes than among those without this disease. Type 2 diabetes was associated with a lower risk of dying in hospital with AP. PMID- 25500342 TI - Massive pancreatic pseudocyst with portal vein fistula: case report and proposed treatment algorithm. AB - Pancreatic pseudocyst is a relatively common occurrence resulting from acute or chronic pancreatitis. However, a rare subset of these patients present with a pseudocyst fistulizing into the portal vein. We present the case of a 58 year-old woman with a rapidly expanding pancreatic pseudocyst with portal venous fistulization causing portal vein thrombosis, in addition to biliary and duodenal obstruction. The patient underwent surgical decompression with a cyst-gastrostomy and was well until one week post-operatively when she experienced massive gastrointestinal hemorrhage leading to her death. A review of the literature is presented and a treatment algorithm to manage patients with pancreatic pseudocyst to portal vein fistula is proposed. PMID- 25500343 TI - Current contraceptive status among women aged 15-44: United States, 2011-2013. AB - Nearly all women use contraception at some point in their lifetimes, although at any given time they may not be using contraception for reasons such as seeking pregnancy, being pregnant, or not being sexually active. Using data from the 2011 2013 National Survey of Family Growth (NSFG) on contraceptive use in the month of the interview, this report provides a snapshot of current contraceptive status among women aged 15-44 in the United States. In addition to describing use of any method by age, Hispanic origin and race, and educational attainment, patterns of use are described for the four most commonly used contraceptive methods: the oral contraceptive pill, female sterilization, the male condom, and long-acting reversible contraceptives, which include contraceptive implants and intrauterine devices. PMID- 25500344 TI - 5-HTTLPR * interpersonal stress interaction and nonsuicidal self-injury in general community sample of youth. AB - No research with youth has investigated whether measured genetic risk interacts with stressful environment (G*E) to explain engagement in non-suicidal self injury (NSSI). Two independent samples of youth were used to test the a priori hypothesis that the Transporter-Linked Polymorphic Region (5-HTTLPR) would interact with chronic interpersonal stress to predict NSSI. We tested this hypothesis with children and adolescents from United States public schools in two independent samples (N's=300 and 271) using identical procedures and methods. They were interviewed in person with the Self-Injurious Thoughts and Behaviors Interview to assess NSSI engagement and with the UCLA Chronic Stress Interview to assess interpersonal stress. Buccal cells were collected for genotyping of 5 HTTLPR. For both samples, ANOVAs revealed the hypothesized G*E. Specifically, short carriers who experienced severe interpersonal stress exhibited the highest level of NSSI engagement. Replicated across two independent samples, results provide the first demonstration that youth at high genetic susceptibility (5 HTTLPR) and high environmental exposure (chronic interpersonal stress) are at heightened risk for NSSI. PMID- 25500345 TI - Maintenance of parasympathetic inhibition following emotional induction in patients with restrictive type anorexia nervosa. AB - This study aimed to explore changes in heart rate variability (HRV), a proxy for parasympathetic activity characterizing emotion regulation processes before, during and after negative emotional induction in patients suffering from restrictive type anorexia nervosa (AN-RT). We compared two methods of HRV analysis, the Fast Fourier Transform high frequency (FFT-HF) and a specific HRV high frequency analysis technique, namely, the wavelet transform HRV (WT-HRV). A sample of 16 inpatients with AN-RT was compared to 24 control participants. Heart rate (HR) was continuously recorded for 5 min before the beginning of the video until 5 min after the video. The participants answered questionnaires concerning their eating behaviors, mood disorders and difficulties in emotion regulation. During the entire procedure, the FFT-HF in patients was lower than that in controls. Using the WT-HRV, the patients did not differ from the controls at baseline, and only the controls showed a decrease during emotional induction. After the video, the WT-HRV in patients began to decrease during the first 2 min of emotional recovery although the WT-HRV in controls was already increased. These results highlighted the disturbances in the physiological dynamics of emotion regulation processes in patients with AN-RT. PMID- 25500346 TI - Minor physical anomalies are more common in schizophrenia patients with the history of homicide. AB - Minor physical anomalies may be external markers of abnormal brain development, so the more common appearance of these signs in homicidal schizophrenia might suggest the possibility of a more seriously aberrant neurodevelopment in this subgroup. The aim of the present study was to investigate the rate and topological profile of minor physical anomalies in patients with schizophrenia with the history of committed or attempted homicide comparing them to patients with schizophrenia without homicide in their history and to normal control subjects. Using a list of 57 minor physical anomalies, 44 patients with the diagnosis of schizophrenia were examined with the history of committed or attempted homicide, as a comparison 22 patients with the diagnosis of schizophrenia without the history of any kind of homicide and violence and 21 normal control subjects were examined. Minor physical anomalies are more common in homicidal schizophrenia patients compared to non-homicidal schizophrenia patients and normal controls, which could support a stronger neurodevelopmental component of etiology in this subgroup of schizophrenia. The higher rate of minor physical anomalies found predominantly in the head and mouth regions in homicidal schizophrenia patients might suggest the possibility of a more seriously aberrant brain development in the case of homicidal schizophrenia. PMID- 25500347 TI - Factors related to the cortisol awakening response of children working on the streets and siblings, before and after 2 years of a psychosocial intervention. AB - The study objective was to observe the cortisol awakening response (CAR) pattern before and after a psychosocial intervention with children from dysfunctional families who had at least one child working on the streets, and to verify factors related to it. Two hundred and eleven children between 7 and 14 years old were selected and 191 were included, 178 were re-evaluated 2 years after, of whom 113 had cortisol measures completed. Besides cortisol, they were evaluated at baseline and at end point regarding: abuse/neglect, mental health symptoms, exposure to urban violence and family environment. There was no significant difference between the CAR area under the curve (AUC) before and after the intervention. Two regression analysis models were built to evaluate factors related to the CAR before and after intervention. Before the intervention, working on the streets (vs. not) was related to a greater cortisol increase after awakening, at follow-up, having suffered physical punishment (vs. not) was related to a flattened cortisol response. The intervention was not associated with changes in the magnitude of the CAR AUC, though the CAR was associated with psychosocial stressors pre- and post-intervention. Effective interventions for children at risk that might shape a physiological cortisol response are still needed. PMID- 25500349 TI - Mortality of firesetters: a follow-up study of Finnish male firesetters who underwent a pretrial forensic examination in 1973-1998. AB - Little is known about mortality among firesetters. However, they hold many risk factors associated with elevated mortality. This study aimed to investigate mortality rates and patterns in the course of a 39-year follow-up of a consecutive sample (n=441) of pretrial male firesetters evaluated in a forensic psychiatric unit in Finland. For each firesetter, four controls matched for age, sex and place of birth were randomly selected from the Central Population Register. Mortality data was obtained from the Causes of Death statistics. By the end of the follow-up period, 48.0% of the firesetters and 22.0% of the controls had died (OR 2.47, 95% CI 2.00-3.05). Altogether, 24.1% of the firesetters and 17.6% of the control subjects had died of natural causes (OR 1.49, 95% CI 1.16 1.92), whereas 20.9% and 3.8% respectively, died an unnatural death (OR 6.71, 95% CI 4.79-9.40). Alcohol-related deaths were more frequent among firesetters than controls. Our findings confirm that fire-setting behavior is associated with high mortality. More attention must be paid to the treatment of suicidality, psychiatric comorbidities and alcohol use disorders within this group both during and after their sentences. PMID- 25500348 TI - Living with tics: reduced impairment and improved quality of life for youth with chronic tic disorders. AB - Pharmacological and behavioral interventions have focused on reducing tic severity to alleviate tic-related impairment for youth with chronic tic disorders (CTDs), with no existing intervention focused on the adverse psychosocial consequences of tics. This study examined the preliminary efficacy of a modularized cognitive behavioral intervention ("Living with Tics", LWT) in reducing tic-related impairment and improving quality of life relative to a waitlist control of equal duration. Twenty-four youth (ages 7-17 years) with Tourette Disorder or Chronic Motor Tic Disorder and psychosocial impairment participated. A treatment-blind evaluator conducted all pre- and post-treatment clinician-rated measures. Youth were randomly assigned to receive the LWT intervention (n=12) or a 10-week waitlist (n=12). The LWT intervention consisted of up to 10 weekly sessions targeted at reducing tic-related impairment and developing skills to manage psychosocial consequences of tics. Youth in the LWT condition experienced significantly reduced clinician-rated tic-impairment, and improved child-rated quality of life. Ten youth (83%) in the LWT group were classified as treatment responders compared to four youth in the waitlist condition (33%). Treatment gains were maintained at one-month follow-up. Findings provide preliminary data that the LWT intervention reduces tic-related impairment and improves quality of life for youth with CTDs. PMID- 25500350 TI - Specific vulnerability of face perception to noise: a similar effect in schizophrenia patients and healthy individuals. AB - Face perception plays a foundational role in the social world. This perceptual ability is deficient in schizophrenia. A noise-filtering mechanism is essential for perceptual processing. It remains unclear as to whether a specific noise filtering mechanism is implicated in the face perception problem or a general noise-filtering mechanism is involved which also mediates non-face visual perception problems associated with this psychiatric disorder. This study examined and compared the effects of external noise on the performance of face discrimination and car discrimination in schizophrenia patients (n=25) and healthy controls (n=27). Superimposing the external visual noise on face or car stimuli elevated perceptual thresholds (i.e. degraded performance levels) for both face and car discrimination. However, the effect of noise was significantly larger on face than on car discrimination, both in patients and controls. This pattern of results suggests specific vulnerability of face processing to noise in healthy individuals and those with schizophrenia. PMID- 25500351 TI - [Usefulness of (18)FDG PET-CT scan as a diagnostic tool of fever of unknown origin]. AB - BACKGROUND AND OBJECTIVE: Classic fever of unknown origin (FUO) is defined as the presence of fever greater than 38.3 degrees C of at least 3 weeks with an uncertain diagnosis. Identification of the etiology is crucial in guiding further diagnostic procedures and subsequent patient management. The aim of this study was to evaluate the role of fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography combined with computed tomography (PET/CT) in the diagnostic orientation of FUO. MATERIAL AND METHOD: An observational retrospective study was performed, including 30 consecutive patients who had been studied between March 2010 and September 2013. Twenty-six out of 30 patients (86.67%) had a definitive diagnosis after pathologic confirmation in 15 cases, microbiological findings in one patient and clinical and radiological follow-up in 10 patients (mean: 16.38 months). RESULTS: Among the positive scans, malignancy (n=10), inflammatory (n=8), infectious (n=4) and miscellaneous causes (n=1) were identified. (18)F-FDG PET/CT had a diagnostic accuracy of 90.00%, sensitivity of 88.46% (95% confidence interval [95% CI] 76-101), specificity of 100.00% (95% CI 100-100), positive predictive values of 100.00% (95% CI100-100) and negative predictive value of 57.14% (95% CI 20-91). CONCLUSIONS: (18)F-FDG PET/CT provided useful for the etiologic diagnosis of FUO, with high sensitivity and specificity. (18)F-FDG PET/CT has an incremental morphological and functional value, especially indicating the best biopsy site. PMID- 25500352 TI - [Vitamin D deficiency: one more piece of the puzzle of cardiovascular risk in human immunodeficiency virus-infected patients?]. PMID- 25500353 TI - [Idiopathic perilobular granulomatous mastitis: Diagnostic and therapeutic considerations]. PMID- 25500354 TI - Informed consent for chiropractic care: Comparing patients' perceptions to the legal perspective. AB - PURPOSE: This study explored chiropractic patients' perceptions of exchanging risk information during informed consent and compared them with the legal perspective of the informed consent process. METHODS: Interviews were conducted with 26 participants, recruited from chiropractic clinics. Transcripts were analysed using a constant comparative method of analysis. FINDINGS: Participants experienced informed consent as an on-going process where risk information informed their decisions to receive treatment throughout four distinct stages. In the first stage, information acquired prior to arriving at the clinic for treatment shaped perceptions of risk. In stage two, participants assessed the perceived competence of their practitioners. Participants then signed the consent form and discussed the risks with their practitioners. Finally, they communicated with their practitioners during treatment to ensure their pain threshold was not crossed. CONCLUSION: These findings suggest that chiropractic patients perceive informed consent as a process involving communication with their practitioners, and that it is possible to educate patients about the risks associated with treatment while satisfying the legal requirements of informed consent. PMID- 25500355 TI - Spinal cord metastasis of squamous cell carcinoma of the maxillary sinus. AB - INTRODUCTION: Squamous cell carcinomas arising from the maxillary sinus have been rarely reported. The authors report the original case of a patient with squamous cell carcinoma of this site with an unusual clinical course. CASE REPORT: A woman presented with squamous cell carcinoma of the maxillary sinus that was only diagnosed 6 months after onset of symptoms. At the time of diagnosis, the tumour had spread to the brain via the maxillary nerve and to the skin. The patient was treated by chemotherapy and radiotherapy. Four months after stopping treatment, the patient presented Brown-Sequard syndrome, for which imaging examinations were performed, demonstrating a spinal cord metastasis from her squamous cell carcinoma. DISCUSSION: This case of squamous cell carcinoma presents several unusual features: the maxillary sinus is a rare site of squamous cell carcinoma and progression and distant metastasis have been only exceptionally described in the literature. PMID- 25500357 TI - Lexical retrieval pre- and posttemporal lobe epilepsy surgery in a pediatric sample. AB - PURPOSE: This study aimed to evaluate lexical retrieval, presurgery and postsurgery, among children and adolescents who had undergone temporal lobe resection for intractable epilepsy and to compare outcomes in patients whose surgery involved the left temporal lobe or the right temporal lobe. MATERIALS AND METHODS: A retrospective chart review identified 36 patients from a major pediatric epilepsy treatment center who had undergone temporal lobe resection (21 underwent left temporal lobe resection; 15 underwent right temporal lobe resection) for intractable epilepsy and who had completed neuropsychological testing that included a measure of confrontation naming (Boston Naming Test, BNT) and verbal fluency (Delis-Kaplan Executive Function System (D-KEFS) Fluency) prior to and after surgery. Linear mixed effects regression models were used to evaluate presurgery and postsurgery changes and to compare the left temporal lobe resection group with the right temporal lobe resection group. PRINCIPAL RESULTS: Confrontation naming performance declined after left, but not right, temporal lobe resection (p<0.05). This effect was not documented for verbal fluency. MAJOR CONCLUSIONS: Left temporal lobe resection for intractable epilepsy is associated with a decline in lexical retrieval. The risk of decline in specific language functions following surgery involving the left temporal lobe should be incorporated in the counseling of patients and families in decision-making with regard to surgery. PMID- 25500356 TI - Lessons learned from counting molecules: how to lure CENP-A into the kinetochore. PMID- 25500358 TI - 'These nodding people': Experiences of having a child with nodding syndrome in postconflict Northern Uganda. AB - BACKGROUND: Nodding syndrome, an epidemic epileptic encephalopathy of unknown etiology, has affected an estimated 1834 children in Northern Uganda. Children are being treated symptomatically but inconsistently with antiepileptic drugs. DESIGN: Ten semistructured interviews with caregivers of affected children and five focus group discussions with 23 relatives, teachers, and religious leaders were conducted to examine the experiences of affected families and communities in Kitgum and Pader districts. The researcher also did participant observation during MoH outreach clinics. Data collection was carried out from July to September 2012, and data were analyzed through inductive thematic analysis. RESULTS: Nodding syndrome severely affects the children's ability to participate in daily life activities. Daily seizures and physical features such as salivating and stunting make them unable to pass as normal, and mood changes make it difficult for some to interact with others. Caregivers of children with nodding syndrome feel confined to their homes, and economic activities are reduced, which affects entire families, especially the education of healthy siblings. The familial clustering and the unknown etiology made many separate from the affected children when eating, sleeping, and having seizures because of a fear of transmission through saliva. Families struggle to provide care with minimal resources and have experienced a reduction in visitors since their children were affected by nodding syndrome. There were signs of apathy in patterns of care, and, generally, parents felt that antiepileptic medicine had brought only slight improvement in their child's condition because many had begun treatment when developmental milestones had already been lost. CONCLUSIONS: A consistent supply of antiepileptic medication is likely to reduce the stigma and fear of transmission, as the affected children's acceptance among others was greatly compromised whenever they had seizures. The loss and suffering involved with nodding syndrome are seen as a continuation of the confinement and trauma once caused by war, and a good regimen of medication is not the whole answer. PMID- 25500359 TI - Incipient preoperative reorganization processes of verbal memory functions in patients with left temporal lobe epilepsy. AB - We previously reported nonlinear correlations between verbal episodic memory performance and BOLD signal in memory fMRI in healthy subjects. The purpose of the present study was to examine this observation in patients with left mesial temporal lobe epilepsy (mTLE) who often experience memory decline and need reliable prediction tools before epilepsy surgery with hippocampectomy. Fifteen patients with left mTLE (18-57years, nine females) underwent a verbal memory fMRI paradigm. Correlations between BOLD activity and neuropsychological data were calculated for the i) hippocampus (HC) as well as ii) extrahippocampal mTL structures. Memory performance was systematically associated with activations within the right HC as well as with activations within the left extrahippocampal mTL regions (amygdala and parahippocampal gyrus). As hypothesized, the analyses revealed cubic relationships, with one peak in patients with marginal memory performance and another peak in patients with very good performance. The nonlinear correlations between memory performance and activations might reflect the compensatory recruitment of neural resources to maintain memory performance in patients with ongoing memory deterioration. The present data suggest an already incipient preoperative reorganization process of verbal memory in non amnesic patients with left mTLE by simultaneously tapping the resources of the right HC and left extrahippocampal mTL regions. Thus, in the preoperative assessment, both neuropsychological performance and memory fMRI should be considered together. PMID- 25500360 TI - An educational campaign about epilepsy among Italian primary school teachers. 2. The results of a focused training program. AB - A cohort of 582 Italian primary school teachers underwent a questionnaire survey to test their knowledge and attitudes toward epilepsy and verify whether an intensive and focused educational program could result in improvement of knowledge and attitudes. The program consisted of a presentation of the clinical manifestations of epilepsy and the distribution of informative brochures and an educational kit on the disease and its management to be used with their students. After several months, 317 teachers were retested using the same questions. Upon retest, the number of "don't know" answers decreased significantly for almost all questions. This was not the case for negative attitudes. The same holds true for teachers believing that epilepsy is a source of learning disability and social disadvantage. These findings support the beliefs that education on epilepsy is more likely to affect ignorance than prejudice and that stronger interventions are needed to counteract stigmatizing behaviors. PMID- 25500362 TI - Single-center study under a French Temporary Authorization for Use (TAU) protocol for ipilimumab in metastatic melanoma: negative impact of baseline corticosteroids. AB - Ipilimumab is an anti-CTLA-4 antibody which has recently been approved in Europe as a monotherapy in the treatment of metastatic melanoma. We report a single center study among patients treated within a Temporary Authorization for Use (TAU) protocol. We also performed a review of the literature involving expanded access program studies with a focus on factors associated with overall survival (OS). PATIENTS AND METHODS: This retrospective, observational study included patients between June 2010 and July 2011 with a diagnosis of non-resectable stage III or IV melanoma with at least one previous line of chemotherapy. Treatment consisted of four courses of ipilimumab at a dose of 3mg/kg every three weeks. RESULTS: 45 patients were included, among whom 23 (51%) had brain metastases. 33 (71%) of the patients completed the induction phase. The best overall response rate (BORR) was 13% and median overall survival (OS) was 8 months (95%CI: 7 to 12). OS was not different between patients with brain metastases at baseline and those without (p = 0.10), regardless of BRAF V600E status (p = 0.61). OS was poorer in patients who were being treated with corticoids at baseline (p<0.001) or with LDH at baseline > 500 UI/ml (p = 0.008). CONCLUSION: A subset of patients most likely to benefit from ipilimumab should be defined. In our series we found a negative association of baseline corticosteroids with OS. Unlike high LDH levels, BRAF V600 E status and brain metastases should not be barriers to the initiation of treatment. PMID- 25500363 TI - Comparative analysis reveals loss of the appetite-regulating peptide hormone ghrelin in falcons. AB - Ghrelin and leptin are key peripherally secreted appetite-regulating hormones in vertebrates. Here we consider the ghrelin gene (GHRL) of birds (class Aves), where it has been reported that ghrelin inhibits rather than augments feeding. Thirty-one bird species were compared, revealing that most species harbour a functional copy of GHRL and the coding region for its derived peptides ghrelin and obestatin. We provide evidence for loss of GHRL in saker and peregrine falcons, and this is likely to result from the insertion of an ERVK retrotransposon in intron 0. We hypothesise that the loss of anorexigenic ghrelin is a predatory adaptation that results in increased food-seeking behaviour and feeding in falcons. PMID- 25500361 TI - Predictors of outpatient kidney function recovery among patients who initiate hemodialysis in the hospital. AB - BACKGROUND: Recent policy clarifications by the Centers for Medicare & Medicaid Services have changed access to outpatient dialysis care at end-stage renal disease (ESRD) facilities for individuals with acute kidney injury in the United States. Tools to predict "ESRD" and "acute" status in terms of kidney function recovery among patients who previously initiated dialysis therapy in the hospital could help inform patient management decisions. STUDY DESIGN: Historical cohort study. SETTING & PARTICIPANTS: Incident hemodialysis patients in the Mayo Clinic Health System who initiated in-hospital renal replacement therapy (RRT) and continued outpatient dialysis following hospital dismissal (2006 through 2009). PREDICTOR: Baseline estimated glomerular filtration rate (eGFR), acute tubular necrosis from sepsis or surgery, heart failure, intensive care unit, and dialysis access. OUTCOMES: Kidney function recovery defined as sufficient kidney function for outpatient hemodialysis therapy discontinuation. RESULTS: Cohort consisted of 281 patients with a mean age of 64 years, 63% men, 45% with heart failure, and baseline eGFR>=30mL/min/1.73m(2) in 46%. During a median of 8 months, 52 (19%) recovered, most (94%) within 6 months. Higher baseline eGFR (HR per 10 mL/min/1.73m(2) increase eGFR, 1.27; 95% CI, 1.16-1.39; P<0.001), acute tubular necrosis from sepsis or surgery (HR, 3.34; 95% CI, 1.83-6.24; P<0.001), and heart failure (HR, 0.40; 95% CI, 0.19-0.78, P=0.007) were independent predictors of recovery within 6 months, whereas first RRT in the intensive care unit and catheter dialysis access were not. There was a positive interaction between absence of heart failure and eGFR>=30mL/min/1.73m(2) for predicting kidney function recovery (P<0.001). LIMITATIONS: Sample size. CONCLUSIONS: Kidney function recovery in the outpatient hemodialysis unit following in-hospital RRT initiation is not rare. As expected, higher baseline eGFR is an important determinant of recovery. However, patients with heart failure are less likely to recover even with a higher baseline eGFR. Consideration of these factors at hospital discharge informs decisions on ESRD status designation and long-term hemodialysis care. PMID- 25500364 TI - Statin use not associated with improved outcomes in patients treated with brachytherapy for prostate cancer. AB - PURPOSE: To investigate the association between statin use and prostate cancer outcomes in intermediate- and high-risk patients treated with brachytherapy for prostate cancer. METHODS AND MATERIALS: Between 1998 and 2010, 754 men with National Comprehensive Cancer Network intermediate- (n = 627) and high-risk (n = 127) prostate cancer were treated with prostate brachytherapy at our institution. Patients received either low-dose-rate or high-dose-rate brachytherapy as monotherapy or in combination with supplemental external beam radiotherapy. Two hundred eighty-five patients (37.8%) also received androgen-deprivation therapy. Two hundred seventy-three men (36.2%) were identified as taking statin medication before initiating radiation therapy. Prostate-specific antigen relapse-free survival (PSA-RFS), distant metastasis-free survival (DMFS), and overall survival were compared using log-rank tests. Associations of patient and treatment characteristics with outcomes were analyzed with univariate and multivariate regression. The median followup was 48 months. RESULTS: The 8-year PSA-RFS for intermediate-risk, high-risk, and all patients was 92.2%, 64.1%, and 87.7%, respectively. The 8-year DMFS was 97.1%, 82.9%, and 94.9%, respectively. The 8 year overall survival for the entire cohort was 86.6%. There were no significant differences between statin users and nonusers when stratified by risk group, nor when analyzed as a full cohort. On multivariate analysis, Gleason score 4 + 3 = 7 and >7 were significantly associated with worse PSA-RFS (p <= 0.003 and <0.001, respectively). Gleason score > 7 (p = 0.008) and the use of neoadjuvant androgen deprivation therapy (p = 0.03) was associated with worse DMFS. Statin use did not significantly impact PSA-RFS or DMFS. CONCLUSIONS: Pretreatment statin use is not associated with improved outcomes in intermediate- and high-risk patients undergoing prostate brachytherapy-based regimens for prostate cancer. PMID- 25500365 TI - Reproductive toxicology. PMID- 25500366 TI - Aging and dyslipidemia: a review of potential mechanisms. AB - Elderly adults constitute a rapidly growing part of the global population, thus resulting in an increase in morbidity and mortality related to cardiovascular disease (CVD), which remains the major cause of death in elderly population, including men and women. Dyslipidemia is a well-established risk factor for CVD and is estimated to account for more than half of the worldwide cases of coronary artery disease (CAD). Many studies have shown a strong correlation between serum cholesterol levels and risk of developing CAD. In this paper, we review the changes of plasma lipids that occur in men and women during aging and the potential mechanisms of age-related disorders of lipoprotein metabolism covering humans and/or animals, in which changes of the liver sinusoidal endothelium, postprandial lipemia, insulin resistance induced by free fatty acid (FFA), growth hormone (GH), androgen (only for men) and expression and activity of peroxisome proliferator-activated receptor alpha (PPARalpha) are mainly focused. PMID- 25500367 TI - Human RORgammat(+)CD34(+) cells are lineage-specified progenitors of group 3 RORgammat(+) innate lymphoid cells. AB - Group 3 innate lymphoid cells (ILC3s) are defined by the expression of the transcription factor RORgammat, which is selectively required for their development. The lineage-specified progenitors of ILC3s and their site of development after birth remain undefined. Here we identified a population of human CD34(+) hematopoietic progenitor cells (HPCs) that express RORgammat and share a distinct transcriptional signature with ILC3s. RORgammat(+)CD34(+) HPCs were located in tonsils and intestinal lamina propria (LP) and selectively differentiated toward ILC3s. In contrast, RORgammat(-)CD34(+) HPCs could differentiate to become either ILC3s or natural killer (NK) cells, with differentiation toward ILC3 lineage determined by stem cell factor (SCF) and aryl hydrocarbon receptor (AhR) signaling. Thus, we demonstrate that in humans RORgammat(+)CD34(+) cells are lineage-specified progenitors of IL-22(+) ILC3s and propose that tonsils and intestinal LP, which are enriched both in committed precursors and mature ILC3s, might represent preferential sites of ILC3 lineage differentiation. PMID- 25500369 TI - Relationship between obesity and sex, and prevalence of asthma-like disease and current wheeze in Han children in Nanjing, China. AB - OBJECTIVE: To investigate the relationships between body mass index (BMI) and sex, and asthma-like disease and current wheeze in Han children in Nanjing, China. METHODS: Han children aged 3-14 years were recruited. Height and weight were measured; individuals were classified into obesity, thinness and normal weight groups on the basis of the calculated BMI. Questionnaires were used to measure prevalence of asthma-like disease and current wheeze. Results were evaluated using the chi(2)-test, odds ratios with 95% confidence intervals and multivariate logistic regression analyses. RESULTS: In total 12 092 children (6,331 boys and 5,761 girls) were included. Rates of normal weight, obesity and thinness were 8915/12 092 (73.73%), 1479/12 092 (12.23%) and 1698/12 092 (14.04%), respectively. Asthma-like disease and current wheeze were reported in 2051/12 092 (16.96%) and 400/12 092 (3.31%), respectively. An increased BMI was associated with a greater risk of asthma-like disease; this relationship was strongest in girls. Current wheeze was associated positively with obesity and negatively with thinness, but only among boys. Boys had a greater risk of asthma like disease and current wheeze than girls. CONCLUSIONS: BMI and sex were associated independently with the prevalence of asthma-like disease and current wheeze in Han Chinese children. PMID- 25500368 TI - Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways. AB - Nonresolving inflammation expands a heterogeneous population of myeloid suppressor cells capable of inhibiting T cell function. This heterogeneity has confounded the functional dissection of individual myeloid subpopulations and presents an obstacle for antitumor immunity and immunotherapy. Using genetic manipulation of cell death pathways, we found the monocytic suppressor-cell subset, but not the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-independent cell death. Development of the granulocyte subset requires MCL-1-mediated control of the intrinsic mitochondrial death pathway. Monocytic suppressors tolerate the absence of MCL-1 provided cytokines increase expression of the MCL-1-related protein A1. Monocytic suppressors mediate T cell suppression, whereas their granulocytic counterparts lack suppressive function. The loss of the granulocytic subset via conditional MCL-1 deletion did not alter tumor incidence implicating the monocytic compartment as the functionally immunosuppressive subset in vivo. Thus, death pathway modulation defines the development, survival, and function of myeloid suppressor cells. PMID- 25500370 TI - Prediabetes, elevated iron and all-cause mortality: a cohort study. AB - OBJECTIVES: Data have indicated low to non-existent increased mortality risk for individuals with prediabetes, but it is unclear if the risk is increased when the patient has elevated iron markers. Our purpose was to examine the mortality risk among adults with prediabetes in the context of coexisting elevated transferrin saturation (TS) or serum ferritin. SETTING: Data collected by the third National Health and Nutrition Examination Survey 1988-1994 (NHANES III) in the USA and by the National Center for Health Statistics for the National Death Index from 1988 to 2006. PARTICIPANTS: Individuals age 40 and older who participated in the NHANES and provided a blood sample. PRIMARY OUTCOME VARIABLE: Mortality was measured as all-cause mortality. RESULTS: Adjusted analyses show that prediabetes has a small increased mortality risk (HR=1.04; 95% CI 1.00 to 1.08). Persons who had prediabetes and elevated serum ferritin had an increased HR for death (HR=1.14; 95% CI 1.04 to 1.24) compared with those who had normal ferritin and normal glucose. Among persons with prediabetes who had elevated TS, they had an increased mortality risk (HR=1.88; 95% CI 1.06 to 3.30) compared with those with normal TS levels and normal glucose. CONCLUSIONS: The mortality risk of prediabetes is low. However, among individuals who have coexisting elevated iron markers, particularly TS, the risk rises substantially. PMID- 25500371 TI - "A little on the heavy side": a qualitative analysis of parents' and grandparents' perceptions of preschoolers' body weights. AB - OBJECTIVES: Parents' difficulties in perceiving children's weight status accurately pose a barrier for family-based obesity interventions; however, the factors underlying weight misinterpretation still need to be identified. This study's objective was to examine parents and grandparents' perceptions of preschoolers' body sizes. Interview questions also explored perceptions of parental responsibility for childhood obesity and appropriate contexts in which to discuss preschoolers' weights. DESIGN: Semistructured interviews, which were videotaped, transcribed and analysed qualitatively. SETTING: Eugene and the Springfield metropolitan area, Oregon, USA PARTICIPANTS: Families of children aged 3-5 years were recruited in February-May 2011 through advertisements about the study, published in the job seekers' sections of a classified website (Craigslist) and in a local newspaper. 49 participants (22 parents and 27 grandparents, 70% women, 60% with overweight/obesity) from 16 low-income families of children aged 3-5 years (50% girls, 56% with overweight/obesity) were interviewed. RESULTS: There are important gaps between clinical definitions and lay perceptions of childhood obesity. While parents and grandparents were aware of their preschoolers' growth chart percentiles, these measures did not translate into recognition of children's overweight or obesity. The participants spoke of obesity as a problem that may affect the children in the future, but not at present. Participants identified childhood obesity as being transmitted from one generation to the next, and stigmatised it as resulting from 'lazy' parenting. Parents and grandparents avoided discussing the children's weights with each other and with the children themselves. CONCLUSIONS: The results suggest that clinicians should clearly communicate with parents and grandparents about the meaning and appearance of obesity in early childhood, as well as counteract the social stigma attached to obesity, in order to improve the effectiveness of family-based interventions to manage obesity in early childhood. PMID- 25500372 TI - Effects of dietary sodium and the DASH diet on the occurrence of headaches: results from randomised multicentre DASH-Sodium clinical trial. AB - OBJECTIVES: Headaches are a common medical problem, yet few studies, particularly trials, have evaluated therapies that might prevent or control headaches. We, thus, investigated the effects on the occurrence of headaches of three levels of dietary sodium intake and two diet patterns (the Dietary Approaches to Stop Hypertension (DASH) diet (rich in fruits, vegetables and low-fat dairy products with reduced saturated and total fat) and a control diet (typical of Western consumption patterns)). DESIGN: Randomised multicentre clinical trial. SETTING: Post hoc analyses of the DASH-Sodium trial in the USA. PARTICIPANTS: In a multicentre feeding study with three 30 day periods, 390 participants were randomised to the DASH or control diet. On their assigned diet, participants ate food with high sodium during one period, intermediate sodium during another period and low sodium during another period, in random order. OUTCOME MEASURES: Occurrence and severity of headache were ascertained from self-administered questionnaires, completed at the end of each feeding period. RESULTS: The occurrence of headaches was similar in DASH versus control, at high (OR (95% CI)=0.65 (0.37 to 1.12); p=0.12), intermediate (0.57 (0.29 to 1.12); p=0.10) and low (0.64 (0.36 to 1.13); p=0.12) sodium levels. By contrast, there was a lower risk of headache on the low, compared with high, sodium level, both on the control (0.69 (0.49 to 0.99); p=0.05) and DASH (0.69 (0.49 to 0.98); p=0.04) diets. CONCLUSIONS: A reduced sodium intake was associated with a significantly lower risk of headache, while dietary patterns had no effect on the risk of headaches in adults. Reduced dietary sodium intake offers a novel approach to prevent headaches. TRIAL REGISTRATION NUMBER: NCT00000608. PMID- 25500375 TI - Bacterial community dynamics in a swine wastewater anaerobic reactor revealed by 16S rDNA sequence analysis. AB - Anaerobic digestion is a microbiological process of converting organic wastes into digestate and biogas in the absence of oxygen. In practice, disturbance to the system (e.g., organic shock loading) may cause imbalance of the microbial community and lead to digester failure. To examine the bacterial community dynamics after a disturbance, this study simulated an organic shock loading that doubled the chemical oxygen demand (COD) loading using a 4.5L swine wastewater anaerobic completely stirred tank reactor (CSTR). Before the shock (loading rate=0.65gCOD/L/day), biogas production rate was about 1-2L/L/day. After the shock, three periods representing increased biogas production rates were observed during days 1-7 (~4.0L/L/day), 13 (3.3L/L/day), and 21-23 (~6.1L/L/day). For culture-independent assessments of the bacterial community composition, the 454 pyrosequencing results indicated that the community contained >2500 operational taxonomic units (OTUs) and was dominated by three phyla: Bacteroidetes, Firmicutes, and Proteobacteria. The shock induced dynamic changes in the community composition, which was re-stabilized after approximately threefold hydraulic retention time (HRT). Intriguingly, upon restabilization, the community composition became similar to that observed before the shock, rather than reaching a new equilibrium. PMID- 25500374 TI - Envelope protein complexes of Mycobacterium avium subsp. paratuberculosis and their antigenicity. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne's disease, a chronic enteric disease of ruminant animals. In the present study, blue native PAGE electrophoresis and 2D SDS-PAGE were used to separate MAP envelope protein complexes, followed by mass spectrometry (MS) to identify individual proteins within the complexes. Identity of individual proteins within complexes was further confirmed by MS upon excision of spots from 2D SDS-PAGE gels. Among the seven putative membrane complexes observed, major membrane protein (MAP2121c), a key MAP antigen involved in invasion of epithelial cells, was found to form a complex with cysteine desulfurase (MAP2120c). Other complexes found included those involved in energy metabolism (succinate dehydrogenase complex) as well as a complex formed by Cfp29, a characterized T cell antigen of Mycobacterium tuberculosis. To determine antigenicity of proteins, Western blot was performed on replicate 2D SDS-PAGE gels with sera from noninfected control cows (n=9) and naturally infected cows in the subclinical (n=10) and clinical (n=13) stages of infection. Clinical animals recognized MAP2121c in greater proportion than subclinical and control cows, whereas cysteine desulfurase recognition was not differentiated by infection status. To further characterize antigenicity, recombinant proteins were expressed for 10 of the proteins identified and evaluated in an interferon-gamma (IFN-gamma) release assay as well as immunoblots. This study reveals the presence of protein complexes in the cell envelope of MAP, suggesting protein interactions in the envelope of this pathogen. Furthermore the identification of antigenic proteins with potential as diagnostic targets was characterized. PMID- 25500376 TI - Segmental origins of cardiac sympathetic nerve activity in rats. AB - The segmental origins of cardiac sympathetic nerve activity (CSNA) were investigated in 8 urethane-anesthetized, artificially ventilated rats. The left upper thoracic sympathetic chain was exposed retropleurally after removing the heads of the second to fourth ribs. The preganglionic inputs to the chain from segments T1-T3 and the trunk distal to T3 were marked for later sectioning. CSNA was recorded conventionally, amplified, rectified and smoothed. Its mean level was quantified before and after each preganglionic input was cut, usually in rostro-caudal sequence. The level after all inputs were cut (i.e. noise and residual ECG pickup) was subtracted from previous measurements. The signal decrement from cutting each preganglionic input was then calculated as a percentage. CSNA in all rats depended on preganglionic drive from two or more segments, which were not always contiguous. Over the population, most preganglionic drive came from T3 and below, while the least came from T1. But there was striking inter-individual variation, such that the strongest drive to CSNA in any one rat could come from T1, T2, T3, or below T3. These findings provide new functional data on the segmental origins of CSNA in rats. PMID- 25500377 TI - Can't stop growing! PMID- 25500378 TI - The complete mitochondrial genome sequence of the network pipefish (Corythoichthys flavofasciatus) and the analyses of phylogenetic relationships within the Syngnathidae species. AB - This study determined the mitochondrial genome sequence of the network pipefish (Corythoichthys flavofasciatus) (Gasterosteiformes: Syngnathidae). The mitogenome was a circular molecule consisting of 16,961 nucleotides, including 13 protein coding genes, 22 tRNA genes, two rRNA genes and a control region. The nucleotide composition of the genome was biased toward A+T content at 59.3%. All tRNA genes had typical cloverleaf secondary structure except for tRNA(Ser (AGY)), in which the dihydrouridine arm was missing. The C. flavofasciatus control region of 1130 bp contained several features common to other teleost, including conserved sequence blocks. We also performed comparative analysis of the network pipefish mitogenome to the available mitogenome sequences of other Syngnathidae species, and phylogenetic relationship of the Syngnathidae species was constructed based on the data sets including all the concatenated nucleotide sequences of the mitogenomes except the third codon positions. Partitioned Bayesian inference and maximum likelihood analyses showed that all seahorse species formed a monophyletic group of Hippocampus with 100% PPs and BPs, but the pipefish species did not form a monophyletic group. Corythoichthys flavofasciatus was placed as a sister relationship to the Hippocampus clade by strong node-supporting values. The availability of mitogenome of the network pipefish will shed light on the molecular systematics, biogeography and genetic differentiation in this species. PMID- 25500379 TI - Preface. Predictive modelling in food. PMID- 25500380 TI - Highlights from the 8th International Conference on Predictive Modelling in Food (ICPMF8). PMID- 25500381 TI - Bacterial economics: adaptation to stress conditions via stage-wise changes in the response mechanism. AB - Common features of microbial adaptation are analysed with mathematical models and extended to stress conditions when the bacterial population declines before growing again. A parallel is drawn between bacterial and human communities in terms of non-mutation-based adaptation (acclimation) to stress. For a case study, the behaviour of Escherichia coli under osmotic stress, is detailed. It is suggested that stress modelling adaptation should be the focus of further developments in predictive food microbiology. PMID- 25500383 TI - An individual-based modeling approach to simulate the effects of cellular nutrient competition on Escherichia coli K-12 MG1655 colony behavior and interactions in aerobic structured food systems. AB - Traditional kinetic models in predictive microbiology reliably predict macroscopic dynamics of planktonically-growing cell cultures in homogeneous liquid food systems. However, most food products have a semi-solid structure, where microorganisms grow locally in colonies. Individual colony cells exhibit strongly different and non-normally distributed behavior due to local nutrient competition. As a result, traditional models considering average population behavior in a homogeneous system do not describe colony dynamics in full detail. To incorporate local resource competition and individual cell differences, an individual-based modeling approach has been applied to Escherichia coli K-12 MG1655 colonies, considering the microbial cell as modeling unit. The first contribution of this individual-based model is to describe single colony growth under nutrient-deprived conditions. More specifically, the linear and stationary phase in the evolution of the colony radius, the evolution from a disk-like to branching morphology, and the emergence of a starvation zone in the colony center are simulated and compared to available experimental data. These phenomena occur earlier at more severe nutrient depletion conditions, i.e., at lower nutrient diffusivity and initial nutrient concentration in the medium. Furthermore, intercolony interactions have been simulated. Higher inoculum densities lead to stronger intercolony interactions, such as colony merging and smaller colony sizes, due to nutrient competition. This individual-based model contributes to the elucidation of characteristic experimentally observed colony behavior from mechanistic information about cellular physiology and interactions. PMID- 25500382 TI - Biofilm-associated persistence of food-borne pathogens. AB - Microbial life abounds on surfaces in both natural and industrial environments, one of which is the food industry. A solid substrate, water and some nutrients are sufficient to allow the construction of a microbial fortress, a so-called biofilm. Survival strategies developed by these surface-associated ecosystems are beginning to be deciphered in the context of rudimentary laboratory biofilms. Gelatinous organic matrices consisting of complex mixtures of self-produced biopolymers ensure the cohesion of these biological structures and contribute to their resistance and persistence. Moreover, far from being just simple three dimensional assemblies of identical cells, biofilms are composed of heterogeneous sub-populations with distinctive behaviours that contribute to their global ecological success. In the clinical field, biofilm-associated infections (BAI) are known to trigger chronic infections that require dedicated therapies. A similar belief emerging in the food industry, where biofilm tolerance to environmental stresses, including cleaning and disinfection/sanitation, can result in the persistence of bacterial pathogens and the recurrent cross contamination of food products. The present review focuses on the principal mechanisms involved in the formation of biofilms of food-borne pathogens, where biofilm behaviour is driven by its three-dimensional heterogeneity and by species interactions within these biostructures, and we look at some emergent control strategies. PMID- 25500384 TI - Simulation of the rate of transfer of antibiotic resistance between Escherichia coli strains cultured under well controlled environmental conditions. AB - It was demonstrated that the tetracycline resistance plasmid in Escherichia coli resembling K-12 23:06 containing the E. coli plasmid DM0133 could be transferred to tetracycline sensitive E. coli K-12 MG1655 YFP. The sensitive recipient strain has a slight metabolic advantage in continuous fermentation in absence of tetracycline pressure and as a result the numbers of the resistant recipient strain increase during fermentation. In presence of tetracycline pressure the sensitive strain is eliminated, but when it acquires tetracycline resistance the strain has still the same metabolic advantage as its sensitive parent strain in absence of tetracycline. Here a model will be shown that could explain the rate of transformation of a sensitive into a resistant recipient strain and its subsequent growth during continuous fermentation. According to the model the probability of formation of mutants would be much higher at the dilution rate of 0.09 compared to 0.28, whereas the growth of mutants would be much faster at high dilution rate. The growth model shows how the recipient mutants and the donor cells behave in relation to the dilution rate and the number of mutants. Apart from a deterministic model describing the growth rate of both the donor strain and the resistant recipient strain a stochastic model was developed that is particularly useful when low numbers of mutants are formed. PMID- 25500385 TI - Effect of heat shock and recovery temperature on variability of single cell lag time of Cronobacter turicensis. AB - The effect of heat stress and subsequent recovery temperature on the individual cellular lag of Cronobacter turicensis was analysed using optical density measurements. Low numbers of cells were obtained through serial dilution and the time to reach an optical density of 0.035 was determined. Assuming the lag of a single cell follows a shifted Gamma distribution with a fixed shape parameter, the effect of recovery temperature on the individual lag of untreated and sublethally heat treated cells of Cr. turicensis were modelled. It was found that the shift parameter (Tshift) increased asymptotically as the temperature decreased while the logarithm of the scale parameter (theta) decreased linearly with recovery temperature. To test the validity of the model in food, growth of low numbers of untreated and heat treated Cr. turicensis in artificially contaminated infant first milk was measured experimentally and compared with predictions obtained by Monte Carlo simulations. Although the model for untreated cells slightly underestimated the actual growth in first milk at low temperatures, the model for heat treated cells was in agreement with the data derived from the challenge tests and provides a basis for reliable quantitative microbiological risk assessments for Cronobacter spp. in infant milk. PMID- 25500386 TI - Comparison of individual-based modeling and population approaches for prediction of foodborne pathogens growth. AB - Individual-based modeling (IBM) approach combined with the microenvironment modeling of vacuum-packed cold-smoked salmon was more effective to describe the variability of the growth of a few Listeria monocytogenes cells contaminating irradiated salmon slices than the traditional population models. The IBM approach was particularly relevant to predict the absence of growth in 25% (5 among 20) of artificially contaminated cold-smoked salmon samples stored at 8 degrees C. These results confirmed similar observations obtained with smear soft cheese (Ferrier et al., 2013). These two different food models were used to compare the IBM/microscale and population/macroscale modeling approaches in more global exposure and risk assessment frameworks taking into account the variability and/or the uncertainty of the factors influencing the growth of L. monocytogenes. We observed that the traditional population models significantly overestimate exposure and risk estimates in comparison to IBM approach when contamination of foods occurs with a low number of cells (<100 per serving). Moreover, the exposure estimates obtained with the population model were characterized by a great uncertainty. The overestimation was mainly linked to the ability of IBM to predict no growth situations rather than the consideration of microscale environment. On the other hand, when the aim of quantitative risk assessment studies is only to assess the relative impact of changes in control measures affecting the growth of foodborne bacteria, the two modeling approach gave similar results and the simplest population approach was suitable. PMID- 25500387 TI - Individual cell heterogeneity as variability source in population dynamics of microbial inactivation. AB - A statistical modeling approach was applied for describing and evaluating the individual cell heterogeneity as variability source in microbial inactivation. The inactivation data (Nt vs time) of Salmonella enterica serotype Agona, with initial concentration N0 = 10(9) CFU/ml in acidified tryptone soy broth (pH 3.5), were transformed to (N0 - Nt)/N0 vs time leading to the cumulative probability distribution of the individual cell inactivation times (ti), which was further fitted to a variety of continuous distributions using @Risk software. The best fitted ti distribution (Gamma) was used to predict the inactivation of S. Agona populations of various N0 using Monte Carlo simulation, with the number of iterations in each simulation being equal to N0 and the number of simulations representing the variability of the population inactivation behavior. The Monte Carlo simulation results for a population with N0 = 10,000 CFU/ml showed that the variability in the predicted inactivation behavior is negligible for concentrations down to 100 cells. As the concentration decreases below 100 cells, however, the variability increases significantly. The results also indicated that the D-value used in deterministic first order kinetic models is valid only for large populations. For small populations, D-value shows a high variability, originating from individual cell heterogeneity, and, thus, can be better characterized by a probability distribution rather than a uniform value. Validation experiments with small populations confirmed the variability predicted by the statistical model. The use of the proposed approach to quantify the variability in the inactivation of mixed microbial populations, consisting of subpopulations with different probability distributions of ti, was also demonstrated. PMID- 25500388 TI - Variability in growth/no growth boundaries of 188 different Escherichia coli strains reveals that approximately 75% have a higher growth probability under low pH conditions than E. coli O157:H7 strain ATCC 43888. AB - This study investigated the variation in growth/no growth boundaries of 188 Escherichia coli strains. Experiments were conducted in Luria-Bertani media under 36 combinations of lactic acid (LA) (0 and 25 mM), pH (3.8, 3.9, 4.0, 4.1, 4.2 and 4.3 for 0 mM LA and 4.3, 4.4, 4.5, 4.6, 4.7 and 4.8 for 25 mM LA) and temperature (20, 25 and 30 degrees C). After 3 days of incubation, growth was monitored through optical density measurements. For each strain, a so-called purposeful selection approach was used to fit a logistic regression model that adequately predicted the likelihood for growth. Further, to assess the growth/no growth variability for all the strains at once, a generalized linear mixed model was fitted to the data. Strain was fitted as a fixed factor and replicate as a random blocking factor. E. coli O157:H7 strain ATCC 43888 was used as reference strain allowing a comparison with the other strains. Out of the 188 strains tested, 140 strains (~75%) presented a significantly higher probability of growth under low pH conditions than the O157:H7 strain ATCC 43888, whereas 20 strains (~11%) showed a significantly lower probability of growth under high pH conditions. PMID- 25500389 TI - Investigating boundaries of survival, growth and expression of genes associated with stress and virulence of Listeria monocytogenes in response to acid and osmotic stress. AB - The objective of this study was to correlate the relative transcription of Listeria monocytogenes (strains C5, 6179) stress- (gad2, sigB) and virulence- (prfA) associated genes following habituation at twenty-five pH (4.8, 5.0, 5.2, 5.5, 6.4) and NaCl (2, 4, 6, 8, 10% w/v) combinations at 7 degrees C, with the survival against subsequent exposure to severe acid stress (pH 2.0 at 37 degrees C). Our findings pointed out the inter-strain variation governing growth inhibiting conditions (pH <=5.0 and NaCl >=6%), where C5 was less affected (a reduction of 2.0-3.0 log CFU/mL) than 6179 which was reduced by 4.0-6.0 log CFU/mL at the end of storage. Nevertheless, the higher the habituation at the growth permitting (pH >=5.5; NaCl <=4% w/v) or growth inhibiting conditions, the higher the acquired acid resistance or sensitization, respectively. At day 2, gad2 increased relative transcriptional levels are more related to elevated acid resistance, while at day 6 both gad2 transcriptional levels and upregulation of sigB were correlated to low log reductions and high DpH:2.0-values against severe acid stress. Regarding virulence, the increased transcriptional levels of prfA at day 2 were correlated to adverse pH and NaCl combinations, while prolonged stay in suboptimal conditions as well as exposure to severe acid stress resulted in general activation of the virulence regulator. Such data could definitely contribute in designing safe intervention strategies and additionally integrate omics aspects in quantitative microbial risk assessment. PMID- 25500390 TI - Modeling number of bacteria per food unit in comparison to bacterial concentration in quantitative risk assessment: impact on risk estimates. AB - When developing quantitative risk assessment models, a fundamental consideration for risk assessors is to decide whether to evaluate changes in bacterial levels in terms of concentrations or in terms of bacterial numbers. Although modeling bacteria in terms of integer numbers may be regarded as a more intuitive and rigorous choice, modeling bacterial concentrations is more popular as it is generally less mathematically complex. We tested three different modeling approaches in a simulation study. The first approach considered bacterial concentrations; the second considered the number of bacteria in contaminated units, and the third considered the expected number of bacteria in contaminated units. Simulation results indicate that modeling concentrations tends to overestimate risk compared to modeling the number of bacteria. A sensitivity analysis using a regression tree suggests that processes which include drastic scenarios consisting of combinations of large bacterial inactivation followed by large bacterial growth frequently lead to a >10-fold overestimation of the average risk when modeling concentrations as opposed to bacterial numbers. Alternatively, the approach of modeling the expected number of bacteria in positive units generates results similar to the second method and is easier to use, thus potentially representing a promising compromise. PMID- 25500391 TI - Modeling transfer of Escherichia coli O157:H7 and Listeria monocytogenes during preparation of fresh-cut salads: impact of cutting and shredding practices. AB - Cutting and shredding of leafy vegetables increases the risk of cross contamination in household settings. The distribution of Escherichia coli O157:H7 and Listeria monocytogenes transfer rates (Tr) between cutting knives and lettuce leaves was investigated and a semi-mechanistic model describing the bacterial transfer during consecutive cuts of leafy vegetables was developed. For both pathogens the distribution of log10Trs from lettuce to knife was towards low values. Conversely log10Trs from knife to lettuce ranged from -2.1 to -0.1 for E. coli O157:H7 and -2.0 to 0 for L. monocytogenes, and indicated a more variable phenomenon. Regarding consecutive cuts, a rapid initial transfer was followed by an asymptotic tail at low populations moving to lettuce or residing on knife. E. coli O157:H7 was transferred at slower rates than L. monocytogenes. These trends were sufficiently described by the transfer-model, with RMSE values of 0.426 0.613 and 0.531-0.908 for L. monocytogenes and E. coli O157:H7, respectively. The model showed good performance in validation trials but underestimated bacterial transfer during extrapolation experiments. The results of the study can provide information regarding cross contamination events in a common household. The constructed model could be a useful tool for the risk-assessment during preparation of leafy-green salads. PMID- 25500392 TI - Extending the gamma concept to non-thermal inactivation: a dynamic model to predict the fate of Salmonella during the dried sausages process. AB - The process of dried fermented sausages is recognized to be favourable to the reduction of the Salmonella population. The objective of this study was to develop a model describing the evolution of Salmonella during the fabrication process of dried sausages and to optimize the food formulation to prevent pathogen presence at the end of the process. An experimental design was set to investigate the effects of the fermentation and drying process for several formulations, taking into account the type of starter culture, the sodium chloride concentration, the dextrose and lactose concentration on the Salmonella Typhimurium strain behaviour. A growth-inactivation model based on the gamma concept was then developed to quantify Salmonella behaviour in dynamic process conditions of temperature, pH, lactic acid and water activity. This behaviour was characterized by a first growth step, followed by an inactivation step. The Salmonella fate was well described by the model in terms of population size variation and transition from growth to inactivation. The Salmonella behaviour was influenced by the initial sugar concentration and the starter type but not by sodium chloride content. This model can be a valuable tool to design the food process and formulation to control Salmonella. PMID- 25500393 TI - Development and validation of a stochastic model for potential growth of Listeria monocytogenes in naturally contaminated lightly preserved seafood. AB - A new stochastic model for the simultaneous growth of Listeria monocytogenes and lactic acid bacteria (LAB) was developed and validated on data from naturally contaminated samples of cold-smoked Greenland halibut (CSGH) and cold-smoked salmon (CSS). During industrial processing these samples were added acetic and/or lactic acids. The stochastic model was developed from an existing deterministic model including the effect of 12 environmental parameters and microbial interaction (O. Mejlholm and P. Dalgaard, Food Microbiology, submitted for publication). Observed maximum population density (MPD) values of L. monocytogenes in naturally contaminated samples of CSGH and CSS were accurately predicted by the stochastic model based on measured variability in product characteristics and storage conditions. Results comparable to those from the stochastic model were obtained, when product characteristics of the least and most preserved sample of CSGH and CSS were used as input for the existing deterministic model. For both modelling approaches, it was shown that lag time and the effect of microbial interaction needs to be included to accurately predict MPD values of L. monocytogenes. Addition of organic acids to CSGH and CSS was confirmed as a suitable mitigation strategy against the risk of growth by L. monocytogenes as both types of products were in compliance with the EU regulation on ready-to-eat foods. PMID- 25500394 TI - Software for predictive microbiology and risk assessment: a description and comparison of tools presented at the ICPMF8 Software Fair. AB - The 8th International Conference on Predictive Modelling in Food was held in Paris, France in September 2013. One of the major topics of this conference was the transfer of knowledge and tools between academics and stakeholders of the food sector. During the conference, a "Software Fair" was held to provide information and demonstrations of predictive microbiology and risk assessment software. This article presents an overall description of the 16 software tools demonstrated at the session and provides a comparison based on several criteria such as the modeling approach, the different modules available (e.g. databases, predictors, fitting tools, risk assessment tools), the studied environmental factors (temperature, pH, aw, etc.), the type of media (broth or food) and the number and type of the provided micro-organisms (pathogens and spoilers). The present study is a guide to help users select the software tools which are most suitable to their specific needs, before they test and explore the tool(s) in more depth. PMID- 25500395 TI - Changes are afoot. PMID- 25500396 TI - Respiratory benefits of deep neuromuscular block during laparoscopic surgery in a patient with end-stage lung disease. PMID- 25500397 TI - Perineural vs intravenous administration of dexamethasone: more data are available. PMID- 25500398 TI - Gastrointestinal morbidity as primary outcome measure in studies comparing crystalloid and colloid within a goal-directed therapy. PMID- 25500399 TI - Reliability of the ASA physical status scale in clinical practice: methodological issues. PMID- 25500400 TI - Cardiac output decrease and propofol: what is the mechanism? PMID- 25500401 TI - Playing with fire: debate about propofol-induced hypotension. PMID- 25500402 TI - Airway management strategy for odentogenous abscess. PMID- 25500403 TI - Tracheal intubation in patients with odentogenous abscesses: plans and more plans. PMID- 25500404 TI - End-expiratory occlusion test: please use the appropriate tools! PMID- 25500405 TI - Clinical practice. PMID- 25500406 TI - Hazards of bone cement: for patient and operating theatre personnel. PMID- 25500407 TI - Respiratory stroke volume variation and fluid responsiveness: how applicable is this? PMID- 25500408 TI - Reply from the authors. PMID- 25500411 TI - BJA 2014; An overview. PMID- 25500418 TI - Sociodemographic correlates of fecal immunotesting for colorectal cancer screening. AB - OBJECTIVES: Community fecal immunochemical testing (FIT) screening programs are important for detecting early disease and can be effective when promoted by primary care physicians. Screening rates remain low across Canada and may be associated with sociodemographic factors. DESIGN AND METHODS: Fecal immunochemical testing results for a new community-based screening program were obtained from Calgary Laboratory Services from November 18, 2013 to May 31, 2014. Screening rates were determined for specific age and sex cohorts and sociodemographic factors were inferred from census Canada data. Poisson regression and generalized estimating equations were used to test associations of screening rate with sociodemographic variables. RESULTS: A total of 27,572 results were screened and included in our analysis. Recent immigrants (RR = 0.18, P = <.0001), Aboriginal First Nations (RR = 0.39, P = 0.01), Aboriginal Metis (RR = 0.14, P = 0.0003), visible minority Black (RR = 0.35, P = 0.0002), and higher education (RR = 0.65, P = <.0001) were associated with decreased screening. Visible minority Chinese (RR = 1.72, P = <.0001) were more likely to be screened. Household income was not associated with screening rate. Older individuals and females were less likely to be screened. CONCLUSION: There is significant geographic variation in screening rates in Calgary. These are associated with a number of sociodemographic factors. PMID- 25500419 TI - Simultaneous and cost-effective determination of ethylene glycol and glycolic acid in human serum and urine for emergency toxicology by GC-MS. AB - OBJECTIVES: A simple, cost-effective, and fast gas chromatography method with mass spectrometry detection (GC-MS) for simultaneous measurement of ethylene glycol, 1,2-propylene glycol and glycolic acid was developed and validated for clinical toxicology purposes. DESIGN AND METHODS: Successful derivatization of glycolic acid with isobutyl chloroformate was achieved directly in serum/urine while glycols are simultaneously derivatized by phenylboronic acid. The entire sample preparation procedure is completed within 10 min. RESULTS: The assay was proved to be quadratic in the range of 50 to 5000 mgL(-1) with adequate accuracy (96.3-105.8%) and precision (CV <= 8.9%). CONCLUSION: The method was successfully applied to quantify the selected compounds in serum of patients from emergency units and the results correlated well with parallel GC-FID measurements (R(2) 0.9933 for ethylene glycol and 0.9943 for glycolic acid). PMID- 25500420 TI - Biochemical and pharmacological characterization of a toxic fraction and its cytotoxin-like component isolated from Russell's viper (Daboia russelii russelii) venom. AB - The pathophysiological significance of a toxic fraction (GF-VI DEAE-II) isolated from Russell's viper venom (RVV) is characterized. GF-VI DEAE-II represents 1.6% of the total RVV protein and it comprises of a 27.6kDa minor component (RP-I) (0.04%, w/w) and a major 6.6kDa non-enzymatic peptide (1.11%, w/w), named Rusvitoxin. The LC-MS/MS analysis of RP-I showed its identity to snake venom serine proteases, whereas Rusvitoxin demonstrated its close identity with snake venom three finger toxins, cytotoxins and cardiotoxins particularly from Naja sp. GF-VI DEAE-II was found to be non-cytotoxic to the tested mammalian cancer cells and non-hemolytic; nevertheless, it demonstrated alpha-fibrin(ogen)ase activity and in vivo toxicity in BALB/c mice with an LD50 (i.p.) of 2.3mg/kg. GF-VI DEAE II induced lethargy and hind-leg paralysis in mice within 10min of i.p. injection. GF-VI DEAE-II induced hyperfibrinogenomia, and significantly altered (p<0.05) the plasma levels of factor X, pro- and anti-inflammatory cytokines viz. TNF-alpha, IL-6 and IL-10 in treated mice. Histological observations of tissues and biochemical properties of serum from GF-VI DEAE-II-treated mice suggested multiple organ dysfunctions. Conversely, Rusvitoxin at a dose of 5mg/kg did not induce toxicity in BALB/c mice. At 1:15 (antigen: antivenom, w/w) ratio, commercially polyvalent and monovalent antivenoms neutralized more than 80% of the fibrinolytic and anticoagulant activities of GF-VI DEAE-II. The present study suggests the significant role of GF-VI DEAE-II in RVV-induced pathogenesis in victim/prey. PMID- 25500421 TI - Acute exposure to waterborne copper inhibits both the excretion and uptake of ammonia in freshwater rainbow trout (Oncorhynchus mykiss). AB - In freshwater fish, exposure to sub-lethal concentrations of waterborne copper (Cu) results in inhibitions of ammonia excretion (Jamm) and Na(+) uptake (J(Na)in), yet the mechanisms by which these occur are not fully understood. In the present study, rainbow trout (Oncorhynchus mykiss) fry exposed to 50MUg/l Cu for 24h displayed a sustained 40% decrease in Jamm and a transient 60% decrease in J(Na)in. Previously, these effects have been attributed to inhibitions of gill Na(+)/K(+)-ATPase and/or carbonic anhydrase (CA) activities by Cu. Trout fry did not display significant reductions in the branchial activities of these enzymes or H(+)-ATPase over 24h Cu exposure. Recently, Rhesus (Rh) glycoproteins, bi directional NH3 gas channels, have been implicated in the mechanism of Cu toxicity. Juvenile trout were exposed to nominal 0, 50, and 200MUg/l Cu for 3-6h under control conditions (ammonia-free water) followed by 6h exposure to high environmental ammonia (HEA; 1.5mmol/l NH4HCO3). HEA led to significant ammonia uptake in control fish (0MUg/l Cu), and exposure to 50 and 200MUg/l Cu resulted in significant reductions of ammonia uptake during HEA exposure. This is the first evidence that Cu inhibits both the excretion and uptake of ammonia, implicating bi-directional Rh glycoproteins as a target for Cu toxicity. We propose a model whereby Rh blockade by Cu causes the sustained inhibition of Jamm and transient inhibition of J(Na)in, with H(+)-ATPase potentially aiding in J(Na)in recovery. More work is needed to elucidate the role of Rh proteins in sub lethal Cu toxicity. PMID- 25500422 TI - Whole-breast irradiation with or without a boost for patients treated with breast conserving surgery for early breast cancer: 20-year follow-up of a randomised phase 3 trial. AB - BACKGROUND: Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results. METHODS: Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT02295033. FINDINGS: Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow up was 17.2 years (IQR 13.0-19.0). 20-year overall survival was 59.7% (99% CI 56.3-63.0) in the boost group versus 61.1% (57.6-64.3) in the no boost group, hazard ratio (HR) 1.05 (99% CI 0.92-1.19, p=0.323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0.65 (99% CI 0.52-0.81, p<0.0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16.4% (99% CI 14.1-18.8) in the no boost group versus 12.0% (9.8 14.4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1.8% (99% CI 1.1-2.5) in the no boost group versus 5.2% (99% CI 3.9-6.4) in the boost group (p<0.0001). INTERPRETATION: A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years. FUNDING: Fonds Cancer, Belgium. PMID- 25500423 TI - Herbal products and the liver: a review of adverse effects and mechanisms. AB - Herbal products have been used for centuries among indigenous people to treat symptoms and illnesses. Recently, their use in Western countries has grown significantly, rivaling that of prescription medications. Currently, herbal products are used mainly for weight loss and bodybuilding purposes but also to improve well-being and symptoms of chronic diseases. Many people believe that because they are natural, they must be effective and safe; however, these beliefs are erroneous. Few herbal products have been studied in well-designed controlled trials of patients with liver or other diseases, despite testimony to the contrary. Moreover, current highly effective antiviral drugs make efforts to treat hepatitis C with herbal products redundant. Herbal products are no safer than conventional drugs and have caused liver injury severe enough to require transplantation or cause death. Furthermore, their efficacy, safety, and claims are not assessed by regulatory agencies, and there is uncertainty about their reported and unreported contents. We review the history of commonly used herbal products, as well as their purported efficacies and mechanisms and their adverse effects. PMID- 25500424 TI - Abdominothoracic mechanisms of functional abdominal distension and correction by biofeedback. AB - BACKGROUND & AIMS: In patients with functional gut disorders, abdominal distension has been associated with descent of the diaphragm and protrusion of the anterior abdominal wall. We investigated mechanisms of abdominal distension in these patients. METHODS: We performed a prospective study of 45 patients (42 women, 24-71 years old) with functional intestinal disorders (27 with irritable bowel syndrome with constipation, 15 with functional bloating, and 3 with irritable bowel syndrome with alternating bowel habits) and discrete episodes of visible abdominal distension. Subjects were assessed by abdominothoracic computed tomography (n = 39) and electromyography (EMG) of the abdominothoracic wall (n = 32) during basal conditions (without abdominal distension) and during episodes of severe abdominal distension. Fifteen patients received a median of 2 sessions (range, 1-3 sessions) of EMG-guided, respiratory-targeted biofeedback treatment; 11 received 1 control session before treatment. RESULTS: Episodes of abdominal distension were associated with diaphragm contraction (19% +/- 3% increase in EMG score and 12 +/- 2 mm descent; P < .001 vs basal values) and intercostal contraction (14% +/- 3% increase in EMG scores and 6 +/- 1 mm increase in thoracic antero-posterior diameter; P < .001 vs basal values). They were also associated with increases in lung volume (501 +/- 93 mL; P < .001 vs basal value) and anterior abdominal wall protrusion (32 +/- 3 mm increase in girth; P < .001 vs basal). Biofeedback treatment, but not control sessions, reduced the activity of the intercostal muscles (by 19% +/- 2%) and the diaphragm (by 18% +/- 4%), activated the internal oblique muscles (by 52% +/- 13%), and reduced girth (by 25 +/- 3 mm) (P <= .009 vs pretreatment for all). CONCLUSIONS: In patients with functional gut disorders, abdominal distension is a behavioral response that involves activity of the abdominothoracic wall. This distension can be reduced with EMG-guided, respiratory-targeted biofeedback therapy. PMID- 25500426 TI - Transumbilical single-access laparoscopic left adrenalectomy for giant malignant pheocromocytoma. PMID- 25500425 TI - Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. AB - BACKGROUND & AIMS: We evaluated the efficacy and safety of obeticholic acid (OCA, alpha-ethylchenodeoxycholic acid) in a randomized controlled trial of patients with primary biliary cirrhosis who had an inadequate response to ursodeoxycholic acid therapy. METHODS: We performed a double-blind study of 165 patients with primary biliary cirrhosis (95% women) and levels of alkaline phosphatase (ALP) 1.5- to 10-fold the upper limit of normal. Patients were randomly assigned to groups given 10 mg, 25 mg, or 50 mg doses of OCA or placebo, once daily for 3 months. Patients maintained their existing dose of ursodeoxycholic acid throughout the study. The primary outcome was change in level of ALP from baseline (day 0) until the end of the study (day 85 or early termination). We also performed an open-label extension of the trial in which 78 patients were enrolled and 61 completed the first year. RESULTS: OCA was superior to placebo in achieving the primary end point. Subjects given OCA had statistically significant relative reductions in mean ALP from baseline to the end of the study (P < .0001 all OCA groups vs placebo). Levels of ALP decreased 21%-25% on average from baseline in the OCA groups and 3% in the placebo group. Sixty-nine percent (68 of 99) of patients given OCA had at least a 20% reduction in ALP compared with 8% (3 of 37) of patients given placebo (P < .0003). Among secondary end points, levels of gamma-glutamyl transpeptidase decreased 48%-63%, on average, among subjects given OCA, vs a 7% decrease in the group given placebo; levels of alanine aminotransferase decreased 21%-35% on average among subjects given OCA vs none of the patients given placebo. Pruritus was the principal adverse event; incidence values in the OCA 10 mg, 25 mg, and 50 mg groups were 47% (not significantly different), 87% (P < .0003), and 80% (P < .006), respectively, vs 50% in the placebo group. In the extension study, levels of ALP continued to decrease to a mean level of 202 +/- 11 U/L after 12 months vs 285 +/- 15 U/L at baseline. CONCLUSIONS: Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, gamma-glutamyl transpeptidase, and alanine aminotransferase, compared with placebo, in patients with primary biliary cirrhosis who had inadequate responses to ursodeoxycholic acid. The incidence and severity of pruritus were lowest among patients who received 10 mg/d OCA. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. ClinicalTrials.gov ID: NCT00550862. PMID- 25500427 TI - Immunosuppressive mediators of oral squamous cell carcinoma in tumour samples and saliva. AB - The goal of this study was to compare the salivary concentrations of IL-10, TGF beta1 and soluble HLA-G (sHLA-G) in patients with oral squamous cell carcinoma (OSCC) to those in healthy individuals (control group), and to correlate the expression of these mediators in saliva with that in the tumour microenvironment. Neoplastic tissue and saliva samples from patients with OSCC (n=22) were analysed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) respectively. We detected high expression of IL-10 and HLA-G in the tumour microenvironment when compared to healthy oral mucosa samples. Determination of IL-10 salivary concentration enabled us to distinguish patients with OSCC from healthy individuals (P=0.038), which showed correlation with tissue expression of this cytokine. HLA-G salivary release was similar in both groups (P=0.17) and no correlation with tumour expression was observed. TGF-beta1 expression was low or absent in tumours, and salivary concentration was similar between groups. Our results suggest that of the three markers analysed, IL-10 is a potential salivary biomarker. Furthermore, the elevated expression of HLA-G and IL-10 in tumour sites could favour the escape of tumour cells from immune defense mechanisms. PMID- 25500428 TI - Allatostatin-C reversibly blocks the transport of citrate out of the mitochondria and inhibits juvenile hormone synthesis in mosquitoes. AB - Aedes aegypti allatostatin-C (AeaAST-C or PISCF-AST) is a strong and fast reversible inhibitor of juvenile hormone III (JH III) synthesis by the corpora allata (CA) of mosquitoes; however, its mechanism of action remains poorly understood. AeaAST-C showed no inhibitory activity in the presence of any of the intermediate precursors of JH III indicating that the AeaAST-C target is located before the entry of acetyl-CoA in the pathway. Stimulation experiments using different sources of carbon (glucose, pyruvate, acetate and citrate) suggest that AST-C acts after pyruvate is transformed to citrate in the mitochondria. In vitro inhibition of the citrate mitochondrial carrier (CIC) mimicked the effect of AeaAST-C, and was overridden by addition of citrate or acetate. Our results provide compelling evidence that AeaAST-C inhibits JH III synthesis by blocking the CIC carrier that transports citrate from the mitochondria to the cytosol, obstructing the production of cytoplasmic acetyl-CoA that sustains JH III synthesis in the CA of mosquitoes. PMID- 25500429 TI - Heart rate significantly influences the relationship between atrial fibrillation and ankle-brachial index. AB - OBJECTIVES: Both atrial fibrillation (AF) and vascular disease share several risk factors and the two diseases often coexist. The patients with AF were reported to have a decreased ankle-brachial index (ABI). However, ABI was also reported to have an inverse relationship with heart rate (HR). Because AF patients often have a transiently or persistently rapid HR, this study aimed to assess whether AF was significantly associated with decreased ABI and whether HR could significantly influence the relationship between AF and ABI. METHODS: We included 166 AF and 1336 non-AF patients from subjects undergoing echocardiographic examinations. ABI was measured using an ABI-form device. RESULTS: Compared to non-AF patients, AF patients had a decreased ABI (p<0.001). In a multivariate model, including covariates of age, sex, blood pressures, etc., the presence of AF was significantly associated with low ABI (beta=-0.069, p=0.026). However, further adjustment for HR made this association disappear (p=0.971). CONCLUSION: This study demonstrated that the presence of AF was associated with decreased ABI, but this association became insignificant after further adjustment for HR, which suggested HR could significantly influence the relationship between AF and ABI. PMID- 25500431 TI - Random Serum Cortisol as a Predictor for Survival of Terminally Ill Patients With Cancer: A Preliminary Study. AB - Although previous research found that serum cortisol levels were associated with cancer prognosis, it is unclear whether this association remains robust even at the very end of life of patients with cancer. We conducted a retrospective chart review of 125 patients with terminal cancer to investigate the role of random serum cortisol levels in predicting the remaining life expectancy. The high random cortisol group had a significantly shorter survival time than the low random cortisol group (7.5 vs 26 days). After adjusting for potential confounders, key factors such as poor performance status, hypoalbuminemia, and high random cortisol level are associated with poor survival. Our results suggest that the random serum cortisol level is an independent predictor of survival time of patients with terminally ill cancer. PMID- 25500430 TI - Identification of differentially-expressed genes in intestinal gastric cancer by microarray analysis. AB - Gastric cancer (GC) is one of the most frequent malignant tumors. In order to systematically characterize the cellular and molecular mechanisms of intestinal GC development, in this study, we used 22K oligonucleotide microarrays and bioinformatics analysis to evaluate the gene expression profiles of GC in 45 tissue samples, including 20 intestinal GC tissue samples, 20 normal appearing tissues (NATs) adjacent to tumors and 5 noncancerous gastric mucosa tissue samples. These profiles allowed us to explore the transcriptional characteristics of GC and determine the change patterns in gene expression that may be of clinical significance. 1519 and 1255 differentially-expressed genes (DEGs) were identified in intestinal GC tissues and NATs, respectively, as determined by Bayesian analysis (P<0.001). These genes were associated with diverse functions such as mucosa secretion, metabolism, proliferation, signaling and development, which occur at different stages of GC development. PMID- 25500432 TI - A Hospice and Palliative Care Bed Dedicated to Patients Admitted to the Emergency Department for End-of-Life Care. AB - A hospice and palliative care (PC) bed was created in 2006, located within a quiet area of our intensive care unit, in order to admit terminally ill patients sent to the emergency department (ED) for end-of-life care. We retrospectively analyze the records of the 342 terminally ill patients sent to the ED from 2007 to 2011. Among them, 176 (51.5%) were admitted to our hospice and PC bed, where 114 died. Besides, 99 (28.9%) of them died on stretchers in the ED. Our intervention led to a significant decrease in the number of terminally ill patients dying on stretchers in the ED. It also allowed both patients and families to have access to a more suitable environment. PMID- 25500433 TI - Why treatments do(n't) work in vitiligo: An autoinflammatory perspective. AB - Vitiligo is a recalcitrant depigmentary skin disorder with significant effects on the quality of life and a frequent association with other autoimmune disorders. The results of the current therapeutic options remain variable and treatment resistance is often encountered. The mainstay of treatment remains topical corticosteroids, topical calcineurin inhibitors and UVB therapy. In more extensive or progressive cases, systemic corticosteroids are effective although their prolonged use is hampered due to safety concerns. A lot of topical and systemic treatments have been investigated during the last decades. Given the elevated TNF-alpha levels in vitiligo lesions, the failure and even paradoxal effects of TNF-alpha inhibitors were highly remarkable. Nonetheless, a lot of progress has been made to unravel the pathophysiology of vitiligo. In this review, we provide an overview of the currently known underlying mechanisms leading to vitiligo and link this to the success or failure of treatments that have been used in clinical trials. We believe that this overview can direct future vitiligo research and rationalise the treatment options. PMID- 25500434 TI - Churg-Strauss syndrome. AB - Churg-Strauss syndrome (CSS), alternatively known as eosinophilic granulomatosis with polyangiitis (EGPA), was first described in 1951 by Churg and Strauss as a rare disease characterized by disseminated necrotizing vasculitis with extravascular granulomas occurring exclusively among patients with asthma and tissue eosinophilia. EGPA is classified as a small-vessel vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs) and the hypereosinophilic syndromes (HESs) in which vessel inflammation and eosinophilic proliferation are thought to contribute to organ damage. Although still considered an idiopathic condition, EGPA is classically considered a Th2-mediated disease. Emerging clinical observations provide compelling evidence that ANCAs are primarily and directly involved in the pathogenesis of AASVs, although recent evidence implicates B cells and the humoral response as further contributors to EGPA pathogenesis. EGPA has traditionally been described as evolving through a prodromic phase characterized by asthma and rhino-sinusitis, an eosinophilic phase marked by peripheral eosinophilia and organ involvement, and a vasculitic phase with clinical manifestations due to small-vessel vasculitis. The American College of Rheumatology defined the classification criteria to distinguish the different types of vasculitides and identified six criteria for EGPA. When four or more of these criteria are met, vasculitis can be classified as EGPA. The French Vasculitis Study Group has identified five prognostic factors that make up the so-called five-factor score (FFS). Patients without poor prognosis factors (FFS=0) have better survival rates than patients with poor prognosis factors (FFS>=1). The treatment of patients with CSS must be tailored to individual patients according to the presence of poor prognostic factors. A combination of high-dose corticosteroids and cyclophosphamide is still the gold standard for the treatment of severe cases, but the use of biological agents such as rituximab or mepolizumab seems to be a promising therapeutic alternative. PMID- 25500435 TI - Dose assessment in contrast enhanced digital mammography using simple phantoms simulating standard model breasts. AB - Slabs of polymethyl methacrylate (PMMA) or a combination of PMMA and polyethylene (PE) slabs are used to simulate standard model breasts for the evaluation of the average glandular dose (AGD) in digital mammography (DM) and digital breast tomosynthesis (DBT). These phantoms are optimized for the energy spectra used in DM and DBT, which normally have a lower average energy than used in contrast enhanced digital mammography (CEDM). In this study we have investigated whether these phantoms can be used for the evaluation of AGD with the high energy x-ray spectra used in CEDM. For this purpose the calculated values of the incident air kerma for dosimetry phantoms and standard model breasts were compared in a zero degree projection with the use of an anti scatter grid. It was found that the difference in incident air kerma compared to standard model breasts ranges between -10% to +4% for PMMA slabs and between 6% and 15% for PMMA-PE slabs. The estimated systematic error in the measured AGD for both sets of phantoms were considered to be sufficiently small for the evaluation of AGD in quality control procedures for CEDM. However, the systematic error can be substantial if AGD values from different phantoms are compared. PMID- 25500436 TI - Elevated plasma cfDNA may be associated with active lupus nephritis and partially attributed to abnormal regulation of neutrophil extracellular traps (NETs) in patients with systemic lupus erythematosus. AB - OBJECTIVE: The abnormal formation and insufficient clearance of neutrophil extracellular traps (NETs) has been reported to be involved in the pathogenesis of lupus nephritis (LN). The abnormal regulation of NETs may contribute to increases in the levels of circulating cell-free DNA (cfDNA). The present study tested the hypothesis that elevated plasma cfDNA levels are related to LN. METHODS: Fifty-four systemic lupus erythematosus (SLE) patients and 43 control subjects were included in this study. The cfDNA concentrations were measured using the Picogreen Kit, the low-density granulocyte (LDG) percentage in peripheral blood mononuclear cells (PBMCs) was tested using a flow cytometer and the DNase I activity was measured according to the radial enzyme-diffusion method. RESULTS: The mean cfDNA concentration in the SLE group was 236.66+/-40.09 ng/mL, which was significantly higher than that observed in the healthy control group (187.96+/-40.55 ng/mL, p<0.0001). Meanwhile, the mean cfDNA concentration in the patients with LN was significantly higher than that observed in the patients without LN (247.27+/-46.79 ng/mL vs. 213.56+/-31.34 ng/mL, p=0.0094), and the mean cfDNA concentration in the patients with active LN was significantly higher than that observed in the patients with inactive LN (254.22+/-50.16 ng/mL vs. 215.93+/-29.10 ng/mL, p=0.0349). In the SLE group, the cfDNA concentration was to positively correlate with the quantitative 24-hour urinary protein (r=0.350, p=0.013), LDG (r=0.6361, p=0.0019) and neutrophil (r=0.5990, p<0.0001) levels and inversely correlate with the albumin level (r=-0.500, p<0.0001) and endogenous creatinine clearance rate (r=-0.354, p=0.044). Compared to that observed in the control group, the SLE group exhibited a significantly increased percentage of LDGs in PBMCs and a significantly decreased DNase I activity. CONCLUSION: Our data indicate that elevated plasma cfDNA concentrations may be associated with active LN and partially attributed to the abnormal regulation of NETs in SLE patients, thus suggesting that NETs constitute an intrinsic link between cfDNA and active LN. PMID- 25500437 TI - Late complications of self-expandable metallic stent placement for malignant gastric outlet obstruction. AB - The patient was a 68-year-old man with pancreatic cancer exhibiting invasion into the superior mesenteric artery and stenosis of the third part of the duodenum. He subsequently received a duodenal stent for malignant gastric outlet obstruction. On day 43 after the placement of the duodenal stent, he reported feeling poorly, with hypotension and hematemesis. High-density areas were observed from the stomach to the rectum on computed tomography. We diagnosed the origin of bleeding as the last third of the duodenum; unfortunately, the patient died. This is the first report of massive gastrointestinal tract bleeding as a late complication of self-expandable metallic stent placement for malignant gastric outlet obstruction. PMID- 25500438 TI - Metastatic seminoma in the duodenum: diagnosis with endoscopy followed by successful treatment. AB - Seminomas rarely metastasize to the gastrointestinal tract. In general, these lesions metastasize to the lungs or retroperitoneal lymph nodes. A 34-year-old Japanese man who had undergone orchiectomy for seminoma two years earlier experienced shortness of breath and tarry stools. The patient presented at our hospital and was diagnosed with metastatic seminoma to the third portion of the duodenum on double balloon endoscopy. He was effectively treated with chemotherapy and continues to progress well, with no episodes of recurrence. PMID- 25500439 TI - Hypercalcemia induced by Rosai-Dorfman disease in a hemodialysis patient: histological evidence of extrarenal calcitriol overproduction. AB - Rosai-Dorfman disease (RDD) is a rare disorder characterized by the proliferation of histiocytes in the sinus of the affected lymph nodes, which leads to massive lymphadenopathy. RDD usually presents as an increased inflammatory response and lymph node swelling. We herein report the case of a hemodialysis patient with a fever, hypercalcemia and increased serum calcitriol level who was histologically diagnosed to have RDD. Immunohistochemistry revealed an increased expression of 1alpha-hydroxylase by histiocytes in the dilated sinus, indicating the extrarenal overproduction of calcitriol. Treatment with oral prednisolone decreased the serum levels of inflammatory markers and calcitriol, normalized the serum calcium level and mitigated the systemic lymph node enlargement. PMID- 25500440 TI - Waldenstrom's macroglobulinemia accompanying systemic amyloidosis: the usefulness of endobronchial ultrasound-guided transbronchial needle aspiration for detecting amyloid deposits. AB - A 75-year-old man with a history of dyspnea lasting for three years presented to our hospital. Chest computed tomography showed bilateral pulmonary nodules, some of which were calcified, in addition to mediastinal/hilar lymphadenopathy and bilateral pleural effusions. Endobronchial ultrasound-guided (EBUS) transbronchial needle aspiration (TBNA) of the subcarinal lymph nodes showed amorphous acellular material compatible with lambda-light chain amyloid deposits. Sternal bone marrow aspiration demonstrated increased small lymphocytes admixed with plasma cells and plasmacytoid lymphocytes. Serum immunoglobulin values were decreased with the exception of immunoglobulin M monoclonal peak. We subsequently diagnosed the patient as having Waldenstrom's macroglobulinemia accompanying AL type amyloidosis. In this case, EBUS-TBNA was useful for detecting AL-type amyloidosis. PMID- 25500441 TI - Invasive mucinous adenocarcinoma mimicking organizing pneumonia associated with Mycobacterium fortuitum infection. AB - We herein report the case of a 68-year-old man diagnosed with invasive mucinous adenocarcinoma of the lungs. Chest computed tomography showed subpleural ground glass opacity and small nodules with cavitation. A culture of the bronchoalveolar lavage fluid resulted in the detection of Mycobacterium fortuitum. The patient's lung consolidation rapidly progressed; however, repeated bronchoscopy showed no atypical cells, thus suggesting a diagnosis of organizing pneumonia associated with M. fortuitum infection. However, the surgical biopsy specimen was diagnostic for adenocarcinoma, with no mycobacterial infection. Invasive mucinous adenocarcinoma should not be excluded in the differential diagnosis of patients with clinical features of organizing pneumonia and nontuberculous mycobacterium infection, even if a transbronchial biopsy confirms the absence of malignancy. PMID- 25500442 TI - Molecular response to nilotinib in a patient with imatinib-intolerant e19a2 positive chronic myeloid leukemia. AB - The BCR-ABL1 fusion gene is the molecular marker of chronic myeloid leukemia (CML). The e19a2 transcript is a rare variant associated with various clinical presentations and courses of CML. We herein present a case of e19a2-positive CML who was intolerant to initial treatment with imatinib and successfully responded to subsequent nilotinib therapy. She achieved a major molecular response and has since be able to sustain it. According to the literature, achieved molecular response by imatinib monotherapy has not yet been reported in e19a2-positive CML patients. Second generation tyrosine kinase inhibitors may therefore be a more effective treatment for e19a2-positive CML patients. PMID- 25500443 TI - Rapid multiorgan failure due to large B-cell lymphoma arising in human herpesvirus-8-associated multicentric Castleman's disease in a patient with human immunodeficiency virus infection. AB - A 46-year-old man presented with a high-grade fever, multiple lymphadenopathies, hepatosplenomegaly and human immunodeficiency virus (HIV) seropositivity, without severe immunosuppression. We suspected human herpesvirus-8 (HHV-8)-associated multicentric Castleman's disease (MCD) based on the results of a physical examination and laboratory investigations, including bone marrow aspiration. However, the patient died eight days after admission due to multiorgan failure. An autopsy revealed MCD and lymphoma cell infiltration in multiple organs. The final diagnosis was large B-cell lymphoma (LBCL) arising in HHV-8-associated MCD. This case illustrates the potential for LBCL in HHV-8 MCD in HIV-infected patients with hepatosplenomegaly and lymphadenopathy without severe immunosuppression and highlights the clinical significance of bone marrow aspiration. PMID- 25500444 TI - Adult-onset Satoyoshi syndrome with prominent laterality of clinical features. AB - We herein report the case of a patient with adult-onset Satoyoshi syndrome. Alopecia was detected on the patient's head, left leg and abdomen, with pigmentation on the left thigh and abdomen. Painful muscle spasms were also noted in the abdomen and left upper and lower extremities, and a sensory disturbance was present in the left thigh. A skin biopsy of this field showed lymphocyte infiltration, and the patient was found to be positive for antinuclear antibodies and rheumatoid factor. These clinical findings were atypical, as they were lateralized. This case is the first report of Satoyoshi syndrome associated with a sensory disturbance. The patient's histological findings and positivity for autoantibodies indicated the presence of immunological abnormalities in this case of Satoyoshi syndrome. PMID- 25500445 TI - Protracted febrile myalgia syndrome in a Japanese patient with fasciitis detected on MRI. AB - Protracted febrile myalgia syndrome (PFMS) is a rare manifestation of familial Mediterranean fever characterized by prolonged severe myalgia. We herein describe a case of PFMS with fasciitis on magnetic resonance imaging. The response to corticosteroid therapy was prompt, as is typical for PFMS. An MEFV gene analysis revealed the patient to be homozygous for E148Q and compound heterozygous for P369S-R408Q. This is the first case report of a Japanese patient with PFMS. MRI findings may help to diagnose such cases. PMID- 25500446 TI - Pleuritis clinically diagnosed as aspergillosis during the course of microscopic polyangiitis. AB - Pleural aspergillosis is a rare fungal infection. We herein report a case of pleuritis clinically diagnosed as aspergillosis without apparent Aspergillus lung lesions. A 75-year-old man receiving immunosuppressive therapy due to microscopic polyangiitis was admitted for treatment of massive pleural effusion. Histology of the parietal pleura revealed septate hyphae. In addition, a hematological marker of Aspergillus indicated Aspergillus pleuritis. The pleural effusion resolved after administration of the voriconazole. The trigger for invasion of Aspergillus into the pleura was thought to be spontaneous pneumothorax, which had occurred five months earlier. PMID- 25500447 TI - Birt-Hogg-Dube syndrome with clear cell renal cell carcinoma in a Chinese family. AB - Birt-Hogg-Dube syndrome (BHDS) is a rare autosomal dominant genodermatosis that presents as a clinical triad including follicular hamartomas, renal neoplasms and lung cysts associated with an increased risk of pneumothorax. FLCN gene defects have been identified as being responsible for BHDS. We herein report the case of a 67-year-old woman with the full-blown BHDS phenotype, characterized by skin lesions, multiple lung bullae and renal neoplasms. In her family history, one of the patient's sons exhibited a similar phenotype, without renal neoplasms. Due to the relatively late age of onset of renal neoplasms among variable BHDS phenotypes, follow-up imaging is recommended for the son who has not yet developed renal neoplasms. PMID- 25500448 TI - Pylephlebitis: a severe complication of intra-abdominal infection. PMID- 25500449 TI - Pacemaker lead perforation through the right ventricle. PMID- 25500450 TI - Cricothyroid perichondritis in a patient with dermatomyositis. PMID- 25500451 TI - Responses of the photosynthetic apparatus to winter conditions in broadleaved evergreen trees growing in warm temperate regions of Japan. AB - Photosynthetic characteristics of two broadleaved evergreen trees, Quercus myrsinaefolia and Machilus thunbergii, were compared in autumn and winter. The irradiance was similar in both seasons, but the air temperature was lower in winter. Under the winter conditions, net photosynthesis under natural sunlight (Anet) in both species dropped to 4 MUmol CO2 m(-2) s(-1), and the quantum yield of photosystem II (PSII) photochemistry in dark-adapted leaves (Fv/Fm) also dropped to 0.60. In both species the maximum carboxylation rates of Rubisco (V(cmax)) decreased, and the amount of Rubisco increased in winter. A decline in chlorophyll (Chl) concentration and an increase in the Chl a/b ratio in winter resulted in a reduction in the size of the light-harvesting antennae. From measurements of Chl a fluorescence parameters, both the relative fraction and the energy flux rates of thermal dissipation through other non-photochemical processes were markedly elevated in winter. The results indicate that the photosynthetic apparatus in broadleaved evergreen species in warm temperate regions responds to winter through regulatory mechanisms involving the downregulation of light-harvesting and photosynthesis coupled with increased photoprotective thermal energy dissipation to minimize photodamage in winter. These mechanisms aid a quick restart of photosynthesis without the development of new leaves in the following spring. PMID- 25500452 TI - Melatonin combined with ascorbic acid provides salt adaptation in Citrus aurantium L. seedlings. AB - Ascorbic acid (AsA) and melatonin (Mel) are known molecules participating in stress resistance, however, their combined role in counteracting the impact of salinity in plants is still unknown. In this work the effect of exogenous application of 0.50 mMU AsA, 1 MUMU Mel and their combination (AsA + Mel) on various stress responses in leaves and roots of Citrus aurantium L. seedlings grown under 100 mMU NaCl for 30 days was investigated. Application of AsA, Mel or AsA + Mel to saline solution decreased NaCl-induced electrolyte leakage and lipid peroxidation and prevented NaCl-associated toxicity symptoms and pigments degradation. Also, leaves exposed to combined AsA + Mel treatment displayed lower Cl(-) accumulation. Treatments with AsA and/or Mel modulated differently carbohydrates, proline, phenols, glutathione and the total antioxidant power of tissues as well as the activities of SOD, APX, POD, GR and PPO compared to NaCl alone treatment. Exposure of leaves and roots to chemical treatments and especially to combined AsA and Mel application was able to regulate CaMIPS, CaSLAH1 and CaMYB73 expression, indicating that sugar metabolism, ion homeostasis and transcription regulation were triggered by AsA and Mel. These results provide evidence that the activation of the metabolic pathways associated with combined AsA and Mel application are linked with salt adaptation in citrus plants. PMID- 25500453 TI - Photosynthesis and chloroplast genes are involved in water-use efficiency in common bean. AB - A recent proposal to mitigate the effects of climatic change and reduce water consumption in agriculture is to develop cultivars with high water-use efficiency. The aims of this study were to characterize this trait as a differential response mechanism to water-limitation in two bean cultivars contrasting in their water stress tolerance, to isolate and identify gene fragments related to this response in a model cultivar, as well as to evaluate transcription levels of genes previously identified. Keeping CO2 assimilation through a high photosynthesis rate under limited conditions was the physiological response which allowed the cultivar model to maintain its growth and seed production with less water. Chloroplast genes stood out among identified genetic elements, which confirmed the importance of photosynthesis in such response. ndhK, rpoC2, rps19, rrn16, ycf1 and ycf2 genes were expressed only in response to limited water availability. PMID- 25500454 TI - Environmental cues induce changes of steviol glycosides contents and transcription of corresponding biosynthetic genes in Stevia rebaudiana. AB - Plant growth and secondary metabolism are commonly regulated by external cues such as light, temperature and water availability. In this study, the influences of low and high temperatures, dehydration, photoperiods, and different growing stages on the changes of steviol glycosides (SGs) contents and transcription levels of fifteen genes involved in SGs biosynthesis of Stevia rebaudiana Bertoni were examined using HPLC and RT-PCR. The observations showed that the transcript levels of all the fifteen genes were maximum under 25 degrees C treatment, and the transcription of SrDXS, SrDXR, SrMCT, SrCMK, SrMDS, SrHDS, SrHDR, SrIDI, SrGGDPS, SrCPPS1, SrUGT85C2 and SrUGT76G1 were restrained both in low temperature (15 degrees C) and high temperature (35 degrees C). Most genes in SGs biosynthesis pathway exhibited down-regulation in dehydration. To elucidate the effect of photoperiods, the plants were treated by different simulated photoperiods (8 L/16 D, 1 0L/14 D, 14 L/10 D and 16 L/8 D), but no significant transcription changes were observed. In the study of growing stages, there were evident changes of SGs contents, and the transcript levels of all the fifteen genes were minimal in fast growing period, and exhibited evident increase both in flower-bud appearing stage and flowering stage. The obtained results strongly suggest that the effect of environmental cues on steviol glycosides contents and transcription of corresponding biosynthetic genes in S. rebaudiana is significant. It is worth to study deeply. PMID- 25500456 TI - Troubleshooting distraction osteogenesis for craniosynostosis. AB - PURPOSE: We previously reported that distraction osteogenesis is less invasive and gives greater skull advancement compared to conventional cranioplasty [Akai et al: Pediatr Neurosurg 2006;42:288-292]. In this study, we analyzed the distraction osteogenesis process and tried to identify and solve various technical problems. PATIENTS AND RESULTS: We operated on 22 patients, 5 syndromic and 17 nonsyndromic. During treatment, we encountered several problems: (i) dural laceration during craniotomy (2 cases), solution: repair by suturing with fascia; (ii) skull fracture at sphenofrontal or coronal sutures (2 cases), solution: completed distraction; (iii) device dislocation during distraction (1 case), solution: the device was secured to the skull with stainless wire; (iv) wound issues around shaft and device (3 cases), solution: treated with antibiotic ointment. DISCUSSION: (1) Extra caution is needed to avoid dural damage at frontal bottom burr holes. (2) Completion of craniotomy should be confirmed by checking if the bone flap moves in sync with brain pulsation. The craniotomy line should be placed forward of coronal sutures. (3) For patients younger than 2 years, employ clamp-type devices. (4) Shafts should be cut short enough to prevent their tips from exerting pressure or puncturing the scalp from beneath. CONCLUSIONS: The distraction osteogenesis technique has complications that may not occur in conventional one-stage cranioplasty. In this study, neither age at operation nor distraction distance were significant causes of complications during distraction osteogenesis. PMID- 25500455 TI - A multicenter study of the importance of systemic chemotherapy for patients with small-cell neuroendocrine carcinoma of the uterine cervix. AB - AIMS: We investigated the prognosis of patients with small-cell neuroendocrine carcinoma of the uterine cervix (SCNEC) in relation to treatment modalities. METHODS: We retrospectively reviewed the medical records and pathological reports of 102 patients who were histologically diagnosed with SCNEC at 5 different institutes. Time to progression (TTP) and overall survival (OS) were analyzed for each treatment modality. RESULTS: Of the patients with early-stage [International Federation of Obstetrics and Gynecology (FIGO) stage IB2 or below] SCNEC, 57.8 and 79.3% underwent radical hysterectomy followed by adjuvant therapy. In advanced-stage SCNEC, concurrent chemoradiation therapy was given to 51.4% of the patients. The overall recurrence rate was 51.6%. In early- and advanced-stage SCNEC, the TTP was not different (22.3 vs. 13.3 months, p = 0.104), but the OS was different (40.7 vs. 21.4 months, p = 0.029). Parametrial involvement and lymph vascular space invasion were found to be associated with an unfavorable prognosis. Interestingly, survival was the most unfavorable in patients with early-stage SCNEC who had never received chemotherapy. FIGO stage and use of chemotherapy were identified as independent prognostic factors in SCNEC patients. CONCLUSIONS: SCNEC requires systemic chemotherapy as part of the initial treatment, along with surgery or radiation, even in patients with early-stage disease. PMID- 25500457 TI - Lysobacter mobilis sp. nov., isolated from abandoned lead-zinc ore. AB - An aerobic and Gram-stain-negative bacterial strain, designated 9NM-14(T), was isolated from abandoned lead-zinc ore from Meizhou, Guangdong Province, south China. Strain 9NM-14(T) was motile by means of a single polar flagellum. Phylogenetic analysis, based on 16S rRNA gene sequences, showed that strain 9NM 14(T) was affiliated with the genus Lysobacter and was most closely related to Lysobacter xinjiangensis RCML-52(T) and Lysobacter bugurensis ZLD-29(T) (97.4 % and 96.3 % 16S rRNA gene sequence similarity, respectively). The DNA-DNA relatedness value between strain 9NM-14(T) and L. xinjiangensis RCML-52(T) was 30.1+/-7.6 %. The major respiratory quinone was unbiquinone 8 (Q-8) and the major cellular fatty acids consisted of iso-C17 : 1omega9c (29.1 %), iso-C15 : 0 (28.9 %), iso-C17 : 0 (9.4 %), iso-C16 : 0 (8.6 %), iso-C11 : 0 3-OH (6.9 %) and iso C11 : 0 (5.8 %). The major polar lipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, an unidentified aminolipid and five unidentified phospholipids. The genomic DNA G+C content of strain 9NM-14(T) was 70.7+/-0.1 mol%. On the basis of the data from this polyphasic taxonomic study, strain 9NM-14(T) should be assigned to a novel species of the genus Lysobacter, for which the name Lysobacter mobilis sp. nov. is proposed. The type strain is 9NM-14(T) ( = GIMCC 1.659(T) = CCTCC AB 2014273(T) = DSM 27574(T)). PMID- 25500458 TI - Glycocaulis alkaliphilus sp. nov., a dimorphic prosthecate bacterium isolated from crude oil. AB - A bacterial strain designated 6B-8(T) was isolated from crude oil from Daqing oilfield, China. Cells of strain 6B-8(T) were Gram-negative, aerobic, dimorphic and reproduced by means of binary fission. Strain 6B-8(T) could grow at 20-37 degrees C, pH 8-10 and 1-5 % (w/v) NaCl. Its genomic DNA G+C content was 62.0 mol%. The predominant cellular fatty acids were C18 : 1omega7c, C17 : 0, C18 : 0 and 11-methyl C18 : 1omega7c and the main hydroxy fatty acids were C12 : 0 3-OH and C12 : 1 3-OH when grown on marine agar 2216. The major quinone was Q-10 and the major polar lipids were three unidentified glycolipids. Phylogenetic analysis revealed that strain 6B-8(T) was a member of the family Hyphomonadaceae, sharing 99.6 and 99.4 % 16S rRNA gene sequence similarity with Glycocaulis abyssi LMG 27140(T) and Glycocaulis albus SLG210-30A1(T), respectively, and less than 94.4 % similarity with the type strains of other members of the family Hyphomonadaceae. However, the DNA-DNA relatedness between strain 6B-8(T) and related strains G. abyssi LMG 27140(T) and G. albus SLG210-30A1(T) was 36+/-5 and 42+/-5 %, respectively. In addition, several phenotypic and genotypic features allowed differentiation of strain 6B-8(T) from G. abyssi LMG 27140(T) and G. albus SLG210 30A1(T). Therefore, strain 6B-8(T) represents a novel species of genus Glycocaulis, for which the name Glycocaulis alkaliphilus sp. nov. is proposed. The type strain is 6B-8(T) ( = CGMCC 1.12428(T) = LMG 27410(T)). PMID- 25500459 TI - Modeling the urban water cycle as part of the city. PMID- 25500460 TI - Hydrological and environmental assessment of urban growth in a sub-tropical town in India. AB - Roorkee, a sub-tropical urban town in India, has shown a rapid unplanned growth in the past. This paper presents the findings of a study of characteristics of urban soil, rainwater, and runoff emanating from different sources areas and the stormwater flows in the drains. Urban soil showed significant increase in the concentration of all constituents in comparison to the nearby rural soil. Soil metal pollution index suggested multi-element contamination. The traffic and transportation system emerged as the major source of metals and organics. Concentration of rainwater ions was observed to follow the pattern Ca2+ > HCO(3)( ) > Cl- > NO(3)(-) > Na+ > Mg2+ > SO(4)(2-) > K+. Runoff results indicated a significant enhancement in the concentration of most measured constituents over their rainfall levels. The values of runoff coefficient varied between 0.05 and 0.58, with the high values displayed by the paved areas. Multiple regression equations were developed relating event mean concentration to various storm characteristics. The total load of all measured constituents was observed to vary considerably among the study sites, the direct runoff loads being much higher than the dry weather loads. PMID- 25500461 TI - Application of an interactive water simulation model in urban water management: a case study in Amsterdam. AB - Water simulation models are available to support decision-makers in urban water management. To use current water simulation models, special expertise is required. Therefore, model information is prepared prior to work sessions, in which decision-makers weigh different solutions. However, this model information quickly becomes outdated when new suggestions for solutions arise and are therefore limited in use. We suggest that new model techniques, i.e. fast and flexible computation algorithms and realistic visualizations, allow this problem to be solved by using simulation models during work sessions. A new Interactive Water Simulation Model was applied for two case study areas in Amsterdam and was used in two workshops. In these workshops, the Interactive Water Simulation Model was positively received. It included non-specialist participants in the process of suggesting and selecting possible solutions and made them part of the accompanying discussions and negotiations. It also provided the opportunity to evaluate and enhance possible solutions more often within the time horizon of a decision-making process. Several preconditions proved to be important for successfully applying the Interactive Water Simulation Model, such as the willingness of the stakeholders to participate and the preparation of different general main solutions that can be used for further iterations during a work session. PMID- 25500462 TI - Assessing the performances of low impact development alternatives by long-term simulation for a semi-arid area in Tianjin, northern China. AB - For areas that are urbanized rapidly, the practice of low impact development (LID) has gained an important place in stormwater management and urban planning due to its capability and beneficial effects in restoring the original hydrological cycle. The performances of LID alternatives can vary substantially due to different climate conditions. This study investigated the performances of five LID alternatives under a semi-arid climate in northern China on water balance and flood control. A numerical model, Storm Water Management Model version 5 (US Environmental Protection Agency), was employed to run 10 years' rainfall events for these objectives. Two evaluation methods were proposed in this study: the efficiency index for water balance and a performance radar chart. The investigation of the five LID alternatives revealed that these LID alternatives functioned differently in flood control and water balance, and porous pavement performed best in all indices except the lag time. The two evaluation methods, in conjunction with the long-term numerical simulation, can facilitate design and decision making by providing a clear picture of the performance and functions for these LID alternatives. PMID- 25500463 TI - Modeling the hydrologic and economic efficacy of stormwater utility credit programs for US single family residences. AB - As regulatory pressure to reduce the environmental impact of urban stormwater intensifies, US municipalities increasingly seek a dedicated source of funding for stormwater programs, such as a stormwater utility. In rare instances, single family residences are eligible for utility discounts for installing green infrastructure. This study examined the hydrologic and economic efficacy of four such programs at the parcel scale: Cleveland (OH), Portland (OR), Fort Myers (FL), and Lynchburg (VA). Simulations were performed to model the reduction in stormwater runoff by implementing bioretention on a typical residential property according to extant administrative rules. The EPA National Stormwater Calculator was used to perform pre- vs post-retrofit comparisons and to demonstrate its ease of use for possible use by other cities in utility planning. Although surface slope, soil type and infiltration rate, impervious area, and bioretention parameters were different across cities, our results suggest that modeled runoff volume was most sensitive to percent of total impervious area that drained to the bioretention cell, with soil type the next most important factor. Findings also indicate a persistent gap between the percentage of annual runoff reduced and the percentage of fee reduced. PMID- 25500464 TI - Risk-based zoning for urbanizing floodplains. AB - Urban floodplain development brings economic benefits and enhanced flood risks. Rapidly growing cities must often balance the economic benefits and increased risks of floodplain settlement. Planning can provide multiple flood mitigation and environmental benefits by combining traditional structural measures such as levees, increasingly popular landscape and design features (green infrastructure), and non-structural measures such as zoning. Flexibility in both structural and non-structural options, including zoning procedures, can reduce flood risks. This paper presents a linear programming formulation to assess cost effective urban floodplain development decisions that consider benefits and costs of development along with expected flood damages. It uses a probabilistic approach to identify combinations of land-use allocations (residential and commercial development, flood channels, distributed runoff management) and zoning regulations (development zones in channel) to maximize benefits. The model is applied to a floodplain planning analysis for an urbanizing region in the Baja Sur peninsula of Mexico. The analysis demonstrates how (1) economic benefits drive floodplain development, (2) flexible zoning can improve economic returns, and (3) cities can use landscapes, enhanced by technology and design, to manage floods. The framework can incorporate additional green infrastructure benefits, and bridges typical disciplinary gaps for planning and engineering. PMID- 25500465 TI - Clustering analysis of water distribution systems: identifying critical components and community impacts. AB - Large water distribution systems (WDSs) are networks with both topological and behavioural complexity. Thereby, it is usually difficult to identify the key features of the properties of the system, and subsequently all the critical components within the system for a given purpose of design or control. One way is, however, to more explicitly visualize the network structure and interactions between components by dividing a WDS into a number of clusters (subsystems). Accordingly, this paper introduces a clustering strategy that decomposes WDSs into clusters with stronger internal connections than external connections. The detected cluster layout is very similar to the community structure of the served urban area. As WDSs may expand along with urban development in a community-by community manner, the correspondingly formed distribution clusters may reveal some crucial configurations of WDSs. For verification, the method is applied to identify all the critical links during firefighting for the vulnerability analysis of a real-world WDS. Moreover, both the most critical pipes and clusters are addressed, given the consequences of pipe failure. Compared with the enumeration method, the method used in this study identifies the same group of the most critical components, and provides similar criticality prioritizations of them in a more computationally efficient time. PMID- 25500466 TI - Urban-Water Harmony model to evaluate the urban water management. AB - Water resources in many urban areas are under enormous stress due to large-scale urban expansion and population explosion. The decision-makers are often faced with the dilemma of either maintaining high economic growth or protecting water resources and the environment. Simple criteria of water supply and drainage do not reflect the requirement of integrated urban water management. The Urban-Water Harmony (UWH) model is based on the concept of harmony and offers a more integrated approach to urban water management. This model calculates four dimensions, namely urban development, urban water services, water-society coordination, and water environment coordination. And the Analytic Hierarchy Process has been used to determine the indices weights. We applied the UWH model to Beijing, China for an 11-year assessment. Our findings show that, despite the severe stress inherent in rapid development and water shortage, the urban water relationship of Beijing is generally evolving in a positive way. The social economic factors such as the water recycling technologies contribute a lot to this change. The UWH evaluation can provide a reasonable analysis approach to combine various urban and water indices to produce an integrated and comparable evaluation index. This, in turn, enables more effective water management in decision-making processes. PMID- 25500467 TI - How much drinking water can be saved by using rainwater harvesting on a large urban area? application to Paris agglomeration. AB - This paper is based on a prospective scenario of development of rainwater harvesting (RWH) on a given large urban area (such as metropolitan area or region). In such a perspective, a new method is proposed to quantify the related potential of potable water savings (PPWS) indicator on this type of area by adapting the reference model usually used on the building level. The method is based on four setting-up principles: gathering (definition of buildings-types and municipalities-types), progressing (use of an intermediate level), increasing (choice of an upper estimation) and prioritizing (ranking the stakes of RWH). Its application to the Paris agglomeration shows that is possible to save up to 11% of the total current potable water through the use of RWH. It also shows that the residential sector offers the most important part because it holds two-thirds of the agglomeration PPWS. PMID- 25500468 TI - An ecohydrologic model for a shallow groundwater urban environment. AB - The urban environment is a patchwork of natural and artificial surfaces that results in complex interactions with and impacts to natural hydrologic cycles. Evapotranspiration is a major hydrologic flow that is often altered through urbanization, although the mechanisms of change are sometimes difficult to tease out due to difficulty in effectively simulating soil-plant-atmosphere interactions. This paper introduces a simplified yet realistic model that is a combination of existing surface runoff and ecohydrology models designed to increase the quantitative understanding of complex urban hydrologic processes. Results demonstrate that the model is capable of simulating the long-term variability of major hydrologic fluxes as a function of impervious surface, temperature, water table elevation, canopy interception, soil characteristics, precipitation and complex mechanisms of plant water uptake. These understandings have potential implications for holistic urban water system management. PMID- 25500469 TI - Development and assessment of an integrated ecological modelling framework to assess the effect of investments in wastewater treatment on water quality. AB - Worldwide, large investments in wastewater treatment are made to improve water quality. However, the impacts of these investments on river water quality are often not quantified. To assess water quality, the European Water Framework Directive (WFD) requires an integrated approach. The aim of this study was to develop an integrated ecological modelling framework for the River Drava (Croatia) that includes physical-chemical and hydromorphological characteristics as well as the ecological river water quality status. The developed submodels and the integrated model showed accurate predictions when comparing the modelled results to the observations. Dissolved oxygen and nitrogen concentrations (ammonium and organic nitrogen) were the most important variables in determining the ecological water quality (EWQ). The result of three potential investment scenarios of the wastewater treatment infrastructure in the city of Varazdin on the EWQ of the River Drava was assessed. From this scenario-based analysis, it was concluded that upgrading the existing wastewater treatment plant with nitrogen and phosphorus removal will be insufficient to reach a good EWQ. Therefore, other point and diffuse pollution sources in the area should also be monitored and remediated to meet the European WFD standards. PMID- 25500470 TI - Simplifying impact of urban development on sewer systems. AB - Linking urban development and urban drainage models is a more and more popular approach when impacts of pavement of urban areas on sewer system performance are evaluated. As such an approach is a difficult task, this is not a feasible procedure for everyday engineering practice. We propose an alternative method, based on a developed simple near-quadratic relationship, which directly translates change (increase or decrease) of paved area into a change in the return period (RP) of the design rainfall event or design rainfall intensity. This formula is simple to use and compatible with existing design guidelines. A further advantage is that the calculated design RP can also be used to communicate the impact of a change in impervious areas to stakeholders or the public community. The method is developed using a set of 250 virtual and two real world case studies and hydrodynamic simulations. It is validated on a small catchment for which we compare system performance and redesigned pipe diameters. Of course such a simplification contains different uncertainties. But these uncertainties have to be seen in the context of overall uncertainties when trying to predict city development into the future. Hence it still is a significant advantage compared to today's engineering practice. PMID- 25500471 TI - Integrated hydraulic modelling of water supply and urban drainage networks for assessment of decentralized options. AB - The impact of climate change, water scarcity, land use change, population growth and also population shrinking can only be predicted with uncertainties. Especially for assets with a long planning horizon this is a critical part for planning and design. One solution is to make centralized organized water infrastructure with a long-planning horizon resilient and adaptive. For existing centralized infrastructure such a transition would be to increasingly implement decentralized measures. But such a transition can cause severe impacts on existing centralized infrastructure. Low flow conditions in urban drainage systems can cause sediment deposition, and for water supply systems water age problems may occur. This work focuses on city-scale analysis for assessing the impact of such measures. For that a coupled model for integrated city-scale analysis is applied and further developed. In addition, a geographic information system (GIS)-based approach for sensitivity analysis is enhanced and also implemented in that model. The developed approach is applied to assess the water infrastructure of an alpine case study. With the obtained results it is demonstrated how the planning process is enhanced by indicating where and where not to implement decentralized measures in an existing water infrastructure. PMID- 25500472 TI - Green-blue water in the city: quantification of impact of source control versus end-of-pipe solutions on sewer and river floods. AB - Urbanization and climate change trends put strong pressures on urban water systems. Temporal variations in rainfall, runoff and water availability increase, and need to be compensated for by innovative adaptation strategies. One of these is stormwater retention and infiltration in open and/or green spaces in the city (blue-green water integration). This study evaluated the efficiency of three adaptation strategies for the city of Turnhout in Belgium, namely source control as a result of blue-green water integration, retention basins located downstream of the stormwater sewers, and end-of-pipe solutions based on river flood control reservoirs. The efficiency of these options is quantified by the reduction in sewer and river flood frequencies and volumes, and sewer overflow volumes. This is done by means of long-term simulations (100-year rainfall simulations) using an integrated conceptual sewer-river model calibrated to full hydrodynamic sewer and river models. Results show that combining open, green zones in the city with stormwater retention and infiltration for only 1% of the total city runoff area would lead to a 30 to 50% reduction in sewer flood volumes for return periods in the range 10-100 years. This is due to the additional surface storage and infiltration and consequent reduction in urban runoff. However, the impact of this source control option on downstream river floods is limited. Stormwater retention downstream of the sewer system gives a strong reduction in peak discharges to the receiving river. However due to the difference in response time between the sewer and river systems, this does not lead to a strong reduction in river flood frequency. The paper shows the importance of improving the interface between urban design and water management, and between sewer and river flood management. PMID- 25500473 TI - The application of a Web-geographic information system for improving urban water cycle modelling. AB - Research in urban water management has experienced a transition from traditional model applications to modelling water cycles as an integrated part of urban areas. This includes the interlinking of models of many research areas (e.g. urban development, socio-economy, urban water management). The integration and simulation is realized in newly developed frameworks (e.g. DynaMind and OpenMI) and often assumes a high knowledge in programming. This work presents a Web based urban water management modelling platform which simplifies the setup and usage of complex integrated models. The platform is demonstrated with a small application example on a case study within the Alpine region. The used model is a DynaMind model benchmarking the impact of newly connected catchments on the flooding behaviour of an existing combined sewer system. As a result the workflow of the user within a Web browser is demonstrated and benchmark results are shown. The presented platform hides implementation specific aspects behind Web services based technologies such that the user can focus on his main aim, which is urban water management modelling and benchmarking. Moreover, this platform offers a centralized data management, automatic software updates and access to high performance computers accessible with desktop computers and mobile devices. PMID- 25500474 TI - Adaptation of sewer networks using integrated rehabilitation management. AB - The urban water structure is aging and in need of rehabilitation. Further, the need to address future challenges (climate change, urban development) also arise lines. This study investigates if it is possible to combine rehabilitation and adaptation measures. To do so, we combined an urban development model, an urban drainage model and a rehabilitation model. A case study of a medium-sized alpine city with a sewer length of 228 km and a population of 125,431 was used to develop and apply this method. A priority model to pinpoint the structures in need of replacement was used. This model considered a deterioration model, vulnerability estimation and other influences. Further different rehabilitation rates and methods were examined. The urban development model used is a simplistic approach specifically tailored for the field of urban infrastructure management. Climate change is considered in terms of climate change factors. All these different influences together create scenarios for which the construction costs and the flooding volume are estimated and compared. Consequently the aim of this paper was to test to which degree it is possible to reduce urban flooding by adapting those parts of the network which require rehabilitation anyway. In our case study it could be reduced by 5%. PMID- 25500475 TI - Modelling the urban water cycle as an integrated part of the city: a review. AB - In contrast to common perceptions, the urban water infrastructure system is a complex and dynamic system that is constantly evolving and adapting to changes in the urban environment, to sustain existing services and provide additional ones. Instead of simplifying urban water infrastructure to a static system that is decoupled from its urban context, new management strategies use the complexity of the system to their advantage by integrating centralised with decentralised solutions and explicitly embedding water systems into their urban form. However, to understand and test possible adaptation strategies, urban water modelling tools are required to support exploration of their effectiveness as the human technology-environment system coevolves under different future scenarios. The urban water modelling community has taken first steps to developing these new modelling tools. This paper critically reviews the historical development of urban water modelling tools and provides a summary of the current state of integrated modelling approaches. It reflects on the challenges that arise through the current practice of coupling urban water management tools with urban development models and discusses a potential pathway towards a new generation of modelling tools. PMID- 25500476 TI - Sampling, testing and modeling particle size distribution in urban catch basins. AB - The study analyzed the particle size distribution of particulate matter (PM) retained in two catch basins located, respectively, near a parking lot and a traffic intersection with common high levels of traffic activity. Also, the treatment performance of a filter medium was evaluated by laboratory testing. The experimental treatment results and the field data were then used as inputs to a numerical model which described on a qualitative basis the hydrological response of the two catchments draining into each catch basin, respectively, and the quality of treatment provided by the filter during the measured rainfall. The results show that PM concentrations were on average around 300 mg/L (parking lot site) and 400 mg/L (road site) for the 10 rainfall-runoff events observed. PM with a particle diameter of <45 MUm represented 40-50% of the total PM mass. The numerical model showed that a catch basin with a filter unit can remove 30 to 40% of the PM load depending on the storm characteristics. PMID- 25500477 TI - Optimise inlet condition and design parameters of a new sewer overflow screening device using numerical model. AB - After heavy rainfall, sewer overflow spills to receiving water bodies cause serious concern for the environment, aesthetics and public health. To overcome these problems this study investigated a new self-cleansing sewer overflow screening device. The device has a sewer overflow chamber, a rectangular tank and a slotted ogee weir to capture the gross pollutants. To design an efficient screening device a numerical computational fluid dynamic (CFD) model was used. A plausibility check of the CFD model was done using a one-dimensional analytical model. Results showed that an inlet parallel to the weir ensured better self cleansing than an inlet perpendicular to the weir. Perforations should be at the bottom of the weir to get increased velocity and shear stress to create a favourable self-cleaning effect of the screening device. Increasing inlet length from 0.3 to 1.5 m reduced wave reflection up to 10%, which increased flow uniformity downstream and improved self-cleansing effect. The orientation of the ogee weir with the rectangular tank was found most uniform with a 1:3 (horizontal:vertical) slope. These results will help to maximise functional efficiency of the new sewer overflow screening device. Otherwise it would be too expensive to alter after installation and at times difficult to customise accordingly to existing urban drainage systems. PMID- 25500478 TI - Uncertainty and urban water recharge for managing groundwater availability using decision support. AB - Quantifying groundwater availability depends upon sound methods and the use of integrated models. To determine availability or sustainable yield, the influence of scientific uncertainty from key sources, such as anthropogenic recharge, must be considered. This study evaluates uncertainty in recharge interpretations on the modeled available water balance for an urban case in Texas, USA. Analyses are completed using the Groundwater Decision Support System, which is a research code base for an integrated modeling. The case study develops spatially and temporally resolved recharge interpretations based on NEXRAD precipitation and detailed land use data. Results demonstrate the implications of scientific uncertainty as it influences recommendations for policy and urban water management decisions that are based on modeled outputs. Geospatial methods account for spatial and temporal components and can be replicated for other systems. These methods are also useful for resolving uncertainty in relation to the influence of urbanization on recharge through land use change. PMID- 25500479 TI - Gout flare-ups are twice as likely at night, study finds. PMID- 25500480 TI - Protective effect of metformin against walker 256 tumor growth is not dependent on metabolism improvement. AB - BACKGROUND/AIMS: The objective of the current work was to test the effect of metformin on the tumor growth in rats with metabolic syndrome. METHODS: We obtained pre-diabetic hyperinsulinemic rats by neonatal treatment with monosodium L-glutamate (MSG), which were chronically treated every day, from weaning to 100 day old, with dose of metformin (250 mg/kg body weight). After the end of metformin treatment, the control and MSG rats, treated or untreated with metformin, were grafted with Walker 256 carcinoma cells. Tumor weight was evaluated 14 days after cancer cell inoculation. The blood insulin, glucose levels and glucose-induced insulin secretion were evaluated. RESULTS: Chronic metformin treatment improved the glycemic homeostasis in pre-diabetic MSG-rats, glucose intolerance, tissue insulin resistance, hyperinsulinemia and decreased the fat tissue accretion. Meanwhile, the metformin treatment did not interfere with the glucose insulinotropic effect on isolated pancreatic islets. Chronic treatment with metformin was able to decrease the Walker 256 tumor weight by 37% in control and MSG rats. The data demonstrated that the anticancer effect of metformin is not related to its role in correcting metabolism imbalances, such as hyperinsulinemia. However, in morphological assay to apoptosis, metformin treatment increased programmed cell death. CONCLUSION: Metformin may have a direct effect on cancer growth, and it may programs the rat organism to attenuate the growth of Walker 256 carcinoma. PMID- 25500483 TI - CE: Long-term outcomes after repair of congenital heart defects: part 1. AB - Many congenital heart defects can be repaired, but long-term monitoring is often required to forestall possible complications. This two-part article reviews 10 common congenital heart defects, their repairs, and their common long-term outcomes, along with the implications for nurses in both cardiac and noncardiac settings. Here, in part 1, the author reviews six defects: bicuspid aortic valve, atrial septal defect, ventricular septal defect, atrioventricular septal defect, coarctation of the aorta, and pulmonic stenosis. PMID- 25500481 TI - In vivo microscopy of microvessel oxygenation and network connections. AB - Abnormal or compromised microvascular function is a key component of various diseases. In vivo microscopy of microvessel function in preclinical models can be useful for the study of a disease state and effects of new treatments. Wide-field imaging of microvascular oxygenation via hemoglobin (Hb) saturation measurements has been applied in various applications alone and in combination with other measures of microvessel function, such as blood flow. However, most current combined imaging methods of microvessel function do not provide direct information on microvessel network connectivity or changes in connections and blood flow pathways. First-pass fluorescence (FPF) imaging of a systemically administered fluorescent contrast agent can be used to directly image blood flow pathways and connections relative to a local supplying arteriole in a quantitative manner through measurement of blood supply time (BST). Here, we demonstrate the utility of information produced by the combination of Hb saturation measurements via spectral imaging with BST measurements via FPF imaging for correlation of microvessel oxygenation with blood flow pathways and connections throughout a local network. Specifically, we show network pathway effects on oxygen transport in normal microvessels, dynamic changes associated with wound healing, and pathological effects of abnormal angiogenesis in tumor growth and development. PMID- 25500484 TI - CE: The obesity epidemic, part 2: nursing assessment and intervention. AB - Although there are many gaps in our understanding of the mechanisms underlying obesity, several nursing strategies have proven effective in combating this public health crisis. This article, the second in a two-part series, presents a theoretical framework to guide nursing assessment of affected patients and their families, thereby informing intervention. The authors discuss the effects of stigma and bias on the treatment of obesity; how to conduct a thorough assessment of an obese patient; the effectiveness of the most common lifestyle, pharmacologic, and surgical interventions for obesity; and issues to consider in the treatment of obese children. Part 1, which appeared in last month's issue, provided background on the epidemic; defined terms used in obesity treatment; and described pathophysiologic, psychological, and social factors that influence weight control. PMID- 25500485 TI - Bioavailability and pharmacokinetic profile of a newly-developed twice-a-day sustained-release paracetamol formulation. AB - OBJECTIVE: A new twice daily sustained-release (SR) paracetamol formulation was developed to improve convenience and enhance patient compliance for treatment of pain from chronic diseases. This research aimed to evaluate bioavailability and compare pharmacokinetic (PK) properties of the new SR paracetamol formulation (2x1,000 mg) with those of immediate-release (IR) paracetamol (2x500 mg) and existing extended-release (ER) paracetamol (2x665 mg). METHODS: Two randomized, single-dose, 4-way crossover studies were conducted. A total of 28 healthy male and female volunteers participated in each study. The relative bioavailability, partial extent of absorption, overall elimination, food effect, and safety were evaluated. RESULTS: The estimates of relative bioavailability of new SR with IR formulation based on dose-adjusted AUC0-inf were 91% (0.86-0.96) for the fasted state and 99% (0.95-1.02) for the fed state, while these estimates comparing new SR with ER formulation were 99% (0.96-1.03) in the fasted state and 98% (0.95 1.02) in the fed state. The accumulated mean time period at or above the minimal therapeutic plasma paracetamol concentration for the new SR was from 90% to 112% longer than that of the IR formulation, in fasted and fed state, respectively. Food significantly increased Cmax of SR formulation, with ratios fast vs. fed 0.79 (p<0.0001) and 0.77 (p<0.0001) in study I and II, respectively. CONCLUSIONS: The new SR formulation was well absorbed, with more than 90% relative bioavailability as compared to the currently marketed IR and ER products and better sustained-release PK characteristics, which make it suitable for twice daily paracetamol treatment. PMID- 25500486 TI - An open-label, randomized bioavailability study with alternative methods of administration of crushed ticagrelor tablets in healthy volunteers. AB - OBJECTIVE: To compare the bioavailability and safety profile of crushed ticagrelor tablets suspended in water and administered orally or via nasogastric tube, with that of whole tablets administered orally. METHODS: In this single center, open-label, randomized, three-treatment crossover study, 36 healthy volunteers were randomized to receive a single 90-mg dose of ticagrelor administered orally as a whole tablet or as crushed tablets suspended in water and given orally or via a nasogastric tube into the stomach, with a minimum 7-day wash-out between treatments. Plasma concentrations of ticagrelor and AR-C124910XX were assessed at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36, and 48 hours post ticagrelor dose for pharmacokinetic analyses. Safety and tolerability was assessed throughout the study. RESULTS: At 0.5 hours postdose, plasma concentrations of ticagrelor and AR-C124910XX were higher with crushed tablets administered orally (148.6 ng/mL and 13.0 ng/mL, respectively) or via nasogastric tube (264.6 ng/mL and 28.6 ng/mL, respectively) compared with whole-tablet administration (33.3 ng/mL and 5.2 ng/mL, respectively). A similar trend was observed at 1 hour postdose. Ticagrelor tmax was shorter following crushed vs. whole-tablet administration (1 vs. 2 hours, respectively). Geometric mean ratios between treatments for AUC and Cmax were contained within the bioequivalence limits of 80-125% for ticagrelor and AR-C124910XX. All treatments were generally well tolerated. CONCLUSIONS: Ticagrelor administered as a crushed tablet is bioequivalent to whole-tablet administration, independent of mode of administration (oral or via nasogastric tube), and resulted in increased plasma concentrations of ticagrelor and ARC124910XX at early timepoints. PMID- 25500487 TI - Single- and multiple-dose pharmacokinetics and pharmacodynamics of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants. AB - OBJECTIVE: To evaluate the pharmacokinetics of oral canagliflozin and its O glucuronide metabolites (M7 and M5) after single and multiple doses in healthy adult participants. The pharmacodynamics, safety, and tolerability of canagliflozin were also evaluated. METHODS: In this open-label, single- (day 1) and multiple-dose (days 4-9), parallel-group, phase 1 study, 27 healthy participants were randomized into three groups (1:1:1) to receive 50, 100, or 300 mg canagliflozin. Pharmacokinetics and pharmacodynamics were assessed at pre pecified timepoints on days 1, 9, and 10. RESULTS: Mean area under the plasma concentration-time curve, and the maximum observed plasma concentration of canagliflozin, M7, and M5 increased in a dose-dependent manner, across all the 3 doses, following single- and multiple-dose administration. The mean apparent elimination half-lives of canagliflozin, M7, and M5 were independent of the dose. Canagliflozin decreased the renal threshold for glucose (RTG) and increased the urinary glucose excretion (UGE) in a concentration- and dose-dependent manner. The relationship between drug concentrations and RTG was described by a sigmoidal relationship with RTGmin (minimum value of RTG) of 37.5 ng/mL (95% confidence interval (CI): 34.3, 40.8) and half-maximal effective concentration (EC50) of 21 ng/mL (95% CI: 18.3, 23.8). No deaths, serious adverse events, hypoglycemic events, or discontinuations due to adverse events were observed. CONCLUSION: Pharmacokinetics of canagliflozin and its metabolites (M7 and M5) were linear, and no time-dependent changes were observed after single- and multiple-dose administration. Similarly, pharmacodynamic effects of canagliflozin on RTG and UGE were found to be dose- and concentration-dependent. Overall, canagliflozin was well-tolerated in healthy participants. PMID- 25500488 TI - Safety, tolerability and pharmacokinetics of liposomal curcumin in healthy humans. AB - INTRODUCTION: Experimental studies have shown that liposomal curcumin can exert a reduction in tumor growth in pancreatic and colorectal cancer. In this phase I clinical trial we investigated the pharmacokinetics, safety, and tolerability of intravenously administered liposomal curcumin in healthy subjects. MATERIAL AND METHODS: 50 male and female participants were included in this randomized, placebo-controlled double-blind phase I dose escalation study. Subjects received a single dose of liposomal curcumin (10 - 400 mg/m2; n = 2 - 6 per group) or placebo over 2 hours intravenously. RESULTS: Dose-dependent increases in the plasma concentrations of curcumin and its metabolite tetrahydrocurcumin (THC) were detected. After the end of drug infusion, curcumin and THC plasma concentrations decreased within 6 - 60 minutes below the limit of quantification. Mean urinary excretion was ~ 0.1% of total systemic clearance. Liposomal curcumin was tolerated well, but a transient red blood cell echinocyte formation with concomitant increase in mean cellular volume was observed at dosages >= 120 mg/m2. CONCLUSION: Short-term intravenous dosing of liposomal curcumin appears to be safe up to a dose of 120 mg/m2. Changes in red blood cell morphology may represent a dose limiting sign of toxicity. PMID- 25500490 TI - Atrial fibrillation: still an issue. PMID- 25500491 TI - The European Heart Academy. AB - One of Dr Panos Vardas' visions for the European Society of Cardiology has been achieved. PMID- 25500489 TI - Hemodynamic responses during induction: comparison of Marsh and Schnider pharmacokinetic models. AB - BACKGROUND: Hemodynamic stability is one of the most critical concerns during induction of anesthesia. Whether the pharmacokinetic model by Marsh or the one by Schnider will produce better hemodynamic stability remains unclear. This study compared hemodynamic changes during induction between the two models. METHODS: 60 patients who underwent elective surgery were randomly assigned to plasma target controlled infusion by Marsh's (n = 30) or Schnider's (n = 30) model with an initial target concentration of 4 MUg*mL-1. The target was then reset and gradually titrated to a sedation level with a narcotrend index (NI) below 64. Stroke volume, cardiac output, systemic vascular resistance, arterial pressure, target, and effect site concentration, and dose of propofol infused were recorded every minute during the first 25 minutes of infusion. RESULTS: Throughout the first 25 minutes, stroke volume index and cardiac index were decreased significantly in both Marsh and Schnider groups, but no statistical difference was detected between the groups (p > 0.05). Central venous pressure (CVP), systemic vascular resistance index (SVRI), and heart rate (HR) did not significantly change during induction (p > 0.05). Time to loss of responsiveness (LOR), and time for NI to decrease to 64 was faster in Marsh than in Schnider (1.51 +/- 0.8 minutes vs. 2.8 +/- 1.2 min, p < 0.001; 3.3 +/- 2.0 minutes vs. 5.2 +/- 2.3 minutes, p < 0.01, respectively). CONCLUSIONS: When target concentrations are titrated according to NI during induction of anesthesia, Marsh's model could induce sedation faster than Schnider's. Meanwhile, hemodynamic changes were not observed to be statistically different between the two models. Hypotension induced by plasma target-controlled infusion of propofol could mainly be attributed to decreased stroke volume instead of vascular dilation. PMID- 25500492 TI - Lack of intracellular trehalose affects formation of Escherichia coli persister cells. AB - Persisters are dormant antibiotic-tolerant cells that usually compose a small fraction of bacterial populations. In this work, we focused on the role of trehalose in persister formation. We found that the DeltaotsA mutant, which is unable to synthesize trehalose, produced increased levels of persisters in the early stationary phase and under heat stress conditions. The lack of trehalose in the DeltaotsA mutant resulted in oxidative stress, manifested by increased membrane lipid peroxidation after heat shock. Stationary DeltaotsA cells additionally exhibited increased levels of oxidized proteins and apurinic/apyrimidinic sites in DNA as compared to WT cells. Oxidative stress caused by the lack of trehalose was accompanied by the overproduction of extracellular indole, a signal molecule that has been shown to stimulate persister formation. Our major conclusion is that intracellular trehalose protects E. coli cells against oxidative stress and limits indole synthesis, which in turn inhibits the formation of persisters. PMID- 25500493 TI - Essential oils have different effects on human pathogenic and commensal bacteria in mixed faecal fermentations compared with pure cultures. AB - A static batch culture system inoculated with human faeces was used to determine the influence of essential oil compounds (EOCs) on mixed faecal microbiota. Bacteria were quantified using quantitative PCR of 16S rRNA genes. Incubation for 24 h of diluted faeces from six individuals caused enrichment of Bifidobacterium spp., but proportions of other major groups were unaffected. Thymol and geraniol at 500 p.p.m. suppressed total bacteria, resulting in minimal fermentation. Thymol at 100 p.p.m. had no effect, nor did eugenol or nerolidol at 100 or 500 p.p.m. except for a slight suppression of Eubacterium hallii. Methyl isoeugenol at 100 or 500 p.p.m. suppressed the growth of total bacteria, accompanied by a large fall in the molar proportion of propionate formed. The relative abundance of Faecalibacterium prausnitzii was unaffected except with thymol at 500 p.p.m. The ability of EOCs to control numbers of the pathogen Clostridium difficile was investigated in a separate experiment, in which the faecal suspensions were amended by the addition of pure culture of C. difficile. Numbers of C. difficile were suppressed by thymol and methyl isoeugenol at 500 p.p.m. and to a lesser extent at 100 p.p.m. Eugenol and geraniol gave rather similar suppression of C. difficile numbers at both 100 and 500 p.p.m. Nerolidol had no significant effect. It was concluded from these and previous pure-culture experiments that thymol and geraniol at around 100 p.p.m. could be effective in suppressing pathogens in the small intestine, with no concern for beneficial commensal colonic bacteria in the distal gut. PMID- 25500494 TI - Inhibition of polysaccharide synthesis by the sinR orthologue PGN_0088 is indirectly associated with the penetration of Porphyromonas gingivalis biofilms by macrolide antibiotics. AB - Microbes commonly adhere to surfaces, aggregate in self-produced extracellular polymeric substances (EPS) and live in biofilms. Periodontitis is a serious oral infection that is initiated by the formation of biofilms by Porphyromonas gingivalis. EPS act as a barrier that protects biofilm-forming cells against sources of stress, including those induced by host immune cells and antimicrobial agents. Therefore, drugs intended to kill such micro-organisms cannot be used for the treatment of biofilm infections. Our previous studies revealed that subminimal inhibitory concentrations (subMIC) of two macrolide antibiotics (azithromycin, AZM and erythromycin, ERY) reduced P. gingivalis biofilms. Furthermore, we demonstrated that the Bacillus subtilis sinR orthologue (PGN_0088) inhibits the synthesis of carbohydrates that are components of EPS in P. gingivalis biofilms. Here, we constructed a novel sinR mutant from P. gingivalis ATCC 33277 and reveal that the increased abundance of carbohydrate in EPS of the mutant led to a reduced infiltration rate of AZM and ERY through EPS, and consequently elevated biofilm resistance to these macrolides. Detailed elucidation of the interaction between the product of the sinR gene and EPS will assist in the development of novel approaches that target EPS to prevent and inhibit the formation of biofilms. PMID- 25500495 TI - Sortase-deficient lactobacilli: effect on immunomodulation and gut retention. AB - Surface proteins of probiotic microbes, including Lactobacillus acidophilus and Lactobacillus gasseri, are believed to promote retention in the gut and mediate host-bacterial communications. Sortase, an enzyme that covalently couples a subset of extracellular proteins containing an LPXTG motif to the cell surface, is of particular interest in characterizing bacterial adherence and communication with the mucosal immune system. A sortase gene, srtA, was identified in L. acidophilus NCFM (LBA1244) and L. gasseri ATCC 33323 (LGAS_0825). Additionally, eight and six intact sortase-dependent proteins were predicted in L. acidophilus and L. gasseri, respectively. Due to the role of sortase in coupling these proteins to the cell wall, DeltasrtA deletion mutants of L. acidophilus and L. gasseri were created using the upp-based counterselective gene replacement system. Inactivation of sortase did not cause significant alteration in growth or survival in simulated gastrointestinal juices. Meanwhile, both DeltasrtA mutants showed decreased adhesion to porcine mucin in vitro. Murine dendritic cells exposed to the DeltasrtA mutant of L. acidophilus or L. gasseri induced lower levels of pro-inflammatory cytokines TNF-alpha and IL-12, respectively, compared with the parent strains. In vivo co-colonization of the L. acidophilus DeltasrtA mutant and its parent strain in germ-free 129S6/SvEv mice resulted in a significant one-log reduction of the DeltasrtA mutant population. Additionally, a similar reduction of the DeltasrtA mutant was observed in the caecum. This study shows for the first time that sortase-dependent proteins contribute to gut retention of probiotic microbes in the gastrointestinal tract. PMID- 25500496 TI - How much should we spend on health care? AB - BACKGROUND: For a tax-funded health service such as the NHS, how much is spent in total is a crucial (and necessary) decision which precedes and determines the consumption of health care by individuals. Determining total spending in private markets is not a particularly important (or necessarily interesting) issue as it is merely the sum of all the private spending decisions of individual consumers in the market. However, economists would argue there are parallels between these (collective) public and (individual) private decisions; both involve balancing costs and benefits, and trade offs with other ways of spending limited budgets. MAIN FINDINGS: Economists would further suggest a decision rule to identify how much to spend on health care (or anything else for that matter); continue increasing spending on health care until the next pound yields greater benefit from spending on some other, non-health, care activity. Although NICE operate a version of this decision rule when assessing the cost effectiveness of individual health technologies, its wider application to decide on total health spending (versus other beneficial uses of society's scarce resources) has prohibitive data implications and requires agreement on the value of the benefits side of the calculation. CONCLUSIONS: Given that a decision has to be made however, in practice the decision process falls within the political sphere, informed, up to a point, by data on the determinants of spending (eg population projections), international benchmarking and the exigencies of prevailing macroeconomic circumstances. PMID- 25500498 TI - Permissive hypercapnia: what to remember. AB - PURPOSE OF REVIEW: Hypercapnia is a central component of diverse respiratory disorders, while 'permissive hypercapnia' is frequently used in ventilatory strategies for patients with severe respiratory failure. This review will present data from recent studies relating to hypercapnia, focusing on issues that are of importance to anesthesiologists caring for the surgical and/or critically ill patient. RECENT FINDINGS: Protective ventilatory strategies involving permissive hypercapnia are widely used in patients with severe respiratory failure, particularly in acute respiratory distress syndrome, status asthmaticus, chronic obstructive pulmonary disease and neonatal respiratory failure. The physiologic effects of hypercapnia are increasingly well understood, and important recent insights have emerged regarding the cellular and molecular mechanisms of action of hypercapnia and acidosis. Acute hypercapnic acidosis is protective in multiple models of nonseptic lung injury. These effects are mediated in part through inhibition of the NF-kappaB pathway. Hypercapnia-mediated NF-kappaB inhibition may also explain several deleterious effects, including delayed epithelial wound healing and decreased bacterial killing, which has been demonstrated to cause worse lung injury in prolonged untreated pneumonia models. SUMMARY: The mechanisms of action of hypercapnia and acidosis continue to be elucidated, and this knowledge is central to determining the safety and therapeutic utility of hypercapnia in protective lung ventilatory strategies. PMID- 25500497 TI - Detailed assessment of renal function in a proband with Harboyan syndrome caused by a novel homozygous SLC4A11 nonsense mutation. AB - BACKGROUND/AIMS: To identify the underlying molecular genetic cause of disease in a patient with Harboyan syndrome and to perform a detailed assessment of her renal function. We also assessed the influence of the SLC4A11 mutation identified on the corneal endothelium in the heterozygous state. METHODS: A 55-year-old female was examined ophthalmologically, audiologically and nephrologically including 24-hour urine collection. The coding region of SLC4A11 was directly sequenced. Specular microscopy was performed in the proband's 21-year-old daughter. RESULTS: The proband had bilateral iridectomy at the age of 3 months because of an initial diagnosis of congenital glaucoma and since the age of 12 years she underwent several keratoplasties in each eye. Nephrological examination did not reveal any abnormalities. Moderate bilateral sensorineural hearing loss was confirmed by audiometry. A novel homozygous mutation predicted to lead to a premature stop codon at the protein level, c.2188C>T; p.(Arg730*), was identified in SLC4A11. No changes in corneal endothelial cell morphology or density were observed in the heterozygous daughter. CONCLUSION: In contrast to the Slc4a11(-/ ) mouse, no abnormalities in daily renal ion excretion or polyuria were observed in the Harboyan syndrome patient. The mutation identified does not affect corneal endothelial cell morphology or density in the heterozygous state. PMID- 25500499 TI - A Two-Week-Old Term Baby With a Black Tongue. PMID- 25500500 TI - Serotype 19A Bacteremic Pneumococcal Pneumonia After 4 Doses of 13-Valent Conjugate Vaccine: A Review of Pneumococcal Conjugate Vaccine Effectiveness. PMID- 25500501 TI - Reversible Teeth Discoloration in Children: A Linezolid Therapy Side Effect. PMID- 25500502 TI - Attentional filtering of visual information by neuronal ensembles in the primate lateral prefrontal cortex. AB - The activity of neurons in the primate lateral prefrontal cortex (LPFC) is strongly modulated by visual attention. Such a modulation has mostly been documented by averaging the activity of independently recorded neurons over repeated experimental trials. However, in realistic settings, ensembles of simultaneously active LPFC neurons must generate attentional signals on a single trial basis, despite the individual and correlated variability of neuronal responses. Whether, under these circumstances, the LPFC can reliably generate attentional signals is unclear. Here, we show that the simultaneous activity of neuronal ensembles in the primate LPFC can be reliably decoded to predict the allocation of attention on a single-trial basis. Decoding was sensitive to the noise correlation structure of the ensembles. Additionally, it was resilient to distractors, predictive of behavior, and stable over weeks. Thus, LPFC neuronal ensemble activity can reliably encode attention within behavioral time frames, despite the noisy and correlated nature of neuronal activity. PMID- 25500503 TI - Clinical response to antiestrogen therapy in platinum-resistant ovarian cancer patients and the role of tumor estrogen receptor expression status. AB - OBJECTIVE: This study aimed to determine the progression-free interval (PFI) for patients with platinum-resistant ovarian cancer on antiestrogen therapy (AET), and to correlate PFI with tumor estrogen receptor (ER) expression status. MATERIALS AND METHODS: This single-institution retrospective cohort study investigated platinum-resistant epithelial ovarian, fallopian tube, and primary peritoneal cancers treated with tamoxifen or an aromatase inhibitor from January 1999 to January 2012. Median PFI was calculated and a 95% confidence interval was constructed by bootstrapping. Relationships of PFI with disease characteristics were examined using 1-way analysis of variance or Pearson correlation. Estrogen receptor status of tumor specimens was assessed by immunohistochemistry. Progression-free interval was compared between ER groups with the Mann-Whitney test. Kaplan-Meier estimate was used to determine overall survival. RESULTS: Ninety-nine patients met inclusion criteria: 77 (78%) received tamoxifen and 22 (22%) an aromatase inhibitor. Patients had a mean of 4 prior chemotherapy regimens (range, 1-14). Median PFI for any AET was 4.0 months (range, 1-49; 95% confidence interval, 3.0-5.0). Progression-free interval was independent of the number of prior treatments and type of AET, but longer with earlier stage at diagnosis. Estrogen receptor status was obtained for 63 patients, 44 were positive and 19 were negative. Progression-free interval was not statistically significant between ER-positive (median, 4.0 months) and ER-negative (median, 2.0 months) tumor status (P = 0.36). CONCLUSIONS: This is the largest study to date investigating AET in heavily pretreated, platinum-resistant ovarian cancer patients. The median PFI of 4.0 months is comparable to standard cytotoxic therapies, and some patients with PFI greater than this median interval had ER negative tumors. Given the limited adverse effects of AET, as well as low cost including oral administration, this treatment should be considered in all patients with platinum-resistant ovarian cancer. PMID- 25500504 TI - Lysophosphatidic acid as a lipid mediator with multiple biological actions. AB - Lysophosphatidic acid (LPA) is one of the simplest glycerophospholipids with one fatty acid chain and a phosphate group as a polar head. Although LPA had been viewed just as a metabolic intermediate in de novo lipid synthetic pathways, it has recently been paid much attention as a lipid mediator. LPA exerts many kinds of cellular processes, such as cell proliferation and smooth muscle contraction, through cognate G protein-coupled receptors. Because lipids are not coded by the genome directly, it is difficult to know their patho- and physiological roles. However, recent studies have identified several key factors mediating the biological roles of LPA, such as receptors and producing enzymes. In addition, studies of transgenic and gene knockout animals for these LPA-related genes, have revealed the biological significance of LPA. In this review we will summarize recent advances in the studies of LPA production and its roles in both physiological and pathological conditions. PMID- 25500505 TI - Identification of two promoters for human D-amino acid oxidase gene: implication for the differential promoter regulation mediated by PAX5/PAX2. AB - D-amino acid oxidase (DAO) is a flavoenzyme that metabolizes d-amino acids. Until now, the DAO expression mechanism is still unclear. Our assessment of human DAO (hDAO) promoter activity using luciferase reporter system indicated the proximal upstream region of exon1 (-237/+1) has promoter activity (P1). Interestingly, we identified an alternative promoter in the proximal upstream region of exon2 (+4,126/+4,929) (P2). This alternative promoter has stronger activity than that of P1. Our results also revealed a negative regulatory segment (+1,163/+1,940) in intron1; that would act in concert with P1 and P2. Bioinformatics analyses elucidated the conservation of transcription factor PAX5 family binding sites among species. These sites (-60/-31) and (+4,464/+4,493), locate in P1 and P2 of hDAO, respectively. Gel shift assays demonstrated P1 contains a site (-60/-31) for PAX5 binding while P2 has three sites for both paired box gene 2 (PAX2) and paired box gene 5 (PAX5) binding. The dual roles of PAX5 family in regulating hDAO transcription by modulating promoter activity of P1 and activating promoter activity of P2 were implicated based on the site-directed mutagenesis experiment. Altogether, our data suggested the differential regulation of hDAO expression by two promoters whose activities may be modulated by the binding of PAX2 and PAX5. PMID- 25500506 TI - Association Between Overweight or Obesity and Lumbar Disk Diseases: A Meta Analysis. AB - STUDY DESIGN: A meta-analysis. OBJECTIVE: We performed this meta-analysis to evaluate the association between overweight and lumbar disease. SUMMARY OF BACKGROUND DATA: An extensive English language literature retrieval regarding the association between overweight and the risk of lumbar disease was conducted on Public Medline and Excerpta Medica Database until May 2014. METHODS: Meta analysis for all the included literatures was performed by STATA 11.0 to summarize test performance with forest plots after heterogeneity test. Moreover, subgroup and sensitivity analyses were performed to examine the potential candidate effect factors. Afterward, the likelihood of publication bias was assessed by constructing funnel plots and performing Begg rank correlation test and Egger linear regression method. RESULTS: A total of 5 studies satisfied the predefined eligibility criteria, including 1749 cases with lumbar disk diseases and 1885 controls. Altogether, overweight was associated with increased risk of lumbar disease [odds ratio (OR)=1.45; 95% confidence interval (CI), 1.27, 1.66; P<0.001]. Moreover, subgroup analysis proved that overweight was a predominant factor in development of lumbar disease compared with age and sex. Although significant publication bias was observed in our meta-analysis, we proved high credibility of meta-analysis result using trim and fill method (OR=1.27; 95% CI, 1.06, 1.53). CONCLUSIONS: We suggest that overweight might increase the risk of lumbar diseases, and weight control should be considered for overweight or obese population to reduce the occurrence and development of lumbar disease. PMID- 25500507 TI - Is there a common water-activity limit for the three domains of life? AB - Archaea and Bacteria constitute a majority of life systems on Earth but have long been considered inferior to Eukarya in terms of solute tolerance. Whereas the most halophilic prokaryotes are known for an ability to multiply at saturated NaCl (water activity (a(w)) 0.755) some xerophilic fungi can germinate, usually at high-sugar concentrations, at values as low as 0.650-0.605 a(w). Here, we present evidence that halophilic prokayotes can grow down to water activities of <0.755 for Halanaerobium lacusrosei (0.748), Halobacterium strain 004.1 (0.728), Halobacterium sp. NRC-1 and Halococcus morrhuae (0.717), Haloquadratum walsbyi (0.709), Halococcus salifodinae (0.693), Halobacterium noricense (0.687), Natrinema pallidum (0.681) and haloarchaeal strains GN-2 and GN-5 (0.635 a(w)). Furthermore, extrapolation of growth curves (prone to giving conservative estimates) indicated theoretical minima down to 0.611 aw for extreme, obligately halophilic Archaea and Bacteria. These were compared with minima for the most solute-tolerant Bacteria in high-sugar (or other non-saline) media (Mycobacterium spp., Tetragenococcus halophilus, Saccharibacter floricola, Staphylococcus aureus and so on) and eukaryotic microbes in saline (Wallemia spp., Basipetospora halophila, Dunaliella spp. and so on) and high-sugar substrates (for example, Xeromyces bisporus, Zygosaccharomyces rouxii, Aspergillus and Eurotium spp.). We also manipulated the balance of chaotropic and kosmotropic stressors for the extreme, xerophilic fungi Aspergillus penicilloides and X. bisporus and, via this approach, their established water-activity limits for mycelial growth (~0.65) were reduced to 0.640. Furthermore, extrapolations indicated theoretical limits of 0.632 and 0.636 a(w) for A. penicilloides and X. bisporus, respectively. Collectively, these findings suggest that there is a common water-activity limit that is determined by physicochemical constraints for the three domains of life. PMID- 25500508 TI - Using the class 1 integron-integrase gene as a proxy for anthropogenic pollution. AB - Around all human activity, there are zones of pollution with pesticides, heavy metals, pharmaceuticals, personal care products and the microorganisms associated with human waste streams and agriculture. This diversity of pollutants, whose concentration varies spatially and temporally, is a major challenge for monitoring. Here, we suggest that the relative abundance of the clinical class 1 integron-integrase gene, intI1, is a good proxy for pollution because: (1) intI1 is linked to genes conferring resistance to antibiotics, disinfectants and heavy metals; (2) it is found in a wide variety of pathogenic and nonpathogenic bacteria; (3) its abundance can change rapidly because its host cells can have rapid generation times and it can move between bacteria by horizontal gene transfer; and (4) a single DNA sequence variant of intI1 is now found on a wide diversity of xenogenetic elements, these being complex mosaic DNA elements fixed through the agency of human selection. Here we review the literature examining the relationship between anthropogenic impacts and the abundance of intI1, and outline an approach by which intI1 could serve as a proxy for anthropogenic pollution. PMID- 25500509 TI - Adult blood-feeding tsetse flies, trypanosomes, microbiota and the fluctuating environment in sub-Saharan Africa. AB - The tsetse fly vector transmits the protozoan Trypanosoma brucei, responsible for Human African Trypanosomiasis, one of the most neglected tropical diseases. Despite a recent decline in new cases, it is still crucial to develop alternative strategies to combat this disease. Here, we review the literature on the factors that influence trypanosome transmission from the fly vector to its vertebrate host (particularly humans). These factors include climate change effects to pathogen and vector development (in particular climate warming), as well as the distribution of host reservoirs. Finally, we present reports on the relationships between insect vector nutrition, immune function, microbiota and infection, to demonstrate how continuing research on the evolving ecology of these complex systems will help improve control strategies. In the future, such studies will be of increasing importance to understand how vector-borne diseases are spread in a changing world. PMID- 25500510 TI - Spatial scales of bacterial community diversity at cold seeps (Eastern Mediterranean Sea). AB - Cold seeps are highly productive, fragmented marine ecosystems that form at the seafloor around hydrocarbon emission pathways. The products of microbial utilization of methane and other hydrocarbons fuel rich chemosynthetic communities at these sites, with much higher respiration rates compared with the surrounding deep-sea floor. Yet little is known as to the richness, composition and spatial scaling of bacterial communities of cold seeps compared with non-seep communities. Here we assessed the bacterial diversity across nine different cold seeps in the Eastern Mediterranean deep-sea and surrounding seafloor areas. Community similarity analyses were carried out based on automated ribosomal intergenic spacer analysis (ARISA) fingerprinting and high-throughput 454 tag sequencing and were combined with in situ and ex situ geochemical analyses across spatial scales of a few tens of meters to hundreds of kilometers. Seep communities were dominated by Deltaproteobacteria, Epsilonproteobacteria and Gammaproteobacteria and shared, on average, 36% of bacterial types (ARISA OTUs (operational taxonomic units)) with communities from nearby non-seep deep-sea sediments. Bacterial communities of seeps were significantly different from those of non-seep sediments. Within cold seep regions on spatial scales of only tens to hundreds of meters, the bacterial communities differed considerably, sharing <50% of types at the ARISA OTU level. Their variations reflected differences in porewater sulfide concentrations from anaerobic degradation of hydrocarbons. This study shows that cold seep ecosystems contribute substantially to the microbial diversity of the deep-sea. PMID- 25500511 TI - Bacterial community responses to a gradient of alkaline mountaintop mine drainage in Central Appalachian streams. AB - Microbial community composition and diversity change along chemical gradients, leading to the expectation that microbial community information might provide new gradient characterizations. Here we examine stream bacteria composition and diversity along a strong chemical gradient in Central Appalachian streams. Coal mining in the region generates alkaline mine drainage (AlkMD), causing dramatic increases in conductivity, alkalinity, sulfate and metals sufficient to degrade stream macrobiota communities throughout the ecoregion. In this study, we examined the relationship between water and biofilm chemistry and biofilm bacteria taxonomic composition in streams where active and reclaimed surface coal mines occupied 0-96% of watershed surface area. We incubated wood veneers in each stream site for 4 months to develop biofilms on similar substrates. We sampled water chemistry at the time of deployment and collection, and after 1 month. Following incubation, we collected biofilms for microbial and chemical characterization. Microbial composition was determined by pyrosequencing 16S rRNA amplicons. Biofilm subsamples were analyzed by inductively coupled plasma mass spectrometry to determine metal concentrations. Our results show that microbial community composition differed significantly between AlkMD-exposed and AlkMD unexposed sites, and that compositional dissimilarity increased with AlkMD loading. Diversity was not correlated with pH or extent of upstream mining, but instead correlated with biofilm concentrations of Cd, Mn, Zn and Ni. Within mined sites, the extent of upstream mining was negatively correlated with taxonomic richness. Despite major compositional shifts, functional capacity predicted with PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) correlated with mining in only 3 of 43 level-2 KEGG (Kyoto Encyclopedia of Genes and Genomes) Orthology groups. PMID- 25500513 TI - Triple negative breast cancer: the role of metabolic pathways. AB - The incidence of breast cancer in Malaysia and other Asian countries is on the increase, reflecting lifestyle changes some of which are known risk factors for the development of breast cancer. Most breast cancers are amenable to adjuvant therapies that target hormone receptors or HER2 receptors on the surface of the cancer cells and bring about significant improvement in survival. However, approximately 17% of Malaysian women with breast cancer, present with tumours that are devoid of these receptors and are consequently termed 'triple negative' breast cancers. These triple negative breast cancers typically occur in women of a younger age than receptor positive cancers, are predominantly of high grade tumours and the prognosis is usually poor. There is therefore a pressing need to understand the biological pathways that drive these tumours, in order that effective strategies are developed to treat these aggressive tumours. With the increasing affluence of developing countries, obesity and Type II Diabetes are also on the rise. These diseases are associated with an increased risk of developing a range of cancers including those of the breast. In particular, the metabolic syndrome has been shown to be associated with triple negative breast cancer. This article reviews some of the metabolic pathways and biomarkers which have been shown to be aberrantly expressed in triple negative breast cancer and highlights some of the ongoing work in this area. PMID- 25500512 TI - Evidence for extensive gene flow and Thermotoga subpopulations in subsurface and marine environments. AB - Oil reservoirs represent a nutrient-rich ecological niche of the deep biosphere. Although most oil reservoirs are occupied by microbial populations, when and how the microbes colonized these environments remains unanswered. To address this question, we compared 11 genomes of Thermotoga maritima-like hyperthermophilic bacteria from two environment types: subsurface oil reservoirs in the North Sea and Japan, and marine sites located in the Kuril Islands, Italy and the Azores. We complemented our genomes with Thermotoga DNA from publicly available subsurface metagenomes from North America and Australia. Our analysis revealed complex non-bifurcating evolutionary history of the isolates' genomes, suggesting high amounts of gene flow across all sampled locations, a conjecture supported by numerous recombination events. Genomes from the same type of environment tend to be more similar, and have exchanged more genes with each other than with geographically close isolates from different types of environments. Hence, Thermotoga populations of oil reservoirs do not appear isolated, a requirement of the 'burial and isolation' hypothesis, under which reservoir bacteria are descendants of the isolated communities buried with sediments that over time became oil reservoirs. Instead, our analysis supports a more complex view, where bacteria from subsurface and marine populations have been continuously migrating into the oil reservoirs and influencing their genetic composition. The Thermotoga spp. in the oil reservoirs in the North Sea and Japan probably entered the reservoirs shortly after they were formed. An Australian oil reservoir, on the other hand, was likely colonized very recently, perhaps during human reservoir development. PMID- 25500514 TI - Prenatal diagnosis of aneuploidies in amniotic fluid by multiple ligation dependent probe amplification (MLPA) analysis. AB - Prenatal diagnosis is essential in the new era of diagnosis and management of genetic diseases in obstetrics. Multiple ligation-dependent probe amplification (MLPA) is a recent technique for prenatal diagnosis for the relative quantification of 40 different nucleic acid sequences in one single reaction. We had utilized the MLPA technique in detecting aneuploidies in amniotic fluid samples from 25 pregnant women from the Obstetrics and Gynaecology Department UKMMC, versus the quantitative fluorescent polymerase chain reaction (QF-PCR) method. Conclusive results were obtained in 18 cases and all were concordant with that of the QF-PCR. All four cases of trisomies were correctly identified including one case with maternal cell contamination. PMID- 25500515 TI - Application of combined immunohistochemical panel of AMACR(P504S)/p63 cocktail, cytokeratin 5 and D2-40 to atypical glands in prostatic needle biopsy. AB - Various immunohistochemical studies using cocktail antibodies to elucidate atypical glands in prostatic biopsy specimens have been previously tried. However, there is scanty information on combined cocktail antibodies and other basal cell markers. We investigated the utility of an immunohistochemical panel of AMACR/p63, cytokeratin 5(CK5) and D2-40 for atypical glands in twenty lesions of fourteen patients obtained from prostatic needle biopsy specimens. The final diagnosis of all lesions, including 13 adenocarcinoma demonstrating AMACR+/basal cell(p63, CK5 and D2-40)- pattern, 5 benign lesions noting AMACR-/basal cell+ pattern, and 2 high grade PIN with AMACR+/basal cell+ pattern, were resolved. The immunohistochemical panel of AMACR(P504S)/ p63 cocktail, CK5 and D2-40 is useful in deciding the final diagnosis for atypical gland foci in the prostatic needle biopsy specimens and is helpful in the reduction of opportunity of further followup or re-biopsy. PMID- 25500516 TI - Diagnosis of common bacterial causes of urethritis in men by Gram stain, culture and multiplex PCR. AB - Urethritis is one of the most important causes of morbidity and mortality in developing countries. The aim of this study was to detect common bacterial causes of urethritis in men by Gram stain, culture and multiplex PCR.185 male patients who presented at the Skin and venereal clinic of the Dhaka Medical College, Bangladesh with clinical symptoms suggestive of urethritis were enrolled in this study. Urethral discharges were tested for detection of Neisseria gonorrhoeae by Gram stain, culture and PCR. Multiplex PCR assay was done to detect DNA of Chlamydia trachomatis, Ureaplasma urealyticum and Mycoplasma genitalium. Out of 185 participants, 30.27% and 14.6% were infected by Neisseria gonorrhoeae and Chlamydia trachomatis respectively. None of the individuals was found positive for either Ureaplasma urealyticum or Mycoplasma genitalium. Among the Neisseria gonorrhoeae positive patients 27.57% were positive from Gram stain, 26.49% were culture positive, 30.27% were positive by PCR (p<0.001). 32.65% of the Neisseria gonorrhoeae isolates were penicillinase producers and 83.67% were susceptible to ceftriaxone. Considering culture as the gold standard, the sensitivity and specificity of PCR for the detection of Neisseria gonorrhoeae was 100%, and 94.85% respectively with an accuracy of 96.22%. 3.73% of the 134 smear negative and 5.15% of the 136 culture negative samples were positive by PCR. PCR was the most sensitive and rapid method for the diagnosis of urethritis. Multiplex PCR may be a useful approach to laboratory diagnosis of urethritis in men for its high sensitivity and specificity. PMID- 25500517 TI - Endoscope versus microscope in the diagnosis of esophageal non-erosive reflux disease: a study of 71 cases. AB - BACKGROUND: Non-erosive reflux disease (NERD) is a type of gastroesophageal reflux disease (GERD) defined as symptomatic GERD without mucosal breaks on endoscopy. There is no gold standard for diagnosis of NERD till date. Biopsy from the distal esophagus in patients of GERD is said to reveal characteristic, although non-specific injury patterns such as squamous cell hyperplasia and intraepithelial inflammatory cell infiltration, collectively known as microscopic esophagitis. Recently, dilated intercellular spaces (DIS) are also shown to be associated with NERD. The present study was undertaken to evaluate the role of biopsy in NERD cases. MATERIALS AND METHODS: Two mucosal biopsies were taken at 3 cm above the squamocolumnar junction (SCJ) from 71 cases of NERD having symptom scores of more than 10. Biopsies were evaluated for features of microscopic esophagitis and DIS, and the results were analyzed. RESULTS: Fifty out of 71 (70.4%) patients with symptomatic NERD had features of microscopic esophagitis. DIS was noted in 46/71 (64.8%) of cases, and correlated significantly with microscopic esophagitis (p<0.0001). Basal cell hyperplasia, papillary elongation, intraepithelial neutrophils, and intraepithelial eosinophils were seen in 83.1%, 76.1%, 40.8%, and 12.7% of NERD cases respectively. CONCLUSION: In symptomatic patients of GERD, when endoscopy does not show mucosal breaks (so called NERD), histopathological evaluation of distal esophageal mucosa may have a diagnostic value. The present study also reinforces the diagnostic utility of DIS in symptomatic NERD. PMID- 25500519 TI - Estimation of platelet count in unstained peripheral blood smears in comparison with stained smears and evaluation of its efficacy. AB - Assessment of platelet count is an important diagnostic parameter in haematology. Automated blood cell counters have largely replaced the manual method. However, all abnormal platelet counts are verified in Leishman's stained peripheral blood smear. Platelets also can be identified in the unstained blood smears. The objective of this study is to compare the unstained peripheral blood smears with the stained smears and determination of the effectiveness of unstained smears in the estimation of platelet count. 250 Venous blood samples sent for blood cell counts were analyzed. Platelets were counted in the unstained smear under 100* objective in 10 fields without placing immersion oil and the average number of platelets was calculated. Same smear was stained by Leishman's stain and platelets were counted under 100* objective after placing a drop of immersion oil. Collected data were analyzed for intra-class correlation coefficient (ICC). ICC showed excellent agreement (ICC > 0.85). The unstained smears were found to be as effective as stained smears for platelet count in most of the cases. However, in case of doubt a stained preparation has to be made to confirm the count. The turnaround time was 3-5 minutes compared to 15-20 minutes by stained smear technique, thus this technique may be used as an initial screening method whenever there is large sample load. PMID- 25500518 TI - Morphometric analysis of epithelial thickness and blood vessels in different grades of oral submucous fibrosis. AB - BACKGROUND: Oral submucous fibrosis (OSF) is a common oral health problem in the Indian subcontinent. It is characterized by a juxtaepithelial inflammatory reaction followed by fibroelastic changes in the lamina propria. Traditionally, it is said to be associated with marked epidermal atrophy and decreased vasculature as the disease advances. OBJECTIVE: To assess the changes in epidermal thickness and mucosal vasculature in various stages of the disease. MATERIAL AND METHODS: Patients with histological diagnosis of OSF were included in the study. Demographic data and oral habits of each patient were collected. The severity of OSF was graded histologically according to Pindborg and Sirsat. Epithelial thickness and subepithelial blood vessel area, diameter and perimeter were measured and analysed using Image analysis software IMAGE PRO PLUS version 6.0. RESULTS: Thirty-five patients with OSF were studied. 25 (71.4%) were males and 10 (28.6%) were females with a male to female ratio of 1.3:1. Most patients were in the 31-40 yrs age group. The majority of patients (40%) chewed areca nut/dohra. Each grade of the disease was found to display either hyperplastic or atrophic epithelial changes. The mean blood vessel area, diameter and perimeter did not show any sustained change with the increasing severity (grade) of the disease. CONCLUSION: These findings question the role of ischaemia in the aetiopathogenesis of oral submucous fibrosis. PMID- 25500520 TI - NK/T cell lymphoma associated with peripheral eosinophilia. AB - NK/T cell lymphoma, nasal type is an aggressive and uncommon malignancy. Disease that occurs outside of the aerodigestive tract exhibits an even more aggressive clinical behaviour and does not respond as well to conventional therapy compared to its nasal counterpart. We report such a case of NK/T cell lymphoma, nasal type, that presented as an anterior chest wall mass, arising from the left pectoralis muscle. An interesting feature we wish to highlight is the associated eosinophilia that corresponded to disease activity, exhibiting fluctuations with surgical resection and chemotherapy. To the best of our knowledge this is the third reported case of NK/T cell lymphoma that is associated with peripheral eosinophilia. Our case highlights the role of certain NK cell subsets that play a major role in eosinophilic activation in NK/T lymphomas and calls for more research into further classification of this disease by virtue of its NK cell subsets. PMID- 25500521 TI - alpha-Thalassemia with Haemoglobin Adana mutation: prenatal diagnosis. AB - Thalassaemia carriers are common in the Asian region including Malaysia. Asymptomatic patients can be undiagnosed until they present for their antenatal visits. Devastating obstetric outcome may further complicate the pregnancy if both parents are thalassaemia carriers leading to hydrophic fetus due to haemoglobin Bart's disease. However in certain cases where unexplained hydrops fetalis occur in parents with heterozygous thalassaemia carrier,mutated alpha genes should be suspected. We report a twenty-nine year old woman in her third pregnancy with two previous pregnancies complicated by early neonatal death at 21 and 28 weeks of gestation due to hydrops fetalis. DNA analysis revealed the patient to have heterozygous (--SEA) alpha-gene deletion, while her husband has a compound heterozygosity for alpha(3.7) deletion and codon 59 (GGC -> GAC) mutation of the alpha-gene. This mutation, also known as hemoglobin Adana, can explain hydrops fetalis resulting from two alpha gene deletions from the patient (mother) and a single alpha gene deletion with mutation from the father. The third pregnancy resulted in a grossly normal baby boy with 3 alpha-gene deletions (HbH disease). We postulate that, in view of heterogenisity of the alpha thalassaemia in this patient with severely unstable haemoglobin Adana chains from her husband, there will be a 25% possibility of fetal hydrops in every pregnancy. PMID- 25500522 TI - Clostridial aortitis causing ruptured dissecting aneurysm in a young adult female. AB - Ruptured dissecting aortic aneurysm more commonly occur in men in the 40 to 70 age group, and most commonly is associated with atherosclerosis. Uncommon causes are previous heart surgery, connective tissue disorders and aortitis. Despite its rarity, Clostridium spp aortitis progresses very rapidly with a mortality rate of approximately 79% in adults, typically occurring within 48 hours of infection. We present a case of sudden death due to clostridial aortitis causing ruptured aortic dissection in an apparently healthy adult female, 7 weeks post-spontaneous vaginal delivery. This case highlights the pathology of aortic dissection and cystic media necrosis as presentations of clostridium spp infection in young female adult. PMID- 25500523 TI - Benign epithelioid peripheral nerve sheath tumour resembling schwannoma. AB - Peripheral nerve sheath tumours (PNST) with epithelial appearing cells compromise a heterogeneous group of neoplasms that are rare and diagnostically challenging. Of these, malignant PNSTs with epithelioid features (epithelioid MPNST) are commonly described in literature. However benign epithelioid PNSTs are rare and till date about 38 cases have been described in the literature. We report a benign epithelioid PNST with light microscopical and immunohistochemical features suggestive of schwannoma, presenting as a thigh mass in a 23-year-old female. The tumour was encapsulated, showed epithelioid cells in aggregates, and expressed vimentin and S-100 positivity. There was no expression of CD34, CK, EMA, CD99, p63 and HMB 45. Typical Antoni A and Antoni B areas were absent. At 18 months follow-up, the patient was well. PMID- 25500525 TI - Gold nanostar based biosensor detects epigenetic alterations on promoter of real cells. AB - Epigenetic changes, particularly in cancer suppressor genes, are novel biomarkers for cancer diagnostics and therapeutics. However, epigenetic studies should not only provide an estimation of the amount of 5-methylcytosine, but also examine the presence of epigenetic proteins to reveal the complete epigenetic alterations for downstream molecular process. The challenge of natural epigenetics is to unveil key factors of epigenetics in one assay, containing low concentrations. This would be valuable for the monitoring of early-stage cancer. On the basic of the nanoplasmonic biosensor, here we report a sensitive sensor to study epigenetics of DNA promoter. The results show detection limit for dual epigenetic biomarkers methyl-CpG group and methyl-CpG binding domain protein 2 (MBD2) are one 5-methylcytosine molecule and 125fM MBD2. Moreover, DNA structure bending, steric competition under interaction of epigenetic proteins and transcription factors; and epigenetics-mediated suppression of transcription are observed during epigenetic alterations. This study provides a platform for full story of epigenetics, as compared with that of methylcytosine-based techniques only. PMID- 25500524 TI - The demographic determinants of human microbiome health. AB - The human microbiome is a vast reservoir of microbial diversity and increasingly recognized to have a fundamental role in human health. In polymicrobial communities, the presence of one species can modulate the demography (i.e., growth and distribution) of other species. These demographic impacts generate feedbacks in multispecies interactions, which can be magnified in spatially structured populations (e.g., host-associated communities). Here, we argue that demographic feedbacks between species are central to microbiome development, shaping whether and how potential metabolic interactions come to be realized between expanding lineages of bacteria. Understanding how demographic feedbacks tune metabolic interactions and in turn shape microbiome structure and function is now a key challenge to our abilities to better manage microbiome health. PMID- 25500526 TI - New molecular beacon for p53 gene point mutation and significant potential in serving as the polymerization primer. AB - Molecular beacon (MB) is usually explored as a convenient probe for various bioassays. In an enzymatic polymerization-based biosensing system, primer, and MB, sometimes involving other oligonucleotides, are often required to collaboratively generate an amplified fluorescent signal to detect target molecules with high sensitivity and specificity. In the current study, a multifunctional primer-integrated MB (MP-MB) was developed to detect the p53 tumor suppressor gene. Compared with the traditional MB, our MP-MB can not only selectively identify the target of interest and signal sensitively its hybridization event, but also act as the primer during enzymatic polymerization. Specifically, hybridization of MP-MB to target p53 gene restored the fluorescence intensity and activated the pre-locked primer designed by changing the molecular configuration of MP-MB. Moreover, the p53 gene could be detected down to 1nM with a linear response range of 1*10(-9)-3*10(-7)M, and p53 gene point mutation was readily distinguished from the wild-type one. Its potential application as a primer of replication in enzymatic polymerization-based assay systems was validated by running parallel gel electrophoreses in comparison with the native counterpart of MP-MB without any chemical modification. Owning to its excellent assay characteristics, less species requirement, broad sequence diversity and preserved intrinsic bioactivity, the proof-of-concept of MP-MB exhibits a great potential in various biomedical applications. PMID- 25500527 TI - Real-time monitoring of mycobacterium genomic DNA with target-primed rolling circle amplification by a Au nanoparticle-embedded SPR biosensor. AB - In this study, we developed a surface plasmon resonance (SPR) DNA biosensor array based on target-primed rolling circle amplification (RCA) for isothermal and rapid detection of two pathogenic mycobacteria, Mycobacterium tuberculosis complex (MTBC) and Mycobacterium avium complex (MAC).The species-specific padlock probe (PLP) was designed to target the sequence in 16S-23S rRNA gene internal transcribed spacer (ITS). After ligation, the circularized PLP could be primed by the target sequence to initial RCA. The RCA performed simultaneously with the cleavage reaction to produce small fragments of single strand DNA which immediately hybridized with the probe immobilized on the sensor chip without denaturation. This process caused SPR angle changes on the chip surface, which made the detection for analysis from the solution achievable, and dynamic real time RCA monitoring of mycobacterium possible. Besides, Au nanoparticles (AuNPs) were directly assembled onto the surface of the sensor chip via hexanedithiol (HDT) for the enhancement of sensitivity as a label-free detection system. Experimental results show that the signal enhancement by the target-primed RCA together with AuNPs-embedded surface caused at least10-fold increased sensitivity as compared with conventional RCA on bare SPR chip method. Within 40min amplification duration as low as 20amol of synthetic targets and 10(4)CFUmL(-1) of genomic DNA from clinical samples can be detected. The proposed method not only provides a simple design idea for liquid-phase amplification monitoring, but also apply it in clinical pathogen detection, which holds great promise in ultrasensitive bioassay in the future. PMID- 25500529 TI - Femoral subtrochanteric shape variation in Albania: implications for use in forensic applications. AB - This paper investigates temporal trends in femoral subtrochanteric shape in Albanian skeletal material to evaluate levels of platymeria in a set of populations with European ancestry. Although flattening of the diaphysis in the subtrochanteric region has been associated with individuals of Native American and Asian ancestry, high levels of platymeria may not be unique to those groups. The forensic utility of Gilbert and Gill's (Skeletal Attribution of Race: Methods for Forensic Anthropology, University of New Mexico, Albuquerque, 1990) method for identifying ancestry from femoral subtrochanteric shape is examined using non American skeletons of European ancestry. Femoral subtrochanteric anteroposterior and mediolateral diameters for Albanian skeletons from Apollonia (n=117) and Lofkend (n=50) are assessed for temporal trends and then compared with published data using one-way ANOVA and post-hoc Tukey tests. High degrees of subtrochanteric flattening are identified in the Albanian samples and statistically significant temporal trends of decreasing platymeria are documented. Although recent publications suggest that subtrochanteric shape is less effective in identifying ancestry then was initially proposed, forensic anthropologists still commonly use femoral subtrochanteric shape to determine ancestry among skeletonized remains. This paper's findings support the assertion that proximal femoral morphology is functionally related, and more likely to be influenced by biomechanical adaptation and body proportions than genetic constraints. PMID- 25500528 TI - Highly sensitive DNA detection using cascade amplification strategy based on hybridization chain reaction and enzyme-induced metallization. AB - A novel highly sensitive colorimetric assay for DNA detection using cascade amplification strategy based on hybridization chain reaction and enzyme-induced metallization was established. The DNA modified superparamagnetic beads were demonstrated to capture and enrich the target DNA in the hybridization buffer or human plasma. The hybridization chain reaction and enzyme-induced silver metallization on the gold nanoparticles were used as cascade signal amplification for the detection of target DNA. The metalization of silver on the gold nanoparticles induced a significant color change from red to yellow until black depending on the concentration of the target DNA, which could be recognized by naked eyes. This method showed a good specificity for the target DNA detection, with the capabilty to discriminate single-base-pair mismatched DNA mutation (single nucleotide polymorphism). Meanwhile, this approach exhibited an excellent anti-interference capability with the convenience of the magentic seperation and washing, which enabled its usage in complex biological systems such as human blood plasma. As an added benefit, the utilization of hybridization chain reaction and enzyme-induced metallization improved detection sensitivity down to 10pM, which is about 100-fold lower than that of traditional unamplified homogeneous assays. PMID- 25500530 TI - Collective secondary cremation in a pit grave: a unique funerary context in Portuguese Chalcolithic burial practices. AB - Perdigoes is a large site with a set of ditched enclosures located at Reguengos de Monsaraz, Alentejo, South Portugal. Recently at the central area of this site burnt human remains were found in a pit (#16). This structure had inside human remains, animal bones (namely pig, sheep or goat, cattle, dog, deer and rabbit), shards, ivory idols and arrowheads. All have been subjected to fire and later deposited in that pit, resulting in a secondary disposal of human bones. The recovered fragmented human bones (4845.18 g) correspond to a minimal number of 9 individuals: 6 adults and 3 sub-adults. The aim of this work is to document and interpret this funerary context based on the study of the recovered human remains. For that purpose, observations of all alterations due to fire, such as colour change and type of bone distortion, as well as anthropological data were collected. The data obtained suggest that these human remains were probably intentionally cremated, carefully collected and finally deposited in this pit. The cremation was conducted on probably complete corpses, some of them still fairly fresh and fleshed, as some bones presented thumbnail fractures. The collective cremation of the pit 16 represents an unprecedented funerary context for Portuguese, and Iberian Peninsula, Chalcolithic burial practices. Moreover, it is an example of the increasing diversity of mortuary practices of Chalcolithic human populations described in present Portuguese territory, as well as, in the Iberian Peninsula. PMID- 25500531 TI - Acute viral hepatitis E presenting with haemolytic anaemia and acute renal failure in a patient with glucose-6-phosphate dehydrogenase deficiency. AB - The association of acute hepatitis E viral (HEV) infection with glucose-6 phosphate dehydrogenase (G6PD) deficiency leading to extensive intravascular haemolysis is a very rare clinical entity. Here we discuss such a patient, who presented with acute HEV illness, developed severe intravascular haemolysis and unusually high levels of bilirubin, complicated by acute renal failure (ARF), and was later on found to have a deficiency of G6PD. The patient recovered completely with haemodialysis and supportive management. PMID- 25500534 TI - Electrically tunable nonlinear plasmonics in graphene nanoislands. AB - Nonlinear optical processes rely on the intrinsically weak interactions between photons enabled by their coupling with matter. Unfortunately, many applications in nonlinear optics are severely hindered by the small response of conventional materials. Metallic nanostructures partially alleviate this situation, as the large light enhancement associated with their localized plasmons amplifies their nonlinear response to record high levels. Graphene hosts long-lived, electrically tunable plasmons that also interact strongly with light. Here we show that the nonlinear polarizabilities of graphene nanoislands can be electrically tuned to surpass by several orders of magnitude those of metal nanoparticles of similar size. This extraordinary behaviour extends over the visible and near-infrared spectrum for islands consisting of hundreds of carbon atoms doped with moderate carrier densities. Our quantum-mechanical simulations of the plasmon-enhanced optical response of nanographene reveal this material as an ideal platform for the development of electrically tunable nonlinear optical nanodevices. PMID- 25500532 TI - The structural basis for receptor recognition of human interleukin-18. AB - Interleukin (IL)-18 is a proinflammatory cytokine that belongs to the IL-1 family and plays an important role in inflammation. The uncontrolled release of this cytokine is associated with severe chronic inflammatory disease. IL-18 forms a signalling complex with the IL-18 receptor alpha (Ralpha) and beta (Rbeta) chains at the plasma membrane, which induces multiple inflammatory cytokines. Here, we present a crystal structure of human IL-18 bound to the two receptor extracellular domains. Generally, the receptors' recognition mode for IL-18 is similar to IL-1beta; however, certain notable differences were observed. The architecture of the IL-18 receptor second domain (D2) is unique among the other IL-1R family members, which presumably distinguishes them from the IL-1 receptors that exhibit a more promiscuous ligand recognition mode. The structures and associated biochemical and cellular data should aid in developing novel drugs to neutralize IL-18 activity. PMID- 25500533 TI - Phosphorylation of LRRK2 by casein kinase 1alpha regulates trans-Golgi clustering via differential interaction with ARHGEF7. AB - LRRK2, a gene relevant to Parkinson's disease, encodes a scaffolding protein with both GTPase and kinase activities. LRRK2 protein is itself phosphorylated and therefore is subject to regulation by cell signalling; however, the kinase(s) responsible for this event have not been definitively identified. Here using an unbiased siRNA kinome screen, we identify and validate casein kinase 1alpha (CK1alpha) as being responsible for LRRK2 phosphorylation, including in the adult mouse striatum. We further show that LRRK2 recruitment to TGN46-positive Golgi derived vesicles is modulated by constitutive LRRK2 phosphorylation by CK1alpha. These effects are mediated by differential protein interactions of LRRK2 with a guanine nucleotide exchange factor, ARHGEF7. These pathways are therefore likely involved in the physiological maintenance of the Golgi in cells, which may play a role in the pathogenesis of Parkinson's disease. PMID- 25500535 TI - Increased expression of fibroblast growth factor receptor 1 in endometriosis and its correlation with endometriosis-related dysmenorrhea and recurrence. AB - OBJECTIVE(S): This study aims to identify a critical molecule that potentially participates in endometriosis pathogenesis and characterize its correlation with dysmenorrhea and recurrence. STUDY DESIGN: We utilized a bioinformatics-based strategy to screen for candidate genes and fibroblast growth factor receptor 1(FGFR1) was chosen for further validation. FGFR1 expression was examined in specimens of ectopic and eutopic endometrium obtained from 48 patients with endometriosis and specimens of eutopic endometrium from 26 healthy control subjects using immunohistochemistry and Western blotting. In addition, FGFR shRNA treatment was applied in a nude mice endometriosis model to examine the functional role of FGFR1 in endometriosis formation in vivo. RESULTS: FGFR1 was found commonly overexpressed in ectopic endometrium of endometriosis compared with either its eutopic counterpart or endometrium from normal patients (P < 0.05). FGFR shRNA treatment impaired endometriosis formation and alleviated endometriosis-related symptoms in vivo. FGFR1 expression in ectopic endometrium was correlated with dysmenorrhea severity (P < 0.05) and recurrence in endometriosis patients (P < 0.05). CONCLUSION(S): FGFR1 might be involved in endometriosis development, which could possibly serve as a novel therapeutic target and prognostic marker for this disease. PMID- 25500536 TI - Evolutionary link between metazoan RHIM motif and prion-forming domain of fungal heterokaryon incompatibility factor HET-s/HET-s. AB - The Rip homotypic interaction motif (RHIM) is a short, non-globular sequence stretch that mediates a key interaction of mammalian necroptosis signaling. In order to understand its unusual oligomerization properties, we set out to trace the evolutionary origins of the RHIM motif by identifying distantly related protein motifs that might employ the same binding mode. The RHIM motif was found to be related to the prion-forming domain of the HET-s protein, which oligomerizes by forming structurally well-characterized fibrils and is involved in fungal heterokaryon incompatibility. This evolutionary relationship explains the recently reported propensity of mammalian RHIM motifs to form amyloid fibrils, but suggests that these fibrils have a different structural architecture than currently assumed. These findings, together with numerous observations of RHIM-like motifs in immunity proteins from a wide range of species, provide insight to the modern innate immunity pathways in animals, plants and fungi. PMID- 25500537 TI - Carbocysteine restores steroid sensitivity by targeting histone deacetylase 2 in a thiol/GSH-dependent manner. AB - Steroid insensitivity is commonly observed in patients with chronic obstructive pulmonary disease. Here, we report the effects and mechanisms of carbocysteine (S CMC), a mucolytic agent, in cellular and animal models of oxidative stress mediated steroid insensitivity. The following results were obtained: oxidative stress induced higher levels of interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha), which are insensitive to dexamethasone (DEX). The failure of DEX was improved by the addition of S-CMC by increasing histone deacetylase 2 (HDAC2) expression/activity. S-CMC also counteracted the oxidative stress-induced increase in reactive oxygen species (ROS) levels and decreases in glutathione (GSH) levels and superoxide dismutase (SOD) activity. Moreover, oxidative stress induced events were decreased by the thiol-reducing agent dithiothreitol (DTT), enhanced by the thiol-oxidizing agent diamide, and the ability of DEX was strengthened by DTT. In addition, the oxidative stress-induced decrease in HDAC2 activity was counteracted by S-CMC by increasing thiol/GSH levels, which exhibited a direct interaction with HDAC2. S-CMC treatment increased HDAC2 recruitment and suppressed H4 acetylation of the IL-8 promoter, and this effect was further ablated by addition of buthionine sulfoximine, a specific inhibitor of GSH synthesis. Our results indicate that S-CMC restored steroid sensitivity by increasing HDAC2 expression/activity in a thiol/GSH-dependent manner and suggest that S-CMC may be useful in a combination therapy with glucocorticoids for treatment of steroid-insensitive pulmonary diseases. PMID- 25500538 TI - Inter-hemispheric language functional reorganization in low-grade glioma patients after tumour surgery. AB - Despite many claims of functional reorganization following tumour surgery, empirical studies that investigate changes in functional activation patterns are rare. This study investigates whether functional recovery following surgical treatment in patients with a low-grade glioma in the left hemisphere is linked to inter-hemispheric reorganization. Based on literature, we hypothesized that reorganization would induce changes in the spatial pattern of activation specifically in tumour homologue brain areas in the healthy right hemisphere. An experimental group (EG) of 14 patients with a glioma in the left hemisphere near language related brain areas, and a control group of 6 patients with a glioma in the right, non-language dominant hemisphere were scanned before and after resection. In addition, an age and gender matched second control group of 18 healthy volunteers was scanned twice. A verb generation task was used to map language related areas and a novel technique was used for data analysis. Contrary to our hypothesis, we found that functional recovery following surgery of low grade gliomas cannot be linked to functional reorganization in language homologue brain areas in the healthy, right hemisphere. Although elevated changes in the activation pattern were found in patients after surgery, these were largest in brain areas in proximity to the surgical resection, and were very similar to the spatial pattern of the brain shift following surgery. This suggests that the apparent perilesional functional reorganization is mostly caused by the brain shift as a consequence of surgery. Perilesional functional reorganization can however not be excluded. The study suggests that language recovery after transient post-surgical language deficits involves recovery of functioning of the presurgical language system. PMID- 25500539 TI - Combined regulation of mTORC1 and lysosomal acidification by GSK-3 suppresses autophagy and contributes to cancer cell growth. AB - There is controversy over the role of glycogen synthase kinase-3 (GSK-3) in cancer progression. Recent work has implicated GSK-3 in the regulation of mammalian target of rapamycin (mTOR), a known player in malignant transformation. Autophagy, a self-degradation pathway, is inhibited by mTOR and is tightly associated with cell survival and tumor growth. Here we show that GSK-3 suppresses autophagy via mTOR complex-1 (mTORC1) and lysosomal regulation. We show that overexpression of GSK-3 isoforms (GSK-3alpha and GSK-3beta) activated mTORC1 and suppressed autophagy in MCF-7 human breast cancer cells as indicated by reduced beclin-1 levels and upregulation of sequestosome 1 (p62/SQSTM1). Further, overexpression of GSK-3 increased the number of autophagosomes and inhibited autophagic flux. This activity was directly related to reduced lysosomal acidification triggered by GSK-3 (in which GSK-3beta has a stronger impact). We found that lysosomal acidification is reduced in MCF-7 cells that also exhibit increased levels of autophagosomes and p62/SQSTM1 and increased activity of mTORC1. Subsequently, treating cells with GSK-3 inhibitors restored lysosomal acidification, enhanced autophagic flux and inhibited mTORC1. Furthermore, GSK-3 inhibitors inhibited cell proliferation. We provide evidence that GSK3-mediated mTORC1 activity and GSK-3-mediated lysosomal acidification occur via distinct pathways, yet both mTORC1 and lysosomes control cell growth. Finally, we show that GSK-3-reduced lysosomal acidification inhibits endocytic clearance as demonstrated by reduced endocytic degradation of the epidermal growth factor receptor. Taken together, our study places GSK-3 as a key regulator coordinating cellular homeostasis. GSK-3 inhibitors may be useful in targeting mTORC1 and lysosomal acidification for cancer therapy. PMID- 25500540 TI - The role of TXNDC5 in castration-resistant prostate cancer-involvement of androgen receptor signaling pathway. AB - Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and the mechanisms behind it remain unclear. Thioredoxin domain containing protein 5 (TXNDC5) is involved in protein folding and chaperone activity, and its overexpression has been reported in multiple malignancies. In the current study, we demonstrated that TXNDC5 is up-regulated following long term androgen-deprivation treatment (ADT) and is highly overexpressed in CRPC tumors compared with hormone-naive prostate cancer (PCa) cases. Functionally, in vitro and in vivo studies demonstrated that TXNDC5 overexpression promotes the growth of both androgen-dependent and castration-resistant PCa xenografts. Mechanistically, TXNDC5 directly interacts with the AR protein to increase its stability and thus enhances its transcriptional activity. TXDNC5-mediated CRPC growth can be fully abolished by AR inhibition, suggesting TXDNC5 up-regulation as an escape pathway for aberrant AR re-activation and CRPC growth in the milieu of low androgen. Indeed, we found that TXNDC5 is increased by ADT-induced hypoxia through HIF-1alpha in an miR-200b-dependent manner. Overall, we defined an important role of TXNDC5 in CRPC and further investigations are needed to screen TXNDC5 antagonists as a novel therapeutic approaches to treat PCa patients with CRPC. PMID- 25500541 TI - Claudin-7 expression induces mesenchymal to epithelial transformation (MET) to inhibit colon tumorigenesis. AB - In normal colon, claudin-7 is one of the highly expressed claudin proteins and its knockdown in mice results in altered epithelial cell homeostasis and neonatal death. Notably, dysregulation of the epithelial homeostasis potentiates oncogenic transformation and growth. However, the role of claudin-7 in the regulation of colon tumorigenesis remains poorly understood. Using a large colorectal cancer (CRC) patient database and mouse models of colon cancer, we found claudin-7 expression to be significantly downregulated in cancer samples. Most notably, forced claudin-7 expression in poorly differentiated and highly metastatic SW620 colon cancer cells induced epithelial characteristics and inhibited their growth in soft agar and tumor growth in vivo. By contrast, knockdown of claudin-7 in HT 29 or DLD-1 cells induced epithelial-to-mesenchymal transition (EMT), colony formation, xenograft-tumor growth in athymic mice and invasion. Importantly, a claudin-7 signature gene profile generated by overlapping the DEGs (differentially expressed genes in a high-throughput transcriptome analysis using claudin-7-manipulated cells) with human claudin-7 signature genes identified high risk CRC patients. Furthermore, Rab25, a colon cancer suppressor and regulator of the polarized cell trafficking constituted one of the highly upregulated DEGs in claudin-7 overexpressing cells. Notably, silencing of Rab25 expression counteracted the effects of claudin-7 expression and not only increased proliferation and cell invasion but also increased the expression of p-Src and mitogen-activated protein kinase-extracellular signal-regulated kinase 1/2 that were suppressed upon claudin-7 overexpression. Of interest, CRC cell lines, which exhibited decreased claudin-7 expression, also exhibited promoter DNA hypermethylation, a modification associated with transcriptional silencing. Taken together, our data demonstrate a previously undescribed role of claudin-7 as a colon cancer suppressor and suggest that loss of claudin-7 potentiates EMT to promote colon cancer, in a manner dependent on Rab25. PMID- 25500542 TI - MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes. AB - Recent advances in cancer biology have emerged important roles for microRNAs (miRNAs) in regulating tumor responses. However, their function in mediating intercellular communication within the tumor microenvironment is thus far poorly explored. Here, we found miR-206 to be abrogated in human pancreatic ductal adenocarcinoma (PDAC) specimens and cell lines. We show that miR-206 directly targets the oncogenes KRAS and annexin a2 (ANXA2), thereby acting as tumor suppressor in PDAC cells by blocking cell cycle progression, cell proliferation, migration and invasion. Importantly, we identified miR-206 as a negative regulator of oncogenic KRAS-induced nuclear factor-kappaB transcriptional activity, resulting in a concomitant reduction of the expression and secretion of pro-angiogenic and pro-inflammatory factors including the cytokine interleukin-8, the chemokines (C-X-C motif) ligand 1 and (C-C motif) ligand 2, and the granulocyte macrophage colony-stimulating factor. We further show that miR-206 abrogates the expression and secretion of the potent pro-lymphangiogenic factor vascular endothelial growth factor C in pancreatic cancer cells through an NF kappaB-independent mechanism. By using in vitro and in vivo approaches, we reveal that re-expression of miR-206 in PDAC cells is sufficient to inhibit tumor blood and lymphatic vessel formation, thus leading to a significant delay of tumor growth and progression. Taken together, our study sheds light onto the role of miR-206 as a pleiotropic modulator of different hallmarks of cancer, and as such raising the intriguing possibility that miR-206 may be an attractive candidate for miRNA-based anticancer therapies. PMID- 25500543 TI - Oncogenic KRAS signalling promotes the Wnt/beta-catenin pathway through LRP6 in colorectal cancer. AB - Aberrant regulation of the Wnt/beta-catenin signaling pathway is one of the major causes of colorectal cancer (CRC). Loss-of-function mutations in APC are commonly found in CRC, leading to inappropriate activation of canonical Wnt signaling. Conversely, gain-of-function mutations in KRAS and BRAF genes are detected in up to 60% of CRCs. Whereas KRAS/mitogen-activated protein kinase (MAPK) and canonical Wnt/beta-catenin pathways are critical for intestinal tumorigenesis, mechanisms integrating these two important signaling pathways during CRC development are unknown. Results herein demonstrate that transformation of normal intestinal epithelial cells (IECs) by oncogenic forms of KRAS, BRAF or MEK1 was associated with a marked increase in beta-catenin/TCF4 and c-MYC promoter transcriptional activities and mRNA levels of c-Myc, Axin2 and Lef1. Notably, expression of a dominant-negative mutant of T-Cell Factor 4 (DeltaNTCF4) severely attenuated IEC transformation induced by oncogenic MEK1 and markedly reduced their tumorigenic and metastatic potential in immunocompromised mice. Interestingly, the Frizzled co-receptor LRP6 was phosphorylated in a MEK dependent manner in transformed IECs and in human CRC cell lines. Expression of LRP6 mutant in which serine/threonine residues in each particular ProlineProlineProlineSerine/ThreonineProline motif were mutated to alanines (LRP6 5A) significantly reduced beta-catenin/TCF4 transcriptional activity. Accordingly, MEK inhibition in human CRC cells significantly diminished beta catenin/TCF4 transcriptional activity and c-MYC mRNA and protein levels without affecting beta-catenin expression or stability. Lastly, LRP6 phosphorylation was also increased in human colorectal tumors, including adenomas, in comparison with healthy adjacent normal tissues. Our data indicate that oncogenic activation of KRAS/BRAF/MEK signaling stimulates the canonical Wnt/beta-catenin pathway, which in turn promotes intestinal tumor growth and invasion. Moreover, LRP6 phosphorylation by ERK1/2 may provide a unique point of convergence between KRAS/MAPK and Wnt/beta-catenin signalings during oncogenesis. PMID- 25500544 TI - The landscape and therapeutic relevance of cancer-associated transcript fusions. AB - Transcript fusions as a result of chromosomal rearrangements have been a focus of attention in cancer as they provide attractive therapeutic targets. To identify novel fusion transcripts with the potential to be exploited therapeutically, we analyzed RNA sequencing, DNA copy number and gene mutation data from 4366 primary tumor samples. To avoid false positives, we implemented stringent quality criteria that included filtering of fusions detected in RNAseq data from 364 normal tissue samples. Our analysis identified 7887 high confidence fusion transcripts across 13 tumor types. Our fusion prediction was validated by evidence of a genomic rearrangement for 78 of 79 fusions in 48 glioma samples where whole-genome sequencing data were available. Cancers with higher levels of genomic instability showed a corresponding increase in fusion transcript frequency, whereas tumor samples harboring fusions contained statistically significantly fewer driver gene mutations, suggesting an important role for tumorigenesis. We identified at least one in-frame protein kinase fusion in 324 of 4366 samples (7.4%). Potentially druggable kinase fusions involving ALK, ROS, RET, NTRK and FGFR gene families were detected in bladder carcinoma (3.3%), glioblastoma (4.4%), head and neck cancer (1.0%), low-grade glioma (1.5%), lung adenocarcinoma (1.6%), lung squamous cell carcinoma (2.3%) and thyroid carcinoma (8.7%), suggesting a potential for application of kinase inhibitors across tumor types. In-frame fusion transcripts involving histone methyltransferase or histone demethylase genes were detected in 111 samples (2.5%) and may additionally be considered as therapeutic targets. In summary, we described the landscape of transcript fusions detected across a large number of tumor samples and revealed fusion events with clinical relevance that have not been previously recognized. Our results support the concept of basket clinical trials where patients are matched with experimental therapies based on their genomic profile rather than the tissue where the tumor originated. PMID- 25500545 TI - RSUME inhibits VHL and regulates its tumor suppressor function. AB - Somatic mutations or loss of von Hippel-Lindau (pVHL) happen in the majority of VHL disease tumors, which present a constitutively active Hypoxia Inducible Factor (HIF), essential for tumor growth. Recently described mechanisms for pVHL modulation shed light on the open question of the HIF/pVHL pathway regulation. The aim of the present study was to determine the molecular mechanism by which RSUME stabilizes HIFs, by studying RSUME effect on pVHL function and to determine the role of RSUME on pVHL-related tumor progression. We determined that RSUME sumoylates and physically interacts with pVHL and negatively regulates the assembly of the complex between pVHL, Elongins and Cullins (ECV), inhibiting HIF 1 and 2alpha ubiquitination and degradation. We found that RSUME is expressed in human VHL tumors (renal clear-cell carcinoma (RCC), pheochromocytoma and hemangioblastoma) and by overexpressing or silencing RSUME in a pVHL-HIF-oxygen dependent degradation stability reporter assay, we determined that RSUME is necessary for the loss of function of type 2 pVHL mutants. The functional RSUME/pVHL interaction in VHL-related tumor progression was further confirmed using a xenograft assay in nude mice. RCC clones, in which RSUME was knocked down and express either pVHL wt or type 2 mutation, have an impaired tumor growth, as well as HIF-2alpha, vascular endothelial growth factor A and tumor vascularization diminution. This work shows a novel mechanism for VHL tumor progression and presents a new mechanism and factor for targeting tumor-related pathologies with pVHL/HIF altered function. PMID- 25500546 TI - High levels of SIRT1 expression enhance tumorigenesis and associate with a poor prognosis of colorectal carcinoma patients. AB - SIRT1, a NAD(+) dependent class III deacetylase, takes part in many important biological processes. Previous studies show that SIRT1 is overexpressed in some cancers and plays an essential role in tumorigenesis. However, the association between SIRT1 and colorectal cancer (CRC) is still unclear. We found that many CRC specimens had strong SIRT1 expression, which had an obvious correlation with poor prognosis of CRC patients. Meanwhile, SIRT1 expression had a co-localization with CD133, a current universal marker to characterize colorectal cancer stem cells (CSCs). In vitro studies also revealed that SIRT1 was overexpressed in colorectal CSC-like cells. Moreover, SIRT1 deficiency decreased percentage of CD133(+) cells, attenuated the abilities of colony and sphere formation, and inhibited tumorigenicity in vivo in CRC cells. Further study demonstrated that the expressions of several stemness-associated genes, including Oct4, Nanog, Cripto, Tert and Lin28, were reduced by SIRT1 knockdown in CRC cells. Taken together, our findings suggest that SIRT1 plays a crucial role in keeping the characteristics of CSCs cells. SIRT1 is a potential independent prognostic factor of CRC patients after tumor resection with curative intent, and will contribute to providing a promising new approach to target at CSCs in CRC treatment. PMID- 25500547 TI - Modelling antibiotic and cytotoxic isoquinoline effects in Staphylococcus aureus, Staphylococcus epidermidis and mammalian cells. AB - Isoquinolines (IQs) are natural substances with an antibiotic potential we aim to optimize. Specifically, IQ-238 is a synthetic analog of the novel-type N,C coupled naphthylisoquinoline (NIQ) alkaloid ancisheynine. Recently, we developed and tested other IQs such as IQ-143. By utilizing genome-wide gene expression data, metabolic network modelling and Voronoi tessalation based data analysis - as well as cytotoxicity measurements, chemical properties calculations and principal component analysis of the NIQs - we show that IQ-238 has strong antibiotic potential for staphylococci and low cytotoxicity against murine or human cells. Compared to IQ-143, systemic effects are less pronounced. Most enzyme activity changes due to IQ-238 are located in the carbohydrate metabolism. Validation includes metabolite measurements on biological replicates. IQ-238 delineates key properties and a chemical space for a good therapeutic window. The combination of analysis methods allows suggestions for further lead development and yields an in-depth look at staphylococcal adaptation and network changes after antibiosis. Results are compared to eukaryotic host cells. PMID- 25500549 TI - Foreign body resulting in chronic otomastoiditis and facial palsy. AB - We present a case of a foreign body in the ear of 5-year-old girl child. She presented with features of chronic suppurative otitis media with facial nerve palsy. On exploration exuberant granulation was found in attic and middle ear. A foreign body (seed) was found buried within the granulation tissue which was removed. Bony facial canal was dehiscent in the tympanic segment. She had recovery of facial nerve function. The case is being reported to increase awareness among otolaryngologist and to consider foreign body as a differential diagnosis in cases of complicated CSOM; especially in children. PMID- 25500548 TI - n-3 PUFA supplementation benefits microglial responses to myelin pathology. AB - Microglia represent rational but challenging targets for improving white matter integrity because of their dualistic protective and toxic roles. The present study examines the effect of Omega-3 polyunsaturated fatty acids (n-3 PUFAs) on microglial responses to myelin pathology in primary cultures and in the cuprizone mouse model of multiple sclerosis (MS), a devastating demyelination disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the two main forms of n-3 PUFAs in the brain, inhibited the release of nitric oxide and tumor necrosis factor-alpha from primary microglia upon IFN-gamma and myelin stimulation. DHA and EPA also enhanced myelin phagocytosis in vitro. Therefore, n-3 PUFAs can inhibit inflammation while at the same time enhancing beneficial immune responses such as microglial phagocytosis. In vivo studies demonstrated that n-3 PUFA supplementation reduced cuprizone-induced demyelination and improved motor and cognitive function. The positive effects of n-3 PUFAs were accompanied by a shift in microglial polarization toward the beneficial M2 phenotype both in vitro and in vivo. These results suggest that n-3 PUFAs may be clinically useful as immunomodulatory agents for demyelinating diseases through a novel mechanism involving microglial phenotype switching. PMID- 25500550 TI - Cochlear implantation and vestibular function in children. AB - OBJECTIVES: To analyze vestibular function Q2 (VF) after cochlear implantation (CI) in children. METHODS: Retrospective cohort study at a tertiary pediatric referral center. 43 children that had vestibular testing (VT) after unilateral cochlear implantation, from 2001 to 2010, were included. CT scan of the temporal bone was done systematically before surgery. VT included three tests: head impulse test, caloric tests, vestibular evoked myogenic potentials. VF was graded in: normal (type 1), partial dysfunction (type 2), severe dysfunction and areflexia (type 3). In 12 cases, VT was done before and after CI. Vestibular function was analyzed looking to side, etiology and preoperative status. RESULTS: Mean age at CI was 2.9 years. Bilateral inner ear malformation were retrieved in 16%. Before surgery, 50% of children had normal vestibular responses, 4/12 had bilateral type 2, two had asymmetrical VF. In this group, after surgery, 2 children had VF worsening, none on the CI side only. Considering all 43 patients, post operative VT showed normal response in 48.8% and type 2&3 in 16.2%. Children had asymmetrical poorer vestibular function on the side of CI in 19%. Among them, 75% had normal contralateral VF. Sensorineural hearing loss etiologies known to be associated with vestibulopathy (Usher/Meningitis/Inner Ear Malformations/CMV) were associated to abnormal vestibular function more frequently than in other causes (p=0.01). CONCLUSION: Half of the children had initial vestibular dysfunction. In our study, 20% of cochlear implantation could have worsened vestibular function. As vestibular function should be part of the choice in cochlear implantation, side of implantation and survey; and vestibular tests are uneasy to achieve in pediatric population, we propose a three-steps evaluation and gradation which allow easier comparison. PMID- 25500551 TI - [Retroperitoneal haematoma in an anticoagulated patient with a femoral catheter]. PMID- 25500553 TI - Chlorella: 125 years of the green survivalist. AB - Chlorella, the archetype of unicellular green algae, is a high-performance primary producer in aquatic and terrestrial ecosystems. Under the simple spherical morphology of Chlorella, many other 'green balls' unfolded as independent phylogenetic lineages as a result of convergent evolution. By contrast, green algae with strikingly different phenotypes were unmasked as close relatives of Chlorella by modern molecular techniques. Here, we point to the increasing impact of these diverse protists on ecology, evolution, and biotechnology in the light of integrative taxonomy. PMID- 25500552 TI - Global satellite monitoring of climate-induced vegetation disturbances. AB - Terrestrial disturbances are accelerating globally, but their full impact is not quantified because we lack an adequate monitoring system. Remote sensing offers a means to quantify the frequency and extent of disturbances globally. Here, we review the current application of remote sensing to this problem and offer a framework for more systematic analysis in the future. We recommend that any proposed monitoring system should not only detect disturbances, but also be able to: identify the proximate cause(s); integrate a range of spatial scales; and, ideally, incorporate process models to explain the observed patterns and predicted trends in the future. Significant remaining challenges are tied to the ecology of disturbances. To meet these challenges, more effort is required to incorporate ecological principles and understanding into the assessments of disturbance worldwide. PMID- 25500554 TI - Providing medication therapy management for smoking cessation patients. AB - Nearly 50 years ago, the Surgeon General of the US Public Health Service released the first report of the Surgeon General's Advisory Committee on Smoking and Health. The report concluded that cigarette smoking caused lung and laryngeal cancer as well as bronchitis. Today, smoking is one of the leading preventable causes of deaths in the United States. Research has shown that it potentially causes more deaths than human immunodeficiency virus, illegal drug use, alcohol use, motor vehicle injuries, and firearm-related incidents. Health care providers play a critical role in guiding and directing patients to quit smoking by introducing them to smoking-cessation options. This is due to the fact that if these patients quit, they can reduce their cardiovascular risk. Pharmacists, being one of the easily accessible health care providers, have an advantage over other clinicians when it comes to influencing patients to quit smoking and to modify their lifestyles. Pharmacists through medication therapy management directly interact with these patients to manage medications as well as behavioral factors. PMID- 25500556 TI - Pharmacist-initiated prior authorization process to improve patient care in a psychiatric acute care hospital. AB - A prior authorization (PA) is a requirement implemented by managed care organizations to help provide medications to consumers in a cost-effective manner. The PA process may be seen as a barrier by prescribers, pharmacists, pharmaceutical companies, and consumers. The lack of a standardized PA process, implemented prior to a patient's discharge from a health care facility, may increase nonadherence to inpatient prescribed medications. Pharmacists and other health care professionals can implement a PA process specific to their institution. This article describes a pharmacist-initiated PA process implemented at an acute care psychiatric hospital. This process was initiated secondary to a need for a standardized process at the facility. To date, the process has been seen as a valuable aspect to patient care. Plans to expand this process include collecting data with regards to adherence and readmissions as well as applying for a grant to help develop a program to automate the PA program at this facility. PMID- 25500555 TI - Pharmacists role in cholesterol management: addressing challenges and barriers. AB - Cholesterol management is an important factor in the modification of primary and secondary cardiovascular events. Guidelines emphasize incorporation of appropriate medication therapy and lifestyle adjustments to reduce low-density lipoprotein cholesterol (LDL-C) for cardiovascular disease (CVD) risk reduction. Of note, studies and nation-wide statistics indicate many patients do not achieve their LDL-C goals. Eliminating barriers and challenges associated with cholesterol management will allow patients to reach prespecified goals for CVD risk reduction. As the nation transitions to covering more individuals, the need for additional health care providers is evident. Pharmacists are accessible and knowledgeable health care contributors who can assist in optimizing patient outcomes. This article discusses the pharmacist's role in addressing challenges and barriers in cholesterol management. PMID- 25500557 TI - Role of medication therapy management in preexposure prophylaxis therapy for HIV prevention. AB - Patient medication adherence is a long-standing problem and is one that raises serious issues for patient health, public health, and health care quality. Medication nonadherence costs the US economy an estimated US$290 billion in avoidable medical spending every year. One of the most costly health conditions is HIV disease, which continues to be a serious health issue for parts of the world. About 34 million people are living with HIV around the world. With the emerging preventative treatment against HIV, known as preexposure prophylaxis (PrEP), come concerns surrounding the potential impact of nonadherence to this newly approved medication therapy. Nonadherence to antiretroviral treatments are commonly the root cause for patients not reaching their treatment goals, putting them at risk of progression and worsening of their disease and complications, such as increased risk of opportunistic infections. Therefore, it is essential to improve antiretroviral medication adherence. By identifying members who are nonadherent to their prescribed antiretroviral medications and working collaboratively with patients, physicians, and pharmacists, Medication Therapy Management (MTM) can potentially increase medication adherence by helping patients identify, resolve, and prevent issues that may affect their decision not to take a medication as intended. PMID- 25500558 TI - Equity in the national rollout of public AIDS treatment in South Africa 2004-08. AB - Low- and middle-income country governments face the challenge of ensuring an equitable distribution of public resources, based on need rather than socioeconomic status, race or political affiliation. This study examines factors that may influence public service provision in developing countries by analysing the 2004-08 implementation of government-provided AIDS treatment in South Africa, the largest programme of its kind in the world. Despite assurances from the National Department of Health, some have raised concerns about whether the rollout was in fact conducted equitably. This study addresses these concerns. This is the first study to assemble high-quality national data on a broad set of census main place (CMP) characteristics that the public health, economic and political science literature have found influence public service provision. Multivariate logistic regression and duration (survival) analysis were used to identify characteristics associated with a more rapid public provision of anti retroviral therapy (ART) in South Africa. Overall, no clear pattern emerges of the rollout systematically favouring better-off CMPs, and in general the magnitude of statistically significant associations is small. The centralization of the early phases of the rollout to maximize ART enrolment led to higher ART coverage rates in areas where district and regional hospitals were located. Ultimately, these results demonstrate that the provision of life-saving AIDS treatment was not disproportionately delayed in disadvantaged areas. The combination of a clear policy objective, limited bureaucratic discretion and monitoring by civil society ensured equitable access to AIDS treatment. This work highlights the potential for future public investment in South Africa and other developing countries to reduce health and economic disparities. PMID- 25500562 TI - Extramammary Paget's disease occurring in the context of Cowden syndrome: true association or mere coincidence? PMID- 25500563 TI - SteatoNet: the first integrated human metabolic model with multi-layered regulation to investigate liver-associated pathologies. AB - Current state-of-the-art mathematical models to investigate complex biological processes, in particular liver-associated pathologies, have limited expansiveness, flexibility, representation of integrated regulation and rely on the availability of detailed kinetic data. We generated the SteatoNet, a multi pathway, multi-tissue model and in silico platform to investigate hepatic metabolism and its associated deregulations. SteatoNet is based on object oriented modelling, an approach most commonly applied in automotive and process industries, whereby individual objects correspond to functional entities. Objects were compiled to feature two novel hepatic modelling aspects: the interaction of hepatic metabolic pathways with extra-hepatic tissues and the inclusion of transcriptional and post-transcriptional regulation. SteatoNet identification at normalised steady state circumvents the need for constraining kinetic parameters. Validation and identification of flux disturbances that have been proven experimentally in liver patients and animal models highlights the ability of SteatoNet to effectively describe biological behaviour. SteatoNet identifies crucial pathway branches (transport of glucose, lipids and ketone bodies) where changes in flux distribution drive the healthy liver towards hepatic steatosis, the primary stage of non-alcoholic fatty liver disease. Cholesterol metabolism and its transcription regulators are highlighted as novel steatosis factors. SteatoNet thus serves as an intuitive in silico platform to identify systemic changes associated with complex hepatic metabolic disorders. PMID- 25500559 TI - Which intervention design factors influence performance of community health workers in low- and middle-income countries? A systematic review. AB - Community health workers (CHWs) are increasingly recognized as an integral component of the health workforce needed to achieve public health goals in low- and middle-income countries (LMICs). Many factors influence CHW performance. A systematic review was conducted to identify intervention design related factors influencing performance of CHWs. We systematically searched six databases for quantitative and qualitative studies that included CHWs working in promotional, preventive or curative primary health services in LMICs. One hundred and forty studies met the inclusion criteria, were quality assessed and double read to extract data relevant to the design of CHW programmes. A preliminary framework containing factors influencing CHW performance and characteristics of CHW performance (such as motivation and competencies) guided the literature search and review.A mix of financial and non-financial incentives, predictable for the CHWs, was found to be an effective strategy to enhance performance, especially of those CHWs with multiple tasks. Performance-based financial incentives sometimes resulted in neglect of unpaid tasks. Intervention designs which involved frequent supervision and continuous training led to better CHW performance in certain settings. Supervision and training were often mentioned as facilitating factors, but few studies tested which approach worked best or how these were best implemented. Embedment of CHWs in community and health systems was found to diminish workload and increase CHW credibility. Clearly defined CHW roles and introduction of clear processes for communication among different levels of the health system could strengthen CHW performance.When designing community-based health programmes, factors that increased CHW performance in comparable settings should be taken into account. Additional intervention research to develop a better evidence base for the most effective training and supervision mechanisms and qualitative research to inform policymakers in development of CHW interventions are needed. PMID- 25500565 TI - A room for the alpps procedure in patients with HCC. PMID- 25500564 TI - An estimate of hernia prevalence in Nepal from a countrywide community survey. AB - BACKGROUND: Herniorrhaphy is one of the most frequently performed general surgical operations worldwide. However, most low- and middle-income countries (LMICs) are unable to provide this essential surgery to the general public, resulting in considerable morbidity and mortality. This study aimed to estimate the prevalence, barriers to care and disability of untreated hernias in Nepal. METHODS: Nepal is a low-income country in South Asia with rugged terrain, infrastructure deficiencies and a severely under-resourced healthcare system resulting in substantial unmet surgical need. A cluster randomized, cross sectional household survey was performed using the validated Surgeons OverSeas Assessment of Surgical (SOSAS) tool. Fifteen randomized clusters consisting of 30 households with two randomly selected respondents each were sampled to estimate surgical need. The prevalence of and disability from groin hernias and barriers to herniorrhaphy were assessed. RESULTS: The survey sampled 1350 households, totaling 2695 individuals (97% response rate). There were 1434 males (53%) with 1.5% having a mass or swelling in the groin at time of survey (95% CI 1.8-4.0). The age-standardized rate for inguinal hernias in men ranged from 1144 per 100,000 persons between age 5 and 49 years and 2941 per 100,000 persons age>=50 years. Extrapolating nationally, there are nearly 310,000 individuals with groin masses and 66,000 males with soft/reducible groin masses in need of evaluation in Nepal. Twenty-nine respondents were not able to have surgery due to lack of surgical services (31%), fear or mistrust of the surgical system (31%) and inability to afford care (21%). Twenty percent were unable to work as previous or perform self-care due to their hernia. CONCLUSIONS: Despite the lower than expected prevalence of inguinal hernias, hundreds of thousands of people in Nepal are currently in need of surgical evaluation. Given that essential surgery is a necessary component in health systems, the prevalence of inguinal hernias and the cost-effectiveness of herniorrhaphy, this disease is an important target for LMICs planning surgical capacity improvements. PMID- 25500566 TI - A Cbx8-containing polycomb complex facilitates the transition to gene activation during ES cell differentiation. AB - Polycomb proteins play an essential role in maintaining the repression of developmental genes in self-renewing embryonic stem cells. The exact mechanism allowing the derepression of polycomb target genes during cell differentiation remains unclear. Our project aimed to identify Cbx8 binding sites in differentiating mouse embryonic stem cells. Therefore, we used a genome-wide chromatin immunoprecipitation of endogenous Cbx8 coupled to direct massive parallel sequencing (ChIP-Seq). Our analysis identified 171 high confidence peaks. By crossing our data with previously published microarray analysis, we show that several differentiation genes transiently recruit Cbx8 during their early activation. Depletion of Cbx8 partially impairs the transcriptional activation of these genes. Both interaction analysis, as well as chromatin immunoprecipitation experiments support the idea that activating Cbx8 acts in the context of an intact PRC1 complex. Prolonged gene activation results in eviction of PRC1 despite persisting H3K27me3 and H2A ubiquitination. The composition of PRC1 is highly modular and changes when embryonic stem cells commit to differentiation. We further demonstrate that the exchange of Cbx7 for Cbx8 is required for the effective activation of differentiation genes. Taken together, our results establish a function for a Cbx8-containing complex in facilitating the transition from a Polycomb-repressed chromatin state to an active state. As this affects several key regulatory differentiation genes this mechanism is likely to contribute to the robust execution of differentiation programs. PMID- 25500567 TI - Evolutionary phylodynamics of Korean noroviruses reveals a novel GII.2/GII.10 recombination event. AB - Viral gastroenteritis is the most common causal agent of public health problems worldwide. Noroviruses cause nonbacterial acute gastroenteritis in humans of all ages. In this study, we investigated the occurrence of norovirus infection in children with acute gastroenteritis admitted to university hospitals in South Korea. We also analyzed the genetic diversity of the viruses and identified novel recombination events among the identified viral strains. Of 502 children with acute gastroenteritis admitted to our three hospitals between January 2011 and March 2012, genotyping of human noroviruses was performed in 171 (34%) norovirus positive samples. Of these samples, 170 (99.5%) were in genogroup II (GII), while only one (0.5%) was in genogroup I (GI). The most common GII strain was the GII.4 2006b variant (n = 96, 56.5%), followed by GII.6 (n = 23, 13.5%), GII.12 (n = 22, 12.9%), GII.3 (n = 20, 11.8%), GII.2 (n = 6, 3.5%), GII.b (n = 2, 1.2%), and GII.10 (n = 1, 0.6%). Potential recombination events (polymerase/capsid) were detected in 39 GII strains (22.9%), and the most frequent genotypes were GII.4/GII.12 (n = 12, 30.8%), GII.4/GII.6 (n = 12, 30.8%), GII.4/GII.3 (n = 8, 20.5%), GII.b/GII.3 (n = 3, 7.7%), GII.16/GII.2 (n = 2, 5.1%), GII.4/GII.2 (n = 1, 2.6%), and GII.2/GII.10 (n = 1, 2.6%). For the first time, a novel GII.2/GII.10 recombination was detected; we also identified the GII.16/GII.2 strain for the first time in South Korea. Our data provided important insights into new recombination events, which may prove valuable for predicting the emergence of circulating norovirus strains with global epidemic potential. PMID- 25500568 TI - Coincidence between geographical distribution of Leptotrombidium scutellare and scrub typhus incidence in South Korea. AB - To clarify the geographical distribution of scrub typhus vectors in Korea, a survey of larval trombiculid mites was conducted from 2005 to 2007 by collecting wild small mammals twice a year (spring and autumn) at 24 sites nationwide. A total of 67,325 mites representing 4 genera and 14 species were collected from 783 trapped rodents, corresponding to a chigger index (number of chigger mites per rodent) of 86.0. The predominant mite species were Leptotrombidium pallidum (52.6%), Leptotrombiduim scutellare (27.1%), Leptotrombidium palpale (8.2%), Leptotrombidium orientale (5.6%), and Neotrombicula tamiyai (1.7%). However, the proportions of L. scutellare in southern areas, including endemic provinces such as Jeollabuk-Do (34.3%), Jeollanam-Do (49.0%), and Gyeongsangnam-Do (88%), were relatively higher than in central Korean regions where L. pallidum was predominant. In autumn, the ratio of L. scutellare increased to 42% while the ratio of L. pallidum decreased. The geographical distribution map of the L. scutellare chigger index was identical to the incidence pattern of scrub typhus, whereas those of overall mites and L. pallidum showed no relationship with case incidence patterns. Distribution mapping analysis shows an identical geographical distribution of L. scutellare and epidemic incidence of scrub typhus in South Korea. L. pallidum could be another vector at all other parts of the Korean peninsula, including the eastern and northern regions that have a low level of scrub typhus incidence. PMID- 25500570 TI - Amphiphilic poly(amino acid) based micelles applied to drug delivery: the in vitro and in vivo challenges and the corresponding potential strategies. AB - Core-shell structured micelles produced from an amphiphilic block copolymer are promising drug delivery vehicles because their hydrophobic core can encapsulate hydrophobic drugs through hydrophobic interactions and their hydrophilic shell can prolong their circulation in the blood. However, the low cargo capacity and the lack of stability in the blood are major problems associated with micellar drug delivery systems. Poly(amino acid) or its derivatives, especially poly(glutamic acid) or poly(aspartic acid) or poly(l-lysine), are widely used as micelle-forming materials because of their remarkable advantages such as easy biodegradability, good biocompatibility and availability of side functional groups. In this review, the structures, synthesis and characteristics of the amphiphilic poly(amino acid) based micelles are initially described, then the driving forces, which may determine the drug loading capacity, and the variants which affect the stability of drug-loaded micelles in blood post-injection are summarized. Furthermore, the strategies for increasing the drug loading capacity and improve the stability in blood are also described. PMID- 25500569 TI - Allelic exclusion of TCR alpha-chains upon severe restriction of Valpha repertoire. AB - Development of thymocytes through the positive selection checkpoint requires the rearrangement and expression of a suitable T cell receptor (TCR) alpha-chain that can pair with the already-expressed beta-chain to make a TCR that is selectable. That is, it must have sufficient affinity for self MHC-peptide to induce the signals required for differentiation, but not too strong so as to induce cell death. Because both alleles of the alpha-chain continue to rearrange until a positively-selectable heterodimer is formed, thymocytes and T cells can in principle express dual alpha-chains. However, cell-surface expression of two TCRs is comparatively rare in mature T cells because of post-transcriptional regulatory mechanisms termed "phenotypic allelic exclusion". We produced mice transgenic for a rearranged beta-chain and for two unrearranged alpha-chains on a genetic background where endogenous alpha-chains could not be rearranged. Both Valpha3.2 and Valpha2 containing alpha-chains were efficiently positively selected, to the extent that a population of dual alpha-chain-bearing cells was not distinguishable from single alpha-chain-expressors. Surprisingly, Valpha3.2 expressing cells were much more frequent than the Valpha2 transgene-expressing cells, even though this Valpha3.2-Vbeta5 combination can reconstitute a known selectable TCR. In accord with previous work on the Valpha3 repertoire, T cells bearing Valpha3.2 expressed from the rearranged minilocus were predominantly selected into the CD8+ T cell subpopulation. Because of the dominance of Valpha3.2 expression over Valpha2 expressed from the miniloci, the peripheral T cell population was predominantly CD8+ cells. PMID- 25500572 TI - Exploitation and recovery of a sea urchin predator has implications for the resilience of southern California kelp forests. AB - Size-structured predator-prey interactions can be altered by the history of exploitation, if that exploitation is itself size-selective. For example, selective harvesting of larger sized predators can release prey populations in cases where only large individuals are capable of consuming a particular prey species. In this study, we examined how the history of exploitation and recovery (inside marine reserves and due to fisheries management) of California sheephead (Semicossyphus pulcher) has affected size-structured interactions with sea urchin prey in southern California. We show that fishing changes size structure by reducing sizes and alters life histories of sheephead, while management measures that lessen or remove fishing impacts (e.g. marine reserves, effort restrictions) reverse these effects and result in increases in density, size and biomass. We show that predation on sea urchins is size-dependent, such that the diet of larger sheephead is composed of more and larger sized urchins than the diet of smaller fish. These results have implications for kelp forest resilience, because urchins can overgraze kelp in the absence of top-down control. From surveys in a network of marine reserves, we report negative relationships between the abundance of sheephead and urchins and the abundance of urchins and fleshy macroalgae (including giant kelp), indicating the potential for cascading indirect positive effects of top predators on the abundance of primary producers. Management measures such as increased minimum size limits and marine reserves may serve to restore historical trophic roles of key predators and thereby enhance the resilience of marine ecosystems. PMID- 25500571 TI - DNA-protein immunization using Leishmania peroxidoxin-1 induces a strong CD4+ T cell response and partially protects mice from cutaneous leishmaniasis: role of fusion murine granulocyte-macrophage colony-stimulating factor DNA adjuvant. AB - BACKGROUND: To date, no universally effective and safe vaccine has been developed for general human use. Leishmania donovani Peroxidoxin-1 (LdPxn-1) is a member of the antioxidant family of proteins and is predominantly expressed in the amastigote stage of the parasite. The aim of this study was to evaluate the immunogenicity and protective efficacy of LdPxn-1 in BALB/c mice in heterologous DNA-Protein immunization regimen in the presence of fusion murine granulocyte macrophage colony-stimulating factor (mGMCSF) DNA adjuvant. METHODOLOGY AND PRINCIPAL FINDINGS: A fusion DNA of LdPxn1 and mGMCSF was cloned into a modified pcDNA vector. To confirm the expression in mammalian system, Chinese hamster ovary cells were transfected with the plasmid vector containing LdPxn1 gene. BALB/c mice were immunized twice with pcDNA-mGMCSF-LdPxn-1 or pcDNA-LdPxn1 DNA and boosted once with recombinant LdPxn-1 protein. Three weeks after the last immunization, mice were infected with Leishmania major promastigotes. The result showed that immunization with pcDNA-mGMCSF-LdPxn1 elicited a mixed Th-1/Th-2 immune response with significantly higher production of IFN-gamma than controls. Intracellular cytokine staining of antigen-stimulated spleen cells showed that immunization with this antigen elicited significantly higher proportion of CD4+ T cells that express IFN-gamma, TNF-alpha, or IL-2. The antigen also induced significantly higher proportion of multipotent CD4+ cells that simultaneously express the three Th-1 cytokines. Moreover, a significant reduction in the footpad swelling was seen in mice immunized with pcDNA-mGMCSF-LdPxn1 antigen. Expression study in CHO cells demonstrated that pcDNA-mGMCSF-LdPxn-1 was expressed in mammalian system. CONCLUSION: The result demonstrates that immunization of BALB/c mice with a plasmid expressing LdPxn1 in the presence of mGMCSF adjuvant elicits a strong specific immune response with high level induction of multipotent CD4+ cells that mediate protection of the mice from Leishmania major infection. To our knowledge, this is the first study showing the vaccine potential of Leishmania peroxidoxin -1. PMID- 25500573 TI - LAMA2-related congenital muscular dystrophy complicated by West syndrome. AB - BACKGROUND: Mutations in the LAMA2 gene cause autosomal recessive laminin alpha2 related congenital muscular dystrophy. In patients with partial laminin alpha2 deficiency the phenotype is usually milder than in those with absent protein. Apart from the typical white matter abnormalities, there is an increased risk of cerebral complications such as epilepsy and mental retardation, despite a structurally normal brain. METHODS/RESULTS: We present a patient with primary partial laminin alpha2 deficiency due to a homozygous novel LAMA2 missense mutation who developed West syndrome in his first year of life. To our knowledge, this combination has not previously been reported. A 5 year-old boy exhibited global hypotonia with generalized muscle weakness from birth. At 8 months of age he presented infantile spasms and an EEG finding of hypsarrhythmia. Seizures were controlled in a few weeks with intramuscular synthetic ACTH, followed by valproic acid. Two years later antiepileptic medication was withdrawn. He achieved unsupported walking at the age of 4, but his cognitive status corresponded to a 2 year-old child. Epilepsy has not recurred and brain MRI showed the typical white matter abnormalities without associated neuronal migration defects. CONCLUSION: This report widens the clinical spectrum of cerebral manifestations related with mutations in LAMA2. The beginning of a severe epileptic encephalopathy modifies the natural history of the disease. PMID- 25500574 TI - Efficacy and safety of intramuscular midazolam versus rectal diazepam in controlling status epilepticus in children. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of intramuscular midazolam in controlling convulsive status epilepticus in children, by comparing it with rectal diazepam. METHODS: In this randomized trial, 100 children (50 in each group) with convulsive status epilepticus aged 1 month to 16 years were enrolled and randomly assigned into two groups to receive either 0.3 mg/kg intramuscular midazolam or 0.5 mg/kg rectal diazepam. Main outcome measure was stopping of all motor activity after drug administration. Another measures were times between patient's arrival to emergency department till drug administration, between drug administration to seizure cessation, and between patient's arrival to seizure cessation. RESULTS: Both medication were effective for seizure control and no significant difference was found between successful treatments after administering the medication (P = 0.061). In the midazolam group, in 96% (48/50) of cases treatment was successful and in the diazepam group, in 94% (47/50) of cases treatment was successful. Time from arrival to administering the medication was significantly shorter in midazolam group (P = 0.017). The majority of seizures in midazolam group were stopped in less than 66 s (median) compared to 130 s (median) for diazepam group, (P < 0.001). No serious adverse effects were seen in both groups. CONCLUSION: IM midazolam is not superior but may be at least as effective as rectal diazepam for controlling of status epilepticus in children. Midazolam via IM route could be one of the choices in children with convulsive status seizures who have difficult IV access. PMID- 25500575 TI - Lethal neonatal rigidity and multifocal seizure syndrome--report of another family with a BRAT1 mutation. AB - We describe two siblings born to consanguineous Arab-Muslim parents who presented in early infancy with myoclonic seizures, hypertonia and contractures, arrested head growth, inability to swallow, and bouts of apnea-bradycardia, culminating in cardiac arrest and death. Whole-genome sequencing yielded a c.1173delG mutation in the BRAT1 gene. Three recent reports identified mutations in the same gene in three infants from three Amish sibships, one Mexican neonate and two Japanese siblings with similar clinical manifestations. The authors speculated that the destabilization of the encoded protein may underlie the catastrophic epilepsy and corticobasal neuronal degeneration. We suggest that BRAT1 be added to the growing list of genes that are related to severe early infantile (neonatal) epileptic encephalopathy. PMID- 25500576 TI - Gene expression of corals in response to macroalgal competitors. AB - As corals decline and macroalgae proliferate on coral reefs, coral-macroalgal competition becomes more frequent and ecologically important. Whether corals are damaged by these interactions depends on susceptibility of the coral and traits of macroalgal competitors. Investigating changes in gene expression of corals and their intracellular symbiotic algae, Symbiodinium, in response to contact with different macroalgae provides insight into the biological processes and cellular pathways affected by competition with macroalgae. We evaluated the gene expression profiles of coral and Symbiodinium genes from two confamilial corals, Acropora millepora and Montipora digitata, after 6 h and 48 h of contact with four common macroalgae that differ in their allelopathic potency to corals. Contacts with macroalgae affected different biological pathways in the more susceptible (A. millepora) versus the more resistant (M. digitata) coral. Genes of coral hosts and of their associated Symbiodinium also responded in species specific and time-specific ways to each macroalga. Changes in number and expression intensity of affected genes were greater after 6 h compared to 48 h of contact and were greater following contact with Chlorodesmis fastigiata and Amphiroa crassa than following contact with Galaxaura filamentosa or Turbinaria conoides. We documented a divergence in transcriptional responses between two confamilial corals and their associated Symbiodinium, as well as a diversity of dynamic responses within each coral species with respect to the species of macroalgal competitor and the duration of exposure to that competitor. These responses included early initiation of immune processes by Montipora, which is more resistant to damage after long-term macroalgal contact. Activation of the immune response by corals that better resist algal competition is consistent with the hypothesis that some macroalgal effects on corals may be mediated by microbial pathogens. PMID- 25500577 TI - Discovery of two beta-1,2-mannoside phosphorylases showing different chain-length specificities from Thermoanaerobacter sp. X-514. AB - We characterized Teth514_1788 and Teth514_1789, belonging to glycoside hydrolase family 130, from Thermoanaerobacter sp. X-514. These two enzymes catalyzed the synthesis of 1,2-beta-oligomannan using beta-1,2-mannobiose and d-mannose as the optimal acceptors, respectively, in the presence of the donor alpha-d-mannose 1 phosphate. Kinetic analysis of the phosphorolytic reaction toward 1,2-beta oligomannan revealed that these enzymes followed a typical sequential Bi Bi mechanism. The kinetic parameters of the phosphorolysis of 1,2-beta-oligomannan indicate that Teth514_1788 and Teth514_1789 prefer 1,2-beta-oligomannans containing a DP >=3 and beta-1,2-Man2, respectively. These results indicate that the two enzymes are novel inverting phosphorylases that exhibit distinct chain length specificities toward 1,2-beta-oligomannan. Here, we propose 1,2-beta oligomannan:phosphate alpha-d-mannosyltransferase as the systematic name and 1,2 beta-oligomannan phosphorylase as the short name for Teth514_1788 and beta-1,2 mannobiose:phosphate alpha-d-mannosyltransferase as the systematic name and beta 1,2-mannobiose phosphorylase as the short name for Teth514_1789. PMID- 25500578 TI - Serum gamma - glutamyltransferase is associated with albuminuria: a population based study. AB - BACKGROUND: Serum gamma - glutamyltransferase (GGT) is implicated in the pathogenesis of endothelial dysfunction and atherosclerosis. Albuminuria is a marker of endothelial damage and correlated with structural and functional integrity of the vasculature. Our objective was to evaluate the association between serum GGT level and prevalence of albuminuria in a Chinese population. MATERIALS AND METHODS: We conducted a population-based cross-sectional study in 9,702 subjects aged 40 years or older. Increased urinary albumin excretion was defined according to the urinary albumin-to-creatinine ratio (ACR) ranges greater or equal than 30 mg/g. Low-grade albuminuria was defined according to the highest quartile of ACR in participants without increased urinary albumin excretion. RESULTS: The prevalence of low-grade albuminuria and increased urinary albumin excretion were respectively 23.4% and 6.6% in this population and gradually increased across the sex-specific serum GGT quartiles (all P for trend <0.05). In logistic regression analysis, compared with subjects in the lowest quartile of serum GGT level, the adjusted odds ratios (ORs) in the highest quartile was 1.22 [95% confidence interval (CI), 1.04-1.43] for low-grade albuminuria and 1.55 (95% CI, 1.18-2.04) for increased urinary albumin excretion. In subgroup analysis, significant relationship of serum GGT level with both low-grade albuminuria and increased urinary albumin excretion were detected in women, younger subjects, overweight subjects and in those with hypertension or glomerular filtration rate greater than 90 (all P <0.05). CONCLUSION: Serum GGT level is associated with urinary albumin excretion in middle-aged and elderly Chinese. PMID- 25500579 TI - Decreased eccentric exercise-induced macrophage infiltration in skeletal muscle after supplementation with a class of ginseng-derived steroids. AB - Dammarane steroids (DS) are a class of chemical compounds present in Panax ginseng. Here, we evaluated the effect of 10 weeks of DS supplementation on inflammatory modulation in the soleus muscle following eccentric exercise (EE) induced muscle damage (downhill running). Eighty rats were randomized into 4 groups of DS supplementation (saline, 20, 60, 120 mg/kg body weight). Inflammatory markers were measured at rest and again 1 h after EE. At rest, NFkappaB signaling, TNF-alpha and IL-6 mRNAs, 3-nitrotyrosine, glutathione peroxidase, and GCS (glutamylcysteine synthetase) levels were significantly elevated in the skeletal muscle of DS-treated rats in a dose-dependent manner. Additionally, there were no detectable increases in the number of necrotic muscle fibers or CD68+ M1 macrophages. However, muscle strength, centronucleation, IL-10 mRNA expression, and the number of CD163+ M2 macrophages increased significantly over controls with DS treatment in rat soleus muscle. Under EE-challenged conditions, significant increases in muscle fiber necrosis, CD68+ M1 macrophage distribution, and 3-nitrotyrosine were absent in rats that received low and medium doses (20 and 60 mg/kg) of DS treatment, suggesting that DS possess anti inflammatory action protecting against a muscle-damaging challenge. However, this protective activity was diminished when a high dose of DS (120 mg/kg) was administered, suggesting that DS possess hormetic properties. In conclusion, our study provides new evidence suggesting that DS is an ergogenic component of ginseng that potentiate inflammation at baseline but that produce anti inflammatory effects on skeletal muscle following muscle-damaging exercise. Furthermore, high doses should be avoided in formulating ginseng-based products. PMID- 25500580 TI - Automatic segmentation of the left ventricle in cardiac MRI using local binary fitting model and dynamic programming techniques. AB - Segmentation of the left ventricle is very important to quantitatively analyze global and regional cardiac function from magnetic resonance. The aim of this study is to develop a novel algorithm for segmenting left ventricle on short-axis cardiac magnetic resonance images (MRI) to improve the performance of computer aided diagnosis (CAD) systems. In this research, an automatic segmentation method for left ventricle is proposed on the basis of local binary fitting (LBF) model and dynamic programming techniques. The validation experiments are performed on a pool of data sets of 45 cases. For both endo- and epi-cardial contours of our results, percentage of good contours is about 93.5%, the average perpendicular distance are about 2 mm. The overlapping dice metric is about 0.91. The regression and determination coefficient between the experts and our proposed method on the LV mass is 1.038 and 0.9033, respectively; they are 1.076 and 0.9386 for ejection fraction (EF). The proposed segmentation method shows the better performance and has great potential in improving the accuracy of computer aided diagnosis systems in cardiovascular diseases. PMID- 25500585 TI - Randomised controlled trials: subgroup analyses. PMID- 25500583 TI - Decreased serum level of miR-146a as sign of chronic inflammation in type 2 diabetic patients. AB - BACKGROUND: There is increasing evidence that chronic inflammation is an important determinant in insulin resistance and in the pathogenesis of type 2 diabetes (T2D). MicroRNAs constitute a newly discovered system of cell regulation and in particular two microRNAs (miR-146a and miR-155) have been described as regulators and biomarkers of inflammation. AIM: To determine a putative association between the levels of miR-146a and miR-155 in serum of T2D patients, clinical parameters and serological indicators of inflammation. METHODS: We performed quantitative Real Time PCR (qPCR) of microRNAs from serum (56 Ecuadorian T2D ambulatory patients and 40 non-diabetic controls). In addition, we evaluated T2D-related serum cytokines.chemokines and growth factors using a commercially available multi-analyte cytometric bead array system. We correlated outcomes to clinical parameters, including BMI, HbA1c and lipid state. RESULTS: The Ecuadorian non-diabetic controls appeared as overweight (BMI>25: patients 85%, controls 82.5%) and as dyslipidemic (hypercholesterolemia: patients 60.7%, controls 67.5%) as the patients. The serum levels of miR-146a were significantly reduced in T2D patients as compared to these non-diabetic, but obese/dyslipidemic control group (mean patients 0.61, mean controls set at 1; p = 0.042), those of miR-155 were normal.The serum levels of both microRNAs correlated to each other (r = 0.478; p<0.001) and to leptin levels. The microRNAs did not correlate to BMI, glycemia and dyslipidemia.From the tested cytokines, chemokines and growth factors, we found IL-8 and HGF significantly raised in T2D patients versus non diabetic controls (p = 0.011 and 0.023 respectively). CONCLUSIONS: This study shows decreased serum anti-inflammatory miR-146a, increased pro-inflammatory IL-8 and increased HGF (a vascular/insular repair factor) as discriminating markers of failure of glucose control occurring on the background of obesity and dyslipidemia. PMID- 25500581 TI - Comprehensive suppression of all apoptosis-induced proliferation pathways as a proposed approach to colorectal cancer prevention and therapy. AB - Mutations in the WNT/beta-catenin pathway are present in the majority of all sporadic colorectal cancers (CRCs), and histone deacetylase inhibitors induce apoptosis in CRC cells with such mutations. This apoptosis is counteracted by (1) the signaling heterogeneity of CRC cell populations, and (2) the survival pathways induced by mitogens secreted from apoptotic cells. The phenomena of signaling heterogeneity and apoptosis-induced survival constitute the immediate mechanisms of resistance to histone deacetylase inhibitors, and probably other chemotherapeutic agents. We explored the strategy of augmenting CRC cell death by inhibiting all survival pathways induced by the pro-apoptotic agent LBH589, a histone deacetylase inhibitor: AKT, JAK/STAT, and ERK signaling. The apoptosis enhancing ability of a cocktail of synthetic inhibitors of proliferation was compared to the effects of the natural product propolis. We utilized colorectal adenoma, drug-sensitive and drug-resistant colorectal carcinoma cells to evaluate the apoptotic potential of the combination treatments. The results suggest that an effective approach to CRC combination therapy is to combine apoptosis-inducing drugs (e.g., histone deacetylase inhibitors, such as LBH589) with agents that suppress all compensatory survival pathways induced during apoptosis (such as the cocktail of inhibitors of apoptosis-associated proliferation). The same paradigm can be applied to a CRC prevention approach, as the apoptotic effect of butyrate, a diet-derived histone deacetylase inhibitor, is augmented by other dietary agents that modulate survival pathways (e.g., propolis and coffee extract). Thus, dietary supplements composed by fermentable fiber, propolis, and coffee extract may effectively counteract neoplastic growth in the colon. PMID- 25500586 TI - Editorial: Wide multidisciplinary rather than narrow subspecialty. PMID- 25500587 TI - Minimally invasive endodontics. AB - Minimally invasive endodontics (MIE) aims to preserve the maximum of tooth structure during root canal therapy. In the last 15 years there has been rapid progress and development in endodontics, making treatment procedures safer, more accurate, and more efficient. Meanwhile, reproducible results can be achieved even in difficult root canal morphologies with severe or double curvatures. In addition to various material improvements, the implementation of the surgical microscope (SM) in endodontics is an important innovation, making it possible to optimize each step in the treatment protocol in terms of substance preservation. PMID- 25500584 TI - Expression of suppressor of cytokine signaling 1 (SOCS1) impairs viral clearance and exacerbates lung injury during influenza infection. AB - Suppressor of cytokine signaling (SOCS) proteins are inducible feedback inhibitors of cytokine signaling. SOCS1-/- mice die within three weeks postnatally due to IFN-gamma-induced hyperinflammation. Since it is well established that IFN-gamma is dispensable for protection against influenza infection, we generated SOCS1-/-IFN-gamma-/- mice to determine whether SOCS1 regulates antiviral immunity in vivo. Here we show that SOCS1-/-IFN-gamma-/- mice exhibited significantly enhanced resistance to influenza infection, as evidenced by improved viral clearance, attenuated acute lung damage, and consequently increased survival rates compared to either IFN-gamma-/- or WT animals. Enhanced viral clearance in SOCS1-/-IFN-gamma-/- mice coincided with a rapid onset of adaptive immune responses during acute infection, while their reduced lung injury was associated with decreased inflammatory cell infiltration at the resolution phase of infection. We further determined the contribution of SOCS1-deficient T cells to antiviral immunity. Anti-CD4 antibody treatment of SOCS1-/-IFN-gamma-/- mice had no significant effect on their enhanced resistance to influenza infection, while CD8+ splenocytes from SOCS1-/-IFN-gamma-/- mice were sufficient to rescue RAG1-/- animals from an otherwise lethal infection. Surprisingly, despite their markedly reduced viral burdens, RAG1-/- mice reconstituted with SOCS1-/-IFN-gamma-/- adaptive immune cells failed to ameliorate influenza-induced lung injury. In conclusion, in the absence of IFN-gamma, the cytoplasmic protein SOCS1 not only inhibits adaptive antiviral immune responses but also exacerbates inflammatory lung damage. Importantly, these detrimental effects of SOCS1 are conveyed through discrete cell populations. Specifically, while SOCS1 expression in adaptive immune cells is sufficient to inhibit antiviral immunity, SOCS1 in innate/stromal cells is responsible for aggravated lung injury. PMID- 25500589 TI - How does one become a family physician? PMID- 25500588 TI - The expression and correlation between the transcription factor FOXP1 and estrogen receptors in epithelial ovarian cancer. AB - BACKGROUND: Estrogen plays an important role in the progression of ovarian cancer in humans. FOXP1 belongs to the forkhead/winged-helix transcription factor family, and previous research indicated that FOXP1 functioned as a tumor suppressor gene. FOXP1 may be similar to FOXA1 and is closely related to steroid hormone receptors, but the relationship between FOXP1 and ER currently remains unclear. METHODS: Ovarian tumors (60 malignant cases, 26 borderline cases, and 13 benign cases) and 14 normal ovarian tissues were collected retrospectively. Immunohistochemistry, western blotting and real-time PCR were used to characterize the expression patterns of FOXP1, ERalpha, and ERbeta both at the mRNA and protein levels. We also used co-immunoprecipitation and immunofluorescent colocalization to investigate whether a correlation exists between FOXP1 and ERalpha/ERbeta in ovarian cancer tissues. RESULTS: The mRNA level for FOXP1 and ERbeta in ovarian carcinoma tissues decreased, while the expression level of ERalpha mRNA increased compared with normal ovarian tissues. With an increase in the degree of ovarian carcinoma malignancy, the ERalpha expression level also increased. The expression pattern of ERbeta in ovarian neoplasms was similar to that of the FOXP1 protein; presenting nuclear staining decreased, while cytoplasmic expression increased. Colocalization of FOXP1, ERalpha, and ERbeta was present in the cytoplasm, with ERbeta specific co localization with FOXP1 in the perinuclear area. While immunoprecipitates created with FOXP1 mouse anti-human monoclonal antibody showed a positive reaction to an anti-ER antibody, immunoprecipitates containing anti-ER antibody and react to anti-FOXP1 antibody. CONCLUSION: Interactions between FOXP1 and ER may play a pivotal role in the progression of ovarian cancer, and the activation or induction of FOXP1 and ERbeta expression in cancer cells may inhibit tumor proliferation. PMID- 25500591 TI - Finding their voices: how a group of academic family physicians became writers. PMID- 25500592 TI - Role of spirometry in primary care. PMID- 25500595 TI - Benefits of TED Talks. PMID- 25500596 TI - Patient-centred approach is the way. PMID- 25500598 TI - Prescribing smoked cannabis for chronic noncancer pain: preliminary recommendations. AB - OBJECTIVE: To offer preliminary guidance on prescribing smoked cannabis for chronic pain before the release of formal guidelines. QUALITY OF EVIDENCE: We reviewed the literature on the analgesic effectiveness of smoked cannabis and the harms of medical and recreational cannabis use. We developed recommendations on indications, contraindications, precautions, and dosing of smoked cannabis, and categorized the recommendations based on levels of evidence. Evidence is mostly level II (well conducted observational studies) and III (expert opinion). MAIN MESSAGE: Smoked cannabis might be indicated for patients with severe neuropathic pain conditions who have not responded to adequate trials of pharmaceutical cannabinoids and standard analgesics (level II evidence). Smoked cannabis is contraindicated in patients who are 25 years of age or younger (level II evidence); who have a current, past, or strong family history of psychosis (level II evidence); who have a current or past cannabis use disorder (level III evidence); who have a current substance use disorder (level III evidence); who have cardiovascular or respiratory disease (level III evidence); or who are pregnant or planning to become pregnant (level II evidence). It should be used with caution in patients who smoke tobacco (level II evidence), who are at increased risk of cardiovascular disease (level III evidence), who have anxiety or mood disorders (level II evidence), or who are taking higher doses of opioids or benzodiazepines (level III evidence). Cannabis users should be advised not to drive for at least 3 to 4 hours after smoking, for at least 6 hours after oral ingestion, and for at least 8 hours if they experience a subjective "high" (level II evidence). The maximum recommended dose is 1 inhalation 4 times per day (approximately 400 mg per day) of dried cannabis containing 9% delta-9 tetrahydrocannabinol (level III evidence). Physicians should avoid referring patients to "cannabinoid" clinics (level III evidence). CONCLUSION: Future guidelines should be based on systematic review of the literature on the safety and effectiveness of smoked cannabis. Further research is needed on the effectiveness and long-term safety of smoked cannabis compared with pharmaceutical cannabinoids, opioids, and other standard analgesics. PMID- 25500599 TI - Travel medicine: what's involved? When to refer? AB - OBJECTIVE: To define the practice of travel medicine, provide the basics of a comprehensive pretravel consultation for international travelers, and assist in identifying patients who might require referral to travel medicine professionals. SOURCES OF INFORMATION: Guidelines and recommendations on travel medicine and travel-related illnesses by national and international travel health authorities were reviewed. MEDLINE and EMBASE searches for related literature were also performed. MAIN MESSAGE: Travel medicine is a highly dynamic specialty that focuses on pretravel preventive care. A comprehensive risk assessment for each individual traveler is essential in order to accurately evaluate traveler-, itinerary-, and destination-specific risks, and to advise on the most appropriate risk management interventions to promote health and prevent adverse health outcomes during travel. Vaccinations might also be required and should be personalized according to the individual traveler's immunization history, travel itinerary, and the amount of time available before departure. CONCLUSION: A traveler's health and safety depends on a practitioner's level of expertise in providing pretravel counseling and vaccinations, if required. Those who advise travelers are encouraged to be aware of the extent of this responsibility and to refer all high-risk travelers to travel medicine professionals whenever possible. PMID- 25500600 TI - Pharmacologic management of adult breakthrough cancer pain. PMID- 25500601 TI - Fatal aortic dissection in a 37-year-old man: missed opportunity. PMID- 25500602 TI - Exercise prescription and referral tool to facilitate brief advice to adults in primary care. PMID- 25500603 TI - Dr William Osler: humour and wonderment. PMID- 25500604 TI - The one among many. PMID- 25500605 TI - Nigel Flook MD CCFP FCFP. PMID- 25500606 TI - Becoming a peer reviewer: engaging in sharing and gaining knowledge. PMID- 25500610 TI - Sixty years later. PMID- 25500612 TI - Novel treatment for infantile hemangiomas. PMID- 25500614 TI - A motion artifact generation and assessment system for the rapid testing of surface biopotential electrodes. AB - Dry electrodes can reduce cost while increasing the usability and comfort of wearable monitoring systems. They are, however, susceptible to motion artifacts. The present electrode testing methods lack reliability and do not separate the factors that affect the motion artifact. In this paper, we introduce a first generation motion artifact generation and assessment system that generates the speed, amplitude, and pattern-wise programmable movement of the electrode. The system simultaneously measures electrode-skin impedance, the motion artifact, and one channel of an electrocardiogram that contains the motion artifact and monitors the mounting force applied to the electrode. We demonstrate the system by comparing the applied movement and the measured signals for electrode movements up to 6 mm and movement frequencies from 0.4 Hz to 4 Hz. Results show that the impedance change and surface potential are visually clearly related to the applied motion, with average correlations of 0.89 and 0.64, respectively. The applied force, electrode location, and electrode structure all affect the motion artifact. The setup enables the motion of the electrode to be accurately controlled. The system can be used as a precursor to the testing of integrated systems because it enables thorough, repeatable, and robust motion artifact studies. The system allows a deeper insight into motion artifacts and the interplay of the various factors that affect them. PMID- 25500616 TI - Pyrolysis of sunflower seed hulls for obtaining bio-oils. AB - Bio-oils from pyrolysis of as received sunflower seed hulls (SSH), hulls previously washed with acid (SSHA) and hulls submitted to a mushroom enzymatic attack (BSSH) were analyzed. The concentration of lignin, hemicellulose and cellulose varied with the pre-treatment. The liquid corresponding to SSH presented a relatively high concentration of acetic acid and a high instability to storage. The bio-oil from SSHA showed a high concentration of furfural and an appreciable amount of levoglucosenone. Lignin was degraded upon enzymatic activity, for this reason BSSH led to the highest yield of bio-oil, with relative high concentration of acetic acid and stability to storage. PMID- 25500615 TI - Asymmetric expression of connexins between luminal epithelial- and myoepithelial- cells is essential for contractile function of the mammary gland. AB - Intercellular communication is essential for glandular functions and tissue homeostasis. Gap junctions couple cells homotypically and heterotypically and co ordinate reciprocal responses between the different cell types. Connexins (Cxs) are the main mammalian gap junction proteins, and the distribution of some Cx subtypes in the heterotypic gap junctions is not symmetrical; in the murine mammary gland, Cx26, Cx30 and Cx32 are expressed only in the luminal epithelial cells and Cx43 is expressed only in myoepithelial cells. Expression of all four Cxs peaks during late pregnancy and throughout lactation suggesting essential roles for these proteins in the functional secretory activity of the gland. Transgenic (Tg) mice over-expressing Cx26 driven by keratin 5 promoter had an unexpected mammary phenotype: the mothers were unable to feed their pups to weaning age leading to litter starvation and demise in early to mid-lactation. The mammary gland of K5-Cx26 female mice developed normally and produced normal levels of milk protein, suggesting a defect in delivery rather than milk production. Because the mammary gland of K5-Cx26 mothers contained excessive milk, we hypothesized that the defect may be in an inability to eject the milk. Using ex vivo three-dimensional mammary organoid cultures, we showed that tissues isolated from wild-type FVB females contracted upon treatment with oxytocin, whereas, organoids from Tg mice failed to do so. Unexpectedly, we found that ectopic expression of Cx26 in myoepithelial cells altered the expression of endogenous Cx43 resulting in impaired gap junction communication, demonstrated by defective dye coupling in mammary epithelial cells of Tg mice. Inhibition of gap junction communication or knock-down of Cx43 in organoids from wild-type mice impaired contraction in response to oxytocin, recapitulating the observations from the mammary glands of Tg mice. We conclude that Cx26 acts as a trans dominant negative for Cx43 function in myoepithelial cells, highlighting the importance of cell type-specific expression of Cxs for optimal contractile function of the mammary myoepithelium. PMID- 25500618 TI - Socioeconomic inequalities in dental caries and their determinants in adolescents in New Delhi, India. AB - OBJECTIVES: To determine whether socioeconomic inequalities are correlated to dental caries experience and decayed teeth of Indian adolescents, and assess whether behavioural and psychosocial factors mediate this association. METHODS: Cross-sectional study of 1386 adolescents living in three diverse areas of New Delhi. Caries experience and number of decayed teeth were assessed clinically and a questionnaire was used to gather sociodemographic and psychosocial data. Zero Inflated Negative Binomial regression models were used to assess the relationship between the outcomes (caries experience and decayed teeth) and area of residence, adjusting for covariates. RESULTS: Significant inequalities in caries experience and number of decayed teeth were observed. Odds of an adolescent being caries free decreased by 66% (OR 0.34, 95% CI 0.23 to 0.49) and 70% (OR 0.30, 95% CI 0.21 to 0.43) in adolescents living in resettlement communities or urban slums, respectively, when compared with the middle class group. No difference was observed among those with caries experience/decayed teeth. Adjusting for covariates did not affect the inequalities. CONCLUSIONS: Area of residence appears to be a very strong and significant determinant for an adolescent to be caries/decay free in India. Psychosocial and behavioural factors do not mediate the association between area of residence and oral health. PMID- 25500619 TI - Aryl hydrocarbon receptor 2 mediates the toxicity of Paclobutrazol on the digestive system of zebrafish embryos. AB - Paclobutrazol (PBZ), a trazole-containing fungicide and plant growth retardant, has been widely used for over 30 years to regulate plant growth and promote early fruit setting. Long-term usage of PBZ in agriculture and natural environments has resulted in residual PBZ in the soil and water. Chronic exposure to waterborne PBZ can cause various physiological effects in fish, including hepatic steatosis, antioxidant activity, and disruption of spermatogenesis. We have previously shown that PBZ also affects the rates of zebrafish embryonic survival and hatching, and causes developmental failure of the head skeleton and eyes; here, we further show that PBZ has embryonic toxic effects on digestive organs of zebrafish, and describe the underlying mechanisms. PBZ treatment of embryos resulted in dose dependent morphological and functional abnormalities of the digestive organs. Real-time RT-PCR and in situ hybridization were used to show that PBZ strongly induces cyp1a1 expression in the digestive system, and slightly induces ahr2 expression in zebrafish embryos. Knockdown of ahr2 with morpholino oligonucleotides prevents PBZ toxicity. Thus, the toxic effect of PBZ on digestive organs is mediated by AhR2, as was previously reported for retene and TCDD. These findings have implications for understanding the potential toxicity of PBZ during embryogenesis, and thus the potential impact of fungicides on public health and the environment. PMID- 25500621 TI - The influence of edge and corner evolution on plasmon properties and resonant edge effect in gold nanoplatelets. AB - In this paper a simulation of the properties of surface plasmons on gold nanoplatelets with various cross-sections inscribed in a circle and an investigation of their field distributions to assign multiple SPRs are described. The manipulated propagation can be obtained through the evolution of edges and corners. Furthermore, the particle morphology and the associated spectral positions alone do not uniquely reflect the important details of the local field distribution or the resonance modes. The plasmon modes were investigated and found to be mainly excited along the edges and in the side and sloped side surfaces. The strong field distributions can generally be found around the corners and how the plasmons transmit through the corners to adjacent edges was also investigated. Besides the plasmons excited along the edges as were found for the triangular nanoplatelets, plasmons were excited in the interior region of the triangular surfaces and were also investigated. Despite this in the infrared region, plasmon modes were found to be along the edges for the hexagonal nanoplatelets. Also, it can be seen that the change of nanoplatelet thickness can support different plasmon modes ranging from dipolar resonance mode to quadrupole resonance mode. The thickness far below the skin depth can display complex plasmon modes along the edges and on the side and sloping side surfaces as well as the strong coupling between the top and bottom surfaces. The observed plasmon resonance modes in this simulation reflect the interference of all these contributions including the plasmons along the edges and on the side surfaces. This is an essential step towards a thorough understanding of plasmon modes and the effect of edge and corner evolution in polygonous nanoplatelets. PMID- 25500620 TI - Trace metal concentrations in post-hatching cuttlefish Sepia officinalis and consequences of dissolved zinc exposure. AB - In this study, we investigated the changes of 13 trace metal and metalloid concentrations (i.e. Ag, As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Se, V, Zn) and their subcellular fractionation in juvenile cuttlefish Sepia officinalis reared in controlled conditions between hatching and 2 months post-hatching. In parallel, metallothionein concentrations were determined. Our results highlighted contrasting changes of studied metals. Indeed, As and Fe concentrations measured in hatchlings suggested a maternal transfer of these elements in cuttlefish. The non-essential elements Ag and Cd presented the highest accumulation during our study, correlated with the digestive gland maturation. During the 6 first weeks of study, soluble fractions of most of essential trace metals (i.e. Co, Cr, Cu, Fe, Se, Zn) slowly increased consistently with the progressive needs of cuttlefish metabolism during this period. In order to determine for the first time in a cephalopod how metal concentrations and their subcellular distributions are impacted when the animals are trace metal-exposed, we studied previously described parameters in juveniles exposed to dissolved Zn at environmental (i.e. 50 MUg l(-1)) and sublethal (i.e. 200 MUg l(-1)) levels. Moreover, oxidative stress (i.e. glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase activities, and lipid peroxidation (LPO)) was assessed in digestive gland and gills after 1 and 2 months exposures. Our results highlighted no or low ability of this stage of life to regulate dissolved Zn accumulation during the studied period, consistently with high sensitivity of this organism. Notably, Zn exposures caused a concentration-dependent Mn depletion in juvenile cuttlefish, and an increase of soluble fraction of Ag, Cd, Cu without accumulation modifications, suggesting substitution of these elements (i.e. Mn, Ag, Cd, Cu) by Zn. In parallel, metallothionein concentrations decreased in individuals most exposed to Zn. Finally, no perturbations in oxidative stress management were detected in gills, whereas modifications of GST, SOD and catalase activity levels were recorded in digestive gland, resulting in an increase of LPO content after a 6-week exposure to low Zn concentration. Altogether, these perturbations are consistent with previously described high sensitivity of juvenile cuttlefish towards Zn. Our results underlined the need to study deeply contamination impact on this animal at this stage of life. PMID- 25500622 TI - Nociceptin/orphanin FQ slows inspiratory rhythm via its direct effects on the pre Botzinger complex. AB - In a previous study, we showed that in an in vitro en bloc preparation of newborn rats perfused with standard [K(+)] (6.2mM) and high [K(+)] (11.2mM) artificial cerebrospinal fluid (aCSF), nociceptin/orphanin FQ (N/OFQ) suppresses bursting of pre-inspiratory neurons with 1:1 coupling to the fictive inspiration. However, it is unclear whether the pre-Botzinger complex (preBotC) is involved in the N/OFQ induced slowing. Using in vitro en bloc preparations with and without the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) perfused with high [K(+)] aCSF, we found the following: (1) there were no differences in the effects of N/OFQ on the inspiratory rhythm between the preparations with and without the RTN/pFRG, (2) N/OFQ decreased the input resistance of inspiratory neurons (Insps) in the preparations without the RTN/pFRG and suppressed their ectopic firing activities, and (3) N/OFQ suppressed the spontaneous firing of Insps under a chemical synaptic transmission blockade. In conclusion, it is possible that the preBotC is involved in N/OFQ-induced inspiratory rhythm slowing. PMID- 25500623 TI - Mn(OAc)3-mediated phosphonation-lactonization of alkenoic acids: synthesis of phosphono-gamma-butyrolactones. AB - A new, general method for the synthesis of phosphono-gamma-butyrolactones has been achieved through Mn(OAc)3-mediated radical oxidative phosphonation and lactonization of alkenoic acids with H-phosphonates and H-phosphine oxide. Mn(OAc)3 can be readily prepared from Mn(OAc)2 in the laboratory. This transformation allows the direct formation of a P-C bond and the construction of a lactone ring in one reaction. PMID- 25500624 TI - The inactivation of JAK2/STAT3 signaling and desensitization of M1 mAChR in minimal hepatic encephalopathy (MHE) and the protection of naringin against MHE. AB - BACKGROUND: We previously reported that elevation of intracranial dopamine (DA) levels from cirrhotic livers is implicated in the pathogenesis of minimal hepatic encephalopathy (MHE). Intracellular events in neurons, which lead to memory loss in MHE by elevated DA, however, remain elusive. METHODS: In our present study, an MHE rat model, a DA - intracerebroventricularly (i.c.v.) injected rat model and DA-treated primary cortical neurons (PCNs) were used to study this issue using behavioral tests, double-labeled fluorescent staining, immunoblotting, and semi quantitative RT-PCR. RESULTS: Cognitive impairment was observed in MHE rats and DA (10 ug, i.c.v.)-treated rats. The levels of DA in the cerebral cortex of both MHE and DA (10 ug)-treated rats were increased. DA conversely modulated the p JAK2/p-STAT3 levels in PCNs. In accordance, DA downregulated an anacetylcholine producing enzyme, choline acetyltransferase (ChAT), and desensitized the M1-type muscarinic acetylcholine receptor (M1 mAChR). Furthermore, naringin completely restored cognitive function in MHE/DA (10 ug)-treated models by activating the JAK2/STAT3 axis, paralleling the upregulation of ChAT and sensitization of M1 mAChR. CONCLUSIONS: We propose a hypothesis accounting for memory impairment related to MHE: DA-dependent inactivation of the JAK2/STAT3 axis causes memory loss through cholinergic dysfunction. Our findings provide not only a novel pathological hallmark in MHE but also a novel target in MHE therapy. PMID- 25500625 TI - Fecal microbiota transplantation for gastrointestinal diseases. AB - Fecal microbiota transplantation (FMT) is a treatment to restore the normal microbial composition of the gut by introducing fecal microbiota obtained from a healthy donor into a diseased individual. There has been a growing interest in the use of FMT as a treatment of various diseases including Clostridium difficile infection (CDI), inflammatory bowel disease, and irritable bowel syndrome. Despite the increasing application of FMT, there are no standard protocols. Many aspects of FMT procedures vary regarding donor selection, preparation of fecal materials, recipient preparation, and route of administration. FMT is most successful in treating recurrent CDI. A randomized controlled trial reported a success rate of approximaetly 90%. Ulcerative colitis (UC) is a potentially good indication for FMT, although limited evidence is available on the use of FMT for the treatment of UC. Only several small case series have been reported, and the results in terms of efficacy are inconsistent. FMT can also be used to treat diseases other than gastrointestinal disorders in which the gut microbiota is disturbed, e.g., cardiovascular diseases, autoimmune diseases, and metabolic disorders. There remain many unanswered questions with regard to FMT, and more research is required in this field. PMID- 25500627 TI - Memory lapse in people with higher education can signal stroke risk, study finds. PMID- 25500626 TI - Photo-induced sequence defined macromolecules via hetero bifunctional synthons. AB - We report the first photochemical protocol for the generation of sequence defined macromolecules employing two hetero bifunctional photoreactive synthons, exploiting the orthogonal nature of photochemical - via the use of caged dienes - and thermally driven ligation protocols. We demonstrate that the iterative alternating synthon addition to an initial bifunctional core under irradiation at ambient temperature enables the generation of a macromolecule with up to 10 units (M = 3231.58 g mol(-1), D = 1.00). The resulting macromolecules are monodisperse and feature absolute chain end fidelity. The unit-by-unit construction of the macromolecule is evidenced by Nuclear Magnetic Resonance Spectroscopy, Electrospray Ionization Mass Spectrometry and Size Exclusion Chromatography. The fundamental principle demonstrated herein paves the way for employing photochemical strategies for the design of sequence defined polymers. PMID- 25500628 TI - A high-performance catalyst support for methanol oxidation with graphene and vanadium carbonitride. AB - In this study, a graphene-vanadium carbonitride (G-V(C, N)) hybrid is reported as a novel support for the Pt catalyst in methanol oxidation. The catalytic activity of the Pt/G-V(C, N) hybrid for methanol oxidation is greatly enhanced compared with that of a commercial Pt/C catalyst with carbon black as the catalyst support. The outstanding catalytic activity of the Pt/G-V(C, N) catalyst suggests the potential of using graphene-metal carbonitride as the catalyst support in fuel cells. PMID- 25500629 TI - Retrospective analysis of a combined endoscopic and transcutaneous technique for the management of parotid salivary gland stones. AB - Sialendoscopy is used in the diagnosis and treatment of various symptoms relating to the salivary gland, e.g. chronic swelling or obstruction and inflammation of the salivary duct. Small intraductal stones can be removed with various instruments during sialendoscopy, whereas larger ones can be fragmented with extracorporeal shockwave lithotripsy or laser. However, 5-10% of the patients with parotid stones cannot be treated with these methods. In patients with large impacted stones or stones in a hilus area, a combined endoscopic and transcutaneous technique can be employed. The stone is approached endoscopically, a skin flap is raised over or a small incision is made through the illuminated area, and the stone is removed by an external route with minimal morbidity. This retrospective study analysed the cases of 8 patients treated using the combined technique, 6 of whom became symptom free. Superficial parotidectomy was performed in 1 patient. No complications were observed, and ductal stents were not used. The average diameter of the stones was 7.6 mm (range 7.0-10.2). The combined technique is recommended for the removal of large and impacted intraductal stones in the parotid gland. No major complications have been reported. PMID- 25500630 TI - Strategies for increasing the Neel temperature of magnetoelectric Fe2TeO6. AB - Ways to increase the Neel temperature TN in the magnetoelectric Fe2TeO6 antiferromagnet are explored with the help of first-principles calculations. Substitution of larger ions like Zr or Hf for tellurium increases the superexchange angles. The compensating O vacancies tend to form bound complexes with Zr dopants, which do not degrade the electronic band gap. TN is estimated to increase by 15% at 12.5% Te -> Zr substitution with such compensation. Substitution of N for O is favorable due to the decreased charge-transfer gap. The overall effect for N(3-) substitution compensated by O vacancies is estimated at 3-4% TN enhancement per 1% O -> N substitution. A 1% compressive (0 0 1) epitaxial strain enhances TN by about 6%. PMID- 25500632 TI - A monolith immobilised iridium Cp* catalyst for hydrogen transfer reactions under flow conditions. AB - An immobilised iridium hydrogen transfer catalyst has been developed for use in flow based processing by incorporation of a ligand into a porous polymeric monolithic flow reactor. The monolithic construct has been used for several redox reductions demonstrating excellent recyclability, good turnover numbers and high chemical stability giving negligible metal leaching over extended periods of use. PMID- 25500633 TI - Anion complexation, transport and structural studies of a series of bis methylurea compounds. AB - A new family of bis-methylureas () have been synthesised and their ability to bind anions both in solution and in the solid state and to transport them through lipid membrane have been studied. From the solid state studies it has emerged that various conformations can be adopted by the receptors allowing the isolation of complexes of different stoichiometries (from 1 : 1 to 1 : 3). The transport studies highlighted the possibility to use bis-methylureas to mediate Cl(-) transport across membranes. PMID- 25500631 TI - Additively manufactured porous tantalum implants. AB - The medical device industry's interest in open porous, metallic biomaterials has increased in response to additive manufacturing techniques enabling the production of complex shapes that cannot be produced with conventional techniques. Tantalum is an important metal for medical devices because of its good biocompatibility. In this study selective laser melting technology was used for the first time to manufacture highly porous pure tantalum implants with fully interconnected open pores. The architecture of the porous structure in combination with the material properties of tantalum result in mechanical properties close to those of human bone and allow for bone ingrowth. The bone regeneration performance of the porous tantalum was evaluated in vivo using an orthotopic load-bearing bone defect model in the rat femur. After 12 weeks, substantial bone ingrowth, good quality of the regenerated bone and a strong, functional implant-bone interface connection were observed. Compared to identical porous Ti-6Al-4V structures, laser-melted tantalum shows excellent osteoconductive properties, has a higher normalized fatigue strength and allows for more plastic deformation due to its high ductility. It is therefore concluded that this is a first step towards a new generation of open porous tantalum implants manufactured using selective laser melting. PMID- 25500634 TI - Changes in gene expression in PBMCs profiles of PPARalpha target genes in obese and non-obese individuals during fasting. AB - BACKGROUND: The prevalence of obesity has risen dramatically and the World Health Organization estimates that 700 million people will be obese worldwide by 2015. Approximately, 50% of the Brazilian population above 20 years of age is overweight, and 16% is obese. AIM: This study aimed to evaluate the differences in the expression of PPARalpha target genes in human peripheral blood mononuclear cells (PBMCs) and free fatty acids (FFA) in obese and non-obese individuals after 24 h of fasting. We first presented evidence that Brazilian people exhibit expression changes in PPARalpha target genes in PBMCs under fasting conditions. METHODS: Q-PCR was utilized to assess the mRNA expression levels of target genes. RESULTS: In both groups, the FFA concentrations increased significantly after 24 h of fasting. The basal FFA mean concentration was two-fold higher in the obese group compared with the non-obese group. After fasting, all genes evaluated in this study showed increased expression levels compared with basal expression in both groups. CONCLUSION: However, our results reveal no differences in gene expression between the obese and non-obese, more studies are necessary to precisely delineate the associated mechanisms, particularly those that include groups with different degrees of obesity and patients with diabetes mellitus type 2 because the expression of the main genes that are involved in beta-oxidation and glucose level maintenance are affected by these factors. PMID- 25500635 TI - A versatile efficient one-step approach for carbazole-pyridine hybrid molecules: highly efficient host materials for blue phosphorescent OLEDs. AB - By using various fluoro-substituted pyridines and carbazole as starting materials, we have synthesized a series of carbazole-pyridine hybrid compounds through an efficient catalyst free C-N coupling reaction with high yields of 85 95%. The bi-, tri- and tetra-carbazole substituted pyridine derivatives exhibit increased thermal stabilities and comparatively high triplet energy levels of ~3.0 eV. By using them as host materials for blue phosphorescent OLEDs, maximum current efficiencies are achieved ranging from 32-42 cd A(-1). PMID- 25500636 TI - Stable feature selection for clinical prediction: exploiting ICD tree structure using Tree-Lasso. AB - Modern healthcare is getting reshaped by growing Electronic Medical Records (EMR). Recently, these records have been shown of great value towards building clinical prediction models. In EMR data, patients' diseases and hospital interventions are captured through a set of diagnoses and procedures codes. These codes are usually represented in a tree form (e.g. ICD-10 tree) and the codes within a tree branch may be highly correlated. These codes can be used as features to build a prediction model and an appropriate feature selection can inform a clinician about important risk factors for a disease. Traditional feature selection methods (e.g. Information Gain, T-test, etc.) consider each variable independently and usually end up having a long feature list. Recently, Lasso and related l1-penalty based feature selection methods have become popular due to their joint feature selection property. However, Lasso is known to have problems of selecting one feature of many correlated features randomly. This hinders the clinicians to arrive at a stable feature set, which is crucial for clinical decision making process. In this paper, we solve this problem by using a recently proposed Tree-Lasso model. Since, the stability behavior of Tree-Lasso is not well understood, we study the stability behavior of Tree-Lasso and compare it with other feature selection methods. Using a synthetic and two real-world datasets (Cancer and Acute Myocardial Infarction), we show that Tree-Lasso based feature selection is significantly more stable than Lasso and comparable to other methods e.g. Information Gain, ReliefF and T-test. We further show that, using different types of classifiers such as logistic regression, naive Bayes, support vector machines, decision trees and Random Forest, the classification performance of Tree-Lasso is comparable to Lasso and better than other methods. Our result has implications in identifying stable risk factors for many healthcare problems and therefore can potentially assist clinical decision making for accurate medical prognosis. PMID- 25500637 TI - Choroid plexus tumors in children: a population-based study. AB - BACKGROUND: Choroid plexus tumors are rare neoplasms that primarily occur in children. The use of the SEER (Surveillance, Epidemiology and End Results) database allows for the analysis of the relationship between prognostic factors and survival. METHODS: We analyzed the SEER database to select pediatric patients (<18 years old) with histologically confirmed diagnoses of choroid plexus papillomas (CPP; WHO Grade 0), atypical CPP (WHO Grade I) and choroid plexus carcinomas (CPC; WHO grade III). In univariate and multivariate analysis, we analyzed the relationship between demographic (age, gender, race, date of diagnosis) and treatment factors (extent of surgical resection, use of adjuvant radiation) on survival. RESULTS: Overall, 168 pediatric subjects with choroid plexus tumors were identified as follows: 75 cases of CPP, 12 cases of atypical CPP and 81 cases of CPC. The median follow-up time was 3.5 years for CPP and 7.7 years for CPC. The median age at diagnosis was 4 years for CPP (10-90th percentile 0-16 years) and 1 year for CPC (10-90th percentile 0-10 years). In univariate regression analysis, CPC histology (beta = -3.2, 95% confidence interval, CI -4.8 to -1.5, p < 0.001) was significantly associated with younger age at diagnosis in comparison to CPP. The mean tumor size was 3.7 cm for CPP and 6.0 cm for CPC (p < 0.001). A higher-grade tumor was associated with significantly increased mortality (hazard ratio, HR = 28.90, 95% CI 3.94-211.83, p = 0.001). Overall survival at 5 years was 98.7% for CPP and 58.5% for CPC (p < 0.001). Among those patients with CPC, gross total resection (GTR) was associated with a significantly lower mortality (HR = 0.21, 95% CI 0.07-0.66, p = 0.007). Overall survival at 5 years was 70.9% after GTR, significantly better than 35.9% after subtotal resection (p = 0.012) and 30% after no surgery (p = 0.003). Radiation treatment was not found to confer a survival benefit in CPC. No demographic characteristics (age, sex, race, date of diagnosis) were significantly associated with mortality. CONCLUSIONS: Analysis of a pediatric cohort of choroid plexus tumors in children in the SEER database shows that tumor grade is predictive of survival. In cases of CPC, the extent of surgical resection, especially GTR, is significantly associated with increased survival. Radiation did not confer survival benefit. PMID- 25500638 TI - [New technique for intestinal lengthening -- from the idea to the clinical application]. AB - INTRODUCTION: In severe short bowel syndrome, as a result of the natural adaptation, the bowel becomes overdilated, this interferes with the persitalsis and may lead to stasis, bacterial translocation and sepsis. At present two techniques are used to improve peristalsis. The Bianchi procedure is technically challenging, the Serial Transverse Enteroplasty (STEP) is easy however it results in an aphysiological ultrastructure altering the orientation of the muscle fibres. Our aim was to develop an easy technique, which does not alter intestinal muscular ultrastructure dramatically. MATERIAL AND METHODS: The idea, Spiral Intestinal Lengthening and Tailoring (SILT), is based on a spiral shape incision of the intestine and retubularisation in a longer but narrower fashion. The feasibility and the effect on the muscular ultrastructure were tested on bowelsimulator and porcine intestine. The intramural microcirculation was checked with intravital microscopy. The outcome was assessed on minipigs (n = 6) than clinical application was commenced. RESULTS: SILT was feasible, did not change the orientation of muscle fibres significantly, did not compromised microcirculation, no surgical complication was noted when tailoring did not exceed 75%. The first clinical application was successful. CONCLUSION: SILT is a safe and easy technique and not altering the intestinal musculature significantly. PMID- 25500639 TI - [Is it radical enough? Transanal endoscopic microsurgery for the treatment of rectal neoplasia -- clinicopathological viewpoint]. AB - The transanal endoscopic microsurgery (TEM) provides lower relapse and complication rate for the the surgical treatment of the neoplasms of the middle and lower third of the rectum in selected cases. Hence, it can be an alternative method of the conventional approaches, if it does not compromise oncological radicality. The TEM procedure has been started at the 1st Department of Surgery, Semmelweis University in the fall of 2013. In this short study we have evaluated the clinicopathological characteristics of patients undergoing TEM between September 2013 and September 2014. Fourty-four patients were included in our retrospective analysis. 12 patients had low grade adenoma, 14 patients had high grade adenoma, 17 patients had invasive adenocarcinoma, while one was operated for a neuroendocrine tumor. There was no difference in the size of neoplasms between the low and high grade adenomas or adenocarcinomas (p = 0.210), tumors below the size of 30 mm or over 30 mm displayed no significant difference either (p = 0.424). The surgical margins were free of tumor in 41 cases (95.3%). In 13 out of 44 cases the preoperative histology proposed a lower grade neoplasm than the final report (p < 0.001). These results demonstrate that the surgical treatment of large adenomas with TEM technique, which involves excision of the whole bowel wall, is more appropriate than the fractionated removal or polypectomy supplemented by mucosectomy. The pT2 stage tumours might be subjected to the TEM method in selected cases (e.g. following neoadjuvant treatment or palliative care), but this has to be confirmed with prospecively evaluated large series clinical studies which are currently ongoing. PMID- 25500640 TI - [Mini-laparoscopic cholecystectomy as an innovative method in minimally invasive abdominal surgery]. AB - INTRODUCTION: In our study, we applied a mini-laparosopic approach during laparoscopic cholecystectomy (LC) (using the minimum size of trocars with the simultaneous intention to reduce their number). The advantages and disadvantages of the mini-LC approach were compared with those of traditional LC. PATIENTS AND METHODS: During mini-LC procedures, we used 3 ports (11 mm, 5 mm, 3.5 mm). Mini LC was performed in 10 patients, and the results were compared with those of 10 cases of traditional LCs. The two groups were homogenous in terms of gender, age, BMI and ASA classification. Comparison criteria included operative time, the need to use an extra port, conversion rate, oral analgesic requirement, early/late complications and cosmetic results. RESULTS: There were no significant differences in terms of operative time, blood loss, hospital stay and complications. Cumulative size of incisions was 19.5 mm with mini-LC- and 41 mm in the LC group, respectively, and the tissue injury was 124.2 mm(2) and 448.2 mm(2). Cosmetic results of mini-LC were highly improved by these values. Increased oral analgetic requirements were detected in LC group. CONCLUSION: Mini LC is a safe procedure with outstanding cosmetic results accompanied by less oral analgetic requirements. In selected patients, it can be recommended as an alternative method of traditional LC. PMID- 25500641 TI - [Objective surgery -- advanced robotic devices and simulators used for surgical skill assessment]. AB - Robotic assistance became a leading trend in minimally invasive surgery, which is based on the global success of laparoscopic surgery. Manual laparoscopy requires advanced skills and capabilities, which is acquired through tedious learning procedure, while da Vinci type surgical systems offer intuitive control and advanced ergonomics. Nevertheless, in either case, the key issue is to be able to assess objectively the surgeons' skills and capabilities. Robotic devices offer radically new way to collect data during surgical procedures, opening the space for new ways of skill parameterization. This may be revolutionary in MIS training, given the new and objective surgical curriculum and examination methods. The article reviews currently developed skill assessment techniques for robotic surgery and simulators, thoroughly inspecting their validation procedure and utility. In the coming years, these methods will become the mainstream of Western surgical education. PMID- 25500642 TI - ["Debranching" -- a new surgical option for the aortic arch and thoracoabdominal aorta hybrid interventions]. AB - INTRODUCTION: Endovascular techniques in vascular surgery are frequently applied to treat aortic diseases. These minimally invasive procedures changed aortic interventions remarkably. We have to be familiar with new terminology and methods. METHOD: New and old surgical procedures gained new role in preparation of endograft implantations. Transforming anatomy of aortic branches - "debranching" - is aimed to create a sufficient fixation of the endografts at safe "landing zones". CONCLUSIONS: Knowing the option of hybrid procedures is a fundamental requirement for the vascular surgeon. Equally important is to know the biomechanical characteristics of the available endografts, the possible complications during and after implantation and the treatment options. We have to be aware of the limitations of these new methods and the role of traditional open surgery in the new era. Our intention in this paper is to summarize methods of debranching. PMID- 25500643 TI - [Report of the 2013 data of the Hungarian Vascular Registry]. AB - INTRODUCTION: Nationwide medical databases started to record observations in the 90s. A Hungarian vascular registry was set up in 2002, which processes data of carotid, aneurysm and lower extremity arterial operations. The Hungarian Society for Angiology and Vascular Surgery decided to analyse the data each year. In this article we show the results of the registered carotid, aneurysmal and lower limb operations which were carried out in 2013. RESULTS: Altogether 3916 vascular surgical cases have been registered: 25.36% of cases were related to carotid arteries, 10.11% to aneurysms and 64.53% to lower limb operations. The surgical procedures were acute in 23.9% and they were performed electively in 76.10%. Stent graft implantation was performed in 31.47% of the abdominal aortic aneurysm cases and 68.53% was operated by open surgery. The average maximum diameter of aneurysms was 62.45 +/- 12.05 mm. The mortality in aortic aneurysm surgery was 7.57% and 2.06% related to lower extremity surgeries. Carotid surgery has a combined mortality and stroke rate of 2.62%. CONCLUSIONS: Registers have been proved to be useful in countries where they are used regularly for decision making. Our best common interest is to maintain a well-established national database. PMID- 25500646 TI - A journey to uncharted territory: new technical frontiers in studying tumor stromal cell interactions. AB - The crosstalk between tumor cells and cells of the tumor stroma dictate malignant progression and represent an intriguing and viable anticancer therapeutic target. The successful development of therapeutics targeting tumor-stroma interactions is tied to the insight provided by basic research on such crosstalk. Tumor-stroma interactions can be transient and dynamic, and they occur within defined spatiotemporal contexts among genetically and compositionally heterogeneous populations of cells, yet methods currently applied to study the said crosstalk do not sufficiently address these features. Emerging imaging and genetic methods, however, can overcome limitations of traditional approaches and provide unprecedented insight into tumor-stroma crosstalk with unparalleled accuracy. The comprehensive data obtained by applying emerging methods will require processing and analysis by multidisciplinary teams, but the efforts will ultimately rejuvenate hope in developing novel therapies against pro-tumorigenic tumor stroma crosstalk. PMID- 25500647 TI - Toxoplasmosis in immunocompromised patients in Iran: a systematic review and meta analysis. AB - Although toxoplasmosis in immunocompetent individuals is generally asymptomatic, in immunocompromised patients (HIV/AIDS, cancer, and transplant patients), it can lead to serious pathological effects. This study included a systematic review and meta-analysis to comprehensively assess the seroprevalence rate of Toxoplasma infection in immunocompromised patients in Iran. Electronic English and Persian databases (PubMed, Google Scholar, ScienceDirect, Scopus, Magiran, Scientific Information Database [SID], IranMedex, and IranDoc), parasitology congresses, and projects and theses of Iranian medical universities, were systematically searched from 1997 to 2013 (published or unpublished data). In this paper, several studies that used serological methods for diagnosis of toxoplasmosis were selected. Analysis of seroprevalence estimates was pooled using a random-effects meta analysis. Twenty-two studies, comprising 2,805 individuals, were included in the meta-analysis. Overall seroprevalence rate of Toxoplasma infection in Iranian immunocompromised patients was 50.01% (95% confidence interval, 43.85 to 56.17); however, there was significant heterogeneity among study groups. The results showed that seroprevalence rate of toxoplasmosis among transplant recipients, HIV/AIDS, and cancer patients in Iran was 55.1%, 50.05%, and 45.06%, respectively. In addition, IgM seroprevalence rate was estimated to be 4.85% (95% confidence interval, 2.22 to 8.41). This systematic review and meta-analysis identified a high seroprevalence rate of Toxoplasma infection among immunocompromised patients (50%). Consideration of management, design and provision of appropriate control measures of toxoplasmosis is highly recommended. PMID- 25500649 TI - Identification of class 1 and 2 integrons from clinical and environmental Salmonella isolates. AB - INTRODUCTION: The indiscriminate use of antimicrobials has selected for the emergence of resistant strains. Many mechanisms contribute to the spread of antimicrobial-resistant genes, and integrons play a key role in this process. The aim of this study was to describe the serotypes and resistance profiles, and to characterize the presence of integrons in Salmonella strains isolated from Dourados, Mato Grosso do Sul, Brazil. METHODOLOGY: Thirty-six isolates from different sources were used. To evaluate the resistance profiles, the determination of minimum inhibitory concentrations together with polymerase chain reaction were used to screen for the presence of class 1 and class 2 integrons. RESULTS: The Infantis serotype of Salmonella was the most frequently isolated serotype. Minimum inhibitory concentrations showed that out of the 36 isolates, 11 (30.5%) were resistant to all the antimicrobials tested. These resistant isolates were separated into three groups: 4 clinical isolates (36.4%), 3 food isolates (36.4%), and 4 water isolates (27.2%). Class 1 integrons occurred in 31 (86.1%) isolates and were found in all 11 resistant isolates (35.5 %) and in 20 (64.5%) of the non-resistant isolates. Class 2 integrons were found in 3 (8.3%) isolates, which were all non-resistant. CONCLUSION: The presence of an integron did not necessarily confer resistance. Future studies will seek to identify the mechanism behind integron-mediated antimicrobial resistance. PMID- 25500648 TI - Biofilm formation and antimicrobial resistance in methicillin-resistant Staphylococcus aureus isolated from burn patients, Iran. AB - INTRODUCTION: Burns are the most serious forms of trauma and a major cause of mortality worldwide. Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common pathogens of burn wound infections; treatment has faced serious problems due to antibiotic resistance in these strains. Biofilm formation, which increases antibiotic resistance capabilities and is considered to be a virulence factor, also causes treatment failure and recurrent staphylococcal infections in burn patients. METHODOLOGY: A total of 135 pus/wound swabs were collected; S. aureus was identified by confirmatory tests. The icaA/D and mecA genes were detected in DNA extracts by polymerase chain reaction assay separately. To determine the prevalence of biofilm formation, a modified Congo red agar and the microtiter plate method were used. Investigation of antibiotic resistance was performed using the disk diffusion method. RESULTS: S. aureus (48.87%) was identified in 65 (48.87%) samples, of which 40 (61.53%) were confirmed to be MRSA. Among MRSA and methicillin-sensitive S. aureus (MSSA) isolates, 97.5% and 60% produced biofilm, respectively. Resistance of MRSA isolates to amikacin, ceftriaxone, ciprofloxacin, erythromycin, gentamicin, mupirocin, rifampin, tetracycline, and tobramycin was 64.1%, 76.92%, 51.28%, 87.18%, 71.8%, 10.26%, 5.13%, 89.74%, and 61.54%, respectively. All MRSA and MSSA isolates were susceptible to fusidic acid, linezolid, teicoplanin, tigecycline, and vancomycin. CONCLUSIONS: The high prevalence of biofilm-producing, drug-resistant S. aureus isolates in our study suggests that epidemiological studies on the characteristics of common strains found in burn centers and a definition of their antibiotic resistance pattern would be helpful for therapeutic decisions. PMID- 25500650 TI - Molecular typing of Shigella sonnei isolates circulating in Nanjing, China, 2007 2011. AB - INTRODUCTION: Shigellosis is a major public health concern worldwide. This study intended to assess the baseline genotyping data among local Shigella sonnei strains spanning over five years. METHODOLOGY: Fifty non-repeat clinical strains of S. sonnei isolated from stools of patients in different hospitals in Nanjing, China, were studied. Three subtyping tools, pulsed-field gel electrophoresis (PFGE), multi-locus sequence typing (MLST), and multi-locus variable-number tandem-repeat (VNTR) analysis (MLVA), were used for routinely subtyping local S. sonnei. RESULTS: DNA sequencing only identified two sequence types (STs) among the 50 isolates in the MLST profiles, whereas PFGE and MLVA both showed suitable discriminatory power and yielded 19 and 30 different patterns, respectively. The major PFGE pattern comprised 21 strains isolated from different years. A total of four complexes were identified by MLVA, with the isolates differing by a single locus (single-locus variants). CONCLUSIONS: The S. sonnei strains circulating in Nanjing, China, in 2007-2011 originated from different clones with a degree of diversity. Most of the clones were closely related to each other. Overall, the strains were distinguishable by PFGE and MLVA. MLVA based on eight selected VNTR loci represented a more favorable degree of discrimination than did PFGE and may be a reliable complement for PFGE for routine subtyping of S. sonnei. The problems of MLST in subtyping regarding S. sonnei were also demonstrated. PMID- 25500651 TI - Phenotypic and genotypic analysis of bio-serotypes of Yersinia enterocolitica from various sources in Brazil. AB - INTRODUCTION: Yersinia enterocolitica is a well-known foodborne pathogen widely distributed in nature with high public health relevance, especially in Europe. METHODOLOGY: This study aimed to analyze the pathogenic potential of Y. enterocolitica isolated strains from human, animal, food, and environmental sources and from different regions of Brazil by detecting virulence genes inv, ail, ystA, and virF through polymerase chain reaction (PCR), phenotypic tests, and antimicrobial susceptibility analysis. Pulsed-field gel electrophoresis (PFGE) was used for the assessment of phylogenetic diversity. RESULTS: All virulence genes were detected in 11/60 (18%) strains of serotype O:3, biotype 4 isolated from human and animal sources. Ten human strains (4/O:3) presented three chromosomal virulence genes, and nine strains of biotype 1A presented the inv gene. Six (10%) strains were resistant to sulfamethoxazole-trimethoprim, seven (12%) to tetracycline, and one (2%) to amikacin, all of which are used to treat yersiniosis. AMP-CEF-SXT was the predominant resistance profile. PFGE analysis revealed 36 unique pulsotypes, grouped into nine clusters (A to I) with similarity >= 85%, generating a diversity discriminatory index of 0.957. Cluster A comprised all bio-serotype 4/O:3 strains isolated from animal and humans sources. CONCLUSIONS: This study shows the existence of strains with the same genotypic profiles, bearing all virulence genes, from human and animal sources, circulating among several Brazilian states. This supports the hypothesis that swine is likely to serve as a main element in Y. enterocolitica transmission to humans in Brazil, and it could become a potential threat to public health as in Europe. PMID- 25500652 TI - The impact of household hygiene on the risk of bacterial diarrhea among Egyptian children in rural areas, 2004-2007. AB - INTRODUCTION: The present study, conducted between January 2004 and April 2007, explored the impact of household hygiene on the risk of bacterial diarrhea, using data from a prospective birth cohort of 348 infants in five villages in the Nile Delta in Egypt. METHODOLOGY: Neonates were enrolled at birth and followed up until 24 months of age. Children were visited twice a week to survey them for acute diarrhea. A detailed observational household hygiene survey was completed in-house every six months. Adjusted relative risk (aRR) of developing bacterial diarrhea was calculated for exposure to different hygiene variables and examined for specific bacterial pathogens. RESULTS: Exclusive breastfeeding reduced the risk of bacterial diarrhea by 70%, while bacterial diarrhea cases were 2.6 times higher in the warm season. Risk of Campylobacter diarrhea increased with the absence of barriers to keep birds and animals out of the eating area, the presence of garbage containers and a bathing facility within the compound, and the presence of feces on the floor of the bathing facility. Use of municipal water for drinking and cooking was associated with a lower risk of Campylobacter diarrhea. Risk of enterotoxigenic Escherichia coli diarrhea increased with uncovered garbage containers and the presence of liquid materials in the garbage containers, but decreased with the use of tap water in the washing facility. CONCLUSION: The results highlight some potential targets for interventions, such as expanding municipal water supply to all houses and comprehensive mass-media awareness programs to change hygiene-promoting behaviors and practices. PMID- 25500653 TI - Cost-effectiveness analysis of pneumococcal conjugate vaccines in preventing pneumonia in Peruvian children. AB - INTRODUCTION: Pneumococcal pneumonia (PP) has a high burden of morbimortality in children. Use of pneumococcal conjugate vaccines (PCVs) is an effective preventive measure. After PCV 7-valent (PCV7) withdrawal, PCV 10-valent (PCV10) and PCV 13-valent (PCV13) are the alternatives in Peru. This study aimed to evaluate cost effectiveness of these vaccines in preventing PP in Peruvian children <5 years-old. METHODOLOGY: A cost-effectiveness analysis was developed in three phases: a systematic evidence search for calculating effectiveness; a cost analysis for vaccine strategies and outcome management; and an economic model based on decision tree analysis, including deterministic and probabilistic sensitivity analysis using acceptability curves, tornado diagram, and Monte Carlo simulation. A hypothetic 100 vaccinated children/vaccine cohort was built. An incremental cost-effectiveness ratio (ICER) was calculated. RESULTS: The isolation probability for all serotypes in each vaccine was estimated: 38% for PCV7, 41% PCV10, and 17% PCV13. Avoided hospitalization was found to be the best effectiveness model measure. Estimated costs for PCV7, PCV10, and PCV13 cohorts were USD13,761, 11,895, and 12,499, respectively. Costs per avoided hospitalization were USD718 for PCV7, USD333 for PCV10, and USD 162 for PCV13. At ICER, PCV7 was dominated by the other PCVs. Eliminating PCV7, PCV13 was more cost effective than PCV10 (confirmed in sensitivity analysis). CONCLUSIONS: PCV10 and PCV13 are more cost effective than PCV7 in prevention of pneumonia in children <5 years-old in Peru. PCV13 prevents more hospitalizations and is more cost effective than PCV10. These results should be considered when making decisions about the Peruvian National Inmunizations Schedule. PMID- 25500654 TI - Genetic diversity of the pandemic influenza A (H1N1) virus in Saudi Arabia. AB - INTRODUCTION: Pandemic influenza A (H1N1) virus emerged and spread globally in the spring of 2009. Saudi Arabia also witnessed a severe H1N1 pandemic virus epidemic with considerable morbidity and mortality in different parts of the kingdom beginning in June 2009. The influenza A(H1N1)pdm09 virus was detected in samples collected between May 2009 and November 2010 from Makkah region. This study provides data on the viral diagnosis and genetic diversity of hemagglutinin (HA) and neuraminidase (NA) genes of influenza A (H1N1)pdm09 virus from Saudi Arabia. METHODOLOGY: Nasopharyngeal swabs from 100 clinically infected patients in the peak of the outbreak were collected from Makkah region and processed for viral diagnosis by viral culture and real-time polymerase chain reaction (PCR). HA and NA genes of 10 selected samples were sequenced and analyzed. RESULTS: A total of 100 samples were collected; only 10 samples were found to be positive for influenza A virus infection by real-time PCR. Nucleotide sequence analysis of the HA and NA genes of influenza A (H1N1) from Saudi Arabia showed significant similarities with selected isolates. The phylogenetic tree constructed for both HA and NA genes formed close clusters with selected reference isolates. CONCLUSIONS: Nucleotide sequence analysis and phylogenetic relationships of the HA and NA genes of influenza A (H1N1) virus from Saudi Arabia with selected reference isolates indicates that they were genetically close and most probably originated from influenza A(H1N1)pdm09. PMID- 25500655 TI - Costs of treatment of children affected by severe malaria in reference hospitals of Kinshasa, Democratic Republic of Congo. AB - INTRODUCTION: Malaria remains a real problem of public health. Its hospital care generates important expenditures for affected households. The present study aimed to estimate direct and indirect costs of severe child malaria in reference hospitals in Kinshasa. METHODOLOGY: This prospective study included 1,350 children under 15 years of age suffering from severe malaria. The study was performed between 1 January and 30 November, 2011. Data were collected in nine reference hospitals. The studied parameters were direct pre-hospital costs, direct hospital costs, and indirect costs. Costs were assessed from the household point of view. RESULTS: Median costs associated with the disease ranged from 114 USD in confessional hospitals to 173 USD in state hospitals and 308 USD in private hospitals. Direct pre-hospital median costs ranged between 3 and 11 USD. Direct hospital costs reached 72 USD in confessional hospitals, 139 USD in state hospitals, and 254 USD in private hospitals. Indirect costs ranged from 22 USD in state hospitals to 30 USD in confessional hospitals and 46 USD in private hospitals, regardless of the status of the accompanying parent or guardian. Factors explaining the variability of costs were the neurological form of malaria, indirect recourse to hospital, socioeconomic level, type of prescribing person, child's status upon leaving the hospital, and child's transfusion status. CONCLUSIONS: The care of severe child malaria appeared to be expensive in private and state hospitals. A state subsidy of health care and regulation of the private sector would contribute to the reduction of malaria's financial impact. PMID- 25500656 TI - Cryptosporidiosis in patients with diarrhea and chronic liver diseases. AB - INTRODUCTION: The aim of this study was to evaluate the epidemiology and clinical significance of Cryptosporidium in patients with diarrhea and chronic liver diseases. METHODOLOGY: The study included 150 patients with chronic liver diseases and diarrhea, and 50 subjects with diarrhea as a control group. Stool samples were screened for the presence of Cryptosporidium by microscopic examination after modified Ziehl-Neelsen staining and detection of Cryptosporidium coproantigen by enzyme-linked immunosorbent assay (ELISA). RESULTS: The prevalence of Cryptosporidium infection in patients with chronic liver diseases was 30% (45/150) versus 14% (7/50) in controls. Cryptosporidium infection increased with the progression of chronic liver diseases from Child Pugh class A to Child-Pugh class C (p< 0.001) and from model for end-stage liver disease (MELD) score <= 9 to MELD score > 9 (p< 0.031). Nine patients in Child Pugh class C with diarrhea associated with Cryptosporidium infection developed hepatic encephalopathy, and only diarrhea was identified as a precipitating factor for hepatic encephalopathy. CONCLUSIONS: Cryptosporidium is one of the important causes of diarrhea in patients with chronic liver diseases. The infection significantly increased with the progression of chronic liver diseases. In patients with advanced chronic liver diseases, Cryptosporidium infection may be a precipitating factor of hepatic encephalopathy. PMID- 25500657 TI - Preponderance of bacterial isolates in urine of HIV-positive malaria-infected pregnant women with urinary tract infection. AB - INTRODUCTION: This study examined HIV and malaria co-infection as a risk factor for urinary tract infections (UTIs) in pregnancy. The study group included 74 pregnant women, 20 to 42 years of age, who attended the antenatal clinic at the Specialist Hospital at Akure, Ondo State, Nigeria. METHODOLOGY: Forty-four of the pregnant women were either HIV seropositive with malaria infection (HIV+Mal+) or HIV seropositive without malaria (HIV+Mal-). The remaining thirty pregnant women served as controls and included women HIV seronegative but with malaria (HIV Mal+) and women HIV seronegative without malaria. UTI was indicated by a bacterial colony count of greater than 105/mL of urine, using cysteine lactose electrolyte deficient medium (CLED) as the primary isolation medium. Bacterial isolates were characterized using convectional bacteriological methods, and antibiotics sensitivity tests were carried out using the disk diffusion method. RESULTS: A total of 246 bacterial isolates were recovered from the cultures, with a mean of 3.53 isolates per subject. Women who were HIV+Mal+ had the most diverse group of bacterial isolates and the highest frequency of UTIs. The bacterial isolates from the HIV+Mal+ women also showed the highest degree of antibiotic resistance. CONCLUSIONS: While pregnancy and HIV infection may each represent a risk factor for UTI, HIV and malaria co-infection may increase its frequency in pregnancy. The higher frequency of multiple antibiotic resistance observed among the isolates, particularly isolates from HIV+Mal+ subjects, poses a serious public health concern as these strains may aggravate the prognosis of both UTI and HIV infection. PMID- 25500658 TI - Predictors of response to pegylated interferon treatment in HBeAg-negative patients with chronic hepatitis B. AB - INTRODUCTION: Although pegylated interferons (pegIFNs) alpha-2a and alpha-2b have been used in chronic hepatitis B (CHB) treatment for many years, there are few studies concerning predictors of sustained virologic response (SVR) to pegIFN therapy. In this study, we aimed to investigate the predictors of response to pegIFN treatment in cases with HBeAg-negative CHB infection. METHODOLOGY: Seventeen tertiary care hospitals in Turkey were included in this study. Data from consecutively treated HBeAg-negative CHB patients, who received either pegIFN alpha-2a or alpha-2b, were collected retrospectively. SVR is defined as an HBV DNA concentration of less than 2,000 IU/mL six months after the completion of therapy RESULTS: SVR was achieved in 40 (25%) of the 160 HBeAg-negative CHB patients. Viral loads in patients with SVR were lower compared to those with no SVR, beginning in the third month of treatment (p < 0.05). The number of cases with a decline of 1 log10 IU/mL in viral load after the first month of treatment and with a serum HBV DNA level under 2,000 IU/mL after the third month of treatment was higher in cases with SVR (p < 0.05). The number of patients who had undetectable HBV DNA levels at week 48 among responders was significantly greater than among post-treatment virological relapsers (p < 0.05). CONCLUSIONS: Detection of a 1 log10 decline in serum HBV DNA level at the first month of treatment and a serum HBV DNA level < 2000 IU/mL at the third month of therapy may be predictors of SVR. PMID- 25500659 TI - Impact of Aeromonas and diarrheagenic Escherichia coli screening in patients with diarrhea in Parana, southern Brazil. AB - INTRODUCTION: A wide diversity of bacterial agents may cause diarrhea, presenting challenges to clinical laboratories to define a diagnosis. Considering that most stool cultures are negative, we screened stool samples from patients with diarrhea for the presence of 14 bacterial enteropathogens, aiming to establish which of them should be included in routine stool analysis. METHODOLOGY: Stool samples from 400 patients with diarrhea were analyzed for the presence of Salmonella, Shigella, Campylobacter, Aeromonas, Plesiomonas shigelloides, Vibrio, Yersinia enterocolitica, and diarrheagenic Escherichia coli using conventional microbiological methods and PCR. Two distinct samples were studied; one included predominantly patients involved in outbreaks, and the other patients of low socioeconomic status presenting sporadic cases of diarrhea. RESULTS: In total, 86 cultures (21.5%) were positive. Mixed infections were found in five patients, leading to recovery of 91 strains of enteropathogenic bacteria: Salmonella Enteritidis (9.2%), Aeromonas (7.2%), diarrheagenic E. coli (5.2%), and C. jejuni (1%). However, Salmonella predominated, with 11.5% frequency in diarrhea outbreaks, while Aeromonas predominated among patients of low socioeconomic status, with 14.6% frequency. CONCLUSION: Aeromonas and diarrheagenic E. coli, which are not routinely screened for, deserve to be included in laboratory screening panels. PMID- 25500660 TI - Similarities between Salmonella Enteritidis isolated from humans and captive wild animals in South Africa. AB - INTRODUCTION: Salmonella is well recognized as an aetiological agent of gastrointestinal and diarrhoeal disease. Salmonella enterica serotype Enteritidis (Salmonella Enteritidis) is one of the commonest serotypes associated with foodborne illness. In South Africa, we compared Salmonella Enteritidis strains isolated from humans with gastroenteritis and strains isolated from captive wild animals, between June 2011 and July 2012. METHODOLOGY: Bacteria were phenotypically characterized using standard microbiological techniques. Genotypic relatedness of isolates was investigated by pulsed-field gel electrophoresis (PFGE) analysis. RESULTS: a diversity of 27 PFGE patterns amongst 196 human non invasive isolates was shown; two PFGE patterns predominated and accounted for 74% of all human isolates. Human isolates showed a 12% prevalence rate for nalidixic acid resistance. Animal isolates from 5 different sources were investigated. With the exception of an isolate from a ground hornbill, all animal isolates (jaguar, crocodile, lion and poultry) showed PFGE pattern matches to a human isolate. Animal isolates showed susceptibility to all antimicrobial agents tested, with the exception of nalidixic acid resistance in isolates from the lion and poultry source. CONCLUSIONS: Our data showed similarities between Salmonella Enteritidis strains isolated from humans and captive wild animals, suggesting a probable common source for strains from humans and animals. PMID- 25500661 TI - One year experience using mycobacterial blood cultures to diagnose tuberculosis in patients with prolonged fever in Vietnam. AB - INTRODUCTION: To evaluate the use of mycobacterial blood cultures (MBC) in diagnosing tuberculosis (TB) in patients with prolonged fever admitted to a Vietnamese referral hospital. RESULTS: MBCs from 94 patients (66% male; median age 33 years; 75% HIV positive) were evaluated: 14 were mycobacterium positive (all HIV positive), and MBC was the only positive specimen in 9 cases (41%). Three positive cases were identified as Mycobacterium avium and the remaining M. tuberculosis (one case could not be identified). CONCLUSION: MBC can be a valuable additional method to diagnose TB, particularly in immunosuppressed HIV patients when sputum cannot be collected. PMID- 25500662 TI - Detection of plasmid-mediated quinolone resistance determinants and qnrS expression in Enterobacteriaceae clinical isolates. AB - INTRODUCTION: Rapid dissemination of plasmid-mediated quinolone resistance (PMQR) has been reported in clinical isolates. METHODOLOGY: A total of 149 clinical isolates of Enterobacteriaceae were collected in Beijing and screened for PMQR genes using polymerase chain reaction (PCR). Real-time quantitative PCR was used to study the expression of qnrS. RESULTS: The rates of qnr and aac(6')-Ib-cr genes were 7.4% and 8.1%, respectively. The higher basal expression of qnrS was observed in transconjugant strains, which had higher minimum inhibitory concentrations (MICs) of quinolones. Furthermore, qnrS expression levels increased in all three isolates when a quinolone was present. CONCLUSIONS: Our data suggest that the level of qnrS expression was associated with quinolone resistance. PMID- 25500663 TI - Occult hepatitis B infection among individuals belonging to the aboriginal Nicobarese tribe of India. AB - INTRODUCTION: The long-lasting persistence of hepatitis B virus (HBV) genomes in the liver (with or without detectable HBV DNA) of individuals with negative for HBV surface antigen (HBsAg) is termed occult HBV infection (OBI). The present study is a part of the follow up on efficacy of vaccination, 10 years post inception, and was designed to understand the prevalence of Occult Hepatitis B infection (OBI) among the aboriginal Nicobarese tribal community. METHODOLOGY: A total of 612 serum samples were collected and tested for various markers including HBsAg, Anti-HBs, Anti-HBc and HBV DNA. Part of S gene of the extracted HBV DNA was amplified by nested PCR. The amplified products were then subjected to sequencing. Genotyping was performed on the basis of phylogenetic relationship along with representative reference sequences from different sub genotypes. RESULTS: The study revealed OBI in 11.1% of the people belonging to the Nicobarese tribe. Phylogenetic analysis showed only one genotype, HBV/D circulating among the Nicobarese population with ayw3 was the major serotype detected. Single or multiple amino acids substitutions were found in 5 of 34 samples (14.7%) which includes I110T, P120T, P/T127I, A128P, M133L and G159V. CONCLUSIONS: The detection of OBI among these aboriginal tribes is of great concern and stresses the need for the continuous surveillance as it may contribute to the progression of liver disease to a more advanced stage. PMID- 25500664 TI - A case of childhood Brucellosis with neurological involvement and epididymo orchitis. AB - Brucellosis is a common zoonotic infection worldwide caused by Brucella species. Central nervous system involvement is a serious complication of brucellosis, and the clinical presentation is quite heterogeneous. The genitourinary system may be affected. Epididymo-orchitis is the most common type of urinary tract involvement, which can cause serious complications. Herein, we present a case of brucellosis in a child with a rare combination of epididymo-orchitis and neurobrucellosis not encountered previously in the literature. PMID- 25500665 TI - First report of chronic hepatitis E in renal transplant recipients in Portugal. AB - Hepatitis E virus (HEV) infection can be responsible for chronic hepatitis in immunocompromised patients, and can rapidly evolve into fibrosis and/or hepatic cirrhosis. We present two cases of chronic hepatitis E, emphasizing the need to be aware of this entity as a growing etiology of hepatitis in transplant and immunocompromised patients. PMID- 25500666 TI - Antibiotic susceptibility pattern and biofilm formation in coagulase negative staphylococci. PMID- 25500667 TI - Presence of neutralizing antibodies to Orthopoxvirus in capybaras (Hydrochoerus hydrochaeris) in Brazil. AB - Cantagalo virus is a strain of vaccinia virus (genus Orthopoxvirus) and the etiological agent of an important vesicopustular disease that affects dairy cows and milkers in Brazil. The reservoirs involved in the maintenance of this virus in nature are unknown. In the present work, the detection of neutralizing antibodies to Orthopoxvirus in capybaras collected in Sao Paulo state is reported. Capybaras are the largest rodent species native to South America and have already been reported as putative reservoirs of other pathogenic microorganisms. Thirteen out of thirty-three serum samples were found positive in plaque-reduction neutralization tests, some of them showing high titers compared to positive controls. These results suggest that capybaras may play a role in the infection cycle of vaccinia virus in Brazil. PMID- 25500668 TI - Gold finger formation studied by high-resolution mass spectrometry and in silico methods. AB - High-resolution mass spectrometry and quantum mechanics/molecular mechanics studies were employed for characterizing the formation of two gold finger (GF) domains from the reaction of zinc fingers (ZF) with gold complexes. The influence of both the gold oxidation state and the ZF coordination sphere in GF formation provided useful insights into the possible design of new gold complexes targeting specific ZF motifs. PMID- 25500669 TI - Segmental approach to lung volume reduction therapy for emphysema patients. AB - Emphysema is often distributed heterogeneously throughout the lungs, even at the segmental level. It is important for interventional lung volume reduction therapies to target and treat the most diseased regions of the lung while preserving the less diseased functional regions. Identification and determination of the severity of emphysema can be done using the various quantification measures reviewed in this article. However, all of these measures are similar in what they quantify and are equally good indicators of emphysema. The tissue/air ratio was chosen for our purposes. Software capable of quantifying emphysema severity at the segmental level exists, and can be utilized to identify the most diseased segments while following anatomical boundaries. The segmental heterogeneity index is a new measure being introduced to help quantify differences in emphysema severity at the segmental level. The goal of segmental targeting is to improve efficacy and safety outcomes of vapor ablation patients. The Sequential Staged Treatment of Emphysema with Upper Lobe Predominance (STEP UP, NCT01719263) trial is currently enrolling patients with upper lobe heterogeneous emphysema using these techniques. PMID- 25500670 TI - Use of expanded criteria in living kidney donors - the crucial factor for improvement of the kidney transplant programme in Republic of Macedonia. AB - Renal transplantation is surely the best treatment for Chronic Kidney Disease (CKD) patients in both developed and developing countries. Due to the tragic events in former Yugoslavia at the beginning of the nineties, it was not possible to develop a really good clinical practice in the field of transplantation. Facing the lack of Deceased Donor Donation Transplantation and any organ-sharing among the Balkan countries, we introduced a large and very ambitious living donor transplant programme including what were called expanded criteria living donors. In the period of the past 20 years elderly (above 65 years), unrelated (emotionally related), marginal and ABO incompatible living donors were accepted. Due to the skilled surgical team, powerful immunosupression and HLA compatibility testing, the results were promising and the number of complications very low. The authors concluded that use of an expanded criteria living donor is fully acceptable, especially in developing countries, and could ameliorate the severe organ shortage in the region. PMID- 25500671 TI - Protocol for performing nephrological activity in the Republic of Macedonia. AB - The fast development of nephrology in the world, especially in the second half of the 20 th century demanded protocol (guidelines) for nephrological activity for all levels of medical care, of doctors and specialists. The International Society of Nephrology, the European Renal Association and other national associations created their own protocol (guidelines) for nephrological activity. The Macedonian Society of Nephrology, Dialysis, Transplantation and Artificial Organs (MSNDTAO) proclaimed the First Protocol for Performing Nephrological Activity in the Republic of Macedonia at the First Congress of the MSNDTAO, held in Ohrid 1993, and it was published in the Macedonian Medical Review, 1994; Supplement 14: 397-406 [1]. The update of the Protocol for Performing Nephrological Activity in the Republic of Macedonia was proclaimed at the Fourth Congress of MSNDTAO, held in Ohrid 2012 and it presented in this text. PMID- 25500672 TI - Methods for molecular surveillance of influenza used in Macedonia. AB - THE AIM: To present and compare different Nucleic Acid Testing assays used for laboratory diagnosis of influenza virus infection in our country. MATERIALS AND METHODS: Respiratory samples used were nose and throat swabs. The RNA extraction was performed with a QIAamp viral RNA kit. During the season 2009-2010 the first 25 samples were tested with: conventional gel-based RT-PCR and CDC rtRT-PCR using published specific matrix and HA gene primers and probes for influenza virus typing and subtyping. RESULTS: Of 25 samples tested with conventional RT-PCR 7(28%) were positive for influenza A, but negative for A/H1seasonal and A/H3. Retested with rtRT-PCR 9(36%) were positive for influenza A, 8(32%) were positive for A/H1pdm and 1(4%) was A/H3. Two samples positive with rtRT-PCR for influenza A were negative with RT-PCR. The sensitivity of the RT-PCR in comparison with rtRT-PCR is 100% and the specificity is 88.89%. Positive predictive value for RT PCR is 77.78%, and negative predictive value is 100%. RT-PCR is a four-step and rtRT-PCR a one-step procedure. The turn-around time of RT-PCR is 6 hours and for rtRT-PCR it is 2 hours. DISCUSSION AND CONCLUSION: For surveillance purposes nose and throat swabs are the more easy and practical to collect. It was proved that RT-PCR is too laborious, multi-step and time-consuming. The sensitivity of both assays is equal. The specificity of rtRT-PCR is higher. NAT assays for detection of influenza viruses have become an integral component of the surveillance programme in our country. They provide a fast, accurate and sensitive detection of influenza. PMID- 25500673 TI - Genotypes of ESBL producing Escherichia coli and Klebsiella pneumoniae in relation to resistance to antimicrobial drugs. AB - The aim of the study was to evaluate the association of drug resistance with beta lactamase gene types in ESBL positive E. coli and Klebsiella pneumoniae-Kp. MATERIAL AND METHODS: A total of 251 ESBL-positive E. coli and Kp isolates obtained from urine, tracheal aspirate, wound swab and blood from patients hospitalised at the University Clinics in Skopje were detected using the ESBL set and automated Vitek 2 system. Vitek was also used for susceptibility testing (determination of MIC of 17 antimicrobial agents). Multiplex PCR was used to identify genes for different types of ESBLs in a 100 randomly selected, ESBL positive strains. RESULTS: More of the 87 ESBL typeable isolates (61%) harbour two or more bla genes and the frequency of antibiotic resistance was high in these isolates, compared to those with a single gene. Isolates with >= 3 genes were highly resistant to beta-lactams and non-beta lactams used. The degree of resistance to 3 rd generation cephalosporins was also high in these isolates (MIC >= 64). More of the ESBL-positive isolates showed higher resistance to cefotaxime than to ceftazidime. CONCLUSION: Identification of the genes is necessary for the surveillance of their transmission in hospitals. Surveillance of antibiotic resistance patterns are crucial to overcome the problems associated with ESBLs. PMID- 25500674 TI - Correlative study between serum matrix metalloproteinase-9 values and neurologic deficit in acute, primary, supratentorial, intracerebral haemorrhage. AB - One of the essential characteristics of intracerebral haemorrhages (ICH) is the occurrence of brain oedema (BE). Matrix metalloproteinase-9 (MMP-9) belongs to the family of proteolytic enzymes connected with zinc, which in brain bleeding or a stroke can induce matrix proteolyse into the neurovascular unit, and increase the BE. The aim of the study was to determine the MMP-9 values in serum, and to assess the degree of correlation with neurological deficit in patients with acute, primary and supratentorial ICH. MATERIALS: The study was prospective and included 62 patients with ICH. The neurological deficit of the patients was evaluated by the National Institute Health Stroke Scale (NIHSS). Serum MMP-9 level was determined by enzyme-linked immune sorbent assay (ELISA). Patients were evaluated in three phases: 1(st), 3(rd) and 7(th) day following the ICH. RESULTS: The mean age of the patients was 64.5 +/- 9.4. Within the follow-up period, there was a significant rise of the NIHSS score in the first three days: 11.48 +/- 3.7; 13.21 +/- 3.78, and a significant rise of serum MMP-9, with greatest values in the third day: 134.7 +/- 26.1 ng/ml (p = 0.000). There was a positive, significant correlation (r = 0.886, p = 0.000) between the serum MMP-9 concentration and the NIHSS score. CONCLUSION: Our study showed that in the first three days of ICH, serum MMP-9 values were rising as well as the neurological deficit and the BE. Determination and evaluation of the MMP-9 in serum is an easy, non-invasive, routine laboratory procedure for the detection and follow-up of BE, and also determines further therapeutic strategy as well as prognosis in these patients. PMID- 25500675 TI - Allostery without a conformational change? Revisiting the paradigm. AB - Classically, allostery induces a functional switch through a conformational change. However, lately an increasing number of studies concluded that the allostery they observe takes place through sheer dynamics. Here we explain that even if a structural comparison between the active and inactive states does not detect a conformational change, it does not mean that there is no conformational change. We list likely reasons for this lack of observation, including crystallization conditions and crystal effects; one of the states is disordered; the structural comparisons disregard the quaternary protein structure; overlooking synergy effects among allosteric effectors and graded incremental switches and too short molecular dynamics simulations. Specific functions are performed by distinct conformations; they emerge through specific interactions between conformationally selected states. PMID- 25500677 TI - Endotracheal tubes for critically ill patients: an in vivo analysis of associated tracheal injury, mucociliary clearance, and sealing efficacy. AB - BACKGROUND: Improvements in the design of the endotracheal tube (ETT) have been achieved in recent years. We evaluated tracheal injury associated with ETTs with novel high-volume low-pressure (HVLP) cuffs and subglottic secretions aspiration (SSA) and the effects on mucociliary clearance (MCC). METHODS: Twenty-nine pigs were intubated with ETTs comprising cylindrical or tapered cuffs and made of polyvinylchloride (PVC) or polyurethane. In specific ETTs, SSA was performed every 2 h. Following 76 h of mechanical ventilation, pigs were weaned and extubated. Images of the tracheal wall were recorded before intubation, at extubation, and 24 and 96 h thereafter through a fluorescence bronchoscope. We calculated the red-to-green intensity ratio (R/G), an index of tracheal injury, and the green-plus-blue (G+B) intensity, an index of normalcy, of the most injured tracheal regions. MCC was assessed through fluoroscopic tracking of radiopaque markers. After 96 h from extubation, pigs were killed, and a pathologist scored injury. RESULTS: Cylindrical cuffs presented a smaller increase in R/G vs tapered cuffs (P = .011). Additionally, cuffs made of polyurethane produced a minor increase in R/G (P = .012) and less G+B intensity decline (P = .022) vs PVC cuffs. Particularly, a cuff made of polyurethane and with a smaller outer diameter outperformed all cuffs. SSA-related histologic injury ranged from cilia loss to subepithelial inflammation. MCC was 0.9 +/- 1.8 and 0.4 +/- 0.9 mm/min for polyurethane and PVC cuffs, respectively (P < .001). CONCLUSIONS: HVLP cuffs and SSA produce tracheal injury, and the recovery is incomplete up to 96 h following extubation. Small, cylindrical-shaped cuffs made of polyurethane cause less injury. MCC decline is reduced with polyurethane cuffs. PMID- 25500678 TI - Extension of the concept of an anomalous water component to images of T-cell organelles. AB - Microscopic images of a living cell are the main source of information on its functional state. Modern interference microscopy techniques allow the numerical parameters of cell images to be obtained with an accuracy not available with other methods. Quantitative analysis of phase images of T lymphocytes (TCs) in different functional states demonstrated that variations of the properties of intracellular water should be taken into account. This conclusion agrees with the current view that the physical parameters of water, including the refractive index (RI) of a water layer, depend on the hydrophilicity and other characteristics of the adjacent surface. Application of this concept to phase images of TCs showed that the contribution of the fourth phase of water (4-water) or the structured water component, which has an increased RI, should be considered. The proportion of 4-water depends on the functional state of the cell determined by the culture medium composition. Normally, the proportion of 4-water in organelles is as high as 30%; it is considerably lower in organelles of cells with inhibited metabolism. PMID- 25500679 TI - Type of anaesthesia and patient quality of recovery: a randomized trial comparing propofol-remifentanil total i.v. anaesthesia with desflurane anaesthesia. AB - BACKGROUND: Two common general anaesthetic methods are total i.v. anaesthesia (TIVA) and inhalation anaesthesia, but it is unclear whether this affects the patient's perception of their quality of recovery. The Quality of Recovery-40 questionnaire (QoR-40) is a valid and reliable method to evaluate the extent of functional recovery after surgery with general anaesthesia. This study therefore compared patient recovery using the QoR-40 in surgical patients who received TIVA with those who received desflurane anaesthesia. METHODS: Eighty females (20-65 years old) undergoing thyroid surgery were prospectively recruited and randomized to either the TIVA (effect-site target controlled infusion using propofol and remifentanil) or DES (desflurane inhalation with manual infusion of remifentanil) groups. The QoR-40 was administered by an investigator blind to group allocation before surgery, and postoperative days 1 and 2 (POD1 and POD2). Additional data including the incidence of nausea or vomiting, the consumption of antiemetic and analgesic agents in the post-anaesthesia care unit, and the duration of the hospital stay, were collected in all cases. RESULTS: The QoR-40 score on POD1 was significantly higher in the TIVA group compared with the DES group (174 vs 161, respectively; P=0.004), indicating a better quality of recovery in the TIVA group. Among the five dimensions of the QoR-40, physical comfort and physical independence were significantly better on POD1 and POD2 in the TIVA group. CONCLUSION: This study demonstrates that the quality of recovery for female thyroid surgery patients is significantly better with TIVA compared with desflurane anaesthesia. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.org; ref.: NCT01760018. PMID- 25500680 TI - Feasibility of closed-loop co-administration of propofol and remifentanil guided by the bispectral index in obese patients: a prospective cohort comparison. AB - BACKGROUND: We used an automated bispectral index (BIS)-guided dual-loop controller to determine propofol and remifentanil requirements during general anaesthesia in obese and lean surgical patients. METHODS: Obese patients, BMI>35 kg m(-2), and lean patients (<25 kg m(-2)) having laparoscopic procedures were prospectively evaluated in this multicentre single-blind study. The automated controller targeted BIS between 40 and 60 by adjusting propofol and remifentanil administration. Propofol and remifentanil consumptions were calculated using both total body weight (TBW) and ideal body weight (IBW). Results are expressed as medians (inter-quartile range). RESULTS: Thirty obese [BMI=43 (40-49) kg m(-2)] and 29 lean [BMI=23 (21-25) kg m(-2)] patients completed the study. BIS was between 40 and 60 during 84 (69-91)% vs 85 (78-92)% of the anaesthetic time, P=0.46. The amount of propofol given during induction [1.2 (1.1-1.6) vs 1.3 (1.0 1.7) mg kg(-1), P=0.47] and maintenance [5.2 (4.1-6) vs 5.3 (4.7-6.4) mg kg(-1) h(-1), P=0.39] calculated using TBW was similar between the two groups. The dual loop controller delivered half as much remifentanil to the obese patients during induction [1.0 (0.8-1.6) vs 2.2 (1.5-2.7) ug kg(-1), P<0.001] and maintenance [0.12 (0.07-0.16) vs 0.25 (0.17-0.29) ug kg(-1) min(-1), P<0.001] calculated using TBW. But when remifentanil consumption was calculated using IBW, the amounts were similar during induction at 2.2 (1.6-3.5) vs 2.0 (1.6-3.0) ug kg(-1) IBW, P=0.48, and during maintenance at 0.26 (0.16-0.34) vs 0.27 (0.18-0.33 ) ug kg(-1) min(-1), P=0.50. CONCLUSIONS: The amount of propofol-remifentanil administered by the controller is consistent with current knowledge, propofol is best dosed using TBW whereas remifentanil is best dosed using IBW. CLINICAL TRIAL REGISTRATION: NCT00779844. PMID- 25500681 TI - Diallyl trisulfide exerts anti-inflammatory effects in lipopolysaccharide stimulated RAW 264.7 macrophages by suppressing the Toll-like receptor 4/nuclear factor-kappaB pathway. AB - Diallyl trisulfide (DATS; di-2-propen-1-yl trisulfide) is an organic polysulfide compound found in garlic and other allium vegetables. Although certain studies have demonstrated that DATS possesses strong anti-inflammatory activity, the underlying molecular mechanisms remain largely unresolved. In the present study, the anti-inflammatory potential of DATS was investigated using the murine macrophage RAW 264.7 cell model. At non-toxic concentrations, DATS inhibited the production of nitric oxide (NO) and prostaglandin E2 by inhibiting inducible NO synthase and cyclooxygenase-2 expression at the transcriptional level in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. DATS attenuated the release of the pro-inflammatory cytokines, tumor necrosis factor-alpha and interleukin-1beta, by inhibiting mRNA expression, respectively. DATS also suppressed LPS-induced DNA-binding activity of nuclear factor-kappaB (NF-kappaB), as well as the nuclear translocation of the NF-kappaB p65, which correlated with the inhibitory effects of DATS on inhibitor kappaB (IkappaB) degradation. In addition, DATS was observed to significantly suppress LPS-induced Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 expression and the binding of LPS to macrophages, indicating the antagonistic effect of DATS against TLR4. Furthermore, blocking TLR4 signaling with the specific TLR4 signaling inhibitor, CLI-095, increased the anti-inflammatory potential of DATS in LPS stimulated RAW 264.7 macrophages. These data demonstrate that DATS may attenuate the initiation of LPS-mediated intracellular signaling cascades by suppressing activation of NF-kappaB and by inhibiting binding of LPS to TLR4 on macrophages. PMID- 25500682 TI - A toddler in distress. PMID- 25500684 TI - Efficacy and safety of valproic acid versus haloperidol in patients with acute agitation: results of a randomized, double-blind, parallel-group trial. AB - The objective of this study was to compare the efficacy of valproate versus haloperidol in decreasing the agitation level in affected patients in the emergency department. We assigned 80 acutely agitated patients to receive either intravenous sodium valproate (20 mg/kg) or intramuscular haloperidol (5 mg/1 ml). Agitation was measured at baseline and 30 min after the first injection using the Agitation-Calmness Evaluation Scale (ACES), the Positive and Negative Syndrome Scale-Excited Component subscale, and the Agitated Behavior Scale. For 80 patients treated with sodium valproate, the mean +/- SD dosage was 1541.5 +/- 286 mg (range 940-2400). The mean postintervention ACES scores from baseline to 30 min after drug injection were 4.73 (SD = 1.93) for the valproate group and 5.45 (SD = 2.09) for the haloperidol group (P = 0.028). No significant differences were observed in terms of the mean changes 30 min after the intervention for two additional agitation scales. A larger proportion of patients in the haloperidol group experienced intense sedation (36.2%, P < 0.001) and extrapyramidal symptoms (8.7%, P = 0.007) compared with the valproate group (2.5% for intense sedation, no patient for extrapyramidal symptoms). The findings suggest that in the clinical practice setting of emergency psychiatry, intravenous valproate is as effective as haloperidol in reducing agitation, with a better safety profile. PMID- 25500683 TI - Ultrasound contrast-enhanced imaging and in vitro antitumor effect of paclitaxel poly(lactic-co-glycolic acid)-monomethoxypoly (ethylene glycol) nanocapsules with ultrasound-targeted microbubble destruction. AB - A combination of diagnostic and therapeutic ultrasound (US) techniques may be able to provide the basis of specific therapeutic protocols, particularly for the treatment of tumors. Nanotechnology may aid the progression towards the use of US for tumor diagnosis and targeted therapy. The current study investigated in vivo and in vitro US contrast imaging using nanocapsules (NCs), and also US and US targeted microbubble destruction (UTMD) therapy using drug-loaded NCs for pancreatic cancer in vitro. In the current study, the NCs were made from the polymer nanomaterial poly(lactic-co-glycolic acid)-monomethoxypoly(ethylene glycol) (PLGA-mPEG), encapsulated with paclitaxel (PTX), to create PTX-PLGA-mPEG NCs. The PTX-PLGA-mPEG NCs were used as a US contrast agent (UCA), which produced satisfactory US contrast-enhanced images in vitro and in vivo of the rabbit kidneys, with good contrast compared with lesions in the peripheral regions. However, clear contrast-enhanced images were not obtained using PTX-PLGA-mPEG NCs as a UCA, when imaging the superficial pancreatic tumors of nude mice in vivo. Subsequently, fluorescence and flow cytometry were used to measure the NC uptake rate of pancreatic tumor cells under various US or UTMD conditions. An MTT assay was used to evaluate the efficiency of PTX and PTX-PLGA-mPEG NCs in killing tumor cells following 24 or 48 h of US or UTMD therapy, compared with controls. The specific US or UTMD conditions had been previously demonstrated to be optimal through repeated testing, to determine the conditions by which cells were not impaired and the efficiency of uptake of nanoparticles was highest. The current study demonstrated high cellular uptake rates of PLGA-mPEG NCs and high tumor cell mortality with PTX-PLGA-mPEG NCs under US or UTMD optimal conditions. It was concluded that the use of NCs in US-mediated imaging and antitumor therapy may provide a novel application for US. PMID- 25500685 TI - Efficacy and safety of vilazodone 20 and 40 mg in major depressive disorder: a randomized, double-blind, placebo-controlled trial. AB - Vilazodone is a selective serotonin reuptake inhibitor and 5-HT1A partial agonist approved for major depressive disorder (MDD) treatment in adults. This was a 10 week, multicenter, double-blind, placebo-controlled and active-controlled, fixed dose trial (NCT01473381). Adult patients with MDD (Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision criteria) were randomized 1 : 1 : 1 : 1 to vilazodone 20 or 40 mg/day, citalopram 40 mg/day, or placebo. Primary efficacy: Montgomery-Asberg Depression Rating Scale (MADRS); secondary efficacy: Clinical Global Impressions-Severity and sustained response (MADRS total score<=12 for at least the last two consecutive double-blind visits). The intent-to-treat population comprised 1133 patients, (placebo=281; vilazodone 20 mg/day=288; vilazodone 40 mg/day=284; citalopram=280). MADRS and Clinical Global Impressions-Severity score change from baseline to week 10 was significantly greater for vilazodone 20 mg/day, vilazodone 40 mg/day, and citalopram versus placebo. Sustained response rates were numerically higher, but not significantly different, in all active treatment groups versus placebo. The most common adverse events (>=5% of vilazodone patients, twice the rate of placebo) were diarrhea, nausea, vomiting (vilazodone 40 mg/day only), and insomnia. Improved sexual function (Changes in Sexual Functioning Questionnaire scores) was seen in all groups; between-group differences were not significant. Vilazodone 20 and 40 mg/day demonstrated efficacy and tolerability in the treatment of MDD. PMID- 25500686 TI - Evaluation of stress and pain in young children with cerebral palsy during early developmental intervention programs: a descriptive study. AB - OBJECTIVE: The aim of this study was to use the Face, Legs, Activity, Cry, Consolability Scale; salivary cortisol levels; and withdrawal reflex thresholds to assess pain, stress, and pain sensitivity in young children with cerebral palsy during early developmental intervention programs. DESIGN: A total of 40 children with cerebral palsy (age range, 1-4 yrs) participated in the early intervention programs, which included neurodevelopmental treatment, neuromuscular electrical stimulation, occupational therapy, head acupuncture, and Chinese traditional manipulation five times per week for 3 wks. The Face, Legs, Activity, Cry, Consolability Scale was applied during the course of each treatment, and salivary cortisol samples were obtained from each child 10 mins before and 10 mins after each treatment. Withdrawal reflex thresholds were assessed via mechanical stimulation of the foot with von Frey hairs. RESULTS: All treatment programs caused some degree of pain. In descending order, the extents of the pain caused by each treatment were head acupuncture, neurodevelopmental treatment, neuromuscular electrical stimulation, Chinese traditional manipulation, and occupational therapy. There were statistically significant increases in salivary cortisol levels after the head acupuncture (P < 0.001), neurodevelopmental treatment (P < 0.001), neuromuscular electrical stimulation (P < 0.001), and Chinese traditional manipulation (P < 0.001) treatments. No significant changes were found in the withdrawal reflex thresholds during the study (P > 0.05). CONCLUSIONS: The results of this study demonstrate that early developmental intervention programs cause pain and stress in young children with cerebral palsy. PMID- 25500687 TI - Preventive and therapeutic noninvasive ventilation in cardiovascular surgery. AB - PURPOSE OF REVIEW: Postoperative pulmonary complications are common after cardiac and vascular surgery, and they are associated with a marked worsening in hospital survival and length of stay. Noninvasive ventilation (NIV) has been successfully applied in the prevention and treatment of postoperative acute respiratory failure (ARF), including the cardiovascular setting. RECENT FINDINGS: Recent findings confirm that ARF is still highly associated with reintubation and ICU readmission, affecting hospital and long-term mortality. The most recent studies suggest that NIV can be effective both in early and in severe ARF, both in ICU and in surgical ward; on the contrary, NIV efficacy, when applied as a preventive tool in unselected patients, is not demonstrated. Limited but promising data are available on NIV use in pediatric patients and in ancillary procedures like coronarography and transesophageal echocardiography. SUMMARY: NIV seems effective when applied to treat postoperative ARF. Its role as a preventive tool is still controversial, and probably should be limited to high-risk patients. Promising findings were reported for NIV application in pediatric patients and in ancillary procedures. So far, a cautious approach should be applied, as NIV failure is associated with poor outcomes if not quickly detected. PMID- 25500688 TI - Novel approaches in pain management in cardiac surgery. AB - PURPOSE OF REVIEW: Open cardiac surgery may cause severe postoperative pain and the activation of a perioperative stress response. If not treated adequately, the patient may suffer increased morbidity, a longer hospital stay, and higher overall costs. This article reviews the literature regarding various modalities for management of postoperative pain after cardiac surgery. RECENT FINDINGS: Paravertebral block of the spinal nerve roots provides similar analgesia to thoracic epidural without the risk of hypotension or epidural hematoma. Continuous alpha-2 agonist infusion reduces opioid requirements in the immediate postoperative period and may convey a morbidity and mortality benefit in cardiac surgery patients that persists for 12 months. Antiepileptics may significantly decrease opioid requirements and improve pain scores. Finally, complementary and alternative practices such as acupuncture, music, and behavioral exercises both pre and postoperatively may improve acute pain and lessen conversion to chronic pain. SUMMARY: Although published data remain limited, recent evidence indicates that patients may benefit from the addition of a variety of novel pain-management strategies currently under investigation. Selection of a multimodal approach to perioperative pain management is advocated, including selective application of regional analgesia, non-narcotic medications, and complimentary alternative options to improve patient comfort and overall outcome. PMID- 25500689 TI - Expanding role of perioperative transesophageal echocardiography in the general anesthesia practice and residency training in the USA. AB - PURPOSE OF REVIEW: To review the perioperative use of noncardiac transesophageal echocardiography in anesthesiology and to explore the current mechanisms of teaching and certification. RECENT FINDINGS: Anesthesiologists frequently use echocardiography in many noncardiac situations with potential impact on outcomes. Certification has evolved to include those who use echocardiography in noncardiac situations. More advanced teaching tools have been developed for the learning of diagnostic and monitoring modality. SUMMARY: Transesophageal echocardiography can have many helpful uses in perioperative patient care. This study summarizes many noncardiac uses, certification, and echocardiography education for anesthesiologists. PMID- 25500690 TI - Thoracic anesthesia. PMID- 25500691 TI - What is new in the blood bank for trauma resuscitation. AB - PURPOSE OF REVIEW: The aim of the present review was to describe recent changes in blood banking thinking, practice, and products that affect trauma care. RECENT FINDINGS: Prompt balanced hemostatic resuscitation of major hemorrhage from trauma improves outcome and reduces blood use. New blood processes and products can help deliver appropriate doses of procoagulant plasma and platelets quicker and more safely. New processes include holding larger inventories of thawed plasma with risk of wastage and rapid plasma thawers. New products in the blood bank include group A or group A low-titer B thawed plasma and AB or A liquid (never-frozen) plasma for resuscitation, prepooled cultured whole blood-derived platelets in plasma, and prepooled cryoprecipitate in varying pool sizes. Single donor apheresis or pooled whole blood-derived platelets in additive solution, designed to reduce plasma-related transfusion reactions, are also increasingly available but are not an appropriate blood component for hemorrhage control resuscitation because they reduce the total amount of administered plasma coagulation factors by 10%. SUMMARY: Early initiation of balanced massive transfusion protocols leading to hemostatic resuscitation is lifesaving. Changing blood product availability and composition will lead to higher complexity of massive transfusion. It is critical that anesthesiologists understand the composition of the available new blood products to use them correctly. PMID- 25500693 TI - Elevated NCX1 and NCKX4 expression in the patent postnatal ductus arteriosus of ductal-dependent congenital heart disease patients. AB - Patency of the ductus arteriosus (DA) after birth is essential in ductal dependent congenital heart disease. The Na(+)/Ca(2+) exchanger (NCX) has been demonstrated to play a key role in regulating vascular tone. The potassium dependent Na(+)/Ca(2+) exchanger (NCKX) is a related family of NCX depending on the K(+) gradients which triggers DA constriction. The present study investigated the comparative expression of NCX and NCKX between a constricted DA and patent DA in human ductal-dependant congenital heart disease. Human DAs, which were patent (n = 10, age = 20.2 +/- 4.3 days) or constricted (n = 10, age = 18.3 +/- 3.9 days), were excised during surgery from neonates with ductal-dependent congenital heart disease. Western blotting analysis, real-time quantitative polymerase chain reaction analysis and immunofluorescence studies were performed to detect the protein and mRNA levels of NCX1, NCKX3, and NCKX4. The expressions of NCX1 and NCKX4 were significantly higher in the patent DA group at both the protein and mRNA levels, and expression was localized to the smooth muscle layer. These findings indicate that NCX1 and NCKX4 are up-regulated in human postnatal patent DAs and may represent potential therapeutic targets for maintaining DA patency in ductal-dependent congenital heart disease. PMID- 25500692 TI - Kaempferol inhibits gastric cancer tumor growth: An in vitro and in vivo study. AB - Kaempferol, which is one of the general flavonoids, has recently been reported to suppress proliferation, induce cell cycle arrest and promote apoptosis in various human cancer cell lines. In the present study, the effect and mechanism of kaempferol on gastric cancer (GC) was examined. The results showed that kaempferol significantly inhibited the proliferation of MKN28 and SGC7901 cell lines. However, no significant inhibition in the GSE-1 normal gastric epithelial cell line in our experimental dose was detected. Additionally, significant apoptosis and G2/M phase cell cycle arrest were identified following the treatment of kaempferol. More importantly, we observed that kaempferol inhibited the growth of the tumor xenografts although no marked effects on liver, spleen or body weight were induced. The expression levels of G2/M cell cycle-regulating factors, cyclin B1, Cdk1 and Cdc25C, were significantly reduced. In addition, kaempferol treatment markedly decreased the level of Bcl-2 concomitant with an increase in Bax expression, resulting in the upregulation of cleaved caspase-3 and -9, which promoted PARP cleavage. Kaempferol-treated cells also led to a decrease in p-Akt, p-ERK and COX-2 expression levels. The present study therefore provided evidence that kaempferol may be a therapeutic agent for GC. PMID- 25500694 TI - Clinical utility of the plasma brain natriuretic peptide level in monitoring tetralogy of fallot patients over the long term after initial intracardiac repair: considerations for pulmonary valve replacement. AB - Clinicians are currently encountering an increasing number of patients in the long-term period after tetralogy of Fallot (TOF) repair presenting with pulmonary valve regurgitation (PR) or right ventricular (RV) dysfunction. The purpose of this study was to evaluate the clinical utility of the plasma brain natriuretic peptide (BNP) level and consider surgical indications and timing of pulmonary valve replacement (PVR). We examined 33 patients (21 males, 12 females, mean age 14.5 +/- 2.8 years) who underwent TOF repair at Kitasato University Hospital. All patients were evaluated using echocardiography and blood sampling. The mean age at the time of initial repair was 1.3 +/- 0.7 years. The patients with moderate severe PR exhibited significantly higher plasma BNP levels than the patients with trivial-mild PR (mean 37.5 +/- 33.1 vs. 17.3 +/- 6.6 pg/ml, p = 0.013). The mean plasma BNP level with cardiac symptoms was higher than that observed in the patients without any symptoms (71.4 +/- 46.1 vs. 25.0 +/- 14.0 pg/ml, p = 0.005). The mean BNP level was significantly decreased after PVR (71.3 +/- 46.1-26.1 +/- 13.2 pg/ml, p = 0.009), and the plasma BNP level was found to be positively correlated with the RV end-diastolic pressure (r = 0.851; p = 0.008). The optimal BNP cut-off value for considering PVR was 32.15 pg/ml (sensitivity, 85.7 %; specificity, 83.3 %). The plasma BNP level may become a useful diagnostic tool for considering the indications and optimal timing of PVR over the long term after TOF repair. PMID- 25500695 TI - Maternal reproductive history and the risk of congenital heart defects in offspring: a systematic review and meta-analysis. AB - Epidemiological studies have reported conflicting results on the association of congenital heart defect (CHD) risk in offspring with a maternal history of prior pregnancies and abortions, but no meta-analysis has been reported. We searched MEDLINE and EMBASE from their inception to April 14, 2014, for relevant studies that assessed the association between maternal reproductive history and CHD risk. Two authors independently assessed eligibility and extracted data. Fixed-effects or random-effects models were used to calculate the pooled odds ratios (ORs). Among 1,599 references, 17 case-control studies and one nested case-control study were included in this meta-analysis. The summary OR for the ever versus nulligravidity was 1.18 (95% CI 1.03-1.34). A dose-response analysis also indicated a positive effect of maternal gravidity on CHD risk, and the summary OR for each increment in number of pregnancies was 1.13 (95% CI 1.08-1.18). A history of abortion was associated with a 24% higher risk of CHD, OR = 1.24 (95% CI 1.11-1.38). When stratified by abortion category, CHD risk increased by 18 and 58% with a history of spontaneous abortion and induced abortion, respectively. The summary OR for each increment of one abortion was 1.28 (95% CI 1.18-1.40). In summary, this study provides evidence that increased maternal gravidity was positively associated with a risk of CHDs in offspring. Meanwhile, our results demonstrate a positive association of any history of abortion with an increased risk of CHDs. PMID- 25500696 TI - Children after fontan have strength and body composition similar to healthy peers and can successfully participate in daily moderate-to-vigorous physical activity. AB - The objective of this study was to evaluate the active lifestyle capacity (daily physical activity, strength, flexibility, body composition) of children after the Fontan procedure; hypothesized to be lower than healthy peers. Participants (n = 64, 25 females) were 9.0 +/- 1.7 years of age (range 6.0-11.7 years). Fontan completion occurred at 3.3 +/- 1.4 years of age (5.7 +/- 2.0 years prior). Canadian Health Measures Survey protocols assessed aerobic endurance (paced walking up/down steps), strength (handgrip), flexibility (sit and reach), body composition (body mass index), and daily moderate-to-vigorous physical activity (7-day accelerometry). Difference scores compared participant data to published norms (t tests). Linear regression evaluated age/gender/demographic factor associations. Children after Fontan had strength scores similar (mean difference 1.1 kg) to their peers were less likely to be obese (mean difference of body mass index = 1.1 +/- 2.5, p = 0.001) and performed 50 min of moderate-to-vigorous activity (MVPA) per day (12 +/- 17 min/day below healthy peers, p < 0.001). Estimated peak endurance (61 % of expected) and flexibility (64 % of expected) were lower than peers (p < 0.001). Almost all (60/63) participants demonstrated the capacity to perform at least 20 min of MVPA per day. Difference from norms was smaller among children younger at Fontan completion (4 +/- 2 min/year) and taking antithrombotic medication (7 +/- 18 and 22 +/- 17 min/day for taking/not taking, respectively). Children after Fontan demonstrate the capacity for the daily physical activity associated with optimal health. They have similar strength and good body composition. We recommend that children after Fontan be counselled that they can successfully participate in healthy, active lifestyles and physically active peer play. PMID- 25500697 TI - Association between migration and physical activity of school-age children left behind in rural Mexico. AB - OBJECTIVES: The purpose of this study was to explore in rural communities of Mexico, the association between physical activity (PA) in school-age children and exposure to migration. METHODS: We measured PA through a questionnaire validated in school-age children and used in Mexican National Surveys. Migration status was measured as the number of years a family member had been in the US, and the amount of remittances that family member had sent to their household in Mexico. We used multivariable linear regression to measure the association between physical activity and migration. RESULTS: School-age children who had a migrant family member spent less time on PA per day, especially recreation activities, compared to school-age children without the migrating influence. Also, children who belonged to a family that received remittances and their migrant relative lived >= 5 years in US were less likely to engage in PA. CONCLUSIONS: Exposure to migration may predict reduction in PA in school-age children left behind in Mexican rural communities from the State of Morelos. These findings call for PA tailored interventions that consider household migration characteristics. PMID- 25500699 TI - Erratum to: 'Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice' and 'Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway'. PMID- 25500698 TI - Change in depressive symptoms and mental health-related quality of life in northeast Germany between 1997-2001 and 2008-2012. AB - OBJECTIVES: Little is known about changes in depression and quality of life in East Germany. We examined changes in the prevalence of lifetime and current depressive symptoms and mental health-related quality of life among adults in northeast Germany between 1997-2001 and 2008-2012. METHODS: Population-based data were drawn from two repeated cross-sectional surveys conducted 11 years apart within the Study of Health of Pomerania project (Ns of 4,228 and 4,251). Assessments included screening items for lifetime depressive symptoms from the Munich Composite International Diagnostic Interview (M-CIDI), the Depression and Exhaustion Scale (DEEX), and the Short Form Health Survey (SF-12). RESULTS: Lifetime depressive symptoms rose from 13.2 to 27.8%. The increase was stronger in men than in women and in individuals aged 35-64 years. No substantial changes occurred in the overall prevalence of current depressive symptoms (DEEX) and mental health-related quality of life (SF-12). A small decrease in current depressive symptoms was observed in middle-aged men and older women and small improvements in mental health-related quality of life in young adults. CONCLUSIONS: Higher reporting of lifetime depressive symptoms might reflect methodological influences as well as lower stigmatization and higher awareness, while the current burden seems similar. PMID- 25500700 TI - Ins1(Cre) knock-in mice for beta cell-specific gene recombination. AB - AIMS/HYPOTHESIS: Pancreatic beta cells play a central role in the control of glucose homeostasis by secreting insulin to stimulate glucose uptake by peripheral tissues. Understanding the molecular mechanisms that control beta cell function and plasticity has critical implications for the pathophysiology and therapy of major forms of diabetes. Selective gene inactivation in pancreatic beta cells, using the Cre-lox system, is a powerful approach to assess the role of particular genes in beta cells and their impact on whole body glucose homeostasis. Several Cre recombinase (Cre) deleter mice have been established to allow inactivation of genes in beta cells, but many show non-specific recombination in other cell types, often in the brain. METHODS: We describe the generation of Ins1(Cre) and Ins1(CreERT2) mice in which the Cre or Cre-oestrogen receptor fusion protein (CreERT2) recombinases have been introduced at the initiation codon of the Ins1 gene. RESULTS: We show that Ins1(Cre) mice induce efficient and selective recombination of floxed genes in beta cells from the time of birth, with no recombination in the central nervous system. These mice have normal body weight and glucose homeostasis. Furthermore, we show that tamoxifen treatment of adult Ins1(CreERT2) mice crossed with Rosa26-tdTomato mice induces efficient recombination in beta cells. CONCLUSIONS/INTERPRETATION: These two strains of deleter mice are useful new resources to investigate the molecular physiology of pancreatic beta cells. PMID- 25500701 TI - Redefining dermatomyositis: a description of new diagnostic criteria that differentiate pure dermatomyositis from overlap myositis with dermatomyositis features. AB - Dermatomyositis (DM) is a major clinical subset of autoimmune myositis (AIM). The characteristic DM rash (Gottron papules, heliotrope rash) and perifascicular atrophy at skeletal muscle biopsy are regarded as specific features for this diagnosis. However, new concepts are challenging the current definition of DM. A modified Bohan and Peter classification of AIM was proposed in which the core concept was the inclusion of the diagnostic significance of overlap connective tissue disease features. In this clinical classification, a DM rash in association with myositis in the absence of overlap features indicates a diagnosis of pure DM. However, overlap features in association with myositis allow a diagnosis of overlap myositis (OM), irrespective of the presence or absence of the DM rash. Perifascicular atrophy may be present in both pure DM and OM. Recently, the presence of perifascicular atrophy in myositis without a DM rash was proposed as diagnostic of a novel entity, adermatopathic DM. We conducted the present study to evaluate these new concepts to further differentiate pure DM from OM.Using the modified Bohan and Peter classification, we performed a follow-up study of a longitudinal cohort of 100 consecutive adult French Canadian patients with AIM, including 44 patients with a DM phenotype, defined as a DM rash, and/or DM-type calcinosis, and/or the presence of perifascicular atrophy on muscle biopsy. A detailed evaluation was performed for overlap features, the extent and natural history of the DM rash, adermatopathic DM, DM-specific and overlap autoantibodies by protein A immunoprecipitation on coded serum samples, and associations with cancer and survival.Two distinct subsets were identified in patients with a DM phenotype: pure DM (n = 24) and OM with DM features, or OMDM (n = 20). In pure DM, the DM rash was a dominant finding. It was the first disease manifestation, was always present at the time of myositis diagnosis, and was associated with a high cutaneous score and chronicity. Concurrent heliotrope rash and Gottron papules (positive predictive value [PPV] 91%), as well as the V-sign and/or shawl sign (PPV 100%), were diagnostic of pure DM. Anti-Mi-2, anti-MJ, and anti-p155 autoantibodies were present in 50% of pure DM patients and were restricted to this subset (PPV 100%). Cancer was present in 21% of pure DM patients. The 15-year survival was excellent (92%).In contrast, in patients with OMDM, the first manifestation was proximal muscle weakness or other skeletal muscle-related complaints. The DM rash appeared at diagnosis or at follow-up, was associated with a low cutaneous extent score and was transient. Adermatopathic DM, which was absent in pure DM, was highly predictive (PPV 100%) of OMDM. Overlap autoantibodies (including anti-Jo-1, anti PL-7, anti-PM-Scl, anti-U1RNP, and/or anti-U5-RNP) were found in 70% of OMDM patients. OMDM was not associated with cancer, but the 15-year survival was significantly decreased (65%).Perifascicular atrophy occurred as commonly in OMDM (n = 6/20, 30%) as in pure DM (n = 4/24, 17%) patients. These 6 OMDM patients had adermatopathic DM at myositis diagnosis, and only 1 of them developed a DM rash at follow-up, emphasizing the lack of specificity of perifascicular atrophy for pure DM.In conclusion, using the modified Bohan and Peter classification of AIM allowed identification of OMDM, a new clinical subset of OM. Furthermore, identification of OMDM allowed recognition of pure DM as a new entity that was distinct from OMDM or from OM without DM features. However, the absolute specificity of a DM rash and perifascicular muscle atrophy for the diagnosis of pure DM was lost. The distinctive clinical manifestations and autoantibody profiles presented are proposed as diagnostic criteria to differentiate pure DM from OMDM. PMID- 25500702 TI - Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8-year observational study at a single center. AB - Expanded clinical experience with patients taking antiangiogenic compounds has come with increasing recognition of the renal adverse effects. Because renal histology is rarely sought in those patients, the renal consequences are underestimated. Antiangiogenic-treated-cancer patients, who had a renal biopsy for renal adverse effects from 2006 to 2013, were included in the current study. Clinical features and renal histologic findings were reviewed. Our cohort was 100 patients (58 women) with biopsy-proven kidney disease using anti-vascular endothelial growth factor (VEGF) therapy with a mean age of 59.8 years (range, 20 85 yr). Patients were referred for proteinuria, hypertension, and/or renal insufficiency. Kidney biopsy was performed 6.87 +/- 7.18 months after the beginning of treatment. Seventy-three patients experienced renal thrombotic microangiopathy (TMA) and 27 patients had variable glomerulopathies, mainly minimal change disease and/or collapsing-like focal segmental glomerulosclerosis (MCN/cFSGS). MCN/cFSGS-like lesions developed mainly with tyrosine-kinase inhibitors, whereas TMA complicated anti-VEGF ligand. Thirty-one percent of TMA patients had proteinuria up to 1 g/24 h. Half of TMA cases are exclusively renal localized. Pathologic TMA features are intraglomerular exclusively. MCN/cFSGS glomeruli displayed a high abundance of KI-67, but synaptopodin was not detected. Conversely, TMA glomeruli exhibited a normal abundance of synaptopodin-like control, whereas KI-67 was absent. Median follow-up was 12 months (range, 1-80 mo). Fifty-four patients died due to cancer progression. Hypertension and proteinuria resolved following drug discontinuation and antihypertensive agents. No patient developed severe renal failure requiring dialysis. Drug continuation or reintroduction resulted in a more severe recurrence of TMA in 3 out of 4 patients requiring maintenance of anti-VEGF agents despite renal TMA. In conclusion, TMA and MCN/cFSGS are the most frequent forms of renal involvement under anti-VEGF therapy. Careful risk-benefit assessment for individual patients should take into account risk factors related to the host and the tumor. PMID- 25500703 TI - Pulmonary fibrosis in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis: a series of 49 patients and review of the literature. AB - Pulmonary fibrosis (PF) is an uncommon manifestation observed in patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), particularly microscopic polyangiitis (MPA). While patients with PF associated with AAV seem to have a worse prognosis, these patients have been described only in case reports or small retrospective case series. In this retrospective multicenter study, we report the main features and long-term outcomes of patients with PF associated with AAV, fulfilling the American College of Rheumatology criteria and/or Chapel Hill definitions. Forty-nine patients (30 men [61%]; median age at diagnosis of AAV, 68 [interquartile range, 58-73] years) with PF associated with AAV were identified. Forty (81.6%) patients had MPA and 9 (18.4%) had granulomatosis with polyangiitis. The diagnosis of PF preceded the onset of vasculitis in 22 (45%) patients. Usual interstitial pneumonia was the main radiologic pattern (n = 18, 43%). ANCA were mostly of antimyeloperoxidase specificity (88%). All patients were treated with glucocorticoids as induction therapy, combined with cyclophosphamide (CYC) (n = 36, 73.5%) or rituximab (RTX) (n = 1, 2%). Factors associated with mortality included occurrence of chronic respiratory insufficiency (hazard ratio [HR], 7.44; 95% confidence interval [CI], 1.6-34.5; p = 0.003), induction therapy with glucocorticoids alone (HR, 2.94; CI, 1.05-8.33; p = 0.04), and initial weigh loss (HR, 2.83; CI, 1.05-7.65; p = 0.041). The 3-year survival rate in patients treated with glucocorticoids alone or combined with an immunosuppressant (CYC or RTX) as induction therapy was 64% (95% CI, 41-99) and 94% (95% CI, 86-100), respectively (p = 0.03). After a median follow-up of 48 months [interquartile range, 14-88 mo], 18 (37%) patients died, including 11 related to respiratory insufficiency. PF is a rare manifestation of AAV with a very poor prognosis. Induction therapy with CYC might improve the outcome. PMID- 25500704 TI - Minimal change nephrotic syndrome associated with non-Hodgkin lymphoid disorders: a retrospective study of 18 cases. AB - Few studies have examined the occurrence of minimal change nephrotic syndrome (MCNS) in patients with non-Hodgkin lymphoma (NHL). We report here a series of 18 patients with MCNS occurring among 13,992 new cases of NHL. We analyzed the clinical and pathologic characteristics of this association, along with the response of patients to treatment, to determine if this association relies on a particular disorder. The most frequent NHLs associated with MCNS were Waldenstrom macroglobulinemia (33.3%), marginal zone B-cell lymphoma (27.8%), and chronic lymphocytic leukemia (22.2%). Other lymphoproliferative disorders included multiple myeloma, mantle cell lymphoma, and peripheral T-cell lymphoma. In 4 patients MCNS occurred before NHL (mean delay, 15 mo), in 10 patients the disorders occurred simultaneously, and in 4 patients MCNS was diagnosed after NHL (mean delay, 25 mo). Circulating monoclonal immunoglobulins were present in 11 patients. A nontumoral interstitial infiltrate was present in renal biopsy specimens from 3 patients without significant renal impairment. Acute kidney injury resulting from tubular lesions or renal hypoperfusion was present in 6 patients. MCNS relapse occurred more frequently in patients treated exclusively by steroid therapy (77.8%) than in those receiving steroids associated with chemotherapy (25%). In conclusion, MCNS occurs preferentially in NHL originating from B cells and requires an aggressive therapeutic approach to reduce the risk of MCNS relapse. PMID- 25500705 TI - Pulmonary tumor thrombotic microangiopathy: report of 3 cases and review of the literature. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinical entity where tumor cell embolisms in pulmonary circulation induce thrombotic microangiopathy (TMA), respiratory failure, and subacute cor pulmonale.We describe 3 cases of PTTM that presented as the initial manifestation of metastatic gastric adenocarcinoma with TMA and pulmonary infiltrates.All 3 cases had similar clinical and laboratory features, which included moderate thrombocytopenia without renal failure, hemolysis with extremely high serum lactate dehydrogenase levels, leukoerythroblastosis in peripheral blood smear, altered coagulation tests, lymphadenopathies, and interstitial pulmonary infiltrates. All patients died within 2 weeks of diagnosis. Two cases were initially misdiagnosed as idiopathic thrombotic thrombocytopenic purpura and treated with plasma exchange with no response. One patient had bone marrow infiltration by malignant cells. Autopsies revealed PTTM associated with gastric disseminated adenocarcinoma (signet-ring cell type in 2 patients and poorly differentiated type in 1).PTTM should be considered in the differential diagnosis of patients with fulminant microangiopathic hemolytic anemia, such as atypical thrombotic thrombocytopenic purpura, mainly those with pulmonary infiltrates, disseminated intravascular coagulation, or Trousseau syndrome. PMID- 25500706 TI - Coxiella burnetii infection in hemodialysis and other vascular grafts. AB - Prosthetic arteriovenous (AV) graft infection is the principal cause of morbidity related to chronic hemodialysis AV graft fistula. Coxiella burnetii is a known pathogen that causes fever, pneumonia, and intravascular infections with the limitation of negative cultures. Herein, we report the first case of a patient who presented to the emergency department of our hospital with a prosthetic hemodialysis AV graft infection due to Coxiella burnetii. We also performed a literature search with PubMed to identify studies reporting cases of Coxiella burnetii vascular graft infection. Overall, we reviewed 15 cases of vascular graft infection, including ours. We found a high prevalence of male patients (87%); mean age +/- standard deviation (SD) of the entire population was 60.4 +/- 9.6 years. The dacron infrarenal aortic and the aortobifemoral bypass were the most common involved grafts. The early diagnosis of infection due to Coxiella burnetii was done by serology or with polymerase chain reaction (PCR), in 12 and 3 cases, respectively. All patients underwent partial or complete resection of the infected grafts; the most common antibiotic treatment for this entity was doxycycline and hydroxycloroquine.Although this is a relatively rare disease, Coxiella burnetii should be included in the differential diagnosis of all patients who present with infection of an endovascular graft of any nature with an inconclusive etiologic diagnosis. PMID- 25500707 TI - Kikuchi-Fujimoto disease: retrospective study of 91 cases and review of the literature. AB - Kikuchi-Fujimoto disease (KFD) is a rare cause of lymphadenopathy, most often cervical. It has been mainly described in Asia. There are few data available on this disease in Europe. We conducted this retrospective, observational, multicenter study to describe KFD in France and to determine the characteristics of severe forms of the disease and forms associated with systemic lupus erythematosus (SLE). We included 91 cases of KFD, diagnosed between January 1989 and January 2011 in 13 French hospital centers (median age, 30 +/- 10.4 yr; 77% female). The ethnic origins of the patients were European (33%), Afro-Caribbean (32%), North African (15.4%), and Asian (13%). Eighteen patients had a history of systemic disease, including 11 with SLE. Lymph node involvement was cervical (90%), often in the context of polyadenopathy (52%), and it was associated with hepatomegaly and splenomegaly in 14.8% of cases. Deeper sites of involvement were noted in 18% of cases. Constitutional signs consisted mainly of fever (67%), asthenia (74.4%), and weight loss (51.2%). Other manifestations included skin rash (32.9%), arthromyalgia (34.1%), 2 cases of aseptic meningitis, and 3 cases of hemophagocytic lymphohistiocytosis. Biological signs included lymphocytopenia (63.8%) and increase of acute phase reactants (56.4%). Antinuclear antibodies (ANAs) and anti-DNA antibodies were present in 45.2% and 18% of the patients sampled, respectively. Concomitant viral infection was detected in 8 patients (8.8%). Systemic corticosteroids were prescribed in 32% of cases, hydroxychloroquine in 17.6%, and intravenous immunoglobulin in 3 patients. The disease course was always favorable. Recurrence was observed in 21% of cases. In the 33 patients with ANA at diagnosis, SLE was known in 11 patients, diagnosed concomitantly in 10 cases and in the year following diagnosis in 2 cases; 6 patients did not have SLE, and 4 patients were lost to follow-up (median follow up, 19 mo; range, 3-39 mo). The presence of weight loss, arthralgia, skin lesions, and ANA was associated with the development of SLE (p < 0.05). Male sex and lymphopenia were associated with severe forms of KFD (p < 0.05). KFD can occur in all populations, irrespective of ethnic origin. Deep forms are common. An association with SLE should be investigated. A prospective study is required to determine the risk factors for the development of SLE. PMID- 25500708 TI - An autoimmune myositis-overlap syndrome associated with autoantibodies to nuclear pore complexes: description and long-term follow-up of the anti-Nup syndrome. AB - Autoimmune myositis encompasses various myositis-overlap syndromes, each being identified by the presence of serum marker autoantibodies. We describe a novel myositis-overlap syndrome in 4 patients characterized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes. The clinical phenotype was characterized by prominent myositis in association with erosive, anti-CCP, and rheumatoid factor-positive arthritis, trigeminal neuralgia, mild interstitial lung disease, Raynaud phenomenon, and weight loss. The myositis was typically chronic, relapsing, and refractory to corticosteroids alone, but remitted with the addition of a second immunomodulating drug. There was no clinical or laboratory evidence for liver disease. The prognosis was good with 100% long-term survival (mean follow-up 19.5 yr).By indirect immunofluorescence on HEp-2 cells, sera from all 4 patients displayed a high titer of antinuclear autoantibodies (ANA) with a distinct punctate peripheral (rim) fluorescent pattern of the nuclear envelope characteristic of nuclear pore complexes. Reactivity with nuclear pore complexes was confirmed by immunoelectron microscopy. In a cohort of 100 French Canadian patients with autoimmune myositis, the nuclear pore complex fluorescent ANA pattern was restricted to these 4 patients (4%). It was not observed in sera from 393 adult patients with systemic sclerosis (n = 112), mixed connective tissue disease (n = 35), systemic lupus (n = 94), rheumatoid arthritis (n = 45), or other rheumatic diseases (n = 107), nor was it observed in 62 normal adults.Autoantibodies to nuclear pore complexes were predominantly of IgG isotype. No other IgG autoantibody markers for defined connective tissue diseases or overlap syndromes were present, indicating a selective and highly focused immune response. In 3 patients, anti-nuclear pore complex autoantibody titers varied in parallel with myositis activity, suggesting a pathogenic link to pathophysiology. The nuclear pore complex proteins, that is, nucleoporins (nup), recognized by these sera were heterogeneous and included Nup358/RanBP2 (n = 2 patients), Nup90 (n = 1), Nup62 (n = 1), and gp210 (n = 1). Taken together the data suggest that nup autoantigens themselves drive the anti nup autoimmune response. Immunogenetically, the 4 patients shared the DQA1*0501 allele associated with an increased risk for autoimmune myositis.In conclusion, we report an apparent novel subset of autoimmune myositis in our population of French Canadian patients with connective tissue diseases. This syndrome is recognized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes that react with nups, consistent with an "anti-nup syndrome." PMID- 25500711 TI - Inhibitors of tissue transglutaminase. AB - Tissue transglutaminase (TG2) catalyzes the cross-linking of proteins by the formation of isopeptide bonds between glutamine (Gln) and lysine (Lys) side chains. Although TG2 is essential for the stabilization of the extracellular matrix, its unregulated activity has been implicated in celiac disease, fibrosis, and cancer metastasis, among other disorders. Given the importance and range of TG2-related pathologies, recent work has focused on the development of potent and selective inhibitors against TG2. In this review, we present the latest and most noteworthy irreversible and reversible inhibitors of TG2, and offer perspectives for the design of future inhibitors, in the hope that lead compounds with therapeutic potential may soon be discovered. PMID- 25500710 TI - Single-organ gallbladder vasculitis: characterization and distinction from systemic vasculitis involving the gallbladder. An analysis of 61 patients. AB - Systemic vasculitis (SV) involving abdominal structures usually has a poor prognosis. Gallbladder vasculitis (GV) has been reported as part of SV (GB-SV) and focal single-organ vasculitis (GB-SOV). We analyzed clinical and histologic characteristics of patients with GV to identify features that differentiate GB SOV from the systemic forms of GV. To identify affected patients with GV we used pathology databases from our institution and an English-language PubMed search. Clinical manifestations, laboratory and histologic features, treatment administered, and outcomes were recorded. Patients were divided in 2 groups, GB SOV and GB-SV. As in previous studies of single-organ vasculitis, GB-SOV was only considered to be a sustainable diagnosis if disease beyond the gallbladder was not apparent after a follow-up period of at least 6 months. Sixty-one well characterized patients with GV were included (6 from our institution). There was no significant sex bias (32 female patients, 29 male). Median age was 52 years (range, 18-94 yr). GB-SOV was found in 20 (33%) and GB-SV in 41 (67%) patients. No differences were observed in age, sex frequency, or duration of gallbladder symptoms between groups. Past episodes of recurrent right-upper quadrant or abdominal pain and lithiasic cholecystitis were more frequent in GB-SOV patients, whereas acalculous cholecystitis occurred more often in GB-SV. In GB-SV, gallbladder-related symptoms occurred more often concomitantly with or after the systemic features, but they sometimes appeared before SV was fully developed (13.5%). Constitutional and musculoskeletal symptoms were reported only in GB-SV patients. Compared to GB-SOV, GB-SV patients presented more often with fever (62.5% vs 20%; p = 0.003) and exhibited higher erythrocyte sedimentation rate levels (80 +/- 28 vs 37 +/- 25 mm/h, respectively; p = 0.006). All GB-SV patients required glucocorticoids and 50% of them also received cytotoxic agents. Mortality in GB-SV was higher than in GB-SOV (35.5% vs 10%; p = 0.05). Nongranulomatous inflammation with fibrinoid necrosis of medium-sized vessels occurred equally in both groups (>90%). Forms of SV affecting the gallbladder included polyarteritis nodosa (n = 10), hepatitis B virus-associated vasculitis (n = 8), cryoglobulinemic (essential or hepatitis C virus-associated) vasculitis (n = 6), vasculitis associated with autoimmune diseases (n = 6), microscopic polyangiitis (n = 4), eosinophilic granulomatosis with polyangiitis (Churg Strauss) (n = 4), IgA vasculitis (Henoch-Schonlein) (n = 2), and giant cell arteritis (n = 1).GV is uncommon. Its histology most often consists of a nongranulomatous necrotizing vasculitis affecting medium-sized vessels. GB-SOV is usually discovered after routine cholecystectomy performed because of the presence of local symptoms, gallstone-associated cholecystitis, and contrary to GB-SV, GB-SOV is usually not associated with systemic symptoms. Acute phase reactants and surrogate markers of autoimmunity are usually normal or negative in GB-SOV. GB-SOV does not require systemic antiinflammatory or immunosuppressive therapy; surgery is adequate to achieve cure. GB-SV always warrants immunosuppressant therapy and is associated with high mortality. The finding of GV may precede the generalized manifestations of SV. Therefore, once GV is discovered, studies to determine disease extent and a vigilant follow-up are mandatory. PMID- 25500713 TI - Perivascular microglia promote blood vessel disintegration in the ischemic penumbra. AB - The contribution of microglia to ischemic cortical stroke is of particular therapeutic interest because of the impact on the survival of brain tissue in the ischemic penumbra, a region that is potentially salvable upon a brain infarct. Whether or not tissue in the penumbra survives critically depends on blood flow and vessel perfusion. To study the role of microglia in cortical stroke and blood vessel stability, CX3CR1(+/GFP) mice were subjected to transient middle cerebral artery occlusion and then microglia were investigated using time-lapse two-photon microscopy in vivo. Soon after reperfusion, microglia became activated in the stroke penumbra and started to expand cellular protrusions towards adjacent blood vessels. All microglia in the penumbra were found associated with blood vessels within 24 h post reperfusion and partially fully engulfed them. In the same time frame blood vessels became permissive for blood serum components. Migration assays in vitro showed that blood serum proteins leaking into the tissue provided molecular cues leading to the recruitment of microglia to blood vessels and to their activation. Subsequently, these perivascular microglia started to eat up endothelial cells by phagocytosis, which caused an activation of the local endothelium and contributed to the disintegration of blood vessels with an eventual break down of the blood brain barrier. Loss-of-microglia-function studies using CX3CR1(GFP/GFP) mice displayed a decrease in stroke size and a reduction in the extravasation of contrast agent into the brain penumbra as measured by MRI. Potentially, medication directed at inhibiting microglia activation within the first day after stroke could stabilize blood vessels in the penumbra, increase blood flow, and serve as a valuable treatment for patients suffering from ischemic stroke. PMID- 25500712 TI - Minimum cement volume for vertebroplasty. AB - PURPOSE: Percutaneous vertebroplasty is a widely used vertebral augmentation technique. It is a minimally invasive and low-risk procedure, but has some disadvantages with a relatively high number of bone cement leaks and adjacent vertebral fractures. The aim of this cadaveric study was to determine the minimum percentage of cement fill volume in vertebroplasty needed to restore vertebral stiffness and adjacent intradiscal pressure. METHODS: Thirteen thoracolumbar spine mobile segments were loaded to induce a vertebral fracture. After fracture vertebroplasty was performed, four times in the same fractured vertebra. The injected cement volume was 5 % of the fractured vertebral volume to reach 5, 10, 15 and 20 % of cement fill. Biomechanical testing was performed before the fracture, after the fracture and after each cement injection. RESULTS: After vertebral fracture compressive stiffness was reduced to 47 % of the pre-fracture value and was partially restored to 61 % after 10 % cement fill. With vertebroplasty intradiscal pressure gradually increased, depending on specimen position, from 48 to a total of 71 % at 15 % of cement fill. CONCLUSIONS: Compressive stiffness and intradiscal pressure increase with the percentage of cement fill. Fifteen per cent of cement fill was the limit beyond which no substantial increase in compressive stiffness or intradiscal pressure could be detected and is the minimum volume of cement we recommend for vertebroplasty. In the average thoracolumbar vertebra this means 4-6 ml of cement. PMID- 25500715 TI - Evaluation of the contribution of radiological imaging to the final diagnosis in medical case reports. AB - PURPOSE: To evaluate the clinical value and impact of radiological imaging in published medial case reports. METHODS: We analysed 671 consecutively published case reports of a peer-reviewed medical journal for case reports. The general use of radiological imaging as well as the specific imaging modality used in each case (ultrasound, x-ray, fluoroscopy, CT, MRI) was documented, and most importantly the 'final problem solver', i.e. the diagnostic modality giving the final clue to the patient's diagnosis, was identified. RESULTS: In 511 of 671 (76.1 %) analysed case reports at least one radiological modality was used in the diagnostic cascade. In 28.6% of all cases the final diagnosis was achieved by radiological imaging. All other cases were solved by the patient's history and physical examination (15.2%), histology (12.4%), and blood analysis (9.6%). When radiology was the 'final problem solver', it was mainly CT (51.6%) and MRI (30.6%). In 52.2% of the case reports the radiological image was included in the article. CONCLUSION: In case reports published in a prominent general medical journal radiological imaging is an important key player in the diagnostic process. In many cases, it is also the diagnostic tool which ultimately leads to determining the final diagnosis. KEY POINTS: * Radiology was the most important specialty for finding the final diagnosis. * CT was the most successful problem solving imaging modality followed by MRI. * MRI and CT had the best solution rates of more than 30%. PMID- 25500714 TI - Lesion morphology on breast MRI affects targeted ultrasound correlation rate. AB - INTRODUCTION: Suspicious lesions on breast MRI are often initially evaluated using targeted ultrasound. However, workup varies. Data on the rate of correlate detection by morphology [mass, non-mass enhancement (NME), or focus] would be useful for developing practice guidelines. MATERIALS AND METHODS: Breast MRI examinations from 1 January 2008 to 31 December 2010 were reviewed. BI-RADS 4 or 5 lesions on MRI evaluated with targeted ultrasound where definitive diagnosis was obtained were included. Statistical analysis was performed on aggregate data and at the lesion level. RESULTS: A total of 204 lesions were included in the study. A statistically significant difference in ultrasound correlate identification by morphology was found; a correlate was found in 49.3 % of masses, 15 % of NME, and 42.3 % of foci (p = 0.0006). Additional analysis within each morphology demonstrated significantly greater rate of malignancy in masses with an ultrasound correlate than masses without a correlate (p = 0.0062), while the rate of malignancy in NME and foci did not differ with ultrasound correlation. CONCLUSIONS: Morphology of a suspicious lesion on breast MRI affects the probability of identifying an ultrasound correlate. As sonographic correlates are found in nearly half of masses and foci, targeted ultrasound should be the initial step in their workup. KEY POINTS: * Lesion morphology on breast MRI affects the probability of ultrasound correlate identification. * An ultrasound correlate is significantly more likely for masses and foci. * Mass or focus should undergo targeted ultrasound before MRI-guided biopsy. PMID- 25500716 TI - Partnering With VA Stakeholders to Develop a Comprehensive Patient Safety Data Display: Lessons Learned From the Field. AB - Health care systems are increasingly burdened by the large numbers of safety measures currently being reported. Within the Veterans Administration (VA), most safety reporting occurs within organizational silos, with little involvement by the frontline users of these measures. To provide a more integrated picture of patient safety, the study team partnered with multiple VA stakeholders and engaged potential frontline users at 2 hospitals to develop a Guiding Patient Safety (GPS) tool. The GPS is currently in its fourth generation; once approval is obtained from senior leadership, implementation will begin. Stakeholders were enthusiastic about the GPS's user-friendly format, comprehensive content, and potential utility for improving safety. These findings suggest that stakeholder engagement is a critical first step in the development of tools that will more likely be used by frontline users. Policy makers and researchers may consider adopting this innovative partnered-research model in developing future national initiatives to deliver meaningful programs to frontline users. PMID- 25500717 TI - Muscle attachment site (MAS) patterns for species determination in European species of Lucilia (Diptera: Calliphoridae). AB - Species identification is generally assessed to be more difficult in larval stages than in adult forms. Especially closely related species such as Lucilia caesar and Lucilia illustris are difficult to identify. The aim of this study was to simplify species determination in Lucilia larvae for entomological and forensic purposes. Muscle attachment site (MAS) patterns were previously found to be a good tool for species determination in blowfly larvae. Here, distinctive MAS patterns are presented for European Lucilia ampullacea, L. caesar, L. illustris, L. richardsi, L. sericata, and L. silvarum. A joint pattern for the genus Lucilia is provided for a quick classification of a larva to the genus. PMID- 25500709 TI - Posttraumatic mucormycosis: a nationwide study in France and review of the literature. AB - Data on clinical, mycologic characteristics, and outcome of posttraumatic mucormycosis are scarce and often limited to case reports. From the French nationwide "RetroZygo" study, we compared posttraumatic mucormycosis cases with other forms of mucormycosis. We also reviewed reports of posttraumatic mucormycosis in the English-language literature from 1993 to 2013. We included all proven or probable cases for which underlying condition, route of infection, surgical and antifungal treatments, and outcome were detailed. From our cohort, posttraumatic mucormycosis (n = 16) differed significantly from other forms (n = 85) by rarity of underlying disease (31.2% vs 81%, p < 0.0001), frequency of cutaneous localization (87% vs 7%, p < 0.0001), short time before diagnosis (4.5 vs 21 d, p = 0.0002), species involved (Apophysomyces elegans complex and Saksenaea vasiformis), surgical requirement (93.7% vs 47%, p = 0.0006) and better survival (87.5% vs 47.6% at day 90, p = 0.03). We studied 122 cases of posttraumatic mucormycosis through our literature review. Most frequently reported traumas were traffic (37%), domestic accidents (15.1%), or natural disasters (13.4%). Mucormycosis occurred after extensive soft-tissue damage in 47.5% cases, with symptoms occurring a median of 9.5 days after trauma with necrosis being reported in 76.2% cases. Dissemination was found in 9% of patients, and bacterial coinfection in 41%. Nineteen percent of cases occurred in the Middle East or in India where Apophysomyces elegans complex was the predominant species recovered. Awareness of mucormycosis as a cause of posttrauma soft-tissue infection is warranted, especially in cases of soil-contaminated wounds. Survival is higher than in other forms of mucormycosis, but morbidity remains high. PMID- 25500718 TI - Awareness of the adverse effects associated with prophylactic corticosteroid use during docetaxel therapy. AB - PURPOSE: Weekly or tri-weekly docetaxel treatment mandates the use of dexamethasone to prevent toxicity. However, the adverse effects of prophylactic steroid use are often overlooked. We investigated the incidence of corticosteroid associated adverse effects during docetaxel therapy, focusing on hyperglycemia and infection as well as the identification of possible risk factors. METHODS: This study was conducted through retrospective chart review of 632 patients who started docetaxel-based chemotherapy between July 2011 and June 2012 at Seoul National University Hospital. Hyperglycemia was defined as more than two random glucose levels >200 mg/dL. All documented episodes of infection that required treatment with antibiotics were regarded as infectious episodes. RESULTS: The incidences of hyperglycemia in overall patients and in patients without previous diabetes mellitus were 13.7 and 10.9%, respectively. Infectious episodes greater than grade 2 and grade 3 developed in 29.6 and 19.9% of patients, respectively. Multivariable logistic regression analysis showed that body mass index and previous diabetes mellitus were independent risk factors for hyperglycemia, whereas corticosteroid dose was not. Treatment duration and frequency of high blood glucose levels over 200 mg/dL were independent risk factors for infection. CONCLUSIONS: Due to the significant difference in patient and treatment characteristics, we could not obtain meaningful comparisons between weekly and tri-weekly docetaxel administration regimens. This study suggests that adverse effects associated with prophylactic steroid use need to be recognized and optimally managed during docetaxel therapy. PMID- 25500719 TI - Overexpression of AT14A confers tolerance to drought stress-induced oxidative damage in suspension cultured cells of Arabidopsis thaliana. AB - Drought stress can affect interaction between plant cell plasma membrane and cell wall. Arabidopsis AT14A, an integrin-like protein, mediates the cell wall-plasma membrane-cytoskeleton continuum (WMC continuum). To gain further insight into the function of AT14A, the role of AT14A in response to drought stress simulated by polyethylene glycol (PEG-6000) in Arabidopsis suspension cultures was investigated. The expression of this gene was induced by PEG-6000 resulting from reverse transcription-PCR, which was further confirmed by the expression data from publically available microarray datasets. Compared to the wild-type cells, overexpression of AT14A (AT14A-OE) in Arabidopsis cultures exhibited a greater ability to adapt to water deficit, as evidenced by higher biomass accumulation and cell survival rate. Furthermore, AT14A-OE cells showed a higher tolerance to PEG-induced oxidative damage, as reflected by less H2O2 content, lipid peroxidation (malondialdehyde (MDA) content), and ion leakage, which was further verified by maintaining high levels of activities of antioxidant defense enzymes such as ascorbate peroxidase and guaiacol peroxidase and soluble protein. Taken together, our results suggest that overexpression of AT14A improves drought stress tolerance and that AT14A is involved in suppressing oxidative damage under drought stress in part via regulation of antioxidant enzyme activities. PMID- 25500720 TI - Bioaccumulation of heavy metals in marine organisms from the Romanian sector of the Black Sea. AB - The aim of this research was to study the accumulation of heavy metals (cadmium - Cd, lead - Pb, chromium - Cr, nickel - Ni, and copper - Cu) from water and sediments into living tissues of relevant marine species from different trophic levels of a food web, representative for shallow waters of the Romanian Black Sea Coast where the main anthropogenic impacts exist. The heavy metals concentrations were analysed by using an Atomic Absorption Spectrometer with graphite furnace, the results being further used to calculate the bioconcentration factors for a few key taxa like green and red algae, molluscs and fishes. Seven sampling sites influenced by anthropogenic pollution sources (municipal wastewater treatment plants and diffuse sources) were considered and a total of 300 samples were analysed for the period 2011-2012, this being the first unitary study for the Romanian Black Sea marine ecosystem. In 2011 and 2012 there were no significant differences between the sampling areas considering the heavy metals concentrations in water. For the sediments significant differences were observed between sampling sites for some heavy metals, namely Pb in 2011 and Pb, Cu and Cd in 2012, the highest concentrations being registered in the southern sector of the Romanian Black Sea shore, where the anthropogenic pollution sources are represented by the harbour and wastewater treatment plants. The values of the bioaccumulation factors (BCFsed) shows that algae are good accumulators for Cu>Pb>Ni>Cr>Cd, in comparison with BCFwater where the order of heavy metal accumulation was different: Cr>Ni>Pb>Cd>Cu. Molluscs have higher bioconcentration factors for Cu and Cd for sediments and for Cu and Ni for water. Rapana venosa accumulated more Cd and Cu. For fishes, Pb, Cu and Ni had the highest values in the tissues of benthonic species Mullus barbatus. In bivalve molluscs and fishes, in the majority of cases, there were not recorded exceeding mean concentrations as compared to the maximum allowed concentrations for Cd and Pb. PMID- 25500721 TI - Age at menarche and non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: The goal of this study was to examine the association between age at menarche and non-alcoholic fatty liver disease (NAFLD) in Korean women and to explore whether any observed associations were mediated by adult adiposity. METHODS: A cross-sectional study was performed for 95,183 Korean women, aged 30 or older, who underwent a regular health screening examination between March 2011 and April 2013. Information regarding age at menarche was collected using standardized, self-administered questionnaires. The presence of fatty liver was determined using ultrasonographic findings. Poisson regression models with robust variance were used to evaluate the association between age at menarche and NAFLD. RESULTS: Of the 76,415 women evaluated in this study, 9601 had NAFLD. Age at menarche was inversely associated with the prevalence of NAFLD. In a multivariable-adjusted model, the prevalence ratios (95% CIs) for NAFLD comparing menarche at <12, 12, 14, 15, and 16-18 years to menarche at 13 years were 1.31 (1.18-1.45), 1.05 (0.97-1.13), 0.93 (0.87-0.99), 0.87 (0.82-0.93), and 0.78 (0.73 0.84), respectively (p for trend <0.001). Adjusting for adult BMI or percent fat mass (%) substantially reduced these associations; however, they remained statistically significant. The association between age at menarche and NAFLD was modified by age. CONCLUSIONS: We identified an inverse association between age at menarche and NAFLD in a large sample of middle-aged women. This association was partially mediated by adiposity. The findings of this study suggest that obesity prevention strategies are needed in women who undergo early menarche to reduce the risk of NAFLD. PMID- 25500722 TI - Reply to: "A scoring system for biliary atresia: Is this the right one?". PMID- 25500723 TI - A scoring system for biliary atresia: is this the right one? PMID- 25500724 TI - Structural insights into 5' flap DNA unwinding and incision by the human FAN1 dimer. AB - Human FANCD2-associated nuclease 1 (FAN1) is a DNA structure-specific nuclease involved in the processing of DNA interstrand crosslinks (ICLs). FAN1 maintains genomic stability and prevents tissue decline in multiple organs, yet it confers ICL-induced anti-cancer drug resistance in several cancer subtypes. Here we report three crystal structures of human FAN1 in complex with a 5' flap DNA substrate, showing that two FAN1 molecules form a head-to-tail dimer to locate the lesion, orient the DNA and unwind a 5' flap for subsequent incision. Biochemical experiments further validate our model for FAN1 action, as structure informed mutations that disrupt protein dimerization, substrate orientation or flap unwinding impair the structure-specific nuclease activity. Our work elucidates essential aspects of FAN1-DNA lesion recognition and a unique mechanism of incision. These structural insights shed light on the cellular mechanisms underlying organ degeneration protection and cancer drug resistance mediated by FAN1. PMID- 25500726 TI - Severe phenotypes in a Charcot-Marie-Tooth 1A patient with PMP22 triplication. AB - Charcot-Marie-Tooth disease (CMT) is a genetically and clinically heterogeneous hereditary motor and sensory neuropathy signified by a distal symmetric polyneuropathy. The most frequent subtype is type 1A (CMT1A) caused by duplication in chromosome 17p12 that includes PMP22. This study reports a woman with a family history of CMT1A due to PMP22 duplication. However, she presented with a more severe phenotype than her sibling or ancestors and was found to have a PMP22 triplication instead of the duplication. This was caused by de novo mutation on her affected mother's duplication chromosome. Her lower limb magnetic resonance imaging revealed severe diffused atrophy and fatty replacement. However, her affected sister with typical PMP22 duplication showed almost intact lower limb. Triplication patient's median motor nerve conduction velocity was far lower compared with her sister. Her onset age was faster (8 years) than her sister (42 years). CMT1A triplication might be generated by a female-specific chromosomal rearrangement mechanism that is different from the frequent paternal originated CMT1A duplication. It also suggests that the wide phenotypic variation of CMT1A might be partly caused by unstable genomic rearrangement, including PMP22 triplication. PMID- 25500727 TI - Does cardioplegia during cardiac surgery protect the heart at any time? PMID- 25500728 TI - Bacterial pericarditis as a fatal complication after endobronchial ultrasound guided transbronchial needle aspiration. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a safe and effective diagnostic tool for mediastinal evaluation. The guidelines for mediastinal evaluation of lung cancer were recently revised for both endoscopic procedures and surgical medical staging, and EBUS-TBNA is expected to be used more often in lung cancer diagnosis and staging. The major complication rate reported in previous meta-analyses is very low at 0.07-.15%; however, the mortality rate has not been reported. We present 2 cases of acute bacterial pericarditis after EBUS-TBNA, with 1 case resulting in mortality, and we discuss the appropriate management. PMID- 25500725 TI - Deep sequencing of RYR3 gene identifies rare and common variants associated with increased carotid intima-media thickness (cIMT) in HIV-infected individuals. AB - Carotid intima-media thickness (cIMT) is a subclinical measure of atherosclerosis with mounting evidence that higher cIMT confers an increased risk of cardiovascular disease. The ryanodine receptor 3 gene (RYR3) has previously been linked to increased cIMT; however, the causal variants have not yet been localized. Therefore, we sequenced 339,480 bp encompassing 104 exons and 2 kb flanking region of the RYR3 gene in 96 HIV-positive white men from the extremes of the distribution of common cIMT from the Fat Redistribution and Metabolic Changes in HIV infection study (FRAM). We identified 2710 confirmed variants (2414 single-nucleotide polymorphisms (SNPs) and 296 insertion/deletions (indels)), with a mean count of 736 SNPs (ranging from 528 to 1032) and 170 indels (ranging from 128 to 214) distributed in each individual. There were 39 variants in the exons and 15 of these were non-synonymous, of which with only 4 were common variants and the remaining 11 were rare variants, one was a novel SNP. We confirmed that the common variant rs2229116 was significantly associated with cIMT in this design (P<7.9 * 10(-9)), and observed seven other significantly associated SNPs (P<10(-8)). These variants including the private non-synonymous SNPs need to be followed up in a larger sample size and also tested with clinical atherosclerotic outcomes. PMID- 25500729 TI - Giant inguinal hernia: the challenging hug technique. AB - PURPOSE: Giant inguinoscrotal hernia are a real challenge for every kind of surgeon. The technique that we adopt is suggested as a good option to deal with this cases. We report our experience in five cases of giant inguinoscrotal hernia with loss of domain from 2005 to 2012. METHOD: Five patients with hernia that descended below the knees in the standing position, with an anteroposterior diameter not inferior to 30 cm and a laterolateral diameter of about 50 cm. Penis was not visible. We did the same procedure for all the five patients: single pararectus incision extended to groin region until proximal half of scrotum, isolation of the entire large sac out of the scrotal cavity, paying attention to not opening it, progressive reduction of the viscera without opening the sac with the hug technique, as shown in the video, placement of a heavyweight polypropylene meshes in the preperitoneal space, scrotal skin reductive plastic. In three of our five cases we obtained restoration of herniated viscera without resection of them. Orchiectomy was performed in all cases. RESULTS: No general neither wound complications were recorded. Long term follow up ranges from 8 years to 18 months: we did not record recurrence or chronic groin pain and scrotal size is normal in each patient. CONCLUSION: The technique proposed permits to treat with success giant inguinaoscrotal hernia, avoiding the use of further specific procedure such as the preoperative progressive pneumoperitoneum. All our patients were satisfied with the surgeries and their quality of daily life had definitely improved. PMID- 25500730 TI - A tetrahelical DNA fold adopted by tandem repeats of alternating GGG and GCG tracts. AB - DNA can form diverse higher-order structures, whose details are greatly dependent on nucleotide sequence. G-rich sequences containing four or more repeats of three guanines are expected to form G-quadruplexes. Here we show that DNA sequences with GGGAGCG repeats found in the regulatory region of the PLEKHG3 gene are capable of forming tetrahelical DNA structures that are distinct from G quadruplexes. The d(GGGAGCGAGGGAGCG) sequence, VK1, forms a dimer. Two VK1 sequences connected by an adenine residue, VK2, fold into a monomer, which shares identical structural characteristics with the VK1 fold. Their four-stranded architectures are stabilized by four G-C, four G-A and six G-G base pairs. No G quartets or Hoogsteen-type hydrogen-bonded guanine residues are present and the overall topology is conserved in the presence of Li(+), Na(+), K(+) and NH4(+) ions. Unique structural features include two edgewise loops on each side of the structure stabilized by three G-G base pairs in N1-carbonyl symmetric geometry. PMID- 25500734 TI - All-electrical deterministic single domain wall generation for on-chip applications. AB - Controlling domain wall (DW) generation and dynamics behaviour in ferromagnetic nanowire is critical to the engineering of domain wall-based non-volatile logic and magnetic memory devices. Previous research showed that DW generation suffered from a random or stochastic nature and that makes the realization of DW based device a challenging task. Conventionally, stabilizing a Neel DW requires a long pulsed current and the assistance of an external magnetic field. Here, we demonstrate a method to deterministically produce single DW without having to compromise the pulse duration. No external field is required to stabilize the DW. This is achieved by controlling the stray field magnetostatic interaction between a current-carrying strip line generated DW and the edge of the nanowire. The natural edge-field assisted domain wall generation process was found to be twice as fast as the conventional methods and requires less current density. Such deterministic DW generation method could potentially bring DW device technology, a step closer to on-chip application. PMID- 25500732 TI - On the failure load and mechanism of polycrystalline graphene by nanoindentation. AB - Nanoindentation has been recently used to measure the mechanical properties of polycrystalline graphene. However, the measured failure loads are found to be scattered widely and vary from lab to lab. We perform molecular dynamics simulations of nanoindentation on polycrystalline graphene at different sites including grain center, grain boundary (GB), GB triple junction, and holes. Depending on the relative position between the indenter tip and defects, significant scattering in failure load is observed. This scattering is found to arise from a combination of the non-uniform stress state, varied and weakened strengths of different defects, and the relative location between the indenter tip and the defects in polycrystalline graphene. Consequently, the failure behavior of polycrystalline graphene by nanoindentation is critically dependent on the indentation site, and is thus distinct from uniaxial tensile loading. Our work highlights the importance of the interaction between the indentation tip and defects, and the need to explicitly consider the defect characteristics at and near the indentation site in polycrystalline graphene during nanoindentation. PMID- 25500731 TI - MinCD cell division proteins form alternating copolymeric cytomotive filaments. AB - During bacterial cell division, filaments of the tubulin-like protein FtsZ assemble at midcell to form the cytokinetic Z-ring. Its positioning is regulated by the oscillation of MinCDE proteins. MinC is activated by MinD through an unknown mechanism and prevents Z-ring assembly anywhere but midcell. Here, using X-ray crystallography, electron microscopy and in vivo analyses, we show that MinD activates MinC by forming a new class of alternating copolymeric filaments that show similarity to eukaryotic septin filaments. A non-polymerizing mutation in MinD causes aberrant cell division in Escherichia coli. MinCD copolymers bind to membrane, interact with FtsZ and are disassembled by MinE. Imaging a functional msfGFP-MinC fusion protein in MinE-deleted cells reveals filamentous structures. EM imaging of our reconstitution of the MinCD-FtsZ interaction on liposome surfaces reveals a plausible mechanism for regulation of FtsZ ring assembly by MinCD copolymers. PMID- 25500735 TI - Digital quantum Rabi and Dicke models in superconducting circuits. AB - We propose the analog-digital quantum simulation of the quantum Rabi and Dicke models using circuit quantum electrodynamics (QED). We find that all physical regimes, in particular those which are impossible to realize in typical cavity QED setups, can be simulated via unitary decomposition into digital steps. Furthermore, we show the emergence of the Dirac equation dynamics from the quantum Rabi model when the mode frequency vanishes. Finally, we analyze the feasibility of this proposal under realistic superconducting circuit scenarios. PMID- 25500736 TI - pH-sensitive expression of calcium-sensing receptor (CaSR) in type-B intercalated cells of the cortical collecting ducts (CCD) in mouse kidney. AB - BACKGROUND: The localization and role of the calcium-sensing receptor (CaSR) along the nephron including the collecting ducts is still open to debate. METHODS: Using the quantitative, highly sensitive in situ hybridization technique and a double-staining immunohistochemistry technique, we investigated the axial distribution and expression of CaSR along the nephron in mice (C57B/6J) treated for 6 days with acid or alkali diets. RESULTS: Under control condition, CaSR was specifically localized in the cortical and medullary thick ascending limb of Henle's loop (CTAL and MTAL), macula densa (MD), distal convoluted tubule (DCT), and CCD (TALs, MD > DCT, CCD). Along the CCD, CaSR was co-localized with an anion exchanger type 4 (AE4), a marker of the basolateral membrane of type-B intercalated cell (IC-B) in mice. On the contrary, CaSR was not detected either in principal cells (PC) or in type-A intercalated cell (IC-A). CaSR expression levels in IC-B significantly (P < 0.005) decreased when mice were fed NH4Cl (acid) diets and increased when animals were given NaHCO3 (alkali) diets. As expected, cell heights of IC-A and IC-B significantly (P < 0.005) increased in the above experimental conditions. Surprisingly, single infusion (ip) of neomycin, an agonist of CaSR, significantly (P < 0.005) increased urinary Ca excretion without further increasing the hourly urine volume and significantly (P < 0.05) decreased urine pH. CONCLUSION: CaSR, cloned from rat kidney, was localized in the basolateral membrane of IC-B and was more expressed during alkali-loading. Its alkali-sensitive expression may promote urinary alkali secretion for body acid-base balance. PMID- 25500737 TI - Clinical significance of serum and urinary soluble urokinase receptor (suPAR) in primary nephrotic syndrome and MPO-ANCA-associated glomerulonephritis in Japanese. AB - BACKGROUND: The soluble urokinase receptor (suPAR) has been implicated as a cause of primary focal segmental glomerulosclerosis (FSGS). However, the clinical significance of suPAR in glomerular diseases currently remains unclear. METHODS: In this retrospective single-center cohort study, we investigated serum (s-) and urinary (u-) suPAR in patients with primary nephrotic syndrome (NS) (serum/urine: 37/32 cases) and MPO-ANCA-associated glomerulonephritis (ANCA-GN) (serum/urine: 13/11 cases). RESULTS: In pretreatment s- and u-suPAR, no significant differences were observed between the primary NS and ANCA-GN groups or among the pathological types of primary NS. An inverse correlation was noted between pretreatment s suPAR and eGFR in the primary NS and ANCA-GN groups. A positive correlation was noted between pretreatment u-suPAR and proteinuria in the primary NS group. Furthermore, time-course changes in s- and u-suPAR over 2 months after therapy were associated with the therapeutic responsiveness of primary NS, particularly the differentiation of MCNS from FSGS (s-suPAR: AUC-ROC = 0.905, p = 0.007; u suPAR: AUC-ROC = 0.816, p = 0.048). In the ANCA-GN group, a positive correlation was found between pretreatment s-suPAR and clinical severity or crescent formation, whereas u-suPAR was not correlated with these parameters. CONCLUSION: S- and u-suPAR after therapy may serve as clinical markers to judge the treatment response of untreated NS and differentiate MCNS from FSGS, but not in pretreatment patients. S-, but not u-suPAR may predict the severity of and crescent formation in ANCA-GN. PMID- 25500738 TI - RORalpha inhibits adipocyte-conditioned medium-induced colorectal cancer cell proliferation and migration and chick embryo chorioallantoic membrane angiopoiesis. AB - Lipid metabolic disturbances are related to many diseases, such as obesity, diabetes, and certain cancers. Notably, lipid metabolic disturbances have been reported to be a risk factor for colorectal cancer. Nuclear receptors act as ligand-dependent transcription regulators and play key roles in the regulation of body lipid metabolism and the development of many cancers. Retinoic acid receptor related orphan receptor alpha (RORalpha) is a nuclear receptor and can regulate several lipid metabolism genes in certain cancers. Herein, we demonstrate that the conditioned medium from adipocytes has a proproliferative and promigratory effect on colorectal cancer cells and enhances angiogenesis in chicken embryonic chorioallantoic membranes. In addition, the conditioned medium leads to a decrease in the expression of RORalpha and its target genes. Meanwhile, RORalpha and its target gene expressions are lower in human colorectal tumor tissue compared with control colorectal tissue. Activation of RORalpha inhibits the effect of conditioned medium on the proliferation and migration of colorectal cancer cells as well as the angiogenesis in chicken embryonic allantoic membranes. In colorectal cancer cells, the putative ligand of RORalpha, cholesterol sulfate (CS), prevents cell cycle progression at the G1/S boundary and concurrently modulates the expression of cell cycle-regulatory genes in colorectal cancer cell. CS inhibits angiogenesis in chicken embryonic chorioallantoic membranes and concurrently decreases the mRNA expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1alpha as well as the secretion of VEGF. In addition, lipogenic gene expression is higher in human colorectal tumor tissue compared with control colorectal tissue. CS inhibits the expression of lipogenic genes in colorectal cancer cells. These results suggest that RORalpha could represent a direct link between local lipid metabolism of colorectal tissue and colorectal cancer. Therefore, the reduction of the expression of RORalpha could represent a potential warning sign of colorectal cancer. PMID- 25500739 TI - Nestin-mediated cytoskeletal remodeling in endothelial cells: novel mechanistic insight into VEGF-induced cell migration in angiogenesis. AB - Nestin is highly expressed in poorly differentiated and newly formed proliferating endothelial cells (ECs); however, the role of this protein in angiogenesis remains unknown. Additionally, the cytoskeleton and associated cytoskeleton-binding proteins mediate the migration of vascular ECs. Therefore, the aim of the present study was to determine whether VEGF regulates the cytoskeleton, as well as other associated proteins, to promote the migration of vascular ECs. The coexpression of nestin and CD31 during angiogenesis in alkali burned rat corneas was examined via immunohistochemical analysis. Western blot analyses revealed that the exposure of human umbilical vein endothelial cells (HUVECs) to hypoxia promoted nestin expression in vitro. Additionally, nestin silencing via siRNA significantly inhibited many of the process associated with VEGF-induced angiogenesis, including tube formation and the migration and proliferation of HUVECs. Moreover, FITC-phalloidin labeling revealed that F-actin filaments were successfully organized into microfilaments in VEGF-treated cells, suggesting a network rearrangement accomplished via F-actin that contrasted with the uniform and loose actin filament network observed in the siRNA-nestin cells. The results of the present study highlight the key role played by nestin in activated HUVECs during angiogenesis. The inhibition of the ERK pathway suppressed the nestin expression induced by VEGF in the HUVECs. Therefore, our study provides the first evidence that nestin-mediated cytoskeleton remodeling in ECs occurs via filopodia formation along the cell edge, facilitating both filopodia localization and cell polarization and ultimately promoting HUVEC migration via VEGF induction, which may be associated with ERK pathway activation. PMID- 25500740 TI - Cyclin I and p35 determine the subcellular distribution of Cdk5. AB - The atypical cyclin-dependent kinase 5 (Cdk5) serves an array of different functions in cell biology. Among these are axonal guidance, regulation of intercellular contacts, cell differentiation, and prosurvival signaling. The variance of these functions suggests that Cdk5 activation comes to pass in different cellular compartments. The kinase activity, half-life, and substrate specificity of Cdk5 largely depend on specific activators, such as p25, p35, p39, and cyclin I. We hypothesized that the subcellular distribution of Cdk5 activators also determines the localization of the Cdk5 protein and sets the stage for targeted kinase activity within distinct cellular compartments to suit the varying roles of Cdk5. Cdk5 localization was analyzed in murine kidney and brain slices of wild-type and cyclin I- and/or p35-null mice by immunohistochemistry and in cultured mouse podocytes using immunofluorescence labeling, as well as cell fractionation experiments. The predominance of cyclin I mediates the nuclear localization of Cdk5, whereas the predominance of p35 results in a membranous localization of Cdk5. These findings were further substantiated by overexpression of cyclin I and p35 with altered targeting characteristics in human embryonic kidney 293T cells. These studies reveal that the subcellular localization of Cdk5 is determined by its specific activators. This results in the directed Cdk5 kinase activity in specific cellular compartments dependent on the activator present and allows Cdk5 to serve multiple independent roles. PMID- 25500741 TI - Cigarette smoke extract induces aberrant cytochrome-c oxidase subunit II methylation and apoptosis in human umbilical vascular endothelial cells. AB - Cigarette smoke-induced apoptosis of vascular endothelial cells contributes to the pathogenesis of chronic obstructive pulmonary disease. However, the mechanisms responsible for endothelial apoptosis remain poorly understood. We conducted an in vitro study to investigate whether DNA methylation is involved in smoking-induced endothelial apoptosis. Human umbilical vascular endothelial cells (HUVECs) were exposed to cigarette smoke extract (CSE) at a range of concentrations (0-10%). HUVECs were also incubated with a demethylating reagent, 5-aza-2'-deoxycytidinem (AZA), with and without CSE. Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and flow cytometry using annexin V-FITC/propidium iodide staining. We found that CSE treatment significantly increased HUVEC apoptosis in a dose- and time-dependent manner. Quantitative real-time RT-PCR and immunoblot revealed that CSE treatment decreased cytochrome-c oxidase subunit II (COX II) mRNA and protein levels and decreased COX activity. Methylation-specific PCR and direct bisulfite sequencing revealed positive COX II gene methylation. AZA administration partly increased mRNA and protein expressions of COX II, and COX activity decreased by CSE and attenuated the toxic effects of CSE. Our results showed that CSE induced aberrant COX II methylation and apoptosis in HUVECs. PMID- 25500743 TI - Uncoupling AMPK from autophagy: a foe that hinders the beneficial effects of metformin treatment on metabolic syndrome-associated atherosclerosis? Focus on "glucose and palmitate uncouple AMPK from autophagy in human aortic endothelial cells". PMID- 25500744 TI - Inhibition of local aldosterone by eplerenone reduces renal structural damage in a novel model of chronic cyclosporine A nephrotoxicity. AB - BACKGROUND AND OBJECTIVE: The fact that mineralocorticoid receptor antagonists reduce structural and functional alterations induced by cyclosporine A (CsA) indicates that aldosterone plays a key role in chronic CsA nephrotoxicity. We and other researchers have reported local renal aldosterone synthesis. To investigate local renal aldosterone's role in chronic CsA nephrotoxicity, we evaluated the effect of eplerenone (Epl) on renal structural damage and renal dysfunction in adrenalectomized (ADX) rats, and assessed whether the therapeutic benefit was associated with reduction of transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF), plasminogen activator inhibitor type 1 (PAI-1) and collagen I (COL-I) expression. METHODS: Male Sprague-Dawley rats fed a normal-sodium diet were divided in four groups: sham-ADX, ADX, CsA, or Epl. Rats in the ADX, CsA and Epl groups were adrenalectomized first. Aldosterone, sodium and potassium levels in serum and urine were measured on the second day. Two weeks later, vehicle (sham-ADX and ADX group), CsA (25mg/kg/d), or CsA and Epl (100 mg/ kg/d) combination was administrated, respectively. After six weeks, urinary protein, creatinine clearance (Ccr), tubulointerstitial fibrosis (TIF), aldosterone level in kidney, and renal aldosterone synthase CYP11B2, COL-I, TGF beta1, CTGF and PAI-1 gene expression levels were determined. RESULTS: On the second day after surgery, adrenalectomized rats showed undetectable aldosterone with natriuresis, hyponatremia, decreased urinary potassium excretion and hyperpotassemia. CsA reduced Ccr, induced urinary proteins and up-regulated COL I, TGF-beta1, CTGF and PAI-1 gene expression with a significant development of TIF. Eplerenone administration prevented TIF and COL-I, TGF-beta1 and PAI-1 up regulation but did not improve renal function. CONCLUSION: Our results suggest local renal aldosterone is an important mediator of renal injury induced by CsA. PMID- 25500742 TI - Comparative mechanisms of cancer cell migration through 3D matrix and physiological microtracks. AB - Tumor cell invasion through the stromal extracellular matrix (ECM) is a key feature of cancer metastasis, and understanding the cellular mechanisms of invasive migration is critical to the development of effective diagnostic and therapeutic strategies. Since cancer cell migration is highly adaptable to physiochemical properties of the ECM, it is critical to define these migration mechanisms in a context-specific manner. Although extensive work has characterized cancer cell migration in two- and three-dimensional (3D) matrix environments, the migration program employed by cells to move through native and cell-derived microtracks within the stromal ECM remains unclear. We previously reported the development of an in vitro model of patterned type I collagen microtracks that enable matrix metalloproteinase-independent microtrack migration. Here we show that collagen microtracks closely resemble channel-like gaps in native mammary stroma ECM and examine the extracellular and intracellular mechanisms underlying microtrack migration. Cell-matrix mechanocoupling, while critical for migration through 3D matrix, is not necessary for microtrack migration. Instead, cytoskeletal dynamics, including actin polymerization, cortical tension, and microtubule turnover, enable persistent, polarized migration through physiological microtracks. These results indicate that tumor cells employ context-specific mechanisms to migrate and suggest that selective targeting of cytoskeletal dynamics, but not adhesion, proteolysis, or cell traction forces, may effectively inhibit cancer cell migration through preformed matrix microtracks within the tumor stroma. PMID- 25500745 TI - Equity and efficiency preferences of health policy makers in China--a stated preference analysis. AB - BACKGROUND: Macroeconomic growth in China enables significant progress in health care and public health. It faces difficult choices regarding access, quality and affordability, while dealing with the increasing burden of chronic diseases. Policymakers are pressured to make complex decisions while implementing health strategies. This study shows how this process could be structured and reports the specific equity and efficiency preferences among Chinese policymakers. METHODS: In total, 78 regional, provincial and national level policymakers with considerable experience participated in a discrete choice experiment, weighting the relative importance of six policy attributes describing equity and efficiency. Results from a conditional logistic model are presented for the six criteria, measuring the associated weights. Observed and unobserved heterogeneities were incorporated and tested in the model. Findings are used to give an example of ranking health interventions in relation to the present disease burden in China. RESULTS: In general, respondents showed strong preference for efficiency criteria i.e. total beneficiaries and cost effectiveness as the most important attributes in decision making over equity criteria. Hence, priority interventions would be those conditions that are most prevalent in the country and cost least per health gain. CONCLUSION: Although efficiency criteria override equity ones, major health threats in China would be targeted. Multicriteria decision analysis makes explicit important trade-offs between efficiency and equity, leading to explicit, transparent and rational policy making. PMID- 25500746 TI - A comprehensive framework and key guideline recommendations for the provision of evidence-based breast cancer survivorship care within the primary care setting. AB - BACKGROUND: Breast cancer survivors continue to experience physical and psychosocial health care needs post-treatment. Primary care involvement is increasing as cancer centres move forward with earlier discharge of stable breast cancer survivors to primary care follow-up. Research suggests primary care providers (PCPs) are willing to provide survivorship care but many lack knowledge and confidence to provide evidence-based care. Although clinical practice guidelines (CPGs) exist for follow-up surveillance and certain aspects of survivorship care, no single comprehensive guideline addresses all significant breast cancer survivorship issues encountered in primary care. PURPOSE: The purpose of this research was to create a comprehensive clinical practice framework to guide the provision of breast cancer survivorship care in primary care settings. METHODS: This study consisted of an extensive search, appraisal and synthesis of CPGs for post-treatment breast cancer care using a modified Delphi method. Breast cancer survivorship issues and relevant CPGs were mapped to four essential components of survivorship care to create a comprehensive clinical practice framework to guide provision of breast cancer survivorship care. RESULTS: The completed framework consists of a one-page checklist outlining breast cancer survivorship issues relevant to primary care, a three-page summary of key recommendations and a one-page list of guideline sources. The framework and key guideline recommendations were verified by a panel of experts for comprehensiveness, importance and relevance to primary care. CONCLUSIONS: This framework may serve as a tool to remind PCPs about issues impacting breast cancer survivors, as well as the evidence-based recommendations and resources to provide the associated care. PMID- 25500747 TI - Reply to Letter: "Extracoporeal life support treatment bundle for refractory cardiac arrest". PMID- 25500749 TI - A statistical index for early diagnosis of ventricular arrhythmia from the trend analysis of ECG phase-portraits. AB - In this paper, we propose a novel statistical index for the early diagnosis of ventricular arrhythmia (VA) using the time delay phase-space reconstruction (PSR) technique, from the electrocardiogram (ECG) signal. Patients with two classes of fatal VA-with preceding ventricular premature beats (VPBs) and with no VPBs-have been analysed using extensive simulations. Three subclasses of VA with VPBs viz. ventricular tachycardia (VT), ventricular fibrillation (VF) and VT followed by VF are analyzed using the proposed technique. Measures of descriptive statistics like mean (u), standard deviation (sigma), coefficient of variation (CV = sigma/u), skewness (gamma) and kurtosis (beta) in phase-space diagrams are studied for a sliding window of 10 beats of the ECG signal using the box-counting technique. Subsequently, a hybrid prediction index which is composed of a weighted sum of CV and kurtosis has been proposed for predicting the impending arrhythmia before its actual occurrence. The early diagnosis involves crossing the upper bound of a hybrid index which is capable of predicting an impending arrhythmia 356 ECG beats, on average (with 192 beats standard deviation) before its onset when tested with 32 VA patients (both with and without VPBs). The early diagnosis result is also verified using a leave one out cross-validation (LOOCV) scheme with 96.88% sensitivity, 100% specificity and 98.44% accuracy. PMID- 25500748 TI - Out-of-hospital cardiac arrests in children and adolescents: incidences, outcomes, and household socioeconomic status. AB - BACKGROUND: There is insufficient knowledge of out-of-hospital cardiac arrest (OHCA) in the very young. OBJECTIVES: This nationwide study sought to examine age stratified OHCA characteristics and the role of parental socioeconomic differences and its contribution to mortality in the young population. METHODS: All OHCA patients in Denmark, <=21 years of age, were identified from 2001 to 2010. The population was divided into infants (<1 year); pre-school children (1-5 years); school children (6-15 years); and high school adolescents/young adults (16-21 years). Multivariate logistic regression analyses were used to investigate associations between pre-hospital factors and study endpoints: return of spontaneous circulation and survival. RESULTS: A total of 459 individuals were included. Overall incidence of OHCA was 3.3 per 100,000 inhabitants per year. The incidence rates for infants, pre-school children, school children and high school adolescents were 11.5, 3.5, 1.3 and 5.3 per 100,000 inhabitants. Overall bystander CPR rate was 48.8%, and for age groups: 55.4%, 41.2%, 44.9% and 63.0%, respectively. Overall 30-day survival rate was 8.1%, and for age groups: 1.4%, 4.5%, 16.1% and 9.3%, respectively. High parental education was associated with improved survival after OHCA (OR 3.48, CI 1.27-9.41). Significant crude difference in survival (OR 3.18, CI 1.22-8.34) between high household incomes vs. low household incomes was found. CONCLUSION: OHCA incidences and survival rates varied significantly between age groups. High parental education was found to be associated with improved survival after OHCA. PMID- 25500750 TI - Nioella nitratireducens gen. nov., sp. nov., a novel member of the family Rhodobacteraceae isolated from Azorean Island. AB - A novel Gram-negative, non-spore forming, rod-shaped aerobic bacterium, designated SSW136(T), was isolated from a surface seawater sample collected at Espalamaca (in Faial Island), Azores. Growth was found to occur from 10 to 37 degrees C, pH 6.0-8.0, and with 2-11 % of NaCl. 16S rRNA gene sequence indicated that the strain SSW136(T) belongs to the family Rhodobacteraceae. Strain SSW136(T) exhibited 96.3, 95.9, 95.7 and 95.5 sequence similarity to the type strains Oceanicola litoreus M-M22(T), Roseovarius aestuarii SMK-122(T), Marivita geojedonensis DPG-138(T), and Pseudoruegeria aquimaris SW-255(T) respectively. Neighbour-joining and maximum-parsimony phylogenetic trees based on 16S rRNA gene sequences revealed that strain SSW136(T) was affiliated to the family Rhodobacteraceae and formed a separate branch. The G+C content was 63.5 mol%. The major respiratory quinone was found to be Q-10. The polar lipids of strain SSW136(T) consisted of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, two unidentified aminolipids and three unidentified phospholipids. The major fatty acids were C18:1 omega7c (46.5 %), Cyclo-C19:0 omega8c (16.0 %) and C16:0 (12.8 %). On the basis of the morphological, genotypic, chemotaxonomic characteristics and low DNA-DNA relatedness, strain SSW136(T) is proposed to represent a novel genus and novel species, Nioella nitratireducens gen. nov., sp. nov., in the family Rhodobacteraceae. The type strain is SSW136(T) (=KCTC 32417(T) = NCIM 5499(T)). PMID- 25500751 TI - The impact of global budgets on pharmaceutical spending and utilization: early experience from the alternative quality contract. AB - In 2009, Blue Cross Blue Shield of Massachusetts implemented a global budget based payment system, the Alternative Quality Contract (AQC), in which provider groups assumed accountability for spending. We investigate the impact of global budgets on the utilization of prescription drugs and related expenditures. Our analyses indicate no statistically significant evidence that the AQC reduced the use of drugs. Although the impact may change over time, early evidence suggests that it is premature to conclude that global budget systems may reduce access to medications. PMID- 25500752 TI - Effects of changes in ownership of the Polish hospital on the patients' opinion about its functioning. AB - System changes in health care centers have been directed at introducing such marketing elements into the Polish health care system as managerial approach to managing the centers and contracting medical services and quality management. High quality of the medical services and patients' satisfaction became the key factors deciding about "the brand" of a health care center. The aim of the work was to assess the effect of changes in ownership of the hospital on the patients' opinion about its functioning. Patients' satisfaction survey was carried out through an anonymous questionnaire among 2702 respondents before and 2795 respondents after the transformation of the hospital. Multivariate analysis of variance (MANOVA) was used to analyze the collected empirical material. The assessment of the functioning of the admission center and hospital wards was significantly higher among the respondents asked after the transformation of the hospital as opposed to the assessment before it. Transforming the public hospital in Poland into a commercial company helped improve its functioning in the opinion of patients. There is a need to carry out further systematic research into the patients' satisfaction better adjust the hospital's offer to the needs of the hospitalized people. PMID- 25500753 TI - A news media analysis of the economic and reputational penalties of the hospital readmissions reduction program. AB - Section 3025 of the Affordable Care Act (ACA) of 2010 established the Hospital Readmissions Reduction Program (HRRP), an initiative designed to penalize hospitals with excess 30-day readmissions. This study investigates whether readmission penalties under HRRP impose significant reputational effects on hospitals. Data extracted from 2012 to 2013 news stories suggest that the higher the actual penalty, the higher the perceived cost of the penalty, the more likely it is that hospitals will state they have no control over the low-income patients they serve or that they will describe themselves as safety net providers. The downside of being singled out as a low-quality hospital deserving a relatively high penalty seems to be larger than the upside of being singled out as a high quality hospital facing a relatively low penalty. Although the financial burden of the penalties seems to be low, hospitals may be reacting to the fact that information about excess readmissions and readmission penalties is being released widely and is scrutinized by the news media and the general public. PMID- 25500754 TI - Varied differences in the health status between Medicare advantage and fee-for service enrollees. AB - This article examines the differences in mortality measured health status between the Medicare Advantage (MA) program and Fee-for-Service (FFS) program from 1999 to 2007. At the national level, differences in mortality rates were associated with MA market share. In some counties, enrollees in the MA program were 40% less likely to die than their peers in the FFS program, but in other counties, they were 20% more likely to die. Cost shifting between the two programs could bias county classifications of average FFS spending, and enlarged disparities in health status could make it difficult to evaluate risk adjusters. PMID- 25500756 TI - Outdoor solar UVA dose assessment with EBT2 radiochromic film using spectrophotometer and densitometer measurements. AB - Direct measurements of solar ultraviolet radiations (UVRs) have an important role in the protection of humans against UVR hazard. This work presents simple technique based on the application of EBT2 GAFCHROMIC((r)) film for direct solar UVA dose assessment. It demonstrates the effects of different parts of the solar spectrum (UVB, visible and infrared) on performed UVA field measurements and presents the measurement uncertainty budget. The gradient of sunlight exposure level permitted the authors to establish the mathematical relationships between the measured solar UVA dose and two measured quantities: the first was the changes in spectral absorbance at the wavelength 633 nm (A633) and the second was the optical density (OD). The established standard relations were also applied to calculate the solar UVA dose variations during the whole day; 15 min of exposure each hour between 8:00 and 17:00 was recorded. Results show that both applied experimental methods, spectrophotometer absorbance and densitometer OD, deliver comparable figures for EBT2 solar UVA dose assessment with relative uncertainty of 11% for spectral absorbance measurements and 15% for OD measurements. PMID- 25500755 TI - Unraveling regulatory mechanisms of atrial remodeling of mitral regurgitation pigs by gene expression profiling analysis: role of type I angiotensin II receptor antagonist. AB - Left atrial enlargement associated with mitral regurgitation (MR) predicts a poor prognosis. However, the underlying regulatory mechanisms of atrial remodeling remain unclear. We used high-density oligonucleotide microarrays and enrichment analysis to identify the alteration of RNA expression pattern and biological processes involved in the atrial remodeling of pigs with and without MR. Gene arrays from left atria tissues were compared in 13 pigs (iatrogenic MR pigs [n = 6], iatrogenic MR pigs treated with valsartan [n = 4], and pigs without MR [n = 3]). A total of 22 genes were differentially upregulated by altered fold change >2.0 (Log2FC > 1), and 49 genes were differentially downregulated by altered fold change <0.5 (Log2FC < -1) in the left atria of the MR pigs compared with the pigs without MR. Enrichment analysis showed that renin-angiotensin system was identified in the Kyoto Encyclopedia of Genes and Genomes pathway. Notably, 12 of the 22 upregulated genes were identified to be downregulated by valsartan and 10 of the 49 downregulated genes were identified to be upregulated by valsartan. The tissue concentrations of angiotensin II and gene expression of hypertrophic gene, myosin regulatory light chain 2, ventricular isoforms, and fibrosis-related genes were significantly increased in the MR pigs compared with pigs without MR. In conclusion, differentially expressed transcriptome and related biological pathways have been identified in the left atria of the MR pigs compared with pigs without MR. Additionally, some of the differentially expressed genes could be regulated by type I angiotensin II receptor blocker. PMID- 25500757 TI - Effects of prenatal exposure to single-wall carbon nanotubes on reproductive performance and neurodevelopment in mice. AB - Carbon nanotubes with extraordinary properties may become a novel drug and gene delivery tool in nanomedicine; however, insufficient information is available regarding their biosafety. Therefore, this work was performed to study the effect of prenatal exposure of single-walled carbon nanotubes (SWCNTs) on reproductive and neurobehavioral endpoints in mice. Thirty pregnant female mice were assigned to three groups (n = 10 for each group). The two treated groups were injected intraperitoneally (i.p.) with 1 or 10 mg/kg body weight (b.w.) of SWCNTs suspended in 1 ml of phosphate buffer saline (PBS) on gestational days 0 and 3. The control group was injected i.p. with an equal volume of PBS. The neurobehavioral ontogeny of pups was evaluated using a modified Fox battery. A decrease in litter size on postnatal day 2 was observed in the group treated with 10 mg/kg b.w. of SWCNTs whereas no significant differences between groups were observed in any other parameters. The behavioral development of pups did not show significant differences during growth except for the surface righting reflex, which showed significant delay compared to control in the group treated with 1 mg/kg b.w. SWCNTs. Moreover, exposed offspring (10 mg/kg b.w. SWCNTs) displayed enhanced anxiety in the elevated plus maze; however, other ethological analysis (Morris water maze and open field test) did not show behavioral changes in the experimental groups. In conclusion, the present results demonstrated small changes in offspring sensory and motor development following exposure to SWCNTs and support the idea that SWCNT risk assessment merits further investigation. PMID- 25500758 TI - Mercury contamination in some marine biota species from Khuzestan shore, Persian Gulf. AB - In this study, concentrations of mercury (Hg) were analyzed in some marine biota species (fish, shrimp, and crab) from Khuzestan shore, north part of the Persian Gulf. It was also our intention to evaluate potential risks to human health associated with seafood consumption. The results indicated that concentrations of Hg in the fish and crustacean were different among the species and tissues. Liver in fish and hepatopancreas in crustacean exhibited higher Hg concentration than the other tissues. The highest concentration of Hg was detected in Acanthopagrus latus liver (1.37 ug/g), followed by Labeo rohita (0.87 ug/g), Johnius belangerii (0.79 ug/g), and Barbus grypus (0.69 ug/g), respectively. Also the highest Hg concentrations were detected in shrimp species, Penaeus semisulcatus hepatopancreas (0.95 ug/g), followed by blue crab Portunus pelagicus (0.76 ug/g) and Metapenaues affinis (0.64 ug/g), respectively. The comparison indicated that benthic species were more contaminated than were other pelagic species. The results indicated that highest concentrations of Hg between different stations were detected in Musa estuary. The Hg concentration in all species were low than standards, expect in A. latus and P. semisulcatus collected from Musa estuary (S4). The variation in Hg levels among the species is likely to have resulted from metal bioavailability, changes in tissue composition, habitat,s and locations. PMID- 25500760 TI - Households with a stunted child and obese mother: trends and child feeding practices in a middle-income country, 1992-2008. AB - Middle-income countries in the intermediate stages of the nutrition transition are facing a complex picture of nutrition-related diseases with child stunting and maternal obesity coexisting within single households (SCOB). A debate exists as to whether SCOB is a true phenomenon or a statistical artefact. In this study, we examine time trends and determinants of SCOB in Egypt and test the hypothesis that increased child sugary snack consumption, and reduced fruit/vegetable consumption (markers of poor dietary diversity) are associated with SCOB. Data on 25,065 mothers and their children from the Egyptian Demographic and Health Surveys from 1992, 1995, 2005 and 2008 are used to examine trends in child stunting, maternal obesity and child-mother household type [normal/non-obese, stunted/non-obese, normal/obese, stunted/obese (SCOB)]. The association of child sugary snack and fruit/vegetable consumption with household type is also examined using multinomial logistic regression adjusting for maternal age, maternal education, child age, breastfeeding, household wealth and urban/rural residence. The prevalence of SCOB increased between the periods 1992/95 and 2005/08 despite reductions in stunting levels. This increase paralleled a rise in maternal obesity. Child sugary snack consumption was associated with higher odds (51 %) of belonging to a SCOB household compared with normal/non-obese households, while fruit/vegetable consumption was associated with lower odds (24 %). The results suggest the existence of a link between the rise in maternal obesity and an increase in SCOB, and an association between child sugary snack consumption and SCOB. Addressing SCOB may require a household-rather than individual-based approach to nutrition. PMID- 25500759 TI - Exposure to Violence, Posttraumatic Stress Symptoms, and Borderline Personality Pathology Among Adolescents in Residential Psychiatric Treatment: The Influence of Emotion Dysregulation. AB - Exposure to violence during adolescence is a highly prevalent phenomenon associated with a range of deleterious outcomes. Theoretical literature suggests that emotion dysregulation is one consequence of exposure to violence associated with the manifestation of posttraumatic stress symptoms (PTSS) and borderline personality (BP) pathology. Thus, the goal of the present study was to examine the mediating role of emotion dysregulation in the relation between exposure to violence and both PTSS and BP pathology in a sample of 144 adolescents (age 10- to 17-years; 51% male; 55% African American) admitted to a psychiatric residential treatment center. Exposure to violence was associated with greater emotion dysregulation, which, in turn, was associated with greater PTSS and BP pathology. Furthermore, emotion dysregulation mediated the associations between exposure to violence and both PTSS and BP pathology. Findings suggest the importance of assessing and treating emotion dysregulation among violence-exposed adolescents in psychiatric residential treatment. PMID- 25500765 TI - Current drug withdrawal strategy in prolactinoma patients treated with cabergoline: a systematic review and meta-analysis. AB - BACKGROUND: Cabergoline is a recommended first-line dopamine agonist for prolactinoma treatment, which is withdrawable for some cases. However, the optimal withdrawal strategy and the accurate recurrence rate associated with cabergoline withdrawal remains uncertain. OBJECTIVE: To assess the current recurrence rate of hyperprolactinemia and possible favorable factors associated with cabergoline withdrawal in prolactinoma patients. METHOD: The databases of PubMed, EMBASE, and Web of Science were searched up to May 2014 to identify studies containing data of recurrent hyperprolactinemia in prolactinoma patients after cabergoline withdrawal. Meta-analysis, including sensitivity analysis, meta regression analysis, and subgroup analysis were performed. RESULTS: When the patients who received cabergoline withdrawal were pooled, it was found that the hyperprolactinemia recurrence rate was 65% by a random effects meta-analysis [95% confidence interval 55-74%]. In a random effects meta-regression adjusting for optimal withdrawal strategies, CAB dose reduced to the lowest level before withdrawal was associated with treatment success (p = 0.006), whereas CAB treatment longer than 2 years showed no trend of effect (p = 0.587). Patients who received the lowest CAB dose and presented a significant reduction in tumor size before withdrawal were more likely to achieve the best success (p < 0.001). CONCLUSIONS: Our meta-analysis shows that hyperprolactinemia recurs after cabergoline withdrawal in a majority of patients. The probability of success favors patients who have achieved normoprolactinemia and considerable reduction in tumor size by low dose of cabergoline treatment. In addition, our study further suggests that a beneficial strategy is associated with tapering CAB dose before withdrawal but not with CAB treatment duration longer than 2 years. PMID- 25500761 TI - A web-based Italian survey of current trends, habits and beliefs in hemodynamic monitoring and management. AB - Significant evidence outlines that the management of the high-risk surgical patient with perioperative hemodynamic optimization leads to significant benefits. This study aimed at studying the current practice of hemodynamic monitoring and management of Italian anesthesiologists. An invitation to participate in a web-based survey was published on the web site of the Societa Italiana di Anestesia Analgesia Rianimazione Terapia Intensiva. Overall, 478 questionnaires were completed. The most frequently used monitoring techniques was invasive blood pressure (94.1 %). Cardiac output was used in 41.3% of the cases mainly throughout less-invasive methods. When cardiac output was not monitored, the main reason given was that other surrogate techniques, mainly central venous oxygen saturation (40.5%). Written protocols concerning hemodynamic management in high-risk surgical patients were used by the 29.1% of the respondents. 6.3% of the respondents reported not to be aware if such document was available at their institution. 86.3% of the respondents reported that they usually optimize high risk patients but to use blood flow assessment rarely (39.7%). The most used parameter in clinical practice to assess the effects of volume loading were an increase in urine output and arterial blood pressure together with a decrease in heart rate and blood lactates. The 45.1% or the respondents outlined that hemodynamic optimization in the high risk patients is of major clinical value. Our study outlines an important gap between available evidence and clinical practice emphasizing the need for a better awareness, more information and knowledge on the specific topic. PMID- 25500766 TI - Radiation Dosimetry Study of [(89)Zr]rituximab Tracer for Clinical Translation of B cell NHL Imaging using Positron Emission Tomography. AB - PURPOSE: We evaluated the dosimetry of [(89)Zr]rituximab, an anti-CD20 immunoPET tracer to image B cell non-Hodgkin's lymphoma (NHL) using a humanized transgenic mouse model that expresses human CD20 transgenic mice (huCD20TM). PROCEDURES: Rituximab was conjugated to desferrioxamine (Df) for radiolabeling of Zirconium 89. [(89)Zr]rituximab (2.8 +/- 0.2 MBq) was tail vein-injected into huCD20T mice. Positron emission tomography (PET)/CT imaging was performed on the two groups of mice (blocking = 2 mg/kg pre-dose of rituximab and non-blocking; n = 5) at eight time points (1, 4, 24, 48, 72, 96, 120, and 168 h) post injection. RESULTS: The novel [(89)Zr]rituximab PET tracer had good immunoreactivity, was stable in human serum, and was able to specifically target human CD20 in mice. The human equivalents of highest dose (mean +/- SD) organs with and without pre-dose are liver (345 +/- 284 MUSv/MBq) and spleen (1165 +/- 149 MUSv/MBq), respectively. CONCLUSIONS: Dosimetry of the human patient whole-body dose was found to be 145 MBq per annum, and the patient dose-limiting organ will be the liver (with rituximab pre-dose blocking) and spleen for non-blocking. The [(89)Zr]rituximab (t1/2 = 78.4 h) imaging of B cell NHL patients could permit the observation of targeting lesions in NHL patients over an extended period due to longer half-life as compared to the [(64)Cu] rituximab (t1/2 = 12.7 h). PMID- 25500767 TI - Exercises in anatomy: the normal heart. AB - In this series of videoclips, we analyze the anatomy of the normal heart. We begin our overview by emphasizing the need, in the current era, to describe the heart in attitudinally appropriate fashion. Increasingly, clinicians are demonstrating the features of the heart as it is located within the body. It is no longer satisfactory, therefore, to describe these components in a 'Valentine' fashion, as continues to be the case in most textbooks of normal or cardiac anatomy.We then emphasize the importance of the so-called morphological method, which states that structures within the heart should be defined on the basis of their own intrinsic morphology, and not according to other parts, which are themselves variable. We continue by using this concept to show how the appendages serve to distinguish between the atrial chambers, while the apical trabecular components provide the features to distinguish the ventricles. We then return to the cardiac chambers, emphasizing features of surgical significance, in particular the locations of the cardiac conduction tissues. We proceed by examining the cardiac valves, and conclude by providing a detailed analysis of the septal structures. PMID- 25500768 TI - Exercises in anatomy: tetralogy of Fallot. AB - It is axiomatic that those performing surgery on the congenitally malformed heart require a thorough knowledge of the lesions they will be called upon to correct. The necessary anatomical knowledge is becoming increasingly difficult to obtain at first hand, since relatively few centres now hold archives of specimens obtained in an appropriately legal fashion from the patients unfortunately dying in previous years. One centre with such an archive is Ann and Robert H. Lurie Children's Hospital in Chicago, known previously as Chicago Memorial Children's Hospital. The archive was established by Farouk S. Idriss, and was subsequently enhanced and consolidated by his son, Rachid. It is now under the care of Carl L. Backer, the current chief of paediatric cardiothoracic surgery at Lurie Children's. With the support of Carl, the archive has been triaged and catalogued by Diane E. Spicer and Robert H. Anderson. It has now been used to create a series of video presentations, illustrating the salient features of surgical anatomy of selected entities, with the videoclips being edited and prepared for publication by Anne Sarwark. This video contains the fruits of the first of these exercises in anatomy, and is devoted to tetralogy of Fallot.We begin the exercise by making comparisons between the normal heart and the arrangement seen in typical tetralogy. We emphasize the need to recognize the 'building blocks' of the normal outflow tracts, and show how they come apart in tetralogy. We then show the variations to be found in the specific morphology of the borders of the hole between the ventricles, with the crest of the apical ventricular septum being overridden by the orifice of the aortic valve such that the latter structure has a biventricular connection. We emphasize that it is the squeeze between the deviated muscular outlet septum and septoparietal trabeculations that is the essential phenotypic feature of the lesion. We then proceed to demonstrate the further variation to be found in the length of the outlet septum, which in extreme cases can be fibrous and hypoplastic rather than muscular. We also show how the ventriculo-arterial connection can vary from being concordant to becoming double outlet from the right ventricle. We conclude by emphasizing that the anatomy of tetralogy can also be recognized when the subpulmonary outflow tract is atretic rather than stenotic. PMID- 25500769 TI - Total thoracoscopic posterior basal segmentectomy for primary lung cancer. AB - This report introduces a hilar side approach for posterior basal segmentectomies by the process of specific vision thoracoscopic surgery, which has been used extensively for peripheral small lung cancer by the author. Although it requires a deeper understanding of hilar anatomy and fine control, it is safer and less invasive to the thoracic wall and results in less postoperative pain than the thoracotomy counterpart and as a hilar side approach allows for less deformation. The necessary order of processes involves specific vision, inflation-deflation and blunt dissection from the hilum. PMID- 25500770 TI - Comparison of endogenous loss and maintenance need for minerals in rainbow trout (Oncorhynchus mykiss) fed fishmeal or plant ingredient-based diets. AB - Mineral needs as affected by changes in dietary protein and oil sources were studied in rainbow trout. Duplicate groups (n = 30 fish per replicate) of rainbow trout (initial BW: 37 g) were fed either a fish meal/fish oil-based (M) or a complete plant ingredient (V)-based diet at four graded ration (R) levels [apparent satiation (AS), R75, R50 and R25 % of AS]; one treatment group was maintained under starvation. The feeding trial lasted 12 weeks at a water temperature of 17 degrees C. Dietary intake, apparent digestibility and initial and final whole-body composition data were used to calculate mineral gain which was regressed against digestible mineral intake (both expressed as mg or ug kg( 0.8) day(-1)). Starvation loss (SL), endogenous loss of fed fish (ELF, y intercept at x = 0) and point of intake for zero balance (PZB, x-intercept at y = 0) were used as estimates of maintenance requirements. SL provided the lowest estimate, ELF provided the net requirement of a mineral for maintenance and PZB provided the digestible dietary intake required to meet maintenance (SL < ELF < PZB). Dietary ingredient composition did not significantly affect the digestible mineral supply required for maintenance (PZB) for any of the minerals (P, Mg, K, Cu and Zn) studied. However, ELF of micro-minerals such as Cu and Zn were significantly affected. The ELF of Cu was significantly lower and that of Zn was significantly higher in V group compared with M-fed fish. Further studies on the effects of such changes in dietary formulations on micro-mineral metabolism are warranted. PMID- 25500773 TI - The JNK-like MAPK KGB-1 of Caenorhabditis elegans promotes reproduction, lifespan, and gene expressions for protein biosynthesis and germline homeostasis but interferes with hyperosmotic stress tolerance. AB - AIMS: This study focused on the role of the JNK-like MAPK (mitogen-activated protein kinase) KGB-1 (kinase, GLH-binding 1) for osmoprotection and other vital functions. METHODS: We mapped KGB-1 expression patterns and determined lifespan, reproduction and survival rates as well as changes in body volume, motility, and GPDH (glycerol-3-phosphate dehydrogenase) activity for glycerol production in wildtype (WT), different signaling mutants (including a kgb-1 deletion mutant, kgb-1?) and RNAi-treated worms under control and hyperosmotic conditions. KGB-1 mediated gene expressions were studied, for instance, by RNA Sequencing, with the resulting transcriptome data analyzed using orthology-based approaches. RESULTS: Surprisingly, mutation/RNAi of kgb-1 and fos-1 (gene for an AP-1, activator protein 1, element) significantly promoted hyperosmotic resistance, even though hyperosmotic GPDH activity was higher in WT than in kgb-1?. KGB-1 and moderate hyperosmolarity promoted and severe hyperosmolarity repressed kgb-1, fos-1, and jun-1 (gene for another AP-1 element) expression. Transcriptome profiling revealed, for instance, down-regulated genes for protein biosynthesis and up regulated genes for membrane transporters in kgb-1? and up-regulated genes for GPDH-1 or detoxification in WT, with the latter indicating cellular damage and less effective osmoprotection in WT. CONCLUSION: KGB-1 promotes reproduction and lifespan and fosters gene expressions for AP-1 elements, protein biosynthesis, and balanced gametogenesis, but inhibits expressions for membrane transporters perhaps in order to control energy consumption. Reduced protein biosyntheses and enhanced membrane transports in kgb-1? most likely contribute to the high hyperosmotic tolerance of the mutant by easing the burden of the existing chaperone machinery and promoting regulatory volume increases upon hyperosmotic stress. PMID- 25500772 TI - Priority setting partnership to identify the top 10 research priorities for the management of Parkinson's disease. AB - OBJECTIVES: This priority setting partnership was commissioned by Parkinson's UK to encourage people with direct and personal experience of the condition to work together to identify and prioritise the top 10 evidential uncertainties that impact on everyday clinical practice for the management of Parkinson's disease (PD). SETTING: The UK. PARTICIPANTS: Anyone with experience of PD including: people with Parkinson's (PwP), carers, family and friends, healthcare and social care professionals. Non-clinical researchers and employees of pharmaceutical or medical devices companies were excluded. 1000 participants (60% PwP) provided ideas on research uncertainties, 475 (72% PwP) initially prioritised them and 27 (37% PwP) stakeholders agreed a final top 10. METHODS: Using a modified nominal group technique, participants were surveyed to identify what issues for the management of PD needed research. Unique research questions unanswered by current evidence were identified and participants were asked to identify their top 10 research priorities from this list. The top 26 uncertainties were presented to a consensus meeting with key stakeholders to agree the top 10 research priorities. RESULTS: 1000 participants provided 4100 responses, which contained 94 unique unanswered research questions that were initially prioritised by 475 participants. A consensus meeting with 27 stakeholders agreed the top 10 research priorities. The overarching research aspiration was an effective cure for PD. The top 10 research priorities for PD management included the need to address motor symptoms (balance and falls, and fine motor control), non-motor symptoms (sleep and urinary dysfunction), mental health issues (stress and anxiety, dementia and mild cognitive impairments), side effects of medications (dyskinesia) and the need to develop interventions specific to the phenotypes of PD and better monitoring methods. CONCLUSIONS: These research priorities identify crucial gaps in the existing evidence to address everyday practicalities in the management of the complexities of PD. PMID- 25500774 TI - A technical perspective for understanding quantitative arterial spin-labeling MR imaging using Q2TIPS. AB - We illustrate the fundamental theoretical principles of arterial spin-labeling (ASL) magnetic resonance imaging (MRI) and show a system that employs the second version of quantitative imaging of perfusion using a single subtraction (Q2TIPS) to quantify cerebral blood flow (CBF). We also discuss the effects of the parameters used in Q2TIPS on CBF values as measured with ASL-MRI. PMID- 25500775 TI - MR imaging-based evaluation of morphological changes in the uterus and ovaries of patients following neoadjuvant chemotherapy for cervical cancer. AB - OBJECTIVE: We used magnetic resonance (MR) imaging and hormonal levels to evaluate the influence of chemotherapy for cervical cancer on female pelvic reproductive organs. MATERIALS AND METHODS: We retrospectively evaluated 16 pre- and 11 postmenopausal patients with cervical cancer who underwent neoadjuvant chemotherapy (NACT) and radical surgery. We evaluated morphological changes in the uterus and ovaries by MR imaging both quantitatively and qualitatively, measuring the volume of the uterine body and bilateral ovaries, endometrial thickness, and signal intensity of the myometrium and bilateral ovaries and assessing visibility of the junctional zone and bilateral ovarian follicles. We compared both quantitative and qualitative factors between pre- and post-NACT. Pre- and post-NACT hormonal values of estradiol, progesterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH) of 8 patients in the premenopausal group were obtained and analyzed statistically. RESULTS: In the premenopausal group, we observed a statistically significant decrease in all quantitative parameters as well as in the visibility of the left ovarian follicle. In the postmenopausal group, only endometrial thickness changed significantly. Premenopausal patients showed a statistically significant decrease in levels of progesterone, FSH, and LH after chemotherapy. CONCLUSIONS: MR demonstrated changes in the uterus and ovaries in premenopausal subjects who underwent chemotherapy that resembled those changes classically reported in physiological postmenopausal subjects. These changes are likely due to ovarian toxicity and secondary hormonal changes. MR imaging might be a valuable tool for obtaining information regarding chemotherapy-induced infertility. PMID- 25500777 TI - Cerebral relaxation times from postmortem MR imaging of adults. AB - PURPOSE: We measured T1 and T2 values of cerebral postmortem magnetic resonance (PMMR) imaging and compared the data of cadavers with that of living human subjects. MATERIALS AND METHODS: We performed PMMR imaging of the brains of 30 adults (22 men, 8 women; mean age, 58.2 years) whose deaths were for reasons other than brain injury or disease at a mean of 29.4 hours after death. Before imaging, the bodies were kept in cold storage at 4 degrees C (mean rectal temperature, 15.6 degrees C). We measured T1 and T2 values in the brain bilaterally at 5 sites (bilateral caudate nucleus, putamen, thalamus and gray matter and white matter of the frontal lobe) and compared the data of PMMR imaging with that from MR imaging of the corresponding sites in 24 healthy volunteers (9 men, 15 women; mean age, 51.8 years). We also investigated the influence of body temperature on T1 and T2 values. RESULTS: Compared with MR imaging findings in the living subjects, PMMR imaging showed significantly shorter T1 values in the caudate nucleus, putamen, thalamus and gray matter and white matter of the frontal lobe and significantly longer T2 values in the gray matter and white matter of the frontal lobe; T2 values in the caudate nucleus, putamen, and thalamus showed no such differences. T1 values correlated significantly with body temperature in all 5 brain sites measured, but T2 values did not. CONCLUSION: Compared with findings of cerebral MR imaging in living adult subjects, those of PMMR imaging tended to demonstrate shorter T1 values and longer T2 values. We attribute this to increased water content of tissue, reduced pH, and reduced body temperature after death. PMID- 25500776 TI - Structure and Size-selective Permeability of the Synovial Membrane of the Temporomandibular Joint of the Mouse Measured by MR Imaging at 7T. AB - PURPOSE: We analyzed the anatomical structure of the temporomandibular joint (TMJ) and molecular weight dependency of synovial membrane permeability in mice using 7-tesla magnetic resonance (MR) imaging. METHODS: We obtained 3-dimensional (3D) T1-weighted gradient echo (3D-T1W) and 3D T2-weighted rapid acquisition with relaxation enhancement (3D-T2W RARE) MR images of the TMJ of male C57BL6 mice with voxel resolution of 65 um. Two-dimensional (2D) T1w images were measured every 45 s before and after bolus intravenous (IV) injection of contrast reagents: gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA; 0.5 kDa); oligomer-based contrast agent (CH3-DTPA-Gd; 2.1 kDa); gadolinium-labeled polylysine (Gd-polylysine; 10 kDa); and gadolinium-labeled albumin (Gd-albumin; 74 kDa). RESULTS: T1W images depicted the temporal bone and mandibular condyle as regions with lower signal intensity and the disc as a region of intermediate intensity. In the Gd-DTPA-enhanced T1W and T2W images, the articular disc could be identified as a region with lower signal intensity than that of the upper and lower joint cavities. After IV injection of Gd-DTPA or CH3-DTPA-Gd, the signal intensity of the joint cavities increased within 10 min, but this increase was not shown with Gd-polylysine and Gd-albumin. CONCLUSION: The structural findings obtained by MR imaging agreed with those obtained by hematoxylin-eosin staining under light microscopy. Contrast-enhanced MR imaging suggested that smaller (<2.1 kDa) but not larger (>10 kDa) molecules can permeate the synovial membrane. Our results suggest the utility of MR imaging for analyzing the structure of the TMJ as well as permeability of the synovial membrane. PMID- 25500778 TI - Time course of osteonecrosis in rabbit articular intercalated bone: line scan spectroscopic imaging and correlation with histology. AB - PURPOSE: Magnetic resonance (MR) imaging offers the highest sensitivity for detecting bone necrosis. We evaluated osteonecrosis in rabbit models by calculating the percentage of fat to (fat + water) [F/(F+W)] on MR spectroscopy (MRS) and compared MR spectroscopy and imaging findings with corresponding histological results. METHODS: To model the natural course of articular osteonecrosis, we removed the fourth tarsal bone in 45 rabbits, froze it for 5 min in liquid nitrogen to produce complete cellular necrosis, and then replaced the bone into the knee joint. We performed Carr-Purcell-Meiboom-Gill proton spectroscopic imaging to assess necrotic bone at 3 days and one, 2, 3, 4, 8, 12, 16, and 20 weeks after osteonecrosis and calculated the percentage of F/(F+W) of each bone. We also performed conventional T1- and T2-weighted imaging and compared all data to histological findings to analyze the natural course of necrosis. RESULTS: T1-weighted MR imaging demonstrated obvious low signal intensity at 2 to 8 weeks and recovery at 12 to 20 weeks, whereas T2-weighted imaging demonstrated inconsistent intensities throughout the period. The postoperative percentage of F/(F+W) measured using line scan MRS decreased to 8.88% at 3 weeks, 6.22% at 8 weeks, and 34.40% at 20 weeks results that were mostly consistent with MR imaging findings. Histological findings demonstrated complete absence of osteocyte nuclei and loss of osteoid-osteogenesis at 3 to 8 weeks. Recovery of bone marrow was identified as an increase in the area of fat after 12 weeks. CONCLUSION: Osteonecrosis delineated by T1-weighted MR imaging demonstrated fat content in the bone marrow that correlated with histology. The present MRS modality can be used to calculate the percentage of F/(F+W) of osteonecrosis to enable objective assessment of recovery and quantification of osteonecrosis to provide a numerical value for osteonecrosis. PMID- 25500779 TI - N-acetylaspartate decrease in acute stage of ischemic stroke: a perspective from experimental and clinical studies. AB - N-acetylaspartate (NAA) appears in a prominent peak in proton magnetic resonance spectroscopy ((1)H-MRS) of the brain. Exhibition by NAA of time-dependent attenuation that reflects energy metabolism during the acute stage of cerebral ischemia makes this metabolite a unique biomarker for assessing ischemic stroke. Although magnetic resonance (MR) imaging is a powerful technique for inspecting the pathological changes that occur during ischemic stroke, biomarkers that directly reflect the drastic metabolic changes associated with acute-stage ischemia are strongly warranted for appropriate therapeutic decision-making in daily clinical settings. In this review, we provide a brief overview of NAA metabolism and focus on the use of attenuation in NAA as a means for assessing the pathophysiological changes that occur during the acute stage of ischemic stroke. PMID- 25500780 TI - Optimal Imaging Parameters for Readout-segmented EPI of the Temporal Bone. AB - Readout-segmented echo planar imaging (rs-EPI) is a form of multi-shot EPI. rs EPI is affected less by susceptibility artifacts than single-shot EPI (ss-EPI), which is widely used for diffusion-weighted imaging, so rs-EPI is expected to produce less image distortion. In this study, we compared rs-EPI and conventional ss-EPI of the temporal bone region, which contains abundant amounts of air and frequently exhibits changes in magnetic susceptibility. In addition, we used a phantom to determine the optimum rs-EPI acquisition conditions for clinical use and investigated the clinical utility of rs-EPI in 20 patients (8 men, 12 women, mean age, 54.3 +/- 16.7-years-old) with cholesteatoma (mean apparent diffusion coefficient on ss-EPI, 0.88 * 10(-3) +/- 0.18 mm(2)/s). The images of the temporal bone region produced using rs-EPI exhibited less distortion than those obtained with ss-EPI (P < 0.05). PMID- 25500782 TI - Imaging of endolymphatic hydrops in 10 minutes: a new strategy to reduce scan time to one third. AB - We measured the size of the endolymph using a newly proposed 10-min magnetic resonance (MR) imaging protocol and compared values with those of the previously reported 31- and 17-min protocols in 15 patients. Values for the 3 protocols did not differ significantly in either the cochlea or vestibule. Correlation among the 3 protocols was strong or relatively strong. Evaluation of endolymphatic hydrops is feasible using the newly proposed 10-min protocol. PMID- 25500781 TI - Intracranial Hemorrhage and Tortuosity of Veins Detected on Susceptibility weighted Imaging of a Child with a Type IV Collagen alpha1 Mutation and Schizencephaly. AB - Type IV collagen alpha1 (COL4A1) forms a sheet-like network beneath the endothelium and surrounding smooth muscle cells. Associations of mutations in COL4A1 with porencephaly, schizencephaly, and intracranial hemorrhages are known. We report susceptibility-weighted imaging (SWI) findings showing hemorrhages in the peripheral portion of the region of schizencephaly, intraparenchymal hemorrhages, and tortuosity of the intracranial veins in a child with a COL4A1 mutation. SWI findings may be helpful for understanding the possible relationship between schizencephaly and COL4A1 mutations. PMID- 25500783 TI - The benefits of revascularization in chronic heart failure. AB - Recent efforts have reduced the mortality from coronary artery disease (CAD), with the consequent increase in heart failure with reduced left ventricular function, referred to as ischaemic cardiomyopathy (ICM). As ischemic left ventricular (LV) dysfunction may be partially or completely reversible by revascularization in the presence of viable myocardium, the assessment of myocardial viability is central to the management of ICM. Decades of observational analyses have provided positive evidence for the role of revascularization in hibernating myocardium in improving survival. However, recently the Surgical Treatment for Ischaemic Heart Failure (STICH) trial has challenged this notion, highlighting the noninferiority of optimal medical therapy (OMT) over revascularization and OMT. In this review, we discuss noninvasive imaging modalities to assess myocardial viability and the impact of myocardial viability on revascularization. We critically appraise the STICH trial and suggest an algorithm for viability testing before revascularization in patients with ICM and significant LV dysfunction. PMID- 25500784 TI - Contrast extravasation into the right upper extremity. PMID- 25500785 TI - Minnesota's Early Experience with Medical Home Implementation: Viewpoints from the Front Lines. AB - BACKGROUND: Evidence is evolving about the impact of patient-centered medical homes (PCMHs) on important outcomes in primary care. Minnesota has developed its own PCMH certification process, envisioned as an all-payer initiative with an emphasis on patient-centeredness, which may add unique experiences and outcomes to the national discussion. OBJECTIVE: We aimed to identify the facilitators and barriers encountered by nine diverse primary care practices selected from the first 80 to achieve PCMH certification in Minnesota. DESIGN: This was a qualitative analysis of semi-structured, in-person interviews. PARTICIPANTS: Thirty-one administrative and clinical leaders, including clinic managers, physician champions, medical directors, nursing supervisors, and care coordinators participated in the study. KEY RESULTS: Six factors emerged as most important to the efforts to become PMCHs: leadership support, organizational culture, finances, quality improvement (QI) experience, information technology (IT) resources, and patient involvement. Facilitators included committed leadership at local and higher levels, prior experience and ongoing support for QI initiatives, and adequate financial and IT resources. Reimbursement was a significant barrier due to perceived inadequacy and inconsistent participation by health plans. The unsuitability of electronic medical records (EMRs) to PCMH documentation requirements likewise presented ongoing challenges. Many interviewees described patient input as helpful to their clinics' PCMH-related changes and were enthusiastic about their "patient partners." The majority of interviewees felt that becoming a PCMH was right for patients and was personally worthwhile, even while acknowledging the tremendous effort involved and voicing skepticism about reimbursement over the short term. CONCLUSIONS: The experience of participants in Minnesota's state-wide initiative to legislate PCMH transformation provides a broad view of facilitators and barriers. Unique facilitators included a requirement for patient involvement, which pushed practices to create patient-centered innovations, and new reimbursement models based on quality indicators for a population. Among barriers were the costs to practices and patients, and EMRs that failed to accommodate PCMH requirements. PMID- 25500786 TI - TRANSFORM-ing patient safety culture: a universal imperative. PMID- 25500788 TI - Surfactant proteins A, B, C and D in the human nasal airway: associated with mucosal glands and ciliated epithelium but absent in fluid-phase secretions and mucus. AB - AIMS: To investigate the presence of surfactant protein (SP) A, B, C and D in nasal airways and to determine whether the proteins exert their main functions in nasal secretions or in the deeper layers of the nasal mucosa. METHODS: Volunteers were recruited from the Department of ENT Head and Neck Surgery, Odense University Hospital, Denmark. The study included 39 subjects. Nasal mucosal biopsies were analyzed by immunohistochemistry, and bronchoalveolar and nasal lavages, nasal brush biopsies and nasal mucus were analyzed for SP-A, -B, -C and D by SDS-PAGE and Western blotting. The presence of SP-A and SP-D in the first three samplings were also analyzed by enzyme-linked immunosorbent assay. RESULTS: In nasal mucosal biopsies, SP-A, -B, -C and -D were all demonstrated in the serous acini of the submucosal glands and in the surface epithelium. SP-D was detected in nasal brush biopsies, whereas the other SPs were absent. Moreover, SP A, -B, -C and -D were absent in nasal lavage and mucus. CONCLUSION: SP-A, -B, -C and -D exert their protective effect in the ductal epithelium of the submucosal glands rather than in nasal secretions and mucus. Further studies are required to clarify the functions of these proteins in nasal secretory pathways for understanding upper airway diseases. PMID- 25500787 TI - Can phone-based motivational interviewing improve medication adherence to antiplatelet medications after a coronary stent among racial minorities? A randomized trial. AB - BACKGROUND: Minorities have lower adherence to cardiovascular medications and have worst cardiovascular outcomes post coronary stent placement OBJECTIVE: The aim of this study is to compare the efficacy of phone-delivered Motivational Interviewing (MINT) to an educational video at improving adherence to antiplatelet medications among insured minorities. DESIGN: This was a randomized study. PARTICIPANTS: We identified minorities with a recently placed coronary stent from an administrative data set by using a previously validated algorithm. INTERVENTIONS: MINT subjects received quarterly phone calls and the DVD group received a one-time mailed video. MAIN MEASURES: Outcome variables were collected at baseline and at 12-month post-stent, using surveys and administrative data. The primary outcome was antiplatelet (clopidogrel and prasugrel) adherence measured by Medication Possession Ratio (MPR) and self- reported adherence (Morisky score). We also measured appropriate adherence defined as an MPR >= 0.80. KEY RESULTS: We recruited 452 minority subjects with a new coronary stent (44 % Hispanics and 56 % Black). The patients had a mean age of 69.5 +/- 8.8, 58 % were males, 78 % had an income lower than $30,000 per year and only 22 % had achieved high school education or higher. The MPR for antiplatelet medications was 0.77 for the MINT group compared to 0.70 for the DVD group (p < 0.05). The percentage of subjects with adequate adherence to their antiplatelet medication was 64 % in the MINT group and 50 % in the DVD group (p < 0.01). Self-reported adherence at 12 months was higher in the MINT group compared to the DVD group (p < 0.01). Results were similar among drug-eluting stent (DES) recipients. CONCLUSIONS: Among racial minorities, a phone-based motivational interview is effective at improving adherence to antiplatelet medications post coronary stent placement. Phone-based MINT seems to be a promising and cost-effective strategy to modify risk behaviors among minority populations at high cardiovascular risk. PMID- 25500789 TI - Activating autoantibodies to the beta1/2-adrenergic and M2 muscarinic receptors associate with atrial tachyarrhythmias in patients with hyperthyroidism. AB - We have previously demonstrated that activating autoantibodies to beta1 adrenergic receptor (beta1AR) and M2 muscarinic receptor (M2R) facilitate atrial fibrillation (AF) in patients with Graves' disease (GD). The objectives of this expanded study were to examine the prevalence of beta1AR, beta2AR, and M2R autoantibodies in hyperthyroidism subjects. Sera from 81 patients including 31 with GD and AF, 36 with GD and sinus rhythm, 9 with toxic multinodular goiter, 5 with subacute thyroiditis, and 10 control subjects were examined for these autoantibodies by ELISA. Sera from 20 ELISA-positive GD subjects, 10 with AF and 10 with sinus rhythm, were assayed for autoantibody bioactivity using cell-based bioassays. In patients with GD and AF, 45, 65, and 77 % were ELISA positive for beta1AR, M2R, and beta2AR autoantibodies, respectively. In patients with GD and sinus rhythm, 17, 39, and 75 % were ELISA positive for beta1AR, M2R, and beta2AR autoantibodies, respectively. beta1AR and M2R autoantibodies were co-present in 39 % of patients with GD and AF compared to 14 % in GD with sinus rhythm (p = 0.026). Patients with toxic multinodular goiter or subacute thyroiditis had a low prevalence of autoantibodies. The mean beta1AR and M2R autoantibody activity was elevated in both GD groups but higher in those with AF than those with sinus rhythm. beta2AR autoantibody activity was also increased in both groups. In conclusion, beta1AR, beta2AR, and M2R autoantibodies were elevated in GD. beta1AR and M2R autoantibodies appear to be related to concurrent AF, while beta2AR autoantibodies were equally prevalent in those with a sinus tachycardia and those with AF. PMID- 25500790 TI - Molecular analysis of PROP1, POU1F1, LHX3, and HESX1 in Turkish patients with combined pituitary hormone deficiency: a multicenter study. AB - To investigate the specific mutations in PROP1, POU1F1, LHX3, and HESX1 genes in patients with combined pituitary hormone deficiency (CPHD) in Turkey. Seventy-six patients with CPHD were included in this study. Based on clinical, hormonal, and neuro-radiological data, relevant transcription factor genes were evaluated by Sanger sequencing and multiplex ligation-dependent probe amplification. Total frequency of mutations was 30.9 % in patients with CPHD. Frequency was significantly higher in familial patients (p = 0.001). Three different types of mutations in PROP1 gene (complete gene deletion, c.301-302delAG, a novel mutation; IVS1+2T>G) were found in 12 unrelated patients (21.8 %). Mutations in PROP1 gene were markedly higher in familial than in sporadic cases (58.8 vs. 5.3 %, p < 0.001). Homozygous complete gene deletion was the most common mutation in PROP1 gene (8/12) and was identified in six familial patients. Four different homozygous mutations [p.Q4X, novel mutations; exons 1-2 deletion, p.V153F, p.I244S] were detected in POU1F1 gene. Central precocious puberty was firstly observed in a sporadic-male patient with homozygous POU1F1 (p.I244S) mutation. A homozygous mutation in HESX1 gene (p.R160H) was detected in one patient. This study is the first to investigate specific mutations in CPHD patients in Turkey. Complete deletion in PROP1 gene was the most common mutation encountered in patients with CPHD. We believe that the results of this study will contribute to the establishment of genetic screening strategies in Turkey, as well as to the studies on phenotype-genotype correlations and early diagnosis of CPHD patients. PMID- 25500793 TI - Unusual electronic properties of clean and disordered zigzag graphene nanoribbons. AB - We revisit the problem of electron transport in clean and disordered zigzag graphene nanoribbons, and expose numerous hitherto unknown peculiar properties of these systems at zero energy, where both sublattices decouple because of chiral symmetry. For clean ribbons, we give a quantitative description of the unusual power-law dispersion of the central energy bands and of its main consequences, including the strong divergence of the density of states near zero energy, and the vanishing of the transverse localization length of the corresponding edge states. In the presence of off-diagonal disorder, which respects the lattice chiral symmetry, all zero-energy localization properties are found to be anomalous. Recasting the problem in terms of coupled Brownian motions enables us to derive numerous asymptotic results by analytical means. In particular the typical conductance gN of a disordered sample of width N and length L is shown to decay as exp(-CNw?L), for arbitrary values of the disorder strength w, while the relative variance of ln gN approaches a non-trivial constant KN. The dependence of the constants CN and KN on the ribbon width N is predicted. From the mere viewpoint of the transfer-matrix formalism, zigzag ribbons provide a case study with many unusual features. The transfer matrix describing propagation through one unit cell of a clean ribbon is not diagonalizable at zero energy. In the disordered case, we encounter non-trivial random matrix products such that all Lyapunov exponents vanish identically. PMID- 25500792 TI - PSP/reg: a potent and enigmatic trophic factor, which is upregulated during the pathogenesis of diabetes. PMID- 25500791 TI - The role of an acute pasireotide suppression test in predicting response to treatment in patients with Cushing's disease: findings from a pilot study. AB - Pasireotide is a multireceptor-targeted somatostatin analog effective in the treatment of Cushing's disease (CD). We evaluate the value of an acute pasireotide suppression test (PST) in predicting response to medium/long-term treatment in CD. Nineteen patients with active CD were prospectively investigated at two referral centers from May 2013 to August 2014. Follow-up data (median 6 months; range 1-9 months) were available for sixteen patients. All patients received at 09:00 h a single subcutaneous (sc) injection of 600 MUg pasireotide. Serum cortisol and plasma ACTH were assessed before, and every 2 h for 8 h after, drug administration. Late-night salivary cortisol (LNSC) was assessed before and after pasireotide administration. After acute PST, all patients were continued on pasireotide 600 MUg sc twice a day. During PST, cortisol and ACTH levels quickly decreased in all patients except one with a mean percentage fall, respectively, of 48.9 +/- 24.3 and 48.1 +/- 25.4 % compared to baseline. LNSC decreased in about 82 % of patients (14/17) achieving a normalization in five of them. Pasireotide treatment was associated with a normalization of 24-h urinary-free cortisol at last follow-up in about 68 % of patients. A fall >27 % of LNSC during PST calculated by ROC curve was the best parameter in predicting a positive response to treatment with pasireotide (sensitivity 91 %; specificity 100 %; positive predictive value 100 %; negative predictive value 75 %). Acute PST may be useful to identify CD patients who will benefit from pasireotide treatment. A LNSC fall >27 % as well as a LNSC normalization during PST is associated with a probability of 100 % of achieving a favorable response to pasireotide treatment in the medium/long term. PMID- 25500794 TI - Asymmetric synthesis of alpha-(1-oxoisoindolin-3-yl)glycine: synthetic and mechanistic challenges. AB - We report herein that the NaOMe-catalyzed reactions between the chiral glycine Schiff base (S)-4 with 2-cyanobenzaldehyde 3a provide for a convenient preparation of the novel alpha-(1-oxoisoindolin-3-yl)glycine 1 of high pharmaceutical potential. The reactions involve at least eight synthetic steps and can mechanistically be realized only with application of Ni(II) complexes described in this study. PMID- 25500795 TI - Ultrafast dynamics of a new class of highly fluorescent boron difluoride dyes. AB - The first ultrafast study of the dimeric fluorescent BF2 dye BOPHY is presented. When compared to a structurally related BODIPY dye, similar photophysical dynamics are observed, including an intermediate kinetic component present in both dye types. PMID- 25500796 TI - The correlation between mental health and multiple chemical sensitivity: a survey study in Japanese workers. AB - OBJECTIVE: This study was designed to determine the correlation between mental health and multiple chemical sensitivity (MCS). METHOD: The present study was conducted at two companies in 2011; both in Kyushu, Japan. The "subjective symptoms" subscale of the "Self-diagnosis Checklist for Assessment of Workers' Accumulated Fatigue" was used as a mental health subscale. To determine if multiple chemical exposure has an impact on mental health, we composed an original path model using structural equation analysis. RESULT: Our final path model can be regarded as good: CMIN/DF = 1.832, CFI = 0.996, and RMSEA = 0.038, AIC = 71.158. As expected, chemical sensitivity and other chemical sensitivity scores predicted the health effects of multiple chemical exposure (beta = 0.19, 0.64). Mental health was predicted by symptom severity and life impact (beta = 0.56 and 0.12), which were both affected by multiple chemical exposure (beta = 0.38 and 0.89, respectively). CONCLUSION: As far as we are aware, this is the first study using path analysis to explore whether MCS can indicate mental health in worker populations worldwide, and we found a significant causal relationship between them. This could indicate that more focus should be placed on the impact of MCS on mental health in future investigations. PMID- 25500797 TI - Comparison of methods for the measurement of body composition in overweight and obese Brazilian children and adolescents before and after a lifestyle modification program. AB - AIM: To compare the body composition of overweight children and adolescents by bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DXA) before and after physical activity program. METHODS: One hundred and eleven patients with mean age (SD) of 12 (1.9) participated in the study. We assessed the weight, height, waist circumference (WC), and body composition by DXA and BIA. Patients underwent a program of diet and physical activity (1 h 30 min/day, 3 times a week for 3 months) and were evaluated before and after this period. RESULTS: Mean initial zBMI were 2.3 (0.5) and waist SDS 5.9 (1.8). Significant differences were observed when we compared the measurements taken by DXA and BIA, respectively: total body fat percentage (40 and 31.5) and fat-free mass (43.1 and 50.6 kg). Regarding the trunk fat by DXA, there was a positive correlation with the WC/height ratio (r = 0.65; p < 0.01). After the intervention period, we observed a reduction in the zBMI, waist SDS, and total body fat and increase of fat-free mass by DXA. BIA only detected reduction in fat. CONCLUSION: BIA underestimates the percentage of fat and overestimates fat-free mass in relation to DXA. There is positive correlation between trunk fat and the ratio WC/height. In addition, DXA detected changes in body composition induced by a short period of physical training, unlike BIA. PMID- 25500798 TI - The Parkinson's disease-related protein DJ-1 protects dopaminergic neurons in vivo and cultured cells from alpha-synuclein and 6-hydroxydopamine toxicity. AB - BACKGROUND: Dopaminergic degeneration is a major finding in brains of patients with Parkinson's disease (PD), together with Lewy bodies, intraneuronal inclusions mainly composed of the fibrillogenic protein alpha-synuclein (alpha syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by alpha-syn or by the dopaminergic-selective neurotoxin 6 hydroxydopamine (6-OHDA). OBJECTIVE: The aim was to further investigate the role of DJ-1 in dopaminergic degeneration and to see whether a cell-permeable recombinant form of DJ-1 (TAT-DJ-1) could restore dopamine depletion in vivo, thus representing an innovative therapeutic approach. METHODS: We developed in vitro (PC12/TetOn cells and mouse primary mesencephalic neurons) and in vivo models [including DJ-1 knockout (-/-) mice] to investigate DJ-1 in dopaminergic degeneration. RESULTS: We found that in PC12/TetOn cells overexpressing alpha-syn with the familial-PD linked mutation A30P, DJ-1 silencing increased alpha-syn (A30P) toxicity. Primary mesencephalic neurons from DJ-1 (-/-) mice were more vulnerable to a cell-permeable form of alpha-syn (TAT-alpha-syn) and to 6-OHDA. Intrastriatally administered TAT-DJ-1 reduced 6-OHDA toxicity in vivo in C57BL/6 mice. Finally, when we injected TAT-alpha-syn (A30P) in the striatum of DJ-1 (-/ ) animals, dopamine was depleted more than in the control strain. CONCLUSION: DJ 1 appears to have a protective role against dopaminergic degeneration triggered by alpha-syn or 6-OHDA, reinforcing the possible therapeutic importance of this protein in PD. PMID- 25500799 TI - Severe chronic kidney disease as a predictor of benefit from aminophylline administration in patients undergoing regadenoson stress myocardial perfusion imaging: A substudy of the ASSUAGE and ASSUAGE-CKD trials. AB - BACKGROUND: Regadenoson is predominantly renally metabolized. Patients with severe chronic kidney disease (CKD) experience more frequent gastrointestinal adverse effects (AE) from regadenoson. Aminophylline use following regadenoson reduces the incidence of regadenoson-related AE. We investigated whether patients with severe CKD receive incremental benefit from aminophylline administration in reducing regadenoson AE. METHODS: We performed post hoc analysis of the pooled database of the ASSUAGE and ASSUAGE-CKD trials. These were randomized placebo controlled clinical trials which tested the benefit of intravenous aminophylline vs placebo after regadenoson injection in patients undergoing a clinically indicated stress MPI. Patients were categorized into two treatment arms: aminophylline vs placebo; and two groups: Severe CKD (GFR < 30 mL.min(-1)/1.73 m(2) or dialysis) and Control (GFR >= 30 mL.min(-1)/1.73 m(2)). The study endpoints were gastrointestinal AE, non-gastrointestinal AE and composite of any regadenoson AE. RESULT: The pooled database of the two trials yielded 548 patients, of whom 274 patients received aminophylline and 274 received placebo. Aminophylline was associated with greater absolute risk reduction (ARR) in gastrointestinal AE among patients with severe CKD vs controls (25% vs 4%, p < .001). A significant interaction was identified between severe CKD and aminophylline in reducing gastrointestinal AE (p = .007), indicating greater reduction in gastrointestinal AE with aminophylline use among patients with severe CKD. Aminophylline use was associated with a trend toward greater ARR in any regadenoson-related AE (32% vs 21%, p = .08). CONCLUSION: Aminophylline is associated with incremental benefit in reducing gastrointestinal AE in patients with severe CKD undergoing regadenoson stress MPI. Potentially, this population could be targeted for prophylactic administration of aminophylline in order to improve their overall experience with the test. PMID- 25500800 TI - The yield, safety and prognostic value of myocardial perfusion imaging with positron emission tomography for risk stratification of high risk chest pain patients. PMID- 25500802 TI - Manganese-calcium clusters supported by calixarenes. AB - The structure of the oxygen-evolving complex of photosystem II, which contains a cubane-like metal-oxo cluster incorporating four manganese(III,IV) cations, along with a calcium cation, has focussed attention on synthetic analogues of this cluster. Despite this activity, there are relatively few structurally characterised coordination clusters with this combination of metal cations. The calixarenes are synthetically versatile and well established cluster-supporting ligands, which to date have not been reported to support a calcium/manganese cluster. Here we report that p-t-butylthiacalix[4]arene supports CaMn2 and Ca2Mn2 clusters, whereas reactions of p-t-butylcalix[4]arene, p-t butylsulfinylcalix[4]arene, and p-t-butylsulfonylcalix[4]arene, under the same conditions, produced only homometallic manganese complexes. PMID- 25500801 TI - Computerized decision making in myocardial perfusion SPECT: The new era in nuclear cardiology? PMID- 25500803 TI - Consecutive three-component synthesis of (hetero)arylated propargyl amides by chemoenzymatic aminolysis-Sonogashira coupling sequence. AB - A novel chemoenzymatic three-component synthesis of (hetero)arylated propargyl amides in good yields based upon Novozyme(r) 435 (Candida antarctica lipase B (CAL-B)) catalyzed aminolysis of methyl carboxylates followed by Sonogashira coupling with (hetero)aryliodides in a consecutive one-pot fashion has been presented. This efficient methodology can be readily concatenated with a CuAAC (Cu catalyzed alkyne azide cycloaddition) as a third consecutive step to furnish 1,4-disubstituted 1,2,3-triazole ligated arylated propargyl amides. This one-pot process can be regarded as a transition metal catalyzed sequence that takes advantage of the copper source still present from the cross-coupling step. PMID- 25500804 TI - Antibody-incompatible kidney transplantation in 2015 and beyond. AB - Rejection caused by donor-specific antibodies (principally ABO and HLA antibodies) has become one of the major barriers to successful long-term transplantation. This review focuses on clinical outcomes in antibody incompatible transplantation, the current state of the science underpinning clinical observations, and how these may be translated into further novel therapies. The clinical outcomes for allografts facing donor-specific antibodies are at present determined largely by the use of agents developed in the 20th century for the treatment of T-lymphocyte-mediated cellular rejection, such as interleukin-2 agents and anti-thymocyte globulin. These treatments are partially effective, because acute antibody-mediated rejection is mediated to a considerable extent by T lymphocytes. However these treatments are essentially ineffective in chronic antibody-mediated rejection. Future therapies for the prevention and treatment of antibody-mediated rejection are likely to fall into the categories of those that reduce antibody production, extracorporeal antibody removal and disruption of the effector arms of antibody-mediated tissue damage. PMID- 25500805 TI - Ranking of factors determining potassium mass balance in bicarbonate haemodialysis. AB - BACKGROUND: One of the most important pathogenetic factors involved in the onset of intradialysis arrhytmias is the alteration in electrolyte concentration, particularly potassium (K(+)). METHODS: Two studies were performed: Study A was designed to investigate above all the isolated effect of the factor time t on intradialysis K(+) mass balance (K(+)MB): 11 stable prevalent Caucasian anuric patients underwent one standard (~4 h) and one long-hour (~8 h) bicarbonate haemodialysis (HD) session. The latter were pair-matched as far as the dialysate and blood volume processed (90 L) and volume of ultrafiltration are concerned. Study B was designed to identify and rank the other factors determining intradialysis K(+)MB: 63 stable prevalent Caucasian anuric patients underwent one 4-h standard bicarbonate HD session. Dialysate K(+) concentration was 2.0 mmol/L in both studies. Blood samples were obtained from the inlet blood tubing immediately before the onset of dialysis and at t60, t120, t180 min and at end of the 4- and 8-h sessions for the measurement of plasma K(+), blood bicarbonates and blood pH. Additional blood samples were obtained at t360 min for the 8 h sessions. Direct dialysate quantification was utilized for K(+)MBs. Direct potentiometry with an ion-selective electrode was used for K(+) measurements. RESULTS: Study A: mean K(+)MBs were significantly higher in the 8-h sessions (4 h: -88.4 +/- 23.2 SD mmol versus 8 h: -101.9 +/- 32.2 mmol; P = 0.02). Bivariate linear regression analyses showed that only mean plasma K(+), area under the curve (AUC) of the hourly inlet dialyser diffusion concentration gradient of K(+) (hcgAUCK(+)) and AUC of blood bicarbonates and mean blood bicarbonates were significantly related to K(+)MB in both 4- and 8-h sessions. A multiple linear regression output with K(+)MB as dependent variable showed that only mean plasma K(+), hcgAUCK(+) and duration of HD sessions per se remained statistically significant. Study B: mean K(+)MBs were -86.7 +/- 22.6 mmol. Bivariate linear regression analyses showed that only mean plasma K(+), hcgAUCK(+) and mean blood bicarbonates were significantly related to K(+)MB. Again, only mean plasma K(+) and hcgAUCK(+) predicted K(+)MB at the multiple linear regression analysis. CONCLUSIONS: Our studies enabled to establish the ranking of factors determining intradialysis K(+)MB: plasma K(+) -> dialysate K(+) gradient is the main determinant; acid-base balance plays a much less important role. The duration of HD session per se is an independent determinant of K(+)MB. PMID- 25500806 TI - Criteria for HNF1B analysis in patients with congenital abnormalities of kidney and urinary tract. AB - BACKGROUND: Congenital anomalies of kidneys and urinary tract (CAKUT) are the most predominant developmental disorders comprising ~20-30% of all anomalies identified in the prenatal period. Mutations in hepatocyte nuclear factor 1-beta (HNF-1beta) involved in the development of kidneys, liver, pancreas and urogenital tract are currently the most frequent monogenetic cause of CAKUT found in 10-30% of patients depending on screening policy and study design. We aimed to validate criteria for analysis of HNF1B in a prospective cohort of paediatric and adult CAKUT patients. METHODS: We included CAKUT patients diagnosed in our paediatric and adult nephrology departments from January 2010 until April 2013 based on predefined screening criteria. Subjects presenting with at least one major renal criterion or one minor renal criterion combined with one or more extra-renal criteria in the personal history or a familial history of renal or extra-renal manifestations were considered eligible. RESULTS: We prospectively screened 205 patients and detected HNF1B mutations in 10% [n = 20, 12 children, median age 4.2 (range 0-13.1) years and 8 adults, median age 34.8 (range 16.6-62) years]. We observed that bilateral renal anomaly, renal cysts from unknown origin, a combination of two major renal anomalies and hypomagnesaemia were predictive for finding HNF1B mutations (P < 0.001; P < 0.001; P = 0.004; P = 0.008, respectively). CONCLUSIONS: We demonstrated that HNF1B mutations are responsible for ~10% of CAKUT cases, both in children and in adults. Based on our results we propose adapted criteria for HNF1B analysis to reduce the screening costs without missing affected patients. These criteria should be reaffirmed in a larger validation cohort. PMID- 25500807 TI - Perception of trigeminal mixtures. AB - The trigeminal system is a chemical sense allowing for the perception of chemosensory information in our environment. However, contrary to smell and taste, we lack a thorough understanding of the trigeminal processing of mixtures. We, therefore, investigated trigeminal perception using mixtures of 3 relatively receptor-specific agonists together with one control odor in different proportions to determine basic perceptual dimensions of trigeminal perception. We found that 4 main dimensions were linked to trigeminal perception: sensations of intensity, warmth, coldness, and pain. We subsequently investigated perception of binary mixtures of trigeminal stimuli by means of these 4 perceptual dimensions using different concentrations of a cooling stimulus (eucalyptol) mixed with a stimulus that evokes warmth perception (cinnamaldehyde). To determine if sensory interactions are mainly of central or peripheral origin, we presented stimuli in a physical "mixture" or as a "combination" presented separately to individual nostrils. Results showed that mixtures generally yielded higher ratings than combinations on the trigeminal dimensions "intensity," "warm," and "painful," whereas combinations yielded higher ratings than mixtures on the trigeminal dimension "cold." These results suggest dimension-specific interactions in the perception of trigeminal mixtures, which may be explained by particular interactions that may take place on peripheral or central levels. PMID- 25500808 TI - Co-expression of anoctamins in cilia of olfactory sensory neurons. AB - Vertebrates can sense and identify a vast array of chemical cues. The molecular machinery involved in chemodetection and transduction is expressed within the cilia of olfactory sensory neurons. Currently, there is only limited information available on the distribution and density of individual signaling components within the ciliary compartment. Using super-resolution microscopy, we show here that cyclic-nucleotide-gated channels and calcium-activated chloride channels of the anoctamin family are localized to discrete microdomains in the ciliary membrane. In addition to ANO2, a second anoctamin, ANO6, also localizes to ciliary microdomains. This observation, together with the fact that ANO6 and ANO2 co-localize, indicates a role for ANO6 in olfactory signaling. We show that both ANO2 and ANO6 can form heteromultimers and that this heteromerization alters the recombinant channels' physiological properties. Thus, we provide evidence for interaction of ANO2 and ANO6 in olfactory cilia, with possible physiological relevance for olfactory signaling. PMID- 25500809 TI - Genetic algorithms coupled with quantum mechanics for refinement of force fields for RNA simulation: a case study of glycosidic torsions in the canonical ribonucleosides. AB - We report the use of genetic algorithms (GA) as a method to refine force field parameters in order to determine RNA energy. Quantum-mechanical (QM) calculations are carried out for the isolated canonical ribonucleosides (adenosine, guanosine, cytidine and uridine) that are taken as reference data. In this particular study, the dihedral and electrostatic energies are reparametrized in order to test the proposed approach, i.e., GA coupled with QM calculations. Overall, RMSE comparison with recent published results for ribonucleosides energies shows an improvement, on average, of 50%. Finally, the new reparametrized potential energy function is used to determine the spatial structure of RNA (PDB code ) that was not taken into account in the parametrization process. This structure was improved about 82% comparable with previously published results. PMID- 25500810 TI - Long term OSLD reader stability in the ACDS level one audit. AB - The Australian Clinical Dosimetry Service (ACDS) has demonstrated the capacity to perform a basic dosimetry audit on all radiotherapy clinics across Australia. During the ACDS's three and a half year trial the majority of the audits were performed using optically stimulated luminescence dosimeters (OSLD) mailed to facilities for exposure to a reference dose, and then returned to the ACDS for analysis. This technical note investigates the stability of the readout process under the large workload of the national dosimetry audit. The OSLD readout uncertainty contributes to the uncertainty of several terms of the dose calculation equation and is a major source of uncertainty in the audit. The standard deviation of four OSLD readouts was initially established at 0.6 %. Measurements over 13 audit batches--each batch containing 200-400 OSLDs--showed variability (0.5-0.9 %) in the readout standard deviation. These shifts have not yet necessitated a change to the audit scoring levels. However, a standard deviation in OSLD readouts greater than 0.9 % will change the audit scoring levels. We identified mechanical wear on the OSLD readout adapter as a cause of variability in readout uncertainty, however, we cannot rule out other causes. Additionally we observed large fluctuations in the distribution of element correction factors (ECF) for OSLD batches. We conclude that the variability in the width of the ECF distribution from one batch to another is not caused by variability in readout uncertainty, but rather by variations in the OSLD stock. PMID- 25500812 TI - Tamoxifen reduces breast cancer rate in at-risk healthy women by nearly a third, finds study. PMID- 25500811 TI - Pyranose dehydrogenase ligand promiscuity: a generalized approach to simulate monosaccharide solvation, binding, and product formation. AB - The flavoenzyme pyranose dehydrogenase (PDH) from the litter decomposing fungus Agaricus meleagris oxidizes many different carbohydrates occurring during lignin degradation. This promiscuous substrate specificity makes PDH a promising catalyst for bioelectrochemical applications. A generalized approach to simulate all 32 possible aldohexopyranoses in the course of one or a few molecular dynamics (MD) simulations is reported. Free energy calculations according to the one-step perturbation (OSP) method revealed the solvation free energies (DeltaGsolv) of all 32 aldohexopyranoses in water, which have not yet been reported in the literature. The free energy difference between beta- and alpha anomers (DeltaGbeta-alpha) of all d-stereoisomers in water were compared to experimental values with a good agreement. Moreover, the free-energy differences (DeltaG) of the 32 stereoisomers bound to PDH in two different poses were calculated from MD simulations. The relative binding free energies (DeltaDeltaGbind) were calculated and, where available, compared to experimental values, approximated from Km values. The agreement was very good for one of the poses, in which the sugars are positioned in the active site for oxidation at C1 or C2. Distance analysis between hydrogens of the monosaccharide and the reactive N5-atom of the flavin adenine dinucleotide (FAD) revealed that oxidation is possible at HC1 or HC2 for pose A, and at HC3 or HC4 for pose B. Experimentally detected oxidation products could be rationalized for the majority of monosaccharides by combining DeltaDeltaGbind and a reweighted distance analysis. Furthermore, several oxidation products were predicted for sugars that have not yet been tested experimentally, directing further analyses. This study rationalizes the relationship between binding free energies and substrate promiscuity in PDH, providing novel insights for its applicability in bioelectrochemistry. The results suggest that a similar approach could be applied to study promiscuity of other enzymes. PMID- 25500813 TI - Toxicity Assessment of Cadinene Sesquiterpenes from Eupatorium adenophorum in Mice. AB - This study evaluated toxic efficacy of Eupatorium adenophorum extracts, against the Kunming mice. In acute study, we firstly tested median lethal dose (LD50) in mice of three cadinene sesquiterpenes 2-deoxo-2-(acetyloxy)-9-oxoageraphorone (DAOA), 9-oxo-agerophorone (OA) and 9-oxo-10,11-dehydro-agerophorone (ODA) from Eupatorium adenophorum (Ea). DAOA (215-4640 mg/kg BW, given orally) showed lowest LD50 at 926 mg/kg BW for male mice in contrast with OA (1470 mg/kg BW) and ODA (1470 mg/kg BW). In sub-acute study, repeated doses (75-300 mg/kg BW, for 7 days) of DAOA/OA increased blood parameters, liver and spleen index in dose dependent relationship, along with decrease in thymus index. The blood biochemical and histopathological examination showed that DAOA/OA dose 300 mg/kg BW significantly causes pathological changes of hepatic lobules and hepatocytes, which are consistent with cholestasis and hepatic injury. 75 mg/kg dose of DAOA/OA was found to be approximately/totally safe over the span of 7 days treatment showing no change in all above described parameters. Cadinene sesquiterpenes guarantee low risk to environment as a type of low toxic botanical components, which may find potential application in biopesticides development field. PMID- 25500814 TI - The rem mutations in the ATP-binding groove of the Rad3/XPD helicase lead to Xeroderma pigmentosum-Cockayne syndrome-like phenotypes. AB - The eukaryotic TFIIH complex is involved in Nucleotide Excision Repair and transcription initiation. We analyzed three yeast mutations of the Rad3/XPD helicase of TFIIH known as rem (recombination and mutation phenotypes). We found that, in these mutants, incomplete NER reactions lead to replication fork breaking and the subsequent engagement of the homologous recombination machinery to restore them. Nevertheless, the penetrance varies among mutants, giving rise to a phenotype gradient. Interestingly, the mutations analyzed reside at the ATP binding groove of Rad3 and in vivo experiments reveal a gain of DNA affinity upon damage of the mutant Rad3 proteins. Since mutations at the ATP-binding groove of XPD in humans are present in the Xeroderma pigmentosum-Cockayne Syndrome (XP-CS), we recreated rem mutations in human cells, and found that these are XP-CS-like. We propose that the balance between the loss of helicase activity and the gain of DNA affinity controls the capacity of TFIIH to open DNA during NER, and its persistence at both DNA lesions and promoters. This conditions NER efficiency and transcription resumption after damage, which in human cells would explain the XP CS phenotype, opening new perspectives to understand the molecular basis of the role of XPD in human disease. PMID- 25500816 TI - Innovation and insight in integrative biology. PMID- 25500815 TI - Low-density lipoprotein receptor-related protein 1 (LRP1) regulates the stability and function of GluA1 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor in neurons. AB - The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor abundantly expressed in neurons. Increasing evidence demonstrates that LRP1 regulates synaptic integrity and function at the post synapses, at least partially by regulating glutamate receptors. The alpha amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are critical ionotropic glutamate receptors consisting of homotetramer or heterotetramer of GluA1-4 subunits and play an essential role in synaptic transmission and synaptic plasticity. Our previous work has shown that neuronal deletion of the Lrp1 gene in mice leads to decreased level of GluA1 and reduced long-term potentiation. To understand the underlying mechanism, we investigated the cellular and functional consequences of LRP1 deletion in primary neurons. Here, we show that LRP1 interacts with and regulates the cellular distribution and turnover of GluA1. LRP1 knockdown in mouse primary neurons led to accelerated turnover and decreased cell surface distribution of GluA1, which correspond to decreased phosphorylation of GluA1 at S845 and S831 sites. Decreased LRP1 expression also attenuated AMPA-evoked calcium influx and reduced GluA1-regulated neurite outgrowth and filopodia density. Our results reveal a novel mechanism by which LRP1 controls synaptic integrity and function, specifically by regulating GluA1 trafficking, phosphorylation and turnover. They further demonstrate that LRP1-GluA1 pathway may hold promises as a therapeutic target for restoring synaptic functions in neurodegenerative diseases. PMID- 25500818 TI - MicroRNAs in atherosclerosis. AB - Micro-ribonucleic acids (miRNAs) are a class of endogenous non-coding ribonucleic acids that regulate gene expression. MiRNAs have been shown to act as key regulators in the vascular system, with wide-ranging physio-pathological effects. Atherosclerotic disease is a leading cause of morbidity and mortality worldwide. This review presents current knowledge on miRNAs implicated in atherosclerosis susceptibility, development and progression. They are involved in cell phenotype switching, response to shear stress, cell senescence, adhesion molecule expression, macrophage response to oxidised low-density lipoprotein, Toll-like receptor 4 expression, neointimal lesion formation, plaque angiogenesis and cellular cholesterol homeostasis. Clinically, early work has demonstrated the utility of miRNAs for differentiating patients with arterial disease from controls and predicting future cardiac events; this highlights potential diagnostic and prognostic roles. MiRNA involvement in the crucial stages of atherosclerosis promises new hope in treating arterial disease. However, issues regarding multiple miRNA targets, stability and delivery continue to present challenges. PMID- 25500817 TI - Transcriptome profiles of the protoscoleces of Echinococcus granulosus reveal that excretory-secretory products are essential to metabolic adaptation. AB - BACKGROUND: Cystic hydatid disease (CHD) is caused by the larval stages of the cestode and affects humans and domestic animals worldwide. Protoscoleces (PSCs) are one component of the larval stages that can interact with both definitive and intermediate hosts. Previous genomic and transcriptomic data have provided an overall snapshot of the genomics of the growth and development of this parasite. However, our understanding of how PSCs subvert the immune response of hosts and maintains metabolic adaptation remains unclear. In this study, we used Roche 454 sequencing technology and in silico secretome analysis to explore the transcriptome profiles of the PSCs from E. granulosus and elucidate the potential functions of the excretory-secretory proteins (ESPs) released by the parasite. METHODOLOGY/PRINCIPAL FINDINGS: A large number of nonredundant sequences as unigenes were generated (26,514), of which 22,910 (86.4%) were mapped to the newly published E. granulosus genome and 17,705 (66.8%) were distributed within the coding sequence (CDS) regions. Of the 2,280 ESPs predicted from the transcriptome, 138 ESPs were inferred to be involved in the metabolism of carbohydrates, while 124 ESPs were inferred to be involved in the metabolism of protein. Eleven ESPs were identified as intracellular enzymes that regulate glycolysis/gluconeogenesis (GL/GN) pathways, while a further 44 antigenic proteins, 25 molecular chaperones and four proteases were highly represented. Many proteins were also found to be significantly enriched in development-related signaling pathways, such as the TGF-beta receptor pathways and insulin pathways. CONCLUSIONS/SIGNIFICANCE: This study provides valuable information on the metabolic adaptation of parasites to their hosts that can be used to aid the development of novel intervention targets for hydatid treatment and control. PMID- 25500819 TI - Effect of urinary protease inhibitor (ulinastatin) on cardiopulmonary bypass: a meta-analysis for China and Japan. AB - OBJECTIVES: A meta-analysis was conducted to investigate the effects of ulinastatin treatment on adult patients undergoing cardiac surgery under cardiopulmonary bypass (CPB). METHODS: Seven electronic databases were searched for reports of randomized, controlled trials conducted up to February 2014 in which patients undergoing cardiac surgery with CPB were administered ulinastatin in the perioperative period. RESULTS: Fifty-two studies with 2025 patients were retained for analysis. The results showed that the ulinastatin can attenuate the plasma levels of pro-inflammatory cytokines and enhance the anti-inflammatory cytokine levels in patients undergoing cardiac surgery with CPB. Meanwhile, the ulinastatin had a significant beneficial effect on myocardial injury. The mean differences (MD) and 95% confidence intervals (95% CI) of biochemical markers were -63.54 (-79.36, -47.72) for lactate dehydrogenase, -224.99 (-304.83, 145.14) for creatine kinase, -8.75 (-14.23, -3.28) for creatine kinase-MB, and 0.14 (-0.20, -0.09] for troponin I (all P<0.01). However, neither hemodynamics nor cardiac function improved significantly, except that the MD and 95% CI of mean arterial pressure were 2.50 (0.19, 4.80) (P = 0.03). There were no statistically significant differences in the use of inotropes, postoperative bleeding, postoperative complications, the intensive care unit (ICU) stay, and the hospital stay; however, the frequency of auto resuscitation increased significantly (OR 1.98, 95%CI 1.19 to 3.30, P<0.01), the duration of intubation (MD -1.58, 95%CI -2.84 to -0.32, P<0.01) and the duration of mechanical ventilation (MD -3.29, 95%CI -4.41 to -2.17, P<0.01) shortened significantly in patients who were treated with ulinastatin. CONCLUSIONS: Ulinastatin can reduce the plasma levels of pro-inflammatory cytokines and elevate anti-inflammatory cytokine in patients from China and Japan undergoing cardiac surgery with CPB. Ulinastatin treatment may have protective effects on myocardial injury, and can increase the frequency of auto resuscitation, shorten the duration of intubation and mechanical ventilation. PMID- 25500820 TI - Studying developmental variation with Geometric Morphometric Image Analysis (GMIA). AB - The ways in which embryo development can vary across individuals of a population determine how genetic variation translates into adult phenotypic variation. The study of developmental variation has been hampered by the lack of quantitative methods for the joint analysis of embryo shape and the spatial distribution of cellular activity within the developing embryo geometry. By drawing from the strength of geometric morphometrics and pixel/voxel-based image analysis, we present a new approach for the biometric analysis of two-dimensional and three dimensional embryonic images. Well-differentiated structures are described in terms of their shape, whereas structures with diffuse boundaries, such as emerging cell condensations or molecular gradients, are described as spatial patterns of intensities. We applied this approach to microscopic images of the tail fins of larval and juvenile rainbow trout. Inter-individual variation of shape and cell density was found highly spatially structured across the tail fin and temporally dynamic throughout the investigated period. PMID- 25500821 TI - Human rhinovirus induced cytokine/chemokine responses in human airway epithelial and immune cells. AB - Infections with human rhinovirus (HRV) are commonly associated with acute upper and lower respiratory tract disease and asthma exacerbations. The role that HRVs play in these diseases suggests it is important to understand host-specific or virus-specific factors that contribute to pathogenesis. Since species A HRVs are often associated with more serious HRV disease than species B HRVs, differences in immune responses they induce should inform disease pathogenesis. To identify species differences in induced responses, we evaluated 3 species A viruses, HRV 25, 31 and 36 and 3 species B viruses, HRV 4, 35 and 48 by exposing human PBMCs to HRV infected Calu-3 cells. To evaluate the potential effect of memory induced by previous HRV infection on study responses, we tested cord blood mononuclear cells that should be HRV naive. There were HRV-associated increases (significant increase compared to mock-infected cells) for one or more HRVs for IP-10 and IL 15 that was unaffected by addition of PBMCs, for MIP-1alpha, MIP-1beta, IFN alpha, and HGF only with addition of PBMCs, and for ENA-78 only without addition of PBMCs. All three species B HRVs induced higher levels, compared to A HRVs, of MIP-1alpha and MIP-1beta with PBMCs and ENA-78 without PBMCs. In contrast, addition of CBMCs had less effect and did not induce MIP-1alpha, MIP-1beta, or IFN-alpha nor block ENA-78 production. Addition of CBMCs did, however, increase IP-10 levels for HRV 35 and HRV 36 infection. The presence of an effect with PBMCs and no effect with CBMCs for some responses suggest differences between the two types of cells possibly because of the presence of HRV memory responses in PBMCs and not CBMCs or limited response capacity for the immature CBMCs relative to PBMCs. Thus, our results indicate that different HRV strains can induce different patterns of cytokines and chemokines; some of these differences may be due to differences in memory responses induced by past HRV infections, and other differences related to virus factors that can inform disease pathogenesis. PMID- 25500822 TI - Adaptive potential of maritime pine (Pinus pinaster) populations to the emerging pitch canker pathogen, Fusarium circinatum. AB - There is a concern on how emerging pests and diseases will affect the distribution range and adaptability of their host species, especially due to different conditions derived from climate change and growing globalization. Fusarium circinatum, which causes pitch canker disease in Pinus species, is an exotic pathogen of recent introduction in Spain that threatens its maritime pine (P. pinaster) stands. To predict the impact this disease will have on the species, we examine host resistance traits and their genetic architecture. Resistance phenotyping was done in a clonal provenance/progeny trial, using three year-old cuttings artificially inoculated with the pathogen and maintained under controlled environmental conditions. A total number of 670 ramets were assessed, distributed in 10 populations, with a total of 47 families, 2 to 5 half-sibs per family, and 3-7 ramets per clone. High genetic variation was found at the three hierarchical levels studied: population, family and clone, being both additive and non-additive effects important. Narrow-sense and broad-sense heritability estimates were relatively high, with respective values of 0.43-0.58 and 0.51-0.8, depending on the resistance traits measured (lesion length, lesion length rate, time to wilting, and survival). These values suggest the species' high capacity of evolutionary response to the F. circinatum pathogen. A population originated in Northern Spain was the most resistant, while another from Morocco was the most susceptible. The total number of plants that did not show lesion development or presented a small lesion (length<30 mm) was 224 out of 670, indicating a high proportion of resistant trees in the offspring within the analyzed populations. We found large differences among populations and considerable genetic variation within populations, which should allow, through natural or artificial selection, the successful adaptation of maritime pine to pitch canker disease. PMID- 25500824 TI - Evaluation of a nonpeptidic ligand for imaging of cholecystokinin 2 receptor expressing cancers. AB - Tumor-specific targeting ligands were recently exploited to deliver both imaging and therapeutic agents selectively to cancer tissues in vivo. Because the cholecystokinin 2 receptor (CCK2R) is overexpressed in various human cancers (e.g., lung, medullary thyroid, pancreatic, colon, and gastrointestinal stromal tumors) but displays limited expression in normal tissues, natural ligands of CCK2R were recently explored for use in the imaging of CCK2R-expressing cancers. Unfortunately, the results from these studies revealed not only that the peptidic CCK2R ligands were unstable in vivo but also that the ligands that mediated good uptake by tumor tissues also promoted a high level of retention of the radioimaging agent in the kidneys, probably because of capture of the conjugates by peptide-scavenging receptors. In an effort to reduce the normal organ retention of CCK2R-targeted drugs, we synthesized a nonpeptidic ligand of CCK2R and examined its specificity for CCK2R both in vitro and in vivo. METHODS: Nonpeptidic agonists and antagonists of CCK2R described in the literature were evaluated for their affinities and specificities for CCK2R. Z-360, a benzodiazepine-derived CCK2R antagonist with subnanomolar affinity, was selected for complexation to (99m)Tc via multiple spacers. After synthesis and purification, 4 complexes with different physicochemical properties were evaluated for binding to CCK2R-transfected HEK 293 cells. The best conjugate, termed CRL-3-(99m)Tc, was injected into mice bearing CCK2R tumor xenografts and examined by gamma scintigraphy and SPECT/CT. The uptake of the conjugate in various organs was also quantified by tissue resection and gamma counting. RESULTS: CRL-3-(99m)Tc was shown to bind with low nanomolar affinity to CCK2R in vitro and was localized to tumor tissues in athymic nu/nu mice implanted with CCK2R-expressing tumors. At 4 h after injection, tumor uptake was measured at 12.0 +/- 2.0 percentage injected dose per gram of tissue. CONCLUSION: Because the uptake of CRL-3-(99m)Tc by nonmalignant tissues was negligible and retention in the kidneys was only transient, we suggest that CRL-3-(99m)Tc may be a useful radioimaging agent for the detection, sizing, and monitoring of CCK2R-expressing tumors. PMID- 25500823 TI - Reproducibility and robustness of graph measures of the associative-semantic network. AB - Graph analysis is a promising tool to quantify brain connectivity. However, an essential requirement is that the graph measures are reproducible and robust. We have studied the reproducibility and robustness of various graph measures in group based and in individual binary and weighted networks derived from a task fMRI experiment during explicit associative-semantic processing of words and pictures. The nodes of the network were defined using an independent study and the connectivity was based on the partial correlation of the time series between any pair of nodes. The results showed that in case of binary networks, global graph measures exhibit a good reproducibility and robustness for networks which are not too sparse and these figures of merit depend on the graph measure and on the density of the network. Furthermore, group based binary networks should be derived from groups of sufficient size and the lower the density the more subjects are required to obtain robust values. Local graph measures are very variable in terms of reproducibility and should be interpreted with care. For weighted networks, we found good reproducibility (average test-retest variability <5% and ICC values >0.4) when using subject specific networks and this will allow us to relate network properties to individual subject information. PMID- 25500825 TI - Impact of 68Ga-DOTATATE PET/CT on the management of neuroendocrine tumors: the referring physician's perspective. AB - Somatostatin receptor imaging with (68)Ga-DOTATATE PET/CT (DOTATATE) is increasingly used for managing patients with neuroendocrine tumors. The objective of this study was to determine referring physicians' perspectives on the impact of DOTATATE on the management of neuroendocrine tumors. METHODS: A set of 2 questionnaires (pre-PET and post-PET) was sent to the referring physicians of 100 consecutive patients with known or suspected neuroendocrine tumors, who were evaluated with DOTATATE. Questionnaires on 88 patients were returned (response rate, 88%). Referring physicians categorized the DOTATATE findings on the basis of the written PET reports as negative, positive, or equivocal for disease. The likelihood for metastatic disease was scored as low, moderate, or high. The intended management before and changes as a consequence of the PET study were indicated. RESULTS: The indications for PET/CT were initial and subsequent treatment strategy assessments in 14% and 86% of patients, respectively. Referring physicians reported that DOTATATE led to a change in suspicion for metastatic disease in 21 patients (24%; increased and decreased suspicion in 9 [10%] and 12 [14%] patients, respectively). Intended management changes were reported in 53 of 88 (60%) patients. Twenty patients (23%) scheduled to undergo chemotherapy were switched to treatments without chemotherapy, and 6 (7%) were switched from watch-and-wait to other treatment strategies. Conversely, 5 patients (6%) were switched from their initial treatment strategy to watch-and wait. CONCLUSION: This survey of referring physicians demonstrates a substantial impact of DOTATATE on the intended management of patients with neuroendocrine tumors. PMID- 25500826 TI - In vivo biodistribution of no-carrier-added 6-18F-fluoro-3,4-dihydroxy-L phenylalanine (18F-DOPA), produced by a new nucleophilic substitution approach, compared with carrier-added 18F-DOPA, prepared by conventional electrophilic substitution. AB - A novel synthetic approach to 6-(18)F-fluoro-3,4-dihydroxy-L-phenylalanine ((18)F DOPA), involving the nucleophilic substitution of a diaryliodonium salt precursor with non-carrier-added (18)F-fluoride, yielded a product with a specific activity that was 3 orders of magnitude higher than the product of the conventional synthesis method, involving an electrophilic substitution of a trialkylstannane precursor with (18)F2. We performed a direct comparison of high- and low-specific activity (18)F-DOPA in a neuroendocrine tumor model to determine whether this difference in specific activity has implications for the biologic behavior and imaging properties of (18)F-DOPA. METHODS: (18)F-DOPA was produced via the novel synthesis method, yielding (18)F-DOPA-H with a high specific activity (35,050 +/- 4,000 GBq/mmol). This product was compared in several experiments with conventional (18)F-DOPA-L with a low specific activity (11 +/- 2 GBq/mmol). In vitro accumulation experiments with the human pancreatic neuroendocrine tumor cell line BON-1 were performed at both 0 degrees C and 37 degrees C and at 37 degrees C in the presence of pharmacologic inhibitors of proteins involved in the uptake mechanism of (18)F-DOPA. Small-animal PET experiments were performed in athymic nude mice bearing a BON-1 tumor xenograft. RESULTS: At 37 degrees C, the uptake of both (18)F-DOPA-H and (18)F-DOPA-L did not differ significantly during a 60-min accumulation experiment in BON-1 cells. At 0 degrees C, the uptake of (18)F-DOPA-L was significantly decreased, whereas the lower temperature did not alter the uptake of (18)F-DOPA-H. The pharmacologic inhibitors carbidopa and tetrabenazine also revealed differential effects between the 2 types of (18)F DOPA in the 60-min accumulation experiment. The small-animal PET experiments did not show any significant differences in distribution and metabolism of (18)F-DOPA H and (18)F-DOPA-L in carbidopa-pretreated mice. CONCLUSION: The advantages of the novel synthesis of (18)F-DOPA, which relies on nucleophilic fluorination of a diaryliodonium salt precursor, lie in the simplicity of the synthesis method, compared with the conventional, electrophilic approach and in the reduced mass of administered, pharmacologically active (19)F-DOPA. (18)F-DOPA-H demonstrated comparable imaging properties in an in vivo model for neuroendocrine tumors, despite the fact that the injected mass of material was 3 orders of magnitude less than (18)F-DOPA-L. PMID- 25500827 TI - Photoimmunotherapy targeting prostate-specific membrane antigen: are antibody fragments as effective as antibodies? AB - Photoimmunotherapy is a highly cell-selective cancer therapy based on an armed antibody conjugate with a phthalocyanine-based photosensitizer, IR700. Photoimmunotherapy induces rapid and highly specific necrosis in targeted cancer cells after exposure to near-infrared (NIR) light. Cells not expressing the antigen are not affected. To date, photoimmunotherapy has been demonstrated only with full antibody-IR700 conjugates. In this study, small and bivalent antibody fragments, including anti-prostate-specific membrane antigen (PSMA) diabody (Db) and minibody (Mb), were compared with intact IgG for their effectiveness as photoimmunotherapy agents. METHODS: Radioiodinated antibody and antibody fragments with (125)I were used to determine the timing of maximum binding of each anti-PSMA antibody fragment on the cell surface in vivo in mice bearing either PSMA-positive or -negative PC3 tumors. Then therapeutic efficacy of photoimmunotherapy was examined by exposing mice to NIR light at 2 time points based on the time of maximum cell surface binding at 6 h after injection for Db IR700 and 24 h after injection for Mb-IR700 and IgG-IR700 as well as 24 h after the peak uptake times. RESULTS: Photoimmunotherapy with the same molar concentration of PSMA-Db-IR700, PSMA-Mb-IR700, and PSMA-IgG-IR700 conjugate showed similar therapeutic effects in vitro and in vivo on PSMA-positive PC3 tumor xenografts in cytotoxicity and survival curves (P > 0.05). CONCLUSION: The use of PSMA-Db-IR700 conjugate results in the shortest time interval between injection and NIR exposure without compromising therapeutic effects of photoimmunotherapy. PMID- 25500828 TI - Toward radioguided surgery with beta- decays: uptake of a somatostatin analogue, DOTATOC, in meningioma and high-grade glioma. AB - A novel radioguided surgery (RGS) technique for cerebral tumors using beta(-) radiation is being developed. Checking for a radiotracer that can deliver a beta( ) emitter to the tumor is a fundamental step in the deployment of such a technique. This paper reports a study of the uptake of (90)Y-DOTATOC in meningiomas and high-grade gliomas (HGGs) and a feasibility study of the RGS technique in these types of tumor. Estimates were performed assuming the use of a beta(-) probe under development with a sensitive area 2.55 mm in radius to detect 0.1-mL residuals. METHODS: Uptake and background from healthy tissues were estimated on (68)Ga-DOTATOC PET scans of 11 meningioma patients and 12 HGG patients. A dedicated statistical analysis of the DICOM images was developed and validated. The feasibility study was performed using full simulation of emission and detection of the radiation, accounting for the measured uptake and background rate. RESULTS: All meningioma patients but one with an atypical extracranial tumor showed high uptake of DOTATOC. In terms of feasibility of the RGS technique, we estimated that by administering a 3 MBq/kg activity of radiotracer, the time needed to detect a 0.1-mL remnant with 5% false-negative and 1% false positive rates is less than 1 s. Actually, to achieve a detection time of 1 s the required activities to administer were as low as 0.2-0.5 MBq/kg in many patients. In HGGs, the uptake was lower than in meningiomas, but the tumor-to-nontumor ratio was higher than 4, which implies that the tracer can still be effective for RGS. It was estimated that by administering 3 mBq/kg of radiotracer, the time needed to detect a 0.1-mL remnant is less than 6 s, with the exception of the only oligodendroma in the sample. CONCLUSION: Uptake of (90)Y-DOTATOC in meningiomas was high in all studied patients. Uptake in HGGs was significantly worse than in meningiomas but was still acceptable for RGS, particularly if further research and development are done to improve the performance of the beta( ) probe. PMID- 25500829 TI - 18F-FDG PET uptake characterization through texture analysis: investigating the complementary nature of heterogeneity and functional tumor volume in a multi cancer site patient cohort. AB - Intratumoral uptake heterogeneity in (18)F-FDG PET has been associated with patient treatment outcomes in several cancer types. Textural feature analysis is a promising method for its quantification. An open issue associated with textural features for the quantification of intratumoral heterogeneity concerns its added contribution and dependence on the metabolically active tumor volume (MATV), which has already been shown to be a significant predictive and prognostic parameter. Our objective was to address this question using a larger cohort of patients covering different cancer types. METHODS: A single database of 555 pretreatment (18)F-FDG PET images (breast, cervix, esophageal, head and neck, and lung cancer tumors) was assembled. Four robust and reproducible textural feature derived parameters were considered. The issues associated with the calculation of textural features using co-occurrence matrices (such as the quantization and spatial directionality relationships) were also investigated. The relationship between these features and MATV, as well as among the features themselves, was investigated using Spearman rank coefficients for different volume ranges. The complementary prognostic value of MATV and textural features was assessed through multivariate Cox analysis in the esophageal and non-small cell lung cancer (NSCLC) cohorts. RESULTS: A large range of MATVs was included in the population considered (3-415 cm(3); mean, 35; median, 19; SD, 50). The correlation between MATV and textural features varied greatly depending on the MATVs, with reduced correlation for increasing volumes. These findings were reproducible across the different cancer types. The quantization and calculation methods both had an impact on the correlation. Volume and heterogeneity were independent prognostic factors (P = 0.0053 and 0.0093, respectively) along with stage (P = 0.002) in non small cell lung cancer, but in the esophageal tumors, volume and heterogeneity had less complementary value because of smaller overall volumes. CONCLUSION: Our results suggest that heterogeneity quantification and volume may provide valuable complementary information for volumes above 10 cm(3), although the complementary information increases substantially with larger volumes. PMID- 25500830 TI - Hybrid PET/MR imaging: an algorithm to reduce metal artifacts from dental implants in Dixon-based attenuation map generation using a multiacquisition variable-resonance image combination sequence. AB - It was the aim of this study to implement an algorithm modifying Dixon-based MR imaging datasets for attenuation correction in hybrid PET/MR imaging with a multiacquisition variable resonance image combination (MAVRIC) sequence to reduce metal artifacts. METHODS: After ethics approval, in 8 oncologic patients with dental implants data were acquired in a trimodality setup with PET/CT and MR imaging. The protocol included a whole-body 3-dimensional dual gradient-echo sequence (Dixon) used for MR imaging-based PET attenuation correction and a high resolution MAVRIC sequence, applied in the oral area compromised by dental implants. An algorithm was implemented correcting the Dixon-based MU maps using the MAVRIC in areas of Dixon signal voids. The artifact size of the corrected MU maps was compared with the uncorrected MR imaging MU maps. RESULTS: The algorithm was robust in all patients. There was a significant reduction in mean artifact size of 70.5% between uncorrected and corrected MU maps from 697 +/- 589 mm(2) to 202 +/- 119 mm(2) (P = 0.016). CONCLUSION: The proposed algorithm could improve MR imaging-based attenuation correction in critical areas, when standard attenuation correction is hampered by metal artifacts, using a MAVRIC. PMID- 25500831 TI - Increased permeability-glycoprotein inhibition at the human blood-brain barrier can be safely achieved by performing PET during peak plasma concentrations of tariquidar. AB - The permeability-glycoprotein (P-gp) efflux transporter is densely expressed at the blood-brain barrier, and its resultant spare capacity requires substantial blockade to increase the uptake of avid substrates, blunting the ability of investigators to measure clinically meaningful alterations in P-gp function. This study, conducted in humans, examined 2 P-gp inhibitors (tariquidar, a known inhibitor, and disulfiram, a putative inhibitor) and 2 routes of administration (intravenous and oral) to maximally increase brain uptake of the avid and selective P-gp substrate (11)C-N-desmethyl-loperamide (dLop) while avoiding side effects associated with high doses of tariquidar. METHODS: Forty-two (11)C-dLop PET scans were obtained from 37 healthy volunteers. PET was performed with (11)C dLop under the following 5 conditions: injected under baseline conditions without P-gp inhibition, injected 1 h after intravenous tariquidar infusion, injected during intravenous tariquidar infusion, injected after oral tariquidar, and injected after disulfiram. (11)C-dLop uptake was quantified with kinetic modeling using metabolite-corrected arterial input function or by measuring the area under the time-activity curve in the brain from 10 to 30 min. RESULTS: Neither oral tariquidar nor oral disulfiram increased brain uptake of (11)C-dLop. Injecting (11)C-dLop during tariquidar infusion, when plasma tariquidar concentrations reach their peak, resulted in a brain uptake of the radioligand approximately 5 fold greater than baseline. Brain uptake was similar with 2 and 4 mg of intravenous tariquidar per kilogram; however, the lower dose was better tolerated. Injecting (11)C-dLop after tariquidar infusion also increased brain uptake, though higher doses (up to 6 mg/kg) were required. Brain uptake of (11)C dLop increased fairly linearly with increasing plasma tariquidar concentrations, but we are uncertain whether maximal uptake was achieved. CONCLUSION: We sought to increase the dynamic range of P-gp function measured after blockade. Performing (11)C-dLop PET during peak plasma concentrations of tariquidar, achieved with concurrent administration of intravenous tariquidar, resulted in greater P-gp inhibition at the human blood-brain barrier than delayed administration and allowed the use of a lower, more tolerable dose of tariquidar. On the basis of prior monkey studies, we suspect that plasma concentrations of tariquidar did not fully block P-gp; however, higher doses of tariquidar would likely be associated with unacceptable side effects. PMID- 25500832 TI - Pharmaceutical availability across levels of care: evidence from facility surveys in Ghana, Kenya, and Uganda. AB - OBJECTIVE: In this study we use facility-level data from nationally representative surveys conducted in Ghana, Kenya, and Uganda to understand pharmaceutical availability within the three countries. METHODS: In 2012, we conducted a survey to capture information on pharmaceuticals and other facility indicators from over 200 facilities in each country. We analyze data on the availability of pharmaceuticals and quantify its association with various facility-level indicators. We analyze both availability of essential medicines, as defined by the various essential medicine lists (EMLs) of each respective country, and availability of all surveyed pharmaceuticals deemed important for treatment of various high-burden diseases, including those on the EMLs. RESULTS: We find that there is heterogeneity with respect to availability across the three countries with Ghana generally having better availability than Uganda and Kenya. To analyze the relationship between facility-level factors and pharmaceutical stock-out we use a binomial regression model. We find that the factors associated with stock-out vary by country, but across all countries both presence of a laboratory at the facility and presence of a vehicle at the facility are significantly associated with reduced stock-out. CONCLUSION: The results of this study highlight the poor availability of essential medicines across these three countries and suggest more needs to be done to strengthen the supply system so that stock remains uninterrupted. PMID- 25500834 TI - Inhomogenous doping induced the imperfect self-assembly of nanocrystals for the synthesis of porous AgPb10BiTe12 nanosheets and their thermoelectric transport properties. AB - For the first time, quaternary single-crystal-like porous AgPb10BiTe12 nanosheets in two solid forms (solid solution and a Bi-rich region coexist) were achieved. A significant enhancement of thermoelectric performance was realized through nanoscale grain boundaries and macroscale porous structures. PMID- 25500833 TI - Apoplastic venom allergen-like proteins of cyst nematodes modulate the activation of basal plant innate immunity by cell surface receptors. AB - Despite causing considerable damage to host tissue during the onset of parasitism, nematodes establish remarkably persistent infections in both animals and plants. It is thought that an elaborate repertoire of effector proteins in nematode secretions suppresses damage-triggered immune responses of the host. However, the nature and mode of action of most immunomodulatory compounds in nematode secretions are not well understood. Here, we show that venom allergen like proteins of plant-parasitic nematodes selectively suppress host immunity mediated by surface-localized immune receptors. Venom allergen-like proteins are uniquely conserved in secretions of all animal- and plant-parasitic nematodes studied to date, but their role during the onset of parasitism has thus far remained elusive. Knocking-down the expression of the venom allergen-like protein Gr-VAP1 severely hampered the infectivity of the potato cyst nematode Globodera rostochiensis. By contrast, heterologous expression of Gr-VAP1 and two other venom allergen-like proteins from the beet cyst nematode Heterodera schachtii in plants resulted in the loss of basal immunity to multiple unrelated pathogens. The modulation of basal immunity by ectopic venom allergen-like proteins in Arabidopsis thaliana involved extracellular protease-based host defenses and non photochemical quenching in chloroplasts. Non-photochemical quenching regulates the initiation of the defense-related programmed cell death, the onset of which was commonly suppressed by venom allergen-like proteins from G. rostochiensis, H. schachtii, and the root-knot nematode Meloidogyne incognita. Surprisingly, these venom allergen-like proteins only affected the programmed cell death mediated by surface-localized immune receptors. Furthermore, the delivery of venom allergen like proteins into host tissue coincides with the enzymatic breakdown of plant cell walls by migratory nematodes. We, therefore, conclude that parasitic nematodes most likely utilize venom allergen-like proteins to suppress the activation of defenses by immunogenic breakdown products in damaged host tissue. PMID- 25500836 TI - Reduction of acute rejection by bone marrow mesenchymal stem cells during rat small bowel transplantation. AB - BACKGROUND: Bone marrow mesenchymal stem cells (BMMSCs) have shown immunosuppressive activity in transplantation. This study was designed to determine whether BMMSCs could improve outcomes of small bowel transplantation in rats. METHODS: Heterotopic small bowel transplantation was performed from Brown Norway to Lewis rats, followed by infusion of BMMSCs through the superficial dorsal veins of the penis. Controls included rats infused with normal saline (allogeneic control), isogeneically transplanted rats (BN-BN) and nontransplanted animals. The animals were sacrificed after 1, 5, 7 or 10 days. Small bowel histology and apoptosis, cytokine concentrations in serum and intestinal grafts, and numbers of T regulatory (Treg) cells were assessed at each time point. RESULTS: Acute cellular rejection occurred soon after transplantation and became aggravated over time in the allogeneic control rats, with increase in apoptosis, inflammatory response, and T helper (Th)1/Th2 and Th17/Treg-related cytokines. BMMSCs significantly attenuated acute cellular rejection, reduced apoptosis and suppressed the concentrations of interleukin (IL)-2, IL-6, IL-17, IL-23, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma while upregulating IL-10 and transforming growth factor (TGF)-beta expression and increasing Treg levels. CONCLUSION: BMMSCs improve the outcomes of allogeneic small bowel transplantation by attenuating the inflammatory response and acute cellular rejection. Treatment with BMMSCs may overcome acute cellular rejection in small bowel transplantation. PMID- 25500837 TI - Causes of death among people living with AIDS in the pre- and post-HAART Eras in the city of Sao Paulo, Brazil. AB - OBJECTIVE: We examine the trend in causes of death among people living with AIDS in the city of Sao Paulo, Brazil, in the periods before and after the introduction of highly active antiretroviral therapy (HAART), and we investigate potential disparities across districts of residence. METHODS: Descriptive study of three periods: pre-HAART (1991-1996); early post-HAART (1997-1999); and late post-HAART (2000-2006). The data source was the Sao Paulo State STD/AIDS Program and Sao Paulo State Data Analysis Foundation. Causes of death were classified by the ICD-9 (1991-1995) and ICD-10 (1996-2006). We estimated age-adjusted mortality rates for leading underlying causes of death and described underlying and associated causes of death according to sociodemographic characteristics and area of residence. We used Pearson's chi-square test or Fisher's exact test to compare categorical variables. Areas of residence were categorized using a socioeconomic index. To analyze trends we apply generalized linear model with Poisson regression. RESULTS: We evaluated 32,808 AIDS-related deaths. Between the pre- and late post-HAART periods, the proportion of deaths whose underlying causes were non-AIDS-related diseases increased from 0.2% to 9.6% (p<0.001): from 0.01% to 1.67% (p<0.001) for cardiovascular diseases; 0.01% to 1.62% (p<0.001) for bacterial/unspecified pneumonia; and 0.03% to 1.46% (p<0.001) for non-AIDS defining cancers. In the late post-HAART period, the most common associated causes of death were bacterial/unspecified pneumonia (35.94%), septicemia (33.46%), cardiovascular diseases (10.11%) and liver diseases (8.0%); and common underlying causes, besides AIDS disease, included non-AIDS-defining cancers in high-income areas, cardiovascular diseases in middle-income areas and assault in low-income areas. CONCLUSIONS: The introduction of HAART has shifted the mortality profile away from AIDS-related conditions, suggesting changes in the pattern of morbidity, but heterogeneously according to area of residence. There is a need for public policies aimed at adapting health care services to address the new scenario. PMID- 25500840 TI - Assessing and Treating Cardiovascular Risk: Traditional Moderation is the Way to Go. AB - No abstract available. PMID- 25500838 TI - Are Iranian obese women candidate for bariatric surgery different cognitively, emotionally and behaviorally from their normal weight counterparts? AB - OBJECTIVE: The purpose of the present study was to examine the cognitive, emotional and behavioral differences between obese and normal weight women. METHODS: The participants consisted of 60 obese women (BMI >= 35, Mean age 35.83) who were candidates for bariatric surgery and 60 normal weight women (BMI <= 24.90, Mean age 33.38) who were selected through convenient sampling method. The two groups were matched with respect to age and education. Measures included the Young Schema Questionnaire-Short Form, Difficulties in Emotion Regulation Scale (DERS) and the Binge Eating Scale. Independent sample t test and Mann-Whitney U tests were conducted to compare the two groups' scores on early maladaptive schemas, DER and binge eating. RESULTS: Results indicated that obese women candidate for bariatric surgery scored significantly higher on emotional deprivation, mistrust, failure, dependency, enmeshment, self-sacrifice, especially abandonment, social isolation, vulnerability, self-control and subjugation schemas, but not on shame, entitlement, emotional inhibition and unrelenting standards. Obese women also displayed higher scores on three subscales of DERS, i.e., goal, impulse and strategies. BE scores were significantly higher in obese women than normal weight ones. CONCLUSION: The findings showed that obese women candidates for bariatric surgery suffered from more cognitive, emotional and behavioral vulnerability compared to women with normal weight. Addressing these vulnerabilities among obese women could improve outcomes of weight loss surgeries and cognitive behavioral interventions so that weight regain is minimized and better outcomes are achieved. PMID- 25500841 TI - Optimal Size AMBU(r) Laryngeal Mask Airway Among Asian Adult Population. AB - AIM: This was a randomized single blinded study to determine optimal size for Ambu(r)LMA (ALMA) among Malaysian adult population. METHODS: One hundred and twenty six non-paralyzed anaesthetized adult patients were block randomized into size 3, 4 and 5 Ambu(r)LMA. Optimal size is defined primarily by oropharyngeal pressure (OLP). Pharyngeal injury and ease of insertion are also taken into consideration. RESULTS: Mean OLP was significantly higher for Size 4 and 5 compared to size 3 (p<0.001) but similar between size 4 and 5. Number of insertion attempts and insertion time were similar between sizes. Size 5 required more manipulations during insertion (p<0.005) and had higher pharyngeal injury (p=0.001) compared to size 3 and 4. DISCUSSION: We recommend size 4 ALMA as the optimal size for Malaysian adults in view of the higher OLP compared to size 3, yet less pharyngeal injury than size 5 in spontaneously breathing patients. PMID- 25500839 TI - Role of IL-1beta in experimental cystic fibrosis upon P. aeruginosa infection. AB - Cystic fibrosis is associated with increased inflammatory responses to pathogen challenge. Here we revisited the role of IL-1beta in lung pathology using the experimental F508del-CFTR murine model on C57BL/6 genetic background (Cftr(tm1eur) or d/d), on double deficient for d/d and type 1 interleukin-1 receptor (d/d X IL-1R1-/-), and antibody neutralization. At steady state, young adult d/d mice did not show any signs of spontaneous lung inflammation. However, IL-1R1 deficiency conferred partial protection to repeated P. aeruginosa endotoxins/LPS lung instillation in d/d mice, as 50% of d/d mice succumbed to inflammation, whereas all d/d x IL-1R1-/- double mutants survived with lower initial weight loss and less pulmonary collagen and mucus production, suggesting that the absence of IL-1R1 signaling is protective in d/d mice in LPS-induced lung damage. Using P. aeruginosa acute lung infection we found heightened neutrophil recruitment in d/d mice with higher epithelial damage, increased bacterial load in BALF, and augmented IL-1beta and TNF-alpha in parenchyma as compared to WT mice. Thus, F508del-CFTR mice show enhanced IL-1beta signaling in response to P. aeruginosa. IL-1beta antibody neutralization had no effect on lung homeostasis in either d/d or WT mice, however P. aeruginosa induced lung inflammation and bacterial load were diminished by IL-1beta antibody neutralization. In conclusion, enhanced susceptibility to P. aeruginosa in d/d mice correlates with an excessive inflammation and with increased IL-1beta production and reduced bacterial clearance. Further, we show that neutralization of IL-1beta in d/d mice through the double mutation d/d x IL-1R1-/- and in WT via antibody neutralization attenuates inflammation. This supports the notion that intervention in the IL-1R1/IL-1beta pathway may be detrimental in CF patients. PMID- 25500842 TI - Assessment of Inter- and Intra-Audiologist Agreements on Auditory Brainstem Response (ABR) Waves Interpretation and ABR Variability. AB - AIM OF STUDY: This study investigated the consistency in Auditory Brainstem Response (ABR) waveform evaluations between two audiologists (inter-audiologist agreement) and within each of the audiologist (intra-audiologist agreement). METHODS: Two audiologists from one of the audiology clinics in Kuantan, Pahang, Malaysia were involved in this study. Both audiologists were required to identify and mark the presence of Waves I, III and V in 66 ABR waveforms. Over a one-month interval, each audiologist was required to carry out the same procedure on the same ABR waveforms. This process was continued until we had three separate reviews from each audiologist. RESULTS: There was a high inter-audiologist ABR waveform identification agreement (over the range 81.71-89.77%), but a lower intra-audiologist ABR waveform identification agreement (over the range 50%-78%) for both audiologists. Our results also showed a high intra-audiologist ABR latency agreement within 0.2 ms (>90%), but a slightly lower inter-audiologist latency agreement (75-84%) within 0.2 ms. CONCLUSION: Our results support the need for the clinic to implement further strategies for improving the respective lower agreements and consistencies. These include conducting a continuous education program and using an objective algorithm to support their interpretations. PMID- 25500843 TI - Transnasal oesophagoscopy: the feasibility and potential impact on service provision of an office based procedure for upper gastrointestinal disorders in malaysia. AB - A Health Technology Assessment (HTA) was conducted in 2011 to evaluate whether transnasal oesophagoscopy (TNE) should be made available at otorhinolaryngology (ORL) clinics in the Ministry of Health facilities. The safety, efficacy or effectiveness and economic implication of using transnasal oesophagoscopy (TNE) were reviewed. This review provides a summary of the HTA and an updated literature review as well as how this technology might potentially affect services in the Ministry of Health. PMID- 25500844 TI - Carotid intima media thickness and high sensitivity C-reactive protein as markers of cardiovascular risk in a malaysian population. AB - INTRODUCTION: Carotid intima media thickness (CIMT) being a cost effective and easily performed technique is useful in the detection of subclinical atherosclerosis and has been shown to be a prognosticator of cardiovascular events. The primary objective of this study was to obtain the distribution of CIMT measurements, highly sensitive C reactive protein (hs-CRP) and assessing health awareness and attitudes of the Malaysian population at cardiovascular disease (CVD) risk and not receiving lipid lowering agents. Secondarily the study sought to assess the significance of the relationship between these measurements against various patient characteristics. METHODS: Measurements of CIMT are obtained by ultrasonography of 12 sites within the common carotid artery was recorded for 123 subjects from a single centre tertiary hospital of Malaysia who had two or more CVD risk factors but were not receiving lipid lowering therapy. CVD risk factors and lipid and glucose profiles were analyzed with respect to distribution of CIMT and high-sensitivity Creactive protein (hs-CRP) values. RESULTS: The mean-max CIMT was 0.916+/-0.129mm (minimum 0.630mm, maximum 1.28mm) and the mean-mean CIMT was 0.743+/-0.110mm (minimum 0.482mm, maximum 1.050mm) and mean hs-CRP was 0.191mg/dL (minimum 0.030mg/dL, maximum 5.440mg/dL). Multivariate analyses confirmed a significant association between increasing CIMT and increasing age, total and low density lipoprotein cholesterol while log transformed hs-CRP levels showed significant association with increasing body mass index, waist circumference, high blood glucose and triglyceride levels. Our patients had good health awareness on CVD. CONCLUSION: Newly defined CIMT measurements and hs-CRP levels may be useful adjunctive tools to screen for atherosclerosis in the Malaysian population. It may help in refining risk stratification on top of traditional clinical assessment. PMID- 25500845 TI - Causes of Low HbA1c in Malaysian University Hospital. AB - INTRODUCTION: Glycohemoglobin (HbA1c) most accurately reflects the previous two to three months of glycaemic control. HbA1c should be measured regularly in all patients with diabetes, and values should be maintained below 7% to prevent the risk of chronic complications. Apart from the genetic variants of haemoglobins many other conditions also known to affect HbA1c measurements. In this study we evaluated the conditions that cause low HbA1c results. METHODS AND MATERIALS: The data was collected retrospectively HbA1c was measured in our laboratory by Biorad Variant II turbo 2.0. The method is based on chromatographic separation of HbA1c on a cation exchange cartridge. This method has been certified by National Glycohemoglobin Standardization Programme (NGSP). 58437 requests were received in a period of one year (January to December 2011). Medical records were reviewed to identify the conditions that might be associated with these low values. RESULTS: Among 58437 samples analysed, 53 patients had HbA1c levels < 4.0%. Fourteen patients had haemoglobinopathy. In 34 patients without Hb variants had conditions such as chronic liver disease, chronic kidney disease, haemolytic anaemia, pregnancy, and anaemia of chronic disease. Five non-pregnant individuals who were screened for diabetes mellitus had HbA1c levels < 4%. CONCLUSION: Our study underscores the importance of that both laboratories and the physicians should be aware of the factors that can influence the HbA1c results. The haematological status should be taken into consideration for proper interpretation of HbA1c results. PMID- 25500846 TI - Management and Clinical Outcome of Children with Transfusion-Dependent Thalassaemia in Hospital Tuanku Ja'afar Seremban. AB - The aim of this study was to evaluate the management and clinical outcome of transfusion-dependent thalassaemia children receiving care in the Paediatric Ambulatory Care Centre, Hospital Tuanku Ja'afar Seremban in comparison to The Malaysian Clinical Practice Guidelines. The demography, management and clinical outcome of the patients were documented using a checklist. Information on compliance to chelation agents was obtained through interview. There were twenty six patients recruited in this study out of thirty seven patients registered in the centre. This study showed that more effort and vigilance should be given to ensure that the management of these patients adheres to the guidelines and clinical outcome of these patients monitored closely. PMID- 25500847 TI - Peripancreatic tuberculous lymphadenitis in an immunocompetent patient. AB - Tuberculosis, an ancient disease continues to be a health care burden in Malaysia in the 21st century. Extrapulmonary tuberculosis is a less common presentation of tuberculosis and in particular peripancreatic tuberculous lymphadenitis is rarely seen. We report a case of a young immunocompetent boy presenting with a two month history of non productive chronic cough associated with loss of appetite and loss of weight. Investigations including CT Scan and Endoscopic ultrasound revealed multiple mediastinal lymphadenopathy and peripancreatic lymphadenopathy with central caseation necrosis. Histology of cervical lymph node was suggestive of tuberculosis and mycobacterium PCR was positive. The patient was subsequently treated with antituberculous therapy and had marked clinical improvement of his symptoms. This case outlines a rare presentation of a common disease and the application of newer investigative tools in making the diagnosis. PMID- 25500848 TI - Airway emergency from spontaneous haemorrhagic thyroid cancer. AB - Spontaneous thyroid haemorrhages are rare. There are reported cases occurring in thyroid nodules and cysts but none in thyroid malignancies. We describe a 48 year old who presented to the on-call ENT team with a rapidly progressing neck swelling that was interfering with his airway. After resuscitation, the patient underwent a right lobectomy to stop the bleeding. Histology showed a thyroid follicular carcinoma. As per the regional multidisciplinary team discussion, he underwent a completion thyroidectomy followed by radioactive iodine treatment. We conclude that spontaneous haemorrhages of the thyroid gland can occur in malignancies and stress the importance of early histological diagnosis. PMID- 25500849 TI - Oesophageal intubation and ventilation as initial airway support of newborn infant with tracheal agenesis. AB - Tracheal agenesis is a rare congenital airway anomaly which presents as an airway emergency at birth. We report a case of late premature Chinese infant with tracheal agenesis type II (by Floyd's classification) who presented with severe respiratory distress at birth. He had multiple failed attempts at intubations with accidental oesophageal intubation and ventilation. Tracheal agenesis with tracheo-oesophageal fistula was suspected from an emergency optical laryngoesophagoscopy done. The infant was subsequently stabilized on oesophageal ventilation. The diagnosis was confirmed on CT scan and parents were counseled regarding the poor outcome and decided for withdrawal at day 7 of life. PMID- 25500850 TI - A rare case of fulminant hemobilia resulting from gallstone erosion of the right hepatic artery. AB - Hemobilia is a rare but potentially lethal condition. The commonest cause of hemobilia is trauma, accounting up to 85% of all cases. Hemobilia caused by gallstones is very rare. Most of the cases of hemobilia are either managed conservatively or treated by embolization. Surgery is indicated only when there is an associated surgical condition or when embolization fails. We report a case of a 72-year-old patient with massive hemobilia caused by gallstone erosion to the adjacent artery, diagnosed intraoperatively. The complication was successfully managed by cholecystectomy and repair of the bleeding vessel. This case highlights the importance that hemobilia should be suspected in patients presenting with upper gastrointestinal bleeding. Although rare, massive hemobilia can be life threatening, leading to significant morbidity and mortality. Therefore, a high index of suspicion and timely intervention are important. PMID- 25500851 TI - Griscelli syndrome. AB - We report a case of Griscelli Syndrome (GS). Our patient initially presented with a diagnosis of haemophagocytic lymphistiocytosis (HLH). Subsequent microscopic analysis of the patient's hair follicle revealed abnormal distribution of melanosomes in the shaft, which is a hallmark for GS. Analysis of RAB27A gene in this patient revealed a homozygous mutation in exon 6, c.550C>T, p.R184X . This nonsense mutation causes premature truncation of the protein resulting in a dysfunctional RAB27A. Recognition of GS allows appropriate institution of therapy namely chemotherapy for HLH and curative haemotopoeitic stem cell transplantation. PMID- 25500852 TI - A Case of Recurrent Respiratory Papillomatosis Successfully Removed Via Endoscopic Argon Plasma Coagulation (APC) With No Evidence of Recurrence. AB - Recurrent respiratory papillomatosis (RRP) is a benign disease caused by the human papilloma virus (HPV), characterized by the formation of recurrent, epithelial neoplastic lesions in the airways. While benign, they can cause significant airway obstruction in some cases. Difficulties in treatment arise from the recurrent nature of the lesions despite repeated procedures. Other known procedures that result in deep tissue damage also cause unacceptable collateral damage to the underlying airway mucosa. We describe a case of recurrent papillomatosis that was successfully treated with argon plasma coagulation ( APC) when laser and electrocautery ablation had failed in the past. After the papillomatasis was treated with APC, there is no recurrence on repeat scope at 4 months and 9 months after the initial procedure. The procedure was done as a day case and there is no complication from the procedure. The property of the APC that allows it to cause only superficial thermal damage to the tissue makes it a suitable adjunct therapy to the treatment of papillomas, which are usually superficial lesions. PMID- 25500853 TI - Tuberculosis of the skull mimicking multiple myeloma. AB - There is a resurgence of tuberculosis globally but lesions affecting the skull are rare. Cases reported are of single, focal lesions as seen on plain x-rays. We report a 34 yearold patient with tuberculosis of the skull where multiple punched out lesions are seen, mimicking that of multiple myeloma. PMID- 25500854 TI - Kimura's Disease of the Parotid: A Complete Clinical-Radiological-Pathology Report. AB - Kimura's disease is rare chronic inflammatory disease with a distinct clinicopathological entity. It has three major components; inflammatory, vascular and fibrosis. It has to be considered as a differential diagnosis in young patient presenting with head and neck swelling. Although of unknown aetiology many hypothesis has been postulated. Inflammation is the most prominent and predominating characteristic in this disease. Although reported to be predominant in Asian literature regarding this disease is scanty. We report a complete clinical-radiological and pathological picture of this disease. PMID- 25500855 TI - Anti-neuronal antibodies in patients with fragile X syndrome: is there a role of autoimmunity in its pathogenesis? AB - BACKGROUND: Fragile X syndrome (FXS) is a single-gene disorder with a broad spectrum of involvement, including cognitive and behavioural impairments of varying degrees with specific physical features and a strong association with autism. OBJECTIVES: In this study, the frequency of serum anti-neural antibodies was investigated in FXS patients who did and those who did not manifest autism spectrum disorders (ASD) in comparison to typically developing controls. METHODS: The study involved 23 males (mean age, 19.78 +/- 6.56 years) who harboured a full mutation in the FMR1 gene. The control group comprised 19 healthy students (mean age 24.63 +/- 1.89 years). Serum anti-neuronal antibodies were analyzed using Western blotting. RESULTS: Serum anti-neuronal antibodies were present in 10/23 (43.48%) FXS males. CONCLUSION: Serum anti-neuronal antibodies were found in a subgroup of FXS patients. Autistic symptoms in FXS may, in part, be caused by auto-immune factors. Further studies in larger patient and control groups are necessary to elucidate the aetiopathogenic role of anti-neuronal antibodies in FXS patients. PMID- 25500856 TI - Precursor salt assisted syntheses of high-index faceted concave hexagon and nanorod-like polyoxometalates. AB - This paper describes an effective method for a precursor salt assisted fabrication and reshaping of two different polyoxometalates [(NH4)2Cu(MoO4)2 (ACM) and Cu3(MoO4)2(OH)2 (CMOH)] into five distinctive shapes through straightforward and indirect routes. Explicit regulation of the structural arrangements of ACM and CMOH has been studied in detail with altered precursor salt concentration employing our laboratory developed modified hydrothermal (MHT) method. Morphologically different ACM 3D architectures are evolved with higher molybdate concentration, whereas 1D growth of CMOH is observed with increased copper concentration. Interesting morphological transformation of the products has been accomplished employing one precursor salt at a time without using any other foreign reagent. It has been proven that large ACMs become labile in the presence of incoming Cu(II) and NH4(+) ions of the precursor salts. A new strategy for the conversion of faceted ACMs (hexagonal plate, circular plate and hollow flower) to exclusive CMOH nanorods through a Cu(II) assisted reaction has been adopted. According to thermodynamic consideration, the synthesis of rare concave nanostructures with high index facet is still challenging due to their higher reactivity. In this study, concave hexagonal ACM with high index facet {hkl} has been successfully prepared for the first time from hexagonal ACM through simple etching with ammonium heptamolybdate (AHM), which is another precursor salt. Hexagonal ACM corrugates to a concave hexagon because of the higher reactivity of the {001} crystal plane than that of the {010} plane. It has been shown that high index facet exposed concave hexagonal ACM serves as a better catalyst for the photodegradation of dye than the other microstructures enclosed by low index facets. PMID- 25500858 TI - A feasibility investigation for modeling and optimization of temperature in bone drilling using fuzzy logic and Taguchi optimization methodology. AB - Drilling of bone is a common procedure in orthopedic surgery to produce hole for screw insertion to fixate the fracture devices and implants. The increase in temperature during such a procedure increases the chances of thermal invasion of bone which can cause thermal osteonecrosis resulting in the increase of healing time or reduction in the stability and strength of the fixation. Therefore, drilling of bone with minimum temperature is a major challenge for orthopedic fracture treatment. This investigation discusses the use of fuzzy logic and Taguchi methodology for predicting and minimizing the temperature produced during bone drilling. The drilling experiments have been conducted on bovine bone using Taguchi's L25 experimental design. A fuzzy model is developed for predicting the temperature during orthopedic drilling as a function of the drilling process parameters (point angle, helix angle, feed rate and cutting speed). Optimum bone drilling process parameters for minimizing the temperature are determined using Taguchi method. The effect of individual cutting parameters on the temperature produced is evaluated using analysis of variance. The fuzzy model using triangular and trapezoidal membership predicts the temperature within a maximum error of +/-7%. Taguchi analysis of the obtained results determined the optimal drilling conditions for minimizing the temperature as A3B5C1.The developed system will simplify the tedious task of modeling and determination of the optimal process parameters to minimize the bone drilling temperature. It will reduce the risk of thermal osteonecrosis and can be very effective for the online condition monitoring of the process. PMID- 25500859 TI - Biomechanical testing of an innovative fixation procedure to stabilize olecranon osteotomy. AB - For the treatment of distal humerus an approach involving olecranon osteotomy is frequently preferred as it offers a clearer view, especially in cases of complex intraarticular fractures. It is however associated with the high risk of osteotomy-related complications such as nonunion, delayed healing, implant failure and migration of wires. The aim of the present study was to evaluate the stability of different new procedures that stabilize olecranon osteotomy compared with conventional tension band wiring. We hypothesize that the new implants provide equivalent stability as the conventional tension band wiring. To test the hypothesis 27 biomechanically evaluated synthetic ulnae were osteotomized and stabilized with either the application of tension band wiring, the Olecranon Hook LCP (Synthes, Switzerland), or the Olecranon Osteotomy nail (Synthes, Switzerland). Loading was performed providing a tensile load to simulate the tensile force applied by the triceps muscle. Cyclic force-controlled loading was performed at 300 alternating forces between 10N and 500N at a speed of 200N/sec. An ultrasound-based system measured displacement to an accuracy of 0.1 mm. Statistical analysis showed significantly less displacement in the Olecranon Hook LCP and Olecranon Osteotomy nail groups compared with tension banding. Comparison of plate and nail yielded no differences in stability. Biomechanical testing did however show significantly higher stability for newer fixation methods for olecranon osteotomies compared with the frequently applied technique of tension band wiring. Whether the use of these implants will also lower complication rates remains to be evaluated in future clinical studies. LEVEL OF EVIDENCE: Basic Science Study, Biomechanical Study. PMID- 25500860 TI - Corneal topography matching by iterative registration. AB - Videokeratography is used for the measurement of corneal topography in overlapping portions (or maps) which must later be joined together to form the overall topography of the cornea. The separate portions are measured from different viewpoints and therefore must be brought together by registration of measurement points in the regions of overlap. The central map is generally the most accurate, but all maps are measured with uncertainty that increases towards the periphery. It becomes the reference (or static) map, and the peripheral (or dynamic) maps must then be transformed by rotation and translation so that the overlapping portions are matched. The process known as registration, of determining the necessary transformation, is a well-understood procedure in image analysis and has been applied in several areas of science and engineering. In this article, direct search optimisation using the Nelder-Mead algorithm and several variants of the iterative closest/corresponding point routine are explained and applied to simulated and real clinical data. The measurement points on the static and dynamic maps are generally different so that it becomes necessary to interpolate, which is done using a truncated series of Zernike polynomials. The point-to-plane iterative closest/corresponding point variant has the advantage of releasing certain optimisation constraints that lead to persistent registration and alignment errors when other approaches are used. The point-to-plane iterative closest/corresponding point routine is found to be robust to measurement noise, insensitive to starting values of the transformation parameters and produces high-quality results when using real clinical data. PMID- 25500861 TI - A standardized representation of spinal quality of motion. AB - The experimentally determined torque-rotation curve of the lumbar spine is mathematically described with a proposed dual-inflection point Boltzmann equation. The result is a method for describing functional spinal unit motion data. The benefit of the model is that each of the coefficients has a specific meaning in relation to the torque-rotation curve: the points A and B identify the respective minimum and maximum rotations of the functional spinal unit, m1 and m2 indicate the inflection points of the curve where the stiffness changes markedly, and alpha1 and alpha2 are associated with the rates of change of the curve at m1 and m2, respectively. The dual-inflection point Boltzmann captures the full quality of motion of the spinal segment and can also be used to derive relevant parameters such as range of motion, midrange stiffness, and hysteresis. PMID- 25500862 TI - Investigations of wear particles and selected cytokines in human osteoarthritic knee joints. AB - Inflammation of the synovial membrane (synovitis) is considered to drive the process that leads to osteoarthritis. However, the relationships between the mediators of inflammation and the properties of wear particles are not fully understood. In this study, the levels of IL-6 and IL-8 were assessed in different grades of osteoarthritis to determine whether their concentrations in the synovial fluid correlate with specific characteristics of wear particles. This study has found that the size, adhesion and nano-surface roughness of wear particles have medium strong to strong correlations with IL-6 and IL-8. This study provided evidence that the characteristics of wear particles contain valuable information for grading the disease process and the need for further evaluation of the association of properties of wear particles and the inflammatory process. PMID- 25500863 TI - Accuracy evaluation of a new stereophotogrammetry-based functional method for joint kinematic analysis in biomechanics. AB - The human joint kinematics is an interesting topic in biomechanics and turns to be useful for the analysis of human movement in several fields. A crucial issue regards the assessment of joint parameters, like axes and centers of rotation, due to the direct influence on human motion patterns. A proper accuracy in the estimation of these parameters is hence required. On the whole, stereophotogrammetry-based predictive methods and, as an alternative, functional ones can be used to this end. This article presents a new functional algorithm for the assessment of knee joint parameters, based on a polycentric hinge model for the knee flexion-extension. The proposed algorithm is discussed, identifying its fields of application and its limits. The techniques for estimating the joint parameters from the metrological point of view are analyzed, so as to lay the groundwork for enhancing and eventually replacing predictive methods, currently used in the laboratories of human movement analysis. This article also presents an assessment of the accuracy associated with the whole process of measurement and joint parameters estimation. To this end, the presented functional method is tested through both computer simulations and a series of experimental laboratory tests in which swing motions were imposed to a polycentric mechanical analogue and a stereophotogrammetric system was used to record them. PMID- 25500865 TI - The effect of in situ/in vitro three-dimensional quantitative computed tomography image voxel size on the finite element model of human vertebral cancellous bone. AB - Quantitative computed tomography-based finite element modeling technique is a promising clinical tool for the prediction of bone strength. However, quantitative computed tomography-based finite element models were created from image datasets with different image voxel sizes. The aim of this study was to investigate whether there is an influence of image voxel size on the finite element models. In all 12 thoracolumbar vertebrae were scanned prior to autopsy (in situ) using two different quantitative computed tomography scan protocols, which resulted in image datasets with two different voxel sizes (0.29 * 0.29 * 1.3 mm(3) vs 0.18 * 0.18 * 0.6 mm(3)). Eight of them were scanned after autopsy (in vitro) and the datasets were reconstructed with two voxel sizes (0.32 * 0.32 * 0.6 mm(3) vs. 0.18 * 0.18 * 0.3 mm(3)). Finite element models with cuboid volume of interest extracted from the vertebral cancellous part were created and inhomogeneous bilinear bone properties were defined. Axial compression was simulated. No effect of voxel size was detected on the apparent bone mineral density for both the in situ and in vitro cases. However, the apparent modulus and yield strength showed significant differences in the two voxel size group pairs (in situ and in vitro). In conclusion, the image voxel size may have to be considered when the finite element voxel modeling technique is used in clinical applications. PMID- 25500864 TI - Computational investigation of the time-dependent contact behaviour of the human tibiofemoral joint under body weight. AB - The knee joint is one of the most common sites for osteoarthritis, the onset and progression of which are believed to relate to the mechanical environment of cartilage. To understand this environment, it is necessary to take into account the complex biphasic contact interactions of the cartilage and menisci. In this study, the time-dependent contact behaviour of an intact and a meniscectomized human tibiofemoral joint was characterized under body weight using a computational model. Good agreement in the contact area and femoral displacement under static loads were found between model predictions of this study and published experimental measurements. The time-dependent results indicated that as loading time progressed, the contact area and femoral vertical displacement of both intact and meniscectomized joints increased. More load was transferred to the cartilage-cartilage interface over time. However, the portions of load borne by the lateral and medial compartments did not greatly vary with time. Additionally, during the whole simulation period, the maximum compressive stress in the meniscectomized joint was higher than that in the intact joint. The fluid pressure in the intact and meniscectomized joints remained remarkably high at the condyle centres, but the fluid pressure at the cartilage-meniscus interface decreased faster than that at the condyle centres as loading time progressed. The above findings provide further insights into the mechanical environment of the cartilage and meniscus within the human knee joint. PMID- 25500866 TI - A population pharmacokinetic study of tacrolimus in healthy Chinese volunteers and liver transplant patients. AB - AIM: To develop a population pharmacokinetic (PopPK) model of tacrolimus in healthy Chinese volunteers and liver transplant recipients for investigating the difference between the populations, and for potential individualized medication. METHODS: A set of 1100 sparse trough concentration data points from 112 orthotopic liver transplant recipients, as well as 851 dense data points from 40 healthy volunteers receiving a single dose of tacrolimus (2 mg, p.o.) were collected. PopPK model of tacrolimus was constructed using the program NONMEM. Related covariates such as age, hepatic and renal functions that were potentially associated with tacrolimus disposition were evaluated. The final model was validated using bootstrapping and a visual predictive check. RESULTS: A two compartment model of tacrolimus could best describe the data from the two populations. The final model including two covariates, population (liver transplant recipients or volunteers) and serum ALT (alanine aminotransferase) level, was verified and adequately described the pharmacokinetic characteristics of tacrolimus. The estimates of V2/F, Q/F and V3/F were 22.7 L, 76.3 L/h and 916 L, respectively. The estimated CL/F in the volunteers and liver transplant recipients was 32.8 and 18.4 L/h, respectively. Serum ALT level was inversely related to CL/F, whereas age did not influence CL/F. Thus, the elderly (>=65 years) and adult (<65 years) groups in the liver transplant recipients showed no significant difference in the clearance of tacrolimus. CONCLUSION: Compared with using the sparse data only, the integrating modeling technique combining sparse data from the patients and dense data from the healthy volunteers improved the PopPK analysis of tacrolimus. PMID- 25500867 TI - A structural perspective on nuclear receptors as targets of environmental compounds. AB - Nuclear receptors (NRs) are members of a large superfamily of evolutionarily related transcription factors that control a plethora of biological processes. NRs orchestrate complex events such as development, organ homeostasis, metabolism, immune function, and reproduction. Approximately one-half of the 48 human NRs have been shown to act as ligand-regulated transcription factors and respond directly to a large variety of endogenous hormones and metabolites that are generally hydrophobic and small in size (eg, retinoic acid or estradiol). The second half of the NR family comprises the so-called orphan receptors, for which regulatory ligands are still unknown or may not exist despite the presence of a C terminal ligand-binding domain, which is the hallmark of all NRs. Several chemicals released into the environment (eg, bisphenols, phthalates, parabens, etc) share some physicochemical properties with natural ligands, allowing them to bind to NRs and activate or inhibit their action. Collectively referred to as endocrine disruptors or endocrine-disrupting chemicals (EDCs), these environmental pollutants are highly suspected to cause a wide range of developmental, reproductive, neurological, or metabolic defects in humans and wildlife. Crystallographic studies are revealing unanticipated mechanisms by which chemically diverse EDCs interact with the ligand-binding domain of NRs. These studies thereby provide a rational basis for designing novel chemicals with lower impacts on human and animal health. In this review, we provide a structural and mechanistic view of endocrine disrupting action using estrogen receptors alpha and beta, (ERalpha/beta), peroxisome proliferator activated receptor gamma (PPARgamma), and their respective environmental ligands as representative examples. PMID- 25500868 TI - ROR nuclear receptors: structures, related diseases, and drug discovery. AB - Nuclear receptors (NRs) are ligand-regulated transcription factors that regulate metabolism, development and immunity. The NR superfamily is one of the major classes of drug targets for human diseases. Retinoic acid receptor-related orphan receptor (ROR) alpha, beta and gamma belong to the NR superfamily, and these receptors are still considered as 'orphan' receptors because the identification of their endogenous ligands has been controversial. Recent studies have demonstrated that these receptors are regulated by synthetic ligands, thus emerge as important drug targets for the treatment of multiple sclerosis, rheumatoid arthritis, psoriasis, etc. Studying the structural basis and ligand development of RORs will pave the way for a better understanding of the roles of these receptors in human diseases. Here, we review the structural basis, disease relevance, strategies for ligand identification, and current status of development of therapeutic ligands for RORs. PMID- 25500869 TI - Deciphering the roles of the constitutive androstane receptor in energy metabolism. AB - The constitutive androstane receptor (CAR) is initially defined as a xenobiotic nuclear receptor that protects the liver from injury. Detoxification of damaging chemicals is achieved by CAR-mediated induction of drug-metabolizing enzymes and transporters. More recent research has implicated CAR in energy metabolism, suggesting a therapeutic potential for CAR in metabolic diseases, such as type 2 diabetes and obesity. A better understanding of the mechanisms by which CAR regulates energy metabolism will allow us to take advantage of its effectiveness while avoiding its side effects. This review summarizes the current progress on the regulation of CAR nuclear translocation, upstream modulators of CAR activity, and the crosstalk between CAR and other transcriptional factors, with the aim of elucidating how CAR regulates glucose and lipid metabolism. PMID- 25500870 TI - Identification of estrogen-responsive genes based on the DNA binding properties of estrogen receptors using high-throughput sequencing technology. AB - Estrogens are important endocrine hormones that control physiological functions in reproductive organs, and play a pivotal role in the generation and progression of breast cancer. Therapeutic drugs including anti-estrogen and aromatase inhibitors are used to treat patients with breast cancer. The estrogen receptors, ERalpha and ERbeta, function as hormone-dependent transcription factors that directly regulate the expression of their target genes. Therefore, a better understanding of the function and regulation of estrogen-responsive genes provides insight into the gene regulation network associated with breast cancer. Recent technological developments in high-throughput sequencing have enabled the genome-wide identification of estrogen-responsive genes. Further elucidating the estrogen gene cascade is critical for advancements in the diagnosis and treatment of breast cancer. PMID- 25500871 TI - The use of marine-derived bioactive compounds as potential hepatoprotective agents. AB - The marine environment may be explored as a rich source for novel drugs. A number of marine-derived compounds have been isolated and identified, and their therapeutic effects and pharmacological profiles are characterized. In the present review, we highlight the recent studies using marine compounds as potential hepatoprotective agents for the treatment of liver fibrotic diseases and discuss the proposed mechanisms of their activities. In addition, we discuss the significance of similar studies in Oman, where the rich marine life provides a potential for the isolation of novel natural, bioactive products that display therapeutic effects on liver diseases. PMID- 25500872 TI - The multiple universes of estrogen-related receptor alpha and gamma in metabolic control and related diseases. AB - The identification of the estrogen-related receptors (ERRs) as the first orphan nuclear receptors ignited a new era in molecular endocrinology, which led to the discovery of new ligand-dependent response systems. Although ERR subfamily members have yet to be associated with a natural ligand, the characterization of these orphan receptors has demonstrated that they occupy a strategic node in the transcriptional control of cellular energy metabolism. In particular, ERRs are required for the response to various environmental challenges that require high energy levels by the organism. As central regulators of energy homeostasis, ERRs may also be implicated in the etiology of metabolic disorders, such as type 2 diabetes and metabolic syndrome. Here, we review the recent evidence that further highlights the role of ERRs in metabolic control, particularly in liver and skeletal muscle, and their likely involvement in metabolic diseases. Consequently, we also explore the promises and pitfalls of ERRs as potential therapeutic targets. PMID- 25500873 TI - Bridging cell surface receptor with nuclear receptors in control of bile acid homeostasis. AB - Bile acids (BAs) are traditionally considered as "physiological detergents" for emulsifying hydrophobic lipids and vitamins due to their amphipathic nature. But accumulating clinical and experimental evidence shows an association between disrupted BA homeostasis and various liver disease conditions including hepatitis infection, diabetes and cancer. Consequently, BA homeostasis regulation has become a field of heavy interest and investigation. After identification of the Farnesoid X Receptor (FXR) as an endogenous receptor for BAs, several nuclear receptors (SHP, HNF4alpha, and LRH-1) were also found to be important in regulation of BA homeostasis. Some post-translational modifications of these nuclear receptors have been demonstrated, but their physiological significance is still elusive. Gut secrets FGF15/19 that can activate hepatic FGFR4 and its downstream signaling cascade, leading to repressed hepatic BA biosynthesis. However, the link between the activated kinases and these nuclear receptors is not fully elucidated. Here, we review the recent literature on signal crosstalk in BA homeostasis. PMID- 25500874 TI - FXR and liver carcinogenesis. AB - Farnesoid X receptor (FXR) is a member of the nuclear receptor family and a ligand-modulated transcription factor. In the liver, FXR has been considered a multi-functional cell protector and a tumor suppressor. FXR can suppress liver carcinogenesis via different mechanisms: 1) FXR maintains the normal liver metabolism of bile acids, glucose and lipids; 2) FXR promotes liver regeneration and repair after injury; 3) FXR protects liver cells from death and enhances cell survival; 4) FXR suppresses hepatic inflammation, thereby preventing inflammatory damage; and 5) FXR can directly increase the expression of some tumor-suppressor genes and repress the transcription of several oncogenes. However, inflammation and epigenetic silencing are known to decrease FXR expression during tumorigenesis. The reactivation of FXR function in the liver may be a potential therapeutic approach for patients with liver cancer. PMID- 25500875 TI - Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis. AB - Non-alcoholic fatty liver disease (NAFLD) is characterized by the aberrant accumulation of triglycerides in hepatocytes in the absence of significant alcohol consumption, viral infection or other specific causes of liver disease. NAFLD has become a burgeoning health problem both worldwide and in China, but its pathogenesis remains poorly understood. Farnesoid X receptor (FXR), a member of the nuclear receptor (NR) superfamily, has been demonstrated to be the primary sensor for endogenous bile acids, and play a crucial role in hepatic triglyceride homeostasis. Deciphering the synergistic contributions of FXR to triglyceride metabolism is critical for discovering therapeutic agents in the treatment of NAFLD and hypertriglyceridemia. PMID- 25500877 TI - Current optimal morphological evaluation of peripheral arterial diseases. AB - Imaging plays a central role in the management of peripheral arterial diseases (PAD), emphasized by the continuously increasing use of modern cross-sectional imaging and the corresponding decline of digital subtraction angiography (DSA) in the diagnostic setting. Imaging is sometimes used as a screening tool in high risk individuals. In symptomatic patients, imaging is mandatory to make an accurate positive diagnosis, grade the severity and the extent of the abnormalities, carefully choose and plan the best therapeutic option and provide adequate follow-up. Non-invasive diagnosis of PAD can be made by Doppler ultrasonography, magnetic resonance angiography (MRA) and computed tomography angiography (CTA). Given the major technological breakouts over the last decade, MRA and especially CTA are nowadays mature and precise enough to properly answer all the questions raised in symptomatic patients. This review article aims at describing state-of-the-art non-invasive imaging of PAD, its involvement in the decision-making for the vascular surgeon and the future trends and developments expected in the coming years. PMID- 25500876 TI - Sitagliptin protects rat kidneys from acute ischemia-reperfusion injury via upregulation of GLP-1 and GLP-1 receptors. AB - AIM: Sitagliptin, an oral glucose-lowering agent, has been found to produce cardiovascular protection possibly via anti-inflammatory and anti-atherosclerotic activities of glucagon-like peptide-1 receptor (GLP-1). The aim of this study was to investigate whether sitagliptin protected the kidney function from acute ischemia-reperfusion (IR) injury in rats. METHODS: Adult male SD rats were categorized into 4 groups: sham control, IR injury, IR+sitagliptin (300 mg/kg) and IR+sitagliptin (600 mg/kg). Acute renal IR injury of both kidneys was induced by clamping the renal pedicles for 1 h. The drug was orally administered at 1, 24 and 48 h after acute IR. Blood samples and 24-h urine were collected before and at 72 h after acute IR. Then the rats were sacrificed, and the kidneys were harvested for biochemical and immunohistochemical studies. RESULTS: Acute IR procedure markedly increased serum levels of creatinine and BUN and the ratio of urine protein to creatinine. The kidney injury score, inflammatory biomarkers (MMP-9, TNF-alpha and NF-kappaB) levels and CD68+ cells in IR kidneys were considerably increased. The expression of oxidized protein, reactive oxygen species (NOX-1, NOX-2) and apoptosis proteins (Bax, caspase-3, PARP) in IR kidneys was also significantly upregulated. All these pathological changes were suppressed by sitagliptin in a dose-dependent manner. Furthermore, the serum GLP 1 level, and the expression of GLP-1 receptor, anti-oxidant biomarkers (HO-1 and NQO-1 cells, as well as SOD-1, NQO-1 and HO-1 proteins), and angiogenesis markers (SDF-1alpha+ and CXCR4+ cells) in IR kidneys were significantly increased, and further upregulated by sitagliptin. CONCLUSION: Sitagliptin dose-dependently protects rat kidneys from acute IR injury via upregulation of serum GLP-1 and GLP 1 receptor expression in kidneys. PMID- 25500878 TI - Bringing home the bacon? The next step in cardiac sodium channelopathies. AB - Mutations in SCN5A, which encodes the alpha subunit of the major cardiac sodium channel Na(V)1.5, are associated with multiple cardiac arrhythmias, including Brugada syndrome. It is not clear why mutations in SCN5A result in such a variety of cardiac phenotypes, and introduction of analogous Scn5a mutations into small animal models has not recapitulated alterations in cardiac physiology associated with human disease. In this issue of the JCI, Park and colleagues present a pig model of cardiac sodium channelopathy that was generated by introducing a human Brugada syndrome-associated SCN5A allele. This large-animal model exhibits many phenotypes seen in patients with SCN5A loss-of-function mutations and has the potential to provide important insight into sodium channelopathies. PMID- 25500879 TI - AGS, SLE, and RNASEH2 mutations: translating insights into therapeutic advances. AB - Systemic lupus erythematosus (SLE) is a severe autoimmune disease characterized by the presence of nucleic acid- and protein-targeting autoantibodies and an aberrant type I IFN expression signature. Aicardi-Goutieres syndrome (AGS) is an autosomal-recessive encephalopathy in children that is characterized by mutations in numerous nucleic acid repair enzymes and elevated IFN levels. Phenotypically, patients with AGS and SLE share many similarities. Ribonuclease H2 (RNase H2) is a nucleic acid repair enzyme that removes unwanted ribonucleotides from DNA. In this issue of the JCI, Gunther and colleagues provide an in-depth investigation of the mechanisms underlying the link between defective removal of ribonucleotides in AGS and SLE, and these findings will likely serve as a strong springboard to provide novel therapeutic inroads. PMID- 25500880 TI - Immune therapy for treating type 1 diabetes: challenging existing paradigms. AB - Patients with type 1 diabetes (T1D) rapidly lose beta cell function and/or mass, leading to a life-long dependence on insulin therapy. beta Cell destruction is mediated by aberrant immune responses; therefore, immune modulation has potential to ameliorate disease. While immune intervention in animal models of diabetes has shown promising results, treatment of patients with T1D with the same agents has not been as successful. In this issue of the JCI, Haller and colleagues present data from a small clinical trial that tested the efficacy of a combination of immunomodulatory agents, anti-thymocyte globulin and pegylated granulocyte CSF, neither of which have shown benefit for T1D as single treatment agents. Many patients that received combination therapy maintained beta cell function at baseline levels up to a year after treatment. The results from this study challenge current trial design paradigm that for combined therapy to be successful individual agents should show benefit. PMID- 25500881 TI - The genetics of hepatitis C virus underlie its ability to escape humoral immunity. AB - Hepatitis C virus (HCV) is a leading cause of chronic liver disease, and efforts to develop therapeutic vaccine strategies have been limited by immune escape due to HCV variants that are resistant to current vaccines or HCV variants that rapidly acquire new resistance-conferring mutations. Recently, the crystal structure of the viral envelope protein E2 region was resolved as well as how E2 docks to the host CD81 protein; therefore, antibodies that block this interaction should prevent viral entry into host cells. In this issue of the JCI, Bailey and colleagues show that immune escape of HCV can occur by naturally occurring polymorphisms in E2 that are distinct from those at mapped sites of antibody binding. These data reveal alternative mechanisms of resistance that need to be considered in both natural viral escape as well as in rationale vaccine design against HCV. PMID- 25500882 TI - Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias. AB - SCN5A encodes the alpha subunit of the major cardiac sodium channel Na(V)1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5A(E558X/+) pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5A(E558X/+) hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5A(E558X/+) pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias. PMID- 25500883 TI - Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. AB - Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutieres syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity. PMID- 25500884 TI - Naturally selected hepatitis C virus polymorphisms confer broad neutralizing antibody resistance. AB - For hepatitis C virus (HCV) and other highly variable viruses, broadly neutralizing mAbs are an important guide for vaccine development. The development of resistance to anti-HCV mAbs is poorly understood, in part due to a lack of neutralization testing against diverse, representative panels of HCV variants. Here, we developed a neutralization panel expressing diverse, naturally occurring HCV envelopes (E1E2s) and used this panel to characterize neutralizing breadth and resistance mechanisms of 18 previously described broadly neutralizing anti HCV human mAbs. The observed mAb resistance could not be attributed to polymorphisms in E1E2 at known mAb-binding residues. Additionally, hierarchical clustering analysis of neutralization resistance patterns revealed relationships between mAbs that were not predicted by prior epitope mapping, identifying 3 distinct neutralization clusters. Using this clustering analysis and envelope sequence data, we identified polymorphisms in E2 that confer resistance to multiple broadly neutralizing mAbs. These polymorphisms, which are not at mAb contact residues, also conferred resistance to neutralization by plasma from HCV infected subjects. Together, our method of neutralization clustering with sequence analysis reveals that polymorphisms at noncontact residues may be a major immune evasion mechanism for HCV, facilitating viral persistence and presenting a challenge for HCV vaccine development. PMID- 25500885 TI - Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a major worldwide health problem. Recent studies suggest that the gut microbiota influences NAFLD pathogenesis. Here, a murine model of high-fat diet-induced (HFD-induced) NAFLD was used, and the effects of alterations in the gut microbiota on NAFLD were determined. Mice treated with antibiotics or tempol exhibited altered bile acid composition, with a notable increase in conjugated bile acid metabolites that inhibited intestinal farnesoid X receptor (FXR) signaling. Compared with control mice, animals with intestine-specific Fxr disruption had reduced hepatic triglyceride accumulation in response to a HFD. The decrease in hepatic triglyceride accumulation was mainly due to fewer circulating ceramides, which was in part the result of lower expression of ceramide synthesis genes. The reduction of ceramide levels in the ileum and serum in tempol- or antibiotic-treated mice fed a HFD resulted in downregulation of hepatic SREBP1C and decreased de novo lipogenesis. Administration of C16:0 ceramide to antibiotic-treated mice fed a HFD reversed hepatic steatosis. These studies demonstrate that inhibition of an intestinal FXR/ceramide axis mediates gut microbiota-associated NAFLD development, linking the microbiome, nuclear receptor signaling, and NAFLD. This work suggests that inhibition of intestinal FXR is a potential therapeutic target for NAFLD treatment. PMID- 25500886 TI - Targeting development of incretin-producing cells increases insulin secretion. AB - Glucagon-like peptide-1-based (GLP-1-based) therapies improve glycemic control in patients with type 2 diabetes. While these agents augment insulin secretion, they do not mimic the physiological meal-related rise and fall of GLP-1 concentrations. Here, we tested the hypothesis that increasing the number of intestinal L cells, which produce GLP-1, is an alternative strategy to augment insulin responses and improve glucose tolerance. Blocking the NOTCH signaling pathway with the gamma-secretase inhibitor dibenzazepine increased the number of L cells in intestinal organoid-based mouse and human culture systems and augmented glucose-stimulated GLP-1 secretion. In a high-fat diet-fed mouse model of impaired glucose tolerance and type 2 diabetes, dibenzazepine administration increased L cell numbers in the intestine, improved the early insulin response to glucose, and restored glucose tolerance. Dibenzazepine also increased K cell numbers, resulting in increased gastric inhibitory polypeptide (GIP) secretion. Using a GLP-1 receptor antagonist, we determined that the insulinotropic effect of dibenzazepine was mediated through an increase in GLP-1 signaling. Together, our data indicate that modulation of the development of incretin-producing cells in the intestine has potential as a therapeutic strategy to improve glycemic control. PMID- 25500887 TI - Anti-thymocyte globulin/G-CSF treatment preserves beta cell function in patients with established type 1 diabetes. AB - BACKGROUND: Previous efforts to preserve beta cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve beta cell function in patients with established T1D (duration of T1D >4 months and <2 years). METHODS: A randomized, single-blinded, placebo-controlled trial was performed on 25 subjects: 17 subjects received ATG (2.5 mg/kg intravenously) followed by pegylated G-CSF (6 mg subcutaneously every 2 weeks for 6 doses) and 8 subjects received placebo. The primary outcome was the 1-year change in AUC C-peptide following a 2-hour mixed-meal tolerance test (MMTT). At baseline, the age (mean +/- SD) was 24.6 +/- 10 years; mean BMI was 25.4 +/- 5.2 kg/m2; mean A1c was 6.5% +/- 1.1%; insulin use was 0.31 +/- 0.22 units/kg/d; and length of diagnosis was 1 +/- 0.5 years. RESULTS: Combination ATG/G-CSF treatment tended to preserve beta cell function in patients with established T1D. The mean difference in MMTT stimulated AUC C-peptide between treated and placebo subjects was 0.28 nmol/l/min (95% CI 0.001-0.552, P = 0.050). A1c was lower in ATG/G-CSF-treated subjects at the 6-month study visit. ATG/G-CSF therapy was associated with relative preservation of Tregs. CONCLUSIONS: Patients with established T1D may benefit from combination immunotherapy approaches to preserve beta cell function. Further studies are needed to determine whether such approaches may prevent or delay the onset of the disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT01106157. FUNDING: The Leona M. and Harry B. Helmsley Charitable Trust and Sanofi. PMID- 25500888 TI - CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer's disease model. AB - Chemokines are important modulators of neuroinflammation and neurodegeneration. In the brains of Alzheimer's disease (AD) patients and in AD animal models, the chemokine CXCL10 is found in high concentrations, suggesting a pathogenic role for this chemokine and its receptor, CXCR3. Recent studies aimed at addressing the role of CXCR3 in neurological diseases indicate potent, but diverse, functions for CXCR3. Here, we examined the impact of CXCR3 in the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD. We found that, compared with control APP/PSI animals, plaque burden and Abeta levels were strongly reduced in CXCR3-deficient APP/PS1 mice. Analysis of microglial phagocytosis in vitro and in vivo demonstrated that CXCR3 deficiency increased the microglial uptake of Abeta. Application of a CXCR3 antagonist increased microglial Abeta phagocytosis, which was associated with reduced TNF-alpha secretion. Moreover, in CXCR3-deficient APP/PS1 mice, microglia exhibited morphological activation and reduced plaque association, and brain tissue from APP/PS1 animals lacking CXCR3 had reduced concentrations of proinflammatory cytokines compared with controls. Further, loss of CXCR3 attenuated the behavioral deficits observed in APP/PS1 mice. Together, our data indicate that CXCR3 signaling mediates development of AD-like pathology in APP/PS1 mice and suggest that CXCR3 has potential as a therapeutic target for AD. PMID- 25500890 TI - A peptide from Porphyra yezoensis stimulates the proliferation of IEC-6 cells by activating the insulin-like growth factor I receptor signaling pathway. AB - Porphyra yezoensis (P. yezoensis) is the most noteworthy red alga and is mainly consumed in China, Japan and Korea. In the present study, the effects of a P. yezoensis peptide (PY-PE) on cell proliferation and the associated signaling pathways were examined in IEC-6 rat intestinal epithelial cells. First, the MTS assay showed that PY-PE induced cell proliferation in a dose-dependent manner. Subsequently, the mechanism behind the proliferative activity induced by PY-PE was determined. The insulin-like growth factor-I receptor (IGF-IR) signaling pathway was the main focus as it plays an important role in the regulation of cell growth and proliferation. PY-PE increased the protein and mRNA expression of IGF-IR, insulin receptor substrate-1, Shc and PY-99. In addition, PY-PE stimulated extracellular signal-regulated kinase phosphorylation and phosphatidylinositol 3-kinase/Akt activation but inhibited p38 and c-Jun N terminal kinase phosphorylation. Furthermore, PY-PE treatment increased protein and mRNA expression levels of activator protein-1, which regulates cell proliferation and survival, in the nuclear fraction. These results have significant implications for understanding the role of cell proliferation signaling pathways in intestinal epithelial cells. PMID- 25500889 TI - TALEN-mediated targeting of HPV oncogenes ameliorates HPV-related cervical malignancy. AB - Persistent HPV infection is recognized as the main etiologic factor for cervical cancer. HPV expresses the oncoproteins E6 and E7, both of which play key roles in maintaining viral infection and promoting carcinogenesis. While siRNA-mediated targeting of E6 and E7 transcripts temporarily induces apoptosis in HPV-positive cells, it does not eliminate viral DNA within the host genome, which can harbor escape mutants. Here, we demonstrated that specifically targeting E6 and E7 within host DNA with transcription activator-like effector nucleases (TALENs) induces apoptosis, inhibits growth, and reduces tumorigenicity in HPV-positive cell lines. TALEN treatment efficiently disrupted E6 and E7 oncogenes, leading to the restoration of host tumor suppressors p53 and retinoblastoma 1 (RB1), which are targeted by E6 and E7, respectively. In the K14-HPV16 transgenic mouse model of HPV-driven neoplasms, direct cervical application of HPV16-E7-targeted TALENs effectively mutated the E7 oncogene, reduced viral DNA load, and restored RB1 function and downstream targets transcription factor E2F1 and cycling-dependent kinase 2 (CDK2), thereby reversing the malignant phenotype. Together, the results from our study suggest that TALENs have potential as a therapeutic strategy for HPV infection and related cervical malignancy. PMID- 25500891 TI - Identification of histamine receptor subtypes in skeletal myogenesis. AB - To date, conventional and/or novel histamine receptors (HRs) have not been investigated in mouse skeletal myogenesis. Therefore, the present study aimed to investigate the HR-subtypes in skeletal myogenesis. The myogenesis of C2C12 skeletal myoblasts was evaluated using desmin, myogenin and myosin heavy chain (Myh) as early, intermediate and late differentiation markers, respectively. Reverse transcription-quantitative polymerase chain reaction and immunostaining were performed and the messenger RNA (mRNA) expression levels of the HR-subtypes and markers were determined. H1R mRNA was found to be highly expressed in myoblasts at day 0; however, the expression levels were reduced as differentiation progressed. By contrast, H2R mRNA expression remained constant, while H3R mRNA expression increased by 28-, 103- and 198-fold at days 2, 4 and 6 compared with the baseline level (day 0), respectively. In addition, Myh expression increased by 7,718-, 94,487- and 286,288-fold on days 2, 4 and 6 compared with the baseline expression level (day 0). Weak positive staining of the cells for H3R protein was observed on day 2, whereas highly positive staining was observed on days 4 and 6. HR expression during myogenesis was, in part, regulated by the stage of differentiation. These results along with previous findings indicated possible involvement of H1R in the regulation of progenitor cell mitogenesis and of H2R in the relaxation of acetylcholine-stimulated contraction of muscle cells, following the activation of professional histamine producing cells, including mast cells. By contrast, H3R may participate in the regulation of specialized myocyte functions, potentially by maintaining the relaxed state under the influence of constitutive H3R activity and low histamine concentrations, locally produced/released by non-professional histamine-producing cells. PMID- 25500892 TI - Assessment of bronchial and pulmonary blood supply in non-small cell lung cancer subtypes using computed tomography perfusion. AB - OBJECTIVES: The aim of this study was to investigate the dual blood supply of non small cell lung cancer (NSCLC) and its association with tumor subtype, size, and stage, using computed tomography perfusion (CTP). MATERIALS AND METHODS: A total of 54 patients (median age, 65 years; range, 42-79 years; 15 women, 39 men) with suspected lung cancer underwent a CTP scan of the lung tumor. Pulmonary and bronchial vasculature regions of interest were used to calculate independently CTP parameters (blood flow [BF], blood volume [BV], and mean transit time [MTT]) of the tumor tissue. The mean and maximum pulmonary and bronchial perfusion indexes (PImean and PImax) were calculated. The tumoral volume and the largest tumoral diameter were assessed. Differences in CTP parameters and indexes among NSCLC subtypes, tumor stages and tumor dimensions were analyzed using non parametric tests. RESULTS: According to biopsy, 37 patients had NSCLC (22 adenocarcinomas [ACs], 8 squamous cell carcinomas [SCCs], 7 large-cell carcinomas [LCC]). The mean bronchial BF/pulmonary BF, bronchial BV/pulmonary BV, and bronchial MTT/pulmonary MTT was 41.2 +/- 30.0/36.9 +/- 24.2 mL/100 mL/min, 11.4 +/- 9.7/10.4 +/- 9.4 mL/100 mL, and 11.4 +/- 4.3/14.9 +/- 4.4 seconds, respectively. In general, higher bronchial BF than pulmonary BF was observed in NSCLC (P = 0.014). Using a tumoral volume cutoff of 3.5 cm, a significant difference in pulmonary PImax was found (P = 0.028). There was a significantly higher mean pulmonary BF in LCCs and SCCs compared with ACs (P = 0.018 and P = 0.044, respectively), whereas the mean bronchial BF was only significantly higher in LCCs compared with ACs (P = 0.024). Correspondingly, the PImax was significantly higher in LCCs and SCCs than in ACs (P = 0.001 for both). Differences between bronchial and pulmonary PImean and PImax among T stages and Union Internationale Contre le Cancer stages were not statistically significant (P values ranging from 0.691 to 0.753). CONCLUSIONS: The known dual blood supply of NSCLC, which depends on tumor size and histological subtype, is reflected in CTP parameters, with parameters depending both on tumor size and histological subtype. This has to be accounted for when analyzing NSCLC with CTP. PMID- 25500893 TI - Stem cells in the management of advanced heart failure. AB - PURPOSE OF REVIEW: Outcomes of stem cell trials in patients with advanced heart failure have been divergent, which has raised some scepticism about this therapy and led to recommending slowing clinical trials until basic issues have been more thoroughly addressed. It is therefore timely and relevant to examine the current data and discuss how recent findings may change the perspectives of stem cell therapy. RECENT FINDINGS: The most important recent change has been a shift in the mechanistic paradigm. Although the initial objective of stem cells was to physically replace dead cardiomyocytes and build a new electromechanically integrated myocardial tissue, it is now recognized that the unavoidable death of most of the transplanted cells makes this objective unrealistic. Indeed, the primary mechanism of action of the cells seems to be paracrine through the release of factors activating the endogenous signalling pathways, leading to cardioprotection. This hypothesis has several implications. First, it leads to focus on the efficiency of early retention, rather than on sustained survival, which, in turn, implies improving delivery approaches, largely through an increased reliance on adjunctive biomaterials; second, it may rationalize the use of allogeneic cells as long as their rejection is delayed to give them enough time for releasing the signalling biomolecules; and, finally, it raises the possibility that transplantation of cells could be replaced by the delivery of their sole secretome, possibly under the form of microvesicles. SUMMARY: Put together, these approaches could streamline the translational process and enhance large-scale clinical applications. PMID- 25500894 TI - Patrinia scabiosaefolia inhibits the proliferation of colorectal cancer in vitro and in vivo via G1/S cell cycle arrest. AB - Patrinia scabiosaefolia (PS) has long been used as an important component in traditional Chinese medicine formulas to treat gastrointestinal malignancies including colorectal cancer (CRC). We recently reported that PS can inhibit CRC growth through induction of apoptosis and inhibition of tumor angiogenesis. To further elucidate the mode of action of PS, in the present study, we used a CRC mouse xenograft model and a human CRC cell line HT-29 to evaluate the effect of the ethanol extract of PS (EEPS) on cancer cell proliferation and investigated the underlying molecular mechanisms. We found that EEPS inhibited CRC growth both in vivo and in vitro, which was associated with the inhibitory effects of EEPS on cancer cell proliferation. In addition, EEPS treatment significantly blocked G1 to S phase cell cycle progression in HT-29 cells. Moreover, EEPS treatment decreased the expression of pro-proliferative CyclinD1 and CDK4, at both the mRNA and protein levels. Thus, inhibition of cell proliferation via G1/S cell cycle arrest might be a potential mechanism whereby PS effectively treats cancers. PMID- 25500895 TI - Negative pressure wound therapy for partial-thickness burns. AB - BACKGROUND: A burn wound is a complex and evolving injury, with both local and systemic consequences. Burn treatments include a variety of dressings, as well as newer strategies, such as negative pressure wound therapy (NPWT), which, by means of a suction force that drains excess fluids from the burn, tries to promote the wound healing process and minimise progression of the burn wound. OBJECTIVES: To assess the effectiveness of NPWT for people with partial-thickness burns. SEARCH METHODS: We searched the Cochrane Wounds Group Specialised Register (searched 04 September 2014); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 8). SELECTION CRITERIA: All randomised controlled trials (RCTs) and controlled clinical trials (CCTs) that evaluated the safety and effectiveness of NPWT for partial-thickness burns. DATA COLLECTION AND ANALYSIS: Two review authors used standardised forms, and extracted the data independently. We assessed each trial for risk of bias, and resolved differences by discussion. MAIN RESULTS: One RCT, that was an interim report, satisfied the inclusion criteria. We undertook a narrative synthesis of results, as the absence of data and poor reporting precluded us from carrying out any formal statistical analysis. The trial was at high risk of bias. AUTHORS' CONCLUSIONS: There was not enough evidence available to permit any conclusions to be drawn regarding the use of NPWT for treatment of partial-thickness burn wounds. PMID- 25500897 TI - Polyubiquitination of lysine-48 is an essential but indirect signal for MHC class I antigen processing. AB - Peptides presented on major histocompatibility complex (MHC) class I molecules are generated via cytosolic proteolysis. However, the nature of the endogenous peptide precursors and the intracellular processing steps preceding protein degradation remain poorly defined. Here, we assessed whether ubiquitination is an essential signal for proteasomal cleavage of antigen substrates in human cells. Conversion into antigenic peptides occurred in the absence of any detectable N terminal ubiquitination of the model antigens, and did not require the presence of any of the four types, nor a minimum number of ubiquitinatable amino acids within the antigen substrate. However, the knockdown of ubiquitin, expression of a lysine 48 (K48) ubiquitin mutant, or inhibition of proteasome-associated deubiquitinases significantly impaired antigen presentation. The results presented here are consistent with a model in which the binding of the antigen substrate by an adaptor protein leads to its K48-polyubiquitination and the subsequent delivery of the antigen cargo for degradation by the 26S proteasome. Altogether, these findings show an important but indirect role of K48 polyubiquitination in preproteasomal antigen sampling. PMID- 25500896 TI - Transformation of intestinal stem cells into gastric stem cells on loss of transcription factor Cdx2. AB - The endodermal lining of the adult gastro-intestinal tract harbours stem cells that are responsible for the day-to-day regeneration of the epithelium. Stem cells residing in the pyloric glands of the stomach and in the small intestinal crypts differ in their differentiation programme and in the gene repertoire that they express. Both types of stem cells have been shown to grow from single cells into 3D structures (organoids) in vitro. We show that single adult Lgr5-positive stem cells, isolated from small intestinal organoids, require Cdx2 to maintain their intestinal identity and are converted cell-autonomously into pyloric stem cells in the absence of this transcription factor. Clonal descendants of Cdx2(null) small intestinal stem cells enter the gastric differentiation program instead of producing intestinal derivatives. We show that the intestinal genetic programme is critically dependent on the single transcription factor encoding gene Cdx2. PMID- 25500898 TI - Coffee intake and the risk of colorectal adenoma: The colorectal adenoma study in Tokyo. AB - Coffee is a commonly consumed beverage which contains several potential anticarcinogenic and chemopreventive compounds, and has been hypothesized to have protective effects in colorectal neoplasia. However, the limited available data on coffee consumption in relation to colorectal adenoma (CRA), a precursor lesion to most colorectal cancers, remain largely inconsistent. In this study, we evaluated the association of coffee intake with the risk of CRA in a middle-aged Japanese population. Study subjects were selected from examinees who underwent total colonoscopy as part of a cancer screening program and responded to self administered dietary and lifestyle questionnaires. A total of 738 patients with adenoma and 697 controls were included in the study. Coffee intake was assessed with a food frequency questionnaire, and divided into quartiles based on the distribution among controls. Unconditional logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI) of CRA, with adjustment for potential confounding factors. High coffee consumption was associated with a reduced risk of CRA, with a multivariate-adjusted OR for the highest versus lowest quartile of coffee intake of 0.67 (95% CI = 0.48-0.93; ptrend = 0.02). The inverse association of coffee intake was limited to proximal (OR = 0.64; 95%CI = 0.44-0.95; ptrend = 0.04) and distal colon adenoma (OR = 0.62; 95%CI = 0.39-0.99; ptrend = 0.06), and appeared to be more evident with small (OR = 0.68; 95%CI = 0.49-0.96; ptrend = 0.04) and single adenomas (OR = 0.65; 95%CI = 0.44-0.95; ptrend = 0.02). Green tea intake was not found to be associated with CRA risk. This study provides support for the protective effect of coffee drinking on colon adenomas, a precursor of colon cancer. PMID- 25500899 TI - Vitamin D receptor gene polymorphisms and plasma renin activity in essential hypertensive individuals. AB - Several studies analyzed 25-hydroxyvitamin D (25[OH]D) and blood pressure (BP) relationship with mixed results. Moreover, a relationship between the risk of hypertension and vitamin D receptor (VDR) gene polymorphisms, FokI and BsmI, was reported. This study was aimed to analyze these relationships in essential hypertensive (EH) patients. Seventy-one EH patients, 18-75 years old, were enrolled. Patients underwent clinical BP, 24-h ambulatory BP monitoring, 25[OH]D and plasma renin activity (PRA) evaluations. FokI and BsmI VDR polymorphisms were analyzed and compared with those of 72 healthy controls. In EH patients, the median 25[OH]D levels were lower than 30 ng ml(-1). We found a significant negative correlation between 25[OH]D and 24-h systolic BP (r = -0.277, P = 0.043). This correlation persisted in backward stepwise multivariate analyses (beta = -0.337; P = 0.022), after adjustment for age, gender, body mass index, glomerular filtration rate, and PRA. We did not observe statistically significant correlation between 25[OH]D and PRA. We compared the allelic frequencies and genotype distribution between patients and controls, and FokI and BsmI VDR polymorphisms were not associated either with hypertensive status or with PRA. Further wide studies are needed to clarify this relationship. PMID- 25500900 TI - Social network, presence of cardiovascular events and mortality in hypertensive patients. AB - The aim of this study was to ascertain the relationship between social network and the appearance of mortality (cardiovascular events (CVEs)) in patients with arterial hypertension (AHT). This is a cohort study of 236 patients with a 9-year follow-up. Measurements included age, sex, blood pressure (BP), diabetes, hypercholesterolemia, marital status, social network, social support, stage of family life cycle (FLC), mortality and CVEs. Patients with a low social network registered higher global mortality (hazards ratio (HR) 2.6 (95% confidence interval (CI) 1.3; 5.5)) as did the oldest patients (HR 5.6 (1.9; 16.8)), men (HR 3.5 (95% CI 1.3; 9.3)) and subjects in the last FLC stages (HR 4.3 (95% CI 1.3;14.1)). Patients with low social support registered higher cardiovascular mortality (HR 2.6 (95% CI 1.1; 6.1)) as did the oldest patients (HR 12.4 (95% CI 2.8; 55.2)) and those with diabetes (HR 3.00 (95% CI 1.2; 7.6)). Patients with a low social network registered more CVEs (HR 2.1 (95% CI 1.1; 4.1)) than patients with an adequate network, as did the oldest patients (HR 3.1 (95% CI 1.4; 6.9)), subjects who presented with a higher grade of severity of AHT (HR 2.7 (1.3; 5.5)) and those in the last FLC stages (HR 2.5 (95% CI 1.0; 6.2)). A low social network is associated with mortality and the appearance of CVEs in patients with AHT. Low functional social support is associated with the appearance of cardiovascular mortality. PMID- 25500902 TI - On the conditions of magma mixing and its bearing on andesite production in the crust. AB - Mixing between magmas is thought to affect a variety of processes, from the growth of continental crust to the triggering of volcanic eruptions, but its thermophysical viability remains unclear. Here, by using high-pressure mixing experiments and thermal calculations, we show that hybridization during single intrusive events requires injection of high proportions of the replenishing magma during short periods, producing magmas with 55-58 wt% SiO2 when the mafic end member is basaltic. High strain rates and gas-rich conditions may produce more felsic hybrids. The incremental growth of crustal reservoirs limits the production of hybrids to the waning stage of pluton assembly and to small portions of it. Large-scale mixing appears to be more efficient at lower crustal conditions, but requires higher proportions of mafic melt, producing more mafic hybrids than in shallow reservoirs. Altogether, our results show that hybrid arc magmas correspond to periods of enhanced magma production at depth. PMID- 25500901 TI - Influence of body height on aortic systolic pressure augmentation and wave reflection in childhood. AB - The enhanced wave reflection in small children is a well-known phenomenon. It is explained on the basis of differences in the body height and the timing of wave reflection. This hypothesis still has not been proved directly. The aim of our study was to determine the reference values of aortic augmentation index (Aix(ao)) and the simultaneously measured return time of the systolic pulse wave (RT) in relation to the body height to test this hypothesis. Aix(ao) and RT were measured by Arteriograph in a healthy population aged 3-18 years (n = 4619, 2489 males). The Aix(ao) decreased with increasing age in boys from 18.6 +/- 8.4% to 4.7 +/- 4.3% and in girls from 22.3 +/- 9.2% to 8.1 +/- 5.1%, whereas the RT increased from 115.5 +/- 16.3 ms to 166.7 +/- 20.8 ms in boys and from 106.7 +/- 21.9 ms to 158.1 +/- 15.5 ms in girls. These changes were constant during childhood, but they slowed down after the onset of puberty. Because aortic pulse wave velocity (PWV(ao)) measured in the same population was unchanged during childhood, the increase of RT can only be explained by the increase of aortic length due to growth. In the puberty PWV(ao) starts increasing indicating that RT (Aix(ao)) does not follow the increase (decrease) of aortic length proportionally. PMID- 25500903 TI - Alcohol intake, hypertension development and mortality in black South Africans. AB - BACKGROUND: Excessive alcohol intake is a risk factor for cardiovascular disease (CVD) and predicts cardiovascular and all-cause mortality. We determined which alcohol marker (self-reported alcohol intake, gamma-glutamyltransferase (GGT) or percentage carbohydrate deficient transferrin (%CDT)) relates best with mortality and predicts hypertension development over five years in black South Africans. DESIGN: This was a longitudinal study as part of the PURE (Prospective Urban and Rural Epidemiology) study in the North West Province, South Africa. METHOD: We included 2010 participants and followed 1471 participants. Over five years, 230 deaths occurred, of which 66 were cardiovascular-related. At enrolment, participants completed questionnaires on alcohol intake (yes, for former and current use; no, for alcohol never used). We measured blood pressure, collected blood samples and measured GGT and %CDT. RESULTS: When comparing hazard ratios (HRs) of self-report, GGT and %CDT, we found that only GGT predicted cardiovascular (HR = 2.76 (1.49-5.12)) and all-cause mortality (HR = 2.47 (1.75 3.47)) and hypertension development ((HR = 1.31 (1.06-1.62)). Participants self reporting yes for alcohol intake had a 30% increased risk of developing hypertension (HR = 1.30 (1.07-1.60)) but not an increased risk for mortality. When adding both GGT and self-report in the prediction model for hypertension, only self-reporting of alcohol was significant (HR = 1.24 (1.01-1.53)). The alcohol marker, %CDT, did not show any significant association with mortality or hypertension development. CONCLUSION: GGT independently predicted cardiovascular and all-cause mortality, as well as hypertension development in black South Africans. Despite non-specificity to excessive alcohol consumption, GGT may be a useful general marker for hypertension development and mortality, also due to its significant association with self-reported alcohol intake. PMID- 25500904 TI - Azithromycin suppresses CD4(+) T-cell activation by direct modulation of mTOR activity. AB - Advanced macrolides, such as azithromycin (AZM) or clarithromycin (CLM), are antibiotics with immunomodulatory properties. Here we have sought to evaluate their in vitro influence on the activation of CD4(+) T-cells. Isolated CD4(+) T cells were stimulated with agonistic anti-CD3/anti-CD28 monoclonal antibodies in the presence of 0.6 mg/L, 2.5 mg/L, 10 mg/L or 40 mg/L AZM or CLM. Cell proliferation, cytokine level in supernatants and cell viability was assessed. Intracellular signaling pathways were evaluated using reporter cell lines, FACS analysis, immunoblotting and in vitro kinase assays. AZM inhibited cell proliferation rate and cytokine secretion of CD4(+) T-cells in a dose-dependent manner. Similarly, high concentrations of CLM (40 mg/L) also suppressed these T cell functions. Analysis of molecular signaling pathways revealed that exposure to AZM reduced the phosphorylation of the S6 ribosomal protein, a downstream target of mTOR. This effect was also observed at 40 mg/L CLM. In vitro kinase studies using recombinant mTOR showed that AZM inhibited mTOR activity. In contrast to rapamycin, this inhibition was independent of FKBP12. We show for the first time that AZM and to a lesser extent CLM act as immunosuppressive agents on CD4(+) T-cells by inhibiting mTOR activity. Our results might have implications for the clinical use of macrolides. PMID- 25500906 TI - Kinome-wide screening of HER2+ breast cancer cells for molecules that mediate cell proliferation or sensitize cells to trastuzumab therapy. AB - Understanding the signaling differences that distinguish human HER2-amplified (HER2-positive (HER2+)) breast cancers from other breast cancer subtypes may help to identify protein drug targets for the specific treatment of HER2+ breast cancers. We performed two kinome-wide small interfering RNA (siRNA) screens on five HER2+ breast cancer cell lines, seven breast cancer cell lines in which HER2 was not amplified and two normal breast cell lines. To pinpoint the main kinases driving HER2 signaling, we performed a comprehensive siRNA screen that identified loss of the HER2/HER3 heterodimer as having the most prominent inhibitory effect on the growth of HER2+ breast cancer cells. In a second siRNA screen focused on identifying genes that could sensitize HER2+ cells to trastuzumab treatment, we found that loss of signaling members downstream of phosphatidylinositol 3 kinase (PI3K) potentiated the growth inhibitory effects of trastuzumab. Loss of HER2 and HER3, as well as proteins involved in mitogenic and environmental stress pathways inhibited the proliferation of HER2+ cells only in the absence of trastuzumab, suggesting that these pathways are inhibited by trastuzumab treatment. Loss of essential G2/M cell cycle mediators or proteins involved in vesicle organization exerted inhibitory effects on HER2+ cell growth that were unaffected by trastuzumab. Furthermore, the use of a sensitization index (SI) identified targeting the PI3K pathway to sensitize to trastuzumab treatment. Antagonism using the SI identified MYO3A, MYO3B and MPZL1 as antagonizers to trastuzumab treatment among HER2+ cell lines. Our results suggest that the dimerization partners of HER2 are important for determining the activation of downstream proliferation pathways. Understanding the complex layers of signaling triggered downstream of HER2 homodimers and heterodimers will facilitate the selection of better targets for combination therapies intended to treat HER2+ breast cancers. PMID- 25500905 TI - Control of membrane gaps by synaptotagmin-Ca2+ measured with a novel membrane distance ruler. AB - Fast synchronous neurotransmitter release is triggered by calcium that activates synaptotagmin-1 (syt-1), resulting in fusion of synaptic vesicles with the presynaptic membrane. Syt-1 possesses two Ca(2+)-binding C2 domains that tether membranes via interactions with anionic phospholipids. It is capable of crosslinking membranes and has recently been speculated to trigger fusion by decreasing the gap between them. As quantitative information on membrane gaps is key to understanding general cellular mechanisms, including the role of syt-1, we developed a fluorescence-lifetime based inter-membrane distance ruler using membrane-anchored DNAs of various lengths as calibration standards. Wild-type and mutant data provide evidence that full-length syt-1 indeed regulates membrane gaps: without Ca(2+), syt-1 maintains membranes at distances of ~7-8 nm. Activation with 100 MUM Ca(2+) decreases the distance to ~5 nm by binding the C2 domains to opposing membranes, respectively. These values reveal that activated syt-1 adjusts membrane distances to the level that promotes SNARE complex assembly. PMID- 25500907 TI - Effects of reciprocity on random walks in weighted networks. AB - It has been recently reported that the reciprocity of real-life weighted networks is very pronounced, however its impact on dynamical processes is poorly understood. In this paper, we study random walks in a scale-free directed weighted network with a trap at the central hub node, where the weight of each directed edge is dominated by a parameter controlling the extent of network reciprocity. We derive two expressions for the mean first passage time (MFPT) to the trap, by using two different techniques, the results of which agree well with each other. We also analytically determine all the eigenvalues as well as their multiplicities for the fundamental matrix of the dynamical process, and show that the largest eigenvalue has an identical dominant scaling as that of the MFPT.We find that the weight parameter has a substantial effect on the MFPT, which behaves as a power-law function of the system size with the power exponent dependent on the parameter, signaling the crucial role of reciprocity in random walks occurring in weighted networks. PMID- 25500908 TI - How is water-use efficiency of terrestrial ecosystems distributed and changing on Earth? AB - A better understanding of ecosystem water-use efficiency (WUE) will help us improve ecosystem management for mitigation as well as adaption to global hydrological change. Here, long-term flux tower observations of productivity and evapotranspiration allow us to detect a consistent latitudinal trend in WUE, rising from the subtropics to the northern high-latitudes. The trend peaks at approximately 51 degrees N, and then declines toward higher latitudes. These ground-based observations are consistent with global-scale estimates of WUE. Global analysis of WUE reveals existence of strong regional variations that correspond to global climate patterns. The latitudinal trends of global WUE for Earth's major plant functional types reveal two peaks in the Northern Hemisphere not detected by ground-based measurements. One peak is located at 20 degrees ~ 30 degrees N and the other extends a little farther north than 51 degrees N. Finally, long-term spatiotemporal trend analysis using satellite-based remote sensing data reveals that land-cover and land-use change in recent years has led to a decline in global WUE. Our study provides a new framework for global research on the interactions between carbon and water cycles as well as responses to natural and human impacts. PMID- 25500909 TI - Human resident CD34+ stromal cells/telocytes have progenitor capacity and are a source of alphaSMA+ cells during repair. AB - We studied the progenitor capacity of human resident CD34+ stromal cells/telocytes (SC/TCs) in the enteric wall affected by inflammatory/repair processes (appendicitis, diverticulitis of large bowel and Crohn's disease of the terminal ileum) at different stages of evolution (inflammatory, proliferative and remodelling). In these conditions, CD34+ SC/TCs are activated, showing changes, which include the following overlapping events: 1) separation from adjacent structures (e.g., from vascular walls) and location in oedematous spaces, 2) morphological modifications (in cell shape and size) with presence of transitional cell forms between quiescent and activated CD34+ SC/TCs, 3) rapid proliferation and 4) loss of CD34 expression and gain of alphaSMA expression. These events mainly occur in the inflammatory and proliferative stages. During the loss of CD34 expression, the following findings are observed: a) irregular cell labelling intensity for anti-CD34, b) co-localization of CD34 and actin, c) concurrent irregular labelling intensity for alphaSMA and d) alphaSMA expression in all stromal cells, with total loss of CD34 expression. While CD34 expression was conserved, a high proliferative capacity (Ki-67 expression) was observed and vice versa. In the segments of the ileum affected by Crohn's disease, the stromal cells around fissures were alphaSMA+ and, in the transitional zones with normal enteric wall, activated CD34+ SC/TCs were observed. In conclusion, human resident CD34+ SC/TCs in the enteric wall have progenitor capacity and are activated with or without differentiation into alphaSMA+ stromal cells during inflammatory/repair processes. PMID- 25500910 TI - Effects of muscle injury severity on localized bioimpedance measurements. AB - Muscle injuries in the lower limb are common among professional football players. Classification is made according to severity and is diagnosed with radiological assessment as: grade I (minor strain or minor injury), grade II (partial rupture, moderate injury) and grade III (complete rupture, severe injury). Tetrapolar localized bioimpedance analysis (BIA) at 50 kHz made with a phase-sensitive analyzer was used to assess damage to the integrity of muscle structures and the fluid accumulation 24 h after injury in 21 injuries in the quadriceps, hamstring and calf, and was diagnosed with magnetic resonance imaging (MRI). The aim of this study was to identify the pattern of change in BIA variables as indicators of fluid [resistance (R)] and cell structure integrity [reactance (Xc) and phase angle (PA)] according to the severity of the MRI-defined injury. The % difference compared to the non-injured contralateral muscle also measured 24-h after injury of R, Xc and PA were respectively: grade I (n = 11; -10.4, -17.5 and -9.0%), grade II (n = 8; -18.4, -32.9 and -16.6%) and grade III (n = 2; -14.1, -52.9 and 43.1%), showing a greater significant decrease in Xc (p < 0.001). The greatest relative changes were in grade III injuries. However, decreases in R, that indicate fluid distribution, were not proportional to the severity of the injury. Disruption of the muscle structure, demonstrated by the localized determination of Xc, increased with the severity of muscle injury. The most significant changes 24 h after injury was the sizeable decrease in Xc that indicates a pattern of disrupted soft tissue structure, proportional to the severity of the injury. PMID- 25500912 TI - Diffusing capacity for carbon monoxide correlates best with tissue volume from quantitative CT scanning analysis. AB - BACKGROUND: Quantitative analysis of high-resolution chest CT scan (QCT) is an established method for determining the severity and distribution of lung parenchymal destruction inpatients with emphysema. Diffusing capacity of the lung for carbon monoxide (D(LCO)) is a traditional physiologic measure of emphysema severity and is probably influenced more by destruction of the alveolar capillary bed than by membrane diffusion per se. We reasoned that D(LCO) should correlate with tissue volume from QCT. METHODS: A total of 460 patients with upper-lobe predominant emphysema were enrolled in the study. Th e mean (SD) of percent predicted values for FEV 1 , total lung capacity, and D(LCO) were 30.6% (8.0%), 129.5% (18.1%), and 6.7% (13.1%), respectively. QCT was performed using custom soft ware; the relationship between D(LCO) and various metrics from QCT were evaluated using Pearson correlation coefficients. RESULTS: On average, whole-body plethysmography volumes were higher by 841 mL compared with QCT-calculated total lung volume. However, there was a strong correlation between these measurements (r=0.824, P < .0001). D(LCO) correlated with total lung volume (r=0.314, P<.0001), total tissue volume (r=0.498, P<.0001), and percentage of lung with low density (-950 Hounsfield units) (r=-0.337, P<.0001). CONCLUSIONS: In patients with severe emphysema, D(LCO) correlates best with total tissue volume,supporting the hypothesis that pulmonary capillary blood volume is the main determinant of D(LCO) in the human lung. Th e relationships between D(LCO) and various anatomic metrics of lung parenchymal destruction from QCT inform our understanding of the relationship between structure and function of the human lung. PMID- 25500911 TI - Cell- and developmental stage-specific Dicer1 ablation in the lung epithelium models cystic pleuropulmonary blastoma. AB - Inherited syndromes provide unique opportunities to identify key regulatory mechanisms governing human disease. We previously identified germline loss-of function DICER1 mutations in a human syndrome defined by the childhood lung neoplasm pleuropulmonary blastoma (PPB), which arises during lung development. DICER1 regulates many biological processes critical in development and disease pathogenesis. Significant challenges in defining the role of DICER1 in human disease are identifying cause-effect relationships and generating manipulatable systems that model the complexity of organ development and disease pathogenesis. Here we report the generation of a murine model for PPB and demonstrate that precise temporal and cell type-specific Dicer1 ablation is necessary and sufficient for the development of cystic lungs that histologically and phenotypically model PPB. Dicer1 ablation in the distal airway epithelium during early stages of lung development resulted in a cystic lung phenotype indistinguishable from PPB, whereas DICER1 function was not required for development of the proximal airway epithelium or during later stages of organogenesis. Mechanistic studies demonstrate that Dicer1 loss results in epithelial cell death, followed by cystic airway dilatation accompanied by epithelial and mesenchymal proliferation. These studies define precise temporal and epithelial cell type-specific DICER1 functions in the developing lung and demonstrate that loss of these DICER1 functions is sufficient for the development of cystic PPB. These results also provide evidence that PPB arise through a novel mechanism of non-cell-autonomous tumour initiation, in which the genetic abnormality initiating the neoplasm does not occur in the cells that ultimately transform, but rather occurs in a benign-appearing epithelial cell component that predisposes underlying mesenchymal cells to malignant transformation. PMID- 25500913 TI - Antibacterial effect of ultrafine nanodiamond against gram-negative bacteria Escherichia coli. AB - We investigate the antibacterial effect of ultrafine nanodiamond particles with an average size of 5 nm against the gram-negative bacteria Escherichia coli (E. coli). UV-visible, Raman spectroscopy, and scanning electron microscopy (SEM) have been employed to elucidate the nature of the interaction. The influence on bacterial growth was monitored by measuring optical densities of E. coli at 600 nm as a function of time in the presence of carboxylated nanodiamond (cND) particles (100 MUg/ml ) in highly nutritious liquid Luria-Bertani medium. The SEM images prove that cND particles are attached to the bacterial cell wall surface and some portion of the bacterial cell wall undergoes destruction. Due to the change of the protein structure on the bacterial wall, a small Raman shift in the region of 1400 to 1700 cm-1 was observed when E. coli interacted with cNDs. Raman mapping images show strong evidence of cND attachment at the bacterial cell wall surface. Electrotransformation of E. coli with a fluorescent protein markers experiment demonstrated that the interaction mechanisms are different for E. coli treated with cND particles, E. coli by lysozyme treatment, and E. coli that suffer lysis. PMID- 25500914 TI - Water harvesting techniques and supplemental irrigation impact on sorghum production. AB - BACKGROUND: In general, rain-fed agriculture is practised in many areas in western Sudan. Therefore, it is imperative to adopt appropriate rainwater harvesting and reuse technique(s) by promoting soil and water management research to sustain crop productivity. Sorghum (Sorghum bicolor L.) is a primary stable crop of Sudan. Extensive field experiments were conducted to study the effect of water harvesting techniques (WHTs) and supplemental irrigation (SI) on infiltration rate (IR), soil moisture content (SMC), growth and productivity of sorghum during two rainy seasons (2012 and 2013). RESULTS: The results showed that the WHTs and SI affected the soil physical properties, growth and productivity parameters of sorghum. The results indicated that the tied-ridging with SI (TRwSI) produced the highest values of accumulative IR, SMC and sorghum productivity (115 mm, 13% and 4000 kg h(-1) , in season 2012, respectively, whereas in season 2013 the values were 145 mm, 10% and 5000 kg h(-1) , for accumulative IR, SMC and sorghum productivity, respectively. Basin with SI (BwSI) ranked second, next to TRwSI in the both seasons. CONCLUSION: Hence, water harvesting and SI are expected to play a significant role in terms of sustainable agricultural and socio-economic development in western Sudan and similar areas. PMID- 25500915 TI - A continuous quality improvement initiative for electronic prescribing in ambulatory care. PMID- 25500918 TI - The effects of demecolcine, alone or in combination with sucrose on bovine oocyte protrusion rate, MAPK1 protein level and c-mos gene expression level. AB - AIMS: Our study aims to clarify the effects of demecolcine, alone or in combination with sucrose on bovine oocyte protrusion rate, MAPK1 protein level and c-mos gene expression level. METHODS: The effects of the demecolcine concentration, treatment duration, and synergistic effects with sucrose solution on the rate of membrane protrusions of bovine oocytes were investigated. Using real-time fluorescent quantitative PCR, western blot analysis, and immunofluorescence assays, the expression of the maternal c-mos gene, the protein level of mitogen-activated protein kinase 1 (MAPK1), and the change in the localization of spindles and nuclei during the demecolcine treatment were analyzed in bovine oocytes. RESULTS: Treatment of bovine oocytes with both demecolcine (0.6 MUg/mL) and sucrose (0.05 M) for 1 h led to the highest rate of membrane protrusions, and synergistic effects were also observed. Real-time fluorescent quantitative PCR analysis revealed that the demecolcine treatment up regulated the expression of the maternal c-mos gene. Western blot analysis indicated that the demecolcine treatment enhanced the protein level of MAPK1 in bovine oocytes. Immunofluorescence analysis indicated that the spindles and nuclei were localized at the place of the membrane protrusions. CONCLUSIONS: The present results suggest that demecolcine might contribute to the activation of the Mos/MAPK pathway and affect spindle structure. These results provide a reference for more efficient generation of enucleated bovine oocytes. PMID- 25500919 TI - Through the eyes of a new dad: experiences of first-time fathers of late-preterm infants. AB - Fathers of late-preterm (34-36 weeks' gestation) infants may experience challenges in parenting. Late-preterm infants are more irritable and less responsive in interactions. The unexpected early birth of an infant may negatively affect fathers' cognitive and emotional experiences. The Father-Infant Interaction Program (FIIP) is a video-modeled play intervention that aims to increase fathers' sensitivity and responsiveness to infant cues. Using data from a larger randomized controlled trial (RCT) to evaluate FIIP, the purpose of the present study was to explore the experiences of first-time fathers of late preterm infants and their perceptions of the intervention. We conducted semistructured qualitative interviews with 85 fathers of 8-month-old infants during the outcome home visit for the RCT and thematically analyzed data. Three main themes about fathers' experiences emerged: Fathers believed they had the "best job in the world," yet saw fathering as the "biggest job ever." Fathers viewed fatherhood as an opportunity for personal growth and reflected on how their lives had changed since the arrival of their infant. Fathers in the intervention and comparison groups liked the convenience of the home visits and validation of their role as a father. Fathers in the intervention group liked the tailored feedback about play. PMID- 25500920 TI - Dental trauma and mouthguard awareness and use among contact and noncontact athletes in central India. AB - We investigated the associations of mouthguard awareness and use with the rate and type of orofacial trauma during sports activities among professional athletes. In this cross-sectional study of athletes aged 12 to 22 years who trained for participation in national and international competitions, data were collected by using a questionnaire and a clinical examination that included an index of dental injury. There were significant differences in mouthguard awareness and use and injury rates, i.e., athletes who did not wear mouthguards had more injuries. Traumatic injuries to teeth were significantly more frequent among contact athletes (15; 9%) than among noncontact athletes (4; 2.5%). Limited mouthguard awareness could be due to lack of information and education on dental injuries and their prevention. PMID- 25500921 TI - Effects of two combinations of triple antibiotic paste used in endodontic regeneration on root microhardness and chemical structure of radicular dentine. AB - We investigated the effects of triple antibiotic paste (TAP) and modified triple antibiotic paste (MTAP) concentrations on the microhardness and chemical structure of radicular dentine. Human root cylinders were instrumented and randomized into four treatment groups and an untreated control group. Two treatment groups received 1 g/mL TAP or MTAP, and the other two treatment groups received 1 mg/mL methylcellulose-based TAP or MTAP. Cylinders were stored at 100% relative humidity for 4 weeks. Each root cylinder was subjected to a microhardness test before and after treatment. Different sets of radicular dentine specimens were treated as mentioned previously, and were examined using attenuated total reflection Fourier transform infrared spectroscopy. All treatment groups showed significant reductions in microhardness of roots when compared to untreated control roots at 1,000 and/or 500 um from the pulp-dentine interface. However, 1 mg/mL methylcellulose-based antibiotics caused significantly less reduction in microhardness when compared to 1 g/mL antibiotics. In addition, 1 g/mL TAP and DAP caused significantly lower phosphate/amide I ratios when compared to other groups. The use of 1 mg/mL methylcellulose-based TAP and MTAP may minimize the reduction in microhardness of roots compared with the currently used 1 g/mL concentration of these antibiotics. PMID- 25500922 TI - MicroRNA expression in inflamed and noninflamed gingival tissues from Japanese patients. AB - Periodontitis is a chronic inflammatory disease caused by specific bacteria and viruses. Local, systemic, and environmental factors affect the rate of disease progression. Immune responses to bacterial products, and the subsequent production of inflammatory cytokines, are crucial in the destruction of periodontal tissue. MicroRNAs (miRNAs) are a class of small RNAs that control various cell processes by negatively regulating protein-coding genes. In this study, we compared miRNA expression in inflamed and noninflamed gingival tissues from Japanese dental patients. Total RNAs were isolated from inflamed and noninflamed gingival tissues. miRNA expression profiles were examined by an miRNA microarray, and the data were analyzed by GeneSpring GX, Ingenuity Pathways Analysis, and the TargetScan databases. Observed miRNA expression levels in inflamed gingiva were confirmed by real-time PCR. The three most overexpressed (by >2.72-fold) miRNAs were hsa-miR-150, hsa-miR-223, and hsa-miR-200b, and the three most underexpressed (by <0.39-fold) miRNAs were hsa-miR-379, hsa-miR-199a 5p, and hsa-miR-214. In IPA analysis, hsa-miR-150, hsa-miR-223, and hsa-miR-200b were associated with inflammatory disease, organismal injury, abnormalities, urological disease, and cancer. The present findings suggest that miRNAs are associated with chronic periodontitis lesions in Japanese. PMID- 25500923 TI - Proinflammatory cytokines induce amelotin transcription in human gingival fibroblasts. AB - Amelotin (AMTN) is a secreted protein transcribed predominantly during the maturation stage of enamel formation and localized in the junctional epithelium. We investigated differences in the levels of AMTN gene expression between non inflamed gingiva and inflamed gingiva from patients with chronic periodontitis. Total RNAs were isolated from these tissues and their gene expression profiles were monitored by DNA microarray. The observed induction of AMTN mRNA in inflamed gingiva and cultured human gingival fibroblasts (HGF) was confirmed by real-time PCR. Transient transfection assays were performed using chimeric constructs of mouse AMTN gene promoter fragments linked to a luciferase reporter gene. Immunohistochemical localization of AMTN in inflamed and non-inflamed gingiva was assessed by immunohistochemistry. Among many differentially expressed genes, the level of AMTN mRNA was significantly increased in inflamed gingiva. Treatment of HGF with interleukin-1beta (IL-1beta), IL-6 and tumor necrosis factor-alpha (TNF alpha) induced the expression of AMTN mRNA, and increased the luciferase activities of the AMTN promoter constructs. AMTN protein was detected in inflamed gingival connective tissue and junctional epithelium. These findings demonstrate that proinflammatory cytokines induce AMTN gene expression in human gingival fibroblasts and suggest a role for AMTN in gingival inflammation. PMID- 25500924 TI - Comparison of cyclic fatigue and torsional resistance in reciprocating single file systems and continuous rotary instrumentation systems. AB - As compared with continuous rotary systems, reciprocating motion is believed to increase the fatigue resistance of NiTi instruments. We compared the cyclic fatigue and torsional resistance of reciprocating single-file systems and continuous rotary instrumentation systems in simulated root canals. Eighty instruments from the ProTaper Universal, WaveOne, MTwo, and Reciproc systems (n = 20) were submitted to dynamic bending testing in stainless-steel simulated curved canals. Axial displacement of the simulated canals was performed with half of the instruments (n = 10), with back-and-forth movements in a range of 1.5 mm. Time until fracture was recorded, and the number of cycles until instrument fracture was calculated. Cyclic fatigue resistance was greater for reciprocating systems than for rotary systems (P < 0.05). Instruments from the Reciproc and WaveOne systems significantly differed only when axial displacement occurred (P < 0.05). Instruments of the ProTaper Universal and MTwo systems did not significantly differ (P > 0.05). Cyclic fatigue and torsional resistance were greater for reciprocating systems than for continuous rotary systems, irrespective of axial displacement. PMID- 25500925 TI - Efficacy of antimicrobial photodynamic therapy for root canals infected with Enterococcus faecalis. AB - Effective decontamination of root canal systems is a constant concern in clinical practice. In this article, we compare the performance of photodynamic therapy (PDT) and sodium hypochlorite (NaOCl) in reducing the amount of Enterococcus faecalis in root canals. Relevant studies were identified by searching electronic databases, including Web of Science, PubMed, BVS (Medline, Scielo, Lilacs and BBO), Scopus, and Cochrane, and by manually searching the references of identified studies. The terms used in the literature search were "photodynamic therapy" and "Enterococcus faecalis". We selected 13 experimental studies that exclusively assessed the performance of PDT in reducing E. faecalis in root canals of human teeth. In an evaluation of methodological quality, 12 articles were classified as moderate-quality reports and 1 as a high-quality report. No article needed to be excluded because of low-quality methodology. The results showed that PDT had a better antimicrobial effect when used as an adjuvant endodontic treatment to NaOCl. However, this finding should be carefully interpreted, as there are few relevant studies and the methods of the selected studies varied. PMID- 25500927 TI - A comprehensive review of the literature and data analysis on hypo-hyperdontia. AB - The objectives of this study were i) to conduct a comprehensive review of the literature on hypo-hyperdontia, and ii) to categorize the reported cases based on occurrence. An extensive search of the literature covering the period from January 1966 to January 2014 was conducted using the Embase, Google Scholar, Medline, and PubMed databases. The key words used in the search strategy were "concomitant", "agenesis", "hypodontia", "hyperdontia", "supernumerary teeth", "syndromes", and "hypohyperdontia" in various combinations. The retrieved data were analyzed based on gender, occurrence, and occurrence of both hypodontia and hyperdontia. Descriptive statistics were carried out using the chi-squared test. For hypo-hyperdontia overall, seven case studies and 40 cases involving 103 patients were reported. Our comprehensive review revealed that hypo-hyperdontia occurs most commonly in males (P < 0.05), and the bimaxillary type (65%) was reported most commonly in comparison with the maxillary, pre-maxillary and mandibular types (P < 0.001). Twenty syndromic cases and two case studies on familial occurrence of hypohyperdontia were reported. Almost 57% of cases affected the anterior region, whereas 43% of cases affected the anteroposterior region. The anterior region was most commonly affected by hyperdontia whereas the posterior region was most commonly affected by hypodontia. Hypo-hyperdontia is commonly seen in males, and the most common type is bimaxillary occurrence. G/BBB syndrome is commonly associated with hypo-hyperdontia, being relatively frequent in the anterior region, where mesiodens is frequently seen, and second premolars are the most commonly missing teeth. PMID- 25500926 TI - Influence of powder composition and morphology on penetration of Gray and White ProRoot mineral trioxide aggregate and calcium hydroxide into dentin tubules. AB - This study examined the influence of powder composition and morphology on the penetration of Gray and White ProRoot mineral trioxide aggregate (GMTA, WMTA) and calcium hydroxide (CH) into open dentin tubules. GMTA, WMTA, and CH particle dimensions were analyzed by flow particle image analysis (FPIA). Penetration of open dentin tubules into dentin discs was studied by scanning electron microscopy. Five samples of each material were randomly selected and prepared for this study. The GMTA averages for length (MUm), width (MUm), perimeter (MUm), and aspect ratio were 1.94 +/- 1.65, 1.43 +/- 1.19, 5.61 +/- 4.27, and 0.76 +/- 0.14, respectively. Corresponding averages for WMTA were 2.04 +/- 1.87, 1.49 +/- 1.33, 5.88 +/- 4.81, and 0.76 +/- 0.14, and for CH were 2.26 +/- 1.99, 1.62 +/- 1.46, 6.70 +/- 5.60, and 0.74 +/- 0.15, respectively. The rank order of the averages for particle length, width and perimeter from the largest to the smallest material was CH > WMTA > GMTA. The rank order of the averaged aspect ratios was GMTA > WMTA > CH. SEM showed that all three materials, when deposited and agitated on dentin discs, penetrated the open dentin tubules. Tubule occlusion occurred as particle surface concentrations increased. Significant differences in particle length, width, perimeter, and aspect ratio were observed for GMTA, WMTA, and CH (P < 0.0001 in all cases). All particle types penetrated into open tubules when agitated on dentin discs; all tubules were eventually occluded as particle concentrations grew. (J Oral Sci 56, 287-293, 2014). PMID- 25500928 TI - Sequential imaging of an impacted mandibular second premolar migrated from angle to condyle. AB - Extreme distal migration of impacted teeth to the subcondylar area and condyle is very rare. Using an interesting sequence of radiographs showing the path of the tooth in the mandible, we describe the intrabony migration of a mandibular second premolar from angle to condyle in a young woman. Cone-beam computed tomography was used to establish the precise location of the tooth. PMID- 25500929 TI - Conservative treatment and follow-up of type III dens invaginatus using cone beam computed tomography. AB - Dens invaginatus is a well-recognized phenomenon, and its endodontic treatment poses a challenge, especially for peri-invagination lesions with vital pulp. Here we describe the outcome of conservative treatment and follow-up in a case of type III dens invaginatus. Cone-beam computed tomography was used for diagnosis and follow-up. Pulp vitality was preserved with endodontic treatment of only an invaginated canal. At the 24-month follow-up examination, the tooth was asymptomatic and repair of the lesion was evident radiographically. This case was managed successfully with endodontic treatment of the invagination. (J Oral Sci 56, 307-310, 2014). PMID- 25500930 TI - Repair of apical root resorption associated with periodontitis using a new intracanal medicament protocol. AB - Endodontic therapy is indicated for cases of traumatic tooth dislocation associated with pulp necrosis and/or inflammatory resorption. Here we describe the management of a maxillary left lateral permanent incisor that suffered lateral luxation, leading to pulp necrosis and root resorption, in a 13-year-old boy. The traumatized tooth was treated successfully by intracanal medication with calcium hydroxide, 2% chlorhexidine gel and zinc oxide for 12 months without any need to change the dressing, followed by conventional root canal filling. The postoperative course was uneventful and a stable clinical outcome was obtained with evidence of periapical lesion repair and stabilization of the resorption process. PMID- 25500931 TI - The non-surgical management of a patient with Kostmann syndrome-associated periodontitis: a case report. AB - Kostmann syndrome is a rare, congenital immunological disorder caused by a mutation of the hematopoietic cell-specific LYN substrate 1-associated protein X1. These patients pose a unique challenge to the dental practitioner due to the severe oral infections that are often seen in this population. The patient described in this report is a 16-year-old female with Kostmann syndrome associated periodontitis. The treatment consisted of scaling and root planing performed in conjunction with subgingival irrigation with povidone-iodine solution. This report details how Kostmann syndrome-associated periodontitis can be successfully treated and maintained long-term, using non-surgical treatment modalities and local antimicrobial therapy. PMID- 25500932 TI - Association between single nucleotide polymorphisms in the OPRM1 gene and intraoperative remifentanil consumption in northern Chinese women. AB - BACKGROUND: Recent studies have suggested that some single nucleotide polymorphisms (SNPs) in the human u-opioid receptor gene (OPRM1) affect the postoperative analgesic efficacy of opioids and their side effects. In this study, we assessed the association between SNPs in the OPRM1 gene and intraoperative remifentanil consumption as well as perioperative side effects during gynecological hysteroscopic surgery in women from Northern China. METHODS: We analyzed 178 women undergoing gynecological hysteroscopic surgery. SNP genotyping was performed using the SNaPshot method. The state anxiety index (SAI) and pressure pain threshold (PPT) of all patients were assessed preoperatively. Monitored anesthesia care was maintained by the intravenous infusion of remifentanil. Intraoperative remifentanil usage and perioperative side effects were recorded. Statistical analyses were performed using SPSS software. RESULTS: Patients carrying one or two copies of the minor allele (G allele) of rs558025 required significantly more intraoperative remifentanil than patients without the minor allele (p = 0.001, corrected p = 0.006). There were no significant associations between the six SNPs and various clinical characteristics. No significant associations between the six SNPs and PPT or SAI were found in our study. CONCLUSIONS: SNP rs558025 in the OPRM1 gene was associated with intraoperative remifentanil consumption during gynecological hysteroscopic surgery in our subjects. PMID- 25500933 TI - Comparison of electronic energy loss in graphene and BN sheet by means of time dependent density functional theory. AB - Time-dependent density functional theory combined with Ehrenfest dynamics are employed to calculate electronic energy loss of energetic ions in two-dimensional graphene and white graphene (BN) targets. Special attention is paid to the effects of different electronic structures on their stopping power. Our results show that the energy transferred to the graphene target is much larger than to BN for both H(+) and He(2+) projectiles. Since the energy is mainly deposited into the electronic degree of freedom, it means that the electronic structure of the target plays an important role in determining the collision process. Our analysis indicates that more excited electrons are observed in graphene compared to BN. At low energies, a velocity proportional relation is found in the electronic energy loss of H(+) and He(2+) in both graphene and BN. In particular, a threshold velocity is observed for He(2+). Finally, we have compared the energy transfer from neutral and charged projectiles when they collide with graphene and BN and the results show that charged projectiles damage the targets more severely. PMID- 25500934 TI - A femtosecond study of the anomaly in electron injection for dye-sensitized solar cells: the influence of isomerization employing Ru(II) sensitizers with anthracene and phenanthrene ancillary ligands. AB - In this study, an intriguing difference caused by structural isomerization based on anthracene and phenanthrene stilbazole type ancillary ligands in Ru(ii) sensitizers for dye sensitized solar cells (DSCs) has been investigated using femtosecond transient absorption spectroscopy. Both anthracene and phenanthrene based sensitizers HD-7 and HD-8, respectively, resulted in a similar extinction coefficient, photophysical and thermodynamic free energy of electron injection and dye regeneration as measured by UV-Vis, excited state lifetime and cyclic voltammetry measurements, respectively. However, TiO2 adsorbed HD-7 resulted in up to 45% less photocurrent density than HD-8 although photovoltage was similar owing to comparable thermodynamic characteristics. It was obvious from the measurement of incident photon to current conversion efficiency (IPCE) that excited electrons in HD-7 are prone to internal energy loss before injection into the TiO2 conduction band. Analysis of photo-induced spectral features measured by femtosecond transient absorption spectroscopy showed that excited electrons in HD 7 are prone to ISC (intersystem crossing) much more than HD-8 and those triplet electrons are not injected into TiO2 efficiently. Interestingly, from impedance measurements, HD-7 showed higher recombination resistance than HD-8 and N719, but a shorter lifetime for electrons injected into the TiO2 conduction band. PMID- 25500935 TI - Glucocorticoids entrain molecular clock components in human peripheral cells. AB - In humans, shift work induces a desynchronization between the circadian system and the outside world, which contributes to shift work-associated medical disorders. Using a simulated night shift experiment, we previously showed that 3 d of bright light at night fully synchronize the central clock to the inverted sleep schedule, whereas the peripheral clocks located in peripheral blood mononuclear cells (PBMCs) took longer to reset. This underlines the need for testing the effects of synchronizers on both the central and peripheral clocks. Glucocorticoids display circadian rhythms controlled by the central clock and are thought to act as synchronizers of rodent peripheral clocks. In the present study, we tested whether the human central and peripheral clocks were sensitive to exogenous glucocorticoids (Cortef) administered in the late afternoon. We showed that 20 mg Cortef taken orally acutely increased PER1 expression in PBMC peripheral clocks. After 6 d of Cortef administration, the phases of central markers were not affected, whereas those of PER2-3 and BMAL1 expression in PBMCs were shifted by ~ 9.5-11.5 h. These results demonstrate, for the first time, that human peripheral clocks are entrained by glucocorticoids. Importantly, they suggest innovative interventions for shift workers and jet-lag travelers, combining synchronizing agents for the central and peripheral clocks. PMID- 25500936 TI - Aural fullness in Meniere's disease. AB - OBJECTIVE: Aural fullness in Meniere's disease and the predisposing and consequential factors were investigated and possible consequences of aural fullness on participation activity were explored. METHODS: 726 subjects of the Finnish Meniere Association replied to a questionnaire focusing on symptoms of Meniere's disease, sense of coherence, attitude, participation restriction, and general health-related quality of life (EQ-5D). In the analysis, the severity of the disease was controlled. RESULTS: 68% of the subjects had aural fullness and in 37% it was moderate or strong. Aural fullness was rated as the worst problem by 4.4% of the subjects. Females reported more aural fullness than males. Tinnitus, hyperacusis and balance problems were significant predictors of aural fullness. Aural fullness was associated with reduced quality of life and complaints such as vertigo attacks, balance problems and hearing loss. Analysis based on participation restriction indicated that severe aural fullness leads to social isolation. CONCLUSIONS: Largely, psychological factors and personal traits modify problems experienced by aural fullness. Relaxation was the only statistically significant method that alleviated aural fullness. PMID- 25500937 TI - The effect of TOMM40 poly-T repeat lengths on age of onset and cerebrospinal fluid biomarkers in Finnish Alzheimer's disease patients. AB - BACKGROUND: Poly-T repeat lengths of rs10524523 in TOMM40 together with APOE polymorphism have been reported to affect the risk of late-onset Alzheimer's disease (LOAD) and the age of onset (AOO). OBJECTIVE: To explore whether the AOO and cerebrospinal fluid biomarkers Abeta42, total tau and phosphorylated tau are associated with different repeat lengths. METHODS: We conducted both the fragment and sequencing analysis of rs10524523 in 336 LOAD patients with a known APOE genotype. RESULTS: AOO and Abeta42 levels associated significantly with certain poly-T repeat lengths of rs10524523 in LOAD patients encompassing APOE 34/44 genotype. CONCLUSION: We conclude that the poly-T repeat associations of rs10524523 in TOMM40 reflect the APOE epsilon4-dependent association in LOAD. PMID- 25500940 TI - LiDCO-based fluid management in patients undergoing hip fracture surgery under spinal anaesthesia: a randomized trial and systematic review. AB - BACKGROUND: Hip fracture is a condition with high mortality and morbidity in elderly frail patients. Intraoperative fluid optimization may be associated with benefit in this population. We investigated whether intraoperative fluid management using pulse-contour analysis cardiac monitoring, compared with standard care in patients undergoing spinal anaesthesia, would provide benefits in terms of reduced time until medically fit for discharge and postoperative complications. METHODS: Patients undergoing surgical repair of fractured neck of femur, aged >60 yr, receiving spinal anaesthesia were enrolled in this single centre, blinded, randomized, parallel group trial. Patients were allocated to either anaesthetist-directed fluid therapy or a pulse-contour-guided fluid optimization strategy using colloid (Gelofusine) boluses to optimize stroke volume. The primary outcome was time until medically fit for discharge. Secondary outcomes included postoperative complications, mobility, and mortality. We updated a systematic review to include relevant trials to 2014. RESULTS: We recruited 130 patients. Time until medically fit for discharge was similar in both groups, mean [95% confidence interval (CI)] 12.2 (11.1-13.5) vs 13.1 (11.9 14.5) days (P=0.31), as was total length of stay 14.2 (12.9-15.8) vs 15.3 (13.8 17.2) days (P=0.32). There were no significant differences in complications, function, or mortality. An updated meta-analysis (four studies, 355 patients) found non-significant reduction in early mortality [relative risk 0.66 (0.24 1.79)] and in-hospital complications [relative risk 0.80 (0.61-1.05)]. CONCLUSIONS: Goal-directed fluid therapy during hip fracture repair under spinal anaesthesia does not result in a significant reduction in length of stay or postoperative complications. There is insufficient evidence to either support or discount its routine use. CLINICAL TRIAL REGISTRATION: ISRCTN88284896. PMID- 25500941 TI - Dynamic preload markers to predict fluid responsiveness during and after major gastrointestinal surgery: an observational substudy of the OPTIMISE trial. AB - BACKGROUND: Stroke volume variation (SVV) and pulse pressure variation (PPV), termed dynamic markers of preload responsiveness, may predict the response to i.v. fluid in critically ill patients. However, the predictive accuracy of these variables during gastrointestinal surgery remains uncertain. METHODS: Observational study of patients aged >=50 yr undergoing major gastrointestinal surgery, enrolled in the OPTIMISE trial. Patients received six 250 ml fluid challenges with i.v. colloid solution (three during and three after surgery), while SVV and PPV were measured using the LiDCOrapid monitor (LiDCO Ltd, UK). Fluid responsiveness was defined as a stroke volume increase >=10%. Area under the receiver operating characteristic curve was calculated with 95% confidence intervals. Adjustment for covariates was performed by regression modelling and a clustering method was used to adjust for intra-patient correlation. RESULTS: One hundred patients were recruited between August 2010 and October 2012. Five hundred and fifty-six fluid challenges were administered and 159 (28.6%) were associated with increased stroke volume. The predictive value of both variables was poor during surgery [SVV 0.69 (0.63-0.77); PPV 0.70 (0.62-0.77)], and also after surgery [SVV 0.69 (0.63-0.78); PPV 0.64 (0.56-0.73)]. The findings were similar when analysed according to whether patients were mechanically ventilated [SVV 0.68 (0.63-0.77); PPV 0.69 (0.61-0.77)] or breathing spontaneously [SVV 0.69 (0.61-0.77); PPV 0.63 (0.56-0.72)]. Predictive value improved slightly in a sensitivity analysis excluding outlier values of SVV and PPV. CONCLUSIONS: In this study, the predictive accuracy of SVV and PPV for fluid responsiveness was insufficient to recommend for routine clinical use during or after major gastrointestinal surgery. PMID- 25500942 TI - Sample size calculation for the one-sample log-rank test. AB - An improved method of sample size calculation for the one-sample log-rank test is provided. The one-sample log-rank test may be the method of choice if the survival curve of a single treatment group is to be compared with that of a historic control. Such settings arise, for example, in clinical phase-II trials if the response to a new treatment is measured by a survival endpoint. Present sample size formulas for the one-sample log-rank test are based on the number of events to be observed, that is, in order to achieve approximately a desired power for allocated significance level and effect the trial is stopped as soon as a certain critical number of events are reached. We propose a new stopping criterion to be followed. Both approaches are shown to be asymptotically equivalent. For small sample size, though, a simulation study indicates that the new criterion might be preferred when planning a corresponding trial. In our simulations, the trial is usually underpowered, and the aspired significance level is not exploited if the traditional stopping criterion based on the number of events is used, whereas a trial based on the new stopping criterion maintains power with the type-I error rate still controlled. PMID- 25500943 TI - A BODIPY-luminol chemiluminescent resonance energy-transfer (CRET) cassette for imaging of cellular superoxide. AB - Spectroscopic and in cellulo studies are here reported on the very first BODIPY luminol chemiluminescent resonance energy-transfer (CRET) cassette where the luminol CL agent is covalently linked to the BODIPY energy-transfer acceptor in a molecular dyad. The efficiency of intramolecular CRET investigated for the BODIPY luminol dyad was found to be 64% resulting in a dual emissive response. Successful in cellulo biochemiluminescence via CRET was achieved in PMA activated splenocytes. PMID- 25500946 TI - High performing smart electrochromic device based on honeycomb nanostructured h WO3 thin films: hydrothermal assisted synthesis. AB - Herein, we report honeycomb nanostructured single crystalline hexagonal WO(3) (h WO(3)) thin films in order to improve electrochromic performance. In the present investigation, honeycomb nanostructured WO(3) with different unit size and nanowire array with highly nanocrystalline frameworks have been synthesized via a hydrothermal technique. The influence of hydrothermal reaction time on the honeycomb unit cells, crystallite size, lithium ion diffusion coefficient and switching time for coloration/bleaching were studied systematically. The electrochromic study reveals that the honeycomb unit cell size has a significant impact on the electrochromic performance. Small unit cells in the honeycomb lead to large optical modulation and fast switching response. A large optical modulation in the visible spectral region (60.74% at lambda = 630 nm) at a potential of -1.2 V with fast switching time (4.29 s for coloration and 3.38 s for bleaching) and high coloration efficiency (87.23 cm(2) C(-1)) is observed in the honeycomb WO(3) thin films with a unit cell diameter of 1.7 MUm. The variation in color on reduction of WO(3) with applied potential has been plotted on an xy-chromaticity diagram and the color space coordinate shows the transition from a colorless to deep blue state. PMID- 25500944 TI - Cellular activity of siRNA oligonucleotides containing synthetic isomorphic nucleoside surrogates. AB - Singly and multiply modified synthetic siRNA oligonucleotides, containing isomorphic surrogate nucleobases, show high interference potency in cell culture, suggesting the highly isomorphic RNA alphabet, based on a thieno[3,4-d] pyrimidine core, is tolerated well by the cellular silencing machinery. PMID- 25500947 TI - Theoretical analysis of dip-coating of uniformly wetting and chemically micropatterned surfaces with an Ellis fluid. AB - Dip-coating of a chemically micropatterned surface is an important technique for selective material deposition in a confined region for various applications. An analysis of the dip-coating of a micropatterned surface with a pure Newtonian liquid was performed by Davis (Phys. Fluids 17, 03852 (2005)). In this study, the analysis of dip-coating of the heterogeneous substrate is extended to the deposition of an Ellis Fluid. Governing equations are derived using lubrication theory to determine the thickness of a liquid film deposited on the O(10 MUm) stripe at small capillary number. A uniformly wetting surface is also considered using a consistent treatment of the governing equations for comparison. The effect of the Ellis model parameters on the thickness of the entrained liquid film is found to be much less for the micropatterned surfaces because of the dominant effect of the lateral fluid confinement due to heterogeneous wettability. This confinement imposes a geometric length scale in case of the patterned surface that replaces the dynamic capillary length used for the analysis of the dip-coating of a uniform surface. A composite equation is further developed for the Ellis fluid to include the effect of gravity on the dip-coated film thickness on both types of surfaces. The film thinning due to gravity drainage is found to be negligible for the case of patterned substrate. PMID- 25500945 TI - Comparing stigmatising attitudes towards people with substance use disorders between the general public, GPs, mental health and addiction specialists and clients. AB - BACKGROUND: Substance use disorders (SUDs) are among the most severely stigmatised conditions; however, little is known about the nature of these stigmatising attitudes. AIMS: To assess and compare stigmatising attitudes towards persons with SUDs among different stakeholders: general public, general practitioners (GPs), mental health and addiction specialists, and clients in treatment for substance abuse. METHODS: Cross-sectional study (N = 3,326) in which stereotypical beliefs, attribution beliefs (e.g. perceptions about controllability and responsibility for having an addiction), social distance and expectations about rehabilitation opportunities for individuals with substance use disorders were assessed and compared between stakeholders. RESULTS: Individuals with substance use disorders elicited great social distance across all stakeholders. Stereotypical beliefs were not different between stakeholders, whereas attribution beliefs were more diverse. Considering social distance and expectations about rehabilitation opportunities, the general public was most pessimistic, followed by GPs, mental health and addiction specialists, and clients. Stereotypical and attribution beliefs, as well as age, gender and socially desirable answering, were not associated with social distance across all stakeholders. CONCLUSION: The general public and GPs expressed more social distance and were more negative in their expectations about rehabilitation opportunities, compared to mental health and addiction specialists and clients. Although stigmatising attitudes were prevalent across all groups, no striking differences were found between stakeholders. PMID- 25500948 TI - Development of a flow rate monitoring method for the wearable ventricular assist device driver. AB - Our research institute has been working on the development of a compact wearable drive unit for an extracorporeal ventricular assist device (VAD) with a pneumatically driven pump. A method for checking the pump blood flow on the side of the drive unit without modifying the existing blood pump and impairing the portability of it will be useful. In this study, to calculate the pump flow rate indirectly from measuring the flow rate of the driving air of the VAD air chamber, we conducted experiments using a mock circuit to investigate the correlation between the air flow rate and the pump flow rate as well as its accuracy and error factors. The pump flow rate was measured using an ultrasonic flow meter at the inflow and outflow tube, and the air flow was measured using a thermal mass flow meter at the driveline. Similarity in the instantaneous waveform was confirmed between the air flow rate in the driveline and the pump flow rate. Some limitations of this technique were indicated by consideration of the error factors. A significant correlation was found between the average pump flow rate in the ejecting direction and the average air flow rate in the ejecting direction (R2 = 0.704-0.856), and the air flow rate in the filling direction (R2 = 0.947-0.971). It was demonstrated that the average pump flow rate was estimated exactly in a wide range of drive conditions using the air flow of the filling phase. PMID- 25500950 TI - Reconstruction of two colonisation pathways of Mantis religiosa (Mantodea) in Germany using four mitochondrial markers. AB - Past and recent climatic changes induced shifts in species ranges. Mantis religiosa has also expanded its range across Germany within the past decades. To determine the ancestry of German M. religiosa we sequenced four mitochondrial genes (COI, COII, Cyt b, ND4) of European M. religiosa populations. We found an east, central and west European lineage of M. religiosa. These distinct lineages are consistent with genetic isolation by distance during glacial periods, and the re-colonization of northern parts of Europe by species from different refugia. Within Germany, we found haplotypes clustering to the central and west European lineage suggesting that M. religiosa immigrated from two directions into Germany. Mismatch distributions, and negative Tajima's D and Fu's Fs values indicate a current range expansion of the central and west European lineage. We hypothesise that ongoing global warming which increases the availability of thermally favourable areas in Germany for M. religiosa adds to its current range expansion. In conclusion, M. religiosa colonized Germany via two directions: west German populations descended from French populations and east German populations from Czech populations. PMID- 25500949 TI - Post-mortem Whole exome sequencing with gene-specific analysis for autopsy negative sudden unexplained death in the young: a case series. AB - Annually, thousands of sudden deaths in individuals under 35 years remain unexplained following comprehensive medico-legal autopsy. Previously, post-mortem genetic analysis by Sanger sequencing of four major cardiac channelopathy genes revealed that approximately one-fourth of these autopsy-negative sudden unexplained death in the young (SUDY) cases harbored an underlying mutation. However, there are now over 100 sudden death-predisposing cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes. Here, we set out to determine whether post-mortem whole exome sequencing (WES) is an efficient strategy to detect ultra-rare, potentially pathogenic variants. We performed post mortem WES and gene-specific analysis of 117 sudden death-susceptibility genes for 14 consecutively referred Caucasian SUDY victims (average age at death 17.4 +/- 8.6 years) to identify putative SUDY-associated mutations. On average, each SUDY case had 12,758 +/- 2,016 non-synonymous variants, of which 79 +/- 15 localized to these 117 genes. Overall, eight ultra-rare variants (seven missense, one in-frame insertion) absent in three publically available exome databases were identified in six genes (three in TTN, and one each in CACNA1C, JPH2, MYH7, VCL, RYR2) in seven of 14 cases (50 %). Of the seven missense alterations, two (T171M CACNA1C, I22160T-TTN) were predicted damaging by three independent in silico tools. Although WES and gene-specific surveillance is an efficient means to detect rare genetic variants that might underlie the pathogenic cause of death, accurate interpretation of each variant is challenging. Great restraint and caution must be exercised otherwise families may be informed prematurely and incorrectly that the root cause has been found. PMID- 25500951 TI - MafA is critical for maintenance of the mature beta cell phenotype in mice. AB - AIMS/HYPOTHESIS: The plasticity of adult somatic cells allows for their dedifferentiation or conversion to different cell types, although the relevance of this to disease remains elusive. Perturbation of beta cell identity leading to dedifferentiation may be implicated in the compromised functions of beta cells in diabetes, which is a current topic of islet research. This study aims to investigate whether or not v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker, is involved in maintaining mature beta cell phenotypes. METHODS: The fate and gene expression of beta cells were analysed in Mafa knockout (KO) mice and mouse models of diabetes in which the expression of MafA was reduced in the majority of beta cells. RESULTS: Loss of MafA reduced the beta to alpha cell ratio in pancreatic islets without elevating blood glucose to diabetic levels. Lineage tracing analyses showed reduced/lost expression of insulin in most beta cells, with a minority of the former beta cells converted to glucagon-expressing cells in Mafa KO mice. The upregulation of genes that are normally repressed in mature beta cells or transcription factors that are transiently expressed in endocrine progenitors was identified in Mafa KO islets as a hallmark of dedifferentiation. The compromised beta cells in db/db and multiple low-dose streptozotocin mice underwent similar dedifferentiation with expression of Mafb, which is expressed in immature beta cells. CONCLUSIONS/INTERPRETATION: The maturation factor MafA is critical for the homeostasis of mature beta cells and regulates cell plasticity. The loss of MafA in beta cells leads to a deeper loss of cell identity, which is implicated in diabetes pathology. PMID- 25500952 TI - Glucose uptake in human brown adipose tissue is impaired upon fasting-induced insulin resistance. AB - AIMS/HYPOTHESIS: Human brown adipose tissue (BAT) has recently emerged as a potential target in the treatment of type 2 diabetes, owing to its capacity to actively clear glucose from the circulation-at least upon cold exposure. The effects of insulin resistance on the capacity of human BAT to take up glucose are unknown. Prolonged fasting is known to induce insulin resistance in peripheral tissues in order to spare glucose for the brain. METHODS: We studied the effect of fasting-induced insulin resistance on the capacity of BAT to take up glucose during cold exposure as well as on cold-stimulated thermogenesis. BAT glucose uptake was assessed by means of cold-stimulated dynamic 2-deoxy-2-[(18)F]fluoro-D glucose positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) imaging. RESULTS: We show that a 54 h fasting period markedly decreases both cold induced BAT glucose uptake and nonshivering thermogenesis (NST) during cold stimulation. In vivo molecular imaging and modelling revealed that the reduction of glucose uptake in BAT was due to impaired cellular glucose uptake and not due to decreased supply. Interestingly, decreased BAT glucose uptake upon fasting was related to a decrease in core temperature during cold exposure, pointing towards a role for BAT in maintaining normothermia in humans. CONCLUSIONS/INTERPRETATION: Cold-stimulated glucose uptake in BAT is strongly reduced upon prolonged fasting. When cold-stimulated glucose uptake in BAT is also reduced under other insulin resistant states, such as diabetes, cold-induced activation of BAT may not be a valid way to improve glucose clearance by BAT under such conditions. TRIAL REGISTRATION: www.trialregister.nl NTR3523 FUNDING: This work was supported by the EU FP7 project DIABAT (HEALTH-F2-2011-278373 to WDvML) and by the Netherlands Organization for Scientific Research (TOP 91209037 to WDvML). PMID- 25500953 TI - Hemodynamic volumetry using transpulmonary ultrasound dilution (TPUD) technology in a neonatal animal model. AB - To analyze changes in cardiac output and hemodynamic volumes using transpulmonary ultrasound dilution (TPUD) in a neonatal animal model under different hemodynamic conditions. 7 lambs (3.5-8.3 kg) under general anesthesia received arterial and central venous catheters. A Gore-Tex((r)) shunt was surgically inserted between the descending aorta and the left pulmonary artery to mimic a patent ductus arteriosus. After shunt opening and closure, induced hemorrhagic hypotension (by repetitive blood withdrawals) and repetitive volume challenges, the following parameters were assessed using TPUD: cardiac output, active circulating volume index (ACVI), central blood volume index (CBVI) and total end-diastolic volume index (TEDVI). 27 measurement sessions were analyzed. After shunt opening, there was a significant increase in TEDVI and a significant decrease in cardiac output with minimal change in CBVI and ACVI. With shunt closure, these results reversed. After progressive hemorrhage, cardiac output and all volumes decreased significantly, except for ACVI. Following repetitive volume resuscitation, cardiac output increased and all hemodynamic volumes increased significantly. Correlations between changes in COufp and changes in hemodynamic volumes (ACVI 0.83; CBVI 0.84 and TEDVI 0.78 respectively) were (slightly) better than between changes in COufp and changes in heart rate (0.44) and central venous pressure (0.7). Changes in hemodynamic volumes using TPUD were as expected under different conditions. Hemodynamic volumetry using TPUD might be a promising technique that has the potential to improve the assessment and interpretation of the hemodynamic status in critically ill newborns and children. PMID- 25500954 TI - Is percutaneous suturing superior to open fibrin gluing in acute Achilles tendon rupture? AB - PURPOSE: Open fibrin gluing is reported to enable anatomical reconstruction with less soft tissue compromise than suture repair. Our main objective was to compare the complication rate, function, pain and disability of the two operative approaches of percutaneous suture using the Paessler technique and open fibrin gluing. METHODS: Sixty-four patients (two centres, retrospective cohort study, 2000-2009) who had undergone acute Achilles tendon repair with either percutaneous suture (n = 27; 44 years) or open fibrin glue (n = 37; 45 years) took part in a follow-up examination after a median of 63 months (range, six to 180). Ankle range of motion, calf and ankle circumferences and return to work and sports activities were evaluated. Isokinetic und sonographic evaluation results were retrieved. RESULTS: Complications were noted in 22 patients (34 %). Delayed wound healing without evidence of surgical site infection was found in three patients in the fibrin group and two patients in the suture group. Postoperative scar tenderness described as pain at the rim of the shoe was significantly more frequent in the suture group (p = 0.03). Re-rupture requiring re-operation occurred in one patient. Transient paresthesia of the heel occurred in 12 patients. No sural nerve lesions were reported. There was no significant difference between groups regarding lower leg circumference, disability, or function. Ultrasound and isokinetic measurements did not reveal a significant difference between the two methods. CONCLUSIONS: The present study suggests that open fibrin gluing is a reasonable alternative to percutaneous repair of acute ruptures of the Achilles tendon and both techniques can yield reliably good results. PMID- 25500955 TI - Introducing prospective national registration of knee osteotomies. A report from the first year in Sweden. AB - PURPOSE: Knee osteotomy is a joint preserving surgery with new techniques and implants introduced during recent years. However the information of its use and outcome is scarce. A national knee osteotomy register was started in Sweden in 2013 from which we report here the information gathered during the first year of registration. METHODS: All patients having knee osteotomy (distal femur and proximal tibia), primaries and re-operations are intended to be included in the prospective registration. Reporting to the register is based on a paper form including information on the patient (ID, sex, age, American Society of Anesthesiologists classification [ASA], weight and height) surgical date, hospital, diagnosis, pre-operative alignment and grade of osteoarthritis (OA), part and LOT numbers of implants, surgical technique, prophylaxis (antithrombotic and antibiotic) and operating time. RESULTS: During the first year (April 2013 to March 2014), 34 clinics reported 220 primary knee osteotomies (209 proximal tibia and 11 distal femur). We estimate that this represents almost 80% of those performed on the adult population during the period. The majority of the patients were classified as healthy (60% ASA grade 1), were men (66%) and the median age was 51 years (range 19-67). Proximal tibia osteotomy for OA performed with open wedge osteotomy using internal fixation without bone transplantation was most commonly reported. CONCLUSIONS: As relatively few patients are being treated with different types of fixation and bone substitution in Sweden as well as the rapid development of techniques and new implants, a nationwide registration of knee osteotomies is relevant. PMID- 25500956 TI - In vitro effects on mobile polyethylene insert under highly demanding daily activities: stair climbing. AB - PURPOSE: Wear and survival of total joint replacements do not depend on the duration of the implant in situ, but rather on the amount of its use, i.e. the patient's activity level. With this in mind, the present study was driven by two questions: (1) How does total knee replacement (TKR) respond to the simulation of daily highly demanding activities? (2) Are certain activities to be advised against or, on the contrary, useful to implanted patients, in order to reduce wear of TKR and its related problems? METHODS: One set of the same total knee prosthesis (TKP), equal in design and size, was tested on a three-plus-one knee joint simulator for two million cycles using a highly demanding daily load waveform, replicating a stair-climbing movement. The results were compared with a set of TKP previously tested with the ISO level walking task. A digital microscope was used to characterise the superficial structure of all the TKPs. Gravimetric and micro-Raman spectroscopic analyses were carried out on the polyethylene inserts. Visual comparison with in vivo explants was carried out. RESULTS: The average volumetric mass loss after two million cycles was 44 +/- 6 mm(3). Microscope examinations showed some deep scratches along the flexion/extension movements for all the components. Also, the metallic backside surface showed intense non-linear scratches and the polyethylene counterface was characterised by some craters. A decrease in crystallinity, induced by mechanical stress was observed on all polyethylene components and was quantitatively confirmed by the orthorhombic fraction alphao value. CONCLUSIONS: The results of this study demonstrated that the forces and motion sustained by the knee are highly activity-dependent. Moreover, this test confirmed that under more severe conditions, the material properties change according to a different wear mechanism and a decrease in crystallinity occurs. Loading characteristics for specific activities should be considered for the design of functional and robust TKRs. PMID- 25500957 TI - Variations of the micro-vascularization of the greater tuberosity in patients with rotator cuff tears. AB - PURPOSE: The aim of the study was to analyse greater tuberosity's (GT) micro vascularization in the context of rotator cuff tear and to identify factors that could affect the rate and distribution of micro-vessels. METHODS: Eighty-seven patients with supraspinatus and/or infraspinatus tendon tears were included in a prospective study. Mean age at surgery was 58 years (41-78) and clinical symptoms were lasting from an average of 20 months before surgery. A bone core of 1-cm depth was obtained from the GT during rotator cuff repair at two localizations, medial and lateral within tuberosity. Micro-vascularization was then analysed with an immunohistochemistry technique based on CD34 antigen tracking endothelial cells at two levels of depth for each sample (more and less than 5 mm). Epidemiologic and pathologic data were correlated with the rate of micro vascularization measured. RESULTS: Median rate of GT's micro-vascularization was 9.8 %, which ranged from 0.13 % to 33.4 %. This rate decreased with preoperative steroid injection (7.4 % vs 11.2) and with localization close to the cartilage of the humeral head (8.7 % vs 11.9 %). However, it remains almost homogenous along the depth's core. Moreover, no significant correlation was found regarding age at surgery, gender, context of previous trauma, smoking habits, duration of symptoms, and specific data regarding the tendon tear. CONCLUSIONS: This study highlighted the variability of GT's micro-vascularization in case of rotator cuff tear. A greater rate was observed at the lateral part of the footprint, whereas medical history of steroid injection has a negative influence on micro vascularization. PMID- 25500959 TI - Transvenous Embolization of a Dural Arteriovenous Fistula Involving the Suboccipital Cavernous Sinus. PMID- 25500960 TI - Risk-stratification in normotensive acute pulmonary embolism. PMID- 25500958 TI - Decision making in displaced fractures of the proximal humerus: fracture or surgeon based? AB - PURPOSE: The aim of this study was to analyse the factors that influence surgeon decision-making in the treatment of proximal humerus fractures that might be considered for arthroplasty or open reduction and internal fixation. METHODS: A total of 217 surgeons evaluated radiographs and clinical vignettes of ten patients with fractures of the proximal humerus. In addition to radiographs, we provided patient age, sex, trauma mechanism, activity level (sedentary-vigorously active), and physical status (normal healthy-moribund). Observers were asked to: (1) choose open reduction and internal fixation or hemiarthroplasty (closed question, one option) and (2) to briefly describe the factors that led to their decision (open-ended question). We assessed interobserver reliability using the Fleiss generalized kappa and analysed factors that influenced decision-making according to treatment choice. RESULTS: Internal fixation was the preferred treatment for the majority of fractures. The overall multirater agreement was fair (kappa = 0.30), with a 75 % proportion of agreement. When asked to describe the factors that influenced decision-making, surgeons favouring internal fixation described patient-based factors in 52 %, fracture morphology in 51 %, surgeon factors in 42 %, and bone quality in 11 %. In contrast, fracture morphology was the most common factor (67 %) described by surgeons recommending replacement. Patient age, sex, activity level, physical status and the presence of angular displacement were associated with a recommendation for internal fixation. CONCLUSION: There is substantial variation in recommendations for internal fixation vs. arthroplasty for fractures of the proximal humerus that arises in large part from patient and surgeon factors. PMID- 25500961 TI - Synthesis of poly(dihydroxystyrene-block-styrene) (PDHSt-b-PSt) by the RAFT process and preparation of organic-solvent-dispersive Ag NPs by automatic reduction of metal ions in the presence of PDHSt-b-PSt. AB - We proposed a block copolymer, poly(dihydroxystyrene-block-styrene) (PDHSt-b PSt), that contains catechol groups in the side chains of PDHSt moieties. Since catechol groups automatically reduce silver (Ag) ions to their metallic state, the block copolymer was used as a reductant to synthesize organic-solvent dispersive Ag NPs (NPs) stabilized with the block copolymer at room temperature. Ag NP sizes were controlled by changing molecular weights of PDHSt of the block copolymer. PMID- 25500962 TI - Radiation exposure from diagnostic imaging in young patients with testicular cancer. AB - OBJECTIVES: Risks associated with high cumulative effective dose (CED) from radiation are greater when imaging is performed on younger patients. Testicular cancer affects young patients and has a good prognosis. Regular imaging is standard for follow-up. This study quantifies CED from diagnostic imaging in these patients. METHODS: Radiological imaging of patients aged 18-39 years, diagnosed with testicular cancer between 2001 and 2011 in two tertiary care centres was examined. Age at diagnosis, cancer type, dose-length product (DLP), imaging type, and frequency were recorded. CED was calculated from DLP using conversion factors. Statistical analysis was performed with SPSS. RESULTS: In total, 120 patients with a mean age of 30.7 +/- 5.2 years at diagnosis had 1,410 radiological investigations. Median (IQR) surveillance was 4.37 years (2.0-5.5). Median (IQR) CED was 125.1 mSv (81.3-177.5). Computed tomography accounted for 65.3 % of imaging studies and 98.3 % of CED. We found that 77.5 % (93/120) of patients received high CED (>75 mSv). Surveillance time was associated with high CED (OR 2.1, CI 1.5-2.8). CONCLUSIONS: Survivors of testicular cancer frequently receive high CED from diagnostic imaging, mainly CT. Dose management software for accurate real-time monitoring of CED and low-dose CT protocols with maintained image quality should be used by specialist centres for surveillance imaging. KEY POINTS: * CT accounted for 98.3 % of CED in patients with testicular cancer. * Median CED in patients with testicular cancer was 125.1 mSv * High CED (>75 mSv) was observed in 77.5 % (93/120) of patients. * Dose tracking and development of low-dose CT protocols are recommended. PMID- 25500963 TI - MRI-detected extramural vascular invasion is an independent prognostic factor for synchronous metastasis in patients with rectal cancer. AB - OBJECTIVES: To determine whether magnetic resonance imaging (MRI)-detected extramural vascular invasion (EMVI) could predict synchronous distant metastases in rectal cancer. METHODS: Patients who underwent rectal MRI between July 2011 and December 2012 were screened. This study included 447 patients with pathologically confirmed rectal adenocarcinoma who had undergone MRI without previous treatment. Distant metastases were recorded at the initial work-up and over a 6-month follow-up. Univariate/multivariate logistic regression models were used to determine the risk of metastasis. The diagnostic performance was calculated using pathologic lymphovascular invasion (LVI) as a gold standard. RESULTS: Among 447 patients, 79 patients (17.7 %) were confirmed to have distant metastases. Three MRI features are significantly associated with a high risk of distant metastasis: positive EMVI (odds ratio 3.02), high T stage (odds ratio 2.10) and positive regional lymph node metastasis (odds ratio 6.01). EMVI in a large vessel (>=3 mm) had a higher risk for metastasis than EMVI in a small vessel (<3 mm). Sensitivity, specificity and accuracy of MRI-detected EMVI were 28.2 %, 94.0 % and 80.3 %, respectively. CONCLUSIONS: MRI-detected EMVI is an independent risk factor for synchronous metastasis in rectal cancer. EMVI in large vessels is a stronger risk factor for distant metastasis than EMVI in small vessels. KEY POINTS: * EMVI, LN metastasis and T staging on MRI are risk factors for metastasis. * EMVI in large vessels has greater risk for metastasis than in small vessels. * Regional LN metastasis on MRI has highest risk for predicting metastasis. * MR findings could be helpful for selecting patients at high risk for metastasis. PMID- 25500964 TI - A study on the existence of Vibrio cholerae non-O1 in the river. AB - OBJECTIVE: The aim of the present study is Vibrio cholerae non-O1 existing in river. Bacteria are known to inhabit all kinds of environment. Vibrionaceae is widely distributed in environmental water. Vibrio spp. have been identified as a cause of toxicity in fish and shellfish. One condition affecting the survival of pathogenic microorganisms in environmental water is the salt concentration, and they have been reported to inhabit brackish water. However, V. cholerae non-O1 has also been detected in fresh water, and its properties suggest that it can survive in river water. METHODS: Sampling was performed 4 times at 4 points during a 5-month period from July to November at about 1-month intervals from the Sagami River in 1985. River water bacteria were identified, and V. cholera non-O1 isolated. I investigated the relationship between the bacterial flora in river water and the detection of V. cholerae non-O1. RESULTS: There were significant differences in the composition of bacterial flora with and without the isolation of V. cholerae non-O1 (Chi-square test) (chi(2) = 24.70 > 22.0 (p = 0.005), df = 8). A correlation between changes in the composition of the river water bacterial flora and detection of V. cholerae non-O1 was identified. CONCLUSION: Therefore, V. cholerae non-O1 exists in the river. PMID- 25500965 TI - An efficient implementation of the synchronization likelihood algorithm for functional connectivity. AB - Measures of functional connectivity are commonly employed in neuroimaging research. Among the most popular measures is the Synchronization Likelihood which provides a non-linear estimate of the statistical dependencies between the activity time courses of different brain areas. One aspect which has limited a wider use of this algorithm is the fact that it is very computationally and memory demanding. In the present work we propose new implementations and parallelizations of the Synchronization Likelihood algorithm with significantly better performance both in time and in memory use. As a result both the amount of required computational time is reduced by 3 orders of magnitude and the amount of memory needed for calculations is reduced by 2 orders of magnitude. This allows performing analyses that were not feasible before from a computational standpoint. PMID- 25500966 TI - Open reduction and internal fixation of Ideberg IV and V glenoid intra-articular fractures through a Judet approach: a retrospective analysis of 11 cases. AB - OBJECTIVES: To evaluate the methods and the outcomes of complex intra-articular glenoid fractures, treated by open reduction and internal fixations. METHODS: The outcomes of 11 cases of complex intra-articular glenoid scapular fractures were retrospectively analyzed. The fractures were classified as type IV in five cases, type Va in two and Vb in four cases, according to Ideberg classification system. The mean step or gap between the main articular fragments was 6.3 +/- 6.2 (4-25) mm. The fractures were openly reduced through a Judet approach and fixed with reconstructive plates or bands placed on the lateral and medial side of affected scapula, respectively. The main articular fragments were strengthened with a 4.0 mm cannulated screw in five cases. The bone union, the anterior flexion, the external and internal rotation of the shoulders were checked and recorded. The functional outcomes were evaluated using DASH questionnaire, Constant and UCLA shoulder score systems, respectively. RESULTS: 11 patients were followed up with an average of 28.2 +/- 12.6 (12-50) months. All the fractures were united smoothly without second intervention. At the latest visiting, the mean anterior flexion of affected shoulder was 157.3 +/- 7.37 degrees (range 150 degrees -170 degrees ), the mean external rotation of the affected shoulder was 58.2 +/- 7.5 degrees (range 50 degrees -70 degrees ). When the shoulder in the internal rotation, the extended thumb reached to L4 or L1 or T10 or T7 in one case, to T12 in two cases and to T8 in four cases, respectively, the mean Constant score was 91.7 +/- 2.8 (86-96) points. The mean UCLA score was 32.7 +/- 1.7 (30-35) points, leading to four cases of excellent and seven cases of good results. The mean DASH score was 7.4 +/- 3.3 (3.4-13) points. CONCLUSION: Good outcomes could be obtained when Ideberg IV and V glenoid fractures were treated by open reduction and internal fixation through a Judet approach. PMID- 25500968 TI - One year into Obamacare: where is it now? PMID- 25500967 TI - The effect of local bone mineral density on the rate of mechanical failure after surgical treatment of distal radius fractures: a prospective multicentre cohort study including 249 patients. AB - INTRODUCTION: The aim of this prospective, multicentre study was to evaluate the influence of local bone mineral density (BMD) on the rate of mechanical failure after locking plate fixation of closed distal radius fractures. MATERIALS AND METHODS: Between June 2007 and April 2010, 230 women and 19 men with a mean age of 67 years were enrolled. Dual energy X-ray absorptiometry measurements for BMD of the contralateral distal radius were made at 6 weeks post-surgery. Follow-up evaluations at 6 weeks, 3 months and 1 year included wrist mobility and strength as well as standard radiographs. Any local bone/fracture or implant/surgery related complications were documented. The Disability of the Arm, Shoulder, and Hand (DASH), Patient Rated Wrist Evaluation (PRWE), and EuroQol-5D scores were also recorded at the nominated time points. RESULTS: Nine patients were reported with mechanical failure at an estimated risk of 3.6 %. The BMD measurements were generally low for the study population with no difference between patients with (0.561 g/cm(2)) and without (0.626 g/cm(2)) mechanical failure (p = 0.148). None of the patients achieved their pre-injury functional level and quality of life status after 1 year. 1-year DASH and PRWE scores as well as the difference in maximum grip strength of the affected wrist relative to the contralateral side were significantly higher for patients with mechanical failure (p <= 0.036). CONCLUSIONS: Our study could not identify a clear association between bone mineral density status and the risk of mechanical failure. Although the risk for mechanical failure after treatment of distal radius fractures with palmar locking plates is low, these complications must be avoided to prevent negative impact on long-term patient functional and quality of life outcome. PMID- 25500970 TI - Laboratory bioassay of Beauveria bassiana against Tetranychus urticae (Acari: Tetranychidae) on leaf discs and potted bean plants. AB - Use of the mycopathogen Beauveria bassiana (strain GHA), marketed as BotaniGard((r)) ES, was evaluated as a plant protection strategy against the spider mite Tetranychus urticae Koch, which is considered one of the most economically important and cosmopolitan pests of many crops. Tetranychus urticae were treated with four concentrations of conidia (1 * 10(5), 1 * 10(6), 1 * 10(7), or 1 * 10(8) conidia/ml), and virulence was assessed on mites held at four relative humidity levels (35, 55, 75, and 95 +/- 2 % RH) at 25 +/- 1 degrees C. At 1 * 10(8) spores/ml, the LT50 value was 9.7 h at 95 % RH, which was significantly lower than values for other RH levels. At 1 * 10(7) spores/ml, the LT50 value was 43.8 h at 95 % RH, which was significantly different from values at 55 and 35 % RH. The efficacy of B. bassiana product was also verified on mites infesting potted bean plants with a concentration of 1 * 10(8) spores/ml. In double spray treatment where applications were made 2 * on days 5 and 10 after mite infestation, the nymphal and adult population of T. urticae were reduced to zero on days 20 and 15, respectively. With a single spray on day 5, the nymphal population was also greatly reduced, but increased rapidly after day 20. Single and double sprays with B. bassiana reduced leaf damage as measured by image analysis by 33 and 94 % compared to no treatment, respectively. These results suggest that 1 * 10(8) spores/ml was the most effective dose and that two applications, at a 5-day interval, provided control of T. urticae in our laboratory assay. PMID- 25500969 TI - A549 cells adapted to high nitric oxide show reduced surface CEACAM expression and altered adhesion and migration properties. AB - The migration and adhesion properties of tumors affect their metastatic rate. In the present study, we investigated carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 1, 5, and 6 expression in high nitric oxide (HNO)-adapted lung cancer cells compared to parent cells. We observed high transcript levels of CEACAM 1 (4S, 4L), CEACAM 5, and CEACAM 6 in HNO cells compared to parent cells. However, the surface expression was low in HNO cells. Interestingly, the intracellular protein levels were high for these three CEACAMs. We confirmed these results with immunohistochemical experiments. Further, the adhesion and migration assays showed reduced clumping in HNO-adapted A549 (A549-HNO) cells and faster migration rates, respectively. These results document the altered adhesion and migration properties of cells adapted to HNO. Further, our studies also indicate a dynamic regulation of CEACAM protein expression and surface transport in HNO cells. PMID- 25500971 TI - Plasma glutamine deficiency is associated with multiple organ failure in critically ill children. AB - A low plasma glutamine concentration (<420 umol/L) is an independent risk factor for mortality in critically ill adult patients. Glutamine metabolism in children is less well characterized. However, pediatric ICU (PICU) mortality is low and, therefore, mortality is difficult to use as an endpoint. Here we evaluated if plasma glutamine concentration at admission to the PICU, relates to the development of multiple organ failure, using pediatric logistic organ dysfunction score (PELOD)-score. In this observational study, consecutive critically ill children (n = 149) admitted to the PICU of a tertiary university hospital as well as a reference group of healthy children (n = 60) were included. Plasma glutamine concentration and the PELOD were determined at admission for all patients and at day 5 for those patients still in the PICU. Plasma glutamine concentration at admission was low in the PICU patients as compared to controls (p = 0.00002) and patients with a low plasma glutamine concentration had more organ failure as compared to patients with higher plasma glutamine concentration (p = 0.0001). Plasma glutamine concentration normalized in patients staying >5 days in the PICU. Plasma glutamine depletion was present in 40 % of patients at PICU admission and it was associated with the development of multiple organ failure. Furthermore, the majority of the critically ill children normalized their plasma glutamine concentration within 5 days, which is different from adult ICU patients. The study suggests that an initial plasma glutamine deficiency is associated with multiple organ failure in critically ill children. PMID- 25500972 TI - Pseudallescheria boydii infection of the central nervous system: first reported case from Turkey. PMID- 25500973 TI - Diffuse choroid plexus hyperplasia (CPH) associated with multiple malformations. PMID- 25500974 TI - Postradiation myokymia of the spinal accessory nerve. PMID- 25500975 TI - Dizziness causes absence from work. AB - The objective of the study was to assess absenteeism from work due to dizziness in patients referred to a tertiary centre. Consecutive patients with a paid employment completed the WHO Health and work Performance Questionnaire, including items on work absence in the past 7 days and 4 weeks, and the Dizziness Handicap Inventory. Of the 400 patients [55% females, mean age 46.3 years (SD 10.8), range 18-68 years], 46 (12%) indicated they were completely disabled to work due to dizziness, while 202 (51%) patients indicated they had worked less than expected due to dizziness. Patients with more disease-related disabilities had more absenteeism from work. Half of the patients who are referred to a tertiary centre for dizziness report work absenteeism due to their complaints, and 12% is completely disabled to work. PMID- 25500978 TI - A community long-term hotline therapeutic intervention model for coping with the threat and trauma of war and terror. AB - Long-term tele-counseling can potentially be a potent intervention mode in war- and terror-related community crisis situations. We aimed to examine a unique long term telephone-administered intervention, targeting community trauma-related crisis situations by use of various techniques and approaches. 142 participants were evaluated using a non-intrusive by-proxy methodology appraising counselors' standard verbatim reports. Various background measures and elements in the intervention were quantitatively assessed, along with symptomatology and functioning at the onset and end of intervention. About 1/4 of the wide variety of clients called for someone else in addition to themselves, and most called due to a past event rather than a present crisis situation. The intervention successfully reduced posttraumatic stress symptoms and improved functioning. Most interventions included psychosocial education with additional elements, e.g., self-help tools, and almost 60% included also in-depth processes. In sum, tele counseling might be a viable and effective intervention model for community related traumatic stress. PMID- 25500980 TI - Functionalization of nanostructured cerium oxide films with histidine. AB - The surfaces of polycrystalline cerium oxide films were modified by histidine adsorption under vacuum and characterized by the synchrotron based techniques of core and valence level photoemission, resonant photoemission and near edge X-ray absorption spectroscopy, as well as atomic force microscopy. Histidine is strongly bound to the oxide surface in the anionic form through the deprotonated carboxylate group, and forms a disordered molecular adlayer. The imidazole ring and the amino side group do not form bonds with the substrate but are involved in the intermolecular hydrogen bonding which stabilizes the molecular adlayer. The surface reaction with histidine results in water desorption accompanied by oxide reduction, which is propagated into the bulk of the film. Previously studied, well-characterized surfaces are a guide to the chemistry of the present polycrystalline surface and histidine bonds via the carboxylate group in both cases. In contrast, bonding via the imidazole group occurs on the well-ordered surface but not in the present case. The morphology and structure of the cerium oxide are decisive factors which define the adsorption geometry of the histidine adlayer. PMID- 25500977 TI - Anti-TNF-alpha loss of response is associated with a decreased percentage of FoxP3+ T cells and a variant NOD2 genotype in patients with Crohn's disease. AB - BACKGROUND: Anti-TNF-alpha therapies interact with the tolerogenic response in patients with Crohn's disease, modulating inflammation. However, drug levels and the genetic background may affect this interaction. METHODS: Patients with Crohn's disease in remission on biologic monotherapy were enrolled in this study. FoxP3+ lymphocytes, NOD2 genotype, serum cytokine, anti-TNF-alpha levels, and anti-drug antibodies were evaluated. Regulatory T cell response to infliximab was evaluated in vitro. RESULTS: Fifty-seven patients were included. Thirty-nine patients (68.4%) were receiving non-intensified biologic therapy whereas 18 patients (31.6%) were under an intensified biologic schedule due to loss of response. Eleven intensified patients (61.1%) showed a variant NOD2 genotype vs 9 on non-intensified biologics (23%, p < 0.01). Percentage of FoxP3+ T cells and serum free anti-TNF-alpha levels were significantly higher in patients with a wild-type vs variant NOD2 genotype, either under non-intensified or intensified schedule. Increasing amounts of infliximab significantly increased the expression of FoxP3+ T cells and anti-TNF-alpha levels in the supernatant from wild-type NOD2 patients cultured cells whereas the induction of FoxP3+ T cells and anti-TNF alpha levels in the supernatant from variant NOD2 patients cultured cells were significantly lower. TNF-alpha and IL-10 showed a correlation with the FoxP3+ T cell population percentage and serum levels of anti-TNF-alpha, irrespective of NOD2 genotype. Eight variant NOD2 patients (66.6%) vs 4 wild-type NOD2 patients (8.8%) showed a perianal phenotype (p = 0.01). A significant reduction of the percentage of FoxP3+ T cells and serum levels of anti-TNF-alpha was observed in patients with the associated perianal disease. CONCLUSION: Anti-TNF-alpha loss of response is associated with a decreased percentage of FoxP3+ T cells and a variant NOD2 genotype in patients with CD. PMID- 25500976 TI - Evidence-based clinical practice guidelines for irritable bowel syndrome. AB - New strategies for the care of irritable bowel syndrome (IBS) are developing and several novel treatments have been globally produced. New methods of care should be customized geographically because each country has a specific medical system, life style, eating habit, gut microbiota, genes and so on. Several clinical guidelines for IBS have been proposed and the Japanese Society of Gastroenterology (JSGE) subsequently developed evidence-based clinical practice guidelines for IBS. Sixty-two clinical questions (CQs) comprising 1 definition, 6 epidemiology, 6 pathophysiology, 10 diagnosis, 30 treatment, 4 prognosis, and 5 complications were proposed and statements were made to answer to CQs. A diagnosis algorithm and a three-step treatment was provided for patients with chronic abdominal pain or abdominal discomfort and/or abnormal bowel movement. If more than one alarm symptom/sign, risk factor and/or routine examination is positive, colonoscopy is indicated. If all of them, or the subsequent colonoscopy, are/is negative, Rome III or compatible criteria is applied. After IBS diagnosis, step 1 therapy consisting of diet therapy, behavioral modification and gut-targeted pharmacotherapy is indicated for four weeks. Non-responders to step 1 therapy proceed to the second step that includes psychopharmacological agents and simple psychotherapy for four weeks. In the third step, for patients non-responsive to step 2 therapy, a combination of gut-targeted pharmacotherapy, psychopharmacological treatments and/or specific psychotherapy is/are indicated. Clinical guidelines and consensus for IBS treatment in Japan are well suited for Japanese IBS patients; as such, they may provide useful insight for IBS treatment in other countries around the world. PMID- 25500979 TI - Characterization of a sleep architectural phenotype in children with Down syndrome. AB - PURPOSE: Evidence suggests that while the high prevalence of obstructive sleep apnea (OSA) in children with Down syndrome (DS) likely contributes to sleep fragmentation, their poor sleep is only partly attributable to the presence of OSA. We hypothesized that a sleep phenotype exists for DS, which would be independent of OSA and evident across childhood. METHODS: This is a retrospective study of sleep architecture in children with DS together with matched controls. All subjects underwent baseline polysomnography between January 1985 and January 2013. Case-control pairs were compared according to age group. RESULTS: Sleep characteristics were compared in 130 DS subjects aged 0-17.8 years (median 5.8 years) and 130 matched controls. Body mass index z-scores were similar between cases and controls. Compared to controls, children with DS had a lower sleep efficiency and higher percentage of slow-wave sleep at 2-6.9, 7-11.9, and 12-17.9 years (p <0.05 for all) as well as reduced rapid-eye movement (REM) sleep percentage, significant at 7-11.9 years (p <0.05). Children with DS exhibited increased N1 sleep at 2-6.9 years but decreased N1 sleep at 12-17.9 years compared to controls (p <0.05 for both). CONCLUSIONS: Children with DS exhibit altered sleep architecture when compared to non-DS children of similar age and OSA severity. Notably, reduced REM sleep and increased slow-wave sleep was seen independent of OSA in children with DS over 2 years. Amounts of both REM and non REM sleep may have important implications for learning, memory, and behavior, all the more significant in this population with baseline neurocognitive impairment. PMID- 25500981 TI - Markers of early atherosclerosis, oxidative stress and inflammation in patients with acromegaly. AB - PURPOSE: Data regarding atherosclerosis in acromegaly is controversial in literature. We aimed to investigate the markers of early atherosclerosis, oxidative stress, inflammation and their relationships with each other in acromegaly. METHODS: Thirty-nine patients with acromegaly and 40 control subjects were enrolled. Patients were classified into two groups; active acromegaly (AA) and controlled acromegaly (CA). Controls were matched by age, gender, body mass index and presence of cardiovascular risk factors. Flow mediated dilatation (FMD), carotid intima media thickness (CIMT), epicardial adipose tissue thickness (EAT) were measured and serum levels of oxidative stress parameters, high mobility group box 1 protein (HMGB1) and high sensitive CRP (hs CRP) were evaluated. RESULTS: Significantly decreased FMD, increased CIMT and EAT were found in patients with acromegaly compared to controls (p < 0.01, p < 0.05, p < 0.001, respectively). EAT correlated negatively with FMD (r = -0.24, p = 0.038) and positively with CIMT (r = 0.37, p < 0.01). Presence of acromegaly, hypertension and age were found to be the predictors of early atherosclerosis (p < 0.05). Hs CRP was decreased in AA compared to controls (p = 0.01). There were no significant differences for HMGB1 and oxidized LDL (ox-LDL) cholesterol levels and total antioxidant capacity (TAC) between AA, CA and controls (p > 0.05). CONCLUSION: Early atherosclerosis measured with FMD, CIMT and EAT may exist in acromegaly. However, decreased hs CRP and unchanged HMGB1, ox-LDL and TAC levels suggest that inflammation and oxidative stress do not seem to contribute to the development of atherosclerosis in these patients. PMID- 25500982 TI - Distribution of internal carotid artery plaque locations among patients with central retinal artery occlusion in the Eagle study population. AB - PURPOSE: Arterial emboli in the internal carotid artery (ICA) mainly cause cerebral ischemia; only 10 % of emboli reach the retinal arteries. Computational blood flow studies suggest that plaques situated in the ICA siphon may be a source of embolism to the ophthalmic artery (OA). To validate these calculated probabilities in patients with central retinal artery occlusion (CRAO), we reanalyzed digital subtraction angiography (DSA) images from the Multicenter Study of the European Assessment Group for Lysis in the Eye (EAGLE) study, a multicenter randomized study in patients with nonarteritic CRAO. METHODS: A reevaluation of 34 DSA studies was done from the interventional arm of the EAGLE study with regards to distribution of arterial plaques at specific ICA siphon locations and ICA stenosis. A comparison was made of plaque distribution to calculated probabilities for emboli reaching the OA from a computational fluid dynamics (CFD) model of a patient-specific ICA siphon. RESULTS: Most of the ICA plaques near the OA's origin were located in the cavernous ICA portion (31.3%). Of these, 12.5 % had plaques in the curvature opposite the OA origin, a location carrying the highest risk for embolization into the OA (according to the CFD model 12.6-13.2 % probability of embolisation into the OA). Also, 15.6 % had plaques in the paraclinoid ICA portion distal to the OA origin. CONCLUSIONS: There were 40.6% of the patients that had plaques in the cavernous and clinoid ICA portions presenting possible sources for embolic material generating RAO. PMID- 25500984 TI - Three-dimensional optic nerve head images using optical coherence tomography with a broad bandwidth, femtosecond, and mode-locked laser. AB - PURPOSE: The aim of this study was to demonstrate the fine laminar structure of the optic nerve head (ONH), in vivo, using a broad wavelength, ultra-high resolution, and optically coherent tomography (OCT) system. METHODS: This high resolution OCT system, based on a 200 nm bandwidth spectrometer and an 8 femtosecond ultra-short, mode-locked, coherent laser light source, enabled in vivo cross-sectional ONH imaging with 2.0 MUm axial resolution. A total of 300 optic disc B-scans, which consisted of 300 * 2048 pixels, were obtained in 10 MUm steps. Three-dimensional images were rendered from these images to obtain n face images of the optic disc. Fundus photography, scanning laser ophthalmoscopy (SLO), and standard OCT were also performed for all subjects. RESULTS: Thirty-six eyes of normal subjects and ten eyes of glaucoma patients with mean age of 40.0 +/- 10.0 years were enrolled in this study. Sequential en face images, from the ONH surface to deeper layers, were reconstructed in 2.0 MUm steps. Observation of the images indicated variations in the shape and arrangement of the lamina pores at different depths. Clear lamina pores were identified by this technique in 44 eyes, compared with the fundus camera (identified in six eyes), SLO (identified in 14 eyes), and standard OCT (identified in 24 eyes) (all comparisons, p < 0.001). CONCLUSIONS: The fine structure of the ONH could be resolved in vivo using our OCT, providing improved imaging that can be used in research and clinical applications for a better characterization of the anatomical and pathological features associated with glaucoma. PMID- 25500983 TI - Anti-interferon alpha antibodies and autoantibodies in patients with Behcet's disease uveitis treated with recombinant human interferon alpha-2a. AB - BACKGROUND: Recombinant human (rh) interferon alpha2a (IFN-alpha2a) therapy is successfully used for the treatment of Behcet's disease (BD) uveitis refractory to conventional immunosuppressive treatment. PURPOSE: Our aim in this study was to investigate the frequency and clinical significance of anti-IFN-alpha antibodies and autoantibodies during recombinant human rhIFN-alpha2a therapy in patients with BD uveitis. METHODS: This comparative, cross-sectional, serological screening study included 30 BD patients treated with rhIFN-alpha2a (Group 1), 29 BD patients treated with conventional immunosuppressive agents (Group 2), 29 BD patients who received only colchicine (Group 3), and 30 healthy subjects (Group 4). Anti-IFN-alpha-binding antibodies and autoantibodies, including anti-nuclear antibody, anti-thyroid peroxidase antibody, and anti-cardiolipin antibody, were measured in serum samples. Antibody seropositivity was compared between study groups. Retrospective clinical data were compared between antibody-positive and antibody-negative patients. RESULTS: A significantly higher proportion of patients in Group 1 had anti-interferon-alpha (26.6 %) and autoantibody (30 %) seropositivity compared to the other groups. No correlation was found between seropositivity for anti-interferon-alpha and other autoantibodies. No significant difference was found in cumulative dose of IFN-alpha, duration of IFN-alpha therapy, time to first uveitis attack, or attack rate between anti-interferon alpha antibody-positive and antibody-negative patients in Group 1. Uveitis attacks were observed in 22 % of autoantibody-positive and 71 % of autoantibody negative patients in Group 1 (p = 0.018). CONCLUSIONS: Patients with BD uveitis develop anti-IFN-alpha-binding antibodies and autoantibodies during treatment with rhIFN-alpha2a. While the clinical relevance of anti-IFN-alpha-binding antibodies remains unclear in this study, induction of autoimmunity was found to be associated with a tendency for better therapeutic response. PMID- 25500985 TI - Ocular surface changes after strabismus surgery with different incisions. AB - OBJECTIVES: To compare ocular surface changes after strabismus surgery with different incisions. METHODS: One hundred and twenty eyes with exotropia were randomly assigned to Group A (limbal incision) or Group B (fornix incision). Dry eye questionnaire, corneal sensitivity, tear film breakup time (TFBUT), Schirmer I test (SIT), and corneal fluorescein staining (CFS) were assessed at 1 day preoperatively and at different postoperative times. RESULTS: In the A group, dry eye questionnaire scores increased and TFBUT decreased at postoperative weeks 1, 2, and 4. Corneal sensitivity decreased at postoperative weeks 1 and 2. In the B group, dry eye questionnaire scores increased and TFBUT decreased at postoperative weeks 1 and 2. Corneal sensitivity did not change. Postoperative between-group differences were significant in dry eye questionnaire scores (P = 0.0009, 1 week; P < 0.0001, 2 weeks; P = 0.0001, 4 weeks) and TFBUT (P = 0.004, 1 week; P = 0.0003, 2 weeks; P = 0.0001, 4 weeks). Between-group differences in CFS were significant postoperatively (P = 0.045, 1 week; P = 0.020, 2 weeks). CONCLUSION: Compared to fornix incision, limbal incision results in more serious dry eye symptoms and has a greater impact on corneal sensitivity and tear film stability. PMID- 25500986 TI - A randomized trial of intravitreal bevacizumab vs. ranibizumab for myopic CNV. AB - AIMS: The aim was to compare the efficacy of intravitreal therapy with bevacizumab and ranibizumab for choroidal neovascularization (CNV) in pathologic myopia (PM). METHODS: This was a prospective multicenter randomized nonblinded trial. RESULTS: In seven centers, 78 eyes were randomized 1:1 to treatment with bevacizumab (group B, 40 eyes) or ranibizumab (group R, 38 eyes) given with an "on demand" regimen (PRN). The mean follow-up was 19 months (SD 2, range 12-24). The mean BCVA at baseline was 0.60 logMAR (20/80 Snellen equivalent, Seq) and 50 letter score (ls). Mean final BCVA was 0.51 LogMAR (20/63 Seq) and 57 ls (p = 0.0009 and p = 0.0002, respectively). In group B, mean basal BCVA was 0.52 logMAR (20/63 Seq) and 54 ls, and final BCVA was 0.51 logMar (20/63 Seq) and 57 ls. In group R, mean basal BCVA was 0.62 logMAR (20/80 Seq) and 45 ls, and the final values were 0.50 logMAR (20/63 Seq) and 58 ls. Statistical comparison of the two groups showed no significant difference (logMAR p = 0.90 and letters p = 0.78). Multivariate analysis showed no influence of age or previous photodynamic treatment (PDT) on final visual changes. The mean number of treatments in the first year was 2.7 in group B and 2.3 in group R (p = 0.09). CONCLUSION: Myopic CNV equally benefits from on-demand intravitreal injection of either bevacizumab or ranibizumab; the therapeutic effect is independent of previous PDT and age. PMID- 25500988 TI - Detaching droplets in immiscible fluids from a solid substrate with the help of electrowetting. AB - The detachment (or removal) of droplets from a solid surface is an indispensable process in numerous practical applications which utilize digital microfluidics, including cell-based assay, chip cooling, and particle sampling. When a droplet that is fully stretched by impacting or electrowetting is released, the conversion of stored surface energy to kinetic energy can lead to the departure of the droplet from a solid surface. Here we firstly detach sessile droplets in immiscible fluids from a hydrophobic surface by electrowetting. The physical conditions for droplet detachment depend on droplet volume, viscosity of ambient fluid, and applied voltage. Their critical conditions are determined by exploring the retracting dynamics for a wide range of driving voltages and physical properties of fluids. The relationships between physical parameters and dynamic characteristics of retracting and jumping droplets, such as contact time and jumping height, are also established. The threshold voltage for droplet detachment in oil with high viscosity is largely reduced (~70%) by electrowetting actuations with a square pulse. To examine the applicability of three-dimensional digital microfluidic (3D-DMF) platforms to biological applications such as cell culture and cell-based assays, we demonstrate the detachment of droplets containing a mixture of human umbilical vein endothelial cells (HUVECs) and collagen (concentration of 4 * 10(4) cells mL(-1)) in silicone oil with a viscosity of 0.65 cSt. Furthermore, to complement the technical limitations due to the use of a needle electrode and to demonstrate the applicability of the 3D DMF platform with patterned electrodes to chemical analysis and synthesis, we examine the transport, merging, mixing, and detachment of droplets with different pH values on the platform. Finally, by using DC and AC electrowetting actuations, we demonstrate the detachment of oil droplets with a very low contact angle (<~13 degrees ) in water on a hydrophobic surface. PMID- 25500987 TI - Patient selection for allogeneic hematopoietic cell transplantation (HCT): the evolution of HCT risk assessment. AB - The use of allogeneic hematopoietic cell transplantation is expanding, with disproportionate growth witnessed in older adults with hematologic malignancies. As the chronological age barrier to transplant fades, refining the pre hematopoietic cell transplantation (HCT) risk assessment to better capture host health status and disease characteristics is essential. This review summarizes recent efforts to move the field forward towards achieving this goal. Many of these risk assessment tools are currently included in prospective clinical trials; routine clinical use requires greater understanding of how to best incorporate this new information into HCT decision making. PMID- 25500990 TI - Factors influencing spatial variation and abundance of a mermithid parasite in sand hoppers. AB - The impact of parasites on host population dynamics depends on local abundance of the parasites, which may vary considerably across spatial scales. In sand hopper populations, mermithid parasites have major impacts on host dynamics, which may vary among spatially separated populations due to the sand hopper's wide, patchy distribution. The present study compared the abundance and biomass of a mermithid parasite (Thaumamermis zealandica Poinar et al., 2002) in sand hoppers (Bellorchestia quoyana (Milne-Edwards)) both within and among disconnected beaches. In addition, several variables were measured and tested as potentially important predictors of the parasite abundance and biomass. It was found that geographic isolation may only be responsible for minor differences in parasite populations compared with other factors. Host size was identified as the most important predictor of mermithid parasite abundance, but epibiont abundance, kelp patch mass and host density were poor predictors of abundance. These factors were also poor predictors of parasite biomass in hosts. This study further supports the notion that studies aiming to elucidate population dynamics or patterns should sample thoroughly across both spatial and temporal scales. PMID- 25500989 TI - Barriers and promoters of an evidenced-based smoking cessation counseling during prenatal care in Argentina and Uruguay. AB - In Argentina and Uruguay, 10.3 and 18.3 %, respectively, of pregnant women smoked in 2005. Brief cessation counseling, based on the 5A's model, has been effective in different settings. This qualitative study aims to improve the understanding of factors influencing the provision of smoking cessation counseling during pregnancy in Argentina and Uruguay. In 2010, we obtained prenatal care providers', clinic directors', and pregnant smokers' opinions regarding barriers and promoters to brief smoking cessation counseling in publicly-funded prenatal care clinics in Buenos Aires, Argentina and Montevideo, Uruguay. We interviewed six prenatal clinic directors, conducted focus groups with 46 health professionals and 24 pregnant smokers. Themes emerged from three issue areas: health professionals, health system, and patients. Health professional barriers to cessation counseling included inadequate knowledge and motivation, perceived low self-efficacy, and concerns about inadequate time and large workload. They expressed interest in obtaining a counseling script. Health system barriers included low prioritization of smoking cessation and a lack of clinic protocols to implement interventions. Pregnant smokers lacked information on the risks of prenatal smoking and underestimated the difficulty of smoking cessation. Having access to written materials and receiving cessation services during clinic waiting times were mentioned as promoters for the intervention. Women also were receptive to non-physician office staff delivering intervention components. Implementing smoking cessation counseling in publicly-funded prenatal care clinics in Argentina and Uruguay may require integrating counseling into routine prenatal care and educating and training providers on best-practices approaches. PMID- 25500991 TI - Vascular function of the mesenteric artery isolated from thyroid hormone receptor alpha knockout mice. AB - OBJECTIVE: This study evaluated the consequences of thyroid hormone receptor alpha (TRalpha) disruption on vascular reactivity. METHODS: The activity of superior mesenteric arteries isolated from TRalpha knockout mice generated in the SV129 background (TRalpha(0/0)SV) or in a pure C57BL/6 background (TRalpha(0/0)C57) was compared to that of their corresponding wild-type strains (SV129 or C57BL/6 mice). RESULTS: The wild-type SV129 mice exhibited an impaired acetylcholine (Ach)-induced mesenteric artery relaxation compared to C57BL/6 mice, associated with greater responses to angiotensin II (AII) and phenylephrine (PE). The disruption of TRalpha decreased the vascular response to sodium nitroprusside and PE in both the SV129 and C57BL/6 genetic backgrounds. Responses to Ach and AII were also blunted, but only in TRalpha(0/0)C57 mice. The administration of 3,3'5-triiodo-L-thyronine sodium salt (T3) elicited a vasodilatation in C57BL/6 mice even at the lowest concentration (10(-9)M); a maximal relaxation of more than 50% was observed with the concentrations between 10(-9) and 10(-8)M. However, the response to T3 was nearly absent in TRalpha(0/0)C57 mice. CONCLUSION: TRalpha is essential for the control of vascular tone, particularly in thyroid hormone-mediated relaxation. The difference in response to Ach observed between the two wild-type mice should be taken into account for interpreting the vascular responses of genetically engineered mice. PMID- 25500992 TI - Dynamic constitutional frameworks for DNA biomimetic recognition. AB - Linear and cross-linked dynamic constitutional frameworks generated from reversibly interacting linear PEG/core constituents and cationic sites shed light on the dominant coiling versus linear DNA binding behaviours, closer to the histone DNA binding wrapping mechanism. PMID- 25500993 TI - Implementing 'self-help friendliness' in German hospitals: a longitudinal study. AB - In Germany, the term 'self-help friendliness' (SHF) describes a strategy to institutionalize co-operation of healthcare institutions with mutual aid or self help groups of chronically ill patients. After a short explanation of the SHF concept and its development, we will present findings from a longitudinal study on the implementation of SHF in three German hospitals. Specifically, we wanted to know (i) to what degree SHF had been put into practice after the initial development phase in the pilot hospitals, (ii) whether it was possible to maintain the level of implementation of SHF in the course of at least 1 year and (iii) which opinions exist about the inclusion of SHF criteria in quality management systems. With only minor restrictions, the findings provide support for the usefulness, practicability, sustainability and transferability of SHF. Limitations of our empirical study are the small number of hospitals, the above average motivation of their staff, the small response rate in the staff-survey and the inability to get enough data from members of self-help groups. The research instrument for measuring SHF was adequate and fulfils the most important scientific quality criteria in a German context. We conclude that the implementation of SHF leads to more patient-centredness in healthcare institutions and thus improves satisfaction, self-management, coping and health literacy of patients. SHF is considered as an adequate approach for reorienting healthcare institutions in the sense of the Ottawa Charta, and particularly suitable for health promoting hospitals. PMID- 25500994 TI - Manifestations of integrated public health policy in Dutch municipalities. AB - Integrated public health policy (IPHP) aims at integrating health considerations into policies of other sectors. Since the limited empirical evidence available may hamper its further development, we systematically analysed empirical manifestations of IPHP, by placing policy strategies along a continuum of less-to more policy integration, going from intersectoral action (IA) to healthy public policy (HPP) to health in all policies (HiAP). Our case study included 34 municipal projects of the Dutch Gezonde Slagkracht Programme (2009-15), which supports the development and implementation of IPHP on overweight, alcohol and drug abuse, and smoking. Our content analysis of project application forms and interviews with all project leaders used a framework approach involving the policy strategies and the following policy variables: initiator, actors, policy goals, determinants and policy instruments. Most projects showed a combination of policy strategies. However, manifestations of IPHP in overweight projects predominantly involved IA. More policy integration was apparent in alcohol/drugs projects (HPP) and in all-theme projects (HiAP). More policy integration was related to broad goal definitions, which allowed for the involvement of actors representing several policy sectors. This enabled the implementation of a mix of policy instruments. Determinants of health were not explicitly used as a starting point of the policy process. If a policy problem justifies policy integration beyond IA, it might be helpful to start from the determinants of health (epidemiological reality), systematically transform them into policy (policy reality) and set broad policy goals, since this gives actors from other sectors the opportunity to participate. PMID- 25500995 TI - Fe/N/C hollow nanospheres by Fe(iii)-dopamine complexation-assisted one-pot doping as nonprecious-metal electrocatalysts for oxygen reduction. AB - In this work, a series of hollow carbon nanospheres simultaneously doped with N and Fe-containing species are prepared by Fe(3+)-mediated polymerization of dopamine on SiO2 nanospheres, carbonization and subsequent KOH etching of the SiO2 template. The electrochemical properties of the hollow nanospheres as nonprecious-metal electrocatalysts for oxygen reduction reaction (ORR) are characterized. The results show that the hollow nanospheres with mesoporous N doped carbon shells of ~10 nm thickness and well-dispersed Fe3O4 nanoparticles prepared by annealing at 750 degrees C (Fe/N/C HNSs-750) exhibit remarkable ORR catalytic activity comparable to that of a commercial 20 wt% Pt/C catalyst, and high selectivity towards 4-electron reduction of O2 to H2O. Moreover, it displays better electrochemical durability and tolerance to methanol crossover effect in an alkaline medium than the Pt/C. The excellent catalytic performance of Fe/N/C HNSs-750 towards ORR can be ascribed to their high specific surface area, mesoporous morphology, homogeneous distribution of abundant active sites, high pyridinic nitrogen content, graphitic nitrogen and graphitic carbon, as well as the synergistic effect of nitrogen and iron species for catalyzing ORR. PMID- 25500996 TI - Promoter-dependent activity on androgen receptor N-terminal domain mutations in androgen insensitivity syndrome. AB - Androgen receptor (AR) mutations are associated with androgen insensitivity syndrome (AIS). Missense mutations identified in the AR-N-terminal domain (AR NTD) are rare, and clinical phenotypes are typically mild. We investigated 7 missense mutations and 2 insertion/deletions located in the AR-NTD. This study aimed to elucidate the pathogenic role of AR-NTD mutants in AIS and to use this knowledge to further define AR-NTD function. AR-NTD mutations (Q120E, A159T, G216R, N235K, G248V, L272F, and P380R) were introduced into AR-expression plasmids. Stably expressing cell lines were established for del57L and ins58L. Transactivation was measured using luciferase reporter constructs under the control of GRE and Pem promoters. Intrinsic fluorescence spectroscopy and partial proteolysis studies were performed for mutations which showed reduced activities by using a purified AR-AF1 protein. Pem-luciferase reporter activation was reduced for A159T, N235K, and G248V but not the GRE-luciferase reporter. Protein structure analysis detected no significant change in the AR-AF1 region for these mutations. Reduced cellular expression and transactivation activity were observed for ins58L. The mutations Q120E, G216R, L272F, P380R, and del57L showed small or no detectable changes in function. Thus, clinical and experimental analyses have identified novel AR-signalling defects associated with mutations in the structurally disordered AR-NTD domain in patients with AIS. PMID- 25500997 TI - Mentorship for Residents in Psychiatry: a Competency-based Medical Education Perspective with Career Counseling Tools. PMID- 25500998 TI - Counseling role of primary care physicians in preventing early childhood caries in children with congenital heart disease. AB - The dental health of preschool children with congenital heart disease (CHD) is usually poor, which may contribute to the development of infective endocarditis (IE). Primary care physicians play an important role in providing access to preventive dental services, particularly for preschool children. The object of this study was to provide epidemiologic evidence for the impact of primary care physicians' (PCP's) counseling role on early childhood caries in children with CHD in Guangzhou, China, which might guide future caries prevention to decrease the risk of IE in children with CHD. A hospital-based, case-control study was performed, which contained 100 children with newly diagnosed early childhood caries and 100 matched (sex and age) children without dental caries. All of the subjects were diagnosed with CHD at birth and recruited from Guangdong Cardiovascular Institute from 2012 through 2013. A conditional multivariate logistic-regression model was used to assess the associations between PCPs' role and early childhood caries with a significance level of 5%. Our findings revealed that mother's education level (OR = 0.36, CL = 0.14-0.92) and knowledge, being educated on the relationship between CHD and infective endocarditis (OR = 0.48, CL = 0.25-0.94) and the impact of oral health on infective endocarditis (OR = 0.37, CL = 0.18-0.79) by the PCP were associated with early childhood caries. PCPs played an important role in preventing early childhood caries among preschool children with CHD in Guangzhou, China. PMID- 25500999 TI - Assessment of sex-related behaviours, human immunodeficiency virus (HIV) knowledge and sexually transmitted infections (STIs) among men of reproductive age in Cameroon. AB - Sexually transmitted infections (STIs), including human immunodeficiency virus (HIV), are among the major public health challenges in Cameroon. This paper determined the effect of men's sex-related behaviors and HIV knowledge on reported STIs. The data came from the 2012 Cameroon's Demographic and Health Survey (DHS) that were collected from 7191 respondents in 2012. Descriptive and logistic regression methods were used for data analysis. Results showed that majority of the respondents were aware of STIs and Acquired Immune Deficiency Syndrome (AIDS), while 3.96% reported STIs. Also, 49.45% of the men had no wife, while 75.58% and 84.58% noted that condoms and keeping of one partner could be used to prevent HIV transmission, respectively. Wrong impressions that mosquito bites and sharing of food could lead to HIV infection were held by 31.94% and 12.44% of the men, respectively. Among those that reported STIs, 33.33%, 30.18% and 13.33% respectively used condom during sex with most recent partner, second to most recent partner and third to most recent partner, compared to 24.69%, 15.04% and 4.17% among those that did not report STIs. Logistic regression results showed that probability of STI increased significantly (p < 0.05) with condom use with third most recent partners, being married, wrong knowledge that mosquito bites cause HIV and being away for more than one month, while it significantly reduced (p < 0.05) with number of children, knowledge that having one partner prevents STIs. It was concluded that policy initiatives and programmes to enhance right sexual knowledge and behavior among men would go a long way in reducing STI incidence in Cameroon. PMID- 25501000 TI - Creating locally-resolved mobile-source emissions inputs for air quality modeling in support of an exposure study in Detroit, Michigan, USA. AB - This work describes a methodology for modeling the impact of traffic-generated air pollutants in an urban area. This methodology presented here utilizes road network geometry, traffic volume, temporal allocation factors, fleet mixes, and emission factors to provide critical modeling inputs. These inputs, assembled from a variety of sources, are combined with meteorological inputs to generate link-based emissions for use in dispersion modeling to estimate pollutant concentration levels due to traffic. A case study implementing this methodology for a large health study is presented, including a sensitivity analysis of the modeling results reinforcing the importance of model inputs and identify those having greater relative impact, such as fleet mix. In addition, an example use of local measurements of fleet activity to supplement model inputs is described, and its impacts to the model outputs are discussed. We conclude that with detailed model inputs supported by local traffic measurements and meteorology, it is possible to capture the spatial and temporal patterns needed to accurately estimate exposure from traffic-related pollutants. PMID- 25501001 TI - Rgs6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra. AB - Parkinson disease (PD) is characterized by the preferential, but poorly understood, vulnerability to degeneration of midbrain dopaminergic (mDA) neurons in the ventral substantia nigra compacta (vSNc). These sensitive mDA neurons express Pitx3, a transcription factor that is critical for their survival during development. We used this dependence to identify, by flow cytometry and expression profiling, the negative regulator of G-protein signaling Rgs6 for its restricted expression in these neurons. In contrast to Pitx3-/- mDA neurons that die during fetal (vSNc) or post-natal (VTA) period, the vSNc mDA neurons of Rgs6 /- mutant mice begin to exhibit unilateral signs of degeneration at around 6 months of age, and by one year cell loss is observed in a fraction of mice. Unilateral cell loss is accompanied by contralateral degenerating neurons that exhibit smaller cell size, altered morphology and reduced dendritic network. The degenerating neurons have low levels of tyrosine hydroxylase (TH) and decreased nuclear Pitx3; accordingly, expression of many Pitx3 target gene products is altered, including Vmat2, Bdnf, Aldh1a1 (Adh2) and Fgf10. These low TH neurons also express markers of increased dopamine signaling, namely increased DAT and phospho-Erk1/2 expression. The late onset degeneration may reflect the protective action of Rgs6 against excessive DA signaling throughout life. Rgs6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neurons that are most affected in PD. PMID- 25501002 TI - How effective is integrated vector management against malaria and lymphatic filariasis where the diseases are transmitted by the same vector? AB - BACKGROUND: The opportunity to integrate vector management across multiple vector borne diseases is particularly plausible for malaria and lymphatic filariasis (LF) control where both diseases are transmitted by the same vector. To date most examples of integrated control targeting these diseases have been unanticipated consequences of malaria vector control, rather than planned strategies that aim to maximize the efficacy and take the complex ecological and biological interactions between the two diseases into account. METHODOLOGY/PRINCIPAL FINDINGS: We developed a general model of malaria and LF transmission and derived expressions for the basic reproductive number (R0) for each disease. Transmission of both diseases was most sensitive to vector mortality and biting rate. Simulating different levels of coverage of long lasting-insecticidal nets (LLINs) and larval control confirms the effectiveness of these interventions for the control of both diseases. When LF was maintained near the critical density of mosquitoes, minor levels of vector control (8% coverage of LLINs or treatment of 20% of larval sites) were sufficient to eliminate the disease. Malaria had a far greater R0 and required a 90% population coverage of LLINs in order to eliminate it. When the mosquito density was doubled, 36% and 58% coverage of LLINs and larval control, respectively, were required for LF elimination; and malaria elimination was possible with a combined coverage of 78% of LLINs and larval control. CONCLUSIONS/SIGNIFICANCE: Despite the low level of vector control required to eliminate LF, simulations suggest that prevalence of LF will decrease at a slower rate than malaria, even at high levels of coverage. If representative of field situations, integrated management should take into account not only how malaria control can facilitate filariasis elimination, but strike a balance between the high levels of coverage of (multiple) interventions required for malaria with the long duration predicted to be required for filariasis elimination. PMID- 25501003 TI - Loss of 4q21.23-22.1 is a prognostic marker for disease free and overall survival in non-small cell lung cancer. AB - This study was performed to assess the prognostic relevance of genomic aberrations at chromosome 4q in NSCLC patients. We have previously identified copy number changes at 4q12-q32 to be significantly associated with the early hematogenous dissemination of non-small cell lung cancer (NSCLC), and now aim to narrow down potential hot-spots within this 107 Mb spanning region. Using eight microsatellite markers at position 4q12-35, allelic imbalance (AI) analyses were performed on a preliminary study cohort (n = 86). Positions indicating clinicopathological and prognostic associations in AI analyses were further validated in a larger study cohort using fluorescence in situ hybridization (FISH) in 209 NSCLC patients. Losses at positions 4q21.23 and 4q22.1 were shown to be associated with advanced clinicopathological characteristics as well as with shortened disease free (DFS) and overall survival (OS) (DFS: P = 0.019; OS: P = 0.002). Multivariate analyses identified the losses of 4q21.23-22.1 to be an independent prognostic marker for both DFS and OS in NSCLC (HR 1.64-2.20, all P<0.04), and especially in squamous cell lung cancer (P<0.05). A case report study of a lung cancer patient further revealed a loss of 4q21.23 in disseminated tumor cells (DTCs). Neither gains at the latter positions, nor genomic aberrations at 4q12, 4q31.2 and 4q35.1, indicated a prognostic relevance. In conclusion, our data indicate that loss at 4q21.23-22.1 in NSCLC is of prognostic relevance in NSCLC patients and thus, includes potential new tumor suppressor genes with clinical relevance. PMID- 25501004 TI - Paramagnetic beads and magnetically mediated strain enhance cardiomyogenesis in mouse embryoid bodies. AB - Mechanical forces play an important role in proper embryologic development, and similarly such forces can directly impact pluripotency and differentiation of mouse embryonic stem cells (mESC) in vitro. In addition, manipulation of the embryoid body (EB) microenvironment, such as by incorporation of microspheres or microparticles, can similarly influence fate determination. In this study, we developed a mechanical stimulation regimen using permanent neodymium magnets to magnetically attract cells within an EB. Arginine-Glycine-Aspartic Acid (RGD) conjugated paramagnetic beads were incorporated into the interior of the EBs during aggregation, allowing us to exert force on individual cells using short term magnetization. EBs were stimulated for one hour at different magnetic field strengths, subsequently exerting a range of force intensity on the cells at different stages of early EB development. Our results demonstrated that following exposure to a 0.2 Tesla magnetic field, ESCs respond to magnetically mediated strain by activating Protein Kinase A (PKA) and increasing phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression. The timing of stimulation can also be tailored to guide ESC differentiation: the combination of bone morphogenetic protein 4 (BMP4) supplementation with one hour of magnetic attraction on Day 3 enhances cardiomyogenesis by increasing contractile activity and the percentage of sarcomeric alpha-actin-expressing cells compared to control samples with BMP4 alone. Interestingly, we also observed that the beads alone had some impact on differentiation by increasingly slightly, albeit not significantly, the percentage of cardiomyocytes. Together these results suggest that magnetically mediated strain can be used to enhance the percentage of mouse ESC-derived cardiomyocytes over current differentiation protocols. PMID- 25501007 TI - Match-study of statin therapy in spontaneous intracerebral hemorrhage: is the discontinuation reasonable? AB - BACKGROUND: We analyzed the relationship between statin continuation or discontinuation and outcome after spontaneous intracerebral hemorrhage (ICH). METHODS: From a databank with 447 data sets, we selected patients with hypertensive or anticoagulation-related hemorrhage (volume 10-250 mL). Of 323 patients available for analysis, 63 were taking statins. This group was divided into those who discontinued (N.=18) or continued therapy (N.=45). Statin users were matched by age, sex, and National Institutes of Health Stroke Scale (NIHSS) status in 1:4 ratio to nonusers. Mortality after 30 days, 3 months, and 12 months was analyzed using Cox regression. The Glasgow Outcome Scale (GOS) scores at discharge and at least 6 months after ICH onset were recorded. RESULTS: Baseline characteristics of patients with continued and discontinued statin use were not different. Patients who discontinued statin therapy were very similar to their matched-cases; however, the control-matched cases for patients who continued statins had lower incidences of diabetes mellitus and cardiovascular diseases. In multivariate analysis, statin discontinuation was associated with a 6.9-fold (95% CI 2.09-23.13, P=0.002) higher risk of death within the first 30 days after ICH onset compared to patients who continued therapy. Patients who discontinued also had an increased risk of death within 30 days of ICH onset compared to their matched-controls (HR=3.87, 95% CI 1.69-8.87, P=0.001). The continued statin group displayed only a slight reduction in mortality risk after 3 month (HR=0.67, 95% CI 0.37-1.21, P=0.19) compared to matched-controls, but the chance to be discharge with a better neurological (NIHSS<15) was increased among patients with continued statin use (51% versus 33%, P=0.02). CONCLUSIONS: The continued use of statins after an ICH led to a small mortality reduction, whereas discontinuing statins might be related to increased mortality. Randomized clinical trials are needed to define the role of statin use in the management of acute ICH. PMID- 25501008 TI - Three time point changes in diffusion tensor values and their association with cognitive sequel among mild injury patients. AB - AIM: Diffusion tensor imaging (DTI) is an advanced and sensitive technique that detects sub--threshold pathology in normal imaging brain injury patients. Currently, there are no 3time--point studies that have considered DTI technique among these patients. The present study has investigated 3time--point DTI imaging and its association with cognitive deficits. METHODS: Twenty--one patients were available for MRI and neuropsychological test (NPT) assessment for all the 3time points. Initially (<36hours), all patients presented with GCS 15 and normal scan findings. The DTI (p<0.0001) and NPT scores (p<0.05) were analyzed using repeated -measure of analysis. The tensor values were correlated with specific time--point NPT scores using partial correlation (0.05). RESULTS: Right cerebral--hemisphere showed significant alterations in both anisotropy and diffusivity values overtime. Cingulate--gyrus and occipital--lobe showed prominent changes in anisotropy value. Significant improvement in thalamo--cortical anisotropy value after 3--4months after injury was seen. The changes in diffusivity values were majorly seen in frontal, parietal lobe, right inferior fronto--occipital & superior longitudinal fasciculus, and posterior supramarginal gyrus. Eventual changes of tensor values of thalamus, frontal and temporal lobe had persistent and significant association with attention and learning/memory aspects. CONCLUSION: The study's findings suggest that DTI detects and observes natural- recovery of brain regions affected by sub--threshold force. PMID- 25501006 TI - Gene expression analysis of parthenogenetic embryonic development of the pea aphid, Acyrthosiphon pisum, suggests that aphid parthenogenesis evolved from meiotic oogenesis. AB - Aphids exhibit a form of phenotypic plasticity, called polyphenism, in which genetically identical females reproduce sexually during one part of the life cycle and asexually (via parthenogenesis) during the remainder of the life cycle. The molecular basis for aphid parthenogenesis is unknown. Cytological observations of aphid parthenogenesis suggest that asexual oogenesis evolved either through a modification of meiosis or from a mitotic process. As a test of these alternatives, we assessed the expression levels and expression patterns of canonical meiotic recombination and germline genes in the sexual and asexual ovaries of the pea aphid, Acyrthosiphon pisum. We observed expression of all meiosis genes in similar patterns in asexual and sexual ovaries, with the exception that some genes encoding Argonaute-family members were not expressed in sexual ovaries. In addition, we observed that asexual aphid tissues accumulated unspliced transcripts of Spo11, whereas sexual aphid tissues accumulated primarily spliced transcripts. In situ hybridization revealed Spo11 transcript in sexual germ cells and undetectable levels of Spo11 transcript in asexual germ cells. We also found that an obligately asexual strain of pea aphid produced little spliced Spo11 transcript. Together, these results suggest that parthenogenetic oogenesis evolved from a meiosis-like, and not a mitosis-like, process and that the aphid reproductive polyphenism may involve a modification of Spo11 gene activity. PMID- 25501005 TI - Vesicular stomatitis virus polymerase's strong affinity to its template suggests exotic transcription models. AB - Vesicular stomatitis virus (VSV) is the prototype for negative sense non segmented (NNS) RNA viruses which include potent human and animal pathogens such as Rabies, Ebola and measles. The polymerases of NNS RNA viruses only initiate transcription at or near the 3' end of their genome template. We measured the dissociation constant of VSV polymerases from their whole genome template to be 20 pM. Given this low dissociation constant, initiation and sustainability of transcription becomes nontrivial. To explore possible mechanisms, we simulated the first hour of transcription using Monte Carlo methods and show that a one time initial dissociation of all polymerases during entry is not sufficient to sustain transcription. We further show that efficient transcription requires a sliding mechanism for non-transcribing polymerases and can be realized with different polymerase-polymerase interactions and distinct template topologies. In conclusion, we highlight a model in which collisions between transcribing and sliding non-transcribing polymerases result in release of the non-transcribing polymerases allowing for redistribution of polymerases between separate templates during transcription and suggest specific experiments to further test these mechanisms. PMID- 25501009 TI - The effect of framing and normative messages in building support for climate policies. AB - Deep cuts in greenhouse gas emissions are required to mitigate climate change. However, there is low willingness amongst the public to prioritise climate policies for reducing emissions. Here we show that the extent to which Australians are prepared to reduce their country's CO2 emissions is greater when the costs to future national income are framed as a "foregone-gain"--incomes rise in the future but not by as much as in the absence of emission cuts--rather than as a "loss"--incomes decrease relative to the baseline expected future levels (Studies 1 & 2). The provision of a normative message identifying Australia as one of the world's largest CO2 emitters did not increase the amount by which individuals were prepared to reduce emissions (Study 1), whereas a normative message revealing the emission policy preferences of other Australians did (Study 2). The results suggest that framing the costs of reducing emissions as a smaller increase in future income and communicating normative information about others' emission policy preferences are effective methods for leveraging public support for emission cuts. PMID- 25501011 TI - High numbers of vacancies exist on NHS boards, survey shows. PMID- 25501010 TI - Haemosiderin-laden sputum macrophages for diagnosis in pulmonary veno-occlusive disease. AB - AIMS: Pulmonary veno-occlusive disease (PVOD) is a rare condition of pulmonary arterial hypertension (PAH), in which post-capillary veins are affected. Since the therapeutic approach in PVOD differs from other forms of PAH, it is crucial to establish the diagnosis. Due to the fact that affected patients are often hemodynamically unstable, minimal invasive procedures are necessary for the diagnostic work-up. Chronic alveolar haemorrhage has been observed during bronchoalveolar lavage in PVOD cases. This study therefore investigates whether signs of alveolar haemorrhage can also be found in the sputum of these patients. METHODS AND RESULTS: Six patients suffering from PVOD were included in this analysis. As controls, patients with idiopathic PAH (n = 11), chronic thromboembolic PH (n = 9) and with sclerodermia-associated PH (n = 10) were assessed. Sputum from every patient was obtained by a non-invasive manner. The amount of haemosiderin-laden macrophages was determined using the Golde score. There were statistically significant more haemosiderin-laden macrophages in the sputum of patients suffering from PVOD as compared to the other groups (P<0.05). Assuming a cut-off of 200 on the Golde score, all of the 6 PVOD patients surpassed this value compared with only 1 out of the 30 cases with precapillary PH. Thus, sensitivity and specificity with respect to the diagnosis of PVOD was 100% and 97%, respectively. CONCLUSION: The content of haemosiderin-laden macrophages in the sputum of patients suffering from PVOD is significantly higher as compared to other forms of PH and may be useful in the non-invasive diagnostic work-up of these patients. PMID- 25501013 TI - A detailed clinicopathologic study of ALK-translocated papillary thyroid carcinoma. AB - Pathogenic ALK translocations have been reported in papillary thyroid carcinoma (PTC). We developed and validated a screening algorithm based on immunohistochemistry (IHC), followed by fluorescence in situ hybridization (FISH) in IHC-positive cases to identify ALK-rearranged PTC. IHC and FISH were performed in a cohort of 259 thyroid carcinomas enriched for aggressive variants. IHC was positive in 8 cases, 6 confirmed translocated by FISH (specificity 75%). All 251 IHC-negative cases were FISH negative (sensitivity 100%). Having validated this approach, we performed screening IHC, followed by FISH in IHC-positive cases in an expanded cohort. ALK translocations were identified in 11 of 498 (2.2%) of all consecutive unselected PTCs and 3 of 23 (13%) patients with diffuse sclerosing variant PTCs. No ALK translocations were identified in 36 PTCs with distant metastases, 28 poorly differentiated (insular) carcinomas, and 20 anaplastic carcinomas. All 14 patients with ALK translocations were female (P=0.0425), and translocations occurred at a younger age (mean 38 vs. 48 y, P=0.0289 in unselected patients). ALK translocation was an early clonal event present in all neoplastic cells and mutually exclusive with BRAF mutation. ALK translocation was not associated with aggressive clinicopathologic features (size, stage, metastasis, vascular invasion, extrathyroidal extension, multifocality, risk for recurrence, radioiodine resistance). We conclude that 2.2% of PTCs are ALK translocated and can be identified by screening IHC followed by FISH. ALK translocations may be more common in young females and diffuse sclerosing variant PTC but do not connote more aggressive disease. PMID- 25501012 TI - RGD surface functionalization of the hydrophilic acrylic intraocular lens material to control posterior capsular opacification. AB - Posterior Capsular Opacification (PCO) is the capsule fibrosis developed on implanted IntraOcular Lens (IOL) by the de-differentiation of Lens Epithelial Cells (LECs) undergoing Epithelial Mesenchymal Transition (EMT). Literature has shown that the incidence of PCO is multifactorial including the patient's age or disease, surgical technique, and IOL design and material. Reports comparing hydrophilic and hydrophobic acrylic IOLs have shown that the former has more severe PCO. On the other hand, we have previously demonstrated that the adhesion of LECs is favored on hydrophobic compared to hydrophilic materials. By combining these two facts and contemporary knowledge in PCO development via the EMT pathway, we propose a biomimetically inspired strategy to promote LEC adhesion without de-differentiation to reduce the risk of PCO development. By surface grafting of a cell adhesion molecule (RGD peptide) onto the conventional hydrophilic acrylic IOL material, the surface-functionalized IOL can be used to reconstitute a capsule-LEC-IOL sandwich structure, which has been considered to prevent PCO formation in literature. Our results show that the innovative biomaterial improves LEC adhesion, while also exhibiting similar optical (light transmittance, optical bench) and mechanical (haptic compression force, IOL injection force) properties compared to the starting material. In addition, compared to the hydrophobic IOL material, our bioactive biomaterial exhibits similar abilities in LEC adhesion, morphology maintenance, and EMT biomarker expression, which is the crucial pathway to induce PCO. The in vitro assays suggest that this biomaterial has the potential to reduce the risk factor of PCO development. PMID- 25501015 TI - miR-23a promotes cisplatin chemoresistance and protects against cisplatin-induced apoptosis in tongue squamous cell carcinoma cells through Twist. AB - Tongue squamous cell carcinoma (TSCC) is one of the most common head and neck cancers. Cisplatin is effective as a single agent or in combination with other drugs for the treatment of TSCC. Treatment with cisplatin-based chemotherapy has been found to improve the prognosis of patients with TSCC. However, one of the most important clinical issues of cisplatin-based TSCC chemotherapy is the intrinsic/acquired chemoresistance to cisplatin. Increased expression of miR-23a reportedly promotes cisplatin chemoresistance in TSCC cells. High expression of Twist is also associated with cancer chemoresistance and poor prognosis of TSCC patients. In the present study, we explored the interaction between miR-23a and Twist in TSCC cells, and assessed its impact on TSCC chemoresistance to cisplatin. miR-23a and/or Twist were overexpressed or knocked down in SCC-4 and Tca8113 human TSCC cells. The expression levels of miR-23a and Twist were determined. The half maximal inhibitory concentration (IC50) of cisplatin and cell apoptosis rate under cisplatin treatment were used as measures of cisplatin chemoresistance. Overexpression of miR-23a in both SCC-4 and Tca8113 cells markedly increased Twist expression, c-Jun N-terminal kinase (JNK) activity and the half maximal inhibitory concentration (IC50) of cisplain, and decreased cisplatin-induced apoptosis, all of which was abolished by knockdown of Twist or selective JNK inhibitor SP600125. On the other hand, knockdown of miR-23a significantly decreased Twist expression, JNK activity and IC50 of cisplain, and increased cisplatin-induced apoptosis, all of which was completely reversed by overexpression of Twist. In conclusion, the present study for the first time demonstrates that miR-23a promotes cisplatin chemoresistance and protects cisplatin-induced apoptosis in TSCC cells through inducing Twist expression by a JNK-dependent mechanism. It adds new insights into the molecular mechanisms underlying TSCC chemoresistance. PMID- 25501014 TI - Mdivi-1, mitochondrial fission inhibitor, impairs developmental competence and mitochondrial function of embryos and cells in pigs. AB - Mitochondria are highly dynamic organelles that undergo constant fusion/fission as well as activities orchestrated by large dynamin-related GTPases. These dynamic mitochondrial processes influence mitochondrial morphology, size and function. Therefore, this study was conducted to evaluate the effects of mitochondrial fission inhibitor, mdivi-1, on developmental competence and mitochondrial function of porcine embryos and primary cells. Presumptive porcine embryos were cultured in PZM-3 medium supplemented with mdivi-1 (0, 10 and 50 MUM) for 6 days. Porcine fibroblast cells were cultured in growth medium with mdivi-1 (0 and 50 MUM) for 2 days. Our results showed that the rate of blastocyst production and cell growth in the mdivi-1 (50 MUM) treated group was lower than that of the control group (P < 0.05). Moreover, loss of mitochondrial membrane potential in the mdivi-1 (50 MUM) treated group was increased relative to the control group (P < 0.05). Subsequent evaluation revealed that the intracellular levels of reactive oxygen species (ROS) and the apoptotic index were increased by mdivi-1 (50 MUM) treatment (P < 0.05). Finally, the expression of mitochondrial fission-related protein (Drp 1) was lower in the embryos and cells in the mdivi-1 treated group than the control group. Taken together, these results indicate that mdivi-1 treatment may inhibit developmental competence and mitochondrial function in porcine embryos and primary cells. PMID- 25501016 TI - Comparison of models and contrast agents for improved signal and signal linearity in dynamic contrast-enhanced pulmonary magnetic resonance imaging. AB - OBJECTIVES: The objectives of this study were to compare pulmonary blood flow (PBF) measurements acquired with 3 previously published models (low-dose "single bolus," "dual bolus" and a "nonlinear correction" algorithm) for addressing the nonlinear relationship between contrast agent concentration and magnetic resonance signal in the arterial input function (AIF) and to compare both lung signal and PBF measurements obtained using gadopentetate dimeglumine (Gd-DTPA, Magnevist) with those obtained using the high-relaxivity agent gadobenate dimeglumine (Gd-BOPTA, Multihance). MATERIALS AND METHODS: Ten of 12 healthy humans were successfully scanned on 2 consecutive days at 1.5 T. Contrast enhanced pulmonary perfusion scans were acquired with a 3-dimensional spoiled gradient echo pulse sequence and interleaved variable density k-space sampling with a 1-second frame rate and 4 * 4 * 4-mm resolution. Each day, 2 perfusion scans were acquired with either Gd-DTPA or Gd-BOPTA; the order of the administered contrast agent was randomized. Region of interest analysis was used to determine PBF on the basis of the indicator dilution theory. Linear mixed effects modeling was used to compare the AIF models and contrast agents. RESULTS: With Gd-DTPA, no significant differences were observed between the mean PBF calculated for the single bolus (323 +/- 110 mL/100mL/min), dual bolus (315 +/- 177 mL/100mL/min), and nonlinear correction (298 +/- 100 mL/100mL/min) approach. With Gd-BOPTA, the mean PBF using the dual bolus approach (245 +/- 103 mL/100mL/min) was lower than with the single bolus (345 +/- 130 mL/100mL/min P < 0.01) and nonlinear correction (321 +/- 115 mL/100mL/min; P = 0.02). Peak lung enhancement was significantly higher in all regions with Gd-BOPTA than with Gd DTPA (P << 0.01). CONCLUSIONS: The dual bolus approach with Gd-BOPTA resulted in a significantly lower PBF than did the other combinations of contrast agent and AIF model. No other statistically significant differences were found. Given the much higher signal in the lung parenchyma using Gd-BOPTA, the use of Gd-BOPTA with either single bolus or the nonlinear correction method appears most promising for voxelwise perfusion quantification using 3-dimensional dynamic contrast-enhanced pulmonary perfusion magnetic resonance imaging. PMID- 25501017 TI - Texture analysis as imaging biomarker of tumoral response to neoadjuvant chemoradiotherapy in rectal cancer patients studied with 3-T magnetic resonance. AB - OBJECTIVE: The aim of this study was to determine whether texture features of rectal cancer on T2-weighted (T2w) magnetic resonance images can predict tumoral response in patients treated with neoadjuvant chemoradiotherapy (CRT). MATERIALS AND METHODS: We prospectively enrolled 15 consecutive patients (6 women, 63.2 +/- 13.4 years) with rectal cancer, who underwent pretreatment and midtreatment 3-T magnetic resonance imaging. Treatment protocol consisted of neoadjuvant CRT with oxaliplatin and 5-fluorouracile. Texture analysis using a filtration-histogram technique was performed using a commercial research software algorithm (TexRAD Ltd, Somerset, England, United Kingdom) on unenhanced axial T2w images by manually delineating a region of interest around the tumor outline for the largest cross-sectional area. The technique selectively filters and extracts textures at different anatomic scales followed by quantification of the histogram using kurtosis, entropy, skewness, and mean value of positive pixels. After CRT, all patients underwent complete surgical resection and the surgical specimen served as the gold standard. RESULTS: Six patients showed pathological complete response (pCR), and 4 patients, partial response (PR). Five patients were classified as nonresponders (NRs). Pretreatment medium texture-scale quantified as kurtosis was significantly lower in the pCR subgroup in comparison with the PR + NR subgroup (P = 0.01). Midtreatment kurtosis without filtration was significantly higher in pCR in comparison with PR + NR (P = 0.045). The change in kurtosis between midtreatment and pretreatment images was significantly lower in the PR + NR subgroup compared with the pCR subgroup (P = 0.038). Pretreatment area under the receiver operating characteristic curves, to discriminate between pCR and PR + NR, was significantly higher for kurtosis (0.907, P < 0.001) compared with all other parameters. The optimal cutoff value for pretreatment kurtosis was 0.19 or less. Using this value, the sensitivity and specificity for pCR prediction were 100% and 77.8%, respectively. CONCLUSION: Texture parameters derived from T2w images of rectal cancer have the potential to act as imaging biomarkers of tumoral response to neoadjuvant CRT. PMID- 25501019 TI - How to ventilate patients without acute respiratory distress syndrome? AB - PURPOSE OF REVIEW: There is convincing evidence for benefit from lung-protective mechanical ventilation with lower tidal volumes in patients with the acute respiratory distress syndrome (ARDS). It is uncertain whether this strategy benefits critically ill patients without ARDS also. The present article summarizes the background and clinical evidence for ventilator settings that have the potential to protect against ventilator-induced lung injury. RECENT FINDINGS: There has been a paradigm shift from treating ARDS to preventing ARDS. In surgical patients, anesthesiologists should consider ventilating patients with a tidal volume of 6-8 ml/kg predicted body weight (PBW), levels of positive end expiratory pressure (PEEP) between 0 and 2 cmH(2)O, and higher levels of FiO(2). Finally, in critically ill patients without ARDS, intensive care physicians could consider ventilating with a PEEP level of 5 cmH(2)O and lower levels of FiO(2). There is insufficient evidence for the benefit of lower tidal volumes in these patients. There is, however, some evidence that tidal volumes of 6 ml/kg PBW or less are associated with better outcomes. SUMMARY: There is increasing and convincing evidence that the use of lower tidal volumes during mechanical ventilation of patients without ARDS prevents against ventilator-induced lung injury. PMID- 25501018 TI - Usefulness of microRNA-375 as a prognostic and therapeutic tool in esophageal squamous cell carcinoma. AB - The aim of this study was to clarify the importance of microRNA-375 (miR-375) expression in patients with esophageal squamous cell carcinoma (ESCC) and to examine the in vivo antitumor effects of miR-375 in a model of ESCC using a non viral delivery system. We estimated the miR-375 and LDHB and AEG-1/MTDH mRNA expression of the ESCC tumors from 85 patients. The correlation between the miR 375 expression and clinicopathological features, including the prognosis, were evaluated. The presence of high miR-375 expression was associated with lymphatic vessel invasion, while a low expression of miR-375 significantly correlated with a poor prognosis for the 85 ESCC patients. We also found that there was a significant inverse correlation between the expression of miR-375 and that of LDHB. Before the examination of miR-375 in the in vivo assay, we confirmed that atelocollagen prolonged the accumulation of miRNA by using fluorescently-labeled miRNA and an in vivo imaging system. We injected the miR-375/atelocollagen complex or a control-miRNA/atelocollagen complex into mice bearing TE2 and T.Tn xenografts via subcutaneous (s.c.) injections. The growth of both the TE2 and T.Tn tumors in the miR-375 groups was significantly suppressed compared with that in the control-miRNA groups. In addition, The LDHB mRNA expression of TE2 xenografts was significantly downregulated after miR-375 treatment. In conclusion, it might be possible for the level of miR-375 expression to be a utilized as a prognostic indicator for ESCC patients. The administration of miR 375 using a non-viral delivery might represent a powerful new treatment for ESCC. PMID- 25501020 TI - Prevention of acute respiratory distress syndrome. AB - PURPOSE OF REVIEW: The paucity of effective therapeutic interventions in patients with the acute respiratory distress syndrome (ARDS) combined with overwhelming evidence on the importance of timely implementation of effective therapies to critically ill patients has resulted in a recent shift in ARDS research. Increasingly, efforts are being directed toward early identification of patients at risk with a goal of prevention and early treatment, prior to development of the fully established syndrome. The focus of the present review is on the prevention of ARDS in patients without this condition at the time of their healthcare encounter. RECENT FINDINGS: The primary thematic categories presented in the present review article include early identification of patients at risk of developing ARDS, optimization of care delivery and its impact on the incidence of ARDS, pharmacological prevention of ARDS, prevention of postoperative ARDS, and challenges and opportunities with ARDS prevention studies. SUMMARY: Recent improvements in clinical care delivery have been associated with a decrease in the incidence of hospital-acquired ARDS. Despite the initial challenges, research in ARDS prevention has become increasingly feasible with several randomized controlled trials on ARDS prevention completed or on the way. PMID- 25501022 TI - A novel fusion of SQSTM1 and FGFR1 in a patient with acute myelomonocytic leukemia with t(5;8)(q35;p11) translocation. PMID- 25501021 TI - Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice. AB - TET2 (Ten Eleven Translocation 2) is a dioxygenase that converts methylcytosine (mC) to hydroxymethylcytosine (hmC). TET2 loss-of-function mutations are highly frequent in subtypes of T-cell lymphoma that harbor follicular helper T (Tfh) cell-like features, such as angioimmunoblastic T-cell lymphoma (30-83%) or peripheral T-cell lymphoma, not otherwise specified (10-49%), as well as myeloid malignancies. Here, we show that middle-aged Tet2 knockdown (Tet2(gt/gt)) mice exhibit Tfh-like cell overproduction in the spleen compared with control mice. The Tet2 knockdown mice eventually develop T-cell lymphoma with Tfh-like features after a long latency (median 67 weeks). Transcriptome analysis revealed that these lymphoma cells had Tfh-like gene expression patterns when compared with splenic CD4-positive cells of wild-type mice. The lymphoma cells showed lower hmC densities around the transcription start site (TSS) and higher mC densities at the regions of the TSS, gene body and CpG islands. These epigenetic changes, seen in Tet2 insufficiency-triggered lymphoma, possibly contributed to predated outgrowth of Tfh-like cells and subsequent lymphomagenesis. The mouse model described here suggests that TET2 mutations play a major role in the development of T-cell lymphoma with Tfh-like features in humans. PMID- 25501023 TI - Diffuse large B cell lymphomas relapsing in the CNS lack oncogenic MYD88 and CD79B mutations. PMID- 25501025 TI - Definition and management of ruxolitinib treatment failure in myelofibrosis. AB - Ruxolitinib, a Janus kinase (JAK)-1 and JAK-2 inhibitor, is the first-in-class drug to be licensed in the United States for the treatment of high- and intermediate-risk myelofibrosis (MF). Several other JAK inhibitors are in development with some currently undergoing phase-3 clinical trial testing. None of the currently available JAK inhibitors are specific to mutant JAK2; their mechanism of action involves attenuation of JAK-STAT signaling with downregulation of proinflammatory cytokines, rather than selective suppression of the disease clone. Accordingly, while ruxolitinib and other JAK inhibitors are effective in controlling splenomegaly and alleviating constitutional symptoms, their benefit in terms of reversing bone marrow fibrosis or inducing complete or partial remissions appears to be limited. The experience to date with ruxolitinib shows that despite its salutary effects on quality of life, over half of the patients discontinue treatment within 2-3 years. In the current perspective, we examine the incidence and causes of ruxolitinib 'treatment failure' in MF patients based on our personal experience as well as a review of the published literature. We also discuss the challenges in defining and classifying ruxolitinib failure, and within the context of several clinical scenarios, we provide recommendations for the post-ruxolitinib management of MF patients. PMID- 25501024 TI - Concurrent IMRT and weekly cisplatin followed by GDP chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell lymphoma. AB - On the basis of the benefits of frontline radiation in early-stage, extranodal natural killer (NK)/T-cell lymphoma (ENKTL), we conducted the trial of concurrent chemoradiotherapy (CCRT) followed by three cycles of gemcitabine, dexamethasone and cisplatin (GDP). Thirty-two patients with newly diagnosed, stage IE to IIE, nasal ENKTL received CCRT (that is, all patients received intensity-modulated radiotherapy 56 Gy and cisplatin 30 mg/m(2) weekly, 3-5 weeks). Three cycles of GDP (gemcitabine 1000 mg/m(2) intravenously (i.v.) on days 1 and 8, dexamethasone 40 mg orally on days 1-4 and cisplatin 75 mg/m(2) i.v. on day 1 (GDP), every 21 days as an outpatient were scheduled after CCRT. All patients completed CCRT, which resulted in 100% response that included 24 complete responses (CRs) and eight partial responses. The CR rate after CCRT was 75.0% (that is, 24 of 32 responses). Twenty-eight of the 32 patients completed the planned three cycles of GDP, whereas four patients did not because they withdrew (n = 1) or because they had an infection (n = 3). The overall response rate and the CR rate were 90.6% (that is, 29 of 32 responses) and 84.4% (that is, 27 of 32 responses), respectively. Only two patient experienced grade 3 toxicity during CCRT (nausea), whereas 13 of the 30 patients experienced grade 4 neutropenia. The estimated 3 year overall survival and progression-free rates were 87.50% and 84.38%, respectively. In conclusion, CCRT followed by GDP chemotherapy can be a feasible and effective treatment strategy for stage IE to IIE nasal ENKTL. PMID- 25501026 TI - Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells. AB - Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34(+) cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor gamma-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML. PMID- 25501028 TI - Microstructural white matter changes underlying cognitive and behavioural impairment in ALS--an in vivo study using DTI. AB - BACKGROUND: A relevant fraction of patients with amyotrophic lateral sclerosis (ALS) exhibit a fronto-temporal pattern of cognitive and behavioural disturbances with pronounced deficits in executive functioning and cognitive control of behaviour. Structural imaging shows a decline in fronto-temporal brain areas, but most brain imaging studies did not evaluate cognitive status. We investigated microstructural white matter changes underlying cognitive impairment using diffusion tensor imaging (DTI) in a large cohort of ALS patients. METHODS: We assessed 72 non-demented ALS patients and 65 matched healthy control subjects using a comprehensive neuropsychological test battery and DTI. We compared DTI measures of fiber tract integrity using tract-based spatial statistics among ALS patients with and without cognitive impairment and healthy controls. Neuropsychological performance and behavioural measures were correlated with DTI measures. RESULTS: Patients without cognitive impairment demonstrated white matter changes predominantly in motor tracts, including the corticospinal tract and the body of corpus callosum. Those with impairments (ca. 30%) additionally presented significant white matter alterations in extra-motor regions, particularly the frontal lobe. Executive and memory performance and behavioural measures were correlated with fiber tract integrity in large association tracts. CONCLUSION: In non-demented cognitively impaired ALS patients, white matter changes measured by DTI are related to disturbances of executive and memory functions, including prefrontal and temporal regions. In a group comparison, DTI is able to observe differences between cognitively unimpaired and impaired ALS patients. PMID- 25501029 TI - REAL-Select: full-length antibody display and library screening by surface capture on yeast cells. AB - We describe a novel approach named REAL-Select for the non-covalent display of IgG-molecules on the surface of yeast cells for the purpose of antibody engineering and selection. It relies on the capture of secreted native full length antibodies on the cell surface via binding to an externally immobilized ZZ domain, which tightly binds antibody Fc. It is beneficial for high-throughput screening of yeast-displayed IgG-libraries during antibody discovery and development. In a model experiment, antibody-displaying yeast cells were isolated from a 1:1,000,000 mixture with control cells confirming the maintenance of genotype-phenotype linkage. Antibodies with improved binding characteristics were obtained by affinity maturation using REAL-Select, demonstrating the ability of this system to display antibodies in their native form and to detect subtle changes in affinity by flow cytometry. The biotinylation of the cell surface followed by functionalization with a streptavidin-ZZ fusion protein is an approach that is independent of the genetic background of the antibody-producing host and therefore can be expected to be compatible with other eukaryotic expression hosts such as P. pastoris or mammalian cells. PMID- 25501030 TI - Inhibitory effects of imatinib on vitamin D3 synthesis in human keratinocytes. AB - Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of the BCR-ABL1 fusion gene, a constitutively active, oncogenic tyrosine kinase that is responsible for the clinical features of CML. Tyrosine kinase inhibitors, such as imatinib, have markedly altered the treatment of CML. However, tyrosine kinase inhibitors are associated with side effects on bone metabolism, in adult and pediatric patients. Vitamin D3 is involved in the complex cycle of bone remodeling, therefore the present study aimed to investigate the influence of imatinib on vitamin D3 metabolism in the HaCaT human keratinocyte cell line, using commercially available enzyme assays. Imatinib was shown to significantly reduce the production of calcidiol and calcitriol. Based on interaction studies of imatinib with the cytochrome P450 (CYP450) inhibitors VID400 and ketoconazole, it is proposed that imatinib may interfere with the vitamin D3 cascade due to its metabolism by CYP27B1, which is involved in vitamin D3 metabolism. PMID- 25501031 TI - Correction: Mycobacterium tuberculosis Lipoprotein LprG Binds Lipoarabinomannan and Determines Its Cell Envelope Localization to Control Phagolysosomal Fusion. AB - [This corrects the article DOI: 10.1371/journal.ppat.1004471.]. PMID- 25501032 TI - Efficacy and Safety of Omalizumab in Patients with Chronic Idiopathic/Spontaneous Urticaria who Remain Symptomatic on H1 Antihistamines: A Randomized, Placebo Controlled Study. PMID- 25501034 TI - TRPA1 is essential for the vascular response to environmental cold exposure. AB - The cold-induced vascular response, consisting of vasoconstriction followed by vasodilatation, is critical for protecting the cutaneous tissues against cold injury. Whilst this physiological reflex response is historic knowledge, the mechanisms involved are unclear. Here by using a murine model of local environmental cold exposure, we show that TRPA1 acts as a primary vascular cold sensor, as determined through TRPA1 pharmacological antagonism or gene deletion. The initial cold-induced vasoconstriction is mediated via TRPA1-dependent superoxide production that stimulates alpha2C-adrenoceptors and Rho-kinase mediated MLC phosphorylation, downstream of TRPA1 activation. The subsequent restorative blood flow component is also dependent on TRPA1 activation being mediated by sensory nerve-derived dilator neuropeptides CGRP and substance P, and also nNOS-derived NO. The results allow a new understanding of the importance of TRPA1 in cold exposure and provide impetus for further research into developing therapeutic agents aimed at the local protection of the skin in disease and adverse climates. PMID- 25501033 TI - miR-214 as a key hub that controls cancer networks: small player, multiple functions. AB - MicroRNAs are short regulatory RNAs that are able to post-transcriptionally modulate gene expression and that have crucial roles in the control of physiological and pathological processes including cancer onset, growth, and progression. miR-214, located inside the sequence of the long noncoding Dmn3os transcript, contributes to the regulation of normal and cancer cell biology, even if it operates in a context-dependent and sometimes contradictory manner. miR-214 is deregulated in several human tumors including melanoma, breast, ovarian, gastric, and hepatocellular carcinomas. miR-214's pleiotropic and tumor-specific contribution to various cancer formation and progression hallmarks is achieved via its several target genes. In fact, miR-214 behaves as a key hub by coordinating fundamental signaling networks such as PTEN/AKT, beta-catenin, and tyrosine kinase receptor pathways. Interestingly, miR-214 also regulates the levels of crucial gene expression modulators: the epigenetic repressor Ezh2, "genome guardian" p53, transcription factors TFAP2, and another microRNA, miR 148b. Thus, miR-214 seems to have essential roles in coordinating tumor proliferation, stemness, angiogenesis, invasiveness, extravasation, metastasis, resistance to chemotherapy, and microenvironment. The sum of current literature reports suggests that miR-214 is a molecular hub involved in the control of cancer networks and, as such, could be a potential diagnostic/prognostic biomarker and target for therapeutic intervention. PMID- 25501035 TI - Developmental regulation of human cortex transcription and its clinical relevance at single base resolution. AB - Transcriptome analysis of human brain provides fundamental insight into development and disease, but it largely relies on existing annotation. We sequenced transcriptomes of 72 prefrontal cortex samples across six life stages and identified 50,650 differentially expression regions (DERs) associated with developmental and aging, agnostic of annotation. While many DERs annotated to non exonic sequence (41.1%), most were similarly regulated in cytosolic mRNA extracted from independent samples. The DERs were developmentally conserved across 16 brain regions and in the developing mouse cortex, and were expressed in diverse cell and tissue types. The DERs were further enriched for active chromatin marks and clinical risk for neurodevelopmental disorders such as schizophrenia. Lastly, we demonstrate quantitatively that these DERs associate with a changing neuronal phenotype related to differentiation and maturation. These data show conserved molecular signatures of transcriptional dynamics across brain development, have potential clinical relevance and highlight the incomplete annotation of the human brain transcriptome. PMID- 25501036 TI - ErbB4 regulation of a thalamic reticular nucleus circuit for sensory selection. AB - Selective processing of behaviorally relevant sensory inputs against irrelevant ones is a fundamental cognitive function whose impairment has been implicated in major psychiatric disorders. It is known that the thalamic reticular nucleus (TRN) gates sensory information en route to the cortex, but the underlying mechanisms remain unclear. Here we show in mice that deficiency of the Erbb4 gene in somatostatin-expressing TRN neurons markedly alters behaviors that are dependent on sensory selection. Whereas the performance of the Erbb4-deficient mice in identifying targets from distractors was improved, their ability to switch attention between conflicting sensory cues was impaired. These behavioral changes were mediated by an enhanced cortical drive onto the TRN that promotes the TRN-mediated cortical feedback inhibition of thalamic neurons. Our results uncover a previously unknown role of ErbB4 in regulating cortico-TRN-thalamic circuit function. We propose that ErbB4 sets the sensitivity of the TRN to cortical inputs at levels that can support sensory selection while allowing behavioral flexibility. PMID- 25501038 TI - Single-channel multiplexing without melting curve analysis in real-time PCR. AB - Multiplex real-time PCR with quantification of targets in a single fluorescence channel has been the demand in biotechnology industry. Here, we develop a novel analytical real-time PCR technique to detect multiple targets in a single fluorescence channel without melting curve analysis. In this technique, we show the intensity of the fluorescence signals of two discrete Tm targets is different at certain temperatures called detection temperatures, by which a high Tm target can be detected regardless of a low Tm target. We then identify the low Tm target by utilizing a change of the fluorescence signals between two different detection temperatures. Furthermore, it enables us to determine quantification of each target in a single channel, possibly facilitating convenient patient care for drug treatment in clinics. PMID- 25501039 TI - Impact of oceanic-scale interactions on the seasonal modulation of ocean dynamics by the atmosphere. AB - Ocean eddies (with a size of 100-300 km), ubiquitous in satellite observations, are known to represent about 80% of the total ocean kinetic energy. Recent studies have pointed out the unexpected role of smaller oceanic structures (with 1-50 km scales) in generating and sustaining these eddies. The interpretation proposed so far invokes the internal instability resulting from the large-scale interaction between upper and interior oceanic layers. Here we show, using a new high-resolution simulation of the realistic North Pacific Ocean, that ocean eddies are instead sustained by a different process that involves small-scale mixed-layer instabilities set up by large-scale atmospheric forcing in winter. This leads to a seasonal evolution of the eddy kinetic energy in a very large part of this ocean, with an amplitude varying by a factor almost equal to 2. Perspectives in terms of the impacts on climate dynamics and future satellite observational systems are briefly discussed. PMID- 25501037 TI - A region-specific neurogenesis mode requires migratory progenitors in the Drosophila visual system. AB - Brain areas each generate specific neuron subtypes during development. However, underlying regional variations in neurogenesis strategies and regulatory mechanisms remain poorly understood. In Drosophila, neurons in four optic lobe ganglia originate from two neuroepithelia, the outer (OPC) and inner (IPC) proliferation centers. Using genetic manipulations, we found that one IPC neuroepithelial domain progressively transformed into migratory progenitors that matured into neural stem cells (neuroblasts) in a second domain. Progenitors emerged by an epithelial-mesenchymal transition-like mechanism that required the Snail-family member Escargot and, in subdomains, Decapentaplegic signaling. The proneural factors Lethal of scute and Asense differentially controlled progenitor supply and maturation into neuroblasts. These switched expression from Asense to a third proneural protein, Atonal. Dichaete and Tailless mediated this transition, which was essential for generating two neuron populations at defined positions. We propose that this neurogenesis mode is central for setting up a new proliferative zone to facilitate spatio-temporal matching of neurogenesis and connectivity across ganglia. PMID- 25501041 TI - Effects of intra-amniotic lipopolysaccharide exposure on the fetal lamb lung as gestation advances. PMID- 25501042 TI - Liquid but durable: molecular dynamics simulations explain the unique properties of archaeal-like membranes. AB - Archaeal plasma membranes appear to be extremely durable and almost impermeable to water and ions, in contrast to the membranes of Bacteria and Eucaryota. Additionally, they remain liquid within a temperature range of 0-100 degrees C. These are the properties that have most likely determined the evolutionary fate of Archaea, and it may be possible for bionanotechnology to adopt these from nature. In this work, we use molecular dynamics simulations to assess at the atomistic level the structure and dynamics of a series of model archaeal membranes with lipids that have tetraether chemical nature and "branched" hydrophobic tails. We conclude that the branched structure defines dense packing and low water permeability of archaeal-like membranes, while at the same time ensuring a liquid-crystalline state, which is vital for living cells. This makes tetraether lipid systems promising in bionanotechnology and material science, namely for design of new and unique membrane nanosystems. PMID- 25501043 TI - Coral spawning in the Gulf of Oman and relationship to latitudinal variation in spawning season in the northwest Indian Ocean. AB - Despite a wealth of information on sexual reproduction in scleractinian corals, there are regional gaps in reproductive records. In the Gulf of the Oman in the Arabian Sea, reproductive timing was assessed in four common species of broadcast spawning corals using field surveys of gamete maturity and aquarium observations of spawning activity. The appearance of mature gametes within the same month for Acropora downingi, A. hemprichii, Cyphastrea microphthalma and Platygyra daedalea (>= 75% of colonies, n = 848) indicated a synchronous and multi-specific spawning season. Based on gamete disappearance and direct observations, spawning predominantly occurred during April in 2013 (75-100% of colonies) and May in 2014 (77-94% of colonies). The difference in spawning months between survey years was most likely explained by sea temperature and the timing of lunar cycles during late-stage gametogenesis. These reproductive records are consistent with a latitudinal gradient in peak broadcast spawning activity at reefs in the northwestern Indian Ocean which occurs early in the year at low latitudes (January to March) and progressively later in the year at mid (March to May) and high (June to September) latitudes. PMID- 25501044 TI - Uncovering genomic features and maternal origin of korean native chicken by whole genome sequencing. AB - The Korean Native Chicken (KNC) is an important endemic biological resource in Korea. While numerous studies have been conducted exploring this breed, none have used next-generation sequencing to identify its specific genomic features. We sequenced five strains of KNC and identified 10.9 million SNVs and 1.3 million InDels. Through the analysis, we found that the highly variable region common to all 5 strains had genes like PCHD15, CISD1, PIK3C2A, and NUCB2 that might be related to the phenotypic traits of the chicken such as auditory sense, growth rate and egg traits. In addition, we assembled unaligned reads that could not be mapped to the reference genome. By assembling the unaligned reads, we were able to present genomic sequences characteristic to the KNC. Based on this, we also identified genes related to the olfactory receptors and antigen that are common to all 5 strains. Finally, through the reconstructed mitochondrial genome sequences, we performed phylogenomic analysis and elucidated the maternal origin of the artificially restored KNC. Our results revealed that the KNC has multiple maternal origins which are in agreement with Korea's history of chicken breed imports. The results presented here provide a valuable basis for future research on genomic features of KNC and further understanding of KNC's origin. PMID- 25501046 TI - Sampling of finite elements for sparse recovery in large scale 3D electrical impedance tomography. AB - This study proposes a method to improve performance of sparse recovery inverse solvers in 3D electrical impedance tomography (3D EIT), especially when the volume under study contains small-sized inclusions, e.g. 3D imaging of breast tumours. Initially, a quadratic regularized inverse solver is applied in a fast manner with a stopping threshold much greater than the optimum. Based on assuming a fixed level of sparsity for the conductivity field, finite elements are then sampled via applying a compressive sensing (CS) algorithm to the rough blurred estimation previously made by the quadratic solver. Finally, a sparse inverse solver is applied solely to the sampled finite elements, with the solution to the CS as its initial guess. The results show the great potential of the proposed CS based sparse recovery in improving accuracy of sparse solution to the large-size 3D EIT. PMID- 25501045 TI - Time Trends of Aspirin and Warfarin Use on Stroke and Bleeding Events in Chinese Patients With New-Onset Atrial Fibrillation. AB - BACKGROUND: Much of the clinical epidemiology and treatment patterns for patients with atrial fibrillation (AF) are derived from Western populations. Limited data are available on antithrombotic therapy use over time and its impact on the stroke or bleeding events in newly diagnosed Chinese patients with AF. The present study investigates time trends in warfarin and aspirin use in China in relation to stroke and bleeding events in a Chinese population. METHODS: We used a medical insurance database involving > 10 million individuals for the years 2001 to 2012 in Yunnan, a southwestern province of China, and performed time trend analysis on those with newly diagnosed AF. Cox proportional hazards time varying exposures were used to determine the risk of stroke or bleeding events associated with antithrombotic therapy among patients with AF. RESULTS: Among the randomly sampled 471,446 participants, there were 1,237 patients with AF, including 921 newly diagnosed with AF, thus providing 4,859 person-years of experience (62% men; mean attained age, 70 years). The overall rate of antithrombotic therapy was 37.7% (347 of 921 patients), with 4.1% (38 of 921) on warfarin and 32.3% (298 of 921) on aspirin. Antithrombotic therapy was not related to stroke/bleeding risk scores (CHADS2 [congestive heart failure, hypertension, age >= 75 years, diabetes, stroke (doubled)] score, P = .522; CHA2DS2-VASc [congestive heart failure, hypertension, age >= 75 years (doubled), diabetes mellitus, stroke or transient ischemic attack (doubled), vascular disease, age 65 to 74 years, and female sex] score, P = .957; HAS-BLED [hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly (> 65 years), drugs/alcohol concomitantly] score, P = .095). The use of antithrombotic drugs (mainly aspirin) increased in both women and men over time, with the rate of aspirin increasing from 4.0% in 2007 to 46.1% in 2012 in the former, and from 7.7% in 2007 to 61.9% in 2012 in the latter (P for trend for both, < .005). In the overall cohort, the annual stroke rate was approximately 6% and the annual major bleeding rate was about 1%. Compared with nonantithrombotic therapy, the hazard ratio for ischemic stroke was 0.68 (95% CI, 0.39-1.18) for aspirin and 1.39 (0.54-3.59) for warfarin. CONCLUSIONS: Aspirin use increased among Chinese patients newly diagnosed with AF, with no relationship to the patient's stroke or bleeding risk. Warfarin use was very low. Given the health-care burden of AF and its complications, our study has major implications for health-care systems in non-Western countries, given the global burden of this common arrhythmia. PMID- 25501047 TI - HIV-testing behavior and associated factors among MSM in Chongqing, China: results of 2 consecutive cross-sectional surveys from 2009 to 2010. AB - The high and climbing human immunodeficiency virus (HIV) rates among Chinese men who have sex with men (MSM) bring huge pressure and challenge to acquired immune deficiency syndrome response work in China. This study examined HIV-testing behavior and describes the characteristics of recently tested MSM in Chongqing to address targeting HIV prevention interventions. Two consecutive cross-sectional surveys were conducted among Chongqing MSM using respondent-driven sampling in 2009 and 2010. Information was collected regarding details on demographic characteristics, sexual practices with male and female partners, and HIV-testing experiences. Univariate and multivariate logistic regression analyses were performed to identify factors independently associated with recent HIV testing.The final sample size included in our analyses was 992. The overall HIV prevalence was 13.4%, and HIV prevalence increased significantly from 11.6% in 2009 to 15.4% in 2010 (P = 0.08). The overall rate of HIV testing in the past 12 months was 44.6%, and the self-reported rates decreased significantly from 47.8% in 2009 to 41.1% in 2010 (P = 0.03). Factors independently associated with recent HIV testing included living in Chongqing >1 year (adjusted odds ratio [AOR] 1.8, 95% confidence interval [CI] 1.1-2.9), the age of most recent male partner <= 25 (AOR 1.5, 95% CI 1.1-2.1), not having unprotected insertive anal sex with most recent male partner in the past 6 months (AOR 1.5, 95% CI 1.1-2.0), disclosing HIV status to most recent male partner (AOR 2.8, 95% CI 2.0-3.8), and holding lower level of HIV-related stigma (AOR 1.1 per scale point, 95% CI 1.0-1.1). The extremely high HIV prevalence and low annual testing level put MSM at high risk of HIV infection and transmission, and it is a priority to promote regular HIV testing among this group in order to control the spread of HIV in Chongqing, China. PMID- 25501048 TI - The coexistence of common pulmonary diseases on the histologic type of lung cancer in both genders in Taiwan: a STROBE-compliant article. AB - Effects of pulmonary diseases [asthma, chronic obstructive pulmonary disease (COPD), and lung tuberculosis (TB)] on subsequent lung cancer development have been reported. However, whether patients with coexisting pulmonary diseases are at greater risk of developing various histologic types of lung cancer remains elusive. Patients newly diagnosed with lung cancer between 2004 and 2008 were identified from National Health Insurance Research Database (Taiwan). The histologic types of lung cancer were further confirmed using Taiwan Cancer Registry Database. Cox proportional hazard regression was used to calculate the hazard ratio (HR) of coexisting asthma, COPD and/or TB to estimate lung cancer risk by histologic type. During the study period, 32,759 cases of lung cancer were identified from 15,219,024 residents age 20 years and older, who were free from the disease before 2003. Coexisting pulmonary diseases showed stronger association with lung cancer than specific lung disorders. Specifically, among men, the HRs for squamous cell carcinoma (SqCC) were 3.98 (95% CI, 3.22-4.93), 2.68 (95% CI, 2.45-2.93), and 2.57 (95% CI, 2.10-3.13) for individuals with asthma+COPD+TB, asthma+COPD, and COPD+TB, respectively. Among women, the HRs for SqCC were 3.64 (95% CI, 1.88-7.05), 3.35 (95% CI, 1.59-7.07), and 2.21 (95% CI, 1.66-2.94) for individuals with TB, COPD+TB, and asthma+COPD, respectively. Adenocarcinoma HRs for men and women were 2.00 (95% CI, 1.54-2.60) and 2.82 (95% CI, 1.97-4.04) for individuals with asthma+COPD+TB, 2.28 (95% CI, 1.91-2.73) and 2.16 (95% CI, 1.57-2.95) for COPD+TB, and 1.76 (95% CI, 1.04-2.97) and 2.04 (95% CI, 1.02-4.09) for individuals with asthma+TB. Specifically, small cell carcinoma (SmCC) HRs among men were 3.65 (95% CI, 1.97-6.80), 2.20 (95% CI, 1.45-3.36), and 2.14 (95% CI, 1.86-2.47) for those with asthma+TB, asthma+COPD+TB, and asthma+ COPD, respectively. Among women, the HRs of SmCC were 8.97 (95% CI, 3.31-24.28), 3.94 (95% CI, 1.25-12.35) and 3.33 (95% CI, 2.23-4.97) for those with asthma+COPD+TB, COPD+TB, and asthma+COPD, respectively. Patients with coexistence of pulmonary diseases were more susceptible to lung cancer. Affected persons deserve greater attention while undergoing cancer screening. PMID- 25501049 TI - Clinicopathological features of gallbladder papillary adenocarcinoma. AB - Although patients with gallbladder papillary adenocarcinoma (GBPA) appear to have better prognoses than patients with other pathological subtypes of gallbladder carcinoma (GBC), the clinicopathological features and outcomes of GBPA have not been fully explored. This study therefore analyzed the clinicopathological characteristics and outcomes of GBPA.This study included 16 patients with GBPA and 101 with gallbladder adenocarcinoma (GBA) not otherwise specified (NOS), all diagnosed pathologically after surgical resection. Clinicopathological and survival data were retrospectively collected and compared. Fever was significantly more common in GBPA (7/16 vs 10/101; P = 0.000). Serum carbohydrate antigen 19-9 level was increased in 1 of 9 patients with GBPA and 39 of 76 with GBA (P = 0.022). More patients with GBPA underwent curative resection (15/16 vs 54/101; P = 0.009). Pathologically, patients with GBPA were at much earlier tumor (T) (4 in situ, 8 T1; P = 0.000) and Tumor, Node, Metastases (TNM) stages (P = 0.000). The overall 1-, 3-, and 5-year survival rates were significantly higher in patients with GBPA (100%, 76.9%, and 76.9%, respectively), than in patients with GBA (72.2%, 38.8%, and 31.0%, respectively; P = 0.001). Preoperative jaundice (odds ratio 7.69; 95% confidence interval, 1.53-38.76; P = 0.013) was a significant prognostic factor in patients with GBA, but was no longer significant when the patients with GBA and GBPA were pooled together. The clinicopathological features of patients with GBPA differed from those in patients with GBA (not otherwise specified). Pooling of patients may mask prognostic factors in each group. PMID- 25501050 TI - Retrospective comparison of fludarabine in combination with intermediate-dose cytarabine versus high-dose cytarabine as consolidation therapies for acute myeloid leukemia. AB - This retrospective study compared efficacy and safety of fludarabine combined with intermediate-dose cytarabine (FA regimen) versus high-dose cytarabine (HiDAC regimen) as consolidation therapy in acute myeloid leukemia (AML) patients who achieved complete remission. Disease-free survival (DFS) and overall survival (OS) based on age (>= 60, <60 years) and cytogenetics were evaluated from data between January 2005 and March 2013. Total 82 patients (FA, n = 45; HiDAC, n = 37; 14-65 years) were evaluated. Five-year DFS was 32.0% and 36.2% for FA and HiDAC groups, respectively (P = 0.729), and 5-year OS was 39.5% and 47.8% (P = 0.568), respectively. Among older patients (>= 60 years), 3-year DFS was 26.0% for FA group and 12.5% for HiDAC group (P = 0.032), and 3-year OS was 34.6% and 12.5%, respectively (P = 0.026). In FA group, hematological toxicities were significantly lower. FA regimen was as effective as HiDAC regimen in patients with good/intermediate cytogenetics and significantly improved DFS and OS in older patients. PMID- 25501051 TI - Signet ring cell histology is not an independent predictor of poor prognosis after curative resection for gastric cancer: a propensity analysis by the KLASS Group. AB - Whether signet ring cell (SRC) histology carries a worse prognosis than other forms of gastric adenocarcinoma has been questioned. The present study investigated the differences in clinicopathologic features and survival between SRC and non-SRC adenocarcinoma. The prospectively collected data of 2643 patients who had undergone curative gastrectomy between 1998 and 2005 by 10 surgeons were reviewed. Additionally, we employed analysis of covariance, propensity-score risk adjustment, and propensity-based matching to account for possible selection bias. The baseline characteristics of prematched patients with SRC or non-SRC adenocarcinoma histology differed: SRC presented in younger patients and less often in men, was more likely found in the middle stomach, and was more likely to be Stage I. After applying the propensity-score strata and propensity-score matching, there was no difference in the baseline characteristics, and SRC was not an independent risk factor for mortality in the same stage. SRC is not an independent predictor of poor prognosis after curative resection for gastric cancer in Korea. PMID- 25501052 TI - Clinical classification and prognosis of isolated right-sided infective endocarditis. AB - From an epidemiologic point of view, right-sided infective endocarditis (RSIE) affects different types of patients: intravenous drug users (IDUs), cardiac device carriers (pacemakers and implantable automatic defibrillators), and the "3 noes" endocarditis group: no left-sided, no IDUs, no cardiac devices. Our objective is to describe and compare the clinical profile and outcome of these groups of patients. Every episode of infective endocarditis (IE) consecutively diagnosed in 3 tertiary centers from 1996 to 2012 was included in an ongoing multipurpose database. We assessed 85 epidemiologic, clinical, echocardiographic, and outcome variables in patients with isolated RSIE. A bivariated comparative analysis between the 3 groups was conducted.Among 866 IE episodes, 121 were classified as isolated RSIE (14%): 36 IDUs (30%), 65 cardiac device carriers (54%), and 20 "3 noes" group (16%). IDUs were mainly young men (36 +/- 7 years) without previous heart disease, few comorbidities, and frequent previous endocarditis episodes (28%). Human immunodeficiency virus infection was frequent (69%). Cardiac device carriers were older (66 +/- 15 years) and had less comorbidities (34%). Removal of the infected device was performed in 91% of the patients without any death. The "3 noes" endocarditis group was composed mainly by middle-age men (56 +/- 18 years), health care related infections (50%), and had many comorbidities (75%). Whereas Staphylococcus aureus were the most frequent cause in IDUs (72% vs 34% in device carriers and 34% in the "3 noes" group, P = 0.001), coagulase negative Staphylococci predominated in the device carriers (58% vs 11% in drug users and 35% in the "3 noes", P < 0.001). Significant differences in mortality were found (17% in drug users, 3% in device carriers, and 30% in the "3 noes" group; P < 0.001). These results suggest that RSIE should be separated into 3 groups (IDUs, cardiac device carriers, and the "3 noes") and considered as independent entities as there are relevant epidemiologic, clinical, microbiological, echocardiographic, and prognostic differences among them. PMID- 25501053 TI - Oral mucosal lesions in Indians from Northeast Brazil: cross-sectional study of prevalence and risk indicators. AB - The aim of this cross-sectional study was to evaluate the prevalence of oral mucosal lesions, and their risk indicators in adult Kiriri Indians from Northeast Brazil. Clinical oral examination was performed on a representative sample of 223 Indians (age >= 19 years). A systematic evaluation of lips, labial mucosa and sulcus, commissures, buccal mucosa and sulcus, gingiva and alveolar ridge, tongue, floor of the mouth, and soft and hard palate was performed. Bivariate analysis was conducted to assess associations between mucosal conditions and age, gender, income, educational level, diabetic status, and smoking status. Mucosal lesions were found in 50 participants (22.4%). The most prevalent lesions were fistulae (6.2%) and traumatic ulcers (4.48%). Oral mucosal was associated with higher age (>= 35 years; odds ratio [OR] = 1.99, 95% confidence interval [CI]: 1.05-3.76, P = 0.03) and lower education level (<9 years; OR = 2.13, 95% CI: 0.96 4.71, P = 0.06). Mucosal conditions are prevalent in Kiriri Indians and the presence of mucosal lesions is associated with advanced age and lower education. A public health program aimed at preventing and treating mucosal lesions and targeted toward the high-risk group is vital to improve the oral health status of this population. PMID- 25501054 TI - Carcinoma ex pleomorphic adenoma of the palate composed of invasive micropapillary salivary duct carcinoma and adenoid cystic carcinoma components: an unusual case with immunohistochemical approach. AB - Carcinoma ex pleomorphic adenoma (CXPA) is an unusual epithelial malignancy that develops from a primary or recurrent pleomorphic adenoma (PA), the most common tumor of salivary glands, and constitutes about 11.5% of all carcinomas that affect these glands. Intraoral minor salivary glands and seromucous glands of the oropharynx are uncommon locations of CXPA. On histopathological examination, the tumor comprises a wide morphological spectrum with a variable proportion between the benign and malignant components with the latter often predominating and overlapping the PA, which may cause misdiagnosis. Here, we report a case of palatal minor salivary gland CXPA composed of invasive micropapillary salivary duct carcinoma and adenoid cystic carcinoma components with multiple nodal metastases in a 74-year-old woman. Neoplastic cells showed heterogeneous immunohistochemical profile with both luminal and myoepithelial differentiation. The invasive micropapillary salivary duct carcinoma component demonstrated overexpression of the oncoprotein human epidermal growth factor receptor-2. This feature should be considered and evaluated as a possible target for adjuvant therapy in case of metastatic disease. PMID- 25501055 TI - Predictive accuracy of amyloid imaging for progression from mild cognitive impairment to Alzheimer disease with different lengths of follow-up: a meta analysis. [Corrected]. AB - In the past decade, amyloid deposition has been shown to begin many years before the clinical symptoms of dementia in mild cognitive impairment (MCI) due to Alzheimer disease (AD). Longitudinal studies with different follow-up durations have suggested that C-Pittsburgh compound B positron emission tomography (C-PIB PET) may play a role in stratifying patients with MCI into risk levels for developing AD. However, the predictive accuracy of amyloid imaging for the progression from MCI to AD with different follow-up durations has not yet been systematically evaluated. A formal systematic evaluation of the sensitivity, specificity, and other properties of C-PIB-PET was performed.This study aimed to systematically review and meta-analyze published data on the diagnostic performance of C-PIB-PET for predicting conversion to AD in patients with MCI and to determine whether long-term follow-up has a positive effect on predictive accuracy. Relevant studies were systematically identified through electronic searches, which were performed in MEDLINE (OvidSP), EMBASE (OvidSP), BIOSIS Previews (ISI Web of Knowledge), Science Citation Index (ISI Web of Knowledge), PsycINFO (Ovid SP), and LILACS (Bireme). The methodological quality of each study was assessed by QUADAS-2. Sensitivities and specificities of C-PIB-PET in individual studies were calculated, and the studies underwent meta-analysis with a random-effects model. A summary receiver-operating characteristic curve (SROC) was constructed with the Moses-Shapiro-Littenberg method. Pooled estimates of sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), diagnostic odds ratio (DOR), and the SROC curve of each subgroup were determined. Heterogeneity was tested, and potential sources for heterogeneity were explored by assessing whether certain covariates significantly influenced the relative DOR.Eleven eligible studies consisting of a total of 352 patients with MCI at baseline were included. Overall, the studies were of moderate-to-high methodological quality. The sensitivity and specificity of C-PIB PET for predicting conversion to AD ranged from 83.3% to 100% and 41.1% to 100%, respectively, with pooled estimates of 94.7% (95% confidence interval [CI]: 89.8% 97.7%) and 57.2% (95% CI: 50.1%-64.2%), respectively . Moderate heterogeneity was observed for specificity between the included studies (I = 42.1%). The pooled estimates for the long-term follow-up subgroup were 95.5% sensitivity (95% CI: 84.5%-99.4%) and 72.4% specificity (95% CI: 59.1%-83.3.8%), whereas the pooled estimates for the short-term follow-up subgroup were 94.4% sensitivity (95% CI: 88.2%-97.9%) and 51.0% specificity (95% CI: 42.6%-59.5%). Homogeneity in each subgroup was significantly higher than that of the included studies, and most diagnostic indicators in the long-term follow-up subgroup were far superior to those in the short-term follow-up subgroup or the entire group. Not all of the methodological quality scores of studies included in this systematic review were high. Current evidence suggests that prolongation of the follow-up duration tended to yield greater accuracy of C-PIB-PET for predicting the progression from MCI to AD. In particular, the specificity, which reflects the exploratory nature of the use of amyloid imaging to identify the process of MCI to AD, was improved with a longer follow-up period. PMID- 25501056 TI - Resistance to vemurafenib can be reversible after treatment interruption: a case report of a metastatic melanoma patient. AB - About 40% to 60% of melanomas present BRAF mutation. Selective BRAF inhibitors such as vemurafenib and dabrafenib are currently approved for the treatment of advanced melanoma patients with BRAF mutation. The treatment-induced tumor regression occurs in the majority of patients; however, acquired resistance to BRAF inhibitors is observed in most of the patients after 6 to 7 months. After progression of the disease, the patient might be offered treatment with ipilimumab followed by chemotherapy. Subsequent lines of systemic treatment of metastatic melanoma patients do not exist.Here we report a case of a 59-year-old woman with a diagnosis of BRAF-mutant metastatic melanoma that responded to initial treatment with vemurafenib. Subsequently, after disease progression, the patient received chemotherapy. Since no clinical response to dacarbazine was observed, carboplatin with paclitaxel were applied. Transient partial response was obtained, which was followed by further disease progression. Then retreatment with vemurafenib was applied. The patient developed very short-term tumor regression and significant biochemical response (serum lactate dehydrogenase, alanine aminotransferase, and aspartate aminotransferase) to the treatment. However, following 5 weeks of retreatment, the patient developed progression of the disease. Our clinical observation indicates that in melanoma patients who developed resistance to selective BRAF inhibitors, rechallenge after treatment interruption might be beneficial. PMID- 25501057 TI - Effect of spironolactone in resistant arterial hypertension: a randomized, double blind, placebo-controlled trial (ASPIRANT-EXT). AB - This study was designed to assess the effect of the addition of low-dose spironolactone on blood pressure (BP) in patients with resistant arterial hypertension. Patients with office systolic blood pressure (SBP) >140 mm Hg or diastolic blood pressure (DBP) >90 mm Hg despite treatment with at least 3 antihypertensive drugs, including a diuretic, were enrolled in this double-blind, placebo-controlled, multicentre trial. One hundred sixty-one patients in outpatient internal medicine departments of 6 hospitals in the Czech Republic were randomly assigned to receive 25 mg of spironolactone (N = 81) or a placebo (N = 80) once daily as an add-on to their antihypertensive medication, using simple randomization. This study was registered with ClinicalTrials.gov, number NCT00524615. A nalyses were done with 150 patients who finished the follow-up (74 in the spironolactone and 76 in the placebo group). At 8 weeks, BP values were decreased more by spironolactone, with differences in mean fall of SBP of -9.8, 13.0, -10.5, and -9.9 mm Hg (P < 0.001 for all) in daytime, nighttime, and 24 hour ambulatory BP monitoring and in the office. The respective DBP differences were -3.2, -6.4, -3.5, and -3.0 mm Hg (P = 0.013, P < 0.001, P = 0.005, and P = 0.003). Adverse events in both groups were comparable. The office SBP goal <14 mm Hg at 8 weeks was reached in 73% of patients using spironolactone and 41% using placebo (P = 0.001). Spironolactone in patients with resistant arterial hypertension leads to a significant decrease of both SBP and DBP and markedly improves BP control. PMID- 25501058 TI - Effects of abiraterone acetate on chronic kidney disease in 2 patients with metastatic castration-resistant prostate cancer. AB - Prostate cancer is the second leading cause of cancer-related death in men in most Western countries. In this report, we present 2 cases of metastatic castration-resistant prostate cancer and chronic kidney disease. Both patients underwent and developed clinical resistance to androgen-deprivation therapy. Subsequently, the patients were treated with the conventional chemotherapeutic approach, which resulted in the worsening of renal function and performance status. Therefore, we opted for treatment with abiraterone acetate, and the patients exhibited improvements in renal function with good response of the disease. PMID- 25501059 TI - Reasons for switching antihypertensive medication in general practice: a cross sectional Czech nationwide survey. AB - To improve blood pressure (BP) control of their patients, physicians either adjust or switch antihypertensive medication. Currently, there is only limited information available on why physicians decide to switch antihypertensive medications. A questionnaire-based survey was performed between November 2011 and March 2012 in the Czech Republic. General practitioners were asked to fill in questionnaires about their hypertensive patients whose antihypertensive medication they were planning to change. These questionnaires recorded data about patient demographic information, cardiovascular risk factors, BP values, and reasons for switching antihypertensive medication. Two hundred eight-six general practitioners surveyed a total of 4341 hypertensive patients. The mean age of the patients was 59.8 years, 68.9% of patients were overweight or obese. Uncontrolled office systolic and diastolic BP >140/90 mm Hg was present in 89.6% and 81.5% of patients, respectively, despite the fact that 49.4% of patients used a combination of 2 or more antihypertensive drugs. The most common reasons for switching medication were insufficient BP control (73.7%), followed by aiming for a better 24-hour effect (38.4%) and increased cardiovascular risk of the patients (37.7%). The major reason for switching antihypertensive treatment in general practice was insufficient BP control. Switching medication because of adverse drug effects is less frequent than reported a decade ago. PMID- 25501060 TI - A qualitative study comparing the assay performance characteristics between the 2007 and the 2013 American Society for Clinical Oncology and College of American Pathologists HER2 scoring methods in mucinous epithelial ovarian cancer. AB - The remarkable success of trastuzumab and other newly developed anti-HER2 (human epidermal growth factor receptor 2) therapies in breast, gastric, or gastroesophageal junction cancer patients has supported us to investigate the HER2 status and its possible therapeutic implication in mucinous epithelial ovarian cancer (EOC). However, there is currently no standardization of HER2 scoring criteria in mucinous EOC. In this study, we aimed to compare both the assay performance characteristics of the 2007 and the 2013 American Society for Clinical Oncology and College of American Pathologists scoring methods. Forty nine tissue microarray samples of mucinous EOC from Asian women were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests using the 2007 and the 2013 criteria, respectively. The overall concordance between IHC and FISH by the 2007 criteria was 97.92 % (kappa = 0.921), and that by the 2013 criteria was 100% (kappa = 1.000). The percentage of Her2 FISH amplified cases showed an increasing trend significantly through their corresponding HER2 IHC ordinals by the 2007 and the 2013 criteria, respectively (P < 0.001, P < 0.001). After excluding equivocal cases, the specificity (100%) and positive predictive value (100%) were unchanged under either the 2007 or the 2013 criteria. The sensitivity (100%), negative predictive value (NPV) (100%), and accuracy (100%) of HER2 IHC were higher under the 2013 criteria than those (sensitivity 87.5%, NPV 97.6%, and accuracy 97.9%) under the 2007 criteria. Of the total 49 cases, the number (n = 4) of HER2 IHC equivocal results under the 2013 criteria was 4-fold higher than that (n = 1) under the 2007 criteria (8.16% vs 2.04%). Conclusively, if first tested by IHC, the 2013 criteria caused more equivocal HER2 IHC cases to be referred to Her2 FISH testing than the 2007 criteria. That decreased the false-negative rate of HER2 status and increased the detection rates of HER2 positivity in mucinous EOC. PMID- 25501061 TI - Nerve fibers in breast cancer tissues indicate aggressive tumor progression. AB - Emerging evidence has indicated nerve fibers as a marker in the progression of various types of cancers, such as pancreatic cancer and prostate cancer. However, whether nerve fibers are associated with breast cancer progression remains unclear. In this study, we evaluated the presence of nerve fibers in 352 breast cancer specimens and 83 benign breast tissue specimens including 43 cases of cystic fibrosis and 40 cases of fibroadenoma from 2 independent breast tumor center using immunohistochemical staining for specific peripheral nerve fiber markers.In all, nerve fibers were present in 130 out of 352 breast cancer tissue specimens, while none were detected in normal breast tissue specimens. Among 352 cases, we defined 239 cases from Sun Yat-Sen Memorial Hospital, Guangzhou, China, as the training set, and 113 cases from the First Affiliated Hospital of Shantou University, Guangdong, China, as the validation set. The thickness of tumor involving nerve fibers is significantly correlated with poor differentiation, lymph node metastasis, high clinical staging, and triple negative subtype in breast cancer. More importantly, Cox multifactor analysis indicates that the thickness of tumor-involving nerve fibers is a previously unappreciated independent prognostic factors associated with shorter disease-free survival of breast cancer patients. Our findings are further validated by online Oncomine database. In conclusion, our results show that nerve fiber involvement in breast cancer is associated with progression of the malignancy and warrant further studies in the future. PMID- 25501062 TI - Risk of pneumonia among patients with chronic kidney disease in outpatient and inpatient settings: a nationwide population-based study. AB - Patients with chronic kidney disease (CKD) are more at risk for pneumonia than the general population. Patients with pneumonia are usually treated as outpatients. However, previous studies were conducted on the basis of inpatient pneumonia. This method may underestimate the risk of pneumonia in patients with CKD. Therefore, we investigated the risk of pneumonia among CKD patients in both outpatient and inpatient settings. A total of 15,562 patients with CKD and 62,109 individuals without CKD (matched for age and gender) were taken as subjects in the Longitudinal Health Insurance Database of Taiwan National Insurance from 1996 to 2010. The incidence density rates of inpatient and outpatient pneumonia were calculated. The risk factors associated with pneumonia were analyzed using Cox proportional hazard models with adjustments for confounders. The incidence density rate of pneumonia was 65.6 per 1000 person-years in patients with CKD and 28.4 per 1000 person-years in individuals without CKD. The incidence density rate of inpatient pneumonia was 43.3 per 1000 person-years in patients with CKD and 16.6 per 1000 person-years in individuals without CKD. CKD was associated with increased risk of pneumonia (adjusted hazard ratio [aHR], 1.97; 95% confidence interval [CI], 1.89-2.05; P < 0.001), outpatient pneumonia (aHR, 1.40; 95% CI, 1.31-1.49), and inpatient pneumonia (aHR, 2.17; 95% CI, 2.07-2.29, P < 0.001). Patients' comorbidities, including diabetes, cardiovascular disease (CVD), asthma, and chronic obstructive pulmonary disease (COPD), were independently associated with increased risk of pneumonia.CKD is associated with the increased risk of both outpatient and inpatient pneumonia. This association is independent of comorbid diabetes, CVD, asthma, and COPD. PMID- 25501063 TI - The polymorphism of CYP2E1 Rsa I/Pst I gene and susceptibility to respiratory system cancer: a systematic review and meta-analysis of 34 studies. AB - The purpose of this articles is to determine whether the cytochrome P450 2E1 (CYP2E1) Rsa I/Pst I gene polymorphism is correlated with respiratory system cancers. Respiratory system cancers included lung cancer, laryngeal cancer, nasopharyngeal cancer, and cancers of other respiratory organs, which are the most common malignant tumors worldwide; the significant relationship between CYP2E1 Rsa I/Pst I gene polymorphism and some respiratory system cancer have been reported, but results of some other studies are controversial. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to assess the association. PubMed, EMBASE, Cochrane Library Databases, China National Knowledge Infrastructure, and Wanfang Database (up to July 20, 2014) were searched for all case-control studies those mainly studied the relationship between CYP2E1 Rsa I/Pst I gene polymorphism and the susceptibility of respiratory system cancer. A total of 332 articles were collected, among which 34 studies that involved 7028 cases and 9822 controls fulfilled the inclusion criteria after being assessed by 2 reviewers. When stratified by cancer site, the C2/C2 polymorphism could increase the risk of nasopharyngeal cancer under the homozygote model (C2C2 vs C1C1: OR = 1.85, 95% CI = 1.20-2.85, P = 0.005) and recessive model (C2C2 vs C1C2/C1C1: OR = 1.89, 95% CI = 1.23-2.89, P = 0.003). Protection effect was found in lung cancer in heterozygote model (C1C2 vs C1C1: OR = 0.82, 95% CI = 0.74 0.91, P < 0.001), dominant model (C1C2/C2C2 vs C1C1: OR = 0.83, 95% CI = 0.76 0.90, P < 0.001), and allele contrast model (C2 vs C1: OR = 0.85, 95% CI = 0.73 1.00, P = 0.045). With regard to ethnicity subgroup analysis, there was significant association in Asian population in heterozygote model (C1C2 vs C1C1: OR = 0.85, 95% CI = 0.78-0.94, P = 0.001), dominant model (C1C2/C2C2 vs C1C1: OR = 0.88, 95% CI = 0.81-0.95, P = 0.001), and recessive model (C2C2 vs C1C2/C1C1: OR = 1.25, 95% CI = 1.01-1.53, P = 0.036). CYP2E1 Rsa I/Pst I gene polymorphism may reduce the risk of respiratory system cancer. Furthermore, significant association was also found in Asian populations. PMID- 25501064 TI - Pre-existing type 2 diabetes mellitus is an independent risk factor for mortality and progression in patients with renal cell carcinoma. AB - Malignancies are one of the main causes of mortality in diabetic patients; however, to date, very limited data have been reported on the specific influence of type 2 diabetes mellitus (T2DM) on the survival of patients with renal cell carcinoma (RCC). In the present long-term retrospective study, we investigated whether T2DM may influence the overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) in patients with surgically treated RCC. Medical records of 924 patients treated by radical or partial nephrectomy for sporadic, unilateral RCC were reviewed. Patients with type-1 DM and with T2 DM receiving insulin treatment were excluded. Survival estimates were calculated according to the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate analyses were performed using the Cox regression model.Of the 924 RCC patients, 152 (16.5%) had T2DM. Mean follow-up was 68.5 months. Mean OS was 41.3 and 96.3 months in T2DM and non-T2DM patients, respectively (P < 0.0001).The estimated CSS rates at 1, 3, and 5 years in T2DM versus non-T2DM patients were 63.4% versus 76.7%, 30.4% versus 56.6%, and 16.3% versus 48.6%, respectively (P = 0.001). Mean PFS was significantly lower (31.5 vs 96.3 months; P < 0.0001) in the T2DM group. At multivariate analysis, T2DM was an independent adverse prognostic factor for OS (hazard ratio [HR] = 3.44; 95% confidence interval [CI]:2.40-4.92), CSS (HR = 6.39; 95% CI: 3.78-10.79), and PFS (HR = 4.71; 95% CI: 3.11-7.15). In conclusion, our findings suggest that patients with RCC and pre-existing T2DM have a shorter OS, increased risk of recurrence, and higher risk for kidney cancer mortality than those without diabetes. PMID- 25501065 TI - Adaptation and promotion of emergency medical service transportation for climate change. AB - The purpose of this study is to find a proper prehospital transportation scenario planning of an emergency medical service (EMS) system for possible burdensome casualties resulting from extreme climate events. This project focuses on one of the worst natural catastrophic events in Taiwan, the 88 Wind-caused Disasters, caused by the Typhoon Morakot; the case of the EMS transportation in the Xiaolin village is reviewed and analyzed. The sequential-conveyance method is designed to promote the efficiency of all the ambulance services related to transportation time and distance. Initially, a proposed mobile emergency medical center (MEMC) is constructed in a safe location near the area of the disaster. The ambulances are classified into 2 categories: the first-line ambulances, which reciprocate between the MEMC and the disaster area to save time and shorten the working distances and the second-line ambulances, which transfer patients in critical condition from the MEMC to the requested hospitals for further treatment. According to the results, the sequential-conveyance method is more efficient than the conventional method for EMS transportation in a mass-casualty incident (MCI). This method improves the time efficiency by 52.15% and the distance efficiency by 56.02%. This case study concentrates on Xiaolin, a mountain village, which was heavily destroyed by a devastating mudslide during the Typhoon Morakot. The sequential-conveyance method for the EMS transportation in this research is not only more advantageous but also more rational in adaptation to climate change. Therefore, the findings are also important to all the decision-making with respect to a promoted EMS transportation, especially in an MCI. PMID- 25501067 TI - Single-stage anterior debridement and fibular allograft implantation followed by posterior instrumentation for complicated infectious spondylitis: report of 20 cases and review of the literature. AB - Complicated infectious spondylitis is an infrequent infection with severe spinal destruction, and is indicated for combined anterior and posterior surgeries. Staged debridement and subsequent reconstruction is advocated in the literature. The purpose of this study is to evaluate the feasibility and clinical outcome of patients who underwent single-stage combined anterior debridement and fibular allograft implantation followed by supplemental posterior fixation for complicated infectious spondylitis. We retrospectively reviewed the medical records of 20 patients who underwent single-stage combined anterior and posterior surgeries for complicated infectious spondylitis from January 2005 to December 2010. Complicated infectious spondylitis was defined as at least 1 vertebral osteomyelitis with pathological fracture or severe bony destruction and adjacent discitis, based on imaging studies. The severity of the neurological status was evaluated using the Frankel scale. The clinical outcomes were assessed by careful physical examination and regular serological tests to determine the visual analog scale (VAS) score and Macnab criteria. Correction of the sagittal Cobb angle on radiography was also compared before and after surgery. The Wilcoxon signed-rank test was used to analyze patient surgical prognosis and radiological findings. All patients with complicated infectious spondylitis were successfully treated by single-stage combined anterior and posterior surgeries. No patients experienced neurologic deterioration. The average VAS score was 7.8 before surgery and significantly decreased to 2.1 at discharge. Three patients had excellent outcomes and 17 had good outcomes, based on Macnab criteria. The average length of the allograft for reconstruction was 64.0 mm. Kyphotic deformity improved in all patients, with an average correction angle of 13.4 degrees . There was no implant breakage or allograft dislodgement during at least 36 months of follow up. Single-stage anterior debridement and fibular allograft implantation followed by posterior pedicle screw instrumentation provide immediate stability, satisfactory alignment, and successful infection control. Fibular allograft implantation seems to be a good alternative for anterior reconstruction; it can proceed to bony incorporation and avoids donor site morbidity. PMID- 25501066 TI - Association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) shares genetic and cytokine profiles with other autoinflammatory diseases. AB - The association of pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) has recently been described and suggested to be a new entity within the spectrum of autoinflammatory syndromes, which are characterized by recurrent episodes of sterile inflammation, without circulating autoantibodies and autoreactive T-cells. We conducted an observational study on 5 patients with PASH syndrome, analyzing their clinical features, genetic profile of 10 genes already known to be involved in autoinflammatory diseases (AIDs), and cytokine expression pattern both in lesional skin and serum. In tissue skin samples, the expressions of interleukin (IL)-1beta and its receptors I and II were significantly higher in PASH (P = 0.028, 0.047, and 0.050, respectively) than in controls. In PASH patients, chemokines such as IL-8 (P = 0.004), C-X-C motif ligand (CXCL) 1/2/3 (P = 0.028), CXCL 16 (P = 0.008), and regulated on activation, normal T cell expressed and secreted (RANTES) (P = 0.005) were overexpressed. Fas/Fas ligand and cluster of differentiation (CD)40/CD40 ligand systems were also overexpressed (P = 0.016 for Fas, P = 0.006 for Fas ligand, P = 0.005 for CD40, and P = 0.004 for CD40 ligand), contributing to tissue damage and inflammation. In peripheral blood, serum levels of the main proinflammatory cytokines, that is, IL-1beta, tumor necrosis factor-alpha, and IL-17, were within the normal range, suggesting that in PASH syndrome, the inflammatory process is mainly localized into the skin. Four out of our 5 PASH patients presented genetic alterations typical of well-known AIDs, including inflammatory bowel diseases, and the only patient lacking genetic changes had clinically evident Crohn disease. In conclusion, overexpression of cytokines/chemokines and molecules amplifying the inflammatory network, along with the genetic changes, supports the view that PASH syndrome is autoinflammatory in origin. PMID- 25501068 TI - Preoperative evaluation of collateral venous anastomoses in meningioma involving cerebral venous sinus by susceptibility weighted imaging. AB - Precise preoperative identification of the collateral venous anastomoses is critical for proper surgical management of patients with meningioma involving sinus. This study was to assess the feasibility of susceptibility weighted imaging (SWI) to delineate the collateral venous anastomoses before surgery. Twenty-five patients with meningiomas that were involved in sinuses underwent surgery and the collateral anastomoses were evaluated with SWI and phase-contrast magnetic resonance venography (MRV) before surgery. The results obtained with SWI were compared with those obtained with MRV. Intraoperative findings were used as the gold standard. By surgery, a total of 98 collateral anastomotic veins were identified in the 25 patients. SWI depicted 85 collateral anastomotic veins close to the meningioma with a sensitivity of 87%, whereas MRV showed 57 collateral anastomotic veins with a sensitivity of 58%. The detectability of collateral anastomotic veins in SWI images was superior to MRV. The results suggest that SWI is superior to MRV and could provide more reliable information on the collateral venous anastomoses in patients with meningioma. PMID- 25501069 TI - Could early rheumatoid arthritis resolve after periodontitis treatment only?: case report and review of the literature. AB - Rheumatoid arthritis (RA) is an immune-mediated polyarthritis; currently no pathogenic agent has been identified as a disease trigger. A patient with RA, presumably caused by periodontal infection, whose remission has been observed after periodontitis treatment in absence of specific RA therapy, is reported here for the first time, to our knowledge. A 61-year-old male patient presented migrant arthritis associated with antibodies against citrullinated protein antigens positivity. The clinical features allowed to make RA diagnosis according to the 2010 European League against Rheumatism/American College of Rheumatology RA classification criteria. X-ray of the second upper molar showed chronic apical periodontitis. After its treatment, arthritis remission has been observed in the absence of specific RA therapy. It has been suggested that periodontitis may have a trigger role in RA pathogenesis. This could be explained by the enzymatic action of Porphyromonas gingivalis, probably leading to break tolerance to collagen. The identification and subsequent treatment of periodontitis should therefore be considered pivotal in RA prophylaxis and management. PMID- 25501071 TI - Diagnosis of neonatal transient tachypnea and its differentiation from respiratory distress syndrome using lung ultrasound. AB - Transient tachypnea of the newborn (TTN) is one of the most common causes of perinatal dyspnea and is traditionally diagnosed by chest x-ray. This study aimed to explore the diagnostic value of lung ultrasonography (LUS) for TTN as well as differentiate it from respiratory distress syndrome (RDS) by using LUS. From January 2013 to February 2014, 60 infants who were diagnosed with TTN based on medical history, clinical manifestations, arterial blood gas analysis, and chest radiography were recruited to the study group. During the same period, 40 hospitalized neonates with nonlung diseases and 20 patients with RDS were recruited to the control group. In a quiet state, infants were placed in the supine, lateral, or prone position for the examination. Each lung of every infant was divided into 3 regions: the anterior, lateral, and posterior regions as bordered by the anterior axillary and posterior axillary lines. The probe was placed perpendicular to the ribs. Each region of both the lungs was carefully scanned.The common ultrasonographic manifestations of TTN were double-lung point (DLP), interstitial syndromes or white lungs, pleural line abnormalities, and A line disappearance. A small number of infants (20%) with TTN exhibited pleural effusions, whereas the main ultrasonographic manifestation of RDS was lung consolidation with air bronchograms, which does not occur in TTN. The sensitivity and specificity of DLP for the diagnosis of TTN were 76.7% and 100%, respectively. LUS can accurately and reliably diagnose TTN. The DLP and lung consolidation possess great value in the diagnosis and differential diagnosis of TTN with RDS. Thus, we believe that LUS can be widely used in neonatal intensive care units. PMID- 25501070 TI - Saturated salt solution method: a useful cadaver embalming for surgical skills training. AB - This article evaluates the suitability of cadavers embalmed by the saturated salt solution (SSS) method for surgical skills training (SST). SST courses using cadavers have been performed to advance a surgeon's techniques without any risk to patients. One important factor for improving SST is the suitability of specimens, which depends on the embalming method. In addition, the infectious risk and cost involved in using cadavers are problems that need to be solved. Six cadavers were embalmed by 3 methods: formalin solution, Thiel solution (TS), and SSS methods. Bacterial and fungal culture tests and measurement of ranges of motion were conducted for each cadaver. Fourteen surgeons evaluated the 3 embalming methods and 9 SST instructors (7 trauma surgeons and 2 orthopedists) operated the cadavers by 21 procedures. In addition, ultrasonography, central venous catheterization, and incision with cauterization followed by autosuture stapling were performed in some cadavers. The SSS method had a sufficient antibiotic effect and produced cadavers with flexible joints and a high tissue quality suitable for SST. The surgeons evaluated the cadavers embalmed by the SSS method to be highly equal to those embalmed by the TS method. Ultrasound images were clear in the cadavers embalmed by both the methods. Central venous catheterization could be performed in a cadaver embalmed by the SSS method and then be affirmed by x-ray. Lungs and intestines could be incised with cauterization and autosuture stapling in the cadavers embalmed by TS and SSS methods. Cadavers embalmed by the SSS method are sufficiently useful for SST. This method is simple, carries a low infectious risk, and is relatively of low cost, enabling a wider use of cadavers for SST. PMID- 25501072 TI - Neoadjuvant FOLFIRINOX application in borderline resectable pancreatic adenocarcinoma: a retrospective cohort study. AB - 5-Fluorouracile, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) has not been extensively used in the neoadjuvant setting because of concerns with safety and toxicity. We evaluated our institutional experience with neoadjuvant FOLFIRINOX in borderline resectable pancreatic adenocarcinoma (BRPAC). The primary endpoints were completion of therapy to surgery and negative resection margin (R0) rate. Patients with BRPAC treated with neoadjuvant FOLFIRINOX were retrospectively analyzed. Between August 2011 and September 2013, 20 patients with BRPAC treated with neoadjuvant FOLFIRINOX were identified. Most patients (88.8%) completed FOLFIRINOX therapy and underwent resection. Abutment of venous structures was identified in 13 cases (72.2%), while short segment portal vein encasement in 3 cases (16.6%) with concomitant arterial involvement in 3 cases (16.6%). Isolated superior mesenteric artery abutment was identified in 2 cases (11.2%). Patients received a median of 4 cycles of FOLFIRINOX. There was 1 case of progression. Vascular resection was performed in 9 cases (52.9%). Preoperative radiation therapy was used in 8 patients (44%). All patients underwent margin negative resection (R0). Histopathologic treatment response was evident in 10 cases (58.8%). Neoadjuvant FOLFIRINOX was generally safe and the expected toxicity did not prevent surgery allowing for a high rate of R0 resection. PMID- 25501073 TI - No direct association between asthma and the microbiome based on currently available techniques. AB - Current uses of culture-independent tools in previous studies have shown a significant relationship between microbiota and asthma. Although these studies are relatively new, there is also evidence of the possibility of new therapeutic strategies for the treatment or prevention of asthma. This article retrospectively examines the possible association between microorganisms and asthma. Data on all patients with different types of asthma were collected from hospital charts from the Department of Internal Medicine, Saarland University Medical Center, Germany, within the study period of 2011 to 2012. The tracheal secretions of asthmatics obtained by bronchoalveolar lavage, bronchial aspirates through flexible bronchoscopy, and directly in sputum were examined microbiologically for microorganisms. Thirty-one (10.47%, 95% CI, 6.98-13.96) of a total of 296 patients were found to have asthma microorganisms in their airways. We could not establish a causal relationship between microorganisms and asthma based on the results of our study (P = 0.893). Additionally, acute respiratory infections did not affect the microbiological colonization in asthmatics' airways (P = 0.472). We were unable to find a direct association between asthma and the microbiome based on existing diagnostic techniques. PMID- 25501074 TI - Effect of blinding with a new pragmatic placebo needle: a randomized controlled crossover study. AB - Placebo control is a useful method for determining the efficacy of a therapy. In acupuncture researches, the preferred method for placebo control is acupuncture using a placebo needle that has a blunt tip and achieves no skin penetration. We performed a crossover study to validate the blinding effect of a new type of placebo needle. Sixty volunteers were randomized to receive acupuncture using 2 types of needles with different sequences: sequence AB, involving first the pragmatic placebo needle and then the real needle, and sequence BA, in a reverse order. Placebo acupuncture was performed by administering the placebo needle through an adhesive pad without skin penetration on the acupoints LI4, RN12, BL25, and BL36. Real acupuncture was performed by needling through the pad and penetrating the skin to 15 mm using a real needle on the same acupoints. The acupuncture was administered every other day with 3 sessions for 1 type of needle. The primary outcome was the perception of needle penetration. Besides degree of acupuncture pain, type, and degree of needle sensation, needle acceptability and factors influencing the subject blinding effect were assessed. Needle penetration was felt by 100%, 90% (54/60), 88.3% (53/60), and 95% (57/60) of volunteers receiving placebo acupuncture and 98.3% (59/60), 96.7% (58/60), 95% (57/60), and 95% (57/60) of volunteers receiving real acupuncture on LI4, RN12, BL25, and BL36, respectively. Differences of the volunteers' perception of needle penetration between the placebo needle and real needle were not significant for the 4 acupoints (all P > 0.05). Volunteers experienced fewer distension sensations (P = 0.01), a lower degree of needle sensation (P = 0.007), and less pain (P = 0.006) during placebo acupuncture than during real acupuncture. The placebo needle was more easily accepted than the real needle (OR = 1.63, 95% CI, 1.01-2.64). The influences of age, sex, educational level, acupuncture experience, needle sensation, acupuncture pain, and needle acceptability on volunteers' perception of needle penetration were not significant. The pragmatic placebo needle is a valid control for acupuncture research. It produces a good subject blinding effect with a similar appearance to conventional acupuncture needles and no skin penetration when applied. PMID- 25501075 TI - Adult perithyroid and cervical thymus-parathyroid unit: case reports of a rare entity. AB - The thymus-parathyroid unit (TPU) occurring in adults is rare.The main symptoms and important clinical findings are as follows: 2 patients presented with neomercazole-resistant Basedow-Graves disease. A third patient presented with thyroid nodules and a fourth patient with a neck mass after thyroid resection for medullary thyroid carcinoma.The main diagnoses were those of thyroid nodules (either in the context of goiter, or not). In the fourth case the diagnosis was of thyroid medullary carcinoma recurrence in the neck. Thyroidectomy was performed in the 2 cases of Basedow-Graves disease and in the third case (wherein selective neck dissection was also performed). In the fourth case, a neck dissection was performed for a possible medullary carcinoma recurrence. A TPU was microscopically detected in 2 cases with perithyroid location, on thyroidectomies for Basedow-Graves disease and in the 2 other cases with neck soft tissue location (associated with thyroid papillary carcinoma and thyroid medullary carcinoma extension). Postsurgical hypocalcemia requiring treatment occurred in both patients with Basedow-Graves disease and in the fourth patient. The presence of TPU should be acknowledged because such lesions can be misdiagnosed as suspect lymph nodes during thyroid surgery for malignant tumors. PMID- 25501076 TI - Long-term survival in patients with T2 hepatocellular carcinoma after primary curative resection can be further stratified by tumor size. AB - Insufficient data are available regarding the validation of long-term survival in patients with T2 (solitary tumor with microvascular invasion [MVI] or multiple tumors, none >5 cm) hepatocellular carcinoma (HCC) after primary hepatectomy. We aim to evaluate the survival and relevant risk factors for T2 HCC patients. Between 2001 and 2007, 312 T2 HCC patients who underwent primary hepatectomy were included. Survival was estimated using the Kaplan-Meier method and compared using Cox proportional hazard model with adjusted independent prognostic factors. The 1, 3, and 5-year overall survival rates of patients with MVI were 85.7%, 68.7%, and 64.8%, respectively; these were inferior to the rates in patients without MVI, which were 93.0%, 89.3%, and 73.7%, respectively (P = 0.037). Within the with-MVI group, the survival rate of patients with tumor sizes >= 5 cm was inferior to that of patients with tumors <5 cm (overall, P = 0.01; recurrence free, P < 0.0001). For patients with the largest tumors in the <5-cm group, those without MVI tended to have a higher probability of recurrence for 2 years after resection (P = 0.088) but a similar overall survival rate relative to those with MVI (P = 0.31). The crude metastasis-free survival was higher in the without-MVI group than in the with-MVI group (P = 0.012). The T2 HCC category comprised heterogeneous patients with differences in survival rates. Extrahepatic recurrence occurred more frequently in patients with MVI than in those without MVI. These results provide evidence for an updated definition of T2 HCC. PMID- 25501077 TI - Management of complicated aortic aneurysms using multiple overlapping uncovered stents: mid-term outcome from a cohort study. AB - This study sought to report the mid-term outcome of a modified flow-diverting strategy in the treatment of complicated aortic aneurysms of different morphology. Historical data suggested aortic aneurysm expansion and rupture after endovascular treatment with current commercial flow-diverters, indicating the essentiality of further investigation of this technique prior to its large-scale clinical application. An alternative flow-diverting strategy using layer-by-layer assembled multiple overlapping uncovered stents was employed in this study. The treatment outcome in aneurysms of different morphology (saccular, fusiform, and dissecting) was assessed during a mid-term follow-up period.Of 42 patients enrolled in this study (30 male, mean age: 63.3 years), technical success was achieved in 40 cases. During an average follow-up period of 20.9 months, mean aneurysm diameter shrunk from 53.4 +/- 13.6 mm to 48.8 +/- 13.9 mm (P < 0.001), while stent-induced sac thrombosis ratio increased significantly (18.1 +/- 14.9% to 93.6 +/- 9.5%, P < 0.001). The majority of side branches (74/76 major visceral branches, 237/244 minor segmental arteries), covered by 3.3 stents on average, maintained their patency after stenting. Saccular aneurysms manifested the highest thrombus deposition speed (18/20 were totally thrombosed within 12 months) and most significant shrinkage (51.4 +/- 13.3 mm pre-operatively vs 43.5 +/- 10.2 mm during follow-up, P < 0.001) compared with fusiform and dissecting aneurysms. This modified flow-diverting strategy could be a feasible alternative in the management of complicated aortic aneurysms where vital branches need to be preserved. The treatment outcome may depend on the aneurysm type. Further studies with larger patient cohort and longer follow-up are required to substantiate these results. PMID- 25501078 TI - The incidence rate, high-risk factors, and short- and long-term adverse outcomes of fetal growth restriction: a report from Mainland China. AB - To investigate the incidence and high-risk factors of fetal growth restriction (FGR) in Mainland China and determine the adverse effects of this condition on fetal-neonatal health. This study was a retrospective chart review. We investigated the incidence rate of FGR using a retrospective analysis of clinical data obtained from mothers and newborns from 7 hospitals in Mainland China from January 1 to December 31, 2011. The short-term outcomes of FGR were analyzed based on data obtained from the neonatal intensive-care unit (NICU) of Bayi Children's Hospital. The long-term outcomes of FGR were determined after a follow up study of 125 cases of FGR in children at 18 months. The physical development index, mental development index (MDI), and psychomotor development index (PDI) were compared between FGR patients and controls. The incidence of FGR was 8.77%. The incidence of FGR was significantly higher in females than in males (9.80% vs 7.84%, P < 0.05). The incidence of FGR in preterm infants was higher than that in full-term infants (16.43% vs 7.87%, P < 0.01). Chronic hypertension, abnormal amniotic fluid, and umbilical cord abnormalities were independent factors of FGR. A significantly higher incidence of complications, including hypoglycemia, asphyxia, hypoxic-ischemic encephalopathy, gastrointestinal bleeding, congenital malformations, polycythemia, lung hemorrhage, apnea, congenital heart disease, and disseminated intravascular coagulation, was observed in FGR patients than in controls. The FGR prolonged the duration of the hospital stay and markedly increased hospitalization expenses (P < 0.05). Children with FGR showed catch-up growth, which reached the level of the control group after 1.5 years, but these individuals still had lower MDI and PDI scores. The incidence rate of FGR in Mainland China was 8.77%. It has a significantly adverse effect on fetal-neonatal health and cognitive development. PMID- 25501079 TI - Metabolic syndrome does not improve the prediction of 5-year cardiovascular disease and total mortality over standard risk markers. Prospective population based study. AB - Metabolic syndrome (MS) is widely believed to be an important risk factor for cardiovascular disease (CVD). We assessed whether a model based on MS improved prediction of CVD and total mortality over the Framingham's general CVD system (FRS) and whether MS was better than its individual components. Prospective cohort study of 855 participants randomly selected from the general population. Cox proportional hazards models were used to estimate the hazard ratios selecting a composite endpoint of CVD and total mortality. The performance of the FRS was compared with that of 4 MS-based models that differed in their use of individual components of MS as well as in the use of optimized cut-points of MS. The assessment included metrics of discrimination, calibration, and risk reclassification. Of all the models, only the model containing the 5 optimized components of MS improved model fit (deviance 10.7, P = 0.005), discrimination (difference of areas under the receiving operating curves 0.018), and risk reclassification in participants without events (net reclassification index 5.97, P = 0.01). The addition of optimized waist circumference to the FRS model improved the performance more than any other MS-based model. Every model containing the dichotomous definition of MS failed to improve model fit, discrimination, and risk reclassification. MS did not contribute predictive information over the FRS for the 5-year risk of CVD and total mortality. Some individual components of MS, in particular waist circumference, might play a role as part of the FRS provided their cut-off points are optimized. PMID- 25501080 TI - Risk factors influencing complications of cardiac implantable electronic device implantation: infection, pneumothorax and heart perforation: a nationwide population-based cohort study. AB - As the number of cardiac implantable electronic devices (CIEDs) is increasing annually, CIED-related complications are becoming increasingly important. The aim of the study was to assess the risks associated with CIEDs by a nationwide database. Patients were selected from the Taiwan National Health Insurance Database. Admissions for CIED implantation, replacement, and revision were evaluated and the evaluation period was 14 years. Endpoints included CIED-related infection, pneumothorax, and heart perforation. The study included 40,608 patients with a mean age of 71.8 +/- 13.3 years. Regarding infection, the incidence rate was 2.45 per 1000 CIED-years. Male gender, younger age, device replacement, and previous infection were risks for infection while old age and high-volume centers (>200 per year) were protectors. The incidence of pneumothorax was 0.6%, with an increased risk in individuals who had chronic obstructive lung disease (COPD) and cardiac resynchronized therapy (CRT). The incidence of heart perforation was 0.09%, with an increased risk in individuals who had pre-operation temporal pacing and steroid use. High-volume center was found to decrease infection rate while male gender, young people, and individuals who underwent replacements were associated with an increased risk of infection. Additionally, pre-operation temporal pacing and steroid use should be avoided if possible. Furthermore, COPD patients or those who accept CRTs should be monitored closely. PMID- 25501082 TI - Risk factors for lymphatic metastasis of malignant bone and soft-tissue tumors: a retrospective cohort study of 242 patients. AB - Metastasis to the lymph nodes is relatively rare in malignant bone and soft tissue tumors, and its risk factors remains unknown, except for tumors of the lymphogenous histotype, including rhabdomyosarcoma, epithelioid sarcoma, and clear cell sarcoma. The purpose of this study was to identify the risk factors for lymph node metastasis of malignant bone and soft-tissue tumors. We retrospectively reviewed 242 patients with malignant bone and soft-tissue tumors. The predictors of interest for the risk of lymph node metastasis included age, sex, histopathological diagnosis, location(s) of the primary tumor(s), local recurrence, residual tumor(s), and the size of the primary tumors. To identify the risk factors for lymph node metastasis, Cox regression analyses were performed. Among the 242 patients with malignant bone and soft-tissue tumors in the current study, 60, 29, and 28 were detected to have lung, lymph node, and bone metastases, respectively. In the univariate analyses, the lymphogenous histotype and a primary tumor invading the subcutis were the risk factors for lymph node metastasis. In the multivariate analysis, the lymphogenous histotype (P < 0.01) and a primary tumor in the subcutis (P < 0.01) remained significantly associated with a higher risk of lymph node metastasis with 5.15 and 3.48 of hazard ratios, respectively. Lymph node metastasis was detected in malignant bone and soft-tissue tumors more frequently than that has been previously reported, and the risk factors for lymph node metastasis were the lymphogenous histotype and primary tumors invading the subcutis. PMID- 25501081 TI - Effects of statin therapy on cardiac sympathetic nerve activity and left ventricular remodeling in patients with chronic heart failure: a propensity score matched analysis. AB - Statin therapy reduces enhanced cardiac sympathetic nerve activity (CSNA) in patients with heart disease, and prevents left ventricular (LV) remodeling in chronic heart failure (CHF) patients. We sought to evaluate the effects of statin therapy on CSNA, as evaluated by I-metaiodobenzylguanidine (MIBG) scintigraphy, and LV remodeling in CHF patients. This study was sub-analysis of our previous report of the result that the serial I-MIBG studies were the most useful prognostic indicator in CHF patients. Patients with CHF (n = 208; left ventricular ejection fraction <45%) but no cardiac events for at least 5 months before the study, were identified according to their history of decompensated acute heart failure requiring hospitalization. The patients underwent I-MIBG scintigraphy and echocardiography immediately before hospital discharge and after 6 months. The delayed % denervation, delayed heart/mediastinum count (H/M) ratio, and washout rate (WR) were determined by I-MIBG scintigraphy. The LV end diastolic volume (EDV) and end-systolic volume (ESV) were also determined by echocardiography. We selected 164 patients and used propensity score matching to compare patients who received oral statin (n = 82), and those who did not (n = 82).The changes in I-MIBG scintigraphic parameters improved, and in echocardiographic LVEDV and LVESV reduced in the statin group compared with those in the non-statin group. Moreover, there were significant correlations between changes in the I-MIBG scintigraphic findings and those in the LVEDV (% denervation, r = 0.534, P < 0.001; H/M ratio, r = -0.516, P < 0.001; and WR, r = 0.558, P < 0.001); or the LVESV (% denervation, r = 0.479, P < 0.001; H/M ratio, r = -0.450, P < 0.001; and WR, r = 0.520, P < 0.001) in the statin group. In contrast, there was no relationship between these parameters in the non-statin group.Statin therapy not only improved CSNA, but also reduced LV volume, in other wards, prevented LV remodeling in CHF patients. PMID- 25501083 TI - Default mode network functional connectivity: a promising biomarker for diagnosing minimal hepatic encephalopathy: CONSORT-compliant article. AB - To investigate the contribution of brain default mode network (DMN) in the early diagnosis of the minimal hepatic encephalopathy (MHE), the mildest form of HE from cirrhotic patients by using resting-state functional magnetic resonance imaging (rs-fMRI). This study was approved by the local ethical committee, and a written informed consent was obtained from each participant. A total of 103 cirrhotic patients (34 MHE, 69 non-HE) and 103 matched healthy controls underwent rs-fMRI scanning. The DMN correlation map was acquired by using unbiased seed based functional connectivity analysis and compared among MHE patients, non-HE patients, and healthy controls with analysis of variance tests. Pearson correlation analysis was performed between the abnormal DMN connectivity and neuropsychological performances. Receiver operator characteristic (ROC) analysis was used to evaluate the contribution of DMN connectivity strength in the differential diagnosis between MHE and non-HE. Compared with the healthy controls, MHE and non-HE patients showed decreased DMN connectivity in medial prefrontal cortex (MPFC), left superior frontal gyrus (SFG), left temporal lobe, and bilateral middle temporal gyri (MTG). The MHE patients showed even more decreased connectivity in MPFC, left SFG, and right MTG when compared with non-HE patients. Pearson correlation analyses revealed that the decreased connectivity strength of some DMN regions correlated with patients' neuropsychological tests scores. Connectivity strength of the MPFC, right MTG, and left SFG could differentiate MHE from non-HE, of which the MPFC had the highest effectiveness (sensitivity = 81.5%, specificity = 70.4%). Cirrhotic patients had gradually reduced DMN functional connectivity from non-HE patients to MHE patients. DMN function, especially the MPFC, might be a useful imaging marker for differentiating MHE from cirrhotic patients. PMID- 25501084 TI - Diagnostic accuracy of Parkinson disease by support vector machine (SVM) analysis of 123I-FP-CIT brain SPECT data: implications of putaminal findings and age. AB - Brain single-photon-emission-computerized tomography (SPECT) with I-ioflupane (I FP-CIT) is useful to diagnose Parkinson disease (PD). To investigate the diagnostic performance of I-FP-CIT brain SPECT with semiquantitative analysis by Basal Ganglia V2 software (BasGan), we evaluated semiquantitative data of patients with suspect of PD by a support vector machine classifier (SVM), a powerful supervised classification algorithm.I-FP-CIT SPECT with BasGan analysis was performed in 90 patients with suspect of PD showing mild symptoms (bradykinesia-rigidity and mild tremor). PD was confirmed in 56 patients, 34 resulted non-PD (essential tremor and drug-induced Parkinsonism). A clinical follow-up of at least 6 months confirmed diagnosis. To investigate BasGan diagnostic performance we trained SVM classification models featuring different descriptors using both a "leave-one-out" and a "five-fold" method. In the first study we used as class descriptors the semiquantitative radiopharmaceutical uptake values in the left (L) and right (R) putamen (P) and in the L and R caudate nucleus (C) for a total of 4 descriptors (CL, CR, PL, PR). In the second study each patient was described only by CL and CR, while in the third by PL and PR descriptors. Age was added as a further descriptor to evaluate its influence in the classification performance.I-FP-CIT SPECT with BasGan analysis reached a classification performance higher than 73.9% in all the models. Considering the "Leave-one-out" method, PL and PR were better predictors (accuracy of 91% for all patients) than CL and CR descriptors; using PL, PR, CL, and CR diagnostic accuracy was similar to that of PL and PR descriptors in the different groups. Adding age as a further descriptor accuracy improved in all the models. The best results were obtained by using all the 5 descriptors both in PD and non-PD subjects (CR and CL + PR and PL + age = 96.4% and 94.1%, respectively). Similar results were observed for the "five-fold" method. I-FP-CIT SPECT with BasGan analysis using SVM classifier was able to diagnose PD. Putamen was the most discriminative descriptor for PD and the patient age influenced the classification accuracy. PMID- 25501085 TI - Prolonged B cell depletion with rituximab is effective in treating refractory pulmonary granulomatous inflammation in granulomatosis with polyangiitis (GPA). AB - Pulmonary nodule formation is a frequent feature of granulomatosis with polyangiitis (GPA). Traditional induction therapy includes methotrexate or cyclophosphamide, however, pulmonary nodules generally respond slower than vasculitic components of disease. Efficacy of rituximab (RTX) solely for the treatment of pulmonary nodules has not been assessed. In this observational cohort study, we report patient outcomes with RTX in GPA patients with pulmonary nodules who failed to achieve remission following conventional immunosuppression. Patients (n = 5) with persistent pulmonary nodules were identified from our clinic database and retrospectively evaluated. Systemic manifestations, inflammatory markers, disease activity, concurrent immunosuppression, and absolute B cell numbers were recorded pre-RTX and at 6 monthly intervals following treatment. Chest radiographs at each time point were scored by an experienced radiologist, blinded to clinical details. Five patients with GPA and PR3-ANCA were evaluated (2 male, 3 female), mean age 34 (22-52) years. Pulmonary nodules (median 4, range 2-6), with or without cavitation were present in all patients. RTX induced initial B cell depletion (<5 cells/MUL) in all patients but re-population was observed in 3 patients. Repeated RTX treatment in these 3 and persistent B cell depletion in the whole cohort was associated with further significant radiological improvement. Radiographic scoring at each time interval showed reduction in both number of nodules (P = <0.0001) and largest nodule diameter (P = <0.0001) in all patients for at least 18 months following B cell depletion. In summary, RTX therapy induces resolution of pulmonary granulomatous inflammation in GPA following prolonged B cell depletion. PMID- 25501087 TI - Sudden death after endoscopic retrograde cholangiopancreatography (ERCP)--case report and literature review. AB - There are only a few cases found in literature regarding air embolism in endoscopic procedures, especially in connection to endoscopic retrograde cholangiopancreatography (ERCP). We are presenting a case of a 56-year-old female patient who suffered from non-Hodgkin lymphoma located in her right groin. She was also diagnosed with choledocholithiasis and underwent ERCP to remove the gallstones. Immediately after the procedure she went into sudden cardiac arrest and subsequently died, despite all of our efforts. We reviewed literature in order to identify possible causes of death because fatal outcome following an uneventful and successful procedure was not expected. It is important to bear in mind all possible complications of ERCP. Our focus during the literature search was on air embolism. PMID- 25501086 TI - Prevalence of high blood pressure in 122,053 adolescents: a systematic review and meta-regression. AB - Several studies have reported high prevalence of risk factors for cardiovascular disease in adolescents. To perform: i) systematically review the literature on the prevalence of high blood pressure (HBP) in adolescents; ii) analyze the possible methodological factors associated with HBP; and iii) compare the prevalence between developed and developing countries. We revised 10 electronic databases up to August 11, 2013. Only original articles using international diagnosis of HBP were considered. The pooled prevalence's of HBP were estimated by random effects. Meta-regression analysis was used to identify the sources of heterogeneity across studies. Fifty-five studies met the inclusion criteria and total of 122,053 adolescents included. The pooled-prevalence of HBP was 11.2%, 13% for boys, and 9.6% for girls (P < 0.01). Method of measurement of BP and year in which the survey was conducted were associated with heterogeneity in the estimates of HBP among boys. The data indicate that HBP is higher among boys than girls, and that the method of measurement plays an important role in the overall heterogeneity of HBP value distributions, particularly in boys. PMID- 25501088 TI - Failure of early diagnosis of infective endocarditis in Japan--a retrospective descriptive analysis. AB - Infective endocarditis (IE) is a severe disease with high morbidity and mortality, and these can be exacerbated by delay in diagnosis. We investigated IE diagnosis in Japan with the emphasis on the delay in diagnosis and its cause and implications. We conducted a retrospective study on 82 definite IE patients at Kobe University Hospital from April 1, 2008, through March 31, 2013. We reviewed charts of the patients for data such as causative pathogens, prescription of inappropriate antibiotic use prior to the diagnosis, existence of risk factors of IE, previous doctor's subspecialty, or duration until the diagnosis, with the primary outcome of 180-day mortality. We also qualitatively, as well as quantitatively, analyzed those cases with delay in diagnosis, and hypothesized its causes and implications. Eighty-two patients were reviewed for this analysis. The average age was 61 +/- 14.5-year-old. Fifty percent of patients had known underlying risk factors for IEs, such as prosthetic heart valve (10), valvular heart disease (21), congenital heart disease (3), or cardiomyopathy (2). The median days until the diagnosis was 14 days (range 2 days to 1 year). Sixty-five percent of patients received inappropriate antibiotic before the diagnosis (53). Forty percent of causative organisms were Staphylococcus aureus (MSSA 20, MRSA 13), 32% were viridans streptococci and Streptococcus bovis, 28% were others or unknown (CNS 5, Corynebacterium 3, Cardiobacterium 1, Candida 1). Subspecialties such as General Internal Medicine (15), and Orthopedics (13) were associated with delay in diagnosis. Ten patients (12%) died during follow up, and 8 of them had been received prior inappropriate antibiotics. Significant delay in the diagnosis of IE was observed in Japan. Inappropriate antibiotics were prescribed frequently and may be associated with poor prognosis. Further improvement for earlier diagnosis of IE is needed. PMID- 25501089 TI - Twenty-four-hour intraocular pressure related changes following adjuvant selective laser trabeculoplasty for normal tension glaucoma. AB - To investigate intraocular pressure (IOP) related patterns before and after selective laser trabeculoplasty (SLT) for normal tension glaucoma (NTG).In this prospective cohort study, 18 NTG patients underwent SLT. Success was defined as IOP reduction >= 20% by Goldmann applanation tonometry. 24-hour IOP-related pattern recording with a contact lens sensor (CLS) (SENSIMED Triggerfish, Sensimed, Switzerland) was done before (baseline) and 1 month after SLT. A cosine function was fitted to the mean CLS patterns for each individual in the SLT success and non-success groups and the amplitude before and after SLT was calculated. Diurnal, nocturnal, and 24-hour CLS pattern local variability was determined for pre- and post-SLT sessions. Cosine amplitude and variability were compared before and after SLT by group using paired t-tests, with alpha = 0.05. Patients (11 women, 7 men) had a mean age of 65.1 +/- 13.7 years. Mean IOP was 15.3 +/- 2.2 mm Hg at baseline and was reduced by 17.0% to 12.7 +/- 1.8 mm Hg 1 month after SLT (P = 0.001). SLT was successful in 8 patients (44%). The amplitude of the fitted cosine was reduced by 24.6% in the success group, but displayed an amplitude increase of 19.2% post-SLT in the non-success group. Higher diurnal local variability of the CLS pattern was observed after SLT in non success subjects (P = 0.002), while nocturnal variability showed no significant change. The increase in diurnal variability in the non-success group led to an increase in 24-hour variability in this group (P = 0.001). No change in local variability (diurnal, nocturnal, and 24-hour) was seen in the success group. The IOP-related pattern cosinor amplitude was reduced in NTG patients with a successful SLT treatment whereas the non-success group exhibited an increase of cosine amplitude. Higher diurnal and 24-hour CLS pattern variability was observed in non-success patients 1 month post-SLT. PMID- 25501090 TI - Sex estimation from sternal measurements using multidetector computed tomography. AB - We aimed to show the utility and reliability of sternal morphometric analysis for sex estimation.Sex estimation is a very important step in forensic identification. Skeletal surveys are main methods for sex estimation studies. Morphometric analysis of sternum may provide high accuracy rated data in sex discrimination. In this study, morphometric analysis of sternum was evaluated in 1 mm chest computed tomography scans for sex estimation. Four hundred forty 3 subjects (202 female, 241 male, mean age: 44 +/- 8.1 [distribution: 30-60 year old]) were included the study. Manubrium length (ML), mesosternum length (2L), Sternebra 1 (S1W), and Sternebra 3 (S3W) width were measured and also sternal index (SI) was calculated. Differences between genders were evaluated by student t-test. Predictive factors of sex were determined by discrimination analysis and receiver operating characteristic (ROC) analysis. Male sternal measurement values are significantly higher than females (P < 0.001) while SI is significantly low in males (P < 0.001). In discrimination analysis, MSL has high accuracy rate with 80.2% in females and 80.9% in males. MSL also has the best sensitivity (75.9%) and specificity (87.6%) values. Accuracy rates were above 80% in 3 stepwise discrimination analysis for both sexes. Stepwise 1 (ML, MSL, S1W, S3W) has the highest accuracy rate in stepwise discrimination analysis with 86.1% in females and 83.8% in males. Our study showed that morphometric computed tomography analysis of sternum might provide important information for sex estimation. PMID- 25501092 TI - A "bone marrow score" for predicting hematological disease in immunocompetent patients with fevers of unknown origin. AB - Delayed diagnosis of hematological malignancies in immunocompetent patients with fever of unknown origin (FUO) remains an exhausting challenge for non hematologist physicians. This retrospective cohort study aimed to establish a scoring system, "bone marrow (BM) score", to identify FUO patients who require early bone marrow biopsy (BMB) to diagnose hematological disease. Two cohorts, comprising 85 (training) and 20 (validation) eligible immunocompetent patients, with FUOs diagnosed between January 1, 2006 and July 31, 2013, underwent BMBs and were enrolled in the study. Demographic, laboratory, imaging, diagnostic, and outcome data were collected and retrospectively analyzed. Factors associated with hematological etiologies diagnosed using BMBs in the training cohort were identified and scored according to the relative hazards. These were further validated using the validation cohort. For the training cohort, 29 of 85 (34.1%) patients had hematological etiologies diagnosed using BMB. Seven factors significantly predicted the diagnostic yield of hematological diseases in the BM and were scored, with the 6 points for leucoerythroblastic changes in peripheral blood smears, 5.5 for elevated ferritin level (>1000 ng/mL), 4 for splenomegaly, 2 for thrombocytopenia, 1.5 for each of elevated lactate dehydrogenase levels and anemia, and 1 for neutropenia. When the cut-off value of the scoring system was set to 6, its sensitivity and specificity to diagnose hematological diseases in the BM of immunocompetent FUO patients were 93% and 58%, respectively. For the validation cohort, 7 of 20 (35%) patients had hematological disease, and all had BM scores higher than the cut-off, with the sensitivity and specificity at 100% and 77%, respectively. As immunocompetent FUO patients with hematological disease have poor prognoses, the "BM score" is valuable for non-hematologist physicians to identify immunocompetent FUO patients requiring early BMB. PMID- 25501091 TI - NT-proBNP: is it a more significant risk factor for mortality than troponin T in incident hemodialysis patients? AB - Numerous studies have demonstrated that cardiac biomarkers are significant predictors of cardiovascular (CV) and all-cause mortality in ESRD patients, but most of the studies were retrospective or included small numbers of patients, only prevalent dialysis patients, or measured 1 or 2 biomarkers. This study was to analyze the association between 3 cardiac biomarkers and mortality in incident HD patients. A prospective cohort of 864 incident HD patients was followed for 30 months. Based on the median values of baseline NT-proBNP, cTnT, and hsCRP, the patients were divided into "high" and "low" groups, and CV and all-cause mortality were compared between each group. Additionally, time-dependent ROC curves were constructed, and the NRI and IDI of the models with various biomarkers were calculated. The CV survival rates were significantly lower in the "high" NT-proBNP and cTnT groups compared to the corresponding "low" groups, while there was no significant difference in CV survival rate between the 2 hsCRP groups. However, all-cause mortality rates were significantly higher in all 3 "high" groups compared to each lower group. In multivariate analyses, only Ln NT proBNP was found to be an independent predictor of mortality. Moreover, NT-proBNP was a more prognostic marker for mortality compared to cTnT. In conclusion, NT proBNP is the biomarker that results in the most added prognostic value on top of traditional risk factors for CV and all-cause mortality in incident HD patients. PMID- 25501093 TI - Multiple oncocytic cystadenoma with intraluminal crystalloids in parotid gland: case report. AB - Oncocytic cystadenoma is a benign tumor of salivary glands, histologically characterized by multicystic growth of the oncocytic epithelial lining. Crystals in different shapes and nature associate oncocytic type of salivary gland neoplasms. An 82 year-old woman with right parotideal mass had an operation of superficial parotidectomy. Histological examination revealed multiple unilocular or multilocular cystic lesions with incomplete fibrous capsule, papillary foldings, and 1 or 2 layers of oncocytic epithelium lines. The epithelium lining the cysts were positive for CK8, CK14, CK18, CK19, and negative for SMA, S-100, and p63 immunohistochemically. Cystadenomas were described as mostly multilocular and we presented a multifocal cystic neoplastic lesion lined by oncocytic type epithelial cells with intraluminal crystalloids. Multiple cysts forming morphology, incomplete fibrous capsule of most cysts and immunohistocemical findings were considered as multiple oncocytic cystadenoma with intraluminal crystalloids in the parotid gland. PMID- 25501094 TI - Chromogranin A as a marker for diagnosis, treatment, and survival in patients with gastroenteropancreatic neuroendocrine neoplasm. AB - Chromogranin A (CgA) not only plays an important role in pathologic diagnosis, but is also used as a circulating biomarker in patients with gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN). However, the relationship between immunohistochemistry (IHC) expression and serum levels of CgA has not been investigated. The value of CgA for evaluating treatment response and prognosis is still not well understood. We conducted this study to assess the significance of CgA in GEP-NEN in terms of diagnosis, curative effects evaluation and prognosis. One hundred forty-five patients comprising 88 patients with active disease and 57 disease-free patients were enrolled in this study from January 2011 to November 2013. The expression of CgA was assessed by IHC, and serial serum CgA levels were measured by enzyme linked immunosorbent assay. The overall expression rate of CgA was 69.0% (100/145). CgA expression was associated with tumor site and stage (P < 0.05), but not correlated with prognosis (P = 0.07). Serum CgA levels were significantly higher in GEP-NEN patients with active disease when compared with disease-free patients (P = 0.001) or healthy participants (P < 0.001). A CgA cutoff value of 95 ng/ml discriminated between healthy subjects or disease-free patients and patients with active disease (sensitivity 51.2% and specificity 87.5%, respectively). There was a correlation between the CgA IHC expression and high serum CgA levels (R = 0.320, P = 0.002). Serum CgA levels were much higher in patients who classified as neuroendocrine carcinoma, mixed adenoendocrine carcinoma (P = 0.035) and who were on stage IV (P = 0.041). Changes in CgA levels normalization or >= 30% decrease suggested that patients had tumor response. Furthermore, patients with serum CgA levels higher than 95 ng/ml had a significantly shorter survival compared with patients with levels lower than 95 ng/ml (P < 0.001). CgA is a reliable pathologic and circulating maker for diagnosis of GEP-NEN. We further confirmed that serial measurement of CgA may be useful for evaluating the efficacy of different kinds of therapies in patients during follow-up, and serum CgA level >= 95 ng/ml may serve as a predictor of overall survial. PMID- 25501095 TI - Auditory musical hallucinations associated with extended-release pramipexole in an elderly patient with Parkinson's disease. AB - Auditory musical hallucinations (AMHs) are rare complex auditory hallucinations in Parkinson's disease (PD) that have been limited previously. The characteristics of AMHs in PD remain uncertain. We describe a 72-year-old woman with PD who presented with AMHs. The AMHs occurred after immediate-release pramipexole was switched to extended-release pramipexole. The AMHs were a quiet piano or often songs on a loud radio or background music over other sounds. The music was unpleasant, but not objectionable, threatening, or ego-syntonic, and it did not interrupt her daily activities. AMHs in PD were non-threatening, and dopaminergic treatment may predispose patients to AMHs or be a unique possible cause of AMHs. The hallucinations can occur after immediate-release pramipexole was switched to extended-release pramipexole. PMID- 25501096 TI - CT-base pulmonary artery measurement in the detection of pulmonary hypertension: a meta-analysis and systematic review. AB - To summarize the performance of CT-based main pulmonary artery diameter or pulmonary artery to aorta ratio (PA:A ratio) measurement in detection of pulmonary hypertension by a systematic review and meta-analysis. A comprehensive literature search was performed to identify studies determining diagnostic accuracy of main pulmonary artery diameter or PA:A ratio measurement for pulmonary hypertension. The Quality Assessment of Diagnostic Accuracy Studies tool was used to assess the quality of the included studies. A bivariate random effects model was used to pool sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), and diagnostic odds ratio (DOR). Summary receiver operating characteristic (SROC) curves and area under the curve (AUC) were used to summarize overall diagnostic performance. This meta-analysis included 20 publications involving 2134 subjects. Summary estimates for main pulmonary artery diameter measurement in the diagnosis of pulmonary hypertension were as follows: sensitivity, 0.79 (95% CI 0.72-0.84); specificity, 0.83 (95% CI 0.75-0.89); PLR, 4.68 (95% CI 3.13-6.99); NLR, 0.26 (95% CI 0.20-0.33); DOR, 18.13 (95% CI 10.87 30.24); and AUC 0.87. The corresponding summary performance estimates for using the PA:A ratio were as follows: sensitivity, 0.74 (95% CI 0.66-0.80); specificity, 0.81 (95% CI 0.74-0.86); PLR, 3.83 (95% CI, 2.70-5.43); NLR, 0.33 (95% CI 0.24-0.44); DOR, 11.77 (95% CI 6.60-21.00); and AUC 0.84. Both main pulmonary artery diameter and PA:A ratio are helpful for diagnosing pulmonary hypertension. Nevertheless, the results of pulmonary artery measurement should be interpreted in parallel with the results of traditional tests such as echocardiography. PMID- 25501097 TI - Lymphopenia predicts poor prognosis in patients with esophageal squamous cell carcinoma. AB - Lymphopenia is a useful predictive factor in several cancers. The aim of this study was to determine the prognostic value of lymphopenia in patients with esophageal squamous cell carcinoma (ESCC).A retrospective analysis of 307 consecutive patients who had undergone esophagectomy for ESCC was conducted. In our study, a lymphocyte count (LC) of fewer than 1.0 Giga/L was defined as lymphopenia. Kaplan-Meier method was used to calculate the cancer-specific survival (CSS). Cox regression analyses were performed to evaluate the prognostic factors. Receiver operating characteristic (ROC) curve was also plotted to verify the accuracy of LC for CSS prediction.The mean LC was 1.55 +/- 0.64 Giga/L (range 0.4-3.7 Giga/L). The incidence of lymphopenia (LC < 1.0 Giga/L) was 16.6% (51/307). Patients with lymphopenia (LC < 1.0 Giga/L) had a significantly shorter 5-year CSS (21.6% vs 43.8%, P = 0.004). On multivariate analysis, lymphopenia (LC < 1.0 Giga/L) was an independent prognostic factor in patients with ESCC (P = 0.013). Lymphopenia had a hazard ratio (HR) of 1.579 [95% confidence interval (CI): 1.100-2.265] for CSS. ROC curve demonstrated that lymphopenia (LC < 1.0 Giga/L) predicts survival with a sensitivity of 86.2% and a specificity of 27.2%. Lymphopenia (LC < 1.0 Giga/L) is still an independent predictive factor for long term survival in patients with ESCC. PMID- 25501098 TI - Gonadotropin releasing hormone agonist treatment to increase final stature in children with precocious puberty: a meta-analysis. AB - In the setting of central precocious puberty (CPP), the motivation for hormonal intervention is to help the child to reach a taller adult stature than she would achieve otherwise. While gonadotropin-releasing hormone analogs (GnRHa) constitute an established treatment for improving adult stature in girls presenting with CPP up to age 6 (true precocious puberty), it is not yet clear whether or not the same is true in the setting of CPP presented in girls beyond age 6 (advance puberty). GnRHa may slow growth velocity, offsetting the anticipated improvement in final height that should have resulted from the increased time before growth plate fusion. Consequently, it's been suggested that growth hormone (GH) should be combined with GnRHa to improve the results.Few controlled prospective studies have been performed with GnRHa in children and many conclusions rely in part on collective expert opinion. Therefore, the literature was searched and relevant studies were selected using the search terms "gonadotropin releasing hormone agonist," "precocious puberty/early puberty," and "GnRH analogue." After selected articles were screened for relevance, the process yielded 8 studies, the results of which were then pooled in a meta-analysis aimed at evaluating the effects of GnRHa therapy both with and without added GH in the setting of early puberty. A significant difference was elucidated in final height and predicted adult height comparing GnRHa and combined GnRHa/GH groups. However, no significant difference was elucidated in final height standard deviation scores (SDS) and initial height SDS when comparing GnRHa and control groups. At the same time, the final analysis revealed no significant difference in final height SDS and initial height SDS when GnRHa and combined GnRHa/GH groups were compared.The results suggest GnRHa therapy may have a positive effect on final adult height in girls with early puberty, while adding GH to the treatment may suggest more advantage. Interpretation of the results requires extreme caution, given the complexity of the outcome analysis. Final height gain may prove to be a more appropriate measure of treatment efficacy in any case. PMID- 25501099 TI - Protective association of tumor necrosis factor superfamily 15 (TNFSF15) polymorphic haplotype with Ulcerative Colitis and Crohn's disease in an Indian population. AB - BACKGROUND: Tumor necrosis factor superfamily (TNFSF) proteins are involved in the genesis of inflammatory bowel disease (IBD). We examined the association of seven single nucleotide polymorphisms (SNP) in the TNFSF15 gene with Crohn's disease (CD) and ulcerative colitis (UC) in the Indian population. METHODS: Seven SNPs in the TNFSF15 gene (rs10114470, rs3810936, rs6478108, rs4263839, rs6478109, rs7848647 and rs7869487) were genotyped in 309 CD patients, 330 UC patients and 437 healthy controls using the Sequenom iPLEX MassArray platform. Disease associations were evaluated for allelotypes and for genotypes. RESULTS: The minor T alleles and the TT genotypes of rs10114470 and rs3810936 were significantly protectively associated with both CD and UC. The CC genotype of rs6478108, AA genotype of rs4263839, the AA genotype of rs6478109, the TT genotype of rs7848647 and the CC genotype of rs7869487 were all protectively associated with CD but not with UC. Two haplotype blocks could be discerned, one where SNPs rs10114470 and rs3810936 were in tight LD (D' = 0.8) and the other where rs6478108, rs4263839, rs6478109, rs7848647 and rs7869487 were in tight LD (D' 0.92-1.00). The second block of haplotypes were not associated with CD or with UC. The first block of haplotypes was very significantly associated with both CD and UC. CONCLUSIONS: Strong associations exist between TNFSF15 gene polymorphisms and IBD (both CD and UC) in the Indian population. PMID- 25501100 TI - Effect of autologous bone marrow cell transplantation combined with off-pump coronary artery bypass grafting on cardiac function in patients with chronic myocardial infarction. AB - OBJECTIVES: This study aimed to investigate the feasibility and effects of intramuscular injections of autologous bone marrow cells (BMC) combined with off pump coronary artery bypass grafts (OPCAB) on improving cardiac function in chronic myocardial infarction patients. METHODS: Ninety patients with chronic myocardial infarction were prospectively enrolled and randomized to an OPCAB with saline or an OPCAB with BMC-treatment group. After finishing CABG, patients received injections of BMC or saline into the marginal area of the infarct. The primary endpoint was incidence of emergent adverse events within 6 months. RESULTS: There were no differences between the control and BMC-treated groups in baseline ejection fractions (EF) or wall motion score indices (WMSI) in the affected segments. At the 6-month follow-up, the ejection fraction was significantly increased in the BMC-treated group compared to controls (47.58 +/- 6.34 vs. 40.11 +/- 7.42; p < 0.05), whereas the WMSI were significantly decreased (1.25 +/- 0.32 vs. 1.54 +/- 0.53; p < 0.05), with no occurrences of life threatening arrhythmias or death. The addition of BMC injections to OPCAB treatment increased regional perfusion to the marginal infarct area. CONCLUSION: These results demonstrate that BMC transplant is beneficial to the cardiac function with no adverse effects, and therefore a safe and feasible adjunct therapy providing beneficial effects in clinical practice. PMID- 25501106 TI - H in alpha-Zr and in zirconium hydrides: solubility, effect on dimensional changes, and the role of defects. AB - Structural, thermodynamic and elastic properties of the hydrogen-zirconium system including all major hydrides are studied from first principles. Interstitial hydrogen atoms occupy preferentially tetrahedral sites. The calculations show that a single vacancy in alpha-Zr can trap up to nine hydrogen atoms. Self interstitial Zr atoms attract hydrogen to a lesser extent. Accumulation of hydrogen atoms near self-interstitials may become a nucleation site for hydrides. By including the temperature-dependent terms of the free energy based on ab initio calculations, hydrogen adsorption isotherms are computed and shown to be in good agreement with experimental data. The solubility of hydrogen decreases in Zr under compressive strain. The volume dependence on hydrogen concentration is similar for hydrogen in solution and in hydrides. The bulk modulus increases with hydrogen concentration from 96 to 132 GPa. PMID- 25501107 TI - The association of nm23-H1 expression with a poor prognosis in patients with peripheral T-cell lymphoma, not otherwise specified. AB - nm23-H1 was originally identified as a protein that is expressed at a lower than usual level in metastatic cancer cells. The nm23 genes play critical roles in cellular proliferation, differentiation, oncogenesis, and tumor metastasis. Peripheral T-cell lymphoma (PTCL) is relatively rare, accounting for only 10% to 15% of non-Hodgkin's lymphomas. We examined whether nm23-H1 is a prognostic factor of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). PTCL is more aggressive and has a poorer prognosis than diffuse large B-cell lymphoma. nm23-H1 was positive in 44.1% of PTCL-NOS patients. nm23-H1 expression was not correlated with age, performance status (PS), lactate dehydrogenase (LDH) level, or stage. The nm23-H1-positive group had significantly shorter overall survival (OS). OS was significantly shorter in patients with the following clinicopathologic features: age > 60 years, PS of 2-4, LDH > normal, bone marrow involvement, or nm23-H1-positive lymphoma. The nm23-H1 protein may be an important prognostic factor in PTCL-NOS. Because our results suggest that nm23-HI is produced by lymphoma cells, we expect to see the development of new treatments targeting nm23 overexpression. PMID- 25501108 TI - Primary central nervous system lymphoma in Miyazaki, southwestern Japan, a human T-lymphotropic virus Type-1 (HTLV-1)-endemic area: clinicopathological review of 31 cases. AB - Primary central nervous system lymphoma (PCNSL) is a rare and aggressive brain tumor. The aim of this study was to clarify the prevalence of T-cell-type PCNSL (T-PCNSL) in a human T-lymphotropic virus type-1 (HTLV-1)-endemic area of Southwestern Japan. We retrospectively investigated 31 PCNSL cases diagnosed between 1996 and 2013 at the University of Miyazaki Hospital. These cases accounted for 4.4% of all nodal or extranodal malignant lymphomas. Histologically, most of these cases were diagnosed as diffuse large B-cell lymphoma, while only two cases were considered to be low-grade and high-grade B cell lymphoma (not otherwise specified). No T-PCNSL was found in this series. In addition, Epstein-Barr virus-encoded RNAs were not detected by in situ hybridization in any of the cases. Overall, no T-PCNSL cases were found in 18 years in a region with a high frequency of HTLV-1 seropositivity, namely, Southwestern Japan. This suggests that PCNSL and lymphomas of other anatomical sites are biologically distinct. PMID- 25501109 TI - Clinical features and outcomes of 9 patients with immunodeficiency-associated lymphoproliferative disorders treated at a single institution. AB - Immunodeficiency-associated lymphoproliferative disorders (LPD) represent a rare life-threatening clinical entity characterized by heterogeneous histological findings that range from polymorphic to monomorphic proliferated abnormal lymphocytes. Currently, there is no standard treatment for LPD. To elucidate the clinical features and treatment outcomes of immunodeficiency-associated LPD patients with rheumatoid arthritis (RA), we retrospectively evaluated 9 cases observed over a 5-year period. The diagnoses of these patients included 5 diffuse large B-cell lymphomas, 3 LPD, and 1 mucosa-associated lymphoid tissue lymphoma. At initial diagnosis, 6 patients had advanced-stage RA, and half of these underwent total knee arthroplasty. All patients with RA received methotrexate (MTX) and low-dose prednisolone. Biologics were administered to 4 of 9 patients. After the development of immunodeficiency-associated LPD, MTX discontinuation resulted in 5 complete remissions (CR), 1 partial remission, and 3 cases of stable disease. Relapse was observed in 3 of 5 CR patients in the MTX-withdrawal remission group. Subsequently, conventional chemotherapy, rituximab, and radiation were administered to 4, 3, and 1 patient, respectively. These treatments induced a second CR. In the chemotherapy group, 1 patient developed acute myocardial infarction and another experienced ileus and pulmonary abscess. In the rituximab group, no severe complications were observed. Consequently, all patients remained disease-free during the median 23-month follow-up period. Our results indicate that, depending on the RA disease stage, performance status, and extent of treatment response, less intensive treatments than those commonly indicated for non-Hodgkin lymphoma, involving MTX discontinuation and subsequent therapy containing rituximab, might be an efficient therapeutic strategy for immunodeficiency-associated LPD. PMID- 25501110 TI - Efficacy of molecular response at 1 or 3 months after the initiation of dasatinib treatment can predict an improved response to dasatinib in imatinib-resistant or imatinib-intolerant Japanese patients with chronic myelogenous leukemia during the chronic phase. AB - Dasatinib is a BCR-ABL kinase inhibitor with improved potency compared with imatinib, for which efficacy and safety in imatinib-resistant and imatinib intolerant patients with chronic myelogenous leukemia (CML) have been established. Here, an open-label phase II study evaluated the efficacy and safety of dasatinib in 50 Japanese patients with imatinib-resistant or imatinib intolerant CML during the chronic phase (CML-CP). Dasatinib was effective in imatinib-resistant and imatinib-intolerant patients. After 12 months of dasatinib therapy, 35 patients (70%) had achieved a major molecular response (MMR) and 16 patients (32%) had achieved a complete molecular response (CMR). Among the imatinib-resistant CML-CP cohort, 21 and 8 patients had achieved an MMR and a CMR after 12 months of dasatinib therapy, respectively. Among the imatinib-intolerant CML-CP cohort, 14 and 8 patients had achieved an MMR and a CMR after 12 months of dasatinib therapy, respectively. After 18 months of dasatinib therapy, 38 out of 50 patients (76.0%) had achieved an MMR and 19 patients (38.0%) had achieved a CMR. A lower level of BCR-ABL transcript at 1 or 3 months after the initiation of dasatinib treatment was more strongly correlated with the BCR-ABL transcript level at 12 and 18 months (p < 0.001) than a higher level of BCR-ABL. The T315I mutation was identified in two patients receiving dasatinib therapy. Dasatinib was generally well tolerated, with only 3 patients (5%) having treatment discontinuation as a result of adverse hematologic events (thrombocytopenia, anemia, neutropenia) and/or non-hematologic events at a 12-month follow-up evaluation. Dasatinib was a safe and effective treatment for Japanese patients with imatinib-resistant or imatinib-intolerant CML. In addition, the molecular response at 1 or 3 months predicted a response to dasatinib at 12 or 18 months. PMID- 25501111 TI - Classical Hodgkin lymphoma occurring in association with progressive transformation of germinal center. AB - Progressive transformation of germinal center (PTGC) represents an asymptomatic persistent form of lymphadenopathy. We present a case of classical Hodgkin lymphoma occurring in association with PTGC. The patient was a 60-year-old woman who had noted swelling of the submandibular lymph nodes. Histopathologically, the enlarged lymph nodes appeared as multiple nodules with ill-defined and irregularly expanded germinal centers. Immunohistochemical studies indicated that the germinal center cells comprised B cells that were positive for CD10 and CD20, and negative for bcl-2. Enlarged vascular endothelial cells were present in the interfollicular areas. CD30-positive Hodgkin & Reed-Sternberg cells were seen between the interfollicular area and the mantle zone, and were surrounded by CD3 positive T-cells. In situ hybridization studies demonstrated no expression of Epstein-Barr virus-encoded small RNA in the Hodgkin & Reed-Sternberg cells. A diagnosis of classical Hodgkin lymphoma complicated by PTGC was made from the lymph node specimen. PMID- 25501112 TI - Development of primary central nervous system lymphoma associated with human immunodeficiency virus and JC virus infection. AB - We report here a case of a 37-year-old man with human immunodeficiency virus (HIV) infection followed by JC virus (JCV) infection and primary central nervous system lymphoma (PCNSL). The patient had been infected with HIV type 1 due to blood products for hemophilia A during infancy. He had progression of nervous symptoms and was diagnosed with progressive multifocal leukoencephalopathy (PML) clinically at the age of 36, when his CD4-positive lymphocyte counts ranged between 350 and 450/MUl. Oral mefloquine, intravenous methylprednisolone pulse therapy, and intravenous immunoglobulin were not effective for the PML, and the patient entered a vegetative state. Brain biopsy revealed JCV infection without pathological findings of PML. Eight months after the clinical diagnosis of PML, he developed respiratory failure and brain magnetic resonance imaging revealed a mass lesion in the brain stem. The patient died 19 months after the diagnosis of PML. Autopsy findings were compatible with PCNSL. EBV-encoded small RNA-1 positive cells were not detected. We present a case of JCV-positive PCNSL with HIV infection complicated with clinical PML. PMID- 25501113 TI - B-cell prolymphocytic leukemia carrying t(8;14)(q24;q32), associated with both autoimmune hemolytic anemia and pure red cell aplasia. AB - An 80-year-old man was referred to our department because of lymphocytosis. His white cell count was 17.1 * 10(3)/MUL, with 64% prolymphocytes. He did not exhibit splenomegaly or lymphadenopathy. Prolymphocytes were CD5(+), CD10(-), CD19(+), CD20(+), CD21(+weak), CD22(+), CD23(-), and HLA-DR(+), and expressed MUdelta/lambda cell-surface immunoglobulins. G-banding and fluorescence in situ hybridization using c-MYC and immunoglobulin heavy-chain (IgH) gene probe revealed that leukemia cells carried the t(8;14)(q24;q32)/c-MYC-IgH fusion gene, and breakage and reunion occurred within the non-coding region of c-MYC exon 1 as well as the alpha switch region of IgH. Nine months after the initial presentation, the patient's hemoglobin level fell to 5.7 g/dL. Coombs' test was positive and marked hypoplasia of erythroid precursors was detected in his bone marrow. The patient was treated with prednisolone followed by 4 weekly doses of rituximab, which led to resolution of the anemia and complete response of the underlying leukemia. The role of t(8;14)(q24;q32)/c-MYC-IgH in the pathogenesis of B-cell prolymphocytic leukemia (B-PLL) may not be identical to that in aggressive lymphoid neoplasms, and, in the present case, autoantibodies targeting both mature red cells and erythroid precursors may have been concurrently produced in the setting of B-PLL. PMID- 25501114 TI - Variant translocation partners of the anaplastic lymphoma kinase (ALK) gene in two cases of anaplastic large cell lymphoma, identified by inverse cDNA polymerase chain reaction. AB - In anaplastic large cell lymphoma (ALCL), the anaplastic lymphoma kinase (ALK) gene is rearranged with diverse partners due to variant translocations/inversions. Case 1 was a 39-year-old man who developed multiple tumors in the mediastinum, psoas muscle, lung, and lymph nodes. A biopsy specimen of the inguinal node was effaced by large tumor cells expressing CD30, epithelial membrane antigen, and cytoplasmic ALK, which led to a diagnosis of ALK(+) ALCL. Case 2 was a 51-year-old man who was initially diagnosed with undifferentiated carcinoma. He developed multiple skin tumors eight years after his initial presentation, and was finally diagnosed with ALK(+) ALCL. He died of therapy related acute myeloid leukemia. G-banding and fluorescence in situ hybridization using an ALK break-apart probe revealed the rearrangement of ALK and suggested variant translocation in both cases. We applied an inverse cDNA polymerase chain reaction (PCR) strategy to identify the partner of ALK. Nucleotide sequencing of the PCR products and a database search revealed that the sequences of ATIC in case 1 and TRAF1 in case 2 appeared to follow those of ALK. We subsequently confirmed ATIC-ALK and TRAF1-ALK fusions by reverse transcriptase PCR and nucleotide sequencing. We successfully determined the partner gene of ALK in two cases of ALK(+) ALCL. ATIC is the second most common partner of variant ALK rearrangements, while the TRAF1-ALK fusion gene was first reported in 2013, and this is the second reported case of ALK(+) ALCL carrying TRAF1-ALK. PMID- 25501115 TI - Fatal visceral varicella-zoster developing early after autologous hematopoietic stem cell transplantation for refractory diffuse large B-cell lymphoma. AB - A middle-aged woman who had undergone autologous hematopoietic stem cell transplantation (HSCT) 1 month previously suffered severe epigastralgia and relapse of lymphoma. The epigastralgia was not relieved by chemotherapy. Thereafter, her pancreatic and hepatic enzyme levels were markedly elevated and disseminated varicella emerged. Despite acyclovir administration, her general condition deteriorated rapidly and she died. Serum varicella zoster virus (VZV) DNA level was shown to be elevated and a diagnosis of disseminated VZV infection was established postmortem. In patients with severe abdominal pain following HSCT, early suspicion and therapeutic intervention for VZV are important, even in the absence of skin lesions. PMID- 25501116 TI - Two granulocytic regions in bone marrow with eosinophilia evaluated by flow cytometry. PMID- 25501117 TI - Adiabatic quantum computing with spin qubits hosted by molecules. AB - A molecular spin quantum computer (MSQC) requires electron spin qubits, which pulse-based electron spin/magnetic resonance (ESR/MR) techniques can afford to manipulate for implementing quantum gate operations in open shell molecular entities. Importantly, nuclear spins, which are topologically connected, particularly in organic molecular spin systems, are client qubits, while electron spins play a role of bus qubits. Here, we introduce the implementation for an adiabatic quantum algorithm, suggesting the possible utilization of molecular spins with optimized spin structures for MSQCs. We exemplify the utilization of an adiabatic factorization problem of 21, compared with the corresponding nuclear magnetic resonance (NMR) case. Two molecular spins are selected: one is a molecular spin composed of three exchange-coupled electrons as electron-only qubits and the other an electron-bus qubit with two client nuclear spin qubits. Their electronic spin structures are well characterized in terms of the quantum mechanical behaviour in the spin Hamiltonian. The implementation of adiabatic quantum computing/computation (AQC) has, for the first time, been achieved by establishing ESR/MR pulse sequences for effective spin Hamiltonians in a fully controlled manner of spin manipulation. The conquered pulse sequences have been compared with the NMR experiments and shown much faster CPU times corresponding to the interaction strength between the spins. Significant differences are shown in rotational operations and pulse intervals for ESR/MR operations. As a result, we suggest the advantages and possible utilization of the time-evolution based AQC approach for molecular spin quantum computers and molecular spin quantum simulators underlain by sophisticated ESR/MR pulsed spin technology. PMID- 25501118 TI - Rapid Characterization and Identification of Flavonoids in Radix Astragali by Ultra-High-Pressure Liquid Chromatography Coupled with Linear Ion Trap-Orbitrap Mass Spectrometry. AB - A simple and effective method was established for separation and characterization of flavonoid constituents in Radix Astragali (RA) by combination of ultra-high pressure liquid chromatography with LTQ-Orbitrap tandem mass spectrometry (u-HPLC LTQ-Orbitrap-MS(n)). For three major structural types of flavonoids, the proposed fragmentation pathways and major diagnostic fragment ions of isoflavones, pterocarpans and isoflavans were investigated to trace isoflavonoid derivatives in crude plant extracts. Based on the systematic identification strategy, 48 constituents were rapidly detected and characterized or tentatively identified, many of which were first reported in RA. The u-PHLC-LTQ-Orbitrap MS(n) platform was proved as an effective tool for rapid qualitative analysis of secondary metabolite productions from natural resources. PMID- 25501119 TI - Recovery of Proteins Affected by Mobile Phase Trifluoroacetic Acid Concentration in Reversed-Phase Chromatography. AB - It was found that recoveries of proteins depend on trifluoroacetic acid concentration in the mobile phase and showed maximum in the range of 0.01-0.1 v/v%. Transferrin and lysozyme were used to evaluate the recoveries of proteins from dedicated reversed-phase columns. Different types of reversed-phase columns were evaluated, such as core shell type materials (Aeris Widepore with C4, C8 and C18 modification) as well as fully porous hybrid particles (Waters BEH, modified with C4 and C18 alkyl chains). Recoveries ranged between 60.7-95.2% for transferrin and 72.1-99.8% for lysozyme. Based on the data presented, at least two different adsorption effects, the well-known hydrophobic and silanophilic/polar interaction might influence the recovery. In addition to this, conformational effects due to ion pairing with the acidic mobile phase additive might change them. PMID- 25501124 TI - Dual inhibition of Bcr-Abl and Hsp90 by C086 potently inhibits the proliferation of imatinib-resistant CML cells. AB - PURPOSE: Although tyrosine kinase inhibitors (TKI) such as imatinib provide an effective treatment against Bcr-Abl kinase activity in the mature cells of patients with chronic myelogenous leukemia (CML), TKIs probably cannot eradicate the leukemia stem cell (LSC) population. Therefore, alternative therapies are required to target both mature CML cells with wild-type (WT) or mutant Bcr-Abl and LSCs. To investigate the effect of C086, a derivative of curcumin, on imatinib-resistant cells, we explored its underlying mechanisms of Bcr-Abl kinase and heat shock protein 90 (Hsp90) function inhibition. EXPERIMENTAL DESIGN: Biochemical assays were used to test ABL kinase activity; fluorescence measurements using recombinant NHsp90, Hsp90 ATPase assay, immunoprecipitation, and immunoblotting were applied to examine Hsp90 function. Colony-forming unit, long-term culture-initiating cells (LTC-IC), and flow cytometry were used to test CML progenitor and stem cells. RESULTS: Biochemical assays with purified recombinant Abl kinase confirmed that C086 can directly inhibit the kinase activity of Abl, including WT and the Q252H, Y253F, and T315I mutations. Furthermore, we identified C086 as a novel Hsp90 inhibitor with the capacity to disrupt the Hsp90 chaperone function in CML cells. Consequently, it inhibited the growth of both imatinib-sensitive and -resistant CML cells. Interestingly, C086 has the capacity to inhibit LTC-ICs and to induce apoptosis in both CD34(+)CD38(+) and CD34(+)CD38(-) cells in vitro. Moreover, C086 could decrease the number of CD45(+), CD45(+)CD34(+)CD38(+), and CD45(+)CD34(+)CD38(-) cells in CML NOD-SCID mice. CONCLUSIONS: Dual suppression of Abl kinase activity and Hsp90 chaperone function by C086 provides a new therapeutic strategy for treating Bcr Abl-induced leukemia resistant to TKIs. PMID- 25501125 TI - Molecular pathways: aspirin and Wnt signaling-a molecularly targeted approach to cancer prevention and treatment. AB - The anti-inflammatory properties of aspirin have resulted in its widespread use as an analgesic, antipyretic, and cardioprotective agent. Beyond these applications, multiple observational studies and randomized controlled trials have demonstrated a chemopreventative role for aspirin, particularly in the development of colorectal neoplasia. Given the critical importance of Wnt dysregulation in colorectal carcinogenesis, the interplay between aspirin and canonical Wnt signaling has become a focus of investigation. These studies have illuminated our understanding of the anticancer mechanisms of aspirin, yielding the identification of potential biomarkers for which aspirin's chemopreventative efficacy can be safely optimized into routine clinical practice and providing leads into the discovery of novel preventive and therapeutic targets. In this review, we summarize key experimental and clinical studies of this interaction, as well as highlighting future strategies to advance their clinical translation. PMID- 25501126 TI - CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. AB - PURPOSE: The G1-S checkpoint of the cell cycle is frequently dysregulated in breast cancer. Palbociclib (PD0332991) is an oral inhibitor of CDK4/6. Based upon preclinical/phase I activity, we performed a phase II, single-arm trial of palbociclib in advanced breast cancer. EXPERIMENTAL DESIGN: Eligible patients had histologically confirmed, metastatic breast cancer positive for retinoblastoma (Rb) protein and measureable disease. Palbociclib was given at 125 mg orally on days 1 to 21 of a 28-day cycle. Primary objectives were tumor response and tolerability. Secondary objectives included progression-free survival (PFS) and assessment of Rb expression/localization, KI-67, p16 loss, and CCND1 amplification. RESULTS: Thirty-seven patients were enrolled; 84% hormone-receptor (HR)(+)/Her2(-), 5% HR(+)/Her2(+), and 11% HR(-)/Her2(-), with a median of 2 prior cytotoxic regimens. Two patients had partial response (PR) and 5 had stable disease >= 6 months for a clinical benefit rate (CBR = PR + 6moSD) of 19% overall, 21% in HR(+), and 29% in HR(+)/Her2(-) who had progressed through >=2 prior lines of hormonal therapy. Median PFS overall was 3.7 months [95% confidence interval (CI), 1.9-5.1], but significantly longer for those with HR(+) versus HR(-) disease (P = 0.03) and those who had previously progressed through endocrine therapy for advanced disease (P = 0.02). Grade 3/4 toxicities included neutropenia (51%), anemia (5%), and thrombocytopenia (22%). Twenty-four percent had treatment interruption and 51% had dose reduction, all for cytopenias. No biomarker identified a sensitive tumor population. CONCLUSIONS: Single-agent palbociclib is well tolerated and active in patients with endocrine-resistant, HR(+), Rb-positive breast cancer. Cytopenias were uncomplicated and easily managed with dose reduction. PMID- 25501127 TI - Prospective validation of a new method of monitoring minimal residual disease in childhood acute myelogenous leukemia. AB - PURPOSE: This study evaluated the prognostic impact of a novel, simple, and standardized assay for monitoring minimal residual disease (MRD) in pediatric acute myelogenous leukemia (AML). EXPERIMENTAL DESIGN: The expression of seven leukemia-associated genes (WT1, PRAME, CCL23, GAGED2, MSLN, SPAG6, and ST18) was measured by TaqMan Low Density Arrays in 112 patients and 52 healthy controls. Patients were treated according to the multicenter study AML-BFM 2004. Samples were collected prospectively at standard time points. The laboratory that measured MRD was blinded to patient outcome. RESULTS: Relapse-free survival (RFS) was 95% (N = 19; SE = 5%) if expression of all genes was down to normal on day 15, 63% (N = 41; SE = 8%) if expression was normalized on day 28, and 38% (N = 21; SE = 11%) in patients who still showed elevated expression on day 28. The prognostic impact of MRD remained significant (P = 0.002) when patients were stratified for the AML-BFM 2004 risk group. Multivariate analysis identified the MRD risk group and day 28 cytology as the only independent prognostic factors. Patients with a cytologic nonremission on day 28, which was confirmed by MRD, had a dismal prognosis. Only 1 out of 8 patients survived without relapse. CONCLUSIONS: This novel method of monitoring MRD has a strong prognostic impact that is independent from established risk factors in childhood AML. PMID- 25501128 TI - Stem cells increase in numbers in perinecrotic areas in human renal cancer. AB - PURPOSE: Developing strategies to overcome resistance to sunitinib is a major challenge in human renal cell carcinoma (RCC). We hypothesized that sunitinib induced tumor necrosis-associated hypoxia could interact with renal cancer stem cells in patients with metastatic RCC. EXPERIMENTAL DESIGN: We studied tissue samples from 7 patients with primary metastatic RCC, before and after sunitinib treatment, and from six xenograft models derived from human RCC. Two xenograft models were responders to sunitinib, the four others were nonresponders. CD133/CXCR4-coexpressing cells derived from the two responder xenograft models were used for in vitro studies. RESULTS: In the seven primary RCCs, we identified a significantly larger number of CD133/CXCR4-coexpressing cells in perinecrotic versus perivascular areas. Their numbers also significantly increased after treatment, in perinecrotic areas. We reproduced these clinical and pathologic results in all six RCC xenograft models with again a preferential perinecrotic distribution of CD133-expressing cells. Necrosis occurred at day 7 in the two responder models treated with sunitinib, whereas it occurred at day 21 in the untreated controls and in the four nonresponder models. Strikingly, when we studied the six RCC xenograft models at the time necrosis, whether spontaneous or sunitinib-induced, occurred, necrosis area correlated with stem-cell number in all 120 xenografted RCCs. When studied under experimental hypoxia, the number of CD133/CXCR4-coexpressing cells and their tumorigenic potency increased whereas their sensitivity to sunitinib decreased. CONCLUSIONS: In human RCC, sunitinib was able to generate resistance to its own therapeutic effect via induced hypoxia in perinecrotic areas where cancer stem cells were found in increased numbers. PMID- 25501130 TI - Standardized Ki67 Diagnostics Using Automated Scoring--Clinical Validation in the GeparTrio Breast Cancer Study. AB - PURPOSE: Scoring proliferation through Ki67 immunohistochemistry is an important component in predicting therapy response to chemotherapy in patients with breast cancer. However, recent studies have cast doubt on the reliability of "visual" Ki67 scoring in the multicenter setting, particularly in the lower, yet clinically important, proliferation range. Therefore, an accurate and standardized Ki67 scoring is pivotal both in routine diagnostics and larger multicenter studies. EXPERIMENTAL DESIGN: We validated a novel fully automated Ki67 scoring approach that relies on only minimal a priori knowledge on cell properties and requires no training data for calibration. We applied our approach to 1,082 breast cancer samples from the neoadjuvant GeparTrio trial and compared the performance of automated and manual Ki67 scoring. RESULTS: The three groups of autoKi67 as defined by low (<= 15%), medium (15.1%-35%), and high (>35%) automated scores showed pCR rates of 5.8%, 16.9%, and 29.5%, respectively. AutoKi67 was significantly linked to prognosis with overall and progression-free survival P values P(OS) < 0.0001 and P(PFS) < 0.0002, compared with P(OS) < 0.0005 and P(PFS) < 0.0001 for manual Ki67 scoring. Moreover, automated Ki67 scoring was an independent prognosticator in the multivariate analysis with P(OS) = 0.002, P(PFS) = 0.009 (autoKi67) versus P(OS) = 0.007, PPFS = 0.004 (manual Ki67). CONCLUSIONS: The computer-assisted Ki67 scoring approach presented here offers a standardized means of tumor cell proliferation assessment in breast cancer that correlated with clinical endpoints and is deployable in routine diagnostics. It may thus help to solve recently reported reliability concerns in Ki67 diagnostics. PMID- 25501131 TI - Molecular Pathways: Targeting NRG1 Fusions in Lung Cancer. AB - The four members of the ERBB (HER) family of transmembrane receptor tyrosine kinases are frequently activated in cancer by several mechanisms, such as mutation, amplification, or autocrine ligand-receptor stimulation. We recently identified gene fusions involving the ERBB ligand gene, NRG1, which represent a novel mechanism for ERBB pathway deregulation. These fusions lead to expression and presentation of the EGF-like domain of NRG1 on the cell surface, which binds to ERBB3 in an autocrine and juxtacrine manner, thus inducing the formation of ERBB2-ERBB3 heterodimers, and subsequent activation of the PI3K-AKT and MAPK signaling pathways. These fusion genes were exclusively detected in lung adenocarcinomas of never smokers of the invasive mucinous subtype, which usually presents as a multifocal and unresectable disease, for which no effective treatment exists. Considering the large amount of drugs that target ERBB2 (HER2) and ERBB3 (HER3), and which are currently in different stages of clinical development, detecting and targeting NRG1 fusions in invasive mucinous lung adenocarcinomas may represent a therapeutic opportunity for this aggressive disease. PMID- 25501129 TI - Activation of vitamin D receptor signaling downregulates the expression of nuclear FOXM1 protein and suppresses pancreatic cancer cell stemness. AB - PURPOSE: Dysregulated signaling of nuclear transcription factors vitamin D receptor (VDR) and Forkhead box M1 (FOXM1) plays important roles in transformation and tumorigenesis. In this study, we sought to determine whether VDR signaling causally affected FOXM1 signaling in and pathogenesis of pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: Genetic and pharmacologic approaches were used to manipulate VDR signaling. The impacts of altered VDR signaling on FOXM1 expression and function in PDAC cells were determined using molecular and biochemical methods, whereas those on PDAC cell biology and tumorigenicity were determined using in vitro and in vivo experimental systems. The clinical relevance of our findings was validated by analyzing human PDAC specimens. RESULTS: There was a striking inverse correlation between reduced expression of VDR and increased expression of FOXM1 in human PDAC cells and tissues. Treatment of PDAC cells with 1,25-dihydroxyvitamin D3 (1,25D), its synthetic analogue EB1089 (EB), and VDR transgenics drastically inhibited FOXM1 signaling and markedly suppressed tumor stemness, growth, and metastasis. Mechanistically, 1,25D and EB repressed FOXM1 transcription and reduced the expression level of nuclear FOXM1 protein. CONCLUSION: Inactivation of Vitamin D/VDR signaling is a critical contributor to PDAC development and progression via elevated expression and function of FOXM1 and enhanced PDAC cell stemness, invasion, and metastasis. PMID- 25501133 TI - Quantifying the vestibulo-ocular reflex with video-oculography: nature and frequency of artifacts. AB - Video-oculography devices are now used to quantify the vestibulo-ocular reflex (VOR) at the bedside using the head impulse test (HIT). Little is known about the impact of disruptive phenomena (e.g. corrective saccades, nystagmus, fixation losses, eye-blink artifacts) on quantitative VOR assessment in acute vertigo. This study systematically characterized the frequency, nature, and impact of artifacts on HIT VOR measures. From a prospective study of 26 patients with acute vestibular syndrome (16 vestibular neuritis, 10 stroke), we classified findings using a structured coding manual. Of 1,358 individual HIT traces, 72% had abnormal disruptive saccades, 44% had at least one artifact, and 42% were uninterpretable. Physicians using quantitative recording devices to measure head impulse VOR responses for clinical diagnosis should be aware of the potential impact of disruptive eye movements and measurement artifacts. PMID- 25501132 TI - CD99 triggering in Ewing sarcoma delivers a lethal signal through p53 pathway reactivation and cooperates with doxorubicin. AB - PURPOSE: The paucity of new drugs for the treatment of Ewing sarcoma (EWS) limits the cure of these patients. CD99 has a strong membranous expression in EWS cells and, being also necessary for tumor survival, is a suitable target to aim at. In this article, we described a novel human monospecific bivalent single-chain fragment variable diabody (dAbd C7) directed against CD99 of potential clinical application. EXPERIMENTAL DESIGN: In vitro and in vivo evaluation of cell death and of the molecular mechanisms triggered by anti-CD99 agents were performed alone or in combination with doxorubicin to demonstrate efficacy and selectivity of the new dAbd C7. RESULTS: The dAbd C7 induced rapid and massive EWS cell death through Mdm2 degradation and p53 reactivation. Mdm2 overexpression as well as silencing of p53 in p53wt EWS cells decreased CD99-induced EWS cell death, whereas treatment with nutlin-3 enhanced it. Furthermore, cell death was associated with induction of p21, bax, and mitochondrial depolarization together with substantial inhibition of tumor cell proliferation. Combined treatment of anti-CD99 dAbd C7 with doxorubicin was additive both in vitro and in vivo against EWS xenografts. Normal mesenchymal stem cells showed no p53 activation and were resistant to cell death, unless transformed by EWS-FLI, the oncogenic driver of EWS. CONCLUSIONS: These results indicate that dAbd C7 is a suitable candidate tool to target CD99 in patients with EWS able to spare normal stem cells from death as it needs an aberrant genetic context for the efficient delivery of CD99 triggered cell death. PMID- 25501134 TI - Nodular melanoma serendipitously detected by airport full body scanners. AB - BACKGROUND: Nodular melanoma is the most dangerous form of melanoma and often evades early detection. METHODS: We present a frequently traveling businessman whose nodular melanoma was detected by airport full body scanners. RESULTS: For about 20 flights over 2 months, the airport full body scanners singled out an area on his left lower leg for a pat-down. Dermatologic examination discovered a nodular melanoma in this area, and after surgical excision, the man traveled without incident. CONCLUSION: This case raises the possibility of using full body imaging in the detection of melanomas, especially of the nodular subtype. In its current form, full body scanning would most likely not be sensitive or specific enough to become a recommended screening tool. Nonetheless, for travelers with areas repeatedly singled out by the machines without a known justification, airport scanners could serve as incidental free screening for suspicious nodular lesions that should prompt dermatologist referral. PMID- 25501135 TI - Rapid access to glycopeptide antibiotic precursor peptides coupled with cytochrome P450-mediated catalysis: towards a biomimetic synthesis of glycopeptide antibiotics. AB - Understanding the mechanisms underpinning glycopeptide antibiotic biosynthesis is key to the future ability to reinvent these compounds. For effective in vitro characterization of the crucial later steps of the biosynthesis, facile access to a wide range of substrate peptides as their Coenzyme A (CoA) conjugates is essential. Here we report the development of a rapid route to glycopeptide precursor CoA conjugates that affords both high yields and excellent purities. This synthesis route is applicable to the synthesis of peptide CoA-conjugates containing racemization-prone arylglycine residues: such residues are hallmarks of non-ribosomal peptide synthesis and have previously been inaccessible to peptide synthesis using Fmoc-type chemistry. We have applied this route to generate glycopeptide precursor peptides in their carrier protein-bound form as substrates to explore the specificity of the first oxygenase enzyme from vancomycin biosynthesis (OxyBvan). Our results indicate that OxyBvan is a highly promiscuous catalyst for phenolic coupling of diverse glycopeptide precursors that accepts multiple carrier protein substrates, even on carrier protein domains from alternate glycopeptide biosynthetic machineries. These results represent the first important steps in the development of an in vitro biomimetic synthesis of modified glycopeptide aglycones. PMID- 25501136 TI - Reaction of common bean lines and aggressiveness of Sclerotinia sclerotiorum isolates. AB - The aims of this study were to evaluate the reaction of common bean lines to white mold, the aggressiveness of different Sclerotinia sclerotiorum isolates from various common bean production areas in Brazil, and comparison of the diallel and GGE (genotype main effect plus genotype-by-environment interaction) biplot analysis procedures via study of the line-by-isolate interaction. Eleven common bean (Phaseolus vulgaris) lines derived from 3 backcross populations were used. Field experiments were performed in the experimental area of the Departamento de Biologia of the Universidade Federal de Lavras, Lavras, MG, Brazil, in the 2011 and 2012 dry crop season and 2011 winter crop season through a randomized block design with 3 replications. This study was also set up in a greenhouse. Inoculations were performed 28 days after sowing by means of the straw test method. The reaction of the bean lines to white mold was assessed according to a diagrammatic scale from 1 (plant without symptoms) to 9 (dead plant). Estimations of general reaction capacity (lines) and general aggressiveness capacity (isolates) indicated different horizontal levels of resistance in the lines and levels of aggressiveness in the isolates. Therefore, it was possible to select more resistant lines and foresee those crosses that are the most promising for increasing the level of resistance. It was also possible to identify the most aggressive isolates that were more efficient in distinguishing the lines. Both diallel and GGE biplot analyses were useful in identifying the genotypic values of lines and isolates. PMID- 25501137 TI - Mapping an aphid resistance gene in soybean [Glycine max (L.) Merr.] P746. AB - Soybean aphid (SA: Aphis glycines Matsumura) is one of the most serious pests of soybean [Glycine max (L.) Merr.] worldwide. A single dominant gene was found to control SA resistance in soybean line P746, which exhibits antibiosis resistance. This study aimed to define the location of the SA resistance gene in P746. A F2:3 mapping population, including 312 individuals, was created based on the cross of P746 and 'Dongnong 47'. Combined with bulked segregant analysis, all of the 1015 simple sequence repeats (SSR) from the soybean consensus map were used to locate the tentative genomic region of the SA resistance gene in P746. The effort resulted in the mapping of R_P746, the SA resistance gene in P746, and was flanked on either side by Satt334 and Satt335 on chromosome 13. By chromosome walking with SSRs from BARCSOYSSR_1.0, R_P746 was mapped between BARCSOYSSR_13_1278 and BARCSOYSSR_13_1363, with distances of 4.2 and 2.6 cM, respectively. The results indicate that R_P746 might be different to the SA resistance genes previously reported. The markers that are closely linked to R_P746 are expected to be useful for marker assisted selection in future soybean aphid resistance breeding programs. PMID- 25501138 TI - Separation, purification, and identification of flagellin, and preparation of its antisera. AB - The aim of this study was to separate, purify, and identify Salmonella paratyphi A flagellin, and to prepare its antisera. Primary flagellin was isolated from S. paratyphi A using the acid lysis method. The flagellin was purified with weak anion exchange chromatography and the protein was identified with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, and negative staining with phosphotungstic acid with scanning electron microscopy (SEM). The production of the obtained flagellin was then quantified. New Zealand white rabbits were then immunized with the isolated flagellin, the presence of serum anti-flagellin antibodies was assessed with the immunoblot test, and its potency was determined with the double immunodiffusion test. The results of SDS-PAGE showed that the molecular weight (m.w.) of the purified flagellin was 52 x 10(3). The immunoblot test also showed a band at 52 x 10(3) m.w. The SEM results showed that the flagellin was filamentous. These three results showed that the protein was homogeneous. The protein quantification analysis found that 4.8 +/- 0.5 mg flagellin could be extracted per 1 g wet weight bacteria. The titer of the anti flagellin antiserum was 1:64. Through this method, we obtained high productions of flagellin, which could be easily purified, identified, and prepared into high titer antiserum. PMID- 25501139 TI - MULTINDELS-BOV: Zebu traceback method based on DNA insertion-deletion polymorphisms. AB - Brazil is a major producer and exporter of beef, with a herd of approximately 210 million animals. For the meat industry, a reliable animal traceback from its origin to the consumer market is paramount. Of all available identification systems, DNA is the only one that survives the slaughterhouse and reaches the dish of the consumer. DNA polymorphisms are already used for cattle traceback, but primarily for the subspecies Bos taurus taurus. However, in Brazil, another subspecies, B. taurus indicus predominates. We describe here the development of a DNA traceback method designed primarily for B. taurus indicus (Zebu), without leaving B. taurus taurus aside. We used insertion/deletion (indel) polymorphisms, which have the advantage of being simple and easily automatable, since in most cases, the variable loci are biallelic. We studied 94 indels, with a difference of two or more base pairs, in DNA pools of 60 Zebu and 60 taurine animals. A set of 22 indels with heterozygosity greater than 0.3 were selected and used to construct two multiplex PCRs. On the basis of the allelic frequency of these indels, the probability of random match was calculated to be 1.12 x 10(-8) for B. taurus indicus and 1.60 x 10(-6) for B. taurus taurus. Moreover, we estimated that an analysis would cost less than US$15.00 per animal. Thus, this system (MULTINDELS-BOV) is perfectly suited for building large genetic databases and offering viable prospects of a national system for cattle traceback DNA in Brazil. PMID- 25501140 TI - Association of the IFNAR1-17470 and IL-10-592 cytokine variants with susceptibility to chronic hepatitis B viral infections in a Chinese population. AB - An association between the sequence variants of cytokine genes and various clinical outcomes in subjects infected with the hepatitis B virus (HBV) has been demonstrated. However, the results are inconsistent and inconclusive. Further studies in other populations and the evaluation of a greater number of individuals may contribute to a better understanding of the influence of the cytokine genetic variants on the evolution of HBV infections. This study was performed to explore the relationships between the sequence variants of TNF-A 308, IFNAR1-17470, and IL-10-592 and the susceptibility to chronic hepatitis B (CHB) in a Chinese population. A total of 160 patients with CHB and 124 individuals who had spontaneously recovered (SR) from hepatitis B were enrolled in the present study. The variants at TNF-A-308, IFNAR1-17470, and IL-10-592 were determined by PCR-restriction fragment length polymorphism analysis and were confirmed by bidirectional DNA sequencing. Significant differences were found between the CHB and the SR groups in the frequency and distribution of the genotypes of both IFNAR1-17470 and IL-10-592 genes. In comparison with the CHB patients with the IFNAR1-17470 G/G variant, the odds ratio (OR) of the CHB patients with the IFNAR1-17470 C/C variant developing chronic hepatitis was 2.06 (95%CI = 1.03-4.14). In addition, the OR of the patients with CHB having the IL 10-592 C/C variant developing chronic hepatitis was 2.77 (95%CI = 1.13-4.57) when compared with that of the patients with the IL-10-592 A/A variant. In conclusion, sequence variants of both the IFNAR1-17470 and IL-10-592 genes were correlated with susceptibility to CHB. PMID- 25501141 TI - Sequence variation and molecular evolution of BMP4 genes. AB - Bone morphogenetic protein 4 (BMP4) regulates skeletogenesis, osteoblastic differentiation, and the induction of hair follicles. Its protein-coding region contains a signal peptide, prodomain (which regulates post-translational synthesis), and a mature domain (which mediates gene function). Previous studies considered this gene to be conserved. By reanalyzing the coding region of BMP4 in 16 mammalian species, we found that the mature domain is conserved in mammals. A comparison of the putative amino acid sequence demonstrates that BMP4 is relatively conserved. Two domains in BMP4 are connected by a random coil. The protein conformation differs between the Muridae family and other species, which might be associated with the body type of the former group. PMID- 25501142 TI - Selection of sugar cane full-sib families using mixed models and ISSR markers. AB - In 2006, an experiment examining families belonging to the first selection stage of the Sugar Cane Breeding Program of Universidade Federal Rural do Rio de Janeiro/Rede Interuniversitaria para o Desenvolvimento do Setor Sucroalcooleiro was conducted. Families and plants within families were evaluated to select superior plants for subsequent stages of the breeding program. The experiment was arranged in a randomized block design, in which progenies were grouped into 4 sets, each with 4 replicates and 100 seedlings per plot. The following traits were evaluated: average stem diameter, total plot weight, number of stems, Brix of the lower stem, and Brix of the upper stem. The study of families used the restricted maximum likelihood/best linear unbiased procedure mixed models. After selection, families were genotyped via inter-simple sequence repeat to assess the genetic distance of genotypes. This approach was found to be efficient for selecting new genotypes. PMID- 25501143 TI - Advanced oxidation protein products as a biomarker of cutaneous lupus erythematosus complicated by nephritis: a case-control study. AB - Oxidative stress is involved in the pathogenesis of lupus nephritis (LN). The current study investigated the significance of advanced oxidation protein products (AOPPs) as a biomarker of LN in patients with cutaneous lupus erythematosus. Ninety-two patients who initially presented with systemic lupus erythematosus were divided into the LN- and LN+ groups. Serum AOPP levels were determined, and the association between AOPP levels and LN was investigated in a case-control study. In the LN+ group, patients with higher AOPP levels exhibited higher levels of dsDNA and proteinuria but lower levels of eGFR and complement C3 compared to those in patients with lower AOPP levels. A multivariable logistic regression model showed that the AOPP level was an independent risk factor for LN. The risk of nephritis specifically increased 24% for each 10 MUM increase in AOPP (95% confidence interval, 1.166-1.915, P = 0.030). In contrast, neither elevated dsDNA level nor decreased complement C3 level was an independent risk factor for LN. Higher serum AOPP levels were associated with an increased risk of LN. Therefore, future studies are warranted to determine the potential clinical value of this novel biomarker. PMID- 25501144 TI - Analysis of key genes and modules during the courses of traumatic brain injury with microarray technology. AB - Gene expression data acquired at different times after traumatic brain injury (TBI) were analyzed to identify differentially expressed genes (DEGs). Interaction network analysis and functional enrichment analysis were performed to extract valuable information, which may benefit diagnosis and treatment of TBI. Microarray data were downloaded from Gene Expression Omnibus and pre-treated with MATLAB. DEGs were screened out with the SAM method. Interaction networks of the DEGs were established, followed by module analysis and functional enrichment analysis to obtain insight into the molecular mechanisms. A total of 39 samples at six time points (30 min, 4, 8, 24 , 72 h, and 21 days) were analyzed and generated 377 DEGs. Eight modules were identified from the networks and network ontology analysis revealed that cell surface receptor-linked signaling pathway, response to wounding and signaling pathway were significantly overrepresented. Altered risk genes and modules in TBI were uncovered through comparing the gene expression data acquired at various time points. These genes or modules could be potential biomarkers for diagnosis and treatment of TBI. PMID- 25501145 TI - Trypsin inhibitors from Capsicum baccatum var. pendulum leaves involved in Pepper yellow mosaic virus resistance. AB - Several plant organs contain proteinase inhibitors, which are produced during normal plant development or are induced upon pathogen attack to suppress the enzymatic activity of phytopathogenic microorganisms. In this study, we examined the presence of proteinase inhibitors, specifically trypsin inhibitors, in the leaf extract of Capsicum baccatum var. pendulum inoculated with PepYMV (Pepper yellow mosaic virus). Leaf extract from plants with the accession number UENF 1624, which is resistant to PepYMV, was collected at 7 different times (0, 24, 48, 72, 96, 120, and 144 h). Seedlings inoculated with PepYMV and control seedlings were grown in a growth chamber. Protein extract from leaf samples was partially purified by reversed-phase chromatography using a C2/C18 column. Residual trypsin activity was assayed to detect inhibitors followed by Tricine SDS-PAGE analysis to determine the N-terminal peptide sequence. Based on trypsin inhibitor assays, trypsin inhibitors are likely constitutively synthesized in C. baccatum var. pendulum leaf tissue. These inhibitors are likely a defense mechanism for the C. baccatum var. pendulum- PepYMV pathosystem. PMID- 25501146 TI - Protein-protein interaction network analysis of osteoarthritis-related differentially expressed genes. AB - The purpose of this study was to identify genes and pathways for osteoarthritis (OA) diagnosis and therapy. We downloaded the gene expression profile of OA from Gene Expression Omnibus (GEO) database including 10 early OA, 9 late OA, and 5 normal control samples. Next, we screened differentially expressed genes (DEGs) between early- and late-stage OA samples comparing with healthy control samples. Then, the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) software was used to construct protein-protein interaction (PPI) network, which was to predict the proteins that may interact with DEGs. The Gene Ontology (GO) enrichment method was used to analyze the function of genes in the PPI networks. Meanwhile network module analysis was performed using Cytoscape. A total of 24 and 29 DEGs were identified for the early and late OA, respectively. TAC1 showed the highest degree in the PPI network. Functional annotation of the TAC1 network module indicated that this gene is associated with the G protein-coupled signal transduction pathway. In summary, TAC1, together with G protein-coupled receptors, appear to play a role in the biogenesis and progress of OA. Further analysis of this gene and pathway could therefore provide a potential target for the diagnosis and treatment of OA. PMID- 25501147 TI - Molecular characterization of aflatoxigenic and non-aflatoxigenic Aspergillus flavus isolates collected from corn grains. AB - Twelve species from six fungal genera were found to be associated with corn (Zea mays L.) grain samples collected from three main regions of Saudi Arabia. The average frequencies of the most common genera were Aspergillus (11.4%), Fusarium (9.5%), Penicillium (5.1%), and Alternaria (5.8%). Fifteen isolates of Aspergillus flavus were screened by HPLC for their ability to produce aflatoxins (AF). The percentage of aflatoxigenic A. flavus isolates was 53%. Eight isolates produced AF, at concentrations ranging 0.7-2.9 ppb. Random amplified polymorphic DNA (RAPD) and inter-simple sequence repeat (ISSR) molecular markers were used to genetically characterize isolates of A. flavus and to discriminate between the aflatoxigenic and non-aflatoxigenic isolates. RAPD and ISSR analysis revealed a high level of genetic diversity in the A. flavus population, which was useful for genetic characterization. The clustering in the RAPD and ISSR dendrograms obtained was unrelated to geographic origin. The RAPD and ISSR markers could not discriminate between aflatoxigenic and non-aflatoxigenic isolates, but the ISSR primers were somewhat better. PMID- 25501148 TI - Association of Hsp60 expression with damage to rat myocardial cells exposed to heat stress in vivo and in vitro. AB - To investigate the protective role of Hsp60 against stress damage and its role in the sudden death of stressed animals, changes in the levels of Hsp60 protein and hsp60 mRNA of myocardial cells in vivo and in vitro were studied. In addition, the relationship between Hsp60 expression and heat-induced damage was also studied. Rats were exposed to a temperature of 42 degrees +/- 1 degrees C for 0, 20, 40, 60, 80, or 100 min. More than 50% of the rats died suddenly within 100 min. With increasing heat stress duration, hsp60 mRNA levels significantly increased in both in vivo and in vitro rat myocardial cells; however, a similar trend was not observed for Hsp60 protein levels. Although the changes observed in Hsp60 expression in myocardial cells in vitro were inconsistent with those of rat heart tissues in vivo, Hsp60 expression levels were consistent with the histopathological damage observed in myocardial cells both in vivo and in vitro. Differences in Hsp60 expression may reflect the degree of injury sustained by myocardial cells in vivo and in vitro. As a mitochondrial protein, Hsp60 represents a potential biomarker of heat stress, and may protect against heat stress induced myocardial cellular damage both in vivo and in vitro. PMID- 25501149 TI - Relation between neutrophil-to-lymphocyte ratio and severity of coronary artery stenosis. AB - This study aimed to investigate the relation between the neutrophil-to-lymphocyte ratio (NLR) and the severity of coronary artery stenosis. A total of 219 patients were included in the study, comprising 51 coronary artery atherosclerosis (CAC) patients, 92 stable angina pectoris (SAP) patients, and 76 acute coronary syndrome (ACS) patients. Based on the results of coronary angiography, all patients were divided into two groups according to the Gensini scores: the low score group (N = 142) and the high-score group (N = 77). The NLR was computed from the ratio of neutrophils and lymphocytes from the complete blood count. The association between the NLR and severity of coronary artery disease was assessed using correlation analysis and logistic regression. The NLR was higher in ACS patients than in SAP and CAC patients (P < 0.05). In addition, the NLR was higher in the high-score group than in the low-score group (P < 0.05). Correlation analysis showed that the NLR was significantly correlated with the Gensini score. After multivariate analysis, high NLRs were independent predictors of high Gensini scores, together with age and high-density lipoprotein. A cutoff NLR of 2.385 predicted high Gensini scores with a sensitivity and specificity of 64 and 63%, respectively. The study suggests that the NLR is an independent predictor of coronary heart disease that may be useful for predicting the severity of coronary artery stenosis. PMID- 25501150 TI - Morphological and molecular characterization of Fusarium spp pathogenic to pecan tree in Brazil. AB - The occurrence of Fusarium spp associated with pecan tree (Carya illinoinensis) diseases in Brazil has been observed in recent laboratory analyses in Rio Grande do Sul State. Thus, in this study, we i) obtained Fusarium isolates from plants with disease symptoms; ii) tested the pathogenicity of these Fusarium isolates to pecan; iii) characterized and grouped Fusarium isolates that were pathogenic to the pecan tree based on morphological characteristics; iv) identified Fusarium spp to the species complex level through TEF-1alpha sequencing; and v) compared the identification methods used in the study. Fifteen isolates collected from the inflorescences, roots, and seeds of symptomatic plants (leaf necrosis or root rot) were used for pathogenicity tests. Morphological characterization was conducted using only pathogenic isolates, for a total of 11 isolates, based on the mycelial growth rate, sporulation, colony pigmentation, and conidial length and width variables. Pathogenic isolates were grouped based on morphological characteristics, and molecular characterization was performed by sequencing TEF 1alpha genes. Pathogenic isolates belonging to the Fusarium chlamydosporum species complex, Fusarium graminearum species complex, Fusarium proliferatum, and Fusarium oxysporum were identified based on the TEF-1alpha region. Morphological characteristics were used to effectively differentiate isolates and group the isolates according to genetic similarity, particularly conidial width, which emerged as a key morphological descriptor in this study. PMID- 25501151 TI - Spectrum and features of congenital heart disease in Xi'an, China as detected using fetal echocardiography. AB - This study aimed to investigate the spectrum and features of congenital heart disease (CHD) in Xi'an, China using fetal echocardiography. All pregnant women referred for fetal echocardiography underwent a systematic fetal echocardiographic examination. Each case of complex defects was diagnosed according to the predominant pathophysiology, and the overall frequency of each defect was recorded and classified according to its location in the fetal heart. CHD was diagnosed in 195 fetuses. The top 5 types of CHD were, in order, single ventricle (15.9%, 31/195), atrioventricular septal defect (12.3%, 24/195), ventricular septal defect (VSD) (11.8%, 23/195), tetralogy of Fallot (10.8%, 21/195), and double-outlet right ventricle (8.2%, 16/195). The 195 cases of CHD comprised 316 defects in total. The most common defect was ventricular malformation (40.5%, 128/316), followed by great artery anomalies (38.0%, 120/316), endocardial cushion abnormalities (11.7%, 37/316), atrial abnormalities (6.6%, 21/316), and semilunar valve abnormalities (3.2%, 10/316). VSD accounted for the largest proportion (24.4%, 77/316) of the ventricular malformations. The total proportion of obstructive lesions in this group was much higher for the right than for the left side of the heart (18.4% (58/316) vs 9.5% (30/316), respectively). The spectrum of fetal CHD detected by echocardiography was much different compared to that accepted in the past. Complex defects were more common prenatally. Ventricular malformations were the largest constituent of all of the defects associated with fetal CHD, and VSD was the most common component of complex defects. Chinese fetal CHD encompassed more right-sided than left-sided obstructive lesions. PMID- 25501152 TI - Functional analysis of differentially expressed genes associated with glaucoma from DNA microarray data. AB - Microarray data of astrocytes extracted from the optic nerves of donors with and without glaucoma were analyzed to screen for differentially expressed genes (DEGs). Functional exploration with bioinformatic tools was then used to understand the roles of the identified DEGs in glaucoma. Microarray data were downloaded from the Gene Expression Omnibus (GEO) database, which contains 13 astrocyte samples, 6 from healthy subjects and 7 from patients suffering from glaucoma. Data were pre-processed, and DEGs were screened out using R software packages. Interactions between DEGs were identified, and networks were built using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). GENECODIS was utilized for the functional analysis of the DEGs, and GOTM was used for module division, for which functional annotation was conducted with the Database for Annotation, Visualization, and Integrated Discovery (DAVID). A total of 371 DEGs were identified between glaucoma-associated samples and normal samples. Three modules included in the PPID database were generated with 11, 12, and 2 significant functional annotations, including immune system processes, inflammatory responses, and synaptic vesicle endocytosis, respectively. We found that the most significantly enriched functions for each module were associated with immune function. Several genes that play interesting roles in the development of glaucoma are described; these genes may be potential biomarkers for glaucoma diagnosis or treatment. PMID- 25501153 TI - Molecular characterization of a cytosolic manganese superoxide dismutase from the Chinese mitten crab, Eriocheir sinensis. AB - A cytosolic manganese superoxide dismutase gene (Es-cMnSOD) was cloned from the Chinese mitten crab Eriocheir sinensis, using reverse transcription-polymerase chain reaction and the rapid amplification of cDNA ends. The open reading frame of Es-cMnSOD is 867 bp in length and encodes a 288-amino acid protein without a signal peptide. The calculated molecular mass of the translated protein of Es cMnSOD is 31.43 kDa, with an estimated isoelectric point of 6.30. The deduced amino acid sequence of Es-cMnSOD has similarities of 90, 89, 84, 87, and 81% to those of white shrimp Litopenaeus vannamei MnSOD, black tiger shrimp Penaeus monodon MnSOD, giant freshwater prawn Macrobrachium rosenbergii MnSOD, blue crab Callinectes sapidus MnSOD, and red swamp crayfish Procambarus clarkii MnSOD, respectively. Es-cMnSOD contains a manganese superoxide dismutase domain (DVWEHAYY) and 4 conserved amino acids responsible for binding manganese. Es cMnSOD was expressed in the hemocytes, eyestalk, muscle, intestine, gill, and hepatopancreas. Es-cMnSOD transcripts in hemocytes of E. sinensis increased at 1.5 and 48 h after injection of Aeromonas hydrophila, indicating that the induction of the SOD system response occurred within a short period of time. This study suggests that MnSOD may play a critical role in crab immunity, allowing efficient activation of an early innate immune response in the crab. PMID- 25501154 TI - A novel method for the evaluation of virus-induced gene silencing efficiency. AB - Virus-induced gene silencing (VIGS) is an important tool for studying gene function. However, a number of factors highly restrict the application of VIGS, such as unstable efficiency and tissue-specific silencing. We developed a novel evaluation method for improving the applicability of VIGS vectors. In this method, 4 indexes were defined and utilized to evaluate VIGS efficiency by silencing the endogenous phytoene desaturase (PDS) gene with a tobacco rattle virus-based VIGS vector. To illustrate the reliability of this evaluation method, we assessed the silencing efficiency of SpPDS and SpMPK1 in Solanum pimpinellifolium. The silencing results of SpPDS showed that an optical density at 600 nm of 2.0 was more suitable than 1.0 for VIGS in S. pimpinellifolium. This suggests that the proposed evaluation method is a valid technique for optimizing the VIGS system of plants. Moreover, the SpMPK1 gene was highly silenced in the 4th-9th leaves with a 50-95% reduction in transcription levels, further demonstrating that this method can be used to select highly silenced candidates for further experiments, particularly when the target gene shows no phenotypic change after being silenced. PMID- 25501155 TI - Comparison of gene regulatory networks of benign and malignant breast cancer samples with normal samples. AB - The aim of this study was to explain the pathogenesis and deterioration process of breast cancer. Breast cancer expression profile data GSE27567 was downloaded from the Gene Expression Omnibus (GEO) database, and breast cancer-related genes were extracted from databases, including Cancer-Resource and Online Mendelian Inheritance In Man (OMIM). Next, h17 transcription factor data were obtained from the University of California, Santa Cruz. Database for Annotation, Visualization, and Integrated Discovery (DAVID)-enrichment analysis was applied and gene regulatory networks were constructed by double-two-way t-tests in 3 states, including normal, benign, and malignant. Furthermore, network topological properties were compared between 2 states, and breast cancer-related bub genes were ranked according to their different degrees between each of the two states. A total of 2380 breast cancer-related genes and 215 transcription factors were screened by exploring databases; the genes were mainly enriched in their functions, such as cell apoptosis and proliferation, and pathways, such as p53 signaling and apoptosis, which were related with carcinogenesis. In addition, gene-regulatory networks in the 3 conditions were constructed. By comparing their network topological properties, we found that there is a larger transition of differences between malignant and benign breast cancer. Moreover, 8 hub genes (YBX1, ZFP36, YY1, XRCC5, XRCC4, ZFHX3, ZMAT3, and XPC) were identified in the top 10 genes ranked by different degrees. Through comparative analysis of gene regulation networks, we identified the link between related genes and the pathogenesis of breast cancer. However, further experiments are needed to confirm our results. PMID- 25501156 TI - Genetic polymorphisms in metabolic enzymes and susceptibility to anti tuberculosis drug-induced hepatic injury. AB - We examined the relationships between N-transacetylase 2 (NAT2), cytochrome P450 (CYP) 2E1 enzyme, glutathione S-transferase M1, T1 (GSTM1/GSTT1) gene polymorphisms, and anti-tuberculosis drug-induced hepatic injury (ADIH). A one-to one matched case-control study was carried out using clinical data. NAT2, CYP2E1, GSTM1, and GSTT1 polymorphisms were identified in 173 pairs of research subjects. Statistical analysis was performed to determine risk factors of ADIH. The results showed that low body mass index and alcohol consumption were risk factors of ADIH, with odds ratios of 6.852 and 3.203, respectively. The frequencies of NAT2 slow acetylator, CYP2E1 -1259G>C, -1019C>T wild-type, and the GSTM1 null genotype were higher in the case group than in the control group, with odds ratios of 2.260, 2.696, 4.714, and 2.440, respectively. GSTT1 was not found to be related to ADIH. Interactive analysis showed that NAT2 slow acetylator and the GSTM1 null genotype were mutually synergistic, while an antagonistic relationship was observed between the CYP2E1 wild-type genotype and the other 3 genetic types. The risks of hepatic injury were higher after anti-tuberculosis therapy in patients carrying the NAT2 slow acetylator, CYP2E1 -1259G>C, -1019C>T wild-type, and GSTM1 null genotype. PMID- 25501157 TI - A female patient with normosmic idiopathic hypogonadotropic hypogonadism carrying a novel mutation in FGFR1. AB - Mutations in the fibroblast growth factor receptor 1 gene (FGFR1) have been reported in patients with Kallmann syndrome and normosmic idiopathic hypogonadotropic hypogonadism (nIHH). Here, we report an nIHH patient with a novel mutation in FGFR1. The patient was a 19-year-old female who presented the nIHH phenotype with primary amenorrhea, cleft lip and palate, mixed hearing disorders, and skeletal malformations. Coding regions of 12 genes that have been implicated in nIHH were analyzed by direct sequencing. Mutation analysis revealed a novel mutation at exon 10 of the FGFR1 gene, 1422 C>G, and a C->G transition in codon 476, which resulted in the replacement of aspartic acid with glutamic acid. The patient's family members did not possess this mutation. We briefly reviewed FGFR1 variants found in Chinese subjects. These results indicate that the mutation in FGFR1 is a cause of nIHH, which is associated with specific non reproductive phenotypes. PMID- 25501158 TI - Fine mapping of a grain weight quantitative trait locus, qGW6, using near isogenic lines derived from Oryza rufipogon IRGC105491 and Oryza sativa cultivar MR219. AB - Grain weight is a major component of rice grain yield and is controlled by quantitative trait loci. Previously, a rice grain weight quantitative trait locus (qGW6) was detected near marker RM587 on chromosome 6 in a backcross population (BC2F2) derived from a cross between Oryza rufipogon IRGC105491 and O. sativa cv. MR219. Using a BC2F5 population, qGW6 was validated and mapped to a region of 4.8 cM (1.2 Mb) in the interval between RM508 and RM588. Fine mapping using a series of BC4F3 near isogenic lines further narrowed the interval containing qGW6 to 88 kb between markers RM19268 and RM19271.1. According to the Duncan multiple range test, 8 BC4F4 near isogenic lines had significantly higher 100-grain weight (4.8 to 7.5% over MR219) than their recurrent parent, MR219 (P < 0.05). According to the rice genome automated annotation database, there are 20 predicted genes in the 88-kb target region, and 9 of them have known functions. Among the genes with known functions in the target region, in silico gene expression analysis showed that 9 were differentially expressed during the seed development stage(s) from gene expression series GSE6893; however, only 3 of them have known functions. These candidates provide targets for further characterization of qGW6, which will assist in understanding the genetic control of grain weight in rice. PMID- 25501159 TI - Genome-wide transcriptional profiling reveals molecular signatures of secondary xylem differentiation in Populus tomentosa. AB - Wood formation occurs via cell division, primary cell wall and secondary wall formation, and programmed cell death in the vascular cambium. Transcriptional profiling of secondary xylem differentiation is essential for understanding the molecular mechanisms underlying wood formation. Differential gene expression in secondary xylem differentiation of Populus has been previously investigated using cDNA microarray analysis. However, little is known about the molecular mechanisms from a genome-wide perspective. In this study, the Affymetrix poplar genome chips containing 61,413 probes were used to investigate the changes in the transcriptome during secondary xylem differentiation in Chinese white poplar (Populus tomentosa). Two xylem tissues (newly formed and lignified) were sampled for genome-wide transcriptional profiling. In total, 6843 genes (~11%) were identified with differential expression in the two xylem tissues. Many genes involved in cell division, primary wall modification, and cellulose synthesis were preferentially expressed in the newly formed xylem. In contrast, many genes, including 4-coumarate:cinnamate-4-hydroxylase (C4H), 4-coumarate:CoA ligase (4CL), cinnamyl alcohol dehydrogenase (CAD), and caffeoyl CoA 3-O methyltransferase (CCoAOMT), associated with lignin biosynthesis were more transcribed in the lignified xylem. The two xylem tissues also showed differential expression of genes related to various hormones; thus, the secondary xylem differentiation could be regulated by hormone signaling. Furthermore, many transcription factor genes were preferentially expressed in the lignified xylem, suggesting that wood lignification involves extensive transcription regulation. The genome-wide transcriptional profiling of secondary xylem differentiation could provide additional insights into the molecular basis of wood formation in poplar species. PMID- 25501160 TI - XRCC3 T241M polymorphism and lung cancer risk in the Han Chinese population: a meta-analysis. AB - Numerous studies have evaluated the association between the X-ray repair cross complementing group 3 (XRCC3) T241M polymorphism and lung cancer risk; however, the actual association is controversial. We examined whether the T241M polymorphism confers a lung cancer risk in China. We searched the PubMed, Google Scholar, and China National Knowledge Infrastructure databases to identify studies that examined the association between the XRCC3 T241M polymorphism and the risk of lung cancer. We estimated the pooled odds ratio with its 95% confidence interval to assess this association. A total of 3977 patients with lung cancer and 3761 controls from 8 comparative studies were included in this meta-analysis. The meta-analysis results revealed no significant association between the XRCC3 T241M polymorphism and lung cancer risk. In the subgroup analysis, 6 studies with sample sizes over 500 found that the T241M polymorphism had no association with lung cancer. The XRCC3 T241M polymorphism may not be a risk factor for lung cancer. However, larger studies involving a stratified case control population and biological characterization are needed to validate this finding. PMID- 25501161 TI - Mutational analysis of podocyte genes in children with sporadic steroid-resistant nephrotic syndrome. AB - Recent studies have demonstrated that mutations in 4 podocyte genes, NPHS1, NPHS2, CD2AP, and WT1, are associated with the pathogenesis of steroid-resistant nephrotic syndrome (SRNS). Systematic investigation of all 4 genes for sporadic SRNS in China has not been performed. We examined 10 Chinese children with sporadic SRNS who showed no response to immunosuppressive agents and 20 SRNS controls who exhibited a response to prolonged steroid or immunosuppressive treatment and achieved complete remission. We analyzed mutations in the 4 podocyte genes, NPHS1, NPHS2, CD2AP, and WT1. Mutational analysis was performed using polymerase chain reaction and direct sequencing. Of the 10 SRNS children who showed no response to immunosuppressive agents, the compound heterozygous NPHS1 mutations 2677A>G (T893A) and *142T>C were identified in 1 patient, while a heterozygous mutation in WT1, 1180C>T (R394W), was found in another patient. Of the 20 SRNS children showing complete remission who responded to prolonged steroid therapy or immunosuppressive agents, 4 heterozygous NPHS1 mutations, 928G>A, IVS8+30C>T, IVS21+14G>A, and IVS25-23C>T, were identified in 4 patients and a heterozygous CD2AP mutation, IVS7-135G>A, was identified in 1 patient. Our results indicate the necessity of genetic examination for mutations in podocyte genes in Chinese SRNS children who show no response to immunosuppressive agents. PMID- 25501162 TI - Evaluation of the antimutagenic activity and mode of action of carrageenan fiber in cultured meristematic cells of Allium cepa. AB - In this study, we evaluated the mutagenic and antimutagenic activities of carrageenan, a sulfated polysaccharide, and described its mode of action by using an Allium cepa assay. The results indicate that carrageenan is not mutagenic, rather it has significant chemopreventive potential that is mediated by both demutagenic and bio-antimutagenic activities. This compound can adsorb agents that are toxic to DNA and inactivate them. Additionally, carrageenan can modulate enzymes of the DNA repair system. The percentage of damage reduction ranged from 62.54 to 96.66%, reflecting the compound's high efficiency in preventing the type of mutagenic damage that may be associated with tumor development. Based on these findings and information available in the literature, we conclude that carrageenan is an important fiber that should be considered as a possible base for functional foods and/or diets with potential anticancer activity. PMID- 25501163 TI - Comparative cytogenetic mapping of rRNA genes among naked catfishes: implications for genomic evolution in the Bagridae family. AB - In the present study, the karyotype and chromosomal characteristics of 9 species of the Bagridae fish family were investigated using conventional Giemsa staining as well as dual-color fluorescence in situ hybridization to detect the 18S and 5S rDNA sites. In addition to describing the karyotype of several Bagridae catfishes, we established molecular cytogenetic techniques to study this group. The 9 species contained a diploid chromosomal number, varying from 50 (Pseudomystus siamensis) to 62 (Hemibagrus wyckii), while none contained heteromorphic sex chromosomes. 18S rDNA sites were detected in only 1 chromosomal pair among all species evaluated. However, 3 different patterns were observed for the distribution of the 5S rDNA: 2 sites were found in the genus Mystus and in P. siamensis, multiple sites were observed in the genus Hemibagrus, and a syntenic condition for the 18S and 5S rDNA sites was identified in H. wyckii. The extensive variation in the number and chromosomal position of rDNA clusters observed among these Bagridae species may be related to the intense evolutionary dynamics of rDNA-repeated units, which generates divergent chromosomal distribution patterns even among closely related species. In summary, the distribution of repetitive DNA sequences provided novel, useful information regarding the evolutionary relationships between Bagridae fishes. PMID- 25501164 TI - Physical wounding and ethylene stimulated embryogenic stem cell proliferation and plantlet regeneration in protocorm-like bodies of Phalaenopsis orchids. AB - Phalaenopsis orchids have been regenerated by inducing protocorm-like bodies (PLBs) from etiolated leaf sections. However, the physiological and molecular mechanisms of secondary PLB development and subsequent proliferation have not been explored. Bisectionally cutting primary PLBs resulted in more secondary PLBs at 5 weeks, suggesting an embryogenic stem cell property imposed by wounding of primary PLB tissues. The ethylene precursors ethephon and 1 aminocyclopropanecarboxylic acid and the ethylene perception inhibitor silver nitrate increased PLB formation, while aminoethoxyvinylglycine decreased PLB formation. Ethylene content in wounded PLB explants increased over culture time in media containing ethylene precursors or inhibitors. mRNA levels of PhACS2, PhACS3, and PhACO were increased by ethephon and decreased by ethylene inhibitors. Expression of genes in the ethylene signaling pathway was enhanced following ethylene-precursor treatment and was mitigated by ethylene inhibitors during PLB proliferation. Transcription of PhETR and PhEIN3, as well as PhERS, PhCTR, and PhGTP, was significantly increased 12 h after ethylene treatment. Ethylene and physical wounding stimulated secondary PLB formation in Phalaenopsis, probably through ethylene biosynthesis and signal transduction. PMID- 25501165 TI - Genome-wide survey and phylogenetic analysis on subunit sequences of eukaryotic DNA polymerase delta. AB - DNA polymerase d is not only the major replicative enzyme in eukaryotic chromosomal DNA synthesis but is also the primary polymerase for most DNA repair pathways. However, the subunit composition of polymerase d varies in different organisms. While polymerase d in many eukaryotic species has all 4 subunits (POLD1, 2, 3, and 4), many other organisms do not possess POLD4. Whether POLD4 is indispensable and why these differences exist are unknown. In the present study, we identified the POLD4 protein sequences of 218 eukaryotic species and determined the POLD1, 2, and 3 protein sequences of 55 species representing various taxonomic groups. No insect and nematode species examined possessed POLD4. Approximately 80% of protozoan species did not contain POLD4. Nearly 50% of fungal species did not contain POLD4. Other animal and plant species are expected to contain POLD4. Phylogenetic analyses of POLD1, 2, 3, and 4 sequences revealed that most animal and plant species inherited DNA polymerase d from protozoa, whereas some other animal and plant species may have inherited polymerase d directly from fungi. Because a large number of protozoan and fungal species do not possess POLD4, current insect and nematode species lacking POLD4 may have evolved from ancestor protozoan species lacking POLD4; thus, other protozoan and animal species lacking POLD4 may share a similar evolutionary history. Future studies should examine the origin and indispensability of POLD4 in various organisms. PMID- 25501166 TI - Physiological and morphological responses induced by alpha-particle radiation on Arabidopsis thaliana embryos. AB - Alpha (alpha)-particle radiation has been thoroughly studied in the occupational and residential environments, but biological mechanisms induced by alpha-particle radiation on plants are not clearly understood. In this study, radiation effects were examined using different total doses (1, 10, 100 Gy, respectively) of 241Am, alpha-particle on Arabidopsis embryos. No significant difference in the germination percentage was observed between the 3 levels of doses and the control. Germination speed and root length were increased by treatment with the 1 Gy dose of a-particles, and decreased by treatment with 10- and 100-Gy doses. Moreover, the bending degree of roots increased with radiation dose, and the roots showed an "S" shape when treated with the 100-Gy dose. Root bending under the 100-Gy dose was inhibited by scavengers of reactive oxygen species (ROS). Root gravitropism and root length may respond to the consistency of ROS induced by irradiation. Further analysis of the physiological effects revealed that an increase in a-particle radiation intensity enhanced the activity of catalase and the content of malondialdehyde, but superoxide dismutase activity was reduced by treatment with 100-Gy radiation of a-particles, suggesting that the high linear energy transfer of a-particles may cause a relatively high level of membrane lipid preoxidation and high accumulation of ROS. ROS showed both physiological and morphological responses following exposure to alpha-particle radiation in Arabidopsis embryos. PMID- 25501167 TI - Genetic diversity of Y-short tandem repeats in Chinese native cattle breeds. AB - The aim of this study is to use Y-chromosome gene polymorphism method to investigate regional differences in genetic variation and population evolution history of the Chinese native cattle breeds. Six Y-chromosome short tandem repeat (Y-STR) loci (UMN0929, UMN0108, UMN0920, INRA124, UMN2404, and UMN0103) were analyzed using 1016 healthy and heterogenetic males and 90 females of 9 native cattle breeds (Qinchuan, Jinnan, Zaosheng, Luxi, Nanyang, Jiaxian, Dabieshan, Yanbian, and Menggu) in China. Allele frequency and gene diversity were calculated for the various populations. The results indicated that Y-STRs in the 6 loci have polymorphisms and genetic diversity in Chinese cattle populations. The genetic diversity analysis revealed that the Chinese cattle populations have a close genetic relationship. The analysis of INRA124, UMN2404, and UMN0103 loci revealed the original history of Chinese cattle because of which cattle belonging to Bos taurus or Bos indicus could be determined. Interestingly, a declining zebu introgression was displayed from South to North and from East to West in the Chinese geographical distribution, which implied that cattle population from various regions of China had been subjected to somewhat different evolutionary history. This conclusion supported other evidences such as earlier archaeological, historical research, and blood protein polymorphism analysis. PMID- 25501168 TI - Association of VDR polymorphisms with type 2 diabetes mellitus in Chinese Han and Hui populations. AB - We investigated the association between vitamin D receptor (VDR) and susceptibility to type 2 diabetes mellitus (T2DM). Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis was conducted to examine single nucleotide polymorphisms (SNPs) of the rs1544410 (BsmI, G>A), rs757343 (Tru9I, G>A), rs731236 (TaqI, T>C), and rs739837 (BglI, G>T) loci of the VDR gene in 334 healthy individuals (Hui 115, Han 219) and 355 T2DM patients (Hui 154, Han 201) living in the Ningxia Hui Autonomous Region of China. The genotypic frequency and allelic frequency distributions in the VDR gene showed no significant difference between T2DM patients and controls in the Chinese Hui population. However, statistical differences in the genotypic frequency at rs739837 and in the genotypic and allelic frequencies at rs1544410 were observed between T2DM patients and controls in the Chinese Han population (P < 0.05). Patient-control haplotype analyses using the SHEsis online haplotype analysis software showed that the G allele frequency of rs1544410 in the T2DM group was higher than that in the control group [odds ratio (OR) = 1.738, 95% confidence interval (CI) = 1.055-2.865], suggesting that the G allele is a risk factor of T2DM in the Chinese Han population. The frequency of haplotype GGCT between cases and controls was significantly different in both Chinese Hui [OR (95%CI) = 4.714 (1.04-21.36)] and Han populations [OR (95%CI) = 1.723 (1.03-2.883)] (P < 0.05), implying that the haplotype GGCT of the VDR gene is associated with susceptibility to T2DM in these ethnicities. PMID- 25501169 TI - Effect of intracoronary tirofiban on platelet alpha-granule membrane protein and myocardial perfusion level during emergency percutaneous coronary intervention. AB - This study aimed to investigate the effect of intracoronary application of tirofiban on platelet alpha-granule membrane protein (GMP-140) and myocardial perfusion levels during emergency percutaneous coronary intervention (PCI). A total of 70 patients who accepted emergency PCI treatment were randomly divided into tirofiban and control groups. We determined GMP-140 and troponin I (cTnI) levels before and 12 h after surgery, as well as N-terminal pro-brain natriuretic peptide levels 1 and 7 days after surgery in the two groups. The results showed that GMP-140 and cTnI levels were significantly (P < 0.01) lower in the tirofiban group than in the control group 12 h after operation (17.99 +/- 1.01 vs 24.56 +/- 1.96 MUg/L and 50.96 +/- 2.20 vs 58.69 +/- 2.34 ng/mL, respectively). The D-value of the N-terminal pro-brain natriuretic peptide levels between 1 and 7 days after operation was significantly higher in the tirofiban group than in the control group (894.19 +/- 90.91 vs 829.50 +/- 84.18 pg/mL; P < 0.01). The intracoronary application of tirofiban during emergency PCI clearly reduced the GMP-140 level, inhibited the activation function of platelets, improved myocardial perfusion, and helped recover cardiac function in patients. PMID- 25501170 TI - Identification of sequence-related amplified polymorphism and insertion-deletion markers linked to the male fertility restorer gene of pol-like CMS06J45 in heading Chinese cabbage (Brassica rapa subsp pekinensis). AB - In order to map the restorer gene BrRfp of the polima (pol)-like cytoplasmic male sterility (CMS) 06J45 line in heading Chinese cabbage, an F2 segregating population with 258 individuals of CMS06J45 and the restorer line 01S325 were tested by sequence-related amplified polymorphism (SRAP) and insertion-deletion (InDel) technologies combined with the bulked segregant analysis method. As a result, two SRAP markers, me3em3.366 and pm88bg5.263, that were linked with the BrRfp gene were identified from 463 SRAP primer pairs. By cloning, sequencing, and basic local alignment search tool analysis, the two markers were targeted to the BGIScaffold000053 of Brassica rapa in the Brassica database. Using the BGIScaffold000053 sequence, four InDel primer pairs were designed and identified to be linked with the BrRfp gene in this population. Linkage analysis showed that these markers were distributed on both sides of the BrRfp gene, the linkage distances of two nearest markers InDel878.1125 and InDel920.713 were 0.82 and 0.46 cM, respectively, and the BrRfp gene was restricted to a 243-kb genomic region of B. rapa. These specific markers provided basic information for map based cloning of the BrRfp gene and will be very valuable for the marker-assisted selection of a new restorer line in heading Chinese cabbage. PMID- 25501171 TI - Identification of the porcine sialoadhesin gene promoter region and its cell specific expression in porcine alveolar macrophage cells. AB - Porcine reproductive and respiratory syndrome (PRRS), which is caused by the PRRS virus (PRRSV), is a communicable disease. PRRS caused huge economic losses to swine breeding. The porcine alveolar macrophage (PAM) cell is the main target cell of PRRSV; therefore, it is very important to identify the specific gene promoter that controls expression in PAM cells so that the anti-PRRSV exogenous gene can be efficiently and specifically expressed in PAM cells to improve porcine resistance to PRRSV. In this study, the transcription initiation site for sialoadhesin (Siglec-1), which is a porcine alveolar macrophage-specific gene, was determined by 5' rapid amplification of cDNA end, and 88 bp of the 5' untranslated region was cloned. Siglec-1 promoter activity was detected by a dual luciferase reporter assay, which showed that the fragment from -173 to +81 bp had the strongest promoter activity. Additionally, the cell-specific expression of the promoter fragments was tested in a PAM cell line (CRL-2844 cells), porcine kidney 15 cell line (PK-15 cells), porcine fetal fibroblast (PEF) cells, and porcine preadipocytes. These results also showed that the fragment from -173 to +81 bp had the strongest cell-specific expression in PAM cells. PMID- 25501172 TI - Isolation and characterization of microsatellite loci from the tick Amblyomma aureolatum (Acari: Ixodidae). AB - Amblyomma aureolatum (Pallas) is the main vector of the bacterium Rickettsia rickettsii, the etiological agent of Brazilian spotted fever. This disease is the most lethal human spotted fever rickettsiosis in the world. Microsatellite loci were isolated from a dinucleotide-enriched library produced from A. aureolatum sampled in Southeastern Brazil. Eight polymorphic microsatellites were further characterized among 38 individuals sampled from Sao Paulo metropolitan region. The number of observed alleles ranged from 2 to 9, observed heterozygosity was 0.184-0.647, and expected heterozygosity was 0.251-0.747. Cross-species amplifications suggested that these loci will be useful for other Amblyomma species. PMID- 25501173 TI - Physical mapping of 18S and 5S genes in pelagic species of the genera Caranx and Carangoides (Carangidae). AB - In Carangidae, Caranx is taxonomically controversial because of slight morphological differences among species, as well as because of its relationship with the genus Carangoides. Cytogenetic data has contributed to taxonomic and phylogenetic classification for some groups of fish. In this study, we examined the chromosomes of Caranx latus, Caranx lugubris, and Carangoides bartholomaei using classical methods, including conventional staining, C-banding, silver staining for nuclear organizer regions, base-specific fluorochrome, and 18S and 5S ribosomal sequence mapping using in situ hybridization. These 3 species showed chromosome numbers of 2n = 48, simple nuclear organizer regions (pair 1), and mainly centromeric heterochomatin. However, C. latus (NF = 50) and C. bartholomaei (NF = 50) showed a structurally conserved karyotype compared with C. lugubris (NF = 54), with a larger number of 2-armed chromosomes. The richness of GC-positive heterochromatic segments and sites in 5S rDNA in specific locations compared to the other 2 species reinforce the higher evolutionary dynamism in C. lugubris. Cytogenetic aspects shared between C. latus and C. bartholomaei confirm the remarkable phylogenetic proximity between these genera. PMID- 25501174 TI - Short communication: novel truncating mutations in the CFTR gene causing a severe form of cystic fibrosis in Italian patients. AB - Cystic fibrosis (CF) is a common recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. More than 1800 different mutations have been described to date. Here, we report 3 novel mutations in CFTR in 3 Italian CF patients. To detect and identify 36 frequent mutations in Caucasians, we used the INNO-LiPA CFTR19 and INNO-LiPA CFTR17+Tn Update kits (Innogenetics; Ghent, Belgium). Our first analysis did not reveal both of the responsible mutations; thus, direct sequencing of the CFTR gene coding region was performed. The 3 patients were compound heterozygous. In one allele, the F508del (c.1521_1523delCTT, p.PHE508del) mutation in exon 11 was observed in each case. For the second allele, in patient No.1, direct sequencing revealed an 11-base pair deletion (GAGGCGATACT) in exon 14 (c.2236_2246del; pGlu746Alafs*29). In patient No. 2, direct sequencing revealed a nonsense mutation at nucleotide 3892 (c.3892G>T) in exon 24. In patient No. 3, direct sequencing revealed a deletion of cytosine in exon 27 (c.4296delC; p.Asn1432Lysfs*16). These 3 novel mutations indicate the production of a truncated protein, which consequently results in a non-functional polypeptide. PMID- 25501175 TI - Increased serum ADAMTS-4 in knee osteoarthritis: a potential indicator for the diagnosis of osteoarthritis in early stages. AB - We compared serum levels of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, matrix metalloproteinase (MMP)-1, and MMP-3 in patients with different stages of knee osteoarthritis (OA), and investigated the clinical significance of diagnosing OA in early stages. OA patients were divided into 2 groups: early OA group (44 cases), intermediate and advanced OA group (26 cases). The healthy control group included 30 samples. ADAMTS-4, ADAMTS-5, MMP-1, and MMP-3 levels in the serum were tested using an enzyme-linked immunosorbent assay. A protein-protein interaction network was constructed by seeding the significantly expressed marker, followed by Gene Ontology enrichment analyses using Database for Annotation, Visualization and Integrated Discovery. ADAMTS-4 levels were significantly higher in patients at early stages of OA compared to intermediate or advanced OA and healthy controls. ADAMTS-5, MMP-1, and MMP-3 levels in intermediate and advanced-stage OA patients were significantly higher than those in early-stage OA patients and healthy controls. The protein-protein interaction network showed that ADAMTS-4 participates in 67 interactions. Gene Ontology enrichment analysis validated that genes associated with ADAMTS-4 participate in collagen metabolism and OA. ADAMTS 4 is a potential biomarker as an early diagnostic indicator of OA. PMID- 25501176 TI - Germline mutation analysis in the CYLD gene in Chinese patients with multiple trichoepitheliomas. AB - Trichoepithelioma is a benign neoplasm that primarily shows follicular germinative differentiation. Classic trichoepithelioma typically presents as a skin-colored papule or nodule on the face or upper trunk; lesions have a predilection for the nose. Trichoepithelioma can be sporadic or familial and solitary or multiple. Most previously reported multiple trichoepithelioma cases are familial, and germline CYLD mutations could be detected in some patients. We performed mutational analysis of the germline CYLD gene in 8 Chinese multiple trichoepitheliomas patients, 6 of which were sporadic cases. A heterozygous missense mutation (c.1112C>A) in the 9th exon of the CYLD gene was detected in some mother-daughter patients. However, the germline CYLD mutation could not be detected in the 6 non-familial cases. The results suggest that the pathogenesis of sporadic multiple trichoepitheliomas may differ from that of familial cases. Our findings also further confirmed the genetic heterogeneity of multiple trichoepitheliomas. PMID- 25501177 TI - Behavior of calf Sertoli cells and fibroblast cells transfected with the human HNP-1 gene. AB - Human neutrophil peptide-1 (HNP-1) is an important defense molecule in neutrophils and Sertoli cells and plays an important role in the blood-testis barrier. In this study, we investigated the behavior of Sertoli cells transfected with the HNP-1 gene and compared the ability of Sertoli cells and fibroblast cells to resist transfection. Total RNA was isolated from human blood. The DNA coding sequence of HNP-1 was amplified by reverse transcription-polymerase chain reaction (RT-PCR) and the eukaryotic expression vector pEGFP-N3-HNP-1 was identified by PCR, endonuclease digestion, and sequencing. Bovine Sertoli cells and fibroblast cells were transfected with pEGFP-N3-HNP-1 using Liposome reagent. The transfection efficiency and the behavior of the transfected cells were evaluated at 24, 48 and 72 h as well as at other times after transfection. The plasmid pEGFP-N3-HNP-1 was successfully constructed. The cells achieved maximum transfection efficiency at 48 h. Two weeks after transfection, the cells began to stop dividing. The ability of Sertoli cells to resist transfection was higher compared to fibroblast cells. The ability of the 2 cell types to resist transfection was higher with plasmid pEGFP-N3-HNP-1 than with the plasmid pEGFP N3. The injury to Sertoli cells caused by transfection with the HNP-1 gene was less pronounced than in fibroblast cells, which may be closely correlated with the physiological function of Sertoli cells. PMID- 25501178 TI - Using volume-time curves with real-time three-dimensional echocardiography to analyze right ventricular function in patients with pneumoconiosis. AB - We evaluated right ventricular function in patients with pneumoconiosis using real-time three-dimensional echocardiography (RT3DE). A total of 80 consecutive patients were prospectively recruited, 44 of whom were diagnosed with pneumoconiosis, and the remaining 36 age- and gender-matched healthy volunteers served as the control group. All patients underwent both 2D and 3DE. The tricuspid regurgitation pressure (TRPG), right ventricular anterior wall thickness and range of motion, right ventricular posterior wall thickness and range of motion, right ventricular end-diastolic volume, right ventricular end systolic volume, and right ventricular ejection fraction (RVEF) were measured. The RVEF of healthy volunteers ranged from 50 to 78%, while the RVEF of pneumoconiosis patients ranged from 29 to 73%. TRPG influenced RVEF by 77.3% (P = 0.006) and showed a negative correlation (r = -0.643, P < 0.01). Volume-time curves (VTC) of patients with pneumoconiosis showed more troughs (low stroke volumes) than the VTCs of normal subjects. Evaluation of right ventricular function in patients with pneumoconiosis using RT3DE can provide additional clinical information. PMID- 25501179 TI - Comparison of genetic diversity between wild-caught broodstock and hatchery produced offspring populations of the vulnerable Korean kelp grouper (Epinephelus bruneus) by microsatellites. AB - The kelp grouper Epinephelus bruneus (Perciformes: Haemulidae), is one of the most economically important fishery resources in Korea. This fish is regarded as a target for prospective aquaculture diversification; therefore, maintenance of stock quality is important. To investigate the effects of current artificial reproduction in a hatchery facility, genetic variation in wild-caught broodstock and hatchery-produced offspring of kelp grouper was analyzed using eight polymorphic nuclear microsatellite DNA loci; 77 alleles were identified. Allelic variability ranged from 2 to 22 in the broodstock and from 1 to 10 in the offspring. The average observed and expected heterozygosities were 0.620 and 0.623 in the broodstock and 0.600 and 0.513 in the offspring, respectively. The possibility of a recent genetic bottleneck was suggested in both populations of E. bruneus. The minor, but significant, genetic differentiation (FST = 0.047, P < 0.05) observed was mainly due to statistically significant reductions in the number of alleles in the offspring compared with the broodstock, suggesting that these genetic changes could be related to genetic drift. Our results demonstrate the usefulness of microsatellite markers to monitor genetic variation and raise concerns about potential harmful genetic effects of inappropriate hatchery procedures. Therefore, genetic variation between broodstock and offspring in a hatchery should be monitored in both breeding and release programs as a routine hatchery operation, and inbreeding should ideally be controlled to improve kelp grouper hatchery management. Our data provide a useful genetic basis for future planning of sustainable culture and management of E. bruneus in fisheries. PMID- 25501180 TI - Molecular cloning, characterization, and bioactivity analysis of interleukin 18 in giant panda (Ailuropoda melanoleuca). AB - Interleukin 18 (IL-18), as a member of IL-1 superfamily, is an important pleiotropic cytokine that modulates Th1 immune responses. In this report, we cloned and identified a homolog of IL-18 in giant panda (Ailuropoda melanoleuca) (designated as AmIL-18) from peripheral blood mononuclear cells stimulated with lipopolysaccharide. The open readin g frame of AmIL-18 cDNA is 579 bp encoding a deduced protein of 192 amino acids. AmIL-18 gDNA fragments contained 5 exons and 4 introns. The amino acid sequence of AmIL-18 shared 23.9 to 87.0% identity with other species. To evaluate the effects of AmIL-18 on the immune response, we expressed the recombinant AmIL-18 in Escherichia coli BL21 (DE3). The fusion protein PET-AmIL-18 was purified by nickel affinity column chromatography and verified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot analysis. The biological function of purified PET-AmIL-18 was determined on mouse splenocytes by quantitative real-time polymerase chain reaction. INF-gamma and other cytokines were increased when stimulated by PET-AmIL-18, particularly when combined with recombinant human interleukin 12, while a Th2-type cytokine, interleukin-4, was strikingly suppressed. These results will provide information for the potential use of recombinant proteins to manipulate the immune response in giant pandas and facilitate the study to protect this treasured species. PMID- 25501181 TI - Assessment of sensitivity and virulence fitness costs of the AvrPik alleles from Magnaporthe oryzae to isoprothiolane. AB - The in vitro sensitivity of AvrPik allele isolates of Magnaporthe oryzae to isoprothiolane was examined and the virulence fitness costs of AvrPik allele isolates to isoprothiolane were assessed. Isoprothiolane was found to suppress the radial growth of AvrPik allele isolates at all concentrations (1, 5, 10, 15, and 20 MUg/mL). Generally, a higher isoprothiolane concentration has a stronger inhibitory effect on mycelial growth in AvrPik allele isolates at 6 and 10 days after inoculation. The inhibitory effect of isoprothiolane also increased with treatment time. To determine whether a correlation existed between the in vitro sensitivity of AvrPik allele isolates and virulence, the half-maximal inhibitor concentration and 75% of the maximum inhibitor concentration were calculated for each mutation isolate and wild-type isolate. Based on these values and virulence, no significant correlation between the susceptibility of AvrPik allele isolates and virulence was detected. In summary, no fitness costs were associated with sensitivity of blast isolates carrying specific AvrPik alleles to different virulence. PMID- 25501182 TI - Prospective molecular markers for the identification of illegally traded angelsharks (Squatina) and dolphin (Sotalia guianensis). AB - Endangered angelsharks and a protected dolphin species are illegally traded in Brazil. In this study, we determined prospective molecular markers for detecting these species in the trade of angelshark carcasses and 'dolphin' eyeball amulets. We compiled publicly available as well as new and unpublished cytochrome b (cyt b) DNA sequences for species involved in these trades. These sequences were digested in silico using restriction enzymes. We then described prospective polymerase chain reaction (PCR)-restriction fragment length polymorphism markers for distinguishing between protected species and the species whose trade was legally allowed in these two trade groups. The prospective marker for identifying angelshark carcasses consists of cyt b PCR and digestion by BstXI, BsgI, BspMI, BsrDI, and HaeII restriction enzymes. The prospective marker for identifying eyeball amulets consists of cyt b PCR and digestion by ApoI, BtsI, HindII, BsaAI, BplI, and SspI restriction enzymes. This is the first study to deposit in GenBank cyt b sequences for the angelshark species Squatina argentina, Squatina guggenheim, and Squatina occulta. Moreover, the S. argentina haplotype is the first DNA sequence for this species deposited in GenBank. PMID- 25501183 TI - Acetate ester production by Chinese yellow rice wine yeast overexpressing the alcohol acetyltransferase-encoding gene ATF2. AB - Acetate ester, which are produced by fermenting yeast cells in an enzyme catalyzed intracellular reaction, are responsible for the fruity character of fermented alcoholic beverages such as Chinese yellow rice wine. Alcohol acetyltransferase (AATase) is currently believed to be the key enzyme responsible for the production of acetate ester. In order to determine the precise role of the ATF2 gene in acetate ester production, an ATF2 gene encoding a type of AATase was overexpressed and the ability of the mutant to form acetate esters (including ethyl acetate, isoamyl acetate, and isobutyl acetate) was investigated. The results showed that after 5 days of fermentation, the concentrations of ethyl acetate, isoamyl acetate, and isobutyl acetate in yellow rice wines fermented with EY2 (pUC-PIA2K) increased to 137.79 mg/L (an approximate 4.9-fold increase relative to the parent cell RY1), 26.68 mg/L, and 7.60 mg/L, respectively. This study confirms that the ATF2 gene plays an important role in the production of acetate ester production during Chinese yellow rice wine fermentation, thereby offering prospects for the development of yellow rice wine yeast starter strains with optimized ester-producing capabilities. PMID- 25501185 TI - Identification of quantitative trait loci conferring blast resistance in Bodao, a japonica rice landrace. AB - Bodao, a japonica landrace from the Taihu Lake region of China, is highly resistant to most Chinese isolates of Magnaporthe oryzea, a form of rice blast. To effectively dissect the influence of genetics on this blast resistance, a population of 155 recombinant inbred lines (F2:8) derived from a cross of Bodao x Suyunuo was inoculated with 12 blast isolates. Using a quantitative trait locus (QTL) mapping approach, 13 QTL on chromosomes 1, 2, 9, 11, and 12 were detected from Bodao. Five QTL, including qtl11-1-1, qtl11-3-7, qtl11-4-9, qtl12-1-1, and qtl12-2-3, have not been previously reported. The qtl11-3-7 and qtl11-4-9 may be the two main effective QTL and resistant to 7 and 9 isolates, respectively. The results of the present study will be valuable for the fine mapping and cloning of these two new resistance genes. PMID- 25501184 TI - Role of Th1/Th2 cytokines in serum on the pathogenesis of chronic hepatitis C and the outcome of interferon therapy. AB - The aim of this study was to investigate the role of T-helper cell (Th)1/Th2 cytokines in the chronicity of hepatitis C virus (HCV) infection and the outcome of interferon (IFN) alpha therapy. A total of 30 patients with chronic hepatitis C were enrolled in the study. The levels of Th1/Th2 cytokines were determined. The differentiation of HCV genotypes was determined by direct sequencing. HCV RNA loads were detected by fluorescence quantitative polymerase chain reaction (qPCR). In chronic hepatitis C, the levels of interleukin (IL)-2 and transforming growth factor (TGF)-beta significantly decreased, and IL-5 and IL-18 levels increased compared with normal controls. The IL-6 serum levels were directly proportional to the serum levels of alanine aminotransferase, and were inversely proportional to the HCV RNA loading levels. Patients with severe hepatitis C had higher levels of IL-4, IL-6, and IL-1beta compared to milder cases. Patients with genotype 1 showed higher serum levels of IL-6 than those with genotype 2. The levels of IL-2 and IL-18 showed a decreasing tendency, whereas TGF-beta, IL-6, and IL-1beta showed an increasing tendency over time. There was no difference in any cytokines detected between the response and nonresponse groups before IFN therapy. However, the IFN-y level increased after IFN therapy in the response group. There was no correlation between the Th1/Th2 cytokine levels in the serum before IFN treatment and in the outcome of IFN therapy. Increasing IFN-y levels in the serum induced by IFN treatment is associated with systemic vascular resistance. PMID- 25501186 TI - Isolation, molecular cloning, and characterization of a novel porcine lymphotoxin beta receptor gene. AB - The lymphotoxin beta receptor (LTbetaR) is a member of the tumor necrosis factor family of receptors (TNFR). It plays a role in regulating lymphoid organogenesis and homeostasis of the immune system. In the present study, the full coding region of a putative LTbetaR gene of Sus scrofa was amplified by reverse transcription-polymerase chain reaction (RT-PCR) and cloned for the first time (accession Nos. JX457347 and AFU74012). In addition, analysis of the tissue expression profile was carried out via RT-PCR. The full-length coding region of porcine LTbetaR had 1266 nucleotides (molecular weight, 45.61 kDa; pI, 5.71) and encoded 421 amino acids. Bioinformatic prediction indicates that LTbetaR belongs to the TNFR superfamily and contains a TNFR domain. The sequence homology analysis revealed that the amino acid sequences of S. scrofa LTbetaR had 82.9, 82.4, 81.3, 80.5, 78.7, 74.6, and 73.0% identity with those of Equus caballus, Canis lupus, Ailuropoda melanoleuca, Oryctolagus cuniculus, Bos taurus, Mus musculus, and Homo sapiens, respectively. The phylogenetic tree based on the amino acid sequences of LTbetaR from 8 species revealed that S. scrofa was more closely related to E. caballus, C. lupus, and A. melanoleuca. RT-PCR analysis showed that the porcine LTbetaR gene was differentially expressed (e.g., high, moderate, low, or nonexistent) in various tissues (e.g., prostate, pituitary, brainstem, and esophagus, respectively). This may be related to differences in the regulation of LTbetaR in the different tissues. PMID- 25501187 TI - Screening of highly informative and representative microsatellite markers for genotyping of major cultivated cotton varieties. AB - We screened and assessed published cotton simple sequence repeat (SSR) primers to establish a set of core SSR markers suitable for cotton major cultivars in China and analyzed genetic diversity based on the core marker set. Using a stepwise screening strategy, 12 leading cultivars for preliminary screening and 96 cultivars for rescreening were evaluated. A total of 184 polymorphic SSR markers were initially screened from 3299 candidates, and a core set of 52 SSR markers with wide genome coverage (2 markers per chromosome) was obtained. Among 96 major cultivars, 273 amplification genotypes were generated using the core marker set. Polymorphism information content values ranged from 0.28-0.83, with an average value of 0.56. The core SSR marker set detected on denaturing polyacrylamide gel electrophoresis indicated that the band genotype was either a single or double band on conventional cultivars, while most were double bands (65.4%). Among 56 hybrids, the average heterozygosis rate was 35.8%, ranging from 7.1-55.4%. Eighteen of 96 cultivars had distinct band genotypes. The genetic diversity analyzed using the of NTSYS-pc V2.10 software indicated that the Yangtze River valley cotton region had the highest polymorphic level, followed by Xinjiang and then the Yellow River valley. The genetic basis of conventional cultivars was narrower than that of hybrids. The core marker set can be used for fingerprint construction, variety identification, and purity tests of major cotton cultivars in China. PMID- 25501188 TI - Alteration of HSF3 and HSP70 mRNA expression in the tissues of two chicken breeds during acute heat stress. AB - This study aimed to estimate changes in HSF3 and HSP70 mRNA expression in stress sensitive tissues of 2 chicken breeds during acute heat stress. Lingshan chickens (LSC) and White Recessive Rock (WRR) (24 chickens of each breed) were randomly divided into 4 groups (0, 2, 3, and 6 h of heat treatment). With increasing heat treatment time, both HSF3 and HSP70 expression first declined and then showed a significant increase in both breeds. However, HSP70 expression decreased in the heart following 6 h of heat treatment, whereas HSF3 expression continued to increase. After 2 h of heat treatment, HSF3 expression was significantly higher in the brain and leg muscle of LSC compared to WRR (P < 0.05, P < 0.01). In comparison, HSP70 expression was significantly higher in the liver and leg muscle of WRR compared to LSC (P < 0.01, P < 0.05). After 3 h of heat treatment, HSF3 expression was significantly higher in the brain and leg muscle of LSC compared to WRR (P < 0.01). In comparison, HSP70 expression was significantly higher in the liver and heart of LSC compared to WRR (P < 0.01). These results indicate that the expression of HSF3 and HSP70 mRNA in LSC and WRR exhibit species specific and tissue-specific differences during heat treatment. PMID- 25501189 TI - Selection of optimized candidate reference genes for qRT-PCR normalization in rice (Oryza sativa L.) during Magnaporthe oryzae infection and drought. AB - Drought and rice blast disease caused by Magnaporthe oryzae are two of the most serious threats to global rice production. To explore the mechanisms underlying gene expression induced in rice by stresses, studies involving transcriptome analyses have been conducted over the past few years. Thus, it is crucial to have a reliable set of reference genes to normalize the expression levels of rice genes affected by different stresses. To identify potential reference genes for studies of the differential expression of target genes in rice under M. oryzae infection and drought conditions, the present study evaluated five housekeeping genes for the normalization of gene expression. The stability of the expression of these genes was assessed using the analytical software packages geNorm and NormFinder. For all samples analyzed, the stability rank was UBQ5 > GAPDH > eIF 4alpha> beta-TUB > 18S rRNA. The data showed that the UBQ5, GAPDH, and eIF 4alphagenes are appropriate, high-performing reference genes and will be highly useful in future expression studies of fungal infections and drought in rice. PMID- 25501190 TI - Georeferenced evaluation of genetic breeding value patterns in Brazilian Holstein cattle. AB - The aim of this study was to analyze the relationship between environmental and genetic values for milk production and type traits in Holstein cattle in Brazil. The genetic value of 65,383 animals for milk production and 53,626 for type classification were available. Socioeconomic and environmental data were obtained from the Brazilian Institute of Geography and Statistics, the Food and Agriculture Organization of the United Nations, the National Aeronautics and Space Administration, and the National Institute of Meteorology. Five to six clusters were generated for each of the groups of type traits and production levels. The relationships between these traits were assessed using the STEPDISC, DISCRIM and CANDISC procedures in SAS((r)). Traits within the clusters behaved differently, but, in general, animals with lower genetic values were found in environments that were more stressful for animal production. These differences were mainly associated with temperature, humidity, precipitation and the Normalized Difference Vegetative Index. Genetic values for milk production showed best discrimination between different environments, while type traits showed poor discrimination, possibly because farmers mainly select for milk production. Environmental variations for genetic values in dairy cattle in Brazil should be further examined. PMID- 25501191 TI - Selection indices to identify drought-tolerant grain sorghum cultivars. AB - Twenty-five cultivars of grain sorghum [Sorghum bicolor (L.) Moench] were examined under both drought stress and normal conditions in 4 experiments. In each condition, genotypes were evaluated in a factorial experiment using a randomized complete block design with 3 replications. Eight drought tolerance indices including stability tolerance index, mean productivity (MP), geometric MP, harmonic mean, stress susceptibility index, tolerance index, yield index, and yield stability index were estimated for each genotype based on grain yield under drought (Ys) and irrigated conditions (Yp). The results indicated that there were positive and significant correlations among Yp and Ys with geometric MP, MP, harmonic mean, and stability tolerance index, indicating that these factors are better predictors of Yp and Ys than tolerance index, stress susceptibility index, yield stability index, and yield index. Based on adjusted means at Yp and Ys, indices geometric MP, MP, harmonic mean, and stability tolerance index, unweighted pair group method with arithmetic mean cluster and biplot analysis, the most tolerant cultivars were '9929020', '9929034', and 'N 95B'. PMID- 25501192 TI - Phenotyping of Passiflora edulis, P. setacea, and their hybrids by a multivariate approach. AB - Morphological characterization is the most accessible and used method to quantify the genetic diversity of the available germplasm. The multivariate statistical method is highly important for this purpose. This study aimed to characterize parents and hybrids of Passiflora according to morphoagronomic descriptors and estimate the genetic divergence between them based on the joint analysis of qualitative and quantitative variables using the Ward-modified location model (MLM) procedure. One hundred and thirty-eight individuals were assessed (10 P. edulis, 10 P. setacea, and 118 interspecific hybrids) using 23 quantitative and 12 qualitative descriptors. The values for the quantitative descriptors were measured and subjected to multivariate statistics using the Ward-MLM strategy. Large genetic variability was detected by the morphoagronomic data in the 138 genotypes that were evaluated, and the hybrids presented higher variability than the parents. Pseudo-F and pseudo-t2 criteria showed that the optimal number of groups was three. Group I was composed of 118 hybrid genotypes; group II was composed of the 10 P. setacea genotypes, and group III was composed of the 10 P. edulis genotypes. The longest distance was found between groups II and III (474.96). The shortest distance was detected between groups I and II (198.78), which indicates that the segregating population is genetically closer to P. setacea than to P. edulis. The Ward-MLM procedure is a useful tool to detect genetic diversity and group accessions using both qualitative and quantitative variables. PMID- 25501193 TI - Cross-species transferability of microsatellite markers in the genus Lippia. AB - The cross-species transferability of 20 microsatellite markers was tested in the genus Lippia. Eleven markers were polymorphic after screening 19 accessions of Lippia sidoides and Lippia gracilis maintained in the Active Germplasm Bank (AGB) from Universidade Federal de Sergipe. Additionally, 40 accessions of Lippia spp were collected in Sergipe to increase the germplasm bank. A total of 23, 22, and 36 alleles were identified, with an average of 2.3, 2.2, and 3.27 alleles per locus, respectively, for each group. The markers that were used were efficient tools to access genetic diversity in the germplasm bank and will be useful for further research aiming at the conservation and management of these important aromatic species. PMID- 25501194 TI - Molecular characterization of bromeliads from northeast Brazil. AB - Bromeliaceae is an important botany family that includes many species with economic value; demand for members of this family is increasing. However, illegal collection frequently occurs, drastically reducing the species populations; thus, it is necessary to collect and store Bromeliaceae genetic material. In this study, we identified and quantified genetic variability of the Bromeliad family using dominant markers to create the first Germplasm Bank in the northeast region of Brazil. Molecular tools were used to characterize the collected accessions. The combination of 11 inter-simple sequence repeats and 13 random amplified polymorphic DNA markers were used to detect the genetic variability of wild bromeliad accessions. PMID- 25501195 TI - Nuclear and mitochondrial genome instability induced by senna (Cassia angustifolia Vahl.) aqueous extract in Saccharomyces cerevisiae strains. AB - Cassia angustifolia Vahl. (senna) is commonly used in self-medication and is frequently used to treat intestine constipation. A previous study involving bacteria and plasmid DNA suggested the possible toxicity of the aqueous extract of senna (SAE). The aim of this study was to extend the knowledge concerning SAE genotoxicity mechanisms because of its widespread use and its risks to human health. We investigated the impact of SAE on nuclear DNA and on the stability of mitochondrial DNA in Saccharomyces cerevisiae (wt, ogg1, msh6, and ogg1msh6) strains, monitoring the formation of petite mutants. Our results demonstrated that SAE specifically increased Can(R) mutagenesis only in the msh6 mutant, supporting the view that SAE can induce misincorporation errors in DNA. We observed a significant increase in the frequency of petite colonies in all studied strains. Our data indicate that SAE has genotoxic activity towards both mitochondrial and nuclear DNA. PMID- 25501196 TI - A suite of microsatellite markers for genetic management of captive cracids (Aves, Galliformes). AB - Cracids are medium to large frugivorous birds that are endemic to the Neotropics. Because of deforestation and overhunting, many species are threatened. The conservation of several species has relied on captive breeding and reintroduction in the wild, but captive populations may be inbred. Microsatellite tools can permit the construction of genetic pedigrees to reduce inbreeding, but only a few loci are available for this group of birds. Here, we present 10 novel polymorphic microsatellite loci and the cross-amplification of these and of 10 additional loci available in the literature in a panel of 5 cracid species, including 3 species with high conservation concern. We provide the first polymorphic loci for the jacutinga, Aburria jacutinga (N = 8), and red-billed curassow, Crax blumenbachii (N = 9), and additional loci for bare-faced curassow, C. fasciolata (N = 8), Alagoas curassow, Pauxi mitu (N = 5), and razor-billed curassow, P. tuberosa (N = 5). The average number of alleles was 2.9 for A. jacutinga, 2.7 for C. blumenbachii, 3.5 for C. fasciolata, 2.6 for P. mitu, and 5.7 for P. tuberosa. The mean expected heterozygosities were 0.42, 0.40, 0.48, 0.37, and 0.59, respectively. The average probabilities that the set of loci would not exclude a pair of parents of an arbitrary offspring were 2.9% in A. jacutinga, 1% in C. blumenbachii, 0.5% in C. fasciolata, 0.4% in P. mitu, and 0.002% in P. tuberosa suggesting that these loci may be adequate for parentage analysis and to implement ex situ genetic management plans. PMID- 25501197 TI - Cloning and sequence analysis of the Blumea balsamifera DC farnesyl diphosphate synthase gene. AB - Blumea balsamifera DC is a member of the Compositae family and is frequently used as traditional Chinese medicine. Blumea balsamifera is rich in monoterpenes, which possess a variety of pharmacological activities, such as antioxidant, anti bacteria, and anti-viral activities. Farnesyl diphosphate synthase (FPS) is a key enzyme in the biosynthetic pathway of terpenes, playing an important regulatory role in plant growth, such as resistance and secondary metabolism. Based on the conserved oligo amino acid residues of published FPS genes from other higher plant species, a cDNA sequence, designated BbFPS, was isolated from B. balsamifera DC using polymerase chain reaction. The clones were an average of 1.6 kb and contained an open reading frame that predicted a polypeptide of 342 amino acids with 89.07% identity to FPS from other plants. The deduced amino acid sequence was dominated by hydrophobic regions and contained 2 highly conserved DDxxD motifs that are essential for proper functioning of FPS. Phylogenetic analysis indicated that FPS grouped with other composite families. Prediction of secondary structure and subcellular localization suggested that alpha helices made up 70% of the amino acids of the sequence. PMID- 25501198 TI - Serum hepcidin level and its clinical significance in maintenance hemodialysis patients. AB - Hepcidin is a key protein of iron metabolism, which may play an important role in the prognosis of patients with chronic renal failure on maintenance hemodialysis. The purpose of this study was to investigate the relationship between the prognosis of maintenance hemodialysis patients and serum hepcidin level. We enrolled 60 patients on maintenance hemodialysis and 30 healthy controls from March 2012 to December 2012 in our hospital. Peripheral blood samples were collected to determine hepcidin by an ELISA method. Hepcidin levels of hemodialysis patients were significantly higher than those of the healthy control group. Hepcidin level was positively correlated with the degree of anemia in the dialysis group. Therefore, we conclude that hepcidin level is significantly increased in patients with chronic renal failure on maintenance hemodialysis and that increased hepcidin seriously affects the prognosis of chronic renal failure. PMID- 25501199 TI - Characterization of a novel anther-specific gene encoding a leucine-rich repeat protein in petunia. AB - In Petunia x hybrida 'Fantasy Red', a leucine-rich repeat (LRR) gene referred to as PhLRR, was identified in a flower bud cDNA library. The open reading frame sequence of PhLRR was 1251 bp, encoding a putative 46.2-kDa protein of 416 amino acids. The PhLRR protein showed high similarity to members of polygalacturonase inhibitor proteins (PGIPs), contained 11 conserved LRR domains, and was an extracellular localization protein. Phylogenetic analysis showed that PhLRR belonged to the same PGIPs subfamily as SHY, indicating that PhLRR may be involved in the development of pollen-like SHY. Expression analysis revealed that PhLRR was abundantly expressed during early stages of flower bud and anther development, while it was not detected in any other examined organs, such as sepals, petals, pistils, roots, stems, leaves, or open flowers. Furthermore, many cis-acting elements (such as AGAAA and GTGA) related to anther-specific gene expression were identified in the PhLRR gene promoter region, indicating that the promoter is also anther-specific. These results suggested that PhLRR is a novel anther-specific gene that may be essential for the early development of anthers. PMID- 25501200 TI - Identification and characterization of a novel splice variant of the PLCzeta1 gene in bull testis tissues. AB - Phospholipase C zeta 1 (PLCzeta1), which transcribes a key protein, has an important function in oocyte activation and embryo development because PLCzeta1 can trigger a series of intracellular Ca2+ oscillations in mammals. In this study, a novel splice variant in the testis tissues of adult and fetal Chinese Holstein bulls was characterized by reverse transcription-polymerase chain reaction (RT-PCR) and sequencing analysis. The novel splice variant PLCzeta1-sv1 was derived from the PLCzeta1 complete transcript (PLCzeta1-complete) by alternative splicing; the alternative splicing pattern exhibited alternative 5' splice sites. The full-length transcript, PLCzeta1-complete, is the main transcript found in fetal and adult cow testis tissue. Quantitative real-time PCR (qPCR) analysis demonstrated that the expression levels of the PLCzeta1-complete transcript were significantly higher than those of the PLCzeta1-sv1 splice variant in bovine testis tissues. PLCzeta1 protein sequencing analysis showed that the amino acids at positions 453 to 457 were deleted in PLCzeta1-sv1, thereby terminating transcription prematurely. In summary, this study provided information to elucidate the structure and function of the bovine PLCzeta1 gene. PMID- 25501201 TI - Transferability of microsatellites for studies on the social behavior of the tufted capuchin monkey (genus Sapajus). AB - Because of relevant results that indicated that molecular techniques can provide increased knowledge of animal social systems, they usually complement observational field studies. Despite the great utility of microsatellites, they are not available for all species. Gathering genetic information using microsatellites that were originally designed for other species is a time-saving procedure. The aim of this study was to test the transferability of microsatellites and their usefulness in studies of social behavior of black capuchin monkeys (Sapajus nigritus). We noninvasively sampled adult and subadult black capuchins of three wild groups in southeastern Brazil. Seventeen microsatellites, which were previously designed for and successfully amplified in multiple Neotropical primate species, were tested. Nine of the 17 microsatellite loci tested produced an average of 6.22 alleles (range 2-12) per locus. The allelic richness and the expected heterozygosity for all loci was 5.93 and 0.70, respectively. The combined non-exclusion probability for one candidate parent across all loci was 0.01. The nine microsatellite loci optimized in this study have a great potential for application in studies of social structure and dispersal patterns in S. nigritus populations and in other Neotropical primate species. PMID- 25501202 TI - Proacrosin activation mechanisms in capacitated and frozen-thawed boar spermatozoa. AB - The main objective of the current study was to explore the different activation mechanisms of capacitation and freeze-thawed spermatozoa. Using SDS-PAGE and Western blotting, the conversion process of boar proacrosin during freeze-thawing and capacitation of spermatozoa was analyzed. The results revealed that capacitated spermatozoa exhibited a greater fluorescence area than that of the freeze-thawed spermatozoa, which were smaller than those of the fresh group. Fresh spermatozoa displayed 45- and 35- kDa protein bands, while those of freeze thawed andcapacitated spermatozoa displayed 45-, 35- and 28-kDa bands. In summary, these data indicate that proacrosin is activated, thus becoming alpha- and beta-acrosins and a 28-kDa protein during capacitation and freeze-thawing. PMID- 25501203 TI - Development-related expression patterns of protein-coding and miRNA genes involved in porcine muscle growth. AB - Muscle growth and development is associated with remarkable changes in protein coding and microRNA (miRNA) gene expression. To determine the expression patterns of genes and miRNAs related to muscle growth and development, we measured the expression levels of 25 protein-coding and 16 miRNA genes in skeletal and cardiac muscles throughout 5 developmental stages by quantitative reverse transcription polymerase chain reaction. The Short Time-Series Expression Miner (STEM) software clustering results showed that growth-related genes were downregulated at all developmental stages in both the psoas major and longissimus dorsi muscles, indicating their involvement in early developmental stages. Furthermore, genes related to muscle atrophy, such as forkhead box 1 and muscle ring finger, showed unregulated expression with increasing age, suggesting a decrease in protein synthesis during the later stages of skeletal muscle development. We found that development of the cardiac muscle was a complex process in which growth-related genes were highly expressed during embryonic development, but they did not show uniform postnatal expression patterns. Moreover, the expression level of miR-499, which enhances the expression of the beta-myosin heavy chain, was significantly different in the psoas major and longissimus dorsi muscles, suggesting the involvement of miR-499 in the determination of skeletal muscle fiber types. We also performed correlation analyses of messenger RNA and miRNA expression. We found negative relationships between miR-486 and forkhead box 1, and miR-133a and serum response factor at all developmental stages, suggesting that forkhead box 1 and serum response factor are potential targets of miR-486 and miR-133a, respectively. PMID- 25501204 TI - Overexpression of protein kinase B/AKT induces phosphorylation of p70S6K and 4E BP1 in goat fetal fibroblasts. AB - Protein kinases regulate many processes, including cell growth, metabolism, molecular interactions, and cell proliferation. Protein kinase B (PKB)/AKT (v-AKT mouse thymoma viral oncogene homolog) is an upstream component of mammalian target of rapamycin (mTOR) signaling and mediates pathophysiological processes in several signaling pathways. This study aimed to construct and overexpress a eukaryotic goat AKT expression vector in goat fetal fibroblasts and examine the effects of AKT on the phosphorylation of p70S6K and 4E-BP1. AKT was subcloned into the expression vector pIRES2-DsRed2 to generate pIRES2-DsRed2-AKT, which was transfected into goat fetal fibroblasts with LipofectamineTM 2000. AKT was measured by reverse transcription-polymerase chain reaction in the transgenic cells, and the expression of AKT and phosphorylation of p70S6K (Thr389) and 4E BP1 (Thr37/46) were analyzed by Western blot. Cell clones that stably emitted red fluorescence were obtained after transfection for 48 h, and the exogenous gene was verified. Exogenous AKT was transcribed, and AKT was overexpressed, inducing the phosphorylation of p70S6K (Thr389) and 4E-BP1 (Thr37/46) in goat fetal fibroblasts. Thus, the overexpression of AKT activates mTOR signaling in goat cells. PMID- 25501205 TI - Effect of siRNA targeting EZH2 on cell viability and apoptosis of bladder cancer T24 cells. AB - We investigated the effect of siRNA targeting enhancer of EZH2 on cell proliferation, invasion, migration, and apoptosis of human bladder cancer T24 cells. An siRNA-expressing plasmid targeting the EZH2 gene was transfected into T24 cells. Quantitative polymerase chain reaction and Western blot analysis were used to detect EZH2 expression at the mRNA and protein levels, respectively. Proliferation, invasion, and migration of T24 cells were examined in vivo using MTT, wound healing, and transwell chamber migration assays, respectively. Annexin V-fluorescein isothiocyanate/propidium iodide flow cytometric analysis was performed to determine cell apoptosis levels. Expression of EZH2 in T24 cells was suppressed at the mRNA and protein levels. Following transfection for 48 h, growth was inhibited by 37.9%, which was markedly lower than that in the negative control group (P < 0.05). Following a wound-healing assay for 24 h, transfected cell migration distance was 1.37 +/- 0.12, which was markedly less than the horizontal migration distance of negative control group cells (P < 0.01). In addition, the cell invasion ability of EZH2- siRNA group cells decreased by 67% compared with negative control group cells (P < 0.01). Following transfection for 48 h, early- and late-stage apoptosis rates for T24 cells were 22.8 and 3.60%, respectively, which were higher than in the negative control group (P < 0.01). EZH2 gene silencing effectively suppressed the proliferation, invasion, and migration abilities of human bladder cancer cells, promoting apoptosis. PMID- 25501206 TI - Evolutionary dynamics of rDNA genes on chromosomes of the Eucinostomus fishes: cytotaxonomic and karyoevolutive implications. AB - Several chromosomal features of Gerreidae fish have been found to be conserved. In this group, it is unclear whether the high degree of chromosomal stasis is maintained when analyzing more dynamic regions of chromosomes, such as rDNA sites that generally show a higher level of variability. Thus, cytogenetic analyses were performed on 3 Atlantic species of the genus Eucinostomus using conventional banding (C-banding, Ag-NOR), AT- and GC-specific fluorochromes, and fluorescence in situ hybridization mapping of telomeric sequences and 5S and 18S rDNA sites. The results showed that although the karyotypical macrostructure of these species is similar (2n = 48 chromosomes, simple Ag-NORs seemingly located on homeologous chromosomes and centromeric heterochromatin pattern), there are differences in the positions of rDNA subunits 5S and 18S. Thus, the ribosomal sites have demonstrated to be effective cytotaxonomic markers in Eucinostomus, presenting a different evolutionary dynamics in relation to other chromosomal regions and allowing access to important evolutionary changes in this group. PMID- 25501207 TI - Case report: visceral leishmaniasis diagnosed by biopsy of an axillary lymph node: case report and literature review. AB - A 56-year-old man presented with fevers up to 40 degrees C and acute pain in the left upper quadrant. Full blood count was normal and biochemical tests revealed increased serum globulin. Abdominal ultrasound revealed hepatomegaly and splenomegaly with multiple enlarged lymph nodes in the neck, axilla, and inguinal regions. The bone marrow smear was negative. Splenectomy was performed and the pathology revealed splenic ischemic infarcts. Biopsy of one of the axillary lymph nodes revealed macrophages filled with leishmanias. The patient tested positive by the rk39 dipstick test. He was treated with sodium stibogluconate and showed full recovery. PMID- 25501209 TI - Meta-analysis demonstrates no association between XRCC1 Arg399Gln polymorphism and bladder cancer risk. AB - We examined whether the X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphism is a risk factor for bladder cancer by conducting a meta analysis. We searched the Pubmed and Embase databases for study retrieval. This meta-analysis examined 16 case-control studies, including 892 prostate cancer cases and 1020 healthy controls. Meta-analysis results based on these studies showed no significant association between the XRCC1 Arg399Gln polymorphism and bladder cancer risk in comparisons of the glutamine (Gln) allele vs arginine (Arg) allele, Arg/Arg vs (Gln/Gln + Gln/Arg), Gln/Gln vs (Gln/Arg + Arg/Arg), Gln/Gln vs Arg/Arg, and Gln/Arg vs Arg/Arg [odds ratio (OR) = 0.96, 95% confidence interval (CI) = 0.80-1.16, P = 0.70; OR = 1.13, 95%CI = 0.70-1.82, P = 0.62; OR = 0.92, 95%CI = 0.79-1.07, P = 0.29; OR = 0.90, 95%CI = 0.69-1.16, P = 0.42; OR = 0.89, 95%CI = 0.75-1.05, P = 0.17, respectively]. In subgroup analysis by ethnicity, no association was observed between the XRCC1 Arg399Gln polymorphism and bladder cancer risk in Caucasian, Mongoloid, or black populations. We identified no association between the XRCC1 Arg399Gln polymorphism and bladder cancer risk. PMID- 25501208 TI - Effect of BMPRIB gene silencing by siRNA on apoptosis and steroidogenesis of porcine granulosa cells. AB - Bone morphogenetic proteins (BMPs) are the key factors in maintaining cell growth and differentiation in ovaries. BMPs initiate signaling by assembling BMP receptors and activating Smads, which in turn alter the expression of target genes. However, little is known about the effect of the deletion of the Bone morphogenetic protein receptor type IB (BMPRIB) on porcine granulosa cell (GCs). The objective of this study was to determine the effects of BMPRIB gene silencing, by small interfering RNA (siRNA), on the apoptosis and steroidogenesis of porcine GCs, and the expression of cell cycle-related and apoptosis-related genes. Results indicate that the BMPRIB siRNA caused specific inhibition of BMPRIB mRNA expression after transfection. Knockdown of the BMPRIB gene significantly inhibited porcine GCs proliferation and estradiol production, while inducing apoptosis of porcine GCs. Additionally, the declined expression of the BMPRIB gene changed the expressions of CylinD2, Cdk2, Bcl-2, and Cyp19a1. These findings provide an important role of BMPRIB in the regulation of apoptosis and steroidogenesis of porcine GCs. PMID- 25501211 TI - PAX-9 polymorphism may be a risk factor for hypodontia: a meta-analysis. AB - To evaluate the association between paired box 9 (PAX9) gene polymorphisms and tooth agenesis in isolated humans, we performed a comprehensive meta-analysis. We examined 6 case-control studies, with a total of 855 hypodontia cases and 1201 healthy controls. The G allele and G carrier (AG + GG) of A1031G were positively associated with hypodontia susceptibility. Similarly, the T allele and T carrier (CT + TT) of C912T and rs12881240 in the PAX9 gene also indicated an increased risk of hypodontia. In addition, the C allele and C carrier (CG + CC) of 718C, IVS2-109, rs4904210, and rs7143727 showed no significant association with oligodontia. The G allele and G carrier (AG + GG) of IVS2-41 in the PAX9 gene were not related factors. Interestingly, the genotype (AG + GG) of IVS2-54 in the PAX9 gene may be a protective factor for oligodontia (odds ratio = 0.21, 95% confidence interval = 0.07-0.63, P = 0.005). However, no significant differences were found in the allele frequency of IVS2-54 in the PAX9 polymorphism between controls and subjects with sporadic tooth agenesis. In conclusion, our meta analysis results revealed 4 genetic sites of the PAX9 gene involved in hypodontia cases, of which 3 sites may be risk factors and 1 may have a protective role. PMID- 25501210 TI - Mutagenic and antimutagenic effects of aqueous extract of rosemary (Rosmarinus officinalis L.) on meristematic cells of Allium cepa. AB - Polyphenolic compounds present in rosemary were found to have antioxidant properties, anticarcinogenic activity, and to increase the detoxification of pro carcinogens. The aim of the study was to determine the effect the aqueous extract of rosemary (AER) on mutagenicity induced by methylmethane sulfonate in meristematic cells of Allium cepa, as well as to describe its mode of action. Anti-mutagenicity experiments were carried out with 3 different concentrations of AER, which alone showed no mutagenic effects. In antimutagenicity experiments, AER showed chemopreventive activity in cultured meristematic cells of A. cepa against exposure to methylmethane sulfonate. Additionally, post-treatment and simultaneous treatment using pre-incubation protocols were the most effective. Evaluation of different protocols and the percent reduction in DNA indicated bioantimutagenic as well desmutagenic modes of action for AER. AER may be chemopreventive and antimutagenic. PMID- 25501212 TI - Association of MSX1 and TGF-beta1 genetic polymorphisms with hypodontia: meta analysis. AB - We conducted a comprehensive meta-analysis of 4 case-control studies to explore the association between polymorphisms of Msh homeobox 1 (MSX1) and transforming growth factor-beta1 (TGF-beta1) genes and hypodontia. A total of 643 tooth agenesis cases and 733 healthy controls were included in this study. The meta analysis results showed that the T allele and T carrier (CT + TT) of rs1095 in the MSX1 gene were positively associated with hypodontia susceptibility. However, the T allele and T carrier (TC + CC) of rs12532 and rs8670 showed no association with cancer susceptibility. In addition, there were no strong associations between the T allele and T carrier (CT + TT) of C509T and the A allele and A carrier (AG + AA) of G800A in the TGF-beta1 gene polymorphisms between patients with tooth agenesis and healthy subjects. In conclusion, these meta-analysis results demonstrated that polymorphisms in the rs1095 region of the MSX1 gene may influence the transcriptional activity of this gene and are associated with hypodontia in humans. However, the association between the TGF-beta1 gene and sporadic tooth agenesis is not well understood, and further studies are required to explore the correlation between the TGF-beta1 gene and hypodontia. PMID- 25501213 TI - Comparative analysis of the river buffalo somatostatin gene. AB - The somatostatin protein plays a crucial role in the regulation of multiple biological functions, such as growth, fat deposition, and nutrient absorption in vertebrates. Polymorphisms in the somatostatin gene have been associated with growth traits in livestock species, including cattle and goat. In this study, we conducted complete molecular characterization of the somatostatin gene in Bubalus bubalis (Murrah breed) by sequencing a Murrah BAC clone spanning 72,489 base pairs (bp) in length. The buffalo somatostatin gene contains 1481 bp organized into a 5'-untranslated region (135 bp), exon 1 (139 bp), intron 1 (839 bp), exon 2 (212 bp), and 3'UTR (156 bp). Comparative analysis between the buffalo somatostatin DNA coding sequence and the amino acid sequence with other bovids (cattle, goat, and sheep), horse, pig, human, rodents (mouse and rat), and chicken. Identity varied from 83-99% on the DNA sequence level and 88-100% on the protein level. In addition, a comparison of gene sequences between Murrah and Mediterranean breeds revealed 6 potential single-nucleotide polymorphisms (1 in exon 1 and 5 in intron 1), which were validated in different buffalo populations. This comparative analysis provides basic information for future studies of different buffalo herds using the position candidate gene approach, quantitative trait loci analysis, and polymorphisms associated with growth traits. PMID- 25501214 TI - In silico analysis of mutations occurring in the protein N-acetylgalactosamine-6 sulfatase (GALNS) and causing mucopolysaccharidosis IVA. AB - The goals were to analyze and characterize the secondary structure, regions of intrinsic disorder and physicochemical characteristics of three classes of mutations described in the enzyme N-acetylgalactosamine-6-sulfatase that cause mucopolysaccharidosis IVA: missense mutations, insertions and deletions. All mutations were compared to wild-type enzyme, and the results showed that with 25 of 129 missense mutations secondary structure was maintained and that 104 mutations showed minor changes, such as an increase or decrease in the size of the elements. The secondary structure of all insertions and deletions introduced important changes, such as increase in the number and size of elements. The results obtained from intrinsic disorder analysis revealed that missense mutations caused no alterations. However, the insertions and deletions led to major regions of intrinsic disorder. The physicochemical characteristics of the amino acids found in missense mutations revealed unchanged characteristics in 32 of the 129 mutations. However, the remainder had changes that could lead to a modification of tertiary structure. The results proved that it was feasible and necessary to obtain the three-dimensional structure of the enzyme with its mutants to better understand the change in function. PMID- 25501215 TI - Fourier transform infrared photoacoustic spectroscopy as a potential tool in assessing the role of diet in cuticular chemical composition of Ectatomma brunneum. AB - The cuticular chemical composition plays a significant role in the recognition of nest mates in social insects, thus functioning as a chemical signature of the colony. The structure of cuticular chemicals is subject to interference from genetic and exogenous factors, including diet. In this study, various colonies of the Ectatomma brunneum ant were removed from their natural environment and housed in a laboratory to monitor the response of the cuticular chemical composition to dietary changes. Analyses were performed using gas chromatography and Fourier transform infrared photoacoustic spectroscopy, which has not been previously used for this type of analysis. The results indicate that this method is useful for analyzing biological and natural systems. We observed changes in the chemical signature with food traces in the first 30 days under feed control. Therefore, genetic information may not be the only criterion that can be used to describe the chemical signature of a species; environmental variations also influence recognition signals. Furthermore, these results reinforce the reliability of the Fourier transform infrared photoacoustic spectroscopy method. PMID- 25501216 TI - Kill curve analysis and response of first generation Capsicum annuum L. B12 cultivar to ethyl methane sulfonate. AB - Pepper seeds (Capsicum annuum L.) var. B12 were mutagenized by four presoaking treatments in ten concentrations of ethyl methane sulfonate (EMS) to determine the sensitivity of the first generation (M1) to mutagens. The spectrum of mutations and induced variability for various quantitative traits, including germination, percent plant height, injury occurrence, survival ratio, first three fruits weight, and number of seeds per first fruit, were observed in the M1 generation. Our results indicated that all of the test parameters decreased with increasing EMS concentration, except for seedling injury. There were significant differences in germination ratio, LD50, plant height, percent injury, and survival ratio among the tested presoaking treatment. The LD50 was 1% EMS in seeds that were not presoaked (T1) and seeds presoaked for 12 h before treating with EMS (T3). In contrast, the LD50 was 0.5% EMS in seeds presoaked for 6 h (T2) and seeds presoaked in water for 6 h then incubated at 28 degrees C for 12 h before EMS treatment (T4). Five dwarf plants were observed in mutagenized seeds without presoaking as compared to control seeds (at the maturity stage of the control plant). PMID- 25501217 TI - Isolation and characterization of polymorphic microsatellite loci from Zelkova schneideriana Hand.-Mazz. AB - Zelkova schneideriana is a highly valued hardwood species. An improved technique for isolating codominant compound microsatellite markers was used to develop simple sequence repeat markers for Z. schneideriana. A total of 12 microsatellite loci were identified. Overall, the number of alleles per locus ranged from 8-19, with an average of 11.75. Observed heterozygosity and expected heterozygosity values ranged from 0.109-0.709 and 0.832-0.929, respectively. Polymorphic information content is from 0.803-0.915, with an average of 0.854. These markers will be very important for future research related to the genetic diversity, population structure, patterns of gene flow, and mating system of this species. PMID- 25501218 TI - Cloning and expression of UDP-glucose: flavonoid 3-O-glucosyltransferase gene in peach flowers. AB - To elucidate the connection between flower coloration and the expression of genes associated with anthocyanin biosynthesis, a gene encoding UDP-glucose: flavonoid 3-O-glucosyltransferase (UFGT) was isolated, and the expression of the last four genes in the anthocyanin biosynthetic pathway during peach flower development was determined. The nucleotide sequence of the peach UFGT (GenBank accession No. JX149550) is highly similar to its homologs in other plants. Total anthocyanin content initially increased during peach flower development, and then decreased over time. Expression of the four anthocyanin biosynthesis genes increased until the full-bloom stage, and then decreased during late florescence. Expression of F3H, DFR, and UFGT increased dramatically at the full-bloom stage, coinciding with an increase in anthocyanin concentration. The UFGT gene may not be the only gene of the anthocyanin pathway to be differentially controlled in red peach flower tissues. Further studies are needed to genetically and physiologically characterize these genes and enzymes in peach flowers and to gain a better understanding of their functions and relationships with flower coloration. PMID- 25501219 TI - Examination of polymorphism in hybrid wheat by using amplified fragment length polymorphism marker. AB - To investigate the polymorphism of two groups of male sterile lines and their maintainer lines, we used amplified fragment length polymorphism markers. Of the 64 primer pairs, five reproducibly demonstrated polymorphism. Group I had 27 polymorphic bands, and Group II had 24 polymorphic bands. The maximum number of polymorphic bands was produced by line 2 (18 polymorphic bands) followed by line 7 (15 polymorphic bands). Of the five primer pairs, the highest number of polymorphic bands was produced by primer pair E1/M4, and the smallest number of polymorphic bands was produced by primer pair E1/M2. DNA fingerprinting, germplasm characterization, and cytogenetic research have especially been emphasized in studies of bread wheat; these methods are highly useful to select appropriate accessions for plant improvement and hybridization through molecular breeding approaches to evolve suitable safeguard strategies. PMID- 25501220 TI - Gene expression of the p16(INK4a)-Rb and p19(Arf)-p53-p21(Cip/Waf1) signaling pathways in the regulation of hematopoietic stem cell aging by ginsenoside Rg1. AB - The elucidation of the molecular mechanisms underlying the effects of traditional Chinese medicines in clinical practice is a key step toward their worldwide application, and this topic is currently a subject of intense research interest. Rg1, a component of ginsenoside, has recently been shown to perform several pharmacological functions; however, the underlying mechanisms of these effects remain unclear. In the present study, we investigated whether Rg1 has an anti senescence effect on hematopoietic stem cells (HSCs) and the possible molecular mechanisms driving any effects. The results showed that Rg1 could effectively delay tert-butyl hydroperoxide (t-BHP)-induced senescence and inhibit gene expression in the p16(INK4a)-Rb and p19(Arf)-p53-p21(Cip/Waf1) signaling pathways in HSCs. Our study suggested that these two signaling pathways might be potential targets for elucidating the molecular mechanisms of the Rg1 anti-senescence effect. PMID- 25501221 TI - Analysis of signaling pathways in recurrent breast cancer. AB - Breast cancer remains the second largest cause of death in women from cancer. By analyzing gene expression profiles in samples from breast cancer patients, 844 differentially expressed genes (DEGs) were identified in breast cancer metastasis. The 10 most significant signaling pathways identified through enrichment analysis contained DEGs were involved in oxidative phosphorylation, DNA replication, extracellular matrix-receptor interactions and others. Furthermore, survival analysis demonstrated that 5 of these signaling pathways were closely related to the survival time of breast cancer patients including basal transcription factors, cell cycle, ECM-receptor interaction, spliceosome, and DNA replication. Our findings increase the understanding of the network of signaling pathways involved in breast cancer metastasis and may provide theoretical support for further therapeutic study. PMID- 25501222 TI - Molecular characterization, expression, and immunological response analysis of the TWEAK and APRIL genes in grass carp, Ctenopharyngodon idella. AB - TWEAK and APRIL are important members of the TNF superfamily, which play a crucial role in several diseases. Here, we describe the identification of grass carp (Ctenopharyngodon idella) homologs of TWEAK and APRIL (designated gcTWEAK and gcAPRIL, respectively) and their response to Aeromonas hydrophila and Aquareovirus infection. The gcTWEAK cDNA sequence contains 2273 bases with an open reading frame of 753 bases encoding 250-amino acid residues. The gcTWEAK protein contains a predicted transmembrane domain, a putative furin protease cleavage site, 3 conserved cysteine residues, and a typical TNF homology domain. The gcAPRIL cDNA sequence contains 1408 bases with an open reading frame of 747 bases encoding 248-amino acid residues. The gcAPRIL protein contains a predicted transmembrane domain, a putative furin protease cleavage site, 2 conserved cysteine residues, and a typical TNF homology domain corresponding to other, known APRIL homologs. Reverse transcription-polymerase chain reaction analysis shows that both gcTWEAK and gcAPRIL transcripts are predominantly expressed in the skin, spleen, and head kidney, and they are significantly upregulated in most immune tissues by A. hydrophila and Aquareovirus infections. Our results demonstrate that liver is the most responsive tissue against bacterial infection, whereas gill is the most responsive tissue against viral infection. The association of increased gcTWEAK and gcAPRIL expression after bacterial and viral infections suggests that they play a potentially important role in the immune system of fish. PMID- 25501223 TI - H3K27me3 may be associated with Oct4 and Sox2 in mouse preimplantation embryos. AB - As a core member of polycomb repressive complex 2, the transcription and enzyme activity of enhancer of zeste homolog 2 (Ezh2) is directly involved in the trimethylation of lysine 27 on histone H3. In this study, the fluorescence intensity of H3K27me3 in mouse in vivo morulae and blastocysts was compared by indirect immunofluorescence staining. We found that demethylation of H3K27me3 occurred during the blastocyst stage. Real-time polymerase chain reaction was performed to investigate Ezh2 expression in oocytes and in preimplantation embryos. Ezh2 expression peaked during the zygote stage and gradually decreased from the 2-cell stage, exhibiting an inverse pattern when compared with Oct4 and Sox2 mRNA in mouse preimplantation embryos. To understand the role of development related genes on the transcription of mouse Ezh2, a promoter assay was performed in NIH/3T3 cells. Ezh2 expression was markedly suppressed by Oct4 and Sox2 alone in a dose-dependent manner, while Ezh2 promoter activity in co-transfection with Nanog, Klf-4, and c-Myc groups showed no significant change as compared with the control. Our data suggest that the demethylation of H3K27me3 is caused by the degressive expression and activity of Ezh2 in blastocysts, leading to increased expression of developmentally important transcription factors. We also observed negative effects of Oct4 and Sox2 on the transcription of Ezh2 and identified Oct4 and Sox2 as novel negative regulators of Ezh2 at the post-translation level in a mouse preimplantation embryo. PMID- 25501224 TI - Use of differential levels of mean observed heterozygosity in microsatellite loci of commercial varieties of sugarcane (Saccharum spp). AB - In this study, we measured the genetic diversity within and among a set of 9 commercial sugarcane varieties used for alcohol and sugar production using 17 microsatellite DNA markers. The UGSM148 and UGSM59 primers were monomorphic for all 74 sugarcane samples. The estimated proportion of simple sequence repeated (SSR) polymorphic loci was 88.23%; 17 alleles were detected. The mean gene diversity of all SSR loci was 0.7279. The highest observed heterozygosity (HO) value was found in the RB72454 variety, whereas the lowest HO value was recorded in the SP813250 variety. The SP813250, RB845210, and RB835054 sugarcane varieties were the most genetically uniform varieties. An extremely high level of population differentiation was detected in the varieties exhibiting similar agronomic characteristics. Analysis of the genetic structure of the 9 sugarcane varieties using SSR markers was especially important to identify SSR loci with high levels of heterozygosity and to identify varieties showing the highest levels of heterozygosity. The monomorphic primers may be used to evaluate the genetic stability of sugarcane during cycles of vegetative multiplication, i.e., propagation via rhizomes. PMID- 25501225 TI - Genetic diversity and relationships in cultivars of Lolium multiflorum Lam. using sequence-related amplified polymorphism markers. AB - Sequence-related amplified polymorphism (SRAP) markers were used to analyze and estimate the genetic variability, level of diversity, and relationships among 20 cultivars and strains of annual ryegrass (Lolium multiflorum Lam.). Eighteen SRAP primer combinations generated 334 amplification bands, of which 298 were polymorphic. The polymorphism information content ranged from 0.4715 (me10 + em1) to 0.5000 (me5 + em7), with an average of 0.4921. The genetic similarity coefficient ranged from 0.4304 to 0.8529, and coefficients between 0.65 and 0.90 accounted for 90.00%. The cluster analysis separated the accessions into five groups partly according to their germplasm resource origins. PMID- 25501226 TI - Correlation between MTP -493G>T polymorphism and non-alcoholic fatty liver disease risk: a meta-analysis. AB - Several studies have found that microsomal transfer protein (MTP) may be important in the development and progression of non-alcoholic fatty liver disease (NAFLD). In this meta-analysis, we evaluated the relationships between a common polymorphism (-493G>T, rs1800591 G>T) in the MTP gene and NAFLD risk. The PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases were searched for relevant articles published before October 1, 2013 without any language restrictions. Meta-analysis was conducted using the STATA 12.0 software. Crude odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated. Eleven case-control studies were included in this meta-analysis. A total of 636 NAFLD patients and 918 healthy control subjects were examined in this meta-analysis. Our results indicate that the MTP -493G/T polymorphism increases the risk of NAFLD (G allele vs T allele: OR = 1.39, 95%CI = 1.17-1.65, P < 0.001; GG + GT vs TT: OR = 1.46, 95%CI = 1.02-2.09, P = 0.038, respectively). Subgroup analyses indicated that the MTP -493G/T polymorphism was associated with an increased risk of NAFLD in population-based, hospital-based, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and large sample size subgroups under the allele and dominant models (all P < 0.05). However, we found no association between non-PCR-RFLP polymorphism and small sample-size subgroups (all P > 0.05). Our findings indicate that the MTP -493G/ T polymorphism may contribute to the development of NAFLD. Thus, the MTP -493G/T polymorphism may be a biomarker for the early detection of NAFLD. PMID- 25501227 TI - Polymorphism of the OLR1 3'UTR potential microRNA binding site and risk of Alzheimer's disease: a meta-analysis. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder that contributes to dementia in the elderly population. Genome-wide linkage analysis has identified chromosome 12p as the AD-susceptible region, which includes lectin like oxidized low-density lipoprotein receptor 1 (OLR1). The OLR1 +1073 C/T single-nucleotide polymorphism is located in the 3'-untranslated region of the gene and may influence the binding of regulatory microRNAs (miRNAs) and OLR1 protein homeostasis. A number of studies have reported an association between this variant and AD. However, the results are controversial. A meta-analysis of case-control studies examining the relationship between the OLR1 +1073 C/T single nucleotide polymorphism and AD risk was performed. Five studies were selected that included 2419 cases and 2381 controls. The results revealed a significantly decreased AD risk in the recessive model (TT vs TC + CC: odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.65-0.96). The control group in one of the studies was in Hardy-Weinberg disequilibrium, so we performed additional meta analysis excluding this study. The significance was much more pronounced in the recessive model (TT vs TC + CC: OR = 0.72, 95%CI = 0.62-0.85). Using miRanda and RNA hybrid methods, the polymorphic allele was shown to influence the binding of various miRNAs. Our results suggested that the +1073 C/T polymorphism decreased the risk of AD. The polymorphic allele was also predicted to affect the binding site of many miRNAs, which may explain the relationship between the +1073 C/T variant and AD. PMID- 25501228 TI - Development and characterization of novel microsatellite markers in Hyptis pectinata (Lamiaceae). AB - A microsatellite-enriched library was constructed and a set of 19 SSR markers were developed to characterize a germplasm collection of Hyptis pectinata (L.) Poit., maintained at the Universidade Federal de Sergipe (UFS). Fifteen markers of 19 ranged from moderately to highly polymorphic. A total of 113 alleles were identified, with a mean of 7.52 alleles per locus. The mean HO and HE were 0.582 and 0.657, respectively. The primers developed were efficient tools for accessing the genetic diversity of the germplasm collection analyzed and may also be useful for other studies involving this species and other species in the genus Hyptis. PMID- 25501229 TI - Identification of a novel duplication mutation in the VHL gene in a large Chinese family with Von Hippel-Lindau (VHL) syndrome. AB - Von Hippel-Lindau (VHL) syndrome is characterized by hemangioblastomas of the brain, spinal cord, and retina, renal cysts, clear cell renal cell carcinoma, and pheochromocytoma. VHL is caused by mutations in the VHL tumor suppressor gene. We attempted to detect mutation in the VHL gene in a 5-generation Chinese family with VHL. We identified a novel small duplication that altered the reading frame downstream and created a premature TGA stop signal, resulting in severely truncated pVHL30 (p.Gly114Serfs*50) and pVHL19 (p.Gly61Serfs*50). This change was predicted to be an elongin-binding domain deletion. PMID- 25501230 TI - Detection of the genetic variation of polygalacturonase-inhibiting protein gene 2 in autotetraploid alfalfa (Medicago sativa) using an improved SSCP technique. AB - In this study, 2 approaches were adopted to obtain good single-strand conformation polymorphism (SSCP) data for autotetraploid alfalfa; primers were added to PCR products, and fluorescent-labeled primers were utilized. PCR-SSCP conditions for a 331-bp fragment in the coding region of polygalacturonase inhibiting protein gene 2 in alfalfa (MsPGIP2) were optimized, and the results showed that the best SSCP gel pattern could be obtained when the loading mixture was made by mixing 1 MUL PCR products, 0.2 to 0.8 MUL unlabeled primers (50 MUM) and 4 to 16 MUL loading buffer. Furthermore, the use of the fluorescent-labeled primers resulted in 2 separated electrophoresis images from 2 complementary single DNA strands, thus making the determination of alleles and idiotypes a relatively easy task. In addition, the results of sequencing prove that the determination of alleles and idiotypes were accurate based on SSCP analysis. Finally, a total of 9 alleles with 18 SNP sites were identified for MsPGIP2 in the alfalfa variety 'Algonquin'. In conclusion, MsPGIP2 possessed great genetic variation, and the addition of primers to the PCR products in combination with the fluorescent labeling of primers could significantly improve the sensitivity and resolution of SSCP analysis. This technique could be used for genetic diversity detection and marker-assisted breeding of useful genes in autopolyploid species such as alfalfa. PMID- 25501231 TI - Association between FTO, MC4R, SLC30A8, and KCNQ1 gene variants and type 2 diabetes in Saudi population. AB - Recent genome wide association studies identified many loci in several genes that have been consistently associated with type 2 diabetes mellitus in various ethnic populations. Among the genes that were most strongly associated with diabetes were fat mass- and obesity-associated, melanocortin 4 receptor, solute carrier family 30 member 8 (SLC30A8), and a member of the potassium voltage-gated channels. In the present study, we examined the association between variants in fat mass- and obesity-associated [rs9939609 (A/T)], melanocortin 4 receptor [rs17782313 (C/T), and rs12970134 (A/G)], SLC30A8 [rs13266634 (C/T)], and a member of the potassium voltage-gated channels [rs2237892(C/T)] genes in diabetes patients from Saudi Arabia. Genotypes were determined using the TaqMan single nucleotide polymorphism genotype analysis technique. Minor allele frequency of the 4 variants tested was comparable between type 2 diabetes cases and controls. We observed an association between allele variants of SLC30A8 [rs13266634 (C/T)] and type 2-diabetes (P = 0.04). The other single-nucleotide polymorphisms examined in this study showed moderate or no correlation with diabetes in Saudis. Our data indicate that the SLC30A8 polymorphisms are associated with type 2 diabetes in the Saudi population. There is no evidence supporting an association between variants in the fat mass- and obesity-associated and melanocortin 4 receptor, and a member of the potassium voltage-gated channels genes and type 2 diabetes in the Saudi population. PMID- 25501232 TI - Effects of hypoxia on proliferation and osteogenic differentiation of periodontal ligament stem cells: an in vitro and in vivo study. AB - Changes in oxygen concentration may influence various innate characteristics of stem cells. The effects of varying oxygen concentration on human periodontal ligament stem cells (HPDLSCs) has not been explored, particularly under hypoxia related conditions. First, HPDLSCs were cultured from the periodontium of human teeth using the outgrowth method. STRO-1 and CD146 expression of HPDLSCs was investigated by flow cytometry. To detect the multilineage differentiation capacities of HPDLSCs, osteogenic-like and adipogenic-like states were induced in cells. Next, HPDLSCs (passage 3) were exposed to normal oxygen (21% O2) or hypoxia (2% O2) conditions for 7 days and cell proliferation was evaluated. After culture in osteogenic medium for 7 days, osteoblastic differentiation was evaluated by semi-quantitative reverse transcription-polymerase chain reaction analysis to detect 3 osteoblastic markers: core-binding factor a 1/runt-related transcription factor 2, osteocalcin, and osteopontin. In addition, each cell group was incubated with a hydroxyapatite/tricalcium phosphate carrier and transplanted subcutaneously into the back of immunocompromised mice to investigate transplantation differences in vivo. HPDLSCs were isolated, cultured, and successfully identified. After exposure of HPDLSCs to hypoxia for 7 days, the proliferation rate was increased and showed higher osteogenic differentiation potential compared to control cells. After 12 weeks of transplantation, hypoxia treated HPDLSCs differentiated into osteoblast-like cells that formed bone-like structures. These results suggest that oxygen concentrations affect various aspects of HPDLSC physiology and that hypoxia enhances osteogenic differentiation both in vivo and in vitro. Oxygen concentration may be a critical parameter for HPDLSCs during expansion and differentiation. PMID- 25501234 TI - Association between the -77T>C polymorphism in the DNA repair gene XRCC1 and lung cancer risk. AB - Numerous studies have evaluated the association between the X-ray repair cross complementing group 1 (XRCC1) DNA repair gene polymorphism -77T>C and lung cancer risk. However, this association is controversial. We used PubMed and Embase to identify 5 case-control studies, which included 2488 lung cancer cases and 2576 controls, for inclusion in a comprehensive meta-analysis in order to assess this association. Two independent reviewers extracted data from the studies, and ORs with 95%CIs were calculated. When all studies were pooled, we found a significant association between the -77T>C polymorphism and lung cancer risk (TT vs CC: OR = 0.52, 95%CI = 0.34-0.80, P = 0.49; TT vs CT: OR = 0.71, 95%CI = 0.62-0.81, P = 0.69; dominant model: OR = 1.45, 95%CI = 1.27-1.66, P = 0.64; recessive model: OR = 0.54, 95%CI = 0.36-0.82, P = 0.24). In a subgroup analysis of nationalities, the -77T>C polymorphism was significantly associated with lung cancer risk in Asian patients. In conclusion, the XRCC1 -77T>C polymorphism might be related to increased risk of lung cancer in Asians. Future studies are needed for conclusive evidence about this association. PMID- 25501233 TI - ERCC1 mRNA expression is associated with the clinical outcome of non-small cell lung cancer treated with platinum-based chemotherapy. AB - We conducted a prospective study to analyze the expression of the excision repair cross-complementing group 1 (ERCC1) and ribonucleotide reductase subunit M1 (RRM1) genes in 297 Chinese patients with advanced non-small cell lung cancer (NSCLC). The goal of this study was to evaluate these genes as potential biomarkers for prediction of tumor response and clinical outcome. Patients with unresectable, locally advanced or metastatic NSCLC were enrolled between September 2007 and September 2009, and they were followed up until September 2012. A fluorescence-based real-time detection method was used to quantify relative levels of ERCC1 and RRM1 cDNA. Relative amounts of ERCC1 and RRM1 cDNA were calculated by comparing to actin. By the end of follow-up, 132 patients had died and 165 patients experienced progression. The median overall survival time was 18.7 months (range, 1-60 months). The median levels of ERCC1 and RRM1 were 2.46 x 10(-2) and 0.97 x 10(-2), respectively. Patients with low ERCC1 expression had a significantly higher rate of complete response to chemotherapy, with an OR (95%CI) of 1.56 (1.03-2.47). Moreover, individuals with low levels of ERCC1 had longer overall survival than patients with high expression, with an adjusted hazard ratio (95%CI) of 0.57 (0.35-0.93). In summary, low ERCC1 mRNA expression was associated with better response to chemotherapy and correlated with longer survival in advanced NSCLC patients treated with platinum-based chemotherapy. PMID- 25501235 TI - Correlation of forkhead box transcription factor O1 and myosin heavy chain isoforms in porcine skeletal muscle. AB - We examined the expression of myosin heavy chain (MyHC) isoforms and forkhead box transcription factor O1 (FoxO1) in porcine soleus and extensor digitorum longus (EDL) muscles to clarify the correlation of FoxO1 and the relative abundance of transcripts of MyHC isoforms. Soleus muscle was found to be redder than EDL muscles in pigs, and immunohistochemical fast MyHC staining showed more oxidative type I fibers compared to EDL. qRT-PCR quantification of MyHC isoforms I, IIa, IIx, and IIb showed that expression of MyHC I and MyHC IIa mRNAs was much higher, whereas expression of MyHC IIx and MyHC IIb mRNAs was much lower in porcine soleus muscle compared to EDL muscle. Expression of FoxO1 mRNA and p-FoxO1 protein was significantly more abundant in porcine soleus muscle compared to EDL muscle. The expression of phosphorylated FoxO1 (p-FoxO1) was positively correlated with the expression of MyHC I (R = 0.9747, P < 0.01) and negatively correlated with the expression of MyHC IIx (R = -0.9963, P < 0.01) and MyHC IIb (R = -0.9834, P < 0.01). Taken together, these results suggested that FoxO1 may play a pivotal role in the determination of muscle fiber type. PMID- 25501236 TI - Molecular characterization of thioredoxin-1 and thioredoxin reductase activity in mud crab Scylla paramamosain. AB - The thioredoxin (Trx) system consists of thioredoxin reductase (TrxR), Trx, and nicotinamide adenine dinucleotide phosphate (NADPH). TrxR is an NADPH-dependent oxidoreductase. Trx is a ubiquitous small protein with a redox-active disulfide bridge that plays important regulatory roles in some vital metabolic reactions. In this study, a cDNA sequence (SpTrx1) showing high identity to the first Trx gene was isolated from a hepatopancreas cDNA library of the mud crab Scylla paramamosain. The full-length cDNA of SpTrx1 consisted of 672 bp and contained a complete open reading frame of 318 bp encoding a polypeptide of 105 amino acids. Quantitative real-time polymerase chain reaction analysis revealed that SpTrx1 expression was ubiquitous in various organs of S. paramamosain, including the gill, muscle, heart, hemolymph, testis, and hepatopancreas. SpTrx1 expression was upregulated significantly after Vibrio parahaemolyticus challenge: it obviously rose at 48 h and reached the highest level at 72 h. Furthermore, TrxR activity was detected in the gill, heart, muscle, hemolymph, and hepatopancreas. The relative TrxR activity in different tissues after V. parahaemolyticus injection had the same tendency in each tissue (P < 0.01) as SpTrx1 expression. The TrxR activity increased 2 h after injection, peaked at 8 h, slowly decreased from 12 to 24 h, and returned to normal levels at 48 h. The consistency of the expression between the Trx transcript and TrxR activity demonstrated that Trx was closely related to TrxR in the Trx system in S. paramamosain, suggesting that it may participate in the immune system of mud crabs. PMID- 25501237 TI - Association between single-nucleotide polymorphisms and milk production traits in buffalo. AB - The aim of this study was to identify single-nucleotide polymorphisms (SNPs) in buffaloes associated with milk yield and content, in addition to somatic cell scores based on the cross-species transferability of SNPs from cattle to buffalo. A total of 15,745 SNPs were analyzed, of which 1562 showed 1% significance and 4742 with 5% significance, which were associated for all traits studied. After application of Bonferroni's correction for multiple tests of the traits analyzed, we found 2 significant SNPs placed on cattle chromosomes BTA15 and BTA20, which are homologous to buffalo chromosomes BBU16 and BBU19, respectively. In this genome association study, we found several significant SNPs affecting buffalo milk production and quality. Furthermore, the use of the high-density bovine BeadChip was suitable for genomic analysis in buffaloes. Although extensive chromosome arm homology was described between cattle and buffalo, the exact chromosomal position of SNP markers associated with these economically important traits in buffalo can be determined only through buffalo genome sequencing. PMID- 25501238 TI - MTA1 promotes cell proliferation via DNA damage repair in epithelial ovarian cancer. AB - We examined whether metastasis-associated gene 1 (MTA1) promotes cell proliferation via DNA damage repair in ovarian cancer. MTA1 was successfully down regulated using small interfering RNA in the epithelial ovarian cancer cell lines SKOV-3 and OVCAR-3. Cell growth was evaluated through MTT and colony formation assays. Fluorescence-activated cell sorting analysis was used to evaluate the distribution of cells in the cell cycle, and cytotoxicity assays were performed to study cell sensitivity to cisplatin. A neutral comet assay was used to measure levels of ionizing radiation-induced DNA damage in SKOV-3 cells, and Western blot analyses were carried out to examine the expression of key proteins involved in DNA damage repair pathways. MTA1 knockdown markedly inhibited cell growth and led to S phase cell cycle arrest. In addition, MTA1 depletion conferred sensitivity of ovarian cancer cells to cisplatin. Moreover, MTA1 depletion increased the level of ionizing radiation-induced DNA damage and caused irreparable damage, which was illustrated by a remarkable increase and persistent existence of a comet tail as well as protein expression levels of gammaH2AX, pRPA, and pChk1, all of which play critical roles in DNA repair. Thus, MTA1 promotes the proliferation of epithelial ovarian cancer cells by enhancing DNA repair. PMID- 25501239 TI - Distribution of constitutive heterochromatin in species of triatomines with fragmentation of sex chromosomes X. AB - Cytogenetic analyses of triatomines are considered to be important taxonomic tools. Thus, we analyzed the pattern of constitutive heterochromatin in 7 species of triatomine with fragmentation of the sex chromosome X, focusing on the cytotaxonomy of these triatomines. The species analyzed included Triatoma vitticeps, Triatoma melanocephala, Triatoma tibiamaculata, Triatoma protracta, Meccus pallidipennis, Panstrongylus megistus, and Panstrongylus lignarius. The seminiferous tubules of the adult males were subjected to C-banding. P. megistus and P. lignarius showed differences in chromosome number and disposition of constitutive heterochromatin, as only P. lignarius showed C-blocks in autosomes. C-banding can differentiate these species, since one of the sex chromosome (X) is heterochromatic in T. vitticeps. T. protracta showed C-blocks in both ends of all autosomes, T. tibiamaculata showed terminal C-dots in some autosomal pairs and M. pallidipennis did not show constitutive heterochromatin in autosomes. Thus, we confirmed the heterochromatic pattern of 7 species of insects and emphasized the importance of cytogenetic techniques for C-banding for taxonomy studies of the triatomines, which are important vectors of Chagas disease. PMID- 25501240 TI - Correlation between DQB1 genetic polymorphism and genetic susceptibility in patients diagnosed with irritable bowel syndrome with diarrhea. AB - We examined patients of Han nationality diagnosed with irritable bowel syndrome with diarrhea (IBS-D) in Guangdong, China, to analyze the correlation between DQB1 allele polymorphisms and the genetic susceptibility to IBS-D. A total of 120 IBS-D patients of Han nationality in Guangdong, China, and 60 healthy control volunteers were included. DQB1 allele polymorphisms were investigated by polymerase chain reaction. Subjects' serum interleukin (IL)-10 level, colonic permeability, and tight junction marker zonula occludens 1 (ZO1) mRNA level were also investigated. Our data showed that the DQB1*02 allele frequency was significantly higher in IBS-D patients, while the DQB1*0603 frequency was lower than in healthy volunteers. The DQB1*03, DQB1*04, DQB1*05, DQB1*0601, DQB1*0602, and DQB1*0604 alleles did not show significant differences between IBS-D patients and healthy controls. Furthermore, patients with DQB1*03- positive and DQB1*0603 negative alleles showed more severe colonic permeability and lower serum IL-10 level and ZO1 level compared to healthy controls or even IBS-D patients with other genotypes. The present study indicated the DQB1*02 or DQB1*0603 alleles are related to IBS-D occurrence in Guangdong, China, and the mechanism of the disease may be related to reduced serum IL-10 levels. PMID- 25501241 TI - Genetic and phenotypic parameters of carcass and organ traits of broiler chickens. AB - The objective of this study was to estimate the genetic and environmental parameters for carcass, carcass part, and organ weights in a paternal strain of broiler chickens that was selected mainly for body weight at 42 days of age (BW42) to provide support for poultry genetic improvement programs. A total of 1448 chickens were used that resulted from the expansion of a pure paternal strain named TT, which was developed by Embrapa Suinos e Aves. The following weights were evaluated: BW42, chilled carcass, wing, drumstick meat, thigh meat, breast meat, breast fillet, back, liver, heart (HRT), and gizzard (GIZ). The variance component was estimated by the restricted maximum likelihood method using a multi-trait animal model. The general model included the additive genetic and residual random effects and the fixed effect of the sex-hatch group (10 levels). The heritability estimates ranged from 0.27 +/- 0.06 for HRT to 0.44 +/- 0.08 for GIZ. These results indicated that all the traits have enough additive genetic variability to respond to selection. The genetic correlation estimates between BW42 and the carcass and carcass part weights were high and positive. However, the genetic correlation estimates between BW42 and organ weights were low. In this population, the carcass traits might respond indirectly to selection applied to BW42. It can be concluded that selection to increase BW42 is not effective in improving broiler organ weight. Therefore, to obtain suitable genetic improvement for these traits, the selection indexes for broilers should include organ weight-based criteria. PMID- 25501242 TI - Influence of aberrant myeloid expression on acute lymphoblastic leukemia in children and adolescents from Maranhao, Brazil. AB - The aim of this study was to evaluate myeloid expression in acute lymphoblastic leukemia (ALL) in children and adolescents who had been referred to the Oncology Department in a hospital in the State of Maranhao based on demographic, laboratory, and clinical data. Myeloid expression was evaluated in 65 patients under 18 years of age who were diagnosed with morphological, cytochemical, and immunophenotypes of ALL. Demographic, laboratory (hemogram), and clinical variables were obtained from medical records. The sample was divided into groups with and without anomalous myeloid expression to analyze the variables. Myeloid expression was observed in 49.2% of the sample. Platelet count was significantly lower in the group of children without aberrant myeloid expression (33,627 platelets/mm(3), P = 0.01). A total of 88.9% of children with B-cell ALL without myeloid expression showed less than 50,000 platelets/mm(3) (P = 0.01). Thus, platelet count may be an important parameter in the diagnosis of children with ALL without myeloid aberrant expression and may indicate a greater risk of bleeding during treatment in this group. PMID- 25501243 TI - Association between DLK1 and IGF-I gene expression and meat quality in sheep. AB - The aim of the present study was to detect delta-like 1 ho-molog (DLK1) and insulin-like growth factor-I (IGF-I) gene expression in the longissimus dorsi of Hu sheep at different growth stages and study the association between these genes and meat quality. The diameter and density of muscle fibers and tenderness of the longissimus dorsi were measured. Growth stage, but not sex, significantly affected DLK1 and IGF-I expression. DLK1 and IGF-I expression in the sheep longissimus dorsi gradually increased with growth, but also decreased during some periods. These results suggest that different growth stages significantly affect DLK1 and IGF-I gene expression in sheep muscle tissue. The ex-pression of DLK1 and IGF-I genes were positively and significantly (P < 0.01) correlated with muscle fiber diameter and muscle fiber shear stress, and negatively and significantly (P < 0.01) correlated with muscle fiber density. Muscle fiber diameter was positively and significantly (P < 0.01) correlated with muscle fiber shear stress, and negatively and significantly (P < 0.01) correlated with muscle fiber density. In addition, DLK-1 expression was significantly (P < 0.01) and positively correlated with IGF-I expression. PMID- 25501244 TI - Comparison of small scale methods for the rapid and efficient extraction of mitochondrial DNA from wheat crop suitable for down-stream processes. AB - We evaluated and compared 2 mitochondrial DNA (mtDNA) extraction methods in terms of DNA quality and success of subsequent polymerase chain reaction (PCR) amplifications from yellow etiolated shoots of wheat crop (Triticum aestivum). mtDNA ex-traction is difficult because the presence of metabolites interfere with DNA isolation procedures and downstream applications such as DNA restriction, amplification, and cloning. The method (with modification) involved inactivation of genomic DNA by DNase I enzyme, RNA by RNase enzyme, contaminant proteins by using proteinase K, and precipitation of polysaccharides in the presence of a high salt concentration. The DNase I and RNA enzyme ratio was adjusted to 10:8 mL. The purity of mtDNA was confirmed by PCR amplification of genomic, mitochondrial, and chloroplast (rbcL) gene. The mitochondrial COXIII gene of 400 bp was amplified; the b-actin and chloroplast genes were not amplified. A260/A280 (1.89) and A260/A230 (2.07) ratios were calculated using a spectrophotometer. The isolated mtDNA was amenable to amplification and restriction digestion. The technique is fast, reproducible, and suitable for PCR-based markers. PMID- 25501245 TI - Increasing genetic variability in black oats using gamma irradiation. AB - The black oat (Avena strigosa Schreb) is commonly used for forage, soil cover, and green manure. Despite its importance, little improvement has been made to this species, leading to high levels of genotypic disuniformity within commercial cultivars. The objective of this study was to evaluate the efficiency of different doses of gamma rays [(60)Co] applied to black oat seeds on the increase of genetic variability of agronomic traits. We applied doses of 0, 10, 50, 100, and 200 Gy to the genotype ALPHA 94087 through exposure to [(60)Co]. Two experiments were conducted in the winter of 2008. The first aimed to test forage trait measurements such as plant height, dry matter yield, number of surviving tillers, and seedling stand. The second test assessed seed traits, such as yield and dormancy levels. Gamma irradiation seems not to increase seed yield in black oats, but it was effective in generating variability for the other traits. Tiller number and plant height are important selection traits to increase dry matter yield. Selection in advanced generations of mutant populations can increase the probability of identifying superior genotypes. PMID- 25501246 TI - DNA barcoding for species identification in the Palmae family. AB - DNA barcoding is a promising tool for species identification at the molecular level. The barcoding system is well established for species differentiation in animals, while it is less common in plants. We evaluated 2 barcoding regions, maturase K (matK) and ribulose bisphosphate carboxylase (rbcL), to compare species of Palmae according to amplification success, discrimination power, and inter- and intra-specific divergence. Both regions appear to have potential to discriminate most species of Palmae, but 2 species, Phoenix dactylifera and Phoenix sylvestris, did not show variation in the nucleotides of the barcode genes. P. sylvestris is said to be the sister species of P. dactilyfera according to its morphological and genetic proximity to the cultivated date palm. Thus, the status of these 2 species needs to be re-evaluated considering more genes as barcodes. Furthermore, rbcL has a higher discrimination power (90%) than matK (66.6%) and can thus be potentially used as a standard barcode to discriminate the species of Palmae. PMID- 25501247 TI - Genetic control of inflorescence in common bean. AB - The number of pods per common bean plant is a primary component of grain yield, which depends on the number of flowers produced and on the flower set. Thus, a larger number of flowers per plant would increase yield. Lines with inflorescences that had a large number of flowers compared to common bean plants now under cultivation were identified. We analyzed the genetic control of this trait and its association with grain yield. The cultivar BRSMG Talisma was crossed with 2 lines, L.59583 and L.59692, which have a large number of flowers. The F1, F2, and F3 generations were obtained. These generations were assessed together with the parents in a randomized block experimental design with 2 replications. The traits assessed included length of inflorescence, number of pods per inflorescence, number of pods per plant, number of grains per plant, 100 grain weight, and grain yield per plant. Mean genetic components and variance were estimated. The traits length of inflorescence and number of pods per inflorescence exhibited genetic control with predominance that showed an additive effect. In the 2 crosses, genetic control of grain yield and of its primary components showed that the allelic interaction of dominance was high. The wide variability in the traits assessed may be used to increase yield of the common bean plant by increasing the number of flowers on the plant. PMID- 25501248 TI - Polymorphic microsatellite markers for the rare and endangered cactus Uebelmannia pectinifera (Cactaceae) and its congeneric species. AB - The cactus genus Uebelmannia includes 3 narrow endemic species associated with rocky savanna habitats in eastern South America. Because of their rarity and illegal over-collection, all of these species are endangered. Taxonomic uncertainties resulting from dramatic local variation in morphology within Uebelmannia species preclude effective conservation efforts, such as the reintroduction or translocation of plants, to restore declining populations. In this study, we developed and characterized 18 perfect, dinucleotide simple sequence repeat markers for U. pectinifera, the most widely distributed species in the genus, and tested the cross-amplification of these markers in the remaining congeneric species and subspecies. All markers were polymorphic in a sample from 2 U. pectinifera populations. The effective number of alleles ranged from 1.6 to 8.7, with an average per population of 3.3 (SE +/- 0.30) and 4.5 (SE +/- 0.50). Expected heterozygosity ranged from 0.375 to 0.847 and 8-10 loci showed departures from Hardy- Weinberg equilibrium in the analyzed populations. Based on the observed polymorphism level of each marker, as well as the analysis of null allele presence and evidence of amplification of duplicate loci, a subset of 12 loci can be used as reliable markers to investigate the genetic structure, diversity, and species limits of the Uebelmannia genus. PMID- 25501249 TI - Genetic-molecular characterization of backcross generations for sexual conversion in papaya (Carica papaya L.). AB - The low number of improved cultivars limits the expansion of the papaya crop, particularly because of the time required for the development of new varieties using classical procedures. Molecular techniques associated with conventional procedures accelerate this process and allow targeted improvements. Thus, we used microsatellite markers to perform genetic-molecular characterization of papaya genotypes obtained from 3 backcross generations to monitor the inbreeding level and parental genome proportion in the evaluated genotypes. Based on the analysis of 20 microsatellite loci, 77 genotypes were evaluated, 25 of each generation of the backcross program as well as the parental genotypes. The markers analyzed were identified in 11 of the 12 linkage groups established for papaya, ranging from 1 to 4 per linkage group. The average values for the inbreeding coefficient were 0.88 (BC1S4), 0.47 (BC2S3), and 0.63 (BC3S2). Genomic analysis revealed average values of the recurrent parent genome of 82.7% in BC3S2, 64.4% in BC1S4, and 63.9% in BC2S3. Neither the inbreeding level nor the genomic proportions completely followed the expected average values. This demonstrates the significance of molecular analysis when examining different genotype values, given the importance of such information for selection processes in breeding programs. PMID- 25501250 TI - Association between CYP1A1m1 gene polymorphism and primary open-angle glaucoma. AB - The CYP1A1 gene is related to the generation of secondary metabolites that are capable of inducing DNA damage. The CYP1A1m1 polymorphism has been examined in many studies, and is located in a region near loci that have been linked to glaucoma, including the locus GLC1I. As a result, this polymorphism has been related to several diseases that are influenced by exposure to xenobiotic as well as primary open-angle glaucoma. We compared the prevalence of the CYP1A1m1 polymorphism in 152 Brazilian patients, 100 patients with primary open-angle glaucoma, and 52 normal controls using restriction fragment length polymorphism analysis. The frequency of the homozygous wild-type (w1/w1) CYP1A1 gene among patients with primary open-angle glaucoma (N = 100) was 16%, for genotype w1/m1, the frequency was 77%, and for m1/m1 it was 7%. Among the control group (N = 52), the frequency of the homozygous wild-type (w1/w1) CYP1A1 gene was 54%, the frequency of w1/m1 was 46%, and the frequency of m1/m1 was 0%. The presence of the CYP1A1m1 polymorphism may interfere with xenobiotic metabolism and exacerbate direct or indirect damage to the optic nerve. These CYP1A1m1 polymorphisms may be risk factors for primary open-angle glaucoma. PMID- 25501251 TI - Microsatellite in Aeschynomene falcata (Leguminosae): diversity, cross amplification, and chromosome localization. AB - Aeschynomene falcata is an important forage species; however, because of low seed production, it is underutilized as forage species. Aeschynomene is a polyphyletic genus with a challenging taxonomic position. Two subgenera have been proposed, and it is suggested that Aeschynomene can be split in 2 genera. Thus, new markers, such as microsatellite sequences, are desirable for improving breeding programs for A. falcata. Based on transferability and in situ localization, these microsatellite sequences can be applied as chromosome markers in the genus Aeschynomene and closely related genera. Here, we report the first microsatellite library developed for this genus; 11 microsatellites were characterized, with observed and expected heterozygosities ranging from 0.0000 to 0.7143 and from 0.1287 to 0.8360, respectively. Polymorphic information content varied from 0.1167 to 0.7786. The departure from Hardy-Weinberg equilibrium may have resulted from frequent autogamy, which is characteristic of A. falcata. Of the 11 microsatellites, 9 loci were cross-amplified in A. brevipes and A. paniculata and 7 in Dalbergia nigra and Machaerium vestitum. Five of these 7 cross-amplified microsatellites were applied as probes during the in situ hybridization assay and 2 showed clear signals on A. falcata chromosomes, ensuring their viability as chromosome markers. PMID- 25501252 TI - Substrate selective amide coupling driven by encapsulation of a coupling agent within a self-assembled hexameric capsule. AB - Encapsulation of a cationic carbodiimide condensing agent within a self-assembled hexameric capsule made of resorcin[4]arene units provides a nano-environment that efficiently steers the substrate selectivity in the amide synthesis reaction between carboxylic acids and primary amines. While in solution pairs of acids react similarly with a given amine, in the presence of the capsule the formation of the shorter amide is greatly favored. PMID- 25501254 TI - In vitro effects of exogenous carbon monoxide on oxidative stress and lipid metabolism in macrophages. AB - Carbon monoxide (CO) is a major constituent of traffic-related air pollution and is also produced endogenously under conditions of oxygen-mediated stress. It has been shown to affect both oxidative stress and inflammation. However, its role in lipid metabolism has been neglected. Using short exposure times, the effect of CO on J774A.1 macrophage atherogenic functions was investigated up to 16 h after exposure. Exposure of macrophages was found to be pro-atherogenic as it significantly increased triglyceride mass, up to 60%, and decreased high-density lipoprotein-mediated cholesterol efflux, up to 27%. In contrast, paraoxonase 2 lactonase activity was increased, up to 65%, and cellular oxidative stress was attenuated by 29%, compared with the control cells. The above results on lipid metabolism may lead to arterial macrophage foam cell formation, the hallmark of early atherogenesis. PMID- 25501255 TI - Effects of pollutants from power plants in Kosova on genetic loads of Drosophila melanogaster. AB - It has been reported by the Ministry of Environment in Kosova that particle emissions from one of the units of the coal-fired power plants (Kosova A) in Kastriot/Obiliq were exceeding the European standard by some 74 times. Besides the particle emission, there is also release of sulphur dioxide, mono-nitrogen oxide (NOx), carbon monoxide, carbon dioxide, organic compounds and heavy metals. In addition, there is also release of heavy metals and organic compounds from a nearby solid waste dumpsite. Together, they are considered to be responsible for the increased health problems of the population living in the vicinity.To study the genetic effects of these emissions we focused on the genetic load, that is, recessive mutations that affect the fitness of their carriers, of exposed wild living Drosophila melanogaster The effects of ash from the dumpsite on the other hand were investigated upon feeding the ash with the nutrient medium. Our results revealed that the D. melanogaster population from the Kastriot/Obiliq area carries a high genetic load of 54.7%. Drosophila fed with the nutrient medium containing ash in a concentration of 1% carried a genetic load of 37.1%, whilst increasing concentrations (2% and 3% of ash) led to higher genetic loads of 68.7% and 67.4%, respectively. PMID- 25501256 TI - Antinociceptive and anti-inflammatory potential of Rhododendron arboreum bark. AB - Rhododendron arboreum Smith. (Ericaceae), an evergreen small tree, is one of the 1000 species that belongs to genus Rhododendron distributed worldwide. In folk medicine, as various parts of this plant exhibit medicinal properties, it is used in the treatment of different ailments.The present study was designed to evaluate the potential anti-inflammatory and antinociceptive effects of methanolic extract of R. arboreum bark, followed by activity-guided fractionation of n-hexane, n butanol, chloroform, ethyl acetate and aqueous fractions.The ethyl acetate fraction (200 mg/kg i.p.) showed the maximum analgesic effect (82%) in acetic acid-induced writhing, followed, to a less extent, by crude extract and chloroform fraction both at a dose of 200 mg/kg i.p. (65.09% and 67.89%, respectively). In carrageenan-induced mouse paw oedema, the crude extract and its related fractions displayed in a dose-dependent manner (50-200 mg/kg i.p.) an anti-inflammatory activity for all time-courses (1-5 hrs). For the active extract/fractions (200 mg/kg i.p.), the maximum effect was observed 5 h after carrageenan injection. These evidences were also supported by in vitro lipoxygenase inhibitory properties. In conclusion, R. arboreum crude methanolic extract and its fractions exhibited anti-inflammatory and antinociceptive effects. For these reasons, this plant could be a promising source of new compounds for the management of pain and inflammatory diseases. PMID- 25501253 TI - Migraine genetics: current findings and future lines of research. AB - In the last two decades, migraine research has greatly advanced our current knowledge of the genetic contributions and the pathophysiology of this common and debilitating disorder. Nonetheless, this knowledge still needs to grow further and to translate into more effective treatments. To date, several genes involved in syndromic and monogenic forms of migraine have been identified, allowing the generation of animal models which have significantly contributed to current knowledge of the mechanisms underlying these rare forms of migraine. Common forms of migraine are instead posing a greater challenge, as they may most often stem from complex interactions between multiple common genetic variants, with environmental triggers. This paper reviews our current understanding of migraine genetics, moving from syndromic and monogenic forms to oligogenic/polygenic migraines most recently addressed with some success through genome-wide association studies. Methodological issues in study design and future perspectives opened by biomarker research will also be briefly addressed. PMID- 25501258 TI - Entry time effects and follow-on drug competition. AB - Pharmaceutical firms have been criticized for concentrating efforts of R&D on the so-called me-too or follow-on drugs. There have been many comments for and against the dissemination of these incremental innovations but few papers have broached the subject from an econometric point of view, possibly because identification of me-too or follow-on drugs is not so obvious. This paper focuses on the impact of entry order on follow-on drug competition in the French market between the years 2001 and 2007. More precisely, this study examines the effects on market share of first entrants in the follow-on drug market and how this possible competitive advantage changes over time. First results are coherent with theoretical microeconomic issues concerning the importance of being first. We find evidence that first movers in the follow-on drug market have the ability to capture and maintain greater market share for a long period of time. The hierarchical market position of follow-on drugs does not seem to be affected by generic drug emergence. From a dynamic perspective, our analysis shows that market share is positively correlated with the ability of follow-on drugs to set prices higher than the average follow-on drug prices in a specific therapeutic class, which means that market power remains considerably important for first movers. Moreover, we found that the optimum level of innovation to maximize market share is the highest one. PMID- 25501257 TI - Spleen stiffness measurements by acoustic radiation force impulse imaging after living donor liver transplantation in children: a potential quantitative index for venous complications. AB - BACKGROUND: Living donor liver transplantation in children often results in venous complications, leading to portal hypertension. Spleen stiffness measurements have been recently proposed as a new, noninvasive parameter for portal hypertension in cirrhotic patients. OBJECTIVE: To evaluate the diagnostic value of spleen stiffness measurements by acoustic radiation force impulse (ARFI) imaging in diagnosing venous complications after pediatric living donor liver transplantation. MATERIALS AND METHODS: We prospectively enrolled 69 patients after pediatric living donor liver transplantation using a left-side liver allograft. Around the time of the protocol liver biopsy examination, spleen stiffness measurements by ARFI imaging were performed via the left intercostal space at the center of the spleen parenchyma and repeated five times. Imaging examinations around the time of the spleen stiffness measurements were retrospectively reviewed. Regarding venous complications, significant portal and hepatic venous stenosis was defined as >50% stenosis on multiphasic computed tomography. RESULTS: After post hoc exclusion, 62 patients were studied. Portal and hepatic venous stenosis was identified in three and two patients, respectively. The median spleen stiffness values were 2.70 and 4.00 m/s in patients without and with venous complications, respectively (P < 0.001). Spleen stiffness measurements showed good diagnostic power for venous complications, and the cutoff value was determined as 2.93 m/s, with 100% sensitivity and 78.9% specificity. Spleen stiffness measurements decreased with the relief of venous stenosis resulting from an interventional radiology procedure. CONCLUSION: Spleen stiffness measurements by ARFI imaging might provide a useful quantitative index for venous complications after pediatric living donor liver transplantation. PMID- 25501259 TI - Wage subsidies and hiring chances for the disabled: some causal evidence. AB - This study evaluated the effectiveness of wage subsidies as a policy instrument to integrate disabled individuals into the labor market. To identify causal effects, a large-scale field experiment was conducted in Belgium. The results show that the likelihood of a disabled candidate receiving a positive response to a job application is not positively influenced by disclosing entitlement to the Flemish Supporting Subsidy. PMID- 25501260 TI - Is personalized medicine a panacea for health management? Some thoughts on its desirability. PMID- 25501261 TI - Fasting serum levels of ferritin are associated with impaired pancreatic beta cell function and decreased insulin sensitivity: a population-based study. AB - AIMS/HYPOTHESIS: Elevated serum ferritin levels are associated with an increased risk of type 2 diabetes, but the nature of this association remains elusive. The aim of this study was to test the hypothesis that an elevated fasting serum ferritin level is associated with an increased risk of type 2 diabetes due to its association with impaired beta cell function and decreased insulin sensitivity. METHODS: We investigated 6,392 individuals from the Danish general population. Surrogate measures of beta cell function and insulin sensitivity were calculated for approximately 6,100 individuals based on OGTT examinations. RESULTS: The ORs for type 2 diabetes were 4.2 (95% CI 2.4, 7.2) for the highest vs the lowest quintile of serum ferritin, and 17 (95% CI 8.9, 33) for serum ferritin levels >=97.5th percentile vs <20th percentile. Elevated serum ferritin levels were associated with elevated plasma glucose levels at 0, 30 and 120 min (p < 0.001), elevated serum insulin levels at 0 and 120 min (p = 0.02 and p < 0.001), decreased beta cell function estimated as the insulinogenic index and corrected insulin response (p < 0.001), and decreased insulin sensitivity estimated by the Matsuda index of insulin sensitivity and HOMA-IR (p < 0.001). Whereas the association with impaired beta cell function was present in both men and women, the association with decreased insulin sensitivity was observed among men and older women but not among younger women. CONCLUSIONS/INTERPRETATION: Elevated fasting serum ferritin levels are associated with surrogate measures of both impaired beta cell function and decreased insulin sensitivity. Menopause seems to modify the association with insulin sensitivity. PMID- 25501262 TI - Alkaloid variation among epichloid endophytes of sleepygrass (Achnatherum robustum) and consequences for resistance to insect herbivores. AB - Epichloid endophytes are well known symbionts of many cool-season grasses that may alleviate environmental stresses for their hosts. For example, endophytes produce alkaloid compounds that may be toxic to invertebrate or vertebrate herbivores. Achnatherum robustum, commonly called sleepygrass, was aptly named due to the presence of an endophyte that causes toxic effects to livestock and wildlife. Variation in alkaloid production observed in two A. robustum populations located near Weed and Cloudcroft in the Lincoln National Forest, New Mexico, suggests two different endophyte species are present in these populations. Genetic analyses of endophyte-infected samples revealed major differences in the endophyte alkaloid genetic profiles from the two populations, which were supported with chemical analyses. The endophyte present in the Weed population was shown to produce chanoclavine I, paspaline, and terpendoles, so thus resembles the previously described Epichloe funkii. The endophyte present in the Cloudcroft population produces chanoclavineI, ergonovine, lysergic acid amide, and paspaline, and is an undescribed endophyte species. We observed very low survival rates for aphids feeding on plants infected with the Cloudcroft endophyte, while aphid survival was better on endophyte infected plants in the Weed population. This observation led to the hypothesis that the alkaloid ergonovine is responsible for aphid mortality. Direct testing of aphid survival on oat leaves supplemented with ergonovine provided supporting evidence for this hypothesis. The results of this study suggest that alkaloids produced by the Cloudcroft endophyte, specifically ergonovine, have insecticidal properties. PMID- 25501263 TI - Validity of a long-term cardiovascular disease risk prediction equation for low incidence populations: the CAMUNI-MATISS Cohorts Collaboration study. AB - BACKGROUND: Before introducing long-term cardiovascular disease (CVD) risk models in clinical practice, their external validity should be investigated. We assessed the validity of the CArdiovascular Monitoring Unit in Northern Italy (CAMUNI) 20 year risk score, developed in Northern Italy, and published previously, when applied to a population with different risk factors distribution and event incidence. METHODS: The validation sample consisted of 5307 35-69 year-old subjects (2418 men) enrolled in Central Italy during the 1980s (Malattia ATerosclerotica Istituto Superiore di Sanita (MATISS) study). Baseline risk factor assessment and follow-up procedures, including MONICA definition of acute events, followed a shared protocol with the derivation cohorts. We estimated model calibration and discrimination (area under the ROC curve, AUC) in the validation set; as well as the net benefit of using the CAMUNI risk score as second-level screening in subjects at different levels of short-term risk. RESULTS: The 20-year risk of event was 14% in men and 7% in women. Model calibration was satisfactory, and the strength of the association between predictors and the endpoint was the same as in the derivation population. The AUC was 0.734 (men) and 0.802 (women). The net benefit of the CAMUNI score was 3.9 (95% confidence interval: 2.1-5.7) and 2.9 (1.7-4.3) in men and women at low 10 year risk, respectively. Among subjects at high short-term risk, a significant net benefit of 9.8 was observed in men only. A pooled CAMUNI-MATISS risk score is provided. CONCLUSIONS: In this low-incidence European population, long-term CVD prediction through the CAMUNI risk score is accurate and it has the potential to improve current primary prevention strategies based on short-term risk scores alone. PMID- 25501265 TI - Impact of Anatomical, Procedural, and Operator Skill Factors on the Success and Duration of Fluoroscopy-Guided Transjugular Intrahepatic Portosystemic Shunt. AB - PURPOSE: To assess the impact of anatomical, procedural, and operator skill factors on the success and duration of fluoroscopy-guided transjugular intrahepatic portoystemic shunt following standard operating procedure (SOP). MATERIAL AND METHODS: During a 32-month period, 102 patients underwent transjugular intrahepatic portosystemic shunt creation (TIPS) by two interventional radiologists (IR) following our institutional SOP based on fluoroscopy guidance. Both demographic and procedural data were assessed. The duration of the intervention (D(Int)) and of the portal vein puncture (D(Punct)) was analyzed depending on the skill level of the IR as well as the anatomic or procedural factors. RESULTS: In 99 of the 102 patients, successful TIPS without peri-procedural complications was performed. The mean D(Int) (IR1: 77 min; IR2: 51 min, P < 0.005) and the mean D(Punct) (IR1: 19 min; IR2: 13 min, P < 0.005) were significantly higher in TIPS performed by IR1 (with 2 years of clinical experience performing TIPS, n = 38) than by IR2 (>10 years of clinical experience performing TIPS, n = 61), (P < 0.005 both, Mann-Whitney U test). D Int showed a higher correlation with D(Punct) for IR2 (R(2) = 0.63) than for IR1 (R(2) = 0.13). There was no significant difference in the D(Punct )for both IRs with regard to the success of the wedged portography (P = 0.90), diameter of the portal vein (P = 0.60), central right portal vein length (P = 0.49), or liver function (MELD-Score before the TIPS procedure; P = 0.14). CONCLUSION: TIPS following SOP is safe, fast, and reliable. The only significant factor for shorter D(Punct) and D(Int) was the clinical experience of the IR. Anatomic variability, successful portography, or liver function did not alter the duration or technical success of TIPS. PMID- 25501264 TI - Functional expression of the Fc-fused extracellular domains of group II membrane proteins. AB - The complicated delivery mechanism of group II membrane proteins makes it difficult to decide the fusion pattern of their extracellular domains (ECDs) with Fc moiety. In this study, we compared the expression of ECDs of three group II membrane proteins including CLEC-2, Dectin-1, and LOX-1 by fusion of Fc moiety. We found that the pattern of ECD-Fc fusion order produced the functionally active recombinant proteins while the pattern of Fc-ECD fusion order led to the altered glycosylation which abolished the binding of these proteins with their ligands. Meanwhile, our results indicated that the secretion of mouse Fc (mFc)-fused ECD of CLEC-2 was more efficient than that of rabbit Fc (rFc)-fused protein, while rFc moiety was more sensitive for detection compared with mFc moiety. Altogether, we provide a favorable fusion pattern of Fc moiety with the ECDs of group II transmembrane proteins. PMID- 25501266 TI - Perfusion angiography of the foot in patients with critical limb ischemia: description of the technique. AB - OBJECTIVE: To study the feasibility of 2D perfusion imaging in critical limb ischemia (CLI). METHODS/RESULTS: Perfusion angiography is a new technology which was tested in 18 patients with CLI of the foot. A standardized protocol was used with a catheter placed at the mid-part of the popliteal artery, and a total of 9 cc of non-ionic iodinated contrast material was injected at a rate of 3 cc/sec. The technology is based on early cardiology research where iodinated contrast agents were used for imaging of cardiac perfusion. During the first pass of the contrast, there is a significant diffusion of the contrast agents into the interstitial space, particularly for non-ionic and low-molecular-weight compounds. DISCUSSION: The original angiography data can be used to make a time density curve, which represents the actual perfusion of the foot in time. Angiographic perfusion imaging is a post-processing modality for which no extra contrast or radiation is needed. With this technique, it is possible to get more information about the perfusion status and microcirculation of the foot. This is a step toward functional imaging in CLI patients. PMID- 25501267 TI - Oligo(ethylene glycol)-incorporated hybrid linear alkyl side chains for n-channel polymer semiconductors and their effect on the thin-film crystalline structure. AB - Oligo(ethylene glycol)-incorporated hybrid linear alkyl side chains, serving as solubilizing groups, are designed and introduced into naphthalene-diimide-based n channel copolymers. The synthesized polymers exhibit unipolar n-type operation with an electron mobility of up to 1.64 cm(2) V(-1) s(-1), which demonstrates the usefulness of the hybrid side chains in polymer electronics applications. PMID- 25501268 TI - Cardiac troponin I for predicting right ventricular dysfunction and intermediate risk in patients with normotensive pulmonary embolism. AB - BACKGROUND: Right ventricular dysfunction (RVD) and cardiac troponin I (cTnI) are important tools for risk stratification in pulmonary embolism (PE). We investigate the association of RVD and cTnI in normotensive PE patients and calculate a cTnI cut-off level for predicting RVD and submassive PE. METHODS: Clinical, laboratory, radiological and echocardiagraphic data were analysed. Patients were categorised into groups with or without RVD and compared focussing on cTnI. Effectiveness of cTnI for predicting RVD and submassive PE was tested. RESULTS: One hundred twenty-nine normotensive PE patients, 71 with and 58 without RVD, were included. Patients with RVD were older (75.0 years (61.3/81.0) vs. 66.0 years (57.7/75.1), P = 0.019). cTnI (0.06 ng/ml (0.02/0.23) vs. 0.01 ng/ml (0.00/0.03), P < 0.0001) and D-dimer values (2.00 mg/l (1.08/4.05) vs. 1.23 mg/l (0.76/2.26), P = 0.016) were higher in PE with RVD. cTnI was associated with RVD (OR 3.95; 95 % CI 1.95-8.02, p = 0.00014). AUC for cTnI diagnosing RVD was 0.79, and for submassive PE0.87. Cut-off values for cTnI predicting RVD and submassive PE were 0.01 ng/ml, with a negative predictive value of 73 %. cTnI was positively correlated with age, D-dimer and creatinine. CONCLUSIONS: In normotensive PE patients, cTnI is helpful for risk stratification and excluding RVD. cTnI elevation is correlated with increasing age and reduced kidney function. PMID- 25501269 TI - Endovascular Treatment of Intracranial Dural Arteriovenous Fistulas Presenting with Intracranial Hemorrhage in 46 Consecutive Patients: With Emphasis on Transarterial Embolization with Onyx. AB - PURPOSE: The purpose of this study was to evaluate the effectiveness and safety as well as the clinical and angiographic results of endovascular treatment (EVT) for patients with hemorrhagic dural arteriovenous fistulas (DAVFs). METHODS: From April 2009 to November 2013, 46 consecutive patients (7 women, 39 men; mean age, 46.7 years) diagnosed with hemorrhagic intracranial DAVFs at our department were enrolled in this study. Clinical and angiographic data were reviewed and evaluated. RESULTS: Two fistulas were cured by transvenous approach, and all other fistulas were embolized through transarterial route. After treatment with last embolization, a residual shunt was observed in 15 patients, including near total obliteration of the fistula in 6 patients (13.0 %) and partial obliteration of the fistula in 9 patients (19.6 %). Seven of them underwent supplementary Gamma knife surgery. Complications occurred during or after EVT in six patients. One patient died 10 days after EVT because of complications of Onyx embolus into the posterior inferior cerebellar artery. Other complications included microcatheter entrapment in one case, trigeminocardiac reflex in one, facial nerve paresis in two, and occulomotor nerve paresis in one. The facial nerve paresis in one patient markedly improved but did not completely resolve during follow-up period. The other four patients recovered well, without symptoms at clinical follow-up. Angiographic follow-up result was obtained in 35 cases, with complete obliteration in 27 of them (77.1 %). Clinical follow-up outcomes were good, with 38 patients (82.6 %) reporting modified Rankin Scale of either 0 or 1. No patient suffered recurrent intracranial hemorrhage during follow-up. CONCLUSIONS: EVT was effective and safe in the modern management of ruptured intracranial DAVFs, with complete cure in most lesions. Clinical outcomes were good despite patients presenting with intracranial hemorrhage. PMID- 25501271 TI - Pancreatic duct "Icicle sign" on MRI for distinguishing autoimmune pancreatitis from pancreatic ductal adenocarcinoma in the proximal pancreas. AB - OBJECTIVE: To determine reliable MRI features of autoimmune pancreatitis (AIP) in the proximal pancreas that could allow its differentiation from pancreatic ductal adenocarcinoma (PDAC). METHODS: Twenty-three patients with AIP and 61 patients with PDAC in the proximal pancreas underwent MRI. Two observers analyzed MRI for lesion morphology, hypointensity degree on T1-weighted images, enhancement pattern during dynamic phases, capsule-like rim, presence of cysts and duct penetrating sign, morphology of bile duct, and icicle appearance and tortuosity of the upstream pancreatic duct. Sensitivity and specificity for the diagnosis of AIP were calculated for each category or combined. RESULTS: When isointensity on the portal and late phase of MRI and/or the icicle sign of pancreatic duct are applied, 100 % sensitivity for the diagnosis of AIP in the proximal pancreas was achieved. Applying both mild T1 hypointensity similar to the spleen and the icicle sign enabled 100 % specificity for the diagnosis of AIP by differentiating it from PDAC. CONCLUSION: The combination of the icicle sign in the upstream pancreatic duct and mild T1 hypointensity or isointensity on portal and late phase of dynamic MRI could be reliable MR features for the diagnosis of AIP in the proximal pancreas by allowing its differentiation from PDAC. KEY POINTS: * The icicle sign of the pancreatic duct is useful for diagnosing AIP. * Mild T1 hypointensity similar to the spleen is useful for diagnosing AIP. * Isointensity on portal and late phases MRI is useful for diagnosing AIP. PMID- 25501272 TI - Multidetector-row computed tomography for prosthetic heart valve dysfunction: is concomitant non-invasive coronary angiography possible before redo-surgery? AB - OBJECTIVES: Retrospective ECG-gated multidetector-row computed tomography (MDCT) is increasingly used for the assessment of prosthetic heart valve (PHV) dysfunction, but is also hampered by PHV-related artefacts/cardiac arrhythmias. Furthermore, it is performed without nitroglycerine or heart rate correction. The purpose was to determine whether MDCT performed before potential redo-PHV surgery is feasible for concomitant coronary artery stenosis assessment and can replace invasive coronary angiography (CAG). METHODS: PHV patients with CAG and MDCT were identified. Based on medical history, two groups were created: (I) patients with no known coronary artery disease (CAD), (II) patients with known CAD. All images were scored for the presence of significant (>50 %) stenosis. CAG was the reference test. RESULTS: Fifty-one patients were included. In group I (n = 38), MDCT accurately ruled out significant stenosis in 19/38 (50 %) patients, but could not replace CAG in the remaining 19/38 (50 %) patients due to non diagnostic image quality (n = 16) or significant stenosis (n = 3) detection. In group II (n = 13), MDCT correctly found no patients without significant stenosis, requiring CAG imaging in all. MDCT assessed patency in 16/19 (84 %) grafts and detected a hostile anatomy in two. CONCLUSION: MDCT performed for PHV dysfunction assessment can replace CAG (100 % accurate) in approximately half of patients without previously known CAD. KEY POINTS: * Retrospective MDCT is increasingly used for prosthetic heart valve dysfunction assessment * In case of PHV reoperation, invasive coronary angiography is also required * MDCT can replace CAG in 50 % of patients without coronary artery disease * When conclusive for coronary assessment, MDCT stenosis rule out is highly accurate * Replacing CAG saves associated risks of distant embolization of thrombi or vegetations. PMID- 25501270 TI - Automated two-point dixon screening for the evaluation of hepatic steatosis and siderosis: comparison with R2-relaxometry and chemical shift-based sequences. AB - OBJECTIVES: To evaluate the automated two-point Dixon screening sequence for the detection and estimated quantification of hepatic iron and fat compared with standard sequences as a reference. METHODS: One hundred and two patients with suspected diffuse liver disease were included in this prospective study. The following MRI protocol was used: 3D-T1-weighted opposed- and in-phase gradient echo with two-point Dixon reconstruction and dual-ratio signal discrimination algorithm ("screening" sequence); fat-saturated, multi-gradient-echo sequence with 12 echoes; gradient-echo T1 FLASH opposed- and in-phase. Bland-Altman plots were generated and correlation coefficients were calculated to compare the sequences. RESULTS: The screening sequence diagnosed fat in 33, iron in 35 and a combination of both in 4 patients. Correlation between R2* values of the screening sequence and the standard relaxometry was excellent (r = 0.988). A slightly lower correlation (r = 0.978) was found between the fat fraction of the screening sequence and the standard sequence. Bland-Altman revealed systematically lower R2* values obtained from the screening sequence and higher fat fraction values obtained with the standard sequence with a rather high variability in agreement. CONCLUSIONS: The screening sequence is a promising method with fast diagnosis of the predominant liver disease. It is capable of estimating the amount of hepatic fat and iron comparable to standard methods. KEY POINTS: * MRI plays a major role in the clarification of diffuse liver disease. * The screening sequence was introduced for the assessment of diffuse liver disease. * It is a fast and automated algorithm for the evaluation of hepatic iron and fat. * It is capable of estimating the amount of hepatic fat and iron. PMID- 25501273 TI - Avulsion fracture of the acromial physis in a 14-year-old boy: a case report. AB - Scapular fractures are uncommon and among them acromial fractures are even more uncommon. Because the vast majority of acromial fractures are either non displaced or minimally displaced, symptomatic and nonoperative management was performed. We describe a case of avulsion fracture of the acromial physis displaced by acromioclavicular ligament treated with open reduction and internal fixation, and include a review of the literature. PMID- 25501274 TI - Insertion of the Ascension PyroCarbon PIP total joint in 152 human cadaver fingers: analysis of implant positions and malpositions. AB - INTRODUCTION: The Ascension PyroCarbon proximal interphalangeal (PIP) total joint is used in osteoarthritis of the PIP finger joint. No systematic study of the positioning of this prosthesis and its relation to proximal and middle phalanx morphology has yet been reported. MATERIALS AND METHODS: Positioning of the proximal and distal components of the Ascension PyroCarbon PIP total joint was radiographically analysed in 152 human cadaver fingers. RESULTS: Ideal implant position in the axis of the phalanx and with contact of the implant head with bone in both the frontal and sagittal planes was seen in only 33 % of the phalanges. Implant malposition was observed in the remaining 67 % of phalanges. CONCLUSION: The current design of the Ascension PyroCarbon PIP total joint can lead to malpositioning that we attribute to its incomplete accommodation of the morphology of the proximal and middle phalanx, the surgical challenges the design poses, or both acting together. PMID- 25501276 TI - Amblyseius swirskii in greenhouse production systems: a floricultural perspective. AB - The predatory mite Amblyseius swirskii Athias-Henriot is a biological control agent that has the potential to play an important role in pest management in many greenhouse crops. Most research on this predatory mite has focused on its use and efficacy in greenhouse vegetables. However, an increasing number of growers of greenhouse ornamental crops also want to adopt biological control as their primary pest management strategy and find that biological control programs developed for vegetables are not optimized for use on floricultural plants. This paper reviews the use of A. swirskii in greenhouse crops, where possible highlighting the specific challenges and characteristics of ornamentals. The effects of different factors within the production system are described from the insect/mite and plant level up to the production level, including growing practices and environmental conditions. Finally, the use of A. swirskii within an integrated pest management system is discussed. PMID- 25501277 TI - Bioactive dietary peptides and amino acids in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD), most commonly ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammation of the gastrointestinal tract. Patients affected with IBD experience symptoms including abdominal pain, persistent diarrhea, rectal bleeding, and weight loss. There is no cure for IBD; thus treatments typically focus on preventing complications, inducing and maintaining remission, and improving quality of life. During IBD, dysregulation of the intestinal immune system leads to increased production of pro-inflammatory cytokines, such as TNF-alpha and IL-6, and recruitment of activated immune cells to the intestine, causing tissue damage and perpetuating the inflammatory response. Recent biological therapies targeting specific inflammatory cytokines or pathways, in particular TNF-alpha, have shown promise, but not all patients respond to treatment, and some individuals become intolerant to treatment over time. Dietary peptides and amino acids (AAs) have been shown to modulate intestinal immune functions and influence inflammatory responses, and may be useful as alternative or ancillary treatments in IBD. This review focuses on dietary interventions for IBD treatment, in particular the role of dietary peptides and AAs in reducing inflammation, oxidative stress, and apoptosis in the gut, as well as recent advances in the cellular mechanisms responsible for their anti-inflammatory activity. PMID- 25501275 TI - Supervised Discriminative Group Sparse Representation for Mild Cognitive Impairment Diagnosis. AB - Research on an early detection of Mild Cognitive Impairment (MCI), a prodromal stage of Alzheimer's Disease (AD), with resting-state functional Magnetic Resonance Imaging (rs-fMRI) has been of great interest for the last decade. Witnessed by recent studies, functional connectivity is a useful concept in extracting brain network features and finding biomarkers for brain disease diagnosis. However, it still remains challenging for the estimation of functional connectivity from rs-fMRI due to the inevitable high dimensional problem. In order to tackle this problem, we utilize a group sparse representation along with a structural equation model. Unlike the conventional group sparse representation method that does not explicitly consider class-label information, which can help enhance the diagnostic performance, in this paper, we propose a novel supervised discriminative group sparse representation method by penalizing a large within class variance and a small between-class variance of connectivity coefficients. Thanks to the newly devised penalization terms, we can learn connectivity coefficients that are similar within the same class and distinct between classes, thus helping enhance the diagnostic accuracy. The proposed method also allows the learned common network structure to preserve the network specific and label related characteristics. In our experiments on the rs-fMRI data of 37 subjects (12 MCI; 25 healthy normal control) with a cross-validation technique, we demonstrated the validity and effectiveness of the proposed method, showing the diagnostic accuracy of 89.19 % and the sensitivity of 0.9167. PMID- 25501278 TI - Chondrocytic cells express the taurine transporter on their plasma membrane and regulate its expression under anisotonic conditions. AB - Taurine is a small organic osmolyte which participates in cell volume regulation. Chondrocytes have been shown to accumulate and release taurine; in bone, taurine participates in bone metabolism. However, its role in skeletal cells is poorly understood, especially in chondrocytes. This study investigated the regulation of taurine transporter in chondrocytic cells. We examined the transcriptional regulation of the taurine transporter under anisotonia by reporter gene and real time RT-PCR assays. The effect of providing supplementary taurine on cell viability was evaluated with the lactate dehydrogenase release assay. The localization of the taurine transporter in human chondrosarcoma cells was studied by overexpressing a taurine transporter-enhanced green fluorescent protein. We observed that the transcription of the taurine transporter gene was up-regulated in hypertonic conditions. Hyperosmolarity-related cell death could be partly abolished by taurine supplementation in the medium. As expected, the fluorescently labeled taurine transporter localized at the plasma membrane. In polarized epithelial MDCK cells, the strongest fluorescence signal was located in the lateral cell membrane area. We also observed that the taurine transporter gene was expressed in several human tissues and malignant cell lines. This is the first study to present information on the transcriptional regulation of taurine transporter gene and the localization of the taurine transporter protein in chondrocytic cells. PMID- 25501279 TI - PCAF-mediated Akt1 acetylation enhances the proliferation of human glioblastoma cells. AB - Glioblastoma is the most aggressive malignant primary brain tumor in humans. The activation of PI3K/Akt1 signaling pathway is involved in the proliferation of glioblastoma; however, the underlying mechanism of Akt1 activation during the development of glioblastoma remains largely unclear. Recently, the modification of molecular molecules at protein level such as acetylation has been shown to be related to the function of these molecules. Thus, in our present studies, the acetylation of Akt1 molecule and its role in the proliferation of glioblastoma cells was explored. The results showed that Akt1 was markedly acetylated in glioblastoma cells compared to normal human astrocytes. Mechanistically, PCAF mediated Akt1 acetylation enhanced Akt1 phosphorylation at both sites of Thr(308) and Ser(473) and further promoted the proliferation of glioblastoma cells. Together, these data implicate that, as a post-translational regulation, PCAF mediated Akt1 acetylation plays an important role in the proliferation of human glioblastoma, suggesting a novel target for clinical application. PMID- 25501280 TI - LASS2/TMSG1 inhibits growth and invasion of breast cancer cell in vitro through regulation of vacuolar ATPase activity. AB - Homo sapiens longevity assurance homologue 2 of yeast LAG1 (LASS2)/tumor metastasis suppressor gene 1 (TMSG1) was a novel tumor metastasis-related gene identified using messenger RNA differential display from non-metastatic human prostate cancer cell variants. The mechanism of LASS2/TMSG1 inhibiting tumor invasion metastasis in breast cancer cells had not been well investigated. In the present study, a full length of 1.2 kb LASS2/TMSG1 complementary DNA (cDNA) coding for a protein of 380 amino acids was cloned. PcDNA3 eukaryotic expression plasmids of LASS2/TMSG1 were constructed and transfected into human breast cancer cell line MCF-7 by lipofectin transfection method. And, the biological effects were observed comparing with control groups. As the result, LASS2/TMSG1 inhibited cell growth in vitro by increasing apoptosis and changing cell cycle distribution. Furthermore, the vacuolar ATPase (V-ATPase) activity and extracellular hydrogen ion concentration were significantly decreased and the activity of secreted matrix metalloproteinase-2 (MMP-2) was downregulated in MCF 7 cells overexpressing LASS2/TMSG1 compared with the controls. Therefore, LASS2/TMSG1 may inhibit growth and invasion of breast cancer cell in vitro through decreasing V-ATPase activity and extracellular hydrogen ion concentration and inactivating secreted MMP-2. The findings provided the evidence that the LASS2/TMSG1 gene had tumor growth and invasion suppressor function in human breast cancer cell and may provide a promising target for cancer metastasis diagnosis and therapy. PMID- 25501281 TI - Targeting prostate cancer cell metabolism: impact of hexokinase and CPT-1 enzymes. AB - Glycolysis has been shown to be required for the cell growth and proliferation in several cancer cells. However, prostate cancer cells were accused of using more fatty acid than glucose to meet their bioenergetic demands. The present study was designed to evaluate the involvement of hexokinase and CPT-1 in the cell growth and proliferation of human prostate cancer cell lines, PC3, and LNCaP-FGC-10. Hexokinase and CPT-1 activities were examined in the presence of different concentrations of their inhibitors, lonidamine and etomoxir, to find the concentration of maximum inhibition ([I max]). To assess cell viability and proliferation, dimethylthiazol (MTT) assay was carried out using [I max] for 24, 48, and 72 h on PC3 and LNCaP cells. Apoptosis was determined using annexin-V, caspase-3 activity assay, Hoechst 33258 staining, and evaluation of mitochondrial membrane potential (MMP). Moreover, ATP levels were measured following lonidamine and etomoxir exposure. In addition, to define the impact of exogenous fatty acid on the cell growth and proliferation, CPT-1 activity was evaluated in the presence of palmitate (50 MUM). Hexokinase and CPT-1 activities were significantly inhibited by lonidamine [600 MUM] and etomoxir [100 MUM] in both cell lines. Treatment of the cells with lonidamine [600 MUM] resulted in a significant ATP reduction, cell viability and apoptosis, caspase-3 activity elevation, MMP reduction, and appearance of apoptosis-related morphological changes in the cells. In contrast, etomoxir [100 MUM] just decreased ATP levels in both cell lines without significant cell death and apoptosis. Compared with glucose (2 g/L), palmitate intensified CPT-1 activity in both cell lines, especially in LNCaP cells. In addition, activity of CPT-1 was higher in LNCaP than PC3 cells. Our results suggest that prostate cancer cells may metabolize glucose as a source of bioenergetic pathways. ATP could also be produced by long chain fatty acid oxidation. In addition, these data might suggest that LNCaP is more compatible with palmitate. PMID- 25501282 TI - Polygala tenuifolia polysaccharide PTP induced apoptosis in ovarian cancer cells via a mitochondrial pathway. AB - One purified polysaccharide protein tyrosine phosphatase (PTP) was isolated from the roots of Polygala tenuifolia. The aim of the present study is to investigate the antitumor effect of PTP on human ovarian cancer OVCAR-3 cells and explore the molecular mechanism of the action involved. The results of MTT assay and apoptosis detection assay showed that PTP inhibited cellular proliferation of OVCAR-3 cells and induced apoptotic cellular death via arresting cell circle at the G0/G1 phase. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis identified that bcl-2 gradually decreased at both transcription and protein levels after PTP treatment for 48 h in OVCAR-3 cells, while those of bax, cytochrome c, caspase-3, and caspase-9 increased. In addition, the low expression of NF-kappaB in PTP-treated OVCAR-3 cells would trigger the extrinsic pathway of programmed cell death signaling in tumor cells. These results together suggest that PTP may induce apoptosis of OVCAR-3 cells through a mitochondrial pathway. PMID- 25501284 TI - Achieving continuous manufacturing. May 20-21, 2014 Continuous Manufacturing Symposium. PMID- 25501283 TI - Multiple sclerosis and hyperprolactinemia: a case-control study. AB - Multiple sclerosis (MS) is an autoimmune disease of central nervous system which is characterized with demyelination. Prolactin, synthesized in the anterior pituitary cells, has a role in maturation of immune cells, suggesting its possible implication in autoreactivity. The aim of the current study is to investigate the role of hyperprolactinemia in MS. Twenty-two MS patients with hyperprolactinemia diagnosed with pituitary adenoma and 66 MS patients without hyperprolactinemia were enrolled in our case-control study. They were matched with regard to age, gender, and MS subtypes. Patients with other concomitant autoimmune diseases and pregnancy were excluded. Statistical analyses were carried out using SPSS (SPSS statistic package, version 21.0.0) statistical software. The Pearson Chi-square test and the t test were used to determine whether there were any significant differences. The level of significance was set at p < 0.05. Greater value of relapse rate among hyperprolactinemic MS patients in comparison to non-hyperprolactinemic MS patients was statistically significant (p < 0.001). Statistically significant difference between the two groups in terms of EDSS was observed (case group vs. CONTROL: 1.3 vs. 1.9; p = 0.007). The correlation between MS duration and duration of hyperprolactinemia was significant in the case group (p < 0.05, R = 0.752). No statistically significant difference was found between two groups regarding duration of MS. This study suggested a protective role of prolactin in demyelinating procedure of MS. PMID- 25501285 TI - Cell cycle marker expression in benign and malignant intraductal papillary lesions of the breast. AB - AIMS: The diagnosis of intraductal papillary lesions of the breast on core biopsy remains challenging in pathology, with most patients requiring formal surgical excision for a definitive diagnosis. The aim of this study was to determine whether a representative panel of proliferative cell cycle immunohistochemical markers (cyclin A2, cyclin B1 and cyclin D1) could improve the specificity of pathological diagnosis of these lesions. METHODS: A series of 68 surgically excised intraductal papillary lesion cases were retrospectively selected, and immunohistochemistry for cyclin A2, cyclin B1 and cyclin D1 was performed. RESULTS: Cyclin B1 (OR 1.80, 95% CI 1.01 to 3.2, p=0.046) and cyclin D1 (OR 1.13, 95% CI 1.05 to 1.22, p=0.002) expression was independently associated with a diagnosis of malignancy in papillary lesions, although expression was frequently heterogeneous and only focal. Cyclin A2 expression (OR 0.76, 95% CI 0.41 to 1.4, p=0.38) was not associated with a malignant diagnosis in multivariable logistic regression models. All three cyclins displayed high sensitivity (80%-95%) for a diagnosis of malignancy, although cyclin B1 showed a superior specificity of 72.7% compared with the low specificity of cyclins A2 and D1. CONCLUSIONS: Our study has identified for the first time that the expression of key cell cycle markers differs between benign and malignant papillary breast lesions and identified changes to the mitotic marker, cyclin B1, as particularly significant. However, given the low level and heterogeneous nature of expression of these markers, there remains a significant risk of undersampling in core biopsies and thus they are unlikely to be useful in routine clinical practice. PMID- 25501286 TI - Association of serum IFN-lambda3 with inflammatory and fibrosis markers in patients with chronic hepatitis C virus infection. AB - BACKGROUND: Hepatitis C virus (HCV) is one of the major causes of liver cancer. The single nucleotide polymorphisms within the IFNL3 gene, which encodes interferon (IFN)-lambda(3), are strongly associated with the response to pegylated IFN-alpha (PEG-IFN-alpha) plus ribavirin (RBV) therapy in chronic hepatitis C (C-CH) patients. However, the roles of IFN-lambda(3) in chronic HCV infection are still elusive. In this study, we aimed to identify clinical and immunological factors influencing IFN-lambda(3) and evaluated whether serum IFN lambda(3) levels are involved or not involved in the response to PEG-IFN-alpha plus RBV therapy. METHODS: We enrolled 119 C-CH patients with HCV genotype 1 infection who underwent 48 weeks of PEG-IFN-alpha plus RBV therapy. As controls, 23 healthy subjects and 56 patients with non-HCV viral hepatitis were examined. Serum IFN-lambda(3) was quantified by chemiluminescence enzyme immunoassay, and 27 cytokines or chemokines were assayed by the multiplexed BioPlex system. RESULTS: Serum IFN-lambda(3) levels were higher in C-CH patients or acute hepatitis E patients than in healthy volunteers. Such levels did not differ between the IFNL3 genotypes. In C-CH patients, serum IFN-lambda(3) was positively correlated with aspartate aminotransferase, alanine aminotransferase, alpha fetoprotein, histological activity, fibrosis index, IFN-gamma-inducible protein 10, and platelet-derived growth factor. Multivariate analysis showed that IFNL3 single nucleotide polymorphisms, fibrosis score, and macrophage inflammatory protein 1alpha were involved in the sustained viral clearance in PEG-IFN-alpha plus RBV therapy; however, serum IFN-lambda(3) levels were not involved. CONCLUSION: Serum IFN-lambda(3) levels are increased in C-CH patients regardless of the IFNL3 genotype. IFN-lambda(3) is a biomarker reflecting the activity and fibrosis of liver disease, but is not correlated with the responsiveness to PEG IFN-alpha plus RBV therapy. PMID- 25501287 TI - Diagnostic strategies for early pancreatic cancer. AB - Diagnosis of pancreatic cancer (PC) at an early stage with curative surgery is the approach with the potential to significantly improve long-term patient outcome. Recently, some reports showed that patients with pancreatic tumors smaller than 10 mm showed a favorable prognosis. However, the rate of tumor detection on computed tomography in patients with small pancreatic tumors is low. For the diagnoses of PC with tumors smaller than 10 mm, the rate of tumor detection was higher on endoscopic ultrasonography (EUS) than on computed tomography or other modalities, and histologic diagnosis using EUS-guided fine needle aspiration was helpful in confirming the diagnosis. For the diagnosis of PC in situ, EUS and magnetic resonance cholangiopancreatography may play important roles in detecting the local irregular stenosis of the pancreatic duct. Endoscopic retrograde pancreatography and sequential cytodiagnosis using pancreatic juice obtained by endoscopic nasopancreatic drainage multiple times was useful in the final diagnosis of PC in situ. At present, improving survival lies in identifying those individuals with high-risk factors or precursor lesions through an effective screening method. For example, these should include ultrasonography, various biological markers, or national familial pancreatic cancer registration. Additionally, the relationship between specialists in PC from medical centers and practicing physicians plays an important role in the early diagnosis of PC. PMID- 25501288 TI - No increase in gastric acid secretion in healthy Japanese over the past two decades. AB - BACKGROUND: The prevalence of gastroesophageal reflux disease (GERD) has been increasing worldwide over recent decades. A previous study demonstrated that gastric acid secretion, thought to be an important factor in the increase in the rate of GERD, in Japanese individuals increased in the era from the 1970s to the 1990s. The aim of this study was to evaluate whether gastric acid secretion has altered over the past two decades with and without the influence of Helicobacter pylori infection in nonelderly and elderly Japanese. METHODS: Gastric acid secretion, the concentrations of serum gastrin, pepsinogen I, and pepsinogen II, and H. pylori infection were determined in 78 healthy Japanese subjects. The findings were compared with data obtained in the 1990s. RESULTS: Basal acid output (BAO) and maximal acid output (MAO) gradually decreased with age in H. pylori-negative subjects. In addition, those with H. pylori infection tended to show decreased gastric acid secretion as compared with those without infection, particularly in the elderly group. MAO decreased gradually with age in males, whereas it remained unchanged with age in females. MAO in H. pylori-negative subjects has not changed over the past two decades (17.7 mEq/h vs 17.6 mEq/h in nonelderly subjects, and 15.2 mEq/h vs 12.7 mEq/h in elderly subjects). CONCLUSIONS: In contrast to the increased prevalence of GERD, gastric acid secretion has not increased over the past two decades in Japanese. However, secretion has decreased with age in males but not in females, which may partly explain the sex difference in the age-related GERD prevalence. PMID- 25501290 TI - Predictors and outcome impact of perioperative serum sodium changes in a high risk population. AB - BACKGROUND: The perioperative period may be associated with a marked neurohumoral stress response, significant fluid losses, and varied fluid replacement regimes. Acute changes in serum sodium concentration are therefore common, but predictors and outcomes of these changes have not been investigated in a large surgical population. METHODS: We carried out a retrospective cohort analysis of 27 068 in patient non-cardiac surgical procedures in a tertiary teaching hospital setting. Data on preoperative conditions, perioperative events, hospital length of stay, and mortality were collected, along with preoperative and postoperative serum sodium measurements up to 7 days after surgery. Logistic regression was used to investigate the association between sodium changes and mortality, and to identify clinical characteristics associated with a deviation from baseline sodium >5 mmol litre(-1). RESULTS: Changes in sodium concentration >5 mmol litre(-1) were associated with increased mortality risk (adjusted odds ratio 1.49 for a decrease, 3.02 for an increase). Factors independently associated with a perioperative decrease in serum sodium concentration >5 mmol litre(-1) included age >60, diabetes mellitus, and the use of patient-controlled opioid analgesia. Factors associated with a similar increase were preoperative oxygen dependency, mechanical ventilation, central nervous system depression, non-elective surgery, and major operative haemorrhage. CONCLUSIONS: Maximum deviation from preoperative serum sodium value is associated with increased hospital mortality in patients undergoing in-patient non-cardiac surgery. Specific preoperative and perioperative factors are associated with significant serum sodium changes. PMID- 25501289 TI - Small bowel injury in low-dose aspirin users. AB - The use of low-dose aspirin (LDA) is well known to be associated with an increased risk of serious upper gastrointestinal complications, such as peptic ulceration and bleeding. Until recently, attention was mainly focused on aspirin induced damage of the stomach and duodenum. However, recently, there has been growing interest among gastroenterologists on the adverse effects of aspirin on the small bowel, especially as new endoscopic techniques, such as capsule endoscopy (CE) and balloon-assisted endoscopy, have become available for the evaluation of small bowel lesions. Preliminary CE studies conducted in healthy subjects have shown that short-term administration of LDA can induce mild mucosal inflammation of the small bowel. Furthermore, chronic use of LDA results in a variety of lesions in the small bowel, including multiple petechiae, loss of villi, erosions, and round, irregular, or punched-out ulcers. Some patients develop circumferential ulcers with stricture. In addition, to reduce the incidence of gastrointestinal lesions in LDA users, it is important for clinicians to confirm the differences in the gastrointestinal toxicity between different types of aspirin formulations in clinical use. Some studies suggest that enteric-coated aspirin may be more injurious to the small bowel mucosa than buffered aspirin. The ideal treatment for small bowel injury in patients taking LDA would be withdrawal of aspirin, however, LDA is used as an antiplatelet agent in the majority of patients, and its withdrawal could increase the risk of cardiovascular/cerebrovascular morbidity and mortality. Thus, novel means for the treatment of aspirin-induced enteropathy are urgently needed. PMID- 25501292 TI - Formation of HNCO from carbon monoxide and atomic nitrogen in their fundamental states. Investigation of the reaction pathway in conditions relevant to the interstellar medium. AB - As a simple molecule containing the four main atoms essential for life as we know it, isocyanic acid can be considered as a prebiotic molecule. As such, the understanding of reaction mechanisms leading to its formation is fundamental. Isocyanic acid is present in different physical environments in the medium. Previous studies have suggested that, in water-containing ices, on the surface of dust grains, HNCO may be formed from N and CO in their fundamental states. To further investigate the reaction process, herein we investigate this reaction by means of the matrix-isolation technique. PMID- 25501291 TI - Inhibition of 4-1BBL-regulated TLR response in macrophages ameliorates endotoxin induced sepsis in mice. AB - Activation of Toll-like receptor (TLR) signaling rapidly induces the expression of inflammatory genes, which is persistent for a defined period of time. However, uncontrolled and excessive inflammation may lead to the development of diseases. 4-1BB ligand (4-1BBL) plays an essential role in sustaining the expression of inflammatory cytokines by interacting with TLRs during macrophage activation. Here, we show that inhibition of 4-1BBL signaling reduced the inflammatory responses in macrophages and ameliorated endotoxin-induced sepsis in mice. A 4 1BB-Fc fusion protein significantly reduced TNF production in macrophages by blocking the oligomerization of TLR4 and 4-1BBL. Administration of 4-1BB-Fc suppressed LPS-induced sepsis by reducing TNF production, and the coadministration of anti-TNF and 4-1BB-Fc provided better protection against LPS induced sepsis. Taken together, these observations suggest that inhibition of the TLR/4-1BBL complex formation may be highly efficient in protecting against continued inflammation, and that 4-1BB-Fc could be a potential therapeutic target for the treatment of inflammatory diseases. PMID- 25501293 TI - Melatonin in Mediterranean diet, a new perspective. AB - The health-promoting properties of the Mediterranean diet have been attributed, at least in part, to the chemical diversity of plant foods. Among phytochemicals, polyphenols represent the paradigm of the relationship between healthy foods and reduced risk of chronic-degenerative diseases, although, in the past few years, a new element has enriched this scenario. Melatonin, and possibly other indoleamines recently discovered in some relevant Mediterranean foods, may represent a new factor contributing to the elucidation of the protective effects of diets rich in plant products. Therefore, in synergy with polyphenols and other bioactive phytochemicals (e.g. carotenoids and glucosinolates), melatonin may contribute to maximizing the benefits of healthy dietary styles. This brief survey deals with the occurrence of melatonin in the Mediterranean diet, with an emphasis on grape products, and focuses on the biological significance of dietary melatonin, an emerging and exciting topic in the field of nutritional sciences. PMID- 25501294 TI - Zopiclone effects on breathing at sleep in stable chronic obstructive pulmonary disease. AB - PURPOSE: More than half of patients with chronic obstructive pulmonary disease (COPD) experiences sleep-related problems and about one fourth uses hypnotics regularly. We explored what the effect zopiclone, a commonly used hypnotic, had on nocturnal gas exchange and the apnea/hypopnea frequency in stable COPD. METHODS: Randomized crossover study of 31 (ten males) inpatients at a pulmonary rehabilitation hospital, median age 64 years, of which 20 had a forced expiratory volume first second <50% of predicted. Subjects investigated in randomized order of either baseline sleep or intervention with 5 mg zopiclone by polysomnography including transcutaneous measurement of carbon dioxide pressure increased (DeltaPtcCO2). RESULTS: Zopiclone increased the mean DeltaPtcCO2 from baseline both in rapid eye movement (REM) sleep, non-REM sleep, and even in stage N0 (awake after sleep onset) with a mean (SD) of 0.25 (0.40) kPa, 0.22 (0.32) kPa, and 0.14 (0.27) kPa, respectively. Subjects with sleep hypoventilation as defined by the American Academy of Sleep Medicine increased from 6 subjects (19%) to 13 subjects (42%) (P = 0.020). REM sleep minimum oxygen saturation (minSpO2) did not change significantly from baseline median (interquartile range [IQR]) minSpO2 81.8 (12.1) % to zopiclone sleep median (IQR) minSpO2 80.0 (12.0) % (P = 0.766). Interestingly, zopiclone reduced the number of apneas/hypopneas per hour (AHI) in subjects with overlap (AHI >= 15) with a median difference (IQR) of -8.5 (7.8) (N = 11, P = 0.016). CONCLUSIONS: In stable COPD, zopiclone moderately increases the mean DeltaPtcCO2 without changing minSpO2 at night and reduces AHI in overlap (COPD and obstructive sleep apnea) subjects. PMID- 25501295 TI - Reply: Long term impact of CPAP on myocardial function in OSA. Always measurable cardiac index? PMID- 25501297 TI - Induction of the estrogen-responsive genes encoding choriogenin H and L in the liver of male medaka (Oryzias latipes) upon exposure to estrogen receptor subtype selective ligands. AB - Choriogenin (Chg) H and L are estrogen-induced chorion precursors. We measured the induction of ChgH and ChgL mRNA in the livers of male medaka fish treated with Orthoester-2k, a selective ligand for estrogen receptor (ER) alpha, and 2-(4 hydroxyphenyl)-5-hydroxy-1,3-benzoxazole (HPHB), a selective ligand of ERbeta. Although both ChgH and ChgL mRNA were induced by treatment with Orthoester-2k or HPHB separately, their combination induced much greater expression of each Chg. ChgH expression correlated more closely with Orthoester-2k dosage when combined with a small fixed dose of HPHB (1 MUm), whereas ChgL mRNA expression was more responsive to HPHB dose when combined with a fixed dose of Orthoester-2k (2.8 nm). Moreover, upon long-term treatment with Orthoester-2k, ChgH mRNA and ERalpha mRNA expression showed similar patterns with peak expression between days 6 and 10. These results imply that ERbeta primarily regulates ChgL mRNA expression and ERalpha action primarily regulates ChgH mRNA expression. Thus, it is necessary to develop screening methods for fish ER subtype-specific ligands. PMID- 25501298 TI - Intravitreal bevacizumab monotherapy for type-1 prethreshold, threshold, and aggressive posterior retinopathy of prematurity - 27 month follow-up results from Turkey. AB - PURPOSE: To study the efficacy of intravitreal bevacizumab (IVB) injection as a single treatment for retinopathy of prematurity (ROP). METHODS: This was a prospective interventional case series study performed in a clinical practice setting; a total of 122 patients including prethreshold (type 1) (n = 79, 152 eyes, six unilateral), threshold (n = 12, 24 eyes), and aggressive posterior (APROP) (n = 31, 62 eyes); cases were included without any randomization or masking. A total of 253 IVB injections, 238 in the first session, 11 in the second session, and four in the third session were performed, and followed up for a mean of 89.155 +/- 4.277 (range 82 to 105) weeks of postmenstrual age (PMA). Regression of ROP, maturation of the retina, and associated complications were evaluated. RESULTS: Total regression was achieved in 227/238 eyes (95.4 %) after the first dose injection. The remaining 11 received a second injection, after which an additional seven (234/238; 98.2 %) regressed; after the third injection, the remaining 4 (238/238; 100 %) regressed. Complete retinal vascular maturation was achieved without any significant complications in all of the cases. CONCLUSIONS: IVB injection as monotherapy seems to be a very effective treatment modality for ROP. Based on timely intervention, IVB as a single treatment modality can salvage almost all ROP cases before stage 4. PMID- 25501296 TI - A Review on Pharmacological and Analytical Aspects of Naringenin. AB - Flavonoids are a widely distributed group of phytochemicals having benzo-pyrone nucleus, and more than 4,000 different flavonoids have been described and categorized into flavonols, flavones, flavanones, isoflavones, catechins and anthocyanidins. Flavonoids occurs naturally in fruits, vegetables, nuts, and beverages such as coffee, tea, and red wine, as well as in medical herbs. Flavonoids are responsible for the different colors of plant parts and are important constituents of the human diet. Flavanoids have different pharmacological activities, such as antioxidant, anti-allergic, antibacterial, anti-inflammatory, antimutagenic and anticancer activity. Naringenin belongs to the flavanones and is mainly found in fruits (grapefruit and oranges) and vegetables. Pharmacologically, it has anticancer, antimutagenic, anti inflammatory, antioxidant, antiproliferative and antiatherogenic activities. Naringenin is used for the treatments of osteoporosis, cancer and cardiovascular diseases, and showed lipid-lowering and insulin-like properties. In the present review, detailed pharmacological and analytical aspects of naringenin have been presented, which revealed the impressive pharmacological profile and the possible usefulness in the treatment of different types of diseases in the future. The information provided in this communication will act as an important source for development of effective medicines for the treatment of various disorders. PMID- 25501299 TI - The role of electrical stimulation therapy in ophthalmic diseases. AB - INTRODUCTION: Electrical stimulation therapy (EST) involves the use of a low intensity electrical current in the treatment of neuromuscular conditions. During the recent two decades, EST has emerged as a potential neuroprotective strategy in certain ophthalmic diseases, aided by a lack of effective management for these conditions. PURPOSE: The aim of this review is to summarize and discuss current available evidence for the use of EST in ophthalmic diseases in the laboratory setting and in human trials. METHODS: The compilation and review of published English-language reports on the use of EST in human ophthalmic disease and animal models of ophthalmic disease. RESULTS: From published reports, research work on the use of EST in ophthalmic diseases began in the last 20 years. Different methods of electrical stimulation have been devised, with varying levels of invasiveness. Results from human trials have favored earlier and repeated treatment after insults to the optic nerve, while EST has shown transient effectiveness in degenerative diseases of photoreceptors. Patients also reported no serious adverse effects from EST in the clinical trials. Results from animal studies have further confirmed survival benefits of EST in retinal cell survival, with the underlying mechanism likely multifactorial, but involving Muller cell modulation. CONCLUSIONS: Results from human and animal studies have demonstrated the relevance and potential effectiveness of EST in ophthalmic disease. However, optimal disease and species-specific stimulation settings need to be defined. PMID- 25501300 TI - The role of the father in child sleep disturbance: child, parent, and parent child relationship. AB - The majority of studies on child sleep problems focus primarily on mothers, neglecting paternal influences. Guided by the transactional framework, we explored how child temperament, paternal and maternal stress, and the parent child interactions differ between families having children with sleep disturbances and a selected comparison group. The role of paternal involvement in child caregiving as a moderator of these differences was assessed. The sample consisted of 51 children (1-3 years old) and their mothers and fathers. Data were collected during home visits, when mothers and fathers completed questionnaires and were interviewed. In addition, mother-child and father-child interactions were videotaped. Results indicate that compared to the comparison group, fathers rated children with sleep disturbances as fussier, both their mothers and fathers experienced higher levels of stress, and reported using more bedtime interactions that interfere with child's sleep-wake self-regulation. In addition, their fathers were less sensitive during father-child interaction and less involved in child caregiving. Finally, paternal involvement moderated the group differences seen in maternal stress, suggesting that high paternal involvement acted as a buffer to protect parents of children with sleep disturbances from experiencing parental stress. The important role of fathers in families having children with sleep disturbances is discussed. PMID- 25501301 TI - Ursodeoxycholic acid for cystic fibrosis-related liver disease. AB - BACKGROUND: Abnormal biliary secretion leads to the thickening of bile and the formation of plugs within the bile ducts; the consequent obstruction and abnormal bile flow ultimately results in the development of cystic fibrosis-related liver disease. This condition peaks in adolescence with up to 20% of adolescents with cystic fibrosis developing chronic liver disease. Early changes in the liver may ultimately result in end-stage liver disease with people needing transplantation. One therapeutic option currently used is ursodeoxycholic acid. OBJECTIVES: To analyse evidence that ursodeoxycholic acid improves indices of liver function, reduces the risk of developing chronic liver disease and improves outcomes in general in cystic fibrosis. SEARCH METHODS: We searched the Cochrane CF and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. We also contacted drug companies.Date of the most recent search of the Group's trials register: 29 May 2014. SELECTION CRITERIA: Randomised controlled trials of the use of ursodeoxycholic acid for at least three months compared with placebo or no additional treatment in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and quality. MAIN RESULTS: Ten trials have been identified, of which three trials involving 118 participants were included; the dose of ursodeoxycholic acid ranged from 10 to 20 mg/kg/day for up to 12 months. The complex design used in two trials meant that data could only be analysed for subsets of participants. There was no significant difference in weight change, mean difference -0.90 kg (95% confidence interval -1.94 to 0.14) based on 30 participants from two trials. Improvement in biliary excretion was reported in only one trial and no significant change after treatment was shown. There were no data available for analysis for long-term outcomes such as death or need for liver transplantation. AUTHORS' CONCLUSIONS: There are few trials assessing the effectiveness of ursodeoxycholic acid. There is insufficient evidence to justify its routine use in cystic fibrosis. PMID- 25501303 TI - NT-3 attenuates the growth of human neuron cells through the ERK pathway. AB - Spinal cord injury is a devastating health problem that affects thousands of individuals each year. The neurons were destroyed. NT-3 is a recently discovered neurotrophin. This study sought to understand the potential involvement of MAPKs in NT-3-mediated growth inhibition of human neurons. We applied different concentrations of NT-3 and observed the growth rate of the cells and the changes in the phosphorylation state of the MAPKs ERK1/2, JNK and p38. This study discovered that NT-3-induced HNC growth was promoted primarily by phosphorylated ERK1/2, and that this phosphorylation, as well p90(rsk)phosphorylation, was mediated by TrkC. The ERK1/2 pathway is known to play an essential role in the NT 3-mediated growth of human neurons. In conclusion, our study suggests that NT-3 promotes the growth of human neurons cells primarily through the TrkC/ERK pathway. PMID- 25501302 TI - Non-esterified fatty acids promote expression and secretion of angiopoietin-like protein 4 in calf hepatocytes cultured in vitro. AB - An elevated plasma non-esterified fatty acids (NEFA) concentration is an important indicator of negative energy balance, which is often associated with metabolic diseases such as fatty liver and ketosis. Angiopoietin-like protein 4 (ANGPTL4) is a hepatokine that plays important roles in the regulation of lipid metabolism. However, the direct effects of high concentrations of NEFA on ANGPTL4 expression and secretion in hepatocytes from cows are not entirely clear. The objective of this study was to investigate the effects of different NEFA concentrations on ANGPTL4 expression and secretion in calf hepatocytes cultured in vitro. NEFA was added to the culture solution at final concentrations of 0.6, 1.2, 1.8, and 2.4 mmol/L. After 24 h of continuous culture, ANGPTL4 mRNA and protein expression levels in the hepatocytes were determined by real-time polymerase chain reaction and western blot, respectively. ANGPTL4 secretion in the supernatant was determined by enzyme-linked immunosorbent assay. The results showed similar levels of ANGPTL4 expression and secretion following treatment with 0.6 and 1.2 mmol/L NEFA, which were higher than those observed for the controls (P < 0.05). ANGPTL4 expression and secretion were also similar at 1.8 and 2.4 mmol/L NEFA and significantly higher than those observed for controls (P < 0.01). These data suggest that high concentrations of NEFA significantly promote ANGPTL4 expression and secretion in bovine hepatocytes. In particular, this promotion occurs in a dose-dependent manner and may be involved in the pathological processes of energy metabolism disorders of dairy cows in the peripartum period. PMID- 25501306 TI - Polymorphism and synergism of angiotensin-converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) genes in coronary artery disease. AB - INTRODUCTION: Among the genetic factors for coronary artery diseases, PAI-1 4G/5G and ACE I/D polymorphisms can be noted. This study was carried out to investigate the association of these two polymorphisms and their synergism in coronary artery disease (CAD) from a sample of the Iranian population. MATERIALS AND METHODS: Sixty-one patients with a history of CAD and 92 healthy controls participated in our study. After DNA extraction from leukocytes, PCR was performed to characterize PAI-1 4G/5G and ACE I/D polymorphisms, using an amplification refractory mutation system technique. RESULTS: In the studied patients, PAI-1 polymorphisms were 24.6%, 45.9%, and 29.5% for 4G/4G, 4G/5G and 5G/5G, respectively; the values for controls were 20.7%, 42.2% and 37.0%. The distribution rates of genotypes I/I, I/D and D/D in patients accounted for 29.5%, 45.9% and 24.6%; in the control group these figures were estimated to be 40.2%, 40.2% and 19.6%. CONCLUSION: Single and multivariate analyses showed a significant difference for the conventional risk factors, including hypertension, diabetes, hyperlipidemia, smoking and family history, for CAD between patients and controls (p value <= 0.001). However, no significant correlation was demonstrated considering ACE and PAI-1 polymorphisms either in association with 4G/4G or D/D genotypes or a combination of them in the Iranian population in the current study. PMID- 25501307 TI - Adiponectin gene polymorphisms contributes to ischemic stroke risk: A meta analysis. AB - BACKGROUND: Previous studies have reported the relation between the adiponectin polymorphisms and the risk of ischemic stroke. However, the findings is inclusive. In the present study, we performed a meta-analysis to clarify the relation between the adiponectin polymorphisms and the stroke. METHODS: Relevant studies were identified by searching PubMed, EMBASE, ISI Web of Science, ScienceDirect, Wiley Online Library, Wanfang database in China, and Chinese National Knowledge Infrastructure databases (CNKI) through July 2013 and other method such as reviewing the reference of retrieved literatures. We selected literatures that reported Odds ratio (OR) and 95% confidence interval (CI) for the relation between the ischemic stroke and the adiponectin genetic polymorphisms. With 1720 stroke cases and 5549 controls, were included. Our results showed that rs2241766 was associated with the risk of ischemic stroke in a recessive model (GG vs (TT+TG), OR = 1.29, 95% CI: 1.01-1.64, p = 0.04). However, rs1501299 and rs266729 were not found to be associated with ischemic stroke in our analysis. CONCLUSION: The present study suggested that rs2241766 polymorphism of adiponectin gene was associated with the risk for ischemic stroke. PMID- 25501305 TI - Role of MiR-30a in cardiomyocyte autophagy induced by Angiotensin II. AB - OBJECTIVE: The aim of this study was to investigate whether MiR-30a regulates autophagy by regulating the Beclin-1 protein, which is the marker for autophagosomes during myocardial injury, when induced by angiotensin II (Ang II). METHODS: We randomly assigned 20 rats into two equal groups: Control group and Ang II group. We detected the expression of MiR-30a by quantitative real-time polymerase chain reaction (RT-PCR), and we employed western blotting to detect the protein expression of Beclin-1. RESULTS: In this study, we found that Ang II induced cardiomyocyte autophagy, together with down-regulation of MiR-30a and upregulation of the Beclin-1 protein. We also found that the Beclin-1 protein is regulated by MiR-30a, by transferring a MiR-30a mimic or AMO-204 into the cardiomyocytes. CONCLUSION: These studies provided evidence that MiR-30a plays an important role in regulating autophagy through the Beclin-1 protein, during myocardial injury induced by Ang II. PMID- 25501308 TI - Dexmedetomidine protects spatial learning and memory ability in rats. AB - BACKGROUND: The authors tested the hypothesis that combined use of dexmedetomidine on fetal rats during isoflurane exposure in maternal anesthesia can attenuate the abnormal spatial learning and memory abilities in adults via the renin-angiotensin-aldosterone system. METHODS: Fifty timed-pregnancy rats were randomly assigned to five groups (Dex+Iso, Sal+Iso, Sal+Oxy, Dex+Oxy, and a control group ) on embryonic day 14 to receive five different dispositions, i.e. combined injection of dexmedetomidine (Dex) or saline (Sal) and inhalation of isoflurane (Iso), oxygen (Oxy), or normal air for 4 h (n = 10). RESULTS: The latency time(s) from day 1 to day 4 all showed a decreasing tendency in all four groups. The synaptic count of the Sal+Iso group was significantly lower than the Control group (p < 0.05), suggesting that severe neurodegeneration occurred under the influence of fetal isoflurane exposure. In contrast, the synapse count of the Dex+Iso group was near to that of Control group. The rats are protected in neurodevelopmental, normal development. CONCLUSION: Combine use of dexmedetomidine during exposure to isoflurane in utero during middle-pregnancy can attenuate the impairment of spatial learning and memory abilities for the rats in adulthood. PMID- 25501304 TI - Inhibition of mesothelioma cancer stem-like cells with adenovirus-mediated NK4 gene therapy. AB - Malignant mesothelioma (MM) is a highly invasive and chemoresistant malignancy induced by asbestos fibers. NK4, a hepatocyte growth factor antagonist and angiogenesis inhibitor, consists of the N-terminal hairpin domain and four kringle domains of the alpha-chain of hepatocyte growth factor. The therapeutic potential of NK4 has been demonstrated in a variety of tumor types. However, the mechanisms by which NK4 inhibits tumor growth have not been well delineated. In this study, it is shown that the NK4 adenovirus (Ad-NK4) potently inhibits cell viability, invasiveness and tumorigenicity of human MM cells. Significantly, this study demonstrates for the first time that Ad-NK4 inhibits cancer stem-like cell (CSC) properties as assessed by spheroid formation assay, side population analysis and flow cytometric sorting of CD24 cells. In addition to inhibiting phosphorylation of Met and AKT, Ad-NK4 markedly suppressed the active form of beta-catenin, a key mediator of both Wnt and AKT pathways. It is further demonstrated that expression of NK4 suppresses beta-catenin nuclear localization and transcriptional activity. Intriguingly, the expression levels of Oct4 and Myc, two critical stem cell factors and downstream targets of beta-catenin, were also diminished by Ad-NK4. Furthermore, the strong antitumor effect of NK4 was found to be linked to its ability to inhibit CSCs as revealed by immunohistochemical examination of tumor specimens from a mouse xenograft model of human MM. These findings suggest that NK4 acts as a CSC inhibitor by impeding Met/AKT/beta-catenin signaling and holds promise for achieving durable therapeutic responses in MM by constraining the CSC component of these aggressive tumors. PMID- 25501311 TI - Abstracts from the 11th International Symposium on Resistance Arteries: From Molecular Machinery to Clinical Challenges, September 7-11, 2014, Banff, Alberta, Canada,. PMID- 25501309 TI - Diversification and distinctive structural features of S-RNase alleles in the genus Solanum. AB - The multigenic and multiallelic S-locus in plants is responsible for the gametophytic self-incompatibility system, which is important to prevent the detrimental effects of self-fertilization and inbreeding depression. Several studies have discussed the importance of punctual mutations, recombination, and natural selection in the generation of allelic diversity in the S-locus. However, there has been no wide-ranging study correlating the molecular evolution and structural aspects of the corresponding proteins in Solanum. Therefore, we evaluated the molecular evolution of one gene in this locus and generated a statistically well-supported phylogenetic tree, as well as evidence of positive selection, helping us to understand the diversification of S alleles in Solanum. The three-dimensional structures of some of the proteins corresponding to the major clusters of the phylogenetic tree were constructed and subsequently submitted to molecular dynamics to stabilize the folding and obtain the native structure. The positively selected amino acid residues were predominantly located in the hyper variable regions and on the surface of the protein, which appears to be fundamental for allele specificity. One of the positively selected residues was identified adjacent to a conserved strand that is crucial for enzymatic catalysis. Additionally, we have shown significant differences in the electrostatic potential among the predicted molecular surfaces in S-RNases. The structural results indicate that local changes in the three-dimensional structure are present in some regions of the molecule, although the general structure seems to be conserved. No previous study has described such structural variations in S RNases. PMID- 25501312 TI - Non-medical prescribing in palliative care: a regional survey. AB - BACKGROUND: The United Kingdom is considered to be the world leader in nurse prescribing, no other country having the same extended non-medical prescribing rights. Arguably, this growth has outpaced research to evaluate the benefits, particularly in areas of clinical practice where patients have complex co-morbid conditions such as palliative care. This is the first study of non-medical prescribing in palliative care in almost a decade. AIM: To explore the current position of nurse prescribing in palliative care and establish the impact on practice of the 2012 legislative changes. DESIGN: An online survey circulated during May and June 2013. PARTICIPANTS: Nurse members (n = 37) of a regional cancer network palliative care group (61% response rate). RESULTS: While this survey found non-medical prescribers have embraced the 2012 legislative changes and prescribe a wide range of drugs for cancer pain, we also identified scope to improve the transition from qualified to active non-medical prescriber by reducing the time interval between the two. CONCLUSION: To maximise the economic and clinical benefit of non-medical prescribing, the delay between qualifying as a prescriber and becoming an active prescriber needs to be reduced. Nurses who may be considering training to be a non-medical prescriber may be encouraged by the provision of adequate study leave and support to cover clinical work. Further research should explore the patients' perspective of non-medical prescribing. PMID- 25501310 TI - Phylogenetic analysis of human group C rotavirus circulating in Brazil reveals a potential unique NSP4 genetic variant and high similarity with Asian strains. AB - Group C rotaviruses (RVC) cause gastroenteritis in humans and animals worldwide, and the evidence for a possible zoonotic role has been recently provided. To gain information on the genetic diversity and relationships between human and animal RVC, we sequenced the VP4, VP7, and NSP4 genes of 12, 19, and 15 human strains, respectively, detected in Sao Paulo state during historical (1988 and 1993) and recent (2007 and 2008) Brazilian rotavirus surveillance. All RVC strains analyzed in the present study grouped into human genotype (G4-P[2]-E2), and did not show any evidence of animal ancestry. Phylogenetic analysis showed that RVC samples detected in 1988 and 1993 clustered together with strains from distinct continents, indicating that historical RVC strains circulating in Sao Paulo were closely related to those strains circulating worldwide. All three genes (VP7, VP4 and NSP4) of Sao Paulo RVC strains isolated in 2007-2008 exhibited close phylogenetic relationship with human RVC strains isolated in China and Japan, suggesting that they are genetically linked, and that a gene flow could be occurring between this Asian countries and Brazil. We identified two distinct clusters in the NSP4 phylogenetic tree. One cluster formed exclusively by human Brazilian strains detected in 1997 and 2003-2004 in Rio de Janeiro, Bahia, and Rio Grande do Sul states (Subgroup II) previously described in a different study, that displayed low sequence identities to other human strains formerly published, and to the Brazilian RVC strains (Subgroup I) characterized in the present study. These data suggests the circulation of two genetic profiles of the NSP4 gene in Brazil. High sequence diversity in NSP4 gene was previously reported in Asia, and additional diversity in NSP4 RVC strains spreading in the world should be expected. More in-depth molecular and epidemiological analysis of human RVC throughout the world will be needed to understand their diversity and clarify their evolution, as well as to develop classifications schemes. PMID- 25501313 TI - A mixed-methods qualitative research study to develop a complex intervention for weight loss and anorexia in advanced cancer: the Family Approach to Weight and Eating. AB - BACKGROUND: Worldwide, most people with incurable cancer experience weight loss and anorexia. These symptoms can distress patients and their family caregivers. Interventions that take account of the relationship between patient and family caregiver may improve outcomes for both members of this dyad. AIM: To report an example of process for the development of a complex intervention, the Family Approach to Weight and Eating. DESIGN: A mixed-methods process informed by the Medical Research Council's guidelines for developing a complex intervention was used to develop a psychosocial intervention for patients with incurable cancer and weight loss or poor appetite and their family caregivers and then to test for its feasibility, acceptability and perceived benefit. SETTING: South of England in 2010/2011. PARTICIPANTS: A purposive sample of patient-family caregiver dyads under the care of a specialist community palliative care team. Patient participants had incurable cancer and were cachectic or at risk of cachexia. RESULTS: The patient-family caregiver dyads comprised seven female and nine male patients (age range 41-84 years) and their carers. The emergent form of the Family Approach to Weight and Eating was found to aid family talk about food, feelings and reciprocity, without adverse consequences. Of the dyads, 15 reported benefits of the Family Approach to Weight and Eating. Three patient participants spoke of the approach evoking sadness and three carers of guilt. CONCLUSION: The Family Approach to Weight and Eating should now be tested in a pilot trial and the effect on emotional health outcomes in patients and their family caregivers evaluated. PMID- 25501318 TI - Current status on histological classification in Cushing's disease. AB - INTRODUCTION: Managing Cushing's disease remains a challenge. Surgery is the first option of treatment and it offers a high success rate. Even in cases where biochemical remission is not achieved, it is crucial to obtain surgical tissue for morphological diagnosis because the therapeutic approach can be modified according to the findings. MATERIALS AND METHODS: A literature search was performed using PubMed for information regarding pathology and Cushing's disease. RESULTS: The histopathological features found in the pituitary gland of patients with Cushing's disease are presented. CONCLUSION: Different subtypes of ACTH producing pituitary tumors are recognized and characterized. The significance of finding a normal pituitary gland with or without Crooke's changes is also discussed. PMID- 25501319 TI - Clinical significance of a false lumen pathway through the arch in acute type A aortic dissection and its influence on cervical branch compromise. AB - OBJECTIVES: Upon onset of acute type A aortic dissection, the aortic true lumen generally becomes fixed around the supra-aortic branches in the greater curvature and Botallo's ligament in the lesser curvature of the aortic arch. Therefore, the pathways of the false lumen through the arch can be categorized as anterior, bilateral and posterior. We investigated the relationship between a false lumen pathway through the arch and cervical branch compromise, stratified by primary tear location. METHODS: Sixty-four consecutive patients with acute type A aortic dissection underwent emergency surgery at our institution between March 2005 and October 2013. Of these, 40 cases (63%) were DeBakey type I, 15 cases (23%) were type II and 9 cases (14%) were type III-D (retrograde type A). We conducted a retrospective review of preoperative computed tomographic angiography using three dimensional image post-processing tools for 43 cases, excluding 15 cases with type II and 6 cases with type I for which preoperative digital image data were not available. RESULTS: Of the 43 cases, 14, 18 and 11 revealed anterior, bilateral and posterior pathways, respectively. Twenty-one cases (49%) showed a primary intimal tear in the ascending aorta (8 anterior, 12 bilateral and 1 posterior), 12 cases (28%) showed a primary intimal tear in the aortic arch (5 anterior, 3 bilateral and 4 posterior) and 10 cases (23%) showed a primary intimal tear in the descending aorta (1 anterior, 3 bilateral and 6 posterior). Twelve of the 14 anterior pathway cases (86%) had a total of 26 supra-aortic branch compromises, 13 of the 18 bilateral pathway cases (72%) had a total of 20 supra-aortic branch compromises, while only 4 of the 11 posterior pathway cases (36%) had a total of four supra-aortic branch compromises. None of the 11 posterior pathway cases had a dissection extending into all 3 supra-aortic branches. CONCLUSIONS: Posterior pathway cases generally showed primary tear locations in the arch or descending aorta, and cervical branch compromise was rare. Aortic dissections tended to extend into the cervical branches through the anterior side of the aortic arch. A false lumen pathway through the arch was strongly associated with cervical branch compromise in acute type A aortic dissections. PMID- 25501320 TI - Bilateral internal thoracic artery grafts for myocardial revascularization in insulin-dependent diabetic patients: time for wide clinical practice? PMID- 25501321 TI - Reply to Hamaji. PMID- 25501322 TI - Does adjuvant chemotherapy following complete resection also have a significant effect on overall survival of thymic epithelial tumours? PMID- 25501323 TI - Impact of surgical experience on outcome in surgery of acute type A aortic dissection. AB - OBJECTIVES: The study was conducted to evaluate our results of acute aortic dissection repair taking into account the impact of surgical experience in aortic surgery. METHODS: Between August 2002 and March 2013, 162 consecutive patients (mean age: 63 +/- 14 years) underwent surgery for acute type A aortic dissection. All patients were operated on by one of the clinic's attending surgeons with wide experience in cardiac surgery (at least 2000 procedures performed personally), however about one-half of the patients (75 patients, 46%) were operated by the aortic team (AT) surgeons with profound experience in complex aortic pathologies. All perioperative data were collected prospectively and retrospective statistical analysis was performed using uni- and multivariate analyses to identify predictors for surgical adverse outcome (AO) containing in-hospital and/or 90-day mortality and new permanent neurological and organ dysfunctions. RESULTS: AO was observed in 36 patients (22.2%) including in-hospital mortality in 22 (13.6%). Multivariate logistic regression analysis identified surgery not performed by the AT as the strongest predictor for AO (odds ratio: 14.1; 95% confidence interval: 3.5-55.6; P < 0.0001) followed by any malperfusion, myocardial infarction and creatinine level. Two groups were built according to the surgery performed by the AT (Group AT) or by the surgeons not on the AT (Group No-AT). The comparison of the groups showed no relevant differences regarding the preoperative characteristics, especially compromised consciousness, malperfusion and extent of dissection. Yet, the outcomes in Group AT vs No-AT were significantly different presenting AO: 8.0 vs 34.5% (P < 0.0001), in-hospital mortality: 4.0 vs and 21.8% (P < 0.001), new permanent neurological deficit: 2.7 vs 11.5% (P = 0.03), even if valve-sparing repairs and complete arch replacements were much more frequent in Group AT. The groups also differed considerably in regard to cannulation and perfusion management, which might play a decisive role in surgical outcome. CONCLUSIONS: Aortic repair in acute type A dissection, when performed by highly specialized aortic surgeons, offers not only much better outcomes but also provides significantly higher rate of curative albeit valve-sparing aortic repairs. Patient-centred care in referral aortic centres with surgery performed by specialized teams should be striven for to improve surgical results in acute aortic dissection surgery. PMID- 25501324 TI - Three-dimensional cell manipulation and patterning using dielectrophoresis via a multi-layer scaffold structure. AB - Cell manipulation is imperative to the areas of cellular biology and tissue engineering, providing them a useful tool for patterning cells into cellular patterns for different analyses and applications. This paper presents a novel approach to perform three-dimensional (3D) cell manipulation and patterning with a multi-layer engineered scaffold. This scaffold structure employed dielectrophoresis as the non-contact mechanism to manipulate cells in the 3D domain. Through establishing electric fields via this multi-layer structure, the cells in the medium became polarized and were attracted towards the interior part of the structure, forming 3D cellular patterns. Experiments were conducted to evaluate the manipulation and the patterning processes with the proposed structure. Results show that with the presence of a voltage input, this multi layer structure was capable of manipulating different types of biological cells examined through dielectrophoresis, enabling automatic cell patterning in the time-scale of minutes. The effects of the voltage input on the resultant cellular pattern were examined and discussed. Viability test was performed after the patterning operation and the results confirmed that majority of the cells remained viable. After 7 days of culture, 3D cellular patterns were observed through SEM. The results suggest that this scaffold and its automated dielectrophoresis-based patterning mechanism can be used to construct artificial tissues for various tissue engineering applications. PMID- 25501325 TI - Molecular markers for bladder cancer screening, early diagnosis, and surveillance: the WHO/ICUD consensus. AB - Due to the lack of disease-specific symptoms, diagnosis and follow-up of bladder cancer has remained a challenge to the urologic community. Cystoscopy, commonly accepted as a gold standard for the detection of bladder cancer, is invasive and relatively expensive, while urine cytology is of limited value specifically in low-grade disease. Over the last decades, numerous molecular assays for the diagnosis of urothelial cancer have been developed and investigated with regard to their clinical use. However, although all of these assays have been shown to have superior sensitivity as compared to urine cytology, none of them has been included in clinical guidelines. The key reason for this situation is that none of the assays has been included into clinical decision-making so far. We reviewed the current status and performance of modern molecular urine tests following systematic analysis of the value and limitations of commercially available assays. Despite considerable advances in recent years, the authors feel that at this stage the added value of molecular markers for the diagnosis of urothelial tumors has not yet been identified. Current data suggest that some of these markers may have the potential to play a role in screening and surveillance of bladder cancer. Well-designed protocols and prospective, controlled trials will be needed to provide the basis to determine whether integration of molecular markers into clinical decision-making will be of value in the future. PMID- 25501326 TI - Staging of locally advanced breast cancer and the prediction of response to neoadjuvant chemotherapy: complementary role of scintimammography and 18F-FDG PET/CT. AB - BACKGROUND: The primary endpoint of the study was to established the role of sestamibi scintimammography and PET/CT findings in locally advanced breast cancer (LABC) before neoadjuvant systemic therapy (NST) in different histological subtypes. The secondary endpoint was to determine the role of FDG PET/CT as multi drug resistance marker. METHODS: From January 2012, we prospectively enrolled 51 consecutive women (median age: 49 years; range: 27-76 yrs) with a biopsy-proven LABC. All patients underwent both sestamibi scintimammography and FDG PET/CT within one week before to start NST. Both examinations were qualitatively and semiquantitatively analysed. For scintimammography we calculated the tumor to background ratio (T/B) and the most intense uptake of the tumor to background ratio (I/B) according the following formula: T/B=[cntsT-cntsB]/ [cntsB] and I/B [cntsI-cntsB]/[cntsB]. Furthermore, the percentage washout index (WO) for T and I were obtained, according to: WOT,I= [cntsT,I]early image-[cntsT,I]delayed image/[cntsT,I]early image. Maximum and average (avg) standardized uptake value (SUV) was computed by PET/CT, using a region of interest. Patients who had an evidence of systemic metastases or a second active cancer at imaging scans, were excluded. At the end of pre-operative therapy, the response to therapy was assessed by the analysis of surgical specimen and then correlated with both scintimammographic and PET/CT data. RESULTS: Based on the inclusion criteria, the final analysis was performed in 49 patients. Scintimammography and PET/CT showed a sensitivity of 100% for the evaluation of primary cancer, while PET/CT showed a slightly higher detection rate for axillary lymph node than scintimammography. According to the biological pattern, SUVmax and SUVavg resulted significantly different among histological subtypes, whereas scintimammographic data did not. At the end of neo-adjuvant therapy, pathological complete response was obtained in 12 (24.4%) patients, while 37 had a partial or no response to NST (identified as no-responders). On the basis of histopathological response to NST, median WOI resulted significantly lower in responders than non-responders (30.5% vs. 44%; P=0.027). Conversely, SUVmax and SUVavg were significantly higher in responders than non-responders (all P<0.05). In this latter subset of patients, high WOTs were associated with low SUVs. On the contrary, in responder group, high SUVs were reported particularly for high WOT values. CONCLUSIONS: Scintimammography with sestamibi did not accurately determine the responsiveness to therapy. FDG PET/CT is more accurate in the prediction of response to therapy, particularly in the aggressive LABC subtype. Moreover, semiquantitative data by FDG PET seems to be linked with the chemosensitivity to NST. PMID- 25501327 TI - Do liberal blood transfusions cause more harm than good? AB - Guidelines and evidence from randomised controlled trials and meta-analyses increasingly support restrictive blood transfusion, but it is being implemented only slowly, explain Lawrence Tim Goodnough: and Michael Murphy: . They argue that electronic systems for clinical decision support could improve blood use. PMID- 25501328 TI - Preparation and enhanced visible light photocatalytic activity of novel g-C3N4 nanosheets loaded with Ag2CO3 nanoparticles. AB - As a potential visible-light photocatalyst, the photocatalytic performance of the bulk g-C3N4 synthesized by heating melamine (denote as g-C3N4-M) is limited due to its low specific surface area and the high recombination rate of the photo induced electron-hole pair. In this paper, a novel g-C3N4-M nanosheet (g-C3N4-MN) obtained from the bulk g-C3N4-M through a thermal exploitation method is employed as an excellent substrate and different amounts of Ag2CO3 nanoparticles are loaded at room temperature. The phase and chemical structure, electronic and optical properties of the Ag2CO3/g-C3N4-MN heterostructures are well characterized. The photocatalytic activities of the as-prepared Ag2CO3/g-C3N4-MN are evaluated by the degradation of methyl orange (MO) and rhodamine B (RhB) pollutants under visible light irradiation. More importantly, the Ag2CO3/g-C3N4 MN heterostructure has been proved to be an excellent photocatalytic system with an enhanced specific surface area and charge separation rate compared with those of the Ag2CO3/g-C3N4-M system. PMID- 25501329 TI - Hydrolysate from eggshell membrane ameliorates intestinal inflammation in mice. AB - Inflammatory bowel diseases (IBD) comprises of ulcerative colitis (UC) and Cohn's disease (CD) as two main idiopathic pathologies resulting in immunologically mediated chronic inflammatory conditions. Several bioactive peptides and hydro lysates from natural sources have now been tested in animal models of human diseases for potential anti-inflammatory effects. Eggshell membrane (ESM) is a well-known natural bioactive material. In this study, we aim to study the anti inflammatory activity of ESM hydro lysate (AL-PS) in vitro and in vivo. In vitro, AL-PS was shown to inhibit pro-inflammatory cytokine IL-8 secretion. In vivo treatment with AL-PS was shown to reduce dextran sodium sulphate (DSS)-induced weight loss, clinical signs of colitis and secretion of interleukin (IL)-6 (p < 0.05). In addition, treatment with AL-PS also attenuated the severity of intestinal inflammation via down-regulation of IL-10 an anti-inflammatory cytokine. This validates potential benefits of AL-PS as a novel preventative target molecule for treatment of IBD. PMID- 25501330 TI - KCNK10, a tandem pore domain potassium channel, is a regulator of mitotic clonal expansion during the early stage of adipocyte differentiation. AB - KCNK10, a member of tandem pore domain potassium channel family, gives rise to leak K+ currents. It plays important roles in stabilizing the negative resting membrane potential and in counterbalancing depolarization. We previously demonstrated that kcnk10 expression is quickly elevated during the early stage of adipogenesis of 3T3-L1 cells and that reduction of kcnk10 expression inhibits adipocyte differentiation. However, the molecular mechanism of KCNK10 in adipocyte differentiation remains unclear. Here we revealed that kcnk10 is induced by 3-isobutyl-1-methylxanthine, a cyclic nucleotide phosphodiesterase inhibitor and a potent inducer of adipogenesis, during the early stage of adipocyte differentiation. We also demonstrated that KCNK10 functions as a positive regulator of mitotic clonal expansion (MCE), a necessary process for terminal differentiation. The reduction of kcnk10 expression repressed the expression levels of CCAAT/enhancer-binding protein beta (C/EBPbeta) and C/EBPdelta as well as the phosphorylation level of Akt during the early phase of adipogenesis. In addition, knockdown of kcnk10 expression suppressed insulin induced Akt phosphorylation. These results indicate that KCNK10 contributes to the regulation of MCE through the control of C/EBPbeta and C/EBPdelta expression and insulin signaling. PMID- 25501331 TI - Lipoprotein lipase, tissue expression and effects on genes related to fatty acid synthesis in goat mammary epithelial cells. AB - Lipoprotein lipase (LPL) serves as a central factor in hydrolysis of triacylglycerol and uptake of free fatty acids from the plasma. However, there are limited data concerning the action of LPL on the regulation of milk fat synthesis in goat mammary gland. In this investigation, we describe the cloning and sequencing of the LPL gene from Xinong Saanen dairy goat mammary gland, along with a study of its phylogenetic relationships. Sequence analysis showed that goat LPL shares similarities with other species including sheep, bovine, human and mouse. LPL mRNA expression in various tissues determined by RT-qPCR revealed the highest expression in white adipose tissue, with lower expression in heart, lung, spleen, rumen, small intestine, mammary gland, and kidney. Expression was almost undetectable in liver and muscle. The expression profiles of LPL gene in mammary gland at early, peak, mid, late lactation, and the dry period were also measured. Compared with the dry period, LPL mRNA expression was markedly greater at early lactation. However, compared with early lactation, the expression was lower at peak lactation and mid lactation. Despite those differences, LPL mRNA expression was still greater at peak, mid, and late lactation compared with the dry period. Using goat mammary epithelial cells (GMEC), the in vitro knockdown of LPL via shRNA or with Orlistat resulted in a similar degree of down-regulation of LPL (respectively). Furthermore, knockdown of LPL was associated with reduced mRNA expression of SREBF1, FASN, LIPE and PPARG but greater expression of FFAR3. There was no effect on ACACA expression. Orlistat decreased expression of LIPE, FASN, ACACA, and PPARG, and increased FFAR3 and SREBF1 expression. The pattern of LPL expression was similar to the changes in milk fat percentage in lactating goats. Taken together, results suggest that LPL may play a crucial role in fatty acid synthesis. PMID- 25501332 TI - Regulated necrosis in HeLa cells induced by ZnPc photodynamic treatment: a new nuclear morphology. AB - Photodynamic therapy (PDT) is a cancer treatment modality based on the administration of a photosensitizer (PS), which accumulates preferentially in tumor cells. Subsequent irradiation of the neoplastic area triggers a cascade of photochemical reactions that leads to the formation of highly reactive oxygen species responsible for cell inactivation. Photodynamic treatments in vitro are performed with the PS, zinc-phthalocyanine (ZnPc). The PS is near the plasma membrane during uptake and internalization. Inactivation clearly occurs by a necrotic process, manifested by nuclear pyknosis, negative TUNEL and Annexin V assays and non-relocation of cytochrome c. In contrast, by increasing the incubation time, ZnPc is accumulated in the Golgi apparatus and produces cell inactivation with characteristics of apoptosis and necrosis: TUNEL positive, relocated cytochrome c and negative Annexin V assay. This type of death produces a still undescribed granulated nuclear morphology, which is different from that of necrosis or apoptosis. This morphology is inhibited by necrostatin-1, a specific inhibitor of regulated necrosis. PMID- 25501333 TI - Enhanced in vivo delivery of 5-fluorouracil by ethosomal gels in rabbit ear hypertrophic scar model. AB - Applying Ethosomal Gels (EGs) in transdermal drug delivery systems has evoked considerable interest because of their good water-solubility and biocompatibility. However, there has not been an explicit description of applying EGs as a vehicle for hypertrophic scars treatment. Here, a novel transdermal EGs loaded with 5-fluorouracil (5-FU EGs) was successfully prepared and characterized. The stability assay in vitro revealed that 5-FU EGs stored for a period of 30 days at 4 +/- 1 degrees C had a better size stability than that at 25 +/- 1 degrees C. Furthermore, using confocal laser scanning microscopy, EGs labeled with Rhodamine 6 G penetrated into the deep dermis of the hypertrophic scar within 24 h in the rabbit ear hypertrophic model suggested that the EGs were an optional delivery carrier through scar tissues. In addition, the value of the Scar Elevation Index (SEI) of 5-FU EGs group in the rabbit ear scar model was lower than that of 5-FU Phosphate Buffered Saline gel and Control groups. To conclude, these results suggest that EGs delivery system loaded 5-fluorouracil is a perfect candidate drug for hypertrophic scars therapy in future. PMID- 25501334 TI - 14-3-3 proteins participate in light signaling through association with PHYTOCHROME INTERACTING FACTORs. AB - 14-3-3 proteins are regulatory proteins found in all eukaryotes and are known to selectively interact with phosphorylated proteins to regulate physiological processes. Through an affinity purification screening, many light-related proteins were recovered as 14-3-3 candidate binding partners. Yeast two-hybrid analysis revealed that the 14-3-3 kappa isoform (14-3-3kappa) could bind to PHYTOCHROME INTERACTING FACTOR3 (PIF3) and CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1). Further analysis by in vitro pull-down assay confirmed the interaction between 14 3-3kappa and PIF3. Interruption of putative phosphorylation sites on the 14-3-3 binding motifs of PIF3 was not sufficient to inhibit 14-3-3kappa from binding or to disturb nuclear localization of PIF3. It was also indicated that 14-3-3kappa could bind to other members of the PIF family, such as PIF1 and PIF6, but not to LONG HYPOCOTYL IN FAR-RED1 (HFR1). 14-3-3 mutants, as well as the PIF3 overexpressor, displayed longer hypocotyls, and a pif3 mutant displayed shorter hypocotyls than the wild-type in red light, suggesting that 14-3-3 proteins are positive regulators of photomorphogenesis and function antagonistically with PIF3. Consequently, our results indicate that 14-3-3 proteins bind to PIFs and initiate photomorphogenesis in response to a light signal. PMID- 25501335 TI - Ionic liquids 2014 and selected papers from ILMAT 2013: highlighting the ever growing potential of ionic liquids. PMID- 25501336 TI - Pheophytin a inhibits inflammation via suppression of LPS-induced nitric oxide synthase-2, prostaglandin E2, and interleukin-1beta of macrophages. AB - Inflammation is a serious health issue worldwide that induces many diseases such as sepsis. There has been a vast search for potentially effective drugs to decrease mortality from sepsis. Pheophytin a is a chlorophyll-related compound derived from green tea. We found that pre-treatment with pheophytin a suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E2 (PGE2), and interleukin-1beta in RAW 264.7 macrophages. NO synthase-2 (NOS2) and cyclooxygenase-2 (COX-2) expression levels were repressed by pre-treatment with pheophytin a at both the transcriptional and translational levels. Pheophytin a inhibited NOS2 promoter activity, but not its mRNA stability, through extracellular signal-regulated kinase (ERK1/2). This suppression was reversed by ERK1/2 inhibitor (U0126). Pheophytin a reduced signal transducers and activators of transcription 1 (STAT-1) activation, without an obvious influence on activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB). These results suggest that pheophytin a functions by down-regulating the transcriptional levels of inflammatory mediators and blocking the ERK and STAT-1 pathways. PMID- 25501337 TI - Biomarkers of treatment toxicity in combined-modality cancer therapies with radiation and systemic drugs: study design, multiplex methods, molecular networks. AB - Organ toxicity in cancer therapy is likely caused by an underlying disposition for given pathophysiological mechanisms in the individual patient. Mechanistic data on treatment toxicity at the patient level are scarce; hence, probabilistic and translational linkages among different layers of data information, all the way from cellular targets of the therapeutic exposure to tissues and ultimately the patient's organ systems, are required. Throughout all of these layers, untoward treatment effects may be viewed as perturbations that propagate within a hierarchically structured network from one functional level to the next, at each level causing disturbances that reach a critical threshold, which ultimately are manifested as clinical adverse reactions. Advances in bioinformatics permit compilation of information across the various levels of data organization, presumably enabling integrated systems biology-based prediction of treatment safety. In view of the complexity of biological responses to cancer therapy, this communication reports on a "top-down" strategy, starting with the systematic assessment of adverse effects within a defined therapeutic context and proceeding to transcriptomic and proteomic analysis of relevant patient tissue samples and computational exploration of the resulting data, with the ultimate aim of utilizing information from functional connectivity networks in evaluation of patient safety in multimodal cancer therapy. PMID- 25501340 TI - Predictive Value of the Logistic Clinical SYNTAX Score. PMID- 25501338 TI - Food derived bioactive peptides and intestinal barrier function. AB - A wide range of food-derived bioactive peptides have been shown to exert health promoting actions and are therefore considered functional foods or nutraceuticals. Some of these actions are related to the maintenance, reinforcement or repairment of the intestinal barrier function (IBF) whose role is to selectively allow the absorption of water, nutrients and ions while preventing the influx of microorganisms from the intestinal lumen. Alterations in the IBF have been related to many disorders, such as inflammatory bowel disease or metabolic syndrome. Components of IBF are the intestinal epithelium, the mucus layer, secretory immunoglobulin A and cells of the innate and adaptive immune systems. Here we review the effects of food derived bioactive peptides on these IBF components. In vitro and in vivo effects, both in healthy and disease states, have been reviewed. Although limited, the available information indicates a potential for food-derived peptides to modify IBF and to contribute to disease treatment, but further research is needed to better isolate responsible peptides, and to help define their mode of action. PMID- 25501339 TI - Ad-p53 enhances the sensitivity of triple-negative breast cancer MDA-MB-468 cells to the EGFR inhibitor gefitinib. AB - Triple-negative breast cancer (TNBC) accounts for 20% of all molecular subtypes of breast cancer. Neither endocrine nor anti-HER2 molecular targeting treatment yield promising results. At present, epidermal growth factor receptor (EGFR) inhibitor, as a single agent, is unable to obtain encouraging results in the treatment of TNBC, even though most of these tumors overexpress EGFR. In the present study, we used recombinant human p53 adenovirus (Ad-p53) and EGFR inhibitor gefitinib to treat the TNBC cell line MDA-MB-468. The combined treatment of gefitinib and Ad-p53 synergistically inhibited the proliferation of MDA-MB-468 cells; it restrained colony formation, enhanced cellular apoptosis and arrested the cell cycle in vitro, and decreased tumor burden of xenografts in nude mice. Western blot analysis revealed that Ad-p53 and gefitinib in combination significantly downregulated the phosphorylation of protein kinase B (p-Akt) and upregulated caspase-9 and cleaved caspase-3, while there were minimal effects on the expression of extracellular signal-regulated kinase (ERK) and phosphorylation of ERK (p-ERK). These results suggest that Ad-p53 may block the PI3K/Akt pathway rather than the Raf/MEK/ERK pathway. Importantly, wild-type p53 was able to reverse the drug resistance of MDA-MB-468 cells to gefitinib through inactivation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. The apoptotic activity induced by this combined treatment may be regulated by caspase cascade-dependent activation. PMID- 25501341 TI - Platelet indices in patients with carotid artery stenosis. PMID- 25501342 TI - A new alkaloid from Helianthemum ordosicum. PMID- 25501343 TI - Addition of D-penicillamine, hypotaurine, and epinephrine (PHE) mixture to IVF medium maintains motility and longevity of bovine sperm and enhances stable production of blastocysts in vitro. AB - The present study aimed to establish an efficient system for bovine embryo production by in vitro fertilization (IVF) that can achieve stable normal fertilization and blastocyst developmental rates in any bull without optimization of the sperm concentration in IVF medium. We examined the effects of a PHE mixture (20 MUM D-penicillamine, 10 MUM hypotaurine and 1 MUM epinephrine), theophylline (2.5 mM), and sperm concentration (1, 2 or 5 * 10(6) cells/ml) on fertilization and blastocyst developmental rates. High cleavage rates (78.3 to 92.4%) and blastocyst developmental rates (31.9 to 62.0%) at day 7 were obtained in the presence of PHE and theophylline in IVF medium with a sperm concentration of 2 * 10(6) cells/ml using sperm from 9 bulls. In addition, the synergistic effect of PHE and theophylline on normal fertilization (2 pronuclei) was clarified at 12 h after IVF with a sperm concentration of 1 * 10(6) cells/ml. Moreover, high linearity, high flagellar beat cross frequency, and low amplitude of lateral head of motile sperm were found by computer-assisted sperm analysis. In conclusion, the combination of the PHE mixture and theophylline synergistically accelerates sperm motility and sperm penetration of bovine oocytes. Theophylline activates sperm motility with increasing intracellular cAMP. However, PHE prevents an excessive increase of cAMP and maintains sperm motility without hyperactivation. When the combination of PHE and theophylline is added to IVF medium at a sperm concentration of 2 * 10(6) cells/ml, we can achieve stable normal fertilization and blastocyst development in any bull. PMID- 25501344 TI - A narrative-based approach to teaching diagnostic criteria. PMID- 25501346 TI - HIV and STI prevalence and risk factors among male sex workers and other men who have sex with men in Nairobi, Kenya. AB - : Previous surveys of men who have sex with men (MSM) in Africa have not adequately profiled HIV status and risk factors by sex work status. MSM in Nairobi, Kenya, were recruited using respondent-driven sampling, completed a behavioral interview, and were tested for HIV and sexually transmitted infections. Overlapping recruitment among 273 male sex workers and 290 other MSM was common. Sex workers were more likely to report receptive anal sex with multiple partners (65.7% versus 18.0%, P < 0.001) and unprotected receptive anal intercourse (40.0% versus 22.8%, P = 0.005). Male sex workers were also more likely to be HIV infected (26.3% versus 12.2%, P = 0.007). PMID- 25501345 TI - Immunodeficiency in children starting antiretroviral therapy in low-, middle-, and high-income countries. AB - BACKGROUND: The CD4 cell count or percent (CD4%) at the start of combination antiretroviral therapy (cART) is an important prognostic factor in children starting therapy and an important indicator of program performance. We describe trends and determinants of CD4 measures at cART initiation in children from low-, middle-, and high-income countries. METHODS: We included children aged <16 years from clinics participating in a collaborative study spanning sub-Saharan Africa, Asia, Latin America, and the United States. Missing CD4 values at cART start were estimated through multiple imputation. Severe immunodeficiency was defined according to World Health Organization criteria. Analyses used generalized additive mixed models adjusted for age, country, and calendar year. RESULTS: A total of 34,706 children from 9 low-income, 6 lower middle-income, 4 upper middle income countries, and 1 high-income country (United States) were included; 20,624 children (59%) had severe immunodeficiency. In low-income countries, the estimated prevalence of children starting cART with severe immunodeficiency declined from 76% in 2004 to 63% in 2010. Corresponding figures for lower middle income countries were from 77% to 66% and for upper middle-income countries from 75% to 58%. In the United States, the percentage decreased from 42% to 19% during the period 1996 to 2006. In low- and middle-income countries, infants and children aged 12-15 years had the highest prevalence of severe immunodeficiency at cART initiation. CONCLUSIONS: Despite progress in most low- and middle-income countries, many children continue to start cART with severe immunodeficiency. Early diagnosis and treatment of HIV-infected children to prevent morbidity and mortality associated with immunodeficiency must remain a global public health priority. PMID- 25501347 TI - Diagnostic value of immunoglobulin kappa light chain gene rearrangement analysis in B-cell lymphomas. AB - Analysis of the immunoglobulin kappa light chain (IGK) gene is an alternative method for B-cell clonality assessment in the diagnosis of mature B-cell proliferations in which the detection of clonal immunoglobulin heavy chain (IGH) gene rearrangements fails. The aim of the present study was to evaluate the added value of standardized BIOMED-2 assay for the detection of clonal IGK gene rearrangements in the diagnostic setting of suspected B-cell lymphomas. With this purpose, 92 specimens from 80 patients with the final diagnosis of mature B-cell lymphoma (37 specimens), mature T-cell lymphoma (26 specimens) and reactive lymphoid proliferation (29 specimens) were analyzed for B-cell clonality. B-cell clonality analysis was performed using the BIOMED-2 IGH and IGK gene clonality assays. The determined sensitivity of the IGK assay was 67.6%, while the determined sensitivity of the IGH assay was 75.7%. The sensitivity of combined IGH+IGK assay was 81.1%. The determined specificity of the IGK assay was 96.2% in the group of T-cell lymphomas and 96.6% in the group of reactive lesions. The determined specificity of the IGH assay was 84.6% in the group of lymphomas and 86.2% in the group of reactive lesions. The comparison of GeneScan (GS) and heteroduplex pretreatment-polyacrylamide gel electrophoresis (HD-PAGE) methods for the analysis of IGK gene rearrangements showed a higher efficacy of GS analysis in a series of 27 B-cell lymphomas analyzed by both methods. In the present study, we demonstrated that by applying the combined IGH+IGK clonality assay the overall detection rate of B-cell clonality was increased by 5.4%. Thus, we confirmed the added value of the standardized BIOMED-2 IGK assay for assessment of B-cell clonality in suspected B-cell lymphomas with inconclusive clinical and cyto/histological diagnosis. PMID- 25501348 TI - Omega-3 polyunsaturated fatty acids and brain aging. AB - PURPOSE OF REVIEW: The literature on the influence of dietary omega-3 polyunsaturated fatty acid (omega-3 PUFA) on brain aging has grown exponentially during the last decade. Many avenues have been explored but no global picture or clear evidence has emerged. Experimental studies have shown that omega-3 PUFA is involved in many neurobiological processes that are involved in neurotransmission and neuroprotection, indicating that these PUFAs may prevent age-related brain damage. Human studies have revealed only a weak link between omega-3 PUFA status and cognitive aging, whereas interventional studies have yet to confirm it. The purpose of this review is to analyze the developments in the area during the last 2 years. RECENT FINDINGS: Human brain MRI studies have confirmed previous findings that omega-3 PUFA can protect the brain during aging; two intervention studies obtained clear evidence. We also analyzed the experimental data clarifying the involvement of omega-3 PUFA in neurotransmission, neuroprotection (including prevention of peroxidation, inflammation, and excitotoxicity), and neurogenesis, thereby helping the brain cope with aging. SUMMARY: These recent human and experimental studies provide support for and clarification of how omega 3 PUFA protect against brain aging and highlight the main lines for future research. PMID- 25501349 TI - Regulation of advanced therapy medicinal products will affect the practice of haematopoietic SCT in the near future: a perspective from the EBMT cell processing committee. PMID- 25501351 TI - A prospective cohort study of the feasibility and efficacy of iron reduction by phlebotomy in recipients of hematopoietic SCT. PMID- 25501350 TI - Impact of IKZF1 deletions on long-term outcomes of allo-SCT following imatinib based chemotherapy in adult Philadelphia chromosome-positive ALL. AB - We investigated the prognostic relevance of IKZF1 deletions in 118 adult Ph positive ALL patients who had minimal residual disease (MRD) data under a uniform treatment of allo-SCT following first-line imatinib-based chemotherapy. IKZF1 deletions were identified in 93 patients (78.8%). IKZF1-deleted patients had a lower proportion of early-stable molecular responders compared with wild-type patients (28.0 vs 56.0%, P=0.028). After a median follow-up of 72 months, IKZF1 deleted patients had a trend for higher cumulative incidence of relapse (CIR) (38.0 vs 13.3%, P=0.052), particularly in a subgroup of early-stable molecular responders (n=40; 21.4 vs 0%, P=0.088), but comparable disease-free survival to wild-type patients. Patients with biallelic-null deletions showed higher CIR (74.6 vs 13.3%, P=0.003) and lower disease-free survival (20.0 vs 67.5%, P=0.022) than wild-type patients. In multivariate analysis, MRD kinetics were closely related to outcomes, while neither IKZF1 deletions nor their functional subtypes retained an independent statistical power. Within the limitation of sample size, however, considering both the negative impact of IKZF1 deletions on MRD kinetics and a trend for relationship between IKZF1 deletions and relapse in early-stable molecular responders, IKZF1 deletions may have a potentially additive effect on unfavorable prognosis in a specific MRD-based subgroup of adult Ph-positive ALL transplants. PMID- 25501353 TI - High temperature increases the masculinization rate of the all-female (XX) rainbow trout "Mal" population. AB - Salmonids are generally considered to have a robust genetic sex determination system with a simple male heterogamety (XX/XY). However, spontaneous masculinization of XX females has been found in a rainbow trout population of gynogenetic doubled haploid individuals. The analysis of this masculinization phenotype transmission supported the hypothesis of the involvement of a recessive mutation (termed mal). As temperature effect on sex differentiation has been reported in some salmonid species, in this study we investigated in detail the potential implication of temperature on masculinization in this XX mal-carrying population. Seven families issued from XX mal-carrying parents were exposed from the time of hatching to different rearing water temperatures ((8, 12 and 18 degrees C), and the resulting sex-ratios were confirmed by histological analysis of both gonads. Our results demonstrate that masculinization rates are strongly increased (up to nearly two fold) at the highest temperature treatment (18 degrees C). Interestingly, we also found clear differences between temperatures on the masculinization of the left versus the right gonads with the right gonad consistently more often masculinized than the left one at lower temperatures (8 and 12 degrees C). However, the masculinization rate is also strongly dependent on the genetic background of the XX mal-carrying families. Thus, masculinization in XX mal-carrying rainbow trout is potentially triggered by an interaction between the temperature treatment and a complex genetic background potentially involving some part of the genetic sex differentiation regulatory cascade along with some minor sex-influencing loci. These results indicate that despite its rather strict genetic sex determinism system, rainbow trout sex differentiation can be modulated by temperature, as described in many other fish species. PMID- 25501355 TI - Long-Term Efficacy of Methylphenidate Immediate-Release for the Treatment of Childhood ADHD. AB - OBJECTIVE: To evaluate the long-term effects of methylphenidate imediate-release (MPH-IR), and to confirm the efficacy established in previous meta-analyses of short-term studies. METHOD: Published and unpublished studies in which participants were treated with MPH-IR for 12 weeks or more were searched. Pooled effect sizes from these studies were computed with the DerSimonian and Laird random-effect model. Meta-regression analysis was conducted to estimate covariates associated with treatment effects. RESULTS: Seven studies were included. Pooled parents ratings for inattention and hyperactivity/impulsivity resulted in standardized mean difference (SMD) = 0.96 (95% confidence interval [CI] = [0.60, 1.32]) and SMD = 1.12 (95% CI = [0.85, 1.39]), respectively; pooled teachers ratings showed SMD = 0.98 (95% CI = [0.09, 1.86]) for inattention and SMD = 1.25 (95% CI = [0.7, 1.81]) for hyperactivity/impulsivity. No evidence of association of any covariates with treatment effect was detected in the meta regression. CONCLUSION: MPH-IR is efficacious for childhood ADHD for periods longer than 12 weeks. PMID- 25501356 TI - Working Memory Training in ADHD: Controlling for Engagement, Motivation, and Expectancy of Improvement (Pilot Study). AB - OBJECTIVE: The aim of this study was to evaluate whether a shortened-length session of CogMed Working Memory Training (CWMT) would be a suitable active control group and evaluate study protocol to aid in design refinements for a larger randomized controlled trial (RCT). METHOD: Thirty-eight post-secondary students diagnosed with ADHD were randomized into 25 sessions of standard (45 min/session) or shortened (15 min/session) CWMT, or into a waitlist control group. RESULTS: There was no significant difference in completion rate or training index score between the standard- and shortened-length groups indicating that both groups showed improvement and put forth good effort during training. CONCLUSION: Preliminary findings suggest that shorter training sessions may induce similar levels of engagement, motivation, and expectancy of improvement in participants. We conclude that a larger scale RCT that utilizes shortened-length training as an active control group is warranted, but that a few modifications to the study protocol will be required. PMID- 25501352 TI - Non-coding roX RNAs prevent the binding of the MSL-complex to heterochromatic regions. AB - Long non-coding RNAs contribute to dosage compensation in both mammals and Drosophila by inducing changes in the chromatin structure of the X-chromosome. In Drosophila melanogaster, roX1 and roX2 are long non-coding RNAs that together with proteins form the male-specific lethal (MSL) complex, which coats the entire male X-chromosome and mediates dosage compensation by increasing its transcriptional output. Studies on polytene chromosomes have demonstrated that when both roX1 and roX2 are absent, the MSL-complex becomes less abundant on the male X-chromosome and is relocated to the chromocenter and the 4th chromosome. Here we address the role of roX RNAs in MSL-complex targeting and the evolution of dosage compensation in Drosophila. We performed ChIP-seq experiments which showed that MSL-complex recruitment to high affinity sites (HAS) on the X chromosome is independent of roX and that the HAS sequence motif is conserved in D. simulans. Additionally, a complete and enzymatically active MSL-complex is recruited to six specific genes on the 4th chromosome. Interestingly, our sequence analysis showed that in the absence of roX RNAs, the MSL-complex has an affinity for regions enriched in Hoppel transposable elements and repeats in general. We hypothesize that roX mutants reveal the ancient targeting of the MSL complex and propose that the role of roX RNAs is to prevent the binding of the MSL-complex to heterochromatin. PMID- 25501357 TI - The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. AB - BACKGROUND: We carried out a systematic review and meta-analysis to evaluate the predictive roles of tumor infiltrating lymphocytes (TILs) in response to neoadjuvant chemotherapy (NAC) in breast cancer. METHOD: A PubMed and Web of Science literature search was designed. Random or fixed effect models were adopted to estimate the summary odds ratio (OR). Heterogeneity and sensitivity analyses were performed to explore heterogeneity among studies and to assess the effects of study quality. Publication bias was evaluated using a funnel plot, Egger's test and Begg's test. We included studies where the predictive significance of TILs, and/or TILs subset on the pathologic complete response (pCR) were determined in NAC of breast cancer. RESULTS: A total of 13 published studies (including 3251 patients) were eligible. In pooled analysis, the detection of higher TILs numbers in pre-treatment biopsy was correlated with better pCR to NAC (OR = 3.93, 95% CI, 3.26-4.73). Moreover, TILs predicted higher pCR rates in triple negative (OR = 2.49, 95% CI: 1.61-3.83), HER2 positive (OR = 5.05, 95% CI: 2.86-8.92) breast cancer, but not in estrogen receptor (ER) positive (OR = 6.21, 95%CI: 0.86-45.15) patients. In multivariate analysis, TILs were still an independent marker for high pCR rate (OR = 1.41, 95% CI: 1.19 1.66). For TILs subset, higher levels of CD8+ and FOXP3+ T-lymphocytes in pre treatment biopsy respectively predicted better pathological response to NAC (OR = 6.44, 95% CI: 2.52-16.46; OR = 2.94, 95% CI: 1.05-8.26). Only FOXP3+ lymphocytes in post-NAC breast tissue were a predictive marker for low pCR rate in univariate (OR = 0.41, 95% CI: 0.21-0.80) and multivariate (OR = 0.36, 95% CI: 0.13-0.95) analysis. CONCLUSION: Higher TILs levels in pre-treatment biopsy indicated higher pCR rates for NAC. TILs subset played different roles in predicting response to NAC. PMID- 25501358 TI - Molecular insights into the dynamics of pharmacogenetically important N-terminal variants of the human beta2-adrenergic receptor. AB - The human beta2-adrenergic receptor (beta2AR), a member of the G-protein coupled receptor (GPCR) family, is expressed in bronchial smooth muscle cells. Upon activation by agonists, beta2AR causes bronchodilation and relief in asthma patients. The N-terminal polymorphism of beta2AR at the 16th position, Arg16Gly, has warranted a lot of attention since it is linked to variations in response to albuterol (agonist) treatment. Although the beta2AR is one of the well-studied GPCRs, the N-terminus which harbors this mutation, is absent in all available experimental structures. The goal of this work was to study the molecular level differences between the N-terminal variants using structural modeling and atomistic molecular dynamics simulations. Our simulations reveal that the N terminal region of the Arg variant shows greater dynamics than the Gly variant, leading to differential placement. Further, the position and dynamics of the N terminal region, further, affects the ligand binding-site accessibility. Interestingly, long-range effects are also seen at the ligand binding site, which is marginally larger in the Gly as compared to the Arg variant resulting in the preferential docking of albuterol to the Gly variant. This study thus reveals key differences between the variants providing a molecular framework towards understanding the variable drug response in asthma patients. PMID- 25501359 TI - Functional and evolutionary significance of human microRNA seed region mutations. AB - MicroRNAs have emerged in recent years as important regulators of cell function in both normal and diseased cells. MiRNAs coordinately regulate large suites of target genes by mRNA degradation and/or translational inhibition. The mRNA target specificities of miRNAs in animals are primarily encoded within a 7 nt "seed region" mapping to positions 2-8 at the molecule's 5' end. We here combine computational analyses with experimental studies to explore the functional significance of sequence variation within the seed region of human miRNAs. The results indicate that a substitution of even a single nucleotide within the seed region changes the spectrum of mRNA targets by >50%. The high functional cost of even single nucleotide changes within seed regions is consistent with their high sequence conservation among miRNA families both within and between species and suggests processes that may underlie the evolution of miRNA regulatory control. PMID- 25501360 TI - Central nervous system effects of the second-generation antihistamines marketed in Japan--review of inter-drug differences using the proportional impairment ratio (PIR)-. AB - BACKGROUND: Second-generation antihistamines (AHs) have, in general, fewer sedative effects than the first-generation. However, important inter-drug differences remain in the degree of cognitive and/or psychomotor impairment. The extent to which a particular compound causes disruption can be conveniently compared, to all other AHs, using the Proportional Impairment Ratio (PIR). Although the PIR can differentiate the relative impairment caused by individual drugs, there is no indication of the reliability of the ratios obtained. OBJECTIVE: To calculate the PIRs -together with 95% confidence intervals (CIs), as an index of reliability- and compare AHs currently, or soon to be, available in Japan, with respect to their intrinsic capacity to cause impairment. METHODS: Results from studies of cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, mequitazine, and olopatadine were included in the PIR calculations. All data utilised came from crossover studies in healthy volunteers which were randomised and placebo and positive-internal controlled. Existing databases from studies reporting the sedative effects of AHs on objective (speed, accuracy, memory) and subjective (feeling) psychometrics were augmented, via results from suitable studies published after the previous reviews. The null value for a PIR was one. RESULTS: A total of 45 studies were finally included for this review. Of the AHs assessed, fexofenadine, ebastine, and levocetirizine showed a PIR for objective tests of 0. However, only fexofenadine (PIR = 0.49) had an upper limit of the 95% CI of less than 1. Fexofenadine, levocetirizine, desloratadine, olopatadine, loratadine, and mequitazine all had a PIR for subjective ratings of 0, but the upper limits of the 95% CIs were all in excess of 1, although fexofenadine (PIR = 2.57) was the lowest. CONCLUSIONS: The results show that there are differences between second-generation AHs in the extent of sedation produced. However, subjective ratings indicate that patients may not necessarily be aware of this. PMID- 25501361 TI - Efficacy and safety of crizotinib among Chinese EML4-ALK-positive, advanced-stage non-small cell lung cancer patients. AB - INTRODUCTION: We report the efficacy and safety of crizotinib treatment among Chinese patients with advanced-stage NSCLC. METHODS: We retrospectively analyzed patients with EML4-ALK positive advanced NSCLC who were treated with crizotinib from May 2012 to Aug 2013. Baseline clinical parameters, treatment protocol, response to therapy and survival were noted. The primary goal was to evaluate the efficacy of crizotinib in patients who were previously treated patients or who had poor ECOG performance status (PS). RESULTS: Forty patients were evaluable for safety and efficacy. Median age was 43 years, 100% had adenocarcinoma and stage IV disease, and 42.5% were female. Six patients received frontline treatment with crizotinib, 17 patients had 1 prior treatment, and 17 patients had more than 2 lines of prior treatment. Patients received a median of 5 cycles of treatment (range 1-15 cycles). After the first cycle, 92.5% (37/40) patients archived partial remission (PR). At the end of the follow-up period, the overall PR rate was 70% (28/40), and progression of disease (PD) occurred in 30% of patients (12/40). The median PFS was 28 weeks (95% CI 15.4 to 40.5 weeks), and median OS was 40 weeks (95% CI 38.6 to 49.3 weeks). The most frequent treatment-related AEs were vomiting (47.5%), vision disorder (27.5%) and increased ALT/AST (42%); most toxicities were Grade 1/2. Observed treatment-related Grade 3/4 AEs included increased ALT/AST (10%) and vomiting (5%). The EML4-ALK fusion rate and number of prior chemotherapy cycles did not appear to significantly affect the efficacy of crizotinib. However, PS 0-2 patients had improved PFS (50 weeks vs. 24 weeks, p = 0.015). CONCLUSIONS: Crizotinib was safe, well-tolerated, and effective in Chinese patients with pre-treated ALK-rearranged NSCLC. QOL was improved and PS appears to have an effect on the efficacy of crizotinib, but prior treatment and ALK fusion rate do not. PMID- 25501363 TI - MicroRNA-133b inhibits connective tissue growth factor in colorectal cancer and correlates with the clinical stage of the disease. AB - Accumulating evidence indicates that dysregulation of microRNA-133b (miR-133b) is an important step in the development of certain types of human cancer and contributes to tumorigenesis. Altered expression of miR-133b has been reported in colon carcinoma, but its association with clinical stage in colorectal cancer (CRC) has remained elusive. Connective tissue growth factor (CTGF), a potentially promising candidate gene for interaction with miR-133b, was screened using microarray analysis. The expression of miR-133b and CTGF was evaluated using reverse transcription-quantitative polymerase chain reaction and western blot analysis. The regulatory effects of miR-133b on CTGF were evaluated using a dual luciferase reporter assay. CTGF was identified as a functional target of miR 133b. The results demonstrated low expression of miR-133b in CRC specimens with poor cell differentiation (P=0.011), lymph node metastasis (P=0.037) and advanced clinical stages (stage III or IV vs. I or II; P=0.036). Furthermore, there was a significant association between a high level of expression of CTGF mRNA and an advanced clinical stage (stage III or IV vs. I or II; P=0.015) and lymph node metastasis (P=0.034). CTGF expression was negatively regulated by miR-133b in the human colorectum, suggesting that miR-133b and CTGF may be candidate therapeutic targets in colorectal cancer. PMID- 25501362 TI - Comparison of retinal nerve fiber layer thickness in vivo and axonal transport after chronic intraocular pressure elevation in young versus older rats. AB - PURPOSE: To compare in young and old rats longitudinal measurements of retinal nerve fiber layer thickness (RNFLT) and axonal transport 3-weeks after chronic IOP elevation. METHOD: IOP was elevated unilaterally in 2- and 9.5-month-old Brown-Norway rats by intracameral injections of magnetic microbeads. RNFLT was measured by spectral domain optical coherence tomography. Anterograde axonal transport was assessed from confocal scanning laser ophthalmolscopy of superior colliculi (SC) after bilateral intravitreal injections of cholera toxin-B-488. Optic nerve sections were graded for damage. RESULTS: Mean IOP was elevated in both groups (young 37, old 38 mmHg, p = 0.95). RNFL in young rats exhibited 10% thickening at 1-week (50.9+/-8.1 um, p<0.05) vs. baseline (46.4+/-2.4 um), then 7% thinning at 2-weeks (43.0+/-7.2 um, p>0.05) and 3-weeks (43.5+/-4.4 um, p>0.05), representing 20% loss of dynamic range. RNFLT in old rats showed no significant change at 1-week (44.9+/-4.1 um) vs. baseline (49.2+/-5.3 um), but progression to 22% thinning at 2-weeks (38.0+/-3.7 um, p<0.01) and 3-weeks (40.0+/-6.6 um, p<0.05), representing 59% loss of dynamic range. Relative SC fluorescence intensity was reduced in both groups (p<0.001), representing 77-80% loss of dynamic range and a severe transport deficit. Optic nerves showed 75-95% damage (p<0.001). There was greater RNFL thinning in old rats (p<0.05), despite equivalent IOP insult, transport deficit and nerve damage between age groups (all p>0.05). CONCLUSION: Chronic IOP elevation resulted in severely disrupted axonal transport and optic nerve axon damage in all rats, associated with mild RNFL loss in young rats but a moderate RNFL loss in old rats despite the similar IOP insult. Hence, the glaucomatous injury response within the RNFL depends on age. PMID- 25501365 TI - Ethnic differences in physiological responses to fear conditioned stimuli. AB - The idea that emotional expression varies with ethnicity is based largely on questionnaires and behavioral observations rather than physiological measures. We therefore compared the skin conductance responses (SCR) of Hispanic (Puerto Rican) and White non-Hispanic subjects in a fear conditioning and fear extinction task. Subjects were recruited from two sites: San Juan, Puerto Rico (PR), and Boston, Massachusetts (MA), using identical methods. A total of 78 healthy subjects (39 from PR, 39 from MA) were divided by sex and matched for age and educational level. Females from the two sites did not differ in their SCRs during any experimental phase of fear conditioning (habituation, conditioning, or extinction). In contrast, PR males responded significantly to the conditioned stimulus than MA males or PR females. Subtracting ethnic differences observed during the habituation phase (prior to conditioning) eliminated differences from subsequent phases, suggesting that PR males are elevated in their response to novelty rather than fear learning. Our findings suggest that, in addition to sex differences, there are ethnic differences in physiological responses to novel stimuli at least in males, which could be relevant for the assessment and treatment of anxiety disorders. PMID- 25501366 TI - Constitutively active ESCRT-II suppresses the MVB-sorting phenotype of ESCRT-0 and ESCRT-I mutants. AB - The endosomal sorting complex required for transport (ESCRT) protein complexes function at the endosome in the formation of intraluminal vesicles (ILVs) containing cargo proteins destined for the vacuolar/lysosomal lumen. The early ESCRTs (ESCRT-0 and -I) are likely involved in cargo sorting, whereas ESCRT-III and Vps4 function to sever the neck of the forming ILVs. ESCRT-II links these functions by initiating ESCRT-III formation in an ESCRT-I-regulated manner. We identify a constitutively active mutant of ESCRT-II that partially suppresses the phenotype of an ESCRT-I or ESCRT-0 deletion strain, suggesting that these early ESCRTs are not essential and have redundant functions. However, the ESCRT III/Vps4 system alone is not sufficient for ILV formation but requires cargo sorting mediated by one of the early ESCRTs. PMID- 25501367 TI - A unique insertion in STARD9's motor domain regulates its stability. AB - STARD9 is a largely uncharacterized mitotic kinesin and putative cancer target that is critical for regulating pericentriolar material cohesion during bipolar spindle assembly. To begin to understand the mechanisms regulating STARD9 function and their importance to cell division, we took a multidisciplinary approach to define the cis and trans factors that regulate the stability of the STARD9 motor domain. We show that, unlike the other ~50 mammalian kinesins, STARD9 contains an insertion in loop 12 of its motor domain (MD). Working with the STARD9-MD, we show that it is phosphorylated in mitosis by mitotic kinases that include Plk1. These phosphorylation events are important for targeting a pool of STARD9-MD for ubiquitination by the SCFbeta-TrCP ubiquitin ligase and proteasome-dependent degradation. Of interest, overexpression of nonphosphorylatable/nondegradable STARD9-MD mutants leads to spindle assembly defects. Our results with STARD9-MD imply that in vivo the protein levels of full length STARD9 could be regulated by Plk1 and SCFbeta-TrCP to promote proper mitotic spindle assembly. PMID- 25501368 TI - Characterization of VAMP isoforms in 3T3-L1 adipocytes: implications for GLUT4 trafficking. AB - The fusion of GLUT4-containing vesicles with the plasma membrane of adipocytes is a key facet of insulin action. This process is mediated by the formation of functional soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes between the plasma membrane t-SNARE complex and the vesicle v SNARE or VAMP. The t-SNARE complex consists of Syntaxin4 and SNAP23, and whereas many studies identify VAMP2 as the v-SNARE, others suggest that either VAMP3 or VAMP8 may also fulfil this role. Here we characterized the levels of expression, distribution, and association of all the VAMPs expressed in 3T3-L1 adipocytes to provide the first systematic analysis of all members of this protein family for any cell type. Despite our finding that all VAMP isoforms form SDS-resistant SNARE complexes with Syntaxin4/SNAP23 in vitro, a combination of levels of expression (which vary by >30-fold), subcellular distribution, and coimmunoprecipitation analyses lead us to propose that VAMP2 is the major v-SNARE involved in GLUT4 trafficking to the surface of 3T3-L1 adipocytes. PMID- 25501370 TI - Genetic mosaic analysis of a deleterious mitochondrial DNA mutation in Drosophila reveals novel aspects of mitochondrial regulation and function. AB - Various human diseases are associated with mitochondrial DNA (mtDNA) mutations, but heteroplasmy-the coexistence of mutant and wild-type mtDNA-complicates their study. We previously isolated a temperature-lethal mtDNA mutation in Drosophila, mt:CoI(T300I), which affects the cytochrome c oxidase subunit I (CoI) locus. In the present study, we found that the decrease in cytochrome c oxidase (COX) activity was ascribable to a temperature-dependent destabilization of cytochrome a heme. Consistently, the viability of homoplasmic flies at 29 degrees C was fully restored by expressing an alternative oxidase, which specifically bypasses the cytochrome chains. Heteroplasmic flies are fully viable and were used to explore the age-related and tissue-specific phenotypes of mt:CoI(T300I). The proportion of mt:CoI(T300I) genome remained constant in somatic tissues along the aging process, suggesting a lack of quality control mechanism to remove defective mitochondria containing a deleterious mtDNA mutation. Using a genetic scheme that expresses a mitochondrially targeted restriction enzyme to induce tissue-specific homoplasmy in heteroplasmic flies, we found that mt:CoI(T300I) homoplasmy in the eye caused severe neurodegeneration at 29 degrees C. Degeneration was suppressed by improving mitochondrial Ca(2+) uptake, suggesting that Ca(2+) mishandling contributed to mt:CoI(T300I) pathogenesis. Our results demonstrate a novel approach for Drosophila mtDNA genetics and its application in modeling mtDNA diseases. PMID- 25501369 TI - Kinesin-13 regulates the quantity and quality of tubulin inside cilia. AB - Kinesin-13, an end depolymerizer of cytoplasmic and spindle microtubules, also affects the length of cilia. However, in different models, depletion of kinesin 13 either lengthens or shortens cilia, and therefore the exact function of kinesin-13 in cilia remains unclear. We generated null mutations of all kinesin 13 paralogues in the ciliate Tetrahymena. One of the paralogues, Kin13Ap, localizes to the nuclei and is essential for nuclear divisions. The remaining two paralogues, Kin13Bp and Kin13Cp, localize to the cell body and inside assembling cilia. Loss of both Kin13Bp and Kin13Cp resulted in slow cell multiplication and motility, overgrowth of cell body microtubules, shortening of cilia, and synthetic lethality with either paclitaxel or a deletion of MEC-17/ATAT1, the alpha-tubulin acetyltransferase. The mutant cilia assembled slowly and contained abnormal tubulin, characterized by altered posttranslational modifications and hypersensitivity to paclitaxel. The mutant cilia beat slowly and axonemes showed reduced velocity of microtubule sliding. Thus kinesin-13 positively regulates the axoneme length, influences the properties of ciliary tubulin, and likely indirectly, through its effects on the axonemal microtubules, affects the ciliary dynein-dependent motility. PMID- 25501373 TI - Progress in translational research. PMID- 25501371 TI - Impacts of infection with different toxigenic Clostridium difficile strains on faecal microbiota in children. AB - Increasing evidence suggests that altered intestinal microbial composition and function result in an increased risk of Clostridium difficile-associated diarrhoea (CDAD); however, the specific changes of intestinal microbiota in children suffering from CDAD and their associations with C. difficile strain toxigenicity are poorly understood. High-throughput pyrosequencing showed that reduced faecal bacterial diversity and dramatic shifts of microbial composition were found in children with CDAD. The Firmicutes/Bacteroidetes ratio was increased significantly in patients with CDAD, which indicated that dysbiosis of faecal microbiota was closely associated with CDAD. C. difficile infection resulted in an increase in lactate-producing phylotypes, with a corresponding decrease in butyrate-producing bacteria. The decrease in butyrate and lactate buildup impaired intestinal colonisation resistance, which increased the susceptibility to C. difficile colonisation. Strains of C. difficile which were positive for both toxin A and toxin B reduced faecal bacterial diversity to a greater degree than strains that were only toxin B-positive, and were associated with unusually abundant Enterococcus, which implies that the C. difficile toxins have different impacts on the faecal microbiota of children. Greater understanding of the relationships between disruption of the normal faecal microbiota and colonisation with C. difficile that produces different toxins might lead to improved treatment. PMID- 25501372 TI - Body mass index and depressive symptoms in older adults: a cross-lagged panel analysis. AB - BACKGROUND: There are conflicting results about the association between body mass index (BMI) and depressive symptoms in older adults. The present study examined the relationship between weight and depressive symptoms over time in older adults in South Korea. METHODS: We used data from three waves of the Korean Longitudinal Study of Aging and ran a series of cross-lagged panel models to test the reciprocal relationship between depressive symptoms and obesity in older Korean adults. We assumed a temporally stable relationship between depressive symptoms and obesity and, thus imposed equality constraints over time. RESULTS: After controlling for the effect of depressive symptoms two years prior, underweight older adults had a higher depressive symptom score than those of normal weight. When controlling for obesity status from two years prior, older adults with higher levels of depressive symptoms were more likely to be underweight and less likely to be overweight than normal weight. The same patterns were observed in data from 2006 to 2008 and from 2008 to 2010. CONCLUSIONS: These results show that there is a correlation between depressive symptoms and weight status. In middle-aged and elderly Asian populations, depression can lead to weight loss rather than obesity, and underweight may develop depressive symptoms. PMID- 25501376 TI - From pathogenesis, epidemiology, and genetics to definitions, diagnosis, and treatments of cutaneous lupus erythematosus and dermatomyositis: a report from the 3rd International Conference on Cutaneous Lupus Erythematosus (ICCLE) 2013. PMID- 25501377 TI - Omalizumab, an Anti-IgE mAb, receives approval for the treatment of chronic idiopathic/spontaneous urticaria. AB - Omalizumab, an anti-IgE mAb, has recently been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of chronic idiopathic urticaria. Saini et al. (2014) (this issue) report on ASTERIA I, a 40-week randomized, double-blinded, placebo-controlled phase III trial evaluating omalizumab for the treatment of this disease. PMID- 25501378 TI - Comparative effectiveness of topical drugs in dermatologic priority diseases: geometry of randomized trial networks. AB - This commentary explores the fundamentals of network theory, a branch of applied mathematics that has numerous applications in many fields. Maruani et al. (2014) used network theory to analyze the geometry of the evidence base for dermatologic treatments. This is a prime example of the innovative nature of network theory: the mapping of a complex system into an abstract geometry for easier analysis. The interpretation rests upon the two concepts of diversity and co-occurrence. The mathematical foundation of these concepts is briefly reviewed. In addition, examples of the application of network geometry in other dermatologic settings as well as in science and technology are presented. PMID- 25501379 TI - Diagnosis by numbers: defining skin disease pathogenesis through collated gene signatures. AB - Disease gene expression profiles can be utilized as biomarkers for diagnostic, prognostic, and targeted therapeutic purposes, although individual data sets may be of limited generic value. To develop broader clinical relevance from disease gene signatures, Inkeles et al. demonstrate how mining publically available microarray data from a range of skin disorders can elucidate disease pathways, generate a multi-disease classifier, and identify potential therapeutic targets. This integrative molecular classification and functional analysis offers a new approach to understanding disease pathogenesis, with significant implications for diagnostics and the development of personalized medicine. PMID- 25501380 TI - Healing refractory venous ulcers: new treatments offer hope. AB - Non-healing wounds are associated with an inflammatory and proteolytic wound environment, and recent therapeutic strategies have been focused on reversing these changes. Connexins, as members of gap junctions, are important in intercellular signaling and wound repair. Connexin 43 (Cx43) downregulation is associated with normal wound healing, and it has been found to be upregulated in non-healing venous leg ulcers (VLUs). Ghatnekar et al. (2014) report findings of a small phase II trial performed in Indian patients with chronic VLUs, reporting that ACT1, a mimetic peptide of Cx43, accelerates healing in the treatment group. Despite standard care with compression therapy and adjuvant therapy for refractory wounds, at present in clinical practice a significant number of patients remain unhealed. The potential for ACT1 exists to help heal refractory VLUs, but it faces additional regulatory hurdles. PMID- 25501381 TI - JID VisualDx Quiz: January 2015. PMID- 25501382 TI - Lineage tracing mediated by cre-recombinase activity. PMID- 25501383 TI - Cells to surgery quiz: January 2015. PMID- 25501384 TI - Percutaneous pericardiocentesis: safety first! PMID- 25501385 TI - Atomic electric fields revealed by a quantum mechanical approach to electron picodiffraction. AB - By focusing electrons on probes with a diameter of 50 pm, aberration-corrected scanning transmission electron microscopy (STEM) is currently crossing the border to probing subatomic details. A major challenge is the measurement of atomic electric fields using differential phase contrast (DPC) microscopy, traditionally exploiting the concept of a field-induced shift of diffraction patterns. Here we present a simplified quantum theoretical interpretation of DPC. This enables us to calculate the momentum transferred to the STEM probe from diffracted intensities recorded on a pixel array instead of conventional segmented bright field detectors. The methodical development yielding atomic electric field, charge and electron density is performed using simulations for binary GaN as an ideal model system. We then present a detailed experimental study of SrTiO3 yielding atomic electric fields, validated by comprehensive simulations. With this interpretation and upgraded instrumentation, STEM is capable of quantifying atomic electric fields and high-contrast imaging of light atoms. PMID- 25501387 TI - Controlling coherence via tuning of the population imbalance in a bipartite optical lattice. AB - The control of transport properties is a key tool at the basis of many technologically relevant effects in condensed matter. The clean and precisely controlled environment of ultracold atoms in optical lattices allows one to prepare simplified but instructive models, which can help to better understand the underlying physical mechanisms. Here we show that by tuning a structural deformation of the unit cell in a bipartite optical lattice, one can induce a phase transition from a superfluid into various Mott insulating phases forming a shell structure in the superimposed harmonic trap. The Mott shells are identified via characteristic features in the visibility of Bragg maxima in momentum spectra. The experimental findings are explained by Gutzwiller mean-field and quantum Monte Carlo calculations. Our system bears similarities with the loss of coherence in cuprate superconductors, known to be associated with the doping induced buckling of the oxygen octahedra surrounding the copper sites. PMID- 25501388 TI - Synchronous turnover of flora, fauna, and climate at the Eocene-Oligocene Boundary in Asia. AB - The Eocene-Oligocene Boundary (~34 million years ago) marks one of the largest extinctions of marine invertebrates in the world oceans and of mammalian fauna in Europe and Asia in the Cenozoic era. A shift to a cooler climate across this boundary has been suggested as the cause of this extinction in the marine environment, but there is no manifold evidence for a synchronous turnover of flora, fauna and climate at the Eocene-Oligocene Boundary in a single terrestrial site in Asia to support this hypothesis. Here we report new data of magnetostratigraphy, pollen and climatic proxies in the Asian interior across the Eocene-Oligocene Boundary; our results show that climate change forced a turnover of flora and fauna, suggesting there was a change from large-size perissodactyl dominant fauna in forests under a warm-temperate climate to small rodent/lagomorph-dominant fauna in forest-steppe in a dry-temperate climate across the Eocene-Oligocene Boundary. These data provide a new terrestrial record for this significant Cenozoic environmental event. PMID- 25501389 TI - CORRIGENDUM: Parametric spectro-temporal analyzer (PASTA) for real-time optical spectrum observation. PMID- 25501390 TI - Performance limits of ICA-based heart rate identification techniques in imaging photoplethysmography. AB - Imaging photoplethysmography is a relatively new technique for extracting biometric information from video images of faces. This is useful in non-invasive monitoring of patients including neonates or the aged, with respect to sudden infant death syndrome, sleep apnoea, pulmonary disease, physical or mental stress and other cardio-vascular conditions. In this paper, we investigate the limits of detection of the heart rate (HR) while reducing the video quality. We compare the performance of three independent component analysis (ICA) methods (JADE, FastICA, RADICAL), autocorrelation with signal conditioning techniques and identify the most robust approach. We discuss sources of increasing error and other limiting conditions in three situations of reduced signal-to-noise ratio: one where the area of the analyzed face is decreased from 100 to 5%, another where the face area is progressively re-sampled down to a single RGB pixel and one where the HR signal is severely reduced with respect to the boundary noise. In most cases, the cardiac pulse rate can be reliably and accurately detected from videos containing only 5% facial area or from a face occupying just 4 pixels or containing only 5% of the facial HR modulation. PMID- 25501391 TI - Evolutionary importance of the intramolecular pathways of hydrolysis of phosphate ester mixed anhydrides with amino acids and peptides. AB - Aminoacyl adenylates (aa-AMPs) constitute essential intermediates of protein biosynthesis. Their polymerization in aqueous solution has often been claimed as a potential route to abiotic peptides in spite of a highly efficient CO2-promoted pathway of hydrolysis. Here we investigate the efficiency and relevance of this frequently overlooked pathway from model amino acid phosphate mixed anhydrides including aa-AMPs. Its predominance was demonstrated at CO2 concentrations matching that of physiological fluids or that of the present-day ocean, making a direct polymerization pathway unlikely. By contrast, the occurrence of the CO2 promoted pathway was observed to increase the efficiency of peptide bond formation owing to the high reactivity of the N-carboxyanhydride (NCA) intermediate. Even considering CO2 concentrations in early Earth liquid environments equivalent to present levels, mixed anhydrides would have polymerized predominantly through NCAs. The issue of a potential involvement of NCAs as biochemical metabolites could even be raised. The formation of peptide phosphate mixed anhydrides from 5(4H)-oxazolones (transiently formed through prebiotically relevant peptide activation pathways) was also observed as well as the occurrence of the reverse cyclization process in the reactions of these mixed anhydrides. These processes constitute the core of a reaction network that could potentially have evolved towards the emergence of translation. PMID- 25501394 TI - Editorial: journal remains strong and vibrant. PMID- 25501395 TI - Time trial performance and pacing in heat is determined by rate of heat gain. PMID- 25501393 TI - 7q11.23 dosage-dependent dysregulation in human pluripotent stem cells affects transcriptional programs in disease-relevant lineages. AB - Cell reprogramming promises to make characterization of the impact of human genetic variation on health and disease experimentally tractable by enabling the bridging of genotypes to phenotypes in developmentally relevant human cell lineages. Here we apply this paradigm to two disorders caused by symmetrical copy number variations of 7q11.23, which display a striking combination of shared and symmetrically opposite phenotypes--Williams-Beuren syndrome and 7q microduplication syndrome. Through analysis of transgene-free patient-derived induced pluripotent stem cells and their differentiated derivatives, we find that 7q11.23 dosage imbalance disrupts transcriptional circuits in disease-relevant pathways beginning in the pluripotent state. These alterations are then selectively amplified upon differentiation of the pluripotent cells into disease relevant lineages. A considerable proportion of this transcriptional dysregulation is specifically caused by dosage imbalances in GTF2I, which encodes a key transcription factor at 7q11.23 that is associated with the LSD1 repressive chromatin complex and silences its dosage-sensitive targets. PMID- 25501396 TI - Response. PMID- 25501399 TI - Conjunctival papillomatous lesion. PMID- 25501400 TI - Peculiar protuberance. PMID- 25501392 TI - Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes. AB - Cancers exhibit extensive mutational heterogeneity, and the resulting long-tail phenomenon complicates the discovery of genes and pathways that are significantly mutated in cancer. We perform a pan-cancer analysis of mutated networks in 3,281 samples from 12 cancer types from The Cancer Genome Atlas (TCGA) using HotNet2, a new algorithm to find mutated subnetworks that overcomes the limitations of existing single-gene, pathway and network approaches. We identify 16 significantly mutated subnetworks that comprise well-known cancer signaling pathways as well as subnetworks with less characterized roles in cancer, including cohesin, condensin and others. Many of these subnetworks exhibit co occurring mutations across samples. These subnetworks contain dozens of genes with rare somatic mutations across multiple cancers; many of these genes have additional evidence supporting a role in cancer. By illuminating these rare combinations of mutations, pan-cancer network analyses provide a roadmap to investigate new diagnostic and therapeutic opportunities across cancer types. PMID- 25501402 TI - Investigation of the physical properties of the tetragonal CeMAl4Si2 (M = Rh, Ir, Pt) compounds. AB - The synthesis, crystal structure and physical properties studied by means of x ray diffraction, magnetic, thermal and transport measurements of CeMAl4Si2 (M = Rh, Ir, Pt) are reported, along with the electronic structure calculations for LaMAl4Si2 (M = Rh, Ir, Pt). These materials adopt a tetragonal crystal structure (space group P4/mmm) comprised of BaAl4 blocks, separated by MAl2 units, stacked along the c-axis. Both CeRhAl4Si2 and CeIrAl4Si2 order antiferromagnetically below TN1 = 14 and 16 K, respectively, and undergo a second antiferromagnetic transitition at lower temperature (TN2 = 9 and 14 K, respectively). CePtAl4Si2 orders ferromagnetically below TC = 3 K with an ordered moment of MUsat = 0.8 MUB for a magnetic field applied perpendicular to the c-axis. Electronic structure calculations reveal quasi-2D character of the Fermi surface. PMID- 25501403 TI - [Picture in clinical hematology no. 77. Intravascular large B-cell lymphoma]. PMID- 25501404 TI - An integrated manual for hematologists and dermatologists to access the guidelines for the management of adult T-cell leukemia-lymphoma (2014). PMID- 25501405 TI - Questionnaire survey on current status of home care and support for patients with hematological diseases. AB - In order to survey the current status of home care and support for patients with hematological diseases, questionnaires were sent to 3,591 hospitals and home care facilities in Tokyo and surrounding prefectures. The first survey showed that 81.7% of medical staff members at hospitals reported that they had experience with home care and support, but only 24.9% of home care facility staff members had such experience. The second questionnaire, surveying 1,202 personnel, identified four factors hampering successful establishment of home care and support networks for hematological diseases. These included insufficient familial support for patients, difficulty making end of life decisions by family members and patients, limited access to transfusion support, and financial problems. PMID- 25501406 TI - Markers of bone metabolism in multiple myeloma patients switched from zoledronic acid to denosumab. AB - To date, intravenous drip infusion of zoledronic acid (ZA) has mainly been used for the treatment and prevention of skeletal-related events (SRE) in patients with multiple myeloma (MM). Recently, denosumab, a fully humanized monoclonal antibody against receptor activator of nuclear factor-kappaB ligand (RANKL), has also become available for the same purpose, but little is known about the impact of switching from ZA to denosumab. Herein, we present a retrospective study on bone metabolic markers in 10 MM patients initially treated with ZA and then switched to denosumab. Consequently, the levels of bone resorption markers, tartrate-resistant acid phosphatase 5b (TRACP-5b) and serum type-I collagen crosslinked N-telopeptide (sNTX), significantly decreased after denosumab treatment, while the levels of bone formation markers, osteocalcin (OC) and bone specific alkaline phosphatase (BAP), showed no apparent changes. No patient developed severe hypocalcemia with denosumab treatment. In one patient not given chemotherapy, the M-protein level increased after switching from ZA to denosumab and plateaued when ZA was restarted. Based on this finding, we anticipate that switching from ZA to denosumab would exert a stronger suppressive effect on osteoclasts, but the anti-myeloma activity of ZA must be taken into consideration. PMID- 25501407 TI - Secondary MGUS following by adenovirus-induced hemorrhagic cystitis after autologous peripheral blood stem cell transplantation in a patient with multiple myeloma. AB - A 61-year-old man with multiple myeloma (IgG-kappa) received autologous peripheral blood stem cell transplantation (PBSCT) after induction of VAD in July 2009, and obtained a very good partial response. In November 2009, he was admitted to our hospital because of adenovirus-induced hemorrhagic cystitis and pneumocystis jiroveci pneumonia. The pneumonia resolved with sulfamethoxazole and steroid pulse therapy, and cystitis subsided spontaneously. In December 2009, serum protein electrophoresis showed two abnormal protein bands (APB)(IgG-lambda, IgA-lambda), different from the original M-protein, and IgG thereafter increased to 2,771 mg/dl with a concomitant increase in anti-adenovirus antibody to 4,096. In October 2010, APB disappeared. To date, he has been in stable complete remission for five years since PBSCT. The emergence of APB is considered to be a surrogate marker for long-term remission. Immune reconstitution syndrome and APB after high dose chemotherapy following PBSCT are discussed herein. PMID- 25501408 TI - B-cell lymphoma developing de novo hepatitis B after salvage therapies including rituximab through seroconversion of surface antibody. AB - The patient was a 73-year-old woman. At 63 years of age, she had developed follicular lymphoma that showed a complete response to R-CHOP therapy. Over the subsequent 8 years, she experienced 4 relapses and was administered rituximab monotherapy once, combined rituximab-fludarabine therapy twice, and CHASE-R therapy once, achieving a complete response each time. Before her first therapy, hepatitis B virus (HBV) surface antigen was negative, while hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody were not measured. Later, before her second salvage therapy, anti-HBs was negative, but then changed to positive before her third salvage therapy. HBV-DNA was negative before CHASE-R therapy. At 16 months after completing the CHASE-R therapy, she developed hepatitis and HBV-DNA had changed to positive. Hepatitis did not become fulminant and entecavir administration was effective. It was surmised that HBV had resolved, but she became negative for anti-HBs following the rituximab-containing chemotherapy. Therefore, this is a rare case in which de novo hepatitis developed after the final chemotherapy. The prognosis of patients with de novo hepatitis accompanying treatment of B-cell lymphoma is poor. In those who undergo lymphoma salvage therapy, the risk for and clinical course of HBV reactivation might differ from those of treatment-naive patients. PMID- 25501409 TI - Pregnancy and delivery in a PNH patient treated with eculizumab. AB - We report a 37-year-old pregnant woman with paroxysmal nocturnal hemoglobinuria (PNH) treated with eculizumab. She had been diagnosed with PNH-aplastic anemia at age 19 years, and started to receive eculizumab at age 35 years. Thereafter, she had no hemolytic attacks. She became pregnant 2 years later, and treatment with eculizumab was continued. During her pregnancy, she showed no exacerbation of hemolysis. She delivered a girl by Caesarean section at 37 weeks and 3 days of gestation. Postpartum, anticoagulant therapy was started. Although mild hemolysis and a rise in FDP/Ddimer were seen, she had no symptoms of thrombosis. Ten days after delivery, she and her baby were discharged. Eculizumab was present in the first breast milk and cord blood but was below detectable levels. The cord blood showed blockage of hemolysis. PMID- 25501410 TI - Successful treatment with allogenic hematopoietic stem cell transplantation of a severe congenital neutropenia patient harboring a novel ELANE mutation. AB - We report a 4-year-old boy with severe congenital neutropenia (SCN), who was successfully treated with hematopoietic stem cell transplantation (HSCT). The patient had frequently developed bacterial infections since 6 months of age, and showed severe neutropenia below 100/MUl at 1 year and 4 months of age. The patient harbored a heterozygous missense mutation in ELANE exon 3 (p.Q73P, g.2253 A>C). This was a novel de novo mutation, and he was thus diagnosed as having SCN. Because of failure to respond to granulocyte colony-stimulating factor treatment and repeated admissions due to bacterial infections, allogeneic HSCT was performed from a serologically matched unrelated donor following the conditioning regimen: fludarabine/melphalan/anti-thymocyte globulin and a low dose of total body irradiation. Tacrolimus and a short course of methotrexate were used for graft-versus-host disease prophylaxis. Engraftment was achieved at day 12, and the patient maintained normal hematopoiesis for over 15 months after HSCT. We concluded that HSCT is a useful treatment for SCN patients, especially those who are at high risk for leukemic transformation. However, a larger number of SCN patients and longer follow-up are necessary to identify appropriate conditioning regimens and long-term prognosis. PMID- 25501411 TI - Successful treatment of chronic disseminated intravascular coagulation using recombinant human soluble thrombomodulin in a dialysis patient with dissecting aortic aneurysm. AB - A 62-year-old man had a history of acute aortic dissection (Stanford type A) and had been diagnosed with polycystic kidney disease three years earlier, and then developed end-stage renal failure. He was referred with chief complaints of difficult hemostasis and consecutive hemorrhagic episodes at the puncture site of the shunt soon after dialysis introduction. We suspected chronic disseminated intravascular coagulation (DIC) due to mild thrombocytopenia and a fibrinolytic system abnormality. Plasma factor XIII activity was decreased, but no inhibitor was detected. In addition, contrast-enhanced computed tomography showed exacerbation of a dissecting aortic aneurysm. We finally diagnosed chronic DIC and secondary factor XIII deficiency associated with the aortic aneurysm. We selected treatment involving recombinant human soluble thrombomodulin (rTM) because he was on maintenance dialysis and required long-term follow-up bofore the operation. Hemostatic function improved with regular administration of rTM, and was well-controlled preoperatively. PMID- 25501412 TI - Acute encephalomyelitis complicated with severe neurological sequelae after intrathecal administration of methotrexate in a patient with acute lymphoblastic leukemia. AB - A four-year-old girl on maintenance therapy for acute lymphoblastic leukemia (ALL) complained of a headache and low back pain on the day she received her 21st intrathecal methotrexate (it-MTX) administration, and the next day experienced numbness and pain in her foot. This numbness gradually spread to her hand. She thereafter developed a fever and was hospitalized on day 8. After antibiotic therapy, the fever disappeared. However, her lower limbs became paralyzed, and she also developed urinary retention. On day 12, her paralysis progressed upwards, and she also developed paralysis of the upper limbs. Finally, she experienced convulsions with an impairment of consciousness. A magnetic resonance imaging study of the brain and spinal cord showed abnormal signals in the brain cortex and anterior horn. Accordingly, we diagnosed acute encephalomyelitis associated with it-MTX. High-dose intravenous immunoglobulin, steroid pulse therapy, plasma exchange, and dextromethorphan administration were initiated, while she received mechanical ventilation. Despite this intensive treatment, she suffered severe neurological damage and had to be maintained on mechanical ventilation due to persistent flaccid quadriplegia one year after the onset. When patients have symptoms of ascending paralysis during it-MTX treatment, clinicians should carefully consider the possibility of acute encephalomyelitis due to it MTX. PMID- 25501413 TI - Development of asymptomatic acquired factor V inhibitor after the administration of antibiotics. AB - Acquired factor V (FV) inhibitor is a rare coagulation disorder, the causes and clinical symptoms of which are known to vary widely. Acquired FV inhibitor mostly occurs with exposure to fibrin glues during surgical procedures. We experienced a case with asymptomatic acquired FV inhibitor caused by antibiotic therapy for aspiration pneumonia.A man in his eighties had been treated for chronic atrial fibrillation, cerebral infarction and spinal canal stenosis. He was admitted after antibiotic therapy for aspiration pneumonia in a previous hospital. On admission, the screening test for blood coagulation revealed extreme prolongation of both prothrombin time (PT) and activated partial thromboplastin time (APTT). Vitamin K was administered intravenously after cessation of warfarin, but neither PT nor APTT showed any improvement. Subsequently, a cross mixing test was performed and showed an inhibitor pattern. Furthermore, a high titer of FV inhibitor was detected by the Bethesda method and an acquired FV inhibitor was thus diagnosed. Despite the presence of FV inhibitor, the patient showed no bleeding symptoms. Eight months later, both PT and APTT had diminished to normal clotting time values without immunosuppressive therapies. PMID- 25501414 TI - Clofarabine-based combination chemotherapy for relapse and refractory childhood acute lymphoblastic leukemia. AB - Clofarabine, one of the key treatment agents for refractory and relapsed acute lymphoblastic leukemia (ALL), achieves a remission rate of approximately 30% with single-agent clofarabine induction chemotherapy. However, a remission rate of approximately 50% was reported with a combination chemotherapy regimen consisting of clofarabine, etoposide, and cyclophosphamide. We treated two cases with refractory and relapsed ALL with combination chemotherapy including clofarabine; one was an induction failure but the other achieved remission. Both cases developed an infectious complication (NCI-CTCAE grade 3) and body pain with infusion. Prophylactic antibiotic and opioid infusions facilitated avoiding septic shock and pain. Further investigation of such cases is required. PMID- 25501415 TI - Evaluation of safety and efficacy of transjugular liver biopsy in allogeneic hematopoietic stem cell transplant recipients. AB - We retrospectively evaluated the safety and utility of transjugular liver biopsy (TJLB) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Ten patients underwent HSCT between 1991 and 2013. Eight patients with thrombocytopenia received platelet transfusions before and/or during TJLB. No complications associated with TJLB were observed. Samples adequate for a pathological diagnosis were obtained in 9 of the 10 patients, and the diagnoses made by TJLB were graft-versus-host-disease in eight patients and non-specific hepatitis in one. These results suggest that TJLB is a safe and effective procedure for the evaluation of liver injury in HSCT recipients. PMID- 25501422 TI - Is sonic Hedgehog involved in human fracture healing? --a prospective study on local and systemic concentrations of SHH. AB - INTRODUCTION: Sonic Hedgehog (SHH) is a new signalling pathway in bone repair. Evidence exist that SHH pathway plays a significant role in vasculogenesis and limb development during embryogenesis. Some in vitro and animal studies has already proven its potential for bone regeneration. However, no data on the role of SHH in the human fracture healing have been published so far. METHODS: Seventy five patients with long bone fractures were included into the study and divided in 2 groups. First group contained 69 patients with normal fracture healing. Four patients with impaired fracture healing formed the second group. 34 volunteers donated blood samples as control. Serum samples were collected over a period of 1 year following a standardized time schedule. In addition, SHH levels were measured in fracture haematoma and serum of 16 patients with bone fractures. RESULTS: Fracture haematoma and patients serum both contained lower SHH concentrations compared to control serum. The comparison between the patients' serum SHH level and the control serum revealed lower levels for the patients at all measurement time points. Significantly lower concentrations were observed at weeks 1 and 2 after fracture. SHH levels were slightly decreased in patients with impaired fracture healing without statistical significance. CONCLUSION: This is the first study to report local and systemic concentration of SHH in human fracture healing and SHH serum levels in healthy adults. A significant reduction of the SHH levels during the inflammatory phase of fracture healing was found. SHH concentrations in fracture haematoma and serum were lower than the concentration in control serum for the rest of the healing period. Our findings indicate that there is no relevant involvement of SHH in human fracture healing. Fracture repair process seem to reduce the SHH level in human. Further studies are definitely needed to clarify the underlying mechanisms. PMID- 25501421 TI - Wild blueberries (Vaccinium myrtillus) alleviate inflammation and hypertension associated with developing obesity in mice fed with a high-fat diet. AB - BACKGROUND: Low-grade metabolic inflammation and hypertension are primary mechanisms involved in obesity-associated adverse health effects. Berries, especially Nordic wild blueberries (hereafter referred to as bilberries), represent an important source of dietary anthocyanins, a group of polyphenols with potential beneficial effects to combat obesity-associated metabolic disturbances. METHODS: The effects of 5% or 10% (w/w) of whole bilberries (BB) were studied on the development of obesity and its metabolic disturbances in C57BL mice fed with a high-fat diet (HFD) for three months. Cytokines, inflammatory cells, systolic blood pressure, glucose tolerance, insulin sensitivity, weight gain, body fat, food consumption and energy metabolism were assessed. RESULTS: Bilberries ameliorated type 1 pro-inflammatory responsiveness induced by HFD. This was indicated by the altered cytokine profile and the reduced prevalence of interferon gamma -producing T-cells, in particular T helper type 1 cells. Bilberries also prevented the progression of obesity associated long term increase in systolic blood pressure in mice. CONCLUSIONS: Bilberries reduce the development of systemic inflammation and prevent the progression of chronic hypertension, thus supporting their potential role in alleviating the adverse health effects associated with developing obesity. PMID- 25501423 TI - Contrasting effects of ascorbate and iron on the pulmonary vascular response to hypoxia in humans. AB - Hypoxia causes an increase in pulmonary artery pressure. Gene expression controlled by the hypoxia-inducible factor (HIF) family of transcription factors plays an important role in the underlying pulmonary vascular responses. The hydroxylase enzymes that regulate HIF are highly sensitive to varying iron availability, and iron status modifies the pulmonary vascular response to hypoxia, possibly through its effects on HIF. Ascorbate (vitamin C) affects HIF hydroxylation in a similar manner to iron and may therefore have similar pulmonary effects. This study investigated the possible contribution of ascorbate availability to hypoxic pulmonary vasoconstriction in humans. Seven healthy volunteers undertook a randomized, controlled, double-blind, crossover protocol which studied the effects of high-dose intravenous ascorbic acid (total 6 g) on the pulmonary vascular response to 5 h of sustained hypoxia. Systolic pulmonary artery pressure (SPAP) was assessed during hypoxia by Doppler echocardiography. Results were compared with corresponding data from a similar study investigating the effect of intravenous iron, in which SPAP was measured in seven healthy volunteers during 8 h of sustained hypoxia. Consistent with other studies, iron supplementation profoundly inhibited hypoxic pulmonary vasoconstriction (P < 0.001). In contrast, supraphysiological supplementation of ascorbate did not affect the increase in pulmonary artery pressure induced by several hours of hypoxia (P = 0.61). We conclude that ascorbate does not interact with hypoxia and the pulmonary circulation in the same manner as iron. Whether the effects of iron are HIF-mediated remains unknown, and the extent to which ascorbate contributes to HIF hydroxylation in vivo is also unclear. PMID- 25501424 TI - Deficient recovery response and adaptive feedback potential in dynamic gait stability in unilateral peripheral vestibular disorder patients. AB - Unilateral peripheral vestibular disorder (UPVD) causes deficient locomotor responses to novel environments due to a lack of accurate vestibular sensory information, increasing fall risk. This study aimed to examine recovery response (stability recovery actions) and adaptive feedback potential in dynamic stability of UPVD-patients and healthy control subjects during perturbed walking. 17 UPVD patients (>6 months since onset) and 17 matched healthy control participants walked on a treadmill and were subjected to eight unexpected perturbations during the swing phase of the right leg. For each perturbation, the margin of stability (MS; state of body's centre of mass in relation to the base of support), was determined at touchdown of the perturbed leg and during the following six recovery steps. The first perturbation caused a reduced MS at touchdown for the perturbed leg compared to baseline, indicating an unstable position, with controls requiring five recovery steps to return to MS baseline and UPVD-patients not returning to baseline level within the analyzed six recovery steps. By the eighth perturbation, control subjects needed two steps, and UPVD-patients required three recovery steps, both thereby improving their recovery response with practice. However, MS at touchdown of the perturbed leg increased only for the controls after repeated perturbations, indicating adaptive feedback-driven locomotor improvements for the controls, but not for the UPVD-patients. We concluded that UPVD-patients have a diminished ability to control dynamic gait stability during unexpected perturbations, increasing their fall risk, and that vestibular dysfunction may inhibit the neuromotor system adapting the reactive motor response to perturbations. PMID- 25501425 TI - Influence of different control strategies on muscle activation patterns in trunk muscles. AB - Adequate training of the trunk muscles is essential to prevent low back pain. Although sit-ups are simple to perform, the perceived high effort is the reason why training the abdominal muscles is seldom continued over a longer period of time. It is well known that the abdominal muscles are inferior to the back muscles in terms of force, but this cannot explain the extreme difference in perceived effort between trunk flexion and extension tasks. Therefore, this study was aimed at the identification of control strategy influences on the muscular stress level. Thirty-nine subjects were investigated. The performed tasks were restricted to the sagittal plane and were implemented with simulated and realized tilt angles. Subjects were investigated in an upright position with their lower bodies fixed and their upper bodies free. Posture-controlled tasks involved graded forward and backward tilting, while force-controlled tasks involved the application of force based on a virtual tilt angle. The Surface EMG (SEMG) was taken from five trunk muscles on both sides. Control strategies seemed to have no systematic influence on the SEMG amplitudes of the back muscles. In contrast, the abdominal muscles exhibited significantly higher stress levels under posture controlled conditions without relevantly increasing antagonistic co-activation of back muscles. The abdominal muscles' relative differences ranged from an average of 20% for the external oblique abdominal muscle to approximately 40% for the rectus abdominal muscle. The perceived high effort expended during sit-ups can now be explained by the posture-controlled contractions that are required. PMID- 25501426 TI - Insufficient insulin administration to diabetic rats increases substrate utilization and maintains lactate production in the kidney. AB - Good glycemic control is crucial to prevent the onset and progression of late diabetic complications, but insulin treatment often fails to achieve normalization of glycemic control to the level seen in healthy controls. In fact, recent experimental studies indicate that insufficient treatment with insulin, resulting in poor glycemic control, has an additional effect on progression of late diabetic complications, than poor glycemic control on its own. We therefore compared renal metabolic alterations during conditions of poor glycemic control with and without suboptimal insulin administration, which did not restore glycemic control, to streptozotocin (STZ)-diabetic rats using noninvasive hyperpolarized (13)C-pyruvate magnetic resonance imaging (MRI) and blood oxygenation level-dependent (BOLD) (1)H-MRI to determine renal metabolic flux and oxygen availability, respectively. Suboptimal insulin administration increased pyruvate utilization and metabolic flux via both anaerobic and aerobic pathways in diabetic rats even though insulin did not affect kidney oxygen availability, HbA1c, or oxidative stress. These results imply direct effects of insulin in the regulation of cellular substrate utilization and metabolic fluxes during conditions of poor glycemic control. The study demonstrates that poor glycemic control in combination with suboptimal insulin administration accelerates metabolic alterations by increasing both anaerobic and aerobic metabolism resulting in increased utilization of energy substrates. The results demonstrate the importance of tight glycemic control in insulinopenic diabetes, and that insulin, when administered insufficiently, adds an additional burden on top of poor glycemic control. PMID- 25501427 TI - Serum uric acid level, blood pressure, and vascular angiotensin II responsiveness in healthy men and women. AB - Uric acid is associated with hypertension and increased renin-angiotensin system activity, although this relationship diminishes after chronic exposure to high levels. Uric acid is more strongly associated with poor outcomes in women compared to men, although whether this is due to a sex-specific uric acid mediated pathophysiology or reflects sex differences in baseline uric acid levels remains unknown. We examined the association between uric acid and vascular measures at baseline and in response to angiotensin-II challenge in young healthy humans. Fifty-two subjects (17 men, 35 premenopausal women) were studied in high salt balance. Serum uric acid levels were significantly higher in men compared to women (328 +/- 14 MUmol/L vs. 248 +/- 10 MUmol/L, P < 0.001), although all values were within normal sex-specific range. Men demonstrated no association between uric acid and blood pressure, either at baseline or in response to angiotensin II. In stark contrast, a significant association was observed between uric acid and blood pressure at baseline (systolic blood pressure, P = 0.005; diastolic blood pressure, P = 0.02) and in response to angiotensin-II (systolic blood pressure, P = 0.035; diastolic blood pressure, P = 0.056) in women. However, this sex difference lost significance after adjustment for baseline uric acid. When all subjects were stratified according to high (>300 MUmol/L) or low (<=300 MUmol/L) uric acid levels, only the low uric acid group showed a positive association between uric acid and measures of vascular tone at baseline and in response to angiotensin-II. Differences in uric acid-mediated outcomes between men and women likely reflect differences in exposure to increased uric acid levels, rather than a sex-specific uric acid-mediated pathophysiology. PMID- 25501428 TI - Rates of carbon monoxide elimination in males and females. AB - The purpose of this study was to verify the previously reported shorter half-time of elimination (t1/2) of carbon monoxide (CO) in females compared to males. Seventeen healthy subjects (nine men) completed three sessions each, on separate days. For each session, subjects were exposed to CO to raise the carboxyhemoglobin percentage (COHb) to ~10%; then breathed in random order, either (a) 100% O2 at poikilocapnia (no CO2 added), or (b) hyperoxia while maintaining normocapnia using sequential gas delivery, or (c) voluntary hyperpnea at~4x the resting minute ventilation. We measured minute ventilation, hemoglobin concentration [Hb] and COHb at 5 min intervals. The half-time of reduction of COHb (t1/2) was calculated from serial blood samples. The total hemoglobin mass (HbTOT) was calculated from [Hb] and estimated blood volume from a nomogram based on gender, height, and weight. The t1/2 in the females was consistently shorter than in males in all protocols. This relationship was sustained even after controlling for alveolar ventilation (P < 0.05), with the largest differences in t1/2 between the genders occurring at low alveolar ventilation rates. However, when t1/2 was further normalized for HbTOT, there was no significant difference in t1/2 between genders at alveolar ventilation rates between 4 and 40 L/min (P = 0.24). We conclude that alveolar ventilation and HbTOT are sufficient to account for a major difference in CO clearance between genders under resting (nonexercising) conditions. PMID- 25501429 TI - Ovalbumin sensitization of guinea pig at birth prevents the ontogenetic decrease in airway smooth muscle responsiveness. AB - Airway smooth muscle (ASM) displays a hyperresponsive phenotype at young age and becomes less responsive in adulthood. We hypothesized that allergic sensitization, which causes ASM hyperresponsiveness and typically occurs early in life, prevents the ontogenetic loss of the ASM hyperresponsive phenotype. We therefore studied whether neonatal allergic sensitization, not followed by later allergen challenges, alters the ontogenesis of ASM properties. We neonatally sensitized guinea pigs to ovalbumin and studied them at 1 week, 3 weeks, and 3 months (adult). A Schultz-Dale response in isolated tracheal rings confirmed sensitization. The occurrence of inflammation was evaluated in the blood and in the submucosa of large airways. We assessed ASM function in tracheal strips as ability to produce force and shortening. ASM content of vimentin was also studied. A Schultz-Dale response was observed in all 3-week or older sensitized animals. A mild inflammatory process was characterized by eosinophilia in the blood and in the airway submucosa. Early life sensitization had no effect on ASM force generation, but prevented the ontogenetic decline of shortening velocity and the increase in resistance to shortening. Vimentin increased with age in control but not in sensitized animals. Allergic sensitization at birth without subsequent allergen exposures is sufficient to prevent normal ASM ontogenesis, inducing persistence to adulthood of an ASM hyperresponsive phenotype. PMID- 25501430 TI - Effects of chronic lithium administration on renal acid excretion in humans and rats. AB - Lithium therapy's most common side effects affecting the kidney are nephrogenic diabetes insipidus (NDI) and chronic kidney disease. Lithium may also induce a distal renal tubular acidosis. This study investigated the effect of chronic lithium exposure on renal acid-base homeostasis, with emphasis on ammonia and citrate excretion. We compared 11 individuals on long-term lithium therapy with six healthy individuals. Under basal conditions, lithium-treated individuals excreted significantly more urinary ammonia than did control subjects. Following an acute acid load, urinary ammonia excretion increased approximately twofold above basal rates in both lithium-treated and control humans. There were no significant differences between lithium-treated and control subjects in urinary pH or urinary citrate excretion. To elucidate possible mechanisms, rats were randomized to diets containing lithium or regular diet for 6 months. Similar to humans, basal ammonia excretion was significantly higher in lithium-treated rats; in addition, urinary citrate excretion was also significantly greater. There were no differences in urinary pH. Expression of the critical ammonia transporter, Rhesus C Glycoprotein (Rhcg), was substantially greater in lithium-treated rats than in control rats. We conclude that chronic lithium exposure increases renal ammonia excretion through mechanisms independent of urinary pH and likely to involve increased collecting duct ammonia secretion via the ammonia transporter, Rhcg. PMID- 25501431 TI - Motor cortical function and the precision grip. AB - While task-dependent changes in motor cortical outputs have been previously reported, the issue of whether such changes are specific for complex hand tasks remains unresolved. The aim of the present study was to determine whether cortical inhibitory tone and cortical output were greater during precision grip and power grip. Motor cortex excitability was undertaken by using the transcranial magnetic stimulation threshold tracking technique in 15 healthy subjects. The motor-evoked potential (MEP) responses were recorded over the abductor pollicis brevis (APB), with the hand in the following positions: (1) rest, (2) precision grip and (3) power grip. The MEP amplitude (MEP amplitude REST 23.6 +/- 3.3%; MEP amplitude PRECISION GRIP 35.2 +/- 5.6%; MEP amplitude POWER GRIP 19.6 +/- 3.4%, F = 2.4, P < 0.001) and stimulus-response gradient (SLOPEREST 0.06 +/- 0.01; SLOPEPRCISION GRIP 0.15 +/- 0.04; SLOPE POWER GRIP 0.07 +/- 0.01, P < 0.05) were significantly increased during precision grip. Short interval intracortical inhibition (SICI) was significantly reduced during the precision grip (SICI REST 15.0 +/- 2.3%; SICI PRECISION GRIP 9.7 +/- 1.5%, SICI POWER GRIP 15.9 +/- 2.7%, F = 2.6, P < 0.05). The present study suggests that changes in motor cortex excitability are specific for precision grip, with functional coupling of descending corticospinal pathways controlling thumb and finger movements potentially forming the basis of these cortical changes. PMID- 25501432 TI - FTO knockdown in rat ventromedial hypothalamus does not affect energy balance. AB - Single nucleotide polymorphisms (SNPs) clustered in the first intron of the fat mass and obesity-associated (FTO) gene has been associated with obesity. FTO expression is ubiquitous, with particularly high levels in the hypothalamic area of the brain. To investigate the region-specific role of FTO, AAV technology was applied to knockdown FTO in the ventromedial hypothalamus (VMH). No effect of FTO knockdown was observed on bodyweight or parameters of energy balance. Animals were exposed twice to an overnight fast, followed by a high-fat high-sucrose (HFHS) diet for 1 week. FTO knockdown did not result in a different response to the diets. A region-specific role for FTO in the VMH in the regulation of energy balance could not be found. PMID- 25501433 TI - Increased postexercise insulin sensitivity is accompanied by increased AS160 phosphorylation in slow-twitch soleus muscle. AB - A single bout of exercise can enhance insulin-stimulated glucose uptake in both fast-twitch (type II) and slow-twitch (type I) skeletal muscle for several hours postexercise. Akt substrate of 160 kDa (AS160) is most distal insulin signaling proteins that have been proposed to contribute to the postexercise enhancement of insulin action in fast-twitch muscle. In this study, we examined whether the postexercise increase in insulin action of glucose uptake in slow-twitch muscle is accompanied by increased phosphorylation of AS160 and its paralog TBC1D1. Male Wistar rats (~1-month-old) were exercised on a treadmill for 180 min (9 m/min). Insulin (50 MUU/mL)-stimulated glucose uptake was increased at 2 h after cessation of exercise in soleus muscle composed of predominantly slow-twitch fibers. This postexercise increase in insulin action of glucose uptake was accompanied by increased phosphorylation of AS160 (detected by phospho-Thr642 and phospho-Ser588 antibody). On the other hand, prior exercise did not increase phosphorylation of TBC1D1 (detected by phospho-Thr590) at 2 h postexercise. These results suggest the possibility that an enhancement in AS160 phosphorylation but not TBC1D1 phosphorylation is involved with increased postexercise insulin action of glucose uptake in slow-twitch muscle. PMID- 25501434 TI - Thyroid hormone does not induce maturation of embryonic chicken cardiomyocytes in vitro. AB - Fetal cardiac growth in mammalian models occurs primarily by cell proliferation (hyperplasia). However, most cardiomyocytes lose the ability to proliferate close to term and heart growth continues by increasing cell size (hypertrophy). In mammals, the thyroid hormone triiodothyronine (T3) is an important driver of this process. Chicken cardiomyocytes, however, keep their proliferating ability long after hatching but little information is available on the mechanisms controlling cell growth and myocyte maturation in the chicken heart. Our aim was to study the role of T3 on proliferation and differentiation of embryonic chicken cardiomyocytes (ECCM), enzymatically isolated from 19-day-old embryos and to compare the effects to those of insulin-like growth factor-1 (IGF-1) and phenylephrine (PE). Hyperplasia was measured using a proliferation assay (MTS) and hypertrophy/multinucleation was analyzed morphologically by phalloidin staining of F-actin and nuclear staining with DAPI. We show that IGF-1 induces a significant increase in ECCM proliferation (30%) which is absent with T3 and PE. PE induced both hypertrophy (61%) and multinucleation (41%) but IGF-1 or T3 did not. In conclusion, we show that T3 does not induce maturation or proliferation of cardiomyocytes, while IGF-1 induces cardiomyocyte proliferation and PE induces maturation of cardiomyocytes. PMID- 25501435 TI - Partial weight support differentially affects corticomotor excitability across muscles of the upper limb. AB - Partial weight support may hold promise as a therapeutic adjuvant during rehabilitation after stroke by providing a permissive environment for reducing the expression of abnormal muscle synergies that cause upper limb impairment. We explored the neurophysiological effects of upper limb weight support in 13 healthy young adults by measuring motor-evoked potentials (MEPs) from transcranial magnetic stimulation (TMS) of primary motor cortex and electromyography from anterior deltoid (AD), biceps brachii (BB), extensor carpi radialis (ECR), and first dorsal interosseous (FDI). Five levels of weight support, varying from none to full, were provided to the arm using a commercial device (Saebo Mobile Arm Support). For each level of support, stimulus-response (SR) curves were derived from MEPs across a range of TMS intensities. Weight support affected background EMG activity in each of the four muscles examined (P < 0.0001 for each muscle). Tonic background activity was primarily reduced in the AD. Weight support had a differential effect on the size of MEPs across muscles. After curve fitting, the SR plateau for ECR increased at the lowest support level (P = 0.004). For FDI, the SR plateau increased at the highest support level (P = 0.0003). These results indicate that weight support of the proximal upper limb modulates corticomotor excitability across the forearm and hand. The findings support a model of integrated control of the upper limb and may inform the use of weight support in clinical settings. PMID- 25501436 TI - alpha-Conotoxin M1 (CTx) blocks alphadelta binding sites of adult nicotinic receptors while ACh binding at alphaepsilon sites elicits only small and short quantal synaptic currents. AB - In 'embryonic' nicotinic receptors, low CTx concentrations are known to block only the alphadelta binding site, whereas binding of ACh at the alphagamma-site elicits short single channel openings and short bursts. In adult muscles the alphagamma- is replaced by the alphaepsilon-site. Quantal EPSCs (qEPSCs) were elicited in adult muscles by depolarization pulses and recorded through a perfused macropatch electrode. One to 200 nmol L(-1) CTx reduced amplitudes and decay time constants of qEPSCs, but increased their rise times. CTx block at the alphadelta binding sites was incomplete: The qEPSCs still contained long bursts from not yet blocked receptors, whereas their average decay time constants were reduced by a short burst component generated by ACh binding to the alphaepsilon site. Two nanomolar CTx applied for 3 h reduced the amplitudes of qEPSCs to less than half with a constant slope. The equilibrium concentration of the block is below 1 nmol L(-1) and lower than that of embryonic receptors. CTx-block increased in proportion to CTx concentrations (average rate 2 *: 10(4) s(-1).mol( 1) L). Thus, the reactions of 'embryonic' and of adult nicotinic receptors to block by CTx are qualitatively the same. - The study of the effects of higher CTx concentrations or of longer periods of application of CTx was limited by presynaptic effects of CTx. Even low CTx concentrations severely reduced the release of quanta by activating presynaptic M2 receptors at a maximal rate of 6 *: 10(5) s(-1).mol(-1) L. When this dominant inhibition was prevented by blocking the M2 receptors with methoctramine, activation of M1 receptors was unmasked and facilitated release. PMID- 25501437 TI - Allopregnanolone preferentially induces energy-rich food intake in male Wistar rats. AB - Obesity is an increasing problem and identification of the driving forces for overeating of energy-rich food is important. Previous studies show that the stress and sex steroid allopregnanolone has a hyperphagic effect on both bland food and palatable food. If allopregnanolone induces a preference for more palatable or for more energy-rich food is not known. The aim of this study was to elucidate the influence of allopregnanolone on food preference. Male Wistar rats were subjected to two different food preference tests: a choice between standard chow and cookies (which have a higher energy content and also are more palatable than chow), and a choice between a low caloric sucrose solution and standard chow (which has a higher energy content and is less palatable than sucrose). Food intake was measured for 1 h after acute subcutaneous injections of allopregnanolone. In the choice between cookies and chow allopregnanolone significantly increased only the intake of cookies. When the standard chow was the item present with the highest caloric load, the chow intake was increased and allopregnanolone had no effect on intake of the 10% sucrose solution. The increased energy intakes induced by the high allopregnanolone dose compared to vehicle were very similar in the two tests, 120% increase for cookies and 150% increase for chow. It appears that in allopregnanolone-induced hyperphagia, rats choose the food with the highest energy content regardless of its palatability. PMID- 25501438 TI - Conditioning effect of transcranial magnetic stimulation evoking motor-evoked potential on V-wave response. AB - The aim of this study was to examine the collision responsible for the volitional V-wave evoked by supramaximal electrical stimulation of the motor nerve during voluntary contraction. V-wave was conditioned by transcranial magnetic stimulation (TMS) over the motor cortex at several inter-stimuli intervals (ISI) during weak voluntary plantar flexions (n = 10) and at rest for flexor carpi radialis muscle (FCR; n = 6). Conditioning stimulations were induced by TMS with intensity eliciting maximal motor-evoked potential (MEPmax). ISIs used were ranging from -20 to +20 msec depending on muscles tested. The results showed that, for triceps surae muscles, conditioning TMS increased the V-wave amplitude (~ +250%) and the associated mechanical response (~ +30%) during weak voluntary plantar flexion (10% of the maximal voluntary contraction -MVC) for ISIs ranging from +6 to +18 msec. Similar effect was observed at rest for the FCR with ISI ranging from +6 to +12 msec. When the level of force was increased from 10 to 50% MVC or the conditioning TMS intensity was reduced to elicit responses of 50% of MEPmax, a significant decrease in the conditioned V-wave amplitude was observed for the triceps surae muscles, linearly correlated to the changes in MEP amplitude. The slope of this correlation, as well as the electro-mechanical efficiency, was closed to the identity line, indicating that V-wave impact at muscle level seems to be similar to the impact of cortical stimulation. All these results suggest that change in V-wave amplitude is a great index to reflect changes in cortical neural drive addressed to spinal motoneurons. PMID- 25501439 TI - An Excel-based implementation of the spectral method of action potential alternans analysis. AB - Action potential (AP) alternans has been well established as a mechanism of arrhythmogenesis and sudden cardiac death. Proper interpretation of AP alternans requires a robust method of alternans quantification. Traditional methods of alternans analysis neglect higher order periodicities that may have greater pro arrhythmic potential than classical 2:1 alternans. The spectral method of alternans analysis, already widely used in the related study of microvolt T-wave alternans, has also been used to study AP alternans. Software to meet the specific needs of AP alternans analysis is not currently available in the public domain. An AP analysis tool is implemented here, written in Visual Basic for Applications and using Microsoft Excel as a shell. This performs a sophisticated analysis of alternans behavior allowing reliable distinction of alternans from random fluctuations, quantification of alternans magnitude, and identification of which phases of the AP are most affected. In addition, the spectral method has been adapted to allow detection and quantification of higher order regular oscillations. Analysis of action potential morphology is also performed. A simple user interface enables easy import, analysis, and export of collated results. PMID- 25501440 TI - Pyrrolidine dithiocarbamate reduces the progression of total kidney volume and cyst enlargement in experimental polycystic kidney disease. AB - Heterocyclic dithiocarbamates have anti-inflammatory and anti-proliferative effects in rodent models of chronic kidney disease. In this study, we tested the hypothesis that pyrrolidine dithiocarbamate (PDTC) reduces the progression of polycystic kidney disease (PKD). Male Lewis polycystic kidney (LPK) rats (an ortholog of Nek8/NPHP9) received intraperitoneal injections of either saline vehicle or PDTC (40 mg/kg once or twice daily) from postnatal weeks 4 until 11. By serial magnetic resonance imaging at weeks 5 and 10, the relative within-rat increase in total kidney volume and cyst volume were 1.3-fold (P = 0.01) and 1.4 fold (P < 0.01) greater, respectively, in LPK + Vehicle compared to the LPK + PDTC(40 mg/kg twice daily) group. At week 11 in LPK rats, PDTC attenuated the increase in kidney weight to body weight ratio by 25% (P < 0.01) and proteinuria by 66% (P < 0.05 vs. LPK + Vehicle) but did not improve renal dysfunction. By quantitative whole-slide image analysis, PDTC did not alter interstitial CD68+ cell accumulation, interstitial fibrosis, or renal cell proliferation in LPK rats at week 11. The phosphorylated form of the nuclear factor (NF)-kappaB subunit, p105, was increased in cystic epithelial cells of LPK rats, but was not altered by PDTC. Moreover, PDTC did not significantly alter nuclear expression of the p50 subunit or NF-kappaB (p65)-DNA binding. Kidney enlargement in LPK rats was resistant to chronic treatment with a proteasome inhibitor, bortezomib. In conclusion, PDTC reduced renal cystic enlargement and proteinuria but lacked anti inflammatory effects in LPK rats. PMID- 25501442 TI - Origin of surface trap states in CdS quantum dots: relationship between size dependent photoluminescence and sulfur vacancy trap states. AB - Monodisperse cadmium sulphide (CdS) quantum dots (QDs) with a tunable size from 1.4 to 4.3 nm were synthesized by a non-injection method, and their surface states were characterized by photoluminescence spectroscopy and X-ray Photoelectron Spectroscopy (XPS). The steady state photoluminescence study identified that the proportion of the trap state emission increased with the QD size decrease, while from the photoluminescence decay study, it appeared that the trap state emission results from the emission via a surface deep trap state. The XPS measurements revealed the existence of surface Cd with sulfur vacancy sites which act as electron trap sites, and the population of these sites increases with the QD size decrease. These results are consistent to conclude that the trap state emission mainly originates from the surface deep trapped electrons at the surface Cd with sulfur vacancy sites. PMID- 25501441 TI - Effects of diaphragmatic contraction on lower limb venous return and central hemodynamic parameters contrasting healthy subjects versus heart failure patients at rest and during exercise. AB - The main objective was to assess the effects of abdominal breathing (AB) versus subject's own breathing on femoral venous blood flow (Qfv) and their repercussions on central hemodynamics at rest and during exercise contrasting healthy subjects versus heart failure (HF) patients. We measured esophageal and gastric pressure (PGA), Qfv and parameters of central hemodynamics in eight healthy subjects and nine HF patients, under four conditions: subject's own breathing and AB ( ?: PGA >= 6 cmH2O) at rest and during knee extension exercises (15% of 1 repetition maximum) until exhaustion. Qfv and parameters of central hemodynamics [stroke volume (SV), cardiac output (CO)] were measured using Doppler ultrasound and impedance cardiography, respectively. At rest, healthy subjects Qfv, SV, and CO were higher during AB than subject's breathing (0.11 +/- 0.02 vs. 0.06 +/- 0.00 L.min(-1), 58.7 +/- 3.4 vs. 50.1 +/- 4.1 mL and 4.4 +/- 0.2 vs. 3.8 +/- 0.1 L.min(-1), respectively, P <= 0.05). ?SV correlated with ?PGA during AB (r = 0.89, P <= 0.05). This same pattern of findings induced by AB was observed during exercise (SV: 71.1 +/- 4.1 vs. 65.5 +/- 4.1 mL and CO: 6.3 +/- 0.4 vs. 5.2 +/- 0.4 L.min(-1); P <= 0.05); however, Qfv did not reach statistical significance. The HF group tended to increase their Qfv during AB (0.09 +/- 0.01 vs. 0.07 +/- 0.03 L.min(-1), P = 0.09). On the other hand, unlike the healthy subjects, AB did not improve SV or CO neither at rest nor during exercise (P > 0.05). In healthy subjects, abdominal pump modulated venous return improved SV and CO at rest and during exercise. In HF patients, with elevated right atrial and vena caval system pressures, these findings were not observed. PMID- 25501443 TI - Dynamic structural transformations of coordination supramolecular systems upon exogenous stimulation. AB - Reactions in the solid state, especially single-crystal-to-single-crystal (SC-SC) transformations, provide an appealing pathway to obtain target crystalline materials with modified properties via a solvent-free green chemistry approach. This feature article focuses on the progress to date in the context of coordination supramolecular systems (CSSs), especially coordination polymers (CPs) or metal-organic frameworks (MOFs), which show interesting dynamic natures upon exposure to various exogenous stimuli, including concentration, temperature, light and mechanical force, as well as their synergic effect. In essence, dynamic CSSs normally possess crucial crystalline-reactive characteristics: (i) metal ions or clusters with unstable or metastable electronic configurations and coordination geometries; (ii) organic ligands bearing physicochemically active functional groups for subsequent reactions; (iii) polymeric networks of high flexibility for structural bending, rotation, swelling, or shrinking; (iv) guest moieties to be freely exchanged or eliminated by varying the environmental conditions. The significant changes in catalytic, sorption, magnetic, or luminescent properties accompanied by the structural transformations will also be discussed, which reveal the proof-of-concept thereof in designing new functional crystalline materials. PMID- 25501444 TI - Benefit of a contralateral routing of signal device for unilateral cochlear implant users. AB - OBJECTIVE: To investigate objective and subjective effects of an adjunctive contralateral routing of signal (CROS) device at the untreated ear in patients with a unilateral cochlear implant (CI). DESIGN: Prospective study of 10 adult experienced unilateral CI users with bilateral severe-to-profound hearing loss. Speech in noise reception (SNR) and sound localization were measured with and without the additional CROS device. SNR was measured by applying speech signals at the untreated/CROS side while noise signals came from the front (S90N0). For S0N90, signal sources were switched. Sound localization was measured in a 12 loudspeaker full circle setup. To evaluate the subjective benefit, patients tried the device for 2 weeks at home, then filled out the abbreviated Speech, Spatial and Qualities of Hearing Scale as well as the Bern benefit in single-sided deafness questionnaires. RESULTS: In the setting S90N0, all patients showed a highly significant SNR improvement when wearing the additional CROS device (mean 6.4 dB, p < 0.001). In the unfavorable setting S0N90, only a minor deterioration of speech understanding was noted (mean -0.66 dB, p = 0.54). Sound localization did not improve substantially with CROS. In the two questionnaires, 12 of 14 items showed an improvement in mean values, but none of them was statistically significant. CONCLUSION: Patients with unilateral CI benefit from a contralateral CROS device, particularly in a noisy environment, when speech comes from the CROS ear side. PMID- 25501445 TI - Patterns of childhood abuse and neglect as predictors of treatment outcome in inpatient psychotherapy: a typological approach. AB - BACKGROUND: Childhood maltreatment is associated with the development and maintenance of mental disorders. The purpose of this naturalistic study was (a) to identify different patterns of childhood maltreatment, (b) to examine how these patterns are linked to the severity of mental disorders and (c) whether they are predictive of treatment outcome. METHODS: 742 adult patients of a university hospital for psychotherapy and psychosomatics were assessed at intake and discharge by standardized questionnaires assessing depression (Beck Depression Inventory, BDI) and general mental distress (Symptom Check List-90-R, SCL-90-R). Traumatic childhood experience (using the Childhood Trauma Questionnaire, CTQ) and ICD-10 diagnoses were assessed at intake. RESULTS: The patients could be allocated to three different patterns of early childhood trauma experience: mild traumatization, multiple traumatization without sexual abuse and multiple traumatization with sexual abuse. The three patterns showed highly significant differences in BDI, General Severity Index (GSI) and in the number of comorbidity at intake. For both BDI and GSI a general decrease in depression and general mental distress from intake to discharge could be shown. The three patterns differed in BDI and GSI at intake and discharge, indicating lowest values for mild traumatization and highest values for multiple traumatization with sexual abuse. Patients with multiple traumatization with sexual abuse showed the least favourable outcome. CONCLUSION: The results provide evidence that the severity of childhood traumatization is linked to the severity of mental disorders and also to the treatment outcome in inpatient psychotherapy. In the study, three different patterns of childhood traumatization (mild traumatization, multiple traumatization without sexual abuse, multiple traumatization with sexual abuse) showed differences in the severity of mental disorder and in the course of treatment within the same therapy setting. PMID- 25501446 TI - Copper-catalyzed O-arylation of N-protected 1,2-aminoalcohols using functionalized trivalent organobismuth reagents. AB - The O-arylation of 1,2-aminoalcohols using functionalized triarylbismuth reagents is reported. The reaction can be performed using substoichiometric amounts of copper acetate and operates under mild conditions. Good functional group tolerance is observed, giving access to a range of beta-aryloxyamines. The effect provided by the amino group in the arylation reaction is investigated. PMID- 25501447 TI - Y-stent assisted coiling of bifurcation aneurysms with Enterprise stent: long term follow-up. AB - BACKGROUND: Y-stent assisted coiling has been proposed for the treatment of wide neck bifurcation aneurysms, but there are many technical variations. We report our single-center experience of Y-stent assisted coiling of bifurcation aneurysms with the closed cell Enterprise stent in order to evaluate the safety and long term results of this technique. The literature on Y-stenting and its hemodynamic effects are reviewed. METHODS: Fifty-two consecutive patients with wide-neck bifurcation aneurysms underwent Y-stent assisted coiling with two Enterprise stents. The procedure was completed in 48 cases (92.3%) and technical failure occurred in 4 cases (7.3%). Cases performed with other stents were excluded. All procedures were performed under double antiplatelet therapy. Periodic clinical and neuroradiological follow-up was performed. RESULTS: Mean neuroradiological follow-up time was 26 months. Complete immediate occlusion was obtained in 87.5% of patients. Two remnants had regrown at follow-up and were recoiled, achieving complete occlusion. The late neuroradiological occlusion rate was: complete occlusion 93.6%, neck remnant 4.3%, sac remnant 2.1%. No in-stent stenosis was detected at follow-up. Among the 48 procedures, two complications occurred (4.2%). Mortality was 2.1%. No delayed ischemic stroke occurred. CONCLUSIONS: Y stent assisted coiling has a high immediate occlusion rate and very good long term stability. The procedure is relatively safe, although the complication and mortality rates are not negligible. Two Enterprise stents can be safely used for Y-stenting and, indeed, offer the advantage of easier catheterization, delivery and deployment into distal and tortuous vessels than open cell stents. PMID- 25501449 TI - Diferrocenyl tosyl hydrazone with an ultrastrong NHFe hydrogen bond as double click switch. AB - The ultrastrong and short intramolecular NHFe hydrogen bond in diferrocenyl hydrazone raises the barrier for intramolecular electron transfer in its mixed valent cation and is only disrupted by double oxidation to . PMID- 25501448 TI - Stroke recurrence rates among patients with symptomatic intracranial vertebrobasilar stenoses: systematic review and meta-analysis. AB - BACKGROUND: A recent randomized trial of patients with primarily anterior circulation intracranial artery stenosis showed that intensive medical therapy was superior to intracranial stenting in preventing recurrent stroke. The rate of stroke recurrence or death in symptomatic intracranial vertebrobasilar stenosis with medical therapy alone may be especially high, and rates compared with endovascular therapy need further study. METHODS: We conducted a systematic review and meta-analysis of studies reporting the rates of stroke recurrence or death (the primary outcome) in symptomatic intracranial vertebrobasilar stenosis with medical or endovascular treatment over a minimum follow-up period of 6 months. We included all studies in any language indexed in MEDLINE or EMBASE, supplemented by bibliography searches and by contacting the authors. The secondary endpoints were stroke recurrence, and basilar artery and vertebral artery stroke recurrence rates. RESULTS: 23 studies (592 medical treatment patients and 480 endovascular treatment patients) were included. The risk of combined stroke recurrence or death was 14.8 per 100 person-years (95% CI 9.5 to 20.1) in the medical group compared with 8.9 per 100 person-years (95% CI 6.9 to 11.0) in the endovascular group. The incidence rate ratio was 1.3 (95% CI 1.0 to 1.7). The stroke recurrence rate was 9.6 per 100 person-years (95% CI 5.1 to 14.1) in the medical group compared with 7.2 per 100 person-years (95% CI 5.5 to 9.0) in the endovascular group. CONCLUSIONS: Our results showed that the risk of stroke recurrence or death or the risk of stroke recurrence alone was comparable between the medical and endovascular therapy groups. A small preventive effect of endovascular therapy may exist, particularly if the 30 day postprocedural risk is reduced. PMID- 25501450 TI - [The role of the neuropsychologist in neurology services: a descriptive study of the users of the specialised neurological assessment unit of the Hospital Complex of Navarra during its first year in service]. AB - INTRODUCTION. A large number of neurological diseases course with impairment of higher cognitive functions, their evaluation being important for diagnostic, prognostic and therapeutic purposes. The main purpose of neuropsychological assessment is to identify behavioral, emotional and cognitive consequences of brain dysfunction. The neuropsychologist's figure was included in Navarra's Hospital Neurology Service in February 2013 through a specialized practice in neuropsychological assessment. AIM. To describe the sociodemographic and clinical profile of all patients referred to the same from March 2013 to March 2014. PATIENTS AND METHODS. A total of 511 people have been treated in this practice. RESULTS. 73.2% are more than 55 years old and the most frequent reason of referral is to characterize the neuropsychological profile to detect and discriminate mild cognitive impairment and dementia, as well as the type of dementia. In younger adults (< 55 years old) the most prevalent cognitive deficit is memory impairment. CONCLUSIONS. The expert neuropsychologist performs thorough neuropsychological evaluations from an interpretative approach. The results of this study suggest the importance of this figures role in neurology services and point out future aims. PMID- 25501451 TI - Multiple sclerosis and motherhood choice: an observational study in Portuguese women patients. AB - INTRODUCTION. Multiple sclerosis (MS) is a disabling disease occurring mainly in women of childbearing age. MS may interfere with family planning and motherhood decision. AIM. To study the influence of MS diagnosis and course of the disease on motherhood decision. PATIENTS AND METHODS. The cohort of 35 to 45-year-old female patients diagnosed with MS for at least ten years was selected from six Portuguese MS centers. A structured questionnaire was applied to all patients in consecutive consultation days. Clinical records were reviewed to characterize and collect information about the disease and pregnancies. RESULTS. One hundred women were included; mean age at MS diagnosis was 26.3 +/- 5.0 years; 90% of the participants presented with a relapsing-remitting MS; 57% had no pregnancies after the diagnosis. MS type and number of relapses were not significantly different between women with or without pregnancies after the diagnosis (p = 0.39 and p = 0.50, respectively). Seventy-seven percent of the patients did not have the intended number of pregnancies. Main reasons given were fear of future disability and the possibility of having relapses. Forty-three women considered that pregnancy might worsen MS. CONCLUSION. In our population, motherhood choice was unrelated to the MS type and the number of relapses. However, a relevant number of women had fewer pregnancies than those intended before MS diagnosis and believed that pregnancy could worsen the disease. An effort to better inform the patients should be made to minimize the impact of MS diagnosis on motherhood decision. PMID- 25501452 TI - [Subjective memory complaints in young adults: the influence of the emotional state]. AB - INTRODUCTION. Many young people today display memory complaints that are not linked to their real cognitive performance. A number of studies have sought to identify the factors involved in this problem, such as anxious-depressive symptoms, the variables of anxiety traditionally being measured as somatic or cognitive manifestations with an activation that is unspecific or not linked to any particular stimulus. AIMS. To perform an exploratory analysis to determine the role played by symptoms of depression and of various subtypes of specific and unspecific anxiety in memory complaints in young adults. PATIENTS AND METHODS. The sample used in this study was made of 193 university students, 71% of whom were females, with a mean age of 22.22 +/- 3.67 years. The variable 'Memory complaints' was measured with the Memory Failures Questionnaire, and the Brief Symptom Check List was used to measure the variables 'Depression', 'Social anxiety', 'Obsessive-compulsive anxiety', 'Agoraphobic anxiety', 'Somatisation' and 'Insomnia'. RESULTS. The variables of specific anxiety show a greater correlation with memory complaints than unspecific anxiety. Multiple regression analysis explained 34.9% of the variance of memory complaints, although the only variable that made a significant contribution was 'Social anxiety', which alone explains 34.4%. CONCLUSIONS. A distinct influence between the different types of anxiety and memory complaints has been observed. The findings obtained are a novelty in this area of knowledge by pointing to a greater relevance of the variables of specific anxiety in comparison to unspecific anxiety in explaining memory complaints and the need to take a personalised approach. PMID- 25501453 TI - [Familial presentation of microdeletion and inverted microduplication with array CGH]. AB - INTRODUCTION. Over the years the field of genetics has advanced significantly. Following the polymerase chain reaction and mass sequencing techniques, the array CGH technique (comparative genomic hybridization) has helped to improve genetic procedures. A resolution of up to 200 kb is currently being accomplished in the human genome. CASE REPORTS. We report the case of two sisters with delays in developmental milestones and a characteristic phenotype with normal results from initial studies of the karyotype and subtelomeric regions. Array-CGH was later used to detect a deletion and duplication that were different in each of the sisters, this being the result of a balanced paternal translocation. In the two cases, despite being the result of the same translocation, the genetic and phenotype expression were different. CONCLUSIONS. The precision achieved by means of array-CGH is making it possible to establish a correlation between minimum gains or losses of the genome and the clinical features. Chromosome 3 codes for genes that play a fundamental role in neurological development (contactins, neurotransmitter modulator proteins, etc.) and chromosome 10 codes for proteins involved in apoptosis and proteins regulating transcription. In the literature there have been reports of chromosome 3 deletion syndrome and monosomy 10. Likewise, there are also descriptions of rearrangements between these chromosomes in individuals from the same family. Nevertheless, we describe two cases of a family with a micro-deletion and an inverted microduplication, detected by means of array-CGH, that have not been reported to date. This technique can provide a diagnostic and prognostic approximation as regards development and offer genetic counselling. PMID- 25501454 TI - [Dementia and mild cognitive impairment in Parkinson's disease: a review]. AB - INTRODUCTION. The cognitive disorders in Parkinson's disease (PD) have traditionally been associated with the presence of dementia in later stages of the disease. Recent studies, however, consider that cognitive impairment can appear as of early stages. Knowing the cognitive profile of PD furthers our understanding of the clinical phenotype, making it easier to reach a timely diagnosis and favouring intervention on the symptoms from the initial stages. AIM. To present a review of the literature on mild cognitive impairment (MCI) and dementia associated with PD. DEVELOPMENT. Several studies report that patients with PD who have a prolonged time to progression develop dementia. Yet, there have also been reports claiming that, as of the early stages, patients can present subtle cognitive alterations known as MCI. The initial neuropsychological profile is mainly of a non-amnesic type, characterised by executive dysfunction, alterations affecting attention, operative memory deficit and faulty retrieval of information. When patients develop dementia, disorders will arise in the storage of information, in semantic fluency, and in visuospatial and visuoperceptual skills. Currently there are criteria available for diagnosing the MCI and dementia associated with PD, as well as valid reliable instruments for detecting those disorders. CONCLUSIONS. Cognitive symptoms are frequent in PD. From the initial stages of the disease onwards patients may present MCI that is mainly characterised by a fronto-subcortical cognitive profile, whereas dementia usually develops at later stages, when a pattern of posterior cortical cognitive disorder is also observed. PMID- 25501455 TI - [Functional morphological correlation in a patient with Morton's neuroma. Ultrasonography and electrophysiology]. PMID- 25501456 TI - [Levodopa-responsive dystonia: Segawa's disease. Report of a case with late onset]. PMID- 25501457 TI - [Neurological onset of Erdheim-Chester disease]. PMID- 25501458 TI - [Mummification of the cauda equina in an individual in Ancient Egypt]. PMID- 25501459 TI - [Olfactory reference syndrome and hyperhidrosis: comorbidity in one patient]. PMID- 25501460 TI - [On the measurement of anosognosia in Alzheimer's disease]. PMID- 25501461 TI - Incorporation of organic crystals into the interspace of oriented nanocrystals: morphologies and properties. AB - Oriented nanocrystals, as seen in biominerals, have both the macroscopic hierarchical morphologies and the nanoscale interspace among the unit crystals. Here we studied the incorporation effects of the specific interspace in the oriented nanocrystals on the morphologies, properties, and applications of organic crystals. Organic crystals, such as 9-vinylcarbazole (VCz), azobenzene (AB), and pyrene (PY), were introduced into the specific interspace of oriented nanocrystals from the melts. The morphologies and properties of the incorporated organic crystals were systematically studied in these model cases. The incorporation of the organic crystals provided the composites with the original oriented nanocrystals. The incorporated organic crystals formed the single crystalline structures even in the nanoscale interspace. The melts of the organic compounds were crystallized and grown in the interspace of the original materials. The incorporated organic crystals showed the specific phase transition behavior. The freezing points of the organic crystals were raised by the incorporation into the nanospace while the melting points were not changed. The hierarchical morphologies of the organic crystals were obtained after the dissolution of the original materials. The hierarchical morphologies of the original materials were replicated to the organic crystals. The incorporated organic crystal was polymerized without deformation of the hierarchical morphologies. The hierarchical polymer can be applied to the donor material for the generation of a larger amount of the charge-transfer complex with the acceptor molecule than the commercial polymer microparticles. The present work shows the potential use of the nanoscale interspace generated in the oriented nanocrystals. PMID- 25501462 TI - Role of bone scan in the assessment of polymyositis/dermatomyositis. AB - The aim of this study was to determine the significance of bone scan findings in Korean polymyositis/dermatomyositis (PM/DM) patients. The participants in this study were 26 PM/DM patients who fulfilled the proposed criteria for definite or probable PM/DM. All patients had been examined by bone scan. The results were analyzed visually and quantitatively using the uptake ratios. Correlations between the bone scan parameters of six proximal muscle groups (trapezius, deltoid, biceps, iliopsoas, quadriceps, and gluteus medius and maximus) and clinical parameters (laboratory values and manual muscle test) representing disease activities were assessed. Based on visual analyses of their bone scans, 10 of 14 (71.4 %) patients with active PM/DM had abnormal muscle uptake. Visual grading of the bone scans had a sensitivity and specificity of 74 and 90.9 %, respectively, for the assessment of muscle inflammation. Maximal proximal muscle uptake ratios, as determined on the bone scans, were significantly higher in patients with active PM/DM than in those with inactive disease (median 1.97 vs. 1.02, p = 0.046). Maximal proximal uptake ratios correlated significantly with creatine kinase (r = 0.394, p = 0.046), lactate dehydrogenase (LDH, r = 0.473, p = 0.015), aldolase (r = 0.428, p = 0.029), erythrocyte sedimentation rate (r = 0.412, p = 0.036), C-reactive protein (r = 0.454, p = 0.002), and manual muscle test results (r = -0.399, p = 0.044). Mean proximal muscle uptake ratios correlated significantly with LDH (r = 0.438, p = 0.025) and aldolase (r = 0.572, p = 0.002). Visually assessed proximal muscle uptake grades and maximal proximal muscle uptake ratios as determined by bone scan correlated significantly with the levels of known PM/DM disease activity markers. The findings of this study suggest that bone scan is a useful imaging technique for the evaluation of PM/DM patients. PMID- 25501463 TI - Health literacy in patients dealing with gout: a qualitative study. AB - The objective of this study was to explore the health literacy of patients dealing with gout and to understand perceptions that might account for non adherence to urate-lowering therapy (ULT). Semi-structured interviews involving patients with gout were conducted. The transcripts of the interviews were scored by two readers and a coding system to categorize the data was developed. Fifteen patients (14 men, mean age 63 years, mean disease duration 11 years) were interviewed; ten patients were recruited from secondary care and five from primary care. Six patients had gout tophi and 12 patients used ULT. Less than half of the patients were sufficiently aware of the pathophysiological processes that cause gout. Twelve patients indicated that treatment of gout only encompasses treatment of the acute attack. Patients were unaware of long-term treatment goals. Six patients admitted medication non-adherence at some point in time. Several reasons for non-adherence, such as healthcare professionals providing conflicting messages about medication, can be considered preventable. Half of the patients expressed that they, especially at the time of diagnosis, wanted to know more about the cause of gout, treatment goals and long-term consequences. In conclusion, the health literacy of patients dealing with gout was low in our study, especially with regard to medication. Yet, patients often recognized these knowledge gaps. Our data suggest that improving knowledge and addressing common misperceptions in training programmes, may ultimately contribute to adherence to ULT and an optimized outcome in patients with gout. This hypothesis needs to be confirmed in future research. PMID- 25501464 TI - Does mechanical stimulation really protect the architecture of trabecular bone? A simulation study. AB - Although it is beyond doubt that mechanical stimulation is crucial to maintain bone mass, its role in preserving bone architecture is much less clear. Commonly, it is assumed that mechanics helps to conserve the trabecular network since an "accidental" thinning of a trabecula due to a resorption event would result in a local increase of load, thereby activating bone deposition there. However, considering that the thin trabecula is part of a network, it is not evident that load concentration happens locally on the weakened trabecula. The aim of this work was to clarify whether mechanical load has a protective role for preserving the trabecular network during remodeling. Trabecular bone is made dynamic by a remodeling algorithm, which results in a thickening/thinning of trabeculae with high/low strain energy density. Our simulations show that larger deviations from a regular cubic lattice result in a greater loss of trabeculae. Around lost trabeculae, the remaining trabeculae are on average thinner. More generally, thin trabeculae are more likely to have thin trabeculae in their neighborhood. The plausible consideration that a thin trabecula concentrates a higher amount of strain energy within itself is therefore only true when considering a single isolated trabecula. Mechano-regulated remodeling within a network-like architecture leads to local concentrations of thin trabeculae. PMID- 25501465 TI - Evaluation of pediatric VCUG at an academic children's hospital: is the radiographic scout image necessary? AB - BACKGROUND: There is heterogeneity in how pediatric voiding cystourethrography (VCUG) is performed. Some institutions, including our own, obtain a radiographic scout image prior to contrast agent instillation. OBJECTIVE: To demonstrate that the radiographic scout image does not augment VCUG interpretation or contribute management-changing information but nonetheless carries a non-negligible effective dose. MATERIALS AND METHODS: We evaluated 181 children who underwent VCUG in 2012, with an age breakdown of less than 1 year (56 children), 1-5 years (66 children), 6-10 years (43 children) and 11-18 years (16 children), with a mean age of 4.0 years. We investigated patient demographics, clinical indication for the examination, scout image findings and estimated effective radiation dose, as well as overall exam findings and impression. RESULTS: No clinically significant or management-changing findings were present on scout images, and no radiopaque urinary tract calculi or concerning incidental finding was identified. Scout image estimated effective radiation dose averaged 0.09 mSv in children younger than 1 y, 0.09 mSv in children age 1-5, 0.13 mSv in children age 6-10 and 0.18 mSv in children age 11-18. Total fluoroscopy time per examination averaged 36.7 s (range 34.8-39.6 s for all age group averages). Evaluation of known or suspected vesicoureteral reflux (VUR) and urinary tract infection (UTI) were the most common clinical indications, stated in 40.9% and 37.0% of exams, respectively. CONCLUSION: Although the estimated effective dose is low for VCUG radiographic scout images, this step did not augment VCUG interpretation or contribute management-changing information. This step should be omitted or substituted to further reduce dose in pediatric VCUG. PMID- 25501466 TI - Cationic, luminescent cyclometalated iridium(III) complexes based on substituted 2-phenylthiazole ligands. AB - Ten cationic heteroleptic iridium(III) complexes, [Ir(emptz)2(N^N)](PF6) were prepared from a cyclometalated iridium bridged-chloride dimer involving two ethyl 4-methylphenylthiazole-5-carboxylate (emptz) ligands. One X-ray crystallographic study was undertaken where the ancillary N^N ligand was 4,7-diphenyl-1,10 phenanthroline and revealed the anticipated structure, showing a distorted octahedral coordination geometry at Ir(III). The complexes were visibly luminescent with modestly structured emission at 540-590 nm and lifetimes (60-340 ns) consistent with phosphorescence. TD-DFT calculations suggest that strong MLCT character contributes to the visible absorption characteristics, whilst the moderately structured emission profiles indicate a (3)MLCT/(3)IL admixture of states to the phosphorescence. PMID- 25501467 TI - Response to Martini and Habeck: Semiochemical dose-response curves fit by kinetic formation functions. PMID- 25501468 TI - Modelling recurrent events: a tutorial for analysis in epidemiology. AB - In many biomedical studies, the event of interest can occur more than once in a participant. These events are termed recurrent events. However, the majority of analyses focus only on time to the first event, ignoring the subsequent events. Several statistical models have been proposed for analysing multiple events. In this paper we explore and illustrate several modelling techniques for analysis of recurrent time-to-event data, including conditional models for multivariate survival data (AG, PWP-TT and PWP-GT), marginal means/rates models, frailty and multi-state models. We also provide a tutorial for analysing such type of data, with three widely used statistical software programmes. Different approaches and software are illustrated using data from a bladder cancer project and from a study on lower respiratory tract infection in children in Brazil. Finally, we make recommendations for modelling strategy selection for analysis of recurrent event data. PMID- 25501469 TI - The changing face of BECT: a citation analysis covering 1966-2009. AB - A citation analysis was completed on articles published in Bulletin of Environmental Contamination and Toxicology over the period of 1966-2009. Articles were grouped into 5 year intervals and the top 50 most-cited papers in each year interval were categorized according to research theme. Over the journal's history, articles in the toxicity research theme dominated top-cited articles published by the journal followed by articles in the environmental concentration theme and the mechanistic theme. The geographic area of submission of top-cited articles has shown large changes with time, initially being dominated by papers from North American and now dominated by papers from Asia. An examination of the citation history for the highest cited paper in each year interval indicated that the average time to achieve 90 % of total citations is 25 years. PMID- 25501470 TI - A robust estimation model for surgery durations with temporal, operational, and surgery team effects. AB - For effective operating room (OR) planning, surgery duration estimation is critical. Overestimation leads to underutilization of expensive hospital resources (e.g., OR time) whereas underestimation leads to overtime and high waiting times for the patients. In this paper, we consider a particular estimation method currently in use and using additional temporal, operational, and staff-related factors provide a statistical model to adjust these estimates for higher accuracy.The results show that our method increases the accuracy of the estimates, in particular by reducing large errors. For the 8093 cases we have in our data, our model decreases the mean absolute deviation of the currently used scheduled duration (42.65 +/- 0.59 minutes) by 1.98 +/- 0.28 minutes. For the cases with large negative errors, however, the decrease in the mean absolute deviation is 20.35 +/- 0.74 minutes (with a respective increase of 0.89 +/- 0.66 minutes in large positive errors). We find that not only operational and temporal factors, but also medical staff and team experience related factors (such as number of nurses and the frequency of the medical team working together) could be used to improve the currently used estimates. Finally, we conclude that one could further improve these predictions by combining our model with other good prediction models proposed in the literature. Specifically, one could decrease the mean absolute deviation of 39.98 +/- 0.58 minutes obtained via the method of Dexter et al (Anesth Analg 117(1):204-209, 2013) by 1.02 +/- 0.21 minutes by combining our method with theirs. PMID- 25501471 TI - Emergence shapes the structure of the seed microbiota. AB - Seeds carry complex microbial communities, which may exert beneficial or deleterious effects on plant growth and plant health. To date, the composition of microbial communities associated with seeds has been explored mainly through culture-based diversity studies and therefore remains largely unknown. In this work, we analyzed the structures of the seed microbiotas of different plants from the family Brassicaceae and their dynamics during germination and emergence through sequencing of three molecular markers: the ITS1 region of the fungal internal transcribed spacer, the V4 region of 16S rRNA gene, and a species specific bacterial marker based on a fragment of gyrB. Sequence analyses revealed important variations in microbial community composition between seed samples. Moreover, we found that emergence strongly influences the structure of the microbiota, with a marked reduction of bacterial and fungal diversity. This shift in the microbial community composition is mostly due to an increase in the relative abundance of some bacterial and fungal taxa possessing fast-growing abilities. Altogether, our results provide an estimation of the role of the seed as a source of inoculum for the seedling, which is crucial for practical applications in developing new strategies of inoculation for disease prevention. PMID- 25501472 TI - Overexpression of penicillin V acylase from Streptomyces lavendulae and elucidation of its catalytic residues. AB - The pva gene from Streptomyces lavendulae ATCC 13664, encoding a novel penicillin V acylase (SlPVA), has been isolated and characterized. The gene encodes an inactive precursor protein containing a secretion signal peptide that is activated by two internal autoproteolytic cleavages that release a 25-amino-acid linker peptide and two large domains of 18.79 kDa (alpha-subunit) and 60.09 kDA (beta-subunit). Based on sequence alignments and the three-dimensional model of SlPVA, the enzyme contains a hydrophobicpocket involved in catalytic activity, including Serbeta1, Hisbeta23, Valbeta70, and Asnbeta272, which were confirmed by site-directed mutagenesis studies. The heterologous expression of pva in S. lividans led to the production of an extracellularly homogeneous heterodimeric enzyme at a 5-fold higher concentration (959 IU/liter) than in the original host and in a considerably shorter time. According to the catalytic properties of SlPVA, the enzyme must be classified as a new member of the Ntn-hydrolase superfamily, which belongs to a novel subfamily of acylases that recognize substrates with long hydrophobic acyl chains and have biotechnological applications in semisynthetic antifungal production. PMID- 25501473 TI - Geochemical niches of iron-oxidizing acidophiles in acidic coal mine drainage. AB - A legacy of coal mining in the Appalachians has provided a unique opportunity to study the ecological niches of iron-oxidizing microorganisms. Mine-impacted, anoxic groundwater with high dissolved-metal concentrations emerges at springs and seeps associated with iron oxide mounds and deposits. These deposits are colonized by iron-oxidizing microorganisms that in some cases efficiently remove most of the dissolved iron at low pH, making subsequent treatment of the polluted stream water less expensive. We used full-cycle rRNA methods to describe the composition of sediment communities at two geochemically similar acidic discharges, Upper and Lower Red Eyes in Somerset County, PA, USA. The dominant microorganisms at both discharges were acidophilic Gallionella-like organisms, "Ferrovum" spp., and Acidithiobacillus spp. Archaea and Leptospirillum spp. accounted for less than 2% of cells. The distribution of microorganisms at the two sites could be best explained by a combination of iron(II) concentration and pH. Populations of the Gallionella-like organisms were restricted to locations with pH>3 and iron(II) concentration of >4 mM, while Acidithiobacillus spp. were restricted to pH<3 and iron(II) concentration of <4 mM. Ferrovum spp. were present at low levels in most samples but dominated sediment communities at pH<3 and iron(II) concentration of >4 mM. Our findings offer a predictive framework that could prove useful for describing the distribution of microorganisms in acid mine drainage, based on readily accessible geochemical parameters. PMID- 25501474 TI - Role of plasmids in Lactobacillus brevis BSO 464 hop tolerance and beer spoilage. AB - Specific isolates of lactic acid bacteria (LAB) can grow in the harsh beer environment, thus posing a threat to brew quality and the economic success of breweries worldwide. Plasmid-localized genes, such as horA, horC, and hitA, have been suggested to confer hop tolerance, a trait required for LAB survival in beer. The presence and expression of these genes among LAB, however, do not universally correlate with the ability to grow in beer. Genome sequencing of the virulent beer spoilage organism Lactobacillus brevis BSO 464 revealed the presence of eight plasmids, with plasmids 1, 2, and 3 containing horA, horC, and hitA, respectively. To investigate the roles that these and the other five plasmids play in L. brevis BSO 464 growth in beer, plasmid curing with novobiocin was used to derive 10 plasmid variants. Multiplex PCRs were utilized to determine the presence or absence of each plasmid, and how plasmid loss affected hop tolerance and growth in degassed (noncarbonated) beer was assessed. Loss of three of the eight plasmids was found to affect hop tolerance and growth in beer. Loss of plasmid 2 (horC and 28 other genes) had the most dramatic effect, with loss of plasmid 4 (120 genes) and plasmid 8 (47 genes) having significant, but smaller, impacts. These results support the contention that genes on mobile genetic elements are essential for bacterial growth in beer and that beer spoilage ability is not dependent solely on the three previously described hop tolerance genes or on the chromosome of a beer spoilage LAB isolate. PMID- 25501475 TI - Individual predisposition to Staphylococcus aureus colonization in pigs on the basis of quantification, carriage dynamics, and serological profiles. AB - Previous research on Staphylococcus aureus in pigs focused on livestock associated methicillin-resistant S. aureus (MRSA) and had a qualitative cross sectional design. This study aimed to elucidate the frequency, load, and stability of S. aureus nasal carriage in pigs over time and investigated possible associations between carriage and immune response. Nasal swabs were collected three times weekly from 480 tagged adult pigs in 20 Danish production farms. S. aureus and MRSA were quantified on selective media by the most-probable-number method. The levels of IgG against 10 S. aureus antigens in serum were quantified in selected pigs by a Luminex assay. All the farms were positive for S. aureus and 15 for MRSA, leading to overall prevalences of persistent and intermittent carriers and noncarriers of 24, 52, and 23%, respectively. Carriage frequency and nasal loads were significantly higher on MRSA-positive farms. Logistic-regression modeling revealed the presence of individual pigs characterized by high nasal loads (>10,000 CFU per swab) and stable carriage regardless of farm- and pen associated factors. On the other hand, the humoral response was strongly influenced by these environmental factors. The existence of a minority of shedders contributing to maintenance of S. aureus within farms opens up new perspectives on the control of MRSA in pig farming. PMID- 25501476 TI - Sensor kinase PA4398 modulates swarming motility and biofilm formation in Pseudomonas aeruginosa PA14. AB - Pseudomonas aeruginosa is an opportunistic human pathogen that is able to sense and adapt to numerous environmental stimuli by the use of transcriptional regulators, including two-component regulatory systems. In this study, we demonstrate that the sensor kinase PA4398 is involved in the regulation of swarming motility and biofilm formation in P. aeruginosa PA14. APA4398 mutant strain was considerably impaired in swarming motility, while biofilm formation was increased by approximately 2-fold. The PA4398 mutant showed no changes in growth rate, rhamnolipid synthesis, or the production of the Pel exopolysaccharide but exhibited levels of the intracellular second messenger cyclic dimeric GMP (c-di-GMP) 50% higher than those in wild-type cells. The role of PA4398 in gene regulation was investigated by comparing the PA4398 mutant to the wildtype strain by using microarray analysis, which demonstrated that 64 genes were up- or downregulated more than 1.5-fold (P<0.05) under swarming conditions. In addition, more-sensitive real-time PCR studies were performed on genes known to be involved in c-di-GMP metabolism. Among the dysregulated genes were several involved in the synthesis and degradation of c-di-GMP or in the biosynthesis, transport, or function of the iron-scavenging siderophores pyoverdine and pyochelin, in agreement with the swarming phenotype observed. By analyzing additional mutants of selected pyoverdine- and pyochelin-related genes,we were able to show that not only pvdQ but also pvdR, fptA, pchA, pchD, and pchH are essential for the normal swarming behavior of P. aeruginosa PA14 and may also contribute to the swarming-deficient phenotype of the PA4398 mutant in addition to elevated c-di-GMP levels. PMID- 25501478 TI - Novel phage group infecting Lactobacillus delbrueckii subsp. lactis, as revealed by genomic and proteomic analysis of bacteriophage Ldl1. AB - Ldl1 is a virulent phage infecting the dairy starter Lactobacillus delbrueckii subsp. lactis LdlS. Electron microscopy analysis revealed that this phage exhibits a large head and a long tail and bears little resemblance to other characterized phages infecting Lactobacillus delbrueckii. In vitro propagation of this phage revealed a latent period of 30 to 40 min and a burst size of 59.9 +/- 1.9 phage particles. Comparative genomic and proteomic analyses showed remarkable similarity between the genome of Ldl1 and that of Lactobacillus plantarum phage ATCC 8014-B2. The genomic and proteomic characteristics of Ldl1 demonstrate that this phage does not belong to any of the four previously recognized L. delbrueckii phage groups, necessitating the creation of a new group, called group e, thus adding to the knowledge on the diversity of phages targeting strains of this industrially important lactic acid bacterial species. PMID- 25501477 TI - Ratiometric imaging of extracellular pH in bacterial biofilms with C-SNARF-4. AB - pH in the extracellular matrix of bacterial biofilms is of central importance for microbial metabolism. Biofilms possess a complex three-dimensional architecture characterized by chemically different microenvironments in close proximity. For decades, pH measurements in biofilms have been limited to monitoring bulk pH with electrodes. Although pH microelectrodes with a better spatial resolution have been developed, they do not permit the monitoring of horizontal pH gradients in biofilms in real time. Quantitative fluorescence microscopy can overcome these problems, but none of the hitherto employed methods differentiated accurately between extracellular and intracellular microbial pH and visualized extracellular pH in all areas of the biofilms. Here, we developed a method to reliably monitor extracellular biofilm pH microscopically with the ratiometric pH-sensitive dye C SNARF-4, choosing dental biofilms as an example. Fluorescent emissions of C-SNARF 4 can be used to calculate extracellular pH irrespective of the dye concentration. We showed that at pH values of <6, C-SNARF-4 stained 15 bacterial species frequently isolated from dental biofilm and visualized the entire bacterial biomass in in vivo-grown dental biofilms with unknown species composition. We then employed digital image analysis to remove the bacterial biomass from the microscopic images and adequately calculate extracellular pH values. As a proof of concept, we monitored the extracellular pH drop in in vivo grown dental biofilms fermenting glucose. The combination of pH ratiometry with C SNARF-4 and digital image analysis allows the accurate monitoring of extracellular pH in bacterial biofilms in three dimensions in real time and represents a significant improvement to previously employed methods of biofilm pH measurement. PMID- 25501479 TI - Detection and genomic characterization of motility in Lactobacillus curvatus: confirmation of motility in a species outside the Lactobacillus salivarius clade. AB - Lactobacillus is the largest genus within the lactic acid bacteria (LAB), with almost 180 species currently identified. Motility has been reported for at least 13 Lactobacillus species, all belonging to the Lactobacillus salivarius clade. Motility in lactobacilli is poorly characterized. It probably confers competitive advantages, such as superior nutrient acquisition and niche colonization, but it could also play an important role in innate immune system activation through flagellin-Toll-like receptor 5 (TLR5) interaction. We now report strong evidence of motility in a species outside the L. salivarius clade, Lactobacillus curvatus (strain NRIC0822). The motility of L. curvatus NRIC 0822 was revealed by phase contrast microscopy and soft-agar motility assays. Strain NRIC 0822 was motile at temperatures between 15 degrees C and 37 degrees C, with a range of different carbohydrates, and under varying atmospheric conditions. We sequenced the L. curvatus NRIC 0822 genome, which revealed that the motility genes are organized in a single operon and that the products are very similar (>98.5% amino acid similarity over >11,000 amino acids) to those encoded by the motility operon of Lactobacillus acidipiscis KCTC 13900 (shown for the first time to be motile also). Moreover, the presence of a large number of mobile genetic elements within and flanking the motility operon of L. curvatus suggests recent horizontal transfer between members of two distinct Lactobacillus clades: L. acidipiscis in the L. salivarius clade and L. curvatus inthe L. sakei clade. This study provides novel phenotypic, genetic, and phylogenetic insights into flagellum-mediated motility in lactobacilli. PMID- 25501480 TI - Complex population structure of Borrelia burgdorferi in southeastern and south central Canada as revealed by phylogeographic analysis. AB - Lyme disease, caused by the bacterium Borrelia burgdorferi sensu stricto, is an emerging zoonotic disease in Canada and is vectored by the blacklegged tick, Ixodes scapularis. Here we used Bayesian analyses of sequence types (STs), determined by multilocus sequence typing (MLST), to investigate the phylogeography of B. burgdorferi populations in southern Canada and the United States by analyzing MLST data from 564 B. burgdorferi-positive samples collected during surveillance. A total of 107 Canadian samples from field sites were characterized as part of this study, and these data were combined with existing MLST data for samples from the United States and Canada. Only 17% of STs were common between both countries, while 49% occurred only in the United States, and 34% occurred only in Canada. However, STs in southeastern Ontario and southwestern Quebec were typically identical to those in the northeastern United States, suggesting a recent introduction into this region from the United States. In contrast, STs in other locations in Canada (the Maritimes; Long Point, Ontario; and southeastern Manitoba) were frequently unique to those locations but were putative descendants of STs previously found in the United States. The picture in Canada is consistent with relatively recent introductions from multiple refugial populations in the United States. These data thus point to a geographic pattern of populations of B. burgdorferi in North America that may be more complex than simply comprising northeastern, midwestern, and Californian groups. We speculate that this reflects the complex ecology and spatial distribution of key reservoir hosts. PMID- 25501481 TI - Prepartum and postpartum rumen fluid microbiomes: characterization and correlation with production traits in dairy cows. AB - Microbes present in the rumen of dairy cows are essential for degradation of cellulosic and nonstructural carbohydrates of plant origin. The prepartum and postpartum diets of high-producing dairy cows are substantially different, but in what ways the rumen microbiome changes in response and how those changes may influence production traits are not well elucidated. Here, we sequenced the 16S and 18S rRNA genes using the MiSeq platform to characterize the prepartum and postpartum rumen fluid microbiomes in 115 high-producing dairy cows, including both primiparous and multiparous animals. Discriminant analysis identified differences between the microbiomes of prepartum and postpartum samples and between primiparous and multiparous cows. 18S rRNA sequencing revealed an overwhelming dominance of the protozoan class Litostomatea, with over 90% of the eukaryotic microbial population belonging to that group. Additionally, fungi were relatively more prevalent and Litostomatea relatively less prevalent in prepartum samples than in postpartum ones. The core rumen microbiome (common to all samples) consisted of 64 bacterial taxa, of which members of the genus Prevotella were the most prevalent. The Chao1 richness index was greater for prepartum multiparous cows than for postpartum multiparous cows. Multivariable models identified bacterial taxa associated with increased or reduced milk production, and general linear models revealed that a metagenomically based prediction of productivity is highly associated with production of actual milk and milk components. In conclusion, the structure of the rumen fluid microbiome shifts between the prepartum and first-week postpartum periods, and its profile within the context of this study could be used to accurately predict production traits. PMID- 25501482 TI - Metatranscriptomic analyses of plant cell wall polysaccharide degradation by microorganisms in the cow rumen. AB - The bovine rumen represents a highly specialized bioreactor where plant cell wall polysaccharides (PCWPs) are efficiently deconstructed via numerous enzymes produced by resident microorganisms. Although a large number of fibrolytic genes from rumen microorganisms have been identified, it remains unclear how they are expressed in a coordinated manner to efficiently degrade PCWPs. In this study, we performed a metatranscriptomic analysis of the rumen microbiomes of adult Holstein cows fed a fiber diet and obtained a total of 1,107,083 high-quality non rRNA reads with an average length of 483 nucleotides. Transcripts encoding glycoside hydrolases (GHs) and carbohydrate binding modules (CBMs) accounted for 1% and 0.1% of the total non-rRNAs, respectively. The majority (98%) of the putative cellulases belonged to four GH families (i.e., GH5, GH9, GH45, and GH48) and were primarily synthesized by Ruminococcus and Fibrobacter. Notably, transcripts for GH48 cellobiohydrolases were relatively abundant compared to the abundance of transcripts for other cellulases. Two-thirds of the putative hemicellulases were of the GH10, GH11, and GH26 types and were produced by members of the genera Ruminococcus, Prevotella, and Fibrobacter. Most (82%) predicted oligosaccharide-degrading enzymes were GH1, GH2, GH3, and GH43 proteins and were from a diverse group of microorganisms. Transcripts for CBM10 and dockerin, key components of the cellulosome, were also relatively abundant. Our results provide metatranscriptomic evidence in support of the notion that members of the genera Ruminococcus, Fibrobacter, and Prevotella are predominant PCWP degraders and point to the significant contribution of GH48 cellobiohydrolases and cellulosome-like structures to efficient PCWP degradation in the cow rumen. PMID- 25501483 TI - Atmospheric hydrogen scavenging: from enzymes to ecosystems. AB - We have known for 40 years that soils can consume the trace amounts of molecular hydrogen (H2) found in the Earth's atmosphere.This process is predicted to be the most significant term in the global hydrogen cycle. However, the organisms and enzymes responsible for this process were only recently identified. Pure culture experiments demonstrated that several species of Actinobacteria, including streptomycetes and mycobacteria, can couple the oxidation of atmospheric H2 to the reduction of ambient O2. A combination of genetic, biochemical, and phenotypic studies suggest that these organisms primarily use this fuel source to sustain electron input into the respiratory chain during energy starvation. This process is mediated by a specialized enzyme, the group 5 [NiFe]-hydrogenase, which is unusual for its high affinity, oxygen insensitivity, and thermostability. Atmospheric hydrogen scavenging is a particularly dependable mode of energy generation, given both the ubiquity of the substrate and the stress tolerance of its catalyst. This minireview summarizes the recent progress in understanding how and why certain organisms scavenge atmospheric H2. In addition, it provides insight into the wider significance of hydrogen scavenging in global H2 cycling and soil microbial ecology. PMID- 25501484 TI - Growth of anaerobic methane-oxidizing archaea and sulfate-reducing bacteria in a high-pressure membrane capsule bioreactor. AB - Communities of anaerobic methane-oxidizing archaea (ANME) and sulfate-reducing bacteria (SRB) grow slowly, which limits the ability to perform physiological studies. High methane partial pressure was previously successfully applied to stimulate growth, but it is not clear how different ANME subtypes and associated SRB are affected by it. Here, we report on the growth of ANME-SRB in a membrane capsule bioreactor inoculated with Eckernforde Bay sediment that combines high pressure incubation (10.1 MPa methane) and thorough mixing (100 rpm) with complete cell retention by a 0.2-m-pore-size membrane. The results were compared to previously obtained data from an ambient-pressure (0.101 MPa methane) bioreactor inoculated with the same sediment. The rates of oxidation of labeled methane were not higher at 10.1 MPa, likely because measurements were done at ambient pressure. The subtype ANME-2a/b was abundant in both reactors, but subtype ANME-2c was enriched only at 10.1 MPa. SRB at 10.1 MPa mainly belonged to the SEEP-SRB2 and Eel-1 groups and the Desulfuromonadales and not to the typically found SEEP-SRB1 group. The increase of ANME-2a/b occurred in parallel with the increase of SEEP-SRB2, which was previously found to be associated only with ANME-2c. Our results imply that the syntrophic association is flexible and that methane pressure and sulfide concentration influence the growth of different ANME-SRB consortia. We also studied the effect of elevated methane pressure on methane production and oxidation by a mixture of methanogenic and sulfate reducing sludge. Here, methane oxidation rates decreased and were not coupled to sulfide production, indicating trace methane oxidation during net methanogenesis and not anaerobic methane oxidation, even at a high methane partial pressure. PMID- 25501485 TI - Transcriptomic analysis of temperature responses of Aspergillus kawachii during barley koji production. AB - The koji mold Aspergillus kawachii is used for making the Japanese distilled spirit shochu. During shochu production, A. kawachii is grown in solid-state culture (koji) on steamed grains, such as rice or barley, to convert the grain starch to glucose and produce citric acid. During this process, the cultivation temperature of A. kawachii is gradually increased to 40 degrees C and is then lowered to 30 degrees C. This temperature modulation is important for stimulating amylase activity and the accumulation of citric acid. However, the effects of temperature on A. kawachii at the gene expression level have not been elucidated. In this study, we investigated the effect of solid-state cultivation temperature on gene expression for A. kawachii grown on barley. The results of DNA microarray and gene ontology analyses showed that the expression of genes involved in the glycerol, trehalose, and pentose phosphate metabolic pathways, which function downstream of glycolysis, was downregulated by shifting the cultivation temperature from 40 to 30 degrees C. In addition, significantly reduced expression of genes related to heat shock responses and increased expression of genes related with amino acid transport were also observed. These results suggest that solid-state cultivation at 40 degrees C is stressful for A. kawachii and that heat adaptation leads to reduced citric acid accumulation through activation of pathways branching from glycolysis. The gene expression profile of A. kawachii elucidated in this study is expected to contribute to the understanding of gene regulation during koji production and optimization of the industrially desirable characteristics of A. kawachii. PMID- 25501486 TI - New mode of energy metabolism in the seventh order of methanogens as revealed by comparative genome analysis of "Candidatus methanoplasma termitum". AB - The recently discovered seventh order of methanogens, the Methanomassiliicoccales (previously referred to as "Methanoplasmatales"), so far consists exclusively of obligately hydrogen-dependent methylotrophs. We sequenced the complete genome of "Candidatus Methanoplasma termitum" from a highly enriched culture obtained from the intestinal tract of termites and compared it with the previously published genomes of three other strains from the human gut, including the first isolate of the order. Like all other strains, "Ca. Methanoplasma termitum" lacks the entire pathway for CO2 reduction to methyl coenzyme Mand produces methane by hydrogen dependent reduction of methanol or methylamines, which is consistent with additional physiological data. However, the shared absence of cytochromes and an energy-converting hydrogenase for the reoxidation of the ferredoxin produced by the soluble heterodisulfide reductase indicates that Methanomassiliicoccales employ a new mode of energy metabolism, which differs from that proposed for the obligately methylotrophic Methanosphaera stadtmanae. Instead, all strains possess a novel complex that is related to the F420:methanophenazine oxidoreductase (Fpo) of Methanosarcinales butlacks an F420-oxidizing module, resembling the apparently ferredoxin-dependent Fpo-like homolog in Methanosaeta thermophila. Since all Methanomassiliicoccales also lack the subunit E of the membrane-bound heterodisulfide reductase (HdrDE), wepropose that the Fpo-like complex interacts directly with subunit D, forming an energy-converting ferredoxin: heterodisulfideoxidoreductase. The dual function of heterodisulfide in Methanomassiliicoccales, which serves both in electron bifurcation and as terminal acceptor in a membrane-associated redox process, may be a unique characteristic of the novel order. PMID- 25501488 TI - The formation of biodegradable micelles from a therapeutic initiator for enzyme mediated drug delivery. AB - The direct grafting of amphiphilic macromolecules by sequential n carboxyanhydride ring-opening polymerisation (NCA ROP) from a therapeutic initiator enables the formation of monodisperse drug-containing micelles. The subsequent enzyme-mediated hydrolysis of the peptide component permits the programmed release of the encapsulated drug molecules, demonstrating a controlled drug delivery platform that negates any challenging payload loading procedures. PMID- 25501487 TI - Global transcriptional response of Clostridium difficile carrying the CD38 prophage. AB - Clostridium difficile is one of the most dangerous pathogens in hospital settings. Most strains of C. difficile carry one or more prophages, and some of them, like CD38-2 and CD119, can influence the expression of toxin genes. However, little is known about the global host response in the presence of a given prophage. In order to fill this knowledge gap, we used high-throughput RNA sequencing (RNA-seq) to conduct a genome-wide transcriptomic analysis of the epidemic C. difficile strain R20291 carrying the CD38-2 prophage. A total of 39 bacterial genes were differentially expressed in the R20291 lysogen, 26 of them being downregulated. Several of the regulated genes encode transcriptional regulators and phosphotransferase system (PTS) subunits involved in glucose, fructose, and glucitol/sorbitol uptake and metabolism. CD38-2 also upregulated the expression of a group of regulatory genes located in phi-027, a resident prophage common to most ribotype 027 isolates. The most differentially expressed gene was that encoding the conserved phase-variable cell wall protein CwpV, which was upregulated 20-fold in the lysogen. Quantitative PCR and immunofluorescence showed that the increased cwpV expression results from a greater proportion of cells actively transcribing the gene. Indeed, 95% of f lysogenic cells express cwpV, as opposed to only 5% of wild-type cells. Furthermore, the higher proportion of cells expressing cwpV results from a higher frequency of recombination of the genetic switch controlling phase variation, which we confirmed to be dependent on the host-encoded recombinase RecV. In summary, CD38 2 interferes with phase variation of the surface protein CwpV and the expression of metabolic genes. PMID- 25501489 TI - Weave pattern of accessory heads to the anterior digastric muscle. AB - During routine anatomical dissection, we discovered bilateral superficial and deep heads of the anterior belly of the digastric muscle with concomitant accessory heads arranged in a weave pattern in the submental triangle. In addition, the left stylohyoid muscle coursed deep into the intermediate tendon of the digastric muscle bellies. PMID- 25501490 TI - Integration of interpreters in mental health interventions with children and adolescents: The need for a framework. AB - Few empirical studies have detailed the specificities of working with interpreters in mental healthcare for children. The integration of interpreters in clinical teams in child mental healthcare was explored in two clinics, in Montreal and Paris. Four focus groups were conducted with interpreters and clinicians. Participants described the development of the working alliance between interpreters and clinicians, the delineation of interpreters' roles, and the effects of translation on the people in the interaction. Integrating interpreters in a clinical team is a slow process in which clinicians and interpreters need to reflect upon a common framework. An effective framework favours trust, mutual understanding, and valorization of the contribution of each to the therapeutic task. The interpreter's presence and activities seem to have some therapeutic value. PMID- 25501491 TI - Appreciation for Prof. Rolf Sauer on the occasion of the transferral of the editorship of "Strahlentherapie und Onkologie". PMID- 25501492 TI - The peripartum anesthesiologist. PMID- 25501493 TI - Anesthetic management and outcomes of parturients with dilated cardiomyopathy in an academic centre. AB - PURPOSE: This study examines the peripartum anesthetic management and outcomes of women with dilated cardiomyopathy in a large university medical centre over a seven-year period. PRINCIPAL FINDINGS: Twenty-five women were included in this series, 18 with a new diagnosis of cardiomyopathy and seven with a history of cardiomyopathy. Sixteen patients (64%) identified themselves as African American, seven (28%) were Caucasian, and two patients (8%) were Hispanic. The median (range) gestational age at the time of a new diagnosis of cardiomyopathy was 29 (7-38) weeks. Eight women (32%) had New York Heart Association class III/IV symptoms at the time of delivery or in the immediate postpartum period. A multidisciplinary team of obstetricians, anesthesiologists, cardiologists, and pediatricians were involved in the care of these women. The median (range) gestational age at the time of delivery was 33.5 (30-40) weeks. There were nine vaginal deliveries and 15 operative deliveries. One patient had fetal loss at 19 weeks gestation. Twelve women had labour induced with an intravenous infusion of oxytocin at a rate of 0.001-0.02 IU.min(-1). An oxytocin infusion at a variable rate with a maximum dose of 0.05 IU.min(-1) was administered after vaginal delivery to maintain uterine tone. Epidural analgesia was initiated prior to induction of labour or in the latent phase of labour. Seven Cesarean deliveries were performed under combined spinal-epidural anesthesia, five were performed under epidural anesthesia, and three women had general anesthesia. Oxytocin was administered via an intravenous infusion at a rate of 0.05-0.2 IU.min(-1) after operative delivery. One patient had a cardiac arrest on induction of general anesthesia and was successfully resuscitated. There were no maternal or neonatal deaths. Ten women were followed up at our institution and at six months postpartum; 50% of these patients were still symptomatic. CONCLUSION: We report favourable outcomes in 25 pregnant women with dilated cardiomyopathy who were managed by a multidisciplinary team. PMID- 25501494 TI - Low-dose intrathecal local anesthetic does not increase the threshold current for the epidural stimulation test: a prospective observational trial of neuraxial analgesia in labouring women. AB - PURPOSE: The purpose of this study was to investigate the ability of the electrical epidural stimulation test (EST) to determine the position of the epidural catheter during combined spinal-epidural (CSE) anesthesia for labour analgesia. METHODS: This was a prospective observational trial of attempted EST during neuraxial analgesia in labouring women. Ten women received a double segment CSE technique and one woman underwent continuous spinal analgesia following inadvertent dural puncture and deliberate placement of the catheter tip in the intrathecal space. In all CSE cases, the spinal injection was performed below the level of the epidural insertion. The motor threshold current (MTC) was determined by EST through the existing epidural/intrathecal catheter immediately following and at five, ten, and 15 mins after intrathecal injection of bupivacaine 1.75 mg and fentanyl 15 MUg. Changes in the MTC were expressed as a percent change compared with baseline. RESULTS: The MTC required to elicit muscle contractions in women with epidurally placed catheters was unaffected by the intrathecal injection of the analgesic mixture (P = 0.731). The MTC increased following an intrathecal injection of the same mixture in a woman who had the catheter placed intrathecally. CONCLUSIONS: The intrathecal injection of a low dose of bupivacaine-fentanyl does not affect the MTC if the catheter is placed in the epidural space; however, it does affect the threshold if the catheter is placed intrathecally. We also confirm that the EST can help to determine the position of the epidural catheter prior to injection of the test dose. This trial was registered at ClinicalTrials.gov (NCT00464841). PMID- 25501495 TI - Parathyroid adenoma in patients with Graves' disease: a report of 21 cases. AB - Graves' disease (GD) is frequently associated with mild hypercalcemia. The hypercalcemia may be due to the activation of osteoclastic bone resorption caused by the excess thyroid hormone. In some cases of GD, the hypercalcemia can be attributable to concomitant parathyroid diseases. In this study, 21 patients with a history of GD developed parathyroid adenoma based on histology, intraoperative parathyroid hormone (IOPTH) monitoring, and other clinical features. There were 11 patients with a history of radioactive iodine therapy (RAI) for GD. The latency time of RAI was from 12 to 41 years. The case cohort was divided into two groups: patients with (group GR: 11 patients) and patients without a history of RAI (group G: 10 patients). Mean age of patients in group GR was 54.8 years compared to 62.2 years of group G (P = 0.08). There were no statistically significant differences regarding the parathyroid weight, serum calcium, and pre- and post-parathyroidectomy PTH levels. There was no histopathologic difference between the two groups. In conclusion, we report 21 cases of parathyroid adenoma in patients with Graves' disease. There may be a possible link between GD patients with a RAI history and an increased risk of parathyroid adenoma. The parathyroid adenomas showed no clinicopathological differences between GD patient with and without a history of RAI. PMID- 25501496 TI - FOXO3-mediated up-regulation of Bim contributes to rhein-induced cancer cell apoptosis. AB - The anthraquinone compound rhein is a natural agent in the traditional Chinese medicine rhubarb. Preclinical studies demonstrate that rhein has anticancer activity. Treatment of a variety of cancer cells with rhein may induce apoptosis. Here, we report that rhein induces atypical unfolded protein response in breast cancer MCF-7 cells and hepatoma HepG2 cells. Rhein induces CHOP expression, eIF2alpha phosphorylation and caspase cleavage, while it does not induce glucose regulated protein 78 (GRP78) expression in both MCF-7 and HepG2 cells. Meanwhile, rhein inhibits thapsigargin-induced GRP78 expression and X box-binding protein 1 splicing. In addition, rhein inhibits Akt phosphorylation and stimulates FOXO transactivation activity. Rhein induces Bim expression in MCF-7 and HepG2 cells, which can be abrogated by FOXO3a knockdown. Knockdown of FOXO3a or Bim abrogates rhein-induced caspase cleavage and apoptosis. The chemical chaperone 4 phenylbutyrate acid antagonizes the induction of FOXO activation, Bim expression and caspase cleavage by rhein, indicating that protein misfolding may be involved in triggering these deleterious effects. We conclude that FOXO3a-mediated up regulation of Bim is a key mechanism underlying rhein-induced cancer cells apoptosis. PMID- 25501497 TI - Quality of life outcomes after radical cystectomy: long-term standardized assessment of Studer Pouch versus I-Pouch. AB - PURPOSE: To investigate whether the ileal length used for the formation of two different orthotopic bladder substitutes [Studer (S)-Pouch vs. I-Pouch; 60 vs. 40 cm] impacts quality of life (QoL). MATERIALS AND METHODS: In this cross-sectional study, a total of 56 patients underwent radical cystectomy with ileal neobladder for bladder cancer [S-Pouch: 23 pat, 19 men, 4 women); I-Pouch: 33 pat (26 men, 7 women)]. They completed general (SF-36), cancer-specific (QLQ-C30) and bladder cancer-specific questionnaires (QLQ-BLM30) as well as a novel neobladder-specific questionnaire (TNQ). The questionnaire-based follow-up was 66 months (IQR 41-104; total range 9-161). RESULTS: I-Pouch patients reported better SF-36 physical health status (p = 0.026), QLQ-BLM30 continence scores (p < 0.001) and a more favorable QLQ-C30 total score compared to S-Pouch patients (p = 0.044). S-Pouch patients reported better QLQ-BLM30 general health status (p = 0.001). For the TNQ, no significant difference was found between both groups (p = 0.09). S-Pouch patients reported use of condom urinals more frequently (p = 0.026). S-Pouch patients tended to be on vitamin B12 substitution (p = 0.06). I-Pouch patients reported significantly higher micturition volumes (>=300 ml) compared to S-Pouch patients (30/33 vs. 16/23; p = 0.040). No differences were found with regard to bicarbonate supplementation and recurrent urinary tract infections. CONCLUSION: Non-neobladder-specific questionnaires show controversial results for QoL outcomes of patients with Studer and I-Pouch. The TNQ suggests that none of these two types of neobladder is superior to the other in terms of QoL. Hence, general questionnaires are not valid enough to adequately address QoL aspects in patients with different neobladders. Development and validation of neobladder-specific questionnaires are needed. PMID- 25501498 TI - Enhancement of MHC-I antigen presentation via architectural control of pH responsive, endosomolytic polymer nanoparticles. AB - Protein-based vaccines offer a number of important advantages over organism-based vaccines but generally elicit poor CD8(+) T cell responses. We have previously demonstrated that pH-responsive, endosomolytic polymers can enhance protein antigen delivery to major histocompatibility complex class I (MHC-I) antigen presentation pathways thereby augmenting CD8(+) T cell responses following immunization. Here, we describe a new family of nanocarriers for protein antigen delivery assembled using architecturally distinct pH-responsive polymers. Reversible addition-fragmentation chain transfer (RAFT) polymerization was used to synthesize linear, hyperbranched, and core-crosslinked copolymers of 2-(N,N diethylamino)ethyl methacrylate (DEAEMA) and butyl methacrylate (BMA) that were subsequently chain extended with a hydrophilic N,N-dimethylacrylamide (DMA) segment copolymerized with thiol-reactive pyridyl disulfide (PDS) groups. In aqueous solution, polymer chains assembled into 25 nm micellar nanoparticles and enabled efficient and reducible conjugation of a thiolated protein antigen, ovalbumin. Polymers demonstrated pH-dependent membrane-destabilizing activity in an erythrocyte lysis assay, with the hyperbranched and cross-linked polymer architectures exhibiting significantly higher hemolysis at pH <= 7.0 than the linear diblock. Antigen delivery with the hyperbranched and cross-linked polymer architecture enhanced in vitro MHC-I antigen presentation relative to free antigen, whereas the linear construct did not have a discernible effect. The hyperbranched system elicited a four- to fivefold increase in MHC-I presentation relative to the cross-linked architecture, demonstrating the superior capacity of the hyperbranched architecture in enhancing MHC-I presentation. This work demonstrates that the architecture of pH-responsive, endosomolytic polymers can have dramatic effects on intracellular antigen delivery, and offers a promising strategy for enhancing CD8(+) T cell responses to protein-based vaccines. PMID- 25501499 TI - Patterns of Antiplatelet Therapy in Patients Who Have Experienced an Acute Coronary Event: A Descriptive Study in UK Primary Care. AB - BACKGROUND: Antiplatelet (AP) therapy is well established for the secondary prevention of acute coronary events. However, patients may discontinue treatment, often owing to gastrointestinal (GI) complications, leaving them at elevated risk of recurrent cardiovascular events. OBJECTIVES: This descriptive retrospective study assessed trends in prescription of AP agents and coprescription of gastroprotective therapy, after an acute coronary event. Discontinuation of AP therapy within 2 years of an event and factors predicting discontinuation were investigated. METHODS: The study was conducted in a UK primary care setting from 2000 to 2008; a total of 27, 351 patients aged 50 to 84 years were included in the analysis. Main outcome measures were exposures to low-dose acetylsalicylic acid (ASA), clopidogrel, and proton pump inhibitors (PPIs). RESULTS: At 90 days after an acute coronary event, 85.9% of patients had been prescribed some form of AP therapy and 33.6% of patients who were issued at least 1 ASA prescription in this period were also issued a PPI prescription. The use of dual antiplatelet therapy (DAT) 90 days after an event increased from 2% in 2000 to over 50% in 2008. An estimated 15.1% of patients on ASA monotherapy and 37.5% on DAT discontinued treatment within 1 year. A bleeding event during follow-up, including upper GI bleeding or hemorrhagic stroke, was the strongest predictor of discontinuation. CONCLUSION: Although most patients were prescribed AP therapy in the 90 days following an acute coronary event, a substantial proportion discontinued DAT or ASA monotherapy within 1 year. It is essential that physicians consider strategies to reduce the risk of discontinuation of AP therapy. PMID- 25501500 TI - Structural analysis of membrane-bound hECE-1 dimer using molecular modeling techniques: insights into conformational changes and Abeta1-42 peptide binding. AB - The human endothelin converting enzyme-1 (hECE-1) is a homodimer linked by a single disulfide bridge and has been identified as an important target for Alzheimer's disease. Structural analysis of hECE-1 dimer could lead to design specific and effective therapies against Alzheimer's disease. Hence, in the present study homology model of transmembrane helix has been constructed and patched with available crystal structure of hECE-1 monomer. Then, membrane-bound whole model of hECE-1 dimer has been developed by considering biophysical properties of membrane proteins. The explicit molecular dynamics simulation revealed that the hECE-1 dimer exhibits conformational restrains and controls total central cavity by regulating the degree of fluctuations in some residues (238-226) for substrate/product entrance/exit sites. In turn, conformational rearrangements of interdomain linkers as well as helices close to the inner surface are responsible for increasing total central cavity of hECE-1 dimer. Further, the model of hECE-1 dimer was docked with Abeta1-42 followed by MD simulation to investigate possible orientation and interactions of Abeta1-42 in catalytic groove of hECE-1 dimer. The free energy calculations exposed the stability of complex and helped us to identify key residues of hECE-1 involved in interactions with Abeta1-42 peptide. Hence, the present study might be useful to understand structural significance of membrane-bound dimeric hECE-1 to design therapies against Alzheimer's disease. PMID- 25501501 TI - Interplay between R513 methylation and S516 phosphorylation of the cardiac voltage-gated sodium channel. AB - Arginine methylation is a novel post-translational modification within the voltage-gated ion channel superfamily, including the cardiac sodium channel, NaV1.5. We show that NaV1.5 R513 methylation decreases S516 phosphorylation rate by 4 orders of magnitude, the first evidence of protein kinase A inhibition by arginine methylation. Reciprocally, S516 phosphorylation blocks R513 methylation. NaV1.5 p.G514C, associated to cardiac conduction disease, abrogates R513 methylation, while leaving S516 phosphorylation rate unchanged. This is the first report of methylation-phosphorylation cross-talk of a cardiac ion channel. PMID- 25501503 TI - Production of disulfide bond-rich peptides by fusion expression using small transmembrane proteins of Escherichia coli. AB - Recombinant expression in Escherichia coli allows the simple, economical, and effective production of bioactive peptides. On the other hand, the production of native peptides, particularly those rich in disulfide bonds, is a major problem. Previous studies have reported that the use of carrier proteins for fusion expression can result in good peptide yields, but few are folded correctly. In this study, two transmembrane small proteins in E. coli, YoaJ and YkgR, which both orientate with their N-termini in cytoplasm and their C-termini in periplasm, were used for fusion expression. The recombinant production of two peptides, asteropsin A (ASPA) and beta-defensin (BD), was induced in the periplasm of E. coli using a selected carrier protein. Both peptides were expressed at high levels, at yields of approximately 5-10 mg/L of culture. Mass spectrometry showed that the resulting peptide had the same molecular weight as their natural forms. After purification, single peaks were observed by reversed phase high-performance liquid chromatography (RP-HPLC), demonstrating the absence of isoforms. Furthermore, cytoplasmically expressed fusion proteins with a carrier at their C-termini did not contain disulfide bonds. This study provides new carrier proteins for fusion expression of disulfide bond-rich peptides in E. coli. PMID- 25501502 TI - Cysteine dioxygenase and cysteine sulfinate decarboxylase genes of the deep-sea mussel Bathymodiolus septemdierum: possible involvement in hypotaurine synthesis and adaptation to hydrogen sulfide. AB - It has been suggested that invertebrates inhabiting deep-sea hydrothermal vent areas use the sulfinic acid hypotaurine, a precursor of taurine, to protect against the toxicity of hydrogen sulfide contained in the seawater from the vent. In this protective system, hypotaurine is accumulated in the gill, the primary site of sulfide exposure. However, the pathway for hypotaurine synthesis in mollusks has not been identified. In this study, we screened for the mRNAs of enzymes involved in hypotaurine synthesis in the deep-sea mussel Bathymodiolus septemdierum and cloned cDNAs encoding cysteine dioxygenase and cysteine sulfinate decarboxylase. As mRNAs encoding cysteamine dioxygenase and cysteine lyase were not detected, the cysteine sulfinate pathway is suggested to be the major pathway of hypotaurine and taurine synthesis. The two genes were found to be expressed in all the tissues examined, but the gill exhibited the highest expression. The mRNA level in the gill was not significantly changed by exposure to sulfides or thiosulfate. These results suggests that the gill of B. septemdierum maintains high levels of expression of the two genes regardless of ambient sulfide level and accumulates hypotaurine continuously to protect against sudden exposure to high level of sulfide. PMID- 25501504 TI - Glycine hydroxamate inhibits tyrosinase activity and melanin contents through downregulating cAMP/PKA signaling pathways. AB - Among the eight amino acid hydroxamates tested, Glycine hydroxamate (GH) was the best inhibitor of mushroom tyrosinase (TYR). With L-tyrosine as substrate, the GH inhibition of the monophenolase activity of the mushroom TYR was noncompetitive. GH decreased not only TYR protein expression, but also melanin content, tyrosinase-related protein (TRP)-1, TRP-2, and microphthalmia-associated transcription factor (MITF) expression in B16F10 melanoma cells while in the presence of alpha-melanocyte-stimulating hormone (alpha-MSH). GH also significantly decreased the isobutylmethylxanthine (IBMX)-induced increase in melanin content, which was not prevented by the ERK inhibitor PD98059. These results suggest GH has the potential for use in cosmetic hypopigmentation. PMID- 25501505 TI - Suppression of skin inflammation in keratinocytes and acute/chronic disease models by caffeic acid phenethyl ester. AB - Skin inflammation plays a central role in the pathophysiology and symptoms of diverse chronic skin diseases including atopic dermatitis (AD). In this study, we examined if caffeic acid phenethyl ester (CAPE), a skin-permeable bioactive compound from propolis, was protective against skin inflammation using in vitro cell system and in vivo animal disease models. CAPE suppressed TNF-alpha-induced NF-kappaB activation and expression of inflammatory cytokines in human keratinocytes (HaCaT). The potency and efficacy of CAPE were superior to those of a non-phenethyl derivative, caffeic acid. Consistently, topical treatment of CAPE (0.5 %) attenuated 12-O-tetradecanoylphorbol-13-acetate(TPA)-induced skin inflammation on mouse ear as CAPE reduced ear swelling and histologic inflammation scores. CAPE suppressed increased expression of pro-inflammatory molecules such as TNF-alpha, cyclooxygenase-2 and inducible NO synthase in TPA stimulated skin. TPA-induced phosphorylation of IkappaB and ERK was blocked by CAPE suggesting that protective effects of CAPE on skin inflammation is attributed to inhibition of NF-kappaB activation. Most importantly, in an oxazolone-induced chronic dermatitis model, topical application of CAPE (0.5 and 1 %) was effective in alleviating AD-like symptoms such as increases of trans epidermal water loss, skin thickening and serum IgE as well as histologic inflammation assessment. Collectively, our results propose CAPE as a promising candidate for a novel topical drug for skin inflammatory diseases. PMID- 25501506 TI - RAB34 was a progression- and prognosis-associated biomarker in gliomas. AB - The objective of this study is to explore the expression pattern, prognostic value, and functional role of RAB34 in gliomas. RAB34 messenger RNA (mRNA) expression was evaluated from low grade to high grade in 220 glioma patients of the Chinese Glioma Genome Atlas (CGGA). We therefore analyzed RAB34 mRNA expression in two validated datasets. For detecting the protein expression level of RAB34, another 104 glioma tissues were stained by immunohistochemistry. Gene ontology (GO) analysis and gene set variation analysis (GSVA) were used for functional annotation of RAB34. The mRNA and protein expression levels of RAB34 were both related to glioma grade progression and were inversely correlated with overall survival (OS) in high-grade glioma patients. GO analysis and GSVA showed that RAB34 sets related to migration were significantly enriched in the cases with RAB34 high expression. Pearson correlation analysis identified that genes including MMP-11, HSPB1, IGFBP2, HSPA6, IGFBP5, and MMP19 were positively correlated with RAB34. The expression of RAB34 is related to glioma grade progression and confers a poor prognosis in high-grade glioma patients. PMID- 25501507 TI - MicroRNA-34a inhibits the proliferation and promotes the apoptosis of non-small cell lung cancer H1299 cell line by targeting TGFbetaR2. AB - MicroRNAs (MiRNAs) are small non-coding RNA molecules which act as important regulators of post-transcriptional gene expression by binding 3'-untranslated region (3'-UTR) of target messenger RNA (mRNA). In this study, we analyzed miRNA 34a (miR-34a) as a tumor suppressor in non-small cell lung cancer (NSCLC) H1299 cell line. The expression level of miR-34a in four different NSCLC cell lines, H1299, A549, SPCA-1, and HCC827, was significantly lower than that in the non tumorigenic bronchial epithelium cell line BEAS-2B. In human NSCLC tissues, miR 34a expression level was also significantly decreased in pT2-4 compared with the pT1 group. Moreover, miR-34a mimic could inhibit the proliferation and triggered apoptosis in H1299 cells. Luciferase assays revealed that miR-34a inhibited TGFbetaR2 expression by targeting one binding site in the 3'-UTR of TGFbetaR2 mRNA. Quantitative real-time PCR (qRT-PCR) and Western blot assays verified that miR-34a reduced TGFbetaR2 expression at both mRNA and protein levels. Furthermore, downregulation of TGFbetaR2 by siRNA showed the same effects on the proliferation and apoptosis as miR-34a mimic in H1299 cells. Our results demonstrated that miR-34a could inhibit the proliferation and promote the apoptosis of H1299 cells partially through the downregulation of its target gene TGFbetaR2. PMID- 25501509 TI - Polygala tenuifolia polysaccharide (PTP) inhibits cell proliferation by repressing Bmi-1 expression and downregulating telomerase activity. AB - In our previous study, we isolated a homogeneous polysaccharide (PTP) with antitumor activity from the roots of Polygala tenuifolia. In view of the close correlation between Bmi-1 expression and progression of ovarian cancer, we intend to elucidate the mechanism of its activity by determining the Bmi-1 expression and the telomerase activity in human ovarian carcinoma OVCAR-3 cells following treatment with PTP at three concentrations of 0.5, 1, and 2 mg/mL for 48 h. MTT and colony-forming assays revealed that PTP had a significant inhibitory effect on the cell growth and colony formation of OVCAR-3 cells. Furthermore, Western blot and real-time PCR analysis showed that PTP inhibited Bmi-1 both in protein and transcript levels. Besides, the telomerase activity in OVCAR-3 cells was also downregulated after PTP treatment for 48 h. Taken together, the inhibitory effect of PTP on the cell growth was at least in part mediated via the downregulation of Bmi-1 expression and the telomerase activity in OVCAR-3 cells, and PTP might be a new candidate for chemotherapeutic agent against human ovarian cancer. PMID- 25501512 TI - A functional polymorphism in microRNA-196a2 is associated with increased susceptibility to non-Hodgkin lymphoma. AB - Aberrant expression and structural alterations of microRNAs (miRNAs) play important roles in tumorigenesis. The miRNA-196a2 polymorphism is associated with tumorigenesis, but its association with non-Hodgkin lymphoma (NHL) remains unexplored. We evaluated the association between the miRNA-196a2 T>C polymorphism (rs11614913) and NHL risk in a case-control study of 318 NHL cases and 320 healthy controls. We also examined miRNA-196a expression in tissue samples from NHL patients (n = 59). The TC and CC genotypes were associated with cancer risk in NHL [odds ratio (OR) = 1.384, confidence interval (CI) = 1.010-1.898 for TC vs. TT, and OR = 1.822, 95 % CI = 1.163-2.853 for CC vs. TT]. Analysis of the association between this polymorphism and the clinicopathology of NHL showed that the combined TC/CC genotypes were associated with Ann Arbor stage (OR = 1.852, 95 % CI = 1.139-3.010), bone marrow invasion (OR = 1.850, 95 % CI = 1.062-3.223), and B symptoms (OR = 1.852, 95 % CI = .154-2.972), but not with immunohistological subtype, lymph node size, age, or gender. In addition, the CC or CC/TC genotypes were associated with significantly higher levels of mature miR 196a (p = 0.002 or 0.008) in a genotype-phenotype correlation analysis. Our findings suggest that the miR-196a2 polymorphism may increase the risk of NHL by altering the expression of mature miR-196a. PMID- 25501511 TI - Secreted frizzled-related protein 4 and its implications in cancer and apoptosis. AB - Secreted frizzled-related protein 4 (SFRP4) is a glycoprotein that acts as an antagonist of Wnt ligands, causing inhibition of the canonical Wnt signalling pathway. First noticed due to high expression levels during times of increased apoptosis, SFRP4 has been implicated in cell proliferation and differentiation and plays an important role in carcinogenesis. Many tumours such as endometrial, cervical, ovarian, prostate, bladder, colorectal, mesothelioma, pancreatic, renal, and oesophageal tumours are characterised by aberrant promoter hypermethylation, which causes variations in the expression level of SFRP4 when compared to normal cells. Combined experimental data appear to confirm the suggested role of SFRP4 as a local initiator of apoptosis; however, increased SFRP4 expression may not always correlate with an increase in apoptosis, possibly due to the complex interactions between different signalling pathways. SFRP4 can be explored for its use in novel therapeutic modalities as well as being a potential diagnostic biomarker. PMID- 25501508 TI - Focusing on long noncoding RNA dysregulation in gastric cancer. AB - As the discovery of functions of long noncoding RNA (lncRNA) HOTAIR lifts ncRNA to new levels, large numbers of research have been demonstrated for the roles of lncRNAs in diverse biological processes, such as development, cellular differentiation, and a wide range of diseases including cancer. And, recent studies have discovered that lncRNAs can participate in almost every step in the life cycle of gene regulation, including chromosome dosage compensation, imprinting, epigenetic regulation, nuclear and cytoplasmic trafficking, transcription, mRNA splicing, and translation, mainly in the four archetypes signals, decoys, guides, and scaffolds. Unsurprisingly, accumulating studies have demonstrated that serious lncRNAs are dysregulated in gastric cancer (GC), one of the major causes of cancer-related mortality worldwide, and closely related to tumorigenesis, metastasis, or prognosis. In this review, we will discuss diverse functions of lncRNAs and highlight the growing evidence for the important roles of lncRNAs acting as biomarkers for the early diagnosis of GC, as indicators of GC prognosis, or even as therapeutic targets in GC. PMID- 25501514 TI - Assessing the risk to people from pets exposed to Ebola virus. PMID- 25501510 TI - Epstein-Barr virus latent antigens EBNA3C and EBNA1 modulate epithelial to mesenchymal transition of cancer cells associated with tumor metastasis. AB - Epithelial-mesenchymal transition is an important mechanism in cancer invasiveness and metastasis. We had previously reported that cancer cells expressing Epstein-Barr virus (EBV) latent viral antigens EBV nuclear antigen EBNA3C and/ or EBNA1 showed higher motility and migration potential and had a propensity for increased metastases when tested in nude mice model. We now show that both EBNA3C and EBNA1 can modulate cellular pathways critical for epithelial to mesenchymal transition of cancer cells. Our data confirms that presence of EBNA3C or EBNA1 result in upregulation of transcriptional repressor Slug and Snail, upregulation of intermediate filament of mesenchymal origin vimentin, upregulation of transcription factor TCF8/ZEB1, downregulation as well as disruption of tight junction zona occludens protein ZO-1, downregulation of cell adhesion molecule E-cadherin, and nuclear translocation of beta-catenin. We further show that the primary tumors as well as metastasized lesions derived from EBV antigen-expressing cancer cells in nude mice model display EMT markers expression pattern suggesting their greater propensity to mesenchymal transition. PMID- 25501513 TI - MicroPET imaging of tumor angiogenesis and monitoring on antiangiogenic therapy with an (18)F labeled RGD-based probe in SKOV-3 xenograft-bearing mice. AB - So far, there is no satisfactory imaging modality to monitor antiangiogenesis therapy of ovarian cancer noninvasively. The aim of this study was to evaluate the effectiveness and sensibility of an (18)F labeled Arg-Gly-Asp (RGD) peptide in imaging and monitoring antiangiogenic responds in SKOV-3 xenograft-bearing mice. (18)F-FB-NH-PEG4-E[PEG4-c(RGDfK)]2 (denoted as (18)F-RGD2) was synthesized and employed in this study. Mice bearing ovarian cancer SKOV-3 tumors were used for biodistribution and microPET imaging studies compared with (18)F-FDG imaging. Animals were treated with low-dose paclitaxel and the effect of paclitaxel therapy on (18)F-RGD2 accumulation was investigated. Microvascular density (MVD) of SKOV-3 tumors was detected to assess the reliability of (18)F-RGD2 in antiangiogenesis monitoring. Biodistribution studies for (18)F-RGD2 revealed favorable in vivo pharmacokinetic properties, with significant levels of receptor specific tumor uptake determined via blocking studies. MicroPET imaging results demonstrated high contrast visualization of SKOV-3 tumors. And tumor to background ratio (T/NT) of (18)F-RGD2 uptake was significantly higher than that of (18)F-FDG. Studies on antiangiogenic therapy demonstrated percentage of injected dose per gram of tissue (%ID/g) tumor uptake of (18)F-RGD2 which was obviously decreased in the treatment group than the control group, especially at 60 min (by 31.31 +/- 7.18 %, P = 0.009) and 120 min (by 38.92 +/- 8.31 %, P < 0.001) after injection of (18)F-RGD2. MVD measurement of SKOV-3 tumors confirmed the finding of the biodistribution studies in monitoring antiangiogenesis therapy. (18)F-RGD2, with favorable biodistribution properties and specific affinity, is a promising tracer for tumor imaging and monitoring antiangiogenesis therapy in ovarian cancer SKOV-3 xenograft-bearing mice. PMID- 25501515 TI - Bursary boost for RVC students. PMID- 25501516 TI - New RCVS Charter to bring changes for veterinary nurses. PMID- 25501517 TI - Parliamentary group calls for a coordinated strategy on dogs. PMID- 25501518 TI - Women as veterinary leaders and entrepreneurs. PMID- 25501519 TI - Animal and human abuse: an uncomfortable link. PMID- 25501520 TI - Seeking local approaches to global disease threats. PMID- 25501521 TI - RCVS to seek views on vets using the courtesy title 'Dr'. PMID- 25501522 TI - Fatal case of fog fever in a cow moved to lush pasture. PMID- 25501523 TI - Similar but not the same: the teaching of veterinary and medical ethics. PMID- 25501524 TI - Role for colostrum and whey in testing for bovine TB and Johne's disease? PMID- 25501525 TI - Pedigree dog health survey. PMID- 25501527 TI - Why a vet--and why a pathologist? PMID- 25501528 TI - First-year student diary. PMID- 25501529 TI - On stability issues in deriving multivariable regression models. AB - In many areas of science where empirical data are analyzed, a task is often to identify important variables with influence on an outcome. Most often this is done by using a variable selection strategy in the context of a multivariable regression model. Using a study on ozone effects in children (n = 496, 24 covariates), we will discuss aspects relevant for deriving a suitable model. With an emphasis on model stability, we will explore and illustrate differences between predictive models and explanatory models, the key role of stopping criteria, and the value of bootstrap resampling (with and without replacement). Bootstrap resampling will be used to assess variable selection stability, to derive a predictor that incorporates model uncertainty, check for influential points, and visualize the variable selection process. For the latter two tasks we adapt and extend recent approaches, such as stability paths, to serve our purposes. Based on earlier experiences and on results from the example, we will argue for simpler models and that predictions are usually very similar, irrespective of the selection method used. Important differences exist for the corresponding variances, and the model uncertainty concept helps to protect against serious underestimation of the variance of a predictor-derived data dependently. Results of stability investigations illustrate severe difficulties in the task of deriving a suitable explanatory model. It seems possible to identify a small number of variables with an important and probably true influence on the outcome, but too often several variables are included whose selection may be a result of chance or may depend on a small number of observations. PMID- 25501530 TI - Achieving continuous manufacturing for final dosage formation: challenges and how to meet them. May 20-21, 2014 Continuous Manufacturing Symposium. AB - We describe the key issues and possibilities for continuous final dosage formation, otherwise known as downstream processing or drug product manufacturing. A distinction is made between heterogeneous processing and homogeneous processing, the latter of which is expected to add more value to continuous manufacturing. We also give the key motivations for moving to continuous manufacturing, some of the exciting new technologies, and the barriers to implementation of continuous manufacturing. Continuous processing of heterogeneous blends is the natural first step in converting existing batch processes to continuous. In heterogeneous processing, there are discrete particles that can segregate, versus in homogeneous processing, components are blended and homogenized such that they do not segregate. Heterogeneous processing can incorporate technologies that are closer to existing technologies, where homogeneous processing necessitates the development and incorporation of new technologies. Homogeneous processing has the greatest potential for reaping the full rewards of continuous manufacturing, but it takes long-term vision and a more significant change in process development than heterogeneous processing. Heterogeneous processing has the detriment that, as the technologies are adopted rather than developed, there is a strong tendency to incorporate correction steps, what we call below "The Rube Goldberg Problem." Thus, although heterogeneous processing will likely play a major role in the near-term transformation of heterogeneous to continuous processing, it is expected that homogeneous processing is the next step that will follow. Specific action items for industry leaders are: Form precompetitive partnerships, including industry (pharmaceutical companies and equipment manufacturers), government, and universities. These precompetitive partnerships would develop case studies of continuous manufacturing and ideally perform joint-technology development, including development of small-scale equipment and processes. Develop ways to invest internally in continuous manufacturing. How best to do this will depend on the specifics of a given organization, in particular the current development projects. Upper managers will need to energize their process developers to incorporate continuous manufacturing in at least part of their processes to gain experience and demonstrate directly the benefits. Training of continuous manufacturing technologies, organizational approaches, and regulatory approaches is a key area that industrial leaders should pursue together. PMID- 25501531 TI - Emerging areas of research in the assessment of pharmacokinetics in patients with chronic kidney disease. AB - Chronic kidney disease (CKD) has been shown to alter the pharmacokinetics of drugs that are eliminated not only via the renal pathway but also by nonrenal clearance and transport. Dosing recommendations in subjects with CKD have historically come from small pharmacokinetic (PK) studies, which have been insulated from the broader clinical development strategy. Opportunities for prospective strategic integration of both preclinical and clinical data on drug clearance mechanisms, model-based approaches, and clinical knowledge of therapeutic index are therefore often missed in designing and analyzing the results of PK studies in subjects with CKD, and eventually providing dosing recommendations. These considerations are valuable in designing informative PK studies in subjects with CKD, as well as for guiding kidney function-related inclusion/exclusion criteria in the broader clinical program and ultimately defining dosing guidelines that optimize benefit-risk balance for these special patient populations based on all available data. This paper offers points to consider for drug developers to increase adoption of a contemporary multidisciplinary approach, which includes key considerations on study design and conduct, methodologies for analysis (population PK and physiologically based PK modeling), and a roadmap to interpret the effect of kidney function on the overall benefit-risk profile of drugs in development. PMID- 25501532 TI - Reflections on fathers and infant mental health. PMID- 25501534 TI - Artificially modified magnetic anisotropy in interconnected nanowire networks. AB - Interconnected or crossed magnetic nanowire networks have been fabricated by electrodeposition into a polycarbonate template with crossed cylindrical nanopores oriented +/-30 degrees with respect to the surface normal. Tailor-made nanoporous polymer membranes have been designed by performing a double energetic heavy ion irradiation with fixed incidence angles. The Ni and Ni/NiFe nanowire networks have been characterized by magnetometry as well as ferromagnetic resonance and compared with parallel nanowire arrays of the same diameter and density. The most interesting feature of these nanostructured materials is a significant reduction of the magnetic anisotropy when the external field is applied perpendicular and parallel to the plane of the sample. This effect is attributed to the relative orientation of the nanowire axes with the applied field. Moreover, the microwave transmission spectra of these nanowire networks display an asymmetric linewidth broadening, which may be interesting for the development of low-pass filters. Nanoporous templates made of well-defined nanochannel network constitute an interesting approach to fabricate materials with controlled anisotropy and microwave absorption properties that can be easily modified by adjusting the relative orientation of the nanochannels, pore sizes and material composition along the length of the nanowire. PMID- 25501533 TI - A comparative meta-analysis of QTL between intraspecific Gossypium hirsutum and interspecific G. hirsutum * G. barbadense populations. AB - KEY MESSAGE: Based on 1075 and 1059 QTL from intraspecific Upland and interspecific Upland * Pima populations, respectively, the identification of QTL clusters and hotspots provides a useful resource for cotton breeding. Mapping of quantitative trait loci (QTL) is a pre-requisite of marker-assisted selection for crop yield and quality. Recent meta-analysis of QTL in tetraploid cotton (Gossypium spp.) has identified regions of the genome with high concentrations of QTL for various traits called clusters and specific trait QTL called hotspots or meta-QTL (mQTL). However, the meta-analysis included all population types of Gossypium mixing both intraspecific G. hirsutum and interspecific G. hirsutum * G. barbadense populations. This study used 1,075 QTL from 58 publications on intraspecific G. hirsutum and 1,059 QTL from 30 publications on G. hirsutum * G. barbadense populations to perform a comprehensive comparative analysis of QTL clusters and hotspots between the two populations for yield, fiber and seed quality, and biotic and abiotic stress tolerance. QTL hotspots were further analyzed for mQTL within the hotspots using Biomercator V3 software. The ratio of QTL between the two population types was proportional yet differences in hotspot type and placement were observed between the two population types. However, on some chromosomes QTL clusters and hotspots were similar between the two populations. This shows that there are some universal QTL regions in the cultivated tetraploid cotton which remain consistent and some regions which differ between population types. This study for the first time elucidates the similarities and differences in QTL clusters and hotspots between intraspecific and interspecific populations, providing an important resource to cotton breeding programs in marker-assisted selection . PMID- 25501535 TI - Cytotoxicity and genotoxicity of butyl cyclohexyl phthalate. AB - Butyl cyclohexyl phthalate (BCP) is frequently used in personal care products, medical and household applications. The aim of this study is therefore to evaluate possible cytotoxicity and genotoxicity of BCP using in vitro and in vivo assays. The in vitro cytotoxic effect of BCP was investigated on mouse fibroblastic cell line (L929 cells) by MTT assay. The result showed that BCP inhibits cell proliferation in a concentration-dependent manner (IC50 value = 0.29 ug/mL). For genotoxicity assessment, tested concentrations of BCP demonstrated mutagenic activity in the presence of S9 mix with the Salmonella strain TA100 in the Ames test. Results showed that BCP is a secondary mutagenic substance even in low concentrations. The data obtained from 28-days repeated toxicity tests on mice revealed that BCP caused abnormalities of chromosome number, in a dose-dependent manner. Additionally, DNA damage, particularly DNA strand breaks, was assessed by Comet assay. The test result shows that BCP seemed to have genotoxic potential at a high level of exposure. PMID- 25501537 TI - DNA damage in human germ cell exposed to the some food additives in vitro. AB - The use of food additives has increased enormously in modern food technology but they have adverse effects in human healthy. The aim of this study was to investigate the DNA damage of some food additives such as citric acid (CA), benzoic acid (BA), brilliant blue (BB) and sunset yellow (SY) which were investigated in human male germ cells using comet assay. The sperm cells were incubated with different concentrations of these food additives (50, 100, 200 and 500 MUg/mL) for 1 h at 32 degrees C. The results showed for CA, BA, BB and SY a dose dependent increase in tail DNA%, tail length and tail moment in human sperm when compared to control group. When control values were compared in the studied parameters in the treatment concentrations, SY was found to exhibit the highest level of DNA damage followed by BB > BA > CA. However, none of the food additives affected the tail DNA%, tail length and tail moment at 50 and 100 MUg/mL. At 200 MUg/mL of SY, the tail DNA% and tail length of sperm were 95.80 +/- 0.28 and 42.56 +/- 4.66, for BB the values were 95.06 +/- 2.30 and 39.56 +/- 3.78, whereas for BA the values were 89.05 +/- 2.78 and 31.50 +/- 0.71, for CA the values were 88.59 +/- 6.45 and 13.59 +/- 2.74, respectively. However, only the highest concentration of the used food additives significantly affected the studied parameters of sperm DNA. The present results indicate that SY and BB are more harmful than BA and CA to human sperm in vitro. PMID- 25501538 TI - Organic additives enhance Fenton treatment of nitrobenzene at near-neutral pH. AB - Nitrobenzene (NB) is considered a toxic and potential carcinogen. Continuous contamination has resulted in an urgent need for remediation. Fenton reagent provides an advanced oxidation process that is capable of remediating recalcitrant nitroaromatic compounds, such as NB. However, one drawback of Fenton chemistry is that the reaction requires acidic pH to prevent precipitation of iron. Our studies have investigated Fenton conversion of NB at near-neutral pH with several organic additives: beta-cyclodextrin (beta-CD), hydroxypropyl-beta cyclodextrin (HPCD), carboxymethyl-beta-cyclodextrin (CMCD), and polyethylene glycol (molecular weight (MW) = 200, 400, and 600) for developing a process for treating NB-contaminated waters. The main factors influencing NB conversion, such as iron concentration, hydroxyl radicals (.OH) scavengers, and kinds or concentration of organic additives, were examined. Meanwhile, the reactive mechanisms and kinetics were investigated for Fenton conversion of NB. The results show that organic additives for Fenton process should be a good alternative for the advanced treatment of NB at near-neutral pH. PMID- 25501536 TI - A comparative study on efficiency of adult fibroblasts and amniotic fluid-derived stem cells as donor cells for production of hand-made cloned buffalo (Bubalus bubalis) embryos. AB - The efficiency of two cell types, namely adult fibroblasts, and amniotic fluid stem (AFS) cells as nuclear donor cells for somatic cell nuclear transfer by hand made cloning in buffalo (Bubalus bubalis) was compared. The in vitro expanded buffalo adult fibroblast cells showed a typical "S" shape growth curve with a doubling time of 40.8 h and stained positive for vimentin. The in vitro cultured undifferentiated AFS cells showed a doubling time of 33.2 h and stained positive for alkaline phosphatase, these cells were also found positive for undifferentiated embryonic stem cell markers like OCT-4, NANOG and SOX-2, which accentuate their pluripotent property. Further, when AFS cells were exposed to corresponding induction conditions, these cells differentiated into osteogenic, adipogenic and chondrogenic lineages which was confirmed through alizaran, oil red O and alcian blue staining, respectively. Cultured adult fibroblasts and AFS cells of passages 10-15 and 8-12, respectively, were used as nuclear donors. A total of 94 embryos were reconstructed using adult fibroblast as donor cells with cleavage and blastocyst production rate of 62.8 +/- 1.8 and 19.1 +/- 1.5, respectively. An overall cleavage and blastocyst formation rate of 71.1 +/- 1.2 and 29.9 +/- 2.2 was obtained when 97 embryos were reconstructed using AFS cells as donor cells. There were no significant differences (P > 0.05) in reconstructed efficiency between the cloned embryos derived from two donor cells, whereas the results showed that there were significant differences (P < 0.05) in cleavage and blastocyst rates between the cloned embryos derived from two donor cell groups. Average total cell numbers for blastocyst generated using AFS cells (172.4 +/- 5.8) was significantly (P < 0.05) higher than from adult fibroblasts (148.2 +/- 6.1). This study suggests that the in vitro developmental potential of the cloned embryos derived from AFS cells were higher than that of the cloned embryos derived from adult fibroblasts in buffalo hand-made cloning. PMID- 25501539 TI - A comprehensive study of the impact of polycyclic aromatic hydrocarbons (PAHs) contamination on salt marsh plants Spartina alterniflora: implication for plant microbe interactions in phytoremediation. AB - These pot experiments aimed to investigate the effects of polycyclic aromatic hydrocarbons (PAHs) on plant uptake, rhizophere, endophytic bacteria, and phytoremediation potentials of contaminated sediments. Salt marsh plant Spartina alterniflora was selected and cultivated in phenanthrene (PHE)- and pyrene (PYR) contaminated sediments (for 70 days). The results indicated that the amount of PHE removed from the sediments ranged from 13 to 36 %, while PYR ranged from 11 to 30 %. In rhizophere sediment, dehydrogenase activities were significantly (P < 0.05) enhanced by higher concentration of PHE treatments, while polyphenol oxidase activities were prohibited more than 10 % in non-rhizophere sediment. Compared with the control, PHE treatments had also significantly (P < 0.05) lower total microbial biomass; especially for gram-negative bacteria, this decrease was more than 24 %. However, the PYR treatments had little effect on the dehydrogenase, polyphenol oxidase, and total phospholipid fatty acid analysis (PLFA) biomass. The greatest abundance of PAH-ring hydroxylating dioxygenases isolated from gram-negative bacteria (PAH-RHDalpha-GN) of rhizoplane and endophyte in roots were found at high concentration of PHE treatments and increased by more than 100- and 3-fold, respectively. These results suggested that PAH pollution would result in the comprehensive effect on S. alterniflora, whose endophytic bacteria might play important roles in the phytoremediation potential of PAH-contaminated sediments. PMID- 25501540 TI - Bioaccumulation of dioxin-like PCBs and PBDEs by detritus-feeding fish in the Rio de la Plata estuary, Argentina. AB - A comparative analysis of bioaccumulation behavior of dioxin-like polychlorinated biphenyls (dlPCBs) and polybrominated biphenyl ethers (PBDEs) was conducted involving simultaneous measurements in settling particles and a detritivorous fish (Sabalo, Prochilodus linneatus) collected in the sewage impacted Buenos Aires coastal area. Focalization of dlPCBs and PBDEs along the detritus food chain is reflected by a 30-40-fold increase of dry weight PBDE and dlPCB concentrations from settling particles to fish (1.8 +/- 1.0 to 58 +/- 31 and 6.8 +/- 3.9 to 281 +/- 155 ng g(-1) dry weight (dw), respectively). In this transference, dlPCB congeners presented more conservative patterns than those of PBDEs, basically due to debromination of BDE 99 and 153 to BDE 47 in fish. Lipid/organic carbon-based biota-sediment accumulation factors (BSAFs) ranged between 5 and 20 (7.3 +/- 3.0 and 16 +/- 8.0 for PBDEs and dlPCBs). Congener specific BSAF of dlPCBs suggested a lower bioavailability of more planar non ortho-PCB versus mono-ortho-PCB suggesting higher affinity to organic matter. BSAFs of PBDEs differed markedly among bromine homolog groups, supporting the biotransformation-formation from higher brominated to lighter congeners. The log BSAFs-log K OW relationship of dlPCBs and PBDEs presented a parabolic pattern maximizing at log K OW 6-7, but PBDE curve differs reflecting biotransformation processes. PMID- 25501541 TI - Transmission of HIV drug resistance: lessons from sensitive screening assays. AB - PURPOSE OF REVIEW: The review discusses new technologies for the sensitive detection of HIV drug resistance, with a focus on applications in antiretroviral treatment (ART)-naive populations. RECENT FINDINGS: Conventional sequencing is well established for detecting HIV drug resistance in routine care and guides optimal treatment selection in patients starting ART. Access to conventional sequencing is nearly universal in Western countries, but remains limited in Asia, Latin America, and Africa. Technological advances now allow detection of resistance with greatly improved sensitivity compared with conventional sequencing, variably increasing the yield of resistance testing in ART-naive populations. There is strong cumulative evidence from retrospective studies that sensitive detection of resistant mutants in baseline plasma samples lacking resistance by conventional sequencing more than doubles the risk of virological failure after starting efavirenz-based or nevirapine-based ART. SUMMARY: Sensitive resistance testing methods are mainly confined to research applications and in this context have provided great insight into the dynamics of drug resistance development, persistence, and transmission. Adoption in care settings is becoming increasingly possible, although important challenges remain. Platforms for diagnostic use must undergo technical improvements to ensure good performance and ease of use, and clinical validation is required to ensure utility. PMID- 25501542 TI - Biochanin A inhibits endothelial cell functions and proangiogenic pathways: implications in glioma therapy. AB - Malignant gliomas, such as glioblastoma multiforme, are highly vascularized tumors of the central nervous system. A rich network of angiogenic vessels supporting glioma growth is an important therapeutic target in glioma therapy. In the past few years, small molecules have gained interest as multitargeting therapies for cancer. Biochanin A is a small, natural dietary isoflavone known for its anticancer potential. Previously, we have found that biochanin A inhibits invasion in human glioblastoma cells. In this study, we elucidated the antiangiogenic mechanisms of biochanin A using rat brain tumor (C6) and murine brain endothelial (bEnd.3) cells and an ex-vivo chick chorioallantoic membrane model. Biochanin A inhibited endothelial cell functions such as cell viability, migration, and invasion, as analyzed using MTT, scratch wound, and gelatin zymography assays. Activation of proangiogenic proteins (ERK/AKT/mTOR) was inhibited. Biochanin A also inhibited chemical hypoxia-inducible factor-1alpha and vascular endothelial growth factor in C6 cells. Results of chick chorioallantoic membrane assay showed that biochanin A inhibited blood vessel formation ex vivo. As these results suggest that biochanin A directly targets different facets of angiogenesis in vitro and ex vivo, this study provides a rationale for future preclinical evaluation of its efficacy against angiogenic gliomas. PMID- 25501543 TI - Values for gender roles and relations among high school and non-high school adolescents in a Maya community in Chiapas, Mexico. AB - In the current study, I describe values for gender roles and cross-sex relations among adolescents growing up in a southern Mexican Maya community in which high school was introduced in 1999. A total of 80 adolescent girls and boys, half of whom were attending the new high school, provided their opinions on two ethnographically derived vignettes that depicted changes in gender roles and relations occurring in their community. Systematic coding revealed that adolescents not enrolled in high school tended to prioritise ascribed and complementary gender roles and emphasise the importance of family mediation in cross-sex relations. Adolescents who were enrolled in high school tended to prioritise equivalent and chosen gender roles, and emphasised personal responsibility and personal fulfillment in cross-sex relations. Perceptions of risks and opportunities differed by gender: girls favourably evaluated the expansion of adult female role options, but saw risks in personal negotiations of cross-sex relations; boys emphasised the loss of the female homemaker role, but favourably evaluated new opportunities for intimacy in cross-sex relations. PMID- 25501544 TI - A high-fat diet modulates iron metabolism but does not promote liver fibrosis in hemochromatotic Hjv-/- mice. AB - Hemojuvelin (Hjv) is a membrane protein that controls body iron metabolism by enhancing signaling to hepcidin. Hjv mutations cause juvenile hemochromatosis, a disease of systemic iron overload. Excessive iron accumulation in the liver progressively leads to inflammation and disease, such as fibrosis, cirrhosis, or hepatocellular cancer. Fatty liver (steatosis) may also progress to inflammation (steatohepatitis) and liver disease, and iron is considered as pathogenic cofactor. The aim of this study was to investigate the pathological implications of parenchymal iron overload due to Hjv ablation in the fatty liver. Wild-type (WT) and Hjv(-/-) mice on C57BL/6 background were fed a standard chow, a high-fat diet (HFD), or a HFD supplemented with 2% carbonyl iron (HFD+Fe) for 12 wk. The animals were analyzed for iron and lipid metabolism. As expected, all Hjv(-/-) mice manifested higher serum and hepatic iron and diminished hepcidin levels compared with WT controls. The HFD reduced iron indexes and promoted liver steatosis in both WT and Hjv(-/-) mice. Notably, steatosis was attenuated in Hjv( /-) mice on the HFD+Fe regimen. Hjv(-/-) animals gained less body weight and exhibited reduced serum glucose and cholesterol levels. Histological and ultrastructural analysis revealed absence of iron-induced inflammation or liver fibrosis despite early signs of liver injury (expression of alpha-smooth muscle actin). We conclude that parenchymal hepatic iron overload does not suffice to trigger progression of liver steatosis to steatohepatitis or fibrosis in C57BL/6 mice. PMID- 25501545 TI - Increased 4-hydroxynonenal protein adducts in male GSTA4-4/PPAR-alpha double knockout mice enhance injury during early stages of alcoholic liver disease. AB - To test the significance of lipid peroxidation in the development of alcoholic liver injury, an ethanol (EtOH) liquid diet was fed to male 129/SvJ mice (wild type, WT) and glutathione S-transferase A4-4-null (GSTA4-/-) mice for 40 days. GSTA4-/- mice were crossed with peroxisome proliferator-activated receptor-alpha null mice (PPAR-alpha-/-), and the effects of EtOH in the resulting double knockout (dKO) mice were compared with the other strains. EtOH increased lipid peroxidation in all except WT mice (P < 0.05). Increased steatosis and mRNA expression of the inflammatory markers CXCL2, tumor necrosis factor-alpha (TNF alpha), and alpha-smooth muscle actin (alpha-SMA) were observed in EtOH GSTA4-/- compared with EtOH WT mice (P < 0.05). EtOH PPAR-alpha-/- mice had increased steatosis, serum alanine aminotransferase (ALT), and hepatic CD3+ T cell populations and elevated mRNA encoding CD14, CXCL2, TNF-alpha, IL-6, CD138, transforming growth factor-beta, platelet-derived growth factor receptor-beta (PDGFR-beta), matrix metalloproteinase (MMP)-9, MMP-13, alpha-SMA, and collagen type 1 compared with EtOH WT mice. EtOH-fed dKO mice displayed elevation of periportal hepatic 4-hydroxynonenal adducts and serum antibodies against malondialdehyde adducts compared with EtOH feeding of GSTA4-/-, PPAR-alpha-/-, and WT mice (P < 0.05). ALT was higher in EtOH dKO mice compared with all other groups (P < 0.001). EtOH-fed dKO mice displayed elevated mRNAs for TNF-alpha and CD14, histological evidence of fibrosis, and increased PDGFR, MMP-9, and MMP-13 mRNAs compared with the EtOH GSTA4-/- or EtOH PPAR-alpha-/- genotype (P < 0.05). These findings demonstrate the central role lipid peroxidation plays in mediating progression of alcohol-induced necroinflammatory liver injury, stellate cell activation, matrix remodeling, and fibrosis. PMID- 25501546 TI - Vasoactive intestinal peptide prevents PKCepsilon-induced intestinal epithelial barrier disruption during EPEC infection. AB - We previously showed that vasoactive intestinal peptide (VIP) protects against bacterial pathogen-induced epithelial barrier disruption and colitis, although the mechanisms remain poorly defined. The aim of the current study was to identify cellular pathways of VIP-mediated protection with use of pharmacological inhibitors during enteropathogenic Escherichia coli (EPEC) infection of Caco-2 cell monolayers and during Citrobacter rodentium-induced colitis. EPEC-induced epithelial barrier disruption involved the PKC pathway but was independent of functional cAMP, Rho, and NF-kappaB pathways. VIP mediated its protective effects by inhibiting EPEC-induced PKC activity and increasing expression of the junctional protein claudin-4. Short-term treatment with TPA, which is known to activate PKC, was inhibited by VIP pretreatment, while PKC degradation via long term treatment with TPA mimicked the protective actions of VIP. Immunostaining for specific PKC isotypes showed upregulated expression of PKCtheta and PKCepsilon during EPEC infection. Treatment with specific inhibitors revealed a critical role for PKCepsilon in EPEC-induced barrier disruption. Furthermore, activation of PKCepsilon and loss of barrier integrity correlated with claudin-4 degradation. In contrast, inhibition of PKCepsilon by VIP pretreatment or the PKCepsilon inhibitor maintained membrane-bound claudin-4 levels, along with barrier function. Finally, in vivo treatment with the PKCepsilon inhibitor protected mice from C. rodentium-induced colitis. In conclusion, EPEC infection increases intracellular PKCepsilon levels, leading to decreased claudin-4 levels and compromising epithelial barrier integrity. VIP inhibits PKCepsilon activation, thereby attenuating EPEC-induced barrier disruption. PMID- 25501547 TI - Cytotoxic T lymphocytes and natural killer cells display impaired cytotoxic functions and reduced activation in patients with alcoholic hepatitis. AB - The dynamics and role of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and NKT cells in the life-threatening inflammatory disease alcoholic hepatitis is largely unknown. These cells directly kill infected and damaged cells through, e.g., degranulation and interferon-gamma (IFNgamma) production, but cause tissue damage if overactivated. They also assist tissue repair via IL 22 production. We, therefore, aimed to investigate the frequency, functionality, and activation state of such cells in alcoholic hepatitis. We analyzed blood samples from 24 severe alcoholic hepatitis patients followed for 30 days after diagnosis. Ten healthy abstinent volunteers and 10 stable abstinent alcoholic cirrhosis patients were controls. Using flow cytometry we assessed cell frequencies, NK cell degranulation capacity following K562 cell stimulation, activation by natural killer group 2 D (NKG2D) expression, and IL-22 and IFNgamma production. In alcoholic hepatitis we found a decreased frequency of CTLs compared with healthy controls (P < 0.001) and a similar trend for NK cells (P = 0.089). The NK cell degranulation capacity was reduced by 25% compared with healthy controls (P = 0.02) and by 50% compared with cirrhosis patients (P = 0.04). Accordingly, the NKG2D receptor expression was markedly decreased on NK cells, CTLs, and NKT cells (P < 0.05, all). The frequencies of IL-22-producing CTLs and NK cells were doubled compared with healthy controls (P < 0.05, all) but not different from cirrhosis patients. This exploratory study for the first time showed impaired cellular cytotoxicity and activation in alcoholic hepatitis. This is unlikely to cause hepatocyte death but may contribute toward the severe immune incompetence. The results warrant detailed and mechanistic studies. PMID- 25501548 TI - Platinum-based chemotherapy: gastrointestinal immunomodulation and enteric nervous system toxicity. AB - The efficacy of chemotherapeutic treatment of colorectal cancer is challenged by severe gastrointestinal side effects, which include nausea, vomiting, constipation, and diarrhea. These symptoms can persist long after the treatment has been ceased. An emerging concept is the ability of platinum-based drugs to stimulate immunity, which is in contrast to conventional chemotherapeutic agents that are immunosuppressive. Here, we review the immunomodulatory aspects of platinum-based anticancer chemotherapeutics and their impact on gastrointestinal innervation. Given the bidirectional communication between the enteric nervous system and gastrointestinal immune system; exploring the consequences of platinum induced immunogenicity will facilitate better understanding of gut dysfunction caused by chemotherapeutic agents. We propose that the development of future successful chemotherapeutics should rely on targeting the mechanisms underlying long-term gastrointestinal side effects. PMID- 25501549 TI - Endothelial Gab1 deficiency aggravates splenomegaly in portal hypertension independent of angiogenesis. AB - Certain pathological changes, including angiogenesis, actively contribute to the pathogenesis of splenomegaly in portal hypertension (PH), although the detailed molecular and cellular mechanisms remain elusive. In this study, we demonstrated that endothelial Grb-2-associated binder 1 (Gab1) plays a negative role in PH associated splenomegaly independent of angiogenesis. PH, which was induced by partial portal vein ligation, significantly enhanced Gab1 expression in endothelial cells in a time-dependent manner. Compared with controls, endothelium specific Gab1 knockout (EGKO) mice exhibited a significant increase in spleen size while their PH levels remained similar. Pathological analysis indicated that EGKO mice developed more severe hyperactive white pulp and fibrosis in the enlarged spleen but less angiogenesis in both the spleen and mesenteric tissues. Mechanistic studies showed that the phosphorylation of endothelial nitric oxide synthase (eNOS) in EGKO mice was significantly lower than in controls. In addition, the dysregulation of fibrosis and inflammation-related transcription factors [e.g., Kruppel-like factor (KLF) 2 and KLF5] and the upregulation of cytokine genes (e.g., TNF-alpha and IL-6) were observed in EGKO mice. We thus propose that endothelial Gab1 mediates multiple pathways in inhibition of the pathogenesis of splenomegaly in PH via prevention of endothelial dysfunction and overproduction of proinflammatory/profibrotic cytokines. PMID- 25501550 TI - Effects of gap junction inhibition on contraction waves in the murine small intestine in relation to coupled oscillator theory. AB - Waves of contraction in the small intestine correlate with slow waves generated by the myenteric network of interstitial cells of Cajal. Coupled oscillator theory has been used to explain steplike gradients in the frequency (frequency plateaux) of contraction waves along the length of the small intestine. Inhibition of gap junction coupling between oscillators should lead to predictable effects on these plateaux and the wave dislocation (wave drop) phenomena associated with their boundaries. It is these predictions that we wished to test. We used a novel multicamera diameter-mapping system to measure contraction along 25- to 30-cm lengths of murine small intestine. There were typically two to three plateaux per length of intestine. Dislocations could be limited to the wavefronts immediately about the terminated wave, giving the appearance of a three-pronged fork, i.e., a fork dislocation; additionally, localized decreases in velocity developed across a number of wavefronts, ending with the terminated wave, which could appear as a fork, i.e., slip dislocations. The gap junction inhibitor carbenoxolone increased the number of plateaux and dislocations and decreased contraction wave velocity. In some cases, the usual frequency gradient was reversed, with a plateau at a higher frequency than its proximal neighbor; thus fork dislocations were inverted, and the direction of propagation was reversed. Heptanol had no effect on the frequency or velocity of contractions but did reduce their amplitude. To understand intestinal motor patterns, the pacemaker network of the interstitial cells of Cajal is best evaluated as a system of coupled oscillators. PMID- 25501552 TI - Phosphorylation dynamics of radixin in hypoxia-induced hepatocyte injury. AB - The most prominent ezrin-radixin-moesin protein in hepatocytes is radixin, which is localized primarily at the canalicular microvilli and appears to be important in regulation of cell polarity and in localizing the multidrug resistance associated protein 2 (Mrp-2) function. Our aim was to investigate how hypoxia affects radixin distribution and Mrp-2 function. We created wild-type and mutant constructs (in adenoviral vectors), which were expressed in WIF-B cells. The cellular distribution of Mrp-2 and radixin was visualized by fluorescence microscopy, and a 5-chloromethylfluorescein diacetate (CMFDA) assay was used to measure Mrp-2 function. Under usual conditions, cells infected with wild-type radixin, nonphosphorylatable radixin-T564A, and radixin-T564D (active phospho mimicking mutant) were found to be heavily expressed in canalicular membrane compartment vacuoles, typically colocalizing with Mrp-2. In contrast, after hypoxia for 24 h, both endogenous and overexpressed wild-type radixin and the radixin-T564A mutant were found to be translocated to the cytoplasmic space. However, distribution of the radixin-T564D mutant, which mimics constant phosphorylation, was remarkably different, being associated with canalicular membranes even in hypoxic conditions. This dominant-active construct also prevented dissociation of radixin from the plasma membrane. Hypoxia also led to Mrp-2 mislocalization and caused Mrp-2 to be dissociated from radixin; the radixin phospho-mimicking mutant (T564D) abrogated this effect of hypoxia. Finally, hypoxia diminished the secretory response (measured using the CMFDA assay) in WIF-B cells, and the dominant-active construct (radixin-T567D) rescued this phenotype. Taken collectively, these findings suggest that radixin regulates Mrp-2 localization and function in hepatocytes and is important in hypoxic liver injury. PMID- 25501553 TI - Child of mother who drank excessively was not victim of crime, court rules. PMID- 25501551 TI - Micro-RNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis. AB - Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) is the common pathophysiological process resulting from chronic liver inflammation and oxidative stress. Although significant research has been carried out on the role of leptin-induced NADPH oxidase in fibrogenesis, the molecular mechanisms that connect the leptin-NADPH oxidase axis in upregulation of transforming growth factor (TGF)-beta signaling have been unclear. We aimed to investigate the role of leptin-mediated upregulation of NADPH oxidase and its subsequent induction of micro-RNA 21 (miR21) in fibrogenesis. Human NASH livers and a high-fat (60% kcal) diet-fed chronic mouse model, where hepatotoxin bromodichloromethane was used to induce NASH, were used for this study. To prove the role of the leptin-NADPH oxidase-miR21 axis, mice deficient in genes for leptin, p47phox, and miR21 were used. Results showed that wild-type mice and human livers with NASH had increased oxidative stress, increased p47phox expression, augmented NF-kappaB activation, and increased miR21 levels. These mice and human livers showed increased TGF beta, SMAD2/3-SMAD4 colocalizations in the nucleus, increased immunoreactivity against Col1alpha, and alpha-SMA with a concomitant decrease in protein levels of SMAD7. Mice that were deficient in leptin or p47phox had decreased activated NF kappaB and miR21 levels, suggesting the role of leptin and NADPH oxidase in inducing NF-kappaB-mediated miR21 expression. Further miR21 knockout mice had decreased colocalization events of SMAD2/3-SMAD4 in the nucleus, increased SMAD7 levels, and decreased fibrogenesis. Taken together, the studies show the novel role of leptin-NADPH oxidase induction of miR21 as a key regulator of TGF-beta signaling and fibrogenesis in experimental and human NASH. PMID- 25501554 TI - Clinical and haemodynamic outcomes in 804 patients receiving the Freedom SOLO stentless aortic valve: results from an international prospective multicentre study. AB - OBJECTIVES: The Freedom SOLOTM valve (Sorin Group, Italy) is a stentless aortic bioprosthesis designed for simplified implantation. The present multicentre study is the largest prospective evaluation of this prosthesis. Herein, we report on outcomes at 3-year follow-up. METHODS: From March 2009 to February 2013, a total of 804 consecutive patients (mean age 74.9 +/- 6.3 years; 45.1% females) underwent aortic valve replacement with the Freedom SOLOTM valve at 33 centres. Concomitant procedures (70.2% coronary artery bypass grafting) were performed in 376 patients. The cumulative follow-up included 1100 patient-years (mean 16.5 +/- 10.8 months; range: 0-40.5 months). RESULTS: Sixty-four patients died (14 early, 50 late); 12 deaths (1 early, 11 late) were valve-related. Operative mortality (30 days) was 1.7%. At 3 years, overall survival was 82.6% [95% confidence interval (CI) 75.5-87.8%] and freedom from valve-related death was 95.5% (95% CI 89.2-98.2%). Linearized late event rates were 0.82%/patient-years for non structural valve dysfunction, 0.55%/patient-years for structural valve deterioration, 1.55%/patient-years for endocarditis, 3.64%/patient-years for thromboembolism and 3.18%/patient-years for bleeding. In total, there were 22 reinterventions [19 valve explants, 2 refixations, 1 transcatheter aortic valve intervention (TAVI)] for endocarditis (11), non-structural dysfunction (9) and structural valve deterioration (2). Freedom from reintervention was 95.2% (95% CI 91.2-97.4%) at 3 years. There were no instances of valve thrombosis or haemolysis. At 1, 2 and 3 years, 97.0, 95.5 and 91.4% of patients were in NYHA class I or II. Between discharge and 3 years after surgery, mean transvalvular gradients exhibited a non-significant increase (6.5 +/- 4.3 vs 8.7 +/- 6.5 mmHg), whereas effective orifice area index remained stable (0.9 +/- 0.2 vs 0.8 +/- 0.3 cm(2)/m(2)). At 3 years, no patient presented with more than mild aortic regurgitation. Left ventricular mass index decreased significantly between discharge and 1 year after surgery (139.4 +/- 40.9 vs 122.4 +/- 35.3 g/m(2), P < 0.001) and remained unchanged thereafter. Left ventricular size and function did not change over time. CONCLUSIONS: The Freedom SOLOTM valve is a unique stentless pericardial bioprosthesis whose design favours haemodynamic performance and thus facilitates left ventricular reverse remodelling. In terms of survival, morbidity and functional status, it is associated with beneficial outcomes up to 3 years after surgery. Ongoing follow-up will assess the valve at the long-term course. PMID- 25501556 TI - Long leukocyte telomere length at diagnosis is a risk factor for dementia progression in idiopathic parkinsonism. AB - Telomere length (TL) is regarded as a marker of cellular aging due to the gradual shortening by each cell division, but is influenced by a number of factors including oxidative stress and inflammation. Parkinson's disease and atypical forms of parkinsonism occur mainly in the elderly, with oxidative stress and inflammation in afflicted cells. In this study the relationship between blood TL and prognosis of 168 patients with idiopathic parkinsonism (136 Parkinson's disease [PD], 17 Progressive Supranuclear Palsy [PSP], and 15 Multiple System Atrophy [MSA]) and 30 controls was investigated. TL and motor and cognitive performance were assessed at baseline (diagnosis) and repeatedly up to three to five years follow up. No difference in TL between controls and patients was shown at baseline, nor any significant difference in TL stability or attrition during follow up. Interestingly, a significant relationship between TL at diagnosis and cognitive phenotype at follow up in PD and PSP patients was found, with longer mean TL at diagnosis in patients that developed dementia within three years. PMID- 25501557 TI - Disrupted calcium release as a mechanism for atrial alternans associated with human atrial fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia, but our knowledge of the arrhythmogenic substrate is incomplete. Alternans, the beat-to-beat alternation in the shape of cardiac electrical signals, typically occurs at fast heart rates and leads to arrhythmia. However, atrial alternans have been observed at slower pacing rates in AF patients than in controls, suggesting that increased vulnerability to arrhythmia in AF patients may be due to the proarrythmic influence of alternans at these slower rates. As such, alternans may present a useful therapeutic target for the treatment and prevention of AF, but the mechanism underlying alternans occurrence in AF patients at heart rates near rest is unknown. The goal of this study was to determine how cellular changes that occur in human AF affect the appearance of alternans at heart rates near rest. To achieve this, we developed a computational model of human atrial tissue incorporating electrophysiological remodeling associated with chronic AF (cAF) and performed parameter sensitivity analysis of ionic model parameters to determine which cellular changes led to alternans. Of the 20 parameters tested, only decreasing the ryanodine receptor (RyR) inactivation rate constant (kiCa) produced action potential duration (APD) alternans seen clinically at slower pacing rates. Using single-cell clamps of voltage, fluxes, and state variables, we determined that alternans onset was Ca2+-driven rather than voltage-driven and occurred as a result of decreased RyR inactivation which led to increased steepness of the sarcoplasmic reticulum (SR) Ca2+ release slope. Iterated map analysis revealed that because SR Ca2+ uptake efficiency was much higher in control atrial cells than in cAF cells, drastic reductions in kiCa were required to produce alternans at comparable pacing rates in control atrial cells. These findings suggest that RyR kinetics may play a critical role in altered Ca2+ homeostasis which drives proarrhythmic APD alternans in patients with AF. PMID- 25501555 TI - The nphp-2 and arl-13 genetic modules interact to regulate ciliogenesis and ciliary microtubule patterning in C. elegans. AB - Cilia are microtubule-based cellular organelles that mediate signal transduction. Cilia are organized into several structurally and functionally distinct compartments: the basal body, the transition zone (TZ), and the cilia shaft. In vertebrates, the cystoprotein Inversin localizes to a portion of the cilia shaft adjacent to the TZ, a region termed the "Inversin compartment" (InvC). The mechanisms that establish and maintain the InvC are unknown. In the roundworm C. elegans, the cilia shafts of amphid channel and phasmid sensory cilia are subdivided into two regions defined by different microtubule ultrastructure: a proximal doublet-based region adjacent to the TZ, and a distal singlet-based region. It has been suggested that C. elegans cilia also possess an InvC, similarly to mammalian primary cilia. Here we explored the biogenesis, structure, and composition of the C. elegans ciliary doublet region and InvC. We show that the InvC is conserved and distinct from the doublet region. nphp-2 (the C. elegans Inversin homolog) and the doublet region genes arl-13, klp-11, and unc 119 are redundantly required for ciliogenesis. InvC and doublet region genes can be sorted into two modules-nphp-2+klp-11 and arl-13+unc-119-which are both antagonized by the hdac-6 deacetylase. The genes of this network modulate the sizes of the NPHP-2 InvC and ARL-13 doublet region. Glutamylation, a tubulin post translational modification, is not required for ciliary targeting of InvC and doublet region components; rather, glutamylation is modulated by nphp-2, arl-13, and unc-119. The ciliary targeting and restricted localization of NPHP-2, ARL-13, and UNC-119 does not require TZ-, doublet region, and InvC-associated genes. NPHP 2 does require its calcium binding EF hand domain for targeting to the InvC. We conclude that the C. elegans InvC is distinct from the doublet region, and that components in these two regions interact to regulate ciliogenesis via cilia placement, ciliary microtubule ultrastructure, and protein localization. PMID- 25501558 TI - Thrombospondin-1 production is enhanced by Porphyromonas gingivalis lipopolysaccharide in THP-1 cells. AB - Periodontitis is a chronic inflammatory disease caused by gram-negative anaerobic bacteria. Monocytes and macrophages stimulated by periodontopathic bacteria induce inflammatory mediators that cause tooth-supporting structure destruction and alveolar bone resorption. In this study, using a DNA microarray, we identified the enhanced gene expression of thrombospondin-1 (TSP-1) in human monocytic cells stimulated by Porphyromonas gingivalis lipopolysaccharide (LPS). TSP-1 is a multifunctional extracellular matrix protein that is upregulated during the inflammatory process. Recent studies have suggested that TSP-1 is associated with rheumatoid arthritis, diabetes mellitus, and osteoclastogenesis. TSP-1 is secreted from neutrophils, monocytes, and macrophages, which mediate immune responses at inflammatory regions. However, TSP-1 expression in periodontitis and the mechanisms underlying TSP-1 expression in human monocytic cells remain unknown. Here using real-time RT-PCR, we demonstrated that TSP-1 mRNA expression level was significantly upregulated in inflamed periodontitis gingival tissues and in P. gingivalis LPS-stimulated human monocytic cell line THP-1 cells. TSP-1 was expressed via Toll-like receptor (TLR) 2 and TLR4 pathways. In P. gingivalis LPS stimulation, TSP-1 expression was dependent upon TLR2 through the activation of NF-kappaB signaling. Furthermore, IL-17F synergistically enhanced P. gingivalis LPS-induced TSP-1 production. These results suggest that modulation of TSP-1 expression by P. gingivalis plays an important role in the progression and chronicity of periodontitis. It may also contribute a new target molecule for periodontal therapy. PMID- 25501559 TI - Spatial normalization of reverse phase protein array data. AB - Reverse phase protein arrays (RPPA) are an efficient, high-throughput, cost effective method for the quantification of specific proteins in complex biological samples. The quality of RPPA data may be affected by various sources of error. One of these, spatial variation, is caused by uneven exposure of different parts of an RPPA slide to the reagents used in protein detection. We present a method for the determination and correction of systematic spatial variation in RPPA slides using positive control spots printed on each slide. The method uses a simple bi-linear interpolation technique to obtain a surface representing the spatial variation occurring across the dimensions of a slide. This surface is used to calculate correction factors that can normalize the relative protein concentrations of the samples on each slide. The adoption of the method results in increased agreement between technical and biological replicates of various tumor and cell-line derived samples. Further, in data from a study of the melanoma cell-line SKMEL-133, several slides that had previously been rejected because they had a coefficient of variation (CV) greater than 15%, are rescued by reduction of CV below this threshold in each case. The method is implemented in the R statistical programing language. It is compatible with MicroVigene and SuperCurve, packages commonly used in RPPA data analysis. The method is made available, along with suggestions for implementation, at http://bitbucket.org/rppa_preprocess/rppa_preprocess/src. PMID- 25501561 TI - Aging of communities: communities of aging. PMID- 25501560 TI - Evidence for a role of the polysaccharide capsule transport proteins in pertussis pathogenesis. AB - Polysaccharide (PS) capsules are important virulence determinants for many bacterial pathogens. Bordetella pertussis, the agent of whooping cough, produces a surface associated microcapsule but its role in pertussis pathogenesis remained unknown. Here we showed that the B. pertussis capsule locus is expressed in vivo in murine lungs and that absence of the membrane-associated protein KpsT, involved in the transport of the PS polymers across the envelope, but not the surface-exposed PS capsule itself, affects drastically B. pertussis colonization efficacy in mice. Microarray analysis revealed that absence of KpsT in B. pertussis resulted in global down-regulation of gene expression including key virulence genes regulated by BvgA/S, the master two-component system. Using a BvgS phase-locked mutant, we demonstrated a functional link between KpsT and BvgA/S-mediated signal transduction. Whereas pull-down assays do not support physical interaction between BvgS sensor and any of the capsule locus encoded proteins, absence of KpsT impaired BvgS oligomerization, necessary for BvgS function. Furthermore, complementation studies indicated that instead of KpsT alone, the entire PS capsule transport machinery spanning the cell envelope likely plays a role in BvgS-mediated signal transduction. Our work thus provides the first experimental evidence of a role for a virulence-repressed gene in pertussis pathogenesis. PMID- 25501562 TI - Determinants of health-related quality of life among residents with and without COPD in a historically industrialised area. AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) is associated with substantial morbidity, including impaired health-related quality of life (HRQoL). Despite the prominent role of occupational factors in the aetiology of COPD, the relationship between these exposures and HRQoL has not been well elucidated. METHODS: A subpopulation from an epidemiological study, designed to assess the workplace contribution to COPD, was administered the EQ5D HRQoL tool. Demographics, an index of economic deprivation, health endpoints including the presence of COPD and lung function were also recorded. Workplace exposures were categorised using both self-reported exposures and also by the use of an established job exposure matrix (JEM). RESULTS: A total of 623 individuals participated (mean age 67.1 years). One hundred and forty-eight (24%) reported having received a physician diagnosis of COPD, 355 (57%) were male, and 386 (62%) were ever smokers. As anticipated, the presence of COPD was associated with a poorer HRQoL. Additionally, however, HRQoL was significantly lower in the presence of both self-reported vapours, gases, dusts and fumes exposure and JEM based exposure irrespective of the presence of COPD. Regression analysis, adjusting for a variety of covariates including the presence of COPD, confirmed a persisting higher likelihood of occupational exposure categorised by JEM being associated with poorer HRQoL scores (beta estimate: -0.069; p < 0.05). CONCLUSIONS: Our findings suggest that work may have an important link to HRQoL and that this effect can persist even among those who have retired. In those with COPD, HRQoL is worse than among those without this condition, but the work associated decrement appears to be similar across both groups. PMID- 25501564 TI - E. coli cells expressing the Baeyer-Villiger monooxygenase 'MO14' (ro03437) from Rhodococcus jostii RHA1 catalyse the gram-scale resolution of a bicyclic ketone in a fermentor. AB - The Baeyer-Villiger monooxygenase (BVMO) 'MO14' from Rhodococcus jostii RHA1, is an enantioselective BVMO that catalyses the resolution of the model ketone substrate bicyclo[3.2.0]hept-2-en-6-one to the (1S,5R)-2-oxa lactone and the residual (1S,5R)-substrate enantiomer. This regio-plus enantioselective behaviour is highly unusual for BVMOs, which often perform enantiodivergent biotransformations of this substrate. The scaleability of the transformation was investigated using fermentor-based experiments, in which variables including gene codon optimisation, temperature and substrate concentration were investigated. E. coli cells expressing MO14 catalysed the resolution of bicyclo[3.2.0]hept-2-en-6 one to yield (1S,5R)-2-oxa lactone of >99% ee and (1S,5R)-ketone of 96% ee after 14 h at a temperature of 16 degrees C and a substrate concentration of 0.5 g L( 1) (4.5 mM). MO14 is thus a promising biocatalyst for the production of enantio enriched ketones and lactones derived from the [3.2.0] platform. PMID- 25501563 TI - Adverse birth outcomes and maternal complications in licensed cosmetologists and manicurists in California. AB - PURPOSE: Due to concerns around occupational chemical exposures, this study sought to examine whether women working as cosmetologists (providing hair and nail care services) and manicurists (providing only nail care services) have an elevated risk for adverse pregnancy outcomes. METHODS: In this population-based retrospective study of cosmetologists and manicurists in California, we linked cosmetology licensee and birth registry files to identify births during 1996 2009. We compared outcomes among cosmetologists and manicurists to those of the general female population and to women from other industries. We also conducted restricted analyses for Vietnamese women, who comprise a significant proportion of the workforce. RESULTS: There was little evidence of increased risk for adverse birth outcomes, but we observed an association for small for gestational age (SGA) among Vietnamese manicurists (OR 1.39; 95 % CI 1.08-1.78) and cosmetologists (OR 1.40; 95 % CI 1.08-1.83) when compared to other working women. Some maternal complications were observed, notably an increased risk for gestational diabetes (OR 1.28; 95 % CI 1.10-1.50 for manicurists; OR 1.19; 95 % CI 1.07-1.33 for cosmetologists) compared with the general population, which further elevated when restricted to Vietnamese workers (OR 1.59; 95 % CI 1.20 2.11 for manicurists; OR 1.49; 95 % CI 1.04-2.11 for cosmetologists). Additionally, we observed an association for placentia previa among manicurists (OR 1.46; 95 % CI 1.08-1.97) and cosmetologists (OR 1.22; 95 % CI 1.02-1.46) compared with the general population. CONCLUSIONS: Women in the nail and hair care industry may be potentially at increased risk for some maternal complications, although further research is warranted. Vietnamese workers may also have increased risk for SGA. PMID- 25501565 TI - Ebola, ethics, and the question of culture. PMID- 25501566 TI - APOBEC3 enzymes restrict marginal zone B cells. AB - In general, a long-lasting immune response to viruses is achieved when they are infectious and replication competent. In the mouse, the neutralizing antibody response to Friend murine leukemia virus is contributed by an allelic form of the enzyme Apobec3 (abbreviated A3). This is counterintuitive because A3 directly controls viremia before the onset of adaptive antiviral immune responses. It suggests that A3 also affects the antibody response directly. Here, we studied the relative size of cell populations of the adaptive immune system as a function of A3 activity. We created a transgenic mouse that expresses all seven human A3 enzymes and compared it to WT and mouse A3-deficient mice. A3 enzymes decreased the number of marginal zone B cells, but not the number of follicular B or T cells. When mouse A3 was knocked out, the retroelement hitchhiker-1 and sialyl transferases encoded by genes close to it were overexpressed three and two orders of magnitude, respectively. We suggest that A3 shifts the balance, from the fast antibody response mediated by marginal zone B cells with little affinity maturation, to a more sustained germinal center B-cell response, which drives affinity maturation and, thereby, a better neutralizing response. PMID- 25501570 TI - Dynamic assembly of DNA and polylysine mediated by electric energy. AB - Under an electric field, the complexes formed by DNA and polylysine exhibit novel features, such as selective merging of particles, ejecting of daughter vehicles, and differentiation of particles of varying mobility. The mobility of the complex could be three times faster than that of free DNA. PMID- 25501567 TI - Bone response to fluoride exposure is influenced by genetics. AB - Genetic factors influence the effects of fluoride (F) on amelogenesis and bone homeostasis but the underlying molecular mechanisms remain undefined. A label free proteomics approach was employed to identify and evaluate changes in bone protein expression in two mouse strains having different susceptibilities to develop dental fluorosis and to alter bone quality. In vivo bone formation and histomorphometry after F intake were also evaluated and related to the proteome. Resistant 129P3/J and susceptible A/J mice were assigned to three groups given low-F food and water containing 0, 10 or 50 ppmF for 8 weeks. Plasma was evaluated for alkaline phosphatase activity. Femurs, tibiae and lumbar vertebrae were evaluated using micro-CT analysis and mineral apposition rate (MAR) was measured in cortical bone. For quantitative proteomic analysis, bone proteins were extracted and analyzed using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS), followed by label-free semi-quantitative differential expression analysis. Alterations in several bone proteins were found among the F treatment groups within each mouse strain and between the strains for each F treatment group (ratio >=1.5 or <=0.5; p<0.05). Although F treatment had no significant effects on BMD or bone histomorphometry in either strain, MAR was higher in the 50 ppmF 129P3/J mice than in the 50 ppmF A/J mice treated with 50 ppmF showing that F increased bone formation in a strain-specific manner. Also, F exposure was associated with dose-specific and strain-specific alterations in expression of proteins involved in osteogenesis and osteoclastogenesis. In conclusion, our findings confirm a genetic influence in bone response to F exposure and point to several proteins that may act as targets for the differential F responses in this tissue. PMID- 25501569 TI - Tissue-specific expression of a soybean hypersensitive-induced response (HIR) protein gene promoter. AB - A Glycine max gene encoding a putative protein similar to hypersensitive-induced response proteins (HIR) was identified as a gene with preferred expressions in flowers and developing seeds by whole transcriptome gene expression profiling. Its promoter gm-hir1 was cloned and revealed to strongly express a fluorescence reporter gene primarily in integuments, anther tapetum, and seed coat with unique tissue-specificity. Expression in the inner integument was apparent prior to pollination, while expression in the outer integument started to develop from the micropylar end outward as the embryo matured. A 5'-deletion study showed that the promoter can be truncated to 600 bp long relative to the translation start site without affecting expression. A positive regulatory element was identified between 600 and 481 bp that controls expression in the inner integument, with no noticeable effect on expression in the outer integument or tapetum. Additionally, removal of the 5'UTR intron had no effect on levels or location of gm-hir1 expression while truncation to 370 bp resulted in a complete loss of expression suggesting that elements controlling both the outer integument and tapetum expression are located within the 481-370 bp region. PMID- 25501571 TI - Pathogenesis and treatment of chronic kidney disease: a review of our recent basic and clinical data. AB - Chronic kidney disease (CKD) is a worldwide public health problem that affects millions of people from all racial and ethnic groups. At end of 2013, over 300,000 Japanese patients had maintenance dialysis therapy (JSDT). In Japan, the major causes of end stage kidney disease (ESKD) are chronic glomerulonephritis (particularly IgA nephropathy), type 2 diabetic nephropathy, and hypertensive nephrosclerosis. Hypertension is a major factor driving the progression of CKD to ESKD. Since many features of the pathogenesis of IgA nephropathy are still obscure, specific treatment is not yet available. However, efforts by investigators around the world have gradually clarified different aspects of the pathogenesis and treatment of IgA nephropathy. Today, around half of all diabetic patients in Japan receive medical treatment. Type 2 diabetic nephropathy is one of the major long-term microvascular complications occurring in nearly 40% of Japanese diabetic patients. The pathogenesis of diabetic nephropathy involves both genetic and environmental factors. However, the candidate genes related to the initiation and progression of the disorder are still obscure in patients with diabetic nephropathy. Regarding environmental factors, the toxicity of persistent hyperglycemia, reactive oxygen species, systemic and/or glomerular hypertension, dyslipidemia and complement are considered to play an important role. The first part of this review covers the pathogenesis of IgA nephropathy and type 2 diabetic nephropathy, and combines the clinicopathological findings in patients with our research on the ddY and KKA-y mouse models (spontaneous animal models for IgA nephropathy and diabetic nephropathy, respectively). In Japan, the major renal replacement therapies (RRT) are peritoneal dialysis (PD) and hemodialysis (HD). The second part of this review focuses on PD and HD. Based on our research findings from patients and as well as from animal models, we discuss strategies for the management of patients on PD and HD. PMID- 25501572 TI - Molecular analysis of Colletotrichum species in the carposphere and phyllosphere of olive. AB - A metagenomic approach based on the use of genus specific primers was developed and utilized to characterize Colletotrichum species associated with the olive phyllosphere and carposphere. Selected markers enabled the specific amplification of almost the entire ITS1-5.8S-ITS2 region of the rDNA and its use as barcode gene. The analysis of different olive samples (green and senescent leaves, floral residues, symptomatic and asymptomatic fruits, and litter leaves and mummies) in three different phenological phases (June, October and December) enabled the detection of 12 genotypes associated with 4 phylotypes identified as C. godetiae, C. acutatum s.s., C. gloeosporioides s.s. and C. kahawae. Another three genotypes were not identified at the level of species but were associated with the species complexes of C. acutatum, C. gloeosporioides and C. boninense sensu lato. Colletotrichum godetiae and C. acutatum s.s. were by far the most abundant while C. gloeosporioides s.s. was detected in a limited number of samples whereas ther phylotypes were rarely found. The high incidence of C. acutatum s.s. represents a novelty for Italy and more generally for the Mediterranean basin since it had been previously reported only in Portugal. As regards to the phenological phase, Colletotrichum species were found in a few samples in June and were diffused on all assessed samples in December. According to data new infections on olive tissues mainly occur in the late fall. Furthermore, Colletotrichum species seem to have a saprophytic behavior on floral olive residues. The method developed in the present study proved to be valuable and its future application may contribute to the study of cycle and aetiology of diseases caused by Colletotrichum species in many different pathosystems. PMID- 25501573 TI - Development of dual-activity vectors by co-envelopment of adenovirus and SiRNA in artificial lipid bilayers. AB - Gene therapy with human adenovirus type 5 (Ad5) has been extensively explored for the treatment of diseases resistant to traditional therapies. Intravenous administration leads to rapid clearance from blood circulation and high liver accumulation, which restrict the use of Ad-based vectors in clinical gene therapy protocols that involve systemic administration. We have previously proposed that such limitations can be improved by engineering artificial lipid envelopes around Ad and designed a variety of artificial lipid bilayer envelopes around the viral capsid. In this study, we sought to explore further opportunities that the artificially enveloped virus constructs could offer, by designing a previously unreported gene therapy vector by simultaneous envelopment of Ad and siRNA within the same lipid bilayer. Such a dual-activity vector can offer efficacious therapy for different genetic disorders where both turning on and switching off genes would be needed. Dynamic light scattering, transmission electron microscopy and atomic force microscopy were used to characterize these vectors. Agarose gel electrophoresis, Ribo green and dot blot assays showed that siRNA and Ad virions can be enveloped together within lipid bilayers at high envelopment efficiency. Cellular uptake and in vitro transfection experiments were carried out to show the feasibility of combining siRNA-mediated gene silencing with viral gene transfer using these newly designed dual-activity vectors. PMID- 25501574 TI - Differential phenotypes of tissue-infiltrating T cells during angiotensin II induced hypertension in mice. AB - Hypertension remains the leading risk factor for cardiovascular disease (CVD). Experimental hypertension is associated with increased T cell infiltration into blood pressure-controlling organs, such as the aorta and kidney; importantly in absence of T cells of the adaptive immune system, experimental hypertension is significantly blunted. However, the function and phenotype of these T cell infiltrates remains speculative and undefined in the setting of hypertension. The current study compared T cell-derived cytokine and reactive oxygen species (ROS) production from normotensive and hypertensive mice. Splenic, blood, aortic, kidney and brain T cells were isolated from C57BL/6J mice following 14-day vehicle or angiotensin (Ang) II (0.7 mg/kg/day, s.c.) infusion. T cell infiltration was increased in aorta, kidney and brain from hypertensive mice. Cytokine analysis in stimulated T cells indicated an overall Th1 pro-inflammatory phenotype, but a similar proportion (flow cytometry) and quantity (cytometric bead array) of IFN-gamma, TNF-alpha, IL-4 and IL-17 between vehicle- and Ang II- treated groups. Strikingly, elevated T cell-derived production of a chemokine, chemokine C-C motif ligand 2 (CCL2), was observed in aorta (~6-fold) and kidney in response to Ang II, but not in brain, spleen or blood. Moreover, T cell derived ROS production in aorta was elevated ~3 -fold in Ang II-treated mice (n = 7; P<0.05). Ang II-induced hypertension does not affect the overall T cell cytokine profile, but enhanced T cell-derived ROS production and/or leukocyte recruitment due to elevated CCL2, and this effect may be further amplified with increased infiltration of T cells. We have identified a potential hypertension specific T cell phenotype that may represent a functional contribution of T cells to the development of hypertension, and likely several other associated vascular disorders. PMID- 25501575 TI - Neuroprotective and anti-inflammatory roles of the phosphatase and tensin homolog deleted on chromosome Ten (PTEN) Inhibition in a Mouse Model of Temporal Lobe Epilepsy. AB - Excitotoxic damage represents the major mechanism leading to cell death in many human neurodegenerative diseases such as ischemia, trauma and epilepsy. Caused by an excess of glutamate that acts on metabotropic and ionotropic excitatory receptors, excitotoxicity activates several death signaling pathways leading to an extensive neuronal loss and a consequent strong activation of astrogliosis. Currently, the search for a neuroprotective strategy is aimed to identify the level in the signaling pathways to block excitotoxicity avoiding the loss of important physiological functions and side effects. To this aim, PTEN can be considered an ideal candidate: downstream the excitatory receptors activated in excitotoxicity (whose inhibition was shown to be not clinically viable), it is involved in neuronal damage and in the first stage of the reactive astrogliosis in vivo. In this study, we demonstrated the involvement of PTEN in excitotoxicity through its pharmacological inhibition by dipotassium bisperoxo (picolinato) oxovanadate [bpv(pic)] in a model of temporal lobe epilepsy, obtained by intraperitoneal injection of kainate in 2-month-old C57BL/6J male mice. We have demonstrated that inhibition of PTEN by bpv(pic) rescues neuronal death and decreases the reactive astrogliosis in the CA3 area of the hippocampus caused by systemic administration of kainate. Moreover, the neurotoxin administration increases significantly the scanty presence of mitochondrial PTEN that is significantly decreased by the administration of the inhibitor 6 hr after the injection of kainate, suggesting a role of PTEN in mitochondrial apoptosis. Taken together, our results confirm the key role played by PTEN in the excitotoxic damage and the strong anti-inflammatory and neuroprotective potential of its inhibition. PMID- 25501576 TI - Phase I dose-escalation trial of the oral investigational Hedgehog signaling pathway inhibitor TAK-441 in patients with advanced solid tumors. AB - PURPOSE: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway. EXPERIMENTAL DESIGN: Patients with advanced, solid tumors received daily oral TAK-441 (50-1,600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1. RESULTS: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1,600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade >=3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n = 4) and fatigue (n = 3) were most common. Oral absorption was fairly rapid; median Tmax was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentration-time curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors). CONCLUSIONS: TAK-441 was generally well tolerated up to MFD of 1,600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling. PMID- 25501577 TI - Real-time, near-infrared fluorescence imaging with an optimized dye/light source/camera combination for surgical guidance of prostate cancer. AB - PURPOSE: The prostate-specific membrane antigen (PSMA) is a surface glycoprotein overexpressed on malignant prostate cells, as well as in the neovasculature of many tumors. Recent efforts to target PSMA for imaging prostate cancer rely on suitably functionalized low-molecular-weight agents. YC-27 is a low-molecular weight, urea-based agent that enables near-infrared (NIR) imaging of PSMA in vivo. EXPERIMENTAL DESIGN: We have developed and validated a laparoscopic imaging system (including an optimized light source, LumiNIR) that is capable of imaging small tumor burdens with minimal background fluorescence in real-time laparoscopic extirpative surgery of small prostate tumor xenografts in murine and porcine models. RESULTS: In a mouse model, we demonstrate the feasibility of using real-time NIR laparoscopic imaging to detect and surgically remove PSMA positive xenografts. We then validate the use of our laparoscopic real-time NIR imaging system in a large animal model. Our novel light source, which is optimized for YC-27, is capable of detecting as little as 12.4 pg/mL of the compound (2.48-pg YC-27 in 200-MUL agarose). Finally, in a mouse xenograft model, we demonstrate that the use of real-time NIR imaging can reduce positive surgical margins (PSM). CONCLUSIONS: These data indicate that a NIR-emitting fluorophore targeted to PSMA may allow improved surgical treatment of human prostate cancer, reduce the rate of PSMs, and alleviate the need for adjuvant radiotherapy postoperatively. PMID- 25501578 TI - Immune escape mechanisms as a guide for cancer immunotherapy. AB - Immunotherapy has demonstrated impressive outcomes for some patients with cancer. However, selecting patients who are most likely to respond to immunotherapy remains a clinical challenge. Here, we discuss immune escape mechanisms exploited by cancer and present strategies for applying this knowledge to improving the efficacy of cancer immunotherapy. PMID- 25501579 TI - Vaccine-induced tumor necrosis factor-producing T cells synergize with cisplatin to promote tumor cell death. AB - PURPOSE: Cancer immunotherapy, such as vaccination, is an increasingly successful treatment modality, but its interaction with chemotherapy remains largely undefined. Therefore, we explored the mechanism of synergy between vaccination with synthetic long peptides (SLP) of human papillomavirus type 16 (HPV16) and cisplatin in a preclinical tumor model for HPV16. EXPERIMENTAL DESIGN: SLP vaccination in this preclinical tumor model allowed the elucidation of novel mechanisms of synergy between chemo- and immunotherapy. By analyzing the tumor immune infiltrate, we focused on the local intratumoral effects of chemotherapy, vaccination, or the combination. RESULTS: Of several chemotherapeutic agents, cisplatin synergized best with SLP vaccination in tumor eradication, without requirement for the maximum-tolerated dose (MTD). Upon SLP vaccination, tumors were highly infiltrated with HPV-specific, tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma)-producing T cells. Upon combined treatment, tumor cell proliferation was significantly decreased compared with single treated and untreated tumors. Furthermore, we showed that TNFalpha strongly enhanced cisplatin-induced apoptotic tumor cell death in a JNK-dependent manner. This is consistent with upregulation of proapoptotic molecules and with enhanced cell death in vivo upon combined SLP vaccination and cisplatin treatment. In vivo neutralization of TNFalpha significantly reduced the antitumor responses induced by the combined treatment. CONCLUSION: Taken together, our data show that peptide vaccination with cisplatin treatment leads to decreased tumor cell proliferation and TNFalpha-induced enhanced cisplatin-mediated killing of tumor cells, together resulting in superior tumor eradication. PMID- 25501580 TI - Lymphotoxin beta receptor signaling induces IL-8 production in human bronchial epithelial cells. AB - Asthma-related mortality has been decreasing due to inhaled corticosteroid use, but severe asthma remains a major clinical problem. One characteristic of severe asthma is resistance to steroid therapy, which is related to neutrophilic inflammation. Recently, the tumor necrosis factor superfamily member (TNFSF) 14/LIGHT has been recognized as a key mediator in severe asthmatic airway inflammation. However, the profiles and intracellular mechanisms of cytokine/chemokine production induced in cells by LIGHT are poorly understood. We aimed to elucidate the molecular mechanism of LIGHT-induced cytokine/chemokine production by bronchial epithelial cells. Human bronchial epithelial cells express lymphotoxin beta receptor (LTbetaR), but not herpesvirus entry mediator, which are receptors for LIGHT. LIGHT induced various cytokines/chemokines, such as interleukin (IL)-6, oncostatin M, monocyte chemotactic protein-1, growth regulated protein alpha and IL-8. Specific siRNA for LTbetaR attenuated IL-6 and IL-8 production by BEAS-2B and normal human bronchial epithelial cells. LIGHT activated intracellular signaling, such as mitogen-activated protein kinase and nuclear factor-kappaB (NF-kappaB) signaling. LIGHT also induced luciferase activity of NF-kappaB response element, but not of activator protein-1 or serum response element. Specific inhibitors of phosphorylation of extracellular signal regulated kinase (Erk) and that of inhibitor kappaB attenuated IL-8 production, suggesting that LIGHT-LTbetaR signaling induces IL-8 production via the Erk and NF-kappaB pathways. LIGHT, via LTbetaR signaling, may contribute to exacerbation of airway neutrophilic inflammation through cytokine and chemokine production by bronchial epithelial cells. PMID- 25501581 TI - Metals in cyanobacteria: analysis of the copper, nickel, cobalt and arsenic homeostasis mechanisms. AB - Traces of metal are required for fundamental biochemical processes, such as photosynthesis and respiration. Cyanobacteria metal homeostasis acquires an important role because the photosynthetic machinery imposes a high demand for metals, making them a limiting factor for cyanobacteria, especially in the open oceans. On the other hand, in the last two centuries, the metal concentrations in marine environments and lake sediments have increased as a result of several industrial activities. In all cases, cells have to tightly regulate uptake to maintain their intracellular concentrations below toxic levels. Mechanisms to obtain metal under limiting conditions and to protect cells from an excess of metals are present in cyanobacteria. Understanding metal homeostasis in cyanobacteria and the proteins involved will help to evaluate the use of these microorganisms in metal bioremediation. Furthermore, it will also help to understand how metal availability impacts primary production in the oceans. In this review, we will focus on copper, nickel, cobalt and arsenic (a toxic metalloid) metabolism, which has been mainly analyzed in model cyanobacterium Synechocystis sp. PCC 6803. PMID- 25501582 TI - Rescue therapy for refractory vasospasm after subarachnoid hemorrhage. AB - Vasospasm and delayed cerebral ischemia remain to be the common causes of increased morbidity and mortality after aneurysmal subarachnoid hemorrhage. The majority of clinical vasospasm responds to hemodynamic augmentation and direct vascular intervention; however, a percentage of patients continue to have symptoms and neurological decline. Despite suboptimal evidence, clinicians have several options in treating refractory vasospasm in aneurysmal subarachnoid hemorrhage (aSAH), including cerebral blood flow enhancement, intra-arterial manipulations, and intra-arterial and intrathecal infusions. This review addresses standard treatments as well as emerging novel therapies aimed at improving cerebral perfusion and ameliorating the neurologic deterioration associated with vasospasm and delayed cerebral ischemia. PMID- 25501584 TI - Arbitrary manipulation of spatial amplitude and phase using phase-only spatial light modulators. AB - Spatial structure of a light beam is an important degree of freedom to be extensively explored. By designing simple configurations with phase-only spatial light modulators (SLMs), we show the ability to arbitrarily manipulate the spatial full field information (i.e. amplitude and phase) of a light beam. Using this approach to facilitating arbitrary and independent control of spatial amplitude and phase, one can flexibly generate different special kinds of light beams for different specific applications. Multiple collinear orbital angular momentum (OAM) beams, Laguerre-Gaussian (LG) beams, and Bessel beams, having both spatial amplitude and phase distributions, are successfully generated in the experiments. Some arbitrary beams with odd-shaped intensity are also generated in the experiments. PMID- 25501585 TI - [Relationship between homebound status and physical fitness in the community dwelling elderly population]. PMID- 25501583 TI - Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells ameliorate radiation induced liver damage in a rat model. AB - Liver damage caused by radiotherapy is associated with a high mortality rate, but no established treatment exists. Adipose-derived mesenchymal stem cells (ADSCs) are capable of migration to injured tissue sites, where they aid in the repair of the damage. Hepatocyte growth factor (HGF) is critical for damage repair due to its anti-apoptotic, anti-fibrotic and cell regeneration-promoting effects. This study was performed to investigate the therapeutic effects of HGF-overexpressing ADSCs on radiation-induced liver damage (RILD). ADSCs were infected with a lentivirus encoding HGF and HGF-shRNA. Sprague-Dawley (SD) rats received 60Gy of irradiation to induce liver injury and were immediately given either saline, ADSCs, ADSCs + HGF or ADSCs + shHGF. Two days after irradiation, a significant reduction in apoptosis was observed in the HGF-overexpressing ADSC group compared with the RILD group, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Scanning electron microscopy showed chromatin condensation after irradiation, which was ameliorated in the group that received ADSCs and was reversed in the group that received HGF-overexpressing ADSCs. HGF overexpressing ADSCs ameliorated radiation- induced liver fibrosis through down regulation of alpha-SMA and fibronectin. Hepatocyte regeneration was significantly improved in rats treated with ADSCs compared with rats from the RILD group), as assessed by Ki-67 immunohistochemistry. Rats that received HGF overexpressing ADSCs showed an even greater level of hepatocyte regeneration. HGF overexpressing ADSCs completely blocked the radiation-induced increase in the enzymes ALT and AST. The effect of mitigating RILD was compromised in the ADSC + shHGF group compared with the ADSC group. Altogether, these results suggest that HGF-overexpressing ADSCs can significantly improve RILD in a rat model, which may serve as a valuable therapeutic alternative. PMID- 25501586 TI - [Prediction of future cost savings in long-term care and medical care if Japan achieves the health expectancy target of Health Japan 21 (second term)]. AB - OBJECTIVES: An earlier study using the data from the Japanese Long-term Care Insurance (LTCI) system reported a scenario for achieving the target of Health Japan 21 (the second term): future gains in health expectancy from 2011 to 2020 must be larger than gains in expectancy. According to this scenario (the Healthy Life Expectancy Extension Scenario), the proportion of disability (cases>=Care Level 2 in LTCI disability certification) will gradually decrease by 1% per year from 2011. The purpose of this study was to estimate the cost savings in long term care and medical care if the Healthy Life Expectancy Extension Scenario is achieved. METHODS: We used data from Japanese national statistics and a survey conducted in Osaki city, Miyagi. The natural course of disability cases (>=Care Level 2) was estimated under the assumption that the future population composition would be equal to the population projections for Japan and the future proportion of disabilities for each age grade would be equal to that of 2010. Then, the decrease in the number of disabilities based on the Healthy Life Expectancy Extension Scenario was calculated. Finally, the cost savings in long term care and medical care associated with the assumed decrease in the number of disability cases was calculated. RESULTS: When the disability cases (>=Care Level 2) were shifted to "no disability certification (not requiring care)," a total estimated cost reduction of 5,291 billion yen was achieved from 2011 to 2020. Furthermore, a total estimated reduction of 2,491 billion yen was achieved for the same period when all disability shifts to "Care Level 1" were accounted for. CONCLUSION: As a rough calculation, if the Health Japan 21 (second term) target is achieved, approximately 2,500-5,300 billion yen will be saved in the cost of long-term care and medical care. PMID- 25501587 TI - [Characteristics of the number of steps in the National Health and Nutrition Survey]. AB - OBJECTIVES: The mean number of steps measured in the National Health and Nutrition Survey is employed for the assessment of physical activity/exercise in "Health Japan 21," and is used to represent the amount of physical activity/exercise that citizens engage in. In this study, we clarified the characteristics of the data on the number of steps, drawn from the National Health and Nutrition Survey. METHODS: Among the data from the National Health and Nutrition Surveys conducted from 2008 to 2010, data from 21,914 participants on daily number of steps and pedometer attachment were analyzed. On a nutritional intake questionnaire, subjects who responded on the physical status item that they had attached the pedometer all day long were assigned to the "Whole-day attached" group. Their means, medians, outliers, and frequency distribution were then compared with those in a "Non- whole-day-attached" group. RESULTS: Subjects assigned to the "Non- whole-day-attached" group accounted for about 8% of cases in 2008, 2009, and 2010. In all three years, the mean number of steps in the "Whole-day-attached" group was 1,076 to 1,472 higher than that in the "Non-whole day-attached" group. In both groups, outliers were present, and the frequency distribution showed a broad range on the side indicating a higher number of steps. Accordingly, the mean value was higher than the median value by approximately 600 steps. CONCLUSION: As data on the number of steps measured in the National Health and Nutrition Survey includes individuals not attaching the pedometer all day (approximately 8% of cases), the data are not normally distributed. Therefore, when utilizing these data as representative of citizens' physical activity/exercise, their characteristics should be taken into consideration. PMID- 25501588 TI - Multifrequency right-side, localized and segmental BIA obtained with different bioimpedance analysers. AB - The aim of this study is to compare two commercial bioimpedance analysers, BioparHom Z-Metrix and Impedimed SFB7, measuring the impedance of three different body segments. The segments measured were 'right-side' (or 'whole-body'), 'segmental right-lower limb' and 'localized longitudinal right-quadriceps'. The comparison was made on electrical models of each segment, including electrode skin impedance, and in vivo on nine healthy volunteers. Both devices are designed to measure right-side impedances and, in the present study, as the length of the segment investigated decreased, the accuracy of the impedance measured was found to decrease. The accuracy of the devices was calculated via measurements performed on RC networks of known values. It was found that adding electrode-skin contact impedances in the electrical model affected the accuracy by both devices. PMID- 25501589 TI - Dissecting the phenotypic components of crop plant growth and drought responses based on high-throughput image analysis. AB - Significantly improved crop varieties are urgently needed to feed the rapidly growing human population under changing climates. While genome sequence information and excellent genomic tools are in place for major crop species, the systematic quantification of phenotypic traits or components thereof in a high throughput fashion remains an enormous challenge. In order to help bridge the genotype to phenotype gap, we developed a comprehensive framework for high throughput phenotype data analysis in plants, which enables the extraction of an extensive list of phenotypic traits from nondestructive plant imaging over time. As a proof of concept, we investigated the phenotypic components of the drought responses of 18 different barley (Hordeum vulgare) cultivars during vegetative growth. We analyzed dynamic properties of trait expression over growth time based on 54 representative phenotypic features. The data are highly valuable to understand plant development and to further quantify growth and crop performance features. We tested various growth models to predict plant biomass accumulation and identified several relevant parameters that support biological interpretation of plant growth and stress tolerance. These image-based traits and model-derived parameters are promising for subsequent genetic mapping to uncover the genetic basis of complex agronomic traits. Taken together, we anticipate that the analytical framework and analysis results presented here will be useful to advance our views of phenotypic trait components underlying plant development and their responses to environmental cues. PMID- 25501591 TI - Practical synthesis of 4'-thioribonucleosides starting from D-ribose. AB - A practical synthesis of 4'-thioribonucleosides, i.e., 4'-thiouridine, -cytidine, -adenosine, and -guanosine, which are versatile units for nucleic acids-based therapeutics, is described. Large-scale synthesis of 4-thiosugar starting from D ribose was achieved (33%) in eight steps and with only three chromatographic purifications. After the appropriate chemical conversion of the 4-thiosugar, the resulting sulfoxide was subjected to the Pummerer reaction in the presence of silylated nucleobases. In reactions with silylated pyrimidine bases, the desired 4'-thioribonucleoside derivatives were obtained in good yield and beta selectively. On the other hand, N-7 isomers were obtained mainly in the Pummerer reaction with purine bases under the same conditions. However, the desired N-9 isomers were obtained in moderate yields when the reaction mixtures were subsequently heated under reflux. As a result, effective synthesis of 4' thioribonucleosides was accomplished. PMID- 25501590 TI - Olefin cross-metathesis for the synthesis of alkenyl acyclonucleoside phosphonates. AB - The detailed synthetic protocol for the straightforward, efficient synthesis of various alkenyl acyclonucleosides, including challenging trisubstituted alkenyl acyclonucleoside phosphonates, is described. The key step of those syntheses is an olefin cross-metathesis reaction between two olefins selected based on their reactivity using well-defined ruthenium alkylidene catalysts. PMID- 25501592 TI - NMR analysis of base-pair opening kinetics in DNA. AB - Base pairing in nucleic acids plays a crucial role in their structure and function. Differences in the base-pair opening and closing kinetics of individual double-stranded DNA sequences or between chemically modified base pairs provide insight into the recognition of these base pairs by DNA processing enzymes. This unit describes how to quantify the kinetics for localized base pairs by observing changes in the imino proton signals by nuclear magnetic resonance spectroscopy. The determination of all relevant parameters using state-of-the art techniques and NMR instrumentation, including cryoprobes, is discussed. PMID- 25501593 TI - Steady-state kinetic analysis of DNA polymerase single-nucleotide incorporation products. AB - This unit describes the experimental procedures for the steady-state kinetic analysis of DNA synthesis across DNA nucleotides (native or modified) by DNA polymerases. In vitro primer extension experiments with a single nucleoside triphosphate species followed by denaturing polyacrylamide gel electrophoresis of the extended products is described. Data analysis procedures and fitting to steady-state kinetic models is presented to highlight the kinetic differences involved in the bypass of damaged versus undamaged DNA. Moreover, explanations concerning problems encountered in these experiments are addressed. This approach provides useful quantitative parameters for the processing of damaged DNA by DNA polymerases. PMID- 25501594 TI - Detection of hydrogen bonds in dynamic regions of RNA by NMR spectroscopy. AB - NMR spectroscopy is a powerful tool to study the structure and dynamics of nucleic acids. In this unit, we give an overview of important experiments to determine and characterize hydrogen bonds in nucleic acids and provide detailed instructions for setting up recently developed sensitivity-improved NMR pulse sequences, i.e., BEST selective long-range HNN-COSY, selective BEST-TROSY HNNCOSY, and Py H(CC)NN-COSY. The strengths and limitations of these experiments will also be discussed. Detailed step-by-step protocols are provided for each of the three pulse sequences, with special emphasis on adjusting and setting of delays and shaped pulses. The NMR pulse sequences with example datasets and optimized, nonstandard adiabatic pulse shapes used for selective (15)N magnetization transfer are provided. These experiments enable NMR analysis of a broad variety of RNAs ranging from low to high molecular weight and complexity. PMID- 25501595 TI - p53 suppresses muscle differentiation at the myogenin step in response to genotoxic stress. AB - Acute muscle injury and physiological stress from chronic muscle diseases and aging lead to impairment of skeletal muscle function. This raises the question of whether p53, a cellular stress sensor, regulates muscle tissue repair under stress conditions. By investigating muscle differentiation in the presence of genotoxic stress, we discovered that p53 binds directly to the myogenin promoter and represses transcription of myogenin, a member of the MyoD family of transcription factors that plays a critical role in driving terminal muscle differentiation. This reduction of myogenin protein is observed in G1-arrested cells and leads to decreased expression of late but not early differentiation markers. In response to acute genotoxic stress, p53-mediated repression of myogenin reduces post-mitotic nuclear abnormalities in terminally differentiated cells. This study reveals a mechanistic link previously unknown between p53 and muscle differentiation, and suggests new avenues for managing p53-mediated stress responses in chronic muscle diseases or during muscle aging. PMID- 25501597 TI - Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa. AB - Retinitis pigmentosa is a group of hereditary retinal dystrophies that normally result in photoreceptor cell death and vision loss both in animal models and in affected patients. The rd10 mouse, which carries a missense mutation in the Pde6b gene, has been used to characterize the underlying pathophysiology and develop therapies for this devastating and incurable disease. Here we show that increased photoreceptor cell death in the rd10 mouse retina is associated with calcium overload and calpain activation, both of which are observed before the appearance of signs of cell degeneration. These changes are accompanied by an increase in the activity of the lysosomal protease cathepsin B in the cytoplasm of photoreceptor cells, and a reduced colocalization of cathepsin B with lysosomal markers, suggesting that lysosomal membrane permeabilization occurs before the peak of cell death. Moreover, expression of the autophagosomal marker LC3-II (lipidated form of LC3) is reduced and autophagy flux is blocked in rd10 retinas before the onset of photoreceptor cell death. Interestingly, we found that cell death is increased by the induction of autophagy with rapamycin and inhibited by calpain and cathepsin inhibitors, both ex vivo and in vivo. Taken together, these data suggest that calpain-mediated lysosomal membrane permeabilization underlies the lysosomal dysfunction and downregulation of autophagy associated with photoreceptor cell death. PMID- 25501599 TI - miR-361-regulated prohibitin inhibits mitochondrial fission and apoptosis and protects heart from ischemia injury. AB - Cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Emerging evidences suggest that the abnormal mitochondrial fission participates in pathogenesis of cardiac diseases, including myocardial infarction (MI) and heart failure. However, the molecular components regulating mitochondrial network in the heart remain largely unidentified. Here we report that miR-361 and prohibitin 1 (PHB1) constitute an axis that regulates mitochondrial fission and apoptosis. The results show that PHB1 attenuates mitochondrial fission and apoptosis in response to hydrogen peroxide treatment in cardiomyocytes. Cardiac-specific PHB1 transgenic mice show reduced mitochondrial fission and myocardial infarction sizes after myocardial infarction surgery. MiR 361 is responsible for the dysfunction of PHB1 and suppresses the translation of PHB1. Knockdown of miR-361 reduces mitochondrial fission and apoptosis in vivo and in vitro. MiR-361 cardiac-specific transgenic mice represent elevated mitochondrial fission and myocardial infarction sizes upon myocardial ischemia injury. This study identifies a novel signaling pathway composed of miR-361 and PHB1 that regulates mitochondrial fission program and apoptosis. This discovery will shed new light on the therapy of myocardial infarction and heart failure. PMID- 25501596 TI - PARP-2 sustains erythropoiesis in mice by limiting replicative stress in erythroid progenitors. AB - Erythropoiesis is a tightly regulated process in which multipotential hematopoietic stem cells produce mature red blood cells. Here we show that deletion of poly(ADP-ribose) polymerase-2 (PARP-2) in mice leads to chronic anemia at steady state, despite increased erythropoietin plasma levels, a phenomenon not observed in mice lacking PARP-1. Loss of PARP-2 causes shortened lifespan of erythrocytes and impaired differentiation of erythroid progenitors. In erythroblasts, PARP-2 deficiency triggers replicative stress, as indicated by the presence of micronuclei, the accumulation of gamma-H2AX (phospho-histone H2AX) in S-phase cells and constitutive CHK1 and replication protein A phosphorylation. Transcriptome analyses revealed the activation of the p53 dependent DNA-damage response pathways in PARP-2-deficient cells, culminating in the upregulation of cell-cycle and cell death regulators, concomitant with G2/M arrest and apoptosis. Strikingly, while loss of the proapoptotic p53 target gene Puma restored hematocrit levels in the PARP-2-deficient mice, loss of the cell cycle regulator and CDK inhibitor p21 leads to perinatal death by exacerbating impaired fetal liver erythropoiesis in PARP-2-deficient embryos. Although the anemia displayed by PARP-2-deficient mice is compatible with life, mice die rapidly when exposed to stress-induced enhanced hemolysis. Our results pinpoint an essential role for PARP-2 in erythropoiesis by limiting replicative stress that becomes essential in the absence of p21 and in the context of enhanced hemolysis, highlighting the potential effect that might arise from the design and use of PARP inhibitors that specifically inactivate PARP proteins. PMID- 25501598 TI - Suppression of epithelial-mesenchymal transition and apoptotic pathways by miR 294/302 family synergistically blocks let-7-induced silencing of self-renewal in embryonic stem cells. AB - The embryonic stem cell (ESC)-enriched miR-294/302 family and the somatic cell enriched let-7 family stabilizes the self-renewing and differentiated cell fates, respectively. The mechanisms underlying these processes remain unknown. Here we show that among many pathways regulated by miR-294/302, the combinatorial suppression of epithelial-mesenchymal transition (EMT) and apoptotic pathways is sufficient in maintaining the self-renewal of ESCs. The silencing of ESC self renewal by let-7 was accompanied by the upregulation of several EMT regulators and the induction of apoptosis. The ectopic activation of either EMT or apoptotic program is sufficient in silencing ESC self-renewal. However, only combined but not separate suppression of the two programs inhibited the silencing of ESC self renewal by let-7 and several other differentiation-inducing miRNAs. These findings demonstrate that combined repression of the EMT and apoptotic pathways by miR-294/302 imposes a synergistic barrier to the silencing of ESC self renewal, supporting a model whereby miRNAs regulate complicated cellular processes through synergistic repression of multiple targets or pathways. PMID- 25501602 TI - Colloids versus crystalloids in the prevention of hypotension induced by spinal anesthesia in elective cesarean section. A systematic review and meta-analysis. AB - The incidence of hypotension associated to spinal anesthesia in elective cesarean section is high. To determine the effects of colloids and crystalloids in the incidence of hypotension induced by spinal anesthesia in elective cesarean section, an attempt was made to define which type of fluid and what total volume should be administered. Following the PRISMA methodology a systematic review and meta-analysis were carried out. A systematic Medline/PubMed, EMBASE and Cochrane Library search was made to identify trials where women were scheduled for elective cesarean section with spinal anesthesia and volume loading (preload or co-load). The primary outcome was the incidence of hypotension. Stratification into subgroups was made for the primary outcome according to the type of colloid administered, differentiating those studies employing new generation colloids (HES 6% 130/0.4) from those not using such colloids, based on the volume of colloid administered and the combination of a vasopressor. The secondary outcome was the incidence of intraoperative nausea and vomiting. Two-hundred and twenty seven controlled clinical trials were analyzed; eleven randomized clinical trials including 990 patients were included. A significative decrease of incidence of hypotension associated to spinal anesthesia was observed with the use of colloids compared to crystalloids (RR [95% CI] 0.70 [0.53-0.92], P=0.01). However, there was no difference between crystalloid and colloid in the risk of intraoperative nausea and vomiting (RR [95% CI] 0.75 [0.41-1.38]; P=0.33). This meta-analysis shows colloid administration to significantly reduce the incidence of hypotension associated to spinal anesthesia in elective cesarean section compared with of crystalloid use. PMID- 25501601 TI - The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling. AB - The MT2 receptor is a principal type of G protein-coupled receptor that mainly mediates the effects of melatonin. Deficits of melatonin/MT2 signaling have been found in many neurological disorders, including Alzheimer's disease, the most common cause of dementia in the elderly, suggesting that preservation of the MT2 receptor may be beneficial to these neurological disorders. However, direct evidence linking the MT2 receptor to cognition-related synaptic plasticity remains to be established. Here, we report that the MT2 receptor, but not the MT1 receptor, is essential for axonogenesis both in vitro and in vivo. We find that axon formation is retarded in MT2 receptor knockout mice, MT2-shRNA electroporated brain slices or primary neurons treated with an MT2 receptor selective antagonist. Activation of the MT2 receptor promotes axonogenesis that is associated with an enhancement in excitatory synaptic transmission in central neurons. The signaling components downstream of the MT2 receptor consist of the Akt/GSK-3beta/CRMP-2 cascade. The MT2 receptor C-terminal motif binds to Akt directly. Either inhibition of the MT2 receptor or disruption of MT2 receptor-Akt binding reduces axonogenesis and synaptic transmission. Our data suggest that the MT2 receptor activates Akt/GSK-3beta/CRMP-2 signaling and is necessary and sufficient to mediate functional axonogenesis and synaptic formation in central neurons. PMID- 25501603 TI - Refractory septic shock: who and how should we purify? PMID- 25501600 TI - The endogenous caspase-8 inhibitor c-FLIPL regulates ER morphology and crosstalk with mitochondria. AB - Components of the death receptor-mediated pathways like caspase-8 have been identified in complexes at intracellular membranes to spatially restrict the processing of local targets. In this study, we report that the long isoform of the cellular FLICE-inhibitory protein (c-FLIP(L)), a well-known inhibitor of the extrinsic cell death initiator caspase-8, localizes at the endoplasmic reticulum (ER) and mitochondria-associated membranes (MAMs). ER morphology was disrupted and ER Ca(2+)-release as well as ER-mitochondria tethering was decreased in c FLIP(-/-) mouse embryonic fibroblasts (MEFs). Mechanistically, c-FLIP ablation resulted in enhanced basal caspase-8 activation and in caspase-mediated processing of the ER-shaping protein reticulon-4 (RTN4) that was corrected by re introduction of c-FLIP(L) and caspase inhibition, resulting in the recovery of a normal ER morphology and ER-mitochondria juxtaposition. Thus, the caspase-8 inhibitor c-FLIP(L) emerges as a component of the MAMs signaling platforms, where caspases appear to regulate ER morphology and ER-mitochondria crosstalk by impinging on ER-shaping proteins like the RTN4. PMID- 25501604 TI - Prognostic factors for pancreatic neuroendocrine neoplasms (pNET) and the risk of small non-functioning pNET. AB - BACKGROUND: Non-functioning (NF) pancreatic neuroendocrine tumors (pNET) often have an indolent outcome. A consensus to submit patients with large (>2 cm) NF pNET to surgery already exists; but a conservative approach for small (<=2 cm) NF neoplasms has been proposed. AIM: To identify prognostic factors for survival and progression free survival (PFS) of NF-pNET, evaluating whether surgery may be avoided for small NF-pNET. SUBJECTS AND METHODS: Retrospective study of 77 consecutive patients with pNET submitted to surgery, of which 60 were NF. Pathological tissues were revised according to the 2000 and 2010 WHO classifications. Risk factors for survival and PFS were evaluated using the Kaplan-Meier method and the Cox regression model. RESULTS: The 8-year cause specific survival of NF-pNET was 79.3%. At univariate analysis, high grading, high staging, large tumors, angioinvasion and peri-pancreatic infiltration were significantly associated with a shorter survival; at multivariate analysis only peri-pancreatic infiltration was significantly associated with a shorter NF-pNET survival. Most small NF-pNET were grade 1 (74%), compared to large NF-pNET (27%). Distant metastases were present in 29.7% (n = 11) and 17.4% (n = 4) of patients with large or small NF-pNET, respectively; among the 19 small NF-pNET without metastasis, five had a local malignancy (lymph node metastasis or local infiltration); thus, 39% of the 23 NF-pNET, turned out to have a malignant potential. CONCLUSIONS: Among NF-pNET, large neoplasms were associated with worse outcomes; however, small NF-pNET do not seem to have an invariable benign behavior. Whether surgery should be avoided in all patients with small NF-pNET is questionable. PMID- 25501605 TI - Increased levels of galectin-3 were associated with prediabetes and diabetes: new risk factor? AB - PURPOSE: Galectin-3 (Gal-3) is a marker of cardiac fibrosis and predicts incident heart failure. Gal-3-deficient mice are resistant to multiple low-dose streptozotocin-induced diabetes. Recent experimental studies suggested an important role for Gal-3 in the regulation of adiposity, metaflammation and type 2 diabetes. This study aimed to examine the relationship between Gal-3 and newly diagnosed prediabetes and diabetes. METHODS: Gal-3 concentrations were measured in 118 participants and 56 age- and sex-matched healthy controls. All subjects underwent a 75-g oral glucose tolerance test and were stratified into normal, prediabetic, and diabetes mellitus subgroups. DM was defined as a plasma glucose level >=126 mg/dL in the fasting state or >=200 mg/dL in the second hour after glucose loading. Impaired fasting glucose was defined as an FPG level of 100-125 mg/dL, and impaired glucose tolerance was defined as a 2-h plasma glucose level of 140-199 mg/dL. RESULTS: Sixty-one patients had prediabetes (Group 1), 57 had diabetes (Group 2), and 56 had neither diabetes nor prediabetes (Group 3). Gal-3 levels correlated with FPG (r = 0.787, P < 0.01), 2hPG (r = 0.833, P < 0.01), CRP (r = 0.501, P < 0.01), and HOMA-IR (r = 0.518, P < 0.01). Gal-3 levels were higher in Group 2 than in Groups 1 and 3 [1,053.9 (358.1) and 744.1 (119.3) vs. 481.7 (175.4) pg/mL; P < 0.001]. Gal-3 is an independent predictor of diabetes in multivariate logistic analysis. In ROC analysis, a Gal-3 cutoff value of 803.55 pg/mL diagnoses diabetes with a sensitivity of 80.7 % and a specificity of 85.5 % (AUC = 0.912). CONCLUSIONS: Gal-3 is a promising biomarker for detecting prediabetes and diabetes. PMID- 25501607 TI - Effects on anthropometry and appetite of vitamins and minerals given in lipid nutritional supplements for malnourished HIV-infected adults referred for antiretroviral therapy: results from the NUSTART randomized controlled trial. AB - BACKGROUND: The evidence base for effects of nutritional interventions for malnourished HIV-infected patients starting antiretroviral therapy (ART) is limited and inconclusive. OBJECTIVE: We hypothesized that both vitamin and mineral deficiencies and poor appetite limit weight gain in malnourished patients starting ART and that vitamin and mineral supplementation would improve appetite and permit nutritional recovery. DESIGN: The randomized controlled Nutritional Support for Africans Starting Antiretroviral Therapy trial was conducted in Mwanza, Tanzania, and Lusaka, Zambia. ART-naive adults referred for ART and with body mass index <18.5 kg/m received lipid-based nutritional supplements either without (LNS) or with added vitamins and minerals (LNS-VM), beginning before ART initiation. Participants were given 30 g/d LNS from recruitment until 2 weeks after starting ART and 250 g/d from weeks 2 to 6 of ART. RESULTS: Of 1815 patients recruited, 365 (20%) died during the study and 813 (45%) provided data at 12 weeks. Controlling for baseline values, anthropometric measures were consistently higher at 12-week ART in the LNS-VM than in the LNS group but statistically significant only for calf and mid-upper arm circumferences and triceps skinfold. Appetite did not differ between groups. Using piecewise mixed effects quadratic models including all patients and time points, the main effects of LNS-VM were seen after starting ART and were significant for weight, body mass index, and mid-upper arm circumference. CONCLUSIONS: Provision of high levels of vitamins and minerals to patients referred for ART, delivered with substantial macronutrients, increased nutritional recovery but did not seem to act through treatment group differences in appetite. PMID- 25501608 TI - The association between HIV status and antenatal care attendance among pregnant women in rural hospitals in Lesotho. AB - OBJECTIVE: Early and frequent antenatal clinic (ANC) attendance is important for promotion of healthy outcomes for mother and child. This study explored the relationship between HIV status at the first ANC visit and subsequent ANC attendance among pregnant women in Lesotho. METHODS: A retrospective review of ANC records from a cohort of pregnant women attending their first ANC visit in December 2009 to May 2010 in 3 rural hospitals was conducted. Wilcoxon rank sum tests compared the distribution of gestational age (GA) and ANC visit number by HIV status. RESULTS: Records from 728 women were reviewed with mean GA at the first ANC visit of 22.3 weeks (SD = 7.2) and 2.7 (SD = 1.4) mean number of ANC visits per woman. Neither number of visits nor GA at first visit differed between HIV-positive and HIV-negative women. In total, 33.9% of women completed 4 ANC visits. Women with documented HIV-positive status before ANC were more likely to present early to ANC than all other women (18.8 vs. 22.6 weeks, adjusted odds ratio = 2.54, 95% confidence interval: 1.41 to 4.57). Geographical region, increasing maternal age, and lower parity were associated with completion of expected ANC visits among all women. Increasing maternal age and CD4 count were associated with completion of expected visits among HIV-positive women. CONCLUSIONS: In Lesotho, number of subsequent visits did not differ between women testing HIV-positive and HIV-negative in ANC. However, women with documented HIV positive status attended ANC earlier than women who were tested in ANC. HIV testing and counseling, particularly for HIV-positive women before pregnancy, can promote early ANC attendance. PMID- 25501606 TI - Characterization of V804M-mutated RET proto-oncogene associated with familial medullary thyroid cancer, report of the largest Turkish family. AB - PURPOSE: Analysis of the RET proto-oncogen is very important for diagnosis and prognosis of medullary thyroid cancer (MTC). Genotype-phenotype correlation is also well known. Here we report features of the largest known family in Turkey with the V804M-mutated RET proto-oncogene. METHODS: Thirty members from three generations were evaluated. A RET proto-oncogen mutation, calcitonin (Ct) measurement and thyroid ultrasound were performed on all individuals. Seventeen members had V804M mutation. Fourteen of these patients underwent total thyroidectomy and additional central lymph node dissection for five subjects. RESULTS: The mean age of patients with MTC was 46.5 (30-61) years. The mean calcitonin level of RET positive members was 13.27 pg/mL (1-49.8 pg/mL). Three had a basal Ct level above normal limits. Seven of the 14 patients were diagnosed with MTC, and two were diagnosed with papillary thyroid cancer without MTC. One patient had central neck metastasis. Hyperparathyroidism or pheochromocytoma was not detected in any case. Patients who were RET negative, had normal Ct levels and no suspected nodule on ultrasound examination. CONCLUSIONS: Our study revealed a relatively good prognosis in patients with V804M mutation. Despite the surgery was performed in older age no advance disease was observed. PMID- 25501610 TI - The rising trend of sexually transmitted infections among HIV-infected persons: a population-based cohort study in Taiwan, 2000 through 2010. AB - OBJECTIVE: Positive prevention interventions for patients living with the HIV include the early detection and treatment of sexually transmitted infections (STIs). This study aimed to determine the incidence of selected STIs, including syphilis, genital warts, gonorrhea, chlamydial infection, and trichomoniasis, in a population-based cohort of individuals living with HIV. METHODS: Clinical data from 2000 to 2010 were obtained from the Taiwan National Health Insurance Research Database identified 15,123 patients with HIV infection. The incidence rates were standardized by age and sex using the direct method that was based on the 2000 World Health Organization world standard population. RESULTS: The overall rate ratio of STI episodes significantly increased [rate ratio: 34.0, 95% confidence interval (CI): 24.3 to 47.6, P < 0.01]. After an HIV diagnosis, 15.9% of patients with HIV had at least 1 of these 5 STIs. An incidence rate of 503.0 STI episodes/10,000 person-years (PYs) (95% CI: 487.1 to 519.5) was detected during the 11-year follow-up period. The most common STIs after an HIV diagnosis were syphilis (381.9 episodes/10,000 PYs; 95% CI: 368.0 to 396.3), followed by genital warts (138.9 episodes/10,000 PYs; 95% CI: 130.6 to 147.6). The incidence of STIs varied significantly according to gender. In women, the annual incidence of STIs remained stable. However, the annual incidence of syphilis, genital warts, and chlamydial infection increased in young men. CONCLUSIONS: An increase in STIs among HIV-positive persons highlights the need to identify the causal factors of these co-infections. Routine STI screenings and early preventive interventions against STIs in HIV-infected persons are crucial. PMID- 25501609 TI - The effect of psychosocial syndemic production on 4-year HIV incidence and risk behavior in a large cohort of sexually active men who have sex with men. AB - BACKGROUND: Cross-sectional studies have suggested that co-occurring epidemics or "syndemics" of psychosocial health problems may accelerate HIV transmission among men who have sex with men (MSM) in the United States. We aimed to assess how 5 syndemic conditions (depressive symptoms, heavy alcohol use, stimulant use, polydrug use, and childhood sexual abuse) affected HIV incidence and sexual risk behavior over time. METHODS: Eligible men in a large prospective cohort of sexually active HIV-uninfected MSM completed HIV testing and behavioral surveys at baseline and every 6 months for 48 months. We examined interrelationships between psychosocial problems and whether these interactions increased the odds of HIV risk behaviors and risk of seroconversion over study follow-up. RESULTS: Among 4295 men, prevalence of psychosocial conditions was substantial at baseline and was positively associated with each other. We identified a statistically significant positive dose-response relationship between numbers of syndemic conditions and HIV seroconversion for all comparisons (with the greatest hazard among those with 4-5 conditions, adjusted hazard ratio = 8.69; 95% confidence interval: 4.78 to 15.44). The number of syndemic conditions also predicted increased HIV-related risk behaviors over time, which mediated the syndemic-HIV seroconversion association. CONCLUSIONS: The accumulation of syndemic psychosocial problems predicted HIV-related sexual risk behaviors and seroconversion in a large sample of US MSM. Given the high prevalence of syndemic conditions among MSM and the moderate effect sizes attained by traditional brief behavioral interventions to date, the HIV prevention agenda requires a shift toward improved assessment of psychosocial comorbidities and stronger integration with mental health and substance abuse treatment services. PMID- 25501612 TI - HIV-1 subtype B/B' and baseline drug resistance mutation are associated with virologic failure: a multicenter cohort study in China. AB - BACKGROUND: Distribution of HIV-1 subtypes, transmitted drug resistance (TDR)/drug resistance mutation (DRM), and their impact on response to combination antiretroviral therapy remain poorly understood in China. METHODS: We analyzed data from our multicenter cohort study with 444 antiretroviral-naive participants recruited between 2008 and 2010. HIV-1 subtype and tropism were determined by V3 sequencing, and TDR/DRM was determined by Pol sequencing. Virologic and immunologic responses were monitored over 96 weeks of follow-up. The initial combination antiretroviral therapy regimen for all patients was nevirapine + lamivudine + zidovudine or stavudine. Analysis 1 included patients who finished 96 weeks of follow-up (n = 379), and analysis 2 included all 444 patients. RESULTS: Subtype B/B' was associated with higher prevalence of TDR/DRM to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors. Median time to HIV-1 suppression was 18 weeks in all 3 subtype groups. In Cox proportional models for viral suppression, neither viral tropism nor HIV-1 subtypes had any impact on viral suppression; however, subtypes CRF01_AE and C/CRF07_BC/CRF08_BC were associated with lower risk of virologic failure compared with subtype B/B', with adjusted hazard ratio of 0.11 (P = 0.032) and 0.06 (P = 0.036), respectively in analysis 1, 0.42 (P = 0.047) and 0.22 (P = 0.008), respectively in analysis 2. This association was attenuated by adding DRM profiles to multivariate regression models. Neither subtype nor HIV-1 tropism affected immunologic response. CONCLUSIONS: HIV-1 subtype tended to be associated with virologic but not immunologic response; this effect could be ascribed to baseline DRM. PMID- 25501611 TI - Initial programmatic implementation of WHO option B in Botswana associated with increased projected MTCT. AB - : Botswana was one of the first African countries to transition from WHO Option A to Option B for prevention of mother-to-child HIV transmission (MTCT). We evaluated the impact of this transition on projected MTCT risk through review of 10,681 obstetric records of HIV-infected women delivering at 6 maternity wards. Compared with Option A, women receiving antenatal care under Option B were more likely to receive combination antiretroviral therapy (ART), adjusted odds ratio (aOR): 2.59 (95% confidence interval: 2.25 to 2.98), but they were also more likely to receive no antenatal antiretrovirals, aOR: 2.10 (95% confidence interval: 1.74 to 2.53). Consequently, initial implementation of Option B was associated with increased projected MTCT at 6 months of age, 3.79% under Option A and 4.69% under Option B (P < 0.001). Successful implementation of Option B or B+ may require that ART can be initiated within antenatal clinics, and novel strategies to remove barriers to rapid ART initiation. PMID- 25501613 TI - Proportions of patients with HIV retained in care and virally suppressed in New York City and the United States: higher than we thought. AB - BACKGROUND: The purpose of this analysis is to compare 2 newly developed methods (a "likelihood" method and a "weighting" method) with the widely used method (the "include-all" method) to estimate the proportions of HIV-infected persons retained in care and virally suppressed in New York City (NYC). METHODS: The NYC HIV registry data were used for the analysis. The include-all method included all patients in the denominator who were diagnosed and/or receiving care in NYC and not known to be dead by December 31, 2012. The likelihood method included patients in the denominator who were likely to reside in NYC in 2012 based on their length of absence from HIV care. The weighting method included patients in the denominator who were residing in NYC in 2012 by weighting each in-care patient based on their probability of receiving HIV care. RESULTS: The include all method estimated that 114,926 persons were diagnosed and living with HIV in NYC, 63.7% were retained in care (>=1 care visit in 2012), and 48.9% were virally suppressed (<=200 copies/mL). The likelihood method and the weighting method produced equivalent estimates with 80,074 and 80,509 persons diagnosed and living with HIV in NYC, 91.5% and 91.0% retained in care, and 70.2% and 71.7% virally suppressed, respectively. CONCLUSIONS: Using 2 newly developed methods, we were able to report more accurate estimates of the proportions of patients retained in care and virally suppressed. Other local health jurisdictions should consider using these new methods to measure care outcomes and monitor the National HIV/AIDS Strategy. PMID- 25501614 TI - High interest in preexposure prophylaxis among men who have sex with men at risk for HIV infection: baseline data from the US PrEP demonstration project. AB - BACKGROUND: Preexposure prophylaxis (PrEP) is the first biomedical intervention with proven efficacy to reduce HIV acquisition in men who have sex with men (MSM) and transgender women. Little is known about levels of interest and characteristics of individuals who elect to take PrEP in real-world clinical settings. METHODS: The US PrEP Demonstration Project is a prospective open-label cohort study assessing PrEP delivery in municipal sexually transmitted disease clinics in San Francisco and Miami and a community health center in Washington, DC. HIV-uninfected MSM and transgender women seeking sexual health services at participating clinics were assessed for eligibility and offered up to 48 weeks of emtricitabine/tenofovir for PrEP. Predictors of enrollment were assessed using a multivariable Poisson regression model, and characteristics of enrolled participants are described. RESULTS: Of 1069 clients assessed for participation, 921 were potentially eligible and 557 (60.5%) enrolled. In multivariable analyses, participants from Miami (adjusted Relative Risk [aRR]: 1.53; 95% confidence interval [CI]: 1.33 to 1.75) or DC (aRR: 1.33; 95% CI: 1.2 to 1.47), those who were self-referred (aRR: 1.48; 95% CI: 1.32 to 1.66), those with previous PrEP awareness (aRR: 1.56; 95% CI: 1.05 to 2.33), and those reporting >1 episode of anal sex with an HIV-infected partner in the last 12 months (aRR: 1.20; 95% CI: 1.09 to 1.33) were more likely to enroll. Almost all (98%) enrolled participants were MSM, and at baseline, 63.5% reported condomless receptive anal sex in the previous 3 months. CONCLUSIONS: Interest in PrEP is high among a diverse population of MSM at risk for HIV infection when offered in sexually transmitted disease and community health clinics. PMID- 25501615 TI - Immunologic, virologic, and pharmacologic characterization of the female upper genital tract in HIV-infected women. AB - : A comparative analysis of cellular and soluble markers of immune activation in HIV-infected women on combination antiretroviral therapy showed that the upper genital tract (UGT) compared to the lower female genital tract was characterized by higher frequencies of potential HIV target cells and increased inflammatory molecules. Despite the activated UGT milieu, HIV RNA could not be detected in paired samples of plasma, cervicovaginal or endometrial lavage. As antiretroviral concentrations were >=3-fold higher in the endometrium than in the lower genital tract, high antiretroviral penetration and/or metabolism may limit viral replication in the UGT. PMID- 25501617 TI - Tumor necrosis factor-alpha and pregnancy complications: a prospective study. AB - OBJECTIVE: The aim of this study was to compare the levels of tumor necrosis factor-alpha (TNF-alpha) produced by peripheral blood mononuclear cells in normal pregnancies and pregnancies with complications. MATERIALS AND METHODS: Maternal peripheral blood mononuclear cells from women with a recurrent spontaneous miscarriage (n = 35), premature rupture of fetal membranes (n = 30), preeclampsia (n = 27) and intrauterine fetal growth retardation (IUGR; n = 36) were stimulated with mitogen or antigen, and the levels of TNF-alpha produced were compared to those produced by peripheral blood mononuclear cells from a normal pregnancy (n = 35). RESULTS: The median levels of mitogen-induced TNF-alpha at the 1st, 2nd and 3rd trimester, and at normal delivery were 1,176.4, 4,320.9, 7,307.4 and 2,463.0 pg/ml, respectively, while those produced in the recurrent spontaneous miscarriage, premature rupture of membranes and preeclampsia cases were 4,159.8, 3,489.5 and 4,149.2 pg/ml, respectively. The differences were statistically significantly higher in these pregnancy complications (p = 0.04, 0.024 and 0.014) as compared to the levels in normal pregnancy. Furthermore, antigen-induced TNF alpha levels were produced at statistically significantly higher levels by women with IUGR (120.4 pg/ml) compared to women with normal pregnancies (17.9 pg/ml; p = 0.041). CONCLUSION: Higher levels of TNF-alpha seem to play a role in these pregnancy complications, suggesting its pathogenesis in such conditions. PMID- 25501616 TI - Models for predicting effective HIV chemoprevention in women. AB - OBJECTIVE: Model systems that rapidly identify tissue drug concentrations protective of HIV infection could streamline the development of chemoprevention strategies. Tissue models are promising, but limited concentration targets exist, and no systematic comparison to cell models or clinical studies has been performed. DESIGN: We explored the efficacy of maraviroc (MVC) and tenofovir (TFV) for HIV prevention by comparing Emax models from TZM-bl cells to vaginal tissue explants and evaluated their predictive capabilities with a dose-challenge clinical study. METHODS: HIV-1JR-CSF was used for viral challenge. Drug efficacy was assessed using a luciferase reporter assay in TZM-bl cells and real-time PCR to quantify spliced RNA in a tissue explant model. Cell and tissue concentrations of MVC, TFV, and the active metabolite tenofovir diphosphate were measured by liquid chromatography with tandem mass spectrometry and used to create Emax models of efficacy. Efficacy after a single oral dose of 600 mg MVC and 600 mg tenofovir disoproxil fumarate was predicted from cell and tissue models and confirmed in a clinical study with viral biopsy challenge postdose. RESULTS: TFV was >10-fold and MVC >1000-fold, more potent in TZM-bl cells compared with vaginal explant tissue. In the dose-challenge study, tissues from 3 of 6 women were protected from HIV infection, which was 49% lower than predicted by TZM-bl data and 36% higher than predicted by tissue explant data. CONCLUSIONS: Comparative effective concentration data were generated for TFV and MVC in 3 HIV chemoprophylaxis models. These results provide a framework for future early investigations of antiretroviral efficacy in HIV prevention to optimize dosing strategies in clinical investigations. PMID- 25501619 TI - Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (review). AB - Hsp90 is a molecular chaperone that maintains the structural and functional integrity of various client proteins involved in signaling and many other functions of cancer cells. The natural inhibitors, ansamycins influence the Hsp90 chaperone function by preventing its binding to client proteins and resulting in their proteasomal degradation. N- and C-terminal inhibitors of Hsp90 and their analogues are widely tested as potential anticancer agents in vitro, in vivo as well as in clinical trials. It seems that Hsp90 competitive inhibitors target different tumor types at nanomolar concentrations and might have therapeutic benefit. On the contrary, some Hsp90 inhibitors increased toxicity and resistance of cancer cells induced by heat shock response, and through the interaction of survival signals, that occured as side effects of treatments, could be very effectively limited via combination of therapies. The aim of our review was to collect the data from experimental and clinical trials where Hsp90 inhibitor was combined with other therapies in order to prevent resistance as well as to potentiate the cytotoxic and/or antiproliferative effects. PMID- 25501618 TI - Comparison of antibody molecules produced from two cell lines with contrasting productivities and aggregate contents. AB - Cell culture processes that produce therapeutic antibodies with high productivity (titer) and low aggregate content reduce the risk of adverse effects and expense to patients. To elucidate the mechanism of aggregate formation, we compared trastuzumab samples produced from two contrasting cell lines: cell line A, which exhibits high titer and low aggregate content, and cell line B, which exhibits low titer and high aggregate content. Cell line B produced significantly fewer (approximately 1/3) antibodies compared with cell line A and contained higher (approximately 3-fold) percentages of aggregates. The aggregates of antibodies found in the protein A-purified samples of cell line B were associated mostly with noncovalent interactions. Cell line B exhibited a low content of monomers/dimers of light chains in the medium and within cells. Because light chains are essential for the correct folding of heavy chains and secretion of mature antibodies, the characteristics of cell line B may be attributed to low levels of light chain production. In addition, protein A-purified antibodies from cell line B (but not those from cell line A) contained fragments that are expected to expose the hydrophobic CH3 domain, which may serve as nuclei for aggregation. PMID- 25501620 TI - Carbon coated K(0.8)Ti(1.73)Li(0.27)O4: a novel anode material for sodium-ion batteries with a long cycle life. AB - Carbon coated K0.8Ti1.73Li0.27O4 (KTLO) has been synthesized by a facile flux method followed by ball-milling and gaseous carbon coating. The carbon coated KTLO delivers a reversible specific capacity of 119.6 mA h g(-1) at 20 mA g(-1) with no capacity loss after 250 cycles as an anode material in sodium ion batteries, exhibiting an improved rate capability of 66 mA h g(-1) at 200 mA g( 1). It was found that carbon coating of KTLO not only enhances its electronic conductivity, but also improves the structure stability, proving that the carbon coated KTLO is a promising anode material for sodium ion batteries. PMID- 25501621 TI - Endovenous ablation of incompetent truncal veins and their perforators with a new radiofrequency system. Mid-term outcomes. AB - This is a prospective trial investigating endovenous radiofrequency ablation with the EVRF system for the treatment of symptomatic varicose veins. Primary endpoints include one-year anatomical and clinical success and procedure-related complications. Secondary endpoints include adjunctive procedures and recanalization rates, periprocedural pain assessment, and time return to normal activities. In 60 patients with 74 limbs, 58 great saphenous vein, 11 small saphenous vein, 2 anterior accessory saphenous vein, and 3 perforators were ablated. Additional ablations for further improvement were necessary in 28.4%. Clinical success was 94.6%. Anatomical success was 96.0% at one month and 89.2% at one year. Primary ablation success was 77%. Revascularization occurred in 12.1%. Clinically driven repeat ablation rate was 4.0%. Perforator ablation due to segmental revascularization was performed in 5.4%. Complications included one puncture-site infection, three scars, two cases of transient paresthesia, and one skin pigmentation. Periprocedural mean pain score was 2.4 +/- 2.6. In 27.0% cases, the patients used analgesics and mean time return was 1.2 +/- 0.5 days. The EVRF system yields satisfactory clinical and anatomical midterm outcomes with very low complication rates. PMID- 25501622 TI - Nineteen-year-old female with idiopathic thrombosis of the internal jugular vein. AB - Internal jugular vein thrombosis is a rarely seen condition which may be due to infection or neoplastic, thrombophilic, traumatic or iatrogenic causes. If the thrombosis in the jugular vein leads to pulmonary embolism, septic emboli or atrial or dural sinus thrombosis, it may be life-threatening. We report a successfully treated case of a 19-year-old female patient presenting with swelling and neck pain who was diagnosed with a stepwise approach of this rare condition. PMID- 25501624 TI - Actual position of interleukin(IL)-33 in atherosclerosis and heart failure: Great Expectations or En attendant Godot? AB - Atherosclerosis has been recognized as an inflammatory/autoimmune disease. The long-standing low-grade inflammation which fuels its development is primarily focused on the components of the vessel wall. Originally, inflammation in atherogenesis was supposed to be driven by the pro-inflammatory Th1 cellular and cytokine immune response. On the basis of accumulating evidence, this view has been re-evaluated to include the Th17/Th1 axis which is shared by most diseases of sterile inflammation. The anti-inflammatory Th2 cellular and cytokine immune response is initiated concomitantly with the former two, the latter dampening their harmful reactions which culminate in full-blown atherosclerosis. Interleukin-33, a novel member of the IL-1 cytokine superfamily, was suggested to take part in the anti-atherogenic response by mediating the Th1-to-Th2 switch of the immune reactions. However, IL-33 is a multifaceted mediator with both pro- and anti-inflammatory activities, also called a "dual factor" or a "Janus face" interleukin. IL-33 occurs both in an extracellular (cytokine-like) and in a nuclear-bound (transcription factor-like) form, each of them performing distinct activities of their own. This review article presents the latest data relevant to IL-33's role in atherosclerosis and cardiac diseases as perceived by a cardiologist and a cardiac surgeon. PMID- 25501623 TI - The inflammatory response between miniaturised and conventional cardiopulmonary bypass after cardiac surgery in an Asian population. AB - INTRODUCTION: We compared the systemic inflammatory response of the MCPB system to the CCPB system with cell salvage and phosphorylcholine-coated tubing amongst Asian patients undergoing coronary artery bypass grafting. METHODS: Seventy-eight patients were randomly assigned to the MCPB or the CCPB groups equally and followed up in a prospective, single-blinded, randomised, controlled trial. Levels of TNF-alpha, IL-6, CRP and LDH were measured peri-operatively. RESULTS: The systemic inflammatory response was similar in both groups (TNF-alpha: p=0.222; IL-6: p=0.991; CRP: p=0.258). Only haemolysis was significantly higher in the CCPB group (LDH: p=0.011). The MCPB system was twice more expensive, but had a near 4-fold cost saving in tranfusions. Overall, the MCPB system cost 20% more than the modified CCPB system. CONCLUSION: These results corroborate with studies that demonstrated the avoidance of cardiotomy suction rather than the MCPB system, itself, leads to an attenuated inflammatory response. The absence of obvious clinical benefit and the higher costs involved with the MCPB system would preclude its routine use. PMID- 25501625 TI - Differential histone modification status of spermatozoa in relation to fertility of buffalo bulls. AB - In this study genome-wide di-methylated H3K4 (H3K4me2) and tri-methylated H3K27 (H3K27me3) modification profiles were analyzed in spermatozoa of buffalo bulls having wide fertility differences. The custom designed 4 * 180 K buffalo (Bubalus bubalis) ChIP-on-chip array was fabricated by employing array-based sequential hybridization using bovine and buffalo genomic DNA for comparative hybridization. The buffalo specific array developed had 177,440 features assembled from Coding sequences, Promoter and CpG regions comprising 2967 unique genes. A total of 84 genes for H3K4me2 and 80 genes for H3K27me3 were found differentially enriched in mature sperm of high and sub-fertile buffalo bulls. Gene Ontology analysis of these genes revealed their association with different cellular functions and biological processes. Genes identified as differentially enriched between high and sub-fertile bulls were found to be involved in the processes of germ cell development, spermatogenesis and embryonic development. This study presents the first genome-wide H3K4me2 and H3K27me3 profiling of buffalo bull sperm. Results provide a list of specific genes which could be made responsible for differential bull fertility. PMID- 25501626 TI - The impact of a toolkit on use of standardised measurement tools in stroke rehabilitation. AB - OBJECTIVE: To evaluate the impact of a toolkit of psychometrically robust measurement tools, the Greater Manchester Assessment for Stroke Rehabilitation (G MASTER) toolkit, on the use of measurement tools during stroke rehabilitation DESIGN: Mixed methods cohort design using non-participant observation of multi disciplinary team meetings and semi-structured interviews with members of the team over three months before and three months after implementation of the assessment toolkit. Development and implementation of the toolkit are also described. SETTING: Ten in-patient stroke services in a large UK city. SUBJECTS: Members of the participating multi-disciplinary stroke teams. RESULTS: Before implementation standardised measures were seldom used in team meetings. After implementation, use of all measurement tools significantly increased (36% to 81% of occasions, P<0.000). Staff were generally positive about the toolkit and felt it enabled more accurate problem identification, effective progress monitoring, timely decision-making, communication and promoted inter-team relationships. CONCLUSIONS: A toolkit of standardised measurement tools can be feasibly and acceptably implemented into stroke rehabilitation. It increases the use of measurement tools by the multi-disciplinary team and improves the processes and quality of care. PMID- 25501627 TI - Mesoscopic interactions and species coexistence in evolutionary game dynamics of cyclic competitions. AB - Evolutionary dynamical models for cyclic competitions of three species (e.g., rock, paper, and scissors, or RPS) provide a paradigm, at the microscopic level of individual interactions, to address many issues in coexistence and biodiversity. Real ecosystems often involve competitions among more than three species. By extending the RPS game model to five (rock-paper-scissors-lizard Spock, or RPSLS) mobile species, we uncover a fundamental type of mesoscopic interactions among subgroups of species. In particular, competitions at the microscopic level lead to the emergence of various local groups in different regions of the space, each involving three species. It is the interactions among the groups that fundamentally determine how many species can coexist. In fact, as the mobility is increased from zero, two transitions can occur: one from a five- to a three-species coexistence state and another from the latter to a uniform, single-species state. We develop a mean-field theory to show that, in order to understand the first transition, group interactions at the mesoscopic scale must be taken into account. Our findings suggest, more broadly, the importance of mesoscopic interactions in coexistence of great many species. PMID- 25501628 TI - Histone deacetylase inhibitor suberoyl bis-hydroxamic acid suppresses cell proliferation and induces apoptosis in breast cancer cells. AB - Suberoyl bis-hydroxamic acid (SBHA) is a histone deacetylase inhibitor that has shown anticancer activity against numerous types of human cancer. The aim of the current study was to explore the effects of SBHA on the proliferation and apoptosis of breast cancer cells. MCF-7 breast cancer cells were treated with different concentrations of SBHA and tested for cell viability, apoptosis and gene expression changes. The results showed that SBHA significantly inhibited the proliferation of MCF-7 cells in a concentration-dependent manner, as determined using a Cell Counting kit-8 assay. SBHA-treated MCF-7 cells showed G0/G1 cell cycle arrest, coupled with elevated expression levels of p21 and p27 proteins. Hoechst 33258 staining revealed cell shrinkage, chromosomal condensation and nuclear fragmentation in MCF-7 cells treated with SBHA. Flow cytometric analysis of Annexin V-stained cells showed that SBHA treatment induced apoptotic cell death in a concentration-dependent manner. Western blot analysis confirmed the upregulation of Bax and the downregulation of Bcl-2 by SBHA. In conclusion, these results indicate that SBHA exerts cytotoxic effects against human breast cancer cells, which involves the modulation of p21, p27 and Bcl-2 family proteins, consequently leading to cell-cycle arrest and apoptosis. PMID- 25501629 TI - Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine. AB - Fetal lymphoid tissue inducer (LTi) cells are required for lymph node and Peyer's patch (PP) organogenesis, but where these specialized group 3 innate lymphoid cells (ILC3s) develop remains unclear. Here, we identify extrahepatic arginase 1(+) Id2(+) fetal ILC precursors that express a transitional developmental phenotype (ftILCPs) and differentiate into ILC1s, ILC2s and ILC3s in vitro. These cells populate the intestine by embryonic day (E) 13.5 and, before PP organogenesis (E14.5-15), are broadly dispersed in the proximal gut, correlating with regions where PPs first develop. At E16.5, after PP development begins, ftILCPs accumulate at PP anlagen in a lymphotoxin-alpha-dependent manner. Thus, ftILCPs reside in the intestine during PP development, where they aggregate at PP anlagen after stromal cell activation and become a localized source of ILC populations. PMID- 25501630 TI - Dynamic expression of transcription factors T-bet and GATA-3 by regulatory T cells maintains immunotolerance. AB - Regulatory T cells (Treg cells) can express the transcription factors T-bet and GATA-3, but the function of this expression and whether such cells represent stable subsets is still unknown. By using various reporter tools, we found that the expression of T-bet and GATA-3 in Treg cells was dynamically influenced by the cytokine environment. Treg cell-specific deletion of the gene encoding either T-bet (Tbx21) or GATA-3 (Gata3) alone did not result in loss of Treg cell function; however, mice with combined deficiency in both genes in Treg cells developed severe autoimmune-like diseases. Loss of Treg cell function correlated with upregulation of expression of the transcription factor RORgammat and reduced expression of the transcription factor Foxp3. Thus, in the steady state, activated Treg cells transiently upregulated either T-bet or GATA-3 to maintain T cell homeostasis. PMID- 25501632 TI - A single nucleotide polymorphism in the TGF-beta1 gene (rs1982073 C>T) may contribute to increased risks of bone fracture, osteoporosis, and osteoarthritis: a meta-analysis. AB - Genetic factors have been shown to be of great importance for the pathogenesis of bone diseases, such as fracture, osteoporosis (OP), and osteoarthritis (OA). However, published studies on the correlations of transforming growth factor beta1 (TGF-beta1) gene polymorphisms with bone diseases have been hampered by small sample sizes or inconclusive findings. We hence aimed at examining the relationships between a single nucleotide polymorphism in the TGF-beta1 gene (rs1982073 C>T) with bone fracture, OP, and OA risks in this meta-analysis. A systematic electronic search of literature was conducted to identify all published studies in English or Chinese on the association between the TGF-beta1 gene and fracture, OP, or OA risks. Data were abstracted independently by two reviewers. To investigate the strength of this relationship, crude odds ratios with 95 % confidence intervals were used. An updated meta-analysis based on nine independent case-control studies were chosen (patients with fracture, OP, or OA = 1569; healthy controls = 1638). Results identified a higher frequency of rs1982073 C>T in patients with fracture, OP, or OA than in healthy controls. Ethnicity and genotyping method-stratified analysis under both models implied that the rs1982073 C>T polymorphism was positively correlated with the risk of fracture, OP, and OA among Asians under detection via the non-PCR-RFLP method. Disease-stratified results yielded that rs1982073 C>T may increase the risk of fracture, OP, and OA under the allele model, but was only significantly related to OP under the dominant model. According to the sample size-stratified analysis, subjects with the rs1982073 C>T polymorphism in the allele model were more likely to develop the three bone diseases in both the small and large sample size groups, and only in the large sample size under the dominant model. Our findings show that TGF-beta1 rs1982073 C>T has a modest effect in increasing susceptibility to bone fracture, OP, and OA. PMID- 25501631 TI - A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus. AB - Dengue is a rapidly emerging, mosquito-borne viral infection, with an estimated 400 million infections occurring annually. To gain insight into dengue immunity, we characterized 145 human monoclonal antibodies (mAbs) and identified a previously unknown epitope, the envelope dimer epitope (EDE), that bridges two envelope protein subunits that make up the 90 repeating dimers on the mature virion. The mAbs to EDE were broadly reactive across the dengue serocomplex and fully neutralized virus produced in either insect cells or primary human cells, with 50% neutralization in the low picomolar range. Our results provide a path to a subunit vaccine against dengue virus and have implications for the design and monitoring of future vaccine trials in which the induction of antibody to the EDE should be prioritized. PMID- 25501633 TI - The global challenges and opportunities in the practice of rheumatology: white paper by the World Forum on Rheumatic and Musculoskeletal Diseases. AB - Rheumatic and musculoskeletal diseases (RMDs) represent a multitude of degenerative, inflammatory and auto-immune conditions affecting millions of people worldwide. Persons with these diseases may potentially experience severe chronic pain, joint damage, increasing disability and even death. With an increasingly ageing population, the prevalence and burden of RMDs are predicted to increase, placing greater demands on the global practice of rheumatology and related healthcare budgets. Effective treatment of RMDs currently faces a number of challenges in both the developed and developing world, and individual countries may face more specific local challenges. However, limited understanding of the burden of RMDs amongst public health professionals and policy-makers means that these diseases are often not considered a public health priority. The objective of this review is to increase awareness of the RMDs and to identify opportunities to address RMD challenges on both a local and global scale. On 26 September 2014, rheumatology experts from five different continents met at the World Forum on Rheumatic and Musculoskeletal Diseases (WFRMD) to discuss and identify some key challenges for the RMDs community today. The outcomes are presented in this review, focusing on access to rheumatology services, diagnostics and therapies, rheumatology education and training and on clinical trials, as well as investigator-initiated and epidemiological research. The long term vision of the WFRMD is to increase perception of the RMDs as a major burden to society and to explore potential opportunities to improve global and local RMD care. PMID- 25501635 TI - A three-dimensional nitrogen-doped graphene structure: a highly efficient carrier of enzymes for biosensors. AB - In recent years, graphene-based enzyme biosensors have received considerable attention due to their excellent performance. Enormous efforts have been made to utilize graphene oxide and its derivatives as carriers of enzymes for biosensing. However, the performance of these sensors is limited by the drawbacks of graphene oxide such as slow electron transfer rate, low catalytic area and poor conductivity. Here, we report a new graphene-based enzyme carrier, i.e. a highly conductive 3D nitrogen-doped graphene structure (3D-NG) grown by chemical vapour deposition, for highly effective enzyme-based biosensors. Owing to the high conductivity, large porosity and tunable nitrogen-doping ratio, this kind of graphene framework shows outstanding electrical properties and a large surface area for enzyme loading and biocatalytic reactions. Using glucose oxidase (GOx) as a model enzyme and chitosan (CS) as an efficient molecular binder of the enzyme, our 3D-NG based biosensors show extremely high sensitivity for the sensing of glucose (226.24 MUA mM(-1) m(-2)), which is almost an order of magnitude higher than those reported in most of the previous studies. The stable adsorption and outstanding direct electrochemical behaviour of the enzyme on the nanocomposite indicate the promising application of this 3D enzyme carrier in high-performance electrochemical biosensors or biofuel cells. PMID- 25501637 TI - Standard nomenclature for renal replacement therapy in acute kidney injury: very much needed! PMID- 25501634 TI - Predictors of treatment failure and mortality in native septic arthritis. AB - The aims of this study are to analyse the characteristics of septic arthritis stratified by age and to identify the predictors of treatment failure and mortality in septic arthritis. A retrospective single-centre study was conducted in patients with native septic arthritis between 1994 and 2012. The primary outcome was treatment failure. Secondary outcomes included mortality, complications, endocarditis, bacteraemia, hospital readmission and the duration of the hospital stay. Logistic regression analyses with a propensity score were performed to identify the predictors of response and mortality. Additional analyses were performed according to age and the initial treatment (surgery or conservative). A total of 186 patients were studied. The median (interquartile range) age was 64 (46, 74) years, and the percentage of male patients was 68.9%. A logistic regression analysis showed that Staphylococcus aureus infection [OR 2.39 (1.20-4.77), p = 0.013], endocarditis [OR 4.74 (1.16-19.24), p = 0.029] and the involvement of joints difficult to access with needle drainage [OR 2.33 (1.06 5.11), p = 0.034] predict treatment failure and that age [OR 1.27 (1.07 = 1.50), p = 0.005], the leucocyte count at baseline [OR 1.01 (1.00-1.02), p = 0.023], bacteraemia [OR 27.66 (1.39-551.20), p = 0.030], diabetes mellitus [OR 15.33 (1.36-172.67), p = 0.027] and chronic renal failure [OR 81.27 (3.32-1990.20), p = 0.007] predict mortality. No significant differences in treatment failure by age were found. In septic arthritis, the predictors of mortality and the predictors of treatment failure differ. The predictors of treatment failure concern local factors and systemic complications, whereas conditions related to the host's immune competence, such as age and comorbidities that hamper the host's response, predict mortality. PMID- 25501636 TI - Ethnic/racial and genetic influences on cerumen odorant profiles. AB - This report describes the volatile organic compounds (VOCs) associated with human cerumen (earwax) and the effects of ethnicity/race and variation on the ATP binding cassette, sub-family C, member 11 gene (ABCC11). A single nucleotide polymorphism (SNP) in ABCC11 affects the cerumen VOC profiles of individuals from African, Caucasian, and Asian descent. Employing gas chromatography/mass spectrometry (GC/MS) we have identified the nature and relative abundance of cerumen VOCs from 32 male donors. Our results show that cerumen contains a complex mixture of VOCs and that the amounts of these compounds vary across individuals as well as across ethnic/racial groups. In six of the seven compounds whose detected concentrations were found to be statistically different across groups, individuals of African descent (AfD) > Caucasian descent (CaD) > Asians descent (AsD). Our findings also reveal that ABCC11 genotype alone does not predict the type and relative levels of volatiles found in human cerumen, and suggest that other biochemical pathways must be involved. Examination of the composition and diversity of external auditory canal microbiota in a small subset of our subject population revealed that the ear microbiota may not be directly correlated with either ethnic group membership or ABCC11 genotype. PMID- 25501639 TI - Source analysis of global anthropogenic lead emissions: their quantities and species. AB - Lead emissions originate primarily from the anthropogenic lead cycle, and research into their characteristics, such as species type, provides essential information for pollution control. A dynamic model for global lead emissions has been established, and their emissions and temporal accumulations were estimated in this study based on the evolution of the lead cycle over 70 years. An inventory of the emissions species was obtained after identifying their physiochemical transformations. The 2010 emissions were 3.56 Mt, with 65 % coming from waste management and recycling. The main species were PbSO4 (42.5 %), PbO2 (16.2 %), and PbS (8.3 %). Between 1930 and 2010, the total lead emissions were 173.8 Mt, mainly from waste management and recycling (48 %), production (26 %), and use (20 %). The main species were PbSO4, PbO, Pb, and PbS, and together, they accounted for 61.2 % of the total emissions. Over time, species, such as tetraethyl lead and Pb, declined, but PbO2 and PbSO4 increased. PMID- 25501638 TI - Decreased expression of CYP27B1 correlates with the increased aggressiveness of ovarian carcinomas. AB - CYP27B1 hydroxylates 25-hydroxyvitamin D3 in position C1alpha into biologically active 1,25-dihydroxyvitamin D3, calcitriol. CYP27B1 is expressed in normal tissues and tumors. Since calcitriol indicates anticancer activities and CYP27B1 expression can be deregulated during malignant progression, we analyzed its expression in ovarian cancers in relation to pathomorphological features of tumors and overall survival (OS). Expression of CYP27B1 was evaluated in 61 ovarian tumors, 18 metastases and 10 normal ovaries. Normal ovarian epithelium showed the highest levels CYP27B1 with a significant decrease in its expression in ovarian cancers. Both poorly differentiated primary tumors and metastases showed the lowest level of CYP27B1 expression, while non-metastasizing tumors showed a higher CYP27B1 level than tumors that developed metastases. The expression of CYP27B1 was positively correlated with a lower proliferation rate, lower dynamism of tumor growth and tumor infiltrating lymphocyte response. Furthermore, CYP27B1 expression was negatively correlated with tumor cell modeling of their microenvironment. CYP27B1 expression was also associated with longer OS time. In summary, our results suggest that local expression of CYP27B1 in ovarian tumor cells can modify their behavior and promote a less aggressive phenotype by affecting local concentrations of active of vitamin D levels within the tumor microenvironment. PMID- 25501640 TI - Alluvial and riparian soils as major sources of lead exposure in young children in the Philippines: the role of floods. AB - The objective of this paper was to determine the prevalence and sources of high lead (Pb) exposure among children in Bulacan, Philippines. A total of 150 children (6-7 years old) and their caregivers were studied. Lead was analyzed in children hair and deciduous teeth. Sources of lead exposure were determined by caregiver interview and Pb analysis of house soil, drinking faucet water, air, and water from seven Bulacan rivers. Lead was positive in 91.3% of children's hair (MC or median concentration = 8.9 MUg/g; range = 0-38.29), in 46.2% of the teeth (MC = 0.000 MUg/mg in positive samples; range = 0.00-0.020), in 100% of soil (MC = 27.06 mg/kg; range = 3.05-1155.80), in 21.1% of air (MC = 0 MUg/Ncm; range = 0-0.10), in 4% of house, faucet water (MC = 0.0 ppm; range = 0-40). There was a significant correlation (Spearman's rho) between Pb in children's hair and soil (r = 0.195; p = 0.017) and between Pb in house water and outdoor air (r = 0.616; p = 0.005). There is no significant correlation between Pb in children's hair and teeth. None of the potential sources of Pb from interview were related to lead exposure in the children. Water from seven Bulacan rivers was 100% positive for lead (MC = 70.00 ppb; range = 30-90). Widespread flooding with river overflow occurred in Bulacan in 2009 which likely caused lead contamination of the soil. There was no significant difference in the lead concentration of the soil whether near or far from the river (p = 0.205, Mann-Whitney U test). High lead exposure in children in Bulacan is likely from soil contaminated by lead polluted rivers during flooding. In areas where flooding is common, alluvial and riparian soils from polluted rivers are important sources of lead exposure in children. PMID- 25501641 TI - Human exposure to mercury in artisanal small-scale gold mining areas of Kedougou region, Senegal, as a function of occupational activity and fish consumption. AB - We investigated mercury (Hg) exposure of food web and humans in the region of Kedougou, Senegal, where Hg is used for gold amalgamation in artisanal small scale gold mining (ASGM). For this purpose, total mercury (THg) concentration was determined in eight fish species and two shellfish species from Gambia River and in human hair from 111 volunteers of different age and sex, living in urban locations (Kedougou and Samekouta) or in ASGM areas (Tinkoto and Bantako). THg concentrations in fish samples range from 0.03 to 0.51 mg kg(-1) wet weight (ww) and 0.5 to 1.05 mg kg(-1) ww for shellfish. THg concentrations in fish are below the WHO guideline of 0.5 mg kg(-1) ww, whereas 100 % of shellfish are above this safety guideline. In the entire set of fish and shellfish samples, we documented a decrease of THg concentrations with increasing selenium to mercury (Se:Hg) ratio suggesting a protection of Se against Hg. However, local population consuming fish from the Gambia River in the two ASGM areas have higher THg concentrations (median = 1.45 and 1.5 mg kg(-1) at Bantako and Tinkoto) in hair than those from others localities (median = 0.42 and 0.32 mg kg(-1) at Kedougou town and Samekouta) who have diverse diets. At ASGM sites, about 30 % of the local population present Hg concentrations in hair exceeding 1 mg kg(-1), defined as the reference concentration of Hg in hair. We also evidence a higher exposure of women to Hg in the Tinkoto ASGM site due to the traditional distribution of daily tasks where women are more involved in the burning of amalgams. The discrepancy between the calculated moderate exposure through fish consumption and the high Hg concentrations measured in hair suggest that fish consumption is not the only source of Hg exposure and that further studies should focus on direct exposure to elemental Hg of population living at ASGM sites. PMID- 25501642 TI - Evaluation of arsenic trioxide genotoxicity in wheat seedlings using oxidative system and RAPD assays. AB - Arsenic is a metalloid that is toxic to living organisms. It is known that high concentration of arsenic causes toxic damage to cells and tissues of plants. While the toxic effect of arsenic is known, limited efforts have been made to study its genotoxic effect on the crops. In the present study, effects of arsenic trioxide (As2O3) on seed germination, root length, reactive oxygen species (ROS), lipid peroxidation (malondialdehyde (MDA)), and activities of antioxidant enzymes, as well as DNA in wheat seedlings were investigated. Seedlings were exposed to different (10 to 40 mg/L) As2O3 concentrations for 7 days. Seed germination and root elongation decreased with increase of As2O3 concentration. The values of hydrogen peroxide (H2O2), superoxide anion (O2 (.-)), and MDA contents significantly increased by As2O3 concentrations. The highest values for H2O2, O2 (.-), and MDA were obtained in 40 mg/L treated wheat seedling. A significant increase of peroxidase (POX) and catalase (CAT) activity in seedlings were observed with increased concentration of As2O3, then decreased when reaching a value of 40 mg/L, whereas the activities of superoxide dismutase (SOD) were gradually enhanced with increasing As2O3 concentration. Alterations of DNA in wheat seedlings were detected using randomly amplified polymorphic DNA (RAPD) technique. The changes occurring in RAPD profiles of seedlings following As2O3 treatment included loss of normal bands and appearance of new bands in comparison to that of control seedlings. The results of our study showed that As2O3 induced DNA damage in a dose-dependent meaner, and the root cells of wheat studied showed a defense against As2O3-induced oxidative stress by enhancing their antioxidant activities. PMID- 25501643 TI - Photoinitiators enhanced 1,2-dichloropropane-induced cytotoxicity in human normal embryonic lung fibroblasts cells in vitro. AB - Dichloromethane (DCM) and 1,2-dichloropsropane (DCP) have various uses, including being solvents for paint removers. Photoinitiators are also used in a wide range of commercial applications such as printing. These chemicals have been shown to induce cytotoxic effects. In the present study, we evaluated the combined effects of DCM or DCP from paint removers and photoinitiators used in printing on normal human embryonic lung fibroblasts with the aim of preventing occupational injuries. We showed that DCP, 2,2-dimethoxy-2-phenylacetophenone (2,2-DMPAP), 2 ethylhexyl-4-(dimethylamino) benzoate (2-EHDAB), 1-hydroxycyclohexyl phenyl ketone (1-HCHPK), and methyl 2-benzoylbenzoate (MBB) induced cytotoxicity, whereas DCM and 2-isopropylthioxanthone (2-ITX) did not. In addition, 2-methyl-4' (methylthio)-2-morpholinopropiophenone (MTMP) caused a slight increase in cytotoxicity. The combination of DCP and the four photoinitiators (2,2-DMPAP, 2 EHDAB, MBB, and MTMP) significantly induced cytotoxicity and also led to apoptosis. In conclusion, the combination of DCP and photoinitiators may increase the risk of respiratory diseases. PMID- 25501645 TI - Erratum to: Performance and bacterial communities of successive alkalinity producing systems (SAPSs) in passive treatment processes treating mine drainages differing in acidity and metal levels. PMID- 25501644 TI - Levels and risk factors of antimony contamination in human hair from an electronic waste recycling area, Guiyu, China. AB - The primitive electronic waste (e-waste) recycling has brought a series of environmental pollutants in Guiyu, China. Antimony is one of the important metal contaminants and has aroused the global concerns recently. We aimed to investigate concentrations of antimony in human hair from Guiyu and compared them with those from a control area where no e-waste recycling exists, and assessed the potential risk factors. A total of 205 human hair samples from Guiyu and 80 samples from Jinping were collected for analysis. All volunteers were asked to complete a questionnaire including socio-demographic characteristics and other possible factors related to hair antimony exposure. The concentrations of hair antimony were analyzed using atomic absorption spectrophotometer. Our results indicated that the level of hair antimony in volunteers from Guiyu (median, 160.78; range, 6.99-4412.59 ng/g) was significantly higher than those from Jinping (median, 61.74; range, 2.98-628.43 ng/g). The residents who engaged in e waste recycling activities in Guiyu had higher hair antimony concentrations than others (P < 0.001). There was no significant difference of hair antimony concentrations among different occupation types in e-waste recycling. Multiple stepwise regression analysis indicated that hair antimony concentrations were associated with education level (beta = -0.064), the time of residence in Guiyu (beta = 0.112), living house also served as e-waste workshop (beta = 0.099), the work related to e-waste (beta = 0.169), and smoking (beta = 0.018). The elevated hair antimony concentrations implied that the residents in Guiyu might be at high risk of antimony contamination, especially the e-waste recycling workers. Work related to e-waste recycling activities and long-time residence in Guiyu contributed to the high hair antimony exposure. PMID- 25501646 TI - Detecting causality from nonlinear dynamics with short-term time series. AB - Quantifying causality between variables from observed time series data is of great importance in various disciplines but also a challenging task, especially when the observed data are short. Unlike the conventional methods, we find it possible to detect causality only with very short time series data, based on embedding theory of an attractor for nonlinear dynamics. Specifically, we first show that measuring the smoothness of a cross map between two observed variables can be used to detect a causal relation. Then, we provide a very effective algorithm to computationally evaluate the smoothness of the cross map, or "Cross Map Smoothness" (CMS), and thus to infer the causality, which can achieve high accuracy even with very short time series data. Analysis of both mathematical models from various benchmarks and real data from biological systems validates our method. PMID- 25501647 TI - Oxidative stress and substance P mediate psychological stress-induced autophagy and delay of hair growth in mice. AB - Neuropeptide substance P (SP) and reactive oxygen species (ROS) have been demonstrated to play an important role in psychological stress-induced alteration of hair cycle, the underlying mechanism remains unknown. The present study aims to investigate possible contribution of SP and ROS in chronic restraint stress (CRS, a chronic psychological stress model) induced abnormal of hair cycle and induction of autophagy. Mouse CRS model was applied for 18 days with or without treatment antioxidant Tempol (a free radical scavenger) or SP receptor (NK1) antagonist (RP67580). After CRS procedure, hair growth cycle, oxidative stress markers and skin tissue autophagy levels were analyzed by ELISA or western blot. Our results revealed that CRS reduced body weight gain, distance of movement and times of standing, affected hair cycle by prolonging the telogen stage and delaying subsequent anagen and catagen stage. In addition, CRS resulted in increase of lipid peroxidation levels and reduction of the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and increase of autophagy markers (microtubule-associated proteins, light chain 3-II, LC3-II, and Beclin-1) in mice skin. Treatment with Tempol restored GSH-Px activity, and significantly reduced increases of lipid peroxidation levels and LC3-II and Beclin-1 expressions, as well as normalized hair cycle. In addition; RP67580 also restored SOD and GSH-Px activities, and markedly reduced increases of lipid peroxidation levels and LC3-II and Beclin-1 expressions, and normalized hair cycle. Our study provides the first strong evidence for SP and ROS play a role not only in alteration of hair cycle but also in induction of autophagy in psychological stress model, suggesting autophagy may contribute to psychological stress-induced abnormal of hair cycle. PMID- 25501649 TI - Exploring the effect of axial ligand substitution (X = Br, NCS, CN) on the photodecomposition and electrochemical activity of [MnX(N-C)(CO)3] complexes. AB - The synthesis, electrochemical activity, and relative photodecomposition rate is reported for four new Mn(i) N-heterocyclic carbene complexes: [MnX(N-ethyl-N'-2 pyridylimidazol-2-ylidine)(CO)3] (X = Br, NCS, CN) and [MnCN(N-ethyl-N'-2 pyridylbenzimidazol-2-ylidine)(CO)3]. All compounds display an electrocatalytic current enhancement under CO2 at the potential of the first reduction, which ranges from -1.53 V to -1.96 V versus the saturated calomel electrode. Catalytic CO production is observed for all species during four-hour preparative-scale electrolysis, but substantial H2 is detected in compounds where X is not Br. All species eventually decompose under both 350 nm and 420 nm light, but cyanide substituted complexes (X = CN) last significantly longer (up to 5*) under 420 nm light as a result of a blue-shifted MLCT band. PMID- 25501648 TI - Nitrite circumvents canonical cGMP signaling to enhance proliferation of myocyte precursor cells. AB - Skeletal muscle tissue has a remarkable high regenerative capacity. The underlying cellular events are governed by complex signaling processes, and the proliferation of skeletal myoblasts is a key initial event. The role of nitric oxide (NO) in cell cycle regulation is well-appreciated. Nitrite, an NO oxidation product, is a stable source for NO-like bioactivity particularly in cases when oxygen shortage compromises NO-synthases activity. Although numerous studies suggest that nitrite effects are largely related to NO-dependent signaling, emerging evidence also implicates that nitrite itself can activate protein pathways albeit under physiological, normoxic conditions. This includes a recently demonstrated cyclic guanosine monophosphate-(cGMP)-independent enhancement of endothelial cell proliferation. Whether nitrite itself has the potential to affect myoblast proliferation and metabolism with or without activation of the canonical NO/cGMP pathway to subsequently support muscle cell regeneration is not known. Here we show that nitrite increases proliferation and metabolic activity of murine cultured myoblasts dose-dependently. This effect is not abolished by the NO scavenger 2-(4-carboxy-phenyl)-4,4,5,5-tetramethylimida zoline-1-oxyl-3 oxide and does not affect intracellular cGMP levels, implicating a cGMP-independent mechanism. Nitrite circumvents the rapamycin induced attenuation of myoblast proliferation and enhances mTOR activity. Our results provide evidence for a novel potential physiological and therapeutic approach of nitrite in skeletal muscle regeneration processes under normoxia independent of NO and cGMP. PMID- 25501650 TI - Geochemistry of silicate-rich rocks can curtail spreading of carbon dioxide in subsurface aquifers. AB - Pools of carbon dioxide are found in natural geological accumulations and in engineered storage in saline aquifers. It has been thought that once this CO2 dissolves in the formation water, making it denser, convection streams will transport it efficiently to depth, but this may not be so. Here, we assess theoretically and experimentally the impact of natural chemical reactions between the dissolved CO2 and the rock formation on the convection streams in the subsurface. We show that, while in carbonate rocks the streaming of dissolved carbon dioxide persists, the chemical interactions in silicate-rich rocks may curb this transport drastically and even inhibit it altogether. These results challenge our view of carbon sequestration and dissolution rates in the subsurface, suggesting that pooled carbon dioxide may remain in the shallower regions of the formation for hundreds to thousands of years. The deeper regions of the reservoir can remain virtually carbon free. PMID- 25501651 TI - Association between the number of injuries sustained and 12-month disability outcomes: evidence from the injury-VIBES study. AB - OBJECTIVE: To determine associations between the number of injuries sustained and three measures of disability 12-months post-injury for hospitalised patients. METHODS: Data from 27,840 adult (18+ years) participants, hospitalised for injury, were extracted for analysis from the Validating and Improving injury Burden Estimates (Injury-VIBES) Study. Modified Poisson and linear regression analyses were used to estimate relative risks and mean differences, respectively, for a range of outcomes (Glasgow Outcome Scale-Extended, GOS-E; EQ-5D and 12-item Short Form health survey physical and mental component summary scores, PCS-12 and MCS-12) according to the number of injuries sustained, adjusted for age, sex and contributing study. FINDINGS: More than half (54%) of patients had an injury to more than one ICD-10 body region and 62% had sustained more than one Global Burden of Disease injury type. The adjusted relative risk of a poor functional recovery (GOS-E<7) and of reporting problems on each of the items of the EQ-5D increased by 5-10% for each additional injury type, or body region, injured. Adjusted mean PCS-12 and MCS-12 scores worsened with each additional injury type, or body region, injured by 1.3-1.5 points and 0.5 points, respectively. CONCLUSIONS: Consistent and strong relationships exist between the number of injury types and body regions injured and 12-month functional and health status outcomes. Existing composite measures of anatomical injury severity such as the NISS or ISS, which use up to three diagnoses only, may be insufficient for characterising or accounting for multiple injuries in disability studies. Future studies should consider the impact of multiple injuries to avoid under-estimation of injury burden. PMID- 25501654 TI - Recommendations for nurse practitioner residency programs. AB - The purpose of this study was to identify and prioritize critical aspects needed in the design and execution of new nurse practitioner (NP) residency programs. Subjects answered a series of questions on formulating residency programs and on key outcomes and cost measures related to their sustainability. These results serve as potential guideposts for future work in NP residency standardization and sustainability development. PMID- 25501652 TI - The link between inequality and population health in low and middle income countries: policy myth or social reality? AB - An influential policy idea states that reducing inequality is beneficial for improving health in the low and middle income countries (LMICs). Our study provides an empirical test of this idea: we utilized data collected by the Demographic and Health Surveys between 2000 and 2011 in as much as 52 LMICs, and we examined the relationship between household wealth inequality and two health outcomes: anemia status (of the children and their mothers) and the women' experience of child mortality. Based on multi-level analyses, we found that higher levels of household wealth inequality related to worse health, but this effect was strongly reduced when we took into account the level of individuals' wealth. However, even after accounting for the differences between individuals in terms of household wealth and other characteristics, in those LMICs with higher household wealth inequality more women experienced child mortality and more children were tested with anemia. This effect was partially mediated by the country's level and coverage of the health services and infrastructure. Furthermore, we found higher inequality to be related to a larger health gap between the poor and the rich in only one of the three examined samples. We conclude that an effective way to improve the health in the LMICs is to increase the wealth among the poor, which in turn also would lead to lower overall inequality and potential investments in public health infrastructure and services. PMID- 25501653 TI - Genome-wide analysis of DNA methylation dynamics during early human development. AB - DNA methylation is globally reprogrammed during mammalian preimplantation development, which is critical for normal development. Recent reduced representation bisulfite sequencing (RRBS) studies suggest that the methylome dynamics are essentially conserved between human and mouse early embryos. RRBS is known to cover 5-10% of all genomic CpGs, favoring those contained within CpG rich regions. To obtain an unbiased and more complete representation of the methylome during early human development, we performed whole genome bisulfite sequencing of human gametes and blastocysts that covered>70% of all genomic CpGs. We found that the maternal genome was demethylated to a much lesser extent in human blastocysts than in mouse blastocysts, which could contribute to an increased number of imprinted differentially methylated regions in the human genome. Global demethylation of the paternal genome was confirmed, but SINE-VNTR Alu elements and some other tandem repeat-containing regions were found to be specifically protected from this global demethylation. Furthermore, centromeric satellite repeats were hypermethylated in human oocytes but not in mouse oocytes, which might be explained by differential expression of de novo DNA methyltransferases. These data highlight both conserved and species-specific regulation of DNA methylation during early mammalian development. Our work provides further information critical for understanding the epigenetic processes underlying differentiation and pluripotency during early human development. PMID- 25501655 TI - Legal issues in clinical nursing education. AB - Nurse educators are concerned about legal implications of teaching students in clinical settings. Although literature is available about legal issues in working with students in the classroom, there is little recent information on clinical nursing faculty's legal liability when working with students and ways to reduce the risk of becoming involved in a lawsuit. This article discusses the major issues in clinical settings that contribute to lawsuits against faculty and offers suggestions to reduce legal liability with students in clinical settings. PMID- 25501657 TI - Multiple dimensions of peer influence in adolescent romantic and sexual relationships: a descriptive, qualitative perspective. AB - Adolescents undergo critical developmental transformations that increase the salience of peer influence. Peer interactions (platonic and romantic) have been found to have both a positive and negative influence on adolescent attitudes and behaviors related to romantic relationships and sexual behavior. This study used qualitative methodology to explore how peers influence romantic and sexual behavior. Forty adolescents participated in individual semi-structured interviews. All interviews were audio recorded and transcribed, and analyzed using a modified grounded theory approach. The concept of peer influence on romantic relationships and sexual behavior emerged as a key theme. Youth described that platonic peers (friends) influenced their relationships and sexual behavior including pressuring friends into relationships, establishing relationships as currency for popularity and social status, and creating relationship norm and expectations. Romantic peers also motivated relationship and sexual behavior as youth described engaging in behavior to avoid hurting and successfully pleasing their partners. Future research should explore multiple types of peer influence in order to better inform interventions to improve the quality of adolescents' romantic and sexual relationships. PMID- 25501656 TI - Unprofessional content posted online among nursing students. AB - This study investigated the posting of unprofessional content online among nursing students. Surveys of 293 schools of nursing revealed that 77% had encountered at least 1 incident of students posting such content. Respondents reported greatest concerns about content pertaining to educational and professional affiliations and to patient confidentiality. Most schools are developing responses to online unprofessionalism. Nursing education must stay current with social networking technologies and students' educational needs. PMID- 25501658 TI - Does the quality of parent-child connectedness matter for adolescents' sexual behaviors in Nairobi informal settlements? AB - This study investigated the associations between parent-child connectedness and sexual behaviors among adolescents living in informal settlements in Nairobi, Kenya, a vulnerable group with respect to reproductive health outcomes. The study was based on data from the Transition to Adulthood project, a study designed to follow adolescents aged 12-22 for 3 years in the informal settlements of Korogocho and Viwandani. Direct face-to-face questions were asked to adolescents about parenting variables and sexual behaviors. This study used a subsample of 689 sexually experienced 12-22-years-olds at Wave 2. Bivariate analysis compared gender differences for three outcomes-sexual activity in the 12 months prior to the survey and, among those who had had sex in this period, multiple sexual partners and condom use at last sex. Multivariate logistic regressions were used to identify associations between these outcomes and the quality of parent-child connectedness. About 60% of adolescent females and males were sexually active in the 12 months prior to the survey. The multivariate results showed a strong association between the quality of parent-child connectedness and condom use among adolescent males. Living with related or unrelated guardians (versus living with biological parents) was also associated with higher odds of multiple sexual partners and lower odds of condom use at last sex among adolescent females and with higher odds of sexual activity among adolescent males. Sexual and reproductive health programs targeting adolescents living in Nairobi informal settlements would benefit from attention to assisting parents to improve their ability to play the connectedness role. PMID- 25501659 TI - Perceived realism moderates the relation between sexualized media consumption and permissive sexual attitudes in Dutch adolescents. AB - This study examined whether the development of sexualized media consumption and permissive sexual attitudes would be more strongly interrelated when adolescents perceived sexualized media images as highly realistic. We used data from a three wave longitudinal sample of 444 Dutch adolescents aged 13-16 years at baseline. Results from parallel process latent growth modeling multigroup analyses showed that higher initial levels of sexualized media consumption were associated with higher initial level of permissive sexual attitudes. Moreover, increases of sexualized media consumption over time were associated with increases of permissive sexual attitudes over time. Considering the moderation by perceived realism, we found these effects only for those who perceived sexualized media as more realistic. Findings for male and female adolescents were similar except for the relations between initial levels and subsequent development. Among male adolescents who perceived sexualized media images to be realistic, higher initial levels of permissive sexual attitudes were related to subsequent less rapid development of sexualized media consumption. For male adolescents who perceived sexualized media to be less realistic, higher initial levels of sexualized media consumption were related to a subsequent less rapid development of permissive sexual attitudes. These relations were not found for female adolescents. Overall, our results suggest that, in male and female adolescents, those with a high level of perceived realism showed a correlated development of sexualized media consumption and permissive sexual attitudes. These findings point to a need for extended information on how to guide adolescents in interpreting and handling sexualized media in everyday life. PMID- 25501660 TI - Comparison and evaluation of three screening tests of hereditary spherocytosis in Chinese patients. AB - The objective of this study is to compare and evaluate the diagnostic value of hereditary spherocytosis (HS) by three screening tests, comparing mean spherical corpuscular volume (MSCV) to mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and flow cytometric osmotic fragility test. Peripheral blood was collected from 237 participators diagnosed at the First Affiliated Hospital of Guangxi Medical University, including 56 hereditary spherocytosis patients, 86 thalassemia patients, and 95 healthy people. The samples were examined by three tests, and the three screening tests were evaluated by the sensitivity and specificity of tests. The sensitivity was only 41.07%, and specificity was 94.47% when using MCHC >355 g/L as diagnostic criteria. The sensitivity was 89.28%, and specificity was 96.14% when using MSCV < MCV as the optimum cutoff point. When using the residual red cell percentage <23.6% as the diagnostic threshold in flow cytometric osmotic fragility test, the sensitivity was 85.71% and the specificity was 97.24%. Flow cytometry osmotic fragility test or comparing MSCV to MCV combined with smear examination of peripheral red blood cells morphology can be a simple, practical, and accurate hereditary spherocytosis (HS) laboratory screening method. PMID- 25501661 TI - RNA-Seq and ChIP-Seq reveal SQSTM1/p62 as a key mediator of JunB suppression of NF-kappaB-dependent inflammation. AB - Mice with epidermal deletion of JunB transcription factor displayed a psoriasis like inflammation. The relevance of these findings to humans and the mechanisms mediating JunB function are not fully understood. Here we demonstrate that impaired JunB function via gene silencing or overexpression of a dominant negative mutant increased human keratinocyte cell proliferation but decreased cell barrier function. RNA-seq revealed over 500 genes affected by JunB loss of function, which included the upregulation of an array of proinflammatory molecules relevant to psoriasis. Among these were tumor necrosis factor alpha (TNFalpha), CCL2, CXCL10, IL6R, and SQSTM1, an adaptor protein involved in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activation. Chromatin immunoprecipitation (ChIP)-Seq and gene reporter analyses showed that JunB directly suppressed SQSTM1 by binding to a consensus AP-1 cis element located around 2 kb upstream of SQSTM1-transcription start site. Similar to JunB loss of function, SQSTM1-overexpression induced TNFalpha, CCL2, and CXCL10. Conversely, NF-kappaB inhibition genetically with a mutant IkappaBalpha or pharmacologically with pyrrolidine dithiocarbamate (PDTC) prevented cytokine, but not IL6R, induction by JunB deficiency. Taken together, our findings indicate that JunB controls epidermal growth, barrier formation, and proinflammatory responses through direct and indirect mechanisms, pinpointing SQSTM1 as a key mediator of JunB suppression of NF-kappaB-dependent inflammation. PMID- 25501662 TI - Downstream targets of Lmo4 are modulated by cisplatin in the inner ear of Wistar rats. AB - Lmo4, a transcriptional regulator, appears to be a key player in mediating the cochlear pathology in cisplatin ototoxicity, as it controls cellular responses by modulating the formation of transcriptional complexes. We provided the first evidence of in vivo nitration of Lmo4 in cisplatin ototoxicity. Our data suggested that nitration of Lmo4 and associated decrease in its cochlear expression has the potential to play a pivotal role in cisplatin ototoxicity. However, the Lmo4 interactomes that signal the downstream events in the cochlea are poorly understood. Therefore, custom-made gene arrays were employed to evaluate the modulation of known binding partners or targets of Lmo4, in Wistar rats treated with 16 mg/kg cisplatin. RT-PCR analysis, 3 days post cisplatin treatment, indicated that cisplatin induced up/down regulation of multiple cochlear genes associated with Lmo4 signaling. The cochlear expression of Esr1 was significantly up-regulated by cisplatin treatment, while the expression of Stat3 was down-regulated. Co-treatment with Trolox, an otoprotective antioxidant, attenuated the cisplatin-induced modulation of 5 genes in the cochlea. Consistent with the changes observed at the gene level, immunoblots with anti-Stat3 indicated that cisplatin-induced decrease in cochlear protein levels were attenuated by Trolox co-treatment. These results suggest that cisplatin-induced decreases in the cochlear Lmo4 upon nitration, and associated modulation in the cochlear expression of its binding partners Esr1 and Jak1, probably facilitates the repression of Stat3, a downstream target of Lmo4 implicated in drug mediated apoptosis. Collectively, these findings provide insights on Lmo4 downstream events and indicate a potential role of Jak/Stat transcriptional machinery in relaying the Lmo4 protein signaling in cisplatin-induced ototoxicity. PMID- 25501664 TI - Urinary tract infections: a common but fascinating infection, with still many research questions. PMID- 25501665 TI - The molecular biology-clinical interface of sexually transmitted infections for evaluating pathophysiology, transmission, resistance and treatment. PMID- 25501663 TI - Protein-protein docking with dynamic residue protonation states. AB - Protein-protein interactions depend on a host of environmental factors. Local pH conditions influence the interactions through the protonation states of the ionizable residues that can change upon binding. In this work, we present a pH sensitive docking approach, pHDock, that can sample side-chain protonation states of five ionizable residues (Asp, Glu, His, Tyr, Lys) on-the-fly during the docking simulation. pHDock produces successful local docking funnels in approximately half (79/161) the protein complexes, including 19 cases where standard RosettaDock fails. pHDock also performs better than the two control cases comprising docking at pH 7.0 or using fixed, predetermined protonation states. On average, the top-ranked pHDock structures have lower interface RMSDs and recover more native interface residue-residue contacts and hydrogen bonds compared to RosettaDock. Addition of backbone flexibility using a computationally generated conformational ensemble further improves native contact and hydrogen bond recovery in the top-ranked structures. Although pHDock is designed to improve docking, it also successfully predicts a large pH-dependent binding affinity change in the Fc-FcRn complex, suggesting that it can be exploited to improve affinity predictions. The approaches in the study contribute to the goal of structural simulations of whole-cell protein-protein interactions including all the environmental factors, and they can be further expanded for pH-sensitive protein design. PMID- 25501666 TI - Ebola virus as a sexually transmitted infection. AB - PURPOSE OF REVIEW: The ongoing Ebola virus epidemic in West Africa is a major global health challenge. The main mode of transmission is through contact with bodily fluids and skin of those infected or who have died. This review was undertaken to consider the evidence for transmission by contact with bodily fluids occurring through sexual activity. RECENT FINDINGS: No cases in the previous 20 outbreaks or the current outbreak in West Africa have been shown to be sexually transmitted, although other types of viral haemorrhagic fever have had sexual transmission implicated. Ebola virus is found in sites and fluids associated with sexual activity but this occurs at different stages of the disease. Persistence in the convalescent period occurs in rectum, vagina and semen, with persistence in semen being longest of up to at least 101 days. Recommendations based on this data are that those recovering from Ebola virus disease should abstain from all sexual intercourse, or if this is not possible, use condoms, for 3 months after the onset of symptoms. SUMMARY: There is theoretical plausibility for sexual transmission of Ebola virus but there has been no evidence of this occurring. Further research is needed to consider if sexual activity contributes to the epidemic in order to inform individuals with regard to avoiding acquisition or transmission by those recovering from Ebola virus disease. PMID- 25501667 TI - Children are three times as likely to try e-cigarettes as tobacco products, study finds. PMID- 25501668 TI - Triplet superconductivity in 3D Dirac semi-metal due to exchange interaction. AB - Conventional phonon-electron interaction induces either triplet or one of two (degenerate) singlet pairing states in time reversal and inversion invariant 3D Dirac semi-metal. Investigation of the order parameters and energies of these states at zero temperature in a wide range of values of chemical potential MU, the effective electron-electron coupling constant lambda and Debye energy TD demonstrates that when the exchange interaction is neglected the singlet always prevails, however, in significant portions of the (MU, lambda, TD) parameter space the energy difference is very small. This means that interactions that are small, but discriminate between the spin singlet and the spin triplet, are important in order to determine the nature of the superconducting order there. The best candidate for such an interaction in the materials under consideration is the exchange (the Stoner term) characterized by constant lambdaex. We show that at values of lambdaex, much smaller than ones creating Stoner instability to ferromagnetism lambdaex ~ 1, the triplet pairing becomes energetically favored over the singlet ones. The 3D quantum critical point at MU = 0 is considered in detail. This can be realized experimentally in optically trapped cold atom systems. PMID- 25501670 TI - In vitro micro-physiological models for translational immunology. AB - The immune system is a source of regulation of the human body and is key for its stable functioning. Animal models have been successfully used for many years to study human immunity and diseases and provided significant contributions to the development of powerful new therapies. However, such models inevitably display differences from the human metabolism and disease state and therefore may correlate poorly with the human conditions. This explains the interest for the use of in vitro models of human cells, which have better potential to assist in understanding the physiological events that characterize the immune response in humans. Microfluidic technologies offer great capabilities to create miniaturized in vivo-like physiological models that mimic tissue-tissue interactions and simulate the body metabolism in both the healthy and diseased states. The micro scale features of these microfluidic systems allow positioning heterogeneous cellular cultures in close proximity to each other in a dynamic fluidic environment, thereby allowing efficient cell-cell interactions and effectively narrowing the gap between in vivo and in vitro conditions. Due to the relative simplicity of these systems, compared to animal models, it becomes possible to investigate cell signaling by monitoring the metabolites transported from one tissue to another in real time. This allows studying detailed physiological events and in consequence understanding the influence of metabolites on a specific tissue/organ function as well as on the healthy/diseased state modulation. Numerous in vitro models of human organs have been developed during the last few years, aiming to mimic as closely as possible the in vivo characteristics of such organs. This technology is still in its infancy, but is promised a bright future in industrial and medical applications. Here we review the recent literature, in which functional microphysiological models have been developed to mimic tissues and to explore multi-tissue interactions, focusing in particular on the study of immune reactions, inflammation and the development of diseases. Also, an outlook on the opportunities and issues for further translational development of functional in vitro models in immunology will be presented. PMID- 25501669 TI - Development of self-control in children aged 3 to 9 years: perspective from a dual-systems model. AB - The current study tested a set of interrelated theoretical propositions based on a dual-systems model of self-control. Data were collected from 2135 children aged 3 to 9 years. The results suggest that (a) there was positive growth in good self control, whereas poor control remained relatively stable; and (b) girls performed better than boys on tests of good self-control. The results are discussed in terms of their implications for a dual-systems model of self-control theory and future empirical work. PMID- 25501671 TI - Effect of brivaracetam on CYP3A activity, measured by oral midazolam. AB - Brivaracetam is a synaptic vesicle protein 2A ligand in phase III development for epilepsy. A phase I, open-label, randomized study was conducted in 42 healthy male participants to assess the effect of brivaracetam on CYP3A activity using midazolam as a probe. Participants were randomized to oral brivaracetam 5, 50, or 150 mg/day from Day 8 to Day 14. A single oral dose (7.5 mg) of midazolam was administered on Days 1, 13, and 20, and full pharmacokinetic profiles were obtained. For all brivaracetam doses, the areas under the plasma concentration time curves from 0 to infinity (AUCinf ) for midazolam and 1'-hydroxymidazolam were similar on Days 13 and 20 compared with Day 1. Following brivaracetam 150 mg/day, the Day 13/Day 1 AUCinf ratio (90% confidence interval) was 1.09 (0.97, 1.21) and 1.04 (0.93, 1.17) for midazolam and 1'-hydroxymidazolam, respectively. For the Day 20/Day 1 comparison, the corresponding AUCinf ratios were 1.10 (0.98, 1.23) and 1.07 (0.97, 1.18). Maximum midazolam plasma concentration was increased on both Day 13 and Day 20 vs. Day 1 but the relevance of this finding was unclear. This study indicates that brivaracetam up to 150 mg/day has no significant inducing or inhibiting effect on CYP3A activity. PMID- 25501672 TI - Children with chronic cough: when is watchful waiting appropriate? development of likelihood ratios for assessing children with chronic cough. AB - BACKGROUND: Chronic cough is associated with poor quality of life and may signify a serious underlying disease. Differentiating nonspecific cough (when watchful waiting can be safely undertaken) from specific cough (treatment and further investigations are beneficial) would be clinically useful. In 326 children, we aimed to (1) determine how well cough pointers (used in guidelines) differentiate specific from nonspecific cough and (2) describe the clinical profile of children whose cough resolved without medications (spontaneous resolution). METHODS: A dataset from a multicenter study involving children newly referred for chronic cough (median duration, 3-4 months) was used to determine the sensitivity, specificity, predictive values, and likelihood ratios (LRs) of cough pointers (symptoms, signs, and simple investigations [chest radiography, spirometry]) recommended in guidelines. RESULTS: The pretest probability of specific cough was 88%. The absence of false-positive results meant that most pointers had strongly positive LRs. The most sensitive pointer (wet cough) had a positive LR of 26.2 (95% CI, 3.8-181.5). Although the absence of other individual pointers did not change the pretest probability much (negative LR close to 1), the absence of all pointers had a strongly negative LR of 0 (95% CI, 0-0.03). Children in the resolved spontaneously group were significantly more likely to be older, to be non-Indigenous, and to have a dry cough and a normal chest radiograph. CONCLUSIONS: Children with chronic dry cough without any cough pointers can be safely managed using the watchful waiting approach. The high pretest probability and high positive LRs of cough pointers support the use of individual cough pointers to identify high risk of specific cough in pediatric chronic cough guidelines. TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry; No.: 12607000526471; URL: www.anzctr.org.au. PMID- 25501673 TI - Role of adrenocorticotropic hormone in the modulation of pollinosis induced by pollen antigens. AB - BACKGROUND: A mild restraint stressor suppressed an increase in the levels of Th2 dependent cytokines and IgE, thereby reducing the symptoms of pollinosis. In the present study, to clarify the mechanism of action of adrenocorticotropic hormone (ACTH) in improving the symptoms of pollinosis, we studied the effects of ACTH on the plasma level of histamine, mast cell number in nasal-associated lymphoid tissue (NALT) and the T cell differentiation in splenocytes. METHODS: The role of ACTH in the development of pollen antigen-induced pollinosis was studied in mice. Allergic symptoms and parameters were measured on day 17 after sensitization. To investigate the effects of ACTH on T cell differentiation, we stimulated splenocytes obtained from control mice with ACTH and CD3/CD28 in vitro, and measured the cytokine production in the culture supernatant. RESULTS: The plasma levels of IL-10, IgE and histamine and mast cell number in NALT were increased in the sensitized animals in association with a concomitant increase in the incidence of sneezing and nasal rubbing. The intraperitoneal administration of ACTH decreased the IL-10, IgE and histamine levels in the plasma and mast cell number in NALT, while increasing the IFN-gamma level and suppressing the incidence of nasal rubbing. Furthermore, the production of IFN-gamma increased, while the IL-4 level was suppressed after 2 days in culture. CONCLUSIONS: The present findings showed that ACTH directly affects T cell differentiation and promotes Th1-type reactions. The regulation of the Th1/Th2 balance by ACTH may result in a decrease in the pathological features of pollinosis. PMID- 25501674 TI - Outcome of bipolar electrocoagulation with lesionectomy in the treatment of epilepsy involving eloquent areas. AB - BACKGROUND/AIMS: We have demonstrated previously that bipolar electrocoagulation on functional cortex (BCFC) is a safe and effective approach for epilepsy involving eloquent areas. Here, we report the results of BCFC with lesionectomy for patients with epileptogenic foci partially overlapping eloquent areas. METHODS: Forty patients who had been treated with lesionectomy with BCFC were retrospectively reviewed with regard to seizure outcome and neurological deficits. Ten similar patients who had received lesionectomy with multiple subpial transections (MST) were examined as a control group. RESULTS: In the lesionectomy group with BCFC, Engel class I was achieved in 18 (45%) patients, class II in 8 (20%) patients, class III in 8 (20%) patients and class IV in 6 (15%) patients. Five (12.5%) patients developed mild hemiparesis and 1 (2.5%) patient mild sensory dysphasia. In the lesionectomy group with MST, Engel class I was achieved in 3 (30%) patients, class II in 2 (20%) patients, class III in 3 (30%) patients and class IV in 2 (20%) patients. Two (20%) patients developed mild hemiparesis and 1 (10%) patient moderate hemiparesis. All these complications recovered within 1-12 months. CONCLUSIONS: Compared with MST, the outcome of BCFC with lesionectomy is similar. But since MST leads to mechanical injury, while BCFC causes thermal injury, the complications of BCFC seem less severe. PMID- 25501675 TI - Direct site-specific glycoform identification and quantitative comparison of glycoprotein therapeutics: imiglucerase and velaglucerase alfa. AB - Gaucher disease, the most common lysosomal metabolic disorder, can be treated with enzyme replacement therapy (ERT). Recombinant human glucocerebrosidase imiglucerase (Cerezyme((r))), produced in Chinese hamster ovary cells, has been used for ERT of Gaucher disease for 20 years. Another recombinant glucocerebrosidase velaglucerase alfa (VPRIV), expressed in a human fibroblast cell line, was approved by the US Food and Drug Administration in 2010. The amino acid sequence difference at residue 495 of these two products is well documented. The overall N-linked qualitative glycan composition of these two products has also been reported previously. Herein, employing our recently developed approach utilizing isobaric tandem mass tag (TMT) labeling and an LTQ Orbitrap XL electron transfer dissociation (ETD) hybrid mass spectrometer, the site-specific glycoforms of these products were identified with ETD and collision-induced dissociation (CID) spectra. The quantitative comparison of site-specific glycans was achieved utilizing higher-energy collisional dissociation (HCD) spectra with a NanoMate used as both a fraction collector and a sample introduction device. From the trypsin-digested mixture of these two products, over 90 glycopeptides were identified by accurate mass matching. In addition to those previously reported, additional glycopeptides were detected with moderate abundance. The relative amount of each glycoform at a specific glycosylation site was determined based on reporter signal intensities of the TMT labeling reagents. This is the first report of site-specific simultaneous qualitative and quantitative comparison of glycoforms for Cerezyme((r)) and VPRIV. The results demonstrate that this method could be utilized for biosimilarity determination and counterfeit identification of glycoproteins. PMID- 25501676 TI - Shoe drop has opposite influence on running pattern when running overground or on a treadmill. AB - PURPOSE: Minimalist running shoes are designed to induce a foot strike made more with the forepart of the foot. The main changes made on minimalist shoe consist in decreasing the height difference between fore and rear parts of the sole (drop). Barefoot and shod running have been widely compared on overground or treadmill these last years, but the key characteristic effects of minimalist shoes have been yet little studied. The purpose of this study is to find whether the shoe drop has the same effect regardless of the task: overground or treadmill running. METHODS: Twelve healthy male subjects ran with three shoes of different drops (0, 4, 8 mm) and barefoot on a treadmill and overground. Vertical ground reaction force (vGRF) (transient peak and loading rate) and lower limb kinematics (foot, ankle and knee joint flexion angles) were observed. RESULTS: Opposite footwear effects on loading rate between the tasks were observed. Barefoot running induced higher loading rates during overground running than the highest drop condition, while it was the opposite during treadmill running. Ankle plantar flexion and knee flexion angles at touchdown were higher during treadmill than overground running for all conditions, except for barefoot which did not show any difference between the tasks. CONCLUSIONS: Shoe drop appears to be a key parameter influencing running pattern, but its effects on vGRF differ depending on the task (treadmill vs. overground running) and must be considered with caution. Unlike shod conditions, kinematics of barefoot condition was not altered by treadmill running explaining opposite conclusions between the tasks. PMID- 25501678 TI - Pericardiocentesis adverse event risk factors: a nationwide population-based cohort study. AB - OBJECTIVES: Echocardiography-guided pericardiocentesis has been the leading procedure for diagnosis and therapy of pericardial effusion. We aimed to identify risk factors for recurrence, complications, and mortality in pericardial effusion patients treated with pericardiocentesis. METHODS: We identified and collected data from 8,101 patients receiving pericardiocentesis between 1997 and 2010 from the Taiwan National Health Insurance Research Database. A multivariate regression model was used to investigate risk factors for recurrence, complications, and death. RESULTS: There were 8,565 admissions among 8,101 patients. The most common underlying condition was malignancy (41%), especially lung cancer (23%), tuberculosis (9.0%), and acute pericarditis (8.2%). Surgical drainage was required in 12.7% of cases. Recurrence was more likely in patients with malignancy (HR 2.20, p < 0.001), but complications were less likely (OR 0.52, p = 0.003). In-hospital death numbers and complication risks (OR 2.38, p < 0.001; OR 1.27, p = 0.01) were greater in the catheter-related cardiac procedure group than in the other groups. CONCLUSIONS: Malignant neoplasms and catheter-based cardiac procedures have become major risk factors for adverse events in patients receiving pericardiocentesis in Taiwan. Malignancy leads to an increase in recurrence and in-hospital mortality but is associated with a lower rate of acute complications. Cardiac catheterization procedures and surgery increase both complications and in-hospital mortality. PMID- 25501677 TI - Exercise intensity and postprandial health outcomes in adolescents. AB - PURPOSE: The effect of exercise intensity and sex on postprandial risk factors for cardiovascular disease in adolescents is unknown. We examined the effect of a single bout of work-matched high-intensity interval exercise (HIIE) and moderate intensity exercise (MIE) on postprandial triacylglycerol (TAG) and systolic blood pressure (SBP) in adolescents. METHOD: Twenty adolescents (10 male, 14.3 +/- 0.3 years) completed three 1-day trials: (1) rest (CON); (2) 8 * 1 min cycling at 90 % peak power with 75 s recovery (HIIE); (3) cycling at 90 % of the gas exchange threshold (MIE), 1 h before consuming a high-fat milkshake (1.50 g fat and 80 kJ kg(-1)). Postprandial TAG, SBP and fat oxidation were assessed over 4 h RESULTS: Compared to CON, the incremental area under the curve for TAG (IAUC-TAG) was not significantly lowered in HIIE [P = 0.22, effect size (ES) = 0.24] or MIE (P = 0.65, ES = 0.04) for boys. For girls, HIIE and MIE lowered IAUC-TAG by 34 % (P = 0.02, ES = 0.58) and 38 % (P = 0.09, ES = 0.73), respectively, with no difference between HIIE and MIE (P = 0.74, ES = 0.14). Changes in TAG were not related to energy expenditure during exercise or postprandial fat oxidation. Postprandial SBP (total-AUC pooled for both sexes) was lower in HIIE compared to CON (P = 0.01, ES = 0.68) and MIE (P = 0.02, ES = 0.60), with no difference between MIE and CON (P = 0.45, ES = 0.14). CONCLUSION: A single bout of HIIE and MIE, performed 1 h before an HFM, can meaningfully attenuate IAUC-TAG in girls but not boys. Additionally, HIIE, but not MIE, may lower postprandial SBP in normotensive adolescents. PMID- 25501680 TI - Eaten out of house and home: impacts of grazing on ground-dwelling reptiles in Australian grasslands and grassy woodlands. AB - Large mammalian grazers can alter the biotic and abiotic features of their environment through their impacts on vegetation. Grazing at moderate intensity has been recommended for biodiversity conservation. Few studies, however, have empirically tested the benefits of moderate grazing intensity in systems dominated by native grazers. Here we investigated the relationship between (1) density of native eastern grey kangaroos, Macropus giganteus, and grass structure, and (2) grass structure and reptiles (i.e. abundance, richness, diversity and occurrence) across 18 grassland and grassy Eucalyptus woodland properties in south-eastern Australia. There was a strong negative relationship between kangaroo density and grass structure after controlling for tree canopy cover. We therefore used grass structure as a surrogate for grazing intensity. Changes in grazing intensity (i.e. grass structure) significantly affected reptile abundance, reptile species richness, reptile species diversity, and the occurrence of several ground-dwelling reptiles. Reptile abundance, species richness and diversity were highest where grazing intensity was low. Importantly, no species of reptile was more likely to occur at high grazing intensities. Legless lizards (Delma impar, D. inornata) were more likely to be detected in areas subject to moderate grazing intensity, whereas one species (Hemiergis talbingoensis) was less likely to be detected in areas subject to intense grazing and three species (Menetia greyii, Morethia boulengeri, and Lampropholis delicata) did not appear to be affected by grazing intensity. Our data indicate that to maximize reptile abundance, species richness, species diversity, and occurrence of several individual species of reptile, managers will need to subject different areas of the landscape to moderate and low grazing intensities and limit the occurrence and extent of high grazing. PMID- 25501679 TI - Association between HBV Pre-S mutations and the intracellular HBV DNAs in HBsAg positive hepatocellular carcinoma in China. AB - This study aimed to investigate the association between HBV mutations and intrahepatic HBV status and to determine the clinical features and the contribution of HBV mutations to postoperative prognosis for hepatocellular carcinoma (HCC) patients with HBsAg (+) in China. Using TaqMan fluorescent real time PCR, HBV covalently closed circular DNA (cccDNA) and total DNA (tDNA) were both quantified in 106 pairs of tumor tissues (TT) and adjacent non-tumor tissues (ANTT) obtained from HCC patients who received no antiviral treatment before surgical treatment. The prevalence of 19 hot spot mutations was evaluated by Sanger sequencing. HBV cccDNA and tDNA were lower in TT than in ANTT. The loads of cccDNA and tDNA in ANTT were associated with serum HBV DNA and HBeAg. Three Pre-S mutants (A2962G and C2964A in Pre-S1 and C105T in Pre-S2) were associated with higher tumor cccDNA levels (P < 0.05), and A2962G/C2964A mutants were associated with higher AFP levels. This would assist to disclose the virological features, to implement a more clinically personalized therapy and to improve the prognosis of HBV-related HCC patients. PMID- 25501682 TI - [Assessment of the transplantation scandal by the media : scientific discourse analysis of selected German newspapers]. AB - BACKGROUND: The press is an important medium and plays a significant role as an information source for people. Moreover, the daily press transmits opinion forming contents. During the German "transplantation scandal" various articles were published in the German press focusing on organ donation, transplantation, allocation of organs and brain death determination. Selected important newspaper articles were analyzed using a scientific text analysis as it was assumed that the publications might have had an important influence on attitudes or mistrust of transplantation medicine. MATERIAL AND METHODS: A total of 216 articles from Suddeutsche Zeitung, Die Welt, Frankfurter Allgemeine Zeitung and Die Zeit published between summer 2012 and early 2013, which focused on the transplantation scandal were analyzed using a modern form of scientific text analysis. From these articles 12 categories of contents were identified which were analyzed quantitatively and qualitatively. RESULTS: Most articles were published between June and August 2012 when the accusations of organ allocation manipulation were made public. A second wave was found in the early months of 2013, when the court proceedings against the predominantly blamed physician began. Most of the categories (63.8 %) transmitted a negative evaluative opinion (i.e. loss of confidence, enrichment of the persons involved, fraud, misconduct, rejection of brain death and disturbing the peace of the dead) leading to mistrust of transplantation per se, while the minority (36.2 %) were categorized as endeavoring to convey objective information, focus on ethical responsibility for organ donation or the problems of organ shortage. Furthermore, a striking increase of articles doubting the concept of brain death was observed. CONCLUSION: German newspapers as important opinion-leading and opinion-forming media have a substantial impact in accomplishing the demands for objective and factual information of transplantation medicine. Physicians, ethicists, journalists and politicians are invoked to have a closer collaboration in the future. PMID- 25501681 TI - Antigenic differences between AS03 adjuvanted influenza A (H1N1) pandemic vaccines: implications for pandemrix-associated narcolepsy risk. AB - BACKGROUND: Narcolepsy results from immune-mediated destruction of hypocretin secreting neurons in hypothalamus, however the triggers and disease mechanisms are poorly understood. Vaccine-attributable risk of narcolepsy reported so far with the AS03 adjuvanted H1N1 vaccination Pandemrix has been manifold compared to the AS03 adjuvanted Arepanrix, which contained differently produced H1N1 viral antigen preparation. Hence, antigenic differences and antibody response to these vaccines were investigated. METHODS AND FINDINGS: Increased circulating IgG antibody levels to Pandemrix H1N1 antigen were found in 47 children with Pandemrix-associated narcolepsy when compared to 57 healthy children vaccinated with Pandemrix. H1N1 antigen of Arepanrix inhibited poorly these antibodies indicating antigenic difference between Arepanrix and Pandemrix. High-resolution gel electrophoresis quantitation and mass spectrometry identification analyses revealed higher amounts of structurally altered viral nucleoprotein (NP) in Pandemrix. Increased antibody levels to hemagglutinin (HA) and NP, particularly to detergent treated NP, was seen in narcolepsy. Higher levels of antibodies to NP were found in children with DQB1*06:02 risk allele and in DQB1*06:02 transgenic mice immunized with Pandemrix when compared to controls. CONCLUSIONS: This work identified 1) higher amounts of structurally altered viral NP in Pandemrix than in Arepanrix, 2) detergent-induced antigenic changes of viral NP, that are recognized by antibodies from children with narcolepsy, and 3) increased antibody response to NP in association of DQB1*06:02 risk allele of narcolepsy. These findings provide a link between Pandemrix and narcolepsy. Although detailed mechanisms of Pandemrix in narcolepsy remain elusive, our results move the focus from adjuvant(s) onto the H1N1 viral proteins. PMID- 25501684 TI - Functional role of EMMPRIN in the formation and mineralisation of dental matrix in mouse molars. AB - Our previous research has shown that the extracellular matrix metalloproteinase inducer (EMMPRIN) is expressed during and may function in the early development of tooth germs. In the present study, we observed the specific expression of EMMPRIN in ameloblasts and odontoblasts during the middle and late stages of tooth germ development using immunohistochemistry. Furthermore, to extend our understanding of the function of EMMPRIN in odontogenesis, we used an anti EMMPRIN function-blocking antibody to remove EMMPRIN activity in tooth germ culture in vitro. Both the formation and mineralisation of dental hard tissues were suppressed in the tooth germ culture after the abrogation of EMMPRIN. Meanwhile, significant reductions in VEGF, MMP-9, ALPL, ameloblastin, amelogenin and enamelin expression were observed in antibody-treated tooth germ explants compared to control and normal serum-treated explants. The current results illustrate that EMMPRIN may play a critical role in the processing and maturation of the dental matrix. PMID- 25501685 TI - Understanding variation in disease risk: the elusive concept of frailty. AB - The concept of frailty plays a major role in the statistical field of survival analysis. Frailty variation refers to differences in risk between individuals which go beyond known or measured risk factors. In other words, frailty variation is unobserved heterogeneity. Although understanding frailty is of interest in its own right, the literature on survival analysis has demonstrated that existence of frailty variation can lead to surprising artefacts in statistical estimation that are important to examine. We present literature that demonstrates the presence and significance of frailty variation between individuals. We discuss the practical content of frailty variation, and show the link between frailty and biological concepts like (epi)genetics and heterogeneity in disease risk. There are numerous suggestions in the literature that a good deal of this variation may be due to randomness, in addition to genetic and/or environmental factors. Heterogeneity often manifests itself as clustering of cases in families more than would be expected by chance. We emphasize that apparently moderate familial relative risks can only be explained by strong underlying variation in disease risk between families and individuals. Finally, we highlight the potential impact of frailty variation in the interpretation of standard epidemiological measures such as hazard and incidence rates. PMID- 25501686 TI - Lifetime cumulative risk factors predict cardiovascular disease mortality in a 50 year follow-up study in Finland. AB - BACKGROUND: Systolic blood pressure, total cholesterol and smoking are known predictors of cardiovascular disease (CVD) mortality. Less is known about the effect of lifetime accumulation and changes of risk factors over time as predictors of CVD mortality, especially in very long follow-up studies. METHODS: Data from the Finnish cohorts of the Seven Countries Study were used. The baseline examination was in 1959 and seven re-examinations were carried out at approximately 5-year intervals. Cohorts were followed up for mortality until the end of 2011. Time-dependent Cox models with regular time-updated risk factors, time-dependent averages of risk factors and latest changes in risk factors, using smoothing splines to discover nonlinear effects, were used to analyse the predictive effect of risk factors for CVD mortality. RESULTS: A model using cumulative risk factors, modelled as the individual-level averages of several risk factor measurements over time, predicted CVD mortality better than a model using the most recent measurement information. This difference seemed to be most prominent for systolic blood pressure. U-shaped effects of the original predictors can be explained by partitioning a risk factor effect between the recent level and the change trajectory. The change in body mass index predicted the risk although body mass index itself did not. CONCLUSIONS: The lifetime accumulation of risk factors and the observed changes in risk factor levels over time are strong predictors of CVD mortality. It is important to investigate different ways of using the longitudinal risk factor measurements to take full advantage of them. PMID- 25501687 TI - Ethnic disparities in end-of-life care after subarachnoid hemorrhage. AB - BACKGROUND: It is common for patients who die from subarachnoid hemorrhage to have a focus on comfort measures at the end of life. The potential role of ethnicity in end-of-life decisions after brain injury has not been extensively studied. METHODS: Patients with subarachnoid hemorrhage were prospectively followed in an observational database. Demographic information including ethnicity was collected from medical records and self-reported by patients or their family. Significant in-hospital events including do-not-resuscitate orders, comfort measures only orders (CMO; care withheld or withdrawn), and mortality were recorded prospectively. RESULTS: 1255 patients were included in our analysis: 650 (52 %) were White, 387 (31 %) Hispanic, and 218 (17 %) Black. Mortality was similar between the groups. CMO was more commonly observed in Whites (14 %) compared to either Blacks (10 %) or Hispanics (9 %) (p = 0.04). In a multivariate analysis controlling for age and Hunt-Hess grade, Hispanics were less likely to have CMO than Whites (OR, 0.6; 95 %CI, 0.4-0.9; p = 0.02). Of the 229 patients who died, 77 % of Whites had CMO compared to 54 % of Blacks and 49 % of Hispanics (p < 0.01). In a multivariate analysis, Blacks (OR, 0.3; 95 %CI, 0.2 0.7; p < 0.01) and Hispanics (OR, 0.3; 95 %CI, 0.2-0.6; p < 0.01) were less likely to die with CMO orders than Whites. CONCLUSION: After subarachnoid hemorrhage, Blacks and Hispanics are less likely to die with CMO orders than Whites. Further research to confirm and investigate the causes of these ethnic differences should be performed. PMID- 25501688 TI - Changes in Cerebral Partial Oxygen Pressure and Cerebrovascular Reactivity During Intracranial Pressure Plateau Waves. AB - BACKGROUND: Plateau waves in intracranial pressure (ICP) are frequently recorded in neuro intensive care and are not yet fully understood. To further investigate this phenomenon, we analyzed partial pressure of cerebral oxygen (pbtO2) and a moving correlation coefficient between ICP and mean arterial blood pressure (ABP), called PRx, along with the cerebral oxygen reactivity index (ORx), which is a moving correlation coefficient between cerebral perfusion pressure (CPP) and pbtO2 in an observational study. METHODS: We analyzed 55 plateau waves in 20 patients after severe traumatic brain injury. We calculated ABP, ABP pulse amplitude (ampABP), ICP, CPP, pbtO2, heart rate (HR), ICP pulse amplitude (ampICP), PRx, and ORx, before, during, and after each plateau wave. The analysis of variance with Bonferroni post hoc test was used to compare the differences in the variables before, during, and after the plateau wave. We considered all plateau waves, even in the same patient, independent because they are separated by long intervals. RESULTS: We found increases for ICP and ampICP according to our operational definitions for plateau waves. PRx increased significantly (p = 0.00026), CPP (p < 0.00001) and pbtO2 (p = 0.00007) decreased significantly during the plateau waves. ABP, ampABP, and HR remained unchanged. PRx during the plateau was higher than before the onset of wave in 40 cases (73 %) with no differences in baseline parameters for those with negative and positive DeltaPRx (difference during and after). ORx showed an increase during and a decrease after the plateau waves, however, not statistically significant. PbtO2 overshoot after the wave occurred in 35 times (64 %), the mean difference was 4.9 +/- 4.6 Hg (mean +/- SD), and we found no difference in baseline parameters between those who overshoot and those who did not overshoot. CONCLUSIONS: Arterial blood pressure remains stable in ICP plateau waves, while cerebral autoregulatory indices show distinct changes, which indicate cerebrovascular reactivity impairment at the top of the wave. PbtO2 decreases during the waves and may show a slight overshoot after normalization. We assume that this might be due to different latencies of the cerebral blood flow and oxygen level control mechanisms. Other factors may include baseline conditions, such as pre-plateau wave cerebrovascular reactivity or pbtO2 levels, which differ between studies. PMID- 25501689 TI - The International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care: a list of recommendations and additional conclusions: a statement for healthcare professionals from the Neurocritical Care Society and the European Society of Intensive Care Medicine. AB - Careful patient monitoring using a variety of techniques including clinical and laboratory evaluation, bedside physiological monitoring with continuous or non continuous techniques and imaging is fundamental to the care of patients who require neurocritical care. How best to perform and use bedside monitoring is still being elucidated. To create a basic platform for care and a foundation for further research the Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to develop recommendations about physiologic bedside monitoring. This supplement contains a Consensus Summary Statement with recommendations and individual topic reviews as a background to the recommendations. In this article, we highlight the recommendations and provide additional conclusions as an aid to the reader and to facilitate bedside care. PMID- 25501691 TI - Sodium bicarbonate and renal function after cardiac surgery: a prospectively planned individual patient meta-analysis. AB - BACKGROUND: The effect of urinary alkalinization in cardiac surgery patients at risk of acute kidney injury (AKI) is controversial and trial findings conflicting. Accordingly, the authors performed a prospectively planned individual patient data meta-analysis of the double-blind randomized trials in this field. METHODS: The authors studied 877 patients from three double-blind, randomized controlled trials enrolled to receive either 24 h of intravenous infusion of sodium bicarbonate or sodium chloride. The primary outcome measure was a postoperative increase in serum creatinine concentration of greater than 25% or 0.5 mg/dl (> 44 MUM/L) within the first five postoperative days. Secondary outcomes included the raw change in serum creatinine, greater than 50% and greater than 100% rises in serum creatinine, developing AKI (Acute Kidney Injury Network criteria), initiation of renal replacement therapy, morbidity, and mortality. RESULTS: Patients were similar in demographics, comorbidities, and cardiac procedures. Sodium bicarbonate increased plasma bicarbonate (P < 0.001) and urine pH (P < 0.001). There were no differences in the development of the primary outcome (Bicarbonate 45% [39-51%] vs. Saline 42% [36-48%], P = 0.29). This result remained unchanged when controlling for study and covariates (odds ratio [OR], 99% confidence interval [CI]: Bicarbonate vs. Control, 1.11 [0.77 1.60], P = 0.45). There was, however, a significant study-adjusted benefit in elective coronary artery bypass surgery patients in terms of renal replacement therapy (Bicarbonate vs. Control, OR: 0.38 [99% CI: 0.25-0.58], P < 0.0001) and the development of an Acute Kidney Injury Network grade = 3 (Bicarbonate vs. Control, OR: 0.45 [99% CI: 0.43-0.48], P < 0.0001). CONCLUSIONS: Urinary alkalinization using sodium bicarbonate infusion is not associated with an overall lower incidence of AKI; however, it reduces severe AKI and need for renal replacement therapy in elective coronary artery bypass patients. PMID- 25501692 TI - Ventricular asystole during pulmonary artery catheter insertion. PMID- 25501693 TI - Sacral and pelvic osteotomies for correction of spinal deformities. AB - INTRODUCTION: Restoring a physiological sagittal spine balance is one of the main goals in spine surgery. Several technics have been described previously, as pedicle subtraction osteotomy. In more complicated cases involving spino-pelvic disorders, three authors proposed sacral osteotomy to restore sagittal balance of the spine. The authors describe the use of pelvic osteotomies for the correction of lumbo-sacral kyphosis, for decreasing pelvic incidence and for achieving sagittal balance correction in cases of lumbo-sacral sagittal deformity as an alternative of pedicle subtraction osteotomies (PSO). MATERIALS AND METHODS: We simulate four types of pelvic osteotomies previously described for hip pathology (Salter, modified Salter, Chiari and posterior sacral osteotomy) on drawing software, and calculate during these osteotomies the variation of pelvic incidence (PI). Then, we compare the behaviour in this simulation to a cadaveric model where we perform the same four pelvic osteotomies. Via X-rays made the study, we calculate also the PI. Then, we analyse 11 patients who underwent pelvic osteotomies for sagittal unbalance, analysing operative and clinical data. RESULTS: We find a mathematical law governing the PI during anterior opening and posterior closing osteotomies (respectively Salter and sacral osteotomy):[Formula: see text]These laws are confirmed in the cadaveric model which retrieves the same behaviour. In the clinical series, Salter osteotomy is easy and efficient on sagittal rebalancing; sacral osteotomy is more powerful. DISCUSSION: The Salter osteotomy is efficient for restoring sagittal balance of the spine. The posterior sacral osteotomy is more powerful but technically demanding. The indications of such special osteotomies are fixed lumbo-sacral kyphosis, especially high-grade spondylolisthesis, previously operated or not. CONCLUSION: A study of a more substantial series would be considered. PMID- 25501690 TI - Anesthesia with Disuse Leads to Autophagy Up-regulation in the Skeletal Muscle. AB - BACKGROUND: It has been known that skeletal muscles show atrophic changes after prolonged sedation or general anesthesia. Whether these effects are due to anesthesia itself or disuse during anesthesia has not been fully clarified. Autophagy dysregulation has been implicated in muscle-wasting conditions. This study tested the hypothesis that the magnitude of skeletal muscle autophagy is affected by both anesthesia and immobility. METHODS: The extent of autophagy was analyzed chronologically during general anesthesia. In vivo microscopy was performed using green fluorescent protein-tagged LC3 for the detection of autophagy using sternomastoid muscles of live mice during pentobarbital anesthesia (n = 6 and 7). Western blotting and histological analyses were also conducted on tibialis anterior muscles (n = 3 to 5). To distinguish the effect of anesthesia from that due to disuse, autophagy was compared between animals anesthetized with pentobarbital and those immobilized by short-term denervation without continuation of anesthesia. Conversely, tibialis anterior and sternomastoid muscles were electrically stimulated during anesthesia. RESULTS: Western blots and microscopy showed time-dependent autophagy up-regulation during pentobarbital anesthesia, peaking at 3 h (728.6 +/- 93.5% of basal level, mean +/ SE). Disuse by denervation without sustaining anesthesia did not lead to equivalent autophagy, suggesting that anesthesia is essential to cause autophagy. In contrast, contractile stimulation of the tibialis anterior and sternomastoid muscles significantly reduced the autophagy up-regulation during anesthesia (85% at 300 min). Ketamine, ketamine plus xylazine, isoflurane, and propofol also up regulated autophagy. CONCLUSIONS: Short-term disuse without anesthesia does not lead to autophagy, but anesthesia with disuse leads to marked up-regulation of autophagy. PMID- 25501694 TI - Answer to the Letter to the Editor of A. Goel concerning "biomechanical evaluation of the Facet Wedge: a refined technique for facet fixation" by R. Hartensuer et al.; Eur Spine J (2014) 23:2321-2329. PMID- 25501695 TI - Physiologic considerations of Enhanced Recovery After Surgery (ERAS) programs: implications of the stress response. AB - PURPOSE: Enhanced Recovery After Surgery (ERAS) programs have increasingly attracted the attention of clinicians who are intent on minimizing postoperative morbidity, decreasing variability in surgical care, and containing hospital costs. The purpose of this review is to discuss the relevant pathophysiology of the surgical stress response and its associated mechanisms that regulate important metabolic changes. PRINCIPAL FINDINGS: The combination of hormonal release and various inflammatory responses inherent in the stress response to surgery contributes to a state of insulin resistance that represents one of the main pathogenic factors modulating perioperative outcome. The consequence of a decrease in insulin sensitivity is a significant change in protein and glucose metabolism characterized by an increase in the production of endogenous hepatic glucose, a decrease in the uptake of peripheral glucose, and an increase in the breakdown of protein. Muscle is the main tissue for uptake of insulin-mediated glucose, and consequent with the reduced activation of a specific glucose transporter protein (GLUT 4), glucose cannot be transported into the muscle cells. Consequently, breakdown of muscle protein, also related to insulin resistance, occurs to supply amino acids for gluconeogenesis, thus leading to the overall loss of lean muscle tissue. Besides the metabolic changes associated with the surgical insult, pain, relative perioperative starvation, and poor mobilization further contribute to a loss of insulin sensitivity and an increased catabolic state. Many of the ERAS elements that are implemented, including perioperative feeding, epidural analgesia, and minimally invasive surgery, modulate the stress response, promote insulin sensitivity, and attenuate the breakdown of protein. CONCLUSIONS: The implementation of a targeted ERAS program has been shown to modulate perioperative insulin sensitivity, thus improving postoperative outcomes and accelerating the return of baseline function. PMID- 25501696 TI - Optimizing pain management to facilitate Enhanced Recovery After Surgery pathways. AB - PURPOSE: The optimal management of postoperative pain using multimodal analgesia is a key component of Enhanced Recovery After Surgery (ERAS). Pain has adverse clinical implications on postoperative recovery, including prolonging the time to recovery milestones and length of hospital stay. Moreover, the ubiquity of opioids in postoperative analgesic regimens results in adverse effects, such as sedation, postoperative nausea and vomiting, urinary retention, ileus, and respiratory depression, which can delay discharge. Thus, multimodal analgesia, i.e., the use of more than one analgesic modality to achieve effective pain control while reducing opioid-related side effects, has become the cornerstone of enhanced recovery. The purpose of this review is to address the analgesic techniques used as part of multimodal analgesic regimens to optimize postoperative pain control and to summarize the evidence for their use in reducing opioid requirements and side effects. PRINCIPAL FINDINGS: There is a wide variety of analgesic techniques available for multimodal postoperative analgesia. These modalities are divided into pharmacological and non pharmacological techniques. Systemic pharmacological modalities involve opioids and non-opioids such as acetaminophen, non-steroidal anti-inflammatory drugs, N methyl-D-aspartate receptor antagonists, anticonvulsants (e.g., gamma aminobutyric acid analogues), beta-blockers, alpha-2 agonists, transient receptor potential vanilloid receptor agonists (capsaicin), and glucocorticoids. Other pharmacological modalities include central neuraxial techniques, surgical-site infiltration, and regional anesthesia. Evidence supports the use of these pharmacological techniques as part of multimodal analgesia, but each has its own advantages and specific safety profile, which highlights the importance of selecting the appropriate analgesics for each patient. Adjunctive non pharmacological techniques include acupuncture, music therapy, transcutaneous electrical nerve stimulation, and hypnosis. There is mixed evidence regarding such techniques, although a lack of harm is associated with their use. CONCLUSION: There are continuing advancements in multimodal analgesic techniques; however, postoperative pain in general continues to be undermanaged. Furthermore, a continuing challenge in multimodal pain research related to ERAS is the difficulty in carrying out randomized trials to determine the relative importance of any one component, including analgesia. PMID- 25501697 TI - Risk of congenital malformations among children of construction painters in Denmark: a nationwide cohort study. AB - OBJECTIVES: Painters' occupational exposure is classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC). Previous studies have shown increased risk of congenital malformations among children of women exposed to organic solvents and paint emissions during pregnancy. In Denmark, women comprise half of those enrolled in vocational paint training. We investigated the association between maternal and paternal occupational painting, respectively, and the risk of congenital malformations among children. METHODS: National register data were used to link childbirths, malformations, and parental occupation. The cohort included >1,300,000 children born to occupationally active women in Denmark 1980-2010. Cases were hospital-diagnosed with malformations within the first year of life. Odds ratios (OR) with 95% confidence intervals (95% CI) were estimated using multiple logistic regression with adjustment for potential confounders. RESULTS: Among 3444 children of female construction painters, we found no increased risk of malformations overall (126 cases, OR 0.88, 95% CI 0.74-1.05) or in organ-specific subgroups compared to children of women in all other occupations (55 045 cases). Sensitivity analyses restricted to severe malformations, children of maternal painters with >=2 years of pre pregnancy exposure, and firstborn children, and analyses with maternal healthcare assistants and kitchen workers as reference supported the main results. Also, no associations were found when including diagnoses within the first 10 years of life, when stratifying by maternal age, birth year, and sex, or for paternal construction painters. CONCLUSIONS: This nationwide cohort study is reassuring with no indications of increased risk of congenital malformations among children of male or of female construction painters. PMID- 25501698 TI - Higher plasma platelet-activating factor levels are associated with increased risk of vertebral fracture and lower bone mineral density in postmenopausal women. AB - Despite experimental and animal evidence showing the detrimental effects of platelet-activating factor (PAF) on bone metabolism, there are no clinical studies relating PAF to osteoporosis-related phenotypes. This case-control study investigates the association between plasma PAF, osteoporotic vertebral fracture (VF), and bone mineral density (BMD) in postmenopausal Korean women. Among 474 eligible women not taking any drug or having any disease that could affect bone metabolism, we identified 73 cases defined as subjects with radiological VF. The controls were randomly selected from the remaining 401 subjects and matched 1:1 to cases in terms of both age and body mass index (BMI). Lateral thoracolumbar radiographs, BMD, and plasma PAF levels were determined for all subjects. Postmenopausal women with VF demonstrated 34.6 % higher plasma PAF levels than subjects without VF after adjusting for age, BMI, smoking habits, alcohol intake, regular exercise, and parental history of osteoporotic fractures (P = 0.021). Multiple logistic regression analyses revealed that the odds ratio for VF linearly increased across increasing PAF quartiles (P for trend = 0.040) and the odds for VF were 2.88-fold higher in subjects in the highest quartile in comparison with those in the lowest quartile (95 % CI 1.04-8.01). Plasma PAF levels were inversely correlated with BMD at various sites (gamma = -0.253 to 0.176, P = 0.003-0.041). These findings suggest that plasma PAF may be a potential biomarker for predicting poor bone health in postmenopausal women. PMID- 25501700 TI - Local curative effect of MRI-guided radiofrequency ablation on small hepatocellular carcinoma. AB - Radiofrequency ablation (RFA) is one of the treatment modes for liver cancer. The trauma caused by RFA is small, and its local curative effect is reliable. Computed tomography (CT) can only be used for axial scans, and parts of the lesion are unclear on plain scans. The aim of this study is to compare the local curative effect of RFA percutaneously guided by MRI and ultrasound for small hepatocellular carcinoma (HCC). This study is a retrospective study. In this study, we examined 60 cases of 88 liver lesions and 50 cases of 52 lesions, in which RFA was guided by MRI and ultrasound, respectively. All cases were clinically diagnosed. The therapeutic effect of ablation lesions was examined by postoperative imaging follow-up. The results indicated that there were 5 (5/88) recurrences of liver lesions with MRI-guided RFA and 14 (14/52) recurrences of liver lesions with ultrasound-guided RFA. The median time to recurrence in the case of recurrent lesions was 7 months. Postoperative ablation lesions showed a low-intensity signal surrounded by a thin high-intensity signal ring on T2WI images. On T1WI images, the ablation lesion showed a concentric pattern and the central area of the original lesion continued to show a low-intensity signal with a clear ring of high-intensity signal that had a clear boundary. In conclusion, the local curative effect of MRI-guided RFA for small HCC is superior to that of ultrasound-guided RFA. PMID- 25501699 TI - Mortality after hip fracture with vertebral compression fracture is poor. AB - Due to the increasing elderly population, the prevalence of osteoporotic hip fractures in Japanese patients continues to rise. It is well established that patients with either hip fracture or both symptomatic and asymptomatic morphometric vertebral compression fracture (VCF) have a poor health prognosis compared with the general population. The purpose of this study was to retrospectively investigate vertebral fracture rates among patients with hip fracture and their influence on mortality. We examined 182 cases of osteoporotic hip fracture in patients admitted to our institution between January 2009 and May 2011. The average age at the time of fracture was 85 years. Radiographs of the lumbar spine were obtained from all of the participants and the lateral spinal radiographs were examined for evidence of VCF. The patients were classified into two groups, those with VCF and those without. A VCF was identified in approximately 78 % of the patients. The mortality rate 1 year after the hip fracture was approximately 22 % and it was significantly higher in patients with VCF. Through multivariate statistics we found that VCF, post-operative complication, loss of ambulation after operation and medication for osteoporosis were statistically significant. In other words, VCF, post-operative complication and loss of ambulation were considered to be poor prognostic factors and medication for osteoporosis was likely to improve the prognosis. We concluded that the risk of mortality after hip fracture is significantly greater in patients who also have VCF compared to patients without VCF, and that medication for osteoporosis is likely to improve prognosis. PMID- 25501701 TI - Cyr61 promotes growth of glioblastoma in vitro and in vivo. AB - The molecular regulation of the growth of glioblastoma (GBM) is not completely understood. Here, we show that the Cyr61 levels were significantly higher in GBM than in the adjacent non-tumor tissues. Overexpression of Cyr61 enhanced the viability of GBM cells, while inhibition of Cyr61 decreased the viability of GBM cells, in vitro and in vivo. Further analyses revealed that Cyr61 seemed to activate PI3K/Akt/mTor signaling pathway to increase cell growth in GBM cells. Taken together, our findings suggest a potential role of Cyr61 in GBM growth and highlight Cyr61 as a novel target for GBM therapy. PMID- 25501702 TI - Emerging role of PR domain containing 5 (PRDM5) as a broad tumor suppressor in human cancers. PMID- 25501703 TI - Serum miR-152, miR-148a, miR-148b, and miR-21 as novel biomarkers in non-small cell lung cancer screening. AB - Lung cancer, predominantly by non-small cell lung cancer (NSCLC), is the leading cause of cancer-related deaths over the world. Late diagnosis is one of important reasons for high mortality rate in lung cancer. Current diagnostic approaches have disadvantages such as low accuracy, high cost, invasive procedure, etc. MicroRNAs were previously proposed as promising novel biomarkers in cancer screening. In this study, we evaluated the predictive power of four candidate miRNAs in NSCLC detection. Our study involved 152 NSCLC patients and 300 healthy controls. Blood samples were obtained from the total 452 subjects. After miRNA extraction from serum, the expression of miRNAs in cases and controls were quantified by qRT-PCR and normalized to the level of U6 small RNA. Statistical analyses were performed to compare miRNA levels between cases and controls. Stratified analyses were employed to compare miRNA levels in NSCLC patients with different clinical characteristics. Serum miR-148a, miR-148b, and miR-152 were significantly downregulated in NSCLC patients. However, overexpression of serum miR-21 was observed in NSCLC patients. The combination of four candidate miRNAs exhibited the highest predictive accuracy in NSCLC screening compared with individual miRNAs (AUC = 0.97). Low level of miRNA-148/152 members may associate with advanced stage, large tumor size, malignant cell differentiation, and metastasis. High expression of miR-21 was possibly correlated with large size tumor and advanced cancer stage. Our results showed the dysregulation of miR 148/152 family and miR-21 in NSCLC patients. Hence, the four candidate miRNAs have great potential to serve as promising novel biomarkers in NSCLC screening. Further large-scale studies are needed to validate our results. PMID- 25501704 TI - Downregulation of Kruppel-like factor 2 is associated with poor prognosis for nonsmall-cell lung cancer. AB - Kruppel-like factor 2 (KLF2) expression is diminished in many malignancies. However, its expression and role in nonsmall-cell lung cancer (NSCLC) remain unknown. In this study, we found that KLF2 levels were decreased in NSCLC tissues compared with adjacent normal tissues. Its expression level was significantly correlated with TNM stages, tumor size, and lymph node metastasis. Moreover, patients with low levels of KLF2 expression had a relatively poor prognosis. Furthermore, knockdown of KLF2 expression by siRNA could promote cell proliferation, while ectopic expression of KLF2 inhibited cell proliferation and promoted apoptosis in NSCLC cells partly via regulating CDKN1A/p21 and CDKN2B/p15 protein expression. Our findings present that decreased KLF2 could be identified as a poor prognostic biomarker in NSCLC and regulate cell proliferation and apoptosis. PMID- 25501705 TI - Gli-1 is crucial for hypoxia-induced epithelial-mesenchymal transition and invasion of breast cancer. AB - Hypoxia can induce HIF-1alpha expression and promote the epithelial-mesenchymal transition (EMT) and invasion of cancer cells. However, their mechanisms remain unclear. The objective of this study was to evaluate the role of Gli-1, an effector of the Hedgehog pathway, in the hypoxia-induced EMT and invasion of breast cancer cells. Human breast cancer MDA-MB-231 cells were transfected with HIF-1alpha or Gli-1-specific small interfering RNA (siRNA) and cultured under a normoxic or hypoxic condition. The relative levels of HIF-1alpha, Gli-1, E cadherin, and vimentin in the cells were characterized by quantitative RT-PCR and Western blot assays, and the invasion of MDA-MB-231 cells was determined. Data was analyzed by Student T test, one-way ANOVA, and post hoc LSD test or Mann Whitney U when applicable. We observed that hypoxia significantly upregulated the relative levels of vimentin expression, but downregulated E-cadherin expression and promoted the invasion of MDA-MB-231 cells, associated with upregulated HIF 1alpha translation and Gil-1 expression. Knockdown of HIF-1alpha mitigated hypoxia-modulated Gil-1, vimentin and E-cadherin expression, and invasion of MDA MB-231 cells. Knockdown of Gil-1 did not significantly change hypoxia-upregulated HIF-1alpha translation but completely eliminated hypoxia-modulated vimentin and E cadherin expression and invasion of MDA-MB-231 cells. These data indicate that Gil-1 is crucial for hypoxia-induced EMT and invasion of breast cancer cells and may be a therapeutic target for intervention of breast cancer metastasis. PMID- 25501706 TI - Investigation of serum lncRNA-uc003wbd and lncRNA-AF085935 expression profile in patients with hepatocellular carcinoma and HBV. AB - Hepatocellular carcinoma (HCC) was among the most common solid tumors which rated third in cancer-related mortality worldwide. Hepatitis B viral (HBV) infection represents an important risk factor for HCC. Long non-coding RNAs (lncRNAs) were a class of newfound non-coding RNAs widely depicted in the genome currently. Nevertheless, the potential roles of them in human cancers were not well comprehended. Through this study, we aimed at exploring the expression profile and the potential clinical value of two lncRNAs (lncRNA-uc003wbd and lncRNA AF085935) in differentiating HCC from both HBV patients and the healthy specimens. Serum samples were extracted from 104 HBV patients, 137 HCC patients, and 138 healthy controls. The lncRNA levels of all the subjects were assayed by quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). We differentiated the three groups by the receiver operating characteristic (ROC) curve of each group. Statistical analyses were conducted by GraphPad software. Two-tailed P value less than 0.05 was considered to be statistically significant. The level of serum lncRNA-uc003wbd and lncRNA-AF085935 was significantly upregulated in HCC patients and HBV patients compared with that in normal controls. LncRNA-AF085935 showed a relatively higher accuracy for HCC screening (area under the curve (AUC) = 0.96, 95 % confidence interval (CI) = 0.93-0.99) than lncRNA-uc003wbd (AUC = 0.86, 95 % CI = 0.82-0.91) from healthy controls, as well as for HCC screening (AUC = 0.86, 95 % CI = 0.80-0.91) which is more accurate than lncRNA-uc003wbd (AUC = 0.70, 95 % CI = 0.63-0.76) from HBV patients. When differentiating HBV patients from the normal group, the descriptive value of lncRNA-AF085935 (AUC = 0.77, 95 % CI = 0.71-0.83) was almost as equal to lncRNA-uc003wbd (AUC = 0.76, 95 % CI = 0.70-0.82). In addition, higher expressions of lncRNAs were observed in HCC patients than in HBV patients. LncRNA-uc003wbd and lncRNA-AF085935 were observed with an aberrant serum level in HCC and HBV patients, which is showing that both lncRNA-uc003wbd and lncRNA AF085935 are able to be potential biomarkers for HCC and HBV screening. PMID- 25501708 TI - Potential impact of air pollution on multiple sclerosis in Tehran, Iran. AB - BACKGROUND: Multiple sclerosis (MS) incidence has dramatically increased in Tehran, Iran. The health impact of air pollution in Tehran underscores the attention to a possible association to this environmental risk factor. In this study, the authors aimed to analyze the spatial distribution of prevalent MS cases and their association with the spatial patterns of air pollution. METHODS: Patient records meeting McDonald's criteria for definite MS diagnosis with disease onset during 2003-2013 were obtained. Next, the location of 2,188 patients was successfully geo-referenced within Tehran metropolis by geographic information system (GIS) bureau of Iran's post office based on their phone numbers. A cluster analysis was performed using the average nearest neighbor index (ANNI) and quadrat analysis. The long-term exposures of MS patients to particulate matter (PM10), sulfur dioxide (SO2), nitrogen oxide (NO), nitrogen dioxide (NO2), and nitrogen oxides (NOx) were estimated using the previously developed land use regression models. RESULTS: Prevalent MS cases had a clustered pattern in Tehran. A significant difference in exposure to PM10, SO2, NO2, and NOx (p < 0.001) was observed in MS cases compared with controls. CONCLUSION: This study revealed the potential role of long-term exposure to air pollutants as an environmental risk factor in MS. PMID- 25501707 TI - Knockdown of the AKT3 (PKBgamma), PI3KCA, and VEGFR2 genes by RNA interference suppresses glioblastoma multiforme T98G cells invasiveness in vitro. AB - Glioblastoma multiforme (GBM) is the most common primary brain malignancy, having a very poor prognosis and is characterized by extensive brain invasion as well as resistance to the therapy. The phosphoinositide 3-kinase (PI3K)/Akt/PTEN signaling pathway is deregulated in GBM. Besides, florid vascularization and aberrantly elevated vascular endothelial growth factor (VEGF) occur very often. The present study was designed to examine the inhibitory effect of AKT3, PI3KCA, and VEGFR2 small interfering RNAs (siRNAs) on GBM cell invasiveness. T98G cells were transfected with AKT3, PI3KCA, and/or VEGFR2 siRNAs. VEGFR2 protein-positive cells were identified by flow cytometry using specific monoclonal anti-VEGFR2 antibodies. Alterations in messenger RNA (mRNA) expression of VEGF, VEGFR2, matrix metalloproteinases (MMPs) (MMP-2, MMP-9, MMP-13, MMP-14), tissue inhibitors of metalloproteinases (TIMPs) (TIMP-1, TIMP-3), c-Fos, c-Jun, hypoxia inducible factor-1alpha (HIF-1alpha), ObRa, and cathepsin D genes were analyzed by qRT-PCR. Cells treated with specific siRNA were also analyzed for invasion using the Matrigel invasion assay. We have found significantly lower mRNA levels of MMPs, cathepsin D, VEGF, VEGFR2, HIF-1alpha, and c-Fos/c-Jun ratio, as well as significantly higher mRNA level of TIMPs in AKT3 and PI3KCA siRNA transfected cells compared to untransfected cells, while significantly lower mRNA levels of MMPs (MMP-2, MMP-9, MMP-14) and TIMP-1, as well as significantly higher mRNA level of TIMP-3, were shown only in cells transfected with VEGFR2 siRNA. The positive correlation between MMP-13 and ObRa mRNA copy number has been found. Summarizing, transfection of T98G cells with AKT3, PI3KCA, or VEGFR2 siRNAs leads to a significant reduction in cell invasiveness. The siRNA-induced AKT3, PI3KCA, and VEGFR2 mRNA knockdown may offer a novel therapeutic strategy to reduce the invasiveness of GBM cells. PMID- 25501710 TI - Low-molecular-weight fibroblast growth factor 2 attenuates hepatic fibrosis by epigenetic down-regulation of Delta-like1. AB - Liver fibrosis, a major cause of end-stage liver diseases, is closely regulated by multiple growth factors and cytokines. The correlation of fibroblast growth factor 2 (FGF2) with chronic liver injury has been reported, but the exact functions of different FGF2 isoforms in liver fibrogenesis remain unclear. Here, we report on the differential expression patterns and functions of low- and high molecular-weight FGF2 (namely, FGF2(lmw) and FGF2(hmw) , respectively) in hepatic fibrogenesis using a CCl4 -induced mouse liver fibrosis model. FGF2(hmw) displayed a robust increase in CCl4 -induced hepatic fibrosis and promoted fibrogenesis. In contrast, endogenous FGF2(lmw) exhibited a slight increase in hepatic fibrosis and suppressed this pathological progression. Moreover, exogenous administration of recombinant FGF2(lmw) potently ameliorated CCl4 induced liver fibrosis. Mechanistically, we showed that FGF2(lmw) treatment attenuated hepatic stellate cell activation and fibrosis by epigenetic down regulation of Delta-like 1 expression through the p38 mitogen-activated protein kinase pathway. CONCLUSION: FGF2(lmw) and FGF2(hmw) have distinct roles in liver fibrogenesis. These findings demonstrate a potent antifibrotic effect of FGF2(lmw) administration, which may provide a novel approach to treat chronic liver diseases. PMID- 25501709 TI - Trajectory of frequency stability in typical development. AB - This work explores a feature of brain dynamics, metastability, by which transients are observed in functional brain data. Metastability is a balance between static (stable) and dynamic (unstable) tendencies in electrophysiological brain activity. Furthermore, metastability is a theoretical mechanism underlying the rapid synchronization of cell assemblies that serve as neural substrates for cognitive states, and it has been associated with cognitive flexibility. While much previous research has sought to characterize metastability in the adult human brain, few studies have examined metastability in early development, in part because of the challenges of acquiring adequate, noise free continuous data in young children. To accomplish this endeavor, we studied a new method for characterizing the stability of EEG frequency in early childhood, as inspired by prior approaches for describing cortical phase resets in the scalp EEG of healthy adults. Specifically, we quantified the variance of the rate of change of the signal phase (i.e., frequency) as a proxy for phase resets (signal instability), given that phase resets occur almost simultaneously across large portions of the scalp. We tested our method in a cohort of 39 preschool age children (age =53 +/- 13.6 months). We found that our outcome variable of interest, frequency variance, was a promising marker of signal stability, as it increased with the number of phase resets in surrogate (artificial) signals. In our cohort of children, frequency variance decreased cross-sectionally with age (r = -0.47, p = 0.0028). EEG signal stability, as quantified by frequency variance, increases with age in preschool age children. Future studies will relate this biomarker with the development of executive function and cognitive flexibility in children, with the overarching goal of understanding metastability in atypical development. PMID- 25501711 TI - [Anterior lumbar interbody fusion. Indications, technique, advantages and disadvantages]. AB - BACKGROUND: Anterior lumbar interbody fusion (ALIF) for lumbar interbody fusion from L2 to the sacrum has been an established technique for decades. OBJECTIVES: The advantages and disadvantages of ALIF compared to posterior interbody fusion techniques are discussed. The operative technique is described in detail. Complications and avoidance strategies are discussed. MATERIAL AND METHODS: This article is based on a selective literature search using PubMed and the experience of the authors in this medical field. RESULTS: The advantages of ALIF compared to posterior fusion techniques are the free approach to the anterior disc space without opening of the spinal canal or the neural foramina. This gives the possibility of an extensive anterior release and placement of the largest possible cages without the risk of neural structure damage. The disadvantages of ALIF are the additional anterior approach and the related complications. The most frequent complication is due to damage of vessels. The rate of complications is significantly increased in revision surgery. CONCLUSION: The ALIF technique meaningfully expands the repertoire of the spinal surgeon especially for the treatment of non-union after interbody fusion, in patients with epidural scar tissue at the index level and spinal infections. Advantages and disadvantages should be considered when evaluating the indications for ALIF. PMID- 25501712 TI - An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles: generality, applications and mechanistic investigations. AB - The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3-alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology. PMID- 25501713 TI - Solution-phase hierarchical self-organization of ultralong Se nanowires into diverse macroarchitectures and their enhanced field emission. AB - A simple solution-phase route was developed for the large-scale synthesis of self organized, closely packed ultralong single crystalline Se nanowire superstructures with diverse morphologies and macroscopic dimensions even extending over several millimeters. The hierarchical architectures of self organized Se nanowires were formed by reducing H2SeO4 with a bisubstituted aniline, such as 3,5-dimethoxyaniline, 2,5-dimethoxyaniline, 2,6 dimethoxyaniline, and 2-methoxy-5-nitroaniline under solvothermal conditions. Scanning electron microscopy studies show 100% morphological yield and morphological uniformity of the self-organized hierarchical architectures. Based on the dependence of the Se nanostructures on the synthetic conditions, especially the molecular structures of reductants and solvent, we proposed a plausible mechanism to account for the formation of the distinctive morphologies of the self-organized nanowire architectures. The field emission characteristics of the Se nanowires synthesized using 2,6-dimethoxyaniline and 2-methoxy-5 nitroaniline as the reductants are studied. These well-aligned Se nanowires show very low turn-on field (Eto) and threshold field (Ethr) as well as high emission current densities under low applied electric fields, which are superior to most of the one-dimensional (1D) nanostructures reported previously, due to their exceptional aspect ratios (>20 000) and sharp tips in combination with the nature of low band gap and high conductivity of Se. Furthermore, the Se nanowire emitters exhibit good emission current stability with small fluctuations (typically, less than 3%) over a period of 1000 min. PMID- 25501714 TI - Characterization of ion processes in a GC/DMS air quality monitor by integration of the instrument to a mass spectrometer. AB - The air quality monitor (AQM), which included a portable gas chromatograph (GC) and a detector was interfaced to a mass spectrometer (MS) by introducing flow from the GC detector to the atmospheric pressure ion source of the MS. This small GC system, with a gas recirculation loop for carrier and detector make-up gases, comprised an inlet to preconcentrate volatile organic compounds (VOCs) in air, a thermal desorber before the GC column, a differential mobility spectrometer (DMS), and another DMS as an atmospheric pressure ionization source for the MS. Return flow to the internally recirculated air system of the AQM's DMS was replenished using purified air. Although ions and unreacted neutral vapors flowed from the detector through Viton(r) tubing into the source of the MS, ions were not detected in the MS without the auxillary ion source, (63)Ni as in the mobility detector. The GC-DMS-MS instrument provided a 3-D measurement platform (GC, DMS, and MS analysis) to explore the gas composition inside the GC-DMS recirculation loop and provide DMS-MS measurement of the components of a complex VOC mixture with performance significantly enhanced by mass-analysis, either with mass spectral scans or with an extracted ion chromatogram. This combination of a mobility spectrometer and a mass spectrometer was possible as vapors and ions are carried together through the DMS analyzer, thereby preserving the chromatographic separation efficiency. The critical benefit of this instrument concept is that all flows in and through the thoroughly integrated GC-DMS analyzer are kept intact allowing a full measure of the ion and vapor composition in the complete system. Performance has been evaluated using a synthetic air sample and a sample of airborne vapors in a laboratory. Capabilities and performance values are described using results from AQM-MS analysis of purified air, ambient air from a research laboratory in a chemistry building, and a sample of synthetic air of known composition. Quantitative measures of a stand-alone AQM are disclosed for VOCs in the ppb to ppm levels with an average precision of 5.8% RSD and accuracy from 4% to 28% error against a standard method. PMID- 25501715 TI - Effects of repulsive interaction on the electric double layer of an imidazolium based ionic liquid by molecular dynamics simulation. AB - The effects of repulsive interaction on the electric double layer (EDL) and differential capacitance (Cd) of an ionic liquid (IL) 1-butyl-3-methyl imidazolium hexafluorophosphate (BMIM(+)/PF6(-)) on the graphite electrode were studied by molecular dynamics (MD) simulations. The strength of repulsive interaction was studied by manually tuning the parameter lambda (lambda) with lambda = 1.00 for normal Lennard-Jones interaction and smaller lambda for stronger repulsion between IL and the electrode. When lambda changes from 1.00 to 0.25, the dependence of Cd on potential (Cd-U) curves at different repulsions is asymmetrically camel-shaped with higher Cd at the negative polarization than that at the positive due to the thinner effective thickness of EDL from the specific adsorption of BMIM(+). Such a trend is opposite in the case of lambda = 0.05. Apart from that, the maximum of Cd at the negative polarization monotonically decreases with increasing repulsion. On the other hand, the maximum of Cd at the positive polarization first increases with increasing repulsion, due to the more effective screening of PF6(-) by weakening the specific adsorption of BMIM(+) as lambda changes from 1.00 to 0.75, and then it decreases with increasing repulsion. PMID- 25501716 TI - Evaluating the psychometric properties of the Maslach Burnout Inventory-Human Services Survey (MBI-HSS) among Italian nurses: how many factors must a researcher consider? AB - BACKGROUND: The Maslach Burnout Inventory (MBI) is the mainstream measure for burnout. However, its psychometric properties have been questioned, and alternative measurement models of the inventory have been suggested. AIMS: Different models for the number of items and factors of the MBI-HSS, the version of the Inventory for the Human Service sector, were tested in order to identify the most appropriate model for measuring burnout in Italy. METHODS: The study dataset consisted of a sample of 925 nurses. Ten alternative models of burnout were compared using confirmatory factor analysis. The psychometric properties of items and reliability of the MBI-HSS subscales were evaluated. RESULTS: Item malfunctioning may confound the MBI-HSS factor structure. The analysis confirmed the factorial structure of the MBI-HSS with a three-dimensional, 20-item assessment. CONCLUSIONS: The factorial structure underlying the MBI-HSS follows Maslach's definition when items are reduced from the original 22 to a 20-item set. Alternative models, either with fewer items or with an increased number of latent dimensions in the burnout structure, do not yield better results to justify redefining the item set or theoretically revising the syndrome construct. PMID- 25501717 TI - Tracing the trans-pacific evolutionary history of a domesticated Seaweed (Gracilaria chilensis) with archaeological and genetic data. AB - The history of a domesticated marine macroalga is studied using archaeological, phylogeographic and population genetic tools. Phylogeographic and population genetic analyses demonstrated that the cultivated red alga Gracilaria chilensis colonised the Chilean coast from New Zealand. Combining archaeological observations with phylogeographic data provided evidence that exchanges between New Zealand and Chile have occurred at least before the Holocene, likely at the end of the Last Glacial Maximum (LGM) and we suggest that migration probably occurred via rafting. Furthermore, the remarkably low microsatellite diversity found in the Chilean populations compared to those in New Zealand is consistent with a recent genetic bottleneck as a result of over-exploitation of natural populations and/or the process of domestication. Therefore, the aquaculture of this seaweed, based essentially on clonal propagation, is occurring from genetically depressed populations and may be driving the species to an extinction vortex in Chile. PMID- 25501718 TI - On measures of dissimilarity between point patterns: classification based on prototypes and multidimensional scaling. AB - This paper presents a collection of dissimilarity measures to describe and then classify spatial point patterns when multiple replicates of different types are available for analysis. In particular, we consider a range of distances including the spike-time distance and its variants, as well as cluster-based distances and dissimilarity measures based on classical statistical summaries of point patterns. We review and explore, in the form of a tutorial, their uses, and their pros and cons. These distances are then used to summarize and describe collections of repeated realizations of point patterns via prototypes and multidimensional scaling. We also show a simulation study to evaluate the performance of multidimensional scaling with two types of selected distances. Finally, a multivariate spatial point pattern of a natural plant community is analyzed through various of these measures of dissimilarity. PMID- 25501719 TI - Impact of isoflurane on malignant capability of ovarian cancer in vitro. AB - BACKGROUND: Metastatic recurrence of ovarian cancer is the foremost cause of postoperative mortality. With recent research indicating that inhalation of anaesthetics may influence cancer cell behaviour, this study investigated the effects of isoflurane on the expression of tumorigenic markers and proliferative capacity in ovarian cancer cells. METHODS: Ovarian cancer (SK-OV3) cells were cultured and then exposed to 2% isoflurane for 2 h. The expression of markers involved in cell proliferation, angiogenesis, and migration were assessed up to 24 h after treatment using immunofluorescence staining, western blotting, and flow cytometry. The effects of isoflurane on in vitro angiogenesis and migration were also determined. RESULTS: Isoflurane exposure significantly increased insulin-like growth factor (IGF)-1 and IGF-1R expression, cell cycle progression, and cell proliferation in SK-OV3 cells. Increased expression of the angiogenic markers vascular endothelial growth factor (VEGF) by 56% (P<0.05) and angiopoietin-1 by 62% (P<0.05) was also observed 24 h after isoflurane exposure together with an enhanced in vitro angiogenesis. Cell migration was significantly increased after exposure to isoflurane together with increased production of both matrix metalloproteinases 2 and 9 (both P<0.05) by almost five-fold relative to control. These effects were abolished when IGF-1R signalling was blocked either by neutralizing antibody or by small interfering RNA. CONCLUSIONS: Our data indicate that isoflurane increases the malignant potential of ovarian cancer cells through the up-regulation of markers associated with the cell cycle, proliferation, and angiogenesis. This study warrants further investigations. PMID- 25501720 TI - Gastric pH and residual volume after 1 and 2 h fasting time for clear fluids in children?. AB - INTRODUCTION: Current guidelines suggest a fasting time of 2 h for clear fluids, which is often exceeded in clinical practice, leading to discomfort, dehydration and stressful anaesthesia induction to patients, especially in the paediatric population. Shorter fluid fasting might be a strategy to improve patient comfort but has not been investigated yet. This prospective clinical trial compares gastric pH and residual volume after 1 vs 2 h of preoperative clear fluid fasting. METHODS: Children (1-16 yr, ASA I or II) undergoing elective procedures in general anaesthesia requiring tracheal intubation were randomized into group A with 60 min or B with 120 min preoperative clear fluid fasting. To determine gastric pH and residual volume, the gastric content was sampled in supine, left and right lateral patient position using an oro-gastric tube after intubation. Data are median (interquartile range) for group A or B (P<0.05). RESULTS: In total, 131 children aged 1.01-16.23 yr were included; gastric pH was determined in 120 cases. Patient characteristic data were similar between the two groups, except for gender (46/33 males in group A/B; P=0.02). Despite significantly shorter fasting times for clear fluids in group A compared with group B (76/136 min; P<0.001), no significant difference was observed regarding gastric pH [1.43 (1.30-1.56)/1.44 (1.29-1.68), P=0.66] or residual volume [0.43 (0.21-0.84)/0.46 (0.19-0.78) ml kg(-1), P=0.47]. CONCLUSION: One hour clear fluid fasting does not alter gastric pH or residual volume significantly compared with 2 h fasting. CLINICAL TRIAL REGISTRATION: The study was approved by the local ethics committee (KEK-ZH-Nr. 2011-0034) and registered with ClinicalTrials.gov (NCT01516775). PMID- 25501721 TI - Usefulness of non-invasive spectrophotometric haemoglobin estimation for detecting low haemoglobin levels when compared with a standard laboratory assay for preoperative assessment. AB - BACKGROUND: Delay in diagnosis of anaemia during preoperative assessment poses logistic problems, leading to multiple clinic visits, inadequate preoperative management, and unnecessary delay of surgery. Therefore, we tested an instant spectrophotometric haemoglobin (SpHb) measurement technique to facilitate this assessment. METHODS: We evaluated portable instant SpHb vs standard laboratory screening of anaemia between March 2012 and December 2013. Paired Hb measurements were performed on 726 patients using SpHb (Pronto-7, Masimo Corporation, Irvine, CA, USA) and Hb measured on the same day using an automated analyser. The results were obtained from a group of 638 patients from the pre-anaesthetic clinic with expected normal Hb values, and 88 patients from the oncology clinic with known low Hb. RESULTS: Median (range) SpHb was 129.5 (67-171) compared with 136 g litre(-1) (63-178) Hb measured using the automated system. Identifying Hb below a threshold of 130 g litre(-1) for males had a high sensitivity (93%), while identifying a threshold of 120 g litre(-1) for females had lower sensitivity (75%). The specificity for males (77%) and females (81%) was similar. Mean measurement bias and agreement: tolerability interval ratio was -8.1 g litre(-1) and 2.78 for men and -3.1 g litre(-1) and 2.44 for women. CONCLUSIONS: SpHb was sensitive as a preliminary screening tool for detecting true low Hb values in males, but less sensitive in females. Instant SpHb measurement may enable prompt routine preoperative anaemia management, but its precision was lower than expected. CLINICAL TRIAL REGISTRATION: This study is approved by the Tasmanian Human Ethics Committee, Australia and was registered prospectively in the Australian and New Zealand Clinical Trials Registry (http://www.ANZCTR.org.au/ ACTRN12611001256965) and the World Health Organization Clinical Trials Registry (http://apps.who.int/trialsearch/trial.aspx?trialid=ACTRN12611001256965). PMID- 25501723 TI - Imaging in abusive head trauma: an in-depth look at current issues. PMID- 25501722 TI - Systemic oxygen extraction during exercise at high altitude. AB - BACKGROUND: Classic teaching suggests that diminished availability of oxygen leads to increased tissue oxygen extraction yet evidence to support this notion in the context of hypoxaemia, as opposed to anaemia or cardiac failure, is limited. METHODS: At 75 m above sea level, and after 7-8 days of acclimatization to 4559 m, systemic oxygen extraction [C(a-v)O2] was calculated in five participants at rest and at peak exercise. Absolute [C(a-v)O2] was calculated by subtracting central venous oxygen content (CcvO2) from arterial oxygen content [Formula: see text] in blood sampled from central venous and peripheral arterial catheters, respectively. Oxygen uptake [Formula: see text] was determined from expired gas analysis during exercise. RESULTS: Ascent to altitude resulted in significant hypoxaemia; median (range) [Formula: see text] 87.1 (82.5-90.7)% and [Formula: see text] 6.6 (5.7-6.8) kPa. While absolute C(a-v)O2 was reduced at maximum exercise at 4559 m [83.9 (67.5-120.9) ml litre(-1) vs 99.6 (88.0-151.3) ml litre(-1) at 75 m, P=0.043], there was no change in oxygen extraction ratio (OER) [C(a-v)O2/CaO2] between the two altitudes [0.52 (0.48-0.71) at 4559 m and 0.53 (0.49-0.73) at 75 m, P=0.500]. Comparison of C(a-v)O2 at peak [Formula: see text] at 4559 m and the equivalent [Formula: see text] at sea level for each participant also revealed no significant difference [83.9 (67.5-120.9) ml litre(1) vs 81.2 (73.0-120.7) ml litre(-1), respectively, P=0.225]. CONCLUSION: In acclimatized individuals at 4559 m, there was a decline in maximum absolute C(a-v)O2 during exercise but no alteration in OER calculated using central venous oxygen measurements. This suggests that oxygen extraction may have become limited after exposure to 7-8 days of hypoxaemia. PMID- 25501724 TI - Diagnosing abusive head trauma: the challenges faced by clinicians. AB - This article highlights five important aspects of the clinical problem of evaluating young children who are suspected of having abusive head trauma: 1) the clinical questions to be addressed, 2) challenges when evaluating young children with suspected abuse, 3) key aspects of clinical practice and data collection, 4) a framework for decision-making and 5) key articles in the literature that can help inform a sound clinical decision about the likelihood of abuse. PMID- 25501726 TI - Long-term outcome of abusive head trauma. AB - Abusive head trauma is a severe inflicted traumatic brain injury, occurring under the age of 2 years, defined by an acute brain injury (mostly subdural or subarachnoidal haemorrhage), where no history or no compatible history with the clinical presentation is given. The mortality rate is estimated at 20-25% and outcome is extremely poor. High rates of impairments are reported in a number of domains, such as delayed psychomotor development; motor deficits (spastic hemiplegia or quadriplegia in 15-64%); epilepsy, often intractable (11-32%); microcephaly with corticosubcortical atrophy (61-100%); visual impairment (18 48%); language disorders (37-64%), and cognitive, behavioral and sleep disorders, including intellectual deficits, agitation, aggression, tantrums, attention deficits, memory, inhibition or initiation deficits (23-59%). Those combined deficits have obvious consequences on academic achievement, with high rates of special education in the long term. Factors associated with worse outcome include demographic factors (lower parental socioeconomic status), initial severe presentation (e.g., presence of a coma, seizures, extent of retinal hemorrhages, presence of an associated cranial fracture, extent of brain lesions, cerebral oedema and atrophy). Given the high risk of severe outcome, long-term comprehensive follow-up should be systematically performed to monitor development, detect any problem and implement timely adequate rehabilitation interventions, special education and/or support when necessary. Interventions should focus on children as well as families, providing help in dealing with the child's impairment and support with psychosocial issues. Unfortunately, follow-up of children with abusive head trauma has repeatedly been reported to be challenging, with very high attrition rates. PMID- 25501725 TI - Alternate theories of causation in abusive head trauma: what the science tells us. AB - When cases of suspected abusive head trauma are adjudicated in courts of law, several alternative theories of causation are frequently presented. This paper reviews common theories and examines their scientific basis. PMID- 25501727 TI - Crying as a trigger for abusive head trauma: a key to prevention. AB - The devastating and for the most part irremediable consequences for an infant, his or her family, and society in cases of abusive head trauma have spurred research into ways of preventing it. In the last four or five decades, increasing interest in infant crying and its clinical manifestation of colic has led to a reconceptualization of crying in early infancy, such that most of the characteristics of colic can be understood as manifestations of the crying typical of normal infants. This includes an early increase and then decrease in the amount of crying, the unexpected and unpredictable appearance of prolonged crying bouts, and the presence of inconsolable crying that occurs in the early months of life. When these concepts are merged with anecdotal clinical experiences, perpetrator confessions and epidemiological evidence of abusive head trauma, it is clear that these crying characteristics--and caregiver responses- are the predominant, and potentially modifiable, risk factors for abusive head trauma. This unfortunate but understandable relationship between early crying, shaking and abuse has opened windows of opportunity for primary, universal prevention efforts that are appropriate for--and support--all parents and may be able to prevent at least some of these tragic cases. PMID- 25501729 TI - The eye in child abuse: key points on retinal hemorrhages and abusive head trauma. AB - This review presents an up-to-date overview of ocular injuries resulting from child abuse, with a spotlight on abusive head trauma. Retinal hemorrhage is a principle finding of inflicted head trauma. The specific pattern of hemorrhages holds valuable diagnostic information, which can help to guide multidisciplinary assessments of the likelihood of abuse. Indirect ophthalmoscopy through dilated pupils by an ophthalmologist is necessary for adequate examination and documentation of retinal findings. Initial pediatrician evaluation of the eye and indications for ophthalmological consultation are reviewed. Focus is then placed upon understanding retinal hemorrhage patterns, their diagnostic significance and likely pathophysiological mechanisms. The differential diagnosis of retinal hemorrhage in young children is discussed, highlighting key distinctions among retinal hemorrhage patterns, severity and frequencies, as well as other ocular findings. The most common cause of retinal hemorrhage in an infant is trauma, and most other causes can be identified by considering the hemorrhage pattern, ocular or systemic signs and the results of laboratory and imaging tests, when indicated. PMID- 25501728 TI - Update on injury mechanisms in abusive head trauma--shaken baby syndrome. AB - Violently shaking a baby leads to clinical presentations ranging from seizures to cardiopulmonary arrest. The main injuries sustained are retinal hemorrhages, subdural hemorrhages, and sometimes fractures and spine injury. It is important to have a global view of the injuries sustained by the infant to correctly discuss the biomechanical aspects of abusive head trauma. Recent works based on finite element models have shown that whiplash-shaking alone is enough to generate vitreo-retinal traction leading to retinal hemorrhage and to cause the rupture of bridging veins leading to subdural hemorrhage. We will review the main papers dealing with the mechanisms of shaken baby syndrome and present the most relevant hypothesis concerning the biomechanical aspects of injuries related to shaken baby syndrome. PMID- 25501730 TI - Dating the abusive head trauma episode and perpetrator statements: key points for imaging. AB - Shaken baby syndrome/abusive head trauma is a leading cause of morbidity and mortality in infants. The presence of a diffuse subdural hematoma without evidence of accident is a key diagnostic clue. The hematoma is typically attributed to rupture of the cerebral bridging veins due to violent shaking, with or without impact. Dating the incident, however, remains controversial. The aim of this article is to review the most reliable features used for dating the incident, based on both legal statements by perpetrators and medical documentation. The key points are: 1) The high (yet likely underestimated) frequency of repeated shaking is around 50%, 2) Children do not behave normally immediately after shaking, and the time of onset of even mild symptoms appears to be the best clue for dating the incident and 3) Brain imaging provides strong indicators of "age-different" injuries but the ranges for dating the causal event are wide. The density pattern in a single subdural hematoma location provides no reliable clues for assessing repeated violence. Only the finding of different density in two distant subdural hematomas argues in favor of "age-different" injuries, i.e. repeated violence. MRI is difficult to interpret in terms of dating subdural hemorrhages and must be analyzed in conjunction with CT. Most importantly, all of the child's previous clinical and radiological data must be carefully studied and correlated to provide accurate information on the date and repetition of the trauma. PMID- 25501731 TI - Imaging abusive head trauma: why use both computed tomography and magnetic resonance imaging? AB - Abusive head trauma is the leading cause of death in child abuse cases. The majority of victims are infants younger than 1 year old, with the average age between 3 and 8 months, although these injuries can be seen in children up to 5 years old. Many victims have a history of previous abuse and the diagnosis is frequently delayed. Neuroimaging is often crucial for establishing the diagnosis of abusive head trauma as it detects occult injury in 37% of cases. Several imaging patterns are considered to be particularly associated with abusive head trauma. The presence of subdural hematoma, especially in multiple locations, such as the interhemispheric region, over the convexity and in the posterior fossa, is significantly associated with abusive head trauma. Although CT is the recommended first-line imaging modality for suspected abusive head trauma, early MRI is increasingly used alongside CT because it provides a better estimation of shear injuries, hypoxic-ischemic insult and the timing of lesions. This article presents a review of the use and clinical indications of the most pertinent neuroimaging modalities for the diagnosis of abusive head trauma, emphasizing the newer and more sensitive techniques that may be useful to better characterize the nature and evolution of the injury. PMID- 25501733 TI - Imaging of skeletal injuries associated with abusive head trauma. AB - Skeletal injuries are commonly encountered in infants and young children with abusive head trauma. Although certain patterns of intracranial injury suggest abuse, none are diagnostic. Therefore demonstration of associated unsuspected skeletal injuries has important implications, particularly when highly specific fractures are present. Skull fractures are commonly associated with intracranial injury, but no fracture pattern is indicative of physical abuse. Other skeletal injuries including classic metaphyseal lesions and rib, spine and scapular fractures are strong predictors of abusive head trauma in infants with intracranial injury. It is mandatory to perform rigorous skeletal surveys in infants and young children with clinical and neuroimaging findings concerning for abusive head trauma. PMID- 25501732 TI - Spinal injuries in abusive head trauma: patterns and recommendations. AB - A growing body of scientific evidence suggests that there is an association between occult spinal injury and abusive head trauma (previously known as shaken baby syndrome). Consideration needs to be given to the nature of these injuries, the possible causal mechanisms and what investigations should be undertaken to delineate the full extent of spinal involvement in infants with suspected abusive head trauma. This association has the potential to influence our understanding of the biomechanics and subsequent neuropathology associated with abusive head trauma. PMID- 25501734 TI - Retroclival collections associated with abusive head trauma in children. AB - Retroclival collections are rare lesions reported almost exclusively in children and strongly associated with trauma. We examine the incidence and imaging characteristics of retroclival collections in young children with abusive head trauma. We conducted a database search to identify children with abusive head trauma <= 3 years of age with brain imaging performed between 2007 and 2013. Clinical data and brain images of 65 children were analyzed. Retroclival collections were identified in 21 of 65 (32%) children. Ten (48%) were subdural, 3 (14%) epidural, 2 (10%) both, and 6 (28%) indeterminate. Only 8 of 21 retroclival collections were identifiable on CT and most were low or intermediate in attenuation. Eighteen of 21 retroclival collections were identifiable on MRI: 3 followed cerebral spinal fluid in signal intensity and 15 were bloody/proteinaceous. Additionally, 2 retroclival collections demonstrated a fluid-fluid level and 2 enhanced in the 5 children who received contrast material. Sagittal T1-weighted images, sagittal fluid-sensitive sequences, and axial FLAIR (fluid-attenuated inversion recovery) images showed the retroclival collections best. Retroclival collections were significantly correlated with supratentorial and posterior fossa subdural hematomas and were not statistically correlated with skull fracture or parenchymal brain injury. Retroclival collections, previously considered rare lesions strongly associated with accidental injury, were commonly identified in this cohort of children with abusive head trauma, suggesting that retroclival collections are an important component of the imaging spectrum in abusive head trauma. Retroclival collections were better demonstrated on MRI than CT, were commonly identified in conjunction with intracranial subdural hematomas, and were not significantly correlated with the severity of brain injury or with skull fractures. PMID- 25501736 TI - Epidemiological data on shaken baby syndrome in France using judicial sources. AB - BACKGROUND: The frequency of and risk factors for shaken baby syndrome remain poorly documented for several reasons: the real number of "benign" cases of shaken baby syndrome are not known; information sources used are diverse, there have been changes over time in the definition of this pathology and few population-based epidemiological studies are available. OBJECTIVE: Estimate the frequency of fatal shaken baby syndrome and determine its risk factors through research carried out on fatal cases in three regions of France while comparing them to data from international publications. MATERIALS AND METHODS: A retrospective epidemiological study of all cases of fatal shaken baby syndrome affecting infants younger than 1 year of age who were examined by the courts during a 5-year period in a defined geographical area. Shaken baby syndrome cases were compared with infanticide cases for risk factors and a comparison was made of family characteristics with those of the general population. RESULTS: Thirty seven cases of shaken baby syndrome were recorded (a rate of 2.9 for 100,000 live births). As in other studies, we found a strong predominance of male victims (78%), young age (median age: 4 months) and a high rate of prematurity (22%). Conversely, results on family educational and socioeconomical levels differ from those reported in numerous studies. Parent perpetrators of shaken baby syndrome belong to higher social classes than those of other types of homicide and socially reflect the population they come from. CONCLUSION: Our study suggests 1) that epidemiological studies on shaken baby syndrome should include both medical and judicial information sources and 2) that primary prevention strategies (especially in maternity wards) should target all social classes. PMID- 25501735 TI - Distinguishing accidental from inflicted head trauma at autopsy. AB - This article will discuss accidental and inflicted head injuries in infants and young children and how forensic pathologists distinguish between these types of injuries. The article begins with a consideration of the special and unique features of the anatomy and development of the child's head and neck and then relates these features to the mechanisms of traumatic brain injury and how these unique features influence the mechanisms of injury. The article very specifically notes that accidental head injuries in young children that occur in and around the home are focal head injuries in distinction to inflicted head injuries, which are diffuse brain injuries. The article discusses the mechanisms by which traumatic brain injury causes loss of consciousness and relates those mechanisms to the differences in the clinical features that occur in both accidental and inflicted head injury. The article discusses and illustrates the pathological findings in accidental head injuries consisting of the crushing head injuries and the head injuries sustained in short falls including epidural hemorrhage and focal subdural hemorrhage. The article discusses and illustrates the pathological findings that occur in inflicted head trauma, including subdural and subarachnoid hemorrhages and retinal and optic nerve sheath hemorrhages. PMID- 25501737 TI - International issues in abusive head trauma. AB - In the decades since Dr. John Caffey described a series of children with chronic subdural hematoma and long bone fractures, there has been a substantial increase in the medical recognition of various forms child abuse. In the United States, the term shaken baby syndrome was coined to explain a constellation of injuries assumed to be the result of violent shaking of infants. After improved understanding of the variety of mechanisms that occur when children are abused, abusive head trauma (AHT) has become the recommended terminology. AHT is a more comprehensive term that reflects the brain injuries that children suffer as the result of abuse. AHT continues to include shaking as a mechanism of injury as well as shaking with impact, impact alone, crushing injuries or combinations of several mechanisms. The medical community in the United States has led the way in developing new terminology and research to describe this unique and devastating form of abuse. The globalization of medicine and rapid information transfer has resulted in AHT becoming well-recognized internationally as a form of serious and fatal child abuse. This paper will review the historical basis in the United States for the diagnosis of AHT. We will also review some of the current international issue in epidemiology, diagnosis, legal processes and outcomes in selected countries/regions where child abuse physicians are actively involved in the evaluation of AHT. PMID- 25501738 TI - Diagnostic guidelines in abusive head trauma: key recommendations of a French public hearing. PMID- 25501739 TI - Portal blood arterialization with an extracorporeal device to treat toxic acute hepatic failure in a swine model. AB - PURPOSE: This study aimed to determine whether a controlled portal blood arterialization by a liver extracorporeal device (L.E.O2 NARDO) is effective in treating acute hepatic failure (AHF) induced through CCl4 administration in a swine model. METHODS: 20 swine with AHF induced by intraperitoneal injection of carbon tetrachloride (CCl4) in oil solution, were randomly divided into two groups: animals receiving L.E.O2 NARDO treatment 48 h after the intoxication (study group); animals sham operated 48 h after the intoxication (control group). Blood was withdrawn from the iliac artery and reversed in the portal venous system by an interposed extracorporeal device. Each treatment lasted 6 h. The survival was assessed at 5 days after L.E.O2 NARDO treatment or sham operation. In both groups blood samples were collected for biochemical analysis at different time points and liver biopsies were collected 48 h after intoxication and at sacrifice. RESULTS: We observed decreased transaminases levels and a more rapid INR recovery in the study group, as compared to the control group. Eight animals of the study group vs. two animals of the control group survived at five days after surgery with a statistically significant difference (p<0.05). Liver biopsies performed at sacrifice showed a reduction of the damaged hepatic areas in the study group as compared to the control group. CONCLUSIONS: Arterial blood supply in the portal system through the L.E.O2 NARDO device is easily applicable, efficacious, and safe in a swine model of AHF induced by CCl4 intoxication. PMID- 25501740 TI - Highly selective synthesis of functionalized polyhydroisoquinoline derivatives via a three-component domino reaction. AB - Two series of novel functionalized polyhydroisoquinoline derivatives have been synthesized via the three-component domino reaction of glutaraldehyde and malononitrile with a series of beta-ketoamides under microwave irradiation conditions in the presence of a catalytic amount of Et3N (10 mol%). This reaction represents the first reported process for the facile conversion of a beta ketoamide to a hydroisoquinoline via a C-N bond cleavage reaction without the need for a multistep reaction process. PMID- 25501742 TI - Focus on phosphoproteomics. PMID- 25501747 TI - Oncogenic Ras influences the expression of multiple lncRNAs. AB - Recent ultrahigh-density tiling array and large-scale transcriptome analysis have revealed that large numbers of long non-coding RNAs (lncRNAs) are transcribed in mammals. Several lncRNAs have been implicated in transcriptional regulation, organization of nuclear structure, and post-transcriptional processing. However, the regulation of expression of lncRNAs is less well understood. Here, we show that the exogenous and endogenous expression of an oncogenic form of small GTPase Ras (called oncogenic Ras) decrease the expression of lncRNA ANRIL (antisense non coding RNA in the INK4 locus), which is involved in the regulation of cellular senescence. We also show that forced expression of oncogenic Ras increases the expression of lncRNA PANDA (p21 associated ncRNA DNA damage activated), which is involved in the regulation of apoptosis. Microarray analysis demonstrated that expression of multiple lncRNAs fluctuated by forced expression of oncogenic Ras. These findings indicate that oncogenic Ras regulates the expression of a large number of lncRNAs including functional lncRNAs, such as ANRIL and PANDA. PMID- 25501748 TI - Exploring relationship between face-to-face interaction and team performance using wearable sensor badges. AB - Quantitative analyses of human-generated data collected in various fields have uncovered many patterns of complex human behaviors. However, thus far the quantitative evaluation of the relationship between the physical behaviors of employees and their performance has been inadequate. Here, we present findings demonstrating the significant relationship between the physical behaviors of employees and their performance via experiments we conducted in inbound call centers while the employees wore sensor badges. There were two main findings. First, we found that face-to-face interaction among telecommunicators and the frequency of their bodily movements caused by the face-to-face interaction had a significant correlation with the entire call center performance, which we measured as "Calls per Hour." Second, our trial to activate face-to-face interaction on the basis of data collected by the wearable sensor badges the employees wore significantly increased their performance. These results demonstrate quantitatively that human-human interaction in the physical world plays an important role in team performance. PMID- 25501749 TI - Interrelations that foster learning: An investigation of two correlational studies. AB - The theoretical tenets of academic engagement, as outlined by Schaufeli and colleagues, have received limited attention. There is credence to indicate that Schaufeli et al.'s conceptualization has educational implications. Extending this avenue of inquiry, we report two longitudinal studies that explore the motivation related attributes of engagement within the framework of self-efficacy. A number of research questions were developed for examination-for example, does enactive learning experience influence academic achievement, via students' engrossment (i.e. absorption) of a subject matter? Does students' sense of resilience and persistence (i.e. vigor) heighten their self-efficacy beliefs for academic learning? For the two studies (Study 1: 311 Year 11 students; Study 2: 249 Year 12 students), utilizing different cohorts, we measured these constructs at multiple time points. Existing Likert-scale inventories were administered repeatedly, and data collected were analysed using causal modeling procedures. MPlus 7.2 yielded a number of key findings-for example: (a) the positive impact of Time 1 enactive learning experience on Time 2 absorption and vigor, (b) the positive impact of Time absorption on Time 3 self-efficacy, (c) the positive impact of Time 2 absorption on Time 4 achievement and (d) the positive impact of Time 1 self-efficacy on Time 2 absorption and vigor. PMID- 25501751 TI - Fragility fracture programs: are they effective and what is the surgeon's role? AB - Fragility fractures are occurring at an ever-increasing rate, creating an enormous economic and societal impact. Outpatient-based fragility fracture programs have been developed to identify at-risk patients, initiate effective treatment of metabolic bone disease, and improve coordination between members of the patient's care team with the goal of reducing future fractures. Inpatient programs focus on effective, efficient management of patients presenting with acute fractures. Both have proven successful in reducing the impact of fragility fractures, but many challenges exist. The orthopedic surgeon, as part of an integrated team of providers, is integral in identifying at-risk patients, ensuring appropriate care of acute fractures, and initiating treatment protocols to reduce the risk of further injuries. PMID- 25501750 TI - A novel role for SIRT-1 in L-arginine protection against STZ induced myocardial fibrosis in rats. AB - BACKGROUND: L-arginine (L-ARG) effectively protects against diabetic impediments. In addition, silent information regulator (SIRT-1) activators are emerging as a new clinical concept in treating diabetic complications. Accordingly, this study aimed at delineating a role for SIRT-1 in mediating L-ARG protection against streptozotocin (STZ) induced myocardial fibrosis. METHODS: Male Wistar rats were allocated into five groups; (i) normal control rats received 0.1 M sodium citrate buffer (pH 4.5); (ii) STZ at the dose of 60 mg/kg dissolved in 0.1 M sodium citrate buffer (pH 4.5); (iii) STZ + sirtinol (Stnl; specific inhibitor of SIRT 1; 2 mg/Kg, i.p.); (iv) STZ + L-ARG given in drinking water (2.25%) or (v) STZ + L-ARG + Stnl. RESULTS: L-ARG increased myocardial SIRT-1 expression as well as its protein content. The former finding was paralleled by L-ARG induced reduction in myocardial fibrotic area compared to STZ animals evidenced histopathologically. The reduction in the fibrotic area was accompanied by a decline in fibrotic markers as evident by a decrease in expression of collagen-1 along with reductions in myocardial TGF-beta, fibronectin, CTGF and BNP expression together with a decrease in TGF-beta and hydroxyproline contents. Moreover, L-ARG increased MMP-2 expression in addition to its protein content while decreasing expression of PAI-1. Finally, L-ARG protected against myocardial cellular death by reduction in NFkappa-B mRNA as well as TNF-alpha level in association with decline in Casp-3 and FAS expressions andCasp-3protein content in addition to reduction of FAS positive cells. However, co-administration of L ARG and Stnl diminished the protective effect of L-ARG against STZ induced myocardial fibrosis. CONCLUSION: Collectively, these findings associate a role for SIRT-1 in L-ARG defense against diabetic cardiac fibrosis via equilibrating the balance between profibrotic and antifibrotic mediators. PMID- 25501753 TI - New therapeutic strategy for hepatocellular carcinoma by molecular targeting agents via inhibition of cellular stress defense mechanisms. AB - The prognosis of advanced hepatocellular carcinoma (HCC) has remained very poor.It has recently been reported that the molecular targeting agent sorafenib can improve the prognosis of patients with advanced HCC. However, the detailed mechanisms of sorafenib, especially its direct effects on hepatoma and hepatocyte cells, are poorly understood, making a more detailed investigation about the molecular mechanism of sorafenib necessary. Endoplasmic reticulum (ER) stress is related to the pathophysiology of various liver diseases, including chronic viral hepatitis, alcoholic and nonalcoholic steatohepatitis and HCC. In this regard, our recent data examining the molecular effects of sorafenib focused on the cellular defense mechanisms from ER stress, the unfolded protein response (UPR) and keratin phosphorylation, demonstrated that sorafenib inhibited both important cytoprotective mechanisms, UPR and keratin phosphorylation, and enhances the anti tumor effect in combination with proteasome inhibitors. This review summarizes the cytoprotective mechanisms from ER stress and our results about the direct effect of sorafenib on the cytoprotective mechanisms. PMID- 25501752 TI - Resveratrol possesses protective effects in a pristane-induced lupus mouse model. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterized by the production of autoantibodies. To date, no therapy has been found to satisfactorily treat SLE. SIRT1 deficiency results in the development of an autoimmune syndrome in mice, including a high titer of anti nuclear antibody in serum, immunoglobulin deposition in the kidney, and immune complex glomerulonephritis. Resveratrol is an activator of SIRT1 and possesses anti-inflammation and immune-regulatory properties. OBJECTIVE: To evaluate the preventative effects of resveratrol on a pristane-induced lupus animal model and assess its putative immune modulation effects. METHODS: BALB/c mice received a single intraperitoneal injection of 0.5 ml of pristane on day 1 and then various doses of resveratrol were given to the mice daily starting on day 2 and continuing for seven months. The autoantibodies in serum and supernatants were measured. Single cells isolated from spleen, isolated CD4+ T cells, and CD19+ B cells were cultured with or without resveratrol in vitro and assessed by flow cytometry. RESULTS: Resveratrol attenuated proteinuria, immunoglobuin depositon in kidney, and glomerulonephritis as well as IgG1 and IgG2a in serum in pristane induced lupus mice. Resveratrol also suppressed CD69 and CD71 expression on CD4+ T cells as well as CD4+ T cell proliferation, induced CD4+ T cell apoptosis, and decreased CD4 IFNgamma+ Th1 cells and the ratio of Th1/Th2 cells in vitro. In vitro antibody production and proliferation of B cells were also inhibited. CONCLUSION: Resveratrol possesses protective effects in pristane-induced lupus mice and may represent a novel approach for the management of SLE. PMID- 25501754 TI - Case of immunoglobulin G4 (IgG4)-related disease diagnosed by transbronchial lung biopsy and endobronchial ultrasound-guided transbronchial needle aspiration. AB - A 62-year-old Japanese man was admitted to our hospital for evaluation of bilateral chest abnormal shadow.His lacrimal, submandibular and parotid glands had been swollen for several years. His serum immunoglobulin G4 (IgG4) level was >1,500 mg/dl, and chest computed tomography showed bilateral reticular opacities with enlarged mediastinal lymph nodes. Transbronchial lung biopsy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) results suggested IgG4-related disease. This is the first report, to our knowledge, in the English literature showing EBUS-TBNA to be useful for diagnosing IgG4-related disease. PMID- 25501755 TI - Case of parathyroid carcinoma with a highly aggressive clinical course. AB - We describe a 59-year-old woman who presented with pathological osteoporosis, cerebral infarction, hypercalcemia, and markedly high parathyroid hormone levels. The diagnosis was primary hyperparathyroidism, and parathyroidectomy was performed. Histopathological examination showed parathyroid adenoma. Surgical exploration for recurrent parathyroid carcinoma was undertaken at 2 and 3 years after the initial neck resection. Pulmonary metastasis was diagnosed at 4 years after the initial surgery.Despite treatment with intravenous bisphosphonates, her calcium and parathyroid hormone (PTH) levels remained elevated, and leg amputation was performed following the development of arteriosclerosis obliterans at 6 years after the initial neck resection. The prognosis for parathyroid carcinoma is often difficult to predict due to recurrence. PMID- 25501756 TI - Keratocystic odontogenic tumor invading the maxillary sinus: a case report of collaborative surgery between an oral surgeon and an otorhinolaryngologist. AB - We report a case of keratocystic odontogenic tumor (KCOT) in a 21-year-old female patient. The patient was referred to our clinic from a dental clinic for the radical treatment of recurrent KCOT in the maxilla. She had undergone conservative drainage surgery twice at that clinic.The tumor was cystic and covered with a bony capsule, which extended high into the maxillary sinus. A pinhole fistula, which was created during a previous surgery, was identified in the gingivobuccal sulcus. The whole tumor was successfully removed using a bidirectional approach from the fistula and from the antrostomy in the middle meatus. This report shows that the intimate collaboration between an otorhinolaryngologist and an oral surgeon could provide a minimally invasive, and at the same time, radical surgical treatment for certain kinds of tumor in the head and neck region. We also recommend the introduction of endoscopic surgeries by the oral surgeon. PMID- 25501758 TI - [Endoscopic gallbladder stenting for acute cholecystitis]. AB - Acute cholecystitis is an inflammatory disease of the gallbladder. Inflammation often remains in the gallbladder, but some patients may take a fatal course with exacerbation of inflammation. Although laparoscopic cholecystectomy is recommended for moderate and severe acute cystitis, sometimes cholecystectomy is impossible in elder patients. Because many elder patients have bad general conditions, cholecystectomy should not be performed. Such patients are generally treated by percutaneous transhepatic gallbladder drainage (PTGBD), but PTGBD has the risk of intra-abdominal bleeding. In previous reports, endoscopic gallbladder stenting (EGBS) has been shown to be an effective strategy in cirrhosis patients with symptomatic cholelithiasis as a bridge to transplantation. Recent studies on EGBS have demonstrated an effective long-term management of acute cholecystitis in elderly patients who are poor surgical candidates. Here, we reviewed EGBS for the management of acute cholecystitis. PMID- 25501757 TI - [Analysis of tendon injuries accompanying distal radius fractures using volar locking plates]. AB - We examined 6 cases of tendon injuries that accompanied distal radius fractures using volar locking plate between April 2006 and March 2012. Male: one case, female: five cases, average age 57.0 (33~70) years old. The fracture type was A2 in one case, A3 in four cases, and C2 in one case by AO classification. The average period for operation waiting was 2.7 days. We analyzed the time of occurrence of tendon rupture (extensor pollicis longus (EPL)?flexor pollicis longus (FPL)), the existence or not of screw prominence and dorsal roof fragment, and the positioning of the plate setting. The tendon ruptures were EPL in four cases, and FPL in two cases. The average period of rupture occurrence was 86.8 (1~182) days. In four EPL tendon ruptures we recognized one marked screw prominence (16.7%), and two dorsal roof fragments (50%), both showing widespread displacement. Moreover, we recognized the malposition of the plate setting in the two cases of FPL tendon rupture (100%). The incidence of tendon ruptures accompanying distal radius fractures using volar locking plates was not low at all, therefore we should more pay attention to the prevention of this occurrence. PMID- 25501759 TI - [Estimate of the number of night shift workers in Japan]. AB - In this study we used governmental statistic data to estimate the number of night shift workers in Japan, referring to the Labour Force Survey by the Ministry of Internal Affairs and Communications to obtain the number of employees in the workforce. We also referred to the Survey on the State of Employees' Health by the Ministry of Health, Labour and Welfare to obtain the work schedules of employees. Our study revealed that the number of night shift workers in Japan has been increasing. The prevalence of night work among Japanese employees was 13.3% in the year 1997, 17.8% in 2002, 17.9% in 2007, and 21.8% in 2012. Our estimation revealed that there are twelve million workers currently engaged in night work. The prevalance of shift workers and shift workers with night shift in Japan is also increasing. PMID- 25501760 TI - [Apathetic hyperthyroidism with heart failure in an elderly patient with Plummer's disease]. AB - We report a case of apathetic hyperthyroidism associated with unrecognized slowly growing functional thyroid adenoma (Plummer's disease), atrial fibrillation and heart failure. An 81-year-old woman with worsening thyroid dysfunction was admitted to our hospital for the treatment of heart failure. The patient had developed heart failure associated with chronic atrial fibrillation at 76 years of age, and one year later was found to have asymptomatic hyperthyroidism. Anti thyroid autoantibodies were negative, but thyroid echography showed a 32-mm tumor devoid of internal blood flow in the left lower lobe. Free thyroxine 4 (FT4) decreased from 3.30 to 2.60 ng/dl without treatment. The patient was diagnosed with transient thyroiditis and was followed-up without treatment. However, a repeat thyroid echography showed growth of the tumor to 41 mm in 4 years. Thyroid scintigraphy showed uptake that matched the thyroid mass. Based on these findings, the established diagnosis was Plummer's disease complicated with heart failure. The patient was treated with anti-thyroid drugs, which resulted in improvement of FT4 and reduced the severity of heart failure. In this rare case of an elderly patient, Plummer's disease was associated with a slowly-growing functional thyroid adenoma, apathetic hyperthyroidism, repeated episodes of atrial fibrillation and heart failure. Since symptoms of thyrotoxicosis are likely to be missed in the elderly, it is necessary to include hyperthyroidism in the pathoetiology of heart failure and atrial fibrillation in this population. PMID- 25501761 TI - [Need for occupational and environmental allergology in occupational health - the 45th Japanese society of Occupational and Environmental Allergy Annual Meeting 2014 in Fukuoka]. AB - The 45th Japanese Society of Occupational and Environmental Allergy (OEA) Annual Meeting 2014 was held in Fukuoka city in conjunction with a technical course for occupational health physicians to learn occupational and environmental diseases more deeply. Allergic reaction due to low concentrations of chemical and biological materials is important in toxicological diseases due to highly concentrated chemical materials in the field of occupational and environmental medicine. In this paper we describe the activities of the OEA, which was established in 1970 and has completely cured patients with severe occupational asthma, such as the regional Konjac asthma in Gunma prefecture and Sea Squirt asthma in Hiroshima prefecture. Regard for the occupational environment will prevent the onset and/or exacerbation of allergic occupational disease in individual employees with allergy. Occupational cancer of the bile duct and asbestosis are also current, serious issues that should be resolved as soon as possible. It is desirable for the occupational health physician to have a large stock of knowledge about toxicological and allergic diseases in various occupational settings to maintain the health and safety of workers. PMID- 25501762 TI - [Case of spontaneous cervical internal carotid artery dissection with embolic stroke after a job-change]. AB - A 51 year old male was admitted to our hospital with sudden consciousness disturbance, global aphagia and right hemiparesis. Magnetic resonance imaging (MRI) revealed fresh infarctions in the territory of the left middle cerebral artery, and MR angiography (MRA) showed occlusion of the left carotid artery and the left middle cerebral artery. We started conservative therapy, including antiplatelet drug and blood pressure control. Three days later, cervical MRA revealed hematoma in the intracranial carotid wall of the petrous portion, leading to a diagnosis of spontaneous intracranial carotid artery dissection of the petrous portion. Two weeks after admission, MRA and angiography showed recanalization and pearl and string sign in the left petrous internal carotid artery. After that, the patient's neurological deficit improved, and the dissection also improved. Four months later, MR-angiography revealed an almost normalized condition. PMID- 25501763 TI - [Association of sleep problems with self-rated health - a large epidemiologic survey in the working population]. AB - To investigate the association between various sleep problems and self-rated health (SRH), a total of 43,092 (34,164 men and 8,928 women) employees were surveyed by means of a self-administered questionnaire. The risk of suboptimal (poor, very poor) SRH associated with sleep problems was estimated using multivariable logistic regression with odds ratios (ORs) as measures of associations. Because the prevalence of suboptimal SRH differed by sex (men 29.4% and women 34.1%, P < 0.001), the analyses were done separately for men and women. Employees sleeping less than 6 hrs/day (OR = 1.39 for men, 1.40 for women), with difficulty initiating sleep (OR=4.44 for men, 3.85 for women), with difficulty maintaining sleep (OR=5.72 for men, 4.85 for women), with early morning awakening (OR=3.87 for men, 4.25 for women), with difficulty waking up in the morning (OR=3.30 for men, 3.40 for women), feeling tired when waking up in the morning (OR=4.97 for men, 4.82 for women), and excessive daytime sleepiness at work (OR=2.34 for men, 2.11 for women) had a significantly higher odds of suboptimal SRH compared to those without sleep problems. The association between sleep problems and suboptimal SRH did not differ between men and women. In conclusion, the data point to an independent relationship between sleep problems and suboptimal SRH among Japanese employees. PMID- 25501766 TI - Extrinsic 2D chirality: giant circular conversion dichroism from a metal dielectric-metal square array. AB - Giant chiroptical responses routinely occur in three dimensional chiral metamaterials (MMs), but their resonance elements with complex subwavelength chiral shapes are challenging to fabricate in the optical region. Here, we propose a new paradigm for obtaining strong circular conversion dichroism (CCD) based on extrinsic 2D chirality in multilayer achiral MMs, showing that giant chiroptical response can be alternatively attained without complex structures. Our structure consists of an array of thin Au squares separated from a continuous Au film by a GaAs dielectric layer, where the Au squares occupy the sites of a rectangular lattice. This structure gives rise to a pronounced extrinsically 2D chiral effect (CCD) in the mid-infrared (M-IR) region under an oblique incidence, where the 2D-chiral effect is due to the mutual orientation of the Au squares array and the incident light propagation direction; the large magnitude of CCD due to the large difference between left-to-left and right-to-right circularly polarized reflectance conversion efficiencies. PMID- 25501765 TI - A review of a priori regression models for warfarin maintenance dose prediction. AB - A number of a priori warfarin dosing algorithms, derived using linear regression methods, have been proposed. Although these dosing algorithms may have been validated using patients derived from the same centre, rarely have they been validated using a patient cohort recruited from another centre. In order to undertake external validation, two cohorts were utilised. One cohort formed by patients from a prospective trial and the second formed by patients in the control arm of the EU-PACT trial. Of these, 641 patients were identified as having attained stable dosing and formed the dataset used for validation. Predicted maintenance doses from six criterion fulfilling regression models were then compared to individual patient stable warfarin dose. Predictive ability was assessed with reference to several statistics including the R-square and mean absolute error. The six regression models explained different amounts of variability in the stable maintenance warfarin dose requirements of the patients in the two validation cohorts; adjusted R-squared values ranged from 24.2% to 68.6%. An overview of the summary statistics demonstrated that no one dosing algorithm could be considered optimal. The larger validation cohort from the prospective trial produced more consistent statistics across the six dosing algorithms. The study found that all the regression models performed worse in the validation cohort when compared to the derivation cohort. Further, there was little difference between regression models that contained pharmacogenetic coefficients and algorithms containing just non-pharmacogenetic coefficients. The inconsistency of results between the validation cohorts suggests that unaccounted population specific factors cause variability in dosing algorithm performance. Better methods for dosing that take into account inter- and intra-individual variability, at the initiation and maintenance phases of warfarin treatment, are needed. PMID- 25501768 TI - A primer on pigmentation. AB - There is at least a temporary loss of skin pigmentation with all but first-degree burns. Commonly, pigment changes persist for months, and sometimes, permanent changes in skin color add to the ultimate change in appearance that commonly affects burn patients. There are many different treatment modalities for the treatment of pigment changes, but most of them have little scientific basis and often lead to disappointing results. The purpose of this review is to discuss the molecular and cellular mechanisms of skin pigmentation, mechanisms of repigmentation after burns, treatment options for dealing with pigmentation changes, and advice for dealing with the sun after burn injury. PMID- 25501767 TI - The histamine H4 -receptor (H4 R) regulates eosinophilic inflammation in ovalbumin-induced experimental allergic asthma in mice. AB - Via the histamine H4 -receptor (H4 R), histamine promotes the pathogenesis of experimental allergic asthma in mice. Application of H4 R antagonists during sensitization as well as during provocation reduces the severity of the disease. However, the specific cell types functionally expressing H4 R in experimental allergic asthma have not been well characterized in vivo. In this study, we identified the cell type(s) responsible for H4 R activity in experimental asthma and related physiological mechanisms. Using H4 R-deficient mice, we studied the role of H4 R in the sensitization and effector phase. DCs lacking H4 R expression during the in vitro sensitization reaction resulted in effector T cells unable to induce an entire eosinophilic inflammation in the lung upon adoptive transfer in vivo. Recipient mice lacking H4 R expression, which were adoptively transferred with H4 R(+/+) T cells polarized in the presence of H4 R(+/+) DCs, showed reduced signs of inflammation and ameliorated lung function. Here, we provide in vivo evidence that in experimental asthma in mice the H4 R specifically regulates activation of DCs during sensitization, while in the effector phase the H4 R is active in cells involved in the activation of eosinophils, and possibly other cells. A putative therapy targeting the H4 R may be an option for asthma patients developing IL-5-dependent eosinophilia. PMID- 25501769 TI - Simulation of Tangential Excision: A Test for Construct Validity. AB - A foundational skill in burn surgery is tangential excision (TE). The purpose of this study was to develop a simulation model for TE, hypothesizing that simulation could be used in surgical training. TE simulation was created using the TE knife, foam, mineral oil, and base. Subjects, surgeons, or surgeons in training, were given a pre- and post-task questionnaire about experience with TE. Subjects were divided into three TE experience groups: novice--none, intermediate -some, and expert--TE in current or past practice. The task was to excise pre marked rectangles, generating four excisional products (EPs). Evaluators blindly assessed performance by EP analysis using a novel scoring tool and reviewed videos using a modified objective structured assessment of technical skill (OSATS) rubric. Inter-rater reliabilities and P values were obtained, comparing Novice and Intermediate with Expert scores. Forty subjects completed the study: 16 were identified as TE novices, 17 as intermediates, and seven as experts. All EPs and videos were reviewed blindly by two evaluators using the EP scoring tool and OSATS methodology, respectively. Intraclass correlation coefficients were calculated to measure inter-rater reliabilities, which were acceptable (ICC => 0.42) for OSATS, time, and EP analysis: border and texture. Statistical differences between Novice and Expert scores were found (P < .0100, P < .0200, P < .0025, and P < .0005, respectively). Statistical differences between Intermediate and Expert scores were also found (P < .0100, P < .0200, P < .0100, and P < .0025, respectively). Post-simulation survey results showed experts 86% of the time agreeing or strongly agreeing that the simulation was similar to the clinical skin and 100% felt it would be a useful for training before clinical performance. Simulation for TE was successfully created to blindly discern level of TE experience. Participants agreed that simulation could play an essential role in burn surgical training. PMID- 25501770 TI - Mid-Level Providers: What Do We Do? AB - Changes in resident physician work hours have made it increasingly more difficult for physicians to meet the needs of their patients. In many facilities, mid-level providers (MLPs; advanced practice nurses and physician assistants) have become integral members of the medical team in both inpatient and outpatient settings. The purpose of this study was to identify the roles of MLPs in the American Burn Association (ABA) and within burn care teams. There was a 49% return survey response rate. Respondents included 28 (58%) nurse practitioners and 16 (33%) physician assistants. Forty-six percentage of the MLPs had at least 11 years of burn care experience. Forty respondents (87%) worked both inpatient and outpatient settings. Thirty-four (74%) of the providers ran independent clinics. Job responsibilities were in areas of direct patient care, education, and administrative duties. The majority of respondents were members of the ABA, attended annual conferences, and were advanced burn life support instructors. Forty-two (91%) of the MLPs were satisfied with their jobs. In conclusion, MLPs are highly experienced, ABA members and assume direct care of the burn patient. PMID- 25501771 TI - Changes in burn scar contracture: utilization of a severity scale and predictor of return to duty for service members. AB - A medical records review of Operation Iraqi Freedom and Operation Enduring Freedom burn injury survivors admitted to the U.S. Army Institute of Surgical Research Burn Center from April 2003 to August 2005 was conducted. The study proposed the use of a newly developed scale, the Burn Scar Contracture Severity Scale, to potentially provide standardization in quantifying burn scar contracture severity. Changes in the active range of motion from in-patient discharge to out-patient follow-up of individuals with upper extremity burn injuries were compared. Changes in the impairment via American Medical Association impairment scores and perceived disability using the disabilities of the arm, shoulder, and hand questionnaire scores from the in-patient discharge to the out-patient follow-up were also compared. A weak, yet positive correlation (r = .417, .451, P <= .001) between the proposed scale and the disabilities of the arm, shoulder, and hand questionnaire and the American Medical Association impairment scores was found, respectively. A receiver operating characteristic curve analysis revealed a cut-off score of 6.5 for the burn scar contracture severity scale, indicating that individuals scoring below a 6.5 returned to duty and those scoring above 6.5 did not return to duty. Results suggest that the burn scar contracture severity scale is able to discriminate between the individuals who returned to duty and those who did not return to duty. PMID- 25501772 TI - Three Years After Black Saturday: Long-Term Psychosocial Adjustment of Burns Patients as a Result of a Major Bushfire. AB - Despite increasing evidence that burn injuries can result in multiple psychological sequelae, little is known about the long-term psychosocial adjustment to burns sustained in a major bushfire. The aim of the present study was to assess long-term psychological distress and health-related quality of life in Australian burns patients as a result of the 2009 Black Saturday bushfires. Eight male and five female burns patients with a mean age of 53.92 (SD = 11.82) years who received treatment at a statewide burns service participated in the study. A battery of standardized questionnaires was administered to assess general psychological distress, burns-specific and generic health-related quality of life, alcohol use, and specific psychological symptoms of posttraumatic stress disorder, depression, and anxiety. The results revealed that more than 3 years after Black Saturday 33% of the burns patients still suffered "high" to "very high" levels of general distress, whereas 58% fulfilled partial or full criteria for posttraumatic stress disorder. Furthermore, participants still experienced significantly impaired physical health functioning as compared to their preinjury status including limitations in work-based activities, increased bodily pain, and lower vitality overall. The trajectory of distress varied for participants. Some individuals experienced little distress overall, whereas others displayed a decline in their stress levels over time. Notwithstanding, some patients maintained high levels of distress throughout or experienced an increase in distress at a later stage of recovery. The results point to the importance of psychosocial screening to identify distress early. Follow-up assessments are crucial to diagnose individuals with chronic or late onset of distress. PMID- 25501773 TI - Whole Arm Water Displacement Volumetry Is a Reliable and Sensitive Measure: A Pilot to Assess Acute Postburn Volume Change. AB - Water displacement volumetry (WDV) is a reliable method for measurement of wrist and hand volume in lymphedema patients. However, within session WDV reliability for the whole upper limb (UL) lacks comprehensive investigation, particularly in acute edema populations. This study aimed to confirm the reliability and investigate the impact of time between repeated trials on the sensitivity of WDV as a measure of whole UL volume change in an uninjured cohort and a burn injured pilot group. Within session, duplicate measures of whole UL WDV were recorded in two groups of noninjured volunteers and a group of burn patients. Each noninjured group differed only in the time between WDV repeats. The reliability trials were performed <10 minutes apart (T10) and 20 to 30 minutes apart (T20). The time between repetitions for burn patients was 20 to 30 minutes, based on the results of the noninjured participant trials. All trial groups demonstrated excellent correlation between trials (ICCT10 = 0.999, ICCT20 = 0.997). The minimum detectable difference calculated for WDV when measuring whole UL volume change of >50 ml for noninjured and >100 ml for burn patients. Despite this, a systematic bias was demonstrated between the T10 group means. The T20 group trials did not indicate such error on statistical testing (P = .297). The study confirms that WDV measurement of whole ULs is reliable and sensitive, if used at least 20 minutes apart. However, a significant and clinically relevant subject-by-method interaction was demonstrated. Researchers and clinicians are reminded to be aware of the performance of the technique when designing investigations in patient populations. PMID- 25501774 TI - Ventilator-Associated Pneumonia Prevention Bundle Significantly Reduces the Risk of Ventilator-Associated Pneumonia in Critically Ill Burn Patients. AB - Ventilator-associated pneumonia (VAP) is a common cause of morbidity and mortality for critically ill burn patients. Prevention of VAP through bundled preventative measures may reduce the risk and incidence of VAP in burn patients. A retrospective chart review was performed of all mechanically ventilated adult (age >= 18 years) burn patients before and after VAP prevention bundle implementation. Data collected included age, TBSA, gender, diagnosis of inhalation injury, mechanism of injury, comorbid illnesses, length of mechanical ventilation, length of hospital stay, development of VAP, discharge disposition, and mortality. Burn patients with VAP had larger burn injuries (47.6 +/- 22.2 vs 23.9 +/- 23.01), more inhalation injuries (44.6% vs 27%), prolonged mechanical ventilation, and longer intensive care unit (ICU) and hospital stays. Mortality was also higher in burn patients who developed VAP (34% vs 19%). On multivariate regression analysis, TBSA and ventilator days were independent risk factors for VAP. In 2010, a VAP prevention bundle was implemented in the burn ICU and overseen by a nurse champion. Compliance with bundle implementation was more than 95%. By 2012, independent of age, TBSA, inhalation injury, ventilator days, ICU and hospital length of stay, VAP prevention bundles resulted in a significantly reduced risk of developing VAP (odds ratio of 0.15). Burn patients with an inhalation injury and a large burn injury are at increased risk of developing VAP. The incidence and risk of VAP can be significantly reduced in burn patients with VAP prevention bundles. PMID- 25501775 TI - Cardiac Fatalities in Firefighters: An Analysis of the U.S. Fire Administration Database. AB - Cardiac fatalities are the leading cause of death among all firefighters. Increasing age has been linked to increased cardiac fatalities in firefighters; however, circumstances surrounding in-line-of-duty cardiac firefighter deaths can also increase the risk of a cardiac death. The authors hypothesize that cardiac fatalities among firefighters will be related to the type of duty and level of physical exertion. The authors analyzed the Firefighter Fatalities and Statistics data collected by the U.S. Fire Administration (http://apps.usfa.fema.gov/firefighter-fatalities/fatalityData/statistics) from January 2002 to December 2012. Data were analyzed for associations between age, firefighter classification, duty-type, and cause of fatal cardiac event. A total of 1153 firefighter fatalities occurred during the 10-year period reviewed. Of these, 47% were cardiac fatalities. Mean age was significantly higher in firefighters who suffered a cardiac fatality (52.0 +/- 11.4 +/- 40.8 +/- 14.7 years; P < .05). Volunteer firefighters suffered significantly higher proportion of cardiac fatalities (62%; P < .05) followed by career firefighters (32%). Additionally, cardiac fatalities were the leading cause of death for volunteer firefighters (54%; P < .05). The highest proportion of cardiac fatalities occurred on-the-scene (29%; P < .05) followed by after-duty fatalities (25%). Stress and overexertion accounted for 98% of the cause of cardiac fatalities. Adjusting for rank and firefighter classification, age (odds ratio, 1.06; 95% confidence interval, 1.05-1.08) and stress or overexertion (odds ratio, 11.9; 95% confidence interval, 1.7-83.4) were independent predictors of a firefighter cardiac fatality. Both career and volunteer firefighters are at significantly higher risk of a fatal cardiac event as they age. These fatalities occur in a significant proportion on-the-scene. National efforts should be aimed at these high-risk populations to improve cardiovascular health. PMID- 25501776 TI - Assisted Ventilation. AB - Controlled Mechanical Ventilation may be essential in the setting of severe respiratory failure but consequences to the patient including increased use of sedation and neuromuscular blockade may contribute to delirium, atelectasis, and diaphragm dysfunction. Assisted ventilation allows spontaneous breathing activity to restore physiological displacement of the diaphragm and recruit better perfused lung regions. Pressure Support Ventilation is the most frequently used mode of assisted mechanical ventilation. However, this mode continues to provide a monotonous pattern of support for respiration which is normally a dynamic process. Noisy Pressure Support Ventilation where tidal volume is varied randomly by the ventilator may improve ventilation and perfusion matching but the degree of support is still determined by the ventilator. Two more recent modes of ventilation, Proportional Assist Ventilation and Neurally Adjusted Ventilatory Assist (NAVA), allow patient determination of the pattern and depth of ventilation. Proposed advantages of Proportional Assist Ventilation and NAVA include decrease in patient ventilator asynchrony and improved adaptation of ventilator support to changing patient demand. Work of breathing can be normalized with these modes as well. To date, however, a clear pattern of clinical benefit has not been demonstrated. Existing challenges for both of the newer assist modes include monitoring patients with dynamic hyperinflation (auto positive end expiratory pressure), obstructive lung disease, and air leaks in the ventilator system. NAVA is dependent on consistent transduction of diaphragm activity by an electrode system placed in the esophagus. Longevity of effective support with this technique is unclear. PMID- 25501777 TI - The effect of transfers between health care facilities on costs and length of stay for pediatric burn patients. AB - Hospitals vary widely in the services they offer to care for pediatric burn patients. When a hospital does not have the ability or capacity to handle a pediatric burn, the decision often is made to transfer the patient to another short-term hospital. Transfers may be based on available specialty coverage for children; which adult and non-teaching hospitals may not have available. The effect these transfers have on costs and length of stay (LOS) has on pediatric burn patients is not well established and is warranted given the prominent view that pediatric hospitals are inefficient or more costly. The authors examined inpatient admissions for pediatric burn patients in 2003, 2006, and 2009 using the Kids' Inpatient Database, which is part of the Healthcare Cost and Utilization Project. ICD-9-CM codes 940 to 947 were used to define burn injury. The authors tested if transfer status was associated with LOS and total charges for pediatric burn patients, while adjusting for traditional risk factors (eg, age, TBSA, insurance status, type of hospital [pediatric vs adult; teaching vs nonteaching]) by using generalized linear mixed-effects modeling. A total of n = 28,777 children had a burn injury. Transfer status (P < .001) and TBSA (P < .001) was independently associated with LOS, while age, insurance status, and type of hospital were not associated with LOS. Similarly, transfer status (P < .001) and TBSA (P < .001) was independently associated with total charges, while age, insurance status, and type of hospital were not associated with total charges. In addition, the data suggest that the more severe pediatric burn patients are being transferred from adult and non-teaching hospitals to pediatric and teaching hospitals, which may explain the increased costs and LOS seen at pediatric hospitals. Larger more severe burns are being transferred to pediatric hospitals with the ability or capacity to handle these conditions in the pediatric population, which has a dramatic impact on costs and LOS. As a result, unadjusted, pediatric hospitals are seen as being inefficient in treating pediatric burns. However, since pediatric hospitals see more severe cases, after adjustment, type of hospital did not influence costs and LOS. TBSA and transfer status were the predictors studied that independently affect costs and LOS. PMID- 25501779 TI - A 15-year review of pediatric toxic epidermal necrolysis. AB - Owing to the rare, yet serious nature of toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), the authors would like to describe our experience with 41 pediatric patients to contribute to the current clinical understanding of the disease. From records at a single institution, 41 patients <=18 years of age with a diagnosis of SJS or TEN were retrospectively identified. Data were obtained from the hospital's medical record, and a variety of variables were collected, including causative agent, percentage of total body surface area (%TBSA) slough, ocular involvement, medical treatment, operative procedures, time to wound closure, ventilator days, intensive care unit length of stay, and associated hospital mortality. Of the pediatric TEN patients included, the mean epidermal sloughing was 39.7 +/- 26% TBSA. The presumptive inciting agent was a medication in 90% of cases. Mycoplasma pneumoniae was implicated in two cases (5%). The average time between onset of symptoms and burn intensive care unit admission was 3.6 +/- 2.0 days. Acutely, 73% of patients exhibited ocular involvement, 90% needed supplemental enteral nutritional support, and 51% required mechanical ventilation. On average, subjects spent 19.9 +/- 13.9 days in the intensive care unit. While acute mortality was 0%, 100% of patients still experienced long-term complications and 30% required follow-up procedures. When compared to current literature, the outcomes of our patients were similar to that of pediatric TEN at other institutions. While acute mortality is typically better within the pediatric population, patients still experience a significant level of morbidity and have serious long-term sequelae. PMID- 25501778 TI - Peripherally inserted central venous catheter safety in burn care: a single center retrospective cohort review. AB - The use of peripherally inserted central catheter (PICC) line for central venous access in thermally injured patients has increased in recent years despite a lack of evidence regarding safety in this patient population. A recent survey of invasive catheter practices among 44 burn centers in the United States found that 37% of burn units use PICC lines as part of their treatment protocol. The goal of this study was to compare PICC-associated complication rates with the existing literature in both the critical care and burn settings. The methodology involved is a single institution retrospective cohort review of patients who received a PICC line during admission to a regional burn unit between 2008 and 2013. Fifty three patients were identified with a total of seventy-three PICC lines. The primary outcome measurement for this study was indication for PICC line discontinuation. The most common reason for PICC line discontinuation was that the line was no longer indicated (45.2%). Four cases of symptomatic upper extremity deep vein thrombosis (5.5%) and three cases of central line-associated bloodstream infection (4.3%, 2.72 infections per 1000 line days) were identified. PICC lines were in situ an average of 15 days (range 1 to 49 days). We suggest that PICC line-associated complication rates are similar to those published in the critical care literature. Though these rates are higher than those published in the burn literature, they are similar to central venous catheter-associated complication rates. While PICC lines can be a useful resource in the treatment of the thermally injured patient, they are associated with significant and potentially fatal risks. PMID- 25501780 TI - Postburn Neck Lateral Contracture Anatomy and Treatment: A New Approach. AB - Lateral contracture of the neck is a rare and insufficiently researched burn consequent. Contracture restricts head motion, can cause a secondary face deformity, presents severe cosmetic defects, and, therefore, requires surgical reconstruction. Literature does not sufficiently address the issue; therefore, anatomy not researched and treatment techniques not developed. The anatomy of postburn lateral cervical flexion contracture was studied in 21 operated patients. Using obtained data, new approaches were investigated, which were directed toward maximal efficacy of the local tissues use. Follow-up results were observed from 6 months to 9 years. Lateral cervical contractures were divided into two types based on their anatomy: edge and medial. Edge contractures were caused by burns and scars located on the posterior neck surface and were characterized by the presence of the fold in central lateral zone. In the fold, only one (posterior) sheet is scars that cause the contracture. Medial contractures were caused by scars located on the lateral cervical surface and were characterized by the presence of the fold in which both sheets were scars. In both types, contracture was caused by scar sheet surface deficiency in length, which has a trapezoid form (contracture cause). In all cases, there was surface surplus in the fold's sheets allowed contracture release with local tissue. The technique that allows the maximum local tissue use and ensures full contracture elimination is the trapeze-flap plasty. Two anatomic types of lateral cervical scar contractures were identified: edge and medial. An anatomically justified efficacy reconstructive technique for both types is trapeze-flap plasty. PMID- 25501781 TI - Evidence-based prevent catheter-associated urinary tract infections guidelines and burn-injured patients: a pilot study. AB - The objective of this pilot study was to describe effectiveness of an evidence based guideline designed to prevent catheter-associated urinary tract infection (CA-UTI) in reducing CA-UTI in the burn-injured patient population. The study used a pre- and post-bundle implementation comparison design. Inclusion criteria included burn-injured patients of all ages with an indwelling urinary catheter. Patient demographic data were collected by medical record review when informed of a CA-UTI. The Rosswurm-Larrabee Model six-step process model guided implementation of practice change. The sample included eight burn-injured patients (7-88 years). Catheter day range was 1 to 27 days. Each patient had a clear indication for an indwelling urinary catheter; the need for accurate urinary output measurement in a critically injured patient. Four patients had a catheter placed twice during the stay. Nurses reported using a bladder scanner to assess bladder volume for post-operative patients with urinary retention avoiding use of an indwelling urinary catheter in some cases. Integration of evidence based guidelines in practice resulted in a reduced CA-UTI rate, reduced catheter days, increased days between CA-UTI, and outperformance of the national benchmark statistic. In 2013, the burn unit reduced catheter days by about 75% and reduced infection incidence by >90% in three quarters after implementation of the practice changes. The unit was able to sustain a CA-UTI rate of zero for 248 days. PMID- 25501782 TI - The Introduction of Standard Operating Procedures to Improve Burn Care in the United Kingdom. AB - United Kingdom (UK) burn units face substantial new obstacles in delivering high quality care because of the advent of full-shift working patterns, cross specialty cover arrangements, and increased trainee turnover. Junior trainees rely heavily on senior colleagues, who may not be readily accessible. The authors therefore proposed the introduction of standard operating procedures (SOPs), detailed written instructions used to achieve uniformity in performance and to improve outcomes. After undertaking a preliminary strength, weaknesses, opportunities, and threats analysis of their use locally and nationally, the authors set out to systematically develop burn-specific SOPs. The authors first mapped our existing local SOPs to the newly introduced UK national burn care pathway to specify gaps in coverage. The authors then administered a questionnaire to other UK burn units to identify SOPs already used elsewhere. Finally, the authors developed and piloted a robust pathway for the development, introduction, and auditing of new SOPs. The strength, weaknesses, opportunities, and threats analysis identified significant benefits and minimal risks. The mapping exercise identified specific deficiencies in our coverage of the national pathway. All 26 UK burn units responded to our questionnaire; only 12 had one or more SOPs (mean, 2.1). These covered initial assessment, inhalational injuries, drug prescribing, wound care, and gastric protection; none were audited. Locally, the authors have begun to develop the additional SOPs required. SOPs have not been instituted widely in the UK, despite the shift toward a standardized national care pathway and their association with improved outcomes. The authors hope that the systematic approach to their development and implementation demonstrates the feasibility of their wider use within UK regional burn centers and beyond. PMID- 25501783 TI - Successful Eradication of Multidrug Resistant Acinetobacter in the Helsinki Burn Centre. AB - Multidrug-resistant (MDR) Acinetobacter is an important pathogen implicated in nosocomial infections in healthcare environments. Virulence factors, resistance mechanisms, and limited therapeutic options make this pathogen a major problem currently facing burn intensive care units (ICUs) worldwide. The purpose of this study was to assess the effect of infection control measures taken in Helsinki Burn Centre in 2001 on MDR Acinetobacter prevalence in ICU burn patients. Data were retrospectively collected from patient files from 1998 to 2012. ICU burn patients were defined as those with either over 30% of total body surface area burnt or requiring mechanical ventilation. Inclusion criteria consisted of patients who tested positive for Acinetobacter sp. in routine bacterial cultures or cultures taken because of a clinically suspected infection. Infection control interventions performed in 2001 consisted of various shower room renovations and changes in hospital hygiene and burn treatment regimes. Between 1998 and 2012, 75 patients were diagnosed with Acinetobacter sp. colonization. Following the infection control interventions the incidence of Acinetobacter sp. radically declined. Between 1998 and 2001, there were 31 cases of MDR Acinetobacter colonizations diagnosed, but from 2002 to 2012 no MDR strains were found. Changes to hospital hygiene and wound treatment protocols as well as structural changes to the hospital environment can have a major impact on preventing and treating Acinetobacter outbreaks in burn centers. PMID- 25501784 TI - Alteration of Leukocyte Count Correlates With Increased Pulmonary Vascular Permeability and Decreased PaO2:FiO2 Ratio Early After Major Burns. AB - Leukocytes are activated systemically and their numbers increase soon after a burn followed by a rapid decline to low normal or subnormal levels, possibly by increased extravasation. Experimental data support that an important target for such extravasation is the lungs and that leukocytes when they adhere to endothelial cells cause an increase in vascular permeability. The authors investigated a possible relation between early increased pulmonary vascular permeability or a decreased PaO2:FiO2 ratio and the dynamic change in concentration of blood leukocytes after a burn. This is a prospective, exploratory, single-center study. The authors measured the dynamic changes of leukocytes in blood starting early after the burn, pulmonary vascular permeability index by thermodilution, and PaO2:FiO2-ratios in 20 patients during the first 21 days after a major burn (>20% TBSA%). Median TBSA was 40% interquartile range (IQR, 25-52) and full thickness burn 28% (IQR, 2-39). There was a correlation between the early (<24 hours) alteration in white blood cell count and both early increased pulmonary vascular permeability (r = .63, P = .004) and the decreased oxygenation index defined as PaO2:FiO2 < 27 kPa (P = .004). The authors have documented a correlation between dynamic change of blood leukocytes and pulmonary failure early after burns. PMID- 25501785 TI - Evaluation of Aquacel Ag for Autogenous Skin Donor Sites. AB - An ongoing objective of burn research is to evaluate wound dressings and develop new treatments to expedite wound healing. This was a single-center, prospective, randomized, controlled study to evaluate the effectiveness of Aquacel Ag as a dressing for autogenous skin donor sites compared with Xeroform. We hypothesized that donor sites treated with Aquacel Ag would heal faster. Patients were considered for enrollment if they required skin grafting with two donor sites >100 cm at least 2 inches apart. Dressings were observed daily starting on post op day #2 until discharge and then weekly in the outpatient burn clinic. Assessments evaluated pain, infection, and reapplication. Photographs were taken on post-op day #2, upon "90% re-epithelialization," and at post-op day #30-45. Scar assessments and blinded photographic reviews were completed to assess cosmetic healing. Twenty-nine patients completed the study. Re-epithelialization occurred faster with Xeroform (15.2 days vs. 17.6 days). Daily pain scores were higher with Xeroform (6.72 vs. 5.68) and Aquacel Ag needed to be replaced more often (1.72 times vs. 0.10 times). Three patients developed donor site infections with Aquacel Ag. Scar scores between the donor sites were not statistically significant. The blinded photo review concluded that Xeroform had a better cosmetic outcome (24 vs. 10%). Although patients complained of more pain with Xeroform, it demonstrated shorter healing times and better cosmetic outcomes. Aquacel Ag needed to be replaced more often and represented the only three donor site infections. PMID- 25501786 TI - Clothing Flammability and Burn Injuries: Public Opinion Concerning an Overlooked, Preventable Public Health Problem. AB - The objective of this study was to describe knowledge of clothing flammability risk, public support for clothing flammability warning labels, and stronger regulation to reduce the risk. As part of a national survey of homeowners about residential sprinkler systems, the authors included questions about clothing flammability. The authors used an online web panel to sample homeowners and descriptive methods to analyze the resulting data. The sample included 2333 homeowners. Knowledge of clothing flammability and government oversight of clothing flammability risk was low. Homeowners were evenly split about the effectiveness of current standards; however, when presented with clothing-related burn injury and death data, a majority (53%) supported stricter standards. Most homeowners (64%) supported warning labels and indicated that such labels would either have no effect on their purchasing decisions (64%) or be an incentive (24%) to purchase an item. Owners of sprinkler-equipped homes were more likely to support these interventions than owners of homes without sprinkler systems. Public knowledge about clothing flammability risks is low. Most homeowners supported clothing labels to inform consumers of this risk and increased government intervention to reduce the risk. PMID- 25501788 TI - The Social Network of a Burn Unit Team. AB - Effective team communication is critical in complex settings like hospital intensive care units. A social network analysis study was conducted in a burn intensive care unit, assuming physicians and key members of the nursing and clinical staff would occupy the core of a robust communication network. Clinical team members reported the frequency (0 to 3+ times) of discussion about patient care issues with every other coworker during a 24-hour period. We calculated the proportion of clinical team members completing the questionnaire, created a map (sociogram) of the network, identified central positions, and searched for weak points. A total of 69 coworkers were listed by 48 clinical team members (70% completion rate). There were 626 connections (arcs) present (density = 13.3%). The analysis revealed three distinct sets of team members caring for two sets of patients. The five clinical team members most central to the network included three physicians, a social worker, and a dietitian. We established the feasibility of collecting social network data on this medical team and identified robust communication patterns. This study will be used to guide subsequent data collection from this and other clinical teams to correlate team structural features with clinical process outcomes and patient safety. PMID- 25501787 TI - Recovery trajectories after burn injury in young adults: does burn size matter? AB - The impact of burn size on mortality is well known, but the association of burn size with the trajectories of long-term functional outcomes remains poorly studied. This prospective multi-center study included burned adults ages 19 to 30 years who completed the Young Adult Burn Outcome Questionnaire at initial baseline contact, 2 weeks, and at 6 and 12 months after initial questionnaire administration. Non-burned adults of comparable ages also completed the questionnaire as a reference group. The association between functional recovery and TBSA burned was analyzed longitudinally using generalized linear models with the generalized estimation equation technique. Functional status was characterized in 15 domains: physical function, fine motor function, pain, itch, social function limited by physical function, perceived appearance, social function limited by appearance, sexual function, emotion, family function, family concern, satisfaction with symptom relief, satisfaction with role, work reintegration, and religion. Scores were standardized to a mean of 50 and a SD of 10 based on non-burned controls. There were 153 burned and 112 non-burned subjects with a total of 620 questionnaires. TBSA burned was 11 +/- 14% (mean +/- SD); 31% had face involvement and 57% had hand involvement. The lag time from burn injury to questionnaire administration was on average 7 +/- 7.7 months, with a maximum of 36 months. Lower recovery levels were associated with increasing burn size for physical function, pain, itch, work reintegration, emotion, satisfaction with symptom relief, satisfaction with role, family function, and family concern (P value ranged from .04-<.0001). No significant differences in recovery levels were found with increasing burn size for fine motor function, social function limited by physical function, sexual function, and religion; these areas tracked toward the age-matched non-burned group regardless of burn size. Perceived appearance and social function limited by appearance remained below the non-burn levels throughout the 3-year period regardless of burn size. Three-year recovery trajectories of survivors with larger burn size showed improvements in most areas, but these improvements lagged behind those with smaller burns. Poor perceived appearance was persistent and prevalent regardless of burn size and was found to limit social function in these young adult burn survivors. Expectations for multidimensional recovery from burns in young adults can be benchmarked based on burn size with important implications for patient monitoring and intervening in clinical care. PMID- 25501790 TI - The accuracy of three predictive models in the evaluation of recurrence rates for gastrointestinal stromal tumors. AB - BACKGROUND: Treatment decisions for gastrointestinal stromal tumors (GIST) are frequently guided by tumor characteristics. An accurate prediction of recurrence is important to determine the benefit from targeted therapy. Our goal was to compare the concordance of three validated risk stratification schemes with observed outcomes in patients undergoing resection for GISTs. METHODS: Patients who underwent surgery for GISTs from 2001 to 2011 at a tertiary centre were identified. Survival was evaluated using the Kaplan-Meier product-limit method. Cox proportional hazard models were used to obtain predicted recurrence for each system and concordance indices were calculated. RESULTS: Of 110 patients identified, 77 (70.0%) had surgery and 29 (26.4%) also received adjuvant therapy. The majority of patients had tumors that were very low (4.5%), low (32.7%), or intermediate (22.7%) in terms of malignant potential. R0 resection was achieved in 89.1% of cases. Observed 2-year and 5-year recurrence rates were significantly lower than those predicted by the Memorial Sloan Kettering Cancer Center nomogram (7.6% vs. 19.3% and 18.4% vs. 27.0%); however, it was the most favorable tool compared to the US National Institutes of Health (NIH)-consensus (P = 0.0017) and modified NIH-consensus (P < 0.001), with a concordance index of 0.811. CONCLUSION: Development of a novel predictive tool that includes additional prognostic factors may better stratify recurrence following resection for GIST. PMID- 25501789 TI - Neutrophil Accumulation in the Small Intestine Contributes to Local Tissue Destruction Following Combined Radiation and Burn Injury. AB - The threat of nuclear disaster makes combined radiation and burn injury (CRI) a relevant topic when discussing modern trauma, as burn injuries are likely to occur with detonation of a conventional nuclear weapon. Previous studies in a murine model have shown that there is a breakdown of the gut epithelium and subsequent bacterial translocation into mesenteric lymph nodes after CRI. This study examines the early innate immune response of the small intestine after CRI. Using a previously established murine model of 5 to 5.5 Gy total body irradiation combined with 15% TBSA burn, the injury response of the small intestine was examined at 24, 48, and 72 hours by visual assessment, myeloperoxidase, and cytokine measurement. At 24 hours, intestinal damage as measured by villus blunting, crypt debris, and decreased mitosis, was apparent in all injury groups but the derangements persisted out to 72 hours only with CRI. The prolonged intestinal damage in CRI was accompanied by a 2-fold (P < .05) elevation in myeloperoxidase activity over sham animals at 48 hours and persisted as a 3-fold (P < .05) elevation at 72 hours after injury. Corresponding levels of KC were 8 fold (P < .05) higher than sham at 48 hours with persistent elevation at 72 hours. An enhanced innate immune response, partially mediated by the influx of neutrophils into the gastrointestinal tract is contributing to the hyperinflammatory state seen after CRI. Attenuation of the local gastrointestinal inflammatory response may play a major role in managing victims after nuclear disaster. PMID- 25501792 TI - Evaluation of the nutritional quality of the grain protein of new amaranths varieties. AB - The efforts for promoting the consumption of food of plant origin are increasingly growing. The amaranth grain is an important vegetable protein source, superior in content and quality to traditional cereals. In the central west region of Argentina, new amaranth varieties have been obtained to optimize its agronomic traits and promote its use. In this work, the analysis of the wholemeal flour protein from seeds of two new varieties of Amaranthus cruentus var. Candil (CC) and Amaranthus hypochondriacus var. Dorado (HD), as well as from advanced lines of Amaranthus hypochondriacus x Amaranthus cruentus H17a (H17) and Amaranthus cruentus G6/17a (CG6), was carried out in order to elucidate their nutritional contribution to human diet. The amino acids profile and the chemical score (CS) were determined, and the protein quality was evaluated in-vivo through the following indexes: net protein utilization (NPU), true digestibility (tD), biological value (BV) and protein digestibility corrected amino acid score (PDCAAS). In general, the amino acids values of the different varieties exceeded the requirements established by the WHO/FAO/UNU; however, valine was the limiting amino acid in all cases. The values obtained (%) were within the following ranges: NPU, 33.56-46.04%; tD, 68.80-75.40%; BV, 44.53-64.28%; and PDCAAS, 23.69 36.19%. These results suggest that the new amaranth flours varieties can be adequate for human consumption and as complementary protein source. PMID- 25501791 TI - N-Heterocyclic carbene-catalyzed [4 + 2] cyclization of 2-bromo-2-enal with 3 alkylenyloxindoles: efficient assembly of spirocarbocyclic oxindole. AB - A NHC-catalyzed [4 + 2] cyclization of 2-bromo-2-enal bearing gamma-H with 3 alkylenyloxindoles under mild reaction conditions gives spirocarbocyclic oxindoles containing one quaternary carbon in moderate to good yields with high diastereoselectivities. The easy availability of the starting materials, the concise assembly and the potential utilization value of the products make this strategy attractive in molecular biology and pharmacy. PMID- 25501793 TI - Cytotoxic polyketides from the deep-sea-derived fungus Engyodontium album DFFSCS021. AB - Eight new chromones, engyodontiumones A-H (1-8), and three new phenol derivatives (9-11) together with eight known polyketides (12-19) were isolated from the deep sea-derived fungus Engyodontium album DFFSCS021. Their structures were identified by extensive spectroscopic analysis. Compounds 8 and 16 showed significant selective cytotoxicity against human histiocytic lymphoma U937 cell line with IC50 values of 4.9 and 8.8 MUM, respectively. In addition, this is the first time to report that 8, 15 and 16 had mild antibacterial activity against Escherichia coli and Bacillus subtilis, and 15 showed potent antilarval activity against barnacle Balanus amphitrite larval settlement. PMID- 25501794 TI - Marine Pseudovibrio sp. as a novel source of antimicrobials. AB - Antibiotic resistance among pathogenic microorganisms is becoming ever more common. Unfortunately, the development of new antibiotics which may combat resistance has decreased. Recently, however the oceans and the marine animals that reside there have received increased attention as a potential source for natural product discovery. Many marine eukaryotes interact and form close associations with microorganisms that inhabit their surfaces, many of which can inhibit the attachment, growth or survival of competitor species. It is the bioactive compounds responsible for the inhibition that is of interest to researchers on the hunt for novel bioactives. The genus Pseudovibrio has been repeatedly identified from the bacterial communities isolated from marine surfaces. In addition, antimicrobial activity assays have demonstrated significant antimicrobial producing capabilities throughout the genus. This review will describe the potency, spectrum and possible novelty of the compounds produced by these bacteria, while highlighting the capacity for this genus to produce natural antimicrobial compounds which could be employed to control undesirable bacteria in the healthcare and food production sectors. PMID- 25501795 TI - Sargassopenillines A-G, 6,6-spiroketals from the alga-derived fungi Penicillium thomii and Penicillium lividum. AB - Seven new 6,6-spiroketals, sargassopenillines A-G (1-7) were isolated from the alga-derived fungi Penicillium thomii KMM 4645 and Penicillium lividum KMM 4663. The structures of these metabolites were determined by HR-MS and 1D and 2D NMR. The absolute configurations of compounds 1, 5 and 6 were assigned by the modified Mosher's method and by CD data. Sargassopenilline C (3) inhibited the transcriptional activity of the oncogenic nuclear factor AP-1 with an IC50 value of 15 uM. PMID- 25501797 TI - Prostate histoscanning true targeting guided prostate biopsy: initial clinical experience. AB - OBJECTIVE: To evaluate the feasibility of prostate histoscanning true targeting (PHS-TT) guided transrectal ultrasound (TRUS) biopsy. METHODS: This is a prospective, single center, pilot study performed during February 2013-September 2013. All consecutive patients planned for prostate biopsy were included in the study, and all the procedure was performed by a single surgeon aided by the specialized true targeting software. Initially, the patients underwent PHS to map the abnormal areas within the prostate that were >=0.2 cm(3). TRUS guided biopsies were performed targeting the abnormal areas with a specialized software. Additionally, routine bisextant biopsies were also taken. The final histopathology of the target cores was compared with the bisextant cores. RESULTS: A total of 43 patients underwent combined 'targeted PHS guided' and 'standard 12 core systematic' biopsies. The mean volume of abnormal area detected by PHS is 4.3 cm(3). The overall cancer detection rate was 46.5 % (20/43) with systemic cores and target cores detecting cancer in 44 % (19/43) and 26 % (11/43), respectively. The mean % cancer/core length of the PHS-TT cores were significantly higher than the systematic cores (55.4 vs. 37.5 %. p < 0.05). In biopsy naive patients, the cancer detection rate (43.7 % vs. 14.8 %. p = 0.06) and the cancer positivity of the cores (30.1 vs. 6.8 %. p < 0.01) of target cores were higher than those patients with prior biopsies. CONCLUSION: PHS-TT is feasible and can be an effective tool for real-time guidance of prostate biopsies. PMID- 25501798 TI - 5-azacytidine enhances efficacy of multiple chemotherapy drugs in AML and lung cancer with modulation of CpG methylation. AB - The DNA methyltransferase (DNMT) inhibitory drugs such as 5-azacytidine induce DNA hypomethylation by inhibiting DNA methyltransferases. While clinically effective, DNMT inhibitors are not curative. A combination with cytotoxic drugs might be beneficial, but this is largely unexplored. In the present study, we analyzed potential synergisms between cytotoxic drugs and 5-azacytidine in acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC) cells. Lung cancer and leukemia cell lines were exposed to low doses of 5-azacytidine with varying doses of cytarabine or etoposide for AML cells (U937 and HL60) as well as cisplatin or gemcitabine for NSCLC cells (A549 and HTB56) for 48 h. Drug interaction and potential synergism was analyzed according to the Chou-Talalay algorithm. Further analyses were based on soft agar colony formation assays, active caspase-3 staining and BrdU incorporation flow cytometry. To identify effects on DNA methylation patterns, we performed genome wide DNA methylation analysis using 450K bead arrays. Azacytidine at low doses was synergistic with cytotoxic drugs in NSCLC and in AML cell lines. Simultaneous exposure to 5 azacytidine with cytotoxic drugs showed strong synergistic activity. In colony formation assays these synergisms were repeatedly verified for 5-azacytidine (25 nM) with low doses of anticancer agents. 5-azacytidine neither affected the cell cycle nor increased apoptosis. 450K methylation bead arrays revealed 1,046 CpG sites in AML and 1,778 CpG sites in NSCLC cells with significant DNA hypomethylation (24-h exposure) to 5-azacytidine combined with the cytotoxic drugs. These CpG-sites were observed in the candidate tumor-suppressor genes MGMT and THRB. Additional incubation time after 24-h treatment led to a 4.1-fold increase of significant hypomethylated CpG-sites in NSCLC cells. These results suggest that the addition of DNA demethylating agents to cytotoxic anticancer drugs exhibits synergistic activity in AML and NSCLC. Dysregulation of an equilibrium of DNA methylation in cancer cells might increase the susceptibility for cytotoxic drugs. PMID- 25501799 TI - A feasibility study to determine the potential of in vivo detection of gadolinium by x-ray fluorescence (XRF) following gadolinium-based contrast-enhanced MRI. AB - The feasibility of using a (109)Cd gamma-ray induced K x-ray fluorescence (K-XRF) system for the in vivo detection of gadolinium (Gd) in bone has been investigated. The K-XRF bone measurement system employs an array of four detectors, and is normally used for the non-invasive study of bone lead levels. The system was used to measure bone simulating phantoms doped with varying levels of gadolinium and fixed amounts of sodium (Na), chlorine (Cl) and calcium (Ca). The detection limits for bare bone phantoms, using a source of activity 0.17 GBq, were determined to be 3.9 ppm and 6.5 ppm (ug Gd per gram phantom) for the Kalpha1 and Kalpha2 Gd x-ray peaks, respectively. This leads to an overall detection limit of 3.3 ppm (ug Gd per gram phantom). Layers of plastic were used to simulate overlying soft tissue and this permitted prediction of a detection limit, using the current strength of our radioisotope source, of 6.1 ppm to 8.6 ppm (ug Gd per gram phantom) for fingers with 2-4 mm of overlying tissue. With a new source of activity 5 GBq, we predict that this system could achieve a detection limit of 4-5.6 ug Gd g(-1) Ca. This is within the range of levels (2-30 ug Gd g(-1) Ca) previously found in the bone of patients receiving Gd based contrast imaging agents. The technique is promising and warrants further investigation. PMID- 25501796 TI - Atlantic salmon (Salmo salar L.) as a marine functional source of gamma tocopherol. AB - Gamma tocopherol (gT) exhibits beneficial cardiovascular effects partly due to its anti-inflammatory activity. Important sources of gT are vegetable oils. However, little is known to what extent gT can be transferred into marine animal species such as Atlantic salmon by feeding. Therefore, in this study we have investigated the transfer of dietary gT into salmon. To this end, fish were fed a diet supplemented with 170 ppm gT for 16 weeks whereby alpha tocopherol levels were adjusted to 190 ppm in this and the control diet. Feeding gT-rich diets resulted in a three-fold increase in gT concentrations in the liver and fillet compared to non-gT-supplemented controls. Tissue alpha tocopherol levels were not decreased indicating no antagonistic interaction between gamma- and alpha tocopherol in salmon. The concentration of total omega 3 fatty acids slightly increased in response to dietary gT. Furthermore, dietary gT significantly decreased malondialdehyde in the fillet, determined as a biomarker of lipid peroxidation. In the liver of gT fed salmon we observed an overall down regulation of genes involved in lipid homeostasis. Additionally, gT improved the antioxidant capacity by up-regulating Gpx4a gene expression in the pyloric caeca. We suggest that Atlantic salmon may provide a marine functional source capable of enriching gT for human consumption. PMID- 25501800 TI - Incidence of ischemic stroke in Japanese patients with atrial fibrillation not receiving anticoagulation therapy--pooled analysis of the Shinken Database, J RHYTHM Registry, and Fushimi AF Registry. AB - BACKGROUND: The incidence rate of ischemic stroke in Japanese non-valvular atrial fibrillation (NVAF) patients without anticoagulation therapy remains unclear. METHODS AND RESULTS: We performed a pooled analysis of 3,588 patients from the Shinken Database (n=1,099), J-RHYTHM Registry (n=1,002), and Fushimi AF Registry (n=1,487) to determine the incidence rate of ischemic stroke in Japanese NVAF patients without anticoagulation therapy. Average patient age was 68.1 years. During the follow-up period (total, 5,188 person-years; average, 1.4 years), 69 patients suffered from ischemic stroke (13.3 per 1,000 person-years; 95% confidence intervals [CI]: 10.5-16.8). The incidence rates of ischemic stroke were 5.4, 9.3, and 24.7 per 1,000 person-years and 5.3, 5.5, and 18.4 per 1,000 person-years in patients with low (0), intermediate (1), and high (>= 2) CHADS2 and CHA2DS2-VASc scores, respectively. History of ischemic stroke or transient ischemic attack (hazard ratio [HR], 3.25; 95% CI: 1.86-5.67), age >= 75 years (HR, 2.31; 95% CI: 1.18-4.52), and hypertension (HR, 1.69; 95% CI: 1.01-2.86) were independent risk factors for ischemic stroke. CONCLUSIONS: A low incidence rate of ischemic stroke was observed in Japanese NVAF patients except for those with CHADS2 score >= 2. In this pooled analysis, history of ischemic stroke or transient ischemic attack, advanced age, and hypertension were identified as independent risk factors for ischemic stroke. PMID- 25501801 TI - Efficacy and safety of non-vitamin K antagonist oral anticoagulants vs. warfarin in Japanese patients with atrial fibrillation - meta-analysis. AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOAC) have been developed as alternatives to warfarin. Until recently, the latter was the standard oral anticoagulant for patients with non-valvular atrial fibrillation (NVAF). The efficacy and safety of NOAC in Japanese patients with NVAF has been investigated in small trials or subgroups from global randomized control trials (RCT). METHODS AND RESULTS: We conducted a systematic review and meta-analysis of RCT, to compare the efficacy and safety of NOAC to those of warfarin in Japanese patients with NVAF. Published research was systematically searched for RCT that compared NOAC to warfarin in Japanese patients with NVAF. Random-effects models were used to pool efficacy and safety data across RCT. Three studies, involving 1,940 patients, were identified. Patients randomized to NOAC had a decreased risk for stroke and systemic thromboembolism (relative risk [RR], 0.45; 95% CI: 0.24 0.85), with a non-significant trend for lower major bleeding (RR, 0.66; 95% CI: 0.29-1.47), intracranial bleeding (RR, 0.46; 95% CI: 0.18-1.16) and gastrointestinal bleeding (RR, 0.52; 95% CI: 0.25-1.08). CONCLUSIONS: NOAC are more efficacious than warfarin for the prevention of stroke and systemic embolism in Japanese patients with NVAF. The present findings offer clinicians a more comprehensive picture of NOAC as a therapeutic option to reduce the risk of stroke in Japanese NVAF patients. PMID- 25501802 TI - Intravitreal ranibizumab for the treatment of choroidal neovascularizations associated with pathologic myopia: a prospective study. AB - PURPOSE: It was the aim of this study to determine the efficacy of intravitreal ranibizumab as treatment of choroidal neovascularizations associated with pathologic myopia. MATERIALS AND METHODS: In an uncontrolled, prospective time series cohort study, 65 eyes of 64 consecutive patients with choroidal neovascularization associated with pathologic myopia were treated with intravitreal ranibizumab and observed over 12 months. The change in best corrected visual acuity (BCVA) at 6 and 12 months served as primary end point. Safety, central retinal thickness, neovascularization activity on fluorescein angiography and the number of ranibizumab injections were secondary end points. RESULTS: BCVA improved significantly throughout the follow-up (p = 0.001). The mean BCVA was 0.2 at baseline (SD 0.13) and 0.4 at 12 months (SD 0.21). Improvement was strongest within the first 3 months (p = 0.0001). The mean central retinal thickness showed a reduction from 313 MUm (SD 82) to 243.5 MUm (SD 31; p = 0.0001). CONCLUSION: Intravitreal ranibizumab offers a safe and effective treatment for choroidal neovascularizations in pathologic myopia. PMID- 25501803 TI - Quantitative superresolution microscopy reveals differences in nuclear DNA organization of multiple myeloma and monoclonal gammopathy of undetermined significance. AB - The mammalian nucleus has a distinct substructure that cannot be visualized directly by conventional microscopy. In this study, the organization of the DNA within the nucleus of multiple myeloma (MM) cells, their precursor cells (monoclonal gammopathy of undetermined significance; MGUS) and control lymphocytes of the representative patients is visualized and quantified by superresolution microscopy. Three-dimensional structured illumination microscopy (3D-SIM) increases the spatial resolution beyond the limits of conventional widefield fluorescence microscopy. 3D-SIM reveals new insights into the nuclear architecture of cancer as we show for the first time that it resolves organizational differences in intranuclear DNA organization of myeloma cells in MGUS and in MM patients. In addition, we report a significant increase in nuclear submicron DNA structure and structure of the DNA-free space in myeloma nuclei compared to normal lymphocyte nuclei. Our study provides previously unknown details of the nanoscopic DNA architecture of interphase nuclei of the normal lymphocytes, MGUS and MM cells. This study opens new avenues to understanding the disease progression from MGUS to MM. PMID- 25501804 TI - BDNF plasma levels variations in major depressed patients receiving duloxetine. AB - It has been frequently reported that brain-derived neurotrophic factor (BDNF) plays an important role in the pathophysiology of major depressive disorder (MDD). Objective of the study was to investigate BDNF levels variations in MDD patients during antidepressant treatment with duloxetine. 30 MDD patients and 32 healthy controls were assessed using Hamilton Depression Scale (HAM-D) and monitored for BDNF plasma levels at baseline, week 6 and week 12 of duloxetine treatment (60 mg/day) and at baseline, respectively. According to early clinical response to duloxetine (defined at week 6 by reduction >50 % of baseline HAM-D score), MDD patients were distinguished in early responders (ER) and early non responders (ENR), who reached clinical response at week 12. Laboratory analysis showed significant lower baseline BDNF levels among patients compared to controls. During duloxetine treatment, in ENR BDNF levels increased, reaching values not significantly different compared to controls, while in ER BDNF levels remained nearly unchanged. Lower baseline BDNF levels observed in patients possibly confirm an impairment of the NEI stress-adaptation system and neuroplasticity in depression, while BDNF increase and normalization observed only in ENR might suggest differential neurobiological backgrounds in ER vs. ENR within the depressive syndrome. PMID- 25501805 TI - Full remission in a patient with catheter-associated ventriculitis due to Acinetobacter baumannii treated with intrathecal and intravenous colistin besides coinfections with other multidrug-resistant bacteria. PMID- 25501806 TI - Paradoxical benefits of dual-task contexts for visuomotor memory. AB - It is generally thought that increased attention helps when one is learning a new task. However, using a dual-task paradigm, we showed that the rate of visuomotor learning was the same regardless of attentional distraction caused by a secondary task. Yet, when participants were tested later, a motor skill learned under distraction was remembered only when a similar distraction was present; when participants were tested without the distracting task, their performance reverted to untrained levels. This paradoxical result, in which the level of performance decreases when more attentional resources are available, suggests that the dual task context, or the lack thereof, acts as a vital context for learning. This task-context-dependent "savings" was evident even when the specific secondary task or sensory modality differed between learning and recall; thus, the dual tasking, rather than the specific stimuli, provides context. This discovery suggests that the success of learning and rehabilitation programs may be diminished if they are developed without consideration of the role of task contexts. PMID- 25501807 TI - aPKC alters the TGFbeta response in NSCLC cells through both Smad-dependent and Smad-independent pathways. AB - Transforming growth factor b (TGFb) signaling controls many cellular responses including proliferation, epithelial to mesenchymal transition and apoptosis, through the activation of canonical (Smad) as well as non-canonical (e.g., Par6) pathways. Previous studies from our lab have demonstrated that aPKC inhibition regulates TGFb receptor trafficking and signaling. Here, we report that downstream TGFb-dependent transcriptional responses in aPKC-silenced NSCLC cells were reduced compared with those of control cells, despite a temporal extension of Smad2 phosphorylation. We assessed SARA-Smad2-Smad4 association and observed that knockdown of aPKC increased SARA (also known as ZFYVE9) levels and SARA Smad2 complex formation, increased cytoplasmic retention of Smad2 and reduced Smad2-Smad4 complex formation, which correlated with reduced Smad2 nuclear translocation. Interestingly, we also detected an increase in p38 MAPK phosphorylation and apoptosis in aPKC-silenced cells, which were found to be TRAF6-dependent. Taken together, our results suggest that aPKC isoforms regulate Smad and non-Smad TGFb pathways and that aPKC inhibition sensitizes NSCLC cells to undergo TGFb dependent apoptosis. PMID- 25501808 TI - FRNK negatively regulates IL-4-mediated inflammation. AB - Focal adhesion kinase (FAK)-related nonkinase (PTK2 isoform 6 in humans, hereafter referred to as FRNK) is a cytoskeletal regulatory protein that has recently been shown to dampen lung fibrosis, yet its role in inflammation is unknown. Here, we show for the first time that expression of FRNK negatively regulates IL-4-mediated inflammation in a human model of eosinophil recruitment. Mechanistically, FRNK blocks eosinophil accumulation, firm adhesion and transmigration by preventing transcription and protein expression of VCAM-1 and CCL26. IL-4 activates STAT6 to induce VCAM-1 and CCL26 transcription. We now show that IL-4 also increases GATA6 to induce VCAM-1 expression. FRNK blocks IL-4 induced GATA6 transcription but has little effect on GATA6 protein expression and no effect on STAT6 activation. FRNK can block FAK or Pyk2 signaling and we, thus, downregulated these proteins using siRNA to determine whether signaling from either protein is involved in the regulation of VCAM-1 and CCL26. Knockdown of FAK, Pyk2 or both had no effect on VCAM-1 or CCL26 expression, which suggests that FRNK acts independently of FAK and Pyk2 signaling. Finally, we found that IL 4 induces the late expression of endogenous FRNK. In summary, FRNK represents a novel mechanism to negatively regulate IL-4-mediated inflammation. PMID- 25501809 TI - Opposing roles for JNK and Aurora A in regulating the association of WDR62 with spindle microtubules. AB - WD40-repeat protein 62 (WDR62) is a spindle pole protein required for normal cell division and neuroprogenitor differentiation during brain development. Microcephaly-associated mutations in WDR62 lead to mitotic mislocalization, highlighting a crucial requirement for precise WDR62 spatiotemporal distribution, although the regulatory mechanisms are unknown. Here, we demonstrate that the WD40-repeat region of WDR62 is required for microtubule association, whereas the disordered C-terminal region regulates cell-cycle-dependent compartmentalization. In agreement with a functional requirement for the WDR62-JNK1 complex during neurogenesis, WDR62 specifically recruits JNK1 (also known as MAPK8), but not JNK2 (also known as MAPK9), to the spindle pole. However, JNK-mediated phosphorylation of WDR62 T1053 negatively regulated microtubule association, and loss of JNK signaling resulted in constitutive WDR62 localization to microtubules irrespective of cell cycle stage. In contrast, we identified that Aurora A kinase (AURKA) and WDR62 were in complex and that AURKA-mediated phosphorylation was required for the spindle localization of WDR62 during mitosis. Our studies highlight complex regulation of WDR62 localization, with opposing roles for JNK and AURKA in determining its spindle association. PMID- 25501810 TI - LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease, but the precise physiological function of the protein remains ill defined. Recently, our group proposed a model in which LRRK2 kinase activity is part of an EndoA phosphorylation cycle that facilitates efficient vesicle formation at synapses in the Drosophila melanogaster neuromuscular junctions.Flies harbor only one Lrrk gene, which might encompass the functions of both mammalian LRRK1 and LRRK2. We therefore studied the role of LRRK2 in mammalian synaptic function and provide evidence that knockout or pharmacological inhibition of LRRK2 results in defects in synaptic vesicle endocytosis, altered synaptic morphology and impairments in neurotransmission. In addition, our data indicate that mammalian endophilin A1 (EndoA1,also known as SH3GL2) is phosphorylated by LRRK2 in vitro at T73 and S75, two residues in the BAR domain. Hence, our results indicate that LRRK2 kinase activity has an important role in the regulation of clathrin-mediated endocytosis of synaptic vesicles and subsequent neurotransmission at the synapse. PMID- 25501811 TI - The dynamic conformational landscape of gamma-secretase. AB - The structure and function of the gamma-secretase proteases are of great interest because of their crucial roles in cellular and disease processes. We established a novel purification protocol for the gamma-secretase complex that involves a conformation- and complex-specific nanobody, yielding highly pure and active enzyme. Using single particle electron microscopy, we analyzed the gamma secretase structure and its conformational variability. Under steady-state conditions, the complex adopts three major conformations, which differ in overall compactness and relative position of the nicastrin ectodomain. Occupancy of the active or substrate-binding sites by inhibitors differentially stabilizes subpopulations of particles with compact conformations, whereas a mutation linked to familial Alzheimer disease results in enrichment of extended-conformation complexes with increased flexibility. Our study presents the csecretase complex as a dynamic population of interconverting conformations, involving rearrangements at the nanometer scale and a high level of structural interdependence between subunits. The fact that protease inhibition or clinical mutations, which affect amyloid beta (Abeta) generation, enrich for particular subpopulations of conformers indicates the functional relevance of the observed dynamic changes, which are likely to be instrumental for highly allosteric behavior of the enzyme. PMID- 25501812 TI - The NuRD nucleosome remodelling complex and NHK-1 kinase are required for chromosome condensation in oocytes. AB - Chromosome condensation during cell division is one of the most dramatic events in the cell cycle. Condensin and topoisomerase II are the most studied factors in chromosome condensation. However, their inactivation leads to only mild defects and little is known about the roles of other factors. Here, we took advantage of Drosophilaoocytes to elucidate the roles of potential condensation factors by performing RNA interference (RNAi). Consistent with previous studies, depletion of condensin I subunits or topoisomerase II in oocytes only mildly affected chromosome condensation. In contrast, we found severe undercondensation of chromosomes after depletion of the Mi-2-containing NuRD nucleosome remodelling complex or the protein kinase NHK-1 (also known as Ballchen in Drosophila). The further phenotypic analysis suggests that Mi-2 and NHK-1 are involved in different pathways of chromosome condensation. We show that the main role of NHK 1 in chromosome condensation is to phosphorylate Barrier-to-autointegration factor (BAF) and suppress its activity in linking chromosomes to nuclear envelope proteins. We further show that NHK-1 is important for chromosome condensation during mitosis as well as in oocytes. PMID- 25501813 TI - Segregation of VE-cadherin from the LBRC depends on the ectodomain sequence required for homophilic adhesion. AB - The lateral border recycling compartment (LBRC) is a reticulum ofperijunctional tubulovesicular membrane that is continuous with the plasmalemma of endothelial cells and is essential for efficient transendothelial migration (TEM) of leukocytes. The LBRC contains molecules involved in TEM, such as PECAM, PVR and CD99, but not VE-cadherin. Despite its importance, how membrane proteins are included in or excluded from the LBRC is not known. Immunoelectronmicroscopy and biochemical approaches demonstrate that inclusion into the LBRC is the default pathway for transmembrane molecules present at endothelial cell borders. A chimeric molecule composed of the extracellular domain of VE-cadherin and cytoplasmic tail of PECAM (VE-CAD/PECAM) did not enter the LBRC, suggesting that VE-cadherin was excluded by a mechanism involving its extracellular domain. Deletion of the homophilic interaction domain EC1 or the homophilic interaction motif RVDAE allowed VE-CAD/PECAM and even native VE-cadherin to enter the LBRC. Similarly, treatment with RVDAE peptide to block homophilic VE-cadherin interactions allowed endogenous VE-cadherin to enter the LBRC. This suggests that homophilic interactions of VE-cadherin stabilize it at cell borders and prevent entry into the LBRC. PMID- 25501814 TI - The septation initiation network controls the assembly of nodes containing Cdr2p for cytokinesis in fission yeast. AB - In the fission yeast Schizosaccharomyces pombe, cortical protein structures called interphase nodes help to prepare the cell for cytokinesis by positioning precursors of the cytokinetic contractile ring, and the septation initiation network (SIN) regulates the onset of cytokinesis and septum formation. Previous work has noted that one type of interphase node disappears during mitosis providing SIN activity is high. Here, we used time-lapse fluorescence microscopy to provide evidence that SIN activity is necessary and sufficient to disperse the type 1 node proteins Cdr2p and Mid1p into the cytoplasm, so these nodes assemble only during interphase through early mitosis when SIN activity is low. Activating the SIN in interphase cells dispersed Cdr2p and anillin Mid1p from type 1 nodes a few min after the SIN kinase Cdc7p-GFP accumulated at spindle pole bodies. If the SIN was then turned off in interphase cells, Cdr2p and Mid1p reappeared in nodes in parallel with the decline in SIN activity. Hyperactivating SIN during mitosis dispersed type 1 nodes earlier than normal, and prolonged SIN activation prevented nodes from reforming at the end of mitosis. PMID- 25501815 TI - A non-mitotic role for Aurora kinase A as a direct activator of cell migration upon interaction with PLD, FAK and Src. AB - Timely activation of Aurora kinase A (AURA, also known as AURKA) is vital for centrosome formation and the progression of mitosis. Nonetheless, it is still unclear if and when other cellular functions are activated by AURA. We report here that Src phosphorylates and activates AURA at T288, and AURA also activates focal adhesion kinase (FAK, also known as PTK2), leading to initiation of cell movement. An additional and new way by which AURA is regulated, is by phospholipase D2 (PLD2), which causes AURA activation. In addition, AURA phosphorylates PLD, so both proteins engage in a positive reinforcement loop. AURA and PLD2 form a protein-protein complex and colocalize to cytoplasmic regions in cells. The reason why PLD activates AURA is because of the production of phosphatidic acid by the lipase, which binds directly to AURA, with the region E171-E211 projected to be a phosphatidic-acid-binding pocket. Furthermore, this direct interaction with phosphatidic acid enhances tubulin polymerization and cooperates synergistically with AURA, FAK and Src in yielding a fully effectual cellular migration. Thus, Src and FAK, and PLD and phosphatidic acid are new upstream regulators of AURA that mediate its role in the non-mitotic cellular function of cell migration. PMID- 25501818 TI - Silencing of polo-like kinase 2 increases cell proliferation and decreases apoptosis in SGC-7901 gastric cancer cells. AB - Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase, which has vital roles during mitosis and the centrosome cycle. In acute myeloblastic leukemia and hepatocarcinogenesis, PLK2 acts as a tumor suppressor; however, the function of PLK2 in gastric cancer remains to be elucidated. In the present study, PLK2 was overexpressed in gastric cancer tissues and three types of gastric cancer cells, SGC-7901, MKN-45 and BGC-823. Transfection of SGC-7901 gastric cancer cells with small interfering (si)RNA against PLK2 exerted no effect on the ratio of cells at different stages of the cell cycle compared with that of the untransfected and control siRNA-transfected cells. In addition, silencing of PLK2 significantly enhanced the growth of SGC-7901 cells through inhibiting apoptosis. Furthermore, apoptosis-associated genes Bax and caspase 3 were found to be downregulated at the protein level. In conclusion, these results suggested that PLK2 may act as a tumor suppressor in gastric cancer, therefore indicating its therapeutic potential. PMID- 25501816 TI - Analysis of S. pombe SIN protein association to the SPB reveals two genetically separable states of the SIN. AB - The Schizosaccharomyces pombe septation initiation network (SIN) regulates cytokinesis, and asymmetric association of SIN proteins with the mitotic spindle pole bodies (SPBs) is important for its regulation. Here, we have used semi automated image analysis to study SIN proteins in large numbers of wild-type and mutant cells. Our principal conclusions are: first, that the association of Cdc7p with the SPBs in early mitosis is frequently asymmetric, with a bias in favour of the new SPB; second, that the early association of Cdc7p-GFP to the SPB depends on Plo1p but not Spg1p, and is unaffected by mutations that influence its asymmetry in anaphase; third, that Cdc7p asymmetry in anaphase B is delayed by Pom1p and by activation of the spindle assembly checkpoint, and is promoted by Rad24p; and fourth, that the length of the spindle, expressed as a fraction of the length of the cell, at which Cdc7p becomes asymmetric is similar in cells dividing at different sizes. These data reveal that multiple regulatory mechanisms control the SIN in mitosis and lead us to propose a two-state model to describe the SIN. PMID- 25501817 TI - Nanoscale histone localization in live cells reveals reduced chromatin mobility in response to DNA damage. AB - Nuclear functions including gene expression, DNA replication and genome maintenance intimately rely on dynamic changes in chromatin organization. The movements of chromatin fibers might play important roles in the regulation of these fundamental processes, yet the mechanisms controlling chromatin mobility are poorly understood owing to methodological limitations for the assessment of chromatin movements. Here, we present a facile and quantitative technique that relies on photoactivation of GFP-tagged histones and paired-particle tracking to measure chromatin mobility in live cells. We validate the method by comparing live cells to ATP-depleted cells and show that chromatin movements in mammalian cells are predominantly energy dependent. We also find that chromatin diffusion decreases in response to DNA breaks induced by a genotoxic drug or by the ISceI meganuclease. Timecourse analysis after cell exposure to ionizing radiation indicates that the decrease in chromatin mobility is transient and precedes subsequent increased mobility. Future applications of the method in the DNA repair field and beyond are discussed. PMID- 25501819 TI - A novel alpha/beta-hydrolase gene IbMas enhances salt tolerance in transgenic sweetpotato. AB - Salt stress is one of the major environmental stresses in agriculture worldwide and affects crop productivity and quality. The development of crops with elevated levels of salt tolerance is therefore highly desirable. In the present study, a novel maspardin gene, named IbMas, was isolated from salt-tolerant sweetpotato (Ipomoea batatas (L.) Lam.) line ND98. IbMas contains maspardin domain and belongs to alpha/beta-hydrolase superfamily. Expression of IbMas was up-regulated in sweetpotato under salt stress and ABA treatment. The IbMas-overexpressing sweetpotato (cv. Shangshu 19) plants exhibited significantly higher salt tolerance compared with the wild-type. Proline content was significantly increased, whereas malonaldehyde content was significantly decreased in the transgenic plants. The activities of superoxide dismutase (SOD) and photosynthesis were significantly enhanced in the transgenic plants. H2O2 was also found to be significantly less accumulated in the transgenic plants than in the wild-type. Overexpression of IbMas up-regulated the salt stress responsive genes, including pyrroline-5-carboxylate synthase, pyrroline-5-carboxylate reductase, SOD, psbA and phosphoribulokinase genes, under salt stress. These findings suggest that overexpression of IbMas enhances salt tolerance of the transgenic sweetpotato plants by regulating osmotic balance, protecting membrane integrity and photosynthesis and increasing reactive oxygen species scavenging capacity. PMID- 25501820 TI - Efficacy of Helicobacter pylori eradication for the 1st line treatment of immune thrombocytopenia patients with moderate thrombocytopenia. AB - The practical usefulness of Helicobacter pylori eradication for immune thrombocytopenia (ITP) patients is still controversial. However, some ITP patients respond to H. pylori eradication. We conducted a multi-center, open label, prospective phase II study to define the efficacy and toxicities of H. pylori eradication as the first line treatment for persistent or chronic ITP patients with moderate thrombocytopenia. Patients with persistent or chronic ITP showing moderate thrombocytopenia (30 * 10(9)/L <= platelet count <= 70 * 10(9)/L) and positive C(13)-urea breath test (UBT) were selected. Medication consisted of lansoprazole 30 mg, amoxicillin 1000 mg, and clarithromycin 500 mg orally twice daily for a week. Complete response (CR) rate at 4 weeks, 3 months, 6 months, 12 months, and maximal response was 19.2, 50.0, 50.0, 26.9, and 65.4%, respectively. Overall response rate (ORR) at 4 weeks, 3 months, 6 months, 12 months, and maximal response was 19.2, 57.7, 65.4, 30.8, and 69.2%, respectively. Median maximal platelet count during the first 3 months was 110 * 10(9)/L (range, 40-274). Median time to CR was 8 weeks (95% CI = 5.429-10.571). Median time to ORR was 4 weeks (95% CI = 1.228-6.772). Only per-protocol population was a response predictor for ORR at 3 months (70.0%, p = 0.054) and maximal ORR (80.0%, p = 0.051), but not for CR at 3 months (60.0%, p = 0.160). Therefore, eradication of H. pylori is an effective and durable first line treatment for persistent or chronic ITP with moderate thrombocytopenia with high ORR and rapid onset in this study. PMID- 25501822 TI - Mutations in global regulators lead to metabolic selection during adaptation to complex environments. AB - Adaptation to ecologically complex environments can provide insights into the evolutionary dynamics and functional constraints encountered by organisms during natural selection. Adaptation to a new environment with abundant and varied resources can be difficult to achieve by small incremental changes if many mutations are required to achieve even modest gains in fitness. Since changing complex environments are quite common in nature, we investigated how such an epistatic bottleneck can be avoided to allow rapid adaptation. We show that adaptive mutations arise repeatedly in independently evolved populations in the context of greatly increased genetic and phenotypic diversity. We go on to show that weak selection requiring substantial metabolic reprogramming can be readily achieved by mutations in the global response regulator arcA and the stress response regulator rpoS. We identified 46 unique single-nucleotide variants of arcA and 18 mutations in rpoS, nine of which resulted in stop codons or large deletions, suggesting that subtle modulations of ArcA function and knockouts of rpoS are largely responsible for the metabolic shifts leading to adaptation. These mutations allow a higher order metabolic selection that eliminates epistatic bottlenecks, which could occur when many changes would be required. Proteomic and carbohydrate analysis of adapting E. coli populations revealed an up-regulation of enzymes associated with the TCA cycle and amino acid metabolism, and an increase in the secretion of putrescine. The overall effect of adaptation across populations is to redirect and efficiently utilize uptake and catabolism of abundant amino acids. Concomitantly, there is a pronounced spread of more ecologically limited strains that results from specialization through metabolic erosion. Remarkably, the global regulators arcA and rpoS can provide a "one-step" mechanism of adaptation to a novel environment, which highlights the importance of global resource management as a powerful strategy to adaptation. PMID- 25501824 TI - Blocking autophagy enhanced cytotoxicity induced by recombinant human arginase in triple-negative breast cancer cells. AB - Depletion of arginine by recombinant human arginase (rhArg) has proven to be an effective cancer therapeutic approach for a variety of malignant tumors. Triple negative breast cancers (TNBCs) lack of specific therapeutic targets, resulting in poor prognosis and limited therapeutic efficacy. To explore new therapeutic approaches for TNBC we studied the cytotoxicity of rhArg in five TNBC cells. We found that rhArg could inhibit cell growth in these five TNBC cells. Intriguingly, accumulation of autophagosomes and autophagic flux was observed in rhArg-treated MDA-MB-231 cells. Inhibition of autophagy by chloroquine (CQ), 3 methyladenine (3-MA) and siRNA targeting Beclin1 significantly enhanced rhArg induced cytotoxic effect, indicating the cytoprotective role of autophagy in rhArg-induced cell death. In addition, N-acetyl-l-cysteine (NAC), a common antioxidant, blocked autophagy induced by rhArg, suggesting that reactive oxygen species (ROS) had an essential role in the cytotoxicity of rhArg. This study provides new insights into the molecular mechanism of autophagy involved in rhArg induced cytotoxicity in TNBC cells. Meanwhile, our results revealed that rhArg, either alone or in combination with autophagic inhibitors, might be a potential novel therapy for the treatment of TNBC.Cell Death and Disease (2014) 5, e1563; doi:10.1038/cddis.2014.503; published online 11 December 2014. PMID- 25501823 TI - Identification of IRF1 as critical dual regulator of Smac mimetic-induced apoptosis and inflammatory cytokine response. AB - Smac (second mitochondria-derived activator of caspase) mimetics are considered as promising anticancer therapeutics and used to induce apoptosis by antagonizing inhibitor of apoptosis proteins, which are often abundantly expressed in cancer cells. Here, we identify interferon regulatory factor 1 (IRF1) as a novel critical regulator of Smac mimetic BV6-induced apoptosis and proinflammatory cytokine secretion with impact on the immune response. IRF1 knockdown rescues cells from BV6-induced apoptosis and attenuates BV6-stimulated upregulation of tumor necrosis factor-alpha (TNFalpha), indicating that IRF1 mediates BV6 triggered cell death, at least in part, by inducing TNFalpha. This notion is supported by data showing that exogenous supply of TNFalpha restores BV6-induced cell death in IRF-knockdown cells. Interestingly, IRF1 selectively controls the induction of nuclear factor-kappaB (NF-kappaB) target genes, as IRF1 depletion attenuates BV6-stimulated upregulation of TNFalpha and interleukin-8 (IL-8) but not p100 and RelB. Concomitant knockdown of IRF1 and p65 cooperate to inhibit BV6 induced cell death, implying a cooperative interaction of IRF1 and NF-kappaB. In addition, IRF1 silencing hampers TNFalpha induction by TNFalpha itself as an another prototypical NF-kappaB stimulus. Importantly, IRF1 depletion impedes BV6 stimulated secretion of additional proinflammatory cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF), IL-8, IL-6 and monocyte chemoattractant protein-1, and migration of primary monocytes to BV6-treated tumor cells. In conclusion, this identification of IRF1 as a dual regulator of BV6-induced apoptosis and inflammatory cytokine secretion provides novel insights into determinants of sensitivity towards Smac mimetic and possible implications of Smac mimetic treatment on tumor microenvironment and immune response. PMID- 25501826 TI - Regulation of caspase-3 processing by cIAP2 controls the switch between pro inflammatory activation and cell death in microglia. AB - The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders. PMID- 25501825 TI - Mir-660 is downregulated in lung cancer patients and its replacement inhibits lung tumorigenesis by targeting MDM2-p53 interaction. AB - Lung cancer represents the leading cause of cancer-related death in developed countries. Despite the advances in diagnostic and therapeutic techniques, the 5 year survival rate remains low. The research for novel therapies directed to biological targets has modified the therapeutic approach, but the frequent engagement of resistance mechanisms and the substantial costs, limit the ability to reduce lung cancer mortality. MicroRNAs (miRNAs) are small noncoding RNAs with known regulatory functions in cancer initiation and progression. In this study we found that mir-660 expression is downregulated in lung tumors compared with adjacent normal tissues and in plasma samples of lung cancer patients with poor prognosis, suggesting a potential functional role of this miRNA in lung tumorigenesis. Transient and stable overexpression of mir-660 using miRNA mimics reduced migration, invasion, and proliferation properties and increased apoptosis in p53 wild-type lung cancer cells (NCI-H460, LT73, and A549). Furthermore, stable overexpression using lentiviral vectors in NCI-H460 and A549 cells inhibited tumor xenograft growth in immunodeficient mice (95 and 50% reduction compared with control, respectively), whereas the effects of mir-660 overexpression were absent in H1299, a lung cancer cell line lacking p53 locus, both in in vitro and in vivo assays. We identified and validated mouse double minute 2 (MDM2) gene, a key regulator of the expression and function of p53, as a new direct target of mir-660. In addition, mir-660 expression reduced both mRNA and protein expression of MDM2 in all cell lines and stabilized p53 protein levels resulting in an upregulation of p21(WAF1/CIP1) in p53 wild-type cells. Our finding supports that mir-660 acts as a tumor suppressor miRNA and we suggest the replacement of mir-660 as a new therapeutic approach for p53 wild-type lung cancer treatment. PMID- 25501827 TI - Caspase-1 cleavage of transcription factor GATA4 and regulation of cardiac cell fate. AB - Caspase-1 or interleukin-1beta (IL-1beta) converting enzyme is a pro-inflammatory member of the caspase family. An IL-1beta-independent role for caspase-1 in cardiomyocyte cell death and heart failure has emerged but the mechanisms underlying these effects are incompletely understood. Here, we report that transcription factor GATA4, a key regulator of cardiomyocyte survival and adaptive stress response is an in vivo and in vitro substrate for caspase-1. Caspase-1 mediated cleavage of GATA4 generates a truncated protein that retains the ability to bind DNA but lacks transcriptional activation domains and acts as a dominant negative regulator of GATA4. We show that caspase-1 is rapidly activated in cardiomyocyte nuclei treated with the cell death inducing drug Doxorubicin. We also find that inhibition of caspase-1 alone is as effective as complete caspase inhibition at rescuing GATA4 degradation and myocyte cell death. Caspase-1 inhibition of GATA4 transcriptional activity is rescued by HSP70, which binds directly to GATA4 and masks the caspase recognition motif. The data identify a caspase-1 nuclear substrate and suggest a direct role for caspase-1 in transcriptional regulation. This mechanism may underlie the inflammation independent action of caspase-1 in other organs. PMID- 25501828 TI - Hypoxia-cultured human adipose-derived mesenchymal stem cells are non-oncogenic and have enhanced viability, motility, and tropism to brain cancer. AB - Adult human adipose-derived mesenchymal stem cells (hAMSCs) are multipotent cells, which are abundant, easily collected, and bypass the ethical concerns that plague embryonic stem cells. Their utility and accessibility have led to the rapid development of clinical investigations to explore their autologous and allogeneic cellular-based regenerative potential, tissue preservation capabilities, anti-inflammatory properties, and anticancer properties, among others. hAMSCs are typically cultured under ambient conditions with 21% oxygen. However, physiologically, hAMSCs exist in an environment of much lower oxygen tension. Furthermore, hAMSCs cultured in standard conditions have shown limited proliferative and migratory capabilities, as well as limited viability. This study investigated the effects hypoxic culture conditions have on primary intraoperatively derived hAMSCs. hAMSCs cultured under hypoxia (hAMSCs-H) remained multipotent, capable of differentiation into osteogenic, chondrogenic, and adipogenic lineages. In addition, hAMSCs-H grew faster and exhibited less cell death. Furthermore, hAMSCs-H had greater motility than normoxia-cultured hAMSCs and exhibited greater homing ability to glioblastoma (GBM) derived from brain tumor-initiating cells from our patients in vitro and in vivo. Importantly, hAMSCs-H did not transform into tumor-associated fibroblasts in vitro and were not tumorigenic in vivo. Rather, hAMSCs-H promoted the differentiation of brain cancer cells in vitro and in vivo. These findings suggest an alternative culturing technique that can enhance the function of hAMSCs, which may be necessary for their use in the treatment of various pathologies including stroke, myocardial infarction, amyotrophic lateral sclerosis, and GBM. PMID- 25501829 TI - Functional expression cloning identifies COX-2 as a suppressor of antigen specific cancer immunity. AB - The efficacy of immune surveillance and antigen-specific cancer immunotherapy equally depends on the activation of a sustained immune response targeting cancer antigens and the susceptibility of cancer cells to immune effector mechanisms. Using functional expression cloning and T-cell receptor (TCR) transgenic mice, we have identified cyclooxygenase 2/prostaglandin-endoperoxide synthase 2 (COX-2) as resistance factor against the cytotoxicity induced by activated, antigen-specific T cells. Expressing COX-2, but not a catalytically inactive COX-2 mutant, increased the clonogenic survival of E1A-transformed murine cancer cells when cocultured with lymphocytes from St42Rag2(-/-) mice harboring a transgenic TCR directed against an E1A epitope. COX-2 expressing tumors established in immune deficient mice were less susceptible to adoptive immunotherapy with TCR transgenic lymphocytes in vivo. Also, immune surveillance of COX-2-positive tumor cells in TCR transgenic mice was less efficient. The growth of murine MC-GP tumors, which show high endogenous COX-2 expression, in immunocompetent mice was effectively suppressed by treatment with a selective COX-2 inhibitor, celecoxib. Mechanistically, COX-2 expression blunted the interferon-gamma release of antigen specific T cells exposed to their respective cellular targets, and increased the expression of interleukin-4 and indoleamine 2,3-dioxygenase by tumor cells. Addition of interferon-gamma sensitized COX-2 expressing cancer cells to tumor suppression by antigen-specific T cells. In conclusion, COX-2, which is frequently induced in colorectal cancer, contributes to immune evasion and resistance to antigen-specific cancer immunotherapy by local suppression of T cell effector functions. PMID- 25501830 TI - Heme oxygenase-1 protects against Alzheimer's amyloid-beta(1-42)-induced toxicity via carbon monoxide production. AB - Heme oxygenase-1 (HO-1), an inducible enzyme up-regulated in Alzheimer's disease, catabolises heme to biliverdin, Fe2+ and carbon monoxide (CO). CO can protect neurones from oxidative stress-induced apoptosis by inhibiting Kv2.1 channels, which mediates cellular K+ efflux as an early step in the apoptotic cascade. Since apoptosis contributes to the neuronal loss associated with amyloid beta peptide (Abeta) toxicity in AD, we investigated the protective effects of HO-1 and CO against Abeta(1-42) toxicity in SH-SY5Y cells, employing cells stably transfected with empty vector or expressing the cellular prion protein, PrP(c), and rat primary hippocampal neurons. Abeta(1-42) (containing protofibrils) caused a concentration-dependent decrease in cell viability, attributable at least in part to induction of apoptosis, with the PrP(c)-expressing cells showing greater susceptibility to Abeta(1-42) toxicity. Pharmacological induction or genetic over expression of HO-1 significantly ameliorated the effects of Abeta(1-42). The CO donor CORM-2 protected cells against Abeta(1-42) toxicity in a concentration dependent manner. Electrophysiological studies revealed no differences in the outward current pre- and post-Abeta(1-42) treatment suggesting that K+ channel activity is unaffected in these cells. Instead, Abeta toxicity was reduced by the L-type Ca2+ channel blocker nifedipine, and by the CaMKKII inhibitor, STO-609. Abeta also activated the downstream kinase, AMP-dependent protein kinase (AMPK). CO prevented this activation of AMPK. Our findings indicate that HO-1 protects against Abeta toxicity via production of CO. Protection does not arise from inhibition of apoptosis-associated K+ efflux, but rather by inhibition of AMPK activation, which has been recently implicated in the toxic effects of Abeta. These data provide a novel, beneficial effect of CO which adds to its growing potential as a therapeutic agent. PMID- 25501832 TI - BMPR2 inhibition induced apoptosis and autophagy via destabilization of XIAP in human chondrosarcoma cells. AB - Bone morphogenetic proteins (BMPs) are multifunctional proteins, and their receptors (BMPRs) have crucial roles in the process of signaling. However, their function in cancer is somewhat inconsistent. It has been demonstrated that more prevalent expression of bone morphogenetic protein receptor 2 (BMPR2) has been detected in dedifferentiated chondrosarcomas than conventional chondrosarcomas. Here, we find that BMPR2 inhibition induces apoptosis and autophagy of chondrosarcoma. We found that BMPR2 expression was correlated with the clinicopathological features of chondrosarcomas, and could predict the treatment outcome. Knockdown of BMPR2 by small interfering RNA results in growth inhibition in chondrosarcoma cells. Silencing BMPR2 promoted G2/M cell cycle arrest, induced chondrosarcoma cell apoptosis through caspase-3-dependent pathway via repression of X-linked inhibitor of apoptosis protein (XIAP) and induced autophagy of chondrosarcoma cells via XIAP-Mdm2-p53 pathway. Inhibition of autophagy induced by BMPR2 small interfering RNA (siBMPR2) sensitized chondrosarcoma cells to siBMPR2-induced apoptotic cell death, suggesting that autophagy has a protective role for chondrosarcoma cells in context of siBMPR2-induced apoptotic cell death. In vivo tumorigenicity assay in mice indicated that inhibition of BMPR2 reduced tumor growth. Taken together, our results suggest that BMPR2 has a significant role in the tumorigenesis of chondrosarcoma, and could be an important prognostic marker for chondrosarcoma. BMPR2 inhibition could eventually provide a promising therapy for chondrosarcoma treatment. PMID- 25501831 TI - XIAP-targeting drugs re-sensitize PIK3CA-mutated colorectal cancer cells for death receptor-induced apoptosis. AB - Mutations in the oncogenic PIK3CA gene are found in 10-20% of colorectal cancers (CRCs) and are associated with poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic TRAIL death receptor antibodies emerged as promising anti-neoplastic therapeutics, but to date failed to prove their capability in the clinical setting as especially primary tumors exhibit high rates of TRAIL resistance. In our study, we investigated the molecular mechanisms underlying TRAIL resistance in CRC cells with a mutant PIK3CA (PIK3CA mut) gene. We show that inhibition of the constitutively active phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway only partially overcame TRAIL resistance in PIK3CA-mut-protected HCT116 cells, although synergistic effects of TRAIL plus PI3K, Akt or cyclin-dependent kinase (CDK) inhibitors could be noted. In sharp contrast, TRAIL triggered full-blown cell death induction in HCT116 PIK3CA-mut cells treated with proteasome inhibitors such as bortezomib and MG132. At the molecular level, resistance of HCT116 PIK3CA mut cells against TRAIL was reflected by impaired caspase-3 activation and we provide evidence for a crucial involvement of the E3-ligase X-linked inhibitor of apoptosis protein (XIAP) therein. Drugs interfering with the activity and/or the expression of XIAP, such as the second mitochondria-derived activator of caspase mimetic BV6 and mithramycin-A, completely restored TRAIL sensitivity in PIK3CA mut-protected HCT116 cells independent of a functional mitochondrial cell death pathway. Importantly, proteasome inhibitors and XIAP-targeting agents also sensitized other CRC cell lines with mutated PIK3CA for TRAIL-induced cell death. Together, our data suggest that proteasome- or XIAP-targeting drugs offer a novel therapeutic approach to overcome TRAIL resistance in PIK3CA-mutated CRC. PMID- 25501834 TI - Subtotal versus total laparoscopic hysterectomy: could women sexual function recovery overcome the surgical outcomes in pre-operatory decision making? AB - PURPOSE: Hysterectomy is the most common surgical procedure performed in gynecology and, in over 95% of the cases, does not necessarily require the removal of the uterine cervix to be completed successfully. In clinical practice, however, less than 20% of gynecologists offer patients the possibility to express a personal preference concerning the choice between total laparoscopic hysterectomy (TLH) and laparoscopic subtotal hysterectomy (LSH). The aim of this study is to compare patients who have undergone TLH versus LSH for benign uterine diseases in terms of intra-operative/peri-operative surgical outcomes and short term recovery of sexual function. METHODS: We performed an observational, retrospective study on 478 women who underwent hysterectomy for benign uterine disease at Gyn/Ob Clinic, Department of Women's and Children's Health of Padua University between January 2003 and December 2012. Surgical data were recorded. We investigated and compared outcomes between the two groups of patients (TLH vs LSH) in terms of the following: surgical complications rate, post-operative therapy, women satisfaction and sexual activity recovery. RESULTS: We found that operating time and length of hospital stay were significantly lower in patients who underwent LSH. A higher rate of post-operative fever was reported in the TLH treatment group although antibiotic prophylaxis was implemented in a similar fashion for both groups. At 60-70 days following surgery, women of LSH group reported a greater ease in recovery of sexual function as opposed to those who underwent TLH. CONCLUSIONS: The advantages and potential drawbacks of both procedures need to be discussed with women presenting with benign disease. LSH is a reasonable option for women, representing both an excellent minimally invasive approach in a proper clinical setting and an appropriate procedure for those women who prefer conservative surgery. PMID- 25501835 TI - Methotrexate management for placenta accreta: a prospective study. AB - OBJECTIVE: To observe efficacy following methotrexate (MTX) management in women with placenta accreta. METHODS: Twenty-four stable patients with placenta accreta were treated with MTX. Beta-hCG values, vascular indices of the residual placenta, and other clinical characteristics were collected prospectively and were compared between the success and failure groups. RESULTS: After MTX management, the residual placentas were expulsed spontaneously in 33.3% of the patients. This was done through dilatation and curettage (D & C) in 45.8% of the patients. The residuals in the uterine wall were completely absorbed within 5.7 months. In the patients who were successfully treated with MTX, their beta-hCG values and vascular indices of the placentas decreased faster than those of failure patients (P < 0.05). Those (20.8%) failing MTX management and subsequent D & C showed that their vascular indices persisted high levels and some even experienced elevations despite significantly decreased hCG values. CONCLUSIONS: MTX management, when the beta-hCG value and vascular indices of placenta decreased significantly, is a conservative option for a stable patient with placenta accreta in China. 3D power Doppler ultrasound should be utilized for the follow-up of this condition. PMID- 25501833 TI - A loss of FUS/TLS function leads to impaired cellular proliferation. AB - Fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is a multifunctional RNA/DNA-binding protein that is pathologically associated with cancer and neurodegeneration. To gain insight into the vital functions of FUS and how a loss of FUS function impacts cellular homeostasis, FUS expression was reduced in different cellular models through RNA interference. Our results show that a loss of FUS expression severely impairs cellular proliferation and leads to an increase in phosphorylated histone H3, a marker of mitotic arrest. A quantitative proteomics analysis performed on cells undergoing various degrees of FUS knockdown revealed protein expression changes for known RNA targets of FUS, consistent with a loss of FUS function with respect to RNA processing. Proteins that changed in expression as a function of FUS knockdown were associated with multiple processes, some of which influence cell proliferation including cell cycle regulation, cytoskeletal organization, oxidative stress and energy homeostasis. FUS knockdown also correlated with increased expression of the closely related protein EWS (Ewing's sarcoma). We demonstrate that the maladaptive phenotype resulting from FUS knockdown is reversible and can be rescued by re-expression of FUS or partially rescued by the small-molecule rolipram. These results provide insight into the pathways and processes that are regulated by FUS, as well as the cellular consequences for a loss of FUS function. PMID- 25501836 TI - The knowledge, practice and opinion of midwives' in the UK on their training in obstetric perineal repair. AB - PURPOSE: To investigate the knowledge and practice of perineal repair by midwives' in the UK, as well as their perception of the adequacy of their training. METHODS: An anonymous structured questionnaire survey was conducted. Standard statistical comparative analysis was performed between groups. Significant differences were quantified by calculating odds ratios and 95% confidence intervals. P < 0.05 was considered significant. RESULTS: Analysis of 592 responses revealed that midwives who believed that they had adequate training were ten times more likely to report that they have an adequate knowledge of pelvic floor anatomy (OR 9.8, 95% CI 6.4-14.9, P < 0.001), six times more likely to be aware of recommended techniques of perineal repair (OR 6.1, 95% CI 3.8-9.7, P < 0.001) and 16 times more likely to feel competent to perform a repair (OR 16.1, 95% CI 9.3-27.2, P < 0.001). Midwives who had formal hands-on perineal repair training were four times more likely to report that they have an adequate knowledge of pelvic floor anatomy (OR 4.1, 95% CI 2.8-5.8, P < 0.001) and four times more likely to feel competent enough to perform a repair (OR 3.6 95% CI 2.4 4.9, P < 0.001). CONCLUSION: The majority of midwives in the study sample report that they were unable to identify key perineal anatomy and believed that their pre-qualification training on perineal repair was inadequate. They also believed that midwives should routinely repair simple second-degree perineal tears. PMID- 25501837 TI - Inclusion of extremes of prematurity in ventricular index centile charts. AB - OBJECTIVE: To assess the relationship between ventricular index (VI) measurements and postmenstrual age in preterm infants and to generate centile charts and normal ranges for frontal horn ratio (FHR) for a large contemporary cohort of preterm infants. STUDY DESIGN: A retrospective cohort study of 253 infants with birth gestation less than 32 weeks admitted between January 2009 and December 2011 to a tertiary NICU in Ireland. RESULTS: A total of 816 cranial ultrasounds were reviewed. Data collected were grouped according to postmenstrual age at the time of scan from 23 weeks to 45 weeks. Median values for VI show a general trend to increase with gestation. FHR did not significantly change with postmenstrual age at scan with a median value of 0.31. CONCLUSION: There is a slight increase in VI as gestation at the time of scans increases. These results provide the basis for updated centile charts which we propose for current practice. PMID- 25501839 TI - High frequency of splice site mutation in 21-hydroxylase deficiency children. AB - PURPOSE: Steroid 21-hydroxylase deficiency (21-OHD) is the common type of congenital adrenal hyperplasia (CAH) caused by defects in the CYP21A2 gene, as an autosomal recessive disease, genetic analysis has a prominent role in its diagnosis. Our objectives were to determine the prevalence of common mutations in a group of Egyptian patients with 21-OHD and their families using rapid methods, and also to detect the rate of deletion, duplication and conversions in CYP21A2 gene. METHODS: Rapid detection methods were used: allele-specific PCR for c.293 13A>G (g.659A>G), c.518T>A (p.I172N) variants and c.332_339del (8-bp deletion in exon 3), and real-time, quantitative PCR assay was used to detect deletion in the CYP21A2 gene. 29 Egyptian patients, 38 family members, and 20 healthy controls were all included in the study. RESULTS: The frequency of c.293-13A>G splice mutation was reported in 96.6 % cases, G allele had 2.5-folds higher risk to develop CAH than other alleles. The c.518T>A mutation was reported in 69 % cases, children carrying the mutant allele were 2.1 times more risk. The most frequent combined mutations detected were c.293-13A/C>G/c.518T>A in 58.6 % cases. CONCLUSION: The genetic analysis of the splice site mutation c.293-13A>G and c.518T>A variant can be used as good biomarkers for early detection of cases and carriers in 21-OHD CAH Egyptian children, since the methods used have rapid turnaround time. PMID- 25501838 TI - Psychiatric support for mothers in the Neonatal Intensive Care Unit. AB - OBJECTIVE: This study describes mental health treatment and follow-up for mothers of infants in a Neonatal Intensive Care Unit (NICU). STUDY DESIGN: Data were collected retrospectively about 204 mothers referred to a Level 3 NICU Psychiatric Consult Liaison Team over 2 years. This included medical, demographic and treatment information about both mother and infant. RESULT: Most mothers (69%) were referred within a week of birth, and 100 (49%) of the referred mothers received a psychiatric diagnosis. Psychiatric follow-up was recommended for 13% on leaving the NICU and additional follow-up referrals were made for another 16%. Mothers with more than one initial reason for referral, a past psychiatric history, receiving therapeutic services, receiving a psychiatric diagnosis and receiving pharmacotherapy were all significantly more likely to have follow-up recommended on discharge. CONCLUSION: Approximately one-sixth of mothers in the NICU were referred, a large proportion received a psychiatric diagnosis, and over a quarter required follow-up after discharge, indicating the importance of the service. PMID- 25501840 TI - Fuel homeostasis and locomotor behavior: role of leptin and melanocortin pathways. AB - BACKGROUND: While it is now accepted that genes and their products affect food intake, the concept that locomotor behavior or the propensity for physical activity is controlled by neuro hum oral regulators is frequently underappreciated. In mammals, complex interactions have developed to allow the cross-talk between fuel homeostasis and physical activity. AIM: The aim of this review is to provide a synopsis of the influence of the leptin-melanocortin pathway, a well-studied pivotal player in body weight regulation, on locomotor behaviors. CONCLUSIONS: In rodents, reductions in leptin levels that physiologically occur following acute food deprivation or a reduction of the fat mass consequent to prolonged caloric restrictions are associated with a decrease in total locomotor activity and simultaneous increase in food-anticipatory activity, a locomotor behavior which reflects a foraging attitude. These actions can be prevented by leptin administration and are at least partially mediated by the neurons of the melanocortin pathway. In humans, twin studies have attributed to genetic factors approximately 50% of the variance of physical activity. An elevated number of the genes or loci which may affect physical activity are involved in body weight homeostasis. Polymorphisms of the melanocortin-4 and leptin receptors have repeatedly been associated with the level of physical activity. Unraveling the complexity of the regulation of locomotor behavior and the interconnections with the pathways involved in energy homeostasis may help explain the substantial individual variability in physical activities in humans and disentangle the harmful effects of sedentary lifestyle, which may be distinct from the detrimental effects of obesity. PMID- 25501841 TI - Incidental ganglioneuromas: a presentation of 14 surgical cases and literature review. AB - BACKGROUND AND AIMS: Ganglioneuromas are benign tumors which originate from the neural crest. This tumor affects mainly young patients rather than adult ones, and its most frequent localizations are mediastinum, retroperitoneum, adrenal glands and cervical region. Usually, ganglioneuromas are discovered as incidentalomas since they are often asymptomatic, even if they could present sympathetic or mass-related symptoms. To obtain a definitive diagnosis, histological exam is necessary since CT scan and MRI are not capable of distinguishing ganglioneuromas from other tumors, such as neuroblastomas or pheocromocytomas. The surgical excision is the chosen treatment and it offers an excellent prognosis. METHODS: We conducted a retrospective analysis of our cases of ganglioneuroma from 2004 to 2014; this study aims to compare our experience with literature review (2000-2014). Data about patients' features, tumor localization, symptoms, treatment and follow-up were analyzed and reported in detailed tables. RESULTS: Between 2004 and 2014 we treated 14 patients affected by ganglioneuroma. For all of them the diagnosis was incidental; 9 out of 12 (64.3 %) patients presented an adrenal mass; in 2 patients (14.3 %) the tumor was localized in cervical region; in other 2 patients (14.3 %) the tumor was in the retroperitoneum and one patient (7.1 %) presented a ganglioneuroma in the costo vertebral space. All our patients underwent surgical removal and none of them present surgery-related complications or recurrences to date. CONCLUSIONS: Our data widen the knowledge about ganglioneuroma and confirm that the surgical approach has an excellent prognosis with very low incidence of surgery-related complications and recurrences. PMID- 25501843 TI - Immunoadsorption versus therapeutic plasma exchange. Will fibrinogen make the difference? PMID- 25501844 TI - Development of tests for disease using genetic markers is slower than expected. PMID- 25501842 TI - Histone acetylation accompanied with promoter sequences displaying differential expression profiles of B-class MADS-box genes for phalaenopsis floral morphogenesis. AB - Five B-class MADS-box genes, including four APETALA3 (AP3)-like PeMADS2~5 and one PISTILLATA (PI)-like PeMADS6, specify the spectacular flower morphology in orchids. The PI-like PeMADS6 ubiquitously expresses in all floral organs. The four AP3-like genes, resulted from two duplication events, express ubiquitously at floral primordia and early floral organ stages, but show distinct expression profiles at late floral organ primordia and floral bud stages. Here, we isolated the upstream sequences of PeMADS2~6 and studied the regulatory mechanism for their distinct gene expression. Phylogenetic footprinting analysis of the 1.3-kb upstream sequences of AP3-like PeMADS2~5 showed that their promoter regions have sufficiently diverged and contributed to their subfunctionalization. The amplified promoter sequences of PeMADS2~6 could drive beta-glucuronidase (GUS) gene expression in all floral organs, similar to their expression at the floral primordia stage. The promoter sequence of PeMADS4, exclusively expressed in lip and column, showed a 1.6~3-fold higher expression in lip/column than in sepal/petal. Furthermore, we noted a 4.9-fold increase in histone acetylation (H3K9K14ac) in the translation start region of PeMADS4 in lip as compared in petal. All these results suggest that the regulation via the upstream sequences and increased H3K9K14ac level may act synergistically to display distinct expression profiles of the AP3-like genes at late floral organ primordia stage for Phalaenopsis floral morphogenesis. PMID- 25501846 TI - Localization of central venous catheter by vascular ultrasound and transthoracic echocardiography: easy and accurate? PMID- 25501845 TI - Physical restraint in the ICU: does it prevent device removal? A critical appraisal. PMID- 25501847 TI - Healthcare workers' challenges in the implementation of tuberculosis infection prevention and control measures in Mozambique. AB - OBJECTIVE: Healthcare Workers (HCWs) have a higher frequency of TB exposure than the general population and have therefore an occupational TB risk that infection prevention and control (IPC) measures aim to reduce. HCWs are crucial in the implementation of these measures. The objective of the study was to investigate Mozambican HCWs' perceptions of their occupational TB risk and the measures they report using to reduce this risk. In addition, we explored the challenges HCWs encounter while using these TBIPC measures. METHODS: Focus group discussion. Analysis according content method. PARTICIPANTS: Four categories of HCWs: auxiliary workers, medical (doctors and clinical officers), nurses and TB program staff. RESULTS: HCWs are aware of their occupational TB risk and use various measures to reduce their risk of infection. HCWs find it challenging to employ measures that minimize such risks and a lack of clear guidelines contributes to these challenges. HCWs' and patient behavior further complicate the use of TBIPC measures. CONCLUSION: HCWs in Mozambique perceive a high occupational risk of TB infection. They report several challenges using measures to reduce this risk such as shortage of material, lack of clear guidelines, insufficient motivation and inadequate training. Robust training with motivational approaches, alongside supervision and support for HCWs could improve implementation of TBIPC measures. Healthcare management should address the areas for improvement that are beyond the individual HCW's control. PMID- 25501848 TI - Case-control study of the PERIOD3 clock gene length polymorphism and colorectal adenoma formation. AB - Clock genes are expressed in a self-perpetuating, circadian pattern in virtually every tissue including the human gastrointestinal tract. They coordinate cellular processes critical for tumor development, including cell proliferation, DNA damage response and apoptosis. Circadian rhythm disturbances have been associated with an increased risk for colon cancer and other cancers. This mechanism has not been elucidated, yet may involve dysregulation of the 'period' (PER) clock genes, which have tumor suppressor properties. A variable number tandem repeat (VNTR) in the PERIOD3 (PER3) gene has been associated with sleep disorders, differences in diurnal hormone secretion, and increased premenopausal breast cancer risk. Susceptibility related to PER3 has not been examined in conjunction with adenomatous polyps. This exploratory case-control study was the first to test the hypothesis that the 5-repeat PER3 VNTR sequence is associated with increased odds of adenoma formation. Information on demographics, medical history, occupation and lifestyle was collected prior to colonoscopy. Cases (n=49) were individuals with at least one histopathologically confirmed adenoma. Controls (n=97) included patients with normal findings or hyperplastic polyps not requiring enhanced surveillance. Unconditional multiple logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), after adjusting for potential confounding. Adenomas were detected in 34% of participants. Cases were more likely to possess the 5-repeat PER3 genotype relative to controls (4/5 OR, 2.1; 95% CI, 0.9-4.8; 5/5 OR, 5.1; 95% CI, 1.4-18.1; 4/5+5/5 OR, 2.5; 95% CI, 1.7 5.4). Examination of the Oncomine microarray database indicated lower PERIOD gene expression in adenomas relative to adjacent normal tissue. Results suggest a need for follow-up in a larger sample. PMID- 25501850 TI - Effects of aging and distractors on detection of redundant visual targets and capacity: do older adults integrate visual targets differently than younger adults? AB - In the redundant target effect, participants respond faster with two (redundant) targets. We compared the magnitude of this effect in younger and older adults, with and without distractors, in a simple visual-detection task. We employed additional measures that allow non-parametric assessment of performance (Townsend's capacity coefficient) and parametric estimates (Linear Ballistic Accumulator model). Older participants' latencies were slower, especially in the presence of distractors, and their calculated capacity indicators increased with distractors. Parametric estimates indicated that these increases were generated by the older adults' increased difficulty in inhibiting the distractors, and not the results of either improved detection of redundant-targets, or of a generalized slowing of processing. PMID- 25501849 TI - Spartan deficiency causes genomic instability and progeroid phenotypes. AB - Spartan (also known as DVC1 and C1orf124) is a PCNA-interacting protein implicated in translesion synthesis, a DNA damage tolerance process that allows the DNA replication machinery to replicate past nucleotide lesions. However, the physiological relevance of Spartan has not been established. Here we report that Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Whereas complete loss of Spartan causes early embryonic lethality, hypomorphic mice with low amounts of Spartan are viable. These mice are growth retarded and develop cataracts, lordokyphosis and cachexia at a young age. Cre-mediated depletion of Spartan from conditional knockout mouse embryonic fibroblasts results in impaired lesion bypass, incomplete DNA replication, formation of micronuclei and chromatin bridges and eventually cell death. These data demonstrate that Spartan plays a key role in maintaining structural and numerical chromosome integrity and suggest a link between Spartan insufficiency and progeria. PMID- 25501852 TI - Future of endemic flora of biodiversity hotspots in India. AB - India is one of the 12 mega biodiversity countries of the world, which represents 11% of world's flora in about 2.4% of global land mass. Approximately 28% of the total Indian flora and 33% of angiosperms occurring in India are endemic. Higher human population density in biodiversity hotspots in India puts undue pressure on these sensitive eco-regions. In the present study, we predict the future distribution of 637 endemic plant species from three biodiversity hotspots in India; Himalaya, Western Ghats, Indo-Burma, based on A1B scenario for year 2050 and 2080. We develop individual variable based models as well as mixed models in MaxEnt by combining ten least co-related bioclimatic variables, two disturbance variables and one physiography variable as predictor variables. The projected changes suggest that the endemic flora will be adversely impacted, even under such a moderate climate scenario. The future distribution is predicted to shift in northern and north-eastern direction in Himalaya and Indo-Burma, while in southern and south-western direction in Western Ghats, due to cooler climatic conditions in these regions. In the future distribution of endemic plants, we observe a significant shift and reduction in the distribution range compared to the present distribution. The model predicts a 23.99% range reduction and a 7.70% range expansion in future distribution by 2050, while a 41.34% range reduction and a 24.10% range expansion by 2080. Integration of disturbance and physiography variables along with bioclimatic variables in the models improved the prediction accuracy. Mixed models provide most accurate results for most of the combinations of climatic and non-climatic variables as compared to individual variable based models. We conclude that a) regions with cooler climates and higher moisture availability could serve as refugia for endemic plants in future climatic conditions; b) mixed models provide more accurate results, compared to single variable based models. PMID- 25501853 TI - Blue phosphorescent N-heterocyclic carbene chelated Pt(II) complexes with an alpha-duryl-beta-diketonato ancillary ligand. AB - C^C* chelated Pt(II) compounds that contain an N-heterocyclic carbene (NHC) donor have recently attracted great interest as blue or white phosphorescent emitters for organic light-emitting devices (OLEDs). To overcome the tendency for excimer formation in Pt(II) compounds, an alpha-duryl-beta-diketonato ligand was selected as the ancillary ligand for blue phosphorescent C^C* chelated Pt(II) compounds. Using this approach, a series of NHC-based C^C* chelated Pt(II) compounds has been designed and synthesized. The chelate ligands used in the new C^C* chelated Pt(II) compounds include 1-phenylimidazol-2-ylidene in Pt1, 1-phenyl-1,2,4 triazol-5-ylidene in Pt2, p-TMS-1-phenylimidazol-2-ylidene in Pt3, and p-TMS-1 phenyl-1,2,4-triazol-5-ylidene in Pt4. A single-crystal X-ray diffraction analysis revealed that the presence of the alpha-duryl-beta-diketonato ligand in the Pt(II) compounds effectively suppresses the dimer formation in the crystal lattice. Pt1, Pt2, Pt3, and Pt4 display blue phosphorescence at room temperature. The p-TMS substituted complex Pt3 was found to display the most efficient blue phosphorescence at lambda(em) = 468 nm with a Phi(PL) of 0.68. Spectroscopic and computational studies established that the blue phosphorescence in the phenyl imidazolylidene chelated complexes originates mainly from a (3)MLCT state while that in the phenyl-triazolylidene chelated compounds arises from a (3)ILCT state. Electroluminescent devices using Pt1 and Pt3 as the dopant were fabricated which display both monomer and exciplex emission, leading to pure white light electroluminescence with CIE coordinates of (0.32, 0.31). PMID- 25501851 TI - Inhibition of pathogenic non-enveloped viruses by 25-hydroxycholesterol and 27 hydroxycholesterol. AB - Recent studies reported a broad but selective antiviral activity of 25 hydroxycholesterol (25HC) against enveloped viruses, being apparently inactive against non-enveloped viruses. Here we show that 25HC is endowed with a marked antiviral activity against three pathogenic non-enveloped viruses, i.e. human papillomavirus-16 (HPV-16), human rotavirus (HRoV), and human rhinovirus (HRhV), thus significantly expanding its broad antiviral spectrum, so far recognized to be limited to viruses with envelope. Moreover, here we disclose the remarkable antiviral activity of another oxysterol of physiological origin, i.e. 27 hydroxycholesterol (27HC), against HPV-16, HRoV and HRhV. We have also identified a much weaker antiviral activity of other oxysterols of pathophysiological relevance, i.e 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol, and 7 ketocholesterol. These findings suggest that appropriate modulation of endogenous production of oxysterols might be a primary host strategy to counteract a broad panel of viral infections. Moreover, 25HC and 27HC could be considered for new therapeutic strategies against HPV-16, HRoV and HRhV. PMID- 25501854 TI - NIR-emitting boradiazaindacene fluorophores -TD-DFT studies on electronic structure and photophysical properties. AB - Density Functional Theory [B3LYP/6-31G(d)] and Time Dependent Density Functional Theory [TD-B3LYP/6-31G(d)] computations have been used to have more understanding of the structural, molecular, electronic and photophysical parameters of recently synthesized near IR-emitting acid switchable di-styryl BODIPY dyes. The structures have been optimized using function B3LYP and basis set used was 6 31G(d) for all the atoms and their geometries which are correlated with corresponding rotational isomers including rotational isomers of diprotonated forms in chloroform solvent. The observed energies of the optimized molecules suggest that there may be rotation about C-C single bond as the observed energy barrier is very low. The results of TD-DFT suggest that there is very good match between the observed and calculated absorptions diprotonated forms of one molecule. There is also good match between experimental and theoretical emission of neutral forms. More deviations are observed in the case emission of the diprotonated forms. PMID- 25501855 TI - Tryptophan residue of the D-galactose/D-glucose-binding protein from E. Coli localized in its active center does not contribute to the change in intrinsic fluorescence upon glucose binding. AB - Changes of the characteristics of intrinsic tryptophan fluorescence of the wild type of D-galactose/D-glucose-binding protein from Escherichia coli (GGBPwt) induced by D-glucose binding were examined by the intrinsic UV-fluorescence of proteins, circular dyhroism in the near-UV region, and acrylamide-induced fluorescence quenching. The analysis of the different characteristics of GGBPwt and its mutant form GGBP-W183A together with the analysis of the microenvironment of tryptophan residues of GGBPwt revealed that Trp 183, which is directly involved in sugar binding, has the least influence on the provoked by D-glucose blue shift and increase in the intensity of protein intrinsic fluorescence in comparison with other tryptophan residues of GGBP. PMID- 25501856 TI - Fluorometric assay to compensate for non-viable cells during electroporation. AB - A fluorometric assay is described that allows adjustment for non-viable cells that result during electroporation. The technique, unlike others, relies on only one dye, requires a single instrument, and eliminates the need for a separate cell counting step. Murine melanoma (B16-F10) cells were electroporated using electric fields ranging from 400 to 2500 V/cm in the presence of SYTOX((r)) green. Compensation for the fluorescence resulting from non-viable cells was facilitated by a correction curve established by lysing a known number of cells in the presence of SYTOX((r))-green. In uncorrected data, an applied electric field of 2500 V/cm increased dye delivery but also reduced cell viability significantly. Compensating for the fluorescence of non-viable cells showed that changing the field strength to 800 V/cm or 2500 V/cm from 400 V/cm had only marginal effects on membrane pore formation. The fluorometric assay was used to compare electroporation in high conductivity (PBS) and a low conductivity medium (LC-PBS). Statistically significant increases of 10 to 30-fold were observed for cells electroporated at 400 V/cm and 800 V/cm in LC-PBS. PMID- 25501857 TI - Reduction of nitro group on derivative of 1,8-napthalimide for quantitative detection of hydrogen sulfide. AB - A fluorescence "turn-on" sensor (HSS) for detection of H2S was developed on the basis of NO2-NH2 reduction. HSS showed a high affinity and sensitivity to H2S over other reducing reagents, particularly for biothiols. Also, the short responding time and high linear dependence between fluorescence enhancement and H2S concentration had HSS behave as a rapid sensor for quantitatively detection of H2S in the biological level. PMID- 25501859 TI - The 12th International HCH and Pesticides Forum in Kiev/Ukraine. PMID- 25501858 TI - Chemoreceptor Responsiveness at Sea Level Does Not Predict the Pulmonary Pressure Response to High Altitude. AB - BACKGROUND: The hypoxic ventilatory response (HVR) at sea level (SL) is moderately predictive of the change in pulmonary artery systolic pressure (PASP) to acute normobaric hypoxia. However, because of progressive changes in the chemoreflex control of breathing and acid-base balance at high altitude (HA), HVR at SL may not predict PASP at HA. We hypothesized that resting oxygen saturation as measured by pulse oximetry (Spo2) at HA would correlate better than HVR at SL with PASP at HA. METHODS: In 20 participants at SL, we measured normobaric, isocapnic HVR (L/min . -%Spo2-1) and resting PASP using echocardiography. Both resting Spo2 and PASP measures were repeated on day 2 (n = 10), days 4 to 8 (n = 12), and 2 to 3 weeks (n = 8) after arrival at 5,050 m. These data were also collected at 5,050 m in life-long HA residents (ie, Sherpa [n = 21]). RESULTS: Compared with SL, Spo2 decreased from 98.6% to 80.5% (P < .001), whereas PASP increased from 21.7 to 34.0 mm Hg (P < .001) after 2 to 3 weeks at 5,050 m. Isocapnic HVR at SL was not related to Spo2 or PASP at any time point at 5,050 m (all P > .05). Sherpa had lower PASP (P < .01) than lowlanders on days 4 to 8 despite similar Spo2. Upon correction for hematocrit, Sherpa PASP was not different from lowlanders at SL but was lower than lowlanders at all HA time points. At 5,050 m, although Spo2 was not related to PASP in lowlanders at any point (all R2 <= 0.05, P > .50), there was a weak relationship in the Sherpa (R2 = 0.16, P = .07). CONCLUSIONS: We conclude that neither HVR at SL nor resting Spo2 at HA correlates with elevations in PASP at HA. PMID- 25501860 TI - Fuel nitrogen conversion and release of nitrogen oxides during coal gangue calcination. AB - The pollution emission during the widespread utilization of coal gangue in construction industry has long been neglected. In present study, the NO x release behaviors in a simulation experiment of coal gangue calcination in construction industry were systematically investigated. The corresponding evolution of nitrogen functionalities in coal gangue was also discussed. Results showed that pyrrolic (N-5) and pyridine N-oxide (N-6-O) forms nitrogen were relatively abundant in the raw gangue. During calcination, the N-5 and N-6-O form nitrogen greatly decreased and converted to quaternary nitrogen (N-Q). It was found that NO2 was formed under slowly heating-up condition and at 600 degrees C under isothermal condition, while only NO was detected with further increase of temperature. From 600 to 1000 degrees C, the conversion ratio of fuel nitrogen to NO x increased from 8 to 12 %. The char nitrogen was found greatly contribute to NO formation, which may bring difficulty to the abatement of NO x emission during coal gangue calcination. PMID- 25501862 TI - Sexual Aggression Experiences Among Male Victims of Physical Partner Violence: Prevalence, Severity, and Health Correlates for Male Victims and Their Children. AB - Although research has documented the prevalence and health correlates of sexual aggression among women who have experienced severe partner violence (PV), no research has documented the parallel issues among male victims of severe PV. Research also suggests that children of female victims of both physical and sexual PV have worse mental health than children of female victims of physical PV only, but no research has assessed the mental health of children whose fathers experienced both physical and sexual PV. We surveyed 611 men who experienced physical PV from their female partners and sought help. We assessed the types and extent of various forms of PV, the men's mental and physical health, and the mental health of their oldest child. Results showed that almost half of the men experienced sexual aggression in their relationship, and 28 % severe sexual aggression. Increasing levels of severity of sexual aggression victimization was associated with greater prevalence and types of other forms of PV. In addition, greater levels of severity of sexual aggression victimization among the men was significantly associated with depression symptoms, post-traumatic stress disorder symptoms, physical health symptoms, and poor health, and attention deficit and affective symptoms among their children. These associations held after controlling for demographics and other violence and trauma exposure. Discussion focused on the importance of broadening our conceptualization of PV against men by women to include sexual aggression as well. PMID- 25501861 TI - Utilizing heavy metal-laden water hyacinth biomass in vermicomposting. AB - We studied the efficiency of water treatment by water hyacinth (Eichhornia crassipes) from heavy metals (Zn, Cd, Pb, Cu), as well as a possibility of using water hyacinth biomass obtained during treatment for vermicomposting by Eisenia fetida and the vermicompost quality in a model experiment. The results showed that the concentration of heavy metals in the trials with water hyacinth decreased within 35 days. We introduced water hyacinth biomass to the organic substrate for vermicomposting, which promoted a significant weight gain of earthworms and growth in their number, as well as a 1.5- to 3-fold increase in coprolite production. In the trial with 40 % of Eichhornia biomass in the mixture, we observed a 26-fold increase in the number and a 16-fold weight gain of big mature individuals with clitellum; an increase in the number of small individuals 40 times and in the number of cocoons 140 times, as compared to the initial substrate. The utilization of water hyacinth biomass containing heavy metals in the mixture led to a 10-fold increase in the number of adult individuals and cocoons, which was higher than in control. We found out that adding 10 % of Eichhornia biomass to the initial mixture affected slightly the number of microorganisms and their species diversity in the vermicompost. Adding Eichhornia biomass with heavy metals reduced the total number of microorganisms and sharply diminished their species diversity. In all trials, adding water hyacinth in the mixture for vermicomposting had a positive impact on wheat biometric parameters in a 14-day laboratory experiment, even in the trial with heavy metals. PMID- 25501864 TI - Punitive attitudes against pedophiles or persons with sexual interest in children: does the label matter? AB - In the present research, we addressed the question of whether people harbor punitive attitudes against individuals sexually interested in children even if no sexual offense is mentioned and whether this effect is amplified by the clinical label pedophilia. In two online studies (total N = 345), participants rated the extent to which they saw individuals sexually interested in children as necessarily committing child sexual abuse (dangerousness), responsible for their sexual interest (intentionality), and clinically disordered (deviance) before judging their endorsement of means of punishment (punitive attitudes). Participants were randomly assigned to one of two conditions in which either the "pedophilia" label or the descriptive term "sexual interest in (prepubescent) children" was included in all items. Across both studies, results showed high degrees of punitive attitudes against sexually deviant men, an effect that was particularly pronounced if the pedophilia label was present. Whereas this was only latently observable in Study 1 (concealed by a suppression effect of reduced ascriptions of intentionality), in Study 2 no such suppression was observed. Unlike any other stigma we know of, punitive attitudes against pedophiles were associated positively with social desirability, suggesting that participants saw it as particularly socially desirable to condemn someone based on their deviant sexual interest. PMID- 25501863 TI - Pubertal timing and sexual risk behaviors among rural African American male youth: testing a model based on life history theory. AB - Life History Theory (LHT), a branch of evolutionary biology, describes how organisms maximize their reproductive success in response to environmental conditions. This theory suggests that challenging environmental conditions will lead to early pubertal maturation, which in turn predicts heightened risky sexual behavior. Although largely confirmed among female adolescents, results with male youth are inconsistent. We tested a set of predictions based on LHT with a sample of 375 African American male youth assessed three times from age 11 to age 16. Harsh, unpredictable community environments and harsh, inconsistent, or unregulated parenting at age 11 were hypothesized to predict pubertal maturation at age 13; pubertal maturation was hypothesized to forecast risky sexual behavior, including early onset of intercourse, substance use during sexual activity, and lifetime numbers of sexual partners. Results were consistent with our hypotheses. Among African American male youth, community environments were a modest but significant predictor of pubertal timing. Among those youth with high negative emotionality, both parenting and community factors predicted pubertal timing. Pubertal timing at age 13 forecast risky sexual behavior at age 16. Results of analyses conducted to determine whether environmental effects on sexual risk behavior were mediated by pubertal timing were not significant. This suggests that, although evolutionary mechanisms may affect pubertal development via contextual influences for sensitive youth, the factors that predict sexual risk behavior depend less on pubertal maturation than LHT suggests. PMID- 25501865 TI - Iron and zinc sensing in cells and the body. PMID- 25501866 TI - Determinants of tree assemblage composition at the mesoscale within a subtropical eucalypt forest. AB - A variety of environmental processes, including topography, edaphic and disturbance factors can influence vegetation composition. The relative influence of these patterns has been known to vary with scale, however, few studies have focused on environmental drivers of composition at the mesoscale. This study examined the relative importance of topography, catchment flow and soil in influencing tree assemblages in Karawatha Forest Park; a South-East Queensland subtropical eucalypt forest embedded in an urban matrix that is part of the Terrestrial Ecosystem Research Network South-East Queensland Peri-urban SuperSite. Thirty-three LTER plots were surveyed at the mesoscale (909 ha), where all woody stems >=1.3 m high rooted within plots were sampled. Vegetation was divided into three cohorts: small (>=1-10 cm DBH), intermediate (>=10-30 cm DBH), and large (>=30 cm DBH). Plot slope, aspect, elevation, catchment area and location and soil chemistry and structure were also measured. Ordinations and smooth surface modelling were used to determine drivers of vegetation assemblage in each cohort. Vegetation composition was highly variable among plots at the mesoscale (plots systematically placed at 500 m intervals). Elevation was strongly related to woody vegetation composition across all cohorts (R2: 0.69 0.75). Other topographic variables that explained a substantial amount of variation in composition were catchment area (R2: 0.43-0.45) and slope (R2: 0.23 0.61). Soil chemistry (R2: 0.09-0.75) was also associated with woody vegetation composition. While species composition differed substantially between cohorts, the environmental variables explaining composition did not. These results demonstrate the overriding importance of elevation and other topographic features in discriminating tree assemblage patterns irrespective of tree size. The importance of soil characteristics to tree assemblages was also influenced by topography, where ridge top sites were typically drier and had lower soil nutrient levels than riparian areas. PMID- 25501867 TI - Dimensions of the operationalized psychodynamic diagnosis system that predict long-term outcome after inpatient psychotherapy. AB - BACKGROUND/AIMS: To determine whether the Operationalized Psychodynamic Diagnosis (OPD) system can be useful in predicting patient outcome in the long term. METHODS: OPD was assessed by the therapists prior to and after inpatient treatment. Patients completed psychometric scales at the start and completion of psychosomatic-psychotherapeutic inpatient treatment and at the follow-up. Outcome was defined by the general factor emerging from a principal component analysis of the Brief Symptom Inventory, Hospital Anxiety and Depression Scale and Inventory of Interpersonal Problems at katamnesis, representing individual differences in general distress. RESULTS: Several dimensions of the OPD system proved to be predictors of general distress at the follow-up in 253 former inpatients. Negative predictors of long-term outcome were the high internal impediments to change, namely high secondary gains from illness and also less integrated structural abilities. Positive OPD predictors of long-term outcome were the treatment success achieved at the end of inpatient psychotherapy in changing the illness concept towards a psychological understanding of symptoms, lower levels of complaints and a higher functional level. Also the achieved level of awareness for the individual maladaptive behavioral pattern is predictive of a favorable long-term outcome. CONCLUSIONS: The results provide evidence for the clinical relevance and the predictive value of OPD. (c) 2014 S. Karger AG, Basel. PMID- 25501868 TI - Randomized, blinded, placebo- and positive-controlled crossover study to determine the effect of multiple doses of apixaban on the QTc interval. AB - Apixaban is an oral, direct factor Xa inhibitor indicated for the prevention and treatment of thromboembolic disease. This randomized, blinded, 4-way crossover study investigated the potential effect of apixaban on the QTc interval. Forty healthy subjects (39 completers) each received 3 days of the following treatments: blinded apixaban 10 mg once daily (QD), 50 mg QD (supratherapeutic), matched apixaban placebo QD, and a single dose of open-label moxifloxacin 400 mg on Day 3, preceded by 2 days of placebo QD. Triplicate electrocardiograms obtained over 24 hours on Days -1 (baseline) and 3 were read by a blinded third party. The mean placebo-adjusted, time-matched, Fridericia-corrected change from baseline QTc (DeltaDeltaQTcF) for apixaban and moxifloxacin was estimated at each time point. The maximum DeltaDeltaQTcF was 1.51 milliseconds (one-sided upper 95% confidence interval [CI] 3.71 milliseconds) after apixaban 50 mg QD, 1.36 milliseconds (one-sided upper 95%CI 3.54 milliseconds) after apixaban 10 mg QD, and 10.21 milliseconds (lower 95%CI 8.07 milliseconds) after moxifloxacin. Concentration-response analysis suggested no evidence of a positive relationship between apixaban concentration and DeltaQTcF. Apixaban doses up to 50 mg QD for 3 days were well tolerated and did not prolong the QTc interval in healthy subjects. PMID- 25501869 TI - Translating thyroid hormone effects into clinical practice: the relevance of thyroid hormone receptor alpha1 in cardiac repair. AB - Thyroid hormone (TH) appears to have a critical role in cardiac repair after injury beyond its role in development and metabolism homeostasis. This unique action is due to the fact that TH effect on the heart is shown to be differentiated depending on its administration on injured or healthy myocardium. Thus, TH can limit ischemia-reperfusion injury via a fine balance between pro apoptotic and pro-survival signaling pathways. This response is thyroid hormone receptor (TRalpha1) dependent. Furthermore, an interaction between stress-induced growth kinase signaling and TRalpha1 is shown to occur and determine postischemic remodeling and cardiac recovery depending on the availability of TH. This new evidence is consistent with clinical observations showing the cardioprotective effect of TH treatment in cardiac surgery, transplantation and heart failure. TH and/or thyroid analogs may be novel agents in treating heart diseases. PMID- 25501870 TI - Preformulation studies on solid self-emulsifying systems in powder form containing magnesium aluminometasilicate as porous carrier. AB - The influence of alkaline and the neutral grade of magnesium aluminometasilicate as a porous solid carrier for the liquid self-emulsifying formulation with ibuprofen is investigated. Ibuprofen is dissolved in Labrasol, then this solution is adsorbed on the silicates. The drug to the silicate ratio is 1:2, 1:4, and 1:6, respectively. The properties of formulations obtained are analyzed, using morphological, porosity, crystallinity, and dissolution studies. Three solid self emulsifying (S-SE) formulations containing Neusilin SG2 and six consisting of Neusilin US2 are in the form of powder without agglomerates. The nitrogen adsorption method shows that the solid carriers are mesoporous but they differ in a specific surface area, pore area, and the volume of pores. The adsorption of liquid SE formulation on solid silicate particles results in a decrease in their porosity. If the neutral grade of magnesium aluminometasilicate is used, the smallest pores, below 10 nm, are completely filled with liquid formulation, but there is still a certain number of pores of 40-100 nm. Dissolution studies of liquid SEDDS carried out in pH = 1.2 show that Labrasol improves the dissolution of ibuprofen as compared to the pure drug. Ibuprofen dissolution from liquid SE formulations examined in pH of 7.2 is immediate. The adsorption of the liquid onto the particles of the silicate causes a decrease in the amount of the drug released. Finally, more ibuprofen is dissolved from S-SE that consist of the neutral grade of magnesium aluminometasilicate than from the formulations containing the alkaline silicate. PMID- 25501871 TI - Pediatric suppositories of sulpiride solid dispersion for treatment of Tourette syndrome: in vitro and in vivo investigations. AB - Pharmaceutical development was adopted in the current study to propose a pediatric rectal formulation of sulpiride as a substitute to the available oral or parenteral formulations in the management of Tourette syndrome (TS). The goal was to formulate a product that is easy to use, stable, and highly bioavailable and to achieve a rapid clinical efficacy. Towards this aim, sulpiride solid dispersion (SD) with tartaric acid at a weight ratio of 1:0.25 was incorporated into different suppository bases, namely witepsol W25, witepsol H15, witepsol E75, suppocire NA, suppocire A, glycerogelatin, and polyethylene glycols. The formulae were evaluated in vitro using different pharmacotechnical methods such as visual, melting, weight and content uniformities, drug release, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and X-ray diffraction (XRD) analyses. In vivo bioavailability was also assessed in rabbits to compare the bioavailability of either raw sulpiride-incorporated or its SD incorporated witepsol H15-based suppositories to its oral suspension (reference). Sulpiride SD-incorporated witepsol H15 formulation showed acceptable in vitro characteristics with a bioavailability of 117% relative to oral dosing, which excel that in humans (27% after dosing of oral product). In addition, the proposed formula not only passed the 6-month stability study but also proposed a promising scale-up approach. Hence, it showed a great potential for pediatric product development to manage TS in rural areas. PMID- 25501872 TI - Polymeric micelles for multi-drug delivery in cancer. AB - Drug combinations are common in cancer treatment and are rapidly evolving, moving beyond chemotherapy combinations to combinations of signal transduction inhibitors. For the delivery of drug combinations, i.e., multi-drug delivery, major considerations are synergy, dose regimen (concurrent versus sequential), pharmacokinetics, toxicity, and safety. In this contribution, we review recent research on polymeric micelles for multi-drug delivery in cancer. In concurrent drug delivery, polymeric micelles deliver multi-poorly water-soluble anticancer agents, satisfying strict requirements in solubility, stability, and safety. In sequential drug delivery, polymeric micelles participate in pretreatment strategies that "prime" solid tumors and enhance the penetration of secondarily administered anticancer agent or nanocarrier. The improved delivery of multiple poorly water-soluble anticancer agents by polymeric micelles via concurrent or sequential regimens offers novel and interesting strategies for drug combinations in cancer treatment. PMID- 25501873 TI - Influence of colloidal silicon dioxide on gel strength, robustness, and adhesive properties of diclofenac gel formulation for topical application. AB - The objective of this study is to identify the extent of stiffness, adhesiveness, and thixotropic character of a three-dimensional gel network of a 1% diclofenac sodium topical gel formulation in the presence and absence of colloidal silicon dioxide (CSD) and assess its ease of application and adhesiveness using both objective and subjective analysis. The 1% diclofenac gel was mixed with different amounts of CSD (e.g., 0.5, 1, 2, 3, and 5% w/w) and allowed to equilibrate prior to testing. The texture analyzer in combination with a cone-cap assembly was used to objectively investigate the changes in spreadability and adhesiveness of the gel system before and after addition of CSD. Results indicate that an increase in pliability and adhesiveness at levels >=2 to <=5% w/w of CSD dispersed in the gel ensues. For subjective analysis, gels with (2% w/w) CSD and in the absence of CSD were uniformly applied to a 20-cm(2) (5 cm * 4 cm) surface area on the forearms of healthy volunteers and vehicle preferences by the volunteers regarding ease of application, durability on the skin, compliance, and feelings concerning its textural properties were assessed. It appears that changes in the gel formulation with the addition of CSD enhance gel viscosity and bonding to the skin. Results further show that changes in physical and rheological characteristics of gel containing 2% w/w CSD did not significantly change subject preferences for the gel preparations. These findings may help formulators to have additional options to develop more robust and cost-effective formulations. PMID- 25501874 TI - Two functional loci in the promoter of EPAS1 gene involved in high-altitude adaptation of Tibetans. AB - EPAS1 involves in the hypoxic response and is suggested to be responsible for the genetic adaptation of high-altitude hypoxia in Tibetans. However, the detailed molecular mechanism remains unknown. In this study, a single nucleotide polymorphism rs56721780:G>C and an insertion/deletion (indel) polymorphism -742 indel in the promoter region showed divergence between Tibetans and non-Tibetan lowlanders. rs56721780:G>C regulated the transcription of EPAS1 by IKAROS family zinc finger 1 (IKZF1), which was identified as a new transcriptional repressor for EPAS1 gene. It demonstrated that the C allele of rs56721780:G>C decreased the binding of IKZF1, leading to the attenuated transcriptional repression of EPAS1 gene. The insertion at -742 indel provided a new binding site for Sp1 and was related to the activation of EPAS1 promoter. Further functional analysis revealed that lysyl oxidase (LOX) gene, which was reported to be responsible for extracellular matrix protein cross-linking of amnion previously, was a direct target of EPAS1. The CC genotype at rs56721780:G>C and the insertion genotype at 742 indel were found associated with higher EPAS1 and LOX expression levels in amnion, as well as higher birth weight of Tibetan newborns, suggesting that EPAS1 gene might play important roles in the development of amnion, fetus growth and high-altitude adaptation of Tibetans. PMID- 25501875 TI - Inhibition of transglutaminase exacerbates polyglutamine-induced neurotoxicity by increasing the aggregation of mutant ataxin-3 in an SCA3 Drosophila model. AB - Transglutaminases (TGs) comprise a family of Ca(2+)-dependent enzymes that catalyze protein cross-linking, which include nine family members in humans but only a single homolog in Drosophila with three conserved domains. Drosophila Tg plays important roles in cuticle morphogenesis, hemolymph clotting, and innate immunity. Mammalian tissue TG (TG2) is involved in polyglutamine diseases (polyQ diseases), and TG6 has been identified as a causative gene of a novel spinocerebellar ataxia, SCA35. Using a well-established SCA3 fly model, we found that RNA interference-mediated suppression of Tg aggravated polyQ-induced neurodegenerative phenotypes. The administration of cystamine, a known effective Tg inhibitor, enhanced ommatidial degeneration in SCA3 flies. We also demonstrated that the aggregates of pathogenic ataxin-3 increased greatly, when the Tg activity was repressed. These findings indicate that Tg is crucial for polyQ-induced neurotoxicity because Tg ablation resulted in more severe neurodegeneration due to the elevated accumulation of insoluble ataxin-3 complexes in the SCA3 Drosophila model. PMID- 25501876 TI - Rupture of the spleen following thoracoscopic spine surgery in a patient with chronic pancreatitis. AB - PURPOSE: To highlight the perioperative risk of intracapsular haematoma of the spleen or splenic ruptures during thoracoscopic spine surgery in patients with chronic pancreatitis. METHODS: A 38-year-old patient with an L1 burst fracture (AO A3.3) underwent a standard thoracoscopic corpectomy and replacement of the vertebral body with an extendable vertebral body replacement 10 days after posterior instrumentation of T12-L2. In patients history chronic abusive alcoholism with related diseases such as pancreatitis, followed by hemipancreatectomy was found. Six hours after the surgery, the patient became hemodynamically unstable. An emergency CT scan revealed a splenic rupture. Emergent splenectomy was performed. RESULTS: After surgical treatment of the L1 burst fracture, a rupture of the spleen was detected. An immediate splenectomy was performed. At the 18-month follow-up, an unchanged stable position of the cage was observed on CT. CONCLUSIONS: Due to its proximity to the thoracolumbar junction, the spleen is vulnerable to injury during spine surgery. If the patient has undergone previous intra-abdominal operations or chronic inflammation of the pancreas is found, special care of the spleen during the operation is necessary. PMID- 25501877 TI - Large-scale quantitative analysis of painting arts. AB - Scientists have made efforts to understand the beauty of painting art in their own languages. As digital image acquisition of painting arts has made rapid progress, researchers have come to a point where it is possible to perform statistical analysis of a large-scale database of artistic paints to make a bridge between art and science. Using digital image processing techniques, we investigate three quantitative measures of images - the usage of individual colors, the variety of colors, and the roughness of the brightness. We found a difference in color usage between classical paintings and photographs, and a significantly low color variety of the medieval period. Interestingly, moreover, the increment of roughness exponent as painting techniques such as chiaroscuro and sfumato have advanced is consistent with historical circumstances. PMID- 25501879 TI - 'Contractual' and 'cooperative' civic engagement: The emergence and roles of 'flood action groups' in England and Wales. AB - Devolution of responsibilities is transforming how flood risk is managed in many countries. Research assessing the emergence and role of a new element in the governance of flood risk management in England explored the numerous 'flood action groups' that have developed over the last decade. We identified two broad categories of relationship between the public and authorities. The first displays 'contractual' characteristics: a level of protection provided by the authority in exchange for taxes or similar support. The second embodies a 'collaborative' relationship: public knowledge, social and financial resources are equal and complementary to those of authority, and seeking 'collective security'. In general, the former were more successful than the latter, but common lessons were that success in FRM should not be defined purely as the ability to prevent flooding, but as the ability to access a variety of resources across different levels of society at different stages of flood risk management. PMID- 25501878 TI - Automatic correction of hand pointing in stereoscopic depth. AB - In order to examine whether stereoscopic depth information could drive fast automatic correction of hand pointing, an experiment was designed in a 3D visual environment in which participants were asked to point to a target at different stereoscopic depths as quickly and accurately as possible within a limited time window (<=300 ms). The experiment consisted of two tasks: "depthGO" in which participants were asked to point to the new target position if the target jumped, and "depthSTOP" in which participants were instructed to abort their ongoing movements after the target jumped. The depth jump was designed to occur in 20% of the trials in both tasks. Results showed that fast automatic correction of hand movements could be driven by stereoscopic depth to occur in as early as 190 ms. PMID- 25501880 TI - Dietary patterns and fatty liver disease. AB - PURPOSE OF REVIEW: The association of dietary intake and fatty liver disease (FLD) is of importance for disease prevention. Dietary pattern analysis enables the investigation of overall diet and permits to take interactions and cumulative effects of dietary components into account. This review summarizes recent findings on the association of dietary patterns and FLD. RECENT FINDINGS: A systematic review of articles published from March 2013 to August 2014 identified four relevant observational (n = 116-995) and one interventional study (n = 12). The Healthy Eating Index and Dietary Diversity Scores were not related to nonalcoholic FLD. A Mediterranean diet intervention resulted in a significant decrease in liver fat content over 6 weeks. Exploratory approaches revealed a 'Western pattern' and a pattern having alcohol, meat (poultry) and tea in common with a hypothesis-driven pattern, which were both associated with FLD. SUMMARY: Most studies were limited by a cross-sectional design and small-to-moderate sample sizes. Observational studies applying exploratory approaches and a Mediterranean diet intervention demonstrated most promising results relating dietary patterns to FLD. Prospective studies with measurement of liver fat on a continuous scale at multiple time points in large samples are important requisites to improve our understanding of FLD cause. PMID- 25501882 TI - Compressibility, thermal expansion coefficient and heat capacity of CH4 and CO2 hydrate mixtures using molecular dynamics simulations. AB - Understanding the thermal and mechanical properties of CH4 and CO2 hydrates is essential for the replacement of CH4 with CO2 in natural hydrate deposits as well as for CO2 sequestration and storage. In this work, we present isothermal compressibility, isobaric thermal expansion coefficient and specific heat capacity of fully occupied single-crystal sI-CH4 hydrates, CO2 hydrates and hydrates of their mixture using molecular dynamics simulations. Eight rigid/nonpolarisable water interaction models and three CH4 and CO2 interaction potentials were selected to examine the atomic interactions in the sI hydrate structure. The TIP4P/2005 water model combined with the DACNIS united-atom CH4 potential and TraPPE CO2 rigid potential were found to be suitable molecular interaction models. Using these molecular models, the results indicate that both the lattice parameters and the compressibility of the sI hydrates agree with those from experimental measurements. The calculated bulk modulus for any mixture ratio of CH4 and CO2 hydrates varies between 8.5 GPa and 10.4 GPa at 271.15 K between 10 and 100 MPa. The calculated thermal expansion and specific heat capacities of CH4 hydrates are also comparable with experimental values above approximately 260 K. The compressibility and expansion coefficient of guest gas mixture hydrates increase with an increasing ratio of CO2-to-CH4, while the bulk modulus and specific heat capacity exhibit the opposite trend. The presented results for the specific heat capacities of 2220-2699.0 J kg(-1) K(-1) for any mixture ratio of CH4 and CO2 hydrates are the first reported so far. These computational results provide a useful database for practical natural gas recovery from CH4 hydrates in deep oceans where CO2 is considered to replace CH4, as well as for phase equilibrium and mechanical stability of gas hydrate-bearing sediments. The computational schemes also provide an appropriate balance between computational accuracy and cost for predicting mechanical and thermal properties of gas hydrates in the high temperature range (>=260 K), and the schemes may be useful for the study of other complex hydrate systems. PMID- 25501881 TI - Rapid and continuous magnetic separation in droplet microfluidic devices. AB - We present a droplet microfluidic method to extract molecules of interest from a droplet in a rapid and continuous fashion. We accomplish this by first marginalizing functionalized super-paramagnetic beads within the droplet using a magnetic field, and then splitting the droplet into one droplet containing the majority of magnetic beads and one droplet containing the minority fraction. We quantitatively analysed the factors which affect the efficiency of marginalization and droplet splitting to optimize the enrichment of magnetic beads. We first characterized the interplay between the droplet velocity and the strength of the magnetic field and its effect on marginalization. We found that marginalization is optimal at the midline of the magnet and that marginalization is a good predictor of bead enrichment through splitting at low to moderate droplet velocities. Finally, we focused our efforts on manipulating the splitting profile to improve the enrichment provided by asymmetric splitting. We designed asymmetric splitting forks that employ capillary effects to preferentially extract the bead-rich regions of the droplets. Our strategy represents a framework to optimize magnetic bead enrichment methods tailored to the requirements of specific droplet-based applications. We anticipate that our separation technology is well suited for applications in single-cell genomics and proteomics. In particular, our method could be used to separate mRNA bound to poly-dT functionalized magnetic microparticles from single cell lysates to prepare single-cell cDNA libraries. PMID- 25501883 TI - Prevalence and determinations of physical inactivity among public hospital employees in Shanghai, China: a cross-sectional study. AB - This study aims to explore the prevalence and determinations of physical inactivity among hospital employees in Shanghai, China. A cross-sectional study of 4612 employees aged 19 to 68 years was conducted through stratified cluster sampling from different classes of Shanghai hospitals in 2011. The total physical activity was evaluated using the metabolic equivalent according to the Global Physical Activity Questionnaire. Among the participants, 38.5%, 32.3%, and 64.6% of the employees are inactive at work, commuting, and taking leisure time, respectively. Up to 41.8% of the men and 37.8% of the women (P = 0.012) are physically inactive. When the age and educational level are adjusted, male doctors and medical technicians show a higher percentage of physical inactivity than male workers in logistics (P = 0.001). Among females, employees who are working in second- and third-class hospitals show a higher proportion of physical inactivity than those who are working in community health care centers. Logistic regression analyses show that the odds ratios (ORs) of leisure-time physical inactivity associated with the intensity of physical activity at work are 2.259, 2.897, and 4.266 for men (P < 0.001) and 2.456, 3.259, and 3.587 for women (P < 0.001), respectively. The time during commuting activities is significantly associated with leisure-time physical inactivity in either sex (OR = 2.116 for men and 2.173 for women, P < 0.001). Hospital employees, particularly doctors and medical technicians, show a higher proportion of physical inactivity than other inhabitants in Shanghai. The time and intensity of activity at work and commuting are associated with leisure-time activities. PMID- 25501884 TI - Peripheral nerve blocks for postoperative pain after major knee surgery. AB - BACKGROUND: Major knee surgery is a common operative procedure to help people with end-stage knee disease or trauma to regain mobility and have improved quality of life. Poorly controlled pain immediately after surgery is still a key issue for this procedure. Peripheral nerve blocks are localized and site-specific analgesic options for major knee surgery. The increasing use of peripheral nerve blocks following major knee surgery requires the synthesis of evidence to evaluate its effectiveness and safety, when compared with systemic, local infiltration, epidural and spinal analgesia. OBJECTIVES: To examine the efficacy and safety of peripheral nerve blocks for postoperative pain control following major knee surgery using methods that permit comparison with systemic, local infiltration, epidural and spinal analgesia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2014), MEDLINE and EMBASE, from their inception to February 2014. We identified ongoing studies by searching trial registries, including the metaRegister of controlled trials (mRCT), clinicaltrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: We included participant-blind, randomized controlled trials of adult participants (15 years or older) undergoing major knee surgery, in which peripheral nerve blocks were compared to systemic, local infiltration, epidural and spinal analgesia for postoperative pain relief. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility and extracted data. We recorded information on participants, methods, interventions, outcomes (pain intensity, additional analgesic consumption, adverse events, knee range of motion, length of hospital stay, hospital costs, and participant satisfaction). We used the 5-point Oxford quality and validity scale to assess methodological quality, as well as criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We conducted meta analysis of two or more studies with sufficient data to investigate the same outcome. We used the I2 statistic to explore the heterogeneity. If there was no significant heterogeneity (I2 value 0% to 40%), we used a fixed-effect model for meta-analysis, but otherwise we used a random-effects model. For dichotomous data, we present results as a summary risk ratio (RR) and a 95% confidence interval (95% CI). Where possible, we calculated the number needed to treat for an additional beneficial outcome (NNTB) or for an additional harmful outcome (NNTH), together with 95% CIs. For continuous data, we used the mean difference (MD) and 95% CI for similar outcome measures. We describe the findings of individual studies where pooling of data was not possible. MAIN RESULTS: According to the eligibility criteria, we include 23 studies with 1571 participants, with high methodological quality overall. The studies compared peripheral nerve blocks adjunctive to systemic analgesia with systemic analgesia alone (19 studies), peripheral nerve blocks with local infiltration (three studies), and peripheral nerve blocks with epidural analgesia (one study). No study compared peripheral nerve blocks with spinal analgesia.Compared with systemic analgesia alone, peripheral nerve blocks adjunctive to systemic analgesia resulted in a significantly lower pain intensity score at rest, using a 100 mm visual analogue scale, at all time periods within 72 hours postoperatively, including the zero to 23 hours interval (MD -11.85, 95% CI 20.45 to -3.25, seven studies, 390 participants), the 24 to 47 hours interval (MD -12.92, 95% CI -19.82 to -6.02, six studies, 320 participants) and the 48 to 72 hours interval (MD -9.72, 95% CI -16.75 to -2.70, four studies, 210 participants). Subgroup analyses suggested that the high levels of statistical variation in our analyses could be explained by larger effects in people undergoing total knee arthroplasty compared with other types of surgery. Pain intensity was also significantly reduced on movement in the 48 to 72 hours interval postoperatively (MD -6.19, 95% CI -11.76 to -0.62, two studies, 112 participants). There was no significant difference on movement between these two groups in the time period of zero to 23 hours (MD -6.95, 95% CI -15.92 to 2.01, five studies, 304 participants) and 24 to 47 hours (MD -8.87, 95% CI -27.77 to 10.03, three studies, 182 participants). The included studies reported diverse types of adverse events, and we did not conduct a meta-analysis on specific types of adverse event. The numbers of studies and participants were also too few to draw conclusions on the other prespecified outcomes of: additional analgesic consumption; median time to remedication; knee range of motion; median time to ambulation; length of hospital stay; hospital costs; and participant satisfaction. There were insufficient data to compare peripheral nerve blocks and local infiltration or between peripheral nerve blocks and epidural analgesia. AUTHORS' CONCLUSIONS: All of the included studies reported the main outcome of pain intensity but did not cover all the secondary outcomes of interest. The current review provides evidence that the use of peripheral nerve blocks as adjunctive techniques to systemic analgesia reduced pain intensity when compared with systemic analgesia alone after major knee surgery. There were too few data to draw conclusions on other outcomes of interest. More trials are needed to demonstrate a significant difference when compared with local infiltration, epidural analgesia and spinal analgesia. PMID- 25501885 TI - Assessing changes over time in healthcare provider performance: addressing regression to the mean over multiple time points. AB - In recent years, the evaluation of healthcare provider performance has become standard for governments, insurance companies, and other stakeholders. Often, performance is compared across providers using indicators in one time period, for example a year. However it is often important to assess changes in the performance of individual providers over time. Such analyses can be used to determine if any providers have significant improvements, deteriorations, unusual patterns or systematic changes in performance. Studies which monitor healthcare provider performance in this way have to date typically been limited to comparing performance in the most recent period with performance in a previous period. It is also important to consider a longer-term view of performance and assess changes over more than two periods. In this paper, we develop test statistics that account for variable numbers of prior performance indicators, and show that these are particularly useful for assessing consecutive improvements or deteriorations in performance. We apply the tests to coronary artery bypass graft mortality rates in New York State hospitals, and mortality data from Australian and New Zealand intensive care units. Although our applications are to medical data, the new tests have broad application in other areas. PMID- 25501886 TI - Characterization of an Endophytic Gloeosporium sp. and Its Novel Bioactivity with "Synergistans". AB - Gloeosporium sp. (OR-10) was isolated as an endophyte of Tsuga heterophylla (Western hemlock). Both ITS and 18S sequence analyses indicated that the organism best fits either Hypocrea spp. or Trichoderma spp., but neither of these organisms possess conidiophores associated with acervuli, in which case the endophytic isolate OR-10 does. Therefore, the preferred taxonomic assignment was primarily based on the morphological features of the organism as one belonging to the genus Gloeosporium sp. These taxonomic observations clearly point out that limited ITS and 18S sequence information can be misleading when solely used in making taxonomic assignments. The volatile phase of this endophyte was active against a number of plant pathogenic fungi including Phytophthora palmivora, Rhizoctonia solani, Ceratocystis ulmi, Botrytis cinerea, and Verticillium dahliae. Among several terpenes and furans, the most abundantly produced compound in the volatile phase was 6-pentyl-2H-pyran-2-one, a compound possessing antimicrobial activities. When used in conjunction with microliter amounts of any in a series of esters or isobutyric acid, an enhanced inhibitory response occurred with each test fungus that was greater than that exhibited by Gloeosporium sp. or the compounds tested individually. Compounds behaving in this manner are hereby designated "synergistans." An expression of the "median synergistic effect," under prescribed conditions, has been termed the mSE50. This value describes the amount of a potential synergistan that is required to yield an additional median 50% inhibition of a target organism. In this report, the mSE50s are reported for a series of esters and isobutyric acid. The results indicated that isoamyl acetate, allyl acetate, and isobutyric acid generally possessed the lowest mSE50 values. The value and potential importance of these microbial synergistic effects to the microbial environment are also discussed. PMID- 25501887 TI - Characterization of Beta-lactamases in Faecal Enterobacteriaceae Recovered from Healthy Humans in Spain: Focusing on AmpC Polymorphisms. AB - The intestinal tract is a huge reservoir of Enterobacteriaceae, some of which are opportunist pathogens. Several genera of these bacteria harbour intrinsic antibiotic resistance genes, such as ampC genes in species of Citrobacter, Enterobacter or Escherichia genera. In this work, beta-lactamases and other resistance mechanisms have been characterized in Enterobacteriaceae isolates recovered from healthy human faecal samples, focusing on the ampC beta-lactamase genes. Fifty human faecal samples were obtained, and 70 Enterobacteriaceae bacteria were isolated: 44 Escherichia coli, 4 Citrobacter braakii, 9 Citrobacter freundii, 8 Enterobacter cloacae, 1 Proteus mirabilis, 1 Proteus vulgaris, 1 Klebsiella oxytoca, 1 Serratia sp. and 1 Cronobacter sp. A high percentage of resistance to ampicillin was detected (57%), observing the AmpC phenotype in 22 isolates (31%) and the ESBL phenotype in 3 isolates. AmpC molecular characterization showed high diversity into bla CMY and bla ACT genes from Citrobacter and Enterobacter species, respectively, and the pulsed-field gel electrophoresis (PFGE) analysis demonstrated low clonality among them. The prevalence of people colonized by strains carrying plasmid-mediated ampC genes obtained in this study was 2%. The unique plasmid-mediated bla AmpC identified in this study was the bla CMY-2 gene, detected in an E. coli isolate ascribed to the sequence type ST405 which belonged to phylogenetic group D. The hybridization and conjugation experiments demonstrated that the ISEcp1-bla CMY-2-blc structure was carried by a ~78-kb self-transferable IncK plasmid. This study shows a high polymorphism among beta-lactamase genes in Enterobacteriaceae from healthy people microbiota. Extensive AmpC-carrier studies would provide important information and could allow the anticipation of future global health problems. PMID- 25501888 TI - Microbial community composition and ultrastructure of granules from a full-scale anammox reactor. AB - Granules in anammox reactors contain besides anammox bacteria other microbial communities whose identity and relationship with the anammox bacteria are not well understood. High calcium concentrations are often supplied to anammox reactors to obtain sufficient bacterial aggregation and biomass retention. The aim of this study was to provide the first characterization of bacterial and archaeal communities in anammox granules from a full-scale anammox reactor and to explore on the possible role of calcium in such aggregates. High magnification imaging using backscattered electrons revealed that anammox bacteria may be embedded in calcium phosphate precipitates. Pyrosequencing of 16S rRNA gene fragments showed, besides anammox bacteria (Brocadiacea, 32%), substantial numbers of heterotrophic bacteria Ignavibacteriacea (18%) and Anaerolinea (7%) along with heterotrophic denitrifiers Rhodocyclacea (9%), Comamonadacea (3%), and Shewanellacea (3%) in the granules. It is hypothesized that these bacteria may form a network in which heterotrophic denitrifiers cooperate to achieve a well functioning denitrification system as they can utilize the nitrate intrinsically produced by the anammox reaction. This network may provide a niche for the proliferation of archaea. Hydrogenotrophic methananogens, which scavenge the key fermentation product H2, were the most abundant archaea detected. Cells resembling the polygon-shaped denitrifying methanotroph Candidatus Methylomirabilis oxyfera were observed by electron microscopy. It is hypothesized that the anammox process in a full-scale reactor triggers various reactions overall leading to efficient denitrification and a sink of carbon as biomass in anammox granules. PMID- 25501889 TI - pH as a Driver for Ammonia-Oxidizing Archaea in Forest Soils. AB - In this study, we investigated the impact of soil pH on the diversity and abundance of archaeal ammonia oxidizers in 27 different forest soils across Germany. DNA was extracted from topsoil samples, the amoA gene, encoding ammonia monooxygenase, was amplified; and the amplicons were sequenced using a 454-based pyrosequencing approach. As expected, the ratio of archaeal (AOA) to bacterial (AOB) ammonia oxidizers' amoA genes increased sharply with decreasing soil pH. The diversity of AOA differed significantly between sites with ultra-acidic soil pH (<3.5) and sites with higher pH values. The major OTUs from soil samples with low pH could be detected at each site with a soil pH <3.5 but not at sites with pH >4.5, regardless of geographic position and vegetation. These OTUs could be related to the Nitrosotalea group 1.1 and the Nitrososphaera subcluster 7.2, respectively, and showed significant similarities to OTUs described from other acidic environments. Conversely, none of the major OTUs typical of sites with a soil pH >4.6 could be found in the ultra- and extreme acidic soils. Based on a comparison with the amoA gene sequence data from a previous study performed on agricultural soils, we could clearly show that the development of AOA communities in soils with ultra-acidic pH (<3.5) is mainly triggered by soil pH and is not influenced significantly by the type of land use, the soil type, or the geographic position of the site, which was observed for sites with acido-neutral soil pH. PMID- 25501890 TI - Sediment bacterial communities associated with anaerobic biodegradation of bisphenol A. AB - Bisphenol A (BPA) is one of the endocrine-disrupting chemicals that are ubiquitous in aquatic environments. Biodegradation is a major way to clean up the BPA pollution in sediments. However, information on the effective BPA biodegradation in anaerobic sediments is still lacking. The present study investigated the biodegradation potential of BPA in river sediment under nitrate- or sulfate-reducing conditions. After 120-day incubation, a high removal of BPA (93 or 89%) was found in sediment microcosms (amended with 50 mg kg(-1) BPA) under these two anaerobic conditions. Illumina MiSeq sequencing analysis indicated that Proteobacteria, Bacteroidetes, Chloroflexi, Firmicutes, Gemmatimonadetes, and Actinobacteria were the major bacterial groups in BPA degrading sediments. The shift in bacterial community structure could occur with BPA biodegradation. PMID- 25501891 TI - Shifts in soil chemical properties and bacterial communities responding to biotransformed dry olive residue used as organic amendment. AB - Dry olive residue (DOR) is a waste product derived from olive oil extraction and has been proposed as an organic amendment. However, it has been demonstrated that a pre-treatment, such as its transformation by saprophytic fungi, is required before DOR soil application. A greenhouse experiment was designed where 0 and 50 g kg(-1) of raw DOR (DOR), Coriolopsis floccosa-transformed DOR (CORDOR) and Fusarium oxysporum-transformed DOR (FUSDOR) were added to soil. Analyses of the soil chemical properties as well as the structure and relative abundance of bacterial and actinobacterial communities were conducted after 0, 30 and 60 days following amendment. The different amendments produced a slight decrease in soil pH and significant increases in carbon fractions, C/N ratios, phenols and K, with these increases being more significant after DOR application. Quantitative PCR assays of the 16S rRNA gene and PLFA analyses showed that all amendments favoured bacterial growth at 30 and 60 days, although actinobacterial proliferation was more evident after CORDOR and FUSDOR application at 60 days. Bacterial and actinobacterial DGGE multivariate analyses showed that the amendments produced structural changes in both communities, especially after 60 days of amendment. PLFA data analysis identified changes in soil microbial communities according to the amendment considered, with FUSDOR and CORDOR being less disruptive than DOR. Finally, integrated analysis of all data monitored in the present study enabled us to conclude that the greatest impact on soil properties was caused by DOR at 30 days and that soil showed some degree of resilience after this time. PMID- 25501892 TI - Bacterial and archaeal communities in sediments of the north Chinese marginal seas. AB - Microbial communities of the Chinese marginal seas have rarely been reported. Here, bacterial and archaeal community structures and abundance in the surface sediment of four sea areas including the Bohai Sea (BS), North Yellow Sea (NYS), South Yellow Sea (SYS), and the north East China Sea (NECS) were surveyed by 16S ribosomal RNA (rRNA) gene pyrosequencing and quantitative PCR. The results showed that microbial communities of the four geographic areas were distinct from each other at the operational taxonomic unit (OTU) level, whereas the microbial communities of the BS, NYS, and SYS were more similar to each other than to the NECS at higher taxonomic levels. Across all samples, Bacteria were numerically dominant relative to Archaea, and among them, Gammaproteobacteria and Euryarchaeota were predominant in the BS, NYS, and SYS, while Deltaproteobacteria and Thaumarchaeota were prevalent in the NECS. The most abundant bacterial genera were putative sulfur oxidizer and sulfate reducer, suggesting that sulfur cycle processes might prevail in these areas, and the high abundance of dsrB (10(7) 10(8) copies g(-1)) in all sites verified the dominance of sulfate reducer in the north Chinese marginal seas. The differences in sediment sources among the sampling areas were potential explanations for the observed microbial community variations. Furthermore, temperature and dissolved oxygen of bottom water were significant environmental factors in determining both bacterial and archaeal communities, whereas chlorophyll a in sediment was significant only in structuring archaeal community. This study presented an outline of benthic microbial communities and provided insights into understanding the biogeochemical cycles in sediments of the north Chinese marginal seas. PMID- 25501893 TI - The guanine nucleotide exchange factor Vav3 regulates differentiation of progenitor cells in the developing mouse retina. AB - The seven main cell types in the mammalian retina arise from multipotent retinal progenitor cells, a process that is tightly regulated by intrinsic and extrinsic signals. However, the molecular mechanisms that control proliferation, differentiation and cell-fate decisions of retinal progenitor cells are not fully understood yet. Here, we report that the guanine nucleotide exchange factor Vav3, a regulator of Rho-GTPases, is involved in retinal development. We demonstrate that Vav3 is expressed in the mouse retina during the embryonic period. In order to study the role of Vav3 in the developing retina, we generate Vav3-deficient mice. The loss of Vav3 results in an accelerated differentiation of retinal ganglion cells and cone photoreceptors during early and late embryonic development. We provide evidence that more retinal progenitor cells express the late progenitor marker Sox9 in Vav3-deficient mice than in wild-types. This premature differentiation is compensated during the postnatal period and late born cell types such as bipolar cells and Muller glia display normal numbers. Taken together, our data imply that Vav3 is a regulator of retinal progenitor cell differentiation, thus highlighting a novel role for guanine nucleotide exchange factors in retinogenesis. PMID- 25501895 TI - c-Src mediated tyrosine phosphorylation of plakophilin 3 as a new mechanism to control desmosome composition in cells exposed to oxidative stress. AB - Plakophilins (PKP1 to PKP3) are essential for the structure and function of desmosomal junctions as demonstrated by the severe skin defects observed as a result of loss-of-function mutations in mice and men. PKPs play additional roles in cell signaling processes, such as those controlling the cellular stress response and cell proliferation. A key post-translational process controlling PKP function is phosphorylation. We have discovered that reactive oxygen species (ROS) trigger the c-Src kinase-mediated tyrosine (Tyr)-195 phosphorylation of PKP3. This modification is associated with a change in the subcellular distribution of the protein. Specifically, PKP3 bearing phospho-Tyr-195 is released from the desmosomes, suggesting that phospho-Tyr-195 is relevant for the control of desmosome disassembly and function, at least in cells exposed to ROS. Tyr-195 phosphorylation is transient under normal physiological conditions and seems to be strictly regulated, as the activation of particular growth factor receptors results in a modification at this site only when tyrosine phosphatases are inactivated by pervanadate. We have identified Tyr-195 of PKP3 as a phosphorylation target of epidermal growth factor receptor signaling. Interestingly, this PKP3 phosphorylation also occurs in certain poorly differentiated adenocarcinomas of the prostate, suggesting a possible role in tumor progression. Our study thus identifies a new mechanism controlling PKP3 and hence desmosome function in epithelial cells. PMID- 25501894 TI - Striatins as plaque molecules of zonulae adhaerentes in simple epithelia, of tessellate junctions in stratified epithelia, of cardiac composite junctions and of various size classes of lateral adherens junctions in cultures of epithelia- and carcinoma-derived cells. AB - Proteins of the striatin family (striatins 1-4; sizes ranging from 90 to 110 kDa on SDS-polyacrylamide gel electrophoresis) are highly homologous in their amino acid sequences but can differ in their cell-type-specific gene expression patterns and biological functions. In various cell types, we have found one, two or three polypeptides of this evolutionarily old and nearly ubiquitous family of proteins known to serve as scaffold proteins for diverse protein complexes. Light and electron microscopic immunolocalization methods have revealed striatins in mammalian cell-cell adherens junctions (AJs). In simple epithelia, we have localized striatins as constitutive components of the plaques of the subapical zonulae adhaerentes of cells, including intestinal, glandular, ductal and urothelial cells and hepatocytes. Striatins colocalize with E-cadherin or E-N cadherin heterodimers and with the plaque proteins alpha- and beta-catenin, p120 and p0071. In some epithelia and carcinomas and in cultured cells derived therefrom, striatins are also seen in lateral AJs. In stratified epithelia and in corresponding squamous cell carcinomas, striatins can be found in plaques of some forms of tessellate junctions. Moreover, striatins are major plaque proteins of composite junctions (CJs; areae compositae) in the intercalated disks connecting cardiomyocytes, colocalizing with other CJ molecules, including plectin and ankyrin-G. We discuss the "multimodulator" scaffold roles of striatins in the initiation and regulation of the formation of various complex particles and structures. We propose that striatins are included in the diagnostic candidate list of proteins that, in the CJs of human hearts, can occur in mutated forms in the pathogeneses of hereditary cardiomyopathies, as seen in some types of genetically determined heart damage in boxer dogs. PMID- 25501896 TI - Non-enzymatic isolation followed by supplementation of basic fibroblast growth factor improves proliferation, clonogenic capacity and SSEA-4 expression of perivascular cells from human umbilical cord. AB - Multipotent perivascular cells (PVCs) have recently gained attention as an alternative source for cell-based regenerative medicine. Because of their rarity in human tissues, the development of efficient methods to isolate and expand PVCs from various fetal and adult tissues is necessary to obtain a clinically relevant number of cells that maintain progenitor potency. We report a simple non enzymatic isolation (NE) method of PVCs from human umbilical cord (HUC) and compare its efficiency with the conventional collagenase treatment method (CT) in terms of proliferation, immunophenotype, clonogenic capacity, and differentiation potential. Cells isolated by NE expressed the accepted surface marker profile of PVCs and possessed multilineage differentiation potential. Whereas both methods provided similar patterns or levels of immunophenotypes and proliferation, PVCs obtained by NE maintained a higher level of CD146(+) frequency compared with that of CT over passages and displayed greater in vitro osteogenic differentiation potential and clonogenic capacity than CT-PVCs. We assess the potential of various exogenous factors to boost the proliferation of NE- and CT-PVCs in vitro. Supplementation of basic fibroblast growth factor (bFGF) provided optimal conditions that significantly enhanced their proliferation rate. This treatment drove the cells into S phase and increased the proportion of stage-specific antigen-4-positive population without altering other immunophenotypes. Thus, the NE method with bFGF supplementation offers an alternative way for obtaining sufficient numbers of HUCPVCs that have good clonogenic and differentiation potential and that are applicable at therapeutic doses for regenerative medicine. PMID- 25501898 TI - Ultrasound for "lung monitoring" of ventilated patients. PMID- 25501899 TI - Spinal peroxynitrite contributes to remifentanil-induced postoperative hyperalgesia via enhancement of divalent metal transporter 1 without iron responsive element-mediated iron accumulation in rats. AB - BACKGROUND: Hyperalgesia is one of the negative consequences following intraoperative analgesia with remifentanil. Peroxynitrite is a critical determinant in nociceptive process. Peroxynitrite inactivates iron-sulfur cluster that results in mitochondrial dysfunction and the release of iron, leading to mitochondrial iron accumulation. Iron accumulation mediated by divalent metal transporter 1 (DMT1) plays a key role in N-methyl-D-aspartate neurotoxicity. This study aims to determine whether peroxynitrite contributes to remifentanil-induced postoperative hyperalgesia via DMT1-mediated iron accumulation. METHODS: Behavior testing was performed in rat model at different time points. Three-nitrotyrosine, nitrated manganese superoxide dismutase, and DMT1 with/without iron-responsive element [DMT1(+)IRE and DMT1(-)IRE] in spinal cord were detected by Western blot and immunohistochemistry. Spinal iron concentration was measured using the Perl stain and atomic absorption spectrophotometer. Hydrogen-rich saline imparting selectivity for peroxynitrite decomposition and iron chelator was applied in mechanistic study on the roles of peroxynitrite and iron, as well as the prevention of hyperalgesia. RESULTS: Remifentanil induced thermal and mechanical hyperalgesia at postoperative 48 h. Compared with control, there were higher levels of 3-nitrotyrosine (mean +/- SD, hyperalgesia vs. control, 1.22 +/- 0.18 vs. 0.25 +/- 0.05, n = 4), nitrated manganese superoxide dismutase (1.01 +/- 0.1 vs. 0.19 +/- 0.03, n = 4), DMT1(-)IRE (1.42 +/- 0.19 vs. 0.33 +/- 0.06, n = 4), and iron concentration (12.87 +/- 1.14 vs. 5.26 +/- 0.61 MUg/g, n = 6) in remifentanil-induced postoperative hyperalgesia, while DMT1(+)IRE was unaffected. Eliminating peroxynitrite with hydrogen-rich saline protected against hyperalgesia and attenuated DMT1(-)IRE overexpression and iron accumulation. Iron chelator prevented hyperalgesia in a dose-dependent manner. CONCLUSIONS: Our study identifies that spinal peroxynitrite activates DMT1(-)IRE, leading to abnormal iron accumulation in remifentanil-induced postoperative hyperalgesia, while providing the rationale for the development of molecular hydrogen and "iron targeted" therapies. PMID- 25501900 TI - Sodium bicarbonate for kidney protection in cardiac surgery: demise of yet another magic bullet? PMID- 25501901 TI - Non-contrast-enhanced computed tomography attenuation in the parotid glands before radioiodine therapy for thyroid carcinoma could be a predictor of radiovulnerability. AB - OBJECTIVE: This study aimed to determine a predictive factor for the effect of radioiodine therapy (RIT) on salivary gland dysfunction through a multiple regression analysis. METHODS: We retrospectively assessed 40 patients with thyroid carcinoma, including 13 men (age range, 21-80 years) and 27 women (age range, 28-75 years), who underwent total thyroidectomy and were treated with RIT. We used multiple regression analysis to evaluate whether factors such as age, sex, dose number, prescintigraphy grade, computed tomography (CT) attenuation, and CT volume of the salivary glands affected the postscintigraphy grade. Receiver operating characteristics analysis was performed for predicting worsening scintigraphy grade of the parotid glands in 20 patients after RIT. RESULTS: The postscintigraphy grade of the parotid glands was positively associated with the dose number and prescintigraphy grade and negatively associated with CT attenuation (beta=0.48, P<0.01; beta=0.47, P<0.01; and beta= 0.26, P<0.05, respectively; adjusted R2=0.50, P<0.05). In the submandibular glands, the postscintigraphy grade was only positively correlated with dose number (beta=0.58, P<0.01; adjusted R=0.32, P<0.01). Area under the curve was 0.775 (P<0.05) and the cutoff CT attenuation was -18.8 HU (sensitivity 0.714 and specificity 0.846). CONCLUSION: The RIT dose number, prescintigraphy grade, and CT attenuation may be important predictors of parotid gland dysfunction after RIT, whereas the dose number alone may be a significant predictor of submandibular gland dysfunction. PMID- 25501897 TI - Stem cell autograft and allograft in autoimmune diseases. AB - Autoimmune diseases are characterized by an insufficiency of immune tolerance and, although treated with a number of useful drugs, may need more unconventional therapeutic strategies for their more severe presentations. Among such unconventional therapeutic approaches, stem cell autograft and allograft have been used, with the aim of stimulating disease remission by modifying the pathogenic mechanisms that induce anomalous responses against self-antigens. Autologous transplantation is performed with the purpose of retuning autoimmune cells, whereas allogeneic transplantation is performed with the purpose of replacing anomalous immune effectors and mediators. In this article, we comprehensively review up-to-date information on the autoimmune diseases for which the transplantation of stem cells is indicated. PMID- 25501902 TI - First-principles investigation of exchange interactions in quasi-one-dimensional antiferromagnet CaV2O4. AB - The effects of orbital degrees of freedom on the exchange interactions in a quasi one-dimensional spin-1 antiferromagnet CaV2O4 are systematically studied. For this purpose a realistic low-energy electron model with the parameters derived from the first-principles calculations is constructed in the Wannier basis for the t2g bands. The exchange interactions are calculated using both the theory of infinitesimal spin rotations near the mean-field ground state and the superexchange model, which provide a consistent description. The obtained behaviour of exchange interactions differs substantially from the previously proposed phenomenological picture based on magnetic measurements and structural considerations, namely: (i) despite the quasi-one-dimensional character of the crystal structure, consisting of the zigzag chains of the edge-sharing VO6 octahedra, the electronic structure is essentially three-dimensional, that leads to finite interactions between the chains; (ii) the exchange interactions along the legs of the chains appear to dominate; and (iii) there is a substantial difference in exchange interactions in two crystallographically inequivalent chains. The combination of these three factors successfully reproduces the behaviour of experimental magnetic susceptibility. PMID- 25501903 TI - Content validity and legacy patient-reported outcome measures in cancer. PMID- 25501904 TI - Chemotherapy cardiotoxicity: cardioprotective drugs and early identification of cardiac dysfunction. AB - BACKGROUND: Chemotherapy cardiotoxicity is an emerging problem and it is very important to prevent cardiac dysfunction caused by anticancer drugs. The aim of this study was to assess the alterations of the cardiac function induced by chemotherapy in a follow-up of 2 years and to evaluate the cardioprotective role of angiotensin-converting enzyme inhibitors (ACEIs) in the prevention of cardiac dysfunction. METHODS: A prospective study was carried out using patients with breast cancer (85 women; median age 57 +/- 12 years) and other inclusion and exclusion criteria. On the basis of treatment, patients were divided into six groups: fluorouracil-epirubicincyclophosphamide, FEC (group A); FEC and trastuzumab (B); trastuzumab (C); FEC and taxotere (D); FEC, paclitaxel and trastuzumab (E); and chemotherapy and cardioprotective drugs (F). Cardiological evaluation including electrocardiogram and conventional echocardiogram with tissue Doppler imaging (TDI) was carried out at T0 (before starting chemotherapy), T1 (after 6 months from the start of chemotherapy) and T2 (2 years after the end of chemotherapy). RESULTS: Significant changes in the TDI parameters of systolic and diastolic function were observed at T1 and T2 in all patients. A significant reduction of left ventricular ejection fraction (LVEF) was observed only at T2. In the patients treated with ACEI (F), these changes were less significant than in other groups and they do not have significant changes in the indices of diastolic function. CONCLUSION: TDI is more sensitive than conventional echocardiogram in the early diagnosis of cardiac dysfunction and ACEIs seem to have an important role in the prevention of cardiotoxicity. PMID- 25501905 TI - Notch controls the survival of memory CD4+ T cells by regulating glucose uptake. AB - CD4+ T cells differentiate into memory T cells that protect the host from subsequent infection. In contrast, autoreactive memory CD4+ T cells harm the body by persisting in the tissues. The underlying pathways controlling the maintenance of memory CD4+ T cells remain undefined. We show here that memory CD4+ T cell survival is impaired in the absence of the Notch signaling protein known as recombination signal binding protein for immunoglobulin kappa J region (Rbpj). Treatment of mice with a Notch inhibitor reduced memory CD4+ T cell numbers and prevented the recurrent induction of experimental autoimmune encephalomyelitis. Rbpj-deficient CD4+ memory T cells exhibit reduced glucose uptake due to impaired AKT phosphorylation, resulting in low Glut1 expression. Treating mice with pyruvic acid, which bypasses glucose uptake and supplies the metabolite downstream of glucose uptake, inhibited the decrease of autoimmune memory CD4+ T cells in the absence of Notch signaling, suggesting memory CD4+ T cell survival relies on glucose metabolism. Together, these data define a central role for Notch signaling in maintaining memory CD4+ T cells through the regulation of glucose uptake. PMID- 25501906 TI - Remote regulation of glucose homeostasis in mice using genetically encoded nanoparticles. AB - Means for temporally regulating gene expression and cellular activity are invaluable for elucidating underlying physiological processes and would have therapeutic implications. Here we report the development of a genetically encoded system for remote regulation of gene expression by low-frequency radio waves (RFs) or a magnetic field. Iron oxide nanoparticles are synthesized intracellularly as a GFP-tagged ferritin heavy and light chain fusion. The ferritin nanoparticles associate with a camelid anti-GFP-transient receptor potential vanilloid 1 fusion protein, alphaGFP-TRPV1, and can transduce noninvasive RF or magnetic fields into channel activation, also showing that TRPV1 can transduce a mechanical stimulus. This, in turn, initiates calcium dependent transgene expression. In mice with stem cell or viral expression of these genetically encoded components, remote stimulation of insulin transgene expression with RF or a magnet lowers blood glucose. This robust, repeatable method for remote regulation in vivo may ultimately have applications in basic science, technology and therapeutics. PMID- 25501907 TI - Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. AB - A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and strength. Although the etiology of sarcopenia is unknown, the correlation during aging between the loss of activity of satellite cells, which are endogenous muscle stem cells, and impaired muscle regenerative capacity has led to the hypothesis that the loss of satellite cell activity is also a cause of sarcopenia. We tested this hypothesis in male sedentary mice by experimentally depleting satellite cells in young adult animals to a degree sufficient to impair regeneration throughout the rest of their lives. A detailed analysis of multiple muscles harvested at various time points during aging in different cohorts of these mice showed that the muscles were of normal size, despite low regenerative capacity, but did have increased fibrosis. These results suggest that lifelong reduction of satellite cells neither accelerated nor exacerbated sarcopenia and that satellite cells did not contribute to the maintenance of muscle size or fiber type composition during aging, but that their loss may contribute to age-related muscle fibrosis. PMID- 25501909 TI - Sweet sixteen: changing time preferences in the transition from middle school to high school, for different scenarios. AB - Teenagers earn, save and spend large amounts of money. Therefore, understanding teenagers' time preference and how it affects their economic behavior is very important. The current study investigates time preferences of high school and middle school students, and the effect of different intertemporal choice scenarios on teenagers' subjective discount rate. One scenario used a standard intertemporal choice question while the other was a wage scenario. We found higher future orientation (lower subjective discount rate) among high school students than among middle school students when using a standard scenario but found no difference between groups in the wage scenario. For both groups, we found the subjective discount rates increased when the teenagers are asked to delay receipt of wages they earned by working (wage scenario). Other variables, like participation in sports and an allowance given by parents, were found to affect teenagers' time preferences. PMID- 25501908 TI - In-depth determination and analysis of the human paired heavy- and light-chain antibody repertoire. AB - High-throughput immune repertoire sequencing has emerged as a critical step in the understanding of adaptive responses following infection or vaccination or in autoimmunity. However, determination of native antibody variable heavy-light pairs (VH-VL pairs) remains a major challenge, and no technologies exist to adequately interrogate the >1 * 10(6) B cells in typical specimens. We developed a low-cost, single-cell, emulsion-based technology for sequencing antibody VH-VL repertoires from >2 * 10(6) B cells per experiment with demonstrated pairing precision >97%. A simple flow-focusing apparatus was used to sequester single B cells into emulsion droplets containing lysis buffer and magnetic beads for mRNA capture; subsequent emulsion RT-PCR generated VH-VL amplicons for next-generation sequencing. Massive VH-VL repertoire analyses of three human donors provided new immunological insights including (i) the identity, frequency and pairing propensity of shared, or 'public', VL genes, (ii) the detection of allelic inclusion (an implicated autoimmune mechanism) in healthy individuals and (iii) the occurrence of antibodies with features, in terms of gene usage and CDR3 length, associated with broadly neutralizing antibodies to rapidly evolving viruses such as HIV-1 and influenza. PMID- 25501910 TI - The effect of age on right ventricular diastolic function parameters. PMID- 25501911 TI - Universal infant immunization and occult hepatitis B virus infection in children and adolescents: a population-based study. AB - To determine whether universal infant immunization affects occult hepatitis B virus (HBV) infection (OBI), serum samples from hepatitis B surface antigen (HBsAg)-negative subjects <18 years enrolled during six sequential seroepidemiological surveys conducted between 1984 (just before universal infant immunization) and 2009 were analyzed. Study subjects were divided into unvaccinated cohorts (born before 1984) and vaccinated cohorts (born after 1984). HBV-DNA positivity was determined by positivity of nested polymerase chain reaction in at least two of three regions (pre-S, S, and pre-core/core genes). OBI frequency was lower in vaccinated than unvaccinated antibody to hepatitis B core antigen (anti-HBc)-negative subjects (0 of 392 [0%] vs. 4 of 218 [1.8%]; P = 0.007), tended to be higher in vaccinated than unvaccinated anti-HBc-positive subjects (16 of 334 [4.8%] vs. 3 of 181 [1.7%]; P = 0.072), and was higher in vaccinated than unvaccinated subjects seropositive for both antibody to hepatitis B surface antigen (anti-HBs) and anti-HBc (13 of 233 [5.6%] vs. 3 of 170 [1.8%]; P = 0.025). By using known anti-HBc seropositivity rate in children in our serosurveys, the estimated OBI frequency per 10(4) HBsAg-negative subjects declined from 160.7 in unvaccinated cohorts to 11.5 in vaccinated cohorts. In vaccinated cohorts, OBI frequency was higher in anti-HBc-positive subjects than in anti-HBc-negative subjects (16 of 334 [4.8%] vs. 0 of 392 [0%]; P < 0.001). Subjects with OBI had much lower viral load (P < 0.001) and a trend of higher mutation rates in "a" determinant of HBsAg than age-comparable, HBsAg-positive subjects. CONCLUSIONS: Reduction of OBI in immunized subjects complements the well-documented universal infant immunization-related benefit of markedly reduced overt HBV infection. Breakthrough infections in immunized subjects seem to associate with more occurrence of OBI than natural infections in unvaccinated subjects. In the postvaccination era, anti-HBc seropositivity is a useful marker for OBI screening in HBsAg-negative subjects, and a very-low-level viral replication and HBsAg expression is the major mechanism underlying OBI. PMID- 25501912 TI - Total synthesis of largamide B. AB - Total synthesis of the cyanobacterial metabolite largamide B and the disproval of its originally assigned stereochemistry as well as confirmation of the revised stereochemistry are reported. PMID- 25501913 TI - Sliding inguinal hernia is a risk factor for recurrence. AB - PURPOSE: A sliding inguinal hernia is defined as a hernia where part of the hernial sac wall is formed by an organ, e.g., the colon or bladder. Thus, repair of a sliding inguinal hernia may have higher risk of complications and recurrence compared with non-sliding inguinal hernia. The aim of this study was to investigate the incidence and reoperation rates following sliding inguinal hernia repair. METHODS: This study was based on data from the Danish Hernia Database covering the period between January 1, 1998 and February 22, 2012. Data were collected prospectively and nationwide. RESULTS: In total, 70,091 primary hernia repairs were included for analysis. The occurrence of sliding inguinal hernias of the total group of included hernia repairs was 9.4 % among males and 2.9 % among females (p < 0.05). Among male patients, the sliding inguinal hernias had a higher cumulated reoperation rate compared with non-sliding inguinal hernias (6.0 versus 4.2 %, log-rank p = 0.001). A Cox regression model was fitted and showed that the type of repair affected the risk for reoperation for recurrence; hazard ratio (95 % confidence interval): open non-mesh: reference, Lichtenstein 0.43 (0.39-0.48), other open mesh 0.46 (0.39-0.54), laparoscopic 0.70 (0.60-0.84). CONCLUSION: The incidence of sliding inguinal hernia is higher in males than in females, and sliding inguinal hernia is a risk factor for reoperation for recurrence. The Lichtenstein repair could be considered over the laparoscopic approach because of lower reoperation rates. PMID- 25501914 TI - [Perioperative care of patients with diastolic heart failure. Interface to anesthesia]. AB - Diastolic heart failure leads to an increase in perioperative morbidity and mortality. The prevalence of this disease is rising and multiple risk factors have already been identified. Besides higher age and female gender, arterial hypertension, diabetes mellitus and coronary artery disease in particular have to be considered. Clinical examination and laboratory analyses are important for preoperative evaluation; however, echocardiography plays the most important role in the diagnostics of diastolic heart failure. The transmitral flow profile can be used to differentiate the grades of diastolic dysfunction using the ratio between early passive ventricular filling (E) and late active filling due to atrial contraction (A). Data concerning the ideal anesthesia technique are for the most part lacking; however, the application of thoracic epidural anesthesia seems to be beneficial. A great deal of attention has to be paid to the intraoperative volume status of patients with diastolic dysfunction as hypovolemia and hypervolemia can both have detrimental effects. Arrhythmias and major changes in blood pressure put this special group of patients at additional risks. PMID- 25501915 TI - Exploring the implications of social change for human development: perspectives, issues and future directions. AB - Researchers have investigated the implications of social change for human development from different perspectives. The studies published in this special section were conducted within Greenfield's theoretical framework (2009). The findings concerning links between specific sociodemographic features (e.g., commercial activities, schooling) and individual cognition and social behaviour are particularly interesting because they tap the underlying forces that drive human development. To further understand the issues in these studies and in the field, a pluralist-constructive perspective is discussed, which emphasises the integration of diverse values and practices in both Western and non-Western societies and its effects on the development of sophisticated competencies in individual adaptation to the changing global community. In addition, several issues are highlighted and some suggestions are provided for future explorations in this field. PMID- 25501916 TI - Re: Madsen et al. "Unnecessary work tasks and mental health: a prospective analysis of Danish human service workers". AB - Madsen et al (1) recently published a secondary analysis on data provided by the Project on Burnout, Motivation and Job Satisfaction (PUMA). The aim of their study, published in the Scandinavian Journal of Work, Environment & Health was to examine the associations between unnecessary work tasks and a decreased level of mental health. Though the topic was quite novel, reading this work proved disturbing and raised issues. Based on the results of this study, the authors stated that there is an association between unnecessary work tasks (assessed by a single question) and a decreased level of mental health, idem [assessed by the Mental Health Inventory (MHI-5)], in the specific population included in this PUMA survey. The authors point out a limitation of the study, namely that unnecessary work tasks were evaluated using one single question: "Do you sometimes have to do things in your job which appear to be unnecessary?". Semmer defines unnecessary work task as "tasks that should not be carried out at all because they do not make sense or because they could have been avoided, or could be carried out with less effort if things were organized more efficiently" (2). De facto, qualifying what an unnecessary task is requires stating or explaining whether the task makes sense. Making sense or not is not an objective notion. It is very difficult for either a manager or an employee to say if a task is necessary or not. Most important is that it makes sense from the worker's point of view. Making sense and being necessary are not synonyms. Some tasks do not make sense but are economically necessary (eg, when, as physicians, we are reporting our activity using ICD-10 on computers instead of being at patients' bedsides or reading this journal). Thus, there is a wide gap between Semmer's definition and the question used by the authors to evaluate his concept. A secondary analysis based on a single question is not adequate to evaluate unnecessary tasks. Nowadays, the general trend is to reduce the size of questionnaires because they are too long and cannot be used in a routine practice. But an analysis performed on a single question is quite risky: in psychometrics, redundancy is used to confirm a measurement. We lose precision on what exactly we are testing by asking a single question. Madsen et al's results show that among workers saying they are always or often performing unnecessary tasks, the MHI mean score was 74.00 versus 78.20 for people who never or almost never perform unnecessary tasks (P=0.0038). Even though it is a statistically significant result, its clinical relevance is never questioned. What is the impact of losing 4.20 points at MHI test instead of losing 20 points for instance? Statistical difference does not mean clinical relevance. These results show a statistical association, not a causality relationship. The authors did not show that performing unnecessary tasks lowers the level of mental health. It may be the exact opposite. Maybe having poorer mental health (eg, depression, with anhedonia) may make the workers think that what they're doing is useless. In their conclusion, Madsen et al suggest that the elimination of unnecessary work tasks may be beneficial for employees' mental health. To our mind, on the contrary, it may increase psychic suffering. If we suggest to fight unnecessary tasks in workplaces, this may encourage reduction of the margin of manoeuvre (3). The principle of removing unnecessary tasks is part of a Taylorized organization. Some tasks may seem unnecessary or bothersome, but may correspond to work periods that allow for temporary rest. Concretely, in the workplace, managers rather than the employee will be the ones to decide whether a task is useless or not. To improve well-being in the workplace, a global vision of work organization is required. From our point of view, the conclusion drawn from this study should not be that we must eliminate unnecessary tasks, but that we should focus on what makes sense for the worker, with a global view on his work and - as usual - the aim of carrying out further studies on this subject. Conflicts of interest The authors declare no conflict of interest. References 1. Madsen IEH, Tripathi M, Borritz M, Rugulies R, Unnecessary work tasks and mental health: a prospective analysis of Danish human service workers, Scand J Work Environ Health. 2014;40(6):631-8. http://dx.doi.org/10.5271/sjweh.3453. 2. Semmer NK, Tschan F, Meier LL, Facchin S, Jacobshagen N, Illegitimate tasks and counterproductive work behavior, Appl Psychol. 2010;59:70-96. http://dx.doi.org/10.1111/j.1464 0597.2009.00416.x. 3. Durand MJ, Vezina N, Baril R, Loisel P, Richard MC, Ngomo S, Margin of manoeuvre indicators in the workplace during the rehabilitation process: a qualitative analysis, J Occup Rehab. 2009;19:194-202. http://dx.doi.org/10.1007/s10926-009-9173-4. PMID- 25501917 TI - LINAC radiosurgery in the management of parasagittal meningiomas. AB - BACKGROUND: At present, there is no general agreement for the best approach to parasagittal meningiomas. Invasion of the superior sagittal sinus is frequent and responsible for relatively high recurrence rates following conventional microsurgery. Radiosurgery has the potential to treat less accessible portions of these tumors, and its application in this pathology is increasing either as a primary or a complementary therapeutic tool. OBJECTIVE: To evaluate our results with LINAC radiosurgery for the treatment of parasagittal meningiomas. METHODS: The patient cohort consisted of 74 patients treated for parasagittal meningioma by LINAC radiosurgery at our institution's Radiosurgery Unit during a 15-year period. Women accounted for 61% of patients. Thirteen patients (18%) underwent radiosurgery as the primary treatment for their meningioma. RESULTS: The overall actuarial control rate was 90.6% at a mean follow-up of 49 months. In 17 patients (22.9%), there was no volumetric change. Fifty patients (67.5%) showed tumor shrinkage ranging from 15 to 80% of the original mass. In 7 patients, tumor recurrence was observed at an average time of 42.2 months after radiosurgery. All the patients with previously untreated tumors were controlled. Symptomatic transient peritumoral edema developed in 5 patients (6.7%) at a mean of 6.4 months after radiosurgery. Three patients complained of protracted headaches after treatment. CONCLUSIONS: LINAC radiosurgery was highly effective for the treatment of parasagittal meningiomas in this series. For small to medium-sized meningiomas with clear invasion of the sinusal lumen, radiosurgery is a reasonable option as a first-line treatment. Either alone or combined with conventional surgery, radiosurgery may improve the control rate for parasagittal meningiomas. PMID- 25501918 TI - Resveratrol inhibits trophoblast apoptosis through oxidative stress in preeclampsia-model rats. AB - Resveratrol has been shown to be a therapeutic agent for cardiovascular disorders by maintaining a lower redox level in vivo through its anti-oxidant properties. Resveratrol can prevent cells from p53- and reactive oxygen species-dependent apoptosis induced by interleukin-1b. We identified an inhibitory effect of resveratrol against oxidative stress and apoptosis using the TUNEL assay in NG Nitro-l-arginine methyl ester-induced preeclampsia in rats. To investigate a possible association between resveratrol and the apoptosis caused by oxidative stress in vitro, assays for superoxide dismutase and malondialdehyde as well as flow cytometric analyses were conducted in HTR-8/SVneo cells after hypoxic treatment with or without resveratrol for 24 h. These data suggest that resveratrol significantly opposes the effects of oxidative stress in vivo and in vitro. PMID- 25501919 TI - Au-nanomaterials as a superior choice for near-infrared photothermal therapy. AB - Photothermal therapy (PPT) is a platform to fight cancer by using multiplexed interactive plasmonic nanomaterials as probes in combination with the excellent therapeutic performance of near-infrared (NIR) light. With recent rapid developments in optics and nanotechnology, plasmonic materials have potential in cancer diagnosis and treatment, but there are some concerns regarding their clinical use. The primary concerns include the design of plasmonic nanomaterials which are taken up by the tissues, perform their function and then clear out from the body. Gold nanoparticles (Au NPs) can be developed in different morphologies and functionalized to assist the photothermal therapy in a way that they have clinical value. This review outlines the diverse Au morphologies, their distinctive characteristics, concerns and limitations to provide an idea of the requirements in the field of NIR-based therapeutics. PMID- 25501920 TI - Physician-Assisted Dying: Acceptance by Physicians Only for Patients Close to Death. AB - This study reports on German physicians' views on legalization of euthanasia and physician-assisted suicide, comparing this with a similar survey of UK doctors. A questionnaire was handed out to attendants of a palliative care and a pain symposium. Complete answers were obtained from 137 physicians. Similar to the UK study, about 30% of the physicians surveyed support euthanasia in case of terminal illness and more support physician-assisted suicide. In contrast, in both countries, a great majority of physicians oppose medical involvement in hastening death in non-terminal illnesses. The public and parliamentary discussion should face this opposition to assisted suicide by pain and palliative specialists. PMID- 25501921 TI - Transforming growth factor (TGF)-beta-induced microRNA-216a promotes acute pancreatitis via Akt and TGF-beta pathway in mice. AB - BACKGROUND: Both transforming growth factor beta (TGF-beta) and MicroRNA-216a (miR-216a) were reported to be upregulated during acute pancreatitis (AP). Moreover, miR-216a can be induced by TGF-beta. AIM: This study aimed to investigate how TGF-beta and miR-216a involved in the pathogenesis of AP both in a mouse model and in rat pancreatic acinar AR42J cells. METHODS: Cerulein-induced AP mouse model was established and pretreated with a TGF-beta inhibitor, SB431542. Serum amylase, lipase, tumor necrosis factor (TNF)-alpha, interleukin 6 (IL-6), TGF-beta and histopathological changes of pancreas were determined. Expression of miR-216a was detected by quantitative real-time RT-PCR. Bioinformatics was utilized to predict the targets of miR-216a. Expression levels of phosphatase and tensin homolog (PTEN), mothers against decapentaplegic homolog 7 (Smad7), TGF-beta receptor I, total Akt and pAkt were detected by Western blot. RESULTS: SB431542 significantly decreased serum amylase, lipase, TNF-alpha, IL-6, TGF-beta, histopathological changes of pancreas and expression of miR-216a in cerulein-induced mouse (P < 0.05). TGF-beta induced miR-216a in AR42J cells. PTEN and Smad7 were identified to be the possible targets of miR-216a. Transfection of miR-216a mimics (or inhibitors) in AR42J cells downregulated (or upregulated) the expression of PTEN and Smad7, thus affected the expression of downstream pAkt and TGF-beta receptor I. The expression changes of these protein caused by miR-216a can be regulated by SB431542 both in mouse model and AR42J cells. CONCLUSIONS: TGF-beta promotes AP by inducing miR-216a targeting PTEN and Smad7, thus through PI3K/Akt and TGF-beta feedback pathway. PMID- 25501922 TI - Clinical significance of C-reactive protein levels in predicting responsiveness to iron therapy in patients with inflammatory bowel disease and iron deficiency anemia. AB - BACKGROUND: Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD). In clinical practice, many patients receive initial treatment with iron tablets although intravenous (i.v.) iron supplementation is often preferable. AIM: This study investigated whether systemic inflammation at initiation of treatment (assessed by C-reactive protein [CRP] and interleukin-6 [IL-6] measurements) predicts response to iron therapy. METHODS: Data from a previously published phase III trial were retrospectively analyzed after stratification of patients according to baseline CRP (> 4 vs. <= 4 mg/L) and IL-6 (> 6 vs. <= 6 pg/mL) levels. The study population consisted of patients with Crohn's disease or ulcerative colitis and IDA (Hb <= 110 g/L and TSAT < 20 % or serum ferritin < 100 ng/mL), randomized to either oral (ferrous sulfate) or i.v. iron (ferric carboxymaltose). RESULTS: A total of 196 patients were evaluated (oral iron: n = 60; i.v. iron: n = 136). Baseline CRP and IL-6 levels were independent of patients' initial Hb levels and iron status (serum ferritin and TSAT; all p > 0.05). Among iron tablet-treated patients, Hb increase was significantly smaller in the high- versus low-CRP subgroup (1.1 vs. 2.0, 2.3 vs. 3.1, and 3.0 vs. 4.0 g/dL at weeks 2, 4, and 8, respectively; all p < 0.05). Differences were less pronounced with stratification according to baseline IL-6. Response to i.v. iron was mainly independent of inflammation. CONCLUSIONS: Patients with high baseline CRP achieved a lower Hb response with oral iron therapy. Our results suggest that CRP may be useful to identify IBD patients who can benefit from first-line treatment with i.v. iron to improve their IDA. PMID- 25501925 TI - Pentaglyme-K salt binary mixtures: phase behavior, solvate structures, and physicochemical properties. AB - We prepared a series of binary mixtures composed of certain K salts (KX) and pentaglyme (G5) with different salt concentrations and anionic species ([X](-): [(CF3SO2)2N](-) = [TFSA](-), [CF3SO3](-) = [TfO](-), [C4F9SO3](-) = [NfO](-), PF6(-), SCN(-)), and characterized them with respect to their phase diagrams, solvate structures, and physicochemical properties. Their phase diagrams and thermal stability strongly implied the formation of equimolar complexes. Single crystal X-ray crystallography was performed on certain equimolar complexes, which revealed that G5 molecules coordinate to K(+) cations in a characteristic manner, like 18-crown-6 ether in the crystalline state, irrespective of the paired anions. The solvate structures in the molten state were elucidated by a combination of temperature-dependent Raman spectroscopy and X-ray crystallography. A drastic spectral variation was observed in the [K(G5)1][TfO] Raman spectra, indicating that solvate structures in the crystalline state break apart upon melting. The solvate stability of [K(G5)1]X is closely related to the ion-ion interaction of the parent salts. A stable solvate forms when the ion dipole interaction between K(+) and G5 overwhelms the ion-ion interaction between K(+) and X(-). Furthermore, the physicochemical properties of certain equimolar mixtures were evaluated. A Walden plot clearly reflects the ionic nature of the molten equimolar complexes. Judging from the structural characteristics and dissociativity, we classified [K(G5)1]X into two groups, good and poor solvate ionic liquids. PMID- 25501924 TI - Hereditary and common familial colorectal cancer: evidence for colorectal screening. AB - Colorectal cancer (CRC) is the fourth most common cancer among men and women. Between 3 and 6% of all CRCs are attributed to well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis and several hamartomatous conditions. Up to 30% of CRC cases exhibit common familial risk, likely related to a combination of inherited factors and environment. Identification of these patients through family history and appropriate genetic testing can provide estimates of cancer risk that inform appropriate cancer screening, surveillance and/or preventative interventions. This article examines the colon cancer syndromes, their genetic basis, clinical management and evidence supporting colorectal screening. It also deals with the category of common (non-syndromic) familial risk including risk determination and screening guidelines. PMID- 25501926 TI - "AND" luminescent "reactive" molecular logic gates: a gateway to multi-analyte bioimaging and biosensing. AB - This review outlines examples that illustrate a recent and highly innovative concept in the field of (bio)molecular sensing, namely the simultaneous multi analyte detection using "reactive" luminescent probes that are able to produce an optical signal only in response to multiple (bio)chemical inputs and through covalent chemical reactions with target (bio)analytes. Unlike conventional "AND" molecular logic gates based on supramolecular photochemical mechanisms, these unusual "smart" optical (bio)probes are suitable tools to track the rise and fall of a wider range of biologically relevant analytes, in complex media and with higher selectivity. The potential utility of this concept for in vivo molecular imaging and possible solutions to adapt the described luminogenic processes to far-red or NIR emitters are also discussed. PMID- 25501923 TI - Medical and surgical complications of inflammatory bowel disease in the elderly: a systematic review. AB - BACKGROUND/AIMS: The complications of therapy, hospitalization, and surgery related to inflammatory bowel disease (IBD) in the elderly are not well described. While multiple reviews have described the management and complications of elderly patients with IBD, none have been performed in a systematic fashion. METHODS: We performed a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to evaluate the association between elderly patients with IBD and complications from therapy, hospitalizations, and surgery. Eligible studies were identified via structured keyword searches in PubMed and manual literature searches. RESULTS: A total of 5,644 publications were identified. Of these, fourteen studies met inclusion criteria, encompassing 963 elderly IBD patients (113 Crohn's disease and 850 ulcerative colitis patients), over 37,000 hospitalizations of elderly IBD patients and over 4,500 controls. Consistent associations were observed between increased age and higher nocturnal stool frequency post-ileal pouch anal anastomosis. Only two studies met inclusion criteria for medication-related complications, one observed an increased mortality and infection risk among elderly patients treated with tumor necrosis factor antagonists and the other observed increased hospital-related complications among elderly patients treated with steroids. CONCLUSIONS: Elderly patients with IBD are at an increased risk of hospital- and therapy-related complications. We found a paucity of high-quality studies evaluating outcomes in elderly patients with IBD. Further studies of elderly patients with IBD are needed to further evaluate the effect of age on medical and surgical complications. PMID- 25501927 TI - Spatial control of functional properties via octahedral modulations in complex oxide superlattices. AB - Control of atomic structure, namely the topology of the corner-connected metal oxygen octahedra, has emerged as an important route to tune the functional properties at oxide interfaces. Here we investigate isovalent manganite superlattices (SLs), [(La(0.7)Sr(0.3)MnO(3))n/(Eu(0.7)Sr(0.3)MnO(3))n] * m, as a route to spatial control over electronic bandwidth and ferromagnetism through the creation of octahedral superstructures. Electron energy loss spectroscopy confirms a uniform Mn valence state throughout the SLs. In contrast, the presence of modulations of the MnO(6) octahedral rotations along the growth direction commensurate with the SL period is revealed by scanning transmission electron microscopy and X-ray diffraction. We show that the Curie temperatures of the constituent materials can be systematically engineered via the octahedral superstructures leading to a modulated magnetization in samples where the SL period is larger than the interfacial octahedral coupling length scale, whereas a single magnetic transition is observed in the short-period SLs. PMID- 25501929 TI - [Importance of morphological and functional diagnostics of the vitreoretinal interface]. AB - Optical coherence tomography (OCT) is the standard examination for assessment of the vitreoretinal interface (VRI); therefore, it is essential to select the appropriate scan modalities to detect the total amount of morphological changes, not only at the VRI but also in all layers of the retina and in both the foveal and parafoveal areas. For the success of a surgical intervention in the treatment of vitreomacular interface disorders, morphological changes, especially in the outer retinal layers, have been determined to be of prognostic interest in high resolution OCT. This article gives an overview of current OCT examination procedures as well as correlative aspects of morphological and functional findings. PMID- 25501930 TI - [Implementation of electronic health records at a tertiary care eye hospital]. AB - BACKGROUND: Although electronic health records (EHR) were introduced into ophthalmology practices many years ago, paper-based medical records are still common in most tertiary care eye hospitals. MATERIAL AND METHODS: We report on the implementation of an EHR system at the university eye hospital in Munster in the time period between January and December 2013. RESULTS: Advantages of an EHR system in the setting of a university eye hospital include ubiquitous access to patient data, structurability as well as scientific interpretability. Data safety, personnel and financial investment and integration into existing hospital software systems represent the main challenges. CONCLUSION: The EHR system will replace paper-based records in the future. In view of the high need for visualization and recording of medical findings, EHR software solutions seem promising particularly in ophthalmology. PMID- 25501928 TI - Mechanistic insights into xanthine oxidoreductase from development studies of candidate drugs to treat hyperuricemia and gout. AB - Xanthine oxidoreductase (XOR), which is widely distributed from humans to bacteria, has a key role in purine catabolism, catalyzing two steps of sequential hydroxylation from hypoxanthine to xanthine and from xanthine to urate at its molybdenum cofactor (Moco). Human XOR is considered to be a target of drugs not only for therapy of hyperuricemia and gout, but also potentially for a wide variety of other diseases. In this review, we focus on studies of XOR inhibitors and their implications for understanding the chemical nature and reaction mechanism of the Moco active site of XOR. We also discuss further experimental or clinical studies that would be helpful to clarify remaining issues. PMID- 25501931 TI - [Pachymetry and intraocular pressure measurement by corneal visualization Scheimpflug technology (Corvis ST): A clinical comparison to the gold standard]. AB - BACKGROUND: Analyses regarding accuracy and reproducibility of intraocular pressure (IOP) measurements and pachymetry with corneal visualization Scheimpflug technology (Corvis ST(r), CST). MATERIAL UND METHODS: Retrospective analysis of 72 eyes with primary open angle glaucoma (POAG) and ocular hypertension (OHT) with no prior surgery or other pathology. The results of Goldmann applanation tonometry (GAT), non-contact tonometry (NCT) and ultrasound pachymetry (USP) were compared with repeat measurements with CST. For statistical analyses the t-test and Bland-Altman plots were applied. RESULTS: The mean IOP was 15.5 +/- 4.4 mmHg (CST), 14.8 +/- 4.4 mmHg (GAT) and 15.6 +/- 4.8 mmHg (NCT). The results of GAT and CST as well as GAT and NCT demonstrated statistically significant differences (p < 0.001) whereas NCT and CST displayed no significant differences in IOP (p = 0.72). The mean differences between the repeat measurements were 0.35 +/- 1.7 mmHg (CST) and 0.04 +/- 0.85 mmHg (GAT). The mean CST pachymetry results showed 551.3 +/- 46.5 um and the USP 526.5 +/- 46.4 um (p < 0.001). The mean difference between the repeated CST measurements was 24.8 +/- 21 um. No repeat measurement data were available for USP. CONCLUSION: The CST is a new device for simultaneously measuring the IOP, pachymetry and biomechanical properties of the cornea. Whether the deviations in the IOP measured by CST and CST pachymetry from the manually performed gold standard has to be evaluated as deficient, tolerable or maybe as an improvement, has to be evaluated in further studies. Because of the automated and contact-free measurement method as well as the potential for simultaneously analyzing biomechanical properties of the cornea, the CST is a device that might help the quest for measuring the 'true' IOP. PMID- 25501932 TI - [Successful brachytherapy of a clinically unapparent ciliary body melanoma]. AB - We report on a typical case of a ciliary body melanoma in a 59-year-old female, which was only noticed due to nonspecific unilateral vision disorders and which could only be seen in maximal mydriasis via a gonioscopic three-mirror lens. We further discuss tumor monitoring via ultrasound biomicroscopy (UBM) and execution and prognosis of Ru-106 brachytherapy. PMID- 25501934 TI - Heavy/light chain assay for monitoring IgA multiple myeloma: digging out the IgA from the beta region. PMID- 25501933 TI - Sex-specific associations of established and emerging cardiac biomarkers with all cause mortality in older adults: the ActiFE study. AB - BACKGROUND: N-terminal pro B-type natriuretic peptide (NT-proBNP) has strong prognostic value for all-cause mortality in the general population. High sensitivity assays now allow detection of cardiac troponins even in asymptomatic populations. We examined the association between NT-proBNP, high-sensitivity cardiac troponin T (hs-cTnT), and hs-cTnI and all-cause mortality in older adults. METHODS: We conducted a longitudinal cohort study [Activity and Function in the Elderly in Ulm (ActiFE Ulm)] including 1506 community-dwelling adults >=65 years old with NT-proBNP, hs-cTnT, and hs-cTnI measured at baseline. We evaluated the associations between log-transformed biomarker concentrations and 4-year total mortality, accounting for possible confounders, with Cox proportional hazards models. RESULTS: We observed 125 deaths among 1422 participants (median follow-up 4 years). We detected effect modification by sex for all biomarkers (all P values <0.05) expressed as hazard ratio (HR) for death per 1-unit increment of ln(biomarker concentration) in women (n = 618, 37 deaths) compared with men (n = 804, 88 deaths): HR 2.97 (95% CI 2.04-4.33) vs 1.73 (1.40-2.13) for NT-proBNP; 3.67 (2.31-5.81) vs 2.15 (1.61-2.87) for hs-cTnT; and 3.32 (2.13-5.18) vs 1.92 (1.55-2.38) for hs-cTnI. Among 777 participants with undetectable hs-cTnT (<5 ng/L), hs-cTnI remained associated with all-cause mortality in age- and sex adjusted analysis. CONCLUSIONS: NT-proBNP, hs-cTnT, and hs-cTnI were independently associated with all-cause mortality in older adults. The strength of these associations varied between men and women, emphasizing the need for additional sex-specific research among older people. PMID- 25501937 TI - Catalytic hydrogen production from paraformaldehyde and water using an organoiridium complex. AB - Paraformaldehyde was decomposed using an organoiridium complex (1, [Ir(III)(Cp*)(4-(1H-pyrazol-1-yl-kappaN(2))benzoic acid-kappaC(3))(H2O)]2SO4) as a catalyst in water to produce H2 and CO2 in a 2 : 1 molar ratio at room temperature. The catalytic cycle is composed of the reduction of 1 by paraformaldehyde under basic conditions to produce formic acid and the hydride complex, which reacts with protons to produce H2. Formic acid further decomposed to H2 and CO2 with 1. PMID- 25501936 TI - Downregulation of high mobility group box 1 modulates telomere homeostasis and increases the radiosensitivity of human breast cancer cells. AB - The functions of the high mobility group box 1 (HMGB1) in tumor cells include replenishing telomeric DNA and maintaining cell immortality. There is a negative correlation between human telomerase reverse transcriptase (hTERT) and radiosensitivity in tumor cells. Our aim was to elucidate the relationship among HMGB1, telomere homeostasis and radiosensitivity in MCF-7 cells. In this study, we established stably transfected control (MCF-7-NC) and HMGB1 knockdown (MCF-7 shHMGB1) cell lines. The expression of HMGB1 mRNA and the relative telomere length were examined by real-time PCR. Radiosensitivity was detected by clonogenic assay. The protein expressions were determined by western blot analysis. The telomerase activity was detected by PCR-ELISA. Proliferation ability was examined by CCK-8 assay. Cell cycle and apoptosis were examined by flow cytometry. DNA damage foci were detected by immunofluorescence. ShRNA mediated downregulation of HMGB1 expression increased the radiosensitivity of MCF 7 cells, and reduced the accumulation of hTERT and cyclin D1. Moreover, knockdown of HMGB1 in MCF-7 cells inhibited telomerase activity and cell proliferation, while increasing the extent of apoptosis. Downregulation of HMGB1 modulated telomere homeostasis by changing the level of telomere-binding proteins, such as TPP1 (PTOP), TRF1 and TRF2. This downregulation also inhibited the ATM and ATR signaling pathways. The current data demonstrate that knockdown of HMGB1 breaks telomere homeostasis, enhances radiosensitivity, and suppresses the repair of DNA damage in human breast cancer cells. These results suggested that HMGB1 might be a potential radiotherapy target in human breast cancer. PMID- 25501935 TI - Transforming growth factor beta signaling overcomes dasatinib resistance in lung cancer. AB - Lung cancer is the second most common cancer and the leading cause of cancer related deaths. Despite recent advances in the development of targeted therapies, patients with advanced disease remain incurable, mostly because metastatic non small cell lung carcinomas (NSCLC) eventually become resistant to tyrosine kinase inhibitors (TKIs). Kinase inhibitors have the potential for target promiscuity because the kinase super family is the largest family of druggable genes that binds to a common substrate (ATP). As a result, TKIs often developed for a specific purpose have been found to act on other targets. Drug affinity chromatography has been used to show that dasatinib interacts with the TGFbeta type I receptor (TbetaR-I), a serine-threonine kinase. To determine the potential biological relevance of this association, we studied the combined effects of dasatinib and TGFbeta on lung cancer cell lines. We found that dasatinib treatment alone had very little effect; however, when NSCLC cell lines were treated with a combination of TGFbeta and dasatinib, apoptosis was induced. Combined TGFbeta-1 + dasatinib treatment had no effect on the activity of Smad2 or other non-canonical TGFbeta intracellular mediators. Interestingly, combined TGFbeta and dasatinib treatment resulted in a transient increase in p-Smad3 (seen after 3 hours). In addition, when NSCLC cells were treated with this combination, the pro-apoptotic protein BIM was up-regulated. Knockdown of the expression of Smad3 using Smad3 siRNA also resulted in a decrease in BIM protein, suggesting that TGFbeta-1 + dasatinib-induced apoptosis is mediated by Smad3 regulation of BIM. Dasatinib is only effective in killing EGFR mutant cells, which is shown in only 10% of NSCLCs. Therefore, the observation that wild-type EGFR lung cancers can be manipulated to render them sensitive to killing by dasatinib could have important implications for devising innovative and potentially more efficacious treatment strategies for this disease. PMID- 25501938 TI - Corrigendum: Blood brain barrier dysfunction and delayed neurological deficits in mild traumatic brain injury induced by blast shock waves. AB - [This corrects the article on p. 232 in vol. 8, PMID: 25165433.]. PMID- 25501939 TI - Using the MEROPS Database for Proteolytic Enzymes and Their Inhibitors and Substrates. AB - MEROPS is a database of proteolytic enzymes as well as their inhibitors and substrates. Proteolytic enzymes and protein inhibitors are organized into protein domain families. In turn, families are organized into clans. Each peptidase, inhibitor, family, and clan has associated annotation, a multiple sequence alignment, a phylogenetic tree, literature references, and links to other databases. Interactions between proteolytic enzymes and inhibitors and between proteolytic enzymes and substrates are also presented. The entries in MEROPS are available via the World Wide Web. This unit contains detailed information on how to access and utilize the information present in the MEROPS database. Details on running MEROPS both remotely and locally are presented. PMID- 25501940 TI - Using the structure-function linkage database to characterize functional domains in enzymes. AB - The Structure-Function Linkage Database (SFLD; http://sfld.rbvi.ucsf.edu/) is a Web-accessible database designed to link enzyme sequence, structure, and functional information. This unit describes the protocols by which a user may query the database to predict the function of uncharacterized enzymes and to correct misannotated functional assignments. The information in this unit is especially useful in helping a user discriminate functional capabilities of a sequence that is only distantly related to characterized sequences in publicly available databases. PMID- 25501941 TI - Using EMBL-EBI Services via Web Interface and Programmatically via Web Services. AB - The European Bioinformatics Institute (EMBL-EBI) provides access to a wide range of databases and analysis tools that are of key importance in bioinformatics. As well as providing Web interfaces to these resources, Web Services are available using SOAP and REST protocols that enable programmatic access to our resources and allow their integration into other applications and analytical workflows. This unit describes the various options available to a typical researcher or bioinformatician who wishes to use our resources via Web interface or programmatically via a range of programming languages. PMID- 25501942 TI - Clustal omega. AB - Clustal Omega is a package for making multiple sequence alignments of amino acid or nucleotide sequences, quickly and accurately. It is a complete upgrade and rewrite of earlier Clustal programs. This unit describes how to run Clustal Omega interactively from a command line, although it can also be run online from several sites. The unit describes a basic protocol for taking a set of unaligned sequences and producing a full alignment. There are also protocols for using an external HMM or iteration to help improve an alignment. PMID- 25501943 TI - Genome Annotation and Curation Using MAKER and MAKER-P. AB - This unit describes how to use the genome annotation and curation tools MAKER and MAKER-P to annotate protein-coding and noncoding RNA genes in newly assembled genomes, update/combine legacy annotations in light of new evidence, add quality metrics to annotations from other pipelines, and map existing annotations to a new assembly. MAKER and MAKER-P can rapidly annotate genomes of any size, and scale to match available computational resources. PMID- 25501944 TI - DXMSMS Match Program for Automated Analysis of LC-MS/MS Data Obtained Using Isotopically Coded CID-Cleavable Cross-Linking Reagents. AB - Cross-linking combined with mass spectrometry for the study of proteins and protein complexes is greatly facilitated by the use of isotopically coded cleavable cross-linking reagents. The isotopic coding of the cross-linker enables confident detection of the cross-link signals, while cleavage of the cross-linker provides masses of the individual peptides composing the cross-link and, therefore, facilitates unambiguous assignment of the cross-links. Here, we describe the DXMSMS Match program, designed for automatic analysis of LC-MS/MS mass spectrometric data obtained with isotopically coded CID-cleavable cross linkers. The program verifies the assignments of the cross-links by precursor mass and by inspection of the MS/MS spectra for the fragments and the cleavage products of the cross-linked peptides. The program produces nonprobabilistic scores for matching the spectra to the theoretical fragmentation of the cross links and a visual interface for the validation of the mass spectral matches. PMID- 25501947 TI - Pigment violet 19 - a test case to define a simple method to simulate the vibronic structure of absorption spectra of organic pigments and dyes in solution. AB - A typical quinacridone pigment, PV19, has been used to analyze the impact of several computational parameters on the UV/vis absorption band shape in solution, simulated using density functional theory and time-dependent density functional theory levels of approximation. These encompass, (i) the choice of exchange correlation functional, (ii) the basis set, (iii) the method for non-equilibrium optimization of the excited state geometry, (iv) the approach for evaluating the vibronic band structure, (v) the peak broadening, and (vi) the scaling of the harmonic vibrational frequencies. Among these, the choice of exchange-correlation functional is certainly of the most importance because it can drastically modify the spectral shape. In the case of PV19, the M05-2X and to a lesser extent CAM B3LYP XC functionals are the most efficient to reproduce the vibronic structure, confirming the important role of exact Hartree-Fock exchange. Still, these functionals are not the most reliable to predict the excitation energies and oscillator strengths, for which M05, a functional with less HF exchange, performs better. For evaluating the vibronic structure, the simple gradient method, where only one step of geometry optimization of the excited state is carried out and the gradients are used to evaluate the Huang-Rhys factors as well as to determine the excited state geometries produces a spectrum that is very similar to the ones obtained with the more involved Duschinsky and geometry methods, opening the way to a fast simulation of the UV/vis absorption spectra of pigments and dyes. Then, the effect of scaling the calculated vibrational frequencies to account for anharmonicity effects as well as for limitation of the method also impacts the shape of the vibronic spectrum and this effect depends on the method used to determine the Huang-Rhys factors. Indeed, scaling the vibrational frequencies by a factor which is typically smaller than 1.0 results in a relative decrease of the 0-1 peak intensity with respect to the 0-0 band when optimizing the geometry of the excited state whereas the effect is opposite and magnified if using the gradient method. PMID- 25501945 TI - High light-dependent phosphorylation of photosystem II inner antenna CP29 in monocots is STN7 independent and enhances nonphotochemical quenching. AB - Phosphorylation of the photosystem II antenna protein CP29 has been reported to be induced by excess light and further enhanced by low temperature, increasing resistance to these stressing factors. Moreover, high light-induced CP29 phosphorylation was specifically found in monocots, both C3 and C4, which include the large majority of food crops. Recently, knockout collections have become available in rice (Oryza sativa), a model organism for monocots. In this work, we have used reverse genetics coupled to biochemical and physiological analysis to elucidate the molecular basis of high light-induced phosphorylation of CP29 and the mechanisms by which it exerts a photoprotective effect. We found that kinases and phosphatases involved in CP29 phosphorylation are distinct from those reported to act in State 1-State 2 transitions. In addition, we elucidated the photoprotective role of CP29 phosphorylation in reducing singlet oxygen production and enhancing excess energy dissipation. We thus established, in monocots, a mechanistic connection between phosphorylation of CP29 and nonphotochemical quenching, two processes so far considered independent from one another. PMID- 25501946 TI - Regulation of specialized metabolism by WRKY transcription factors. AB - WRKY transcription factors (TFs) are well known for regulating plant abiotic and biotic stress tolerance. However, much less is known about how WRKY TFs affect plant-specialized metabolism. Analysis of WRKY TFs regulating the production of specialized metabolites emphasizes the values of the family outside of traditionally accepted roles in stress tolerance. WRKYs with conserved roles across plant species seem to be essential in regulating specialized metabolism. Overall, the WRKY family plays an essential role in regulating the biosynthesis of important pharmaceutical, aromatherapy, biofuel, and industrial components, warranting considerable attention in the forthcoming years. PMID- 25501948 TI - An MRI-compatible hand sensory vibrotactile system. AB - Recently, the application of vibrotactile noise to the wrist or back of the hand has been shown to enhance fingertip tactile sensory perception (Enders et al 2013), supporting the potential for an assistive device worn at the wrist, that generates minute vibrations to help the elderly or patients with sensory deficit. However, knowledge regarding the detailed physiological mechanism behind this sensory improvement in the central nervous system, especially in the human brain, is limited, hindering progress in development and use of such assistive devices. To enable investigation of the impact of vibrotactile noise on sensorimotor brain activity in humans, a magnetic resonance imaging (MRI)-compatible vibrotactile system was developed to provide vibrotactile noise during an MRI of the brain. The vibrotactile system utilizes a remote (outside the MR room) signal amplifier which provides a voltage from -40 to +40 V to drive a 12 mm diameter piezoelectric vibrator (inside the MR room). It is portable and is found to be MRI-compatible which enables its use for neurologic investigation with MRI. The system was also found to induce an improvement in fingertip tactile sensation, consistent with the previous study. PMID- 25501950 TI - Left ventricular assist device-acquired aortic insufficiency. PMID- 25501949 TI - Linking tumor mutations to drug responses via a quantitative chemical-genetic interaction map. AB - There is an urgent need in oncology to link molecular aberrations in tumors with therapeutics that can be administered in a personalized fashion. One approach identifies synthetic-lethal genetic interactions or dependencies that cancer cells acquire in the presence of specific mutations. Using engineered isogenic cells, we generated a systematic and quantitative chemical-genetic interaction map that charts the influence of 51 aberrant cancer genes on 90 drug responses. The dataset strongly predicts drug responses found in cancer cell line collections, indicating that isogenic cells can model complex cellular contexts. Applying this dataset to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene, including resistance to AKT-PI3K pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic lethal manner, providing new drug and biomarker pairs for clinical investigation. This scalable approach enables the prediction of drug responses from patient data and can accelerate the development of new genotype directed therapies. SIGNIFICANCE: Determining how the plethora of genomic abnormalities that exist within a given tumor cell affects drug responses remains a major challenge in oncology. Here, we develop a new mapping approach to connect cancer genotypes to drug responses using engineered isogenic cell lines and demonstrate how the resulting dataset can guide clinical interrogation. PMID- 25501952 TI - Unraveling new therapeutic targets of coronary artery disease by genetic approaches. AB - Coronary artery disease (CAD) is the most common cause of death and physical disabilities in developed countries, even though efforts to identify and target causal factors such as hypertension and dyslipidemia have brought tremendous improvements in prevention and treatment. A rapid advance in technology has unraveled new genetic variants associated with CAD and also provided great opportunities to identify novel pathogenic mechanisms and to develop new drugs with higher specificity. Whole-genome sequencing and whole-exome sequencing has made it possible to find rare alleles that are responsible for CAD in small, affected families and case-control studies in a very efficient manner. At present, genome-wide association studies have identified more than 50 loci that explain approximately 10% of the heritability of CAD, most of which is unrelated to traditional risk factors. Mendelian randomization studies enable identification of causal factors among numerous biomarkers and to narrow down promising therapeutic targets. This review highlights new genetic approaches and demonstrates the extent to which the outcome contributes to the finding of new therapeutic targets. PMID- 25501951 TI - Similar survival in patients following heart transplantation receiving induction therapy using daclizumab vs. basiliximab. AB - BACKGROUND: Induction therapy with interleukin-2 receptor antagonists has been established as an effective immunosuppressive strategy in the management of heart transplant (HTx) recipients. We compared outcomes following HTx in patients receiving basiliximab, daclizumab, or no induction therapy. METHODS AND RESULTS: We investigated post-transplant prognosis of patients receiving basiliximab (n=67), daclizumab (n=98) or no induction therapy (n=70). Patients treated with daclizumab (50.3 +/- 14.7 years) were younger than those receiving basiliximab (55.8 +/- 11.2 years) or no induction therapy (54.9 +/- 14.1 years; both P<0.05). Patients receiving either induction therapy showed better survival 1 year after HTx (95%) than those without induction therapy (82%; P<0.001). Survival was similar between patients receiving basiliximab and daclizumab. The incidence of acute cellular or antibody-mediated rejections did not differ among the groups. The main reason that patients did not receive induction therapy was ongoing infection (65.7%), which was more common in patients on ventricular assist device (VAD) support than those without VAD (76.1% vs. 45.8%; P=0.004). The VAD-related infection rate in the entire study cohort was 29.7% (35/118 VAD recipients). CONCLUSIONS: Survival following HTx was worse in patients not receiving induction therapy. No differences were noted in survival or the incidence of rejection between the daclizumab- and basiliximab-treated groups. Induction therapy was less used in patients with infection, which was related to prior VAD support. PMID- 25501953 TI - Microbial urease in health and disease. PMID- 25501954 TI - Diagnose and adios: practical tips for the ongoing evaluation and care of TAC patients taking indomethacin. AB - Paroxysmal hemicrania and hemicrania continua are primary headache disorders characterized by unilateral attacks of severe pain around the orbit with associated autonomic features. They are unique in their absolute response to indomethacin. Diagnosis is made when patients with suspected paroxysmal hemicrania or hemicrania continua have the resolution of headache with therapeutic doses of indomethacin. Once diagnosis is made, limited data exists on the ongoing management of these patients. For patients who do not tolerate indomethacin, or wish to come off medication, there remain few options. This article will discuss the diagnosis of paroxysmal hemicrania and hemicrania continua and the ongoing management of patients on indomethacin, as well as options for patients who do not tolerate or need to come off indomethacin. PMID- 25501955 TI - Hemiplegia and headache: a review of hemiplegia in headache disorders. AB - The most common scenario wherein the practicing neurologist is likely to encounter a patient with headache and hemiplegia will vary depending on his/her specific type of practice. A neurologist providing consultative service to an emergency department is far more likely to see patients with "secondary" headache and hemiplegia in the setting of either ischemic or hemorrhagic stroke than hemiplegia as a transient feature of a primary headache disorder. Neurologists subspecializing in headache medicine who practice in a tertiary referral headache clinic are more likely to encounter hemiplegic migraine, but even in that clinical setting hemiplegic migraine is by no means a frequent diagnosis. The acute onset of hemiplegia can be very frightening not only to the patient but also to the medical personnel. Given the abundance of mimicry, practitioners must judiciously ascertain the correct diagnosis as treatment may greatly vary depending on the cause of both headache and hemiplegia. In this review, we will address the most common causes of hemiplegia associated with headache. PMID- 25501956 TI - Tic versus TAC: differentiating the neuralgias (trigeminal neuralgia) from the cephalalgias (SUNCT and SUNA). AB - Trigeminal neuralgia, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) are classified as distinct disorders in the International Classification of Headache Disorders 3 beta (ICHD-3 beta). SUNCT and SUNA are primary headache disorders included among the trigeminal autonomic cephalalgias. Trigeminal neuralgia is classified under painful cranial neuropathies and other facial pains. The classification criteria of these conditions overlap significantly which could lead to misdiagnosis. The reported overlap among these conditions has called into question whether they should be considered distinct entities or rather a continuum of the same disorder. This review explores the known overlap and how other features not included in the ICHD-3 beta criteria may better differentiate the "Tics" (trigeminal neuralgia) from the "TACs" (SUNCT and SUNA). PMID- 25501957 TI - Purification, cloning, characterization, and N-glycosylation analysis of a novel beta-fructosidase from Aspergillus oryzae FS4 synthesizing levan- and neolevan type fructooligosaccharides. AB - beta-Fructosidases are a widespread group of enzymes that catalyze the hydrolysis of terminal fructosyl units from various substrates. These enzymes also exhibit transglycosylation activity when they function with high concentrations of sucrose, which is used to synthesize fructooligosaccharides (FOS) in the food industry. A beta-fructosidase (BfrA) with high transglycosylation activity was purified from Aspergillus oryzae FS4 as a monomeric glycoprotein. Compared with the most extensively studied Aspergillus spp. fructosidases that synthesize inulin-type beta-(2-1)-linked FOS, BfrA has unique transfructosylating property of synthesizing levan- and neolevan-type beta-(2-6)-linked FOS. The coding sequence (bfrAFS4, 1.86 kb) of BfrA was amplified and expressed in Escherichia coli and Pichia pastoris. Both native and recombinant proteins showed transfructosylation and hydrolyzation activities with broad substrate specificity. These proteins could hydrolyze the following linkages: Glc alpha-1, 2-beta Fru; Glc alpha-1, 3-alpha Fru; and Glc alpha-1, 5-beta Fru. Compared with the unglycosylated E. coli-expressed BfrA (E.BfrA), the N-glycosylated native (N.BfrA) and the P. pastoris-expressed BfrA (P.BfrA) were highly stable at a wide pH range (pH 4 to 11), and significantly more thermostable at temperatures up to 50 degrees C with a maximum activity at 55 degrees C. Using sucrose as substrate, the Km and kcat values for total activity were 37.19+/-5.28 mM and 1.0016+/ 0.039*104 s-1 for N.BfrA. Moreover, 10 of 13 putative N-glycosylation sites were glycosylated on N.BfrA, and N-glycosylation was essential for enzyme thermal stability and optima activity. Thus, BfrA has demonstrated as a well characterized A. oryzae fructosidase with unique transfructosylating capability of synthesizing levan- and neolevan-type FOS. PMID- 25501958 TI - Spp24 derivatives stimulate a Gi-protein coupled receptor-Erk1/2 signaling pathway and modulate gene expressions in W-20-17 cells. AB - Secreted phosphoprotein 24 kDa (Spp24) is an apatite- and BMP/TGF-beta cytokine binding phosphoprotein found in serum and many tissues, including bone. N terminally intact degradation products ranging in size from 14 kDa to 23 kDa have been found in bone. The cleavage sites in Spp24 that produce these short forms have not been definitively identified, and the biological activities and mechanisms of action of Spp24 and its degradation products have not been fully elucidated. We found that the C-terminus of Spp24 is labile to proteolysis by furin, kallikrein, lactoferrin, and trypsin, indicating that both extracellular and intracellular proteolytic events could account for the generation of biologically-active Spp18, Spp16, and Spp14. We determined the effects of these truncation products on kinase-mediated signal transduction, gene expression, and osteoblastic differentiation in W-20-17 bone marrow stromal cells cultured in basal or pro-osteogenic media. After culturing for five days, all forms inhibited BMP-2-stimulated osteoblastic differentiation, assessed as induction of alkaline phosphatase activity, in basal, but not pro-osteogenic media. After 10 days, they also inhibited BMP-2-stimulated mineral deposition in pro-osteogenic media. Spp24 had no effect on Erk1/2 phosphorylation, but Spp18 stimulated short-term Erk1/2, MEK 1/2, and p38 phosphorylation. Pertussis toxin and a MEK1/2 inhibitor ablated Spp18-stimulated Erk 1/2 phosphorylation, indicating a role for Gi proteins and MEK1/2 in the Spp18-stimulated Erk1/2 phosphorylation cascade. Truncation products, but not full-length Spp24, stimulated RUNX2, ATF4, and CSF1 transcription. This suggests that Spp24 truncation products have effects on osteoblastic differentiation mediated by kinase pathways that are independent of exogenous BMP/TGF-beta cytokines. PMID- 25501959 TI - Clinical, pathological, and genetic features of dynamin-2-related centronuclear myopathy in China. AB - Mutations in the dynamin-2 (DNM2) gene can cause autosomal dominant or sporadic centronuclear myopathy (CNM). We aimed to analyze the clinical, pathological and genetic characteristic of patients with DNM2-related CNM in China. We studied seven patients, all of whom underwent clinical examination, muscle biopsy, electromyography, and genetic tests. DNM2 gene analysis revealed two sporadic patients harboring the p.E368K mutation, two patients from one family carrying p.R369Q, one with p.R369W, one with p.R523G and one with compound heterozygous mutations of p.R522H and p.R718Q. In DNM2-related CNM, ptosis, ophthalmoplegia/paresis, and facial weakness are the frequently observed manifestations. However, among these seven patients, only one had bilateral ptosis; one, external ophthalmoplegia and one, facial weakness. Muscle biopsy showed that the percentage of muscle fibers with centrally located nuclei ranged from 67 to 93 %, all with radial sarcoplasmic strands. To date, five different CNM-related DNM2 mutations have been observed in China. Here, a patient with compound heterozygous DNM2 mutations was reported for the first time. Facial weakness, ptosis and ophthalmoplegia did not appear to be common in Chinese patients. This study on Chinese patients broadens the spectrum of DNM2-related CNM. PMID- 25501960 TI - Neurogenic pulmonary edema caused by bilateral medial medullary infarction. PMID- 25501961 TI - Hemicrania continua with visual aura successfully treated with a combination of indomethacin and topiramate. PMID- 25501962 TI - Intima-media thickness and endothelial dysfunction in GCK and HNF1A-MODY patients. AB - OBJECTIVE: Mutations in the glucokinase (GCK) gene, along with hepatocyte nuclear factor 1A (HNF1A) gene mutations, are the most frequent cause of maturity-onset diabetes of the young (MODY). GCK-MODY patients are typically characterized by a moderate fasting hyperglycemia; however, little is known about atherosclerosis and intermediate-related phenotypes in these subjects. DESIGN: To examine carotid artery intima-media thickness (IMT) and endothelial function assessed by brachial artery flow-mediated dilatation (FMD) in GCK gene mutations carriers and HNF1A MODY. METHODS: A total of 64 subjects with GCK gene mutations, and 52 HNF1A gene mutation carriers as well as 53 nondiabetic controls were examined. IMT and FMD were assessed by ultrasonography. Appropriate statistical tests were performed to assess differences between the groups, and multivariate linear regression was done for the association with IMT and FMD. RESULTS: The clinical characteristics of all groups were similar with the mean age at examination of 35.1, 41.1, and 39.5 years for GCK, HNF1A and the control group respectively. The highest mean IMT value was in the HNF1A-MODY group: 7.0+/-1.4 mm, whereas it reached 6.3+/-1.4 mm in GCK mutation carriers and 6.3+/-1.3 mm in controls (P=0.008). After adjustment for possible clinical and biochemical cofounders, IMT remained higher in HNF1A-MODY patients as compared with GCK-MODY patients (P=0.02) and controls (P=0.0003). FMD was significantly lower in HNF1A (9.9+/-4.6%) and GCK-MODY (11.1+/-4.6%) patients in comparison with controls (13.9+/-4.7%; P=0.0001). After adjustment, FMD remained lower in HNF1A-MODY (P=0.0005) and GCK-MODY patients (P=0.01) as compared with controls. CONCLUSIONS: Both examined MODY groups demonstrated evidence of endothelial dysfunction. In addition, HNF1-MODY patients seem to be more prone to an early atherosclerotic phenotype. PMID- 25501963 TI - From first symptoms to final diagnosis of Cushing's disease: experiences of 176 patients. AB - OBJECTIVE: To obtain structured information on the diagnostic delay in patients with Cushing's disease (CD) from the patients perspective to provide leverage points for earlier diagnosis. DESIGN: The study includes 176 patients with ACTH dependent CD who had received pituitary surgery completed a self-developed questionnaire on their symptomatology before the illness was diagnosed, the course and length of the diagnostic process, and the role of the involved health care professionals. METHODS: Data were analyzed statistically. Answers in free text options were categorized and counted. RESULTS: The overall diagnostic process took 3.8+/-4.8 years (median 2 years), during which 4.6+/-3.8 (1-30) physicians were consulted, most frequently the family physician (FP; 83.0%). The presented symptoms were various and often vague, e.g. 'poor general condition' (at FPs), or very common in the field of the visited specialist (i.e. 'skin changes' at dermatologists). Women recognized the first CD symptoms themselves significantly more frequently than men, whereas physicians recognized CD symptoms significantly more frequently in males. CONCLUSION: A clear difficulty of diagnosing CD seems that patients describe isolated symptoms to the FP or the respective specialists according to their fields of specialization. As FPs are contacted most frequently, they should be trained to recognize the broad spectrum of CD symptoms, especially in female patients with weight gain, and initiate endocrinological referral. PMID- 25501964 TI - Pregnancy may favour the development of severe autoimmune central diabetes insipidus in women with vasopressin cell antibodies: description of two cases. AB - Recently, an increased incidence of central diabetes insipidus (CDI) in pregnancy, and less frequently in the post partum period, has been reported, most probably favoured by some conditions occurring in pregnancy. This study was aimed at investigating the influence of pregnancy on a pre-existing potential/subclinical hypothalamic autoimmunity. We studied the longitudinal behaviour of arginine-vasopressin cell antibodies (AVPcAbs) and post-pituitary function in two young women with a positive history of autoimmune disease and presence of AVPcAbs, but without clinical CDI, and who became pregnant 5 and 7 months after our first observation. The behaviour of post-pituitary function and AVPcAbs (by immunofluorescence) was evaluated at baseline, during pregnancy and for 2 years after delivery. AVPcAbs, present at low/middle titres at baseline in both patients, showed a titre increase during pregnancy in one patient and after delivery in the other patient, with development of clinically overt CDI. Therapy with 1-deamino-8-d-arginine vasopressin (DDAVP) caused a prompt clinical remission. After a first unsuccessful attempt of withdrawal, the therapy was definitively stopped at the 6th and the 7th month of post partum period respectively, when AVPcAbs disappeared, accompanied by post-pituitary function recovery, persisting until the end of the follow-up. The determination of AVPcAbs is advisable in patients with autoimmune diseases planning their pregnancy, because they could be considered good predictive markers of gestational or post partum autoimmune CDI. The monitoring of AVPcAb titres and post-pituitary function during pregnancy in these patients may allow for an early diagnosis and an early replacement therapy, which could induce the disappearance of these antibodies with consequent complete remission of CDI. PMID- 25501965 TI - Fluid forces enhance the performance of an aspirant leader in self-organized living groups. AB - In this paper, the performance of an individual aiming at guiding a self organized group is numerically investigated. A collective behavioural model is adopted, accounting for the mutual repulsion, attraction and orientation experienced by the individuals. Moreover, these represent a set of solid particles which are supposed to be immersed in a fictitious viscous fluid. In particular, the lattice Boltzmann and Immersed boundary methods are used to predict the fluid dynamics, whereas the effect of the hydrodynamic forces on particles is accounted for by solving the equation of the solid motion through the time discontinuous Galerkin scheme. Numerical simulations are carried out by involving the individuals in a dichotomous process. On the one hand, an aspirant leader (AL) additional individual is added to the system. AL is forced to move along a prescribed direction which intersects the group. On the other hand, these tend to depart from an obstacle represented by a rotating lamina which is placed in the fluid domain. A numerical campaign is carried out by varying the fluid viscosity and, as a consequence, the hydrodynamic field. Moreover, scenarios characterized by different values of the size of the group are investigated. In order to estimate the AL's performance, a proper parameter is introduced, depending on the number of individuals following AL. Present findings show that the sole collective behavioural equations are insufficient to predict the AL's performance, since the motion is drastically affected by the presence of the surrounding fluid. With respect to the existing literature, the proposed numerical model is enriched by accounting for the presence of the encompassing fluid, thus computing the hydrodynamic forces arising when the individuals move. PMID- 25501967 TI - Cyanidin-3-glucoside isolated from mulberry fruits protects pancreatic beta-cells against glucotoxicity-induced apoptosis. AB - The present study investigated the cytoprotective effects of cyanidin-3-glucoside (C3G), isolated from mulberry fruits, on the glucotoxicity-induced apoptosis of pancreatic beta-cells to evaluate the antidiabetic effects of this compound. MIN6N pancreatic beta-cells were used to investigate the cytoprotective effects of C3G. In addition, the effects of C3G on the glucotoxicity-induced apoptosis of pancreatic beta-cells was evaluated using MTT assay, immunofluorescent staining, flow cytometric and western blot analyses. The pancreatic beta-cells cultured under high glucose conditions exhibited distinct apoptotic features. C3G decreased the generation of intracellular reactive oxygen species, DNA fragmentation and the rate of apoptosis. C3G also prevented pancreatic beta-cell apoptosis induced by high glucose conditions by interfering with the intrinsic apoptotic pathways. In addition, C3G treatment resulted in increased insulin secretion compared with treatment with high glucose only. In conclusion, the results of the present study suggested that C3G obtained from mulberry fruits may be a potential phytotherapeutic agent for the prevention of diabetes. PMID- 25501966 TI - Sepsis in Poland: why do we die? AB - OBJECTIVE: To investigate the adverse events and potential risk factors in patients who develop sepsis. SUBJECTS AND METHODS: Fifty-five medico-legal opinion forms relating to sepsis cases issued by the Department of Forensic Medicine, Wroclaw, Poland, between 2004 and 2013 were analyzed for medical errors and risk factors for adverse events. RESULTS: The most common causes of medical errors were a lack of knowledge in recognition, diagnosis and therapy as well as ignorance of risk. The common risk factors for adverse events were deferral of a diagnostic or therapeutic decision, high-level anxiety of patients or their families about the patient's health and actively seeking for help. The most significant risk factors were communication errors, not enough medical staff, stereotype-based thinking about diseases and providing easy explanations for serious symptoms. CONCLUSION: The most common cause of adverse events related to sepsis in the Polish health-care system was a lack of knowledge about the symptoms, diagnosis and treatment as well as the ignoring of danger. A possible means of improving safety might be through spreading knowledge and creating medical management algorithms for all health-care workers, especially physicians. PMID- 25501968 TI - Olav Bijvoet 1928-2014. PMID- 25501969 TI - Repair mechanisms for microdamage in bone. PMID- 25501971 TI - Theranostic properties of a survivin-directed molecular beacon in human melanoma cells. AB - Survivin is an inhibitor of apoptosis overexpressed in different types of tumors and undetectable in most terminally differentiated normal tissues. In the current study, we sought to evaluate the in vitro theranostic properties of a molecular beacon-oligodeoxynucleotide (MB) that targets survivin mRNA. We used laser scanning confocal microscopy to study MB delivery in living cells and real-time PCR and western blot to assess selective survivin-targeting in human malignant melanoma cells. We further assess the pro-apoptotic effect of MB by measuring internucleosomal DNA fragmentation, dissipation of mitochondrial membrane potential (MMP) and changes in nuclear morphology. Transfection of MB into A375 and 501 Mel cells generated high signal intensity from the cytoplasm, while no signal was detected in the extracellular environment and in survivin-negative cells (i.e., human melanocytes and monocytes). MB time dependently decreased survivin mRNA and protein expression in melanoma cells with the maximum effect reached at 72 h. Treatment of melanoma cells with MB induced apoptosis by significant changes in MMP, accumulation of histone-complexed DNA fragments in the cytoplasm and nuclear condensation. MB also enhanced the pro-apoptotic effect of standard chemotherapeutic drugs tested at clinically relevant concentrations. The MB tested in the current study conjugates the ability of imaging with the pharmacological silencing activity against survivin mRNA in human melanoma cells and may represent an innovative approach for cancer diagnosis and treatment. PMID- 25501972 TI - Fibrinogen reduction and bleeding complications in plasma exchange, immunoadsorption and a combination of the two. AB - BACKGROUND: Immunoadsorption (IAS) and therapeutic plasma exchange (TPE) are considered safe although fibrinogen is removed. To date no comparison of fibrinogen reduction and associated risk of bleeding in apheresis exists. METHODS: Retrospective analysis of TPE, three IAS adsorbers, and combined TPE/IAS regarding fibrinogen reduction and bleeding incidence in 67 patients (1,032 treatments). RESULTS: TPE and TPE/IAS reduced fibrinogen by 64 +/- 11% and 58 +/- 9%, leading to concentrations <100 mg/dl in 20 and 17% of treatments, respectively. IAS decreased fibrinogen less than TPE (26 +/- 6%, p < 0.0001), resulting in fibrinogen concentrations <100 mg/dl in 1% of treatments. The processed volume correlated with reduction in TPE (r = 0.64, p < 0.01), but not in IAS. Bleeding occurred in 1.3% (IAS), 2.3% (TPE) and 3.1% (TPE/IAS) of treatments. CONCLUSION: Hypofibrinogenemia occurs in 20% of patients after TPE and TPE/IAS, but rarely after IAS. IAS removes fibrinogen independently of volume processed. Overall, bleeding is rare in apheresis. PMID- 25501973 TI - Lessons from the public health response to Ebola. PMID- 25501975 TI - Prognosis of patients with diffuse large B cell lymphoma not reaching complete response or relapsing after frontline chemotherapy or immunochemotherapy. AB - A retrospective study was performed to assess the outcome of patients with diffuse large B cell lymphoma (DLBCL) who did not achieve complete response or who relapsed before and after the use of rituximab. Clinical features and outcome of 816 (425 M/391 F; median age 63 years) patients diagnosed from 1991 to 2001 (pre-rituximab era, N = 348) and from 2002 to 2012 (rituximab era, N = 468) in a single institution were evaluated. Five hundred fifty-three patients achieved complete remission (CR), 57 partial response (PR), and 206 were refractory with a median overall survival of 15, 1.5, and 0.4 years, respectively. Patients receiving rituximab had lower risk of refractoriness or relapse. In primarily refractory and PR patients, there was not a difference in survival depending on whether patients received or not rituximab-containing frontline treatment. Early death rate was 11%, including 3.6% due to infectious complications. Rituximab did not modify these figures. In the relapse setting, 5-year survival from relapse was 25% for patients who never received rituximab, 54% for those who received rituximab only at relapse, and 48% for those treated with immunochemotherapy both as frontline and at relapse. In conclusion, relapsed/refractory patients with DLBCL show poor prognosis despite the use of frontline immunochemotherapy. New therapeutic approaches are needed in this group of patients. PMID- 25501974 TI - In vitro reconstitution of yeast tUTP/UTP A and UTP B subcomplexes provides new insights into their modular architecture. AB - Eukaryotic ribosome biogenesis is a multistep process involving more than 150 biogenesis factors, which interact transiently with pre-ribosomal particles to promote their maturation. Some of these auxiliary proteins have been isolated in complexes found separate from the ribosomal environment. Among them, are 3 large UTP subcomplexes containing 6 or 7 protein subunits which are involved in the early steps of ribosome biogenesis. The composition of the UTP subcomplexes and the network of binary interactions between protein subunits have been analyzed previously. To obtain further insights into the structural and biochemical properties of UTP subcomplexes, we established a heterologous expression system to allow reconstitution of the yeast tUTP/UTP A and UTP B subcomplexes from their candidate subunits. The results of a series of reconstitution experiments involving different combinations of protein subunits are in good agreement with most of the previously observed binary interactions. Moreover, in combination with additional biochemical analyses, several stable building blocks of the UTP subcomplexes were identified. Based on these findings, we present a refined model of the tUTP/UTP A and UTP B architecture. PMID- 25501976 TI - Cometary science. 67P/Churyumov-Gerasimenko, a Jupiter family comet with a high D/H ratio. AB - The provenance of water and organic compounds on Earth and other terrestrial planets has been discussed for a long time without reaching a consensus. One of the best means to distinguish between different scenarios is by determining the deuterium-to-hydrogen (D/H) ratios in the reservoirs for comets and Earth's oceans. Here, we report the direct in situ measurement of the D/H ratio in the Jupiter family comet 67P/Churyumov-Gerasimenko by the ROSINA mass spectrometer aboard the European Space Agency's Rosetta spacecraft, which is found to be (5.3 +/- 0.7) * 10(-4)-that is, approximately three times the terrestrial value. Previous cometary measurements and our new finding suggest a wide range of D/H ratios in the water within Jupiter family objects and preclude the idea that this reservoir is solely composed of Earth ocean-like water. PMID- 25501977 TI - Risk stratification and prognostic value of GRACE and TIMI risk scores for female patients with non-ST segment elevation acute coronary syndrome. AB - AIM: The aim of this paper was to investigate the value of Global Registry of Acute Coronary Events (GRACE) and thrombolysis in myocardial infarction (TIMI) risk scores for risk stratification and prognosis in female patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS). METHODS: Non-elderly (<65 years) and elderly (>=65 years) female patients with NSTE-ACS (totally 869 cases) were enrolled in this study. The patients were further divided into low, intermediate and high-risk groups according to their GRACE and TIMI scores. Patients were followed up for 1 year to record the mortality and incidence of major adverse cardiac events (MACE). Differences in mortality and MACE incidence between the two scoring systems were compared by the area under the ROC curve. RESULTS: The area under ROC curve (AUC) corresponding to the mortality and MACE incidence in any period by the GRACE scoring system was significantly larger than the TIMI scoring system in the elderly patients at 1 year of follow-up (AUC of mortality, 0.79 vs. 0.68; AUC of MACE, 0.78 vs. 0.72; P<0.05). Mortality and MACE incidence increased in parallel with the scores. Risk ratio values of Cox regression analysis based on GRACE and TIMI scores were greater than 1 (P<0.001). CONCLUSION: Both GRACE and TIMI were adoptable in clinical risk stratification and prognosis of female patients with NSTE-ACS at different age groups. GRACE showed better accuracy than the TIMI scores. PMID- 25501978 TI - Association between 1019C/T polymorphism in the connexin 37 gene and dilated cardiomyopathy. AB - BACKGROUND: The aim of this paper was to investigate the association between the connexin 37 (CX37) 1019C/T polymorphism and susceptibility to dilated cardiomyopathy (DCM). METHODS: Han Chinese diagnosed with DCM between 2005 and 2013 were studied, and they were compared with a control group of 816 persons without DCM from a patient cohort from the Provincial Hospital Affiliated to Anhui Medical University, China. A total of 873 patients with DCM were included. All study and control cases were genotyped by DNA sequencing. RESULTS: Polymorphism C1019T on the Connexin37 gene (CX37) was found in the whole population. The distribution of three genotype frequencies in both groups was in accordance with Hardy-Weinberg equilibrium. The frequency of the CX37 C allele was higher in DCM patients (57.33% vs. 42.03%, P<0.01) compared to the control group. The frequency of C carriers (CC+TC) was 80.41% in DCM patients, compared to 66.7% in controls (P<0.01). DCM risk was significantly increased in carriers of the C allele (CC+TC) than in TT homozygotes (odds ratio [OR]=2.05, 95% confidence interval [CI]: 1.65-2.56). Subsequent stratified analyses demonstrate that a significant difference exists in the frequency of C carriers between male DCM patients and controls (77.61% vs. 69.04%, P<0.01) and in female DCM patients and controls (85.62 % vs. 62.19%, P<0.01). Carriers of the C allele had higher DCM risk compared with TT homozygotes with sex differences (male: OR=1.64, 95% CI: 1.39-1.95; female: OR=2.32, 95% CI: 1.84-2.94). CONCLUSIONS: The C allele in the CX37 gene might be associated with susceptibility to DCM in Chinese Han. Female carriers of the C allele had higher DCM risk compared with TT homozygotes than males. PMID- 25501979 TI - Erratum to: Role of hysteroscopy in the detection of endometrial pathologies in women presenting with postmenopausal bleeding and thickened endometrium. PMID- 25501980 TI - The use of intravenous magnesium in non-preeclamptic pregnant women: fetal/neonatal neuroprotection. AB - PURPOSE: To review the effect of intravenous magnesium in obstetrics on fetal/neonatal neuroprotection. METHODS: A systematic review of published studies. RESULTS: Five randomized trials and 4 meta-analyses have shown a significant 32% reduction of cerebral palsy when administering magnesium sulfate in case of preterm delivery. The pathophysiologic mechanism is not fully unraveled: modulation of the inflammatory process, both in the mother and the fetus, and downregulation of neuronal stimulation seem to be involved. After long term high-dose intravenous administration of magnesium, maternal and neonatal adverse effects such as maternal and neonatal hypotonia and osteoporosis and specific fetal/neonatal cerebral lesions have been described. In case of administration for less than 48 h at 1 g/h and a loading dose of 4 g, these toxic amounts are not achieved. American, Canadian and Australian guidelines recommend the use of intravenous magnesium in any threatening delivery at less than 32 weeks. The "number needed to treat" to avoid 1 cerebral palsy is between 15 and 35. CONCLUSIONS: Intravenous magnesium significantly reduces the risk for cerebral palsy in preterm birth. Open questions remain the optimal dosing schedule, whether or not repeating when delivery has been successfully postponed and a new episode of preterm labor occurs. Some concern has been raised on a too optimistic value for random error which might have led to over-optimistic conclusions in classic meta-analysis. Randomized trials comparing different doses and individual patient data meta-analysis might resolve these issues. PMID- 25501981 TI - Clinical determinants of reduced physical activity in hemodialysis and peritoneal dialysis patients. AB - OBJECTIVES: The phenotype associated to reduced physical activity (PA) in dialysis patients is poorly documented. We here evaluate weekly PA in two independent cohorts. METHODS: Cross-sectional study with PA assessed by the number of steps/day measured by pedometer in two cohorts of prevalent dialysis patients: (1) peritoneal dialysis (PD) patients (n = 64; 62 +/- 14 years; 70 % men) from Stockholm, Sweden using the pedometer for 7 consecutive days; (2) hemodialysis (HD) patients (n = 78; 63 +/- 12 years; 65% men) from a single center in Madrid, Spain using the pedometer for 6 consecutive days: 2 HD days, 2 non-HD midweek days and 2 non-HD weekend days. In both cohorts, comorbidities, body composition, nutritional status, and related biomarkers were assessed. Cohorts were not merged; instead data were analyzed separately serving as reciprocal replication analyses. RESULTS: Most patients (63% of PD and 71% of HD) were considered sedentary (<5,000 steps/day). PD patients had on average 4,839 +/ 3,313 steps/day. HD patients had 3,767 +/- 3,370 steps/day on HD-free days, but fewer steps/day on HD days (2,274 +/- 2,048 steps/day; p < 0.0001). In both cohorts, and across increasing PA tertiles, patients were younger and had less comorbidities. Higher PA was also accompanied by better nutritional status (depicted by albumin, pre-albumin, creatinine and normalized protein catabolic rate in HD, and by albumin and subjective global assessment [SGA] in PD), higher lean body mass, and lower fat body mass (bioimpedance and/or dual-energy X-ray absorptiometry [DEXA]). Higher levels of PA were accompanied by lower levels of C reactive protein in PD. Age and lean body mass were the strongest multivariate predictors of PA in both cohorts. CONCLUSION: There is a high prevalence of sedentary behavior in dialysis patients. Better physical activity was consistently associated with younger age, lower presence of comorbidities and better nutritional status. Pedometers represent a simple and inexpensive tool to objectively evaluate physical activity in this patient population. PMID- 25501982 TI - HOXA7 stimulates human hepatocellular carcinoma proliferation through cyclin E1/CDK2. AB - HOX genes are transcription factors that control morphogenesis, organogenesis and differentiation. Increasing evidence suggests that HOX genes play a role in hepatocellular carcinoma (HCC) progression; however few studies have defined the functional roles and mechanisms of action. In the present study, we used siRNA and forced-expression in multiple cell lines to define the role of HOXA7 in the regulation of proliferation of HCC in vitro and in vivo. Knockdown of endogenous HOXA7 decreased the proliferation of HepG2 and QGY-7703 cells. These changes were not associated with significant changes in cyclin D1 and CDK4. However, downregulation of HOXA7 significantly reduced cyclin E1 and CDK2 protein levels. Conversely, overexpression of HOXA7 in QSG-7701 cells stimulated proliferation and increased cyclin E1 and CDK2 protein levels. Our results confirmed that HOXA7 promoted cell proliferation, and these changes were mediated by cyclin E1/CDK2. These observations contribute to our understanding of the important roles of HOXA7 in HCC development and progression and HOXA7 could be a promising molecular target for the development of new diagnostic and therapeutic strategies for HCC. PMID- 25501984 TI - Sexual and mother-to-child transmission of Ebola virus in the postconvalescent period. PMID- 25501985 TI - Catheter tip cultures: are they really relegated to the archives of historical medical interest? PMID- 25501983 TI - Featural and temporal attention selectively enhance task-appropriate representations in human primary visual cortex. AB - Our perceptions are often shaped by focusing our attention towards specific features or periods of time irrespective of location. Here we explore the physiological bases of these non-spatial forms of attention by imaging brain activity while subjects perform a challenging change-detection task. The task employs a continuously varying visual stimulus that, for any moment in time, selectively activates functionally distinct subpopulations of primary visual cortex (V1) neurons. When subjects are cued to the timing and nature of the change, the mapping of orientation preference across V1 systematically shifts towards the cued stimulus just prior to its appearance. A simple linear model can explain this shift: attentional changes are selectively targeted towards neural subpopulations, representing the attended feature at the times the feature was anticipated. Our results suggest that featural attention is mediated by a linear change in the responses of task-appropriate neurons across cortex during appropriate periods of time. PMID- 25501986 TI - Delay in diagnosis of invasive surgical site infections following knee arthroplasty versus hip arthroplasty. AB - BACKGROUND: The timing of diagnosis of invasive surgical site infection (SSI) following joint replacement surgery is an important criterion used to determine subsequent medical and surgical management. METHODS: We compared time to diagnosis of invasive SSI following hip vs knee arthroplasty. SSIs were included in the analysis if they occurred within 365 days following procedures performed from 1 January 2007 through 31 December 2011 at 36 community acute care hospitals and 1 ambulatory surgery center in the Duke Infection Control Outreach Network. A Cox regression model was fitted to estimate the association between procedure type and time to diagnosis of SSI, adjusted for age, pathogen virulence, American Society of Anesthesiologists' score, and hospital surgical volume. RESULTS: Six hundred sixty-one invasive SSIs were identified; 401 (61%) occurred following knee arthroplasties. The median time to diagnosis of SSI was 25 days (interquartile range [IQR], 17-48 days) following hip arthroplasty vs 42 days (IQR, 21-114 days) following knee arthroplasty (unadjusted hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.37-1.87; P < .001). Time to diagnosis of invasive SSI remained significantly shorter for hip than for knee arthroplasties after adjusting for age, pathogen virulence, and hospital surgical volume (HR, 1.51; 95% CI, 1.28-1.78; P < .001). CONCLUSIONS: The diagnosis of invasive SSI was delayed following knee arthroplasty compared with hip arthroplasty. We hypothesize that differences in symptom manifestation and disparities in access to care may contribute to the observed differential timing of diagnosis. Our findings have important implications for the management of prosthetic joint infections, because treatment strategies depend on the timing of diagnosis. PMID- 25501987 TI - Seasonal influenza vaccination rates in the HIV outpatient study-United States, 1999-2013. PMID- 25501989 TI - Antisite-disorder, magnetic and thermoelectric properties of Mo-rich Sr2Fe1 yMo1+yO6 (0 <=y<= 0.2) double perovskites. AB - Structure analysis using X-ray and neutron powder diffraction and elemental mapping has been used to demonstrate that nominal A-site deficient Sr(2-x)FeMoO(6 delta) (0 <=x<= 0.5) compositions form as Mo-rich Sr(2)Fe(1-y)Mo(1+y)O(6) (0 <=y<= 0.2) perovskites at high temperatures and under reducing atmospheres. These materials show a gradual transition from the Fe and Mo rock salt ordered double perovskite structure to a B-site disordered arrangement. Analysis of the fractions of B-O-B' linkages revealed a gradual increase in the number of Mo-O-Mo linkages at the expense of the ferrimagnetic (FIM) Fe-O-Mo linkages that dominate the y = 0 material. All samples contain about 10-15% antiferromagnetic (AF) Fe-O Fe linkages, independent of the degree of B-site ordering. The magnetic susceptibility of the y = 0.2 sample is characteristic of a small domain ferrimagnet (T(c)~ 250 K), while room temperature neutron powder diffraction demonstrated the presence of G-type AF ordering linked to the Fe-O-Fe linkages (m(Fe) = 1.25(7)MU(B)). The high temperature thermoelectric properties are characteristic of a metal with a linear temperature dependence of the Seebeck coefficient, S (for all y) and electrical resistivity rho (y>= 0.1). The largest thermoelectric power factor S(2)/rho = 0.12 mW m(-1) K(-1) is observed for Sr(2)FeMoO(6) at 1000 K. PMID- 25501988 TI - Cerebrospinal fluid exposure of efavirenz and its major metabolites when dosed at 400 mg and 600 mg once daily: a randomized controlled trial. AB - BACKGROUND: The optimal penetration of antiretroviral agents into the central nervous system may be a balance between providing adequate drug exposure to inhibit human immunodeficiency virus (HIV) replication while avoiding concentrations associated with neuronal toxicities. METHODS: Cerebrospinal fluid (CSF) exposure of efavirenz and the metabolites 7-hydroxy (7OH) and 8-hydroxy (8OH) efavirenz were assessed after at least 12 weeks of therapy in HIV-infected subjects randomized to commence antiretroviral regimens containing efavirenz at either 400 mg or 600 mg once daily. RESULTS: Of 28 subjects (14 and 14 on efavirenz 400 mg and 600 mg, respectively), CSF HIV RNA was undetectable in all. Geometric mean CSF efavirenz, 7OH-, and 8OH-efavirenz concentrations (with 90% confidence intervals [CIs]) for the 400-mg and 600-mg dosing groups were 16.5 (13 21) and 19.5 (15-25) ng/mL; 0.6 (.4-.9) and 0.6 (.4-1) ng/mL; and 5.1 (4.0-6.4) and 3.1 (2.1-4.4) ng/mL, respectively. Efavirenz concentration in CSF was >0.51 ng/mL (proposed CSF 50% maximal inhibitory concentration for wild-type virus) in all subjects, and 8OH-efavirenz concentration in CSF was >3.3 ng/mL (a proposed toxicity threshold) in 11 of 14 and 7 of 14 subjects randomized to the 400 mg and 600 mg doses of efavirenz, respectively. Whereas CSF efavirenz concentration was significantly associated with plasma concentration (P < .001) and cytochrome P450 2B6 genotype (CSF efavirenz GG to GT/TT geometric mean ratio, 0.56 [90% CI, .42 .74]), CSF 8OH-efavirenz concentration was not (P = .242 for association and CSF 8OH-efavirenz GG to GT/TT geometric mean ratio, 1.52 [90% CI, .97-2.36]). CONCLUSIONS: With both doses of efavirenz studied, CSF concentrations were considered adequate to inhibit HIV replication, although concentrations of 8OH efavirenz were greater than those reportedly associated with neuronal toxicity. CSF exposure of 8OH-efavirenz was not dependent on plasma exposure and, as we postulate, may be subject to saturable pharmacokinetic effects. CLINICAL TRIALS REGISTRATION: NCT01011413. PMID- 25501990 TI - Succession and replacement of bacterial populations in the caecum of egg laying hens over their whole life. AB - In this study we characterised the development of caecal microbiota in egg laying hens over their commercial production lifespan, from the day of hatching until 60 weeks of age. Using pyrosequencing of V3/V4 variable regions of 16S rRNA genes for microbiota characterisation, we were able to define 4 different stages of caecal microbiota development. The first stage lasted for the first week of life and was characterised by a high prevalence of Enterobacteriaceae (phylum Proteobacteria). The second stage lasted from week 2 to week 4 and was characterised by nearly an absolute dominance of Lachnospiraceae and Ruminococcaceae (both phylum Firmicutes). The third stage lasted from month 2 to month 6 and was characterised by the succession of Firmicutes at the expense of Bacteroidetes. The fourth stage was typical for adult hens in full egg production aged 7 months or more and was characterised by a constant ratio of Bacteroidetes and Firmicutes formed by equal numbers of the representatives of both phyla. PMID- 25501992 TI - An armed, YB-1-dependent oncolytic adenovirus as a candidate for a combinatorial anti-glioma approach of virotherapy, suicide gene therapy and chemotherapeutic treatment. AB - We investigated the novel recombinant oncolytic adenovirus Ad-delo-sr39TK-RGD, armed with a mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39TK) as a suicide gene, and explored its antitumor efficacy in combination with HSV1 sr39TK/ganciclovir (GCV) gene therapy and temozolomide (TMZ). Ad-delo-sr39TK-RGD is an E1-mutated conditionally replicating adenovirus dependent on the human Y box binding protein 1 (YB-1). Thus, we utilized the YB-1 dependency of the vector to target human glioma cells in vitro, using two-dimensional cell culture and three-dimensional multicellular spheroids, and demonstrated the strong replication competence and oncolytic potential of the virus. The cytotoxicity mediated by HSV1-sr39TK and its prodrug GCV enhanced the oncolytic effect even at <0.1 MUg ml(-1) GCV and induced cell killing of > 95% after adding GCV 0-1 days following infection. An increased bystander effect of viral replication and GCV in co-cultured infected and uninfected cells was observed. Co-administrating Ad delo-sr39TK-RGD with TMZ and GCV, spheroid growth was reduced drastically. Gamma counting of infected spheroids demonstrated successful accumulation of the radiotracer (18)F-labeled 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine mediated by HSV1-sr39TK. Hence, our results show that the combination of YB-1-dependent virotherapy with suicide genes and TMZ effectively induces glioma cell killing and may allow for in vivo non-invasive imaging within a limited time frame. PMID- 25501991 TI - Early mesozoic coexistence of amniotes and hepadnaviridae. AB - Hepadnaviridae are double-stranded DNA viruses that infect some species of birds and mammals. This includes humans, where hepatitis B viruses (HBVs) are prevalent pathogens in considerable parts of the global population. Recently, endogenized sequences of HBVs (eHBVs) have been discovered in bird genomes where they constitute direct evidence for the coexistence of these viruses and their hosts from the late Mesozoic until present. Nevertheless, virtually nothing is known about the ancient host range of this virus family in other animals. Here we report the first eHBVs from crocodilian, snake, and turtle genomes, including a turtle eHBV that endogenized >207 million years ago. This genomic "fossil" is >125 million years older than the oldest avian eHBV and provides the first direct evidence that Hepadnaviridae already existed during the Early Mesozoic. This implies that the Mesozoic fossil record of HBV infection spans three of the five major groups of land vertebrates, namely birds, crocodilians, and turtles. We show that the deep phylogenetic relationships of HBVs are largely congruent with the deep phylogeny of their amniote hosts, which suggests an ancient amniote-HBV coexistence and codivergence, at least since the Early Mesozoic. Notably, the organization of overlapping genes as well as the structure of elements involved in viral replication has remained highly conserved among HBVs along that time span, except for the presence of the X gene. We provide multiple lines of evidence that the tumor-promoting X protein of mammalian HBVs lacks a homolog in all other hepadnaviruses and propose a novel scenario for the emergence of X via segmental duplication and overprinting of pre-existing reading frames in the ancestor of mammalian HBVs. Our study reveals an unforeseen host range of prehistoric HBVs and provides novel insights into the genome evolution of hepadnaviruses throughout their long-lasting association with amniote hosts. PMID- 25501995 TI - Coupling of carboxylic acids with internal alkynes by supported ruthenium catalysts: direct and selective syntheses of multi-substituted phthalide derivatives. AB - Supported ruthenium catalysts promote coupling of various kinds of aromatic carboxylic acids with internal alkynes, giving the corresponding multi substituted phthalide derivatives in high yields. The supported Ru catalyst can be recycled at least five times with no loss of activity. PMID- 25501993 TI - Genetic modification of neurons to express bevacizumab for local anti angiogenesis treatment of glioblastoma. AB - The median survival of glioblastoma multiforme (GBM) is approximately 1 year. Following surgical removal, systemic therapies are limited by the blood-brain barrier. To circumvent this, we developed a method to modify neurons with the genetic sequence for therapeutic monoclonal antibodies using adeno-associated virus (AAV) gene transfer vectors, directing persistent, local expression in the tumor milieu. The human U87MG GBM cell line or patient-derived early passage GBM cells were administered to the striatum of NOD/SCID immunodeficient mice. AAVrh.10BevMab, an AAVrh.10-based vector coding for bevacizumab (Avastin), an anti-human vascular endothelial growth factor (VEGF) monoclonal antibody, was delivered to the area of the GBM xenograft. Localized expression of bevacizumab was demonstrated by quantitative PCR, ELISA and western blotting. Immunohistochemistry showed that bevacizumab was expressed in neurons. Concurrent administration of AAVrh.10BevMab with the U87MG tumor reduced tumor blood vessel density and tumor volume, and increased survival. Administration of AAVrh.10BevMab 1 week after U87MG xenograft reduced growth and increased survival. Studies with patient-derived early passage GBM primary cells showed a reduction in primary tumor burden with an increased survival. These data support the strategy of AAV-mediated central nervous system gene therapy to treat GBM, overcoming the blood-brain barrier through local, persistent delivery of an anti angiogenesis monoclonal antibody. PMID- 25501994 TI - Immediate-Early (IE) gene regulation of cytomegalovirus: IE1- and pp71-mediated viral strategies against cellular defenses. AB - Three crucial hurdles hinder studies on human cytomegalovirus (HCMV): strict species specificity, differences between in vivo and in vitro infection, and the complexity of gene regulation. Ever since the sequencing of the whole genome was first accomplished, functional studies on individual genes have been the mainstream in the CMV field. Gene regulation has therefore been elucidated in a more detailed fashion. However, viral gene regulation is largely controlled by both cellular and viral components. In other words, viral gene expression is determined by the virus-host interaction. Generally, cells respond to viral infection in a defensive pattern; at the same time, viruses try to counteract the cellular defense or else hide in the host (latency). Viruses evolve effective strategies against cellular defense in order to achieve replicative success. Whether or not they are successful, cellular defenses remain in the whole viral replication cycle: entry, immediate-early (IE) gene expression, early gene expression, DNA replication, late gene expression, and viral egress. Many viral strategies against cellular defense, and which occur in the immediate-early time of viral infection, have been documented. In this review, we will summarize the documented biological functions of IE1 and pp71 proteins, especially with regard to how they counteract cellular intrinsic defenses. PMID- 25501998 TI - An instantaneous colorimetric protein assay based on spontaneous formation of a protein corona on gold nanoparticles. AB - Commercial protein assays used ubiquitously in laboratories typically require long incubation times due to the inherently slow protein-reagent reactions. In this study, we report a novel facile technique for the instantaneous measurement of total protein concentration by exploiting the rapid aggregation dynamics of gold nanoparticles (NPs). By adsorbing different amounts of proteins on their surface to form a protein corona, these NPs can be sterically stabilized to different degrees by aggregation, thus exhibiting a spectrum of color change which can be quantitatively characterized by UV-Vis absorption spectroscopy. We evaluated this technique on four model proteins with different structures: bovine serum albumin (BSA), normal mouse immunoglobulin G (IgG), fibrinogen (FBG) and apolipoprotein A-I (Apo-A1) using two approaches, sequential and simultaneous. We obtained an approach-dependent linear concentration range up to 80 MUg mL(-1) and 400 MUg mL(-1) for sequential and simultaneous approaches, respectively. This linear working range was wider than that of the commercial Bradford assay and comparable to the Micro BCA assay. The simultaneous approach was also able to produce a linear working range of 200 to 1000 MUg mL(-1) (R(2) = 0.995) in human urine, while the sequential approach was non-functional in urine. Similar to Micro BCA, the NP-based protein assay was able to elicit a linear response (R(2) > 0.87) for all four proteins with different structures. However, unlike Micro BCA which requires up to 120 min of incubation, we were able to obtain the read out almost instantaneously without the need for incubation. The NP-based technique using the simultaneous approach can thus be exploited as a novel assay for instantaneous protein quantification to increase the productivity of laboratory processes. PMID- 25501999 TI - Ceria loaded nanoreactors: a nontoxic superantioxidant system with high stability and efficacy. AB - Medical applications of the superantioxidant ceria nanoparticles (CeNP) are limited due to their high toxicity and low stability. CeNP toxicity is related to their aggregation in solution, and the possible generation of reactive oxygen species (ROS) by a Fenton-like reaction. For the efficient medical application of CeNP, it is necessary to find new solutions, which simultaneously reduce their inherent toxicity while preserving their unique catalytic regenerative qualities. Here we introduce a straightforward strategy based on CeNP encapsulation in polymer vesicles which reduces their toxicity, but preserves their superantioxidant character. We have engineered antioxidant nanoreactors, which serve the dual purpose of: (i) separation of CeNP, which inhibits aggregate formation, and (ii) protection of CeNP from hydrogen peroxide, thus eliminating the Fenton-like reaction which induces cytotoxicity. Nanoreactors containing CeNP possess a higher scavenging activity than free CeNP for both hydroxyl and superoxide radicals, as indicated by spin trapping EPR. Due to the regenerative redox chemistry of ceria, the nanoreactors are active for long periods of time, without requiring additional reducing agents. Upon uptake by cells, the nanoreactors show almost no toxicity compared with the free CeNP after a long term exposure, thus proving their high efficacy as ROS scavengers. Our strategy of engineering CeNP-containing nanoreactors represents a versatile, simple and economical solution to reduce CeNP toxicity, while preserving their functionality; thus nanoreactors are the ideal candidates for fighting oxidative stress in a large variety of medical situations. PMID- 25501997 TI - Thyroid hormone receptor regulates most genes independently of fibroblast growth factor 21 in liver. AB - Thyroid hormone (TH) acts through specific receptors (TRs), which are conditional transcription factors, to induce fibroblast growth factor 21 (FGF21), a peptide hormone that is usually induced by fasting and that influences lipid and carbohydrate metabolism via local hepatic and systemic endocrine effects. While TH and FGF21 display overlapping actions when administered, including reductions in serum lipids, according to the current models these hormones act independently in vivo. In this study, we examined mechanisms of regulation of FGF21 expression by TH and tested the possibility that FGF21 is required for induction of hepatic TH-responsive genes. We confirm that active TH (triiodothyronine (T3)) and the TRbeta-selective thyromimetic GC1 increase FGF21 transcript and peptide levels in mouse liver and that this effect requires TRbeta. T3 also induces FGF21 in cultured hepatocytes and this effect involves direct actions of TRbeta1, which binds a TRE within intron 2 of FGF21. Gene expression profiles of WT and Fgf21 knockout mice are very similar, indicating that FGF21 is dispensable for the majority of hepatic T3 gene responses. A small subset of genes displays diminished T3 response in the absence of FGF21. However, most of these are not obviously directly involved in T3-dependent hepatic metabolic processes. Consistent with these results, T3-dependent effects on serum cholesterol are maintained in the Fgf21(-/-) background and we observe no effect of the Fgf21 knockout background on serum triglycerides and glucose. Our findings indicate that T3 regulates the genes involved in classical hepatic metabolic responses independently of FGF21. PMID- 25502000 TI - In vivo quantification of lumbar disc degeneration: assessment of ADC value using a degenerative scoring system based on Pfirrmann framework. AB - PURPOSE: To evaluate the role of apparent diffusion coefficient (ADC) as a quantitative means to assess the degree of intervertebral disc (IVD) degeneration contextually within the framework of a widely used Pfirrmann classification rather than in a direct correlation with Pfirrmann grades. METHODS: DWI and T2 weighted (T2w) of lumbar spine were acquired from nine healthy volunteers (age range 27-62 years, mean age 45 years) with a 3T MR scanner. ADC values were obtained from each of the five lumbar discs via a pixel-by-pixel ADC calculation as well as via region of interest-averaged image intensities. Disc degeneration was assessed by a scoring system via sequential application of Pfirrmann scale and use of intensity ratio of IVD/cerebrospinal fluid in T2w for discs in each Pfirrmann grade to be further separated. RESULTS: A significant correlation was observed between degenerative scores and ADC independent of how ADC was obtained (Spearman's rho < -0.85, P < 2 * 10(-14)). CONCLUSIONS: This study demonstrates that previously perceived as an overlap in ADC value existing between different degenerative categories based on a visual inspection can be viewed as a quantitative role of ADC in assessment of disc degeneration. This reinforces the Pfirrmann classification system but also proceeds beyond mere qualitatively determining morphologic states. PMID- 25502001 TI - Evaluation of quality of life and neuropathic pain in patients with low back pain using the Japanese Orthopedic Association Back Pain Evaluation Questionnaire. AB - PURPOSE: To examine the impact that neuropathic or nociceptive pain has on the quality of life (QOL) in patients with low back pain (LBP) using the Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ) and the Japanese version of the PainDETECT Questionnaire (PDQ-J). METHODS: Between June 2012 and December 2013, 650 new patients were treated at our institution for LBP. All patients between the ages of 20 and 79 were asked to complete a set of questionnaires including the PDQ-J, a pain visual analog scale (VAS), the JOABPEQ, and the Short Form 36 (SF-36). Based on the PDQ-J scores, participants were classified into three groups: a neuropathic pain group, a nociceptive pain group, and an intermediate mixed pain group. Among them, patients with clear neuropathic and nociceptive LBP were selected. To investigate the differences between neuropathic and nociceptive LBP, diagnosis of spinal disorder, prevalence, age, gender, duration of symptoms, VAS scores, and self-reported general health (SF-36 and JOABPEQ) were compared between the neuropathic and nociceptive pain groups. RESULTS: Of 650 patients with LBP, 331 completed the questionnaires and were enrolled in the study. There were 193 men (58.3 %) and 138 women (41.7 %) with a mean age of 54.5 years (range 20-79 years). From the PDQ-J survey, 49 patients (15 %) were classified as having neuropathic pain, and 190 (58 %) were categorized as having nociceptive pain. Patients in the neuropathic pain group had significantly higher VAS scores and lower SF-36 and JOABPEQ scores compared to the nociceptive pain group. CONCLUSION: We examined the impact of nociceptive or neuropathic LBP on QOL. A comparison of JOABPEQ scores between LBP patients assessed by PDQ-J as having neuropathic pain or nociceptive pain suggests that neuropathic pain affects the social and psychological well-being of LBP patients. PMID- 25502003 TI - Creation of a National, At-home Model for Ashkenazi Jewish Carrier Screening. AB - Ethnicity-based carrier screening for the Ashkenazi Jewish population has been available and encouraged by advocacy and community groups since the early 1970's. Both the American College of Medical Genetics and the American Congress of Obstetricians and Gynecologists recommend carrier screening for this population (Obstetrics and Gynecology, 114(4), 950-953, 2009; Genetics in Medicine, 10(1), 55-56, 2008). While many physicians inquire about ethnic background and offer appropriate carrier screening, studies show that a gap remains in implementing recommendations (Genetic testing and molecular biomarkers, 2011). In addition, education and outreach efforts targeting Jewish communities have had limited success in reaching this at-risk population. Despite efforts by the medical and Jewish communities, many Jews of reproductive age are not aware of screening, and remain at risk for having children with preventable diseases. Reaching this population, preferably pre-conception, and facilitating access to screening is critically important. To address this need, genetic counselors at Emory University developed JScreen, a national Jewish genetic disease screening program. The program includes a national marketing and PR campaign, online education, at-home saliva-based screening, post-test genetic counseling via telephone or secure video conferencing, and referrals for face-to-face genetic counseling as needed. Our goals are to create a successful education and screening program for this population and to develop a model that could potentially be used for other at-risk populations. PMID- 25502002 TI - Significance of urinary full-length megalin in patients with IgA nephropathy. AB - BACKGROUND AND OBJECTIVES: Megalin is highly expressed at the apical membranes of proximal tubular epithelial cells. A urinary full-length megalin (C-megalin) assay is linked to the severity of diabetic nephropathy in type 2 diabetes. This study examined the relationship between levels of urinary C-megalin and histological findings in adult patients with IgA nephropathy (IgAN). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Urine samples voided in the morning on the day of renal biopsy were obtained from 73 patients with IgAN (29 men and 44 women; mean age, 33 years) and 5 patients with membranous nephropathy (MN). Renal pathologic variables were analyzed using the Oxford classification of IgAN, the Shigematsu classification and the Clinical Guidelines of IgAN in Japan. The levels of urinary C-megalin were measured by sandwich ELISA. RESULTS: Histological analysis based on the Oxford classification revealed that the levels of urinary C-megalin were correlated with mesangial hypercellularity in IgAN patients (OR = 1.76, 95% CI: 1.04-3.27, P<0.05). There was a significant correlation between the levels of urinary C-megalin and the severity of chronic extracapillary abnormalities according to the Shigematsu classification in IgAN patients (beta = 0.33, P = 0.008). The levels of urinary C-megalin were significantly higher in all risk levels of IgAN patients requiring dialysis using the Clinical Guidelines of IgAN in Japan than in the control group. The levels of urinary C-megalin were significantly higher in the high risk and very high risk grades than in the low risk grade (P<0.05). The levels of urinary C-megalin were significantly higher in MN patients compared to the control group. CONCLUSIONS: The levels of urinary C-megalin are associated with histological abnormalities in adult IgAN patients. There is a possibility that urinary C-megalin is an independent predictor of disease progression of IgAN. In addition, our results suggest that urinary C-megalin is a marker of glomerular abnormalities in various glomerular diseases as well as IgAN. PMID- 25502004 TI - Low resting metabolic rate is associated with greater lifespan because of a confounding effect of body fatness. AB - A negative association between resting metabolic rate (RMR) and lifespan is the cornerstone of the rate of living and free-radical damage theories of aging. Empirical studies supporting a negative association of RMR to lifespan may arise from the correlation between RMR and both daily energy expenditure (DEE) and thermoregulatory activity energy expenditure (TAEE). We screened 540 female mice for higher and lower DEE and measured RMR in the resulting 324 (60 %). We then selected 92 mice in which there was no link between residual from the regression of RMR against body mass (BM) and residual of DEE against BM to separate the effects of these traits. Lifespan was not significantly related to body mass, DEE and TAEE, but significantly negatively related to RMR. Fat-free mass (FFM) and fat mass (FM) were both significantly positively related to RMR. After removing the effect of FFM on RMR, the association between RMR and lifespan remained significantly negative; however, after statistically removing the effect of FM on RMR, the significant association between RMR and lifespan disappeared. We conclude that the negative association between RMR and lifespan is primarily due to the effect of FM, with FM positively related to both RMR and mortality and hence RMR negatively to lifespan. In 40 additional screened mice, greater FM was also associated with greater oxidative damage to DNA. PMID- 25502006 TI - An atmospheric-pressure, high-aspect-ratio, cold micro-plasma. AB - An atmospheric pressure nonequilibrium Ar micro-plasma generated inside a micro tube with plasma radius of 3 MUm and length of 2.7 cm is reported. The electron density of the plasma plume estimated from the broadening of the Ar emission line reaches as high as 3 * 10(16) cm(-3). The electron temperature obtained from CR model is 1.5 ev while the gas temperature of the plasma estimated from the N2 rotational spectrum is close to room temperature. The sheath thickness of the plasma could be close to the radius of the plasma. The ignition voltages of the plasma increase one order when the radius of the dielectric tube is decreased from 1 mm to 3 MUm. PMID- 25502007 TI - Improving Self-Monitoring of Blood Glucose among Adults with Type 1 Diabetes: Results of the MobileTM Study. AB - INTRODUCTION: The objective of this study was to determine whether people with type 1 diabetes are more likely to self-monitor their blood glucose (SMBG) as recommended by their diabetes health care professional using the Accu-Chek MobileTM (F. Hoffmann-La Roche AG, Basel, Switzerland) monitoring system compared to the Freestyle OptiumTM (Abbott, North Chicago, IL, USA). METHODS: Thirty-five participants with type 1 diabetes participating in a randomized cross-over study were assigned to monitor their blood glucose levels for a 3-month period using the Accu-Chek Mobile or the Freestyle Optium monitoring system and then to cross over to the alternative device. After completion of the 6-month cross-over period, participants were invited to select their meter of choice and were followed for a further 3 months. RESULTS: SMBG frequency increased in both groups but participants monitored significantly more often using the Accu-Chek Mobile meter (frequency SMBG/week median: 19 vs. 10, P = 0.04). After 3 months using each meter, 77% of participants indicated a preference for the Accu-Chek Mobile meter. Monitoring frequency in this group remained higher than baseline during the 3-month post-cross-over follow-up period. CONCLUSION: Our results indicate that the Accu-Chek Mobile meter improves SMBG frequency. After experience of both systems, Accu-Chek Mobile was the meter of choice for the majority of participants in this study. FUNDING: Roche Diabetes Care Unconditional Education Grant. PMID- 25502005 TI - Age and gender effects on submental motor-evoked potentials. AB - It is not known whether there are age- and/or gender-related differences in magnitude of motor-evoked potentials (MEPs) of the submental muscles. Knowledge of this is important in investigations of neurophysiological aspects of swallowing. Forty healthy participants (20 males, 20 females; 20 young [21-35 years], 20 old [53-88 years]) were recruited. Surface electromyography (EMG) electrodes were placed at midline underlying the submental muscle group. Age- and gender-related differences were evaluated in two neurophysiologic measures of swallowing: MEPs stimulated by single-pulse transcranial magnetic stimulation (TMS) over the motor cortex and surface electromyography (sEMG) recorded from the same submental muscle group during non-stimulated swallows. The older participants had larger MEPs during saliva swallowing than the young participants (p = 0.04, d = 0.86). Conversely, the older participants had lower amplitude submental EMG activity during non-stimulated swallows (p = 0.045, d = 0.67). Gender had no significant effect on MEP magnitude and on submental activity during saliva swallowing. There were no effects of age or gender on MEP latencies. These findings suggest deterioration in muscle function with age in a sample of healthy adults presenting with functional swallowing. We speculate that muscular decline is partially ameliorated by increased cortical activity-i.e., increased submental MEPs-so as to preserve swallowing function in healthy older subjects. These findings emphasize the need for different reference points for evaluation of submental MEPs of different age groups. PMID- 25502008 TI - The effect of nifedipine tocolysis on Doppler indices of the uterine and umbilical arteries. AB - PURPOSE: The aim of this study was to evaluate the effect of oral nifedipine on Doppler indices of the uterine artery (UtA) and umbilical artery (UA) before and 24 hours, 48 hours, and 1 week after tocolytic treatment. METHODS: This was a prospective, self-controlled, cohort study of 65 pregnant women undergoing nifedipine tocolysis. Doppler assessment of the UtA and UA was performed before treatment and 24 hours, 48 hours, and 1 week after the initial 4 doses of 10 mg of oral nifedipine, administered at 20-minute intervals. The maintenance dosage was 20 mg of oral nifedipine administered every 6 hours for 48 hours, for a total dose of 80 mg/day. RESULTS: There was a decrease in the 24-hour values of the UA pulsatility index, resistance index (RI), systolic-diastolic (S:D) ratio, right UtA pulsatility index, RI, S:D ratio, and left UtA RI and S:D ratio with nifedipine therapy in comparison with the values recorded prior to nifedipine therapy. However, these differences were not statistically significant. There were no statistically significant differences between the data recorded prior to nifedipine administration and those obtained at 48 hours and 1 week after treatment. CONCLUSIONS: Oral nifedipine is a safe tocolytic agent with no long term effect on fetomaternal circulation in pregnant women at risk of preterm delivery. PMID- 25502010 TI - The use of flow cytometry to assess a novel drug efficacy in multiple sclerosis. AB - Applying different technologies to monitor disease activity and treatment efficacy are essential in a complex disease such as multiple sclerosis. Combining current assays with flow cytometry could create a powerful tool for such analyses. The cell surface expression level of CD74, the MHC class II invariant chain, is a potential disease biomarker that could be monitored by FACS analysis in order to assess disease progression and the clinical efficacy of partial MHC class II constructs in treating MS. These constructs, which can bind to and down regulate CD74 cell-surface expression on monocytes and inhibit macrophage migration inhibitory factor (MIF) effects, can reverse clinical and histological signs of EAE. These properties of partial class II constructs are highly compatible with a flow cytometry approach for monitoring CD74 expression as a possible biomarker for disease activity/progression and as a treatment response marker. PMID- 25502011 TI - Neuroprotective activity of hydroponic Teucrium polium following bilateral ovariectomy. AB - Ovariectomy is known as "surgical menopause" with decreased levels of estrogen in female rodents. Its reported risks and adverse effects include cognitive impairment. The action of hydroponic Teucrium polium on nucleus basalis of Meynert (bnM) neurons following 6 weeks of ovariectomy was carried out. The analysis of spike activity was observed by on-line selection and the use of a software package. Early and late tetanic, - posttetanic potentiation and depression of neurons to high frequency stimulation of hippocampus were studied. The complex averaged peri-event time and frequency histograms were constructed. The histochemical study of the activity of Sa(2+)-dependent acid phosphatase was observed. In conditions of hydroponic Teucrium polium administration, positive changes in neurons and gain of metabolism leading to cellular survival were revealed. The administration of Teucrium polium elicited neurodegenerative changes in bnM. PMID- 25502009 TI - p38alpha (MAPK14) critically regulates the immunological response and the production of specific cytokines and chemokines in astrocytes. AB - In CNS lesions, "reactive astrocytes" form a prominent cellular response. However, the nature of this astrocyte immune activity is not well understood. In order to study astrocytic immune responses to inflammation and injury, we generated mice with conditional deletion of p38alpha (MAPK14) in GFAP+ astrocytes. We studied the role of p38alpha signaling in astrocyte immune activation both in vitro and in vivo, and simultaneously examined the effects of astrocyte activation in CNS inflammation. Our results showed that specific subsets of cytokines (TNFalpha, IL-6) and chemokines (CCL2, CCL4, CXCL1, CXCL2, CXCL10) are critically regulated by p38alpha signaling in astrocytes. In an in vivo CNS inflammation model of intracerebral injection of LPS, we observed markedly attenuated astrogliosis in conditional GFAPcre p38alpha(-/-) mice. However, GFAPcre p38alpha(-/-) mice showed marked upregulation of CCL2, CCL3, CCL4, CXCL2, CXCL10, TNFalpha, and IL-1beta compared to p38alphafl/fl cohorts, suggesting that in vivo responses to LPS after GFAPcre p38alpha deletion are complex and involve interactions between multiple cell types. This finding was supported by a prominent increase in macrophage/microglia and neutrophil recruitment in GFAPcre p38alpha(-/-) mice compared to p38alphafl/fl controls. Together, these studies provide important insights into the critical role of p38alpha signaling in astrocyte immune activation. PMID- 25502012 TI - Electroacupuncture improves cognitive deficits associated with AMPK activation in SAMP8 mice. AB - Perturbations of brain energy metabolism are involved in Alzheimer's disease (AD). Adenosine monophosphate-activated kinase (AMPK) is a master energy sensor that monitors the levels of key energy metabolites. Electroacupuncture (EA) has demonstrated therapeutic potential for the treatment of AD. The effects of EA on cognitive functions and the changes of AMPK and its phosphorylated form (p-AMPK) expression were investigated in senescence-accelerated mouse prone 8 (SAMP8) mice. Cognitive function of SAMP8 mice was assessed using Morris water maze test after EA treatment. Then mice were sacrificed for immunohistochemistry and western blot analysis. EA stimulation significantly alleviated memory impairment of AD mice, and increased the levels of p-AMPK in the hippocampus. These results suggest that EA improved cognitive function associated with AMPK activation, AMPK may be a molecular target of EA in treating AD. PMID- 25502014 TI - Successful percutaneous transluminal septal myocardial ablation through a right superior septal artery for a patient with hypertrophic obstructive cardiomyopathy. AB - Percutaneous transluminal septal myocardial ablation (PTSMA) has been widely accepted as a therapeutic option for patients with hypertrophic obstructive cardiomyopathy (HOCM). To achieve success in PTSMA, we need to explore the target septal arteries, including any anomalous branches that feed the hypertrophic septal myocardium causing left ventricular outflow tract obstruction. An HOCM case in which PTSMA was performed through a dominant right superior septal (RSS) artery is presented. In cases without an effective septal branch artery arising from the left anterior descending artery, an RSS artery should be sought as an alternative route for PTSMA. PMID- 25502013 TI - Does workplace social capital associate with hazardous drinking among Chinese rural-urban migrant workers? AB - BACKGROUND: The present study sought to investigate the associations between workplace social capital and hazardous drinking (HD) among Chinese rural-urban migrant workers (RUMW). METHODS: A cross sectional study with a multi-stage stratified sampling procedure was conducted in Shanghai during July 2012 to January 2013. In total, 5,318 RUMWs from 77 workplaces were involved. Work-place social capital was assessed using a validated and psychometrically tested eight item measure. The Chinese version of Alcohol Use Disorders Identification Test (AUDIT) was used to assess hazardous drinking. Control variables included gender, age, marital status, education level, salary, and current smoking. Multilevel logistic regression analysis was conducted to test whether individual- and workplace-level social capital was associated with hazardous drinking. RESULTS: Overall, the prevalence of HD was 10.6%. After controlling for individual-level socio-demographic and lifestyle variables, compared to workers in the highest quartile of individual-level social capital, the odds of HD for workers in the three bottom quartiles were 1.13(95%CI: 1.04-1.23), 1.17(95%CI: 1.05-1.56) and 1.26(95%CI: 1.13-1.72), respectively. However, contrary to hypothesis, there was no relationship between workplace-level social capital and hazardous drinking. CONCLUSIONS: Higher individual-level social capital may protect against HD among Chinese RUMWs. Interventions to build individual social capital among RUMWs in China may help reduce HD among this population. PMID- 25502015 TI - Nanofabrication of highly ordered, tunable metallic mesostructures via quasi-hard templating of lyotropic liquid crystals. AB - The synthesis of metal frameworks perforated with nanotunnels is a challenge because metals have high surface energies that favor low surface area structures; traditional liquid-crystal templating techniques cannot achieve the synthetic control required. We report a synthetic strategy to fabricate metal nanomaterials with highly ordered, tunable mesostructures in confined systems based on a new quasi-hard-templating liquid-crystals mechanism. The resulting platinum nanowires exhibit long range two-dimensional hexagonally ordered mesopore structures. In addition, single crystalline hexagonal mesoporous platinum nanowires with dominant {110} facets have been synthesized. Finally, we demonstrate that the mesostructures of metal nanomaterials can be tuned from hexagonal to lamellar mesostructures. PMID- 25502016 TI - Extracorporeal shock wave therapy for injection site panniculitis in multiple sclerosis patients. AB - BACKGROUND: Painful cutaneous injection site reactions may hamper treatment with interferon beta (IFN-beta) and glatiramer acetate (GA) in multiple sclerosis (MS) patients. OBJECTIVE: To maintain therapy adherence, efficient therapeutic modalities for these subcutaneous inflammatory lesions are urgently needed. We tested the application of local extracorporeal shock wave therapy (ESWT). METHODS: We applied 5 sessions of ESWT to 8 patients suffering from MS who had developed painful panniculitis at the injection sites of either IFN-beta or GA. Clinical outcomes, i.e. pain reduction and regression of induration, were assessed 3 and 6 months after completion of the ESWT using a visual analogue score. RESULTS: All patients showed both significant pain reduction and reduction of the skin induration in the treated lesions, while in untreated control lesions there was no improvement. CONCLUSION: ESWT proved to be a non-invasive, safe and efficient physical treatment modality for injection-induced painful cutaneous side effects of disease-modifying drugs in MS. PMID- 25502018 TI - Testosterone replacement therapy faces FDA scrutiny. PMID- 25502017 TI - Oligomerization, conformational stability and thermal unfolding of Harpin, HrpZPss and its hypersensitive response-inducing c-terminal fragment, C-214 HrpZPss. AB - HrpZ-a harpin from Pseudomonas syringae-is a highly thermostable protein that exhibits multifunctional abilities e.g., it elicits hypersensitive response (HR), enhances plant growth, acts as a virulence factor, and forms pores in plant plasma membranes as well as artificial membranes. However, the molecular mechanism of its biological activity and high thermal stability remained poorly understood. HR inducing abilities of non-overlapping short deletion mutants of harpins put further constraints on the ability to establish structure-activity relationships. We characterized HrpZPss from Pseudomonas syringae pv. syringae and its HR inducing C-terminal fragment with 214 amino acids (C-214-HrpZPss) using calorimetric, spectroscopic and microscopic approaches. Both C-214-HrpZPss and HrpZPss were found to form oligomers. We propose that leucine-zipper-like motifs may take part in the formation of oligomeric aggregates, and oligomerization could be related to HR elicitation. CD, DSC and fluorescence studies showed that the thermal unfolding of these proteins is complex and involves multiple steps. The comparable conformational stability at 25 degrees C (~10.0 kcal/mol) of HrpZPss and C-214-HrpZPss further suggest that their structures are flexible, and the flexibility allows them to adopt proper conformation for multifunctional abilities. PMID- 25502019 TI - Heat shock cognate protein 70 isoform D is required for clathrin-dependent endocytosis of Japanese encephalitis virus in C6/36 cells. AB - Japanese encephalitis virus (JEV), one of encephalitic flaviviruses, is naturally transmitted by mosquitoes. During infection, JEV generally enters host cells via receptor-mediated clathrin-dependent endocytosis that requires the 70 kDa heat shock protein (Hsp70). Heat-shock cognate protein 70 (Hsc70) is one member of the Hsp70 family and is constitutively expressed; thus, it may be expressed under physiological conditions. In C6/36 cells, Hsc70 is upregulated in response to JEV infection. Since Hsc70 shows no relationship with viruses attaching to the cell surface, it probably does not serve as the receptor according to our results in the present study. In contrast, Hsc70 is evidently associated with virus penetration into the cell and resultant acidification of intracellular vesicles. It suggests that Hsc70 is highly involved in clathrin-mediated endocytosis, particularly at the late stage of viral entry into host cells. Furthermore, we found that Hsc70 is composed of at least three isoforms, including B, C and D; of these, isoform D helps JEV to penetrate C6/36 cells via clathrin-mediated endocytosis. This study provides relevant evidence that sheds light on the regulatory mechanisms of JEV infection in host cells, especially on the process of clathrin-mediated endocytosis. PMID- 25502022 TI - An open source image processing method to quantitatively assess tissue growth after non-invasive magnetic resonance imaging in human bone marrow stromal cell seeded 3D polymeric scaffolds. AB - Monitoring extracellular matrix (ECM) components is one of the key methods used to determine tissue quality in three-dimensional (3D) scaffolds for regenerative medicine and clinical purposes. This is even more important when multipotent human bone marrow stromal cells (hMSCs) are used, as it could offer a method to understand in real time the dynamics of stromal cell differentiation and eventually steer it into the desired lineage. Magnetic Resonance Imaging (MRI) is a promising tool to overcome the challenge of a limited transparency in opaque 3D scaffolds. Technical limitations of MRI involve non-uniform background intensity leading to fluctuating background signals and therewith complicating quantifications on the retrieved images. We present a post-imaging processing sequence that is able to correct for this non-uniform background intensity. To test the processing sequence we investigated the use of MRI for in vitro monitoring of tissue growth in three-dimensional poly(ethylene oxide terephthalate)-poly(butylene terephthalate) (PEOT/PBT) scaffolds. Results showed that MRI, without the need to use contrast agents, is a promising non-invasive tool to quantitatively monitor ECM production and cell distribution during in vitro culture in 3D porous tissue engineered constructs. PMID- 25502023 TI - Genetic characterization of Bombyx mori (Lepidoptera: Bombycidae) breeding and hybrid lines with different geographic origins. AB - The domesticated silkworm Bombyx mori L. comprises a large number of geographical breeds and hybrid lines. Knowing the genetic structure of those may provide information to improve the conservation of commercial lines by estimating inbreeding over generations and the consequences of excessive use of those lineages. Here, we analyzed the genetic diversity of seven breeds and eight hybrid lines from Eastern Europe and Asia using highly polymorphic microsatellites markers to determine its genetical impact on their use in global breeding programs. No consistent pattern of deviation from Hardy-Weinberg equilibrium was found for most breed and hybrids; and the absence of a linkage disequilibrium also suggests that the strains are in equilibrium. A principal coordinate analysis revealed a clear separation of two silkworm breeds from the rest: one (IBV) originated from India and the other one (RG90) from Romania/Japan. The tendency of the other breeds from different geographic origins to cluster together in a general mix might be due to similar selection pressures (climate and anthropogenic factors) in different geographic locations. Phylogenetic analyses grouped the different silkworm breeds but not the hybrids according to their geographic origin and confirmed the pattern found in the principal coordinate analysis. PMID- 25502024 TI - Subterranean ants: the case of Aphaenogaster cardenai (Hymenoptera: Formicidae). AB - Recently, a series of systematized studies of the Milieu Souterrain Superficiel (MSS) are being carried in several enclaves of the Iberian Peninsula, which have entailed the finding of the enigmatic ant Aphaenogaster cardenai Espadaler, 1981, hitherto considered as hypogean, in a mountain range far away from its known distribution area. Its ecological role and its possible area of distribution are discussed due to this finding, as well as its known morphology, distribution, habitat use, flight ability of the sexual forms, and moment of activity. This enabled reviewing and discussing the actual knowledge on the possible adaptations and exaptations of the Formicidae to the subterranean environments in wide sense and concretely to the MSS. According to all above, ants might adapt to the deepest hypogean environments by means of changes in their social structure, but without those changes, the MSS would be their last frontier in their process of colonization of hypogean environments. PMID- 25502025 TI - Effects of exogenous plant growth regulator abscisic acid-induced resistance in rice on the expression of vitellogenin mRNA in Nilaparvata lugens (Hemiptera: Delphacidae) adult females. AB - Recent study showed that exogenous abscisic acid (ABA) acts as a regulator of plant resistance. This study investigated average injury scale and callose contents of rice, and vitellogenin (Nlvg) mRNA expression in Nilaparvata lugens (Stal) (Hemiptera: Delphacidae) adult females after third instar nymphs fed on exogenous ABA-treated susceptible [Taichung Native one (TN1)] and moderately resistant (IR42) rice cultivars. The results showed that exogenous ABA significantly decreased average injury scale of rice and Nlvg mRNA expression in N. lugens adults compared with the control (without ABA spraying). Nlvg mRNA expression in N. lugens adults decreased significantly after third instar nymphs fed on ABA-treated (5, 20, and 40 mg/liter) TN1 for 1 and 2 d, and for IR42, after fed on ABA-treated (20 and 40 mg/liter) rice plants for 1 d and after fed on ABA-treated (5, 20, and 40 mg/liter) rice for 2 d decreased significantly. The callose contents showed no significant change for TN1, while for IR42, significantly increased in roots and sheathes after N. lugens infestation under ABA treatments (20 and 40 mg/liter) compared with the control. The decrease of Nlvg mRNA expression may be partially attributed to the increase of callose content of plants. The results provide a profile for concerning the effects of ABA-induced rice plants' defenses on phloem-feeding insects. PMID- 25502026 TI - Incomplete homogenization of chemical recognition labels between Formica sanguinea and Formica rufa ants (Hymenoptera: Formicidae) living in a mixed colony. AB - Formica sanguinea Latreille (Hymenoptera: Formicidae) is a slave-making species, i.e., it raids colonies of host species and pillages pupae, which are taken to develop into adult workers in a parasite colony. However, it has been unclear if the coexistence of F. sanguinea with slave workers requires uniformity of cuticular hydrocarbons (CHCs), among which those other than n-alkanes are believed to be the principal nestmate recognition cues utilized by ants. In this study, a mixed colony (MC) of F. sanguinea and Formica rufa L. as a slave species was used to test the hypothesis that CHCs are exchanged between the species. Chemical analysis of hexane extracts from ants' body surfaces provided evidence for interspecific exchange of alkenes and methyl-branched alkanes. This result was confirmed by behavioral tests during which ants exhibited hostility toward conspecific individuals from the MC but not toward ones from homospecific colonies of their own species. However, it seems that species-specific differences in chemical recognition labels were not eliminated completely because ants from the MC were treated differently depending on whether they were con- or allospecific to the individuals whose behavioral reactions were tested. These findings are discussed in the context of mechanisms of colony's odor formation and effective integration of slaves into parasite colony. PMID- 25502027 TI - The potential uses of sarcosaprophagous flesh flies and blowflies for the evaluation of the regeneration and conservation of forest clearings: a case study in the Amazon forest. AB - The level of association between dipterans of the families Calliphoridae and Sarcophagidae and habitats with different levels of vegetation cover was analyzed at Porto Urucu in Coari, Amazonas, Brazil, with the aim of identifying the potential of these taxa as bioindicators for the assessment of forest regeneration and conservation. The flies were collected in 16 sample areas, 12 of which were clearings at different stages of regeneration (C1--early regeneration; C2--moderate regeneration; and C3--advanced regeneration) and 4 in continuous forest (F). According to the IndVal analysis, nine sarcophagid species--Peckia (Sarcodexia) lambens (Wiedemann), Peckia (Peckia) chrysostoma (Wiedemann), Peckia (Squamatodes) ingens (Walker), Sarcofahrtiopsis cuneata (Townsend), Oxysarcodexia thornax (Walker), Peckia (Euboettcheria) collusor (Curran & Walley), Oxysarcodexia fringidea (Curran & Walley), Oxysarcodexia amorosa (Schiner), and Helicobia pilifera (Lopes)--were associated indiscriminately with clearings (C1 + C2 + C3). In contrast, only one calliphorid species Chrysomya albiceps (Wiedemann) was associated with clearings in the early moderate regeneration (C1 + C2) phases, and four calliphorids were associated with continuous forest or mature clearings (C3 + F): Mesembrinella bicolor (F.), Eumesembrinella randa (Walker), Mesembrinella bellardiana (Aldrich), and Lucilia eximia (Wiedemann). These results indicate that sarcophagids may be useful for evaluating the degree of anthropogenic impact but are not suitable for the detection of minor variations in forest cover. In contrast, calliphorids may be appropriate for the evaluation of both anthropogenic impacts and the degree of forest regeneration and conservation. PMID- 25502028 TI - Biological characteristics of geographically isolated populations of Meccus mazzottii (Hemiptera: Reduviidae) in southern Mexico. AB - Chagas disease, caused by Trypanosoma cruzi Chagas, is one of the most epidemiologically important vector-borne zoonoses in Mexico. Among the 32 reported triatomine species from Mexico, Meccus mazzottii (Usinger) (Hemiptera: Reduviidae) is one of the most important vectors of T. cruzi in the southern part of the country. Variability among populations of triatomines has been recorded for several species (Meccus longipennis (Usinger) and Meccus pallidipennis (Stal)) that are closely related to M. mazzottii, showing an apparent influence of local environmental conditions on the biology of each population, which could modify the impact of vector control measurements. Therefore, this study sought to compare the biological features of populations of M. mazzottii from two geographically far apart areas that have similar environmental characteristics and to compare populations from close geographical areas that have different environmental characteristics. The mean longevity, percentages of mortality of nymphs, the total mean number of bloodmeals to molt (considered instar by instar), the mean number of eggs laid by females, and the percentage of hatched eggs were similar between the two localities that are geographically far apart but have similar environmental characteristics. On the other hand, important differences were noticed when a comparison was carried out on the two localities with similar environmental conditions with respect to that locality with different conditions, independent of geographic distance. Most of the studied parameters led us to conclude that the three studied populations are very highly influenced by local environmental conditions. The results of this study indicate the importance of studying the biological characteristics of local populations of triatomines to carry out specific control measurements, instead of using standard ones that could fail if they are not adapted to the target population. PMID- 25502029 TI - Evolutionary diversification of insect innexins. AB - Phylogenetic analysis of insect innexins supported the hypothesis that six major clades of insect innexins arose by gene duplication prior to the origin of the endopterygote insects. Within one of the six clades (the Zpg Clade), two independent gene duplication events were inferred to have occurred in the lineage of Drosophila, after the most recent common ancestor of the dipteran families Culicidae and Drosophilidae. The relationships among this clades were poorly resolved, except for a sister relationship between ShakB and Ogre. Gene expression data from FlyAtlas supported the hypothesis that the latter gene duplication events gave rise to functional differentiation, with Zpg showing a high level of expression in ovary, and Inx5 and Inx6 showing a high level of expression in testis. Because unduplicated members of this clade in Bombyx mori and Anopheles gambiae showed high levels of expression in both ovary and tests, the expression patterns of the Drosophila members of this clade provide evidence of subdivision of an ancestral gene function after gene duplication. PMID- 25502030 TI - Toxicity and transmission of thiamethoxam in the Asian subterranean termite Coptotermes gestroi (Isoptera: Rhinotermitidae). AB - The toxicity and horizontal transmission of thiamethoxam was evaluated in the workers of the Asian subterranean termite Coptotermes gestroi Wasmann (Isoptera: Rhinotermitidae). Brief exposure to sand treated with thiamethoxam at concentration ranging from 0.25 to 50 ug/ml resulted in a dose-dependent mortality in C. gestroi. Sand treated with 50 ug/ml thiamethoxam resulted in very high mortality within 30-60 min of exposure. Termites exposed to sand treated with 0.25-25 ug/ml exhibited delayed toxicity and nonrepellency in C. gestroi. A horizontal transmission study using 25 ug/ml of thiamethoxam at donor-recipient ratio of at least 2:5 (treated:untreated) indicated that thiamethoxam can be transferred between exposed and unexposed workers, resulting in significant termite mortality in unexposed termites within 1-3 d post exposure. PMID- 25502031 TI - Probing behavior of Empoasca vitis (Homoptera: Cicadellidae) on resistant and susceptible cultivars of tea plants. AB - Feeding activities of the tea green leafhopper, Empoasca vitis (Gothe) (Homoptera: Cicadellidae), on resistant and susceptible cultivars of tea plants (Camellia sinensis L.) were recorded and analyzed using the direct current electrical penetration graph (EPG) system. Six distinct EPG waveforms characterizing the feeding behavior of the tea green leafhopper, categorized as waveforms A, C, E, S, F, and R, were obtained during the investigation. Duration of passive ingestion, possibly of phloem (E), was the longest among all the probing waveforms on susceptible cultivars, whereas durations of the salivation (S) waveform and stylet work waveform (F) became longer on resistant cultivars. The durations of waveforms S and F on the resistant cultivar Jiandecha were slightly longer than those on the less resistant cultivar Yunguidaye, and both were significantly longer than those on the susceptible cultivars Hangzhoudaye and Zhushan-1. Waveform E was shorter on the resistant cultivar Jiandecha than on the less resistant cultivars Yunguidaye and was significantly shorter than on the susceptible cultivars (Hangzhoudaye and Zhushan-1). It is suggested that E, S, and F are the important waveforms related to leafhopper feeding behavior and tea plant resistance. Based on the results, the resistance levels of tea cultivars against the tea leafhopper can be evaluated quickly by direct current EPG. PMID- 25502032 TI - Metabonomic analysis of Bombyx mori (Heterocera: Bombysidae) treated with acetaminophen. AB - The feasibility of using Bombyx mori as model animal is attracting more attention. Whether the effect of drugs on the metabolite profiling was consistent with those in mammals was an aspect to evaluate the feasibility of B. mori as model animal. In this study, we used acetaminophen to treat Dazao fifth-instar B. mori, and its metabolites in hemolymph were detected by gas chromatography-mass spectrometry. The corresponding data were processed and analyzed by total model analysis, principal component analysis, partial least squares-discriminant analysis, orthogonal partial least squares-discriminant analysis, and finally, the difference metabolites between acetaminophen group and control group were selected and identified by our reference material database and the National Institute of Standard and Technology database. The results showed that acetaminophen administration induced elevation of metabolites related to energy source, the intermediate of cholesterol synthesis, and the metabolites related to melanization and also induced the decrease of metabolites in pathway of Krebs cycle, the cholesterol, and sitosterol, which suggested that acetaminophen administration inhibited energy metabolism and promoted the expenditure and imbalance of hormone and melanization. PMID- 25502033 TI - Comparative proteomic analysis of midgut proteins from male and female Bombyx mori (Lepidoptera: Bombycidae). AB - Many biological phenotypes of male and female silkworms (Bombyx mori) are quite different, and one of the major differences is the growth rate at various larval stages. Nutrient utilization by midgut varies with sexes. However, the molecular basis of this variation is not clear. To understand the molecular mechanism, comparative proteomic approach was employed to investigate the variation of midgut proteomes between male and female silkworms. Totally, 32 proteins that were grouped into four categories were differentially expressed and subsequently identified by mass spectrometry. Gene ontology analysis revealed that these proteins were attributed with biological functions such as binding, catalytic, and transporter, and these proteins were involved in biological process such as cellular process, localization, and metabolic process. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that these proteins were involved in pathways such as glycolysis, gluconeogenesis, oxidative phosphorylation, and purine metabolism. At transcription level, the expressional variation was confirmed for six identified proteins including muscle glycogen phosphorylase, uridine 5'-monophosphate synthase, cone cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha, ATP synthase, thiol peroxiredoxin, and serpin-2. This study provides useful information for understanding the mechanisms of nutrient absorption and the protein-protein interaction in the silkworm. PMID- 25502035 TI - Effect of temperature on developmental rate of Sesamia cretica (Lepidoptera: Noctuidae) immature stages. AB - Effect of temperature on development of pink stem borer, Sesamia cretica Lederer, was studied at eight constant temperatures (15, 18, 20.5, 24, 27, 30, 34, and 38 degrees C), a photoperiod of 16:8 (L:D) h, and 50-60% rela?tive humidity. The larvae of pink stem borer were reared on cutting stems of maize. The results showed that temperature had statistically significant effect on developmental times of the all developmental stages. The most commonly used six nonlinear models applied for modeling developmental rate of immature stages as a function of temperature. Evaluation of the models fit to data took place based on the coefficient of determination, residual sum of squires, adjusted coefficient of determination, and Akaike information criterion. Besides statistical criteria, biological significance was used to determine the best model. All the examined models statistically fit the data well. In addition, Briere-2 was selected as the best model considering biological significance of the estimated values for the biologically interpretable parameters of models. Based on the results, the values of the lower temperature threshold were 10.82, 11.81, 9.35, and 10.67 degrees C, the optimal temperature were 35.50, 31.80, 33.35, and 32.22 degrees C, and the upper temperature threshold were 38.93, 39.19, 37.41, and 36.55 degrees C, for incubation period, larva, pupa, and overall immature stages of pink stem borer, respectively. PMID- 25502034 TI - Measure post-bloodmeal dispersal of mosquitoes and duration of radioactivity by using the isotope 32P. AB - The radioactive isotope (32)P-labeled disodium phosphate (Na2H(32)PO4) was injected via the jugular vein into a cow kept in a shed in Maozhuang Village, Cao Township of Shanxian County, China. Over the following 5 d, mosquitoes feeding on the cow were captured at distances up to 400 m to determine dispersal distance. The duration of radioactivity in the cow and marked mosquitoes was 10 d. The results showed that after blood feeding, Anopheles sinensis and Culex tritaeniorhynchus temporarily rested in the cattle shed and then flew outdoors. In contrast, Culex pipiens pallens remained in the cattle shed after feeding. These findings confirmed that local An. sinensis and Cx. tritaeniorhynchus were partially endophilic and tended to rest out of doors, whereas Cx. pipiens pallens was endophilic. For marked An. sinensis and Cx. tritaeniorhynchus, there was a significant tendency for dispersal to be in a northeast and east direction, probably because of the presence of heavy shading by an agricultural field, a small river for mosquito oviposition sites, and locations downwind from the blood source. The furthest flight distances for An. sinensis and Cx. tritaeniorhynchus were 210 and 240 m; therefore, control of these mosquitoes should include resting places indoors and outdoors within a radius of 250 m from confirmed cases. PMID- 25502036 TI - Temporal dynamics of arthropods on six tree species in dry woodlands on the Caribbean Island of Puerto Rico. AB - The seasonal dynamics of foliage arthropod populations are poorly studied in tropical dry forests despite the importance of these studies for understanding arthropod population responses to environmental change. We monitored the abundance, temporal distributions, and body size of arthropods in five naturalized alien and one native tree species to characterize arthropod seasonality in dry novel Prosopis-Leucaena woodlands in Puerto Rico. A branch clipping method was used monthly to sample foliage arthropod abundance over 39 mo. Seasonal patterns of rainfall and abundance within various arthropod taxa were highly variable from year to year. Abundance for most taxa did not show significant seasonality over the 3 yr, although most taxa had abundance peaks each year. However, Homoptera displayed high seasonality with significant temporal aggregations in each year. Formicidae, Orthoptera, and Coleoptera showed high variation in abundance between wet and dry periods, whereas Hemiptera were consistently more abundant in the wet period. Seasonal differences in mean abundance were found only in a few taxa on Tamarindus indica L., Bucida buceras L., Pithecellobium dulce, and (Roxburgh) Benth. Mean arthropod abundance varied among tree species, with highest numbers on Prosopis juliflora, (Swartz) De Candolle, Pi. dulce, Leucaena leucocephala, and (Lamarck) de Wit. Abundance of Araneae, Orthoptera, Coleoptera, Lepidoptera larvae, and all arthropods showed weak relationships with one or more climatic variables (rainfall, maximum temperature, or relative humidity). Body size of arthropods was usually largest during the dry periods. Overall, total foliage arthropod abundance showed no consistent seasonality among years, which may become a more common trend in dry forests and woodlands in the Caribbean if seasonality of rainfall becomes less predictable. PMID- 25502037 TI - Insect herbivores associated with Ludwigia species, Oligospermum section, in their Argentine distribution. AB - The South American water primroses, Ludwigia grandiflora (Michx.) Greuter & Burdet, L. grandiflora subsp. hexapetala (Hook. & Arn.) G.L. Nesom & Kartesz, Ludwigia peploides (Kunth) P.H. Raven, and L. p. subsp. montevidensis (Spreng.) P.H. Raven (Onagraceae, Section Oligospermum), have become invasive in several watersheds of the United States and Europe. Surveys were carried out in center east of Argentina to find insect species that might serve as biological control agents for L. g. subsp. hexapetala in California and elsewhere. Stems (0.5-0.6 m) of Ludwigia species, Sect. Oligospermum, were collected in 41 sites and analyzed in the laboratory; immature insects were reared to adults. The plant species found in the area were L. grandiflora (2 sites), L. g. subsp. hexapetala (33 sites), and L. p. subsp. montevidensis (4 sites). There was a variety of insect guilds feeding on L. g. subsp. hexapetala, including six species with stem-borer larvae, one species with fruit-feeding larvae, four species with defoliating larvae, two species with defoliating larvae on young leaves and axil meristems, one species of cell content feeder, and three species of sap feeders. Nine of these species also have defoliating adults. Biological information on most of them is provided. Of these insect herbivores, only two species were also found on L. grandiflora, and one on L. peploides. Several of the species found on L. g. hexapetala, such as the cell-content feeder Liothrips ludwigi (Thysanoptera), the stem-borers Merocnemus binotatus (Boheman) and Tyloderma spp. (Coleoptera), are promising candidates for biocontrol agents. PMID- 25502038 TI - Larvicidal activity of selected aloe species against Aedes aegypti (Diptera: Culiciade). AB - Management of mosquito vectors by current classes of mosquitocides is relatively ineffective and necessitates prospecting for novel insecticides with different modes of action. Larvicidal activities of 15 crude extracts from three geographically isolated Aloe ngongensis (Christian), Aloe turkanensis (Christian), and Aloe fibrosa (Lavranos & L.E.Newton) (Xanthorrhoeaceae) species (five each) were evaluated against Aedes aegypti (Linnaeus in Hasselquist) (Diptera: Culiciade L.) yellow fever mosquito. Freshly collected leaves were separately shade-dried to constant weight at room temperature (25 +/- 2 degrees C) and powdered. Each powder was macerated in solvents of increasing polarity (hexane, chloroform, ethyl acetate, acetone, and methanol) for 72 h and subsequently filtered. Third-instar larvae (n = 25) of the mosquito were exposed to the extracts at different concentrations for 24 h to establish dose response relationships. All the fractions of A. ngongensis were active below 1 mg/ml except A. fibrosa and A. turkanensis. The highest activity (LC50) mg/ml was obtained with extracts of A. fibrosa hexane (0.05 [0.04-0.06]), followed by A. ngongensis hexane (0.11 [0.08-0.15]) and A. turkanensis ethyl acetate (0.11 [0.09 0.12]). The activities are apparently Aloe species specific and extraction solvent dependent. These findings suggest that extracts from selected Aloe species have mosquitocidal principles that can be exploited in development of new insecticides. PMID- 25502039 TI - Development and characterization of seven polymorphic microsatellite loci in Bembidion atrocaeruleum (Coleoptera: Carabidae). AB - We isolated seven polymorphic microsatellite loci from a ground beetle (Bembidion atrocaeruleum, Coleoptera, Carabidae (Stephens, 1826)) associated with naturally and regularly disturbed floodplain habitat in northwest Europe. Loci were tested on 157 individuals collected from five distinct habitat patches across two adjacent drainage basins in Wales, United Kingdom, to assess their potential for revealing population structure across a relatively short spatial extent. Alleles per locus ranged from 4 to 12. For a central representative population, expected heterozygosity ranged from 0.23 to 0.78 (mean: 0.63), and observed heterozygosity ranged from 0.16 to 0.94 (mean: 0.56). Analysis of molecular variance indicated significant structure among populations, even when one locus potentially containing null alleles was removed. These loci have the potential to aid the study of dispersal mechanisms of this important riparian species along and between river corridors, a recurring question in floodplain conservation studies. In addition, given the diversity of the Bembidion genus, they may have utility in the study of sister species. PMID- 25502040 TI - Departure mechanisms for host search on high-density patches by the Meteorus pulchricornis. AB - Less attention has been paid to the parasitoid-host system in which the host occurs in considerably high density with a hierarchical patch structure in studies on time allocation strategies of parasitoids. This study used the parasitoid Meteorus pulchricornis (Wesmael) (Hymenoptera: Braconidae) and the Oriental leafworm, Spodoptera litura (Fabricius) (Lepidoptera: Noctuidae) as the parasitoids-host model system to investigate patch-leaving mechanisms as affected by the high-host density, hierarchical patch structure, and foraging behaviors on both former and current patches. The results showed that three out of eight covariates tested had significant effects on the patch-leaving tendency, including the host density, ovipositor insertion, and host rejection on the current patch. The parasitoid paid more visits to the patch with high-density hosts. While the patch with higher host densities decreased the leaving tendency, the spatial distribution of hosts examined had no effect on the leaving tendency. Both oviposition and host rejection decreased the patch-leaving tendency. The variables associated with the former patch, such as the host density and number of ovipositor insertions, however, did not have an effect on the leaving tendency. Our study suggested that M. pulchricornis females may use an incremental mechanism to exploit high-density patches to the fullest. PMID- 25502041 TI - Spermidine enhances the silk production by mulberry silkworm. AB - Polyamines are ubiquitous low molecular weight polycationic aliphatic amines involved in diverse cellular processes. Spermidine (Spd), a polyamine, has been proved to be crucial for cell survival in various organisms. Our study reports the effect of Spd on the growth of Bombyx mori. Silkworms showed improved silk gland weight and economic parameters in the fifth instar larval stage when treated with different concentrations of Spd, in the range of 25-75 uM. The worms treated with Spd produced 31% more silk when compared with the control worms. Altogether, this study establishes that Spd-treated leaves can be fed into the larvae for better silk production. PMID- 25502042 TI - Postteneral protein feeding may improve biological control efficiency of Aphytis lingnanensis and Aphytis melinus. AB - The augmentative releases of mass-reared Aphytis spp. (Hymenoptera: Aphelinidae) parasitoids are widely used against armored scales. The nutritional status and the initial egg load of Aphytis spp. females are key to their success as biological control agents. For these reasons, this work focuses on the study of providing a protein feed to Aphytis lingnanensis (Compere) and A. melinus DeBach to improve the egg load before their release. The addition of protein to a honey diet during the first 2 d after the adult parasitoid emergence increased the initial egg load in both species of parasitoids by more than five eggs. Furthermore, the addition of protein increased the total number of eggs laid by A. lingnanensis on oleander scale, Aspidiotus nerii Bouche (Hemiptera: Diaspididae). In contrast, this effect was not observed on A. melinus probably because A. nerii is considered a suboptimal host for this parasitoid. The host feeding activities of the two Aphytis species were differentially affected by the addition of protein to their diets. These results may have direct implications for augmentative biological control programs, especially during transportation from insectaries to the field, a period of time when parasitoids are deprived of hosts. PMID- 25502043 TI - Sexual dimorphism and mating behavior in Anomala testaceipennis. AB - The beetle, Anomala testaceipennis Blanchard (Coleoptera: Scarabaeidae), occurs in central-western Brazil where larvae feed on the roots of plants causing damage. This research aimed to study sexual dimorphism and mating behavior of A. testaceipennis. Adults of A. testaceipennis were collected with light traps in the experimental area of the State University of Mato Grosso do Sul, in Aquidauana. Laboratory experiments were performed to describe copulation behavior and adult morphology of males and females. In males the last abdominal segment has a pronounced constriction, which is absent in females, and the male's last segment of the first pair of legs has a ventral projection, which is poorly developed in females. The mating activities of adults begin soon after sunset, when adults leave the soil and fly. When the male encounters a female, he touches her with antennae and tarsi. If accepted, the male climbs on the female and remains on her back, and soon after the copulation begins. When the female does not accept the male for mating, she moves rapidly and can roll on the ground, and by so removing the male. In the field, adults feed and mate on bloomed trees of Oiti, Licania tomentosa Benth (Malpighiales: Chrysobalanaceae) and Louro, Cordia glabrata Martius (Boraginaceae). In trees without inflorescences no adults of this species were found. PMID- 25502044 TI - Genus Exitianus (Auchenorrhyncha, Cicadellidae, Deltocephalinae, and Chiasmini) in Tando Jam, Sindh, Pakistan. AB - Exitianus Ball, 1929 is studied from Tando Jam, Pakistan. Two species, Exitianus indicus (Distant, 1908) and Exitianus nanus (Distant, 1908), are reviewed and their characters, habitus, and line drawing are given. PMID- 25502046 TI - Biodiversity analysis of true bug assemblages (Hemiptera, Heteroptera) in four habitats in the Garraf Natural Park (Barcelona, Spain). AB - With the aim of gaining insight into true bugs assemblages, and of giving tools to enhance environmental manager tasks, an analysis was made of the alpha and beta diversity of true bug assemblages in the NE Iberian Peninsula. The study took place during the years 1999, 2000, and 2001. The diversity of true bug assemblages among four typical Mediterranean plant communities (dry grassland, calcicolous rosemary scrub, kermes oak scrub, and evergreen oak forest) in a protected natural area was compared. In each plant community, a stratified sampling, taking into account plants with highest coverage percentage, was performed. Collections were performed monthly using direct observation plus beating or sweeping of the entomological net. Objectives were 1) to assess whether true bug assemblages are different in each plant community surveyed, by means of the analysis of their alpha and beta diversity, 2) to assess if any of the four true bug assemblages may be prioritized according to the biodiversity parameters studied. In total, 3,071 specimens, belonging to 12 families and 77 species were identified. Fifty percent of specimens collected belonged to only three species, and ~33% of species was represented by only one or two individuals. In each Heteroptera assemblage, the distribution pattern of species frequency classes followed a lognormal model. Thirty-five percent of species represented by three or more specimens were found in only one plant community. Abundance, species richness, and diversity were found to be different for each true bug assemblage and along the year. Abundance was highest in the evergreen oak forest and in spring. Species richness and diversity were highest in the kermes oak scrub and in early summer. Nonparametric species richness estimators showed that completeness of species inventory was >80%. In the study zone, true bug diversity may be considered low medium. Our results show that true bugs assemblages are characteristic of specific plant communities, and thus, true bugs fit as candidate monitoring group in environmental and conservation management. PMID- 25502045 TI - Members of Bemisia tabaci (Hemiptera: Aleyrodidae) cryptic species and the status of two invasive alien species in the Yunnan Province (China). AB - Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) is a cryptic species complex that includes some of the most significant pests of agriculture and horticulture worldwide. To understand the diversity and distribution of B. tabaci cryptic species in Yunnan, a famous biodiversity hotspot in China, a large-scale sampling was conducted from year 2010 to 2013 in 10 prefectures. Mitochondrial cytochrome oxidase I gene sequences were used to identify different cryptic species. Phylogenetic analyses were performed using Bayesian methods to assess the position of a new B. tabaci cryptic species in the context of the B. tabaci diversity in Asia. The survey indicates at least eight B. tabaci cryptic species are present in Yunnan, two invasive (MEAM1 and MED) and six indigenous (China 2, China3, China 4, Asia I, Asia II 1, and Asia II 6), MEAM1, MED, and Asia I being the three predominant cryptic species in Yunnan. Compared with MEAM1, MED has a wider distribution. Based on molecular data, a new cryptic species, here named China 4, was identified that appears to be related to China 1, China 2, and China 3. Future efforts should focus on the interactions between predominant B. tabaci cryptic species and begomoviruses and on the development of effective control strategies. PMID- 25502047 TI - Mild traumatic brain injury: neurosensory effects. AB - PURPOSE OF REVIEW: The purpose of this review is to examine recent advances in the diagnosis and treatment of mild traumatic brain injury with attention to the neurosensory sequelae. RECENT FINDINGS: There has been a great deal of work done in this area over the last 18 months. Much of the work focuses on diagnosing the disorder. The neurosensory sequelae can be difficult to diagnose with headache relying on subjective information and cognitive effects and fatigue being very difficult to accurately measure. Dizziness is a very common disorder and probably the easiest effect to measure objectively and evidence is mounting that diagnosing and treating dizziness is very important in this patient group. Advances in treatment have occurred in the last 18 months but there is still a great deal of work necessary in this area. There is one reported pharmaceutical countermeasure and it is vital that this medicine be further tested and developed. Therapies remain the mainstay of treatment and work in this area needs to be supported. SUMMARY: It is clear from this review that mild traumatic brain injury is a rapidly growing public health issue and it vital for those who see these patients to be well versed in the neurosensory manifestations so that appropriate diagnosis and treatment are provided and accurate prognostic implications can be provided for patients and their families. PMID- 25502048 TI - Pathophysiology and treatment of motion sickness. AB - PURPOSE OF REVIEW: Motion sickness remains bothersome in conventional transport and is an emerging hazard in visual information technologies. Treatment remains unsatisfactory but advances in brain imaging, neurophysiology, and neuropharmacology may provide insights into more effective drug and behavioural management. We review these major developments. RECENT FINDINGS: Recent progress has been in identifying brain mechanisms and loci associated with motion sickness and nausea per se. The techniques have included conventional neurophysiology, pathway mapping, and functional MRI, implicating multiple brain regions including cortex, brainstem, and cerebellum. Understanding of the environmental and behavioural conditions provocative of and protective against motion sickness and how vestibular disease may sensitize to motion sickness has increased. The problem of nauseogenic information technology has emerged as a target for research, motivated by its ubiquitous applications. Increased understanding of the neurophysiology and brain regions associated with motion sickness may provide for more effective medication in the future. However, the polysymptomatic nature of motion sickness, high interindividual variability, and the extensive brain regions involved may preclude a single, decisive treatment. SUMMARY: Motion sickness is an emerging hazard in information technologies. Adaptation remains the most effective countermeasure together with established medications, notably scopolamine and antihistamines. Neuropharmacological investigations may provide more effective medication in the foreseeable future. PMID- 25502049 TI - Vertigo and dizziness in children. AB - PURPOSE OF REVIEW: Vertigo and dizziness occur with considerable frequency in childhood and adolescence. Most causes are benign and treatable. This review aims to make physicians more alert to the frequent causes of dizziness in the young. RECENT FINDINGS: Epidemiological data confirm that migraine-related syndromes are the most common cause of vertigo in children. Vestibular migraine and benign paroxysmal vertigo have now been defined by the International Classification of Headache Disorders. About half of the adolescents with vertigo and dizziness show psychiatric comorbidity and somatization. Vestibular paroxysmia has been described as a new entity in children that can be treated with low doses of carbamazepine. To assess vestibular deficits, video head impulses (for the semicircular canals) and vestibular-evoked myogenic potentials (for the otoliths) are increasingly being used. SUMMARY: Pediatricians and neuro-otologists should be aware of the full spectrum of causes of vertigo and dizziness in children and adolescents. Vestibular function can reliably be tested nowadays. Although treatment for the common migraine-related syndromes can be done in analogy to the treatment of migraine in general, specific approaches are required for somatoform vertigo, the most frequent diagnosis in adolescent girls. PMID- 25502050 TI - Cervicogenic causes of vertigo. AB - PURPOSE OF REVIEW: Herein we discuss the recent literature concerning cervicogenic vertigo including vertigo associated with rotational vertebral artery syndrome, as well as whiplash and degenerative disturbances of the cervical spine. We conclude with a summary of progress regarding diagnostic methods for cervicogenic vertigo. RECENT FINDINGS: Several additional single case studies of the exceedingly rare rotational vertebral artery syndrome have been added to the literature over the last year. Concerning whiplash and degenerative disturbances of the cervical spine, four reviews were published concerning using physical therapy as treatment, and two reviews reported successful surgical management. Publications regarding diagnostic methodology remain few and unconvincing, but the cervical torsion test appears the most promising. SUMMARY: Little progress has been made over the last year concerning cervicogenic vertigo. As neck disturbances combined with dizziness are commonly encountered in the clinic, the lack of a diagnostic test that establishes that a neck disturbance causes vertigo remains the critical problem that must be solved. PMID- 25502051 TI - Visual consciousness and bodily self-consciousness. AB - PURPOSE OF REVIEW: In recent years, consciousness has become a central topic in cognitive neuroscience. This review focuses on the relation between bodily self consciousness - the feeling of being a subject in a body - and visual consciousness - the subjective experience associated with the perception of visual signals. RECENT FINDINGS: Findings from clinical and experimental work have shown that bodily self-consciousness depends on specific brain networks and is related to the integration of signals from multiple sensory modalities including vision. In addition, recent experiments have shown that visual consciousness is shaped by the body, including vestibular, tactile, proprioceptive, and motor signals. SUMMARY: Several lines of evidence suggest reciprocal relationships between vision and bodily signals, indicating that a comprehensive understanding of visual and bodily self-consciousness requires studying them in unison. PMID- 25502052 TI - Caffeine as an analgesic adjuvant for acute pain in adults. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 3, 2012. Caffeine has been added to common analgesics such as paracetamol, ibuprofen, and aspirin, in the belief that it enhances analgesic efficacy. Evidence to support this belief is limited and often based on invalid comparisons. OBJECTIVES: To assess the relative efficacy of a single dose of an analgesic plus caffeine against the same dose of the analgesic alone, without restriction on the analgesic used or the pain condition studied. We also assessed serious adverse events. SEARCH METHODS: We searched CENTRAL, MEDLINE, and EMBASE from inception to 28 August 2014, the Oxford Pain Relief Database, and also carried out Internet searches and contacted pharmaceutical companies known to have carried out trials that have not been published. SELECTION CRITERIA: We included randomised, double-blind studies that compared a single dose of analgesic plus caffeine with the same dose of the analgesic alone in the treatment of acute pain. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and quality of studies, and extracted data. Any disagreements or uncertainties were settled by discussion with a third review author. We sought any validated measure of analgesic efficacy, but particularly the number of participants experiencing at least 50% of the maximum possible pain relief over four to six hours, participants reporting a global evaluation of treatment of very good or excellent, or headache relief after two hours. We pooled comparable data to look for a statistically significant difference, and calculated numbers needed to treat to benefit (NNT) with caffeine. We also looked for any numerical superiority associated with the addition of caffeine, and information about any serious adverse events. MAIN RESULTS: We identified no new studies with available results for this update. The earlier review included 20 studies (7238 participants) in valid comparisons, but because we used different outcomes for some headache studies, the number of participants in the analyses of the effects of caffeine is now 4262 when previously it was 5243. The studies were generally of good methodological quality, using standard designs and mostly standard scales of pain measurement, although many of those treating postoperative pain were small.Most studies used paracetamol or ibuprofen, with 100 mg to 130 mg caffeine, and the most common pain conditions studied were postoperative dental pain, postpartum pain, and headache. There was a small but statistically significant benefit with caffeine used at doses of 100 mg or more, which was not dependent on the pain condition or type of analgesic. About 5% to 10% more participants achieve a good level of pain relief (at least 50% of the maximum over four to six hours) with the addition of caffeine, giving a NNT of about 14 (high quality evidence).Most comparisons individually demonstrated numerical superiority with caffeine, but not statistical superiority. One serious adverse event was reported with caffeine, but was considered unrelated to any study medication.We know of the existence of around 25 additional studies with almost 12,500 participants for which data for analysis were not obtainable. The additional analgesic effect of caffeine remained statistically significant but clinically less important even if all the known missing data had no effect; the bulk of the unobtainable data are reported to have similar results as this review. AUTHORS' CONCLUSIONS: The addition of caffeine (>= 100 mg) to a standard dose of commonly used analgesics provides a small but important increase in the proportion of participants who experience a good level of pain relief. PMID- 25502053 TI - Prioritizing candidate disease-related long non-coding RNAs by walking on the heterogeneous lncRNA and disease network. AB - Accumulated evidence has shown that long non-coding RNAs (lncRNA) act as a widespread layer in gene regulatory networks and are involved in a wide range of biological processes. The dysregulation of lncRNA has been implicated in various complex human diseases. Although several computational methods have been developed to predict disease-related lncRNA, this still remains a considerable challenging task. In this study, we tried to construct an lncRNA-lncRNA crosstalk network by examining the significant co-occurrence of shared miRNA response elements on lncRNA transcripts from the competing endogenous RNAs viewpoint. As expected, functional analysis showed that lncRNA sharing significantly enriched interacting miRNAs tend to be involved in similar diseases and have more functionally related flanking gene sets. We further proposed a novel rank-based method, RWRHLD, to prioritize candidate lncRNA-disease associations by integrating three networks (miRNA-associated lncRNA-lncRNA crosstalk network, disease-disease similarity network and known lncRNA-disease association network) into a heterogeneous network and implementing a random walk with restart on this heterogeneous network. We used leave-one-out cross-validation to test the performance of this rank-based method in this study based on known experimentally verified lncRNA-disease associations and obtained a reliable AUC value of 0.871, which is much higher than RWR merely based on an lncRNA network, hypergeometric test and random situation. Furthermore, several novel lncRNA-disease associations predicted in case studies of ovarian cancer and prostate cancer have been confirmed in new studies by literature surveys. PMID- 25502054 TI - Resolving stress tensor components in space from polarized Raman spectra: polycrystalline alumina. AB - A method of Raman spectroscopic analysis has been proposed for evaluating tensorial stress fields stored in alumina polycrystals with a corundum structure (alpha-Al2O3). Raman selection rules for all the vibrational modes of the structure were expanded into explicit functions of both 3 Euler angles in space and 4 Raman tensor elements (RTE) of corundum. A theoretical treatment was then worked out according to the phonon deformation potential (PDP) formalism, which explicitly expressed the changes in force constants under stress in matricial form. Close-form solutions could be obtained for the matrix eigenvalues as a function of 9 unknown variables, namely 6 independent stress tensor components and 3 Euler angles in space, the latter parameters being representatives of local crystal orientation. Successively, two separate sets of Raman calibration experiments were performed for the determination of both RTE and PDP constants of the corundum structure of alumina. Calibration experiments provided a quantitative frame to the newly developed Raman formalism. Polarized Raman spectra were systematically recorded in both single-crystalline and polycrystalline samples, with both A1g and Eg vibrational bands being characterized. Regarding polycrystalline samples, a validation of the proposed Raman method could be done through a comparison between Raman and fluorescence data collected at the same locations across an alumina/metal interface embedded in a steeply graded residual stress field. PMID- 25502055 TI - Health equity research: a new, ongoing series in nursing research. PMID- 25502056 TI - Frequent emergency department utilization and behavioral health diagnoses. AB - BACKGROUND: There are 12 million emergency department (ED) visits each year related to behavioral health diagnoses. Frequent ED utilization among subpopulations, such as those with behavioral health diagnoses, flags the need for more accessible and effective healthcare delivery systems. Reducing frequent ED use is essential to controlling healthcare cost and poor outcomes of ED overcrowding. OBJECTIVES: The purpose of this study is to stratify individuals by overall health complexity and examine the relationship of behavioral health diagnoses (psychiatric and substance abuse) as well as frequent treat-and-release ED utilization in a cohort of Medicaid recipients. METHODS: This study was a retrospective analysis of 2009 Medicaid claims from two Western New York State counties. The claims represented 56,491 individuals (18-64 years old). Individuals were stratified into four separate cohorts for analysis based on underlying disease complexity. Data were analyzed using logistic regression models. RESULTS: The following factors significantly increased the odds of frequent treat-and-release ED use in all the four complexity cohorts: psychiatric diagnosis (ORs = 1.4-2.3), substance abuse (ORs = 2.4-3.8), and smoking (ORs = 1.7-4.0). Medicaid patients with behavioral health diagnoses show high risk of frequent treat-and-release ED use. DISCUSSION: The results of this study show that psychiatric diagnosis, substance abuse, and smoking are associated with increased odds of frequent treat-and-release ED utilization for Medicaid recipients in all categories of underlying disease complexity. Our findings support associations reported in the literature. PMID- 25502057 TI - Evaluation of the implementation of a PhD capacity-building program for nurses in South Africa. AB - BACKGROUND: Nursing is experiencing a significant deficit in research capacity needed to meet future global healthcare demands-there is a call to double the number of nurses and healthcare professionals with a doctorate. AIM: The aim of this research was to evaluate the implementation of a national PhD capacity building program for academic and practice-based nurses and other healthcare professionals in South Africa. METHODS: An implementation science framework was used. Implementation of the program across two national, longitudinal cohorts of participants was studied. Evidence of enablers and barriers to implementation was obtained from multiple data sources, including the curriculum for the program, regular evaluation reports from program participants and program facilitators after each stage of the PhD curriculum delivery, and meeting notes. Supplementary sources included rates of PhD candidate recruitment, retention, and successful completion. RESULTS: Evidence for the presence of enablers for successful implementation was found, including stakeholder consultation and buy-in, leadership, resources, staff capacity, and implementation teams. No evidence of an implementation plan, a supportive organizational culture, or effective ongoing communication at Stage 4 of the implementation process was found. Barriers to implementation included external environmental factors, resistance to change, and vested interests. DISCUSSION: Within the context of a recognized worldwide shortage of nursing scientists, the application of an implementation science framework to evaluate the initial stages of a national PhD development program rollout provided information on how effective implementation can be strengthened and how barriers to success can be overcome. PMID- 25502058 TI - Self-management intervention for long-term indwelling urinary catheter users: randomized clinical trial. AB - BACKGROUND: People using long-term indwelling urinary catheters experience multiple recurrent catheter problems. Self-management approaches are needed to avoid catheter-related problems. OBJECTIVES: The aim was to determine effectiveness of a self-management intervention in prevention of adverse outcomes (catheter-related urinary tract infection, blockage, and accidental dislodgement). Healthcare treatment associated with the adverse outcomes and catheter-related quality of life was also studied. METHODS: A randomized clinical trial was conducted. The intervention involved learning catheter-related self monitoring and self-management skills during home visits by a study nurse (twice during the first month and at 4 months-with a phone call at 2 months). The control group received usual care. Data were collected during an initial face-to face home interview followed by bimonthly phone interviews. A total of 202 adult long-term urinary catheter users participated. Participants were randomized to treatment or control groups following collection of baseline data. Generalized estimating equations were used for the analysis of treatment effect. RESULTS: In the intervention group, there was a significant decrease in reported blockage in the first 6 months (p = .02), but the effect did not persist. There were no significant effects for catheter-related urinary tract infection or dislodgment. Comparison of baseline rates of adverse outcomes with subsequent periods suggested that both groups improved over 12 months. DISCUSSION: A simple-to-use catheter problems calendar and the bimonthly interviews might have functioned as a modest self-monitoring intervention for persons in both groups. A simplified intervention using a self-monitoring calendar is suggested-with optimal and consistent fluid intake likely to add value. PMID- 25502060 TI - The Dutch functional performance inventory: validity and reliability in patients with chronic obstructive lung disease. AB - BACKGROUND: Performing activities of daily living (ADLs) is an important outcome measure in chronic obstructive pulmonary disease (COPD). The functional performance inventory (FPI) can be used to measure ADL performance in people with COPD. OBJECTIVE: The aims are to report translation of the FPI into the Dutch language and evaluate the validity and reliability of the translated version in a Dutch COPD population. METHODS: The FPI was translated, after which validation and test-retest reliability studies were conducted. The Consensus-Based Standards for Selection of Health Status Measurement Instruments checklist was used. The Clinical COPD Questionnaire (CCQ), the self-administered Chronic Respiratory Questionnaire-Standardized, and the Medical Research Council Dyspnea Scale were used in the validation study. Test-retest reliability was estimated across 2 weeks in patients with stable COPD. RESULTS: Participants were patients with COPD from the Netherlands who took part in either the validation (n = 90) or reliability study (n = 60). The validity analyses showed that, as hypothesized, the household maintenance and physical exercise subscales of the Dutch version of the FPI had high correlations with the CCQ functional status domain; the total FPI had a correlation of -.44, with CCQ functional status domain. Across the subscales, score reliability estimated with Cronbach's alpha ranged from .55 (Body Care) to .97 (Household Maintenance); total score alpha was .98. Intraclass correlations (ICCs) ranged from .84 (Social Activities) to .97 (Body Care and Household Maintenance); total scale ICC was .98. Recreation and Spiritual Activity subscales varied significantly on retesting at 2 weeks. DISCUSSION: Scores on the Dutch FPI were reliable and reproducible. Evidence for validity was reasonable, but less strong than that reported in studies from other populations. PMID- 25502059 TI - Malpractice claims in Swedish telenursing: lessons learned from interviews with telenurses and managers. AB - BACKGROUND: This study deals with serious malpractice claims within Swedish Healthcare Direct, the national telephone helpline in Sweden. At least 33 claims of malpractice have been filed since the service was created in 2003. Although a low number, consequences have been tragic. Research in Swedish telenursing on contributing systemic and organizational factors and consequences of malpractice claims is sparse. OBJECTIVE: The objective was to explore the direct experience of telenurses' and call center managers' involvement in actual malpractice claims with focus on factors that may have contributed to the claims-and on the consequences of the claims. METHODS: Six telenurses and five managers agreed to participate in open-ended interviews. A directed content analysis approach was chosen to analyze the transcribed interview texts. RESULTS: Stress, shiftwork, fatigue, multitasking, understaffing, and factors embedded in the system could have contributed to the malpractice claims. Safety management was treated locally, with no attempts at organizational reforms. DISCUSSION: The solitary nature of the telenursing task emphasizes the importance of an organization, which works toward providing an environment where telenurses can feel safe and supported. This may require, in turn, a change in both organizational and professional attitudes toward safety and risk of error. The greatest hinder may be healthcare providers themselves. If the difficulties in recruiting participants for this study are any indication, reaching out to healthcare providers who remain silent may be the greatest challenge. PMID- 25502061 TI - Reactive oxygen and nitrogen species: impact on endothelial dysfunction. AB - BACKGROUND: Reactive oxygen and nitrogen species, known as free radicals, play a key role in the etiology and progression of atherosclerotic cardiovascular disease by creating vascular oxidative stress. PURPOSE: This review will discuss current biological research about the enzymatic and nonenzymatic sources of oxidative stress, free radical chemistry, and how it pertains to endothelial dysfunction-a hallmark of cardiovascular disease. METHODS: An integrative review of the literature was conducted. FINDINGS: Free radicals lower the bioavailability of the potent vasodilator nitric oxide and therefore, through numerous chemical reactions, negatively affect vascular biology and endothelial function. Endothelial dysfunction is considered to be integral in the initiation of atherosclerosis. CONCLUSIONS: The success and failures of current therapies to reduce oxidative stress are discussed in terms of implications for nursing research on exogenous antioxidants, pharmacotherapy, and lifestyle change. PMID- 25502062 TI - Using timed event sequential data in nursing research. AB - BACKGROUND: Measuring behavior is important in nursing research, and innovative technologies are needed to capture the "real-life" complexity of behaviors and events. PURPOSE: The purpose of this article is to describe the use of timed event sequential data in nursing research and to demonstrate the use of this data in a research study. DISCUSSION: Timed event sequencing allows the researcher to capture the frequency, duration, and sequence of behaviors as they occur in an observation period and to link the behaviors to contextual details. Timed event sequential data can easily be collected with handheld computers, loaded with a software program designed for capturing observations in real time. CONCLUSION: Timed event sequential data add considerable strength to analysis of any nursing behavior of interest, which can enhance understanding and lead to improvement in nursing practice. PMID- 25502063 TI - The patient-centered outcomes research institute: research done differently. AB - BACKGROUND: The Patient-Centered Outcomes Research Institute (PCORI) was authorized by the Patient Protection and Affordable Care Act of 2010 to fund comparative clinical effectiveness research to provide reliable evidence to help patients and their healthcare providers make informed decisions. OBJECTIVE: The aim of this paper is to describe the synergy between nursing research and PCORI funding priorities, discuss unique aspects of PCORI funding, and identify the implications for nurse researchers. DISCUSSION: Goals of nursing research are well aligned with PCORI interests. Given this synergy, many phenomena that nursing scientists study could become topics of a competitive proposal for PCORI funding. Major aspects of PCORI funding with implications for nurse researchers include the nature of the questions asked, funding priorities, engagement of patients and stakeholders, compliance with the PCORI's methodology standards, and the proposal review criteria and process. PMID- 25502064 TI - Reversal of dabigatran effects in models of thrombin generation and hemostasis by factor VIIa and prothrombin complex concentrate. AB - BACKGROUND: The oral thrombin inhibitor dabigatran has the drawbacks that it does not have a validated antidote. Data from animal studies and plasma coagulation assays suggest that prothrombin complex concentrate (PCC) or recombinant factor VIIa (FVIIa) might reverse dabigatran anticoagulation. METHODS: Cellular elements make a significant contribution to hemostasis. Our goals were to (1) test the hypothesis that both FVIIa and a 4-factor PCC improve parameters of thrombin generation in the presence of dabigatran in a cell-based model; and (2) determine whether results in a cell-based model correlate with hemostasis in vivo. RESULTS: PCC reversed dabigatran effects on the rate, peak, and total amount of thrombin but did not shorten the lag (n = 6 experiments in triplicate). By contrast, FVIIa shortened the lag, increased the rate and peak, but did not improve total thrombin (n = 6). Effects of PCC were seen at both therapeutic and markedly supratherapeutic dabigatran levels, whereas beneficial effects of FVIIa decreased as the dabigatran level increased. The PCC effect was reproduced by adding prothrombin, factor X, and factor IX. At therapeutic dabigatran levels, both PCC and FVIIa normalized hemostasis time in a mouse saphenous vein bleeding model. CONCLUSIONS: A cell-based model reflects the effects on thrombin generation of clinically relevant levels of FVIIa and PCC in the presence of dabigatran. Enhancing the rate of thrombin generation and peak thrombin level appear to correlate best with hemostasis in vivo. The ineffectiveness of FVIIa at supratherapeutic dabigatran levels may explain conflicting reports of its efficacy in dabigatran reversal. PMID- 25502066 TI - Preventing respiratory depression. PMID- 25502065 TI - Phase 1 safety assessment of intrathecal oxytocin. AB - BACKGROUND: Preclinical data suggest that oxytocin reduces hypersensitivity by actions in the spinal cord, but whether it produces antinociception to acute stimuli is unclear. In this article, the authors examined the safety of intrathecal oxytocin and screened its effects on acute noxious stimuli. METHODS: After institutional review board and Food and Drug Administration approval, healthy adult volunteers received 5, 15, 50, or 150 MUg intrathecal oxytocin in a dose-escalating manner in cohorts of five subjects. Hemodynamic and neurologic assessments were performed for 4 h after injections and 24 h later, at which time serum sodium was also measured. Cerebrospinal fluid was obtained 60 min after injection, and responses to noxious heat stimuli in arm and leg as well as temporal summation to repeated application of a von Frey filament were obtained. RESULTS: One subject receiving the highest dose experienced transient hypotension and bradycardia as well as subjective numbness in a lumbo-sacral distribution. No other subject experienced subjective or objective neurologic symptoms. Overall, blood pressure and heart rate increased 1 to 4 h after injection by less than 15% with no dose dependency. There was no effect on serum sodium, and cerebrospinal fluid oxytocin increased in a dose-dependent manner after injection. Pain scores to noxious heat stimuli were unaffected by oxytocin, and the temporal summation protocol failed to show summation before or after drug treatment. CONCLUSION: This small study supports further investigation on oxytocin for analgesia for hypersensitivity states, with continued systematic surveillance for possible effects on blood pressure, heart rate, and neurologic function. PMID- 25502067 TI - Phenyl-beta-D-Glucopyranoside Exhibits Anti-inflammatory Activity in Lipopolysaccharide-Activated RAW 264.7 Cells. AB - Phenyl-beta-D-glucopyranoside is a component of Phellodendron amurense with anti cancer and anti-inflammatory activities. In the present study, we investigated the role of phenyl-beta-D-glucopyranoside in inflammation using lipopolysaccharide (LPS)-stimulated murine Raw 264.7 macrophages. Phenyl-beta-D glucopyranoside not only inhibited nitric oxide (NO) production but also significantly inhibited the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) without inducing cytotoxicity. Phenyl-beta-D glucopyranoside also attenuated proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and other inflammation-related genes, such as IL-6 in a concentration-dependent manner. Furthermore, phenyl-beta-D-glucopyranoside abolished increased adhesion, ninjurin 1 (Ninj1) expression, and matrix metalloproteinase (MMP) activity induced by endotoxin treatment. Finally, phenyl-beta-D-glucopyranoside inhibited the nuclear translocation of nuclear factor-kappaB (NF-kappaB), which is one of the most important transcription factors involved in the inflammatory process. Taken together, phenyl-beta-D-glucopyranoside may be beneficial for the prevention and treatment of anti-inflammatory diseases. PMID- 25502068 TI - Markers of Bone Metabolism in Obese Individuals Undergoing Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Besides its advantages, bariatric surgery implicates a risk of nutritional deficiencies, which might result in impaired bone metabolism. We assessed the effect of laparoscopic sleeve gastrectomy (LSG) on blood markers of bone metabolism in obese patients during a 3-year observation period. METHODS: In 39 obese patients (29 women, 10 men, mean BMI 51.8 +/- 6.8 kg/m(2)) undergoing LSG, we measured blood concentrations of 25-hydroxyvitamin D (25(OH)D), calcium, parathyroid hormone (PTH), bone alkaline phosphatase (BAP), and N-telopeptides crosslinks (NTx) before LSG and up to 3 years postoperatively. Vitamin D and calcium supplementations were recorded. RESULTS: LSG caused an excess weight loss (EWL) of 54 +/- 20 % after 3 years. Before surgery, we found decreased levels of 25(OH)D and calcium in 80 and 5 % of the subjects, respectively, while increased levels of PTH, BAP, and NTx were found in 39, 28, and 21 %, respectively. Mean levels of NTx and the prevalence of elevated levels of NTx increased within 2 years (p < 0.001 and p < 0.01). Neither mean blood concentrations of 25(OH)D, calcium, PTH, and BAP nor relative prevalence of deficiencies regarding these markers changed during the study period. The supplementation rates of calcium and vitamin D increased postoperatively. CONCLUSIONS: Morbid obesity is associated with pronounced changes of markers of bone metabolism; LSG did neither aggravate nor ameliorate vitamin D metabolism within a 3-year time period, but led to increased bone resorption 2 years postoperatively. Routine supplementation of calcium and vitamin D is not likely sufficient to compensate the obesity associated deficiencies in bone metabolism. PMID- 25502069 TI - Laparoscopic Sleeve Gastrectomy for Morbid Obesity with Intra-operative Endoscopy: Lessons We Learned After 100 Consecutive Patients. AB - BACKGROUND: Sleeve gastrectomy has become the second most common bariatric operation due to its low rates of morbidity and mortality, satisfactory treatment of patients' obesity, and resolution of associated co-morbidities. According to standard technique, calibration of the stomach is performed with varying sizes of bougies while use of intra-operative endoscopy has only sparsely been reported. METHODS: Between 2004 and 2013, 100 patients have undergone laparoscopic or robotic sleeve gastrectomy with intra-operative endoscopic guidance. Technical aspects of the operation, results concerning morbidity, progressive weight loss, and resolution of co-morbidities were retrospectively reviewed. RESULTS: Morbidity and mortality was zero. Rates of excess weight loss at 6 months and 1 and 3 years were 52.1, 67.4, and 61.3 %, respectively. Patients' highest rate of excess weight loss was achieved 18 months post-operatively. These rates were inversely related with preoperative age, body mass index, and the existence of preoperative co-morbidities. CONCLUSION: Sleeve gastrectomy with intra-operative endoscopic guidance is at least as safe and effective as with the bougie. Given the available expertise and equipment, the use of this technique can increase the intra-operative sense of safety with no compromise or even improvement of the immediate or long-term results. PMID- 25502070 TI - The name of mini gastric bypass. PMID- 25502071 TI - Global and regional brain mean diffusivity changes in patients with heart failure. AB - Heart failure (HF) patients show gray and white matter changes in multiple brain sites, including autonomic and motor coordination areas. It is unclear whether the changes represent acute or chronic tissue pathology, a distinction necessary for understanding pathological processes that can be resolved with diffusion tensor imaging (DTI)-based mean diffusivity (MD) procedures. We collected four DTI series from 16 HF (age 55.1 +/- 7.8 years, 12 male) and 26 control (49.7 +/- 10.8 years, 17 male) subjects with a 3.0-Tesla magnetic resonance imaging scanner. MD maps were realigned, averaged, normalized, and smoothed. Global and regional MD values from autonomic and motor coordination sites were calculated by using normalized MD maps and brain masks; group MD values and whole-brain smoothed MD maps were compared by analysis of covariance (covariates; age and gender). Global brain MD (HF vs. controls, units * 10(-6) mm(2) /sec, 1103.8 +/- 76.6 vs. 1035.9 +/- 69.4, P = 0.038) and regional autonomic and motor control site values (left insula, 1,085.4 +/- 95.7 vs. 975.7 +/- 65.4, P = 0.001; right insula, 1,050.2 +/- 100.6 vs. 965.7 +/- 58.4, P = 0.004; left hypothalamus, 1,419.6 +/- 165.2 vs. 1,234.9 +/- 136.3, P = 0.002; right hypothalamus, 1,446.5 +/- 178.8 vs. 1,273.3 +/- 136.9, P = 0.004; left cerebellar cortex, 889.1 +/- 81.9 vs. 796.6 +/- 46.8, P < 0.001; right cerebellar cortex, 797.8 +/- 50.8 vs. 750.3 +/- 27.5, P = 0.001; cerebellar deep nuclei, 1,236.1 +/- 193.8 vs. 1,071.7 +/- 107.1, P = 0.002) were significantly higher in HF vs. control subjects, indicating chronic tissue changes. Whole-brain comparisons showed increased MD values in HF subjects, including limbic, basal-ganglia, thalamic, solitary tract nucleus, frontal, and cerebellar regions. Brain injury occurs in autonomic and motor control areas, which may contribute to deficient function in HF patients. The chronic tissue changes likely result from processes that develop over a prolonged period. PMID- 25502072 TI - The carboxyl-terminal tail of the stalk of Arabidopsis NACK1/HINKEL kinesin is required for its localization to the cell plate formation site. AB - Plant cytokinesis is achieved by formation of cell plates in the phragmoplast, a plant-specific cytokinetic apparatus, which consists of microtubules (MTs) and microfilaments. During cytokinesis, the cell plate is expanded centrifugally outward from the inside of cells in a process that is supported by dynamic turnover of MTs. M-phase-specific kinesin NACK1, which comprises the motor domain at the amino-terminal half to move on MT bundles and the stalk region in the carboxyl-terminal half, is a key player in the process of MT turnover. That is, the specific region in the stalk binds the MAP kinase kinase kinase to activate the whole MAP kinase cascade, which stimulates depolymerization of MTs for the MT turnover. The stalk is also responsible for recruiting the activated kinase cascade to the mid-zone of the phragmoplast, which corresponds to the cell-plate formation site. It should be crucial to uncover roles of the NACK1 kinesin stalk as well as the motor domain in the formation of cell plates in order to understand the mechanisms of cell plate formation. Using dissected Arabidopsis NACK1 (AtNACK1/HINKEL) molecules and AtNACK1-fused GFP, we showed that the C terminal tail of the stalk in addition to the motor domain is critical for its proper localization to the site of cell plate formation in the phragmoplast, probably by affecting its motility activity. PMID- 25502073 TI - Arundina graminifolia var. revoluta (Arethuseae, Orchidaceae) has fern-type rheophyte characteristics in the leaves. AB - Morphological and molecular variation between Arundina graminifolia var. graminifolia and the dwarf variety, A. graminifolia var. revoluta, was examined to assess the validity of their taxonomic characteristics and genetic background for identification. Morphological analysis in combination with field observations indicated that A. graminifolia var. revoluta is a rheophyte form of A. graminifolia characterized by narrow leaves, whereas the other morphological characteristics described for A. graminifolia var. revoluta, such as smaller flowers and short stems, were not always accompanied by the narrower leaf phenotype. Molecular analysis based on matK sequences indicated that only partial differentiation has occurred between A. graminifolia var. graminifolia and A. graminifolia var. revoluta. Therefore, we should consider the rheophyte form an ecotype rather than a variety. Anatomical observations of the leaves revealed that the rheophyte form of A. graminifolia possessed characteristics of the rheophytes of both ferns and angiosperms, such as narrower palisade tissue cells and thinner spongy tissue cells, as well as fewer cells in the leaf-width direction and fewer mesophyll cell layers. PMID- 25502074 TI - Abundance and diversity of bacteria in oxygen minimum drinking water reservoir sediments studied by quantitative PCR and pyrosequencing. AB - Reservoir sediment is one of the most stressful environments for microorganisms due to periodically oxygen minimum conditions. In this study, the abundance and composition of bacteria associated with sediments from three drinking water reservoirs (Zhoucun, ZCR; Shibianyu, SBYR; and Jinpen, JPR) were investigated by quantitative polymerase chain reaction and 16S rRNA-based 454 pyrosequencing. The results of physico-chemical analysis of sediments showed that the organic matter and total nitrogen were significantly higher in ZCR as compared to JPR (P < 0.01). The bacterial abundance was 9.13 * 10(6), 1.14 * 10(7), and 6.35 * 10(6) copies/ng DNA in sediments of SBYR, ZCR, and JPR, respectively (P < 0.01). The pyrosequencing revealed a total of 9,673 operational taxonomic units, which were affiliated with 17 phyla. The dominant phylum was Firmicutes (56.83%) in JPR; whereas, the dominance of Proteobacteria was observed in SBYR with 40.38% and ZCR with 39.56%. The Shannon-Wiener diversity (H') was high in ZCR; whereas, Chao 1 richness was high in SBYR. The dominant genera were Clostridium with 42.15% and Bacillus with 20.44% in JPR. Meanwhile, Dechloromonas with 14.80% and Smithella with 7.20% were dominated in ZCR, and Bacillus with 45.45% and Acinetobacter with 5.15% in SBYR. The heat map profiles and redundancy analysis indicated substantial differences in sediment bacterial community composition among three reservoirs. Moreover, it appears from the results that physico-chemical variables of sediments including pH, organic matter, total nitrogen, and available phosphorous played key roles in shaping the bacterial community diversity. The results obtained from this study will broaden our understanding on the bacterial community structure of sediments in oxygen minimum and stressful freshwater environments. PMID- 25502076 TI - Health services utilisation in breast cancer survivors in Taiwan. AB - Surveillance guidelines for breast cancer survivors recommend regular history and physical and mammography, and against routine imaging for detecting distant metastasis. Stage 0, I, II breast cancer cases treated at a major cancer center were identified from the Taiwan Cancer Registry. We used multivariable negative binomial and logistic regression analyses on institutional claims data to examine factors contributing to utilisation patterns of surveillance visits and tests in disease-free survivors. The mean number of surveillance visits during months 13 to 60 after cancer treatment initiation was 18.5 (SD 8.2) among the 2,090 breast cancer survivors followed for at least five years. After adjusting for patient and disease factors, the number of visits was the highest among patients mainly followed by medical oncologists compared to surgeons and radiation oncologists. Patient cohorts treated in more recent years had lower number of visits associated with care coordination effort, the adjusted mean being 19.2 visits for the 2002 cohort, and 16.3 visits for the 2008 cohort (p < 0.0001). Although imaging tests were highly utilised, there was a significant decrease in tumor marker testing from the 2002 to the 2008 treatment cohort (adjusted rate 99.4% to 35.1% respectively, p < 0.0001) in association with an institutional guideline change. PMID- 25502077 TI - Blistering disease: insight from the hemidesmosome and other components of the dermal-epidermal junction. AB - The hemidesmosome is a specialized transmembrane complex that mediates the binding of epithelial cells to the underlying basement membrane. In the skin, this multiprotein structure can be regarded as the chief adhesion unit at the site of the dermal-epidermal junction. Focal adhesions are additional specialized attachment structures located between hemidesmosomes. The integrity of the skin relies on well-assembled and functional hemidesmosomes and focal adhesions (also known as integrin adhesomes). However, if these adhesion structures are impaired, e.g., as a result of circulating autoantibodies or inherited genetic mutations, the mechanical strength of the skin is compromised, leading to blistering and/or tissue inflammation. A particular clinical presentation emerges subject to the molecule that is targeted. None of these junctional complexes are simply compounds of adhesion molecules; they also play a significant role in signalling pathways involved in the differentiation and migration of epithelial cells such as during wound healing and in tumour invasion. We summarize current knowledge about hereditary and acquired blistering diseases emerging from pathologies of the hemidesmosome and its neighbouring proteins as components of the dermal epidermal junction. PMID- 25502075 TI - Forest health in a changing world. AB - Forest pathology, the science of forest health and tree diseases, is operating in a rapidly developing environment. Most importantly, global trade and climate change are increasing the threat to forest ecosystems posed by new diseases. Various studies relevant to forest pathology in a changing world are accumulating, thus making it necessary to provide an update of recent literature. In this contribution, we summarize research at the interface between forest pathology and landscape ecology, biogeography, global change science and research on tree endophytes. Regional outbreaks of tree diseases are requiring interdisciplinary collaboration, e.g. between forest pathologists and landscape ecologists. When tree pathogens are widely distributed, the factors determining their broad-scale distribution can be studied using a biogeographic approach. Global change, the combination of climate and land use change, increased pollution, trade and urbanization, as well as invasive species, will influence the effects of forest disturbances such as wildfires, droughts, storms, diseases and insect outbreaks, thus affecting the health and resilience of forest ecosystems worldwide. Tree endophytes can contribute to biological control of infectious diseases, enhance tolerance to environmental stress or behave as opportunistic weak pathogens potentially competing with more harmful ones. New molecular techniques are available for studying the complete tree endobiome under the influence of global change stressors from the landscape to the intercontinental level. Given that exotic tree diseases have both ecologic and economic consequences, we call for increased interdisciplinary collaboration in the coming decades between forest pathologists and researchers studying endophytes with tree geneticists, evolutionary and landscape ecologists, biogeographers, conservation biologists and global change scientists and outline interdisciplinary research gaps. PMID- 25502078 TI - Changes in perinatal care and outcomes in newborns at the limit of viability in Spain: the EPI-SEN Study. AB - BACKGROUND: Advances in perinatal care can influence morbidity and mortality in newborns at the limit of viability. Knowledge of these changes over time may help improve clinical decision making, optimize resource allocation and increase quality of care. OBJECTIVES: To evaluate the influence on morbidity and mortality of changes introduced in the perinatal care of preterm infants (22-26 weeks' gestational age, GA) in Spain between two consecutive periods (2002-2006 and 2007 2011). METHODS: An analysis of prospectively collected data in a national database network (SEN1500) was performed. All live newborn infants of 22-26 weeks' GA born in or transferred to referral centers of the SEN1500 network in the first 28 days of life were included. Perinatal interventions, clinical management, neonatal morbidity, and survival until hospital discharge were retrieved. RESULTS: A total of 5,470 newborns were included (2,533 and 2,937 in each period, respectively). The major changes introduced during the second period were as follows: (1) lower proportion of extramural births (11.0 vs. 8.9%, p = 0.01), (2) increase in antenatal steroids (69.5 vs. 80.8%, p < 0.001), (3) delivery by C-section (41.8 vs. 48.3%, p < 0.001) and (4) use of CPAP during resuscitation (7.8 vs. 20.7%, p < 0.001). Death in the delivery room decreased from 5.1 to 3.2% (p < 0.001). Survival increased from 49.9 to 57.9% (p < 0.001), and survival without major morbidity increased from 18.1 to 21.2% (p = 0.006). CONCLUSIONS: During the second period, a greater attachment to practices proven to have a beneficial impact on survival and reduction of morbidity in the extremely preterm infant was noted, and survival and survival without major morbidity increased. A more conservative approach was detected for newborns of 22 weeks' GA. PMID- 25502079 TI - The preliminary study of p53 codon 72 polymorphism and risk of cervical carcinoma in Gabonese women. AB - Cervical cancer is the leading cause of cancer-related death in Africa and the first most common cancer in Gabonese women due to infection of high-risk human papillomavirus (HPV). However, other cofactors such as genetic factors also come into play. A common polymorphism of the p53 codon 72 in exon 4 with two alleles encoding arginine or proline is known at this locus. The homozygous arginine form of this polymorphism has been associated with the development of cervical cancer as an increased genetic risk factor. However, the results are still controversial. This study aims to investigate whether the genotype distribution of p53 codon 72 may be a risk factor for cervical cancer among Gabonese women. Samples from 102 Gabonese women, 31 diagnosed with cervical cancer and 71 healthy controls, were used. HPV detection was done by nested PCR with MY09/11 and GP5+/6+ primers followed by sequencing for HPV genotyping. p53 codon 72 polymorphism determination was performed by allele-specific PCR assay. Viral DNA was detected in 87.1 % of cases and in 54.93 % of control. HPV 16 was the most predominant in cancer and controls cases. The distribution of Arg/Arg, Arg/Pro and Pro/Pro genotypes was 35.5, 51.6 and 12.9 % in the cervical cancer group and 22.5, 62 and 15.5 % in the control group. No significant association was found between polymorphism of p53 itself as well as in combination with HPV16/18 infection and risk of development of cervical cancer among Gabonese women. Thus, the polymorphism of p53 codon 72 in exon 4 does not seem to play a role in the development of cervical cancer among Gabonese women. PMID- 25502080 TI - Down-regulation of miR-24-3p in colorectal cancer is associated with malignant behavior. AB - Deregulation of microRNAs is a frequent event in the tumorigenesis and tumor progression. The aim of this study was to investigate the clinical significance and potential role of miR-24-3p expression in colorectal cancer (CRC). The expression level of miR-24-3p was determined in 95 CRC patients who underwent radical resection by quantitative real-time PCR. The associations between miR-24 3p expression and clinicopathological parameters were analyzed. In vitro function assays including cell proliferation, cell migration and invasion were further explored. We found that miR-24-3p was reduced in CRC tissues compared with their corresponding non-cancerous tissues (P < 0.001) and significantly correlated with local invasion (P = 0.002), lymph node metastasis (P = 0.0007) and clinical stage (P < 0.001). Moreover, Kaplan-Meier survival analysis showed that patients with low miR-24-3p level had a significantly poorer prognosis than those with high miR 24-3p level (P < 0.001). Multivariate analysis revealed that miR-24-3p (HR 2.767; 95 % CI 1.203-6.364; P = 0.017) and clinical TNM stage (HR 0.456; 95 % CI 0.212 0.978; P = 0.044) could be independent prognostic indicators for overall survival rates of CRC patients. In addition, functional assays showed that over-expression of miR-24-3p suppressed CRC cell proliferation, cell migration and invasion. miR 24-3p functions as a tumor suppressor in CRC. Down-regulation of miR-24-3p contributes to the development and progression of CRC and may have a potential role in prognosis and therapy. PMID- 25502081 TI - Protective effect of ulinastatin in patients with non-small cell lung cancer after radiation therapy: a randomized, placebo-controlled study. AB - Radiation-induced lung injury (RILI) is a frequent, sometimes life-threatening complication of radiation therapy for the treatment of lung cancer. The anti inflammatory role of ulinastatin has been well documented, and the potential application of ulinastatin in management of acute lung injury has been suggested in multiple animal studies. In this article, we described a double-blind, randomized, placebo-controlled study in patients with non-small cell lung cancer. A total of 120 patients were randomized into two groups: the trial group was treated with ulinastatin for 3 days prior to and for the first 7 days of radiation therapy and the control group was treated with placebo for 10 days following the same schedule. The results from follow-up studies showed that the incidence and grade of RILI were significantly lower in the trial group than in the control group. Reduction in pulmonary function from baseline was significantly smaller in the trial group than that in the control group. Production of serum TGF-beta1, TNF-alpha and IL-6 decreased significantly in the trial group promptly following radiation therapy. However, no difference in survival or tumour response rate was found between the two groups. The results indicated that ulinastatin exerted a protective effect on radiation-induced lung injury. Treatment with ulinastatin could be an effective management strategy and greatly improve the clinical efficacy of radiation therapy for patients with lung cancer. PMID- 25502082 TI - B-Myb regulates snail expression to promote epithelial-to-mesenchymal transition and invasion of breast cancer cell. AB - Breast cancer is the leading cause of cancer death in women worldwide, which is closely related to metastasis. Recent studies argue that breast cancer cells that have undergone epithelial-to-mesenchymal transition (EMT) acquire aggressive malignant properties, but the molecular mechanisms underlying this transition are poorly understood. In this study, we found that siRNA-mediated attenuation of B Myb expression restored E-cadherin expression and cell-cell junction formation in breast cancer cells, suppressing cell invasion, anchorage-independent growth, and tumor formation. In contrast, the forced B-Myb expression decreased the expression of the epithelial marker E-cadherin, but increased the mesenchymal markers in breast cancer cells. We found that B-Myb upregulated expression of the key EMT regulator snail and that it mediated EMT activation and cell invasion by B-Myb. PMID- 25502083 TI - Gene expression profile analysis identifies metastasis and chemoresistance associated genes in epithelial ovarian carcinoma cells. AB - The purpose of this study was to identify genes that associated with higher ability of metastasis and chemotherapic resistance in epithelial ovarian carcinoma (EOC) cells. An oligonucleotide microarray with probe sets complementary to 41,000(+) unique human genes and transcripts was used to determine whether gene expression profile may differentiate three epithelial ovarian cell lines (RMG-I-C, COC1 and HO8910) from their sub-lines (RMG-I-H, COCI/DDP and HO8910/PM) with higher ability of metastasis and chemotherapic resistance. Quantitative real-time PCR and immunohistochemical staining validated the microarray results. Hierarchic cluster analysis of gene expression identified 49 genes that exhibited >=2.0-fold change and P value <=0.05. Highly differential expression of GCET2, NLRP4, FOXP1 and SNX29 genes was validated by quantitative PCR in all cell line samples. Finally, FOXP1 was validated at the protein level by immunohistochemistry in paraffin embedded ovarian tissues (i.e., for metastasis, 15 primary EOC and 10 omental metastasis [OM]; for chemoresistance, 13 sensitive and 13 resistant EOC). The identification of higher ability of metastasis and chemotherapic resistance-associated genes may provide a foundation for the development of new type-specific diagnostic strategies and treatment for metastasis and chemotherapic resistance in epithelial ovarian cancer. PMID- 25502084 TI - The downregulation of miR-200c/141 promotes ZEB1/2 expression and gastric cancer progression. AB - Gastric cancer is the fourth most common malignancy in the world. Although microRNA-200 (miR-200) family members are thought to play roles in tumorigenesis, their functions in carcinogenesis are tumor specific, and the underlying mechanism of action still remains elusive. Few studies to date have addressed the dysregulation and function of miR-200 family members in gastric cancer progression. Here, we report that the miR-200 family members, miR-200c and miR 141, were significantly downregulated in gastric cancer specimens and gastric cancer cell lines. Importantly, on clinical samples, the expression of miR-200c and miR-141 was inversely correlated with TNM stage, tumor invasion depth (T), tumor embolus and disease-free survival. Wound-healing assay results showed that co-transfected miR-200c/141 could inhibit the migration and invasion capability of the gastric cell line SGC-7901. We also found that miR-200c and miR-141 directly targeted zinc finger E-box-binding homeobox 1/2 (ZEB1/2) and upregulated E-cadherin expression. In specimens from gastric cancer patients, reduced expression of miR-200c/141 was associated with increased expression of ZEB1 and/or ZEB2. In addition, the downregulation of miR-200c and miR-141 was found to be due to a highly methylated CpG island located upstream of their genomic sequence and/or upregulated TGF-beta signaling. Treatment with the chemotherapeutic agent decitabine, a known DNA methyltransferase inhibitor, increased miR-200c/141 expression and ameliorated decreased expression of miR 200c/141 induced by TGF-beta in SGC-7901 cells. Our study revealed that miR 200c/141 was downregulated by CpG island methylation and TGF-beta signaling, which decreased ZEB1/2 expression and increased E-cadherin expression to inhibit migration and invasion of gastric cancer cells and provides powerful evidence for the application of decitabine in gastric cancer treatment. PMID- 25502085 TI - Utility and cost-effectiveness of screening for hepatocellular carcinoma in a resource-limited setting. AB - The utility, efficacy and cost-effectiveness of establishing a prospective screening program for hepatocellular carcinoma (HCC) in a low-cost setting as Egypt has not been previously studied. Eligible patients in this observational study were screened by ultrasound and alpha-fetoprotein (AFP) every 6 months. A focal lesion on ultrasound or AFP >200 ng/ml or significant increase in 6 months indicated a recall. Characteristics of cases detected on screening were compared to patients diagnosed outside the screening program. Of 1,920 eligible patients, 1,286 patients participated and 102 patients (7.9 %) developed HCC, with an annual incidence of 5.3 %. Ninety-one (89.2 %) were BCLC stage 0 or A and 11 (10.8 %) stage D. Ultrasound detected a hepatic focal lesion in 99 patients, of which 74 were confirmed to be HCC, and AFP added another 28 HCC cases. The annual cost of detecting a treatable HCC case by ultrasound was 3,980 EGP ( 400) and by both ultrasound and AFP 4,645 EGP ( 500). Adding the cost of treatment, the cost/quality-adjusted life year (QALY) gained was 7,907 EGP ( 800)/QALY for screening with ultrasound only, and 8,430 EGP ( 850)/QALY for using both ultrasound and AFP, which in both cases is <50 % of the per capita GDP and <20 % of the accepted cost/QALY for Egypt. Screening for HCC is feasible and is highly cost-effective in a resource-limited setting. Adding AFP to ultrasound increased detection with a trivial addition to cost/QALY. PMID- 25502086 TI - Overexpression of cyclin D1 in meningioma is associated with malignancy grade and causes abnormalities in apoptosis, invasion and cell cycle progression. AB - Cyclin D1 has been reported overexpressed in many malignant cancers. However, the expression pattern and biological function of cyclin D1 in meningiomas are still unknown. In this study, we examined the expression of cyclin D1 in meningioma with immunohistochemistry and correlated the measure to the recurrence. Potential effects of cyclin D1 on tumor growth and apoptosis were also examined in representative cell lines (IOMM-Lee and CH157) by inhibiting cyclin D1 with RNA interference. We demonstrate that cyclin D1 mRNA and protein expression are positively correlated with meningioma grade and that higher cyclin D1 expression correlates with higher recurrence. Knockdown of cyclin D1 by the siRNA decreased IOMM-Lee and CH157 cell proliferation, promoted the rate of apoptosis and attenuated invasive capacity. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot analysis revealed that cells stably underexpressing cyclin D1 showed lower expression of survivin and the antiapoptotic protein B cell lymphoma-2 (Bcl-2) compared to control cells. These results indicate that high cyclin D1 expression is associated with a poor outcome of meningioma patients and knockdown of cyclin D1 expression may be a potential treatment for malignant meningioma. PMID- 25502087 TI - The role of BRAF mutation in patients with high-risk malignant melanoma treated with high-dose adjuvant interferon therapy. AB - Data regarding the prognostic importance of BRAFV600 tumor mutations in high risk, non-metastatic, stage 2 and 3 malignant melanoma (MM) patients are controversial. There is not sufficient information in the medical literature regarding the reliability of BRAF mutations as a predictive factor in prognosis and adjuvant treatment decision issues in this patient group. The data of 50 operated high-risk, non-metastatic, stage 2B/2C and 3 MM patients who received high-dose interferon alfa-2b therapy were evaluated retrospectively. BRAF mutations were analyzed by using microarray-based molecular methods. The associations between BRAF mutations and both clinicopathological characteristics and survival were assessed. Of the 50 patients, 52 % was female and 48 % was male, and the median age was 51.5 years. Twenty-three (46 %) and 27 (54 %) patients had stage 2B/2C and stage 3 disease, respectively. BRAF mutation was detected in 21 patients. The median overall survival (OS) was 58.1 months, whereas the median disease-free survival (DFS) was 22.7 months. When the OS and DFS were compared according to the BRAF mutation status, no difference was detected between the two groups. BRAF mutations were detected more frequently in tumors with mitosis and ulceration; however, no statistically significant difference was observed in other clinicopathological parameters. In conclusion, it is not appropriate to use BRAF mutations as a prognostic and predictive marker for selecting the treatment and assessing its outcomes in patients with early stage, high-risk MM. PMID- 25502089 TI - Anorectal malignant melanoma: retrospective analysis of management and outcome in a single Portuguese Institution. AB - Anorectal melanoma is an uncommon cancer with a poor prognosis. We aim to describe the clinical presentation, treatment and outcome of patients with anorectal melanoma in our center. Retrospective study of patients with anorectal melanoma treated between 2000 and 2011 at a cancer center in Lisbon. Ten patients were identified, eight females and two males, with median age 70.5 years (32-79). Symptoms at presentation were rectal bleeding (8), anal pain (4) and discomfort (3). Tumor location was anal (6), rectal (3) and anorectal transition (2). Seven patients had surgery: abdomino-pelvic resection (5) and local resection (2). Among the two patients who underwent local resection, one was an incidental finding in a hemorrhoidectomy specimen. This patient had further adjuvant chemotherapy (dacarbazine). Three patients had distant metastasis at diagnosis, one had chemotherapy and two had best supportive care. Six of the seven operated patients relapsed in a median time of 5.4 months: distant metastasis (4), local recurrence (1), both (1). The two local relapse patients had surgical widening of resection margins (1) and radiotherapy (2). One-year survival was 30 %; 3-year survival was 20 %. Anorectal melanoma has a poor prognosis due to advanced disease at presentation and aggressive course, with relapse in almost all operated patients. Treatment guidelines have not been established due to the lack of randomized studies. However, recent studies show that sphincter-sparing surgical procedures along with low dose intensity radiotherapy seem to achieve a local control similar to abdomino-pelvic resection. No systemic therapy is considered standard of care for advanced disease, and regimens are extrapolated from cutaneous melanoma experience. PMID- 25502088 TI - Impact of bevacizumab on survival outcomes in primary tumor resected metastatic colorectal cancer. AB - We have studied the efficacy of bevacizumab in colorectal cancer with unresectable metastasis patients who had undergone resection of primary tumor. The patients with unresectable metastasis during diagnosis who had undergone resection of primary tumor without chemotherapy and the patients without resection of primary tumor were included. Among patients who had met the inclusion criteria, 46 patients with resection of primary tumor and 47 without resection of primary tumor were included in the study. A total of 93 unresectable metastatic colorectal cancer patients were included in the study. Median PFS was 9 months (95 % CI 7.37-10.62) in patients with resected primary tumor and bevacizumab containing first-line chemotherapy combination. Median PFS was 10 months (95 % CI 8.06-11.93) in patients without bevacizumab (P = 0.66) Median OS was 25 months (95 % CI 17.92-32.07) in patients with resected primary tumor and bevacizumab containing first-line chemotherapy combination. Median OS was 16 months (95 % CI 9.71-22.28) in patients without bevacizumab (P = 0.36) Median OS was 16 months (95 % CI 13.06-8.939) in patients without resected primary tumor and bevacizumab containing first-line chemotherapy combination. Median OS was 9 months (95 % CI 1.48-16.51) in patients without bevacizumab (P = 0.012). Bevacizumab seems ineffective in mCRC patients with resected primary tumor. An increase in number of retrospective literature data and randomized, prospective studies is required about this subject. PMID- 25502090 TI - The unfolded protein response potentiates epithelial-to-mesenchymal transition (EMT) of gastric cancer cells under severe hypoxic conditions. AB - The hypoxic condition occurs in most types of solid tumors and has been shown to be associated with the metastatic ability of gastric cancer. A previous study has demonstrated that hypoxia might stimulate epithelial-to-mesenchymal transition (EMT) of gastric cancer cells. Nevertheless, the mechanism has not yet been completely understood. In the current study, the human gastric cancer cell lines HGC27 and MGC803 were presented to normoxic (21 % O2), hypoxic (1 % O2) or severe hypoxic (0.1 % O2) conditions for 24 h. We found that hypoxia exposure induced EMT of gastric cancer cells, which was promoted by severe hypoxia condition. Meanwhile, expressions of PERK, ATF4 and ATF6 proteins were elevated in cells under conditions of severe hypoxia but not by normoxia or hypoxia. Knockdown of PERK, ATF4 or ATF6 impeded EMT of gastric cancer cells induced by severe hypoxia. Furthermore, severe hypoxia exposure extremely boosted the expression of TGF beta, which was blocked by the knockdown of PERK, ATF4 or ATF6 expression. Additionally, we found that TGF-beta release caused by hypoxia is facilitated by elevated UPR proteins and led to the activation of Smad2/3 and PI3K/Akt signaling. Our data suggest that UPR potentiates the EMT of gastric cancer cells under conditions of severe hypoxia. PMID- 25502091 TI - Gaps between patients' reported current and preferred abilities versus clinicians' emphases during an episode of care: any agreement? AB - PURPOSE: To be patient-centered, assessment must extract what patients prefer to be able to do along with what they can do now so health care can specifically address the gap between current and preferred abilities. In this project, we compared patient-perceived current-preferred gaps with the assessments and interventions reported by clinicians in a rehabilitation clinic. METHODS: Sixty two patients in outpatient physical therapy completed a computer-adaptive test version of the patient-reported Movement Ability Measure (MAM-CAT) at initial visit and discharge. The MAM-CAT calculated the gaps between the movement patients perceived that they could do "Now" and what movement ability they "Would Like" to have across six dimensions of movement: flexibility, strength, accuracy, speed, adaptability, and endurance. Physical therapists' notes regarding assessments and interventions were categorized based on these same six dimensions of movement. Frequency of agreement between the largest patient-perceived gaps and clinician-documented emphases was recorded (kappa analyses), along with MAM CAT changes at discharge (paired t tests). RESULTS: Although patient progress was noted in both the MAM-CAT and the clinician notes (p < .05), comparison showed poor or slight agreement (kappa < .05) between the specific movement dimensions patients regarded as having the largest gaps and the dimensions on which clinicians focused. CONCLUSION: The MAM-CAT facilitated direct comparison of patients' current-preferred gaps at initiation and discharge with clinicians' emphases during episodes of care. While interventions were perceived as effective, collaboration between patients and clinicians using gap data could increase alignment between patient priorities and clinician emphases, potentially resulting in improved patient engagement and rehabilitative outcomes. PMID- 25502093 TI - Ten big mistakes in intensive care medicine. PMID- 25502094 TI - Isolation in patients with Ebola virus disease. PMID- 25502092 TI - Role functioning is associated with survival in patients with hepatocellular carcinoma. AB - BACKGROUND: Prior studies assessing quality of life (QOL) in patients with hepatocellular carcinoma (HCC) primarily included patients with preserved liver function and/or early HCC, leading to overestimation of QOL. Our study's aim was to evaluate the association of QOL with survival among a cohort of cirrhotic patients with HCC that was diverse with respect to liver function and tumor stage. METHODS: We conducted a prospective cohort study among cirrhotic patients with HCC from a large urban safety-net hospital between April 2011 and September 2013. Patients completed two self-administered surveys, the EORTC QLQ-C30 and QLQ HCC18, prior to the treatment. We used generalized linear models to identify correlates of QOL. Survival curves were generated using Kaplan-Meier analysis and compared using log rank test to determine whether QOL is associated with survival. RESULTS: A total of 130 treatment-naive patients completed both surveys. Patients reported high cognitive and social function (median scores 67) but poor global QOL (median score 50) and poor role function (median score 50). QOL was associated with cirrhosis-related (p = 0.02) and tumor-related (p = 0.02) components of Barcelona Clinic Liver Cancer (BCLC) tumor stage. QOL was associated with survival on univariate analysis (HR 0.37, 95 % CI 0.16-0.85) but became nonsignificant (HR 0.82, 95 % CI 0.37-1.80) after adjusting for BCLC stage and treatment. Role functioning was significantly associated with survival (HR 0.40, 95 % CI 0.20-0.81), after adjusting for Caucasian race (HR 0.31, 95 % CI 0.16-0.59), BCLC stage (HR 1.51, 95 % CI 0.21-1.89), and treatment (HR 0.57, 95 % CI 0.33-0.97). CONCLUSIONS: Role function has prognostic significance and is important to assess in patients with HCC. PMID- 25502095 TI - Response to the paper by Demirkol et al. entitled 'The effect of age on right ventricular diastolic function parameters'. PMID- 25502096 TI - Coexistence of superconductivity and antiferromagnetism in (Li0.8Fe0.2)OHFeSe. AB - Iron selenide superconductors exhibit a number of unique characteristics that are helpful for understanding the mechanism of superconductivity in high-Tc iron based superconductors more generally. However, in the case of AxFe2Se2 (A = K, Rb, Cs), the presence of an intergrown antiferromagnetic insulating phase makes the study of the underlying physics problematic. Moreover, FeSe-based systems intercalated with alkali metal ions, NH3 molecules or organic molecules are extremely sensitive to air, which prevents the further investigation of their physical properties. It is therefore desirable to find a stable and easily accessible FeSe-based superconductor to study its physical properties in detail. Here, we report the synthesis of an air-stable material, (Li0.8Fe0.2)OHFeSe, which remains superconducting at temperatures up to ~40 K, by means of a novel hydrothermal method. The crystal structure is unambiguously determined by a combination of X-ray and neutron powder diffraction and nuclear magnetic resonance. Moreover, antiferromagnetic order is shown to coexist with superconductivity. This synthetic route opens a path for exploring superconductivity in other related systems, and confirms the appeal of iron selenides as a platform for understanding superconductivity in iron pnictides more broadly. PMID- 25502098 TI - Valley-selective optical Stark effect in monolayer WS2. AB - Breaking space-time symmetries in two-dimensional crystals can markedly influence their macroscopic electronic properties. Monolayer transition metal dichalcogenides (TMDs) are prime examples where the intrinsically broken crystal inversion symmetry permits the generation of valley-selective electron populations, even though the two valleys are energetically degenerate, locked by time-reversal symmetry. Lifting the valley degeneracy in these materials is of great interest because it would allow for valley-specific band engineering and offer additional control in valleytronic applications. Although applying a magnetic field should, in principle, accomplish this task, experiments so far have not shown valley-selective energy level shifts in fields accessible in the laboratory. Here, we show the first direct evidence of lifted valley degeneracy in the monolayer TMD WS2. By applying intense circularly polarized light, which breaks time-reversal symmetry, we demonstrate that the exciton level in each valley can be selectively tuned by as much as 18 meV through the optical Stark effect. These results offer a new way to control the valley degree of freedom, and may provide a means to realize new Floquet topological phases in two dimensional TMDs. PMID- 25502097 TI - Light-triggered in vivo activation of adhesive peptides regulates cell adhesion, inflammation and vascularization of biomaterials. AB - Materials engineered to elicit targeted cellular responses in regenerative medicine must display bioligands with precise spatial and temporal control. Although materials with temporally regulated presentation of bioadhesive ligands using external triggers, such as light and electric fields, have recently been realized for cells in culture, the impact of in vivo temporal ligand presentation on cell-material responses is unknown. Here, we present a general strategy to temporally and spatially control the in vivo presentation of bioligands using cell-adhesive peptides with a protecting group that can be easily removed via transdermal light exposure to render the peptide fully active. We demonstrate that non-invasive, transdermal time-regulated activation of cell-adhesive RGD peptide on implanted biomaterials regulates in vivo cell adhesion, inflammation, fibrous encapsulation, and vascularization of the material. This work shows that triggered in vivo presentation of bioligands can be harnessed to direct tissue reparative responses associated with implanted biomaterials. PMID- 25502099 TI - Negative capacitance in a ferroelectric capacitor. AB - The Boltzmann distribution of electrons poses a fundamental barrier to lowering energy dissipation in conventional electronics, often termed as Boltzmann Tyranny. Negative capacitance in ferroelectric materials, which stems from the stored energy of a phase transition, could provide a solution, but a direct measurement of negative capacitance has so far been elusive. Here, we report the observation of negative capacitance in a thin, epitaxial ferroelectric film. When a voltage pulse is applied, the voltage across the ferroelectric capacitor is found to be decreasing with time--in exactly the opposite direction to which voltage for a regular capacitor should change. Analysis of this 'inductance'-like behaviour from a capacitor presents an unprecedented insight into the intrinsic energy profile of the ferroelectric material and could pave the way for completely new applications. PMID- 25502100 TI - Soft 3D acoustic metamaterial with negative index. AB - Many efforts have been devoted to the design and achievement of negative refractive-index metamaterials since the 2000s. One of the challenges at present is to extend that field beyond electromagnetism by realizing three-dimensional (3D) media with negative acoustic indices. We report a new class of locally resonant ultrasonic metafluids consisting of a concentrated suspension of macroporous microbeads engineered using soft-matter techniques. The propagation of Gaussian pulses within these random distributions of 'ultra-slow' Mie resonators is investigated through in situ ultrasonic experiments. The real part of the acoustic index is shown to be negative (up to almost - 1) over broad frequency bandwidths, depending on the volume fraction of the microbeads as predicted by multiple-scattering calculations. These soft 3D acoustic metamaterials open the way for key applications such as sub-wavelength imaging and transformation acoustics, which require the production of acoustic devices with negative or zero-valued indices. PMID- 25502101 TI - P37 latency mismatch between lateral and midline potentials is influenced by transversal afference. AB - SUMMARY: P37 cortical peak latency registered on Ci' (lateral) is usually approximately 1 millisecond shorter than Cz' (midline) in lower limb somatosensory evoked potential. At the present time, the underlying mechanism that leads to this mismatch remains unknown. Superficial peroneal nerve, posttibial nerve, and sural nerve somatosensory evoked potentials were obtained from 26 anesthetized individuals by using Ci'-Cc', Cc'-Fpz, and Cz'-Fpz recording montages. P37 latency mismatches between the lateral (Ci'-Cc') and midline (Cz' Fpz) potentials (P < 0.001) were recorded in superficial peroneal nerve, posttibial nerve, and sural nerve somatosensory evoked potentials; all showed shorter Ci'-Cc' P37 latency (1-1.7 milliseconds). However, in individuals who had minimal or no N37 potential on Cc' recording, the mean P37 latencies of Ci'-Cc' and Cz'-Fpz equalized with the P37 latency of Ci'-Cc' approaching to default Cz' Fpz value. The data showed that N37 seemed to potentiate the P37 latency difference between Ci-Cc' and Cz'-Fpz recordings. We postulate that N37 may preferentially reflect the dipoles of transversal afference; lack of it thereof suggests poor dipole sources primarily perpendicular to the mesial hemisphere. PMID- 25502103 TI - Mnemonic multiples: the case of the columbia panel studies. AB - This article uses the Bureau of Applied Social Research's mid-century book-length panel studies-The People's Choice (1944), Voting (1954), and Personal Influence (1955)-to identify and illustrate a neglected phenomenon in the remembered history of social science: mnemonic multiples. The article describes the way that the Bureau books, originally published into a post-World War II interdisciplinary social science milieu, have since come to be remembered along distinct disciplinary tracks by sociologists, political scientists, and communication researchers. A contextual analysis of references to the Bureau studies in the flagship journals of the three disciplines, from 1960 through 2011, provides tentative support for the mnemonic multiples concept. PMID- 25502102 TI - Effect of formulation variables on preparation of celecoxib loaded polylactide-co glycolide nanoparticles. AB - Polymer based nanoparticle formulations have been shown to increase drug bioavailability and/or reduce drug adverse effects. Nonsteroidal anti inflammatory drugs (e.g. celecoxib) reduce prostaglandin synthesis and cause side effects such as gastrointestinal and renal complications. The aim of this study was to formulate celecoxib entrapped poly lactide-co-glycolide based nanoparticles through a solvent evaporation process using didodecyldimethylammonium bromide or poly vinyl alcohol as stabilizer. Nanoparticles were characterized for zeta potential, particle size, entrapment efficiency, and morphology. Effects of stabilizer concentration (0.1, 0.25, 0.5, and 1% w/v), drug amount (5, 10, 15, and 20 mg), and emulsifier (lecithin) on nanoparticle characterization were examined for formula optimization. The use of 0.1, 0.25, and 0.5% w/v didodecyldimethylammonium bromide resulted in a more than 5-fold increase in zeta potential and a more than 1.5-fold increase in entrapment efficiency with a reduction in particle size over 35%, when compared to stabilizer free formulation. Nanoparticle formulations were also highly influenced by emulsifier and drug amount. Using 0.25% w/v didodecyldimethylammonium bromide NP formulations, peak zeta potential was achieved using 15 mg celecoxib with emulsifier (17.15+/-0.36 mV) and 20 mg celecoxib without emulsifier (25.00+/-0.18 mV). Peak NP size reduction and entrapment efficiency was achieved using 5 mg celecoxib formulations with (70.87+/-1.24 nm and 95.55+/-0.66%, respectively) and without (92.97+/-0.51 nm and 95.93+/-0.27%, respectively) emulsifier. In conclusion, formulations using 5 mg celecoxib with 0.25% w/v didodecyldimethylammonium bromide concentrations produced nanoparticles exhibiting enhanced size reduction and entrapment efficiency. Furthermore, emulsifier free formulations demonstrated improved zeta potential when compared to formulations containing emulsifier (p<0.01). Therefore, our results suggest the use of emulsifier free 5 mg celecoxib drug formulations containing 0.25% w/v didodecyldimethylammonium bromide for production of polymeric NPs that demonstrate enhanced zeta potential, small particle size, and high entrapment efficiency. PMID- 25502104 TI - Correlation of superparamagnetic relaxation with magnetic dipole interaction in capped iron-oxide nanoparticles. AB - Six nanometer sized iron-oxide nanoparticles capped with an organic surfactant and/or silica shell of various thicknesses have been synthesized by a microemulsion method to enable controllable contributions of interparticle magnetic dipole interaction via tunable interparticle distances. Bare particles with direct surface contact were used as a reference to distinguish between interparticle interaction and surface effects by use of Mossbauer spectroscopy. Superparamagnetic relaxation behaviour was analyzed by SQUID-magnetometry techniques, showing a decrease of the blocking temperature with decreasing interparticle interaction energies kBT0 obtained by AC susceptibility. A many state relaxation model enabled us to describe experimental Mossbauer spectra, leading to an effective anisotropy constant Keff ~ 45 kJm(-3) in case of weakly interacting particles, consistent with results from ferromagnetic resonance. Our unique multi-technique approach, spanning a huge regime of characteristic time windows from about 10 s to 5 ns, provides a concise picture of the correlation of superparamagnetic relaxation with interparticle magnetic dipole interaction. PMID- 25502105 TI - Genetically predicted testosterone and electrocardiographic QT interval duration in Chinese: a Mendelian randomization analysis in the Guangzhou Biobank Cohort Study. AB - BACKGROUND: QT interval prolongation, a predictor of cardiac arrhythmias, and elevated heart rate are associated with higher risk of cardiovascular mortality. Observationally testosterone is associated with shorter corrected QT interval and slower heart rate; however, the evidence is open to residual confounding and reverse causality. We examined the association of testosterone with electrocardiogram (ECG) parameters using a separate-sample instrumental variable (SSIV) estimator. METHODS: To minimize reverse causality, a genetic score predicting testosterone was developed in 289 young Chinese men from Hong Kong, based on a parsimonious set of single nuclear polymorphisms (rs10046, rs1008805 and rs1256031). Linear regression was used to examine the association of genetically predicted testosterone with QT interval, corrected QT interval [using the Framingham formula (QTf) and Bazett formula (QTb)] and heart rate in 4212 older (50+ years) Chinese men from the Guangzhou Biobank Cohort Study. RESULTS: Predicted testosterone was not associated with QT interval [-0.08 ms per nmol/l testosterone, 95% confidence interval (CI) -0.81 to 0.65], QTf interval (0.40 ms per nmol/l testosterone, 95% CI -0.12 to 0.93) or heart rate (0.26 beats per minute per nmol/l testosterone, 95% CI -0.04 to 0.56), but was associated with longer QTb interval (0.66 ms per nmol/l testosterone, 95% CI 0.02 to 1.31). CONCLUSIONS: Our findings do not corroborate observed protective associations of testosterone with QT interval or heart rate among men, but potentially suggest effects in the other direction. Replication in a larger sample is required. PMID- 25502106 TI - Risk factors for pancreatic cancer: a summary review of meta-analytical studies. AB - BACKGROUND: The aetiology of pancreatic cancer (PC) has been extensively studied and is the subject of numerous meta-analyses and pooled analyses. We have summarized results from these pooled and meta-analytical studies to estimate the fraction of PCs attributable to each of the identified risk factors. METHODS: Using a comprehensive strategy, we retrieved 117 meta-analytical or pooled reports dealing with the association between specific risk factors and PC risk. We combined estimates of relative risk and estimates of exposure to calculate the fraction of PCs caused or prevented by a particular exposure. RESULTS: Tobacco smoking ('strong' evidence) and Helicobacter pylori infection ('moderate' evidence) are the major risk factors associated with PC, with respective estimated population attributable fractions of 11-32% and 4-25%. The major protective factors are history of allergy ('strong' evidence) and increasing fruit or folate intake ('moderate' evidence), with respective population preventable fractions of 3-7% and 0-12%. CONCLUSIONS: We summarized results of 117 meta-analytical or pooled data reports dealing with 37 aetiological exposures, to obtain robust information about the suspected causes of PC. By combining these estimates with their prevalences in the population, we calculated population attributable or population preventable fractions. About two-thirds of the major risk factors associated with PC are potentially modifiable, affording a unique opportunity for preventing one of our deadliest cancers. PMID- 25502107 TI - Cohort Profile: LifeLines, a three-generation cohort study and biobank. AB - The LifeLines Cohort Study is a large population-based cohort study and biobank that was established as a resource for research on complex interactions between environmental, phenotypic and genomic factors in the development of chronic diseases and healthy ageing. Between 2006 and 2013, inhabitants of the northern part of The Netherlands and their families were invited to participate, thereby contributing to a three-generation design. Participants visited one of the LifeLines research sites for a physical examination, including lung function, ECG and cognition tests, and completed extensive questionnaires. Baseline data were collected for 167 729 participants, aged from 6 months to 93 years. Follow-up visits are scheduled every 5 years, and in between participants receive follow-up questionnaires. Linkage is being established with medical registries and environmental data. LifeLines contains information on biochemistry, medical history, psychosocial characteristics, lifestyle and more. Genomic data are available including genome-wide genetic data of 15 638 participants. Fasting blood and 24-h urine samples are processed on the day of collection and stored at -80 degrees C in a fully automated storage facility. The aim of LifeLines is to be a resource for the national and international scientific community. Requests for data and biomaterials can be submitted to the LifeLines Research Office [LLscience@umcg.nl]. PMID- 25502108 TI - Monocytes regulate systemic coagulation and inflammation in abdominal sepsis. AB - Abdominal sepsis is associated with significant changes in systemic inflammation and coagulation. The purpose of the present study was to examine the role of peripheral blood monocytes for systemic coagulation, including thrombin generation and consumption of coagulation factors. Abdominal sepsis was induced by cecal ligation and puncture (CLP) in C57BL/6 mice. Plasma and lung levels of IL-6 and C-X-C motif (CXC) chemokines [chemokine CXC ligand (CXCL)1, CXCL2, and CXCL5], pulmonary activity of myeloperoxidase, thrombin generation, and coagulation factors were determined 6 h after CLP induction. Administration of clodronate liposomes decreased circulating levels of monocytes by 96%. Time to peak thrombin formation was increased and peak and total thrombin generation was decreased in plasma from CLP animals. Monocyte depletion decreased time to peak formation of thrombin and increased peak and total generation of thrombin in septic animals. In addition, monocyte depletion decreased the CLP-induced increase in the levels of thrombin-antithrombin complexes in plasma. Depletion of monocytes increased plasma levels of prothrombin, factor V, factor X, and protein C in septic mice. Moreover, depletion of monocytes decreased CLP-induced levels of IL-6 and CXC chemokines in the plasma and lung by >59% and 20%, respectively. CLP-induced myeloperoxidase activity in the lung was attenuated by 44% in animals depleted of monocytes. Taken together, our findings show, for the first time, that peripheral blood monocytes regulate systemic coagulation. The results of our study improve our understanding of the pathophysiology of sepsis and encourage further attempts to target innate immune cell functions in abdominal sepsis. PMID- 25502109 TI - The complex distribution of arterial system mechanical properties, pulsatile hemodynamics, and vascular stresses emerges from three simple adaptive rules. AB - Arterial mechanical properties, pulsatile hemodynamic variables, and mechanical vascular stresses vary significantly throughout the systemic arterial system. Although the fundamental principles governing pulsatile hemodynamics in elastic arteries are widely accepted, a set of rules governing stress-induced adaptation of mechanical properties can only be indirectly inferred from experimental studies. Previously reported mathematical models have assumed mechanical properties adapt to achieve an assumed target stress "set point." Simultaneous prediction of the mechanical properties, hemodynamics, and stresses, however, requires that equilibrium stresses are not assumed a priori. Therefore, the purpose of this work was to use a "balance point" approach to identify the simplest set of universal adaptation rules that simultaneously predict observed mechanical properties, hemodynamics, and stresses throughout the human systemic arterial system. First, we employed a classical systemic arterial system model with 121 arterial segments and removed all parameter values except vessel lengths and peripheral resistances. We then assumed vessel radii increase with endothelial shear stress, wall thicknesses increase with circumferential wall stress, and material stiffnesses decrease with circumferential wall stress. Parameters characterizing adaptive responses were assumed to be identical in all arterial segments. Iteratively predicting local mechanical properties, hemodynamics, and stresses reproduced five trends observed when traversing away from the aortic root towards the periphery: decrease in lumen radii, wall thicknesses, and pulsatile flows and increase in wall stiffnesses and pulsatile pressures. The extraordinary complexity of the systemic arterial system can thus arise from independent adaptation of vessels to local stresses characterized by three simple adaptive rules. PMID- 25502112 TI - Thiourea dioxide as a unique eco-friendly coreactant for luminol chemiluminescence in the sensitive detection of luminol, thiourea dioxide and cobalt ions. AB - Thiourea dioxide, a green industrial reductant, has been explored as an efficient chemiluminescence coreactant for the first time. Luminol-thiourea dioxide chemiluminescence can be significantly enhanced by Co(2+). This system enables the sensitive detection of thiourea dioxide, luminol and Co(2+), being particularly selective for Co(2+) detection. PMID- 25502110 TI - Dual regulation of tumor necrosis factor-alpha on myosin light chain phosphorylation in vascular smooth muscle. AB - We previously demonstrated that inhibitor kappaB kinase 2 (IKK2) is a myosin light chain kinase (MLCK). In the present study, we assess whether the prototypical activator of IKK2 tumor necrosis factor-alpha (TNF-alpha) regulates the MLCK activity of IKK2 and thus MLC phosphorylation in vascular smooth muscle cells (VSMCs). Kinase activity assay revealed that TNF-alpha downregulated the MLCK activity of IKK2 in human VSMCs (HVSMCs). However, Western blot analysis did not demonstrate a significant effect of TNF-alpha on MLC phosphorylation in HVSMCs, and myograph analysis did not reveal a significant effect of TNF-alpha on the contraction of the aorta from Sprague-Dawley rats and C57Bl/6j mice, suggesting a dual regulation of MLC phosphorylation by TNF-alpha. Confirming this notion, TNF-alpha significantly increased MLC phosphorylation in IKK2(-/-) but not wild-type cells. Furthermore, our results show that TNF-alpha increased GTP bound RhoA and MLC phosphatase subunit MYPT1 phosphorylation and markedly reduced MLC phosphorylation in the presence of Rho-kinase inhibitor Y-27632, suggesting that downregulation of MLCK activity of IKK2 by TNF-alpha is antagonized by simultaneous RhoA/Rho-kinase activation. These results indicate that TNF-alpha dually regulates MLC phosphorylation through both IKK2 and RhoA/Rho-kinase pathways. PMID- 25502111 TI - Glutamatergic receptor dysfunction in spinal cord contributes to the exaggerated exercise pressor reflex in heart failure. AB - Excitatory amino acids (e.g., glutamate) released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR) in physiological conditions. However, the role of glutamate and glutamate receptors in mediating the exaggerated EPR in the chronic heart failure (CHF) state remains to be determined. In the present study, we performed microinjection of glutamate receptor antagonists into ipisilateral L4/L5 dorsal horns to investigate their effects on the pressor response to static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots in decerebrate sham-operated (sham) and CHF rats. Microinjection of glutamate (10 mM, 100 nl) into the L4 or L5 dorsal horn caused a greater pressor response in CHF rats compared with sham rats. Furthermore, microinjection of either the broad-spectrum glutamate receptor antagonist kynurenate (10 mM, 100 nl) or the N-methyl-d-aspartate (NMDA) receptor antagonist dl-2-amino-5-phosphonovalerate (50 mM, 100 nl) or the non-NMDA sensitive receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (5 mM, 100 nl) into L4/5 dorsal horns decreased the pressor response to static contraction in CHF rats to a greater extent than in sham rats. Molecular evidence showed that the protein expression of glutamate receptors (both non-NMDA and NMDA) was elevated in the dorsal horn of the lumbar spinal cord in CHF rats. In addition, data from microdialysis experiments demonstrated that although basal glutamate release at the dorsal horn at rest was similar between sham and CHF rats (225 +/- 50 vs. 260 +/- 63 nM in sham vs. CHF rats, n = 4, P > 0.05), CHF rats exhibit greater glutamate release into the dorsal horn during muscle contraction compared with sham rats (549 +/- 60 vs. 980 +/- 65 nM in sham vs. CHF rats, n = 4, P < 0.01). These data indicate that the spinal glutamate system contributes to the exaggerated EPR in the CHF state. PMID- 25502113 TI - Potential of human induced pluripotent stem cells in studies of liver disease. AB - Liver disease is a leading cause of death in the Western world. However, our insight into the underlying disease mechanisms and the development of novel therapeutic agents has been hindered by limited availability of primary tissue, intraspecies variability associated with the use of animal models, and reduced long-term viability of isolated and diseased liver cells. The emergence of human induced pluripotent stem cells and differentiation protocols to generate hepatocyte-like cells has opened the possibility of addressing these issues. Here, we discuss the recent progress and potential in the production of various cell types constituting the liver and their applications to model liver diseases and test drug toxicity in vitro. PMID- 25502114 TI - Primary aldosteronism and salt. AB - For many years, primary aldosteronism was thought (and taught) to be a relatively rare (< 1 %) and benign form of high blood pressure: now we know that neither is the case. Currently, the prevalence is considered to be 5-10 % of hypertensives, on the basis of more or less stringent cutoffs for the aldosterone/renin ratio and plasma aldosterone concentration: increasingly, evidence is mounting that the true prevalence of (relatively) autonomous aldosterone secretion may be ~ 30 % of hypertensives. There is, in addition, a consensus that the risk profile for patients with primary aldosteronism is substantially higher than in age-, sex-, and blood pressure-matched essential hypertensives; the cardiovascular/renal damage in primary aldosteronism is thus not a primary effect of raised blood pressure. The nexus between salt and primary aldosteronism is clear, as equivalently raised or even higher levels of plasma aldosterone in chronic sodium deficiency are homeostatic and do not cause cardiovascular damage, thus ruling out deleterious effects of aldosterone acting alone. In primary aldosteronism the normal homeostatic feedback loops between sodium status and aldosterone levels are disturbed, so that cardiovascular/renal damage reflects inappropriate aldosterone levels for sodium status. One possible actor in such a scenario is endogenous ouabain (or similar compounds), which is elevated in the sodium-loaded state and a vasoconstrictor, and thus potentially be able both to raise blood pressure and to cause cardiovascular/renal damage. A second consideration is that of the epidemiologic data linking a chronically high salt intake to a raised blood pressure. If autonomous aldosterone secretion is in fact present in ~ 30 % of hypertensives, this may be the group sensitive to the pressor effects of high salt, with the remainder much less affected. Finally, at a practical level given even the currently accepted prevalence of primary aldosteronism, a radical reconsideration of first-line antihypertensive therapy is proposed. PMID- 25502116 TI - [Patient safety through risk management]. PMID- 25502117 TI - Graphene-based transition metal oxide nanocomposites for the oxygen reduction reaction. AB - The development of low cost, durable and efficient nanocatalysts to substitute expensive and rare noble metals (e.g. Pt, Au and Pd) in overcoming the sluggish kinetic process of the oxygen reduction reaction (ORR) is essential to satisfy the demand for sustainable energy conversion and storage in the future. Graphene based transition metal oxide nanocomposites have extensively been proven to be a type of promising highly efficient and economic nanocatalyst for optimizing the ORR to solve the world-wide energy crisis. Synthesized nanocomposites exhibit synergetic advantages and avoid the respective disadvantages. In this feature article, we concentrate on the recent leading works of different categories of introduced transition metal oxides on graphene: from the commonly-used classes (FeOx, MnOx, and CoOx) to some rare and heat-studied issues (TiOx, NiCoOx and Co MnOx). Moreover, the morphologies of the supported oxides on graphene with various dimensional nanostructures, such as one dimensional nanocrystals, two dimensional nanosheets/nanoplates and some special multidimensional frameworks are further reviewed. The strategies used to synthesize and characterize these well-designed nanocomposites and their superior properties for the ORR compared to the traditional catalysts are carefully summarized. This work aims to highlight the meaning of the multiphase establishment of graphene-based transition metal oxide nanocomposites and its structural-dependent ORR performance and mechanisms. PMID- 25502115 TI - Salt feedback on the renin-angiotensin-aldosterone system. AB - The renin-angiotensin-aldosterone system (RAAS) is a central element in the control of the salt and water balance of the body and arterial blood pressure. The activity of the RAAS is controlled by the protease renin, which is released from renal juxtaglomerular epithelioid cells (JGE cells) into the circulation. Renin release is regulated by a complex interplay of several locally acting hormones or mechanisms and longer feedback loops one of which involves salt intake. Acute NaCl loads or longer lasting high salt intakes suppress plasma renin activity, whereas reductions in NaCl intake stimulate it. Because the activation of the RAAS conserves the salt content of the body, a classical feedback loop between salt intake/body salt content and renin is established. Despite of its important role for body fluid homeostasis, the precise signaling pathways connecting salt intake with the synthesis and release of renin are only incompletely understood. Four putative controllers of the salt-dependent regulation of the RAAS have been suggested: (1) the macula densa mechanism which adjusts renin release in response to changes in the renal tubular salt concentration; (2) salt-dependent changes in the arterial blood pressure; (3) circulating salt-dependent hormones, particularly the atrial natriuretic peptide (ANP); and (4) renal sympathetic nervous activity, which is regulated by extracellular volume and arterial blood pressure. In this review, the role of these known controllers of the RAAS will be discussed with special emphasis on their relative contributions to the salt-dependent regulation of the RAAS at different time frames. PMID- 25502118 TI - The optimal pallidal target in deep brain stimulation for dystonia: a study using a functional atlas based on nonlinear image registration. AB - BACKGROUND: Deep brain stimulation (DBS) of the globus pallidus internus is established as efficacious for dystonia, yet the optimal target within this structure is not well defined. Published evidence suggests that spatial normalization provides a better estimate of DBS lead location than traditional methods based on standard stereotactic coordinates. METHODS: We retrospectively reviewed our pallidal implanted dystonia population. Patient imaging scans were morphed into an MRI atlas using a nonlinear image registration algorithm. Active contact locations were projected onto the atlas and clusters analyzed for the degree of variance in two groups: (1) good and poor responders and (2) cervical (CD) and generalized dystonia (GD). RESULTS: The average active contact location between CD and GD good responders was distinct but not significantly different. The mean active contact for CD poor responders was significantly different from CD responders and GD poor responders in the dorsoventral direction. CONCLUSIONS: A normalized imaging space is arguably more accurate in visualizing postoperative leads. Despite some separation between groups, this data suggests there was not an optimal pallidal target for common dystonia patients. Degrees of variance overlapped due to a large degree of individual target variation. Patient selection may ultimately be the key to maximizing patient outcomes. PMID- 25502119 TI - Prevalence and clinical features of coagulation syndrome after endoscopic submucosal dissection for colorectal neoplasms. AB - BACKGROUND AND OBJECTIVES: There are several published studies examining the major complications (bleeding and perforation) of colon endoscopic submucosal dissection (ESD). However, little is known about the other complications, such as post-ESD coagulation syndrome (CS). The aims of this study were to evaluate the prevalence and the clinical features of CS after colon ESD. METHODS: There were 183 cases treated with ESD for either a colorectal laterally spreading tumor or a polypoid mass in Konkuk University Medical Center. There were 151 cases enrolled in this study after excluding patients with perforation, bleeding, nonlifting sign, or nonneoplastic lesions. Patients with a fever above 37.7 degrees C, abdominal pain, and localized tenderness after ESD without macro- or microperforation, regardless of the symptoms of peritoneal irritation, were deemed as showing post-colon ESD CS. RESULTS: There were 151 cases enrolled in this study, and 13 patients (8.6 %) showed CS after colorectal ESD. There were no differences in the demographic and endoscopic characteristics between the patients with CS and those without CS. The mean hospitalization stay was 3.0 +/- 0.3 days longer in the CS (+) group (6.9 +/- 1.9 days) than that in the CS (-) group (3.9 +/- 1.6 days) (p = 0.001). All patients with CS were treated with conservative, nonsurgical management, such as fasting and intravenous antibiotics. CONCLUSIONS: The rate of post-ESD CS was less than 9 % in this study. Although CS occurred, all of the patients with CS showed a favorable progression within 1 week. PMID- 25502120 TI - Stimulated mass enhancement strategy-based highly sensitive detection of a protein in serum using quartz crystal microbalance technique. AB - A stimulated mass enhancement strategy based on enormous biocatalytic precipitation of 4-chloro-1-naphthol using magnetic bead-supported horseradish peroxidase and glucose oxidase bienzymes was developed for the highly sensitive detection of interleukin-6 in serum using a quartz crystal microbalance technique. PMID- 25502122 TI - Use of the Fluocinolone Acetonide Intravitreal Implant for the Treatment of Noninfectious Posterior Uveitis: 3-Year Results of a Randomized Clinical Trial in a Predominantly Asian Population. AB - INTRODUCTION: The fluocinolone acetonide (FA) intravitreal implant 0.59 mg (Retisert((r)), Bausch + Lomb, Rochester, NY, USA) provides sustained release of FA directly to the vitreous cavity over a prolonged period of time. The purpose of this study was to evaluate the safety and efficacy of a 0.59- and 2.1-mg FA intravitreal implant in patients with noninfectious posterior uveitis. METHODS: A prospective, multicenter, randomized, double-masked, dose-controlled study was performed. Patients were randomized to the 0.59- or 2.1-mg FA implant surgically placed in the vitreous cavity through a pars plana incision and were evaluated at visits through 3 years. Patients with bilateral disease had the more severely affected eye implanted. Outcomes included uveitis recurrence rate, best-corrected visual acuity (BCVA), use of adjunctive therapy, and safety. RESULTS: A total of 239 patients, predominantly Asian, were implanted (n = 117, 0.59-mg implant; n = 122, 2.1-mg implant). Approximately 80% of patients had bilateral disease. Recurrence rates for implanted eyes decreased from 42.3% during the 1-year pre implantation period to 25.9% during the 3-year post-implantation period (P = 0.0003) and increased for nonimplanted fellow eyes from 19.8 to 59.7% (P < 0.0001). More implanted eyes gained >=3 lines of BCVA compared to nonimplanted fellow eyes (P <= 0.0046); and implanted eyes required less adjunctive systemic therapy and fewer periocular injections (P < 0.0001). Elevations of intraocular pressure (>=10 mm Hg) were frequent in implanted eyes (67.8%, 0.59-mg implant; 71.3%, 2.1-mg implant); nearly all (94.9%) phakic implanted eyes required cataract surgery. CONCLUSION: The FA intravitreal implant significantly reduced uveitis recurrence rates and led to improvements in visual acuity and reductions in adjunctive therapy. Lens clarity and intraocular pressure require monitoring. PMID- 25502121 TI - The curvilinear effect of work engagement on employees' turnover intentions. AB - Numerous studies have shown the positive consequences of work engagement for both organisations and employees experiencing it. For instance, research has demonstrated that work-engaged employees have lower levels of turnover intentions than non-engaged employees. However, in this research, we examined whether there is a dark side of work engagement. More precisely, we investigated whether the relationship between work engagement and employees' turnover intentions might be non-linear. Based on two different samples, our results indicated that the relationship between work engagement and employees' turnover intentions is curvilinear. The theoretical and practical implications of these results are discussed. PMID- 25502123 TI - On the potential usefulness of Fourier spectra of delayed fluorescence from plants. AB - Delayed fluorescence (DF) from photosystem II (PSII) of plants can be potentially used as a biosensor for the detection of plant physiological status and environmental changes. It has been analyzed mainly in the time domain. Frequency domain analysis through Fourier transform allows viewing a signal from another angle, but the usefulness of DF spectra has not been well studied. In this work, experiments were conducted to show the differences and similarities in DF spectra of different plants with short pulse excitation. The DF spectra show low-pass characteristics with first-order attenuation of high frequencies. The results also show that the low-frequency components differ while the high-frequency components are similar. These may imply the potential usefulness of Fourier spectra of DF to analyze photoelectron transport in plants and classify samples. PMID- 25502124 TI - Performance enhancement for a GPS vector-tracking loop utilizing an adaptive iterated extended Kalman filter. AB - This paper deals with the problem of state estimation for the vector-tracking loop of a software-defined Global Positioning System (GPS) receiver. For a nonlinear system that has the model error and white Gaussian noise, a noise statistics estimator is used to estimate the model error, and based on this, a modified iterated extended Kalman filter (IEKF) named adaptive iterated Kalman filter (AIEKF) is proposed. A vector-tracking GPS receiver utilizing AIEKF is implemented to evaluate the performance of the proposed method. Through road tests, it is shown that the proposed method has an obvious accuracy advantage over the IEKF and Adaptive Extended Kalman filter (AEKF) in position determination. The results show that the proposed method is effective to reduce the root-mean-square error (RMSE) of position (including longitude, latitude and altitude). Comparing with EKF, the position RMSE values of AIEKF are reduced by about 45.1%, 40.9% and 54.6% in the east, north and up directions, respectively. Comparing with IEKF, the position RMSE values of AIEKF are reduced by about 25.7%, 19.3% and 35.7% in the east, north and up directions, respectively. Compared with AEKF, the position RMSE values of AIEKF are reduced by about 21.6%, 15.5% and 30.7% in the east, north and up directions, respectively. PMID- 25502125 TI - Heterogeneous oxidation of nitrite anion by gas-phase ozone in an aqueous droplet levitated by laser tweezers (optical trap): is there any evidence for enhanced surface reaction? AB - The oxidation of nitrite anion within an aqueous atmospheric droplet may be a sink for HONO in the lower atmosphere. An optical trap with Raman spectroscopy is used to demonstrate that the oxidation of aqueous nitrite anion in levitated, micron sized, aqueous droplets by gas-phase ozone is consistent with bulk aqueous phase kinetics and diffusion. There is no evidence of an enhanced or retarded reaction at the droplet surface at the concentrations used in the experiment or likely to be found in the atmosphere. The oxidation of nitrite in an aqueous droplet by gas-phase ozone does not cause the droplet to hydrodynamically change in size and demonstrates use of an optical trap as a wall-less reactor to measuring aqueous-phase rate coefficients. PMID- 25502127 TI - Facilitating anticoagulation for safer transitions: preliminary outcomes from an emergency department deep vein thrombosis discharge program. AB - INTRODUCTION: Patients presenting to the emergency department (ED) with an acute uncomplicated deep vein thrombosis (DVT) may be eligible for outpatient treatment. This study aims to establish a transition of care program in the ED for patients with DVT presenting with an acute uncomplicated DVT. METHODS: This article specifies the transition of care program for DVT patients in the ED. Data was collected on patients admitted and discharged from the ED who had an acute DVT both prior to the initiation of facilitating anticoagulation for safer transitions (FAST) and after initiation of FAST. Follow-up phone calls were made to patients discharged from the ED after the initiation of FAST, and data were collected on follow-up appointments, anticoagulation adherence, readmission rates, and patient satisfaction. RESULTS: The FAST program has been successfully implemented. By the 30-day follow-up phone call, 100% of patients had attended a follow-up appointment. The average time to the follow-up appointment post discharge was 4.4 days (range, 1-7 days). None of the patients at the 3- to 5-day follow-up phone call and 30-day phone call had any issues taking their anticoagulant, and none reported side effects of significant bleeding. One patient was re-admitted after discharge with a pulmonary embolism. Patient satisfaction has also been very high with the program, with all patients indicating at the 30-day phone call that they would recommend the program to a friend or family member. The educational components of this program also improved the discharge process for this population compared with patients discharged prior to the initiation of FAST. CONCLUSION: The FAST program is an example of a successful transition-of-care program for discharging DVT patients from the ED. Reassessment and improvements to the program are underway to ensure it remains current, sustainable, and provider friendly. PMID- 25502128 TI - Does knowledge of the cost of cardiovascular tests influence physician ordering patterns? AB - INTRODUCTION: The United States spends a higher percentage of its gross domestic product on health care than any other country. Previous efforts to curtail health care spending have had minimal impact. We hypothesized that informing physicians of the cost of expensive cardiovascular diagnostic tests would change their ordering behavior. MATERIALS AND METHODS: Hospitalist physicians (n = 38) were randomly assigned to either seeing or not seeing the cost of diagnostic tests, via a computer pop-up screen, at the time of order entry. Patients were inpatients on a general medical service. Cost-aware physicians were shown the cost of the test they ordered as well as the cost of similar tests with different costs. There was a 4-month baseline period prior to randomization followed by a 4 month intervention period. The primary outcome measure was a change in the proportion of imaging stress tests in the study period. RESULTS: Of the total number of stress tests ordered (imaging and nonimaging), cost-aware physicians ordered 89% of their tests with imaging during both the baseline and study periods. Cost-unaware physicians ordered 91% imaging tests during the baseline period and 87% during the study period. There were no significant differences between the groups regarding change in ordering from baseline to study period. Both groups showed a slight increase (P < 0.03) in ordering the more expensive regadenoson nuclear stress tests (cost-aware: 30% baseline, 44% study period; cost-unaware: 36% baseline, 41% study period). DISCUSSION: Informing physicians of the cost of certain diagnostic tests is not a sufficient intervention to influence their ordering behavior. PMID- 25502126 TI - Point-of-care platelet reactivity determination with VerifyNow-P2Y12 following administration of clopidogrel or prasugrel: data from a real-world, clinical care inpatient setting. AB - OBJECTIVES: To describe VerifyNow-P2Y12 (VN-P2Y12, Accumetrics, San Diego, CA) results from patients treated with either clopidogrel or prasugrel who were seeking care in a hospital setting. BACKGROUND: VN-P2Y12 is a point-of-care device that measures platelet reactivity to adenosine diphosphate. Past assessments of thienopyridine therapy utilizing VN-P2Y12 have largely come from clinical trial settings. There are limited data from real-world settings. METHODS: Electronic medical record data from Huntsville Hospital (Huntsville, AL) for those who underwent VN-P2Y12 testing for clopidogrel or prasugrel between January 1, 2009 and October 31, 2010 were analyzed. The VN-P2Y12 data included P2Y12 reaction units (PRUs) and device-reported percentage of inhibition. Descriptive analyses were conducted with t tests, and a logistic regression model was estimated to assess the association between patient characteristics and the likelihood of platelet nonresponse. RESULTS: In total, 2882 tests (2476 with clopidogrel and 406 with prasugrel) were analyzed. For clopidogrel and prasugrel, respectively, mean PRU standard deviation (SD) was 206 (90) and 107 (93; P < 0.0001) and mean % inhibition (SD) was 31% (26%) and 63% (31%; P < 0.0001). Treatment with clopidogrel alone (odds ratio [OR] = 5.25; P < 0.0001), being non Caucasian (OR = 1.48; P = 0.0440), obese (OR = 1.49; P = 0.0010), anemic (OR = 3.29; P < 0.0001), diabetic (OR = 1.75; P < 0.0001), and having a history of myocardial infarction (OR = 1.57; P < 0.0001) were significant predictors of having PRU >= 235. CONCLUSION: This real-world data analysis shows results that are consistent with clinical trial results, namely that compared with clopidogrel, prasugrel is associated with significantly lower PRU and greater percentage of inhibition, regardless of age, race, gender, diabetes, obesity, or proton pump inhibitor use. PMID- 25502129 TI - Is glycemic control of the critically ill cost-effective? AB - Intensive monitoring of blood glucose levels and treatment of hyperglycemia have been associated with significant improvements in morbidity and mortality in the critically ill. In contrast to the large prospective and observational body of data relating glycemic control and clinical outcomes, the financial impact of glycemic control implementation has not been as well described. This article details data from interventional trials of intensive insulin therapy; investigations that relate dysglycemia to morbidity, particularly intensive care unit (ICU)-acquired infections and increased ICU length of stay; and evaluations of the attributable cost of nosocomial infection in order to construct a sensitivity analysis of the net economic impact of glycemic control. It concludes that glycemic control is associated with positive financial outcomes, even using very conservative assumptions, and provides the reader with an automated spreadsheet to estimate the financial implications of glycemic control using assumptions based on locally derived data. PMID- 25502130 TI - Treatment patterns and outcomes among hospitalized patients with venous thromboembolism in the United States: an analysis of electronic health records data. AB - BACKGROUND: With the advent of new treatment options for venous thromboembolism (VTE), it is valuable to gain insights into current clinical practices. OBJECTIVE: Assess treatment patterns and recurrence among patients hospitalized for VTE. METHODS: This retrospective study evaluated patients hospitalized with an incident VTE diagnosis (index) from 2008 to 2012 in a de-identified electronic health record database. Patients were further required to receive anticoagulant treatment and/or a VTE-related procedure for study inclusion. Patients were excluded if they: (1) did not have a medical encounter in the 6 months before index (baseline); (2) had a prior VTE diagnosis or used an anticoagulant during the baseline period; or (3) had a diagnosis of atrial fibrillation/flutter, cardiomyopathy, or a coagulation disorder during baseline or the year after index (follow-up). Hospitalization for recurrent VTE and bleeding were evaluated. RESULTS: A total of 2060 patients were identified (mean age, 60.9 years; 53.0% women), with a mean length of stay of 8.1 days. Of the VTE types, acute DVT was the most common (41.9%), followed by PE (33.3%), and DVT + PE (24.7%). Almost all patients (96.9%) received anticoagulants, of which 94.3% received heparin and 76.5% received warfarin. Although 77.4% of warfarin users were prescribed it at discharge, only (40.2%) had a warfarin prescription within 30 days of discharge. Overall 30 day, 90 day and 1-year VTE recurrence rates were 2.0%, 4.2%, and 7.5%, respectively, and the major bleeding rate was 6.8%. CONCLUSION: In a real-world population of hospitalized VTE patients, heparin treatment in combination with warfarin was common. However, continuation of warfarin post-discharge was challenging. Initiatives to improve continuation of therapy may be important to reduce VTE recurrence. PMID- 25502131 TI - Managing bleeding and emergency reversal of newer oral anticoagulants: a review for primary care providers. AB - The therapeutic landscape for anticoagulation management is undergoing a shift from the use of traditional anticlotting agents such as heparins and warfarin as the only options to the growing adoption of newer target-specific oral anticoagulants (TSOACs) with novel mechanisms of action. Dabigatran, the first TSOAC approved for use in the United States, is a direct competitive inhibitor of thrombin. It has predictable kinetics, with an elimination half-life of 12 to 17 hours in healthy volunteers. Apixaban and rivaroxaban are selective inhibitors of factor Xa, and also display first-order kinetics. In younger healthy individuals, apixaban has an apparent half-life of approximately 12 hours, whereas rivaroxaban has an elimination half-life of 5 to 9 hours. Understanding the pharmacologic properties of these newer drugs can lead to better insights regarding their respective safety and efficacy profiles and their application in clinical practice. Laboratory assessments have been developed to measure the anticoagulant efficacy of these newer agents. However, the results of these tests can be highly variable, and are therefore not always useful for monitoring the anticoagulation effects of these agents. In addition, several strategies have been documented for the potential reversal of the anticoagulant effects of these drugs, from the temporary discontinuation of an agent before elective surgery to suggested emergency procedures in the case of major bleeding events. New, specific reversal agents for dabigatran, apixaban, and rivaroxaban are currently being developed, and dabigatran has received fast-track designation from the US Food and Drug Administration. Until comprehensive clinical guidelines are developed, institutions involved in emergency care should establish their own procedures for the management of patients undergoing anticoagulation who require emergency treatment. These protocols should include appropriate laboratory testing to assess anticoagulant activity as part of the inpatient workup if time allows, and the potential use of hemodialysis, prohemostatic agents, and reversal agents when available. PMID- 25502132 TI - Coronary artery stents: advances in technology. AB - The introduction of percutaneous coronary intervention (PCI) in the late 1970s revolutionized the management of stable and unstable coronary artery disease, providing an effective, quick, safe, and increasingly widely available method for coronary revascularization for many patients. Rapid development in this field led to the introduction of a number of new technologies, including intracoronary stents that have resulted in improved efficacy and long-term safety. In this manuscript we review the experience with the 2 major available classes of stents (bare metal [BMS], drug-eluting [DES]) and describe the delivery systems for these stents. An evidence review of the large trial data comparing balloon angioplasty, BMS, and DES demonstrates the incremental advances over time, with the latest generation of DES achieving the lowest rates of restenosis, stent thrombosis, and recurrent myocardial infarction. In addition, we provide an overview of the latest developments in stent technology, including the introduction of bioresorbable stents and new stent delivery systems. These latest advances are hoped to further improve outcomes while reducing costs due to a reduction in the need for future procedures and hospitalizations due to recurrent coronary disease. PMID- 25502133 TI - Integrated medical processes: redesigning transitions of care. PMID- 25502135 TI - Management of hospitalized patients with diabetic foot infections. AB - Diabetic foot infections (DFIs), which present with a variety of clinical manifestations, are commonly encountered by clinicians. They are associated with a high morbidity, a high amputation rate, a high mortality, and increased health care costs. An effective management of DFIs requires a multidisciplinary approach with a strong collaboration among all involved health care providers as well as patient involvement. Diagnosing DFIs appropriately requires consideration of the clinical symptoms and signs of infection in addition to supplementary laboratory testing such as inflammatory markers and imaging studies. The comprehensive patient assessment should include the predisposing risk factors for infection; the type, severity, and extent of the infection; and the assessment of neurologic and vascular status, comorbid conditions, and psychosocial factors. The comprehensive management of DFIs include not only effective antibiotic therapy but also surgical debridement, pressure offloading, wound care and moisture, maintaining good vascular perfusion, control of edema and pain, correction of metabolic abnormalities such as hyperglycemia, and addressing psychosocial and nutritional issues. Discharge planning that addresses full medical and social needs along with suitable follow-up, patient education and counseling, and clear communication with outpatient providers are critical for ensuring a safe and successful transition to outpatient management of hospitalized patients with DFIs. PMID- 25502134 TI - The role of aclidinium bromide in the treatment of chronic obstructive pulmonary disease. AB - INTRODUCTION: Inhaled bronchodilators remain a cornerstone of treatment for chronic obstructive pulmonary disease (COPD); current guidelines recommend initiating inhaled bronchodilators as either monotherapy or combination therapy depending on disease severity and exacerbation risk to improve air flow and reduce breathlessness. Aclidinium bromide is a twice-daily, long-acting muscarinic antagonist recently approved in the United States and Europe and carries significant promise as an alternative long-acting inhaled antimuscarinic agent for the treatment of moderate-to-severe COPD. OBJECTIVE: This review describes the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of aclidinium bromide. DISCUSSION: Clinical trials have demonstrated improvement in forced expiratory volume in 1 second, nighttime symptom control, disease-related quality of life, and delay in time to first COPD exacerbation with aclidinium use compared with placebo. Commonly reported adverse effects include headache, nasopharyngitis, and cough. One trial reported narrow-angle glaucoma; however, no other serious adverse events have been reported to date. CONCLUSION: Overall, aclidinium bromide has been found to be safe and effective for the treatment of moderate-to-severe COPD. Further clinical trials comparing aclidinium bromide to standard therapies are needed to fully elucidate its role in the treatment of COPD. PMID- 25502136 TI - Perioperative cardiovascular medicine: an update of the literature 2013-2014. AB - Perioperative medicine is an important and rapidly expanding area of interest across multiple specialties, including internal medicine, anesthesiology, surgery, cardiology, and hospital medicine. A multispecialty team approach that ensures the best possible patient outcomes has fostered collaborative strategies across the continuum of patient care. Staying current in this multidisciplinary field is difficult, because physicians interested in perioperative medicine would need to review multiple specialty journals on a regular basis. To facilitate this process, the authors performed a focused review of this literature published in 2013 and early 2014. In this update, key articles are reviewed that potentially impact clinical practice in perioperative cardiovascular risk prediction and risk management. PMID- 25502137 TI - Impact of levels of simulation fidelity on training of interns in ACLS. AB - AIM: Identifying the modality and fidelity of simulation that offers the greatest benefit to the learner is critical to Advanced Cardiac Life Support (ACLS) training. Our hypothesis is that participants who receive ACLS training on high fidelity mannequins will perform better than those trained on low-fidelity mannequins. METHODS: The study was performed in the context of an ACLS Initial Provider course for new postgraduate year 1 residents and involved 3 training arms: (1) low-fidelity, (2) mid-fidelity, and (3) high-fidelity. Educational outcomes were evaluated by written scores, student evaluations of the course, and expert rater reviews of megacode performance. RESULTS: A convenience sample of 54 subjects was randomized to 1 of the 3 training arms. All 3 groups significantly improved based on written posttest scores (P < 0.0001); however, pretest to posttest improvement among the 3 training arms was not significantly different: low-fidelity = 42.3 (95% CI, 35.7-48.9); mid-fidelity = 41.3 (95% CI, 34.7-47.9); high-fidelity = 40.8 (95% CI, 34.3-47.5; P = 0.95). All participants felt the simulator environment was realistic regardless of level of fidelity. Participants in the high-fidelity group were less likely to feel comfortable in the simulator environment (P = 0.0045). Clinical performance as assessed by expert raters' megacode scores was better for high-fidelity (66.3) than mid-fidelity (60.1) (P = 0.04). CONCLUSION: Overall, there was no difference among the 3 groups in test scores or perceived instructor or course quality; however, subjects trained on high-fidelity mannequins performed better than those trained on mid-fidelity with respect to megacode performance. PMID- 25502138 TI - Hospital-acquired thrombocytopenia. AB - The development of thrombocytopenia is common in hospitalized patients and is associated with increased mortality. Frequent and important causes of thrombocytopenia in hospitalized patients include etiologies related to the underlying illness for which the patient is admitted, such as infection and disseminated intravascular coagulation, and iatrogenic etiologies such as drug induced immune thrombocytopenia, heparin-induced thrombocytopenia, posttransfusion purpura, hemodilution, major surgery, and extracorporeal circuitry. This review presents a brief discussion of the pathophysiology, distinguishing clinical features, and management of these etiologies, and provides a diagnostic approach to hospital-acquired thrombocytopenia that considers the timing and severity of the platelet count fall, the presence of hemorrhage or thrombosis, the clinical context, and the peripheral blood smear. This approach may offer guidance to clinicians in distinguishing among the various causes of hospital-acquired thrombocytopenia and providing management appropriate to the etiology. PMID- 25502139 TI - Non-vitamin K antagonist oral anticoagulants in atrial fibrillation and venous thromboembolism: where are we now? AB - Four non-vitamin-K antagonist oral anticoagulants (NOACs) are now available and are variously approved for stroke prevention in atrial fibrillation and the management of venous thromboembolism. On the whole, these drugs offer clear benefits over warfarin, overcoming problems with unpredictable individual responses and avoiding the need for frequent and resource-intensive monitoring. Sufficient data are now available to recommend the use of particular NOACs in defined settings. As a group these drugs offer a real alternative to warfarin; their more widespread use for stroke prevention in atrial fibrillation, in the management of venous thromboembolism, and perhaps in other settings promises to bring real clinical gains for at-risk populations worldwide. This review highlights the growing importance of effective anticoagulation therapy at a time when cardiovascular risk profiles are evolving, discusses the relative merits of the NOACs over warfarin, and describes the use of specific agents in specific patient populations. PMID- 25502140 TI - Hypoglycemia in the hospital: systems-based approach to recognition, treatment, and prevention. AB - Hypoglycemia causes immediate adverse reactions and is associated with unfavorable clinical outcomes and increased health care costs. It is also one of the barriers to optimization of inpatient glycemic control. Prioritizing quality improvement efforts to address hypoglycemia in hospitalized patients with diabetes is of critical importance. Acute illness, hospital routine, and gaps in quality care predispose patients to hypoglycemia. Many of these factors can be minimized when approached from a systems-based perspective. This requires creation of a multidisciplinary team to develop strategies to prevent hypoglycemic events by targeting many factors, such as systemic analysis of blood glucometrics, policies and protocols, coordination of nutrition and insulin administration, transitions of care, staff and patient education, and communication. This article reviews recommendations of the American Diabetes Association, the Endocrine Society, and the Society of Hospital Medicine, and highlights our institution's approach in each of these areas. Despite a multitude of challenges, we believe that it is feasible to improve the safety and quality of inpatient diabetes care and avoid hypoglycemia without requiring significant additional hospital resources. Physician leaders play a major role in guiding this process and encouraging participation of interdisciplinary members of the hospital team. PMID- 25502141 TI - Trigonal scaffolds for multivalent targeting of melanocortin receptors. AB - Melanocortin receptors can be used as biomarkers to detect and possibly treat melanoma. To these ends, molecules bearing one, two, or three copies of the weakly binding ligand MSH(4) were attached to scaffolds based on phloroglucinol, tripropargylamine, and 1,4,7-triazacyclononane by means of the copper-assisted azide-alkyne cyclization. This synthetic design allows rapid assembly of multivalent molecules. The bioactivities of these compounds were evaluated using a competitive binding assay that employed human embryonic kidney cells engineered to overexpress the melanocortin 4 receptor. The divalent molecules exhibited 10- to 30-fold higher levels of inhibition when compared to the corresponding monovalent molecules, consistent with divalent binding. The trivalent molecules were only statistically (~2-fold) better than the divalent molecules, still consistent with divalent binding but inconsistent with trivalent binding. Possible reasons for these behaviors and planned refinements of the multivalent constructs targeting melanocortin receptors based on these scaffolds are discussed. PMID- 25502143 TI - [Bilateral retinal detachment?]. PMID- 25502144 TI - Anchors weigh more than power: why absolute powerlessness liberates negotiators to achieve better outcomes. AB - The current research shows that having no power can be better than having a little power. Negotiators prefer having some power (weak negotiation alternatives) to having no power (no alternatives). We challenge this belief that having any alternative is beneficial by demonstrating that weak alternatives create low anchors that reduce the value of first offers. In contrast, having no alternatives is liberating because there is no anchor to weigh down first offers. In our experiments, negotiators with no alternatives felt less powerful but made higher first offers and secured superior outcomes compared with negotiators who had weak alternatives. We established the role of anchoring through mediation by first offers and through moderation by showing that weak alternatives no longer led to worse outcomes when negotiators focused on a countervailing anchor or when negotiators faced an opponent with a strong alternative. These results demonstrate that anchors can have larger effects than feelings of power. Absolute powerlessness can be psychologically liberating. PMID- 25502145 TI - Commentary on kubota, li, bar-david, banaji, and phelps (2013): a more optimistic view of the data. PMID- 25502142 TI - Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. AB - Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas. PMID- 25502146 TI - Contribution of anion-pi interactions to the stability of Sm/LSm proteins. AB - We have analyzed the influence of anion-pi interactions to the stability of Sm/LSm assemblies. The side chain of Glu is more likely to be in anion-pi interactions than Asp. Phe has the highest occurrence in these interactions than the other two pi residues. Among the anion-pi residue pairs, Glu-Phe residue pair showed the maximum number of anion-pi. We have found hot-spot residues forming anion-pi interactions, and Glu-Phe is the most common hot-spot interacting pair. The significant numbers of anion-pi interacting residues identified in the dataset were involved in the formation of multiple anion-pi interactions. More than half of the residues involved in these interactions are evolutionarily conserved. The anion-pi interaction energies are distance and orientation dependent. It was found that anion-pi interactions showed energy less than -15 kcal mol(-1), and most of them have energy in the range -2 to -9 kcal mol(-1). Solvent accessibility pattern of Sm/LSm proteins reveals that all of the interacting residues are preferred to be in buried regions. Most of the interacting residues preferred to be in strand. A significant percentage of anion pi interacting residues are located as stabilization centers and thus might provide additional stability to these proteins. The simultaneous interaction of anions and cations on different faces of the same pi-system has been observed. On the whole, the results presented in this work will be very useful for understanding the contribution of anion-pi interaction to the stability of Sm/LSm proteins. PMID- 25502147 TI - CCL18 promotes epithelial-mesenchymal transition, invasion and migration of pancreatic cancer cells in pancreatic ductal adenocarcinoma. AB - CCL18 is a chemokine that is primarily expressed in monocytes, macrophages and immature dendritic cells and plays a crucial role in immune and inflammation responses. Recently, CCL18 was found to play pivotal roles in the development of several kinds of cancers, but its expression status and role during the tumorigenesis of pancreatic cancer remain unknown. In this study, we performed immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) to evaluate the expression of CCL18 in human pancreatic ductal adenocarcinoma (PDAC) tissues and preoperative serum, respectively. The results showed that both cancer epithelial cells and mesenchymal macrophages in PDAC tissues positively expressed CCL18. Serum CCL18 levels were significantly higher in patients with PDAC in comparison to healthy controls. The expression of CCL18 in both cancer epithelial cells and mesenchymal cells was correlated with lymph node metastasis, histopathological grading and overall survival in 62 PDAC patients. In vitro assays showed that the gene and protein expression of CCL18 from U937 and THP-1 cell- derived macrophages were significantly higher than that from unstimulated U937 cells and THP-1 cells. In contrast, pancreatic cancer cell lines showed little to no CCL18 expression even after IL4 stimulation. Intriguingly, pancreatic cancer cell lines expressed the potential CCL18 receptors PITPNM3, CCR6 and GPR3. Furthermore, treatment with recombinant human CCL18 promoted the migration and invasion of pancreatic cancer cells, but had no effect on cell proliferation. Consistent with these results, CCL18 induced the expression of the epithelial-mesenchymal transition (EMT) related gene SNAIL1. Our findings suggest that the serum level of CCL18 is a potential biomarker for the diagnosis and prognosis of PDAC, and that the combined functions of CCL18 in mesenchymal and cancer cells might accelerate the progression of PDAC by promoting the epithelial mesenchymal transition, invasion and migration of pancreatic cancer cells. PMID- 25502148 TI - Teen driving behaviors in a rural southern state. AB - OBJECTIVES: Motor vehicle crashes are the leading cause of death for teenagers. Alabama ranks fourth in the United States for teen crash fatalities. We sought to describe risky driving behaviors among teens in the rural areas of the state's most populous county. METHODS: A questionnaire was adapted from the Youth Risk Behavior Surveillance System. Each of the schools in Jefferson County, Alabama, participated in 2009 and 2010. Surveys were anonymous and data were entered into an Excel spreadsheet. Inclusion criteria were age 15 years and older. RESULTS: A total of 1399 surveys met inclusion criteria. A total of 52% of respondents were boys; 64% were white, 29% were African American, and 3% were Hispanic. Respondents were 15 (38%), 16 (36%), 17 (21%), and 18 (5%) years old. When asked about behaviors during driving in the last 30 days, 41% reported texting and 11% reported driving after drinking. Teens reported being a passenger in a car with the driver texting (67%) or after the driver had been drinking (27%) in the last 30 days. Overall, 58% reported not wearing a seatbelt; 13% reported driving after using drugs; 60% reported routinely exceeding the speed limit; 80% reported having discussed safe driving with a parent, but only 16% with their doctor; 25% had signed a safe driving contract; and 63% had taken a driving class. CONCLUSIONS: Many risky behaviors were identified for both teen drivers and passengers. A concerning number of teens are not receiving safe driving educational messages from parents, doctors, or driver's education classes. Some interventions have been instituted; however, more outreach efforts should be made to focus on strengthening driving laws and educating parents and teens. PMID- 25502149 TI - Where are the rest of us? Improving representation of minority faculty in academic medicine. AB - OBJECTIVES: Low numbers of underrepresented minority faculty members in academic medicine (black, Hispanic, Asian/Pacific Islander, Native American/Alaskan) continue to be a concern for medical schools because there is higher attrition and talent loss among this group. Although much has been written on this topic, there has not been a systematic review of the indexed literature published. METHODS: We searched MEDLINE, Web of Knowledge, ProQuest, and Google Scholar for articles relating to minority faculty and identified relevant articles. We then graded the evidence using the Strength of Recommendation Taxonomy. The same criteria were applied to extract evidence-based observations of challenges faced by minority faculty and provide recommendations. RESULTS: Of the 548 studies identified and reviewed, 15 met inclusion criteria for this literature review. Of the 15, 9 were cross-sectional studies and 6 were analyses of existing Association of American Medical Colleges workforce data. The cross-sectional studies documented perceived bias in the recruitment of faculty, quantified the lack of minority mentors, and revealed that black and Hispanic faculty members are more prevalent in states with higher minority populations. Studies using the Association of American Medical College workforce data also documented evidence of promotion bias, the lack of diversity in academic plastic surgery, and the lack of minority researchers funded by the National Cancer Institute. CONCLUSIONS: This systematic review provides evidence that racism, promotion disparities, funding disparities, lack of mentorship, and diversity pressures exist and affect minority faculty in academic medicine. Based on these observed challenges, this review also provides specific recommendations that could improve representation of minority faculty members in academic medicine. These recommendations include implementing proven pipeline programs to increase the number of minority medical students, a systemwide adoption of proven culture change initiatives, reexamination of assignments to ensure equitable time distribution, and a reduction of medical school debt. PMID- 25502150 TI - Commentary on "Where are the rest of us? Improving representation of minority faculty in academic medicine". PMID- 25502151 TI - Association between orthopaedic in-training examination subsection scores and ABOS Part I examination performance. AB - OBJECTIVES: The Orthopaedic In-Training Examination (OITE) is administered yearly to assess a resident's progression, compare his or her performance with that of other residents, and evaluate the educational structure of a residency program. The American Board of Orthopaedic Surgery (ABOS) Part I examination is used to ensure competence in orthopedic knowledge and must be passed to achieve certification. Previous studies have correlated OITE and ABOS performance, but analysis between OITE subsection performance and ABOS Part I examination performance has not been reported. The purpose of this study was to evaluate the relation between individual OITE subsection performance and overall ABOS Part I performance. METHODS: Performance on the 12 subsections comprising the OITE from 1999 to 2009 was evaluated and compared with overall ABOS Part I examination performance. Spearman correlation coefficients (SCCs) were used to quantify the association between OITE subsection and overall ABOS percentile ranks. RESULTS: The OITE subsections of musculoskeletal trauma (SCC 0.29; P = 0.0002), hip and knee reconstruction (SCC 0.21; P = 0.0064), spine (SCC 0.16; P = 0.04), orthopedic science (SCC 0.17; P = 0.03), and orthopedic disease (SCC 0.18; P = 0.02) correlated with ABOS percentile ranks. Five of the top seven subsections by question volume on the OITE were found to correlate with ABOS performance. CONCLUSIONS: OITE subsections with greater representation and breadth of subject matter had stronger performance correlations with ABOS Part I examination performance. These findings may allow residency training programs to better predict ABOS Part I performance of their residents by evaluating particular subsections on the OITE in addition to overall OITE performance. PMID- 25502152 TI - EMS patients and walk-in patients presenting with severe sepsis: differences in management and outcome. AB - OBJECTIVES: Sepsis is a significant problem. The differences between patients with sepsis who walk into the emergency department (ED) and those who are transported via emergency medical services (EMS) have not been clarified. The aim of the study was to determine whether there was a difference in outcome between patients arriving by EMS and those presenting directly to the ED. METHODS: We prospectively collected and reviewed a cohort of all cases of severe sepsis and septic shock admitted to the medical intensive care unit from the ED from November 2009 to March 2012. Extracted data were basic demographic information (including mode of ED arrival), clinical data, and treatments. We calculated Systemic Inflammatory Response Syndrome criteria, Acute Physiology and Chronic Health Evaluation II scores, and Sequential Organ Failure Assessment (SOFA) scores. The primary outcome was mortality in severely ill patients with sepsis. RESULTS: A total of 378 subjects (78%) presented by EMS and 107 subjects were walk-in patients (22%). Patients transported via EMS were older (P < 0.01), had fewer lactates >4 (P < 0.02), a more altered mental status (P < 0.01), and higher respiratory rates (P < 0.05) than did walk-in patients. Patients transported by EMS had worse disease severity when measured by an Acute Physiology and Chronic Health Evaluation II score (P < 0.01) but not by SOFA score. EMS patients had a shorter time to receiving antibiotics (P = 0.02) and central line placement (P < 0.01) than did walk-in patients. In a logistic model, mortality was associated with increasing age (adjusted odds ratio 1.3; 95% confidence interval [CI] 1.2 1.4), higher first-measured ED lactates (1.2; 95% CI 1.1-1.2), and increased initial SOFA score (adjusted odds ratio 1.2; 95% CI 1.1-1.3) but not EMS arrival or prehospital fluids. CONCLUSIONS: Neither arrival by EMS nor fluid administration by EMS is associated with decreased mortality in severe sepsis. PMID- 25502153 TI - Cholecystectomy for biliary dyskinesia in gastroparesis: mimic or misfortune? AB - OBJECTIVES: Biliary dyskinesia and gastroparesis are associated with upper abdominal discomfort and dyspeptic symptoms in the absence of structural abnormalities. We hypothesized that the similarity in symptoms would trigger testing and surgical treatment for biliary abnormalities in a significant number of patients, with refractory symptoms ultimately demonstrating impairment of gastric function. METHODS: The study was designed as a retrospective review of patients seen between April 1, 2008 and December 31, 2009. Patients were identified using diagnosis code for gastroparesis (International Classification of Diseases, Ninth Revision code 536.3). Demographic information, duration, etiology and severity of disease, coexisting psychiatric illness, pain and functional gastrointestinal disorders, medication use, and abdominal surgery with a focus on cholecystectomy were abstracted from the medical records. RESULTS: A total of 131 patients were identified. Women predominated (77.86%), and the idiopathic form of gastroparesis was the most common etiology. A total of 59 (45%) patients had undergone cholecystectomies. Although symptomatic cholelithiasis was the primary indication, more than one-third of these patients underwent surgery for biliary dyskinesia (n = 19) or chronic acalculous cholecystitis (n = 2). In this subgroup, improvement was either absent (n = 13) or transient only (n = 8), lasting for 1.0 +/- 0.6 months. Patients who underwent cholecystectomy were younger compared with the rest of the group; all other variables did not show significant differences. CONCLUSIONS: Considering the overlap and correlation between gastric and gallbladder function, we should raise the threshold for biliary dyskinesia and reassess the appropriateness of surgical therapy, especially in patients with coexisting dyspeptic symptoms. PMID- 25502155 TI - Airway assessment of patients undergoing endoscopic procedures. AB - OBJECTIVES: In advance of endoscopic procedures, an evaluation to assess the risk of sedation is performed by the gastroenterologist. Based on regulations, gastroenterologists are required to perform an airway assessment. At this time, data supporting this regulation are limited; therefore, we evaluated airway assessment accuracy by gastroenterologists before endoscopic procedures. METHODS: A retrospective, single tertiary care center study was performed from May 2012 through August 2013. Patients who underwent an endoscopy or colonoscopy performed at the University of Missouri-Columbia with documented Mallampati scores were included in the analysis. Three primary cohorts of patients were included in our study: gastroenterologist versus anesthesiologist, gastroenterologist versus other gastroenterologists, and gastroenterologists versus themselves. Data were collected and recorded for patient age, body mass index, and Mallampati score. Statistical analysis was performed using descriptive statistics and linear weighted kappa analysis for agreement. RESULTS: For gastroenterologists versus anesthesiologists and versus other gastroenterologists, the agreement on Mallampati scores was poor (weighted kappa index 0.103, 95% confidence interval [CI] -0.0126 to 0.219; percentage of agreement 42% and 0.120, 95% CI -0.0211 to 0.260; percentage of agreement 46%, respectively). For gastroenterologists versus themselves for the same patient, the agreement on Mallampati scores was only moderate (weighted kappa index 0.420, 95% CI 0.119-0.722; percentage of agreement 65%). CONCLUSIONS: Gastroenterologists performing a preprocedure assessment using Mallampati scores have poor agreement with anesthesiologists and colleagues and only moderate agreement with themselves. PMID- 25502154 TI - Commentary on "Cholecystectomy for biliary dyskinesia in gastroparesis: mimic or misfortune?". PMID- 25502156 TI - Edmonton Symptom Assessment System for outpatient symptom monitoring of sickle cell disease. AB - OBJECTIVES: Although the extension of palliative care methodology to sickle cell disease (SCD) care has been proposed, there is no current standard for symptom assessment. Our goal was to assess the feasibility of integrating the Edmonton Symptom Assessment System (ESAS) into the outpatient management of SCD. METHODS: Seventy-five adult patients presenting for outpatient visits at a comprehensive SCD center were enrolled. Patients completed the ESAS (self-report of 10 symptoms during the last 24 hours) and a survey regarding their opinion of the ESAS at enrollment and follow-up. RESULTS: Pain (P = 0.0272) was the only symptom score that changed significantly between the initial and follow-up visits. In patients with a self-reported pain crisis, pain (P < 0.0001), fatigue (P = 0.0025), depression (P = 0.0458), nausea (P = 0.0384), and symptom distress scores (P = 0.0019) were significantly higher than for patients without a pain crisis. On the initial visit, 92% of all patients agreed or strongly agreed that the ESAS was easy to complete; 83% were satisfied or very satisfied with the ESAS as a way to report symptoms. CONCLUSIONS: Our data suggest that the ESAS is well received and can be successfully included as part of the longitudinal symptom management strategy for SCD. PMID- 25502157 TI - Commentary on "Edmonton Symptom Assessment System for outpatient symptom monitoring of sickle cell disease". PMID- 25502158 TI - Metformin use and the risk of esophageal cancer in Barrett esophagus. AB - OBJECTIVES: Diabetes mellitus is a significant risk factor for total cancer incidence and mortality. Metformin, a commonly used antidiabetic drug, has been shown to be protective against different types of cancers; however, its role in esophageal cancer is unknown. The goal of this study was to determine whether the use of metformin modifies the risk of development of esophageal adenocarcinoma in patients with Barrett esophagus. METHODS: Patients with diagnoses of Barrett esophagus and esophageal cancer were identified during a 20-year period. Demographic and clinical data were collected. The outcome variable was esophageal adenocarcinoma. Univariate analysis was performed using two-sample t tests for continuous variables or the Fisher exact test for categorical variables. Multiple logistic regression analysis was then performed using the significant variables. RESULTS: A total of 583 patients were identified with the diagnosis of Barrett esophagus or esophageal adenocarcinoma from 1992 to 2012. Of these, 115 had esophageal adenocarcinoma and 468 had Barrett esophagus. Age, smoking, and diabetes mellitus were found to be significant risk factors for the development of esophageal cancer with the following results: age (P < 0.001), smoking (P = 0.003), diabetes mellitus (P = 0.007). Statin use was protective against the development of cancer with P = 0.001. Metformin use was neither associated with an increased nor a decreased risk of esophageal cancer. CONCLUSIONS: The three independent variables that predicted progression of Barrett esophagus to esophageal adenocarcinoma in our study were older age, smoking, and diabetes mellitus. Statin use showed protective effect against development of esophageal adenocarcinoma. Metformin use did not demonstrate any statistically significant protective effect. PMID- 25502159 TI - Can alpha-lipoic acid mitigate progression of aging-related decline caused by oxidative stress? AB - Aging is progressively deteriorating physiological function that leads to increasing risks of illness and death. Increases in life expectancy and the aging of a large segment of the population have made age-related disability and morbidity increasingly important issues. Supplements such as alpha-lipoic acid may have antiaging effects by positively affecting oxidative stress, cognitive function, and cardiovascular function. PMID- 25502160 TI - Eosinophilia in HIV-infected cases. PMID- 25502161 TI - Authors' response. PMID- 25502162 TI - Limb salvage is a viable option in managing diabetic foot ulcers. PMID- 25502165 TI - Photophysics and photochemistry of cis- and trans-hydroquinone, catechol and their ammonia clusters: a theoretical study. AB - Excited state hydrogen transfer in hydroquinone- and catechol-ammonia clusters has been extensively investigated by high level ab initio methods. The potential energy profiles of the title systems at different electronic states have been determined at the MP2/CC2 levels of theory. It has been predicted that double hydrogen transfer (DHT) takes place as the main consequence of photoexcited tetra ammoniated systems. Consequently, the DHT processes lead the excited systems to the (1)pisigma*-S0 conical intersections, which is responsible for the ultrafast non-radiative relaxation of UV-excited clusters to their ground states. Moreover, according to our calculated results, the single hydrogen detachment or hydrogen transfer process essentially governs the relaxation dynamics of smaller sized clustered systems (mono- and di-ammoniated). PMID- 25502166 TI - Concomitant septal myectomy in patients undergoing aortic valve replacement for severe aortic stenosis. AB - BACKGROUND: Patients with severe aortic stenosis (AS) are often found to have asymmetric septal hypertrophy (ASH). With low sensitivity of echocardiography for detecting dynamic left ventricular outflow tract (LVOT) obstruction in severe AS, we adopted a routine intraoperative inspection of LVOT strategy for aortic valve replacement (AVR), and performed concomitant septal myectomy (CSM) as necessary. We sought to (1) evaluate surgical outcomes of CSM, (2) suggest preoperative echocardiographic parameters that correlate with findings of ASH, and (3) determine the predictors of CSM. METHODS AND RESULTS: A single surgeon performed AVR for moderate-to-severe AS in 301 patients from 2007 to 2012. CSM was performed in 35 (11.6%) patients, resulting in AVR vs. AVR+CSM groups. Echocardiographic parameters, including the ratio of LVOT to aortic annular diameter (LVOT/AA), were compared. Mortality rate was comparable between groups (P=0.37). There were no postoperative complications related to CSM. The AVR+CSM group had a smaller LVOT/AA ratio (P=0.0012). The predictor of CSM was implanted valve size <= 21 mm (odds ratio 3.2, confidence interval 1.54-6.65, P=0.002). CONCLUSIONS: CSM can be performed safely at the time of AVR. The preoperative echocardiographic LVOT/AA ratio may help in detecting ASH. As an implanted valve size <= 21 mm was the only risk factor for CSM, careful assessment of LVOT is important in patients with a small aortic annulus. PMID- 25502167 TI - Early neointimal coverage and vasodilator response following biodegradable polymer sirolimus-eluting vs. durable polymer zotarolimus-eluting stents in patients with acute coronary syndrome -HATTRICK-OCT trial. AB - BACKGROUND: Patients at high bleeding risk would benefit from a shorter dual antiplatelet therapy after PCI. Compared to first-generation devices, the design of newer generation drug-eluting stents may facilitate more rapid anatomical and functional healing of stented vessel based on thinner stent platforms, biodegradable/biocompatible polymers and rapid drug elution. METHODS AND RESULTS: Forty-four non-diabetic patients with acute coronary syndrome (ACS) and culprit lesion in the LAD were randomized to receive either biodegradable polymer sirolimus-eluting stent (BP-SES) or durable polymer zotarolimus-eluting stent (DP ZES). Neointimal strut coverage was examined using optical coherence tomography, and vasodilator response on invasive thermodilution-derived coronary flow reserve (CFR) at 3-month follow-up. The primary endpoints were percent uncovered struts and CFR. A total of 425 cross-sections (4,897 struts) were analyzed in the BP-SES group, and 425 cross-sections (5,467 struts) in the DP-ZES group. The percent uncovered struts was lower in the BP-SES group compared with the DP-ZES group, both at strut level (3.9% vs. 8.9%, respectively, P<0.001), and stent level (3.9 +/- 3.2% vs. 8.9 +/- 6.9%, respectively, P=0.019). No significant difference was found between the 2 groups regarding CFR (3.0 +/- 1.3 vs. 3.2 +/- 1.0, respectively, P>0.05). CONCLUSIONS: In non-diabetic patients with ACS, BP-SES provided slightly better stent strut coverage at 3 months compared with DP-ZES, but neither stent was fully covered. No difference in vasodilator response was seen. PMID- 25502164 TI - Relationships of maternal and paternal anthropometry with neonatal body size, proportions and adiposity in an Australian cohort. AB - The patterns of association between maternal or paternal and neonatal phenotype may offer insight into how neonatal characteristics are shaped by evolutionary processes, such as conflicting parental interests in fetal investment and obstetric constraints. Paternal interests are theoretically served by maximizing fetal growth, and maternal interests by managing investment in current and future offspring, but whether paternal and maternal influences act on different components of overall size is unknown. We tested whether parents' prepregnancy height and body mass index (BMI) were related to neonatal anthropometry (birthweight, head circumference, absolute and proportional limb segment and trunk lengths, subcutaneous fat) among 1,041 Australian neonates using stepwise linear regression. Maternal and paternal height and maternal BMI were associated with birthweight. Paternal height related to offspring forearm and lower leg lengths, maternal height and BMI to neonatal head circumference, and maternal BMI to offspring adiposity. Principal components analysis identified three components of variability reflecting neonatal "head and trunk skeletal size," "adiposity," and "limb lengths." Regression analyses of the component scores supported the associations of head and trunk size or adiposity with maternal anthropometry, and limb lengths with paternal anthropometry. Our results suggest that while neonatal fatness reflects environmental conditions (maternal physiology), head circumference and limb and trunk lengths show differing associations with parental anthropometry. These patterns may reflect genetics, parental imprinting and environmental influences in a manner consistent with parental conflicts of interest. Paternal height may relate to neonatal limb length as a means of increasing fetal growth without exacerbating the risk of obstetric complications. PMID- 25502168 TI - Report of the American Heart Association (AHA) Scientific Sessions 2014, Chicago. AB - The American Heart Association (AHA) Scientific Sessions were held in Chicago on November 15-19, 2014. The meeting attracted more than 17,000 participants, including physicians, research scientists, students, and paramedical personnel, from more than 100 countries. Sessions over the 5 days included comprehensive and unparalleled education delivered via more than 5,000 presentations, with 1,000 invited faculty members and 4,000 abstract presentations from world leaders in cardiovascular (CV) disease. There were 16 trials scheduled in 4 late-breaking clinical trial sessions. The Dual Antiplatelet Therapy study revealed that aspirin plus a thienopyridine beyond 1 year subsequent to placement of a drug eluting stent, as compared with aspirin therapy alone, significantly reduced stent thrombosis and major CV and cerebrovascular events but was associated with increased risk of bleeding. The IMPROVE-IT research showed that, relative to simvastatin with placebo, simvastatin with 10 mg of ezetimibe daily led to a significantly lower primary combined endpoint in moderate- to high-risk patients, who stabilized following acute coronary syndrome. This was the first trial to demonstrate incremental clinical benefit by adding a nonstatin agent to statin therapy and reaffirmed the low-density lipoprotein (LDL) hypothesis stating that reducing LDL-cholesterol prevents CV events. Summaries and overviews of both the late-breaking trials and the sessions to which members of the Japanese Circulation Society contributed are presented. PMID- 25502170 TI - Combating obesity through healthy eating behavior: a call for system dynamics optimization. AB - Poor eating behavior has been identified as one of the core contributory factors of the childhood obesity epidemic. The consequences of obesity on numerous aspects of life are thoroughly explored in the existing literature. For instance, evidence shows that obesity is linked to incidences of diseases such as heart disease, type-2 diabetes, and some cancers, as well as psychosocial problems. To respond to the increasing trends in the UK, in 2008 the government set a target to reverse the prevalence of obesity (POB) back to 2000 levels by 2020. This paper will outline the application of system dynamics (SD) optimization to simulate the effect of changes in the eating behavior of British children (aged 2 to 15 years) on weight and obesity. This study also will identify how long it will take to achieve the government's target. This paper proposed a simulation model called Intervention Childhood Obesity Dynamics (ICOD) by focusing the interrelations between various strands of knowledge in one complex human weight regulation system. The model offers distinct insights into the dynamics by capturing the complex interdependencies from the causal loop and feedback structure, with the intention to better understand how eating behaviors influence children's weight, body mass index (BMI), and POB measurement. This study proposed a set of equations that are revised from the original (baseline) equations. The new functions are constructed using a RAMP function of linear decrement in portion size and number of meal variables from 2013 until 2020 in order to achieve the 2020 desired target. Findings from the optimization analysis revealed that the 2020 target won't be achieved until 2026 at the earliest, six years late. Thus, the model suggested that a longer period may be needed to significantly reduce obesity in this population. PMID- 25502172 TI - Fragmented QRS complex as an emerging risk indicator in severe aortic stenosis. PMID- 25502171 TI - ORC4 surrounds extruded chromatin in female meiosis. AB - Six proteins, ORC1-6, make up the origin recognition complex (ORC) that initiates licensing of DNA replication origins. We have previously reported that subunit ORC2 is localized between the separating maternal chromosomes at anaphase II just after fertilization and is present in zygotic pronuclei at G1. Here, we found that ORC1, 3, and 5 all localize between the chromosomes at anaphase II, but could not be detected in zygotic G1. ORC6 localized to the periphery of the nucleoli at all zygotic stages. We identified an unexpected potential role for ORC4 in polar body formation. We found that in both female meiotic divisions, ORC4 surrounds the set of chromosomes, as a sphere-like structure, that will eventually be discarded in the polar bodies, but not the chromosomes that segregate into the oocyte. None of the other five ORC proteins are involved in this structure. In Zygotic G1, ORC4 surrounds the nuclei of the polar bodies, but was not detectable in the pronuclei. When the zygote entered mitosis ORC4 was only detected in the polar body. However, ORC4 appeared on both sets of separating chromosomes at telophase. At this point, the ORC4 that was in the polar body also migrated into the nuclei, suggesting that ORC4 or an associated protein is modified during the first embryonic cell cycle to allow it to bind DNA. Our results suggest that ORC4 may help identify the chromosomes that are destined to be expelled in the polar body, and may play a role in polar body extrusion. ORC4 surrounds the chromatin that will be extruded in the polar body in both female meiotic divisions, then makes a transition from the cytoplasm to the chromosomes at zygotic anaphase, suggesting multiple roles for this replication licensing protein. PMID- 25502173 TI - Gender-Specific Differences in the Skeletal Response to Continuous PTH in Mice Lacking the IGF1 Receptor in Mature Osteoblasts. AB - The primary goal of this study was to determine whether the IGF1R in mature osteoblasts and osteocytes was required for the catabolic actions of continuous parathyroid hormone (cPTH). Igf1r was deleted from male and female FVN/B mice by breeding with mice expressing cre recombinase under control of the osteocalcin promoter ((0CN) Igfr1(-/-) ). Littermates lacking the cre recombinase served as controls. PTH, 60 MUg/kg/d, was administered continuously by Alzet minipumps for 4 weeks. Blood was obtained for indices of calcium metabolism. The femurs were examined by micro-computed tomography for structure, immunohistochemistry for IGF1R expression, histomorphometry for bone formation rates (BFR), mRNA levels by qPCR, and bone marrow stromal cell cultures (BMSC) for alkaline phosphatase activity (ALP(+) ), mineralization, and osteoblast-induced osteoclastogenesis. Whereas cPTH led to a reduction in trabecular bone volume/tissue volume (BV/TV) and cortical thickness in the control females, no change was found in the control males. Although trabecular BV/TV and cortical thickness were reduced in the (0CN) Igfr1(-/-) mice of both sexes, no further reduction after cPTH was found in the females, unlike the reduction in males. BFR was stimulated by cPTH in the controls but blocked by Igf1r deletion in the females. The (0CN) Igfr1(-/-) male mice showed a partial response. ALP(+) and mineralized colony formation were higher in BMSC from control males than from control females. These markers were increased by cPTH in both sexes, but BMSC from male (0CN) Igfr1(-/-) also were increased by cPTH, unlike those from female (0CN) Igfr1(-/-) . cPTH stimulated receptor activator of NF-kappaB ligand (RANKL) and decreased osteoprotegerin and alkaline phosphatase expression more in control female bone than in control male bone. Deletion of Igf1r blocked these effects of cPTH in the female but not in the male. However, PTH stimulation of osteoblast-driven osteoclastogenesis was blocked by deleting Igfr1 in both sexes. We conclude that cPTH is catabolic in female but not male mice. Moreover, IGF1 signaling plays a greater role in the skeletal actions of cPTH in the female mouse than in the male mouse, which may underlie the sex differences in the response to cPTH. PMID- 25502175 TI - Curcumin and its major metabolites inhibit the inflammatory response induced by lipopolysaccharide: translocation of nuclear factor-kappaB as potential target. AB - The aim of the present study was to investigate and compare the anti-inflammatory activities of curcumin and its three metabolites, tetrahydrocurcumin, hexahydrocurcumin and octahydrocurcumin in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The results demonstrated that overproduction of nitric oxide (NO) was potently inhibited following treatment with curcumin and its three metabolites. In addition, curcumin and tetrahydrocurcumin significantly inhibited the release of prominent cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6); however, hexahydrocurcumin and octahydrocurcumin did not significantly alter cytokine release. Furthermore, the present study investigated the effect of curcumin and its metabolites on the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and activated-nuclear factor kappa B (NF-kappaB); the results showed that curcumin and its three metabolites significantly inhibited LPS-mediated upregulation of iNOS and COX-2 as well as NF-kappaB activation. However, curcumin exerted a more potent effect on LPS-stimulated RAW 264.7 cells compared to that of its three metabolites, of which tetrahydrocurcuim was found to be the most pharmacologically active. In conclusion, the results of the present study demonstrated that curcumin and its major metabolites inhibited the LPS-induced inflammatory response via the mechanism of inhibiting NF-kappaB translocation to the nucleus. PMID- 25502174 TI - MTHFD1 polymorphism as maternal risk for neural tube defects: a meta-analysis. AB - Recently, the association between methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) G1958A polymorphism and neural tube defects (NTD) susceptibility has been widely investigated; however, the results remained inconclusive. Hence, we conducted a meta-analysis to evaluate the effect of MTHFD1 G1958A polymorphism on NTD. The relative literatures were identified by search of the electronic databases PubMed, MEDLINE, and EMBASE. The extracted data were statistically analyzed, and pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated to estimate the association strength using Stata version 11.0 software. Finally, ten studies met our inclusion criteria, including 2,132/4,082 in NTD infants and controls; 1,402/3,136 in mothers with NTD offspring and controls; and 993/2,879 in fathers with NTD offspring and controls. This meta analysis showed that, compared with the mothers with GG genotype, the women with AA genotype had an increased risk of NTD in their offspring, with OR values and 95 % CI at 1.39 (1.16-1.68), p < 0.001. Interestingly, fathers with AG genotype had a significant decreased risk of NTD offspring (OR = 0.79, 95 % CI = 0.66 0.94, p = 0.009). However, there was no significant association between the MTHFD1 G1958A polymorphism in NTD patients and the risk of NTD. In conclusion, the present meta-analysis provided evidence of the association between maternal MTHFD1 G1958A polymorphism and NTD susceptibility. PMID- 25502176 TI - Quantitative measurement of cancer tissue biomarkers in the lab and in the clinic. AB - Detection of biomolecules in tissues provides contextual information and the possibility to assess the interaction of different cell types and markers. Routine qualitative assessment of immune- and oligonucleotide-based methods in research and the clinic has been associated with assay variability because of lack of stringent validation and subjective interpretation of results. As a result, the vast majority of in situ assays in clinical usage are nonquantitative and, although useful, often of questionable scientific validity. Here, we revisit the reporters and methods used for single- and multiplexed in situ visualization of protein and RNA. Then we examine methods for the use of quantitative platforms for in situ measurement of protein and mRNA levels. Finally, we discuss the challenges of the transition of these methods to the clinic and their potential role as tools for development of companion diagnostic tests. PMID- 25502177 TI - Cholesterol gallstone disease: focusing on the role of gallbladder. AB - Gallstone disease (GSD) is one of the most common biliary tract diseases worldwide in which both genetic and environmental factors have roles in its pathogenesis. Biliary cholesterol supersaturation from metabolic defects in the liver is traditionally seen as the main pathogenic factor. Recently, there have been renewed investigative interests in the downstream events that occur in gallbladder lithogenesis. This article focuses on the role of the gallbladder in the pathogenesis of cholesterol GSD (CGD). Various conditions affecting the crystallization process are discussed, such as gallbladder motility, concentrating function, lipid transport, and an imbalance between pro-nucleating and nucleation inhibiting proteins. PMID- 25502178 TI - A modified murine model of systemic sclerosis: bleomycin given by pump infusion induced skin and pulmonary inflammation and fibrosis. AB - Daily subcutaneous (sc) injection of bleomycin (BLM) causes dermal fibrosis but rarely causes lung changes in mice. There are also significant disadvantages to this traditional model for systemic sclerosis, including a variable distribution of lesions and a requirement for repetitive procedures. The present study was undertaken to develop a convenient method of BLM administration that yields stable dermal inflammation and fibrosis with extensive and reproducible interstitial lung disease (ILD) in mice. Osmotic minipumps containing BLM (150 mg/kg) or saline were implanted sc in C57BL/6 mice and the drug was delivered as a continuous infusion over 1~4 weeks. The time course of morphological features, collagen content, and pro-inflammatory cytokine expression in the skin and the lungs were analyzed. Pathological examination demonstrated dominant inflammatory infiltrates at week 1 and significant fibrosis at week 4. Decreased microvessel density and increased myofibroblast counts were observed in the skin of BLM treated mice at week 4. In addition, there were obvious increases in dermal infiltration of CD45(+) leukocytes, including F4/80(+) macrophages, Gr-1(+) neutrophils, and CD3(+) T lymphocytes in BLM-treated mice. IL-1beta, IL-4, and CXCL2 transcripts were continually upregulated by BLM in the skin and lung tissues. In addition, lungs from BLM-treated mice showed significant inflammatory infiltrates and confluent subpleural fibrosis at week 4. In conclusion, this modified murine model for drug-induced systemic inflammation and fibrosis uses a single procedure and provides reproducible skin and lung lesions, mimicking human systemic sclerosis (SSc) with ILD-like manifestation. PMID- 25502179 TI - A randomized control study on the procedure for switching epoetin beta (EPO) to epoetin beta pegol (CERA) in the treatment of renal anemia in maintenance hemodialysis patients. AB - BACKGROUND/AIMS: We investigated the method of switching EPO to CERA that does not cause a decrease in the Hb level. METHODS: Fifty EPO-treated patients were randomly divided into two groups in which CERA was administered every two weeks (Q2W) or every four weeks (Q4W). After 8 weeks of treatment, the frequency of administration was changed to Q4W in the former. Follow-up was performed for 24 weeks. RESULTS: There was no difference in the Hb level between the two groups until 6 weeks. In the Q2W group, the Hb maintained a stable level throughout a study period. However, in the Q4W group, the Hb level was significantly lower than in the Q2W group at weeks 9, 11, and 13. CONCLUSION: EPO switching to CERA without a decrease in the Hb level could be achieved by administering CERA every two weeks, but not every four weeks, for a specific period after switching. PMID- 25502180 TI - A natural genetic variant of granzyme B confers lethality to a common viral infection. AB - Many immune response genes are highly polymorphic, consistent with the selective pressure imposed by pathogens over evolutionary time, and the need to balance infection control with the risk of auto-immunity. Epidemiological and genomic studies have identified many genetic variants that confer susceptibility or resistance to pathogenic micro-organisms. While extensive polymorphism has been reported for the granzyme B (GzmB) gene, its relevance to pathogen immunity is unexplored. Here, we describe the biochemical and cytotoxic functions of a common allele of GzmB (GzmBW) common in wild mouse. While retaining 'Asp-ase' activity, GzmBW has substrate preferences that differ considerably from GzmBP, which is common to all inbred strains. In vitro, GzmBW preferentially cleaves recombinant Bid, whereas GzmBP activates pro-caspases directly. Recombinant GzmBW and GzmBP induced equivalent apoptosis of uninfected targets cells when delivered with perforin in vitro. Nonetheless, mice homozygous for GzmBW were unable to control murine cytomegalovirus (MCMV) infection, and succumbed as a result of excessive liver damage. Although similar numbers of anti-viral CD8 T cells were generated in both mouse strains, GzmBW-expressing CD8 T cells isolated from infected mice were unable to kill MCMV-infected targets in vitro. Our results suggest that known virally-encoded inhibitors of the intrinsic (mitochondrial) apoptotic pathway account for the increased susceptibility of GzmBW mice to MCMV. We conclude that different natural variants of GzmB have a profound impact on the immune response to a common and authentic viral pathogen. PMID- 25502181 TI - Phase II study evaluating efficacy and safety of everolimus with letrozole for management of advanced (unresectable or metastatic) non-small cell lung cancer after failure of platinum-based treatment: a preliminary analysis of toxicity. AB - INTRODUCTION: Lung cancer is one of the most common malignancies worldwide. Non small cell lung cancer (NSCLC) comprises the majority of the cases of lung cancer. Previous studies have demonstrated a role for both the estrogen pathway and mammalian target of rapamycin (mTOR) in NSCLC. METHODS: This single-arm phase 2 study was designed to assess the safety and efficacy of combination treatment with aromatase inhibitor-letrozole-and mTOR inhibitor-everolimus-in the treatment of patients with advanced (unresectable stage III or stage IV) NSCLC who had failed at least one line of platinum-based chemotherapy. RESULTS: The study was closed after enrolling five patients due to safety concerns. Of the five patients treated with the study combination, two patients developed grade 5 pulmonary toxicity and another patient developed reversible grade 4 pulmonary toxicity. CONCLUSIONS: There is a probable causal relationship between the study medication and the reported serious adverse events. In the absence of additional clinical data in lung cancer patients, we recommend that extreme caution be exercised in the use of combined letrozole and everolimus regimens in patients with advanced lung cancers, active pulmonary pathologies, or both. PMID- 25502182 TI - Newborn blood spot screening test using multiplexed real-time PCR to simultaneously screen for spinal muscular atrophy and severe combined immunodeficiency. AB - BACKGROUND: Spinal muscular atrophy (SMA) is a motor neuron disorder caused by the absence of a functional survival of motor neuron 1, telomeric (SMN1) gene. Type I SMA, a lethal disease of infancy, accounts for the majority of cases. Newborn blood spot screening (NBS) to detect severe combined immunodeficiency (SCID) has been implemented in public health laboratories in the last 5 years. SCID detection is based on real-time PCR assays to measure T-cell receptor excision circles (TREC), a byproduct of T-cell development. We modified a multiplexed real-time PCR TREC assay to simultaneously determine the presence or absence of the SMN1 gene from a dried blood spot (DBS) punch in a single reaction well. METHOD: An SMN1 assay using a locked nucleic acid probe was initially developed with cell culture and umbilical cord blood (UCB) DNA extracts, and then integrated into the TREC assay. DBS punches were placed in 96-well arrays, washed, and amplified directly using reagents specific for TREC, a reference gene [ribonuclease P/MRP 30kDa subunit (RPP30)], and the SMN1 gene. The assay was tested on DBS made from UCB units and from peripheral blood samples of SMA affected individuals and their family members. RESULTS: DBS made from SMA affected individuals showed no SMN1-specific amplification, whereas DBS made from all unaffected carriers and UCB showed SMN1 amplification above a well-defined threshold. TREC and RPP30 content in all DBS were within the age-adjusted expected range. CONCLUSIONS: SMA caused by the absence of SMN1 can be detected from the same DBS punch used to screen newborns for SCID. PMID- 25502183 TI - UMG Lenti: novel lentiviral vectors for efficient transgene- and reporter gene expression in human early hematopoietic progenitors. AB - Lentiviral vectors are widely used to investigate the biological properties of regulatory proteins and/or of leukaemia-associated oncogenes by stably enforcing their expression in hematopoietic stem and progenitor cells. In these studies it is critical to be able to monitor and/or sort the infected cells, typically via fluorescent proteins encoded by the modified viral genome. The most popular strategy to ensure co-expression of transgene and reporter gene is to insert between these cDNAs an IRES element, thus generating bi-cistronic mRNAs whose transcription is driven by a single promoter. However, while the product of the gene located upstream of the IRES is generally abundantly expressed, the translation of the downstream cDNA (typically encoding the reporter protein) is often inconsistent, which hinders the detection and the isolation of transduced cells. To overcome these limitations, we developed novel lentiviral dual-promoter vectors (named UMG-LV5 and -LV6) where transgene expression is driven by the potent UBC promoter and that of the reporter protein, EGFP, by the minimal regulatory element of the WASP gene. These vectors, harboring two distinct transgenes, were tested in a variety of human haematopoietic cell lines as well as in primary human CD34+ cells in comparison with the FUIGW vector that contains the expression cassette UBC-transgene-IRES-EGFP. In these experiments both UMG LV5 and UMG-LV6 yielded moderately lower transgene expression than FUIGW, but dramatically higher levels of EGFP, thereby allowing the easy distinction between transduced and non-transduced cells. An additional construct was produced, in which the cDNA encoding the reporter protein is upstream, and the transgene downstream of the IRES sequence. This vector, named UMG-LV11, proved able to promote abundant expression of both transgene product and EGFP in all cells tested. The UMG-LVs represent therefore useful vectors for gene transfer-based studies in hematopoietic stem and progenitor cells, as well as in non hematopoietic cells. PMID- 25502184 TI - Follicle-stimulating hormone receptor gene polymorphisms in women with endometriosis. AB - OBJECTIVES: The purpose of this study was to evaluate the influence of the follicle-stimulating hormone (FSH) receptor poymorphisms Asn680Ser and Thr307Ala on endometriosis in Turkish women. METHODS: Polymorphic analysis of the FSH receptor gene was performed in 100 patients with endometriosis and 100 controls. Genomic DNA was obtained from peripheral blood leukocytes and polymorphisms were investigated using restriction fragment length polymorphism analysis. RESULTS: There were no significant differences in genotype frequencies of FSH receptor gene between endometriosis patients and controls. When the patients were divided into two groups according to disease severity, we found that the patients with the SS (680 Ser/Ser) or AA (307 Ala/Ala) genotype were less likely to develop stage 3-4 endometriosis compared to the stage 1-2 endometriosis group (P = 0.004; OR: 0.177, 95% CI 0.055-0.568 and P = 0.040; OR: 0.240, 95% CI 0.061-0.938; respectively). CONCLUSIONS: The distributions of FSHR polymorphisms may not have an effect on endometriosis development but they are associated with the severity of the disease. The polymorphisms encoding SS at the position 680 and AA at the position 307 and the patients with the genotype that included alanine or serine were less likely to develop stage 3-4 endometriosis compared to the stage 1-2 endometriosis group. PMID- 25502185 TI - Plasma serotonin levels are elevated in pregnant women with hyperemesis gravidarum. AB - PURPOSE: This study aimed to determine the association between serotonin and hyperemesis gravidarum. MATERIALS AND METHODS: Plasma samples of 87 women in their first trimester pregnancies with HG (n = 28), morning sickness of pregnancy (n = 30) and control (n = 29) groups were obtained. Plasma levels of serotonin were compared between the groups, and the correlations with severity of symptoms using modified PUQE (Pregnancy Unique Quantification of Emesis) scoring, BMI, E2, hCG and TSH were calculated. RESULTS: When the groups were compared with respect to serotonin levels, the group with hyperemesis gravidarum was found to have significantly higher serotonin levels (p = 0.001). A significant positive correlation was found between the serotonin level and the PUQE score in all study subjects (r = 0.578, p = 0.0001). A serotonin threshold of >277.58 ng/mL had a sensitivity of 75%, specificity of 86.4%, positive predictive value of 72.4%, negative predictive value of 87.9%, and a likelihood ratio of 5.53 (p = 0.0001). CONCLUSIONS: Our findings support the possible role of serotonin in the pathogenesis of hyperemesis gravidarum. PMID- 25502187 TI - A novel "pro-healing" approach: the COMBOTM dual therapy stent from a pathological view. AB - Current generations of monotherapy drug-eluting stents only inhibit neointimal hyperplasia. However, these stent designs have other drawbacks such as delayed arterial healing, hypersensitivity, late stent thrombosis, and neoatherosclerosis, creating a need for a new generation of safer devices. The novel 'pro-healing' COMBOTM dual therapy stent aims to address these issues by reducing neointimal hyperplasia via an abluminal bioabsorbable polymer eluting sirolimus, and by simultaneously capturing circulating endothelial progenitor cells via luminally immobilized anti-CD34+ antibodies. Short-term preclinical data shows promising results as compared to 1st generation and 2nd generation drug-eluting stents; however long-term literature remains unavailable until now. This review aims to evaluate, histopathologically, drawbacks of the current era of stents at autopsy, review short-term preclinical and clinical data from the REMEDEE trial, and present original long-term preclinical data. To date, preclinical data shows good performance of the COMBOTM stent comparable with the safety profile of bare metal stents with minimal inflammation, increased endothelialization, and acceptable neointimal hyperplasia with no statistical evidence of late catch-up. Clinical data from the REMEDEE trial at 12 months shows non-inferiority to paclitaxel drug-eluting stents, no evidence of late stent thrombosis, and a low rate of adverse clinical events. PMID- 25502186 TI - Biocompatibility, cell growth and clinical relevance of synthetic meshes and biological matrixes for internal support in implant-based breast reconstruction. AB - PURPOSE: Biological matrixes and synthetic meshes are increasingly used in implant-based breast reconstruction (IBBR). The objective was to test different materials used for internal support in IBBR in regards to biocompatibility and discuss possible limitations in a clinical context. MATERIALS AND METHODS: In vitro investigations were performed on four relevant cell lines: Normal Human Dermal Fibroblasts (NHDF), Human White Preadipocytes (HWP), Endothelial cells (HDMEC) and Skeletal muscle cells (SkMC). A titanium-coated polypropylene mesh (TiLOOP Bra), a partially resorbable mesh (SERAGYN BR) and a porcine derived biologic matrix (Strattice) were investigated. Test of cytotoxicity, cell proliferation and oxidative stress was performed. Real-time cell analysis was used to determine adhesion rate. Light- and scanning electron microscopy investigated cell migration. RESULTS: No relevant cytotoxicity was detected for any mesh or matrix. Good cell proliferation was observed in all materials with best results for NHDF and SkMC. For HWP and HDMEC decreased proliferation and adherence to the synthetic meshes and biologic matrix were observed. Real-time cell analysis of fibroblasts incubated with the corresponding material, showed increased impedance for the synthetic meshes. A morphologic cell change was observed within all materials. Scanning electron microscopy showed good cell penetration into the meshes and matrix. The material compositions did not seem to influence the clinical outcome, although the biological matrix was much thicker compared to the synthetic meshes. CONCLUSION: Biochemical examination showed good biocompatibility for the investigated meshes and matrix. All products seem to have their value in IBBR and can be recommended for IBBR. PMID- 25502188 TI - Role of new sirolimus self-apposing stent in coronary interventions. AB - Device technology in interventional cardiology is continuously evolving. Self expandable (SE) coronary artery stents were the first device to be implanted within a human coronary artery. However, because of their initial limitations, balloon-expandable (BE) stents were predominantly developed and used in the last 30 years. Unfortunately, in challenging anatomical settings such as bifurcation lesions, large, ectatic or aneurysmal vessels, tapered vessels or vasoconstricted arteries, outcomes with BE stents are not always optimal. The Stentys (Stentys SA, Paris, France) SE nitinol stents were initially developed for the treatment of coronary bifurcation lesions. The understanding of the underlying mechanism involved in incomplete stent apposition and subsequent stent thrombosis led to the introduction of self-apposing stents in the treatment of acute coronary syndrome in order to overcome the limitations of drug-eluting stents in presence of high thrombus burden. In this regard, Stentys allows a progressive stent expansion which could reduce the rates of incomplete stent apposition by conforming to vascular remodeling. Enhancing the advantages of this technology by adding the release of an antiproliferative drug to prevent restenosis is even more attractive and potentially effective. Recently, the results of the new Stentys sirolimus-eluting stent have been reported. This article provides an overview of the pathobiological rational, device characteristics and results of the new Stentys self-expandable sirolimus-eluting stent. PMID- 25502192 TI - PiMS: a data management system for structural proteomics. AB - PiMS (Protein Information Management System) is a laboratory information management system for protein scientists. It enables researchers to enter data, track samples, and report results during the production of recombinant proteins for structural and functional applications. PiMS is the only custom LIMS for protein production, recording data from the selected target to the sample of soluble protein. The xtalPIMS extension supports crystallogenesis and has recently been extended to support crystal fishing and crystal treatment. PiMS can be configured to match local working methods by defining protocols. These are used to provide templates for recording details of the experiments. PiMS will continue to be developed in response to the needs of users to provide a unified and extensible set of software tools for protein sciences. The vision for PiMS is that it will become the laboratory standard for protein-related data management. The Science and Technology Facilities Council (STFC) distributes PiMS free to academic users under the Community Model. PMID- 25502189 TI - Genetic relationship between the addiction diagnosis in adults and their childhood measure of addiction liability. AB - Transmissible liability index (TLI), developed employing a high-risk design and item response theory, enables quantification of the latent trait of liability to drug use disorders (DUD) in children. TLI has been shown to have high heritability and predict DUD in young adulthood. This study extends prior research and determines the genetic contribution of DUD liability measured by TLI to adult liability as indexed by DUD diagnosis. The study utilizes data from a twin sample tracked from age 11 to age 25. In addition to confirming TLI's high heritability and predictive validity, it shows that the genetic component of variance in TLI assessed in childhood accounts for over half of the genetic variance in DUD diagnosis and the entire phenotypic relationship between the two liability measures. This validates TLI as an early measure of DUD liability and supports its utility in early-age genetic and other mechanistic studies of DUD. PMID- 25502191 TI - Protein structure annotation resources. AB - A key reason three-dimensional (3-D) protein structures are annotated with supporting or derived information is to understand the molecular basis of protein function. To this end, protein structure annotation databases curate key facts and observations, based on community-accepted standards, about the ~100,000 3-D experimental protein structures to date. This review will introduce the primary structure repositories, databases, and value-added structural annotation databases, as well as the range of information they provide. The different levels of annotation data (primary vs. derived vs. inferred) and how they should all be considered accordingly will also be described. PMID- 25502190 TI - The exosome and trans-acting small interfering RNAs regulate cuticular wax biosynthesis during Arabidopsis inflorescence stem development. AB - The primary aerial surfaces of land plants are covered with a cuticle, a protective layer composed of the cutin polyester matrix and cuticular waxes. Previously, we discovered a unique mechanism of regulating cuticular wax biosynthesis during Arabidopsis (Arabidopsis thaliana) stem elongation that involves ECERIFERUM7 (CER7), a core subunit of the exosome. Because loss-of function mutations in CER7 result in reduced expression of the wax biosynthetic gene CER3, we proposed that CER7 is involved in degrading a messenger RNA encoding a CER3 repressor. To identify this putative repressor, we performed a cer7 suppressor screen that resulted in the isolation of the posttranscriptional gene-silencing components RNA-DEPENDENT RNA POLYMERASE1 and SUPPRESSOR OF GENE SILENCING3, indicating that small RNAs regulate CER3 expression. To establish the identity of the effector RNA species and determine whether these RNAs control CER3 transcript levels directly, we cloned additional genes identified in our suppressor screen and performed next-generation sequencing of small RNA populations that differentially accumulate in the cer7 mutant in comparison with the wild type. Our results demonstrate that the trans-acting small interfering RNA class of small RNAs are the effector molecules involved in direct silencing of CER3 and that the expression of five additional genes (EARLY RESPONSE TO DEHYDRATION14, AUXIN RESISTANT1, a translation initiation factor SUI1 family protein, and two genes of unknown function) is controlled by both CER7 and trans acting small interfering RNAs. PMID- 25502193 TI - Prediction and analysis of intrinsically disordered proteins. AB - Intrinsically disordered proteins and protein regions (IDPs/IDRs) do not adopt a well-defined folded structure under physiological conditions. Instead, these proteins exist as heterogeneous and dynamical conformational ensembles. IDPs are widespread in eukaryotic proteomes and are involved in fundamental biological processes, mostly related to regulation and signaling. At the same time, disordered regions often pose significant challenges to the structure determination process, which generally requires highly homogeneous proteins samples. In this book chapter, we provide a brief overview of protein disorder, describe various bioinformatics resources that have been developed in recent years for their characterization, and give a general outline of their applications in various types of structural genomics projects. Traditionally, disordered segments were filtered out to optimize the yield of structure determination pipelines. However, it is becoming increasingly clear that the structural characterization of proteins cannot be complete without the incorporation of intrinsically disordered regions. PMID- 25502194 TI - Characterization and production of protein complexes by co-expression in Escherichia coli. AB - The functional units within cells are often macromolecular complexes rather than single species. Production of these complexes as assembled homogenous samples is a prerequisite for their biophysical and structural characterization and hence an understanding of their function in molecular terms. Co-expression in Escherichia coli has been used routinely to decipher the subunit composition, assembly, and production of whole protein complexes. Such complexes can then be used to reconstitute protein/nucleic acid complexes in vitro. In this chapter we present protocols for the widely utilized ACEMBL and pET-MCN/pET-MCP vector series which enable the rapid and automated co-expression of protein complexes in Escherichia coli. PMID- 25502196 TI - Production of cell surface and secreted glycoproteins in mammalian cells. AB - Mammalian protein expression systems are becoming increasingly popular for the production of eukaryotic secreted and cell surface proteins. Here we describe methods to produce recombinant proteins in adherent or suspension human embryonic kidney cell cultures, using transient transfection or stable cell lines. The protocols are easy to scale up and cost-efficient, making them suitable for protein crystallization projects and other applications that require high protein yields. PMID- 25502197 TI - Cell-free protein synthesis systems derived from cultured mammalian cells. AB - We present a technology for the production of target proteins using novel cell free systems derived from cultured human K562 cells and Chinese hamster ovary (CHO) cells. The protocol includes the cultivation of cells, the preparation of translationally active lysates, and the cell-free synthesis of desired proteins. An efficient expression vector based on the internal ribosome entry site (IRES) from the intergenic region (IGR) of the cricket paralysis virus (CrPV) was constructed for both systems. The coupled batch-based platforms enable the synthesis of a broad range of target proteins such as cytosolic proteins, secreted proteins, membrane proteins embedded into endogenous microsomes, and glycoproteins. The glycosylation of erythropoietin demonstrates the successful performance of posttranslational modifications in the novel cell-free systems. Protein yields of approximately 20 MUg/ml (K562-based cell-free system) and 50 MUg/ml (CHO-based cell-free system) of active firefly luciferase are obtained in the coupled transcription-translation systems within 3 h. As a result, both cell free protein synthesis systems serve as powerful tools for high-throughput proteomics. PMID- 25502195 TI - The production of multiprotein complexes in insect cells using the baculovirus expression system. AB - The production of a homogeneous protein sample in sufficient quantities is an essential prerequisite not only for structural investigations but represents also a rate-limiting step for many functional studies. In the cell, a large fraction of eukaryotic proteins exists as large multicomponent assemblies with many subunits, which act in concert to catalyze specific activities. Many of these complexes cannot be obtained from endogenous source material, so recombinant expression and reconstitution are then required to overcome this bottleneck. This chapter describes current strategies and protocols for the efficient production of multiprotein complexes in large quantities and of high quality, using the baculovirus/insect cell expression system. PMID- 25502198 TI - Crystallization: digging into the past to learn lessons for the future. AB - Crystals of biological macromolecules have been observed and grown for well over a century. More effort has been put into biological crystallization in the last few decades due to the importance of X-ray crystal structures, the advent of synchrotron radiation sources, improved computational speed, better software, and the availability of recombinant protein. Here we focus on two important areas of crystal growth: firstly, on techniques for stabilizing the protein sample, and secondly, on strategies and approaches for selecting the crystallization cocktails most suitable for different strategies. PMID- 25502199 TI - Screening of stable G-protein-coupled receptor variants in Saccharomyces cerevisiae. AB - G-protein-coupled receptors (GPCRs) are not only the largest protein family, but as a whole, they represent the largest group of therapeutic drug targets. Recent successes in the determination of GPCR structures have relied on the stabilization of receptors to overcome the difficulties in expression and purification. Although a large quantity of purified protein is needed for structural determination, the majority of wild-type GPCRs are too unstable to express and purify on a large scale. Therefore, rapid screening of highly expressed stable receptor "variants" is crucial. It has been demonstrated that fusing green fluorescent protein (GFP) to a target membrane protein facilitates the evaluation of the physical properties of the membrane protein in detergent. Furthermore, the budding yeast Saccharomyces cerevisiae enables rapid construction of an expression vector via its own efficient homologous recombination system. Herein, we describe the protocols for rapid construction and screening of stable GPCR variants using GFP and S. cerevisiae. PMID- 25502200 TI - Cell-free expression of G-protein-coupled receptors. AB - Cell-free expression has emerged as a new standard for the production of membrane proteins. The reduction of expression complexity in cell-free systems eliminates central bottlenecks and allows the reliable and efficient synthesis of many different types of membrane proteins. Furthermore, the open accessibility of cell free reactions enables the co-translational solubilization of cell-free expressed membrane proteins in a large variety of supplied additives. Hydrophobic environments can therefore be adjusted according to the requirements of individual membrane protein targets. We present different approaches for the preparative scale cell-free production of G-protein-coupled receptors using the extracts of Escherichia coli cells. We exemplify expression conditions implementing detergents, nanodiscs, or liposomes. The generated protein samples could be directly used for further functional characterization. PMID- 25502202 TI - Methods for the successful crystallization of membrane proteins. AB - In recent years much effort has been put towards innovative developments to overcome the numerous obstacles associated with structure determination of membrane proteins by X-ray crystallography. The advent of genomics and proteomics initiatives combined with high-throughput technologies, such as automation, miniaturization, integration, and third-generation synchrotrons, has enhanced membrane protein structure determination rate. Nevertheless, crystallization of membrane proteins still remains one of the most troublesome hurdles that every structural group must undertake. This chapter presents high-throughput methods easily available to any researcher interested in membrane protein characterization and crystallization. It is our hope this chapter can be used as a positive guide to all who are attempting crystallizing membrane proteins. PMID- 25502201 TI - GFP-based expression screening of membrane proteins in insect cells using the baculovirus system. AB - A key step in the production of recombinant membrane proteins for structural studies is the optimization of protein yield and quality. One commonly used approach is to fuse the protein to green fluorescent protein (GFP), enabling expression to be tracked without the need to purify the protein. Combining fusion to green fluorescent protein with the baculovirus expression system provides a useful platform for both screening and production of eukaryotic membrane proteins. In this chapter we describe our protocol for the expression screening of membrane proteins in insect cells using fusion to GFP as a reporter. We use both SDS-PAGE with in-gel fluorescence imaging and fluorescence-detection size exclusion chromatography (FSEC) to screen for expression. PMID- 25502204 TI - CD spectroscopy: an essential tool for quality control of protein folding. AB - The production of diffraction quality protein crystals for X-ray crystallography has been greatly accelerated by the development of high-throughput protein (HTP) methods, which enable a large number of crystallization conditions to be rapidly investigated. Monitoring sample quality and the effect of crystallization buffers on protein behavior in solution should be considered as part of the crystallization experiment. Circular Dichroism (CD) spectroscopy is the ideal technique for these tasks as it can be operated in a high-throughput mode. Using CD to screen ligand binding interactions could show whether protein function/activity is retained, altered, or lost under different crystallization conditions. In this chapter, several methods for high-throughput CD (HTCD) applied to the preparation of proteins for crystallization will be presented. Quality control (QC) of protein batches in terms of conformational folding is often disregarded in protein production. Examples of batch-to-batch variation in the local tertiary structure of aromatic side chain residues revealed by CD will be discussed. In some of the examples, the fact that ligand binding properties were affected by changes in folding clearly shows that the characterization of folding of recombinant protein batches should not be ignored but be implemented as an important part of protein quality control. PMID- 25502205 TI - High-throughput studies of protein shapes and interactions by synchrotron small angle X-ray scattering. AB - Solution-based small angle X-ray scattering (SAXS) affords the opportunity to extract accurate structural parameters and global shape information from diverse biological macromolecular systems. SAXS is an ideal complementary technique to other structural and biophysical methods but it can also be applied alone to access structural information that is otherwise unobtainable using high resolution methods. Macromolecular structures ranging from kilodaltons to gigadaltons can be analyzed, which encompasses the size of most proteins and functional cellular complexes. The SAXS analysis is performed using only a few microliters of solution containing microgram quantities of purified material in sample environments that can be tailored to mimic physiological conditions or altered to suit a particular question. High-brilliance synchrotron X-ray sources and parallel advances in hardware and computing have reduced data acquisition times to the millisecond range and the application of automated methods have allowed data processing and low resolution shape modelling to be completed within minutes. These developments have paved the way for high-throughput studies that generate significant quantities of structural information over a short period of time. Here, we briefly consider the basics of SAXS and describe major methods and protocols employed in high-throughput SAXS studies. PMID- 25502203 TI - Application of in situ diffraction in high-throughput structure determination platforms. AB - Macromolecular crystallography (MX) is the most powerful technique available to structural biologists to visualize in atomic detail the macromolecular machinery of the cell. Since the emergence of structural genomics initiatives, significant advances have been made in all key steps of the structure determination process. In particular, third-generation synchrotron sources and the application of highly automated approaches to data acquisition and analysis at these facilities have been the major factors in the rate of increase of macromolecular structures determined annually. A plethora of tools are now available to users of synchrotron beamlines to enable rapid and efficient evaluation of samples, collection of the best data, and in favorable cases structure solution in near real time. Here, we provide a short overview of the emerging use of collecting X ray diffraction data directly from the crystallization experiment. These in situ experiments are now routinely available to users at a number of synchrotron MX beamlines. A practical guide to the use of the method on the MX suite of beamlines at Diamond Light Source is given. PMID- 25502206 TI - Automated structure determination from NMR spectra. AB - Three-dimensional structures of proteins in solution can be calculated on the basis of conformational restraints derived from NMR measurements. This chapter gives an overview of the computational methods for NMR protein structure analysis highlighting recent automated methods for the assignment of NMR spectra, the collection of conformational restraints, and the structure calculation. PMID- 25502207 TI - Solid-state nuclear magnetic resonance spectroscopy for membrane protein structure determination. AB - Solid-state NMR (ssNMR) is a versatile technique that can provide high-resolution (sub-angstrom) structural data for integral membrane proteins embedded in native and model membrane environments. The methodologies for a priori structure determination have for the most part been developed using samples with crystalline and fibrous morphologies. However, the techniques are now being applied to large, polytopic membrane proteins including receptors, ion channels, and porins. ssNMR data may be used to annotate and refine existing structures in regions of the protein not fully resolved by crystallography (including ligand binding sites and mobile solvent accessible loop regions). This review describes the spectroscopic experiments and data analysis methods (including assignment) used to generate high-resolution structural data for membrane proteins. We also consider the range of sample morphologies that are appropriate for study by this method. PMID- 25502209 TI - The journal clinical anatomy publishes fast! PMID- 25502208 TI - Native mass spectrometry: towards high-throughput structural proteomics. AB - Native mass spectrometry (MS) has become a sensitive method for structural proteomics, allowing practitioners to gain insight into protein self-assembly, including stoichiometry and three-dimensional architecture, as well as complementary thermodynamic and kinetic aspects. Although MS is typically performed in vacuum, a body of literature has described how native solution-state structure is largely retained on the timescale of the experiment. Native MS offers the benefit that it requires substantially smaller quantities of a sample than traditional structural techniques such as NMR and X-ray crystallography, and is therefore well suited to high-throughput studies. Here we first describe the native MS approach and outline the structural proteomic data that it can deliver. We then provide practical details of experiments to examine the structural and dynamic properties of protein assemblies, highlighting potential pitfalls as well as principles of best practice. PMID- 25502210 TI - Competition between spontaneous symmetry breaking and single-particle gaps in trilayer graphene. AB - Many physical phenomena can be understood by single-particle physics; that is, treating particles as non-interacting entities. When this fails, many-body interactions lead to spontaneous symmetry breaking and phenomena such as fundamental particles' mass generation, superconductivity and magnetism. Competition between single-particle and many-body physics leads to rich phase diagrams. Here we show that rhombohedral-stacked trilayer graphene offers an exciting platform for studying such interplay, in which we observe a giant intrinsic gap ~42 meV that can be partially suppressed by an interlayer potential, a parallel magnetic field or a critical temperature ~36 K. Among the proposed correlated phases with spatial uniformity, our results are most consistent with a layer antiferromagnetic state with broken time reversal symmetry. These results reflect the interplay between externally induced and spontaneous symmetry breaking whose relative strengths are tunable by external fields, and provide insight into other low-dimensional systems. PMID- 25502212 TI - Baicalein inhibits the invasion of gastric cancer cells by suppressing the activity of the p38 signaling pathway. AB - Baicalein, one of the major flavonoids in Scutellaria baicalensis, has been used in anti-inflammatory and anticancer therapies for a long time. However, the antimetastatic effects and related mechanism(s) in gastric cancer remain unclear. In the present study, we tested the hypothesis that administration of baicalein may inhibit the proliferation, motility and invasion of human gastric cancer cell lines by regulating the p38 signaling pathway. In the present study, we found that baicalein could inhibit migration and invasion of gastric cancer cells. Additionally, after treating with baicalein for 24 h, the expression levels of matrix metalloproteinase (MMP)-2 and -9 as well as proteinase activity in gastric cancer cells were reduced in a dose-dependent manner. Moreover, baicalein clearly reduced the phosphorylated levels of p38. Combined treatment with p38 activator partially blocked the antimetastatic effects of baicalein, while p38 inhibitor (SB203580) and baicalein resulted in a synergistic reduction in MMP-2 and -9 expression; the invasive ability of gastric cancer cells was also inhibited. In conclusion, baicalein inhibits gastric cancer cell invasion and metastasis by reducing cell motility and migration via suppression of the p38 signaling pathway, suggesting that baicalein is a potential therapeutic agent for gastric cancer. PMID- 25502211 TI - Nanobody mediated inhibition of attachment of F18 Fimbriae expressing Escherichia coli. AB - Post-weaning diarrhea and edema disease caused by F18 fimbriated E. coli are important diseases in newly weaned piglets and lead to severe production losses in farming industry. Protective treatments against these infections have thus far limited efficacy. In this study we generated nanobodies directed against the lectin domain of the F18 fimbrial adhesin FedF and showed in an in vitro adherence assay that four unique nanobodies inhibit the attachment of F18 fimbriated E. coli bacteria to piglet enterocytes. Crystallization of the FedF lectin domain with the most potent inhibitory nanobodies revealed their mechanism of action. These either competed with the binding of the blood group antigen receptor on the FedF surface or induced a conformational change in which the CDR3 region of the nanobody displaces the D"-E loop adjacent to the binding site. This D"-E loop was previously shown to be required for the interaction between F18 fimbriated bacteria and blood group antigen receptors in a membrane context. This work demonstrates the feasibility of inhibiting the attachment of fimbriated pathogens by employing nanobodies directed against the adhesin domain. PMID- 25502214 TI - First magnetic resonance coronary artery imaging of bioresorbable vascular scaffold in-patient. PMID- 25502213 TI - Differential expression of the fractalkine chemokine receptor (CX3CR1) in human monocytes during differentiation. AB - Circulating monocytes (Mos) may continuously repopulate macrophage (MAC) or dendritic cell (DC) populations to maintain homeostasis. MACs and DCs are specialized cells that play different and complementary immunological functions. Accordingly, they present distinct migratory properties. Specifically, whereas MACs largely remain in tissues, DCs are capable of migrating from peripheral tissues to lymphoid organs. The aim of this work was to analyze the expression of the fractalkine receptor (CX3CR1) during the monocytic differentiation process. Freshly isolated Mos express high levels of both CX3CR1 mRNA and protein. During the Mo differentiation process, CX3CR1 is downregulated in both DCs and MACs. However, MACs showed significantly higher CX3CR1 expression levels than did DC. We also observed an antagonistic CX3CR1 regulation by interferon (IFN)-gamma and interleukin (IL)-4 during MAC activation through the classical and alternative MAC pathways, respectively. IFN-gamma inhibited the loss of CX3CR1, but IL-4 induced it. Additionally, we demonstrated an association between CX3CR1 expression and apoptosis prevention by soluble fractalkine (sCX3CL1) in Mos, DCs and MACs. This is the first report demonstrating sequential and differential CX3CR1 modulation during Mo differentiation. Most importantly, we demonstrated a functional link between CX3CR1 expression and cell survival in the presence of sCX3CL1. PMID- 25502217 TI - Biochemical changes of the endothelium in the murine model of NO-deficient hypertension. AB - The main spectral differences between the biochemical compositions of the vascular endothelium of control, hypertensive NO-deficient, and NO-deficient mice supplemented with nitrate were studied using Raman microimaging. A significantly different Raman signature of the endothelium in these three groups in the 1200 1400 cm(-1) region was assigned to the alpha-helix and beta-sheet alterations in the protein secondary structure upon the development of hypertension. The second pronounced biochemical marker of endothelium alterations was the lipid to protein ratio. A lower intensity of the band at 2940 cm(-1) relative to the feature at 1007 cm(-1) in the endothelium in hypertension compared to the control indicated a decrease of the lipid content relative to proteins during the progress of the pathology. The nitrate-based treatment partially reversed the effects of hypertension. The nitrate supplementation restored the lipid to protein ratio in the endothelium to the control level, while the changes in the secondary structure of proteins were irreversible upon nitrate administration. PMID- 25502216 TI - A study on the formation of the nitro radical anion by ornidazole and its significant decrease in a structurally characterized binuclear Cu(II)-complex: impact in biology. AB - An acetate-bridged binuclear Cu((II)) complex of the antiparasitic drug ornidazole was synthesized and characterized by different techniques. Single crystal X-ray diffraction revealed that the complex had a paddle wheel structure. Enzymatic assay experiments performed under anaerobic conditions on ornidazole and its Cu((II))-complex using xanthine oxidase as a model nitro-reductase showed that complex formation is able to cause a significant decrease in the reduction of the nitro group on the imidazole ring. Reduction products of 5-nitroimidazoles interact with DNA, causing destruction of the double helical structure and strands, leading to the inhibition of protein synthesis. Although not directly coordinated to the metal center, such a decrease in the generation of nitro radical anion through complex formation would result in decreased cytotoxicity of the complex, which could be a disadvantage from the standpoint of drug efficacy. For this reason, other aspects associated with the drug action of 5 nitroimidazoles, such as DNA binding, were studied. Experiments using cyclic voltammetry revealed that the binding of the complex was almost comparable to ornidazole. Bactericidal activity of ornidazole and the complex was studied on two separate bacterial strains, showing that the complex was comparable to ornidazole. Nitro radical anions are known to adversely affect the central nervous system, and this study showed that the Cu((II)) complex has the ability to decrease the generation of NO2(-) to an extent that struck the correct balance for beneficial activity, as cytotoxicity due to ornidazole was not affected. PMID- 25502218 TI - Compact multi-enzyme pathways in P. pastoris. AB - We report for the first time the functional simultaneous expression of nine genes from a single 2A peptide based polycistronic expression construct. The feasibility and arising opportunities for the biosynthetic pathway balancing for chemical production were demonstrated by the co-expression of the violacein and carotenoid biosynthesis pathways. PMID- 25502215 TI - Altered resting-state connectivity in college students with nonclinical depressive symptoms. AB - BACKGROUND: The underlying brain basis of nonclinical depressive symptoms (nCDSs) is largely unknown. Recently, the seed-based functional connectivity (FC) approach for analyzing resting-state fMRI (rs-fMRI) data has been increasingly used to explore the neural basis of depressive disorders. Other than common seed based FC method using an a priori seed region, we conducted FC analysis based on regions with altered spontaneous activity revealed by the fractional amplitude of low-frequency fluctuations (fALFF) approach. The aim of the present study was to provide novel insight in the underlying mechanism of nCDSs in college students. METHODOLOGY/PRINCIPAL FINDINGS: A total number of 1105 college students were recruited to participant in a survey for assessing depressive symptoms. Subsequently, 17 individuals with nCDSs and 20 healthy controls (HCs) were enrolled to perform MR studies. Alternations of fALFF were identified in the right superior parietal lobule (SPL) and left lingual gyrus, both of which were used as ROIs for further FC analysis. With right SPL, compare with HCs, subjects with nCDSs showed reduced FCs in the bilateral dorsal lateral prefrontal cortex (DLPFC), left inferior frontal gurus (IFG), left premotor cortex (PMC), DMN network [i.e., bilateral precuneus, posterior cingulate cortex (PCC), right supramarginal gyrus (SMG), right parahippocampal gyrus (PHG), bilateral inferior temporal gurus (ITG)] and left cerebellum posterior lobe (CPL). In addition, increased FCs were observed between the left lingual gyrus and right fusiform gyrus as well as in the left precuneus. CONCLUSION/SIGNIFICANCE: Our results indicate the abnormalities of spontaneous activity in the right SPL and left lingual gyrus and their corresponding dysfunction of the brain circuits might be related to the pathophysiology of nCDSs. PMID- 25502220 TI - Is sacroiliac joint pain associated with changes in the pubic symphysis? A radiographic pilot study. AB - BACKGROUND CONTEXT: Disorders of the sacroiliac joint are challenging to diagnose. This is partially due to similarity in symptom presentation to other lumbar spinal disorders and poor visibility of the joint on imaging studies. The pubic symphysis is clearly visualized in the anteroposterior view on plain film radiographs. As a closed ring, changes in the anterior and posterior portion of the pelvis may be reciprocal. The purpose of this study was to assess the correlation between pubic symphyseal changes observed on X-ray and SI joint disorders. METHODS: Thirty patients with a confirmed diagnosis of SI joint disorders were compared with 30 patients with low back pain without the evidence of SI joint involvement. Plain film radiographs were blinded and independently reviewed by two orthopedic surgeons. Changes in the pubic symphysis were classified as (0) no change, (1) osteoarthritic degeneration, (2) vertical displacement, or (3) ligament ossification. RESULTS: There was no significant difference between groups in age, gender, or parturition status. The majority of both groups were female. Mean (+/-SD) subject age was 61 (+/-11) and 59 (+/-9) years, and parity was 44% and 39% for the study and control groups, respectively. The prevalence of observable changes in the pubic symphysis was 97% in the study group and 30% in the control group (p < 0.001). CONCLUSION: Results of this study suggest that pubic symphyseal changes in the presence of low back pain and positive provocative maneuvers could serve as a marker for SI joint disease. Further investigation of the potential relationship between SI joint symptoms and symphyseal changes should be examined. PMID- 25502219 TI - gamma-Glutamyl hydrolase modulation significantly influences global and gene specific DNA methylation and gene expression in human colon and breast cancer cells. AB - gamma-Glutamyl hydrolase (GGH) plays an important role in folate homeostasis by catalyzing hydrolysis of polyglutamylated folate into monoglutamates. Polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence, GGH modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, and in chromatin modifications, and aberrant or dysregulation of DNA methylation has been mechanistically linked to the development of human diseases including cancer. Using a recently developed in vitro model of GGH modulation in HCT116 colon and MDA-MB-435 breast cancer cells, we investigated whether GGH modulation would affect global and gene-specific DNA methylation and whether these alterations were associated with significant gene expression changes. In both cell lines, GGH overexpression decreased global DNA methylation and DNA methyltransferase (DNMT) activity, while GGH inhibition increased global DNA methylation and DNMT activity. Epigenomic and gene expression analyses revealed that GGH modulation influenced CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation. Some of the observed altered gene expression appeared to be regulated by changes in CpG promoter DNA methylation. Our data suggest that the GGH modulation-induced changes in total intracellular folate concentrations and content of long-chain folylpolyglutamates are associated with functionally significant DNA methylation alterations in several important biological pathways. PMID- 25502221 TI - The nuclear receptor genes HR3 and E75 are required for the circadian rhythm in a primitive insect. AB - Insect circadian rhythms are generated by a circadian clock consisting of transcriptional/translational feedback loops, in which CYCLE and CLOCK are the key elements in activating the transcription of various clock genes such as timeless (tim) and period (per). Although the transcriptional regulation of Clock (Clk) has been profoundly studied, little is known about the regulation of cycle (cyc). Here, we identify the orphan nuclear receptor genes HR3 and E75, which are orthologs of mammalian clock genes, Roralpha and Rev-erbalpha, respectively, as factors involved in the rhythmic expression of the cyc gene in a primitive insect, the firebrat Thermobia domestica. Our results show that HR3 and E75 are rhythmically expressed, and their normal, rhythmic expression is required for the persistence of locomotor rhythms. Their RNAi considerably altered the rhythmic transcription of not only cyc but also tim. Surprisingly, the RNAi of HR3 revealed the rhythmic expression of Clk, suggesting that this ancestral insect species possesses the mechanisms for rhythmic expression of both cyc and Clk genes. When either HR3 or E75 was knocked down, tim, cyc, and Clk or tim and cyc, respectively, oscillated in phase, suggesting that the two genes play an important role in the regulation of the phase relationship among the clock genes. Interestingly, HR3 and E75 were also found to be involved in the regulation of ecdysis, suggesting that they interconnect the circadian clock and developmental processes. PMID- 25502223 TI - The Long and Short of Genetic Counseling Summary Letters: A Case-control Study. AB - Genetic counseling summary letters are intended to reinforce information received during genetic counseling, but little information is available on patient/family responses to these letters. We conducted a case-control study to assess the effectiveness of two different letter formats. Parents of children receiving a new diagnosis were enrolled. The control group (n = 85) received a genetic counseling summary letter in a narrative format, 4-5 pages in length. After the control enrollment period, genetic counselors were trained by a professional medical writer to develop a concise letter format. The case group (n = 64) received a concise letter, approximately 1.5 pages in length, utilizing simple sentences, lay terms, and lists/bullet points. Parents completed a survey 4 weeks after the visit to rate the letter's format, usefulness, and their emotional reaction. Results show that parents in the case group rated the letter more highly (p = 0.023), particularly in the emotional response dimension (rating changes in anxiety, depression, fear, ability to cope, and confidence in response to the letter). Parents in the case group also rated the genetic counseling session more highly (p = 0.039). In the control group, parents without a college degree were more likely to rate the letter as too long and the level of medical detail as too high. In the case group, no significant differences were seen between parents with or without a college degree. These data suggest that a short genetic counseling summary letter is rated higher by parents, and is particularly associated with a more positive emotional reaction. A short letter format highlighting the basic facts related to the genetic condition may be more useful to parents of diverse educational backgrounds, and may support a positive emotional adaptation at the time of a new diagnosis. Genetic counselors may benefit from specific instruction in medical and educational writing. PMID- 25502222 TI - Better futures: a randomized field test of a model for supporting young people in foster care with mental health challenges to participate in higher education. AB - The purpose of the study was to conduct a preliminary efficacy evaluation of the Better Futures model, which is focused on improving the postsecondary preparation and participation of youth in foster care with mental health challenges. Sixty seven youth were randomized to either a control group that received typical services or an intervention group, which involved participation in a Summer Institute, individual peer coaching, and mentoring workshops. Findings indicate significant gains for the intervention group on measures of postsecondary participation, postsecondary and transition preparation, hope, self determination, and mental health empowerment, as compared to the control group. Youth in the intervention group also showed positive trends in the areas of mental health recovery, quality of life, and high school completion. Implications for future research and practice are discussed, while emphasizing the capacities of youth in foster care with mental health conditions to successfully prepare for and participate fully in high education. PMID- 25502224 TI - Association between changes in reproductive activity and D-glucose metabolism in the tephritid fruit fly, Bactrocera dorsalis (Hendel). AB - Reproduction is an important life process in insects; however, few studies have attempted to demonstrate the association between reproductive activity and energy metabolism. To address this problem, we focused on the reproductive changes in Bactrocera dorsalis males. We analyzed B. dorsalis male gene expression profiles during mating (DM), 3 h after mating (A3HM) and 12 h after mating (A12HM). Gene annotation and pathway analyses of differentially expressed genes show that galactose metabolism and the starch and sucrose metabolism pathway activities were significantly higher in A12HM group. Moreover, the maltase D gene was the most strongly up-regulated gene. The D-glucose levels were significantly higher in A12HM group. Maltase D expression level was significantly higher in males reared with sucrose. Body weights of the males reared with D-glucose and sucrose were significantly higher than those of the males reared with yeast extract. We observed more mated males from the groups fed sucrose and D-glucose than from those fed yeast extract. The D-glucose levels in individual males were highest at 18:00 h, when flies exhibit the most active mating behavior. This study shows that the maltase D gene and D-glucose are the critical gene and substrate, respectively, in male B. dorsalis mating process. PMID- 25502227 TI - Patient Characteristics are not Associated with Clinically Important Differential Response to Dapagliflozin: a Staged Analysis of Phase 3 Data. AB - INTRODUCTION: This study aimed to determine if data mining methodologies could identify reproducible predictors of dapagliflozin-specific treatment response in the phase 3 clinical program dataset. METHODS: Baseline and early treatment response variables were selected and data mining used to identify/rank all variables associated with reduction in glycated hemoglobin (HbA1c) at week 26. Generalized linear modeling was then employed using an independent dataset to identify which (if any) variables were predictive of dapagliflozin-specific treatment response as compared with treatment response in the study's control arm. The most parsimonious (i.e., simplest) model was validated by meta-analysis of nine other trials. This staged approach was used to minimize risk of type I errors. RESULTS: From the large dataset, 22 variables were selected for model generation as potentially predictive for dapagliflozin-specific reduction in HbA1c. Although baseline HbA1c was the variable most strongly associated with reduction in HbA1c at study end (i.e., the best prognostic variable), baseline fasting plasma glucose (FPG) was the only predictive dapagliflozin-specific variable in the model. Placebo-adjusted treatment effect of dapagliflozin plus metformin vs. metformin alone for change in HbA1c from baseline was -0.65% at the average baseline FPG of 192.3 mg/dL (10.7 mmol/L). This response changed by 0.32% for every SD [57.2 mg/dL (3.2 mmol/L)] increase in baseline FPG. Effect of baseline FPG was confirmed in the meta-analysis of nine studies, but the magnitude was smaller. No other variable was independently predictive of a dapagliflozin-specific reduction in HbA1c. CONCLUSIONS: This methodology successfully identified a reproducible baseline predictor of differential response to dapagliflozin. Although baseline FPG was shown to be a predictor, the effect size was not of sufficient magnitude to suggest clinical usefulness in identifying patients who would uniquely benefit from dapagliflozin treatment. The findings do support potential benefit for dapagliflozin treatment that is consistent with current recommended use. PMID- 25502225 TI - Mesenchymal phenotype predisposes lung cancer cells to impaired proliferation and redox stress in response to glutaminase inhibition. AB - Recent work has highlighted glutaminase (GLS) as a key player in cancer cell metabolism, providing glutamine-derived carbon and nitrogen to pathways that support proliferation. There is significant interest in targeting GLS for cancer therapy, although the gene is not known to be mutated or amplified in tumors. As a result, identification of tractable markers that predict GLS dependence is needed for translation of GLS inhibitors to the clinic. Herein we validate a small molecule inhibitor of GLS and show that non-small cell lung cancer cells marked by low E-cadherin and high vimentin expression, hallmarks of a mesenchymal phenotype, are particularly sensitive to inhibition of the enzyme. Furthermore, lung cancer cells induced to undergo epithelial to mesenchymal transition (EMT) acquire sensitivity to the GLS inhibitor. Metabolic studies suggest that the mesenchymal cells have a reduced capacity for oxidative phosphorylation and increased susceptibility to oxidative stress, rendering them unable to cope with the perturbations induced by GLS inhibition. These findings elucidate selective metabolic dependencies of mesenchymal lung cancer cells and suggest novel pathways as potential targets in this aggressive cancer type. PMID- 25502228 TI - Blood thixotropy in patients with sickle cell anaemia: role of haematocrit and red blood cell rheological properties. AB - We compared the blood thixotropic/shear-thinning properties and the red blood cells' (RBC) rheological properties between a group of patients with sickle cell anaemia (SS) and healthy individuals (AA). Blood thixotropy was determined by measuring blood viscosity with a capillary viscometer using a "loop" protocol: the shear rate started at 1 s-1 and increased progressively to 922 s-1 and then re-decreased to the initial shear rate. Measurements were performed at native haematocrit for the two groups and at 25% and 40% haematocrit for the AA and SS individuals, respectively. RBC deformability was determined by ektacytometry and RBC aggregation properties by laser backscatter versus time. AA at native haematocrit had higher blood thixotropic index than SS at native haematocrit and AA at 25% haematocrit. At 40% haematocrit, SS had higher blood thixotropic index than AA. While RBC deformability and aggregation were lower in SS than in AA, the strength of RBC aggregates was higher in the former population. Our results showed that 1) anaemia is the main modulator of blood thixtropy and 2) the low RBC deformability and high RBC aggregates strength cause higher blood thixotropy in SS patients than in AA individuals at 40% haematocrit, which could impact blood flow in certain vascular compartments. PMID- 25502229 TI - From joint thinking to joint action: a call to action on improving water, sanitation, and hygiene for maternal and newborn health. AB - Yael Velleman and colleagues argue for stronger integration between the water, sanitation, and hygiene (WASH) and maternal and newborn health sectors. Please see later in the article for the Editors' Summary. PMID- 25502230 TI - The Bouma law of crowding, revised: critical spacing is equal across parts, not objects. AB - Crowding is the inability to identify an object among flankers in the periphery. It is due to inappropriate incorporation of features from flanking objects in perception of the target. Crowding is characterized by measuring critical spacing, the minimum distance needed between a target and flankers to allow recognition. The existing Bouma law states that, at a given point and direction in the visual field, critical spacing, measured from the center of a target object to the center of a similar flanking object, is the same for all objects (Pelli & Tillman, 2008). Because flipping an object about its center preserves its center-to-center spacing to other objects, according to the Bouma law, crowding should be unaffected. However, because crowding is a result of feature combination, the location of features within an object might matter. In a series of experiments, we find that critical spacing is affected by the location of features within the flanker. For some flankers, a flip greatly reduces crowding even though it maintains target-flanker spacing and similarity. Our results suggest that the existing Bouma law applies to simple one-part objects, such as a single roman letter or a Gabor patch. Many objects consist of multiple parts; for example, a word is composed of multiple letters that crowd each other. To cope with such complex objects, we revise the Bouma law to say that critical spacing is equal across parts, rather than objects. This accounts for old and new findings. PMID- 25502226 TI - Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism. AB - Pinpointing the small number of causal variants among the abundant naturally occurring genetic variation is a difficult challenge, but a crucial one for understanding precise molecular mechanisms of disease and follow-up functional studies. We propose and investigate two complementary statistical approaches for identification of rare causal variants in sequencing studies: a backward elimination procedure based on groupwise association tests, and a hierarchical approach that can integrate sequencing data with diverse functional and evolutionary conservation annotations for individual variants. Using simulations, we show that incorporation of multiple bioinformatic predictors of deleteriousness, such as PolyPhen-2, SIFT and GERP++ scores, can improve the power to discover truly causal variants. As proof of principle, we apply the proposed methods to VPS13B, a gene mutated in the rare neurodevelopmental disorder called Cohen syndrome, and recently reported with recessive variants in autism. We identify a small set of promising candidates for causal variants, including two loss-of-function variants and a rare, homozygous probably-damaging variant that could contribute to autism risk. PMID- 25502231 TI - Rapid analysis of colipase gene variants by multicapillary electrophoresis. AB - Despite of the fact that the Human Genome Project was completed more than a decade ago, identification of the genetic background of polygenic diseases is still challenging. Several somewhat different approaches are available to investigate inheritable factors of complex phenotypes, all require, however efficient, high-throughput techniques for SNP genotyping. In this paper, we report a robust and reliable multiplex PCR-RFLP for genotype and haplotype analysis of six SNPs (rs41270082, rs3748051, rs142027015, rs3748048, rs73404011, and rs72925892) of the colipase (CLPS) gene. A multicapillary (12 capillaries) electrophoresis unit was used for high throughput and sensitive analysis of the digestion fragments. A Microsoft Excel-based spreadsheet was designed for the flexible visualization and evaluation of the electrophoretic separations, which is readily adaptable for any kind of electrophoresis application. Haplotype analysis of the two loci localized in close proximity of each other was carried out by molecular method, extended haplotypes including all five SNPs in the 5' upstream region were calculated. The techniques were applied in a case-control association study of type 2 diabetes mellitus. Although, single marker analysis did not reveal any significant association, it was observed that the rare GGCCG haplotype of the five 5' upstream region SNPs was about three times more frequent among patients compared to healthy control population. Our results demonstrated the applicability of multicapillary CGE in large-scale, high-throughput SNP analysis, and suggested that the CLPS gene polymorphisms might be considered as genetic risk factor for type 2 diabetes mellitus. PMID- 25502232 TI - Use of a new wireless transducer for femoral venous vascular cannulation. PMID- 25502233 TI - The reaction of 2-amino-4H-pyrans with N-bromosuccinimide. AB - The reaction of racemic 2-amino-4H-pyrans, such as 3-amino-1-aryl-1H benzo[f]chromene-2-carbonitriles, with N-bromosuccinimide (NBS), in CH2Cl2, at room temperature, is a very quick, regio, stereoselective, and high yielding process, affording major racemic (1S, 2S)-2-bromo-3-imino-benzo[f]chromene or racemic (1S, 2S)-2-bromo-3-(bromoimino)-benzo[f]chromene derivatives, when using 1.0 or 2.2 equivalents of NBS, respectively. This reaction, extended to isomeric 2-amino-4-aryl-4H-benzo[h]chromene-3-carbonitriles, showed an unexpected reactivity, affording racemic (3S,4S)-3-bromo-2-(bromoimino)-benzo[h]chromene-3 carbonitriles or 2-oxo-2H-benzo[h]chromene-3-carbonitriles, when using 2.2 or 1.0 equivalents of NBS, respectively. The reaction of alkyl 6-amino-5-cyano-2-methyl 4H-pyran-3-carboxylates has yielded unstable racemic (3S,4S)-alkyl 3-bromo-2 (bromoimino)-3-cyano-6-methyl-3,4-dihydro-2H-pyran-5-carboxylates. The mechanism of these reactions has been investigated by computational methods. PMID- 25502234 TI - Role of breast cancer resistance protein (BCRP) as active efflux transporter on blood-brain barrier (BBB) permeability. AB - Nowadays most of the CNS acting therapeutic molecules are failing in clinical trials due to efflux transporters at the blood brain barrier (BBB) which imparts resistance and poor ADMET properties of these molecules. CNS acting drug molecules interact with the BBB prior to their target site, so there is a need to develop predictive models for BBB permeability which can be used in the initial phases of drug discovery process. Most of the drug molecules are transported to the brain via passive diffusion which is explored extensively; on the other hand, the role of active efflux transporters in BBB permeability is unclear. Our aim is to develop predictive models for BBB permeability that include active efflux transporters. An in silico model has been developed to assess the role of BCRP on BBB permeation. Eight descriptors were selected, which also include BCRP substrate probabilities used for model development and show a relationship between BCRP and logBB. From our analysis, it was found that 11 molecules satisfied all criteria required for BBB permeation but have low logBB values. These 11 molecules are predicted as BCRP substrates from the model developed, suggesting that the molecules are effluxed by the BCRP transporter. This predictive ability was further validated by docking of these 11 molecules into BCRP protein. This study provides a new mechanistic insight into correlation of low logBB values and efflux mechanism of BCRP in BBB. PMID- 25502235 TI - Endoscopic lung volume reduction with endobronchial valves in patients with severe emphysema and established pulmonary hypertension. AB - BACKGROUND: One of the most common forms of pulmonary hypertension (PH) is that associated with chronic obstructive pulmonary disease (COPD). So far, patients with severe emphysema and established PH have been excluded from endoscopic lung volume reduction (ELVR) therapy due to the risk of right heart decompensation. OBJECTIVE: The aim of this pilot study was to evaluate the feasibility and efficacy of ELVR using one-way endobronchial valves (EBV) in this specific group of patients. METHODS: We prospectively included 6 patients with COPD, severe heterogeneous emphysema, and established PH who underwent right heart catheterization and clinical assessments before and 90 days after ELVR with unilateral EBV placement. RESULTS: This study was not powered to measure any statistical differences in endpoints. Ninety days after ELVR, the symptoms, lung function, and hemodynamics improved in 5 out of 6 patients (1 patient normalized and 1 slightly worsened). The mean hemodynamics improved from baseline to 90 days after ELVR as follows: mean pulmonary artery pressure, -2.5 +/- 3.5 mm Hg; pulmonary arterial wedge pressure, -4.3 +/- 8.3 mm Hg; cardiac index, +0.3 +/- 0.6 l/min/m(2), and 6-min walk distance, +59 +/- 99 m. ELVR was performed without PH-related complications in all patients. CONCLUSION: To our knowledge, this is the first prospective, single-center pilot study to evaluate the feasibility and efficacy of ELVR in patients with established PH. ELVR was feasible and resulted in an improvement of clinical and hemodynamic parameters in 5 out of 6 patients. These results have to be further confirmed in larger-scale controlled studies. PMID- 25502236 TI - Cautious application of pleural N-terminal pro-B-type natriuretic peptide in diagnosis of congestive heart failure pleural effusions among critically ill patients. AB - BACKGROUND AND OBJECTIVE: Several studies on diagnostic accuracy of pleural N terminal pro-B-type natriuretic peptide (NT-pro-BNP) for effusions from congestive heart failure (CHF) conclude that pleural NT-pro-BNP is a useful biomarker with high diagnostic accuracy for distinguishing CHF effusions. However, its applicability in critical care settings remains uncertain and requires further investigations. METHODS: NT-proBNP was measured in pleural fluid samples of a prospective cohort of intensive care unit patients with pleural effusions. Receiver operating characteristic curve analysis was performed to determine diagnostic accuracy of pleural NT-proBNP for prediction of CHF effusions. RESULTS: One hundred forty-seven critically ill patients were evaluated, 38 (26%) with CHF effusions and 109 (74%) with non-CHF effusions of various causes. Pleural NT-proBNP levels were significantly elevated in patients with CHF effusions. Pleural NT-pro-BNP demonstrated the area under the curve of 0.87 for diagnosing effusions due to CHF. With a cutoff of 2200 pg/mL, pleural NT proBNP displayed high sensitivity (89%) but moderate specificity (73%). Notably, 29 (27%) of 109 patients with non-CHF effusions had pleural NT-proBNP levels >2200 pg/mL and these patients were more likely to experience septic shock (18/29 vs. 10/80, P<0.001) or acute kidney injury (19/29 vs. 9/80, P<0.001). CONCLUSIONS: Among critically ill patients, pleural NT-proBNP measurements remain a useful diagnostic aid in evaluation of pleural effusions. However, patients with non-CHF effusions may exhibit high pleural NT-proBNP concentrations if they suffer from septic shock or acute kidney injury. Accordingly, it is suggested that clinical context should be taken into account when interpreting pleural NT proBNP values in critical care settings. PMID- 25502238 TI - Spatial overlap between environmental policy instruments and areas of high conservation value in forest. AB - In order to safeguard biodiversity in forest we need to know how forest policy instruments work. Here we use a nationwide network of 9400 plots in productive forest to analyze to what extent large-scale policy instruments, individually and together, target forest of high conservation value in Norway. We studied both instruments working through direct regulation; Strict Protection and Landscape Protection, and instruments working through management planning and voluntary schemes of forest certification; Wilderness Area and Mountain Forest. As forest of high conservation value (HCV-forest) we considered the extent of 12 Biodiversity Habitats and the extent of Old-Age Forest. We found that 22% of productive forest area contained Biodiversity Habitats. More than 70% of this area was not covered by any large-scale instruments. Mountain Forest covered 23%, while Strict Protection and Wilderness both covered 5% of the Biodiversity Habitat area. A total of 9% of productive forest area contained Old-Age Forest, and the relative coverage of the four instruments was similar as for Biodiversity Habitats. For all instruments, except Landscape Protection, the targeted areas contained significantly higher proportions of HCV-forest than areas not targeted by these instruments. Areas targeted by Strict Protection had higher proportions of HCV-forest than areas targeted by other instruments, except for areas targeted by Wilderness Area which showed similar proportions of Biodiversity Habitats. There was a substantial amount of spatial overlap between the policy tools, but no incremental conservation effect of overlapping instruments in terms of contributing to higher percentages of targeted HCV-forest. Our results reveal that although the current policy mix has an above average representation of forest of high conservation value, the targeting efficiency in terms of area overlap is limited. There is a need to improve forest conservation and a potential to cover this need by better targeting high conservation value areas. PMID- 25502240 TI - Aging and place--neighborhoods and health in a world growing older. AB - The articles in this special issue make it clear that there are interesting and policy-relevant research to identify place-based strategies to improve health and reduce health disparities among older adults. The articles also reveal important areas of future research and policy innovation that are needed related to place and aging. PMID- 25502237 TI - Dissociable neural mechanisms underlying the modulation of pain and anxiety? An FMRI pilot study. AB - The down-regulation of pain through beliefs is commonly discussed as a form of emotion regulation. In line with this interpretation, the analgesic effect has been shown to co-occur with reduced anxiety and increased activity in the ventrolateral prefrontal cortex (VLPFC), which is a key region of emotion regulation. This link between pain and anxiety modulation raises the question whether the two effects are rooted in the same neural mechanism. In this pilot fMRI study, we compared the neural basis of the analgesic and anxiolytic effect of two types of threat modulation: a "behavioral control" paradigm, which involves the ability to terminate a noxious stimulus, and a "safety signaling" paradigm, which involves visual cues that signal the threat (or absence of threat) that a subsequent noxious stimulus might be of unusually high intensity. Analgesia was paralleled by VLPFC activity during behavioral control. Safety signaling engaged elements of the descending pain control system, including the rostral anterior cingulate cortex that showed increased functional connectivity with the periaqueductal gray and VLPFC. Anxiety reduction, in contrast, scaled with dorsolateral prefrontal cortex activation during behavioral control but had no distinct neural signature during safety signaling. Our pilot data therefore suggest that analgesic and anxiolytic effects are instantiated in distinguishable neural mechanisms and differ between distinct stress- and pain-modulatory approaches, supporting the recent notion of multiple pathways subserving top-down modulation of the pain experience. Additional studies in larger cohorts are needed to follow up on these preliminary findings. PMID- 25502239 TI - 4-Hydroxytamoxifen probes for light-dependent spatiotemporal control of Cre-ER mediated reporter gene expression. AB - The tamoxifen inducible Cre-ER/loxP system provides tissue specific temporal control of gene recombination events, and can be used to induce expression of reporter genes (e.g. GFP, LacZ) for lineage tracing studies. Cre enzyme fused with estrogen receptor (Cre-ER) is released upon tamoxifen binding, resulting in permanent activation of reporter genes within cells and their progeny. Tamoxifen and its active metabolite, hydroxytamoxifen (4OHT) diffuses rapidly in vivo, making it difficult to restrict labeling to specific locations. In this study, we developed a photocaged 4OHT molecule by covalently attaching 4OHT to an ortho nitrobenzyl (ONB1) group, rendering 4OHT inactive. Exposure to UV radiation cleaves the bond between ONB1 and 4OHT, freeing the 4OHT to bind Cre-ER to result in downstream genetic recombination and reporter activation. We show that caged ONB1-4OHT crosses the cell membrane and uncages after short UV exposure, resulting in Cre-driven genetic recombination that can be localized to specific regions or tissues. ONB1-4OHT can provide spatial control of reporter activation and be adapted with any existing Cre-ER/loxP based system. PMID- 25502242 TI - Gender differences in neighborhood walking in older adults. AB - OBJECTIVE: This study examined mobility, self-efficacy, outcome expectations, neighborhood (density, destinations, and design), and neighborhood walking in older men (n = 106, 60-99 years, M = 76.78, SD = 8.12) and women (n = 216, 60-99 years, M = 75.81, SD = 8.46). METHOD/RESULTS: In hierarchical regression, the variables explained 32% of the variance in neighborhood walking in men (p < .001) and 27% of the variance in women (p < .01). Self-efficacy (beta = .49, p < .01), density (beta= .22, p < .05), and design (beta= .21, p = .05) were associated with walking in men. Significant design characteristics included sidewalks (beta= .25, p < .05) and crime (beta= .36, p < .01). In women, self-efficacy (beta= .48, p < .001) and destinations (beta= .15, p < .05) were associated with walking. Walking was associated with self-efficacy for walking despite individual barriers in women (beta= .38, p < .001) and neighborhood barriers in men (beta= .30, p < .05). CONCLUSION: Walking interventions targeting older women should incorporate local destinations. In older men, interventions should consider neighborhood sidewalk design and crime. Walking interventions for all older adults should include enhancement of self-efficacy, but gender differences may exist in the types of self-efficacy on which to focus. PMID- 25502243 TI - Neighborhood social capital and achieved mobility of older adults. AB - OBJECTIVE: Evaluate associations of neighborhood social capital and mobility of older adults. METHOD: A community-based survey (Philadelphia, 2010) assessed mobility (Life-Space Assessment [LSA]; range = 0-104) of older adults (n = 675, census tracts = 256). Social capital was assessed for all adults interviewed from 2002-2010 (n = 13,822, census tracts = 374). Generalized estimating equations adjusted for individual- and neighborhood-level characteristics estimated mean differences and 95% confidence intervals (CIs) in mobility by social capital tertiles. Interactions by self-rated health, living arrangement, and race were tested. RESULTS: Social capital was not associated with mobility after adjustment for other neighborhood characteristics (mean difference for highest versus lowest tertile social capital = 0.79, 95% CI = [-3.3, 4.8]). We observed no significant interactions. In models stratified by race, Black participants had higher mobility in high social capital neighborhoods (mean difference = 7.4, CI = [1.0, 13.7]). DISCUSSION: Social capital may not contribute as much as other neighborhood characteristics to mobility. Interactions between neighborhood and individual-level characteristics should be considered in research on mobility. PMID- 25502241 TI - Racial disparities in disability among older adults: finding from the exploring health disparities in integrated communities study. AB - OBJECTIVE: Persistent and consistently observed racial disparities in physical functioning likely stem from racial differences in social resources and environmental conditions. METHOD: We examined the association between race and reported difficulty performing instrumental activities of daily living (IADL) in 347 African American (45.5%) and Whites aged 50 or above in the Exploring Health Disparities in Integrated Communities-Southwest Baltimore, Maryland Study (EHDIC SWB). RESULTS: Contrary to previous studies, African Americans had lower rates of disability (women: 25.6% vs. 44.6%, p = .006; men: 15.7% vs. 32.9%; p = .017) than Whites. After adjusting for sociodemographics, health behaviors, and comorbidities, African American women (odds ratio [OR] = 0.32, 95% confidence interval [CI] = [0.14, 0.70]) and African American men (OR = 0.34, 95% CI = [0.13, 0.90]) retained their functional advantage compared with White women and men, respectively. CONCLUSION: These findings within an integrated, low-income urban sample support efforts to ameliorate health disparities by focusing on the social context in which people live. PMID- 25502244 TI - Aging and place in long-term care settings: influences on social relationships. AB - OBJECTIVE: This article presents results of a qualitative research study that examined how living in a long-term care (LTC) home influences the quality of residents' relationships with peers, family members, and outside friends. METHOD: Semistructured interviews using a phenomenological approach were conducted with 23 residents of a LTC home. Thematic analysis was employed to illuminate residents' perspectives on the nature of social relationships in this setting. RESULTS: Four key themes were identified that highlight the role of place in social relationships. Residing in a LTC home influences the context of social interactions, impacts their quality and process, clusters individuals with health and functional declines that hinder socialization, and poses structural and cultural barriers that impede social interactions. Health and functional limitations posed the greatest challenge to socialization relative to characteristics of the facility itself. DISCUSSION: Residents' insights emphasize how personal characteristics influence community culture and the experience of place. PMID- 25502245 TI - Aging, place, and technology: toward improving access and wellness in older populations. AB - OBJECTIVE: To review the range of promising technologies (e.g., smart phones, remote monitoring devices) designed to enhance aging in place; identify challenges for implementation of those technologies; and recommend ways to improve access to technologies in older populations. METHOD: A narrative review of research, practice, and policies from multiple fields, including information science, gerontology, engineering, housing and social services, health care and public health. RESULTS: Despite a wide range of emerging and current technologies, there are significant challenges for implementation, including an uneven evidence base, economic barriers, and educational and ergonomic issues that adversely affect many older adults. DISCUSSION: Recommendations for future development and adoption include improving the evidence base through field testing of "packages" of devices in diverse populations of older adults; development of innovative funding mechanisms involving multidisciplinary teams, older adults, and caregivers; and promotion of safety and security in the use of these technologies in older populations. PMID- 25502246 TI - Developing age-friendly cities and communities in Australia. AB - OBJECTIVE: The aim of the study is to present case studies and assess the impact of political, policy, consultative, and research processes used to implement Age Friendly Cities (AFC) initiatives in Australia. METHOD: A review and interpretation was conducted based on public documents, community consultations, survey analyses, and participant observation. RESULTS: Governments in Australia have drawn on World Health Organization (WHO) concepts to establish AFC initiatives. In Melbourne, state political leadership established Positive Ageing plans that have reinforced local government actions. In Canberra, a baseline survey and an Older Persons Assembly were followed by modest positive ageing plans. In Sydney, a State Ageing Strategy developed a whole-of-government plan that has yet to be incorporated into budget processes. DISCUSSION: AFC initiatives in Australia have had promising and varied starts with some aims to benefit disadvantaged older people. Notwithstanding the potential benefits, AFC influence on mainstream actions of government has been limited by uncertain political commitment and growing fiscal austerity. PMID- 25502247 TI - Unusual case of a stage I thymoma of the posterior mediastinum: endoscopic ultrasound-guided fine needle aspiration alone clinches the diagnosis. PMID- 25502248 TI - Successful endoscopic removal of a cocaine capsule in the stomach: should it be considered a safe therapeutic option? PMID- 25502249 TI - Endoscopic palliative management of esophageal and tracheal rupture. PMID- 25502250 TI - Endoscopic treatment of a duodenal duplication cyst. PMID- 25502251 TI - Hepatic infarction caused by vascular migration of fiducial marker previously placed under endosonographic guidance to assist radiotherapy. PMID- 25502252 TI - Carbon dioxide enterography: a useful method for double-balloon enteroscopy assisted ERCP. PMID- 25502253 TI - A simple ex vivo pig stomach model for learning endoscopic submucosal dissection. PMID- 25502254 TI - EUS-FNA of a portal vein thrombosis in a patient with a hidden hepatocellular carcinoma: confirmation technique after contrast-enhanced ultrasound. PMID- 25502256 TI - Transplanted liver graft ischemia caused by pediatric ERCP in the prone position. PMID- 25502255 TI - Diagnosis of polypoid portal hypertensive enteropathy due to superior mesenteric vein thrombosis by capsule endoscopy and double-balloon enteroscopy. PMID- 25502257 TI - A rare and potentially fatal complication of endoscopic submucosal dissection: iatrogenic type B aortic dissection. PMID- 25502258 TI - Lymphangioma as a rare cause of acute recurrent pancreatitis. PMID- 25502259 TI - Fasciola hepatica as an uncommon cause of cholangitis. PMID- 25502260 TI - Antibiotic-associated hemorrhagic colitis with ischemic change. PMID- 25502261 TI - Single-channel endoscopic closure of ERCP-related large duodenal perforations. PMID- 25502263 TI - Intramural esophageal hematoma: an unusual cause of acute chest pain. PMID- 25502262 TI - Successful use of Hemospray to control refractory duodenal diverticular bleeding. PMID- 25502264 TI - Endoscopic treatment of a completely obstructed ileorectal anastomosis. PMID- 25502265 TI - The clip-and-snare method with a pre-looping technique during gastric endoscopic submucosal dissection. PMID- 25502266 TI - Primary small-bowel adult T-cell leukemia/lymphoma with gastric AL amyloidosis. PMID- 25502267 TI - Successful en bloc endoscopic submucosal dissection of a giant rectal laterally spreading adenoma. PMID- 25502268 TI - Scarring mucous membrane pemphigoid presenting as double stenosis of the larynx and esophagus: precautions during therapy can avoid complications. PMID- 25502269 TI - Usefulness of the rendezvous technique for deep scope insertion during endoscopic retrograde cholangiography in a patient with a Roux-en-Y hepaticojejunostomy. PMID- 25502270 TI - Primary malignant melanoma involving the whole esophagus: a rare case with rarer presentation. PMID- 25502271 TI - Full-thickness endoscopic suturing of staple-line leaks following laparoscopic sleeve gastrectomy. PMID- 25502273 TI - Endoscopic submucosal tunnel dissection of a bronchogenic esophageal cyst. PMID- 25502272 TI - Colonic mucosa-associated lymphoid tissue (MALT) lymphoma: an important differential diagnosis for a slow-growing colonic polyp. PMID- 25502274 TI - Percutaneous transhepatic biliary drainage after failed endoscopic approach in patients with pancreatic cancer and situs inversus totalis. PMID- 25502275 TI - Hemorrhagic gastritis at the excluded stomach after Roux-en-Y gastric bypass. PMID- 25502276 TI - Endoscopic resection of early esophageal neoplasia in patients with esophageal varices: how to succeed while preventing the bleed. PMID- 25502277 TI - What is early brain injury? PMID- 25502278 TI - Bead block embolization of a retinal arteriole. PMID- 25502279 TI - Sound pressure level gain in an acoustic metamaterial cavity. AB - The inherent attenuation of a homogeneous viscous medium limits radiation propagation, thereby restricting the use of many high-frequency acoustic devices to only short-range applications. Here, we design and experimentally demonstrate an acoustic metamaterial localization cavity which is used for sound pressure level (SPL) gain using double coiled up space like structures thereby increasing the range of detection. This unique behavior occurs within a subwavelength cavity that is 1/10(th) of the wavelength of the incident acoustic wave, which provides up to a 13 dB SPL gain. We show that the amplification results from the Fabry Perot resonance of the cavity, which has a simultaneously high effective refractive index and effective impedance. We also experimentally verify the SPL amplification in an underwater environment at higher frequencies using a sample with an identical unit cell size. The versatile scalability of the design shows promising applications in many areas, especially in acoustic imaging and underwater communication. PMID- 25502281 TI - Clinical management of women at high risk of breast cancer. AB - PURPOSE OF REVIEW: This article reviews the evidence that underpins breast cancer screening and prevention strategies for women at high risk of the disease, with a particular focus on evidence published in the last 18 months. The review is timely because the US National Comprehensive Cancer Network, the UK National Institute for Health and Care Excellence and the American Society of Clinical Oncology have recently updated relevant guidelines that inform practice. RECENT FINDINGS: In the recently published literature, there have been several important findings. A meta-analysis of randomized trials of selective oestrogen receptor modulators (SERMs), along with the first results from the International Breast Cancer Intervention Study II trial, further support the use of SERMs and aromatase inhibitors in the primary prevention of breast cancer. A large observational study has provided evidence that the SERM tamoxifen may be efficacious for breast cancer prevention in women who carry mutations in the breast cancer predisposition genes, BRCA1 and BRCA2. Several observational studies have suggested that contralateral risk-reducing mastectomy, following a diagnosis of breast cancer, may reduce mortality. SUMMARY: Evidence regarding the optimal management of women at high risk of breast cancer continues to evolve and needs to be rapidly implemented into clinical practice. PMID- 25502280 TI - Taurine in drinking water recovers learning and memory in the adult APP/PS1 mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a lethal progressive neurological disorder affecting the memory. Recently, US Food and Drug Administration mitigated the standard for drug approval, allowing symptomatic drugs that only improve cognitive deficits to be allowed to accelerate on to clinical trials. Our study focuses on taurine, an endogenous amino acid found in high concentrations in humans. It has demonstrated neuroprotective properties against many forms of dementia. In this study, we assessed cognitively enhancing property of taurine in transgenic mouse model of AD. We orally administered taurine via drinking water to adult APP/PS1 transgenic mouse model for 6 weeks. Taurine treatment rescued cognitive deficits in APP/PS1 mice up to the age-matching wild-type mice in Y-maze and passive avoidance tests without modifying the behaviours of cognitively normal mice. In the cortex of APP/PS1 mice, taurine slightly decreased insoluble fraction of Abeta. While the exact mechanism of taurine in AD has not yet been ascertained, our results suggest that taurine can aid cognitive impairment and may inhibit Abeta-related damages. PMID- 25502282 TI - Selective nickel- and manganese-catalyzed decarboxylative cross coupling of some alpha,beta-unsaturated carboxylic acids with cyclic ethers. AB - A nickel- and manganese-catalyzed decarboxylative cross coupling of alpha, beta unsaturated carboxylic acids with cyclic ethers such as tetrahydrofuran and 1, 4 dioxane was developed. Oxyalkylation was achieved when nickel acetate was used as catalyst, while manganese acetate promoted the reaction of alkenylation. PMID- 25502285 TI - Morphological and structural evolution of WS2 nanosheets irradiated with an electron beam. AB - The morphological and structural evolution of WS2 nanosheets under electron irradiation is investigated using high-resolution transmission electron microscopy. During irradiation, the sulfur atoms that interacted with the electrons were sputtered first and the tungsten atoms began to sputter when the surrounding sulfur atoms had been sputtered. With an increasing irradiation time, the remaining tungsten atoms rearranged to form new structures. In addition, the damage to the WS2 nanosheets became more severe with increasing electron energies and irradiation times. PMID- 25502286 TI - Clinical implications from a single-center study of colorectal adenocarcinoma in transplant recipients. AB - BACKGROUND: With the increasing burden of organ transplant recipients and improvements in allograft outcome, the incidence of neoplasms rising from these patients is an important issue. OBJECTIVE: In this study, we investigated transplant recipients with colorectal cancer to determine its incidence, clinicopathological characteristics, and prognosis. METHODS: The database of Severance Hospital was queried for all cases of colorectal adenocarcinoma among transplant recipients from August 2005 to January 2013. RESULTS: A total of 29 patients were diagnosed with colorectal adenocarcinoma after transplantation, and the median age at diagnosis was 58.6 years. As for primary tumor stage, 17 (58.6%) patients had stage >=3, and distant metastasis was found in 10 (34.4%) patients. The mean time from transplantation to tumor detection was 13.7 years. The median disease-free survival was 11.0 months and the median overall survival (OS) was 18.1 months. In multivariate analysis of prognostic factors for OS, surgical resection was a positive prognostic factor (HR 1.357, p = 0.010) and the presence of distant metastasis at diagnosis was a negative prognostic factor (HR 1.047, p = 0.006). CONCLUSION: The behavior of colorectal cancer in posttransplant patients is more aggressive and refractory to treatment. A separate guideline for the colorectal screening program for the posttransplant patients needs to be established. PMID- 25502287 TI - One versus two-step Roux-en-Y gastric bypass after gastric banding-data analysis of the German Bariatric Surgery Registry. AB - BACKGROUND: Bariatric surgery outcomes have been examined in Germany since January 1, 2005. All data were registered prospectively in cooperation with the Institute of Quality Assurance in Surgery at the Otto-von-Guericke University Magdeburg. METHODS: The data were collected from an online data bank. Data collection began in 2005 for gastric banding (GB) and Roux-en-Y gastric bypass (RYGB) results. In addition to primary bariatric operations, data regarding the complications of revision procedures and redo operations were analyzed. Participation in the quality assurance study was required for all certified centers in Germany. RESULTS: RYGBs are a popular redo operation after failed gastric banding. In the German Bariatric Surgery Registry (GBSR), we analyzed data from 263 RYGB operations that used a one-step approach after GB and 116 operations that used a two-step approach. The leakage rates for primary RYGB decreased to 1.8%. The incidence of leakage after a one-step RYGB after GB was lower (1.9%) than after the two-step procedure (2.6%). CONCLUSION: RYGBs are popular procedures after failed GB in Germany. The multivariable analysis for overall intraoperative complications revealed a significant difference between the two-step and the one-step procedure. In an unadjusted and multivariate assessment, the one-step procedure had statistically lower general postoperative complications than the two-step approach. Therefore, we suggest performing band removal and RYGB as a one-step procedure. Further analysis is necessary to evaluate the risk factors for the one-step procedure. Follow-up investigations must be performed to determine whether RYGB is an effective and safe option after GB. PMID- 25502288 TI - Integrating positive psychology into health-related quality of life research. AB - PURPOSE: Positive psychology is an increasingly influential force in theory and research within psychology and many related fields, including behavioral medicine, sociology, and public health. This article aims to review the ways in which positive psychology and health-related quality of life (HRQOL) research currently interface and to suggest fruitful future directions. METHODS: This article reviews the basic elements of positive psychology and provides an overview of conceptual and empirical links between positive psychology and HRQOL. The role of one central aspect of positive psychology (meaning) within HRQOL is highlighted, and unresolved issues (e.g., lack of definitional clarity) are discussed. RESULTS: Some research on HRQOL has taken a positive psychology perspective, demonstrating the usefulness of taking a positive psychology approach. However, many areas await integration. CONCLUSIONS: Once conceptual and methodological issues are resolved, positive psychology may profitably inform many aspects of HRQOL research and, perhaps, clinical interventions to promote HRQOL as well. PMID- 25502290 TI - Unique competitive effects of lianas and trees in a tropical forest understory. AB - Lianas are an important component of tropical forests, contributing up to 25% of the woody stems and 35% of woody species diversity. Lianas invest less in structural support but more in leaves compared to trees of similar biomass. These physiological and morphological differences suggest that lianas may interact with neighboring plants in ways that are different from similarly sized trees. However, the vast majority of past liana competition studies have failed to identify the unique competitive effects of lianas by controlling for the amount of biomass removed. We assessed liana competition in the forest understory over the course of 3 years by removing liana biomass and an equal amount of tree biomass in 40 plots at 10 sites in a secondary tropical moist forest in central Panama. We found that growth of understory trees and lianas, as well as planted seedlings, was limited due to competitive effects from both lianas and trees, though the competitive impacts varied by species, season, and size of neighbors. The removal of trees resulted in greater survival of planted seedlings compared to the removal of lianas, apparently related to a greater release from competition for light. In contrast, lianas had a species-specific negative effect on drought-tolerant Dipteryx oleifera seedlings during the dry season, potentially due to competition for water. We conclude that, at local scales, lianas and trees have unique and differential effects on understory dynamics, with lianas potentially competing more strongly during the dry season, and trees competing more strongly for light. PMID- 25502283 TI - Metabolic engineering of carbon and redox flow in the production of small organic acids. AB - The review describes efforts toward metabolic engineering of production of organic acids. One aspect of the strategy involves the generation of an appropriate amount and type of reduced cofactor needed for the designed pathway. The ability to capture reducing power in the proper form, NADH or NADPH for the biosynthetic reactions leading to the organic acid, requires specific attention in designing the host and also depends on the feedstock used and cell energetic requirements for efficient metabolism during production. Recent work on the formation and commercial uses of a number of small mono- and diacids is discussed with redox differences, major biosynthetic precursors and engineering strategies outlined. Specific attention is given to those acids that are used in balancing cell redox or providing reduction equivalents for the cell, such as formate, which can be used in conjunction with metabolic engineering of other products to improve yields. Since a number of widely studied acids derived from oxaloacetate as an important precursor, several of these acids are covered with the general strategies and particular components summarized, including succinate, fumarate and malate. Since malate and fumarate are less reduced than succinate, the availability of reduction equivalents and level of aerobiosis are important parameters in optimizing production of these compounds in various hosts. Several other more oxidized acids are also discussed as in some cases, they may be desired products or their formation is minimized to afford higher yields of more reduced products. The placement and connections among acids in the typical central metabolic network are presented along with the use of a number of specific non-native enzymes to enhance routes to high production, where available alternative pathways and strategies are discussed. While many organic acids are derived from a few precursors within central metabolism, each organic acid has its own special requirements for high production and best compatibility with host physiology. PMID- 25502291 TI - Predictive and Prognostic Roles of Abnormal Expression of Tissue miR-125b, miR 221, and miR-222 in Glioma. AB - Glioma is the most prevalent primary brain tumors in adults. In addition to the high incidence and mortality rate, the 5-year survival rate of glioma is also extremely low. MicroRNAs (miRNAs), as a class of small non-coding RNAs, may play an important role in carcinogenesis. It was also proposed that miRNAs might also be associated with glioma diagnosis and prognosis. In this study, we aimed at investigating the predictive and prognostic values of miR-125b, miR-221, and miR 222 in glioma and, hopefully, to provide some evidence for novel therapy of glioma. Tissue specimens were obtained from tumor tissue and adjacent non-tumor tissue. RNA was extracted and qRT-PCR was performed with U6 being the internal control. Receiver-operating characteristic (ROC) curves were constructed, and the area under the ROC curves (AUC) was calculated to evaluate the significance of candidate miRNAs in distinguishing glioma tumor tissues and adjacent normal tissues. Survival curves of Kaplan-Meier method were constructed for both high expression group and low expression group, and the difference between curves was evaluated by log-rank test. All the statistical analyses were performed using Stata version 12.0 software, and graphs were generated by GraphPad Prism 5.0. The significance of miR-125b, miR-221, and miR-222 expression level in distinguishing glioma tumor from adjacent non-tumor tissues was further validated. Combination of miR-125b, miR-221, and miR-22 was significantly superior compared to the clinical standard of using these miRNAs alone. A clear demarcation was shown by survival analysis between patients with high miR-125b, miR-221, and miR-222 expression and patients with poor prognosis. Similarly, panel of these miRNAs could play a better prognostic role in glioma. In this study, we confirmed the significance of miR-125b, miR-221, and miR-222 in distinguishing glioma tumor from adjacent non-tumor tissues. Higher expressions of miR-125b and miR-222 have also been proved to be associated with glioma. Furthermore, glioma patients with higher miR-125b, miR-221, and miR-222 expression were manifested to have poorer prognostic status, which might be attributed to their attenuated sensitivity to chemotherapy and radiotherapy. PMID- 25502289 TI - NOD1 and NOD2 Interact with the Phagosome Cargo in Mast Cells: A Detailed Morphological Evidence. AB - Mast cells (MC) play a key role in triggering the inflammatory process and share some functions with professional phagocytes. It is not clear whether or not the phagocytic process in MC follows the same route and has the same meaning of that of professional phagocytes. Herein we analyze in detail the structure of the phagosome in rat peritoneal mast cells (RPMC). The ultrastructural analysis of the phagosome, containing either model particles or bacteria, reveals that these vacuoles are very tight, and in several areas, their membrane seems to have dissolved. RPMC express NOD1 and NOD2 proteins whose role is to recognize intracellular foreign components and induce the production of pro-inflammatory mediators. Following Escherichia coli ingestion, both these molecules are found on the phagosome membrane and on ingested pathogens, together with phagosome maturation markers. These findings suggest that in RPMC the ingested cargo can, through interruptions of the phagosome membrane, interact directly with NODs, which act as switches in the process of cytokine production. PMID- 25502293 TI - Erratum to: Thioredoxin-interacting protein: a novel target for neuroprotection in experimental thromboembolic stroke in mice. PMID- 25502292 TI - The Ephrin-A5/EphA4 Interaction Modulates Neurogenesis and Angiogenesis by the p Akt and p-ERK Pathways in a Mouse Model of TLE. AB - Studies have shown that neurogenesis and angiogenesis do exist in temporal lobe epilepsy (TLE). The ephrin ligands and Eph receptors are the largest members of receptor tyrosine kinases, and their interaction via cell-cell contact participates in cell proliferation, differentiation, migration, and tissue remodeling. However, there is little information about the function of the ephrin A5/EphA4 complex in TLE. In the current study, we found that ephrin-A5 was expressed in astrocytes, while EphA4 existed in endothelial cells in the hippocampus in a mouse model of TLE. Furthermore, the messenger RNA (mRNA) and protein levels of both ephrin-A5 and EphA4 and the binding capacity of ephrin A5/EphA4 showed gradual increase in spatiotemporal course. When ephrin-A5-Fc was injected into the hippocampus at 3 days post-status epilepticus (SE) for 7 days, the spontaneous recurrent seizure (SRS) frequency and intensity of the mice attenuated in the following 2 weeks. Furthermore, doublecortin-positive neuronal progenitor cells were reduced in the subgranular zone, and the density of microvessels decreased in the hilus. The molecular mechanism was attributed to ephrin-A5-Fc-induced inhibition of phosphorylated ERK (p-ERK) and phosphorylated Akt (p-Akt), and also EphA4 and VEGF reduction. In summary, interaction between ephrin-A5 and EphA4 could mediate the ERK and Akt signaling pathways in pilocarpine-induced epilepsy, and intervention of the ephrin/Eph interaction may play an essential role in the suppression of newborn neuron generation, microvessel remodeling, and SRS in a mouse model of TLE. The ephrin-A5/EphA4 communication may provide a potential therapy for the treatment of TLE. PMID- 25502294 TI - Role of P2X7 Receptor in an Animal Model of Mania Induced by D-Amphetamine. AB - The objective of this study was to explore the association between the P2X7 purinergic receptor (P2X7R) and neuroinflammation using a preclinical model of acute bipolar mania. We analyzed the modulatory effects of P2X7R agonist (3'-O-(4 benzoyl)benzoyl-adenosine 5'-triphosphate, BzATP) and antagonists (brilliant blue, BBG and 3-[[5-(2,3 dichlorophenyl)-1H-tetrazol-1-yl]methyl]pyridine hydrochloride, A438079) on assessments related to behavior (locomotor activity), neuroinflammation (interleukin-1 beta, IL-1beta; tumor necrosis factor alpha, TNF alpha; and interleukin- 6, IL-6), oxidative stress (thiobarbituric acid reactive substances, TBARS) and neuroplasticity (brain-derived neurotrophic factor, BDNF) markers in a pharmacological model of mania induced by acute and chronic treatment with D-amphetamine (AMPH) (2 mg/kg) in mice. An apparent lack of responsiveness to AMPH was observed in terms of the locomotor activity in animals with blocked P2X7R or with genetic deletion of P2X7R in knockout (P2X7R(-/-)) mice. Likewise, P2X7R participated in the AMPH-induced increase of the proinflammatory and excitotoxic environment, as demonstrated by the reversal of IL-1beta, TNF-alpha, and TBARS levels caused by P2X7R blocking. Our results support the hypothesis that P2X7R plays a role in the neuroinflammation induced by AMPH in a preclinical model of mania, which could explain the altered behavior. The present data suggest that P2X7R may be a therapeutic target related to the neuroinflammation reported in bipolar disorder. PMID- 25502295 TI - TRPM7 Regulates Axonal Outgrowth and Maturation of Primary Hippocampal Neurons. AB - Transient receptor potential melastatin 7 (TRPM7) is a calcium-permeable divalent cation channel and mediates neuronal cell death under ischemic stresses. In this study, we investigated the contribution of TRPM7 to neuronal development in mouse primary hippocampal neurons. We demonstrated that TRPM7 channels are highly expressed in the tips of the growth cone. Either knockdown of TRPM7 with target specific shRNA or blocking channel conductance by a specific blocker waixenicin A enhanced axonal outgrowth in culture. Blocking TRPM7 activity by waixenicin A reduced calcium influx and accelerated the polarization of the hippocampal neurons as characterized by the development of distinct axons and dendrites. Furthermore, TRPM7 coprecipitated and colocalized with F-actin and alpha-actinin 1 at the growth cone. We conclude that calcium influx through TRPM7 inhibits axonal outgrowth and maturation by regulating the F-actin and alpha-actinin-1 protein complex. Inhibition of TRPM7 channel promotes axonal outgrowth, suggesting its therapeutic potential in neurodegenerative disorders. PMID- 25502296 TI - Immunomodulator CD200 Promotes Neurotrophic Activity by Interacting with and Activating the Fibroblast Growth Factor Receptor. AB - The CD200 ligand is expressed by a variety of cell types, including vascular endothelia, kidney glomeruli, some subsets of T and B cells, and neurons in the brain and periphery. In contrast, the receptor of CD200, CD200R, has a limited expression pattern and is mainly expressed by cells of myeloid origin. A recently solved crystal structure of the CD200-CD200R ectodomain complex suggests involvement of the first immunoglobulin (Ig)-like modules in ligand-receptor binding, resulting in the inhibition of myeloid cell function. In the central nervous system, CD200 has been implicated in the suppression of microglia activation. We for the first time demonstrated that CD200 can interact with and transduce signaling through activation of the fibroblast growth factor receptor (FGFR), thereby inducing neuritogenesis and promoting neuronal survival in primary neurons. CD200-induced FGFR phosphorylation was abrogated by CD200R, whereas FGF2-induced FGFR activation was inhibited by CD200. We also identified a sequence motif located in the first Ig-like module of CD200, likely representing the minimal CD200 binding site for FGFR. The FGFR binding motif overlaps with the CD200R binding site, suggesting that they can compete for CD200 binding in cells that express both receptors. We propose that CD200 in neurons functions as a ligand of FGFR. PMID- 25502299 TI - Differential effects of cocaine on extracellular signal-regulated kinase phosphorylation in nuclei of the extended amygdala and prefrontal cortex of psychogenetically selected Roman high- and low-avoidance rats. AB - Roman high (RHA)- and low (RLA)-avoidance rats are selectively bred for rapid vs. poor acquisition of active avoidance, respectively, and differ markedly in emotional reactivity, coping style, and behavioral and neurochemical responses to morphine and psychostimulants. Accordingly, acute cocaine induces more robust increments in locomotion and dopamine output in the nucleus accumbens shell (AcbSh) of RHA than of RLA rats. Cocaine induces short- and long-term neuronal plasticity via activation of the extracellular signal-regulated kinase (ERK) pathway. This study compares the effects of acute cocaine on ERK phosphorylation (pERK) in limbic brain areas of Roman rats. In RHA but not RLA rats, cocaine (5 mg/kg) increased pERK in the infralimbic prefrontal cortex and AcbSh, two areas involved in its acute effects, but did not modify pERK in the prelimbic prefrontal cortex and Acb core, which mediate the chronic effects of cocaine. Moreover, cocaine failed to affect pERK immunolabeling in the bed nucleus of stria terminalis pars lateralis and central amygdala of either line but increased it in the basolateral amygdala of RLA rats. These results extend to pERK expression previous findings on the greater sensitivity to acute cocaine of RHA vs. RLA rats and confirm the notion that genetic factors influence the differential responses of the Roman lines to addictive drugs. Moreover, they support the view that the Roman lines are a useful tool to investigate the molecular underpinnings of individual vulnerability to drug addiction. PMID- 25502300 TI - Conflicts of interest, disclosures, CME credits, and censorship. PMID- 25502301 TI - Ralph Ger, MD: an innovator in reconstructive surgery. PMID- 25502302 TI - Island thoracodorsal artery perforator-based V-Y advancement flap after radical excision of axillary hidradenitis: reply. PMID- 25502303 TI - The Indian method of rhinoplasty. PMID- 25502297 TI - Epigenetics of Stress, Addiction, and Resilience: Therapeutic Implications. AB - Substance use disorders (SUDs) are highly prevalent. SUDs involve vicious cycles of binges followed by occasional periods of abstinence with recurrent relapses despite treatment and adverse medical and psychosocial consequences. There is convincing evidence that early and adult stressful life events are risks factors for the development of addiction and serve as cues that trigger relapses. Nevertheless, the fact that not all individuals who face traumatic events develop addiction to licit or illicit drugs suggests the existence of individual and/or familial resilient factors that protect these mentally healthy individuals. Here, I give a brief overview of the epigenetic bases of responses to stressful events and of epigenetic changes associated with the administration of drugs of abuse. I also discuss the psychobiology of resilience and alterations in epigenetic markers that have been observed in models of resilience. Finally, I suggest the possibility that treatment of addiction should involve cognitive and pharmacological approaches that enhance resilience in at risk individuals. Similar approaches should also be used with patients who have already succumbed to the nefarious effects of addictive substances. PMID- 25502298 TI - Oxidative Stress and Neurobiology of Demyelination. AB - Despite a large amount of research which aims at defining the pathophysiology of human demyelination (i.e., multiple sclerosis), etiological bases of disease have been unknown so far. The point of intersection of all assumed etiological factors, which are mainly based upon immunological cascades, is neuroinflammation. The precise definition of the place and role of all pathogenetic factors in the occurrence and development of the disease is of crucial importance for understanding the clinical nature and for finding more effective therapeutic options. There are few studies whose results give more precise data about the role and the importance of other factors in neuroinflammation, besides immunological ones, with regard to clinical and paraclinical correlates of the disease. The review integrates results found in previously performed studies which have evaluated oxidative stress participation in early and late neuroinflammation. The largest number of studies indicates that the use of antioxidants affects the change of neuroinflammation course under experimental conditions, which is reflected in the reduction of the severity and the total reversibility in clinical presentation of the disease, the faster achieving of remission, and the delayed and slow course of neuroinflammation. Therapies based on the knowledge of redox biology targeting free radical generation hold great promise in modulation of the neuroinflammation and its clinical presentations. PMID- 25502304 TI - Dilated, arrhythmogenic cardiomyopathy in emery-dreifuss muscular dystrophy due to the emerin splice-site mutation c.449 + 1G>A. AB - OBJECTIVE: Cardiac involvement in X-linked Emery-Dreifuss muscular dystrophy (X EDMD) usually includes arrhythmias but not dilative cardiomyopathy (dCMP). Here, we report an X-EDMD patient with severe dCMP and life-threatening ventricular arrhythmias associated with other phenotypic features unusual for X-EDMD. CASE REPORT: A 46-year-old patient with X-EDMD due to the known splice-site mutation c.449 + 1G>A in the emerin gene experienced palpitations for the first time at the age of 21 years, and a first syncope at the age of 23 years. He was started on phenprocoumon due to atrial fibrillation and systolic dysfunction. At the age of 28 years he received his first pacemaker. Echocardiography at the age of 36 years showed left ventricular dilatation, enlarged atria, myocardial thickening, 28% ejection fraction and diastolic dysfunction. dCMP was suspected. At the age of 38 years, a cardiac resynchronization therapy system was implanted, which was upgraded to an implantable cardioverter defibrillator (ICD) because of ventricular tachycardias (at the age of 42 years). During the following months, the ICD discharged 30 times due to ventricular tachycardias. In May 2013, he required recurrent cardio-pulmonary resuscitation because ventricular fibrillation occurred with no discharge of the ICD. He was listed for heart transplantation. He also had hypothyroidism, liver hemangiomas, thrombopenia, anemia and diverticulosis. CONCLUSIONS: X-EDMD may occur along with dCMP. An ICD may be ineffective for ventricular fibrillation in X-EDMD. X-EDMD may be associated with unusual, atypical phenotypic features. PMID- 25502305 TI - GR-127935-sensitive mechanism mediating hypotension in anesthetized rats: are 5 HT5B receptors involved? AB - The 5-HT1B/1D receptor antagonist, GR-127935, inhibits hypotensive responses produced by the 5-HT1A, 5-HT1B/1D and 5-HT7 receptor agonist, and 5-HT5A/5B receptor ligand, 5-carboxamidotryptamine (5-CT), in rats. This work further characterized the above mechanism using more selective 5-HT1B and 5-HT1D receptor antagonists. Also, expression of 5-HT5A and 5-HT5B receptor mRNAs in blood vessels was searched by reverse transcription polymerase chain reaction. Decreases in diastolic blood pressure induced by 5-CT (0.001-10 MUg/kg, intravenously) were analyzed in anesthetized rats that had received intravenous vehicle (1 mL/kg), SB-224289 (5-HT1B antagonist; 0.3 and 1.0 mg/kg), BRL15572 (5 HT1D antagonist; 0.3 and 1.0 mg/kg), SB-224289 + BRL15572 (0.3 mg/kg, each), or SB-224289 + BRL15572 (0.3 mg/kg, each) + GR-127935 (1 mg/kg). Because only the latter treatment inhibited 5-CT-induced hypotension, suggestive of a mechanism unrelated to 5-HT1B/1D receptors, the effects of antagonists/ligands at 5-HT5A (SB-699551, 1 mg/kg), 5-HT6 (SB-399885, 1 mg/kg), and 5-HT1B/1D/5A/5B/7 receptors (ergotamine, 0.1 mg/kg) on 5-CT-induced hypotension were tested. Interestingly, only ergotamine blocked 5-CT-induced responses; this effect closely paralleled that of SB-224289 + BRL-15572 + GR-127935. Neither did ergotamine nor GR-127935 inhibit hypotensive responses induced by the 5-HT7 receptor agonist, LP-44. Faint but clear bands corresponding to 5-HT5A and 5-HT5B receptor mRNAs in aorta and mesenteric arteries were detected. Results suggest that the GR-127935-sensitive mechanism mediating hypotension in rats is unrelated to 5-HT1B, 5-HT1D, 5-HT5A, 5 HT6, and 5-HT7 receptors. This mechanism, however, resembles putative 5-HT5B receptors. PMID- 25502306 TI - Low-level transcutaneous electrical stimulation of the auricular branch of vagus nerve ameliorates left ventricular remodeling and dysfunction by downregulation of matrix metalloproteinase 9 and transforming growth factor beta1. AB - Vagus nerve stimulation improves left ventricular (LV) remodeling by downregulation of matrix metalloproteinase 9 (MMP-9) and transforming growth factor beta1 (TGF-beta1). Our previous study found that low-level transcutaneous electrical stimulation of the auricular branch of the vagus nerve (LL-TS) could be substituted for vagus nerve stimulation to reverse cardiac remodeling. So, we hypothesize that LL-TS could ameliorate LV remodeling by regulation of MMP-9 and TGF-beta1 after myocardial infarction (MI). Twenty-two beagle dogs were randomly divided into a control group (MI was induced by permanent ligation of the left coronary artery, n = 8), an LL-TS group (MI with long-term intermittent LL-TS, n = 8), and a normal group (sham ligation without stimulation, n = 6). At the end of 6 weeks follow-up, LL-TS significantly reduced LV end-systolic and end diastolic dimensions, improved ejection fraction and ratio of early (E) to late (A) peak mitral inflow velocity. LL-TS attenuated interstitial fibrosis and collagen degradation in the noninfarcted myocardium compared with the control group. Elevated level of MMP-9 and TGF-beta1 in LV tissue and peripheral plasma were diminished in the LL-TS treated dogs. LL-TS improves cardiac function and prevents cardiac remodeling in the late stages after MI by downregulation of MMP 9 and TGF-beta1 expression. PMID- 25502307 TI - Rubicon deficiency enhances cardiac autophagy and protects mice from lipopolysaccharide-induced lethality and reduction in stroke volume. AB - : Rubicon has been suggested to suppress autophagosome maturation by negatively regulating PI3KC3/Vps34 activity. However, the physiological function of Rubicon remains elusive. We hypothesized that Rubicon deficiency enhances autophagic flux in the heart and affects cardiac function. Rubicon knockout (KO) mice were generated by piggyBac transposition. Loss of Rubicon was demonstrated at both mRNA and protein levels. Rubicon KO mice were born in Mendelian ratios. Autophagic flux, assessed by bafilomycin A1-induced changes in LC3 II protein abundance, was enhanced in the heart of Rubicon KO mice compared with wild-type (WT) controls. Hematoxylin-eosin staining and picrosirius red staining showed that Rubicon KO mice exhibited normal baseline cardiac morphology. Echocardiography revealed that ejection fraction and fractional shortening, 2 indices of cardiac function, were comparable between Rubicon KO mice at 2, 8, and 12 months of age (n = 6-8 for each age group) and the corresponding WT controls (n = 6-8 for each age group). In a mouse model of lipopolysaccharide (LPS) induced sepsis, the survival time of LPS-treated Rubicon KO mice (n = 10) was prolonged compared with LPS-treated WT controls (n = 11). Echocardiography revealed that Rubicon deficiency partially normalized LPS-induced reduction in stroke volume and cardiac output 12 hours after LPS administration compared with LPS-treated WT controls (n = 6 for each group). Autophagic flux was enhanced in Rubicon-deficient hearts 12 hours after LPS treatment compared with LPS-treated WT controls. Real-time quantitative polymerase chain reaction suggested that proinflammatory cytokine expression was not significantly different between LPS treated Rubicon KO mice and WT controls (n = 3 for each group). Our data demonstrate for the first time that Rubicon deficiency enhances autophagic flux in the heart and protects mice from lethality and reduction in stroke volume induced by LPS. PMID- 25502308 TI - Impact of renin-angiotensin-aldosterone system-blocking agents on the risk of contrast-induced acute kidney injury: a prospective study and meta-analysis. AB - OBJECTIVE: We sought to assess the impact of the pretreatment with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for coronary intervention on the risk of contrast-induced acute kidney injury (CI AKI) after 72-hour postcontrast administration, together with a comprehensive meta-analysis in this aspect. METHODS AND RESULTS: In this prospective study, 401 patients referred for percutaneous coronary intervention were enrolled with 134 patients in non-renin-angiotensin-aldosterone system group, 204 patients in ACEIs group and 63 patients in ARBs group. For further meta-analysis, articles were identified through PubMed, EMBASE, Wanfang, and VIP. Data extraction and study quality were assessed in duplicate. Altogether, 14 qualified trials (including this prospective study) with 1960 patients taking ACEIs or ARBs and 1457 patients receiving no renin-angiotensin-aldosterone system blockers were analyzed. There was an overall 1.28-fold increased risk for CI-AKI in patients taking ACEIs or ARBs (odds ratio [OR] = 1.28; 95% confidence interval [CI], 0.79-2.09; P = 0.315). Overall changes in serum creatinine, estimated GFR, and blood urea nitrogen were also nonsignificant. Subgroup analyses identified a significantly increased risk for CI-AKI in patients taking ARBs (OR = 3.31; 95% CI, 1.89-5.78; P < 0.0005), and no significance was observed for patients taking ACEIs (OR = 0.86; 95% CI, 043-1.72; P = 0.664). Also, patients taking ARBs had serum creatinine markedly increased by 0.05 mg/dL (95% CI, 0.02-0.09; P = 0.005). CONCLUSIONS: The findings of this meta-analysis provide clear evidence for a deleterious impact of ARBs on the development of CI-AKI. PMID- 25502309 TI - Cardioprotective effects of luteolin on ischemia/reperfusion injury in diabetic rats are modulated by eNOS and the mitochondrial permeability transition pathway. AB - Myocardial ischemia/reperfusion (I/R) injury in diabetes is associated with oxidative stress, endothelial nitric oxide synthase (eNOS) dysfunction, and mitochondrial collapse, whereas luteolin is known to protect the cardiovascular system against diabetes and I/R injury. Here, we investigated whether luteolin pretreatment diminishes myocardial I/R injury in diabetic rats by affecting eNOS and the mitochondrial permeability transition pore (mPTP). After diabetic rats were produced by streptozotocin treatment (65 mg/kg) for 3 weeks, luteolin (100 mg.kg.d) or L-NAME (25 mg.kg.d) was administered intragastrically for 2 weeks. Hearts were then isolated and subjected to 30 minutes of global ischemia followed by 120 minutes of reperfusion. Pretreatment with luteolin significantly improved left ventricular function and coronary flow throughout reperfusion, increased cardiac tissue viability and manganese superoxide dismutase (MnSOD) activity, and reduced coronary lactate dehydrogenase release, and the myocardial malonaldehyde level in diabetic I/R rat hearts. All these improving effects of luteolin were significantly attenuated by L-NAME. Luteolin also significantly upregulated eNOS expression in diabetic rat hearts after I/R. Ca-induced mPTP opening and mitochondrial inner membrane potential reduction were significantly inhibited in ventricular myocytes isolated from luteolin-treated diabetic rats, and this effect was attenuated by L-NAME. These findings indicate that luteolin protects the diabetic heart against I/R injury by upregulating the myocardial eNOS pathway, and downstream effects include the enhancement of MnSOD and inhibition of mPTP. PMID- 25502310 TI - Treatment outcomes of the patients with early glottic cancer treated with initial radiotherapy and salvaged by conservative surgery. AB - OBJECTIVE: This retrospective study analyzed the oncological and treatment outcomes of the patients with T1-T2N0 glottic cancer, who were treated with radiotherapy as initial treatment and salvaged by conservative surgery for radiation failure. METHODS: Between May 1999 and December 2010, 115 patients with glottic laryngeal cancer were treated at Kobe University Hospital. At presentation, 54 patients had stage T1a disease, 26 had stage T1b disease and 35 had stage T2 disease. Seventy-nine patients were treated with conventional radiotherapy and 36 patients were treated with hyperfractionated radiotherapy as initial treatment. RESULTS: Median duration of follow-up was 61 months. Five-year local control rates of radiotherapy were 92% in T1a, 83% in T1b and 86% in T2. Of 12 patients who developed local recurrence, larynx was successfully preserved in 3 patients by laryngomicrosurgery, 7 patients by vertical partial laryngectomy and one patient by subtotal laryngectomy. Ultimate 5-year laryngeal preservation rate and local control rate of all cases were 99 and 100%, respectively. CONCLUSIONS: Present results suggest that initial treatment with radiotherapy salvaged by organ preservation surgery is an effective strategy for laryngeal preservation in the treatment of T1-T2N0 glottic laryngeal cancer. PMID- 25502311 TI - Control of quantum magnets by atomic exchange bias. AB - Mixing of discretized states in quantum magnets has a radical impact on their properties. Managing this effect is key for spintronics in the quantum limit. Magnetic fields can modify state mixing and, for example, mitigate destabilizing effects in single-molecule magnets. The exchange bias field has been proposed as a mechanism for localized control of individual nanomagnets. Here, we demonstrate that exchange coupling with the magnetic tip of a scanning tunnelling microscope provides continuous tuning of spin state mixing in an individual nanomagnet. By directly measuring spin relaxation time with electronic pump-probe spectroscopy, we find that the exchange interaction acts analogously to a local magnetic field that can be applied to a specific atom. It can be tuned in strength by up to several tesla and cancel external magnetic fields, thereby demonstrating the feasibility of complete control over individual quantum magnets with atomically localized exchange coupling. PMID- 25502312 TI - A multichannel nanosensor for instantaneous readout of cancer drug mechanisms. AB - Screening methods that use traditional genomic, transcriptional, proteomic and metabonomic signatures to characterize drug mechanisms are known. However, they are time consuming and require specialized equipment. Here, we present a high throughput multichannel sensor platform that can profile the mechanisms of various chemotherapeutic drugs in minutes. The sensor consists of a gold nanoparticle complexed with three different fluorescent proteins that can sense drug-induced physicochemical changes on cell surfaces. In the presence of cells, fluorescent proteins are rapidly displaced from the gold nanoparticle surface and fluorescence is restored. Fluorescence 'turn on' of the fluorescent proteins depends on the drug-induced cell surface changes, generating patterns that identify specific mechanisms of cell death induced by drugs. The nanosensor is generalizable to different cell types and does not require processing steps before analysis, offering an effective way to expedite research in drug discovery, toxicology and cell-based sensing. PMID- 25502313 TI - The politics of psycholinguistics. AB - This article narrates the history of the interdisciplinary field of psycholinguistics from its modern organization in the 1950s to its application and influence in the field of reading instruction. Beginning as a combination of structural linguistics, behaviorist psychology, and information theory, the field was revolutionized by the collaboration of the psychologist George Miller and the linguist Noam Chomsky. This transformation was, at root, the adoption of the view that humans should be best understood as creative users of language and the rejection of behaviorist or machine models. Under their influence the field came to treat humans as creative, nonmechanical learners and users of language who, like scientists, hypothesize in order to understand and even perceive the world. This vision of language as a nondeterministic process shaped the field of reading instruction by providing the central model to advocates of the whole-language pedagogical method. PMID- 25502315 TI - Earth history. U-Pb geochronology of the Deccan Traps and relation to the end Cretaceous mass extinction. AB - The Chicxulub asteroid impact (Mexico) and the eruption of the massive Deccan volcanic province (India) are two proposed causes of the end-Cretaceous mass extinction, which includes the demise of nonavian dinosaurs. Despite widespread acceptance of the impact hypothesis, the lack of a high-resolution eruption timeline for the Deccan basalts has prevented full assessment of their relationship to the mass extinction. Here we apply uranium-lead (U-Pb) zircon geochronology to Deccan rocks and show that the main phase of eruptions initiated ~250,000 years before the Cretaceous-Paleogene boundary and that >1.1 million cubic kilometers of basalt erupted in ~750,000 years. Our results are consistent with the hypothesis that the Deccan Traps contributed to the latest Cretaceous environmental change and biologic turnover that culminated in the marine and terrestrial mass extinctions. PMID- 25502314 TI - Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. AB - The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from <=0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites. PMID- 25502317 TI - Effective dose conversion coefficients for health care provider exposed to pediatric and adult victims in radiological dispersal device incident. AB - After an incident of radiological dispersal devices (RDD), health care providers will be exposed to the contaminated patients in the extended medical treatments. Assessment of potential radiation dose to the health care providers will be crucial to minimize their health risk. In this study, we compiled a set of conversion coefficients (mSv MBq(-1) s(-1)) to readily estimate the effective dose from the time-integrated activity for the health care providers while they deal with internally contaminated patients at different ages. We selected Co-60, Ir-192, Am-241, Cs-137, and I-131 as the major radionuclides that may be used for RDD. We obtained the age-specific organ burdens after the inhalation of those radionuclides from the Dose and Risk Calculation Software (DCAL) program. A series of hybrid computational phantoms (1-, 5-, 10-, and 15 year-old, and adult males) were implemented in a general purpose Monte Carlo (MC) transport code, MCNPX v 2.7, to simulate an adult male health care provider exposed to contaminated patients at different ages. Two exposure scenarios were taken into account: a health care provider (a) standing at the side of patients lying in bed and (b) sitting face to face with patients. The conversion coefficients overall depended on radionuclides, the age of the patients, and the orientation of the patients. The conversion coefficient was greatest for Co-60 and smallest for Am 241. The dose from the 1 year-old patient phantom was up to three times greater than that from the adult patient phantom. The conversion coefficients were less dependent on the age of the patients in the scenario of a health care provider sitting face to face with patients. The dose conversion coefficients established in this study will be useful to readily estimate the effective dose to the health care providers in RDD events. PMID- 25502316 TI - Drug resistance. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. AB - Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate malaria. Polymorphisms in the kelch domain-carrying protein K13 are associated with artemisinin resistance, but the underlying molecular mechanisms are unknown. We analyzed the in vivo transcriptomes of 1043 P. falciparum isolates from patients with acute malaria and found that artemisinin resistance is associated with increased expression of unfolded protein response (UPR) pathways involving the major PROSC and TRiC chaperone complexes. Artemisinin-resistant parasites also exhibit decelerated progression through the first part of the asexual intraerythrocytic development cycle. These findings suggest that artemisinin-resistant parasites remain in a state of decelerated development at the young ring stage, whereas their up-regulated UPR pathways mitigate protein damage caused by artemisinin. The expression profiles of UPR related genes also associate with the geographical origin of parasite isolates, further suggesting their role in emerging artemisinin resistance in the Greater Mekong Subregion. PMID- 25502318 TI - Serological evidence for non-lethal exposures of Mongolian wild birds to highly pathogenic avian influenza H5N1 virus. AB - Surveillance for highly pathogenic avian influenza viruses (HPAIV) in wild birds is logistically demanding due to the very low rates of virus detection. Serological approaches may be more cost effective as they require smaller sample sizes to identify exposed populations. We hypothesized that antigenic differences between classical Eurasian H5 subtype viruses (which have low pathogenicity in chickens) and H5N1 viruses of the Goose/Guangdong/96 H5 lineage (which are HPAIV) may be used to differentiate populations where HPAIVs have been circulating, from those where they have not. To test this we performed hemagglutination inhibition assays to compare the reactivity of serum samples from wild birds in Mongolia (where HPAIV has been circulating, n = 1,832) and Europe (where HPAIV has been rare or absent, n = 497) to a panel of reference viruses including classical Eurasian H5 (of low pathogenicity), and five HPAIV H5N1 antigens of the Asian lineage A/Goose/Guangdong/1/96. Antibody titres were detected against at least one of the test antigens for 182 Mongolian serum samples (total seroprevalence of 0.10, n = 1,832, 95% adjusted Wald confidence limits of 0.09-0.11) and 25 of the European sera tested (total seroprevalence of 0.05, n = 497, 95% adjusted Wald confidence limits of 0.03-0.07). A bias in antibody titres to HPAIV antigens was found in the Mongolian sample set (22/182) that was absent in the European sera (0/25). Although the interpretation of serological data from wild birds is complicated by the possibility of exposure to multiple strains, and variability in the timing of exposure, these findings suggest that a proportion of the Mongolian population had survived exposure to HPAIV, and that serological assays may enhance the targeting of traditional HPAIV surveillance toward populations where isolation of HPAIV is more likely. PMID- 25502320 TI - Beyond scar formation: portal myofibroblast-mediated angiogenesis in the fibrotic liver. PMID- 25502319 TI - Dexamethasone activates transient receptor potential canonical 4 (TRPC4) channels via Rasd1 small GTPase pathway. AB - Canonical transient receptor potential 4 (TRPC4) channels are calcium-permeable, nonselective cation channels that are widely distributed in mammalian cells. It is generally speculated that TRPC4 channels are activated by Gq/11-PLC pathway or directly activated by Gi/o proteins. Although many mechanistic studies regarding TRPC4 have dealt with heterotrimeric G proteins, here, we first report the functional relationship between TRPC4 and small GTPase, Rasd1. Rasd1 selectively activated TRPC4 channels, and it was the only Ras protein among Ras protein family that can activate TRPC4 channels. For this to occur, it was found that certain population of functional Galphai1 and Galphai3 proteins are essential. Meanwhile, dexamethasone, a synthetic glucocorticoid and anti-inflammatory drug was known to increase messenger RNA (mRNA) level of Rasd1 in pancreatic beta cells. We have found that dexamethasone triggers TRPC4-like cationic current in INS-1 cells via increasing protein expression level of Rasd1. This relationship among dexamethasone, Rasd1, and TRPC4 could suggest a new therapeutic agent for hospitalized diabetes mellitus (DM) patients with prolonged dexamethasone prescription. PMID- 25502321 TI - [Intraoperative avoidance and recognition of recurrent laryngeal nerve palsy in thyroid surgery]. AB - Recurrent laryngeal nerve palsy is an intrinsic complication of thyroid surgery. Prevention of nerve palsy is considered to be a feature of quality in this very frequently performed operation. Risk factors and prevention strategies are demonstrated and discussed with reference to the current literature. Exact knowledge of the anatomy and possible variants of the track of the recurrent laryngeal nerve as well as its visualization and careful dissection are the cornerstones for nerve preservation. The use of intraoperative neuromonitoring allows preservation of the anatomical structure and functional integrity of the nerve and lesions which are not visible can be detected. Preconditions for correct interpretation are a standardized application and preoperative and postoperative laryngoscopy. PMID- 25502322 TI - Quality and extent of informed consent for invasive procedures: a pilot study at the institutional level in Turkey. AB - OBJECTIVE: To assess the quality of informed consent for patients undergoing invasive procedures and to reveal patient preferences for being informed about the potential risks of treatment and alternatives to treatment. DESIGN: This study was planned as a pilot study. Hospitalized patients' perceptions and expectations about the informed-consent process were explored in a general surgery department. The prepared questionnaire was completed by patients via interview. SETTING: Inpatient services of the general surgery department of a large academic hospital in Istanbul, Turkey. PARTICIPANTS: The study population consisted of hospitalized patients in a general surgery department who underwent invasive procedures in March 2013. MAIN OUTCOME MEASURES: Recognition of consent forms by the patients, rate of patients' recall of risks, rate of patients who were willing to be involved in decision making, and rate of patients who were satisfied with the whole decision-making process were measured. RESULTS: All patients signed consent forms. Most patients did not properly read the consent form since they trusted their physician. Potential exposure to risk seemed to be important for patient expectations. CONCLUSIONS: Paternalism seemed to dominate our clinical setting. The informed-consent process was definitely a separate issue from signing the consent forms. We conclude that the informed-consent process should be modified to be more functional and appropriate to human psychology. We suggest that education is necessary for informed consent to promote better quality and safety in health care. PMID- 25502324 TI - Morphologic differentiation of viruses beyond the family level. AB - Electron microscopy has been instrumental in the identification of viruses by being able to characterize a virus to the family level. There are a few cases where morphologic or morphogenesis factors can be used to differentiate further, to the genus level. These include viruses in the families Poxviridae, Reoviridae, Retroviridae, Herpesviridae, Filoviridae, and Bunyaviridae. PMID- 25502328 TI - How to review a paper for Heart. PMID- 25502325 TI - In between: gypsy in Drosophila melanogaster reveals new insights into endogenous retrovirus evolution. AB - Retroviruses are RNA viruses that are able to synthesize a DNA copy of their genome and insert it into a chromosome of the host cell. Sequencing of different eukaryote genomes has revealed the presence of many such endogenous retroviral sequences. The mechanisms by which these retroviral sequences have colonized the genome are still unknown, and the endogenous retrovirus gypsy of Drosophila melanogaster is a powerful experimental model for deciphering this process in vivo. Gypsy is expressed in a layer of somatic cells, and then transferred into the oocyte by an unknown mechanism. This critical step is the start of the endogenization process. Moreover gypsy has been shown to have infectious properties, probably due to its envelope gene acquired from a baculovirus. Recently we have also shown that gypsy maternal transmission is reduced in the presence of the endosymbiotic bacterium Wolbachia. These studies demonstrate that gypsy is a unique and powerful model for understanding the endogenization of retroviruses. PMID- 25502323 TI - Active amplification in insect ears: mechanics, models and molecules. AB - Active amplification in auditory systems is a unique and sophisticated mechanism that expends energy in amplifying the mechanical input to the auditory system, to increase its sensitivity and acuity. Although known for decades from vertebrates, active auditory amplification was only discovered in insects relatively recently. It was first discovered from two dipterans, mosquitoes and flies, who hear with their light and compliant antennae; only recently has it been observed in the stiffer and heavier tympanal ears of an orthopteran. The discovery of active amplification in two distinct insect lineages with independently evolved ears, suggests that the trait may be ancestral, and other insects may possess it as well. This opens up extensive research possibilities in the field of acoustic communication, not just in auditory biophysics, but also in behaviour and neurobiology. The scope of this review is to establish benchmarks for identifying the presence of active amplification in an auditory system and to review the evidence we currently have from different insect ears. I also review some of the models that have been posited to explain the mechanism, both from vertebrates and insects and then review the current mechanical, neurobiological and genetic evidence for each of these models. PMID- 25502329 TI - Almanac 2014: congenital heart disease. AB - This Almanac summarises important congenital heart disease articles published between 2012 and 2014 in Heart and other major cardiac journals. It highlights what the authors perceive to be highly relevant articles in the field. While the aim was to provide a comprehensive overview of the area, a focus on certain areas of interest was required. The selection is, therefore, by necessity a subjective one. PMID- 25502326 TI - "Menage a Trois": the evolutionary interplay between JSRV, enJSRVs and domestic sheep. AB - Sheep betaretroviruses represent a fascinating model to study the complex evolutionary interplay between host and pathogen in natural settings. In infected sheep, the exogenous and pathogenic Jaagsiekte sheep retrovirus (JSRV) coexists with a variety of highly related endogenous JSRVs, referred to as enJSRVs. During evolution, some of them were co-opted by the host as they fulfilled important biological functions, including placental development and protection against related exogenous retroviruses. In particular, two enJSRV loci, enJS56A1 and enJSRV-20, were positively selected during sheep domestication due to their ability to interfere with the replication of related competent retroviruses. Interestingly, viruses escaping these transdominant enJSRVs have recently emerged, probably less than 200 years ago. Overall, these findings suggest that in sheep the process of endogenization is still ongoing and, therefore, the evolutionary interplay between endogenous and exogenous sheep betaretroviruses and their host has not yet reached an equilibrium. PMID- 25502330 TI - The antimicrobial peptides psoriasin (S100A7) and koebnerisin (S100A15) suppress extracellular matrix production and proliferation of human fibroblasts. AB - BACKGROUND/AIMS: Keloids result from aberrations in the normal wound healing cascade and can lead to pruritus, contractures and pain. The underlying mechanisms of excessive scarring are not yet understood, and most therapeutic strategies remain unsatisfactory. Psoriasin (S100A7) and koebnerisin (S100A15) are released by keratinocytes during physiological wound healing. We found S100 production is markedly decreased in keloid scar tissue. The disturbed epidermal S100 expression might contribute to keloid formation; thus, we studied their effect on dermal fibroblasts and extracellular matrix (ECM) production. METHODS: S100 peptides, ECM regulation and distribution were analysed in normal and keloid tissue by quantitative PCR (qPCR), immunoblotting and immunofluorescent staining. Isolated dermal fibroblasts were incubated with S100 proteins, and the regulation of ECM and transforming growth factor (TGF)-beta was determined using qPCR. Fibroblast proliferation and viability were determined by the 5-bromo-2' deoxyuridine assay and crystal violet assay. RESULTS: Keloid tissue featured a pronounced expression of ECMs, such as collagen types 1 and 3, whereas the production of psoriasin and koebnerisin was markedly decreased in keloid-derived cells and keloid tissue. Both S100 proteins inhibited the expression of collagens, fibronectin-1, alpha-smooth-muscle actin and TGF-beta by fibroblasts. Further, they also suppressed fibroblast proliferation. CONCLUSION: Psoriasin and koebnerisin show antifibrotic effects and may lead to novel preventive and therapeutic strategies for fibroproliferative diseases. PMID- 25502331 TI - Novel peapod-like Ni2P nanoparticles with improved electrochemical properties for hydrogen evolution and lithium storage. AB - A novel peapod-like Ni2P/C nanocomposite is designed and synthesized using NiNH4PO4H2O nanorods as templates. With enriched nanoporosity and large active surface areas, the peapod-like composites offer superb dual functionality as both electrocatalysts for the hydrogen evolution reaction (HER) and anodes for lithium ion batteries (LIBs). Electrochemical tests demonstrate that the Ni2P/C nanocomposite exhibits an overpotential as low as 60 mV and a notably low Tafel slope of 54 mV dec.(-1). When used as an anode material for lithium-ion batteries, the resulting peapod-like Ni2P/C nanocomposite delivers high specific capacitances of 632 mA h g(-1) at 0.1 A g(-1) and 439 mA h g(-1) at 3 A g(-1), and also exhibits a superior cycling performance, with nearly 100% capacity retention even after 200 charge-discharge cycles at a charge-discharge rate of 0.1 A g(-1). The work demonstrates that the peapod-like materials reported herein are promising materials for electrochemical energy-related applications such as HER and LIBs. PMID- 25502332 TI - Significance of 18F-Fluorodeoxyglucose Uptake at the Gastroesophageal Junction: Comparison of PET to Esophagogastroduodenoscopy. AB - BACKGROUND: Positron emission tomography-computed tomography (PET/CT) occasionally reveals unexpected uptake of (18)F-fluorodeoxyglucose ((18)F-FDG) at the gastroesophageal junction (GEJ). The aim of this study was to determine the importance of unexpected (18)F-FDG uptake at the GEJ on PET/CT by correlating this finding with endoscopy results. METHODS: We reviewed medical records from June 2009 to October 2012 to identify patients in our Veterans Affairs Medical Center who had an esophagogastroduodenoscopy (EGD) performed within 6 months of a PET/CT. Metabolic activity at the GEJ was quantified with standardized uptake values (SUV) and correlated with EGD and histopathology results. RESULTS: A total of 219 patients were identified and assigned to one of five groups based upon EGD findings: esophageal malignancy (n = 34), esophagitis (n = 21), Barrett's esophagus (n = 8), other non-malignant disorders (n = 5), and normal (n = 151). The mean SUV Max for the groups was 6.72, 2.47, 2.40, 3.48, and 2.06, respectively. SUV Max and SUV Mean were significantly higher in the esophageal malignancy group than in all other groups (p < 0.001). SUV for patients with high grade esophagitis was greater than in patients with low-grade esophagitis. A SUV Max >= 3.5 was found to predict necessity for EGD with a positive predictive value of 79 %. A SUV Max <= 2.2 yielded a negative predictive value of 86 %. CONCLUSION: Differentiation between benign and potentially significant disease at the GEJ may be possible with quantification of incidental (18)F-FDG uptake at PET/CT. Our results suggest thresholds that may help determine need for further endoscopic evaluation in patients with abnormal metabolic activity at the GEJ. PMID- 25502333 TI - Investigation of protective effect of L-carnitine on L-asparaginase-induced acute pancreatic injury in male Balb/c mice. AB - INTRODUCTION: The present analysis deals with the biochemical and histopathological effects of L-carnitine in mice with L-asparaginase (ASNase) induced experimental acute pancreatic injury (API). METHODS: A total of 32 male Balb/c mice were divided into four groups as follows. Group I (control) was injected with single saline via the intraperitoneal route. Group II received 500 mg/kg of L-carnitine daily with the injected volume of 62.5-75 MUl for 25-30 g mice using a Hamilton microinjector applied for 5 days. Group III received a single 10,000 IU Escherichia coli ASNase/kg body weight dose of ASNase at a dose of 500 mg/kg. Group IV received 500 mg/kg of L-carnitine daily and a single dose of 500 mg/kg of ASNase and were decapitated on the fifth day following the injection. Blood and pancreatic tissue samples were obtained for evaluation of histopathological structure and levels of malondialdehyde (MDA), reduced glutathione (GSH), total sialic acid (TSA), glucose, amylase and triglyceride. RESULTS: In group III, compared to group IV and group I it was determined that levels of GSH and amylase were significantly lower while levels of MDA, TSA, glucose and triglyceride were higher. Levels of GSH, MDA, TSA, glucose, triglyceride and amylase, especially in group IV, approached that of group I. As a result, L-carnitine for ASNase-induced API mice may be protective against pancreatic tissue degeneration and oxidative stress or lipid peroxidation. PMID- 25502334 TI - Coronary anatomy, anatomic variations and anomalies: a retrospective coronary angiography study. AB - INTRODUCTION: The incidence of coronary artery anomalies (CAAs) varies from 0.2% to 8.4%. Knowledge of such anatomical variations is important as coronary procedures are regularly performed these days. We aimed to find the coronary dominance pattern, intermediate artery (IMA) frequency and CAA incidence in our clinic, and compare them to those in the literature. METHODS: The medical reports of 5,548 patients who had undergone coronary angiography (CAG) between 2005 and 2009 were retrospectively investigated. Dominance pattern and presence of IMA and CAA were recorded. CAAs were described using two different classifications: Angelini and Khatami's classification, and a new modified classification that was derived from Angelini and Khatami's classification. Some procedural details and clinical features of the patients with CAA were also investigated. RESULTS: Coronary dominance pattern was: 81.6% right coronary artery, 12.2% circumflex artery and 6.2% co-dominant. IMA was present in 613 (11.0%) patients. The incidences of overall anomaly were 2.7% and 1.4%, according to the different classifications. Absent left main coronary artery, which was the most common anomaly in the present study, was found in 51 (0.9%) patients. Incidences of myocardial bridge, coronary arteriovenous fistulae and aneurysms were 1.1%, 0.2% and 0.3%, respectively. CONCLUSION: CAAs are generally asymptomatic, isolated lesions. Some may lead to anginal symptoms, myocardial infarction or sudden death. We found that CAA was associated with increased radiation and contrast exposure in patients who underwent CAG. This risk could be reduced if appropriate catheters were designed and training programmes on ostial cannulation were developed. PMID- 25502335 TI - A feasible ambulatory mini-incision microsurgical vasovasostomy under local anaesthesia using a specially designed double-ringed clamp that simplifies surgery. AB - INTRODUCTION: In line with the effort to evaluate feasible surgical options for vasectomy reversal and to increase patients' willingness to undergo the procedure, this study reported on a technique for ambulatory mini-incision microsurgical vasovasostomy using a double-ringed clamp (i.e. Moon's clamp). This technique does not require the use of dilators, approximators and other accessory devices. METHODS: Ambulatory mini-incision microsurgical vasovasostomy was conducted on 263 patients who satisfied the surgical eligibility requirements for vasovasostomy and the safety criteria for local anaesthesia. The operation time, details on postoperative recovery and results of the postoperative semen analysis were recorded and retrospectively analysed. RESULTS: The mean time used to isolate the bilateral vas deferens was 25.5 minutes. All patients were discharged on the day of surgery and all patients returned to their normal activities within 24-48 hours after surgery. No haematoma or infection occurred except in one patient. Postoperative semen analysis showed that the surgery was successful in 182 (96.8%) of the 188 patients who complied with the postoperative patient instructions. CONCLUSION: Ambulatory mini-incision microsurgical vasectomy reversal using Moon's clamp and under local anaesthesia is a surgically feasible option that offers the advantages of a low-risk operation. It also achieves successful vasovasostomy without other accessory devices and allows patients to return to their daily activities quickly with minimal complications. PMID- 25502337 TI - Chronic kidney disease and the ageing population. AB - Due to improvements in socioeconomic development and increased life expectancy, the proportion of older people in the general population is increasing worldwide. While this trend is something to celebrate, it also brings with it challenges for health care systems. One particular challenge is an increase in chronic kidney disease, the prevalence of which is higher in older people. This article reviews the key links between kidney function, age, health and illness, and discusses the implications of the ageing population for the care of people with chronic kidney disease. PMID- 25502338 TI - Detection of DNA sequences refractory to PCR amplification using a biophysical SERRS assay (Surface Enhanced Resonant Raman Spectroscopy). AB - The analysis of ancient or processed DNA samples is often a great challenge, because traditional Polymerase Chain Reaction - based amplification is impeded by DNA damage. Blocking lesions such as abasic sites are known to block the bypass of DNA polymerases, thus stopping primer elongation. In the present work, we applied the SERRS-hybridization assay, a fully non-enzymatic method, to the detection of DNA refractory to PCR amplification. This method combines specific hybridization with detection by Surface Enhanced Resonant Raman Scattering (SERRS). It allows the detection of a series of double-stranded DNA molecules containing a varying number of abasic sites on both strands, when PCR failed to detect the most degraded sequences. Our SERRS approach can quickly detect DNA molecules without any need for DNA repair. This assay could be applied as a pre requisite analysis prior to enzymatic reparation or amplification. A whole new set of samples, both forensic and archaeological, could then deliver information that was not yet available due to a high degree of DNA damage. PMID- 25502339 TI - Parthenolide enhances sensitivity of colorectal cancer cells to TRAIL by inducing death receptor 5 and promotes TRAIL-induced apoptosis. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent. Recombinant human TRAIL has been evaluated in clinical trials, however, various malignant tumors are resistant to TRAIL. Parthenolide (PT) has recently been demonstrated as a highly effective anticancer agent and has been suggested to be used for combination therapy with other anticancer agents. In this study, we investigate the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. HT-29 (TRAIL resistant) and HCT116 (TRAIL-sensitive) cells were treated with PT and/or TRAIL. The results demonstrated that combined treatment induced apoptosis which was determined using MTT, cell cycle analysis, Annexin V assay and Hoechst 33258 staining. Interestingly, we confirmed that HCT116 cells have much higher death receptor (DR) 5 than HT-29 cells and PT upregulates DR5 protein level and surface expression in both cell lines. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, p53 cytochrome C release, and caspase cascades. These results suggest that PT sensitizes TRAIL induced apoptosis via upregulation of DR5 and mitochondria-dependent pathway. Combination treatment using PT and TRAIL may offer an effective strategy to overcome TRAIL resistance of certain CRC cells. PMID- 25502340 TI - Fixation of sulfur dioxide into small molecules. AB - Sulfonyl-derived functional groups can be found in a broad range of natural products, pharmaceuticals, and materials. Among the methods for the introduction of the sulfonyl group into small molecules, the approach using sulfur dioxide is the most promising and attractive one. In the past several years, the insertion of sulfur dioxide into small molecules under transition metal catalysis or metal free conditions via a radical process has been developed. In this review, recent advances in the insertion of sulfur dioxide are presented. PMID- 25502336 TI - A chromatin activity-based chemoproteomic approach reveals a transcriptional repressome for gene-specific silencing. AB - Immune cells develop endotoxin tolerance (ET) after prolonged stimulation. ET increases the level of a repression mark H3K9me2 in the transcriptionally silent chromatin specifically associated with pro-inflammatory genes. However, it is not clear what proteins are functionally involved in this process. Here we show that a novel chromatin activity-based chemoproteomic (ChaC) approach can dissect the functional chromatin protein complexes that regulate ET-associated inflammation. Using UNC0638 that binds the enzymatically active H3K9-specific methyltransferase G9a/GLP, ChaC reveals that G9a is constitutively active at a G9a-dependent mega dalton repressome in primary endotoxin-tolerant macrophages. G9a/GLP broadly impacts the ET-specific reprogramming of the histone code landscape, chromatin remodelling and the activities of select transcription factors. We discover that the G9a-dependent epigenetic environment promotes the transcriptional repression activity of c-Myc for gene-specific co-regulation of chronic inflammation. ChaC may also be applicable to dissect other functional protein complexes in the context of phenotypic chromatin architectures. PMID- 25502341 TI - Depletion of Amyloid Precursor Protein (APP) causes G0 arrest in non-small cell lung cancer (NSCLC) cells. AB - We recently reported that Amyloid Precursor Protein (APP) regulates global protein synthesis in a variety of human dividing cells, including non-small cell lung cancer (NSCLC) cells. More specifically, APP depletion causes an increase of both cap- and IRES-dependent translation. Since growth and proliferation are tightly coupled processes, here, we asked what effects artificial downregulation of APP could have elicited in NSCLC cells proliferation. APP depletion caused a G0/G1 arrest through destabilization of the cyclin-C protein and reduced pRb phosphorylation at residues Ser802/811. siRNA to cyclin-C mirrored the cell cycle distribution observed when silencing APP. Cells arrested in G0/G1 (and with augmented global protein synthesis) increased their size and underwent a necrotic cell death due to cell membrane permeabilization. These phenotypes were reversed by overexpression of the APP C-terminal domain, indicating a novel role for APP in regulating early cell cycle entry decisions. It is seems that APP moderates the rate of protein synthesis before the cell clears growth factors- and nutrients-dependent checkpoint in mid G1. Our results raise questions on how such processes interact in the context of (at least) dividing NSCLC cells. The data presented here suggest that APP, although required for G0/G1 transitions, moderates the rate of protein synthesis before the cell fully commits to cell cycle progression following mechanisms, which seem additional to concurrent signals deriving from the PI3-K/Akt/mTORC-1 axis. APP appears to play a central role in regulating cell cycle entry with the rate of protein synthesis; and its loss-of-function causes cell size abnormalities and death. PMID- 25502343 TI - Antegrade intramedullary pinning versus retrograde intramedullary pinning for displaced fifth metacarpal neck fractures. AB - BACKGROUND: Severe angulation or shortening can be a surgical indication for fifth metacarpal neck fracture. In a previous meta-analysis, antegrade intramedullary pinning was shown to produce better hand function outcomes than percutaneous transverse pinning or miniplate fixation for treatment of fifth metacarpal neck fractures. However, the outcomes of retrograde intramedullary pinning, to our knowledge, have not been compared with those of antegrade intramedullary pinning. QUESTIONS/PURPOSES: We asked whether the clinical and radiographic outcomes of antegrade intramedullary pinning are different from those of percutaneous retrograde intramedullary pinning for treating patients with displaced fifth metacarpal neck fractures. METHODS: Forty-six patients with displaced fifth metacarpal neck fractures with an apex dorsal angulation greater than 30 degrees were enrolled in our prospective study. Subjects were treated randomly by antegrade intramedullary pinning (antegrade group) or by percutaneous retrograde intramedullary pinning (retrograde group). Clinical evaluations, which included active ROM of the fifth metacarpophalangeal joint, VAS for pain, grip strength, and DASH score, were performed at 3 months and 6 months postoperatively. Radiographic evaluations of apex dorsal angulation and axial shortening were performed preoperatively and 6 months postoperatively. RESULTS: Patients in the antegrade group achieved better outcomes than patients in the retrograde group for all clinical parameters at 3 months postoperatively (ROM: antegrade median 80 degrees [range, 57 degrees -90 degrees ] versus retrograde 69 degrees [range, 45 degrees -90 degrees ], difference of medians 11 degrees , p < 0.001; VAS: antegrade median of 2 [range, 0-5] versus retrograde 4 [range, 0 7], difference of medians 2, p < 0.001; grip strength: antegrade median 81% [range, 60%-100%] versus retrograde 71% [range, 49%-98%], differences of medians 10%, p < 0.001; DASH: antegrade median 4.3 [range, 0-15.8] versus retrograde 10.3 [range, 0-28.4], difference of medians 6, p < 0.001), but these differences, with the numbers available, were not observed at 6 months postoperatively for any clinical parameters (ROM: antegrade median 88 degrees [range, 81 degrees -90 degrees ] versus retrograde 87 degrees [range, 80 degrees -90 degrees ], difference of medians 1 degrees , p = 0.35; VAS: antegrade median 1 [range, 0-2] versus retrograde 1[range, 0-3], difference of medians 0, p = 0.67; grip strength: antegrade median 93% [range, 78%-104%] versus retrograde 91% [range, 76%-101%], difference of medians 2%, p = 0.41; DASH: antegrade median 3 [range, 0 12.5] versus retrograde of 4.3 [range, 0-15.8], difference of medians 1.3, p = 0.48). At 6 months postoperatively, there also were no differences, with the numbers available, in radiographic parameters between the antegrade and retrograde fixation groups. Residual angulation was not different (antegrade median: 7 degrees [range, 2 degrees -11 degrees ], retrograde: 9 degrees [range, 3 degrees -13 degrees ], difference of medians 2 degrees , p = 0.56). Shortening between the two groups also was not different (antegrade median: 1 mm [range, 0 mm-2 mm], retrograde median: 1 mm [range, 0 mm-2 mm], difference of medians 0, p = 0.78). CONCLUSION: Our study findings suggest antegrade intramedullary pinning has some clinical advantages during the early recovery period over percutaneous retrograde intramedullary pinning for treatment of displaced fifth metacarpal neck fractures, but the advantages are not evident at 6 months postoperatively. In addition, our study showed no differences in radiographic outcomes between antegrade and retrograde techniques. For patients who require an early return of hand function, such as athletes, antegrade intramedullary pinning can be recommended. Otherwise, treatment could be decided according to the surgeon's preference and patient status, and based on consideration of the need for an accessory procedure for pin removal after antegrade intramedullary pinning. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 25502344 TI - Mendelian randomization analysis to examine for a causal effect of urate on bone mineral density. AB - In observational studies, serum urate concentrations are positively associated with bone mineral density (BMD) and reduced risk of fragility fractures, raising the possibility that urate is a direct mediator of bone density. We used Mendelian randomization analysis to examine whether urate has a causal effect on BMD. We analyzed data from the Generation 3 cohort in the Framingham Heart Study (FHS) (N = 2501 total; 1265 male, 1236 female). A weighted genetic urate score was calculated using the SLC2A9, ABCG2, SLC17A1, SLC22A11, and SLC22A12 single nucleotide polymorphisms (SNPs) that explains 3.4% of the variance in serum urate. Mendelian randomization analysis was performed using the two-stage least squares method with >80% power at alpha = 0.05 to detect an effect size equivalent to that observed in the ordinary least squares analysis between serum urate and total femur BMD. A strong association between serum urate and BMD was observed in the crude ordinary least squares analysis (total femur crude beta = 0.47, p = 1.7E-51). In the two-stage least squares analysis using the weighted genetic urate score as the instrumental variable, no significant relationship was observed between serum urate and BMD (total femur crude beta =-0.36, p = 0.06). Similar findings were observed in both the male and female subgroups, and there was no evidence for causality when individual SNPs were analyzed. Serum urate is strongly associated with BMD. However, controlling for confounders by Mendelian randomization analysis does not provide evidence that increased urate has a causal effect on increasing BMD. PMID- 25502342 TI - Narrow- versus mini-implants at crestal and subcrestal bone levels. Experimental study in beagle dogs at three months. AB - OBJECTIVE: The objective of this study was to evaluate the osseointegration and crestal bone loss (CBL) in two implant designs with different diameters (Mini Sky(r) and Narrow Sky(r)) implants, placed at different vertical levels at healed canine ridges. MATERIAL AND METHODS: The second, third, and fourth mandibular premolars of six Beagle dogs were extracted bilaterally. After 2 months healing, four implants divided into two groups according to their diameters (i.e., Narrow Sky(r) and Mini Sky(r)) were placed in each hemi-mandible at the level of the bone crest or 2 mm subcrestally. The animals were euthanized at 12 weeks and undecalcified samples were processed for histology. Histomorphometric analysis was carried out to compare bone-to-implant contacts (BIC) and crestal bone loss (CBL). RESULTS: There were not significant differences in CBL between groups when the implants were placed at subcrestal bone level (p > 0.05), meanwhile the CBL was significantly higher for both groups when the implants were inserted at crestal level (p < 0.05). All implants were osseointegrated presenting a minimum BIC percentage of 56%. The major percentages of BIC were found for both groups at subcrestal level (p < 0.05). CONCLUSIONS: Within the limitations of this experimental study may be concluded that the implant diameter does not affect the CBL. BIC values are affected by implant diameter and design been higher for narrow implants compared to mini-implants. Subcrestal insertion of both implants favors crestal bone preservation but crestal insertion of both designs is associated with crestal bone loss CLINICAL RELEVANCE: The study shows that narrow implants protect peri-implant crestal bone. PMID- 25502346 TI - Beliefs about low back pain: Status quo in Indian general population. AB - BACKGROUND: Low back pain (LBP) is a major public health problem and is the leading musculoskeletal cause of disability. Various bio-behavioral factors which can be associated with disability due to LBP have been identified. When considering these factors associated with LBP, beliefs that people hold are among the most important factors to consider. OBJECTIVE: To find out the prevalence of LBP among the general population and to investigate their beliefs towards LBP. METHODS: A cross-sectional survey of the general population was conducted. Demographic information and information on beliefs regarding low back pain was gathered from 921 individuals. The respondents were asked to rate their agreement with 7 statements, corresponding to Deyo's 7 myths. RESULTS: 75% of the population reported lifetime prevalence of LBP. Regarding the beliefs about LBP, general population exhibited diverse attitudes. Out of 7 myths explored, 3 myths were found to be dead and buried in more than 50% of the sampled population. However, 4 out of 7 myths still exist among the population. CONCLUSIONS: Prevalence of Low Back Pain was found to be high among the general population sampled and also myths regarding LBP still exist among them. PMID- 25502345 TI - Surface electromyography analysis of contralateral lower extremity tremor following thalamic hemorrhage. PMID- 25502347 TI - Towards a new protocol of scoliosis assessments and monitoring in clinical practice: A pilot study. AB - BACKGROUND: Although intensively investigated, the procedures for assessment and monitoring of scoliosis are still a subject of controversies. OBJECTIVE: The aim of this study was to assess validity and reliability of a number of physiotherapeutic measurements that could be used for clinical monitoring of scoliosis. METHODS: Fifteen healthy (symmetric) subjects were subjected to a set of measurements two times, by two experienced and two inexperienced physiotherapists. Intra-observer and inter-observer reliability of measurements were determined. Following measurements were performed: body height and weight, chest girth in inspirium and expirium, the length of legs, the spine translation, the lateral pelvic tilt, the equality of the shoulders, position of scapulas, the equality of stature triangles, the rib hump, the existence of m. iliopsoas contracture, Frohner index, the size of lumbar lordosis and the angle of trunk rotation. RESULTS: Intraclass correlation coefficient was high (> 0.8) for majority of measurements when experienced physiotherapists performed them, while inexperienced physiotherapists performed precisely only basic, easy measurements. CONCLUSIONS: We showed in this pilot study on healthy subjects, that majority of basic physiotherapeutic measurements are valid and reliable when performed by specialized physiotherapist, and it can be expected that this protocol will gain high value when measurements on subjects with scoliosis are performed. PMID- 25502348 TI - Effects of visual illusion and transcutaneous electrical nerve stimulation on neuropathic pain in patients with spinal cord injury: A randomised controlled cross-over trial. AB - BACKGROUND: Chronic pain is a common consequence of spinal cord injury (SCI). No therapeutic drugs or drug groups are proven to be superior for neuropathic pain and treatments only aim to convert pain from dull to tolerable levels and not to remove it. OBJECTIVE: This study was planned to compare the effect of visual illusion (VI) and transcutaneous electrical nerve stimulation (TENS) on pain intensity, pain quality and functional capacity in SCI patients with neuropathic pain. METHODS: Twenty-four patients were included and randomly categorized into two groups. In the first group (n= 12), visual illusion was applied for first two weeks, 1 week wash out period and then TENS was applied for 2 weeks. In second group (n= 12), TENS was applied firstly, 1 week wash out and then %visual illusion VI were applied. Pain severity, pain quality, and functional capacity were assessed with the visual analog scale (VAS), the neuropathic pain scale (NPS), and the brief pain inventory (BPI), respectively. A pre-post-treatment and cross over design was used. RESULTS: Wilcoxon signed-rank tests were used for within group analyses. Mann-Whitney U tests were used for analyses that compared different groups. It was observed that pain intensity decrease immediately after both applications (VI: p= 0.07, TENS: p= 0.08). After TENS application for 2 weeks, it was observed that significant decrease in most (p= 0.04) and less (p= 0.02) pain intensity; while there was no significant decrease in pain intensity after 2 weeks for VI (p> 0.05). When findings of NPS were analyzed, hot (p= 0.047), sharp (p= 0.02), unpleasant (p= 0.03) and deep items (p= 0.047) decreased after VI application. When the results of BPI were detected, they were observed that the negative effect of pain on moving ability (p= 0.04) after visual illusion application and the negative effect of pain on mood (p= 0.03), relationships with others (p= 0.04) and sleep (p= 0.04) after TENS application decreased significantly. CONCLUSION: TENS and VI therapies can be successfully used in clinical practice as an alternative treatment or as a supportive method separetely or together. PMID- 25502349 TI - Graphene field effect transistor as a probe of electronic structure and charge transfer at organic molecule-graphene interfaces. AB - The electronic structure of physisorbed molecules containing aromatic nitrogen heterocycles (triazine and melamine) on graphene is studied using a combination of electronic transport, X-ray photoemission spectroscopy and density functional theory calculations. The interfacial electronic structure and charge transfer of weakly coupled molecules on graphene is found to be governed by work function differences, molecular dipole moments and polarization effects. We demonstrate that molecular depolarization plays a significant role in these charge transfer mechanisms even at submonolayer coverage, particularly for molecules which possess strong dipoles. Electronic transport measurements show a reduction of graphene conductivity and charge carrier mobility upon the adsorption of the physisorbed molecules. This effect is attributed to the formation of additional electron scattering sites in graphene by the molecules and local molecular electric fields. Our results show that adsorbed molecules containing polar functional groups on graphene exhibit different coverage behaviour to nonpolar molecules. These effects open up a range of new opportunities for recognition of different molecules on graphene-based sensor devices. PMID- 25502350 TI - Electronic structure aspects of the complete O2 transfer reaction between Ni(II) and Mn(II) complexes with cyclam ligands. AB - This work explores the electronic structure aspects involving the complete intermolecular O2 transfer between Ni(ii) and Mn(ii) complexes, both containing N tetramethylated cyclams (TMC). The energy of the low-lying states of reactants, intermediates and products is established at the CASSCF level and also the DDCI level when possible. The orthogonal valence bond analysis of the wave functions obtained from CASSCF and DDCI calculations indicates the dominant superoxide nature of all the adducts participating in the reaction, and consequently that the whole reaction can be described as the transfer of the superoxide O2(-) between Ni(ii) and Mn(ii) complexes, without any additional change in the electronic structure of the fragments. PMID- 25502351 TI - The role of carotid intima-media thickness in predicting longitudinal cognitive function in an older adult cohort. AB - BACKGROUND AND PURPOSE: Carotid atherosclerosis is a risk factor for cerebrovascular disease in older adults. Although age-related cognitive decline has been associated with cerebrovascular disease, not much is known about the consequences of carotid atherosclerosis on longitudinal cognitive function. This study examines the longitudinal relationship between atherosclerosis and cognition in a sample of non-demented older subjects using baseline measurements of carotid intima media thickness (CIMT) and annual cognitive measures of executive function (EXEC) and verbal memory (MEM). METHODS: Baseline measurements included CIMT derived from B-mode carotid artery ultrasound, structural T1 weighted images of white matter hypointensities (WMH), white matter lesions (WML), and cerebral infarct. Hypertension, low-density lipoprotein (LDL), diabetes, and waist to hip ratios (WHR) were included as covariates in our models to control for cerebrovascular risks and central adiposity. Annual composite scores of EXEC and MEM functions were derived from item response theory. Linear mixed models were used to model longitudinal cognitive change. RESULTS: A significant inverse relationship was found between baseline CIMT and annual EXEC score, but not annual MEM score. Subjects included in the highest 4th quartile of CIMT showed a rate of annual decline in EXEC score that was significant relative to subjects in lower quartile groups (p<0.01). The relationship between the 4th quartile of CIMT and annual EXEC score remained significant after independently adjusting for imaging measures of white matter injury and cerebral infarct. CONCLUSIONS: Older adult subjects with the highest index of CIMT showed an annual decline in EXEC scores that was significant relative to subjects with lower quartile measurements of CIMT, independent of our measures of white matter injury and cerebral infarct. Our findings suggest that elevated measures of CIMT may mark an atherosclerotic state, resulting in a decline in executive function and not memory in non-demented older adults. PMID- 25502353 TI - Interview with Dr John Morris, 28 February 2013. PMID- 25502352 TI - Interview with Dr Carol Brayne, 5 April 2013. PMID- 25502354 TI - Interview with Professor John Bond, 30 April 2013. PMID- 25502355 TI - Interview with Dr David Healy, 13 February 2013. PMID- 25502356 TI - Interview with Dr Anne Davis Basting, 21 May 2013. PMID- 25502357 TI - Interview with Dr Constantine Lyketsos, 14 May 2013. PMID- 25502358 TI - Interview with Dr Holly Tuokko, 22 March 2013. PMID- 25502359 TI - Interview with Dr Ronald Petersen, 7 February 2013. PMID- 25502360 TI - Interview with Dr Peter Whitehouse, 23 July 2012. PMID- 25502362 TI - Chiral recognition of tyrosine enantiomers based on decreased resonance scattering signals with silver nanoparticles as optical sensor. AB - A novel chiral sensing platform, employing silver nanoparticles capped with N acetyl-L-cysteine (NALC-Ag NPs), was utilized for the discrimination of L tyrosine and D-tyrosine. This nanosensor, which could be used as an optical sensing unit and chiral probe, was characterized by transmission electron microscopy (TEM) and resonance Rayleigh scattering (RRS) spectroscopy. After the proposed sensing platform interacted with L-tyrosine and D-tyrosine, a decreased resonance scattering signal was only obtained from L-tyrosine. This phenomenon offered a useful assay for the selectivity and determination of L-tyrosine with the RRS method. The linear range and detection limit of L-tyrosine were 0.2838 20.0 ug?mL(-1) and 0.0860 ug?mL(-1) , respectively. In addition, experimental factors such as acidity, interaction time, and the concentration of enantiomers were investigated with regard to the effect on enantioselective interaction. PMID- 25502361 TI - Combination of Taxol(r) and dichloroacetate results in synergistically inhibitory effects on Taxol-resistant oral cancer cells under hypoxia. AB - Cancer cells preferentially catalyze glucose through the glycolytic pathway in the presence of adequate oxygen. This phenomenon is known as the Warburg effect. As is the case with numerous cancer therapeutic agents, resistance remains a significant problem when using Taxol(r) to treat malignancies. The present study reported that expression of pyruvate dehydrogenase kinase 1 (PDK1) was induced by Taxol treatment at low toxic concentrations in oral cancer cells. In addition, Taxol-resistant cells exhibited upregulated PDK1 protein and mRNA expression. Elevated PDK1 levels contribute to Taxol resistance under hypoxic conditions. Inhibition of PDK1 expression was observed when oral cancer cells were treated with the PDK1 inhibitor dichloroacetate (DCA). The combination of Taxol with DCA showed synergistic inhibitory effects on Taxol-resistant cells under hypoxic conditions; these effects were not observed in Taxol-sensitive oral cancer cells under normoxic conditions. The present study provides a novel mechanism for overcoming Taxol resistance in oral cancer cells, and will contribute towards the development of clinical therapeutics for cancer patients. PMID- 25502363 TI - Immunohistochemical and histoplanimetrical study on the endothelial receptor involved in transportation of minute chylomicrons into subepithelial portal blood in intestinal villi of the rat jejunum. AB - A portion of the minute chylomicrons less than 75 nm in diameter are transcytosed from the extravascular tissue into the subepithelial blood capillaries (sBC) in the villous apices of the rat jejunum. However, the details of the transportation mechanism have not been clarified. In this study, the endothelial receptor involved in the transportation of minute chylomicrons into the sBC's lumina was immunohistochemically and histoplanimetrically examined in intestinal villi of the rat jejunum. Immunopositivity for very low density lipoprotein (VLDL) receptor was detected on the luminal and basal surfaces of the endothelial cells of sBC in approximately 68% of those apices of jejunal villi that possessed numerous chylomicrons in the lamina propria, while VLDL receptor was detected on the endothelial cells of sBC in only approximately 8% of intestinal villi that possessed few or no chylomicrons in the lamina propria. No immunopositivity for LDL receptor was detected in the sBC of all intestinal villi. These findings suggest that VLDL receptor is expressed by the endothelial cells of the sBC in conjunction with the filling of the lamina propria of jejunal villi with many chylomicrons produced by the villous columnar epithelial cells and that the VLDL receptor mediates the transportation of minute chylomicrons, maybe VLDL, into the subepithelial portal blood from the extravascular tissue of the rat jejunal villi. PMID- 25502365 TI - Longevity and aging: role of genes and of the extracellular matrix. AB - Longevity is different for every animal species as well as their genome, suggesting a correlation between genes and life-span. Estimates put the genetic effect from 5 to 35% approximately, suggesting that even genetic effects are dependent on environmental conditions. This contention is largely confirmed by the study of identical twins raised apart. They do not die at the same age and also for different reasons. Aging is not "genetically programmed", it is outside evolutionary constraint. Evolution favors early and efficient reproduction, but does not care for longevity. A number of mechanisms were shown to be involved in the age-dependent decline of vital functions, among them the Maillard reaction (non-enzymatic glycosylation) and the age-dependent upregulation of proteolytic activity. Aging of ECM is a complex process, comprising progressive modification of its macromolecular components and of cell-matrix interactions. An important process is the uncoupling with age of the elastin-receptor from its "young" transmission pathway loosing all physiological effects, but enhancing free radical and elastase release. These processes contribute to age-related ECM degradation, production of matrikins (ECM degradation products with biological activity) aggravating functional loss with age. Both genetic and post-genetic mechanisms are susceptible to be influenced by medical, pharmacological and dietary interventions. Among the genetic mechanisms, those attributed to Sirtuins (7 orthologs identified in the human genome) are especially important. Among the environmental effects, nutrition, hygiene and weather conditions play a role. These data justify some predictions on the evolution of life expectancy taking in account also socio-economic factors. Biological constraints become evident by the comparison of centenarians and supercentenarians (less than 1% of the centenarians) putting an upper limit to the attainable human lifespan. PMID- 25502364 TI - Modulation of systemic and mucosal immunity against an inactivated vaccine of Newcastle disease virus by oral co-administration of live attenuated Salmonella enterica serovar Typhimurium expressing chicken interleukin-18 and interferon alpha. AB - Newcastle disease (ND) is a highly contagious disease of chickens causing significant economic losses worldwide. Due to limitations in the efficacy against currently circulating ND viruses, existing vaccination strategies require improvements, and incorporating immunomodulatory cytokines with existing vaccines might be a novel approach. Here, we investigated the systemic and mucosal immunomodulatory properties of oral co-administration of chicken interleukin-18 (chIL-18) and chicken interferon-alpha (chIFN-alpha) using attenuated Salmonella enterica serovar Typhimurium on an inactivated ND vaccine. Our results demonstrate that oral administration of S. enterica serovar Typhimurium expressing chIL-18 or chIFN-alpha provided enhanced systemic and mucosal immune responses, as determined by serum hemagglutination inhibition antibody and NDV Ag specific IgG as well as NDV Ag-specific IgA in lung and duodenal lavages of chickens immunized with inactivated ND vaccine via the intramuscular or intranasal route. Notably, combined oral administration of S. enterica serovar Typhimurium expressing chIL-18 and chIFN-alpha significantly enhanced systemic and mucosal immunity in ND-vaccinated chickens, compared to single administration of S. enterica serovar Typhimurium expressing chIL-18 or chIFN-alpha. In addition, oral co-administration of S. enterica serovar Typhimurium expressing chIL-18 and chIFN-alpha provided enhanced NDV Ag-specific proliferation of peripheral blood mononuclear cells and Th1-biased cell-mediated immunity, compared to single administration of either construct. Therefore, our results provide valuable insight into the modulation of systemic and mucosal immunity by incorporation of immunomodulatory chIL-18 and chIFN-alpha using Salmonella vaccines into existing ND vaccines. PMID- 25502366 TI - Kaposi-Juliusberg varicelliform eruption in patients suffering from Darier-White Disease: a case report and review of the literature. AB - Darier-White Disease (DW), otherwise known as keratosis follicularis, is a rare genodermatosis with autosomal dominant inheritance, characterized by loss of adhesion between epidermal cells and abnormal keratinization. The distinctives lesions of DW Disease include rough papules in seborrheic areas, palmoplantar pits, mucosal involvement, and nail changes. DW Disease can be occasionally associated with bacterial complications, but rarely with viral ones. Kaposi's varicelliform eruption (KVE) is a secondary herpes simplex virus infection that affects patients in the setting of primary dermatologic conditions. KVE, frequently misdiagnosed as impetigo, can be severe, progressing to disseminated infections and potentially life threatening. It occurs with a variety of skin disorders, although association with DW Disease has rarely been reported in the literature. This report describes a case of KVE in a patient suffering from DW Disease, focusing on its clinical course. A review of the literature on KVE including disease associations, pathogenesis, and treatment has been also reported. PMID- 25502367 TI - Diffuse dermal angiomatosis: a clinical mimicker of vasculitis associated with calciphylaxis and monoclonal gammopathy. AB - Diffuse dermal angiomatosis is a form of cutaneous reactive angiomatosis characterized clinically by painful erythematous or violaceous lesions with ulcers that may mimic cutaneous vasculitis/vasculopathy. Histologically it shows a benign, diffuse proliferation of endothelial cells with tiny blood vessels in the papillary and reticular dermis. Herein, we report four patients with diffuse dermal angiomatosis in the setting of calciphylaxis and monoclonal gammopathy and review the cases previously published in the literature. Comorbidities and management will also be discussed. PMID- 25502368 TI - Autoamputation of a pedunculated, subserosal uterine leiomyoma presenting as a giant peritoneal loose body. AB - Peritoneal loose bodies (PLBs) are defined as fibrotic or calcified-free bodies within the peritoneal cavity; they commonly autoamputate from appendices epiploicae that have undergone torsion. Pedunculated, subserosal uterine leiomyomas (PSULs) are subserosal uterine leiomyomas connected to the uterus via a pedicle. In the present report, we describe the case of a PLB that originated from the autoamputation of a PSUL, confirmed based on histological evidence consistent with a uterine leiomyoma and the laparoscopic findings of a broken pedicle. This case clearly demonstrates the potential for a uterine leiomyoma to be the source of a PLB. Our findings contribute to the understanding of the etiological relationship between PLBs and uterine leiomyomas. PMID- 25502369 TI - A high cell density transient transfection system for therapeutic protein expression based on a CHO GS-knockout cell line: process development and product quality assessment. AB - Transient gene expression (TGE) is a rapid method for the production of recombinant proteins in mammalian cells. While the volumetric productivity of TGE has improved significantly over the past decade, most methods involve extensive cell line engineering and plasmid vector optimization in addition to long fed batch cultures lasting up to 21 days. Our colleagues have recently reported the development of a CHO K1SV GS-KO host cell line. By creating a bi-allelic glutamine synthetase knock out of the original CHOK1SV host cell line, they were able to improve the efficiency of generating high producing stable CHO lines for drug product manufacturing. We developed a TGE method using the same CHO K1SV GS KO host cell line without any further cell line engineering. We also refrained from performing plasmid vector engineering. Our objective was to setup a TGE process to mimic protein quality attributes obtained from stable CHO cell line. Polyethyleneimine (PEI)-mediated transfections were performed at high cell density (4 * 10(6) cells/mL) followed by immediate growth arrest at 32 degrees C for 7 days. Optimizing DNA and PEI concentrations proved to be important. Interestingly, found the direct transfection method (where DNA and PEI were added sequentially) to be superior to the more common indirect method (where DNA and PEI are first pre-complexed). Moreover, the addition of a single feed solution and a polar solvent (N,N dimethylacetamide) significantly increased product titers. The scalability of process from 2 mL to 2 L was demonstrated using multiple proteins and multiple expression volumes. Using this simple, short, 7 day TGE process, we were able to successfully produce 54 unique proteins in a fraction of the time that would have been required to produce the respective stable CHO cell lines. The list of 54 unique proteins includes mAbs, bispecific antibodies, and Fc-fusion proteins. Antibody titers of up to 350 mg/L were achieved with the simple 7-day process. Titers were increased to 1 g/L by extending the culture to 16 days. We also present two case studies comparing product quality of material generated by transient HEK293, transient CHO K1SV GS KO, and stable CHO K1SV KO pool. Protein from transient CHO was more representative of stable CHO protein compared to protein produced from HEK293. PMID- 25502371 TI - Immune responses to airborne fungi and non-invasive airway diseases. AB - Inhalation of fungal particles is a ubiquitous way of exposure to microorganisms during human life; however, this exposure may promote or exacerbate respiratory diseases only in particular exposure conditions and human genetic background. Depending on the fungal species and form, fungal particles can induce symptoms in the lung by acting as irritants, aeroallergens or pathogens causing infection. Some thermophilic species can even act in all these three ways (e.g. Aspergillus, Penicillium), mesophilic species being only involved in allergic and/or non allergic airway diseases (e.g. Cladosporium, Alternaria, Fusarium). The goal of the present review is to present the current knowledge on the interaction between airborne fungal particles and the host immune system, to illustrate the differences of immune sensing of different fungal species and to emphasise the importance of conducting research on non-conventional mesophilic fungal species. Indeed, the diversity of fungal species we inhale and the complexity of their composition have a direct impact on fungal particle recognition and immune system decision to tolerate or respond to those particles, eventually leading to collateral damages promoting airway pathologies. PMID- 25502370 TI - Innate lymphoid cells, possible interaction with microbiota. AB - Recent studies have identified novel lymphocyte subsets named innate lymphoid cells (ILCs) lacking antigen-specific receptors. ILCs are present in a wide variety of epithelial compartments and occupy an intermediate position between acquired immune cells and myeloid cells. ILCs are now classified into three groups: group 1 ILC, group 2 ILC, and group 3 ILC based on their cytokine production patterns that correspond to the helper T cell subsets Th1, Th2, and Th17, respectively. ILCs play important roles in protection against various invading microbes including multicellular parasites, and in the maintenance of homeostasis and repair of epithelial layers. Excessive activation of ILCs, however, leads to various inflammatory disease conditions. ILCs have thus attracted interests of many researchers in the fields of infectious immunity, inflammatory diseases, and allergic diseases. Because epithelial cells sense alterations in environmental cues, it is important to understand the functional interaction between epithelial cells, ILCs, and environmental factors such as commensal microbiota. We discuss in this review developmental pathways of ILCs, their functions, and contribution of commensal microbiota to the differentiation and function of ILCs. PMID- 25502372 TI - Introduction to the analysis of the intracellular sorting information in protein sequences: from molecular biology to artificial neural networks. AB - A precise spatial-temporal organization of cell components is required for basic cellular activities such as proliferation and for complex multicellular processes such as embryo development. Particularly important is the maintenance and control of the cellular distribution of proteins, as these components fulfill crucial structural and catalytic functions. Membrane protein localization within the cell is determined and maintained by intracellular elements known as adaptors that interpret sorting information encoded in the amino acid sequence of cargoes. Understanding the sorting sequence code of cargo proteins would have a profound impact on many areas of the life sciences. For example, it would shed light onto the molecular mechanisms of several genetic diseases and would eventually allow us to control the fate of proteins. This chapter constitutes a primer on protein sorting information analysis and localization/trafficking prediction. We provide the rationale for and a discussion of a simple basic protocol for protein sequence dissection looking for sorting signals, from simple sequence inspection techniques to more sophisticated artificial neural networks analysis of sorting signal recognition data. PMID- 25502374 TI - Predicting bacterial community assemblages using an artificial neural network approach. AB - Microbial communities are found in nearly all environments and play a critical role in defining ecosystem service. Understanding the relationship between these microbial communities and their environment is essential for prediction of community structure, robustness, and response to ecosystem changes. Microbial Assemblage Prediction (MAP) describes microbial community structure as an artificial neural network (ANN) that models the microbial community as functions of environmental parameters and community intra-microbial interactions. MAP models can be used to predict community assemblages over a wide range of possible environmental parameters, extrapolate the results of point observations across spatial scales, and make predictions about how microbial communities may fluctuate as the result of changes in their environment. PMID- 25502373 TI - Protein structural information derived from NMR chemical shift with the neural network program TALOS-N. AB - Chemical shifts are obtained at the first stage of any protein structural study by NMR spectroscopy. Chemical shifts are known to be impacted by a wide range of structural factors, and the artificial neural network based TALOS-N program has been trained to extract backbone and side-chain torsion angles from (1)H, (15)N, and (13)C shifts. The program is quite robust and typically yields backbone torsion angles for more than 90 % of the residues and side-chain chi 1 rotamer information for about half of these, in addition to reliably predicting secondary structure. The use of TALOS-N is illustrated for the protein DinI, and torsion angles obtained by TALOS-N analysis from the measured chemical shifts of its backbone and (13)C(beta) nuclei are compared to those seen in a prior, experimentally determined structure. The program is also particularly useful for generating torsion angle restraints, which then can be used during standard NMR protein structure calculations. PMID- 25502375 TI - A general ANN-based multitasking model for the discovery of potent and safer antibacterial agents. AB - Bacteria have been one of the world's most dangerous and deadliest pathogens for mankind, nowadays giving rise to significant public health concerns. Given the prevalence of these microbial pathogens and their increasing resistance to existing antibiotics, there is a pressing need for new antibacterial drugs. However, development of a successful drug is a complex, costly, and time consuming process. Quantitative Structure-Activity Relationships (QSAR)-based approaches are valuable tools for shortening the time of lead compound identification but also for focusing and limiting time-costly synthetic activities and in vitro/vivo evaluations. QSAR-based approaches, supported by powerful statistical techniques such as artificial neural networks (ANNs), have evolved to the point of integrating dissimilar types of chemical and biological data. This chapter reports an overview of the current research and potential applications of QSAR modeling tools toward the rational design of more efficient antibacterial agents. Particular emphasis is given to the setup of multitasking models along with ANNs aimed at jointly predicting different antibacterial activities and safety profiles of drugs/chemicals under diverse experimental conditions. PMID- 25502376 TI - Use of artificial neural networks in the QSAR prediction of physicochemical properties and toxicities for REACH legislation. AB - With the introduction of the REACH legislation in the European Union, there is a requirement for property and toxicity data on chemicals produced in or imported into the EU at levels of 1 tonne/year or more. This has meant an increase in the in silico prediction of such data. One of the chief predictive approaches is QSAR (quantitative structure-activity relationships), which is widely used in many fields. A QSAR approach that is increasingly being used is that of artificial neural networks (ANNs), and this chapter discusses its application to the range of physicochemical properties and toxicities required by REACH. ANNs generally outperform the main QSAR approach of multiple linear regression (MLR), although other approaches such as support vector machines sometimes outperform ANNs. Most ANN QSARs reported to date comply with only two of the five OECD Guidelines for the Validation of (Q)SARs. PMID- 25502377 TI - Artificial neural network for charge prediction in metabolite identification by mass spectrometry. AB - Collision-induced dissociation (CID) is widely used in mass spectrometry to identify biologically important molecules by gaining information about their internal structure. Interpretation of experimental CID spectra always involves some form of in silico spectra of potential candidate molecules. Knowledge of how charge is distributed among fragments is an important part of CID simulations that generate in silico spectra from the chemical structure of the precursor ions entering the collision chamber. In this chapter we describe a method to obtain this knowledge by machine learning. PMID- 25502378 TI - Prediction of bioactive peptides using artificial neural networks. AB - Peptides are molecules of varying complexity, with different functions in the organism and with remarkable therapeutic interest. Predicting peptide activity by computational means can help us to understand their mechanism of action and deliver powerful drug-screening methodologies. In this chapter, we describe how to apply artificial neural networks to predict antimicrobial peptide activity. PMID- 25502379 TI - AutoWeka: toward an automated data mining software for QSAR and QSPR studies. AB - In biology and chemistry, a key goal is to discover novel compounds affording potent biological activity or chemical properties. This could be achieved through a chemical intuition-driven trial-and-error process or via data-driven predictive modeling. The latter is based on the concept of quantitative structure activity/property relationship (QSAR/QSPR) when applied in modeling the biological activity and chemical properties, respectively, of compounds. Data mining is a powerful technology underlying QSAR/QSPR as it harnesses knowledge from large volumes of high-dimensional data via multivariate analysis. Although extremely useful, the technicalities of data mining may overwhelm potential users, especially those in the life sciences. Herein, we aim to lower the barriers to access and utilization of data mining software for QSAR/QSPR studies. AutoWeka is an automated data mining software tool that is powered by the widely used machine learning package Weka. The software provides a user-friendly graphical interface along with an automated parameter search capability. It employs two robust and popular machine learning methods: artificial neural networks and support vector machines. This chapter describes the practical usage of AutoWeka and relevant tools in the development of predictive QSAR/QSPR models. AVAILABILITY: The software is freely available at http://www.mt.mahidol.ac.th/autoweka. PMID- 25502381 TI - GENN: a GEneral Neural Network for learning tabulated data with examples from protein structure prediction. AB - We present a GEneral Neural Network (GENN) for learning trends from existing data and making predictions of unknown information. The main novelty of GENN is in its generality, simplicity of use, and its specific handling of windowed input/output. Its main strength is its efficient handling of the input data, enabling learning from large datasets. GENN is built on a two-layered neural network and has the option to use separate inputs-output pairs or window-based data using data structures to efficiently represent input-output pairs. The program was tested on predicting the accessible surface area of globular proteins, scoring proteins according to similarity to native, predicting protein disorder, and has performed remarkably well. In this paper we describe the program and its use. Specifically, we give as an example the construction of a similarity to native protein scoring function that was constructed using GENN. The source code and Linux executables for GENN are available from Research and Information Systems at http://mamiris.com and from the Battelle Center for Mathematical Medicine at http://mathmed.org. Bugs and problems with the GENN program should be reported to EF. PMID- 25502380 TI - Ligand biological activity predictions using fingerprint-based artificial neural networks (FANN-QSAR). AB - This chapter focuses on the fingerprint-based artificial neural networks QSAR (FANN-QSAR) approach to predict biological activities of structurally diverse compounds. Three types of fingerprints, namely ECFP6, FP2, and MACCS, were used as inputs to train the FANN-QSAR models. The results were benchmarked against known 2D and 3D QSAR methods, and the derived models were used to predict cannabinoid (CB) ligand binding activities as a case study. In addition, the FANN QSAR model was used as a virtual screening tool to search a large NCI compound database for lead cannabinoid compounds. We discovered several compounds with good CB2 binding affinities ranging from 6.70 nM to 3.75 MUM. The studies proved that the FANN-QSAR method is a useful approach to predict bioactivities or properties of ligands and to find novel lead compounds for drug discovery research. PMID- 25502383 TI - Application of artificial neural networks in computer-aided diagnosis. AB - Computer-aided diagnosis is a diagnostic procedure in which a radiologist uses the outputs of computer analysis of medical images as a second opinion in the interpretation of medical images, either to help with lesion detection or to help determine if the lesion is benign or malignant. Artificial neural networks (ANNs) are usually employed to formulate the statistical models for computer analysis. Receiver operating characteristic curves are used to evaluate the performance of the ANN alone, as well as the diagnostic performance of radiologists who take into account the ANN output as a second opinion. In this chapter, we use mammograms to illustrate how an ANN model is trained, tested, and evaluated, and how a radiologist should use the ANN output as a second opinion in CAD. PMID- 25502382 TI - Modulation of grasping force in prosthetic hands using neural network-based predictive control. AB - This chapter describes the implementation of a neural network-based predictive control system for driving a prosthetic hand. Nonlinearities associated with the electromechanical aspects of prosthetic devices present great challenges for precise control of this type of device. Model-based controllers may overcome this issue. Moreover, given the complexity of these kinds of electromechanical systems, neural network-based modeling arises as a good fit for modeling the fingers' dynamics. The results of simulations mimicking potential situations encountered during activities of daily living demonstrate the feasibility of this technique. PMID- 25502384 TI - Developing a multimodal biometric authentication system using soft computing methods. AB - Robust personal authentication is becoming ever more important in computer-based applications. Among a variety of methods, biometric offers several advantages, mainly in embedded system applications. Hard and soft multi-biometric, combined with hard and soft computing methods, can be applied to improve the personal authentication process and to generalize the applicability. This chapter describes the embedded implementation of a multi-biometric (voiceprint and fingerprint) multimodal identification system based on hard computing methods (DSP) for feature extraction and matching, an artificial neural network (ANN) for soft feature pattern matching, and a fuzzy logic engine (FLE) for data fusion and decision. PMID- 25502385 TI - Using neural networks to understand the information that guides behavior: a case study in visual navigation. AB - To behave in a robust and adaptive way, animals must extract task-relevant sensory information efficiently. One way to understand how they achieve this is to explore regularities within the information animals perceive during natural behavior. In this chapter, we describe how we have used artificial neural networks (ANNs) to explore efficiencies in vision and memory that might underpin visually guided route navigation in complex worlds. Specifically, we use three types of neural network to learn the regularities within a series of views encountered during a single route traversal (the training route), in such a way that the networks output the familiarity of novel views presented to them. The problem of navigation is then reframed in terms of a search for familiar views, that is, views similar to those associated with the route. This approach has two major benefits. First, the ANN provides a compact holistic representation of the data and is thus an efficient way to encode a large set of views. Second, as we do not store the training views, we are not limited in the number of training views we use and the agent does not need to decide which views to learn. PMID- 25502387 TI - Preparation of Ta-O-based tunnel junctions to obtain artificial synapses based on memristive switching. AB - Magnetron sputtering and optical lithography are standard techniques to prepare magnetic tunnel junctions with lateral dimensions in the micrometer range. Here we present the materials and techniques to deposit the layer stacks, define the structures, and etch the devices. In the end, we obtain tunnel junction devices exhibiting memristive switching for potential use as artificial synapses. PMID- 25502386 TI - Jump neural network for real-time prediction of glucose concentration. AB - Prediction of the future value of a variable is of central importance in a wide variety of fields, including economy and finance, meteorology, informatics, and, last but not least important, medicine. For example, in the therapy of Type 1 Diabetes (T1D), in which, for patient safety, glucose concentration in the blood should be maintained in a defined normoglycemic range, the ability to forecast glucose concentration in the short-term (with a prediction horizon of around 30 min) might be sufficient to reduce the incidence of hypoglycemic and hyperglycemic events. Neural Network (NN) approaches are suitable for prediction purposes because of their ability to model nonlinear dynamics and handle in their inputs signals coming from different domains. In this chapter we illustrate the design of a jump NN glucose prediction algorithm that exploits past glucose concentration data, measured in real-time by a minimally invasive continuous glucose monitoring (CGM) sensor, and information on ingested carbohydrates, supplied by the patient himself or herself. The methodology is assessed by tuning the NN on data of ten T1D individuals and then testing it on a dataset of ten different subjects. Results with a prediction horizon of 30 min show that prediction of glucose concentration in T1D via NN is feasible and sufficiently accurate. The average time anticipation obtained is compatible with the generation of preventive hypoglycemic and hyperglycemic alerts and the improvement of artificial pancreas performance. PMID- 25502388 TI - Architecture and biological applications of artificial neural networks: a tuberculosis perspective. AB - Advancement of science and technology has prompted researchers to develop new intelligent systems that can solve a variety of problems such as pattern recognition, prediction, and optimization. The ability of the human brain to learn in a fashion that tolerates noise and error has attracted many researchers and provided the starting point for the development of artificial neural networks: the intelligent systems. Intelligent systems can acclimatize to the environment or data and can maximize the chances of success or improve the efficiency of a search. Due to massive parallelism with large numbers of interconnected processers and their ability to learn from the data, neural networks can solve a variety of challenging computational problems. Neural networks have the ability to derive meaning from complicated and imprecise data; they are used in detecting patterns, and trends that are too complex for humans, or other computer systems. Solutions to the toughest problems will not be found through one narrow specialization; therefore we need to combine interdisciplinary approaches to discover the solutions to a variety of problems. Many researchers in different disciplines such as medicine, bioinformatics, molecular biology, and pharmacology have successfully applied artificial neural networks. This chapter helps the reader in understanding the basics of artificial neural networks, their applications, and methodology; it also outlines the network learning process and architecture. We present a brief outline of the application of neural networks to medical diagnosis, drug discovery, gene identification, and protein structure prediction. We conclude with a summary of the results from our study on tuberculosis data using neural networks, in diagnosing active tuberculosis, and predicting chronic vs. infiltrative forms of tuberculosis. PMID- 25502389 TI - Neural networks and Fuzzy clustering methods for assessing the efficacy of microarray based intrinsic gene signatures in breast cancer classification and the character and relations of identified subtypes. AB - In the classification of breast cancer subtypes using microarray data, hierarchical clustering is commonly used. Although this form of clustering shows basic cluster patterns, more needs to be done to investigate the accuracy of clusters as well as to extract meaningful cluster characteristics and their relations to increase our confidence in their use in a clinical setting. In this study, an in-depth investigation of the efficacy of three reported gene subsets in distinguishing breast cancer subtypes was performed using four advanced computational intelligence methods-Self-Organizing Maps (SOM), Emergent Self Organizing Maps (ESOM), Fuzzy Clustering by Local Approximation of Memberships (FLAME), and Fuzzy C-means (FCM)-each differing in the way they view data in terms of distance measures and fuzzy or crisp clustering. The gene subsets consisted of 71, 93, and 71 genes reported in the literature from three comprehensive experimental studies for distinguishing Luminal (A and B), Basal, Normal breast-like, and HER2 subtypes. Given the costly procedures involved in clinical studies, the proposed 93-gene set can be used for preliminary classification of breast cancer. Then, as a decision aid, SOM can be used to map the gene signature of a new patient to locate them with respect to all subtypes to get a comprehensive view of the classification. These can be followed by a deeper investigation in the light of the observations made in this study regarding overlapping subtypes. Results from the study could be used as the base for further refining the gene signatures from later experiments and from new experiments designed to separate overlapping clusters as well as to maximally separate all clusters. PMID- 25502390 TI - QSAR/QSPR as an application of artificial neural networks. AB - Quantitative Structure-Activity Relationships (QSARs) and Quantitative Structure Property Relationships (QSPRs) are mathematical models used to describe and predict a particular activity/property of compounds. On the other hand, the Artificial Neural Network (ANN) is a tool that emulates the human brain to solve very complex problems. The exponential need for new compounds in the drug industry requires alternatives for experimental methods to decrease development time and costs. This is where chemical computational methods have a great relevance, especially QSAR/QSPR-ANN. This chapter shows the importance of QSAR/QSPR-ANN and provides examples of its use. PMID- 25502392 TI - Erratum: Smile rejuvenation: A case report: Erratum. AB - [This corrects the article on p. 495 in vol. 17, PMID: 25298657.]. PMID- 25502391 TI - MicroRNA Expression can be a Promising Strategy for the Detection of Barrett's Esophagus: A Pilot Study. AB - OBJECTIVES: Patient outcomes for esophageal adenocarcinoma (EAC) have not improved despite huge advances in endoscopic therapy because cancers are being diagnosed late. Barrett's esophagus (BE) is the primary precursor lesion for EAC, and thus the non-endoscopic molecular diagnosis of BE can be an important approach to improve EAC outcomes if robust biomarkers for timely diagnosis are identified. MicroRNAs (miRNAs) are tissue-specific novel biomarkers that regulate gene expression and may satisfy this requirement. METHODS: Patients with gastroesophageal reflux disease (GERD) and BE were selected from an ongoing tissue and serum repository. BE was defined by the presence of intestinal metaplasia. Previously published miRNA sequencing profiles of GERD and BE patients allowed us to select three miRNAs, miR-192-5p, -215-5p, and -194-5p, for further testing in a discovery cohort and an independent validation cohort. Receiver operating curves were generated to calculate the diagnostic accuracy of these miRNAs for BE diagnosis. To test specificity, the miRNA signature was compared with those of the gastric cardia epithelium and the non-intestinal-type columnar epithelium (another definition of BE). In addition, to gain insights into BE origin (intestinal vs non-intestinal), global BE miRNA profiles were compared with the published miRNA profiles of other columnar epithelia in the gastrointestinal tract, that is, normal stomach and small and large intestine. RESULTS: The discovery cohort included 67 white male patients (40 with GERD and 27 with BE). The validation cohort included 28 patients (19 with GERD and 11 with BE). In the discovery cohort, the sensitivity, specificity and area under the curve (AUC) of the three mRNAs for BE diagnosis were 92-100%, 94-95%, and 0.96 0.97, respectively. During validation, the sensitivity and specificity of miRNAs for BE diagnosis were as follows: miR-192-5p, 92% and 94%, AUC 0.94 (0.80-0.99, P=0.0004); miR-215-5p, 100% and 94%, AUC 0.98 (0.84-1, P=0.0004); and miR-194-5p, 91% and 94%, AUC 0.96 (0.80-0.99, P=0.0001), respectively. The tested miRNAs identified all BE patients in both the discovery and the validation cohorts. When compared with non intestinal-type columnar and gastric cardia epithelia, the miRNA signature was specific to the intestinal-type columnar epithelium. Comparisons of BE miRNA sequencing data to published data sets for the normal stomach, small intestine and large intestine confirmed that two of the three miRNAs (miR-215-5p and -194-5p) were specific to the intestinal-type epithelium. CONCLUSIONS: MicroRNAs are highly accurate for detecting intestinal-type BE epithelia and should be tested further for the non-endoscopic molecular diagnosis of BE. PMID- 25502393 TI - Inhibitory effects of the recombinant human serine protease inhibitor Hespintor on the proliferation, migration and invasion of hepatocellular carcinoma cells. AB - Hespintor is a new Kazal-type serine proteinase inhibitor (Serpin) screened from the HepG2 hepatoblastoma cell line using the suppression subtractive hybridization (SSH) technique. Seprin is closely associated with the progression and remission of malignant tumors, and has certain significance in the diagnosis and treatment of tumors. Investigations on the antitumor activity of Serpin are expected to aid in the development of a new method for tumor treatment based on the serine protease inhibitor. Although the Hespintor prokaryotic expression strain and recombinant Hespintor protein (recombinant fusion protein of Hespintor and rHespintor) have already been obtained, the protein extraction efficiency is low due to the low initial amount of extracted protein and large number of purification steps, which affect the study of the protein function. The aim of the present study was to improve the purification method of rHespintor, increase the protein extraction efficiency, and investigate its effects on the proliferation, migration and invasion of the HepG2 hepatoblastoma cell line. The results demonstrated that the application of urea gradient washing of inclusion body of the protein may effectively remove the majority of impure proteins from the targeted protein. After one-step purification, the target protein rHespintor exhibited a high inhibitory effect of Trypsin Hydrolysis, which was exhibited in a dose-dependent manner. Hoechst 33258 staining was used to determine cell apoptosis. After treating HepG2 hepatoblastoma cells with rHespintor, the cell growth was inhibited, the proliferation ability was reduced, and the number of migrated and invaded cells were significantly decreased. Hoechst 33258 staining and flow cytometry assay results showed clear cell apoptosis. The results reveal showed that rHespintor significantly inhibited proliferation, migration and invasion of the HepG2 hepatoblastoma cell line in vitro, and induced cell apoptosis to a certain extent, indicating that the recombinant protein Hespintor exerts an antitumor effect in vitro, and has the potential and feasibility to become an antitumor drug. PMID- 25502395 TI - New heteroleptic magnesium complexes for MgO thin film application. AB - Novel heteroleptic magnesium complexes, [Mg(dmamp)(acac)]2 (), [Mg(dmamp)(tmhd)]2 (), [Mg(dmamp)(tfac)]2 (), and [Mg(dmamp)(hfac)]2 (), were successfully synthesized using dmamp and beta-diketonate as ligands. The thermogravimetric analyses and volatile studies of the complexes showed that the complexes and display high volatility and thermal stability. The single crystal X-ray study of the complexes reveals that both the complexes and were crystalized in the triclinic space group and as dimers, where magnesium atoms are in the pentacoordinate state with distorted trigonal bipyramidal geometry. PMID- 25502396 TI - A trident dithienylethene-perylenemonoimide dyad with super fluorescence switching speed and ratio. AB - Photoswitchable fluorescent diarylethenes are promising in molecular optical memory and photonic devices. However, the performance of current diarylethenes is far from satisfactory because of the scarcity of high-speed switching capability and large fluorescence on-off ratio. Here we report a trident perylenemonoimide dyad modified by triple dithienylethenes whose photochromic fluorescence quenching ratio at the photostationary state exceeds 10,000 and the fluorescence quenching efficiency is close to 100% within seconds of ultraviolet irradiation. The highly sensitive fluorescence on/off switching of the trident dyad enables recyclable fluorescence patterning and all-optical transistors. The prototype optical device based on the trident dyad enables the optical switching of incident light and conversion from incident light wavelength to transmitted light wavelength, which is all-optically controlled, reversible and wavelength convertible. In addition, the trident dyad-staining block copolymer vesicles are observed via optical nanoimaging with a sub-100 nm resolution, portending a potential prospect of the dithienylethene dyad in super-resolution imaging. PMID- 25502394 TI - Rapid evolution of virus sequences in intrinsically disordered protein regions. AB - Nodamura Virus (NoV) is a nodavirus originally isolated from insects that can replicate in a wide variety of hosts, including mammals. Because of their simplicity and ability to replicate in many diverse hosts, NoV, and the Nodaviridae in general, provide a unique window into the evolution of viruses and host-virus interactions. Here we show that the C-terminus of the viral polymerase exhibits extreme structural and evolutionary flexibility. Indeed, fewer than 10 positively charged residues from the 110 amino acid-long C-terminal region of protein A are required to support RNA1 replication. Strikingly, this region can be replaced by completely unrelated protein sequences, yet still produce a functional replicase. Structure predictions, as well as evolutionary and mutational analyses, indicate that the C-terminal region is structurally disordered and evolves faster than the rest of the viral proteome. Thus, the function of an intrinsically unstructured protein region can be independent of most of its primary sequence, conferring both functional robustness and sequence plasticity on the protein. Our results provide an experimental explanation for rapid evolution of unstructured regions, which enables an effective exploration of the sequence space, and likely function space, available to the virus. PMID- 25502398 TI - Isolation and characterization of dengue virus serotype 2 from the large dengue outbreak in Guangdong, China in 2014. AB - Dengue has been well recognized as a global public health threat, but only sporadic epidemics and imported cases were reported in recent decades in China. Since July 2014, an unexpected large dengue outbreak has occurred in Guangdong province, China, resulting in more than 40000 patients including six deaths. To clarify and characterize the causative agent of this outbreak, the acute phase serum from a patient diagnosed with severe dengue was subjected to virus isolation and high-throughput sequencing (HTS). Traditional real-time RT-PCR and HTS with Ion Torrent PGM detected the presence of dengue virus serotype 2 (DENV 2). A clinical DENV-2 isolate GZ05/2014 was obtained by culturing the patient serum in mosquito C6/36 cells. The complete genome of GZ05/2014 was determined and deposited in GenBank under the access number KP012546. Phylogenetic analysis based on the complete envelope gene showed that the newly DENV-2 isolate belonged to Cosmopolitan genotype and clustered closely with other Guangdong strains isolated in the past decade. No amino acid mutations that are obviously known to increase virulence or replication were identified throughout the genome of GZ05/2014. The high homology of Guangdong DENV-2 strains indicated the possibility of establishment of local DENV-2 circulation in Guangdong, China. These results help clarify the origin of this epidemic and predict the future status of dengue in China. PMID- 25502399 TI - Dengue in China: not a passing problem. PMID- 25502400 TI - "Inner GPS", a far-reaching influence in brain research-For the Nobel Prize in Physiology or Medicine 2014. PMID- 25502397 TI - EpCAM knockdown alters microRNA expression in retinoblastoma--functional implication of EpCAM regulated miRNA in tumor progression. AB - The co-ordinated regulation of oncogenes along with miRNAs play crucial role in carcinogenesis. In retinoblastoma (RB), several miRNAs are known to be differentially expressed. Epithelial cell adhesion molecule (EpCAM) gene is involved in many epithelial cancers including, retinoblastoma (RB) tumorigenesis. EpCAM silencing effectively reduces the oncogenic miR-17-92 cluster. In order to investigate whether EpCAM has wider effect as an inducer or silencer of miRNAs, we performed a global microRNA expression profile in EpCAM siRNA knockdown Y79 cells. MicroRNA profiling in EpCAM silenced Y79 cells showed seventy-three significantly up regulated and thirty-six down regulated miRNAs. A subset of these miRNAs was also validated in tumors. Functional studies on Y79 and WERI-Rb 1 cells transfected with antagomirs against two miRNAs of miR-181c and miR-130b showed striking changes in tumor cell properties in RB cells. Treatment with anti miR-181c and miR-130b showed significant decrease in cell viability and cell invasion. Increase in caspase-3 level was noticed in antagomir transfected cell lines indicating the induction of apoptosis. Possible genes altered by EpCAM influenced microRNAs were predicted by bioinformatic tools. Many of these belong to pathways implicated in cancer. The study shows significant influence of EpCAM on global microRNA expression. EpCAM regulated miR-181c and miR-130b may play significant roles in RB progression. EpCAM based targeted therapies may reduce carcinogenesis through several miRNAs and target genes. PMID- 25502401 TI - Grey matter volume abnormalities in patients with bipolar I depressive disorder and unipolar depressive disorder: a voxel-based morphometry study. AB - Bipolar disorder and unipolar depressive disorder (UD) may be different in brain structure. In the present study, we performed voxel-based morphometry (VBM) to quantify the grey matter volumes in 23 patients with bipolar I depressive disorder (BP1) and 23 patients with UD, and 23 age-, gender-, and education matched healthy controls (HCs) using magnetic resonance imaging. We found that compared with the HC and UD groups, the BP1 group showed reduced grey matter volumes in the right inferior frontal gyrus and middle cingulate gyrus, while the UD group showed reduced volume in the right inferior frontal gyrus compared to HCs. In addition, correlation analyses revealed that the grey matter volumes of these regions were negatively correlated with the Hamilton depression rating scores. Taken together, the results of our study suggest that decreased grey matter volume of the right inferior frontal gyrus is a common abnormality in BP1 and UD, and decreased grey matter volume in the right middle cingulate gyrus may be specific to BP1. PMID- 25502404 TI - Wing base structural data support the sister relationship of megaloptera and neuroptera (insecta: neuropterida). AB - The phylogenetic status and the monophyly of the holometabolous insect order Megaloptera has been an often disputed and long unresolved problem. The present study attempts to infer phylogenetic relationships among three orders, Megaloptera, Neuroptera, and Raphidioptera, within the superorder Neuropterida, based on wing base structure. Cladistic analyses were carried out based on morphological data from both the fore- and hindwing base. A sister relationship between Megaloptera and Neuroptera was recovered, and the monophyly of Megaloptera was corroborated. The division of the order Megaloptera, the traditional higher classification, into Corydalidae (Corydalinae + Chauliodinae) and Sialidae, was also supported by our wing base data analyses. PMID- 25502403 TI - Clinical significance of perineural invasion diagnosed by immunohistochemistry with anti-S100 antibody in Stage I-III colorectal cancer. AB - PURPOSE: Perineural invasion (PN) diagnosed by hematoxylin-eosin (HE) staining is an important prognostic factor after curative-intent surgery in patients with colorectal cancer. However, the clinical significance of PN diagnosed by immunohistochemistry (IHC) has not been investigated. The present study assessed the clinical significance of PN diagnosed by IHC with an anti-S100 antibody in patients with colorectal cancer. METHODS: We retrospectively enrolled 184 consecutive patients with stage I-III colorectal cancer who had undergone curative-intent surgery. We analyzed the absence/presence of PN diagnosed by HE staining (HE-PN) compared to that diagnosed by IHC with the anti-S100 antibody (S100-PN). Potential prognostic factors were identified by univariate and multivariate analyses of the overall and relapse-free survival. The [Formula: see text] statistics were used to assess the inter-observer reproducibility. RESULTS: The incidence of HE-PN and S100-PN among the 184 patients was 60 patients (32.6%) and 113 patients (61.4%), respectively (P < 0.001). A multivariate Cox proportional hazards regression model analysis indicated that S100-PN was an independent prognostic factor for both the overall and relapse-free survival. The [Formula: see text] value was 0.77 for S100-PN and 0.47 for HE-PN. CONCLUSION: PN diagnosed by IHC is an important prognostic factor in patients with colorectal cancer. An inter-observer assessment showed superior judgment reproducibility for S100-PN compared with HE-PN. PMID- 25502402 TI - Enhanced cytotoxic activity of cetuximab in EGFR-positive lung cancer by conjugating with gold nanoparticles. AB - Cetuximab (C225) is a unique agent, targeting epidermal growth factor receptor (EGFR)-positive cancer. However, the therapeutic effect of C225 in EGFR high expressing non-small cell lung cancer (NSCLC) remains poor. Here, we report that conjugation of C225 with gold nanoparticles (AuNPs) enhances the cytotoxicity of C225 in NSCLC both in vitro and in vivo. The NSCLC cell lines A549 (EGFR(high)) and H1299 (EGFR(low)) were employed to investigate different responses to C225, IgG-AuNPs and C225-AuNPs. The antitumor properties of C225-AuNPs were explored in vivo by establishing a tumor xenograft model in nude mice. Overall, the therapeutic effect of C225-AuNPs was more pronounced in EGFR(high) A549 cells compared with EGFR(low) H1299 cells. The cytotoxic effect of C225-AuNPs in A549 cells increased in a dose-dependent manner. C225-AuNPs significantly suppressed A549 cell proliferation and migration capacity and accelerated apoptosis compared with C225, and this effect was probably due to enhanced EGFR endocytosis and the subsequent suppression of downstream signaling pathway. Finally in the tumor xenograft of nude mice, treatment with C225-AuNPs also led to a significant reduction in tumor weight and volume with low toxicity. Our findings suggest that C225-AuNPs conjugate has promising potential for targeted therapy of EGFR positive NSCLC patients. PMID- 25502406 TI - Genetic counselors and health literacy: the role of genetic counselors in developing a web-based resource about the Affordable Care Act. AB - The Western States Genetic Services Collaborative (WSGSC) recognized the need for clear and understandable information about the Affordable Care Act (ACA) for families throughout the life course. The genetic counselors working in the WSGSC developed, tested, and implemented a web resource ( http://www.westernstatesgenetics.org/ACA_home.htm ) to help families navigate information about the ACA tailored to their life situation. The training and experience of genetic counselors provide the skills needed to translate complicated information, like that of the ACA, into formats that the general public can comprehend. The website went public in October 2013, and it has been positively received. The development of this website is a good case study in how genetic counseling skills can be applied to public health education and improving health literacy. PMID- 25502405 TI - Association between PPAR-gamma2 Pro12Ala polymorphism and obesity: a meta analysis. AB - The peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene has been reported in the pathogeny of obesity. However, the results have been inconsistent. The purpose of this meta-analysis was to acquire a more accurate assessment of the association between PPAR-gamma2 Pro12Ala polymorphism and obesity. PubMed, Wan Fang (Chinese) databases, Chinese Biomedical Medical databases, and Chinese National Knowledge Infrastructure were searched to identify eligible studies. Finally, 25 studies (6491 cases and 8242 controls) were enrolled in this meta-analysis. The effect summary odds ratio (OR) with 95 % confidence interval (CI) was applied. Random-effects or fixed-effects model was performed based on the heterogeneity. STATA 12.0 was applied for this meta analysis. The combined results showed that PPAR-gamma Pro12Ala polymorphism was associated with the obesity risk (Ala vs. Pro: OR = 1.55, 95 % CI 1.34-1.80; Pro/Ala vs. Pro/Pro: OR = 1.54, 95 % CI 1.31-1.82; Ala/Ala + Pro/Ala vs. Pro/Pro: OR = 1.61, 95 % CI 1.36-1.90). Subgroup analysis by ethnicity showed that there were significant associations between PPAR-gamma Pro12Ala polymorphism and obesity risk in Caucasians, Asians, and Mixed population. Subgroup analysis by obesity's cutoff points showed that the associations were found among the patients with the cutoff point of BMI >=24 and BMI >=30 but not among the patients with the cutoff point of BMI >=95th percentile. These results suggested that PPAR-gamma Pro12Ala polymorphism might be a risk factor for obesity susceptibility. PMID- 25502408 TI - Antenatal sonographic diagnosis of choledochal cyst: Case report and imaging review. AB - In this report, we present the antenatal two- and three-dimensional sonographic findings from a fetus with choledochal cyst as well as confirmatory postnatal MRI. A delayed diagnosis of choledochal cyst is common, leading to significant morbidity and mortality. Visualizing bile ducts entering a right upper quadrant cyst is pathognomonic, and early diagnosis can facilitate definitive treatment with Roux-en-Y hepaticojejunostomy. PMID- 25502407 TI - Patient-Perceived Outcomes and Quality of Life in ALS. AB - A variety of outcome measures are used in clinical practice and in research to assess patients with amyotrophic lateral sclerosis (ALS). However, there may be discordance between traditional outcome measures such as strength and physical function, and patient-perceived measures of well-being. One such self-perceived measure, reflecting the patient's view, is quality of life (QOL). QOL in patients with severe medical disorder is often underestimated by others. Patients with ALS often have high QOL, and this may persist throughout the disease due to shifting expectations and to reprioritization of factors contributing to QOL. QOL instruments can measure health-related QOL (HRQOL) or global QOL, and can be generic or disease-specific. HRQOL refers primarily to physical and mental health. Global QOL is much broader, and is also determined by non-health-related factors. The choice of a QOL instrument depends on whether the setting is routine patient care or clinical research, whether or not the outcome of a specific intervention is being assessed, and upon the expected efficacy or toxicity of the intervention. Global QOL instruments are best for individual clinical patient care or for comparing groups. HRQOL or a combination of HRQOL and global QOL instruments are most appropriate for assessing specific interventions. PMID- 25502409 TI - Left adrenal biopsy using the convex curvilinear ultrasound scope. AB - Effective use of the convex curvilinear ultrasound bronchoscope in the esophagus (EUS-B) is well described. EUS-B has not been described for diagnostic sampling of the left adrenal gland. We describe 6 cases of diagnostic fine-needle aspiration of the left adrenal gland using EUS-B. This capacity increases the diagnostic capabilities of the pulmonologist experienced in EUS-B. PMID- 25502411 TI - Investigation of the enantiomerization barriers of the phthalimidone derivatives EM12 and lenalidomide by dynamic electrokinetic chromatography. AB - The phthalimidone derivatives EM12 and lenalidomide, which are both structurally related to thalidomide, are highly interesting drugs and very recently lenalidomide attracted great attention as an antitumor and immune-modulating drug in the therapy for multiple myeloma. EM12 and lenalidomide are chiral, and the stereogenic carbon C-3 in the piperidine-2,6-dione moiety of these phthalimidone derivatives is prone to interconversion due to keto-enol tautomerization. The knowledge of the enantiomerization barrier is mandatory for pharmacokinetic studies and to develop a tailored therapy using the enantiopure or racemic drug. Here, we used dynamic EKC in combination with direct-calculation methods to determine the enantiomerization barriers of EM12 and lenalidomide. The separations of the enantiomers of EM12 and lenalidomide were performed in 50 mM aqueous disodium hydrogen phosphate buffer at pH 8 and 50 mM aqueous sodium tetraborate buffer at pH 9.3, respectively, using 20 mg/mL heptakis-(2,3-diacetyl 6-sulfato)-beta-CD as a chiral additive. Enantiomerization of the compounds during the electrokinetic chromatographic separation resulted in pronounced plateau formation between the well-separated enantiomers. Peak form analysis of the experimentally obtained interconversion profiles yielded the enantiomerization rate constants k1 of EM12 and lenalidomide as well as the kinetic activation parameters DeltaG(?), DeltaH(??), and DeltaS(?) of enantiomerization by the evaluation of temperature-dependent measurements. The enantiomerization barrier DeltaG(?) was determined to be 98.3 +/- 1.0 kJ/mol; the activation parameters DeltaH(?) = 46.1 +/- 2.4 kJ/mol and DeltaS(?) = -170 +/- 61 J/(K.mol) for EM12 and DeltaG(?) = 91.5 +/- 1.0 kJ/mol, DeltaH(?) = 62.4 +/- 5.4 kJ/mol, and DeltaS(?) = -98 +/- 7 J/(K.mol) for lenalidomide. These findings were corroborated by density functional theory calculations at the B3LYP/3-21G level of theory of the ground state and intermediates considering an enantiomerization pathway via a keto-enol tautomerism. PMID- 25502412 TI - Molecular modelling studies of sirtuin 2 inhibitors using three-dimensional structure-activity relationship analysis and molecular dynamics simulations. AB - Sirtuin 2 (SIRT2) is a nicotinamide-adenine-dinucleotide-dependent histone deacetylase that plays a vital role in various biological processes related to DNA regulation, metabolism, and longevity. Recent studies on SIRT2 have indicated its therapeutic potential for neurodegenerative diseases such as Parkinson's disease. In this study, a series of SIRT2 inhibitors with a 2-anilinobenzamide core was analysed using a combination of molecular modelling techniques. A three dimensional structure-activity relationship (3D-QSAR) model adopting a comparative molecular field analysis (CoMFA) method with a non-cross-validated correlation coefficient R(2) = 0.992 (for training set) and a correlation coefficient Rtest(2) = 0.804 (for test set) was generated to determine the structural requirements for inhibitory activity. Furthermore, we employed molecular dynamics (MD) simulations and the molecular mechanics/generalized Born surface area (MM/GBSA) method to compare the binding modes of a potent and selective compound interacting with SIRT1, SIRT2, and SIRT3 and also their binding free energies to shed light on the selectivity of the footing of structural and energetic investigations. The steric and electrostatic contour maps from the 3D-QSAR analysis identified several key interactions also observed in the MD simulations. According to these results, we provide guidelines for developing novel potent and selective SIRT2 inhibitors. PMID- 25502410 TI - Down-regulation of Kelch domain-containing F-box protein in Arabidopsis enhances the production of (poly)phenols and tolerance to ultraviolet radiation. AB - Phenylpropanoid biosynthesis in plants engenders myriad phenolics with diverse biological functions. Phenylalanine ammonia-lyase (PAL) is the first committed enzyme in the pathway, directing primary metabolic flux into a phenylpropanoid branch. Previously, we demonstrated that the Arabidopsis (Arabidopsis thaliana) Kelch domain-containing F-box proteins, AtKFB01, AtKFB20, and AtKFB50, function as the negative regulators controlling phenylpropanoid biosynthesis via mediating PAL's ubiquitination and subsequent degradation. Here, we reveal that Arabidopsis KFB39, a close homolog of AtKFB50, also interacts physically with PAL isozymes and modulates PAL stability and activity. Disturbing the expression of KFB39 reciprocally affects the accumulation/deposition of a set of phenylpropanoid end products, suggesting that KFB39 is an additional posttranslational regulator responsible for the turnover of PAL and negatively controlling phenylpropanoid biosynthesis. Furthermore, we discover that exposure of Arabidopsis to ultraviolet (UV)-B radiation suppresses the expression of all four KFB genes while inducing the transcription of PAL isogenes; these data suggest that Arabidopsis consolidates both transcriptional and posttranslational regulation mechanisms to maximize its responses to UV light stress. Simultaneous down regulation of all four identified KFBs significantly enhances the production of (poly)phenols and the plant's tolerance to UV irradiation. This study offers a biotechnological approach for engineering the production of useful phenolic chemicals and for increasing a plant's resistance to environmental stress. PMID- 25502414 TI - Phencyclidine Intoxication Case Series Study. AB - BACKGROUND: Phencyclidine (PCP) is a synthetic compound derived from piperidine and used as an anesthetic and hallucinogenic. Little has been recently published regarding the clinical presentation of PCP intoxication. PCP use as a recreational drug is resurging. OBJECTIVE: Our objective was to describe clinical findings in patients presenting to the emergency department (ED) under the influence of PCP. METHODS: This was a case series study conducted at a tertiary care center with an annual census of 100,000 patients/year. Emergency physicians, residents, physician assistants, and research assistants identified patients with possible PCP intoxication. Self-reported PCP use, report by bystanders or Emergency Medical Services (EMS) staff, was used in this process. A structured data collection form was completed, documenting both clinical and behavioral events observed by the treating team during the ED visit. RESULTS: We collected data on 219 patients; 184 were analyzed; two patients were excluded secondary to incomplete data. The mean age of patients was 32.5 years (+/-7 years) with 65.2 % being males. PCP use was self-reported by 60.3 % of patients. Of the 184 patients, 153 (83.1 %) received a urine drug screen (UDS); 152 (98.7 %) were positive for PCP. On arrival, 78.3 % of patients were awake and alert, and 51.6 % were oriented to self, time/date, and place. Mean physiological parameters were the following: heart rate 101.1 bpm (+/-24.3), RR 18.9 bpm (+/-3.4), BP 146.3 (+/ 19.4)/86.3 (+/-14.0) mmHg, 36.9 degrees C (+/-0.5), and pulse oximetry 98.2 % (+/-1.9). Clinical findings were the following: retrograde amnesia in 46 (25 %), horizontal nystagmus in 118 (64.1 %), vertical nystagmus in 90 (48.9 %), hypertension in 87 (47.3 %), and agitation in 71 (38.6 %). Concomitant use of at least one other substance was reported by 99 (53.8 %) patients. The mean length of stay in the ED for all subjects was 261.1 (+/-172.8) minutes. Final disposition for 152 (82.6 %) patients was to home. Of the 184 patients, 14 (7.6 %) required admission; 12 were referred to Crisis Response Center. CONCLUSION: Patients with PCP intoxication tended to be young males. The prevalent clinical signs and symptoms were the following: retrograde amnesia, nystagmus, hypertension, and psychomotor agitation. Co-use of other substances was the norm. Most patients presenting to the ED with PCP intoxication do well and can be discharged home after a period of observation. PMID- 25502413 TI - Predicting growth conditions from internal metabolic fluxes in an in-silico model of E. coli. AB - A widely studied problem in systems biology is to predict bacterial phenotype from growth conditions, using mechanistic models such as flux balance analysis (FBA). However, the inverse prediction of growth conditions from phenotype is rarely considered. Here we develop a computational framework to carry out this inverse prediction on a computational model of bacterial metabolism. We use FBA to calculate bacterial phenotypes from growth conditions in E. coli, and then we assess how accurately we can predict the original growth conditions from the phenotypes. Prediction is carried out via regularized multinomial regression. Our analysis provides several important physiological and statistical insights. First, we show that by analyzing metabolic end products we can consistently predict growth conditions. Second, prediction is reliable even in the presence of small amounts of impurities. Third, flux through a relatively small number of reactions per growth source (~10) is sufficient for accurate prediction. Fourth, combining the predictions from two separate models, one trained only on carbon sources and one only on nitrogen sources, performs better than models trained to perform joint prediction. Finally, that separate predictions perform better than a more sophisticated joint prediction scheme suggests that carbon and nitrogen utilization pathways, despite jointly affecting cellular growth, may be fairly decoupled in terms of their dependence on specific assortments of molecular precursors. PMID- 25502416 TI - Violence Against Women. Editor's introduction. PMID- 25502417 TI - Why Straus's "Reanalysis" of physical tactics used by female partners is wrong: a response to "Addressing violence by female partners is vital to prevent or stop violence against women: evidence from the multisite batterer intervention evaluation," by Murray Straus, Violence Against Women, 20, 889-899. AB - This article refutes Straus's reinterpretation of our study, "Physical Tactics of Female Partners Against Male Batterer Program Participants," drawing on our extended follow-up of batterer program participants and their partners in four cities (Gondolf, 2002). Straus claims that the rate of women's violence in the sample is "high" and asserts the need to address women's violence to reduce the men's violence, which is the opposite of our findings and interpretation. We contend that our focus on the men and women who both used tactics in the total sample addresses the research question. We elaborate why our regression analyses to "explain" the women's violence are sound, despite Straus's unsubstantiated speculations. We argue further that the evidence points to women's "violent resistance" against severe, repeated violence, and that those cases do not fit the "both victim" dyad type that Straus promotes. Moreover, they are inappropriate for couples counseling. Finally, we revisit the limitations of the Conflict Tactics Scales (CTS) as a sufficient measure of the women's experience of male violence and raise concern about the implications of Straus's claims. PMID- 25502418 TI - Safety and efficacy of endoscopic submucosal dissection of rectal tumors extending to the dentate line. AB - BACKGROUND AND STUDY AIMS: Unique anatomical features render endoscopic resection for rectal tumors extending to the dentate line (RTDL) technically challenging. The aim of this study was to evaluate the feasibility of endoscopic submucosal dissection (ESD) for RTDLs. PATIENTS AND METHODS: This retrospective study compared ESD for RTDLs with proximal rectal tumors between September 2002 and June 2012. En bloc resection rate, R0 resection rate, complications, and tumor recurrences were assessed. RESULTS: A total of 45 RTDLs (median age 69 years; 15 males; median lesion size 38.4 mm) and 94 proximal rectal tumors were identified. En bloc resection and R0 resection rates were 95.6 % (43/45) and 53.3 % (24/45), respectively. The perforation rate was 4.4 %. Compared with proximal rectal ESD, ESD for RTDLs showed longer procedure time (104 vs. 60 minutes; P < 0.001), lower R0 resection rate (53.3 % vs. 70.2 %; P = 0.019), and more frequent high grade fever (22.2 % vs. 4.3 %; P = 0.002). No residual adenoma was observed at the first surveillance colonoscopy. Recurrence rate did not differ significantly between the two groups. CONCLUSIONS: ESD for RTDLs demonstrated safety and effectiveness comparable to ESD in proximal rectal lesions. PMID- 25502419 TI - Molecular nanomagnets with switchable coupling for quantum simulation. AB - Molecular nanomagnets are attractive candidate qubits because of their wide inter and intra-molecular tunability. Uniform magnetic pulses could be exploited to implement one- and two-qubit gates in presence of a properly engineered pattern of interactions, but the synthesis of suitable and potentially scalable supramolecular complexes has proven a very hard task. Indeed, no quantum algorithms have ever been implemented, not even a proof-of-principle two-qubit gate. Here we show that the magnetic couplings in two supramolecular {Cr7Ni}-Ni {Cr7Ni} assemblies can be chemically engineered to fit the above requisites for conditional gates with no need of local control. Microscopic parameters are determined by a recently developed many-body ab-initio approach and used to simulate quantum gates. We find that these systems are optimal for proof-of principle two-qubit experiments and can be exploited as building blocks of scalable architectures for quantum simulation. PMID- 25502420 TI - Intraoperative high-dose rate of radioactive phosphorus 32 brachytherapy for diffuse recalcitrant conjunctival neoplasms: a retrospective case series and report of toxicity. AB - IMPORTANCE: Adjunct treatments for conjunctival malignancies are needed when standard therapy provides limited benefits or fails. OBJECTIVE: To describe the results of patients with diffuse conjunctival neoplasms treated with radioactive phosphorus 32 (32P)-impregnated flexible film. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series between January 1, 2010, and January 1, 2013, was conducted at Memorial Sloan-Kettering Cancer Center, a tertiary referral center. The study was conducted on 7 eyes of 6 patients treated for diffuse conjunctival squamous cell carcinoma, sebaceous carcinoma, or lymphoma that had recurrent or residual disease after primary treatment. INTERVENTIONS: Patients underwent mapping biopsies and detailed conjunctival drawings to delineate the pathologic extent of the disease. The brachytherapy film used for treatment was the RIC Conformal Source Model 100 (RIC-100, RI Consultants). The RIC-100 is a flexible, thin (approximately 0.5-mm) film made of a polymer chemically bound to 32P. The radioactive 32P film was placed intraoperatively, allowed to stay in place until the prescription dose was reached, and then removed. The median dose at the prescription point (1 mm from the surface of the film) was 15 Gy (range, 5-17 Gy). MAIN OUTCOMES AND MEASURES: Patients were tested for best-corrected visual acuity, recurrence-free survival, and adverse events scored by using the Adult Comorbidity Evaluation-27 scale. RESULTS: Between 2010 and 2013, 7 eyes of 6 patients were treated. The median age of patients was 70 years. All patients had a recurrent or persistent neoplasm. Four patients with squamous cell carcinoma, 1 with sebaceous carcinoma, and 1 with metachronous bilateral lymphomas were treated. The median treatment time was 19 minutes (range, 10-52 minutes). The median follow-up was 24.9 months (range, 3.1-38.2 months). Recurrence-free survival 24 months after brachytherapy was 75% (95% CI, 19-89.1). Two moderate adverse events and 1 severe adverse event occurred. Visual acuity was stable or improved in 5 of the 7 eyes (ie, better than 20/70 in the 5 patients who retained their treated eye). CONCLUSIONS AND RELEVANCE: Our results show the use of an intraoperative high-dose rate of 32P brachytherapy in selected cases of recalcitrant diffuse conjunctival neoplasms. This technique offers a novel adjunct in the treatment of these cancers. Further follow-up and study are warranted. PMID- 25502421 TI - A low-noise solid-state nanopore platform based on a highly insulating substrate. AB - A solid-state nanopore platform with a low noise level and sufficient sensitivity to discriminate single-strand DNA (ssDNA) homopolymers of poly-A40 and poly-T40 using ionic current blockade sensing is proposed and demonstrated. The key features of this platform are (a) highly insulating dielectric substrates that are used to mitigate the effect of parasitic capacitance elements, which decrease the ionic current RMS noise level to sub-10 pA and (b) ultra-thin silicon nitride membranes with a physical thickness of 5 nm (an effective thickness of 2.4 nm estimated from the ionic current) are used to maximize the signal-to-noise ratio and the spatial depth resolution. The utilization of an ultra-thin membrane and a nanopore diameter as small as 1.5 nm allow the successful discrimination of 40 nucleotide ssDNA poly-A40 and poly-T40. Overall, we demonstrate that this platform overcomes several critical limitations of solid-state nanopores and opens the door to a wide range of applications in single-molecule-based detection and analysis. PMID- 25502422 TI - Highly sensitive ultraviolet photodetectors fabricated from ZnO quantum dots/carbon nanodots hybrid films. AB - Ultraviolet photodetectors have been fabricated from ZnO quantum dots/carbon nanodots hybrid films, and the introduction of carbon nanodots improves the performance of the photodetectors greatly. The photodetectors can be used to detect very weak ultraviolet signals (as low as 12 nW/cm(2)). The detectivity and noise equivalent power of the photodetector can reach 3.1 * 10(17) cmHz(1/2)/W and 7.8 * 10(-20) W, respectively, both of which are the best values ever reported for ZnO-based photodetectors. The mechanism for the high sensitivity of the photodetectors has been attributed to the enhanced carrier-separation at the ZnO/C interface. PMID- 25502423 TI - Diagnostics of primary immunodeficiency diseases: a sequencing capture approach. AB - Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. Thanks to the advent of "next generation" sequencing technologies and target enrichment methods, the development of multiplex diagnostic assays is now possible. In this study, we applied a selector based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach. Causal mutations identified in the unknown patient samples were located in STAT3, IGLL1, RNF168 and PGM3. Based on our results, we propose a stepwise approach for PID diagnostics, involving targeted resequencing, followed by whole transcriptome and/or whole genome sequencing if causative variants are not found in the targeted exons. PMID- 25502426 TI - Sentinel lymph node biopsy in the management of gynecologic cancer. AB - PURPOSE OF REVIEW: To summarize current knowledge and recent advances in sentinel lymph node (SLN) concept in the three most frequent gynecological cancers. RECENT FINDINGS: In cervical cancer, SLN biopsy and ultrastaging has high sensitivity in lymph node staging in patients with bilaterally detected SLN. The presence of micrometastasis is associated with shortened survival. In endometrial cancer, SLN biopsy incorporating an institutional mapping algorithm and ultrastaging has been shown to significantly reduce false-negative rates and increase sensitivity and negative predictive value. SUMMARY: SLN biopsy and ultrastaging is useful in current management of patients with early-stage cervical cancer for multiple reasons, such as the reliable detection of key lymph nodes, identification of micrometastasis and intraoperative triage of patients. Although a complete or selective pelvic and paraaortic lymphadenectomy for adequate staging remains the standard treatment approach in patients with early-stage endometrial cancer, SLN biopsy has been shown to be safe and effective in detecting lymph node metastases. The application of the SLN procedure is safe in patients with early stage unifocal squamous cell cancer of the vulva (<4 cm) and no suspicious enlarged lymph nodes at imaging. PMID- 25502425 TI - Next-generation sequencing for hereditary breast and gynecologic cancer risk assessment. AB - PURPOSE OF REVIEW: To summarize advances in next-generation sequencing and their application to breast and gynecologic cancer risk assessment. RECENT FINDINGS: Next-generation sequencing panels of 6-112 cancer-associated genes are increasingly used in patient care. Studies report a 4-16% prevalence of mutations other than BRCA1/2 among patients who meet evidence-based practice guidelines for BRCA1/2 testing, with a high rate (15-88%) of uninterpretable variants of uncertain significance. Despite uncertainty about results interpretation and communication, there is early evidence of a benefit from multiple-gene sequencing panels for appropriately selected patients. SUMMARY: Multiple-gene sequencing panels appear highly promising for the assessment of breast and gynecologic cancer risk, and they may usefully be administered in the context of cancer genetics expertise and/or clinical research protocols. PMID- 25502424 TI - Interactive performances of betaine on the metabolic processes of Pseudomonas denitrificans. AB - The performances of betaine on the metabolic processes of vitamin B12-producing Pseudomonas denitrificans were investigated in this paper. The results showed that betaine was an indispensable methyl-group donor for vitamin B12 biosynthesis, but large amounts of the extracellular glycine accompanied by betaine metabolism would impose a severe restriction on the cell growth of P. denitrificans. By further using a comparative metabolomics approach coupled with intracellular free amino acids analysis for the fermentation processes with betaine addition (10 g/l) or not, it was found that betaine could highly strengthen the formation of some key precursors and intermediates facilitating vitamin B12 biosynthesis, such as delta-aminolevulinic acid (ALA, the first precursor of vitamin B12), glutamate (an intermediate of ALA via C5 pathway), glycine (an intermediate of ALA via C4 pathway), and methionine (directly participating in the methylation reaction involved in vitamin B12 biosynthetic pathway). Therefore, the performances of betaine on P. denitrificans metabolic processes were not only serving as a decisive methyl-group donor for vitamin B12 biosynthesis, but also playing a powerfully promoting role in the generation of vitamin B12 precursors and intermediates. PMID- 25502427 TI - Genetic risk assessment for breast and gynecological malignancies. AB - PURPOSE OF REVIEW: Breast cancer and gynecological cancers impact a significant portion of women each year. Identifying women at high risk is essential for implementation of screening and risk reduction recommendations. Risk assessment for these cancers involves an evaluation of many factors. This review discusses an overview of hereditary breast and gynecological cancers and the process of a cancer genetic risk assessment. RECENT FINDINGS: Risk assessment models for breast cancer should be used with caution, especially in populations in which they are not validated. Additionally, the BRCAPRO model may underestimate the likelihood of BRCA mutations in certain populations.The utilization of next generation sequencing panels is increasing. Benefits and limitations of panel testing are described in the literature. There are currently no guidelines for the use of panel testing; however, some reports of institutional experiences and recommendations are available. SUMMARY: Cancer genetic risk assessment is complex, and models developed to estimate risk may not apply to all populations. Identifying genetic factors related to cancer risk is also becoming increasingly complex with the clinical implementation of panel testing. This testing approach should be critically evaluated by healthcare providers. Further research is needed to create evidence-based guidelines for panel testing and management recommendations for moderately penetrant genes. PMID- 25502428 TI - New treatment strategies for patients with triple-negative breast cancer. AB - PURPOSE OF REVIEW: Although patients with hormone receptor-positive and/or HER2 positive breast cancer benefit from endocrine and HER2-targeted agents in addition to combination chemotherapy regimens, patients with triple-negative breast cancer (TNBC) suffer from a particularly unfavorable prognosis particularly when not responding well to anthracycline-taxane chemotherapy. Novel treatment options are urgently needed to improve prognosis of these patients as well. RECENT FINDINGS: Potential options for optimized therapy of patients with TNBC consist in, first, optimization of chemotherapy through optimization of chemotherapy regimens with may be reached through optimized (i.e., dose-dense) scheduling, second, optimization of chemotherapy through introduction of novel chemotherapy agents (such as platinum compounds as alternative of additional chemotherapy), third, identification and development of novel targeted agents, and fourth, identification of patients with or without response through biomarkers to individual treatments to allow for a more personalized treatment approach. SUMMARY: We summarize recent findings for novel treatment options particularly focusing on platinum-based chemotherapy, potential novel targeted therapies such as antiangiogenic agents or inhibition of poly-A-ribose polymerase, and prognostic/predictive biomarkers such as tumor-infiltrating lymphocytes or BRCA. PMID- 25502430 TI - Managing symptoms and maximizing quality of life after preventive interventions for cancer risk reduction. AB - PURPOSE OF REVIEW: The prevention of breast, ovarian and endometrial cancer frequently involves hormonal or surgical interventions. Each of these may have noncancerous sequelae and can affect quality of life in women with hereditary cancer syndromes. The purpose of this review is to discuss the medical management of hormonal suppression and surgical menopause in hereditary breast and ovarian cancer syndromes and in Lynch syndrome. RECENT FINDINGS: As we gain a better understanding of genetic cancer risk, we are able to reduce the development of cancer with risk-reducing surgery. Understanding the significance of noncancer outcomes helps improve surveillance and treatment strategies and improves our understanding of the interaction between our interventions and their effects on quality of life. SUMMARY: Advances in our understanding of the pathogenesis of hereditary breast and ovarian cancer, as well as the difference in ovarian ageing in these high-risk women, allow us to improve our counselling and interventions for family planning and risk-reducing surgery. Studies are ongoing regarding the optimal surveillance of cardiovascular and bone health after risk-reducing salpingo-oophorectomy, although more studies are needed regarding the optimal management of sexual health and other quality of life measures. PMID- 25502429 TI - New ways to successfully target tumor vasculature in ovarian cancer. AB - PURPOSE OF REVIEW: The aim of this article was to review the recent literature on potential therapeutic strategies for overcoming resistance to antivascular endothelial growth factor drugs in ovarian cancer. RECENT FINDINGS: Although clinical benefits of antivascular endothelial growth factor therapy were observed in ovarian cancer treatment trials, this use yielded only modest improvement in progression-free survival and, with the exception of cediranib, no effect on overall survival. Adaptive resistance and escape from antiangiogenesis therapy is likely a multifactorial process, including induction of hypoxia, vascular modulators, and immune response. New drugs targeting the tumor vasculature or other components of the surrounding microenvironment have shown promising results. SUMMARY: When to start and end antiangiogenesis therapy and the choice of optimal treatment combinations remain controversial. Further evaluation of personalized novel angiogenesis-based therapy is warranted. Defining the critical interaction of these agents and pathways and the appropriate predictive markers will become an increasingly important objective for effective treatment. PMID- 25502432 TI - WITHDRAWN: Robotic assisted surgery for gynaecological cancer. PMID- 25502431 TI - Genomic profiling of breast cancers. AB - PURPOSE OF REVIEW: To describe recent advances in the application of advanced genomic technologies towards the identification of biomarkers of prognosis and treatment response in breast cancer. RECENT FINDINGS: Advances in high-throughput genomic profiling such as massively parallel sequencing have enabled researchers to catalogue the spectrum of somatic alterations in breast cancers. These tools also hold promise for precision medicine through accurate patient prognostication, stratification, and the dynamic monitoring of treatment response. For example, recent efforts have defined robust molecular subgroups of breast cancer and novel subtype-specific oncogenes. In addition, previously unappreciated activating mutations in human epidermal growth factor receptor 2 have been reported, suggesting new therapeutic opportunities. Genomic profiling of cell-free tumor DNA and circulating tumor cells has been used to monitor disease burden and the emergence of resistance, and such 'liquid biopsy' approaches may facilitate the early, noninvasive detection of aggressive disease. Finally, single-cell genomics is coming of age and will contribute to an understanding of breast cancer evolutionary dynamics. SUMMARY: Here, we highlight recent studies that employ high-throughput genomic technologies in an effort to elucidate breast cancer biology, discover new therapeutic targets, improve prognostication and stratification, and discuss the implications for precision cancer medicine. PMID- 25502433 TI - WITHDRAWN: Robotic surgery for benign gynaecological disease. PMID- 25502435 TI - Risk Factors for Postoperative Morbidity After Totally Robotic Gastric Bypass in 302 Consecutive Patients. AB - BACKGROUND: Totally robotic gastric bypass (robotic Roux-en-Y gastric bypass, R RYGBP) has been adopted in some centers on the basis of large retrospective studies. In view of some data showing higher morbidity and higher costs, some authors have considered that robotic gastric bypass may no longer be justified with the existing system. Although low postoperative complication rates after R RYGBP have been reported, risk factors for postoperative morbidity have never been evaluated. The goal of this study was to identify risk factors for postoperative morbidity after R-RYGBP. METHODS: A retrospective analysis of a prospectively maintained database was performed and included 302 consecutive patients after R-RYGBP performed between 2007 and 2013. This subset of patients represented 34 % of all gastric bypass procedures performed during this study period. Univariate and multivariate analyses were performed in order to identify risk factors for postoperative overall morbidity (Clavien scores 1-4 versus 0) and major morbidity (Clavien score >=3 versus 0-1-2). RESULTS: Postoperative morbidity and mortality rates were 24.4 and 0.6 %, respectively. In multivariate analysis, independent risk factors for overall morbidity were American Society of Anesthesiologists (ASA) score >=3 (odds ratio (OR) 2.0) and previous bariatric surgery (revisional gastric bypass) (OR 2.0). Independent risk factors for major morbidity (Clavien >=3) were previous bariatric surgery (revisional gastric bypass) (OR 3.7), low preoperative hematocrit level (OR 0.9), and revisional gastric bypass procedure with concomitant gastric banding removal (OR 5.7). CONCLUSIONS: R-RYGBP is prone to increased complications in the setting of a high preoperative ASA score and revisional surgery. This should be taken into consideration by clinicians when evaluating R-RYGBP. PMID- 25502434 TI - Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: a systematic review and meta-analysis. AB - BACKGROUND: The role of dietary restriction regimens such as caloric restriction, ketogenic diet and intermittent fasting in development of cancers has been detected via abundant preclinical experiments. However, the conclusions are controversial. We aim to review the relevant animal studies systematically and provide assistance for further clinical studies. METHODS: Literatures on associations between dietary restriction and cancer published in PubMed in recent twenty years were comprehensively searched. Animal model, tumor type, feeding regimen, study length, sample size, major outcome, conclusion, quality assessment score and the interferential step of cancer were extracted from each eligible study. We analyzed the tumor incidence rates from 21 studies about caloric restriction. RESULTS: Fifty-nine studies were involved in our system review. The involved studies explored roles of dietary restriction during initiation, progression and metastasis of cancer. About 90.9% of the relevant studies showed that caloric restriction plays an anti-cancer role, with the pooled OR (95%CI) of 0.20 (0.12, 0.34) relative to controls. Ketogenic diet was also positively associated with cancer, which was indicated by eight of the nine studies. However, 37.5% of the related studies obtained a negative conclusion that intermittent fasting was not significantly preventive against cancer. CONCLUSIONS: Caloric restriction and ketogenic diet are effective against cancer in animal experiments while the role of intermittent fasting is doubtful and still needs exploration. More clinical experiments are needed and more suitable patterns for humans should be investigated. PMID- 25502437 TI - Efficacy of vitamin D supplementation after bariatric operation: letter to the editor. PMID- 25502436 TI - Effects of Posture and Meal Volume on Gastric Emptying, Intestinal Transit, Oral Glucose Tolerance, Blood Pressure and Gastrointestinal Symptoms After Roux-en-Y Gastric Bypass. AB - BACKGROUND: The purpose of this study is to determine the effects of posture and drink volume on gastric/pouch emptying (G/PE), intestinal transit, hormones, absorption, glycaemia, blood pressure and gastrointestinal (GI) symptoms after gastric bypass (Roux-en-Y gastric bypass (RYGB)). METHODS: Ten RYGB subjects were studied on four occasions in randomized order (sitting vs. supine posture; 50 vs. 150 ml of labelled water mixed with 3 g 3-O-methyl-D-glucose (3-OMG) and 50 g glucose). G/PE, caecal arrival time (CAT), blood glucose, plasma insulin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY), 3-OMG, blood pressure, heart rate and GI symptoms were assessed over 240 min. Controls were ten volunteers with no medical condition or previous abdominal surgery, who were studied with the 150-ml drink in the sitting position. RESULTS: Compared to controls, PE (P < 0.001) and CAT (P < 0.001) were substantially more rapid in RYGB subjects. In RYGB, PE was more rapid in the sitting position (2.5 +/- 0.7 vs. 16.6 +/- 5.3 min, P = 0.02) and tends to be faster after 150 ml than the 50-ml drinks (9.5 +/- 2.9 vs. 14.0 +/- 3.5 min, P = 0.16). The sitting position and larger volume drinks were associated with greater releases of insulin, GLP-1 and PYY, as well as more hypotension (P < 0.01), tachycardia (P < 0.01) and postprandial symptoms (P < 0.001). CONCLUSIONS: Pouch emptying, blood pressure and GI symptoms after RYGB are dependent on both posture and meal volume. PMID- 25502439 TI - Experimental climate warming enforces seed dormancy in South African Proteaceae but seedling drought resilience exceeds summer drought periods. AB - Two hypotheses-that elevated night-time temperatures due to climate warming would enforce post-fire dormancy of Proteaceae seed due to low moisture, and that periods without rain during summer would exceed desiccation periods tolerated by Proteaceae seedlings-were tested empirically. Enforced dormancy, i.e., the inability to germinate due to an environmental restraint, was tested by measuring seed germination in 11 Proteaceae species in experimental mesocosms whose soils were artificially elevated by 1.4 and 3.5 degrees C above ambient by far-red wavelength filtered infrared lamps. Diminished totality of germination and velocities were observed in 91 and 64%, respectively, of the Proteaceae species tested. Drought resilience was tested in one-year-old seedlings of 16 Proteaceae species by withholding water from potted plants during summer in a greenhouse. The most drought-resilient Proteaceae species displayed the lowest initial transpiration rates at field capacity, the smallest declines in transpiration rate with decreasing soil water content, and the lowest water losses by transpiration. Projected drought periods leading to the complete cessation of transpiration in all Proteaceae species greatly exceeded the number of days without rain per month during summer in the current distribution ranges of those species. It was therefore concluded that enforced seed dormancy induced by elevated night-time temperatures is the post-fire recruitment stage of Proteaceae that is most sensitive to climate warming. PMID- 25502440 TI - Natural abundance (delta15N) indicates shifts in nitrogen relations of woody taxa along a savanna-woodland continental rainfall gradient. AB - Water and nitrogen (N) interact to influence soil N cycling and plant N acquisition. We studied indices of soil N availability and acquisition by woody plant taxa with distinct nutritional specialisations along a north Australian rainfall gradient from monsoonal savanna (1,600-1,300 mm annual rainfall) to semi arid woodland (600-250 mm). Aridity resulted in increased 'openness' of N cycling, indicated by increasing delta(15)N(soil) and nitrate:ammonium ratios, as plant communities transitioned from N to water limitation. In this context, we tested the hypothesis that delta(15)N(root) xylem sap provides a more direct measure of plant N acquisition than delta(15)N(foliage). We found highly variable offsets between delta(15)N(foliage) and delta(15)N(root) xylem sap, both between taxa at a single site (1.3-3.4 0/00) and within taxa across sites (0.8-3.4 0/00). As a result, delta(15)N(foliage) overlapped between N-fixing Acacia and non fixing Eucalyptus/Corymbia and could not be used to reliably identify biological N fixation (BNF). However, Acacia delta(15)N(root) xylem sap indicated a decline in BNF with aridity corroborated by absence of root nodules and increasing xylem sap nitrate concentrations and consistent with shifting resource limitation. Acacia dominance at arid sites may be attributed to flexibility in N acquisition rather than BNF capacity. delta(15)N(root) xylem sap showed no evidence of shifting N acquisition in non-mycorrhizal Hakea/Grevillea and indicated only minor shifts in Eucalyptus/Corymbia consistent with enrichment of delta(15)N(soil) and/or decreasing mycorrhizal colonisation with aridity. We propose that delta(15)N(root) xylem sap is a more direct indicator of N source than delta(15)N(foliage), with calibration required before it could be applied to quantify BNF. PMID- 25502442 TI - Multiple cutaneous nodules in an HIV-infected patient. PMID- 25502438 TI - The miR9863 family regulates distinct Mla alleles in barley to attenuate NLR receptor-triggered disease resistance and cell-death signaling. AB - Barley (Hordeum vulgare L.) Mla alleles encode coiled-coil (CC), nucleotide binding, leucine-rich repeat (NB-LRR) receptors that trigger isolate-specific immune responses against the powdery mildew fungus, Blumeria graminis f. sp. hordei (Bgh). How Mla or NB-LRR genes in grass species are regulated at post transcriptional level is not clear. The microRNA family, miR9863, comprises four members that differentially regulate distinct Mla alleles in barley. We show that miR9863 members guide the cleavage of Mla1 transcripts in barley, and block or reduce the accumulation of MLA1 protein in the heterologous Nicotiana benthamiana expression system. Regulation specificity is determined by variation in a unique single-nucleotide-polymorphism (SNP) in mature miR9863 family members and two SNPs in the Mla miR9863-binding site that separates these alleles into three groups. Further, we demonstrate that 22-nt miR9863s trigger the biogenesis of 21 nt phased siRNAs (phasiRNAs) and together these sRNAs form a feed-forward regulation network for repressing the expression of group I Mla alleles. Overexpression of miR9863 members specifically attenuates MLA1, but not MLA10 triggered disease resistance and cell-death signaling. We propose a key role of the miR9863 family in dampening immune response signaling triggered by a group of MLA immune receptors in barley. PMID- 25502441 TI - Phenolic compounds and expression of 4CL genes in silver birch clones and Pt4CL1a lines. AB - A small multigene family encodes 4-coumarate:CoA ligases (4CLs) catalyzing the CoA ligation of hydroxycinnamic acids, a branch point step directing metabolites to a flavonoid or monolignol pathway. In the present study, we examined the effect of antisense Populus tremuloides 4CL (Pt4CL1) to the lignin and soluble phenolic compound composition of silver birch (Betula pendula) Pt4CL1a lines in comparison with non-transgenic silver birch clones. The endogenous expression of silver birch 4CL genes was recorded in the stems and leaves and also in leaves that were mechanically injured. In one of the transgenic Pt4CL1a lines, the ratio of syringyl (S) and guaiacyl (G) lignin units was increased. Moreover, the transcript levels of putative silver birch 4CL gene (Bp4CL1) were reduced and contents of cinnamic acid derivatives altered. In the other two Pt4CL1a lines changes were detected in the level of individual phenolic compounds. However, considerable variation was found in the transcript levels of silver birch 4CLs as well as in the concentration of phenolic compounds among the transgenic lines and non-transgenic clones. Wounding induced the expression of Bp4CL1 and Bp4CL2 in leaves in all clones and transgenic lines, whereas the transcript levels of Bp4CL3 and Bp4CL4 remained unchanged. Moreover, minor changes were detected in the concentrations of phenolic compounds caused by wounding. As an overall trend the wounding decreased the flavonoid content in silver birches and increased the content of soluble condensed tannins. The results indicate that by reducing the Bp4CL1 transcript levels lignin composition could be modified. However, the alterations found among the Pt4CL1a lines and the non-transgenic clones were within the natural variation of silver birches, as shown in the present study by the clonal differences in the transcripts levels of 4CL genes, soluble phenolic compounds and condensed tannins. PMID- 25502443 TI - Protective and therapeutic effect of apocynin on bleomycin-induced lung fibrosis in rats. AB - We aimed to investigate the preventive and therapeutic effect of apocynin (APO) on bleomycin (BLC)-induced lung injury in rats. Rats were assigned into groups as follows: control group; APO group, 20 mg/kg APO was given intraperitoneal for 29 days; BLC-1 and BLC-2 groups, a single intratracheal injection of BLC (2.5 mg/kg); APO+BLC-preventive group, 20 mg/kg APO was administered 12 h before the intratracheal BLC injection and continued for 14 days; BLC+APO-treatment group, 20 mg/kg APO was given on the 14th day after the intratracheal BLC injection and continued to sacrifice. The BLC-1 group was sacrificed on the 14th day of BLC administration to validate BLC-induced lung inflammation and fibrosis on the 14th of study initiation. All other groups were sacrificed on the 29th day after BLC administration. The semiquantitative histopathological assessment, tissue levels of malondialdehyde (MDA), superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant capacity, total oxidant status (TOS), and oxidative stress index (OSI) were measured. An addition to the serum myeloperoxidase (MPO), the cell count and cytokines (IL-1beta, IL-6, and IL-8) of bronchoalveolar lavage (BAL) fluid were assayed. BLC-provoked histological changes were significantly detected compared to the control group. APO restored these histological damages in different quantity in the treatment and prevention groups. BLC caused a significant decrease in GSH, CAT, and GPX, which were accompanied with significantly the increased MDA, TOS levels, and OSI in the lung tissue concomitant with increased levels of the cellular account and proinflammatory cytokines in the BAL fluid. Otherwise, APO administration, both before and after BLC, reversed all biochemical markers and cytokine as well as histopathological changes induced by BLC. Interestingly, APO treatment reversed MPO activity in serum increased by BLC. In this study, both protective and therapeutic effects of APO against BLC-induced lung fibrosis were demonstrated for the first time. PMID- 25502444 TI - In vitro oxidation of fibrinogen promotes functional alterations and formation of advanced oxidation protein products, an inflammation mediator. AB - Fibrinogen (FB) is a soluble blood plasma protein and is a key molecule involved in coagulation. Oxidative modification of proteins, such as the formation of advanced oxidation protein products (AOPP), a heterogeneous family of protein compounds structurally modified and derived from oxidative stress, may be associated with the pathophysiology of a number of chronic inflammatory diseases. Therefore, the aim of this study was to determine whether the formation of this mediator of inflammation occurs from FB and whether its generation is associated with structural changes. Results of the present study suggest that the oxidation of FB may provoke the formation of AOPP, which in turn, may promote functional alterations in FB, thus causing changes in its structural domains and increasing its procoagulant activity. PMID- 25502445 TI - Beneficial effects of simulated gastro-intestinal digests of fried egg and its fractions on blood pressure, plasma lipids and oxidative stress in spontaneously hypertensive rats. AB - BACKGROUND: We have previously characterized several antihypertensive peptides in simulated digests of cooked eggs and showed blood pressure lowering property of fried whole egg digest. However, the long-term effects of this hydrolysate and its fractions on blood pressure are not known. Therefore, the objectives of the study were to determine the effects of long term administration of fried whole egg hydrolysate and its fractions (i.e. egg white and egg yolk) on regulation of blood pressure and associated factors in cardiovascular disease such as plasma lipid profile and tissue oxidative stress. METHODS AND RESULTS: We used spontaneously hypertensive rats (SHR), an animal model of essential hypertension. Hydrolysates of fried egg and its fractions were prepared by simulated gastro intestinal digestion with pepsin and pancreatin. 16-17 week old male SHRs were orally administered fried whole egg hydrolysate, non-hydrolyzed fried whole egg, egg white hydrolysate or egg yolk hydrolysates (either defatted, or not) daily for 18 days. Blood pressure (BP) and heart rate were monitored by telemetry. Animals were sacrificed at the end of the treatment for vascular function studies and evaluating plasma lipid profile and tissue oxidative stress. BP was reduced by feeding fried whole egg hydrolysate but not by the non-hydrolyzed product suggesting a critical role for in vitro digestion in releasing anti-hypertensive peptides. Egg white hydrolysate and defatted egg yolk hydrolysate (but not egg yolk hydrolysate) also had similar effects. Reduction in BP was accompanied by the restoration of nitric oxide (NO) dependent vasorelaxation and reduction of plasma angiotensin II. Fried whole egg hydrolysate also reduced plasma levels of triglyceride although it was increased by the non-hydrolyzed sample. Additionally the hydrolyzed preparations attenuated tissue oxidative stress. CONCLUSION: Our results demonstrate that fried egg hydrolysates exert anti-hypertensive effects, improve plasma lipid profile and attenuate tissue oxidative stress in vivo. PMID- 25502446 TI - Dacarbazine combined targeted therapy versus dacarbazine alone in patients with malignant melanoma: a meta-analysis. AB - BACKGROUND: Malignant melanoma is the most aggressive and deadly form of skin cancer. Dacarbazine (DTIC) has been the approved first-line treatment for metastatic melanoma in routine clinical practice. However, response rates with single-agent DTIC are low. The objective of this study was to compare the efficacy and safety of DTIC with or without placebo and DTIC-based combination therapies in patients with advanced metastatic melanoma. METHODS: We searched from electronic databases such as The Cochrane Library, MEDLINE, EBSCO, EMBASE, Ovid, CNKI, and CBMDisc from 2003 to 2013. The primary outcome measures were overall response and 1-year survival, and the secondary outcome measurements were adverse events. RESULTS: Nine randomized controlled trials (RCTs) involving 2,481 patients were included in the meta-analysis. DTIC-based combination therapies was superior to DTIC alone in overall response (combined risk ratio [RR] = 1.60, 95% confidence interval [CI]: 1.27-2.01) and 1-year survival (combined RR = 1.26, 95% CI: 1.14-1.39). Patients with DTIC-based combination therapies had higher incidence of adverse events including nausea (combined RR = 1.23, 95% CI: 1.10 1.36), vomiting (combined RR = 1.73, 95% CI: 1.41-2.12) and neutropenia (combined RR = 1.75, 95% CI: 1.42-2.16) compared to the group for DTIC alone. CONCLUSION: These data suggested that DTIC-based combination therapies could moderately improve the overall response and the 1-year survival but increased the incidence of adverse events. Further large-scale, high-quality, placebo-controlled, double blind trials are needed to confirm this conclusion. PMID- 25502447 TI - Dose escalation and pharmacokinetic study of carboplatin plus pemetrexed for elderly patients with advanced nonsquamous non-small-cell lung cancer: Kumamoto thoracic oncology study group trial 1002. AB - OBJECTIVES: This study was designed to determine the recommended dose of carboplatin and pemetrexed for elderly (>=70-year-old) chemotherapy-naive patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) and to investigate the pharmacokinetics of pemetrexed. METHODS: The patients were treated with 4-6 cycles of carboplatin plus a fixed dose of pemetrexed (500 mg/m(2)) every 3 weeks; the dose of carboplatin was escalated [from area under the curve (AUC) 4 to AUC 6]. To examine the pharmacokinetics of pemetrexed, blood samples were collected before and after pemetrexed infusion, and the blood levels of pemetrexed were measured by liquid chromatography-mass spectrometry. RESULTS: Grade 3 infection as a dose-limiting toxicity was observed at a carboplatin dose of AUC 6. We therefore determined a carboplatin dose of AUC 5 and a pemetrexed dose of 500 mg/m(2) as the recommended doses from this study. The pharmacokinetic study showed a significant inverse correlation between the AUC of pemetrexed and the creatinine clearance. CONCLUSIONS: For elderly chemotherapy-naive patients with advanced nonsquamous NSCLC, the combination of carboplatin AUC 5 plus pemetrexed 500 mg/m(2) is recommended as a promising regimen; however, a reduction of the pemetrexed dose may be required for patients with renal dysfunction because of the high risk of hematotoxicities. PMID- 25502448 TI - The role of species traits in mediating functional recovery during matrix restoration. AB - Reversing anthropogenic impacts on habitat structure is frequently successful through restoration, but the mechanisms linking habitat change, community reassembly and recovery of ecosystem functioning remain unknown. We test for the influence of edge effects and matrix habitat restoration on the reassembly of dung beetle communities and consequent recovery of dung removal rates across tropical forest edges. Using path modelling, we disentangle the relative importance of community-weighted trait means and functional trait dispersion from total biomass effects on rates of dung removal. Community trait composition and biomass of dung beetle communities responded divergently to edge effects and matrix habitat restoration, yielding opposing effects on dung removal. However, functional dispersion--used in this study as a measure of niche complementarity- did not explain a significant amount of variation in dung removal rates across habitat edges. Instead, we demonstrate that the path to functional recovery of these altered ecosystems depends on the trait-mean composition of reassembling communities, over and above purely biomass-dependent processes that would be expected under neutral theory. These results suggest that any ability to manage functional recovery of ecosystems during habitat restoration will demand knowledge of species' roles in ecosystem processes. PMID- 25502449 TI - Topical review: a comprehensive risk model for disordered eating in youth with type 1 diabetes. AB - OBJECTIVES: Provide an updated literature review on prevalence, measurement, and correlates of disordered eating in youth with Type 1 diabetes (T1D), present a novel theoretical risk model (i.e., The Modified Dual Pathway Model) for disordered eating in youth with T1D incorporating psychosocial and physiological risk factors, and discuss clinical implications. METHODS: Literature review of prevalence, correlates, risk factors, and outcomes of disordered eating behavior (DEB) in youth with T1D. RESULTS: Insulin treatment, subsequent weight gain, and disruptions to hunger and satiety regulation are hypothesized disease-related mechanisms through which the treatment of T1D may increase vulnerability to development of behavior characterized as DEB. The Modified Dual Pathway Model integrates these factors with a validated psychosocial risk (body dissatisfaction, depression, and abstinence violation) model for DEB in nondiabetic youth. CONCLUSIONS: The Modified Dual Pathway model of DEB in youth with T1D is a comprehensive representation of both psychosocial and T1D-related risk factors with the potential to inform future interventions for this population. PMID- 25502451 TI - Cochlear implantation for patients with single-sided deafness or asymmetrical hearing loss: a systematic review of the evidence. AB - OBJECTIVE: A systematic review of the literature to evaluate the clinical outcome of cochlear implantation for patients with single-sided deafness (SSD) or asymmetrical hearing loss (AHL). DATA SOURCES: We searched the PubMed, Embase, Cochrane Library, and CINAHL databases from their inception up to December 10, 2013 for SSD or AHL and cochlear implantation or their synonyms. STUDY SELECTION: In total, 781 articles were retrieved, of which 15 satisfied the eligibility criteria. Our outcomes of interest were speech perception in noise, sound localization, quality of life (QoL), and tinnitus. DATA EXTRACTION: Critical appraisal showed that six studies reported on less than five patients or that they carried a low directness of evidence or a high risk of bias. Therefore, we extracted the data of nine studies (n = 112). Patient numbers, age, duration of deafness, classification of deafness, pure tone audiometry, follow-up duration, and outcome measurements were extracted from all nine articles. DATA SYNTHESIS: Because of large heterogeneity between studies, we were not able to pool data in a meta-analysis. We therefore summarized the results of the studies specified per outcome. CONCLUSION: There are no high-level-of-evidence studies concerning cochlear implantation in patients with SSD or AHL. Current literature suggests important benefits of cochlear implantation regarding sound localization, QoL, and tinnitus. Varying results were reported for speech perception in noise, possibly caused by the large clinical heterogeneity between studies. Larger and high-quality studies are certainly warranted. PMID- 25502452 TI - Patients with Vestibular Loss, Tullio Phenomenon, and Pressure-induced Nystagmus: Vestibular Atelectasis? PMID- 25502453 TI - Comparison of the gaze stabilization test and the dynamic visual acuity test in unilateral vestibular loss patients and controls. AB - OBJECTIVE: Compare the dynamic visual acuity test (DVAT) and gaze stabilization test (GST) in patients with unilateral vestibular loss (UVL) and healthy control subjects using a novel computerized testing system prototype. STUDY DESIGN: Cross sectional study. SETTING: Tertiary academic referral laboratory. PATIENTS: Seventeen UVL patients (median age 62 yr) with bithermal caloric asymmetry (>=49%) or ablative surgery and 17 control subjects (median age 57 yr). INTERVENTION(S): Diagnostic. MAIN OUTCOME MEASURE(S): Comparison of DVAT and GST results during self-generated sinusoidal head movements using transient unpredictable target presentations less than 95 milliseconds in duration. RESULTS: UVL patients had significantly higher DVAT scores toward the lesioned side compared with controls (p = 0.001) and the non-lesioned side (p = 0.003), but the non-lesioned side was not significantly different from controls (p = 0.157). When comparing GST scores, UVL patients required a slower head velocity to maintain visual acuity with movement toward the lesioned side compared with controls (p < 0.001) and the non-lesioned side (p = 0.004). In addition, UVL patients had significantly lower scores toward the non-lesioned side (p = 0.002) compared to controls. ROC curve analysis identified optimal thresholds for abnormal test results to discriminate the lesioned side from controls. A DVAT score greater than or equal to 0.3 DeltalogMAR provided 65% sensitivity and 88% specificity while a GST score less than or equal to 95 degrees/s provided 71% sensitivity and 100% specificity. When GST results were normal, adding DVAT increased overall sensitivity to 88% with 88% specificity. CONCLUSIONS: Both GST and DVAT demonstrated reduced gaze stabilization toward the lesioned side in the patient group compared with normal controls. Performing GST first and utilizing DVAT when GST was normal provides optimal identification of patients with vestibular dysfunction. PMID- 25502454 TI - Cochlear implantation requiring a retrofacial approach to the round window. AB - OBJECTIVE: To describe three cases of cochlear implantation utilizing a retrofacial approach to the round window. STUDY DESIGN: Retrospective case review. PATIENTS: Three patients with sensorineural hearing loss undergoing cochlear implantation. INTERVENTIONS: Cochlear implantation via a retrofacial approach to the round window. RESULTS: Three patients were noted to have inadequate visualization of the round window using a standard posterior tympanotomy at the time of their cochlear implant surgery. A retrofacial approach was performed to provide exposure of the round window to ensure correct placement of the electrode array. Intraoperative photos and postoperative imaging are demonstrated. CONCLUSION: When a laterally or anteriorly positioned facial nerve obscures visualization of the round window, a retrofacial approach is a possible route to visualize the round window. PMID- 25502450 TI - Inflammation in sleep apnea: an update. AB - Obstructive sleep apnea (OSA) is a common disorder associated with cardiovascular disease (CVD). One theory to explain this relationship proposes that OSA can induce systemic inflammation, thereby inducing CVD. This theory is based on the premise that obesity is a pro-inflammatory state, and that physiological derangements during sleep in subjects with OSA further aggravate inflammation. In support of this theory, some clinical studies have shown elevated inflammatory biomarkers in OSA subjects, or improvement in these markers following treatment of OSA. However, the data are inconsistent and often confounded by the effects of comorbid obesity. Animal models of OSA have been developed, which involve exposure of rodents or cells to intermittent hypoxia, a hallmark feature of OSA. Several of these experiments demonstrate that intermittent hypoxia can stimulate inflammatory pathways and lead to cardiovascular or metabolic pathology. In this review, we review relationships between OSA and inflammation, with particular attention to studies published within the last year. PMID- 25502455 TI - Effect of hearing loss, age, and gender on the outcome of the cochlear hydrops analysis masking procedure. AB - OBJECTIVE: The aims of the study are to investigate the effect of hearing loss, age, and gender on the outcome of the cochlear hydrops analysis masking procedure (CHAMP) and to assess the clinical utility of CHAMP for the diagnosis of Meniere's disease (MD). STUDY DESIGN: Prospective observational study. SETTING: Otolaryngology department of a tertiary referral hospital. PATIENTS: We recruited MD patients (MD, 12 subjects) and hearing loss patients (HL, 10 subjects). Control subjects (NC, 43 subjects) were matched for gender and age. INTERVENTION: CHAMP was performed in the patients and control subjects. MAIN OUTCOME MEASURE: The mean difference in latency between the wave V for the click alone response and wave V for the 0.5-kHz high-pass masking noise condition was compared among groups, and the effects of gender and age on the results were analyzed in the NC group. RESULTS: Both the MD group and the HL group had a smaller difference in latency compared to the NC group. The MD group and HL group showed no significant difference in latency. In the NC group, there were no significant differences in latency depending on gender and age. CONCLUSIONS: Hearing level seems to significantly affect the CHAMP results, making it unreliable to differentiate between MD patients and non-MD hearing loss patients. Therefore, the diagnostic value of CHAMP might be limited in MD. PMID- 25502456 TI - An ER clamp for endosome fission. AB - Endosomes are known to undergo budding and fission reactions that separate regions destined for lysosomal degradation from carriers to be recycled to the plasma membrane. A recent paper (Rowland et al, 2014) shows that contact sites between endosomes and the endoplasmic reticulum (ER) define the position and timing for fission. This uncovers an unanticipated role for the ER in controlling endosomal sorting and maturation. PMID- 25502457 TI - Bacteriophage exclusion, a new defense system. AB - The ability to withstand viral predation is critical for survival of most microbes. Accordingly, a plethora of phage resistance systems has been identified in bacterial genomes (Labrie et al, 2010), including restriction-modification systems (R-M) (Tock & Dryden, 2005), abortive infection (Abi) (Chopin et al, 2005), Argonaute-based interference (Swarts et al, 2014), as well as clustered regularly interspaced short palindromic repeats (CRISPR) and associated protein (Cas) adaptive immune system (CRISPR-Cas) (Barrangou & Marraffini, 2014; Van der Oost et al, 2014). Predictably, the dark matter of bacterial genomes contains a wealth of genetic gold. A study published in this issue of The EMBO Journal by Goldfarb et al (2015) unveils bacteriophage exclusion (BREX) as a novel, widespread bacteriophage resistance system that provides innate immunity against virulent and temperate phage in bacteria. PMID- 25502459 TI - Erratum to: Functional Characteristics and Molecular Mechanism of a New scFv Antibody Against Abeta42 Oligomers and Immature Protofibrils. PMID- 25502461 TI - Transient Receptor Potential Vanilloid 4-Induced Modulation of Voltage-Gated Sodium Channels in Hippocampal Neurons. AB - Transient receptor potential vanilloid 4 (TRPV4) is reported to control the resting membrane potential and increase excitability in many types of cells. Voltage-gated sodium channels (VGSCs) play an important role in initiating action potentials in neurons. However, whether VGSCs can be modulated by the activation of TRPV4 in hippocampal pyramidal neurons remains unknown. In this study, we tested the effect of TRPV4 agonists (GSK1016790A and 4alpha-PDD) on voltage-gated sodium current (I Na) in hippocampal CA1 pyramidal neurons and the protein levels of alpha/beta-subunit of VGSCs in the hippocampus of mice subjected to intracerebroventricular (icv.) injection of GSK1016790A (GSK-injected mice). Herein, we report that I Na was inhibited by acute application of GSK1016790A or 4alpha-PDD. In the presence of TRPV4 agonists, the voltage-dependent inactivation curve shifted to the hyperpolarization, whereas the voltage-dependent activation curve remained unchanged. The TRPV4 agonist-induced inhibition of I Na was blocked by the TRPV4 antagonist or tetrodotoxin. Moreover, blocking protein kinase A (PKA) markedly attenuated the GSK1016790A-induced inhibition of I Na, whereas antagonism of protein kinase C or p38 mitogen-activated protein kinase did not change GSK1016790A action. Finally, the protein levels of Nav1.1, Nav1.2, and Nav1.6 in the hippocampus increased in GSK-injected mice, whereas those of Nav1.3 and Navbeta1 remained nearly unchanged. We conclude that I Na is inhibited by the acute activation of TRPV4 through PKA signaling pathway in hippocampal pyramidal neurons, but protein expression of alpha-subunit of VGSCs is increased by sustained TRPV4 activation, which may compensate for the acute inhibition of I Na and provide a possibility for hyper-excitability upon sustained TRPV4 activation. PMID- 25502460 TI - Chromosomal Instability and Phosphoinositide Pathway Gene Signatures in Glioblastoma Multiforme. AB - Structural rearrangements of chromosome 10 are frequently observed in glioblastoma multiforme and over 80 % of tumour samples archived in the catalogue of somatic mutations in cancer database had gene copy number loss for PI4K2A which encodes phosphatidylinositol 4-kinase type IIalpha. PI4K2A loss of heterozygosity mirrored that of PTEN, another enzyme that regulates phosphoinositide levels and also PIK3AP1, MINPP1, INPP5A and INPP5F. These results indicated a reduction in copy number for a set of phosphoinositide signalling genes that co-localise to chromosome 10q. This analysis was extended to a panel of phosphoinositide pathway genes on other chromosomes and revealed a number of previously unreported associations with glioblastoma multiforme. Of particular note were highly penetrant copy number losses for a group of X-linked phosphoinositide phosphatase genes OCRL, MTM1 and MTMR8; copy number amplifications for the chromosome 19 genes PIP5K1C, AKT2 and PIK3R2, and also for the phospholipase C genes PLCB1, PLCB4 and PLCG1 on chromosome 20. These mutations are likely to affect signalling and trafficking functions dependent on the PI(4,5)P2, PI(3,4,5)P3 and PI(3,5)P2 lipids as well as the inositol phosphates IP3, IP5 and IP6. Analysis of flanking genes with functionally unrelated products indicated that chromosomal instability as opposed to a phosphoinositide-specific process underlay this pattern of copy number variation. This in silico study suggests that in glioblastoma multiforme, karyotypic changes have the potential to cause multiple abnormalities in sets of genes involved in phosphoinositide metabolism and this may be important for understanding drug resistance and phosphoinositide pathway redundancy in the advanced disease state. PMID- 25502462 TI - Ursodeoxycholic Acid Ameliorates Apoptotic Cascade in the Rotenone Model of Parkinson's Disease: Modulation of Mitochondrial Perturbations. AB - The recent emergence of ursodeoxycholic acid (UDCA) as a contender in modifying neurotoxicity in human dopaminergic cells as well as its recognized anti apoptotic and anti-inflammatory potentials in various hepatic pathologies raised impetus in investigating its anti-parkinsonian effect in rat rotenone model. UDCA prominently improved motor performance in the open field test and halted the decline in the striatal dopamine content. Meanwhile, it improved mitochondrial function as verified by elevation of ATP associated with preservation of mitochondrial integrity as portrayed in the electron microscope examination. In addition, through its anti-inflammatory potential, UDCA reduced the rotenone induced nuclear factor-kappaB expression and tumor necrosis factor alpha level. Furthermore, UDCA amended alterations in Bax and Bcl-2 and reduced the activities of caspase-8, caspase-9, and caspase-3, indicating that it suppressed rotenone induced apoptosis via modulating both intrinsic and extrinsic pathways. In conclusion, UDCA can be introduced as a novel approach for the management of Parkinson's disease via anti-apoptotic and anti-inflammatory mechanisms. These effects are probably linked to dopamine synthesis and mitochondrial regulation. PMID- 25502463 TI - Inhibitor of Differentiation-1 and Hypoxia-Inducible Factor-1 Mediate Sonic Hedgehog Induction by Amyloid Beta-Peptide in Rat Cortical Neurons. AB - One major pathological hallmark of Alzheimer's disease (AD) is the accumulation of senile plaques mainly composed of neurotoxic amyloid beta-peptide (Abeta) in the patients' brains. Sonic hedgehog (SHH) is a morphogen critically involved in the embryonic development of the central nervous system (CNS). In the present study, we tested whether Abeta may induce SHH expression and explored its underlying mechanisms. We found that both Abeta25-35 and Abeta1-42 enhanced SHH expression in the primary cortical neurons derived from fetal rat brains. Immunohistochemistry revealed heightened expression of SHH in the cortex and hippocampus of aged (9 and 12 months old) AD transgenic mouse brains as compared to age-matched littermate controls. Chromatin immunoprecipitation (ChIP) assay demonstrated that Abeta25-35 enhanced binding of hypoxia-inducible factor-1 (HIF 1) to the promoter of the Shh gene in primary cortical cultures; consistently, Abeta25-35 induction of SHH was abolished by HIF-1alpha small interfering RNA (siRNA). Abeta25-35 also time-dependently induced inhibitor of differentiation-1 (Id1) that has been shown to stabilize HIF-1alpha; further, Abeta25-35-mediated induction of HIF-1alpha and SHH was both suppressed by Id1 siRNA. Pharmacological induction of HIF-1alpha by cobalt chloride and application of the cell-permeable recombinant Id1 proteins were both sufficient to induce SHH expression. Finally, both the SHH pathway inhibitor cyclopamine and its neutralizing antibody attenuated Abeta cytotoxicity, albeit to a minor extent. These results thus established a signaling cascade of "Abeta -> Id1 -> HIF-1 -> SHH" in primary rat cortical cultures; furthermore, SHH may in part contribute to Abeta neurotoxicity. PMID- 25502464 TI - Identification of a Premature Termination Mutation in the Proline-Rich Transmembrane Protein 2 Gene in a Chinese Family with Febrile Seizures. AB - Febrile seizures (FS), the most frequent type of seizures in children, occur in neurologically normal infants and children between the ages of 3 months and 5 years with genetic predisposition. The aim of this study was to identify the responsible gene in a four-generation Chinese Han pedigree with autosomal dominant FS. Seven family members (three affected and four unaffected) were enrolled in this study. Exome sequencing was conducted and a duplication mutation c.649dupC (p.R217Pfs*8) in the proline-rich transmembrane protein 2 gene (PRRT2) was identified. The mutation co-segregated with the disorder and was absent in normal controls. To our knowledge, this is the first report of a pedigree with complete penetrance of FS, which is caused by mutation in the PRRT2 gene. FS is a novel phenotype of the c.649dupC (p.R217Pfs*8) mutation. Our discovery broadens the spectrum of genetic causes of FS and the spectrum of phenotypes linked to mutation in the PRRT2 gene. PMID- 25502458 TI - TRPC Channels: Prominent Candidates of Underlying Mechanism in Neuropsychiatric Diseases. AB - Alterations in intracellular Ca(2+) concentration ([Ca(2+)]i) play a crucial role in fundamental cellular events from transcriptional regulation to migration and proliferation. The transient receptor potential (TRP) channels contribute to changes in [Ca(2+)]i by providing or modulating Ca(2+) entry pathways, as well as by releasing Ca(2+) from intracellular stores. On the basis of sequence homology, the TRP family can be divided into seven subfamilies: the TRPC ("canonical") family, the TRPV ("vanilloid") family, the TRPM ("melastatin") family, the TRPP ("polycystin") family, the TRPML ("mucolipin") family, the TRPA ("ankyrin") family, and the TRPN ("NOMPC") family. In this review, we focus on the physiology and pathophysiology of mammalian TRPC channels in the nervous system. Seven mammalian TRPC proteins (TRPC1-7) have been described and are widely distributed in the brain from early embryonic days till adulthood, with the exception of TRPC2. TRPC channels are nonselective Ca(2+)-permeable channels, which can be activated by G-protein-coupled receptors and receptor tyrosine kinases. These channels have been reported to act as essential cellular sensors in multiple processes during neuronal development, including neural stem cell proliferation and differentiation, neuronal survival, neurite outgrowth and axon path finding, and synaptogenesis. Not surprisingly, studies on these channels also provide new insights into underlying mechanisms of various neuropsychiatric disorders. The present review summarizes the expressions of all TRPC subtypes in different brain regions and different neural cell types, aiming to serve as a useful reference for future studies in this field. We also discuss the most updated evidence implicating involvement of TRPC channels in the generation of pathophysiological states in nervous system and their potentials as being promising targets for drug development. PMID- 25502467 TI - Protein-DNA interactions: a novel approach to improve the fluorescence stability of DNA/Ag nanoclusters. AB - Protein-DNA interactions are known to play an important role in a variety of biological processes. We have shown here that protein-DNA binding events can also be used to greatly improve the fluorescence stability of DNA-templated Ag nanoclusters (Ag NCs), which would be highly beneficial for Ag NCs in applications of biosensing/imaging. PMID- 25502466 TI - Stress effects on mood, HPA axis, and autonomic response: comparison of three psychosocial stress paradigms. AB - Extensive experimental psychology research has attempted to parse the complex relationship between psychosocial stress, mood, cognitive performance, and physiological changes. To do so, it is necessary to have effective, validated methods to experimentally induce psychosocial stress. The Trier Social Stress Test (TSST) is the most commonly used method of experimentally inducing psychosocial stress, but it is resource intensive. Less resource intense psychosocial stress tasks include the Socially Evaluative Cold Pressor Task (SECPT) and a computerized mental arithmetic task (MAT). These tasks effectively produce a physiological and psychological stress response and have the benefits of requiring fewer experimenters and affording data collection from multiple participants simultaneously. The objective of this study was to compare the magnitude and duration of these three experimental psychosocial stress induction paradigms. On each of four separate days, participants completed either a control non-stressful task or one of the three experimental stressors: the TSST, SECPT, or MAT. We measured mood, working memory performance, salivary cortisol and alpha amylase (AA), and heart rate. The TSST and SECPT exerted the most robust effects on mood and physiological measures. TSST effects were generally evident immediately post-stress as well as 10- and 20-minutes after stress cessation, whereas SECPT effects were generally limited to the duration of the stressor. The stress duration is a key determinant when planning a study that utilizes an experimental stressor, as researchers may be interested in collecting dependent measures prior to stress cessation. In this way, the TSST would allow the investigator a longer window to administer tasks of interest. PMID- 25502468 TI - Role of gamma-delta (gammadelta) T cells in autoimmunity. AB - gammadelta T cells represent a small population of overall T lymphocytes (0.5-5%) and have variable tissue distribution in the body. gammadelta T cells can perform complex functions, such as immune surveillance, immunoregulation, and effector function, without undergoing clonal expansion. Heterogeneous distribution and anatomic localization of gammadelta T cells in the normal and inflamed tissues play an important role in alloimmunity, autoimmunity, or immunity. The cross-talk between gammadelta T cells and other immune cells and phenotypic and functional plasticity of gammadelta T cells have been given recent attention in the field of immunology. In this review, we discussed the cellular and molecular interaction of gammadelta T cells with other immune cells and its mechanism in the pathogenesis of various autoimmune diseases. PMID- 25502469 TI - Reply to Letter: "A Randomized Study on 1-Week Versus 4-Week Prophylaxis for Venous Thromboembolism After Laparoscopic Surgery for Colorectal Cancer". PMID- 25502465 TI - Exosomes as a Nanodelivery System: a Key to the Future of Neuromedicine? AB - Since the beginning of the last decade, exosomes have been of increased interest in the science community. Exosomes represent a new kind of long distance transfer of biological molecules among cells. This review provides a comprehensive overview about the construction of exosomes, their targeting and their fusion mechanisms to the recipient cells. Complementarily, the current state of research regarding the cargo of exosomes is discussed. A particular focus was placed on the role of exosomes in the central nervous system. An increasing number of physiological processes in the brain could be associated with exosomes. In this context, it is becoming more apparent that exosomes are involved in several neurological and specifically neurodegenerative diseases. The treatment of these kinds of diseases is often difficult not least because of the blood-brain barrier. Exosomes are very stable, can pass the blood-brain barrier and, therefore, reveal bright perspectives towards diagnosis and therapeutic treatments. A prerequisite for clinical applications is a standardised approach. Features necessary for a standardised diagnosis using exosomes are discussed. In therapeutic terms, exosomes represent a promising drug delivery system able to pass the blood-brain barrier. One option to overcome the disadvantages potentially associated with the use of endogenous exosomes is the design of artificial exosomes. The artificial exosomes with a clearly defined therapeutic active cargo and surface marker ensuring the specific targeting to the recipient cells is proposed as a promising approach. PMID- 25502470 TI - Optically transparent polymer devices for in situ assessment of cell electroporation. AB - In order to study cell electroporation in situ, polymer devices have been fabricated from poly-dimethyl siloxane with transparent indium tin oxide parallel plate electrodes in horizontal geometry. This geometry with cells located on a single focal plane at the interface of the bottom electrode allows a longer observation time in both transmitted bright-field and reflected fluorescence microscopy modes. Using propidium iodide (PI) as a marker dye, the number of electroporated cells in a typical culture volume of 10-100 MUl was quantified in situ as a function of applied voltage from 10 to 90 V in a series of ~2-ms pulses across 0.5-mm electrode spacing. The electric field at the interface and device current was calculated using a model that takes into account bulk screening of the transient pulse. The voltage dependence of the number of electroporated cells could be explained using a stochastic model for the electroporation kinetics, and the free energy for pore formation was found to be 45.6 +/- 0.5 kT at room temperature. With this device, the optimum electroporation conditions can be quickly determined by monitoring the uptake of PI marker dye in situ under the application of millisecond voltage pulses. The electroporation efficiency was also quantified using an ex situ fluorescence-assisted cell sorter, and the morphology of cultured cells was evaluated after the pulsing experiment. Importantly, the efficacy of the developed device was tested independently using two cell lines (C2C12 mouse myoblast cells and yeast cells) as well as in three different electroporation buffers (phosphate buffer saline, electroporation buffer and 10% glycerol). PMID- 25502471 TI - Circumspectives: the promise of ketamine. PMID- 25502472 TI - Intra-Hippocampal Transplantation of Neural Precursor Cells with Transgenic Over Expression of IL-1 Receptor Antagonist Rescues Memory and Neurogenesis Impairments in an Alzheimer's Disease Model. PMID- 25502473 TI - Brain transient receptor potential channels and stroke. AB - Transient receptor potential (TRP) channels have been increasingly implicated in the pathological mechanisms of CNS disorders. TRP expression has been detected in neurons, astrocytes, oligodendrocytes, microglia, and ependymal cells as well as in the cerebral vascular endothelium and smooth muscle. In stroke, TRPC3/4/6, TRPM2/4/7, and TRPV1/3/4 channels have been found to participate in ischemia induced cell death, whereas other TRP channels, in particular those expressed in nonneuronal cells, have been less well studied. This review summarizes the current knowledge on the expression and functions of the TRP channels in various cell types in the brain and our current understanding of TRP channels in stroke pathophysiology. In an aging society, the occurrence of stroke is expected to increase steadily, and there is an urgent requirement to improve the current stroke management strategy. Therefore, elucidating the roles of TRP channels in stroke could shed light on the development of novel therapeutic strategies and ultimately improve stroke outcome. PMID- 25502474 TI - Plasmon-induced transparency in coupled triangle-rod arrays. AB - We demonstrate polarization-dependent plasmon-induced transparency in coupled triangle-rod arrays. The observed phenomenon is the result of the destructive interference between the bright and dark resonators in this coupled system, which is verified through the numerical simulations using the finite-difference time domain (FDTD) method. By precisely controlling the structural parameters of the coupled triangle-rod system, the plasmon-induced transparency can be effectively manipulated. This plasmonically coupled nanostructure could be potentially useful for designing and developing artificial plasmonic molecules and metamaterials with desired functions, which may further find promising applications in biosensing, nanoparticle trapping and optical filters. PMID- 25502475 TI - Single injection of platelet-rich plasma (PRP) for the treatment of refractory distal biceps tendonitis: long-term results of a prospective multicenter cohort study. AB - PURPOSE: There is a lack of evidence regarding the use of PRP in the treatment of distal biceps tendonitis. The purpose of this study was to assess the effectiveness of ultrasound (US)-guided injection of PRP in relieving pain and functional impairment in the treatment of refractory distal biceps tendonitis. METHODS: Twelve patients from two large tertiary referral hospitals were recruited over a period of 20 months. Clinical diagnosis of distal biceps tendonitis was confirmed using magnetic resonance imaging. All patients had a single US-guided injection of PRP carried out by the two senior authors. Patients were objectively assessed for clinical and functional improvement using visual analogue (VAS) rest and activity pain scores, subjective satisfaction scale, elbow functional assessment (EFA) and isometric muscular (biceps) strength. Symptom severity and subsequent functional outcome were measured pre-injection and at final follow-up. RESULTS: At a median follow-up of 47 months (36-52 months), all patients showed significant improvement in pain (p < 0.002) and functional outcome (p < 0.004). Median resting VAS score improved from 6 (3-8) to 0.5 (0-2) and the activity VAS score improved from 8 (6-9) to 2.5 (0-4). EFA improved from 63 to 90. In the English cases, isometric muscular strength also showed significant improvement. All patients were satisfied with the clinical and functional outcomes at final follow-up. CONCLUSION: US-guided PRP injection seems to be an effective treatment modality for symptomatic refractory distal biceps tendonitis. LEVEL OF EVIDENCE: III. PMID- 25502476 TI - A case of asymptomatic bilateral massive pulmonary embolism after arthroscopic multiple knee ligament reconstruction. AB - Venous thromboembolism, which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), is a serious complication after operations involving the lower extremities, and it can be fatal. However, few reports have described the incidence of PE and its associated risk factors after arthroscopic knee surgery. We present a case of bilateral massive PE of the main pulmonary arteries and DVT detected on multi-detector row computed tomography after arthroscopic multiple knee ligament reconstruction. Our patient was asymptomatic despite having several risk factors for thromboembolic events (43 years of age, a long operation time, obesity, and diabetes mellitus) and receiving no pharmacologic thromboembolic prophylaxis. Although fatality due to PE is relatively uncommon, when a patient has several risk factors for PE, perioperative thromboprophylaxis should be considered. Level of evidence IV. PMID- 25502478 TI - Increased risk of periprosthetic femur fractures associated with a unique cementless stem design. AB - BACKGROUND: Postoperative periprosthetic femur fractures are an increasing concern after primary total hip arthroplasty (THA). Identifying and understanding predisposing factors are important to mitigating future risk. Femoral stem design may be one such factor. QUESTIONS/PURPOSES: The goals of our study were to compare the (1) frequency of periprosthetic femur fracture and implant survivorship; (2) time to fracture in those patients who experienced periprosthetic femur fracture; and (3) predictive risk factors for periprosthetic femur fracture between a unique stem design with an exaggerated proximal taper angle and other contemporary cementless, proximally fixed, tapered stems. METHODS: We reviewed all hips in which a femoral hip component with a uniquely exaggerated proximal taper angle (ProxiLock) was implanted during primary THA at a single academic institution. That group of patients was compared with a cohort of patients who underwent primary THA during the same time interval (1995-2008) in which any other cementless, proximally fixed, tapered stem design was used. The two groups differed somewhat in terms of sex, age, and body mass index, although these differences were of unclear clinical significance. During the study, 3964 primary THAs were performed using six different designs of cementless, proximally fixed, tapered femoral hip prostheses. There were 736 stems in the ProxiLock (PL) patient group and 3228 stems in the non-ProxiLock (non-PL) group. In general, the stem highlighted in this study became the routine cementless stem used for primary THA for three arthroplasty surgeons without specific patient or radiographic indications. Periprosthetic fractures were identified within each group. The incidence, timing, type, and treatment required for each fracture were analyzed. The Kaplan-Meier method was used to determine study patient survival free of any postoperative fracture. Radiographs and the electronic medical record of each patient who sustained a fracture were reviewed. Followup was comparable between groups at all time points. RESULTS: The Kaplan Meier estimate for fracture-free patient survival was worse in the PL group at all time points with survival of 98.4% (range, 97.4%-99.3%), 97.1% (range, 95.9% 98.3%), 95.4% (range, 93.8%-97.0%), and 92.6% (range, 89.6%-95.3%) at 30 days, 1 year, 5 years, and 10 years, respectively, for the PL patient group compared with 99.8% (range, 99.7%-99.9%), 99.6% (range, 99.3%-99.8%), 99.3% (range, 99.0% 99.6%), and 98.4% (range, 97.5%-99.1%) in the non-PL patient group (p < 0.001). Patients in the PL group had increased cumulative probability of both early and late fractures with cumulative probabilities of fracture of 2.5% (range, 1.3% 3.6%) at 90 days and 7.4% (range, 4.7%-10.4%) at 10 years compared with probabilities of 0.3% (range, 0.1%-0.5%) at 90 days and 1.6% (range, 0.8%-2.5%) at 10 years in the non-PL group (p < 0.001). Patients in the PL group had an increased risk of postoperative periprosthetic femur fracture (hazard ratio [HR], 5.6; 95% confidence interval [CI], 3.4-9.1; p < 0.001); fracture requiring reoperation (HR, 8.4; 95% CI, 4.4-15.9); p < 0.001); and fracture requiring stem revision (HR, 9.1; 95% CI, 4.5-18.5; p < 0.001). Age older than 60 years was also a risk factor for fracture (HR, 3.7; 95% CI, 2.1-6.4), but sex, body mass index, and preoperative diagnosis were not predictive. CONCLUSIONS: Hips implanted with an uncemented femoral stem, which has a uniquely exaggerated proximal taper angle, had an increased risk of both early and late postoperative periprosthetic femur fracture. The majority of patients with a fracture underwent reoperation or stem revision. The unique proximal geometry, lack of axial support from the smooth cylindrical distal stem as well as resorption of the hydroxyapatite coating and poor ongrowth with subsequent subsidence may contribute to increased risk of fracture. Although this particular stem has recently been discontinued by the manufacturer, these findings are important in regard to followup care for patients with this stem implanted as well as for future cementless stem design in general. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25502477 TI - Decision-making in massive rotator cuff tear. AB - Treatment of massive rotator cuff tears has developed over many years ranging from conservative treatment to open and arthroscopic repair, muscle transfers and reversed arthroplasty. The evolution of more advanced techniques in arthroscopic repair has changed the treatment approach and improved the prognosis for functional outcome despite low healing rates. Due to this rapid development, our evidence-based knowledge today is mainly founded in Level 3 and Level 4 studies. Based on the literature, the current knowledge on treatment of symptomatic massive rotator cuff tears is proposed in an algorithm. Level of evidence V. PMID- 25502479 TI - Modified Dunn Procedure is Superior to In Situ Pinning for Short-term Clinical and Radiographic Improvement in Severe Stable SCFE. AB - BACKGROUND: In situ pinning is the conventional treatment for a stable slipped capital femoral epiphysis (SCFE). However, with a severe stable SCFE the residual deformity may lead to femoroacetabular impingement and articular cartilage damage. A modified Dunn subcapital realignment procedure has been developed to allow for correction at the level of the deformity while preserving the blood supply to the femoral head. QUESTIONS/PURPOSES: We compared children with severe stable SCFE treated with the modified Dunn procedure or in situ pinning in terms of (1) proximal femoral radiographic deformity; (2) Heyman and Herndon clinical outcome; (3) complication rate; and (4) number of reoperations performed after the initial procedure. METHODS: In this nonmatched retrospective study, 15 patients treated with the modified Dunn procedure (between 2007 and 2012) and 15 treated with in situ pinning (between 2001 and 2009) for severe but stable SCFE were followed for a mean of 2.5 years (range, 1-6 years). During the period in question, the decision regarding which procedure to use was based on the on-call surgeon's discretion; six surgeons performed in situ pinning and three surgeons performed the modified Dunn procedure. A total of 15 other patients were treated for the same diagnosis during the study period but were lost to followup before 1 year; of those, 12 were in the in situ pinning group. Radiographs were reviewed to measure the AP and lateral alpha angles, femoral head-neck offset, and Southwick angle preoperatively and at the latest clinical visit. The Heyman and Herndon clinical outcome, complications, and subsequent hip surgeries were recorded. RESULTS: At latest followup, the median AP alpha angle (52 degrees , range 41 degrees -59 degrees versus 76 degrees , interquartile range [IQR]: 68 degrees -88 degrees ; p = 0.0017), median lateral alpha angle (44 degrees , IQR: 40 degrees -51 degrees versus 87 degrees , IQR: 74 degrees -96 degrees ; p < 0.001), median head-neck offset (7 mm, IQR: 5-9 mm versus -5, IQR: -11 to -4 mm; p < 0.001), and median Southwick angle (16 degrees , IQR: 6 degrees -23 degrees versus 58 degrees , IQR: 47 degrees -66 degrees ; p < 0.001) revealed better deformity correction with the modified Dunn procedure compared with in situ pinning. Nine patients had good or excellent results in the modified Dunn group compared with four of 15 in the in situ pinning group (p = 0.0343; odds ratio, 5.86; 95% CI, 1.13-40.43). With the numbers available, there were no differences in the numbers of complications in each group (five versus three complications in the in situ and modified Dunn groups, respectively; p = 0.66), but there were more reoperations in the in situ pinning group (three versus seven; p = 0.0230). CONCLUSIONS: The modified Dunn procedure results in better morphologic features of the femur, a higher rate of good and excellent Heyman and Herndon clinical outcome, a lower reoperation rate, and a similar occurrence of complications when compared with in situ pinning for treatment of severe stable SCFE. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25502481 TI - High liver fibrosis index FIB-4 is highly predictive of hepatocellular carcinoma in chronic hepatitis B carriers. AB - Screening for hepatocellular carcinoma (HCC) is clinically important given that its early detection has remarkable survival benefits. We investigated the possible role of FIB-4, a recently developed noninvasive marker for liver fibrosis based on routine laboratory tests, as a clinical indicator for predicting future HCC among hepatitis B surface antigen (HBsAg) carriers. Our retrospective cohort study involved 986 Korean HBsAg carriers 40 years of age or older who visited Seoul National University Hospital for a health checkup. National medical service claims data were used to determine HCC incidence. Median follow-up time was 5.4 years (interquartile range: 4.4 years). Adjusted for age, sex, body mass index, smoking, alcohol, and antiviral medication for hepatitis B, compared to subjects with FIB-4 <1.25, subjects with 1.7<= FIB-4 <2.4 showed an adjusted hazard ratio (aHR) of 4.57 (95% confidence interval [CI]: 1.50-13.92) and subjects with FIB-4 >=2.4 showed an aHR of 21.34 (95% CI: 7.73-58.92) for HCC incidence. FIB-4 was shown to have incremental predictive value to ultrasonographic liver cirrhosis for HCC incidence (C-index: 0.701 vs. 0.831; P = 0.001). FIB-4 was also better predictive of HCC incidence, compared to that of ultrasonographic liver cirrhosis (C-index: 0.775 vs. 0.701; P = 0.040). CONCLUSION: High FIB-4 is a highly predictive risk factor for HCC incidence among Korean HBsAg carriers. FIB-4 is a promising, easily applicable, and cost effective clinical tool in identifying a subpopulation of HBsAg carriers who are at heightened risk. Our study needs to be replicated in larger future studies on various ethnic groups; nonetheless, our study suggests that FIB-4 may play a valuable role in HCC screening among HBsAg carriers. PMID- 25502480 TI - Redox proteomics and physiological responses in Cistus albidus shrubs subjected to long-term summer drought followed by recovery. AB - MAIN CONCLUSION: The interaction between enzymatic and non-enzymatic antioxidants, endogenous levels of ABA and ABA-GE, the rapid recuperation of photosynthetic proteins under re-watering as well the high level of antioxidant proteins in previously drought-stressed plants under re-watering conditions, will contribute to drought resistance in plants subjected to a long-term drought stress under Mediterranean field conditions. This work provides an overview of the mechanisms of Cistus albidus acclimation to long-term summer drought followed by re-watering in Mediterranean field conditions. To better understand the molecular mechanisms of drought resistance in these plants, a proteomic study using 2-DE and MALDI-TOF/TOF MS/MS was performed on leaves from these shrubs. The analysis identified 57 differentially expressed proteins in water-stressed plants when contrasted to well watered. Water-stressed plants showed an increase, both qualitatively and quantitatively, in HSPs, and downregulation of photosynthesis and carbon metabolism enzymes. Under drought conditions, there was considerable upregulation of enzymes related to redox homeostasis, DHA reductase, Glyoxalase, SOD and isoflavone reductase. However, upregulation of catalase was not observed until after re-watering was carried out. Drought treatment caused an enhancement in antioxidant defense responses that can be modulated by ABA, and its catabolites, ABA-GE, as well as JA. Furthermore, quantification of protein carbonylation was shown to be a useful marker of the relationship between water and oxidative stress, and showed that there was only moderate oxidative stress in C. albidus plants subjected to water stress. After re-watering plants recovered although the levels of ABA-GE and antioxidant enzymes still remain higher than in well-watered plants. We expect that our results will provide new data on summer acclimation to drought stress in Mediterranean shrubs. PMID- 25502482 TI - Association of 49245A>G (rs868) polymorphism in the 3'UTR of donor TGFBR1 gene with course of hepatitis C following orthotopic liver transplantation. AB - BACKGROUND: Terminal hepatitis C is one of the leading indications for orthotopic liver transplantation (OLT). However, hepatitis C virus (HCV) reinfection occurs in almost all recipients and usually leads to progressive fibrosis and graft failure. Transforming growth factor-b (TGF-beta) plays a part in transplanted liver cirrhosis, but nothing is known about the possible role of genetic diversity of TGF-beta receptor system. Therefore, the aim of our study was to investigate whether genetic variation in 3' untranslated region (3'UTR) of TGF beta receptor type I (TGFBR1) gene is associated with recurrence and severity of hepatitis C and liver fibrosis following OLT in HCV-infected patients. MATERIAL AND METHODS: The study group included 95 chronic hepatitis C patients following OLT. The recipients and donors were genotyped for 49245A>G (rs868) and 51976G>A (rs334349) single nucleotide polymorphisms (SNP). RESULTS: Donor rs868 AA genotype was strongly associated with worse clinical course of recurrent hepatitis C. The rs868 AA group displayed more severe symptoms of hepatitis C during the follow-up and the fibrosis score in this group was significantly higher 3 years after OLT. CONCLUSIONS: Clinical course of hepatitis C after OLT may depend on donor rs868 SNP located in TGFBR1 3'UTR. PMID- 25502484 TI - Genetic overlap between antipsychotic response and susceptibility to schizophrenia. PMID- 25502485 TI - Occipital seizures and visual pseudohallucinations associated with the addition of bupropion to clozapine: a case report. PMID- 25502486 TI - As-needed use of cyproheptadine for treatment of selective serotonin reuptake inhibitor-related female anorgasmia. PMID- 25502483 TI - A systematic review of aspirin in primary prevention: is it time for a new approach? AB - BACKGROUND AND OBJECTIVES: While evidence in support of aspirin use in secondary prevention is well documented, the role of aspirin in primary prevention remains unclear. We conducted a systematic literature review to evaluate aspirin use in cardiovascular disease (CVD) and cancer primary prevention, and consider whether aspirin's role is set to become more clearly defined based on past and prospective studies. DATA SOURCES: Utilizing PubMed, the reviewers identified appropriate Medical Subject Headings (MeSH) terms to establish CVD-based studies, cancer-based studies, and studies on adherence. STUDY ELIGIBILITY CRITERIA: Date restrictions of May 31, 2008 to May 31, 2013 were applied to capture the most robust meta-analyses and randomized controlled trials. Websites of relevant EU and US scientific societies were used to identify the key guidelines for aspirin use in primary prevention of CVD, and ClinicalTrials.gov was used to establish future or ongoing trials. RESULTS: Evidence in support of aspirin prophylaxis is conflicting, though some meta-analyses have underlined potential benefit in reducing cardiovascular events. Despite this apparent benefit, bleeding risk with aspirin is consistently higher versus control, and remains a concern. A reduction of cancer incidence and mortality after a least 3 and 5 years treatment, respectively, is also apparent with aspirin. CONCLUSION: Available data on aspirin in primary prevention suggest a modest benefit for patients at high risk of CVD, and a promising benefit for those at risk of cancer. Future studies should help to elucidate whether the benefit of aspirin outweighs risk in appropriate patient groups. PMID- 25502487 TI - Memory reconsolidation for treatment-resistant aggression and self-injurious behaviors. PMID- 25502488 TI - Blonanserin ameliorated the tendency toward QTc prolongation associated with risperidone in a patient with schizophrenia. PMID- 25502489 TI - Bupropion-associated galactorrhea: a case report. PMID- 25502490 TI - The effects of sodium nitroprusside treatment on cognitive deficits in schizophrenia: a pilot study. PMID- 25502491 TI - Duration of initial antidepressant treatment and subsequent relapse of major depression. AB - BACKGROUND: The efficacy, limitations, and methods of studying antidepressant treatment continued beyond initial weeks of acute major depression remain incompletely resolved. AIMS: For subjects treated in controlled trials for acute depression, we analyzed the relationship of relapse risk within 12 months of rerandomizing to placebo versus duration of initial treatment and putative stabilization. METHODS: With data from placebo arms of 45 relevant controlled trials identified in recent, systematic reviews were pooled and analyzed by regression modeling. RESULTS: There was a strong inverse correlation of shorter initial treatment and greater relapse risk after rerandomizing to placebo treatment, best fit to a power function (P <= 0.003); relapse risk differed by 11.4-fold, declining sharply as initial treatment continued for 16 to 20 weeks or more. CONCLUSIONS: Discontinuation of antidepressant treatment for major depressive episodes at times less than 6 months was associated with rising risks after randomization to continuation with placebo. This relationship requires critical consideration in both clinical management of depressed patients and the design and interpretation of treatment discontinuation trials. PMID- 25502492 TI - Polypharmacy in the Elderly: A Marker of Increased Risk of Mortality in a Population-Based Prospective Study (NEDICES). AB - BACKGROUND: Little information is available on the potential association between polypharmacy and risk of mortality. OBJECTIVE: To determine in a population-based study whether polypharmacy is associated with increased risk of mortality in elderly persons. METHODS: In this population-based, prospective study of 5,052 people aged 65 years and older (Neurological Disorders in Central Spain), current medications were recorded. Cox proportional hazards models, adjusted for sociodemographics and comorbidity factors, were used to assess the risk of death up to 13.3 years later, comparing the polypharmacy group (>=6 drugs) to those who were taking 1-5 drugs and those in a nonmedicated group (0 drugs). RESULTS: Out of 5,052 participants, 2,550 (50.5%) died over a median follow-up of 6.5 years, including 361 (28.8%) deaths among 931 nonmedicated participants, 1,946 (51.4%) deaths among 3,787 participants taking 1-5 drugs daily, and 243 (72.8%) among 334 participants on polypharmacy. In an unadjusted Cox model, risk of mortality was increased in participants on polypharmacy [hazard ratio (HR) = 2.78, 95% confidence interval [CI]: 2.36-3.27, p < 0.001) and in those taking between 1 and 5 drugs (HR = 1.47, 95% CI: 1.31-1.64, p < 0.001) versus those who were nonmedicated (reference group). In a Cox model that adjusted for a variety of demographic factors and comorbidities, HR remained increased in participants on polypharmacy (HR = 1.83, 95% CI: 1.51-2.21, p < 0.001). CONCLUSION: This study provides evidence that polypharmacy is associated with increased risk of mortality in elderly people. The extent to which polypharmacy is the proximate cause rather than a marker of this increase risk remains to be determined. PMID- 25502493 TI - Decision Making Concepts for the Remote, Personalized Evaluation of COPD Patients' Health Status. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Biosignal Interpretation: Advanced Methods for Neural Signals and Images". OBJECTIVES: This paper presents the main concepts of a decision making approach for the remote management of COPD patients based on the early detection of disease exacerbation episodes. METHODS: An e-diary card is defined to evaluate a number of physiological variables and clinical parameters acquired remotely by means of wearable and environmental sensors deployed in patients' long-stay settings. The automatic evaluation of the card results in a so-called Chronic Status Index (CSI) whose computation is tailored to patients' specific manifestation of the disease (i.e., patient's phenotype). The decision support method relies on a parameterized analysis of CSI variations so as to early detect worsening changes, identify exacerbation severity and track the patterns of recovery. RESULTS: A preliminary study, carried out in real settings with 30 COPD patients monitored at home, has shown the validity and sensitivity of the method proposed, which was effectively able to timely and correctly identify patients' critical situation. CONCLUSION: The preliminary results showed that the proposed e-diary card, which presents several novel features with respect to other solutions presented in the literature, can be practically used to remotely monitor COPD patients. PMID- 25502495 TI - Synthesis, and QSAR analysis of anti-oncological active spiro-alkaloids. AB - QSAR study describes the anti-neoplastic spiro-alkaloids with relevant molecular descriptors using CODESSA III software. The dispiro[3H-indole-3,2'-pyrrolidine 3',3"-piperidines] 24-48 were synthesized via [3 + 2]-cycloaddition reaction of azomethine ylides, (generated in situ via decarboxylative condensation of isatins 21-23 with sarcosine) and 3E,5E-1-alkyl-3,5-bis(arylmethylidene)-4-piperidones 10 20. Some of the synthesized analogues exhibited promising antitumor properties against HELA (cervical), HEPG2 (liver), T-47D, MCF7 (breast), and HCT116 (colon) human tumor cell lines, demonstrating activity close to or even better than the standard Doxorubicin, based on in vitro Sulfo-Rhodamine-B bio-assay. PMID- 25502494 TI - A comparison of structural and functional changes in patients screened for hydroxychloroquine retinopathy. AB - PURPOSE: The aims of this retrospective study were to compare the results of recommended screening tests for hydroxychloroquine-related retinal toxicity and analyze disparities between the structural and functional findings. METHODS: Thirty-four patients (31 women and 3 men) were included in the study. All were evaluated with standard automated perimetry using the 10-2 and/or 24-2 visual field program (Zeiss, Meditec), multifocal electroretinography (mfERG), spectral domain optical coherence tomography (SD-OCT), and short-wavelength fundus autofluorescent imaging (SW-FAF). The results for the right eye from each patient were analyzed. Visual fields were classified as normal or abnormal based on pattern deviation plots, and mfERGs based on a comparison of R5 ring ratios to values from 20 controls. The SW-FAF images were examined for areas/rings of abnormal hypo- and/or hyperautofluorescence, and the SD-OCT line scans were classified as abnormal based on visual inspection and thickness measurements of the outer segment plus retinal pigment epithelial layer and total receptor layers compared to mean thicknesses from 35 controls. RESULTS: Fifteen patients had abnormal results on at least one test; however, only two patients had abnormal results on all four tests. Excluding SW-FAF, seven of the 15 had abnormal visual fields, mfERG ring ratios, and SD-OCTs. The remaining eight had either abnormal mfERGs and/or visual fields and normal SD-OCTs. We found no evidence of abnormal SD-OCTs in the presence of normal mfERG and visual field results. CONCLUSIONS: The findings suggest that functional deficits precede structural changes seen on SD-OCT in these patients. PMID- 25502496 TI - A luminescent metal-organic framework constructed using a tetraphenylethene-based ligand for sensing volatile organic compounds. AB - By using a tetraphenylethene (TPE)-based ligand, tetrakis[4-(4 carboxyphenyl)phenyl]ethene (H4TCPPE), a porous metal-organic framework [Zn2(TCPPE)] (1) is synthesized, which exhibits strong fluorescence and is capable of gas adsorption and sensing volatile organic compounds. PMID- 25502497 TI - Pancreatic ductal adenocarcinoma cell lines display a plastic ability to bi directionally convert into cancer stem cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed when metastatic events have occurred. Cancer stem cells (CSCs) play an important role in tumor initiation, metastasis, chemoresistance and relapse. A growing number of studies have suggested that CSCs exist in a dynamic equilibrium with more differentiated cancer cells via a bi-directional regeneration that is dependent on the environmental stimuli. In this investigation, we obtain, by using a selective medium, PDAC CSCs from five out of nine PDAC cell lines, endowed with different tumorsphere-forming ability. PDAC CSCs were generally more resistant to the action of five anticancer drugs than parental cell lines and were characterized by an increased expression of EpCAM and CD44v6, typical stem cell surface markers, and a decreased expression of E-cadherin, the main marker of the epithelial state. PDAC CSCs were able to re-differentiate into parental cells once cultured in parental growth condition, as demonstrated by re-acquisition of the epithelial morphology, the decreased expression levels of EpCAM and CD44v6 and the increased sensitivity to anticancer drugs. Finally, PDAC CSCs injected into nude mice developed a larger subcutaneous tumor mass and showed a higher metastatic activity compared to parental cells. The present study demonstrates the ability to obtain CSCs from several PDAC cell lines and that these cells are differentially resistant to various anticancer agents. This variability renders them a model of great importance to deeply understand pancreatic adenocarcinoma biology, to discover new biomarkers and to screen new therapeutic compounds. PMID- 25502498 TI - [Avoidance and management of hypoparathyroidism after thyroid gland surgery]. AB - Postoperative hypoparathyroidism after bilateral thyroid gland surgery or after interventions for recurrence is defined as intact parathyroid hormone levels (iPTH) < 15 pg/ml with simultaneous normal, below normal and markedly decreased serum calcium levels. After bilateral thyroid surgery and after reoperations a single iPTH measurement performed 12-24 h postoperatively can be used to predict parathyroid metabolism. Patients with an iPTH level >= 15 pg/ml may be discharged safely, patients with an iPTH < 10 pg/ml must be substituted with calcium and vitamin D and patients with an iPTH between 10 and 15 pg/ml (grey zone) may be discharged if a second measurement 48 h after surgery documents an iPTH >= 15 pg/ml. This procedure increases the length of hospital stay. Patients in the (grey zone) must be substituted. The iPTH level and its course determine the necessity, dose and length of calcium and vitamin D substitution. PMID- 25502499 TI - [Complications of minimally invasive adrenalectomy]. AB - Over the last decade minimally invasive adrenalectomy has become the gold standard in adrenal surgery. Laparoscopic adrenalectomy with the patient in the lateral decubitus position and posterior retroperitoneoscopic adrenalectomy have gained worldwide acceptance. In this overview the complications of minimally invasive adrenalectomy are analyzed based on the published data. Die incidence of intraoperative and postoperative complications ranges from 0 % to 15 % for unilateral adrenalectomy and rises up to 23 % for bilateral surgery. No significant differences were found between laparoscopic and retroperitoneoscopic operations. Nevertheless, splenic injuries and intra-abdominal abscesses are reported only after laparoscopic procedures, while relaxation and/or hypoesthesia of the abdominal wall are typical for posterior retroperitoneoscopic surgery. Conversion to open surgery significantly influences the rate of perioperative and postoperative complications (odds ratio 6.2); therefore, high surgeon and center case volume could improve the results of adrenal surgery. PMID- 25502500 TI - Hypoxia-induced proliferation of tissue-resident endothelial progenitor cells in the lung. AB - Exposure to hypoxia induces changes in the structure and functional phenotypes of the cells composing the pulmonary vascular wall from larger to most peripheral vessels. Endothelial progenitor cells (EPCs) may be involved in vascular endothelial repair. Resident EPCs with a high proliferative potential are found in the pulmonary microcirculation. However, their potential location, identification, and functional role have not been clearly established. We investigated whether resident EPCs or bone marrow (BM)-derived EPCs play a major role in hypoxic response of pulmonary vascular endothelial cells (PVECs). Mice were exposed to hypoxia. The number of PVECs transiently decreased followed by an increase in hypoxic animals. Under hypoxic conditions for 1 wk, prominent bromodeoxyuridine incorporation was detected in PVECs. Some Ki67-positive cells were detected among PVECs after 1 wk under hypoxic conditions, especially in the capillaries. To clarify the origin of proliferating endothelial cells, we used BM chimeric mice expressing green fluorescent protein (GFP). The percentage of GFP positive PVECs was low and constant during hypoxia in BM-transplanted mice, suggesting little engraftment of BM-derived cells in lungs under hypoxia. Proliferating PVECs in hypoxic animals showed increased expression of CD34, suggesting hypoxia-induced gene expression and cell surface antigen of EPC or stem/progenitor cells markers. Isolated PVECs from hypoxic mice showed colony- and tube-forming capacity. The present study indicated that hypoxia could induce proliferation of PVECs, and the origin of these cells might be tissue-resident EPCs. PMID- 25502502 TI - Distinct macrophage phenotypes in allergic and nonallergic lung inflammation. AB - Chronic exposure to farm environments is a risk factor for nonallergic lung disease. In contrast to allergic asthma, in which type 2 helper T cell (Th2) activation is dominant, exposure to farm dust extracts (FDE) induces Th1/Th17 lung inflammation, associated with neutrophil infiltration. Macrophage influx is a common feature of both types of lung inflammation, allergic and nonallergic. However, macrophage functions and phenotypes may vary according to their polarized state, which is dependent on the cytokine environment. In this study, we aimed to characterize and quantify the lung macrophage populations in two established murine models of allergic and nonallergic lung inflammation by means of fluorescence-activated cell sorting and immunohistochemistry. We demonstrated that, whereas in allergic asthma M2-dominant macrophages predominated in the lungs, in nonallergic inflammation M1-dominant macrophages were more prevalent. This was confirmed in vitro using a macrophage cell line, where FDE exerted a direct effect on macrophages, inducing M1-dominant polarization. The polarization of macrophages diverged depending on the exposure and inflammatory status of the tissue. Interfering with this polarization could be a target for treatment of different types of lung inflammation. PMID- 25502503 TI - Ebola: history, treatment, and lessons from a new emerging pathogen. PMID- 25502501 TI - Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. AB - Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-beta signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis. PMID- 25502506 TI - Steric engineering of metal-halide perovskites with tunable optical band gaps. AB - Owing to their high energy-conversion efficiency and inexpensive fabrication routes, solar cells based on metal-organic halide perovskites have rapidly gained prominence as a disruptive technology. An attractive feature of perovskite absorbers is the possibility of tailoring their properties by changing the elemental composition through the chemical precursors. In this context, rational in silico design represents a powerful tool for mapping the vast materials landscape and accelerating discovery. Here we show that the optical band gap of metal-halide perovskites, a key design parameter for solar cells, strongly correlates with a simple structural feature, the largest metal-halide-metal bond angle. Using this descriptor we suggest continuous tunability of the optical gap from the mid-infrared to the visible. Precise band gap engineering is achieved by controlling the bond angles through the steric size of the molecular cation. On the basis of these design principles we predict novel low-gap perovskites for optimum photovoltaic efficiency, and we demonstrate the concept of band gap modulation by synthesising and characterising novel mixed-cation perovskites. PMID- 25502504 TI - Dental fear in children: the role of previous negative dental experiences. AB - OBJECTIVES: The aims of this study were to determine the potential main sources of anxiety in children visiting the dental office and to examine whether negative experiences influence the development of dental fear. METHODS: Six hundred six subjects from the same pediatric dental office were consecutively invited to participate in the study (303 children/303 parents). An adapted version of the Wong-Baker FACES Pain Rating Scale and Corah's Dental Anxiety Scale were used to rate anxiety in children and parents. Clinical variables were collected by the same experienced pediatric dentist, with a view to determining their potential influence upon the development of fears. Descriptive statistics (mean, standard deviation), along with the Mann-Whitney U test, were used to determine the association between clinical variables and anxiety levels. Correlations were established using the Spearman coefficient (r) (p < 0.05). RESULTS: No statistical differences were observed in anxiety levels with respect to patient gender (p > 0.05). Greater anxiety levels were observed in 4- and 5-year-old children (n = 56/55, respectively), with a negative correlation between age and anxiety level (r = -0.176; p = 0.002) and between parent anxiety level and patient age (r = -0.154; p = 0.007). A strong positive correlation was found between the anxiety levels of the parents and children (r = 0.954; p < 0.001). In addition, a moderate positive correlation was found between elevated anxiety levels in children (r = 0.381; p < 0.001) and parents (r = 0.454; p < .001) and the number of previous treatments in other dental offices. CONCLUSIONS: Dental fear in children is strongly associated with inadequate dental management, causing anxiety levels to increase in both the children and parents. PMID- 25502505 TI - Quality of life of adult men with Duchenne muscular dystrophy in the Netherlands: implications for care. AB - OBJECTIVE: To assess quality of life of adults with Duchenne muscular dystrophy in the Netherlands and to identify domains and major problems influencing quality of life. DESIGN: Cross-sectional. SUBJECTS: Seventy-nine men aged >= 20 years with Duchenne muscular dystrophy. METHODS: The Medical Outcome Study Short Form 36 (SF-36), World Health Organization Quality of Life - BREF (WHOQOL-BREF) and an interview were used to assess quality of life and problems. RESULTS: Compared with Dutch general population reference values, the SF-36 domains scores were lower on all domains except mental health and role limitations due to emotional problems. On the WHOQOL-BREF the social relationships domain score was lower. Main problems were intimate relationships, work, leisure, transport and meaningfulness of life. Seventy-three percent stated overall quality of life as "(very) good". The SF-36 domains mental health (rs 0.53, p < 0.001) and vitality (rs 0.49, p < 0.001) had the strongest associations with overall quality of life. CONCLUSION: Adult men with Duchenne muscular dystrophy assess their health status as low in the physical, but not in the mental, domains. Experienced problems are mainly in the area of participation. They are generally satisfied with their overall quality of life. PMID- 25502507 TI - Pectoral sound generation in the blue catfish Ictalurus furcatus. AB - Catfishes produce pectoral stridulatory sounds by "jerk" movements that rub ridges on the dorsal process against the cleithrum. We recorded sound synchronized with high-speed video to investigate the hypothesis that blue catfish Ictalurus furcatus produce sounds by a slip-stick mechanism, previously described only in invertebrates. Blue catfish produce a variably paced series of sound pulses during abduction sweeps (pulsers) although some individuals (sliders) form longer duration sound units (slides) interspersed with pulses. Typical pulser sounds are evoked by short 1-2 ms movements with a rotation of 2 degrees -3 degrees . Jerks excite sounds that increase in amplitude after motion stops, suggesting constructive interference, which decays before the next jerk. Longer contact of the ridges produces a more steady-state sound in slides. Pulse pattern during stridulation is determined by pauses without movement: the spine moves during about 14 % of the abduction sweep in pulsers (~45 % in sliders) although movement appears continuous to the human eye. Spine rotation parameters do not predict pulse amplitude, but amplitude correlates with pause duration suggesting that force between the dorsal process and cleithrum increases with longer pauses. Sound production, stimulated by a series of rapid movements that set the pectoral girdle into resonance, is caused by a slip-stick mechanism. PMID- 25502508 TI - A miRNA Signature in Human Cord Blood Stem and Progenitor Cells as Potential Biomarker of Specific Acute Myeloid Leukemia Subtypes. AB - MicroRNAs (miRNAs) are important regulators of several cellular processes. During hematopoiesis, specific expression signatures have been reported in different blood cell lineages and stages of hematopoietic stem cell (HSC) differentiation. Here we explored the expression of miRNAs in umbilical cord blood stem (HSC) and progenitor cells (HPC) and compared it to unilineage granulocyte and granulo monocyte differentiation as well as to primary blasts from patients with acute myeloid leukemia (AML). CD34 + CD38- ad CD34 + CD38 + cells were profiled using a global array consisting of about 2000 miRNAs. An approach combining bioinformatic prediction of miRNA targets with mRNA expression profiling was used to search for putative biologically enriched functions and networks. At least 15 miRNAs to be differentially expressed between HSC and HPC cell population, a cluster of 7 miRNAs are located in the q32 region of human chromosome 14 (miR-377 3p, -136-5p, 376a-3p, 495-3p, 654-3p, 376c-3p and 381-3p) whose expression decreased during the early stages of normal myelopoiesis but were markedly increased in a small set of AML. Interestingly, miR-4739 and -4516, two novel microRNA whose function and targets are presently unknown, showed specific and peculiar expression profile during the hematopoietic stem cells differentiation into unilineages and resulted strongly upregulated in almost all AML subsets. miR 181, -126-5p, -29b-3p and -22-3p resulted dis-regulated in specific leukemias phenotypes. This study provides the first evidence of a miRNA signature in human cord blood stem and progenitor cells with a potential role in hematopoietic stemness properties and possibly in leukemogenesis of specific AML subtypes. PMID- 25502510 TI - Nucleation and growth kinetics of zirconium-oxo-alkoxy nanoparticles. AB - Nucleation and growth of zirconium-oxo-alkoxy (ZOA) nanoparticles were studied in a sol-gel process in n-propanol solution at a hydrolysis ratio H between 1.0 and 2.7 and zirconium-n-propoxyde precursor concentrations between 0.10 and 0.15 mol l(-1). The chemical transformations were conducted in quasi-perfect micromixing conditions (Damkohler number Da <= 1) and the nanoparticle size evolution was monitored in situ with the light scattering method. The size of primary nanoparticles (nuclei) 2R0 = 3.6 nm was found to be almost independent of the preparation conditions. A remarkable similarity with the titanium-oxo-alkoxy (TOA) nanoparticles was observed. In particular, both systems show the induction stage of the sol-gel growth for a hydrolysis ratio H > 2.0 and stable oxometallate units for H<= 2.0. However in contrast to TOA, no stable hierarchical ZOA units (clusters) with R0>=R>= 1.0 nm were observed, which makes this system less stable against aggregation, leading to polydispersed nanoparticles. PMID- 25502509 TI - The significance of persistent fever in the treatment of suspected bacterial infections among inpatients: a prospective cohort study. AB - Antibiotic escalations are frequently guided by fever persistence. Unnecessary antibiotic escalation is associated with resistance induction. We examined whether fever persistence is associated with adverse outcomes among medical inpatients with sepsis. In a single-center prospective cohort study, we included consecutive medical inpatients with suspected or documented bacterial infections. Data were collected on days 0, 2, 4, and 30 days from episode onset. We examined the association between fever persistence at 4 days and 30-day mortality on univariate and multivariate analysis. Inappropriate empirical antibiotic treatment (IAET) was defined for patients with microbiologically documented infections (MDIs). Odds ratios (ORs) are presented with 95% confidence intervals (CIs). A total of 1,621 patients were included. Among patients with MDIs, 38/206 (18.4%) given appropriate empiric therapy had continued fever on day 4, compared to 64/231 (27.7%) of patients receiving IAET, OR 0.59, 95% CI 0.37-0.93. Fever persistence was not associated with mortality after adjustment for other risk factors. Among patients with presumed sepsis who did not have MDIs, persistent fever was significantly associated with 30-day mortality on a multivariate analysis, adjusted OR 2.77 (95% CI 1.78-4.31). Other risk factors for mortality included older age, nosocomial infections, malignancy, dyspnea, shock, decreased albumin, and elevated creatinine. For patients with MDIs, fever persistence for up to 4 days is a marker of IAET, but is not associated with mortality, and should not, in itself, trigger antibiotic escalation. For patients without MDIs, fever persistence should trigger careful re-evaluation, as it is associated with mortality. PMID- 25502511 TI - Enzyme replacement therapy stabilized white matter lesion progression in Fabry disease. AB - BACKGROUND: The central nervous system manifestations in Fabry disease (FD) include progressive white matter lesions (WMLs) and stroke. Due to progressive microvascular involvement, men and women with FD over 35 years of age develop WMLs. Moreover, the prevalence of stroke has been estimated to be 12 times higher in FD compared with the general population. Enzyme replacement therapy (ERT) is available and has shown beneficial effects on renal, cardiac, and peripheral nerve function in FD, but the ERT effect on the progression of WMLs, or the reduction in cerebrovascular events, remains unknown. METHODS: The WML burden and the effect of agalsidase beta 1 mg/kg biweekly on WML progression were assessed longitudinally in a Phase 4 agalsidase-beta placebo-controlled analysis of untreated and treated FD patients with mild-to-moderate renal involvement (serum creatinine measurements of >=1.2 mg/dl and <3.0 mg/dl). The primary end point was the difference in the number of patients with increased WML burden between the agalsidase beta and placebo groups at the end of treatment. The diameters of the WMLs were determined manually using axial flow-attenuated-inversion-recovery weighted magnetic resonance imaging (MRI) scans taken at baseline and follow-up. RESULTS: MRI scans from 41 FD patients (mean age 43.9, age range 20-68, 3 females; n=25 on ERT, n=16 on placebo) were analyzed. WML burden was present in 63% of patients at baseline, increased over a mean of 27 months (range 12-33 months) follow-up, and correlated with left ventricular hypertrophy (LVPW). Patients with previous or recent strokes (n=11, 39-68 years) showed an increase in the number of WMLs (p=0.005). A greater proportion of younger patients (<=50 years) on ERT (n=18) had stable WML burden compared with younger patients in the placebo group (n=13): 44% (8 of 18) versus 31% (4 of 13), p=0.014. The number needed to treat was 8. CONCLUSIONS: This FD patient cohort, with mild-to-moderate renal involvement, had a significant WML burden and high inter-individual variability associated with the degree of LVPW but not the degree of kidney dysfunction. These advanced patients with increased LVPW and stroke evidence may have had a higher cerebrovascular risk. The WML burden in patients on ERT was more likely to remain stable, compared with patients on placebo. Thus, ERT may reduce the progression of vascular disease, even in advanced FD patients, suggesting that early treatment may stabilize WML progression and stroke risk. PMID- 25502512 TI - Enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7. AB - UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation conjugation reaction plays an important role in the elimination of many important clinical drugs and endogenous substances. The present study aims to investigate the enantioselective inhibition of carprofen towards UGT isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation mixture was used to screen the inhibition potential of (R)-carprofen and (S)-carprofen towards multiple UGT isoforms. The results showed that (S) carprofen exhibited stronger inhibition potential than (R)-carprofen towards UGT2B7. However, no significant difference was observed for the inhibition of (R) carprofen and (S)-carprofen towards other UGT isoforms. Furthermore, the inhibition kinetic behavior was compared for the inhibition of (S)-carprofen and (R)-carprofen towards UGT2B7. A Lineweaver-Burk plot showed that both (S) carprofen and (R)-carprofen exhibited competitive inhibition towards UGT2B7 catalyzed 4-MU glucuronidation. The inhibition kinetic parameter (Ki ) was calculated to be 7.0 MUM and 31.1 MUM for (S)-carprofen and (R)-carprofen, respectively. Based on the standard for drug-drug interaction, the threshold for (S)-carprofen and (R)-carprofen to induce a drug-drug interaction is 0.7 MUM and 3.1 MUM, respectively. In conclusion, enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7 was demonstrated in the present study. Using the in vitro inhibition kinetic parameter, the concentration threshold of (S)-carprofen and (R)-carprofen to possibly induce the drug-drug interaction was obtained. Therefore, clinical monitoring of the plasma concentration of (S)-carprofen is more important than (R)-carprofen to avoid a possible drug-drug interaction between carprofen and the drugs mainly undergoing UGT2B7-catalyzed metabolism. PMID- 25502513 TI - Identification of differentially expressed genes and small molecule drugs for the treatment of tendinopathy using microarray analysis. AB - Tendinopathy is a critical clinical problem as it is often asymptomatic at onset and during development, and is only recognized upon rupture of the tendon. It is common among recreational and competitive athletes. The present study sought to examine the molecular mechanism of the progression of tendinopathy by screening out differentially expressed genes (DEGs) and investigating their functions. In addition, the present study aimed to identify the small molecules, which exhibit potential effects, which could be utilized for the treatment of tendinopathy. The gene expression profile of tendinopathy, GSE26051 was downloaded from the Gene Expression Omnibus database, which included 23 control samples and 18 samples of tendinopathy. The DEGs were identified using the Limma package in the R programming language, and gene ontology and pathway enrichment analysis were performed. In addition, the potential regulatory microRNAs and the target sites of the transcription factors were screened out based on the molecular signature database. In addition, the DEGs were mapped to the connectivity map database to identify the potential small molecule drugs. A total of 318 genes were filtered as DEGs between diseased samples and normal control tendons. Additionally, genes, including laminin, alpha4, platelet-derived growth factor alpha, laminin gamma1 and Src homology 2 transforming protein 1 may induce tendinopathy through the focal adhesion pathway. Furthermore, the transcription factor, lymphoid enhancer binding factor 1 and its target genes, pantothenate kinase 2 and G protein coupled receptor kinase 5 were identified. The most significant microRNA, miR 499, was screened and was found to regulate specific genes, including CUGBP2 and MYB. Additionally, the small molecules, Prestwick-1082 and viomycin were identified to have the potential to repair disordered metabolic pathways and furthermore to remedy tendinopathy. The results of the present study assessed the mechanism of tendinopathy and screened small molecule drugs as potential treatments for this condition. In addition, the present findings have the potential for use in a clinical setting for the treatment of tendinopathy in the future. PMID- 25502514 TI - Sinusoidal immunity: macrophages at the lymphohematopoietic interface. AB - Macrophages are widely distributed throughout the body, performing vital homeostatic and defense functions after local and systemic perturbation within tissues. In concert with closely related dendritic cells and other myeloid and lymphoid cells, which mediate the innate and adaptive immune response, macrophages determine the outcome of the inflammatory and repair processes that accompany sterile and infectious injury and microbial invasion. This article will describe and compare the role of specialized macrophage populations at two critical interfaces between the resident host lymphohematopoietic system and circulating blood and lymph, the carriers of cells, humoral components, microorganisms, and their products. Sinusoidal macrophages in the marginal zone of the spleen and subcapsular sinus and medulla of secondary lymph nodes contribute to the innate and adaptive responses of the host in health and disease. Although historically recognized as major constituents of the reticuloendothelial system, it has only recently become apparent that these specialized macrophages in close proximity to B and T lymphocytes play an indispensable role in recognition and responses to exogenous and endogenous ligands, thus shaping the nature and quality of immunity and inflammation. We review current understanding of these macrophages and identify gaps in our knowledge for further investigation. PMID- 25502517 TI - Obesity and sudden death: visceral response? PMID- 25502516 TI - How do astrocytes participate in neural plasticity? AB - Work over the past 20 years has implicated electrically nonexcitable astrocytes in complex neural functions. Despite controversies, it is increasingly clear that many, if not all, neural processes involve astrocytes. This review critically examines past work to identify the commonalities among the many published studies of neuroglia signaling. Although several studies have shown that astrocytes can impact short-term and long-term synaptic plasticity, further work is required to determine the requirement for astrocytic Ca(2+) and other second messengers in these processes. One of the roadblocks to the field advancing at a rapid pace has been technical. We predict that the novel experimental tools that have emerged in recent years will accelerate the field and likely disclose an entirely novel path of neuroglia signaling within the near future. PMID- 25502515 TI - Sexual conflict and seminal fluid proteins: a dynamic landscape of sexual interactions. AB - Sexual reproduction requires coordinated contributions from both sexes to proceed efficiently. However, the reproductive strategies that the sexes adopt often have the potential to give rise to sexual conflict because they can result in divergent, sex-specific costs and benefits. These conflicts can occur at many levels, from molecular to behavioral. Here, we consider sexual conflict mediated through the actions of seminal fluid proteins. These proteins provide many excellent examples in which to trace the operation of sexual conflict from molecules through to behavior. Seminal fluid proteins are made by males and provided to females during mating. As agents that can modulate egg production at several steps, as well as reproductive behavior, sperm "management," and female feeding, activity, and longevity, the actions of seminal proteins are prime targets for sexual conflict. We review these actions in the context of sexual conflict. We discuss genomic signatures in seminal protein (and related) genes that are consistent with current or previous sexual conflict. Finally, we note promising areas for future study and highlight real-world practical situations that will benefit from understanding the nature of sexual conflicts mediated by seminal proteins. PMID- 25502519 TI - The potentiation of zinc toxicity by soil moisture in a boreal forest ecosystem. AB - Northern boreal forests often experience forest dieback as a result of metal ore mining and smelting. The common solution is to lime the soil, which increases pH, reducing metal toxicity and encouraging recovery. In certain situations, however, such as in Flin Flon, Manitoba, Canada, liming has yielded only moderate benefits, with some locations responding well to liming and other locations not at all. In an effort to increase the effectiveness of the ecorestoration strategy, the authors investigated if these differences in liming responsiveness were linked to differences in toxicity. Toxicity of metal-impacted Flin Flon soils on the oribatid mite Oppia nitens and the collembolan Folsomia candida was assessed, with a view toward identifying the metal of concern in the area. The effects of moisture content on metal sorption, uptake, and toxicity to the invertebrates were also investigated. Toxicity tests with the invertebrates were conducted using either Flin Flon soils or artificial soils with moisture content adjusted to 30%, 45%, 60%, or 75% of the maximum water-holding capacity of the soil samples. The Relative to Cd Toxicity Model identified Zn as the metal of concern in the area, and this was confirmed using validation tests with field contaminated soils. Furthermore, increasing the moisture content in soils increased the amount of mobile Zn available for uptake with the ion exchange resin. Survival and reproduction of both invertebrates were reduced under Zn exposure as moisture level increased. Thus, moisture-collecting landforms, which are often also associated with high Zn concentrations at Flin Flon, have, as a result, higher Zn toxicity to the soil ecosystem because of increases in soil moisture. PMID- 25502521 TI - FilmArray: correction of previously false-positive results by improved software. PMID- 25502518 TI - Autonomous inhibition of apoptosis correlates with responsiveness of colon carcinoma cell lines to ciglitazone. AB - Colorectal cancer is a leading cause of mortality worldwide. Resistance to therapy is common and often results in patients succumbing to the disease. The mechanisms of resistance are poorly understood. Cells basically have two possibilities to survive a treatment with potentially apoptosis-inducing substances. They can make use of their existing proteins to counteract the induced reactions or quickly upregulate protective factors to evade the apoptotic signal. To identify protein patterns involved in resistance to apoptosis, we studied two colorectal adenocarcinoma cell lines with different growth responses to low-molar concentrations of the thiazolidinedione Ciglitazone: HT29 cells underwent apoptosis, whereas SW480 cells increased cell number. Fluorescence detection and autoradiography scans of 2D-PAGE gels were performed in both cell lines to assess protein synthesis and turnover, respectively. To verify the data we performed shotgun analysis using the same treatment procedure as in 2D experiments. Biological functions of the identified proteins were mainly associated with apoptosis regulation, chaperoning, intrinsic inflammation, and DNA repair. The present study suggests that different growth response of two colorectal carcinoma cell lines after treatment with Ciglitazone results from cell-specific protein synthesis and differences in protein regulation. PMID- 25502520 TI - Comparison of Hybribio GenoArray and Roche human papillomavirus (HPV) linear array for HPV genotyping in anal swab samples. AB - Human papillomavirus (HPV) is causally associated with anal cancer, as HPV DNA is detected in up to 90% of anal intraepithelial neoplasias and anal cancers. With the gradual increase of anal cancer rates, there is a growing need to establish reliable and clinically relevant methods to detect anal cancer precursors. In resource-limited settings, HPV DNA detection is a potentially relevant tool for anal cancer screening. Here, we evaluated the performance of the Hybribio GenoArray (GA) for genotyping HPV in anal samples, against the reference standard Roche Linear Array (LA). Anal swab samples were obtained from sexually active men who have sex with men. Following DNA extraction, each sample was genotyped using GA and LA. The overall interassay agreement, type-specific, and single and multiple genotype agreements were evaluated by kappa statistics and McNemar's chi(2) tests. Using GA and LA, 68% and 76% of samples were HPV DNA positive, respectively. There was substantial interassay agreements for the detection of all HPV genotypes (kappa = 0.70, 86% agreement). Although LA was able to detect more genotypes per sample, the interassay agreement was acceptable (kappa = 0.53, 63% agreement). GA had poorer specific detection of HPV genotypes 35, 42, and 51 (kappa < 0.60). In conclusion, GA and LA showed good interassay agreement for the detection of most HPV genotypes in anal samples. However, the detection of HPV DNA in up to 76% of anal samples warrants further evaluation of its clinical significance. PMID- 25502523 TI - Biographical feature: Henry D. Isenberg, Ph.D. PMID- 25502522 TI - Nonstructural protein 1-specific immunoglobulin M and G antibody capture enzyme linked immunosorbent assays in diagnosis of flaviviral infections in humans. AB - IgM antibody- and IgG antibody-capture enzyme-linked immunosorbent assays (MAC/GAC-ELISAs) targeted at envelope protein (E) of dengue viruses (DENV), West Nile virus, and Japanese encephalitis virus (JEV) are widely used as serodiagnostic tests for presumptive confirmation of viral infection. Antibodies directed against the flavivirus nonstructural protein 1 (NS1) have been proposed as serological markers of natural infections among vaccinated populations. The aim of the current study is to optimize an IgM and IgG antibody-capture ELISA (MAC/GAC-ELISA) to detect anti-NS1 antibodies and compare it with anti-E MAC/GAC ELISA. Plasmids to express premembrane/envelope (prM/E) or NS1 proteins of six medically important flaviviruses, including dengue viruses (DENV-1 to DENV-4), West Nile virus (WNV), and Japanese encephalitis virus (JEV), were constructed. These plasmids were used for the production of prM/E-containing virus-like particles (VLPs) and secreted NS1 (sNS1) from COS-1 cells. Archived clinical specimens from patients with confirmed DENV, JEV, and WNV infections, along with naive sera, were subjected to NS1-MAC/GAC-ELISAs before or after depletion of anti-prM/E antibodies by preabsorption with or without VLPs. Human serum specimens from previously confirmed DENV infections showed significantly enhanced positive-to-negative (P/N) ratios for NS1-MAC/GAC-ELISAs after the depletion of anti-prM/E antibodies. No statistical differences in sensitivities and specificities were found between the newly developed NS1- and VLP-MAC/GAC-ELISAs. Further application of the assays to WNV- and JEV-infected serum panels showed similar results. A novel approach to perform MAC/GAC-ELISAs for NS1 antibody detection was successfully developed with great potential to differentiate antibodies elicited by the tetravalent chimeric yellow fever-17D/dengue vaccine or DENV infection. PMID- 25502524 TI - Accurate quantification of episomal HIV-1 two-long terminal repeat circles by use of optimized DNA isolation and droplet digital PCR. AB - Episomal HIV-1 two-long terminal repeat (2-LTR) circles are considered markers for ongoing viral replication. Two sample processing procedures were compared to accurately quantify 2-LTR in patients by using droplet digital PCR (ddPCR). Here, we show that plasmid isolation with a spiked non-HIV plasmid for normalization enables more accurate 2-LTR quantification than genomic DNA isolation. PMID- 25502525 TI - Molecular and epidemiological review of toxigenic diphtheria infections in England between 2007 and 2013. AB - Human infections caused by toxigenic corynebacteria occur sporadically across Europe. In this report, we undertook the epidemiological and molecular characterization of all toxigenic corynebacterium strains isolated in England between January 2007 and December 2013. Epidemiological aspects include case demographics, risk factors, clinical presentation, treatment, and outcome. Molecular characterization was performed using multilocus sequence typing (MLST) alongside traditional phenotypic methods. In total, there were 20 cases of toxigenic corynebacteria; 12 (60.0%) were caused by Corynebacterium ulcerans, where animal contact was the predominant risk factor. The remaining eight (40.0%) were caused by Corynebacterium diphtheriae strains; six were biovar mitis, which were associated with recent travel abroad. Adults 45 years and older were particularly affected (55.0%; 11/20), and typical symptoms included sore throat and fever. Respiratory diphtheria with the absence of a pharyngeal membrane was the most common presentation (50.0%; 10/20). None of the eight C. diphtheriae cases were fully immunized. Diphtheria antitoxin was issued in two (9.5%) cases; both survived. Two (9.5%) cases died, one due to a C. diphtheriae infection and one due to C. ulcerans. MLST demonstrated that the majority (87.5%; 7/8) of C. diphtheriae strains represented new sequence types (STs). By adapting several primer sequences, the MLST genes in C. ulcerans were also amplified, thereby providing the basis for extension of the MLST scheme, which is currently restricted to C. diphtheriae. Despite high population immunity, occasional toxigenic corynebacterium strains are identified in England and continued surveillance is required. PMID- 25502526 TI - Identification and susceptibility of Aspergillus section nigri in china: prevalence of species and paradoxical growth in response to echinocandins. AB - Molecular identification and in vitro antifungal susceptibility tests of 43 Aspergillus section Nigri isolates from China were performed. Aspergillus niger and Aspergillus tubingensis were present in almost equal numbers. All of the isolates had low MIC/MECs (minimum effective concentrations) for the 7 common antifungals, and a paradoxical effect was observed for the first time in response to caspofungin and micafungin. PMID- 25502527 TI - Performance of the molecular Alere I influenza A&B test compared to that of the xpert flu A/B assay. AB - Data on the performance of rapid molecular point-of-care use platforms for diagnosis of influenza are lacking. We validated nasopharyngeal (NP) flocked specimens in universal transport medium (UTM) and evaluated the clinical sensitivity and specificity of the Alere i influenza A&B test compared to those of the Xpert flu A/B assay. The Alere i influenza A&B test had an overall sensitivity and specificity of 93.8% and 62.5% for influenza A, respectively, and of 91.8% and 53.6% for influenza B, respectively. The poor specificity was due to influenza virus samples determined positive for both type A and B. PMID- 25502528 TI - Equal performance of self-collected and health care worker-collected pharyngeal swabs for group a streptococcus testing by PCR. AB - A process employing patient- or parent-collected pharyngeal swabs for group A Streptococcus (GAS) testing would expedite diagnosis and treatment, reduce patient exposure to the health care setting, and decrease health care costs. Our aim was to determine the concordance between patient- or parent-collected (self collected) and health care worker (HCW)-collected pharyngeal swabs for detection of GAS by PCR. From 9 October 2012 to 21 March 2013, patients presenting with a sore throat meeting criteria for GAS testing and not meeting criteria for severe disease were offered the opportunity to collect their own pharyngeal swab. The HCW also collected a swab. Paired swabs were tested by GAS real-time PCR, allowing semiquantitative comparisons between positive results. Of the 402 participants, 206 had a swab collected by the patient and 196 a swab collected by the parent. The percent positivity results were 33.3% for HCW-collected swabs and 34.3% for self-collected swabs (P = 0.41). The overall concordance between the two collection strategies was 94.0% (95% confidence interval [CI], 91.3 to 96.0). Twenty-four of the paired swabs had discordant results, with 10 and 14 positives detected only with the HCW- and self-collected swabs, respectively (P = 0.41). The person collecting the swab in the self-collected arm, the order of collection, and prior swab collection training did not influence results. Among the 124 specimens that were positive by both collection methods, the amount of GAS DNA was higher in the self-collected versus the HCW-collected swabs (P = 0.008). Self-collected pharyngeal swabs provide a reliable alternative to HCW collection for detection of GAS and offer a strategy for improved health care delivery. PMID- 25502531 TI - Geographically distinct Escherichia coli O157 isolates differ by lineage, Shiga toxin genotype, and total shiga toxin production. AB - While the differential association of Escherichia coli O157 genotypes with animal and human hosts has recently been well documented, little is known about their distribution between countries and how this might affect regional disease rates. Here, we used a 48-plex single nucleotide polymorphism (SNP) assay to segregate 148 E. coli O157 isolates from Australia, Argentina, and the United States into 11 SNP lineages. We also investigated the relationship between SNP lineages, Shiga toxin (Stx) gene profiles, and total Stx production. E. coli O157 isolates clearly segregated into SNP lineages that were differentially associated with each country. Of the 11 SNP lineages, seven were detected among isolates from a single country, two were detected among isolates from all three countries, and another two were detected only among U.S. and Argentinean isolates. A number of Australian (30%) and Argentinean (14%) isolates were associated with novel, previously undescribed SNP lineages that were unique to each country. Isolates within SNP lineages that were strongly associated with the carriage of stx2a produced comparatively more Stx on average than did those lacking the stx2a subtype. Furthermore, the proportion of isolates in stx2a-associated SNP lineages was significantly higher in Argentina and the United States than Australia (P < 0.05). This study provides evidence for the geographic divergence of E. coli O157 and for a prominent role of stx2a in total Stx production. These results also highlight the need for more comprehensive studies of the global distribution of E. coli O157 lineages and the impacts of regionally predominant E. coli O157 lineages on the prevalence and severity of disease. PMID- 25502529 TI - A diagnostic HIV-1 tropism system based on sequence relatedness. AB - Key clinical studies for HIV coreceptor antagonists have used the phenotyping based Trofile test. Meanwhile various simpler-to-do genotypic tests have become available that are compatible with standard laboratory equipment and Web-based interpretation tools. However, these systems typically analyze only the most prominent virus sequence in a specimen. We present a new diagnostic HIV tropism test not needing DNA sequencing. The system, XTrack, uses physical properties of DNA duplexes after hybridization of single-stranded HIV-1 env V3 loop probes to the clinical specimen. Resulting "heteroduplexes" possess unique properties driven by sequence relatedness to the reference and resulting in a discrete electrophoretic mobility. A detailed optimization process identified diagnostic probe candidates relating best to a large number of HIV-1 sequences with known tropism. From over 500 V3 sequences representing all main HIV-1 subtypes (Los Alamos database), we obtained a small set of probes to determine the tropism in clinical samples. We found a high concordance with the commercial TrofileES test (84.9%) and the Web-based tool Geno2Pheno (83.0%). Moreover, the new system reveals mixed virus populations, and it was successful on specimens with low virus loads or on provirus from leukocytes. A replicative phenotyping system was used for validation. Our data show that the XTrack test is favorably suitable for routine diagnostics. It detects and dissects mixed virus populations and viral minorities; samples with viral loads (VL) of <200 copies/ml are successfully analyzed. We further expect that the principles of the platform can be adapted also to other sequence-divergent pathogens, such as hepatitis B and C viruses. PMID- 25502532 TI - Improved detection of Staphylococcus intermedius group in a routine diagnostic laboratory. AB - The Staphylococcus intermedius group (SIG) includes zoonotic pathogens traditionally associated with dog bites. We describe a simple scheme for improved detection of SIG using routine laboratory methods, report its effect on isolation rates, and use sequencing to confirm that, apart from one atypical SIG strain, most isolates are Staphylococcus pseudintermedius. PMID- 25502530 TI - Aspergillus citrinoterreus, a new species of section Terrei isolated from samples of patients with nonhematological predisposing conditions. AB - The use of molecular identification techniques has revealed an increasing number of new species within Aspergillus section Terrei. We phenotyped a set of 26 clinical isolates that showed genetic differences from Aspergillus terreus sensu stricto by analyzing sequences from PCR-amplified beta-tubulin and calmodulin genes and the internal transcribed spacer region. Since the isolates were phylogenetically and morphologically different from all of the members of Aspergillus section Terrei, they are described here as a new species, Aspergillus citrinoterreus, so named because it produces a diffusible yellowish pigment in agar. A. citrinoterreus isolates were significantly more susceptible to itraconazole, voriconazole, and posaconazole than A. terreus sensu stricto isolates were; in contrast, the amphotericin B MICs for both species were high. A. citrinoterreus was found in clinical samples from patients with proven or probable invasive aspergillosis and colonized patients, none of whom had hematological malignancies as predisposing conditions. However, they did have other underlying conditions such as chronic obstructive pulmonary disease, cirrhosis, and cancer or had received a solid organ transplants and presented not only with invasive pulmonary aspergillosis but also with mediastinitis. A. citrinoterreus isolates were detected for the first time in 2002. In all cases of invasive aspergillosis, A. citrinoterreus was found to be a copathogen, mostly with A. fumigatus. PMID- 25502533 TI - Identification of TL-Om1, an adult T-cell leukemia (ATL) cell line, as reference material for quantitative PCR for human T-lymphotropic virus 1. AB - Quantitative PCR (qPCR) for human T-lymphotropic virus 1 (HTLV-1) is useful for measuring the amount of integrated HTLV-1 proviral DNA in peripheral blood mononuclear cells. Many laboratories in Japan have developed different HTLV-1 qPCR methods. However, when six independent laboratories analyzed the proviral load of the same samples, there was a 5-fold difference in their results. To standardize HTLV-1 qPCR, preparation of a well-defined reference material is needed. We analyzed the integrated HTLV-1 genome and the internal control (IC) genes of TL-Om1, a cell line derived from adult T-cell leukemia, to confirm its suitability as a reference material for HTLV-1 qPCR. Fluorescent in situ hybridization (FISH) showed that HTLV-1 provirus was monoclonally integrated in chromosome 1 at the site of 1p13 in the TL-Om1 genome. HTLV-1 proviral genome was not transferred from TL-Om1 to an uninfected T-cell line, suggesting that the HTLV-1 proviral copy number in TL-Om1 cells is stable. To determine the copy number of HTLV-1 provirus and IC genes in TL-Om1 cells, we used FISH, digital PCR, and qPCR. HTLV-1 copy numbers obtained by these three methods were similar, suggesting that their results were accurate. Also, the ratio of the copy number of HTLV-1 provirus to one of the IC genes, RNase P, was consistent for all three methods. These findings indicate that TL-Om1 cells are an appropriate reference material for HTLV-1 qPCR. PMID- 25502534 TI - Acanthamoeba encephalitis: isolation of genotype T1 in mycobacterial liquid culture medium. AB - We report a case of Acanthamoeba encephalitis diagnosed from an antemortem brain biopsy specimen, where the organism was first isolated in mycobacterial liquid medium and first identified by using a sequence generated by a commercial panfungal sequencing assay. We correlate susceptibility results with clinical outcome. PMID- 25502536 TI - Localized aquagenic acrokeratoderma on the right hand. PMID- 25502535 TI - First report of an infant botulism case due to Clostridium botulinum type Af. AB - Most infant botulism cases worldwide are due to botulinum toxin types A and B. Rarely, Clostridium botulinum strains that produce two serotypes (Ab, Ba, and Bf) have also been isolated from infant botulism cases. This is the first reported case of infant botulism due to C. botulinum type Af worldwide. PMID- 25502537 TI - IgA anti-epidermal transglutaminase autoantibodies: a simple test to improve differential diagnosis between dermatitis herpetiformis and atopic dermatitis. PMID- 25502538 TI - Acute siliconomas of the face triggered by skin rejuvenation mesotherapy with low weight hyaluronic acid: surgical treatment and pathogenetic hypothesis. PMID- 25502539 TI - Cutaneous and systemic vasculitis: cellular players and pathogenetic aspects. AB - Vascular wall damage, inflammatory cell recruitment and subsequent structural remodelling define a vasculitic process. Histopathological classification of vasculitis is based on the caliber of the vessel involved and on the prevalent type of inflammatory cells (neutrophils in acute forms, lymphocytic for chronic, histiocytic for granulomatous). A large amount of information is emerging from the literature on the complex pathophysiology of the cellular components of vessel wall. For instance, endothelial cells not only have the task to cover the inner surface of the vascular system but they also play an active role in tuning the immunological response in a very sophisticated way. Neutrophils are not only terminally differentiated cells sacrificed for a valuable cause. Cellular types of the perivascular microenvironment play roles one time not expected. The spread of the inflammatory process into the vascular wall is not necessarily inside-out. These and other selected concepts will be discussed in this paper. PMID- 25502540 TI - The genetic organization of the capsular polysaccharide biosynthesis region of Actinobacillus pleuropneumoniae serotype 15. AB - Nucleotide sequence determination and analysis of the cps gene involved in the capsular polysaccharide biosynthesis of Actinobacillus pleuropneumoniae serotype 15 revealed the presence of three open reading frames, designated as cps15ABC genes. At the protein level, Cps15A and Cps15B showed considerably high homology to CpsA (67.0 to 68.7%) and CpsB (31.7 to 36.8%), respectively, of A. pleuropneumoniae serotypes 1, 4 and 12, revealing the common genetic organization of the cps among serotypes 1, 4, 12 and 15. However, Cps15C showed no homology to any proteins of A. pleuropneumoniae serotypes, indicating that cps15C may be specific to serotype 15. This study will provide the basic molecular knowledge necessary for the development of diagnostics and a vaccine for A. pleuropneumoniae serotype 15. PMID- 25502541 TI - Organic acids induce tolerance to zinc- and copper-exposed fungi under various growth conditions. AB - Heavy metals, Zn and Cu, in high concentration (2 mM for Zn and 0.5 mM for Cu) have some inhibiting effect on the growth of Aspergillus niger and Penicillium citrinum. Toxic effects of these metals considerably depend on cultivation conditions including nitrogen sources, pH of nutrient media, and its consistency (presence or absence of agar). In general, nitrate media provides less inhibiting effect on fungal growth under heavy metal exposure than ammonium-containing media. Adding of Zn in nitrate media induces oxalic acid production by fungi. Importance of oxalic acid production in detoxification of heavy metals is confirmed by the formation of Zn-containing crystals in fungal cultures. Cu bringing to the cultural media had no stimulating effect on oxalic acid production as well as no copper-containing crystals were observed. But proceeding from essential increase in oxalic acid production during a long-term fungi adaptation to Cu, it may be proposed that oxalic acid plays some functional role in Cu tolerance of fungi as well. It may be concluded that the role of organic acids and oxalate, in particular, in fungi tolerance and adaptation to heavy metals can be determined by the nature of the metal and its ability to form stable complexes with an acid anion. Stimulating effect of metals on acid production is not universal for all species of fungi and largely depends on metal concentration, nitrogen form in a medium, and other cultivation conditions. PMID- 25502543 TI - Comparison of FTIR transmission and transfection substrates for canine liver cancer detection. AB - FTIR spectroscopy is a widely used technique that provides insights into disease processes at the molecular level. Due to its numerous advantages it is becoming an increasingly powerful tool for the study of biological materials and has the potential to become an excellent diagnostic method, especially considering the low cost of transflection substrates. However, questions about the usefulness of the transflection measurement mode due to the complicated nature of physical processes occurring during the measurement and in particular the Electric Field Standing Wave (EFSW) effect have been raised. In this paper we present a comparison of the two most common FT-IR measurement modes: transmission and transfection using healthy and pathologically altered tissue (histiocytic sarcoma). We found that the major differences between normal and cancerous tissue were associated with changes DNA and carbohydrate content. In particular we identified a band at 964 cm(-1) assigned to a nucleic acid phosphodiester backbone mode, which appeared more pronounced in cancerous tissue irrespective of the substrate. We applied Principal Component Analysis, Unsupervised Hierarchical Cluster Analysis and k-means clustering to transmission and transflection substrates and found that both measurement modes were equally capable of discrimination normal form cancerous tissue. Moreover, the differences between spectra from cancerous and normal tissue were significantly more important than the ones arising from the measurement modes. PMID- 25502542 TI - Expression of difficult-to-remove host cell protein impurities during extended Chinese hamster ovary cell culture and their impact on continuous bioprocessing. AB - During biopharmaceutical manufacturing, Chinese hamster ovary (CHO) cells produce hundreds of extracellular host cell protein (HCP) impurities, which must be removed from the therapeutic product by downstream purification operations to ensure patient safety. A subset of 118 of these HCPs have been reported as exceptionally difficult to remove during downstream purification because they co purify due to retention characteristics on chromatographic media and/or product association through strongly attractive interactions to the therapeutic protein. As the biopharmaceutical industry moves towards continuous bioprocessing, it is important to consider the impact of extended culture of CHO cells on the expression of extracellular HCP impurities, especially those HCPs known to challenge downstream purification. Two complementary proteomic techniques, two dimensional electrophoresis (2DE) and shotgun, were applied to detect variations in the extracellular CHO HCP profile over 500 days of culture. In total, 92 HCPs exhibited up to 48-fold changes in expression, with 34 of these HCPs previously reported as difficult to purify. Each proteomic technique detected differential expression by a distinct set of HCPs, with 10 proteins exhibiting significant variable expression by both methods. This study presents the impact of cell age on the extracellular CHO HCP impurity profile and identifies HCPs with variable expression levels, which warrant further investigation to facilitate their clearance in downstream purification. PMID- 25502544 TI - Evidence for an Association Between Vitamin D and Multiple Sclerosis. AB - The cause of MS remains unknown, but a number of genetic and environmental risk factors, and their interactions, are thought to contribute to disease risk. A substantial evidence base now exists supporting an association between vitamin D and MS, primarily illustrated by a latitudinal gradient of MS prevalence, a month of birth effect, an interaction of vitamin D with MS-associated genes and the fact that high vitamin D levels have been associated with a reduced MS risk in longitudinal prospective work. The association is primarily based on epidemiological studies which renders the more elusive question of whether this association truly represents causation, or indeed reverse causality in the light of a potentially uncharacterised pro-dromal phase of the disease. The prospect of vitamin D supplementation preventing MS is a very attractive notion, but a number of areas of inconsistencies and unanswered questions exist. Most notably, future work will need to establish appropriate dosing, timing and method of vitamin D supplementation in optimising any potential clinical benefit. In this chapter, we discuss the strong epidemiological and growing mechanistic evidence supporting an association between vitamin D and MS, and aim to highlight areas of current debate and where future efforts would be well worth targeting. Given that MS is currently the most common, and a rising, cause of neurological disability in young adults in the Western world, elucidating the relationship between vitamin D and MS is a necessary priority in aiming to further develop therapeutic and preventative strategies against this disease. PMID- 25502545 TI - Developing Biomarkers for MS. AB - Existing clinical outcomes of disease activity, including relapse rates, are inherently insensitive to the underlying pathological process in MS. Moreover, it is extremely difficult to measure clinical disability in patients, which is often a retrospective assessment, and definitely not within the time frame of a clinical trial. Biomarkers , conversely are more specific for a pathologic process and if used correctly can prove invaluable in the diagnosis, stratification and monitoring of disease activity, including any subclinical activity which is not visible to the naked eye. In this chapter, we discuss the development of neurofilaments as surrogate outcomes of disability in MS. The validation and qualification are vital steps in biomarker development and to gaining acceptance in scientific community, and the pitfalls leading up to this are also discussed. PMID- 25502547 TI - Detection of clonal aberrations by cytogenetic analysis after different culture methods and by FISH in 129 patients with Chronic Lymphocytic Leukemia. AB - There are only a few cytogenetic analysis (CA) studies that directly compare the novel cultivation technique using immunostimulatory CpG-oligonucleotide DSP30/interleukin-2 (DSP30/IL2) with other culture methods. Therefore, parallel cultures of peripheral blood of 129 chronic lymphocytic leukemia (CLL) patients were set up in unstimulated cultures, in the presence of pokeweed medium (PWM), and with DSP30/IL2. Furthermore, CA results were compared with data obtained by FISH. Clonal aberrations were observed by CA in 6% of the cases in unstimulated cultures, in 27% of the cases with PWM, and in 40% of the cases with DSP30/IL2. Some clonal aberrations were detected by CA only with one culture method. Using 3 different culture methods, clonal aberrations were detected in 41% of the cases by CA and in 71% of the cases by FISH. Altogether, 78% of the cases exhibited clonal aberrations discovered by CA and FISH. Also, CA detected clonal aberrations not targeted by FISH in 7% of the cases, and FISH identified clonal aberrations not detected by CA in 36% of the cases. Our study demonstrates that the combined use of CA with different culture methods together with FISH increases our knowledge of the genetic complexity and heterogeneity in CLL pathogenesis. PMID- 25502546 TI - Optogenetic control of hypocretin (orexin) neurons and arousal circuits. AB - In 1998, our group discovered a cDNA that encoded the precursor of two putative neuropeptides that we called hypocretins for their hypothalamic expression and their similarity to the secretin family of neuropeptides. In the last 16 years, numerous studies have placed the hypocretin system as an integrator of homeostatic functions with a crucial, non-redundant function as arousal stabilizer. We recently applied optogenetic methods to interrogate the role of individual neuronal circuits in sleep-to-wake transitions. The neuronal connections between the hypocretin system and the locus coeruleus (LC) seem to be crucial in establishing the appropriate dynamic of spontaneous awakenings. PMID- 25502548 TI - MTA1 downregulation inhibits malignant potential in a small cell lung cancer cell line. AB - As a component of the nuclear remodeling and deacetylation complex (NuRD complex), metastasis-associated gene 1 (MTA1) has been reported to play a key role in cancer malignancy. However, whether MTA1 functions in small cell lung cancer (SCLC) malignant behavior and whether it is feasible to be used as a therapeutic target have not been evaluated. The present study aimed to investigate the effects of MTA1 downregulation on SCLC malignancy. First we demonstrated the overexpression of MTA1 in SCLC specimens. After knocking down the MTA1 level by specific siRNA sequence, the biological consequences on proliferation, migration, invasion and apoptosis were evaluated. The results showed that MTA1 silencing had potent suppressive effects on SCLC proliferation, migration and invasion. Apoptosis but not cell cycle arrest was induced in the MTA1-silenced SCLC cells. In summary, MTA1 plays a critical role in regulating the malignant behaviors of SCLC. Depleting MTA1 level may be an effective strategy by which to suppress SCLC growth and metastasis in future biotherapeutic attempts. PMID- 25502549 TI - Dementia RED (Respect Empathy Dignity): Collaborating to build dementia supportive communities in North Wales--reporting on a pilot project (innovative practice). AB - There is increasing interest in developing dementia supportive communities world wide. Dementia RED (Respect Empathy Dignity) is a unique example from North Wales which is based on the twin concepts of people living with dementia as citizens in their community and developing 'bottom up' rather than 'top down' approaches to dementia supportive communities. Most people with dementia prefer to live at home thus making community connectivity key to maintaining healthy relationships and wellbeing. For those living with dementia, the community plays a pivotal role in providing value, meaning, purpose and acceptance. Building dementia supportive communities helps to raise awareness about dementia in the community through engagement and from identifying champions in the locality to voice issues. Dementia RED is an initiative and service which helps to develop such a philosophy in creating a dementia supportive community. PMID- 25502551 TI - Is the novel SCKL3 at 14q23 the predominant Seckel locus? PMID- 25502552 TI - Patient experiences of inpatient hospital care: a department matter and a hospital matter. AB - OBJECTIVE: To examine the added value of measuring and possibly presenting patient experiences at the department level, in addition to the hospital level, and to explore the possibility that patient experiences differ according to the 'type' of hospital department. DESIGN: Secondary analysis of data from a widely used survey on patient experiences of Dutch inpatient hospital care [Consumer Quality Index (CQI) Inpatient Hospital Care]. SETTING: Inpatient hospital care experience survey of patients of 78 Dutch hospitals. PARTICIPANTS: A total of 15 171 randomly selected inpatients from 78 Dutch hospitals, who had at least one night of hospitalization between October 2006 and October 2007. MAIN OUTCOME MEASURES: Explained variance in patient experiences at the department level, compared with the explained variance at the hospital level. Significant differences in patient experiences between types of departments, expressed in regression coefficients. Patient experiences were measured using validated quality indicators, calculated from specific survey items. RESULTS: Adding the department level to the analyses of patient experiences is statistically worthwhile for a number of quality indicators of the CQI Inpatient Hospital Care, and will enable the presentation of more detailed results within hospitals. Furthermore, the results indicated that there are some systematic differences in patient experiences between specific types of hospital departments across hospitals. However, the proportion of variance in experiences explained by both department and hospital is limited (max. 14%). CONCLUSIONS: Analyses of quality information on patient experiences of inpatient hospital care should not only take the hospital level, but also at the more specific department level into account. PMID- 25502553 TI - Organizational culture affecting quality of care: guideline adherence in perioperative antibiotic use. AB - OBJECTIVE: The objective of this work was to elucidate aspects of organizational culture associated with hospital performance in perioperative antibiotic prophylaxis using quantitative data in a multicenter and multidimensional study. DESIGN: Cross-sectional retrospective study using a survey data and administrative data. SETTING: Eighty-three acute hospitals in Japan. PARTICIPANTS: A total of 4856 respondents in the organizational culture study, and 23 172 patients for the quality indicator analysis. MAIN OUTCOME MEASURE: Multilevel models of various cultural dimensions were used to analyze the association between hospital organizational culture and guideline adherence. The dependent variable was adherence or non-adherence to Japanese and CDC guidelines at the patient level and main independent variable was hospital groups categorized according to organizational culture score. Other control variables included hospital characteristics such as ownership, bed capacity, region and urbanization level of location. RESULTS: The multilevel analysis showed that hospitals with a high score in organizational culture were more likely to adhere to the Japanese and CDC guidelines when compared with lower scoring hospitals. In particular, the hospital group with high scores in the 'collaboration' and 'professional growth' dimensions had three times the odds for Japanese guideline adherence in comparison with low-scoring hospitals. CONCLUSIONS: Our study revealed that various aspects of organizational culture were associated with adherence to guidelines for perioperative antibiotic use. Hospital managers aiming to improve quality of care may benefit from improving hospital organizational culture. PMID- 25502555 TI - Texture variations suppress suprathreshold brightness and colour variations. AB - Discriminating material changes from illumination changes is a key function of early vision. Luminance cues are ambiguous in this regard, but can be disambiguated by co-incident changes in colour and texture. Thus, colour and texture are likely to be given greater prominence than luminance for object segmentation, and better segmentation should in turn produce stronger grouping. We sought to measure the relative strengths of combined luminance, colour and texture contrast using a suprathreshhold, psychophysical grouping task. Stimuli comprised diagonal grids of circular patches bordered by a thin black line and contained combinations of luminance decrements with either violet, red, or texture increments. There were two tasks. In the Separate task the different cues were presented separately in a two-interval design, and participants indicated which interval contained the stronger orientation structure. In the Combined task the cues were combined to produce competing orientation structure in a single image. Participants had to indicate which orientation, and therefore which cue was dominant. Thus we established the relative grouping strength of each cue pair presented separately, and compared this to their relative grouping strength when combined. In this way we observed suprathreshold interactions between cues and were able to assess cue dominance at ecologically relevant signal levels. Participants required significantly more luminance and colour compared to texture contrast in the Combined compared to Separate conditions (contrast ratios differed by about 0.1 log units), showing that suprathreshold texture dominates colour and luminance when the different cues are presented in combination. PMID- 25502556 TI - Magnetic and structural properties of dinuclear singly bridged-phenoxido metal(II) complexes. AB - The reaction of a methanolic solution containing the bi-compartmental phenolic ligand 2,6-bis[bis(2-pyridylmethyl)aminomethyl]-4-chlorophenol (L(Cl)-OH) with MCl2.nH2O in the presence of NH4PF6 or NaClO4 afforded the dinuclear bridged phenoxido dichlorido-metal(ii) complexes [Co2(MU-L(Cl)O)(H2O)2Cl2][Co2(MU L(Cl)O)(MeOH)2Cl2](PF6)2 (), [Ni2(MU-L(Cl)O)(MeOH)2Cl2]PF6 (), [Ni2(MU L(Cl)O)(MeOH)(H2O)Cl2]ClO4.1.25H2O (), [Cu2(MU-L(Cl)O)Cl2]PF6.1/2MeOH () and [Zn2(MU-L(Cl)O)Cl2]PF6.MeOH (). The complexes were characterized by elemental microanalyses, conductivity measurements, IR and UV-Vis spectroscopy, mass spectrometry and single crystal X-ray crystallography. Each M(ii) center within the dinuclear complex cations is octahedrally coordinated in complexes , and five coordinated distorted square pyramidal in and . Magnetic susceptibility measurements at variable temperature of the complexes revealed weak to moderate antiferromagnetic coupling with |J| values = 8.38, 39.0, 30.2 and 0.79 cm(-1), respectively. The results of DFT calculations correlate well with the experimentally determined antiferromagnetic coupling and show that the magnetic exchange coupling occurs mainly through the phenoxido bridge M-O-M. Implications of geometry around the central metal ion, MM distance, M-O-M bond angle and overlapping of magnetic orbitals on the magnetic exchange coupling are discussed. PMID- 25502554 TI - The role of the NADPH oxidase NOX2 in prion pathogenesis. AB - Prion infections cause neurodegeneration, which often goes along with oxidative stress. However, the cellular source of reactive oxygen species (ROS) and their pathogenetic significance are unclear. Here we analyzed the contribution of NOX2, a prominent NADPH oxidase, to prion diseases. We found that NOX2 is markedly upregulated in microglia within affected brain regions of patients with Creutzfeldt-Jakob disease (CJD). Similarly, NOX2 expression was upregulated in prion-inoculated mouse brains and in murine cerebellar organotypic cultured slices (COCS). We then removed microglia from COCS using a ganciclovir-dependent lineage ablation strategy. NOX2 became undetectable in ganciclovir-treated COCS, confirming its microglial origin. Upon challenge with prions, NOX2-deficient mice showed delayed onset of motor deficits and a modest, but significant prolongation of survival. Dihydroethidium assays demonstrated a conspicuous ROS burst at the terminal stage of disease in wild-type mice, but not in NOX2-ablated mice. Interestingly, the improved motor performance in NOX2 deficient mice was already measurable at earlier stages of the disease, between 13 and 16 weeks post inoculation. We conclude that NOX2 is a major source of ROS in prion diseases and can affect prion pathogenesis. PMID- 25502557 TI - CASP8 SNP D302H (rs1045485) is associated with worse survival in MYCN-amplified neuroblastoma patients. AB - BACKGROUND: Neuroblastoma is a pediatric cancer that exhibits a wide clinical spectrum ranging from spontaneous regression in low-risk patients to fatal disease in high-risk patients. The identification of single nucleotide polymorphisms (SNPs) may help explain the heterogeneity of neuroblastoma and assist in identifying patients at higher risk for poor survival. SNPs in the TP53 pathway are of special importance, as several studies have reported associations between TP53 pathway SNPs and cancer. Of note, less than 2% of neuroblastoma tumors have a TP53 mutation at diagnosis. PATIENTS AND METHODS: We selected 21 of the most frequently studied SNPs in the TP53 pathway and evaluated their association with outcome in 500 neuroblastoma patients using TaqMan allelic discrimination assays. RESULTS AND CONCLUSION: We investigated the impact of 21 SNPs on overall survival, event-free survival, age at diagnosis, MYCN status, and stage of the disease in 500 neuroblastoma patients. A missense SNP in exon 10 of the CASP8 gene SNP D302H was associated with worse overall and event-free survival in patients with MYCN-amplified neuroblastoma tumors. PMID- 25502559 TI - Structure-affinity properties of a high-affinity ligand of FKBP12 studied by molecular simulations of a binding intermediate. AB - With a view to explaining the structure-affinity properties of the ligands of the protein FKBP12, we characterized a binding intermediate state between this protein and a high-affinity ligand. Indeed, the nature and extent of the intermolecular contacts developed in such a species may play a role on its stability and, hence, on the overall association rate. To find the binding intermediate, a molecular simulation protocol was used to unbind the ligand by gradually decreasing the biasing forces introduced. The intermediate was subsequently refined with 17 independent stochastic boundary molecular dynamics simulations that provide a consistent picture of the intermediate state. In this state, the core region of the ligand remains stable, notably because of the two anchoring oxygen atoms that correspond to recurrent motifs found in all FKBP12 ligand core structures. Besides, the non-core regions participate in numerous transient intermolecular and intramolecular contacts. The dynamic aspect of most of the contacts seems important both for the ligand to retain at least a part of its configurational entropy and for avoiding a trapped state along the binding pathway. Since the transient and anchoring contacts contribute to increasing the stability of the intermediate, as a corollary, the dissociation rate constant [Formula: see text] of this intermediate should be decreased, resulting in an increase of the affinity constant [Formula: see text]. The present results support our previous conclusions and provide a coherent rationale for explaining the prevalence in high-affinity ligands of (i) the two oxygen atoms found in carbonyl or sulfonyl groups of dissimilar core structures and of (ii) symmetric or pseudo-symmetric mobile groups of atoms found as non-core moieties. Another interesting aspect of the intermediate is the distortion of the flexible 80 s loop of the protein, mainly in its tip region, that promotes the accessibility to the bound state. PMID- 25502558 TI - A model of metabolic syndrome and related diseases with intestinal endotoxemia in rats fed a high fat and high sucrose diet. AB - AIM: We sought develop and characterize a diet-induced model of metabolic syndrome and its related diseases. METHODS: The experimental animals (Spague Dawley rats) were randomly divided into two groups, and each group was fed a different feed for 48 weeks as follows: 1) standard control diet (SC), and 2) a high sucrose and high fat diet (HSHF). The blood, small intestine, liver, pancreas, and adipose tissues were sampled for analysis and characterization. RESULTS: Typical metabolic syndrome (MS), non-alcoholic fatty liver disease (NAFLD), and type II diabetes (T2DM) were common in the HSHF group after a 48 week feeding period. The rats fed HSHF exhibited signs of obesity, dyslipidemia, hyperglycaemia, glucose intolerance, and insulin resistance (IR). At the same time, these animals had significantly increased levels of circulating LPS, TNFalpha, and IL-6 and increased ALP in their intestinal tissue homogenates. These animals also showed a significant reduction in the expression of occluding protein. The HSHF rats showed fatty degeneration, inflammation, fibrosis, cirrhosis, and lipid accumulation when their liver pathologies were examined. The HSHF rats also displayed increased islet diameters from 12 to 24 weeks, while reduced islet diameters occurred from 36 to 48 weeks with inflammatory cell infiltration and islet fat deposition. The morphometry of adipocytes in HSHF rats showed hypertrophy and inflammatory cell infiltration. HSHF CD68 analysis showed macrophage infiltration and significant increases in fat and pancreas size. HSHF Tunel analysis showed significant increases in liver and pancreas cell apoptosis. CONCLUSIONS: This work demonstrated the following: 1) a characteristic rat model of metabolic syndrome (MS) can be induced by a high sucrose and high fat diet, 2) this model can be used to research metabolic syndrome and its related diseases, such as NAFLD and T2DM, and 3) intestinal endotoxemia (IETM) may play an important role in the pathogenesis of MS and related diseases, such as NAFLD and T2DM. PMID- 25502560 TI - Indirect modulation of sensitivity to 5-fluorouracil by microRNA-96 in human colorectal cancer cells. AB - 5-FU is an anticancer drug that is widely used to treat cancers, including colorectal cancer (CRC); however, chemoresistance to 5-FU remains an important problem to be resolved. The role of microRNAs (miRs) in chemosensitivity has recently been studied in the development of therapeutic strategies to overcome drug resistance. Here, we focused on miR-96, which has been reported to demonstrate chemosensitivity. We investigated whether 5-FU sensitivity may be modulated by miR-96 in monolayer cells and whether this relationship also applies for drug resistance in 3D tumor spheroids (TSs). When the level of miR-96 increased, the expression of the anti-apoptotic regulator XIAP and p53 stability regulator UBE2N decreased, resulting in increased apoptosis and growth inhibition following 5-FU exposure. Transfection of miR-96 inhibitors resulted in an overexpression of XIAP and UBE2N, yet only minimal change was induced in apoptosis. Nonetheless, luciferase assay failed to show direct interactions between miR-96 and these genes. In TSs, 5-FU resistance corresponded to a significantly lower level of miR-96, however only XIAP, not UBE2N, was up regulated demonstrating partial agreement with the 2D condition regarding target expression. Overall, these results suggest that miR-96 may modulate 5-FU sensitivity in CRC cells by promoting apoptosis; however, differential expression of target genes in TSs warrants further studies on the 5-FU resistance mechanism under 3D conditions. PMID- 25502561 TI - Chemical constituents from Belamcanda chinensis and their inhibitory effects on nitric oxide production in RAW 264.7 macrophage cells. AB - Belamcanda chinensis (L.) DC., which belongs to the family of Iridaceae, has been used as a folk medicine for the treatment of inflammation, asthma, tonsillitis, and many other throat disorders. Bioactivity-guided purification of the methylene chloride-soluble fraction of the rhizomes of B. chinensis based on the inhibition of nitric oxide production led to the identification of seventeen known compounds. Their structures were elucidated on the basis of extensive spectroscopic measurement such as NMR and ESI-MS. All of the isolated compounds were evaluated for their inhibitory effects on nitric oxide production in LPS induced RAW 264.7 macrophage cells. PMID- 25502562 TI - Unexpected DNA loss mediated by the DNA binding activity of ribonuclease A. AB - Ribonuclease A (RNase A) is widely used in molecular biology research both for analytical assays and for nucleic acid preparation. The catalytic mechanism of RNase A is well understood and absolutely precludes activity on DNA; however anecdotal reports of DNA degradation by RNase A are not uncommon. Here we describe a mechanism by which RNase A treatment can lead to apparent DNA degradation. This results from the surprising finding that RNase A remains functional in a phenol:chloroform mixture, to our knowledge the only enzyme that survives this highly denaturing solvent environment. Although RNase A does not cleave the DNA backbone it is capable of binding to DNA, forming stable RNase A DNA complexes that partition to the interphase or organic phase during phenol:chloroform purification. The unexpected survival of the RNase A DNA binding activity in phenol means that these complexes are not dissolved and a substantial amount of RNase A-bound DNA is permanently removed from the aqueous phase and lost on phase separation. This effect will impact DNA recovery from multiple procedures and is likely to represent a source of sequence bias in genome-wide studies. Our results also indicate that the results of analytical studies performed using RNase A must be considered with care. PMID- 25502563 TI - May-Thurner syndrome and other obstructive iliac vein lesions: meaning, myth, and mystery. AB - Acute and chronic venous disorders of the lower extremities affect millions of people and cause substantial disability. Long ago, surgeons and pathologists identified the presence of 'spur-like' abnormalities of the left common iliac vein; these abnormalities were hypothesized to result from compression and/or irritation from the adjacent crossing right common iliac artery. In the 1990s, physicians, starting to perform catheter-directed thrombolysis to treat extensive deep vein thrombosis (DVT), observed that about 50% of patients had an iliac vein stenosis. Vascular physicians have become aware of the occasional patient with otherwise-unexplained extremity swelling and/or pain but without a DVT history who is subsequently found to have an iliac vein abnormality. These 'lesions' have been hypothesized to elevate ambulatory venous pressures and thereby produce lower-extremity symptoms, increase the risk of initial and recurrent DVT episodes, and increase the risk of treatment failure with medical and endovascular therapies for thrombotic and non-thrombotic venous conditions. As a result, many practitioners now actively seek iliac venous obstructive 'lesions' when evaluating patients with known or suspected venous disease. However, for many patients, it continues to be unclear what degree of obstruction to venous blood flow is being caused by such lesions, how clinically significant they are, how much emphasis should be placed on identifying them, and when they should be treated. This article seeks to improve the knowledge base of vascular practitioners who make clinical decisions about the diagnosis and treatment of obstructive iliac vein lesions. PMID- 25502565 TI - Quantum state-controlled directional spontaneous emission of photons into a nanophotonic waveguide. AB - The spin of light in subwavelength-diameter waveguides can be orthogonal to the propagation direction of the photons because of the strong transverse confinement. This transverse spin changes sign when the direction of propagation is reversed. Using this effect, we demonstrate the directional spontaneous emission of photons by laser-trapped caesium atoms into an optical nanofibre and control their propagation direction by the excited state of the atomic emitters. In particular, we tune the spontaneous emission into the counter-propagating guided modes from symmetric to strongly asymmetric, where more than % of the optical power is launched into one or the other direction. We expect our results to have important implications for research in quantum nanophotonics and for implementations of integrated optical signal processing in the quantum regime. PMID- 25502564 TI - The effect of virus-blocking Wolbachia on male competitiveness of the dengue vector mosquito, Aedes aegypti. AB - BACKGROUND: The bacterial endosymbiont Wolbachia blocks the transmission of dengue virus by its vector mosquito Aedes aegypti, and is currently being evaluated for control of dengue outbreaks. Wolbachia induces cytoplasmic incompatibility (CI) that results in the developmental failure of offspring in the cross between Wolbachia-infected males and uninfected females. This increases the relative success of infected females in the population, thereby enhancing the spread of the beneficial bacterium. However, Wolbachia spread via CI will only be feasible if infected males are sufficiently competitive in obtaining a mate under field conditions. We tested the effect of Wolbachia on the competitiveness of A. aegypti males under semi-field conditions. METHODOLOGY/PRINCIPAL FINDINGS: In a series of experiments we exposed uninfected females to Wolbachia-infected and uninfected males simultaneously. We scored the competitiveness of infected males according to the proportion of females producing non-viable eggs due to incompatibility. We found that infected males were equally successful to uninfected males in securing a mate within experimental tents and semi-field cages. This was true for males infected by the benign wMel Wolbachia strain, but also for males infected by the virulent wMelPop (popcorn) strain. By manipulating male size we found that larger males had a higher success than smaller underfed males in the semi-field cages, regardless of their infection status. CONCLUSIONS/SIGNIFICANCE: The results indicate that Wolbachia infection does not reduce the competitiveness of A. aegypti males. Moreover, the body size effect suggests a potential advantage for lab-reared Wolbachia-males during a field release episode, due to their better nutrition and larger size. This may promote Wolbachia spread via CI in wild mosquito populations and underscores its potential use for disease control. PMID- 25502567 TI - Use of gold nanoparticles to detect water uptake in vascular plants. AB - Direct visualization of water-conducting pathways and sap flows in xylem vessels is important for understanding the physiology of vascular plants and their sap ascent. Gold nanoparticles (AuNPs) combined with synchrotron X-ray imaging technique is a new promising tool for investigating plant hydraulics in opaque xylem vessels of vascular plants. However, in practical applications of AuNPs for real-time quantitative visualization of sap flows, their interaction with a vascular network needs to be verified in advance. In this study, the effect of AuNPs on the water-refilling function of xylem vessels is experimentally investigated with three monocot species. Discrepancy in the water uptakes starts to appear at about 20 min to 40 min after the supply of AuNP solution to the test plant by the possible gradual accumulation of AuNPs on the internal structures of vasculature. However conclusively, it is observed that the water-refilling speeds in individual xylem vessels are virtually unaffected by hydrophilically surface modified AuNPs (diameter ~20 nm). Therefore, the AuNPs can be effectively used as flow tracers in the xylem vessels in the first 20~30 min without any physiological barrier. As a result, AuNPs are found to be useful for visualizing various fluid dynamic phenomena occurring in vascular plants. PMID- 25502568 TI - A new strategy to construct a FRET platform for ratiometric sensing of hydrogen sulfide. AB - We introduce a new FRET strategy to construct a ratiometric fluorescent H2S sensor. The ratio emission signal of the coumarin-naphthalimide dyad is modulated by the FRET process, which works in coordination with the ICT mechanism. The FRET process on/off is controlled through tuning the overlap level of the donor emission spectrum with the acceptor absorption via modulation of the acceptor fluorophore absorption wavelength. was applied to visualize both the intracellular exogenous and endogenous H2S through blue and green emission channels. PMID- 25502566 TI - Maf1 is a novel target of PTEN and PI3K signaling that negatively regulates oncogenesis and lipid metabolism. AB - Maf1 was initially identified as a transcriptional repressor of RNA pol III transcribed genes, yet little is known about its other potential target genes or its biological function. Here, we show that Maf1 is a key downstream target of PTEN that drives both its tumor suppressor and metabolic functions. Maf1 expression is diminished with loss of PTEN in both mouse models and human cancers. Consistent with its role as a tumor suppressor, Maf1 reduces anchorage independent growth and tumor formation in mice. PTEN-mediated changes in Maf1 expression are mediated by PTEN acting on PI3K/AKT/FoxO1 signaling, revealing a new pathway that regulates RNA pol III-dependent genes. This regulatory event is biologically relevant as diet-induced PI3K activation reduces Maf1 expression in mouse liver. We further identify lipogenic enzymes as a new class of Maf1 regulated genes whereby Maf1 occupancy at the FASN promoter opposes SREBP1c mediated transcription activation. Consistent with these findings, Maf1 inhibits intracellular lipid accumulation and increasing Maf1 expression in mouse liver abrogates diet-mediated induction of lipogenic enzymes and triglycerides. Together, these results establish a new biological role for Maf1 as a downstream effector of PTEN/PI3K signaling and reveal that Maf1 is a key element by which this pathway co-regulates lipid metabolism and oncogenesis. PMID- 25502571 TI - Metabolomic analysis reveals functional overlapping of three signal transduction proteins in regulating ethanol tolerance in cyanobacterium Synechocystis sp. PCC 6803. AB - Low ethanol tolerance is a crucial factor that restricts the feasibility of bioethanol production in renewable cyanobacterial systems. Our previous studies showed that several transcriptional regulators were differentially regulated by exogenous ethanol in Synechocystis. In this study, by constructing knockout mutants of 34 Synechocystis putative transcriptional regulator-encoding genes and analyzing their phenotypes under ethanol stress, we found that three mutants of regulatory gene sll1392, sll1712 and slr1860 grew poorly in the BG11 medium supplemented with ethanol when compared with the wild type in the same medium, suggesting that the genes may be involved in the regulation of ethanol tolerance. To decipher the regulatory mechanism, targeted LC-MS and untargeted GC-MS approaches were employed to determine metabolic profiles of the three mutants and the wild type under both normal and ethanol stress conditions. The results were then subjected to PCA and WGCNA analyses to determine the responsive metabolites and metabolic modules related to ethanol tolerance. Interestingly, the results showed that there was a significant overlapping of the responsive metabolites and metabolic modules between three regulatory proteins, suggesting that a possible crosstalk between various regulatory proteins may be involved in combating against ethanol toxicity in Synechocystis. The study provided new insights into ethanol-tolerance regulation and knowledge important to rational tolerance engineering in Synechocystis. PMID- 25502570 TI - Double dissociation of neural responses supporting perceptual and cognitive components of social cognition: evidence from processing of others' pain. AB - Models on how perceptual and cognitive information on others' mental states are treated by the cognitive architecture are often framed as duplex models considering two independent systems. In the context of the neuroscience of empathy analogous systems have been described. Using event-related potentials (i.e., ERPs) technique, we tested the hypothesis of temporal dissociation of two functional systems. We implemented a design in which perceptual (i.e., painful or neutral facial expressions) and contextual (i.e., painful or neutral related sentences) cues on others' mental states were orthogonally manipulated. Painful expressions selectively modulated the early activity at 110-360 ms over fronto central and centro-parietal regions, whereas painful contexts selectively modulated the late activity at 400-840 ms over these same regions. Notably, the reactions to pain triggered by these cues added up when both were available, that is the joint reaction was characterized by additive effects. These findings favor a model assuming distinct neural paths of perceptual and cognitive processing, at least when the cognitive component is triggered by language. PMID- 25502569 TI - Cellular responses during morphological transformation in Azospirillum brasilense and Its flcA knockout mutant. AB - FlcA is a response regulator controlling flocculation and the morphological transformation of Azospirillum cells from vegetative to cyst-like forms. To understand the cellular responses of Azospirillum to conditions that cause morphological transformation, proteins differentially expressed under flocculation conditions in A. brasilense Sp7 and its flcA knockout mutant were investigated. Comparison of 2-DE protein profiles of wild-type (Sp7) and a flcA deletion mutant (Sp7-flcADelta) revealed a total of 33 differentially expressed 2 DE gel spots, with 22 of these spots confidently separated to allow protein identification. Analysis of these spots by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and MASCOT database searching identified 48 proteins (>=10% emPAI in each spot). The functional characteristics of these proteins included carbon metabolism (beta-ketothiolase and citrate synthase), nitrogen metabolism (Glutamine synthetase and nitric oxide synthase), stress tolerance (superoxide dismutase, Alkyl hydroperoxidase and ATP-dependent Clp protease proteolytic subunit) and morphological transformation (transducer coupling protein). The observed differences between Sp7 wild-type and flcA- strains enhance our understanding of the morphological transformation process and help to explain previous phenotypical observations. This work is a step forward in connecting the Azospirillum phenome and genome. PMID- 25502574 TI - Erratum: Comparative evaluation of the effects of multiple autoclaving on cyclic fatigue resistance of three different rotary Ni-Ti instruments: An in vitro study: Erratum. AB - [This corrects the article on p. 323 in vol. 16, PMID: 23956534.]. PMID- 25502573 TI - Genomic profiling of human penile carcinoma predicts worse prognosis and survival. AB - The molecular mechanisms underlying penile carcinoma are still poorly understood, and the detection of genetic markers would be of great benefit for these patients. In this study, we assessed the genomic profile aiming at identifying potential prognostic biomarkers in penile carcinoma. Globally, 46 penile carcinoma samples were considered to evaluate DNA copy-number alterations via array comparative genomic hybridization (aCGH) combined with human papillomavirus (HPV) genotyping. Specific genes were investigated by using qPCR, FISH, and RT qPCR. Genomic alterations mapped at 3p and 8p were related to worse prognostic features, including advanced T and clinical stage, recurrence and death from the disease. Losses of 3p21.1-p14.3 and gains of 3q25.31-q29 were associated with reduced cancer-specific and disease-free survival. Genomic alterations detected for chromosome 3 (LAMP3, PPARG, TNFSF10 genes) and 8 (DLC1) were evaluated by qPCR. DLC1 and PPARG losses were associated with poor prognosis characteristics. Losses of DLC1 were an independent risk factor for recurrence on multivariate analysis. The gene-expression analysis showed downexpression of DLC1 and PPARG and overexpression of LAMP3 and TNFSF10 genes. Chromosome Y losses and MYC gene (8q24) gains were confirmed by FISH. HPV infection was detected in 34.8% of the samples, and 19 differential genomic regions were obtained related to viral status. At first time, we described recurrent copy-number alterations and its potential prognostic value in penile carcinomas. We also showed a specific genomic profile according to HPV infection, supporting the hypothesis that penile tumors present distinct etiologies according to virus status. PMID- 25502572 TI - In vivo early intervention and the therapeutic effects of 20(s)-ginsenoside rg3 on hypertrophic scar formation. AB - BACKGROUND: Intra-lesional injections of corticosteroids, interferon, and chemotherapeutic drugs are currently the most popular treatments of hypertrophic scar formation. However, these drugs can only be used after HS is formed, and not during the inflammatory phase of wound healing, which regulates the HS forming process. OBJECTIVE: To investigate a new, effective, combining therapeutic and safe drug for early intervention and treatment for hypertrophic scars. METHODS: Cell viability assay and flow cytometric analysis were studied in vitro. Animal studies were done to investigate the combining therapeutic effects of 20(S) ginsenoside Rg3 (Rg3) on the inflammatory phase of wound healing and HS formation. RESULTS: In vitro studies showed that Rg3 can inhibit HS fibroblasts proliferation and induce HSF apoptosis in a concentration-dependent manner. In vivo studies demonstrated that Rg3 can limit the exaggerated inflammation, and do not delay the wound healing process, which indicates that Rg3 could be used as an early intervention to reduce HS formation. Topical injection of 4 mg/mL Rg3 can reduce HS formation by 34%. Histological and molecular studies revealed that Rg3 injection inhibits fibroblasts proliferation thus reduced the accumulation of collagen fibers, and down-regulates VEGF expression in the HS tissue. CONCLUSION: Rg3 can be employed as an early intervention and a combining therapeutic drug to reduce inflammation and HS formation as well. PMID- 25502575 TI - Anti-inflammatory and anti-fibrotic profile of fish oil emulsions used in parenteral nutrition-associated liver disease. AB - Home parenteral nutrition (PN) is associated with many complications including severe hepatobiliary dysfunction. Commercial omega-6 fatty acid-soybean based lipid emulsions in PN may mediate long term PN associate liver disease (PNALD) whereas omega-3-fish oil parenteral emulsions have shown to reverse PNALD in children. However, its clinical effectiveness in adults has been scarcely reported. In this work, we study the role of soybean and fish oil lipid commercial emulsions on inflammatory and profibrotic liver markers in adults with long term PNALD and in in vitro cellular models. Inflammatory and profibrotic markers were measured in serum of ten adults with long term PNALD and in culture supernatants of monocytes. Liver epithelial to mesenchymal transition (EMT) was induced by transforming growth factor beta 1 (TGFbeta1) to evaluate in vitro liver fibrosis. Omegaven(r), a 100% fish oil commercial emulsion, was infused during four months in two patients with severe long term PNALD reversing, at the first month, the inflammatory, profibrotic and clinical parameters of PNALD. The effect was maintained during the treatment course but impaired when conventional lipid emulsions were reintroduced. The other patients under chronic soybean oil based PN showed elevated inflammatory and profibrotic parameters. In vitro human monocytes stimulated with lipopolysaccharide induced a strong inflammatory response that was suppressed by Omegaven(r), but increased by soybean emulsions. In other experiments, TGFbeta1 induced EMT that was suppressed by Omegaven(r) and enhanced by soybean oil lipid emulsions. Omegaven(r) improves clinical, anti inflammatory and anti-fibrotic parameters in adults with long-term home PNALD. PMID- 25502577 TI - Sex-dependent association between heart rate variability and pulse pressure in haemodialysis patients. AB - AIMS: Increased pulse pressure (PP) is associated with increased cardiovascular mortality in haemodialysis (HD) patients. Autonomic imbalance is common in HD patients and predisposes to sudden cardiac death, but its relationship to PP is unknown. We investigated the relationship between cardiac autonomic modulation assessed by heart rate variability (HRV) and PP in HD patients. METHODS: Continuous electrocardiograms recorded during HD sessions were repeated 5 times at 2-week intervals in stable HD patients. The high-frequency (HF) and low frequency (LF) components and the LF/HF ratio of HRV were calculated during the first and last hour of the recordings. These values and the corresponding systolic blood pressure (SBP), diastolic blood pressure (DBP) and PP measurements were averaged in repeated recordings of each patient. RESULTS: Seventy-six patients were included in the final analysis (aged 61 +/- 15 years, 32% females, 37% diabetics). In male patients, LF/HF correlated inversely with pre- and post HD PP (r = -0.369, p = 0.007 and r = -0.546, p = 0.000, respectively), positively with pre- and post-HD DBP (r = 0.358, p = 0.009 and r = 0.306, p = 0.028, respectively) and inversely with post-HD SBP (r = -0.350, p = 0.011). In female patients, LF/HF correlated positively with post-HD SBP (r = 0.422, p = 0.040). CONCLUSION: We observed an association between PP and HRV in male HD patients. Sex differences may be important for cardiac risk assessment. PMID- 25502576 TI - In silico models for dynamic connected cell cultures mimicking hepatocyte endothelial cell-adipocyte interaction circle. AB - The biochemistry of a system made up of three kinds of cell is virtually impossible to work out without the use of in silico models. Here, we deal with homeostatic balance phenomena from a metabolic point of view and we present a new computational model merging three single-cell models, already available from our research group: the first model reproduced the metabolic behaviour of a hepatocyte, the second one represented an endothelial cell, and the third one described an adipocyte. Multiple interconnections were created among these three models in order to mimic the main physiological interactions that are known for the examined cell phenotypes. The ultimate aim was to recreate the accomplishment of the homeostatic balance as it was observed for an in vitro connected three culture system concerning glucose and lipid metabolism in the presence of the medium flow. The whole model was based on a modular approach and on a set of nonlinear differential equations implemented in Simulink, applying Michaelis Menten kinetic laws and some energy balance considerations to the studied metabolic pathways. Our in silico model was then validated against experimental datasets coming from literature about the cited in vitro model. The agreement between simulated and experimental results was good and the behaviour of the connected culture system was reproduced through an adequate parameter evaluation. The developed model may help other researchers to investigate further about integrated metabolism and the regulation mechanisms underlying the physiological homeostasis. PMID- 25502578 TI - Ozone partially prevents diabetic neuropathy in rats. AB - Neuropathy is one of the most common complications of diabetes mellitus. Although the beneficial effects of good blood glucose control on diabetic neuropathy are known, this control cannot completely prevent the occurrence and progression of diabetic neuropathy. The aim of this study was to investigate whether ozone prevents diabetic neuropathy. 36 adult female Sprague-Dawley rats were randomly divided into 6 groups (n=6): control (C), ozone (O), diabetic (D), ozone-treated diabetic (DO), insulin-treated diabetic (DI), and ozone- and insulin-treated diabetic (DOI). Diabetes was induced by a single injection of streptozotocin (60 mg/kg, intraperitoneal [i.p.]), after which insulin was administered (3 IU, i.p.) to the DI and DOI groups for 28 days, and 1.1 mg/kg (50 ug/ml) ozone was given to the O, DO, and DOI groups for 15 days. 4 weeks after the induction of diabetes, the nerve conduction velocity (NCV), amplitude of the compound action potential (CAP), total oxidant status (TOS), and total antioxidant status (TAS) were measured, and the oxidative stress index (OSI) was calculated. The NCV, amplitude of CAP, and TAS of the DI and DOI groups were higher than those of the D group; the amplitudes of CAP and TAS of the DO group were higher than those of the D group; and the TOS and OSI of the DO, DI, and DOI groups were lower than those of the D group. These findings indicate that ozone partially prevents diabetic neuropathy in rats. It appears that the preventive effects of ozone are mediated through oxidant/antioxidant mechanisms. PMID- 25502579 TI - Amelioration of high fat diet-induced glucose intolerance by blockade of Smad4 in pancreatic beta-cells. AB - BACKGROUND: In this study, we investigated whether Smad4 signaling is involved in the regulation of beta-cell function using a high fat diet (HFD)-induced obesity mouse model. METHODS: Beta-cell-specific Smad4-knockout mice (Smad4(-/-)RIP Cre(+); beta-Smad4KO) were generated by mating Smad4 (flox/flox) mice with rat insulin promoter (RIP)-Cre mice. Mice were fed a HFD beginning at 6 weeks of age for 16 weeks. Body weight, food intake, fasting and fed glucose levels, and glucose and insulin tolerance were measured. RESULTS: The expression of Smad4 mRNA was significantly decreased in the islets of beta-Smad4KO mice. In wild-type mice, Smad4 mRNA was significantly decreased at 18 weeks of age as compared with 8 weeks of age. On a regular chow diet, beta-Smad4KO mice showed no differences in body weight, fed and fasting blood glucose levels, and glucose tolerance compared with wild-type mice. When fed a HFD, body weight gain was significantly reduced in beta-Smad4KO mice as compared with wild-type mice, although the amount of food intake was not different. During the HFD, fed and fasting blood glucose levels, glucose stimulated insulin secretion, disposition index and glucose tolerance were significantly improved in beta-Smad4KO mice as compared with wild type mice. However, insulin tolerance tests showed no differences between the 2 groups. CONCLUSION: Inhibition of Smad4 in beta-cells conferred mild but significant improvements in glucose levels and glucose tolerance in HFD-induced obese mice. Therefore, regulation of Smad4 expression may be one of the mechanisms regulating physiological expansion of beta-cells during development of type 2 diabetes. PMID- 25502580 TI - Effects of different gastrointestinal surgical approaches on pancreatic beta-cell function in type 2 diabetic patients with BMIs<30. AB - OBJECTIVE: Gastrointestinal surgery has been performed for many years to achieve durable and effective treatments of type 2 diabetes mellitus (T2DM). This study determined the effects of different surgical operations on pancreatic beta-cell function in patients with T2DM with BMIs<30 kg/m(2). DESIGN AND PATIENTS: A total of 46 patients with diabetes and BMIs<30 kg/m(2) underwent gastrointestinal surgery; 23 patients underwent Roux-en-Y gastric bypass (RYGB), and 23 patients underwent Billroth Iota gastrectomy (BIotaG). Oral glucose tolerance tests were used to evaluate pancreatic beta cell function. Serum insulin was measured by enzyme-linked immunosorbent assay (ELISA), and blood glucose was detected with the glucose oxidase method. HOMA-IR and HOMA-beta were evaluated with the HOMA equation. RESULTS: The T2DM remission rates were 21.7% (5/23) in the BIotaG group and 82.6% (19/23) in the RYGB group. There was a significant difference in the improvements in postoperative glycosylated hemoglobin A1c (GHbA1c) and glycated hemoglobin A1 (GHbA1) between the BIotaG and RYGB groups (P=0.001, P=0.002). OGTT revealed that both fasting blood glucose (FBG) and blood glucose at the designated time points after glucose loading were significantly lower in the RYGB group than in the BIotaG group. Insulin levels (at 30 and 60 min), insulin release indices (at 30 and 60 min), HOMA-beta and DeltaI30/DeltaG30 were significantly higher in the RYGB group than in the BIotaG group (P<0.05). CONCLUSIONS: Patients with BMIs<30 kg/m(2) who underwent RYGB surgery exhibited significantly greater improvements or resolutions of T2DM and significantly better recoveries of beta-cells function than did those in the BIotaG group. PMID- 25502581 TI - Losartan reduces insulin resistance by inhibiting oxidative stress and enhancing insulin signaling transduction. AB - BACKGROUND: Inhibition of the rennin-angiotensin system (RAS) could reduce insulin resistance in patients with hypertension and diabetic kidney disease (DKD), but whether the effect of losartan on insulin resistance is associated with reduction of oxidative stress and enhancement of insulin signaling transduction has not been fully elucidated. METHODS: 130 patients with type 2 DKD were randomly assigned into 2 groups, the losartan group (n=65, 100 mg orally daily for 12 months) and the amlodipine group (n=65, 10 mg orally daily for 12 months). Oxidative stress markers in plasma, urine concentrations of 8-hydroxy-2' deoxyguanosine (8-OHdG) and nitrotyrosine (NT) as well as SOD activity were measured by ELISA. After in vitro treatment with different doses of losartan (10, 100 MUmol/L) or amlodipine for 48 h, the size of H2O2-induced adipocytes and glucose consumption were measured. Western blot was performed to investigate IRS 1 serine phosphorylation level as well as the protein expressions of phosphorylated insulin receptor (pIR), phosphatidylinositol 3- kinase (PI3K) and insulin receptor substrate 1 (IRS-1) in 3T3-L1 adipocytes. RESULTS: After 12 month treatment, there were no significant differences in systolic and diastolic blood pressures decreases, plasma fasting blood glucose and HbA1c between the 2 groups. Compared with amlodipine group, fasting blood insulin levels and insulin resistance index (HOMA-IR) were significantly decreased in losartan group, and in addition, the circulating levels of 8-OHdG and NT were significantly decreased in losartan group, while the serum SOD activity was enhanced. There were significant positively correlations of HOMA-IR with inflammatory oxidative stress markers. In vitro study showed that losartan could increase glucose uptake in 3T3-L1 adipocytes (P<0.01) and decrease adipocyte size (P<0.01), while amlodipine can't. Losartan can also enhance adiponectin (P<0.05) and decrease TNF-alpha (P<0.05) and IL-6 (P<0.01) secretion, while amlodipine can't. The protein expressions of pIR, IRS-1 and PI3K were significantly increased after treatment with losartan (P<0.01), while the level of IRS-1 serine phosphorylation was decreased (P<0.01), which could be blocked by specific PI3K inhibitor wortmannin. CONCLUSIONS: These results suggest that the effect of losartan on insulin resistance is associated with the reduction of oxidative stress and inflammation in patients with type 2 DKD as well as the activation of insulin signal pathway in insulin-resistance 3T3 L1 adipocytes through modulation of PI3K pathway. (Clinical Trials. gov number, NCT 00774904). PMID- 25502582 TI - The polymorphism of type 1 collagen (COL1A1) gene does not correlate with an increased risk of foot ulcers in patients with diabetes mellitus. AB - AIM: Diabetic foot syndrome (DFS) is a multifactorial debilitating complication of diabetes mellitus (DM). The identification of markers for predicting the risk of developing DFS could help and direct the efforts in the prevention to the highest risk patients. Type I collagen alpha1 (COL1A1) is the main component of type I collagen, the most abundant structural protein of the extracellular matrix of subcutaneous tissue. COL1A1 polymorphism has been previously investigated with regard to many clinical conditions affecting the bone or the skin. In this prospective study, we have assessed COL1A1 polymorphism in patients without and with DFS. PATIENTS AND METHODS: 202 DM patients without and 103 patients with DFS have been recruited. COL1A1 polymorphism, due to a mutation affecting the zinc finger transcription factor specific protein, has been investigated. The most relevant clinical data (HbA1c, vascular risk factors, insulin treatment) have been collected and analyzed. RESULTS: No statistically significant difference in the distribution of the 3 genotypes constituting COL1A1 polymorphism between patients without and with DFS has been observed. Almost all DFS patients had at least one vascular risk factor, with a high rate of arterial hypertension and dyslipidemia. CONCLUSION: A multifaceted set of factors is involved in the development of DFS and only a combination of them may lead to such occurrence. In our DM patient population, COL1A1 polymorphism does not correlate with the occurrence of DFS, which appears to depend mostly on the presence of vascular risk factors. However, the impact of genetic factors affecting other components of the subcutaneous tissue cannot be excluded. PMID- 25502583 TI - A comprehensive review of erectile dysfunction in men with diabetes. AB - Erectile dysfunction (ED) is more common in men with diabetes (DM). Dependent on the selected population, age, DM type and duration, the prevalence of diabetic ED (DED) varies from 32 to 90%. In 12-30% of men ED is the first sign of diabetes, diagnosed later. Today men with diabetes live longer than ever, and develop more late diabetic complications. Having in mind also the global ageing of the world population all this data suggests an increasing number of men with DED in the future. The main factors playing in the complex pathogenesis of DED are diabetic neuropathy (oxidative stress, polyol pathway, advanced glycation end-products, nerve growth factor deficiency, dysfunction of protein kinase C, tissue remodeling, etc.), macrovascular arterial disease (endothelial dysfunction, abnormal collagen deposition and smooth muscle degeneration, dyslipidemia, arterial hypertension, veno-occlusive dysfunction, etc.), hypogonadism, structural remodeling of the corporeal tissue, psychogenic components and adverse drug reactions. The diagnostic process is based on the results of questionnaires, neurological, vascular (Doppler) and other more rarely used investigations.Because of the complex pathogenesis of DED diabetic men represent a "difficult" treatment group. The difficulties are from the "beginning", because patients do not talk about their problem spontaneously, and doctors do not ask about it. The treatment of DED should be team work, preferably including also specialists in sexual medicine. Psychological support and counseling of the couple is necessary in most cases. The general measures include implementation of a healthier lifestyle, improved glycemic-, lipids-, and arterial pressure control, and careful re-evaluation of the concomitant medications. The specific treatment includes as first line therapy the inhibitors of phosphodiesterase type 5 (PDE-5) with lesser effectiveness compared to non-DM men. There are rare studies with selected diabetic populations and even less with head-to-head comparisons between the PDE-5 inhibitors. Men with DM have a higher prevalence of hypogonadism. Testosterone replacement therapy should be started in symptomatic men with proven hypogonadism and no contraindications. Vacuum constriction devices and intracavernous or intraurethral applications of vasoactive drugs are the second line therapy. Vascular surgery rarely comes into consideration. The penile implant is the last and effective option in men with severe DED. PMID- 25502584 TI - Attributable risk calculations for testicular microlithiasis. PMID- 25502585 TI - Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). PMID- 25502586 TI - Etiological spectrum of heart failure in pediatric population. PMID- 25502587 TI - Evaluation of medical costs avoided when new oral anticoagulants are used for extended treatment of venous thromboembolism based on clinical trial results. AB - This study evaluated avoidances in medical costs associated with clinical endpoints from randomized clinical trials that evaluated the efficacy and safety of the new oral anticoagulants (NOACs), dabigatran, rivaroxaban, and apixaban for extended treatment of patients with venous thromboembolism (VTE). Event rates of efficacy and safety endpoints from the clinical trials (RE-SONATE, EINSTEIN-EXT, and AMPLIFY-EXT) were obtained from published literature. Incremental annual medical costs among patients with clinical events from a US payer perspective were obtained from the literature or healthcare claims databases and inflation adjusted to 2013 costs. Differences in total medical costs associated with clinical endpoints for patients treated with NOACs versus placebo were then estimated. One-way univariate and Monte Carlo sensitivity analyses were additionally carried out. In all three NOAC trials lower rates of recurrent VTE occurred with NOAC use versus placebo. As a result of the reduction in VTE recurrence the overall medical costs avoided were -$2,794, -$2,948, -$4,249, and $4,244 for VTE patients treated with dabigatran, rivaroxaban, apixaban 2.5 mg, and apixaban 5 mg respectively versus patients treated with placebo. Apixaban was associated with the greatest avoidance in medical costs, which was driven mainly by a greater reduced rate in recurrent VTE than other NOACs versus placebo and also a reduction in major bleeding rate. Further evaluation is needed to validate these results in the real-world setting. PMID- 25502588 TI - The role of metformin on vitamin B12 deficiency: a meta-analysis review. AB - Metformin is the only biguanide oral hypoglycemic drug, that is used to treat patients with type-2 diabetes mellitus. There are some reports of metformin being associated with decreased serum levels of vitamin B12 (VB12). The objective of this study is to systematically analyze the impact of metformin on the frequency of VB12 deficiency and serum levels of VB12. A search of various databases provided 18 retrospective cohort studies and 11 randomized controlled trials. Pooled estimates of odds ratio with 95% confidence interval using random effect model were conducted. Studies were examined for heterogeneity, publication bias and sensitivity analysis. Separate analysis of randomized control trials (RCTs) including both low-risk and high-risk bias was also conducted. 29 studies were selected with a total of 8,089 patients. 19 studies were rated intermediate or high quality. Primary outcome suggested increased incidence of VB12 deficiency in metformin group (OR = 2.45, 95% CI 1.74-3.44, P < 0.0001.) Heterogeneity was relatively high (I(2) = 53%), with minor publication bias. Secondary outcome suggested lower serum VB12 concentrations in metformin group (Mean difference = 65.8, 95% CI -78.1 to -53.6 pmol/L, P < 0.00001) with high heterogeneity (I(2) = 98%,) and low publication bias. RCTs analysis of low-and high-risk group revealed similar trends. We conclude that metformin treatment is significantly associated with an increase in incidence of VB12 deficiency and reduced serum VB12 levels. PMID- 25502589 TI - The new ACCF/AHA guidelines on the treatment of dyslipidemia: pros. PMID- 25502590 TI - The new ACC/AHA guidelines on the treatment of dyslipidemia: cons. PMID- 25502592 TI - Parameters influencing in-hospital mortality in patients hospitalized in intensive cardiac care unit: is there an influence of anemia and iron deficiency? AB - We investigated the incidence and prognostic value of anemia as well as of the iron status in non-selected patients admitted to an intensive cardiac care unit (ICCU). 392 patients (mean age 70 +/- 13.8 years, 43% women), 168 with acute coronary syndromes (ACS), 122 with acute decompensated heart failure, and 102 with other acute cardiac disorders were consecutively, prospectively assessed. The biomarkers of iron status-serum iron concentration (SIC), total iron binding capacity (TIBC), and transferrin saturation (TSAT) together with standard clinical, biochemical and echocardiographic variables-were analyzed. In-hospital mortality was 3.8% (15 patients). The prevalences of anemia (according to WHO criteria), and iron deficiency (ID) were 64 and 63%, respectively. The level of biomarkers of iron status, but not anemia, was lower in patients who died (p < 0.05). Anemia was less frequent in patients with ACS as compared to the remaining ICCU population (p = 0.019). The analysis by logistic regression indicated the highest risk of death for age [odds ratio (OD) 1.38, 95% CI 1.27-1.55], SIC (OR 0.85, 95% CI 0.78-0.94), TIBC (OR 0.95, 95% CI 0.91-0.98), left ventricle ejection fraction (OR 0.85, 95% CI 0.77-0.93), as well as hospitalization for non ACS (OR 0.25, 95% CI 0.14-0.46), (p < 0.05). The risk of death during hospitalization tended to increase with decreasing levels of TIBC (p = 0.49), as well as with the absence of ACS (p = 0.54). The incidence of anemia and ID in heterogeneous ICCU patients is high. Parameters of the iron status, but not anemia per se, independently influence in-hospital mortality. The prevalence of anemia is higher in non-ACS patients, and tends to worsen the prognosis. PMID- 25502591 TI - Under-reporting of venous and arterial thrombotic events in randomized clinical trials: a meta-analysis. AB - For the detection of unwanted outcomes of new interventions, physicians rely on adverse event reporting. We attempt to quantify the reported incidence of venous thromboembolism (VTE) and arterial thrombosis (AT) in randomized clinical trials (RCTs), and evaluate the extent of under-reporting. We selected all therapeutic RCTs published in the four highest-impact general medicine journals between January 2011 and July 2011. Patients were categorized according to VTE risk. The occurrences of VTE and AT, either as predefined outcome or adverse event, were assessed. We identified 131 RCTs. VTE and AT were not reported in 89 and 70 % of these studies, respectively. The raw-unweighted reported incidence in the 3 studies with predefined outcomes for VTE was 8.4 (7.8-9.1) per 1,000 person years. In the 128 studies without predefined outcomes for VTE, (consisting of 322,029 individuals, including patients with cancer, inflammatory disease, cardiovascular disease, surgery, adding up to a follow-up >500,000 person-years), an incidence of 0.4 (0.4-0.5) per 1,000 person-years was found. The reported incidence of AT in 18 studies in which AT was part of predefined outcomes was 25.6 (24.9-26.3) per 1,000 person-years. In 92 studies without predefined outcomes for AT (231,638 individuals, follow-up >200,000 person-years,), the incidence was 2.5 (2.3-2.7) per 1,000 person-years. The incidence of VTE and AT in RCTs is highly under-reported. Uniform registration of adverse events, even when unlikely to be related to the intervention, is necessary to be able to inform physicians about the potential toxicities of new therapeutic strategies. PMID- 25502594 TI - Opinion: Mathematical models: a key tool for outbreak response. PMID- 25502593 TI - Data for Program Management: An Accuracy Assessment of Data Collected in Household Registers by Community Health Workers in Southern Kayonza, Rwanda. AB - Community health workers (CHWs) collect data for routine services, surveys and research in their communities. However, quality of these data is largely unknown. Utilizing poor quality data can result in inefficient resource use, misinformation about system gaps, and poor program management and effectiveness. This study aims to measure CHW data accuracy, defined as agreement between household registers compared to household member interview and client records in one district in Eastern province, Rwanda. We used cluster-lot quality assurance sampling to randomly sample six CHWs per cell and six households per CHW. We classified cells as having 'poor' or 'good' accuracy for household registers for five indicators, calculating point estimates of percent of households with accurate data by health center. We evaluated 204 CHW registers and 1,224 households for accuracy across 34 cells in southern Kayonza. Point estimates across health centers ranged from 79 to 100% for individual indicators and 61 to 72% for the composite indicator. Recording error appeared random for all but the widely under-reported number of women on modern family planning method. Overall, accuracy was largely 'good' across cells, with varying results by indicator. Program managers should identify optimum thresholds for 'good' data quality and interventions to reach them according to data use. Decreasing variability and improving quality will facilitate potential of these routinely-collected data to be more meaningful for community health program management. We encourage further studies assessing CHW data quality and the impact training, supervision and other strategies have on improving it. PMID- 25502597 TI - Go natural and smarter: fenugreek as a hydration designer of collagen based biomaterials. AB - Collagen-based biomaterials have received considerable attention for smarter biomedical applications due to their inherent superior mechano-biological properties. However, accumulating evidence suggests that water, as a probe liquid bound in collagen, might be investigated to explore the influence of additives on the static and dynamic solvation behavior of collagen. The structure and dynamics of water near the surface/interface of collagen-fenugreek composites were demonstrated via circular dichroic spectroscopy, thermoporometry and impedimetric measurements to enlighten about the configuration-function relationship of collagen. Thermodynamic parameters of the composites signify the fenugreek concentration dependent structural robustness of collagen. Thermodynamic parameters such as free energies for unfolding, enthalpies, entropies and activation energies indicate that the residual structure modulates the stability of the denatured state up to 22 kcal mol(-1) and the parameters correlate with structural data for collagen complexed with fenugreek. The association constant of fenugreek is found to be 0.5807 M(-1). The binding of fenugreek influences rearrangement of the collagen-water network, resulting in the transition from a disordered (high entropy) unbound state to a structured (lower entropy) bound state. Fenugreek concentration plays a crucial role in shaping up the free energy that governs the folding, structure and stability of collagen. Dielectric data emphasize the effect of hydrophobic and hydrophilic clusters on the side chain motion constraints. The thermoporometry technique probes the pore size distributions of the composites. These methods provide insights into the role of excluded volume, chain stiffness and stability of a new collagen-galactomannan based composite, expanding its utility in "smart biomaterial applications". PMID- 25502596 TI - 1,10-phenanthroline inhibits the metallopeptidase secreted by Phialophora verrucosa and modulates its growth, morphology and differentiation. AB - Phialophora verrucosa is one of the etiologic agents of chromoblastomycosis, a fungal infection that affects cutaneous and subcutaneous tissues. This disease is chronic, recurrent and difficult to treat. Several studies have shown that secreted peptidases by fungi are associated with important pathophysiological processes. Herein, we have identified and partially characterized the peptidase activity secreted by P. verrucosa conidial cells. Using human serum albumin as substrate, the best hydrolysis profile was detected at extreme acidic pH (3.0) and at 37 degrees C. The enzymatic activity was completely blocked by classical metallopeptidase inhibitors/chelating agents as 1,10-phenanthroline and EGTA. Zinc ions stimulated the metallo-type peptidase activity in a dose-dependent manner. Several proteinaceous substrates were cleaved, in different extension, by the P. verrucosa metallopeptidase activity, including immunoglobulin G, fibrinogen, collagen types I and IV, fibronectin, laminin and keratin; however, mucin and hemoglobin were not susceptible to proteolysis. As metallopeptidases participate in different cellular metabolic pathways in fungal cells, we also tested the influence of 1,10-phenanthroline and EGTA on P. verrucosa development. Contrarily to EGTA, 1,10-phenanthroline inhibited the fungal viability (MIC 0.8 ug/ml), showing fungistatic effect, and induced profound morphological alterations as visualized by transmission electron microscopy. In addition, 1,10 phenanthroline arrested the filamentation process in P. verrucosa. Our results corroborate the supposition that metallopeptidase inhibitors/chelating agents have potential to control crucial biological events in fungal agents of chromoblastomycosis. PMID- 25502595 TI - Investigation of terpene diversification across multiple sequenced plant genomes. AB - Plants produce an array of specialized metabolites, including chemicals that are important as medicines, flavors, fragrances, pigments and insecticides. The vast majority of this metabolic diversity is untapped. Here we take a systematic approach toward dissecting genetic components of plant specialized metabolism. Focusing on the terpenes, the largest class of plant natural products, we investigate the basis of terpene diversity through analysis of multiple sequenced plant genomes. The primary drivers of terpene diversification are terpenoid synthase (TS) "signature" enzymes (which generate scaffold diversity), and cytochromes P450 (CYPs), which modify and further diversify these scaffolds, so paving the way for further downstream modifications. Our systematic search of sequenced plant genomes for all TS and CYP genes reveals that distinct TS/CYP gene pairs are found together far more commonly than would be expected by chance, and that certain TS/CYP pairings predominate, providing signals for key events that are likely to have shaped terpene diversity. We recover TS/CYP gene pairs for previously characterized terpene metabolic gene clusters and demonstrate new functional pairing of TSs and CYPs within previously uncharacterized clusters. Unexpectedly, we find evidence for different mechanisms of pathway assembly in eudicots and monocots; in the former, microsyntenic blocks of TS/CYP gene pairs duplicate and provide templates for the evolution of new pathways, whereas in the latter, new pathways arise by mixing and matching of individual TS and CYP genes through dynamic genome rearrangements. This is, to our knowledge, the first documented observation of the unique pattern of TS and CYP assembly in eudicots and monocots. PMID- 25502598 TI - Queen signals in a stingless bee: suppression of worker ovary activation and spatial distribution of active compounds. AB - In most species of social insect the queen signals her presence to her workers via pheromones. Worker responses to queen pheromones include retinue formation around the queen, inhibition of queen cell production and suppression of worker ovary activation. Here we show that the queen signal of the Brazilian stingless bee Friesella schrottkyi is a mixture of cuticular hydrocarbons. Stingless bees are therefore similar to ants, wasps and bumble bees, but differ from honey bees in which the queen's signal mostly comprises volatile compounds originating from the mandibular glands. This shows that cuticular hydrocarbons have independently evolved as the queen's signal across multiple taxa, and that the honey bees are exceptional. We also report the distribution of four active queen-signal compounds by Matrix-assisted laser desorption/ionization (MALDI) imaging. The results indicate a relationship between the behavior of workers towards the queen and the likely site of secretion of the queen's pheromones. PMID- 25502599 TI - Characterization of the startup transient electrokinetic flow in rectangular channels of arbitrary dimensions, zeta potential distribution, and time-varying pressure gradient. AB - The solution to the startup transient EOF in an arbitrary rectangular microchannel is derived analytically and validated experimentally. This full 2D transient solution describes the evolution of the flow through five distinct periods until reaching a final steady state. The derived analytical velocity solution is validated experimentally for different channel sizes and aspect ratios under time-varying pressure gradients. The experiments used a time resolved micro particle image velocimetry technique to calculate the startup transient velocity profiles. The measurements captured the effect of time-varying pressure gradient fields derived in the analytical solutions. This is tested by using small reservoirs at both ends of the channel which allowed a time-varying pressure gradient to develop with a time scale on the order of the transient EOF. Results showed that under these common conditions, the effect of the pressure build up in the reservoirs on the temporal development of the transient startup EOF in the channels cannot be neglected. The measurements also captured the analytical predictions for channel walls made of different materials (i.e., zeta potentials). This was tested in channels that had three PDMS and one quartz wall, resulting in a flow with an asymmetric velocity profile due to variations in the zeta potential between the walls. PMID- 25502601 TI - What is the optimal maxillary antrostomy size during sinus surgery? AB - PURPOSE OF REVIEW: To review all the journal articles relevant to chronic maxillary sinusitis in order to discuss the optimal size of maxillary antrostomy during endoscopic sinus surgery. RECENT FINDINGS: Although endoscopic maxillary antrostomy is a longstanding and frequently performed procedure, there is limited evidence about the optimal size of the antrostomy. Commonly employed surgical options include dilation via balloon sinuplasty, traditional antrostomy with uncinectomy using forceps and powered microdebriders, enlargement of the natural ostium, and the mega-antrostomy or modified medial maxillectomy. Historically, inferior antrostomies or nasal-antral windows were commonly utilized in the preendoscopic era, although this procedure is less commonly used today. SUMMARY: Balloon sinuplasty can be effective in dilating the ethmoid infundibulum and natural ostium for select patients with isolated maxillary sinusitis or mild disease. A standard antrostomy using biting forceps and powered instrumentation is more appropriate for advanced disease such as severe mucosal hyperplasia or nasal polyps, as it allows for visualization of the maxillary sinus cavity and more effective topical delivery of saline irrigations and medications. For recalcitrant maxillary sinusitis, the mega-antrostomy allows for gravity dependent drainage and is most appropriate for patients with inherent mucociliary defects. PMID- 25502602 TI - Treatment of cerebrospinal fluid rhinorrhea. AB - PURPOSE OF REVIEW: Cerebrospinal fluid (CSF) rhinorrhea is a rare entity that can arise from a variety of causes. Successful management has been reported using a variety of repair techniques. The goal of this study is to make recommendations on intraoperative and postoperative management of CSF fistulas across all causes. RECENT FINDINGS: Pooled analysis of case series reveals that free graft repairs are successful in closing most traumatic and iatrogenic CSF leaks. In contrast, multilayered, vascularized repairs are often required for large defects with high flow leaks that communicate with a cistern and/or ventricles. Spontaneous CSF leaks are associated with idiopathic intracranial hypertension in the vast majority of cases, and when present, postoperative medical management is necessary for long-term success. SUMMARY: Patients with CSF rhinorrhea require surgical repair to prevent life-threatening complications. Many techniques and materials are effective at achieving closure of CSF fistula across causes. Evidence suggests that patients with high-flow CSF fistulas have improved outcomes with multilayered, vascularized repairs to decrease the risk of postoperative CSF leaks. Patients with idiopathic intracranial hypertension need long-term management of the underlying disease process. PMID- 25502600 TI - An infectious murine model for studying the systemic effects of opioids on early HIV pathogenesis in the gut. AB - Opioids are known to exacerbate HIV pathogenesis, however current studies have been limited by models of HIV infection. Given that HIV causes many systemic effects via direct infection of host cells as well as indirect bystander effects, it is important to establish a systemic infection model in a small animal so that genetic tools can be utilized to elucidate the mechanisms of action. In this study, the systemic effects of EcoHIV infection, a modified HIV which can infect mouse cells, are examined in conjunction with morphine. EcoHIV infection with opioid treatment induced bacterial translocation from the lumen of the gut into systemic compartments such as liver, which is similar to observations in human patients with LPS. Bacterial translocation corresponds with alterations in gut morphology, disorganization of the tight junction protein occludin, and a concurrent increase in systemic inflammation in both IL-6 and TNFalpha. Long term infection also had increased expression of inflammatory cytokines in the CNS when co-treated with morphine. Overall, this study shows that EcoHIV is an appropriate model to study the effects of opioids on HIV pathogenesis, including the HIV induced pathology at early stages of pathogenesis in the gut. PMID- 25502603 TI - Lessons learned from the reimbursement profile of a mature private medical toxicology practice: office-based practice pays. AB - We previously reported the financial data for the first 5 years of one of the author's medical toxicology practice. The practice has matured; changes have been made. The practice is increasing its focus on office-based encounters and reducing hospital-based acute care encounters. We report the reimbursement rates and other financial metrics of the current practice. Financial records from October 2009 through September 2013 were reviewed. This is a period of 4 fiscal years and represents the currently available financial data. Charges, payments, and reimbursement rates were recorded according to the type and setting of the medical toxicology encounter: forensic consultations, outpatient clinic encounters, nonpsychiatric inpatient consultations, emergency department (ED) consultations, and inpatient psychiatric consultations. All patients were seen regardless of ability to pay or insurance status. The number of billed Current Procedural Terminology (CPT) codes for office-based encounters increased over the study period; the number of billed CPT codes for inpatient and ED consultations reduced. Office-based encounters demonstrate a higher reimbursement rate and higher payments. In the fiscal year (FY) of 2012, office-based revenue exceeded hospital-based acute care revenue by over $140,000 despite a higher number of billed CPT encounters in acute care settings, and outpatient payments were 2.39 times higher than inpatient, inpatient psychiatry, observation unit, and ED payments combined. The average payment per CPT code was higher for outpatient clinic encounters than inpatient encounters for each fiscal year studied. There was an overall reduction in CPT billing volume between FY 2010 and FY 2013. Despite this, there was an increase in total practice revenue. There was no change in payor mix, practice logistics, or billing/collection service company. In this medical toxicology practice, office-based encounters demonstrate higher reimbursement rates and overall payments compared to inpatient and ED consultations. While consistent with our previous studies, these differences have been accentuated. This study demonstrates the results of changes to the practice- reduced inpatient/ED consultations and increased outpatient encounters. These practice changes resulted in higher overall revenue despite a lower patient volume. In this analysis, the office-based practice of medical toxicology has higher reimbursement rates, nearly 2.5 times higher, when compared to hospital based acute care consultations. PMID- 25502606 TI - The influence of nanofiller alignment on transverse percolation and conductivity. AB - Nanocomposites have unprecedented potential for conductivity-based damage identification when used as matrices in structural composites. Recent research has investigated nanofiller alignment in structural composites, but because damage identification often requires in-plane measurements, percolation and conductivity transverse to the alignment direction become crucial considerations. We herein contribute indispensable guidance to the development of nanocomposites with aligned nanofiller networks and insights into percolation trends transverse to the alignment direction by studying the influence of alignment on transverse critical volume fraction, conductivity, and rate of transition from non percolating to percolating in three-dimensional carbon nanotube composite systems. PMID- 25502605 TI - Increased temperature and entropy production in cancer: the role of anti inflammatory drugs. AB - Some cancers have been shown to have a higher temperature than surrounding normal tissue. This higher temperature is due to heat generated internally in the cancer. The higher temperature of cancer (compared to surrounding tissue) enables a thermodynamic analysis to be carried out. Here I show that there is increased entropy production in cancer compared with surrounding tissue. This is termed excess entropy production. The excess entropy production is expressed in terms of heat flow from the cancer to surrounding tissue and enzymic reactions in the cancer and surrounding tissue. The excess entropy production in cancer drives it away from the stationary state that is characterised by minimum entropy production. Treatments that reduce inflammation (and therefore temperature) should drive a cancer towards the stationary state. Anti-inflammatory agents, such as aspirin, other non-steroidal anti-inflammatory drugs, corticosteroids and also thyroxine analogues have been shown (using various criteria) to reduce the progress of cancer. PMID- 25502604 TI - Risk factors for developing thyroid-associated ophthalmopathy among individuals with Graves disease. AB - IMPORTANCE: Thyroid-associated ophthalmopathy (TAO) is a common and debilitating manifestation of Graves disease (GD). Presently little is known about factors that may increase the risk of developing TAO among patients with GD. OBJECTIVE: To identify risk factors associated with the development of TAO among individuals with newly diagnosed GD. DESIGN, SETTING, AND PARTICIPANTS: In this longitudinal cohort study, all beneficiaries 18 years of age or older with newly diagnosed GD who were continuously enrolled in a large nationwide US managed care network and who visited an eye care professional 1 or more times from 2001 to 2009 were identified. International Classification of Diseases, Ninth Revision, Clinical Modification billing codes were used to identify those who developed manifestations of TAO. Multivariable Cox regression was used to determine the hazard of developing TAO among persons with newly diagnosed GD, with adjustment for sociodemographic factors, systemic medical conditions, thyrotropin levels, and medical and surgical interventions for management of hyperthyroidism. MAIN OUTCOMES AND MEASURES: Manifestations of TAO measured by hazard ratios (HRs) with 95% CIs. RESULTS: Of 8404 patients with GD who met the inclusion criteria, 740 (8.8%) developed TAO (mean follow-up, 374 days since initial GD diagnosis). After adjustment for potential confounders, surgical thyroidectomy, alone or in combination with medical therapy, was associated with a 74% decreased hazard for TAO (adjusted HR, 0.26 [95% CI, 0.12-0.51]) compared with radioactive iodine therapy alone. Statin use (for >=60 days in the past year vs <60 days or nonuse) was associated with a 40% decreased hazard (adjusted HR, 0.60 [CI, 0.37-0.93]). No significant association was found for the use of nonstatin cholesterol lowering medications or cyclooxygenase 2 inhibitors and the development of TAO. CONCLUSIONS AND RELEVANCE: If prospective studies can confirm our finding that a thyroidectomy and statin use are associated with substantially reduced hazards for TAO among patients with GD, preventive measures for this burdensome manifestation of GD may become a reality. PMID- 25502607 TI - A mixed-methods feasibility trial of protein kinase C iota inhibition with auranofin in asymptomatic ovarian cancer patients. AB - PURPOSE: This trial was undertaken (1) to determine the feasibility of enrolling asymptomatic ovarian cancer patients with CA-125 elevation in a trial with the protein kinase C iota (PKCiota) inhibitor auranofin and (2) to understand patients' perceptions of CA-125 monitoring. METHODS: Asymptomatic ovarian cancer patients with CA-125 elevation received 3 mg auranofin orally twice per day and were evaluated. The patients participated in interviews about CA-125 monitoring. RESULTS: Ten patients were enrolled in slightly over 6 months, exceeding our anticipated accrual rate. Four manifested stable CA-125 levels for 1 month or longer. The median progression-free survival was 2.8 months (95% CI: 1.3-3.8); auranofin was well tolerated. One patient had baseline and monthly CA-125 levels of 5,570, 6,085, 3,511, and 2,230 U/ml, respectively, stopped auranofin because of radiographic progression at 3 months, and manifested an increase in CA-125 to 7,168 U/ml approximately 3 months later. Patient interviews revealed (1) the important role of CA-125 in cancer monitoring, (2) ardent advocacy of CA-125 testing, and (3) an evolution toward CA-125 assuming a life of its own. CONCLUSIONS: This study showed the feasibility of enrolling asymptomatic ovarian cancer patients with CA-125 elevation in a trial with auranofin. One patient had a decline in CA-125, suggesting that PKCiota inhibition merits further study in ovarian cancer. PMID- 25502608 TI - Functional strategies drive community assembly of stream fishes along environmental gradients and across spatial scales. AB - Trade-offs among functional traits produce multi-trait strategies that shape species' interactions with the environment and drive the assembly of local communities from regional species pools. Stream fish communities vary along stream size gradients and among hierarchically structured habitat patches, but little is known about how the dispersion of strategies varies along environmental gradients and across spatial scales. We used null models to quantify the dispersion of reproductive life history, feeding, and locomotion strategies in communities sampled at three spatial scales in a prairie stream network in Kansas, USA. Strategies were generally underdispersed at all spatial scales, corroborating the longstanding notion of abiotic filtering in stream fish communities. We tested for variation in strategy dispersion along a gradient of stream size and between headwater streams draining different ecoregions. Reproductive life history strategies became increasingly underdispersed moving from downstream to upstream, suggesting that abiotic filtering is stronger in headwaters. This pattern was stronger among reaches compared to mesohabitats, supporting the premise that differences in hydrologic regime among reaches filter reproductive life history strategies. Feeding strategies became increasingly underdispersed moving from upstream to downstream, indicating that environmental filters associated with stream size affect the dispersion of feeding and reproductive life history in opposing ways. Weak differences in strategy dispersion were detected between ecoregions, suggesting that different abiotic filters or strategies drive community differences between ecoregions. Given the pervasiveness of multi-trait strategies in plant and animal communities, we conclude that the assessment of strategy dispersion offers a comprehensive approach for elucidating mechanisms of community assembly. PMID- 25502609 TI - A comment on the role of propagule pressure in the establishment success of introduced birds. AB - In a recent paper, Cassey et al. (Oecologia 175: 417-428, 2014) presented a population model of establishment success among birds introduced to New Zealand. They found that net reproductive rate was more important than propagule pressure in three separate cases involving species that reflect life history type of three avian types. Although Cassey et al. (Oecologia 175: 417-428, 2014) claim this result was unexpected, in fact it supports previous studies that have questioned the role of propagule pressure in determining introduction outcomes. PMID- 25502610 TI - Comparing the effectiveness of automated online counseling to standard web-based education on improving acne knowledge: a randomized controlled trial. AB - BACKGROUND: Evidence regarding what comprises effective education for acne vulgaris patients is lacking. Internet-based education may improve patient knowledge of this condition. OBJECTIVES: Our objective was to compare the effectiveness of standard web-based education and an automated counseling website in improving acne knowledge. DESIGN: In a randomized trial, participants visited either a standard website or an automated counseling website to learn about acne. Multiple-choice questions were administered at baseline and after 12 weeks to assess change in acne knowledge. RESULTS: A total of 97 high school students were enrolled, and 95 completed the study. The standard website group had a significant increase in knowledge from baseline (3.61 +/- 1.22) to 12-week follow up (5.46 +/- 1.31, p < 0.001). Similarly, the automated counseling website group had a significant increase in knowledge between both time points (3.53 +/- 1.50 vs. 6.49 +/- 1.06, p < 0.001). After 12 weeks, mean improvement in knowledge was higher in the automated counseling group (2.96 +/- 1.85) than in the standard website group (1.85 +/- 1.46, d = 0.67, p = 0.002). The number of website visits was positively correlated with improvement in knowledge in both groups. Finally, the automated counseling website group rated their educational material more useful (p = 0.004) and more enjoyable to view (p = 0.003) than did the standard website group. LIMITATIONS: This study is limited to adolescents with mild-to moderate acne vulgaris. CONCLUSION: Internet-based patient education appears to be an effective method of improving acne knowledge among adolescents. PMID- 25502611 TI - Different patterns of lateral meniscus root tears in ACL injuries: application of a differentiated classification system. AB - PURPOSE: Posterior lateral meniscus root tears (PLMRTs) affect the intra articular pressure distribution in the lateral compartment of the knee. The biomechanical consequences of these injuries are significantly influenced by the integrity of the meniscofemoral ligaments (MFLs). A newly introduced arthroscopic classification system for PLMRTs that takes MFL integrity into account has not yet been clinically applied but may be useful in selecting the optimal method of PLMRT repair. METHODS: Prospective ACL reconstruction data were collected. Concomitant injuries of the lateral meniscus posterior horn were classified according to their shape and MFL status. The classifications were: type 1, avulsion of the root; type 2, radial tear of the lateral meniscus posterior horn close to the root with an intact MFL; and type 3, complete detachment of the posterior meniscus horn. RESULTS: Between January 2011 and May 2012, 228 consecutive ACL reconstructions were included. Lateral and medial meniscus tears were identified in 38.2% (n = 87) and 44.7% (n = 102), respectively. Of the 87 lateral meniscus tears, 32 cases had PLMRTs; the overall prevalence of PLMRTs was 14% (n = 32). Two medial meniscus root tears were detected. All PLMRTs were classified according to the classification system described above, and the fixation procedure was adapted to the type of meniscus tear. CONCLUSION: The PLMRT tear is a common injury among patients undergoing ACL repair and can be arthroscopically classified into three different types. Medial meniscus root tears are rare in association with ACL tears. The PLMRT classification presented here may help to estimate the injury's impact on the lateral compartment and to identify the optimal treatment. These tears should not be overlooked, and the treatment strategy should be chosen with respect to the type of root tear. LEVEL OF EVIDENCE: IV. PMID- 25502613 TI - Talking About Maternal Breast Cancer With Young Children: A Content Analysis of Text in Children's Books. AB - OBJECTIVE: Examine the content of children's books and summarize the main issues related to communication with young children about maternal cancer, especially breast cancer. METHODS: A search of English books discussing early-stage (breast) cancer and written for children aged 3-12 years was conducted on the Amazon.com Web site. Each of 45 identified books was analyzed independently by two of three coders using inductive qualitative content analysis. RESULTS: The main contents of these books included cancer-related knowledge, impacts of maternal cancer, and coping strategies. The concept of (breast) cancer and its treatment was introduced in plain language and some common misunderstandings were clarified. The consequences of maternal cancer were highlighted. CONCLUSIONS: These books are beneficial to children and adults. However, impacts on school life, children's concerns about financial burdens, and instructions about age appropriate use of the books have been neglected. Additional studies should be undertaken to explore the value of these books. PMID- 25502612 TI - Initial dosing regimen of vancomycin to achieve early therapeutic plasma concentration in critically ill patients with MRSA infection based on APACHE II score. AB - It is essential to assure the efficacy of antimicrobials at the initial phase of therapy. However, increasing the volume of distribution (Vd) of hydrophilic antimicrobials in critically ill patients leads to reduced antimicrobial concentration in plasma and tissue, which may adversely affect the efficacy of that therapy. The aim of the present study was to establish a theoretical methodology for setting an appropriate level for initial vancomycin therapy in individual patients based on Acute Physiology and Chronic Health Evaluation (APACHE) II score. We obtained data from patients who received intravenous vancomycin for a suspected or definitively diagnosed Gram-positive bacterial infection within 72 h after admission to the intensive care unit. The Vd and elimination half-life (t 1/2) of vancomycin values were calculated using the Bayesian method, and we investigated the relationship between them and APACHE II score. There were significant correlations between APACHE II scores and Vd/actual body weight (ABW), as well as t 1/2 (r = 0.58, p < 0.05 and r = 0.74, p < 0.01, respectively). Our results suggested that the Vd and t 1/2 of vancomycin could be estimated using the following regression equations using APACHE II score.[Formula: see text] [Formula: see text]We found that APACHE II score was a useful index for predicting the Vd and t 1/2 of vancomycin, and used that to establish an initial vancomycin dosing regimen comprised of initial dose and administration interval for individual patients. PMID- 25502614 TI - The relationship between weight status and emotional and behavioral problems in Spanish preschool children. AB - OBJECTIVE: To examine cross-sectional and longitudinal associations between behavioral problems and weight status, considering body mass index (BMI) z-scores and overweight status, in a community sample of preschoolers. METHODS: The Strengths and Difficulties Questionnaire and the Diagnostic Interview for Children and Adolescents were administered to 611 parents. Adjusted general linear models and binary logistic regressions were used. RESULTS: Children who were overweight and had a higher BMI were at increased risk of peer problems and attention-deficit/hyperactivity disorder (ADHD) symptoms. Prospective analyses showed that a higher BMI at the age of 3 years was predictive of peer problems at ages 4 and 5 years and hyperactivity and ADHD symptoms at the age of 4 years. CONCLUSION: This is the first study using a diagnostic-based instrument that shows a relationship between weight status and ADHD symptoms in preschoolers. Overweight children might benefit from screening for behavioral disorders and peer relationship problems. PMID- 25502616 TI - Comparing velocity and fluid shear stress in a stenotic phantom with steady flow: phase-contrast MRI, particle image velocimetry and computational fluid dynamics. AB - OBJECT: This study aims to validate phase-contrast magnetic resonance imaging (PC MRI) measurements of a steady flow through a severe stenotic phantom using particle image velocimetry (PIV) and computational fluid dynamics (CFD). MATERIALS AND METHODS: The study was performed in an axisymmetric 87 % area stenosis model using an inlet Reynolds number (Re) of 160, corresponding to a jet Re of 444. Velocity patterns and estimated fluid shear stresses from three modalities were analyzed and compared qualitatively and quantitatively. RESULTS: Visual analysis via contour subtraction and Bland-Altman plots showed good agreement for flow velocities and less agreement for maximum shear stress (MSS). The Pearson's coefficients of correlation between PC-MRI and PIV were 0.97 for the velocity field and 0.82 for the MSS. The corresponding parameters between PC MRI and CFD were 0.96 and 0.84, respectively. CONCLUSION: Findings indicate that PC-MRI can be implemented to estimate velocity flow fields and MSS; however, this method is not sufficiently accurate to quantify the MSS at regions of high shear rate. PMID- 25502618 TI - Silicon-organic hybrid slot waveguide based three-input multicasted optical hexadecimal addition/subtraction. AB - By exploiting multiple non-degenerate four-wave mixing in a silicon-organic hybrid slot waveguide and 16-ary phase-shift keying signals, we propose and simulate three-input (A, B, C) multicasted 40-Gbaud (160-Gbit/s) optical hexadecimal addition/subtraction (A + B - C, A + C - B, B + C - A, A + B + C, A - B - C, B - A - C). The error vector magnitude (EVM) and dynamic range of signal power are analyzed to evaluate the performance of optical hexadecimal addition/subtraction. PMID- 25502617 TI - Do good actions inspire good actions in others? AB - Actions such as sharing food and cooperating to reach a common goal have played a fundamental role in the evolution of human societies. Despite the importance of such good actions, little is known about if and how they can spread from person to person to person. For instance, does being recipient of an altruistic act increase your probability of being cooperative with a third party? We have conducted an experiment on Amazon Mechanical Turk to test this mechanism using economic games. We have measured willingness to be cooperative through a standard Prisoner's dilemma and willingness to act altruistically using a binary Dictator game. In the baseline treatments, the endowments needed to play were given by the experimenters, as usual; in the control treatments, they came from a good action made by someone else. Across four different comparisons and a total of 572 subjects, we have never found a significant increase of cooperation or altruism when the endowment came from a good action. We conclude that good actions do not necessarily inspire good actions in others. While this is consistent with the theoretical prediction, it challenges the majority of other experimental studies. PMID- 25502615 TI - PharmGKB summary: ibuprofen pathways. PMID- 25502619 TI - A short, rigid linker between pyrene and guanidiniocarbonyl-pyrrole induced a new set of spectroscopic responses to the ds-DNA secondary structure. AB - A novel pyrene-guanidiniocarbonyl-pyrrole dye, characterised by a short, rigid linker between the two chromophores, interacts strongly with ds-DNA but only negligibly with ds-RNA. Under neutral conditions the dye shows strong selectivity toward AT-DNA (with respect to GC-DNA). Binding is accompanied by a specific ICD band at 350 nm and fluorescence quenching for all DNAs/RNAs studied. At pH 5 the affinity of the dye is reversed, now favouring GC-DNA over AT-DNA. A strong emission increase for AT-DNA is observed but with quenching for GC-DNA. PMID- 25502620 TI - Levodopa: effect on cell death and the natural history of Parkinson's disease. AB - This review article considers the question of whether or not levodopa is toxic in Parkinson's disease (PD). l-dopa is the most effective symptomatic treatment for PD and has provided benefit for millions of patients. However, there has been a longstanding concern that l-dopa might be toxic and accelerate neuronal degeneration and clinical progression as a consequence of reactive oxygen species generated by the drug's oxidative metabolism. In vitro, l-dopa can induce degeneration of dopaminergic neurons, but it is not clear that the effects of the drug on cultured dopamine neurons reflect what happens in the PD brain. In vivo, l-dopa has not been demonstrated to have toxic effects on dopamine neurons in normal, dopamine-lesioned, or oxidatively stressed animal models, but none of these models precisely replicates the PD condition. Clinical trials have tested the effect of l-dopa on clinical progression and have not demonstrated any findings indicative of toxicity. However, the symptomatic and long-duration effects of the drug could mask ongoing neuronal degeneration. Furthermore, l-dopa induces a greater decline in imaging measures of dopaminergic function than placebo or dopamine agonists, consistent with toxicity. Pathological studies have not demonstrated evidence of accelerated loss of dopamine neurons, but prospective and properly controlled studies with stereological unbiased counting have not been performed. Thus, although there is no hard evidence to suggest that l-dopa is toxic in PD patients, the issue has not been fully resolved. It is generally recommended that physicians continue to use l-dopa, but in the lowest dose that provides satisfactory clinical control. PMID- 25502621 TI - CORR Insights((r)): how do different anterior tibial tendon transfer techniques influence forefoot and hindfoot motion? PMID- 25502624 TI - Immersive technology and the elderly: a mini-review. AB - Technologies that provide immersive experiences continue to become more ubiquitous across all age groups. This paper presents a review of the literature to provide a snapshot of the current state of research involving the use of immersive technologies and the elderly. A narrative literature review was conducted using the ScienceDirect, EBSCOhost, Springerlink and ERIC databases to summarize primary studies from which conclusions were drawn into a holistic interpretation. The majority of the studies examined the effect of immersive technologies on elder peoples' age-related declines, including sensory and motor changes (vision, hearing, motor skills), cognitive changes and social changes. Various immersive technologies have been described and tested to address these age-related changes, and have been categorized as 'games and simulations', 'robotics' and 'social technologies'. In most cases, promising results were found for immersive technologies to challenge age-related declines, especially through the increase of morale. PMID- 25502622 TI - Arteries are formed by vein-derived endothelial tip cells. AB - Tissue vascularization entails the formation of a blood vessel plexus, which remodels into arteries and veins. Here we show, by using time-lapse imaging of zebrafish fin regeneration and genetic lineage tracing of endothelial cells in the mouse retina, that vein-derived endothelial tip cells contribute to emerging arteries. Our movies uncover that arterial-fated tip cells change migration direction and migrate backwards within the expanding vascular plexus. This behaviour critically depends on chemokine receptor cxcr4a function. We show that the relevant Cxcr4a ligand Cxcl12a selectively accumulates in newly forming bone tissue even when ubiquitously overexpressed, pointing towards a tissue-intrinsic mode of chemokine gradient formation. Furthermore, we find that cxcr4a mutant cells can contribute to developing arteries when in association with wild-type cells, suggesting collective migration of endothelial cells. Together, our findings reveal specific cell migratory behaviours in the developing blood vessel plexus and uncover a conserved mode of artery formation. PMID- 25502623 TI - Prolonged postocclusive hyperemia response in patients with normal-tension glaucoma. AB - BACKGROUND: It is believed that endothelial dysfunction may be a link between systemic and ocular dysregulation in glaucoma. The aim of this study was to evaluate peripheral vascular reactive hyperemia in response to occlusion test and to correlate peripheral vascular findings with retrobulbar hemodynamics parameters in patients with normal-tension glaucoma. MATERIAL AND METHODS: Forty eight patients with normal-tension glaucoma (mean age 58.1 years, 38 women) and 40 control subjects (mean age 54.1 years, 36 women) were subjected to a brachial arterial occlusion test and color Doppler imaging (LOGIQ 9, GE Medical Systems) of the retrobulbar arteries. Finger hyperemia was assessed by using a 2-channel laser Doppler flowmeter (MBF-3D, Moor Instruments, Ltd.). Time parameters (time to peak flow, half-time of hyperemia, time of recovery) and amplitude parameters (maximum hyperemia response, biological zero) of the post-occlusive reactive hyperemia signal pattern as well as velocities and resistance index of the ophthalmic, central retinal, and short posterior ciliary arteries were evaluated and compared between study groups. RESULTS: In glaucoma patients, time to peak flow and half-time of hyperemia were significantly longer (21.4 vs. 12.0 s, p=0.02 and 74.1 vs. 44.2 s, p=0.03, respectively) and biological zero was significantly lower (2.4 vs. 3.2, p=0.01) comparing with healthy subjects. In glaucoma patients, peak-systolic and end-diastolic velocities of central retinal artery were significantly lower (12.8 vs.14.1, p=0.03 and 3.9 vs. 4.7, p=0.01, respectively) and resistance index of this artery was significantly higher (0.69 vs. 0.67, p=0.03) compared to controls. In the glaucoma group, maximum hyperemic response was negatively correlated with the resistance index of temporal short posterior ciliary arteries (r=-0.4, p=0.01), whereas in the control group half time of hyperemia was negatively correlated with end-diastolic velocity of the central retinal artery (r=-0.3, p=0.03). CONCLUSIONS: Arterial occlusion test elicited a prolonged systemic hyperemia response in patients with glaucoma as compared with healthy subjects. Retrobulbar blood flow alterations in glaucoma patients may be related to systemic vascular dysregulation. PMID- 25502625 TI - Reply: To PMID 25302781. PMID- 25502627 TI - iRobot, MD--are we ready for the future becomes the present? PMID- 25502626 TI - Ovarian cyst aspiration prior to in vitro fertilization treatment for subfertility. AB - BACKGROUND: Ten per cent to 15% of couples have difficulty in conceiving. A proportion of these couples will ultimately require assisted reproduction. Prior to controlled ovarian hyperstimulation (COH) a baseline ultrasound is performed to detect the presence of ovarian cysts.Previous research has suggested that there is a relationship between the presence of an ovarian cyst prior to COH and poor outcome during IVF. OBJECTIVES: The aim of this review was to determine the effectiveness and safety of functional ovarian cyst aspiration prior to ovarian stimulation versus a conservative approach in women with an ovarian cyst who were undergoing IVF or ICSI. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO, CINAHL, ClinicalTrials.gov, Google Scholar and PubMed. The evidence was current to April 2014 and no language restrictions were applied. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing functional ovarian cyst aspiration versus conservative management of ovarian cysts that have been seen on transvaginal ultrasound (TVS) prior to COH for IVF or ICSI. Ovarian cysts were defined as simple, functional ovarian cysts > 20 mm in diameter. Oocyte donors and women undergoing donor oocyte cycles were excluded. DATA COLLECTION AND ANALYSIS: Study selection, data extraction and risk of bias assessments were conducted independently by two review authors. The primary outcome measures were live birth rate and adverse events. The overall quality of the evidence for each comparison was rated using GRADE methods. MAIN RESULTS: Three studies were eligible for inclusion (n = 339), all of which used agonist protocols. Neither live birth rate nor adverse events were reported by any of the included studies. There was no conclusive evidence of a difference between the group who underwent ovarian cyst aspiration and the conservatively managed group in the clinical pregnancy rate (OR 1.40, 95% CI 0.67 to 2.94, 3 studies, 339 women, I(2) = 0%, low quality evidence). This suggested that if the clinical pregnancy rate in women with conservative management was assumed to be 5%, the chance following cyst aspiration would be between 4% and 14%. There was no evidence of a difference between the groups in the mean number of follicles recruited (0.55 follicles, 95% CI -0.48 to 1.59, 2 studies, 159 women, I(2) = 0%, low quality evidence) or mean number of oocytes collected (0.41 oocytes, 95% CI -0.04 to 0.85, 3 studies, 339 women, I(2) = 0%, low quality evidence). Findings for the cancellation rate (two studies) were inconsistent but neither study reported a benefit for the aspiration group. The main limitations of the evidence were imprecision, inconsistency, questionable applicability, and poor reporting of study methods. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether drainage of functional ovarian cysts prior to controlled ovarian hyperstimulation influences live birth rate, clinical pregnancy rate, number of follicles recruited, or oocytes collected in women with a functional ovarian cyst. The findings of this review do not provide supportive evidence for this approach, particularly in view of the requirement for anaesthesia, extra cost, psychological stress and risk of surgical complications. PMID- 25502628 TI - Accumulation of oxidized LDL in the tendon tissues of C57BL/6 or apolipoprotein E knock-out mice that consume a high fat diet: potential impact on tendon health. AB - OBJECTIVE: Clinical studies have suggested an association between dyslipidemia and tendon injuries or chronic tendon pain; the mechanisms underlying this association are not yet known. The objectives of this study were (1) to evaluate the impact of a high fat diet on the function of load-bearing tendons and on the distribution in tendons of oxidized low density lipoprotein (oxLDL), and (2) to examine the effect of oxLDL on tendon fibroblast proliferation and gene expression. METHODS: Gene expression (Mmp2, Tgfb1, Col1a1, Col3a1), fat content (Oil Red O staining), oxLDL levels (immunohistochemistry) and tendon biomechanical properties were examined in mice (C57Bl/6 or ApoE -/-) receiving a standard or a high fat diet. Human tendon fibroblast proliferation and gene expression (COL1A1, COL3A1, MMP2) were examined following oxLDL exposure. RESULTS: In both types of mice (C57Bl/6 or ApoE -/-), consumption of a high fat diet led to a marked increase in oxLDL deposition in the load-bearing extracellular matrix of the tendon. The consumption of a high fat diet also reduced the failure stress and load of the patellar tendon in both mouse types, and increased Mmp2 expression. ApoE -/- mice exhibited more pronounced reductions in tendon function than wild-type mice, and decreased expression of Col1a1 compared to wild type mice. Human tendon fibroblasts responded to oxLDL by increasing their proliferation and their mRNA levels of MMP2, while decreasing their mRNA levels for COL1A1 and COL3A1. CONCLUSION: The consumption of a high fat diet resulted in deleterious changes in tendon function, and these changes may be explained in part by the effects of oxLDL, which induced a proliferative, matrix-degrading phenotype in human tenocytes. PMID- 25502629 TI - Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors. PMID- 25502630 TI - 'Second-generation' mephedrone analogs, 4-MEC and 4-MePPP, differentially affect monoamine transporter function. AB - The nonmedical use of synthetic cathinones is increasing on a global scale. 4 Methyl-N-methylcathinone (mephedrone) is a popular synthetic cathinone that is now illegal in the United States and other countries. Since the legislative ban on mephedrone, a number of 'second-generation' analogs have appeared in the street drug marketplace, including 4-methyl-N-ethylcathinone (4-MEC) and 4' methyl-alpha-pyrrolidinopropiophenone (4-MePPP). Here we characterized the interactions of 4-MEC and 4-MePPP with transporters for 5-HT (SERT) and dopamine (DAT) using molecular, cellular, and whole-animal methods. In vitro transporter assays revealed that 4-MEC displays unusual 'hybrid' activity as a SERT substrate (ie, 5-HT releaser) and DAT blocker, whereas 4-MePPP is a blocker at both transporters but more potent at DAT. In vivo microdialysis experiments in rat brain demonstrated that 4-MEC (1-3 mg/kg, i.v.) produced large increases in extracellular 5-HT, small increases in dopamine, and minimal motor stimulation. In contrast, 4-MePPP (1-3 mg/kg, i.v.) produced selective increases in dopamine and robust motor stimulation. Consistent with its activity as a SERT substrate, 4 MEC evoked inward current in SERT-expressing Xenopus oocytes, whereas 4-MePPP was inactive in this regard. To examine drug-transporter interactions at the molecular level, we modeled the fit of 4-MEC and 4-MePPP into the binding pockets for DAT and SERT. Subtle distinctions in ligand-transporter binding were found that account for the differential effects of 4-MEC and 4-MePPP at SERT. Collectively, our results provide key information about the pharmacology of newly emerging mephedrone analogs, and give clues to structural requirements that govern drug selectivity at DAT vs SERT. PMID- 25502631 TI - Measuring cigarette smoking-induced cortical dopamine release: A [11C]FLB-457 PET study. AB - Striatal dopamine (DA) is thought to have a fundamental role in the reinforcing effects of tobacco smoking and nicotine. Microdialysis studies indicate that nicotine also increases DA in extrastriatal brain areas, but much less is known about its role in addiction. High-affinity D2/3 receptor radiotracers permit the measurement of cortical DA in humans using positron emission tomography (PET). [(11)C]FLB-457 PET scans were conducted in 10 nicotine-dependent daily smokers after overnight abstinence and reinstatement of smoking. Voxel-wise [(11)C]-FLB 457-binding potential (BPND) in the frontal lobe, insula, and limbic regions was estimated in the two conditions. Paired t-tests showed BPND values were reduced following smoking (an indirect index of DA release). The overall peak t was located in the cingulate gyrus, which was part of a larger medial cluster (BPND change -12.1+/-9.4%) and this survived false discovery rate correction for multiple comparisons. Clusters were also identified in the left anterior cingulate cortex/medial frontal gyrus, bilateral prefrontal cortex (PFC), bilateral amygdala, and the left insula. This is the first demonstration of tobacco smoking-induced cortical DA release in humans; it may be the result of both pharmacological (nicotine) and non-pharmacological factors (tobacco cues). Abstinence increased craving but had minimal cognitive effects, thus limiting correlation analyses. However, given that the cingulate cortex, PFC, insula, and amygdala are thought to have important roles in tobacco craving, cognition, and relapse, these associations warrant investigation in a larger sample. [(11)C]FLB 457 PET imaging may represent a useful tool to investigate individual differences in tobacco addiction severity and treatment response. PMID- 25502632 TI - Evidence revealing deregulation of the KLF11-MAO A pathway in association with chronic stress and depressive disorders. AB - The biochemical pathways underlying major depressive disorder (MDD) and chronic stress are not well understood. However, it has been reported that monoamine oxidase A (MAO A, a major neurotransmitter-degrading enzyme) is significantly increased in the brains of human subjects affected with MDD and rats exposed to chronic social defeat (CSD) stress, which is used to model depression. In the current study, we compared the protein levels of a MAO A-transcriptional activator, Kruppel-like factor 11 (KLF11 , also recognized as transforming growth factor-beta-inducible early gene 2) between the brains of 18 human subjects with MDD and 18 control subjects. We found that, indeed, the expression of KLF11 is increased by 36% (p<0.02) in the postmortem prefrontal cortex of human subjects with MDD compared with controls. We also observed a positive correlation between KLF11 levels and those of its target gene, MAO A, both in association with MDD. KLF11 protein expression was also increased by 44% (p<0.02) in the frontal cortex of KLF11 wild-type mice (Klf11(+/+)) vs Klf11(-/-) when both exposed to CSD stress. In contrast, locomotor activities, central box duration and sucrose preference were significantly reduced in the stressed Klf11(+/+) mice, suggesting that Klf11(+/+) mice are more severely affected by the stress model compared with Klf11(-/-) mice. These results serve to assign an important role of KLF11 in upregulating MAO A in MDD and chronic social stress, suggesting that inhibition of the pathways regulated by this transcription factor may aid in the therapeutics of neuropsychiatric illnesses. Thus, the new knowledge derived from the current study extends our understanding of transcriptional mechanisms that are operational in the pathophysiology of common human diseases and thus bears significant biomedical relevance. PMID- 25502633 TI - Fear of the unknown: uncertain anticipation reveals amygdala alterations in childhood anxiety disorders. AB - Children with anxiety disorders (ADs) experience persistent fear and worries that are highly debilitating, conferring risk for lifelong psychopathology. Anticipatory anxiety is a core clinical feature of childhood ADs, often leading to avoidance of uncertain and novel situations. Extensive studies in non-human animals implicate amygdala dysfunction as a critical substrate for early life anxiety. To test specific amygdala-focused hypotheses in preadolescent children with ADs, we used fMRI to characterize amygdala activation during uncertain anticipation and in response to unexpected stimuli. Forty preadolescent (age 8-12 years) children, 20 unmedicated AD patients and 20 matched controls completed an anticipation task during an fMRI scan. In the task, symbolic cues preceded fear or neutral faces, such that 'certain' cues always predicted the presentation of fear or neutral faces, whereas 'uncertain' cues were equally likely to be followed by fear or neutral faces. Both AD children and controls showed robust amygdala response to faces. In response to the uncertain cues, AD children had increased amygdala activation relative to controls. Moreover, in the AD children, faces preceded by an 'uncertain' cue elicited increased amygdala activation, as compared with the same faces following a 'certain' cue. Children with ADs experience distress both in anticipation of and during novel and surprising events. Our findings suggest that increased amygdala activation may have an important role in the generation of uncertainty-related anxiety. These findings may guide the development of neuroscientifically informed treatments aimed at relieving the suffering and preventing the lifelong disability associated with pediatric ADs. PMID- 25502635 TI - Autologous stem cell transplantation with in vivo purged progenitor cells shows long-term efficacy in relapsed/refractory follicular lymphoma. AB - High-dose chemotherapy with autologous stem cell transplantation (ASCT) has been shown effective in the control of relapsed/refractory follicular lymphoma. We evaluate the long-term outcome of patients with relapsed or refractory follicular lymphoma treated with ASCT with in vivo purged progenitors cells. We report the long-term results of a prospective multicenter phase 2 trial on 124 relapsed/refractory follicular lymphoma patients treated with a program of anthracycline-based debulking chemotherapy, immunochemotherapy, mobilization of in vivo purged PBSC followed by ASCT. Median age was 52 years; 14% of patients had grade 3A histology. Debulking chemotherapy produced CR in 16% and PR in 71%, while 13% of patients progressed. After rituximab, cyclophosphamide, vincristine, prednisone (R-COP), CR was obtained in 60% and PR in 35%; 118 patients successfully mobilized PBSC and 117 proceeded to ASCT. The harvest in all the 32 molecularly informative patients was bcl-2 negative. TRM was 0%. The 5-year PFS was 54% and the 5-year OS was 83%. After a median f-up of 6.7 years (range 1.5 13.6), 54% are still in CR. These data show that prolonged PFS is achievable in relapsed/refractory patients with high dose autologous transplantation of in vivo purged progenitor cells. PMID- 25502634 TI - Properties of membranes derived from the total lipids extracted from clear and cataractous lenses of 61-70-year-old human donors. AB - Human lens-lipid membranes prepared from the total lipids extracted from clear and cataractous lens cortexes and nuclei of 61-70-year-old donors by use of a rapid solvent-exchange method were investigated. The measured cholesterol-to phospholipid (Chol/PL) molar ratio in these membranes was 1.8 and 4.4 for cortex and nucleus of clear lenses, respectively, and 1.14 and 1.45 for cataractous lenses. Properties and organization of the lipid bilayer were investigated by use of electron paramagnetic resonance spin-labeling methods. Formation of Chol crystals was confirmed by use of differential scanning calorimetry. Pure cholesterol bilayer domains (CBDs) were formed in all the membranes investigated. It was shown that in clear lens membranes of the nucleus, Chol exists in three different environments: (1) dispersed in phospholipid bilayers (PCDs), (2) in CBDs, and (3) in Chol crystals. In clear lens membranes of the cortex, and in cortical and nuclear cataractous lens membranes, Chol crystals were not detected, because of the lower Chol content. Profiles of membrane properties (alkyl-chain order, fluidity, oxygen transport, and hydrophobicity) across the PCD were very similar for clear and cataractous membranes. Profiles of the oxygen transport parameter across the CBD were, however, different for cortical clear and cataractous membranes-the amount and size of CBDs was less in cataractous membranes. These results suggest that high Chol content, formation of CBDs, and formation of Chol crystals should not be regarded as major predispositions for the development of age-related cataracts. PMID- 25502636 TI - WWOX suppresses cell growth and induces cell apoptosis via inhibition of P38 nuclear translocation in cholangiocarcinoma. AB - BACKGROUND: Extrahepatic cholangiocarcinoma (EHCC) is the second most common primary hepatic malignancy, and is associated with high morbidity and mortality. We previously reported the decreased expression of WWOX in EHCC samples, but the underlying mechanism remained unclear. METHODS: Immunoprecipitation and immunofluorescence were performed to examine the interaction of WWOX and P38 MAPK. Western blot was carried out to detect the expression of ATF2 and eIF-4E. MTT, colony formation, and Annexin V-FITC assays were performed to detect the cell proliferation and apoptosis. IHC was performed to detect the protein expression in clinical samples. RESULTS: WWOX interacted with P38 and modulated its sub-cellular localization, leading to the cytoplasmic retention of P38. WWOX over-expression inhibited the phosphorylation of ATF2 and eIF-4E, while exogenous P38 reversed this reduction in phosphorylation. Ectopic expression of WWOX in EHCC cells led to inhibited proliferation and stimulated apoptosis in a P38 MAPK dependent manner. In addition, we found a negative association of WWOX with nuclear localization of P38 and expression of phosphorylated ATF2 in EHCC samples. CONCLUSION: Our data demonstrated the role of WWOX in EHCC progression, revealing the potential of WWOX/p-ATF2 as a novel diagnostic and prognostic marker, and therapeutic target for EHCC. PMID- 25502637 TI - The water permeability reduction after successive hypo-osmotic shocks in kidney principal cells is apically regulated. AB - BACKGROUND/AIMS: Renal principal cells maintain their intracellular water and electrolyte content despite significant fluctuations of the extracellular water and salt concentrations. Their water permeability decreases rapidly (within a few seconds) after successive hypo-osmotic shocks. Our aim was to investigate the contribution of the apical and basolateral surface to this effect and the potential influence of fast reduction in AQP-2, -3 or -4 plasma membrane content. METHODS: Rat principal cells of kidney collecting duct fragments underwent hypo osmotic challenge applied apically or basolaterally and the regulatory volume decrease (RVD) was measured by the calcein quenching method. The AQP -2, -3 and 4 content of the plasma membrane fraction was quantified by Western blotting. RESULTS: The hypo-osmotic shock applied apically causes rapid swelling with high apparent water permeability and fast RVD. An identical successive shock after 15 20 sec causes significantly lower swelling rate with 3-fold reduction in apparent water permeability. This reaction is accompanied by AQP2 decrease in the plasma membrane while AQP3 and AQP4 are unaffected. The contribution of the basolateral cell surface to RVD is significantly lower than the apical. CONCLUSION: These results indicate that in principal cells the effective mechanism of RVD is mainly regulated by the apical cell plasma membrane. PMID- 25502638 TI - Computation of pump-leak flux balance in animal cells. AB - BACKGROUND/AIMS: Many vital processes in animal cells depend on monovalent ion transport across the plasma membrane via specific pathways. Their operation is described by a set of nonlinear and transcendental equations that cannot be solved analytically. Previous computations had been optimized for certain cell types and included parameters whose experimental determination can be challenging. METHODS: We have developed a simpler and a more universal computational approach by using fewer kinetic parameters derived from the data related to cell balanced state. A file is provided for calculating unidirectional Na(+), K(+), and Cl(-) fluxes via all major pathways (i.e. the Na/K pump, Na(+), K(+), Cl(-) channels, and NKCC, KC and NC cotransporters) under a balanced state and during transient processes. RESULTS: The data on the Na(+), K(+), and Cl(-) distribution and the pump flux of K(+) (Rb(+)) are obtained on U937 cells before and after inhibiting the pump with ouabain. There was a good match between the results of calculations and the experimentally measured dynamics of ion redistribution caused by blocking the pump. CONCLUSION: The presented approach can serve as an effective tool for analyzing monovalent ion transport in the whole cell, determination of the rate coefficients for ion transfer via major pathways and studying their alteration under various conditions. PMID- 25502639 TI - Increased osteogenic differentiation of periodontal ligament stem cells on polydopamine film occurs via activation of integrin and PI3K signaling pathways. AB - BACKGROUND/AIMS: Mussel-inspired polydopamine (PDA) is known to be an effective bioadhesive and bioactive material for controlling stem cell fate, which is important in stem cell-based regenerative medicine; however, the effect of PDA on osteogenic differentiation of periodontal ligament stem cells (PDLSCs) is not fully understood. In this study, we investigated the osteoinductive effect of PDA on PDLSCs and examined how this phenomenon is encouraged. METHODS: Osteogenic induction of PDLSCs was established by culturing cells on PDA film or on an uncoated polystyrene surface as a control. Osteogenic differentiation of PDLSCs was assessed by measurement of intracellular calcium levels and alkaline phosphatase (ALP) activity as well as by evaluation of protein expression of osteocalcin (OCN), osterix (OSX), and runt-related transcription factor 2 (RUNX2). RESULTS: The PDLSCs cultured on PDA film showed higher osteogenic activity than those on the control surface. Moreover, PDLSCs on PDA film expressed increased levels of the integrin adhesion receptors integrin alpha5 and beta1 compared to control cells. Expression of one isoform of the intracellular signaling protein phosphatidylinositol-3-kinase (PI3K), p110gamma, was increased in PDLSCs on PDA film in a PDA dose-dependent manner. This signaling protein was found to interact with integrin beta1, demonstrating integrin-linked PI3K activation in response to PDA. Finally, the blockage of PI3K reduced the PDA induced osteogenic activity of PDLSCs. CONCLUSION: our findings suggest that the bioadhesive PDA stimulates osteogenic differentiation of PDLSCs via activation of the integrin alpha5/beta1 and PI3K signaling pathways. PMID- 25502640 TI - Building connections. PMID- 25502642 TI - Life Chart Methodology: risks associated with failing to assess patient preferences and the sources of poor insight for patients with bipolar disorder. PMID- 25502643 TI - Modeling food web structure and selenium biomagnification in Lake Macquarie, New South Wales, Australia, using stable carbon and nitrogen isotopes. AB - As a consequence of coal-fired power station operations, elevated selenium concentrations have been reported in the sediments and biota of Lake Macquarie (New South Wales, Australia). In the present study, an ecosystem-scale model has been applied to determine how selenium in a seagrass food web is processed from sediments and water through diet to predators, using stable isotopes (delta(13) C and delta(15) N) to establish the trophic position of organisms. Trophic position, habitat, and feeding zone were examined as possible factors influencing selenium bioaccumulation. Selenium concentrations ranged from 0.2 MUg/g dry weight in macroalgae species to 12.9 MUg/g in the carnivorous fish Gerres subfasciatus. A mean magnification factor of 1.39 per trophic level showed that selenium is biomagnifying in the seagrass food web. Habitat and feeding zone influenced selenium concentrations in invertebrates, whereas feeding zone was the only significant factor influencing selenium concentrations in fish. The sediment water partitioning coefficient (Kd ) of 4180 showed that partitioning of selenium entering the lake to particulate organic material (POM) is occurring, and consequently availability to food webs from POM is high. Trophic transfer factors (invertebrate = 1.9; fish = 1.2) were similar to those reported for other water bodies, showing that input source is not the main determinant of the magnitude of selenium bioaccumulation in a food web, but rather the initial partitioning of selenium into bioavailable POM. Environ Toxicol Chem 2015;34:608-617. (c) 2014 SETAC. PMID- 25502644 TI - ISCEV Standard for full-field clinical electroretinography (2015 update). AB - This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV), presents an updated and revised ISCEV Standard for full-field clinical electroretinography (ffERG or simply ERG). The parameters for Standard flash stimuli have been revised to accommodate a variety of light sources including gas discharge lamps and light emitting diodes. This ISCEV Standard for clinical ERGs specifies six responses based on the adaptation state of the eye and the flash strength: (1) Dark-adapted 0.01 ERG (rod ERG); (2) Dark-adapted 3 ERG (combined rod-cone standard flash ERG); (3) Dark-adapted 3 oscillatory potentials; (4) Dark-adapted 10 ERG (strong flash ERG); (5) Light-adapted 3 ERG (standard flash "cone" ERG); and (6) Light-adapted 30 Hz flicker ERG. ISCEV encourages the use of additional ERG protocols for testing beyond this minimum standard for clinical ERGs. PMID- 25502645 TI - CRISPR/Cas9-mediated genome editing of Epstein-Barr virus in human cells. AB - The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated 9) system is a highly efficient and powerful tool for RNA guided editing of the cellular genome. Whether CRISPR/Cas9 can also cleave the genome of DNA viruses such as Epstein-Barr virus (EBV), which undergo episomal replication in human cells, remains to be established. Here, we reported on CRISPR/Cas9-mediated editing of the EBV genome in human cells. Two guide RNAs (gRNAs) were used to direct a targeted deletion of 558 bp in the promoter region of BART (BamHI A rightward transcript) which encodes viral microRNAs (miRNAs). Targeted editing was achieved in several human epithelial cell lines latently infected with EBV, including nasopharyngeal carcinoma C666-1 cells. CRISPR/Cas9 mediated editing of the EBV genome was efficient. A recombinant virus with the desired deletion was obtained after puromycin selection of cells expressing Cas9 and gRNAs. No off-target cleavage was found by deep sequencing. The loss of BART miRNA expression and activity was verified, supporting the BART promoter as the major promoter of BART RNA. Although CRISPR/Cas9-mediated editing of the multicopy episome of EBV in infected HEK293 cells was mostly incomplete, viruses could be recovered and introduced into other cells at low m.o.i. Recombinant viruses with an edited genome could be further isolated through single-cell sorting. Finally, a DsRed selectable marker was successfully introduced into the EBV genome during the course of CRISPR/Cas9-mediated editing. Taken together, our work provided not only the first genetic evidence that the BART promoter drives the expression of the BART transcript, but also a new and efficient method for targeted editing of EBV genome in human cells. PMID- 25502647 TI - The significance of the individual Meq-clustered miRNAs of Marek's disease virus in oncogenesis. AB - Marek's disease virus (MDV) is an important oncogenic alphaherpesvirus that induces rapid-onset T-cell lymphomas in its natural hosts. The Meq-clustered miRNAs encoded by MDV have been suggested to play potentially critical roles in the induction of lymphomas. Using the technique of bacterial artificial chromosome mutagenesis, we have presently constructed a series of specific miRNA deleted mutants and demonstrate that these miRNAs are not essential for replication of MDV and have no effects on the early cytolytic or latent phases of the developing disease. However, compared to the parental GX0101, mortality of birds infected with the mutants GXDeltamiR-M2, GXDeltamiR-M3, GXDeltamiR-M5, GXDeltamiR-M9 and GXDeltamiR-M12 was reduced from 100 % to 18 %, 30 %, 48 %, 24 % and 14 %, coupled with gross tumour incidence reduction from 28 % to 8 %, 4 %, 12 %, 8 % and 0 %, respectively. Our data confirm that except for mdv1-miR-M4, the other Meq-clustered miRNAs also play critical roles in MDV oncogenesis. Further work will be needed to elucidate the miRNA-mediated regulatory mechanisms that trigger the development of MD lymphomas. PMID- 25502648 TI - Silencing the shutoff protein of Epstein-Barr virus in productively infected B cells points to (innate) targets for immune evasion. AB - During productive infection with Epstein-Barr virus (EBV), a dramatic suppression of cellular protein expression is caused by the viral alkaline exonuclease BGLF5. Among the proteins downregulated by BGLF5 are multiple immune components. Here, we show that shutoff reduces expression of the innate EBV-sensing Toll-like receptor-2 and the lipid antigen-presenting CD1d molecule, thereby identifying these proteins as novel targets of BGLF5. To silence BGLF5 expression in B cells undergoing productive EBV infection, we employed an shRNA approach. Viral replication still occurred in these cells, albeit with reduced late gene expression. Surface levels of a group of proteins, including immunologically relevant molecules such as CD1d and HLA class I and class II, were only partly rescued by depletion of BGLF5, suggesting that additional viral gene products interfere with their expression. Our combined approach thus provides a means to unmask novel EBV (innate) immune evasion strategies that may operate in productively infected B cells. PMID- 25502649 TI - Chimeric neuraminidase and mutant PB1 gene constellation improves growth and yield of H5N1 vaccine candidate virus. AB - We previously showed that a mutated PB1 gene improved the growth kinetics of a H3N2 influenza reassortant. Here, we showed that the same mutations improved the growth kinetics of a virus containing the A/Vietnam/1203/2004 (H5N1) haemagglutinin and neuraminidase (NA). Total protein yield and NA activity were increased when a chimeric NA was included. These increases indicated that the synergistic effect was due to the gene constellation containing both the altered PB1 gene and the chimeric NA gene. PMID- 25502650 TI - Interaction between non-structural protein Pns10 of rice dwarf virus and cytoplasmic actin of leafhoppers is correlated with insect vector specificity. AB - Many insect-transmissible pathogens are transmitted by specific insect species and not by others, even if the insect species are closely related. The molecular mechanisms underlying such strict pathogen-insect specificity are poorly understood. Rice dwarf virus (RDV), a plant reovirus, is transmitted mainly by the leafhopper species Nephotettix cincticeps but is transmitted ineffectively by the leafhopper Recilia dorsalis. Here, we demonstrated that virus-containing tubules composed of viral non-structural protein Pns10 of RDV associated with the intestinal microvilli of N. cincticeps but not with those of R. dorsalis. Furthermore, Pns10 of RDV specifically interacted with cytoplasmic actin, the main component of microvilli of N. cincticeps, but not with that of R. dorsalis, suggesting that the interaction of Pns10 with insect cytoplasmic actin is consistent with the transmissibility of RDV by leafhoppers. All these results suggested that the interaction of Pns10 of RDV with insect cytoplasmic actin may determine pathogen-vector specificity. PMID- 25502651 TI - Inhibition of microtubules and dynein rescues human immunodeficiency virus type 1 from owl monkey TRIMCyp-mediated restriction in a cellular context-specific fashion. AB - IFN-induced restriction factors can significantly affect the replicative capacity of retroviruses in mammals. TRIM5alpha (tripartite motif protein 5, isoform alpha) is a restriction factor that acts at early stages of the virus life cycle by intercepting and destabilizing incoming retroviral cores. Sensitivity to TRIM5alpha maps to the N-terminal domain of the retroviral capsid proteins. In several New World and Old World monkey species, independent events of retrotransposon-mediated insertion of the cyclophilin A (CypA)-coding sequence in the trim5 gene have given rise to TRIMCyp (also called TRIM5-CypA), a hybrid protein that is active against some lentiviruses in a species-specific fashion. In particular, TRIMCyp from the owl monkey (omkTRIMCyp) very efficiently inhibits human immunodeficiency virus type 1 (HIV-1). Previously, we showed that disrupting the integrity of microtubules (MTs) and of cytoplasmic dynein complexes partially rescued replication of retroviruses, including HIV-1, from restriction mediated by TRIM5alpha. Here, we showed that efficient restriction of HIV-1 by omkTRIMCyp was similarly dependent on the MT network and on dynein complexes, but in a context-dependent fashion. When omkTRIMCyp was expressed in human HeLa cells, restriction was partially counteracted by pharmacological agents targeting MTs or by small interfering RNA-mediated inhibition of dynein. The same drugs (nocodazole and paclitaxel) also rescued HIV-1 from restriction in cat CRFK cells, although to a lesser extent. Strikingly, neither nocodazole, paclitaxel nor depletion of the dynein heavy chain had a significant effect on the restriction of HIV-1 in an owl monkey cell line. These results suggested the existence of cell-specific functional interactions between MTs/dynein and TRIMCyp. PMID- 25502652 TI - Rhesus enteric calicivirus surrogate model for human norovirus gastroenteritis. AB - Human noroviruses are one of the major causes of acute gastroenteritis worldwide. Due to the lack of an efficient human norovirus cell culture system coupled with an animal model, human norovirus research mainly relies on human volunteer studies and surrogate models. Current models either utilize human norovirus infected animals including the gnotobiotic pig or calf and the chimpanzee models, or employ other members of the family Caliciviridae including cell culture propagable surrogate caliciviruses such as the feline calicivirus, murine norovirus and most recently the Tulane virus. One of the major features of human noroviruses is their extreme biological diversity, including genetic, antigenic and histo-blood group antigen binding diversity, and possible differences of virulence and environmental stability. This extreme biological diversity and its effect on intervention/prevention strategies cannot be modelled by uniform groups of surrogates, much less by single isolates. Tulane virus, the prototype recovirus strain, was discovered in 2008. Since then, several other novel recoviruses have been described and cell culture adapted. Recent studies indicate that the epidemiology, the biological features and diversity of recoviruses and the course of infection and clinical disease in recovirus-infected macaques more closely reflect those properties of human noroviruses than any of the current surrogates. This review aims to summarize what is currently known about recoviruses, highlight their biological similarities to human noroviruses and discuss applications of the model in addressing questions relevant for human norovirus research. PMID- 25502653 TI - Subcellular localization and membrane association of the replicase protein of grapevine rupestris stem pitting-associated virus, family Betaflexiviridae. AB - As a member of the newly established Betaflexiviridae family, grapevine rupestris stem pitting-associated virus (GRSPaV) has an RNA genome containing five ORFs. ORF1 encodes a putative replicase polyprotein typical of the alphavirus superfamily of positive-strand ssRNA viruses. Several viruses of this superfamily have been demonstrated to replicate in structures designated viral replication complexes associated with intracellular membranes. However, structure and cellular localization of the replicase complex have not been studied for members of Betaflexiviridae, a family of mostly woody plant viruses. As a first step towards the elucidation of the replication complex of GRSPaV, we investigated the subcellular localization of full-length and truncated versions of its replicase polyprotein via fluorescent tagging, followed by fluorescence microscopy. We found that the replicase polyprotein formed distinctive punctate bodies in both Nicotiana benthamiana leaf cells and tobacco protoplasts. We further mapped a region of 76 amino acids in the methyl-transferase domain responsible for the formation of these punctate structures. The punctate structures are distributed in close proximity to the endoplasmic reticulum network. Membrane flotation and biochemical analyses demonstrate that the N-terminal region responsible for punctate structure formation associated with cellular membrane is likely through an amphipathic alpha helix serving as an in-plane anchor. The identity of this membrane is yet to be determined. This is, to our knowledge, the first report on the localization and membrane association of the replicase proteins of a member of the family Betaflexiviridae. PMID- 25502654 TI - Crystal structure of calcium binding protein-5 from Entamoeba histolytica and its involvement in initiation of phagocytosis of human erythrocytes. AB - Entamoeba histolytica is the etiological agent of human amoebic colitis and liver abscess, and causes a high level of morbidity and mortality worldwide, particularly in developing countries. There are a number of studies that have shown a crucial role for Ca2+ and its binding protein in amoebic biology. EhCaBP5 is one of the EF hand calcium-binding proteins of E. histolytica. We have determined the crystal structure of EhCaBP5 at 1.9 A resolution in the Ca2+-bound state, which shows an unconventional mode of Ca2+ binding involving coordination to a closed yet canonical EF-hand motif. Structurally, EhCaBP5 is more similar to the essential light chain of myosin than to Calmodulin despite its somewhat greater sequence identity with Calmodulin. This structure-based analysis suggests that EhCaBP5 could be a light chain of myosin. Surface plasmon resonance studies confirmed this hypothesis, and in particular showed that EhCaBP5 interacts with the IQ motif of myosin 1B in calcium independent manner. It also appears from modelling of the EhCaBP5-IQ motif complex that EhCaBP5 undergoes a structural change in order to bind the IQ motif of myosin. This specific interaction was further confirmed by the observation that EhCaBP5 and myosin 1B are colocalized in E. histolytica during phagocytic cup formation. Immunoprecipitation of EhCaBP5 from total E. histolytica cellular extract also pulls out myosin 1B and this interaction was confirmed to be Ca2+ independent. Confocal imaging of E. histolytica showed that EhCaBP5 and myosin 1B are part of phagosomes. Overexpression of EhCaBP5 increases slight rate (~20%) of phagosome formation, while suppression reduces the rate drastically (~55%). Taken together, these experiments indicate that EhCaBP5 is likely to be the light chain of myosin 1B. Interestingly, EhCaBP5 is not present in the phagosome after its formation suggesting EhCaBP5 may be playing a regulatory role. PMID- 25502655 TI - [Vertigo/dizziness and syncope from a neurological perspective]. AB - Vertigo/dizziness and syncope are among the most frequent clinical entities encountered in neurology. In patients with presumed syncope, it is important to distinguish it from neurological and psychiatric diseases causing a transient loss of consciousness due to another etiology. Moreover, central nervous disorders of autonomic blood pressure regulation as well as affections of the peripheral autonomic nerves can be responsible for the onset of real syncope. This is particularly relevant in recurrent syncope. Vertigo occurs in the context of temporary disorders, relatively harmless diseases associated with chronic impairment, as well as in acute life-threatening states. Patient history and clinical examination play an important role in classifying these symptoms. It is of crucial importance in this context, e.g., to establish whether the patient is experiencing an initial manifestation or whether such episodes have been known to occur recurrently over a longer period of time, as well as how long the episodes last. Clinical investigations include a differential examination of the oculomotor system with particular regard to nystagmus. The present article outlines the main underlying neurological diseases associated with syncope and vertigo, their relevant differential diagnoses as well as practical approaches to their treatment. PMID- 25502656 TI - [Diseases of the peripheral vestibular system: contribution of ENT medical diagnostics and therapy]. AB - The most common types of vertigo caused by diseases of the peripheral vestibular system are benign paroxysmal positional vertigo (BPPV), Meniere's disease and vestibular neuritis. A thorough examination of the medical history and clinical examination are usually sufficient for the differential diagnostics. Treatment includes differentiated repositioning maneuvers, medicinal treatment and physiotherapy. PMID- 25502657 TI - [ANCA-associated vasculitis]. AB - The vasculitides represent one group of the systemic rheumatic diseases. Among the vasculitides we distinguish between large- (i.e. giant cell arteritis), medium- (i.e. polyarteritis nodosa) and small-vessel vasculitides (i.e. ANCA associated vasculitides). Granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis belong to the ANCA associated vasculitides. They share the features of vasculitic manifestations in small- to medium-sized vessel beds (which can occur in almost any organ system) and the presence of ANCA, the detection of which, however, is not necessarily mandatory. The treatment of AAV depends on disease stage and activity and is carried out on the basis of randomized controlled trials with an initial regimen aimed at inducing remission followed by maintenance treatment. In addition to glucocorticoids, conventional immunosuppressants (such as methotrexate, azathioprine and cyclophosphamide) form the basis of treatment, whereby rituximab, first licensed for the treatment of severe active GPA and MPA in 2013, has emerged as new treatment option. PMID- 25502659 TI - Does global progress on sanitation really lag behind water? An analysis of global progress on community- and household-level access to safe water and sanitation. AB - Safe drinking water and sanitation are important determinants of human health and wellbeing and have recently been declared human rights by the international community. Increased access to both were included in the Millennium Development Goals under a single dedicated target for 2015. This target was reached in 2010 for water but sanitation will fall short; however, there is an important difference in the benchmarks used for assessing global access. For drinking water the benchmark is community-level access whilst for sanitation it is household level access, so a pit latrine shared between households does not count toward the Millennium Development Goal (MDG) target. We estimated global progress for water and sanitation under two scenarios: with equivalent household- and community-level benchmarks. Our results demonstrate that the "sanitation deficit" is apparent only when household-level sanitation access is contrasted with community-level water access. When equivalent benchmarks are used for water and sanitation, the global deficit is as great for water as it is for sanitation, and sanitation progress in the MDG-period (1990-2015) outstrips that in water. As both drinking water and sanitation access yield greater benefits at the household level than at the community-level, we conclude that any post-2015 goals should consider a household-level benchmark for both. PMID- 25502660 TI - Draft Genome Sequence of Enterobacter cloacae Strain S611. AB - We report draft genomes of Enterobacter cloacae strain S611, an endophytic bacterium isolated from surface-sterilized germinating wheat seeds. We present the assembly and annotation of its genome, which may provide insights into the metabolic pathways involved in adaptation. PMID- 25502658 TI - Activity, abundance and expression of Ca2+-activated proteases in skeletal muscle of the aestivating frog, Cyclorana alboguttata. AB - In most mammals, prolonged muscle disuse (e.g. bed-rest, limb casting or spaceflight) results in atrophy of muscle fibres which is largely due to unregulated proteolysis. Although numerous proteolytic pathways are known to participate in muscle disuse atrophy, recent evidence suggests that activation of Ca2+-dependent cysteine proteases (calpains) is required for disuse atrophy in limb skeletal muscles. In contrast to typical models of muscle disuse (humans and rodents), animals that experience natural bouts of chronic muscle inactivity, such as hibernating mammals and aestivating frogs, consistently exhibit limited or no change in skeletal muscle size. In the current study, we examined enzyme activity, protein abundance and gene expression levels of calpain isoforms in gastrocnemius muscle of the aestivating frog, Cyclorana alboguttata. We predicted that in aestivating C. alboguttata there would be a downregulation of the abundance, activity and gene expression of calpain 1 and calpain 2. In contrast to our hypothesis, there was no significant decrease in the enzyme activity levels or the relative protein abundances of calpain 1 and calpain 2. Similarly, gene expression assays (both qRT-PCR and RNA Seq data) indicated that calpains were unaffected by aestivation. Western blotting of 'muscle-specific' calpain 3, which is consistently downregulated during atrophic conditions, indicated that this isoform is present in C. alboguttata muscle where it appears to be in its autolysed state. The absence of any increase in enzyme activity, protein and mRNA abundance of calpains in aestivators is consistent with the protection of gastrocnemius muscle against uncontrolled proteolysis throughout aestivation. PMID- 25502662 TI - Complete Genome Sequence of the Autographa californica Multiple Nucleopolyhedrovirus Strain E2. AB - Many vectors that are commonly used in the baculovirus/insect cell system (BICS) are derived from the Autographa californica multiple nucleopolyhedrovirus (AcMNPV) strain E2. To facilitate work with these vectors, we sequenced the E2 genome, compared it to that of the AcMNPV C6 strain, and found that they are very similar overall. PMID- 25502661 TI - Draft Genome Sequence of the Biofilm-Producing Bacillus subtilis Strain B-1, Isolated from an Oil Field. AB - We report here the draft genome sequence of the Bacillus subtilis strain B-1, a strain known to form biofilms. The biofilm matrix mainly consists of the biopolymer gamma-polyglutamate (gamma-PGA). The sequence of the genome of this strain allows the study of specific genes involved in biofilm formation. PMID- 25502664 TI - Molecular characterization of the full muscovy duck parvovirus, isolated in guangxi, china. AB - We report the complete genomic sequence of the full Muscovy duck parvovirus (MDPV) strain, designated GX2011-5, isolated from a Muscovy duck in Guangxi Province, China. The complete genomic sequence was 5,132 bp in length and contained two major open reading frames encoding a 1,844-nucleotide (nt) nonstructural protein and a 2,199-nt capsid protein. Comparison of the complete sequence of GX2011-5 with other published sequences of Muscovy duck parvovirus revealed that this strain exhibited 90.4% to 95.1% sequence homology. This report will advance our understanding of the epidemiology and molecular characteristics of MDPV in the Muscovy duck population in Guangxi, China. PMID- 25502665 TI - Draft Genome Sequence of Pseudoalteromonas sp. Strain PLSV, an Ulvan-Degrading Bacterium. AB - We present the draft genome sequence of Pseudoalteromonas sp. strain PLSV, isolated from the feces of an Aplysia sea slug. The addition of the PLSV genome to the existing genomes of three other ulvan-degrading bacterial species will enhance our understanding of ulvan utilization. PMID- 25502666 TI - Complete Genome Sequence of Nervous Necrosis Virus Isolated from Sevenband Grouper (Epinephelus septemfasciatus) in South Korea. AB - The draft genome sequence of the nervous necrosis virus (NNV) SGYeosu08, isolated from sevenband grouper (Epinephelus septemfasciatus) in Yeosu, South Korea, was cloned and analyzed. The full-length RNA1 was a 3,103-nucleotide-encoding region of RNA-dependent RNA polymerase, and the RNA2 encoding a coat protein was 1,433 nucleotides in length. This genome sequence might be useful in the development of an accurate diagnostic tool. PMID- 25502663 TI - Genome Sequence of Bacillus simplex Strain P558, Isolated from a Human Fecal Sample. AB - Bacillus simplex strain P558 was isolated from a fecal sample of a 25-year-old Saudi male. We sequenced the 5.98-Mb genome of the strain and compared it to that of B. simplex strain 1NLA3E. PMID- 25502667 TI - Draft Genome Sequence and Annotation of the Entomopathogenic Bacterium Photorhabdus luminescens LN2, Which Shows Nematicidal Activity against Heterorhabditis bacteriophora H06 Nematodes. AB - We present here the 5.6-Mb genome sequence of Photorhabdus luminescens strain LN2, a Gram-negative bacterium that is a symbiont of Heterorhabditis indica LN2 and shows nematicidal activity against Heterorhabditis bacteriophora H06 nematodes. PMID- 25502668 TI - Genome Sequence of Streptococcus phocae subsp. salmonis Strain C-4T, Isolated from Atlantic Salmon (Salmo salar). AB - Streptococcus phocae subsp. salmonis is a fish pathogen that has an important impact on the Chilean salmon industry. Here, we report the genome sequence of the type strain C-4(T) isolated from Atlantic salmon (Salmo salar), showing a number of interesting features and genes related to its possible virulence factors. PMID- 25502669 TI - Draft Genome Sequence of the Betaproteobacterial Endosymbiont Associated with the Fungus Mortierella elongata FMR23-6. AB - The fungus Mortierella elongata FMR23-6 harbors an endobacterium inside its mycelium. Attempts to isolate the endobacterium from the fungus were not yet successful, but a highly purified bacterial fraction was prepared. Here, we report the draft genome sequence of the endobacterium. PMID- 25502670 TI - Draft Genome Sequence of Photorhabdus temperata Strain Meg1, an Entomopathogenic Bacterium Isolated from Heterorhabditis megidis Nematodes. AB - Photorhabdus temperata strain Meg1 is an entomopathogenic bacterium that forms a symbiotic association with Heterorhabditis nematodes. We report here a 4.9-Mbp draft genome sequence for P. temperata strain Meg1, with a G+C content of 43.18% and containing 4,340 candidate protein-coding genes. PMID- 25502671 TI - Draft Genome Sequence of Bivalent Clostridium botulinum Strain IBCA10-7060, Encoding Botulinum Neurotoxin B and a New FA Mosaic Type. AB - Here we report the genome sequence of a Clostridium botulinum strain IBCA10-7060 producing botulinum neurotoxin serotype B and a new toxin serotype. Multilocus sequence typing analysis revealed that this strain belongs to a new sequence type, and whole-genome single nucleotide polymorphism analysis showed that this strain clustered with strains in lineage 2 from group I. PMID- 25502672 TI - Complete Genome Sequence of Pluralibacter gergoviae FB2, an N-Acyl Homoserine Lactone-Degrading Strain Isolated from Packed Fish Paste. AB - Pluralibacter gergoviae FB2, a bacterial strain isolated from packed food, has been found to exhibit quorum-quenching properties. Hence, we report the first, complete genome of P. gergoviae sequenced using the Pacific Biosciences single molecule, real-time (SMRT) platform. PMID- 25502673 TI - Genome Sequence of the Petroleum Hydrocarbon-Degrading Bacterium Alcanivorax sp. Strain 97CO-5. AB - Alcanivorax sp. strain 97CO-5 was isolated from a crude-oil-degrading consortium, enriched from Yellow Sea sediment of China. Here, we present the draft genome of strain 97CO-5, which comprises 3,251,558 bp with a G+C content of 54.54% and contains 2,962 protein-coding genes and 42 tRNAs. PMID- 25502674 TI - Draft Genome Sequence of a Xylanase-Producing Bacterial Strain, Cellvibrio mixtus J3-8. AB - The xylanase-producing bacterial strain Cellvibrio mixtus J3-8 was isolated from grassland giant snails. The draft genome of strain J3-8 comprises 5,171,890 bp in 152 contigs with a G+C content of 46.66%. This is the first genome report about this bacterial species. PMID- 25502675 TI - Full Genome Sequence of a Reassortant Human G9P[4] Rotavirus Strain. AB - This is a report of the complete genomic sequence of a reassortant rotavirus group A G9-P[4]-I2-R2-C2-M2-A2-N2-T2-E6-H2 strain designated RVA/Human-wt/USA/ LB1562/2010/G9P[4]. PMID- 25502676 TI - The Complete Genome Sequence of the San Miguel Sea Lion Virus-8 Reveals that It Is Not a Member of the Vesicular Exanthema of Swine Virus/San Miguel Sea Lion Virus Species of the Caliciviridae. AB - The complete genome sequence of the San Miguel sea lion virus-8 (SMSV-8) was determined in this study. A comparison of this sequence to other calicivirus sequences in GenBank showed that this virus is genetically distinct from the vesicular exanthema of swine virus/San Miguel sea lion virus (VESV/SMSV) strains and belongs to a novel clade within the Vesivirus genus. PMID- 25502677 TI - Whole-Genome Sequence of Marine Bacterium Phaeodactylibacter xiamenensis Strain KD52, Isolated from the Phycosphere of Microalga Phacodactylum tricornutum. AB - Phaeodactylibacter xiamenensis KD52 is a novel bacterium isolated from a culture of the alga Phaeodactylum tricornutum in Xiamen, Fujian Province, China. Here, we present the first draft genome sequence of this strain, which will provide an opportunity to further understand the functional genes related to signing for nutrition from the host algae and the molecular mechanisms underlying its beneficial properties. PMID- 25502678 TI - Draft Genome Sequence of the Mannitol-Producing Strain Lactobacillus mucosae CRL573. AB - Lactobacillus mucosae CRL573, isolated from child fecal samples, efficiently converts fructose and/or sucrose into the low-calorie sugar mannitol when cultured in modified MRS medium at pH 5.0. Also, the strain is capable of producing bacteriocin. The draft genome sequence of this strain with potential industrial applications is presented here. PMID- 25502679 TI - Draft Genome Sequence of Lactobacillus sakei Strain wikim 22, Isolated from Kimchi in Chungcheong Province, South Korea. AB - We report the draft genome sequence of Lactobacillus sakei strain wikim 22, a Lactobacillus species isolated from kimchi in North Chungcheong Province, South Korea, having 155 contigs with 2,447 genes and an average G+C content of 40.61%. PMID- 25502680 TI - Draft Genome Sequence of Propane- and Butane-Oxidizing Actinobacterium Rhodococcus ruber IEGM 231. AB - We report a draft genome sequence of Rhodococcus ruber IEGM 231, isolated from a water spring near an oil-extracting enterprise (Perm region, Russian Federation). This sequence provides important insights into the genetic mechanisms of propane and n-butane metabolism, organic sulfide and beta-sitosterol biotransformation, glycolipid biosurfactant production, and heavy metal resistance in actinobacteria. PMID- 25502681 TI - Draft Genome Sequence of Gephyronic Acid Producer Cystobacter violaceus Strain Cb vi76. AB - A draft genome sequence of Cystobacter violaceus strain Cb vi76, which produces the eukaryotic protein synthesis inhibitor gephyronic acid, has been obtained. The genome contains numerous predicted secondary metabolite clusters, including the gephyronic acid biosynthetic pathway. This genome will contribute to the investigation of secondary metabolism in other Cystobacter strains. PMID- 25502682 TI - Draft Genome Sequences of Streptococcus agalactiae Strains Isolated from Nile Tilapia (Oreochromis niloticus) Farms in Thailand. AB - During 2009-2011, two clinical and one environmental strains of Streptococcus agalactiae were isolated from Nile tilapia (Oreochromis niloticus) farms in Thailand. Draft genome sequences of two clinical isolates comprise 2,048,343 and 2,105,006 bp, while environmental isolates comprise 2,097,115 bp, having 1,573 to 1,578 coding sequences, respectively. PMID- 25502683 TI - Draft Genome Sequence of Methylobacterium sp. Strain L2-4, a Leaf-Associated Endophytic N-Fixing Bacterium Isolated from Jatropha curcas L. AB - Methylobacterium sp. strain L2-4 is an efficient nitrogen-fixing leaf colonizer of biofuel crop Jatropha curcas. This strain is able to greatly improve the growth and seed yield of Jatropha curcas and is the second reported genome sequence of plant growth-promoting bacteria isolated from Jatropha curcas. PMID- 25502684 TI - Draft Genome Sequence of Erwinia oleae, a Bacterium Associated with Olive Knots Caused by Pseudomonas savastanoi pv. savastanoi. AB - Erwinia oleae is a nonpathogenic bacterial species isolated from olive knots caused by Pseudomonas savastanoi pv. savastanoi. Since the presence of E. oleae in the knots increases disease severity, interspecies interactions with the pathogen are hypothesized. Here, we report the first draft genome sequence of the E. oleae type strain. PMID- 25502686 TI - Incidence of white spot lesions among patients treated with self- and conventional ligation systems. AB - OBJECTIVES: The aim of this study was to investigate the incidence of white spot lesions (WSLs) and its relationship with various patient and treatment variables, in patients treated with self-ligation and conventional ligation orthodontic bracket systems. METHODS: Two-hundred randomly selected patient records (136 female, 64 male) for self-ligation and (108 female, 92 male) for conventional ligation groups were examined to determine WSL development. In the self-ligation group, Damon 3MX (Ormco, Glendora, Calif) brackets had been used, and in the conventional ligation group, Equilibrium 2 (Dentaurum, Phorzeim, Germany) had been used. Labial surfaces of 24 teeth in the pre- and post-treatment photographic records were scored using the WSL index. RESULTS: The prevalence of patients who developed at least 1 WSL before treatment was 19%, whereas after treatment, it was 49% in the self-ligation and 54% in the conventional ligation groups. Before treatment, the patients had only mild WSL, but after treatment, severe WSL and cavitation were observed in both groups. Bracket type, age, and hygiene care were significantly associated with new WSL development (P = 0.008, P = 0.004, P = 0.013, respectively). CONCLUSION: Bracket type and more importantly, the hygiene care therapy provided appeared to influence the development of new WSLs. Ligation can promote plaque accumulation and thereby new WSL development in conventional bracket systems. CLINICAL RELEVANCE: This article investigates the incidence of WSLs in patients treated with self-ligation and conventional ligation. The present study showed that incidence of WSL less in the self ligation than in the conventional ligation but hygiene care was mostly important factor in developed WSL. PMID- 25502685 TI - Abieslactone induces cell cycle arrest and apoptosis in human hepatocellular carcinomas through the mitochondrial pathway and the generation of reactive oxygen species. AB - Abieslactone is a triterpenoid lactone isolated from Abies plants. Previous studies have demonstrated that its derivative abiesenonic acid methyl ester possesses anti-tumor-promoting activity in vitro and in vivo. In the present study, cell viability assay demonstrated that abieslactone had selective cytotoxicity against human hepatoma cell lines. Immunostaining experiments revealed that abieslactone induced HepG2 and SMMC7721 cell apoptosis. Flow cytometry and western blot analysis showed that the apoptosis was associated with cell cycle arrest during the G1 phase, up-regulation of p53 and p21, and down regulation of CDK2 and cyclin D1. Furthermore, our results revealed that induction of apoptosis through a mitochondrial pathway led to upregulation of Bax, down-regulation of Bcl-2, mitochondrial release of cytochrome c, reduction of mitochondrial membrane potential (MMP), and activation of caspase cascades (Casp-9 and -3). Activation of caspase cascades also resulted in the cleavage of PARP fragment. Involvement of the caspase apoptosis pathway was confirmed using caspase inhibitor Z-VAD-FMK pretreatment. Recent studies have shown that ROS is upstream of Akt signal in mitochondria-mediated hepatoma cell apoptosis. Our results showed that the accumulation of ROS was detected in HepG2 cells when treated with abieslactone, and ROS scavenger partly blocked the effects of abieslactone-induced HepG2 cell death. In addition, inactivation of total and phosphorylated Akt activities was found to be involved in abieslactone-induced HepG2 cell apoptosis. Therefore, our findings suggested that abieslactone induced G1 cell cycle arrest and caspase-dependent apoptosis via the mitochondrial pathway and the ROS/Akt pathway in HepG2 cells. PMID- 25502687 TI - Criminal justice system contact and mortality among offenders with mental illness in British Columbia: an assessment of mediation. AB - BACKGROUND: Persons with mental illness are over-represented in prison populations around the world. They are more vulnerable to arrest and more likely to experience repeated encounters with the criminal justice system. Whether criminal justice involvement, in and of itself, is associated with higher mortality, particularly among offenders with mental illness, is unknown. METHODS: The authors conducted a mediation analysis of mortality rates in a cohort of 79,088 offenders from British Columbia using administrative records spanning 2001 2010, where the mediating variable was the individual-level rate of criminal sentencing. RESULTS: During 339,506 person-years of follow-up, there were 1841 deaths. The diagnosis of mental illness had no direct association with higher mortality after adjustment for confounders (HR=0.98, 95% CI 0.86 to 1.06). However, mental illness had an indirect association with mortality that was mediated through more frequent criminal justice involvement (HR=1.02, 95% CI 1.01 to 1.04). CONCLUSIONS: These findings support the hypothesis that offenders with mental illness experience higher mortality that is mediated by higher rates of criminal justice contact. The results of our study indicate that criminal justice diversion programmes are further warranted because they may contribute to the prevention of mortality among offenders with mental illness. PMID- 25502688 TI - Mechanistic aspects of the photodynamic inactivation of vancomycin-resistant Enterococci mediated by 5-aminolevulinic acid and 5-aminolevulinic acid methyl ester. AB - Vancomycin-resistant Enterococci (VRE) is a serious concern for public health. Serious infections with VRE have very limited effective antimicrobial therapy, and alternative treatment approaches are highly desirable. One promising approach might be the photodynamic antimicrobial chemotherapy. In the present study, we investigated the photodynamic inactivation (PDI) of two VRE strains mediated by 5 aminolevulinic acid (5-ALA) and its derivative 5-ALA methyl ester (MAL). The photodynamic damages to bacteria on the level of genomic DNA, the leakage of cell components, and the changes of membrane structure were investigated. After treated with 10 mM 5-ALA and irradiated by the 633 +/- 10 nm LED for 60 min, 5.37 and 5.22 log10 reductions in bacterial survival were achieved for the clinical isolate of VRE and E. faecalis (ATCC 51299), respectively. After treated with 10 mM MAL and irradiated by the LED for 60 min, 5.02 and 4.91 log10 reductions in bacterial survival were observed for the two VRE strains, respectively. In addition, the photocleavage on genomic DNA and the rapid release of intracellular biopolymers were detected in PDI-treated bacteria. The intensely denatured cytoplasm and the aggregated ribosomes were also found in PDI-treated bacteria by transmission electron microscopy. Although 5-ALA and MAL-mediated PDI could induce the photocleavage on genomic DNA, the PDI of the two VRE strains might be predominantly attributed to the envelope injury, the intracellular biopolymers leakage, and the cytoplasm denature. PMID- 25502689 TI - Addition of local hepatic therapy to sorafenib in patients with advanced hepatocellular carcinoma (stage BCLC C). AB - BACKGROUND/AIMS: For most patients with hepatocellular carcinoma (HCC), diagnosis is invariably done only in the advanced stages of the disease. For advanced, non metastatic stage, standard therapy is transarterial chemoembolization (TACE). For metastatic disease, the recommended therapy is systemic treatment with sorafenib. In this study, we evaluated the benefit of an additional local hepatic treatment for patients with advanced metastatic disease. METHODS: In a retrospective study, we assessed the overall survival (OS), time to progression (TTP), and disease control rate (DCR) in 37 patients with metastasized HCC treated with sorafenib. Sixteen patients received additional local therapy, while 21 patients received only sorafenib. RESULTS: Median OS of patients with combined therapy was significantly higher with 25 months (95% CI: 13.7-36.3 months) as compared to 11 months (95% CI: 6.2-15.8 months) in patients treated with sorafenib alone. TTP was 7 months (95% CI: 5.3-8.7 months) compared to 5 months (95% CI: 3-7 months) and DCR was 87 versus 72% after 3 months and 31 versus 22% after 9 months. CONCLUSION: These data suggest that control of the liver tumor burden by local therapy in combination with sorafenib might prove beneficial for metastasized HCC. Randomised studies are needed to confirm this exploratory finding. PMID- 25502690 TI - Isolation and characterization of an ubiquitin extension protein gene (JcUEP) promoter from Jatropha curcas. AB - MAIN CONCLUSION: The JcUEP promoter is active constitutively in the bio-fuel plant Jatropha curcas , and is an alternative to the widely used CaMV35S promoter for driving constitutive overexpression of transgenes in Jatropha. Well characterized promoters are required for transgenic breeding of Jatropha curcas, a biofuel feedstock with great potential for production of bio-diesel and bio-jet fuel. In this study, an ubiquitin extension protein gene from Jatropha, designated JcUEP, was identified to be ubiquitously expressed. Thus, we isolated a 1.2 kb fragment of the 5' flanking region of JcUEP and evaluated its activity as a constitutive promoter in Arabidopsis and Jatropha using the beta glucuronidase (GUS) reporter gene. As expected, histochemical GUS assay showed that the JcUEP promoter was active in all Arabidopsis and Jatropha tissues tested. We also compared the activity of the JcUEP promoter with that of the cauliflower mosaic virus 35S (CaMV35S) promoter, a well-characterized constitutive promoter conferring strong transgene expression in dicot species, in various tissues of Jatropha. In a fluorometric GUS assay, the two promoters showed similar activities in stems, mature leaves and female flowers; while the CaMV35S promoter was more effective than the JcUEP promoter in other tissues, especially young leaves and inflorescences. In addition, the JcUEP promoter retained its activity under stress conditions in low temperature, high salt, dehydration and exogenous ABA treatments. These results suggest that the plant derived JcUEP promoter could be an alternative to the CaMV35S promoter for driving constitutive overexpression of transgenes in Jatropha and other plants. PMID- 25502691 TI - Disruption of gene pqqA or pqqB reduces plant growth promotion activity and biocontrol of crown gall disease by Rahnella aquatilis HX2. AB - Rahnella aquatilis strain HX2 has the ability to promote maize growth and suppress sunflower crown gall disease caused by Agrobacterium vitis, A. tumefaciens, and A. rhizogenes. Pyrroloquinoline quinone (PQQ), a cofactor of aldose and alcohol dehydrogenases, is required for the synthesis of an antibacterial substance, gluconic acid, by HX2. Mutants of HX2 unable to produce PQQ were obtained by in-frame deletion of either the pqqA or pqqB gene. In this study, we report the independent functions of pqqA and pqqB genes in relation to PQQ synthesis. Interestingly, both the pqqA and pqqB mutants of R. aquatilis eliminated the ability of strain HX2 to produce antibacterial substance, which in turn, reduced the effectiveness of the strain for biological control of sunflower crown gall disease. The mutation also resulted in decreased mineral phosphate solubilization by HX2, which reduced the efficacy of this strain as a biological fertilizer. These functions were restored by complementation with the wild-type pqq gene cluster. Additionally, the phenotypes of HX2 derivatives, including colony morphology, growth dynamic, and pH change of culture medium were impacted to different extents. Our findings suggested that pqqA and pqqB genes individually play important functions in PQQ biosynthesis and are required for antibacterial activity and phosphorous solubilization. These traits are essential for R. aquatilis efficacy as a biological control and plant growth promoting strain. This study enhances our fundamental understanding of the biosynthesis of an environmentally significant cofactor produced by a promising biocontrol and biological fertilizer strain. PMID- 25502692 TI - A sero-epidemiological study of arboviral fevers in Djibouti, Horn of Africa. AB - Arboviral infections have repeatedly been reported in the republic of Djibouti, consistent with the fact that essential vectors for arboviral diseases are endemic in the region. However, there is a limited recent information regarding arbovirus circulation, and the associated risk predictors to human exposure are largely unknown. We performed, from November 2010 to February 2011 in the Djibouti city general population, a cross-sectional ELISA and sero-neutralisation based sero-epidemiological analysis nested in a household cohort, which investigated the arboviral infection prevalence and risk factors, stratified by their vectors of transmission. Antibodies to dengue virus (21.8%) were the most frequent. Determinants of infection identified by multivariate analysis pointed to sociological and environmental exposure to the bite of Aedes mosquitoes. The population was broadly naive against Chikungunya (2.6%) with risk factors mostly shared with dengue. The detection of limited virus circulation was followed by a significant Chikungunya outbreak a few months after our study. Antibodies to West Nile virus were infrequent (0.6%), but the distribution of cases faithfully followed previous mapping of infected Culex mosquitoes. The seroprevalence of Rift valley fever virus was 2.2%, and non-arboviral transmission was suggested. Finally, the study indicated the circulation of Toscana-related viruses (3.7%), and a limited number of cases suggested infection by tick-borne encephalitis or Alkhumra related viruses, which deserve further investigations to identify the viruses and vectors implicated. Overall, most of the arboviral cases' predictors were statistically best described by the individuals' housing space and neighborhood environmental characteristics, which correlated with the ecological actors of their respective transmission vectors' survival in the local niche. This study has demonstrated autochthonous arboviral circulations in the republic of Djibouti, and provides an epidemiological inventory, with useful findings for risk mapping and future prevention and control programs. PMID- 25502693 TI - Polyphenolic compounds progress during olive mill wastewater sludge and poultry manure co-composting, and humic substances building (Southeastern Tunisia). AB - In Mediterranean areas, olive mill wastes pose a major environmental problem owing to their important production and their high polyphenolic compounds and organic acids concentrations. In this work, the evolution of polyphenolic compounds was studied during co-composting of olive mill wastewater sludge and poultry manure, based on qualitative (G-50 sephadex) and quantitative (Folin Ciocalteu), as well as high pressure liquid chromatography analyses. Results showed a significant polyphenolic content decrease of 99% and a noticeable transformation of low to high molecular weight fraction during the compost maturation period. During this step, polyphenols disappearance suggested their assimilation by thermophilic bacteria as a carbon and energy source, and contributed to humic substances synthesis. Polyphenolic compounds, identified initially by high pressure liquid chromatography, disappeared by composting and only traces of caffeic, coumaric and ferulic acids were detected in the compost. In the soil, the produced compost application improved the chemical and physico chemical soil properties, mainly fertilising elements such as calcium, magnesium, nitrogen, potassium and phosphorus. Consequently, a higher potato production was harvested in comparison with manure amendment. PMID- 25502695 TI - Ocular ultrasound as an easy applicable tool for detection of Terson's syndrome after aneurysmal subarachnoid hemorrhage. AB - INTRODUCTION: Intraocular hemorrhage in patients suffering from aneurysmal subarachnoid hemorrhage is known as Terson's syndrome and is an underestimated but common pathology. We therefore designed a prospective single-blinded study to evaluate the validity of ocular ultrasound compared to the gold standard indirect funduscopy in the diagnosis of Terson's syndrome. MATERIAL AND METHODS: Fifty-two patients (104 eyes in total) suffering from aneurysmal subarachnoid hemorrhage were enrolled in this study. Two investigators independently performed a single blinded ocular ultrasound using a standard intensive care ultrasound system to detect an intraocular hemorrhage. Indirect funduscopy following iatrogenic mydriasis served as the gold standard for confirmation or exclusion of an intraocular hemorrhage. Statistical analyses were performed to evaluate the sensitivity and specificity, positive and negative predictive values of the method as well as the learning curve of ocular ultrasound. RESULTS: Indirect funduscopy detected Terson's syndrome in 11 of 52 (21.2%) respectively in 21 of 104 (20.2%) eyes in patients suffering from subarachnoid hemorrhage. Sensitivity and specificity increased with the number of ocular ultrasound examinations for both investigators, reaching 81.8% and 100% respectively. Positive and negative predictive values were different for both investigators (63.6% vs. 100% positive and 100% vs. 95.7% negative) but were both correlated to the amount of intraocular hemorrhage. A low Glasgow Coma scale (p = 0.015) and high Hunt & Hess grade (p = 0.003) was associated with a higher rate of Terson's syndrome. CONCLUSIONS: Ocular ultrasound using standard ultrasound equipment has been confirmed as a reliable, easy-to-handle bedside screening tool for detecting Terson's syndrome. Nevertheless funduscopy remains the gold standard to detect Terson's syndrome. PMID- 25502696 TI - Type-IV Pilus deformation can explain retraction behavior. AB - Polymeric filament like type IV Pilus (TFP) can transfer forces in excess of 100 pN during their retraction before stalling, powering surface translocation(twitching). Single TFP level experiments have shown remarkable nonlinearity in the retraction behavior influenced by the external load as well as levels of PilT molecular motor protein. This includes reversal of motion near stall forces when the concentration of the PilT protein is loweblack significantly. In order to explain this behavior, we analyze the coupling of TFP elasticity and interfacial behavior with PilT kinetics. We model retraction as reaction controlled and elongation as transport controlled process. The reaction rates vary with TFP deformation which is modeled as a compound elastic body consisting of multiple helical strands under axial load. Elongation is controlled by monomer transport which suffer entrapment due to excess PilT in the cell periplasm. Our analysis shows excellent agreement with a host of experimental observations and we present a possible biophysical relevance of model parameters through a mechano-chemical stall force map. PMID- 25502697 TI - Interaction mechanisms of cavitation bubbles induced by spatially and temporally separated fs-laser pulses. AB - The emerging use of femtosecond lasers with high repetition rates in the MHz regime together with limited scan speed implies possible mutual optical and dynamical interaction effects of the individual cutting spots. In order to get more insight into the dynamics a time-resolved photographic analysis of the interaction of cavitation bubbles is presented. Particularly, we investigated the influence of fs-laser pulses and their resulting bubble dynamics with various spatial as well as temporal separations. Different time courses of characteristic interaction effects between the cavitation bubbles were observed depending on pulse energy and spatio-temporal pulse separation. These ranged from merely no interaction to the phenomena of strong water jet formation. Afterwards, the mechanisms are discussed regarding their impact on the medical application of effective tissue cutting lateral to the laser beam direction with best possible axial precision: the mechanical forces of photodisruption as well as the occurring water jet should have low axial extend and a preferably lateral priority. Furthermore, the overall efficiency of energy conversion into controlled mechanical impact should be maximized compared to the transmitted pulse energy and unwanted long range mechanical side effects, e.g. shock waves, axial jet components. In conclusion, these experimental results are of great importance for the prospective optimization of the ophthalmic surgical process with high-repetition rate fs-lasers. PMID- 25502698 TI - Absence of bone sialoprotein (BSP) alters profoundly hematopoiesis and upregulates osteopontin. AB - Matrix proteins of the SIBLING family interact with bone cells, extracellular matrix and mineral and are thus in a key position to regulate the microenvironment of the bone tissue, including its hematopoietic component. In this respect, osteopontin (OPN) has been implicated in the hematopoietic stem cell (HSC) niche as negative regulator of the HSC function. We investigated the impact on hematopoietic regulation of the absence of the cognate bone sialoprotein (BSP). BSP knockout (-/-) mice display increased bone marrow cellularity, and an altered commitment of hematopoietic precursors to myeloid lineages, leading in particular to an increased frequency of monocyte/macrophage cells. The B cell pool is increased in -/- bone marrow, and its composition is shifted toward more mature lymphocyte stages. BSP-null mice display a decreased HSC fraction among LSK cells and a higher percentage of more committed progenitors as compared to +/+. The fraction of proliferating LSK progenitors is higher in -/- mice, and after PTH treatment the mutant HSC pool is lower than in +/+. Strikingly, circulating levels of OPN as well as its expression in the bone tissue are much higher in the -/-. Thus, a BSP-null bone microenvironment affects the hematopoietic system both quantitatively and qualitatively, in a manner in part opposite to the OPN knockout, suggesting that the effects might in part reflect the higher OPN expression in the absence of BSP. PMID- 25502694 TI - Molecular and cellular effects of in vitro shockwave treatment on lymphatic endothelial cells. AB - Extracorporeal shockwave treatment was shown to improve orthopaedic diseases and wound healing and to stimulate lymphangiogenesis in vivo. The aim of this study was to investigate in vitro shockwave treatment (IVSWT) effects on lymphatic endothelial cell (LEC) behavior and lymphangiogenesis. We analyzed migration, proliferation, vascular tube forming capability and marker expression changes of LECs after IVSWT compared with HUVECs. Finally, transcriptome- and miRNA analyses were conducted to gain deeper insight into the IVSWT-induced molecular mechanisms in LECs. The results indicate that IVSWT-mediated proliferation changes of LECs are highly energy flux density-dependent and LEC 2D as well as 3D migration was enhanced through IVSWT. IVSWT suppressed HUVEC 3D migration but enhanced vasculogenesis. Furthermore, we identified podoplaninhigh and podoplaninlow cell subpopulations, whose ratios changed upon IVSWT treatment. Transcriptome- and miRNA analyses on these populations showed differences in genes specific for signaling and vascular tissue. Our findings help to understand the cellular and molecular mechanisms underlying shockwave-induced lymphangiogenesis in vivo. PMID- 25502699 TI - Can platelet-rich plasma enhance bone healing during distraction osteogenesis: a novel molecular mechanism? PMID- 25502700 TI - Malignant peripheral nerve sheath tumor of the forehead. PMID- 25502713 TI - Oro nasal communication closure in smoker patient. PMID- 25502704 TI - Endogenous cell therapy improves bone healing. AB - BACKGROUND: Although bone repair is often a relatively rapid and efficient process, many bone defects do not heal. Because an adequate blood supply is essential for new bone formation, we hypothesized that augmenting new blood vessel formation by increasing the number of circulating vasculogenic progenitor cells (PCs) with AMD3100 and enhancing their trafficking to the site of injury with recombinant human parathyroid hormone (rhPTH) will improve healing. METHODS: Critical-sized 3-mm cranial defects were trephined into the right parietal bone of C57BLKS/J 6 mice (N = 120). The mice were divided into 4 equal groups (n = 30 for each). The first group received daily subcutaneous injections of AMD3100 (5 mg/kg). The second group received daily subcutaneous injections of rhPTH (5 mg/kg). The third group received both AMD3100 and rhPTH. The fourth group received subcutaneous injections of saline. Circulating vasculogenic PC numbers, new blood vessel formation, and bony regeneration were assessed. Progenitor cell adhesion, migration, and tubule formation were assessed in the presence of rhPTH and AMD3100. RESULTS: Flow cytometry demonstrated that combination therapy significantly increased the number of circulating PCs compared with all other groups. In vitro, AMD3100-treated PCs had significantly increased adhesion migration, and tubule formation was assessed in the presence of rhPTH. Combination therapy significantly improved new blood vessel formation in those with cranial defect compared with all other groups. Finally, bony regeneration was significantly increased in the combination therapy group compared with all other groups. CONCLUSIONS: The combination of a PC-mobilizing and traffic enhancing agent improved bony regeneration of calvarial defects in mice. PMID- 25502714 TI - Concerning the article "Neutrophil-lymphocyte ratio: a new predictive and prognostic factor in patients with Bell palsy". PMID- 25502715 TI - Endoscopic sinus surgery and intraoral approaches in sinus oral pathology. PMID- 25502716 TI - Hypoplastic mandibular labial frenulum with accessory frenulum in a healthy child. PMID- 25502717 TI - Brooke-Spiegler syndrome clinically misdiagnosed as neurofibromatosis type 1. PMID- 25502718 TI - Navigation-aided endoscopic sinus surgery. PMID- 25502719 TI - A propranolol nonresponsive mass: lymphangioma-mimicking hemangioma. PMID- 25502720 TI - Achondroplasia and multiple-suture craniosynostosis. AB - Genetic mutations in the fibroblast growth factor receptor 3 gene may lead to achondroplasia or syndromic forms of craniosynostosis. Despite sharing a common genetic basis, craniosynostosis has rarely been described in cases of confirmed achondroplasia. We report an infant with achondroplasia who developed progressive multiple-suture craniosynostosis to discuss the genetic link between these clinical entities and to describe the technical challenges associated with the operative management. PMID- 25502721 TI - Incidental findings on preoperative computed tomography for nonsyndromic single suture craniosynostosis by Magge et al. PMID- 25502722 TI - An NMR-based metabolomic approach to investigate the effects of supplementation with glutamic acid in piglets challenged with deoxynivalenol. AB - Deoxynivalenol (DON) has various toxicological effects in humans and pigs that result from the ingestion of contaminated cereal products. This study was conducted to investigate the protective effects of dietary supplementation with glutamic acid on piglets challenged with DON. A total of 20 piglets weaned at 28 d of age were randomly assigned to receive 1 of 4 treatments (5 piglets/treatment): 1) basal diet, negative control (NC); 2) basal diet +4 mg/kg DON (DON); 3) basal diet +2% (g/g) glutamic acid (GLU); 4) basal diet +4 mg/kg DON +2% glutamic acid (DG). A 7-d adaptation period was followed by 30 days of treatment. A metabolite analysis using nuclear magnetic resonance spectroscopy (1H-NMR)-based metabolomic technology and the determination of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities for plasma, as well as the activity of Caspase-3 and the proliferation of epithelial cells were conducted. The results showed that contents of low-density lipoprotein, alanine, arginine, acetate, glycoprotein, trimethylamine-N-oxide (TMAO), glycine, lactate, and urea, as well as the glutamate/creatinine ratio were higher but high-density lipoprotein, proline, citrate, choline, unsaturated lipids and fumarate were lower in piglets of DON treatment than that of NC treatment (P<0.05). Compared with DON treatment, dietary supplementation with glutamic acid increased the plasma concentrations of proline, citrate, creatinine, unsaturated lipids, and fumarate, and decreased the concentrations of alanine, glycoprotein, TMAO, glycine, and lactate, as well as the glutamate/creatinine ratio (P<0.05). Addition glutamic acid to DON treatment increased the plasma activities of SOD and GSH-Px and the proliferating cell nuclear antigen (PCNA) labeling indexes for the jejunum and ileum (P<0.05). These novel findings indicate that glutamic acid has the potential to repair the injuries associated with oxidative stress as well as the disturbances of energy and amino acid metabolism induced by DON. PMID- 25502723 TI - Platelets are associated with xenograft tumor growth and the clinical malignancy of ovarian cancer through an angiogenesis-dependent mechanism. AB - Platelets are known to facilitate tumor metastasis and thrombocytosis has been associated with an adverse prognosis in ovarian cancer. However, the role of platelets in primary tumour growth remains to be elucidated. The present study demonstrated that the expression levels of various markers in platelets, endothelial adherence and angiogenesis, including, platelet glycoprotein IIb (CD41), platelet endothelial cell adhesion molecule 1 (CD31), vascular endothelial growth factor (VEGF), lysyl oxidase, focal adhesion kinase and breast cancer anti-estrogen resistance 1, were expressed at higher levels in patients with malignant carcinoma, compared with those with borderline cystadenoma and cystadenoma. In addition, the endothelial markers CD31 and VEGF were found to colocalize with the platelet marker CD41 in the malignant samples. Since mice transplanted with human ovarian cancer cells (SKOV3) demonstrated elevated tumor size and decreased survival rate when treated with thrombin or thrombopoietin (TPO), the platelets appeared to promote primary tumor growth. Depleting platelets using antibodies or by pretreating the cancer cells with hirudin significantly attenuated the transplanted tumor growth. The platelets contributed to late, but not early stages of tumor proliferation, as mice treated with platelet-depleting antibody 1 day prior to and 11 days after tumor transplantation had the same tumor volumes. By contrast, tumor size in the early TPO-injected group was increased significantly compared with the late TPO injected group. These findings suggested that the interplay between platelets and angiogenesis may contribute to ovarian cancer growth. Therefore, platelets and their associated signaling and adhesive molecules may represent potential therapeutic targets for ovarian cancer. PMID- 25502725 TI - Photoisomerisation of azobenzene crystals in aqueous dispersions examined by higher order derivative spectra. AB - Photo-induced UV-Vis spectral changes of azobenzene (Az) in solution and aqueous crystalline dispersions were analysed by means predominantly of fourth order derivatives. Weak bands due to vibration level transitions (VLT) of E-isomers in solution were well-resolved in derivatives to estimate conversion of photoisomerisation by tracing extrema of a VLT sub-peak. The photo-induced derivative-spectral changes of Az crystals dispersed in aqueous PVA solutions generated many common crossing points to indicate that Az dissolves partially in a PVA solution to lead to photoisomerisation in a homogeneous phase and the reversible alteration of particle size. The solid-state photoisomerisation of Az was investigated by the preparation of PVA-free aqueous dispersions of powdery nanohybrids comprised of Az and silica nanoparticles. The fourth order derivatives of spectral changes revealed that the photochemical process involves three kinds of species including non-aggregated and aggregated E-isomers as well as Z-isomers. PMID- 25502724 TI - Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease. AB - Analyses of circulating metabolites in large prospective epidemiological studies could lead to improved prediction and better biological understanding of coronary heart disease (CHD). We performed a mass spectrometry-based non-targeted metabolomics study for association with incident CHD events in 1,028 individuals (131 events; 10 y. median follow-up) with validation in 1,670 individuals (282 events; 3.9 y. median follow-up). Four metabolites were replicated and independent of main cardiovascular risk factors [lysophosphatidylcholine 18?1 (hazard ratio [HR] per standard deviation [SD] increment = 0.77, P-value<0.001), lysophosphatidylcholine 18?2 (HR = 0.81, P-value<0.001), monoglyceride 18?2 (MG 18?2; HR = 1.18, P-value = 0.011) and sphingomyelin 28?1 (HR = 0.85, P-value = 0.015)]. Together they contributed to moderate improvements in discrimination and re-classification in addition to traditional risk factors (C-statistic: 0.76 vs. 0.75; NRI: 9.2%). MG 18?2 was associated with CHD independently of triglycerides. Lysophosphatidylcholines were negatively associated with body mass index, C reactive protein and with less evidence of subclinical cardiovascular disease in additional 970 participants; a reverse pattern was observed for MG 18?2. MG 18?2 showed an enrichment (P-value = 0.002) of significant associations with CHD associated SNPs (P-value = 1.2*10-7 for association with rs964184 in the ZNF259/APOA5 region) and a weak, but positive causal effect (odds ratio = 1.05 per SD increment in MG 18?2, P-value = 0.05) on CHD, as suggested by Mendelian randomization analysis. In conclusion, we identified four lipid-related metabolites with evidence for clinical utility, as well as a causal role in CHD development. PMID- 25502727 TI - In my life. PMID- 25502728 TI - Correction. PMID- 25502726 TI - Tea and coffee consumption and risk of laryngeal cancer: a systematic review meta analysis. AB - BACKGROUND: Tea and coffee are the most commonly consumed beverages in the worldwide. The relationship between tea and coffee consumption on the risk of laryngeal cancer was still unclear. METHODS: Relevant studies were identified by searching electronic database (Medline and EMBASE) and reviewing the reference lists of relevant articles until Oct. 2013. Observational studies that reported RRs and 95% CIs for the link of tea and coffee consumption on the risk of laryngeal cancer were eligible. A meta-analysis was obtained to combine study specific RRs with a random-effects model. RESULTS: A total of 2,803 cases and 503,234 controls in 10 independent studies were identified. The overall analysis of all 10 studies, including the case-control and cohort studies, found that tea drinking was not associated with laryngeal carcinoma (RR = 1.03; 95% CI: 0.66 1.61). However, coffee consumption was significantly associated with the laryngeal carcinoma (RR = 1.47; 95% CI: 1.03-2.11). A dose-response relationship between coffee intake and laryngeal carcinoma was detected; however, no evidence of dose-response link between tea consumption and laryngeal carcinoma risk was detected. CONCLUSIONS: The results from this meta-analysis of observational studies demonstrate that coffee consumption would increase the laryngeal cancer risk, while tea intake was not associated with risk of laryngeal carcinoma. PMID- 25502730 TI - Mutual stabilization of rhythmic vocalization and whole-body movement. AB - The current study investigated the rhythmic coordination between vocalization and whole-body movement. Previous studies have reported that spatiotemporal stability in rhythmic movement increases when coordinated with a rhythmic auditory stimulus or other effector in a stable coordination pattern. Therefore, the present study conducted two experiments to investigate (1) whether there is a stable coordination pattern between vocalization and whole-body movement and (2) whether a stable coordination pattern reduces variability in whole-body movement and vocalization. In Experiment 1, two coordination patterns between vocalizations and whole-body movement (hip, knee, and ankle joint flexion-on-the-voice vs. joint extension-on-the-voice) in a standing posture were explored at movement frequencies of 80, 130, and 180 beats per minute. At higher movement frequencies, the phase angle in the extension-on-the-voice condition deviated from the intended phase angle. However, the angle of the flexion-on-the-voice was maintained even when movement frequency increased. These results suggest that there was a stable coordination pattern in the flexion-on-the-voice condition. In Experiment 2, variability in whole-body movement and voice-onset intervals was compared between two conditions: one related to tasks performed in the flexion-on the-voice coordination (coordination condition) that was a stable coordination pattern, and the other related to tasks performed independently (control condition). The results showed that variability in whole-body movement and voice onset intervals was smaller in the coordination condition than in the control condition. Overall, the present study revealed mutual stabilization between rhythmic vocalization and whole-body movement via coordination within a stable pattern, suggesting that coupled action systems can act as a single functional unit or coordinative structure. PMID- 25502733 TI - Initial lymphocyte count in patients with acute immune thrombocytopenic purpura: Can it predict persistence of the disease? AB - BACKGROUND: It has been suggested that initial total leukocyte count (TLC) and initial absolute lymphocyte count (ALC) can predict development of chronic/persistent disease in children with acute immune thrombocytopenia purpura (ITP). However, this association has not confirmed by other studies. This study aims to investigate probable association between initial TLC and ALC with development of chronic/persistent ITP. METHODS: The present study was carried out at Aliasghar children hospital and all children with diagnosis of acute ITP were identified from 2001 to 2008. Data gathered retrospectively by reviewing patients' records. Initial TLC and ALC were compared between recovered patients and those with chronic/persistent ITP. RESULTS: 116 children with diagnosis of acute ITP were included in the study. Respectively, 59 (50.8%) and 57 (49.2%) cases were categorized in recovered (group 1) and chronic/persistent (group 2) ITP. Mean TLC was 8470+/-342 Cell/L in study patients, 8644+/-546 Cell/L in group 1 and 8290+/-412 Cell/L in group 2 which was not statistically significant (p=0.60). Mean ALC was 4176+/- 189 Cell/L. Mean lymphocyte count in group 1 was significantly higher at 4542+/- 273 Cell/L in group 1 compared to group 2 at 3797+/-253 Cell/L (p=0.04). Logistic regression analysis showed that ALC < 5000 Cell/L is a predictor of chronic/persistent ITP (Odds ratio: 2.757, 95% CI 1.215 6.260, p=0.015). Sensitivity, positive and negative predicative values for ALC of <5000 Cell/L were calculated as 80%, 57%, and 68%, respectively. CONCLUSIONS: Our findings indicated that initial ALC but not TLC is a predictor of chronic/persistent ITP in children with acute ITP. Further studies are recommended to explore underlying mechanisms that a lower initial ALC contributes to development of chronic/persistent ITP. PMID- 25502731 TI - A fast sensor for in vivo quantification of cytosolic phosphate in Saccharomyces cerevisiae. AB - Eukaryotic metabolism consists of a complex network of enzymatic reactions and transport processes which are distributed over different subcellular compartments. Currently, available metabolite measurement protocols allow to measure metabolite whole cell amounts which hinder progress to describe the in vivo dynamics in different compartments, which are driven by compartment specific concentrations. Phosphate (Pi) is an essential component for: (1) the metabolic balance of upper and lower glycolytic flux; (2) Together with ATP and ADP determines the phosphorylation energy. Especially, the cytosolic Pi has a critical role in disregulation of glycolysis in tps1 knockout. Here we developed a method that enables us to monitor the cytosolic Pi concentration in S. cerevisiae using an equilibrium sensor reaction: maltose + Pi < = > glucose + glucose-1-phosphate. The required enzyme, maltose phosphorylase from L. sanfranciscensis was overexpressed in S. cerevisiae. With this reaction in place, the cytosolic Pi concentration was obtained from intracellular glucose, G1P and maltose concentrations. The cytosolic Pi concentration was determined in batch and chemostat (D = 0.1 h(-1) ) conditions, which was 17.88 umol/gDW and 25.02 umol/gDW, respectively under Pi-excess conditions. Under Pi-limited steady state (D = 0.1 h(-1) ) conditions, the cytosolic Pi concentration dropped to only 17.7% of the cytosolic Pi in Pi-excess condition (4.42 umol/gDW vs. 25.02 umol/gDW). In response to a Pi pulse, the cytosolic Pi increased very rapidly, together with the concentration of sugar phosphates. Main sources of the rapid Pi increase are vacuolar Pi (and not the polyPi), as well as Pi uptake from the extracellular space. The temporal increase of cytosolic Pi increases the driving force of GAPDH reaction of the lower glycolytic reactions. The novel cytosol specific Pi concentration measurements provide new insight into the thermodynamic driving force for ATP hydrolysis, GAPDH reaction, and Pi transport over the plasma and vacuolar membranes. PMID- 25502734 TI - Adolescence: psychopathological discomfort, distress or psychiatric disorder? Clinical experience, description and analysis of a sample. AB - BACKGROUND: The aim of this study was to highlight how many psychopathological disorders emerging during adolescence are not easily detectable and interpretable. METHODS: We investigated the social, emotional and demographic factors related to psychopathological distress, measuring the overall functioning of the child/adolescent and the consequent impact on academic and social functioning, along with its implications on the emergence of feelings of discomfort and anxiety. RESULTS: Many psychopathological disorders are easily detectable and diagnosable in this particular stage of life, and although they are rooted in adolescent distress, they can generate real psychiatric disorders. CONCLUSIONS: The data emerging from clinical practice stress the need for a comprehensive in order to identify possible subclinical symptoms for onset of mental illness, so as to be able to implement more targeted and less invasive therapeutic strategies. PMID- 25502729 TI - Continued observation of the natural history of low-grade ductal carcinoma in situ reaffirms proclivity for local recurrence even after more than 30 years of follow-up. AB - Opportunities to study the natural history of ductal carcinoma in situ are rare. A few studies of incompletely excised lesions in the premammographic era, retrospectively recognized as ductal carcinoma in situ, have demonstrated a proclivity for local recurrence in the original site. The authors report a follow up study of 45 women with low-grade ductal carcinoma in situ treated by biopsy only, recognized retrospectively during a larger review of surgical pathology diagnoses and original histological slides for 26 539 consecutive breast biopsies performed at Vanderbilt, Baptist and St Thomas Hospitals in Nashville, TN from 1950 to 1989. Long-term follow-up was previously reported on 28 of these women. Sixteen women (36%) developed invasive breast carcinoma, all in the same breast and quadrant as their incident ductal carcinoma in situ. Eleven invasive breast carcinomas were diagnosed within 10 years of the ductal carcinoma in situ biopsy. Subsequent cases were diagnosed at 12, 23, 25, 29 and 42 years. Seven women, including one who developed invasive breast cancer 29 years after her ductal carcinoma in situ biopsy, developed distant metastasis, resulting in death 1-7 years postdiagnosis of invasive breast carcinoma. The natural history of low grade ductal carcinoma in situ may extend more than four decades, with invasive breast cancer developing at the same site as the index lesion. This protracted natural history differs markedly from that of patients with high-grade ductal carcinoma in situ or any completely delimited ductal carcinoma in situ excised to negative margins. This study reaffirms the importance of complete margin evaluation in women treated with breast conservation for ductal carcinoma in situ as well as balancing recurrence risk with possible treatment-related morbidity for older women. PMID- 25502735 TI - Assessment of abdominal muscle function in individuals with motor-complete spinal cord injury above T6 in response to transcranial magnetic stimulation. AB - OBJECTIVE: To use transcranial magnetic stimulation and electromyography to assess the potential for preserved function in the abdominal muscles in individuals classified with motor-complete spinal cord injury above T6. SUBJECTS: Five individuals with spinal cord injury (C5-T3) and 5 able-bodied individuals. METHODS: Transcranial magnetic stimulation was delivered over the abdominal region of primary motor cortex during resting and sub-maximal (or attempted) contractions. Surface electromyography was used to record motor-evoked potentials as well as maximal voluntary (or attempted) contractions in the abdominal muscles and the diaphragm. RESULTS: Responses to transcranial magnetic stimulation in the abdominal muscles occurred in all spinal cord injury subjects. Latencies of muscle response onsets were similar in both groups; however, peak-to-peak amplitudes were smaller in the spinal cord injury group. During maximal voluntary (or attempted) contractions all spinal cord injury subjects were able to elicit electromyography activity above resting levels in more than one abdominal muscle across tasks. CONCLUSION: Individuals with motor-complete spinal cord injury above T6 were able to activate abdominal muscles in response to transcranial magnetic stimulation and during maximal voluntary (or attempted) contractions. The activation was induced directly through corticospinal pathways, and not indirectly by stretch reflex activations of the diaphragm. Transcranial magnetic stimulation and electromyography measurements provide a useful method to assess motor preservation of abdominal muscles in persons with spinal cord injury. PMID- 25502736 TI - Microbiological survey of mice (Mus musculus) purchased from commercial pet shops in Kanagawa and Tokyo, Japan. AB - Information regarding the prevalence of infectious agents in mice in pet shops in Japan is scarce. This information is particularly useful for minimizing the risk of potential transmission of infections to laboratory mice. Therefore, we surveyed infectious agents in mice from pet shops in Kanagawa and Tokyo, Japan. The survey was conducted in 28 mice from 5 pet shops to screen for 47 items (17 viruses, 22 bacteria and fungi, 10 parasites) using culture tests, serology, PCR, and microscopy. The most common viral agent detected was murine norovirus (17 mice; 60.7%), followed by Theiler's murine encephalomyelitis virus (13 mice; 46.4%), and mouse hepatitis virus (12 mice; 42.8%). The most common agent amongst the bacteria and fungi was Pasteurella pneumotropica (10 mice; 35.7%), followed by Helicobacter ganmani and Pneumocystis murina (8 mice; 28.5%, for both). Tritrichomonas muris was the most common parasite (19 mice; 67.8%), followed by Spironucleus muris (13 mice; 46.4%), Aspiculuris tetraptera, and Syphacia obvelata (8 mice each; 28.5%). Remarkably, a zoonotic agent, Hymenolepis nana, was found in 7 mice (25%). Given these results, we suggest that the workers in laboratory animal facilities should recognize again the potential risks of mice outside of the laboratory animal facilities as an infectious source, and avoid keeping mice as pets or as feed for carnivorous reptiles as much as possible for risk management. PMID- 25502738 TI - In situ preparation of 3D graphene aerogels@hierarchical Fe3O4 nanoclusters as high rate and long cycle anode materials for lithium ion batteries. AB - We describe a novel strategy for in situ fabrication of hierarchical Fe3O4 nanoclusters-GAs. Fe3O4 NCs-GAs deliver excellent rate capability (the reversible capacities obtained were 1442, 392 and 118 mA h g(-1) at 0.1C, 12C and 35C rates), and a high reversible capacity of 577 mA h g(-1) over 300 cycles at the current density of 5.2 A g(-1) (6C). PMID- 25502737 TI - Efficacy and safety of echinocandins versus triazoles for the prophylaxis and treatment of fungal infections: a meta-analysis of RCTs. AB - Echinocandins and triazoles were proven to be effective antifungal drugs against invasive fungal infections (IFI), which may cause significant morbidity and mortality in immunocompromised patients. The aim of this study was to compare the efficacy and safety between echinocandins and triazoles for the prophylaxis and treatment of fungal infections. PubMed, Embase, and the Cochrane Library were searched to identify relevant randomized controlled trials (RCTs) up to July 2014. The quality of trials was assessed with the Jadad scoring system. The primary outcomes of interest were treatment success, microbiological success, breakthrough infection, drug-related adverse events (AEs), withdrawals due to AEs, and all-cause mortality. Ten RCTs, involving 2,837 patients, were included, as follows: caspofungin versus fluconazole (n = 1), caspofungin versus itraconazole (n = 1), anidulafungin versus fluconazole (n = 1), micafungin versus fluconazole (n = 4), micafungin versus voriconazole (n = 2), and micafungin versus itraconazole (n = 1). Echinocandins and triazoles showed similar effects in terms of favorable treatment success rate [relative risk (RR) = 1.02, 95% confidence interval (CI), 0.97-1.08], microbiological success rate (RR = 0.98, 95% CI, 0.90-1.15), breakthrough infection (RR = 1.09; 95% CI, 0.59-2.01), drug related AEs (RR = 0.94; 95% CI, 0.71-1.15), and all-cause mortality (RR = 0.85; 95% CI, 0.66-1.10) in the prophylaxis and treatment of fungal infections. Additionally, echinocandins were more effective than triazoles for prophylaxis in patients undergoing hematologic malignancies or those who received hematopoietic stem cell transplantation (HSCT; RR = 1.08; 95% CI, 1.02-1.15). Echinocandins significantly decreased the AE-related withdrawals rate compared with triazoles (RR = 0.47; 95% CI, 0.33-0.67). This meta-analysis revealed that echinocandins are as effective and safe as triazoles for the prophylaxis and treatment of patients with fungal infections. PMID- 25502739 TI - Long-term vocal outcomes of refined nerve-muscle pedicle flap implantation combined with arytenoid adduction. AB - The objective of this study is to evaluate long-term efficacy of refined nerve muscle pedicle (NMP) flap implantation combined with arytenoid adduction (AA) for treatment of unilateral vocal fold paralysis (UVFP). The authors retrospectively reviewed 33 patients with UVFP who received refined NMP flap implantation with AA and were followed up over a 1-year period. Evaluation of vocal fold vibration (regularity, amplitude, and glottal gap), aerodynamic analysis (maximum phonation time [MPT] and mean airflow rate [MFR]), and perceptual evaluation (Grade and Breathiness) were performed preoperatively and at five different time points (1, 3, 6, 12, and 24 months) postoperatively. All voice parameters improved significantly postoperatively. All parameters except MFR also continued to improve over the course of 24 months. In the videostroboscopic analysis, the parameter for regularity 24 months after surgery was significantly improved compared with that at 1, 3, and 6 months after surgery. There were also significant improvements in amplitude and the glottal gap 24 months after surgery in comparison with values at 3 and 6 months after surgery and 3 months after surgery, respectively. Significant improvement in aerodynamic and perceptual measurements during the follow-up period together with near-normal vocal fold vibration was achieved by delayed reinnervation with refined NMP flap implantation and AA. The combined surgical technique is effective in the treatment of severe breathy dysphonia due to UVFP. Level of evidence 4. PMID- 25502741 TI - Superselective microcoil embolization in severe intractable epistaxis: an analysis of 12 consecutive cases from an otorhinolaryngologic and an interventional neuroradiologic point of view. AB - From 2006 to 2013, 12 patients with severe epistaxis refractory to prior conservative and surgical therapy were treated by superselective embolization of nasal arteries. Supersoft platinum microcoils with smallest diameters were used as the sole embolic agent in all cases. Coils were applied far distally in a stretched position for obtaining ideal target vessel superselectivity. The objective of this study is to evaluate efficacy and complications of superselective coil embolization for treatment of severe intractable epistaxis and to discuss results from an otorhinolaryngologic and an interventional neuroradiologic point of view. Retrospectively, all epistaxis inpatients between 2006 and 2013 were identified and subdivided by form of treatment: conservative, surgical and interventional therapy. Medical records of interventionally treated patients were reviewed for demographics, medical history, risk factors, clinical data, complications and short-term success, and patients were followed up for long-term success. Mean follow-up was 37 months. In 12 patients, 14 embolizations were carried out, with short-term success in 9 patients (75%), while early post interventional rebleeding occurred in 3 patients (25%). Of 9 patients with short term success, 1 died during stay, 1 was lost to follow-up and 1 had minor re bleeding after 30 months. Six patients had short-term and long-term success. Before the first embolization, 3 +/- 1 conservative and/or surgical procedures had been undertaken. Length of stay was 12.8 +/- 3.6 days. 8 patients (67%) received red cell concentrates. Most frequent complications were mucosal damage and nasal pain, but these were related to repeated packing and surgery. Typical embolic complications as neurological or visual impairment or soft tissue necrosis were not observed in any patient. From the otorhinolaryngologic point of view, surgery is the treatment of choice in severe refractory epistaxis, but in case of repeated failure, superselective microcoil embolization is a valuable addition to the therapeutic spectrum. From the interventional neuroradiologic point of view, superselective microcoil embolization is an effective, well tolerable and safe procedure and complications may be reduced in comparison to microparticle embolization. Modern supersoft microcoils with smallest diameters enable ideal superselectivity of the target vessels. PMID- 25502740 TI - Correlation between hippocampal sulcus width and severity of obstructive sleep apnea syndrome. AB - The aim of the present study was to evaluate the relationship between obstructive sleep apnea syndrome (OSAS) severity and the hippocampal sulcus width in a cohort of subjects with OSAS and controls. A total of 149 OSAS patients and 60 nonapneic controls were included in the study. Overnight polysomnograpy was performed in all patients. Hippocampal sulcus width of the patients was measured by a radiologist blinded to the diagnosis of the patients. Other variables noted for each patient were as follows: gender, age, body mass index, apnea hypopnea index, Epworth sleepiness scale, sleep efficacy, mean saturation, lowest O2 saturation, longest apnea duration, neck circumference, waist circumference, hip circumference. A total of 149 OSAS patients were divided into three groups: mild OSAS (n = 54), moderate OSAS (n = 40), severe OSAS (n = 55) groups. The control group consisted of patients with AHI <5 (n = 60). Hippocampal sulcus width was 1.6 +/- 0.83 mm in the control group; while 1.9 +/- 0.81 mm in mild OSAS, 2.1 +/- 0.60 mm in moderate OSAS, and 2.9 +/- 0.58 mm in severe OSAS groups (p < 0.001). Correlation analysis of variables revealed that apnea hypopnea index (rs = 0.483, p < 0.001) was positively correlated with hippocampal sulcus width. Our findings demonstrated that severity of OSAS might be associated with various pathologic mechanisms including increased hippocampal sulcus width. PMID- 25502743 TI - Effect of distribution of nasal polyps in ostiomeatal complex on long-term outcomes after endoscopic surgery. AB - The objective of the study was to elucidate the characteristics of spatial distribution of nasal polyps in the ostiomeatal complex (OMC) and the corresponding correlation with long-term quality of life in patients who underwent endoscopic sinus surgery. 107 patients with unilateral or bilateral nasal polyps who had undergone functional endoscopic sinus surgery from September 2009 to June 2010 were enrolled in this study. Distribution of nasal polyps in the study subjects was documented. Long-term quality of life assessment was carried out at 1-year after surgery by SNOT-20 analysis. Observation of a total of 214 sides of rhinal cavities revealed that nasal polyps were distributed inside the OMC at 573 sites out of the total 635 sites (90.2 %), and predominantly distributed at the middle turbinate, the ethmoid sinus, the middle meatus, the uncinate process, the maxillary sinus, and the ethmoid bulla and significantly differed from the nasal polyps which were found outside the OMC (P < 0.01). Statistical analysis indicated that pre-operative Sinonasal Outcome Test 20 (SNOT-20) scores and 1-year post-operative scores were statistically significant (P < 0.05). The score changes of the left maxillary sinus, both sides ethmoid bulla were significant, respectively (P < 0.05). Nasal polyps predominantly distribute in the OMC. The differences among the sites of nasal polyps do not significantly impact the long-term score for quality of life except for the maxillary sinus and ethmoid bulla. PMID- 25502744 TI - Inhibition of CO poisoning on Pt catalyst coupled with the reduction of toxic hexavalent chromium in a dual-functional fuel cell. AB - We propose a method to enhance the fuel cell efficiency with the simultaneous removal of toxic heavy metal ions. Carbon monoxide (CO), an intermediate of methanol oxidation that is primarily responsible for Pt catalyst deactivation, can be used as an in-situ reducing agent for hexavalent chromium (Cr (VI)) with reactivating the CO-poisoned Pt catalyst. Using electro-oxidation measurements, the oxidation of adsorbed CO molecules coupled with the concurrent conversion of Cr (VI) to Cr (III) was confirmed. This concept was also successfully applied to a methanol fuel cell to enhance its performance efficiency and to remove toxic Cr (VI) at the same time. PMID- 25502745 TI - A systematic review: is there an app for that? Translational science of pediatric behavior change for physical activity and dietary interventions. AB - OBJECTIVE: Systematically review and meta-analyze the pediatric literature on behavior-change techniques (BCT) as defined by Abraham & Michie (Health Psychology, 27, 379-387, 2008), and describe whether the most effective BCTs are incorporated in physical activity (PA) and dietary mobile apps. METHODS: Randomized controlled trials (n = 74) targeting diet or PA were meta-analyzed. Metaregressions were used to determine which BCTs predict aggregate effect size (ES). iTunesTM apps were coded for presence/absence of BCTs that produce larger ES. RESULTS: Modeling was the only predictor of PA ES in children (aged 6-13 years). Consequences for behavior, other's approval, self-monitoring, intention formation, and behavioral contracting significantly predicted PA for adolescents. Modeling and social support predicted dietary ES in adolescents and children, respectively. Practice was also a significant predictor for children. A majority of effective strategies for children were not widely incorporated in apps; however, the picture is more optimistic for adolescents. CONCLUSIONS: More collaboration is needed between pediatric psychologists and technologists to incorporate evidence-based BCTs into developmentally appropriate mobile apps. PMID- 25502742 TI - Population-based analysis of tonsil surgery and postoperative hemorrhage. AB - Although tonsil surgery is one of the most frequent otorhinolaryngological procedures, not many population-based regional or country-wide studies are published on the incidence of postoperative bleeding and its risk factors. 2,216 patients underwent tonsil surgery in 2012 in Thuringia, a federal state in Germany. Most frequent indications were recurrent tonsillitis (44 % of all cases), tonsillar abscess (27 %), and tonsillar hyperplasia (20 %). 29 % of the patients were <10 years of age. Most frequent methods of surgery were tonsillectomy (73 %) and tonsillotomy (19 %). 215 patients (10 %) had 221 events of a postoperative hemorrhage. Re-surgery for hemostasis was necessary in 137 patients (6 %). The interval to re-surgery was 4.4 +/- 4.6 days. The re-surgery rate was 8, 0.2, and 15 % after tonsillectomy, tonsillotomy, and radical tonsillectomy, respectively. In cases of recurrent tonsillitis, male gender (p < 0.001), age >24.78 years (median; (p = 0.018), and waiving of perioperative antibiotics (p = 0.029) were independent factors associated with hemorrhage. In cases of tonsillar hyperplasia tonsillectomy instead of tonsillotomy, the only significant risk factor was postoperative hemorrhage (p = 0.005). The overall incidence of tonsillar surgery was 87.6/100,000. The highest incidence was seen for patients 3-4 years of age with 862.7/100,000. In children <10 years, the incidence was always higher for boys than for girls. Throughout all age groups, a reverse gender relation was only seen, if surgery was indicated for recurrent tonsillitis. We recommend establishing national guidelines for indication of tonsil surgery, especially of tonsillectomy, including recommendations for perioperative care to decrease variations in tonsil surgery rates and minimize postoperative complications. PMID- 25502748 TI - The impact of Myriad and Mayo: will advancements in the biological sciences be spurred or disincentivized? (Or was biotech patenting not complicated enough?). AB - For years, purified and isolated naturally occurring biological substances of great medical importance--including genes--have been the subject of U.S. patents. Similarly, methods in which the detection of a biological substance (e.g., in a blood sample) dictates subsequent actions, as in disease diagnostics and treatment, have long enjoyed patent protection. However, two recent Supreme Court cases, Association for Molecular Pathology v. Myriad Genetics, Inc. (133 S. Ct. 2107) (2013) and Mayo Collaborative Services v. Prometheus Laboratories, Inc. (132 S. Ct. 1289) (2012), have shaken up the status quo of biotech patenting. The highest court in our land unanimously agreed with patent challengers that much of what we took for granted as patentable subject matter is not, as a matter of law, eligible for patenting after all. This review discusses the Myriad and Mayo cases, their impact on which biology-based innovations we may or may not continue to patent, and whether the altered status quo is benignly corrective or gravely disruptive. Is what happened here a good thing or not? PMID- 25502749 TI - Orexin system is expressed in avian muscle cells and regulates mitochondrial dynamics. AB - Orexin A and B, orexigenic peptides produced primarily by the lateral hypothalamus that signal through two G protein-coupled receptors, orexin receptors 1/2, have been implicated in the regulation of several physiological processes in mammals. In avian (nonmammalian vertebrates) species; however, the physiological roles of orexin are not well defined. Here, we provide novel evidence that not only is orexin and its related receptors 1/2 (ORXR1/2) expressed in chicken muscle tissue and quail muscle (QM7) cell line, orexin appears to be a secretory protein in QM7 cells. In vitro administration of recombinant orexin A and B (rORX-A and B) differentially regulated prepro-orexin expression in a dose-dependent manner with up-regulation for rORX-A (P < 0.05) and downregulation for rORX-B (P < 0.05) in QM7 cells. While both peptides upregulated ORXR1 expression, only a high dose of rORX-B decreased the expression of ORXR2 (P < 0.05). The presence of orexin and its related receptors and the regulation of its own system in avian muscle cells indicate that orexin may have autocrine, paracrine, and/or endocrine roles. rORXs differentially regulated mitochondrial dynamics network. While rORX-A significantly induced the expression of mitochondrial fission-related genes (DNM1, MTFP1, MTFR1), rORX-B increased the expression of mitofusin 2, OPA1, and OMA1 genes that are involved in mitochondrial fusion. Concomitant with these changes, rORXs differentially regulated the expression of several mitochondrial metabolic genes (av-UCP, av ANT, Ski, and NRF-1) and their related transcriptional regulators (PPARgamma, PPARalpha, PGC-1alpha, PGC-1beta, and FoxO-1) without affecting ATP synthesis. Taken together, our data represent the first evidence of the presence and secretion of orexin system in the muscle of nonmammalian species and its role in mitochondrial fusion and fission, probably through mitochondrial-related genes and their related transcription factors. PMID- 25502750 TI - Adult exercise effects on oxidative stress and reproductive programming in male offspring of obese rats. AB - Exercise improves health but few data are available regarding benefits of exercise in offspring exposed to developmental programming. There is currently a worldwide epidemic of obesity. Obesity in pregnant women predisposes offspring to obesity. Maternal obesity has well documented effects on offspring reproduction. Few studies address ability of offspring exercise to reduce adverse outcomes. We observed increased oxidative stress and impaired sperm function in rat offspring of obese mothers. We hypothesized that regular offspring exercise reverses adverse effects of maternal obesity on offspring sperm quality and fertility. Female Wistar rats ate chow (C) or high-energy, obesogenic diet (MO) from weaning through lactation, bred at postnatal day (PND) 120, and ate their pregnancy diet until weaning. All offspring ate C diet from weaning. Five male offspring (different litters) ran on a wheel for 15 min, 5 times/week from PND 330 to 450 and were euthanized at PND 450. Average distance run per session was lower in MO offspring who had higher body weight, adiposity index, and gonadal fat and showed increases in testicular oxidative stress biomarkers. Sperm from MO offspring had reduced antioxidant enzyme activity, lower sperm quality, and fertility. Exercise in MO offspring decreased testicular oxidative stress, increased sperm antioxidant activity and sperm quality, and improved fertility. Exercise intervention has beneficial effects on adiposity index, gonadal fat, oxidative stress markers, sperm quality, and fertility. Thus regular physical exercise in male MO offspring recuperates key male reproductive functions even at advanced age: it's never too late. PMID- 25502746 TI - Mycobacterium tuberculosis metabolism. AB - Metabolism underpins the physiology and pathogenesis of Mycobacterium tuberculosis. However, although experimental mycobacteriology has provided key insights into the metabolic pathways that are essential for survival and pathogenesis, determining the metabolic status of bacilli during different stages of infection and in different cellular compartments remains challenging. Recent advances-in particular, the development of systems biology tools such as metabolomics-have enabled key insights into the biochemical state of M. tuberculosis in experimental models of infection. In addition, their use to elucidate mechanisms of action of new and existing antituberculosis drugs is critical for the development of improved interventions to counter tuberculosis. This review provides a broad summary of mycobacterial metabolism, highlighting the adaptation of M. tuberculosis as specialist human pathogen, and discusses recent insights into the strategies used by the host and infecting bacillus to influence the outcomes of the host-pathogen interaction through modulation of metabolic functions. PMID- 25502747 TI - Stem cells as tools for studying the genetics of inherited retinal degenerations. AB - The ability to provide early clinical intervention for inherited disorders is heavily dependent on knowledge of a patient's disease-causing mutations and the resultant pathophysiologic mechanism(s). Without knowing a patient's disease causing gene, and how gene mutations alter the health and functionality of affected cells, it would be difficult to develop and deliver patient-specific molecular or small molecule therapies. Many believe that the field of stem cell biology holds the keys to the future development of disease-, patient-, and cell specific therapies. In the case of the eye, which is susceptible to an extremely common late-onset degenerative disease known as age-related macular degeneration, stem cell-based therapies could increase the quality of life for millions of patients worldwide. Furthermore, autologous, patient-specific induced pluripotent stem cells could be a viable source to treat rare Mendelian retinal degenerative diseases such as retinitis pigmentosa, Stargardt disease, and Best disease, to name a few. PMID- 25502751 TI - The truncated TrkB receptor influences mammalian sleep. AB - Brain-derived neurotrophic factor (BDNF) is a neurotrophin hypothesized to play an important role in mammalian sleep expression and regulation. In order to investigate the role of the truncated receptor for BDNF, TrkB.T1, in mammalian sleep, we examined sleep architecture and sleep regulation in adult mice constitutively lacking this receptor. We find that TrkB.T1 knockout mice have increased REM sleep time, reduced REM sleep latency, and reduced sleep continuity. These results demonstrate a novel role for the TrkB.T1 receptor in sleep expression and provide new insights into the relationship between BDNF, psychiatric illness, and sleep. PMID- 25502752 TI - Anti-alpha4 antibody treatment blocks virus traffic to the brain and gut early, and stabilizes CNS injury late in infection. AB - Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-alpha4 blocking antibody (natalizumab) once a week for three weeks beginning on 28 days post-infection (late). Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS), and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+) in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early) for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV - RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity. PMID- 25502753 TI - Egr-1 activation by cancer-derived extracellular vesicles promotes endothelial cell migration via ERK1/2 and JNK signaling pathways. AB - Various mammalian cells, including cancer cells, shed extracellular vesicles (EVs), also known as exosomes and microvesicles, into surrounding tissues. These EVs play roles in tumor growth and metastasis by promoting angiogenesis. However, the detailed mechanism of how cancer-derived EVs elicit endothelial cell activation remains unknown. Here, we provide evidence that early growth response 1 (Egr-1) activation in endothelial cells is involved in the angiogenic activity of colorectal cancer cell-derived EVs. Both RNA interference-mediated downregulation of Egr-1 and ERK1/2 or JNK inhibitor significantly blocked EV mediated Egr-1 activation and endothelial cell migration. Furthermore, lipid raft mediated endocytosis inhibitor effectively blocked endothelial Egr-1 activation and migration induced by cancer-derived EVs. Our results suggest that Egr-1 activation in endothelial cells may be a key mechanism involved in the angiogenic activity of cancer-derived EVs. These findings will improve our understanding regarding the proangiogenic activities of EVs in diverse pathological conditions including cancer, cardiovascular diseases, and neurodegenerative diseases. PMID- 25502754 TI - Succession of bacterial community structure and diversity in soil along a chronosequence of reclamation and re-vegetation on coal mine spoils in China. AB - The growing concern about the effectiveness of reclamation strategies has motivated the evaluation of soil properties following reclamation. Recovery of belowground microbial community is important for reclamation success, however, the response of soil bacterial communities to reclamation has not been well understood. In this study, PCR-based 454 pyrosequencing was applied to compare bacterial communities in undisturbed soils with those in reclaimed soils using chronosequences ranging in time following reclamation from 1 to 20 year. Bacteria from the Proteobacteria, Chloroflexi, Actinobacteria, Acidobacteria, Planctomycetes and Bacteroidetes were abundant in all soils, while the composition of predominant phyla differed greatly across all sites. Long-term reclamation strongly affected microbial community structure and diversity. Initial effects of reclamation resulted in significant declines in bacterial diversity indices in younger reclaimed sites (1, 8-year-old) compared to the undisturbed site. However, bacterial diversity indices tended to be higher in older reclaimed sites (15, 20-year-old) as recovery time increased, and were more similar to predisturbance levels nearly 20 years after reclamation. Bacterial communities are highly responsive to soil physicochemical properties (pH, soil organic matter, Total N and P), in terms of both their diversity and community composition. Our results suggest that the response of soil microorganisms to reclamation is likely governed by soil characteristics and, indirectly, by the effects of vegetation restoration. Mixture sowing of gramineae and leguminosae herbage largely promoted soil geochemical conditions and bacterial diversity that recovered to those of undisturbed soil, representing an adequate solution for soil remediation and sustainable utilization for agriculture. These results confirm the positive impacts of reclamation and vegetation restoration on soil microbial diversity and suggest that the most important phase of microbial community recovery occurs between 15 and 20 years after reclamation. PMID- 25502756 TI - Influence of imidazolium based green solvents on volume phase transition temperature of crosslinked poly(N-isopropylacrylamide-co-acrylic acid) hydrogel. AB - The volume phase transition temperature (VPTT) of crosslinked poly(N isopropylacrylamide-co-acrylic acid) (PNIPAM-co-AA) hydrogel in water in the presence of five imidazolium based ionic liquids (ILs) was studied. The VPTT of PNIPAM-co-AA hydrogel can be modulated to different extents by the addition of different amounts of ILs. The modulations in VPTT values can be attributed to the IL-induced alterations in hydrophobic, hydrophilic and hydrogen bonding interactions of PNIPAM-co-AA hydrogel with the neighboring solvent and molecular chains. The influence of ILs having a common cation, 1-butyl-3-methylimidazolium cation ([Bmim]) and different anions, such as iodide (I-), tetrafluoroborate (BF4 ), chloride (Cl-), acetate (CH3COO-) and hydrogen sulfate (HSO4-), on the phase transition of PNIPAM-co-AA hydrogel was monitored by the aid of differential scanning calorimetry (DSC), dynamic light scattering (DLS) and Fourier transform infrared (FT-IR) spectroscopy. Furthermore, the interfacial properties between aqueous IL and polymer surface were scrutinized with the help of contact angle (CA) measurements. The overall specific ranking of ILs in preserving the hydration layer around the PNIPAM-co-AA hydrogel in water was [Bmim][I]>[Bmim][BF4]>[Bmim][Cl]>[Bmim][Ac]>[Bmim][HSO4]. The trend of these ILs followed the well-known Hofmeister series. Interestingly, the PNIPAM-co-AA hydrogel in water shows abnormal salting-out property in the presence of [Bmim][BF4] at higher concentration and this abnormal behavior can be explained based on the lack of sufficient binding sites on the macromolecule for higher number of [Bmim][BF4] at a higher concentration. PMID- 25502755 TI - An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins. AB - DNA methylation has a great potential for understanding the aetiology of common complex traits such as Type 2 diabetes (T2D). Here we perform genome-wide methylated DNA immunoprecipitation sequencing (MeDIP-seq) in whole-blood-derived DNA from 27 monozygotic twin pairs and follow up results with replication and integrated omics analyses. We identify predominately hypermethylated T2D-related differentially methylated regions (DMRs) and replicate the top signals in 42 unrelated T2D cases and 221 controls. The strongest signal is in the promoter of the MALT1 gene, involved in insulin and glycaemic pathways, and related to taurocholate levels in blood. Integrating the DNA methylome findings with T2D GWAS meta-analysis results reveals a strong enrichment for DMRs in T2D susceptibility loci. We also detect signals specific to T2D-discordant twins in the GPR61 and PRKCB genes. These replicated T2D associations reflect both likely causal and consequential pathways of the disease. The analysis indicates how an integrated genomics and epigenomics approach, utilizing an MZ twin design, can provide pathogenic insights as well as potential drug targets and biomarkers for T2D and other complex traits. PMID- 25502758 TI - Global programme to eliminate lymphatic filariasis: the processes underlying programme success. PMID- 25502757 TI - Role of LPA and the Hippo pathway on apoptosis in salivary gland epithelial cells. AB - Lysophosphatidic acid (LPA) is a bioactive lysophospholipid involved in numerous physiological responses. However, the expression of LPA receptors and the role of the Hippo signaling pathway in epithelial cells have remained elusive. In this experiment, we studied the functional expression of LPA receptors and the associated signaling pathway using reverse transcriptase-PCR, microspectrofluorimetry, western blotting and immunocytochemistry in salivary gland epithelial cells. We found that LPA receptors are functionally expressed and involved in activating the Hippo pathway mediated by YAP/TAZ through Lats/Mob1 and RhoA/ROCK. Upregulation of YAP/TAZ-dependent target genes, including CTGF, ANKRD1 and CYR61, has also been observed in LPA-treated cells. In addition, based on data suggesting that tumor necrosis factor (TNF)-alpha induces cell apoptosis, LPA upregulates TNF-induced caspase-3 and cleaved Poly(ADP ribose)polymerase (PARP). However, small interfering RNA treatment to Yes associated protein (YAP) or transcriptional co-activator with a PDZ-binding motif (TAZ) significantly decreased TNF-alpha- and LPA-induced apoptosis, suggesting that YAP and TAZ modulate the apoptotic pathway in salivary epithelial cells. PMID- 25502760 TI - Mediastinal pancreatic pseudocyst with hemorrhage and left gastric artery pseudoaneurysm, managed with left gastric artery embolization and placement of percutaneous trans-hepatic pseudocyst drainage. AB - Mediastinal pancreatic pseudocyst (MPP) is a rare, but known, complication of both acute and chronic pancreatitis. Most pseudocysts are associated with alcoholic pancreatitis. Recent advances in endoscopic techniques have shown promising results, with reduced chances of infection and recurrence than with percutaneous drainage, but limited availability restricts widespread use. Left gastric artery pseudoaneurysm with mediastinal pseudocyst has not been described in the literature to date. We report a successful resolution of hemorrhagic MPP with embolization of pseudoaneurysm and percutaneous trans-hepatic pseudocyst drainage. PMID- 25502761 TI - Erratum to: Characterization of a GH family 8 beta-1,3-1,4-glucanase with distinctive broad substrate specificity from Paenibacillus sp. X4. PMID- 25502763 TI - Echoes of the past: hereditarianism and A Troublesome Inheritance. PMID- 25502762 TI - The first rapid assessment of avoidable blindness (RAAB) in Thailand. AB - BACKGROUND: The majority of vision loss is preventable or treatable. Population surveys are crucial for planning, implementation, and monitoring policies and interventions to eliminate avoidable blindness and visual impairments. This is the first rapid assessment of avoidable blindness (RAAB) study in Thailand. METHODS: A cross-sectional study of a population in Thailand age 50 years old or over aimed to assess the prevalence and causes of blindness and visual impairments. Using the Thailand National Census 2010 as the sampling frame, a stratified four-stage cluster sampling based on a probability proportional to size was conducted in 176 enumeration areas from 11 provinces. Participants received comprehensive eye examination by ophthalmologists. RESULTS: The age and sex adjusted prevalence of blindness (presenting visual acuity (VA) <20/400), severe visual impairment (VA <20/200 but >=20/400), and moderate visual impairment (VA <20/70 but >=20/200) were 0.6% (95% CI: 0.5-0.8), 1.3% (95% CI: 1.0-1.6), 12.6% (95% CI: 10.8-14.5). There was no significant difference among the four regions of Thailand. Cataract was the main cause of vision loss accounted for 69.7% of blindness. Cataract surgical coverage in persons was 95.1% for cut off VA of 20/400. Refractive errors, diabetic retinopathy, glaucoma, and corneal opacities were responsible for 6.0%, 5.1%, 4.0%, and 2.0% of blindness respectively. CONCLUSION: Thailand is on track to achieve the goal of VISION 2020. However, there is still much room for improvement. Policy refinements and innovative interventions are recommended to alleviate blindness and visual impairments especially regarding the backlog of blinding cataract, management of non-communicative, chronic, age-related eye diseases such as glaucoma, age related macular degeneration, and diabetic retinopathy, prevention of childhood blindness, and establishment of a robust eye health information system. PMID- 25502759 TI - Metabolomic perfusate analysis during kidney machine perfusion: the pig provides an appropriate model for human studies. AB - INTRODUCTION: Hypothermic machine perfusion offers great promise in kidney transplantation and experimental studies are needed to establish the optimal conditions for this to occur. Pig kidneys are considered to be a good model for this purpose and share many properties with human organs. However it is not established whether the metabolism of pig kidneys in such hypothermic hypoxic conditions is comparable to human organs. METHODS: Standard criteria human (n = 12) and porcine (n = 10) kidneys underwent HMP using the LifePort Kidney Transporter 1.0 (Organ Recovery Systems) using KPS-1 solution. Perfusate was sampled at 45 minutes and 4 hours of perfusion and metabolomic analysis performed using 1-D 1H-NMR spectroscopy. RESULTS: There was no inter-species difference in the number of metabolites identified. Of the 30 metabolites analysed, 16 (53.3%) were present in comparable concentrations in the pig and human kidney perfusates. The rate of change of concentration for 3-Hydroxybutyrate was greater for human kidneys (p<0.001). For the other 29 metabolites (96.7%), there was no difference in the rate of change of concentration between pig and human samples. CONCLUSIONS: Whilst there are some differences between pig and human kidneys during HMP they appear to be metabolically similar and the pig seems to be a valid model for human studies. PMID- 25502765 TI - Procedural learning of semantic categorization in Parkinson's disease. AB - This paper studies the procedural learning of semantic categorization in 29 patients with non-demented Parkinson's disease (PD). We investigated whether the PD group was able to develop semantic skill, using a cognitive procedural task developed in our laboratory, applying a manual and serial reaction time paradigm to semantic categorization. The PD group showed similar scores to those of the control group on semantic categorization. Both groups showed reaction time reduction over the semantic procedural task, but the PD group produced longer reaction times than the control subjects. Contrary to our prediction, we observed an improvement in semantic categorization reaction times with practice, even with new verbal material for the PD patients to categorize despite their motor impairments and executive deficits. By contrast, we found a significant negative correlation between axial motor signs and the ratio of semantic procedural learning, but not for lateral motor signs. The present results support the notion that non-demented PD patients may be capable of acquiring comparable semantic skill to those of the control group. PMID- 25502764 TI - Serum leptin and risk of cognitive decline in elderly italians. AB - BACKGROUND: US studies suggest that leptin, a fat-derived hormone, may be protective against the development of dementia. OBJECTIVE: To investigate the complex relationship between leptin levels and cognitive decline in elderly Italians. METHODS: We studied circulating fasting leptin levels in 809 elderly adults free from dementia who participated in the prospective Italian population based InCHIANTI study between 1998 and 2009 (mean follow-up of 8.0 years). Global cognitive decline was defined as a reduction of >=5 points on the Mini-Mental State Examination (MMSE). Trail-Making Tests A and B were also incorporated, with cognitive decline defined as discontinued testing or the worst 10% of change from baseline. We also investigated whether any association could be explained by midlife weight and whether cognitive decline was associated with changing leptin levels. RESULTS: The multivariate adjusted relative risk ([RR]; 95% confidence interval [CI]) of cognitive decline on the MMSE was 0.84 (95% CI 0.73-0.97) in relation to baseline sex-standardized log-leptin levels. High leptin levels showed a non-significant trend toward a reduced risk of decline on the Trail Making Tests A (RR = 0.85, 95% CI 0.71-1.02) and B (RR = 0.90, 0.79-1.02). Adjusting for midlife weight or change in weight did not alter the pattern of results, and cognitive decline was not associated with changing leptin levels. CONCLUSIONS: High leptin levels were independently associated with a reduced risk of cognitive decline in elderly Italians. PMID- 25502767 TI - Biomimetic niche for neural stem cell differentiation using poly-L lysine/hyaluronic acid multilayer films. AB - Polyelectrolyte multilayer films have been suggested as tunable substrates with flexible surface properties that can modulate cell behavior. However, these films' biological effects on neural stem/progenitor cells have rarely been studied. Herein, biomimetic multilayer films composed of hyaluronic acid and poly L-lysine were chosen to mimic the native extracellular matrix niche of brain tissue and were evaluated for their inductive effects, without the addition of chemical factors. Because neural stem/progenitor cells are sensitive to substrate properties, it is important that this system provides control over the surface charge, and slight stiffness variations are also possible. Both of these factors affect neural stem/progenitor cell differentiation. The results showed that neural stem/progenitor cells were induced to differentiate on the poly-L lysine/hyaluronic acid multilayer films with 0.5-4 alternating layers. In addition, the neurite outgrowth length was regulated by the surface charge of the terminal layer but did not increase with the layer number. In contrast, the quantity of differentiated neurons was enhanced slightly as the number of layers increased but was not affected by the surface charge of the terminal layer. In sum, material pairs in the form of native poly-L-lysine/hyaluronic acid films achieved important targets for neural regenerative medicine, including enhancement of the neurite outgrowth length, regulation of neuron differentiation, and the formation of a network. These extracellular matrix mimetic poly-L-lysine/hyaluronic acid multilayer films may provide a versatile platform that could be useful for surface modification for applications in neural engineering. PMID- 25502766 TI - Translational study of Alzheimer's disease (AD) biomarkers from brain tissues in AbetaPP/PS1 mice and serum of AD patients. AB - The aim of this study was to investigate potential biomarkers of Alzheimer's disease (AD). Changes in protein expression in brain tissues from AbetaPP/PS1 transgenic mice were evaluated using two-dimensional gel electrophoresis combined with LC-MS/MS. A total of 23 differentially expressed proteins were successfully identified in brain tissues of which 11 were validated by western blot. Then, the levels of these differentially expressed proteins in serum from AD patients and healthy controls were examined. Of these 11 proteins, levels of 5 changed in the same direction in the serum of AD patients as they did in mouse brain: cathepsin B, VDAC1, and cofilin-2 increased, and Alix and ACAP1 decreased. Alix, cofilin-2, and ACAP1 have not been previously associated with AD. More importantly, the serum levels of Alix, cofilin-2, and ACAP1 were significantly different between AD patients and healthy controls. Furthermore, the expressions of cathepsin B, cofilin-2, VDAC1, and ACAP1 strongly correlated with the Mini-Mental State Examination scores of the AD patients. The results indicate that these proteins are putative biomarkers of AD which may be useful in its diagnosis and in the evaluation of new anti-AD drugs both in pre-clinical and clinical studies. PMID- 25502768 TI - High interest in a long-acting injectable formulation of pre-exposure prophylaxis for HIV in young men who have sex with men in NYC: a P18 cohort substudy. AB - OBJECTIVE: In the context of continued high rates of condomless anal intercourse and HIV-1 infection, young men who have sex with men (YMSM) need additional effective and desirable HIV prevention tools. This study reports on the willingness of a racially-ethnically diverse cohort of YMSM to use a new biomedical prevention approach, a long-acting injectable pre-exposure prophylaxis (LAI-PrEP) agent. METHODS: A cross-sectional study conducted between June-August 2013 recruited participants from an ongoing cohort study of YMSM in NYC. Participants included 197 YMSM, of whom 72.6% (n = 143) identified as men of color. Two outcomes were measured through computer-assisted self-interviews: 1) willingness to use long-acting injectable PrEP and 2) preference for route of administration of PrEP. In addition, concerns about perceived impacts of PrEP on health and risk behavior, access to health services, and stigma were investigated. RESULTS: Over 80% (n = 159/197, p<0.001) of participants stated they would be willing to use LAI-PrEP. With regards to preference for mode of delivery 79.2% (n = 156/197, p<0.001) stated they would prefer an injection administered every three months over a daily pill or neither one. CONCLUSIONS: This study is the first to explore acceptability of LAI-PrEP in the US. A significant majority of participants expressed willingness to use LAI and the majority preferred LAI-PrEP. LAI-PrEP holds great promise in that it could circumvent the adherence challenges associated with daily dosing, especially if nested within appropriate psycho-behavioral support. Medical providers whose patients include YMSM at high risk for HIV infection should note the positive attitudes toward PrEP, and specifically LAI-PrEP. PMID- 25502769 TI - High levels of oxysterol sulfates in serum of patients with steroid sulfatase deficiency. AB - Steroid sulfatase (STS) deficiency is the underlying cause of the skin condition known as recessive X-linked ichthyosis (RXLI). RXLI patients show scales on their skin caused by high concentrations of cholesterol sulfate (CS), as they are not capable of releasing the sulfate group from its structure to obtain free cholesterol. CS has been reported, so far, as the sole sulfated steroid with increased concentrations in the blood of RXLI patients. A non-targeted LC-MS approach in negative mode detection (LC-MS precursor ion scan mode) was applied to serum samples of 12 RXLI patients and 19 healthy males. We found that CS was not the only sulfated compound consistently elevated in RXLI patients, because a group of compounds with a m/z of 481 was found in high concentrations too. Further LC-MS/MS demonstrated that the main contributor to the m/z 481 signal in RXLI serum is 27-hydroxycholesterol-3-sulfate (27OHC3S). Accordingly, a new method for 27OHC3S quantification in the context of RXLI has been developed and validated. Other hydroxycholesterol sulfate compounds were elevated as well in RXLI patients. PMID- 25502770 TI - Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations. AB - Retinoic acid (RA), the active metabolite of vitamin A, is required for spermatogenesis and many other biological processes. RA formation requires irreversible oxidation of retinal to RA by aldehyde dehydrogenase enzymes of the 1A family (ALDH1A). While ALDH1A1, ALDH1A2, and ALDH1A3 all form RA, the expression pattern and relative contribution of these enzymes to RA formation in the testis is unknown. In this study, novel methods to measure ALDH1A protein levels and intrinsic RA formation were used to accurately predict RA formation velocities in individual human testis samples and an association between RA formation and intratesticular RA concentrations was observed. The distinct localization of ALDH1A in the testis suggests a specific role for each enzyme in controlling RA formation. ALDH1A1 was found in Sertoli cells, while only ALDH1A2 was found in spermatogonia, spermatids, and spermatocytes. In the absence of cellular retinol binding protein (CRBP)1, ALDH1A1 was predicted to be the main contributor to intratesticular RA formation, but when CRBP1 was present, ALDH1A2 was predicted to be equally important in RA formation as ALDH1A1. This study provides a comprehensive novel methodology to evaluate RA homeostasis in human tissues and provides insight to how the individual ALDH1A enzymes mediate RA concentrations in specific cell types. PMID- 25502773 TI - Mini profile of potential anticancer properties of propofol. AB - BACKGROUND: Propofol (2, 6-diisopropylphenol) is an intravenous sedative-hypnotic agent administered to induce and maintain anesthesia. It has been recently revealed that propofol has anticancer properties including direct and indirect suppression of the viability and proliferation of cancer cells by promoting apoptosis in some cancer cell lines. METHODOLOGY/PRINCIPAL FINDINGS: This study aimed to establish a profile to quantitatively and functionally evaluate the anticancer properties of propofol in three cancer cell lines: non-small cell lung carcinoma cell line A549, human colon carcinoma cell line LoVo, and human breast cancer cell line SK-BR-3. We demonstrated that the expression level of caspase-3, an apoptosis biomarker, significantly increased in a dose-dependent manner after 24-h stimulation with 100 uM propofol in A549 cells, and slightly increased in LoVo cells. However, there was no change in caspase-3 expression in SK-BR-3 cells. High caspase-3 expression in A549 cells may be modulated by the ERK1/2 pathway because phosphorylated ERK1/2 dramatically reduced after propofol treatment. BAX, a major protein that promotes apoptosis in the regulation phase, was highly expressed in A549 cells after treatment with 25 uM propofol. Apoptosis induced by propofol may be associated with cancer cells carrying Kras mutations. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the anti-cancer effects of propofol, which are consistent with those of previous studies, are likely associated with the Kras mutation status. Only Kras mutation in Codon 12 instead of other Kras status has been demonstrated to play an important role in sensitizing the propofol-induced apoptosis in cancer cell lines from our study. These findings may enable us a detailed investigation of propofol/Kras-mediated cancer cell apoptosis in the future. PMID- 25502771 TI - Tetrahydrocurcumin protects against cadmium-induced hypertension, raised arterial stiffness and vascular remodeling in mice. AB - BACKGROUND: Cadmium (Cd) is a nonessential heavy metal, causing oxidative damage to various tissues and associated with hypertension. Tetrahydrocurcumin (THU), a major metabolite of curcumin, has been demonstrated to be an antioxidant, anti diabetic, anti-hypertensive and anti-inflammatory agent. In this study, we investigated the protective effect of THU against Cd-induced hypertension, raised arterial stiffness and vascular remodeling in mice. METHODS: Male ICR mice received CdCl2 (100 mg/l) via drinking water for 8 weeks. THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment. RESULTS: Administration of CdCl2 significantly increased arterial blood pressure, blunted vascular responses to vasoactive agents, increased aortic stiffness, and induced hypertrophic aortic wall remodeling by increasing number of smooth muscle cells and collagen deposition, decreasing elastin, and increasing matrix metalloproteinase (MMP)-2 and MMP-9 levels in the aortic medial wall. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition. The reduction on the adverse response of Cd treatment was associated with upregulated eNOS and downregulated iNOS protein expressions, increased nitrate/nitrite level, alleviated oxidative stress and enhanced antioxidant glutathione. Moreover, THU also reduced the accumulation of Cd in the blood and tissues. CONCLUSIONS: Our results suggest that THU ameliorates cadmium-induced hypertension, vascular dysfunction, and arterial stiffness in mice through enhancing NO bioavailability, attenuating oxidative stress, improving vascular remodeling and decreasing Cd accumulation in other tissues. THU has a beneficial effect in moderating the vascular alterations associated with Cd exposure. PMID- 25502774 TI - Electronic evidence of an insulator-superconductor crossover in single-layer FeSe/SrTiO3 films. AB - In high-temperature cuprate superconductors, it is now generally agreed that superconductivity is realized by doping an antiferromagnetic Mott (charge transfer) insulator. The doping-induced insulator-to-superconductor transition has been widely observed in cuprates, which provides important information for understanding the superconductivity mechanism. In the iron-based superconductors, however, the parent compound is mostly antiferromagnetic bad metal, raising a debate on whether an appropriate starting point should go with an itinerant picture or a localized picture. No evidence of doping-induced insulator superconductor transition (or crossover) has been reported in the iron-based compounds so far. Here, we report an electronic evidence of an insulator superconductor crossover observed in the single-layer FeSe film grown on a SrTiO3 substrate. By taking angle-resolved photoemission measurements on the electronic structure and energy gap, we have identified a clear evolution of an insulator to a superconductor with increasing carrier concentration. In particular, the insulator-superconductor crossover in FeSe/SrTiO3 film exhibits similar behaviors to that observed in the cuprate superconductors. Our results suggest that the observed insulator-superconductor crossover may be associated with the two dimensionality that enhances electron localization or correlation. The reduced dimensionality and the interfacial effect provide a new pathway in searching for new phenomena and novel superconductors with a high transition temperature. PMID- 25502775 TI - Influence of repressive coping style on cortical activation during encoding of angry faces. AB - BACKGROUND: Coping plays an important role for emotion regulation in threatening situations. The model of coping modes designates repression and sensitization as two independent coping styles. Repression consists of strategies that shield the individual from arousal. Sensitization indicates increased analysis of the environment in order to reduce uncertainty. According to the discontinuity hypothesis, repressors are sensitive to threat in the early stages of information processing. While repressors do not exhibit memory disturbances early on, they manifest weak memory for these stimuli later. This study investigates the discontinuity hypothesis using functional magnetic resonance imaging (fMRI). METHODS: Healthy volunteers (20 repressors and 20 sensitizers) were selected from a sample of 150 students on the basis of the Mainz Coping Inventory. During the fMRI experiment, subjects evaluated and memorized emotional and neutral faces. Subjects performed two sessions of face recognition: immediately after the fMRI session and three days later. RESULTS: Repressors exhibited greater activation of frontal, parietal and temporal areas during encoding of angry faces compared to sensitizers. There were no differences in recognition of facial emotions between groups neither immediately after exposure nor after three days. CONCLUSIONS: The fMRI findings suggest that repressors manifest an enhanced neural processing of directly threatening facial expression which confirms the assumption of hyper responsivity to threatening information in repression in an early processing stage. A discrepancy was observed between high neural activation in encoding relevant brain areas in response to angry faces in repressors and no advantage in subsequent memory for these faces compared to sensitizers. PMID- 25502776 TI - Functional role of Calstabin2 in age-related cardiac alterations. AB - Calstabin2 is a component of the cardiac ryanodine receptor (RyR2) macromolecular complex, which modulates Ca(2+) release from the sarcoplasmic reticulum in cardiomyocytes. Previous reports implied that genetic deletion of Calstabin2 leads to phenotypes related to cardiac aging. However, the mechanistic role of Calstabin2 in the process of cardiac aging remains unclear. To assess whether Calstabin2 is involved in age-related heart dysfunction, we studied Calstabin2 knockout (KO) and control wild-type (WT) mice. We found a significant association between deletion of Calstabin2 and cardiac aging. Indeed, aged Calstabin2 KO mice exhibited a markedly impaired cardiac function compared with WT littermates. Calstabin2 deletion resulted also in increased levels of cell cycle inhibitors p16 and p19, augmented cardiac fibrosis, cell death, and shorter telomeres. Eventually, we demonstrated that Calstabin2 deletion resulted in AKT phosphorylation, augmented mTOR activity, and impaired autophagy in the heart. Taken together, our results identify Calstabin2 as a key modulator of cardiac aging and indicate that the activation of the AKT/mTOR pathway plays a mechanistic role in such a process. PMID- 25502777 TI - Identification of genomic alterations in pancreatic cancer using array-based comparative genomic hybridization. AB - BACKGROUND: Genomic aberration is a common feature of human cancers and also is one of the basic mechanisms that lead to overexpression of oncogenes and underexpression of tumor suppressor genes. Our study aims to identify frequent genomic changes in pancreatic cancer. MATERIALS AND METHODS: We used array comparative genomic hybridization (array CGH) to identify recurrent genomic alterations and validated the protein expression of selected genes by immunohistochemistry. RESULTS: Sixteen gains and thirty-two losses occurred in more than 30% and 60% of the tumors, respectively. High-level amplifications at 7q21.3-q22.1 and 19q13.2 and homozygous deletions at 1p33-p32.3, 1p22.1, 1q22, 3q27.2, 6p22.3, 6p21.31, 12q13.2, 17p13.2, 17q21.31 and 22q13.1 were identified. Especially, amplification of AKT2 was detected in two carcinomas and homozygous deletion of CDKN2C in other two cases. In 15 independent validation samples, we found that AKT2 (19q13.2) and MCM7 (7q22.1) were amplified in 6 and 9 cases, and CAMTA2 (17p13.2) and PFN1 (17p13.2) were homozygously deleted in 3 and 1 cases. AKT2 and MCM7 were overexpressed, and CAMTA2 and PFN1 were underexpressed in pancreatic cancer tissues than in morphologically normal operative margin tissues. Both GISTIC and Genomic Workbench software identified 22q13.1 containing APOBEC3A and APOBEC3B as the only homozygous deletion region. And the expression levels of APOBEC3A and APOBEC3B were significantly lower in tumor tissues than in morphologically normal operative margin tissues. Further validation showed that overexpression of PSCA was significantly associated with lymph node metastasis, and overexpression of HMGA2 was significantly associated with invasive depth of pancreatic cancer. CONCLUSION: These recurrent genomic changes may be useful for revealing the mechanism of pancreatic carcinogenesis and providing candidate biomarkers. PMID- 25502778 TI - Submandibular venous hemangioma: Case report and review of the literature. AB - Hemangiomas of the submandibular space are very rare. Only 11 cases have been reported in the English literature, all of which were cavernous hemangiomas. In this report, we describe the case of a venous hemangioma in a 70-year-old woman. Ultrasound examination revealed a lobulated, homogeneous, hypoechoic mass, and minimal flow was detected on power Doppler evaluation. The mass and the submandibular gland were surgically excised, and the endothelium was found to be positive for CD31 and D2-40 markers, consistent with venous hemangioma. To our knowledge, this is the first reported case of a venous hemangioma in the submandibular space. PMID- 25502786 TI - Ampelopsin reduces the migration and invasion of ovarian cancer cells via inhibition of epithelial-to-mesenchymal transition. AB - Ampelopsin has displayed anticancer activity in several types of cancers. However, no evidence has been reported for the direct effect of ampelopsin on ovarian cancer cell migration and invasion, and the underling mechanisms have not yet been clearly established. The aim of the present study was to investigate the influence of ampelopsin on the migration and invasion of ovarian cancer. Proliferation and viability of the ovarian cancer cells were detected by MTT assay. Migration and invasion of the cells were detected, respectively, by scratch wound healing assay and Transwell assay. The expression levels of epithelial-to-mesenchymal transition (EMT) markers were detected at the protein level after stimulation with ampelopsin. Then, the expression levels of NF-kappaB and p-IkappaBalpha were detected with western blot analysis. Meanwhile, an inhibitor of NF-kappaB was used to investigate the effect of ampelopsin. Finally, the expression of Snail was also detected. Proliferation, migration and invasion of the A2780 cells were all inhibited following the application of ampelopsin. Ampelopsin upregulated E-cadherin and downregulated N-cadherin and vimentin in a concentration- and time-dependent manner. Ampelopsin also exerted its ability to suppress the nuclear translocation of the NF-kappaB pathway. Administration of the inhibitor BAY11-7082 confirmed the roles of NF-kappaB in the expression of EMT markers and its transcription factor. These results demonstrated that ampelopsin inhibited EMT and reduced the invasion of ovarian cancer cells via the NF-kappaB/Snail pathway. PMID- 25502788 TI - The Role of HLA in MS Susceptibility and Phenotype. AB - One of the most consistent findings in multiple sclerosis (MS) is that development of MS is linked with carriage of the class II human leucocyte antigen (HLA) molecule HLA-DRB1*15:01; around 60 % of Caucasian MS patients carry this allele compared to 25-30 % of ethnically matched healthy individuals. However, other HLA molecules have also been linked to the development of MS. In this chapter, the association between different HLA types and susceptibility to MS will be reviewed, and other linkages between the carriage of specific HLA molecules and clinical and experimental findings in MS will be considered. PMID- 25502787 TI - Effects of acupuncture on sensory perception: a systematic review and meta analysis. AB - BACKGROUND: The effect of acupuncture on sensory perception has never been systematically reviewed; although, studies on acupuncture mechanisms are frequently based on the idea that changes in sensory thresholds reflect its effect on the nervous system. METHODS: Pubmed, EMBASE and Scopus were screened for studies investigating the effect of acupuncture on thermal or mechanical detection or pain thresholds in humans published in English or German. A meta analysis of high quality studies was performed. RESULTS: Out of 3007 identified articles 85 were included. Sixty five studies showed that acupuncture affects at least one sensory threshold. Most studies assessed the pressure pain threshold of which 80% reported an increase after acupuncture. Significant short- and long term effects on the pressure pain threshold in pain patients were revealed by two meta-analyses including four and two high quality studies, respectively. In over 60% of studies, acupuncture reduced sensitivity to noxious thermal stimuli, but measuring methods might influence results. Few but consistent data indicate that acupuncture reduces pin-prick like pain but not mechanical detection. Results on thermal detection are heterogeneous. Sensory threshold changes were equally frequent reported after manual acupuncture as after electroacupuncture. Among 48 sham-controlled studies, 25 showed stronger effects on sensory thresholds through verum than through sham acupuncture, but in 9 studies significant threshold changes were also observed after sham acupuncture. Overall, there is a lack of high quality acupuncture studies applying comprehensive assessments of sensory perception. CONCLUSIONS: Our findings indicate that acupuncture affects sensory perception. Results are most compelling for the pressure pain threshold, especially in pain conditions associated with tenderness. Sham acupuncture can also cause such effects. Future studies should incorporate comprehensive, standardized assessments of sensory profiles in order to fully characterize its effect on sensory perception and to explore the predictive value of sensory profiles for the effectiveness of acupuncture. PMID- 25502789 TI - Amphipathic alpha-helices in apolipoproteins are crucial to the formation of infectious hepatitis C virus particles. AB - Apolipoprotein B (ApoB) and ApoE have been shown to participate in the particle formation and the tissue tropism of hepatitis C virus (HCV), but their precise roles remain uncertain. Here we show that amphipathic alpha-helices in the apolipoproteins participate in the HCV particle formation by using zinc finger nucleases-mediated apolipoprotein B (ApoB) and/or ApoE gene knockout Huh7 cells. Although Huh7 cells deficient in either ApoB or ApoE gene exhibited slight reduction of particles formation, knockout of both ApoB and ApoE genes in Huh7 (DKO) cells severely impaired the formation of infectious HCV particles, suggesting that ApoB and ApoE have redundant roles in the formation of infectious HCV particles. cDNA microarray analyses revealed that ApoB and ApoE are dominantly expressed in Huh7 cells, in contrast to the high level expression of all of the exchangeable apolipoproteins, including ApoA1, ApoA2, ApoC1, ApoC2 and ApoC3 in human liver tissues. The exogenous expression of not only ApoE, but also other exchangeable apolipoproteins rescued the infectious particle formation of HCV in DKO cells. In addition, expression of these apolipoproteins facilitated the formation of infectious particles of genotype 1b and 3a chimeric viruses. Furthermore, expression of amphipathic alpha-helices in the exchangeable apolipoproteins facilitated the particle formation in DKO cells through an interaction with viral particles. These results suggest that amphipathic alpha helices in the exchangeable apolipoproteins play crucial roles in the infectious particle formation of HCV and provide clues to the understanding of life cycle of HCV and the development of novel anti-HCV therapeutics targeting for viral assembly. PMID- 25502790 TI - Metal ions, not metal-catalyzed oxidative stress, cause clay leachate antibacterial activity. AB - Aqueous leachates prepared from natural antibacterial clays, arbitrarily designated CB-L, release metal ions into suspension, have a low pH (3.4-5), generate reactive oxygen species (ROS) and H2O2, and have a high oxidation reduction potential. To isolate the role of pH in the antibacterial activity of CB clay mixtures, we exposed three different strains of Escherichia coli O157:H7 to 10% clay suspensions. The clay suspension completely killed acid-sensitive and acid-tolerant E. coli O157:H7 strains, whereas incubation in a low-pH buffer resulted in a minimal decrease in viability, demonstrating that low pH alone does not mediate antibacterial activity. The prevailing hypothesis is that metal ions participate in redox cycling and produce ROS, leading to oxidative damage to macromolecules and resulting in cellular death. However, E. coli cells showed no increase in DNA or protein oxidative lesions and a slight increase in lipid peroxidation following exposure to the antibacterial leachate. Further, supplementation with numerous ROS scavengers eliminated lipid peroxidation, but did not rescue the cells from CB-L-mediated killing. In contrast, supplementing CB-L with EDTA, a broad-spectrum metal chelator, reduced killing. Finally, CB-L was equally lethal to cells in an anoxic environment as compared to the aerobic environment. Thus, ROS were not required for lethal activity and did not contribute to toxicity of CB-L. We conclude that clay-mediated killing was not due to oxidative damage, but rather, was due to toxicity associated directly with released metal ions. PMID- 25502791 TI - Current trends in the development of molecularly imprinted polymers in CEC. AB - This review focused on the developments in the field of molecularly imprinted polymers (MIPs) for CEC since 2009. New preparation techniques of MIP-based CEC, such as, portable microchip with macroporous monolithic imprinted microchannel, and low cross-linking MIPs based on liquid crystalline monomers, were discussed. Using selected cases rather than a comprehensive review of the entire field, our goal is to highlight the studies of the interest with an emphasis on recent work, and offers suggestions for future development in the field of imprinted materials for CEC separation. PMID- 25502792 TI - Health Status of Immigrant Children and Environmental Survey of Child Daycare Centers in Samut Sakhon Province, Thailand. AB - Samut Sakhon is a Thai province popular among immigrants attracted to work in factories and the Thai food industry, especially people from Myanmar. Poor personal-hygiene behaviors, crowded accommodation and limited sanitation, result in health problems among immigrant workers. Various infectious diseases among this group are seen and managed by Samut Sakhon General Hospital. The impact of intestinal parasitic infections on public health is well known; they can spread from infected immigrant areas to uninfected areas via close contact and fecal oral transmission from contaminated food and water. This study aimed to determine the prevalence of intestinal parasitic infections among 372 immigrant children at 8 child-daycare centers during their parents' work time, by physical examination, fecal examination, and examination of the environment around the centers. Physical examinations were generally unremarkable, except that head-lice and fingernail examinations were positive in two cases (0.8 %). The results showed intestinal parasitic infections to be highly prevalent, at 71.0 %. These infections comprised both helminths and protozoa: Trichuris trichiura (50.8 %), Enterobius vermicularis (25.2 %), Ascaris lumbricoides (15.3 %), hookworm (11.6 %), Giardia lamblia (10.2 %), Endolimax nana (3.5 %), Entamoeba coli (2.7 %), and Blastocystis hominis (0.5 %). The environmental survey found a small number of houseflies near the accommodation to be positive for helminthic eggs (0.2 %), including A. lumbricoides, E. vermicularis, hookworms, Taenia spp., and minute intestinal flukes. Regarding the high prevalence of intestinal parasitic infections among children, it has been conjectured whether they were infected, along with their parents, during their daily lives before or after settling in Thailand. Intestinal parasites among immigrant children may involve a significant epidemiological impact, since immigrant children can serve as carriers and transmitters of disease. PMID- 25502793 TI - No differences in cervical cancer stage at diagnosis for Blacks and Whites in the Mountain West. AB - This study assesses cervical cancer disparities between Blacks and Whites in terms of stage at diagnosis in a Mountain West state. A total of 1,408 women diagnosed with cervical cancer between 1995 and 2010 were identified from the Nevada Central Cancer Registry. Logistic regression modeling examined the effect of race on stage at diagnosis in both Nevada and the Surveillance, Epidemiology and End Results (SEER) population. After controlling for the main confounders, no significant differences in stage at diagnosis were observed between Black and White females in Nevada (aOR 0.91; 95% CI 0.57-1.43). In contrast, Black women in SEER areas had a 21% higher odds of being diagnosed at an advanced stage compared to Whites. Our findings suggest a favorable disparity balance for cervical cancer in Nevada where Blacks are largely recent arrivals in relation to the remaining US, where Blacks have long been established. PMID- 25502794 TI - Janus kinase/signal transducer and activator of transcription inhibitors enhance the protective effect mediated by tanshinone IIA from hypoxic/ischemic injury in cardiac myocytes. AB - Tanshinone IIA is a lipophilic abietane diterpene compound, which exhibits protective effects against ischaemia/reperfusion injury; however, the pathways responsible for the myocardial protective activities of tanshinone IIA remain to be elucidated. The aim of the present study was to investigate the effect of tanshinone IIA on the Janus-activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, which is associated with cardiac dysfunction during ischemia/reperfusion. The results demonstrated that tanshinone IIA protected myocardial cells from hypoxia/ischemia-induced injury in vitro and recovered decreased cell viability due to activation of the JAK2/STAT3 pathway, with 10 uM tanshinone IIA exhibiting the most potent protective effects. Flow cytometric analysis revealed that tanshinone IIA reversed the apoptotic aggravation induced by JAK2/STAT3 inhibitors following hypoxic ischemia. However, JAK2 inhibitors promoted the myocardial protective effect of tanshinone IIA from hypoxic-ischemic injury. Furthermore, tanshinone IIA and JAK2/STAT3 inhibitors in combination augmented the protection of myocardial cells from apoptosis induced by ischemia/reperfusion preconditioning in vivo. In conclusion, the results of the present study indicated that JAK2/STAT3 inhibitors may enhance the protective effect of tanshinone IIA on cardiac myocytes from hypoxic ischemia-induced injury, therefore suggesting that JAK2/STAT3 inhibitors may have a potential application in combination therapies with tanshinone IIA. PMID- 25502796 TI - Maintenance intravenous fluids for children with central nervous system infections. PMID- 25502797 TI - Childhood obesity, metabolic syndrome and Pentraxin-3. PMID- 25502795 TI - P53 and cancer-associated sialylated glycans are surrogate markers of cancerization of the bladder associated with Schistosoma haematobium infection. AB - BACKGROUND: Bladder cancer is a significant health problem in rural areas of Africa and the Middle East where Schistosoma haematobium is prevalent, supporting an association between malignant transformation and infection by this blood fluke. Nevertheless, the molecular mechanisms linking these events are poorly understood. Bladder cancers in infected populations are generally diagnosed at a late stage since there is a lack of non-invasive diagnostic tools, hence enforcing the need for early carcinogenesis markers. METHODOLOGY/PRINCIPAL FINDINGS: Forty-three formalin-fixed paraffin-embedded bladder biopsies of S. haematobium-infected patients, consisting of bladder tumours, tumour adjacent mucosa and pre-malignant/malignant urothelial lesions, were screened for bladder cancer biomarkers. These included the oncoprotein p53, the tumour proliferation rate (Ki-67>17%), cell-surface cancer-associated glycan sialyl-Tn (sTn) and sialyl-Lewisa/x (sLea/sLex), involved in immune escape and metastasis. Bladder tumours of non-S. haematobium etiology and normal urothelium were used as controls. S. haematobium-associated benign/pre-malignant lesions present alterations in p53 and sLex that were also found in bladder tumors. Similar results were observed in non-S. haematobium associated tumours, irrespectively of their histological nature, denoting some common molecular pathways. In addition, most benign/pre-malignant lesions also expressed sLea. However, proliferative phenotypes were more prevalent in lesions adjacent to bladder tumors while sLea was characteristic of sole benign/pre-malignant lesions, suggesting it may be a biomarker of early carcionogenesis associated with the parasite. A correlation was observed between the frequency of the biomarkers in the tumor and adjacent mucosa, with the exception of Ki-67. Most S. haematobium eggs embedded in the urothelium were also positive for sLea and sLex. Reinforcing the pathologic nature of the studied biomarkers, none was observed in the healthy urothelium. CONCLUSION/SIGNIFICANCE: This preliminary study suggests that p53 and sialylated glycans are surrogate biomarkers of bladder cancerization associated with S. haematobium, highlighting a missing link between infection and cancer development. Eggs of S. haematobium express sLea and sLex antigens in mimicry of human leukocytes glycosylation, which may play a role in the colonization and disease dissemination. These observations may help the early identification of infected patients at a higher risk of developing bladder cancer and guide the future development of non-invasive diagnostic tests. PMID- 25502798 TI - "Globe Luxation": A Dramatic Complication of Forceps Assisted Vaginal Delivery. PMID- 25502799 TI - Single arginine mutation in two yeast isocitrate dehydrogenases: biochemical characterization and functional implication. AB - Isocitrate dehydrogenase (IDH), a housekeeping gene, has drawn the attention of cancer experts. Mutation of the catalytic Arg132 residue of human IDH1 (HcIDH) eliminates the enzyme's wild-type isocitrate oxidation activity, but confer the mutant an ability of reducing alpha-ketoglutarate (alpha-KG) to 2 hydroxyglutarate (2-HG). To examine whether an analogous mutation in IDHs of other eukaryotes could cause similar effects, two yeast mitochondrial IDHs, Saccharomyces cerevisiae NADP+-IDH1 (ScIDH1) and Yarrowia lipolytica NADP+-IDH (YlIDH), were studied. The analogous Arg residues (Arg148 of ScIDH1 and Arg141 of YlIDH) were mutated to His. The Km values of ScIDH1 R148H and YlIDH R141H for isocitrate were determined to be 2.4-fold and 2.2-fold higher, respectively, than those of the corresponding wild-type enzymes. The catalytic efficiencies (kcat/Km) of ScIDH1 R148H and YlIDH R141H for isocitrate oxidation were drastically reduced by 227-fold and 460-fold, respectively, of those of the wild type enzymes. As expected, both ScIDH1 R148H and YlIDH R141H acquired the neomorphic activity of catalyzing alpha-KG to 2-HG, and the generation of 2-HG was confirmed using gas chromatography/time of flight-mass spectrometry (GC/TOF MS). Kinetic analysis showed that ScIDH1 R148H and YlIDH R141H displayed 5.2-fold and 3.3-fold higher affinities, respectively, for alpha-KG than the HcIDH R132H mutant. The catalytic efficiencies of ScIDH1 R148H and YlIDH R141H for alpha-KG were 5.5-fold and 4.5-fold, respectively, of that of the HcIDH R132H mutant. Since the HcIDH Arg132 mutation is associated with the tumorigenesis, this study provides fundamental information for further research on the physiological role of this IDH mutation in vivo using yeast. PMID- 25502800 TI - Amphiphilic benzothiadiazole-triphenylamine-based aggregates that emit red light in water. AB - In this study, we report a preparation and an aggregate emission behavior of an amphiphilic donor-acceptor dye, which is composed of a triphenylamine benzothiadiazole donor-acceptor chromophore and two water-soluble hexa(ethylene glycol) chains. The dye is strongly fluorescent in nonpolar solutions such as cyclohexane and toluene, whereas the emission intensity is reduced in aprotic polar solutions such as DMF and acetonitrile. This fluorescence reduction correlates with the increase in polarity, by which the transition from a local excited state to a highly polarized excited state is facilitated, leading to an increased nonradiative deactivation rate. Furthermore, significant fluorescence quenching is observed in protic polar solutions such as ethanol and methanol. Hydrogen-bonding interactions between the dye and the protic solvent molecules further accelerate the deactivation rate. In contrast, in a water solution, red light emission is achieved distinctly at 622 nm with a relatively large fluorescence quantum yield of 0.20. This red emission is related to the aggregation of the dye molecules grown in water. The kinetic analysis from the fluorescence rate constant and nonradiative rate constant indicates that the nonradiative deactivation channel is restricted in water. The formed aggregate, which was indicated by transmittance electron microscopy as a spherical aggregate morphology with a diameter of 3-4 nm, provides a less polar hydrophobic space inside the aggregate structure, by which hydrogen-bonding and the subsequent quenching are restricted, leading to the reduction of the nonradiative deactivation rate. PMID- 25502801 TI - Role of PGC-1alpha in sarcopenia: etiology and potential intervention - a mini review. AB - Sarcopenia is age-associated deterioration of muscle mass and function caused by a wide scope of physiological and pathological changes ranging from hormonal disorders to loss of subcellular homeostasis. Recent research indicates that mitochondrial dysregulation with advanced age plays a central role in the development of sarcopenia due to the multifactorial functions of this organelle in energy supply, redox regulation, crosstalk with nuclear gene expression and apoptosis. In order to fulfill these roles, it is crucial that mitochondria maintain their own structural and functional integrity through biogenesis, antioxidant defense, fusion/fission dynamics and autophagy (mitophagy). Unfortunately, mitochondria undergo age-associated changes that compromise the above-mentioned properties that eventually contribute to the development of sarcopenia. The peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) is involved in the transcriptional regulation of numerous nuclear and mitochondrial gene products participating in the cellular events that control muscle mass and function. Thus, it is not surprising that maintaining an optimal intracellular PGC-1alpha level and signaling activity is crucial in protecting the muscle from many degradative and destructive processes, such as proteolysis, oxidative damage, inflammation, uncontrolled autophagy and apoptosis. Physical exercise is a powerful stimulus to PGC-1alpha expression and signaling. Recent research indicates that PGC-1alpha-controlled mitochondrial biogenesis is not limited by old age per se and that elderly individuals can still benefit from increased muscular activity in terms of skeletal muscle health that ultimately contributes to quality of life in old age. PMID- 25502802 TI - Influence of MoO3(110) crystalline plane on its self-charging photoelectrochemical properties. AB - Nanocrystalline molybdenum oxide (alpha-MoO3) thin films with iso-oriented crystalline layers were synthesised by the anodisation of Mo foils. Upon band-gap excitation using light illumination, alpha-MoO3 generates excited electrons for reductive reactions and stores some of the excited electrons in its layered crystalline structure via alkali cation intercalation. These stored electrons can be subsequently discharged from alpha-MoO3 to allow reductive reactions to continue to occur under non-illuminated conditions. The modulation of water concentrations in the organic/aqueous anodisation electrolytes readily produces alpha-MoO3 crystals with high degree of (kk0) crystallographic orientation. Moreover, these (kk0)-oriented MoO3 crystals exhibit well-developed {hk0} and {0k0} crystal facets. In this paper, we show the benefits of producing alpha-MoO3 thin films with defined crystal facets and an iso-oriented layered structure for in situ storing of excited charges. alpha-MoO3 crystals with dominant (kk0) planes can achieve fast charging and a strong balance between charge release for immediate exploitation under illuminated conditions and charge storage for subsequent utilisation in dark. In comparison, alpha-MoO3 crystals with dominant (0k0) planes show a preference for excited charge storage. PMID- 25502803 TI - AMG 580: a novel small molecule phosphodiesterase 10A (PDE10A) positron emission tomography tracer. AB - Phosphodiesterase 10A (PDE10A) inhibitors have therapeutic potential for the treatment of psychiatric and neurologic disorders, such as schizophrenia and Huntington's disease. One of the key requirements for successful central nervous system drug development is to demonstrate target coverage of therapeutic candidates in brain for lead optimization in the drug discovery phase and for assisting dose selection in clinical development. Therefore, we identified AMG 580 [1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1 yl)-2-fluoropropan-1-one], a novel, selective small-molecule antagonist with subnanomolar affinity for rat, primate, and human PDE10A. We showed that AMG 580 is suitable as a tracer for lead optimization to determine target coverage by novel PDE10A inhibitors using triple-stage quadrupole liquid chromatography tandem mass spectrometry technology. [(3)H]AMG 580 bound with high affinity in a specific and saturable manner to both striatal homogenates and brain slices from rats, baboons, and human in vitro. Moreover, [(18)F]AMG 580 demonstrated prominent uptake by positron emission tomography in rats, suggesting that radiolabeled AMG 580 may be suitable for further development as a noninvasive radiotracer for target coverage measurements in clinical studies. These results indicate that AMG 580 is a potential imaging biomarker for mapping PDE10A distribution and ensuring target coverage by therapeutic PDE10A inhibitors in clinical studies. PMID- 25502804 TI - The regions within the N-terminus critical for human glucagon like peptide-1 receptor (hGLP-1R) cell surface expression. AB - The hGLP-1R is a target for the treatment of type 2 diabetes and belongs to the class B family of GPCRs. Like other class B GPCRs, the GLP-1R contains an N terminal signal peptide (SP) and undergoes N-linked glycosylation, which are important for its trafficking and maturation. This study analysed the role of the SP, the hydrophobic region after the SP (HRASP), glycosylation and the conserved residues within the N-terminus in GLP-1R trafficking. HGLP-1R targeted to the cell surface showed no SP, and the SP deleted mutant, but not the mutants defective in SP cleavage, showed cell surface expression, demonstrating the importance of SP cleavage for hGLP-1R cell surface expression. The N-terminal deletions of hGLP-1R revealed that the HRASP, not the SP, is essential for cell surface expression of GLP-1R. Further, inhibition of hGLP-1R glycosylation prevented cell surface expression of the receptor. Mutation of Trp(39), Tyr(69) and Tyr(88), which are required for agonist binding, in the GLP-1R abolished cell surface expression of the receptor independent of the SP cleavage or N-linked glycosylation. In conclusion, the N-terminus of hGLP-1R regulates receptor trafficking and maturation. Therefore this study provides insight into the role of hGLP-1R N-terminus on the receptor cell surface expression. PMID- 25502807 TI - The molecular mechanisms underlying the therapeutic resistance of cancer stem cells. AB - Chemo-resistance and radio-resistance are a major cause of recurrence and progression of many cancers, regardless of improvements in therapies. Since cancer stem cells (CSCs) were identified as a rare population with the abilities of self-renewal; tumor initiation; aberrant differentiation, which contributes to tumor heterogeneity; and resistance to anticancer therapeutics, they have been considered a major cause of tumor recurrence post-therapy and a primary therapeutic target in relapse prevention. A number of studies have demonstrated the mechanisms underlying chemo-resistance and radio-resistance of CSCs. In this review, we describe intrinsic and extrinsic factors underlying CSC chemo resistance and radio-resistance. The intrinsic factors regulate CSC signaling pathways involved in stem cell signaling, anti-apoptotic pathways, ABC transporter expression, and DNA damage repair systems. The extrinsic factors include the resistance mechanisms resulting from the interactions between CSCs and the microenvironment composed of vessels, fibroblasts, immune cells, extracellular matrix, and diverse soluble factors. Furthermore, we introduce diverse therapeutic agents used in experimental or clinical trials to target CSCs. Understanding how CSCs acquire resistance to anticancer therapeutics will give us opportunity to develop improved therapeutic approaches. PMID- 25502805 TI - A massively parallel pipeline to clone DNA variants and examine molecular phenotypes of human disease mutations. AB - Understanding the functional relevance of DNA variants is essential for all exome and genome sequencing projects. However, current mutagenesis cloning protocols require Sanger sequencing, and thus are prohibitively costly and labor-intensive. We describe a massively-parallel site-directed mutagenesis approach, "Clone-seq", leveraging next-generation sequencing to rapidly and cost-effectively generate a large number of mutant alleles. Using Clone-seq, we further develop a comparative interactome-scanning pipeline integrating high-throughput GFP, yeast two-hybrid (Y2H), and mass spectrometry assays to systematically evaluate the functional impact of mutations on protein stability and interactions. We use this pipeline to show that disease mutations on protein-protein interaction interfaces are significantly more likely than those away from interfaces to disrupt corresponding interactions. We also find that mutation pairs with similar molecular phenotypes in terms of both protein stability and interactions are significantly more likely to cause the same disease than those with different molecular phenotypes, validating the in vivo biological relevance of our high throughput GFP and Y2H assays, and indicating that both assays can be used to determine candidate disease mutations in the future. The general scheme of our experimental pipeline can be readily expanded to other types of interactome mapping methods to comprehensively evaluate the functional relevance of all DNA variants, including those in non-coding regions. PMID- 25502806 TI - Quantifying unruptured giant intracranial aneurysms by measuring diameter and volume--a comparative analysis of 69 cases. AB - BACKGROUND: Intracranial aneurysms (IA) are usually quantified according to their largest diameter. However, volumetry has recently been increasingly conducted as well, especially in giant intracranial aneurysms (GIAs). Since so far the true value of GIA volumetry is unknown, we designed a trial to examine correlations between GIA diameter and volume with special focus on clinical implications. METHODS: Magnetic resonance imaging of 69 unruptured GIAs in 66 patients was retrospectively evaluated. The largest diameter and volume were measured. Also, potential associations to the patients' clinical conditions were examined. RESULTS: Comparing GIA sizes of our patient cohort produced different results depending on whether GIA diameter or volume was measured. Measuring the diameter identified posterior circulation GIAs as the largest ones (39.2 mm, IQR 37.3 48.3), while measuring the volume found GIAs of the MCA to be the largest ones (12.3 cm(3), IQR 7.2-27.8). A correlation of GIA diameter and volume was only found in anterior circulation GIAs, which were predominantly saccular in shape, but not in those of the posterior circulation, of which most were fusiform. Neither GIA diameter nor GIA volume but only GIA location was associated with neurological deficits. CONCLUSION: Diameter and volume measurements are not interchangeable modes of GIA quantification. Our data suggest that the idea of distinguishing different sizes of GIA may be clinically less relevant than examining their location, shape or mass effect. PMID- 25502808 TI - Serum Lipids and Proliferative Diabetic Retinopathy and Macular Edema in Persons With Long-term Type 1 Diabetes Mellitus: The Wisconsin Epidemiologic Study of Diabetic Retinopathy. AB - IMPORTANCE: Total serum and high-density lipoprotein cholesterol have been considered risk factors for severe vascular outcomes in persons with type 1 diabetes mellitus. OBJECTIVE: To examine the long-term relationships between these 2 serum lipids and the incidence and prevalence of proliferative diabetic retinopathy and macular edema. DESIGN, SETTING, AND PARTICIPANTS: Nine-hundred three persons with younger-onset type 1 diabetes mellitus who participated in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. EXPOSURES: Serum total and high-density cholesterol and history of statin use during the course of 5 visits spanning approximately 30 years (April 10, 1984, to February 13, 2014). MAIN OUTCOMES AND MEASURES: Prevalence and incidence of proliferative diabetic retinopathy and macular edema. RESULTS: A modest association was found for higher levels of high-density lipoprotein cholesterol and decreased prevalence of proliferative diabetic retinopathy (odds ratio per 10 mg/dL, 0.87; 95% CI, 0.82 0.93), adjusting for duration of diabetes mellitus, glycosylated hemoglobin A1c, statin use, and end-stage renal disease. While adjusting for covariates, no associations of serum total or high-density lipoprotein cholesterol and incident proliferative diabetic retinopathy or macular edema, nor of statin use with decreased incidence of proliferative diabetic retinopathy or macular edema, were identified. CONCLUSIONS AND RELEVANCE: In the course of long-duration diabetes mellitus during a time of changing medical care, there appeared to be little effect of serum lipids or statins on the incidence of proliferative diabetic retinopathy and macular edema. PMID- 25502809 TI - Mechanism and consequences of the shift in cardiac arginine metabolism following ischaemia and reperfusion in rats. AB - Cardiac ischaemia and reperfusion leads to irreversible injury and subsequent tissue remodelling. Initial reperfusion seems to shift arginine metabolism from nitric oxide (NO) to polyamine formation. This may limit functional recovery at reperfusion. The hypothesis was tested whether ischaemia/reperfusion translates such a shift in arginine metabolism in a tumour necrosis factor (TNF)-alpha dependent way and renin-angiotensin system (RAS)-dependent way into a sustained effect. Both, the early post-ischaemic recovery and molecular adaptation to ischaemia/reperfusion were analysed in saline perfused rat hearts undergoing global no-flow ischaemia and reperfusion. Local TNF-alpha activation was blocked by inhibition of TNF-alpha sheddase ADAM17. To interfere with RAS captopril was administered. Arginase was inhibited by administration of Nor-NOHA. Long-term effects of ischemia/reperfusion on arginine metabolism were analysed in vivo in rats receiving an established ischaemia/reperfusion protocol in the closed chest mode. mRNA expression analysis indicated a shift in the arginine metabolism from NO formation to polyamine metabolism starting within 2 hours (h) of reperfusion and translated into protein expression within 24 h. Inhibition of the TNF-alpha pathway and captopril attenuated these delayed effects on post-ischaemic recovery. This shift in arginine metabolism was associated with functional impairment of hearts within 24 h. Inhibition of arginase but not that of TNF alpha and RAS pathways improved functional recovery immediately. However, no benefit was observed after four months. In conclusion, this study identified TNF alpha and RAS to be responsible for depressed cardiac function that occurred a few hours after reperfusion. PMID- 25502812 TI - Comparison of three current sets of electrocardiographic interpretation criteria for use in screening athletes. AB - BACKGROUND: An increasing number of sporting bodies report unacceptably high levels of false-positive ECGs when undertaking pre-participation cardiac screening. To address this issue, modified ECG interpretation criteria have become available for use within athletes. OBJECTIVE: This study assessed the accuracy of the new 2014 'Refined Criteria' against the 2013 Seattle Criteria and the 2010 European Society of Cardiology (ESC) recommendations in a cohort of Arabic, black and Caucasian athletes. METHODS: 2491 male athletes (1367 Arabic, 748 black and 376 Caucasian) undertook pre-participation screening including a 12 lead ECG, with further investigation(s) upon indication. RESULTS: Ten athletes (0.4%) were identified with cardiac pathology; seven with hypertrophic cardiomyopathy (HCM; five black and two Arabic) and three Arabs with Wolff Parkinson-White syndrome (WPW). All three ECG criteria were 100% sensitive identifying all cases of HCM and WPW. The 2014 Refined Criteria reduced (p<0.0001) the prevalence of an abnormal ECG to 5.3% vs 11.6% (Seattle Criteria) and 22.3% (2010 ESC recommendations). The 2014 Refined Criteria significantly (p<0.0001) improved specificity (94.0%) across all ethnicities compared with the Seattle Criteria (87.5%) and ESC recommendations (76.6%). Black athletes continue to present a higher prevalence (p<0.0001) of abnormal ECGs compared with Arabic and Caucasian athletes (10% vs 3.6% and 2.1%). CONCLUSIONS: The 2014 Refined Criteria for athlete ECG interpretation outperformed both the 2013 Seattle Criteria and the 2010 ESC recommendations by significantly reducing the number of false-positive ECGs in Arabic, black and Caucasian athletes while maintaining 100% sensitivity for serious cardiac pathologies. PMID- 25502813 TI - Association between mitral valve prolapse and open-angle glaucoma. AB - OBJECTIVE: Proteoglycans and glycosoaminoglycans play many roles in connective tissue formation, their accumulation in myxomatous tissues may influence the associated mechanical behaviour of the mitral valve, as well as the extracellular matrix of the eye. Open-angle glaucoma (OAG) and mitral valve prolapse (MVP) may share similar phathophysiology. We hypothesised that MVP increased the risk of developing glaucoma. METHODS: The research was a retrospective cohort study using a longitudinal health insurance database from the National Health Insurance programme. The database was a randomly sampled population of 1,073,891 followed for 13 years from 1996 to 2008. There were 21,677 subjects with MVP, and 86,708 subjects without MVP were propensity score matched and served as a comparison group. Cox proportional hazards analysis was performed and adjusted for several comorbidities to evaluate the adjusted HR for OAG in the MVP group. RESULTS: The incidence rate of OAG in patients in the non-MVP and MVP groups were 10.17 and 16.05 per 10,000 person-years, respectively. The adjusted HR for OAG in the MVP group was 1.88 (95% CI 1.58 to 2.23). A significantly elevated risk of OAG in patients with MVP was also identified in the four stratified age groups. The cumulative incidence of OAG was assessed by Kaplan-Meier analysis. The analysis revealed that the MVP group had a higher incidence of OAG than the comparison group during the follow-up period (p < 0.001). CONCLUSIONS: This population-based study demonstrated that pre-existing MVP is a significant predictor for the development of OAG, after adjusting for possible confounding factors. PMID- 25502811 TI - Patients infected with CRF07_BC have significantly lower viral loads than patients with HIV-1 subtype B: mechanism and impact on disease progression. AB - The circulating recombinant form (CRF) 07_BC is the most prevalent HIV-1 strain among injection drug users (IDUs) in Taiwan. It contains a 7 amino-acid deletion in its p6gag. We conducted a cohort study to compare viral loads and CD4 cell count changes between patients infected with subtype B and CRF07_BC and to elucidate its mechanism. Twenty-one patients infected with CRF07_BC and 59 patients with subtype B were selected from a cohort of 667 HIV-1/AIDS patients whom have been followed up for 3 years. Generalized estimated equation was used to analyze their clinical data and the results showed that patients infected with CRF07_BC had significantly lower viral loads (about 58,000 copies per ml less) than patients with subtype B infection (p = 0.002). The replicative capacity of nine CRF07_BC and four subtype B isolates were compared and the results showed that the former had significantly lower replicative capacity than the latter although all of them were CCR5- tropic and non-syncytium inducing viruses. An HIV 1-NL4-3 mutant virus which contains a 7 amino-acid deletion in p6gag (designated as 7d virus) was generated and its live cycle was investigated. The results showed that 7d virus had significantly lower replication capacity, poorer protease-mediated processing and viral proteins production. Electron microscopic examination of cells infected with wild-type or 7d virus demonstrated that the 7d virus had poorer and slower viral maturation processes: more viruses attached to the cell membrane and higher proportion of immature virions outside the cells. The interaction between p6gag and Alix protein was less efficient in cells infected with 7d virus. In conclusion, patients infected with CRF07_BC had significantly lower viral loads than patients infected with subtype B and it may due to the deletion of 7 amino acids which overlaps with Alix protein-binding domain of the p6gag. PMID- 25502814 TI - Anthropometric measures in cardiovascular disease prediction: comparison of laboratory-based versus non-laboratory-based model. AB - OBJECTIVE: Body mass index (BMI) has been used to simplify cardiovascular risk prediction models by substituting total cholesterol and high-density lipoprotein cholesterol. In the elderly, the ability of BMI as a predictor of cardiovascular disease (CVD) declines. We aimed to find the most predictive anthropometric measure for CVD risk to construct a non-laboratory-based model and to compare it with the model including laboratory measurements. METHODS: The study included 2675 women and 1902 men aged 55-79 years from the prospective population-based Rotterdam Study. We used Cox proportional hazard regression analysis to evaluate the association of BMI, waist circumference, waist-to-hip ratio and a body shape index (ABSI) with CVD, including coronary heart disease and stroke. The performance of the laboratory-based and non-laboratory-based models was evaluated by studying the discrimination, calibration, correlation and risk agreement. RESULTS: Among men, ABSI was the most informative measure associated with CVD, therefore ABSI was used to construct the non-laboratory-based model. Discrimination of the non-laboratory-based model was not different than laboratory-based model (c-statistic: 0.680-vs-0.683, p=0.71); both models were well calibrated (15.3% observed CVD risk vs 16.9% and 17.0% predicted CVD risks by the non-laboratory-based and laboratory-based models, respectively) and Spearman rank correlation and the agreement between non-laboratory-based and laboratory-based models were 0.89 and 91.7%, respectively. Among women, none of the anthropometric measures were independently associated with CVD. CONCLUSIONS: Among middle-aged and elderly where the ability of BMI to predict CVD declines, the non-laboratory-based model, based on ABSI, could predict CVD risk as accurately as the laboratory-based model among men. PMID- 25502815 TI - Considerations on the poor discriminatory power of the FRANCE-2 risk score: Authors' reply. PMID- 25502816 TI - A peculiar mutation spectrum emerging from young peruvian patients with hepatocellular carcinoma. AB - Hepatocellular carcinoma usually afflicts individuals in their later years following longstanding liver disease. In Peru, hepatocellular carcinoma exists in a unique clinical presentation, which affects patients around age 25 with a normal, healthy liver. In order to deepen our understanding of the molecular processes ongoing in Peruvian liver tumors, mutation spectrum analysis was carried out on hepatocellular carcinomas from 80 Peruvian patients. Sequencing analysis focused on nine genes typically altered during liver carcinogenesis, i.e. ARID2, AXIN1, BRAF, CTNNB1, NFE2L2, H/K/N-RAS, and TP53. We also assessed the transcription level of factors involved in the control of the alpha fetoprotein expression and the Hippo signaling pathway that controls contact inhibition in metazoans. The mutation spectrum of Peruvian patients was unique with a major class of alterations represented by Insertions/Deletions. There were no changes at hepatocellular carcinoma-associated mutation hotspots in more than half of the specimens analyzed. Furthermore, our findings support the theory of a consistent collapse in the Hippo axis, as well as an expression of the stemness factor NANOG in high alpha-fetoprotein-expressing hepatocellular carcinomas. These results confirm the specificity of Peruvian hepatocellular carcinoma at the molecular genetic level. The present study emphasizes the necessity to widen cancer research to include historically neglected patients from South America, and more broadly the Global South, where cancer genetics and tumor presentation are divergent from canonical neoplasms. PMID- 25502817 TI - HGV&TB: a comprehensive online resource on human genes and genetic variants associated with tuberculosis. AB - Tuberculosis (TB) is an infectious disease caused by fastidious pathogen Mycobacterium tuberculosis. TB has emerged as one of the major causes of mortality in the developing world. Role of host genetic factors that modulate disease susceptibility have not been studied widely. Recent studies have reported few genetic loci that provide impetus to this area of research. The availability of tools has enabled genome-wide scans for disease susceptibility loci associated with infectious diseases. Till now, information on human genetic variations and their associated genes that modulate TB susceptibility have not been systematically compiled. In this work, we have created a resource: HGV&TB, which hosts genetic variations reported to be associated with TB susceptibility in humans. It currently houses information on 307 variations in 98 genes. In total, 101 of these variations are exonic, whereas 78 fall in intronic regions. We also analysed the pathogenicity of the genetic variations, their phenotypic consequences and ethnic origin. Using various computational analyses, 30 variations of the 101 exonic variations were predicted to be pathogenic. The resource is freely available at http://genome.igib.res.in/hgvtb/index.html. Using integrative analysis, we have shown that the disease associated variants are selectively enriched in the immune signalling pathways which are crucial in the pathophysiology of TB. Database URL: http://genome.igib.res.in/hgvtb/index.html PMID- 25502818 TI - ADARs and the Balance Game between Virus Infection and Innate Immune Cell Response. AB - All viruses that have dsRNA structures at any stages of their life cycle may potentially undergo RNA editing events mediated by the ADAR enzymes. Indeed, an increasing number of studies that describe A-to-I sequence changes in viral genomes and/or transcripts, consistent with ADAR deaminase activity, are reported. These modifications can appear either as hyperediting during persistent viral infections or as specific RNA editing events in viral dsRNAs. It is now well established that ADAR enzymes can affect viruses and viral interaction with the host cell in both an editing-dependent and -independent manner, with ADARs acting as pro- or anti-viral factors. Despite the discovery of editing events on viral RNAs dates back to thirty years ago, the biological consequences of A-to-I changes during viral infection is still far to be completely elucidated. In this review, past and recent studies on the importance of ADAR enzymes on several viruses will be examined. PMID- 25502819 TI - Instability of misoprostol tablets stored outside the blister: a potential serious concern for clinical outcome in medical abortion. AB - INTRODUCTION: Misoprostol (Cytotec) is recognised to be effective for many gynaecological indications including termination of pregnancy, management of miscarriage and postpartum haemorrhage. Although not licensed for such indications, it has been used for these purposes by millions of women throughout the world. Misoprostol tablets are most often packaged as multiple tablets within an aluminium strip, each within an individual alveolus. When an alveolus is opened, tablets will be exposed to atmospheric conditions. OBJECTIVE: To compare the pharmaco technical characteristics (weight, friability), water content, misoprostol content and decomposition product content (type A misoprostol, type B misoprostol and 8-epi misoprostol) of misoprostol tablets Cytotec (Pfizer) exposed to air for periods of 1 hour to 720 hours (30 days), to those of identical non exposed tablets. METHODS: Four hundred and twenty (420) tablets of Cytotec (Pfizer) were removed from their alveoli blister and stored at 25 degrees C/60% relative humidity. Water content, and misoprostol degradation products were assayed in tablets exposed from 1 to 720 hours (30 days). Comparison was made with control tablets (N=60) from the same batch stored in non-damaged blisters. Statistical analyses were carried out using Fisher's exact test for small sample sizes. RESULTS: By 48 hours, exposed tablets demonstrated increased weight (+4.5%), friability (+1 300%), and water content (+80%) compared to controls. Exposed tablets also exhibited a decrease in Cytotec active ingredient dosage ( 5.1% after 48 hours) and an increase in the inactive degradation products (+25% for type B, +50% for type A and +11% for 8-epi misoprostol after 48 hours) compared to controls. CONCLUSION: Exposure of Cytotec tablets to 'typical' European levels of air and humidity results in significant time-dependent changes in physical and biological composition that could impact adversely upon clinical efficacy. Health professionals should be made aware of the degradation of misoprostol with inappropriate storage of misoprostol tablets. PMID- 25502820 TI - HIV and hepatitis C mortality in Massachusetts, 2002-2011: spatial cluster and trend analysis of HIV and HCV using multiple cause of death. AB - BACKGROUND: Infectious diseases, while associated with a much smaller proportion of deaths than they were 50 years ago, still play a significant role in mortality across the state of Massachusetts. Most analysis of infectious disease mortality in the state only take into account the underlying cause of death, rather than contributing causes of death, which may not capture the full extent of mortality trends for infectious diseases such as HIV and the Hepatitis C virus (HCV). METHODS: In this study we sought to evaluate current trends in infectious disease mortality across the state using a multiple cause of death methodology. We performed a mortality trend analysis, identified spatial clusters of disease using a 5-step geoprocessing approach and examined spatial-temporal clustering trends in infectious disease mortality in Massachusetts from 2002-2011, with a focus on HIV/AIDS and HCV. RESULTS: Significant clusters of high infectious disease mortality in space and time throughout the state were detected through both spatial and space time cluster analysis. The most significant clusters occurred in Springfield, Worcester, South Boston, the Merrimack Valley, and New Bedford with other smaller clusters detected across the state. Multiple cause of death mortality rates were much higher than underlying cause mortality alone, and significant disparities existed across race and age groups. CONCLUSIONS: We found that our multi-method analyses, which focused on contributing causes of death, were more robust than analyses that focused on underlying cause of death alone. Our results may be used to inform public health resource allocation for infectious disease prevention and treatment programs, provide novel insight into the current state of infectious disease mortality throughout the state, and benefited from approaches that may more accurately document mortality trends. PMID- 25502821 TI - Overexpression of afsR and Optimization of Metal Chloride to Improve Lomofungin Production in Streptomyces lomondensis S015. AB - As a global regulatory gene in Streptomyces, afsR can activate the biosynthesis of many secondary metabolites. The effect of afsR on the biosynthesis of a phenazine metabolite, lomofungin, was studied in Streptomyces lomondensis S015. There was a 2.5-fold increase of lomofungin production in the afsR-overexpressing strain of S. lomondensis S015 N1 compared with the wild-type strain. Meanwhile, the transcription levels of afsR and two important genes involved in the biosynthesis of lomofungin (i.e., phzC and phzE) were significantly upregulated in S. lomondensis S015 N1. The optimization of metal chlorides was investigated to further increase the production of lomofungin in the afsR-overexpressing strain. The addition of different metal chlorides to S. lomondensis S015 N1 cultivations showed that CaCl2, FeCl2, and MnCl2 led to an increase in lomofungin biosynthesis. The optimum concentrations of these metal chlorides were obtained using response surface methodology. CaCl2 (0.04 mM), FeCl2 (0.33 mM), and MnCl2 (0.38 mM) gave a maximum lomofungin production titer of 318.0 +/- 10.7 mg/l, which was a 4.1-fold increase compared with that of S. lomondensis S015 N1 without the addition of a metal chloride. This work demonstrates that the biosynthesis of phenazine metabolites can be induced by afsR. The results also indicate that metal chlorides addition might be a simple and useful strategy for improving the production of other phenazine metabolites in Streptomyces. PMID- 25502822 TI - In vivo hair growth promotion effects of ultra-high molecular weight poly-gamma glutamic acid from Bacillus subtilis (Chungkookjang). AB - We investigated the effect of ultra-high molecular weight poly-gamma-glutamic acid (UHMW gamma-PGA) on hair loss in vitro and in vivo. 5-Alpha reductase is an enzyme that metabolizes the male hormone testosterone into dihydrotestosterone. By performing an in vitro experiment to analyze the inhibitory effects of UHMW gamma-PGA on 5-alpha reductase activity, we determined that UHMW gamma-PGA did in fact inhibit 5-alpha reductase activity, indicating the use of UHMW gamma-PGA as a potential 5-alpha reductase inhibitor in the treatment of men with androgenetic alopecia. To evaluate the promotion of hair growth in vivo, we topically applied UHMW gamma-PGA and minoxidil on the shaved dorsal skin of telogenic C57BL/6 mice for 4 weeks. At 4 weeks, the groups treated with UHMW gamma-PGA showed hair growth on more than 50% of the shaved skin, whereas the control group showed less hair growth. To investigate the progression of hair follicles in the hair cycle, hematoxylin and eosin staining was performed. Histological observations revealed that the appearance of hair follicles was earlier in the UHMW gamma-PGA-treated group than in the control group. The number of hair follicles on the relative area of shaved skin in the UHMW gamma-PGA-treated group was higher than that observed on the shaved skin in the control group. These results indicate that UHMW gamma-PGA can promote hair growth by effectively inducing the anagen phase in telogenic C57BL/6 mice. PMID- 25502823 TI - In silico metagenomes mining to discover novel esterases with industrial application by sequential search strategies. AB - We present here an in silico search of fungal sterol-esterase/lipase and bacterial depolymerase sequences from environmental metagenomes. Both enzyme types contain the alpha/beta-hydrolase protein fold. Analysis of DNA conserved motifs, protein homology search, phylogenetic analysis, and protein 3D modeling have been used, and the efficiency of these screening strategies is discussed. The presence of bacterial genes in the metagenomes was higher than those from fungi, and the sequencing depth of the metagenomes seemed to be crucial to allow finding enough diversity of enzyme sequences. As a result, a novel putative PHA depolymerase is described. PMID- 25502824 TI - A composite dermal filler comprising cross-linked hyaluronic acid and human collagen for tissue reconstruction. AB - In this study, we developed a composite filler comprising cross-linked hyaluronic acid (HA) and human collagen (COL) derived from the human umbilical cord with the aim of improving its biocompatibility and longevity compared with commercially available fillers. After HA/ COL composite fillers were made in two different ratios (10:1 and 5:1), the physical properties of the fillers were evaluated. The interior morphologies and in vivo weight change of these hydrogels were also characterized at 1-16 weeks after injection into mice. To evaluate their biocompatibility and durability in vivo, we injected the composite fillers into nude mice subcutaneously. The variations of injected gel weight were measured and compared with the commercial dermal fillers (Restylane and TheraFill). The composites showed improved or similar physical properties (complex viscosity of 19-22 * 10(5) cP, and injection force of 10- 12 N) over the commercial dermal fillers. Sixteen weeks following the injection, the ratio of remaining composite filler weight to initial weight (75.5 +/- 16.9%; 10:1) was shown to be greater than that of the commercial fillers (43.2 +/- 8.1%, Restylane; 12.3 +/- 5.3%, TheraFill). In addition, immunohistochemical analysis with angiogenesis-related markers such as isolectin and vWF revealed newly formed blood vessels and cellular influx into the composite filler, which were not observed in the other fillers. These results clearly suggest that the HA/COL composite filler is a superior candidate for soft tissue reconstruction. The filler we developed may be a suitable candidate as an injectable dermal filler for tissue augmentation in humans. PMID- 25502825 TI - Alpha-glucosidase inhibitor isolated from coffee. AB - The potent alpha-glucosidase inhibitor (compound I) was isolated from coffee brews by the activity-based fractionation and identified as a beta-carboline alkaloid norharman (9H-pyrido[ 3.4-b]indole) on the basis of mass spectroscopy and nuclear magnetic resonance spectra ((1)H NMR, (13)C NMR, and COSY). The norharman showed a potent inhibition against alpha-glucosidase enzyme in a concentration dependent manner with an IC50 value of 0.27 mM for maltase and 0.41 mM for sucrase, respectively. A Lineweaver-Burk plot revealed that norharman inhibited alpha-glucosidase enzyme uncompetitively, with a Ki value of 0.13 mM. PMID- 25502826 TI - Synergistic effect of reductase and keratinase for facile synthesis of protein coated gold nanoparticles. AB - We have synthesized gold nanoparticles (GNPs) using chicken feathers (poultry waste) and Bacillus subtilis RSE163. Disulfide reductase and keratinase produced by Bacillus subtilis during the degradation of chicken feather has been used to reduce Au(3+) from HAuCl4 precursor to produce gold nanoparticles. The synthesized biogenic GNPs were characterized by UV-visible spectroscopy, transmission electron microscopy (TEM), and zeta potential measurements. Fourier transform infrared (FTIR) spectroscopy indicated the presence of protein capping on synthesized GNPs, imparting multifunctionality to the GNP surface. Furthermore, the nontoxic nature of biogenic GNPs was insured by interaction with Escherichia coli (ATCC11103), where TEM images and enhancement of growth rate of E. coli in log phase signified their nontoxic nature. The results indicate that the synthesis of biocompatible GNPs using poultry waste may find potential applications in drug delivery and sensing. PMID- 25502827 TI - Effects of 1,7-substituted methylxanthine derivatives on LPS-stimulated expression of cytokines and chemokines in Raw 264.7 and HK-2 cells. AB - Chronic kidney diseases are based on uncontrolled immunological and inflammatory responses to pathophysiological renal circumstances such as glomerulonephritis, which is caused by immunological mechanisms of glomerular inflammation with increased production of renal pro-inflammatory cytokines. Pentoxifylline (PTX) exhibits anti-inflammatory properties by inhibiting cytokine and chemokine production through aggregation of erythrocytes and thrombocytes. We synthesized a series of 1,7-substituted methylxanthine derivatives by the Traube purine reaction, and the formation of purine ring was completed through nitrosation, a reduction of the nitroso to the amine by catalytic hydrogenation as derivatives of PTX. Then we studied biological activities such as renal anti-inflammatory effects of the synthesized compounds in the production of cytokines such as nitric oxide (NO), interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) and of chemokines such as monocyte chemoattractant protein-1 and IL-8 in Raw 264.7 and HK-2 cells. Renal antiinflammatory activities of this novel series of N-1 and N-7-substituted methylxanthine showed that the N-7 methyl-group substituted analogs (S7b) showed selective 61% and 77% inhibition of the production of NO and IL-8. The other replacement of the N-1-(CH2)4COCH3 group, as in the case of compound S6c, also showed an effective 50% and 77% inhibition of TNF-alpha and IL-8 production in LPS-stimulated Raw 264.7 and HK-2 cells. PMID- 25502828 TI - Impact of Solvent pH on Direct Immobilization of Lysosome-Related Cell Organelle Extracts on TiO2 for Melanin Treatment. AB - Techniques for immobilizing effective enzymes on nanoparticles for stabilization of the activity of free enzymes have been developing as a pharmaceutical field. In this study, we examined the effect of three different pH conditions of phosphate buffer, as a dissolving solvent for lysosomal enzymes, on the direct immobilization of lysosomal enzymes extracted from Hen's egg white and Saccharomyces cerevisiae. Titanium(IV) oxide (TiO2) nanoparticles, which are extensively used in many research fields, were used in this study. The lysosomal enzymes immobilized on TiO2 under each pH condition were evaluated to maintain the specific activity of lysosomal enzymes, so that we can determine the degree of melanin treatment in lysosomal enzymes immobilized on TiO2. We found that the immobilization efficiency and melanin treatment activity in both lysosomal enzymes extracted from Hen's egg white and S. cerevisiae were the highest in an acidic condition of phosphate buffer (pH 4). However, the immobilization efficiency and melanin treatment activity were inversely proportional to the increase in pH under alkaline conditions. In addition, enhanced immobilization efficiency was shown in TiO2 pretreated with a divalent, positively charged ion, Ca(2+), and the melanin treatment activity of immobilized lysosomal enzymes on TiO2 pretreated with Ca(2+) was also increased. Therefore, this result suggests that the immobilization efficiency and melanin treatment activity of lysosomal enzymes can be enhanced according to the pH conditions of the dissolving solvent. PMID- 25502829 TI - Symptoms and function in patients with articular cartilage lesions in 1,000 knee arthroscopies. AB - PURPOSE: Focal chondral lesions of the knee are commonly occurring. A lot is known about their frequency, size and localisation in arthroscopic series, but less about the symptoms they elicit and little about how the arthroscopic findings and symptoms correlate. The purposes of the present study included to investigate the relationship between articular cartilage lesion factors and patient factors, and to compare the symptoms and function of cartilage lesion patients to those of patients with a deficient ACL. METHODS: A prospective registration was conducted of preoperative data including Lysholm knee score and perioperative findings in 1,000 consecutive patients undergoing an arthroscopic procedure of the knee-including microfracture of articular cartilage defects and ACL reconstructions. RESULTS: Chondral or osteochondral lesions were found in 57 % of the arthroscopies. The mean Lysholm score in this subgroup was 55. The mean Lysholm score was significantly lower in women (50, SD 19) compared to men (59, SD 18, p < 0.001). Among the chondral lesion factors, only kissing (vs. non kissing) lesions and multiple (vs. single) lesions influenced symptoms and function to a more than negligible degree. Microfracture in one or two articular cartilage defects was performed in 187 patients. The microfracture group had a significant lower mean Lysholm score (54, SD 18) than a group of patients (N = 71) undergoing ACL reconstruction group (67, SD 17, p < 0.001). CONCLUSION: The study confirms that articular cartilage lesions are both common and cumbersome. Women seem to have more problems than men, whereas chondral lesion factors-such as localisation and size-seem to influence symptoms and function to a small degree. These aspects should be addressed when designing outcome studies, and should also be of interest to the orthopaedic surgeon-in the day-by-day clinical work. When treating these patients, our prime focus need to be on knee function rather than the cartilage defect as the relationship between the latter and the former is unclear. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 25502830 TI - Safety of posterior ankle arthroscopy portals in different ankle positions: a cadaveric study. AB - PURPOSE: To investigate anatomic relation of standard and coaxial ankle arthroscopy portals with neurovascular structures during different degrees of ankle motion. METHODS: Twenty posterior ankles of ten fresh cadavers were assessed. Posteromedial, posterolateral and coaxial (transmalleolar) portals were created using 4-mm Steinmann pins in accordance with the defined technique in neutral position. The ankles were then dissected, and the distance from the portals to the peroneal tendons, short saphenous vein and sural nerve was measured laterally and that from the tibial nerve, flexor hallucis longus tendon and posterior tibial artery was measured medially. Changes in the distance between these structures were noted in neutral positions, 15 degrees of dorsiflexion and 30 degrees plantar flexion. RESULTS: In the neutral position, the mean distance of the conventional posterolateral portal to the sural nerve was 6 mm (SD 2.9, range 2.7-14.5). The mean distance of the posterolateral coaxial portal to the peroneal tendon was 1.6 mm (SD 0.55, range 1.1-2.9). The mean distance of the posteromedial portal to the FHL was 2.11 mm (SD 1.1, range 0 4.7). The mean distance of the posteromedial coaxial portal to the posterior tibial artery was 6 mm (SD 1.4, range 3.9-9.5). Although not statistically significant, the distance between the portal and neurovascular structures increased in dorsiflexion for the portals placed posteriorly to the neurovascular structures and increased in plantar flexion for the portals placed anterior to the neurovascular structures. CONCLUSIONS: In comparison with the portals made in the neutral position, the distance between neurovascular structures and portals changes with portal placement in plantar flexion and dorsiflexion. In clinical practice, therefore, it might be safer to place the posteromedial-posterolateral portals in dorsiflexion and posterolateral-posteromedial coaxial portals in plantar flexion. The tibial nerve is closer to the posteromedial coaxial in dorsiflexion and could be in danger if making this portal with the foot in this position. PMID- 25502831 TI - Photodynamic therapy in root canals contaminated with Enterococcus faecalis using curcumin as photosensitizer. AB - The aim of the study was to evaluate the photodynamic therapy (PDT) effect on root canals contaminated with Enterococcus faecalis using a light emitting diode (LED) light and a curcumin solution (CUR) as photosensitizer (PS). Eighty root canals from uniradicular human teeth were prepared with Protaper Universal rotary system and contaminated with E. faecalis for 21 days. They were divided as: GIa PDT (CUR, pre-irradiation for 5 + 5 min of irradiation); GIb-PDT (CUR, pre irradiation for 5 + 10 min of irradiation); GIIa-(CUR, pre-irradiation for 5 + 5 min without irradiation); GIIb-(CUR pre-irradiation for 5 + 10 min of irradiation); GIIIa-(physiological solution and irradiation for 5 min); and GIIIb (physiological solution and irradiation for 10 min); positive and negative control groups. Collections from root canals were made at time intervals of 21 days after contamination, immediately after treatment, and 7 days after treatment, and submitted to colony forming units per milliter (CFU mL(-1)) counts. The data were submitted to ANOVA and Tukey multiple comparison tests, at a level of significance of 5 %. In the immediate post-treatment collection, group GIa showed greater bacterial reduction in comparison with GIIa, GIIb, GIIIa, GIIIb, and positive control (P < 0.05). At 7 days post-treatment, GIa showed significant bacterial reduction only in comparison with GIIIa (P < 0.05). Curcumin as sensitizer was effective by 5 min LED irradiation but not by 10 min irradiation PDT using LED light, and curcumin as PS was not effective in eliminating E. faecalis. No difference was observed for periods of irradiation. PMID- 25502835 TI - A fully atomistic computer simulation study of cold denaturation of a beta hairpin. AB - Cold denaturation is a fundamental phenomenon in aqueous solutions where the native structure of proteins disrupts on cooling. Understanding this process in molecular details can provide a new insight into the detailed natures of hydrophobic forces governing the stability of proteins in water. We show that the cold-denaturation-like phenomenon can be directly observed at low temperatures using a fully atomistic molecular dynamics simulation method. Using a highly optimized protein force field in conjunction with three different explicit water models, a replica exchange molecular dynamics simulation scheme at constant pressures allows for the computation of the melting profile of an experimentally well-characterized beta-hairpin peptide. For all three water models tested, the simulated melting profiles are indicative of possible cold denaturation. From the analysis of simulation ensembles, we find that the most probable cold-denatured structure is structurally compact, with its hydrogen bonds and native hydrophobic packing substantially disrupted. PMID- 25502834 TI - TM6SF2 as a genetic risk factor for fibrosis. PMID- 25502833 TI - Intravitreal ranibizumab versus isovolemic hemodilution in the treatment of macular edema secondary to central retinal vein occlusion: twelve-month results of a prospective, randomized, multicenter trial. AB - PURPOSE: This is a prospective, randomized, multicenter, investigator-initiated trial to evaluate the 12-month effectiveness of isovolemic hemodilution (IH) with prompt versus deferred intravitreal injections (IVI) of ranibizumab 0.5 mg for the treatment of macular edema secondary to early central retinal vein occlusion (CRVO). METHODS: Eyes with macular edema due to CRVO having occurred not more than 8 weeks previously received either monthly ranibizumab IVI in combination with IH (group I, n = 28) or IH alone (group II, n = 30). From month 2 to 12, the patients in both groups could be treated with monthly intravitreal ranibizumab. The main outcome variables were gain of visual acuity and the course of central retinal thickness as measured with optical coherence tomography. RESULTS: At 12 months, eyes in group I on average gained +28.1 (+/-19.3) letters compared to +25.2 (+/-20.9) letters in group II (p = 0.326). This result was achieved with significantly fewer injections in group II. Additionally, 30% of the eyes in group II did not need ranibizumab IVI during the 12 months of the trial. CONCLUSION: Ranibizumab IVI in addition to IH proved to be highly effective in increasing visual acuity and reducing macular edema secondary to CRVO. Initial IH in early CRVO may be a first treatment option in patients anxious about IVI. PMID- 25502836 TI - Katoite under pressure: an ab initio investigation of its structural, elastic and vibrational properties sheds light on the phase transition. AB - The evolution under pressures up to 65 GPa of structural, elastic and vibrational properties of the katoite hydrogarnet, Ca3Al2(OH)12, is investigated with an ab initio simulation performed at the B3LYP level of theory, by using all-electron basis sets with the Crystal periodic program. The high-symmetry Ia3d phase of katoite, stable under ambient conditions, is shown to be destabilized, as pressure increases, by interactions involving hydrogen atoms and their neighbors which weaken the hydrogen bonding network of the structure. The corresponding thermodynamical instability is revealed by anomalous deviations from regularity of its elastic constants and by numerous imaginary phonon frequencies, up to 50 GPa. Interestingly, as pressure is further increased above 50 GPa, the Ia3d structure is shown to become stable again (all positive phonon frequencies and regular elastic constants). However, present calculations suggest that, above about 15 GPa and up to at least 65 GPa, a phase of I4[combining macron]3d symmetry (a non-centrosymmetric subgroup of Ia3d) becomes more stable than the Ia3d one, being characterized by strengthened hydrogen bonds. At low-pressures (between about 5 GPa and 15 GPa), both phases show some instabilities (more so for I4[combining macron]3d than for Ia3d), thus suggesting either the existence of a third phase or a possible phase transition of second order. PMID- 25502832 TI - The evolution of nitric oxide signalling in vertebrate blood vessels. AB - Nitric oxide is one of the most important signalling molecules involved in the regulation of physiological function. It first came to prominence when it was discovered that the vascular endothelium of mammals synthesises and releases nitric oxide (NO) to mediate a potent vasodilation. Subsequently, it was shown that NO is synthesised in the endothelium by a specific isoform of nitric oxide synthase (NOS) called NOS3. Following this discovery, it was assumed that an endothelial NO/NOS3 system would be present in all vertebrate blood vessels. This review will discuss the latest genomic, anatomical and physiological evidence which demonstrates that an endothelial NO/NOS3 signalling is not ubiquitous in non-mammalian vertebrates, and that there have been key evolutionary steps that have led to the endothelial NO signalling system being a regulatory system found only in reptiles, birds and mammals. Furthermore, the emerging role of nitrite as an endocrine source of NO for vascular regulation is discussed. PMID- 25502839 TI - A meta-analysis of IL-13 polymorphisms and pediatric asthma risk. AB - BACKGROUND: IL13-1112C/T and +2044A/G polymorphisms have been reported to be correlated with pediatric asthma susceptibility, but study results were still debatable. Thus, a meta-analysis was conducted. MATERIAL/METHODS: PubMed and EMBASE databases were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to calculate the strength of association in the random-effects model or fixed-effects model. RESULTS: Fourteen case-control studies with 4710 asthma cases and 6086 controls were included in this meta-analysis. IL13-1112C/T and +2044A/G polymorphisms were significantly associated with an increased risk of pediatric asthma (OR=1.14, 95% CI 1.01-1.28, P=0.04, I2=0%; OR=1.20, 95% CI 1.09-1.32, P<0.01, I2=0%), respectively. In the subgroup analysis by ethnicity, IL13-1112C/T polymorphism was significantly associated with pediatric asthma risk in whites (OR=1.29, 95% CI 1.02-1.63, P=0.03, I2=16%). IL13 +2044A/G polymorphism was significantly associated with pediatric asthma risk in Asians (OR=1.21, 95% CI 1.10-1.34, P<0.01, I2=24%). CONCLUSIONS: The results of this meta-analysis suggest that IL13-1112C/T and +2044A/G polymorphisms contribute to the development of pediatric asthma. PMID- 25502840 TI - Acute macular neuroretinopathy misdiagnosed as optic neuritis. AB - This study aims to report a case of acute macular neuroretinopathy (AMN) misdiagnosed as optic neuritis. The methods include review of the clinical, photographic, angiographic, visual field, infrared imaging, and optical coherence tomography records of a patient with AMN. A 30-year-old female who was initially diagnosed with optic neuritis and at first was treated with systemic corticosteroid because of this misdiagnosis. She was admitted with no decrease in her complaint of central scotoma in both eyes. Her visual acuities were 20/20 and fundoscopy showed reddish brownish pigment changes in the macula of both eyes. Infrared (IR) imaging disclosed bilateral hyporeflective lesions, optical coherence tomography revealed a disrupted inner segment-outer segment junction of the right eye, and visual field assessment showed central scotomas in both eyes. Three years later, fundus examination of the hyporeflective lesions by IR imaging revealed that the lesions had decreased and were only slightly perceptible. This rare case is presented to focus the attention of clinicians and to emphasize the importance of careful ophthalmic examination and imaging techniques. PMID- 25502837 TI - PDGFRalpha and beta play critical roles in mediating Foxq1-driven breast cancer stemness and chemoresistance. AB - Many epithelial-mesenchymal transition (EMT)-promoting transcription factors have been implicated in tumorigenesis and metastasis as well as chemoresistance of cancer. However, the underlying mechanisms mediating these processes are unclear. Here, we report that Foxq1, a forkhead box-containing transcription factor and EMT-inducing gene, promotes stemness traits and chemoresistance in mammary epithelial cells. Using an expression profiling assay, we identified Twist1, Zeb2, and PDGFRalpha and beta as Foxq1 downstream targets. We further show that PDGFRalpha and beta can be directly regulated by Foxq1 or indirectly regulated through the Foxq1/Twist1 axis. Knockdown of both PDGFRalpha and beta results in more significant effects on reversing Foxq1-promoted oncogenesis in vitro and in vivo than knockdown of either PDGFRalpha or beta alone. In addition, PDGFRbeta is a more potent mediator of Foxq1-promoted stemness traits than PDGFRalpha. Finally, pharmacologic inhibition or gene silencing of PDGFRs sensitizes mammary epithelial cells to chemotherapeutic agents in vitro and in vivo. These findings collectively implicate PDGFRs as critical mediators of breast cancer oncogenesis and chemoresistance driven by Foxq1, with potential implications for developing novel therapeutic combinations to treat breast cancer. PMID- 25502841 TI - A Phase IIa, randomized, double-blind study of remimazolam (CNS 7056) versus midazolam for sedation in upper gastrointestinal endoscopy. AB - BACKGROUND: This exploratory study was the first study of remimazolam in patients to assess the safety and efficacy of different single doses for procedural sedation. METHODS: Patients scheduled to undergo a diagnostic upper gastrointestinal endoscopy were randomized to receive 1 of 3 doses of remimazolam or midazolam (25 per group) in a double-blind manner. After a single dose of study drug to achieve sedation, patients underwent gastroscopy. We assessed the success of the procedure, sedation levels, recovery from sedation, and safety. RESULTS: A single dose of remimazolam resulted in a successful procedure in 32%, 56%, and 64% of patients in the low (0.10), middle (0.15), and high (0.20 mg/kg) dose groups compared with 44% of patients in the midazolam (0.075 mg/kg) dose group. The onset of sedation was 1.5 to 2.5 minutes in the remimazolam dose groups compared with 5 minutes for midazolam. Because this was a single administration study, sedation could be maintained for as long as necessary to complete the procedure, using rescue midazolam or propofol. Recovery from sedation was rapid for all treatment groups but was influenced by the choice of rescue medication. There were no obvious differences in the safety profiles of remimazolam and midazolam. CONCLUSIONS: This exploratory dose-finding study showed that a single administration of remimazolam (0.10-0.20 mg/kg) was capable of inducing rapid sedation with a quick recovery profile in patients undergoing a diagnostic upper gastrointestinal endoscopy. The safety profile was favorable and appeared to be similar to that of midazolam, warranting further development of this short-acting compound. PMID- 25502838 TI - Host miR155 promotes tumor growth through a myeloid-derived suppressor cell dependent mechanism. AB - miR155 is a regulator of immune cell development and function that is generally thought to be immunostimulatory. However, we report here that genetic ablation of miR155 renders mice resistant to chemical carcinogenesis and the growth of several transplanted tumors, suggesting that miR155 functions in immunosuppression and tumor promotion. Host miR155 deficiency promoted overall antitumor immunity despite the finding of defective responses of miR155-deficient dendritic cells and antitumor T cells. Further analysis of immune cell compartments revealed that miR155 regulated the accumulation of functional myeloid-derived suppressive cells (MDSC) in the tumor microenvironment. Specifically, miR155 mediated MDSC suppressor activity through at least two mechanisms, including SOCS1 repression and a reduced ability to license the generation of CD4(+)Foxp3(+) regulatory T cells. Importantly, we demonstrated that miR155 expression was required for MDSC to facilitate tumor growth. Thus, our results revealed a contextual function for miR155 in antitumor immunity, with a role in MDSC support that appears to dominate in tumor-bearing hosts. Overall, the balance of these cellular effects appears to be a root determinant of whether miR155 promotes or inhibits tumor growth. PMID- 25502842 TI - The effects of exogenous surfactant treatment in a murine model of two-hit lung injury. AB - BACKGROUND: Because pulmonary endogenous surfactant is altered during acute respiratory distress syndrome, surfactant replacement may improve clinical outcomes. However, trials of surfactant use have had mixed results. We designed this animal model of unilateral (right) lung injury to explore the effect of exogenous surfactant administered to the injured lung on inflammation in the injured and noninjured lung. METHODS: Mice underwent hydrochloric acid instillation (1.5 mL/kg) into the right bronchus and prolonged (7 hours) mechanical ventilation (25 mL/kg). After 3 hours, mice were treated with 1 mL/kg exogenous surfactant (Curosurf(r)) (surf group) or sterile saline (NaCl 0.9%) (vehicle group) in the injured (right) lung or did not receive any treatment (hydrochloric acid, ventilator-induced lung injury). Gas exchange, lung compliance, and bronchoalveolar inflammation (cells, albumin, and cytokines) were evaluated. After a significant analysis of variance (ANOVA) test, Tukey post hoc test was used for statistical analysis. RESULTS: At least 8 to 10 mice in each group were analyzed for each evaluated variable. Surfactant treatment significantly increased both the arterial oxygen tension to fraction of inspired oxygen ratio and respiratory system static compliance (P = 0.027 and P = 0.007, respectively, for surf group versus vehicle). Surfactant therapy increased indices of inflammation in the acid-injured lung compared with vehicle: inflammatory cells (685 [602-773] and 216 [125-305] * 1000/mL, respectively; P < 0.001) and albumin in bronchoalveolar lavage (BAL) (1442 +/- 588 and 743 +/- 647 MUg/mL, respectively; P = 0.027). These differences were not found (P = 0.96 and P = 0.54) in the contralateral (uninjured) lung (inflammatory cells 131 [78-195] and 119 [87-149] * 1000/mL and albumin 135 +/- 100 and 173 +/- 115 MUg/mL). CONCLUSIONS: Exogenous surfactant administration to an acid-injured right lung improved gas exchange and whole respiratory system compliance. However, markers of inflammation increased in the right (injured) lung, although this result was not found in the left (uninjured) lung. These data suggest that the mechanism by which surfactant improves lung function may involve both uninjured and injured alveoli. PMID- 25502843 TI - A multi-functional probe to discriminate Lys, Arg, His, Cys, Hcy and GSH from common amino acids. AB - The co-existence and similar properties of amino acids make the detection of individual amino acids challenging. Herein we discovered that probe 1 may act as a smart example to classify and differentiate basic amino acids (Arg/Lys/His), thiol-containing amino acids (Cys/HCy), and GSH through different sensing mechanisms in selected environments. PMID- 25502845 TI - The plasma osteoprotegerin level and osteoprotegerin expression in renal biopsy tissue are increased in type 2 diabetes with nephropathy. AB - OBJECTIVE: To investigate the plasma osteoprotegerin level and osteoprotegerin expression in renal biopsy tissue in type 2 diabetes with nephropathy. METHODS: Plasma osteoprotegerin level was measured by enzyme-linked immunoassay in 48 type 2 diabetes with normoalbuminuria, 48 patients with microalbuminuria, 44 patients with macroalbuminuria and 40 healthy persons. Part of diabetes patients with nephropathy were performed kidney biopsy by ultrasound guide. The osteoprotegerin expression in kidney biopsy tissue is examined by immunohistochemistry. RESULTS: The plasma osteoprotegerin levels were significantly elevated in patients with microalbuminuria (3.73+/-0.75 ng/l) and macroalbuminuria (4.68+/-0.82 ng/l) as compared with patients with normoalbuminuria (2.71+/-0.69 ng/l) and control subjects (2.11+/-0.42 ng/l). And the plasma osteoprotegerin level in macroalbuminuric group was also higher than that in microalbuminuria group. The plasma osteoprotegerin level had a positive correlation with the fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), glycohemoglobinA1c (HbA1C), high sensitive C-reactive protein (hsCRP) and log(UAER). Multivariate regression analysis revealed that plasma osteoprotegerin level was an independent factor associated with albuminuria in type 2 diabetes. The immunohistochemistry results showed that positive immunostaining for osteoprotegerin was observed in the renal tubule cells of biopsy and not in glomerulus, and the osteoprotegerin expression was higher in macroalbuminuria group than that in microalbuminuria group. CONCLUSIONS: The plasma osteoprotegerin level and the osteoprotegerin expression in renal tubule cells of biopsy tissue were increased in nephropathy of type 2 diabetes. This finding supports the growing concept that osteoprotegerin may act as an important regulatory molecule in the angiopathy, and particularly, that it may be involved in the occurrence and development of nephropathy in type 2 diabetes. PMID- 25502844 TI - A 3-hydroxy beta-end group in xanthophylls is preferentially oxidized to a 3-oxo epsilon-end group in mammals. AB - We previously found that mice fed lutein accumulated its oxidative metabolites (3'-hydroxy-epsilon,epsilon-caroten-3-one and epsilon,epsilon-carotene-3,3' dione) as major carotenoids, suggesting that mammals can convert xanthophylls to keto-carotenoids by the oxidation of hydroxyl groups. Here we elucidated the metabolic activities of mouse liver for several xanthophylls. When lutein was incubated with liver postmitochondrial fraction in the presence of NAD(+), (3'R,6'R)-3'-hydroxy-beta,epsilon-caroten-3-one and (6RS,3'R,6'R)-3'-hydroxy epsilon,epsilon-caroten-3-one were produced as major oxidation products. The former accumulated only at the early stage and was assumed to be an intermediate, followed by isomerization to the latter. The configuration at the C3' and C6' of the epsilon-end group in lutein was retained in the two oxidation products. These results indicate that the 3-hydroxy beta-end group in lutein was preferentially oxidized to a 3-oxo epsilon-end group via a 3-oxo beta-end group. Other xanthophylls such as beta-cryptoxanthin and zeaxanthin, which have a 3-hydroxy beta-end group, were also oxidized in the same manner as lutein. These keto carotenoids, derived from dietary xanthophylls, were confirmed to be present in plasma of normal human subjects, and beta,epsilon-caroten-3'-one was significantly increased by the ingestion of beta-cryptoxanthin. Thus, humans as well as mice have oxidative activity to convert the 3-hydroxy beta-end group of xanthophylls to a 3-oxo epsilon-end group. PMID- 25502846 TI - Algebraic double cut and join : A group-theoretic approach to the operator on multichromosomal genomes. AB - Establishing a distance between genomes is a significant problem in computational genomics, because its solution can be used to establish evolutionary relationships including phylogeny. The "double cut and join" (DCJ) model of chromosomal rearrangement proposed by Yancopoulos et al. (Bioinformatics 21:3340 3346, 2005) has received attention as it can model inversions, translocations, fusion and fission on a multichromosomal genome that may contain both linear and circular chromosomes. In this paper, we realize the DCJ operator as a group action on the space of multichromosomal genomes. We study this group action, deriving some properties of the group and finding group-theoretic analogues for the key results in the DCJ theory. PMID- 25502847 TI - Generalized superficial mycosis caused by Trichophyton raubitschekii in China: case report and review of the literature. AB - This is a generalized superficial mycosis case from which Trichophyton raubitschekii was isolated. A male adult was presented with a 3-year history of fingernail and toenail changes, and a 50-day history of severe and multiple skin lesions. He also complained of intense itching. T. raubitschekii was identified from every skin lesion (trunk, extremities and nail) through microscopic examination, physiological experiment and DNA sequencing. Generalized superficial mycosis was diagnosed and treated by administering a combination of oral (terbinafine tablets) and topical (naftifine hydrochloride and ketoconazole cream) antimycotic drugs. After treatment, the patient was cured and no recurrence has been observed. PMID- 25502848 TI - Arsenolipids in oil from blue whiting Micromesistius poutassou--evidence for arsenic-containing esters. AB - Arsenic-containing lipids in the oil from the blue whiting fish (Micromesistius poutassou) were separated into three broad polarity groups and investigated by HPLC and mass spectrometry. A total of 11 arsenolipids including 4 new compounds were identified. The polar lipid fraction constituting 24% of the total arsenolipid content (which totalled 2.16 MUg As/g) contained four known dimethylarsinoyl fatty acids and three known dimethylarsinoyl hydrocarbons. The less polar fraction (ca 30% of the total arsenolipids) contained four new dimethylarsinoyl hydrocarbons with chain lengths 22-30 carbons, in addition to more complex arsenicals that hydrolysed to known dimethylarsinoyl fatty acids suggesting they were conjugated carboxylic acids, presumably esters. The rest of the lipid-soluble arsenic (ca 45% of the total) remained in the non-polar fraction together with the bulk of the fish oil lipids, a complex mixture of compounds that precluded identification of the small amounts of arsenolipids. PMID- 25502849 TI - [The assessment of bite injuries from a forensic point of view]. AB - The identification of a bite injury and its differentiation between human and animal origin demand a high level of special knowledge from the examining physician. The evaluation of bite injuries in terms of their hazard potential, risk profile and origin is usually done by a forensic specialist based on medical record documentation after immediate medical treatment. Therefore, as a first responder, a detailed documentation of the entire injury pattern is essential. If necessary, samples for further DNA analysis should be taken.The present article is intended to give a brief introduction to various aspects of bite injuries as well as to point out possibilities and limitations of the assessment of such cases. PMID- 25502851 TI - Upconversion luminescence enhancement of Yb(3+), Nd(3+) sensitized NaYF4 core shell nanocrystals on Ag grating films. AB - Here, we report the wavelength-dependent and angle-dependent upconversion luminescence (UCL) enhancement of NaYF4:Yb(3+),Tm(3+)@NaYF4:Yb(3+),Nd(3+) core shell nanocrystals (NCs) resulting from Ag grating structures, which provides a novel insight for improving UCL. PMID- 25502852 TI - Detection of occult paroxysmal atrial fibrillation. AB - This work introduces a novel approach to the detection of brief episodes of paroxysmal atrial fibrillation (PAF). The proposed detector is based on four parameters which characterize RR interval irregularity, P-wave absence, f-wave presence, and noise level, of which the latter three are determined from a signal produced by an echo state network. The parameters are used for fuzzy logic classification where the decisions involve information on prevailing signal quality; no training is required. The performance is evaluated on a large set of test signals with brief episodes of PAF. The results show that episodes with as few as five beats can be reliably detected with an accuracy of 0.88, compared to 0.82 for a detector based on rhythm information only (the coefficient of sample entropy); this difference in accuracy increases when atrial premature beats are present. The results also show that the performance remains essentially unchanged at noise levels up to [Formula: see text] RMS. It is concluded that the combination of information on ventricular activity, atrial activity, and noise leads to substantial improvement when detecting brief episodes of PAF. PMID- 25502853 TI - Characteristics of YouTubeTM Videos Related to Mammography. AB - With a monthly total of more than one billion unique visitors, YouTubeTM is one of the Internet's most visited websites and contributes to the growing amount of health-related information on the Internet. The purpose of this study was to analyze coverage of mammography screening in popular YouTubeTM videos. A total of 173 videos were included in the analysis. Compared with professionally created videos, consumer-created videos had a significantly greater number of comments (>9 comments 38.0% for consumer vs. 11.8% for professional videos, p=<0.001). Videos created by professionals more often portrayed general mammography information (97.1 vs. 88.7%) compared to those created by consumers. The vast majority of videos presented general information (93.6%) related to mammography, and almost two thirds addressed preparing for the test. Less than 20% dealt with other types of examinations. Approximately 30% discussed pain associated with the examination (35.3%) and addressed issues of anxiety (32.4%) and fear (29.5%). Nearly half of the videos presented information about the test results (46.2%). Over 25% covered medical or family history. The majority did not pertain to a specific age group. Future research should focus on analyzing the accuracy of the information in the videos. PMID- 25502855 TI - Trans-abdominal wall traction as a universal solution to the management of giant ventral hernias. AB - BACKGROUND: Domain loss following damage-control laparotomy is a challenging problem many surgeons face. The authors recently developed trans-abdominal wall traction, which closed 100 percent of domain loss abdomens in the acute setting. They hypothesized that it can be used successfully in patients with chronic giant ventral defects. METHODS: From 2008 to 2013, 44 patients with acute loss of domain and 10 with chronically giant ventral defects were enrolled in the open abdomen protocol with subsequent placement of the trans-abdominal wall traction device. RESULTS: Patients' average age in the acute and chronic groups was 28.2 and 35.3 years and average body mass index was 26.4 and 32.4 kg/m2, respectively. Ventral hernia size was reduced with the first trans-abdominal wall traction insertion from 610.5 cm2 to 274.6 cm2 in the acute setting and from 598 cm2 to 236.9 cm2 in the chronic setting. Average time from damage-control laparotomy to device insertion was 12.9 days in the acute group and more than 3 years in the chronic group. Lost domain was achieved with an average of less than 2.5 trans abdominal wall traction tightenings, correlating to 9.2 and 8.2 days in the acute and chronic groups, respectively. Enterocutaneous fistula occurrence was 9 percent in the acute group and 0 percent in the chronic group. CONCLUSIONS: All patients were successfully closed after reestablishment of the lost domain. Trans abdominal wall traction is an effective means of reestablishing abdominal domain and achieving primary abdominal wall closure in all patients with giant ventral defects, both acute and chronic. PMID- 25502854 TI - Coping with congenital hand differences. AB - BACKGROUND: Although functional outcomes following reconstruction for congenital hand differences are frequently described, much less is known regarding children's ability to cope with the psychosocial effects of these conditions. The authors qualitatively explored stress and coping mechanisms among children following reconstructive surgery for congenital hand differences. METHODS: Forty patients and their parents participated in semistructured interviews examining children's stress related to hand functioning and appearance, emotional responses to stress, and coping strategies. Interviews were audio-taped, transcribed, and analyzed thematically. A consensus taxonomy for classifying content evolved from comparisons of coding by two reviewers. Themes expressed by participants were studied for patterns of connection and grouped into broader categories. RESULTS: In this sample, 58 percent of children and 40 percent of parents reported stress related to congenital hand differences, attributed to functional deficits (61 percent), hand appearance (27 percent), social interactions (58 percent), and emotional reactions (46 percent). Among the 18 children who reported stress, 43 percent of parents were not aware of the presence of stress. Eight coping strategies emerged, including humor (12 percent), self-acceptance (21 percent), avoidance (27 percent), seeking external support (30 percent), concealment (30 percent), educating others (9 percent), support programs (21 percent), and religion (24 percent). CONCLUSIONS: Although children with congenital hand differences often experience emotional stress related to functional limitations and aesthetic deformities, many apply positive coping mechanisms that enhance self-esteem. Clinicians caring for children with congenital hand differences should inform families about potential sources of stress to direct resources toward strengthening coping strategies and support systems. PMID- 25502856 TI - The importance of timing in optimizing cranial vault remodeling in syndromic craniosynostosis. AB - BACKGROUND: The purpose of this study was to gain insight into the impact of age at repair on relapse rates in syndromic patients undergoing cranial vault remodeling. METHODS: Retrospective chart review was performed for patients surgically treated for syndromic craniosynostosis from 1990 to 2013. Surgical procedures were assigned a Whitaker category based on need for reoperation as follows: no additional surgery required (category I); minor contouring revisions required (II); major revisions required (III); or failure of original surgery (IV). Age at surgery was grouped as follows: younger than 6 months; aged 6 to 9 months; and older than 9 months. Multivariable logistic regression analysis was performed to determine the relationship between age at surgery and need for reoperation by Whitaker category. RESULTS: Fifty-two patients undergoing a total of 65 planned cranial vault remodeling procedures were included. Multivariate logistic regression analysis revealed that patients younger than 6 months at the time of primary surgery carried a 4.10 greater odds (95 percent CI, 1.31 to 12.87; p = 0.016) of requiring a subsequent major reoperation, and being older than 9 months of age carried a 13.2 greater odds (95 percent CI, 1.39 to 124.30; p = 0.024) of requiring a subsequent minor revision. CONCLUSIONS: Timing of surgery is an important factor to consider when planning vault remodeling in syndromic craniosynostosis. Based on our institution's experience, when there is no concern for elevated intracranial pressure the ideal operative window for these procedures in the syndromic population appears to be 6 to 9 months of age. PMID- 25502850 TI - Treatment of osteoporosis: current state of the art. AB - Osteoporosis can be treated with medications and lifestyle changes, including avoiding a sedentary lifestyle, alcohol, and smoking. We will identify medications that protect against hip fractures in addition to vertebral fractures, and explore new evidence of adverse effects and risks. Bisphosphonates are used as first-line treatment. We will discuss the latest osteoporosis medications, drug interactions, potential bone protective effects of other drug classes, and the evidence of exercise and kyphoplasty. PMID- 25502857 TI - Long-term use of the Fogli temporal lift technique. AB - BACKGROUND: The temporal lift by galeapexy is a short-scar lifting of the lateral third of the eyebrow and temporal region described in 2003 by Alain Fogli. The senior authors (A.M.V., P.L.T.) have been early adopters of this technique, albeit with some modifications. METHODS: The technique was used in 923 cases, of which 20 percent were performed as an isolated procedure and 80 percent were performed in combination with a minimal access cranial suspension lift. RESULTS: Over 8 years of experience has proven the technique to have good reliability, and to be predictable and safe. Patients with follow-up of 5 years or more were reviewed, and showed a marked improvement of both lateral hooding and eyebrow position in more than 90 percent of cases, with a relapse rate of less than 10 percent after 5 years. The complication rate was below 5 percent. CONCLUSION: Both surgeon satisfaction and patient satisfaction with this technique are high. PMID- 25502858 TI - Biomechanical and safety testing of a simplified negative-pressure wound therapy device. AB - BACKGROUND: There is a large, unmet need for acute and chronic wound care worldwide. Application of proven therapies such as negative-pressure wound therapy in resource-constrained settings is limited by cost and lack of electrical supply. To provide an alternative to existing electrically powered negative-pressure wound therapy systems, a bellows-powered negative-pressure wound therapy system was designed and iteratively improved during field-based testing. The authors describe the design process and the results of safety and biomechanical testing of their simplified negative-pressure wound therapy system. METHODS: Simplified negative-pressure wound therapy was tested at two hospitals in Rwanda. Patients with wounds ranging from 2 to 150 cm and meeting inclusion and exclusion criteria were enrolled. Wounds were categorized by difficulty of dressing application according to location and contour. Outcomes were maintenance of negative pressure and occurrence of adverse events. RESULTS: Thirty-seven patients with 42 wounds were treated with simplified negative-pressure wound therapy. Eighty-five dressings in total were applied. On average, the final simplified negative-pressure wound therapy dressing maintained negative pressure for 31.7 hours on all wounds (n = 37), and 52.7 hours on wounds in easy-to-dress locations. No unexpected adverse events occurred. CONCLUSIONS: This is the first systematic report of the performance of a bellows-powered negative-pressure wound therapy device designed specifically for use in resource-constrained settings. The authors found that elimination of air leaks in the simplified negative pressure wound therapy dressing is essential, and that their system is safe and feasible for use in these environments. Subsequent trials will study the system's efficacy. PMID- 25502859 TI - Anatomical variability of the anterolateral thigh flap perforators: vascular anatomy and its clinical implications. AB - BACKGROUND: Anatomical variability of perforators of the anterolateral thigh flap has been reported. The authors introduce a classification based on the number, location, and origin of the cutaneous perforators to comprehensively illustrate their vascular patterns in hopes that unfavorable anatomical variations of the anterolateral thigh flap can be overcome in clinical applications. METHODS: The authors enrolled and reviewed 110 anterolateral thigh flaps created between September of 2010 and January of 2013 for head and neck reconstruction after cancer ablation. The location of the perforators was defined by Yu's ABC system. Its corresponding origin from the descending or transverse branch of the lateral circumflex femoral artery was clarified by Shieh's vascular anatomical classification for the anterolateral thigh flap. RESULTS: Of the 110 flaps, a single perforator (A or B or C) was observed in 20 flaps (18.2 percent), double perforators (A + B or B + C or A + C) were observed in 59 flaps (53.6 percent), and triple perforators (A + B + C) in 31 flaps (28.2 percent). The origin of perforators was the descending branch in 76 flaps (69.1 percent), the transverse branch in 10 flaps (9.1 percent), and both descending and transverse branches in 24 flaps (21.8 percent). The authors observed 16 vascular patterns. The most common type was double perforators, with perforators B and C originating from the descending branch [n = 40 (36.4 percent)]. CONCLUSIONS: The clinical significance of each pattern is delineated, and surgical technical considerations are suggested according to flap requirements and types of vascular anatomy. PMID- 25502861 TI - Dynamics of the alar rim graft. AB - BACKGROUND: The purpose of this study was to review the dynamics and frequency of the use of the alar rim graft. METHODS: The recorded intraoperative information for the purpose of rhinoplasty research was reviewed to investigate the frequency of the use of alar rim grafts. Intraoperative observations were also made while inserting the alar rim graft to identify the changes that occur in the structures that could be influenced by placement of this graft. The data were tabulated in an Excel file and analyzed. RESULTS: Of the 1427 patients who underwent nose reconstruction or rhinoplasty in this study, 565 (39.56 percent) received alar rim grafts. This included 73 primary nose reconstructions, 20 secondary nose reconstructions, two revision nose reconstructions, 304 primary rhinoplasties, 107 secondary rhinoplasties, 43 revision operations following primary rhinoplasties, and seven revision operations following secondary rhinoplasties. However, when 100 more recent consecutive cases were reviewed, 88 percent of primary rhinoplasty patients and 67 percent of secondary rhinoplasty patients received alar rim grafts. The observed dynamic changes after insertion of each graft included (1) correction of the concavity of the ala, (2) caudal advancement of the alar rim, (3) elongation of nostril, and (4) widening of the nostril. CONCLUSIONS: The majority of patients who undergo rhinoplasty would benefit from the alar rim graft, and this study demonstrates a steady increase in its use. Placement of an alar rim graft results in elongation of the short nostril, correction of the alar concavity, widening of the nostril, and slight caudal transposition of the alar rim. PMID- 25502860 TI - Studies in fat grafting: Part IV. Adipose-derived stromal cell gene expression in cell-assisted lipotransfer. AB - BACKGROUND: Fat graft volume retention remains highly unpredictable, but addition of adipose-derived stromal cells to fat grafts has been shown to improve retention. The present study aimed to investigate the mechanisms involved in adipose-derived stromal cell enhancement of fat grafting. METHODS: Adipose derived stromal cells isolated from human lipoaspirate were labeled with green fluorescent protein and luciferase. Fat grafts enhanced with adipose-derived stromal cells were injected into the scalp and bioluminescent imaging was performed to follow retention of adipose-derived stromal cells within the fat graft. Fat grafts were also explanted at days 1, 5, and 10 after grafting for adipose-derived stromal cell extraction and single-cell gene analysis. Finally, CD31 immunohistochemical staining was performed on fat grafts enriched with adipose-derived stromal cells. RESULTS: Bioluminescent imaging demonstrated significant reduction in luciferase-positive adipose-derived stromal cells within fat grafts at 5 days after grafting. A similar reduction in viable green fluorescent protein-positive adipose-derived stromal cells retrieved from explanted grafts was also noted. Single-cell analysis revealed expression of multiple genes/markers related to cell survival and angiogenesis, including BMPR2, CD90, CD105, FGF2, CD248, TGFbeta1, and VEGFA. Genes involved in adipogenesis were not expressed by adipose-derived stromal cells. Finally, CD31 staining revealed significantly higher vascular density in fat grafts explanted at day 10 after grafting. CONCLUSIONS: Although adipose-derived stromal cell survival in the hypoxic graft environment decreases significantly over time, these cells provide multiple angiogenic growth factors. Therefore, improved fat graft volume retention with adipose-derived stromal cell enrichment may be attributable to improved graft vascularization. PMID- 25502862 TI - SERI surgical scaffold, prospective clinical trial of a silk-derived biological scaffold in two-stage breast reconstruction: 1-year data. AB - BACKGROUND: SERI Surgical Scaffold is a long-term bioresorbable silk-derived biological scaffold developed to provide soft-tissue support and repair. METHODS: SURE-001 (ClinicalTrials.gov identification no. NCT01256502) is a prospective, single-arm study in the United States of patients undergoing two-stage, implant based breast reconstruction using SERI. RESULTS: A total of 139 patients were enrolled and will be followed for 2 years; in this article, the authors report interim data on 71 patients followed for 1 year. Investigator satisfaction scores (mean +/- SD) at 6 and 12 months were 9.2 +/- 0.98 and 9.4 +/- 0.91, respectively (10 = very satisfied). SERI was rated easy/very easy to use in 98 percent or more of cases across five categories in stage I surgery. Patient satisfaction with the treated breast(s) (mean +/- SD) was higher at 6 (4.3 +/- 0.87; 5 = very satisfied) and 12 months (4.5 +/- 0.82) compared with screening (3.6 +/- 1.09; p < 0.0001). Key complication rates (per breast) were tissue necrosis (6.7 percent), seroma (5.7 percent), hematoma (4.8 percent), implant loss (3.8 percent), capsular contracture (1.9 percent), and breast infection (1.0 percent). None were attributed to SERI by the investigators. In 13 patients (14 breasts) who underwent unplanned radiation therapy, one complication was reported. CONCLUSIONS: In this interim report, high levels of investigator and patient satisfaction, and ease of use of SERI were reported. Prospectively collected complication rates were similar to those reported in primarily retrospective studies of two-stage, implant-based breast reconstructions using other implantable soft-tissue support materials such as acellular dermal matrices. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 25502864 TI - The Application of sEMG in Aging: A Mini Review. AB - The aim of this mini-review is to describe the potential application of surface electromyography (sEMG) techniques in aging studies. Aging is characterized by multiple changes of the musculoskeletal system physiology and function. This paper will examine some of the innovative methods used to monitor age-related alterations of the neuromuscular system from sEMG signals. A description of critical assumptions which underlie some of these approaches is emphasized. The first part focuses on the evolution of the recording techniques and describes some methodological issues. The second part focuses on how to use the following techniques to characterize aging: amplitude and spectral sEMG signal analysis, muscle fiber conduction velocity estimation, and myoelectric fatigue assessment. The last part describes a number of advanced sEMG approaches which seem promising in the geriatric population to estimate motor unit number, size, recruitment thresholds, and firing rates. PMID- 25502863 TI - Phase I study of amatuximab, a novel monoclonal antibody to mesothelin, in Japanese patients with advanced solid tumors. AB - Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5%) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4%) and pyrexia (23.5%). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784). PMID- 25502866 TI - The fate of ophthalmology trainees in the UK-CCT holders 2007 to 2010. PMID- 25502867 TI - Surgical outcome of safe surgery system trabeculectomy combined with cataract extraction. AB - PURPOSE: To determine the efficacy of safe surgery system trabeculectomy combined with manual small incision cataract surgery/phacoemulsification in primary glaucoma coexistent with cataract. METHODS: This is a retrospective analysis of 105 cases who underwent single-site combined surgery between January 2008 and December 2009. Safe surgery system trabeculectomy with diffuse and posterior application of mitomycin C was performed in all cases. Cataract extraction was done either by Manual Small Incision Cataract Surgery (MSICS) or phacoemulsification. Main outcome measures were success rate of trabeculectomy, as determined by four different IOP goals and incidence of postoperative complications. Analysis was performed using R-2.15, and the significance was tested at 5% level. RESULTS: The minimum follow-up period was 12 months. The overall success rates (with or without medication) when safe surgery system trabeculectomy was combined with MSICS were 91, 70, and 51% for IOP <=18, <=15, and <=12 mm Hg, respectively, and target IOP was achieved in 72% cases. The mean IOP reduction was 43.8% with MSICS and 42.08% with phacoemulsification. The surgical outcome was not significantly different for both techniques. Postoperative complications were infrequent and comparable. CONCLUSION: The Safe Surgery System Trabeculectomy combined with cataract surgery offers excellent IOP control with minimal postoperative complications. It offers an effective and improved solution for primary glaucoma coexistent with cataract found in developing countries. PMID- 25502868 TI - Choroid thickness and ocular pulse amplitude in migraine during attack. AB - AIM: To compare the choroidal thickness and ocular pulse amplitude (OPA) measurements obtained during the attack period in migraine patients and age and gender matched control group participants using high definition optical coherence tomography (OCT). METHODS: Thirty eyes at the side of the headache of 30 subjects with a diagnosis of migraine with or without aura and unilateral migraine and 29 age and gender matched healthy participants were enrolled in this observational, cross-sectional study. OCT scans were performed to all participants. Choroidal thicknesses were measured at the fovea, 1500 MUm nasal and 1500 MUm temporal to the fovea. Intraocular pressure (IOP) and OPA were also measured. RESULTS: The choroidal thickness measurements obtained during the attack period in migraine patients were (mean+/-SD) 279.82+/-35.87, 250.05+/-29.49, and 239.58+/-27.92 and in control group were 308.20+/-44.97, 276.95+/-41.39, and 281.60+/-41.38 at foveal, nasal, and temporal measurement points, respectively. Choroidal thickness significantly decreased according to the control group (P<0.05) at all measured points in migraine patients during attack. IOP (mean+/-SD) values were 16.71+/ 3.26 and17.40+/-3.19 and OPA (mean+/-SD) values were 2.26+/-0.81 and 2.64+/-1.03 in migraine and control groups, respectively, and did not seem to be changed (P>0.05). CONCLUSIONS: Choroidal thickness was found to be significantly decreased in unilateral migraine patients during the attack period when compared with the control group, whereas OPA did not change. The possible implications of these findings on the association between migraine and glaucoma are discussed. PMID- 25502869 TI - Computerized tomography of the otic capsule and otoliths in the oyster toadfish, Opsanus tau. AB - The neurocranium of the toadfish (Opsanus tau) exhibits a distinct translucent region in the otic capsule (OC) that may have functional significance for the auditory pathway. This study used ultrahigh resolution computerized tomography (100 um voxels) to compare the relative density of three sites along the OC (dorsolateral, midlateral, and ventromedial) and two reference sites (dorsal: supraoccipital crest; ventral: parasphenoid bone) in the neurocranium. Higher attenuation occurs where structural density is greater; thus, we compared the X ray attenuations measured, which provided a measure of relative density. The maximum attenuation value was recorded for each of the five sites (x and y) on consecutive sections throughout the OC and for each of the three calcareous otoliths associated with the sensory maculae (lagena, saccule, and utricle) in the OC. All three otoliths had higher attenuations than any sites in the neurocranium. Both dorsal and ventral reference sites (supraoccipital crest and parasphenoid bone, respectively) had attenuation levels consistent with calcified bone and had relatively small, irregular variations along the length of the OC in all individuals. The lowest relative attenuations (lowest densities) occurred consistently at the three sites along the OC. In addition, the lowest attenuations measured along the OC occurred at the ventromedial site around the saccular otolith for all seven fish. The decrease in bone density along the OC is consistent with the hypothesis that there is a low-density channel in the skull to facilitate transmission of acoustic stimuli to the auditory endorgans of the ear. PMID- 25502870 TI - YICAP/ECAP international young investigators paper and grant writing workshop. PMID- 25502871 TI - Spectratype analysis of the T cell receptor delta CDR3 region of bovine gammadelta T cells responding to leptospira. AB - Gamma delta T cells comprise the majority of blood T cells in ruminants at birth and remain at high levels for several years with most expressing the WC1 co receptor. A subpopulation of Bos taurus WC1(+) cells expressing a restricted set of WC1 molecules respond immediately by proliferation and interferon-gamma production to leptospira following vaccination, preceding the response by CD4 T cells. Our goal is to define the gammadelta T cell recognition elements involved. Previously, we showed that the responding cells employed a variety of TRDV genes indicating that the CDR1 and CDR2 of TCRdelta could vary and may not be principally involved in antigen specificity. Murine and human gammadelta T cells bind T22 and self lipids through their CDR3delta. Like mice, cattle use up to five TRDD genes in a single CDR3delta adding flexibility to length and configuration for antigen binding. Here, we used spectratyping to evaluate the CDR3delta of leptospira-responsive cells. Little or no compartmentalization of CDR3delta was found for antigen-responsive cells that incorporated TRDV1, TRDV2, or TRDV3 even though they comprise the majority of the leptospira-responding population. Compartmentalization occurred for TRDV4-containing transcripts and was maintained over time and among cattle. However, no common amino acid motif was apparent in those CDR3delta sequences, although a bias in D gene usage occurred. We hypothesize that the restricted set of WC1 co-receptors expressed by the responding cells may lend specificity to the response through their ability to bind bacteria facilitating interaction of various TCRs with bacterial components resulting in cross-linking and activation. PMID- 25502873 TI - Rac1 regulates myosin II phosphorylation through regulation of myosin light chain phosphatase. AB - Phosphorylation of regulatory light chain (MLC) activates myosin II, which enables it to promote contractile and motile activities of cells. We report here a novel signaling mechanism that activates MLC phosphorylation and smooth muscle contraction. Contractile agonists activated Rac1, and Rac1 inhibition diminished agonist-induced MLC phosphorylation, thus inhibiting smooth muscle contraction. Rac1 inhibits the activity of MLC phosphatase (MLCP) but not that of MLC kinase, through a phosphatase that targets MYPT1 (a regulatory subunit of MLCP) and CPI 17 (a MLCP specific inhibitor) rather than through the RhoA-Rho dependent kinase (ROCK) pathway. Rac1 inhibition decreased the activity of protein kinase C (PKC), which also contributes to the change in CPI-17 phosphorylation. We propose that activation of Rac1 increases the activity of PKC, which increases the phosphorylation of CPI-17 and MYPT1 by inhibiting the phosphatase that targets these proteins, thereby decreasing the activity of MLCP and increasing phosphorylation of MLC. Our results suggest that Rac1 coordinates with RhoA to increase MLC phosphorylation by inactivation of CPI-17/MYPT1 phosphatase, which decreases MLCP activity thus promoting MLC phosphorylation and cell contraction. PMID- 25502872 TI - Different binding motifs of the celiac disease-associated HLA molecules DQ2.5, DQ2.2, and DQ7.5 revealed by relative quantitative proteomics of endogenous peptide repertoires. AB - Celiac disease is caused by intolerance to cereal gluten proteins, and HLA-DQ molecules are involved in the disease pathogenesis by presentation of gluten peptides to CD4(+) T cells. The alpha- or beta-chain sharing HLA molecules DQ2.5, DQ2.2, and DQ7.5 display different risks for the disease. It was recently demonstrated that T cells of DQ2.5 and DQ2.2 patients recognize distinct sets of gluten epitopes, suggesting that these two DQ2 variants select different peptides for display. To explore whether this is the case, we performed a comprehensive comparison of the endogenous self-peptides bound to HLA-DQ molecules of B lymphoblastoid cell lines. Peptides were eluted from affinity-purified HLA molecules of nine cell lines and subjected to quadrupole orbitrap mass spectrometry and MaxQuant software analysis. Altogether, 12,712 endogenous peptides were identified at very different relative abundances. Hierarchical clustering of normalized quantitative data demonstrated significant differences in repertoires of peptides between the three DQ variant molecules. The neural network-based method, NNAlign, was used to identify peptide-binding motifs. The binding motifs of DQ2.5 and DQ7.5 concurred with previously established binding motifs. The binding motif of DQ2.2 was strikingly different from that of DQ2.5 with position P3 being a major anchor having a preference for threonine and serine. This is notable as three recently identified epitopes of gluten recognized by T cells of DQ2.2 celiac patients harbor serine at position P3. This study demonstrates that relative quantitative comparison of endogenous peptides sampled from our protein metabolism by HLA molecules provides clues to understand HLA association with disease. PMID- 25502876 TI - Effect of viscosity on the mixing efficiency in a self-agitation anaerobic baffled reactor. AB - One special self-agitation reactor, which does not require a mechanical mixer or other equipment for mixing, has been introduced. Self-agitation is affected by variation in viscosity property. To obtain and research the effect of viscosity on mixing behavior in the self-agitation reactor, Fluent(r) was used to create numerical simulations and to visualize the fluid flow status. The results show that when the viscosity of the liquid is 1 mPa s, the entire self-agitation results in an almost completely mixed reactor. The substrate becomes difficult to agitate, and the diffusion of the substrate and the tracer become quite after every self-agitation, as the viscosity increases. Once the viscosity is higher than 25 mPa s, the substrate and tracer could not be mixed in the entire reactor, and the reactor is recognized as the combination of several completely mixed reactors between which little exchange of liquid occurs. PMID- 25502874 TI - Residual platelet reactivity to predict long-term clinical outcomes after clopidogrel loading in patients with acute coronary syndromes: comparison of different cutoff values by light transmission aggregometry from the responsiveness to clopidogrel and stent thrombosis 2-acute coronary syndrome (RECLOSE 2-ACS) study. AB - The aim of this study was the identification of the optimal cutoff value of high residual platelet reactivity (HRPR) assessed by light transmission aggregometry (LTA) in the responsiveness to clopidogrel and stent thrombosis 2-acute coronary syndrome (RECLOSE 2-ACS) patient cohort to discriminate patients with and without major adverse cardiac events (MACE) and cardiac death at 2 years. The RECLOSE 2 ACS study included 1,789 patients with ACS who underwent LTA after clopidogrel loading. A post hoc cutoff value for HRPR was defined with the ROC curve and the Youden index and compared with the protocol-defined cutoff of 70 %. By ROC analysis, 63 % resulted the optimal cutoff value to predict both MACE and cardiac death at 2 years follow-up. A significant sensitivity improvement for the ROC based cutoff value was noted (p < 0.001), at the price of lower specificity and predictive accuracy. The latter were 81 % for MACE and 85 % for cardiac death with the 70 % cutoff, while the respective figures were 73 and 75 % with the 63 % cutoff. The areas under the curve were virtually identical with the 70 and 63 % cutoffs both for MACE (0.71) and cardiac death (0.79). A residual platelet reactivity cutoff of 70 % by LTA, compared to the ROC-based cutoff of 63 %, allows for the identification of a subset of patients at very high risk of adverse ischemic events, making LTA-ADP test more acceptable in clinical practice for the identification of subjects at risk than other platelet function assays with broader definitions of HRPR. PMID- 25502875 TI - Use of a Guinea pig-specific transcriptome array for evaluation of protective immunity against genital chlamydial infection following intranasal vaccination in Guinea pigs. AB - Guinea pigs have been used as a second animal model to validate putative anti chlamydial vaccine candidates tested in mice. However, the lack of guinea pig specific reagents has limited the utility of this animal model in Chlamydia sp. vaccine studies. Using a novel guinea pig-specific transcriptome array, we determined correlates of protection in guinea pigs vaccinated with Chlamydia caviae (C. caviae) via the intranasal route, previously reported by us and others to provide robust antigen specific immunity against subsequent intravaginal challenge. C. caviae vaccinated guinea pigs resolved genital infection by day 3 post challenge. In contrast, mock vaccinated animals continued to shed viable Chlamydia up to day 18 post challenge. Importantly, at day 80 post challenge, vaccinated guinea pigs experienced significantly reduced genital pathology - a sequelae of genital chlamydial infections, in comparison to mock vaccinated guinea pigs. Sera from vaccinated guinea pigs displayed antigen specific IgG responses and increased IgG1 and IgG2 titers capable of neutralizing GPIC in vitro. Th1-cellular/inflammatory immune genes and Th2-humoral associated genes were also found to be elevated in vaccinated guinea pigs at day 3 post-challenge and correlated with early clearance of the bacterium. Overall, this study provides the first evidence of guinea pig-specific genes involved in anti chlamydial vaccination and illustrates the enhancement of the utility of this animal model in chlamydial pathogenesis. PMID- 25502878 TI - Boronic acid-modified lipid nanocapsules: a novel platform for the highly efficient inhibition of hepatitis C viral entry. AB - The search for viral entry inhibitors that selectively target viral envelope glycoproteins has attracted increasing interest in recent years. Amongst the handful of molecules reported to show activity as hepatitis C virus (HCV) entry inhibitors are a variety of glycan-binding proteins including the lectins, cyanovirin-N (CV-N) and griffithsin. We recently demonstrated that boronic acid modified nanoparticles are able to reduce HCV entry through a similar mechanism to that of lectins. A major obstacle to any further development of these nanostructures as viral entry inhibitors is their only moderate maximal inhibition potential. In the present study, we report that lipid nanocapsules (LNCs), surface-functionalized with amphiphilic boronic acid (BA) through their post-insertion into the semi-rigid shell of the LNCs, are indeed far superior as HCV entry inhibitors when compared with previously reported nanostructures. These 2(nd) generation particles (BA-LNCs) are shown to prevent HCV infection in the micromolar range (IC50 = 5.4 MUM of BA moieties), whereas the corresponding BA monomers show no significant effects even at the highest analyzed concentration (20 MUM). The new BA-LNCs are the most promising boronolectin-based HCV entry inhibitors reported to date and are thus observed to show great promise in the development of a pseudolectin-based therapeutic agent. PMID- 25502877 TI - Investigating the association between polymorphisms in connective tissue growth factor and susceptibility to colon carcinoma. AB - There have been numerous studies on the gene expression of connective tissue growth factor (CTGF) in colorectal cancer, however very few have investigated polymorphisms in this gene. The present study aimed to determine whether single nucleotide polymorphisms (SNPs) in the CTGF gene are associated with a higher susceptibility to colon cancer and/or an invasive tumor growth pattern. The CTGF gene was genotyped for seven SNPs (rs6918698, rs1931002, rs9493150, rs12526196, rs12527705, rs9399005 and rs12527379) by pyrosequencing. Formalin-fixed paraffin embedded tissue samples (n=112) from patients diagnosed with colon carcinoma, and an equal number of blood samples from healthy controls, were selected for genomic DNA extraction. The complexity index was measured using images of tumor samples (n=64) stained for cytokeratin-8. The images were analyzed and correlated with the identified CTGF SNPs and clinicopathological parameters of the patients, including age, gender, tumor penetration, lymph node metastasis, systemic metastasis, differentiation and localization of tumor. It was demonstrated that the frequency of the SNP rs6918698 GG genotype was significantly associated (P=0.05) with an increased risk of colon cancer, as compared with the GC and CC genotypes. The other six SNPs (rs1931002, rs9493150, rs12526196, rs12527705, rs9399005 and rs12527379) exhibited no significant difference in the genotype and allele frequencies between patients diagnosed with colon carcinoma and the normal healthy population. A trend was observed between genotype variation at rs6918698 and the complexity index (P=0.052). The complexity index and genotypes for any of the studied SNPs were not significantly correlated with clinical or pathological parameters of the patients. These results indicate that the rs6918698 GG genotype is associated with an increased risk of developing colon carcinoma, and genetic variations at the rs6918698 are associated with the growth pattern of the tumor. The present results may facilitate the identification of potential biomarkers of the disease in addition to drug targets. PMID- 25502879 TI - Protoporphyrin IX induces a necrotic cell death in human THP-1 macrophages through activation of reactive oxygen species/c-Jun N-terminal protein kinase pathway and opening of mitochondrial permeability transition pore. AB - BACKGROUND: Protoporphyrin IX (PpIX) and its derivatives are widely used in photodynamic therapy (PDT) to kill cancer cells. Studies showed that the application of these drugs could cause systemic toxic effects in human. However, the molecular pathways involved in PpIX-induced cytotoxicity are not well defined. Macrophages represent the primary system for protecting tissues from toxicants and initiating the resolution of inflammation. Thus, this study aims to investigate the toxicity of PpIX on macrophages and provide strategies to prevent the toxic effects. METHODS: THP-1 macrophages were incubated with PpIX and cell death was measured by MTT assay and Annexin V-PI staining. Intracellular reactive oxygen species (ROS) were evaluated by 2', 7'-Dichlorodihydrofluorescin diacetate (DCFH-DA) and MitoSOX(r) Red staining and mitochondrial membrane potential (DeltaPsim) was detected by tetramethylrhodamine methyl ester (TMRM) staining. Mitogen-activated protein (MAP) kinase activation was assayed by western blotting. Mitochondrial permeability transition pore (mPTP) opening was measured by calcein loading/Co(2+) quenching technique and evaluating the release of mitochondrial content. RESULTS: PpIX reduced cell viability in a dose- and time dependent manner. The cell death was characterized by increasing PI-positive cells, ATP depletion, LDH releasing and rapid DeltaPsim loss favoring necrotic features. In addition, PpIX successively induced ROS production, c-Jun N-terminal protein kinase (JNK) activation and mPTP opening. ROS scavengers, N acetylcysteine (NAC) and deferoxamine (DFX), JNK inhibitor, SP600125, and mPTP inhibitor, cyclosporin A (CsA), all significantly rescued this cell death. Furthermore, mPTP opening was directly regulated by ROS/JNK pathway. CONCLUSION: PpIX induces a necrotic cell death in THP-1 macrophages through ROS production, JNK activation, and mPTP opening. It is tempting to speculate that blocking the pathways involved in the cytotoxic effects of PpIX will alleviate its side effects. PMID- 25502881 TI - A novel DC microplasma sensor constructed in a cavity PDMS chamber with needle electrodes for fast detection of methanol-containing spirit. AB - A novel microplasma device, for the first time, was constructed in a cavity Poly (dimethylsiloxane) (PDMS) chamber with two normal syringe needles serve as both the gas channels and the electrodes. This device employs argon plasma with direct current for molecular fragmentation and excitation. The microplasma is generated at atmospheric pressure in the PDMS chamber of 0.5 mL (5 * 10 * 10 mm(3)) volume with a sealable plug. Since the microplasma is maintained in a chamber by separation of the discharge zone and the substrate, stability for a long time of the microplasma is realized which could be observed by argon background emission fluctuation and SEM characterization. This property is beneficial for spectrometric detection of many volatile organics in this chamber. Besides, this kind of microplasma sensor has advantages such as flexibility in replacement of electrodes, convenience in clearance of the discharge chamber, small instrument volume, simple structure, and ease of operation. In addition, methanol-containing spirit samples were chosen to estimate the detecting performance of this microplasma for volatile organic compounds (VOCs) analysis by molecular emission spectrometry. Significant differences are observed upon the introduction of the spirit and the methanol-containing spirit samples. A detection limit of 0.3% is obtained on this microplasma device. PMID- 25502882 TI - Erratum: A very rare case of HPV-53-related cervical cancer, in a 79-year-old woman with a previous history of negative Pap cytology [corrigendum]. AB - [This corrects the article on p. 683 in vol. 9, PMID: 24790420.]. PMID- 25502883 TI - "Change is possible": Patients' experience of a multimodal chronic pain rehabilitation programme. AB - OBJECTIVE: To explore patients' experiences of activity, participation and quality of life one year after a rehabilitation programme for chronic pain, and to determine the impact of the programme on their current life situation. DESIGN: Qualitative study with emergent design. SUBJECTS AND METHODS: The 14 informants were patients with chronic pain who had participated in rehabilitation at a pain clinic. Individual semi-structured interviews were analysed with inductive, qualitative content analysis. RESULTS: The core theme "Change is possible" and the themes "A life ruled by pain" (the situation before rehabilitation), "The penny's dropped" (experience during rehabilitation) and "Live a life, not only survive" (the situation at the time of the interviews) emerged from the data. These themes represent a process through which, during and after rehabilitation, the informants integrated earlier disabling symptoms into a functioning lifestyle. CONCLUSION: Individuals living with disabling chronic pain can create a better life by integrating their illness. A prerequisite is that healthcare professionals empower patients to develop the strength to take responsibility for their daily lives. This process is facilitated by skills to reduce pain and handle life, plus support from significant others. PMID- 25502880 TI - Comprehensive evaluation of the association of APOE genetic variation with plasma lipoprotein traits in U.S. whites and African blacks. AB - Although common APOE genetic variation has a major influence on plasma LDL cholesterol, its role in affecting HDL-cholesterol and triglycerides is not well established. Recent genome-wide association studies suggest that APOE also affects plasma variation in HDL-cholesterol and triglycerides. It is thus important to resequence the APOE gene to identify both common and uncommon variants that affect plasma lipid profile. Here, we have sequenced the APOE gene in 190 subjects with extreme HDL-cholesterol levels selected from two well defined epidemiological samples of U.S. non-Hispanic Whites (NHWs) and African Blacks followed by genotyping of identified variants in the entire datasets (623 NHWs, 788 African Blacks) and association analyses with major lipid traits. We identified a total of 40 sequence variants, of which 10 are novel. A total of 32 variants, including common tagSNPs (>=5% frequency) and all uncommon variants (<5% frequency) were successfully genotyped and considered for genotype-phenotype associations. Other than the established associations of APOE*2 and APOE*4 with LDL-cholesterol, we have identified additional independent associations with LDL cholesterol. We have also identified multiple associations of uncommon and common APOE variants with HDL-cholesterol and triglycerides. Our comprehensive sequencing and genotype-phenotype analyses indicate that APOE genetic variation impacts HDL-cholesterol and triglycerides in addition to affecting LDL cholesterol. PMID- 25502885 TI - Reconstituting actomyosin-dependent mechanosensitive protein complexes in vitro. AB - In many mechanosensitive biological processes, actin-binding proteins (ABPs) sense the force generated by the actomyosin cytoskeleton and respond by recruiting effector proteins. We developed an in vitro assay, with pure proteins, to observe the force-dependent binding of a protein to a cryptic binding site buried in the stretchable domain of an ABP. Here we describe the protocol to study the actomyosin-dependent binding of vinculin to the ABP talin. In this assay, talin is immobilized in 5-MUm-diameter disc-shaped islands, which are regularly spaced by 35 MUm and micropatterned on a glass coverslip. In response to the force generated by an actomyosin network, talin extension reveals cryptic vinculin-binding sites (VBSs). To follow this reaction, fluorescent proteins are visualized by total internal refection fluorescence (TIRF) microscopy. EGFP vinculin fluorescence in talin-coated discs reveals the binding of vinculin to stretched talin. Actomyosin structures are visualized by the fluorescence of Alexa Fluor 594-labeled actin. This protocol describes the purification of the proteins, the preparation of the chamber in which talin is coated on a micropatterned surface, and the biochemical conditions to study several kinetic parameters of the actomyosin-dependent binding of vinculin to talin. A stable actomyosin network is used to measure the steady-state dissociation of vinculin from talin under constant force. In the presence of alpha-actinin-1, actomyosin cables undergo cycles of force application and release, allowing the measurement of vinculin dissociation associated with talin re-folding. Expression and purification of the proteins requires at least 3 weeks. The assay can be completed within 1 d. PMID- 25502884 TI - Quantitative assessment of angiogenesis, perfused blood vessels and endothelial tip cells in the postnatal mouse brain. AB - During development and in various diseases of the CNS, new blood vessel formation starts with endothelial tip cell selection and vascular sprout migration, followed by the establishment of functional, perfused blood vessels. Here we describe a method that allows the assessment of these distinct angiogenic steps together with antibody-based protein detection in the postnatal mouse brain. Intravascular and perivascular markers such as Evans blue (EB), isolectin B4 (IB4) or laminin (LN) are used alongside simultaneous immunofluorescence on the same sections. By using confocal laser-scanning microscopy and stereological methods for analysis, detailed quantification of the 3D postnatal brain vasculature for perfused and nonperfused vessels (e.g., vascular volume fraction, vessel length and number, number of branch points and perfusion status of the newly formed vessels) and characterization of sprouting activity (e.g., endothelial tip cell density, filopodia number) can be obtained. The entire protocol, from mouse perfusion to vessel analysis, takes ~10 d. PMID- 25502886 TI - Particle generation, functionalization and sortase A-mediated modification with targeting of single-chain antibodies for diagnostic and therapeutic use. AB - Antibody fusion to nonprotein materials such as contrast agents or radio-tracers, nano- or microparticles or small-molecule drugs is attracting major interest for molecular imaging and drug delivery. Nondirected bioconjugation techniques may impair antibody affinity, result in lower amounts of functional antibodies and generate multicomponent mixtures. We present a detailed protocol for the enzymatic bioconjugation of small recombinant antibodies to imaging particles, and we also describe the generation of and conjugation to a low-fouling capsule assembled for drug delivery from PEG and PVPON (poly(N-vinylpyrrolidone) by a layer-by-layer (LbL) technique. The single-chain variable fragment (scFv) is equipped with a short C-terminal LPETG tag and the fusion partners are functionalized with an N-terminal GGG nucleophilic group for sortase A conjugation. The LbL capsules are assembled through hydrogen bonding by depositing alkyne-modified poly(vinylpyrrolidone) and poly(methacrylic acid) layers on silica particles, followed by depositing alkyne-modified PEG. The generation of the antibodies and LbL capsules takes ~1-2 weeks each. The conjugation and functional testing takes another 3-4 d. PMID- 25502887 TI - Genome-scale RNAi screens for high-throughput phenotyping in bloodstream-form African trypanosomes. AB - The ability to simultaneously assess every gene in a genome for a role in a particular process has obvious appeal. This protocol describes how to perform genome-scale RNAi library screens in bloodstream-form African trypanosomes, a family of parasites that causes lethal human and animal diseases and also serves as a model for studies on basic aspects of eukaryotic biology and evolution. We discuss strain assembly, screen design and implementation, the RNAi target sequencing approach and hit validation, and we provide a step-by-step protocol. A screen can yield from one to thousands of 'hits' associated with the phenotype of interest. The screening protocol itself takes 2 weeks or less to be completed, and high-throughput sequencing may also be completed within weeks. Pre- and post screen strain assembly, validation and follow-up can take several months, depending on the type of screen and the number of hits analyzed. PMID- 25502888 TI - Relative food prices and obesity in US Metropolitan areas: 1976-2001. AB - This study investigates the impact of food price on obesity, by exploring the co occurrence of obesity growth with relative food price reduction between 1976 and 2001. Analyses control for female labor participation and metropolitan outlet densities that might affect body weight. Both the first-difference and fixed effects approaches provide consistent evidence suggesting that relative food prices have substantial impacts on obesity and such impacts were more pronounced among the low-educated. These findings imply that relative food price reductions during the time period could plausibly explain about 18% of the increase in obesity among the U.S. adults in metropolitan areas. PMID- 25502892 TI - [Erratum to: Obituary for Christian Muller (1921-2013)]. PMID- 25502891 TI - Effective transfer of chromosomes carrying leaf rust resistance genes from Aegilops tauschii Coss. into hexaploid triticale (X Triticosecale Witt.) using Ae. tauschii * Secale cereale amphiploid forms. AB - This paper shows the results of effective uses of a molecular cytogenetics toolbox and molecular marker to transfer leaf rust resistance genes from Aegilops tauschii * Secale cereale (DDRR, 2n = 4x = 28) amphiploid forms to triticale cv. Bogo (AABBRR, 2n = 6x = 42). The molecular markers of resistance genes and in situ hybridization analysis of mitotic metaphase of root meristems confirmed the stable inheritance of chromosome 3D segments carrying Lr32 from the BC2F2 to the BC2F5 generation of (Ae. tauschii * S. cereale) * triticale hybrids. The chromosome pairing analysis during metaphase I of meiosis of BC2F4 and BC2F5 hybrids showed increasing regular bivalent formation of 3D chromosome pairs and decreasing number of univalents in subsequent generations. The results indicate that using amphiploid forms as a bridge between wild and cultivated forms can be a successful technology to transfer the D-genome chromatin carrying leaf rust resistance genes into triticale. PMID- 25502893 TI - Update on biology and treatment of T-cell acute lymphoblastic leukaemia. AB - PURPOSE OF REVIEW: In this article, new insights into the clinical and biological features of paediatric T-lineage acute lymphoblastic leukaemia (ALL) and their impact on treatment outcome have been described. RECENT FINDINGS: T-lineage ALL has considerable phenotypic and biological heterogeneity. Compared with B-lineage ALL, the prognostic significance of the presenting white cell count is weaker and the rate of decline in minimal residual disease is slower in patients with T lineage ALL. Contemporary, response stratified, treatment protocols incorporating dexamethasone have been associated with significant improvements in outcomes and demonstrated that cranial radiotherapy is not essential for preventing central nervous system relapse. Relapse risk remains higher than for B-lineage ALL and outcome after relapse is poor. Early T-precursor phenotype and genetic abnormalities such as activating ABL1 fusions, NOTCH1/FBXW7, and cytosolic 5' nucleotidase II gene mutations identify patient groups who may benefit from alternative treatment. New agents such as nelarabine, bortezomib, and clofarabine may be effective in preventing unsalvageable relapses identified by slow response to first-line therapy. SUMMARY: Around 85% of children and young people with T lineage ALL are cured by current therapy. Further improvements in outcome can be expected from genetic profile and response-targeted therapeutics. PMID- 25502890 TI - Targeted changes of the cell wall proteome influence Candida albicans ability to form single- and multi-strain biofilms. AB - Biofilm formation is an important virulence trait of the pathogenic yeast Candida albicans. We have combined gene overexpression, strain barcoding and microarray profiling to screen a library of 531 C. albicans conditional overexpression strains (~10% of the genome) for genes affecting biofilm development in mixed population experiments. The overexpression of 16 genes increased strain occupancy within a multi-strain biofilm, whereas overexpression of 4 genes decreased it. The set of 16 genes was significantly enriched for those encoding predicted glycosylphosphatidylinositol (GPI)-modified proteins, namely Ihd1/Pga36, Phr2, Pga15, Pga19, Pga22, Pga32, Pga37, Pga42 and Pga59; eight of which have been classified as pathogen-specific. Validation experiments using either individually or competitively-grown overexpression strains revealed that the contribution of these genes to biofilm formation was variable and stage-specific. Deeper functional analysis of PGA59 and PGA22 at a single-cell resolution using atomic force microscopy showed that overexpression of either gene increased C. albicans ability to adhere to an abiotic substrate. However, unlike PGA59, PGA22 overexpression led to cell cluster formation that resulted in increased sensitivity to shear forces and decreased ability to form a single-strain biofilm. Within the multi-strain environment provided by the PGA22-non overexpressing cells, PGA22-overexpressing cells were protected from shear forces and fitter for biofilm development. Ultrastructural analysis, genome-wide transcript profiling and phenotypic analyses in a heterologous context suggested that PGA22 affects cell adherence through alteration of cell wall structure and/or function. Taken together, our findings reveal that several novel predicted GPI-modified proteins contribute to the cooperative behaviour between biofilm cells and are important participants during C. albicans biofilm formation. Moreover, they illustrate the power of using signature tagging in conjunction with gene overexpression for the identification of novel genes involved in processes pertaining to C. albicans virulence. PMID- 25502889 TI - First trimester screening of circulating C19MC microRNAs can predict subsequent onset of gestational hypertension. AB - OBJECTIVE: The objective of the study was to evaluate risk assessment for gestational hypertension based on the profile of circulating placental specific C19MC microRNAs in early pregnancy. STUDY DESIGN: The prospective longitudinal cohort study of women enrolled at first trimester screening at 10 to 13 weeks was carried out (n = 267). Relative quantification of placental specific C19MC microRNAs (miR-516-5p, miR-517*, miR-518b, miR-520a*, miR-520h, miR-525 and miR 526a) was determined in 28 normal pregnancies and 18 pregnancies which developed gestational hypertension using real-time PCR and a comparative Ct method relative to synthetic C. elegans microRNA (cel-miR-39). RESULTS: Increased extracellular C19MC microRNA plasmatic levels (miR-516-5p, p<0.001; miR-517*, p = 0.007; miR 520h, p<0.001; miR-518b, p = 0.002) were detected in patients destined to develop gestational hypertension. MiR-520h had the best predictive performance with a PPV of 84.6% at a 7.1% false positive rate. The combination of miR-520h and miR-518b was able to predict 82.6% of women at the same false positive rate. The overall predictive capacity of single miR-518b (73.3% at 14.3% FPR), miR-516-5p (70.6% at 17.9% FPR) and miR-517* (57.9% at 28.6% FPR) biomarkers was lower. CONCLUSION: The study brought interesting finding that the up-regulation of miR-516-5p, miR 517*, miR-520h and miR-518b is associated with a risk of later development of gestational hypertension. First trimester screening of extracellular miR-520h alone or in combination with miR-518b identified a significant proportion of women with subsequent gestational hypertension. PMID- 25502894 TI - Local control of metastatic sarcoma. AB - PURPOSE OF REVIEW: Survival rates for children with metastatic sarcoma have remained dismal despite intensified multiagent chemotherapy protocols. The local treatment of metastatic disease has been promoted as a way to eliminate colonies of genetically unstable, heterogeneous metastatic cells in an attempt to improve survival amongst this most unfortunate patient population. RECENT FINDINGS: The survival benefit offered by pulmonary metastasectomies in patients with metastatic osteosarcoma is well substantiated. Utilization of other local treatment modalities, such as radiation therapy and percutaneous thermal ablation, offers the opportunity to intervene in a wide range of pulmonary and extrapulmonary metastatic disease. Patients who have the entirety of their identifiable disease addressed by local control modalities consistently demonstrate improved survival compared with patients who are treated with systemic therapy in isolation. SUMMARY: The current state of the literature prevents a definitive conclusion about the utility of local control for metastatic sarcoma. The retrospective trials are clouded by selection bias and the prospective studies are designed to address alternative questions. However, the techniques utilized for local control impart minimal risk to the patient and, in amenable cases, have been shown to provide an opportunity to effect a cure in children with an otherwise dismal prognosis. PMID- 25502895 TI - Translating genomic discoveries to the clinic in pediatric oncology. AB - PURPOSE OF REVIEW: The present study describes the recent advances in the identification of targetable genomic alterations in pediatric cancers, along with the progress and associated challenges in translating these findings into therapeutic benefit. RECENT FINDINGS: Each field within pediatric cancer has rapidly and comprehensively begun to define genomic targets in tumors that potentially can improve the clinical outcome of patients, including hematologic malignancies (leukemia and lymphoma), solid malignancies (neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), and brain tumors (gliomas, ependymomas, and medulloblastomas). Although each tumor has specific and sometimes overlapping genomic targets, the translation to the clinic of new targeted trials and precision medicine protocols is still in its infancy. The first clinical tumor profiling studies in pediatric oncology have demonstrated feasibility and patient enthusiasm for the personalized medicine paradigm, but have yet to demonstrate clinical utility. Complexities influencing implementation include rapidly evolving sequencing technologies, tumor heterogeneity, and lack of access to targeted therapies. The return of incidental findings from the germline also remains a challenge, with evolving policy statements and accepted standards. SUMMARY: The translation of genomic discoveries to the clinic in pediatric oncology continues to move forward at a brisk pace. Early adoption of genomics for tumor classification, risk stratification, and initial trials of targeted therapeutic agents has led to powerful results. As our experience grows in the integration of genomic and clinical medicine, the outcome for children with cancer should continue to improve. PMID- 25502896 TI - The tibial eminence fracture in skeletally immature patients. AB - PURPOSE OF REVIEW: Although tibial eminence fractures are uncommon, their importance cannot be overemphasized in skeletally immature patients because of the fracture's close proximity to both the tibial physis as well as the attachment between the tibial eminence and the anterior cruciate ligament, the latter being a key component in maintaining knee stability. This review focuses on recent trends in treatment concepts and devices. RECENT FINDINGS: Recent literature on this topic addresses the existence of a variety of treatment modalities, but the majority of these articles analyzed a limited number of cases and insisted on the merits of their own methods. Nevertheless, some consensus has been reached regarding treatment direction and how much laxity should be considered acceptable. SUMMARY: Although the review failed to reveal a gold standard modality in treating tibial eminence fractures, most studies agreed on several issues. Displaced intra-articular fractures should be fixed operatively. PMID- 25502897 TI - Early versus delayed oral fluids and food for reducing complications after major abdominal gynaecologic surgery. AB - BACKGROUND: This is an updated version of the original Cochrane review published in 2007. Traditionally, after major abdominal gynaecologic surgery postoperative oral intake is withheld until the return of bowel function. There has been concern that early oral intake would result in vomiting and severe paralytic ileus with subsequent aspiration pneumonia, wound dehiscence, and anastomotic leakage. However, evidence-based clinical studies suggest that there may be benefits from early postoperative oral intake. OBJECTIVES: To assess the effects of early versus delayed (traditional) initiation of oral intake of food and fluids after major abdominal gynaecologic surgery. SEARCH METHODS: We searched the Menstrual Disorders and Subfertility Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), electronic databases (MEDLINE, EMBASE, CINAHL), and the citation lists of relevant publications. The most recent search was conducted 1 April 2014. We also searched a registry for ongoing trials (www.clinicaltrials.gov) on 13 May 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) were eligible that compared the effect of early versus delayed initiation of oral intake of food and fluids after major abdominal gynaecologic surgery. Early feeding was defined as oral intake of fluids or food within 24 hours post-surgery regardless of the return of bowel function. Delayed feeding was defined as oral intake after 24 hours post-surgery and only after signs of postoperative ileus resolution. DATA COLLECTION AND ANALYSIS: Two review authors selected studies, assessed study quality and extracted the data. For dichotomous data, we calculated the risk ratio (RR) with a 95% confidence interval (CI). We examined continuous data using the mean difference (MD) and a 95% CI. We tested for heterogeneity between the results of different studies using a forest plot of the meta-analysis, the statistical tests of homogeneity of 2 x 2 tables and the I2 value. We assessed the quality of the evidence using GRADE methods. MAIN RESULTS: Rates of developing postoperative ileus were comparable between study groups (RR 0.47, 95% CI 0.17 to 1.29, P = 0.14, 3 RCTs, 279 women, I2 = 0%, moderate-quality evidence). When we considered the rates of nausea or vomiting or both, there was no evidence of a difference between the study groups (RR 1.03, 95% CI 0.64 to 1.67, P = 0.90, 4 RCTs, 484 women, I2 = 73%, moderate-quality evidence). There was no evidence of a difference between the study groups in abdominal distension (RR 1.07, 95% CI 0.77 to 1.47, 2 RCTs, 301 women, I2 = 0%) or a need for postoperative nasogastric tube placement (RR 0.48, 95% CI 0.13 to 1.80, 1 RCT, 195 women).Early feeding was associated with shorter time to the presence of bowel sound (MD -0.32 days, 95% CI -0.61 to -0.03, P = 0.03, 2 RCTs, 338 women, I2 = 52%, moderate-quality evidence) and faster onset of flatus (MD -0.21 days, 95% CI -0.40 to -0.01, P = 0.04, 3 RCTs, 444 women, I2 = 23%, moderate-quality evidence). In addition, women in the early feeding group resumed a solid diet sooner (MD -1.47 days, 95% CI 2.26 to -0.68, P = 0.0003, 2 RCTs, 301 women, I2 = 92%, moderate-quality evidence). There was no evidence of a difference in time to the first passage of stool between the two study groups (MD -0.25 days, 95% CI -0.58 to 0.09, P = 0.15, 2 RCTs, 249 women, I2 = 0%, moderate-quality evidence). Hospital stay was shorter in the early feeding group (MD -0.92 days, 95% CI -1.53 to -0.31, P = 0.003, 4 RCTs, 484 women, I2 = 68%, moderate-quality evidence). Infectious complications were less common in the early feeding group (RR 0.20, 95% CI 0.05 to 0.73, P = 0.02, 2 RCTs, 183 women, I2 = 0%, high-quality evidence). In one study, the satisfaction score was significantly higher in the early feeding group (MD 11.10, 95% CI 6.68 to 15.52, P < 0.00001, 143 women, moderate-quality evidence). AUTHORS' CONCLUSIONS: Early postoperative feeding after major abdominal gynaecologic surgery for either benign or malignant conditions appeared to be safe without increased gastrointestinal morbidities or other postoperative complications. The benefits of this approach include faster recovery of bowel function, lower rates of infectious complications, shorter hospital stay, and higher satisfaction. PMID- 25502899 TI - Vedolizumab: a review of its use in adult patients with moderately to severely active ulcerative colitis or Crohn's disease. AB - Vedolizumab (EntyvioTM) is a humanized monoclonal antibody alpha4beta7 integrin receptor antagonist indicated for the treatment of adult patients with moderately to severely active ulcerative colitis or Crohn's disease. This article reviews the pharmacological properties of intravenous infusions of vedolizumab and its clinical efficacy in adult patients with these diseases. In phase III clinical trials, patients with ulcerative colitis had significantly higher rates of clinical response and clinical remission when treated with vedolizumab than when receiving placebo at both 6 and 52 weeks. However, outcomes with vedolizumab in patients with Crohn's disease were mixed. In a study that evaluated both clinical remission rate and CDAI-100 response rate as primary endpoints, only the clinical remission rate at 6 weeks was significantly higher with vedolizumab than placebo. In another trial, there was no significant between-group difference in the clinical remission rate in TNF-antagonist failure patients at 6 weeks (primary endpoint), although there was a significant difference at 10 weeks. In the Crohn's disease study that included maintenance treatment, vedolizumab was significantly more effective at 52 weeks than placebo in both endpoints (clinical remission was the only primary endpoint in the maintenance study). Vedolizumab was generally well tolerated in these trials. As vedolizumab is a specific alpha4beta7 integrin antagonist, with gut-specific effects, it is unlikely to be associated with the development of progressive multifocal leukoencephalopathy, a risk observed with the less selective alpha4beta7/alpha4beta1 integrin antagonist natalizumab. Vedolizumab is a useful addition to the treatment options available for patients with moderately to severely active ulcerative colitis and Crohn's disease. PMID- 25502900 TI - Two important legal events that may radically shape the future delivery of dementia care in England and Wales. PMID- 25502898 TI - Tumor evolution and progression in multifocal and paired non-invasive/invasive urothelial carcinoma. AB - Although multifocal tumors and non-invasive/invasive components are commonly encountered in surgical pathology, their genetic relationship is often poorly characterized. We used next-generation sequencing (NGS) to characterize somatic alterations in a patient with five spatially distinct, high-grade papillary urothelial carcinomas (UCs), with one tumor harboring an underlying invasive component. NGS of 409 cancer-related genes was performed on DNA isolated from formalin-fixed paraffin-embedded (FFPE) blocks representing each papillary tumor (n = 5), the invasive component of one tumor, and matched normal tissue. We identified nine unique non-synonymous somatic mutations across the six UC samples, including five present in each carcinoma sample, consistent with clonal origin and limited intertumoral heterogeneity. Copy number and loss of heterogeneity (LOH) profiles were similar in all six carcinomas; however, the invasive carcinoma component uniquely showed focal CDKN2A loss and chromosome 9 LOH and did not harbor gains of chromosomes 5p or X that were present in the other tumor samples. Phylogenetic analysis supported the invasive component arising from a shared progenitor prior to the outgrowth of cells in the non invasive tumors. Results were extended to three additional cases of upper tract UC with paired non-invasive/invasive components, which identified driving alterations exclusive to both non-invasive and invasive components. Lastly, we performed targeted RNA sequencing (RNAseq) using a custom bladder cancer panel, which confirmed gene expression signature differences between paired non invasive/invasive components. The results and approaches presented here may be useful in understanding the clonal relationships in multifocal cancers or paired non-invasive/invasive components from routine FFPE specimens. PMID- 25502901 TI - The accuracy of the anxiety inventory respiratory disease scale for patients with chronic obstructive pulmonary disease. PMID- 25502902 TI - 'Rydym Eisiau Gwybod'--the dementia diagnosis disclosure preferences of people in North Wales. PMID- 25502903 TI - In vivo AAV1 transduction with hRheb(S16H) protects hippocampal neurons by BDNF production. AB - Recent evidence has shown that Ras homolog enriched in brain (Rheb) is dysregulated in Alzheimer's disease (AD) brains. However, it is still unclear whether Rheb activation contributes to the survival and protection of hippocampal neurons in the adult brain. To assess the effects of active Rheb in hippocampal neurons in vivo, we transfected neurons in the cornu ammonis 1 (CA1) region in normal adult rats with an adeno-associated virus containing the constitutively active human Rheb (hRheb(S16H)) and evaluated the effects on thrombin-induced neurotoxicity. Transduction with hRheb(S16H) significantly induced neurotrophic effects in hippocampal neurons through activation of mammalian target of rapamycin complex 1 (mTORC1) without side effects such as long-term potentiation impairment and seizures from the alteration of cytoarchitecture, and the expression of hRheb(S16H) prevented thrombin-induced neurodegeneration in vivo, an effect that was diminished by treatment with specific neutralizing antibodies against brain-derived neurotrophic factor (BDNF). In addition, our results showed that the basal mTORC1 activity might be insufficient to mediate the level of BDNF expression, but hRheb(S16H)-activated mTORC1 stimulated BDNF production in hippocampal neurons. These results suggest that viral vector transduction with hRheb(S16H) may have therapeutic value in the treatment of neurodegenerative diseases such as AD. PMID- 25502905 TI - An update on the role of adipokines in arterial stiffness and hypertension. AB - Adipokines are hormones produced by adipocytes and have been involved in multiple pathologic pathways, including inflammatory and cardiovascular complications in essential hypertension. Arterial stiffness is a frequent vascular complication that represents increased cardiovascular risk in hypertensive patients. Adipokines, such as adiponectin, leptin and resistin, might be implicated in hypertension, as well as in vascular alterations associated with this condition. Arterial stiffness has proven to be a predictor of cardiovascular events. Obesity and target-organ damage such as arterial stiffness are features associated with hypertension. This review aims to update the association between adipokines and arterial stiffness in essential and resistant hypertension (RHTN). PMID- 25502904 TI - Inhibitory/suppressive oligodeoxynucleotide nanocapsules as simple oral delivery devices for preventing atopic dermatitis in mice. AB - Here, we report a simple and low-cost oral oligodeoxynucleotide (ODN) delivery system targeted to the gut Peyer's patches (PPs). This system requires only Dulbecco's modified eagle's medium, calcium chloride, ODNs, and basic laboratory equipment. ODN nanocapsules (ODNcaps) were directly delivered to the PPs through oral administration and were taken up by macrophages in the PPs, where they induced an immune response. Long-term continuous oral dosing with inhibitory/suppressive ODNcaps (iODNcaps, "iSG3caps" in this study) was evaluated using an atopic dermatitis mouse model to visually monitor disease course. Administration of iSG3caps improved skin lesions and decreased epidermal thickness. Underlying this effect is the ability of iSG3 to bind to and prevent phosphorylation of signal transducer and activator of transcription 6, thereby blocking the interleukin-4 signaling cascade mediated by binding of allergens to type 2 helper T cells. The results of our iSG3cap oral delivery experiments suggest that iSG3 may be useful for treating allergic diseases. PMID- 25502906 TI - Hippocampal spatial position evaluation on MRI for research and clinical practice. AB - In clinical practice as well as in many volumetric studies we use different reorientations of the brain position towards x and y axis on the magnetic resonance imaging (MRI) scans. In order to find out whether it has an overall effect on the resulting 2D data, manual hippocampal area measurements and rotation variability of the brain (in two reoriented axes) and the skull were performed in 23 Alzheimer's disease patients and 31 healthy controls. After the MRI scanning, native brain scans (nat) were reoriented into the two different artificial planes (anterior commissure-posterior commissure axis (AC-PC) and hippocampal horizontal long axis (hipp)). Hippocampal area and temporal horn of the lateral ventricle was measured manually using freeware Image J program. We found that 1) hippocampal area of nat images is larger compared to hipp images, area of the nat images is equal to the AC-PC images and area of the hipp images is smaller compared to AC-PC images, 2) hippocampal area together with the area of the temporal horn for nat images is larger compared to hipp images, area of the hipp images is smaller compared to the AC-PC images and area of the nat images is smaller compared to the AC-PC images. The conclusion is that the measured area of the hippocampus in the native MRI is almost the same as the area of MRI reoriented only into the AC-PC axis. Therefore, when performing 2D area studies of the hippocampus or in the clinical practice we recommend usage of not reoriented MRI images or to reorient them into the AC-PC axis. Surprising finding was that rotation of both AC-PC and hipp line towards x-axis among patients varies up to 35 degrees and the same is true for the skull rotation so that it is not only a matter of the brain position. PMID- 25502907 TI - Mesenchymal stromal cells from female donors enhance breast cancer cell proliferation in vitro. AB - The interplay between tumor stroma and breast cancer cells (BCCs) is thought to play a significant role in breast cancer. The current knowledge of human mesenchymal stromal cell (MSC) and BCC interaction is contradictory, and the donor sex issue is not addressed at all. We hypothesized that donor sex could have an effect on proliferation of MSCs or BCCs in co-culture in vitro. Three estrogen receptor-negative BCC lines, 19 primary human MSCs and breast tissue derived fibroblasts from 4 donors were used. MSCs from female donors enhanced BCC proliferation (p = 0.005). The change in BCC proliferation was only partly due to soluble factors excreted by MSCs. The highly aggressive BCC line MDA-MB- 231 induced the proliferation of MSCs (p < 0.001) and fibroblasts (p = 0.037) in co culture experiments. The magnitude in proliferation change was cell line dependent and partly sex dependent. PMID- 25502908 TI - Modularized evolution in archaeal methanogens phylogenetic forest. AB - Methanogens are methane-producing archaea that plays a key role in the global carbon cycle. To date, the evolutionary history of methanogens and closely related nonmethanogen species remains unresolved among studies conducted upon different genetic markers, attributing to horizontal gene transfers (HGTs). With an effort to decipher both congruent and conflicting evolutionary events, reconstruction of coevolved gene clusters and hierarchical structure in the archaeal methanogen phylogenetic forest, comprehensive evolution, and network analyses were performed upon 3,694 gene families from 41 methanogens and 33 closely related archaea. Our results show that 1) greater than 50% of genes are in topological dissonance with others; 2) the prevalent interorder HGTs, even for core genes, in methanogen genomes led to their scrambled phylogenetic relationships; 3) most methanogenesis-related genes have experienced at least one HGT; 4) greater than 20% of the genes in methanogen genomes were transferred horizontally from other archaea, with genes involved in cell-wall synthesis and defense system having been transferred most frequently; 5) the coevolution network contains seven statistically robust modules, wherein the central module has the highest average node strength and comprises a majority of the core genes; 6) different coevolutionary module genes boomed in different time and evolutionary lineage, constructing diversified pan-genome structures; 7) the modularized evolution is also closely related to the vertical evolution signals and the HGT rate of the genes. Overall, this study presented a modularized phylogenetic forest that describes a combination of complicated vertical and nonvertical evolutionary processes for methanogenic archaeal species. PMID- 25502910 TI - Cell resolved, multiparticle model of plastic tissue deformations and morphogenesis. AB - We propose a three-dimensional mechanical model of embryonic tissue dynamics. Mechanically coupled adherent cells are represented as particles interconnected with elastic beams which can exert non-central forces and torques. Tissue plasticity is modeled by a stochastic process consisting of a connectivity change (addition or removal of a single link) followed by a complete relaxation to mechanical equilibrium. In particular, we assume that (i) two non-connected, but adjacent particles can form a new link; and (ii) the lifetime of links is reduced by tensile forces. We demonstrate that the proposed model yields a realistic macroscopic elasto-plastic behavior and we establish how microscopic model parameters determine material properties at the macroscopic scale. Based on these results, microscopic parameter values can be inferred from tissue thickness, macroscopic elastic modulus and the magnitude and dynamics of intercellular adhesion forces. In addition to their mechanical role, model particles can also act as simulation agents and actively modulate their connectivity according to specific rules. As an example, anisotropic link insertion and removal probabilities can give rise to local cell intercalation and large scale convergent extension movements. The proposed stochastic simulation of cell activities yields fluctuating tissue movements which exhibit the same autocorrelation properties as empirical data from avian embryos. PMID- 25502911 TI - Long-term effectiveness of preserved celiac branch of vagal nerve after Roux-en-Y reconstruction in laparoscopy-assisted distal gastrectomy. AB - BACKGROUND: The aim of this retrospective cohort study was to clarify the effectiveness of preserving the celiac branch (CB) of the vagal trunk after the Roux-en-Y (R-Y) reconstruction in laparoscopy-assisted distal gastrectomy (LADG). METHODS: One hundred twenty patients with pathological stage I gastric cancer underwent R-Y reconstruction after LADG with D1 + beta lymphadenectomy between January 2004 and March 2009 and were followed up for 5 years. The patients were divided into 2 groups: the preservation group (P-CB) and the resection group (R CB). Evaluated variables included symptoms, endoscopic findings, nutritional status, and gallstone formation at 5 years after gastrectomy. RESULTS: Gallstone formation was significantly less common in P-CB than in R-CB (16 vs. 33%, p = 0.035). One patient (2%) in P-CB and 4 (7%) in R-CB underwent surgery for symptomatic gallstones. On multivariate analysis of gallstone formation, R-CB was an independent risk factor for gallstone formation (odds ratio = 2.5, 95% confidential interval: 1.0-6.1, p = 0.049). Symptoms and endoscopic findings did not differ significantly between the groups. Relative values of body weight, serum albumin level, and total cholesterol level also did not significantly differ between the groups. CONCLUSION: Preserving the CB independently contributes to the prevention of gallstone formation during long-term follow-up after R-Y reconstruction following LADG. PMID- 25502912 TI - The long-chain alkane metabolism network of Alcanivorax dieselolei. AB - Alkane-degrading bacteria are ubiquitous in marine environments, but little is known about how alkane degradation is regulated. Here we investigate alkane sensing, chemotaxis, signal transduction, uptake and pathway regulation in Alcanivorax dieselolei. The outer membrane protein OmpS detects the presence of alkanes and triggers the expression of an alkane chemotaxis complex. The coupling protein CheW2 of the chemotaxis complex, which is induced only by long-chain (LC) alkanes, sends signals to trigger the expression of Cyo, which participates in modulating the expression of the negative regulator protein AlmR. This change in turn leads to the expression of ompT1 and almA, which drive the selective uptake and hydroxylation of LC alkanes, respectively. AlmA is confirmed as a hydroxylase of LC alkanes. Additional factors responsible for the metabolism of medium-chain length alkanes are also identified, including CheW1, OmpT1 and OmpT2. These results provide new insights into alkane metabolism pathways from alkane sensing to degradation. PMID- 25502913 TI - Direct observation of Dirac cone in multilayer silicene intercalation compound CaSi2. AB - Calcium-intercalated multilayer silicene CaSi2 exhibits a massless Dirac-cone pi electron-band dispersion like graphene, while the Dirac point is about 2 eV away from the Fermi level due to diiimide-based charge transfer from the Ca atoms to the silicene layers. This indicates that the graphene-like electronic structure with a massless Dirac cone is stably formed in the metal-intercalated multilayer silicene. PMID- 25502909 TI - Evolutionary Dynamics of GLD-1-mRNA complexes in Caenorhabditis nematodes. AB - Given the large number of RNA-binding proteins and regulatory RNAs within genomes, posttranscriptional regulation may be an underappreciated aspect of cis regulatory evolution. Here, we focus on nematode germ cells, which are known to rely heavily upon translational control to regulate meiosis and gametogenesis. GLD-1 belongs to the STAR-domain family of RNA-binding proteins, conserved throughout eukaryotes, and functions in Caenorhabditis elegans as a germline specific translational repressor. A phylogenetic analysis across opisthokonts shows that GLD-1 is most closely related to Drosophila How and deuterostome Quaking, both implicated in alternative splicing. We identify messenger RNAs associated with C. briggsae GLD-1 on a genome-wide scale and provide evidence that many participate in aspects of germline development. By comparing our results with published C. elegans GLD-1 targets, we detect nearly 100 that are conserved between the two species. We also detected several hundred Cbr-GLD-1 targets whose homologs have not been reported to be associated with C. elegans GLD-1 in either of two independent studies. Low expression in C. elegans may explain the failure to detect most of them, but a highly expressed subset are strong candidates for Cbr-GLD-1-specific targets. We examine GLD-1-binding motifs among targets conserved in C. elegans and C. briggsae and find that most, but not all, display evidence of shared ancestral binding sites. Our work illustrates both the conservative and the dynamic character of evolution at the posttranslational level of gene regulation, even between congeners. PMID- 25502914 TI - Multi-year and short-term responses of soil ammonia-oxidizing prokaryotes to zinc bacitracin, monensin, and ivermectin, singly or in combination. AB - A field experiment was initiated whereby a series of replicated plots received annual applications of ivermectin, monensin, and zinc bacitracin, either singly or in a mixture. Pharmaceuticals were added at concentrations of 0.1 mg/kg soil or 10 mg/kg soil. The authors collected soil samples in 2013, before and after the fourth annual application of pharmaceuticals. In addition, a 30-d laboratory experiment was undertaken with the same soil and same pharmaceuticals, but at concentrations of 100 mg/kg soil. The impact of the pharmaceuticals on nitrification rates, on the abundance of ammonia-oxidizing bacteria (AOB), and on the abundance of ammonia-oxidizing archaea (AOA) was assessed. None of the pharmaceuticals at 0.1 mg/kg had any effect on nitrification. Referenced to control soil, nitrification was accelerated in soil exposed to 100 mg/kg zinc bacitracin or 10 mg/kg of the pharmaceutical mixture, but none of the treatments inhibited nitrification. Neither AOB abundance nor AOA abundance was affected by the pharmaceuticals at 0.1 mg/kg. At 10 mg/kg, monensin, zinc bacitracin, and a mixture of all 3 pharmaceuticals suppressed the abundance of AOB, and zinc bacitracin and the mixture increased AOA abundance. The decrease in AOB abundance and increase in AOA abundance when exposed to 10 mg/kg soil suggests that AOB are more sensitive to these chemicals and that AOA populations can expand to occupy the partially vacated niche. PMID- 25502916 TI - Erratum to: Characteristics of the perception for unilateral facial nerve palsy. PMID- 25502915 TI - Laser-Doppler microvascular measurements in the peri-implant areas of different osseointegrated bone conductor implant systems. AB - The objective of this study was to evaluate the impact of hydroxyapatite coating of newly designed osseointegrated fixtures' abutments on the postoperative complication rates. The integrity of peri-implant microcirculation was used as a marker to compare tissue viability after different surgical techniques. Laser Doppler Flowmetry (LDF) measures alone, and coupled with heat provocation tests were applied to test the different microcircular patterns. Measures for 17 consecutively implanted patients (8 women, 9 men, ages ranged from 18 to 77 years) were recruited; seven with soft tissue reduction (STR); and 10 with soft tissue preservation (STP).Thirteen non-operated retro-auricular areas were examined as naive controls. In isotherm conditions the baseline blood flow remained stable in all groups. The naive control patients demonstrated significant changes of blood flux in the intact skin. The non-implanted yet previously operated contralateral sides of the patients demonstrated marginally lower (p = 0.09) blood flux index. The STR sides however, showed significantly lower (average 217 %) provoked blood flux compared to controls (p < 0.001). At the STP sides a maladaptation could be observed (average 316 %) compared to the contralateral sides (p = 0.53). STP sides demonstrated a significantly better blood flow improvement compared to the STR sides (p = 0.02). These results suggest a favorable postoperative condition of vascular microcirculation after STP, than after STR surgery. The possibly faster wound healing and lower potential complication rate may widen the inclusion criteria and maybe beneficial for the patient compliance with a better quality-of-life. PMID- 25502917 TI - Graves' disease in childhood: new epidemiological, pathophysiological and therapeutic insights. AB - In this review, the authors analyze the main epidemiological, pathophysiological, clinical and prognostic features of Graves' disease in childhood and provide some therapeutic insights. PMID- 25502918 TI - APECED syndrome in childhood: clinical spectrum is enlarging. AB - Autoimmune polyendocrinopathy-candidiasis-ectodermal-distrophy (APECED) is a rare autosomal recessive disease, which is mainly characterized by the association of many autoimmune diseases, with a classic triad including chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical failure. Its clinical spectrum has significantly enlarged in the last years and other non-classic components have been recently described. Aim of this review was to alert pediatricians to these novel clinical aspects of this syndrome, that have been recently included among the autoimmune APECED manifestations: a) chronic lung disease, that may evolve to cor pulmonale and terminal respiratory failure; b) chronic inflammatory demyelinating polineuropathy, with progressive muscular weakness of both arms and legs and sensory loss; c) gastrointestinal dysfunction, with recurrent diarrhea, malabsorption and steatorrhea or chronic constipation. For each of these novel components of APECED, specific autoantibodies against either lung autoantigens or peripheral nerves or tryptophan hydroxylase have been just recently identified. PMID- 25502919 TI - 'The medical' and 'health' in a critical medical humanities. AB - As befits an emerging field of enquiry, there is on-going discussion about the scope, role and future of the medical humanities. One relatively recent contribution to this debate proposes a differentiation of the field into two distinct terrains, 'medical humanities' and 'health humanities,' and calls for a supersession of the former by the latter. In this paper, we revisit the conceptual underpinnings for a distinction between 'the medical' and 'health' by looking at the history of an analogous debate between 'medical geography' and 'the geographies of health' that has, over the last few years, witnessed a re blurring of the distinction. Highlighting the value of this debate within the social sciences for the future development of the medical humanities, we call for scholars to take seriously the challenges of critical and cultural theory, community-based arts and health, and the counter-cultural creative practices and strategies of activist movements in order to meet the new research challenges and fulfill the radical potential of a critical medical humanities. PMID- 25502920 TI - Algal productivity modeling: a step toward accurate assessments of full-scale algal cultivation. AB - A new biomass productivity model was parameterized for Chlorella vulgaris using short-term (<30 min) oxygen productivities from algal microcosms exposed to 6 light intensities (20-420 W/m(2)) and 6 temperatures (5-42 degrees C). The model was then validated against experimental biomass productivities recorded in bench scale photobioreactors operated under 4 light intensities (30.6-74.3 W/m(2)) and 4 temperatures (10-30 degrees C), yielding an accuracy of +/- 15% over 163 days of cultivation. This modeling approach addresses major challenges associated with the accurate prediction of algal productivity at full-scale. Firstly, while most prior modeling approaches have only considered the impact of light intensity on algal productivity, the model herein validated also accounts for the critical impact of temperature. Secondly, this study validates a theoretical approach to convert short-term oxygen productivities into long-term biomass productivities. Thirdly, the experimental methodology used has the practical advantage of only requiring one day of experimental work for complete model parameterization. The validation of this new modeling approach is therefore an important step for refining feasibility assessments of algae biotechnologies. PMID- 25502921 TI - Theoretical evaluation of the surface electrochemistry of perovskites with promising photon absorption properties for solar water splitting. AB - In this work, we present first-principles calculations describing the catalytic activity for of a set of photoelectrocatalysts identified as candidates for total water splitting in a previous screening study for bulk stability and bandgap. Our Density Functional Theory (DFT) calculations of the intermediate energetics for hydrogen evolution and oxygen evolution suggest that none of the proposed materials has the ideal combination of bandgap and surface chemical properties that should allow for total water splitting in a single material. This result suggests that co-catalysts are necessary to overcome the kinetic limitations of the both reactions, although some materials may catalyze one half-reaction, as has been observed in experiment. PMID- 25502922 TI - Fibronectin immobilization on to robotic-dispensed nanobioactive glass/polycaprolactone scaffolds for bone tissue engineering. AB - Bioactive nanocomposite scaffolds with cell-adhesive surface have excellent bone regeneration capacities. Fibronectin (FN)-immobilized nanobioactive glass (nBG)/polycaprolactone (PCL) (FN-nBG/PCL) scaffolds with an open pore architecture were generated by a robotic-dispensing technique. The surface immobilization level of FN was significantly higher on the nBG/PCL scaffolds than on the PCL scaffolds, mainly due to the incorporated nBG that provided hydrophilic chemical-linking sites. FN-nBG/PCL scaffolds significantly improved cell responses, including initial anchorage and subsequent cell proliferation. Although further in-depth studies on cell differentiation and the in vivo animal responses are required, bioactive nanocomposite scaffolds with cell-favoring surface are considered to provide promising three-dimensional substrate for bone regeneration. PMID- 25502923 TI - Solid pseudopapillary tumors of the pancreas: Findings from routine screening sonographic examination and the value of contrast-enhanced ultrasound. AB - BACKGROUND: Solid pseudopapillary tumors (SPTs) are rare neoplasms of the pancreas. We describe the features of these small tumors identified on routine screening sonographic (US) examination and the potential value of using contrast enhanced ultrasound (CEUS) scanning. METHODS: We retrospectively reviewed records from 17 patients who had undergone screening via US examination at Peking University Third Hospital between January 2000 and June 2011. Each of these patients had been confirmed by a pathologist to have an SPT. Six patients had undergone CEUS prior to surgery. We recorded all features on both gray-scale US and CEUS. RESULTS: All patients (4 men and 13 women; ages 23-35 years; mean age, 27.2 years) were initially screened by US. The largest mass identified was 5.0 cm in diameter (mean diameter, 4.2 cm), and most tumors showed homogeneous hypoechogenicity. A hyperechoic rim was detected in four masses. CEUS showed peripheral-rim hyperenhancement in the arterial phase of all six masses. CONCLUSIONS: Routine screening US examinations are capable of identifying small (<5.0 cm) SPTs. These screening examinations allow diagnosis on the basis of typical imaging features, such as a homogeneously hypoechoic mass with a hyperechoic rim. CEUS shows greater detail of the rim and cystic areas in the tumor, which significantly improves the proper diagnosis. PMID- 25502924 TI - Electroosmosis of Powell-Eyring fluids under interfacial slip. AB - We investigate the EOF of a Powell-Eyring fluid through a slit microchannel, employing Navier slip boundary condition. Using an analytical scheme consistent with the homotopy perturbation method, we bring out the alteration in the underlying flow dynamics as attributable to the nonlinear interactions between fluid rheology and electrostatics over interfacial scales. We validate the approximate analytical solutions by comparing those with results from numerical analysis. We unveil a regime of phenomenal amplification in the net volumetric flow rate, realized as a consequence of an intricate interplay between interfacial electromechanics, slipping hydrodynamics, and the flow rheology. Our results may have far ranging consequences in the design of various biomicrofluidic devises/systems, which are often used for the manipulation of non Newtonain fluids. PMID- 25502925 TI - Alginate as a cell culture substrate for growth and differentiation of human retinal pigment epithelial cells. AB - The purpose of this study was to evaluate retinal pigment epithelium (RPE) cells' behavior in alginate beads that establish 3D environment for cellular growth and mimic extracellular matrix versus the conventional 2D monolayer culture. RPE cells were encapsulated in alginate beads by dripping alginate cell suspension into CaCl2 solution. Beads were suspended in three different media including Dulbecco's modified Eagle's medium (DMEM)/F12 alone, DMEM/F12 supplemented with 10 % fetal bovine serum (FBS), and DMEM/F12 supplemented with 30 % human amniotic fluid (HAF). RPE cells were cultivated on polystyrene under the same conditions as controls. Cell phenotype, cell proliferation, cell death, and MTT assay, immunocytochemistry, and real-time RT-PCR were performed to evaluate the effect of alginate on RPE cells characteristics and integrity. RPE cells can survive and proliferate in alginate matrixes. Immunocytochemistry analysis exhibited Nestin, RPE65, and cytokeratin expressions in a reasonable number of cultured cells in alginate beads. Real-time PCR data demonstrated high levels of Nestin, CHX10, RPE65, and tyrosinase gene expressions in RPE cells immobilized in alginate when compared to 2D monolayer culture systems. The results suggest that alginate can be used as a reliable scaffold for maintenance of RPE cells' integrity and in vitro propagation of human retinal progenitor cells for cell replacement therapies in retinal diseases. PMID- 25502926 TI - Molecular cloning and expression analysis of the gene encoding proline dehydrogenase from Jatropha curcas L. AB - Proline dehydrogenase (ProDH) (EC 1.5.99.8) is a key enzyme in the catabolism of proline. The enzyme JcProDH and its complementary DNA (cDNA) were isolated from Jatropha curcas L., an important woody oil plant used as a raw material for biodiesels. It has been classified as a member of the Pro_dh superfamily based on multiple sequence alignment, phylogenetic characterization, and its role in proline catabolism. Its cDNA is 1674 bp in length with a complete open reading frame of 1485 bp, which encodes a polypeptide chain of 494 amino acids with a predicted molecular mass of 54 kD and a pI of 8.27. Phylogenetic analysis indicated that JcProDH showed high similarity with ProDH from other plants. Reverse transcription PCR (RT-PCR) analysis revealed that JcProDH was especially abundant in the seeds and flowers but scarcely present in the stems, roots, and leaves. In addition, the expression of JcProDH increased in leaves experiencing environmental stress such as cold (5 degrees C), heat (42 degrees C), salt (300 mM), and drought (30 % PEG6000). The JcProDH protein was successfully expressed in the yeast strain INVSc1 and showed high enzyme activity in proline catabolism. This result confirmed that the JcProDH gene negatively participated in the stress response. PMID- 25502929 TI - Amide-triazole isosteric substitution for tuning self-assembly and incorporating new functions into soft supramolecular materials. AB - The proof-of-concept for the modular synthesis of new functional soft gel materials based on amide-triazole isosteric replacement has been demonstrated. A coassembly approach of isosteric amino acid-based hydrogelators was fruitfully applied for fine-tuning the release of entrapped drugs. PMID- 25502927 TI - Profile of Trypanosoma cruzi infection in a tropical medicine reference center, Northern Italy. AB - BACKGROUND: Chagas disease (CD) is endemic in Central and South America, Mexico and even in some areas of the United States. However, cases have been increasingly recorded also in non-endemic countries. The estimated number of infected people in Europe is in a wide range of 14000 to 181000 subjects, mostly resident in Spain, Italy and the United Kingdom. METHODOLOGY/PRINCIPAL FINDINGS: Retrospective, observational study describing the characteristics of patients with CD who attended the Centre for Tropical Diseases (Negrar, Verona, Italy) between 2005 and 2013. All the patients affected by CD underwent chest X-ray, ECG, echocardiography, barium X-ray of the oesophagus and colonic enema. They were classified in the indeterminate, cardiac, digestive or mixed category according to the results of the screening tests. Treatment with benznidazole (or nifurtimox in case of intolerance to the first line therapy) was offered to all patients, excluding the ones with advanced cardiomiopathy, pregnant and lactating women. Patients included were 332 (73.9% women). We classified 68.1% of patients as having Indeterminate Chagas, 11.1% Cardiac Chagas, 18.7% as Digestive Chagas and 2.1% as Mixed Form. Three hundred and twenty-one patients (96.7%) were treated with benznidazole, and most of them (83.2%) completed the treatment. At least one adverse effect was reported by 27.7% of patients, but they were mostly mild. Only a couple of patients received nifurtimox as second line treatment. CONCLUSIONS/SIGNIFICANCE: Our case series represents the largest cohort of T. cruzi infected patients diagnosed and treated in Italy. An improvement of the access to diagnosis and cure is still needed, considering that about 9200 infected people are estimated to live in Italy. In general, there is an urgent need of common guidelines to better classify and manage patients with CD in non endemic countries. PMID- 25502930 TI - Indications and outcomes for use of Montgomery cannulas. AB - IMPORTANCE: To our knowledge, we report the first series to analyze use of the Montgomery cannula as an airway management tool for indications other than obstructive sleep apnea. OBJECTIVES: To analyze the use and outcomes of Montgomery cannula placement for airway management and to identify indications for placement. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of 20 patients who received a Montgomery cannula from 2003 through 2012 at the University of Iowa Hospitals and Clinics. INTERVENTION: Montgomery cannula placement. MAIN OUTCOMES AND MEASURES: Indications for cannula placement, comorbidities, body mass index, reasons for failure of cannula use, and complications. RESULTS: Indications included glottic stenosis (n = 7), obstructive sleep apnea (n = 5), bilateral vocal cord paralysis (n = 4), subglottic stenosis (n = 4), supraglottic swelling after radiation or chemoradiation therapy (n = 4), bulbar dystonia with paradoxical vocal cord motion (n = 1), vocal cord fixation secondary to rheumatoid arthritis and gastroesophageal reflux disease (n = 1), and airway obstruction associated with seizure disorder (n = 1). Comorbidities included obesity or overweight (n = 14), gastroesophageal reflux disease (n = 9), hypertension (n = 7), and diabetes mellitus (n = 6). Fifteen patients successfully used a Montgomery cannula, including all patients with 3 or fewer comorbidities. Five patients required replacement with a Jackson tracheostomy tube due to persistent tracheostomal granulation tissue (n = 2), feeling safer with the tracheostomy tube (n = 1), a posterior scar band causing airway obstruction (n = 1), and inability to care for the cannula because of poor manual dexterity from arthritis (n = 1). The mean (range) body mass index of successful and unsuccessful users was 27.5 (18.2-37.7) and 33.8 (24.1-42.7), respectively. Complications included the cannula being blocked by adipose tissue (n = 2) or pushed posteriorly into the airway (n = 2). The Montgomery cannula was used as a successful decannulation tool in 4 patients with the cannula serving as an interim airway management tool leading to tracheostome closure. CONCLUSIONS AND RELEVANCE: We identified features associated with successful use of the cannula and an additional indication for a Montgomery cannula as a step-down management tool for decannulation. PMID- 25502931 TI - The sludge loading rate regulates the growth and release of heterotrophic bacteria resistant to six types of antibiotics in wastewater activated sludge. AB - Wastewater treatment plants are considered as hot reservoirs of antimicrobial resistance. However, the fates of antibiotic-resistant bacteria during biological treatment processes and relevant influencing factors have not been fully understood. This study evaluated the effects of the sludge loading rate on the growth and release of six kinds of antibiotic-resistant bacteria in an activated sludge system. The results indicated that higher sludge loading rates amplified the growth of all six types of antibiotic resistant bacteria. The release of most antibiotic-resistant bacteria through both the effluent and biosolids was amplified with increased sludge loading rate. Biosolids were the main pattern for all antibiotic-resistant bacteria release in an activated sludge system, which was determined primarily by their growth in the activated sludge. A higher sludge loading rate reactor tended to retain more antibiotic resistance. An activated sludge system with lower sludge loading rates was considered more conducive to the control of antibiotic resistance. PMID- 25502933 TI - Quantitative analogy between polymer-grafted nanoparticles and patchy particles. AB - We establish a quantitative analogy between polymer grafted nanoparticles (PGNPs) and patchy nanoparticles (NPs). Over much of the experimentally relevant parameter space, we show that PGNPs behave quantitatively like Janus NPs, with the patch size having a universal dependence on the number of grafts and the ratio of the size of the NPs to the grafted chain size. The widely observed anisotropic self-assembly of PGNP into superstructures can thus be understood through simple geometric considerations of single patch models, in the same spirit as the geometry-based surfactant models of Israelachvili. PMID- 25502928 TI - A hypothetical model of crossing Bombyx mori nucleopolyhedrovirus through its host midgut physical barrier. AB - Bombyx mori nucleopolyhedrovirus (BmNPV) is a primary pathogen of silkworm (B. mori) that causes severe economic losses each year. However, the molecular mechanisms of silkworm-BmNPV interactions, especially the silkworm proteins that can interact with the virus, are still largely unknown. In this study, the total and membrane proteins of silkworm midguts were displayed using one- and two dimensional electrophoresis. A virus overlay assay was used to detect B. mori proteins that specifically bind to BmNPV particles. Twelve proteins were located and identified using mass spectrometry, and the different expression of the corresponding genes in BmNPV susceptible and resistant silkworm strains also indicated their involvement in BmNPV infection. The 12 proteins are grouped based on their potential roles in viral infection, for example, endocytosis, intracellular transportation, and host responses. Based on these results, we hypothesize the following: I) vacuolar ATP synthase catalytic subunit A and subunit B may be implicated in the process of the membrane fusion of virus and the release of the nucleocapsid into cytoplasm; II) actin, enolase and phosphoglycerate kinase are cytoskeleton associated proteins and may play an important role in BmNPV intracellular transportation; III) mitochondrial prohibitin complex protein 2, ganglioside-induced differentiation-associated protein, calreticulin, regucalcin-like isoform X1 and 60 kDa heat shock protein are involved in cell apoptosis regulation during BmNPV infection in larvae midguts; IV) ribosomal P0 may be associated with BmNPV infection by regulating gene expression of BmNPV; V) arginine kinase has a role in the antiviral activities against BmNPV. Our work should prove informative by providing multiple protein targets and a novel direction to investigate the molecular mechanisms of the interactions between silkworms and BmNPV. PMID- 25502932 TI - Cytotoxic effects of tetracycline analogues (doxycycline, minocycline and COL-3) in acute myeloid leukemia HL-60 cells. AB - Tetracycline analogues (TCNAs) have been shown to inhibit matrix metalloproteinases and to induce apoptosis in several cancer cell types. In the present study, the cytotoxic effects of TCNAs doxycycline (DOXY), minocycline (MINO) and chemically modified tetracycline-3 (COL-3) were investigated in the human acute myeloid leukemia HL-60 cell line. Cells were incubated with TCNAs in final concentrations of 0.5-100 ug/ml for 24 h. Viability of the leukemic cells was inhibited in a concentration-dependent manner using resazurin assay. The estimated IC50s were 9.2 ug/ml for DOXY, 9.9 ug/ml for MINO and 1.3 ug/ml for COL 3. All three TCNAs induced potent cytotoxic effects and cell death. Apoptosis, which was assessed by morphological changes and annexin V positivity, was concentration- and time-dependent following incubation with any one of the drugs. TCNAs induced DNA double strand breaks soon after treatment commenced as detected by gammaH2AX and western blot. The loss of mitochondrial membrane potential (Deltapsim), caspase activation and cleavage of PARP and Bcl-2 were observed; however, the sequence of events differed among the drugs. Pancaspase inhibitor Z VAD-FMK improved survival of TCNAs-treated cells and decreased TCNAs-induced apoptosis. In summary, we demonstrated that TCNAs had a cytotoxic effect on the HL-60 leukemic cell line. Apoptosis was induced via mitochondria-mediated and caspase-dependent pathways in HL-60 cells by all three TCNAs. COL-3 exerted the strongest anti-proliferative and pro-apoptotic effects in concentrations that have been achieved in human plasma in reported clinical trials. These results indicate that there is a therapeutic potential of TCNAs in leukemia. PMID- 25502934 TI - Glucose-dependent glucose transporter 1 expression and its impact on viability of thyroid cancer cells. AB - Cancer cells exhibit an altered metabolism characterized by enhanced glycolysis and glucose consumption. In glucose-addicted cancer cells upregulation of glucose transport across the plasma membrane is mediated by a family of facilitated glucose transporter proteins, particularly glucose transporter 1 (GLUT1). The aim of the present study was to investigate the impact of GLUT1 expression on glucose uptake and viability of FTC-133 and 8305c thyroid cancer cells growing in hypoglycemic, normoglycemic and hyperglycemic conditions. The results showed that the total expression of GLUT1 was higher in the two cell types growing in low glucose compared to cells growing in normoglycemia or hyperglycemia and this was correlated with AKT Ser473 phosphorylation but not with the expression of hypoxia inducible factor alpha (HIF1alpha). However, the membrane expression of GLUT1 was correlated with HIF1alpha expression. HIF1alpha expression was positively correlated with the glucose concentration in FTC-133 cells, whereas this expression was inversely correlated in 8305c cells. Glucose uptake was dependent on the membrane level of GLUT1 but not total GLUT1 expression. Downregulation of GLUT1 expression by RNAi in FTC-133 cells caused a reduction in glucose uptake but did not significantly affect cell viability. In the case of 8305c cells showing low endogenous GLUT1 expression and lack of HIF1alpha expression in normoxic conditions GLUT1 RNAi impacted cell viability. These data suggested that GLUT1 may be part of an AKT1-dependent mechanism allowing cells to survive in low levels of glucose. Glucose concentration inversely affected HIF1alpha expression and the level of GLUT1 in membrane as well as glucose uptake in FTC-133 and 8305c cells. The extent of GLUT1 impact on cell viability was also cell-type-dependent. PMID- 25502936 TI - Acidically oxidized carbon cloth: a novel metal-free oxygen evolution electrode with high catalytic activity. AB - The efficiency of many energy storage technologies is limited by the sluggish kinetics of the oxygen evolution reaction (OER) and it is thus of great importance to develop highly active OER electrocatalysts made from earth-abundant elements. In this communication, we report a novel metal-free oxygen evolution electrode with high catalytic activity and stability through simple acidic oxidation of commercially available carbon cloth (CC). The resulting acidically oxidized CC exhibits an overpotential of 328 mV and a Tafel slope of 82 mV dec( 1) with 100% Faradaic efficiency. This electrode needs an overpotential of 477 mV to afford a current density of 10 mA cm(-2) and maintains its catalytic activity for at least 24,000 s. It offers us a low-cost flexible electrocatalytic electrode for device integration toward water splitting and rechargeable metal air battery applications. PMID- 25502935 TI - Evaluation of patient knowledge, desire, and psychosocial background regarding postmastectomy breast reconstruction in Hungary: a questionnaire study of 500 cases. AB - BACKGROUND: According to European guidelines, breast cancer patients requiring mastectomy should be informed about available options regarding breast reconstruction. There are clear differences in the quality standards of oncoplastic care throughout Europe, with slight improvements in Central European countries like Hungary. The aim of the present investigation was to evaluate patients' knowledge and demand for postmastectomy breast reconstruction, as well as their psychosocial background regarding decision-making. MATERIAL AND METHODS: A questionnaire containing 15 structured questions was given to 500 breast cancer patients on the day before undergoing mastectomy. The questions focused on the emotional impact of the malignant disease and the loss of a breast; the importance of environmental conditions; the desire for breast reconstruction; and patients' knowledge and sources of information about the procedure. All answers were statistically analyzed in the context of patient age, marital status, educational level, and place of residence. RESULTS: Descriptive statistical results of the answers to all questions, as well as associations of the different aspects of the decision-making process, are presented. CONCLUSIONS: Hungarian breast cancer patients have very limited knowledge regarding breast reconstruction. We confirmed that patients scheduled for mastectomy have a great degree of anxiety due to their disease and breast loss. Almost 50% of the responders declared their desire for postmastectomy breast reconstruction. Patient's age, residence, educational level, marital status, and profession were confirmed as predictive factors in the decision-making process for breast reconstruction. PMID- 25502937 TI - Primary epithelioid hemangioendothelioma of the bladder: case report and review of the literature. AB - Epithelioid hemangioendothelioma (EHE) is a rare tumor of the urinary system. Only three cases of EHE of the bladder have been reported to date, and the biological properties of the tumor in this location remain poorly characterized. We report a case of primary EHE of the urinary bladder in a 58-year-old woman who was treated by transurethral resection and review the existing literature on the diagnosis and treatment of EHE of the bladder. PMID- 25502938 TI - The dissection of meiotic chromosome movement in mice using an in vivo electroporation technique. AB - During meiosis, the rapid movement of telomeres along the nuclear envelope (NE) facilitates pairing/synapsis of homologous chromosomes. In mammals, the mechanical properties of chromosome movement and the cytoskeletal structures responsible for it remain poorly understood. Here, applying an in vivo electroporation (EP) technique in live mouse testis, we achieved the quick visualization of telomere, chromosome axis and microtubule organizing center (MTOC) movements. For the first time, we defined prophase sub-stages of live spermatocytes morphologically according to GFP-TRF1 and GFP-SCP3 signals. We show that rapid telomere movement and subsequent nuclear rotation persist from leptotene/zygotene to pachytene, and then decline in diplotene stage concomitant with the liberation of SUN1 from telomeres. Further, during bouquet stage, telomeres are constrained near the MTOC, resulting in the transient suppression of telomere mobility and nuclear rotation. MTs are responsible for these movements by forming cable-like structures on the NE, and, probably, by facilitating the rail-tacking movements of telomeres on the MT cables. In contrast, actin regulates the oscillatory changes in nuclear shape. Our data provide the mechanical scheme for meiotic chromosome movement throughout prophase I in mammals. PMID- 25502939 TI - Venom-related transcripts from Bothrops jararaca tissues provide novel molecular insights into the production and evolution of snake venom. AB - Attempts to reconstruct the evolutionary history of snake toxins in the context of their co-option to the venom gland rarely account for nonvenom snake genes that are paralogous to toxins, and which therefore represent important connectors to ancestral genes. In order to reevaluate this process, we conducted a comparative transcriptomic survey on body tissues from a venomous snake. A nonredundant set of 33,000 unigenes (assembled transcripts of reference genes) was independently assembled from six organs of the medically important viperid snake Bothrops jararaca, providing a reference list of 82 full-length toxins from the venom gland and specific products from other tissues, such as pancreatic digestive enzymes. Unigenes were then screened for nontoxin transcripts paralogous to toxins revealing 1) low level coexpression of approximately 20% of toxin genes (e.g., bradykinin-potentiating peptide, C-type lectin, snake venom metalloproteinase, snake venom nerve growth factor) in body tissues, 2) the identity of the closest paralogs to toxin genes in eight classes of toxins, 3) the location and level of paralog expression, indicating that, in general, co expression occurs in a higher number of tissues and at lower levels than observed for toxin genes, and 4) strong evidence of a toxin gene reverting back to selective expression in a body tissue. In addition, our differential gene expression analyses identify specific cellular processes that make the venom gland a highly specialized secretory tissue. Our results demonstrate that the evolution and production of venom in snakes is a complex process that can only be understood in the context of comparative data from other snake tissues, including the identification of genes paralogous to venom toxins. PMID- 25502941 TI - Analysis of aberrantly spliced transcripts of a novel de novo GNAS mutant in a male with albright hereditary osteodystrophy and PHP1A. AB - Pseudohypoparathyroidism (PHP) is a genetic disorder due to target-organ unresponsiveness to parathyroid hormone (PTH). PHP type 1A (PHP1A) is an autosomal dominant disease characterized by Albright hereditary osteodystrophy (AHO) and PTH resistance caused by defects at the GNAS locus. We analyzed the GNAS gene in a male with typical AHO and elevated PTH levels. We identified a novel de novo heterozygous mutation at the splice donor site in intron-7 (IVS7+1G>A, c.585+1G>A) of the GNAS gene. No GNAS mutations were detected in his parents. Our patient was diagnosed with PHP1A due to a heterozygous de novo mutation in the GNAS gene. Reverse transcriptase (RT) PCR analysis and sequencing revealed that this de novo splice mutation generated alternative splicing errors leading to the formation of 2 mutant transcripts: one with exon-7 deleted, the other with whole intron-7 included. To investigate whether these aberrantly spliced transcripts were stable, we assessed the differential expression of GNAS mRNAs in the proband's blood by real-time quantitative RT-PCR. In the proband, the relative expression levels of wild-type, exon-7-deleted, and intron-7 included GNAS mRNAs were 0.21, 6.12E-07, and 1.08E-04, respectively, relative to wild-type GNAS mRNA from a healthy control (set at 1.0). This suggests that this novel de novo splicing mutation generates rapidly decaying mutant transcripts, which might affect stimulatory G-protein activity and give rise to this sporadic case. In conclusion, this is an interesting report of aberrantly spliced mRNAs from a de novo splice mutation of the GNAS gene causing PHP1A in a male. PMID- 25502942 TI - Leptin level lowers in proportion to the amount of aerobic work after four weeks of training in obesity. AB - Leptin values are higher in obesity. Physical exercise reduces fat mass (FM) and decreases leptin levels. Intensity of physical training seems to play a role in reducing circulating leptin. In 16 obese subjects (8 men and 8 women, age 38.6+/ 3.9 years, BMI 35.9+/-1.8 kg/m(2)), leptin was sampled before and after 4 weeks of controlled training. Eight subjects (4 men and 4 women) performed an aerobic training schedule (Group A), the remainders an aerobic training program with a bout of work beyond the anaerobic threshold (AT) (Group B). Training determined a reduction in leptin levels in both groups, which was significant in Group A (12.2 vs. 27.8 MUg/l, p<0.05), even when related to the change in FM (0.372 vs. 0.762 MUg/l/kg, p<0.05). FM decreased significantly in Group B when compared to Group A (-7.4 vs. -2.6 kg, respectively, p<0.001). While in Group A the slight loss of FM was aggregated to a significant decrease in leptin levels, the opposite occurred in Group B. In Group A, leptin lowering was proportional to the amount of total work performed (p<0.001, R(2)=0.89). In obesity, a reduction is observed in leptin levels after short-term training, which is seemingly dissociated from concomitant decrease of FM. Aerobic training alone appears to be linked to a greater leptin reduction, which is well correlated with the amount of work performed. PMID- 25502940 TI - Gene turnover in the avian globin gene families and evolutionary changes in hemoglobin isoform expression. AB - The apparent stasis in the evolution of avian chromosomes suggests that birds may have experienced relatively low rates of gene gain and loss in multigene families. To investigate this possibility and to explore the phenotypic consequences of variation in gene copy number, we examined evolutionary changes in the families of genes that encode the alpha- and beta-type subunits of hemoglobin (Hb), the tetrameric alpha2beta2 protein responsible for blood-O2 transport. A comparative genomic analysis of 52 bird species revealed that the size and membership composition of the alpha- and beta-globin gene families have remained remarkably constant during approximately 100 My of avian evolution. Most interspecific variation in gene content is attributable to multiple independent inactivations of the alpha(D)-globin gene, which encodes the alpha-chain subunit of a functionally distinct Hb isoform (HbD) that is expressed in both embryonic and definitive erythrocytes. Due to consistent differences in O2-binding properties between HbD and the major adult-expressed Hb isoform, HbA (which incorporates products of the alpha(A)-globin gene), recurrent losses of alpha(D) globin contribute to among-species variation in blood-O2 affinity. Analysis of HbA/HbD expression levels in the red blood cells of 122 bird species revealed high variability among lineages and strong phylogenetic signal. In comparison with the homologous gene clusters in mammals, the low retention rate for lineage specific gene duplicates in the avian globin gene clusters suggests that the developmental regulation of Hb synthesis in birds may be more highly conserved, with orthologous genes having similar stage-specific expression profiles and similar functional properties in disparate taxa. PMID- 25502943 TI - Interacting Effects of TSH and Insulin on Human Differentiated Adipocytes. AB - Subclinical hypothyroidism, characterized by an isolated rise in TSH serum levels with normal thyroid function, is a pro-inflammatory state associated with insulin resistance. Adipocytes express TSH receptors, but it is not known if TSH can directly inhibit insulin signaling. Using primary human differentiated adipocytes, we examined the effects of TSH on insulin-stimulated Akt phosphorylation, and whether conventional PKC (cPKC) were involved. The effect of insulin on TSH-stimulated lipolysis was also investigated. TSH inhibited insulin stimulated Akt phosphorylation in adipocytes by 54%. TSH activated cPKC, and Go6976, a PKCalpha and -beta1 inhibitor, prevented the inhibitory effect of TSH on the insulin response. Insulin reduced the ability of TSH to activate cPKC and to stimulate lipolysis.Our data reveal novel interactions between TSH and insulin. TSH inhibits insulin-stimulated Akt signaling in a cPKC-dependent fashion, whereas insulin blocks TSH-stimulated cPKC activity and lipolysis. TSH and insulin act on differentiated human adipocytes to modulate their respective intracellular signals. PMID- 25502945 TI - Genetics of neuroendocrine factors in rheumatoid arthritis. AB - Inadequate production of cortisol related to inflammation and decrease in adrenal androgen production are hallmarks of hypothalamic-pituitary-adrenal (HPA)-related endocrine findings in rheumatoid arthritis (RA). In particular, lower dehydroepiandrosterone sulfate (DHEAS) levels were consistently found in a subset of premenopausal RA females. Recently, several new gene variants have been identified in association with serum DHEAS concentrations, such as in SULT2A1 and HHEX genes. These DHEAS-related genes and other variants involved in HPA regulation may play a role in the adrenal androgen deficiency in RA. The aim of our study was to review involvement of genetic mechanisms of HPA regulation, with focus on adrenal androgens, in the context of RA pathophysiology. Although, effects of the DHEAS-related gene variants appear to be relatively small compared to other well-known factors such as age, complex interactions between DHEAS associated genotypes and adrenal androgen hypofunction phenotype may exist in RA. Further studies analyzing specific neuroendocrine phenotype/genotype in RA are needed. PMID- 25502946 TI - Serotonergic neurons respond to nutrients and regulate the timing of steroid hormone biosynthesis in Drosophila. AB - The temporal transition of development is flexibly coordinated in the context of the nutrient environment, and this coordination is essential for organisms to increase their survival fitness and reproductive success. Steroid hormone, a key player of the juvenile-to-adult transition, is biosynthesized in a nutrient dependent manner; however, the underlying genetic mechanism remains unclear. Here we report that the biosynthesis of insect steroid hormone, ecdysteroid, is regulated by a subset of serotonergic neurons in Drosophila melanogaster. These neurons directly innervate the prothoracic gland (PG), an ecdysteroid-producing organ and share tracts with the stomatogastric nervous system. Interestingly, the projecting neurites morphologically respond to nutrient conditions. Moreover, reduced activity of the PG-innervating neurons or of serotonin signalling in the PG strongly correlates with a delayed developmental transition. Our results suggest that serotonergic neurons form a link between the external environment and the internal endocrine system by adaptively tuning the timing of steroid hormone biosynthesis. PMID- 25502948 TI - Dopaminergic modulation of arm swing during gait among Parkinson's disease patients. AB - BACKGROUND: Reduced arm swing amplitude, symmetry, and coordination during gait have been reported in Parkinson's disease (PD), but the relationship between dopaminergic depletion and these upper limb gait changes remains unclear. OBJECTIVE: We aimed to investigate the effects of dopaminergic drugs on arm swing velocity, symmetry, and coordination in PD. METHODS: Forearm angular velocity was recorded in 16 PD and 17 control subjects (Controls) during free walking trials. Angular velocity amplitude of each arm, arm swing asymmetry, and maximum cross correlation were compared between control and PD groups, and between OFF- and ON medication states among PD subjects. RESULTS: Compared to Controls, PD subjects in the OFF-medication state exhibited lower angular velocity amplitude of the slower- (p = 0.0018), but not faster- (p = 0.2801) swinging arm. In addition, PD subjects demonstrated increased arm swing asymmetry (p = 0.0046) and lower maximum cross-correlation (p = 0.0026). Following dopaminergic treatment, angular velocity amplitude increased in the slower- (p = 0.0182), but not faster- (p = 0.2312) swinging arm among PD subjects. Furthermore, arm swing asymmetry decreased (p = 0.0386), whereas maximum cross-correlation showed no change (p = 0.7436). Pre-drug angular velocity amplitude of the slower-swinging arm was correlated inversely with the change in arm swing asymmetry (R = -0.73824, p = 0.0011). CONCLUSIONS: This study provides quantitative evidence that reduced arm swing and symmetry in PD can be modulated by dopaminergic replacement. The lack of modulations of bilateral arm coordination suggests that additional neurotransmitters may also be involved in arm swing changes in PD. Further studies are warranted to investigate the longitudinal trajectory of arm swing dynamics throughout PD progression. PMID- 25502950 TI - Effect of serum uric acid on the positive predictive value of dobutamine stress echocardiography. AB - There is controversial data regarding the relationship between uric acid (UA) and coronary artery disease and cardiovascular events. Despite the deleterious effects of hyperuricemia on endothelial function, the effect of UA on myocardial ischemia has not been previously studied. We aimed to investigate the relationship between UA and myocardial ischemia that was identified using dobutamine stress echocardiography (DSE). In this retrospective study, the laboratory and DSE reports of 548 patients were reviewed. The patients were divided into two groups based on the presence of ischemia and further subdivided into three groups according to the extent of ischemia (none, ischemia in 1-3 segments, ischemia in >3 segments). Serum UA levels were compared. Determinants of ischemia were assessed using a regression model. UA was increased in patients with ischemia and was correlated with the number of ischemic segments (p < 0.001). A cutoff value of UA > 5 mg/dl had 63.9 % sensitivity, 62.0 % specificity, 42.5 % positive predictive value (PPV), and 79.6 % negative predictive value for ischemia. When the positive DSE exams were further sorted according to the UA cutoff, the PPV of DSE increased from 80.2 to 94.0 %. Uric acid (odds ratio 1.51; 95 % CI 1.14-1.99), diabetes mellitus, HDL and glomerular filtration rate were found to be independent determinants of myocardial ischemia in DSE. Increased UA is associated with both the presence and extent of DSE identified myocardial ischemia. A UA cutoff may be a good method to improve the PPV of DSE. PMID- 25502949 TI - Circadian mechanisms of food anticipatory rhythms in rats fed once or twice daily: clock gene and endocrine correlates. AB - Circadian clocks in many brain regions and peripheral tissues are entrained by the daily rhythm of food intake. Clocks in one or more of these locations generate a daily rhythm of locomotor activity that anticipates a regular mealtime. Rats and mice can also anticipate two daily meals. Whether this involves 1 or 2 circadian clocks is unknown. To gain insight into how the circadian system adjusts to 2 daily mealtimes, male rats in a 12?12 light-dark cycle were fed a 2 h meal either 4 h after lights-on or 4 h after lights-off, or a 1 h meal at both times. After 30 days, brain, blood, adrenal and stomach tissue were collected at 6 time points. Multiple clock genes from adrenals and stomachs were assayed by RT-PCR. Blood was assayed for corticosterone and ghrelin. Bmal1 expression was quantified in 14 brain regions by in situ hybridization. Clock gene rhythms in adrenal and stomach from day-fed rats oscillated in antiphase with the rhythms in night-fed rats, and at an intermediate phase in rats fed twice daily. Corticosterone and ghrelin in 1-meal rats peaked at or prior to the expected mealtime. In 2-meal rats, corticosterone peaked only prior the nighttime meal, while ghrelin peaked prior to the daytime meal and then remained elevated. The olfactory bulb, nucleus accumbens, dorsal striatum, cerebellum and arcuate nucleus exhibited significant daily rhythms of Bmal1 in the night-fed groups that were approximately in antiphase in the day-fed groups, and at intermediate levels (arrhythmic) in rats anticipating 2 daily meals. The dissociations between anticipatory activity and the peripheral clocks and hormones in rats anticipating 2 daily meals argue against a role for these signals in the timing of behavioral rhythms. The absence of rhythmicity at the tissue level in brain regions from rats anticipating 2 daily meals support behavioral evidence that circadian clock cells in these tissues may reorganize into two populations coupled to different meals. PMID- 25502952 TI - Cerebrosides from a Far-Eastern Glass Sponge Aulosaccus sp. AB - Nine new cerebrosides 1a-d, 2a, 2b, 3a-c were found in the extract of a Far Eastern glass sponge Aulosaccus sp. (class Hexactinellida). These beta-D glucopyranosyl-(1 -> 1)-ceramides contain sphingoid bases (2S,3S,4R,11Z)-2 aminoeicos-11-ene-1,3,4-triol (in 1a-d), (2S,3S,4R,13Z)-2-aminoeicos-13-ene-1,3,4 triol (in 2a, b) and (2S,3S,4R,13S*,14R*)-2-amino-13,14-methylene-eicosane-1,3,4 triol (in 3a-c), which are N-acylated by (2R,15Z)-2-hydroxydocos-15-enoic (in 1a, 2a, 3a), (2R,16Z)-2-hydroxytricos-16-enoic (in 1b, 2b, 3b), (2R,17Z)-2 hydroxytetracos-17-enoic (in 1d) and (2R)-2-hydroxydocosanoic (in 1c, 3c) acids. The monoenoic and cyclopropane-containing sphingoid bases of compounds 1a-d, 2a, 2b, 3a-c have not been found previously in any sphingolipids. The structures of the cerebrosides were elucidated on the basis of (1)H-, (13)C-NMR spectroscopy, mass spectrometry, optical rotation data and chemical transformations. A simplified method for the assignment of the absolute configuration of 2-hydroxy fatty acids by GC analysis of their (2R)- and (2S)-oct-2-yl esters was proposed. PMID- 25502951 TI - The cardiopulmonary effects of ambient air pollution and mechanistic pathways: a comparative hierarchical pathway analysis. AB - Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2-3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system. PMID- 25502953 TI - The phospholipidomic signatures of human blood microparticles, platelets and platelet-derived microparticles: a comparative HILIC-ESI-MS investigation. AB - The phospholipidomic signatures of human blood microparticles and platelets, evaluated by hydrophilic interaction liquid chromatography coupled to electrospray ionization--mass spectrometry, were compared. The phospholipidome of platelet-derived microparticles, obtained by platelets stimulation with a mixture of Ca(II), thrombin and collagen, was also considered for the comparison. Platelets, blood microparticles and platelet-derived microparticles displayed qualitatively similar phospholipidomes, all based on eight major phospholipid classes, namely: phosphatidylcholines, diacyl- and plasme(a)nyl phosphatidylethanolamines, phosphatidylserines, phosphatidylinositols, sphingomyelins and lyso forms of phosphatidylcholines and phosphatidylethanolamines. However, while the phospholipidomes of platelets and platelet-derived microparticles were found to be generally similar also from a quantitative point of view, a higher relative incidence of species bearing polyunsaturated side chains, especially in phospholipid classes sharing the choline head (i.e. phosphatidylcholines and lyso-phosphatidylcholines), was observed in the case of blood microparticles. As a further peculiar feature, never reported before, the relative abundance of lyso-phosphatidylcholines among the eight identified phospholipid classes was found to be significantly higher in the lipid extracts of blood microparticles. PMID- 25502954 TI - Safety of fibrinogen concentrate: analysis of more than 27 years of pharmacovigilance data. AB - Fibrinogen concentrate use as a haemostatic agent has been increasingly explored. This study evaluates spontaneous reports of potential adverse drug reactions (ADRs) that occurred during postmarketing pharmacovigilance of Haemocomplettan P/RiaSTAP, and reviews published safety data. This descriptive study analysed postmarketing safety reports recorded in the CSL Behring pharmacovigilance database from January 1986 to December 2013. A literature review of clinical studies published during the same period was performed. Commercial data indicated that 2,611,294 g of fibrinogen concentrate were distributed over the pharmacovigilance period, corresponding to 652,824 standard doses of 4 g each, across a range of clinical settings and indications. A total of 383 ADRs in 106 cases were reported (approximately 1 per 24,600 g or 6,200 standard doses). Events of special interest included possible hypersensitivity reactions in 20 cases (1 per 130,600 g or 32,600 doses), possible thromboembolic events in 28 cases (1 per 93,300 g or 23,300 doses), and suspected virus transmission in 21 cases (1 per 124,300 g or 31,000 doses). One virus transmission case could not be analysed due to insufficient data; for all other cases, a causal relationship was assessed as unlikely due to negative polymerase chain reaction tests and/or alternative explanations. The published literature revealed a similar safety profile. In conclusion, underreporting of ADRs is a known limitation of pharmacovigilance. However, the present assessment indicates that fibrinogen concentrate is administered across a range of indications, with few ADRs and a low thromboembolic event rate. Overall, fibrinogen concentrate showed a promising safety profile. PMID- 25502955 TI - Pressure ulcers in the hospitalized neonate: rates and risk factors. AB - Pressure ulcers (PU) are serious, reportable events causing pain, infection and prolonged hospitalization, particularly among critically ill patients. The literature on PUs in neonates is limited. The objective was to determine the etiology, severity and influence of gestational age on PUs among hospitalized infants. A two-year prospective study was conducted among 741 neonatal intensive care patients over 31,643 patient-days. Risk factors were determined by comparing the characteristics of infants who developed PUs with those who did not. There were 1.5 PUs per 1000 patient days with 1.0 PU per 1000 days in premature infants and 2.7 per 1000 days in term infants. The number of PUs associated with devices was nearly 80% overall and over 90% in premature infants. Infants with PUs had longer hospitalizations and weighed more than those who did not. Infants with device-related PUs were younger, of lower gestational age and developed the PU earlier than patients with PUs due to conventional pressure. The time to PU development was longer in prematurely born versus term infants. Hospitalized neonates are susceptible to device-related injury and the rate of stage II injury is high. Strategies for early detection and mitigation of device-related injury are essential to prevent PUs. PMID- 25502956 TI - Study of Mycobacterium tuberculosis complex genotypic diversity in Malaysia reveals a predominance of ancestral East-African-Indian lineage with a Malaysia specific signature. AB - BACKGROUND: Tuberculosis (TB) still constitutes a major public health problem in Malaysia. The identification and genotyping based characterization of Mycobacterium tuberculosis complex (MTBC) isolates causing the disease is important to determine the effectiveness of the control and surveillance programs. OBJECTIVES: This study intended a first assessment of spoligotyping based MTBC genotypic diversity in Malaysia followed by a comparison of strains with those prevailing in neighboring countries by comparison with an international MTBC genotyping database. METHODS: Spoligotyping was performed on a total of 220 M. tuberculosis clinical isolates collected in Kelantan and Kuala Lumpur. The results were compared with the SITVIT2 international database of the Pasteur Institute of Guadeloupe. RESULTS: Spoligotyping revealed 77 different patterns: 22 corresponded to orphan patterns while 55 patterns containing 198 isolates were assigned a Spoligo International Type (SIT) designation in the database (the latter included 6 newly created SITs). The eight most common SITs grouped 141 isolates (5 to 56 strains per cluster) as follows: SIT1/Beijing, n = 56, 25.5%; SIT745/EAI1-SOM, n = 33, 15.0%; SIT591/EAI6-BGD1, n = 13, 5.9%; SIT256/EAI5, n = 12, 5.5%; SIT236/EAI5, n = 10, 4.6%; SIT19/EAI2-Manila, n = 9, 4.1%; SIT89/EAI2-Nonthaburi, n = 5, 2.3%; and SIT50/H3, n = 3, 1.4%. The association between city of isolation and lineages was statistically significant; Haarlem and T lineages being higher in Kuala Lumpur (p<0.01). However, no statistically significant differences were noted when comparing drug resistance vs. major lineages, nor between gender and clades. CONCLUSIONS: The ancestral East-African-Indian (EAI) lineage was most predominant followed by the Beijing lineage. A comparison of strains with those prevailing in neighboring countries in South Asia, East Asia and South East Asia underlined the phylogeographical specificity of SIT745 for Malaysia, and its probable ongoing evolution with locally evolved strains sharing a specific signature characterized by absence of spacers 37, 38, and 40. Pending complementary genotyping confirmation, we propose that SIT745/EAI-SOM is tentatively reclassified as SIT745/EAI-MYS. PMID- 25502957 TI - Polarity continuation and frustration in ZnSe nanospirals. AB - ZnSe nanospirals including structures with polarity continuation and polarity frustration are simultaneously observed at atomic resolution. Through careful analysis of polarity within each dumbbell based on aberration-corrected high angle annular-dark-field imaging, polarity continuation across parallel polytype interfaces as well as the surrounding Z-shape faulted dipoles is verified. Moreover, polarity frustration across regions with different stacking sequence, which would lead to accumulations of boundary interface charges in the triangular shaped mixed regions with potential optoelectronic applications, is carefully studied. PMID- 25502958 TI - Decline in immunization coverage across well-performing districts in India: an urban conundrum? Correspondence. PMID- 25502959 TI - Decline in immunization coverage across well-performing districts in India: an urban conundrum? Authors' reply. PMID- 25502960 TI - Continuous positive airway pressure in neonates. PMID- 25502961 TI - Cognitive improvement in meningioma patients after surgery: clinical relevance of computerized testing. AB - Cognitive dysfunction is common in patients with primary brain tumors, and may have a major impact on activities of daily living and on quality of life. This is the first prospective study that investigated the incidence and severity of cognitive dysfunction in meningioma patients before and after surgery, and the change in dysfunction over time, both at group and individual patient level. Sixty-eight meningioma patients were neuropsychologically tested one day before brain surgery. Sixty-two patients were followed up 3 months after surgery. All patients were assessed with a brief (30 min) computerized screening battery of neuropsychological tests (i.e., CNS Vital Signs). Pre- and post-operatively, meningioma patients demonstrated significantly lower scores in all cognitive domains; memory, psychomotor speed, reaction time, complex attention, cognitive flexibility, processing speed, and executive functioning, in comparison with normative data. Pre-operatively, 47 out of 68 patients (69 %) scored low or very low in one or more cognitive domains. Post-operatively, 27 out of 62 patients (44 %) scored within this range. Test performance improved in all cognitive domains post-operatively, with the exception of psychomotor speed and reaction time. In line with previous studies with conventional neuropsychological tests, meningioma patients are faced with cognitive dysfunction in several cognitive domains both pre- and post-operatively. However, a large proportion of patients shows post operative improvement in cognitive functioning. Longer-term follow-up is recommended to identify potential predictors of cognitive improvement after surgery. Diagnosis and treatment of these cognitive deficits will improve outcomes and quality of life in meningioma patients. PMID- 25502963 TI - Studies towards the synthesis of bielschowskysin. Construction of the highly functionalized bicyclo[3.2.0]heptane segment. AB - A stereocontrolled approach for the construction of a highly functionalized bicyclo[3.2.0]heptane derivative embodying the bridged lactone present in the diterpene bielschowskysin is reported. The key step involves a stereoselective Cu(I)-catalyzed [2 + 2] photocycloaddition of a 1,6-diene embedded in a sugar derivative. PMID- 25502962 TI - Involvement of the neural stem cell compartment by pediatric and adult gliomas: a retrospective review of 377 cases. AB - To assess frequency of neural stem cell compartment (NSC) involvement in adult and pediatric gliomas [World Health Organization (WHO) grades 1-4], and to assess whether NSC involvement at presentation impacts on survival, recurrence rates, and/or transformation from low grade (WHO grade 1-2) to high grade disease (WHO grades 3-4). Cranial MRIs for 154 pediatric and 223 adult glioma patients treated from 2000 to 2012 were reviewed. NSC involvement was documented. Tumors were stratified by age (adult vs. pediatric), histology, tumor grade, tumor location, and involvement of midline structures. Odds ratios (OR) for death were calculated based on NSC status at presentation. Rates of transformation and recurrence rates (ORR) were compared using Fisher's Exact Test. Time to recurrence (TTR) was calculated using student t test. Among recurrent and transformed tumors, we also assessed the rate of NSC involvement at time of recurrence or transformation. 74.8 % of tumors had NSC involvement. Higher rates of NSC involvement were seen among adult (p = .0001); high grade (p = .0001)); grade 2 versus grade 1 (p = .0001) and other grade 1 histologies (p = .0001) versus JPA (juvenile pilocytic astrocytoma) patients); grade 2-4 tumors (p = .0001); and supratentorial tumors (p < .0001). No transformation was noted among pediatric low grade tumors or adult grade 1 tumors. 22/119 (18.5 %) adult grade 2 tumors transformed. Rates of transformation were not impacted by NSC status (p = .47). ORR was 15.1 %, and was greater for NSC+ tumors at presentation (p = .05). 36/41 recurrences (87.8 %) involved NSC at time of recurrence. OR for death was 2.62 (1.16-5.9), p = .02 for NSC+ tumors at presentation. Adult and pediatric gliomas (all grades) frequently involve NSC at presentation, although rates are lower in pediatric JPA and all infratentorial tumors. NSC involvement at presentation increases OR death and reduces TTR for pediatric gliomas (all grades) and adult low grade gliomas, and shows a strong trend toward increased ORR. PMID- 25502964 TI - Evidence valued and used by health promotion practitioners. AB - The use of evidence has become a foundational part of health promotion practice. Although there is a general consensus that adopting an evidence-based approach is necessary for practice, disagreement remains about what types of evidence practitioners should use to guide their work. An empirical understanding of how practitioners conceptualize and use evidence has been lacking in the literature. In this article, we explore (i) practitioners' purposes for using evidence, (ii) types of evidence they valued, and (iii) qualities that made evidence useful for practice. 58 semi-structured interviews and 250 h of participant and non participant observation were conducted with 54 health promotion practitioners working across New South Wales, Australia. Interviews were recorded and transcribed, and field notes were written during the observations; these were analysed using Grounded Theory methods. Practitioners used evidence for practical and strategic purposes, and valued four different types of evidence according to their relevance and usefulness for these purposes. Practitioners' ideal evidence was generated within their practice settings, and met both substantive and procedural evaluation criteria. We argue that due to the complex nature of their work, practitioners rely on a diverse range of evidence and require organizational structures that will support them in doing so. PMID- 25502965 TI - Monosomy 20 mosaicism revealed by extensive karyotyping in blood and skin cells: case report and review of the literature. AB - We describe a 13-year-old boy with developmental delay and proximal muscle weakness who has monosomy 20 mosaicism in blood and skin cells. Because of asymmetric features (difference in foot size, slightly asymmetric intergluteal cleft), we performed extensive cytogenetic studies in peripheral blood and skin. In cultured and uncultured blood lymphocytes, we found 0.9 and 6.5% of cells with monosomy 20, respectively. In addition, 3.3% of uncultured skin fibroblasts and 1.5% of buccal mucosa cells had monosomy 20. This is the fifth patient published with this chromosomal condition. These patients show variable clinical features, ranging from normal to delayed motor and speech development. There is no apparent relation between the percentage of monosomic cells as studied in blood and the severity of the phenotype. This could be due to different degrees of mosaicism in the other tissues and organs, which may vary considerably from patient to patient. The degree of monosomy 20 mosaicism in blood is in most patients below the detection limit of microarray technology. Therefore, this work illustrates the necessity of detailed cytogenetic investigation of multiple cell types in developmentally retarded patients with normal microarray results, especially when there are subtle physical indications of chromosomal mosaicism. PMID- 25502966 TI - Extinction measurements for optical band gap determination of soot in a series of nitrogen-diluted ethylene/air non-premixed flames. AB - Visible light extinction was measured in a series of nitrogen-diluted, ethylene/air, non-premixed flames and this data was used to determine the optical band gap, OBG, as a function of flame position. Collimated light from a supercontinuum source is telescopically expanded and refocused to match the f- number of a dispersing monochromator. The dispersed light is split into a power metering channel and a channel that is periscoped and focused into the flame. The transmitted light is then recollimated and focussed onto a silicon photodiode detector. After tomographic reconstruction of the radial extinction field, the OBG was derived from the near-edge absorption feature using Tauc/Davis-Mott analysis. A slight evolution in OBG was observed throughout all flame systems with a consistent range of OBG observed between approximately 1.85 eV and 2.35 eV. Averaging over all positions the mean OBG was approximately 2.09 eV for all flame systems. Comparing these results to previously published computational results relating calculated HOMO-LUMO gaps for a variety of D2h PAH molecules to the number of aromatic rings in the structure, showed that the observed optical band gap is consistent with a PAH of about 14 rings or a conjugation length of 0.97 nm. This work provides experimental support to the model of soot formation where the transition from chemical to physical growth starts at a modest molecular size; about the size of circumpyrene. PMID- 25502967 TI - Is petoxifylline still an option in severe alcoholic hepatitis? PMID- 25502968 TI - Providing a roadmap to predict tissue viability. PMID- 25502969 TI - Matching editorial content to the educational needs of wound care professionals. PMID- 25502970 TI - 2015: "key word" for wound care business success. AB - Wound care professionals should consider all this attention to the key word documentation as your 2015 "heads-up." You should conduct a self-audit and request an external audit of your own documentation against all the regulations, LCDs, Policy Articles, newsletters, and educational programs that CMS and your MACs are providing. You should also embrace the questioning and assistance, pertaining to your documentation, which you may receive from your coders and billers. These coding and billing professionals should be your "best friends" to help you improve your clinical documentation as soon as possible. You cannot afford to be one of the professionals who are requested to repay for services you actually provided just because you did not take the time to document your excellent wound care work. PMID- 25502971 TI - Validation of commercially available infrared thermometers for measuring skin surface temperature associated with deep and surrounding wound infection. AB - OBJECTIVE: Increased local skin temperature is a classic sign of wound infection, repetitive trauma, and deep inflammation. Noncontact infrared thermometers can help to detect increases in skin surface temperatures; however, most scientifically tested devices are far too expensive for everyday wound care providers to use in routine clinical practice. This noninferiority study was conducted in an attempt to determine whether 4 less expensive, commercially available noncontact infrared thermometers have a similar level of accuracy as the scientifically accepted Exergen DermaTemp 1001 (Exergen Products, Watertown, Massachusetts). DESIGN, SETTING, AND PARTICIPANTS: Using an observational study design, participants with open wounds were randomly selected from a chronic wound clinic (n = 108). Demographic data and wound location were documented for all participants. Skin temperatures were recorded using 5 noncontact infrared thermometers under consistent environmental conditions. The thermometer brands were as follows: Exergen DermaTemp, Mastercool MSC52224-A (Mastercool Inc, Randolph, New Jersey), ATD Tools 70001 Infrared Thermometer (ATD Tools Inc, Wentzville, Missouri), Mastercraft Digital Temperature Reader (Mastercraft Canada, Toronto, Ontario, Canada), and Pro Point Infrared Thermometer (Princess Auto, Winnipeg, Manitoba, Canada). Data analysis was based on the skin surface temperature difference (DeltaT in degrees Fahrenheit) between the wound site and an equivalent contralateral control site. OUTCOME MEASURES: One-way analysis of variance was used to compare the mean DeltaT values for all the 5 thermometers, followed by post hoc analysis. Demographic data were analyzed using descriptive statistics. Interrater reliability was assessed for consistency using the intraclass correlation coefficient. MAIN RESULTS: No statistical difference was reported between the DeltaT values for the 5 different thermometers (F4,514 = 0.339, P = .852). Post hoc analysis showed no significant difference when the thermometers were compared with the Exergen DermaTemp 1001, and Mastercool MSC52224-A (P = .987), ATD Tools 70001 Infrared Thermometer (P = .985), Mastercraft Digital Temperature Reader (P = .972), and Pro Point Infrared Thermometer (P = .774). The results for intraclass correlation demonstrated a high reliability and agreement between raters, as the intraclass correlation coefficient values for all thermometers were greater than 0.95. CONCLUSIONS: The results of this study demonstrate that less expensive, industrial-grade noncontact infrared thermometers have reliable temperature readings to identify and quantify the temperature gradients that along with other signs may be associated with deep and surrounding wound infection or tissue injury due to repeated microtrauma. PMID- 25502972 TI - Antimicrobial-impregnated dressing combined with negative-pressure wound therapy increases split-thickness skin graft engraftment: a simple effective technique. AB - OBJECTIVE: Immobilization and adequate surface contact to wounds are critical for skin graft take. Techniques such as the tie-over dressing, cotton bolster, and vacuum-assisted closure are used to address this, but each has its limitations. This study is designed to assess the effect of antimicrobial-impregnated dressing (AMD) combined with negative-pressure wound therapy (NPWT) on skin graft survival. DESIGN: Retrospective case-control study PARTICIPANTS: : Patients with chronic or contaminated wounds treated with split-thickness skin graft. A broad spectrum of wounds was included, from causes such as trauma, burns, chronic diabetic ulcers, and infection. INTERVENTIONS: Antimicrobial-impregnated dressing, which contains 0.2% polyhexamethylene biguanide, with NPWT MAIN OUTCOME MEASURE:: Success of skin graft MAIN RESULTS: : In the AMD group, all skin grafts achieved 100% take without secondary intervention. No infection or graft failure was observed in any patients, and no complications, such as hematoma or seroma formation, were noted, although in the control group partial loss of skin grafts was noted in 3 patients. Infection and inadequate immobilization were thought to be the main reasons. There were no hematoma or seroma formations in the control group. CONCLUSION: Use of an AMD dressing with NPWT after split-thickness skin grafting can be an effective method to ensure good graft to wound contact and enhances skin graft take in chronic and contaminated wounds. PMID- 25502973 TI - Pilot study compares scores of the Resident Assessment Instrument Minimum Data Set Version 2.0 (MDS 2.0) Pressure Ulcer Risk Scale with the Braden Pressure Ulcer Risk assessment for patients in complex continuing care. AB - OBJECTIVE: To determine if the Braden Scale for Predicting Pressure Sore Risk (Braden Scale) and the Resident Assessment Instrument Minimum Data Set Version 2.0 (MDS 2.0) Pressure Ulcer Risk Scale (PURS) provide a comparable assessment of the level of risk of developing a pressure ulcer at admission in complex continuing care. SETTING: Saint-Vincent Hospital, Bruyere Continuing Care, a 336 bed complex continuing care facility that provides restorative, complex, specialized, and supportive care to adults in Ottawa, Ontario, Canada. METHODS: A retrospective chart review was conducted from February 2012 to April 2012 on 51 patient charts that were chosen based on the completion of an admission Braden Scale assessment within a maximum of 4 weeks from admission and completed admission MDS 2.0. RESULTS: The Braden Scale categorized 63% of patients at risk when using scores between 15 and 23, compared with 33% for the MDS 2.0 PURS scores of 0-2 (low and very low risk). Both scales were comparable in identifying patients in the lower risk categories when data was reviewed using a cutoff point of 18 for the Braden. At the high risk end of the spectrum, the MDS 2.0 PURS categorized more patients, 45%, as high or very high risk, compared with 21% for using the Braden Scale. CONCLUSION: This preliminary study may provide some evidence that the MDS 2.0 PURS may be an alternative risk assessment tool option that utilizes mandatory collected data, reduces workload duplication, and would generate a Resident Assessment Protocol, when indicated, in complex continuing care. PMID- 25502974 TI - Educational opportunities, expert faculty, and vendor exhibits seen at the mirage. PMID- 25502975 TI - Infrared skin thermometry: an underutilized cost-effective tool for routine wound care practice and patient high-risk diabetic foot self-monitoring. AB - PURPOSE: To provide information about the use of infrared skin thermometry for routine wound care practice and patient high-risk diabetic foot self-monitoring. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant will be able to:1. Describe infrared thermometer use and the authors' study findings.2. Summarize studies that have evaluated the use of infrared thermometers for measuring skin temperature of the diabetic foot. ABSTRACT: The aim of this article is to provide practitioners with an overview of infrared skin thermometry for everyday wound care practice. Thermometers have the potential for home use by patients with neuropathy to self-detect damage from repetitive trauma that will increase the risk of foot ulceration. PMID- 25502977 TI - Your wound care department checklist for 2015. PMID- 25502978 TI - Reduction of fibroproliferative changes in irradiated rat lung with soluble transforming growth factor-beta receptor. AB - The present study investigated whether established fibroproliferative changes in the irradiated rat lung are histopathologically reduced by an adenovirus-mediated soluble transforming growth factor (TGF)-beta type II receptor. Replication defective adenoviral vectors expressing a type II human TGF-beta receptor (AdTbeta-ExR) were prepared. Male Fisher-344 rats were divided into the C, R and R + T groups. The rats in the C group did not receive irradiation or treatment. The rats in the R and R + T group each received 30 Gy irradiation to the right lung. Eight weeks following irradiation, the rats in the R and R + T group were treated with saline or AdTbeta-ExR, respectively. To analyze the TGF-beta expression, myofibroblast proliferation and macrophage/monocyte infiltration, sections of the lung were immunohistochemically stained at 16 weeks following irradiation. Silver staining was performed for semi-quantitative evaluation of the fibroproliferative changes. Definitive TGF-beta expression, myofibroblast proliferation and macrophage/monocyte infiltration were observed in the lungs of the R group, but were significantly lower in the lungs of the R + T group. With respect to the fibroproliferative changes, the proportion of red-stained areas in the R + T group was markedly lower than that in the R group. These data indicate that fibroproliferative changes induced by radiation are reversible and that TGF beta has a critical role in fibroproliferative changes in the irradiated lung. The present results suggest that gene therapy with an adenoviral vector expressing a soluble TGF-beta receptor may be effective in reducing the established pulmonary fibrosis caused by radiation. PMID- 25502980 TI - Separation of two major chalcones from Angelica keiskei by high-speed counter current chromatography. AB - Angelica keiskei (Shin-sun cho) is an edible higher plant with the beneficial preventive effects on cancer, hypertension, and coronary heart disease. Two bioactive chalcones of Shin-sun cho, xanthoangelol (1) and 4-hydroxyderricin (2), were separated simultaneously by using high-speed counter-current chromatography with a two-phase solvent system composed of n-hexane-EtOAc-MeOH-H2O (9:5:9:4). Only nonconsuming processes, solvent fractionations and Sephadex LH-20 column chromatography, were conducted as presteps. Xanthoangelol (1, 35.9 mg, 99.9 % purity at 254 and 365 nm) and 4-hydroxyderricin (2, 4.4 mg, 98.7 % purity at 254 nm and 98.8 % purity at 365 nm) were successfully purified from 70 mg of the processed extract from A. keiskei. The structures of two compounds were confirmed by (1)H- and (13)C-NMR analysis. PMID- 25502979 TI - A cruciate suture technique for rotator cuff repair. AB - PURPOSE: Re-establishment of the native footprint during rotator cuff repair is important for maximizing healing potential and fixation strength. The purpose of this study was to evaluate the contact area, contact pressure, stiffness and tensile strength of a new single-row cruciate suture repair and to compare these results to those of the Mason-Allen, double-row and transosseous repairs. METHODS: Infraspinatus tendons from fifty-six lamb shoulders were harvested and randomly assigned to cruciate suture, Mason-Allen, double-row and transosseous repair groups. Repairs were performed over pressure-sensitive film and footprint contact area and pressure measured. Repaired tendon specimens were also loaded in uniaxial tension, and ultimate tensile strength and stiffness measured. RESULTS: The cruciate suture repair established significantly greater footprint contact area compared to the Mason-Allen repair (mean difference = 101 mm(2), p = 0.003). The ultimate tensile strength and stiffness of the double-row repair was significantly higher than that of all other repair groups (p < 0.05). The average footprint contact pressure of the cruciate suture repair (0.78 MPa) was similar to that of the Mason-Allen (0.74 MPa) and double-row repairs (0.79 MPa). The ultimate tensile strength of the cruciate suture repair was significantly greater than that of the transosseous repair (mean difference 62.4 N, p = 0.002). CONCLUSION: The cruciate suture repair may improve strength and healing at the repaired tendon rotator cuff insertion relative to other single-row repair techniques. It may represent a faster, easier and more cost-effective alternative to double-row repairs. PMID- 25502981 TI - Inhibition of melanogenesis by 2-[4-(5-chlorobenzo[d]thiazol-2-yl)phenoxy]-2 methylpropanoic acid (MHY908). AB - Tyrosinase inhibitors might have potential use in cosmetic and medicinal products for the prevention of pigmentation disorders. However, only a few inhibitors are currently used due to their cytotoxicity, and lack of selectivity and stability. In this study, we synthesized several tyrosinase inhibitors and investigated their activity. To investigate the action of 2-[4-(5-chlorobenzo[d]thiazol-2 yl)phenoxy]-2-methylpropanoic acid (MHY908) specifically in the inhibition of melanogenesis, a mushroom tyrosinase activity assay was performed. We confirmed the inhibitory effect of MHY908 at various melanin concentrations using alpha-MSH induced melanoma cells. Our results indicate that MHY908 potently inhibited mushroom tyrosinase activity (IC50 = 8.19 MUM) in a dose-dependent manner. Through a docking simulation, we also analyzed its binding mode to inhibit tyrosinase activity. MHY908 also decreased melanin synthesis without inducing cytotoxicity. These results suggest that MHY908 is a good candidate for prevention and treatment of pigmentation disorders. PMID- 25502983 TI - Cutaneous squamous cell carcinoma with perineural invasion: report on eight cases and review of the literature. AB - BACKGROUND: Perineural invasion (PNI) in cutaneous squamous cell carcinoma (SCC) is considered to be a negative prognostic factor. A lot of uncertainty remains regarding the classification, diagnosis, treatment and prognosis of SCC with PNI. OBJECTIVE: To describe typical courses of SCC with PNI and associated findings in order to suggest an optimized diagnostic and therapeutic approach. METHODS: We present eight cases of SCC with PNI, considering patient and tumor characteristics, histology, treatment and clinical course regarding local recurrence and metastasization. RESULTS: SCC patients with PNI have a higher rate of local recurrences and greater risk for metastasization than SCC patients without PNI. Age ranged from 68 to 77 years, 6 patients were male and 2 female, with all tumors localized on the head. Three patients had chronic lymphocytic leukemia. CONCLUSION: Based on the data of this series and the current literature, we make suggestions for better diagnostic and therapeutic management. PMID- 25502982 TI - Phase II trial of combination therapy of gemcitabine plus anti-angiogenic vaccination of elpamotide in patients with advanced or recurrent biliary tract cancer. AB - Background Elpamotide is an HLA-A*24:02-restricted epitope peptide of vascular endothelial growth factor receptor 2 (VEGFR-2) and induces cytotoxic T lymphocytes (CTLs) against VEGFR-2/KDR. Given the high expression of VEGFR-2 in biliary tract cancer, combination chemoimmunotherapy with elpamotide and gemcitabine holds promise as a new therapy. Patients and Methods Patients with unresectable advanced or recurrent biliary tract cancer were included in this single-arm phase II trial, with the primary endpoint of overall survival. Survival analysis was performed in comparison with historical control data. The patients concurrently received gemcitabine once a week for 3 weeks (the fourth week was skipped) and elpamotide once a week for 4 weeks. Results Fifty-five patients were registered, of which 54 received the regimen and were included in the full analysis set as well as the safety analysis set. Median survival was 10.1 months, which was longer than the historical control, and the 1-year survival rate was 44.4%. Of these patients, injection site reactions were observed in 64.8%, in whom median survival was significantly longer (14.8 months) compared to those with no injection site reactions (5.7 months). The response rate was 18.5%, and all who responded exhibited injection site reactions. Serious adverse reactions were observed in five patients (9%), and there were no treatment-related deaths. Conclusion Gemcitabine and elpamotide combination therapy was tolerable and had a moderate antitumor effect. For future development of therapies, it will be necessary to optimize the target population for which therapeutic effects could be expected. PMID- 25502984 TI - Highly reversible capacity at the surface of a lithium-rich manganese oxide: a model study using an epitaxial film system. AB - Epitaxial films of Li2MnO3 were synthesized using pulsed laser deposition. A 12.6 nm film exhibited a high discharge capacity of over 300 mA h g(-1) following its fiftieth cycle and better stability than 29.8 and 47.8 nm films. The surfaces of such films are intrinsically active at the electrochemical interface. PMID- 25502985 TI - Comparison of event-based analysis of glaucoma progression assessed subjectively on visual fields and retinal nerve fibre layer attenuation measured by optical coherence tomography. AB - The purpose is to study the ability of an event-based analysis of retinal nerve fibre layer (RNFL) attenuation measured by Stratus((r)) optical coherence tomography (OCT) and to detect progression across the spectrum of glaucoma. Adult glaucoma suspects, ocular hypertensives and glaucoma patients who had undergone baseline RNFL thickness measurement on Stratus OCT and reliable automated visual field examination by Humphrey's visual field analyser prior to March 2007 and had 5-year follow-up data were recruited. Progression on OCT was defined by two criteria: decrease in average RNFL thickness from baseline by at least 10 and 20 u. Visual field progression was defined by the modified Hodapp-Parrish-Anderson criteria. Absolute and percentage change in RNFL thickness from baseline was compared in progressors and non-progressors on visual fields. Concordance between structural and functional progression was analysed. 318 eyes of 162 patients were analysed. 35 eyes (11 %) progressed by visual fields, 8 (2.5 %) progressed using the 20 u loss criterion, while 30 eyes (9.4 %) progressed using the 10 u loss criterion. In glaucoma suspects, mean absolute RNFL attenuation was 8.6 u (12.1 % of baseline) in those who progressed to glaucoma by visual fields. OCT was more useful to detect progression in early glaucoma, but performed poorly in advanced glaucoma. The 10 u criterion appears to be closer to visual field progression. However, the ability to detect progression varies considerably between functional and structural tools depending upon the severity of the disease. PMID- 25502986 TI - Association of drug exposure with toxicity and clinical response in metastatic renal cell carcinoma patients receiving an attenuated dosing regimen of sunitinib. AB - An attenuated dosing (AD) regimen of 37.5 mg daily in repeated 4 week on, 2 week off cycles has been proposed to ameliorate frequent dose modifications caused by the toxicity observed with the approved dosing regimen of sunitinib for metastatic renal cell carcinoma (mRCC). This study aimed to determine the effect of drug exposure on toxicity and clinical response in patients receiving this regimen. All mRCC patients receiving AD sunitinib were invited to participate. In week 4 of each cycle, toxicity and plasma levels were assessed. Clinical responses were assessed after two cycles. A total of 36 patients were recruited. Patients who manifested >=grade 2 mucositis (126.46 vs 84.81 ng/mL, p = 0.04) and altered taste (159.91 vs 105.22 ng/mL, p = 0.05) had higher total exposure than those who had grade 1 or no toxicity. Twenty-six patients completed two treatment cycles; four (15%) had partial responses, 15 (58%) had a stable disease and 7 (27%) had progressive disease. No difference in the exposure levels was found among the patients with different clinical outcomes. The AD regimen of sunitinib in Asian mRCC patients provided sufficient drug exposure with a lower incidence of toxicity, with higher drug exposure being observed in patients who experienced toxicity. PMID- 25502987 TI - Exploring the space of gene/species reconciliations with transfers. AB - Reconciliations between gene and species trees have important applications in the study of genome evolution (e.g. sequence orthology prediction or quantification of transfer events). While numerous methods have been proposed to infer them, little has been done to study the underlying reconciliation space. In this paper, we characterise the reconciliation space for two evolutionary models: the [Formula: see text] (duplication, loss and transfer) model and a variant of it the no-[Formula: see text] model-which does not allow [Formula: see text] events (a transfer immediately followed by a loss). We provide formulae to compute the size of the corresponding spaces and define a set of transformation operators sufficient to explore the entire reconciliation space. We also define a distance between two reconciliations as the minimal number of operations needed to transform one into the other and prove that this distance is easily computable in the no-[Formula: see text] model. Computing this distance in the [Formula: see text] model is more difficult and it is an open question whether it is NP-hard or not. This work constitutes an important step toward reconciliation space characterisation and reconciliation comparison, needed to better assess the performance of reconciliation inference methods through simulations. PMID- 25502988 TI - Microvascular decompression under neuroendoscopic view in hemifacial spasm: rostral-type compression and perforator-type compression. AB - We report microvascular decompression (MVD) under neuroendoscopic view in hemifacial spasm (HFS) patients with rostral- and perforator-type compression of the root exit zone (REZ) of the facial nerve. Using either a wireless iPad Mini as a monitor on the microscope or a high-resolution monitor, microscopic and endoscopic views enabled MVD for complete cure of HFS with rostral-type compression (the offender compressing the REZ on the opposite rostral side to the operative approach) or perforator-type compression (the offender tethered to the REZ by the perforator). MVD under neuroendoscopic view may offer more accurate MVD and complete resolution of HFS. PMID- 25502989 TI - Breaking the cycle (BTC)- 20 years of breaking records in managing addicted mothers and their young children. AB - In 1994, a coalition of Toronto-based organizations dealing with the social and medical aspects of child care, inaugurated BTC with the hope of creating an effective and sustainable model to support these mothers and their children. PMID- 25502990 TI - Fertility preservation in a family with a novel NR5A1 mutation. AB - The common phenotype of nuclear receptor superfamily 5, group A, member 1 (NR5A1) gene mutations in 46,XY is gonadal dysgenesis without adrenal deficiency. Though the phenotype of gonadal dysgenesis is variable, ranging from complete female to normal male genitalia, an asymptomatic 46,XY male is rare. Preserved fertility has so far been described in only three affected 46,XY males with different mutations, but no functional analysis of these mutations has been performed. Here, we report on male siblings with hypospadias and their asymptomatic father in whom we identified a heterozygous NR5A1 mutation of c.910G>A, p.E304K. Western blotting and subcellular localization revealed no significant difference between the wild type (WT) and E304K. Electrophoretic mobility shift assay experiments showed that E304K abrogated DNA-binding ability. E304K reduced transactivation and had no dominant negative effect. In conclusion, we report on a novel hypomorphic NR5A1 mutation, which may be associated with the phenotype of the family. PMID- 25502991 TI - A family of RTHbeta with p.R316C mutation presenting occasional syndrome of inappropriate secretion of TSH. AB - The syndrome of inappropriate secretion of thyrotropin (SITSH) is a hallmark of resistance to thyroid hormone (RTH) due to mutations in the beta isoform of the thyroid hormone receptor (TRbeta). Here, we report on a family of RTH due to a TRbeta mutation (RTHbeta) and presenting occasional SITSH. The proband was a 16 year-old girl with a goiter, detected at a school physical examination. She was initially diagnosed as having euthyroid Hashimoto thyroiditis because her thyroid function was normal with a positive anti-thyroglobulin antibody. Follow-up examinations resulted in mild SITSH on some occasions and euthyroid on the other occasions. A magnetic resonance imaging (MRI) revealed a normal pituitary gland. Because her mother also had mild SITSH, genetic analysis was performed and revealed a heterozygous point mutation in TRbeta (p.R316C). Previously, the p.R316C had only been found in severe RTH cases with homozygous mutations or with an ectopic thyroid. Her mother with a heterozygous mutation showed variable RTH phenotype on T3 suppression testing. In conclusion, the prevalence of RTHbeta might be underestimated and occasional SITSH could also suggest RTHbeta. TRbeta gene mutation is not always correlated with the RTH phenotype. PMID- 25502992 TI - Reconfigurable electro-optical directed-logic circuit using carrier-depletion micro-ring resonators. AB - Here we demonstrate a reconfigurable electro-optical directed-logic circuit based on a regular array of integrated optical switches. Each 1*1 optical switch consists of a micro-ring resonator with an embedded lateral p-n junction and a micro-heater. We achieve high-speed on-off switching by applying electrical logic signals to the p-n junction. We can configure the operation mode of each switch by thermal tuning the resonance wavelength. The result is an integrated optical circuit that can be reconfigured to perform any combinational logic operation. As a proof-of-principle, we fabricated a multi-spectral directed-logic circuit based on a fourfold array of switches and showed that this circuit can be reconfigured to perform arbitrary two-input logic functions with speeds up to 3 GB/s. PMID- 25502993 TI - Polarization-multiplexed multifocal arrays by a pi-phase-step-modulated azimuthally polarized beam. AB - We demonstrate a polarization-multiplexed multifocal array capable of individually manipulating the focal polarization state in each focal spot. Breaking the rotational phase symmetry through adding a pi-phase-step to an azimuthally polarized beam leads to a linear focal polarization state with high polarization purity. Through the superposition of such modulated azimuthal polarization fields at the back aperture of the objective, multifocal arrays with individually controllable and non-identical polarization states can be achieved. In addition, this approach exhibits a sub-diffraction-limited feature with an improved lateral resolution of 10% reduced full width at half-maximums in each linearly polarized focal spot. Consequently, applying this technique to parallel polarization-multiplexed optical recording is demonstrated. PMID- 25502994 TI - Effect of multiphoton ionization on performance of crystalline lens. AB - This Letter presents a model for propagation of a laser pulse in a human crystalline lens. The model contains a transverse beam diffraction effect, laser induced optical breakdown for the creation of plasma via a multiphoton ionization process, and the gradient index (GRIN) structure. Plasma introduces the nonlinearity in the crystalline lens which affects the propagation of the beam. The multiphoton ionization process generates plasma that changes the refractive index and hence leads to the defocusing of the laser beam. The Letter also points out the relevance of the present investigation to cavitation bubble formation for restoring the elasticity of the eyes. PMID- 25502995 TI - Asymmetric Cherenkov radiation for improved terahertz generation in the Si-prism coupled LiNbO3 layer. AB - We show that a Cherenkov emission of terahertz waves from a femtosecond optical pulse propagating in a LiNbO(3) crystal can be strongly spatially asymmetric with respect to the direction of the optical pulse propagation. We propose using this phenomenon to improve the spectral characteristics of one of the most efficient optical-to-terahertz converters: a thin LiNbO(3) layer attached to a Si-prism outcoupler. PMID- 25502996 TI - Degree of polarization uniformity with high noise immunity using polarization sensitive optical coherence tomography. AB - A new metric representing polarization uniformity is presented. Noise corrected degree of polarization uniformity (DOPU) is computed from polarization-sensitive optical coherence tomography (OCT), and selectively visualizes tissue with the multiple scattering, such as highly pigmented tissues. The new metric is designed to be minimally sensitive to systematic additive noise. The performance of this new metric is analyzed by numerical simulation and in vivo human retinal imaging, using Jones matrix OCT. The new metric exhibited only a small dependency on the signal-to-noise ratio. Selective in vivo visualization of pigmented tissues in the human retina is demonstrated, with cross sectional and en-face images. PMID- 25502997 TI - Key native fluorophores analysis of human breast cancer tissues using Gram Schmidt subspace method. AB - The native fluorescence (NFL) spectra of human cancerous and normal breast tissues were excited by a selected wavelength of 300 nm to investigate the efficacy of two key fluorophores: tryptophan and reduced nicotinamide adenine dinucleotide (NADH), as cancer biomarkers. The basis spectra of these key fluorophores' subspaces spanned by the corresponding emission spectra are obtained by the Gram-Schmidt method. A support vector machine (SVM) classifier is trained in the subspace to evaluate the sensitivity, specificity, and accuracy. This research demonstrates that the NFL spectroscopy measurements are effective to detect changes of fluorophores compositions in tissues due to the development of cancer. PMID- 25502998 TI - Airy beams generated by ultrafast laser-imprinted space-variant nanostructures in glass. AB - We demonstrate a technique to generate accelerating Airy beams with a femtosecond laser-imprinted space variant birefringent structure in silica glass. Our approach enables the generation of dual Airy beams with polarization sensitive beam deflection. The produced beam is used for the glass scribing. After the glass-breaking process, a spontaneous self-detachment of a fiber-like structure occurs that can be exploited as an alternative way for fabricating glass cantilevers. PMID- 25503000 TI - Intracavity frequency converted Raman laser producing 10 deep blue to cyan emission lines with up to 0.94 W output power. AB - Here we report 10 laser emission lines in the attractive deep blue to cyan spectral region from an intracavity frequency doubled Raman laser. The fundamental laser field that drives the Raman laser is based on the three-level transition of Nd:YLF. A maximum extracted quasi-continuous wave (qcw) output power of 0.94 W is achieved in the deep blue to cyan spectral regime. PMID- 25502999 TI - Electrically switchable multi-stable cholesteric liquid crystal based on chiral ionic liquid. AB - A multi-stable and electrically switchable cholesteric liquid crystal based on chiral ionic liquid is demonstrated. The cholesteric liquid crystal can be switched among the planar texture, focal conic texture, wide-band reflected state, and fingerprint texture by applying specific electric fields. Each of these four states exists stably for several hours without any obvious change observed at room temperature. The electro-optical properties and driving scheme of the cholesteric liquid crystal are also reported. PMID- 25503001 TI - Spectrally encoded extended source optical coherence tomography. AB - We have developed an extended source optical coherence tomography (SEES-OCT) technique in an attempt to improve signal strength for ophthalmic imaging. A line illumination with a visual angle of 7.9 mrad is produced by introducing a dispersive element in the infinity space of the sample arm. The maximum permissible exposure (MPE) of such an extended source is 3.1 times larger than that of a "standard" point source OCT, which corresponds to sensitivity improvement of 5 dB. The advantage of SEES-OCT in providing superior penetration depth over a point source system is demonstrated using swine eye tissues ex vivo. PMID- 25503002 TI - Hand scanning optical coherence tomography imaging using encoder feedback. AB - We present a new method for generating micron-scale OCT images of interstitial tissue with a hand scanning probe and a linear optical encoder that senses probe movement relative to a fixed reference point, i.e., tissue surface. Based on this approach, we demonstrate high resolution optical imaging of biological tissues through a very long biopsy needle. Minor artifacts caused by tissue noncompliance are corrected using a software algorithm which detects the simple repetition of the adjacent A-scans. This hand-scanning OCT imaging approach offers the physician the freedom to access imaging sites of interest repeatedly. PMID- 25503003 TI - Enhancing the sensitivity of mid-IR quantum cascade laser-based cavity-enhanced absorption spectroscopy using RF current perturbation. AB - The sensitivity of mid-IR quantum cascade laser (QCL) off-axis cavity-enhanced absorption spectroscopy (CEAS), often limited by cavity mode structure and diffraction losses, was enhanced by applying a broadband RF noise to the laser current. A pump-probe measurement demonstrated that the addition of bandwidth limited white noise effectively increased the laser linewidth, thereby reducing mode structure associated with CEAS. The broadband noise source offers a more sensitive, more robust alternative to applying single-frequency noise to the laser. Analysis of CEAS measurements of a CO(2) absorption feature at 1890 cm( 1) averaged over 100 ms yielded a minimum detectable absorption of 5.5*10(-3) Hz(-1/2) in the presence of broadband RF perturbation, nearly a tenfold improvement over the unperturbed regime. The short acquisition time makes this technique suitable for breath applications requiring breath-by-breath gas concentration information. PMID- 25503004 TI - Effect of dynamical instability on timing jitter in passively mode-locked quantum dot lasers. AB - We study the effect of noise on the dynamics of passively mode-locked semiconductor lasers both experimentally and theoretically. A method combining analytical and numerical approaches for estimation of pulse timing jitter is proposed. We investigate how the presence of dynamical features such as wavelength bistability in a quantum-dot laser affects timing jitter. PMID- 25503005 TI - Wave-optics description of self-healing mechanism in Bessel beams. AB - Bessel beams' great importance in optics lies in that these propagate without spreading and can reconstruct themselves behind an obstruction placed across their path. However, a rigorous wave-optics explanation of the latter property is missing. In this work, we study the reconstruction mechanism by means of a wave optics description. We obtain expressions for the minimum distance beyond the obstruction at which the beam reconstructs itself, which are in close agreement with the traditional one determined from geometrical optics. Our results show that the physics underlying the self-healing mechanism can be entirely explained in terms of the propagation of plane waves with radial wave vectors lying on a ring. PMID- 25503006 TI - Enhanced attosecond bursts of relativistic high-order harmonics driven by two color fields. AB - We study the generation of attosecond x-ray and ultraviolet pulses from relativistically driven overdense plasma targets with two-color incident light. Particle-in-cell simulations show that significant improvement in pulse intensity and isolation is achievable with appropriate laser and plasma parameters. Conversion of 5% of incident laser energy to its second harmonic can enhance the intensity of generated attosecond pulses by an order of magnitude. This approach allows the generation of higher attosecond pulse intensities with existing experimental laser technology and offers a powerful tool for the analysis of the dynamics of relativistic laser-plasma interaction. PMID- 25503007 TI - Plasmonic Bloch oscillations in monolayer graphene sheet arrays. AB - We investigate the spatial plasmonic Bloch oscillations (BOs) in the monolayer graphene sheet arrays (MGSAs) as the surface plasmon polaritons (SPPs) between graphene in the arrays experience weak coupling. In order to realize BOs, linear gradient of the potential is introduced by changing the chemical potentials of individual graphene sheets or the interlayer space between graphene. Numerical simulations show that the complete plasmonic BOs can be observed in the former MGSAs. However, only harmonic oscillations occur in the latter of varying interlayer space. Theoretical analysis based on the coupled-mode theory agrees well with the numerical simulations. PMID- 25503008 TI - Radiation-loss management in modulated waveguides. AB - In this work, we discuss the management of radiation loss in photonic waveguides. As an experimental basis, we introduce a new technique of fabricating waveguides with tunable loss, which is particularly useful when implementing non-Hermitian (PT-symmetric) systems. To this end, we employ laser-written waveguides with a transverse sinusoidal modulation, which causes well-controllable radiation losses of almost arbitrary amount. Numerical simulations support our experimental findings. Our study shows that the radiation loss not only depends on the local waveguide curvature but also is influenced by interference effects. As a consequence, the loss is a nonmonotonous function of the bending parameters, such as period length. PMID- 25503009 TI - Tilted Bragg gratings in step-index polymer optical fiber. AB - We report the first slightly tilted Bragg gratings photo-inscription in polymer optical fiber (POF). For this, we make use of trans-4-stilbenemethanol-doped photosensitive step-index poly(methyl methacrylate) (PMMA) POFs. Tilted fiber Bragg gratings (TFBGs) are inscribed in the near-infrared wavelength range using the scanning phase mask technique with a tilted phase mask in the plane perpendicular to the laser beam direction. The transmitted amplitude spectrum evolution of a 3 degrees TFBG is analyzed as a function of the surrounding refractive index. A maximum sensitivity close to 13 nm/RIU (refractive index unit) is obtained in the range 1.42-1.49. PMID- 25503010 TI - Ultra-thin curved transmission crystals for high resolving power (up to E/DeltaE = 6300) x-ray spectroscopy in the 6-13 keV energy range. AB - Ultra-thin curved transmission crystals operating in the Cauchois spectrometer geometry were evaluated for the purpose of achieving high spectral resolution in the 6-13 keV x-ray energy range. The crystals were silicon (111) and sapphire R cut wafers, each 18 MUm thick, and a silicon (100) wafer of 50-MUm thickness. The W Lalpha(1) spectral line at 8.398 keV from a laboratory source was used to evaluate the resolution. The highest crystal resolving power, E/DeltaE=6300, was achieved by diffraction from the (33-1) planes of the Si(100) wafer that was cylindrically bent to a radius of curvature of 254 mm, where the (33-1) planes have an asymmetric angle of 13.26 degrees from the normal of the crystal surface facing the x-ray source. This work demonstrates the ability to measure highly resolved line shapes of the K transitions of the elements Fe through Kr and the L transitions of the elements Gd through Th using a relatively compact spectrometer optical system and readily available thin commercial wafers. The intended application is as a diagnostic of laser-produced plasmas where the presence of multiple charged states and broadenings from high temperature and density requires high-resolution methods that are robust in a noisy source environment. PMID- 25503011 TI - Efficient spectral broadening in the 100-W average power regime using gas-filled kagome HC-PCF and pulse compression. AB - We present nonlinear pulse compression of a high-power SESAM-modelocked thin-disk laser (TDL) using an Ar-filled hypocycloid-core kagome hollow-core photonic crystal fiber (HC-PCF). The output of the modelocked Yb:YAG TDL with 127 W average power, a pulse repetition rate of 7 MHz, and a pulse duration of 740 fs was spectrally broadened 16-fold while propagating in a kagome HC-PCF containing 13 bar of static argon gas. Subsequent compression tests performed using 8.4% of the full available power resulted in a pulse duration as short as 88 fs using the spectrally broadened output from the fiber. Compressing the full transmitted power through the fiber (118 W) could lead to a compressed output of >100 W of average power and >100 MW of peak power with an average power compression efficiency of 88%. This simple laser system with only one ultrafast laser oscillator and a simple single-pass fiber pulse compressor, generating both high peak power >100 MW and sub-100-fs pulses at megahertz repetition rate, is very interesting for many applications such as high harmonic generation and attosecond science with improved signal-to-noise performance. PMID- 25503012 TI - 3D direct laser writing using a 405 nm diode laser. AB - Three-dimensional (3D) direct laser writing commonly uses near-infrared femtosecond laser pulses. Here, we use a quasi-cw blue diode laser at a 405 nm wavelength. As prerequisite, we identify photoresist systems that unambiguously show nonlinear multiphoton polymerization at this excitation wavelength. Next, we obtain a diffraction-limited focus with a high-numerical-aperture objective lens (NA=1.4), which is crucial to actually benefit from the wavelength advantage. To evaluate the anticipated reduced linewidths and improved resolution, we fabricate and characterize 2D and 3D benchmark structures. Finally, we also demonstrate dip in direct laser writing with our setup. PMID- 25503013 TI - Development of variable pulse width mode-locked femtosecond laser by applying coherent coupling technology. AB - A novel femtosecond mode-locked variable-pulse-width laser system is developed based on coherent coupling technology. The laser system is composed of two fiber ring lasers that share an output coupler. Output longitudinal modes are emitted by the corresponding longitudinal modes of the laser modules. In this study, one longitudinal-mode spacing is changed arbitrarily by tuning the cavity length to control the output longitudinal modes. In the experiment, the laser system generates about 150 fs pulse width. The coupling result, which is the output pulse width, is changed by a length deviation of about 500 MUm. As a result, the laser successful widens the pulse width to 1.5 ps at maximum and the tuning pulse width with 10 fs resolution at minimum. PMID- 25503014 TI - Three-dimensional integral imaging with flexible sensing. AB - We present to the best of our knowledge the first report on three-dimensional (3D) integral imaging capture and reconstruction method with unknown poses of sensors placed on a flexible surface. Compared to a conventional integral imaging system, where a lenslet or sensor array is commonly located on a planar surface, the flexible sensing integral imaging system allows sensors to be placed on a nonplanar surface that can increase the field of view of the 3D imaging system. To obtain the poses of the sensor array on a flexible surface, an estimation algorithm is developed based on two-view geometry theory and the camera projective model. In addition, a super-resolution image is generated from a sequence of low-resolution 2D images with sub-pixel shifts. Super-resolution 3D reconstruction results at different depths are presented to validate the proposed approach. PMID- 25503015 TI - Sub-100 fs passively mode-locked holmium-doped fiber oscillator operating at 2.06 MUm. AB - We demonstrate a simple and compact Holmium-doped fiber femtosecond oscillator, in-band pumped by a commercial Tm-doped fiber laser. The oscillator operates in the dispersion managed soliton regime at net zero intracavity dispersion and delivers >1 nJ pulse energy at 35 MHz repetition rate. The pulse duration directly at the oscillator output is 160 fs FWHM, close to the Fourier-limit of 145 fs FWHM. Using an additional nonlinear compressor stage, sub-100 fs FWHM pulse durations could be achieved. The nonlinear fiber compressor is implemented by a solid core highly nonlinear fiber for spectral broadening and a single mode fiber for pulse compression. PMID- 25503016 TI - Macroscopic three-dimensional particle location using stereoscopic imaging and astigmatic aberrations. AB - This Letter presents a stereoscopic imaging concept for measuring the locations of particles in three-dimensional space. The method is derived from astigmatism particle tracking velocimetry (APTV), a powerful technique that is capable of determining 3D particle locations with a single camera. APTV locates particle xy coordinates with high accuracy, while the particle z coordinate has a larger location uncertainty. This is not a problem for 3D2C (i.e., three dimensions, two velocity components) measurements, but for highly three-dimensional flows, it is desirable to measure three velocity components with similar accuracy. The stereoscopic APTV approach discussed in this report has this capability. The technique employs APTV for giving an initial estimate of the particle locations. With this information, corresponding particle images on both sensors of the stereoscopic imaging system are matched. Particle locations are then determined by mapping the two particle image sensor locations to physical space. The measurement error of stereo APTV, determined by acquiring images of 1-MUm DEHS particles in a 40 mm*40 mm*20 mm measurement volume in air at Deltaxyz->0 between two frames, is less than 0.012 mm for xy and 0.025 mm for z. This error analysis proves the excellent suitability of stereo APTV for the measurement of three dimensional flows in macroscopic domains. PMID- 25503017 TI - Distributed calculation method for large-pixel-number holograms by decomposition of object and hologram planes. AB - A method has been proposed to reduce the communication overhead in computer generated hologram (CGH) calculations on parallel and distributed computing devices. The method uses the shifting property of Fourier transform to decompose calculations, thereby avoiding data dependency and communication. This enables the full potential of parallel and distributed computing devices. The proposed method is verified by simulation and optical experiments and can achieve a 20 times speed improvement compared to conventional methods, while using large data sizes. PMID- 25503018 TI - Uniform free-space cell shaping using diffractive-type beam diffusers for optical wireless links. AB - This Letter presents the design of a diffractive beam diffuser to homogenize the irradiance within optical free-space cells generated from multimode fibers in an indoor high-speed network environment. Native speckled beams with a Gaussian envelope are transformed into circular flat-top distributions to guarantee a constant signal-to-noise ratio at the wireless receiving stage. Design considerations followed by the device fabrication and test results are given, showing its ability to shape narrow line-of-sight optical wireless cells operating at the Gbps range. PMID- 25503019 TI - 22 GW peak-power fiber chirped-pulse-amplification system. AB - In this Letter, we report on a femtosecond fiber chirped-pulse-amplification system based on the coherent combination of the output of four ytterbium-doped large-pitch fibers. Each single channel delivers a peak power of about 6.2 GW after compression. The combined system emits 200 fs long pulses with a pulse energy of 5.7 mJ at 230 W of average power together with an excellent beam quality. The resulting peak power is 22 GW, which to the best of our knowledge is the highest value directly emitted from any fiber-based laser system. PMID- 25503020 TI - Products of Schell-model cross-spectral densities. AB - The condition under which a product of two cross-spectral densities (CSD) constitutes a valid correlation function is established. The results are obtained for the CSDs of two one-dimensional, scalar Schell-model sources, but can be readily generalized to other situations. It is shown via a number of numerical examples how new source classes of Schell-model type and the beam-like fields they radiate can be designed. PMID- 25503021 TI - Broadband mid-IR frequency comb with CdSiP2 and AgGaS2 from an Er,Tm:Ho fiber laser. AB - We report on the generation of a 2500 nm bandwidth frequency comb at 6.5 MUm central wavelength based on critically phase-matched parametric down-conversion in the nonlinear crystal CdSiP(2) (CSP), driven by a compact Er,Tm:Ho fiber laser. The generated ultra-broadband pulses show a transform-limited duration of 2.3 optical cycles and carry up to 150 pJ of energy at a 100 MHz pulse repetition rate. For comparison, the spectrum generated in AgGaS(2) (AGS) spans from 6.2 to 7.4 MUm at full-width at half-maximum (FWHM) with a pulse energy of 3 pJ. A full 3D nonlinear wave propagation code is used for optimization of the noncollinear angle, propagation direction, and crystal thickness. PMID- 25503022 TI - Surface plasmon resonance in eccentric femtosecond-laser-induced fiber Bragg gratings. AB - Highly localized refractive index modulations are photo-written in the core of pure silica fiber using point-by-point focused UV femtosecond pulses. These specific gratings exhibit a comb-like transmitted amplitude spectrum, with polarization-dependent narrowband cladding mode resonances. In this work, eccentric gratings are surrounded by a gold sheath, allowing the excitation of surface plasmon polaritons (SPP) for radially-polarized light modes. The spectral response is studied as a function of the surrounding refractive index and a maximum sensitivity of 50 nm/RIU (refractive index unit) is reported for a well defined cladding-mode resonance among the spectral comb. This novel kind of plasmonic fiber grating sensor offers rapidity of production, design flexibility, and high temperature stability. PMID- 25503023 TI - Hybrid polarization-angle multiplexing for volume holography in gold nanoparticle doped photopolymer. AB - We report on volume holographic hybrid polarization-angle multiplexing in a gold nanoparticle-doped photopolymer. When doping the gold nanoparticles, the linear photoinduced birefringence of the phenanthrenequinone-doped poly (methyl methacrylate) (PQ/PMMA) photopolymer could be increased by nearly 38%. The data pages could be recorded with the orthogonal circular polarization multiplexing, and the reconstructed images have a symbol-error rate of 3.81% and 4.46% for left circular polarization and right circular polarization state, respectively. Two biological image sets multiplexed both with the angle interval of 0.1 degrees and with orthogonal circular polarization are reconstructed separately and simultaneously. PMID- 25503024 TI - Second-harmonic generation enhancement in the presence of Tamm plasmon polaritons. AB - Resonant enhancement of second-harmonic generation (SHG) intensity from a thin metal film is demonstrated in a Tamm plasmon-polariton mode excited at a metal/photonic crystal interface using nonlinear spectroscopy. Nonlinear effects enhancement in proposed structures exhibit strong polarization dependence (1:200 for the orthogonal fundamental polarizations). SHG enhancement factor evinces considerable angular dependence, rising from 50 for the 45 degrees angle of incidence to 170 for the 10 degrees angle of incidence. The results are analyzed numerically using a nonlinear transfer matrix technique. The findings elucidate the potential of Tamm plasmon-polaritons in the nonlinear optical applications. PMID- 25503025 TI - Split-mode fiber Bragg grating sensor for high-resolution static strain measurements. AB - We demonstrate a strain sensor with very high sensitivity in the static and low frequency regime based on a fiber ring cavity that includes a pi phase-shifted fiber Bragg grating. The grating acts as a partial reflector that couples the two counter-propagating cavity modes, generating a splitting of the resonant frequencies. The presence of a sharp transition within the pi phase-shifted fiber Bragg grating's spectral transmittance makes this frequency splitting extremely sensitive to length, temperature, and the refractive index of the fiber in the region where the grating is written. The splitting variations caused by small mechanical deformations of the grating are tracked in real time by interrogating a cavity resonance with a locked-carrier scanning-sideband technique. The measurable strain range and bandwidth are characterized, and a resolution of 320 pepsilon/Hz(1/2) at 0 Hz is experimentally demonstrated, the highest achieved to date with a fiber Bragg grating sensor. PMID- 25503026 TI - Super stereoscopy technique for comfortable and realistic 3D displays. AB - Two well-known problems of stereoscopic displays are the accommodation convergence conflict and the lack of natural blur for defocused objects. We present a new technique that we name Super Stereoscopy (SS3D) to provide a convenient solution to these problems. Regular stereoscopic glasses are replaced by SS3D glasses which deliver at least two parallax images per eye through pinholes equipped with light selective filters. The pinholes generate blur-free retinal images so as to enable correct accommodation, while the delivery of multiple parallax images per eye creates an approximate blur effect for defocused objects. Experiments performed with cameras and human viewers indicate that the technique works as desired. In case two, pinholes equipped with color filters per eye are used; the technique can be used on a regular stereoscopic display by only uploading a new content, without requiring any change in display hardware, driver, or frame rate. Apart from some tolerable loss in display brightness and decrease in natural spatial resolution limit of the eye because of pinholes, the technique is quite promising for comfortable and realistic 3D vision, especially enabling the display of close objects that are not possible to display and comfortably view on regular 3DTV and cinema. PMID- 25503027 TI - Low-power-penalty wavelength multicasting for 36 Gbit/s 16-QAM coherent optical signals in a silicon waveguide. AB - All-optical wavelength multicasting has been experimentally demonstrated for 36 Gbit/s 16-quadrature amplitude modulation signals based on four-wave mixing processes in a silicon waveguide with multiple pumps. In our experiment, dual pumps are injected together with the signal into the waveguide and nine idlers are generated, involving five wavelength multicasting channels. Coherent detection and advanced digital signal processing are employed, and the recovered constellation diagrams of the multicasting idlers show a root-mean-square error vector magnitude degradation as small as 2.74%. The bit error rate (BER) results are measured for these multicasting idlers, and the power penalties are all lower than 0.96 dB at the BER of 3.8*10(-3) (corresponding to the forward error correction threshold). PMID- 25503028 TI - Wavelength control of random polymer fiber laser based on adaptive disorder. AB - We demonstrate the realization of two different kinds of random polymer optical fiber lasers to control the random lasing wavelength by changing the disorder of polymer optical fibers (POFs). One is a long-range disorder POF based on copolymer refractive-index inhomogeneity, and the other is a short-range disorder POF based on polyhedral oligomeric silsesquioxanes scattering. By end pumped both disorder POFs, the coherent random lasing for both is observed. Meanwhile, the random lasing wavelength of the short-range disorder POF because of a small scattering mean-free path has been found to be blue shifted with respect to the long-range disorder POF, which will give a way to control the random lasing wavelength. PMID- 25503029 TI - Integrated single grating compressor for variable pulse front tilt in simultaneously spatially and temporally focused systems. AB - A Ti:Al(3)O(2) multipass chirped pulse amplification system is outfitted with a single-grating, simultaneous spatial and temporal focusing (SSTF) compressor platform. For the first time, this novel design has the ability to easily vary the beam aspect ratio of an SSTF beam, and thus the degree of pulse-front tilt at focus, while maintaining a net zero-dispersion system. Accessible variation of pulse front tilt gives full spatiotemporal control over the intensity distribution at the focus and could lead to better understanding of effects such as nonreciprocal writing and SSTF-material interactions. PMID- 25503030 TI - Optical systems for controlled specular depolarization. AB - Optical coatings are known to be highly polarizing at oblique incidence. On the other hand, they cannot reduce the degree of polarization of light. We show how to overcome this difficulty and reach spatial depolarization with significant efficiency. Applications concern space optical systems. PMID- 25503031 TI - Functional optical coherence tomography reveals transient phototropic change of photoreceptor outer segments. AB - Dynamic near infrared microscopy has revealed transient retinal phototropism (TRP) correlated with oblique light stimulation. Here, by developing a hybrid confocal microscopy and optical coherence tomography (OCT), we tested sub cellular source of the TRP in living frog retina. Dynamic confocal microscopy and OCT consistently revealed photoreceptor outer segments as the anatomic source of the TRP. Further investigation of the TRP can provide insights in better understanding of Stiles-Crawford effect (SCE) on rod and cone systems, and may also promise an intrinsic biomarker for early detection of eye diseases that can produce photoreceptor dysfunction. PMID- 25503032 TI - Bismuth-doped optical fibers and fiber lasers for a spectral region of 1600-1800 nm. AB - Bismuth-doped optical fibers and fiber lasers operating in 1625-1775 nm range have been developed for the first time to the best of our knowledge. Now the existing bismuth-doped lasers, including the result presented in this Letter, can cover O, E, S, C, L, and U telecommunication bands. In addition, new data on the nature of the bismuth-related active center were obtained and discussed. PMID- 25503033 TI - Polarization splitter and rotator with subwavelength grating for enhanced fabrication tolerance. AB - We propose a novel method to implement a compact and fabrication-tolerant polarization splitter and rotator (PSR) on the silicon-on-insulator platform. The PSR consists of a silicon wire waveguide coupled to a subwavelength grating (SWG) waveguide in an asymmetrical directional coupler. The SWG effect allows an additional degree of design freedom to engineer the equivalent material refractive index. This is advantageously used to effectively compensate for fabrication inaccuracies in PSRs. Our simulation results show that the PSR has a low TM-to-TE polarization conversion loss of -0.13 dB (a conversion efficiency of 97%) at the wavelength of 1550 nm, and better than -0.4 dB conversion loss over the entire C-band wavelength range. Compared to the PSRs made of conventional wire waveguides, the use of SWG index engineering improves the waveguide width fabrication tolerance substantially, from +/-3 nm to +/-40 nm. A compact device size with a coupling length of 25 MUm is achieved. PMID- 25503035 TI - SESAM mode-locked red praseodymium laser. AB - We present the first semiconductor saturable absorber mirror (SESAM) mode-locked praseodymium solid-state laser. The laser is based on a Pr(3+):LiYF(4) crystal as gain medium and a GaInP-quantum well-based SESAM. Self-starting continuous-wave mode-locked laser operation with an average output power of 16 mW is achieved at a center wavelength of 639.5 nm. The laser operates at a repetition rate of ~85.55 MHz and emits pulses with a duration of ~18 ps. PMID- 25503034 TI - Diffraction optical tomography using a quantitative phase imaging unit. AB - A simple and practical method to measure three-dimensional (3-D) refractive index (RI) distributions of biological cells is presented. A common-path self-reference interferometry consisting of a compact set of polarizers is attached to a conventional inverted microscope equipped with a beam scanning unit, which can precisely measure multiple 2-D holograms of a sample with high phase stability for various illumination angles, from which accurate 3-D optical diffraction tomograms of the sample can be reconstructed. 3-D RI tomograms of nonbiological samples such as polystyrene microspheres, as well as biological samples including human red blood cells and breast cancer cells, are presented. PMID- 25503036 TI - High-speed multispectral videography with a periscope array in a spectral shaper. AB - We present a simple method for continuous snapshot multispectral imaging or multispectral videography that achieves high-speed spectral video recording without the need for mechanical scanning and much computation for datacube construction. The enabling component of this method is an array of periscopes placed in a prism-based spectral shaper that spectrally separates the image without image deformation. As a proof-of-principle demonstration, we show five color multispectral video recording in the visible range (200*200 pixels per spectral image frame) at a record high frame rate of at least 2800 frames per second. Our experimental results indicate that this method holds promise for various industrial and biomedical applications such as remote sensing, food inspection, and endoscopy. PMID- 25503037 TI - Linearized Bragg grating assisted electro-optic modulator. AB - We propose a new linearized electro-optic modulator in which linearization is achieved by modulating the index of a Bragg grating reflector placed in the arm(s) of a Michelson Interferometer. This grating-assisted Michelson (GAMI) modulator can operate as either an intensity or amplitude modulator, and is shown to significantly improve the linearity of microwave photonics links. PMID- 25503038 TI - Theoretical analysis and modeling of a photonic integrated circuit for frequency 8-tupled and 24-tupled millimeter wave signal generation. AB - A photonic circuit design for implementing frequency 8-tupling and 24-tupling is proposed. The front- and back-end of the circuit comprises 4*4 MMI couplers enclosing an array of four pairs of phase modulators and 2*2 MMI couplers. The proposed design for frequency multiplication requires no optical or electrical filters, the operation is not limited to carefully adjusted modulation indexes, and the drift originated from static DC bias is mitigated by making use of the intrinsic phase relations of multi-mode interference couplers. A transfer matrix approach is used to represent the main building blocks of the design and hence to describe the operation of the frequency 8-tupling and 24-tupling. The concept is theoretically developed and demonstrated by simulations. Ideal and imperfect power imbalances in the multi-mode interference couplers, as well as ideal and imperfect phases of the electric drives to the phase modulators, are analyzed. PMID- 25503039 TI - Fiber-optic magnetic-field imaging. AB - We demonstrate a scanning fiber-optic probe for magnetic-field imaging where nitrogen-vacancy (NV) centers are coupled to an optical fiber integrated with a two-wire microwave transmission line. The electron spin of NV centers in a diamond microcrystal attached to the tip of the fiber probe is manipulated by a frequency-modulated microwave field and is initialized by laser radiation transmitted through the optical tract of the fiber probe. The two-dimensional profile of the magnetic field is imaged with a high speed and high sensitivity using the photoluminescence spin-readout return from NV centers, captured and delivered by the same optical fiber. PMID- 25503040 TI - Properties of two-dimensional resonant reflectors with zero-contrast gratings. AB - The spectral properties of high-reflection mirrors imbued with two-dimensional (2D) subwavelength periodicity are investigated. The reflectors are designed in a silicon-on-glass film that is partially etched to implement a zero-contrast interface between the grating pillars and the sublayer, thereby annulling the local reflections and phase changes associated with hard interfaces. This approach has shown impressive results for 1D polarized reflectors; here we strive to discover analogous wideband unpolarized reflectors. Using particle swarm optimization, we report wideband unpolarized reflectors in the 1.4-2.0 MUm wavelength band. A 2D reflector with square pillars exhibits 99% reflectance across a bandwidth exceeding 350 nm and possesses tolerance against angular deviations. The complementary structure with rectangular periodic voids achieves a bandwidth of 370 nm. A comparable, optimized 2D high-contrast grating reflector with grating pillars residing directly on the substrate yields a 99% bandwidth of 240 nm. PMID- 25503041 TI - Diamond photonic crystals for the IR spectral range. AB - 2D photonic crystals formed inside monocrystalline diamond to operate in the IR spectral range are reported. The photonic structures consisting of 150-MUm-long graphitized wires arranged in a square matrix with a period of 4 MUm were produced by laser writing with ultrashort pulses. Transmittance spectra (lambda=1 14 MUm) measured for the structures with increasing thickness demonstrate the occurrence of few minima being different for TM and TE polarization modes. Complex refraction index of the laser-modified material was evaluated for the first time in order to be used in computer simulation of the structures. PMID- 25503042 TI - Spatial-phase-shift imaging interferometry using a spectrally modulated white light source. AB - An extension of the white light spatial-phase-shift (WLSPS) for object surface measurements is described. Using WLSPS, surface measurements can be obtained from any real object image without the need of a reference beam, thus achieving inherent vibration cancellation. The surface topography is obtained by acquiring multiple images of an object illuminated by a spectrally modulated white light source and using an appropriate algorithm. The modulation of the light source obviates the need for the continuous phase delay to obtain the interferograms. PMID- 25503043 TI - Fractional Talbot lithography with extreme ultraviolet light. AB - Fractional Talbot effect leads to the possibility to implement patterning of structures with smaller periods than the master mask. This is particularly attractive when using short wavelength illumination in the extreme ultraviolet because of attainable resolution in the sub-100-nm range. In this Letter, we demonstrate the Talbot lithography with the fractional Talbot effect under coherent illumination generated with a capillary discharge Ne-like Ar extreme ultraviolet laser. Various spatial frequency multiplications up to 5x are achieved using a parent grating. This technique allows a fabrication of nanostructures with high-resolution patterns, which is of high interest in many applications such as the manufacturing of plasmonic surfaces and photonic devices. PMID- 25503044 TI - Ultra-compact channel drop filter based on photonic crystal nanobeam cavities utilizing a resonant tunneling effect. AB - The design, fabrication, and characterization of a compact photonic crystal nanobeam drop filter based on the tunneling effect of the degenerate modes are presented. The degeneracy was achieved by tuning the coupling distance between the nanobeam and input/output waveguides. The tunneling effect of degenerate resonances with different symmetries has been verified experimentally. Channel drop filters with an extinction ratio larger than 10 dB and a quality factor of ~5000 have been experimentally demonstrated. PMID- 25503045 TI - Plasmonic spiderweb nanoantenna surface for broadband hotspot generation. AB - In this study, we demonstrate a general framework for obtaining a plasmonic nanoantenna surface with a broadband polarization-independent response. The plasmonic spiderweb nanoantenna surface is composed of unit cells, which form multiple resonance paths due to patterning of the metallic conductor such that electrons can find multiple ways to oscillate between the poles of the conductor. The tailoring of the conductor paths and shapes of the unit cells' patterns results in a broadband spectral response. At various resonance frequencies, the electrons oscillate along different paths between the poles of the antenna, generating broadband hot spots around those poles. PMID- 25503046 TI - Super-resolution technique for CW lidar using Fourier transform reordering and Richardson-Lucy deconvolution. AB - An interpolation method is described for range measurements of high precision altimetry with repeating intensity modulated continuous wave (IM-CW) lidar waveforms using binary phase shift keying (BPSK), where the range profile is determined by means of a cross-correlation between the digital form of the transmitted signal and the digitized return signal collected by the lidar receiver. This method uses reordering of the array elements in the frequency domain to convert a repeating synthetic pulse signal to single highly interpolated pulse. This is then enhanced further using Richardson-Lucy deconvolution to greatly enhance the resolution of the pulse. We show the sampling resolution and pulse width can be enhanced by about two orders of magnitude using the signal processing algorithms presented, thus breaking the fundamental resolution limit for BPSK modulation of a particular bandwidth and bit rate. We demonstrate the usefulness of this technique for determining cloud and tree canopy thicknesses far beyond this fundamental limit in a lidar not designed for this purpose. PMID- 25503047 TI - Reconfigurable dual-channel dropping filters based on a self-coupled resonator Sagnac interferometer. AB - We report a reconfigurable dual-mode resonator-based dual-channel dropping filter. The dual dropping channels are generated within a free spectral range (FSR) via the interference between the electromagnetically induced transparency (EIT)-like and electromagnetically induced absorption (EIA)-like resonances despite only one resonator used. The reconfiguration of the dual channels enabling the truly on/off switching mechanism is realized, and the output modes resembling the add/drop/neutral states are provided. The compact, reliable, flexible, versatile, and extendable filter has profound implications for wavelength division multiplexing (WDM) applications in optical interconnection networks. PMID- 25503048 TI - On the origin of flicker noise in carrier-envelope phase stabilization. AB - The origin of a 1/f noise contribution in the long-term carrier-envelope phase (CEP) measurements of mode-locked lasers is discussed. Using two different collinear interferometers for the out-of-loop characterization of feed-forward stabilized Ti:sapphire oscillators, we suppress a possible technical origin of 1/f noise to the extent possible. Both measurements indicate a lower limit of CEP frequency noise of 1 mHz/?Hz. Investigating several possible origins of this noise floor, we find a good agreement with a quantum noise mechanism that is directly induced by intracavity-amplified spontaneous emission (ASE). These findings enable direct access to ASE noise in short-pulse oscillators, which is very hard to characterize via repetition rate fluctuations. Finally, we discuss the possible consequences for frequency-comb-based timekeeping and frequency metrology, as well as for attosecond science. PMID- 25503049 TI - Silicon hybrid demultiplexer with 64 channels for wavelength/mode-division multiplexed on-chip optical interconnects. AB - A monolithically integrated 64-channel hybrid demultiplexer on silicon is demonstrated experimentally to enable wavelength-division-multiplexing and mode division-multiplexing simultaneously for realizing an ultra-large capacity optical-interconnect link. The present hybrid demultiplexer consists of a four channel mode multiplexer realized with three cascaded asymmetrical directional couplers and four identical arrayed-waveguide gratings (AWGs) with 16 channels. For the fabricated hybrid multiplexer, the excess loss and the crosstalk are about -7 and -10 dB, respectively. Better performances can be achieved by minimizing the imperfections (particularly in AWGs) in the fabrication processes. The present hybrid demultiplexer is scalable to have more channels by utilizing more wavelengths, modes, and polarizations. PMID- 25503050 TI - Frequency-scanning interferometry for dynamic absolute distance measurement using Kalman filter. AB - We propose a frequency-scanning interferometry using the Kalman filtering technique for dynamic absolute distance measurement. Frequency-scanning interferometry only uses a single tunable laser driven by a triangle waveform signal for forward and backward optical frequency scanning. The absolute distance and moving speed of a target can be estimated by the present input measurement of frequency-scanning interferometry and the previously calculated state based on the Kalman filter algorithm. This method not only compensates for movement errors in conventional frequency-scanning interferometry, but also achieves high precision and low-complexity dynamic measurements. Experimental results of dynamic measurements under static state, vibration and one-dimensional movement are presented. PMID- 25503052 TI - 2012 International Cancer Education Conference Proceedings. PMID- 25503051 TI - Surprise is a Neglected Aspect of Emerging Infectious Disease. PMID- 25503053 TI - Differences in Electronic Cigarette Awareness, Use History, and Advertisement Exposure Between Black and White Hospitalized Cigarette Smokers. AB - E-cigarette use has increased rapidly over the past decade. There is growing concern about e-cigarette use and advertising given limited regulation of these products. This cross-sectional study reports on data collected at baseline from hospitalized cigarette smokers (N=944) recruited in monthly cohorts between December 2012 and September 2013. Participants were queried regarding e-cigarette awareness and use, and number and sources of e-cigarette advertisement exposures in the previous 6 months. Most Whites (99%) reported ever hearing of an e cigarette compared to 96% of Blacks (p<0.001). Over two thirds (64%) of Whites reported ever using an e-cigarette compared to 30% of Blacks (p<0.001). There were significant trends in increasing e-cigarette use for both racial groups with an average increase of 13% each month (p<0.005) and in increasing e-cigarette advertisement exposure reported for the previous 6 months, with a 14% increase each month (p<0.0001). Whites reported 56% greater advertisement exposure than Blacks (mean=25 vs. 8 in month 1 to 79 vs. 45 in month 9, respectively; p<0.0001). For Blacks, advertisement exposure was significantly associated with e cigarette use (p<0.001). Whites reported more advertisement exposure from stores and the Internet, and Blacks reported more advertisement exposure from radio or television. Results suggest that e-cigarette marketing is beginning to breach the Black population who are, as a consequence, "catching up" with Whites with regard to e-cigarette use. Given the significant disparities for smoking-related morbidity and mortality between Blacks and Whites, these findings identify new areas for future research and policy. PMID- 25503055 TI - Free-standing Fe2O3 nanomembranes enabling ultra-long cycling life and high rate capability for Li-ion batteries. AB - With Fe2O3 as a proof-of-concept, free-standing nanomembrane structure is demonstrated to be highly advantageous to improve the performance of Li-ion batteries. The Fe2O3 nanomembrane electrodes exhibit ultra-long cycling life at high current rates with satisfactory capacity (808 mAh g(-1) after 1000 cycles at 2 C and 530 mAh g(-1) after 3000 cycles at 6 C) as well as repeatable high rate capability up to 50 C. The excellent performance benefits particularly from the unique structural advantages of the nanomembranes. The mechanical feature can buffer the strain of lithiation/delithiation to postpone the pulverization. The two-dimensional transport pathways in between the nanomembranes can promote the pseudo-capacitive type storage. The parallel-laid nanomembranes, which are coated by polymeric gel-like film and SEI layer with the electrolyte in between layers, electrochemically behave like numerous "mini-capacitors" to provide the pseudo capacitance thus maintain the capacity at high rate. PMID- 25503054 TI - Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. AB - Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown. We analyzed mucosal Th17 cells in 42 acute HIV infection (AHI) subjects (Fiebig (F) stage I-V) with a median duration of infection of 16 days and the short-term impact of early initiation of ART. Th17 cells were defined as IL-17+ CD4+ T cells and their function was assessed by the co-expression of IL-22, IL-2 and IFNgamma. While intact during FI/II, depletion of mucosal Th17 cell numbers and function was observed during FIII correlating with local and systemic markers of immune-activation. ART initiated at FI/II prevented loss of Th17 cell numbers and function, while initiation at FIII restored Th17 cell numbers but not their polyfunctionality. Furthermore, early initiation of ART in FI/II fully reversed the initially observed mucosal and systemic immune-activation. In contrast, patients treated later during AHI maintained elevated mucosal and systemic CD8+ T-cell activation post initiation of ART. These data support a loss of Th17 cells at early stages of acute HIV infection, and highlight that studies of ART initiation during early AHI should be further explored to assess the underlying mechanism of mucosal Th17 function preservation. PMID- 25503059 TI - Potassium stress growth characteristics and energetics in the haloarchaeon Haloarcula marismortui. AB - Growth characteristics surrounding halophilic archaeal organisms are extremely limited in the scientific literature, with studies tending toward observing changes in cellular generation times under growth conditions limited to changes in temperature and sodium chloride concentrations. Currently, knowledge of the ionic stress experienced by haloarchaeal species through an excess or depletion of other required ions is lacking at best. The halophilic archaeon, Haloarcula marismortui, was analyzed under extreme ionic stress conditions with a specific focus on induced potassium ion stress using growth curves and analysis of the intracellular ion concentrations. Generation times were determined under potassium chloride concentrations ranging from 8 to 720 mM, and also in the presence of the alternative monovalent cations of lithium, rubidium, and cesium under limiting potassium conditions. Intracellular ion concentrations, as determined by inductively coupled mass spectrometry (ICP-MS), indicate a minimum intracellular total ion requirement of 1.13 M while tolerating up to 2.43 M intracellular concentrations. The presence of intracellular rubidium and cesium indicates that monovalent ion transport is important for energy production. Comparison of eight archaeal genomes indicates an increased diversity of potassium transport complex subunits in the halophilic organisms. Analysis of the generation times, intracellular concentrations and genome survey shows Har. marismortui exhibits an ability to cope with monovalent cation concentration changes in its native environment and provides insight into the organisms ion transport capability and specificity. PMID- 25503061 TI - Twenty years of trans-disciplinary approach development for dysphagia rehabilitation in Japan. PMID- 25503060 TI - Functionally selective signaling for morphine and fentanyl antinociception and tolerance mediated by the rat periaqueductal gray. AB - Functionally selective signaling appears to contribute to the variability in mechanisms that underlie tolerance to the antinociceptive effects of opioids. The present study tested this hypothesis by examining the contribution of G protein coupled receptor kinase (GRK)/Protein kinase C (PKC) and C-Jun N-terminal kinase (JNK) activation on both the expression and development of tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray of the rat. Microinjection of morphine or fentanyl into the periaqueductal gray produced a dose-dependent increase in hot plate latency. Microinjection of the non-specific GRK/PKC inhibitor Ro 32-0432 into the periaqueductal gray to block mu-opioid receptor phosphorylation enhanced the antinociceptive effect of morphine but had no effect on fentanyl antinociception. Microinjection of the JNK inhibitor SP600125 had no effect on morphine or fentanyl antinociception, but blocked the expression of tolerance to repeated morphine microinjections. In contrast, a microinjection of Ro 32-0432 blocked the expression of fentanyl, but not morphine tolerance. Repeated microinjections of Ro 32-0432 blocked the development of morphine tolerance and inhibited fentanyl antinociception whether rats were tolerant or not. Repeated microinjections of SP600125 into the periaqueductal gray blocked the development of tolerance to both morphine and fentanyl microinjections. These data demonstrate that the signaling molecules that contribute to tolerance vary depending on the opioid and methodology used to assess tolerance (expression vs. development of tolerance). This signaling difference is especially clear for the expression of tolerance in which JNK contributes to morphine tolerance and GRK/PKC contributes to fentanyl tolerance. PMID- 25503062 TI - ViVar: a comprehensive platform for the analysis and visualization of structural genomic variation. AB - Structural genomic variations play an important role in human disease and phenotypic diversity. With the rise of high-throughput sequencing tools, mate pair/paired-end/single-read sequencing has become an important technique for the detection and exploration of structural variation. Several analysis tools exist to handle different parts and aspects of such sequencing based structural variation analyses pipelines. A comprehensive analysis platform to handle all steps, from processing the sequencing data, to the discovery and visualization of structural variants, is missing. The ViVar platform is built to handle the discovery of structural variants, from Depth Of Coverage analysis, aberrant read pair clustering to split read analysis. ViVar provides you with powerful visualization options, enables easy reporting of results and better usability and data management. The platform facilitates the processing, analysis and visualization, of structural variation based on massive parallel sequencing data, enabling the rapid identification of disease loci or genes. ViVar allows you to scale your analysis with your work load over multiple (cloud) servers, has user access control to keep your data safe and is easy expandable as analysis techniques advance. URL: https://www.cmgg.be/vivar/ PMID- 25503063 TI - Highly selective colorimetric bacteria sensing based on protein-capped nanoparticles. AB - A rapid and cost-effective colorimetric sensor has been developed for the detection of bacteria (Bacillus subtilis was selected as an example). The sensor was designed to rely on lysozyme-capped AuNPs with the advantages of effective amplification and high specificity. In the sensing system, lysozyme was able to bind strongly to Bacillus subtilis, which effectively induced a color change of the solution from light purple to purplish red. The lowest concentration of Bacillus subtilis detectable by the naked eye was 4.5 * 10(3) colony-forming units (CFU) mL(-1). Similar results were discernable from UV-Vis absorption measurements. A good specificity was observed through a statistical analysis method using the SPSS software (version 17.0). This simple colorimetric sensor may therefore be a rapid and specific method for a bacterial detection assay in complex samples. PMID- 25503065 TI - "Nuclear FGF receptor-1 and CREB binding protein: an integrative signaling module". AB - In this review we summarize the current understanding of a novel integrative function of Fibroblast Growth Factor Receptor-1 (FGFR1) and its partner CREB Binding Protein (CBP) acting as a nuclear regulatory complex. Nuclear FGFR1 and CBP interact with and regulate numerous genes on various chromosomes. FGFR1 dynamic oscillatory interactions with chromatin and with specific genes, underwrites gene regulation mediated by diverse developmental signals. Integrative Nuclear FGFR1 Signaling (INFS) effects the differentiation of stem cells and neural progenitor cells via the gene-controlling Feed-Forward-And-Gate mechanism. Nuclear accumulation of FGFR1 occurs in numerous cell types and disruption of INFS may play an important role in developmental disorders such as schizophrenia, and in metastatic diseases such as cancer. Enhancement of INFS may be used to coordinate the gene regulation needed to activate cell differentiation for regenerative purposes or to provide interruption of cancer stem cell proliferation. PMID- 25503064 TI - Analysis of RNAseq datasets from a comparative infectious disease zebrafish model using GeneTiles bioinformatics. AB - We present a RNA deep sequencing (RNAseq) analysis of a comparison of the transcriptome responses to infection of zebrafish larvae with Staphylococcus epidermidis and Mycobacterium marinum bacteria. We show how our developed GeneTiles software can improve RNAseq analysis approaches by more confidently identifying a large set of markers upon infection with these bacteria. For analysis of RNAseq data currently, software programs such as Bowtie2 and Samtools are indispensable. However, these programs that are designed for a LINUX environment require some dedicated programming skills and have no options for visualisation of the resulting mapped sequence reads. Especially with large data sets, this makes the analysis time consuming and difficult for non-expert users. We have applied the GeneTiles software to the analysis of previously published and newly obtained RNAseq datasets of our zebrafish infection model, and we have shown the applicability of this approach also to published RNAseq datasets of other organisms by comparing our data with a published mammalian infection study. In addition, we have implemented the DEXSeq module in the GeneTiles software to identify genes, such as glucagon A, that are differentially spliced under infection conditions. In the analysis of our RNAseq data, this has led to the possibility to improve the size of data sets that could be efficiently compared without using problem-dedicated programs, leading to a quick identification of marker sets. Therefore, this approach will also be highly useful for transcriptome analyses of other organisms for which well-characterised genomes are available. PMID- 25503066 TI - [Estimation of prevalence and treatment needs of mental disorders. The problem of diagnostic thresholds]. AB - BACKGROUND: Uncertainties in the context of threshold-based diagnostics represent a theoretically unsolved methodological problem that may require multidimensional solutions. Pragmatically, current research focuses on establishing reliable and valid operationalized criteria within the framework of diagnostic systems, such as the International Classification of Diseases (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders (DSM). AIM AND METHODS: By means of model calculations based on epidemiological data we show how exemplified changes in the disorder spectrum and diagnostic criteria influence case numbers. Furthermore, we investigate how threshold-based constructs, such as DSM-IV diagnoses, relate to the general criteria of illness and sickness. RESULTS: Variations in the disorder spectrum and thresholds lead to slight to moderate changes in case numbers. Regarding distress and impairment, mental disorders are associated with significantly reduced health-related quality of life and an increased number of days out of role (due to mental and/or physical problems). With increasing distress and impairment, the percentage of mental disorders increases significantly; in the 5 % of the general population with the highest distress and impairment, the proportion is nearly 80 %. DISCUSSION: Despite fuzzy boundaries, threshold-based diagnoses (DSM-IV) represent a satisfactory and reproducible disease classification (in terms of illness and sickness) for estimation of prevalence. There is a lack of definitions and instruments to assess treatment needs. It is still debated whether diagnostic symptom criteria always represent pathological disorders (i. e. disease). PMID- 25503068 TI - Notoginsenoside R1 ameliorates podocyte adhesion under diabetic condition through alpha3beta1 integrin upregulation in vitro and in vivo. AB - BACKGROUND: Decreased expression of alpha3beta1 integrin may contribute to reduction in podocyte adhesion to glomerular basement membrane (GBM), which represents a novel early mechanism leading to diabetic kidney disease (DKD). Here, we examined the protective effects of Notoginsenoside R1 (NR1) on podocyte adhesion and alpha3beta1 integrin expression under diabetic condition in vitro and in vivo. METHODS: Conditionally immortalized mouse podocytes were exposed to high glucose (HG) with 10 and 100MUg /ml of NR1 for 24 h. Podocyte adhesion, albuminuria, oxidative markers, renal histopathology, podocyte number per glomerular volume, integrin-linked kinase (ILK) activity and alpha3beta1 integrin expression were measured in vitro and in vivo. RESULTS: HG decreased podocyte adhesive capacity and alpha3beta1 integrin expression, the main podocyte anchoring dimer to the GBM. However, NR1 ameliorated impaired podocyte adhesive capacity and partially restored alpha3beta1 integrin protein and mRNA expression. These in vitro observations were confirmed in vivo. In streptozotocin(STZ) induced diabetic rats, treatment with NR1 (5 and 10 mg. kg(-1). d(-1)) for 12 weeks partially restored the number of podocytes per glomerular volume and glomerular alpha3beta1 integrin expression, as well as ameliorated albuminuria, histopathology and oxidative stress. NR1 also inhibited glomerular ILK activity in diabetic rats. CONCLUSION: NR1, a novel antioxidant, ameliorated glucose induced impaired podocyte adhesive capacity and subsequent podocyte depopulation partly through alpha3beta1 integrin upregulation. These findings might provide a potential new therapeutic option for the treatment of DKD. PMID- 25503067 TI - Changes in the expression of DNA-binding/differentiation protein inhibitors in neurons and glial cells of the gerbil hippocampus following transient global cerebral ischemia. AB - Inhibitors of DNA-binding/differentiation (ID) proteins bind to basic helix-loop helix (bHLH) transcription factors, including those that regulate differentiation and cell-cycle progression during development, and regulate gene transcription. However, little is known about the role of ID proteins in the brain under transient cerebral ischemic conditions. In the present study, we examined the effects of ischemia-reperfusion (I-R) injury on the immunoreactivity and protein levels of IDs 1-4 in the gerbil hippocampus proper Cornu Ammonis regions CA1-3 following 5 min of transient cerebral ischemia. Strong ID1 immunoreactivity was detected in the nuclei of pyramidal neurons in the hippocampal CA1-3 regions; immunoreactivity was significantly changed following I-R in the CA1 region, but not in the CA2/3 region. Five days following I-R, ID1 immunoreactivity was not detected in the CA1 pyramidal neurons. ID1 immunoreactivity was detected only in GABAergic interneurons in the ischemic CA1 region. Weak ID4 immunoreactivity was detected in non-pyramidal cells, and immunoreactivity was again only changed in the ischemic CA1 region. Five days following I-R, strong ID4 immunoreactivity was detected in non-pyramidal cells, which were identified as microglia, and not astrocytes, in the ischemic CA1 region. Furthermore, changes in the protein levels of ID1 and ID4 in the ischemic CA1 region studied by western blot were consistent with patterns of immunoreactivity. In summary, these results indicate that immunoreactivity and protein levels of ID1 and ID4 are distinctively altered following transient cerebral ischemia only in the CA1 region, and that the changes in ID1 and ID4 expression may relate to the ischemia-induced delayed neuronal death. PMID- 25503069 TI - Autophagic marker MAP1LC3B expression levels are associated with carotid atherosclerosis symptomatology. AB - OBJECTIVES: The mechanism by which atheroma plaque becomes unstable is not completely understood to date but analysis of differentially expressed genes in stable versus unstable plaques may provide clues. This will be crucial toward disclosing the mechanistic basis of plaque instability, and may help to identify prognostic biomarkers for ischaemic events. The objective of our study was to identify differences in expression levels of 59 selected genes between symptomatic patients (unstable plaques) and asymptomatic patients (stable plaques). METHODS: 80 carotid plaques obtained by carotid endarterectomy and classified as symptomatic (>70% stenosis) or asymptomatic (>80% stenosis) were used in this study. The expression levels of 59 genes were quantified by qPCR on RNA extracted from the carotid plaques obtained by endarterectomy and analyzed by means of various bioinformatic tools. RESULTS: Several genes associated with autophagy pathways displayed differential expression levels between asymptomatic and symptomatic (i.e. MAP1LC3B, RAB24, EVA1A). In particular, mRNA levels of MAP1LC3B, an autophagic marker, showed a 5-fold decrease in symptomatic samples, which was confirmed in protein blots. Immune system-related factors and endoplasmic reticulum-associated markers (i.e. ERP27, ITPR1, ERO1LB, TIMP1, IL12B) emerged as differently expressed genes between asymptomatic and symptomatic patients. CONCLUSIONS: Carotid atherosclerotic plaques in which MAP1LC3B is underexpressed would not be able to benefit from MAP1LC3B-associated autophagy. This may lead to accumulation of dead cells at lesion site with subsequent plaque destabilization leading to cerebrovascular events. Identified biomarkers and network interactions may represent novel targets for development of treatments against plaque destabilization and thus for the prevention of cerebrovascular events. PMID- 25503070 TI - Association of dietary factors with presence and severity of tinnitus in a middle aged UK population. AB - OBJECTIVE: The impact of dietary factors on tinnitus has received limited research attention, despite being a considerable concern among people with tinnitus and clinicians. The objective was to examine the link between dietary factors and presence and severity of tinnitus. DESIGN: This study used the UK Biobank resource, a large cross-sectional study of adults aged 40-69. 171,722 eligible participants were asked questions specific to tinnitus (defined as noises such as ringing or buzzing in the head or ears). Dietary factors included portions of fruit and vegetables per day, weekly fish consumption (oily and non oily), bread type, cups of caffeinated coffee per day, and avoidance of dairy, eggs, wheat and sugar. We controlled for lifestyle, noise exposure, hearing, personality and comorbidity factors. RESULTS: Persistent tinnitus, defined as present at least a lot of the time, was elevated with increased: (i) fruit/vegetable intake (OR = 1.01 per portion/day), (ii) bread (wholemeal/wholegrain, OR = 1.07; other bread, 1.20) and (iii) dairy avoidance (OR = 1.27). Persistent tinnitus was reduced with: (i) fish consumption (non oily, OR = 0.91; oily, 0.95), (ii) egg avoidance (OR = 0.87) and (iii) caffeinated coffee consumption (OR = 0.99 per cup/day). Reports of "bothersome" tinnitus (moderate-severe handicap) reduced with wholemeal/wholegrain bread intake (OR = 0.86) [corrected].Reports of less frequent transient tinnitus increased with dairy avoidance (OR = 1.18) and decreased with caffeinated coffee (OR = 0.98 per cup/day) and brown bread (OR = 0.94). CONCLUSIONS: This is the first population study to report the association between dietary factors and tinnitus. Although individually dietary associations are mostly modest, particular changes in diet, such as switching between foodstuffs, may result in stronger associations. These findings offer insights into possible dietary associations with tinnitus, and this may be useful when discussing management options in combination with other lifestyle changes and therapies. PMID- 25503072 TI - Immunotherapy: Checkpoint parley. PMID- 25503071 TI - Preoperative risk factors for postoperative delirium following hip fracture repair: a systematic review. AB - OBJECTIVE: Systematically identify preoperative clinical risk factors for incident postoperative delirium in individuals undergoing hip fracture repair in order to guide clinicians in identifying high risk patients at admission. METHODS: This is a systematic review of prospective observational studies with estimation of association between preoperative risk factors and incident postoperative delirium in multivariate models. Electronic searches were conducted in PubMed, Embase, PsycINFO, CINAHL, Cochrane Library, Proquest Dissertations and Theses, and WorldCatDissertations. Hand searches were conducted in selected journals and their supplements. RESULTS: Search yielded 6380 titles and abstracts from electronic databases and 72 titles from hand searches, and 10 studies met inclusion criteria. The following risk factors were significant in bivariate models: cognitive impairment, age, gender, institutionalization, functional impairment, body mass index (BMI), albumin, comorbidities, American Society of Anesthesiologist classification, acute medical conditions, polypharmacy, and vision impairment. Among all of these risk factors, cognitive impairment most consistently remained statistically significant after adjusting for other risk factors in multivariate models, followed by BMI/albumin and multiple comorbidities. CONCLUSION: In our systematic review, cognitive impairment was one of the strongest preoperative risk factors for postoperative delirium after hip fracture surgery. Preoperative cognitive assessment may be one of the most useful methods of identifying those who are at high risk for postoperative delirium and prioritizing delivery of delirium prevention measures. PMID- 25503073 TI - Metabolism: Feed a cold, starve a tumour. PMID- 25503074 TI - Molecular markers for recurrence and sensitivity to preoperative chemoradiotherapy in locally advanced rectal tumours. AB - BACKGROUND: The objective of our study is to provide predictive markers of locally advanced rectal tumour sensitivity to preoperative chemoradiotherapy in order to identify tumours that present a high risk of recurrence after standard total mesorectal excision surgery and preoperative chemoradiotherapy, according to histological response and microsatellite allelic imbalance (AI). METHODS: Twenty-nine locally advanced tumours were included in the study and the genomic alterations and the tumour regression grade of paired rectal biopsies (before chemoradiotherapy) and carcinomas (after surgery) were assessed. Clinical and allelotyping data were analysed for local and distant recurrence. RESULTS: The global AI frequency significantly decreased from 47.4 to 20.3% (p < 0.01) after preoperative treatment. Preoperative chemoradiotherapy significantly induced the loss of cells bearing AI at 8 microsatellites: D18S61, D8S264, D1S305, D10S191, D4S394, D14S65, D17S790 and D10S192. Among these, AI at the D8S264 locus was significantly associated with recurrence in our rectal tumour cohort (p = 0.039). CONCLUSION: Loss of AI at D8S264 is predictive of sensitivity to neoadjuvant treatment; thus, we concluded that the persistence of AI at D8S264 in rectal tumours after preoperative chemoradiotherapy could be considered a molecular marker of recurrence. PMID- 25503075 TI - Detection and genotyping of Chlamydia species responsible for reproductive disorders in Algerian small ruminants. AB - Chlamydiosis in small ruminants is a zoonotic disease mainly related to Chlamydia abortus. This bacterium is responsible for abortions and reproductive disorders in sheep and goats. Stillbirth and infertility, leading to important economic losses, are also associated with this pathology. In Algeria, abortion cases are frequently reported by veterinarians but, except for brucellosis which is a notifiable disease in this country, abortive diseases are in general poorly studied. In order to detect and genotype Chlamydia species in small ruminants in different areas of Algeria, a study was conducted on samples collected from females (164 blood samples and 199 vaginal swabs) between October 2011 and March 2013. Serum samples were tested with a C. abortus-specific indirect ELISA test. Fourteen samples (8.5 %), from six farms (6/20, 30 %) were tested positive. Vaginal swabs were analysed with a real-time PCR targeting all Chlamydiaceae spp. Thirty samples (15 %) were diagnosed positive in 16 farms (16/25, 64 %). Positive samples were all re-tested with a C. abortus- and a C. pecorum-specific real-time PCR. Finally, 13/30 (43.3 %) and 6/30 (20 %) were identified as C. abortus and C. pecorum, respectively. Enough concentrated C. abortus samples were genotyped by multi-loci variable number of tandem repeat (VNTR) analysis (MLVA), and all were related to the genotype [2] group which mainly includes French C. abortus isolates. C. pecorum-positive samples were genotyped by multi-locus sequence typing (MLST). Interestingly, two of them were successfully genotyped and showed identical MLST sequences to VB2, AB10, E58 and SBE, a group which includes C. pecorum isolates considered as highly pathogenic. These findings suggest a possible role of C. abortus and C. pecorum strains in the aetiology of abortion in Algerian small ruminants. PMID- 25503076 TI - Functional upregulation of nav1.8 sodium channels on the membrane of dorsal root Ganglia neurons contributes to the development of cancer-induced bone pain. AB - We have previously reported that enhanced excitability of dorsal root ganglia (DRG) neurons contributes to the development of bone cancer pain, which severely decreases the quality of life of cancer patients. Nav1.8, a tetrodotoxin resistant (TTX-R) sodium channel, contributes most of the sodium current underlying the action potential upstroke and accounts for most of the current in later spikes in a train. We speculate that the Nav1.8 sodium channel is a potential candidate responsible for the enhanced excitability of DRG neurons in rats with bone cancer pain. Here, using electrophysiology, Western blot and behavior assays, we documented that the current density of TTX-R sodium channels, especially the Nav1.8 channel, increased significantly in DRG neurons of rats with cancer-induced bone pain. This increase may be due to an increased expression of Nav1.8 on the membrane of DRG neurons. Accordantly, blockade of Nav1.8 sodium channels by its selective blocker A-803467 significantly alleviated the cancer-induced mechanical allodynia and thermal hyperalgesia in rats. Taken together, these results suggest that functional upregulation of Nav1.8 channels on the membrane of DRG neurons contributes to the development of cancer-induced bone pain. PMID- 25503077 TI - Mammary analogue secretory carcinoma of salivary glands: a new entity associated with ETV6 gene rearrangement. AB - Mammary analogue secretory carcinoma (MASC) is a recently described salivary gland tumour that harbours the recurrent ETV6-NTRK3 translocation. This is the first series of MASC cases identified in the historic cohort of carcinomas of salivary glands with clinical/pathological correlation and follow-up data. We reviewed 183 primary carcinomas of major and minor salivary glands resected at the Medical University of Gdansk, Poland, between 1992 and 2012. Based on morphology and immunohistochemistry, cases suspicious for MASC were selected, and the diagnosis was confirmed by fluorescence in situ hybridization (FISH) for ETV6 rearrangement and by RT-PCR for the ETV6-NTRK3 fusion transcript. Seven carcinomas met the criteria of MASC, as they exhibited a typical appearance with solid/microcystic and papillary architecture and intraluminal secretions, and cells completely devoid of basophilic cytoplasmic zymogen granules indicative of true acinar differentiation. The only paediatric case was an unencapsulated tumour composed of macrocystic structures covered by a mostly single but, focally, double layer of cells with apocrine morphology. In all cases, the neoplastic cells revealed immunoreactivity for S100, mammaglobin, cytokeratin CK7, CK8, STAT5a and vimentin. FISH for ETV6 gene rearrangement was positive in six out of seven cases, and RT-PCR was positive in three cases. MASC is a new entity of malignant epithelial salivary gland tumours not included in the 2005 WHO Classification of Head and Neck Tumours. There is a growing body of evidence that it is not as rare as was assumed, as is also indicated by our series (3.8 %). In most cases, MASC shares some microscopic features with AciCC, adenocarcinoma/cystadenocarcinoma NOS and low-grade MEC. In rare cases, MASC with high-grade transformation may mimic the morphological appearances of high-grade salivary gland malignancies, such as salivary duct carcinoma. PMID- 25503079 TI - 5-Methoxysalicylic acid matrix for ganglioside analysis with matrix-assisted laser desorption/ionization mass spectrometry. AB - In this note, we report that high quality ganglioside profiles with minimal loss of sialic acid residues can be obtained in the positive ion mode by using a 5 methoxysalicylic acid (MSA) matrix for matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS). Our results showed that MSA produced much less sialic acid losses from gangliosides than DHB, although MSA and DHB are differ only by their functional groups at their 5-positions (-OH for DHB and -OCH(3) for MSA). Furthermore, our data also demonstrated that addition of an alkali metal additive was effective for simplifying ganglioside profiles, but not necessary for stabilizing glycosidic bonds of gangliosides if MSA was used as a matrix. This suggests that MALDI MS with MSA has a potential to gain additional benefits from the positive-ion mode analyses without losing performance in ganglioside profiling. PMID- 25503078 TI - WRN protein as a novel erythroblast immunohistochemical marker with applications for the diagnosis of Werner syndrome. AB - Genetic testing for mutations in the WRN gene is critical for the diagnosis of Werner syndrome (WS); however, these tests cannot be performed in a clinical setting. Nearly all of the WRN mutations result in expression of truncated WRN proteins that are missing the C-terminal nuclear localization signal. We evaluated the use of WRN protein immunohistochemistry for diagnosing WS using paraffin-embedded bone marrow sections. Using a well-defined commercially available polyclonal antibody against the C terminus of WRN, we found that of all the cell types tested, bone marrow erythroid precursors showed the strongest nuclear expression of WRN. Immunohistochemical analysis of bone marrow samples from 120 patients with non-WS hematological disorders (age range, 7 days-90 years) revealed WRN staining of the nuclei of CD71-positive early and late erythroid precursors. Erythroblasts negative for WRN immunostaining were only observed in two patients, both of whom were diagnosed with WS: one with concomitant myelodysplastic syndrome and the other with erythroleukemia with overexpression of TP53. Western blot analysis and immunocytochemistry indicated WRN was localized in the nuclei of the four positive control cell lines from non WS patients but not in the five cell lines from WS patients, who had three different types of WRN mutations. Thus, immunohistochemical detection of WRN in erythroblasts from bone marrow paraffin sections could be useful in screening of WS cases and worthy of further molecular confirmation. PMID- 25503080 TI - UV photodissociation of proline-containing peptide ions: insights from molecular dynamics. AB - UV photodissociation of proline-containing peptide ions leads to unusual product ions. In this paper, we report laser-induced dissociation of a series of proline containing peptides at 213 nm. We observe specific fragmentation pathways corresponding to the formation of (y-2), (a + 2) and (b + 2) fragment ions. This was not observed at 266 nm or for peptides which do not contain proline residues. In order to obtain insights into the fragmentation dynamics at 213 nm, a small peptide (RPK for arginine-proline-lysine) was studied both theoretically and experimentally. Calculations of absorption spectra and non-adiabatic molecular dynamics (MD) were made. Second and third excited singlet states, S(2) and S(3), lie close to 213 nm. Non-adiabatic MD simulation starting from S(2) and S(3) shows that these transitions are followed by C-C and C-N bond activation close to the proline residue. After this first relaxation step, consecutive rearrangements and proton transfers are required to produce unusual (y-2), (a + 2) and (b + 2) fragment ions. These fragmentation mechanisms were confirmed by H/D exchange experiments. PMID- 25503081 TI - A facile and selective route to remarkably inert monocyclic NHC-stabilized boriranes. AB - Herein we report a facile and selective synthetic route to monocyclic NHC stabilized boriranes. We have succeeded in obtaining two highly stable new boriranes through salt elimination of NHC-stabilized dichloroboranes with the dianion of trans-stilbene, Na2[C14H12]. One borirane was observed to undergo reaction with [Pt(PEt3)3], in which the Pt(0) center oxidatively adds a backbone C-H bond of the NHC, leading to the isolation of the Pt(II) complex trans [(Et3P)2PtH{C=CH(NMe)2C.BPh(C14H12)}]. The remarkable inertness of the NHC boriranes suggests a strong stabilising effect of quaternization of the boron atom. PMID- 25503082 TI - A pooled analysis evaluating the efficacy and tolerability of tapentadol extended release for chronic, painful diabetic peripheral neuropathy. AB - BACKGROUND AND OBJECTIVE: Data from two similarly designed studies of tapentadol extended release (ER) for managing neuropathic pain associated with diabetic peripheral neuropathy (DPN; NCT00455520, NCT01041859) in adults were pooled for this analysis, allowing a detailed evaluation of efficacy in patient subgroups and secondary endpoints. METHODS: In each study, patients were titrated to their optimal dose of open-label tapentadol ER [100-250 mg twice daily (bid)] over 3 weeks. Patients with >=1-point improvement in average pain intensity [11-point numerical rating scale (NRS)] were randomized (1:1) to receive placebo or tapentadol ER during a 12-week, double-blind maintenance period. RESULTS: Mean (standard deviation [SD]) changes in pain intensity from baseline to week 12 of maintenance in the placebo (n = 343) and tapentadol ER (n = 360) groups, respectively, were 1.28 (2.41) and 0.08 (1.87) [least squares mean difference (LSMD): -1.14 (95 % confidence interval [CI]: -1.435, -0.838); P < 0.001, in favour of tapentadol ER]. Significant between-group differences were also observed in changes from the start of the double-blind treatment period to the double-blind endpoint for the Short Form-36 physical functioning, role-physical, bodily pain, social functioning and role-emotional subscale and physical component summary scores, and the EuroQol 5-Dimension health status index (all P < 0.05, in favour of tapentadol ER). No clinically relevant differences were observed in the efficacy of tapentadol ER across patient subgroups divided by age, sex, race, opioid experience and pain intensity. Incidences of treatment emergent adverse events were 56.0 % (192/343) with placebo and 74.7 % (269/360) with tapentadol ER during maintenance. CONCLUSION: Results of this pooled analysis indicate that tapentadol ER was effective for managing DPN-related pain, and provided consistent analgesic efficacy across different patient subgroups. PMID- 25503083 TI - Exploring the Potential of Nucleic Acid Bases in Organic Light Emitting Diodes. AB - Naturally occurring biomolecules have increasingly found applications in organic electronics as a low cost, performance-enhancing, environmentally safe alternative. Previous devices, which incorporated DNA in organic light emitting diodes (OLEDs), resulted in significant improvements in performance. In this work, nucleobases (NBs), constituents of DNA and RNA polymers, are investigated for integration into OLEDs. NB small molecules form excellent thin films by low temperature evaporation, enabling seamless integration into vacuum deposited OLED fabrication. Thin film properties of adenine (A), guanine (G), cytosine (C), thymine (T), and uracil (U) are investigated. Next, their incorporation as electron-blocking (EBL) and hole-blocking layers (HBL) in phosphorescent OLEDs is explored. NBs affect OLED performance through charge transport control, following their electron affinity trend: G < A < C < T < U. G and A have lower electron affinity (1.8-2.2 eV), blocking electrons but allowing hole transport. C, T, and U have higher electron affinities (2.6-3.0 eV), transporting electrons and blocking hole transport. A-EBL-based OLEDs achieve current and external quantum efficiencies of 52 cd A(-1) and 14.3%, a ca. 50% performance increase over the baseline device with conventional EBL. The combination of enhanced performance, wide diversity of material properties, simplicity of use, and reduced cost indicate the promise of nucleobases for future OLED development. PMID- 25503084 TI - Equivalent peak resolution: characterization of the extent of separation for two components based on their relative peak overlap. AB - Although the classical formula of peak resolution was derived to characterize the extent of separation only for Gaussian peaks of equal areas, it is often used even when the peaks follow non-Gaussian distributions and/or have unequal areas. This practice can result in misleading information about the extent of separation in terms of the severity of peak overlap. We propose here the use of the equivalent peak resolution value, a term based on relative peak overlap, to characterize the extent of separation that had been achieved. The definition of equivalent peak resolution is not constrained either by the form(s) of the concentration distribution function(s) of the peaks (Gaussian or non-Gaussian) or the relative area of the peaks. The equivalent peak resolution value and the classically defined peak resolution value are numerically identical when the separated peaks are Gaussian and have identical areas and SDs. Using our new freeware program, Resolution Analyzer, one can calculate both the classically defined and the equivalent peak resolution values. With the help of this tool, we demonstrate here that the classical peak resolution values mischaracterize the extent of peak overlap even when the peaks are Gaussian but have different areas. We show that under ideal conditions of the separation process, the relative peak overlap value is easily accessible by fitting the overall peak profile as the sum of two Gaussian functions. The applicability of the new approach is demonstrated on real separations. PMID- 25503087 TI - Identification of HSP20 gene family in wheat and barley and their differential expression profiling under heat stress. AB - Small heat shock proteins (sHSPs) are chaperones that play an important role in various developmental, biotic and abiotic stresses. The sHSP family possess a conserved domain of approximately 80 to 100 amino acids called alpha-crystalline domain (ACD), flanked by N- and C-terminal regions. Search for complete proteomes and expressed sequenced tag (EST) database of wheat and barley using Hidden Markov Model and BLAST algorithm was conducted. Here, we report genome-wide identification and characterization of 27 newly TaHSP20 candidate genes in wheat and 13 HvHSP20 in barley, describing structures, phylogenetic relationships, conserved protein motifs, and expression patterns. The structural analysis highlights that this gene family possesses a conserved ACD region at the C terminal. Detailed pattern analysis of HSP20 revealed presence of P-G doublet and I/V/L-X-I/V/L motif that helps in oligomerization. Identification of conserved motif sequences of wheat and barley HSP20 strongly supported their identity as sHSP families. This study illustrates for the first time 3D model prediction of full-length wheat HSP20 (TaHSP20) protein and ACD region. Digital expression analysis was also carried out in order to reveal a widespread distribution of the sHSP family genes at various developmental stages of wheat and barley. In addition, five selected transcripts of both wheat and barley were validated for their expression profile under 35 degrees C and 42 degrees C heat stress conditions. Results indicate up-regulation of all the transcripts under heat stress condition except TaCBM38894 candidate, which showed down-regulation in wheat. PMID- 25503088 TI - Evaluation of point mutation detection in Mycobacterium tuberculosis with isoniazid resistance using real-time PCR and TaqMan probe assay. AB - Rapid methods for diagnosis of Mycobacterium tuberculosis (Mtb) drug resistance and choosing appropriate antibiotic treatment are pivotal. Thirty isoniazid (INH) resistant and 30 INH-susceptible Mtb isolates were evaluated using minimum inhibitory concentration (MIC) method followed by multiplex real-time PCR (RT PCR). Amplification refractory mutation system (ARMS) for detection of mutation in 315 codon of katG gene and single-nucleotide polymorphism (SNP) for detection of mutation in -15 (C>T) in the regulatory zone of mabA-inhA were carried out using the TaqMan method. Primers and probe were used for IS6110 region of Mtb as an internal amplification control. The sensitivity and specificity of the RT-PCR TaqMan probe for detection of Mtb complex were 100 %. Detection of INH-resistant Mtb using the ARMS method for KatG had 69 % sensitivity and 100 % specificity. The sensitivity and specificity of SNP in mabA-inhA fragment for detection of INH resistant Mtb were 53 and 100 %, respectively. Furthermore, considering both regions, the sensitivity of RT-PCR has increased to 75 %. This study revealed that the qPCR-TaqMan method can be used as a standard tool for diagnosis of Mtb. Moreover, ARMS and SNP RT-PCR TaqMan methods can be used as rapid screening methods for detection of INH-resistant Mtb. PMID- 25503085 TI - Multiple lineages of ancient CR1 retroposons shaped the early genome evolution of amniotes. AB - Chicken repeat 1 (CR1) retroposons are long interspersed elements (LINEs) that are ubiquitous within amniote genomes and constitute the most abundant family of transposed elements in birds, crocodilians, turtles, and snakes. They are also present in mammalian genomes, where they reside as numerous relics of ancient retroposition events. Yet, despite their relevance for understanding amniote genome evolution, the diversity and evolution of CR1 elements has never been studied on an amniote-wide level. We reconstruct the temporal and quantitative activity of CR1 subfamilies via presence/absence analyses across crocodilian phylogeny and comparative analyses of 12 crocodilian genomes, revealing relative genomic stasis of retroposition during genome evolution of extant Crocodylia. Our large-scale phylogenetic analysis of amniote CR1 subfamilies suggests the presence of at least seven ancient CR1 lineages in the amniote ancestor; and amniote-wide analyses of CR1 successions and quantities reveal differential retention (presence of ancient relics or recent activity) of these CR1 lineages across amniote genome evolution. Interestingly, birds and lepidosaurs retained the fewest ancient CR1 lineages among amniotes and also exhibit smaller genome sizes. Our study is the first to analyze CR1 evolution in a genome-wide and amniote-wide context and the data strongly suggest that the ancestral amniote genome contained myriad CR1 elements from multiple ancient lineages, and remnants of these are still detectable in the relatively stable genomes of crocodilians and turtles. Early mammalian genome evolution was thus characterized by a drastic shift from CR1 prevalence to dominance and hyperactivity of L2 LINEs in monotremes and L1 LINEs in therians. PMID- 25503089 TI - Foot deformities in children with cerebral palsy. AB - PURPOSE OF REVIEW: The present article describes common foot deformities in children with cerebral palsy and discusses treatment options for each of those deformities. RECENT FINDINGS: Bracing is a useful treatment to correct foot deformities during gait. Surgical correction of foot deformities is typically performed as a part of multilevel single-event gait improvement surgery that has increasingly become the standard of care for ambulatory children with cerebral palsy. Foot realignment may improve knee function during stance, probably because of change of lever arm. SUMMARY: Foot deformities are common among children with cerebral palsy. The three most common among them are equinus, planovalgus and equinovarus/equinocavovarus. Treatment consists of orthotics, physical therapy, spasticity reduction treatment and surgical correction. Guidelines for treatment are individualized and multifactorial. Important considerations include the child's level of function, the severity and flexibility of the deformity, the presence or absence of pain and skin irritation, and the changes in alignment observed over time. PMID- 25503090 TI - Insulin resistance in adult primary care patients with a surrogate index, Guadalajara, Mexico, 2012. AB - INTRODUCTION: Insulin resistance (IR) is a key molecular disorder related with diabetes mellitus, obesity, and cardiovascular disease. The objective of this study was to determine IR in adult primary care patients using the triglyceride/glucose (TyG) index [(Ln TG (mg/dL) * FG (mg/dL))/2]. METHODS: We conducted a cross-sectional secondary analysis and identified IR subjects according to the TyG index. RESULTS: There were 1500 patients included. Significant differences were found between the IR group versus the insulin sensitive group, respectively: age (in years), 46.4 +/- 9.34 versus 40.24 +/- 11.27 (P < 0.001); fasting glucose (mg/dL), 99.87 +/- 11.95 versus 84.62 +/- 6.59 (P < 0.001); total cholesterol (mg/dL), 203.21 +/- 37.38 versus 173.91 +/- 33.99 (P < 0.001); triglycerides (mg/dL), 226.40 +/- 96.66 versus 111.27 +/- 23.44 (P < 0.001); uric acid (mg/dL), 6.09 +/- 1.59 versus 4.77 +/- 1.40 (P < 0.001); and TyG index, 4.96 +/- 0.21 versus 4.48 +/- 0.13 (P < 0.001). The cutoff of the TyG index for IR was 4.68 or greater. CONCLUSIONS: The TyG index allows for early diagnosis of IR in primary health care. PMID- 25503091 TI - Impact of Staphylococcus epidermidis lysates on middle ear epithelial proinflammatory and mucogenic response. AB - BACKGROUND: Chronic otitis media with effusion (COME) develops after sustained inflammation and is characterized by secretory middle ear epithelial metaplasia and effusion, most frequently mucoid. Staphylococcus epidermidis, typically considered a commensal organism, is very frequently recovered in chronic middle ear fluid and in middle ear biofilms. Although it has been shown to drive inflammation in sinonasal epithelium, the impact of S. epidermidis on COME is markedly understudied. The goal of this study was to examine the in vitro effects of S. epidermidis lysates on murine and human middle ear epithelial cells. METHODS: Staphylococcus epidermidis lysates were generated and used to stimulate submerged and differentiated human and murine epithelial cells (MEECs) for 24 to 48 hours. Quantitative real time-polymerase chain reaction, Western blot, enzyme linked immunosorbent assay, and immunocytochemistry techniques were performed to interrogate the mucin gene MUC5AC and MUC5B expression and protein production, chemokine response, as well as NF-kappaB activation. Luciferase reporter assays were performed to further evaluate nuclear factor kappaB (NF-kappaB) activation and query specific promoter responses after S. epidermidis exposure. RESULTS: Staphylococcus epidermidis induced a time- and dose-dependent MUC5AC and MUC5B overexpression along with a parallel overexpression of Cxcl2 in mouse MEEC and IL 8 in human MEEC. Further investigations in mMEEC showed a 1.3 to 1.5 induction of the MUC5AC and MUC5B promoters. As potential mechanisms for these responses, induction of an oxidative stress marker, along with early nuclear translocation and activation of NF-kappaB, was found. Finally, chronic exposure induced marked epithelial thickening of cells differentiated at the air liquid interface. CONCLUSIONS: Staphylococcus epidermidis lysates activate a proinflammatory response in MEEC, including mucin gene expression and protein production. Although typically considered a nonpathogenic commensal organism in the ear, these results suggest that they may play a role in the perpetuation of an inflammatory and mucogenic response in COME. PMID- 25503092 TI - Morphometric analysis of the infraorbital foramen and its localization relative to surgical landmarks. AB - AIM: The infraorbital foramen (IOF) is an important anatomic landmark for maxillofacial surgery; therefore, its location should be well documented. In morphometric analyses of the IOF, various methods have been applied and differences have been found among the results of the measurements. The aim of this study was to facilitate localization of the IOF during clinical practice. METHODS: In the current study, in order to perform anatomic and morphometric analyses of the IOF, 112 skulls were used. The shortest distance from each IOF to certain determined points was identified and measured by digital calipers. RESULTS: The longest and the shortest diameters of the IOF were measured as 4.21+/-0.91 mm and 3.11+/-0.62 mm, respectively. The shortest distances between the IOF and the landmarks were measured as follows: the maxillary mid-line (ML) as 28.47+/-2.49 mm; the supraorbital foramen/supraorbital notch (SOF/SON) as 43.43+/-3.39 mm; the lower end of the nasomaxillary suture (LENS) as 26.47+/-3.05 mm; the lower end of the alveolar juga of the canines (LAJC) as 31.62+/-3.09 mm; the infra-orbital margin (IOM) as 6.98+/-1.72 mm; and the opposite IOF as 56.85+/ 3.89 mm. CONCLUSION: Among the landmarks, the most useful ones in clinical practice might be the distances between the IOF and the IOM, IOF and LAJC, and even IOF and ML. SOF/SON and LENS provide more accurate localization when they are used together with the other parameters. Moreover, their importance increases when other parameters are not available for use (because of fractures or damage). PMID- 25503093 TI - Prognostic factors for surgically resected squamous cell carcinoma of the lower oral cavity. AB - AIM: The objective of this study was to evaluate the impact of clinical variables on survival rates in patients with squamous cell carcinomas in the lower oral cavity. METHODS: We conducted a retrospective study of patients who exhibited a histological diagnosis of squamous cell carcinoma of the lower oral cavity, who underwent surgery. Data on clinical, histological, and treatment variables were collected to assess the effect of these variables on global survival and disease free curves. RESULTS: We studied 117 patients, 86 (73.5%) males and 31 (26.5%) females, who underwent surgery between January 2005 and June 2009. The overall survival rate was 74.4% after two years, and the disease-free rate was 67.5%. Midline invasion by the primary tumor negatively impacted overall survival (P=0.02) and disease-free survival (P=0.01). The disease-free survival rate of patients with histologically confirmed neck metastases was 76.8% versus 59% for patients without metastases (P=0.01). Disease-free survival of patients with one affected lymph node was 89.5%, and 45.2% for more than one affected lymph node (P<0.01). Patients who ended radiotherapy in less than 60 days exhibited a disease-free rate of 59.0%, and patients whose treatment lasted more than 60 days exhibited a rate of 77.1% (P=0.06). CONCLUSION: In our study, primary tumor invasion of the midline, the presence of more than one affected lymph node as confirmed by histology, the delaying radiotherapy for more than 56 days and radiotherapy that lasted longer than 60 days worsen patient prognosis. PMID- 25503095 TI - Orofacial pain and Eagle Syndrome: cues from a clinical series. AB - AIM: Watt Eagle, firstly described the Elongated Stylohyoid Process Syndrome (ESPS), or Eagle Syndrome, in 1937. Since then, several authors have further studied this syndrome and some classifications have been proposed in relation to signs, symptoms and etiopathogenesis. Aim of this paper was to present the clinical features of a cohort of patients affected by Eagle syndrome that underwent surgical treatment. METHODS: Retrospective study. A cohort of ten patients that underwent surgical intervention for Eagle syndrome from January 2000 to December 2012 has been selected. For each subject, medical history, clinical features, treatment and follow-up after surgery were evaluated. RESULTS AND CONCLUSIONS: The surgical treatment resulted effective in 8 of 10 patients. Two patients are still complaining neck pain, although the discomfort has a lower grade and is pharmacologically controllable. Although rare, Eagle's Syndrome should be always considered in the differential diagnosis in patients with chronic orofacial pain refractory to conventional treatments. PMID- 25503094 TI - Spontaneous bone formation on the maxillary sinus floor in association with surgery to remove a migrated dental implant: a case report. AB - AIM: A variety of surgical techniques have been developed to reconstruct the posterior maxilla when bone volume is insufficient. For some decades, sinus augmentation, using various bone substitutes, has been used to reconstruct the posterior maxilla for dental implant placement. Even if new bone formation is achieved in the sinus after bone grafting, the possibility of new bone formation with only a membrane elevation in the maxillary sinus has been reported in human and animal studies. The aim of this case report was to document an unexpected healing pattern after the removal of a dental implant migrated in the maxillary sinus. METHODS: In October 2009 a 49-year-old man with a partially edentulous maxilla underwent implant placement. Specifically, a total of 5 implants were inserted, 2 in the left and 3 in the right posterior maxilla. Four months later, at the time of abutment connection, the implant at the site of the maxillary left first molar was accidentally pushed in the sinus. A surgical removal of the implant from the maxillary sinus was proposed and the patient consented to the surgical intervention. Computed axial tomography (CAT) scan images revealed opacification of the left maxillary sinus with mucosal thickening, and the dental implant displaced within the sinus. The planned treatment sequence was: 1) removal of the implant; 2) sinus augmentation procedure after 5 months; 3) implant insertion 5 months after the bone graft. The implant was removed. Five months later, the patient was admitted for the bone-grafting augmentation procedure. A new CAT scan image revealed normal mucosal thickness and no opacification of the left maxillary sinus; bone formation was evident. The surgery was undertaken with local anesthesia and conscious sedation. RESULTS: At reentry, the sinus wall was found to be totally healed. Newly formed bone (21.2%) with wide osteocyte lacunae and large marrow spaces (73.8%) were present with newly formed vessels and no inflammatory cell infiltrate. CONCLUSION: The surgical trauma and the creation of a secluded space between the bone surfaces and the healed sinus mucosa resulted in a spontaneous bone formation in the maxillary sinus. The surgical approach described may be used to achieve bone formation to enable placement of dental implants without the addition of any grafting material. PMID- 25503096 TI - Rhinorrhea triggered by obturator prosthesis after surgical intervention of partial maxillary resection: a clinical report. AB - This clinical report describes a case of rhinorrhea that arose after surgical intervention of partial maxillary resection and obturator prosthesis positioning. Ultimately, the diagnosis was that rhinorrhea was induced by mechanical irritation of the nasal mucosa determined by the nasal part of the obturator prosthesis. The differential diagnosis of nasal irritation, vasomotor rhinitis, gustatory rhinorrhea are presented and discussed, as well as the technical notes and measures taken to reach the final diagnosis and a satisfactory functional and aesthetic result for the patient. PMID- 25503097 TI - Cyclic voltammetry using silver as cathode material: a simple method for determining electro and chemical features and solubility values of CO2 in ionic liquids. AB - A report is presented on the use of cyclic voltammetry using silver as a working electrode. The combined electrocatalytic properties of silver and ionic liquids allow cyclic voltammetry to be turned into an ideal tool for the rapid and accurate access to diffusion coefficient values and solubility values of carbon dioxide in ionic liquids under standard conditions. PMID- 25503098 TI - Efficacy of continuous positive airway pressure on testosterone in men with obstructive sleep apnea: a meta-analysis. AB - OBJECTIVE: To evaluate the efficacy of continuous positive airway pressure (CPAP) on serum testosterone in men with obstructive sleep apnea (OSA). METHODS: Two reviewers independently searched PubMed, Cochrane library, Embase and Web of Science before June 2014. Information on characteristics of subjects, study design, pre- and post-CPAP treatment of serum total testosterone, free testosterone and sexual hormone blinding protein (SHBG) was extracted for analysis. RESULTS: A total of 7 studies with 9 cohorts that included 232 men were pooled into meta-analysis. There was no change of total testosterone levels before and after CPAP treatment in OSA men (standardized mean difference (SMD) = 0.14, 95%CI: -0.63 to 0.34, z = 0.59, p = 0.558), even subdivided by CPAP therapeutic duration (>3 months). Meanwhile, no significant differences in free testosterone and SHBG were detected after CPAP treatment (SMD = 0.16, 95%CI: 0.09 to 0.40, z = 1.25, p = 0.211 and SMD = -0.58, 95%CI: -1.30 to 0.14, z = 1.59, p = 0.112, respectively). CONCLUSION: CPAP has no influence on testosterone levels in men with OSA, further large-scale, well-design interventional investigation is needed. PMID- 25503099 TI - Corrigendum to "The ALS/FTLD-related RNA-binding proteins TDP-43 and FUS have common downstream RNA targets in cortical neurons" [FEBS Open Bio 4 (2014) 1-10]. AB - [This corrects the article DOI: 10.1016/j.fob.2013.11.001.]. PMID- 25503100 TI - Effects of nasal septum perforation repair surgery on three-dimensional airflow: an evaluation using computational fluid dynamics. AB - The purpose of this research is to determine the cause of nasal perforation symptoms and to predict post-operative function after nasal perforation repair surgery. A realistic three-dimensional (3D) model of the nose with a septal perforation was reconstructed using a computed tomography (CT) scan from a patient with nasal septal defect. The numerical simulation was carried out using ANSYS CFX V13.0. Pre- and post-operative models were compared by their velocity, pressure gradient (PG), wall shear (WS), shear strain rate (SSR) and turbulence kinetic energy in three plains. In the post-operative state, the crossflows had disappeared, and stream lines bound to the olfactory cleft area had appeared. After surgery, almost all of high-shear stress areas were disappeared comparing pre-operative model. In conclusion, the effects of surgery to correct nasal septal perforation were evaluated using a three-dimensional airflow evaluation. Following the surgery, crossflows disappeared, and WS, PG and SSR rate were decreased. A high WS.PG and SSR were suspected as causes of nasal perforation symptoms. PMID- 25503102 TI - The sperm structure of Cryptocercus punctulatus Scudder (Blattodea) and sperm evolution in Dictyoptera. AB - Sperm of the dictyopteran key taxon Cryptocercus punctulatus was examined. It has largely maintained a blattodean groundplan condition, with a three-layered acrosome, an elongate nucleus, a single centriole, a conspicuous centriole adjunct material, two connecting bands (=accessory bodies), and a long functional flagellum with a 9+9+2 axoneme provided with accessory tubules with 16 protofilaments and intertubular material. These sperm characters are shared with several other polyneopterans. The sperm of C. punctulatus is very similar to what is found in Periplaneta americana and species of other groups of roaches, including the sperm of Loboptera decipiens described here for the first time. The general sperm organization here described can be assumed for the groundplan of Insecta and Pterygota. The following evolutionary path can be suggested: after the split between Cryptocercidae and the common ancestor of Isoptera, the typical pattern of sperm formation was altered very distinctly, resulting in a duplication or multiplication (Mastotermitidae) of the centrioles. Mastotermes has maintained a certain sperm motility, but with a very unusual apparatus of multiple flagella with a 9+0 axoneme pattern. After the split into Mastotermitidae and the remaining Isoptera, sperm motility was completely abandoned, and different modifications of sperm components occurred, and even the loss of the sperm flagellum. PMID- 25503101 TI - Adenoid cystic carcinoma sphenoid sinus with intracranial extension treated by radical radiotherapy: a rare case. PMID- 25503103 TI - Quantitative PCR in epidemiology for early detection of visceral leishmaniasis cases in India. AB - INTRODUCTION: Studies employing serological, DTH or conventional PCR techniques suggest a vast proportion of Leishmania infected individuals living in regions endemic for Visceral Leishmaniasis (VL) remain asymptomatic. This study was designed to assess whether quantitative PCR (qPCR) can be used for detection of asymptomatic or early Leishmania donovani infection and as a predictor of progression to symptomatic disease. METHODS: The study included 1469 healthy individuals living in endemic region (EHC) including both serology-positive and negative subjects. TaqMan based qPCR assay was done on peripheral blood of each subject using kDNA specific primers and probes. RESULTS: A large proportion of EHC 511/1469 (34.78%) showed qPCR positivity and 56 (3.81% of 1469 subjects) had more than 1 calculated parasite genome/ml of blood. However, the number of individuals with parasite load above 5 genomes/ml was only 20 (1.36% of 1469). There was poor agreement between serological testing and qPCR (k = 0.1303), and 42.89% and 31.83% EHC were qPCR positive in seropositive and seronegative groups, respectively. Ten subjects had developed to symptomatic VL after 12 month of their follow up examination, of which eight were initially positive according to qPCR and among these, five had high parasite load. DISCUSSION: Thus, qPCR can help us to detect significant early parasitaemia, thereby assisting us in recognition of potential progressors to clinical disease. This test could facilitate early intervention, decreased morbidity and mortality, and possibly interruption of disease transmission. PMID- 25503104 TI - Consideration of the effects of intense tissue heating on the RF electromagnetic fields during MRI: simulations for MRgFUS in the hip. AB - Due to the strong dependence of tissue electrical properties on temperature, it is important to consider the potential effects of intense tissue heating on the RF electromagnetic fields during MRI, as can occur in MR-guided focused ultrasound surgery. In principle, changes of the RF electromagnetic fields could affect both efficacy of RF pulses, and the MRI-induced RF heating (SAR) pattern. In this study, the equilibrium temperature distribution in a whole-body model with 2 mm resolution before and during intense tissue heating up to 60 degrees C at the target region was calculated. Temperature-dependent electric properties of tissues were assigned to the model to establish a temperature-dependent electromagnetic whole-body model in a 3T MRI system. The results showed maximum changes in conductivity, permittivity, [absolute value]B(1)(+)[absolute value] and SAR of about 25%, 6%, 2%, and 20%, respectively. Though the B1 field and SAR distributions are both temperature-dependent, the potential harm to patients due to higher SARs is expected to be minimal and the effects on the B1 field distribution should have minimal effect on images from basic MRI sequences. PMID- 25503105 TI - Mohs micrographic surgery versus surgical excision for periocular basal cell carcinoma. AB - BACKGROUND: Basal cell carcinoma (BCC) is the commonest skin cancer in the white population. It is traditionally treated by surgical excision (SE) or by Mohs micrographic surgery (MMS). OBJECTIVES: The objective of this review was to compare the effectiveness, cost, complications and acceptability of periocular BCCs when operated by MMS or SE. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 1), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to February 2014), EMBASE (January 1980 to February 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 25 February 2014. SELECTION CRITERIA: We planned to include only randomised controlled trials (RCTs) comparing SE with MMS for treatment of periocular BCC. DATA COLLECTION AND ANALYSIS: We did not find any studies that met the inclusion criteria for this review. MAIN RESULTS: We did not find any studies that met the inclusion criteria for this review and hence none were included for analysis. Results of non-randomised studies describing the individual techniques are reported. AUTHORS' CONCLUSIONS: No reliable conclusions could be reached regarding which method of treatment (SE or MMS) resulted in a lower recurrence or complication rate for periocular BCC. No studies were found comparing the cost of either method directly. High quality RCTs are therefore needed to improve the evidence base for the management of this condition. PMID- 25503106 TI - Claudin-4 is required for AMPK-modulated paracellular permeability in submandibular gland cells. AB - Tight junction plays an important role in mediating paracellular permeability in epithelia. We previously found that activation of AMP-activated protein kinase (AMPK) increased saliva secretion by modulating paracellular permeability in submandibular glands. However, the molecular mechanisms underlying AMPK-modulated paracellular permeability are unknown. In this study, we found that AICAR, an AMPK agonist, increased saliva secretion in the isolated rat submandibular glands, decreased transepithelial electrical resistance (TER), and increased 4 kDa FITC-dextran flux in cultured SMG-C6 cells. AICAR also induced redistribution of tight junction protein claudin-4, but not claudin-1, claudin-3, occludin, or ZO-1, from the cytoplasm to the membrane. Moreover, knockdown of claudin-4 by shRNA suppressed while claudin-4 re-expression restored the TER and 4 kDa FITC dextran flux responses to AICAR. Additionally, AICAR increased ERK1/2 phosphorylation, and inhibition of ERK1/2 by U0126, an ERK1/2 kinase inhibitor, or by siRNA decreased AICAR-induced TER responses. AICAR induced the serine S199 phosphorylation of claudin-4 and enhanced the interaction of claudin-4 and occludin. Furthermore, pretreatment with U0126 significantly suppressed AMPK modulated phosphorylation, redistribution, and interaction with occludin of claudin-4. Taken together, these results indicated that claudin-4 played a crucial role in AMPK-modulated paracellular permeability and ERK1/2 was required in AMPK-modulated tight junction barrier function in submandibular gland. PMID- 25503107 TI - Tumor-derived microvesicles mediate human breast cancer invasion through differentially glycosylated EMMPRIN. AB - Tumor cells secrete not only a variety of soluble factors, but also extracellular vesicles that are known to support the establishment of a favorable tumor niche by influencing the surrounding stroma cells. Here we show that tumor-derived microvesicles (T-MV) also directly influence the tumor cells by enhancing their invasion in a both autologous and heterologous manner. Neither the respective vesicle-free supernatant nor MV from benign mammary cells mediate invasion. Uptake of T-MV is essential for the proinvasive effect. We further identify the highly glycosylated form of the extracellular matrix metalloproteinase inducer (EMMPRIN) as a marker for proinvasive MV. EMMPRIN is also present at high levels on MV from metastatic breast cancer patients in vivo. Anti-EMMPRIN strategies, such as MV deglycosylation, gene knockdown, and specific blocking peptides, inhibit MV-induced invasion. Interestingly, the effect of EMMPRIN-bearing MV is not mediated by matrix metalloproteinases but by activation of the p38/MAPK signaling pathway in the tumor cells. In conclusion, T-MV stimulate cancer cell invasion via a direct feedback mechanism dependent on highly glycosylated EMMPRIN. PMID- 25503108 TI - Single and combined use of human parathyroid hormone (PTH) (1-34) on areal bone mineral density (aBMD) in postmenopausal women with osteoporosis: evidence based on 9 RCTs. AB - BACKGROUND: Human parathyroid hormone (PTH) (1-34) or teriparatide (TPTD) is an anabolic agent for osteoporosis. This recombinant protein stimulates positive bone formation balance and bone remodeling. However, when concomitantly used with antiresorptive (AR) agents, previous studies reported conflicting results in their potential additive and synergistic effects on bone metabolism and bone mineral density (BMD). This study aimed to integrate previous evidence to assess the effect of TPTD monotherapy and the additive effect of TPTD on AR agents in postmenopausal women with osteoporosis. MATERIAL AND METHODS: This meta-analysis identified 9 RCTs from databases. To assess the therapeutic effect on osteoporosis, the weighted mean differences (WMDs) were used to pool the percentage change of BMD along with the 95% confidence intervals (CIs). BMD of 3 skeletal sites, including lumbar spine, total hip, and femoral neck were assessed. RESULTS: TPTD alone could significantly improve BMD of all 3 skeletal sites compared with placebo, although the effect on the femoral neck was less conclusive. The additive effect of TPTD over hormone replacement therapy (HRT) and denosumab (DEN) agents is evident in all 3 skeletal sites. But TPTD plus Alendronate (ALN) did not demonstrate additive effect in total hip and femoral neck. CONCLUSIONS: TPTD alone could significantly improve BMD of lumbar spine, total hip, and femoral neck. BMD outcomes of concomitant use of TPTD and AR agents are site-dependent and vary depending on the specific AR agent used and the timing of AR therapy initiation. PMID- 25503109 TI - Preeclampsia: what could happen in a subsequent pregnancy? AB - IMPORTANCE: Preeclampsia is the most common type of the hypertensive disorders of pregnancy, affecting nearly 5% of pregnant women. The risk of recurrence influences the choices of parents regarding subsequent pregnancies and necessitates the counseling of obstetricians. OBJECTIVE: To review the risk of recurrence of hypertensive disorders in a subsequent pregnancy. EVIDENCE ACQUISITION: Women with a history of preeclampsia are at an increased risk of preeclampsia and other adverse pregnancy outcomes in subsequent pregnancies. The magnitude of this risk is dependent on gestational age at the time of disease onset, severity of disease, and presence or absence of preexisting medical disorders. RESULTS: For preeclamptic women with severe features in an initial pregnancy, recurrence rates for any type of preeclampsia are very high, approaching 50% in some studies. Significant maternal and fetal complications are more common in recurrent preeclampsia compared with an initial episode. Because women with previous preeclampsia are at an increased risk for adverse pregnancy outcomes (preterm delivery, fetal growth restriction, abruptio placentae, and fetal death) in subsequent pregnancies, we recommend more frequent monitoring for signs and symptoms of severe hypertension or preeclampsia than that recommended for normal pregnancy. CONCLUSIONS: The best option is to review the existing literature with patients, allow them to make informed decisions, and provide them the best available prenatal care. PMID- 25503110 TI - Energy sources for gynecologic laparoscopic surgery: a review of the literature. AB - IMPORTANCE: A range of energy sources are used in gynecologic laparoscopy. These energy sources include monopolar electrosurgery, bipolar electrosurgery (including "advanced bipolar" devices that incorporate tissue feedback monitoring), and various types of laser and ultrasonic technologies. Gynecologists using these tools should be aware of the potential benefits and potential dangers of these instruments. OBJECTIVE: This review provides an overview of the biophysics of these energy sources, their tissue effects, and the complications that may arise. It aims to highlight any potential advantages or disadvantages of various energy sources, as reported by clinical and laboratory studies. EVIDENCE ACQUISITION: Literature relating to energy sources used in gynecologic laparoscopy was reviewed. RESULTS: While laboratory-based studies have reported differences between various energy sources, these differences may not be clinically significant. The choice of instrumentation may depend on the nature of the surgical task being performed, but other factors, such as the surgeon's training/experience, cost, and industry marketing, may also influence the decision. CONCLUSIONS: TAn awareness of the pros and cons of each energy modality and their relative efficacy profiles is paramount. RELEVANCE: It is important that surgeons have an understanding of the biophysics of these technologies in order to understand their limitations and potential dangers and to utilize the most appropriate energy source(s) in the appropriate clinical setting, in order to both minimize the risk of inadvertent injuries during gynecologic laparoscopy and to maximize cost-efficient delivery of health care. PMID- 25503111 TI - Prenatal vitamins: what is in the bottle? AB - Nearly all obstetricians routinely prescribe prenatal vitamins to their pregnant patients at the time of the first prenatal visit. Many times, patients' understanding of the health benefits of prenatal vitamins differs substantially from that of the prescribing physician. The following is a review of the most common ingredients found in prenatal vitamins and their purported health benefits. PMID- 25503112 TI - The role of dietary factors in prevention and progression of breast cancer. AB - BACKGROUND/AIM: Breast cancer (BC) is the leading global cause of cancer-related death in women. There is growing evidence for a role for dietary factors in BC pathophysiology. The aim of the present review was to evaluate the impact of dietary factors in BC risk. MATERIALS AND METHODS: Bibliographical searches were performed in PubMed, using the following terms: "nutrition and breast cancer", "nutrition and breast carcinoma", "dietary factors and breast cancer", "risk factors and breast cancer", "diet and breast cancer, "breast cancer epidemiology", "breast cancer and prevention". RESULTS: Consumption of well-done red meat appears to be associated with increased risk of BC, whereas fish may be protective. Total cholesterol, triglyceride levels and glycaemic load should be monitored and controlled in at risk populations because they may be associated with increased risk of BC, although the exact mechanisms involved are not clear. Alcohol intake should be minimized since it is a risk factor for BC. High intake of polyphenol/phyto-oestrogen -rich food (i.e. flavonoids, soya products), as well as fibres, fruits and vegetables, may have potential protective effects against BC occurrence but the results might vary according to hormonal status. Vitamin D supplements appear protective against BC development and similarly other vitamins and oligo-elements might decrease BC risk, although further large prospective studies are required. CONCLUSION: There exist increasing evidence that dietary factors can play an important role in both the development and prevention of BC. Large randomized clinical and epidemiological studies are required but are difficult to design due to the number of variable factors. PMID- 25503113 TI - Transcatheter arterial embolic therapies for hepatocellular carcinoma: a literature review. AB - Palliative therapies for hepatocellular carcinoma (HCC) include transcatheter arterial embolic therapies, radiation therapy and systemic chemotherapies such as sorafenib. Conventional transcatheter arterial chemoembolization (cTACE) is the golden standard for the treatment of intermediate-stage HCC, and involves the administration of chemotherapuetic drugs, with or without lipiodol, by means of a catheter directly to the feeding artery of the targeted tumor followed by administration of embolic agents, while the concept of drug-eluting bead TACE (DEB-TACE) builds on the rationale for cTACE. DEB-TACE has been demonstrated to substantially improve the pharmacokinetic profile of TACE, providing levels of consistency and repeatability in patients that are not available with cTACE. On the other hand, the technique of radioembolization therapy for HCC involves the delivery of high-dose radiation via the hepatic artery. In the present review, we summarize the current status of these transcatheter arterial embolic therapies in HCC. PMID- 25503114 TI - Non coding RNAs in head and neck squamous cell carcinoma (HNSCC): a clinical perspective. AB - BACKGROUND: Head and neck squamous cell carcinoma is a common cause of cancer death. Despite decades of clinical studies exploring new treatments and considerable advance in multimodality treatment, satisfactory curative rates have not yet been reached. In the last few decades the emerging data from both tumor biology and clinical trials led to growing interest for research of predictive biomarkers. However, no molecular markers were discovered to improve clinical outcomes and to be used as new anticancer agents. Non coding RNAs (ncRNAs) are promising biomarkers. They are important regulators both in normal biological process and in proliferation, metastasis, chemo-radioresistance. MATERIALS AND METHODS: We revised the literature on this topic to summarize current findings on ncRNAs. RESULTS: Several studies reported an altered regulation of ncRNAs and a specific cancer site signature has also been described among different primary head and neck squamous cell carcinomas (HNSCC). Moreover, expression of ncRNAs correlates with poor prognosis and resistance to treatment. CONCLUSION: ncRNAs are emerging potential molecular markers and anticancer agents. PMID- 25503115 TI - Nuclear receptors in pancreatic tumor cells. AB - AIM: This review focuses on nuclear receptors expressed in pancreatic cancer. MATERIALS AND METHODS: An extensive search of articles published up to March 2013 was conducted using the MEDLINE database. The key words used were "pancreatic cancer", "molecular receptors" and "growth factors". A total of 112 articles referred to pancreatic cancer, molecular receptors and/or growth factors were included. RESULTS: Receptors of growth factors, such as the epithelial growth factor receptor, insulin-like growth factor-1 receptor, vascular endothelial growth factor receptor and others, such as integrin alpha5beta1, somatostatin receptors, the death receptor 5, claudin, notch receptors, mesothelin receptors, follicle-stimulating hormone receptors, the MUC1 receptor, the adrenomedullin receptor, the farnesoid X receptor, the transferrin receptor, sigma-2 receptors, the chemokine receptor CXCR4, the urokinase plasminogen activator receptor, the ephrine A2 receptor, the GRIA3 receptor, the RON receptor and the angiotensin II receptor AT-1 are expressed in pancreatic tumor cells. These molecules are implicated in tumor growth, apoptosis, angiogenesis, metastasis etc. CONCLUSION: After identifying the molecular receptors associated with the pancreatic cancer, many more target molecules playing important roles in tumor pathophysiology and senescence-associated signal transduction in cancer cells will be identified. This may have a significant influence on diagnosis, therapy and prognosis of pancreatic cancer. PMID- 25503116 TI - Radiotherapeutic treatment approaches for brain metastases. AB - Brain metastases represent an important healthcare problem. Approximately 20%-40% of patients develop disease metastatic to the brain over the course of their cancer history. Palliative treatment of brain metastases requires for immediate control and, at least temporarily, a remission of the symptoms because many of the symptoms associated with brain metastases reduce the patient's quality of life. Radiation therapy is used to treat this clinical circumstance. The aim of this review is to assess the efficacy and the toxicity of radiotherapeutic treatment approaches and to provide treatment recommendation for brain metastases. PMID- 25503117 TI - Expression of the chondroitin sulphate proteoglycan, NG2, in paediatric brain tumors. AB - BACKGROUND/AIM: While neuron-glia 2 (NG2) is well-characterized in the developing brain and in adult high-grade gliomas, little is known about NG2 expression in paediatric brain tumors. Here, NG2 expression was examined in a range of paediatric brain tumors. MATERIALS AND METHODS: A retrospective immunohistopathological analysis of 57 paediatric brain tumor biopsies of various tumor types was carried out. Paediatric cell lines, including two medulloblastomas and one dysembryoplastic neuroepithelial tumor, in addition to one adult high-grade glioma, were also assessed for NG2 expression. RESULTS: NG2 positive staining was seen in all dysembryoplastic neuroepithelial tumors (DNETs) examined; however, only two of the fourteen medulloblastomas examined were NG2 positive. Compared to adult glioma, there was a lack of NG2 staining in the vasculature of paediatric brain tumors. CONCLUSION: NG2 expression in paediatric brain tumors differs depending upon type and, unlike adult glioma, includes expression on lower-grade tumors. PMID- 25503118 TI - Bioregulation of kallikrein-related peptidases 6, 10 and 11 by the kinin B1 receptor in breast cancer cells. AB - The sera of patients with breast cancer have higher levels of des[Arg(9)]bradykinin, a kinin B1 receptor (B1R) agonist, than that from healthy individuals. Stimulation of breast cancer cells with the analog Lys des[Arg(9)]bradykinin causes release of metalloproteinases-2 and -9 and increases cell proliferation. We examined the possibility that breast cancer cells, in addition to B1R, express the kinin-forming protease true tissue kallikrein (KLK1) and the endogenous proteins termed kininogens from which kinins are enzymatically released. Furthermore, we investigated whether stimulation of breast cancer cells with a B1R agonist would modify the cellular levels of KLK6, KLK10 and KLK11, three kallikrein-related peptidases with a still poorly-understood biological role in breast cancer. We found that breast cancer cells expressed KLK1 and kininogens, and that stimulation of estrogen-sensitive breast cancer cells with the B1R agonist produced down-regulation of KLK10 (a protease associated with growth suppression) but up-regulation of KLK11 and KLK6 (peptidases related to increased cell proliferation and invasiveness, respectively). Furthermore, we showed that the B1R agonist acts as a functional stimulus for the secretion of KLK1 and KLK6, an event relevant for kinin production and cell invasion, respectively. PMID- 25503119 TI - Evaluation of a special combination of glucan with organic selenium derivative in different murine tumor models. AB - beta-glucans are well-established immunomodulators with strong effects resulting in slowing or even inhibiting cancer growth. Recent studies have repeatedly suggested that the biological activities of beta-glucan can be potentiated by the addition of other bioactive agents. In the current study, we focused on the anticancer effects of a combination of yeast-derived beta-glucan and a selenium linked pseudodisaccharide. Using three different models of murine cancer, we showed that this combination strongly suppressed the growth of all three types of cancers, most likely via the interaction with natural anticancer antibodies. PMID- 25503120 TI - Differential spheroid formation by oral cancer cells. AB - Squamous cell carcinomas (SCC) make up 96% of all oral cancers. Most laboratory SCC studies grow cells as a monolayer, which does not accurately represent the disease in vivo. We used a more relevant multicellular spheroid (MCS) model to study this disease. The SCC9beta6KDFyn cell line, which expresses full-length beta6 and a kinase dead Fyn formed the largest MCS. Cell adhesive properties are dynamic and N-cadherin was increased in the largest MCS. c-Raf mediates the survival of tumor cells and was consistently expressed both in monolayers and in the MCS by SCC9beta6D1 cells which lack the beta6 cytoplasmic tail and, do not activate Fyn. SCC9beta6KDFyn cells also express high levels of c-Raf when grown as spheroids in which Fyn suppression stimulates MCS formation. Tumor microenvironment and growth patterns modulate cell behavior and suppression of Fyn kinase may promote MCS growth. PMID- 25503121 TI - A novel cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to gemcitabine. AB - RX-3117 (fluorocyclopentenylcytosine) is a cytidine analog and this class of drugs, including gemcitabine, has been widely used for the treatment of various types of cancers. However, there is no oral formulation of gemcitabine and drug resistance to gemcitabine is common. In this study, the efficacy of orally administered RX-3117 was examined in 9 different human tumor xenograft models (colon, non-small cell lung, small cell lung, pancreatic, renal and cervical), grown subcutaneously in athymic nude mice. In the Colo 205, H460, H69 and CaSki models, gemcitabine treatment resulted in 28%, 30%, 25% and 0% tumor growth inhibition (TGI), respectively, whereas oral treatment with RX-3117 induced 100%, 78%, 62% and 66% TGI, respectively. This indicates that RX-3117 may have the potential to be used for the treatment of tumors that do not respond to gemcitabine. RX-3117 was also evaluated in a single primary low-passage human pancreatic TumorgraftTMCTG-0298 (TGI 76%), which is relatively resistant to gemcitabine (TGI 38%) and has a favorable RX-3117-activating enzyme profile. These studies demonstrated the therapeutic potential and anticancer efficacy of RX-3117. PMID- 25503122 TI - Expression of MSH2 and MSH6 on a tissue microarray in patients with osteosarcoma. AB - BACKGROUND/AIM: Reliable prognostic factors for the outcome of patients with osteosarcoma (OS) remain elusive. We analyzed the relationship between immunohistochemical expression of deoxyribonucleic acid (DNA) mismatch repair (MMR) proteins, MutS protein homolog 2 (MSH2) and MSH6 using a tissue microarray (TMA) with respect to OS patient demographics and survival time. MATERIALS AND METHODS: We retrieved tumor tissue specimens from bone tissue originating from surgical primary tumor specimens of OS patients to generate a TMA and stained sections with antibodies against MSH2 and MSH6. RESULTS: Tumor resections of 67 patients with a mean follow-up of 98 months were evaluated. MSH2 was expressed in nine (13%), MSH6 in ten (15%) and combined MSH2 and MSH6 (MSH2/6) in six (9%) patients. Significantly shorter survival times were associated with expression of MSH6, MSH2/6, as well as simultaneous non-response to chemotherapy and presence of metastasis. CONCLUSION: The survival time of patients with OS may be predicted by local expression of MSH6 and MSH2/6 in surgical primary tumor resections. This study shows the prognostic value of the local expression of DNA MMR proteins, as markers for poor prognosis of OS patients. PMID- 25503123 TI - p53 up-regulation during colorectal carcinogenesis. AB - BACKGROUND: We previously found foci of p53 up-regulation in dysplasia in colorectal adenomas (CRAs). The present study aimed at exploring the frequency of this phenomenon in CRAs with and without submucosal invasive carcinoma. MATERIALS AND METHODS: Sections from 568 polypectomies or surgical resections harbouring a CRA (without or with submucosal invasion) or overt colorectal carcinomas were challenged with p53 immunostaining. The largest section from single colorectal neoplasias was measured by the aid of a calibrated ocular scale in a conventional microscope. Lesions were divided into small adenomas (<=10 mm in size), large adenomas (>=11 mm in size), adenomas with submucosal invasion, and overt invasive carcinomas (without any recognizable adenoma remnant tissue). RESULTS: CRAs with three or more dysplastic foci of p53-up-regulation gradually increased from 8% in small adenomas (size: <=10 mm) to 48% in large adenomas (size: >=11 mm), and to 65% in the adenomatous tissue in adenomas displaying submucosal invasion), but plummeted to 13% in the submucosal carcinomatous tissue and to 11% in overt carcinomas. In contrast, extensive p53 up-regulation predominated in the submucosal carcinomatous tissue (87%) and in overt carcinomas (89%). CONCLUSION: The frequency of foci of dysplastic glands with up-regulation of p53 (hotspots) gradually increased from small to larger CRAs, being highest in the adenomatous tissue of CRAs with submucosal invasive carcinoma. The foci of p53 up-regulation became confluent (appreciated as extensive up-regulation) in the submucosal carcinomatous tissue and in overt carcinomas. It is concluded that a high number of foci with p53 up-regulation in adenomatous tissue might be required before submucosal invasive carcinoma ensues. PMID- 25503124 TI - Inhibition of P-TEFb by DRB suppresses SIRT1/CK2alpha pathway and enhances radiosensitivity of human cancer cells. AB - BACKGROUND: Positive transcription elongation factor-b (P-TEFb) is a complex containing CDK9 and a cyclin (T1, T2 or K). The effect of inhibition of P-TEFb by 5,6-dichloro-l-beta-D-ribofuranosyl benzimidazole (DRB) on cell radiosensitivity and the underlying mechanisms were investigated. MATERIALS AND METHODS: Six human cancer cell lines were subjected to (3)H-uridine incorporation, cell viability and clonogenic cell survival assays; cell-cycle redistribution and apoptosis assay; western blots and nuclear 53BP1 foci analysis after exposing the cells to DRB with/without gamma-radiation. RESULTS: DRB suppressed colony formation and enhanced radiosensitivity of all cell lines. DRB caused a further increase in radiation-induced apoptosis and cell-cycle redistribution depending on p53 status. DRB prolonged the presence of radiation-induced nuclear p53 binding protein-1 (53BP1) foci and suppressed the expression of sirtuin-1 (SIRT1) and casein kinase 2-alpha (CK2alpha), suggesting an inhibition of DNA repair processes. CONCLUSION: Our findings indicate that DRB has the potential to increase the efficacy of radiotherapy and warrants further investigation using in vivo tumor models. PMID- 25503125 TI - Combination of arginine deprivation with TRAIL treatment as a targeted-therapy for mesothelioma. AB - In the present study we present data to show that certain tumor cells including malignant pleural mesothelioma (MPM) cells do not express argininosuccinate synthetase (ASS), and thus are unable to synthesize arginine from citrulline. Exposure of these ASS-negative cells to the arginine degrading enzyme, arginine deiminase (ADI-PEG20), for 72 h results in significant increases in cleaved caspase-3. Importantly, this apoptotic signal is further strengthened by the addition of TNF-related apoptosis-inducing ligand (TRAIL). Using flow cytometry, we showed that the combination treatment (ADI-PEG20 at 50 ng/ml and TRAIL at 10 ng/ml) for 24 h resulted in profound cell death with 67% of cells positive for caspase-3 activity, while ADI-PEG20 alone or TRAIL alone resulted in only 10-15% cell death. This positive amplification loop is mediated through the cleavage of proapototic protein "BID". CONCLUSION: Our work represents a new strategy for treating patients with malignant pleural mesothelioma using targeted molecular therapeutics based on selected tumor markers, thus avoiding the use of potentially cytotoxic chemotherapy. PMID- 25503126 TI - Genotype of DNA double-strand break repair gene XRCC7 is associated with lung cancer risk in Taiwan males and smokers. AB - AIM: The present study aimed to evaluate the contribution of X-ray repair cross complementing group 7 (XRCC7) G6721T (rs7003908) genetic polymorphism and smoking habit on the risk of lung cancer in Taiwanese. MATERIALS AND METHODS: In this hospital-based case-control study, association of single nucleotide polymorphism XRCC7 G6721T with lung cancer risk were examined among 358 patients with lung cancer and 716 age- and gender-matched healthy controls. The genetic-lifestyle interaction was also investigated. RESULTS: The results showed that the percentages of TT, GT and GG genotypes for XRCC7 G6721T were differentially distributed as 60.9%, 34.9% and 4.2% in the group of patients with lung cancer and 48.7%, 43.3% and 8.0% in the non-cancer control group, respectively (p=3.6*10(-7)). We further stratified the populations by gender and smoking behavior to investigate their combinatorial effects with XRCC7 G6721T genotype on lung cancer risk. The results showed that the GG genotype of XRCC7 G6721T had a protective effect on lung cancer susceptibility which was obvious among males and smokers (p=2.2*10(-4) and 3.1*10(-4), respectively). CONCLUSION: The GG and GT genotypes of XRCC7 rs7003908 compared to the TT genotype had a protective effect on lung cancer risk in Taiwan, particularly among males and smokers. PMID- 25503127 TI - Doxorubicin overcomes resistance to drozitumab by antagonizing Inhibitor of Apoptosis Proteins (IAPs). AB - BACKGROUND/AIM: Drozitumab is a fully human agonistic monoclonal antibody that binds to death receptor DR5 and induces apoptosis. However, drozitumab resistance is a major obstacle limiting anticancer efficacy. MATERIALS AND METHODS: We examined the potential for the chemotherapeutic agent doxorubicin to overcome resistance against drozitumab-resistant breast cancer cells both in vitro and in vivo. RESULTS: Treatment with doxorubicin increased cell surface expression of DR5, reduced levels of Inhibitors of Apoptosis Proteins (cIAPs) and re-sensitised cells to drozitumab-induced apoptosis. Animals implanted with resistant breast cancer cells into the mammary fat pad and treated with a combination of drozitumab and doxorubicin showed inhibition of tumor growth and a substantial delay in tumor progression compared to untreated controls and mice treated with each agent alone. CONCLUSION: These results suggest that combination of drozitumab with chemotherapy and agents that modulate IAP levels could potentially be a useful strategy in the treatment of breast cancer. PMID- 25503129 TI - The N-nitrosodiethylamine mouse model: sketching a timeline of evolution of chemically-induced hepatic lesions. AB - BACKGROUND/AIM: Hepatocellular carcinoma (HCC) is a frequent and aggressive malignancy associated with multiple environmental risk factors. The chemically induced mouse model of diethylnitrosamine (DEN) provides useful insight into liver carcinogenesis, namely HCC. This work aimed to study the multistep process of hepato-carcinogenesis, providing a systematic framework for animal studies on this subject. MATERIALS AND METHODS: Male ICR mice were divided into six control and six DEN-exposed groups. Saline solution and DEN were injected intra peritoneally, respectively, for eight consecutive weeks. Two groups (DEN vs. control) were euthanized at 8, 15, 22, 29, 36 and 40 weeks after the first administration. RESULTS: Hydropic degeneration, necrosis and apoptosis were acutely induced at eight weeks and onwards. Hyperplastic foci occurred at 29 to 40 weeks along with diffuse dysplastic areas and hepatocellular adenoma. Peliosis hepatis were also identified at 36 and 40 weeks. HCC were only noted at 40 weeks, showing characteristic histological features of malignancy. CONCLUSION: Results allowed sketching of a timeline of evolution of DEN-induced hepatic lesions in mice, from initial lesions to malignant neoplasms. PMID- 25503128 TI - MAD2 expression in oral squamous cell carcinoma and its relationship to tumor grade and proliferation. AB - BACKGROUND: Defects in the cell-cycle surveillance mechanism, called the spindle checkpoint, might contribute to the chromosomal instability observed in human cancers, including oral squamous cell carcinoma. MAD2 and BUBR1 are key components of the spindle checkpoint, whose role in oral carcinogenesis and clinical relevance still need to be elucidated. MATERIALS AND METHODS: We analyzed the expression of MAD2 in 49 cases of oral squamous cell carcinoma by immunohistochemistry and compared the findings with clinicopathological parameters, proliferative activity, BUBR1 expression and DNA ploidy. RESULTS: MAD2 was over-expressed in 18 (36.7%) cases. Tumors with over-expression of MAD2 were associated with the progression of histological grade from well to poor differentiation (p<0.001), the extent of lymph nodes involvement (PN) (p=0.0339) and Ki-67 labeling index (p<0.001). CONCLUSION: MAD2 may be involved in oral carcinogenesis and may represent an important prognostic factor associated with a more malignant phenotype of oral squamous cell carcinoma. PMID- 25503130 TI - Interleukin-10 (IL-10) promoter genotypes are associated with lung cancer risk in Taiwan males and smokers. AB - Interleukin-10 (IL-10) is an immunosuppressive cytokine involved in carcinogenesis via immune escape. The present study aimed at evaluating the contribution of IL-10 promoter A-1082G (rs1800896), T-819C (rs3021097), A-592C (rs1800872) genetic polymorphisms to the risk of lung cancer in Taiwan. Associations of three IL-10 polymorphic genotypes with lung cancer risk were investigated among 358 lung cancer patients and 716 age- and gender-matched healthy controls. In addition, the genetic-lifestyle interaction was also examined. The results showed that the percentages of TT, TC and CC for IL-10 T 819C genotypes were differentially represented as 59.2%, 35.8% and 5.0% in the lung-cancer patient group and 52.0%, 37.0% and 11.0% in the non-cancer control group, respectively (p for trend=0.0025). The CC genotype carriers were of lower risk for lung cancer (OR=0.4, 95% CI=0.23-0.69, p=0.0005). Further stratification of the population by gender and smoking behavior showed that the IL-10 T-819C genotype conducted a protective effect on lung cancer susceptibility, which was obvious among males and smokers (p=0.0003 and 0.0004, respectively). The CC and TC genotypes of IL-10 T-819C compared to the TT genotype may have a protective effect on lung cancer risk in Taiwan, particularly among males and smokers. PMID- 25503131 TI - Lectin histochemistry of murine WAP-T mammary cancer reveals similar glycoconjugate changes to those in human breast cancer. AB - BACKGROUND: The WAP-T mouse model is an established clinically relevant model of breast cancer. Lectins have been used to study malignant progression in clinical studies. We investigated lectin binding sites to test for the clinical relevance of this model. MATERIALS AND METHODS: Samples of the WAP-T mouse mammary tissues, from normal tissues to undifferentiated higher tumor grades were stained using an indirect technique with nine different lectins for intensity of lectin binding. RESULTS: HPA bound to the luminal epithelium in higher tumor grades in a similar pattern to that in human breast cancer. BSA-IB4 bound to luminal epithelium in hyperplasia and increased towards higher grades, comparable to previous clinical studies. PHA-L-binding to myoepithelium and luminal epithelium increased from hyperplasia to higher grades, comparable to findings in human breast cancer. CONCLUSION: The results of our study support the hypothesis that lectin binding sites change similarly in WAP-T and human breast cancer, stressing the similarity of this model with the clinical setting. PMID- 25503132 TI - In vitro oxygen availability modulates the effect of artesunate on HeLa cells. AB - BACKGROUND/AIM: Hypoxia can affect chemotherapeutic drug efficacy in cancer patients, yet related in vitro assays in oxygen-rich environment remain the norm. Such levels are well beyond normoxic/hypoxic levels typically experienced by normal tissues/tumor masses. The present study evaluated how artesunate anti tumor efficacy is modulated by oxygen availability in HeLa cells and its implications for future in vitro analyses. MATERIALS AND METHODS: Real-time cell analysis was employed to evaluate HeLa cell toxicity to artesunate at 21%, 4% or 1% oxygen. Cell count analysis was performed to validate real-time data. RESULTS: An increase in artesunate efficacy was observed when oxygen concentration was reduced from atmospheric levels down to in vivo-relevant levels. CONCLUSION: Artesunate is more potent than originally reported using standard oxygen conditions during in vitro studies. The inclusion of this long overlooked variable as standard in future in vitro analysis procedures is warranted. PMID- 25503133 TI - Incomplete epithelial-mesenchymal transition in p16-positive squamous cell carcinoma cells correlates with beta-catenin expression. AB - BACKGROUND: The epithelial-mesenchymal transition (EMT) is suggested to be a crucial factor for the development of an invasive and metastatic cell phenotype, which is characterized by down-regulation of epithelial adhesive proteins (e.g. E cadherin) and induction of mesenchymal proteins (e.g. vimentin). Therefore, there is a great clinical interest to specify this phenotype. Different growth factors induce EMT, such as epithelial growth factor (EGF) and transforming growth factor beta 1 (TGFbeta1). The role of EMT in human papilloma virus (HPV)-positive squamous cell carcinoma (SCC) is still not understood. The aim of this study was to investigate the expression pattern in p16-positive and -negative SCC cells of vimentin, beta-catenin and E-cadherin after stimulation with growth factors. MATERIALS AND METHODS: We incubated the p16-positive CERV196 and p16-negative HNSCC22B SCC cell lines with EGF and EGF/TGFbeta1 (10 ng/ml) and detected E cadherin, vimentin and beta-catenin by immunocytochemistry and enzyme-linked immunosorbent assay after 5, 24 and 96 h. RESULTS: We found a low expression of vimentin in all studied tumor cell lines. The negative control of HNSCC22B cells showed a higher intrinsic level of membranous E-cadherin and beta-catenin. We found statistically significant EGF/TGFbeta1-induced expression of vimentin dependent on incubation time in p16-negative HNSCC22B cells. Particularly in the presence of EGF, we detected an increase of beta-catenin and vimentin expression in p16-positive SCC tumor cell lines in addition to induced cell scattering and unexpected expression of E-cadherin. CONCLUSION: In conclusion, E-cadherin, beta catenin and vimentin expression are important features to characterize EMT-like events. We were able to show incomplete EGF-induced EMT with beta-catenin expression in p16-positive SCC. Extended studies are required to investigate the mechanistic role of EMT markers, especially in p16-positive SCC, in order to develop new anti-SCC therapies to block EMT progression. PMID- 25503134 TI - Growth-modulatory effects of heparin and VEGF165 on the choriocarcinoma cell-line JEG-3 and its expression of heparanase. AB - BACKGROUND: Expression of heparanase (HPSE) in tumor cells is strongly associated with invasion, metastasis and angiogenesis. It also plays a key role during pregnancy, in processes of implantation as well as placentation. Vascular endothelial growth factor (VEGF) and heparin are known to alter HPSE expression, with heparin given prophylactically to women with a history of placenta-mediated complications in subsequent pregnancies. MATERIALS AND METHODS: We examined the growth-modulatory effects of different concentrations of heparin and VEGF on the choriocarcinoma cell-line JEG-3 and the expression of heparanase under VEGF and heparin by proliferation assays, PCR, and western blot. RESULTS: Proliferation of JEG-3 cells was induced by heparin in a dose-dependent manner, whereas highly concentrated VEGF led to a decreased cell proliferation. Both agents did not influence the HPSE-expression. CONCLUSION: The presumed pregnancy-protecting effects of heparin may partially be due to an increase of trophoblast proliferation and not via regulation of HPSE expression. PMID- 25503135 TI - Synthesis of a monofunctional platinum compound and its activity alone and in combination with phytochemicals in ovarian tumor models. AB - Currently used platinum drugs fail to provide long-term cure for ovarian cancer mainly because of acquired drug resistance. In this study, a new monofunctional planaramineplatinum(II) complex, namely tris(8 hydroxyquinoline)monochloroplatinum(II) chloride (coded as LH3), was synthesised and investigated for its activity against human ovarian A2780, cisplatin resistant A2780 (A2780(cisR)) and ZD0473-resistant A2780 (A2780(ZD0473R)) cancer cell lines, alone and in combination with the phytochemicals curcumin, genistein and resveratrol. Cellular levels of glutathione in A2780 and A2780(cisR) cell lines before and after treatment with LH3 and its combinations with genistein and curcumin were also determined. Interaction of the compounds with salmon sperm DNA, pBR322 plasmid DNA and damage to DNA in A2780 and A2780(cisR) cells due to interaction with LH3-alone and in combination with phytochemicals were also investigated. LH3 was found to be much more active than cisplatin against the resistant tumor models and greatest synergism in activity was observed when combinations of LH3 with genistein and curcumin were administered as a bolus. For combinations of LH3 with the phytochemicals, platinum accumulation and the level of Pt-DNA binding were found to be greater in the resistant A2780(cisR) cell line than in the parental A2780 cell line. Greater activity of LH3 than cisplatin against the resistant ovarian cell lines indicates that it may have the potential for development as a novel anticancer drug and that its combination with phytochemicals can serve to further enhance drug efficacy. PMID- 25503136 TI - Cleaved CD147 shed from the surface of malignant melanoma cells activates MMP2 produced by fibroblasts. AB - BACKGROUND: Cluster of differentiation 147 (CD147)/basigin on the malignant tumor cell surface is critical for tumor proliferation, invasiveness, metastasis, and angiogenesis. CD147 expressed on malignant melanoma cells can induce tumor cell invasion by stimulating the production of matrix metalloproteinases (MMPs) by surrounding fibroblasts. Membrane vesicles, microvesicles and exosomes have attracted attention, as vehicles of functional molecules and their association with CD147 has been reported. Cleaved CD147 fragments released from tumor cells were reported to interact with fibroblasts. We investigated the intercellular mechanisms by which CD147 stimulates fibroblasts to induce MMP2 activity. MATERIALS AND METHODS: CD147 was knocked-down using short hairpin RNA (shRNA). The stimulatory effect of CD147 in cell culture supernatants, microvesicles, and exosomes on the enzymatic activity of MMP2 was examined by gelatin zymography. RESULTS: Supernatants from A375 control cells induced increased enzymatic activity of fibroblasts; such activity was significantly lower in CD147 knock down cells. CONCLUSION: Cleaved CD147 plays a pivotal role in stimulating fibroblasts to induce MMP2 activity. PMID- 25503137 TI - Tanshinone IIA inhibits gastric carcinoma AGS cells through increasing p-p38, p JNK and p53 but reducing p-ERK, CDC2 and cyclin B1 expression. AB - Tanshinone IIA (Tan-IIA) is extracted from Danshen (Salviae miltiorrhizae radix). It possesses antitumor activity against a variety of human cancer cells and its induction of apoptosis and inhibition of proliferation of gastric cancer cells are well-documented. However, the molecular mechanisms by which Tan-IIA inhibits gastric cancer have not been well-elucidated. In the present study, we evaluated the cytotoxicity of Tan-IIA against human gastric cancer AGS cells by the (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) MTT assay. The protein expression of tumor necrosis factor-alpha (TNF-alpha), FAS, p53, p21, cyclin A, cyclin B1, extracellular-related kinase (ERK), phospho extracellular-related kinase (p-ERK), p38, p-p38, Jun-amino-terminal kinase (JNK), phospho Jun-amino terminal kinase (p-JNK) and beta-actin in AGS cells were measured by western blotting. The cell-cycle distribution was analyzed by flow cytometry. The results showed that Tan-IIA inhibited AGS cells with time- and dose-dependent manners. AGS cells treated with Tan-IIA up-regulated the protein expression of TNFalpha, FAS, p-p38, p-JNK, p53, p21, caspase-3 and caspase-8 but reduced that of p-ERK, CDC2, cyclin A, and cyclin B1. The results also showed that Tan-IIA dose dependently induced G2/M phase arrest. These findings demonstrate that Tan-IIA can inhibit AGS human gastric cancer cells; one of the molecular mechanisms may be through increasing the protein expression of p-p38 and p-JNK, but decreasing that of p-ERK to induce the activation of p53, followed by increasing the protein expression of p21 to down-regulate CDC2 and cyclin B1 expression which then induces G2/M phase arrest. Another route may be through increasing the protein expression of TNF-alpha, FAS, caspase-8 and caspase-3 to induce apoptosis. PMID- 25503138 TI - Cisplatin at sub-toxic levels mediates integrin switch in lung cancer cells. AB - BACKGROUND: Resistance to chemotherapeutic agents, as well as enhanced metastasis, have been frequently reported in lung cancer. MATERIALS AND METHODS: Cytotoxicity and proliferative effects of cisplatin on H460 lung cancer cells were evaluated by the MTT assay. Migration capacity was evaluated by the wound healing assay. The number of filopodia per cell were detected by rhodamine phalloidin staining assay. The changes of protein levels of integrins, and migration-related proteins in response to cisplatin at sub-toxic concentrations were determined by western blotting. RESULTS: Herein we demonstrate for the first time that exposure to low concentrations of cisplatin results in increase of cell motility with the alteration of integrin expression. Cisplatin-treated cells exhibited a significant increase in the number of filopodia per cell in correlation with enhanced migration. Migration regulatory proteins, namely activated forms of focal-adhesion kinase (FAK) and ATP-dependent tyrosine kinase (AKT), were found to significantly be up-regulated in cisplatin-treated cells in comparison to those of the non-treated control. Active Rho A-GTP and Rac-GTP were found to be increased in accordance with activation of FAK/AKT signals. Furthermore, we found that such migration enhancement may be in part due to the integrin switch mediated by cisplatin treatment. Cisplatin induced a dramatic alteration in the integrin expression pattern by up-regulating integrin alpha4, alphav, beta1, and beta5 which were previously reported to increase cell motility, while it had no effect on integrin alpha5, and beta3. CONCLUSION: As the integrin switch is a hallmark of highly aggressive cancer, these findings may provide insights for better understanding of cancer cell adaptation after exposure to cisplatin. PMID- 25503139 TI - Numerical and structural chromosomal anomalies in undifferentiated pleomorphic sarcoma. AB - BACKGROUND: Malignant fibrous histiocytoma (MFH) or undifferentiated pleomorphic sarcoma (UPS) is the most common soft-tissue sarcoma of late adult life. Further advances in genetic characterization are warranted. The aim of this study was to search for numerical and structural chromosomal anomalies in UPS. MATERIALS AND METHODS: We investigated five sarcoma-specific chromosomal translocations, five oncogene amplifications as well as the numerical karyotype of 19 UPS samples and one UPS/MFH cell line (U2197) using FISH probes on interphase nuclei. RESULTS: Our results demonstrate that chromosomal translocations involving CHOP, SYT, EWS, FUS and FKHR genes are absent. Furthermore, amplification of ERBB2 (10.5%) and MDM2 (10.5%) was observed whereas the EGFR, C-MYC and N-MYC genes were not amplified. Interestingly, predominant aneuploidies were found in eight chromosomes. CONCLUSION: The data demonstrate rarity of sarcoma-specific chromosomal breaks and oncogene amplifications in UPS, yet polysomic chromosomes appear more characteristically in this condition. PMID- 25503140 TI - A positive correlation between neutrophils in regional lymph nodes and progression of gastric cancer. AB - BACKGROND/AIM: Recent evidence indicates that inflammation is a hallmark of cancer. Tumor-associated neutrophils (TANs) contribute to tumor invasion. However, whether TANs and lymph node metastasis are related is unknown. Intranodal lymphatic vessel density (LVD) is significantly correlated with tumor progression, lymph node metastasis in gastric cancer. Herein, we investigated the effects of TANs in regional lymph nodes. MATERIALS AND METHODS: We investigated the association of the density of TANs in regional lymph nodes with clinicopathological features by immunohistochemistry. Furthermore, we examined the prognostic value of TANs in lymph nodes. RESULTS: The number of TANs in regional lymph nodes was positively correlated with intranodal LVD and micrometastases. Patients with higher cluster of differentiation 15(+) TAN counts had significantly poorer prognosis than those with lower counts. CONCLUSION: Our results suggest that TANs in regional lymph nodes promote the invasion of lymph nodes by cancer cells via augmentation of lymphangiogenesis and thereby contribute to tumor progression. PMID- 25503141 TI - The potential of SIRT6 and SIRT7 as circulating markers for head and neck squamous cell carcinoma. AB - BACKGROUND: We have previously demonstrated altered SIRT gene family in head and neck squamous cell carcinoma (HNSCC). In the present study we aimed to investigate whether the SIRT gene family was also altered in peripheral blood (PB) of patients with HNSCC and the possibility to be used as circulating biomarkers. PATIENTS AND METHODS: The expression profiles of the 7 SIRT genes of PB leukocytes from 34 patients with HNSCC before and after surgery and 31 healthy individuals were investigated. RESULTS: In the cancer group, the expression level of SIRT1 was down-regulated (p<0.05); in contrast, SIRT6 and SIRT7 were significantly up-regulated (p<0.001). Patients with advanced-stage HNSCC had lower expression of SIRT1 and SIRT3. Recovery of SIRT6 and SIRT7 was observed in postoperative patients (p<0.005). CONCLUSION: SIRT genes were altered in PB leukocytes of HNSCC patients and SIRT6 and SIRT7 are potential circulating prognostic markers for HNSCC. PMID- 25503142 TI - Induction of apoptosis by eicosapentaenoic acid in esophageal squamous cell carcinoma. AB - BACKGROUND: Eicosapentaenoic acid (EPA) suppresses the proliferation of cell lines derived from colon, pancreatic, breast and other cancers. Few reports have described the effect of EPA on esophageal cancer cell lines. MATERIALS AND METHODS: We investigated the effect of EPA on the proliferation of the esophageal squamous cell carcinoma cell lines TE11 and KYSE180 with a WST-1 assay. Apoptosis was evaluated with a DNA fragmentation assay. Levels of apoptosis-related proteins (caspase-3, -7, -9 and poly (ADP-ribose) polymerase (PARP)) and cleaved caspase-3, -7, -9 and PARP were evaluated by western blot analysis. RESULTS: After exposure to EPA for 24 h, KYSE180 and TE11 cell proliferation was suppressed in a dose-dependent manner (p<0.05). In addition, caspase -3, -7, -9 and PARP were activated. EPA (0.1 MUM, 1 MUM, 10 MUM) induced apoptosis in a dose dependent manner, as detected by the DNA fragmentation assay. CONCLUSION: EPA shows potential as a new treatment for esophageal cancer. PMID- 25503143 TI - Cell-cycle disturbance and induction of programmed death by new formamidine analogs of daunorubicin. AB - BACKGROUND/AIM: Structural modifications of daunorubicin are an important way to change its anticancer activity. For this reason, formamidinodaunorubicins have been synthesized. The present study was undertaken to determine and compare the in vitro effects of daunorubicin and its new formamidine derivatives on human acute leukemia MOLT-4 and ML-1 cells. MATERIALS AND METHODS: The experiments were performed on human acute lymphoblastic leukemia MOLT-4 cells and human acute myeloblastic leukemia ML-1 cells. The study was conducted using flow cytometry and light microscopy methods. RESULTS: The various patterns of temporary changes in the cell cycle and DNA fragmentation, as well as the extent of mitotic catastrophe, apoptosis, and necrosis, were determined. The anti-leukemic activities of the new daunorubicin analogs were weaker than that of daunorubicin. CONCLUSION: The influence of these anthracyclines on cell-cycle progression, DNA damage, and induction of mitotic catastrophe and cell death depended on the agent and its concentration, the time interval after application, and the cell line used. The structural modifications of daunorubicin were responsible for the different cytotoxic effects of the two formamidinodaunorubicins. PMID- 25503144 TI - Comparison of prostate cancer gene 3 score, prostate health index and percentage free prostate-specific antigen for differentiating histological inflammation from prostate cancer and other non-neoplastic alterations of the prostate at initial biopsy. AB - AIM: To determine if prostate cancer gene 3 (PCA3) score, Prostate Health Index (PHI), and percent free prostate-specific antigen (%fPSA) may be used to differentiate prostatitis from prostate cancer (PCa), benign prostatic hyperplasia (BPH) and high-grade prostate intraepithelial neoplasia (HG-PIN) in patients with elevated PSA and negative digital rectal examination (DRE). PATIENTS AND METHODS: in the present prospective study, 274 patients, undergoing PCA3 score, PHI and %fPSA assessments before initial biopsy, were enrolled. Three multivariate logistic regression models were used to test PCA3 score, PHI and %fPSA as risk factors for prostatitis vs. PCa, vs. BPH, and vs. HG-PIN. All the analyses were performed for the whole patient cohort and for the 'gray zone' of PSA (4-10 ng/ml) cohort (188 individuals). RESULTS: The determinants for prostatitis vs. PCa were PCA3 score, PHI and %fPSA (Odds Ratio [OR]=0.97, 0.96 and 0.94, respectively). Unit increase of PHI was the only risk factor for prostatitis vs. BPH (OR=1.06), and unit increase of PCA3 score for HG-PIN vs. prostatitis (OR=0.98). In the 'gray zone' PSA cohort, the determinants for prostatitis vs. PCa were PCA3 score, PHI and %fPSA (OR=0.96, 0.94 and 0.92, respectively), PCA3 score and PHI for prostatitis vs. BPH (OR=0.96 and 1.08, respectively), and PCA3 score for prostatitis vs. HG-PIN (OR=0.97). CONCLUSION: The clinical benefit of using PCA3 score and PHI to estimate prostatitis vs. PCa was comparable; even %fPSA had good diagnostic performance, being a faster and cheaper marker. PHI was the only determinant for prostatitis vs. BPH, while PCA3 score for prostatitis vs. HG-PIN. PMID- 25503145 TI - PSCA and MUC1 gene polymorphisms are associated with gastric cancer and pre malignant gastric conditions [corrected]. AB - BACKGROUND/AIM: Genome-wide association studies revealed a link between gastric cancer (GC) and single nucleotide polymorphisms (SNPs) of prostate stem cell antigen (PSCA), phospholipase C epsilon-1 (PLCE1) and mucin-1 (MUC1) genes. Herein, we aimed to evaluate associations between PSCA (C>T, rs2294008; G>A, rs2976392), MUC1 (C>T, rs4072037) and PLCE1 (A>G, rs2274223) SNPs and GC or high risk gastritis (HRAG). MATERIALS AND METHODS: Using TaqMan system, SNPs were genotyped in 252 patients with GC, 136 patients with HRAG and 246 controls. RESULTS: PSCA rs2294008 allele T was associated with risk of GC (odds ratio (OR)=1.88, p<0.001) and HRAG (OR=1.49, p=0.009). Allele A of PSCA rs2976392 was associated with development of GC (OR=1.88, p<0.001) and HRAG (OR=1.56, p<0.01). MUC1 rs4072037 allele G was protective against development of GC (OR=0.64, p=0.0005), while no differences were found for PLCE1 rs2274223. CONCLUSION: Polymorphisms of PSCA (rs2976392, rs2294008) and MUC1 (rs4072037) genes are associated with GC and HRAG. PMID- 25503146 TI - An improved and versatile immunosuppression protocol for the development of tumor xenograft in mice. AB - BACKGROUND: The objective of the present study was to evaluate the efficacy of a simple, versatile and cost-effective immunosuppression protocol, using cyclosporine, ketoconazole and cyclophosphamide drug regimen to develop human tumor xenograft in mice. MATERIALS AND METHODS: Cyclosporine, ketoconazole and cyclophosphamide drug regimen was administered to C57BL/6 mice to induce immunosuppression. Five million A549, LNCaP and KB cells were injected subcutaneously in the immunocompromised mice for the development of tumor xenograft. Tumor volume was calculated every week. Histopathology of tumor tissue was analyzed. RESULTS: Prolong immunosuppression was achieved by this combination treatment. The average tumor volume was found to be greater than 600 mm(3). Histopathology of tumor tissue revealed the presence of large and irregular nucleus and scanty cytoplasm, which are characteristic of malignant cells. CONCLUSION: A versatile immunosuppression protocol was developed which was validated for xenograft development using three different cell lines, with a 100% take rate and no mortality. PMID- 25503147 TI - Regulatory T-cells and micrometastasis in lymph nodes of stage I NSCLC. AB - BACKGROUND: Regulatory T-cells (Tregs) have a pivotal role not only in abrogating autoimmune disease, but also in tumor immune escape. The purpose of the present study was to evaluate the clinical significance of the relative expression of forkhead/winged helix transcription factor (FOXP3) and micrometastasis in the regional lymph nodes (RLNs) of patients with stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The RLNs in 131 patients who underwent complete surgical resection for stage I NSCLC were collected at the time of surgery. The relative expression levels of FOXP3 and cytokeratin 19 (CK19) in RLNs were determined by quantitative RT-PCR. RESULTS: The pathological stage was diagnosed as stage IA in 97 patients (74.0%) and stage IB in 34 patients (26.0%). The relative expression levels of FOXP3 and CK19 in the RLNs were 0.062+/-0.0083% and 0.025+/-0.056%, respectively. The relative expression of FOXP3 tended to increase with increasing relative expression of CK19. The five-year overall survival rate of the patients with low expression of FOXP3 was better (90.3%) than that of patients with high expression (79.3%) (p=0.0419). A multivariate analysis using the significant variables (gender, age, histology and FOXP3 expression) showed that the FOXP3 expression in RLNs was a significant independent prognostic factor. CONCLUSION: The expression of CK19 tended to be positively correlated with the expression of FOXP3. High expression of FOXP3 in RLNs was a significant unfavorable prognostic factor in patients with stage I NSCLC. PMID- 25503148 TI - In vitro chemoresponse in metachronous pairs of ovarian cancers. AB - BACKGROUND/AIM: An in vitro chemoresponse assay may aid effective therapy selection in epithelial ovarian cancer (EOC). This study explores changes in chemoresponse between paired primary and recurrent EOC tumors. PATIENTS AND METHODS: RESULTS from metachronous tumors were examined in 242 patients. Changes in in vitro chemoresponse, measured by the area under the dose response curve (AUC) between paired tumors were assessed. RESULTS: A significant increase in AUC was identified in most first-line therapies over time. No significant difference was observed in most recurrent therapies. When the elapsed time between occurrences was <17 months, no difference was observed for any recurrent therapies, and half of first-line therapies exhibited significant increases in AUC. When >=17 months, all 7 therapies showed significant increases. CONCLUSION: These results suggest an increase in chemoresistance over time, which is more pronounced for first-line therapies. This is consistent with clinical observations and suggests the biologic concordance between assay results and response to chemotherapy. PMID- 25503149 TI - Independence of cytotoxic drug sensitivity profiles and receptor subtype of invasive ductal breast carcinoma demonstrated by the histoculture drug response assay (HDRA). AB - AIM: Breast cancer can be divided into four subtypes: luminal-A, luminal-B, HER-2 enriched and triple negative breast cancer (TNBC) by the presence or absence of receptors. Each subtype has a typical clinical behavior and prognosis. Many chemotherapeutic agents are used clinically for breast cancer. The histoculture drug response assay (HDRA) is used for selection of effective chemotherapeutic agents for individual patients Materials and Methods: In the present study, the HDRA was used for eleven frequently-used single-agent or combinations on the four subtypes of breast cancer in order to determine the correlation of drug sensitivity profile and breast-cancer subtype. Fifty invasive ductal breast carcinoma patients who underwent cancer surgery and adjuvant chemotherapy between January 2012 and January 2013 had their tumors analyzed in the HDRA. Age, gender, height and weight, tumor-nodes-metastasis (TNM) stage, immunohistochemical (IHC profiles, breast-cancer subtypes and HDRA results were recorded. RESULTS: The inhibition rate (IR) of each agent or combination for each breast-cancer subtype was determined. Drug to drug IRs were statistically distinct in all subtypes (p<0.05) but no correlation between response to chemotherapeutic agents and breast-cancer subtype was found (p=0.851 by two-way ANOVA test). CONCLUSION: The clear difference between average sensitivity of the chemotherapeutic agents tested and lack of correlation with breast-cancer subtype suggest the importance of individualized treatment for breast-cancer patients. PMID- 25503150 TI - Estrogen and androgen receptors in inflammatory fibroid polyp (Vanek's tumor): case report. AB - BACKGROUND/AIM: Vanek's tumor is an inflammatory fibroid polyp (IFP) of very low incidence, which originates in the submucosa of the stomach, duodenum, jejunum and ileum. The etiology of this tumor is still unknown. Histologically, IFP is characterized by submucosal spindle cell proliferation in fibromyxoid stroma with inflammatory infiltrate. The aim of the present study was to investigate the presence of estrogen and androgen receptors in IFP and compare it with its proliferative loci. PATIENTS AND METHODS: The study analyzed a 79-year-old patient suffering from IFP. Analyses were performed by immunohistochemistry. RESULTS: Androgen-positive spindle cells were detected at the periphery of onion skin-like formations. Estrogen receptor-positive cells were not detected and Ki67 showed low proliferative activity. CONCLUSION: This case report shows for the first time the presence of androgen receptor-positive cells whose location corresponds with the distribution of Ki67-positive cells in IFP. PMID- 25503151 TI - MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma. AB - Mycosis fungoides (MF) is the most common variant of cutaneous T-cell lymphoma (CTCL). MF is characterized by chronic inflammation dominated by cluster of differentiation 4-positive (CD4(+)) T-cells and T helper 2 cytokines, and as the malignant T-cell clone is initially elusive, early diagnosis is often impossible. MF usually takes an indolent course, but for unknown reasons may turn into an aggressive disease with a poor prognosis. Herein, we used a global quantitative real-time polymerase chain reaction platform to study microRNA (miR) expression in patients with early MF (n=13), more advanced CTCL (n=42), and atopic dermatitis (AD, n=20). Thirty-eight miRs were differentially expressed (>=2-fold) in early MF vs. AD and 36 in early MF vs. more advanced disease. miRs that distinguish early MF from AD included both up-regulated (miR-155, miR-146a, 146b 5p, miR-342-3p, let-7i*) and down-regulated (miR-203, miR-205) miRs previously implicated in advanced CTCL. When comparing early MF to more advanced CTCL, additional miRs were significantly up-regulated including miRs which are part of the oncogenic miR-17/92, 106b/25 and 106a/363 clusters. In 16 patients for whom detailed follow-up data were available, 72 miRs were found differentially expressed between patients with progressive vs. those with non-progressive disease, again including miRs with a known relevance for lymphomagenesis, e.g. miR-155, miR-21, let-7i, miR-16, miR-142-3p, miR-146b-5p, miR-92a, miR-93 and miR 106a. In conclusion, we showed that early MF and AD display very different miR profiles despite their clinical, histological, and immunological similarities. During progression, an additional set of miRs becomes deregulated, suggesting their role in disease progression. These data suggest that miR profiling in CTCL may be a key to improving both diagnosis and risk prediction. PMID- 25503152 TI - Clinical significance of an inflammation-based prognostic system for gastric cancer patients with a preoperative normal serum level of carcinoembryonic antigen. AB - AIM: To investigate the significance of the Glasgow Prognostic Score (GPS) for predicting the postoperative survival of gastric cancer (GC) patients with a normal preoperative serum level of carcinoembryonic antigen (CEA). Because CEA is a useful marker for prognostication of several types of cancer, some patients with GC have a normal CEA level. On the other hand, the GPS has been established as a valuable inflammation-based prognostic system for cancer patients. PATIENTS AND METHODS: Among 650 patients who had undergone elective surgery for GC, 425 with a normal preoperative serum CEA level (<=5.0 ng/ml) were enrolled. Uni- and multivariate analyses were performed to evaluate the relationship of the GPS to overall survival. The Kaplan-Meier analysis and log rank test were used to compare the survival curves among patients with GPS 0, 1 and 2. RESULTS: Multivariate analysis using clinical characteristics selected from univariate analyses revealed that the GPS (0, 1/2) was associated with overall survival (hazard ratio=2.048; 95% C.I. (confidence interval)=1.002-4.185; p=0.049) along with age (<=70/>70) (years), sex, tumor type (3, 4, 5/0, 1, 2), lymph node metastasis (presence/absence) and platelet count (<=35/>35) (*10(4)/mm(3)). The Kaplan-Meier analysis and log rank test demonstrated that there were significant differences in overall survival among patients with GPS 0, 1 and 2 (p<0.001). CONCLUSION: Even if GC patients have a normal serum level of CEA, the GPS is able to predict their postoperative survival and classify such patients into three independent groups before surgery. PMID- 25503153 TI - Outcome of esophagojejunostomy during totally laparoscopic total gastrectomy: a single-center retrospective study. AB - AIM: The present study aimed to clarify the safety and feasibility of esophagojejunostomy during totally laparoscopic total gastrectomy (TLTG). PATIENTS AND METHODS: In 45 consecutive patients who underwent TLTG for gastric cancer, esophagojejunostomy was performed with a functional end-to-end anastomosis (FEEA) using a linear stapler in 24 patients or with a double stapling technique (DST) using a trans-orally inserted anvil (OrVilTM) in 21 patients. RESULTS: The DST was more likely to be chosen in patients with tumors located in the upper stomach. In the FEEA group, both the mean length of the operation and the mean postoperative hospital stay were significantly shorter compared to those in the DST group. Two patients in the FEEA group and four patients in the DST group developed postoperative complications but there were no postoperative deaths in either group. CONCLUSION: Both FEEA and DST in esophagojejunostomy during TLTG are safe and feasible. PMID- 25503154 TI - Simultaneous 24 h-infusion of high-dose 5-fluorouracil and sodium-folinate as alternative to capecitabine in advanced breast cancer. AB - BACKGROUND/AIM: Prognosis of metastatic breast cancer is poor with a 5-year survival rate of 21%. Even though it is incurable, the majority of patients needs a treatment to ameliorate symptoms and prolong survival. If chemotherapy is indicated, toxicity of multi-drug regimens often out-weighs the possible gain, making single-agent chemotherapy the preferred choice. Although capecitabine is frequently used for the treatment of metastatic breast cancer, it is not a therapeutic option for all patients. PATIENTS AND METHODS: Since simultaneous application of 5-fluorouracil (5-FU) and sodium folinate is a promising alternative treatment for certain patients, we reviewed the cases of 26 patients treated at our site. RESULTS: Progression-free survival (PFS) was 8.6 months and overall survival (OS) was 18.5 months with a beneficial toxicity profile. CONCLUSION: The efficacy of simultaneous high level 5-FU and sodium folinate is comparable to other frequently used single-agent chemotherapies, while the toxicity profile is favorable. PMID- 25503155 TI - Concomitant capecitabine with hepatic delivery of drug eluting beads in metastatic colorectal cancer. AB - BACKGROUND: Effectiveness and toxicity of transcatheter arterial injection of irinotecan-eluting beads (DEBIRI) with and without concurrent capecitabine in pre treated patients with metastatic colorectal cancer (CRC). PATIENTS AND METHODS: An Institutional Review Board-approved, multi-institutional registry from 5/2008 to 8/2013 was reviewed. Patients who received DEBIRI with (X-DEBIRI) or without (DEBIRI) capecitabine were compared. RESULTS: Twenty-two X-DEBIRI and 149 DEBIRI patients were compared. There was no difference in the two groups with regards to adverse events (p=0.56). During a 3- and 6-month evaluation, the disease control rate (DCR) was similar in both groups. During the 12-month evaluation, there was better DCR in the X-DEBIRI group (p=0.03). Median survival was 13 months in the DEBIRI group and 22 months in the X-DEBIRI group (log-rank test, p=0.217). CONCLUSION: There is no additional toxicity when adding capecitabine with DEBIRI. Concurrent capecitabine may offer more durable disease control rate compared to DEBIRI-alone. Survival benefit with concurrent capecitabine was not statistically significant but there may be a trend towards improved survival. PMID- 25503156 TI - Comparison of two transarterial chemoembolization strategies for hepatocellular carcinoma. AB - AIM: This retrospective study aimed to compare the efficacy of and tolerance to two center-related conventional transarterial chemoembolization (TACE) strategies in the management of unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: All HCC patients in whom TACE was initiated in the two centers from June 2008 to July 2011 were included. The TACE strategy performed in center 1 was "on demand" with selective injections of idarubicin, whereas the TACE strategy in center 2 was based "on scheduled" non-selective injections of epirubicin. Toxicity was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. RESULTS: One hundred and fifty HCC patients were included. Median time to treatment failure was significantly higher in center 1, 13.1 months vs. 7.9 months in center 2 (hazard ratio, 2.32; p<10-3 in multivariate analysis). Median overall survival was 21.1 months in center 1 vs. 18.4 months in center 2 (p=NS). The proportion of grade >= 3 adverse events and mean hospitalisation duration for the overall TACE treatment were significantly greater in center 2 than in center 1: 56% vs. 32% (p<0.01) and 14.2 +/- 7.2 days vs. 10.3 +/- 7.0 days (p<0.01), respectively. CONCLUSION: Our results failed to show any significant survival differences between two center-related TACE strategies but showed a significantly smaller proportion of grade >= 3 adverse events and shorter hospitalisation for the overall treatment when the "on-demand" strategy was used. PMID- 25503157 TI - Association between radiation dose and pathological complete response after preoperative radiochemotherapy in esophageal squamous cell cancer. AB - AIM: This study was undertaken to examine the impact of radiation dose on pathological complete response (pCR) rates following neoadjuvant radiochemotherapy (N-RCT) for squamous cell esophageal cancer (ESCC). PATIENTS AND METHODS: From 1988 to 2011, 218 patients were treated with 30-30.6 Gy (1.8-2 Gy per fraction), 39.6-40 Gy (1.8-2 Gy per fraction) or 44-45 Gy (1.8-2 Gy per fraction) and concomitant cisplatin +/- 5-fluorouracil (5-FU), oxaliplatin + 5-FU or 5-FU alone. The most commonly used concomitant chemotherapy was continuous infusion of 5-FU-alone with a dose of 300 mg/m(2)/day during the whole course of treatment (n=111). To eliminate the dispersing effect of potentially different efficacy levels of these drug regimens on pCR, we excluded patients with regimens other than 5-FU-alone. RESULTS: Histomorphological regression grade 1a (0% residual tumor), 1b (<10% residual tumor), 2 (10-50% residual tumor) and 3 (>50% residual tumor) was observed in 26 (23%), 24 (22%), 36 (32%) and 25 (23%) patients, respectively. pCR was observed in 9 out of 71 (13%) patients treated with 30 Gy-30.6 Gy, 13 of 34 (38%) patients treated with 39.6-40 Gy and 4 of 6 (67%) patients treated with 44-45 Gy (p=0.001). Median follow-up time from the start of N-RCT was 191 months (range=2-262 months). The estimated 5-year overall survival (OS) was 33% for the whole cohort. OS at 5 years was 58% for patients with pCR compared to 25% for patients with less favorable response to N-RCT (p=0.009), respectively. CONCLUSION: The dose of radiation correlates significantly with the likelihood of achieving a pCR in stage II/III squamous cell esophageal cancer patients. Prospective randomized trials are required to definitively evaluate the impact of application of higher radiation doses on efficacy and safety/tolerability in the context of N-RCT on the clinical outcomes. PMID- 25503158 TI - Preoperative serum C-reactive protein and its prognostic significance in patients with stage III-IV colorectal cancer. AB - The molecular mechanism underlying the development of colorectal cancer (CRC) is not yet fully-understood, but there is evidence that inflammation plays a key role. Several circulating tumor and inflammatory markers can be useful for studying patients with CRC. It has been suggested that high serum levels of C reactive protein (CRP) are associated with elevated risk of various malignancies and that CRP may affect survival of patients with CRC. We analyzed the relationship existing between the stage of the disease and baseline CRP serum levels in a group of 91 patients undergoing surgery for stage III (N=72, 79.1%) and IVa (N=19, 20.9%) CRC. There were 51 (56%) men and 40 (44%) women, with a median age of 66 years. Prior to surgery, all patients underwent quantitative serum CRP measurement. The overall 5-year survival was 37.1 +/- 13.0 months. Patients with stage III disease and the sub-group with CRP<3 mg/l (N=43, 47.3%) had a longer survival (p<0.01) than patients with stage IVa and the sub-group with CRP >= 3 mg/l (N=48, 52.7%). No relationship between the age of the patients and CRP levels was found (R=-0.005, p=0.96), whilst there was a significant inverse relationship between survival and CRP level (R=-0.37, y=37.5343-0.5868x, p=0.0003). Using multivariate Cox model analysis (forward stepwise method), adjusted for age, CRP and CRC stage were independent parameters related to survival, with a relative risk of 3.5 (95% confidence interval=1.5-8.2) and 8.1 (95% confidence interval=3.0-21.3), respectively. In conclusion, CRP is a sensitive and easily detectable serum marker that can be useful in patients with CRC, allowing their better clinical stratification. PMID- 25503159 TI - Congestive heart failure secondary to gemcitabine nab-paclitaxel in patients with pancreatic cancer. AB - BACKGROUND: Gemcitabine plus nab-paclitaxel is a novel combination chemotherapy that is currently being used in patients with metastatic pancreatic cancer. Phase III trials have shown improved survival, response rates, and disease-free progression. The most significant side-effects include peripheral neuropathy and myelotoxicity. Review of literature has shown rare cases of congestive heart failure associated with gemcitabine plus nab-paclitaxel. We describe two cases of women who were treated with gemcitabine plus nab-paclitaxel for pancreatic adenocarcinoma who developed acute exacerbation of congestive heart failure. PATIENTS AND METHODS: Two women with pancreatic adenocarcinoma were both treated with gemcitabine plus nab-paclitaxel and developed acute decompensated heart failure requiring hospitalization and standard treatment for heart failure including i.v. diuretics. Once chemotherapy was discontinued, symptoms resolved. CONCLUSION: Based on review of literature, as far as we are aware of, this is the first report of congestive heart failure as an adverse effect of combination therapy. Both patients had evidence of diastolic dysfunction which may have predisposed them to cardiac toxicity secondary to gemcitabine plus nab paclitaxel. The exact mechanism of action is currently unknown and requires further studies. However, it is imperative for physicians to be aware of this adverse effect and closely monitor patients with underlying heart disease who are undergoing treatment with gemcitabine plus nab-paclitaxel. PMID- 25503160 TI - Polaprezinc prevents oral mucositis in patients treated with high-dose chemotherapy followed by hematopoietic stem cell transplantation. AB - We have previously reported that polaprezinc in sodium alginate suspension (P-AG) inhibited the incidence of oral mucositis induced by radiochemotherapy in patients with head and neck cancer. The present study was designed to investigate whether P-AG prevents oral mucositis in all patients (36 patients) with hematological malignancy receiving high-dose chemotherapy and radiotherapy followed by hematopoietic stem cell transplantation (HSCT). P-AG dramatically reduced the incidence of moderate-to-severe oral mucositis as compared to the control group treated with azulene gargle (20% versus 82% for grade >= 2, p<0.01; 0% versus 45% for grade >= 3, p<0.01). Pain associated with oral mucositis was also significantly (p=0.004) relieved by P-AG, resulting in a reduction in the use of analgesic agents (28% versus 73%, p=0.025). The incidence of xerostomia and taste disturbance tended to be lowered but not significantly by P-AG. On the other hand, P-AG had no influence on the incidence of other adverse events, tumor remission rate or the survival rate. Therefore, P-AG was found to be highly effective in preventing oral mucositis induced not only by radiochemotherapy for head and neck cancer but also by high-dose chemotherapy and radiotherapy followed by HSCT. PMID- 25503161 TI - Portal vein embolisation with application of haematopoietic stem cells in patients with primarily or non-resectable colorectal liver metastases. AB - BACKGROUND: Insufficient future liver remnant volume (FLRV) is the main cause of low resectability of liver metastases from colorectal cancer (CLMs). One option for enhancing FLVR growth is the use of portal vein embolisation (PVE) with the application of autologous haematopoietic stem cells (HSCs). PATIENTS AND METHODS: PVE with the application of HSCs was used in 11 patients (group 1) with primarily non-resectable CLMs due to insufficient FLRV without signs of extrahepatic metastases. The control group (group 2) consisted of 14 patients in whom only PVE was performed. We evaluated the product quality, FLRV growth, CLM volume, median survival and progression-free survival (PFS). RESULTS: Product quality was achieved in all collections. In all group-I patients, sufficient FLRV growth occurred within three weeks. In the first and second weeks, FLRV increased optimally in most patients (p<0.006). In 13 out of the 14 group-2 patients, optimum FLVR growth was observed within three weeks following PVE (p<0.002). More rapid FLVR growth was observed in group 1 patients (p<0.01). CLM volume was significantly increased in both the group-2 (p<0.0005) and group-1 (p<0.008) patients at the time of liver resection. There was no significant difference in the growth of the CLM volume between the groups (p<0.18). The median survival was 7.3 and 6.8 months for group 1 and 2 patients, respectively, and the two-year PFS was 28% and 22% (p<0.18), respectively. CONCLUSION: PVE with HSC application is a promising method for effectively stimulating FLRV growth in patients with primarily non-resectable CLMs. PMID- 25503162 TI - Febuxostat for management of tumor lysis syndrome including its effects on levels of purine metabolites in patients with hematological malignancies - a single institution's, pharmacokinetic and pilot prospective study. AB - BACKGROUND/AIM: Tumor lysis syndrome (TLS) is a life-threatening oncological emergency, and control of serum uric acid level (S-UA) is most important. In this single-institution, short-term and pilot prospective study, the efficacy of a new xanthine oxidase inhibitor, febuxostat, as an alternative to conventional allopurinol, including its effects on hypoxanthine and xanthine, was evaluated in 10 consecutive patients with hematological malignancies at intermediate risk for TLS. PATIENTS AND METHODS: Febuxostat at 40 mg (n=7) or 60 mg (n=3) daily was administered according to renal function, and induction chemotherapy was started within 24 h. The primary end-point was the reduction of S-UA to <= 7.5 mg/dl by day 5. RESULTS: The median S-UA at base-line was 8.0 mg/dl (range=3.2-10.6 mg/dl). The median S-UA on day 5 after chemotherapy was 3.3 mg/dl (range=1.1-5.8 mg/dl) (p<0.0001, by paired t-test), indicating successful control of S-UA during chemotherapy. All patients achieved S-UA <= 7.5 mg/dl. A simultaneous decrease in serum creatinine and increase in estimated glomerular filtration rate were seen. Serum hypoxanthine and xanthine levels (as the consequence of inhibition of xanthine oxidase) were elevated along with the decrease in S-UA. Xanthine level was elevated higher compared to hypoxanthine level and reached the level reported to cause xanthine nephropathy, but no advance of renal impairment was observed. Serum febuxostat concentrations at 2 h after administration were 891.8 +/- 285.0 ng/ml (mean +/- SE) for the 40-mg dose and 770.6 +/- 242.7 ng/ml for the 60-mg dose (p=0.80, unpaired t-test), showing no accumulation in patients with renal impairment. No febuxostat-related adverse reactions were noted. No patients experienced progressive TLS. CONCLUSION: Febuxostat is promising for the management of TLS of an intermediate-risk patient and further observation and reevaluation regarding xanthine nephropathy should be performed. PMID- 25503163 TI - Feasibility study of supportive care using lafutidine, a histamine H2 receptor antagonist, to prevent gastrointestinal toxicity during chemotherapy for gastric cancer. AB - The present study evaluated the efficacy of lafutidine, a histamine H2 receptor antagonist, for reducing gastrointestinal toxicities during adjuvant chemotherapy using oral fluorouracil anticancer drugs for gastric cancer. PATIENTS AND METHODS: Patients with stage II (T1 cases excluded) or stage III gastric adenocarcinoma who underwent gastrectomy with D2 lymphadenectomy achieving R0 resection from 2011 to 2013 were prospectively enrolled in the study. Patients were randomly assigned to either S-1 treatment or S-1 plus lafutidine treatment. Quality of life and gastrointestinal toxicity were evaluated before chemotherapy and at 2, 4, and 6 weeks after the beginning of treatment. RESULTS: The incidence of diarrhea during chemotherapy was significantly lower in the S-1 plus lafutidine group than in the group treated with S-1 alone (10% vs. 83%, respectively; p=0.002). The grades of diarrhea and nausea during chemotherapy were also significantly lower compared to those before chemotherapy in patients receiving S-1 plus lafutidine than in those administered S-1 alone. The rate of patients requiring a dose reduction or interruption of S-1 was significantly lower in the S-1 plus lafutidine group than in the group treated with S-1 alone (30% vs. 83%, respectively; p=0.027). CONCLUSION: Lafutidine might be useful not only for preventing gastrointestinal toxicities during adjuvant chemotherapy for gastric cancer, but also for improving compliance with taking oral fluorouracil anticancer drugs. However, this indication needs to be confirmed in a larger, prospective, randomized, controlled trial. PMID- 25503164 TI - Ovarian sarcoma carries a poorer prognosis than ovarian epithelial cancer throughout all FIGO stages: a single-center case-control matched study. AB - BACKGROUND: Ovarian sarcomas are poorly-studied rare tumors. AIM: To compare evolutions of sarcomas and epithelial ovarian carcinomas treated similarly. PATIENTS AND METHODS: Eleven patients with ovarian sarcomas were retrospectively identified over 12 years at a single tertiary center, the Fundeni Clinical Institute, Bucharest. They were matched to similar patients with epithelial ovarian cancer treated in the same center, by the same surgical teams and according to the same principles in an attempt to clarify the survival difference according to histopathological type with interference given by the above mentioned variables (surgeon, center, management strategies) eliminated. RESULTS: For International Federation of Gynecology and Obstetrics (FIGO) stage II, overall survival for patients with sarcoma was 90.5 months while for those with epithelial carcinoma it was 113 months (p=0.048). For stage IIIB, overall survival for those with sarcomas was 62 months, while for those with epithelial carcinoma it was 81 months. For stage IIIC, overall survival for those with sarcoma was 14.5 months while it was 55 months for patients with epithelial ovarian cancer (p=0.007). For stage IV overall survival for sarcomas is 2 months while for epithelial cancer is 6 months (p=0.09). CONCLUSION: Survival and disease-free interval for patients with ovarian sarcoma are lower than those for patients with epithelial ovarian carcinoma. Re-laparotomy for ovarian sarcoma relapse does not seem to bring any survival benefit. PMID- 25503165 TI - Comparison of two dose levels of stereotactic radiosurgery for 1-3 brain metastases from non-small cell lung cancer. AB - AIM: Two dose groups of patients treated with stereotactic radiosurgery (SRS) alone for 1-3 brain metastases from non-small cell lung cancer (NSCLC) were compared for outcomes. PATIENTS AND METHODS: Based on the SRS dose administered to the margins of the brain lesions, 46 patients were assigned to groups treated with 15-18 Gy (n=13) or with 20 Gy (n=33). Seven additional factors were investigated: age (<= 58 vs. >= 59 years), gender, Karnofsky performance score (KPS 70-80 vs. 90-100), number of brain metastases (1 vs. 2-3), histology (adenocarcinoma vs. other) extracerebral metastases and interval from NSCLC diagnosis to SRS (<= 6 vs. >6 months). RESULTS: Local control rates for 15-18-Gy and 20-Gy groups were 75% and 92% at one year (p=0.043). SRS dose was significant on multivariate analysis (p=0.030). SRS dose was not associated with freedom from new brain metastases (p=0.24) or survival (p=0.37). CONCLUSION: SRS with 20 Gy resulted in better control of the irradiated metastases than 15-18 Gy did. PMID- 25503166 TI - Fatal bilateral pneumonitis after locoregional thoracic chemoradiation in a transplanted patient under immunosuppressive therapy. AB - BACKGROUND: After thoracic radiotherapy a pneumonitis may occur, mostly confined to the irradiated volume of the lung. In general, it resolves spontaneously without long-term effects. CASE REPORT: A 68-year-old man was diagnosed with a stage IIIA adenocarcinoma of the lung and was treated with sequential chemoradiation. He had a heart and kidney transplant for which an immunosuppressant was taken. During the fourth week of radiotherapy, he developed a bilateral interstitial pneumonia. Despite antibiotics and steroids, the patient died twelve days after the onset of complaints due to respiratory failure. Autopsy showed in all pulmonary lobes extensive diffuse alveolar damage, probably leading to respiratory insufficiency and death. Literature and Conclusion: Bilateral pneumonitis after radiotherapy is thought to be an immunologically mediated response, which usually resolves without long-term effects. Since in radiation pneumonitis an increase in T-cells is described, the suppression of these cells by an immunosuppressant might have exaggerated the pulmonary toxicity. PMID- 25503167 TI - Safety and efficacy of pegylated liposomal doxorubicin-based adjuvant chemotherapy in patients with stage I-III triple-negative breast cancer. AB - BACKGROUND/AIM: Pegylated liposomal doxorubicin (PLD) has been proven to be an effective antitumor drug for metastatic breast cancer, with less toxicity than conventional anthracycline. Our objective was to evaluate the efficacy and safety of PLD-based adjuvant chemotherapy compared to conventional chemotherapy for patients with stages I-III Triple-negative breast cancer (TNBC). PATIENTS AND METHODS: A total of 162 patients, histologically proven to have TNBC at stages I III between 2003 and 2010, were enrolled to evaluate the impact of PLD- and non PLD-based adjuvant chemotherapy by using the end-pint of overall survival (OS) and relapse-free survival (RFS). RESULTS: Forty-nine (30.2%) patients received PLD-based adjuvant chemotherapy and 113 (69.8%) a non-PLD regimen, including 84 (52%) patients receiving non-PLD anthracycline. The Kaplan-Meier calculation indicated no differences in RFS and OS between the PLD and non-PLD groups. Multivariate analysis adjusted for tumor size and lymph node status also revealed similar RFS (HR=0.86, 95% CI=0.43-1.73, p=0.678) and OS (HR=0.86, 95% CI=0.41 1.79, p=0.692) for PLD-based chemotherapy compared with non-PLD-based. Patients receiving PLD-based chemotherapy had a relatively lower incidence of grade 3-4 neutropenia (25% vs. 41.6%, respectively; p=0.054) and significantly higher incidence of hand-foot syndrome (16.3% vs. 4.4%, respectively; p=0.010). CONCLUSION: PLD-based adjuvant chemotherapy was as effective as conventional chemotherapy for patients with TNBC. PLD is an alternative for patients with TNBC when conventional anthracycline is inappropriate. PMID- 25503168 TI - Melatonin in patients with cancer receiving chemotherapy: a randomized, double blind, placebo-controlled trial. AB - BACKGROUND: The MIRCIT trial was a randomized, double-blind, placebo-controlled study of advanced Non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized to receive 10 mg or 20 mg of melatonin or placebo. Assessment of health-related quality of life (HRQoL) was completed at baseline, and at 2, 3 and 7 months. Survival and adverse events were collected. DNA damage marker 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) was measured during the first three months of chemotherapy. RESULTS: Patients in the melatonin-treated group had better adjusted HRQoL scores, with a slightly significantly better score (2.69 points, 95% confidence interval (CI)=0.01-5.38, p=0.049) being found in social well-being. Median survival was 7.3 months (95% CI=3.42-11.14) without significant difference. A great amont of DNA damage marker was observed in the placebo-treated group, and this was associated with lower survival (r(2)=-0.656, p=0.02), implying the protective effect of melatonin in healthy cells. CONCLUSION: Melatonin in combination with chemotherapy did not affect survival and adverse events of advanced patients with NSCLC, but there was a trend for better HRQoL. PMID- 25503169 TI - Radiation recall gastritis secondary to erlotinib in a patient with pancreatic cancer. AB - BACKGROUND: Radiation recall refers to chemotherapy-triggered inflammation in healthy areas previously exposed to irradiation. Chemotherapeutics known to be associated with radiation recall phenomenon include anthracyclines, taxanes and antimetabolites, such as gemcitabine and capecitabine. Case reports detailing radiation recall dermatitis and pneumonitis associated with erlotinib have been previously described in the literature, however, there are no reported cases describing radiation gastritis associated with erlotinib. We report a patient with pancreatic cancer who developed gastrointestinal bleeding secondary to radiation recall gastritis related to erlotinib exposure. CASE REPORT: A 57-year old Hispanic male with pancreatic cancer initially received 7 cycles of FOLFIRINOX followed by capecitabine with radiation therapy for 28 fractions for a total of 5,040 cGy. Re-staging with computed tomography demonstrated stable disease. The patient was then treated with erlotinib and capecitabine for approximately two months before restaging demonstrated progressive disease. Shortly after discontinuing erlotinib and capecitabine, the patient reported maroon colored stools. Laboratory studies demonstrated a precipitous drop in hemoglobin and hematocrit from pre-treatment baseline, ultimately requiring transfusion with packed red blood cells. Subsequent esophagogastroduodenoscopy demonstrated findings consistent with radiation gastritis, with oozing in the gastric body and antrum, which was treated therapeutically with argon plasma coagulation. The patient's gastrointestinal bleed was difficult to control. Over the course of a two-month period - the patient required multiple admissions, repeat therapeutic esophagogastroduodenoscopies and transfusions. DISCUSSION: Radiation recall from erlotinib is rare but can potentially arise in any site that has been previously irradiated. There may be an association between the pathogenesis of radiation recall and erlotinib's up-regulation of the angiogenic growth factor thymidine phosphorylase. Treating physicians are reminded of the potential toxicity from erlotinib either given concomitantly or followed by radiation. We suggest discontinuing erlotinib if radiation gastritis is observed. We encourage physicians with similar experiences with erlotinib to report their findings. Further studies are warranted to investigate the pathogenesis of this unique phenomenon and its association with erlotinib. PMID- 25503170 TI - Two-team simultaneous total radical vulvectomy and inguino-femoral lymphadenectomy via separate incisions for locally advanced (FIGO stages IB >= 4 cm-III) squamous vulvar cancer. AB - AIM: To describe the feasibility, safety, and oncological outcomes of a modified triple-incision total radical vulvectomy and inguino-femoral lymphadenectomy in patients with locally advanced squamous vulvar cancer. PATIENTS AND METHODS: A modified triple-incision technique performed by two surgical teams operating simultaneously under regional anesthesia was performed on a consecutive series of 57 patients with Federation Internationale de Gynecologie Ostetrique (FIGO) stages IB >= 4 cm to III squamous vulvar cancer. Adjuvant radiation therapy was delivered according to margin status and groin involvement. Surgical outcomes and follow-up data were retrospectively analyzed. RESULTS: The mean age of patients was 75.5 +/- 10.7 years and 54 (94.7%) had at least one comorbidity. Fifteen (26.3%) had disease of clinical FIGO stage I >= 4 cm, 7 (12.3%) had stage II, and 35 (61.4%) had a stage III. All surgical procedures were completed as planned. The mean surgical duration was 108 +/- 37 min. Major intraoperative complications were observed in two cases (3.5%). Twenty-one (36.8%) patients received adjuvant radiation therapy. During a mean follow-up of 51.6 +/- 50.5 months, 29 (50.9%) patients developed local, regional or distant recurrence. The disease-free survival was 39.5 +/- 20.9 months. Nineteen (33.3%) patients died of primary disease. Overall survival for the entire cohort was 65.4%, with 3-year and 5-year overall survival of 60.5% and 48.6%, respectively. CONCLUSION: Our results seem to reveal that the procedure is safe, with surgical and oncological outcomes comparable to classic sequential triple-incision technique. The shortening of surgical duration along with the use of regional anesthesia can have significant advantages for perioperative care, reducing the global burden of treatment and increasing the number of patients eligible for therapeutic surgery. PMID- 25503171 TI - Expression of adhesion molecules and the proliferative activity of carcinosarcoma of the ovary. AB - BACKGROUND: To clarify the mechanism underlying the formation of a sarcomatous component of ovarian carcinosarcoma, we investigated the expression of adhesion molecules and the proliferative activity of carcinosarcomas. MATERIALS AND METHODS: We immunohistochemically examined the expression of E-cadherin and beta catenin, and the Ki-67 labeling index (Ki-67 LI) in six carcinosarcomas containing endometrioid carcinoma as a carcinomatous component. RESULTS: The sarcomatous components of the carcinosarcomas did not express E-cadherin or beta catenin. All carcinomatous components expressed these molecules but the expression was reduced compared to that in endometrioid ovarian carcinomas. In five of the six carcinosarcomas, the Ki-67 LI of the sarcomatous component was less than that of the carcinomatous component. CONCLUSION: The present results suggest that a carcinomatous component transforms more easily than an ordinary endometrioid carcinoma from the viewpoint of the cell adhesion, and cells in a carcinomatous component continuously transform into sarcomatous cells during the growth of carcinosarcoma. PMID- 25503172 TI - A case series of patients with HER2-overexpressed primary metastatic gastroesophageal adenocarcinoma. AB - BACKGROUND: Overexpression of the human epidermal growth factor 2 (HER2) is associated with an aggressive metastatic phenotype in patients with breast cancer but its prognostic impact is not well-characterized in gastroesophageal adenocarcinoma. PATIENTS AND METHODS: This is a retrospective series of three cases of HER2-positive gastroesophageal cancer. RESULTS: In this case series, we describe three patients presenting with widespread metastatic disease prior to development of symptoms from the primary tumor. Two patients presented with brain metastases, while one demonstrated lymphangitic spread to lungs. CONCLUSION: Pooled analyses of outcomes among sub-populations of contemporary trials are needed to better understand the natural history and prognostic impact of HER2 over-expression in patients with gastroesophageal cancers. PMID- 25503173 TI - Sunitinib-induced complete response in metastatic renal cancer expressing neuroendocrine markers: a new predictive factor? AB - BACKGROUND: To date, no predictive factors are recognized and applied in the therapeutic choice for metastatic renal cell carcinoma. Due to significant side effects and costs, which are relevant issues in this setting, optimization of treatments has become a priority. CASE REPORT: We herein report a case of complete remission of metastatic renal cell carcinoma after 1 year of treatment with sunitinib. Since pancreatic metastases were detected by a 68Ga-DOTA-NOC positron emission tomography, it was decided to perform a histological revision of the specimens, with immunohistochemical staining for neuroendocrine markers on the primary tumor. CONCLUSION: On the basis of the detection of neuroendocrine markers on the primary neoplasm, together with pancreatic metastases positive on a 68Ga-DOTA-NOC positron emission tomography (PET), we hypothesize and discuss about a potential role of specific neuroendocrine markers as predictive indicators of response to sunitinib (and allegedly to other target therapies) in the treatment of this neoplasm. PMID- 25503174 TI - Assessment of risk of late rectal bleeding for patients with prostate cancer started on anticoagulation before or after radiation treatment. AB - AIM: To evaluate the risk of late rectal bleeding and its association with the timing and type of anticoagulation use in patients receiving dose-escalated radiation therapy (RT) (>= 7,560 cGy) for prostate cancer. PATIENTS AND METHODS: Between 2003-2010, 465 patients were treated at our Institution with dose escalated RT and included in this analysis. Patients were placed into the following categories: no anticoagulation use, aspirin during RT, clopidogrel/warfarin during RT, aspirin after completion of RT, clopidogrel/warfarin after completion of RT. RESULTS: The overall bleeding rate was 7.5%. For those on aspirin during RT, the 4-year freedom from rectal bleeding (FFBS) rate was 91%, compared to 94.7% for patients who were never on anticoagulation (p=0.16). For those on warfarin/clopidogrel during RT the 4-year FFBS rate was 78.2%, compared to 94.7% in those never on anticoagulation (p<0.001). On multivariate analysis, use of warfarin/clopidogrel during radiation treatment were strongly associated with an increased risk of rectal bleeding (multivariate HR=4.84, 95% CI=1.84-12.68, p=0.001). However, initiation of anticoagulation after completion of radiation treatment did not significantly increase the risk of rectal bleeding (multivariate HR=0.78, 95% CI=0.21-2.91, p=0.71). CONCLUSION: The use of clopidogrel or warfarin during radiation is associated with significantly increased risk of rectal bleeding. However, initiation of these medications after completion of radiation does not appear to impact such risk. PMID- 25503175 TI - Frequency and predisposing factors for interfractional rectal displacement requiring repeated precaution in prostate cancer patients treated with image guided intensity-modulated radiation therapy. AB - AIM: To investigate the frequency and characteristics of interfractional rectal displacement in patients with prostate cancer treated with image-guided intensity modulated radiation therapy (IG-IMRT) using helical tomotherapy. PATIENTS AND METHODS: Data for a total of 256 patients were analyzed. Megavoltage computed tomography (MVCT) images were acquired before radiation therapy and interfractional rectal displacement was assessed with soft-tissue matching by comparing treatment planning images within 9,445 fractions. Anterior rectal region displacement larger than 5 mm, requiring repeated precaution, was defined as the action level of rectal displacement (ARD). RESULTS: ARD was identified in 676 (7.2%) out of 9,445 fractions and at least once in 75% (190/256) of patients. Univariate analysis identified three predisposing factors for ARD: body mass index (BMI), rectal volume and prostate volume. Multivariate logistic regression analysis revealed that lower BMI and large rectal volume were statistically significant predictors of ARD. The highest incidence of ARD (13.6% and 9.1%) was found during the initial two weeks of treatment (first five and next five fractions), after which the incidence decreased to 5.96% (p<0.0001). CONCLUSION: ARD was identified in 7.9% of fractions and in 74.8% of patients and was most likely to occur in patients with a low BMI and/or large rectal volume. ARD occurred predominantly during the initial two weeks of treatment and became less likely over time. PMID- 25503176 TI - Palifermin in children undergoing autologous stem cell transplantation: a matched pair analysis. AB - BACKGROUND: Keratinocyte growth factor (palifermin) is used for prevention of mucositis in adults following autologous and allogeneic hematopoietic stem cell transplantation (HSCT). It is known that palifermin decreases length of initial hospital stay, mean number of days of total parenteral nutrition (TPN) and the use of opioids for pain control in oral mucositis in adults. There are limited data evaluating palifermin use in children following autologous HSCT. AIM: The objective of the present study was the analysis of efficacy and safety of palifermin in children undergoing auto-HSCT. PATIENTS AND METHODS: This matched pair analysis study included 62 pediatric patients undergoing first auto-HSCT receiving palifermin on a compassionate-use basis (study group, n=31) or not (control group, n=31). RESULTS: Palifermin decreased the incidence of severe (grade 3-4 WHO) oral mucositis (p=0.041), length of hospitalization (p=0.047) and contributed to the shorter duration of oral mucositis (p=0.035) and lower incidence of clinically or microbiologically documented infections (p=0.038). There were no differences between groups in opioid use, neutrophil and platelet recovery, TPN use and gastrointestinal hemorrhage. CONCLUSION: Palifermin decreases the incidence and severity of oral mucositis in children undergoing autologous HSCT. PMID- 25503177 TI - Analysis of intrafractional organ motion by megavoltage computed tomography in patients with lung cancer treated with image-guided stereotactic body radiotherapy using helical tomotherapy. AB - AIM: To analyze intrafractional organ motion in patients with lung cancer treated with image-guided stereotactic body radiotherapy using helical tomotherapy (SBRT HT). PATIENTS AND METHODS: Data from 25 patients with lung cancer who received 50 Gy/5 fractions of SBRT-HT were analyzed. Slow-scan megavoltage computed tomography (MVCT) images were acquired before (pre-MVCT) and after (post-MVCT) each fraction. We analyzed the imaging quality of the 124 post-MVCT images to identify tumor contours using low-density settings. Next we examined tumor contour deviations from the planning target volume (PTV) in post-MVCT images for intrafractional tumor displacement. RESULTS: Image quality was determined as good in 111/124 images from 22 patients (92%). None of the upper lung tumor images were of poor quality (74 images in 15 patients), whereas lower lung tumors yielded 14 poor-quality images out of the 50 images (3/10 patients). The difference in image quality between upper and lower lung tumors was statistically significant (p<0.01), especially when accompanied by interstitial lung shadows. Deviations in tumor position in post-MVCT images were analyzed in 110 images from 23 patients and revealed 99 images (90%) with tumor contours confined to PTV. In upper lung tumors, 4/74 images in 15 patients (5.4%) showed tumor contour deviations outside PTV. Lower lung tumors showed a higher rate of deviation with 7/36 images in 8 patients (19.4%) showing tumor contour deviations outside PTV (p<0.05). The maximum deviation was 1 mm for upper lung tumors and 2 mm for lower lung tumors. CONCLUSION: Upper lung tumors are good candidates for MVCT image guided SBRT-HT. However, lower lung tumors, especially those adjacent to the diaphragm or pleura, can be difficult to assess, warranting precise dose delivery by MVCT image-guided SBRT-HT. PMID- 25503178 TI - Risk factors for pericardial effusion in patients with stage I esophageal cancer treated with chemoradiotherapy. AB - AIM: We investigated clinical and dosimetric factors influencing the risk of developing pericardial effusion (PCE) in patients with Stage I esophageal cancer undergoing definitive chemoradiotherapy. PATIENTS AND METHODS: Sixty-nine patients with Stage I esophageal cancer who underwent definitive chemoradiotherapy were retrospectively analyzed. Treatment comprised of three dimensional conformal radiotherapy (60 Gy in 30 fractions) with concurrent chemotherapy. Clinical and dosimetric factors associated with PCE development were analyzed. RESULTS: The median follow-up was 37 months (range=8-111 months); the crude PCE incidence rate was 52.2%. Grade 2 and 3 incidence rate was 47.8% and 4.3%, respectively. The median time to PCE onset was 5.7 months after radiotherapy. In multivariate analysis, pericardial V30 >= 41.6%, age >= 66 years, body mass index (BMI) >= 19 and diabetes mellitus (DM) were significant predictors of developing PCE. CONCLUSION: The present study suggests that higher pericardial V30, advanced age, high BMI and DM are risk factors for developing PCE. PMID- 25503179 TI - Ponticulus posticus is a frequent radiographic finding on lateral cephalograms in nevoid basal cell carcinoma syndrome (Gorlin-Goltz syndrome). AB - Nevoid basal cell carcinoma syndrome (NBCCS) is a predisposition to a rare tumor type with a variable phenotype. Besides tumors, skeletal alterations, such as bifid ribs or frontal bossing constitute the phenotype. Recently, a variant of the first cervical vertebra, the ponticulus posticus, was reported to occur in 50% of patients with NBCCS as revealed by analysis of lateral cephalograms. MATERIALS AND METHODS: Lateral cephalograms of eight patients with NBCCS were studied for the presence of ponticulus posticus. RESULTS: The ponticulus posticus was present in all patients. In one case, a series of cephalograms performed during a period of 20 years allowed the slow and continuous recording of a ponticulus posticus formation. DISCUSSION: Besides the predisposition to developing neoplasms, NBCCS also affects bone development. Some diagnostic criteria for NBCCS rely on certain osseous transformations either in hard tissues, e.g. keratocystic odontogenic tumor in jaws, or in soft tissues, e.g. calcification of the falx cerebri. Furthermore, the physiognomy can be affected by skeletal alterations, e.g. frontal bossing or hypertelorism. Given this wide spectrum of osseous involvement in NBCCS, the high prevalence rate of ponticulus posticus should be added to the relevant diagnostic findings of the skull and vertebral column. However, the onset of ponticulus posticus formation in the life of such patients is unclear and thus the relevance of this finding in early diagnosis of NBCCS remains to be elucidated. PMID- 25503180 TI - Does pulmonary resection promote the progression of unresected ground-glass nodules? AB - BACKGROUND: The routine use of thin-section, whole-lung computed tomographic scanning helps detect persistent ground-glass nodules (GGNs) co-existing with the target lesion in the underlying lung. PATIENTS AND METHODS: The cases of 10 patients with persistent co-existing GGNs detected on whole-lung computed tomography performed prior to surgery for lung cancer were retrospectively reviewed. The co-existing lesions were not resected at the initial procedure. RESULTS: Although no masses exhibited progression during the 15.5-month preoperative follow-up period, all lesions displayed enlargement during the first year after the initial procedure, with the exception of one tumor. Three lesions arose in the ipsilateral lung, while the remaining lesions arose in the contralateral lung. The nine enlarged lesions were diagnosed as adenocarcinoma on subsequent resection. CONCLUSION: Lung adenocarcinoma with persistent GGNs tends to progress after lung resection for other lesions. This phenomenon should be kept in mind when selecting for surgical procedure in patients with persistent co existing GGNs. PMID- 25503181 TI - Post-operative aspirin use and colorectal cancer-specific survival in patients with stage I-III colorectal cancer. AB - BACKGROUND: Recent observational studies suggest that postoperative aspirin use may improve Colorectal cancer (CRC)-specific survival and overall survival (OS). In this study, we aimed to assess the effects of aspirin use on outcomes in a predominantly Asian cohort of patients with CRC. PATIENTS AND METHODS: Case records of patients undergoing curative resection for stage I-III CRC were retrieved for clinical data and patterns of aspirin use and vital data were determined from hospital electronic prescription records, hospital pharmacy dispensing records, national clinical and prescription databases. CRC-specific and recurrence-free survival (RFS) amongst aspirin users and non-users were analyzed and compared using the Cox proportional hazards model. RESULTS: Out of 726 patients with CRC, 103 were regular aspirin users and 623 were non-users. The median age of the cohort was 65 years (range=22-94 years) and the majority of patients were Chinese (90%). Nineteen percent, 31% and 47% had stage I, II and III CRC respectively; tumor staging was unknown for 3%. After adjusting for prognostic factors (age, stage, lymph node stage, grade, lesion site, perineural invasion, lymphvascular invasion), the risk of CRC relapse or death from CRC was approximately 60% lower compared to patients who were not postoperative aspirin users (Hazard Ratio=0.38, 95% Confidence Interval=0.17-0.84, p=0.017). No benefit was observed for preoperative use of aspirin. CONCLUSION: In this single Institution study, with long-term follow-up of patients with stage I-III-resected CRC, postoperative aspirin use was associated with reduced risk of relapse of and death from CRC. PMID- 25503182 TI - Detection of circulating tumor cells in bladder cancer using multiplex PCR assays. AB - AIM: The aim of this study was to develop multiplex-PCR assays for the detection of circulating tumor cells in peripheral blood and urine samples of patients with bladder cancer. MATERIALS AND METHODS: Peripheral blood and urine samples were collected from 208 patients (169 patients and 39 healthy volunteers). After RNA extraction and cDNA synthesis, the samples were analyzed for the expression of cytokeratin 19 (CK19), CK20 and epidermal growth factor receptor (EGFR) mRNA in blood and for SURVIVIN, human telomerase reverse transcriptase (hTERT), cytokeratin 20 (CK20) mRNA in urine, using multiplex-PCR assays. RESULTS: EGFR and CK20 alone or in combination as well as all urine markers correlated well with histological grade. hTERT correlated well with primary tumor size T>=3. Patients with positive urine markers had significantly worse progression-free survival. CONCLUSION: Multiplex-PCR assays can be a useful tool for staging and monitoring purposes in patients with bladder cancer. PMID- 25503183 TI - Mesothelin in serum and pleural effusion in the diagnosis of malignant pleural mesothelioma with non-positive cytology. AB - BACKGROUND/AIM: Mesothelin (SMRP) is regarded as a biomarker of malignant pleural mesothelioma (MPM). Herein, we analyzed the contribution of SMRP detection in pleural effusion and in serum to the diagnosis of MPM with non-positive cytology. MATERIALS AND METHODS: The present study included 52 cases of MPM, 43 of pleural benign lesions and 25 of non-MPM pleural metastases. SMRP was measured by MesoMark ELISA (Cis-Bio International Gif/Yvette; France). RESULTS: In non positive cytology, effusion-SMRP showed higher diagnostic performance than serum SMRP. We found 38 out of 52 (73.1%) cases of non-positive cytology MPM, out of which 27 (71.0%) were positive for effusion-SMRP (cut-off=12.70 nM) and 18 (47.4%) for serum-SMRP (cut-off=1.08 nM). When cytology, effusion- and serum-SMRP were used in combination, an overall sensitivity in detection of MPM of 78.9% was achieved. The same sensitivity was obtained by combining cytology with effusion SMRP alone, whereas the combination of serum-SMRP with cytology led to a sensitivity of 61.5%. CONCLUSION: Detection of both effusion- and serum-SMRP can contribute to improve the diagnosis of MPM with non-positive cytology. However, the analysis of SMRP in effusion makes it unnecessary to test SMRP in the serum. PMID- 25503184 TI - Analysis of preoperative serum levels of MMP1, -2, and -9 in patients with site specific head and neck squamous cell cancer. AB - BACKGROUND: Head and neck squamous cell cancer (HNSCC) includes tumors of various anatomical sites sharing common etiological factors. Serum levels of MMP1, MMP2, and MMP9 were analyzed in patients with oropharyngeal, laryngeal, and hypopharyngeal carcinomas in an effort to elucidate the pathobiology and in order to find useful biomarkers of site-specific HNSCC. PATIENTS AND METHODS: The study group comprised of 46 patients with HNSCC (21 with oropharyngeal, 21 with laryngeal and 4 with hypopharyngeal cancer). Serum levels of MMP1, -2, and -9 were determined by the MAGPIX multiplex method. P16 protein was detected by immunohistochemistry. Serum levels of matrix metalloproteinases (MMPs) were correlated with clinicopathological features of carcinomas and were compared with respect to tumor site. RESULTS: Significant correlations were confirmed between p16 positivity and oropharyngeal cancer, MMP1 and p16 positivity, and recurrence and smoking. Statistically significant differences in serum levels of MMPs between cancer of different locations were not found. CONCLUSION: MMP1 expression is significantly affected by smoking habit and by p16 and might mediate etiopathogenetical process in cancerogenesis of HNSCC. Our pilot study did not establish any utility of MMP1, -2, or -9 in clinical practice as diagnostic/prognostic markers. PMID- 25503185 TI - Kinetics of circulating levels of miR-195, miR-155 and miR-21 in patients with breast cancer undergoing mastectomy. AB - BACKGROUND: MicroRNAs are small RNA molecules that negatively regulate the expression of the majority of proteins, mainly at the post-transcriptional level. Being stable in the circulation and resistant to storage handling, they are potentially promising biomarkers. MATERIALS AND METHODS: We measured RNA levels of three microRNAs with tumorigenic or angiogenic potential (miR-155, miR-195, and miR-21) in blood samples taken from patients with early breast cancer, both preoperatively and postoperatively. RESULTS: We found that persistently elevated postoperative levels of miR-195 were detected only in patients who developed early tumor relapse and that miR-155 levels tended to increase three days postoperatively (p=0.05) and fell below baseline one month post-surgery (p<0.05). We had no major findings for miR-21. CONCLUSION: The results of this pilot study indicate a possible involvement of miR-155 in surgery-induced angiogenesis and potential prognostic significance of high postoperative levels of circulating miR 195 in patients with breast cancer. PMID- 25503186 TI - Baseline central nervous system magnetic resonance imaging in early detection of trilateral retinoblastoma: pitfalls in the diagnosis of pineal gland lesions. AB - BACKGROUND: Trilateral retinoblastoma (TRB) is a rare disease associating bilateral retinoblastoma (RB) with primitive intracranial neuroblastic tumor. AIM: To verify the occurrence of TRB in a single-Center case series and point out the clinical relevance of a baseline brain magnetic resonance imaging (MRI) in RB, focusing on pineal gland lesions. PATIENTS AND METHODS: Baseline MRI was routinely performed in all cases of RB from 1999. All MRIs were reviewed for this study and the RB database was checked in order to identify patients characteristics, treatments and follow-up. RESULTS: A total of 107 patients with RB were diagnosed between 1999 and 2012. Sixty-two patients had unilateral RB and 45 bilateral RB. MRI revealed the presence of pineal gland lesions in 10 patients (9%); seven were considered pineal benign cysts (6.5%), while in three patients (2.8%), TRB was suspected. All patients with TRB presented hereditary RB. In one patient, the suspected TRB was metachronous and in the other two patients was synchronous. Biopsy was not performed. Cerobrospinal fluid (CSF) was negative in all patients. The MRI modification, before treatment in the first case and later in the second case, confirmed the TRB diagnosis. The third patient died due to progressive Central Nervous System (CNS) disease that clearly confirmed the TRB diagnosis. None of the three patients had received prior chemotherapeutic treatment. DISCUSSION: TRB represents a rare condition in this series, occurring in three (2.8%) out of all patients with RB. A synchronous presentation with small lesion seems more frequent when a baseline MRI is performed. When a histologically-proven diagnosis is not available, a suspected diagnosis should be considered with caution and only follow-up will confirm the diagnosis. A wait-and see approach should be considered. PMID- 25503187 TI - Esophageal carcinosarcoma: management and prognosis at a single Italian series. AB - BACKGROUND: Esophageal carcinosarcoma (ESC) is a rare malignant lesion of the esophagus with controversial characteristics and prognostic factors. PATIENTS AND METHODS: Seventeen consecutive patients with esophageal carcinosarcoma were referred to the Center for Esophageal Diseases located in Padua from January 1, 1980 to December 31, 2011. Clinical characteristics, pathological features, treatment and outcome were retrospectively analyzed in a prospectively collected database. RESULTS: Five patients received palliative treatment and one refused surgery; they died of unresected tumor or progression of disease within 0.6-43.5 months after diagnosis. Eleven patients underwent surgical treatment with complete tumor resection; recurrence rate was 80%, leading to death within 2 years after surgery. Only two resected patients are currently alive and free of disease over 20 years after surgery. CONCLUSION: Our results did not support the better prognosis concept of esophageal carcinosarcoma and suggested the importance of radical esophagectomy with adequate lymph node dissection. PMID- 25503188 TI - Predictive and prognostic significance of sodium levels in patients with NSCLC treated by erlotinib. AB - BACKGROUND: Hyponatremia is a well-known phenomenon in cancer patients. The aim of our retrospective study was to assess the relationship of natremia levels to predict treatment with erlotinib and also to assess the prognosis of patients with hyponatremia. PATIENTS AND METODS: We analyzed data of 544 patients with advanced-stage non-small cell lung cancer (NSCLC) treated with erlotinib. RESULTS: Hyponatremia was measured in 21.5 % of patients before treatment with erlotinib. We found a significant increase in the effectiveness of treatment with erlotinib in patients with normal levels of sodium to hyponatremic patients. Progression-free survival (PFS) and overall survival (OS) were also significantly higher in patients with normal natremia. Multivariate Cox model analysis demonstrated that natremia was an independent factor for PFS and OS. CONSLUSION: We reported hyponatremia not only as a prognostic marker in NSCLC patients but also as predictive marker of erlotinib treatment efficacy, being an independent factor at the present large retrospective study. Its possible effect in clinical practice is bigger thanks the simple possibility of testing of hyponatremia and the low cost of this biomarker. PMID- 25503189 TI - Clinicopathological factors affecting progression-free survival of patients with previously treated advanced non-small cell lung cancer after S-1 therapy with or without bevacizumab. AB - OBJECTIVES: The aim of the present study was to analyze factors that affect progression-free survival (PFS) of patients with previously treated advanced non small cell lung cancer (NSCLC) after S-1 therapy, in particular epidermal growth factor receptor (EGFR) mutation status. PATIENTS AND METHODS: Between October 2009 and June 2013, 56 patients with advanced NSCLC were analyzed for EGFR somatic mutations and treated with S-1 with or without bevacizumab. Risk factors associated with PFS were evaluated using a Cox proportional hazards regression model with a step-down procedure. Proportional hazards assumptions were checked and satisfied and only variables with statistical significance in univariate analysis were included in multivariate analysis. RESULTS: The median PFS of patients with EGFR mutations who received S-1 therapy was significantly longer than that of patients with wild-type EGFR. The median PFS of patients with good performance status (PS) was significantly longer than that of patients with poor PS. In multivariate analysis, wild-type EGFR and poor PS were significant and independent negative factors that affect PFS after S-1 therapy. CONCLUSION: EGFR mutation and good PS were positive predictive factors for PFS after S-1 therapy, suggesting that S-1 therapy is efficacious for patients with EGFR-activating mutations even in a multi-line setting. PMID- 25503190 TI - L-[3-18F]-alpha-methyltyrosine uptake by lymph node metastasis is a predictor of complete response to CRT in esophageal cancer. AB - BACKGROUND/AIM: The amino acid positron emission tomography (PET) tracer [(18)F] 3-fluoro-alpha-methyltyrosine ((18)F-FAMT) is known to be highly specific for malignancies. We evaluated the accumulation of (18)F-FDG or (18)F-FAMT in lymph nodes (LN) prior to definitive chemoradiotherapy (CRT) for esophageal cancer. PATIENTS AND METHODS: We retrospectively reviewed 30 patients with esophageal squamous cell carcinoma. All patients received definitive CRT. The relationship between the accumulation of (18)F-FDG PET or (18)F-FAMT PET in LNs prior to CRT and clinical outcomes was assessed. RESULTS: A correlation was observed between LNs in which most of (18)F-FAMT was accumulated and complete response (CR) rate, but was not for (18)F-FDG. Additionally, for (18)F-FAMT, the CR rate was significantly higher in the LN accumulated lesion <= 1 group than in the LN accumulated lesion >2 group. DISCUSSION: To predict the outcome of definitive CRT in patients with esophageal cancer, it is important to evaluate the LN status. PMID- 25503193 TI - Oxidized low-density lipoprotein inhibits THP-1-derived macrophage autophagy via TET2 down-regulation. AB - Oxidized low-density lipoprotein (ox-LDL) is an independent risk factor of atherosclerosis. However, the mechanism underlying its pro-atherosclerosis roles has not yet been well explored. DNA demethylation modification, via DNA methyltransferases or ten-eleven-translocation (TET) family, is a crisis epigenetic regulation for various biological and pathological processes. This study aimed to investigate the effects of ox-LDL on macrophage autophagy and its potential epigenetic mechanism. Results showed that after treatment with 0, 10, 20, 40 or 80 mg/L ox-LDL for 24 h, the autophagy markers Beclin 1 and LC3 expression were obviously decreased at protein levels (P < 0.05). The mRNA and protein expression of TET2 was evidently decreased (P < 0.05). After pre treatment with TET2 siRNA, the mRNA and protein levels of Beclin 1 and LC3 decreased compared with the 80 mg/L treatment group (P < 0.01). The mRNA and protein levels of Beclin 1 and LC3-II were up-regulated (P < 0.05) in the 5-aza 2'-deoxycytidine (a DNA methyltransferase inhibitor) of pretreatment group. Consistent with the Western blot results, cell immunofluorescence showed that the protein concentration of LC3-II decreased in the TET2 siRNA group and increased in the 5-aza-2'-deoxycytidine group. Taken together, these results showed that DNA demethylation modifications regulate ox-LDL-treated THP-1 macrophages autophagy and TET2 might be a novel regulator. PMID- 25503196 TI - Room for growth. PMID- 25503197 TI - Ethical overkill. PMID- 25503194 TI - The CDC13-STN1-TEN1 complex stimulates Pol alpha activity by promoting RNA priming and primase-to-polymerase switch. AB - Emerging evidence suggests that Cdc13-Stn1-Ten1 (CST), an RPA-like ssDNA-binding complex, may regulate primase-Pol alpha (PP) activity at telomeres constitutively, and at other genomic locations under conditions of replication stress. Here we examine the mechanisms of PP stimulation by CST using purified complexes derived from Candida glabrata. While CST does not enhance isolated DNA polymerase activity, it substantially augments both primase activity and primase to-polymerase switching. CST also simultaneously shortens the RNA and lengthens the DNA in the chimeric products. Stn1, the most conserved subunit of CST, is alone capable of PP stimulation. Both the N-terminal OB fold and the C-terminal winged-helix domains of Stn1 can bind to the Pol12 subunit of the PP complex and stimulate PP activity. Our findings provide mechanistic insights on a well conserved pathway of PP regulation that is critical for genome stability. PMID- 25503195 TI - Hereditary cancer-associated mutations in women diagnosed with two primary cancers: an opportunity to identify hereditary cancer syndromes after the first cancer diagnosis. AB - OBJECTIVES: Patients with hereditary cancer syndromes are at high risk for a second primary cancer. Early identification of these patients after an initial cancer diagnosis is the key to implementing cancer risk-reducing strategies. METHODS: A commercial laboratory database was searched for women with a history of both breast and ovarian or colorectal and endometrial cancer who underwent genetic testing for hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS). RESULTS: Among women with both breast and ovarian cancer, 22.4% (2,237/9,982) had a BRCA1 or BRCA2 mutation. Among women with both colorectal and ovarian cancer, 28.1% (264/941) had a mutation associated with LS. In 66.6% of BRCA1 or BRCA2 mutation carriers and in 58.3% of LS mutation carriers, >5 years passed between the cancer diagnoses. Of patients with HBOC and LS, 56 and 65.2%, respectively, met the National Comprehensive Cancer Network guidelines for hereditary cancer testing after their initial diagnosis based on their personal cancer history alone. CONCLUSIONS: A substantial number of women tested for LS or HBOC after being diagnosed with two successive primary cancers were diagnosed with a hereditary cancer syndrome. In many cases, the time interval between the diagnoses was long enough to allow for the implementation of surveillance and/or prophylactic measures. PMID- 25503198 TI - Protect and serve. PMID- 25503199 TI - Assess the real cost of research assessment. PMID- 25503212 TI - Europe plans Moon landing. PMID- 25503211 TI - Tsunami alerts fall short. PMID- 25503213 TI - Ebola experts seek to expand testing. PMID- 25503214 TI - T-cell therapy extends cancer survival to years. PMID- 25503215 TI - Microsoft billionaire takes on cell biology. PMID- 25503217 TI - Biodiversity: Life--a status report. PMID- 25503218 TI - Stem cells: The black box of reprogramming. PMID- 25503219 TI - Microbiology: Ditch the term pathogen. PMID- 25503222 TI - Conservation: Manage military land for the environment. PMID- 25503223 TI - Publishing: Biodiversity reports need author rules. PMID- 25503224 TI - Science policy: Europe is failing young researchers. PMID- 25503225 TI - Medical research: Several fields still need primates. PMID- 25503226 TI - Longitudinal studies: Engaged cohort good for science. PMID- 25503227 TI - Stem cells: A designer's guide to pluripotency. PMID- 25503229 TI - Applied physics: The virtues of tiling. PMID- 25503230 TI - Hydrology: When wells run dry. PMID- 25503231 TI - Catalytic enantioselective synthesis of quaternary carbon stereocentres. AB - Quaternary carbon stereocentres-carbon atoms to which four distinct carbon substituents are attached-are common features of molecules found in nature. However, before recent advances in chemical catalysis, there were few methods of constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for the synthesis of single stereoisomers of such organic molecules. This progress now makes it possible to incorporate quaternary stereocentres selectively in many organic molecules that are useful in medicine, agriculture and potentially other areas such as flavouring, fragrances and materials. PMID- 25503232 TI - Divergent reprogramming routes lead to alternative stem-cell states. AB - Pluripotency is defined by the ability of a cell to differentiate to the derivatives of all the three embryonic germ layers: ectoderm, mesoderm and endoderm. Pluripotent cells can be captured via the archetypal derivation of embryonic stem cells or via somatic cell reprogramming. Somatic cells are induced to acquire a pluripotent stem cell (iPSC) state through the forced expression of key transcription factors, and in the mouse these cells can fulfil the strictest of all developmental assays for pluripotent cells by generating completely iPSC derived embryos and mice. However, it is not known whether there are additional classes of pluripotent cells, or what the spectrum of reprogrammed phenotypes encompasses. Here we explore alternative outcomes of somatic reprogramming by fully characterizing reprogrammed cells independent of preconceived definitions of iPSC states. We demonstrate that by maintaining elevated reprogramming factor expression levels, mouse embryonic fibroblasts go through unique epigenetic modifications to arrive at a stable, Nanog-positive, alternative pluripotent state. In doing so, we prove that the pluripotent spectrum can encompass multiple, unique cell states. PMID- 25503235 TI - Formation and properties of ice XVI obtained by emptying a type sII clathrate hydrate. AB - Gas hydrates are ice-like solids, in which guest molecules or atoms are trapped inside cages formed within a crystalline host framework (clathrate) of hydrogen bonded water molecules. They are naturally present in large quantities on the deep ocean floor and as permafrost, can form in and block gas pipelines, and are thought to occur widely on Earth and beyond. A natural point of reference for this large and ubiquitous family of inclusion compounds is the empty hydrate lattice, which is usually regarded as experimentally inaccessible because the guest species stabilize the host framework. However, it has been suggested that sufficiently small guests may be removed to leave behind metastable empty clathrates, and guest-free Si- and Ge-clathrates have indeed been obtained. Here we show that this strategy can also be applied to water-based clathrates: five days of continuous vacuum pumping on small particles of neon hydrate (of structure sII) removes all guests, allowing us to determine the crystal structure, thermal expansivity and limit of metastability of the empty hydrate. It is the seventeenth experimentally established crystalline ice phase, ice XVI according to the current ice nomenclature, has a density of 0.81 grams per cubic centimetre (making it the least dense of all known crystalline water phases) and is expected to be the stable low-temperature phase of water at negative pressures (that is, under tension). We find that the empty hydrate structure exhibits negative thermal expansion below about 55 kelvin, and that it is mechanically more stable and has at low temperatures larger lattice constants than the filled hydrate. These observations attest to the importance of kinetic effects and host guest interactions in clathrate hydrates, with further characterization of the empty hydrate expected to improve our understanding of the structure, properties and behaviour of these unique materials. PMID- 25503234 TI - Ultrasensitive mechanical crack-based sensor inspired by the spider sensory system. AB - Recently developed flexible mechanosensors based on inorganic silicon, organic semiconductors, carbon nanotubes, graphene platelets, pressure-sensitive rubber and self-powered devices are highly sensitive and can be applied to human skin. However, the development of a multifunctional sensor satisfying the requirements of ultrahigh mechanosensitivity, flexibility and durability remains a challenge. In nature, spiders sense extremely small variations in mechanical stress using crack-shaped slit organs near their leg joints. Here we demonstrate that sensors based on nanoscale crack junctions and inspired by the geometry of a spider's slit organ can attain ultrahigh sensitivity and serve multiple purposes. The sensors are sensitive to strain (with a gauge factor of over 2,000 in the 0-2 per cent strain range) and vibration (with the ability to detect amplitudes of approximately 10 nanometres). The device is reversible, reproducible, durable and mechanically flexible, and can thus be easily mounted on human skin as an electronic multipixel array. The ultrahigh mechanosensitivity is attributed to the disconnection-reconnection process undergone by the zip-like nanoscale crack junctions under strain or vibration. The proposed theoretical model is consistent with experimental data that we report here. We also demonstrate that sensors based on nanoscale crack junctions are applicable to highly selective speech pattern recognition and the detection of physiological signals. The nanoscale crack junction-based sensory system could be useful in diverse applications requiring ultrahigh displacement sensitivity. PMID- 25503233 TI - Genome-wide characterization of the routes to pluripotency. AB - Somatic cell reprogramming to a pluripotent state continues to challenge many of our assumptions about cellular specification, and despite major efforts, we lack a complete molecular characterization of the reprograming process. To address this gap in knowledge, we generated extensive transcriptomic, epigenomic and proteomic data sets describing the reprogramming routes leading from mouse embryonic fibroblasts to induced pluripotency. Through integrative analysis, we reveal that cells transition through distinct gene expression and epigenetic signatures and bifurcate towards reprogramming transgene-dependent and independent stable pluripotent states. Early transcriptional events, driven by high levels of reprogramming transcription factor expression, are associated with widespread loss of histone H3 lysine 27 (H3K27me3) trimethylation, representing a general opening of the chromatin state. Maintenance of high transgene levels leads to re-acquisition of H3K27me3 and a stable pluripotent state that is alternative to the embryonic stem cell (ESC)-like fate. Lowering transgene levels at an intermediate phase, however, guides the process to the acquisition of ESC like chromatin and DNA methylation signature. Our data provide a comprehensive molecular description of the reprogramming routes and is accessible through the Project Grandiose portal at http://www.stemformatics.org. PMID- 25503236 TI - Isotopic constraints on marine and terrestrial N2O emissions during the last deglaciation. AB - Nitrous oxide (N2O) is an important greenhouse gas and ozone-depleting substance that has anthropogenic as well as natural marine and terrestrial sources. The tropospheric N2O concentrations have varied substantially in the past in concert with changing climate on glacial-interglacial and millennial timescales. It is not well understood, however, how N2O emissions from marine and terrestrial sources change in response to varying environmental conditions. The distinct isotopic compositions of marine and terrestrial N2O sources can help disentangle the relative changes in marine and terrestrial N2O emissions during past climate variations. Here we present N2O concentration and isotopic data for the last deglaciation, from 16,000 to 10,000 years before present, retrieved from air bubbles trapped in polar ice at Taylor Glacier, Antarctica. With the help of our data and a box model of the N2O cycle, we find a 30 per cent increase in total N2O emissions from the late glacial to the interglacial, with terrestrial and marine emissions contributing equally to the overall increase and generally evolving in parallel over the last deglaciation, even though there is no a priori connection between the drivers of the two sources. However, we find that terrestrial emissions dominated on centennial timescales, consistent with a state of-the-art dynamic global vegetation and land surface process model that suggests that during the last deglaciation emission changes were strongly influenced by temperature and precipitation patterns over land surfaces. The results improve our understanding of the drivers of natural N2O emissions and are consistent with the idea that natural N2O emissions will probably increase in response to anthropogenic warming. PMID- 25503241 TI - Latest anomalocaridid affinities challenged. PMID- 25503242 TI - Cong et al. reply. PMID- 25503243 TI - Laboratory evaluation of bioaugmentation for aerobic treatment of RDX in groundwater. AB - The potential for bioaugmentation with aerobic explosive degrading bacteria to remediate hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) contaminated aquifers was demonstrated. Repacked aquifer sediment columns were used to examine the transport and RDX degradation capacity of the known RDX degrading bacterial strains Gordonia sp. KTR9 (modified with a kanamycin resistance gene) Pseudomonas fluorescens I-C, and a kanamycin resistant transconjugate Rhodococcus jostii RHA1 pGKT2:Km+. All three strains were transported through the columns and eluted ahead of the conservative bromide tracer, although the total breakthrough varied by strain. The introduced cells responded to biostimulation with fructose (18 mg L(-1), 0.1 mM) by degrading dissolved RDX (0.5 mg L(-1), 2.3 uM). The strains retained RDX-degrading activity for at least 6 months following periods of starvation when no fructose was supplied to the column. Post-experiment analysis of the soil indicated that the residual cells were distributed along the length of the column. When the strains were grown to densities relevant for field-scale application, the cells remained viable and able to degrade RDX for at least 3 months when stored at 4 degrees C. These results indicate that bioaugmentation may be a viable option for treating RDX in large dilute aerobic plumes. PMID- 25503244 TI - Light-limited growth rate modulates nitrate inhibition of dinitrogen fixation in the marine unicellular cyanobacterium Crocosphaera watsonii. AB - Biological N2 fixation is the dominant supply of new nitrogen (N) to the oceans, but is often inhibited in the presence of fixed N sources such as nitrate (NO3-). Anthropogenic fixed N inputs to the ocean are increasing, but their effect on marine N2 fixation is uncertain. Thus, global estimates of new oceanic N depend on a fundamental understanding of factors that modulate N source preferences by N2-fixing cyanobacteria. We examined the unicellular diazotroph Crocosphaera watsonii (strain WH0003) to determine how the light-limited growth rate influences the inhibitory effects of fixed N on N2 fixation. When growth (u) was limited by low light (u = 0.23 d-1), short-term experiments indicated that 0.4 uM NH4+ reduced N2-fixation by ~90% relative to controls without added NH4+. In fast growing, high-light-acclimated cultures (u = 0.68 d-1), 2.0 uM NH4+ was needed to achieve the same effect. In long-term exposures to NO3-, inhibition of N2 fixation also varied with growth rate. In high-light-acclimated, fast-growing cultures, NO3- did not inhibit N2-fixation rates in comparison with cultures growing on N2 alone. Instead NO3- supported even faster growth, indicating that the cellular assimilation rate of N2 alone (i.e. dinitrogen reduction) could not support the light-specific maximum growth rate of Crocosphaera. When growth was severely light-limited, NO3- did not support faster growth rates but instead inhibited N2-fixation rates by 55% relative to controls. These data rest on the basic tenet that light energy is the driver of photoautotrophic growth while various nutrient substrates serve as supports. Our findings provide a novel conceptual framework to examine interactions between N source preferences and predict degrees of inhibition of N2 fixation by fixed N sources based on the growth rate as controlled by light. PMID- 25503245 TI - Behaviour and mobility of U and Ra in sediments near an abandoned uranium mine, Cornwall, UK. AB - Sediment samples were collected from the vicinity of the abandoned South Terras uranium mine in south-west UK and analysed for uranium and (226)Ra to explore their geochemical dispersion. The radioactivity concentrations in the sediment samples were measured using alpha spectrometry for uranium, and gamma spectrometry for radium. Sequential chemical extraction was applied to selected sediments in order to investigate the speciation of the radionuclides and their association with stable elements. The activity ratio of the uranium isotopes was used to explore the mobility of uranium, and scanning electron microscopy (SEM) and electron microprobe analysis (EMPA) were used to characterise the sediments. The radiochemical results identified two locations with enhanced radioactivity, so two samples from these locations were further investigated. The geochemical distribution of the radionuclides in these two samples varies within the five operationally-defined fractions. In one sample, the majority of the uranium was released from the 'carbonate' fraction, followed by the organic fractions. Similarly, in the second sample, the uranium was mainly resealed from the carbonate fraction, although a considerable percentage associated with the resistant fraction. The fractionation trend of radium noticed to show some similarities to that of barium, as expected from the similarity in their chemistries. Geochemical distributions of the stable elements, such as Mn, Ti and As, were different in the enhanced radioactivity samples. The activity ratio of (234)U/(238)U shows different trends in the two sediments, signifying the impact of organic matter and/or the exchange between water and sediment. SEM and EMPA analysis identified uranium-bearing phases in association with potassium, calcium, iron, manganese and arsenic. PMID- 25503248 TI - Structure of the DMPC lipid bilayer ripple phase. AB - High resolution structure is presented for the ripple (Pbeta') phase of the phospholipid dimyristoylphosphatidylcholine. Low angle X-ray scattering from oriented samples yielded 57 orders, more than twice as many as recorded previously. The determined electron density map has a sawtooth profile similar to the result from lower resolution data, but the features are sharper allowing better estimates for the modulated bilayer profile and the distribution of headgroups along the aqueous interface. Analysis of high resolution wide angle X ray data shows that the hydrocarbon chains in the longer, major side of the asymmetric sawtooth are packed similarly to the LbetaF gel phase, with chains in both monolayers coupled and tilted by 18 degrees in the same direction. The absence of Bragg rods that could be associated with the minor side is consistent with disordered chains, as often suggested in the literature. However, the new high resolution bilayer profile strongly suggests that the chains in the two monolayers in the minor side and the curved region are not in registry. This staggered monolayer modulated melting suggests a direction for improving theories of the ripple phase. PMID- 25503246 TI - Genome-wide analysis of leafbladeless1-regulated and phased small RNAs underscores the importance of the TAS3 ta-siRNA pathway to maize development. AB - Maize leafbladeless1 (lbl1) encodes a key component in the trans-acting short interfering RNA (ta-siRNA) biogenesis pathway. Correlated with a great diversity in ta-siRNAs and the targets they regulate, the phenotypes conditioned by mutants perturbing this small RNA pathway vary extensively across species. Mutations in lbl1 result in severe developmental defects, giving rise to plants with radial, abaxialized leaves. To investigate the basis for this phenotype, we compared the small RNA content between wild-type and lbl1 seedling apices. We show that LBL1 affects the accumulation of small RNAs in all major classes, and reveal unexpected crosstalk between ta-siRNA biogenesis and other small RNA pathways regulating transposons. Interestingly, in contrast to data from other plant species, we found no evidence for the existence of phased siRNAs generated via the one-hit model. Our analysis identified nine TAS loci, all belonging to the conserved TAS3 family. Information from RNA deep sequencing and PARE analyses identified the tasiR-ARFs as the major functional ta-siRNAs in the maize vegetative apex where they regulate expression of AUXIN RESPONSE FACTOR3 (ARF3) homologs. Plants expressing a tasiR-ARF insensitive arf3a transgene recapitulate the phenotype of lbl1, providing direct evidence that deregulation of ARF3 transcription factors underlies the developmental defects of maize ta-siRNA biogenesis mutants. The phenotypes of Arabidopsis and Medicago ta-siRNA mutants, while strikingly different, likewise result from misexpression of the tasiR-ARF target ARF3. Our data indicate that diversity in TAS pathways and their targets cannot fully account for the phenotypic differences conditioned by ta-siRNA biogenesis mutants across plant species. Instead, we propose that divergence in the gene networks downstream of the ARF3 transcription factors or the spatiotemporal pattern during leaf development in which these proteins act constitute key factors underlying the distinct contributions of the ta-siRNA pathway to development in maize, Arabidopsis, and possibly other plant species as well. PMID- 25503249 TI - Fatal juvenile xanthogranuloma presenting as a sellar lesion: case report and literature review. AB - INTRODUCTION: Juvenile xanthogranuloma (JXG) is a histiocytic condition in the spectrum of non-Langerhans histiocytosis that preferentially affects children. Rarely this condition can involve the central nervous system (CNS) with devastating consequences. METHODS: The authors report the unique case of an 11 year-old child who initially presented with a sellar lesion without evidence of the cutaneous stigmata typical of JXG. She was later discovered to have JXG following initial diagnosis of granulomatous hypophysitis, with development of widespread intracranial disease and subsequent neurological deterioration. She underwent subtotal resection of her sellar lesion followed by whole brain radiation and systemic chemotherapy; however, she succumbed to her disseminated disease within 1 month of the JXG diagnosis. CONCLUSIONS: This is a rare case of fatal disseminated intracranial JXG without cutaneous manifestations. Additionally, the initial presentation as a sellar lesion is particularly unusual and seldom described in the literature. PMID- 25503250 TI - Network-based gene expression analysis of vascular wall of juvenile Moyamoya disease. AB - SUBJECTS: Little is known about the pathology and pathogenesis of the Moyamoya disease (MMD). To better understand the molecular processes involved in MMD gene expression analysis of Moyamoya artery tissue to a control artery, this study was conducted. METHODS: Tissue samples of two MMD and two non-MMD were profiled using oligonucleotide microarrays. Gene ontology classification of the differentially expressed genes was analyzed, and regulatory functional networks and pathways were identified with a network-based computational pathway analysis tool. Analysis of MMD and control tissue revealed 104 differentially expressed genes. RESULTS: The two major significantly associated gene ontology terms was cellular development and cellular movement. Further network-based analysis showed significant interaction between RNF213 downstream gene networks and the top 3 score gene networks of MMD. Three major nodes of this network were evident in the merged network and were showing interactions with downstream network of RNF213. CONCLUSIONS: Our results demonstrate that cellular development and cellular movement in MMD are the key role of mechanisms. PMID- 25503251 TI - CX3CL1/CX3CR1 and CCL2/CCR2 chemokine/chemokine receptor complex in patients with AMD. AB - PURPOSE: The chemokine receptors CX3CR1 and CCR2 have been implicated in the development of age-related macular degeneration (AMD). The evidence is mainly derived from experimental cell studies and murine models of AMD. The purpose of this study was to investigate the association between expression of CX3CR1 and CCR2 on different leukocyte subsets and AMD. Furthermore we measured the plasma levels of ligands CX3CL1 and CCL2. METHODS: Patients attending our department were asked to participate in the study. The diagnosis of AMD was based on clinical examination and multimodal imaging techniques. Chemokine plasma level and chemokine receptor expression were measured by flow-cytometry. RESULTS: A total of 150 participants were included. We found a significantly lower expression of CX3CR1 on CD8+ T cells in the neovascular AMD group compared to the control group (p = 0.04). We found a significant positive correlation between CCR2 and CX3CR1 expression on CD8+ cells (r = 0.727, p = 0.0001). We found no difference in plasma levels of CX3CL1 and CCL2 among the groups. CONCLUSIONS: Our results show a down regulation of CX3CR1 on CD8+ cells; this correlated to a low expression of CCR2 on CD8+ cells. Further studies are needed to elucidate the possible role of this cell type in AMD development. PMID- 25503252 TI - Developmental programming of long non-coding RNAs during postnatal liver maturation in mice. AB - The liver is a vital organ with critical functions in metabolism, protein synthesis, and immune defense. Most of the liver functions are not mature at birth and many changes happen during postnatal liver development. However, it is unclear what changes occur in liver after birth, at what developmental stages they occur, and how the developmental processes are regulated. Long non-coding RNAs (lncRNAs) are involved in organ development and cell differentiation. Here, we analyzed the transcriptome of lncRNAs in mouse liver from perinatal (day -2) to adult (day 60) by RNA-Sequencing, with an attempt to understand the role of lncRNAs in liver maturation. We found around 15,000 genes expressed, including about 2,000 lncRNAs. Most lncRNAs were expressed at a lower level than coding RNAs. Both coding RNAs and lncRNAs displayed three major ontogenic patterns: enriched at neonatal, adolescent, or adult stages. Neighboring coding and non coding RNAs showed the trend to exhibit highly correlated ontogenic expression patterns. Gene ontology (GO) analysis revealed that some lncRNAs enriched at neonatal ages have their neighbor protein coding genes also enriched at neonatal ages and associated with cell proliferation, immune activation related processes, tissue organization pathways, and hematopoiesis; other lncRNAs enriched at adolescent ages have their neighbor protein coding genes associated with different metabolic processes. These data reveal significant functional transition during postnatal liver development and imply the potential importance of lncRNAs in liver maturation. PMID- 25503253 TI - Water dispersible upconverting nanoparticles: effects of surface modification on their luminescence and colloidal stability. AB - We present a systematic study on the effect of surface ligands on the luminescence properties and colloidal stability of beta-NaYF4:Yb(3+),Er(3+) upconversion nanoparticles (UCNPs), comparing nine different surface coatings to render these UCNPs water-dispersible and bioconjugatable. A prerequisite for this study was a large-scale synthetic method that yields ~2 g per batch of monodisperse oleate-capped UCNPs providing identical core particles. These ~23 nm sized UCNPs display an upconversion quantum yield of ~0.35% when dispersed in cyclohexane and excited with a power density of 150 W cm(-2), underlining their high quality. A comparison of the colloidal stability and luminescence properties of these UCNPs, subsequently surface modified with ligand exchange or encapsulation protocols, revealed that the ratio of the green (545 nm) and red (658 nm) emission bands determined at a constant excitation power density clearly depends on the surface chemistry. Modifications relying on the deposition of additional (amphiphilic) layer coatings, where the initial oleate coating is retained, show reduced non-radiative quenching by water as compared to UCNPs that are rendered water-dispersible via ligand exchange. Moreover, we could demonstrate that the brightness of the upconversion luminescence of the UCNPs is strongly affected by the type of surface modification, i.e., ligand exchange or encapsulation, yet hardly by the chemical nature of the ligand. PMID- 25503254 TI - Catalytic synthesis of amides via aldoximes rearrangement. AB - Amide bond formation reactions are among the most important transformations in organic chemistry because of the widespread occurrence of amides in pharmaceuticals, natural products and biologically active compounds. The Beckmann rearrangement is a well-known method to generate secondary amides from ketoximes. However, under the acidic conditions commonly employed, aldoximes RHC=NOH rarely rearrange into the corresponding primary amides RC(=O)NH2. In recent years, it was demonstrated that this atom-economical transformation can be carried out efficiently and selectively with the help of metal catalysts. Several homogeneous and heterogenous systems have been described. In addition, protocols offering the option to generate the aldoximes in situ from the corresponding aldehydes and hydroxylamine, or even from alcohols, have also been developed, as well as a series of tandem processes allowing the access to N-substituted amide products. In this Feature article a comprehensive overview of the advances achieved in this particular research area is presented. PMID- 25503255 TI - Public insurance and timing of polysomnography and surgical care for children with sleep-disordered breathing. AB - IMPORTANCE: Although children with low socioeconomic status (SES) have increased risk for sleep-disordered breathing (SDB), their access to subspecialty care is often limited. Polysomnography (PSG) is the gold standard diagnostic test used to characterize SDB and diagnose obstructive sleep apnea; however, it is unknown whether SES impacts timeliness of obtaining PSG and surgical treatment with adenotonsillectomy (AT). OBJECTIVE: To evaluate the impact of SES on the timing of PSG, surgery with AT, and loss to follow-up for children with SDB. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort analysis conducted in tertiary outpatient pediatric otolaryngology clinics among patients newly evaluated for SDB over a 3-month period who did not have prior PSG ordered and had a minimum of 1-year follow-up. MAIN OUTCOMES AND MEASURES: Public insurance (Medical Assistance [MA]) was used as a proxy for low SES. Demographics and disposition between groups were compared using t tests and chi2 analysis. Logistic regression adjusting for disposition and insurance was used to predict loss to follow-up. Days to PSG and days to AT were evaluated using the Kaplan-Meier estimator, and the log-rank test was used to compare distribution of time to events between insurance groups. RESULTS: A total of 136 children (without PSG) were evaluated for SDB over the course of 3 months; 62 (45.6%) had MA. Polysomnography was recommended for 55 children (27 of 55 [49%] with MA vs 28 of 55 [50%] with private insurance; P > .99). After the initial visit, 24 of 55 children with PSG requested (44%) were completely lost to follow-up (9 of 27 [33%] with MA vs 15 of 28 [54%] private insurance; P = .34). Children with MA who obtained PSG experienced longer intervals between initial encounter and PSG (mean interval, 141.1 days) than privately insured children (mean interval, 49.9 days) (P = .001). For those children who ultimately underwent AT surgery after obtaining PSG (n = 14), mean (SD) time to AT was longer for children with MA (222.3 [48.2] days vs 95.2 [66.1] days; P = .001). CONCLUSIONS AND RELEVANCE: Children with public insurance experienced longer intervals from initial evaluation to PSG or surgery. Almost half of patients with PSG requested were lost to follow-up, regardless of SES. These findings suggest that PSG may be a deterrent for definitive care for all children, and particularly for children with public insurance or low SES. This study emphasizes the need to understand factors contributing to disparities surrounding delay in care with PSG and surgery for children with SDB. PMID- 25503256 TI - Should we use standard survival models or the illness-death model for interval censored data to investigate risk factors of chronic kidney disease progression? AB - BACKGROUND: In studies investigating risk factors of chronic kidney disease (CKD) progression, one may be interested in estimating factors effects on both a fall of glomerular filtration rate (GFR) below a specific level (i.e., a CKD stage) and death. Such studies have to account for the fact that GFR is measured at intermittent visit only, which implies that progression to the stage of interest is unknown for patients who die before being observed at that stage. Our objective was to compare the results of an illness-death model that handles this uncertainty, with frequently used survival models. METHODS: This study included 1,519 patients from the NephroTest cohort with CKD stages 1-4 at baseline (69% males, 59+/-15 years, median protein/creatinine ratio [PCR] 27.4 mg/mmol) and subsequent annual measures of GFR (follow-up time 4.3+/-2.7 years). Each model was used to estimate the effects of sex, age, PCR, and GFR at baseline on the hazards of progression to CKD stage 5 (GFR<15 mL/min/1.73 m2, n = 282 observed) and death (n = 168). RESULTS: For progression to stage 5, there were only minor differences between results from the different models. The differences between results were higher for the hazard of death before or after progression. Our results also suggest that previous findings on the effect of age on end-stage renal disease are more likely due to a strong impact of age on death than to an effect on progression. The probabilities of progression were systematically under estimated with the survival model as compared with the illness-death model. CONCLUSIONS: This study illustrates the advantages of the illness-death model for accurately estimating the effects of risk factors on the hazard of progression and death, and probabilities of progression. It avoids the need to choose arbitrary time-to-event and time-to-censoring, while accounting for both interval censoring and competition by death, using a single analytical model. PMID- 25503257 TI - A Pilot Study of Reasons and Risk Factors for "No-Shows" in a Pediatric Neurology Clinic. AB - Missed clinic appointments lead to decreased patient access, worse patient outcomes, and increased healthcare costs. The goal of this pilot study was to identify reasons for and risk factors associated with missed pediatric neurology outpatient appointments ("no-shows"). This was a prospective cohort study of patients scheduled for 1 week of clinic. Data on patient clinical and demographic information were collected by record review; data on reasons for missed appointments were collected by phone interviews. Univariate and multivariate analyses were conducted using chi-square tests and multiple logistic regression to assess risk factors for missed appointments. Fifty-nine (25%) of 236 scheduled patients were no-shows. Scheduling conflicts (25.9%) and forgetting (20.4%) were the most common reasons for missed appointments. When controlling for confounding factors in the logistic regression, Medicaid (odds ratio 2.36), distance from clinic, and time since appointment was scheduled were associated with missed appointments. Further work in this area is needed. PMID- 25503258 TI - Origin and elimination of photocurrent hysteresis by fullerene passivation in CH3NH3PbI3 planar heterojunction solar cells. AB - The large photocurrent hysteresis observed in many organometal trihalide perovskite solar cells has become a major hindrance impairing the ultimate performance and stability of these devices, while its origin was unknown. Here we demonstrate the trap states on the surface and grain boundaries of the perovskite materials to be the origin of photocurrent hysteresis and that the fullerene layers deposited on perovskites can effectively passivate these charge trap states and eliminate the notorious photocurrent hysteresis. Fullerenes deposited on the top of the perovskites reduce the trap density by two orders of magnitude and double the power conversion efficiency of CH(3)NH(3)PbI(3) solar cells. The elucidation of the origin of photocurrent hysteresis and its elimination by trap passivation in perovskite solar cells provides important directions for future enhancements to device efficiency. PMID- 25503259 TI - Oxidative stress in benign prostatic hyperplasia: a systematic review. AB - BACKGROUND: Several parameters including inflammatory mediators, hormones, dietary factors, inflammatory genes, and oxidative stress (OS) have been considered to play a role in the development of benign prostatic hyperplasia (BPH). Prostate tissue damage and OS may lead to compensatory cellular proliferation with resulting hyperplastic growth. METHODS: We searched MEDLINE for articles in English published up to March 2014 using the key words 'oxidative stress', 'antioxidants' and 'benign prostatic hyperplasia'. RESULTS: Prostatic inflammation can cause the generation of free radicals. The extent of oxidative damage can be exacerbated by a decreased efficiency of antioxidant defense mechanisms. The balance between OS and the antioxidant component also has a role in developing prostate disease. Several works show the role of oxidant products and of depletion of antioxidant substances in BPH patients. It is accepted that free radicals play a role in carcinogenesis and that BPH should be considered a premalignant condition which may evolve into prostate cancer. High OS parameters and low antioxidant activity are more prominent in prostate cancer patients compared with BPH and controls. CONCLUSIONS: Further studies are needed to clarify the potential role of antioxidants in BPH also in view of preventing the progression to prostate cancer. PMID- 25503260 TI - The local application of a flavonoid, (-)-epicatechin, increases the spiking of globus pallidus neurons in a dose-dependent manner and diminishes the catalepsy induced by haloperidol. AB - Flavonoids are natural substances obtained from plants. Most flavonoids cross the blood-brain barrier and exert a wide range of effects on the central nervous system. These actions have been attributed to the modulation of GABA-A receptors. Although motor systems in the central nervous system express a high density of GABA-A receptors, physiological studies about the effects of flavonoids on motor nuclei are scarce. Among the nuclei of the basal ganglia, the globus pallidus is potentially important for the processing of information related to movement. The electrical activity of globus pallidus neurons depends on the GABAergic fibers coming from the striatum and recurrent collateral fibers. It is known that the basal activity of the globus pallidus is modified by blocking dopaminergic receptors. In the present work, we analyzed the effects of the local application of a flavonoid, (-)-epicatechin, on the spiking of globus pallidus neurons in chloral hydrate-anesthetized rats and determined whether (-)-epicatechin applied bilaterally to the globus pallidus can modify the catalepsy induced by systemic administration of haloperidol. The results showed that (-)-epicatechin increased the basal firing of globus pallidus neurons in a dose-dependent manner and antagonized the inhibitory effect of GABA. Bilateral infusion of (-)-epicatechin to the globus pallidus diminished the catalepsy induced by haloperidol. PMID- 25503262 TI - Reaction sampling and reactivity prediction using the stochastic surface walking method. AB - The prediction of chemical reactivity and thus the design of new reaction systems are the key challenges in chemistry. Here, we develop an unbiased general-purpose reaction sampling method, the stochastic surface walking based reaction sampling (SSW-RS) method, and show that the new method is a promising solution for reactivity prediction of complex reaction systems. The SSW-RS method is capable of sampling both the configuration space of the reactant and the reaction space of pathways, owing to the combination of two recently developed theoretical methods, namely, the stochastic surface walking (SSW) method for potential energy surface (PES) exploration and the double-ended surface walking (DESW) method for building pathways. By integrating with first principles calculations, we show that the SSW-RS method can be applied to investigate the kinetics of complex organic reactions featuring many possible reaction channels and complex hydrogen bonding networks, as demonstrated here using two examples, epoxypropane hydrolysis in aqueous solution and beta-d-glucopyranose decomposition. Our results show that simultaneous sampling of the soft hydrogen-bonding conformations and the chemical reactions involving hard bond making/breaking can be achieved in the SSW-RS simulation, and the mechanism and kinetics can be predicted without a priori information on the system. Unexpected new chemistry for these reactions is revealed and discussed. In particular, despite many possible pathways for beta-d-glucopyranose decomposition, the SSW-RS shows that only beta-d-glucose and levoglucosan are kinetically preferred direct products and the 5- or 7-member ring products should be secondary products derived from beta-d-glucose or levoglucosan. As a general tool for reactivity prediction, the SSW-RS opens a new route for the design of rational reactions. PMID- 25503261 TI - 5-HT1A receptor-dependent control of nigrostriatal dopamine neurotransmission in the pharmacotherapy of Parkinson's disease and schizophrenia. AB - Dysfunctions of the basal ganglia are associated with a number of neurological and psychiatric conditions including Parkinson's disease and schizophrenia. Current treatments of these disorders are mostly symptomatic and inadequate, and are often associated with a number of unwanted side-effects. The striatum, the terminal region of the nigrostriatal dopamine pathway, is the main input nucleus of the basal ganglia, and dopamine neurotransmission through the nigrostriatal pathway plays a crucial role in the modulation of basal ganglia output and mediated behaviors. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the modulation of dopamine neurotransmission and in improving pharmacotherapy in schizophrenia and Parkinson's disease. This review concerns the role of 5-HT1A receptors in the modulation of nigrostriatal dopamine neurotransmission, with the aim of providing guidelines for future research to improve pharmacotherapy. The current state of knowledge suggests that drugs simultaneously targeting dopamine D2 and 5-HT1A receptors may improve pharmacotherapy for schizophrenia and Parkinson's disease. Activation of somatodendritic 5-HT1A receptors in the dorsal raphe nucleus has an important role in the alleviation of extrapyramidal symptoms and levodopa-induced dyskinesia induced by antipsychotic treatment. Drugs acting exclusively through dopamine D2 and 5-HT1A receptors are highly needed to validate the potential role of 5-HT1A receptors in improving therapeutics for Parkinson's disease and schizophrenia. PMID- 25503263 TI - Moderate inappropriately high aldosterone/NaCl constellation in mice: cardiovascular effects and the role of cardiovascular epidermal growth factor receptor. AB - Non-physiological activation of the mineralocorticoid receptor (MR), e.g. by aldosterone under conditions of high salt intake, contributes to the pathogenesis of cardiovascular diseases, although beneficial effects of aldosterone also have been described. The epidermal growth factor receptor (EGFR) contributes to cardiovascular alterations and mediates part of the MR effects. Recently, we showed that EGFR is required for physiological homeostasis and function of heart and arteries in adult animals. We hypothesize that moderate high aldosterone/NaCl, at normal blood pressure, affects the cardiovascular system depending on cardiovascular EGFR. Therefore we performed an experimental series in male and female animals each, using a recently established mouse model with EGFR knockout in vascular smooth muscle cells and cardiomyocytes and determined the effects of a mild-high aldosterone-to-NaCl constellation on a.o. marker gene expression, heart size, systolic blood pressure, impulse conduction and heart rate. Our data show that (i) cardiac tissue of male but not of female mice is sensitive to mild aldosterone/NaCl treatment, (ii) EGFR knockout induces stronger cardiac disturbances in male as compared to female animals and (iii) mild aldosterone/NaCl treatment requires the EGFR in order to disturb cardiac tissue homeostasis whereas beneficial effects of aldosterone seem to be independent of EGFR. PMID- 25503265 TI - Drug resistance and plasma viral RNA level after ineffective use of oral pre exposure prophylaxis in women. AB - BACKGROUND: Pre-exposure prophylaxis (PrEP) with daily oral emtricitabine (FTC)/tenofovir disoproxil fumarate may select for drug resistance if there is low adherence. METHODS: Plasma viral HIV-1 RNA level, CD4+ T-cell counts, and drug resistance were evaluated among seroconverting women in the FEM-PrEP trial (clinicaltrials.gov NCT00625404) using standard clinical tests, allele-specific PCR (ASPCR), and by deep sequencing. Tenofovir, FTC, and their intracellular metabolites were measured in plasma and cells. RESULTS: There was no difference in plasma HIV-1 RNA level or CD4+ cell count among seroconverters in the active arm versus those receiving placebo. Tenofovir resistance was not observed. FTC resistance was detected using clinical assays in five seroconverters (four in the active arm and one in the placebo arm); two in the active arm occurred among women having moderate concentrations of PrEP drugs in the blood. The first evidence of infection occurred at the first postenrollment visit in three of the four with FTC resistance, although none had detectable viral nucleic acids at enrollment. FTC-resistant minor variants were detected in an additional four seroconverters (one in the active arm and three in the placebo arm). CONCLUSIONS: Drug resistance detected during ineffective PrEP use had characteristics suggesting transmitted infection or incubating infection prior to starting PrEP. PMID- 25503266 TI - ESMO 2014: new trends in precision medicine. PMID- 25503264 TI - Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection. AB - HIV/SIV infections break down the integrity of the gastrointestinal mucosa and lead to chronic immune activation and associated disease progression. Innate lymphoid cells (ILCs), distinguishable by high expression of NKp44 and RORgammat, play key roles in mucosal defense and homeostasis, but are depleted from gastrointestinal (GI) tract large bowel during chronic SIV infection. However, less is known about the kinetics of ILC loss, or if it occurs systemically. In acute SIV infection, we found a massive, up to 8-fold, loss of NKp44+ILCs in all mucosae as early as day 6 post-infection, which was sustained through chronic disease. Interestingly, no loss of ILCs was observed in mucosa-draining lymph nodes. In contrast, classical NK cells were not depleted either from gut or draining lymph nodes. Both ILCs and NK cells exhibited significantly increased levels of apoptosis as measured by increased Annexin-V expression, but while classical NK cells also showed increased proliferation, ILCs did not. Interestingly, ILCs, which are normally noncytolytic, dramatically upregulated cytotoxic functions in acute and chronic infection and acquired a polyfunctional phenotype secreting IFN-gamma, MIP1-beta, and TNF-alpha, but decreased production of the prototypical cytokine, IL-17. Classical NK cells had less dramatic functional change, but upregulated perforin expression and increased cytotoxic potential. Finally, we show that numerical and functional loss of ILCs was due to increased apoptosis and ROR gammat suppression induced by inflammatory cytokines in the gut milieu. Herein we demonstrate the first evidence for acute, systemic, and permanent loss of mucosal ILCs during SIV infection associated with reduction of IL-17. The massive reduction of ILCs involves apoptosis without compensatory de novo development/proliferation, but the full mechanism of depletion and the impact of functional change so early in infection remain unclear. PMID- 25503267 TI - FOXO1-mediated epigenetic modifications are involved in the insulin-mediated repression of hepatocyte aquaporin 9 expression. AB - Aquaporin (AQP) 9 transports glycerol and water, and belongs to the aquaglyceroporin subfamily. Insulin acts as a negative regulator of AQP9, and FOXO1 has the ability to mediate the regulatory effects of insulin on target gene expression. The aim of the present study was to determine whether insulin-induced repression of AQP9 involved an epigenetic mechanism. HepG2 human hepatocyte cells were treated with 500 uM insulin for different durations. AQP9 mRNA expression levels were determined by quantitative polymerase chain reaction (qPCR), and histone H3 acetylation, phosphorylation and methylation at the insulin responsive element (IRE) of the AQP9 promoter was assessed using chromatin immunoprecipitation coupled with qPCR. The effects of lentiviral FOXO1 overexpression on AQP9 expression levels and H3 modifications at the AQP9 promoter were also determined. The insulin treatment resulted in a significant and time-dependent reduction in AQP9 mRNA expression levels in HepG2 cells, as compared with untreated cells (P<0.05). In the insulin-treated cells, the levels of H3 acetylation and phosphorylation were significantly reduced (P<0.05), but the level of H3 methylation was increased. Enforced expression of FOXO1 increased AQP9 mRNA and protein expression levels in HepG2 cells. Furthermore, FOXO1 overexpression promoted H3 acetylation and phosphorylation, and reduced H3 methylation at the IRE locus of the AQP9 promoter. These data provide, to the best of our knowledge, the first evidence that insulin-induced transcriptional suppression of AQP9 expression in hepatocytes involves FOXO1-mediated H3 modifications at the IRE locus in the promoter. PMID- 25503268 TI - Recycling gene carrier with high efficiency and low toxicity mediated by L cystine-bridged bis(beta-cyclodextrin)s. AB - Constructing safe and effective gene delivery carriers is becoming highly desirable for gene therapy. Herein, a series of supramolecular crosslinking system were prepared through host-guest binding of adamantyl-modified low molecular weight of polyethyleneimine with L-cystine-bridged bis(beta cyclodextrin)s and characterized by (1)H NMR titration, electron microscopy, zeta potential, dynamic light-scattering, gel electrophoresis, flow cytometry and confocal fluorescence microscopy. The results showed that these nanometersized supramolecular crosslinking systems exhibited higher DNA transfection efficiencies and lower cytotoxicity than the commercial DNA carrier gold standard (25 kDa bPEI) for both normal cells and cancer cells, giving a very high DNA transfection efficiency up to 54% for 293T cells. Significantly, this type of supramolecular crosslinking system possesses a number of enzyme-responsive disulfide bonds, which can be cleaved by reductive enzyme to promote the DNA release but recovered by oxidative enzyme to make the carrier renewable. These results demonstrate that these supramolecular crosslinking systems can be used as promising gene carriers. PMID- 25503270 TI - Sacred spaces, healing places: therapeutic landscapes of spiritual significance. AB - Understandings of the relationship between space, culture and belief are formative in the experience of seeking healing. This paper examines the relationship between place, healing and spirituality in the context of interdisciplinary perspectives (particularly those of the medical humanities) on healing and well-being. The paper examines places of spiritual significance and their relationship to healing in the 'uncertain' quest for alleviation or cure, exploring these thematics in the context of the work on the geographies of 'therapeutic landscapes.' Through a discussion of fieldwork at two sites in Perthshire, Scotland, a framework is proposed for the investigation of therapeutic sites of spiritual significance, detailing features such as connection, renewal, reproduction, participation, alleviation and expectation. A deeper examination of sites of healing with spiritual significance, it is proposed, has the potential to develop greater understandings of the ways in which people experience illness and well-being. PMID- 25503269 TI - New energy geographies: a case study of yoga, meditation and healthfulness. AB - Beginning with a routine day in the life of a practitioner of yoga and meditation and emphasising the importance of nurturing, maintaining and preventing the dissipation of diverse 'energies', this paper explores the possibilities for geographical health studies which take seriously 'new energy geographies'. It is explained how this account is derived from in-depth fieldwork tracing how practitioners of yoga and meditation find times and spaces for these practices, often in the face of busy urban lifestyles. Attention is paid to the 'energy talk' featuring heavily in how practitioners describe the benefits that they perceive themselves to derive from these practices, and to claims made about 'energies' generated during the time-spaces of these practices which seemingly flow, usually with positive effects, into other domains of their lives. The paper then discusses the implications of this energy talk in the context of: (a) critically reviewing conventional approaches to studying 'energy geographies'; (b) identifying an alertness to the likes of 'affective energies' surfacing in recent theoretically-attuned works of human geography (and cognate disciplines); and (c) exploring differing understandings of energy/energies extant in geographical studies of health and in step with the empirical research materials presented about yoga, meditation and healthfulness. While orientated towards explicitly geographical inquiries, the paper is intended as a statement of interest to the wider medical humanities. PMID- 25503272 TI - Syntheses of arabinose-derived pyrrolidine catalysts and their applications in intramolecular Diels-Alder reactions. AB - Six chiral hydroxylated pyrrolidine catalysts were synthesized from commercially available D-arabinose in seven steps. Various aromatic substituents alpha to the amine can be introduced readily by a Grignard reaction, which enables facile optimization of the catalyst performance. The stereoselectivities of these catalysts have been assessed by comparing with those of MacMillan's imidazolidinone in a known intramolecular Diels-Alder (IMDA) reaction of a triene. Two additional IMDA reactions of symmetrical dienals with concomitant desymmetrisation further established the potential use of these novel amine catalysts. These pyrrolidines are valuable catalysts for other synthetic transformations. PMID- 25503271 TI - Impact of MIF gene promoter polymorphism on F508del cystic fibrosis patients. AB - Macrophage migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine sustaining the acute response to gram-negative bacteria and a regulatory role for MIF in Cystic Fibrosis has been suggested by the presence of a functional, polymorphic, four-nucleotide repeat in this gene's promoter at position -794, with the 5-repeat allele displaying lower promoter activity. We aimed at assessing the association of this polymorphism with disease severity in a group of Cystic Fibrosis patients homozygous for F508del CFTR gene mutation. Genotype frequencies were determined in 189 Cystic Fibrosis and 134 control subjects; key clinical features of patients were recorded and compared among homozygous 5 allele patients and the other MIF genotypes. Patients homozygous for the 5-repeat allele of MIF promoter displayed a slower rate of lung function decline (p = 0.027) at multivariate survival analysis. Multiple regression analysis on age normalized respiratory volume showed no association of the homozygous 5-repeat genotype with lung function under stable conditions and no correlation with P.aeruginosa chronic colonization. Therefore, only the Homozygous 5-repeat genotype at MIF -794 is associated with milder disease in F508del Cystic Fibrosis patients. PMID- 25503273 TI - Formulation development and in vivo hepatoprotective activity of self nanoemulsifying drug delivery system of antioxidant coenzyme Q10. AB - Coenzyme Q10 (CQ10) is known as an endogenous cellular antioxidant, naturally found in every cell of the human body and plays an important role in maintaining human health. It is widely used as a nutritional supplement and pharmaceutical drug for various disorders like diabetes mellitus, carcinomas, neurodegenerative disorders etc. However, CQ10 is practically insoluble even in the presence of 5 % sodium lauryl sulfate in water and poorly absorbed from the gastrointestinal tract. The present research is aimed to formulate and evaluate self nanoemulsifying drug delivery system (SNEDDS) of CQ10 primarily to improve its aqueous solubility, dissolution velocity as well as hepatoprotective activity and thus enhancing its nutraceutical and pharmaceutical values. Robustness to dilution, thermodynamic stability study, droplet size analysis and drug release were adopted to optimize liquid SNEDDS. Droplet size of the SNEDDS was found to be size less than 200 nm and appeared round in shape without aggregation under transmission electron microscopy examination. Liquid SNEDDS were adsorbed on porous carrier to get solid SNEDDS (S-SNEDDS). S-SNEDDS gave rapid (>90 %) drug release within 30 min while pure drug was not practically dissolved within 1 h. In vivo hepatoprotective activity showed that S-SNEDDS achieved the most liver protection as compared to the pure drug. Further S-SNEDDS was successfully converted to self nanoemulsifying mouth dissolving tablet. The enhanced solubility, dissolution velocity as well as hepatoprotective activity of CQ10, unravels the potential of S-SNEDDS as suitable carrier for enhancing nutraceutical and pharmaceutical values of CQ10. PMID- 25503274 TI - The role of membrane-mediated interactions in the assembly and architecture of chemoreceptor lattices. AB - In vivo fluorescence microscopy and electron cryo-tomography have revealed that chemoreceptors self-assemble into extended honeycomb lattices of chemoreceptor trimers with a well-defined relative orientation of trimers. The signaling response of the observed chemoreceptor lattices is remarkable for its extreme sensitivity, which relies crucially on cooperative interactions among chemoreceptor trimers. In common with other membrane proteins, chemoreceptor trimers are expected to deform the surrounding lipid bilayer, inducing membrane mediated anisotropic interactions between neighboring trimers. Here we introduce a biophysical model of bilayer-chemoreceptor interactions, which allows us to quantify the role of membrane-mediated interactions in the assembly and architecture of chemoreceptor lattices. We find that, even in the absence of direct protein-protein interactions, membrane-mediated interactions can yield assembly of chemoreceptor lattices at very dilute trimer concentrations. The model correctly predicts the observed honeycomb architecture of chemoreceptor lattices as well as the observed relative orientation of chemoreceptor trimers, suggests a series of "gateway" states for chemoreceptor lattice assembly, and provides a simple mechanism for the localization of large chemoreceptor lattices to the cell poles. Our model of bilayer-chemoreceptor interactions also helps to explain the observed dependence of chemotactic signaling on lipid bilayer properties. Finally, we consider the possibility that membrane-mediated interactions might contribute to cooperativity among neighboring chemoreceptor trimers. PMID- 25503277 TI - Direct detection of microRNA based on plasmon hybridization of nanoparticle dimers. AB - MicroRNAs (miRNA) are important for regulating a range of biochemical pathways. Abnormal levels of miRNA in cells or secreted into biological fluids have been identified in diseases. MiRNA can therefore be potential biomarkers for early disease diagnosis; however their detection and quantification are challenging. Herein we apply the sensing platform of discrete actuatable dimers for the detection of human miR-210 (hsa-miR-210-3p). The detection signal is a spectral blue shift in the hybridized plasmon mode as monitored by single-nanostructure spectroscopy. We investigate the specificity and detection limit of the platform and quantify miR-210 levels in RNA extracts of cells cultured under different oxygen tensions. In addition we demonstrate the feasibility of detection in complex media by examining miR-210 secreted in cell media. This sensing platform may be developed as a bioanalytical tool for validating miRNA profiles of biological fluids. PMID- 25503275 TI - An immunohistochemical marker panel including claudin-18, maspin, and p53 improves diagnostic accuracy of bile duct neoplasms in surgical and presurgical biopsy specimens. AB - Biliary tract cancers have an extremely poor outcome, and specific diagnostic markers and effective treatments are needed urgently. In this study, we assessed the capacity of panel of immunohistochemical markers including claudin-18, maspin, and p53 to distinguish biliary tract carcinoma and biliary intraepithelial neoplasia (BilIN) from non-neoplastic epithelium. We performed a retrospective study of 66 biliary tract cancer specimens and 63 specimens with non-neoplastic lesions. Of the surgical specimens, 96.7 % with adenocarcinoma/BilIN were detected as neoplastic, and all 63 specimens histologically diagnosed as non-neoplastic lesion were detected as non-neoplastic with high sensitivity (91.1 %) and specificity (100 %). Of presurgical endobiliary forceps biopsy specimens, all with adenocarcinoma/BilIN and only 1 of the 19 with a non-neoplastic lesion were distinguished as neoplastic with high sensitivity (100 %) and specificity (94.7 %). Moreover, this panel provided good separation of neoplasm from malignancy-undetermined atypical epithelium (18/21, 85.7 %). This panel achieves a more reliable distinction of biliary tract cancers and BilINs from non-neoplastic epithelia in both surgical and biopsy specimens than immunohistochemical analysis with single antibodies and is useful in supporting a diagnosis of adenocarcinoma and BilIN. PMID- 25503278 TI - Intimate partner violence against women in Nepal: an analysis through individual, empowerment, family and societal level factors. AB - BACKGROUND: The current study estimated the national prevalence rate of intimate partner violence against women (IPVAW) in Nepal. Besides, the individual level, empowerment level, family and societal level factors were assessed to relate with the victims of IPAVW in Nepal. METHODS: Nationally representative sample of 4210 women of reproductive age (15-49 yr) were included in the study. Household surveys using two stage sampling procedures, face to face interview with pre tested questionnaires were performed. Emotional, physical and sexual violence were target variables. A violence variable was constructed from these three types of violence. Individual level factors were measured by age, residency, education, religion and husband's education. Empowerment factors included employment status and various decision making elements. Family and societal factors included economic status, neighborhood socioeconomic disadvantage index, history of family violence, husband's controlling behavior and other issues. Cross tabulation with chi-square tests and multivariate logistic regression were employed. RESULTS: Prevalence of emotional IPVAW was 17.5%, physical IPAVW 23.4% and sexual IPAVW 14.7%. Overall the prevalence of IPVAW in Nepal was 32.4%. Joint decision making for contraception, husband's non-controlling behavior to wives and friendly feelings were emerged as less likely to be IPVAW perpetration. CONCLUSIONS: The findings have immense policy importance as a nationally representative study and indicating necessity of more gender equality. PMID- 25503276 TI - First emergence of acrAB and oqxAB mediated tigecycline resistance in clinical isolates of Klebsiella pneumoniae pre-dating the use of tigecycline in a Chinese hospital. AB - Tigecycline is one of the few therapeutic options for treating infections caused by some multi-drug resistant pathogens, such as Klebsiella pneumoniae. However, tigecycline-resistant K. pneumoniae has been discovered recently in China. From 2009 to 2013, nine tigecycline-resistant K. pneumoniae isolates were identified in our hospital. Six of nine strains were identified before using tigecycline. To investigate the efflux-mediated resistance mechanisms of K. pneumoniae, the expression of efflux pump genes (acrA, acrB, tolC, oqxA and oqxB) and pump regulators (acrR, marA, soxS, rarA, rob and ramA) were examined by real-time RT PCR. Molecular typing of the tigecycline resistant strains was performed. ST11 was the predominant clone of K. pneumoniae strains, while ST1414 and ST1415 were novel STs. Efflux pump inhibitor (EPI)-carbonyl cyanide chlorophenylhydrazone (CCCP) was able to reverse the resistance patterns of 5 resistant K. pneumoniae strains. In comparison with strain A111, a tigecycline-susceptible strain (negative control), we found that the expression levels of efflux pump genes and pump regulators were higher in a majority of resistant strains. Higher expression levels of regulators rarA (2.41-fold, 9.55-fold, 28.44-fold and 18.31-fold, respectively) and pump gene oqxB (3.87-fold, 31.96-fold, 50.61-fold and 29.45 fold, respectively) were observed in four tigecycline resistant strains (A363, A361, A368, A373, respectively). Increased expression of acrB was associated with ramA and marA expression. To our knowledge, studies on tigecycline resistance mechanism in K. pneumoniae are limited especially in China. In our study, we found that both efflux pump AcrAB-TolC and OqxAB contributed to tigecycline resistance in K. pneumoniae isolates. PMID- 25503279 TI - High prevalence of type 2 diabetes melitus and its risk factors among the rural population of Pondicherry, South India. AB - BACKGROUND: We aimed to assess the prevalence of type-2 diabetes in rural Pondicherry and to study the determinants of Diabetes Mellitus (DM) in the rural population of Pondicherry, south Induia. METHODS: It was a cross-sectional community-based study conducted from November 2010 to January 2012 in two of the field practice villages affiliated to a Medical College in Pondicherry. Sample size was calculated using open source software, Open Epi Version 2.3.10. The sampling frame comprised individuals aged above 25 years and single stage cluster random sampling was carried out. After obtaining the verbal informed consent each of the study participants were interviewed face-to-face using a pre-tested structured questionnaire. Data were analyzed using the SPSS version 16. RESULTS: The age of the study participants ranged from 25 to 98 years with mean of 42.6 (+/-13.7) and majority of the study participants 339 (32.5%) from the age-group of 30-39 years. The prevalence of diabetes was 19.8% (60-69 years), 17.1% (40-49 years), 16.8% (50-59 years), and 13.6% (>69 years) among study subjects. In univariate analysis, higher age, being educated, unemployed and poor was associated with higher risk of diabetes mellitus (DM). Furthermore, a high triglyceride level was significantly associated with increase in the risk of DM (adjusted odds ratio: 3.01; 95% CI: 1.86, 4.86). CONCLUSIONS: Type-2 diabetes mellitus (T2DM) is an important public health problem in the adults of rural Pondicherry. Among non-modifiable factors, higher age, better socio-educational background and positive family history of diabetes was significantly associated with T2DM. PMID- 25503280 TI - The effect of six-week aerobic training program on cardiovascular fitness, body composition and mental health among female students. AB - BACKGROUND: The purpose of the present study was to evaluate the effects of six week aerobic training program including running and rope skipping on cardiovascular fitness, body mass index (BMI), and mental health among female students at the University of Isfahan, Iran. METHODS: In this interventional study we included 30 female students in academic year 2011-12. The participants were randomly assigned in experimental group (n=15, mean+/-SD for age=26.06+/ 1.18, weight (kg)=57.43+/-5.67, height (cm)=160.06+/-4.16) and control group (n=15, mean+/-SD for age=26.33+/-1.30, weight=57.66+/-5.08, height=161.86+/ 3.29). Pre-test and post-test measurements include VO2 max with Queen Step test; BMI and General Health Questionnaire-28 as a measure of mental health were done. Analysis of covariance (ANCOVA) was used to test the effects of aerobic training as intervention (P<0.05). RESULTS: There was statistically significance difference between experimental and control groups after adjustment for their own baseline values concerning cardiovascular fitness (P=0.004), BMI (P<0.001) and mental health indices (P<0.001). CONCLUSIONS: A six-week aerobic practice improves cardiovascular strength, mental health and BMI considerably and could be more encouraged at universities. PMID- 25503281 TI - Prevalence of Hookah smoking in relation to religiosity and familial support in college students of Tabriz, northwest of Iran. AB - BACKGROUND: Hookah smoking has increased worldwide especially among youth and young adults and has been identified as an emerging threat to public health. The aim of the present study was to determine the prevalence of hookah use and related factors in a sample of Iranian college students. METHODS: This study took place in Tabriz (northwest of Iran) in April and May 2011. The randomly selected sample consisted of 1837 college students. Data was collected in a survey. A self administered questionnaire was used to measure religious belief, parental support and risk taking behaviors including hookah smoking. Logistic regression model was performed in data analysis. RESULTS: The prevalence of hookah smoking was 8.5% (CI95%: 7.3-9.9). After adjustment, being male (OR= 2.01), living in single house in comparison with living with parents (OR= 2.22), smoking (OR= 5.96) and ever drug abuse (OR= 3.02) were factors associated with students' hookah use. CONCLUSIONS: Our results showed a low prevalence of hookah smoking in Iranian college female students and revealed some of its associated factors. We demonstrated the co-occurrence of risky behaviors which emphasizes the importance of interventions aimed at reducing or preventing different high risk behaviors simultaneously. PMID- 25503282 TI - The application of network scale up method on estimating the prevalence of some disabilities in the southeast of Iran. AB - BACKGROUND: More than a billion people have some form of disabilities worldwide. Persons living with a disability have many needs (including physically, mentally, and socially needs). Estimating the size of disabled population is a challenge in health systems. An innovative indirect method to estimate the size of populations is network scale up (NSU) having widely used for hidden populations. The method is based-on the social network of individuals. We assessed the capability of NSU to estimate persons living with a disability being a middle population (neither non-hidden nor hidden populations) in the Southeast of Iran (Kerman City, southeast Iran). METHODS: A total of 3052 of Kermanian people over 20 year old were interviewed by simple random sampling. We asked them whether they knew acquaintances with complete blindness, severe visual impairment, deafness, severe hearing impairment, limb defects, and mental retardation, if yes; we wanted them to count them. RESULTS: Based on the network scale up method, the prevalence of the populations was estimated at 5.21/1000 in Kerman City where severe visual impairment was 1.35, mental retardation was 1.039, severe hearing impairment was 1.005, limb defects was 0.78, deafness was 0.59, and complete blindness was 0.56 (per 1000 inhabitants). CONCLUSIONS: The results were not exactly comparable to previous studies using different methods such as surveys. Although the method has some limitations, considering its easiness and cost-effectiveness, modified NSU could be used when direct methods are not practicable. PMID- 25503283 TI - The discriminatory performance of body mass index, waist circumference, waist-to hip ratio and waist-to-height ratio for detection of metabolic syndrome and their optimal cutoffs among Iranian adults. AB - BACKGROUND: The superiority of either of body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) for prediction of metabolic syndrome (MetS) is remained controversial in Asian population. The objective of this study was to compare the discriminative capacity of either of these measures in prediction of non-adipose components of MetS. METHODS: In this population-based cross sectional study, 1000 representative samples of adults were recruited in Babol, northern Iran. The demographic, anthropometric measures and blood pressure were determined by standard method. Fasting plasma glucose (FPG), triglycerides (TG), total cholesterol (CHL), high density lipoprotein (HDL) cholesterol levels were measured with enzymatic methods by an auto analyzer. The presence of two or more any of four non-obese components were considered as MetS. RESULTS: The diagnostic accuracies (AUCs) of four different measures were rather similar. While AUC for BMI (AUC=0.684; 95% CI: 0.633, 0.736) slightly tended to be higher than that of WC (AUC=0.640; 95% CI: 0.587, 0.693) and WHtR (AUC=0.649; 95% CI: 0.596, 0.701) in men but the accuracy of WC (equivalently WHtR (AUC=0.708; 95% CI: 0.664, 0.751) is tended to be greater than that of BMI in women. The optimal cut-off value for WC was higher in men compared with women. CONCLUSIONS: Overall, BMI, WC and WHtR were significant predictors of MetS equally but WC (equivalently WHtR) was a better predictor than BMI and WHR in women. The optimal cut-offs of WC are lower compared with western population for men but not for women. PMID- 25503284 TI - The effects of prioritize inspections on occupational health hazards control in workplaces in Iran. AB - BACKGROUND: Iran, a newly industrializing country in Middle East, has a workforce of 25 million people. Most employees are working in agriculture, manufacturing, services, construction, commerce sectors, carpet weaving and mining. This article aims to explore the improvement of occupational harmful agents in workplaces due to implement "prioritize inspections". METHODS: In 2012, the system of "prioritize inspections "was defined for surveillance on enterprises replace of routine inspection. From this system, the enterprises classified on four groups based on health hazards and enterprises with high risk were under more surveillance. The information about each enterprise was collected by health centers, in five provinces and reported by a recommended form to Centre of Environmental and Occupational Health (CEOH). At this program, the inspections from high and medium hazards were increased in all of provinces. RESULTS: The results showed there was a significant difference between the control of health hazards in before and after beginning of "prioritize inspections"(P=0.048). The control of noise, fumes and providing of proper illumination increased from 8 to 10%, 9 to 9.5%, 12.9 to 15.4%, respectively, at under study provinces in 2012 compared to 2011. CONCLUSIONS: The surveillance based on "prioritize inspections" increased the quality of occupational health inspections that causes to prevent occupational health diseases. PMID- 25503285 TI - An intervention for noise control of blast furnace in steel industry. AB - BACKGROUND: Noise pollution is currently a major health risk factor for workers in industries. The aim of this study was to investigate noise pollution and implement a control intervention plan for blast furnace in a steel industry. METHODS: The measurement of sound pressure level (SPL) along with frequency analysis was done with the sound-level-meter Cell-450. Personal noise exposure was performed using dosimeter TES-1345 calibrated with CEL-282. Before planning noise controls, acoustic insulation properties of the furnace control unit and workers' rest room were assessed. Control room and workers' rest room were redesigned in order to improve acoustical condition. RESULTS: The SPL before intervention around the Blast Furnace was 90.3 dB (L) and its dominant frequency was 4000 Hz. Besides, noise transmission loss of the control and rest rooms were 10.3 dB and 4.2 dB, respectively. After intervention, noise reduction rates in the control and rest rooms were 27.4 dB and 27.7 dB, respectively. The workers' noise dose before and after the intervention was 240% and less than 100%, respectively. CONCLUSIONS: Improvement the workroom acoustic conditions through noise insulation can be considered effective method for preventing workers exposure to harmful noise. PMID- 25503286 TI - Predictors of treatment retention in a major methadone maintenance treatment program in iran: a survival analysis. AB - BACKGROUND: To identify correlates related to retention time of a cohort study of the opioid-dependent patients participating in the Methadone Maintenance Treatment (MMT) program offered by a major addiction treatment clinic in Tehran, Iran between April 2007 and March 2011. METHODS: Several parametric Survival models assuming Weibull, Log-normal and Log-logistic distributions were compared to search for association between covariates and risk of relapse and dropping out of treatment among 198 patient participants. RESULTS: According to Akaike Information Criterion (AIC), Log-normal model had the best fitting. Estimates of this model indicated that increase in average methadone dosage was associated with longer retention time. Correlates associated with shorter retention time were suffering from mental disorders, using stimulant drugs, being poly-substance dependents and having prior treatments. CONCLUSIONS: Findings of this study provide support for giving more attention to patients who are poly-substance or stimulant-drug dependents, have non-substance psychiatric comorbidity and the ones with addiction treatment history. Independent of patient characteristics, retention improved as the dose of methadone increased. PMID- 25503287 TI - A structural equation model to predict the social-cognitive determinants related to physical activity in Iranian women with diabetes mellitus. AB - BACKGROUND: Lifestyle-modification programs including physical activity are essential for both treatment and prevention of Type 2 Diabetes Mellitus (T2DM). However, factors associated with physical activity among patients are poorly understood. This study applied Social-Cognitive Theory (SCT) for predicting determinants of physical activity among women with T2DM in Iran, 2013. METHODS: In this cross-sectional study, partial least square path modeling (PLS-PM) was used as an estimation technique for structural equation model. This model specified hypotheses between components of Social-cognitive Theory on physical activity behavior. A random sample of 300 women with T2DM was selected, and completed SCT constructs instrument. Data were analyzed using statistical software WarpPLS Ver. 4.0. RESULTS: The model explained 26% of the variance in physical activity. Self-regulation, task self-efficacy and barrier self-efficacy were significantly direct predictors of physical activity among women with T2DM. Task self-efficacy, social support and modeling had significantly indirect effects on physical activity behavior (P<0.001). CONCLUSIONS: Our findings showed evidence for adequacy of a theoretical framework that could be used to predict physical activity behavior among women with T2DM. PMID- 25503288 TI - Modifiable lifestyle risk factors and metabolic syndrome: opportunities for a web based preventive program. AB - BACKGROUND: Lifestyle is recognized as a key factor as the cause and management of the metabolic syndrome. The aim of this study was to identify individuals at increased cardiovascular diseases risk and determine main features of lifestyle of participants with metabolic syndrome via internet. METHODS: The study was conducted from Jun 22 to August 22, 2012 in Tehran, Iran. Recruitment was carried out through the study website. Participants with metabolic syndrome who were interested and met the study criteria were invited for free clinic visits and clinical assessments. Baseline measurements were metabolic syndrome risk factors. Physical activity and dietary intake were measured by international physical activity questionnaire (IPAQ- short form) and the frequency food questionnaire (FFQ) respectively. Metabolic syndrome was defined according to Adult Treatment Panel III diagnostic criteria. RESULTS: Mean (SD) age for men and women were 41.9 (10.4) and 48.1 (7.8) yr respectively. Men were well educated and more likely to participate in the study than women. Men with metabolic syndrome had larger waist circumference (105.5) and lower BMI (29.1) than women with metabolic syndrome (P<0.001). Approximately 73% of the sample was inactive and 3% of participants had health enhancing physical activity. There were significant differences in the intakes of total fat and cholesterol between men and women (P<0.001). CONCLUSIONS: Because of the high prevalence of metabolic syndrome, national lifestyle modification policies must be developed for population. Web-based healthy lifestyle programs may contribute to the reduction of the metabolic syndrome components. PMID- 25503290 TI - NMR assignments of actin depolymerizing factor (ADF) like UNC-60A and cofilin like UNC-60B proteins of Caenorhabditis elegans. AB - The actin filament dynamics in nematode, Caenorhabditis elegans, is regulated by differential activity of two proteins UNC-60A and UNC-60B. UNC-60A exhibits strong pointed end depolymerization on C. elegans actin (Ce-actin), strong inhibition of polymerization, strong monomer sequestering activity, weak severing activity, and low affinity for F-actin binding, while UNC-60B exhibits strong pointed end depolymerization on rabbit muscle actin, strong severing activity, and high affinity for F-actin binding. Structural characterization of these proteins will help to understand (1) molecular mechanism of actin dynamics regulation and (2) the differential activity of these proteins. Here, we report (1)H, (13)C, and (15)N chemical shift assignments of these two proteins as determined by heteronuclear NMR experiments (at pH 6.5 and temperature 298 K). PMID- 25503289 TI - Subgenotypes and mutations in the s and polymerase genes of hepatitis B virus carriers in the West Bank, palestine. AB - The mutation rate and genetic variability of hepatitis B virus (HBV) are crucial factors for efficient treatment and successful vaccination against HBV. Until today, genetic properties of this virus among the Palestinian population remain unknown. Therefore, we performed genetic analysis of the overlapping S and polymerase genes of HBV, isolated from 40 Palestinian patients' sera. All patients were HBsAg positive and presented with a viral load above 105 HBV genome copies/ml. The genotyping results of the S gene demonstrated that HBV D1 was detected in 90% of the samples representing the most prominent subgenotype among Palestinians carrying HBV. Various mutations existed within the S gene; in five patients four known escape mutations including the common G145R and D144E were found. Furthermore, a ratio of 4.25 of non-synonymous to synonymous mutations in the S gene indicated a strong selection pressure on the HBs antigen loops of HBV strains circulating in those Palestinian patients. Although all patients were treatment-naive, with the exception of one, several mutations were found in the HBV polymerase gene, but none pointed to drug resistance. The study presented here is the first report to address subgenotypes and mutation analyses of HBV S and polymerase genes in Palestine. PMID- 25503291 TI - Chemical shift assignments and secondary structure determination of the ectodomain of Bacillus subtilis morphogenic protein RodZ. AB - RodZ (also known as YfgA) is a component of the core bacterial morphogenic apparatus. RodZ is a key cell shape determinant in rod-shaped bacteria and it interacts with the actin-like cytoskeletal protein MreB. In Bacillus subtilis, this 304-residue transmembrane protein is composed of three distinct domains: a cytoplasmic domain (RodZn), a transmembrane domain, and an extra-cytoplasmic domain (RodZc). Here we report the (1)H, (13)C and (15)N backbone and side chain resonance assignments of the RodZc domain from B. subtilis by NMR spectroscopy, and the resulting secondary structure prediction. PMID- 25503292 TI - N-terminal Pro-B-type Natriuretic Peptide is Associated with Arterial Stiffness as Measured According to the Brachial-ankle Pulse Wave Velocity in Patients with Takayasu Arteritis. AB - AIM: Takayasu arteritis (TA) is associated with increased cardiovascular morbidity and mortality, and the degree of arterial stiffness is an independent predictor of cardiovascular mortality in a variety of diseases. In addition, the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of ventricular dysfunction, have been found to be higher in patients with TA than in healthy controls. In this study, we aimed to investigate the relationship between the plasma NT-proBNP levels and arterial stiffness in patients with TA. METHODS: Seventy-two patients with TA were recruited in this study. The participants were analyzed with respect to the NT-proBNP levels, cardiovascular risk factors, TA related variables and arterial stiffness assessed according to the brachial-ankle pulse wave velocity (baPWV). The patients were divided into two groups based on the mean baPWV, and the association between the NT-proBNP and baPWV values was tested using uni- and multivariate analyses. RESULTS: Twenty-four patients (33.3%) were classified into the high-baPWV group. The body mass index (p=0.035), systolic blood pressure (p<0.001), diastolic blood pressure (p=0.001), mean blood pressure (p<0.001), plasma NT-proBNP levels (p=0.036) and total cholesterol levels (p=0.030) were significantly higher in the high-baPWV group than in the low-baPWV group. A stepwise multiple linear regression analysis revealed the mean blood pressure (p<0.001), age (p=0.002), and NT-proBNP level (p=0.002) to be independent determinants of the ba-PWV after adjusting for other confounding factors. CONCLUSIONS: The plasma NT-proBNP levels are independently associated with the degree of arterial stiffness measured according to the baPWV in patients with TA. PMID- 25503293 TI - Upregulation of D site of albumin promoter binding protein in the brain of patients with intractable epilepsy. AB - The mechanisms that underlie the pathogenesis of intractable epilepsy (IE) remain to be elucidated. The present study aimed to investigate the expression of D site of albumin promoter binding protein (DBP) and mitogen-activated protein kinases (MAPKs) in the temporal lobes of patients with IE, in order to examine the possible roles of DBP in the pathogenesis of IE. The expression of DBP and MAPK was detected by immunohistochemistry and double-label immunofluorescence staining against DBP/MAPK in 35 patients with IE, and the data were compared with those of the 15 controls. The results demonstrated that DBP expression in IE group (0.31+/ 0.03) was significantly higher compared with that in the controls (0.18+/-0.02; P<0.05) and MAPK expression in the IE group (0.19+/-0.03) was also higher compared with that in the controls (0.12+/-0.02; P<0.05). DBP and MAPK were mainly expressed in the cytoplasm of neurons and the double-label immunofluorescence staining demonstrated that DBP and MAPK expression occurred in the same neurons. Therefore, the expression of DBP and MAPK in epilepsy patients was upregulated, suggesting a possible pathogenetic role in IE. PMID- 25503295 TI - Clinical epidemiology of eosinophilic pustular folliculitis: results from a nationwide survey in Japan. AB - BACKGROUND: No epidemiological study has examined the clinical characteristics, including medication use, of patients with eosinophilic pustular folliculitis (EPF). OBJECTIVE: To describe the clinical characteristics for EPF and to examine the factors associated with the effectiveness of oral indomethacin for EPF. METHODS: A cross-sectional study was performed of patients with EPF who visited the dermatology departments of the 67 main teaching facilities in Japan. We documented the patient characteristics and examined factors associated with the effectiveness of oral indomethacin. RESULTS: A total of 145 patients with EPF were enrolled; 62.8% were prescribed oral indomethacin. A multivariable analysis revealed that female patients were more likely to exhibit complete response to oral indomethacin after adjustment for confounders (adjusted proportion ratio = 1.93, p = 0.04). CONCLUSION: Oral indomethacin has been accepted as a first-line treatment in EPF. Our results suggest that there is a sex difference in the treatment response to oral indomethacin. PMID- 25503294 TI - Activation of the transforming growth factor-beta/SMAD transcriptional pathway underlies a novel tumor-promoting role of sulfatase 1 in hepatocellular carcinoma. AB - In vitro studies have proposed a tumor suppressor role for sulfatase 1 (SULF1) in hepatocellular carcinoma (HCC); however, high expression in human HCC has been associated with poor prognosis. The reason underlying this paradoxical observation remains to be explored. Using a transgenic (Tg) mouse model overexpressing Sulf1 (Sulf1-Tg), we assessed the effects of SULF1 on the diethylnitrosamine model of liver carcinogenesis. Sulf1-Tg mice show a higher incidence of large and multifocal tumors with diethylnitrosamine injection compared to wild-type mice. Lung metastases were found in 75% of Sulf1-Tg mice but not in wild-type mice. Immunohistochemistry, immunoblotting, and reporter assays all show a significant activation of the transforming growth factor-beta (TGF-beta)/SMAD transcriptional pathway by SULF1 both in vitro and in vivo. This effect of SULF1 on the TGF-beta/SMAD pathway is functional; overexpression of SULF1 promotes TGF-beta-induced gene expression and epithelial-mesenchymal transition and enhances cell migration/invasiveness. Mechanistic analyses demonstrate that inactivating mutation of the catalytic site of SULF1 impairs the above actions of SULF1 and diminishes the release of TGF-beta from the cell surface. We also show that SULF1 expression decreases the interaction between TGF beta1 and its heparan sulfate proteoglycan sequestration receptor, TGFbetaR3. Finally, using gene expression from human HCCs, we show that patients with high SULF1 expression have poorer recurrence-free survival (hazard ratio 4.1, 95% confidence interval 1.9-8.3; P = 0.002) compared to patients with low SULF1. We also found strong correlations of SULF1 expression with TGF-beta expression and with several TGF-beta-related epithelial-mesenchymal transition genes in human HCC. CONCLUSION: Our study proposes a novel role of SULF1 in HCC tumor progression through augmentation of the TGF-beta pathway, thus defining SULF1 as a potential biomarker for tumor progression and a novel target for drug development for HCC. PMID- 25503296 TI - The lack of relationship between intracranial pressure and cerebral ventricle indices based on brain computed tomography in patients undergoing ventriculoperitoneal shunt. AB - BACKGROUND: In this study we investigated whether cerebral ventricle indices based on brain computed tomography (CT) scans are reliable for predicting intracranial pressure (ICP) in hydrocephalic patients. METHODS: Electronic medical records of 221 patients undergoing ventriculoperitoneal shunt due to hydrocephalus were retrospectively reviewed. Cerebral ventricle indices including Evans' index, third ventricle index, cella media index, and ventricular score were calculated from transverse diameters measured at various levels on preoperative brain CT scans. ICP was considered as CSF opening pressure. Patients were categorized into three groups: communicating hydrocephalus, non communicating hydrocephalus, and normal pressure hydrocephalus (NPH). The non communicating hydrocephalus group was further divided according to the obstruction site; aqueduct, fourth ventricle outlet, third ventricle, and the foramen of Monro. The primary endpoint was the extent of the correlation between cerebral ventricle indices and ICP in each hydrocephalus group. RESULTS: No cerebral ventricle index correlated with ICP in patients with communicating hydrocephalus (n = 113) and NPH (n = 62). In the non-communicating hydrocephalus group (n = 46), only the third ventricle index revealed moderate negative correlation with ICP (r = -0.395, p < 0.01). In subgroup analyses, the third ventricle index showed a strong negative relationship with ICP only in patients with the third ventricle obstruction (r = -0.779, p < 0.05). CONCLUSIONS: In this study we showed that although an inverse correlation existed between ICP and the third ventricle index only in patients with non-communicating hydrocephalus due to obstruction of the third ventricle, cerebral ventricle indices based on brain CT scan were non-reliable predictors of ICP in hydrocephalic patients. PMID- 25503297 TI - Pathological characteristics of cyst formation following gamma knife surgery for arteriovenous malformation. AB - BACKGROUND: The pathological characteristics of cyst development after gamma knife surgery (GKS) for arteriovenous malformation (AVM) were analysed. METHOD: Sixteen male and 12 female patients aged 17-67 years (mean 31.3 years) were retrospectively identified among 868 patients who underwent GKS for AVM at our hospital. The pathological characteristics of the reddish nodular lesion and chronic encapsulated expanding haematoma associated with cyst following GKS for AVM were examined. RESULTS: Cyst was associated with chronic encapsulated expanding haematoma in 13, and with nodular lesion in 12 patients. The nidus volume at GKS was 0.1-36 ml (median 6.0 ml), and the prescription dose at the nidus margin was 18-25 Gy (median 20 Gy). Cyst formation was detected from 1.1 to 16 years (mean 7.3 years) after GKS. Seven of the 12 patients with nodular lesion underwent surgery. Ten of the 13 patients with expanding haematoma underwent surgical removal of expanding haematoma. Histological examination was possible in 17 cases. Dilated capillary vessels with wall damage such as hyalinisation and fibrinoid necrosis, marked protein exudation and haemorrhage were the most common findings. Brain parenchyma was observed among the dilated vessels in some cases. Structureless necrotic tissue was not evident. CONCLUSIONS: The present study suggests that enhanced nodular lesion on magnetic resonance imaging and chronic encapsulated expanding haematoma associated with cyst may have common aetiopathology caused by late radiation effects, mainly consisting of dilated capillary vessels with wall damage. Massive protein exudation from such damaged capillary vessels is important in cyst development. PMID- 25503298 TI - Long-term follow-up of incidentally discovered meningiomas. AB - BACKGROUND: Many incidental meningiomas are detected and need to be assessed for further management. Better knowledge of the long-term natural history is necessary for optimal management. METHODS: We have retrospectively evaluated a cohort of consecutive patients who were referred to the authors at the Department of Neurosurgery with incidentally diagnosed asymptomatic meningiomas from 1991 1998 and followed prospectively. All patients were followed for a minimum of 10 years or until they reached the endpoint of demonstrated tumour growth or died. RESULTS: During follow-up, 35.4 % of the tumours grew, resulting in a 75 % 15 year growth rate by life-table statistics. The growth rates were similar in smaller (<2 cm) and larger tumours, while calcified tumours grew at a lower rate. The latter difference was, however, not statistically significant. CONCLUSION: Long-term tumour growth of incidentally detected asymptomatic meningiomas appeared to be much higher than expected. This information needs to be considered when discussing surgery, since the indication for surgery may be stronger than previously stated, especially for younger patients with tumours that can be reached at low risk. PMID- 25503300 TI - Neurodevelopmental profiles of children with glutaric aciduria type I diagnosed by newborn screening: a follow-up case series. AB - Glutaric aciduria type I (GA-I) is an inherited metabolic disorder that may lead to severe motor disorder and cognitive impairment. GA-I is now included in the newborn screening programme in many countries as early detection allows for prompt treatment and effectively reduces the risk of poor developmental outcome. Information regarding the long-term neurodevelopmental outcome of children with GA-I treated early is sparse.We recruited children with a confirmed diagnosis of GA-I diagnosed via newborn screening, treated in our centre and >3 years of age (n = 6). Children were assessed at two time points using a comprehensive neuropsychological test battery. Four of these had been the subject of a previous report. All participants were male, 3-6 years at the initial assessment and 6-12 years of age at the follow-up assessment.Fine motor skills were below average in all patients. Speech, which was affected in all four patients reported previously, improved following speech therapy. IQ scores remained generally stable within the normal range. Executive functioning was average to high average in four patients. Behaviour, as assessed through parental questionnaires, was problematic in two patients. Compounding factors included child neglect, family history of autism and multiple admissions to hospital (n = 1 in each).GA-I affects fine motor skills and speech, regardless of early treatment, but not IQ scores. Patients with GA-I should be referred for assessment and appropriate early intervention. Further research is needed to correlate specific neuropsychological deficits with neuroimaging. PMID- 25503299 TI - On the split personality of penultimate proline. AB - The influence of the position of the amino acid proline in polypeptide sequences is examined by a combination of ion mobility spectrometry-mass spectrometry (IMS MS), amino acid substitutions, and molecular modeling. The results suggest that when proline exists as the second residue from the N-terminus (i.e., penultimate proline), two families of conformers are formed. We demonstrate the existence of these families by a study of a series of truncated and mutated peptides derived from the 11-residue peptide Ser(1)-Pro(2)-Glu(3)-Leu(4)-Pro(5)-Ser(6)-Pro(7) Gln(8)-Ala(9)-Glu(10)-Lys(11). We find that every peptide from this sequence with a penultimate proline residue has multiple conformations. Substitution of Ala for Pro residues indicates that multiple conformers arise from the cis-trans isomerization of Xaa(1)-Pro(2) peptide bonds as Xaa-Ala peptide bonds are unlikely to adopt the cis isomer, and examination of spectra from a library of 58 peptides indicates that ~80% of sequences show this effect. A simple mechanism suggesting that the barrier between the cis- and trans-proline forms is lowered because of low steric impedance is proposed. This observation may have interesting biological implications as well, and we note that a number of biologically active peptides have penultimate proline residues. PMID- 25503301 TI - Effect of optical clearing agents on optical coherence tomography images of cervical epithelium. AB - Optical coherence tomography (OCT) can be used as an adjunct to colposcopy in order to detect precancerous and cancerous cervical lesions. Optical clearing agents (OCAs) temporarily reduce the optical scattering of biological tissues. The purpose of this study was to investigate their influence on OCT imaging. OCT images were taken from unsuspicious and suspicious areas of fresh conization specimens immediately after resection and 5, 10, and 20 min after application of dimethyl sulfoxide (DMSO) or polyethylene glycol (PEG). Corresponding histologies were obtained from all sites. The images taken 5, 10, and 20 min after application of OCA were compared to the initial images with respect to changes in brightness, contrast, and scanning depth using a standard nonparametric test of differences of proportions. Further, mean intensity backscattering curves were calculated from all OCT images in the histological groups CIN2, CIN3, inflammation, and normal epithelium. Mean difference profiles within each of these groups were determined, reflecting the mean differences between the condition before the application of OCA and the exposure times 5, 10, and 20 min, respectively. The null hypothesis was tested employing the Dicky-Fuller-test, Hotelings-test and run test. The visual analysis of 434 OCT images from 109 different sites of 24 conization specimens showed a statistically significant increase in brightness and contrast for normal and dysplastic epithelium after application of DMSO or PEG. Further, the analysis of mean intensity profiles suggests the existence of an increased backscattering intensity after application of DMSO or PEG. DMSO and PEG contribute substantially to optical clearing in cervical squamous epithelium and therefore influence OCT imaging in a positive way. With further refinement of the OCT technology, the observed changes may be beneficial in interpreting the tissue microstructure and identifying cervical intraepithelial neoplasia. PMID- 25503302 TI - Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study. AB - Targeting specific molecular alterations in glioblastoma (GBM) might more effectively kill tumor cells and increase survival. Vandetanib inhibits epidermal growth factor receptor and vascular endothelial growth factor receptor 2. Sirolimus inhibits mammalian target of rapamycin (mTOR), a member the phosphoinositide 3-Kinase signaling pathway. We sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vandetanib combined with sirolimus. Twenty-two patients (14 men; 8 women) with recurrent GBM enrolled. Median age and KPS were 52.5 years and 90 %, respectively. Patients were naive to anti-VEGF and anti-EGF therapy and mTOR inhibitors, and not on CYP3A4-inducing drugs. Vandetanib and sirolimus were orally administered on a continuous daily dosing schedule in escalating dose cohorts. Ten patients enrolled in the dose escalation phase. Twelve more enrolled at the MTD to explore progression-free survival at 6 months (PFS6) in a single arm, single stage phase II-type design. In total, 19 patients received at least one dose at the MTD, and 15 completed at least 1 cycle at MTD. MTD was 200 mg vandetanib plus 2 mg sirolimus. The DLT was elevated AST/SGOT. The most common toxicities were lymphopenia, fatigue, rash, and hypophosphatemia. For 19 patients who received at least one dose at the MTD, including seven from the phase I group, two had a partial response [10.5 %; 95 % CI (1, 33 %)] and PFS6 was 15.8 % [95 % CI (3.9, 34.9 %)]. Vandetanib and sirolimus can be safely co-administered on a continuous, daily dosing schedule. PMID- 25503303 TI - Identification of two glioblastoma-associated stromal cell subtypes with different carcinogenic properties in histologically normal surgical margins. AB - Glioblastoma (GB) is a highly infiltrative tumor recurring within a few centimeters of the resection cavity in 85 % of cases, even in cases of complete tumor resection and adjuvant chemo/radiotherapy. We recently isolated GB associated stromal cells (GASCs) from the GB peritumoral zone, with phenotypic and functional properties similar to those of the cancer-associated fibroblasts present in the stroma of carcinomas. In particular, GASCs promote blood vessel development and have tumor-promoting effects on glioma cells in vitro and in vivo. In this study, we characterized these cells further, by analyzing the transcriptome and methylome of 14 GASC and five control stromal cell preparations derived from non-GB peripheral brain tissues. We identified two subtypes of GASCs in surgical margins in GB patients: GASC-A and GASC-B. GASC-B promoted the development of tumors and endothelium, whereas GASC-A did not. A difference in DNA methylation may underlie these two subtypes. We identified various proteins as being produced in the procarcinogenic GASC-B. Some of these proteins may serve as prognostic factors for GB and/or targets for anti-glioma treatment. In conclusion, in this era of personalized therapy, the status of GASCs in GB-free surgical margins should be taken into account, to improve treatment and the prevention of recurrence. PMID- 25503305 TI - Photoswitching of triplet-triplet annihilation upconversion showing large emission shifts using a photochromic fluorescent dithienylethene-Bodipy triad as a triplet acceptor/emitter. AB - A photoswitchable fluorescent triad based on dithienylethene and Bodipy was used as a triplet acceptor/emitter for reversible photoswitching of triplet-triplet annihilation upconversion (with Pd(II) tetraphenyltetrabenzoporphyrin as a triplet photosensitizer), which shows green/near IR emission changes with an emission energy difference of 0.79 eV (Deltalambda = 268 nm). PMID- 25503304 TI - Autism spectrum disorder risk factors and autistic traits in gender dysphoric children. AB - Gender dysphoria (GD) and autism spectrum disorder (ASD) are associated. In 49 GD children (40 natal males), we examined ASD risk factors (i.e., birth weight, parental age, sibling sex ratio) in relation to autistic traits. Data were gathered on autistic traits, birth weight, parents' ages at birth, sibling sex ratio, gender nonconformity, age, maternal depression, general behavioral and emotional problems, and IQ. High birth weight was associated with both high gender nonconformity and autistic traits among GD children. Developmental processes associated with high birth weight are, therefore, likely to underlie the GD-ASD link either directly or indirectly. The present study is the first to provide quantitative data bearing on possible mechanisms that lead GD and ASD to co-occur. PMID- 25503306 TI - The potential of the capillary electrophoresis techniques for quality control of biopharmaceuticals-a review. AB - CE is considered as a powerful technique in biopharmaceutical industry, owing to its inherent advantages such as high resolution, efficient separation, and its flexibility to couple with high-sensitive detecting methods. Present review provides a summary of the applications of CE-based methods in the quality control of biopharmaceuticals according to the papers published between 1994 and July 2014. This article is divided into the sections based on different CE modes applied in the analysis of biopharmaceuticals and gives detailed information about the employed experimental conditions. At the end some overall conclusions and perspectives are given. PMID- 25503307 TI - One-by-one single-molecule detection of mutated nucleobases by monitoring tunneling current using a DNA tip. AB - A DNA molecule was utilized as a probe tip to achieve single-molecule genetic diagnoses. Hybridization of the probe and target DNAs resulted in electron tunneling along the emergent double-stranded DNA. Simple stationary monitoring of the tunneling current leads to single-molecule DNA detection and discovery of base mismatches and methylation. PMID- 25503308 TI - Determination of ploidy level and isolation of genes encoding acetyl-CoA carboxylase in Japanese Foxtail (Alopecurus japonicus). AB - Ploidy level is important in biodiversity studies and in developing strategies for isolating important plant genes. Many herbicide-resistant weed species are polyploids, but our understanding of these polyploid weeds is limited. Japanese foxtail, a noxious agricultural grass weed, has evolved herbicide resistance. However, most studies on this weed have ignored the fact that there are multiple copies of target genes. This may complicate the study of resistance mechanisms. Japanese foxtail was found to be a tetraploid by flow cytometer and chromosome counting, two commonly used methods in the determination of ploidy levels. We found that there are two copies of the gene encoding plastidic acetyl-CoA carboxylase (ACCase) in Japanese foxtail and all the homologous genes are expressed. Additionally, no difference in ploidy levels or ACCase gene copy numbers was observed between an ACCase-inhibiting herbicide-resistant and a herbicide-sensitive population in this study. PMID- 25503310 TI - [Plasma cell myeloma in the stomach?]. AB - The detection of a diffuse infiltrate of heterogeneous small B-cells in the lamina propria mucosae invading the epithelium and destroying the glandular tissue by discrete aggregates of three or more marginal zone B-cells above the basal membrane (so-called lymphoepithelial lesions) is suspicious of a mucosa associated lymphoid tissue (MALT) lymphoma of the stomach. The demonstration of a monoclonal B-cell population by immunohistochemistry, in situ hybridization or PCR excludes a benign lymphatic lesion. In the differential diagnosis with other small B-cell lymphomas in the stomach, a panel of five different immunohistochemical markers is useful to diagnose a small lymphocytic lymphoma (CD5 and CD23 positive), a mantle cell lymphoma (CD5 and cyclin D1 positive) or a follicular lymphoma (BCL2 and CD10 positive). The presence of the translocation t(11;18)(q21;q21) or the API2/MALT1 rearrangement could give further information about the clinical course and the prognosis of a gastric MALT lymphoma. PMID- 25503309 TI - Altered microRNA expression profile in exosomes during osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. AB - The physiological role of microRNAs (miRNAs) in osteoblast differentiation remains elusive. Exosomal miRNAs isolated from human bone marrow-derived mesenchymal stem cells (BMSCs) culture were profiled using miRNA arrays containing probes for 894 human matured miRNAs. Seventy-nine miRNAs (~8.84%) could be detected in exosomes isolated from BMSC culture supernatants when normalized to endogenous control genes RNU44. Among them, nine exosomal miRNAs were up regulated and 4 miRNAs were under regulated significantly (Relative fold>2, p<0.05) when compared with the values at 0 day with maximum changes at 1 to 7 days. Five miRNAs (miR-199b, miR-218, miR-148a, miR-135b, and miR-221) were further validated and differentially expressed in the individual exosomal samples from hBMSCs cultured at different time points. Bioinformatic analysis by DIANA mirPath demonstrated that RNA degradation, mRNA surveillance pathway, Wnt signaling pathway, RNA transport were the most prominent pathways enriched in quantiles with differential exosomal miRNA patterns related to osteogenic differentiation. These data demonstrated exosomal miRNA is a regulator of osteoblast differentiation. PMID- 25503311 TI - Novel insights in the genomic organization and hotspots of recombination in the human KIR locus through analysis of intergenic regions. AB - The Killer Immunoglobulin-like Receptor (KIR) proteins constitute a family of highly homologous surface receptors involved in the regulation of the innate cytotoxicity of natural killer (NK) cells. Within the human genome, 17 KIR genes are present, many of which show large variation across the population owing to the high number of allelic variants and copy number variation (CNV). KIR genotyping and CNV determination were used to map the KIR locus in a large cohort of >400 Caucasian individuals. Gene order and structure was determined by sequence-specific polymerase chain reaction of the intergenic regions. In this way, we could show that KIR3DL1 and KIR2DS4 gene variants are linked and that- contrary to current views--the gene KIR2DS5 is only present in the telomeric half of the KIR locus. Our study revealed novel insights in the highly organized distribution of KIR genes. Novel recombination hotspots were identified that contribute to the diversity of KIR gene distribution in the Caucasian population. Next-generation sequencing of the KIR intergenic regions allowed for a detailed single-nucleotide polymorphism analysis, which demonstrated several gene-specific as well as haplotype-specific nucleotides for a more accurate genotyping of this notoriously complex gene cluster. PMID- 25503312 TI - Dose to 'water-like' media or dose to tissue in MV photons radiotherapy treatment planning: still a matter of debate. AB - The difference between Monte Carlo Treatment Planning (MCTP) based on the assumption of 'water-like' tissues with densities obtained from CT procedures, or on tissue compositions derived from CT-determined densities, have been investigated. Stopping powers and electron fluences have been calculated for a range of media and body tissues for 6 MV photon beams, including changes in their physical data (density and stopping powers). These quantities have been used to determine absorbed doses using cavity theory. It is emphasized that tissue compositions given in ICRU or ICRP reports should not be given the standing of physical constants as they correspond to average values obtained for a limited number of human-body samples. It has been shown that mass stopping-power ratios to water are more dependent on patient-to-patient composition differences, and therefore on their mean excitation energies (I-values), than on mass density. Electron fluence in different media are also more dependent on media composition (and their I-values) than on density. However, as a consequence of the balance between fluence and stopping powers, doses calculated from their product are more constant than what the independent stopping powers and fluence variations suggest. Additionally, cancelations in dose ratios minimize the differences between the 'water-like' and 'tissue' approaches, yielding practically identical results except for bone, and to a lesser extent for adipose tissue. A priori, changing from one approach to another does not seem to be justified considering the large number of approximations and uncertainties involved throughout the treatment planning tissue segmentation and dose calculation procedures. The key issue continues to be the composition of tissues and their I-values, and as these cannot be obtained for individual patients, whatever approach is selected does not lead to significant differences from a water reference dose, the maximum of these being of the order of 5% for bone tissues. Considering, however, current developments in advanced dose calculation methods, planning in terms of dose-to tissue should be the preferred choice, under the expectancy that progress in the field will gradually improve some of the crude approximations included in MCTP and numerical transport methods. The small differences obtained also show that a retrospective conversion from dose-to-tissue to dose-to-water, based on a widely used approach, would mostly increase the final uncertainty of the treatment planning process. It is demonstrated that, due to the difference between electron fluence distributions in water and in body tissues, the conversion requires an additional fluence correction that has so far been neglected. An improved expression for the conversion and data for the fluence correction factor are provided. These will be necessary even in a dose-to-tissue environment, for the normalization of the treatment plan to the reference dosimetry of the treatment unit, always calibrated in terms of absorbed dose to water. PMID- 25503314 TI - Monosomal karyotype acute myeloid leukemia: tread lightly. PMID- 25503313 TI - How water molecules affect the catalytic activity of hydrolases--a XANES study of the local structures of peptide deformylase. AB - Peptide deformylase (PDF) is a prokaryotic enzyme that catalyzes the deformylation of nascent peptides generated during protein synthesis and water molecules play a key role in these hydrolases. Using X-ray absorption near edge spectroscopy (XANES) and ab initio calculations we accurately probe the local atomic environment of the metal ion binding in the active site of PDF at different pH values and with different metal ions. This new approach is an effective way to monitor existing correlations among functions and structural changes. We show for the first time that the enzymatic activity depends on pH values and metal ions via the bond length of the nearest coordinating water (Wat1) to the metal ion. Combining experimental and theoretical data we may claim that PDF exhibits an enhanced enzymatic activity only when the distance of the Wat1 molecule with the metal ion falls in the limited range from 2.15 to 2.55 A. PMID- 25503315 TI - Anaerobic humus and Fe(III) reduction and electron transport pathway by a novel humus-reducing bacterium, Thauera humireducens SgZ-1. AB - In this study, an anaerobic batch experiment was conducted to investigate the humus- and Fe(III)-reducing ability of a novel humus-reducing bacterium, Thauera humireducens SgZ-1. Inhibition tests were also performed to explore the electron transport pathways with various electron acceptors. The results indicate that in anaerobic conditions, strain SgZ-1 possesses the ability to reduce a humus analog, humic acids, soluble Fe(III), and Fe(III) oxides. Acetate, propionate, lactate, and pyruvate were suitable electron donors for humus and Fe(III) reduction by strain SgZ-1, while fermentable sugars (glucose and sucrose) were not. UV-visible spectra obtained from intact cells of strain SgZ-1 showed absorption peaks at 420, 522, and 553 nm, characteristic of c-type cytochromes (cyt c). Dithionite-reduced cyt c was reoxidized by Fe-EDTA and HFO (hydrous ferric oxide), which suggests that cyt c within intact cells of strain SgZ-1 has the ability to donate electrons to extracellular Fe(III) species. Inhibition tests revealed that dehydrogenases, quinones, and cytochromes b/c (cyt b/c) were involved in reduction of AQS (9, 10-anthraquinone-2-sulfonic acid, humus analog) and oxygen. In contrast, only NADH dehydrogenase was linked to electron transport to HFO, while dehydrogenases and cyt b/c were found to participate in the reduction of Fe-EDTA. Thus, various different electron transport pathways are employed by strain SgZ-1 for different electron acceptors. The results from this study help in understanding the electron transport processes and environmental responses of the genus Thauera. PMID- 25503316 TI - The ligninolytic peroxidases in the genus Pleurotus: divergence in activities, expression, and potential applications. AB - Mushrooms of the genus Pleurotus are comprised of cultivated edible ligninolytic fungi with medicinal properties and a wide array of biotechnological and environmental applications. Like other white-rot fungi (WRF), they are able to grow on a variety of lignocellulosic biomass substrates and degrade both natural and anthropogenic aromatic compounds. This is due to the presence of the non specific oxidative enzymatic systems, which are mainly consisted of lacasses, versatile peroxidases (VPs), and short manganese peroxidases (short-MnPs). Additional, less studied, peroxidase are dye-decolorizing peroxidases (DyPs) and heme-thiolate peroxidases (HTPs). During the past two decades, substantial information has accumulated concerning the biochemistry, structure and function of the Pleurotus ligninolytic peroxidases, which are considered to play a key role in many biodegradation processes. The production of these enzymes is dependent on growth media composition, pH, and temperature as well as the growth phase of the fungus. Mn(2+) concentration differentially affects the expression of the different genes. It also severs as a preferred substrate for these preoxidases. Recently, sequencing of the Pleurotus ostreatus genome was completed, and a comprehensive picture of the ligninolytic peroxidase gene family, consisting of three VPs and six short-MnPs, has been established. Similar enzymes were also discovered and studied in other Pleurotus species. In addition, progress has been made in the development of molecular tools for targeted gene replacement, RNAi-based gene silencing and overexpression of genes of interest. These advances increase the fundamental understanding of the ligninolytic system and provide the opportunity for harnessing the unique attributes of these WRF for applied purposes. PMID- 25503318 TI - Improving mycoinsecticides for insect biological control. AB - The desire for decreased reliance on chemical pesticides continues to fuel interest in alternative means for pest control including the use of naturally occurring microbial insect pathogens. Insects, as vectors of disease causing agents or as agricultural pests, are responsible for millions of deaths and significant economic losses worldwide, placing stresses on productivity (GDP) and human health and welfare. In addition, alterations in climate change are likely to affect insect ranges, expanding their access to previously constrained geographic areas, a potentially worrisome outcome. Metarhizium anisopliae and Beauveria bassiana, two cosmopolitan fungal pathogens of insects found in almost all ecosystems, are the most commonly applied mycoinsecticides for a variety of insect control purposes. The availability of the complete genomes for both organisms coupled to robust technologies for their transformation has led to several advances in engineering these fungi for greater efficacy and/or utility in pest control applications. Here, we will provide an overview of the fungal insect and fungal-plant interactions that occur and highlight recent advances in the genetic engineering of these fungi. The latter work has resulted in the development of strains displaying (1) increased resistance to abiotic stress, (2) increased cuticular targeting and degradation, (3) increased virulence via expression of insecticidal protein/peptide toxins, (4) the ability to block transmission of disease causing agents, and (5) the ability to target specific insect hosts, decrease host fecundity, and/or alter insect behaviors. PMID- 25503317 TI - Exploiting mixtures of H2, CO2, and O2 for improved production of methacrylate precursor 2-hydroxyisobutyric acid by engineered Cupriavidus necator strains. AB - Current manufacturing of most bulk chemicals through petrochemical routes considerably contributes to common concerns over the depletion of fossil carbon sources and greenhouse gas emissions. Sustainable future production of commodities thus requires the shift to renewable feedstocks in combination with established or newly developed synthesis routes. In this study, the potential of Cupriavidus necator H16 for autotrophic synthesis of the building block chemical 2-hydroxyisobutyric acid (2-HIBA) is evaluated. A novel biosynthetic pathway was implemented by heterologous expression of the 2-hydroxyisobutyryl-coenzyme A (2 HIB-CoA) mutase from Aquincola tertiaricarbonis L108, relying on a main intermediate of strain H16's C4 overflow metabolism, 3-hydroxybutyryl-CoA. The intention was to direct the latter to 2-HIBA instead or in addition to poly-3 hydroxybutyrate (PHB). Autotrophic growth and 2-HIBA (respectively, PHB) synthesis of wild-type and PHB-negative mutant strains were investigated producing maximum 2-HIBA titers of 3.2 g L(-1) and maximum specific 2-HIBA synthesis rates (q 2-HIBA) of about 16 and 175 MUmol g(-1) h(-1), respectively. The obtained specific productivity was the highest reported to date for mutase dependent 2-HIBA synthesis from heterotrophic and autotrophic substrates. Furthermore, expression of a G protein chaperone (MeaH) in addition to the 2-HIB CoA mutase subunits yielded improved productivity. Analyzing the inhibition of growth and product synthesis due to substrate availability and product accumulation revealed a strong influence of 2-HIBA, when cells were cultivated at high titers. Nevertheless, the presented results imply that at the time the autotrophic synthesis route is superior to thus far established heterotrophic routes for production of 2-HIBA with C. necator. PMID- 25503319 TI - A common active site of polyhydroxyalkanoate synthase from Bacillus cereus YB-4 is involved in polymerization and alcoholysis reactions. AB - Polyhydroxyalkanoate (PHA) synthase from Bacillus cereus YB-4 (PhaRCYB4) catalyzes not only PHA polymerization but also alcoholytic cleavage of PHA chains. The alcoholysis activity of PhaRCYB4 is expressed when a hydroxyacyl-CoA monomer is absent but an alcohol compound is present. In this study, we performed alanine mutagenesis of the putative catalytic triad (Cys(151), Asp(306), and His(335)) in the PhaCYB4 subunit to identify the active site residues for polymerization and alcoholysis activities. Individual substitution of each triad residue with alanine resulted in loss of both polymerization and alcoholysis activities, suggesting that these residues are commonly shared between polymerization and alcoholysis reactions. The loss of activity was also observed following mutagenesis of the triad to other amino acids, except for one PhaRCYB4 mutant with a C151S substitution, which lost polymerization activity but still possessed cleavage activity towards PHA chains. The low-molecular-weight PHA isolated from the PhaRCYB4(C151S)-expressing strain showed a lower ratio of alcohol capping at the P(3HB) carboxy terminus than did that from the wild-type expressing strain. This observation implies that hydrolysis activity of PhaRCYB4 might be elicited by the C151S mutation. PMID- 25503322 TI - A novel cinnamide YLT26 induces breast cancer cells apoptosis via ROS mitochondrial apoptotic pathway in vitro and inhibits lung metastasis in vivo. AB - BACKGROUND: Breast cancer is the leading cause of cancer death among women worldwide and metastasis is the major cause of treatment failure. Thus, new treatment options for breast cancer, especially, drugs which could prevent metastasis, are pressingly needed. METHODS: In the present study, we designed and synthesized a novel cinnamide derivative, (E)-N-(4-(1,1,1,3,3,3-hexafluoro-2 hydroxypropan-2-yl)phenyl)-3-(3,4,5-trimethoxyphenyl)acrylamide (YLT26), which displayed potent inhibitory effects on breast cancer cells. The cell viability, apoptosis-inducing effect and reactive oxygen species (ROS) production were examined in 4T1 cells following treatment with YLT26. Meanwhile, apoptosis related proteins levels were determined by western blotting. Finally, we evaluated the effects of YLT26 on breast tumor growth, lung metastases in vivo and the infiltration of myeloid-derived suppressor cells (MDSCs) in lung tissue. RESULTS: Our results showed that the proliferation inhibitory effects of YLT26 were correlated with its apoptosis-inducing effect. Exposure to YLT26 induced mitochondrial transmembrane potential (?Psim) change, activated caspase-9, and downregulated the Bcl-2 expression, as well as enhanced ROS accumulation in 4T1 cells. Moreover, YLT26 significantly inhibited tumor growth without obvious side effects in the 4T1 tumor-bearing mice model. Immunohistochemistry analyze revealed YLT26 also induced apoptosis in vivo. More importantly, YLT26 also significantly inhibited lung metastases, which may be associated with the reduction of MDSCs. CONCLUSION: The present study suggested that YLT26 could inhibit breast cancer cells proliferation via ROS-mitochondrial apoptotic pathway, delay breast tumor progression, and suppress lung metastases by impacting on the immunologic microenvironment in vivo. (c) 2015 S. Karger AG, Basel. PMID- 25503323 TI - Gordon Syndrome: a continuing story. AB - Gordon Syndrome (GS) is a rare familial hypertension syndrome with a characteristic hyperkalaemia which distinguishes it from other syndromic forms of hypertension that typically cause hypokalaemia. Patients with GS respond to aggressive salt-restriction or relatively small doses of thiazide diuretics, which suggests that activation of the thiazide-sensitive Na/Cl cotransporter (NCC) in the distal nephron is to blame. However, the mechanism has proved to be complex. In 2001, mutations in genes encoding two serine/threonine kinases, WNK1 and WNK4, were identified as causing GS. However, it took several years to appreciate that these kinases operated in a cascade with downstream serine/threonine kinases (SPAK and OSR1) actually phosphorylating and activating NCC and the closely related cotransporters NKCC1 and NKCC2. The hyperkalaemia in GS arises from an independent action of WNK1/WNK4 to reduce cell-surface expression of ROMK, the secretory K-channel in the collecting ducts. However, mutations in WNK1/4 are present in a small minority of GS families, and further genes have emerged (CUL3 and KLHL3) that code for Cullin-3 (a scaffold protein in an ubiquitin-E3 ligase) and an adaptor protein, Kelch3, respectively. These new players regulate the ubiquitination and proteasomal degradation of WNK kinases, thereby adding to the complex picture we now have of NCC regulation in the distal nephron. PMID- 25503324 TI - Antibody-mediated rejection in young kidney transplant recipients: the dilemma of noncompliance and insufficient immunosuppression. AB - BACKGROUND: Antibody-mediated rejection (ABMR) is a recognized cause of late kidney allograft loss. Although ABMR may occur despite appropriate chronic immunosuppressive therapy, non-adherence both facilitates and accelerates the activation of the effector phase of the humoral immune response against the donor tissue, leading in turn to progressive kidney allograft rejection. Given the poor efficacy of rescue therapies for both acute and chronic late ABMR, establishing appropriate preventive strategies at different times before and after transplantation is a critical management goal. CASE-DIAGNOSIS/TREATMENT: In this report, we discuss the differential diagnoses and management of ABMR based on the clinical case report of a young kidney transplant recipient with progressive ABMR due to poor immunosuppressive adherence. In the absence of sensitive and specific non-invasive monitoring tools for alloimmune activation, the clinical dilemma in the management of the adolescent patient lies in differentiating between suboptimal prescribed immunosuppression and deliberate non-adherence to adequate immunosuppression dosing. Despite the advent of therapies to reduce ABMR injury, the graft is destined for untimely functional loss. CONCLUSIONS: New biomarkers and tools for the accurate characterization of alloimmune risk before and after transplantation, and serial testing for de novo changes in circulating donor specific alloantibodies, are urgently needed to support the delivery of optimized immunosuppression exposure. PMID- 25503325 TI - The RIVUR study: a review of its findings. AB - BACKGROUND: The conclusion drawn by the authors of the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial is that antimicrobial prophylaxis reduces the risk of recurrent urinary tract infection (UTI)-but not of renal scarring-in patients with vesicoureteral reflux (VUR). RESULTS: A review of the findings showed that the decreased recurrent UTI rate was only present at the end of the 2-year follow-up period and was only slightly increased (12.3%) above the 10% cutoff for statistical significance. The difference was not observed in children younger than two years of age with VUR grade III and IV. In addition, the rate of new renal scarring was not statistically different between the prophylaxis and placebo groups (8.2 vs. 8.4%, respectively). A high rate of uropathogen antibiotic resistance was observed in the prophylaxis group (68.4 vs. 24.6%, respectively). CONCLUSION: The analysis of the RIVUR findings questions the validity of its authors suggestion that the results may warrant reconsideration of the current recommendations by the American Academy of Pediatrics on obtaining a voiding cystourethrogram after the first febrile UTI and the use of urinary antibiotic prophylaxis in VUR patients. PMID- 25503327 TI - Estimation of Anticipated Performance Index and Air Pollution Tolerance Index and of vegetation around the marble industrial areas of Potwar region: bioindicators of plant pollution response. AB - Mitigating industrial air pollution is a big challenge, in such scenario screening of plants as a bio monitor is extremely significant. It requires proper selection and screening of sensitive and tolerant plant species which are bio indicator and sink for air pollution. The present study was designed to evaluate the Air Pollution Tolerance Index (APTI) and Anticipated Performance Index (API) of the common flora. Fifteen common plant species from among trees, herb and shrubs i.e. Chenopodium album (Chenopodiaceae), Parthenium hysterophorus (Asteraceae), Amaranthus viridis (Amaranthaceae), Lantana camara (Verbenaceaea), Ziziphus nummulari (Rhamnaceae), Silibum merianum (Asteraceae), Cannabis sativa (Cannabinaceae), Calatropis procera (Asclepediaceae), Ricinus communis (Euphorbiaceae), Melia azadirachta (Meliaceae), Psidium guajava (Myrtaceae), Eucalyptus globules (Myrtaceae), Broussonetia papyrifera (Moraceae), Withania somnifera (Solanaceae) and Sapium sabiferum (Euphorbiaceae) were selected growing frequently in vicinity of Marble industries in Potwar region. APTI and API of selected plant species were analyzed by determining important biochemical parameter i.e. total chlorophyll, ascorbic acid, relative water content and pH etc. Furthermore the selected vegetation was studied for physiological, economic, morphological and biological characteristics. The soil of studied sites was analyzed. It was found that most the selected plant species are sensitive to air pollution. However B. papyrifera, E. globulus and R. communis shows the highest API and therefore recommended for plantation in marble dust pollution stress area. PMID- 25503326 TI - Overlapping genes: a new strategy of thermophilic stress tolerance in prokaryotes. AB - Overlapping genes (OGs) draw the focus of recent day's research. However, the significance of OGs in prokaryotic genomes remained unexplored. As an adaptation to high temperature, thermophiles were shown to eliminate their intergenic regions. Therefore, it could be possible that prokaryotes would increase their OG content to adapt to high temperature. To test this hypothesis, we carried out a comparative study on OG frequency of 256 prokaryotic genomes comprising both thermophiles and non-thermophiles. It was found that thermophiles exhibit higher frequency of overlapping genes than non-thermophiles. Moreover, overlap frequency was found to correlate with optimal growth temperature (OGT) in prokaryotes. Long overlap frequency was found to hold a positive correlation with OGT resulting in an abundance of long overlaps in thermophiles compared to non-thermophiles. On the other hand, short overlap (1-4 nucleotides) frequency (SOF) did not yield any direct correlation with OGT. However, the correlation of SOF with CAIavg (extent of variation of codon usage bias measured as the mean of codon adaptation index of all genes in a given genome) and IG% (proportion of intergenic regions) indicate that they might upregulate the aforementioned factors (CAIavg and IG%) which are already known to be vital forces for thermophilic adaptation. From these evidences, we propose that the OG content bears a strong link to thermophily. Long overlaps are important for their genome compaction and short overlaps are important to uphold high CAIavg. Our findings will surely help in better understanding of the significance of overlapping gene content in prokaryotic genomes. PMID- 25503328 TI - Potential-induced electronic structure changes in supercapacitor electrodes observed by in operando soft X-ray spectroscopy. AB - The dynamic physiochemical response of a functioning graphene-based aerogel supercapacitor is monitored in operando by soft X-ray spectroscopy and interpreted through ab initio atomistic simulations. Unanticipated changes in the electronic structure of the electrode as a function of applied voltage bias indicate structural modifications across multiple length scales via independent pseudocapacitive and electric double layer charge storage channels. PMID- 25503330 TI - Market watch: Upcoming catalysts in Q1 2015. PMID- 25503331 TI - The Innovative Medicines Initiative: an engine for regulatory science. AB - Since its launch in 2008, the Innovative Medicines Initiative has catalysed the formation of many consortia to address challenges in drug development and regulation. As it moves into its second phase, we highlight key outcomes so far and the lessons learned. PMID- 25503336 TI - Cardiovascular diseases: Reversing anticoagulants. PMID- 25503335 TI - Biologics: Transferrin' bispecific antibodies across the blood-brain barrier. PMID- 25503337 TI - Market watch: Evolution of Chinese bioclusters as a framework for investment policies in emerging markets. PMID- 25503338 TI - An alternative long-term culture system for highly-pure mouse spermatogonial stem cells. AB - Increasing evidence suggests that spermatogonial stem cells (SSCs) have great clinical potential to give rise to a variety of cell types besides all spermatogenic lineage cells. The development of an efficient method for long-term culture of highly-pure SSCs is essential for further studies related to SSC biological events. Here, we describe an in vitro culture system obtaining mouse SSC cultures of high purity, viability, and proliferation. For establishing long term cultures of SSCs, we mainly focused on isolation procedures and culture conditions. These included co-coating of extracellular substrates, that is, poly L-lysine (PLL) and laminin, as well as combinatiorial use of three milder enzymes and simultaneously less trypsin to minimize enzyme-mediated degradation of SSCs. Furthermore, a unique purification procedure was performed to effectively eliminate contaminating non-SSCs. Finally, a critical step is to ensure SSC maintenance and expansion by utilizing optimal culture medium. Obtained data suggest that applying our optimally modified method, SSCs can be cultured for over 90 days with high purity (around 93.5%). Moreover, SSCs isolated and expanded using our protocol fulfills all criteria of SSCs without losing their stemness-characterized by SSC-phenotypic gene expression and long-term self renewal. This study describes for the first time a protocol allowing isolation and expansion of SSCs suitable for numerous studies related to SSC-based clinical therapies of various diseases. PMID- 25503339 TI - Apexification, apexogenesis and regenerative endodontic procedures: a review of the literature. AB - AIM: Aim of this paper was to present the therapeutical approaches to the management of the immature apex and discuss the evolution of materials and techniques. METHODS: A Medline search was performed limited to human studies published. The keywords searched were apexogenesis, apexification, pulp regeneration, revascularization. RESULTS: Apexogenesis and apexification techniques using Calcium hydroxide or MTA give a high succes rate. Recent regeneration procedures may be helpful for apexification in non vital elements. CONCLUSION: Calcium hydroxide is the gold standard material used in apexogenesis and apexification. New technologies are promoting the growing interest in strategies used for vitality preservation and pulp regeneration. PMID- 25503340 TI - The impact of subcrestal placement on short locking-taper implants placed in posterior maxilla and mandible: a retrospective evaluation on hard and soft tissues stability after 2 years of loading. AB - AIM: Objective of this study was to assess the influence of the subcrestal placement level of short implants with a locking-taper connection design on crestal bone levels and soft tissues health. METHODS: A clinical retrospective case-control study was conducted between May 2013 and September 2013. The sample was composed of patients who had received at least one 5-to-8-mm-long, plateau design implant with a locking-taper connection system (Bicon LLC, Boston, MA, USA) in posterior areas of maxilla and mandible, in the period between January 2009 and Dicember 2011. A radiographic evaluation of the degree of subcrestal positioning(t0) was conducted to identify two implant groups: Group 1 was composed of implants placed less than 2 mm under the crestal bone; Group 2 was composed of implants placed 2 mm or more under the crest. The primary outcome variables were the crestal bone levels and the peri-implant bone loss between prosthetic loading and last control visit (t1at2). Clinical parameters including the keratinized gingival (KG) width, modified bleeding index (mBI), modified plaque index (mPI), and probing depth (PD) were assessed at the follow-up visit. T tests were conducted to identify statistically significant differences between implants groups. Linear regression models were developed to test the dependence of the study variables by the degree of subcrestal surgical implant placement. Significance level was set at P<0.05. RESULTS: One hundred and thirty-seven implants were followed for an average period of 31 months. At the surgery, the implants were placed, on average, 2.04 mm (mesial) and 1.86 mm (distal) subcrestally. Eighty implants were placed less than 2 mm under the crest (average 1.28 mm), while fifty-seven implants were placed more than 2 mm under the crestal bone (average 2.97 mm). At the prosthetic loading (t1), the average crestal bone level was 1.11 mm, 0.79 mm in Shallow group and 1.86 mm in Deep group, with statistically significant differences between implant groups (P<0.05). At the follow-up visit (t2) the mean crestal bone levels were respectively 0.51 mm and 1.35 mm, with statistically significant differences between implant groups (P<0.05). The average peri-implant bone loss between prosthetic loading and control visit (t1at2) was 0.04 mm in the Group 1 and 0.33 mm in Group 2. The average keratinized mucosa width was 2.16 mm, the average mBI was 0.24 , the average mPI was 0.17 and the average PD was 2.34 mm. Significant difference between groups was observed regarding to keratinized gingival width (Group 1: 1.97 mm; Group 2: 2.41 mm; P<0.05) but not for the other clinical parameters. Linear regression models confirmed the dependence of crestal bone levels by the degree of subcrestal placement (P<0.05). CONCLUSION: After two years of observation, the implant of this study have shown minimal peri-implant bone resorption. The greater subcrestal implant placement has resulted in a higher level of the peri-implant bone crest, both after the osseointegration period and after the loading period. Both the study implants groups have shown good health of peri-implant soft tissues. PMID- 25503341 TI - Titanium orthodontic appliances for allergic patients. AB - AIM: The aim of our study was to assess the use of orthodontic appliances made in titanium for patients with an allergy to resin and nickel. We aim to highlight the resolution of problems such as stomatitis and peri-labial dermatitis, which generally manifest in patients who use traditional orthodontic appliances in acrylic resin and steel. METHODS: A total of 120 patients of ages between ten and fifteen undergoing orthodontic treatment requiring a rapid palatal expander or a mobile appliance were evaluated and two patch sensitivity tests were done to assess the presence of allergies. RESULTS: The biocompatibility of a material is directly dependent on its corrosion effect. If a metal does not allow the release of ions it will not have a damaging action or cause destruction on the cellular DNA. The oxidation status of an ion is related to the reactivity of the ion itself and thus may give the latter a carcinogenic effect. Titanium appliances used for this study have obtained excellent results due to their ability to form superficial oxides, which block the oxidation phenomenon and thus corrosion. CONCLUSION: We have noticed a total regression of the symptoms after the use of titanium appliances in patients who had a sensitivity reaction. PMID- 25503342 TI - Role of matrix metalloproteinases in radicular cysts and periapical granulomas. AB - AIM: The aim of the present study was to evaluate the expression and distribution of different classes of matrix metalloproteinases (MMPs) in radicular cysts and periapical granulomas. METHODS: Twenty consecutive specimens of radicular cysts and 20 of periapical granulomas were selected. Expression of MMP-2, -9, -8, -13, 3 was immunohistochemically evaluated. The intensity of expression of the MMPs was evaluated using a semi-quantitative analysis: low = +; intermediate = ++; high = +++. RESULTS: Positive expression of MMPs was present with different distribution. MMP-9 expressed differently in the lesions. Indeed, in periapical granulomas low expression was found in endothelial cells and fibroblasts, whilst high intensities were only detected in inflammatory cells. On the contrary, in radicular cysts the high intensities were mainly present in keratinocytes and fibroblasts. MMP-8 was mainly expressed in inflammatory cells of periapical granulomas. MMP-2 and -3 presented a low intensity of expression in both groups. MMP-13 showed a variable pattern of distribution in the different cell types of the two different lesions. CONCLUSION: The present investigation supports the role of MMPs in the inflammatory process leading to the development of radicular cysts and periapical granulomas. The results of the present study suggested that the increased enlargement of radicular cysts, compared to periapical granulomas, might be related to a higher expression of MMP-9. On the other hands, the higher intensity of expression of MMP-8 in periapical granulomas could be related to an active inflammatory process. MMP-8 could play an important role in the inflammation processes during the development of periapical lesions. PMID- 25503343 TI - Evaluation of salivary flow and drug interactions in patients with a diagnosis of diabetes mellitus. AB - AIM: Diabetes mellitus (DM) is one of the most common chronic diseases responsible for substantial loss on the quality of life in elderly. Oral manifestations in these patients include xerostomia and alterations in salivary flow and salivary pH. The aim of this study was to analyze the relationship between salivary flow, pH and medication. METHODS: The sample consisted of 53 subjects aged 60 years and older, including 30 patients with a diagnosis of type 2 DM and 23 controls. RESULTS: Salivary flow was 1.066+/-0.814 mL/min in the control group and 0.955+/-0.606 mL/min in the DM group, with no significant difference between groups (P=0.588). There was a significant difference (P=0.045) in mean salivary pH (DM: 5.267+/-0.828; control: 5.783+/-0.951). Only 32.07% of the patients reported to remove their denture while sleeping. Three of 53 subjects using medications presented severe drug interactions. CONCLUSION: In summary, dentists must be able to make the diagnosis, to recognize all factors related to salivary alterations in DM, and to prescribe adequate treatment related to oral condition. Patients with DM presented salivary pH below normal reference values. It is important to advice patients to remove their denture while sleeping in order to prevent traumatic irritations and infections with Candida albicans. Potentially harmful cases of drug interactions have to be observed in elderly patient. Further studies focusing on the nature of drug interactions as the cause of adverse events such as xerostomia and increased salivary pH are needed. PMID- 25503345 TI - Histological and Molecular Subclassification of Pancreatic and Nonpancreatic Periampullary Cancers: Implications for (Neo) Adjuvant Systemic Treatment. AB - The benefit of adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC) has been confirmed in randomized controlled trials. For nonpancreatic periampullary cancers (NPPC) originating from the distal bile duct, duodenum, ampulla, or papilla of Vater, the role of adjuvant therapy remains largely unclear. This review describes methods for distinguishing PDAC from NPPC by means of readily available and recently developed molecular diagnostic methods. The difficulties of reliably determining the exact origin of these cancers pathologically also is discussed. The review also considers the possibility of unintentional inclusion of NPPC in the most important adjuvant trials on PDAC and the subsequent implications for interpretation of the results. The authors conclude that correct determination of the origin of periampullary cancers is essential for clinical management and should therefore be systematically incorporated into clinical practice and future studies. PMID- 25503346 TI - Effects of Preoperative Chemoradiotherapy on the Likelihood of Sphincter Preservation Surgery in Locally Advanced Distal Rectal Cancer: A Longitudinal Study Based on Pelvic Magnetic Resonance Imaging. AB - BACKGROUND: It is unclear whether preoperative chemoradiotherapy (pCRT) increases the rate of sphincter-preserving surgery (SPS), avoiding abdominoperineal resection (APR), for the treatment of distal rectal cancer. We examined whether pCRT increases the likelihood of SPS based on changes in tumor height using pelvic magnetic resonance imaging (MRI). METHODS: Between January 2009 and December 2013, 105 patients underwent long-course pCRT for locally advanced distal rectal cancer (<=5 cm from the anal verge) and were included in this study. The surgical procedures were analyzed in terms of radiologic findings, including the distance from the inferior margin of tumor to the superior margin of the anorectal ring (tumor height) measured by pelvic MRI before and after pCRT. RESULTS: Eighty-six (81.9 %) patients underwent SPS. Overall clinical downstaging occurred in 48 (45.7 %) patients. Tumor height increased significantly after pCRT (from 15.0 +/- 15.3 to 18.1 +/- 16.9 mm, change 3.1 +/- 9.7 mm, p = 0.01). The mean change in tumor height was not significantly different between patients who underwent SPS or APR (mean change 3.3 +/- 9.6 vs. 2.3 +/- 10.5 mm, p = 0.68). The mean change was significantly greater in the double-stapled anastomosis group than in the handsewn anastomosis group (mean change 5.6 +/- 9.9 vs. -0.6 +/- 8.6 mm, p = 0.02). CONCLUSIONS: This was the first MRI-based longitudinal study to show that pCRT does not appear to increase the likelihood of SPS in locally advanced distal rectal cancer, although it could improve the potential of double-stapled anastomoses. PMID- 25503347 TI - Severe Obesity Impacts Recurrence-Free Survival of Women with High-Risk Endometrial Cancer: Results of a French Multicenter Study. AB - BACKGROUND: Studies focusing on the impact of obesity on survival in endometrial cancer (EC) have reported controversial results and few data exist on the impact of obesity on recurrence rate and recurrence-free survival (RFS). The aim of this study was to assess the impact of obesity on surgical staging and RFS in EC according to the European Society of Medical Oncology (ESMO) risk groups. METHODS: Data of 729 women with EC who received primary surgical treatment between January 2000 and December 2012 were abstracted from a multicenter database. RFS distributions according to body mass index (BMI) in each ESMO risk group were estimated using the Kaplan-Meier method. Survival was evaluated using the log-rank test, and the Cox proportional hazards model was used to determine influence of multiple variables. RESULTS: Distribution of the 729 women with EC according to BMI was BMI < 30 (n = 442; 60.6 %), 30 <= BMI < 35 (n = 146; 20 %) and BMI >= 35 (n = 141; 19.4 %). Nodal staging was less likely to be performed in women with a BMI >= 35 (72 %) than for those with a BMI < 30 (90 %) (p < 0.0001). With a median follow-up of 27 months (interquartile range 13-52), the 3-year RFS was 84.5 %. BMI had no impact on RFS in obese women in the low-/intermediate-risk groups, but a BMI >= 35 was independently correlated to a poorer RFS (hazard ratio 12.5; 95 % confidence interval 3.1-51.3) for women in the high-risk group. CONCLUSION: Severe obesity negatively impacts RFS in women with high-risk EC, underlining the importance of complete surgical staging and adapted adjuvant therapies in this subgroup of women. PMID- 25503348 TI - Erratum to: Pathologic Complete Response to Intralesional Interleukin-2 Therapy Associated with Improved Survival in Melanoma Patients with In-Transit Disease. PMID- 25503349 TI - Pain management and the perioperative surgical home: getting the desired outcome right. PMID- 25503350 TI - Impairment of sciatic nerve function during adductor canal block. PMID- 25503351 TI - Is the devil in the details?: discerning the impact of anesthetic technique. PMID- 25503352 TI - Reply to Dr Bhatia. PMID- 25503353 TI - Fascia iliaca compartment block administered by emergency medical service nurses at home. PMID- 25503354 TI - Safety in regional blocks for ophthalmic procedures. PMID- 25503355 TI - Doderlein-Kronig vaginal hysterectomy: an alternative to the traditional Heaney hysterectomy. AB - AIM: The aim of this study was to demonstrate the surgical steps of performing the Doderlein-Kronig hysterectomy. METHOD: A video recording was made of the hysterectomy using an alternative technique described by Drs. Doderlein and Kronig in 1906. The patient in the video had stage 3 prolapse and desired surgical correction. The video demonstrates an exam under anesthesia, an anterior colpotomy, delivery of the uterine fundus through the colpotomy, and completion of the hysterectomy. The surgery was performed by a urogynecologist and a resident physician. The patient tolerated the procedure well and had no symptom recurrence at her 1-year follow-up visit. This video was presented at the 2014 International Urogynecological Association Annual Meeting in Washington, DC, as a nondiscussed video poster. CONCLUSIONS: This video can assist and educate others in using this technique for performing a hysterectomy. Possible benefits of this approach include decreased blood loss and improved visualization, especially in women with pelvic organ prolapse. PMID- 25503356 TI - A systematic review on skin complications of bone-anchored hearing aids in relation to surgical techniques. AB - A systematic review to study the skin complications associated with the bone anchored hearing aid in relation to surgical techniques. The following databases have been searched: MEDLINE, EMBASE, the Cochrane Library , Google scholar and the PubMed. The literature search date was from January 1977 until November 2013. Randomised controlled trials and retrospective studies were included. Initial search identified 420 publications. Thirty articles met the inclusion criteria of this review. The most common surgical techniques identified were full-thickness skin graft, Dermatome and linear incision techniques. The result shows that dermatome technique is associated with higher rate of skin complications when compared to linear incision and skin graft techniques. Based on the available literature, the use of a linear incision technique appears to be associated with lower skin complications; however, there is limited data available supporting this. Higher quality studies would allow a more reliable comparison between the surgical techniques. PMID- 25503358 TI - Surgery of isolated malleus fixation due to tympanosclerosis. AB - The aim of the present study was to describe our surgical approach for isolated malleus fixation in patients with tympanosclerosis and to analyze the postoperative results. A total of 30 patients presented with isolated malleus fixation were operated. The fixation was reached via canalplasty. Fixated areas were cleaned without damaging the ossicle. Pre- and postoperative audiometric results were evaluated for each patient. Improvement of the pure-tone average (PTA) by at least 10 dB and an air-bone gap (ABG) of less than 20 dB after 12 months of follow-up was accepted to indicate success. The recovery of the postoperative PTA and ABG measurements was significant. Pre- and postoperative PTA was 48.00 +/- 11.86 and 24.90 +/- 12.45 dB, respectively (p < 0.001). According to PTA measurements, 40-50 dB recovery was achieved in four (13.3 %) patients, 31-40 dB in six (20 %) patients, 21-30 dB in ten (33.3 %) patients, and 11-20 dB in five (16.6 %) patients, with a total success rate of 25/30 (83.2 %). Pre- and postoperative ABG levels were 38.95 +/- 9.92 and 16.10 +/- 7.79 dB (p < 0.001), respectively. The ABG level was between 0 and 10 dB for 8 (26.6 %) patients, and 11-20 dB for 16 (53.3 %), with a total success rate of 24/30 (80 %). In cases of isolated malleus fixation with tympanosclerosis, performing a canalplasty to clean the sclerotic plaques without damaging the normal anatomy of the ossicle system using a diamond burr is a safe surgical option that provides significant recovery in hearing levels. PMID- 25503357 TI - Interesting association of squamous cell carcinoma of soft palate and tuberculous lymphadenitis. AB - Squamous cell carcinoma is the most common malignancy of the soft palate. In some cases, it mimics mycobacterial infections and in others it can develop against the background of a previous tuberculosis infection. Here we report a case of a 68-year-old male who presented with squamous cell carcinoma of the soft palate. He had metastatic lymphadenopathy on the right side and, simultaneously, two caseating granulomatous lymphadenopathies without metastatic lymph nodes on the left side. The patient was treated with soft palate excision and bilateral functional neck dissection. Standard antitubercular therapy and radiotherapy were added postoperatively. To our knowledge this is the first case in the English language medical literature of a head and neck cancer in the setting of tuberculosis. Tuberculosis may mimic head and neck cancers and vice versa, and both conditions may have atypical clinical and radiological presentations. Our case points out the need to consider tuberculosis in the differential diagnosis of squamous cell carcinoma of the head and neck. PMID- 25503360 TI - Hydrophobic aggregation and collective absorption of dioxin into lipid membranes: insights from atomistic simulations. AB - Dioxins are a highly toxic class of chlorinated aromatic chemicals. They have been extensively studied, but several molecular-level details of their action are still missing. Here we present molecular dynamics simulations of their absorption and diffusion through cell membranes. We show that, due to their hydrophobic character, dioxins can quickly penetrate into a lipid membrane, both as single molecules and as aggregates. We find clear evidence for their ability to accumulate in cell membranes. Our free energy calculations indicate that subsequent transport into the cell is unlikely to be a simple diffusive process. PMID- 25503359 TI - Effect of laparoscopic antireflux surgery on esophageal motility. AB - BACKGROUND/AIMS: The effect of laparoscopic antireflux surgery on esophageal motility is incompletely understood, and any indication for this procedure in patients with motility disorder is disputed in literature. We evaluated the influence of laparoscopic Nissen fundoplication on impaired esophageal motility. METHODS: In this pathological manometric study, we divided the patients into two groups preoperatively: the hypomotility group (mean amplitude of esophageal contraction wave <40 mm Hg; HYPO group, n = 11) and the normal group (mean amplitude of esophageal contraction wave >40 mm Hg; NORM group, n = 43). The amplitudes of esophageal contraction waves 3 and 8 cm above the lower esophageal sphincter and the percentage of peristaltic contraction waves of the tubular esophagus were analyzed pre- and postoperatively. RESULTS: In total, 54 patients with GERD underwent esophageal manometry before and 6 months after Nissen fundoplication. The length and pressure of the lower esophageal sphincter were increased in both groups postoperatively (p < 0.01). Patients in the HYPO group (n = 11) showed a statistically significant increase of mean amplitude of esophageal contraction (32.8 vs. 57.3 mm Hg; p < 0.01), while no change was found in the NORM group (n = 43). A total of 72% of patients with preoperative motility disorder showed normal postoperative manometry. CONCLUSION: Nissen fundoplication normalizes esophageal motility, especially in patients with preoperative hypomotility. Patients with impaired esophageal motility should not per se be excluded from antireflux surgery. PMID- 25503361 TI - Repetitive Gly-Leu-Lys-Gly-Glu-Asn-Arg-Gly-Asp peptide derived from collagen and fibronectin for improving cell-scaffold interaction. AB - Suitable scaffolds for tissue engineering should provide a microenvironment for cell dwelling and directing cell behavior that resemble the native environment. Three-dimensional geometry of electrospun scaffolds well supports cell deposition, but they often lack biomacromolecules to induce cell responses. In this work, the repetitive collagen and fibronectin motif (rCF) peptide containing multiple repeats of Gly-Leu-Lys-Gly-Glu-Asn-Arg-Gly-Asp sequence derived from the cell adhesion motifs of collagen and fibronectin was produced as the alternative agent to induce cell-scaffold interaction. The DNA fragment encoding rCF peptide was amplified by a polymerase chain reaction using overlap primers without a DNA template, cloned into a protein expression vector, and expressed as a His-tag fusion peptide in Escherichia coli. The purified rCF peptide possessed cell adhesion activity about 1.5-fold of the commercial RGD peptide. The rCF peptide was grafted onto the electrospun PCL scaffold via RF plasma of Ar/O2 discharge and acrylic acid treatment. The immobilized rCF peptide significantly increased surface hydrophilicity and enhanced cell proliferation of the electrospun PCL scaffold. These findings suggest the potential application of rCF peptide for improving the biomimetic functions of polymeric scaffolds for tissue engineering. PMID- 25503362 TI - Comparative analysis of the effectiveness of C-terminal cleavage intein-based constructs in producing a recombinant analog of anophelin, an anticoagulant from Anopheles albimanus. AB - Production of small recombinant peptides by expressing them as fusion proteins, with subsequent proteolytic or chemical cleavage of the latter, is a widespread approach in modern biotechnology. An alternative method is to produce such peptides as self-cleaving fusion proteins with inteins. To date, only a small proportion of known inteins have been used for this purpose, and analysis of other inteins for the ability to cleave off the target polypeptide can significantly expand the range of intein-based transgenic constructs available to researchers. Most interesting in practical terms are S-terminal cleavage constructs for producing target polypeptides without an N-terminal methionine residue. We prepared two new such constructs with mini-inteins GyrA from Mycobacterium xenopi and RIR1 from Methanobacterium thermoautotrophicum. Together with the previous construct based on the artificial mini-intein derived from Synechocystis sp. DnaB intein, they were used to produce a recombinant analog of anophelin, the naturally occurring thrombin inhibitor from the mosquito Anopheles albimanus. The effectiveness of the constructs with Ssp DnaB and Mth RIR1 proved to be relatively low because of spontaneous fusion protein cleavage during the producer strain culturing in the former case and a low degree of its cleavage upon purification in the latter case. The most effective Mxe GyrA construct was used to develop a semipreparative procedure for producing recombinant anophelin, with its yield reaching 91 +/- 2 mg protein per liter of culture medium. As determined by an amidolytic assay, the antithrombin activity and K i of recombinant anophelin were 3362.8 ATU/mg and 87 +/- 3 rM, respectively. PMID- 25503363 TI - Isolation of a ribonuclease with antiproliferative and HIV-1 reverse transcriptase inhibitory activities from Japanese large brown buckwheat seeds. AB - A ribonuclease, with a molecular mass of 22.5 kDa and an N-terminal sequence exhibiting resemblance to previously isolated buckwheat storage proteins and allergens, was isolated from Japanese large brown buckwheat seeds. The ribonuclease was purified using a simple protocol that comprised ion exchange chromatography on Q-Sepharose and DEAE-cellulose and gel filtration on Superdex 75. The ribonuclease exhibited low activity toward poly U, lower activity toward poly C, and very low activity toward poly A and poly G. The enzyme was activated upon exposure to 10 mM of Fe(2+) and Zn(2+) ions but was inhibited by Ca(2+), Mg(2+), and Mn(2+) ions at the same concentration. The optimum pH and optimum temperature for the enzyme were pH 9 and 60 degrees C, respectively. It inhibited proliferation of HepG2 hepatoma and MCF 7 breast cancer cells, with an IC50 value of 79.2 and 63.8 MUM, respectively. It potently inhibited HIV-1 reverse transcriptase activity with an IC50 of 48 MUM. However, there were no antifungal and mitogenic activities. PMID- 25503364 TI - Cardiac rehabilitation for people with heart disease: an overview of Cochrane systematic reviews. AB - BACKGROUND: Overviews are a new approach to summarising evidence and synthesising results from related systematic reviews. OBJECTIVES: To conduct an overview of Cochrane systematic reviews to provide a contemporary review of the evidence for delivery of cardiac rehabilitation, to identify opportunities for merging or splitting existing Cochrane reviews, and to identify current evidence gaps to inform new cardiac rehabilitation systematic review titles. METHODS: We searched The Cochrane Database of Systematic Reviews (2014, Issue 10) to identify systematic reviews that addressed the objectives of this overview. We assessed the quality of included reviews using the Revised Assessment of Multiple Systematic Reviews (R-AMSTAR) measurement tool and the quality of the evidence for reported outcomes using the GRADE framework. The focus of the data presentation was descriptive with detailed tabular presentations of review level and trial level characteristics and results. MAIN RESULTS: We found six Cochrane systematic reviews and judged them to be of high methodological quality. They included 148 randomised controlled trials (RCTs) in 98,093 participants. Compared with usual care alone, the addition of exercise-based cardiac rehabilitation in low-risk people after myocardial infarction or percutaneous coronary intervention or with heart failure appeared to have no impact on mortality, but did reduce hospital admissions and improved health-related quality of life. Psychological- and education-based interventions alone appeared to have little or no impact on mortality or morbidity but may have improved health-related quality of life. Home and centre-based programmes were equally effective in improving quality of life outcomes at similar healthcare costs. Selected interventions can increase the uptake of cardiac rehabilitation programmes whilst there is currently only weak evidence to support interventions that improve adherence to cardiac rehabilitation programmes. The quality of the primary RCTs in the included systematic reviews was variable, and limitations in the methodological quality of the RCTs led to downgrading of the quality of the evidence, which varied widely by review and by outcome. AUTHORS' CONCLUSIONS: Exercise-based cardiac rehabilitation is an effective and safe therapy to be used in the management of clinically stable people following myocardial infarction or percutaneous coronary intervention or who have heart failure. Future RCTs of cardiac rehabilitation need to improve their reporting methods and reflect the real world practice better including the recruitment of higher risk people and consideration of contemporary models of cardiac rehabilitation delivery, and identify effective interventions for enhancing adherence to rehabilitation. PMID- 25503365 TI - TDP-43 N terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be shifted by binding to ssDNA. AB - Transactivation response element (TAR) DNA-binding protein 43 (TDP-43) is the principal component of ubiquitinated inclusions characteristic of most forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia-frontotemporal lobar degeneration with TDP-43-positive inclusions (FTLD-TDP), as well as an increasing spectrum of other neurodegenerative diseases. Previous structural and functional studies on TDP-43 have been mostly focused on its recognized domains. Very recently, however, its extreme N terminus was identified to be a double edged sword indispensable for both physiology and proteinopathy, but thus far its structure remains unknown due to the severe aggregation. Here as facilitated by our previous discovery that protein aggregation can be significantly minimized by reducing salt concentrations, by circular dichroism and NMR spectroscopy we revealed that the TDP-43 N terminus encodes a well-folded structure in concentration-dependent equilibrium with its unfolded form. Despite previous failure in detecting any sequence homology to ubiquitin, the folded state was determined to adopt a novel ubiquitin-like fold by the CS-Rosetta program with NMR chemical shifts and 78 unambiguous long-range nuclear Overhauser effect (NOE) constraints. Remarkably, this ubiquitin-like fold could bind ssDNA, and the binding shifted the conformational equilibrium toward reducing the unfolded population. To the best of our knowledge, the TDP-43 N terminus represents the first ubiquitin-like fold capable of directly binding nucleic acid. Our results provide a molecular mechanism rationalizing the functional dichotomy of TDP-43 and might also shed light on the formation and dynamics of cellular ribonucleoprotein granules, which have been recently linked to ALS pathogenesis. As a consequence, one therapeutic strategy for TDP-43-causing diseases might be to stabilize its ubiquitin-like fold by ssDNA or designed molecules. PMID- 25503366 TI - Cellular resolution optical access to brain regions in fissures: imaging medial prefrontal cortex and grid cells in entorhinal cortex. AB - In vivo two-photon microscopy provides the foundation for an array of powerful techniques for optically measuring and perturbing neural circuits. However, challenging tissue properties and geometry have prevented high-resolution optical access to regions situated within deep fissures. These regions include the medial prefrontal and medial entorhinal cortex (mPFC and MEC), which are of broad scientific and clinical interest. Here, we present a method for in vivo, subcellular resolution optical access to the mPFC and MEC using microprisms inserted into the fissures. We chronically imaged the mPFC and MEC in mice running on a spherical treadmill, using two-photon laser-scanning microscopy and genetically encoded calcium indicators to measure network activity. In the MEC, we imaged grid cells, a widely studied cell type essential to memory and spatial information processing. These cells exhibited spatially modulated activity during navigation in a virtual reality environment. This method should be extendable to other brain regions situated within deep fissures, and opens up these regions for study at cellular resolution in behaving animals using a rapidly expanding palette of optical tools for perturbing and measuring network structure and function. PMID- 25503367 TI - Quantum delocalization of protons in the hydrogen-bond network of an enzyme active site. AB - Enzymes use protein architectures to create highly specialized structural motifs that can greatly enhance the rates of complex chemical transformations. Here, we use experiments, combined with ab initio simulations that exactly include nuclear quantum effects, to show that a triad of strongly hydrogen-bonded tyrosine residues within the active site of the enzyme ketosteroid isomerase (KSI) facilitates quantum proton delocalization. This delocalization dramatically stabilizes the deprotonation of an active-site tyrosine residue, resulting in a very large isotope effect on its acidity. When an intermediate analog is docked, it is incorporated into the hydrogen-bond network, giving rise to extended quantum proton delocalization in the active site. These results shed light on the role of nuclear quantum effects in the hydrogen-bond network that stabilizes the reactive intermediate of KSI, and the behavior of protons in biological systems containing strong hydrogen bonds. PMID- 25503368 TI - Reply to Lopez et al.: Sustainable implementation of taxi sharing requires understanding systemic effects. PMID- 25503369 TI - The smarter, the cleaner? Collaborative footprint: a further look at taxi sharing. PMID- 25503370 TI - The structure and function of a muscle articulation-type jaw joint of a polychaete worm. AB - The arrangement of the musculature and the fibers of the extracellular matrix (ECM) in the flexible jaw joint of the sandworm Alitta virens (Annelida, Polychaeta) was studied using dissection and histology. The jaws are capable of a wide range of motions principally related to defense and feeding. The left and right jaws are embedded in and moved by a compact pharyngeal bulb of muscle and ECM that also forms the mouth and esophagus. Eight pharyngeal bulbs were removed and dissected to document gross anatomical features or preserved and embedded in plastic for sectioning in multiple planes. The sections were stained with toluidine blue and basic fuchsin to differentiate muscle and ECM. The sections were then digitized and used to develop a three-dimensional computer illustration. We hypothesize that the muscle and fibers in the ECM are arranged as a muscular hydrostat to support the movement of the jaws. Four specimens were recorded using a digital video camera and a tank with an angled mirror to record lateral and ventral views of jaw movements during locomotion and biting associated with burrow guarding and feeding. Frame by frame kinematic analysis of this video showed that the jaws move symmetrically in a roughly horizontal plane. Although the angle between the jaws increases and then decreases after maximum gape has been reached, the jaws also translate relative to each other such that the axis of rotation is not fixed. Together, these functional morphological and behavioral data identify the jaw mechanism as a flexible joint known as a muscle articulation. As muscle articulations have been previously described only in the beaks of cephalopods and flatworms, this study implies that this type of joint is more common and important than previously recognized. PMID- 25503372 TI - At Risk Care Plans: a way to reduce readmissions and adverse events. AB - The purpose of this article is to describe an "At Risk Care Plan." The goal of an At Risk Care Plan is to improve safety and quality care by proactively anticipating individual safety and care needs of patients at risk and to communicate those needs to the health care team. This innovative intervention has dramatically reduced hospital readmissions, costs, and adverse events for high risk adult inpatients in a small community hospital. PMID- 25503371 TI - Inflammation and cognitive functioning in African Americans and Caucasians. AB - OBJECTIVE: To examine associations between inflammation and cognitive performance in African Americans and Caucasians. METHODS: The sample included 59 African Americans and 219 Caucasians >= 50 years old who had a baseline visit at the Emory/Georgia Tech Center for Health Discovery and Well Being. Peripheral levels of inflammation (interleukin-6, interleukin-8, C-reactive protein, and tumor necrosis factor-alpha) were examined in relation to performance on tests of visual processing (Identify the Odd Pattern), attention (Digit Span Forward), visuomotor set shifting (Digit Symbol Substitution), verbal set shifting (Digit Span Backwards), and memory (Recall a Pattern). RESULTS: Multiple regression models adjusting for potential demographic and vascular/metabolic confounders were conducted, with markers of inflammation included as either continuous or categorical (quartiles) variables. There were significant interactions between IL 8 and race for the Recall a Pattern (p = .006) and the Digit Symbol Substitution (p = .014) tests. Race-specific analyses (using a continuous variable for IL-8) demonstrated slower response times on the Recall a Pattern and Digit Symbol Substitution tests for African Americans but not for Caucasians. Categorical analyses among African Americans indicated that all of the top three quartiles of IL-8 were associated with slower reaction times on the Recall a Pattern test compared to the lowest quartile, while for Digit Symbol, the highest quartile of IL-8 was associated with the slowest cognitive performance. CONCLUSIONS: These preliminary findings suggest a stronger association between IL-8 and cognitive performance in African Americans than Caucasians. This relationship should be further examined in larger samples that are followed over time. PMID- 25503373 TI - Implementation of patient-centered bedside rounds in the pediatric intensive care unit. AB - Implementation of effective family-centered rounds in an intensive care unit environment is fraught with challenges. We describe the application of PDSA (Plan, Do, Study, Act) cycles in a quality improvement project to improve the process of rounds and increase family participation and provider satisfaction. We conducted pre-/postintervention surveys and used 5 process measures for a total of 1296 daily patient rounds over 7 months. We were successful in conducting family-centered rounds for 90% of patients, with 40% family participation and a 64.6% satisfactory rating by pediatric intensive care unit providers. PMID- 25503375 TI - Transcription factors and epigenetic modulation: its therapeutic implication in chronic kidney disease. AB - Recently emerging evidence has shown that epigenetic mechanisms are involved in initiation and progression of various diseases, including kidney diseases. In the present article, we review the current data regarding the role of epigenetic modulation in chronic kidney disease (CKD) and kidney fibrosis, including DNA methylation and histone modification. Especially we focused on the role of transcription factors in epigenetic modulation and the possibility of therapeutic target of CKD. We have recently reported that transcription factor Kruppel-like factor 4 (also known as gut-enriched Kruppel-like factor) is expressed in kidney podocytes (visceral epithelial cells) and modulates podocyte phenotype by gene selective epigenetic control. Targeting transcription factors for epigenetic modification may be a good candidate for remission and regression of CKD. It is necessary for the therapy of CKD with an epigenetic-based approach to investigate organ-, tissue-, or gene-specific treatment methods for reduction of side effects. PMID- 25503374 TI - Deciphering the genome repertoire of Pseudomonas sp. M1 toward beta-myrcene biotransformation. AB - Pseudomonas sp. M1 is able to mineralize several unusual substrates of natural and xenobiotic origin, contributing to its competence to thrive in different ecological niches. In this work, the genome of M1 strain was resequenced by Illumina MiSeq to refine the quality of a published draft by resolving the majority of repeat-rich regions. In silico genome analysis led to the prediction of metabolic pathways involved in biotransformation of several unusual substrates (e.g., plant-derived volatiles), providing clues on the genomic complement required for such biodegrading/biotransformation functionalities. Pseudomonas sp. M1 exhibits a particular sensory and biotransformation/biocatalysis potential toward beta-myrcene, a terpene vastly used in industries worldwide. Therefore, the genomic responsiveness of M1 strain toward beta-myrcene was investigated, using an RNA sequencing approach. M1 cells challenged with beta-myrcene(compared with cells grown in lactate) undergo an extensive alteration of the transcriptome expression profile, including 1,873 genes evidencing at least 1.5-fold of altered expression (627 upregulated and 1,246 downregulated), toward beta-myrcene-imposed molecular adaptation and cellular specialization. A thorough data analysis identified a novel 28-kb genomic island, whose expression was strongly stimulated in beta-myrcene-supplemented medium, that is essential for beta-myrcene catabolism. This island includes beta-myrcene-induced genes whose products are putatively involved in 1) substrate sensing, 2) gene expression regulation, and 3) beta-myrcene oxidation and bioconversion of beta-myrcene derivatives into central metabolism intermediates. In general, this locus does not show high homology with sequences available in databases and seems to have evolved through the assembly of several functional blocks acquired from different bacteria, probably, at different evolutionary stages. PMID- 25503377 TI - Exploring the potential for a mass media campaign to influence support for a ban on tobacco promotion at the point of sale. AB - This study explores whether exposure to advertisements that focus on the negative effects of tobacco industry advertising and promotion at the point of sale (anti POS advertising) influence: (i) attitude toward POS advertising; (ii) perceived impact of POS advertising on youth smoking; and (iii) support for a ban on tobacco promotion at the POS among adult non-smokers in New York. Data are from a split-sample, experimental study, using an online media tracking survey with embedded TV, radio and print advertising. Exposure to anti-POS advertising was associated with higher odds of holding a negative attitude toward POS advertising (OR 2.43, P < 0.001) and support for a ban on tobacco promotion at the POS (OR 1.77, P < 0.05), but not with perceived impact of POS tobacco advertisements on youth smoking. Findings suggest the possibility that a mass media campaign could be used to influence public attitude toward POS advertising and support for a ban on tobacco promotion at the POS. PMID- 25503376 TI - Does airway surgery lower serum lipid levels in obstructive sleep apnea patients? A retrospective case review. AB - BACKGROUND: Obstructive sleep apnea (OSA) is tightly linked to increased cardiovascular disease. Surgery is an important method to treat OSA, but its effect on serum lipid levels in OSA patients is unknown. We aimed to evaluate the effect of upper airway surgery on lipid profiles. MATERIAL AND METHODS: We performed a retrospective review of 113 adult patients with OSA who underwent surgery (nasal or uvulopalatopharyngoplasty [UPPP]) at a major, urban, academic hospital in Beijing from 2012 to 2013 who had preoperative and postoperative serum lipid profiles. RESULTS: Serum TC (4.86+/-0.74 to 4.69+/-0.71) and LP(a) (median 18.50 to 10.90) all decreased significantly post-operatively (P<0.01, 0.01, respectively), with no changes in serum HDL, LDL, or TG (P>0.05, all). For UPPP patients (n=51), serum TC, HDL and LP(a) improved (P=0.01, 0.01,<0.01, respectively). For nasal patients (n=62), only the serum LP(a) decreased (P<0.01). In patients with normal serum lipids at baseline, only serum LP(a) decreased (P<0.01). In contrast, in patients with isolated hypertriglyceridemia, the serum HDL, TG and LP(a) showed significant improvements (P=0.02, 0.03, <0.01, respectively). In patients with isolated hypercholesterolemia, the serum LP(a) decreased significantly (P=0.01), with a similar trend for serum TC (P=0.06). In patients with mixed hyperlipidemia, the serum TC and LDL also decreased (P=0.02, 0.03, respectively). CONCLUSIONS: Surgery may improve blood lipid levels in patients with OSA, especially in patients with preoperative dyslipidemia, potentially yielding a major benefit in metabolism and cardiovascular sequelae. Prospective studies should examine this potential metabolic effect of airway surgery for OSA. PMID- 25503378 TI - Understanding school health environment through interviews with key stakeholders in Lao PDR, Mongolia, Nepal and Sri Lanka. AB - Studies on health promoting schools (HPS) in low- and middle-income countries (LMICs) are scarce. To contribute to the development of HPS in these countries, we conducted formative research to understand the school environment in Lao PDR, Mongolia, Nepal, and Sri Lanka. Forty-three teachers, 10 government workers and 5 parents participated in three one-on-one interviews and 14 natural group interviews. Six themes emerged that centered on insufficient resources as reasons for suboptimal health conditions. At the individual level, participants mentioned the deficiency of personal resources to cope with cold weather and poor diet. At the school level, the lack of physical resources such as water purifiers and latrines was discussed. Interviewees also pointed out the schools' overdependence on external resources and therefore the lack of sustainability. Last, the shortage of health services at the school and community level was commonly mentioned. Based on these results, we believe that the basic concept of HPSs should also be applied when working with schools in LMICs. In conclusion, there was a lack of perception of the importance of policy and capacity development programs, which are important in developing HPSs. Therefore, future school health programs should stress improving these elements. PMID- 25503379 TI - Erratum: An iteration normalization and test method for differential expression analysis of RNA-seq data. AB - [This corrects the article DOI: 10.1186/1756-0381-7-15.]. PMID- 25503380 TI - Caspase-12 silencing attenuates inhibitory effects of cigarette smoke extract on NOD1 signaling and hBDs expression in human oral mucosal epithelial cells. AB - Cigarette smoke exposure is associated with increased risk of various diseases. Epithelial cells-mediated innate immune responses to infectious pathogens are compromised by cigarette smoke. Although many studies have established that cigarette smoke exposure affects the expression of Toll-liked receptor (TLR), it remains unknown whether the nucleotide-binding oligomerization domain-containing protein 1 (NOD1) expression is affected by cigarette smoke exposure. In the study, we investigated effects of cigarette smoke extract (CSE) on NOD1 signaling in an immortalized human oral mucosal epithelial (Leuk-1) cell line. We first found that CSE inhibited NOD1 expression in a dose-dependent manner. Moreover, CSE modulated the expression of other crucial molecules in NOD1 signaling and human beta defensin (hBD) 1, 2 and 3. We found that RNA interference-induced Caspase-12 silencing increased NOD1 and phospho-NF-kappaB (p-NF-kappaB) expression and down-regulated RIP2 expression. The inhibitory effects of CSE on NOD1 signaling can be attenuated partially through Caspase-12 silencing. Intriguingly, Caspase-12 silencing abrogated inhibitory effects of CSE on hBD1, 3 expression and augmented induced effect of CSE on hBD2 expression. Caspase-12 could play a vital role in the inhibitory effects of cigarette smoke on NOD1 signaling and hBDs expression in oral mucosal epithelial cells. PMID- 25503381 TI - Risk factors associated with malnutrition in one-year-old children living in the Peruvian Amazon. AB - BACKGROUND: Children under two years of age are in the most critical window for growth and development. As mobility increases, this time period also coincides with first exposure to soil-transmitted helminth (STH) infections in tropical and sub-tropical environments. The association between malnutrition and STH infection, however, has been understudied in this vulnerable age group. METHODOLOGY/PRINCIPAL FINDINGS: A nested cross-sectional survey was conducted in 12 and 13-month old children participating in a deworming trial in Iquitos, an STH-endemic area of the Peruvian Amazon. An extensive socio-demo-epi questionnaire was administered to the child's parent. Length and weight were measured, and the Bayley Scales of Infant and Toddler Development were administered to measure cognition, language, and fine motor development. Stool specimens were collected to determine the presence of STH. The association between malnutrition (i.e. stunting and underweight) and STH infection, and other child, maternal, and household characteristics, was analyzed using multivariable Poisson regression. A total of 1760 children were recruited between September 2011 and June 2012. Baseline data showed a prevalence of stunting and underweight of 24.2% and 8.6%, respectively. In a subgroup of 880 randomly-allocated children whose specimens were analyzed by the Kato-Katz method, the prevalence of any STH infection was 14.5%. Risk factors for stunting in these 880 children included infection with at least one STH species (aRR = 1.37; 95% CI 1.01, 1.86) and a lower development score (aRR = 0.97; 95% CI: 0.95, 0.99). A lower development score was also a significant risk factor for underweight (aRR = 0.92; 95% CI: 0.89, 0.95). CONCLUSIONS: The high prevalence of malnutrition, particularly stunting, and its association with STH infection and lower developmental attainment in early preschool-age children is of concern. Emphasis should be placed on determining the most cost-effective, integrated interventions to reduce disease and malnutrition burdens in this vulnerable age group. PMID- 25503382 TI - Biopolymer implants enhance the efficacy of adoptive T-cell therapy. AB - Although adoptive T-cell therapy holds promise for the treatment of many cancers, its clinical utility has been limited by problems in delivering targeted lymphocytes to tumor sites, and the cells' inefficient expansion in the immunosuppressive tumor microenvironment. Here we describe a bioactive polymer implant capable of delivering, expanding and dispersing tumor-reactive T cells. The approach can be used to treat inoperable or incompletely removed tumors by situating implants near them or at resection sites. Using a mouse breast cancer resection model, we show that the implants effectively support tumor-targeting T cells throughout resection beds and associated lymph nodes, and reduce tumor relapse compared to conventional delivery modalities. In a multifocal ovarian cancer model, we demonstrate that polymer-delivered T cells trigger regression, whereas injected tumor-reactive lymphocytes have little curative effect. Scaffold based T-cell delivery may provide a viable treatment option for inoperable tumors and reduce the rate of metastatic relapse after surgery. PMID- 25503384 TI - Large-scale test of the natural refuge strategy for delaying insect resistance to transgenic Bt crops. AB - The 'natural refuge strategy" for delaying insect resistance to transgenic cotton that produces insecticidal proteins from Bacillus thuringiensis (Bt) relies on refuges of host plants other than cotton that do not make Bt toxins. We tested this widely adopted strategy by comparing predictions from modeling with data from a four-year field study of cotton bollworm (Helicoverpa armigera) resistance to transgenic cotton producing Bt toxin Cry1Ac in six provinces of northern China. Bioassay data revealed that the percentage of resistant insects increased from 0.93% in 2010 to 5.5% in 2013. Modeling predicted that the percentage of resistant insects would exceed 98% in 2013 without natural refuges, but would increase to only 1.1% if natural refuges were as effective as non-Bt cotton refuges. Therefore, the results imply that natural refuges delayed resistance, but were not as effective as an equivalent area of non-Bt cotton refuges. The percentage of resistant insects with nonrecessive inheritance of resistance increased from 37% in 2010 to 84% in 2013. Switching to Bt cotton producing two or more toxins and integrating other control tactics could slow further increases in resistance. PMID- 25503383 TI - Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases. AB - Although great progress has been made in the characterization of the off-target effects of engineered nucleases, sensitive and unbiased genome-wide methods for the detection of off-target cleavage events and potential collateral damage are still lacking. Here we describe a linear amplification-mediated modification of a previously published high-throughput, genome-wide, translocation sequencing (HTGTS) method that robustly detects DNA double-stranded breaks (DSBs) generated by engineered nucleases across the human genome based on their translocation to other endogenous or ectopic DSBs. HTGTS with different Cas9:sgRNA or TALEN nucleases revealed off-target hotspot numbers for given nucleases that ranged from a few or none to dozens or more, and extended the number of known off targets for certain previously characterized nucleases more than tenfold. We also identified translocations between bona fide nuclease targets on homologous chromosomes, an undesired collateral effect that has not been described previously. Finally, HTGTS confirmed that the Cas9D10A paired nickase approach suppresses off-target cleavage genome-wide. PMID- 25503385 TI - A novel MitoNEET ligand, TT01001, improves diabetes and ameliorates mitochondrial function in db/db mice. AB - The mitochondrial outer membrane protein mitoNEET is a binding protein of the insulin sensitizer pioglitazone (5-[[4-[2-(5-ethylpyridin-2 yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione) and is considered a novel target for the treatment of type II diabetes. Several small-molecule compounds have been identified as mitoNEET ligands using structure-based design or virtual docking studies. However, there are no reports about their therapeutic potential in animal models. Recently, we synthesized a novel small molecule, TT01001 [ethyl 4-(3-(3,5-dichlorophenyl)thioureido)piperidine-1-carboxylate], designed on the basis of pioglitazone structure. In this study, we assessed the pharmacological properties of TT01001 in both in vitro and in vivo studies. We found that TT01001 bound to mitoNEET without peroxisome proliferator-activated receptor-gamma activation effect. In type II diabetes model db/db mice, TT01001 improved hyperglycemia, hyperlipidemia, and glucose intolerance, and its efficacy was equivalent to that of pioglitazone, without the pioglitazone-associated weight gain. Mitochondrial complex II + III activity of the skeletal muscle was significantly increased in db/db mice. We found that TT01001 significantly suppressed the elevated activity of the complex II + III. These results suggest that TT01001 improved type II diabetes without causing weight gain and ameliorated mitochondrial function of db/db mice. This is the first study that demonstrates the effects of a mitoNEET ligand on glucose metabolism and mitochondrial function in an animal disease model. These findings support targeting mitoNEET as a potential therapeutic approach for the treatment of type II diabetes. PMID- 25503386 TI - A UGT2B10 splicing polymorphism common in african populations may greatly increase drug exposure. AB - RO5263397 [(S)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine], a new compound that showed promising results in animal models of schizophrenia, is mainly metabolized in humans by N-glucuronidation. Enzyme studies, using the (then) available commercial uridine 5'-diphosphate-glucuronosyltransferases (UGTs), suggested that UGT1A4 is responsible for its conjugation. In the first clinical trial, in which RO5263397 was administered orally to healthy human volunteers, a 136-fold above-average systemic exposure to the parent compound was found in one of the participants. Further administration in this trial identified two more such poor metabolizers, all three of African origin. Additional in vitro studies with recombinant UGTs showed that the contribution of UGT2B10 to RO5263397 glucuronidation is much higher than UGT1A4 at clinically relevant concentrations. DNA sequencing in all of these poor metabolizers identified a previously uncharacterized splice site mutation that prevents assembly of full length UGT2B10 mRNA and thus functional UGT2B10 protein expression. Further DNA database analyses revealed the UGT2B10 splice site mutation to be highly frequent in individuals of African origin (45%), moderately frequent in Asians (8%) and almost unrepresented in Caucasians (<1%). A prospective study using hepatocytes from 20 individual African donors demonstrated a >100-fold lower intrinsic clearance of RO5263397 in cells homozygous for the splice site variant allele. Our results highlight the need to include UGT2B10 when screening the human UGTs for the enzymes involved in the glucuronidation of a new compound, particularly when there is a possibility of N-glucuronidation. Moreover, this study demonstrates the importance of considering different ethnicities during drug development. PMID- 25503388 TI - Glutamate-mediated upregulation of the multidrug resistance protein 2 in porcine and human brain capillaries. AB - As a member of the multidrug-resistance associated protein (MRP) family, MRP2 affects the brain entry of different endogenous and exogenous compounds. Considering the role of this transporter at the blood-brain barrier, the regulation is of particular interest. However, there is limited knowledge regarding the factors that regulate MRP2 in neurologic disease states. Thus, we addressed the hypothesis that MRP2 might be affected by a glutamate-induced signaling pathway that we previously identified as one key mechanism in the regulation of P-glycoprotein. Studies in isolated porcine brain capillaries confirmed that glutamate and N-methyl-d-aspartic acid (NMDA) exposure upregulates expression and function of MPR2. The involvement of the NMDA receptor was further suggested by the fact that the NMDA receptor antagonist MK-801 [(5S,10R)-(+)-5 methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], as well as the NMDA receptor glycine binding site antagonist L-701,324 [7-chloro-4-hydroxy-3-(3 phenoxy)phenyl-2(1H)-quinolinone], prevented the impact of glutamate. A role of cyclooxygenase-2 was indicated by coincubation with the cyclooxygenase-2 inhibitor celecoxib and the cyclooxygenase-1/-2 inhibitor indomethacin, which both efficaciously abolished a glutamate-induced upregulation of MRP2. Translational studies in human capillaries from surgical specimen demonstrated a relevant MRP2 efflux function and indicated an effect of glutamate exposure as well as its prevention by cyclooxygenase-2 inhibition. Taken together the findings provide first evidence for a role of a glutamate-induced NMDA receptor/cyclooxygenase-2 signaling pathway in the regulation of MRP2 expression and function. The response to excessive glutamate concentrations might contribute to overexpression of MRP2, which has been reported in neurologic diseases including epilepsy. The overexpression might have implications for brain access of various compounds including therapeutic drugs. PMID- 25503387 TI - Suppression of mitochondrial biogenesis through toll-like receptor 4-dependent mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling in endotoxin-induced acute kidney injury. AB - Although disruption of mitochondrial homeostasis and biogenesis (MB) is a widely accepted pathophysiologic feature of sepsis-induced acute kidney injury (AKI), the molecular mechanisms responsible for this phenomenon are unknown. In this study, we examined the signaling pathways responsible for the suppression of MB in a mouse model of lipopolysaccharide (LPS)-induced AKI. Downregulation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a master regulator of MB, was noted at the mRNA level at 3 hours and protein level at 18 hours in the renal cortex, and was associated with loss of renal function after LPS treatment. LPS-mediated suppression of PGC-1alpha led to reduced expression of downstream regulators of MB and electron transport chain proteins along with a reduction in renal cortical mitochondrial DNA content. Mechanistically, Toll-like receptor 4 (TLR4) knockout mice were protected from renal injury and disruption of MB after LPS exposure. Immunoblot analysis revealed activation of tumor progression locus 2/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (TPL-2/MEK/ERK) signaling in the renal cortex by LPS. Pharmacologic inhibition of MEK/ERK signaling attenuated renal dysfunction and loss of PGC-1alpha, and was associated with a reduction in proinflammatory cytokine (e.g., tumor necrosis factor-alpha [TNF-alpha], interleukin-1beta) expression at 3 hours after LPS exposure. Neutralization of TNF-alpha also blocked PGC-1alpha suppression, but not renal dysfunction, after LPS-induced AKI. Finally, systemic administration of recombinant tumor necrosis factor-alpha alone was sufficient to produce AKI and disrupt mitochondrial homeostasis. These findings indicate an important role for the TLR4/MEK/ERK pathway in both LPS-induced renal dysfunction and suppression of MB. TLR4/MEK/ERK/TNF-alpha signaling may represent a novel therapeutic target to prevent mitochondrial dysfunction and AKI produced by sepsis. PMID- 25503389 TI - R-(+) and S-(-) isomers of cotinine augment cholinergic responses in vitro and in vivo. AB - The nicotine metabolite cotinine (1-methyl-5-[3-pyridynl]-2-pyrrolidinone), like its precursor, has been found to exhibit procognitive and neuroprotective effects in some model systems; however, the mechanism of these effects is unknown. In this study, both the R-(+) and S-(-) isomers of cotinine were initially evaluated in an extensive profiling screen and found to be relatively inactive across a wide range of potential pharmacologic targets. Electrophysiological studies on human alpha4beta2 and alpha7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes confirmed the absence of agonistic activity of cotinine at alpha4beta2 or alpha7 nAChRs. However, a significant increase in the current evoked by a low concentration of acetylcholine was observed at alpha7 nAChRs exposed to 1.0 MUM R-(+)- or S-(-)-cotinine. Based on these results, we used a spontaneous novel object recognition (NOR) procedure for rodents to test the hypothesis that R-(+)- or S-(-)-cotinine might improve recognition memory when administered alone or in combination with the Alzheimer's disease (AD) therapeutic agent donepezil. Although both isomers enhanced NOR performance when they were coadministered with donepezil, neither isomer was active alone. Moreover, the procognitive effects of the drug combinations were blocked by methyllycaconitine and dihydro-beta-erythroidine, indicating that both alpha7 and alpha4beta2 nAChRs contribute to the response. These results indicate that cotinine may sensitize alpha7 nAChRs to low levels of acetylcholine (a previously uncharacterized mechanism), and that cotinine could be used as an adjunctive agent to improve the effective dose range of cholinergic compounds (e.g., donepezil) in the treatment of AD and other memory disorders. PMID- 25503392 TI - A stable ZnCo2O4 cocatalyst for photocatalytic CO2 reduction. AB - Spinel ZnCo2O4 nanostructures have shown great opportunities in energy related areas. However, the applications of ZnCo2O4 for the conversion of CO2 are much less reported. Herein, we present the use of mesoporous ZnCo2O4 nanorods as efficient and high stable cocatalysts for the photochemical reduction of CO2 under mild reaction conditions. PMID- 25503393 TI - Loss of AT-rich interactive domain 1A expression in gastrointestinal malignancies. AB - OBJECTIVE: AT-rich interactive domain 1A (ARID1A) has recently been identified as a novel tumor suppressor in various tumor types. This study was designed to explore the clinical relevance and prognostic impact of ARID1A expression loss in colorectal cancer (CRC) and gastric cancer (GC). METHODS: Immunohistochemistry for ARID1A was performed using tissue microarray blocks containing 196 CRCs and 275 GCs, along with paired normal mucosa. Data on clinicopathologic variables and oncologic outcomes of patients were collected and analyzed. RESULTS: We identified 6.1% (12/196) CRC and 8.0% (22/275) GC cases showing loss of ARID1A expression. Expression of ARID1A in paired mucosal epithelial cells was normal in all patients. Loss of ARID1A expression was significantly correlated with negative lymphatic invasion (p = 0.003) in CRC, with large tumor size (p = 0.037) in GC, and with expanding tumor border in both tumor types (CRC, p = 0.010; GC, p = 0.031). However, no association was evident between ARID1A expression and 5 year overall survival in both tumor types. CONCLUSIONS: Loss of ARID1A expression is uncommon and not associated with oncologic outcome but may be related to less invasive clinicopathologic features in CRC and GC. Further studies with a larger number of subjects are needed to establish the possible prognostic impact of ARID1A expression loss. PMID- 25503391 TI - Clusterin facilitates stress-induced lipidation of LC3 and autophagosome biogenesis to enhance cancer cell survival. AB - We define stress-induced adaptive survival pathways linking autophagy with the molecular chaperone clusterin (CLU) that function to promote anticancer treatment resistance. During treatment stress, CLU co-localizes with LC3 via an LIR-binding sequence within autophagosome membranes, functioning to facilitate LC3-Atg3 heterocomplex stability and LC3 lipidation, and thereby enhance autophagosome biogenesis and autophagy activation. Stress-induced autophagy is attenuated with CLU silencing in CLU(-/-) mice and human prostate cancer cells. CLU-enhanced cell survival occurs via autophagy-dependent pathways, and is reduced following autophagy inhibition. Combining CLU inhibition with anticancer treatments attenuates autophagy activation, increases apoptosis and reduces prostate cancer growth. This study defines a novel adaptor protein function for CLU under stress conditions, and highlights how co-targeting CLU and autophagy can amplify proteotoxic stress to delay cancer progression. PMID- 25503390 TI - Docosahexaenoic acid supplementation promotes erythrocyte antioxidant defense and reduces protein nitrosative damage in male athletes. AB - The aim of this study was to determine the influence of long-term docosahexaenoic acid (DHA) dietary supplementation on the erythrocyte fatty acid profile and oxidative balance in soccer players after training and acute exercise. Fifteen volunteer male athletes (age 20.0 +/- 0.5 years) were randomly assigned to a placebo group that consumed an almond-based beverage (n = 6), or to an experimental group that consumed the same beverage enriched with DHA (n = 9) for 8 weeks. Blood samples were taken in resting conditions at the beginning and after 8 weeks of nutritional intervention and training in resting and in post exercise conditions. Oxidative damage markers (malonyldialdehyde, carbonyl and nitrotyrosine indexes) and the activity and protein level of antioxidant enzymes (catalase, superoxide dismutase, glutathione reductase and peroxidase) were assessed. The results showed that training increased antioxidant enzyme activities in erythrocytes. The experimental beverage increased DHA from 34.0 +/- 3.6 to 43.0 +/- 3.6 nmol/10(9) erythrocytes. DHA supplementation increased the catalytic activity of superoxide dismutase from 1.48 +/- 0.40 to 10.5 +/- 0.35 pkat/10(9) erythrocytes, and brought about a reduction in peroxidative damage induced by training or exercise. In conclusion, dietary supplementation with DHA changed the erythrocyte membrane composition, provided antioxidant defense and reduced protein peroxidative damage in the red blood cells of professional athletes after an 8-week training season and acute exercise. PMID- 25503394 TI - The role of heat shock proteins in oxidative stress damage induced by Se deficiency in chicken livers. AB - Selenium (Se) is an essential dietary trace element, which acts as an antioxidant. Heat shock proteins (HSPs) are a family of intracellular proteins whose synthesis is greatly increased upon exposure of cells to environmental stressors including oxidative metabolites, heavy metals, amino acid analogues and so on. However, little is known about the role of HSPs in oxidative stress damage induced by Se deficiency in the chicken liver. The aim of this study was to investigate the effects of Se deficiency on the expression levels of HSPs (Hsps27, 40, 60, 70, and 90) and oxidative indexes in the chicken liver. A total of 300 1-day-old sea blue white laying hens were divided into two groups (n = 150/group), and each of those groups was randomly divided into groups so that the trials were conducted in triplicate. The Se-deficient group (-Se) was fed a Se deficient corn-soy basal diet (the Se content was 0.02 mg/kg); the Se-adequate group as control (+Se) was fed the same basal diet supplemented with Se at 0.2 mg/kg (sodium selenite). The liver tissue was collected and examined for pathological observations, oxidative indexes, mRNA and protein levels of HSPs genes at 15, 25, 35, 45, 55 and 65 days old. The histopathological analysis showed that liver tissues were injured seriously in the Se-deficient group. The oxidative indexes data showed that the malondialdehyde (MDA) level increased and the activity of L-glutathione (GSH) and glutathione peroxidase (GSH-Px) in the chicken liver decreased in Se-deficient group (p < 0.05). Additionally, the mRNA levels of HSPs (27, 40, 60, 70, and 90) increased significantly (p < 0.05) in the Se-deficient group compare to the corresponding control group. Meanwhile, the protein expression of HSPs (60, 70, and 90) also increased significantly (p < 0.05) in the Se-deficient group. These results suggested that oxidative stress and the levels of HSPs expression levels in chicken liver can be influenced by dietary Se deficiency. And HSPs played an important role in the protection of the liver after oxidative stress due to Se deficiency. PMID- 25503395 TI - Pyrosequencing revealed highly microbial phylogenetic diversity in ferromanganese nodules from farmland. AB - There is renewed interest in the origin and makeup of ferromanganese nodules (FMNs), long known to soil mineralogists as unusual secondary minerals. However, new evidence suggests that microorganisms play a significant role in the generation of FMNs. The biogenic origin of nodules has remained elusive because until recently, little has been known about the overall microbial community structure in their microbiota. To learn more about the microbial community and to determine the relative abundance, diversity, and composition of the microbial communities present in FMNs and their surrounding soil, we used pyrosequencing to investigate 16S rRNA genes obtained from vertical soil profiles of both paddy fields and sugarcane fields. Using pyrotaq 16S rRNA gene sequencing, we show that the microbial phylogenetic diversity of nodules was higher than those reported in previous studies of this biosphere, and we identified many previously unidentified microorganisms. Here, we show that the microbial community of these nodules is dominated by Burkholderiales, Rhodocyclales, Acidobacteriales, Desulfuromonales, and Clostridiales, and there were no statistically significant differences found when comparing the microbial community structures of FMNs obtained from vertical soil sequences. Although the microbial composition was markedly different between the surrounding soil and the FMNs, the microbes found within the FMNs were very similar to other FMNs from both field types examined here. In addition to their geochemical properties and the microbial community composition of FMNs, we found that the levels of iron (Fe), manganese (Mn), and SiO2 greatly impact the microbial diversity among FMN communities. Our results indicate that the FMN microbial communities from different land-use types are very similar and suggest that natural selection of these microbes is based on the oligotrophic conditions and the high metal content. Researching FMNs in these two land-use patterns, which represent two different redox potentials, deepens our understanding of Fe-Mn biogeochemical cycling in these oligotrophic biospheres and suggests a biogenetical origin for these nodules. PMID- 25503396 TI - Concentration-dependent and light-responsive self-assembly of bolaamphiphiles bearing alpha-cyanostilbene based photochromophore. AB - In this paper, a new bolaamphiphile bearing 1-cyano-1,2-bis(phenyl)ethene (CNBE) has been synthesized. The self-assembly of this molecule in aqueous solution is concentration-dependent. Two distinct morphologies, monomolecular layered lamellas and helical nanofibres have been obtained with the as-prepared molecular configuration. Note worthily, the helical nanofibres provide an experimental evidence for the pure twisted structure in the liquid crystals, which is theoretically proposed by De Gennes. Due to the photoisomerization of CNBE, the self-assembled nanostructures undergo morphological changes upon irradiation. Although various nanostructures were observed in the solution-state, only nanofibres were obtained after the solution was cast on a substrate, which was attributed to a strong dewetting effect. This work illustrates concentration dependent and light-responsive self-assembly and provides a novel avenue for fabricating smart soft materials. PMID- 25503398 TI - Selective disruption of each part of Janus molecular assemblies by lateral diffusion of stimuli-responsive amphiphilic peptides. AB - Stimuli-responsive Janus-type assemblies with a round-bottom flask shape are prepared from amphiphilic helical peptides using the patchwork self-assembly technique. It can disassemble selectively at the neck or the round-bottom part of the Janus assemblies at low pH upon heat treatment accompanied by the lateral diffusion of the peptides. PMID- 25503399 TI - Are thermodynamic cycles necessary for continuum solvent calculation of pKas and reduction potentials? AB - Continuum solvent calculations of pKas and reduction potentials usually entail the use of a thermodynamic cycle to express the reaction free energy in terms of gas phase energies and free energies of solvation. In this work, we present a systematic study comparing the solution phase free energy changes obtained in this manner with those directly computed within the SMD solvation model against a large test set of 117 pKas and 42 reduction potentials in water and DMSO. The inclusion of vibrational contributions in the free energy of solvation has a negligible impact on the accuracy of thermodynamic cycle predictions of pKas and reduction potentials. Additionally, when gas phase energies in the thermodynamic cycle are computed at more accurate levels of theory, very similar results (mean unsigned difference of 0.5 kcal mol(-1)) can be achieved when the high-level computations (MP2/GTMP2Large and G3(MP2)-RAD(+)) are directly carried out within the continuum model. Increasing the accuracy of the electronic structure theory may or may not improve the agreement with experiment suggesting that the error is largely in the solvation model. For amino acids where their gas and solution phase species exist as different tautomers, the direct approach provided a significant improvement in calculated pKas. These results demonstrate that direct calculation of solution phase pKas and reduction potentials within the SMD model provides a general and reliable approximation to corresponding thermodynamic cycle based protocols, and is recommended for systems where solvation induced changes in geometry are significant. Further studies are necessary to ascertain whether the results are generalisable to other continuum solvation models. PMID- 25503400 TI - A diffusely hardened thyroid gland and multiple neck lymphadenopathies. PMID- 25503397 TI - Poly(A) binding protein 1 enhances cap-independent translation initiation of neurovirulence factor from avian herpesvirus. AB - Poly(A) binding protein 1 (PABP1) plays a central role in mRNA translation and stability and is a target by many viruses in diverse manners. We report a novel viral translational control strategy involving the recruitment of PABP1 to the 5' leader internal ribosome entry site (5L IRES) of an immediate-early (IE) bicistronic mRNA that encodes the neurovirulence protein (pp14) from the avian herpesvirus Marek's disease virus serotype 1 (MDV1). We provide evidence for the interaction between an internal poly(A) sequence within the 5L IRES and PABP1 which may occur concomitantly with the recruitment of PABP1 to the poly(A) tail. RNA interference and reverse genetic mutagenesis results show that a subset of virally encoded-microRNAs (miRNAs) targets the inhibitor of PABP1, known as paip2, and therefore plays an indirect role in PABP1 recruitment strategy by increasing the available pool of active PABP1. We propose a model that may offer a mechanistic explanation for the cap-independent enhancement of the activity of the 5L IRES by recruitment of a bona fide initiation protein to the 5' end of the message and that is, from the affinity binding data, still compatible with the formation of 'closed loop' structure of mRNA. PMID- 25503401 TI - Neurourology and Urodynamics. Editorial. PMID- 25503402 TI - A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias. AB - Dilated cardiomyopathy (DCM) is the most prevalent type of primary myocardial disease, which is the third most common cause of heart failure and the most frequent reason for heart transplantation. Aggregating evidence demonstrates that genetic risk factors are involved in the pathogenesis of idiopathic DCM. Nevertheless, DCM is of remarkable genetic heterogeneity and the genetic defects underpinning DCM in an overwhelming majority of patients remain unknown. In the present study, the whole coding exons and splice junction sites of the NKX2-5 gene, which encodes a homeodomain transcription factor crucial for cardiac development and structural remodeling, were sequenced in 130 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped for the NKX2-5 gene. The functional effect of the mutant NKX2-5 was characterized in contrast to its wild-type counterpart using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2-5 mutation, p.S146W, was identified in a family with DCM inherited as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. Notably, the mutation carriers also had arrhythmias, such as paroxysmal atrial fibrillation and atrioventricular block. The missense mutation was absent in 400 reference chromosomes and the altered amino acid was completely conserved evolutionarily among species. Functional analysis revealed that the NKX2-5 mutant was associated with a significantly reduced transcriptional activity. The findings expand the mutational spectrum of NKX2-5 linked to DCM and provide novel insight into the molecular mechanisms underlying DCM, contributing to the antenatal prophylaxis and allele-specific management of DCM. PMID- 25503405 TI - Dynamically controlling the emission of single excitons in photonic crystal cavities. AB - Single excitons in semiconductor microcavities represent a solid state and scalable platform for cavity quantum electrodynamics, potentially enabling an interface between flying (photon) and static (exciton) quantum bits in future quantum networks. While both single-photon emission and the strong coupling regime have been demonstrated, further progress has been hampered by the inability to control the coherent evolution of the cavity quantum electrodynamics system in real time, as needed to produce and harness charge-photon entanglement. Here using the ultrafast electrical tuning of the exciton energy in a photonic crystal diode, we demonstrate the dynamic control of the coupling of a single exciton to a photonic crystal cavity mode on a sub-nanosecond timescale, faster than the natural lifetime of the exciton. This opens the way to the control of single-photon waveforms, as needed for quantum interfaces, and to the real-time control of solid-state cavity quantum electrodynamics systems. PMID- 25503404 TI - Cranial distraction osteogenesis: a proposal of minimal consolidation period. AB - PURPOSE: Cranial distraction osteogenesis (DO) has many advantages for correcting skull deformities: Thus, DO is extensively used for the treatment of skull deformities. However, diverse, unexpected complications are associated with this procedure. In this study, we present the surgical outcomes and complications of DO. Moreover, we propose a modified protocol for DO to reduce complications. METHODS: This is a retrospective study on managed patients that underwent DO between March 2008 and May 2013. Their clinical courses were reviewed. Distraction protocols were individually inspected, and the final surgical outcomes, including complications, were evaluated. RESULTS: During the study period, a total of ten patients (seven boys and three girls) were treated at our institute. The median distraction period was 20.5 days (ranging from 17 to 50 days). The range of total distraction length was 19-22 mm. The median consolidation period was 96 days (ranging from 0 to 343 days). All patients achieved the goals of distraction. At follow-up evaluations, all patients, except one, showed good surgical outcomes in both head shape and neurologic symptoms. There were six patients with wound complications during the treatment period. Among them, the distractors were removed early in three patients. Interestingly, even these three patients, without a sufficient consolidation period, showed good outcomes. CONCLUSIONS: Although DO has many merits for correcting skull deformities, it frequently causes severe wound complications. To reduce these complications, we propose a modified protocol with a minimal or even no consolidation period. PMID- 25503406 TI - Global analysis of photosynthesis transcriptional regulatory networks. AB - Photosynthesis is a crucial biological process that depends on the interplay of many components. This work analyzed the gene targets for 4 transcription factors: FnrL, PrrA, CrpK and MppG (RSP_2888), which are known or predicted to control photosynthesis in Rhodobacter sphaeroides. Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) identified 52 operons under direct control of FnrL, illustrating its regulatory role in photosynthesis, iron homeostasis, nitrogen metabolism and regulation of sRNA synthesis. Using global gene expression analysis combined with ChIP-seq, we mapped the regulons of PrrA, CrpK and MppG. PrrA regulates ~34 operons encoding mainly photosynthesis and electron transport functions, while CrpK, a previously uncharacterized Crp-family protein, regulates genes involved in photosynthesis and maintenance of iron homeostasis. Furthermore, CrpK and FnrL share similar DNA binding determinants, possibly explaining our observation of the ability of CrpK to partially compensate for the growth defects of a DeltaFnrL mutant. We show that the Rrf2 family protein, MppG, plays an important role in photopigment biosynthesis, as part of an incoherent feed-forward loop with PrrA. Our results reveal a previously unrealized, high degree of combinatorial regulation of photosynthetic genes and significant cross-talk between their transcriptional regulators, while illustrating previously unidentified links between photosynthesis and the maintenance of iron homeostasis. PMID- 25503408 TI - A somatic permeability barrier around the germline is essential for Drosophila spermatogenesis. AB - Interactions between the soma and germline are essential for gametogenesis. In the Drosophila testis, differentiating germ cells are encapsulated by two somatic cells that surround the germline throughout spermatogenesis. chickadee (chic), the fly ortholog of Profilin, mediates soma-germline interactions. Knockdown of Chic in the soma results in sterility and severely disrupted spermatogenesis due to defective encapsulation. To study this defect further, we developed a permeability assay to analyze whether the germline is isolated from the surrounding environment by the soma. We find that germline encapsulation by the soma is, by itself, insufficient for the formation of a permeability barrier, but that such a barrier gradually develops during early spermatogenesis. Thus, germline stem cells, gonialblasts and early spermatogonia are not isolated from the outside environment. By late spermatocyte stages, however, a permeability barrier is formed by the soma. Furthermore, we find that, concomitant with formation of the permeability barrier, septate junction markers are expressed in the soma and localize to junctional sites connecting the two somatic cells that surround the germline. Importantly, knockdown of septate junction components also disrupts the permeability barrier. Finally, we show that germline differentiation is delayed when the permeability barrier is compromised. We propose that the permeability barrier around the germline serves an important regulatory function during spermatogenesis by shaping the signaling events that take place between the soma and the germline. PMID- 25503407 TI - UPF2, a nonsense-mediated mRNA decay factor, is required for prepubertal Sertoli cell development and male fertility by ensuring fidelity of the transcriptome. AB - Nonsense-mediated mRNA decay (NMD) represents a highly conserved RNA surveillance mechanism through which mRNA transcripts bearing premature termination codons (PTCs) are selectively degraded to maintain transcriptomic fidelity in the cell. Numerous in vitro studies have demonstrated the importance of the NMD pathway; however, evidence supporting its physiological necessity has only just started to emerge. Here, we report that ablation of Upf2, which encodes a core NMD factor, in murine embryonic Sertoli cells (SCs) leads to severe testicular atrophy and male sterility owing to rapid depletion of both SCs and germ cells during prepubertal testicular development. RNA-Seq and bioinformatic analyses revealed impaired transcriptomic homeostasis in SC-specific Upf2 knockout testes, characterized by an accumulation of PTC-containing transcripts and the transcriptome-wide dysregulation of genes encoding splicing factors and key proteins essential for SC fate control. Our data demonstrate an essential role of UPF2-mediated NMD in prepubertal SC development and male fertility. PMID- 25503410 TI - Investigating CNS synaptogenesis at single-synapse resolution by combining reverse genetics with correlative light and electron microscopy. AB - Determining direct synaptic connections of specific neurons in the central nervous system (CNS) is a major technical challenge in neuroscience. As a corollary, molecular pathways controlling developmental synaptogenesis in vivo remain difficult to address. Here, we present genetic tools for efficient and versatile labeling of organelles, cytoskeletal components and proteins at single neuron and single-synapse resolution in Drosophila mechanosensory (ms) neurons. We extended the imaging analysis to the ultrastructural level by developing a protocol for correlative light and 3D electron microscopy (3D CLEM). We show that in ms neurons, synaptic puncta revealed by genetically encoded markers serve as a reliable indicator of individual active zones. Block-face scanning electron microscopy analysis of ms axons revealed T-bar-shaped dense bodies and other characteristic ultrastructural features of CNS synapses. For a mechanistic analysis, we directly combined the single-neuron labeling approach with cell specific gene disruption techniques. In proof-of-principle experiments we found evidence for a highly similar requirement for the scaffolding molecule Liprin alpha and its interactors Lar and DSyd-1 (RhoGAP100F) in synaptic vesicle recruitment. This suggests that these important synapse regulators might serve a shared role at presynaptic sites within the CNS. In principle, our CLEM approach is broadly applicable to the developmental and ultrastructural analysis of any cell type that can be targeted with genetically encoded markers. PMID- 25503409 TI - The carboxy-terminus of p63 links cell cycle control and the proliferative potential of epidermal progenitor cells. AB - The transcription factor p63 (Trp63) plays a key role in homeostasis and regeneration of the skin. The p63 gene is transcribed from dual promoters, generating TAp63 isoforms with growth suppressive functions and dominant-negative DeltaNp63 isoforms with opposing properties. p63 also encodes multiple carboxy (C)-terminal variants. Although mutations of C-terminal variants have been linked to the pathogenesis of p63-associated ectodermal disorders, the physiological role of the p63 C-terminus is poorly understood. We report here that deletion of the p63 C-terminus in mice leads to ectodermal malformation and hypoplasia, accompanied by a reduced proliferative capacity of epidermal progenitor cells. Notably, unlike the p63-null condition, we find that p63 C-terminus deficiency promotes expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) (Cdkn1a), a factor associated with reduced proliferative capacity of both hematopoietic and neuronal stem cells. These data suggest that the p63 C-terminus plays a key role in the cell cycle progression required to maintain the proliferative potential of stem cells of many different lineages. Mechanistically, we show that loss of Calpha, the predominant C-terminal p63 variant in epithelia, promotes the transcriptional activity of TAp63 and also impairs the dominant-negative activity of DeltaNp63, thereby controlling p21(Waf1/Cip1) expression. We propose that the p63 C-terminus links cell cycle control and the proliferative potential of epidermal progenitor cells via mechanisms that equilibrate TAp63 and DeltaNp63 isoform function. PMID- 25503412 TI - Characterisation and quantification of F8 transcripts of ten putative splice site mutations. AB - Mutations affecting splice sites comprise approximately 7.5 % of the known F8 gene mutations but only a few were verified at mRNA level. In the present study, 10 putative splice site mutations were characterised by mRNA analysis using reverse transcription PCR (RT-PCR). Quantitative real-time RT-PCR (RT-qPCR) and co-amplification fluorescent PCR were used in combination to quantify the amount of each of multiple F8 transcripts. All of the mutations resulted in aberrant splicing. One of them (c.6187+1del1) generated one form of F8 transcript with exon skipping, and the remaining nine mutations (c.602-6T>C, c.1752+5_1752+6insGTTAG, c.1903+5G>A, c.5219+3A>G, c.5586+3A>T, c.969A>T, c.265+4A>G, c.601+1_601+5del5 and c.1444-8_1444del9) produced multiple F8 transcripts with exon skipping, activation of cryptic splice site and/or normal splicing. Residual wild-type F8 transcripts were produced by the first six of the nine mutations with amounts of 3.9 %, 14.2 %, 5.2 %, 19.2 %, 1.8 % and 2.5 % of normal levels, respectively, which were basically consistent with coagulation phenotypes in the related patients. In comparison with the mRNA findings, software Alamut v2.3 had values in the prediction of pathogenic effects on native splice sites but was not reliable in the prediction of activation of cryptic splice sites. Our quantification of F8 transcripts may provide an alternative way to evaluate the low expression levels of residue wild-type F8 transcripts and help to explain the severity of haemophilia A caused by splicing site mutations. PMID- 25503411 TI - Cyclic AMP in oocytes controls meiotic prophase I and primordial folliculogenesis in the perinatal mouse ovary. AB - In mammalian ovaries, a fixed population of primordial follicles forms during the perinatal stage and the oocytes contained within are arrested at the dictyate stage of meiotic prophase I. In the current study, we provide evidence that the level of cyclic AMP (cAMP) in oocytes regulates oocyte meiotic prophase I and primordial folliculogenesis in the perinatal mouse ovary. Our results show that the early meiotic development of oocytes is closely correlated with increased levels of intra-oocyte cAMP. Inhibiting cAMP synthesis in fetal ovaries delayed oocyte meiotic progression and inhibited the disassembly and degradation of synaptonemal complex protein 1. In addition, inhibiting cAMP synthesis in in vitro cultured fetal ovaries prevented primordial follicle formation. Finally, using an in situ oocyte chromosome analysis approach, we found that the dictyate arrest of oocytes is essential for primordial follicle formation under physiological conditions. Taken together, these results suggest a role for cAMP in early meiotic development and primordial follicle formation in the mouse ovary. PMID- 25503414 TI - The effect of intensive education on concordance with the Age-Related Eye Disease Study (AREDS) recommendations in a tertiary referral practice. AB - BACKGROUND/AIMS: The Age-Related Eye Disease Study (AREDS) showed that supplementation with their formula led to a significant decrease in progression of age-related macular degeneration (AMD). This study aims to assess the effect of different education protocols on concordance with the trial recommendations in two retinal clinics. METHODS: A prospective controlled survey of concordance with the AREDS recommendations in two retinal clinics was administered to 330 patients with AREDS category 3 or 4 AMD. The results were evaluated to assess the effect of differing levels of patient education. In clinic 1, there was a formal policy of giving the patient both verbal and written instructions and verbal repetition of these instructions from each staff member on each patient visit; in clinic 2, there was no specific education policy. RESULTS: Clinic 1 had a concordance rate of 81.6% and clinic 2 of 44.1%. There were no significant differences in the patient demographics between the two clinics. CONCLUSION: A high concordance rate can be achieved in clinical practice with rigorous patient education that includes a policy of having continual repetition of instructions. PMID- 25503413 TI - Impact of ambient humidity on child health: a systematic review. AB - BACKGROUND AND OBJECTIVES: Changes in relative humidity, along with other meteorological factors, accompany ongoing climate change and play a significant role in weather-related health outcomes, particularly among children. The purpose of this review is to improve our understanding of the relationship between ambient humidity and child health, and to propose directions for future research. METHODS: A comprehensive search of electronic databases (PubMed, Medline, Web of Science, ScienceDirect, OvidSP and EBSCO host) and review of reference lists, to supplement relevant studies, were conducted in March 2013. All identified records were selected based on explicit inclusion criteria. We extracted data from the included studies using a pre-designed data extraction form, and then performed a quality assessment. Various heterogeneities precluded a formal quantitative meta analysis, therefore, evidence was compiled using descriptive summaries. RESULTS: Out of a total of 3797 identified records, 37 papers were selected for inclusion in this review. Among the 37 studies, 35% were focused on allergic diseases and 32% on respiratory system diseases. Quality assessment revealed 78% of the studies had reporting quality scores above 70%, and all findings demonstrated that ambient humidity generally plays an important role in the incidence and prevalence of climate-sensitive diseases among children. CONCLUSIONS: With climate change, there is a significant impact of ambient humidity on child health, especially for climate-sensitive infectious diseases, diarrhoeal diseases, respiratory system diseases, and pediatric allergic diseases. However, some inconsistencies in the direction and magnitude of the effects are observed. PMID- 25503416 TI - Noninvasive blood glucose sensing using near infra-red spectroscopy and artificial neural networks based on inverse delayed function model of neuron. AB - In this paper, a non-invasive blood glucose sensing system is presented using near infra-red(NIR) spectroscopy. The signal from the NIR optodes is processed using artificial neural networks (ANN) to estimate the glucose level in blood. In order to obtain accurate values of the synaptic weights of the ANN, inverse delayed (ID) function model of neuron has been used. The ANN model has been implemented on field programmable gate array (FPGA). Error in estimating glucose levels using ANN based on ID function model of neuron implemented on FPGA, came out to be 1.02 mg/dl using 15 hidden neurons in the hidden layer as against 5.48 mg/dl using ANN based on conventional neuron model. PMID- 25503415 TI - Helicobacter pylori genetic diversity and gastro-duodenal diseases in Malaysia. AB - Helicobacter pylori infection results in diverse clinical conditions ranging from chronic gastritis and ulceration to gastric adenocarcinoma. Among the multiethnic population of Malaysia, Indians consistently have a higher H. pylori prevalence as compared with Chinese and Malays. Despite the high prevalence of H. pylori, Indians have a relatively low incidence of peptic ulcer disease and gastric cancer. In contrast, gastric cancer and peptic ulcer disease incidence is high in Chinese. H. pylori strains from Chinese strains predominantly belong to the hspEAsia subpopulation while Indian/Malay strains mainly belong to the hspIndia subpopulation. By comparing the genome of 27 Asian strains from different subpopulations, we identified six genes associated with risk of H. pylori-induced peptic ulcer disease and gastric cancer. This study serves as an important foundation for future studies aiming to understand the role of bacterial factors in H. pylori-induced gastro-duodenal diseases. PMID- 25503417 TI - A RFID specific participatory design approach to support design and implementation of real-time location systems in the operating room. AB - Information technology, such as real-time location (RTL) systems using Radio Frequency IDentification (RFID) may contribute to overcome patient safety issues and high costs in healthcare. The aim of this work is to study if a RFID specific Participatory Design (PD) approach supports the design and the implementation of RTL systems in the Operating Room (OR). A RFID specific PD approach was used to design and implement two RFID based modules. The Device Module monitors the safety status of OR devices and the Patient Module tracks the patients' locations during their hospital stay. The PD principles 'multidisciplinary team', 'participation users (active involvement)' and 'early adopters' were used to include users from the RFID company, the university and the hospital. The design and implementation process consisted of two 'structured cycles' ('iterations'). The effectiveness of this approach was assessed by the acceptance in terms of level of use, continuity of the project and purchase. The Device Module included eight strategic and twelve tactical actions and the Patient Module included six strategic and twelve tactical actions. Both modules are now used on a daily basis and are purchased by the hospitals for continued use. The RFID specific PD approach was effective in guiding and supporting the design and implementation process of RFID technology in the OR. The multidisciplinary teams and their active participation provided insights in the social and the organizational context of the hospitals making it possible to better fit the technology to the hospitals' (future) needs. PMID- 25503418 TI - Determinants of RFID adoption in Malaysia's healthcare industry: occupational level as a moderator. AB - With today's highly competitive market in the healthcare industry, Radio Frequency Identification (RFID) is a technology that can be applied by hospitals to improve operational efficiency and to gain a competitive advantage over their competitors. The purpose of this study is to investigate the factors that may effect RFID adoption in Malaysia's healthcare industry. In addition, the moderating role of occupational level was tested. Data was collected from 223 managers as well as healthcare and supporting staffs. This data was analyzed using the partial least squares technique. The results show that perceived ease of use and usefulness, government policy, top management support, and security and privacy concerns have an effect on the intent to adopt RFID in hospitals. There is a wide gap between managers and healthcare staff in terms of the factors that influence RFID adoption. The results of this study will help decision makers as well as managers in the healthcare industry to better understand the determinants of RFID adoption. Additionally, it will assist in the process of RFID adoption, and therefore, spread the usage of RFID technology in more hospitals. PMID- 25503419 TI - The impact of initial and residual thrombus burden on the no-reflow phenomenon in patients with ST-segment elevation myocardial infarction. AB - BACKGROUND: Limited data are available on the clinical significance of residual thrombi after thrombectomy and prestenting reduced epicardial coronary flow in ST segment elevation myocardial infarct (STEMI) patients. MATERIALS AND METHODS: The incidence of the no-reflow phenomenon, defined as a final thrombolysis in myocardial infarction (TIMI) flow grade of up to 2 or a myocardial blush grade of up to 1, was compared in 260 STEMI patients undergoing primary percutaneous coronary intervention according to thrombotic burden. Large thrombotic burden (LTB), defined as a thrombus score of at least 3, was observed in 134 patients, among whom 66 (49.3%) underwent aspiration thrombectomy. No-reflow incidence was compared on the basis of thrombectomy treatment, thrombus residue after thrombectomy, and prestenting TIMI flow grade. RESULTS: The no-reflow phenomenon occurred most frequently in LTB patients without thrombectomy, followed by those who underwent thrombectomy and the small thrombus burden group (33.8 vs. 21.2 vs. 10.3%, respectively, P<0.001). Patients with a prestenting residual thrombus or a TIMI flow grade of up to 2 had higher no-reflow incidence than those with no visible prestenting thrombus and a TIMI flow grade of 3 (74 vs. 6.2%, P<0.001). Multiple logistic regression analysis identified a prestenting TIMI flow grade of up to 2 (odds ratio 36.422, 95% confidence interval 13.952-95.079) as an independent predictor of the no-reflow phenomenon. CONCLUSION: Manual thrombus aspiration reduced no-reflow incidence in STEMI patients with LTB. However, even after thrombectomy, prestenting residual thrombi and decreased coronary flow were related to a higher occurrence of the no-reflow phenomenon. PMID- 25503421 TI - Biologic strategies to improve nerve regeneration after peripheral nerve repair. AB - BACKGROUND: Peripheral nerve injuries remain a challenging problem for microsurgeons. Direct repair is the gold standard, but often the surgeon is left with a gap that prevents tension-free repair. The use of empty tubes/conduits/allograft has resulted in regeneration of some sensory and motor function, but the results remain suboptimal compared with autograft. However, the use of nerve autograft has associated donor site morbidity and limited availability. METHODS: A review of the literature was performed to determine current biologic strategies to improve nerve regeneration after nerve repair. RESULTS: Nerve conduits, various neurotrophic factors, and stem cells are currently being studied as alternatives to the use of nerve autograft. CONCLUSIONS: Sensory and motor recovery after peripheral nerve regeneration remains suboptimal, especially in cases where primary nerve repair is not possible. Current strategies to augment nerve regeneration have focused on modulating the presence and activity of Schwann cells, either through direct implantation or by stimulating stem cells to differentiate toward Schwann cells, and through the use of neurotrophic factors to enhance the speed and quality of axon growth. Clinical studies will be necessary to determine the benefit of these strategies. PMID- 25503420 TI - Predictive value of endothelial function by noninvasive peripheral arterial tonometry for coronary artery disease. AB - BACKGROUND: Endothelial dysfunction is a key step in the initiation and progression of atherosclerosis and subsequent cardiovascular complications. We examined whether peripheral endothelial function, as assessed by fingertip reactive hyperemia-peripheral arterial tonometry (RH-PAT), can provide additional clinical value to traditional risk factors for cardiovascular diseases in predicting coronary artery disease (CAD). METHODS: We included 118 stable patients who were referred for coronary angiography for chest pain evaluation or due to abnormal stress test results. A natural logarithmic value of the RH-PAT index (Ln_RHI) was obtained before cardiac catheterization by an independent operator. Significant CAD was defined as luminal stenosis of at least 70% (>=50% at left main) and/or fractional flow reserve of up to 0.80 in one or more major coronary arteries or their major branches. RESULTS: Levels of Ln_RHI were significantly lower in patients with CAD (n=60) compared with patients without CAD (n=58; 0.69+/-0.29 vs. 0.88+/-0.27, P<0.001). Ln_RHI was significantly associated with CAD independent from traditional risk factors (odds ratio for a 0.1 decrease in Ln_RHI=1.25, 95% confidence interval: 1.04-1.52, P=0.01). The net reclassification index was improved when Ln_RHI was added to traditional risk factors (0.62, 95% confidence interval: 0.27-0.97, P=0.001). CONCLUSION: Peripheral endothelial function, as assessed by RH-PAT, improved risk stratification when added to traditional risk factors. RH-PAT is potentially useful for identifying patients at high risk for CAD. PMID- 25503422 TI - Role of anatomical region and hypoxia on angiogenic markers in adipose-derived stromal cells. AB - BACKGROUND: Recent research into adipose-derived stem cells (ASCs) suggests that anatomical location has a major impact on the metabolic profile and differentiation capacity of ASCs. By having a better understanding of how various ASCs respond to cellular stressors such as hypoxia, which are induced during routine surgical procedures, we can facilitate future development of cell-based therapies to improve wound healing. PATIENTS AND METHODS: Human ASCs were isolated from the superficial and deep adipose layers of four patients undergoing elective abdominoplasty. ASCs were cultured in hypoxic (1% O2, 5% CO2, and 94% N2) conditions. After 12 and 48 hours, ASCs were assessed for markers of angiogenesis by mRNA levels of vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and hypoxia inducible factor 1 alpha (HIF-1alpha). Western blot analysis was performed to assess levels of VEGF A, p-NF-kappaB, and NF-kappaB. In addition, in vitro analysis of angiogenesis was performed using Matrigel assay (BD Biosciences, Franklin Lakes, NJ). RESULTS: We observed significant increases in deep ASC's VEGF-A, VEGF-B, and HIF-1alpha mRNA expression compared with the superficial layer after 24-hour hypoxia (p < 0.05). Similar results were found when examining protein expression levels, with the deep ASCs expressing significantly larger amounts of VEGF-A and p-NF-kappaB (p < 0.05) compared with the superficial layer. CONCLUSION: Our results suggest that significant variations exist in the angiogenic profile of superficial and deep ASCs. We demonstrate that superficial ASCs are less prone to transcribe potent chemokines for angiogenesis, such as VEGF-A, VEGF-B, and HIF-1alpha and are less likely to translate VEGF-A and NF-kappaB. This may help with the selection of specific stem cell donor sites in future models for stem cell therapy. PMID- 25503424 TI - A Computational Model of the Dendron of the GnRH Neuron. AB - Gonadotropin-releasing hormone (GnRH) neurons have two major processes that have properties of both dendrites (they receive synaptic input from other neurons) and axons (they actively propagate action potentials to the synaptic terminal). These processes have thus been termed dendrons. We construct a stochastic spatiotemporal model of the dendron of the GnRH neuron, with the goal of studying how stochastic synaptic input along the length of the dendron affects the initiation and propagation of action potentials. We show (1) that synaptic inputs closer to the soma are effective controllers of action potential initiation and electrical bursting and (2) that although the effects on the amplitude and width of propagating action potentials are critically dependent on the timing and location of synaptic input addition, the effects remain small. We conclude that although stochastic synaptic input along the length of the dendron is likely to be a major determinant of action potential initiation, it is an unlikely mechanism for controlling whether or not action potentials reach the synaptic terminal. Thus, the role of synaptic inputs situated along the dendron a long way from the site of action potential initiation remains unclear. We also show that the actions of kisspeptin can result in significant modulation of the amount of calcium released by an action potential at the synaptic terminal. Furthermore, we show that the actions of kisspeptin are greatest when multiple effects operate together and that a kisspeptin-induced increase in firing rate is, by itself, less effective at increasing Ca2+ release than is a combination of an increased firing rate, an increase in Ca2+ influx, and an increase in inositol trisphosphate (IP3) production. We conclude that the inherent synergies in the various actions of kisspeptin make it a likely candidate for the precise control of Ca2+ transients at the synaptic terminal. PMID- 25503423 TI - Kinetically guided neoadjuvant chemoradiotherapy based on 5-Fluorouracil in patients with locally advanced rectal cancer. AB - BACKGROUND AND PURPOSE: This study estimated patients' early response following neoadjuvant chemoradiotherapy (CHRT) of locally advanced rectal cancer based on 5 fluorouracil (5-FU). The target was to achieve pathological complete response (pCR; residual disease-free stage) and toxicities of grade <=2, using individual dosing predicted according to the steady-state plasma concentration (C ss) and pharmacokinetic parameters of 5-FU: the area under the time-concentration curve at steady state (AUC) and clearance (CL). PATIENTS AND METHODS: This open-label prospective study enrolled 33 adult patients treated with 5-FU administered as a continuous intravenous infusion over 4-5 weeks, as follows: in Group 1a (N = 6), the patients received a standard dose of 300 mg/m(2)/24 h. In Group 1b (N = 7), the patients were treated with an escalated dose of 400-1,000 mg/m(2)/24 h. In Group 2 (N = 20), the patients were given dosing kinetically guided in order to reach the target range of 5-FU C ss 50-100 ug/L. Tolerability was tested according to Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Radiotherapy was delivered with 10-15 MV photon beams at 1.8 Gy/fraction up to 50.4 Gy in 28 daily fractions for 5 days a week. Surgery followed 4-6 weeks after the completion of CHRT and clinical restaging. The pCR and residual tumour stage were evaluated using preoperative tumour downstaging in magnetic resonance, postoperative histopathological staging and tumour regression rate (residual disease). RESULTS AND CONCLUSION: The cumulative AUC of 5-FU (total exposure to the drug) correlated with cumulative 5-FU dose (r = 0.61; p < 0.001) and residual disease (r s = -0.53; p < 0.005). A higher target pCR rate was reached in patients individually treated (Group 2) who finished the whole 5-week CHRT. The individual daily dose needed to reach the target C ss should be >350 mg/m(2) (up to 600 mg/m(2)) provided that 5-FU metabolic ratio is within the range of 2.5-6 and the cumulative AUC5wks is within 50-100 mg.h/L. PMID- 25503425 TI - Locally Advanced Malignant Myoepithelioma of the Parotid Gland Treated With Radiotherapy: A Case Study and Review of the BC Cancer Agency Experience. AB - OBJECTIVES: Malignant myoepithelioma of salivary glands is a rare neoplasm; most arise in the parotid gland and minor salivary glands of the palate. Surgery has been the mainstay of treatment. METHODS: This is case report of a patient treated with primary radical radiotherapy and retrospective review of institutional experience. RESULTS: An 87-year-old man with locoregionally advanced malignant myoepithelioma of the parotid gland received radiotherapy alone with complete clinical response and sustained 39 months of posttreatment. Between 1981 and 2012, 15 cases of malignant myoepithelioma of the parotid were seen. Thirteen patients received surgical excision and adjuvant radiotherapy. At a median follow up of 47 months, 12 patients were alive without recurrence, 2 died without recurrence, and 1 died with metastatic myoepithelioma. CONCLUSIONS: Durable locoregional disease control and disease-free-survival was achieved in the majority of patients. The case reported suggests radiation therapy may be an effective treatment option for inoperable cases. PMID- 25503427 TI - Resection of Colorectal Cancer With Versus Without Preservation of Inferior Mesenteric Artery. AB - OBJECTIVE: To assess the clinical significance of preservation of the inferior mesenteric artery (IMA) in comparison with IMA ligation in surgery for sigmoid colon or rectal (colorectal) cancer. METHODS: Consecutive patients (n=862) with colorectal cancer who underwent intended surgical resection of the main tumor between 1986 and 2011 were retrospectively analyzed. The patients were divided into 2 groups: IMA preserved (n=745) and IMA ligated (n=117). RESULTS: No significant difference was observed in incidence of advanced stage III or IV disease between the 2 groups (P=0.56 and 0.51, respectively), whereas a longer operation time (287 [95 to 700] vs. 215 [60 to 900] min, respectively; P<0.001) and greater amount of intraoperative bleeding (595 [15 to 4530] vs. 235 [1 to 11565] mL, respectively; P<0.001) were observed in the IMA-ligated group. The overall incidence of surgery-related complications was higher in the IMA-ligated group than in the IMA-preserved group (53.0% vs. 38.5%, respectively; P=0.003). Urinary dysfunction and abdominal abscess were significantly more frequent in the IMA-ligated group (11.1% vs. 4.0%, P=0.001; and 6.8% vs. 2.6%, P=0.01, respectively), and postoperative hospitalization was longer (11 to 140, median 28 vs. 5 to 153, median 19 d, respectively; P<0.001). No significant difference was found in overall survival rate between the 2 groups. CONCLUSIONS: For colorectal cancer resection, IMA preservation may be no change to IMA ligation as to patient' survival, with small risk of operative morbidity. PMID- 25503428 TI - Lymph Node Burden as a Predictive Factor for Selective Chemoradiotherapy in Patients With Locally Advanced Gastric Cancer After a D2 Dissection: A Retrospective Study. AB - OBJECTIVES: The role of adjuvant radiation in locally advanced gastric cancer after a D2 lymph node dissection is not well defined. The Adjuvant Chemoradiation Therapy in Stomach Cancer trial demonstrated a benefit in selected patients with positive lymph nodes. This study further defines lymph node burden as a predictive factor for adjuvant radiation in locally advanced gastric cancer after radical D2 lymph node dissection. MATERIALS AND METHODS: One hundred eighty-six patients with locally advanced gastric cancer and D2 dissections were retrospectively investigated. Patients were divided into 2 equal and well balanced groups based on clinicopathologic characteristics, with half receiving chemoradiation and the other half chemotherapy alone. Clinical outcomes and recurrence patterns were compared. Lymph node ratio (LNR) was defined as ratio of positive to examined nodes. Chemotherapies were fluorouracil-based regimens. Radiation was prescribed to 45 Gy (range, 45 to 50.4 Gy) using 3-dimensional conformal or intensity-modulated radiation therapy techniques. RESULTS: There was no difference between patients treated with or without radiation in 3-year disease-free survival (DFS) (57.0% vs. 62.0%, P=0.30) or 3-year overall survival (72.8% vs. 77.4%, P=0.23). However, patients with LNR>0.65 or 3 to 6 positive nodes (N2) had improved 3-year DFS and 3-year distant metastasis-free survival (DMFS) in the chemoradiation group (LNR>0.65 vs. LNR<=0.65: 3-y DFS: 35.8% vs. 0%, P=0.052, 3-y DMFS: 75.2% vs. 0%, P=0.026; N2 vs. non-N2: 3-y DFS: 84.7% vs. 57.1%, P=0.046, 3-y DMFS: 100.0% vs. 65.3%, P=0.036). CONCLUSIONS: N2 or LNR>0.65 may be indications for adjuvant chemoradiotherapy. Further randomized studies are needed for validation. PMID- 25503426 TI - Influence of NSAID Use Among Colorectal Cancer Survivors on Cancer Outcomes. AB - PURPOSE: Colorectal cancer (CRC) is the third most common cancer diagnosed in men and women in the United States. Given the availability of effective screening, most tumors are found early enough to offer patients substantial long-term survival. Thus there is a resulting significant population of CRC survivors for whom modifiable risk factors for recurrence and survival would be of interest. METHODS: We conducted a population-based retrospective cohort study among patients enrolled in 2 large Midwestern health plans for which claims data, including pharmacy fill data, and medical record data were available. Men and women who were 40 years of age or older at the time of CRC diagnosis with disease less than stage IV and no history of Crohn disease, ulcerative colitis, and irritable bowel syndrome were included. CRC cases diagnosed between January 1, 1990 and December 31, 2000 were included if they met the inclusion criteria. Adjusted Cox proportional hazard models were used with exposure modeled as a time dependent covariate. We assessed progression-free survival, defined as an aggressive polyp or invasive disease, and overall survival. RESULTS: After adjustment for age at diagnosis, sex, race, body mass index, stage, side of initial tumor, and tumor histology, we found that current users of nonsteroidal anti-inflammatory drugs had a 3-fold decreased risk of recurrence and a >7-fold decreased risk of death. Our results are statistically significant with P-values <0.05. CONCLUSIONS: Our results suggest that current use of nonsteroidal anti inflammatory drugs provides significant improvements in CRC outcomes. PMID- 25503429 TI - Predictors and Patterns of Local, Regional, and Distant Failure in Squamous Cell Carcinoma of the Vulva. AB - OBJECTIVE: To identify factors predicting for recurrence in vulvar cancer patients undergoing surgical treatment. METHODS: We retrospectively evaluated data of consecutive patients with squamous cell vulvar cancer treated between January 1, 1990 and December 31, 2013. Basic descriptive statistics and multivariable analysis were used to design predicting models influencing outcomes. Five-year disease-free survival (DFS) and overall survival (OS) were analyzed using the Cox model. RESULTS: The study included 101 patients affected by vulvar cancer: 64 (63%) stage I, 12 (12%) stage II, 20 (20%) stage III, and 5 (5%) stage IV. After a mean (SD) follow-up of 37.6 (22.1) months, 21 (21%) recurrences occurred. Local, regional, and distant failures were recorded in 14 (14%), 6 (6%), and 3 (3%) patients, respectively. Five-year DFS and OS were 77% and 82%, respectively. At multivariate analysis only stromal invasion >2 mm (hazard ratio: 4.9 [95% confidence interval, 1.17-21.1]; P=0.04) and extracapsular lymph node involvement (hazard ratio: 9.0 (95% confidence interval, 1.17-69.5); P=0.03) correlated with worse DFS, although no factor independently correlated with OS. Looking at factors influencing local and regional failure, we observed that stromal invasion >2 mm was the only factor predicting for local recurrence, whereas lymph node extracapsular involvement predicted for regional recurrence. CONCLUSIONS: Stromal invasion >2 mm and lymph node extracapsular spread are the most important factors predicting for local and regional failure, respectively. Studies evaluating the effectiveness of adjuvant treatment in high risk patients are warranted. PMID- 25503430 TI - Two-week Course of Preoperative Radiotherapy for Locally Advanced Rectal Adenocarcinoma: 8 Years' Experience in a Single Institute. AB - OBJECTIVES: To evaluate local control and survival in locally advanced rectal adenocarcinoma patients who underwent a preoperative 2-week course of radiotherapy (RT) and to identify prognostic factors influencing the survival rate. METHODS: We analyzed 377 consecutively treated patients with locally advanced (T3/T4 or node positive) rectal adenocarcinoma. All patients underwent a preoperative 2-week course of RT (30 Gy in 10 fractions) followed by curative surgery. Regression model was used to examine prognostic factors for the disease free survival (DFS) and overall survival (OS) rates. The Statistical Analysis System software package, version 9.3, was used for analysis. RESULTS: The median follow-up for all living patients was 63.8 months (range, 5.1 to 131.7). The 5 year DFS and OS rates were 64.5% (95% CI, 59.0-69.4) and 75.6% (95% CI, 70.5 80.0), respectively. The 5-year cumulative incidences of local recurrence and distant metastases were 5.4% (95% CI, 2.9-7.9) and 29.0% (95% CI, 23.9-30.1), respectively. The pathologic complete response rate was achieved in 17 patients (4.5%). The Multivariate Cox Regression model showed that factors affecting DFS were the surgical technique, pre-RT pathologic grade, ypT, ypN, and comorbidity; and factors improving OS were low anterior resection, low pre-RT grade, low ypT, and low ypN. CONCLUSIONS: Patients treated with preoperative RT with 30 Gy in 10 fractions had similar local control, 5-year DFS and OS to reported long course RT regimen. The surgical technique, pre-RT pathologic grade, ypT, and ypN seemed to affect the OS. Further study on combining a 2-week course of preoperative RT with concurrent chemotherapy would be warranted. PMID- 25503431 TI - The Prognostic Significance of Facial Nerve Involvement in Carcinomas of the Parotid Gland. AB - IMPORTANCE AND BACKGROUND: Facial nerve (FN) palsy and perineural invasion (PNI) are adverse features in carcinomas of the parotid gland. FN sacrifice at the time of surgery is associated with significant morbidity. The role of adjuvant radiotherapy in patients with high-risk features, including FN involvement, remains unclear. OBJECTIVE: Analyze the disease-free survival (DFS) and overall survival (OS) and the impact of tumor characteristics, including FN involvement, for patients treated with surgical resection for carcinoma of the parotid gland. DESIGN: This is a retrospective chart review. SETTING: University of Utah and Intermountain Healthcare, Utah. PARTICIPANTS: A total of 129 patients who were treated with primary surgery for nonmetastatic primary malignancies of the parotid gland from 1988 to 2006. INTERVENTIONS: Parotidectomy with or without adjuvant therapy. MAIN OUTCOME(S) AND MEASURES: Kaplan-Meier analysis was used to obtain 5-year estimates of DFS and OS. Recurrence risk factors, particularly the impact of FN involvement, were analyzed. RESULTS: Five-year DFS and OS rates were 79% and 78%, respectively. Thirty-two (28%) patients developed recurrent disease. Disease recurrence occurred in 64% of patients with both FN palsy and PNI, in 43% with FN palsy without PNI, in 27% with only PNI, and in 16% without either feature. CONCLUSIONS AND RELEVANCE: FN involvement, particularly FN palsy, is a predictor of increased risk of recurrence and death. Radiotherapy cannot substitute for FN sacrifice in high-risk patients. PMID- 25503432 TI - Phase I Study of Amrubicin and Cyclophosphamide in Patients With Advanced Solid Organ Malignancies: HOG LUN 07-130. AB - OBJECTIVES: Relapsed small cell lung cancer (SCLC) has limited treatment options. Anthracyclines and cyclophosphamide have shown synergy in many tumors. Amrubicin (AMR) and cyclophosphamide both have single-agent activity in SCLC. This phase I trial evaluated the combination of AMR and cyclophosphamide in refractory solid organ malignancies and in relapsed SCLC. MATERIALS AND METHODS: The primary endpoint was to determine maximum-tolerated dose and dose-limiting toxicities of the combination. Eligible patients were enrolled in sequential dose escalation cohorts in a standard 3+3 design. Treatment consisted of cyclophosphamide IV at 500 mg/m on day 1 with escalating doses of AMR IV on days 1 to 3 (25 to 40 mg/m with increments of 5 mg/m per cohort). Cycles were repeated every 21 days. Exploratory objectives analyzed the presence of NQO1 polymorphisms and topoisomerase IIA amplification and correlation with response. RESULTS: Thirty six patients were enrolled, of whom 18 patients had SCLC (50%). Maximum-tolerated dose was determined to be dose level 2 (cyclophosphamide 500 mg/m, AMR 30 mg/m) due to grade 4 thrombocytopenia. The main grade 3 to 4 toxicities were hematologic. Efficacy results are available for 34 patients. Partial responses, stable disease, and progressive disease rates in the overall study population were 20.6% (n=7), 38.2% (n=13), and 41.2% (n=14), respectively. Partial response, stable disease, and progressive disease rates in the SCLC patients and 1 patient with extrathoracic small cell were 36.8% (n=7), 26.3% (n=5), and 36.8% (n=7), respectively. There was no correlation between topoisomerase IIA amplification or NQO1 polymorphisms and response. CONCLUSIONS: AMR and cyclophosphamide can be safely combined with little activity observed in heavily pretreated SCLC patients. PMID- 25503433 TI - Neurocognitive Deficits After Radiation Therapy for Brain Malignancies. AB - Radiotherapy (RT) has proven to be an effective therapeutic tool in treatment of a wide variety of brain tumors; however, it has a negative impact on quality of life and neurocognitive function. Cognitive dysfunction associated with both the disease and adverse effects of RT is one of the most concerning complication among long-term survivors. The effects of RT to brain can be divided into acute, early delayed, and late delayed. It is, however, the late delayed effects of RT that lead to severe neurological consequences such as minor-to-severe cognitive deficits due to irreversible focal or diffuse necrosis of brain parenchyma. In this review, we discuss current and emerging data regarding the relationship between RT and neurocognitive outcomes, and therapeutic strategies to prevent/treat postradiation neurocognitive deficits. PMID- 25503434 TI - Thyroid V50 Highly Predictive of Hypothyroidism in Head-and-Neck Cancer Patients Treated With Intensity-modulated Radiotherapy (IMRT). AB - OBJECTIVES: Radiation-induced hypothyroidism affects a significant number of patients with head-and-neck squamous cell cancer (HNSCC). We examined detailed dosimetric and clinical parameters to better determine the risk of hypothyroidism in euthyroid HNSCC patients treated with intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: From 2006 to 2010, 75 clinically euthyroid patients with HNSCC were treated with sequential IMRT. The cohort included 59 men and 16 females with a median age of 55 years (range, 30 to 89 y) who were treated to a median dose of 70 Gy (range, 60 to 75 Gy) with concurrent chemotherapy in nearly all (95%) cases. Detailed thyroid dosimetric parameters including maximum dose, mean dose, and other parameters (eg, V50-percent volume receiving at least 50 Gy) were obtained. Freedom from hypothyroidism was evaluated using the Kaplan Meier method. Univariate and multivariate analyses were conducted using Cox regression. RESULTS: After a median follow-up period of 50 months, 25 patients (33%) became hypothyroid. On univariate analysis, thyroid V50 was highly correlated with developing hypothyroidism (P=0.035). Other dosimetric paramaters including mean thyroid dose (P=0.11) and maximum thyroid dose (P=0.39) did not reach statistical significance. On multivariate analysis incorporating patient, tumor, and treatment variables, V50 remained highly statistically significant (P=0.037). Regardless of other factors, for V50>60%, the odds ratio of developing hypothyroidism was 6.76 (P=0.002). CONCLUSIONS: In HNSCC patients treated with IMRT, thyroid V50 highly predicts the risk of developing hypothyroidism. V50>60% puts patients at a significantly higher risk of becoming hypothyroid. This can be a useful dose constraint to consider during treatment planning. PMID- 25503435 TI - Interaction of Salicylates and the Other Nonsteroidal Anti-Inflammatory Agents With Breast Cancer Endocrine Treatment: Systematic Review. AB - Despite advances in breast cancer treatment, mortality from breast cancer is still high. Undoubtedly, novel treatment strategies are needed for chemoprevention of high-risk women and for the treatment of receptor-negative breast cancer. An appealing strategy would be the combination of breast endocrine treatment with salicylates and the other nonsteroidal anti-inflammatory agents (NSAIDs). This systematic review aimed to synthesize evidence on the possible synergistic antitumor effect of breast cancer endocrine treatment with salicylates and the other NSAIDs. Electronic databases were searched with the appropriate search terms. Most of the identified studies investigated the possible synergistic effect of exemestane with celecoxib in different clinical settings including metastatic treatment, adjuvant treatment, ductal carcinoma in situ. The possible synergistic effect of tamoxifen with celecoxib was investigated in one experimental study and the possible synergistic effect of exemestane with aspirin was investigated in another experimental study. Synergistic effect was detected in the majority of the studies. In conclusion, existing limited evidence suggests synergistic interaction of salicylates and the other NSAIDs in the treatment of estrogen responsive breast cancer with clinical implications in the reversal of acquired resistance to breast cancer endocrine treatment and in chemoprophylaxis. PMID- 25503436 TI - Stage I Lung SBRT Clinical Practice Patterns. AB - OBJECTIVES: Stereotactic body radiation therapy (SBRT) has become increasingly utilized over the last decade in the treatment of inoperable stage I non-small cell lung cancer (NSCLC) patients, although no standardized dosing guidelines exist. In this retrospective study, we investigated the dose prescription pattern use in the United States for patients receiving SBRT. METHODS: Patients with stage I NSCLC treated with SBRT between 2004 and 2011 were identified within the National Cancer Database (NCDB). Trends in SBRT use and dose prescriptions were analyzed. RESULTS: A total of 5246 patients met criteria as receiving SBRT. The overall mean and median BED10 were 134.5 and 132 Gy, respectively. Of these patients, 94.5% were prescribed a regimen with a BED10>=100 Gy. The most common prescriptions overall were 60 Gy in 3 fractions (24.1%), 48 Gy in 4 fractions (17.8%), 50 Gy in 5 fractions (13.0%), and 54 Gy in 3 fractions (12.8%). Analysis of prescription trends revealed decreased utilization of 54 to 60 Gy in 3 fractions (47.9% in 2006 to 27.9% in 2011, combined) and increased utilization of 50 Gy in 5 fractions (3.1% in 2006 to 20.4% in 2011). CONCLUSIONS: Our findings suggest increasing use of SBRT over the last decade with a majority of patients being treated with regimens employing a BED10>=100 Gy. Since 2006, there has been a decline in the use of 54 to 60 Gy in 3 fractions, with an increase in the use of 50 Gy in 5 fractions. Possible explanations include concern for increased toxicity with higher BED regimens and increasing treatment of centrally located tumors. PMID- 25503438 TI - Medical marijuana for cancer. AB - Answer questions and earn CME/CNE Marijuana has been used for centuries, and interest in its medicinal properties has been increasing in recent years. Investigations into these medicinal properties has led to the development of cannabinoid pharmaceuticals such as dronabinol, nabilone, and nabiximols. Dronabinol is best studied in the treatment of nausea secondary to cancer chemotherapy and anorexia associated with weight loss in patients with acquired immune deficiency syndrome, and is approved by the US Food and Drug Administration for those indications. Nabilone has been best studied for the treatment of nausea secondary to cancer chemotherapy. There are also limited studies of these drugs for other conditions. Nabiximols is only available in the United States through clinical trials, but is used in Canada and the United Kingdom for the treatment of spasticity secondary to multiple sclerosis and pain. Studies of marijuana have concentrated on nausea, appetite, and pain. This article will review the literature regarding the medical use of marijuana and these cannabinoid pharmaceuticals (with emphasis on indications relevant to oncology), as well as available information regarding adverse effects of marijuana use. PMID- 25503439 TI - Multicomponent one-pot synthesis of highly-functionalized pyrrole-3-carbonitriles in aqueous medium and their computational study. AB - A one-pot green protocol involving four-components in aqueous medium is developed to synthesize highly-functionalized pyrroles in good yields. Two of the newly synthesized compounds were subjected to in silico analysis on the Pharm Mapper web-server and the human mitogen-activated protein kinase1 (MEK1) enzyme was identified as a potential target protein for these compounds. For target validation, MEK-1 inhibition was performed with two representative compounds (5g and 5h) using docking simulations. These functionalized pyrroles were also tested for their respective IC50 values on human cancer cell lines to evaluate their biocompatibility. Several of these functionalized pyrrole molecules were found to possess higher growth inhibition activity than standard doxorubicin and cisplatin. PMID- 25503437 TI - The Pseudomonas syringae type III effector HopF2 suppresses Arabidopsis stomatal immunity. AB - Pseudomonas syringae subverts plant immune signalling through injection of type III secreted effectors (T3SE) into host cells. The T3SE HopF2 can disable Arabidopsis immunity through Its ADP-ribosyltransferase activity. Proteomic analysis of HopF2 interacting proteins identified a protein complex containing ATPases required for regulating stomatal aperture, suggesting HopF2 may manipulate stomatal immunity. Here we report HopF2 can inhibit stomatal immunity independent of its ADP-ribosyltransferase activity. Transgenic expression of HopF2 in Arabidopsis inhibits stomatal closing in response to P. syringae and increases the virulence of surface inoculated P. syringae. Further, transgenic expression of HopF2 inhibits flg22 induced reactive oxygen species production. Intriguingly, ADP-ribosyltransferase activity is dispensable for inhibiting stomatal immunity and flg22 induced reactive oxygen species. Together, this implies HopF2 may be a bifunctional T3SE with ADP-ribosyltransferase activity required for inhibiting apoplastic immunity and an independent function required to inhibit stomatal immunity. PMID- 25503440 TI - Centuries of domestication has not impaired oviposition site-selection function in the silkmoth, Bombyx mori. AB - Oviposition site-selection in insects is mediated through innate recognition templates (IRTs) tuned to specific chemical cues. These cues aid gravid insects in choosing suitable oviposition sites and may even enhance the fitness of their offspring by warding off predators and parasitoids. However, studies on the evolution of oviposition site-selection and cues instigating oviposition in domesticated insects remain elusive. Using the interaction between the silkmoth, Bombyx mori, and its host plant mulberry, Morus alba, as a model system, we demonstrate that centuries of domestication of silkmoth has not impaired its oviposition site-selection function. Silkmoths significantly preferred mulberry leaves to filter paper as oviposition sites. Oviposition assays with filter paper, filter paper treated with leaf volatiles and leaf alone proved that surface texture was not a significant criterion for oviposition site-selection, but volatile cues were. Oviposition assays with electrophysiologically active compounds from mulberry revealed that two of the volatiles, valencene and alpha humulene, aided moths in choosing suitable oviposition sites and enhanced egg laying significantly. Moreover, we show that generalist egg-parasitoids are strongly repelled by valencene and alpha-humulene. Our results demonstrate that IRTs tuned to cues that aid crucial functions like oviposition site-selection are less likely to be impaired even after centuries of domestication. PMID- 25503441 TI - Results of treatment of distal extra: articular femur fractures with locking plates using minimally invasive approach--experience with 25 consecutive geriatric patients. AB - PURPOSE: Fractures involving the femur in older adults are reasonably common. The aim of this study was to evaluate the results of MIPO technique using locking plates in geriatric patients for distal extra-articular femur fractures. METHODS: About 25 consecutive patients with distal extra-articular femur fractures aged 60 years and above were treated using locking plates and minimally invasive technique. Patients were studied prospectively over a period of 3 years. Parameters studied included patient demographics, fracture type, time taken for the surgery, time to union and any complications. RESULTS: Mean age of patients was 66.5 years. Nineteen (76%) patients were females. Most of fractures in our study were type 33A2 fractures (64%). Average time to full weight bearing was 14.32 weeks, and fractures united at an average of 16.88 weeks. There were two (8%) patients with superficial infection, two (8%) with implant tenderness. One (4%) patient developed knee stiffness. Five (20%) patients had extension lag of average 5 degrees . One (4%) patient sustained a peri-implant fracture at 2 months. None of the patients developed non-union or delayed union. According to criteria laid by Schatzker's and Lambert, excellent results were achieved in 22 (88%) patients. CONCLUSIONS: Outcome of minimally invasive fixation of distal extra-articular femur fractures with locking plates in patients of age 60 years and above seems to be good with high union rate despite high prevalence of osteoporosis and comminution. PMID- 25503442 TI - WSKY, a traditional Chinese decoction, rescues cognitive impairment associated with NMDA receptor antagonism by enhancing BDNF/ERK/CREB signaling. AB - Warm-supplementing kidney yang (WSKY) is an herbal prescription that has been used in Traditional Chinese Medicine for the treatment of psychiatric conditions. A previous study by our group found that WSKY significantly improved cognitive function of schizophrenia patients. In the present study, the effects of WSKY on cognitive function and their underlying mechanisms were investigated. WSKY was administered to an MK-801-induced rat model of chronic schizophrenia for 14 days. Memory performance was assessed using the Morris water maze (MWM) test. The expression of brain-derived neurotrophic factor (BDNF), activation of cAMP response element binding protein (pCREB/CREB) and activation of extracellular signal-regulated kinase (pERK/ERK) in the hippocampus was detected using western blot analysis. In the acquisition phase of the MWM test, the escape latency was significantly increased in the MK-801-treated group compared with the normal control group (P<0.01). Treatment with WSKY for 14 days at doses of 100 or 250 mg/kg rescued this cognitive impairment (P<0.05). In the probe test, 250 mg/kg WSKY treatment increased the time spent in the target quadrant (P<0.05) and number of platform crossings (P<0.01). Western blot analysis demonstrated that the levels of BDNF expression in the hippocampus of rats without behavioral tests were elevated following 14 days of WSKY treatment, and the effect of WSKY treatment on hippocampal BDNF expression was presented in an inverted U-shaped dose-response pattern. The pERK1/2 in the hippocampus was significantly enhanced following 100 mg/kg (P<0.01) and 250 mg/kg (P<0.01) WSKY treatment, while only 250 mg/kg WSKY increased the phosphorylation of CREB (P<0.01). The results of the present study indicated that WSKY enhances cognitive performance via the upregulation of BDNF/ERK/CREB signaling, and that WSKY has potential therapeutic implications for cognitive impairment of schizophrenia. PMID- 25503443 TI - Threonine 32 (Thr32) of FoxO3 is critical for TGF-beta-induced apoptosis via Bim in hepatocarcinoma cells. AB - Transforming growth factor-beta (TGF-beta) exerts apoptotic effects on various types of malignant cells, including liver cancer cells. However, the precise mechanisms by which TGF-beta induces apoptosis remain poorly known. In the present study, we have showed that threonine 32 (Thr32) residue of FoxO3 is critical for TGF-beta to induce apoptosis via Bim in hepatocarcinoma Hep3B cells. Our data demonstrated that TGF-beta induced FoxO3 activation through specific de phosphorylation at Thr32. TGF-beta-activated FoxO3 cooperated with Smad2/3 to mediate Bim up-regulation and apoptosis. FoxO3 (de)phosphorylation at Thr32 was regulated by casein kinase I-epsilon (CKI-epsilon). CKI inhibition by small molecule D4476 could abrogate TGF-beta-induced FoxO/Smad activation, reverse Bim up-regulation, and block the sequential apoptosis. More importantly, the deregulated levels of CKI-epsilon and p32FoxO3 were found in human malignant liver tissues. Taken together, our findings suggest that there might be a CKI FoxO/Smad-Bim engine in which Thr32 of FoxO3 is pivotal for TGF-beta-induced apoptosis, making it a potential therapeutic target for liver cancer treatment. PMID- 25503444 TI - A novel supramolecular metallogel-based high-resolution anion sensor array. AB - A novel anion sensor array based on supramolecular metallogels has been developed. It could accurately identify CN(-), SCN(-), S(2-) and I(-) in water. Interestingly, this sensor array is based on a novel design approach termed "competitive coordination control AIE mode" to develop anion-responsive gels which need only one synthesized gelator G1. PMID- 25503445 TI - Fasting blood glucose, but not 2-h postload blood glucose or HbA1c, is associated with mild decline in estimated glomerular filtration rate in healthy Chinese. AB - BACKGROUND: The association of blood glucose [including fasting blood glucose (FBG), 2-h postload blood glucose, and glycated hemoglobin (HbA1c)] with the risk of a mild decline in the estimated glomerular filtration rate (eGFR) in healthy subjects was unclear. The aim of the study was to investigate this association in middle-aged and elderly healthy Chinese. METHODS: The study included 1,112 healthy Chinese who were >=40 years old, and all the subjects were divided into two groups based on FBG value of 5.6 mmol/L. A mildly reduced eGFR was defined as 60-90 mL/min/1.73 m2. Multiple linear or logistic regression analysis was used to estimate the association of blood glucose with eGFR and the risk of a mildly reduced eGFR, respectively. A generalized additive model was used to explore a possible nonlinear relationship between FBG and eGFR. RESULTS: FBG was significantly associated with decreased eGFR and increased risk of a mildly reduced eGFR independent of age, gender, body mass index, waist circumference, systolic blood pressure (BP), diastolic BP, triglyceride, high-density lipoprotein cholesterol, fasting insulin, smoking, and drinking. Additionally, FBG and eGFR showed a nonlinear association (P<0.001). Interestingly, the group with FBG>=5.6 mmol/L significantly increased the risk of a mildly reduced eGFR (OR 2.06, P=0.001) after multivariable adjustment. CONCLUSIONS: FBG is closely associated with decreased eGFR and increased risk of a mildly reduced eGFR. The ADA criteria using FBG=5.6 mmol/L instead of 6.1 mmol/L as cutoff point to define prediabetes are more suitable for the prevention of diabetes and related kidney disease. PMID- 25503446 TI - A prospective, observational study to assess the association between dry mouth and solifenacin treatment in patients with overactive bladder syndrome. AB - PURPOSE: Dry mouth is among the most common side effects of antimuscarinic therapy. This study evaluated the drug-related change in dry mouth after the solifenacin treatment and the impact of dry mouth on the drug efficacy against overactive bladder syndrome (OAB). MATERIALS AND METHODS: OAB patients (n = 331) were enrolled in a prospective, multicenter, 8-week observational study of solifenacin treatment. Participants were >20 years of age and presented with OAB symptoms for >=3 months, a total overactive bladder symptom score (OABSS) of >=3, and an urgency score of >=2. Primary endpoints were changes in dry mouth according to baseline dry mouth status using Xerostomia Inventory (XI) and the effect of dry mouth to the drug efficacy according to improvements in the OABSS. RESULTS AND CONCLUSIONS: Three hundred and thirty-three patients were initially screened for the study, with 331 actually enrolled. One hundred and ninety-four patients completed the study. Mean total XI scores increased by 2.8 points in the entire patient population, with larger increases for patients stratified into the non-dry mouth group (NDG) versus the dry mouth group (DG) (4.0 vs. 1.9, p = 0.015) at study baseline. Mean total OABSSs decreased by 3.2 points, with no significant differences between the NDG and the DG (-3.4 vs. -3.0 points, p = 0.578). The dry mouth aggravated in 71 patients (29.2 %) (NDG 30.1 % and DG 27.1 %), but only 10/331 individuals (3.0 %) stopped medication due to xerostomia. Dry mouth progressed in approximately 30 % of the OAB patients, regardless of its presence before solifenacin treatment. However, OAB symptoms were well relieved by solifenacin, and the adverse influence of dry mouth on drug persistence was low. PMID- 25503447 TI - Impact of home-based aerobic exercise on the physical capacity of overweight patients with chronic kidney disease. AB - BACKGROUND: Home-based exercise has been shown to provide benefits in terms of physical capacity in the general population, but has been scarcely investigated in patients with chronic kidney disease (CKD). AIMS: To evaluate the impact of a home-based aerobic training on the cardiopulmonary and functional capacities of overweight non-dialysis-dependent patients with CKD (NDD-CKD). METHODS: Twenty nine sedentary patients (55.1 +/- 11.6 years, BMI = 31.2 +/- 6.1 kg/m(2), eGFR = 26.9 +/- 17.4 mL/min/1.73 m(2)) were randomly assigned to a home-based exercise group (n = 14) or to a control group (n = 15) that remained without performing exercise. Aerobic training was performed three times per week for 12 weeks. A cardiopulmonary exercise test, functional capacity and clinical parameters were evaluated. RESULTS: A significant increase, ranging from 8.3 to 17 %, was observed in the cardiopulmonary capacity parameters, such as maximal ventilation (p = 0.005), VO2peak (p = 0.049), ventilatory threshold (p = 0.040) and respiratory compensation point (p < 0.001), of the exercise group. A simultaneous improvement in the functional capacity tests [6-min walk test (p < 0.001), time up and go test (p < 0.001), arm curl test (p < 0.001), sit and stand test (p < 0.001), 2-min step test (p < 0.001) and back scratch test (p = 0.042)] was also found in patients who were submitted to the exercise. Exercised patients experienced a decrease in systolic and diastolic blood pressure, average 10.6 % (p < 0.001) and 9.2 % (p = 0.007), respectively, and a trend toward improved renal function (p = 0.1). No change in any parameter was found in the control group during the follow-up. CONCLUSION: The home-based aerobic exercise program was feasible, safe and effective for the improvement in the cardiopulmonary and functional capacities of overweight NDD-CKD patients. PMID- 25503448 TI - Evaluation of the utility of different scoring systems (FGSI, LRINEC and NLR) in the management of Fournier's gangrene. AB - PURPOSE: To evaluate the mortality and morbidity prediction capability of three different scoring systems: Fournier's gangrene severity index (FGSI), Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) and neutrophile-lymphocyte ratio (NLR) with this retrospective cohort study. METHODS: Medical records of all patients treated for FG with the final histopathological diagnosis between October 2008 and January 2013 were retrospectively evaluated. Data were collected from medical history, physical examination findings, biochemical and microbiological tests and tissue cultures. FGSI and LRINEC scores and NLR were determined for all patients. Then, it was explored whether higher FGSI (<4 vs. >=4), LRINEC (<6 vs. >=6) or NLR (<10 vs. >=10) were associated with worse prognosis. RESULTS: A total of 33 patients were evaluated; 3 died (9.1 %) and 30 (90.9 %) survived. Mean age was 57.6 +/- 13.2 years. Survivors were younger than nonsurvivors (56 +/- 12.8 vs. 72.9 +/- 7.3, p < 0.05). Diabetes mellitus was the most encountered predisposing factor with 66.7 % prevalence. All patients with localized disease (100 %) and 8/11 patients (72.7 %) with extended disease survived (p < 0.05). Patients with higher FGSI scores, LRINEC scores and NLR were more likely to require mechanical ventilation in intensive care unit and longer hospitalization times and were more likely to die compared to patients with lower scores. CONCLUSION: In conclusion, all evaluated scoring systems, FGSI, LRINEC and NLR, are capable of pointing out worse prognosis including mechanical ventilation requirement and mortality. NLR has the advantage of its rapid, simple and low-cost characteristics. PMID- 25503449 TI - Afferent projections to the different medial amygdala subdivisions: a retrograde tracing study in the mouse. AB - The medial amygdaloid nucleus (Me) is a key node in the socio-sexual brain, composed of anterior (MeA), posteroventral (MePV) and posterodorsal (MePD) subdivisions. These subdivisions have been suggested to play a different role in reproductive and defensive behaviours. In the present work we analyse the afferents of the three Me subdivisions using restricted injections of fluorogold in female outbred CD1 mice. The results reveal that the MeA, MePV and MePD share a common pattern of afferents, with some differences in the density of retrograde labelling in several nuclei. Common afferents to Me subdivisions include: the accessory olfactory bulbs, piriform cortex and endopiriform nucleus, chemosensory amygdala (receiving direct inputs from the olfactory bulbs), posterior part of the medial bed nucleus of the stria terminalis (BSTM), CA1 in the ventral hippocampus and posterior intralaminar thalamus. Minor projections originate from the basolateral amygdala and amygdalo-hippocampal area, septum, ventral striatum, several allocortical and periallocortical areas, claustrum, several hypothalamic structures, raphe and parabrachial complex. MeA and MePV share minor inputs from the frontal cortex (medial orbital, prelimbic, infralimbic and dorsal peduncular cortices), but differ in the lack of main olfactory projections to the MePV. By contrast, the MePD receives preferential projections from the rostral accessory olfactory bulb, the posteromedial BSTM and the ventral premammillary nucleus. In summary, the common pattern of afferents to the Me subdivisions and their interconnections suggest that they play cooperative instead of differential roles in the various behaviours (e.g., sociosexual, defensive) in which the Me has been shown to be involved. PMID- 25503450 TI - Puberty and testosterone shape the corticospinal tract during male adolescence. AB - Some of the known sex differences in white matter emerge during adolescence. Here, we replicate and extend our previous findings of sex differences in the structure of the corticospinal tract (Perrin et al. 2009; Herve et al. 2009). In a large normative sample of adolescents, we observed age * sex interactions in the signal intensity of T1-weighted (T1W) images (n = 941) and in magnetization transfer ratio (MTR; n = 761); both features were inversely associated with age in males but not in females. Moreover, we hypothesized that the age-related differences in CST structure exhibited by males would be mediated by differences in puberty stage and levels of bioavailable testosterone. We confirmed this prediction using mediation analysis with bootstrapping. These findings suggest that sex differences in the CST structure observed during male adolescence may be due to multiple processes associated with puberty, including (but not limited to) the rising levels of testosterone. PMID- 25503451 TI - Ocular higher-order wavefront aberrations in the Japanese adult population: the Yamagata Study (Funagata). AB - PURPOSE: To investigate the relationship between age and ocular higher-order wavefront aberrations (HOAs) in an adult Japanese population, in addition to factors associated with HOA variations. METHODS: In the Yamagata Study (Funagata) cohort, 227 adult Japanese participants (aged 37-86 years) underwent systemic and ophthalmologic examinations in 2012. Ocular, corneal, and internal HOAs were measured in micrometers. From the Zernike coefficients, we calculated the root mean square of the total HOA, coma, and spherical aberration for a pupil diameter of 4 mm. Linear regression analyses were used to determine whether HOAs were associated with age or other factors. RESULTS: Multiple adjusted linear regression analyses demonstrated that all components of logarithmic HOAs increase with age. Ocular, corneal, and internal HOAs increased by 0.012/y (P < 0.001), 0.007/y (P = 0.010), and 0.014/y (P < 0.001), respectively. Ocular coma also significantly increased with age (0.010/y, P = 0.007), but corneal (P = 0.963) and internal (P = 0.476) coma did not. Age-related spherical aberration increased only in the internal component (0.019/y, P = 0.001). In addition to age, ocular and corneal HOAs were mainly affected by corneal indexes. CONCLUSIONS: Aging is associated with increases in ocular HOAs, independent of other possible confounding factors. The association of ocular HOAs with corneal parameters indicates that ocular HOAs are mainly generated by the cornea. Internal HOAs, supposedly generated from cataract progression, may be associated with systemic factors, including serum creatinine levels and blood pressure. PMID- 25503453 TI - Involvement of the receptor-associated prorenin system in the pathogenesis of human conjunctival lymphoma. AB - PURPOSE: Extranodal marginal zone B-cell lymphoma (EMZL) is the most common subtype of conjunctival lymphoma, though its molecular mechanisms of pathogenesis are largely unknown. We attempted to explore the association of the renin angiotensin system (RAS) and (pro)renin receptor ([P]RR) in the pathogenesis of conjunctival lymphoma. METHODS: Surgically removed conjunctiva EMZL samples were used for gene expression, and immunohistochemical and immunofluorescence analyses of (P)RR and RAS components. Human B-lymphoblast IM-9 cells were treated with prorenin or angiotensin II (Ang II), and gene expression levels were analyzed using real-time quantitative PCR (qPCR). In addition, immunofluorescence analysis of EMZL samples was used to evaluate the in vivo expression of those components. RESULTS: Gene expression and immunohistochemical analyses revealed the expression of RAS components, including (P)RR and angiotensin II type 1 receptor (AT1R), in EMZL tissues. Double-labeling analyses demonstrated that (P)RR and AT1R were detected in cells positive for CD20, a marker for B-cells, where they colocalized with prorenin and angiotensinogen, respectively. Prorenin stimulation of human B lymphoblast IM-9 cells increased mRNA expression levels of fibroblast growth factor 2 (FGF2), while angiotensin II treatment upregulated the expression levels of basigin (BSG), matrix metallopeptidase (MMP)2, 9, and 14, which were abolished by (P)RR and AT1R blockades, respectively. Immunofluorescence analyses of clinical samples showed colocalizations of (P)RR and AT1R with the products of these upregulated genes. CONCLUSIONS: The present study suggests that activation of (P)RR and AT1R is associated with the pathogenesis of conjunctival EMZL by stimulating the production of FGF2 and MMPs. PMID- 25503452 TI - Developmental regulation of trigeminal TRPA1 by the cornea. AB - PURPOSE: The cornea is densely innervated with nociceptive nerves that detect deleterious stimuli at the ocular surface and transduce these stimuli as sensations of pain. Thus, nociception is a major factor involved in preventing damage to corneal tissues. One class of molecules that is thought to be involved in detecting such stimuli is the transient receptor potential (TRP) family of ion channels. However, little is known about the acquisition of these channels during corneal development. Therefore, the present study examined the developmental acquisition of these receptors and elucidated certain parameters involved in this acquisition. METHODS: Quantitative RT-PCR was used to measure the expression of genes including TRPA and Ret in vivo. In vitro cocultures between cornea and the ophthalmic lobe of the trigeminal ganglion were used to test interactions between nerves and corneas along with recombinant proteins. RESULTS: TRPA1 mRNA showed a progressive temporal increase in the ophthalmic lobe of the trigeminal ganglion in vivo during embryonic development. In vitro, TRPA1 expression was significantly increased in the ganglion when cocultured with cornea, compared to ganglia cultured alone. Similarly, the addition of exogenous neurotrophin-3 (NT3) protein to cultured ganglia increased the expression of TRPA1 more than 100-fold. Addition of NT3 and neurturin synergistically increased TRPA1 expression in embryonic day (E)8 ganglia, but this effect was lost at E12. At E8, Ret+ nonpeptidergic neurons are specified in the trigeminal ganglion. CONCLUSIONS: Corneal-derived factors increase TRPA1 expression in trigeminal nonpeptidergic neurons during their embryonic specification. PMID- 25503454 TI - Functional evaluation using multifocal electroretinogram after selective retina therapy with a microsecond-pulsed laser. AB - PURPOSE: To evaluate the changes of retinal function with multifocal electroretinogram (mfERG), and estimate the association between functional and structural changes after selective retina therapy (SRT) with microsecond-pulsed laser in comparison to continuous wave laser photocoagulation (cwPC). METHODS: Selective retina therapy and cwPC were applied with 10 * 10 shots and 1/2 lesion width on the retina in the right and left eyes of 20 healthy Chinchilla Bastard rabbits, respectively. Optical coherence tomography (OCT), fundus fluorescein angiography (FFA), and mfERG were performed before, and on days 1, 7, and 30 after both laser treatments. The mean ratios of amplitudes and implicit times of N1 and P1 from eight hexagons covering laser-treated retinal lesions/total retina were measured. Histology was obtained after killing three rabbits at each time period to observe the anatomic changes after both laser treatments. RESULTS: The mean ratios of amplitudes of N1 and P1 in SRT lesions did not change significantly for 30 days after laser treatment. Only subtle reductions of the mean ratios of N1 and P1 amplitudes on day 1, thereafter the amplitudes showed the trend to recover toward baseline values. Histology and OCT revealed temporary and reversible morphologic changes after SRT, which restored to normal within 1 month. However, the mean ratios of N1 amplitudes on days 7 and 30 (P = 0.010, P < 0.001, respectively), and P1 amplitudes on days 7 and 30 (P < 0.001, P < 0.001, respectively) declined significantly in cwPC lesions compared with baseline. Disorganization and atrophic changes were identified on histology and OCT after cwPC. CONCLUSIONS: The results suggest that SRT preserved retinal function as well as anatomical structure after treatment. PMID- 25503455 TI - Baseline characteristics of the infant aphakia treatment study population: predicting recognition acuity at 4.5 years of age. AB - PURPOSE: To identify patient baseline characteristics that predict recognition acuity at 4.5 years of age in the Infant Aphakia Treatment Study, a study of patients with monocular infantile cataracts. METHODS: We analyzed baseline characteristics of the 114 infants enrolled in the Infant Aphakia Treatment Study to determine which were most predictive of visual outcome at 4.5 years of age. All infants underwent cataract surgery between 1 and 7 months of age. Monocular acuity was assessed at 4.5 years of age by a traveling examiner using the Amblyopia Treatment Study HOTV protocol. RESULTS: Age at cataract surgery was weakly associated with visual acuity (Spearman rank correlation coefficient = 0.19, P = 0.041) with median visual acuity better among the younger patients (28 48 days: 0.50 logMAR, 49-210 days: 1.10 logMAR, P = 0.046). Patients from families with private insurance had significantly better median visual acuity (0.60 vs. 1.40 logMAR, P = 0.0004). No other baseline characteristic revealed a significant bivariate relationship with visual acuity. A multiple linear regression relating visual acuity to all baseline characteristics demonstrated that only the availability of private insurance was statistically significant, accounting for 12% of the variance. CONCLUSIONS: This analysis concurs with previous studies that early surgery is important for good visual outcomes in patients with unilateral infantile cataracts. The fact that only one baseline variable (private insurance) contributed to the multivariate analysis, accounting for 12% of the variance, suggests that predicting visual outcome for these patients is complicated at best, and cannot be estimated from baseline characteristics alone. (ClinicalTrials.gov number, NCT00212134.). PMID- 25503457 TI - Protective effects of beta1/2 adrenergic receptor deletion in a model of oxygen induced retinopathy. AB - PURPOSE: beta-adrenergic receptors (beta-ARs) regulate angiogenesis in proliferative retinopathies. We studied the effects of beta1/2-AR deletion in a model of oxygen-induced retinopathy (OIR) to confirm the role of beta1- and/or beta2-ARs in regulating angiogenesis and to get insights into the role of beta3 ARs. METHODS: Mice with beta1/2-AR deletion (KO) were used. Levels of norepinephrine (NE), beta3-ARs, transcription, and proangiogenic factors were evaluated. Retinas were analyzed for avascular area and neovascular tufts in the superficial plexus. Deep plexus and blood-retinal barrier (BRB) were also analyzed. Neovascularization, proangiogenic factors, protein kinase A (PKA) activity, and nitrite production were assessed after BRL 37344, a beta3-AR agonist. RESULTS: Oxygen-induced retinopathy was characterized by NE upregulation with higher levels in wild type (WT) than in KO. Wild type and KO displayed comparable levels of beta3-ARs, transcription, and proangiogenic factors, but differed in VEGF receptor (VEGFR) expression with VEGFR-1 in WT lower than in KO and VEGFR-2 in WT higher than in KO. Blood-retinal barrier dysfunction did not differ between WT and KO. Vascular abnormalities in the superficial plexus were abolished by beta1/2-AR deletion, which also helped the development of the deep plexus. In both WT and KO, beta3-AR agonism, acting through the nitric oxide pathway, caused enhanced neovascular responses with increased levels of VEGF. CONCLUSIONS: We confirm that beta1- and beta2-ARs play a pivotal role in retinal angiogenesis. In their presence, beta3-ARs potentiate angiogenic responses, whereas, in their absence, beta3-ARs sustain the angiogenic drive. These results suggest beta-ARs as promising targets for therapies aimed to counteract proliferative retinopathies. PMID- 25503456 TI - Relationship of retinal morphology and retinal sensitivity in the treatment of neovascular age-related macular degeneration using aflibercept. AB - PURPOSE: To relate the functional response to distinct morphological features of the retina during aflibercept treatment for neovascular AMD (nAMD). METHODS: A total of 726 retinal locations in 22 consecutive eyes presenting with treatment naive nAMD underwent a standardized examination with spectral-domain optical coherence tomography (SD-OCT) and topographic microperimetry (MP) at baseline, after 3 and 12 months of continuous intravitreal aflibercept therapy. The retinal sensitivity at each stimulus location was registered to the corresponding location on SD-OCT morphology. Subsequently, the microperimetric responses were evaluated with respect to the following underlying SD-OCT features: neovascular complex (NVC), subretinal fluid (SRF), intraretinal fluid (IRF), intraretinal cystoid space (IRC), serous pigment epithelium detachment (sPED), and fibrovascular pigment epithelium detachment (fPED). RESULTS: Baseline sensitivity was reduced to mean values of 1.8 dB in NVC, 2.2 dB in IRC, 2.8 dB in IRF, 2.6 dB in sPED, 3.6 dB in SRF, and 4.6 dB in fPED. Improvements in retinal sensitivity were most pronounced during the initial 3-month interval, when significant recovery was documented for SRF and sPED with +4.0/5.5 dB (P < 0.0001) and to a lesser extent for IRF, IRC, fPED, with +1.1, 1.7, 2.3 dB, respectively. From month 3 to 12, the additional benefit ranged from 0.3 to 1.0 dB (P > 0.05 for each category). CONCLUSIONS: Significant functional benefits following intravitreal aflibercept treatment could be detected over all defined morphological pathologies. The level of improvement varied dependent on the associated feature with the best prognosis for visual improvement in SRF and sPED and least with intraretinal fluid and particularly intraretinal cysts. PMID- 25503458 TI - Inverse relationship between the intraretinal concentration of bioavailable nitric oxide and blood glucose in early experimental diabetic retinopathy. AB - PURPOSE: To directly measure in vivo retinal nitric oxide (NO) concentration in experimental early diabetic retinopathy and correlate measurements with blood glucose to determine how intraretinal NO changes with severity of diabetes. METHODS: Long-Evans rats were made diabetic with streptozotocin (STZ). Three weeks post STZ injection, intraretinal NO concentration profiles were recorded using a dual NO/electroretinogram microelectrode. Diabetic profiles were compared with profiles from healthy controls, healthy rats injected with the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME), and healthy rats that received acute glucose injections ("acute hyperglycemia"). The NO values at the retina/RPE boundary (100% retinal depth) and retinal surface (0% depth) were analyzed for correlation with blood glucose. RESULTS: The average NO concentrations in the outer retina, inner retina, and vitreous humor of mild diabetic rats (250-400 mg/dL) were significantly higher than controls by 73%, 47%, and 70%, respectively. The average NO concentrations in the outer retina, inner retina, and vitreous humor of severe diabetic rats (500-600 mg/dL) were lower than controls, with NO at 41%, 36%, and 36% of controls, respectively, similar to L-NAME-treated eyes (38%, 36%, 20% of control). The NO levels in moderate diabetic rats (400-500 mg/dL) and acute hyperglycemia rats were similar to controls. The NO was significantly and inversely correlated with blood glucose for diabetic rats at 100% depth (R = -0.91) and 0% depth (R = -0.79) but not for acute hyperglycemia rats. CONCLUSIONS: The higher-than-control level of NO in mild diabetic rats and lower-than-control level in severe diabetic rats show that severity of diabetes is an important factor when measuring the bioavailability of NO in diabetic retinopathy. PMID- 25503459 TI - Enhanced structure-function relationship in glaucoma with an anatomically and geometrically accurate neuroretinal rim measurement. AB - PURPOSE: To evaluate the structure-function relationship between disc margin based rim area (DM-RA) obtained with confocal scanning laser tomography (CSLT), Bruch's membrane opening-based horizontal rim width (BMO-HRW), minimum rim width (BMO-MRW), peripapillary retinal nerve fiber layer thickness (RNFLT) obtained with spectral-domain optical coherence tomography (SD-OCT), and visual field sensitivity. METHODS: We examined 151 glaucoma patients with CSLT, SD-OCT, and standard automated perimetry on the same day. Optic nerve head (ONH) and RNFL with SD-OCT were acquired relative to a fixed coordinate system (acquired image frame [AIF]) and to the eye-specific fovea-BMO center (FoBMO) axis. Visual field locations were mapped to ONH and RNFL sectors with fixed Garway-Heath (VF(GH)) and patient-specific (VF(PS)) maps customized for various biometric parameters. RESULTS: Globally and sectorally, the structure-function relationships between DM RA and VF(GH), BMO-HRW(AIF) and VF(GH), and BMO-HRW(FoBMO) and VF(PS) were equally weak. The R(2) for the relationship between DM-RA and VF(GH) ranged from 0.1% (inferonasal) to 11% (superotemporal) whereas that between BMO-HRW(AIF) and VF(GH) ranged from 0.1% (nasal) to 10% (superotemporal). Relatively stronger global and sectoral structure-function relationships with BMO-MRW(AIF) and with BMO-MRW(FoBMO) were obtained. The R(2) between BMO-MRW(AIF) and VF(GH) ranged from 5% (nasal) to 30% (superotemporal), whereas that between BMO-MRW(FoBMO) and VF(PS) ranged from 5% (nasal) to 25% (inferotemporal). The structure-function relationship with RNFLT was not significantly different from that with BMO-MRW, regardless of image acquisition method. CONCLUSIONS: The structure-function relationship was enhanced with BMO-MRW compared with the other neuroretinal rim measurements, due mainly to its geometrically accurate properties. PMID- 25503462 TI - The neuroprotective effect of magnesium sulfate in preterm fetal mice. AB - OBJECTIVE: To investigate the use of magnesium sulfate (MgSO4) as a neuroprotective agent in a mouse model of inflammation-associated and noninflammation-associated preterm birth. METHODS: On embryonic day 15 of gestation, lipopolysaccharide (LPS) and mifepristone (RU486) were used, respectively, to create mouse models of inflammation and noninflammation associated preterm birth. After intraperitoneal injection of LPS, RU486, or normal saline solution (NS), dams were randomized to intraperitoneal MgSO4 or NS injection. From the 6 treatment groups (NS+NS, LPS+NS, NS+MgSO4, LPS+MgSO4, RU486+NS and RU486+MgSO4), fetal brains were collected for Western blot analysis and neuronal cultures. Protein expression of S100B was assessed, and immunohistochemistry was performed to detect NeuN. The numbers of NeuN-labeled cells were counted using confocal laser scanning microscopy. RESULTS: The expression of S100B significantly differed among the groups and was decreased in the LPS+MgSO4 group compared to the LPS+NS group. The expression of S100B did not differ between the RU486+NS and RU486+MgSO4 groups. NeuN-labeled cells were increased in the LPS+MgSO4 group compared with the LPS+NS group. NeuN-labeled cells were decreased in the RU486+MgSO4 group compared with the RU486+NS group. CONCLUSIONS: We observed that prenatal treatment with MgSO4 was associated with decreased expression of S100B and increased numbers of NeuN-labeled cells in an inflammation-associated preterm mouse model but not in a noninflammation associated preterm mouse model. Our results suggest that prenatal treatment of MgSO4 reduces inflammation-associated brain injury in fetal mice. PMID- 25503460 TI - Independent active contraction of extraocular muscle compartments. AB - PURPOSE: Intramuscular innervation of horizontal rectus extraocular muscle (EOMs) is segregated into superior and inferior (transverse) compartments, whereas all EOMs are also divided into global (GL) and orbital (OL) layers with scleral and pulley insertions, respectively. Mechanical independence between both types of compartments has been demonstrated during passive tensile loading. We examined coupling between EOM compartments during active, ex vivo contraction. METHODS: Fresh bovine EOMs were removed, and one compartment of each was coated with hydrophobic petrolatum. Contraction of the uncoated compartment was induced by immersion in a solution of 50 mM CaCl2 at 38 degrees C labeled with sodium fluorescein dye, whereas tensions in both compartments were monitored by strain gauges. Control experiments omitted petrolatum so that the entire EOM contracted. After physiological experiments, EOMs were sectioned transversely to demonstrate specificity of CaCl2 permeation by yellow fluorescence dye excited by blue light. RESULTS: In control experiments without petrolatum, both transverse and GL and OL compartments contracted similarly. Selective compartmental omission of petrolatum caused markedly independent compartmental contraction whether measured at the GL or the OL insertions or for transverse compartments at the scleral insertion. Although some CaCl2 spread occurred, mean (+/-SD) tension in the coated compartments averaged only 10.5 +/- 3.3% and 6.0 +/- 1.5% in GL/OL and transverse compartments, respectively relative to uncoated compartments. Fluorescein penetration confirmed selective CaCl2 permeation. CONCLUSIONS: These data confirm passive tensile findings of mechanical independence of EOM compartments and extend results to active contraction. EOMs behave actively as if composed of mechanically independent parallel fiber bundles having different insertional targets, consistent with the active pulley and transverse compartmental hypotheses. PMID- 25503461 TI - Complete genome sequence and comparative genomic analysis of Mycobacterium massiliense JCM 15300 in the Mycobacterium abscessus group reveal a conserved genomic island MmGI-1 related to putative lipid metabolism. AB - Mycobacterium abscessus group subsp., such as M. massiliense, M. abscessus sensu stricto and M. bolletii, are an environmental organism found in soil, water and other ecological niches, and have been isolated from respiratory tract infection, skin and soft tissue infection, postoperative infection of cosmetic surgery. To determine the unique genetic feature of M. massiliense, we sequenced the complete genome of M. massiliense type strain JCM 15300 (corresponding to CCUG 48898). Comparative genomic analysis was performed among Mycobacterium spp. and among M. abscessus group subspp., showing that additional beta-oxidation-related genes and, notably, the mammalian cell entry (mce) operon were located on a genomic island, M. massiliense Genomic Island 1 (MmGI-1), in M. massiliense. In addition, putative anaerobic respiration system-related genes and additional mycolic acid cyclopropane synthetase-related genes were found uniquely in M. massiliense. Japanese isolates of M. massiliense also frequently possess the MmGI-1 (14/44, approximately 32%) and three unique conserved regions (26/44; approximately 60%, 34/44; approximately 77% and 40/44; approximately 91%), as well as isolates of other countries (Malaysia, France, United Kingdom and United States). The well conserved genomic island MmGI-1 may play an important role in high growth potential with additional lipid metabolism, extra factors for survival in the environment or synthesis of complex membrane-associated lipids. ORFs on MmGI-1 showed similarities to ORFs of phylogenetically distant M. avium complex (MAC), suggesting that horizontal gene transfer or genetic recombination events might have occurred within MmGI-1 among M. massiliense and MAC. PMID- 25503463 TI - Cross-reactivity of adrenal steroids with aldosterone may prevent the accurate diagnosis of congenital adrenal hyperplasia. AB - During the first weeks of life, salt-wasting crisis, hyperkalemia, acidosis, hypoglycemia, and shock are the main findings of congenital adrenal hyperplasia (CAH). Pseudohypoaldosteronism type 1 (PHA1) is a rare disease of mineralocorticoid resistance, which is characterized with high aldosterone levels, hyponatremia and hyperkalemia without clinical findings of glucocorticoid deficiency. Patients with PHA1 are often initially diagnosed with CAH; however, it is unusual that a CAH patient is misdiagnosed as PHA1. In this report, we describe two cases with severe salt-losing crisis, hyperkalemia, and mild acidosis, which were initially diagnosed with PHA1, due to the high aldosterone levels along with normal adrenocorticotropic hormone and cortisol levels. However, subsequent investigation and genetic analysis led to the diagnosis of CAH with a homozygous I2 splice mutation in both alleles of the CYP21 gene. With this report, we emphasize that high blood levels of adrenal steroid precursors may cross-react with aldosterone and lead to confusing laboratory results that prevent making the accurate differential diagnosis between CAH and PHA1. PMID- 25503464 TI - Adamantinomatous craniopharyngioma: pathology, molecular genetics and mouse models. AB - Adamantinomatous craniopharyngiomas (ACPs) are histologically benign but clinically aggressive epithelial tumours of the sellar region that are associated with high morbidity and occasional mortality. Research from the last 3 years has provided important insights into the molecular and cellular pathogenesis of these tumours. It has become established that mutations in CTNNB1 (encoding beta catenin), leading to the over-activation of the WNT pathway, underlie the molecular aetiology of human ACP. Interestingly, the effect of these mutations is restricted to a small number of tumour cells, mostly forming clusters, which recent research has shown to be critical for tumorigenesis in mice and humans. Several pathways have been found to be activated in these clusters including the epidermal growth factor receptor and the sonic hedgehog pathways, offering potential therapeutic targets. A novel and unexpected role for pituitary stem cells has been proposed, which is fundamentally distinct from the cancer stem cell paradigm. The study of these benign tumours could reveal important insights into general mechanisms underlying the initial steps of tumorigenesis and facilitate novel tools to improve managements of the patients. PMID- 25503465 TI - MicroRNA-210 is involved in the regulation of postmenopausal osteoporosis through promotion of VEGF expression and osteoblast differentiation. AB - MicroRNAs (miRNAs) are small non-protein-codingRNAs that function as negative gene expression regulators. miRNA-210 (miR-210) has recently been recognized in the pathogenesis of osteonecrosis associated with angiogenesis. Herein we aimed to explore the clinical significance of miR-210 treatment for postmenopausal osteoporosis. The expression of miR-210 was detected in bone marrow mesenchymal stem cells (BMSCs) in vitro and miR-210 significantly promoted the expression of vascular edothelial growth factor (VEGF) in BMSCs in a time-dependent manner (p<0.05). And miR-210 suppressed PPARgamma expression but increased the expression of ALP and osterix, demonstrating that miR-210 inhibited adipocyte differentiation and promoted osteoblast differentiation of BMSCs in vitro. The protein expression of hypoxia-inducible factor 1 alpha (HIF-1alpha) and VEGF in 17beta-estradiol (E2) treated osteoblasts were significantly increased in a dose- and time-dependent manner (p<0.05). And E2 inducted the VEGF expression through the PI3K/AKT signaling pathway in osteoblasts. Taken together, these data implied that miR-210 played an important role in ameliorating the estrogen deficiency caused-postmenopausal osteoporosis through promotion the VEGF expression and osteoblast differentiation. PMID- 25503466 TI - Thromboembolic risk in hematological malignancies. AB - There are a growing number of studies documenting that, similarly to patients with solid cancers, also patients with hematological malignancies (i.e., acute leukemia, lymphoproliferative and myeloproliferative neoplasms and plasma cell disorders) are at increased risk of thrombosis. The pathogenesis of the hypercoagulable state associated with hematological cancers is often multifactorial. Contributor factors include tumor cell-derived procoagulants, antineoplastic therapies, central venous catheters, concomitant infections and advanced age. In this narrative review, the epidemiology, pathogenesis and management of thrombosis in patients with hematological malignancies are reviewed. PMID- 25503468 TI - (1)H, (13)C and (15)N assignments of EGF domains 4 to 7 of human Notch-1. AB - The Notch pathway is a core cell-cell signaling system in Metazoa which plays a key role in development and adult homeostasis. Whereas most Notch structural biology research has focused on the negative regulatory region and the intracellular domain, relatively little structural information is available for the extracellular part of human Notch-1 (hN-1) which mediates ligand recognition. This region consists of 36 epidermal growth factor-like (EGF) domains, many of which contain a calcium-binding consensus sequence. The calcium-binding site in each case is located within the N-terminal portion of the domain, and is associated with both intra- and inter-domain rigidity. The absence of calcium binding sites in EGF6, EGF10 and EGF22, however, suggests that these domains might represent regions of flexibility in the receptor which could influence the cell-surface architecture (usually depicted as an extended rod projecting from the cell surface). To probe this, we have purified a quadruple-domain construct from hN-1, in which the non-calcium-binding EGF6 is flanked by EGF4-5 and EGF7. Here, we report (1)H, (13)C and (15)N resonance assignments for this four-domain 157 amino acid construct. The assignments presented here are the prerequisite for a detailed study of the structure and dynamics of this region of the Notch receptor. PMID- 25503471 TI - Twin trap or hyphenation of a 3D Paul- and a Cassinian ion trap. AB - A new, generalized form of electrostatic, harmonic ion trap mass analyzer, referred to as a Cassinian trap, was introduced in 2009. The present work couples a second order Cassinian trap with a 3D Paul trap in an effort to produce an instrument having the advantages of both (i.e., MS(n) and high mass resolution and accuracy). The present study demonstrates the trapping of ions in the 3D Paul trap and their subsequent transfer to the Cassinian trap. The simultaneous transfer of ions over a broad (factor of 13) mass range is shown. Once in the Cassinian trap, ions can be mass analyzed by Fourier transform means, producing resolving powers as high as 53,000 for the fundamental FID and 140,000 for the third harmonic in 1 s. PMID- 25503469 TI - Discovery of replicating circular RNAs by RNA-seq and computational algorithms. AB - Replicating circular RNAs are independent plant pathogens known as viroids, or act to modulate the pathogenesis of plant and animal viruses as their satellite RNAs. The rate of discovery of these subviral pathogens was low over the past 40 years because the classical approaches are technical demanding and time consuming. We previously described an approach for homology-independent discovery of replicating circular RNAs by analysing the total small RNA populations from samples of diseased tissues with a computational program known as progressive filtering of overlapping small RNAs (PFOR). However, PFOR written in PERL language is extremely slow and is unable to discover those subviral pathogens that do not trigger in vivo accumulation of extensively overlapping small RNAs. Moreover, PFOR is yet to identify a new viroid capable of initiating independent infection. Here we report the development of PFOR2 that adopted parallel programming in the C++ language and was 3 to 8 times faster than PFOR. A new computational program was further developed and incorporated into PFOR2 to allow the identification of circular RNAs by deep sequencing of long RNAs instead of small RNAs. PFOR2 analysis of the small RNA libraries from grapevine and apple plants led to the discovery of Grapevine latent viroid (GLVd) and Apple hammerhead viroid-like RNA (AHVd-like RNA), respectively. GLVd was proposed as a new species in the genus Apscaviroid, because it contained the typical structural elements found in this group of viroids and initiated independent infection in grapevine seedlings. AHVd-like RNA encoded a biologically active hammerhead ribozyme in both polarities, and was not specifically associated with any of the viruses found in apple plants. We propose that these computational algorithms have the potential to discover novel circular RNAs in plants, invertebrates and vertebrates regardless of whether they replicate and/or induce the in vivo accumulation of small RNAs. PMID- 25503470 TI - Analysis of polycyclic aromatic hydrocarbons using desorption atmospheric pressure chemical ionization coupled to a portable mass spectrometer. AB - Desorption atmospheric pressure chemical ionization (DAPCI) is implemented on a portable mass spectrometer and applied to the direct detection of polycyclic aromatic hydrocarbons (PAHs) and alkyl substituted benzenes. The presence of these compounds in the environment poses a significant threat to the health of both humans and wildlife because of their carcinogenic, toxic, and mutagenic properties. As such, instant detection outside of the laboratory is of particular importance to allow in-situ measurement at the source. Using a rapid, high throughput, miniature, handheld mass spectrometer, several alkyl substituted benzenes and PAHs (i.e., 1,2,3,5-tetramethylbenzene, pentamethylbenzene, hexamethylbenzene, fluoranthene, anthracene, benzo[k]fluoranthene, dibenz[a,h]anthracene, acenaphthene, indeno[1,2,3-c,d]pyrene, 9-ethylfluorene, and 1-benzyl-3-methyl-naphthalene) were identified and characterized using tandem mass spectrometry (MS/MS) from ambient surfaces, in the open air. This method can provide almost instantaneous information while minimizing sample preparation, which is advantageous in terms of both cost and simplicity of analysis. This MS based technique is applicable to a wide range of environmental organic molecules. PMID- 25503472 TI - Positive nin one binding protein expression predicts poor outcome in prostate cancer. AB - Nin one binding protein (NOB) 1 has been reported to be involved in cancer. However, the role of NOB1 in prostate cancer (PCa) has yet to be elucidated. The present study aimed to investigate the clinical role of NOB1 in PCa. The gene and protein expression levels of NOB1 were detected using quantitative polymerase chain reaction and western blot analysis in fresh samples of PCa and matched adjacent noncancerous tissues (n=32). NOB1 expression was also assessed using immunohistochemistry in a large number of patients with PCa (n=456) and paired adjacent noncancerous tissues between December 2003 and December 2010. The association between NOB1 expression and clinicopathological features and prognosis was investigated. The expression of NOB1 was found to be higher in the fresh samples of PCa than in the paired adjacent noncancerous tissues at the gene and protein levels. Immunohistochemistry revealed that the positive expression rates of NOB1 in PCa and the paired adjacent noncancerous tissues were 53% (242/456) and 6.1% (28/456), respectively. NOB1 expression was significantly correlated with Gleason score (P<0.001) and distant metastasis (P<0.001). Furthermore, patients with PCa with positive NOB1 expression had lower overall survival and recurrence-free survival (RFS) compared with those with negative NOB1 expression. Multivariate analysis showed that NOB1 was an independent marker of RFS (hazard ratio, 3.45; 95% confidence interval, 1.41-6.35; P=0.006). These findings suggest that NOB1 may be a potential prognostic indicator for PCa. PMID- 25503473 TI - Retrospective, observational study in patients receiving a dexamethasone intravitreal implant 0.7 mg for macular oedema secondary to retinal vein occlusion. AB - PURPOSE: To retrospectively evaluate the re-injection interval, efficacy and safety of dexamethasone (DEX) intravitreal implant 0.7 mg in the treatment of macular oedema (ME) due to retinal vein occlusion (RVO) in Germany in 2009-2012. METHODS: Retrospective, multicentre, anonymised observational study of data collected from the first DEX implant 0.7 mg injection through 3-6 months following the last injection. Data were included if the patient was >18 years old, had a diagnosis of ME secondary to branch or central RVO, and received at least 2 DEX implant 0.7 mg injections during routine practice. RESULTS: Data from 87 patients were analysed. Mean time to re-injection between first and second treatments was 5.03 months in the total RVO population, and 5.46 and 4.52 months for the branch and central RVO subpopulations, respectively. An intraocular pressure increase of >25 mm Hg was recorded in 20% of patients, and 34% of patients began treatment with anti-glaucoma medication, but surgery was not needed for this condition. CONCLUSIONS: DEX implant 0.7 mg was found to be well tolerated and effective with repeat treatments in clinical practice. PMID- 25503474 TI - Detection and viability of Lactococcus lactis throughout cheese ripening. AB - Recent evidences highlighted the presence of Lactococcus lactis during late cheese ripening. For this reason, the role of this microorganism, well known as dairy starter, should be reconsidered throughout cheese manufacturing and ripening. Thus, the main objective of this study was to develop a RT-qPCR protocol for the detection, quantification and determination of the viability of L. lactis in ripened cheese samples by direct analysis of microbial nucleic acids. Standard curves were constructed for the specific quantification of L. lactis in cheese matrices and good results in terms of selectivity, correlation coefficient and efficiency were obtained. Thirty-three ripened cheeses were analyzed and, on the basis of RNA analysis, twelve samples showed 106 to 108 CFU of L. lactis per gram of product, thirteen from 103 to 105 CFU/g, and in eight cheeses, L. lactis was not detected. Traditional plating on M17 medium led to loads ranging from 105 to 109 CFU/g, including the cheese samples where no L. lactis was found by RT-qPCR. From these cheeses, none of the colonies isolated on M17 medium was identified as L. lactis species. These data could be interpreted as a lack of selectivity of M17 medium where colony growth is not always related to lactococcal species. At the same time, the absence or low abundance of L. lactis isolates on M17 medium from cheese where L. lactis was detected by RT-qPCR support the hypothesis that L. lactis starter populations are mainly present in viable but not culturable state during ripening and, for this reason, culture dependent methods have to be supplemented with direct analysis of cheese. PMID- 25503475 TI - Preserving quality of life is not incompatible with increasing overall survival in diffuse low-grade glioma patients. PMID- 25503476 TI - Determining the fate of hepatic cells by lineage tracing: facts and pitfalls. AB - Slow renewal of the epithelial cells by proliferation ensures homeostasis of the liver, but extensive proliferation may occur upon injury. When proliferation is impaired, transdifferentiation of mature cells or differentiation of stem cells allows production of new hepatocytes and cholangiocytes. While lineage tracings using cyclization recombinase (Cre) recombinase-mediated cell labeling represent the gold standard for defining cell fate, there are more variables than was initially realized. This led to controversies about the capacity of liver cells to switch their fate. Here, I review how cells are traced in the liver and highlight the experimental pitfalls that may cause misinterpretations and controversies. PMID- 25503477 TI - Interdental cleaning and gingival injury potential of interdental toothbrushes. AB - The effective cleaning of interdental spaces using toothbrushes is a challenge. The aim of the present in vitro study was to evaluate on the one hand the interdental cleaning efficiency and on the other hand the gingival injury potential of an electric single-headed sonic toothbrush (Water-pik) and two single-tufted manual toothbrushes (Curaprox 1009; Lactona Interdental Brush). Brushes were evaluated using a brushing device. Test dental casts (maxillary sextants) consisting of black teeth coated with white paint were brushed using standardized horizontal movements. Thereafter, black (i.e. cleaned) areas were measured planimetrically. The soft tissue injury potential was evaluated using front segments of porcine mandibles. In the same brushing device, test brushes were moved over the gingiva. Before and after each treatment, the porcine mucosa was stained with a plaque disclosing agent to visualize injured areas, which could then be measured planimetrically as well. These evaluations were each made after 15, 30, 60, and 120 seconds of brushing. The statistical analysis was performed using non-parametric Mann-Whitney tests, and the level of significance was set at 5%. The best cleaning performance of 46% across all interdental spaces assessed was found with the electric sonic toothbrush (Waterpik), while the performances of the manual brushes from Lactona and Curaprox were 14.8% and 5%, respectively. At each point of evaluation, the gingiva was injured most markedly by the powered sonic toothbrush (Waterpik), followed by the manual Curaprox brush. The smallest damage of the porcine gingiva was produced by the manual Lactona brush. When comparing the manual toothbrushes, the Lactona product revealed a better cleaning performance combined with a smaller injury potential than the Curaprox brush. Thus, the prophylactic goal to achieve high degrees of cleaning while producing minimal damage is important and should have priority when evaluating and selecting toothbrushes. PMID- 25503478 TI - Partially covered self-expandable metallic stent for postoperative benign strictures associated with laparoscopy-assisted gastrectomy. AB - BACKGROUND: A partially covered self-expandable metallic stent (PCSEMS) is of proven benefit in palliation of unresectable or inoperable malignant gastric outlet obstruction. However, its use in patients with benign anastomotic stricture after laparoscopy-assisted gastrectomy (LAG) is not well established. METHODS: Patients who between May 2007 and June 2012 underwent PCSEMS placement for management of benign gastrointestinal obstruction after LAG were included in this retrospective analysis. The primary outcomes were the technical success and clinical success of the PCSEMS. The secondary outcomes were procedure-related complications and PCSEMS dysfunction. RESULTS: Eleven patients (six women, five men, mean age 53.5 years, range 15-76 years) underwent successful placement of a PCSEMS for management of benign anastomotic strictures after LAG and were followed-up for a mean of 20.6 months (range 7.9-55.6 months). The mean gastric outlet obstruction scoring system (GOOSS) score was 0.36 before PCSEMS placement and 1.55 (p = 0.010) 24-48 h after PCSEMS placement. All of the patients were able to tolerate a solid diet (GOOSS score 3) after 1 week. There were no major or minor procedure-related complications. Stent dysfunction occurred in four patients (three distal migrations, one proximal migration), and stent removal was successful in all of the remaining patients after a mean of 2.0 months (1.1-3.0 months). Obstructive symptoms recurred in two patients (one after proximal migration, one after stent removal) and were treated successfully with PCSEMS reinsertion and balloon dilation. CONCLUSIONS: A PCSEMS may be a feasible and effective option for management of benign anastomotic strictures after LAG which could avoid secondary surgery. PMID- 25503479 TI - Photothrombotic stroke induces persistent ipsilateral and contralateral astrogliosis in key cognitive control nuclei. AB - While astrocytes are recognised to play a central role in repair processes following stroke, at this stage we do not have a clear understanding of how these cells are engaged during the chronic recovery phase. Accordingly, the principal aim of this study was to undertake a quantitative multi-regional investigation of astrocytes throughout the recovery process. Specifically, we have induced experimental vascular occlusion using cold-light photothrombotic occlusion of the somatosensory/motor cortex in adult male C57B6 mice. Four weeks following occlusion we collected, processed, and immunolabelled tissue using an antibody directed at the glial fibrillary acidic protein (GFAP), an astrocyte specific cytoskeletal protein marker. We investigated GFAP changes in 13 regions in both the contra- and ipsi-lateral hemispheres from control and occluded animals. Specifically, we examined the infra-limbic (A24a), pre-limbic (A25), anterior cingulate (A32), motor (M1 and M2) cortices, the forceps minor fibre tract, as well the shell of the accumbens, thalamus, cingulate cortex (A29c), hippocampus (CA1-3) and lateral hypothalamus. Tissue from occluded animals was compared against sham treated controls. We have identified that the focal occlusion produced significant astrogliosis (p < 0.05), as defined by a marked elevation in GFAP expression, within all 13 sites assessed within the ipsilateral (lesioned) hemisphere. We further observed significant increases in GFAP expression (p < 0.05) in 9 of the 13 contralesional sites examined. This work underscores that both the ipsilateral and contralesional hemispheres, at sites distal to the infarct, are very active many weeks after the initial occlusion, a finding that potentially has significant implications for understanding and improving the regeneration of the damaged brain. PMID- 25503481 TI - Splaying hyperthin polyelectrolyte multilayers to increase their gas permeability. AB - The concept of splayed, hyperthin polyelectrolyte multilayers (PEMs) is introduced in which a bulky, hydrophilic and charged pendant group is used to increase the gas permeability of a PEM without reducing its permeation selectivity. Proof of principle studies are reported using nm-thick PEMs made from poly(sodium 4-styrene sulfonate) () and poly(allylamine hydrochloride) () bearing bulky cobaltocenium ions. PMID- 25503480 TI - Protective effects of (E)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeine against hydrogen peroxide-induced injury in PC12 cells. AB - (E)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeine (HOEC), a naturally caffeic ester isolated from Incarvillea mairei, has been reported to possess anti inflammatory activity by targeting 5-lipoxygenase. However, its other potential activities have yet to be explored. In this study, we measured antioxidant activity of HOEC using the DPPH free radical-scavenging assay. Then, we exposed rat pheochromocytoma (PC12) cells to hydrogen peroxide (H2O2)-induced damage and investigated the antioxidant activity of HOEC. Cell viability, lactate dehydrogenase (LDH) release, cellular morphology, Hoechst 33342 fluorescent staining, and apoptosis of the PC12 cells were assessed after treatment with 0.3 10 MUM HOEC for 2 h and exposure to 600 MUM H2O2. Additionally, glutathione reductase (GR), superoxide dismutase (SOD), lipid peroxidation malondialdehyde (MDA), and intracellular reactive oxygen species (ROS) accumulation were assayed after the PC12 cells were exposed to H2O2. To investigate mechanism, apoptosis related protein were evaluated, including cleaved caspase 3/7, cleaved PARP, Bcl 2, Bcl-XL, and cytochrome c. The results showed that HOEC possessed potent antioxidant activity and pre-treatment with HOEC prior to H2O2 exposure significantly increased cell viability, reduced the release of LDH, ameliorated changes in cell morphology, and inhibited apoptosis. Further, HOEC did the following: reduced intracellular accumulation of ROS and MDA; rescued loss of SOD and GR activities; inhibited activated caspase-3 and caspase-7, cleaved PARP, and cytochrome c release; up-regulated the antiapoptosis-related protein Bcl-2 and Bcl-XL; and down-regulated the apoptosis-related proteins Bax and Bad. These findings suggested that HOEC may be a therapeutic agent for treating oxidative stress-derived neurodegenerative disorders. PMID- 25503482 TI - Theonellasterone, a steroidal metabolite isolated from a Theonella sponge, protects peroxiredoxin-1 from oxidative stress reactions. AB - Peroxiredoxin-1, a key enzyme in the cellular detoxification pathway, has been identified through a chemoproteomic approach as the main partner of theonellasterone, a marine bioactive metabolite. A combination of chemical and biochemical assays disclosed its mechanism of action at the molecular level. PMID- 25503483 TI - Emotional Disclosure Through Journal Writing: Telehealth Intervention for Maternal Stress and Mother-Child Relationships. AB - This study examines emotional disclosure through the activity of journaling as a means of coping with maternal stress associated with parenting a child with disruptive behaviors. Through a randomized control and pre-test post-test study design of an online journal writing intervention, change to maternal stress and quality of mother-child relationship for children with ASD, ADHD and SPD was addressed. Behavioral symptoms were found to be the primary source of parenting stress for mothers and a significant relationship between child characteristics and maternal stress was identified. Emotional disclosure through the online journal writing program (especially in the presence of high disclosure of negative emotions) was shown to reduce maternal stress and improve the quality of mother-child relationship. These findings suggest cost-effective telehealth interventions may support maternal health. Important clinical implications are discussed. PMID- 25503484 TI - Sketching to remember: episodic free recall task support for child witnesses and victims with autism spectrum disorder. AB - Deficits in episodic free-recall memory performance have been reported in children with autism spectrum disorder (ASD), yet best practice dictates that child witness/victim interviews commence with a free-recall account. No 'tools' exist to support children with ASD to freely recall episodic information. Here, the efficacy of a novel retrieval technique, Sketch reinstatement of context (Sketch-RC), is compared with mental reinstatement of context and a no support control. Ninety children (45 with ASD; 45 matched typically developing) viewed a stimulus film, and were interviewed using one of the aforementioned techniques. The Sketch-RC technique was most effective, improving ASD participants' remembering without a concomitant increase in intrusions. This procedure offers a population-appropriate method for supporting free recall in criminal justice settings. PMID- 25503485 TI - Variation in the Profile of Anxiety Disorders in Boys with an ASD According to Method and Source of Assessment. AB - To determine any variation that might occur due to the type of assessment and source used to assess them, the prevalence of 7 anxiety disorders were investigated in a sample of 140 boys with an Autism spectrum disorder (ASD) and 50 non-ASD (NASD) boys via the Child and Adolescent Symptom Inventory and the KIDSCID Clinical Interview. Boys with an ASD were significantly more anxious than their NASD peers. Data collected from the boys with an ASD themselves showed differences in the severity and diagnostic criterion of anxiety disorders to data collected from the boys' parents. There were age-related variations to the pattern of anxiety disorder differences across reports from the boys with an ASD and reports from their parents. PMID- 25503487 TI - A systematic study of rare gas atoms encapsulated in small fullerenes using dispersion corrected density functional theory. AB - The most stable fullerene structures from C20 to C60 are chosen to study the energetics and geometrical consequences of encapsulating the rare gas elements He, Ne, or Ar inside the fullerene cage using dispersion corrected density functional theory. An exponential increase in stability is found with increasing number of carbon atoms. A similar exponential law is found for the volume expansion of the cage due to rare gas encapsulation with decreasing number of carbon atoms. We show that dispersion interactions become important with increasing size of the fullerene cage, where Van der Waals forces between the rare gas atom and the fullerene cage start to dominate over repulsive interactions. The smallest fullerenes where encapsulation of a rare gas element is energetically still favorable are He@C48, Ne@C52, and Ar@C58. While dispersion interactions follow the trend Ar > Ne > He inside C60 due to the trend in the rare gas dipole polarizabilities, repulsive forces become soon dominant with smaller cage size and we have a complete reversal for the energetics of rare gas encapsulation at C50. PMID- 25503490 TI - Editorial from the new Editor-in-Chief. PMID- 25503486 TI - Cloning of the cryptochrome-encoding PeCRY1 gene from Populus euphratica and functional analysis in Arabidopsis. AB - Cryptochromes are photolyase-like blue/UV-A light receptors that evolved from photolyases. In plants, cryptochromes regulate various aspects of plant growth and development. Despite of their involvement in the control of important plant traits, however, most studies on cryptochromes have focused on lower plants and herbaceous crops, and no data on cryptochrome function are available for forest trees. In this study, we isolated a cryptochrome gene, PeCRY1, from Euphrates poplar (Populus euphratica), and analyzed its structure and function in detail. The deduced PeCRY1 amino acid sequence contained a conserved N-terminal photolyase-homologous region (PHR) domain as well as a C-terminal DQXVP-acidic STAES (DAS) domain. Secondary and tertiary structure analysis showed that PeCRY1 shares high similarity with AtCRY1 from Arabidopsis thaliana. PeCRY1 expression was upregulated at the mRNA level by light. Using heterologous expression in Arabidopsis, we showed that PeCRY1 overexpression rescued the cry1 mutant phenotype. In addition, PeCRY1 overexpression inhibited hypocotyl elongation, promoted root growth, and enhanced anthocyanin accumulation in wild-type background seedlings grown under blue light. Furthermore, we examined the interaction between PeCRY1 and AtCOP1 using a bimolecular fluorescence complementation (BiFc) assay. Our data provide evidence for the involvement of PeCRY1 in the control of photomorphogenesis in poplar. PMID- 25503491 TI - An indirect transmission measurement-based spectrum estimation method for computed tomography. AB - The characteristics of an x-ray spectrum can greatly influence imaging and related tasks. In practice, due to the pile-up effect of the detector, it's difficult to directly measure the spectrum of a CT scanner using an energy resolved detector. An alternative solution is to estimate the spectrum using transmission measurements with a step phantom or another CT phantom. In this work, we present a new spectrum estimation method based on indirect transmission measurement and a model spectra mixture approach. The estimated x-ray spectrum was expressed as a weighted summation of a set of model spectra, which can significantly reduce the degrees of freedom of the spectrum estimation problem. Next, an estimated projection was calculated with the assumed spectrum. By iteratively updating the unknown weights, we minimized the difference between the estimated projection data and the raw projection data. The final spectrum was calculated with these calibrated weights and the model spectra. Both simulation and experimental data were used to evaluate the proposed method. In the simulation study, the estimated spectra were compared to the raw spectra which were used to generate the raw projection data. For the experimental study, the ground truth measurement of the raw x-ray spectrum was not available. Therefore, the estimated spectrum was compared against the spectra generated using the SpekCalc software with tube configurations provided by the scanner manufacturer. The results show the proposed method has the potential to accurately estimate x ray spectra using the raw projection data. The difference between the mean energy of the raw spectra and the mean energy of the estimated spectra was less than 0.5 keV for both the simulation and experimental data. Further tests show the method was robust with respect to the model spectra generator. PMID- 25503492 TI - Oscillation-induced signal transmission and gating in neural circuits. AB - Reliable signal transmission constitutes a key requirement for neural circuit function. The propagation of synchronous pulse packets through recurrent circuits is hypothesized to be one robust form of signal transmission and has been extensively studied in computational and theoretical works. Yet, although external or internally generated oscillations are ubiquitous across neural systems, their influence on such signal propagation is unclear. Here we systematically investigate the impact of oscillations on propagating synchrony. We find that for standard, additive couplings and a net excitatory effect of oscillations, robust propagation of synchrony is enabled in less prominent feed forward structures than in systems without oscillations. In the presence of non additive coupling (as mediated by fast dendritic spikes), even balanced oscillatory inputs may enable robust propagation. Here, emerging resonances create complex locking patterns between oscillations and spike synchrony. Interestingly, these resonances make the circuits capable of selecting specific pathways for signal transmission. Oscillations may thus promote reliable transmission and, in co-action with dendritic nonlinearities, provide a mechanism for information processing by selectively gating and routing of signals. Our results are of particular interest for the interpretation of sharp wave/ripple complexes in the hippocampus, where previously learned spike patterns are replayed in conjunction with global high-frequency oscillations. We suggest that the oscillations may serve to stabilize the replay. PMID- 25503494 TI - Genetics educational needs in China: physicians' experience and knowledge of genetic testing. AB - PURPOSE: The aims of this study were to explore the relationship between physicians' knowledge and utilization of genetic testing and to explore genetics educational needs in China. METHODS: An anonymous survey about experience, attitudes, and knowledge of genetic testing was conducted among physicians affiliated with Peking Union Medical College Hospital during their annual health evaluation. A personal genetics knowledge score was developed and predictors of personal genetics knowledge score were evaluated. RESULTS: Sixty-four physicians (33% male) completed the survey. Fifty-eight percent of them had used genetic testing in their clinical practice. Using a 4-point scale, mean knowledge scores of six common genetic testing techniques ranged from 1.7 +/- 0.9 to 2.4 +/- 1.0, and the average personal genetics knowledge score was 2.1 +/- 0.8. In regression analysis, significant predictors of higher personal genetics knowledge score were ordering of genetic testing, utilization of pedigrees, higher medical degree, and recent genetics training (P < 0.05). Sixty-six percent of physicians indicated a desire for specialized genetic services, and 84% reported a desire for additional genetics education. CONCLUSION: This study demonstrated a sizable gap between Chinese physicians' knowledge and utilization of genetic testing. Participants had high self-perceived genetics educational needs. Development of genetics educational platforms is both warranted and desired in China.Genet Med 17 9, 757 760. PMID- 25503493 TI - A high-resolution copy-number variation resource for clinical and population genetics. AB - PURPOSE: Chromosomal microarray analysis to assess copy-number variation has become a first-tier genetic diagnostic test for individuals with unexplained neurodevelopmental disorders or multiple congenital anomalies. More than 100 cytogenetic laboratories worldwide use the new ultra-high resolution Affymetrix CytoScan-HD array to genotype hundreds of thousands of samples per year. Our aim was to develop a copy-number variation resource from a new population sample that would enable more accurate interpretation of clinical genetics data on this microarray platform and others. METHODS: Genotyping of 1,000 adult volunteers who are broadly representative of the Ontario population (as obtained from the Ontario Population Genomics Platform) was performed with the CytoScan-HD microarray system, which has 2.7 million probes. Four independent algorithms were applied to detect copy-number variations. Reproducibility and validation metrics were quantified using sample replicates and quantitative-polymerase chain reaction, respectively. RESULTS: DNA from 873 individuals passed quality control and we identified 71,178 copy-number variations (81 copy-number variations/individual); 9.8% (6,984) of these copy-number variations were previously unreported. After applying three layers of filtering criteria, from our highest confidence copy-number variation data set we obtained >95% reproducibility and >90% validation rates (73% of these copy-number variations overlapped at least one gene). CONCLUSION: The genotype data and annotated copy number variations for this largely Caucasian population will represent a valuable public resource enabling clinical genetics research and diagnostics. PMID- 25503495 TI - Is there a duty to recontact in light of new genetic technologies? A systematic review of the literature. AB - PURPOSE: With rapid advances in genetic technologies, new genetic information becomes available much faster today than just a few years ago. This has raised questions about whether clinicians have a duty to recontact eligible patients when new genetic information becomes available and, if such duties exist, how they might be implemented in practice. METHODS: We report the results of a systematic literature search on the ethical, legal, social (including psychological), and practical issues involved in recontacting former patients who received genetic services. We identified 1,428 articles, of which 61 are covered in this review. RESULTS: The empirical evidence available indicates that most but not all patients value being recontacted. A minority of (older) articles conclude that recontacting should be a legal duty. Most authors consider recontacting to be ethically desirable but practically unfeasible. Various solutions to overcome these practical barriers have been proposed, involving efforts of laboratories, clinicians, and patients. CONCLUSION: To advance the discussion on implementing recontacting in clinical genetics, we suggest focusing on the question of in what situations recontacting might be regarded as good standard of care. To this end, reaching a professional consensus, obtaining more extensive empirical evidence, and developing professional guidelines are important. PMID- 25503496 TI - The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population. AB - PURPOSE: Molecular karyotyping has rapidly become the test of choice in patients with neurocognitive phenotypes, but studies of its clinical utility have largely been limited to outbred populations. In consanguineous populations, single-gene recessive causes of neurocognitive phenotypes are expected to account for a relatively high percentage of cases, thus diminishing the yield of molecular karyotyping. The aim of this study was to test the clinical yield of molecular karyotyping in the highly consanguineous population of Saudi Arabia. METHODS: We have reviewed the data of 584 patients with neurocognitive phenotypes (mainly referred from pediatric neurology clinics), all evaluated by a single clinical geneticist. RESULTS: At least 21% of tested cases had chromosomal aberrations that are likely disease-causing. These changes include both known and novel deletion syndromes. The higher yield of molecular karyotyping in this study as compared with the commonly cited 11% can be explained by our ability to efficiently identify single-gene disorders, thus enriching the samples that underwent molecular karyotyping for de novo chromosomal aberrations. We show that we were able to identify a causal mutation in 37% of cases on a clinical basis with the help of autozygome analysis, thus bypassing the need for molecular karyotyping. CONCLUSION: Our study confirms the clinical utility of molecular karyotyping even in highly consanguineous populations. PMID- 25503499 TI - Researchers' views on informed consent for return of secondary results in genomic research. AB - PURPOSE: Previous studies have suggested that genomic investigators generally favor offering to return at least some secondary findings to participants and believe that participants' preferences should determine the information they receive. We surveyed investigators to ascertain their views on four models of informed consent for this purpose: traditional consent, staged consent, mandatory return, and outsourced consent. METHODS: We performed an online survey of the views regarding return of secondary results held by 198 US genetic researchers drawn from our subject pool for an earlier study. Potential participants were identified through the National Institutes of Health RePORTER database and abstracts from the 2011 American Society of Human Genetics meeting. RESULTS: Under circumstances in which resource constraints are not an issue, approximately a third of respondents would endorse either staged consent or traditional consent; outsourced consent and mandatory return are favored by only a small minority. However, taking resource constraints into account, roughly half the sample would favor traditional consent, with support for staged consent dropping to 13%. CONCLUSION: Despite their liabilities, traditional approaches to consent are seen as the most viable under current circumstances. However, there is considerable interest in staged consent, assuming the infrastructure to support it can be provided. PMID- 25503500 TI - Challenges in managing genetic cancer risk: a long-term qualitative study of unaffected women carrying BRCA1/BRCA2 mutations. AB - PURPOSE: Women carrying BRCA1/BRCA2 germ-line mutations have an increased risk of developing breast/ovarian cancer. To minimize this risk, international guidelines recommend lifelong surveillance and preventive measures. This study explores the challenges that unaffected women genetically predisposed to breast/ovarian cancer face in managing their risk over time and the psychosocial processes behind these challenges. METHODS: Between 2011 and 2013, biographical qualitative interviews were conducted in Switzerland with 32 unaffected French- and Italian-speaking women carrying BRCA1/BRCA2 mutations. Their mutation status had been known for at least 3 years (mean, 6 years). Data were analyzed through constant comparative analysis using software for qualitative analysis. RESULTS: From the time these women received their positive genetic test results, they were encouraged to follow medical guidelines. Meanwhile, their adherence to these guidelines was constantly questioned by their social and medical environments. As a result of these contradictory pressures, BRCA1/BRCA2 mutation carriers experienced a sense of disorientation about the most appropriate way of dealing with genetic risk. CONCLUSION: Given the contradictory attitudes of health-care professionals in caring for unaffected BRCA1/BRCA2 mutation carriers, there is an urgent need to educate physicians in dealing with genetically at-risk women and to promote a shared representation of this condition among them.Genet Med 17 9, 726-732. PMID- 25503502 TI - Under-water superoleophobicity of fish scales. AB - Recent surge in the development of superhydrophobic/superoleophobic surfaces has been motivated by surfaces like fish scales that have hierarchical structures, which are believed to promote water or oil repellency. In this work, we show that the under-water oil repellency of fish scales is entirely due to the mucus layer formation as part of its defense mechanism, which produces unprecedented contact angle close to 180 degrees . We have identified the distinct chemical signatures that are responsible for such large contact angle, thereby making fish scale behave highly superoleophobic inside the water medium. In absence of the mucus layer, it is found that the contact angle decreases quite dramatically to around 150 degrees , making it less oleophobic, the degree of such oleophobicity can then be contributed to its inherent hierarchical structures. Hence, through this systematic study, for the first time we have conclusively shown the role of the fish's mucus layer to generate superoleophobicity and negate the common notion that hierarchical structure is the only reason for such intrinsic behavior of the fish scales. PMID- 25503497 TI - Blood ammonia and glutamine as predictors of hyperammonemic crises in patients with urea cycle disorder. AB - PURPOSE: The aim of this study was to examine predictors of ammonia exposure and hyperammonemic crises in patients with urea cycle disorders. METHODS: The relationships between fasting ammonia, daily ammonia exposure, and hyperammonemic crises were analyzed in >100 patients with urea cycle disorders. RESULTS: Fasting ammonia correlated strongly with daily ammonia exposure (r = 0.764; P < 0.001). For patients with fasting ammonia concentrations <0.5 upper limit of normal (ULN), 0.5 to <1.0 ULN, and >=1.0 ULN, the probability of a normal average daily ammonia value was 87, 60, and 39%, respectively, and 10.3, 14.1, and 37.0% of these patients, respectively, experienced >=1 hyperammonemic crisis over 12 months. Time to first hyperammonemic crisis was shorter (P = 0.008) and relative risk (4.5*; P = 0.011) and rate (~5*, P = 0.006) of hyperammonemic crises were higher in patients with fasting ammonia >=1.0 ULN vs. <0.5ULN; relative risk was even greater (20*; P = 0.009) in patients >=6 years old. A 10- or 25-umol/l increase in ammonia exposure increased the relative risk of a hyperammonemic crisis by 50 and >200% (P < 0.0001), respectively. The relationship between ammonia and hyperammonemic crisis risk seemed to be independent of treatment, age, urea cycle disorder subtype, dietary protein intake, or blood urea nitrogen. Fasting glutamine correlated weakly with daily ammonia exposure assessed as 24 hour area under the curve and was not a significant predictor of hyperammonemic crisis. CONCLUSION: Fasting ammonia correlates strongly and positively with daily ammonia exposure and with the risk and rate of hyperammonemic crises, suggesting that patients with urea cycle disorder may benefit from tight ammonia control. PMID- 25503501 TI - Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. AB - PURPOSE: Clinical testing for germ-line variation in multiple cancer susceptibility genes is available using massively parallel sequencing. Limited information is available for pretest genetic counseling regarding the spectrum of mutations and variants of uncertain significance in defined patient populations. METHODS: We performed massively parallel sequencing using targeted capture of 22 cancer susceptibility genes in 278 BRCA1/2-negative patients with early-onset breast cancer (diagnosed at younger than 40 years of age). RESULTS: Thirty-one patients (11%) were found to have at least one deleterious or likely deleterious variant. Seven patients (2.5% overall) were found to have deleterious or likely deleterious variants in genes for which clinical guidelines exist for management, namely TP53 (4), CDKN2A (1), MSH2 (1), and MUTYH (double heterozygote). Twenty four patients (8.6%) had deleterious or likely deleterious variants in a cancer susceptibility gene for which clinical guidelines are lacking, such as CHEK2 and ATM. Fifty-four patients (19%) had at least one variant of uncertain significance, and six patients were heterozygous for a variant in MUTYH. CONCLUSION: These data demonstrate that massively parallel sequencing identifies reportable variants in known cancer susceptibility genes in more than 30% of patients with early-onset breast cancer. However, only few patients (2.5%) have definitively actionable mutations given current clinical management guidelines.Genet Med 17 8, 630-638. PMID- 25503503 TI - Outcomes of allogeneic hematopoietic cell transplantation in acute myeloid leukemia patients with monosomal karyotypes. AB - This study investigated the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in acute myeloid leukemia (AML) patients with monosomal karyotypes (MK). A total of 114 AML patients who received allo-HCT were retrospectively analyzed. At the time of diagnosis, 13 patients were categorized with a favorable cytogenetic risk, 78 with an intermediate risk, and 23 with an adverse risk. MK was found in 12 patients among 23 with adverse cytogenetic risk. Pretransplant disease status was active disease in 5 cases (45.5%) in the adverse risk without MK group, and 8 cases (66.7%) in the corresponding group with MK, 15 (19.2%) in the intermediate group and 4 (30.8%) in the favorable group. In multivariate analysis, active disease before transplant (hazard ratio, HR 3.913, p < 0.001), acute graft-versus-host disease (GVHD) >=grade 2 (HR 1.908, p = 0.048) and chronic GVHD (HR 0.364, p = 0.001) affected overall survival (OS). The initial cytogenetic risk groups were not a significant risk factor for OS in allogeneic settings. The 2-year OS rate was 44.0 +/- 15.9% without MK and 20.7 +/ 17.9% with MK (p = 0.246). However, the OS rate was better for patients with chronic GVHD (p = 0.025). In conclusion, a survival benefit was observed for MK positive patients with chronic GVHD in an allogeneic setting. However, the prognosis still remained poor for patients with MK. PMID- 25503504 TI - Photosynthetic and extracellular production of glucosylglycerol by genetically engineered and gel-encapsulated cyanobacteria. AB - Glucosylglycerol (GG) has a range of potential applications in health, pharmacy, and cosmetics due to its physiological, protein-stabilizing, and antioxidative properties. In addition to chemical synthesis and enzymatic catalysis, GG can be produced as a protective osmolyte in salt-stressed bacteria, such as the cyanobacterium Synechocystis sp. PCC 6803. Here, we presented an efficient GG production and secretion by genetically modified and encapsulated Synechocystis cells grown in a semicontinuous manner. We improved the production and secretion of GG in Synechocystis by first disrupting both the ggtC and ggtD genes, which encode the subunits of a GG uptake transporter, as well as the ggpR gene, which encodes a repressor for GG synthesis. Then, we confirmed that the rapid GG release from salt-stressed cells of Synechocystis depended on the ion gradient across the cell membrane. Finally, we proved the feasibility of an agar gel encapsulation method in supporting cell growth and the GG production of Synechocystis under semicontinuous culturing conditions. PMID- 25503498 TI - Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. AB - PURPOSE: The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients. METHODS: The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. RESULTS: Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease. CONCLUSION: The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease. PMID- 25503505 TI - Plasma membrane proteins Yro2 and Mrh1 are required for acetic acid tolerance in Saccharomyces cerevisiae. AB - Yro2 and its paralogous protein Mrh1 of Saccharomyces cerevisiae have seven predicted transmembrane domains and predominantly localize to the plasma membrane. Their physiological functions and regulation of gene expression have not yet been elucidated in detail. We herein demonstrated that MRH1 was constitutively expressed, whereas the expression of YRO2 was induced by acetic acid stress and entering the stationary phase. Fluorescence microscopic analysis revealed that Mrh1 and Yro2 were distributed as small foci in the plasma membrane under acetic acid stress conditions. The null mutants of these genes (mrh1?, yro2?, and mrh1?yro2?) showed delayed growth and a decrease in the productivity of ethanol in the presence of acetic acid, indicating that Yro2 and Mrh1 are involved in tolerance to acetic acid stress. PMID- 25503506 TI - Development of a new DNA vaccine based on mycobacterial ESAT-6 antigen delivered by recombinant invasive Lactococcus lactis FnBPA+. AB - The use of the food-grade bacterium Lactococcus lactis as a vehicle for the oral delivery of DNA vaccine plasmids constitutes a promising strategy for vaccination. The delivery of DNA plasmids into eukaryotic cells is of critical importance for subsequent DNA expression and effectiveness of the vaccine. In this context, the use of the recombinant invasive L. lactis FnBPA+ (fibronectin binding protein A) strain for the oral delivery of the eukaryotic expression vector vaccination using lactic acid bacteria (pValac), coding for the 6-kDa early secreted antigenic target (ESAT-6) gene of Mycobacterium tuberculosis, could represent a new DNA vaccine strategy against tuberculosis. To this end, the ESAT-6 sequence was cloned into the pValac vector; the L. lactis fibronectin binding protein A (FnBPA)+ (pValac:ESAT-6) strain was obtained, and its immunological profile was checked in BALB/c mice. This strain was able to significantly increase interferon gamma (IFN-gamma) production in spleen cells, showing a systemic T helper 1 (Th1) cell response. The mice also showed a significant increase in specific secretory immunoglobulin A (sIgA) production in colon tissue and fecal extracts. Thus, this is the first time that L. lactis has been used to deliver a plasmid DNA harboring a gene that encodes an antigen against tuberculosis through mucous membranes. PMID- 25503507 TI - Functional recovery after experimental spinal cord compression and whole body vibration therapy requires a balanced revascularization of the injured site. AB - PURPOSE: Based on several positive effects of whole-body-vibration (WBV) therapy on recovery after SCI, we looked for correlations between functional (analysis of locomotion), electrophysiological (H-reflex) and morphological (density of functioning capillaries) measurements after SCI and WBV-treatment. METHODS: Severe compression SCI at low-thoracic level (T8) in adult female Wistar rats was followed by WBV twice a day (2 * WBV) over a 12-week post-injury period. Intact rats and rats with SCI but no WBV-therapy ("No-WBV") served as controls. Recovery of locomotion was determined by BBB-locomotor rating, foot stepping angle (FSA), rump-height index (RHI), correct ladder steps (CLS) and H-reflex at 1, 3, 6, 9, and 12 weeks after SCI. Animals were sacrificed by an overdose of Isoflurane (Abbott). One hour later their spinal cords were fixed in 4% PFA for 24 h. Samples from the thoracic cord containing the lesion site and from the lumbar intumescence were cut into 10 MUm thick longitudinal frozen sections. RESULTS: All functioning capillaries were unequivocally identified because the endogenous peroxidase of the erythrocytes was clearly visualized with 0.05% diaminobenzidine (DAB). A determination of their absolute (in MUm2) and proportional areas (percent of photographed tissue) revealed a significantly denser capillary network in the WBV-treated rats: 1,66 +/- 0,41% in the "vibrated" rats versus 0,79 +/- 0,19% in the "No-WBV" animals. The portion of the capillary network in intact rats was 1,51 +/- 0,69%. Surprisingly, even though the vascularization in the treated animals was significantly increased, this had no beneficial influence on the recovery of functions after SCI. CONCLUSION: The results of this study provide for the first time evidence that intensive WBV-therapy leads to a significantly denser capillary network in the lesioned spinal cord. However, since this higher capillary density is not associated with improved functional recovery (possibly because it exceeded the balance necessary for functional improvements), optional treatments with lower intensity or less time of WBV therapy should be tested. PMID- 25503508 TI - Ipsilesional motor area size correlates with functional recovery after stroke: a 6-month follow-up longitudinal TMS motor mapping study. AB - PURPOSE: Transcranial magnetic stimulation (TMS) and measurements of upper limb function were longitudinally applied to gain further insights into processes involved in functional recovery from the acute to the chronic stage after stroke. METHODS: 10 acute stroke patients were monitored over 6 months behaviourally and with established TMS protocols. By using neuronavigated motor mapping, behavioural parameters, and a mixed model analysis, the role of the frontal and parietal part of the motor area of both hemispheres for functional recovery was determined. RESULTS: Size and volume of the ipsilesional motor area (MAipsi) were significantly decreased in the acute phase compared to the contralesional motor area (MAcontra). Size of MAipsi, especially its frontal part, changed over time and was positively correlated with functional recovery, whereas resting motor threshold, volume of both MA or the shift of its center of gravity did not show any association with recovery. CONCLUSION: The present data suggests the presence of a positive correlation between changes of the motor representation of the lesioned hemisphere and functional recovery after stroke. A possible interpretation is that rather (re-)activated corticomotor outputs are substrates of functional recovery after stroke than increased efficacy of residual, non lesioned pathways. PMID- 25503509 TI - Distinct DNA methylomes of human placentas between pre-eclampsia and gestational diabetes mellitus. AB - BACKGROUND: The placenta acts not only as a conduit of nutrient and waste exchange between mother and developing fetus but also functions as a regulator of the intrauterine environment. Pre-eclampsia (PE) and gestational diabetes mellitus (GDM) are leading causes of complications during pregnancy. Pathophysiologies show that they are associated with one another. Epigenetics provides a link between environmental factors that have previously been linked to poor pregnancy outcomes and fetal programming. METHODS AND RESULTS: The present study investigated genome-wide DNA methylation changes in PE and GDM compared with control subjects through DNA methylation microarray. We found that the methylation patterns of placentas from PE and GDM women were similar; 64.4% of the annotated genes with differential methylation presented concordant changes between PE and GDM patients. Significantly, the same functional processes were affected by PE and GDM, with cell adhesion and cell differentiation being the most populated clusters and including genes related to carbohydrate metabolism and lipid metabolism. CONCLUSION: Our work showed that of DNA methylation patterns in human placentas are reliably and significantly associated with PE and GDM. DNA methylation status in the human placenta can function as a marker for the intrauterine environment and potentially play a functional role in PE and GDM development. PMID- 25503510 TI - Outcomes associated with the use of renal replacement therapy in children receiving extracorporeal membrane oxygenation after heart surgery: a multi institutional analysis. AB - BACKGROUND: The primary objective of this investigation was to study the association between renal replacement therapy (RRT) and outcomes in children receiving extracorporeal membrane oxygenation (ECMO). METHODS: Patients aged <=18 years receiving ECMO before or after a pediatric heart operation at a Pediatric Health Information System (PHIS)-participating hospital (2004-2013) were included. The associations between RRT and study outcomes were computed using multivariate logistic regression analysis. RESULTS: A total of 3,502 patients from 43 hospitals qualified for inclusion. Of these, 484 (14 %) patients received RRT at some point during their hospital stay. After adjusting for patient and center characteristics, the odds of mortality were significantly higher in the RRT group (OR: 1.86, 95 % CI: 1.46- 2.37, p < 0.0001). However, there were considerable reductions in adjusted odds of mortality, compared to unadjusted odds of mortality. In adjusted models, length of ECMO was longer by 0.81 days (95 % CI: 0.13- 1.49, p = 0.02) in patients receiving RRT. CONCLUSIONS: We demonstrated worsening outcomes in children receiving ECMO with RRT compared to children receiving ECMO without RRT. Although the results could reflect confounding by severity of illness, they provide a rationale for prospective testing of use of RRT in critically ill children receiving ECMO with heart surgery. PMID- 25503512 TI - Distribution and bioaccumulation of lead in the coastal watersheds of the Northern Bohai and Yellow Seas in China. AB - In this study, the concentration of lead ([Pb]) in the surface water, sediments, soils and muscles of carp and crab in the upstream and downstream coastal watersheds along the Northern Bohai and Yellow Seas (NBYS) in China was investigated and the risks of Pb were evaluated. The mean [Pb] in the downstream water (2.62 MUg/L) and sediments [24.5 mg/kg, dry mass (dm)] was greater than the Chinese seawater quality standard for class I (1 MUg/L) and the regional background soil concentration (11.5 mg Pb/kg, dm), respectively. Approximately 37 % of the soils, mainly from the upstream regions, had [Pb] greater than the regional background concentration of 21.4 mg/kg, dm. The sites with relatively large [Pb] in the water, sediments and soils were located in the coastal watersheds of Tangshan and Huludao. The large enrichment factors in the sediments (2.41) and soils (2.22) suggested that human activities influenced the soils and sediments in this region more than in the other regions. Relatively large [Pb] was found in the crabs that were obtained from the upstream reaches of the Shuanglong and Daliao Rivers and the downstream reaches of the Luanhe and Liugu Rivers. Most of the crabs from the upstream regions contained greater [Pb] than the permissible limit for human consumption [0.3 mg/kg, wet mass (wm)]. The risk indices of the water, carp and crabs for humans were 0.002, 0.01 and 0.006, respectively. Based on the bioaccumulation factors, biota-sediment accumulation factors (BSAFs) and human risk indices, it was concluded that the human risks associated with crab were lower than those of carp despite the greater accumulation of Pb by the crabs from the water and sediments. Finally, the [Pb] in the sediments was significantly correlated with the [Pb] in the soils, which indicated that the same sources of Pb were responsible for the [Pb] in the sediments and soils in the coastal watersheds of the NBYS in China. PMID- 25503511 TI - An Insight into the proteome of Crithidia fasciculata choanomastigotes as a comparative approach to axenic growth, peanut lectin agglutination and differentiation of Leishmania spp. promastigotes. AB - The life cycle of the trypanosomatid Crithidia fasciculata is monogenetic, as the unique hosts of these parasites are different species of culicids. The comparison of these non-pathogenic microorganisms evolutionary close to other species of trypanosomatids that develop digenetic life cycles and cause chronic severe sickness to millions of people worldwide is of outstanding interest. A ground breaking analysis of differential protein abundance in Crithidia fasciculata is reported herein. The comparison of the outcome with previous gene expression profiling studies developed in the related human pathogens of the genus Leishmania has revealed substantial differences between the motile stages of these closely related organisms in abundance of proteins involved in catabolism, redox homeostasis, intracellular signalling, and gene expression regulation. As L. major and L. infantum agglutinate with peanut lectin and non-agglutinating parasites are more infective, the agglutination properties were evaluated in C. fasciculata. The result is that choanomastigotes are able to agglutinate with peanut lectin and a non-agglutinating subpopulation can be also isolated. As a difference with L. infantum, the non-agglutinating subpopulation over-expresses the whole machinery for maintenance of redox homeostasis and the translation factors eIF5a, EF1alpha and EF2, what suggests a relationship between the lack of agglutination and a differentiation process. PMID- 25503513 TI - Colloidal superstructures programmed into magnetic Janus particles. AB - By engineering thin magnetic films onto homogeneous colloidal particles, various crystalline lattices are induced from simple magnetic Janus spheres. In situ formation of dicolloids amplifies the diversity of achievable dynamic structures. The competition between shape anisotropy and dipole orientation generates mesoscopic isomerism. This opens design space for anisotropic building blocks for smart colloidal materials. PMID- 25503514 TI - A decade of innovation in pharmaceutical R&D: the Chorus model. AB - Chorus is a small, operationally independent clinical development organization within Eli Lilly and Company that specializes in drug development from candidate selection to clinical proof of concept. The mission of Chorus is to achieve proof of concept rapidly and at a low cost while positioning successful projects for 'pharma-quality' late-stage development. Chorus uses a small internal staff of experienced drug developers and a network of external vendors to design and implement chemistry, manufacturing and control processes, preclinical toxicology and biology, and Phase I/II clinical trials. In the decade since it was established, Chorus has demonstrated substantial productivity improvements in both time and cost compared to traditional pharmaceutical research and development. Here, we describe its development philosophy, organizational structure, operational model and results to date. PMID- 25503516 TI - Regulation of Cigarette Smoke Induction of IL-8 in Macrophages by AMP-activated Protein Kinase Signaling. AB - Inhaled cigarette smoke (CS) causes persistent lung inflammation in smokers. Interleukin 8 (IL-8) released from macrophages is a key chemokine during initiation and progression of CS-induced lung inflammation, yet its regulation is largely unknown. AMP-activated protein kinase (AMPK), a crucial energy homeostasis regulator, may modulate inflammation. Here we report that CS extract (CSE) increased the level of intracellular reactive oxygen species (ROS), activating AMPK, mitogen-activated protein kinases (MAPKs), and NF-kappaB, as well as inducing IL-8, in human macrophages. N-acetyl-cysteine (ROS scavenger) or hexamethonium [nicotinic acetylcholine receptor (nAChR) antagonist] attenuated the CSE-induced increase in intracellular ROS, activation of AMPK and NF-kappaB, as well as IL-8 induction, which suggests that nAChRs and ROS are important. Prevention of AMPK activation by compound C or AMPK siRNA reduced CSE-induced IL 8 production, confirming the role of AMPK. Compound C or AMPK siRNA also inhibited the activation of MAPKs and NF-kappaB by CSE, which suggests that these molecules are downstream of AMPK. Additionally, exposure of human macrophages to nicotine activated AMPK and induced IL-8 and that these effects were lessened by hexamethonium or compound C, implying that nicotine in CS may be causative. Furthermore, chronic CS exposure in mice promoted AMPK phosphorylation and expression of MIP-2 (an IL-8 homolog) in infiltrated macrophages and in lung tissues, as well as induced lung inflammation, all of which were reduced by compound C treatment. Thus, we identified a novel nAChRs-dependent, ROS sensitive, AMPK/MAPKs/NF-kappaB signaling pathway, which seems to be important to CS-induced macrophage IL-8 production and possibly to lung inflammation. PMID- 25503517 TI - [Update interstitial lung diseases]. PMID- 25503518 TI - [HRCT patterns of the most important interstitial lung diseases]. AB - Interstitial lung diseases are a mixed group of diffuse parenchymal lung diseases which can have an acute or chronic course. Idiopathic diseases and diseases with an underlying cause (e.g. collagen vascular diseases) share the same patterns. Thin section computed tomography (CT) plays a central role in the diagnostic work up. The article describes the most important interstitial lung diseases following a four pattern approach with a predominant nodular or reticular pattern or a pattern with increased or decreased lung density. PMID- 25503519 TI - [MRI of interstitial lung diseases: what is possible?]. AB - BACKGROUND: Magnetic resonance imaging (MRI) of the lungs is becoming increasingly appreciated as a third diagnostic imaging modality besides chest x ray and computed tomography (CT). Its value is well acknowledged for pediatric patients or for scientific use particularly when radiation exposure should be strictly avoided. However, the diagnosis of interstitial lung disease is the biggest challenge of all indications. The objective of this article is a summary of the current state of the art for diagnostic MRI of interstitial lung diseases. MATERIAL AND METHODS: This article reflects the results of a current search of the literature and discusses them against the background of the authors own experience with lung MRI. RESULTS: Due to its lower spatial resolution and a higher susceptibility to artefacts MRI does not achieve the sensitivity of CT for the detection of small details for pattern recognition (e.g. fine reticulation and micronodules) but larger details (e.g. coarse fibrosis and honeycombing) can be clearly visualized. Moreover, it could be shown that MRI has the capability to add clinically valuable information on regional lung function (e.g. ventilation, perfusion and mechanical properties) and inflammation with native signal and contrast dynamics. DISCUSSION: In its present state MRI can be used for comprehensive cardiopulmonary imaging in patients with sarcoidosis or for follow up of lung fibrosis after initial correlation with CT. Far more indications are expected when the capabilities of MRI for the assessment of regional lung function and activity of inflammation can be transferred into robust protocols for clinical use. PMID- 25503520 TI - A systematic literature search on psychological first aid: lack of evidence to develop guidelines. AB - BACKGROUND: Providing psychological first aid (PFA) is generally considered to be an important element in preliminary care of disaster victims. Using the best available scientific basis for courses and educational materials, the Belgian Red Cross-Flanders wants to ensure that its volunteers are trained in the best way possible. OBJECTIVE: To identify effective PFA practices, by systematically reviewing the evidence in existing guidelines, systematic reviews and individual studies. METHODS: Systematic literature searches in five bibliographic databases (MEDLINE, PsycINFO, The Cochrane Library, PILOTS and G-I-N) were conducted from inception to July 2013. RESULTS: Five practice guidelines were included which were found to vary in the development process (AGREE II score 20-53%) and evidence base used. None of them provides solid evidence concerning the effectiveness of PFA practices. Additionally, two systematic reviews of PFA were found, both noting a lack of studies on PFA. A complementary search for individual studies, using a more sensitive search strategy, identified 11 237 references of which 102 were included for further full-text examination, none of which ultimately provides solid evidence concerning the effectiveness of PFA practices. CONCLUSION: The scientific literature on psychological first aid available to date, does not provide any evidence about the effectiveness of PFA interventions. Currently it is impossible to make evidence-based guidelines about which practices in psychosocial support are most effective to help disaster and trauma victims. PMID- 25503522 TI - Plasmonic nanorod arrays of a two-segment dimer and a coaxial cable with 1 nm gap for large field confinement and enhancement. AB - Seeking plasmonic nanostructures with large field confinement and enhancement is significant for photonic and electronic nanodevices with high sensitivity, reproducibility, and tunability. Here, we report the synthesis of plasmonic arrays composed of two-segment dimer nanorods and coaxial cable nanorods with ~1 nm gap insulated by a self-assembled Raman molecule monolayer. The gap-induced plasmon coupling generates an intense field in the gap region of the dimer junction and the cable interlayer. As a result, the longitudinal plasmon resonance of nanorod arrays with high tunability is obviously enhanced. Most interestingly, the field enhancement of dimer nanorod arrays can be tuned by the length ratio L1/L2 of the two segments, and the maximal enhancement appears at L1/L2 = 1. In that case, the two-photon luminescence (TPL) of dimer nanorod arrays and the Raman intensity in the dimer junction is enhanced by 27 and 30 times, respectively, under resonant excitation. In the same way, the Raman intensity in the gap region is enhanced 16 times for the coaxial cable nanorod arrays. The plasmonic nanorod arrays synthesized by the facile method, having tunable plasmon properties and large field enhancement, indicate an attractive pathway to the photonic nanodevices. PMID- 25503523 TI - Optical Flow-Based Tracking of Needles and Needle-Tip Localization Using Circular Hough Transform in Ultrasound Images. AB - Image-guided interventions have become the standard of care for needle-based procedures. The success of the image-guided procedures depends on the ability to precisely locate and track the needle. This work is primarily focused on 2D ultrasound-based tracking of a hollow needle (cannula) that is composed of straight segments connected by shape memory alloy actuators. An in-plane tracking algorithm based on optical flow was proposed to track the cannula configuration in real-time. Optical flow is a robust tracking algorithm that can easily run on a CPU. However, the algorithm does not perform well when it is applied to the ultrasound images directly due to the intensity variation in the images. The method presented in this work enables using the optical flow algorithm on ultrasound images to track features of the needle. By taking advantage of the bevel tip, Circular Hough transform was used to accurately locate the needle tip when the imaging is out-of-plane. Through experiments inside tissue phantom and ex-vivo experiments in bovine kidney, the success of the proposed tracking methods were demonstrated. Using the methods presented in this work, quantitative information about the needle configuration is obtained in real-time which is crucial for generating control inputs for the needle and automating the needle insertion. PMID- 25503521 TI - Comparative genome analyses reveal distinct structure in the saltwater crocodile MHC. AB - The major histocompatibility complex (MHC) is a dynamic genome region with an essential role in the adaptive immunity of vertebrates, especially antigen presentation. The MHC is generally divided into subregions (classes I, II and III) containing genes of similar function across species, but with different gene number and organisation. Crocodylia (crocodilians) are widely distributed and represent an evolutionary distinct group among higher vertebrates, but the genomic organisation of MHC within this lineage has been largely unexplored. Here, we studied the MHC region of the saltwater crocodile (Crocodylus porosus) and compared it with that of other taxa. We characterised genomic clusters encompassing MHC class I and class II genes in the saltwater crocodile based on sequencing of bacterial artificial chromosomes. Six gene clusters spanning ~452 kb were identified to contain nine MHC class I genes, six MHC class II genes, three TAP genes, and a TRIM gene. These MHC class I and class II genes were in separate scaffold regions and were greater in length (2-6 times longer) than their counterparts in well-studied fowl B loci, suggesting that the compaction of avian MHC occurred after the crocodilian-avian split. Comparative analyses between the saltwater crocodile MHC and that from the alligator and gharial showed large syntenic areas (>80% identity) with similar gene order. Comparisons with other vertebrates showed that the saltwater crocodile had MHC class I genes located along with TAP, consistent with birds studied. Linkage between MHC class I and TRIM39 observed in the saltwater crocodile resembled MHC in eutherians compared, but absent in avian MHC, suggesting that the saltwater crocodile MHC appears to have gene organisation intermediate between these two lineages. These observations suggest that the structure of the saltwater crocodile MHC, and other crocodilians, can help determine the MHC that was present in the ancestors of archosaurs. PMID- 25503524 TI - Artery Remodeling Under Axial Twist in Three Days Organ Culture. AB - Arteries often endure axial twist due to body movement and surgical procedures, but how arteries remodel under axial twist remains unclear. The objective of this study was to investigate early stage arterial wall remodeling under axial twist. Porcine carotid arteries were twisted axially and maintained for three days in ex vivo organ culture systems while the pressure and flow remained the same as untwisted controls. Cell proliferation, internal elastic lamina (IEL) fenestrae shape and size, endothelial cell (EC) morphology and orientation, as well as the expression of matrix metalloproteinases (MMPs), MMP-2 and MMP-9, and tissue inhibitor of metalloproteinase-2 (TIMP-2) were quantified using immunohistochemistry staining and immunoblotting. Our results demonstrated that cell proliferation in both the intima and media were significantly higher in the twisted arteries compared to the controls. The cell proliferation in the intima increased from 1.33 +/- 0.21% to 7.63 +/- 1.89%, and in the media from 1.93 +/- 0.84% to 8.27 +/- 2.92% (p < 0.05). IEL fenestrae total area decreased from 26.07 +/- 2.13% to 14.74 +/- 0.61% and average size decreased from 169.03 +/- 18.85 MUm(2) to 80.14 +/- 1.96 MUm(2) (p < 0.01), but aspect ratio increased in the twist group from 2.39 +/- 0.15 to 2.83 +/- 0.29 (p < 0.05). MMP-2 expression significantly increased (p < 0.05) while MMP-9 and TIMP-2 showed no significant difference in the twist group. The ECs in the twisted arteries were significantly elongated compared to the controls after three days. The angle between the major axis of the ECs and blood flow direction under twist was 7.46 +/- 2.44 degrees after 3 days organ culture, a decrease from the initial 15.58 +/- 1.29 degrees. These results demonstrate that axial twist can stimulate artery remodeling. These findings complement our understanding of arterial wall remodeling under mechanical stress resulting from pressure and flow variations. PMID- 25503525 TI - Ethical procedures and patient consent differ in Europe. AB - BACKGROUND: Research ethics approvals, procedures and requirements for institutional research ethics committees vary considerably by country and by type of organisation. OBJECTIVE: To evaluate the requirements and procedures of research ethics committees, details of patient information and informed consent based on a multicentre European trial. DESIGN: Survey of European hospitals participating in the prospective observational study on chronic postsurgical pain (euCPSP) using electronic questionnaires. SETTING: Twenty-four hospitals in 11 European countries. PARTICIPANTS: From the 24 hospitals, 23 local investigators responded; 23 answers were analysed. OUTCOME MEASURES: Comparison of research ethics procedures and committee requirements from the perspective of clinical researchers. Comparison of the institutions' procedures regarding patient information and consent. Description of further details such as costs and the duration of the approval process. RESULTS: The approval process lasted from less than 2 weeks up to more than 2 months with financial fees varying between 0 and 575 &OV0556;. In 20 hospitals, a patient information sheet of variable length (half page up to two pages) was provided. Requirements for patients' informed consent differed. Written informed consent was mandatory at 12, oral at 10 and no form of consent at one hospital. Details such as enough time for consideration, possibility for withdrawal and risks/benefits of participation were provided in 25 to 30% of the institutions. CONCLUSION: There is a considerable variation in the administrative requirements for approval procedures by research ethics committees in Europe. This results in variation of the extent of information and consent procedures for the patients involved. TRIAL REGISTRATION: euCPSP in Clinicaltrials.gov identifier: NCT01467102; PAIN-OUT in Clinicaltrials.gov identifier: NCT02083835. PMID- 25503526 TI - Prevalence analysis of de novo hepatic steatosis following pylorus-preserving pancreaticoduodenectomy. AB - BACKGROUND: Prevalence of hepatic steatosis following pylorus-preserving pancreaticoduodenectomy (PPPD) is high. This study intended to reveal the prevalence and patterns of de novo hepatic steatosis following PPPD. METHODS: We investigated postoperative de novo hepatic steatosis following PPPD (n = 101) with a control group of bile duct resection (BDR) (n = 54). RESULTS: At postoperative 1 year, hepatic steatosis occurred in 21 of 82 patients (25.6%) of PPPD group and in 2 of 47 patients (4.3%) of BDR group (p = 0.001). Thereafter, at 2 to 5 years, a high prevalence of hepatic steatosis persisted in the PPPD group, but no further occurrence developed in BDR group. Once steatosis developed, it persisted until the end of the study period or patient death. Five year cumulative incidence of hepatic steatosis was 26.7% in the PPPD group and 3.7% in BDR group (p < 0.001). Univariate analyses showed that patient sex, age, body mass index, blood lipid profile, recurrence of tumor, and diabetes did not have significant influence on the development of hepatic steatosis following PPPD. CONCLUSIONS: De novo hepatic steatosis may develop in a not negligible proportion of patients undergone PPPD. Multicenter studies with a high number of patients are needed to elucidate its pathogenesis and to find effective treatment for pancreaticoduodenectomy-associated hepatic steatosis. PMID- 25503528 TI - Simulation as a critical resource in the response to Ebola virus disease. PMID- 25503529 TI - Is clinical trial registration for simulation-based research necessary? AB - Summary statement: The International Committee of Medical Journal Editors requires that all clinical trials be prospectively registered before being considered for publication in their member journals. Clinical trial registries are Web-based databases of clinical trials, providing researchers, journal editors, and reviewers detailed study information to help inform trial results. What is unclear is whether clinical trial registration is required for simulation based studies, where typically health care providers are the subjects and where the outcomes may be provider based or patient based. In this article, we describe the background and reasoning behind clinical trial registration and discuss whether simulation-based studies should be registered as a prerequisite to publication. PMID- 25503527 TI - Bone histomorphometry in a long-term hemodialysis patient with hypoparathyroidism and sarcoidosis. AB - A bone biopsy specimen in a long-term hemodialysis patient with sarcoidosis coexisting with severe hypoparathyroidism has demonstrated that a persistent near physiological level of 1,25-dihydroxyvitamin D3 contributes to the preservation of bone remodeling and has the potential to retard the development of vascular calcification and atherosclerosis. Sarcoidosis-related hypercalcemia and hypoparathyroidism, which is characterized by 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) overproduction, is rarely seen in hemodialysis patients. Herein, we describe a 60-year-old Japanese woman on hemodialysis for 35 years who presented with malaise and hypercalcemia. Severe hypoparathyroidism without parathyroidectomy and a preserved 1,25(OH)2D3 level were detected. Computed tomography showed bilateral axillary lymphadenopathy and minimal aortic and soft tissue calcification. The axillary node biopsy led to a definite diagnosis of sarcoidosis. A bone biopsy specimen obtained from the right iliac crest showed remodeling of normal lamellar bone with scalloped cement lines and clear double labeling by tetracycline on fluorescence microscopy. Histomorphometric analysis revealed that the bone formation rate was preserved (30.0 %/year), together with a decrease of osteoid volume (5.75 %) and fibrous volume (0 %), indicating that the patient did not have adynamic bone disease and only showed mild disease. This is the first documented case of sarcoidosis-related hypercalcemia associated with severe hypoparathyroidism in a long-term hemodialysis patient who underwent bone histomorphometry. Our findings suggest that, in hemodialysis patients with sarcoidosis coexisting with severe hypoparathyroidism, a persistent near physiological level of 1,25(OH)2D3 contributes to the preservation of bone remodeling and has the potential to retard the development of vascular calcification and atherosclerosis. PMID- 25503530 TI - External validation of scoring instruments for evaluating pediatric resuscitation. AB - INTRODUCTION: Although many methods have been proposed to assess clinical performance during resuscitation, robust and generalizable metrics are still lacking. Further research is necessary to develop validated clinical performance assessment tools and show an improvement in outcomes after training. We aimed to establish evidence for validity of a previously published scoring instrument--the Clinical Performance Tool (CPT)--designed to evaluate clinical performance during simulated pediatric resuscitations. METHODS: This was a prospective experimental trial performed in the simulation laboratory of a pediatric tertiary care facility, with a pretest/posttest design that assessed residents before and after pediatric advanced life support (PALS) certification. Thirteen postgraduate year 1 (PGY1) and 11 PGY3 pediatric residents completed 5 simulated pediatric resuscitation scenarios each during 2 consecutive sessions; between the 2 sessions, they completed a full PALS certification course. All sessions were video recorded. Sessions were scored by raters using the CPT; total scores were expressed as a percentage of maximum points possible for each scenario. Validity evidence was established and interpreted according to Messick's framework. Evidence regarding relations to other variables was assessed by calculating differences in scores between pre-PALS and post-PALS certification and PGY1 and PGY3 using a repeated-measures analysis of variance test. Internal structure evidence was established by assessing interrater reliability using intraclass correlation coefficients (ICCs) for each scenario, a G-study, and a variance component analysis of individual measurement facets (scenarios, raters, and occasions) and associated interactions. RESULTS: Overall scores for the entire study cohort improved by 10% after PALS training. Scores improved by 9.9% (95% confidence interval [CI], 4.5-15.4) for the pulseless nonshockable arrest (ICC, 0.85; 95% CI, 0.74-0.92), 14.6% (95% CI, 6.7-22.4) for the pulseless shockable arrest (ICC, 0.98; 95% CI, 0.96-0.99), 4.1% (95% CI, -4.5 to 12.8) for the dysrhythmias (ICC, 0.92; 95% CI, 0.87-0.96), 18.4% (95% CI, 9.7-27.1) for the respiratory scenario (ICC, 0.97; 95% CI, 0.95-0.98), and 5.3% (95% CI, -1.4 to 2.0) for the shock scenarios (ICC, 0.94; 95% CI, 0.90-0.97). There were no differences between PGY1 and PGY3 scores before or after the PALS course. Reliability of the instrument was acceptable as demonstrated by a mean ICC of 0.95 (95% CI, 0.94-0.96). The G-study coefficient was 0.94. Most variance could be attributed to the subject (57%). Interactions between subject and scenario and subject and occasion were 9.9% and 1.4%, respectively, and variance attributable to rater was minimal (0%). CONCLUSIONS: Pediatric residents improved scores on CPT after completion of a PALS course. Clinical Performance Tool scores are sensitive to the increase in skills and knowledge resulting from such a course but not to learners' levels. Validity evidence from scores for the CPT confirms implementation in new contexts and partially supports internal structure. More evidence is required to further support internal structure and especially to support relations with other variables and consequence evidence. Additional modifications should be made to the CPT before considering its use for high stakes certification such as PALS. PMID- 25503531 TI - Preoperative simulation for the planning of microsurgical clipping of intracranial aneurysms. AB - INTRODUCTION: The safety and success of intracranial aneurysm (IA) surgery could be improved through the dedicated application of simulation covering the procedure from the 3-dimensional (3D) description of the surgical scene to the visual representation of the clip application. We aimed in this study to validate the technical feasibility and clinical relevance of such a protocol. METHODS: All patients preoperatively underwent 3D magnetic resonance imaging and 3D computed tomography angiography to build 3D reconstructions of the brain, cerebral arteries, and surrounding cranial bone. These 3D models were segmented and merged using Osirix, a DICOM image processing application. This provided the surgical scene that was subsequently imported into Blender, a modeling platform for 3D animation. Digitized clips and appliers could then be manipulated in the virtual operative environment, allowing the visual simulation of clipping. This simulation protocol was assessed in a series of 10 IAs by 2 neurosurgeons. RESULTS: The protocol was feasible in all patients. The visual similarity between the surgical scene and the operative view was excellent in 100% of the cases, and the identification of the vascular structures was accurate in 90% of the cases. The neurosurgeons found the simulation helpful for planning the surgical approach (ie, the bone flap, cisternal opening, and arterial tree exposure) in 100% of the cases. The correct number of final clip(s) needed was predicted from the simulation in 90% of the cases. The preoperatively expected characteristics of the optimal clip(s) (ie, their number, shape, size, and orientation) were validated during surgery in 80% of the cases. CONCLUSIONS: This study confirmed that visual simulation of IA clipping based on the processing of high-resolution 3D imaging can be effective. This is a new and important step toward the development of a more sophisticated integrated simulation platform dedicated to cerebrovascular surgery. PMID- 25503532 TI - Pediatric and neonatal intubation training gap analysis: instruction, assessment, and technology. AB - Summary statement: Intubating adult patients presents numerous challenges for clinicians. Procedural complexities associated with performing pediatric and neonatal intubation, along with a lower frequency of a need for intubating pediatric and neonatal patients, further amplifies the difficulties associated with acquiring and maintaining relevant clinical skills. Clinicians must develop and maintain competency through training and continuing medical education. A systematic review was conducted through June 2012 to examine current instructional methods, assessment tools, and training models in pediatric and neonatal intubation training. Variability among the included literature on instruction, assessment, and models used to support training makes direct comparison problematic. The results of this review emphasize the need for improvement of current instructional methods to promote competency acquisition; development of valid, reliable assessment tools to evaluate clinician competency; and identification of a superior training model to promote acquisition and maintenance of skills associated with intubation of pediatric patients. PMID- 25503533 TI - Adapting to the 30-degree visual perspective by emulating the angled laparoscope: a simple and low-cost solution for basic surgical training. AB - INTRODUCTION: The ability to handle and adapt to the visual perspectives generated by angled laparoscopes is crucial for skilled laparoscopic surgery. However, the control of the visual work space depends on the ability of the operator of the camera, who is often not the most experienced member of the surgical team. Here, we present a simple, low-cost option for surgical training that challenges the learner with static and dynamic visual perspectives at 30 degrees using a system that emulates the angled laparoscope. METHODS: A system was developed using a low-cost camera and readily available materials to emulate the angled laparoscope. Nine participants undertook 3 tasks to test spatial adaptation to the static and dynamic visual perspectives at 30 degrees. Completing each task to a predefined satisfactory level ensured precision of execution of the tasks. Associated metrics (time and error rate) were recorded, and the performance of participants were determined. RESULTS: A total of 450 repetitions were performed by 9 residents at various stages of training. All the tasks were performed with a visual perspective of 30 degrees using the system. Junior residents were more proficient than senior residents. CONCLUSIONS: This system is a viable and low-cost alternative for developing the basic psychomotor skills necessary for the handling and adaptation to visual perspectives of 30 degrees, without depending on a laparoscopic tower, in junior residents. More advanced skills may then be acquired by other means, such as in the operating theater or through clinical experience. PMID- 25503534 TI - Simulation of intraoperative pacemaker failure: kudos and suggestions. PMID- 25503536 TI - Strain effects on oxygen migration in perovskites. AB - Fast oxygen transport materials are necessary for a range of technologies, including efficient and cost-effective solid oxide fuel cells, gas separation membranes, oxygen sensors, chemical looping devices, and memristors. Strain is often proposed as a method to enhance the performance of oxygen transport materials, but the magnitude of its effect and its underlying mechanisms are not well-understood, particularly in the widely-used perovskite-structured oxygen conductors. This work reports on an ab initio prediction of strain effects on migration energetics for nine perovskite systems of the form LaBO3, where B = [Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Ga]. Biaxial strain, as might be easily produced in epitaxial systems, is predicted to lead to approximately linear changes in migration energy. We find that tensile biaxial strain reduces the oxygen vacancy migration barrier across the systems studied by an average of 66 meV per percent strain for a single selected hop, with a low of 36 and a high of 89 meV decrease in migration barrier per percent strain across all systems. The estimated range for the change in migration barrier within each system is +/-25 meV per percent strain when considering all hops. These results suggest that strain can significantly impact transport in these materials, e.g., a 2% tensile strain can increase the diffusion coefficient by about three orders of magnitude at 300 K (one order of magnitude at 500 degrees C or 773 K) for one of the most strain responsive materials calculated here (LaCrO3). We show that a simple elasticity model, which assumes only dilative or compressive strain in a cubic environment and a fixed migration volume, can qualitatively but not quantitatively model the strain dependence of the migration energy, suggesting that factors not captured by continuum elasticity play a significant role in the strain response. PMID- 25503535 TI - Community low-dose CT lung cancer screening: a prospective cohort study. AB - BACKGROUND: The National Lung Screening Trial (NLST) in 2011 showed that low-dose CT (LDCT) screening in high-risk groups reduces lung cancer deaths. Major professional organizations, as well as the U.S. Preventative Services Task Force, have endorsed LDCT screening in these select populations. However, major questions remain about whether widespread deployment of CT screening can achieve results similar to the NLST, especially in the community setting. METHODS: A prospective cohort study was initiated in November 2010. Participants at least 50 years old and with at least 20 pack-years of smoking history underwent LDCT screening in a community setting. RESULTS: One hundred and fifty four participants underwent LDCT screening with median follow-up of 2.7 years. Compared with the NLST, there was a higher rate of positive screening tests (35.7 vs. 27.3 %), higher false positive rate (100 vs. 96.4 %), and poor adherence (43 vs. 95 %). Invasive diagnostic follow-up was uncommon and uncomplicated. No interval lung cancer was detected. Late follow-up was mostly attributed to participant or primary care provider preference (67.5 %), participants lost to follow-up (17.5 %), and lack of insurance (10 %). CONCLUSIONS: These findings highlight the potential challenges of generalizing the NLST mortality benefits in the broad deployment of CT screening. Our results support current recommendations that LDCT screening be performed in a highly structured and integrated setting. PMID- 25503537 TI - Otolith patterns of rockfishes from the northeastern Pacific. AB - Sagitta otolith shape was analysed in twenty sympatric rockfishes off the southern California coast (Northeastern Pacific). The variation in shape was quantified using canonical variate analysis based on fifth wavelet function decomposition of otolith contour. We selected wavelets because this representation allow the identifications of zones or single morphological points along the contour. The entire otoliths along with four subsections (anterior, ventral, posterodorsal, and anterodorsal) with morphological meaning were examined. Multivariate analyses (MANOVA) showed significant differences in the contours of whole otolith morphology and corresponding subsection among rockfishes. Four patterns were found: fusiform, oblong, and two types of elliptic. A redundancy analysis indicated that anterior and anterodorsal subsections contribute most to define the entire otolith shape. Complementarily, the eco-morphological study indicated that the depth distribution and strategies for capture prey were correlated to otolith shape, especially with the anterodorsal zone. PMID- 25503538 TI - Radiotherapy versus open surgery versus endolaryngeal surgery (with or without laser) for early laryngeal squamous cell cancer. AB - BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 2, 2002 and previously updated in 2004, 2007 and 2010.Radiotherapy, open surgery and endolaryngeal excision (with or without laser) are all accepted modalities of treatment for early-stage glottic cancer. Case series suggest that they confer a similar survival advantage, however radiotherapy and endolaryngeal surgery offer the advantage of voice preservation. There has been an observed trend away from open surgery in recent years, however equipoise remains between radiotherapy and endolaryngeal surgery as both treatment modalities offer laryngeal preservation with similar survival rates. Opinions on optimal therapy vary across disciplines and between countries. OBJECTIVES: To compare the effectiveness of open surgery, endolaryngeal excision (with or without laser) and radiotherapy in the management of early glottic laryngeal cancer. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 8); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 18 September 2014. SELECTION CRITERIA: Randomised controlled trials comparing open surgery, endolaryngeal resection (with or without laser) and radiotherapy. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified only one randomised controlled trial, which compared open surgery and radiotherapy in 234 patients with early glottic laryngeal cancer. The overall risk of bias in this study was high.For T1 tumours, the five-year survival was 91.7% following radiotherapy and 100% following surgery and for T2 tumours, 88.8% following radiotherapy and 97.4% following surgery. There were no significant differences in survival between the two groups.For T1 tumours, the five-year disease-free survival rate was 71.1% following radiotherapy and 100.0% following surgery, and for the T2 tumours, 60.1% following radiotherapy and 78.7% following surgery. Only the latter comparison was statistically significant (P value = 0.036), but statistical significance would not have been achieved with a two-sided test.Data were not available on side effects, quality of life, voice outcomes or cost.We identified no randomised controlled trials that included endolaryngeal surgery. A number of trials comparing endolaryngeal resection and radiotherapy have terminated early because of difficulty recruiting participants. One randomised controlled trial is still ongoing. AUTHORS' CONCLUSIONS: There is only one randomised controlled trial comparing open surgery and radiotherapy but its interpretation is limited because of concerns about the adequacy of treatment regimens and deficiencies in the reporting of the study design and analysis. PMID- 25503539 TI - Comparison of hemicellulose extracts from two pulping woodchips with green liquor followed by scale-up pre-hemicellulose extraction. AB - This study investigates the effects of different pre-pulping extraction conditions on two types of raw material, hardwood oak chips and softwood pine chips. The chips were air-dried, and 2-g samples were extracted in a Dionex ASE 200 with alkaline solutions of a partially recovered form of kraft pulping liquor called green liquor (GL). The GL was applied at different alkali charges of 0-5 % on dry wood weight. The extractions were performed at various H-factors from 500 to 1100 with temperatures ranging from 170 to 190 degrees C. As the alkali charge decreased, the amount of monosaccharides in the extracts increased while the remaining solids decreased. The highest xylose + mannose + galactose (xmg) concentrations (12.73 and 11.12 g/L for extracts derived from hardwood and softwood, respectively) were detected with a hot water extraction (GL 0 %) at 180 degrees C and an H-factor of 900. However, low amounts of remaining solids were obtained under these conditions (65.77% and 74.42%, for hard- and soft woods, respectively). We also performed an extraction that was scaled-up in a 1-L Parr reactor with 80 g of woodchips under pre-optimized condition through ASE-200. In this condition, the xmg and acetic acid concentrations of the hardwood extracts were 9.74 and 9.94 g/L, respectively, whereas their concentrations in the softwood extracts were 3.59 and 3.76 g/L, respectively. PMID- 25503540 TI - The relation between social network site usage and loneliness and mental health in community-dwelling older adults. AB - BACKGROUND: Loneliness is expected to become an even bigger social problem in the upcoming decades, because of the growing number of older adults. It has been argued that the use of social network sites can aid in decreasing loneliness and improving mental health. The purpose of this study was to examine whether and how social network sites usage is related to loneliness and mental health in community-dwelling older adults. METHOD: The study population included community dwelling older adults aged 60 and over residing in the Netherlands (n = 626) collected through the LISS panel (www.lissdata.nl). Univariate and multivariate linear regression analyses, adjusted for potentially important confounders, were conducted in order to investigate the relation between social network sites usage and (emotional and social) loneliness and mental health. RESULTS: More than half of the individuals (56.2%) reported to use social network sites at least several times per week. Social network sites usage appeared unrelated to loneliness in general, and to emotional and social loneliness in particular. Social network sites usage also appeared unrelated to mental health. Several significant associations between related factors and the outcomes at hand were detected. CONCLUSION: In this sample, which was representative for the Dutch population, social network sites usage was unrelated to loneliness and/or mental health. The results indicate that a simple association between social network site usage and loneliness and mental health as such, cannot automatically be assumed in community-dwelling older adults. PMID- 25503541 TI - Predictors of poor hospital discharge outcome in acute stroke due to atrial fibrillation. AB - Atrial fibrillation (AF) is a frequent cause of acute ischemic stroke that results in severe neurological disability and death despite treatment with intravenous thrombolysis (intravenous recombinant tissue plasminogen activator [rtPA]). We performed a retrospective review of a single-center registry of patients treated with intravenous rtPA for stroke. The purposes of this study were to compare intravenous rtPA treated patients with stroke with and without AF to examine independent predictors of poor hospital discharge outcome (in-hospital death or hospital discharge to a skilled nursing facility, long-term acute care facility, or hospice care). A univariate analysis was performed on 144 patients receiving intravenous rtPA for stroke secondary to AF and 190 patients without AF. Characteristics that were significantly different between the two groups were age, initial National Institutes of Health Stroke Scale score, length of hospital stay, gender, hypertension, hyperlipidemia, smoking status, presence of large cerebral infarct, and hospital discharge outcome. Bivariate logistic regression analysis indicated that patients with stroke secondary to AF with a poor hospital discharge outcome had a greater likelihood of older age, higher initial National Institutes of Health Stroke Scale scores, longer length of hospital stay, intubation, and presence of large cerebral infarct compared with those with good hospital discharge outcome (discharged to home or inpatient rehabilitation or signed oneself out against medical advice). A multivariate logistic regression analysis showed that older age, longer length of hospital stay, and presence of large cerebral infarct were independent predictors of poor hospital discharge outcome. These predictors can guide nursing interventions, aid the multidisciplinary treating team with treatment decisions, and suggest future directions for research. PMID- 25503542 TI - Implementation of an epilepsy self-management protocol. AB - It is essential that patients with epilepsy receive educational information about their disease and its management, but there is dissatisfaction with the education received. The purposes of this evidence-based project were to examine the current knowledge level and disease management behaviors of patients with epilepsy in an outpatient clinic and to measure the effectiveness of implementing a self management protocol using the Epilepsy Self-Management Scale (ESMS). Pender's health promotion model and Rogers' diffusion of innovation theory were used to guide the development and completion of this project. An evidence-based epilepsy self-management protocol was developed and implemented at an outpatient neurology clinic by an interprofessional clinic team that consisted of (a) evaluation of self-management behaviors (ESMS), (b) individual education using the ESMS and developed resources, (c) follow-up telephone call, and (d) measurement of outcomes of the self-management protocol (patient self-management [ESMS] and process). Twenty patients participated in all or portions of the protocol. Scores on the ESMS increased from preimplementation to postimplementation of the protocol (t = -2.67). Seizure management and information management were identified as the most difficult self-management areas. Recommended changes in protocol implementation include adding information about safety measures such as medical alert bracelets and driving to the educational packets. Follow-up telephone calls were discontinued because of difficulties reaching patients. The results of this study suggest that the ESMS is an acceptable tool for evaluating patients' self-management behaviors. Epilepsy self-management protocols need to include both verbal and written educational materials. Educating patients with epilepsy about positive self-management behaviors may lead to better health outcomes. PMID- 25503543 TI - Current evidence in the management of poststroke hemiplegic shoulder pain: a review. AB - Hemiplegic shoulder pain is a common, complex, and distressing complication, which is related to stroke and occurs in the paralytic side of the patient. It not only presents in the early stage but also can persist into the chronic stage of stroke. The incidence of this complication varies from 12% to 58%, and the most common period of occurrence is at 8-10 weeks poststroke. The multifactorial etiology and underlying mechanisms make it intractable. It is difficult to get a clear description of the percentage of patients receiving adequate pain relief because of a large number of treatments and different results found in interventional studies performed in subjects in different stages of stroke. This review summarizes the incidence, temporal presentation, and etiology of hemiplegic shoulder pain and the current advances in its management and analyzes the reliability and validity of the studies. It suggests careful and regular assessment, and an integrated care model is necessary in practice. PMID- 25503544 TI - Risk factors for catheter-associated urinary tract infections in critically ill patients with subarachnoid hemorrhage. AB - BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) are preventable adverse outcomes that cause increased morbidity, mortality, and financial burdens to hospitals. These are particularly prevalent in intensive care units (ICUs). Patients with subarachnoid hemorrhage (SAH) in neurological ICUs have extended lengths of stay and may be at higher risk for CAUTIs. PURPOSE: The purpose of this study was to assess the prevalence of and risk factors for CAUTIs among patients with SAH in the neurological ICU of a large urban teaching hospital in the eastern United States. METHODS: This is a retrospective analysis using the Columbia University SAH Outcomes Project data set collected between 2005 and 2012. Logistic regression is used to identify predictors of CAUTI. RESULTS: Catheterized adult patients (n = 242) with SAH over the 8-year period were included. The rate of CAUTIs was 20.7 per 1,000 catheter days, six times higher than the reported national average. Variables significantly associated with CAUTI were older age (odds ratio [OR] = 1.06, 95% confidence interval [CI] [1.01, 1.11]), blood sugar > 200 mg/dl (OR = 13.0, 95% CI [1.28, 107.4]), and anemia requiring transfusion (OR = 3.78, 95% CI [0.977, 14.67]). CONCLUSIONS: Higher CAUTI rates in this study were likely associated with prolonged catheterization. On the basis of these findings, careful assessment of the need for catheterization and increased vigilance regarding urinary catheter care in patients with SAH is indicated, particularly among those who are older, with anemia requiring transfusion and elevated blood glucose levels. PMID- 25503546 TI - National institutes of health stroke scale item profiles as predictor of patient outcome: external validation on independent trial data. AB - BACKGROUND AND PURPOSE: National Institutes of Health Stroke Scale (NIHSS) item profiles that were recently proposed may prove useful both clinically and for research studies. We aimed to validate the NIHSS item profiles in an acute cohort. METHODS: We conducted a retrospective analysis on pooled data from randomized clinical trials. We applied the latent class analysis probabilities of profile membership developed from the derivation study to obtain symptom grouping, a-NIHSS item profiles. We implemented an independent latent class analysis to derive secondary symptom grouping, b-NIHSS item profiles. Validation was performed by assessing the associations with outcomes and evaluating both sets of NIHSS item profiles' discrimination and calibration to the data. The outcomes evaluated included modified Rankin Scale (mRS; using the full distribution and dichotomized, mRS, 0-1) at day 90 and mortality by 90 days. RESULTS: We identified 10 271 patients. Ordinal analysis of mRS confirmed increased odds of better outcome across the profiles in a stepwise manner, adjusted for age and thrombolysis treatment, for each set of NIHSS item profiles. Similar patterns were observed for mRS 0 to 1, and inverse patterns were seen for mortality. The c-statistics of a-NIHSS and b-NIHSS item profiles for mRS 0 to 1 were similar at 0.71 (95% confidence interval, 0.70-0.72) and for mortality, 0.74 (0.73-0.75) and 0.75 (0.73-0.76), respectively. Calibration was good. CONCLUSIONS: These NIHSS item profiles identified using latent class analysis offer a reliable approach to capture the true response patterns that are associated with functional and outcome and mortality post stroke. This approach has the potential to enhance the clinical value of the overall NIHSS score. PMID- 25503545 TI - Subjective memory complaints and the risk of stroke. AB - BACKGROUND AND PURPOSE: Persons with cognitive impairment, as assessed by cognitive tests, are at a higher risk of stroke. Subjective memory complaints might be an earlier marker for stroke, especially in persons with higher education. Their cognitive reserve might mask their cognitive impairment during cognitive testing. In a population-based setting, we investigated the association between subjective memory complaints and stroke. We simultaneously investigated the association between Mini-Mental State Examination and stroke. We also assessed whether these associations varied with educational level. METHODS: 9152 participants from the Rotterdam Study (baseline 1990-1993 or 2000-2001) completed the subjective memory complaints questionnaire and underwent Mini-Mental State Examination assessment. Subsequently, the entire cohort was followed for incident stroke until 2012. We used Cox proportional hazard models to estimate the associations between subjective memory complaints and Mini-Mental State Examination, with stroke. RESULTS: During a follow-up of 111 593 person years, 1134 strokes were identified, of which 663 were ischemic and 99 hemorrhagic. In the fully adjusted model, presence of subjective memory complaints was independently associated with a higher risk of stroke (hazard ratio, 1.20; 95% confidence interval, 1.04-1.39), but a higher Mini-Mental State Examination was not (hazard ratio per point increase, 0.99; 95% confidence interval, 0.95-1.02). The association between subjective memory complaints and risk of stroke was modified by educational level, with a higher risk of stroke in persons with a higher level of education (hazard ratio, 1.39; 95% confidence interval, 1.07 1.81). CONCLUSIONS: Subjective memory complaints might be an early indicator of stroke risk, especially in highly educated individuals. PMID- 25503548 TI - Response to letter regarding article, "coated-platelets improve prediction of stroke and transient ischemic attack in asymptomatic internal carotid artery stenosis". PMID- 25503547 TI - NURR1 involvement in recombinant tissue-type plasminogen activator treatment complications after ischemic stroke. AB - BACKGROUND AND PURPOSE: Despite the effectiveness of recombinant tissue-type plasminogen activator (r-tPA) during the acute phase of ischemic stroke, the therapy remains limited by a narrow time window and the occurrence of occasional vascular side effects, particularly symptomatic hemorrhages. Our aim was to investigate the mechanisms underlying the endothelial damage resulting from r-tPA treatment in ischemic-like conditions. METHODS: Microarray analyses were performed on cerebral endothelial cells submitted to r-tPA treatment during oxygen and glucose deprivation to identify novel biomarker candidates. Validation was then performed in vivo in a mouse model of thromboembolic stroke and culminated in an analysis in a clinical cohort of patients with ischemic stroke treated with thrombolysis. RESULTS: The transcription factor NURR1 (NR4A2) was identified as a downstream target induced by r-tPA during oxygen and glucose deprivation. Silencing NURR1 expression reversed the endothelial-toxicity induced by the combined stimuli, a protective effect attributable to reduced levels of proinflammatory mediators, such as nuclear factor-kappa-beta 2 (NF-kappa-B2), interleukin 1 alpha (IL1alpha), intercellular adhesion molecule 1 (ICAM1), SMAD family member 3 (SMAD3), colony stimulating factor 2 (granulocyte-macrophage; CSF2). The detrimental effect of delayed thrombolysis, in conditions in which NURR1 gene expression was enhanced, was confirmed in the preclinical stroke model. Finally, we determined that patients with stroke who had a symptomatic hemorrhagic transformation after r-tPA treatment exhibited higher baseline serum NURR1 levels than did patients with an asymptomatic or absence of cerebral bleedings. CONCLUSIONS: Our results suggest that NURR1 upregulation by r-tPA during ischemic stroke is associated with endothelial dysfunction and inflammation and the enhancement of hemorrhagic complications associated to thrombolysis. PMID- 25503549 TI - Does respiratory muscle training improve cough flow in acute stroke? Pilot randomized controlled trial. AB - BACKGROUND AND PURPOSE: Cough protects the lungs from aspiration. We investigated whether respiratory muscle training may improve respiratory muscle and cough function, and potentially reduce pneumonia risk in acute stroke. METHODS: We conducted a single-blind randomized placebo-controlled trial in 82 patients with stroke (mean age, 64+/-14 years; 49 men) within 2 weeks of stroke onset. Participants were masked to treatment allocation and randomized to 4 weeks of daily expiratory (n=27), inspiratory (n=26), or sham training (n=25), using threshold resistance devices. Primary outcome was the change in peak expiratory cough flow of maximal voluntary cough. Intention-to-treat analyses were conducted using ANCOVA, adjusting for baseline prognostic covariates. RESULTS: There were significant improvements in the mean maximal inspiratory (14 cmH2O; P<0.0001) and expiratory (15 cmH2O; P<0.0001) mouth pressure and peak expiratory cough flow of voluntary cough (74 L/min; P=0.0002) between baseline and 28 days in all groups. Peak expiratory cough flow of capsaicin-induced reflex cough was unchanged. There were no between-group differences that could be attributed to respiratory muscle training. There were also no differences in the 90-day incidence of pneumonia between the groups (P=0.65). CONCLUSIONS: Respiratory muscle function and cough flow improve with time after acute stroke. Additional inspiratory or expiratory respiratory muscle training does not augment or expedite this improvement. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN40298220. PMID- 25503550 TI - Clinical prediction algorithm (BRAIN) to determine risk of hematoma growth in acute intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: We developed and validated a simple algorithm to predict the risk of hematoma growth in acute spontaneous intracerebral hemorrhage (ICH) to better inform clinicians and researchers in their efforts to improve outcomes for patients. METHODS: We analyzed data from the computed tomography substudies of the pilot and main phases of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials (INTERACT1 and 2, respectively). The study group was divided into a derivation cohort (INTERACT2, n=964) and a validation cohort (INTERACT1, n=346). Multivariable logistic regression was used to identify factors associated with clinically significant (>=6 mL) increase in hematoma volume at 24 hours after symptom onset. A parsimonious risk score was developed on the basis of regression coefficients derived from the logistic model. RESULTS: A 24-point BRAIN score was derived from INTERACT2 (C-statistic, 0.73) based on baseline ICH volume (mL per score, <=10=0, 10-20=5, >20=7), recurrent ICH (yes=4), anticoagulation with warfarin at symptom onset (yes=6), intraventricular extension (yes=2), and number of hours to baseline computed tomography from symptom onset (<=1=5, 1-2=4, 2-3=3, 3-4=2, 4-5=1, >5=0) predicted the probability of ICH growth (ranging from 3.4% for 0 point to 85.8% for 24 points) with good discrimination (C-statistic, 0.73) and calibration (Hosmer-Lemeshow P=0.82) in INTERACT1. CONCLUSIONS: The simple BRAIN score predicts the probability of hematoma growth in ICH. This could be used to improve risk stratification for research and clinical practice. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00226096 and NCT00716079. PMID- 25503551 TI - Acute ischemic stroke in pediatric patients. PMID- 25503552 TI - One, two, three steps toward cell therapy for stroke. PMID- 25503553 TI - Changes of pH and energy state in subacute human ischemia assessed by multinuclear magnetic resonance spectroscopy. AB - BACKGROUND AND PURPOSE: In vivo changes in tissue pH and energy metabolism are key to understanding stroke pathophysiology. Our goal was to study pH changes in subacute ischemic stroke and their relation to energy metabolism, which, unlike acidosis in acute stroke, are not yet well understood. METHODS: We measured tissue pH and phospholipid as well as cell energy markers, including creatine, phosphocreatine, and N-acetyl-aspartate in subacute stroke with combined (1)H and (31)P magnetic resonance spectroscopy. We included 19 patients with first-ever ischemic stroke (mean time after stroke, 6 days). We then compared metabolite concentrations in the ischemic tissue to contralateral (healthy) tissue using multivariate ANOVA to assess significant differences in metabolite levels between both tissue compartments. RESULTS: In subacute stroke, a tissue fraction with significantly increased tissue pH was observed as compared with healthy contralateral tissue (pH, 7.09 versus 7.03; P=0.002) concurrent with splitting of the pH signal with 1 peak being more alkalotic. Furthermore, only a moderate decrease of energy-rich metabolites (phosphocreatine reduced by 17%, ATP reduced by 19%) was present, whereas total creatine was reduced by 51%. CONCLUSIONS: The finding of an alkalotic pH split in subacute ischemia is unprecedented. The pH split and only incomplete energy loss in subacute stroke suggest 2 differently viable cellular moieties, best explained by active compensatory mechanisms after acute cerebral ischemia. PMID- 25503554 TI - Letter by Sabour regarding article, "coated-platelets improve prediction of stroke and transient ischemic attack in asymptomatic internal carotid artery stenosis". PMID- 25503556 TI - Expression of the receptor for advanced glycation end products, a target for high mobility group box 1 protein, and its role in chronic recalcitrant rhinosinusitis with nasal polyps. AB - A receptor for advanced glycation end products (RAGE) and its ligand high mobility group box 1 (HMGB1) protein has been linked to several chronic diseases, and acts as a trigger for inflammation signaling. Here, we study RAGE and HMGB1 expression in chronic, recalcitrant rhinosinusitis with nasal polyps (CRSwNP) to determine its potential clinical significance, i.e., disease recurrence and severity. RAGE and HMGB1 expression in CRSwNP was evaluated by immunohistochemistry in epithelial cells of fresh sinonasal mucosa samples obtained from the patients diagnosed with recalcitrant CRSwNP (n = 25) and normal control mucosa (NC) (n = 26). RAGE and HMGB1 expression levels in tissues were correlated with disease severity assessed by nasal endoscopy, CT scan, number of previous sinus surgeries, allergy status and nasosinusal microbiology. RAGE and HMGB1 were moderately or strongly expressed in CRSwNP tissue. No or weak RAGE expression was found in NC. HMGB1 was equally strongly expressed in NC. We observed a strong correlation between RAGE and disease severity, recurrence, undergone operations, asthma and aspirin exacerbated respiratory disease (AERD). Elevated RAGE expression is associated with increased disease severity, as well as allergy and AERD in patients with recalcitrant CRSwNP. It is possible that the explanation for recurrent CRSwNP pathogenesis might be related to RAGE overexpression with subsequent sinus mucosa hyperproliferation, necessitating several operations. PMID- 25503557 TI - Effect of a bolus dose of fentanyl on the ED50 and ED95 of sevoflurane in neonates. AB - BACKGROUND: The minimum alveolar concentration (MAC) of sevoflurane in neonates is 3.3%, but this value has not been verified in Chinese neonates and the effect of different doses of fentanyl on MAC in neonates has not been investigated. This study was designed to determine the ED50 and ED95 values of sevoflurane in Chinese neonates with and without fentanyl. MATERIAL AND METHODS: Ninety-three neonates were randomly assigned to receive sevoflurane alone (control group, n=30), 1 ug/kg sevoflurane (group fent1, n=29), or 2 ug/kg fentanyl (group fent2, n=32). Following inhalational induction and tracheal intubation, the end-tidal concentration of sevoflurane was adjusted to achieve the designated concentration, which was determined using the modified Dixon's up-and-down method starting with 3.0% in each group, with a 0.25% step size. Success was defined as no motor response within 60 s of skin incision. RESULTS: The MAC (standard deviation) values of sevoflurane were 2.91% (0.27) in the control group, 2.53% (0.31) in the fent1 group, and 2.34% (0.33) in the fent2 group according to Dixon's up-and-down method. Logistic probit regression analysis revealed that the ED50 and ED95 (95% CI) of sevoflurane in neonates were 2.82% (2.66-2.98) and 3.39% (2.89-3.89), respectively, in the control group; 2.44% (2.19-2.68) and 3.30% (2.51-4.09), respectively, in the fent1 group; and 2.21% (1.97-2.45) and 3.11% (2.35-3.88), respectively, in the fent2 group. CONCLUSIONS: The MAC value of sevoflurane in Chinese neonates was lower than previously reported and was reduced by the addition of fentanyl. PMID- 25503555 TI - Transmission-Blocking Vaccines: Focus on Anti-Vector Vaccines against Tick-Borne Diseases. AB - Tick-borne diseases are a potential threat that account for significant morbidity and mortality in human population worldwide. Vaccines are not available to treat several of the tick-borne diseases. With the emergence and resurgence of several tick-borne diseases, emphasis on the development of transmission-blocking vaccines remains increasing. In this review, we provide a snap shot on some of the potential candidates for the development of anti-vector vaccines (a form of transmission-blocking vaccines) against wide range of hard and soft ticks that include Ixodes, Haemaphysalis, Dermacentor, Amblyomma, Rhipicephalus and Ornithodoros species. PMID- 25503559 TI - Epigenetic silencing of miR-490-3p reactivates the chromatin remodeler SMARCD1 to promote Helicobacter pylori-induced gastric carcinogenesis. AB - Chromatin remodeling has emerged as a hallmark of gastric cancer, but the regulation of chromatin regulators other than genetic change is unknown. Helicobacter pylori causes epigenetic dysregulation to promote gastric carcinogenesis, but the roles and functions of microRNAs (miRNA) in this multistage cascade are not fully explored. In this study, miRNA expression in preneoplastic and neoplastic lesions in murine stomachs induced by H. pylori and N-methyl-N-nitrosourea (MNU) was profiled by miRNA expression array. miR-490-3p exhibited progressive downregulation in gastritis, intestinal metaplasia, and adenocarcinoma during H. pylori and MNU-induced gastric carcinogenesis. Significant downregulation of miR-490-3p was confirmed in human gastric cancer tissues in which its regulatory region was found to be hypermethylated. miR-490 3p exerted growth- and metastasis-suppressive effects on gastric cancer cells through directly targeting SMARCD1, a SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex subunit. Knockdown of SMARCD1 significantly attenuated the protumorigenic effects of miR-490-3p inhibitor, whereas enforced expression of SMARCD1 promoted in vitro and in vivo oncogenic phenotypes of gastric cancer cells. SMARCD1 was markedly upregulated in gastric cancer in which its high expression was associated with shortened patients' survival independent of TNM staging. In conclusion, hypermethylation-mediated silencing of miR-490-3p reactivates SMARCD1 to confer malignant phenotypes, mechanistically linking H. pylori, chromatin remodeling, and gastric carcinogenesis. PMID- 25503558 TI - Acute tissue injury activates satellite cells and promotes sarcoma formation via the HGF/c-MET signaling pathway. AB - Some patients with soft-tissue sarcoma (STS) report a history of injury at the site of their tumor. Although this phenomenon is widely reported, there are relatively few experimental systems that have directly assessed the role of injury in sarcoma formation. We recently described a mouse model of STS whereby p53 is deleted and oncogenic Kras is activated in muscle satellite cells via a Pax7(CreER) driver following intraperitoneal injection with tamoxifen. Here, we report that after systemic injection of tamoxifen, the vast majority of Pax7 expressing cells remain quiescent despite mutation of p53 and Kras. The fate of these muscle progenitors is dramatically altered by tissue injury, which leads to faster kinetics of sarcoma formation. In adult muscle, quiescent satellite cells will transition into an active state in response to hepatocyte growth factor (HGF). We show that modulating satellite cell quiescence via intramuscular injection of HGF increases the penetrance of sarcoma formation at the site of injection, which is dependent on its cognate receptor c-MET. Unexpectedly, the tumor-promoting effect of tissue injury also requires c-Met. These results reveal a mechanism by which HGF/c-MET signaling promotes tumor formation after tissue injury in a mouse model of primary STS, and they may explain why some patients develop a STS at the site of injury. PMID- 25503562 TI - In reply: Paravertebral block: the first procedure with "no contraindications"...really? PMID- 25503560 TI - alpha-Tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion, and invasive migration. AB - Metastatic cases of breast cancer pose the primary challenge in clinical management of this disease, demanding the identification of effective therapeutic strategies that remain wanting. In this study, we report that elevated levels of alpha-tubulin acetylation are a sufficient cause of metastatic potential in breast cancer. In suspended cell culture conditions, metastatic breast cancer cells exhibited high alpha-tubulin acetylation levels that extended along microtentacle (McTN) protrusions. Mutation of the acetylation site on alpha tubulin and enzymatic modulation of this posttranslational modification exerted a significant impact on McTN frequency and the reattachment of suspended tumor cells. Reducing alpha-tubulin acetylation significantly inhibited migration but did not affect proliferation. In an analysis of more than 140 matched primary and metastatic tumors from patients, we found that acetylation was maintained and in many cases increased in lymph node metastases compared with primary tumors. Proteomic analysis of an independent cohort of more than 390 patient specimens further documented the relationship between increased alpha-tubulin acetylation and the aggressive behaviors of basal-like breast cancers, with a trend toward increased risk of disease progression and death in patients with high-intensity alpha-tubulin acetylation in primary tumors. Taken together, our results identify a tight correlation between acetylated alpha-tubulin levels and aggressive metastatic behavior in breast cancer, with potential implications for the definition of a simple prognostic biomarker in patients with breast cancer. PMID- 25503561 TI - Current status of right ventricular outflow tract reconstruction: complete translation of a review article originally published in Kyobu Geka 2014;67:65-77. AB - Right ventricular outflow tract (RVOT) reconstruction is becoming more prevalent as the number of adult patients who require repeated surgery long after definitive repair of congenital heart defects during childhood has increased. Early primary repair and annulus-preserving surgery have been the two current strategies of RVOT reconstruction from the viewpoint of timing and indications for surgical intervention; however, the long-term outcomes of both procedures remain unknown. Although various materials have been used for pulmonary valve replacement during RVOT reconstruction, deficient durability due primarily to immunological rejection frequently arises, particularly when implanted into young patients. A multicenter study in Japan showed that the clinical outcomes of expanded polytetrafluoroethylene (ePTFE) valved patches/conduits that we developed and manufactured comprised an excellent alternative material for RVOT reconstruction. Such enhanced outcomes might have partly been attributable to the biocompatibility and low antigenicity of ePTFE, and also to the fluid dynamic properties arising from the structural characteristics of a bulging sinus and a fan-shaped valve. However, numerous issues concerning RVOT reconstruction, such as indications for and the timing of definitive repair, as well as the choice of materials for pulmonary valve replacement, must be resolved to achieve better patient prognoses and quality of life. This review describes recent surgical strategies and outstanding issues associated with RVOT reconstruction. PMID- 25503563 TI - Complete resection of a large phosphaturic mesenchymal tumour by chest wall resection and reconstruction. AB - Phosphaturic mesenchymal tumour is an extremely rare mesenchymal neoplasm of bone or soft tissue. It is associated with paraneoplastic oncogenic osteomalacia through secretion of fibroblast growth factor-23 (FGF-23) which inhibits renal proximal tubule phosphate re-uptake. We report a case of a 36-year-old woman with a large chest wall tumour completely excised by extensive chest wall resection and reconstruction with polypropylene mesh-methylmethacrylate composite and pedicled muscle flaps. PMID- 25503566 TI - Erratum to "Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock" [Mol Metab 3 (2014) 29-41]. AB - [This corrects the article DOI: 10.1016/j.molmet.2013.10.005.]. PMID- 25503564 TI - Degradation of Cep68 and PCNT cleavage mediate Cep215 removal from the PCM to allow centriole separation, disengagement and licensing. AB - An intercentrosomal linker keeps a cell's two centrosomes joined together until it is dissolved at the onset of mitosis. A second connection keeps daughter centrioles engaged to their mothers until they lose their orthogonal arrangement at the end of mitosis. Centriole disengagement is required to license centrioles for duplication. We show that the intercentrosomal linker protein Cep68 is degraded in prometaphase through the SCF(betaTrCP) (Skp1-Cul1-F-box protein) ubiquitin ligase complex. Cep68 degradation is initiated by PLK1 phosphorylation of Cep68 on Ser 332, allowing recognition by betaTrCP. We also found that Cep68 forms a complex with Cep215 (also known as Cdk5Rap2) and PCNT (also known as pericentrin), two PCM (pericentriolar material) proteins involved in centriole engagement. Cep68 and PCNT bind to different pools of Cep215. We propose that Cep68 degradation allows Cep215 removal from the peripheral PCM preventing centriole separation following disengagement, whereas PCNT cleavage mediates Cep215 removal from the core of the PCM to inhibit centriole disengagement and duplication. PMID- 25503567 TI - Prognostic factors in patients with hepatocellular carcinoma refractory or intolerant to sorafenib. AB - OBJECTIVE: The aim of this study was to identify the prognostic factors in patients with advanced hepatocellular carcinoma (HCC) who are refractory or intolerant to sorafenib and to exclude unsuitable candidates from subsequent therapy. METHODS: The study cohort consisted of 111 patients who had discontinued sorafenib therapy. Uni- and multivariate analyses were conducted to identify the prognostic factors for survival after discontinuation of sorafenib therapy. RESULTS: The median age of the patients was 70 years, and 96 of them (86%) were male. The Eastern Cooperative Oncology Group performance status was 0-1 in 94 patients (85%). Forty patients (36%) were classified as Child-Pugh class A and 57 (51%) as Child-Pugh class B. The median survival time after discontinuation of sorafenib therapy was 146 days. Hepatitis C viral antibody negativity, presence of ascites, absence of a history of previous treatment excluding sorafenib, elevated serum total bilirubin level, and elevated serum alpha-fetoprotein level were identified as the independent unfavorable prognostic factors by multivariate analysis. The median survival time of the patients with 4 or 5 unfavorable prognostic factors was 59 days. CONCLUSIONS: We should judge the indication of any subsequent therapy carefully in patients with 4 or 5 of the aforementioned factors. PMID- 25503569 TI - epsilon-Iron carbide as a low-temperature Fischer-Tropsch synthesis catalyst. AB - epsilon-Iron carbide has been predicted to be promising for low-temperature Fischer-Tropsch synthesis (LTFTS) targeting liquid fuel production. However, directional carbidation of metallic iron to epsilon-iron carbide is challenging due to kinetic hindrance. Here we show how rapidly quenched skeletal iron featuring nanocrystalline dimensions, low coordination number and an expanded lattice may solve this problem. We find that the carbidation of rapidly quenched skeletal iron occurs readily in situ during LTFTS at 423-473 K, giving an epsilon iron carbide-dominant catalyst that exhibits superior activity to literature iron and cobalt catalysts, and comparable to more expensive noble ruthenium catalyst, coupled with high selectivity to liquid fuels and robustness without the aid of electronic or structural promoters. This finding may permit the development of an advanced energy-efficient and clean fuel-oriented FTS process on the basis of a cost-effective iron catalyst. PMID- 25503568 TI - Effect of donor chimerism to reduce the level of glycosaminoglycans following bone marrow transplantation in a murine model of mucopolysaccharidosis type II. AB - Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficient activity of the iduronate-2-sulfatase. This leads to accumulation of glycosaminoglycans (GAGs) in the lysosomes of various cells. Although it has been proposed that bone marrow transplantation (BMT) may have a beneficial effect for patients with MPS II, the requirement for donor-cell chimerism to reduce GAG levels is unknown. To address this issue, we transplanted various ratios of normal and MPS II bone marrow cells in a mouse model of MPS II and analyzed GAG accumulation in various tissues. Chimerism of whole leukocytes and each lineage of BMT recipients' peripheral blood was similar to infusion ratios. GAGs were significantly reduced in the liver, spleen, and heart of recipients. The level of GAG reduction in these tissues depends on the percentage of normal-cell chimerism. In contrast to these tissues, a reduction in GAGs was not observed in the kidney and brain, even if 100 % donor chimerism was achieved. These observations suggest that a high degree of chimerism is necessary to achieve the maximum effect of BMT, and donor lymphocyte infusion or enzyme replacement therapy might be considered options in cases of low-level chimerism in MPS II patients. PMID- 25503565 TI - Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis. AB - Insulin resistance is a cardinal feature of Type 2 diabetes (T2D) and a frequent complication of multiple clinical conditions, including obesity, ageing and steroid use, among others. How such a panoply of insults can result in a common phenotype is incompletely understood. Furthermore, very little is known about the transcriptional and epigenetic basis of this disorder, despite evidence that such pathways are likely to play a fundamental role. Here, we compare cell autonomous models of insulin resistance induced by the cytokine tumour necrosis factor-alpha or by the steroid dexamethasone to construct detailed transcriptional and epigenomic maps associated with cellular insulin resistance. These data predict that the glucocorticoid receptor and vitamin D receptor are common mediators of insulin resistance, which we validate using gain- and loss-of-function studies. These studies define a common transcriptional and epigenomic signature in cellular insulin resistance enabling the identification of pathogenic mechanisms. PMID- 25503570 TI - Occurrence, seasonal variation and removal efficiency of antibiotics and their metabolites in wastewater treatment plants, Jiulongjiang River Basin, South China. AB - Wastewater treatment plants (WWTPs) are regarded as one of the most important sources of antibiotics in the environment. The occurrence, seasonal variation and removal efficiency of 21 antibiotics and 10 metabolites, including five sulfonamides and three of their metabolites, six quinolones, two macrolides, two beta-Lactams and five tetracyclines and seven of their metabolites, were investigated in five WWTPs in different seasons in the Jiulongjiang River Region, South China. 16 antibiotics and 6 metabolites in summer and 14 antibiotics and 6 metabolites in winter were found, respectively. The most frequently detected antibiotics were sulfamethazine, sulfamethoxazole, n-acetyl sulfamethazine, n acetyl sulfamethoxazole, ofloxacin, cephalexin monohydrate and cephradine; of these, the concentration of cephradine was the highest in most of the influent and effluent samples. The highest level of total antibiotics was found in Longyan City WWTPs, where there are more population and swine farms. Seasonal variation of the antibiotics in wastewater samples was also studied. The concentrations of antibiotics in winter were higher than those in summer. The antibiotics could not be removed completely by the WWTPs, and the mean removal efficiency ranged from 71.6 to 56.3%. Of all the antibiotics, the tetracyclines were removed comparatively more efficiently, probably due to their adsorption to sludge. The low removal efficiency of antibiotics in WWTPs could be one of the important reasons for the presence of antibiotics in the environment in Jiulongjiang Region. PMID- 25503571 TI - Energetic contributions of residues to the formation of early amyloid-beta oligomers. AB - Low-weight amyloid-beta (Abeta) oligomers formed at early stages of oligomerization rather than fibril assemblies seem to be the toxic components that drive neurodegeneration in Alzheimer's disease. Unfortunately, detailed knowledge of the structure of these early oligomers at the residue level is not yet available. In this study, we performed all-atom explicit solvent molecular dynamics simulations to examine the oligomerization process of Abeta10-35 monomers when forming dimers, trimers, tetramers and octamers, with four independent simulations of a total simulated time of 3 MUs for each oligomer system. The decomposition of the stability free energy by MM-GBSA methodology allowed us to unravel the network of energetic interactions that stabilize such oligomers. The contribution of the intermonomeric van der Waals term is the most significant energy feature of the oligomerization process, consistent with the so called hydrophobic effect. Furthermore, the decomposition of the stability free energy into residues and residue-pairwise terms revealed that it is mainly apolar interactions between the three specific hydrophobic fragments 31-35 (C-terminal region), 17-20 (central hydrophobic core) and 12-14 (N-terminal region) that are responsible for such a favourable effect. The conformation in which the hydrophobic cthr-chc interaction is oriented perpendicularly is particularly important. We propose three other model substructures that favour the oligomerization process and can thus be considered as molecular targets for future inhibitors. Understanding Abeta oligomerization at the residue level could lead to more efficient design of inhibitors of this process. PMID- 25503572 TI - A polycation-induced secondary assembly of amphiphilic calixarene and its multi stimuli responsive gelation behavior. AB - A calixarene-based supramolecular hydrogel with a porous network structure was successfully constructed via a hierarchical induced assembly strategy, showing reversible or irreversible gelation behaviors in response to several external stimuli including thermal, redox and ionic strength. PMID- 25503573 TI - Surface tension and the mechanics of liquid inclusions in compliant solids. AB - Eshelby's theory of inclusions has wide-reaching implications across the mechanics of materials and structures including the theories of composites, fracture, and plasticity. However, it does not include the effects of surface stress, which has recently been shown to control many processes in soft materials such as gels, elastomers and biological tissue. To extend Eshelby's theory of inclusions to soft materials, we consider liquid inclusions within an isotropic, compressible, linear-elastic solid. We solve for the displacement and stress fields around individual stretched inclusions, accounting for the bulk elasticity of the solid and the surface tension (i.e. isotropic strain-independent surface stress) of the solid-liquid interface. Surface tension significantly alters the inclusion's shape and stiffness as well as its near- and far-field stress fields. These phenomena depend strongly on the ratio of the inclusion radius, R, to an elastocapillary length, L. Surface tension is significant whenever inclusions are smaller than 100L. While Eshelby theory predicts that liquid inclusions generically reduce the stiffness of an elastic solid, our results show that liquid inclusions can actually stiffen a solid when R<3L/2. Intriguingly, surface tension cloaks the far-field signature of liquid inclusions when R=3L/2. These results are have far-reaching applications from measuring local stresses in biological tissue, to determining the failure strength of soft composites. PMID- 25503574 TI - Bilateral vocal fold immobility. PMID- 25503575 TI - Prognostic factors and scoring system for death from visceral leishmaniasis: an historical cohort study in Brazil. AB - BACKGROUND: In Brazil, case-fatality rates attributable to visceral leishmaniasis (VL) are high and knowledge of the risk factors associated with death may help reduce mortality. The aim of this study was to construct and validate a scoring system for prognosis of death from VL by using all cases reported in Brazil from 2007 to 2011. METHODOLOGY: In this historical cohort study, 18,501 VL cases were analyzed; of these, 17,345 cases were cured and 1,156 cases caused death. The database was divided into two series: primary (two-thirds of cases), to develop the model score, and secondary (one-third of cases), to validate the scoring system. Multivariate logistic regression models were performed to identify factors associated with death from VL, and these were included in the scoring system. PRINCIPAL FINDINGS: The factors associated with death from VL were: bleeding (score 3); splenomegaly (score 1); edema (score 1); weakness (score 1); jaundice (score 1); Leishmania-HIV co-infection (score 1); bacterial infection (score 1); and age (<=0.5 years [score 5]; >0.5 and <=1 [score 2]; >19 and <=50 [score 2]; >50 and <65 [score 3]; >=65 [score 5]). It was observed that patients with a score of 4 had a probability of death of approximately 4.5% and had a worse prognosis. The sensitivity, specificity, and accuracy of this score were 89.4, 51.2, and 53.5, respectively. CONCLUSIONS/SIGNIFICANCE: The scoring system based on risk factors for death showed good performance in identifying patients with signs of severity at the time of clinical suspicion of VL and can contribute to improving the surveillance system for reducing case fatalities. The classification of patients according to their prognosis for death may assist decision-making regarding the transfer of the patients to hospitals more capable of handling their condition, admission to the intensive care unit, and adequate support and specific treatment. PMID- 25503577 TI - Continuous irradiation with a 633-nm light-emitting diode exerts an anti-aging effect on human skin cells. AB - Accumulating evidence has indicated that the light source emitted from light emitting diode (LED) has a potential anti-aging effect on human skin. Studies using single and interval LED irradiation have documented such effects; however, to the best of our knowledge, the anti-aging effects of continuous LED irradiation have not yet been investigated. In the present study, we demonstrated that continuous irradiation with a 633+/-3-nm LED exerted anti-aging effects in both in vitro and ex vivo experiments. More specifically, irradiation with a 633 nm LED for 2 days increased the synthesis of type 1 procollagen and decreased the expression of matrix metalloproteinase (MMP)1 and MMP2 in skin fibroblasts. In addition, irradiation with a 633-nm LED decreased the expression levels of inflammatory genes, such has cyclooxygenase-2 (COX-2), and interleukin-1-alpha (IL-1alpha) in keratinocytes. Furthermore, a 14-day LED irradiation moderately increased keratinocyte proliferation. Using human skin explants, we confirmed the safety of this 633-nm LED irradiation, which resulted in unaltered morphology and allergy-free potential in human tissue. Overall, these data provide insight into the anti-aging effects of continuous LED irradiation on human skin. PMID- 25503576 TI - Screening for vulnerability in older cancer patients: the ONCODAGE Prospective Multicenter Cohort Study. AB - BACKGROUND: Geriatric Assessment is an appropriate method for identifying older cancer patients at risk of life-threatening events during therapy. Yet, it is underused in practice, mainly because it is time- and resource-consuming. This study aims to identify the best screening tool to identify older cancer patients requiring geriatric assessment by comparing the performance of two short assessment tools the G8 and the Vulnerable Elders Survey (VES-13). PATIENTS AND METHODS: The diagnostic accuracy of the G8 and the (VES-13) were evaluated in a prospective cohort study of 1674 cancer patients accrued before treatment in 23 health care facilities. 1435 were eligible and evaluable. Outcome measures were multidimensional geriatric assessment (MGA), sensitivity (primary), specificity, negative and positive predictive values and likelihood ratios of the G8 and VES 13, and predictive factors of 1-year survival rate. RESULTS: Patient median age was 78.2 years (70-98) with a majority of females (69.8%), various types of cancer including 53.9% breast, and 75.8% Performance Status 0-1. Impaired MGA, G8, and VES-13 were 80.2%, 68.4%, and 60.2%, respectively. Mean time to complete G8 or VES-13 was about five minutes. Reproducibility of the two questionnaires was good. G8 appeared more sensitive (76.5% versus 68.7%, P = 0.0046) whereas VES-13 was more specific (74.3% versus 64.4%, P<0.0001). Abnormal G8 score (HR = 2.72), advanced stage (HR = 3.30), male sex (HR = 2.69) and poor Performance Status (HR = 3.28) were independent prognostic factors of 1-year survival. CONCLUSION: With good sensitivity and independent prognostic value on 1-year survival, the G8 questionnaire is currently one of the best screening tools available to identify older cancer patients requiring geriatric assessment, and we believe it should be implemented broadly in daily practice. Continuous research efforts should be pursued to refine the selection process of older cancer patients before potentially life-threatening therapy. PMID- 25503578 TI - Electromyographic pelvic floor activity: Is there impact during the female life cycle? AB - AIM: To evaluate the pelvic floor muscle (PFM) electromyographic activity in different phases of the female life cycle, correlating electromyographic activity with age, Body Mass Index (BMI), parity as well as the presence and severity of urinary symptoms. METHODS: A clinical, observational, transversal and controlled study was conducted in 384 women: 49 nulliparous, 103 primigravid pregnant, 92 primiparous postpartum (vaginal delivery: n = 43; cesarean section delivery: n = 49), 22 climacteric, 65 postmenopausal, and 53 women identified as being unable to perform voluntary maximum contraction. All subjects were evaluated with digital palpation and PFM surface electromyography (sEMG) and completed the questionnaires: International Consultation on Incontinence Urinary Incontinence Short Form (ICIQ IU-SF) and International Consultation on Incontinence Questionnaire Overactive Bladder (ICIQ-OAB). Spearman's Correlation Coefficient and ANOVA were used to analyze the variables. RESULTS: The nulliparous women had higher PFM electromyographic activity than the other groups. The primigravid pregnant, cesarean section and vaginal delivery groups had higher electromyographic activity than the postmenopausal group. Studying PFM electromyographic activity with the factors evaluated, a negative correlation between age, parity, and the presence and severity of urinary symptoms was observed. There was no correlation between PFM electromyographic activity and BMI. CONCLUSION: Fourteen percent of women participating were not able to perform active contraction of the PFM. PFM electromyographic activity changed during the female life cycle. PFM electromyographic activity correlated inversely with age, parity, and the presence and severity of urinary symptoms. PMID- 25503579 TI - Understanding barriers to safer sex practice in Zimbabwean marriages: implications for future HIV prevention interventions. AB - Against the backdrop of high human immunodeficiency virus (HIV) prevalence in stable relationships in Southern Africa, our study presents sociocultural barriers to safer sex practice in Zimbabwean marriages. We conducted 36 in-depth interviews and four focus group discussions with married men and women in Zimbabwe in 2008. Our aim was to identify barriers faced by married women when negotiating for safer sex. Participants identified individual, relational and community-level barriers. Individual level barriers made women voiceless to negotiate for safer sex. Being voiceless emanated from lack sexual decision making power, economic dependence, low self-efficacy or fear of actual or perceived consequences of negotiating for safer sex. Relational barriers included trust and self-disclosure. At the community level, extended family members and religious leaders were said to explicitly or implicitly discourage women's safer sex negotiation. Given the complexity and multi-levelled nature of barriers affecting sexual behaviour in marriage, our findings suggest that HIV prevention interventions targeted at married women would benefit from empowering individual women, couples and also addressing the wider community. PMID- 25503580 TI - Prevalence of metabolic syndrome and cardiovascular risk factors among voluntary screened middle-aged and elderly Egyptians. AB - BACKGROUND: Central obesity and diabetes mellitus are recorded at high percentages among Egyptians. The aim of this study is to determine the prevalence of metabolic syndrome (MetS) and cardiovascular risk factors among a group of middle-aged and elderly Egyptians. METHODS: Our study included 220 middle-aged and senior Egyptians voluntary screened in an Egyptian private hospital with 800 bed capacity. Detailed medical history was obtained from all subjects, followed by clinical examination with weight and height measurement, body mass index calculation, waist hip ratio and arterial blood pressure measurement. Laboratory investigations done were complete blood picture, lipid profile and fasting blood glucose measurements. The diagnosis of MetS was based on the American Heart Association/Updated NCEP ATP III criteria. Cardiovascular risk assessment was calculated for each subject based on the Framingham/ATP III criteria. RESULTS: The prevalence of MetS in this study was of 55% among the whole sample, 85.6% among diabetics and 76.6% among hypertensive patients. Based on Framingham scoring system, 48.2% of the sample had moderate to high risk of developing cardiovascular disease. Odds ratio for patients with MetS for developing cardiovascular disease in the next 10 years was 2.8 (95% confidence interval: 1.6 4.8). CONCLUSION: The high prevalence of MetS among middle-aged and elderly Egyptians with the documented high prevalence of chronic diseases in Egypt calls for a nationwide screening program to detect MetS and tackle preventive strategies to face the epidemic of obesity and outcomes of MetS, particularly cardiovascular diseases. PMID- 25503581 TI - Effect of probiotic supplementation on bacterial translocation in common bile duct obstruction. AB - OBJECTIVE: To investigate the effects of probiotics on bacterial translocation in the obstructive common bile duct with comparison to an enteral product containing arginine and glutamine. MATERIAL AND METHOD: In our study, 40 Sprague-Dawley rats each weighing 250-300 g were used. Animals in Group 1 (sham) were laparatomized and fed standard chow supplemented with physiologic saline at daily doses of 2 ml through orogastric tube for 7 days. Common bile ducts of the animals in the other groups were ligated with 3/0 silk sutures. Group 2 (control group) was fed standard chow supplemented with daily doses of 2 ml physiologic saline. Group 3 (probiotic group) was fed standard chow supplemented with a probiotic solution (Acidophilus plus) containing strains of Lactobacillus acidophilus, Bifidobacterium bifidum and Lactobacillus bulgaricus at a daily doses of 2 * 10(9) colony forming units (CFU). Group 4 (formula group) was fed only an enteral solution (Stresson Multi Fiber) containing glutamine, arginine and a medium-chain fatty acid at daily doses of 2 g/kg. At the end of the 7th day, all animals were relaparatomized, and to determine bacterial translocation, aerobic, and anaerobic cultures were obtained from the specimens of mesenteric lymph nodes, intestinal mucosa, and blood samples. Smear cultures prepared from caecum were examined to determine the number of CFU. Finally, for histological examination specimens were excised from terminal ileum, and oxidative damage was assessed in liver tissues. Afterwards all animals were killed. RESULTS: Moderately lesser degrees of bacterial translocation, and mucosal damage were seen in Groups 3, and 4 relative to Group 2 (p < 0.05). In Group 4, any difference was not seen in the number of cecal bacteria relative to baseline values, while in Group 3, significant decrease in cecal colonization was seen. Among all groups, a significant difference between levels of malondialdehyde, and glutathione was not observed. CONCLUSION: At the end of our study, we have concluded that both probiotics, and enteral diets which contain immunomodulators such as glutamine, and arginine alleviate bacterial translocation, and impairment of intestinal mucosa. PMID- 25503584 TI - Venous thromboembolism diagnosis: unresolved issues. AB - Recent advances in the management of patients with suspected VTE have both improved diagnostic accuracy and made management algorithms safer, easier to use and well standardised. These diagnostic algorithms are mainly based on the assessment of clinical pretest probability, D-dimer measurement and imaging tests, mainly represented by compression ultrasound (CUS) for suspected DVT and computed tomography pulmonary angiography (CTPA) or lung ventilation-perfusion scan for pulmonary embolism. These diagnostic algorithms allow a safe and cost effective diagnosis for most patients with suspected VTE. In this review, we focus on the challenge of diagnosing VTE in special patient populations, such as elderly patients, pregnant women, or patients with a prior VTE. Some additional challenges are arising that might require adjustments to current diagnostic strategies, such as the reduced clinical suspicion threshold, resulting in a lower proportion of VTE among suspected patients; the overdiagnosis and overtreatment of VTE, especially regarding calf deep-vein thrombosis (DVT) and subsegmental pulmonary embolism (SSPE). PMID- 25503582 TI - STAT3 restrains RANK- and TLR4-mediated signalling by suppressing expression of the E2 ubiquitin-conjugating enzyme Ubc13. AB - The transcriptional regulator STAT3 curbs pro-inflammatory cytokine production mediated by NF-kappaB signalling in innate immune cells, yet the mechanism by which this occurs has been unclear. Here we identify STAT3 as a pivotal negative regulator of Ubc13, an E2 ubiquitin-conjugating enzyme that facilitates TRAF6 K63 linked ubiquitination and NF-kappaB activation. Ubc13 accumulates intracellularly in the absence of STAT3. Depletion of Ubc13 in Stat3-deficient macrophages subdues excessive RANKL- or LPS-dependent gene expression, indicating that Ubc13 overexpression mediates enhanced transcriptional responses in the absence of STAT3. In RANKL-activated macrophages, STAT3 is stimulated by autocrine IL-6 and inhibits accrual of Ets-1, Set1 methyltransferase and trimethylation of histone H3 lysine 4 (H3K4me3) at the Ube2n (Ubc13) promoter. These results delineate a mechanism by which STAT3 operates as a transcriptional repressor on Ube2n, thus modulating NF-kappaB activity by regulation of Ubc13 abundance. Our data suggest that this pathway plays important roles in bone homeostasis and restraint of inflammation. PMID- 25503583 TI - Cytokine network in adults with falciparum Malaria and HIV-1: increased IL-8 and IP-10 levels are associated with disease severity. AB - BACKGROUND: Co-infection with malaria and HIV increases the severity and mortality of both diseases, but the cytokine responses related to this co infection are only partially characterised. The aim of this study was to explore cytokine responses in relation to severity and mortality in malaria patients with and without HIV co-infection. METHODS: This was a prospective cross-sectional study. Clinical data and blood samples were collected from adults in Mozambique. Plasma was analysed for 21 classical pro- and anti-inflammatory cytokines, including interleukins, interferons, and chemokines. RESULTS: We included 212 in patients with fever and/or suspected malaria and 56 healthy controls. Falciparum malaria was diagnosed in 131 patients, of whom 70 were co-infected with HIV-1. The malaria patients had marked increases in their cytokine responses compared with the healthy controls. Some of these changes, particularly interleukin 8 (IL 8) and interferon-gamma-inducing protein 10 (IP-10) were strongly associated with falciparum malaria and disease severity. Both these chemokines were markedly increased in patients with falciparum malaria as compared with healthy controls, and raised levels of IL-8 and IP-10 were associated with increased disease severity, even after adjusting for relevant confounders. For IL-8, particularly high levels were found in malaria patients that were co-infected with HIV and in those who died during hospitalization. INTERPRETATIONS: Our findings underscore the complex role of inflammation during infection with P. falciparum, and suggest a potential pathogenic role for IL-8 and IP-10. However, the correlations do not necessarily mean any causal relationship, and further both clinical and mechanistic research is necessary to elucidate the role of cytokines in pathogenesis and protection during falciparum malaria. PMID- 25503585 TI - Mortality and cardiovascular morbidity associated with haemoglobin levels: a pooled analysis of randomised controlled trials. AB - BACKGROUND/AIMS: Several randomised controlled trials (RCTs) have raised concerns about potential harm associated with erythropoiesis-stimulating agents (ESAs) in chronic kidney disease patients, especially when haemoglobin (Hb) levels above 13 g/dl were targeted. We report the relationship between Hb levels and outcomes in the methoxy polyethylene glycol-epoetin beta RCT programme. METHODS: We assessed the association between Hb and a composite end point, as well as its components [all-cause mortality, myocardial infarction (MI) or cerebrovascular events (CVE)], in multiple post hoc analyses of 9 prospective RCTs (3,405 chronic kidney disease patients). Mean Hb levels over time and deviation from target were analysed using a Cox regression model. Time-adjusted average Hb, deviation from target, the last Hb, Hb slope and within-patient Hb variability preceding an event were analysed using a time-dependent Cox model. Hazard ratios and 95% confidence intervals were calculated. RESULTS: Average Hb <10 g/dl, decrease from stable baseline Hb >1 g/dl, last Hb <10 g/dl, Hb decline >1.5 g/dl/4 weeks and increased Hb variability were associated with a higher risk of the composite end point and all-cause mortality. An increased risk for CVE and MI was found with a last Hb <10 g/dl and with a decrease from baseline >1 g/dl in the preceding month. CONCLUSION: In multiple analyses from a large programme of prospective clinical trials of ESA treatment, risk of all-cause mortality and cardiovascular morbidity risk was consistently higher at Hb <10 g/dl and in patients whose Hb fell below target. PMID- 25503586 TI - Photonic architectures for equilibrium high-temperature Bose-Einstein condensation in dichalcogenide monolayers. AB - Semiconductor-microcavity polaritons are composite quasiparticles of excitons and photons, emerging in the strong coupling regime. As quantum superpositions of matter and light, polaritons have much stronger interparticle interactions compared with photons, enabling rapid equilibration and Bose-Einstein condensation (BEC). Current realizations based on 1D photonic structures, such as Fabry-Perot microcavities, have limited light-trapping ability resulting in picosecond polariton lifetime. We demonstrate, theoretically, above-room temperature (up to 590 K) BEC of long-lived polaritons in MoSe2 monolayers sandwiched by simple TiO2 based 3D photonic band gap (PBG) materials. The 3D PBG induces very strong coupling of 40 meV (Rabi splitting of 62 meV) for as few as three dichalcogenide monolayers. Strong light-trapping in the 3D PBG enables the long-lived polariton superfluid to be robust against fabrication-induced disorder and exciton line-broadening. PMID- 25503587 TI - When Matching Fails: Understanding the Process of Matching Pain-Disability Treatment to Risk Profile. AB - PURPOSE: A previous study (Bergbom et al. in J Occup Rehabil, 2013) showed that matching people at risk for pain-related disability to an intervention aimed at targeting their psychological problem profile did not, as hypothesized, improve the effect of the intervention. Methodological issues were suggested to explain the lack of differential effect. It was questioned whether the profiles used to allocate people to treatment were adequate. The aim of this study was to investigate if the risk profiles used to determine matching were sufficiently stable and valid by comparing the original profiles with profiles constructed using other methods. METHODS: Ninety-five people suffering musculoskeletal problems were screened, profiled, and matched to workplace based early interventions according to profiles. We studied stability and validity of their psychological risk profiles by investigating their concordance at different time points. People were originally assigned to profiles at inclusion, using a brief screening questionnaire. Then, they were profiled just before treatment start, using the same items. Finally, they were profiled again at treatment start, using extensive questionnaires. Concordance among the three sets of profiles was investigated. RESULTS: Profiles at inclusion were unstable until treatment start. People moved from profiles with more severe elevations in psychological variables, to a profile with moderate elevations. Concordance between the two means of profiling at treatment start was better; the brief screening and the extensive questionnaires assigned people to similar profiles. CONCLUSIONS: Risk level may be determined with brief instruments at an early stage of problem development. However, profiles and targets for interventions should be determined immediately prior to treatment start, preferably using full questionnaires. PMID- 25503588 TI - Nicotine and cotinine exposure from electronic cigarettes: a population approach. AB - BACKGROUND AND OBJECTIVES: Electronic cigarettes (e-cigarettes) are a recent technology that has gained rapid acceptance. Still, little is known about them in terms of safety and effectiveness. A basic question is how effectively they deliver nicotine; however, the literature is surprisingly unclear on this point. Here, a population pharmacokinetic model was developed for nicotine and its major metabolite cotinine with the aim to provide a reliable framework for the simulation of nicotine and cotinine concentrations over time, based solely on inhalation airflow recordings and individual covariates [i.e., weight and breath carbon monoxide (CO) levels]. METHODS: This study included ten adults self identified as heavy smokers (at least one pack of cigarettes per day). Plasma nicotine and cotinine concentrations were measured at regular 10-min intervals for 90 min while human subjects inhaled nicotine vapor from a modified e cigarette. Airflow measurements were recorded every 200 ms throughout the session. A population pharmacokinetic model for nicotine and cotinine was developed based on previously published pharmacokinetic parameters and the airflow recordings. All of the analyses were performed with the non-linear mixed effect modeling software NONMEM((r)) version 7.2. RESULTS: The results show that e-cigarettes deliver nicotine effectively, although the pharmacokinetic profiles are lower than those achieved with regular cigarettes. Our pharmacokinetic model effectively predicts plasma nicotine and cotinine concentrations from the inhalation volume, and initial breath CO. CONCLUSION: E-cigarettes are effective at delivering nicotine. This new pharmacokinetic model of e-cigarette usage might be used for pharmacodynamic analysis where the pharmacokinetic profiles are not available. PMID- 25503589 TI - Pharmacokinetics of clobazam and N-desmethylclobazam in children with dravet syndrome receiving concomitant stiripentol and valproic Acid. AB - AIM: The aim of this study was to describe the pharmacokinetics of clobazam and its active metabolite N-desmethylclobazam (N-CLB) in children with Dravet syndrome receiving the stiripentol/valproic acid/clobazam combination therapy of reference and to determine the concentrations of clobazam and N-CLB obtained in this population for the usual 0.2 mg/kg twice-daily dose. METHODS: Thirty-five children with epilepsy were included in a prospective population pharmacokinetic study (using NONMEM((r)) software). Four blood samples were drawn per patient. Area under the plasma concentration-time curve (AUC) and trough concentration (C trough) values for clobazam and N-CLB were simulated for 12,000 theoretical children weighing between 10 and 60 kg. RESULTS: The pharmacokinetics of clobazam were described by a one-compartment model with first-order absorption, and elimination, formation and elimination of N-CLB were also first-order processes. The apparent total clearance (CL/F) and distribution volume (V CLB/F) of clobazam and the elimination rate constant of N-CLB (Kem) were related to body weight by allometric equations. Mean population estimates (% inter-individual variability) were 1.23 L/h (29%) for CL/F, 39.1 L (18%) for V CLB/F and 0.0706 h(-1) (26%) for Kem. The AUC values for clobazam and N-CLB were found to increase by 100% when bodyweight increased from 10 to 60 kg, and the simulated C trough values were higher than the currently accepted target values (0.03-0.3 mg/L for clobazam and 0.3-3 mg/L for N-CLB). CONCLUSION: This is the first simultaneous pharmacokinetic model for clobazam and N-CLB in epileptic children. Indicative values for the routine therapeutic drug monitoring of clobazam in children with Dravet syndrome treated by stiripentol are provided. The possible consequences of the weight related changes on clobazam and N-CLB exposures should be further evaluated. PMID- 25503590 TI - [The OPD structure questionnaire captures the general features of personality disorder]. AB - INTRODUCTION: The alternative DSM-5 model of personality disorder (PD) links general criteria and severity of PD to impairments in self and interpersonal functioning. This approach is very similar to the Level of Structural Impairment Axis of the Operationalized Psychodynamic Diagnosis (OPD-2). In this study we investigate the relationship of these 2 approaches based on 2 new self-report questionnaires. METHODS: 228 psychotherapeutic inpatients filled out the OPD Structure Questionnaire (OPD-SQ), the General Assessment of Personality Disorder (GAPD), and the Patient Health Questionnaire (PHQ-D). RESULTS: The correlation between the latent general factors of OPD-SQ and GAPD was 0,91. After controlling for depressive symptoms the correlation was 0,86. DISCUSSION: The general factors of the OPD-SQ and the GAPD are almost identical. CONCLUSION: The OPD-SQ captures the general features of PD in terms of self-reported impairments in self and interpersonal functioning. PMID- 25503591 TI - [The extension of the Leipzig questionnaire of motives to have a child (LKM) for use in oncology--test construction and psychometric review]. AB - Many young cancer patients had not completed family planning at the time of diagnosis. A cancer disease may change procreative attitudes and the development of specific motivations of having a child (for and against) is possible. This paper addresses the extension of the Leipzig questionnaire on motives for wanting children (LKM) in the context of cancer. Specific motivations of cancer patients are presented and test-statistically verified. Based on previous findings and a qualitative questioning (patients, professionals) items for specific motivations were developed and pre-tested. The revised version (20 items) was tested on a sample of 175 young cancer patients. Good to adequate item discrimination parameter and reliability (alpha=0.86) were shown. The factor analysis revealed the 2 scales "PRO - motivations for having children after cancer" and "CON - motivations against having children after cancer". These additional scales of specific motivations allow for a reliable and economical measure of motivations to have a child in young cancer patients. In the future the scales can be also used for other serious physical disease in young adulthood. PMID- 25503593 TI - Automatic segmentation of the nasal cavity and paranasal sinuses from cone-beam CT images. AB - PURPOSE: A patient-specific upper airway model is important for clinical, education, and research applications. Cone-beam computed tomography (CBCT) is used for imaging the upper airway but automatic segmentation is limited by noise and the complex anatomy. A multi-step level set segmentation scheme was developed for CBCT volumetric head scans to create a 3D model of the nasal cavity and paranasal sinuses. METHODS: Gaussian mixture model thresholding and morphological operators are first employed to automatically locate the region of interest and to initialize the active contour. Second, the active contour driven by the Kullback-Leibler (K-L) divergence energy in a level set framework to segment the upper airway. The K-L divergence asymmetry is used to directly minimize the K-L divergence energy on the probability density function of the image intensity. Finally, to refine the segmentation result, an anisotropic localized active contour is employed which defines the local area based on shape prior information. The method was tested on ten CBCT data sets. The results were evaluated by the Dice coefficient, the volumetric overlap error (VOE), precision, recall, and F-score and compared with expert manual segmentation and existing methods. RESULTS: The nasal cavity and paranasal sinuses were segmented in CBCT images with a median accuracy of 95.72 % [93.82-96.72 interquartile range] by Dice, 8.73 % [6.79-12.20] by VOE, 94.69 % [93.80-94.97] by precision, 97.73 % [92.70-98.79] by recall, and 95.72 % [93.82-96.69] by F-score. CONCLUSION: Automated CBCT segmentation of the airway and paranasal sinuses was highly accurate in a test sample of clinical scans. The method may be useful in a variety of clinical, education, and research applications. PMID- 25503592 TI - 2D-3D radiograph to cone-beam computed tomography (CBCT) registration for C-arm image-guided robotic surgery. AB - PURPOSE: C-arm radiographs are commonly used for intraoperative image guidance in surgical interventions. Fluoroscopy is a cost-effective real-time modality, although image quality can vary greatly depending on the target anatomy. Cone beam computed tomography (CBCT) scans are sometimes available, so 2D-3D registration is needed for intra-procedural guidance. C-arm radiographs were registered to CBCT scans and used for 3D localization of peritumor fiducials during a minimally invasive thoracic intervention with a da Vinci Si robot. METHODS: Intensity-based 2D-3D registration of intraoperative radiographs to CBCT was performed. The feasible range of X-ray projections achievable by a C-arm positioned around a da Vinci Si surgical robot, configured for robotic wedge resection, was determined using phantom models. Experiments were conducted on synthetic phantoms and animals imaged with an OEC 9600 and a Siemens Artis zeego, representing the spectrum of different C-arm systems currently available for clinical use. RESULTS: The image guidance workflow was feasible using either an optically tracked OEC 9600 or a Siemens Artis zeego C-arm, resulting in an angular difference of Deltatheta:~ 30 degrees . The two C-arm systems provided TRE mean <= 2.5 mm and TRE mean <= 2.0 mm, respectively (i.e., comparable to standard clinical intraoperative navigation systems). CONCLUSIONS: C-arm 3D localization from dual 2D-3D registered radiographs was feasible and applicable for intraoperative image guidance during da Vinci robotic thoracic interventions using the proposed workflow. Tissue deformation and in vivo experiments are required before clinical evaluation of this system. PMID- 25503594 TI - The Reduction of Fear of Movement-related Pain: Does Motivational Context Matter? AB - OBJECTIVES: Previous research indicates that reducing fear of movement-related pain is hampered by engaging in safety-seeking behavior. We tested the hypothesis that fear reduction is only disrupted by behavior that serves a pain-avoidance goal (safety-seeking), but not when it is serving an achievement goal. METHODS: Using the voluntary joystick movement paradigm, fear of a painful joystick arm movement was successfully acquired by repeatedly pairing this joystick movement with a painful electrocutaneous stimulus (unconditioned stimulus [pain-US]) and this fear was subsequently extinguished using a Pavlovian extinction procedure. During extinction, a Safety group and Reward group both pressed a safety button, whereas a third Control group did not. RESULTS: Pain-US expectancy and fear of movement-related pain ratings show a gradual fear reduction in the Control Group, but a return of fear when the button is pressed to avoid the pain-US (Safety group). When the same button is used to attain a reward (Reward group), subsequent return of fear is attenuated. In addition, we investigated the reliability of the return of fear in the Safety group and Reward group, using a customized Reliable Change Index. This index confirms that the return of fear was only reliable in the Safety group, and that this return of fear is associated with more perceived control over the nonoccurrence of the pain-US when pressing the button. DISCUSSION: These results highlight the importance of motivational context in understanding the role of safety-seeking behavior in exposure-based therapies. PMID- 25503595 TI - The Process of Change in Pain During Cognitive-Behavior Therapy for Chronic Fatigue Syndrome. AB - BACKGROUND: Cognitive-behavior therapy (CBT) leads to a reduction of fatigue and pain in chronic fatigue syndrome. The processes underlying the reduction in pain have not been investigated. Recently, it was shown that increased self-efficacy, decreased focusing on symptoms, increased physical functioning, and a change in beliefs about activity contribute to the decrease in fatigue. OBJECTIVES: The present study has 2 objectives: (1) to determine the relationship between the reduction of fatigue and pain during CBT; (2) test to what extent the model for change in fatigue is applicable to the reduction in pain. MATERIALS AND METHODS: One hundred forty-two patients meeting United States centers for Disease Control and Prevention criteria for chronic fatigue syndrome, currently reporting pain, and starting CBT were included. A cross-lagged analysis was performed to study the causal direction of change between pain and fatigue. Pain and process variables were assessed before therapy, 3 times during CBT, and after therapy. Actual physical activity was also assessed. The model was tested with multiple regression analyses. RESULTS: The direction of change between pain and fatigue could not be determined. An increase in physical functioning and decrease in focusing on symptoms explained 4% to 14% of the change in pain. CONCLUSIONS: Pain and fatigue most probably decrease simultaneously during CBT. Pain reduction can partly be explained by a reduction of symptom focusing and increased physical functioning. Additional, yet unknown cognitive-behavioral factors also play a role in the reduction of pain. PMID- 25503596 TI - Measurement of Lumbar Spine Functional Movement in Low Back Pain. AB - OBJECTIVES: Individuals with low back pain (LBP) present with alterations or limitations of spinal mobility. The identification of simple clinical methods for evaluating functional movement of the spine is necessary to allow quantification of the degree of movement impairment and permit monitoring of patient improvement with rehabilitation. This study evaluated movement of the spine in 20 patients with chronic nonspecific LBP compared with 19 pain-free participants using a novel measurement device that permits the dynamic assessment of spinal movement in a rapid and subject-specific manner. METHODS: Two flexible sensor strips were fixed paravertebrally to the spine with each sensor strip measuring angles in 12 predetermined, adjacent, 25-mm-long segments. Maximum range of motion (ROM) and average angular velocity (AAV) of lumbar and pelvic movement were measured within identical angular and temporal frames during the descending and ascending phase of active lumbar flexion, extension, rotation, and lateral flexion following a standard choreography. Participants with LBP completed a number of questionnaires including the Tampa Scale of Kinesiophobia, Pain Catastrophizing Scale, and Spielberger State-Trait Anxiety Inventory. RESULTS: Across all movements, the individuals with LBP displayed 10% to 15% less ROM (P<0.05) and 15% to 30% less AAV (P<0.05) at both the pelvis and lumbar regions compared with controls. ROM as well as AAV, in most cases, were negatively correlated (R=-0.49 to -0.75) with the Tampa Scale of Kinesiophobia, Pain Catastrophizing Scale, and Spielberger State-Trait Anxiety Inventory in the LBP group (all P<0.05) especially during the initial descending phase of movement. DISCUSSION: This study provide support for the utility of this device for quantifying movement impairments in individuals with fairly low levels of LBP and general functional limitations. The results show that velocity measurements rather than ROM show the greatest differences in individuals with LBP compared with asymptomatic participants. Impaired lumbar and pelvis movement was correlated to the individuals with LBP's degree of anxiety, fear, and catastrophizing. PMID- 25503597 TI - Student Expectations of Peer and Teacher Reactions to Students With Chronic Pain: Implications for Improving Pain-related Functioning. AB - OBJECTIVES: Social interactions can influence the experience and impact of chronic pain. Children and adolescents expectations of how others respond to them could therefore influence their adjustment to pain. This study examined how children and adolescents expected their peers and teachers would react to classmates with chronic pain. METHODS: 211 school children participated in this study. We presented each participant 1 of 4 vignettes that described a boy or a girl who did or did not have chronic pain. Participants were then asked to describe how they think other children and their teachers would react to the child depicted in the vignette with respect to solicitous, discouraging, and coping responses. RESULTS: Discouraging responses from peers and teachers were viewed as being relatively unlikely. However, both coping and solicitous responses-the latter being a response known to be linked to increased pain and disability in children and adults-were viewed by the participating children as being relatively likely. Moreover, the expected likelihood of solicitous responses from teachers was thought to be even more probable for children and adolescents with chronic pain than for those without chronic pain. DISCUSSION: The results of this study have important practical implications, given the well known importance of significant other's responses to chronic pain problems. Further research is needed to understand how social interactions at school may influence functioning of children with chronic pain and their development. This information could provide an important empirical basis for determining how best to manage individuals with chronic pain problems in the school setting. PMID- 25503598 TI - Predictors of Response in Patients With Postherpetic Neuralgia and HIV-Associated Neuropathy Treated With the 8% Capsaicin Patch (Qutenza). AB - OBJECTIVES: Qutenza is a high-dose capsaicin patch used to relieve neuropathic pain from postherpetic neuralgia (PHN) and HIV-associated neuropathy (HIV-AN). In clinical studies, some patients had a dramatic response to the capsaicin patch. Our objective was to determine the baseline characteristics of patients who best benefit from capsaicin patch treatment. METHODS: We conducted a meta-analysis of 6 completed randomized and controlled Qutenza studies by pooling individual patient data. Sustained response was defined as>50% decrease in the mean pain intensity from baseline to weeks 2 to 12, and Complete Response as an average pain intensity score<=1 during weeks 2 to 12. Logistic regression was used to identify predictors of response and Complete Response, and subgroups of patients who respond best to the capsaicin patch. RESULTS: Baseline pain intensity score (BPIS)<=4 was a predictor of Sustained and Complete Response in PHN and HIV-AN patients; absence of allodynia and presence of hypoesthesia, and a McGill Pain Questionnaire (MPQ) sensory score <22 were predictors of Sustained Response in PHN patients; female sex was a predictor of Sustained and Complete Response in HIV-AN patients. Thus, characteristics associated with the highest chance of responding to the capsaicin patch were, for PHN, BPIS<=4, MPQ sensory score<=22, absence of allodynia, and presence of hypoesthesia; for HIV-AN, they were female sex and BPIS<=4. Patients with these characteristics had a statistically significantly greater chance of responding to the capsaicin patch than other patients. DISCUSSION: We identified subpopulations of PHN and HIV-AN patients likely to benefit from the capsaicin patch. PMID- 25503599 TI - Changes in coping, pain, and activity after cognitive-behavioral training: a randomized clinical trial for pediatric sickle cell disease using smartphones. AB - OBJECTIVES: We examined the outcomes of a cognitive-behavioral therapy (CBT) intervention for pain in pediatric sickle cell disease (SCD) using smartphones as a novel delivery method. MATERIALS AND METHODS: Forty-six children with SCD received CBT coping skills training using a randomized, waitlist control design. The intervention involved a single session of CBT training and home-based practice using smartphones for 8 weeks. Pre-post questionnaires between the randomized groups were used to evaluate changes in active psychological coping and negative thinking using the Coping Strategies Questionnaire. Daily diaries completed by the full sample during the treatment period were used to assess whether CBT skill use was related to reductions in next-day pain intensity and increases in same-day functional activity. RESULTS: The pre-post group comparison suggested that the youth increased active psychological coping attempts with the intervention. Daily diary data indicated that when children used CBT skills on days with higher pain, there were reductions in next-day pain intensity. There was no such association between skill use and functional activity. DISCUSSION: CBT coping skills training supported using smartphones can increase coping and reduce pain intensity for children with SCD; however, additions to the study protocols are recommended in future studies. Advantages and caveats of using smartphones are also discussed. PMID- 25503600 TI - Effectiveness and Safety of Transdermal Buprenorphine Versus Sustained-release Tramadol in Patients With Moderate to Severe Musculoskeletal Pain: An 8-Week, Randomized, Double-Blind, Double-Dummy, Multicenter, Active-controlled, Noninferiority Study. AB - OBJECTIVES: The aim of this noninferiority study was to investigate clinical effectiveness and safety of buprenorphine transdermal system (BTDS) in patients with moderate to severe musculoskeletal pain inadequately controlled with nonsteroidal anti-inflammatory drugs, compared with sustained-release tramadol tablets. MATERIALS AND METHODS: Eligible patients were randomized (1:1) to receive low-dose 7-day BTDS (5, 10, and 20 MUg/h, maximum dosage of 20 MUg/h) or sustained-release tramadol tablets (100 mg, maximum dosage of 400 mg/d) over an 8 week double-blind treatment period (3-week titration, 5-week maintenance). The primary endpoint was the difference in the visual analogue scale (VAS) pain scores from baseline to treatment completion. Noninferiority was assumed if the treatment difference on the VAS scale was within +/-1.5 cm, this threshold indicating a clinically meaningful result. ClinicalTrials.gov identifier: NCT01476774. RESULTS: Two hundred eighty patients were randomized to BTDS (n=141) or to tramadol (n=139). Both treatments were associated with a significant reduction in pain by the end of the treatment. The least squares mean difference of the change from baseline in VAS scores between the BTDS and tramadol groups were 0.45 (95% confidence interval, -0.02 to 0.91), which was within the +/-1.5 cm predefined threshold, indicating that the effectiveness of BTDS was not inferior to the effectiveness of sustained-release tramadol tablets. The incidence of adverse events was comparable between the 2 treatment groups. CONCLUSIONS: Our results suggest that BTDS is a good therapeutic option for patients experiencing chronic musculoskeletal pain of moderate to severe intensity that is insufficiently controlled by nonsteroidal anti-inflammatory drugs. PMID- 25503602 TI - Natural CMT2 variation is associated with genome-wide methylation changes and temperature seasonality. AB - As Arabidopsis thaliana has colonized a wide range of habitats across the world it is an attractive model for studying the genetic mechanisms underlying environmental adaptation. Here, we used public data from two collections of A. thaliana accessions to associate genetic variability at individual loci with differences in climates at the sampling sites. We use a novel method to screen the genome for plastic alleles that tolerate a broader climate range than the major allele. This approach reduces confounding with population structure and increases power compared to standard genome-wide association methods. Sixteen novel loci were found, including an association between Chromomethylase 2 (CMT2) and temperature seasonality where the genome-wide CHH methylation was different for the group of accessions carrying the plastic allele. Cmt2 mutants were shown to be more tolerant to heat-stress, suggesting genetic regulation of epigenetic modifications as a likely mechanism underlying natural adaptation to variable temperatures, potentially through differential allelic plasticity to temperature stress. PMID- 25503603 TI - Unconscious local motion alters global image speed. AB - Accurate motion perception of self and object speed is crucial for successful interaction in the world. The context in which we make such speed judgments has a profound effect on their accuracy. Misperceptions of motion speed caused by the context can have drastic consequences in real world situations, but they also reveal much about the underlying mechanisms of motion perception. Here we show that motion signals suppressed from awareness can warp simultaneous conscious speed perception. In Experiment 1, we measured global speed discrimination thresholds using an annulus of 8 local Gabor elements. We show that physically removing local elements from the array attenuated global speed discrimination. However, removing awareness of the local elements only had a small effect on speed discrimination. That is, unconscious local motion elements contributed to global conscious speed perception. In Experiment 2 we measured the global speed of the moving Gabor patterns, when half the elements moved at different speeds. We show that global speed averaging occurred regardless of whether local elements were removed from awareness, such that the speed of invisible elements continued to be averaged together with the visible elements to determine the global speed. These data suggest that contextual motion signals outside of awareness can both boost and affect our experience of motion speed, and suggest that such pooling of motion signals occurs before the conscious extraction of the surround motion speed. PMID- 25503604 TI - Incidental simultaneous finding of intravascular histiocytosis and reactive angioendotheliomatosis: a case report. AB - Reactive angioendotheliomatosis (RAE) is a rare cutaneous vascular disorder characterized by intravascular hyperplasia of endothelial cells, sometimes with a vascular proliferation. Intravascular histiocytosis (IH) is a similar vascular disorder characterized by the presence of dilated vessels containing aggregates of mononuclear histiocytes (macrophages) within their lumina. Although their pathogenesis remains uncertain, there has been speculation about the possible relationship between IH and RAE. We report a case of coexistence of RAE and IH in a patient who underwent a wide reexcision of a metastatic malignant melanoma. The excision specimen did not show any residual melanoma but exhibited an intravascular collection of CD-68-positive histiocytes admixed with CD-31 positive endothelial cells and fibrin surrounded by D2-40-positive vascular wall. The presence of intravascular cells initially raised concern of intravascular invasion by melanoma. As there was no clinical lesion and immunohistochemical stains for melanocytic makers were negative, we interpret this as an incidental finding. Knowledge of this benign vascular disorder is important because the histologic changes may be mistaken for intravascular invasion of a malignant neoplasm. PMID- 25503605 TI - Placebo and deception: a commentary. AB - In a recent article in this Journal, Shlomo Cohen and Haim Shapiro (2013) introduce the concept of "comparable placebo treatments" (CPTs)--placebo treatments with biological effects similar to the drugs they replace--and argue that doctors are not being deceptive when they prescribe or administer CPTs without revealing that they are placebos. We critique two of Cohen and Shapiro's primary arguments. First, Cohen and Shapiro argue that offering undisclosed placebos is not lying to the patient, but rather is making a self-fulfilling prophecy--telling a "lie" that, ideally, will become true. We argue that offering undisclosed placebos is not a "lie" but is a straightforward case of deceptively misleading the patient. Second, Cohen and Shapiro argue that offering undisclosed CPTs is not equivocation. We argue that it typically is equivocation or deception of another sort. If justifiable, undisclosed placebo use will have to be justified as a practice that is deceptive in most instances. PMID- 25503606 TI - A trifocal perspective on medicine as a moral enterprise: towards an authentic philosophy of medicine. AB - The fundamental claim that the practice of medicine is essentially a moral enterprise remains highly contentious, not least among the dominant traditional moral theories. The medical profession itself is today characterized by multicultural pluralism and moral relativism that have left the Hippocratic moral tradition largely in disarray. In this paper, I attempt to clarify the ambiguity about practicing medicine as a moral enterprise and echo Pellegrino's call for a phenomenologically and teleologically derived philosophy of medicine. I proffer a realistic trifocal matrix in which the virtuous moral agency and the teleologically derived moral imperative of the physician are comprehensively integrated with an action-guiding practical analytical framework for the resolution of ethical dilemmas in medicine. I argue that this trifocal perspective points us towards an authentic philosophy of medicine that is not only verifiable through Lonerganian self-appropriation, but also authentically objective through the possible moral self-transcendence of the good physician. PMID- 25503607 TI - Ravines and sugar pills: defending deceptive placebo use. AB - In this paper, I argue that deceptive placebo use can be morally permissible, on the grounds that the deception involved in the prescription of deceptive placebos can differ in kind to the sorts of deception that undermine personal autonomy. In order to argue this, I shall first delineate two accounts of why deception is inimical to autonomy. On these accounts, deception is understood to be inimical to the deceived agent's autonomy because it either involves subjugating the deceived agent's will to another's authority or because it precludes the agent from acting effectively in pursuit of their ends. I shall argue that providing an agent with false beliefs is not inimical to their autonomy if they are only able to effectively pursue their autonomously chosen ends by virtue of holding those particular false beliefs. Finally, I show that deceptive placebo use need only involve this latter sort of deception. PMID- 25503608 TI - A philosophical taxonomy of ethically significant moral distress. AB - Moral distress is one of the core topics of clinical ethics. Although there is a large and growing empirical literature on the psychological aspects of moral distress, scholars, and empirical investigators of moral distress have recently called for greater conceptual clarity. To meet this recognized need, we provide a philosophical taxonomy of the categories of what we call ethically significant moral distress: the judgment that one is not able, to differing degrees, to act on one's moral knowledge about what one ought to do. We begin by unpacking the philosophical components of Andrew Jameton's original formulation from his landmark 1984 work and identify two key respects in which that formulation remains unclear: the origins of moral knowledge and impediments to acting on that moral knowledge. We then selectively review subsequent literature that shows that there is more than one concept of moral distress and that explores the origin of the values implicated in moral distress and impediments to acting on those values. This review sets the stage for identifying the elements of a philosophical taxonomy of ethically significant moral distress. The taxonomy uses these elements to create six categories of ethically significant moral distress: challenges to, threats to, and violations of professional integrity; and challenges to, threats to, and violations of individual integrity. We close with suggestions about how the proposed philosophical taxonomy of ethically significant moral distress sheds light on the concepts of moral residue and crescendo effect of moral distress and how the proposed taxonomy might usefully guide prevention of and future qualitative and quantitative empirical research on ethically significant moral distress. PMID- 25503609 TI - Medical bribery and the ethics of trust: the Romanian case. AB - Medical bribery seems to be a global problem from Eastern Europe and the Balkans to China, a diffuse phenomenon, starting with morally acceptable gratitude and ending with institutional bribery. I focus my attention on Romania and analyze similar cases in Eastern European and postcommunist countries. Medical bribery can be regarded as a particular form of human transaction, a kind of primitive contract that occurs when people do not trust institutions or other forms of social contract that are meant to guarantee their rights and protect their interests. Concluding with strategies to fight medical bribery, I will underline better public policies for financing health and social care, and an ethic of trust that may help to restore trustworthiness of institutions and to rebuild interpersonal trust. This should be complemented by an educational program dedicated to understanding the negative consequences and mechanisms of corruption and the importance of ethical behavior. PMID- 25503611 TI - Effects of enzymatic degradation after loading in temporomandibular joint. AB - Synovial fluid of the joint decreases friction between the cartilage surfaces and reduces cartilage wear during articulation. Characteristic changes of synovial fluid have been shown in patients with osteoarthritis (OA) in the temporomandibular joint (TMJ). OA is generally considered to be induced by excessive mechanical stress. However, whether the changes in synovial fluid precede the mechanical overloading or vice versa remains unclear. In the present study, our purpose was to examine if the breakdown of joint lubrication affects the frictional properties of mandibular condylar cartilage and leads to subsequent degenerative changes in TMJ. We measured the frictional coefficient in porcine TMJ by a pendulum device after digestion with hyaluronidase (HAase) or trypsin. Gene expressions of interleukin-1beta (IL-1beta), cyclooxygenase-2 (COX 2), matrix metalloproteinases (MMPs), type II collagen, and histology were examined after prolonged cyclic loading by an active pendulum system. The results showed that the frictional coefficient increased significantly after HAase (35%) or trypsin (74%) treatment. Gene expression of IL-1beta, COX-2, and MMPs-1, -3, and -9 increased significantly in enzyme-treated TMJs after cyclic loading. The increase in the trypsin-treated group was greater than that in the HAase-treated group. Type II collagen expression was reduced in both enzyme-treated groups. Histology revealed surface fibrillation and increased MMP-1 in the trypsin treated group, as well as increased IL-1beta in both enzyme-treated groups after cyclic loading. The findings demonstrated that the compromised lubrication in TMJ is associated with altered frictional properties and surface wear of condylar cartilage, accompanied by release of pro-inflammatory and matrix degradation mediators under mechanical loading. PMID- 25503610 TI - Elevated serum 25(OH)-vitamin D levels are negatively correlated with molar incisor hypomineralization. AB - To date, the precise etiology of molar-incisor hypomineralization (MIH) is uncertain. Vitamin D plays a key role in hard tissue formation. Therefore, this study aimed to analyze the relationship between serum 25-hydroxy-vitamin D (25(OH)D) status and dental health data obtained from 1,048 children in a 10-year follow-up of the Munich GINIplus and LISAplus birth cohorts. The dental examination included the diagnosis of MIH and recording of (non-)cavitated caries lesions in primary and permanent teeth. Serum 25(OH)D concentrations were taken from blood samples of the 10-year investigation and measured with a fully automated, modular system. Different logistic regression and Poisson hurdle models were calculated. MIH was diagnosed in 13.6% of the study population. Approximately 16.4% of the children demonstrated caries-related defects (D3-4MFS > 0). The mean season-adjusted concentration of 25(OH)D was 75.8 nmol/l (standard deviation 22.0 nmol/l). After adjusting for sex, age, body mass index, parental education, equivalent income, and television/personal computer (TV/PC) viewing hours, a 10 nmol/l increase in serum 25(OH)D concentrations was significantly associated with a lower odds ratio of having MIH (OR = 0.89; P = 0.006). Furthermore, higher 25(OH)D values were associated with a lower number of caries affected permanent teeth. It is concluded that elevated serum 25(OH)D concentrations were associated with better dental health parameters. PMID- 25503612 TI - Prospective study of dental intervention for hematopoietic malignancy. AB - Various chemotherapeutic agents used in patients with hematopoietic malignancy cause serious side effects, including myelosuppression and immunosuppression. Immunosuppression makes patients more susceptible to infection, resulting in an increased risk of infectious complications, including the development of severe septicemia that may be life-threatening. It is necessary for dental staff to be familiar with an appropriate protocol in such cases and to share information about the chemotherapy with a hematologist. To verify the effectiveness of our dental intervention protocol, we conducted a prospective study on the incidence of complications for each myelosuppressive grade of chemotherapy in patients with hematopoietic malignancy. We compared the incidence of complications between treatment P (patients who finished all the dental treatments according to the protocol) and treatment Q (patients who did not) per grade (A, B, C, D) and incidence of systemic or oral findings. We also compared the incidence of oral complication related to the residual teeth between first chemo (patients who were undergoing chemotherapy for the first time) and prior chemo (not the first time). There were significant differences in inflammatory complications between treatment P and treatment Q. We found that both systemic and oral inflammatory complications increased with higher-grade myelosuppressive chemotherapy. Additionally, there was a significant difference between the incidence of oral complications related to the residual teeth between first chemo and prior chemo. Complete implementation of the dental intervention protocol was associated with fewer oral and systemic infectious and inflammatory complications in patients with hematopoietic malignancies undergoing chemotherapy. The incidence of oral and systemic complications also increased with grade of chemotherapy. These results support the validity of our dental intervention protocol. We should pay close attention to the oral state of de novo hematopoietic malignancy patients. PMID- 25503615 TI - Effects of neonatal fluoxetine exposure on behavior across development in rats selectively bred for an infantile affective trait. AB - Infants born to women with depressive symptoms are at higher risk for insecure attachment and behavioral problems. Thus current medical practice is to continue psychotropic medication of pregnant women with depression despite concerns about its behavioral teratology. There are few animal studies focused on long-term behavioral effects of prenatal antidepressant exposure; in addition, studies have not looked at individual differences in baseline affective state as a source of response variability. In this study, fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was administered to male and female rat pups from postnatal days 2-7 to model exposure to antidepressants in the human third trimester. Four behavioral measures were conducted from the neonatal to adult age periods in Low and High lines selectively bred for their rate of ultrasonic vocalizations after brief maternal separation. Neonatal fluoxetine administration decreased distress calls in both lines, but to a greater extent in High line rats than Low line. Neonatal fluoxetine also impaired motor coordination in neonates. Neonatal fluoxetine administration decreased social behavior in both juvenile and adult subjects. Fluoxetine-related reductions in anxiety behavior were not observed at the two older ages. As expected, High line subjects displayed more anxiety behavior than Low line subjects at all three test ages. These results suggest that there are may be significant behavioral consequences of antidepressant use during late pregnancy on offspring maternal attachment and social behavior, with implications for increased risk of autism spectrum disorders. PMID- 25503613 TI - Detecting and treating occlusal caries lesions: a cost-effectiveness analysis. AB - The health gains and costs resulting from using different caries detection strategies might not only depend on the accuracy of the used method but also the treatment emanating from its use in different populations. We compared combinations of visual-tactile, radiographic, or laser-fluorescence-based detection methods with 1 of 3 treatments (non-, micro-, and invasive treatment) initiated at different cutoffs (treating all or only dentinal lesions) in populations with low or high caries prevalence. A Markov model was constructed to follow an occlusal surface in a permanent molar in an initially 12-y-old male German patient over his lifetime. Prevalence data and transition probabilities were extracted from the literature, while validity parameters of different methods were synthesized or obtained from systematic reviews. Microsimulations were performed to analyze the model, assuming a German health care setting and a mixed public-private payer perspective. Radiographic and fluorescence-based methods led to more overtreatments, especially in populations with low prevalence. For the latter, combining visual-tactile or radiographic detection with microinvasive treatment retained teeth longest (mean 66 y) at lowest costs (329 and 332 Euro, respectively), while combining radiographic or fluorescence based detections with invasive treatment was the least cost-effective (<60 y, >700 Euro). In populations with high prevalence, combining radiographic detection with microinvasive treatment was most cost-effective (63 y, 528 Euro), while sensitive detection methods combined with invasive treatments were again the least cost-effective (<59 y, >690 Euro). The suitability of detection methods differed significantly between populations, and the cost-effectiveness was greatly influenced by the treatment initiated after lesion detection. The accuracy of a detection method relative to a "gold standard" did not automatically convey into better health or reduced costs. Detection methods should be evaluated not only against their criterion validity but also the long term effects resulting from their use in different populations. PMID- 25503618 TI - Who's responsible to refer for epilepsy surgery? We all are! PMID- 25503617 TI - Oxytocin for frontotemporal dementia: a randomized dose-finding study of safety and tolerability. AB - OBJECTIVE: To determine the safety and tolerability of 3 doses of intranasal oxytocin (Syntocinon; Novartis, Bern, Switzerland) administered to patients with frontotemporal dementia (FTD). METHODS: We conducted a randomized, parallel group, double-blind, placebo-controlled study using a dose-escalation design to test 3 clinically feasible doses of intranasal oxytocin (24, 48, or 72 IU) administered twice daily for 1 week to 23 patients with behavioral variant FTD or semantic dementia (clinicaltrials.gov registration number NCT01386333). Primary outcome measures were safety and tolerability at each dose. Secondary measures explored efficacy across the combined oxytocin vs placebo groups and examined potential dose-related effects. RESULTS: All 3 doses of intranasal oxytocin were safe and well tolerated. CONCLUSIONS: A multicenter trial is warranted to determine the therapeutic efficacy of long-term intranasal oxytocin for behavioral symptoms in FTD. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with FTD, intranasal oxytocin is not significantly associated with adverse events or significant changes in the overall neuropsychiatric inventory. PMID- 25503616 TI - Absence of neurocognitive effect of hepatitis C infection in HIV-coinfected people. AB - OBJECTIVE: To investigate the effect of hepatitis C virus (HCV) on neurocognitive performance in chronically HIV-infected patients enrolled in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study. METHODS: A total of 1,582 participants in CHARTER who were tested for HCV antibody underwent neurocognitive testing; serum HCV RNA was available for 346 seropositive patients. Neurocognitive performance was compared in 408 HCV-seropositive and 1,174 HCV-seronegative participants and in a subset of 160 seropositive and 707 seronegative participants without serious comorbid neurologic conditions that might impair neurocognitive performance, using linear regression and taking into account HIV-associated and demographic factors (including IV drug use) and liver function. RESULTS: Neurocognitive performance characterized by global deficit scores and the proportion of individuals who were impaired were the same in the HCV-seropositive and HCV-seronegative groups. In univariable analyses in the entire sample, only verbal domain scores showed small statistically different superior performance in the HCV+ group that was not evident in multivariable analysis. In the subgroup without significant comorbidities, scores in all 7 domains of neurocognitive functioning did not differ by HCV serostatus. Among the HCV-seropositive participants, there was no association between neurocognitive performance and serum HCV RNA concentration. CONCLUSION: In HIV-infected patients, HCV coinfection does not contribute to neurocognitive impairment, at least in the absence of substantial HCV-associated liver damage, which was not evident in our cohort. PMID- 25503619 TI - AQP4 in biopsied demyelinating lesions as a diagnostic clue to NMOSD and MS: final answer? PMID- 25503620 TI - Brain white matter volume abnormalities in Lesch-Nyhan disease and its variants. AB - OBJECTIVE: We sought to examine brain white matter abnormalities based on MRI in adults with Lesch-Nyhan disease (LND) or an attenuated variant (LNV) of this rare, X-linked neurodevelopmental disorder of purine metabolism. METHODS: In this observational study, we compared 21 adults with LND, 17 with LNV, and 33 age-, sex-, and race-matched healthy controls using voxel-based morphometry and analysis of covariance to identify white matter volume abnormalities in both patient groups. RESULTS: Patients with classic LND showed larger reductions of white (26%) than gray (17%) matter volume relative to healthy controls. Those with LNV showed comparable reductions of white (14%) and gray (15%) matter volume. Both patient groups demonstrated reduced volume in medial inferior white matter regions. Compared with LNV, the LND group showed larger reductions in inferior frontal white matter adjoining limbic and temporal regions and the motor cortex. These regions likely include such long association fibers as the superior longitudinal and uncinate fasciculi. CONCLUSIONS: Despite earlier reports that LND primarily involves the basal ganglia, this study reveals substantial white matter volume abnormalities. Moreover, white matter deficits are more severe than gray matter deficits in classic LND, and also characterize persons with LNV. The brain images acquired for these analyses cannot precisely localize white matter abnormalities or determine whether they involve changes in tract orientation or anisotropy. However, clusters of reduced white matter volume identified here affect regions that are consistent with the neurobehavioral phenotype. PMID- 25503622 TI - Is there a higher risk of neuropsychological impairment in HIV-HCV coinfected patients? PMID- 25503621 TI - Diagnostic utility of aquaporin-4 in the analysis of active demyelinating lesions. AB - OBJECTIVE: To assess, in a surgical biopsy cohort of active demyelinating lesions, the diagnostic utility of aquaporin-4 (AQP4) immunohistochemistry in identifying neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD) and describe pathologic features that should prompt AQP4 immunohistochemical analysis and AQP4-immunoglobulin G (IgG) serologic testing. METHODS: This was a neuropathologic cohort study of 20 surgical biopsies (19 patients; 11 cord/9 brain), performed because of diagnostic uncertainty, interpreted as active demyelinating disease and containing 2 or more of the following additional features: tissue vacuolation, granulocytic infiltrates, or astrocyte injury. RESULTS: AQP4 immunoreactivity was lost in 18 biopsies and increased in 2. Immunopathologic features of the AQP4 loss cohort were myelin vacuolation (18), dystrophic astrocytes and granulocytes (17), vascular hyalinization (16), macrophages containing glial fibrillary acid protein (GFAP)-positive debris (14), and Creutzfeldt-Peters cells (0). All 14 cases with available serum tested positive for AQP4-IgG after biopsy. Diagnosis at last follow-up was NMO/NMOSD (15) and longitudinally extensive transverse myelitis (1 each relapsing and single). Immunopathologic features of the AQP4 increased cohort were macrophages containing GFAP-positive debris and granulocytes (2), myelin vacuolation (1), dystrophic astrocytes (1), Creutzfeldt-Peters cells (1), and vascular hyalinization (1). Diagnosis at last follow-up was multiple sclerosis (MS) and both tested AQP4-IgG seronegative after biopsy. CONCLUSIONS: AQP4 immunohistochemistry with subsequent AQP4-IgG testing has diagnostic utility in identifying cases of NMO/NMOSD. This study highlights the importance of considering NMOSD in the differential diagnosis of tumefactive brain or spinal cord lesions. AQP4-IgG testing may avert biopsy and avoid ineffective therapies if these patients are erroneously treated for MS. PMID- 25503623 TI - Reduced trigeminovascular cyclicity in patients with menstrually related migraine. AB - OBJECTIVE: A case-control study to investigate the effect of the menstrual cycle on trigeminal nerve-induced vasodilation in healthy women and patients with menstrually related migraine (MRM). METHODS: Using a laser-Doppler imager, we compared the vasodilator effects of capsaicin application and electrical stimulation (ES) on the forehead skin, a trigeminal nerve-innervated dermatome, in premenopausal patients with MRM (n = 22), healthy controls (n = 20), and postmenopausal women without migraine (n = 22). Blood samples were collected for female sex hormone measurements. RESULTS: Dermal blood flow (DBF) responses to capsaicin were higher in controls during days 1-2 than during days 19-21 of their menstruation cycle (mean Emax +/- SEM: 203 +/- 28 AU vs 156 +/- 27 AU [p = 0.031] for 0.06 mg/mL capsaicin and 497 +/- 25 AU vs 456 +/- 24 AU [p = 0.009] for 6.0 mg/mL capsaicin). In contrast, patients with MRM demonstrated DBF responses without significant cycle-dependent variability (days 1-2 vs days 19-21: Emax 148 +/- 20 AU vs 154 +/- 20 AU [p = 0.788] for 0.06 mg/mL capsaicin and 470 +/- 17 AU vs 465 +/- 20 AU [p = 0.679] for 6.0 mg/mL capsaicin). DBF responses to ES were not different between either patients with MRM or controls, at either occasion. Estradiol levels on days 19-21 of the menstrual cycle were higher in healthy controls (mean +/- SEM: 75 +/- 8 pg/mL) than in patients with MRM (52 +/- 4 pg/mL, p = 0.014). In postmenopausal women, DBF responses to capsaicin and ES, as well as estradiol levels at both visits, were all significantly reduced compared to patients with MRM and controls (in all cases, p < 0.05). CONCLUSIONS: Our study provides evidence for a reduced menstrual cyclicity of both estradiol levels and the trigeminovascular vasodilator system in patients with MRM. PMID- 25503624 TI - Neurologists' knowledge of and attitudes toward epilepsy surgery: a national survey. AB - OBJECTIVES: In the current study, we aim to assess potential neurologist-related barriers to epilepsy surgery among Canadian neurologists. METHODS: A 29-item, pilot-tested questionnaire was mailed to all neurologists registered to practice in Canada. Survey items included the following: (1) type of medical practice, (2) perceptions of surgical risks and benefits, (3) knowledge of existing practice guidelines, and (4) barriers to surgery for patients with epilepsy. Neurologists who did not complete the questionnaire after the initial mailing were contacted a second time by e-mail, fax, or telephone. After this reminder, the survey was mailed a second time to any remaining nonresponders. RESULTS: In total, 425 of 796 neurologists returned the questionnaire (response rate 53.5%). Respondents included 327 neurologists who followed patients with epilepsy in their practice. More than half (56.6%) of neurologists required patients to be drug-resistant and to have at least one seizure per year before considering surgery, and nearly half (48.6%) failed to correctly define drug-resistant epilepsy. More than 75% of neurologists identified inadequate health care resources as the greatest barrier to surgery for patients with epilepsy. CONCLUSIONS: A substantial proportion of Canadian neurologists are unaware of recommended standards of practice for epilepsy surgery. Access also appears to be a significant barrier to epilepsy surgery and surgical evaluation. As a result, we are concerned that patients with epilepsy are receiving inadequate care. A greater emphasis must be placed on knowledge dissemination and ensuring that the infrastructure and personnel are in place to allow patients to have timely access to this evidence-based treatment. PMID- 25503625 TI - Double-blind, randomized, controlled, crossover trial of pregabalin for neurogenic claudication. AB - OBJECTIVES: To test the effects of pregabalin on the induction of neurogenic claudication. METHODS: This study was a randomized, double-blind, active placebo controlled, 2-period, crossover trial. Twenty-nine subjects were randomized to receive pregabalin followed by active placebo (i.e., diphenhydramine) or active placebo followed by pregabalin. Each treatment period lasted 10 days, including a 2-step titration. Periods were separated by a 10-day washout period, including a 3-day taper phase after the first period. The primary outcome variable was the time to first moderate pain symptom (Numeric Rating Scale score >=4) during a 15 minute treadmill test (Tfirst). Secondary outcome measures included pain intensity at rest, pain intensity at the end of the treadmill test, distance walked, and validated self-report measures of pain and functional limitation including the Roland-Morris Disability Questionnaire, modified Brief Pain Inventory-Short Form, Oswestry Disability Index, and Swiss Spinal Stenosis Questionnaire. RESULTS: No significant difference was found between pregabalin and active placebo for the time to first moderate pain symptom (difference in median Tfirst = -1.08 [95% confidence interval -2.25 to 0.08], p = 0.61). In addition, none of the secondary outcome measures of pain or functional limitation were significantly improved by pregabalin compared with active placebo. CONCLUSIONS: Pregabalin was not more effective than active placebo in reducing painful symptoms or functional limitations in patients with neurogenic claudication associated with lumbar spinal stenosis. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with neurogenic claudication, compared with diphenhydramine, pregabalin does not increase the time to moderate pain during a treadmill test. PMID- 25503628 TI - Dementia and Prescribed Dis-engagement. PMID- 25503627 TI - Effects of a randomized intervention to improve workplace social capital in community health centers in China. AB - OBJECTIVE: To examine whether workplace social capital improved after implementing a workplace social capital intervention in community health centers in China. METHODS: This study was conducted in 20 community health centers of similar size in Jinan of China during 2012-2013. Using the stratified site randomization, 10 centers were randomized into the intervention group; one center was excluded due to leadership change in final analyses. The baseline survey including 447 staff (response rate: 93.1%) was conducted in 2012, and followed by a six-month workplace social capital intervention, including team building courses for directors of community health centers, voluntarily public services, group psychological consultation, and outdoor training. The follow-up survey in July 2013 was responded to by 390 staff members (response rate: 86.9%). Workplace social capital was assessed with the translated and culturally adapted scale, divided into vertical and horizontal dimensions. The facility-level intervention effects were based on all baseline (n = 427) and follow-up (n = 377) respondents, except for Weibei respondents. We conducted a bivariate Difference-in-Difference analysis to estimate the facility-level intervention effects. RESULTS: No statistically significant intervention effects were observed at the center level; the intervention increased the facility-level workplace social capital, and its horizontal and vertical dimensions by 1.0 (p = 0.24), 0.4 (p = 0.46) and 0.8 (p = 0.16), respectively. CONCLUSIONS: The comprehensive intervention seemed to slightly improve workplace social capital in community health centers of urban China at the center level. High attrition rate limits any causal interpretation of the results. Further studies are warranted to test these findings. PMID- 25503626 TI - Associations of brain lesions at autopsy with polysomnography features before death. AB - OBJECTIVE: To determine how sleep-disordered breathing, nocturnal hypoxia, and changes in sleep architecture in the elderly may be related to the development of the neuropathologic correlates of dementia. METHODS: The Honolulu-Asia Aging Study is a prospective cohort study of Japanese American men in Honolulu, HI. We examined brain lesions at autopsy (Braak stage, neurofibrillary tangle and neuritic plaque counts, microinfarcts, generalized brain atrophy, lacunar infarcts, Lewy bodies [LBs], neuronal loss and gliosis in the locus ceruleus) in 167 participants who underwent polysomnography in 1999-2000 (mean age, 84 years) and died through 2010 (mean 6.4 years to death). Polysomnography measures included the apnea-hypopnea index, duration of apnea or hypopnea, duration of hypoxemia, minimum oxygen saturation (SpO2), duration of slow-wave sleep (SWS, non-REM stage N3), and arousals. RESULTS: Sleep duration with SpO2 <95% was associated with higher levels of microinfarcts (adjusted odds ratio [OR] 3.88, 95% confidence interval [CI] 1.10-13.76, comparing the highest to lowest quartiles of %sleep with SpO2 <95%). Greater SWS duration was associated with less generalized atrophy (adjusted OR 0.32, 95% CI 0.10-1.03, comparing highest to lowest quartiles of %sleep in SWS). LBs were less common with greater %sleep with SpO2 <95% (adjusted OR 0.17, 95% CI 0.04-0.78, comparing highest to lowest quartiles). Higher minimum SpO2 during REM sleep was associated with less gliosis and neuronal loss in the locus ceruleus. Cognitive scores declined less among men with greater SWS duration. CONCLUSIONS: The findings support a role for lower nocturnal oxygenation and SWS in the development of microinfarcts and brain atrophy, but not Alzheimer lesions or LBs. PMID- 25503635 TI - Eggshell membrane ameliorates hepatic fibrogenesis in human C3A cells and rats through changes in PPARgamma-Endothelin 1 signaling. AB - Our previous nutrigenomic findings indicate that eggshell membrane (ESM) may prevent liver fibrosis. Here we investigated the effects and mechanisms underlying ESM intervention against liver injury by using DNA microarray analysis and comparative proteomics. In vitro hydrolyzed ESM attenuated the TGFbeta1 induced procollagen production of human hepatocyte C3A cells and inhibited the expression of Endothelin 1 (EDN1) and its two receptors, and extracellular matrix components. In vivo male Wistar rats were allocated into a normal control group, a CCl4 group (hypodermic injection of 50% CCl4 2*/wk) and an ESM group (20 g ESM/kg diet with CCl4 injection) for 7 wks. Dietary ESM ameliorated the elevated activity of ALT/AST, oxidative stress and collagen accumulation in liver, accompanied by the down-regulated expression of Edn1 signaling and notable profibrogenic genes and growth factors as well as peroxisome proliferator activated receptor gamma (PPARgamma). Concomitantly, the decreased expressions of Galectin-1 and Desmin protein in the ESM group indicated the deactivation of hepatic stellate cells (HSCs). Through a multifaceted integrated omics approach, we have demonstrated that ESM can exert an antifibrotic effect by suppressing oxidative stress and promoting collagen degradation by inhibiting HSCs' transformation, potentially via a novel modulation of the PPARgamma-Endothelin 1 interaction signaling pathway. PMID- 25503634 TI - Innate endogenous adjuvants prime to desirable immune responses via mucosal routes. AB - Vaccination is an effective strategy to prevent infectious or immune related diseases, which has made remarkable contribution in human history. Recently increasing attentions have been paid to mucosal vaccination due to its multiple advantages over conventional ways. Subunit or peptide antigens are more reasonable immunogens for mucosal vaccination than live or attenuated pathogens, however adjuvants are required to augment the immune responses. Many mucosal adjuvants have been developed to prime desirable immune responses to different etiologies. Compared with pathogen derived adjuvants, innate endogenous molecules incorporated into mucosal vaccines demonstrate prominent adjuvanticity and safety. Nowadays, cytokines are broadly used as mucosal adjuvants for participation of signal transduction of immune responses, activation of innate immunity and polarization of adaptive immunity. Desired immune responses are promptly and efficaciously primed on basis of specific interactions between cytokines and corresponding receptors. In addition, some other innate molecules are also identified as potent mucosal adjuvants. This review focuses on innate endogenous mucosal adjuvants, hoping to shed light on the development of mucosal vaccines. PMID- 25503636 TI - NT-proBNP linking low-moderately impaired renal function and cardiovascular mortality in diabetic patients: the population-based Casale Monferrato Study. AB - BACKGROUND: Few data are available to assess whether a low-moderate reduction in estimated glomerular filtration rates (eGFR) has a role per se on cardiovascular (CV) mortality or other biomarkers such as NT-proBNP allow to explain such association. METHODS AND FINDINGS: In a prospective study including 1,645 type 2 diabetic subjects of the population-based Casale Monferrato Study, who had no clinical evidence of heart failure and eGFR >45 ml/min/1.73 m2, we examined 6 years CV mortality. Multivariate Cox proportional hazards modeling were used to estimate the effect of NT-proBNP on the association between eGFR and mortality, independently of baseline CV risk factors, albumin excretion rate (AER) and C reactive protein (CRP). During follow-up, 327 people died (149 of CV diseases) out of 8334.5 person-years. Compared to eGFR>=90 ml/min/1.73 m2, values of 60-89 and 45-59 ml/min/1.73 m2 conferred a fully adjusted hazard ratios (HRs) of CV mortality of 1.74 (1.08-2.82) and 1.95 (1.03-3.68), respectively. After further adjustment for NT-proBNP, however, HRs were no longer significant (HRs 1.42, 0.83 2.42 and 1.22, 0.59-2.51). In this model, HR for logNT-proBNP was 1.84 (1.52 2.22). Adding NT-proBNP to the model improved the C-statistic of CV mortality from 0.79 (0.76-0.83) to 0.84 (0.81-0.87), yielded an IDI of 0.03 (p = 0.02), and a NRI of 0.44 (p = 0.016). CONCLUSIONS: In diabetic people a modest reduction in renal function increased 6-year CV mortality independently of albuminuria. This association, however, was mainly explained by the effect of NT-proBNP, that remained the strongest prognostic marker for a worse CV outcome, even after adjustment for other CV risk factors and pre-existing CVD. PMID- 25503637 TI - Beneficial Effects of AMP-Activated Protein Kinase Agonists in Kidney Ischemia Reperfusion: Autophagy and Cellular Stress Markers. AB - Background: Kidney ischemia-reperfusion is a form of acute kidney injury resulting in a cascade of cellular events prompting rapid cellular damage and suppression of kidney function. A cellular response to ischemic stress is the activation of AMP-activated protein kinase (AMPK), where AMPK induces a number of homeostatic and renoprotective mechanisms, including autophagy. However, whether autophagy is beneficial or detrimental in ischemia-reperfusion remains controversial. We investigated the effects of agonist induction of AMPK activity on autophagy and cell stress proteins in the model of kidney ischemia reperfusion. Methods: AMPK agonists, AICAR (0.1 g/kg) and metformin (0.3 g/kg), were administered 24 h prior to ischemia, with kidneys harvested at 24 h of reperfusion. Results: We observed a paradoxical decrease in AMPK activity accompanied by increases in mammalian target of rapamycin (mTOR) C1 activity and p62/SQSTM1 expression. These results led us to propose that AMPK and autophagy are insufficient to properly counter the cellular insults in ischemia reperfusion. Agonist induction of AMPK activity with AICAR or metformin increased macroautophagy protein LC3 and normalized p62/SQSTM1 expression and mTOR activity. Ischemia-reperfusion increases in Beclin-1 and PINK1 expressions, consistent with increased mitophagy, were also mitigated with AMPK agonists. Stress-responsive and apoptotic marker expressions increase in ischemia reperfusion and are significantly attenuated with agonist administration, as are early indicators of fibrosis. Conclusions: Our data suggest that levels of renoprotective AMPK activity and canonical autophagy are insufficient to maintain cellular homeostasis, contributing to the progression of ischemia-reperfusion injury. We further demonstrate that induction of AMPK activity can provide beneficial cellular effects in containing injury in ischemia-reperfusion. (c) 2014 S. Karger AG, Basel. PMID- 25503638 TI - Sinonasal Tract Neurofibroma: A Clinicopathologic Series of 12 Cases with a Review of the Literature. AB - Neurofibroma (NF), a benign peripheral nerve sheath tumor, is very uncommon in the sinonasal tract, with only a few reported cases in the English literature. Cases within the files of the authors' institutions confined to the sinonasal tract were compared to cases reported in the English literature (Medline 1966 2014). The 12 patients included 6 females and 6 males, aged 26-75 years (mean 46.2 years). The patients usually presented clinically with a mass lesion (n = 11), obstruction (n = 4) or pain (n = 3), with an average symptom duration of 42.9 months. Two patients had neurofibromatosis (NF1). Tumors involved the nasal cavity alone (n = 8), maxillary sinus alone (n = 2), or mixed sites (n = 2), with a range of 0.4-4.1 cm (mean 2.2 cm). The tumors were circumscribed, composed of spindled to wavy cells with curvilinear nuclei set in a background of collagenized stroma and mast cells. Nuclear palisading and perivascular hyalinization were not seen. Mitoses were scant. Pleomorphism, necrosis and increased cellularity were absent. By immunohistochemistry, the lesional cells were S100 protein, SOX10 and NFP positive, while CD34 highlighted the perineurium. INI1 was intact, with strong nuclear expression in all cases. All patients had surgical excision without recurrence (mean follow-up 8.6 years). The principle differential diagnoses include schwannoma, perineurioma, fibromatosis, and solitary fibrous tumor. NF of the sinonasal tract occurs in middle-aged patients without a gender predilection, usually with non-specific symptoms present for a long duration. Tumors are relatively large (mean 2.2), and usually affect one site only. Surgery is curative, with only 16.7 % NF1 associated. S100 protein, SOX10 and NFP highlight the Schwann cells, with CD34 highlighting the perineural fibroblasts. PMID- 25503640 TI - Quantified power Doppler as a predictor of delayed graft function after renal transplantation. AB - PURPOSE: No safe ultrasound (US) parameters have been established to differentiate the causes of graft dysfunction. OBJECTIVES: To define US parameters and identify the predictors of normal graft evolution, delayed graft function (DGF), and rejection at the early period after kidney transplantation. METHODS: Between June 2012 and August 2013, 79 renal transplant recipients underwent US examination 1-3 days posttransplantation. Resistive index (RI), power Doppler (PD), and RI + PD (quantified PD) were assessed. Patients were allocated into three groups: normal graft evolution, DGF, and rejection. RESULTS: Resistive index of upper and middle segments and PD were higher in the DGF group than in the normal group. ROC curve analysis revealed that RI + PD was the index that best correlated with DGF (cutoff = 0.84). In the high RI + PD group, time to renal function recovery (6.33 +/- 6.5 days) and number of dialysis sessions (2.81 +/- 2.8) were greater than in the low RI + PD group (2.11 +/- 5.3 days and 0.69 +/- 1.5 sessions, respectively), p = 0.0001. Multivariate analysis showed that high donor final creatinine with a relative risk (RR) of 19.7 (2.01-184.7, p = 0.009) and older donor age (RR = 1.17 (1.04-1.32), p = 0.007) correlated with risk DGF. CONCLUSIONS: Quantified PD (RI + PD) was the best DGF predictor. PD quantification has not been previously reported. PMID- 25503642 TI - Crystallization of hollow mesoporous silica nanoparticles. AB - Complex 3D macrostructured nanoparticles are transformed from amorphous silica into pure polycrystalline alpha-quartz using catalytic quantities of alkaline earth metals as devitrifying agent. Walls as thin as 10 nm could be crystallized without losing the architecture of the particles. The roles of cation size and the mol% of the incorporated devitrifying agent in crystallization behavior are studied, with Mg(2+), Ca(2+), Sr(2+) and Ba(2+) all producing pure alpha-quartz under certain conditions. PMID- 25503639 TI - A negative feedback modulator of antigen processing evolved from a frameshift in the cowpox virus genome. AB - Coevolution of viruses and their hosts represents a dynamic molecular battle between the immune system and viral factors that mediate immune evasion. After the abandonment of smallpox vaccination, cowpox virus infections are an emerging zoonotic health threat, especially for immunocompromised patients. Here we delineate the mechanistic basis of how cowpox viral CPXV012 interferes with MHC class I antigen processing. This type II membrane protein inhibits the coreTAP complex at the step after peptide binding and peptide-induced conformational change, in blocking ATP binding and hydrolysis. Distinct from other immune evasion mechanisms, TAP inhibition is mediated by a short ER-lumenal fragment of CPXV012, which results from a frameshift in the cowpox virus genome. Tethered to the ER membrane, this fragment mimics a high ER-lumenal peptide concentration, thus provoking a trans-inhibition of antigen translocation as supply for MHC I loading. These findings illuminate the evolution of viral immune modulators and the basis of a fine-balanced regulation of antigen processing. PMID- 25503643 TI - Specific activation of operculum 3 (OP3) brain region during provoked tinnitus related phantom auditory perceptions in humans. AB - The phantom sound perception mechanism by which a sound perception occurs without any external sound source is still enigmatic. According to our previous fMRI study, a small region in the parietal operculum 3 was hyperactivated as a function of tinnitus periodicity in subjects with acoustic trauma tinnitus sequelae. This region was localized in the vicinity of neural correlates of middle-ear tympano-ossicular chain movements due to pressure variations. Disturbed proprioceptors are known to trigger illusory perceptions; therefore, we hypothesized that a disturbance of middle-ear proprioceptors may originate phantom sound perceptions. We designed an fMRI study that aimed to stimulate middle-ear proprioceptors by repetitive vibrations using various rates of click trains. In this study, we report that exposure to specific rates of stimuli for a few minutes at comfortable intensity level in healthy subjects distinctly triggered transient tinnitus-like aftereffects. The fMRI neural correlates of the aftereffects were unequivocally localized in the same parietal region as in acoustic trauma tinnitus sufferers. Our results strongly suggest that a middle ear kinesthetic/proprioceptive illusion exists at the origin of acoustic trauma tinnitus via a somatosensory pathway encompassing the trigeminal system. PMID- 25503644 TI - Ganglioside GM3 exerts opposite effects on motility via epidermal growth factor receptor and hepatocyte growth factor receptor-mediated migration signaling. AB - The ganglioside GM3 exerts its different effects via various growth factor receptors. The present study investigated and comparatively analyzed the opposing effects exerted by GM3 on the migration of mouse hepatocellular carcinoma Hepa1-6 cells via epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (HGFR/cMet). The results demonstrated that GM3 inhibited EGF-stimulated motility, but promoted HGF-stimulated motility of the Hepa1-6 cells via phosphatidylinositol 3-kinase/Akt-mediated migration signaling. It is well established that the main cytokines modulating cell proliferation, invasion and metastasis are different in different types of tumor. This difference may, at least in part, explain why GM3 exerted its actions in a tumor-type specific manner. PMID- 25503645 TI - Identification of benzenesulfonamide quinoline derivatives as potent HIV-1 replication inhibitors targeting Rev protein. AB - Human immunodeficiency virus type 1 (HIV-1) Rev protein facilitates the export of viral RNA from nucleus to cytoplasm, which is a key step in HIV-1 pathogenesis and transmission. In this study, we have screened a commercial library and identified the hit compound 1 bearing a benzenesulfonamide quinoline scaffold that inhibited Rev activity and HIV-1 infectivity. Compounds bearing this scaffold were synthesized and their SAR was studied. We identified compound 20 with low toxicity and potent activity to inhibit HIV-1 replication by affecting Rev function. PMID- 25503646 TI - Knowledge of different medical and dental professional groups in Switzerland about halitosis. AB - Although halitosis is a widespread condition, it is still seen as too personal or embarrassing to talk about. The cause of real halitosis can be intraoral or extraoral. In order to determine the level of knowledge of health care providers in Switzerland, a survey was conducted over a period of three years in which 150 family physicians, 150 ear, nose and throat specialists, 154 dentists and 151 dental hygienists were personally interviewed. The survey shows that only 46.7% of the dentists and only 47.0% of the dental hygienists are consulted by patients for their halitosis, whereas 58.0% of the family physicians and 50.7% of the ENT specialists reported treating 1-10 patients for halitosis per year, while 46.7% of the ENT doctors even reported treating 11-100 patients for halitosis per year. 81.5% of all interviewed doctors and dental hygienists were of the opinion that halitosis mainly originates intraorally. 76.0% of the dentists and 72.8% of the dental hygienists as well as 33.3% of the family physicians recommend periodontitis therapy as halitosis treatment. This proves that a large percentage of medical professionals thinks that marginal periodontitis is the most common cause of halitosis. This study also shows that patients seek first consultations with dentists and dental hygienists less often than with family physicians and ENT specialists, despite the fact that the cause of halitosis is primarily intraoral. PMID- 25503647 TI - Arsenate stimulates glutathione export from viable cultured rat cerebellar granule neurons. AB - Arsenate is an environmental pollutant which contaminates the drinking water of millions of people worldwide. Numerous in vitro studies have investigated the toxicity of arsenate for a large number of different cell types. However, despite the known neurotoxic potential of arsenicals, little is known so far about the consequences of an exposure of neurons to arsenate. To investigate acute effects of arsenate on the viability and the glutathione (GSH) metabolism of neurons, we have exposed primary rat cerebellar granule neuron cultures to arsenate. Incubation of neurons for up to 6 h with arsenate in concentrations of up to 10 mM did not acutely compromise the cell viability, although the cells accumulated substantial amounts of arsenate. However, exposure to arsenate caused a time- and concentration-dependent increase in the export of GSH from viable neurons with significant effects observed for arsenate in concentrations above 0.3 mM. The arsenate-induced stimulation of GSH export was abolished upon removal of arsenate and completely prevented by MK571, an inhibitor of the multidrug resistance protein 1. These results demonstrate that arsenate is not acutely toxic to neurons but can affect the neuronal GSH metabolism by stimulating GSH export. PMID- 25503648 TI - Biomodulatory Treatment of Patients with Castration-Resistant Prostate Cancer: A Phase II Study of Imatinib with Pioglitazone, Etoricoxib, Dexamethasone and Low Dose Treosulfan. AB - Therapeutic options for patients with castration-resistant prostate cancer (CRPC) remain limited. In a multicenter, Phase II study, 65 patients with histologically confirmed CRPC received a biomodulatory regimen during the six-month core study. Treatment comprised daily doses of imatinib mesylate, pioglitazone, etoricoxib, treosulfan and dexamethasone. The primary endpoint was prostate-specific antigen (PSA) response. Responders could enter an extension phase until disease progression or intolerable toxicity occurred. Mean PSA was 45.3 ng/mL at baseline, and 77 % of patients had a PSA doubling time <3 months. Of the 61 evaluable patients, 37 patients (60.6 %) responded or had stable disease and 23 of them (37.7 % of 61 patients) were PSA responders. Among the 23 responders mean PSA decreased from 278.9 +/- 784.1 ng/mL at baseline to 8.8 +/- 11.6 ng/mL at the final visit (week 24). The progression-free survival (PFS) was 467 days in the ITT population. Of the 947 adverse events, 57.6 % were suspected to be drug related, 13.8 % led to dose adjustment or permanent discontinuation and 40.2 % required concomitant medication. This novel combination approach led to an impressive PSA response rate of 37.7 % in CRPC patients. The good PSA response and PFS rate combined with the manageable toxicity profile suggest an alternative treatment option. PMID- 25503650 TI - Ultrasonography of peripheral entheses in the diagnosis and understanding of diffuse idiopathic skeletal hyperostosis (DISH). AB - The aim of this study was to investigate musculoskeletal ultrasound (MSUS) as a diagnostic modality in DISH and to explore whether it might help in elucidating its pathogenesis and events that precede the calcification/ossification process. Fifty patients with DISH and 34 patients with osteoarthritis of the lower limbs without DISH were investigated. Data regarding demographics and traditional cardiovascular risk factors were collected from all patients. An ultrasonography was performed according to the Glasgow Ultrasound Enthesitis Scoring System (GUESS) by observers who were blinded to the diagnosis or the clinical findings in the patients. The total mean GUESS score for patients with DISH was 14.12 +/- 5.2 and for patients without DISH 5.32 +/- 4.99 (P < 0.0001). Univariate logistic regression analysis found a strong association between the GUESS and the probability of having DISH (P < 0.0001). The area under the ROC curve (AUC) revealed that the GUESS accuracy in diagnosing DISH was 88.53% with sensitivity and specificity of 92 and 70.6%, respectively, at a cutoff value of 6.36. A stepwise logistic regression analysis of the statistically significant items in the GUESS isolated four items, and the presence of either all of them or the first three items yielded the likelihood of having DISH to be 98.8 and 90.6%, respectively. The GUESS and the stepwise logistic regression analysis of the GUESS items demonstrated a high likelihood of having DISH. MSUS might help to identify entheseal changes in DISH. Further studies are needed to confirm these results. PMID- 25503649 TI - Zipper-interacting protein kinase interacts with human cell division cycle 14A phosphatase. AB - Zipper-interacting protein kinase (ZIPK) is a novel serine/threonine protein kinase and a member of a large family of protein kinases, known as the death associated protein kinases. However, the function of ZIPK has yet to be fully elucidated, as few physiological substrates have currently been identified. In the present study, a yeast two-hybrid screen was used and the human cell division cycle 14A (HsCdc14A) phosphatase was identified as a novel ZIPK binding protein. To the best of our knowledge, this is the first study to report the interaction between these proteins. The interaction between ZIPK and HsCdc14A was confirmed by in vitro experiments. In addition, ZIPK-mediated phosphorylation was shown to activate the phosphatase activity of HsCdc14A. These findings indicated that ZIPK may also be involved in the regulation of the cell cycle in human cells, by interacting with HsCdc14A. PMID- 25503651 TI - Effects of three month nasal continuous positive airway pressure treatment on electrocardiographic, echocardiographic and overnight polysomnographic parameters in newly diagnosed moderate/severe obstructive sleep apnea patients. AB - The objective of the study was to determine the effects of nasal continuous positive airway pressure (nCPAP) therapy on left ventricular (LV) function and electrocardiographic parameters in newly diagnosed moderate/severe obstructive sleep apnea (OSA) patients without cardiovascular comorbidities and medical treatments. We examined 44 patients who underwent overnight polysomnography together with 24-hour Holter electrocardiography, cardiopulmonary exercise testing including heart rate recovery at 1 minute (HRR-1), echocardiography, surface electrocardiography, and those who were diagnosed with moderate/severe OSA apnea--hypopnea index >= 15. After 3 months of nCPAP treatment, the above mentioned examinations were repeated. Forty-four patients completed the treatment period. Twelve weeks on effective nCPAP induced a significant increase in the mitral E/A ratio (P = 0.001), as well as reductions in isovolumic relaxation time (P = 0.001) and mitral deceleration time (DT) (P = 0.002). There were no significant differences in LV ejection fraction, LV mass index, and pulsed wave Doppler parameters. Mean heart rate was 79.2 +/- 12.5 pulses/minute, maximum P wave duration 117.5 +/- 8.6 msec, P-wave dispersion (PWd) 54.6 +/- 10.2 msec, corrected QT interval (QTc) 436.5 +/- 40.5 msec, and QT dispersion (QTd) 46.3 +/- 7.1 msec, which significantly decreased to 70.4 +/- 9.6 pulses/minute (P < 0.001), 111.5 +/- 8.7 msec (P < 0.001), 51.6 +/- 8.9 msec (P < 0.001), 418.4 +/- 31.2 msec (P < 0.001), and 33.8 +/- 3.4 msec (P < 0.001), respectively. Exercise capacity at baseline determined as 10.5 +/- 2.2 metabolic equivalents (METS) and HRR-1 (20.6 +/- 11.7 bpm) significantly increased (12.1 +/- 1.5 METS and 27.4 +/- 8.6 bpm). There was no significant difference in aortic root parameters. Three month nCPAP therapy significantly increased LV shortening fraction, with no effect on systolic function or aortic root diameters and a positive effect on heart rate, PWd, HRR-1, QTc and QTd time following nCPAP therapy. PMID- 25503652 TI - Risk factors for late right ventricular systolic dysfunction in pediatric patients with repaired tetralogy of Fallot. AB - To evaluate independent risk factors for late right ventricular systolic dysfunction after correction of Tetralogy of Fallot (TOF) in a single-centre, retrospective and observational clinical trial.Patients less than 3 years of age who underwent correction of TOF and subsequently routine clinical follow-up of more than 36 months were included in this study and were divided either into an experimental group (right ventricular systolic dysfunction) or a control group (normal right ventricular systolic function) according to the tricuspid annular peak systolic velocity (TAPSV) value measured by pulsed wave-tissue Doppler imaging (pulsed wave-TDI). The relevant data of all selected patients were investigated and analyzed. From January 2012 to December 2012, a total of 113 consecutive eligible patients were enrolled in this study and were divided either into an experimental group (n = 41) or control group (n = 72). Through univariate analysis and subsequent logistic regression, low preoperative arterial oxygen saturation (OR = 1.66, 95%CI 1.22-4.58, P = 0.0163), age less than 6 months at the time of surgery (OR = 3.45, 95%CI 1.87-9.17, P = 0.0021), and transannular patch (OR = 2.15, 95%CI 1.31-5.38, P = 0.0015) were 3 independent risk factors for late right ventricular systolic dysfunction after correction of TOF.This clinical trial suggested low preoperative arterial oxygen saturation was associated with late right ventricular systolic dysfunction after correction of TOF, and appropriate age at the time of surgery and selection of a proper surgical method to reconstruct the right ventricular outflow tract contributed to improving late right ventricular systolic function in pediatric patients with repaired TOF. PMID- 25503653 TI - Is the internal jugular vein or femoral vein a better approach site for endomyocardial biopsy in heart transplant recipients? AB - Scheduled serial endomyocardial biopsies are executed by an internal jugular vein (IJV) or femoral vein (FV) approach to survey acute rejection after heart transplantation (HTx). However, a better approach site is needed. A total of 379 sessions consisting of 329 IJV approaches and 50 FV approaches in 48 HTx recipients executed at 75 +/- 127 days (41182 days) after HTx between September 2007 and April 2014 at University of Tokyo Hospital were retrospectively analyzed. The IJV approach had shorter operation and radiation exposure times, and a lower dose of radiation exposure and lower usage of contrast agents than the FV approach (all P < 0.001). There were no fatal complications requiring surgical management or resulting in death during all sessions. The IJV approach had less complications than the FV approach (2.7% versus 10.0%, P = 0.011). Among the complications, atrial tachyarrhythmia occurred only with the IJV approach (0.9%), whereas transient ventricular tachyarrhythmia and bundle branch block were more frequently observed in the FV approach (8.0% versus 0.9%, P = 0.042). In conclusion, endomyocardial biopsy from the IJV approach was safer and less invasive than that of the FV approach if we only consider the incidence of atrial tachyarrhythmia. PMID- 25503654 TI - Calorie restriction improves cognitive decline via up-regulation of brain-derived neurotrophic factor: tropomyosin-related kinase B in hippocampus ofobesity induced hypertensive rats. AB - In metabolic syndrome (MetS), previous studies have suggested that cognitive decline is worsened. Among the factors associated with cognition, decreased brain derived neurotrophic factor (BDNF) in the hippocampus causes cognitive decline. We previously reported that exercise training with calorie restriction yielded protection against cognitive decline via BDNF in the hippocampus of hypertensive rats. The aim of the present study was to determine whether or not calorie restriction results in protection against cognitive decline via BDNF and its receptor tropomyosin-related kinase B (TrkB) in the hippocampus of MetS model rats. We divided dietary-induced obesity-prone and hypertensive rats (OP), as metabolic syndrome model rats, into three groups, fed with a high fat diet (HF), treated with calorie restriction (CR) plus vehicle, and treated with CR and ANA 12 (a TrkB antagonist) (CR+A). After treatment for 28 days, body weight, insulin, fasting blood glucose, adiponectin, systolic blood pressure, and oxidative stress in the hippocampus were significantly lower, and BDNF expression in the hippocampus was significantly higher in CR and CR+A than in HF. Cognitive performance determined by the Morris water maze test was significantly higher in CR than in HF, whereas the benefit was attenuated in CR+A. In conclusion, calorie restriction protects against cognitive decline via up-regulation of BDNF/TrkB through an antioxidant effect in the hippocampus of dietary-induced obesity rats. PMID- 25503655 TI - Impact of smoking on coronary microcirculatory resistance in patients with coronary artery disease. AB - The aim of this study was to investigate the relationship between coronary microvascular function and smoking using the 3 parameters fractional flow reserve (FFR), coronary flow reserve (CFR(thermo)), and index of microcirculatory resistance (IMR) in patients with coronary artery disease (CAD). A total of 97 CAD patients with 148 intermediate stenotic lesions were divided into two groups: current and former smokers (Smokers: n = 54), and those who had never smoked (Non smokers: n = 43). Coronary physiology measurements were made following coronary angiography at rest and during hyperemia induced with intravenous adenosine triphosphate. If a patient had several intermediate lesions, the lesion producing the largest IMR value and minimum FFR(myo) and CFR(thermo) value was selected. Averaged over all patients, the FFR(myo), CFR(thermo), and IMR values were 0.86 +/- 0.10, 2.66 +/- 1.50, and 20.8 +/- 10.7, respectively. There was no significant correlation between FFR(myo) and IMR. There were no significant differences between smokers and non-smokers in FFR(myo) value (median: 0.85 [IQR: 0.74-0.90] versus 0.87 [IQR: 0.83-0.90], P = 0.15) and CFR(thermo) value (median: 1.90 [IQR: 1.56-3.16] versus 2.10 [IQR: 1.50-2.67] U, P = 0.95). The IMR value was significantly greater in smokers (median: 24.2 [IQR: 16.8-32.5] U versus 18.5 [IQR: 15.4-27.0] U, P = 0.04). In multivariate analysis, smoking was an independent predictor of increased IMR. Smoking appears to have a detrimental effect on coronary microvascular function as measured by IMR. PMID- 25503656 TI - Angiographic patterns of restenosis with 2nd generation drug-eluting stent: comparative analysis from a 10-year single-center experience . AB - The angiographic features of restenosis contain prognostic information. However, restenosis patterns of the new generation drug-eluting stents (DES), everolimus (EES) and resolute zotarolimus-eluting stent (ZES) have not been described.A total of 210 consecutive patients with DES restenosis were enrolled from 2003 to 2012. We analyzed 217 restenotic lesions after DES implantation, and compared the morphologic characteristics of the 2nd generation DES restenosis to those of restenosis with 2 first generation DES, sirolimus-(SES) and paclitaxel-eluting stent (PES).Baseline characteristics were comparable between the different stent groups. The incidence of focal restenosis was significantly lower for PES than the other stents (49.5% versus 87.0%, 76.2%, and 82.1% for PES versus SES, EES, and ZES, respectively, P < 0.001). When considering the pattern of restenosis solely within the stent margins, a further clear distinction between PES and other stents was observed (40.0% versus 92.9%, 88.9%, and 81.2% in PES versus SES, EES, and ZES, respectively, P < 0.001). There were no significant differences in restenosis patterns among SES, EES, and ZES. In multivariate analysis, PES implantation, hypertension, and age were associated with non-focal type of restenosis after DES implantation. After the introduction of EES and ZES into routine clinical practice in 2008, focal restenosis significantly increased from 63.9% to 76.7% and diffuse restenosis significantly decreased from 26.4% to 11.0% (P = 0.045).Focal restenosis was the most common pattern of restenosis in the new generation DES and the incidence of diffuse restenosis significantly decreased with the introduction of the 2nd generation DES. PMID- 25503657 TI - Improvement of cardiac function by increasing stimulus strength during left ventricular pacing in cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is an established therapy in patients with severe heart failure due to left ventricular (LV) dyssynchrony. Increasing stimulus strength (SS) of LV pacing could capture an enlarged myocardial area and provide rapid electrical conduction. The aim of the present study was to investigate whether increasing SS of LV pacing improves LV mechanical dyssynchrony and cardiac function in patients treated with CRT.We enrolled 26 patients with CRT and changed the SS of LV pacing: 2.5 V (standard SS) and 5 V (high SS). Electrocardiography and echocardiography were performed to assess QRS duration, LV mechanical dyssynchrony, and cardiac function under each condition.The QRS duration (138.6 +/- 21.4 ms versus 126.8 +/- 23.1 ms, P < 0.001), septal-posterior wall motion delay (126.5 +/- 42.7 ms versus 111.4 +/- 55.3 ms, P = 0.012), standard deviation of time from QRS (69.6 +/- 21.8 ms versus 55.6 +/- 19.4 ms, P < 0.001), LV ejection fraction (29.4 +/- 10.6% versus 33.4 +/ 11.6%, P = 0.005), and LV stroke volume (50.7 +/- 15.5 mL versus 63.8 +/- 18.3 mL, P < 0.001) improved significantly in high SS compared with standard SS.Increasing SS of LV pacing in CRT improves LV mechanical dyssynchrony and cardiac function. The capture of an enlarged myocardial area by increasing SS of LV pacing might offer an acute hemodynamic benefit to patients treated with CRT. PMID- 25503658 TI - Quantitative optical coherence tomography analysis for late in-stent restenotic lesions. AB - Coronary optical coherence tomography (OCT) has the potential to identify in stent neoatherosclerosis, which is a possible risk factor for late acute coronary events after drug-eluting stent implantation. The purpose of this study was to investigate differences between mid-term and late in-stent restenosis after stent implantation by quantitative and semiautomated tissue property analysis using OCT. In total, 1063 OCT image frames of 16 lesions in 15 patients were analyzed. This included 346 frames of 6 lesions in late in-stent restenosis, which was defined as restenosis that was not detected at 6 to 12 months but >= 12 months after follow-up coronary angiography. Signal attenuation was circumferentially analyzed using a dedicated semiautomated software. Attenuation was assessed along 200 lines delineated radially for analysis of the in-stent restenotic lesions (between the lumen and stent contours). All lines were anchored by the image wire to avoid artifacts resulting from wire location. Stronger signal attenuation at the frame level (2.46 +/- 0.78 versus 1.47 +/- 0.32, P < 0.001) and higher maximum signal intensity at the lesion level (9.19 +/- 0.19 versus 8.84 +/- 0.32, P = 0.018) were observed in late in-stent restenotic lesions than in mid-term in stent restenotic lesions. OCT demonstrated stronger signal attenuation and higher maximum signal intensity in late in-stent restenotic lesions than in mid-term in stent restenotic lesions, indicating the possibility of neoatherosclerosis. PMID- 25503659 TI - Periprocedural anticoagulation of patients undergoing pericardiocentesis for cardiac tamponade complicating catheter ablation of atrial fibrillation. AB - Anticoagulation of patients with cardiac tamponade (CT) complicating catheter ablation of atrial fibrillation (AF) is an ongoing problem. The aim of this study was to survey the clinical practice of periprocedural anticoagulation in such patients. This study analyzed the periprocedural anticoagulation of 17 patients with CT complicating AF ablation. Emergent pericardiocentesis was performed once CT was confirmed. The mean drained volume was 410.0 +/- 194.1 mL. Protamine sulfate was administered to neutralize heparin (1 mg neutralizes 100 units heparin) in 11 patients with persistent pericardial bleeding and vitamin K1 (10 mg) was given to reverse warfarin in 3 patients with supratherapeutic INR (INR > 2.1). Drainage catheters were removed 12 hours after echocardiography confirmed absence of intrapericardial bleeding and anticoagulation therapy was restored 12 hours after removing the catheter. Fifteen patients took oral warfarin and 10 of them were given subcutaneous injection of LMWH (1 mg/kg, twice daily) as a bridge to resumption of systemic anticoagulation with warfarin. Two patients with a small amount of persistent pericardial effusion were given LMWH on days 5 and 13, and warfarin on days 6 and 24. The dosage of warfarin was adjusted to keep the INR within 2-3 in all patients. After 12 months of follow-up, all patients had no neurological events and no occurrence of delayed CT. The results showed that it was effective and safe to resume anticoagulation therapy 12 hours after removal of the drainage catheter. This may help to prevent thromboembolic events following catheter ablation of AF. PMID- 25503660 TI - Intermediate monocytes lead to enhanced myocardial remodelling in STEMI patients with diabetes. AB - This study aimed to evaluate the potential associations of intermediate monocytes (CD14(++)CD16(+)) with myocardial remodelling in ST segment elevation myocardial infarction (STEMI) patients with diabetes.A total of 67 STEMI patients with diabetes were enrolled. The control group consisted of 65 STEMI patients without diabetes. All patients received emergency medical services for reperfusion therapy in less than 12 hours after onset of AMI. Blinded to patient clinical characteristics, monocyte subset analysis was performed using flow cytometry immediately after admission. mRNA of Chemokine Decoy Receptor D6 in each subset of monocytes was validated by Q-PCR. Expression of CCL2 in patient plasma was determined with an Elisa kit. Infarct size and left ventricular ejection fraction (LVEF) were measured using 3-dimensional echocardiography 3 days and 6 months after AMI. The incidences of recurrent cardiovascular events and death in each group were measured using the Kaplan-Meier estimator in follow-up during the next 24 months. Cox proportional-hazard models were further used to analyze the relationship of monocyte cell counts and event-free survival after adjusting for confounding factors.The number of circulating intermediate monocytes was significantly correlated with LVEF% and infarct size (r = -0.32; P = 0.008; r = 0.57, P < 0.001) in STEMI patients with diabetes compared with those without diabetes 6 months after AMI. Chemokine Decoy Receptor D6 transcript levels were lower in intermediate monocytes of STEMI patients with diabetes compared to the subsets in STEMI patients without diabetes (P < 0.001). Higher levels of CCL2 (pg/mL) were observed in STEMI patients with diabetes compared to STEMI patients without diabetes (P < 0.001). During a mean follow-up period of 24 +/- 1 month, recurrent cardiovascular events or death occurred in 23 patients belonging to the STEMI with diabetes group and 10 belonging to the control group. Univariate Kaplan-Meier analysis revealed that counts of the intermediate monocytes according to median showed statistical significance in STEMI patients with diabetes (P = 0.010). After full adjustment for confounding factors, the cells were found to remain independently related to recurrent cardiovascular events or death in this group (P = 0.004, 95% CI: 1.62-12.49).Intermediate monocytes were associated with LV remodelling in STEMI patients with diabetes. The cells were predictive for recurrent cardiovascular events or death in these patients. A low level of D6 mRNA in the intermediate monocytes of STEMI patients with diabetes and high level of CCL2 in these patients may partially explain the causality. PMID- 25503662 TI - Merton Sandler (March 1926-August 2014). PMID- 25503663 TI - Correlation of cervical length, fetal fibronectin, phIGFBP-1, and cytokines in spontaneous preterm birth up to 14 days from sampling. AB - OBJECTIVE: The aim of this study was to determine the relationship between sonographic cervical length, fetal fibronectin (fFN), phIGFBP-1 (actim partus test), cytokines (IL-6, IL-2R, and TNF-alpha), and spontaneous preterm birth (SPTB) up to 14 days from sampling. METHODS: Fifty-eight patients were recruited in a period of 6 months from September 2013 until March 2014 with symptoms or complaints suggestive of preterm labor. Consenting women were treated according to usual hospital protocol, with addition of vaginal swabs taken for fetal fibronectin, phIGFBP-1 (actim partus test) and cervical IL6, IL2R, and TNF-alpha. The outcome variable was occurrence of preterm delivery within 14 days from the day of hospital admission. RESULTS: Thirty-six patients (62.07%) were delivered within 14 days from admission. Our results indicated that the cervical length significantly inversely correlates with the concentration of IL-6 in the CVF (Spearman's coefficient R=-0.382, P<0.05). Cervical length also correlated with a positive phIGFBP-1 test, i.e., patients with a positive test had an average cervical length of 18.5+/-4.63 mm, which is significantly lower than patients with a negative test -23.43+/-7.39 mm (P=0.003). CONCLUSIONS: The studied biochemical markers were only moderately successful in the prediction of preterm delivery. PMID- 25503664 TI - Charging of the penis: an unusual method for sexual gratification. AB - The presence of a foreign object in the bladder or urethra may cause a serious problem to the patient. Most of the cases are self-inserted as a result of sexual gratification. Here, we present a rare case of self introduction of the wire of a mobile charger within the bladder and urethra for sexual gratification. This case has yet to be reported in any previous work. PMID- 25503665 TI - IGF-II expression and methylation in small for gestational age infants. AB - BACKGROUND: Low birth weight is associated with an increased risk of adverse outcomes in many diseases in adult life. We investigated the expression of IGF-II and the status of differentially methylated regions (DMR) in small for gestational age (SGA) infants after birth. METHODS: Plasma IGF-II, IGF-II receptor (IGF2R), IGF-I, and IGF-binding protein 3 (IGFBP3) levels were measured after birth in 150 newborn infants. These included 30 term appropriate for gestational age (AGA), 30 term SGA, 30 term large for gestational age (LGA), 30 preterm AGA, and 30 preterm SGA infants. H19 and IGF2 mRNA levels were quantified by fluorescence quantitative polymerase chain reaction (PCR). The methylation status of H19 DMR and IGF2 DMR2 was assessed by methylation-specific PCR (MSP). Plasma IGF-II, IGF2R, IGF-I, and IGFBP3 levels were measured by enzyme-linked immunosorbent assay in AGA infants of different gestational ages and term AGA infants on different days. RESULT: Plasma IGF-II levels after birth were lower in both term SGA (435.1+/-33.82 vs. 620.4+/-44.79, p=0.002) and LGA infants (483.7+/ 33.8 vs. 620.42+/-44.79, p=0.018) than in term AGA infants. The expression of IGF2 mRNA was higher in the term SGA group than in the preterm SGA group (p=0.014) and the preterm SGA group displayed lower expression than the preterm AGA group (p=0.048). The H19 DMR methylation level was higher in both term SGA (p=0.044) and term LGA infants (p=0.027) compared to term AGA infants. CONCLUSIONS: IGF-II was associated with birth weight and expressed at high levels, which suggests that IGF-II may continue to play an important role after birth. H19 DMR methylation may be involved in controlling IGF-II expression. PMID- 25503661 TI - Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer's disease. AB - Sporadic Alzheimer disease (sAD) is associated with impairment of insulin receptor (IR) signalling in the brain. Rats used to model sAD develop insulin resistant brain state following intracerebroventricular treatment with a betacytotoxic drug streptozotocin (STZ-icv). Brain IR signalling has been explored usually at only one time point in periods <=3 months after the STZ-icv administration. We have investigated insulin signalling in the rat hippocampus at five time points in periods <=9 months after STZ-icv treatment. Male Wistar rats were given vehicle (control)- or STZ (3 mg/kg)-icv injection and killed 0.5, 1, 3, 6 and 9 months afterwards. Insulin-1 (Ins-1), IR, phospho- and total (p/t) glycogen synthase kinase 3-beta (GSK-3beta), p/t-tau and insulin degrading enzyme (IDE) mRNA and/or protein were measured. Acute upregulation of tau and IR mRNA (p < 0.05) was followed by a pronounced downregulation of Ins-1, IR and IDE mRNA (p < 0.05) in the course of time. Acute decrement in p/t-tau and p/t-GSK-3beta ratios (p < 0.05) was followed by increment in both ratios (3-6 months, p < 0.05) after which p/t-tau ratio demonstrated a steep rise and p/t-GSK-3beta ratio a steep fall up to 9 months (p < 0.05). Acute decline in IDE and IR expression (p < 0.05) was followed by a slow progression of the former and a slow recovery of the latter in 3-9 months. Results indicate a biphasic pattern in time dependency of onset and progression of changes in brain insulin signalling of STZ-icv model (partly reversible acute toxicity and chronic AD-like changes) which should be considered when using this model as a tool in translational sAD research. PMID- 25503666 TI - Early screening of FTO and MC4R variants in newborns of Greek origin. AB - BACKGROUND: Variants of fat mass and obesity associated gene (FTO) and melanocortin-4 receptor gene (MC4R) are related to obesity, overweight and type 2 diabetes. OBJECTIVES: To examine the presence of FTO and MC4R variants in Greek newborns. SUBJECTS AND METHODS: A total 1530 newborns of Greek origin were subjected to genetic testing for rs9939609 (FTO) and for rs17782313 (MC4R) variants using dried blood spot (DBS) analysis. RESULTS: Some 20.2% of newborns carried none of the tested variants. FTO homozygotes and FTO heterozygotes correspond to 18.0% and 45.9% of neonates, respectively. MC4R homozygotes and MC4R heterozygotes were identified in 6.7% and 36.3% of neonates, respectively. Of the infants, 2.2% carried both variants in homozygosity, whereas heterozygotes for both variants correspond to 16.7% of the tested neonates. CONCLUSION: The results indicate high prevalence of homozygosity and heterozygosity for tested variants. Early screening via DBS may be beneficial in order to adopt a healthy lifestyle. PMID- 25503667 TI - The reliability of body mass index in the diagnosis of obesity and metabolic risk in children. AB - BACKGROUND: Body mass index (BMI) is the most widespread and the simplest method for the evaluation of body mass; it is often used as a sole technique in the diagnosis of obesity in children. The objective of the study was to evaluate the relationship between anthropometric and biochemical parameters and the incidence of the metabolic syndrome in obese children. METHODOLOGY: A total of 110 children, aged 2-17 years, participated in the study. No overweight children (BMI 85-95 percentiles) were included. BMI was interpreted using the 2000 Centers for Disease Control and Prevention Growth Charts. The skinfold measurements were performed using an John Bull British Indicators Ltd. calipers, and interpreted using an the reference table values. RESULTS: In addition to lower sensitivity (mentioned in several earlier studies), BMI also shows a lower specificity in the diagnosis of obesity in children: BMI showed at least 10% of non-concomitance with skinfold thickness and waist circumferences and 8% with waist-to-height ratio. In addition, subscapular skinfold thickness, waist circumference, and waist/height ratio showed stronger correlations with serum insulin levels, low density lipoprotein cholesterol, and family history than BMI itself. CONCLUSION: The unreliability of BMI as the sole parameter for diagnosing obesity in children was found in our study. Even when overweight children were excluded from the study, the lack of specificity of BMI was demonstrated. We propose utilization of waist circumference and waist/height ratio along with the BMI for definitive diagnosis instead of relying on BMI only. In addition, waist circumference and subscapular fold thickness may be even better in estimation of metabolic risk than BMI. PMID- 25503668 TI - Childhood craniopharyngioma - current status and recent perspectives in diagnostics and treatment. PMID- 25503669 TI - Benchmarking by HbA1c in a national diabetes quality register--does measurement bias matter? AB - BACKGROUND: Bias in HbA1c measurement could give a wrong impression of the standard of care when benchmarking diabetes care. The aim of this study was to evaluate how measurement bias in HbA1c results may influence the benchmarking process performed by a national diabetes register. METHODS: Using data from 2012 from the Norwegian Diabetes Register for Adults, we included HbA1c results from 3584 patients with type 1 diabetes attending 13 hospital clinics, and 1366 patients with type 2 diabetes attending 18 GP offices. Correction factors for HbA1c were obtained by comparing the results of the hospital laboratories'/GP offices' external quality assurance scheme with the target value from a reference method. RESULTS: Compared with the uncorrected yearly median HbA1c values for hospital clinics and GP offices, EQA corrected HbA1c values were within +/-0.2% (2 mmol/mol) for all but one hospital clinic whose value was reduced by 0.4% (4 mmol/mol). Three hospital clinics reduced the proportion of patients with poor glycemic control, one by 9% and two by 4%. CONCLUSIONS: For most participants in our study, correcting for measurement bias had little effect on the yearly median HbA1c value or the percentage of patients achieving glycemic goals. However, at three hospital clinics correcting for measurement bias had an important effect on HbA1c benchmarking results especially with regard to percentages of patients achieving glycemic targets. The analytical quality of HbA1c should be taken into account when comparing benchmarking results. PMID- 25503670 TI - Influence of ABO type on global coagulation assay results: effect of coagulation factor VIII. AB - BACKGROUND: As ABO blood type influences the plasma level of coagulation factor VIII (FVIII), it likely also affects activated partial thromboplastin time (aPTT) and thrombin generation assay (TGA) values. Here, we aimed to investigate the effect of ABO type on the normal values of three global coagulation assays: prothrombin time (PT), aPTT, and TGA. METHODS: PT, aPTT, TGA [1 or 5 pmol/L tissue factor (TF)], coagulation factors, anticoagulation factors, and ABO type were measured in 200 healthy adults. RESULTS: aPTT was significantly prolonged in those with type O compared with those with type non-O, whereas PT was not significantly different between those with type O and type non-O. The time to peak induced by 5 pmol/L TF was significantly prolonged, and the peak thrombin level was decreased in those with type O compared with those with type non-O. FVIII was a major contributor to the ABO-specific reference range of aPTT, 5 pmol/L TF-induced time to peak, and peak thrombin level. CONCLUSIONS: The reference ranges of aPTT and TGA (time to peak and peak thrombin level) differed by ABO type. FVIII level is considered a major contributor to ABO type-specific differences with respect to aPTT and TGA. PMID- 25503671 TI - Dacryocytes are a common morphologic feature of autoimmune and microangiopathic haemolytic anaemia. AB - BACKGROUND: Dacryocytes are teardrop-shaped erythrocytes which are most frequently observed in peripheral blood smears of patients with primary or secondary myelofibrosis as well as malignant infiltrative disorders of the bone marrow. Dacryocytes have rarely been described in blood smears of patients with autoimmune (AIHA) and microangiopathic haemolytic anaemia (MAHA). The clear prevalence of dacryocytes in AIHA and MAHA is unknown. METHODS: We compared the dacryocyte counts in blood smears stained according to the May-Grunwald-Giemsa technique between 20 subjects with AIHA and MAHA with those from 21 controls. The dacryocytes, defined as erythrocytes tapered to a point at one end, were counted as cells per 20 high power fields (HPF) at 630-fold magnification. RESULTS: In AIHA, MAHA and controls, dacryocytes were found in 89%, 91% and 19% of the slides, respectively. The rate of dacryocyte positivity and the dacryocyte counts between haemolytic anaemias and controls differed statistically highly significant (p<0.0001). CONCLUSIONS: The results of this study indicate that dacryocytes are commonly apparent in blood smears of patients with AIHA and MAHA. Knowledge of this frequent feature may be beneficial in clinical routine diagnosis. PMID- 25503672 TI - When is Menzerath-Altmann law mathematically trivial? A new approach. AB - Menzerath's law, the tendency of Z (the mean size of the parts) to decrease as X (the number of parts) increases, is found in language, music and genomes. Recently, it has been argued that the presence of the law in genomes is an inevitable consequence of the fact that Z=Y/X, which would imply that Z scales with X as Z ~ 1/X. That scaling is a very particular case of Menzerath-Altmann law that has been rejected by means of a correlation test between X and Y in genomes, being X the number of chromosomes of a species, Y its genome size in bases and Z the mean chromosome size. Here we review the statistical foundations of that test and consider three non-parametric tests based upon different correlation metrics and one parametric test to evaluate if Z ~ 1/X in genomes. The most powerful test is a new non-parametric one based upon the correlation ratio, which is able to reject Z ~ 1/X in nine out of 11 taxonomic groups and detect a borderline group. Rather than a fact, Z ~ 1/X is a baseline that real genomes do not meet. The view of Menzerath-Altmann law as inevitable is seriously flawed. PMID- 25503673 TI - Markovianness and conditional independence in annotated bacterial DNA. AB - We explore the probabilistic structure of DNA in a number of bacterial genomes and conclude that a form of Markovianness is present at the boundaries between coding and non-coding regions, that is, the sequence of START and STOP codons annotated for the bacterial genome. This sequence is shown to satisfy a conditional independence property which allows its governing Markov chain to be uniquely identified from the abundances of START and STOP codons. Furthermore, we show that the annotated sequence of STARTs and STOPs complies with Chargaff's second parity rule. PMID- 25503674 TI - Exploring homogeneity of correlation structures of gene expression datasets within and between etiological disease categories. AB - The literature shows that classifiers perform differently across datasets and that correlations within datasets affect the performance of classifiers. The question that arises is whether the correlation structure within datasets differ significantly across diseases. In this study, we evaluated the homogeneity of correlation structures within and between datasets of six etiological disease categories; inflammatory, immune, infectious, degenerative, hereditary and acute myeloid leukemia (AML). We also assessed the effect of filtering; detection call and variance filtering on correlation structures. We downloaded microarray datasets from ArrayExpress for experiments meeting predefined criteria and ended up with 12 datasets for non-cancerous diseases and six for AML. The datasets were preprocessed by a common procedure incorporating platform-specific recommendations and the two filtering methods mentioned above. Homogeneity of correlation matrices between and within datasets of etiological diseases was assessed using the Box's M statistic on permuted samples. We found that correlation structures significantly differ between datasets of the same and/or different etiological disease categories and that variance filtering eliminates more uncorrelated probesets than detection call filtering and thus renders the data highly correlated. PMID- 25503676 TI - Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells. AB - The deregulation of microRNAs (miRNAs) plays an important role in human hepatocarcinogenesis. In this study, we highlight exosomes as mediators involved in modulating miRNA profiles in hepatocellular carcinoma (HCC) cells. First, we examined the different miRNA expression profiles in HCC cells and HCC cell derived exosomes. Next, coculture experiments indicated that HCC cell-derived exosomes promoted the cell growth, migration, and invasion of HCC cells and had the ability to shuttle miRNAs to recipient cells. Further, our data showed that Vps4A, a key regulator of exosome biogenesis, was frequently down-regulated in HCC tissues. The reduction of Vps4A in HCC tissues was associated with tumor progression and metastasis. In vitro studies revealed that Vps4A repressed the growth, colony formation, migration, and invasion of HCC cells. We further investigated the role and involvement of Vps4A in suppressing the bioactivity of exosomes and characterized its ability to weaken the cell response to exosomes. By small RNA sequencing, we demonstrated that Vps4A facilitated the secretion of oncogenic miRNAs in exosomes as well as accumulation and uptake of tumor suppressor miRNAs in cells. A subset of Vps4A-associated miRNAs was identified. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the phosphatidylinositol-3-kinase/Akt signaling pathway was the most likely candidate pathway for modulation by these miRNAs. Indeed, we proved that the phosphatidylinositol-3-kinase/Akt pathway was inactivated by Vps4A overexpression. CONCLUSION: Exosome-mediated miRNA transfer is an important mechanism of self-modulation of the miRNA expression profiles in HCC cells, and Vps4A may function as a tumor suppressor, which utilizes exosomes as mediators to regulate the secretion and uptake of miRNAs in hepatoma cells; these observations provide new insights into the development of HCC. PMID- 25503677 TI - Laparoscopic gastrectomy for remnant gastric cancer: a comprehensive review and case series. AB - BACKGROUND: Remnant gastric cancer is increasing with the earlier detection of gastric cancer and improved medical care. Laparoscopic gastrectomy for remnant gastric cancer has been reported sporadically in association with the increased use of minimally invasive techniques. However, because of the rarity of remnant gastric cancer, the number of cases reported per study has been small. We therefore reviewed all published English-language reports, including our experience, to better characterize the technical aspects of currently used procedures. METHODS: Ten patients who underwent laparoscopic gastrectomy for remnant cancer between August 2005 and March 2014 were retrospectively studied. A comprehensive literature search was performed using the PubMed database to identify English-language studies on laparoscopic gastrectomy for remnant gastric cancer that were published before May 2014. RESULTS: There was no conversion to open surgery. The mean operating time was 325 min, and mean intraoperative blood loss was 55 g. The mean number of retrieved lymph nodes was 22, and mean postoperative hospital stay was 13 days. There was only one minor wound infection (overall morbidity rate, 10%). From the literature review, all comparative studies revealed that laparoscopic gastrectomy for remnant gastric cancer required a longer operating time, and most studies reported less intraoperative blood loss, an equivalent number of harvested lymph nodes, and a shorter postoperative stay as compared with open surgery. CONCLUSION: Proficiency in advanced laparoscopic surgical techniques, such as proper adhesiolysis and stable laparoscopic anastomosis, will allow laparoscopic gastrectomy for remnant gastric cancer to be performed with satisfactory short-term results. This minimally invasive approach can be one treatment option for remnant gastric cancer. PMID- 25503679 TI - Summer Treatment Program Improves Behavior of Children with High-Functioning Autism Spectrum Disorder. AB - This study evaluated the effects of a behavioral summer treatment program for children with high-functioning autism spectrum disorder (HFASD). Twenty boys (M = 9.2 years) diagnosed with HFASD participated in the 6-week program across 6 years. Detailed daily behavioral data were collected on a variety of positive and negative social behaviors. Repeated measures ANOVAs of weekly behavior frequencies indicated substantial improvements in a number of behaviors over the 6 weeks of the program, including following activity rules, contributing to a group discussion, paying attention, and less complaining/whining. Overall, results highlight the potential efficacy of treating chronic functional impairments of HFASD and associated problem behaviors in the context of an intensive behavioral summer treatment program. PMID- 25503678 TI - Solution and solid-phase halogen and C-H hydrogen bonding to perrhenate. AB - (1)H NMR spectroscopic and X-ray crystallographic investigations of a 1,3-bis(4 ethynyl-3-iodopyridinium)benzene scaffold with perrhenate reveal strong halogen bonding in solution, and bidentate association in the solid state. A nearly isostructural host molecule demonstrates significant C-H hydrogen bonding to perrhenate in the same phases. PMID- 25503680 TI - Brief Report: Development of a Robotic Intervention Platform for Young Children with ASD. AB - Increasingly researchers are attempting to develop robotic technologies for children with autism spectrum disorder (ASD). This pilot study investigated the development and application of a novel robotic system capable of dynamic, adaptive, and autonomous interaction during imitation tasks with embedded real time performance evaluation and feedback. The system was designed to incorporate both a humanoid robot and a human examiner. We compared child performance within system across these conditions in a sample of preschool children with ASD (n = 8) and a control sample of typically developing children (n = 8). The system was well-tolerated in the sample, children with ASD exhibited greater attention to the robotic system than the human administrator, and for children with ASD imitation performance appeared superior during the robotic interaction. PMID- 25503682 TI - Virtues and limitations of Pittsburgh green for ozone detection. AB - A recently proposed 2',7'-dichlorofluorescein (DCF)-derived fluorescent probe for the detection of ozone shows good selectivity against a number of reactive oxygen species and good pH stability for biological and environmental applications. It is found, however, that over oxidation of the fluorescent product (Pittsburgh green) can occur. This could render quantitative measurements inaccurate due to a reduction in fluorescence and overlapping fluorescence signals from over oxidation by-products and it requires careful experimental design. Although difficult to assess by fluorescence measurements, the over oxidation can be conveniently monitored by (1)H NMR spectroscopy. PMID- 25503684 TI - Particle size distribution and air pollution patterns in three urban environments in Xi'an, China. AB - Three urban environments, office, apartment and restaurant, were selected to investigate the indoor and outdoor air quality as an inter-comparison in which CO2, particulate matter (PM) concentration and particle size ranging were concerned. In this investigation, CO2 level in the apartment (623 ppm) was the highest among the indoor environments and indoor levels were always higher than outdoor levels. The PM10 (333 ug/m(3)), PM2.5 (213 ug/m(3)), PM1 (148 ug/m(3)) concentrations in the office were 10-50% higher than in the restaurant and apartment, and the three indoor PM10 levels all exceeded the China standard of 150 ug/m(3). Particles ranging from 0.3 to 0.4 um, 0.4 to 0.5 um and 0.5 to 0.65 um make largest contribution to particle mass in indoor air, and fine particles number concentrations were much higher than outdoor levels. Outdoor air pollution is mainly affected by heavy traffic, while indoor air pollution has various sources. Particularly, office environment was mainly affected by outdoor sources like soil dust and traffic emission; apartment particles were mainly caused by human activities; restaurant indoor air quality was affected by multiple sources among which cooking-generated fine particles and the human steam are main factors. PMID- 25503681 TI - Fragile spectral and temporal auditory processing in adolescents with autism spectrum disorder and early language delay. AB - We investigated low-level auditory spectral and temporal processing in adolescents with autism spectrum disorder (ASD) and early language delay compared to matched typically developing controls. Auditory measures were designed to target right versus left auditory cortex processing (i.e. frequency discrimination and slow amplitude modulation (AM) detection versus gap-in-noise detection and faster AM detection), and to pinpoint the task and stimulus characteristics underlying putative superior spectral processing in ASD. We observed impaired frequency discrimination in the ASD group and suggestive evidence of poorer temporal resolution as indexed by gap-in-noise detection thresholds. These findings question the evidence of enhanced spectral sensitivity in ASD and do not support the hypothesis of superior right and inferior left hemispheric auditory processing in ASD. PMID- 25503685 TI - Comparison of physical and chemical properties of ambient aerosols during the 2009 haze and non-haze periods in Southeast Asia. AB - Recurrent smoke-haze episodes that occur in Southeast Asia (SEA) are of much concern because of their environmental and health impacts. These haze episodes are mainly caused by uncontrolled biomass and peat burning in Indonesia. Airborne particulate matter (PM) samples were collected in the southwest coast of Singapore from 16 August to 9 November in 2009 to assess the impact of smoke-haze episodes on the air quality due to the long-range transport of biomass and peat burning emissions. The physical and chemical characteristics of PM were investigated during pre-haze, smoke-haze, and post-haze periods. Days with PM2.5 mass concentrations of >=35 MUg m(-3) were considered as smoke-haze events. Using this criterion, out of the total 82 sampling days, nine smoke-haze events were identified. The origin of air masses during smoke-haze episodes was studied on the basis of HYSPLIT backward air trajectory analysis for 4 days. In terms of the physical properties of PM, higher particle surface area concentrations and particle gravimetric mass concentrations were observed during the smoke-haze period, but there was no consistent pattern for particle number concentrations during the haze period as compared to the non-haze period except that there was a significant increase at about 08:00, which could be attributed to the entrainment of PM from aloft after the breakdown of the nocturnal inversion layer. As for the chemical characteristics of PM, among the six key inorganic water-soluble ions (Cl(-), NO3(-), nss-SO4(2-), Na(+), NH4(+), and nss-K(+)) measured in this study, NO3(-), nss-SO4(2-), and NH4(+) showed a significant increase in their concentrations during the smoke-haze period together with nss-K(+). These observations suggest that the increased atmospheric loading of PM with higher surface area and increased concentrations of optically active secondary inorganic aerosols [(NH4)2SO4 or NH4HSO4 and NH4NO3] resulted in the atmospheric visibility reduction in SEA due to the advection of biomass and peat burning emissions. PMID- 25503683 TI - The role of tumor necrosis factor alpha in regulating the expression of Tamm Horsfall Protein (uromodulin) in thick ascending limbs during kidney injury. AB - BACKGROUND: Tamm-Horsfall Protein (THP) is a glycoprotein expressed exclusively by cells of the thick ascending loop (TAL) of Henle. THP has a protective role in acute kidney injury (AKI), and its expression is downregulated in the early stages of injury. Tumor necrosis factor alpha (TNFalpha) is a cytokine endogenously expressed by the TAL and is also induced by AKI. Therefore, we hypothesized that TNFalpha is a key regulator of THP expression. METHODS: We used a mouse model of AKI (ischemia-reperfusion injury, IRI) and a cell culture system of a TAL cell line (MKTAL). RESULTS: We show that TNFalpha is upregulated by TAL cells early after AKI in vivo. The expression of THP and its transcription factor Hepatocyte nuclear factor 1beta (HNF1beta) were concomitantly decreased at the peak of injury. Furthermore, recombinant TNFalpha inhibits significantly, and in a dose-dependent manner, the expression of THP, but not HNF1beta in MKTAL cells. Interestingly, neither TNFalpha neutralization nor genetic deletion of TNFalpha increased THP or HNF levels after injury in vivo. CONCLUSION: Our data suggest that TNFalpha can inhibit the expression of THP in TAL cells via an HNF1beta independent mechanism, but the downregulation of THP expression in the early AKI does not depend on TNFalpha. We propose that TNFalpha regulates THP expression in a homeostatic setting, but the impact of TNFalpha on THP during kidney injury is superseded by other factors that could inhibit HNF1beta-mediated expression of THP. PMID- 25503686 TI - A model-based analysis of a simplified beam-specific dose output in proton therapy with a single-ring wobbling system. AB - In radiation therapy, it is necessary to preset a monitor unit in an irradiation control system to deliver a prescribed absolute dose to a reference point in the planning target volume. The purpose of this study was to develop a model-based monitor unit calculation method for proton-beam therapy with a single-ring wobbling system. The absorbed dose at a calibration point per monitor unit had been measured for each beam-specific measurement condition without a patient specific collimator or range compensator before proton therapeutic irradiation at Shizuoka Cancer Center. In this paper, we propose a simplified dose output model to obtain the output ratio between a beam-specific dose and a reference field dose, from which a monitor unit for the proton treatment could be derived without beam-specific measurements. The model parameters were determined to fit some typical data measured in a proton treatment room, called a Gantry 1 course. Then, the model calculation was compared with 5456 dose output ratios that had been measured for 150-, 190- and 220 MeV therapeutic proton beams in two treatment rooms over the past decade. The mean value and standard deviation of the difference between the measurement and the model calculation were respectively 0.00% and 0.27% for the Gantry 1 course, and -0.25% and 0.35% for the Gantry 2 course. The model calculation was in good agreement with the measured beam specific doses, within 1%, except for conditions less frequently used for treatment. The small variation for the various beam conditions shows the high long-term reproducibility of the measurement and high degree of compatibility of the two treatment rooms. Therefore, the model was expected to assure the setting value of the dose monitor for treatment, to save the effort required for beam specific measurement, and to predict the dose output for new beam conditions in the future. PMID- 25503687 TI - Survival analysis of infected mice reveals pathogenic variations in the genome of avian H1N1 viruses. AB - Most influenza pandemics have been caused by H1N1 viruses of purely or partially avian origin. Here, using Cox proportional hazard model, we attempt to identify the genetic variations in the whole genome of wild-type North American avian H1N1 influenza A viruses that are associated with their virulence in mice by residue variations, host origins of virus (Anseriformes-ducks or Charadriiformes shorebirds), and host-residue interactions. In addition, through structural modeling, we predicted that several polymorphic sites associated with pathogenicity were located in structurally important sites, especially in the polymerase complex and NS genes. Our study introduces a new approach to identify pathogenic variations in wild-type viruses circulating in the natural reservoirs and ultimately to understand their infectious risks to humans as part of risk assessment efforts towards the emergence of future pandemic strains. PMID- 25503688 TI - BROMOC suite: Monte Carlo/Brownian dynamics suite for studies of ion permeation and DNA transport in biological and artificial pores with effective potentials. AB - The transport of ions and solutes by biological pores is central for cellular processes and has a variety of applications in modern biotechnology. The time scale involved in the polymer transport across a nanopore is beyond the accessibility of conventional MD simulations. Moreover, experimental studies lack sufficient resolution to provide details on the molecular underpinning of the transport mechanisms. BROMOC, the code presented herein, performs Brownian dynamics simulations, both serial and parallel, up to several milliseconds long. BROMOC can be used to model large biological systems. IMC-MACRO software allows for the development of effective potentials for solute-ion interactions based on radial distribution function from all-atom MD. BROMOC Suite also provides a versatile set of tools to do a wide variety of preprocessing and postsimulation analysis. We illustrate a potential application with ion and ssDNA transport in MspA nanopore. PMID- 25503691 TI - [Long-term opioid therapy in chronic noncancer pain. A systematic review and meta analysis of efficacy, tolerability and safety in open-label extension trials with study duration of at least 26 weeks]. AB - BACKGROUND: The efficacy and safety of long-term (>= 6 months) opioid therapy (LtOT) in chronic noncancer pain (CNCP) is under debate. A systematic review with meta-analysis of the efficacy and harms of opioids in open-label extension studies of randomized controlled trials (RCTs) has not been conducted until now. METHODS: We screened MEDLINE and clinicaltrials.gov (through to December 2013), as well as reference sections of systematic reviews of long-term RCTs of opioids in CNCP. We included open-label extension trials with a study duration >= 26 weeks of RCTs of >= 2 weeks duration. Using a random effects model, pooled estimates of event rates for categorical data and standardized mean differences (SMD) for continuous variables were calculated. RESULTS: We included 11 open label extension studies with 2445 participants with nociceptive (low back, osteoarthritis) and neuropathic (radicular, polyneuropathy) pain. Median study duration was 26 (range 26-108) weeks. Four studies tested oxycodone, two studies tramadol and buprenorphine; hydromorphone, morphine, oxymorphone and tapentadol were each tested in one study. Of the patients randomized at baseline, 28.5 % (95 % confidence interval, CI, 17.9-39.2 %) finished the open-label period; 53.5 % (95 % CI 38.1-68.2 %) of patients entering the open-label period finished the open-label period. In sum, the total loss was 71.5 % (95 % CI 60.9-83.1 %) of all patients primarily included into the RCT. A total of 4.9 % (95 % CI 2.9-8.2 %) of patients dropped out due lack of efficacy; 16.8 % (95 % CI 11.0-24.8 %) dropped out to due adverse events (AE) in the open-label period and 0.08 % (95 % CI 0.001 0.05 %) of patients died during the open-label period. Only one study systematically assessed aberrant drug behavior of the patients: 5.7 % (95 % CI 3.4-9.6 %) showed aberrant drug behavior in the opinion of the investigators and 2.6 % (95 % CI 1.2-5.8 %) were judged to show aberrant drug behavior by independent expert assessment. There was no significant change (p = 0.50) in pain intensity between the end of the randomized period and the end of open-label phase (SMD 0.19 [- 0.03, 0.41]; six studies with 1360 participants). CONCLUSION: Only a minority of patients selected for opioid therapy at randomization finished the long-term open-label study. However, sustained effects of pain reduction could be demonstrated in these patients. LtOT can be considered in carefully selected and monitored CNCP patients who experience clinically meaningful pain reduction with at least tolerable AE in short-term opioid therapy. The English full-text version of this article is freely available at SpringerLink (under "Supplementary Material"). PMID- 25503692 TI - Inhibition of choroidal fibrovascular membrane formation by new class of RNA interference therapeutic agent targeting periostin. AB - Age-related macular degeneration (AMD) is a vision-threatening disease characterized by choroidal fibrovascular membrane (FVM) formation, choroidal neovascularization (CNV) and choroidal fibrosis. No safe and effective therapeutic method has been developed for the choroidal fibrosis, although anti vascular endothelial growth factor therapy can partially shrink the CNV. We recently reported that periostin (POSTN), which is produced by retinal pigment epithelial cells, has an important role in the formation of preretinal FVMs, but its role in choroidal FVMs has not been determined. In this study, we used Postn knockout mice to investigate the role played by POSTN in choroidal FVM formation. In addition, we used a new class of RNA interference (RNAi) agent (NK0144) that targets POSTN and determined its effect on choroidal FVM development. Genetic ablation of Postn had an inhibitory effect not only on CNV formation but also on choroidal fibrosis in a mouse CNV model. NK0144 also had a greater inhibitory effect on both the CNV and choroidal fibrosis than control RNAi with no apparent adverse effects. These findings suggest a causal relationship between POSTN and choroidal FVM formation, and also a potential therapeutic role of intravitreal NK0144 for AMD. PMID- 25503693 TI - The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer. AB - In an effort to develop a new therapy for prostate cancer (PCa) bone metastases, we have created Ad.dcn, a recombinant oncolytic adenovirus carrying the human decorin gene. Infection of PC-3 and DU-145, the human prostate tumor cells, with Ad.dcn or a non-replicating adenovirus Ad(E1-).dcn resulted in decorin expression; Ad.dcn produced high viral titers and cytotoxicity in human prostate tumor cells. Adenoviral-mediated decorin expression inhibited Met, the Wnt/beta catenin signaling axis, vascular endothelial growth factor A, reduced mitochondrial DNA levels and inhibited tumor cell migration. To examine the antitumor response of Ad.dcn, PC-3-luc cells were inoculated in the left heart ventricle to establish bone metastases in nude mice. Ad.dcn, in conjunction with control replicating and non-replicating vectors were injected via tail vein. The real-time monitoring of mice, once a week, by bioluminescence imaging and X-ray radiography showed that Ad.dcn produced significant inhibition of skeletal metastases. Analyses of the mice at the terminal time point indicated a significant reduction in the tumor burden, osteoclast number, serum tartrate resistant acid phosphatase 5b levels, osteocalcin levels, hypercalcemia, inhibition of cancer cachexia and an increase in the animal survival. Based on these studies, we believe that Ad.dcn can be developed as a potential new therapy for PCa bone metastasis. PMID- 25503694 TI - Hydrodynamic delivery of interleukin 15 gene promotes resistance to high fat diet induced obesity, fatty liver and improves glucose homeostasis. AB - The objective of this study is to examine the effect of hydrodynamic delivery of plasmid containing Il-15 gene on high fat diet-induced obesity and obesity associated metabolic disorders. We demonstrate that Il-15 gene transfer results in multiple beneficial effects, including blockade of weight gain, alleviation of fatty liver and improvement in glucose homeostasis in mice. These effects are accompanied by suppressed expression of genes involved in lipogenesis and gluconeogenesis including Scd-1, Fas, Pdk4, Pepck and G6p, and enhanced expression of genes responsible for lipolysis and glucose metabolism such as Cpt1 alpha, Cpt1-beta, Acadm, Acadl and Glut-4. Collectively, our results suggest that Il-15 gene transfer is an effective approach in preventing diet-induced obesity and obesity-associated complications. PMID- 25503697 TI - Establishing an optimal trajectory for calcaneotibial K-wire fixation in emergent treatment of unstable ankle fractures. AB - OBJECTIVE: In unstable ankle fractures the associated soft tissue damage can be a therapeutic challenge. The aim of this study was to optimize planning of minimally invasive stabilization of ankle fractures by calcaneotibial transfixation, which is a demanding technique due to the complex hind foot anatomy. METHODS: In a retrospective radiographic analysis the angles and dimensions of a safe drill tunnel for calcaneotibial K-wire insertion were defined on standard radiographs of the ankle joint. 165 lateral weight-bearing radiographs (77 right; 88 left) and 147 (80 right; 67 left) mortise views of 186 (90 right; 96 left) uninjured feet from 123 patients (74 women (114 feet); 49 men (72 feet)) were included in this study. The average patient age was 49 (range, 13 85) years. Inter- and intra-observer reliability was evaluated on 20 randomized radiographs that were analyzed in a default set, three times, by two different examiners on three different days. RESULTS: In the lateral view the drilling tunnel was orientated at 59.4 degrees to the plantar plane with a maximum proximal variance of 7.1 image-mm. Distal variance cannot be tolerated since an ankle joint injury would ensue. In the mortise view the drill tunnel was directed with a mean angle of 18.4 degrees to the distal tibial articular surface. At most a mean of 11 degrees fibular- and 13.4 degrees tibial- expansion can be tolerated. Intra- and inter-observer reliability was higher for the angles than for the drill corridors. CONCLUSION: The three-dimensional (3D) orientation for safe K-wire placement for calcaneotibial transfixation should adhere to the drill tunnels established in this study. PMID- 25503695 TI - Adeno-associated virus inverted terminal repeats stimulate gene editing. AB - Advancements in genome editing have relied on technologies to specifically damage DNA which, in turn, stimulates DNA repair including homologous recombination (HR). As off-target concerns complicate the therapeutic translation of site specific DNA endonucleases, an alternative strategy to stimulate gene editing based on fragile DNA was investigated. To do this, an episomal gene-editing reporter was generated by a disruptive insertion of the adeno-associated virus (AAV) inverted terminal repeat (ITR) into the egfp gene. Compared with a non structured DNA control sequence, the ITR induced DNA damage as evidenced by increased gamma-H2AX and Mre11 foci formation. As local DNA damage stimulates HR, ITR-mediated gene editing was investigated using DNA oligonucleotides as repair substrates. The AAV ITR stimulated gene editing >1000-fold in a replication independent manner and was not biased by the polarity of the repair oligonucleotide. Analysis of additional human DNA sequences demonstrated stimulation of gene editing to varying degrees. In particular, inverted yet not direct, Alu repeats induced gene editing, suggesting a role for DNA structure in the repair event. Collectively, the results demonstrate that inverted DNA repeats stimulate gene editing via double-strand break repair in an episomal context and allude to efficient gene editing of the human chromosome using fragile DNA sequences. PMID- 25503698 TI - Biomimetic structured surfaces increase primary adhesion capacity of cartilage implants. AB - BACKGROUND: In cartilage repair, scaffold-assisted single-step techniques are used to improve the cartilage regeneration. Nevertheless, the fixation of cartilage implants represents a challenge in orthopaedics, particularly in the moist conditions that pertain during arthroscopic surgery. Within the animal kingdom a broad range of species has developed working solutions to intermittent adhesion under challenging conditions. Using a top-down approach we identified promising mechanisms for biomimetic transfer OBJECTIVE: The tree-frog adhesive system served as a test case to analyze the adhesion capacity of a polyglycolic acid (PGA) scaffold with and without a structural modification in a bovine articular cartilage defect model. METHODS: To this end, PGA implants were modified with a simplified foot-pad structure and evaluated on femoral articular bovine cartilage lesions. Non-structured PGA scaffolds were used as control. Both implants were pressed on 20 mm * 20 mm full-thickness femoral cartilage defects using a dynamometer. RESULTS: The structured scaffolds showed a higher adhesion capacity on the cartilage defect than the non-structured original scaffolds. CONCLUSIONS: The results suggest that the adhesion ability can be increased by means of biomimetic structured surfaces without the need of additional chemical treatment and thus significantly facilitate primary fixation procedures. PMID- 25503696 TI - Antibody neutralization poses a barrier to intravitreal adeno-associated viral vector gene delivery to non-human primates. AB - Gene delivery vectors based on adeno-associated viruses (AAV) have exhibited promise in both preclinical disease models and human clinical trials for numerous disease targets, including the retinal degenerative disorders Leber's congenital amaurosis and choroideremia. One general challenge for AAV is that preexisting immunity, as well as subsequent development of immunity following vector administration, can severely inhibit systemic AAV vector gene delivery. However, the role of neutralizing antibodies (NABs) in AAV transduction of tissues considered to be immune privileged, such as the eye, is unclear in large animals. Intravitreal AAV administration allows for broad retinal delivery, but is more susceptible to interactions with the immune system than subretinal administration. To assess the effects of systemic anti-AAV antibody levels on intravitreal gene delivery, we quantified the anti-AAV antibodies present in sera from non-human primates before and after intravitreal injections with various AAV capsids. Analysis showed that intravitreal administration resulted in an increase in anti-AAV antibodies regardless of the capsid serotype, transgene or dosage of virus injected. For monkeys injected with wild-type AAV2 and/or an AAV2 mutant, the variable that most significantly affected the production of anti-AAV2 antibodies was the amount of virus delivered. In addition, post-injection antibody titers were highest against the serotype administered, but the antibodies were also cross-reactive against other AAV serotypes. Furthermore, NAB levels in serum correlated with those in vitreal fluid, demonstrating both that this route of administration exposes AAV capsid epitopes to the adaptive immune system and that serum measurements are predictive of vitreous fluid NAB titers. Moreover, the presence of preexisting NAB titers in the serum of monkeys correlated strongly (R=0.76) with weak, decaying or no transgene expression following intravitreal administration of AAV. Investigating anti-AAV antibody development will aid in understanding the interactions between gene therapy vectors and the immune system during ocular administration and can form a basis for future clinical studies applying intravitreal gene delivery. PMID- 25503699 TI - Optoelectronic and nonlinear optical properties of triarylamine helicenes: a DFT study. AB - This work involved the design of a new series of triarylaminehelicenes (TAH) with significant hole transport capacity and enhanced nonlinear optical response. The geometries, electronic properties and nonlinear response of TAH derivatives were studied using density functional theory at the B3PW91/6-311++G (2d, 2p) level. Charge transfer and nonlinear optical response were analyzed and correlated with modifications in geometry and energy levels. Calculations indicated that trivial changes in the torsional angle occur in TAH derivatives with electron-donating substituents as compared to those with electron-withdrawing substituents, resulting in lower reorganization energies for TAH derivatives 2-6. TAH derivatives with an -N(CH3)2 group have the greatest highest occupied molecular orbital (HOMO) level, and thus the least ionization potential, indicating significant hole transfer efficiency as compared to unsubstituted TAH. A decrease in the HOMO-LUMO gap occurs upon substitution with electron-releasing groups, whereas there is an increase in the case of -NO2, -COOH, and -CN TAH derivatives. Topological analysis of the HOMOs of the neutral molecules revealed that these orbitals are concentrated mainly in the helicene backbone, with an important contribution from fused phenyl rings, nitrogen atoms and carbonyl groups. However, the lowest unoccupied molecular orbitals (LUMO) are invariably constituted by fused phenyl rings without any contribution from the central nitrogen atom. Studying the effect of substitution on the nonlinear optical response of TAH derivatives, the calculated polarizability and hyperpolarizability at B3PW91/6-311++G (2d,2p) level of theory exhibited a prominent improvement as compared to unsubstituted TAH. Both electron-donating groups and electron-withdrawing groups result in a red shift in the electronic absorption bands of the substitution derivatives, in particular those with N(CH3)2 and -NH2 groups. PMID- 25503700 TI - Functionalization of the pristine and stone-wales defected BC3 graphenes with pyrene. AB - The functionalization of pristine and Stone-Wales defected BC3 nanosheets with a pyrene molecule was investigated using density functional theory. Frontier molecular analysis shows that the main interaction is pi-pi stacking, releasing energies in the range of 143.6 to 169.1 kJ mol(-1). We predicted that after the functionalization process, the electrical conductance of the pristine sheet may be increased. Also, it modifies the work function of the pristine sheet and, as a consequence, its field-emission current densities may significantly enhance. However, the pyrene functionalization results in little change in the electronic properties of the defected sheet. PMID- 25503701 TI - Understanding the cytotoxicity or cytoprotective effects of biological and synthetic quinone derivatives by redox mechanism. AB - Quinones represent an important class of biological compounds, but are also involved with toxicological intermediates and among their hazardous effects include cytotoxicity, immunotoxicity, and carcinogenesis. The structure-toxicity relationship for quinone derivatives has been used to cytotoxicity or cytoprotective effects by redox mechanism is determined using quantum chemical calculations through the density functional theory (DFT). According to our DFT study, the electron acceptance is related with LUMO, electron affinity, and stabilization energy values. The highest spin density distribution in the heteroatoms is more favored for the more cytotoxic compounds. The electrophilic capacities of these compounds have been related with LUMO values. The cytotoxic properties of quinones are related to the stabilization energy after electron accepting by redox mechanism. Electron affinity is the most relevant parameter related to toxicity mechanism. Regioisomers has different electrophilic capacity. The electrophilicity increases on molecules containing electron-withdrawing groups (EWG) and reduces on molecules containing electron-donating groups (EDG). These results explain the toxic difference between natural and synthetic quinone derivatives and can be used in the design and study of new drugs. PMID- 25503702 TI - An ab initio study on the concerted interaction between chalcogen and pnicogen bonds. AB - We analyzed cooperation between chalcogen-bonding and pnicogen-bonding interactions in XHS...NCH2P...NCY (X = F, Cl; Y = H, OH, NH2, CN and NC) complexes at the MP2/6-311++G** level. These effects were studied in terms of geometric and energetic properties, harmonic frequencies, and nuclear magnetic resonance (NMR). A cooperativity factor was adopted to measure the cooperativity between the two types of interaction in triads based on S-X and P-CN stretching frequencies. The size of the cooperative effect in each complex depends on the strength of S...N and P...N interactions. It is largest for FHSN?CH2P?NCNH2 and smallest for ClHS?NCH2P?NCCN and ClHS?NCH2P?NCNC complexes. The total spin-spin coupling constants across the chalcogen and pnicogen bonds in the ternary complexes are always larger than those in the binary systems. This trend can be also interpreted as a cooperative effect between chalcogen and pnicogen bond interactions. The enhancing mechanism was analyzed in terms of electron redistribution effects in XHS...NCH2P...NCY complexes. PMID- 25503703 TI - How does the increment of hetero-cyclic conjugated moieties affect electro optical and charge transport properties of novel naphtha-difuran derivatives? A computational approach. AB - We have investigated computationally the effects of pi-conjugation extension on naphtha[2,1-b:6,5-b'] difuran (DPNDF); where we increase the number of fused NDF (central core) and furan rings in the parent molecule. The molecular structures of all analogues have been optimized at the ground (S0) and first excited (S1) states using density functional theory (DFT) and time-dependent density functional theory (TD-DFT), respectively. Then highest occupied molecular orbitals (HOMOs), the lowest unoccupied molecular orbitals (LUMOs), photophysical properties, adiabatic/vertical electron affinities (EAa)/(EAv), adiabatic/vertical ionization potentials (IPa)/(IPv), and hole/electron reorganization energies lambdah/lambdae have been investigated. The effect of NDF and furan rings on structural and electro-optical properties has also been studied. Our calculated reorganization energies of 1a, 1b, and 2c reveal them, materials with balanced hole/electron charge transport, whereas 2a and 2b are good hole-transport materials. By increasing the number of furan rings; the photostability was augmented in 2a, 2b, and 2c. PMID- 25503704 TI - Involvement of toll-like receptor 2 and pro-apoptotic signaling pathways in bone remodeling in osteomyelitis. AB - BACKGROUND AND AIMS: Osteomyelitis is a common manifestation of invasive Staphylococcus aureus infection characterized by bone loss and destruction. We investigated the role of toll-like receptor 2 (TLR2) in bacterial recognition and clearance in response to infection with an osteomyelitis isolate of S. aureus. METHODS: Apoptosis was assessed in the osteoblastic cell line MC3T3-E1 by Annexin V-FITC/PI staining and flow cytometry. The expression of TLR2 and apoptosis related and mitogen-activated protein kinase pathway proteins was assessed by qRT PCR and western blotting. Alkaline phosphatase (ALP) activity and calcium deposition were assessed by ALP activity assay and Alizarin red staining. RESULTS: S. aureus induced apoptosis, upregulated TLR2 expression, and activated mitogen-activated protein kinase pathways in a time dependent manner. Inhibition of the c-Jun N-terminal kinase (JNK) pathway downregulated TLR2 and suppressed the S. aureus induced activation of pro-apoptotic pathways. Short-hairpin RNA mediated silencing of TLR2 reversed S. aureus induced apoptosis and decrease in ALP activity and calcium deposition, and inhibition of JNK had a similar effect. CONCLUSION: We showed that osteoblast apoptosis and osteogenic differentiation in response to bacterial invasion are dependent on TLR2 expression and JNK activation, suggesting novel potential therapeutic targets for the treatment of osteomyelitis. PMID- 25503706 TI - Fabrication of organic light-emitting devices comprising stacked light-emitting units by solution-based processes. AB - Multi-organic light-emitting devices comprising two light-emitting units stacked in series through a charge-generation layer are fabricated by solution processes. A zinc oxide nanoparticles/polyethylene-imine bilayer is used as the electron injection layer and phosphomolybdic acid is used as the charge-generation layer. Appropriate choice of solvents during spin-coating of each layer ensures the nine layered structure fabricated by solution processes. PMID- 25503707 TI - Lung injury and respiratory mechanics in rugby union. AB - BACKGROUND: Rugby is a highly popular team contact sport associated with high injury rates. Specifically, there is a chance of inducing internal lung injuries as a result of the physical nature of the game. Such injuries are only identified with the use of specific invasive protocols or equipment. This study presents a model-based method to assess respiratory mechanics of N=11 rugby players that underwent a low intensity experimental Mechanical Ventilation (MV) Test before and after a rugby game. METHODS: Participants were connected to a ventilator via a facemask and their respiratory mechanics estimated using a time-varying elastance model. RESULTS: All participants had a respiratory elastance <10 cmH2O/L with no significant difference observed between pre and postgame respiratory mechanics (P>0.05). Model-based respiratory mechanics estimation has been used widely in the treatment of the critically ill in intensive care. However, the application of a ventilator to assess the respiratory mechanics of healthy human beings is limited. CONCLUSIONS: This method adapted from ICU mechanical ventilation can be used to provide insight to respiratory mechanics of healthy participants that can be used as a more precise measure of lung inflammation/injury that avoids invasive procedures. This is the first study to conceptualize the assessment of respiratory mechanics in healthy athletes as a means to monitor postexercise stress and therefore manage recovery. PMID- 25503708 TI - Effect of online pedometer program on physical activity in Qatar. AB - BACKGROUND: The aim of this study is to assess the effectiveness of pedometers as motivation for individuals to walk 10,000 steps and more a day. METHODS: A cross sectional longitudinal study conducted during for 12 weeks. The intervention consists of goal setting to reach 10,000 steps or more and to keep it as daily target. The pedometer was issued for every participant after they were registered at the website and given a self-monitoring on line account. Participants were informed to upload their data every week. An automated e-mail and text messages were sent to participant didn't upload the data. Average daily steps measured in the 1st week were taken as baseline, and the average weekly steps were measured at the 4, 8, and 12 weeks. RESULTS: The study included 970 adults, and showed a significant increase in average daily steps from 6.833+/-4.144 steps/day at baseline into 10.600+/-6,385 steps/week at the 12th week (P<0.001), 19.3% met the daily target of 10,000 steps or more at the baseline with considerable increase to 45.0% by the 12th week. However this increase is more obvious in females as only 11.7% of them met the daily target of 10,000 steps at start and reached to 38.5% at the 12th week. At the 12th week the age group >=45 years became more active with pedometer than the younger age group (48.5% vs. 43.2%). Although adults from different races showed increasing physical activity however Arabs remain less active than other ethnic groups (39.0% and 53.3% respectively). CONCLUSIONS: Pedometer program was found to be effective in promoting physical activity in Qatar. Daily steps goal is encouraging adults for achieving their recommended daily physical activity level. This intervention is more useful for adults and women in particular. PMID- 25503709 TI - Brief review of the state of art in futsal. AB - Futsal (the official name of "five side indoor football") has become very popular in recent years, and it counts more than 12 million players in over 100 countries. Futsal is played on a field of 40 x 20 m between 2 teams of 5 players, (four outfield players and the goalkeeper). Despite its rise of popularity, the number of scientific studies related to training modalities as the demands of the match or factors linked to the performance, are quite limited. This brief review aims to explore the few papers published on futsal, taking in consideration some conclusions that can be drawn from previous studies related only to futsal and indoor football players. Future studies should examine the physical demands during the matches, the variation of physical performances during the season and compare different classic training modalities to sport specific exercises, aiming to improve the current knowledge for coaching. PMID- 25503711 TI - Effect of flow-resistive inspiratory loading on pulmonary and respiratory muscle function in sub-elite swimmers. AB - BACKGROUND: The aim of this study was to evaluate the effects of a 12-week swim training and inspiratory muscle training program on respiratory muscle and pulmonary function in competitively trained sub-elite swimmers. METHODS: A double blind, parallel-group experimental design was employed to compare the effects of swim training alone, swim training with sham-inspiratory muscle training, and swim training with true inspiratory muscle training. Twenty-four competitively trained sub-elite swimmers combined swim training with either flow-resistive inspiratory muscle training set at 80% sustained maximal inspiratory pressure with progressively increased work-rest ratios until task failure for 3 days/week (swim training with inspiratory muscle training, N.=8), or swim training with sham-inspiratory muscle training (N.=8), or acted as controls (swim training only, N.=8). Measures of pulmonary and respiratory muscle function were assessed at the beginning and end of the 12-week study period. RESULTS: At baseline, there were no significant differences (P>0.05) in respiratory muscle and pulmonary function between groups. Following the 12-week training period, the swim training with inspiratory muscle training group demonstrated improvements in maximal inspiratory pressure, sustained maximal inspiratory pressure, maximal inspiratory muscle power output, inspiratory muscle work capacity, inspiratory time of contraction, time to fatigue, maximal voluntary ventilation in 12 seconds, and forced inspiratory volume in 1-second (P<0.05). No improvements in pulmonary or respiratory muscle function were observed in the swim training only or swim training with sham-inspiratory muscle training groups (P>0.05). CONCLUSIONS: Inspiratory muscle training in conjunction with swim training improves respiratory muscle function in sub-elite swimmers when compared to swim training only. PMID- 25503710 TI - Comparison of physical performance among Brazilian elite soccer players of different age-categories. AB - BACKGROUND: The purpose of this study was to compare the physical performance (i.e., strength, power, speed and endurance) between Brazilian elite soccer players from different categories of the same club: professionals (PRO), under-20 (U-20), and under-17 (U-17). METHODS: Seventy-one soccer players from three categories (PRO=24; U-20=21 and U-17=26) were assessed at the beginning of pre season. Before the tests, they were familiarized with all experimental procedures. Squat jump (SJ), countermovement jump (CMJ), sprint (10 m/20 m), maximum dynamic strength (1RM), and Yo-Yo intermittent recovery tests level 1 were performed in three non-consecutive sessions. RESULTS: No significant differences were found between the categories for sprint times. The PRO players presented higher outcomes in the 1RM, SJ, CMJ, and Yo-Yo tests than the U-20 and U-17 players (P<=0.05). No significant differences were found between the U-20 and U-17 players in 1RM, and SJ/CMJ heights. The U-20 presented superior performance than the U-17 in the Yo-Yo test (P<=0.05). CONCLUSIONS: The findings indicated that PRO performed better than younger players in all assessments, except for the sprint tests. This may have been possible due to the differences in training experience, technical expertise and individual levels of strength/power. However, the absence of differences between the U-20 and U-17 groups highlighted the necessity of developing specific training strategies in order to improve the physical capacities of younger players, throughout the maturation process. Moreover, due to the importance of sprinting in soccer, it is strongly recommended that fitness coaches develop more effective strategies to improve speed ability in professional players. PMID- 25503712 TI - Collegiate coaches' knowledge of the female athlete triad in relation to sport type. AB - BACKGROUND: The purpose of this study was to determine what coaches of female athletes know about the three components of the female athlete triad with regard to type of sport coached and the characteristics of the coach. METHODS: The sample consisted of 309 NCAA Division I coaches of female athletes in the sports of: sports with subjective scoring of performance (gymnastics and diving), low body weight sports (cross country and rowing), revealing or fitted clothing (volleyball and swimming), and other (soccer and basketball). An original, self report questionnaire, and a 4-point Likert scale to measure confidence in answer was used. The variables were: knowledge, confidence, and coach's characteristics (coach's gender, degree held, years of experience in coaching females, continuing education participation specific to the triad and triad components, and type of sport coached). RESULTS: Coaches of low body weight sports scored significantly higher than both coaches of sports requiring fitted clothing and "other" sports in the overall score. They further had significantly more confidence in their answers than coaches of "other" sports. No significant differences in the overall score in any of the types of sport or total values were found regarding gender, experience, and degree. Coaches who had received training about the triad or its components scored significantly higher than coaches who did not receive training. CONCLUSIONS: The results demonstrated a lack of information among coaches and that participating in formative training can help to reduce this problem. The results found can help in the design of continuing education for coaches. PMID- 25503713 TI - Identifying MRI markers associated with early response following laser ablation for neurological disorders: preliminary findings. AB - There is a renewed interest in MR-guided laser interstitial thermal therapy (LITT) as a minimally invasive alternative to craniotomy for local treatment of various brain tumors and epilepsy. LITT allows for focused delivery of laser energy monitored in real time by MRI, for precise ablation of the lesion. Although highly promising, the long-term effects of laser ablation as a viable treatment option for neurological disorders have yet to be rigorously studied and quantified. In this work, we present a quantitative framework for monitoring per voxel thermal-induced changes post-LITT over time on multi parametric MRI. We demonstrate that voxel-by-voxel quantification of MRI markers over time can enable a careful and accurate (a) characterization of early LITT-related changes (if and when they are exaggerated and when they subside), and (b) identification and monitoring of MRI markers that potentially allow for better quantification of response to LITT therapy. The framework was evaluated on two distinct cohorts of patients (GBM, epilepsy), who were monitored post-LITT at regular time-intervals via multi-parametric MRI. On a cohort of six GBM studies we found that (a) it may be important for the initial treatment-related changes to subside to more reliably capture MRI markers relating to tumor recurrence, and (b) T1w MRI and T2 GRE may better differentiate changes that may correspond to tumor recurrence from patients with no recurrence, as compared to T2w-MRI, and FLAIR. Similarly, our preliminary analysis of four epilepsy studies suggests that (a) early LITT changes (attributed to swelling, edema) appear to subside within 4-weeks post LITT, and (b) ADC may be more reflective of early treatment changes (up to 1 month), while T1w may be more reflective of early delayed treatment changes (1 month, 3 months), while T2-w and T2-FLAIR appeared to be more sensitive to late treatment related changes (6-months post-LITT) compared to the other MRI protocols under evaluation. PMID- 25503714 TI - Retinal projections in the short-tailed fruit bat, Carollia perspicillata, as studied using the axonal transport of cholera toxin B subunit: Comparison with mouse. AB - To provide a modern description of the Chiropteran visual system, the subcortical retinal projections were studied in the short-tailed fruit bat, Carollia perspicillata, using the anterograde transport of eye-injected cholera toxin B subunit, supplemented by the silver-impregnation of anterograde degeneration following eye removal, and compared with the retinal projections of the mouse. The retinal projections were heavily labeled by the transported toxin in both species. Almost all components of the murine retinal projection are present in Carollia in varying degrees of prominence and laterality. The projections: to the superior colliculus, accessory optic nuclei, and nucleus of the optic tract are predominantly or exclusively contralateral; to the dorsal lateral geniculate nucleus and posterior pretectal nucleus are predominantly contralateral; to the ventral lateral geniculate nucleus, intergeniculate leaflet, and olivary pretectal nucleus have a substantial ipsilateral component; and to the suprachiasmatic nucleus are symmetrically bilateral. The retinal projection in Carollia is surprisingly reduced at the anterior end of the dorsal lateral geniculate and superior colliculus, suggestive of a paucity of the relevant ganglion cells in the ventrotemporal retina. In the superior colliculus, in which the superficial gray layer is very thin, the projection is patchy in places where the layer is locally absent. Except for a posteriorly located lateral terminal nucleus, the other accessory optic nuclei are diminutive in Carollia, as is the nucleus of the optic tract. In both species the cholera toxin labeled sparse groups of apparently terminating axons in numerous regions not listed above. A question of their significance is discussed. PMID- 25503715 TI - Reducing hospital-acquired infections and improving the rational use of antibiotics in a developing country: an effectiveness study. AB - BACKGROUND: Prevention of hospital-acquired infections (HAI) is central to providing safe and high quality healthcare. Transmission of infection between patients by health workers, and the irrational use of antibiotics have been identified as preventable aetiological factors for HAIs. Few studies have addressed this in developing countries. AIMS: To implement a multifaceted infection control and antibiotic stewardship programme and evaluate its effectiveness on HAIs and antibiotic use. METHODS: A before-and-after study was conducted over 27 months in a teaching hospital in Indonesia. All children admitted to the paediatric intensive care unit and paediatric wards were observed daily. Assessment of HAIs was made based on the criteria from the Centers for Disease Control and Prevention. The multifaceted intervention consisted of a hand hygiene campaign, antibiotic stewardship (using the WHO Pocket Book of Hospital Care for Children guidelines as standards of antibiotic prescribing for community acquired infections), and other elementary infection control practices. Data were collected using an identical method in the preintervention and postintervention periods. RESULTS: We observed a major reduction in HAIs, from 22.6% (277/1227 patients) in the preintervention period to 8.6% (123/1419 patients) in the postintervention period (relative risk (RR) (95% CI) 0.38 (0.31 to 0.46)). Inappropriate antibiotic use declined from 43% (336 of 780 patients who were prescribed antibiotics) to 20.6% (182 of 882 patients) (RR 0.46 (0.40 to 0.55)). Hand hygiene compliance increased from 18.9% (319/1690) to 62.9% (1125/1789) (RR 3.33 (2.99 to 3.70)). In-hospital mortality decreased from 10.4% (127/1227) to 8% (114/1419) (RR 0.78 (0.61 to 0.97)). CONCLUSIONS: Multifaceted infection control interventions are effective in reducing HAI rates, improving the rational use of antibiotics, increasing hand hygiene compliance, and may reduce mortality in hospitalised children in developing countries. PMID- 25503717 TI - "Bioinformatics: introduction and methods," a bilingual Massive Open Online Course (MOOC) as a new example for global bioinformatics education. PMID- 25503716 TI - Reference genes selection and normalization of oxidative stress responsive genes upon different temperature stress conditions in Hypericum perforatum L. AB - Reverse transcription-quantitative real-time PCR (RT-qPCR) is a widely used technique for gene expression analysis. The reliability of this method depends largely on the suitable selection of stable reference genes for accurate data normalization. Hypericum perforatum L. (St. John's wort) is a field growing plant that is frequently exposed to a variety of adverse environmental stresses that can negatively affect its productivity. This widely known medicinal plant with broad pharmacological properties (anti-depressant, anti-tumor, anti-inflammatory, antiviral, antioxidant, anti-cancer, and antibacterial) has been overlooked with respect to the identification of reference genes suitable for RT-qPCR data normalization. In this study, 11 candidate reference genes were analyzed in H. perforatum plants subjected to cold and heat stresses. The expression stability of these genes was assessed using GeNorm, NormFinder and BestKeeper algorithms. The results revealed that the ranking of stability among the three algorithms showed only minor differences within each treatment. The best-ranked reference genes differed between cold- and heat-treated samples; nevertheless, TUB was the most stable gene in both experimental conditions. GSA and GAPDH were found to be reliable reference genes in cold-treated samples, while GAPDH showed low expression stability in heat-treated samples. 26SrRNA and H2A had the highest stabilities in the heat assay, whereas H2A was less stable in the cold assay. Finally, AOX1, AOX2, CAT1 and CHS genes, associated with plant stress responses and oxidative stress, were used as target genes to validate the reliability of identified reference genes. These target genes showed differential expression profiles over time in treated samples. This study not only is the first systematic analysis for the selection of suitable reference genes for RT-qPCR studies in H. perforatum subjected to temperature stress conditions, but may also provide valuable information about the roles of genes associated with temperature stress responses. PMID- 25503718 TI - [Clinical and histopathological parameters of prostate cancer: influence of anthropometric indices]. AB - BACKGROUND: Adipose tissue is increasingly considered as an endocrinal active organ and may have an influence on the development and progression of prostate cancer. Adverse body fat distribution, considered a risk factor for cardiovascular disease, is not reflected by the body mass index (BMI). OBJECTIVE: The purpose of this work was to assess anthropometric indices which provide a better estimate of body fat distribution and to evaluate their association with clinical and histopathological parameters of prostate cancer. PATIENTS AND METHODS: In patients scheduled for radical prostatectomy between March 2011 and March 2013, height, weight, waist circumference (WC) and hip circumference were measured, then the BMI, waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were calculated. The relationships between anthropometric measures and indices and clinical and histopathological features of PCA were evaluated with uni- and multivariate analyses. RESULTS: In 668 patients available for evaluation, obesity rates were 22.8 %, 50.6% and 30.2 % as defined by BMI >= 30, WHR >= 1 and WHtR >= 0.6, respectively. On univariate analysis, WC and WHtR >= 0.6 correlated with tumor volume (TV) > 2.1 cm(2) (p < 0.05), respectively. WC and WHtR were independent predictors of a TV >= 2.1 cm(2) (p < 0.05) and a WHtR >= 0.6 was an independent predictor of a TV >= 2.1 cm(2) (p < 0.018, risk ratio 1.506, 95 % confidence interval 1.072-2.115). CONCLUSION: In general a higher degree of adiposity seems to correlate with a higher tumor volume. Whether anthropometric indices have prognostic impact needs to be clarified during follow-up. PMID- 25503719 TI - [Treatment of invasive bladder cancer: robot-assisted radical cystectomy and intracorporeal urinary diversion]. AB - PURPOSE: Robot-assisted radical cystectomy (RARC) and intracorporeal urinary diversion are only performed in a few centers of excellence worldwide. Functional and oncologic outcomes are comparable. We report on our experience with RARC and intracorporeal diversion. PATIENTS AND METHODS: We retrospectively identified 86 RARCs in 72 men and 14 women (mean age 69.7 years). All patients underwent robot assisted radical cystectomy and pelvic lymphadenectomy followed by intracorporeal urinary diversion using ileal conduit or neobladder. Of the 86 patients, 24 patients (28%) underwent intracorporeal ileal conduit and 62 patients (72%) underwent intracorporeal neobladder formation. A Studer pouch was created in all who underwent intracorporeal neobladder diversion. Cancer specific survival (CSS) and overall survival (OS) are reported. RESULTS: The mean operative time was 418.9 min (range 205-690 min) and blood loss was 380 ml (range 100-1000 ml). The mean hospital stay was 17.5 days (range 5-62 days). All the surgeries were completed with no open conversions. Minor complications (grade I and II) were reported in 23 patients, while major complications (grade III and above) were reported in 21 patients. The mean nodal yield was 20.3 (range 0-46). Positive margins were found in in 8%. The average follow-up was 31.5 months (range 3-52 months). Continence could be achieved in 88% of patients who received an intracorporeal neobladder. The cancer-specific survival (CSS) and overall survival (OS) were 80% and 70%, respectively. CONCLUSION: RARC with intracorporeal diversion seems to be safe and reproducible in tertiary centers with robotic expertise. Operative times are acceptable and complications as well as functional and oncologic outcomes are comparable. Further standardization of RARC with intracorporeal diversion may lead to a wider adoption of the approach. PMID- 25503720 TI - [Indications for nephron-sparing surgery. Analysis over a 13-year period in the context of changing guidelines]. AB - BACKGROUND: The indications for nephron-sparing surgery have been considerably extended by guideline recommendations in recent years. It remains unclear whether clinical practice still reflects these new guidelines. OBJECTIVE: In this retrospective, monocentric analysis at a tertiary referral center the indications for partial nephrectomy over a 13-year period were evaluated. METHODS: In a retrospective database analysis all cases of surgically treated renal masses from 2001 to 2013 were evaluated. Besides demographic, tumor-specific and perioperative variables the development of the surgical technique depending on the tumor stage was evaluated. RESULTS AND DISCUSSION: The proportion of nephron sparing surgery cases increased from below 20 % in 2001 to 35 % in 2013 in the entire cohort. For stage T1a tumors, partial nephrectomy increased from approximately 50 % to over 90 % and for T1b tumors it rose from 10 % to 50 %. Logistic regression revealed stage 1 tumors to be predictive of partial nephrectomy over the complete evaluation period. Extending the indications for partial nephrectomy even to higher stages is under discussion but not yet supported by data from prospective, controlled studies. PMID- 25503721 TI - [Therapy of retroperitoneal fibrosis: functional therapeutic outcome]. AB - BACKGROUND: The most frequent complication of retroperitoneal fibrosis (RPF) is an extrinsic compression of the ureter resulting in hydronephrosis. Because of the rareness of this uncommon chronic inflammatory disease, therapeutic results concerning the treatment of the obstructive uropathy are often known only for small study groups. MATERIAL AND METHODS: The Else Kroner-Fresenius registry is a nationwide register of patients suffering from RPF in which all disease-related data are prospectively recorded. We performed a retrospective analysis of treatment outcome of different therapy strategies for all patients who underwent standardized treatment in our department since 2007. RESULTS: From April 2007 to January 2014 a total of 97 patients with RPF were treated in our department. The mean age was 54.9 years and the male to female ratio was 3.2:1 (74 males and 23 females). Assessment of 85 out of 97 cases revealed 78 patients and 118 renal units with hydronephrosis. Of these patients 46 received prednisolone, 35 patients tamoxifen and 4 patients a combination therapy. Successful removal of double J stents was possible in 49 out of the 78 cases (62.8%) and in 72 out of 118 renal units (61.0%). Of the patients 26.9% received final surgical treatment of ureter compression and 7.7% of patients were permanently treated with a double J stents. Patients treated with prednisolone were significantly younger (p=0.040) and decided for surgical therapy significantly earlier (p=0.041). Otherwise there were no differences in functional outcome of patients treated with either prednisolone or tamoxifen. CONCLUSION: Removal of double J stents was possible in 63% of patients regardless of the medicinal approach to therapy, which supports the strategy of using medicinal treatment before the application of surgical solutions. Nevertheless, surgical interventions were necessary in more than 25% of cases. PMID- 25503722 TI - [Retroperitoneal fibrosis: development of a biomarker profile for diagnosis and therapy monitoring]. AB - INTRODUCTION: Retroperitoneal fibrosis (RPF) is a rare chronic inflammatory disease which is characterized by fibrotic tissue in the retroperitoneal space. There have only been a few studies on serum markers of this disease. The main goal of the current investigation was to identify biological markers which are increased in the serum of patients suffering from RPF and which may correlate with the extent of fibrosis. MATERIAL AND METHODS: The serum of 42 patients with primary and yet untreated retroperitoneal fibrosis was examined for biomarkers known to be specific for fibrotic diseases and compared to a control group. In addition, patients were stratified according to the extent and volume of the retroperitoneal mass using cross-sectional imaging. To estimate the discriminatory power of the evaluated biomarkers, receiver operating characteristic (ROC) curves were created. RESULTS: Independent of the extent of fibrosis, calprotectin, fibrinogen, osteopontin, matrix metallopeptidase 9 (MMP 9), tenascin C and TIMP metallopeptidase inhibitor 1 (TIMP-1) were significantly increased (p<0.01) in patients suffering from RPF compared to the control group. Connective tissue growth factor (CTGF) was significantly elevated (p<0.01) in patients with high RPF burden only but monocyte chemoattractant protein 1 (MCP-1) and heart-type fatty acid binding protein (H-FABP) showed no increase in serum levels. The discriminatory power of these parameters was ranked by the ROC analysis which demonstrated an area under the curve (AUC) >0.87 for MMP-9, TIMP 1, osteopontin, tenascin C, asymmetric dimethylarginine (ADMA), fibrinogen and calprotectin and an AUC <0.64 for MMP-2, CTGF, H-FABP and MCP-1. CONCLUSION: Several biomarkers of fibrogenesis were significantly elevated in patients suffering from RPF as compared to a control group. These biomarker candidates will be further evaluated for their potential to allow a differentiation between other diseases or if they could be used for disease monitoring. PMID- 25503723 TI - [Social media - do's and don'ts]. PMID- 25503725 TI - Mechanical stress enhances CD9 expression in cultured podocytes. AB - Elevated glomerular pressure represents a high risk for the development of severe kidney diseases and causes an increase in mechanical load to podocytes. In this study, we investigated whether mechanical stress alters gene expression in cultured podocytes using gene arrays. We found that tetraspanin CD9 is significantly upregulated in cultured podocytes after mechanical stress. The differential expression of CD9 was confirmed by RT-PCR and Western blotting under stretched and unstretched conditions. Furthermore, mechanical stress resulted in a relocalization of CD9. To get an insight into the functional role of CD9, podocytes were transfected with pEGFP-CD9. The expression of CD9 induced the formation of substratum-attached thin arborized protrusions. Ca(2+) depletion revealed that podocytes overexpressing CD9 possess altered adhesive properties in contrast to the control transfected cells. Finally, elevated CD9 expression increased migration of podocytes in a wound assay. In summary, our results suggest that upregulation of CD9 may play an important role in podocyte morphology, adhesion, and migration. PMID- 25503724 TI - Vitamin D receptor agonist VS-105 improves cardiac function in the presence of enalapril in 5/6 nephrectomized rats. AB - Vitamin D receptor (VDR) agonists (VDRAs) are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). Patients with CKD experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRA therapy may be associated with cardio-renal protective and survival benefits in patients with CKD. The 5/6 nephrectomized (NX) Sprague-Dawley rat with established uremia exhibits elevated serum parathyroid hormone (PTH), hypertension, and abnormal cardiac function. Treatment of 5/6 NX rats with VS-105, a novel VDRA (0.05 and 0.5 MUg/kg po by gavage), once daily for 8 wk in the presence or absence of enalapril (30 mg/kg po via drinking water) effectively suppressed serum PTH without raising serum calcium. VS-105 alone reduced systolic blood pressure (from 174 +/- 6 to 145 +/- 9 mmHg, P < 0.05) as effectively as enalapril (from 174 +/- 6 to 144 +/- 7 mmHg, P < 0.05). VS-105 improved cardiac functional parameters such as E/A ratio, ejection fraction, and fractional shortening with or without enalapril. Enalapril or VS 105 alone significantly reduced left ventricular hypertrophy (LVH); VS-105 plus enalapril did not further reduce LVH. VS-105 significantly reduced both cardiac and renal fibrosis. The lack of hypercalcemic toxicity of VS-105 is due to its lack of effects on stimulating intestinal calcium transport and inducing the expression of intestinal calcium transporter genes such as Calb3 and TRPV6. These studies demonstrate that VS-105 is a novel VDRA that may provide cardiovascular benefits via VDR activation. Clinical studies are required to confirm the cardiovascular benefits of VS-105 in CKD. PMID- 25503726 TI - A functional (pro)renin receptor is expressed in human lymphocytes and monocytes. AB - The renin-angiotensin system (RAS) is involved in inflammation. The signaling via the ANG II type 1 receptor in human lymphocytes and monocytes, which play key roles in pathophysiology of glomerulonephritis (GN), can enhance inflammation. However, the role of the (pro)renin receptor [(P)RR], a component of the RAS, in inflammatory reactions is unknown. We assessed whether (P)RR is expressed in human lymphocytes and monocytes by RT-PCR, Western blotting, flow cytometry, and immunohistochemistry, and whether (P)RR functions in inflammation. (P)RR mRNA and protein were expressed in human peripheral blood mononuclear cells (PBMCs). Flow cytometric analysis revealed high expression of (P)RR on monocytes. (P)RR was present on PBMCs, infiltrating lymphocytes, and macrophages around glomeruli with a crescent in anti-neutrophil cytoplasmic antibody (ANCA)-associated GN. Renin stimulation of PBMCs from healthy subjects in the presence of the ANG II type 1 receptor and ANG II type 2 receptor blockers induced ERK1/2 phosphorylation and release of IL-6 and expression of cyclooxygenase-2 (COX-2). The increases in cytokine release and COX-2 expression were inhibited in the presence of an ERK1/2 inhibitor. (P)RR knockdown by small interfering RNA in U937 cells, a human leukemic monocyte lymphoma cell line, significantly decreased ERK1/2 phosphorylation after renin stimulation. Thus (P)RR expressed in human inflammatory cells might contribute to inflammation in ANCA-associated GN. PMID- 25503727 TI - Loss of Rho-GDIalpha sensitizes podocytes to lipopolysaccharide-mediated injury. AB - Nephrotic syndrome is a disease of glomerular permselectivity that can arise as a consequence of heritable or acquired changes to the integrity of the glomerular filtration barrier. We recently reported two siblings with heritable nephrotic syndrome caused by a loss of function mutation in the gene ARHGDIA, which encodes for Rho guanine nucleotide dissociation inhibitor-alpha (GDIalpha). GDIs are known to negatively regulate Rho-GTPase signaling. We hypothesized that loss of GDIalpha sensitizes podocytes to external injury via hyperactivation of Rho GTPases and p38 MAPK. We examined the response of cultured podocytes with and without knockdown of GDIalpha to LPS injury by assessing the levels of phospho p38 as well as the degree of synaptopodin loss. GDIalpha knockdown podocytes showed more pronounced and sustained p38 phosphorylation in response to LPS compared with control podocytes, and this was blunted significantly by the Rac1 inhibitor. In LPS-treated control podocytes, synaptopodin degradation occurred, and this was dependent on p38, the proteasome, and cathepsin L. In GDIalpha knockdown podocytes, the same events were triggered, but the levels of synaptopodin after LPS treatment were significantly lower than in control podocytes. These experiments reveal a common pathway by which heritable and environmental risk factors converge to injure podocytes, from Rac1 hyperactivation to p38 phosphorylation and synaptopodin degradation via the ubiquitin-proteasome pathway and cathepsin L. PMID- 25503728 TI - IL-1 receptor blockade alleviates endotoxin-mediated impairment of renal drug excretory functions in rats. AB - The aim of our study was to investigate whether two potent anti-inflammatory agents, dexamethasone and anakinra, an IL-1 receptor antagonist, may influence acute kidney injury (AKI) and associated drug excretory functions during endotoxemia (LPS) in rats. Ten hours after LPS administration, untreated endotoxemic rats developed typical symptoms of AKI, with reduced GFR, impaired tubular excretion of urea and sodium, and decreased urinary excretion of azithromycin, an anionic substrate for multidrug resistance-transporting proteins. Administration of both immunosuppressants attenuated the inflammatory response, liver damage, AKI, and increased renal clearance of azithromycin mainly by restoration of GFR, without significant influence on its tubular secretion. The lack of such an effect was related to the differential effect of both agents on the renal expression of individual drug transporters. Only dexamethasone increased the urinary clearance of bile acids, in accordance with the reduction of the apical transporter (Asbt) for their tubular reabsorption. In summary, our data demonstrated the potency of both agents used for the prevention of AKI, imposed by endotoxins, and for the restoration of renal drug elimination, mainly by the improvement of GFR. The influence of both drugs on altered tubular functions and the expression of drug transporters was differential, emphasizing the necessity of knowledge of transporting pathways for individual drugs applied during sepsis. The effect of anakinra suggests a significant contribution of IL-1 signaling to the pathogenesis of LPS-induced AKI. PMID- 25503729 TI - Effects of hydration in rats and mice with polycystic kidney disease. AB - Vasopressin and V2 receptor signaling promote polycystic kidney disease (PKD) progression, raising the question whether suppression of vasopressin release through enhanced hydration can delay disease advancement. Enhanced hydration by adding 5% glucose to the drinking water has proven protective in a rat model orthologous to autosomal recessive PKD. We wanted to exclude a glucose effect and explore the influence of enhanced hydration in a mouse model orthologous to autosomal dominant PKD. PCK rats were assigned to normal water intake (NWI) or high water intake (HWI) groups achieved by feeding a hydrated agar diet (HWI agar) or by adding 5% glucose to the drinking water (HWI-glucose), with the latter group used to recapitulate previously published results. Homozygous Pkd1 R3277C (Pkd1(RC/RC)) mice were assigned to NWI and HWI-agar groups. To evaluate the effectiveness of HWI, kidney weight and histomorphometry were assessed, and urine vasopressin, renal cAMP levels, and phosphodiesterase activities were measured. HWI-agar, like HWI-glucose, reduced urine vasopressin, renal cAMP levels, and PKD severity in PCK rats but not in Pkd1(RC/RC) mice. Compared with rat kidneys, mouse kidneys had higher phosphodiesterase activity and lower cAMP levels and were less sensitive to the cystogenic effect of 1-deamino-8-d-arginine vasopressin, as previously shown for Pkd1(RC/RC) mice and confirmed here in Pkd2(WS25/-) mice. We conclude that the effect of enhanced hydration in rat and mouse models of PKD differs. More powerful suppression of V2 receptor-mediated signaling than achievable by enhanced hydration alone may be necessary to affect the development of PKD in mouse models. PMID- 25503730 TI - Chronic ANG II infusion induces sex-specific increases in renal T cells in Sprague-Dawley rats. AB - Recent studies suggest that sex of the animal and T cell impact ANG II hypertension in Rag(-/-) mice, with females being protected relative to males. This study tested the hypothesis that ANG II results in greater increases in proinflammatory T cells and cytokines in males than in females. Male and female Sprague-Dawley (SD) rats, aged 12 wk, were treated with vehicle or ANG II (200 ng.kg(-1).min(-1)) for 2 wk. Renal CD4(+) T cells and Tregs were comparable between vehicle-treated males and females, although males expressed more Th17 and IL-17(+) T cells and fewer IL-10(+) T cells than females. ANG II resulted in greater increases in CD4(+) T cells, Th17 cells, and IL-17(+) cells in males; Tregs increased only in females. We previously showed that ANG (1-7) antagonizes ANG II-induced increases in blood pressure in females and ANG (1-7) has been suggested to be anti-inflammatory. Renal ANG (1-7) levels were greater in female SD at baseline and following ANG II infusion. Additional rats were treated with ANG II plus the ANG (1-7)-mas receptor antagonist A-779 (48 MUg.kg(-1).h(-1)) to test the hypothesis that greater ANG (1-7) in females results in more Tregs relative to males. Inhibition of ANG (1-7) did not alter renal T cells in either sex. In conclusion, ANG II induces a sex-specific effect on the renal T cell profile. Males have greater increases in proinflammatory T cells, and females have greater increases in anti-inflammatory Tregs; however, sex differences in the renal T cell profile are not mediated by ANG (1-7). PMID- 25503731 TI - TIGAR regulates glycolysis in ischemic kidney proximal tubules. AB - Tp53-induced glycolysis and apoptosis regulator (TIGAR) activation blocks glycolytic ATP synthesis by inhibiting phosphofructokinase-1 activity. Our data indicate that TIGAR is selectively induced and activated in renal outermedullary proximal straight tubules (PSTs) after ischemia-reperfusion injury in a p53 dependent manner. Under severe ischemic conditions, TIGAR expression persisted through 48 h postinjury and induced loss of renal function and histological damage. Furthermore, TIGAR upregulation inhibited phosphofructokinase-1 activity, glucose 6-phosphate dehydrogenase (G6PD) activity, and induced ATP depletion, oxidative stress, autophagy, and apoptosis. Small interfering RNA-mediated TIGAR inhibition prevented the aforementioned malevolent effects and protected the kidneys from functional and histological damage. After mild ischemia, but not severe ischemia, G6PD activity and NADPH levels were restored, suggesting that TIGAR activation may redirect the glycolytic pathway into gluconeogenesis or the pentose phosphate pathway to produce NADPH. The increased level of NADPH maintained the level of GSH to scavenge ROS, resulting in a lower sensitivity of PST cells to injury. Under severe ischemia, G6PD activity and NADPH levels were reduced during reperfusion; however, blockade of TIGAR enhanced their levels and reduced oxidative stress and apoptosis. Collectively, these results demonstrate that inhibition of TIGAR may protect PST cells from energy depletion and apoptotic cell death in the setting of severe ischemia-reperfusion injury. However, under low ischemic burden, TIGAR activation induces the pentose phosphate pathway and autophagy as a protective mechanism. PMID- 25503732 TI - Pharmacological inhibition of galectin-3 protects against hypertensive nephropathy. AB - Galectin-3 activation is involved in the pathogenesis of renal damage and fibrogenesis. Limited data are available to suggest that galectin-3-targeted intervention is a potential therapeutic candidate for the prevention of chronic kidney disease. Homozygous TGR(mREN)27 (REN2) rats develop severe high blood pressure (BP) and hypertensive end-organ damage, including nephropathy and heart failure. Male REN2 rats were treated with N-acetyllactosamine [galectin-3 inhibitor (Gal3i)] for 6 wk; untreated REN2 and Sprague-Dawley rats served as controls. We measured cardiac function with echocardiogram and invasive hemodynamics before termination. BP and proteinuria were measured at baseline and at 3 and 6 wk. Plasma creatinine was determined at 6 wk. Renal damage was assessed for focal glomerular sclerosis, glomerular desmin expression, glomerular and interstitial macrophages, kidney injury molecule-1 expression, and alpha smooth muscle actin expression. Inflammatory cytokines and extracellular matrix proteinases were quantified by quantitative real-time PCR. Systolic BP was higher in control REN2 rats, with no effect of Gal3i treatment. Plasma creatinine and proteinuria were significantly increased in control REN2 rats; Gal3i treatment reduced both. Renal damage (focal glomerular sclerosis, desmin, interstitial macrophages, kidney injury molecule-1, alpha-smooth muscle actin, collagen type I, and collagen type III) was also improved by Gal3i. All inflammatory markers (CD68, IL-68, galectin-3, and monocyte chemoattractant protein-1) were elevated in control REN2 rats and attenuated by Gal3i. Markers of extracellular matrix turnover were marginally altered in untreated REN2 rats compared with Sprague Dawley rats. In conclusion, galectin-3 inhibition attenuated hypertensive nephropathy, as indicated by reduced proteinuria, improved renal function, and decreased renal damage. Drugs binding to galectin-3 may be therapeutic candidates for the prevention of chronic kidney disease. PMID- 25503734 TI - Renal oxygenation: preglomerular vasculature is an unlikely contributor to renal oxygen shunting. AB - The primary aim of this study was to assess the plausibility of preglomerular arterial-to-venous oxygen shunting in the kidney. To this end, we have developed a segment-wise three-dimensional computational model that takes into account transport processes in arteries, veins, cortical tissue, and capillaries. Our model suggests that the amount of preglomerular oxygen shunting is negligible. Consequently, it is improbable that preglomerular shunting contributes to the hypothesized regulation of renal oxygenation. Cortical tissue oxygenation is more likely determined by the interplay between oxygen supply, either from the preglomerular vasculature or from capillaries, and oxygen consumption. We show that reported differences in permeability to oxygen between perfused and unperfused tissue may be explained by what we refer to as advection-facilitated diffusion. We further show that the preglomerular vasculature is the primary source of oxygen for the tissue when cortical consumption is high or renal arterial blood is highly oxygenated, i.e., under hyperoxemic conditions. Conversely, when oxygen demand in the tissue is decreased, or under hypoxemic conditions, oxygen is supplied predominantly by capillaries. PMID- 25503736 TI - Continuum of historical controversies regarding the structural-functional relationship of the glomerular ultrafiltration unit. PMID- 25503737 TI - Post Mortem Human Surrogate Injury Response of the Pelvis and Lower Extremities to Simulated Underbody Blast. AB - Military vehicle underbody blast (UBB) is the cause of many serious injuries in theatre today; however, the effects of these chaotic events on the human body are not well understood. The purpose of this research was to replicate both UBB loading conditions and investigate occupant response in a controlled laboratory setting. In addition to better understanding the response of the human to high rate vertical loading, this test series also aimed to identify high rate injury thresholds. Ten whole body post mortem human surrogate (PMHS) tests were completed using the University of Virginia's ODYSSEY simulated blast rig under a range of loading conditions. Seat pan accelerations ranged from 291 to 738 g's over 3 ms of positive phase duration, and foot pan accelerations from 234 to 858 g's over 3 ms of positive phase duration. Post-test computed tomography (CT) scans and necropsies were performed to determine injuries, and revealed a combination of pelvic, lumbar, thoracic, and lower extremity injuries. The research in this paper discusses pelvis and lower extremity injuries under high rate vertical loads. PMID- 25503735 TI - Endogenous flow-induced nitric oxide reduces superoxide-stimulated Na/H exchange activity via PKG in thick ascending limbs. AB - Luminal flow stimulates endogenous nitric oxide (NO) and superoxide (O2 (-)) production by renal thick ascending limbs (TALs). The delicate balance between these two factors regulates Na transport in TALs; NO enhances natriuresis, whereas O2 (-) augments Na absorption. Endogenous, flow-stimulated O2 (-) enhances Na/H exchange (NHE). Flow-stimulated NO reduces flow-induced O2 (-), a process mediated by cGMP-dependent protein kinase (PKG). However, whether flow stimulated, endogenously-produced NO diminishes O2 (-)-stimulated NHE activity and the signaling pathway involved are unknown. We hypothesized that flow-induced NO reduces the stimulation of NHE activity caused by flow-induced O2 (-) via PKG in TALs. Intracellular pH recovery after an acid load was measured as an indicator of NHE activity in isolated, perfused rat TALs. l-Arginine, the NO synthase substrate, decreased NHE activity by 34 +/- 5% (n = 5; P < 0.04). The O2 (-) scavenger tempol decreased NHE activity by 46 +/- 8% (n = 6; P < 0.004) in the absence of NO. In the presence of l-arginine, the inhibitory effect of tempol on NHE activity was reduced to -19 +/- 6% (n = 6; P < 0.03). The soluble guanylate cyclase inhibitor LY-83583 blocked the effect of l-arginine thus restoring tempol's effect on NHE activity to -42 +/- 4% (n = 6; P < 0.0005). The PKG inhibitor KT-5823 also inhibited l-arginine's effect on tempol-reduced NHE activity (-43 +/- 5%; n = 5; P < 0.03). We conclude that flow-induced NO reduces the stimulatory effect of endogenous, flow-induced O2 (-) on NHE activity in TALs via an increase in cGMP and PKG activation. PMID- 25503733 TI - Deciphering physiological role of the mechanosensitive TRPV4 channel in the distal nephron. AB - Long-standing experimental evidence suggests that epithelial cells in the renal tubule are able to sense osmotic and pressure gradients caused by alterations in ultrafiltrate flow by elevating intracellular Ca(2+) concentration. These responses are viewed as critical regulators of a variety of processes ranging from transport of water and solutes to cellular growth and differentiation. A loss in the ability to sense mechanical stimuli has been implicated in numerous pathologies associated with systemic imbalance of electrolytes and to the development of polycystic kidney disease. The molecular mechanisms conferring mechanosensitive properties to epithelial tubular cells involve activation of transient receptor potential (TRP) channels, such as TRPV4, allowing direct Ca(2+) influx to increase intracellular Ca(2+) concentration. In this review, we critically analyze the current evidence about signaling determinants of TRPV4 activation by luminal flow in the distal nephron and discuss how dysfunction of this mechanism contributes to the progression of polycystic kidney disease. We also review the physiological relevance of TRPV4-based mechanosensitivity in controlling flow-dependent K(+) secretion in the distal renal tubule. PMID- 25503738 TI - Intramucosal gastric cancer: the rate of lymph node metastasis in signet ring cell carcinoma is as low as that in well-differentiated adenocarcinoma. AB - OBJECTIVE: Endoscopic resection (ER) plays a major role in the management of early gastric cancer. Less lymph node metastasis (LNM) and better survival rates were reported in early gastric signet ring cell carcinoma (SRC) than adenocarcinoma. We investigated and compared the clinicopathologic characteristics of endoscopic and surgical features in early gastric SRC and adenocarcinoma in accordance with histologic differentiation to examine the feasibility of ER in early gastric SRC. PATIENTS AND METHODS: From January 2003 to September 2011, patients diagnosed with early gastric cancer among patients who had undergone a curative gastrectomy with lymph node dissection were enrolled. Patients' age, sex, tumor size, location, macroscopic type, depth of invasion, lymphovascular invasion (LVI), and LNM were determined. RESULTS: A total of 696 patients were enrolled. SRC was more frequent in women and more common at the mid-body than differentiated adenocarcinoma. SRC was more common in patients younger than 50 years of age (P < 0.001) and the elevated type was less common in SRC than other adenocarcinomas (P < 0.001). The incidence of submucosal invasion, LVI, and LNM in SRC were similar to well-differentiated adenocarcinoma. Moderately and poorly differentiated group, tumor size greater than 20 mm, submucosal invasion, and LVI were independent risk factors predicting LNM. Intramucosal SRC less than 20 mm had no LNM. CONCLUSION: Rate of LNM and submucosal invasion in early SRC was as low as those in early well-differentiated adenocarcinoma. ER for early gastric SRC may be an alternative to surgical gastrectomy under certain conditions. PMID- 25503739 TI - Boceprevir and telaprevir-based regimens for the treatment of hepatitis C virus in HIV/HCV coinfected patients. AB - BACKGROUND AND AIM: Hepatitis C virus (HCV) treatment in patients coinfected with HIV has historically been limited by poor efficacy and medication toxicities. Direct-acting antivirals (e.g. boceprevir and telaprevir) improve treatment results in clinical trials, but little is known about the outcomes in community based coinfected populations. This project aimed to describe the real-world effectiveness of boceprevir-based or telaprevir-based therapies in HIV/HCV coinfected patients. MATERIALS AND METHODS: We identified HIV/HCV coinfected patients of all genotypes in the Veterans Affairs healthcare system who initiated pegylated interferon and ribavirin with or without boceprevir or telaprevir from June 2011 to November 2012 (n = 134). RESULTS: Sustained virologic response (SVR) was higher in genotype 1 patients receiving boceprevir or telaprevir [n = 62, SVR = 50.0%, 95% confidence interval (CI) 37-63] versus pegylated interferon/ribavirin alone (n = 48, SVR = 33.3%, 95% CI 20-47). Patients with genotypes 2/3 treated with pegylated interferon/ribavirin (n = 24) achieved an SVR of 41.7% (95% CI 20-63). Only a few patients (15-25%) of each genotype completed more than 44 of 48 projected weeks. Treatment with boceprevir or telaprevir was the only characteristic independently associated with SVR in genotype 1 (adjusted odds ratio 2.2, 95% CI 1.1-4.7). CONCLUSION: Addition of boceprevir or telaprevir to pegylated interferon/ribavirin improves treatment response in genotype 1 HIV/HCV coinfected patients. Treatment response is similar to reports from HCV monoinfected Veterans Affairs patients but lower than those reported in clinical trials. Early treatment discontinuation was common. PMID- 25503740 TI - Diagnosis and management of autonomic failure in neurodegenerative disorders. AB - BACKGROUND: One of the hallmarks of the alpha-synucleinopathies is the degeneration of the autonomic nervous system. SUMMARY: This review discusses the diagnosis and management of cardiovascular autonomic failure within the context of the alpha-synucleinopathies. In addition, it outlines the utility of various laboratory assessments including cardiovascular reflex tests for the differential diagnoses of these disorders, as well as general disease management strategies. Key Messages: Laboratory investigations assessing the autonomic control of the cardiovascular system are useful in the differential diagnosis of alpha synucleinopathies, especially in early stages of disease. CLINICAL IMPLICATIONS: The characterization of the different features of AF in patients with alpha synucleinopathies is challenging because it might help to improve the accuracy of the differential diagnosis between these diseases at onset. Further cardiovascular AF has been demonstrated to have a negative prognostic role in alpha-synucleinopathies, therefore an early detection of cardiovascular dysautonomia allows to positively impact the disease course guiding the appropriate therapy. PMID- 25503741 TI - Effect of Sex and Impaired Glucose Tolerance on Organ-Specific Dietary Fatty Acid Metabolism in Humans. AB - Oral 14(R,S)-[(18)F]-fluoro-6-thia-heptadecanoic acid was used to determine whether an increase in cardiac dietary fatty acid (DFA) metabolism in impaired glucose tolerance (IGT) is different in men and women. Myocardial DFA partitioning after 6 h was higher in IGT versus control subjects (P = 0.006) in both men (2.14 [95% CI 1.70-2.18] vs. 1.28 standard uptake value [SUV] units [0.80-1.76]) and women (1.95 [1.57-2.33] vs. 1.64 SUV units [1.32-1.96]) without difference between sexes. Myocardial DFA fractional uptake (Ki) between time 90 and 120 min postprandially was also higher in IGT versus control subjects (P < 0.001) in men (0.063 [0.032-0.095] vs. 0.016 min(-1) [0.007-0.025]) and women (0.050 [0.024-0.077] vs. 0.030 min(-1) [0.013-0.047]) without significant sex difference. Men had higher net myocardial DFA uptake between time 90 and 120 min driven by higher chylomicron-triglyceride (TG) levels. IGT-associated increased cardiac DFA partitioning was directly related to obesity in women, whereas it was associated with IGT per se in men. We conclude that early cardiac DFA uptake is higher in men driven by change in postprandial chylomicron-TG level but that increase in 6-h postprandial cardiac DFA partitioning nevertheless occurs with IGT both in men and women. PMID- 25503742 TI - Hepatic Phosphoserine Aminotransferase 1 Regulates Insulin Sensitivity in Mice via Tribbles Homolog 3. AB - Phosphoserine aminotransferase 1 (PSAT1) is an enzyme participating in serine synthesis. A role of PSAT1 in the regulation of insulin sensitivity, however, is unknown. In this study, we showed that hepatic PSAT1 expression and liver serine levels are reduced in genetically engineered leptin receptor-deficient (db/db) mice and high-fat diet (HFD)-induced diabetic mice. Additionally, overexpression of PSAT1 by adenovirus expressing PSAT1 improved insulin signaling and insulin sensitivity in vitro and in vivo under normal conditions. Opposite effects were observed when PSAT1 was knocked down by adenovirus expressing small hairpin RNA specific for PSAT1 (Ad-shPSAT1). Importantly, overexpression of PSAT1 also significantly ameliorated insulin resistance in diabetic mice. In addition, PSAT1 inhibited the expression of hepatic tribbles homolog 3 (TRB3) in vitro and in vivo, and adenoviruses expressing small hairpin RNA against TRB3-mediated inhibition of TRB3 reversed the attenuated insulin sensitivity in Ad-shPSAT1 mice. Interestingly, we found that serine mediates PSAT1 regulation of TRB3 expression and insulin signaling in vitro. These results identify a novel function for hepatic PSAT1 in regulating insulin sensitivity and provide important insights in targeting PSAT1 for treating insulin resistance and type 2 diabetes. Our results also suggest that nonessential amino acid serine may play an important role in regulating insulin sensitivity. PMID- 25503744 TI - Role of a putative tungsten-dependent formylmethanofuran dehydrogenase in Methanosarcina acetivorans. AB - Methanogenesis, the biological production of methane, is the sole means for energy conservation for methanogenic archaea. Among the few methanogens shown to grow on carbon monoxide (CO) is Methanosarcina acetivorans, which produces, beside methane, acetate and formate in the process. Since CO-dependent methanogenesis proceeds via formation of formylmethanofuran from CO2 and methanofuran, catalyzed by formylmethanofuran dehydrogenase, we were interested whether this activity could participate in the formate formation from CO. The genome of M. acetivorans encodes four putative formylmethanofuran dehydrogenases, two annotated as molybdenum-dependent and the remaining two as tungsten-dependent enzymes. A mutant lacking one of the putative tungsten enzymes grew very slowly on CO and only after a prolonged adaptation period, which suggests an important role for this isoform during growth on CO. Methanol- and CO-dependent growth of the mutant required the presence of molybdenum indicating an indispensable function of this metal in the remaining isoforms. CO-dependent formate formation could not be observed in the mutant indicating involvement of the respective isoform in the process. However, addition of formaldehyde, which spontaneously reacts with tetrahydrosarcinapterin (H4SPT) to methenyl-H4SPT, led to near-wild type formate production rates, which argues for an alternative route of formate formation in this organism. PMID- 25503743 TI - Peripheral arterial disease and ankle-brachial index abnormalites in young and middle-aged HIV-positive patients in lower Silesia, Poland. AB - BACKGROUND: Peripheral arterial disease (PAD) is a clinical manifestation of atherosclerosis and mainly refers to elderly patients, having a negative impact on their functionality and quality of life. The findings of previous studies in HIV-infected patients have shown that cardiovascular risk is higher and PAD occurs more frequently than in the general population. There are also contradictory observations. Much less is known about the ankle-brachial index (ABI) value in asymptomatic HIV-infected patients. The aim of this study was to evaluate the prevalence of PAD and ankle-brachial index abnormalities as well as to determine risk factors related to the disease in a group of Polish HIV positive patients. METHODS AND FINDINGS: One hundred and eleven young to middle aged HIV-positive subjects and 40 noninfected subjects were enrolled into the study. Resting ABI measurements were performed and cardiovascular risk was analysed as well. Subgroups were created according to the ABI values: low (PAD), borderline, normal, high and altered ABI. Symptomatic PAD was observed in 2 HIV positive patients, asymptomatic PAD was not diagnosed. The ABI value is lower and more varied, in 22.5% of the study group altered ABI values were found. Six subjects demonstrated borderline ABI, and 15 high ABI, including >1.4. In the control group no low or very high values were reported. A relation between low ABI and cardiovascular family history and between altered ABI and high-density lipoprotein cholesterol (HDL-C) level was demonstrated. CONCLUSIONS: In young and middle-aged HIV-positive patients, symptomatic PAD prevalence is comparable to that observed in the overall population. Among asymptomatic patients PAD is not reported. The ABI value in HIV-positive patients is more varied compared to the HIV-negative subjects; the altered ABI shows a strong relation with low HDL-C levels and metabolic syndrome. PMID- 25503745 TI - Expression and evolution of the non-canonically translated yeast mitochondrial acetyl-CoA carboxylase Hfa1p. AB - The Saccharomyces cerevisiae genome encodes two sequence related acetyl-CoA carboxylases, the cytosolic Acc1p and the mitochondrial Hfa1p, required for respiratory function. Several aspects of expression of the HFA1 gene and its evolutionary origin have remained unclear. Here, we determined the HFA1 transcription initiation sites by 5' RACE analysis. Using a novel "Stop codon scanning" approach, we mapped the location of the HFA1 translation initiation site to an upstream AUU codon at position -372 relative to the annotated start codon. This upstream initiation leads to production of a mitochondrial targeting sequence preceding the ACC domains of the protein. In silico analyses of fungal ACC genes revealed conserved "cryptic" upstream mitochondrial targeting sequences in yeast species that have not undergone a whole genome duplication. Our Deltahfa1 baker's yeast mutant phenotype rescue studies using the protoploid Kluyveromyces lactis ACC confirmed functionality of the cryptic upstream mitochondrial targeting signal. These results lend strong experimental support to the hypothesis that the mitochondrial and cytosolic acetyl-CoA carboxylases in S. cerevisiae have evolved from a single gene encoding both the mitochondrial and cytosolic isoforms. Leaning on a cursory survey of a group of genes of our interest, we propose that cryptic 5' upstream mitochondrial targeting sequences may be more abundant in eukaryotes than anticipated thus far. PMID- 25503747 TI - New endoscopic thyroidectomy with the transareola single-site approach: a comparison with the bilateral areolar approach. AB - PURPOSE: We developed the transareola single-site approach (TASSA) for less invasive endoscopic thyroidectomy to avoid scars on exposed areas. Here, we report our experience with the TASSA technique in treatment of benign thyroid tumors and evaluate its feasibility through comparison with the bilateral areolar approach (BAA). METHODS: From September 2009 to December 2011, 129 patients with benign thyroid tumors were enrolled in the study. Of these patients, 51 patients underwent endoscopic thyroidectomy by TASSA and 78 patients by BAA. The TASSA technique was performed using one 10 mm trocar and one 5 mm trocar through circumareolar incisions using conventional endoscopic instruments. The BAA procedure was performed using one 10 mm trocar and two 5 mm trocars through bilateral circumareolar incisions. RESULTS: Comparing TASSA with BAA, there were significant differences in the mean operative time (141.96 +/- 19.85 vs. 98.14 +/ 14.15 min) for lobectomy (P<0.05) and in the subcutaneous dissection area (101.00 +/- 6.33 vs. 132.51 +/- 5.25 cm, P<0.05). However, there were no significant differences in the duration of hospitalization, amount of drainage, occurrence of postoperative complications, and postoperative pain. All the patients were satisfied with the cosmetic result in the 2 groups. CONCLUSIONS: Endoscopic thyroidectomy using the TASSA procedure is feasible and safe, and affords the advantages of minimal invasiveness and excellent cosmesis results compared with other approaches including BAA. The 2 procedures are technically more challenging procedures, which may become alternative procedures for treatment of patients with benign thyroid tumors, especially those with strong desire for cervical cosmesis. PMID- 25503746 TI - High-throughput genome editing and phenotyping facilitated by high resolution melting curve analysis. AB - With the goal to generate and characterize the phenotypes of null alleles in all genes within an organism and the recent advances in custom nucleases, genome editing limitations have moved from mutation generation to mutation detection. We previously demonstrated that High Resolution Melting (HRM) analysis is a rapid and efficient means of genotyping known zebrafish mutants. Here we establish optimized conditions for HRM based detection of novel mutant alleles. Using these conditions, we demonstrate that HRM is highly efficient at mutation detection across multiple genome editing platforms (ZFNs, TALENs, and CRISPRs); we observed nuclease generated HRM positive targeting in 1 of 6 (16%) open pool derived ZFNs, 14 of 23 (60%) TALENs, and 58 of 77 (75%) CRISPR nucleases. Successful targeting, based on HRM of G0 embryos correlates well with successful germline transmission (46 of 47 nucleases); yet, surprisingly mutations in the somatic tail DNA weakly correlate with mutations in the germline F1 progeny DNA. This suggests that analysis of G0 tail DNA is a good indicator of the efficiency of the nuclease, but not necessarily a good indicator of germline alleles that will be present in the F1s. However, we demonstrate that small amplicon HRM curve profiles of F1 progeny DNA can be used to differentiate between specific mutant alleles, facilitating rare allele identification and isolation; and that HRM is a powerful technique for screening possible off-target mutations that may be generated by the nucleases. Our data suggest that micro-homology based alternative NHEJ repair is primarily utilized in the generation of CRISPR mutant alleles and allows us to predict likelihood of generating a null allele. Lastly, we demonstrate that HRM can be used to quickly distinguish genotype-phenotype correlations within F1 embryos derived from G0 intercrosses. Together these data indicate that custom nucleases, in conjunction with the ease and speed of HRM, will facilitate future high-throughput mutation generation and analysis needed to establish mutants in all genes of an organism. PMID- 25503748 TI - Carrier dynamics of a visible-light-responsive Ta3N5 photoanode for water oxidation. AB - The physicochemical properties of a tantalum nitride (Ta3N5) photoanode were investigated in detail to understand the fundamental aspects associated with the photoelectrochemical (PEC) water oxidation. The Ta3N5 thin films were synthesized using DC magnetron sputtering followed by annealing in air and nitridation under ammonia (NH3). A polycrystalline structure with a dense morphology of the monoclinic Ta3N5 films was obtained. A relatively low absorption coefficient (10(4) to 10(5) cm(-1)) in the visible light range was measured for Ta3N5, consistent with the nature of the indirect band-gap. Ultra-fast spectroscopic measurements revealed that the Ta3N5 with different thicknesses films possess low transport properties and fast carrier recombination (<10 ps). These critical kinetic properties of Ta3N5 as a photoanode may necessitate high overpotentials to achieve appreciable photocurrents for water oxidation (onset ~0.6 V vs. RHE). PMID- 25503749 TI - The effects of dexamethasone and oxygen in ventilated adult sheep with early phase acute respiratory distress syndrome. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threating condition with high morbidity and mortality. Inflammation is the main factor in the pathogenesis of ARDS. Therefore systemic corticosteroids are a rational therapeutic approach, but the effect of corticosteroids is still unclear. In this study, we looked at the effects of corticosteroids in ventilated sheep with ARDS, induced by lung lavage. METHODS: We performed a prospective, randomised study in 64 ventilated sheep with ARDS, to evaluate the effect of corticosteroids and oxygen concentration on gas exchange and lung injury. Oxygenation index (OI) and ventilation efficacy index (VEI) were calculated to evaluate gas exchange. Lung injury was assessed by inflammatory response in broncho-alveolar lavage fluid (BALF) and plasma and histology of the lung. RESULTS: OI, VEI, lung inflammation, surfactant production, or lung histology was not influenced by corticosteroids. In the 100 % oxygen groups, OI was higher and total number of cells and disaturated phospholipids were lower in BALF. CONCLUSION: Our study showed that corticosteroids did not influence inflammation in early phase ARDS and that hyperoxia aggravated lung injury which could not be modulated by dexamethasone in early phase ARDS. PMID- 25503751 TI - South Asian older adults with memory impairment: improving assessment and access to dementia care. AB - OBJECTIVE: With increasing international migration, mental health care of migrants and ethnic minorities is a public health priority. South Asian older adults experience difficulties in accessing services for memory impairment, dementia and mental illness. This review examines barriers and facilitators in the pathway to culturally appropriate mental health care. METHODS: Web of Knowledge, Pubmed and Ovid databases were searched for literature on South Asian older adults or their family carers, their understandings of mental illness and dementia and their pattern of service use. Dates were from 1984 to 2012. Abstracts were assessed for relevance, followed by detailed reading of salient papers. Three researchers rated the quality of each included study. A narrative synthesis was undertaken of extracted and charted data. RESULTS: Eighteen studies met the eligibility criteria for the review. South Asians and health professionals highlighted several difficulties which deterred help seeking and access to care: a lack of knowledge of dementia and mental illness, and of local services; stigma; culturally preferred coping strategies; and linguistic and cultural barriers in communication and decision making. CONCLUSIONS: To improve access for these groups, service users and providers need to be better informed; services need to be more culturally tailored, sometimes employing staff with similar cultural backgrounds; and health professionals can benefit from dementia education and knowledge of local services. These factors are key to the delivery of the National Dementia Strategy in England. PMID- 25503753 TI - Introduction: the theorist and the theory. PMID- 25503752 TI - Life of Pi and the moral wound. AB - The "moral wound," rendered symbolically in the form of the tiger in Life of Pi, is a complex trauma in which the victim, in order to survive in life-threatening circumstances, commits an ethical transgression against his or her deeply held values. Pi experiences such a trauma and deals with it by dissociating it in the form of the tiger and then has to simultaneously both preserve the tiger and wish it to disappear. Jonathan Shay's work relating the experiences of returning Vietnam veterans to Homer's Odyssey is used to further an understanding of both Life of Pi and American soldiers returning from the wars in Iraq and Afghanistan. Reasons are considered for the possible delayed effect of trauma as a factor in the increased suicide rate of older veterans. Finally, the concept of the "moral wound" is discussed, with an eye to its treatment. PMID- 25503750 TI - Physical activity and the frequency of acute exacerbations in patients with chronic obstructive pulmonary disease. AB - PURPOSE: Acute exacerbations (AE) in patients with COPD are associated with a decline in lung function, increased risk of hospitalization, and mortality. In this cross-sectional study we tested whether the level of objectively measured daily physical activity and exercise capacity are associated with the number of COPD exacerbations. METHODS: In 210 patients with COPD (67 % men; mean (SD) age: 63 (8) years) enrolled in The Obstructive Pulmonary Disease Outcomes Cohort of Switzerland (TOPDOCS) physical activity (PA) (steps per day, physical activity level, (PAL)), exercise capacity (6-min walking distance, (6MWD)), comorbidities, lung function, and medication were assessed. Differences between COPD patients with frequent (>=2 year) and infrequent (0-1 year) exacerbations were assessed. Univariate and multivariate analyses were performed to investigate whether the level of objectively measured daily physical activity and exercise capacity are associated with the number of COPD exacerbations. RESULTS: Patients with frequent AE had a significantly lower FEV1 and 6MWD compared to patients with infrequent AE. In univariate analysis, the number of exacerbations was inversely associated with FEV1, 6MWD, BMI, and smoking status while there was a positive association with RV/TLC and combined inhaled medication. However, there was no significant association with PAL and steps per day. In multivariate analysis, FEV1 and the use of combined inhaled medication were independently associated with the number of AE, after correction for covariates. CONCLUSIONS: The findings of this study imply that FEV1, independent of inhaled medication, is significantly associated with COPD exacerbations. Neither physical activity nor exercise capacity was independently associated with COPD exacerbations. PMID- 25503754 TI - Freud's Jewish identity and psychoanalysis as a science. AB - Ludwik Fleck, the Polish philosopher of science, maintained that scientific discovery is influenced by social, political, historical, psychological, and personal factors. The determinants of Freud's Jewish identity are examined from this Fleckian perspective, as is the impact of that complex identity on his creation of psychoanalysis as a science. Three strands contributing to his Jewish identity are identified and explored: his commitment to the ideal of Bildung, the anti-Semitism of the times, and his "godlessness." Finally, the question is addressed of what it means that psychoanalysis was founded by a Jew. For Freud, psychoanalysis was a kind of liberation philosophy, an attempt to break free of his ethnic and religious inheritance. Yet it represented at the same time his ineradicable relationship with that inheritance. It encapsulated both the ambivalence of his Jewish identity and the creativity of his efforts to resolve it. PMID- 25503755 TI - Introduction: how does talking cure? PMID- 25503756 TI - Curative speech: symbol, body, dialogue. PMID- 25503757 TI - Raids on the unsayable: talk in psychoanalysis. PMID- 25503758 TI - The interpretive process: the power of "mere" words. PMID- 25503759 TI - Language in the analytic hour: clinical discussion of Harris, Kirshner, and Spivak. PMID- 25503760 TI - Speech as the confluence of words, body, and relationship: discussion of Harris, Kirshner, and Spivak. PMID- 25503761 TI - Research on the relation of psychoanalysis and neuroscience: clinical meaning and empirical science. PMID- 25503762 TI - Journal Watch review of Long-term outcome of psychodynamic therapy and cognitive behavioral therapy in social anxiety disorder. PMID- 25503763 TI - Journal Watch review of Connectomics: a new paradigm for understanding brain disease. PMID- 25503765 TI - Online and on-the-couch virtuality: the real, the imagined, and the perverse. Panel report. PMID- 25503764 TI - Journal Watch review of Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. PMID- 25503771 TI - Using more than the oldest fossils: dating osmundaceae with three Bayesian clock approaches. AB - A major concern in molecular clock dating is how to use information from the fossil record to calibrate genetic distances from DNA sequences. Here we apply three Bayesian dating methods that differ in how calibration is achieved-"node dating" (ND) in BEAST, "total evidence" (TE) dating in MrBayes, and the "fossilized birth-death" (FBD) in FDPPDiv-to infer divergence times in the royal ferns. Osmundaceae have 16-17 species in four genera, two mainly in the Northern Hemisphere and two in South Africa and Australasia; they are the sister clade to the remaining leptosporangiate ferns. Their fossil record consists of at least 150 species in ~17 genera. For ND, we used the five oldest fossils, whereas for TE and FBD dating, which do not require forcing fossils to nodes and thus can use more fossils, we included up to 36 rhizomes and frond compression/impression fossils, which for TE dating were scored for 33 morphological characters. We also subsampled 10%, 25%, and 50% of the 36 fossils to assess model sensitivity. FBD derived divergence ages were generally greater than those inferred from ND; two of seven TE-derived ages agreed with FBD-obtained ages, the others were much younger or much older than ND or FBD ages. We prefer the FBD-derived ages because they best fit the Osmundales fossil record (including Triassic fossils not used in our study). Under the preferred model, the clade encompassing extant Osmundaceae (and many fossils) dates to the latest Paleozoic to Early Triassic; divergences of the extant species occurred during the Neogene. Under the assumption of constant speciation and extinction rates, the FBD approach yielded speciation and extinction rates that overlapped those obtained from just neontological data. However, FBD estimates of speciation and extinction are sensitive to violations in the assumption of continuous fossil sampling; therefore, these estimates should be treated with caution. PMID- 25503770 TI - Impact of the lab-score on antibiotic prescription rate in children with fever without source: a randomized controlled trial. AB - BACKGROUND: The Lab-score, based on the combined determination of procalcitonin, C-reactive protein and urinary dipstick results, has been shown accurate in detecting serious bacterial infections (SBI) in children with fever without source (FWS) on retrospective cohorts. We aimed to prospectively assess the utility of the Lab-score in safely decreasing antibiotic prescriptions in children with FWS and to determine its diagnostic characteristics compared to common SBI biomarkers. METHODS: Randomized controlled trial in children 7 days to 36 months old with FWS, allocated either to the Lab-score group (Lab-score reported, blinded WBC count) or to the control group (WBC, bands and C-reactive protein determined, blinded procalcitonin and Lab-score), followed up until recovery. Demographic data, antibiotic prescription rate, admission rate and diagnostic properties of the Lab-score were analyzed. RESULTS: 271 children were analyzed. No statistically significant difference concerning antibiotic prescription rate was observed: 41.2% (54 of 131) in the Lab-score group and 42.1% (59 of 140) in the control group (p = 1.000). If recommendations based on the Lab-score had been strictly applied, a hypothetical 30.6% treatment rate would have been encountered, compared to the overall 41.7% observed rate (p = 0.0095). A Lab-score >=3 showed the following characteristics: sensitivity 85.1% (95% CI: 76.5-93.6%), specificity 87.3% (95% CI: 82.7-91.8%), positive predictive value 68.7% (95% CI: 58.7-78.7%), negative predictive value 94.1% (95% CI: 91.5 97.9%), positive and negative likelihood ratios: 6.68 and 0.17 respectively. Area under the receiver operating characteristic curve was best for the Lab-score (0.911, 95% CI: 0.871-0.950). DISCUSSION: No difference regarding antibiotic treatment rate was observed when using the Lab-score, due to lack of adherence to the related recommendations. However, if strictly followed, a significant 26.5% reduction of antibiotic prescriptions would have been encountered. Medical education needs to be reinforced in order to observe rather than treat low-risk well-appearing children with FWS. TRIAL REGISTRATION: ClinicalTrials.gov NCT02179398. PMID- 25503772 TI - Genetic distance for a general non-stationary markov substitution process. AB - The genetic distance between biological sequences is a fundamental quantity in molecular evolution. It pertains to questions of rates of evolution, existence of a molecular clock, and phylogenetic inference. Under the class of continuous-time substitution models, the distance is commonly defined as the expected number of substitutions at any site in the sequence. We eschew the almost ubiquitous assumptions of evolution under stationarity and time-reversible conditions and extend the concept of the expected number of substitutions to nonstationary Markov models where the only remaining constraint is of time homogeneity between nodes in the tree. Our measure of genetic distance reduces to the standard formulation if the data in question are consistent with the stationarity assumption. We apply this general model to samples from across the tree of life to compare distances so obtained with those from the general time-reversible model, with and without rate heterogeneity across sites, and the paralinear distance, an empirical pairwise method explicitly designed to address nonstationarity. We discover that estimates from both variants of the general time-reversible model and the paralinear distance systematically overestimate genetic distance and departure from the molecular clock. The magnitude of the distance bias is proportional to departure from stationarity, which we demonstrate to be associated with longer edge lengths. The marked improvement in consistency between the general nonstationary Markov model and sequence alignments leads us to conclude that analyses of evolutionary rates and phylogenies will be substantively improved by application of this model. PMID- 25503773 TI - Ethylene glycol poisoning: a rare but life-threatening cause of metabolic acidosis-a single-centre experience. AB - BACKGROUND: Intoxication with ethylene glycol happen all around the world and without rapid recognition and early treatment, mortality from this is high. METHODS: In our study, we retrospectively analysed six cases of ethylene glycol intoxication in our department. We measured ethylene glycol or glycolate levels, lactate levels and calculated the osmolal and anion gap. RESULTS: Data from six patients admitted to the nephrology department between 1999 and 2011 with ethylene glycol poisoning are reported. All patients were men. The mean pH on admission was 7.15 +/- 0.20 and the anion and osmolal gap were elevated in five of six patients. Four patients had an acute kidney injury and one patient had an acute-on-chronic kidney injury. All patients survived and after being discharged, two patients required chronic intermittent haemodialysis. Interestingly, at the time of admission, all patients had elevated lactate levels but there was no linear regression between toxic levels and lactate levels and no linear correlation was found between initial lactate levels and anion gap and osmolal gap. CONCLUSIONS: The initial diagnosis of ethylene glycol poisoning is difficult and poisoning with ethylene glycol is rare but life threatening and needs rapid recognition and early treatment. Therefore, intoxication with ethylene glycol should not be misdiagnosed as lactic acidosis in patients with metabolic acidosis and elevated lactate levels. PMID- 25503775 TI - Osteotomy for treating knee osteoarthritis. AB - BACKGROUND: Patients with unicompartmental osteoarthritis of the knee can be treated with an osteotomy. The goal of an osteotomy is to unload the diseased compartment of the knee. This is the second update of the original review published in The Cochrane Library, Issue 1, 2005. OBJECTIVES: To assess the benefits and harms of an osteotomy for treating patients with knee osteoarthritis, including the following main outcomes scores: treatment failure, pain and function scores, health-related quality of life, serious adverse events, mortality and reoperation rate. SEARCH METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE (Current Contents, HealthSTAR) were searched until November 2013 for this second update. SELECTION CRITERIA: Randomised and controlled clinical trials comparing an osteotomy with other treatments for patients with unicompartmental osteoarthritis of the knee. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data and assessed risk of bias using the domains recommended in the 'Risk of bias' tool of The Cochrane Collaboration. The quality of the results was analysed by performing overall grading of evidence by outcome using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach. MAIN RESULTS: Eight new studies were included in this update, for a total of 21 included studies involving 1065 people.In four studies, the randomised sequence was adequately generated and clearly described. In eight studies, allocation concealment was adequately generated and described. In four studies, the blinding procedures were sufficient. In six studies, incomplete outcome data were not adequately addressed. Furthermore, in 11 studies, the selective outcome reporting item was unclear because no study protocol was provided.Follow-up of studies comparing different osteotomy techniques was too short to measure treatment failure, which implicates revision to a knee arthroplasty.Four studies evaluated a closing wedge high tibial osteotomy (CW-HTO) with another high tibial osteotomy (aHTO). Based on these studies, the CW-HTO group had 1.8% (95% confidence interval (CI) -7.7% to 4.2%; low-quality evidence) more pain compared with the aHTO group; this finding was not statistically significant. Pooled function in the CW-HTO group was 0.5% (95% CI -3.8% to 2.8%; low-quality evidence) higher compared with the aHTO group; this finding was not statistically significant. No data on health-related quality of life and mortality were presented.Serious adverse events were reported in only four studies and were not significantly different (low-quality evidence) between groups. The reoperation rate were scored as early hardware removal because of pain and pin track infection due to the external fixator. Risk of reoperation was 2.6 (95% CI 1.5 to 4.5; low-quality evidence) times higher in the aHTO group compared with the CW-HTO group, and this finding was statistically significant.The quality of evidence for most outcomes comparing different osteotomy techniques was downgraded to low because of the numbers of available studies, the numbers of participants and limitations in design.Two studies compared high tibial osteotomy versus unicompartmental knee replacement. Treatment failure and pain and function scores were not different between groups after a mean follow-up of 7.5 years. The osteotomy group reported more adverse events when compared with the unicompartmental knee replacement group, but the difference was not statistically significant. No data on health related quality of life and mortality were presented.No study compared an osteotomy versus conservative treatment.Ten included studies compared differences in perioperative or postoperative conditions after high tibial osteotomy. In most of these studies, no statistically significant differences in outcomes were noted between groups. AUTHORS' CONCLUSIONS: The conclusion of this update did not change: Valgus high tibial osteotomy reduces pain and improves knee function in patients with medial compartmental osteoarthritis of the knee. However, this conclusion is based on within-group comparisons, not on non-operative controls. No evidence suggests differences between different osteotomy techniques. No evidence shows whether an osteotomy is more effective than alternative surgical treatment such as unicompartmental knee replacement or non-operative treatment. So far, the results of this updated review do not justify a conclusion on benefit of specific high tibial osteotomy technique for knee osteoarthritis. PMID- 25503774 TI - Heat shock protein-90 inhibitors enhance antigen expression on melanomas and increase T cell recognition of tumor cells. AB - In an effort to enhance antigen-specific T cell recognition of cancer cells, we have examined numerous modulators of antigen-expression. In this report we demonstrate that twelve different Hsp90 inhibitors (iHsp90) share the ability to increase the expression of differentiation antigens and MHC Class I antigens. These iHsp90 are active in several molecular and cellular assays on a series of tumor cell lines, including eleven human melanomas, a murine B16 melanoma, and two human glioma-derived cell lines. Intra-cytoplasmic antibody staining showed that all of the tested iHsp90 increased expression of the melanocyte differentiation antigens Melan-A/MART-1, gp100, and TRP-2, as well as MHC Class I. The gliomas showed enhanced gp100 and MHC staining. Quantitative analysis of mRNA levels showed a parallel increase in message transcription, and a reporter assay shows induction of promoter activity for Melan-A/MART-1 gene. In addition, iHsp90 increased recognition of tumor cells by T cells specific for Melan-A/MART 1. In contrast to direct Hsp90 client proteins, the increased levels of full length differentiation antigens that result from iHsp90 treatment are most likely the result of transcriptional activation of their encoding genes. In combination, these results suggest that iHsp90 improve recognition of tumor cells by T cells specific for a melanoma-associated antigen as a result of increasing the expressed intracellular antigen pool available for processing and presentation by MHC Class I, along with increased levels of MHC Class I itself. As these Hsp90 inhibitors do not interfere with T cell function, they could have potential for use in immunotherapy of cancer. PMID- 25503776 TI - Effects of fixed orthodontic treatment on hair nickel and chromium levels: a 6 month prospective preliminary study. AB - Although nickel and chromium are known as allergen and cytotoxic orthodontic metals, very few and controversial studies have assessed the effect of orthodontic treatment on their systemic levels reflected by their best biomarker of exposure, hair. This prospective preliminary study was conducted to evaluate hair nickel and chromium levels in fixed orthodontic patients. Scalp hair nickel/chromium concentrations of 12 female and 12 male fixed orthodontic patients were measured before treatment and 6 months later, using atomic absorption spectrophotometry. The effects of treatment, gender, and age on hair ions were analyzed statistically (alpha = 0.05). The patients' mean age was 18.38 +/- 3.98 years. The mean nickel levels were 0.1380 +/- 0.0570 and 0.6715 +/- 0.1785 MUg/g dry hair mass, respectively, in the baseline and sixth month of treatment. Chromium concentrations were 0.1455 +/- 0.0769 and 0.1683 +/- 0.0707 MUg/g dry hair mass, respectively. After 6 months, nickel increased for 387 % (paired t test P = 0.0000) and chromium increased for 16 % (P = 0.0002). No significant correlations were observed between any ion levels with age or gender (Spearman P > 0.2). Within the limitations of this preliminary study, it seems that 6 months of fixed orthodontic treatment might increase levels of hair nickel and chromium. Future larger studies are necessary to validate these results. PMID- 25503777 TI - Bartonella henselae endocarditis in Laos - 'the unsought will go undetected'. AB - BACKGROUND: Both endocarditis and Bartonella infections are neglected public health problems, especially in rural Asia. Bartonella endocarditis has been described from wealthier countries in Asia, Japan, Korea, Thailand and India but there are no reports from poorer countries, such as the Lao PDR (Laos), probably because people have neglected to look. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a retrospective (2006-2012), and subsequent prospective study (2012 2013), at Mahosot Hospital, Vientiane, Laos, through liaison between the microbiology laboratory and the wards. Patients aged >1 year admitted with definite or possible endocarditis according to modified Duke criteria were included. In view of the strong suspicion of infective endocarditis, acute and convalescent sera from 30 patients with culture negative endocarditis were tested for antibodies to Brucella melitensis, Mycoplasma pneumoniae, Bartonella quintana, B. henselae, Coxiella burnetii and Legionella pneumophila. Western blot analysis using Bartonella species antigens enabled us to describe the first two Lao patients with known Bartonella henselae endocarditis. CONCLUSIONS/SIGNIFICANCE: We argue that it is likely that Bartonella endocarditis is neglected and more widespread than appreciated, as there are few laboratories in Asia able to make the diagnosis. Considering the high prevalence of rheumatic heart disease in Asia, there is remarkably little evidence on the bacterial etiology of endocarditis. Most evidence is derived from wealthy countries and investigation of the aetiology and optimal management of endocarditis in low income countries has been neglected. Interest in Bartonella as neglected pathogens is emerging, and improved methods for the rapid diagnosis of Bartonella endocarditis are needed, as it is likely that proven Bartonella endocarditis can be treated with simpler and less expensive regimens than "conventional" endocarditis and multicenter trials to optimize treatment are required. More understanding is needed on the risk factors for Bartonella endocarditis and the importance of vectors and vector control. PMID- 25503778 TI - Breast cancer risk after diagnosis by screening mammography of nonproliferative or proliferative benign breast disease: a study from a population-based screening program. AB - Benign breast disease increases the risk of breast cancer. This association has scarcely been evaluated in the context of breast cancer screening programs although it is a prevalent finding in mammography screening. We assessed the association of distinct categories of benign breast disease and subsequent risk of breast cancer, as well as the influence of a family history of breast cancer. A retrospective cohort study was conducted in 545,171 women aged 50-69 years biennially screened for breast cancer in Spain. The median of follow-up was 6.1 years. The age-adjusted rate ratio (RR) of breast cancer for women with benign breast disease, histologically classified into nonproliferative and proliferative disease with and without atypia, compared with women without benign breast disease was estimated by Poisson regression analysis. A stratified analysis by family history of breast cancer was performed in a subsample. All tests were two sided. The age-adjusted RR of breast cancer after diagnosis of benign breast disease was 2.51 (95 % CI: 2.14-2.93) compared with women without benign breast disease. The risk was higher in women with proliferative disease with atypia (RR = 4.56, 95 % CI: 2.06-10.07) followed by those with proliferative disease without atypia (RR = 3.58; 95 % CI = 2.61-4.91). Women with nonproliferative disease and without a family history of breast cancer remained also at increased risk of cancer (OR = 2.23, 95 % CI: 1.86-2.68). An increased risk of breast cancer was observed among screening participants with proliferative or nonproliferative benign breast disease, regardless of a family history of breast cancer. This information may be useful to explore risk-based screening strategies. PMID- 25503779 TI - HDAC inhibition does not induce estrogen receptor in human triple-negative breast cancer cell lines and patient-derived xenografts. AB - Several publications have suggested that histone deacetylase inhibitors (HDACis) could reverse the repression of estrogen receptor alpha (ERalpha) in triple negative breast cancer (TNBC) cell lines, leading to the induction of a functional protein. Using different HDACis, vorinostat, panobinostat, and abexinostat, we therefore investigated this hypothesis in various human TNBC cell lines and patient-derived xenografts (PDXs). We used three human TNBC cell lines and three PDXs. We analyzed the in vitro toxicity of the compounds, their effects on the hormone receptors and hormone-related genes and protein expression both in vitro and in vivo models. We then explored intra-tumor histone H3 acetylation under abexinostat in xenograft models. Despite major cytotoxicity of all tested HDAC inhibitors and repression of deactylation-dependent CCND1 gene, neither ERalpha nor ERbeta, ESR1 or ESR2 genes respectively, were re-expressed in vitro. In vivo, after administration of abexinostat for three consecutive days, we did not observe any induction of ESR1 or ESR1-related genes and ERalpha protein expression by RT-qPCR and immunohistochemical methods in PDXs. This observation was concomitant to the fact that in vivo administration of abexinostat increased intra-tumor histone H3 acetylation. These observations do not allow us to confirm previous studies which suggested that HDACis are able to convert ER-negative (ER ) tumors to ER-positive (ER+) tumors, and that a combination of HDAC inhibitors and hormone therapy could be proposed in the management of TNBC patients. PMID- 25503781 TI - Efficacy of EGFR tyrosine kinase inhibitors in non-small-cell lung cancer patients with/without EGFR-mutation: evidence based on recent phase III randomized trials. AB - BACKGROUND: EGFR mutation might be a predictive factor for applying EGFR-tyrosine kinase inhibitors (EGFR-TKIs, including gefitinib, erlotinib and afatinib) in non small-cell lung cancer (NSCLS) patients. Thus, it is necessary to pool previous trials to compare the effect of EGFR-TKIs versus cytotoxic chemotherapy in EGFR mutation positive (mut+) and negative (mut-) patients. MATERIAL AND METHODS: This study identified 8 first-line and 9 second-line phase III trials in databases. Hazard ratio (HR) was pooled to assess the risk of progression-free survival (PFS), and overall survival (OS), while odds ratio (OR) was pooled to assess objective response, disease control, and toxicity of EGFR-TKIs verses chemotherapy. RESULTS: In EGFR mut+ patients, EGFR-TKIs were associated with significantly lower risk of disease progression in the first-line setting, but this trend was only observed in the gefitinib group, not in the erlotinib group in the second-line setting. In EGFR mut- patients, gefitinib and erlotinib had significantly higher risk of disease progression in first-line and second-line setting, respectively. Compared with chemotherapy, the effects of EGFR-TKIs on OS in both first-line and second-line settings were not evident. Regarding toxicity, EGFR-TKIs had significantly higher risk of rash and lower hematological toxicity compared with chemotherapy. CONCLUSIONS: All of the 3 EGFR-TKIs and gefitinib alone regimens had better effects in prolonging PFS in EGFR mut+ patients in first-line and second-line setting, respectively, but chemotherapy seemed more effective in EGFR mut- patients than EGFR-TKIs. Therefore, accurate identification of EGFR mutation status is useful to decide on an appropriate regimen for treatment of NSCLC patients. PMID- 25503782 TI - Ontogenetic criteria to distinguish vertebral types on the debated xenarthran synsacrum. AB - The presence of a synsacrum formed by the fusion of vertebrae that come into closed contact with the ilium and ischium is a feature that characterizes the clade Xenarthra. Nevertheless, the proper identity of each vertebral element that forms it is a matter of discussion. In this article, we provide ontogenetic information about skeletal ossification of the xenarthran synsacrum and define the position of the sacrocaudal limit within it. We analyzed the synsacrum of 25 specimens of nonadult and 101 adult armadillos and anteaters: Dasypus hybridus, D. novemcinctus, Chaetophractus vellerosus, C. villosus, Tamandua tetradactyla, and Myrmecophaga tridactyla. Two sets of vertebrae were identified: an anterior set, often attached to the iliac bones, in which transverse processes are originated mainly from an expansion of the base of the neural arches, and secondarily from a lateroventral ossification center. A posterior set is characterized by a series of vertebrae along which extra lateral ossifications (described here for the first time) are developed and form exclusively the transverse processes. Among armadillos, the sacrocaudal limit is set between the last vertebrae attached to the iliac bones and the first vertebrae that form the dorsal border of the sacroischial fenestra. In addition, anterior free caudals also showed extra lateral ossifications forming exclusively the transverse processes, supporting the notion that more posterior synsacrals are in fact caudal vertebrae that were incorporated to the synsacrum. In pilosans, the sacrocaudal limit is set between the first vertebrae that come into contact with the ischial bones and the immediately anterior one. However, the pattern of homologies is obscured by the low resolution in the ontogenetic sequence when compared to that of armadillos. PMID- 25503783 TI - Mineralization pathways of organic matter deposited in a river-lake transition of the Rhone River Delta, Lake Geneva. AB - During the eLEMO endeavour (a research project in which the Russian MIR submersibles were used for studying Lake Geneva) four sediment cores were retrieved on a transect from the delta of the Rhone River towards the profundal part of the lake. The degradation pathways of organic material (OM) were investigated considering different electron acceptors. Essentially, OM at the delta sites had a higher fraction of terrestrial material than the lake sites indicated by higher C/N ratios, and higher long-chain n-alkane and alcohol concentrations. The concentrations of chlorins were higher at the distant sites indicating more easily degradable OM in the sediments. However, the chlorin index that was used to determine the degradation state of the OM material indicated that pigment derived OM of deltaic sediments was less degraded than that of the profundal sediments. The fluxes of reduced species from the sediments decreased from the delta to the profundal for CH4 (from 2.3 to 0.5 mmol m(-2) d(-1)) and NH4(+) (from 0.31 to 0.13 mmol m(-2) d(-1)). Fluxes of Fe(ii) and Mn(ii), however, increased although they were generally very low (between 9 * 10(-5) and 7.6 * 10(-3) mmol m(-2) d(-1)). Oxygen concentration profiles in the pore waters revealed lower fluxes close to the river inflow with 4.3 and 4.1 mmol m(-2) d(-1) compared to two times higher fluxes at the profundal sites (8.8 and 8.2 mmol m( 2) d(-1)). The rates for totally mineralized OM (Rtotal) at the shallower sites (4.7 mmol C m(-2) d(-1)) were only half of those of the deeper sites (9.7 mmol C m(-2) d(-1)). Accordingly, not only the rates but also the mineralization pathways differed between the shallow and profundal sites. Whereas only 0-6% of the OM was mineralized aerobically at the shallow sites (since almost all O2 was used to oxidize the large flux of CH4 from below) the situation was reversed at the deeper sites and the fraction of aerobically degraded OM was 72-78%. We found a better efficiency in CH4 production per carbon equivalent deposited at the deeper sites as a result of the higher degradability of the mainly autochthonous OM in spite of the lower deposition rate and the higher degradation state of the OM compared to the delta sites. PMID- 25503784 TI - Mental disorders in asylum seekers: the role of the refugee determination process and employment. AB - The refugee determination process (RDP) and social factors putatively impact on the psychiatric morbidity of adult asylum seekers (ASs) living in the community. Clinical and sociodemographic data relevant to AS experience in the RDP were collected using self-report measures to assess posttraumatic stress (Harvard Trauma Questionnaire-Revised) and depressive and anxiety symptoms (25-item Hopkins Symptom Checklist), and the Mini-International Neuropsychiatric Interview 6.0 psychiatric interview was used to establish a cutoff for caseness. The prevalence of major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) was 61% and 52%, respectively. Unemployment and greater numbers of both potentially traumatic events and RDP rejections were predictors of symptom severity. Unemployed ASs were more than twice as likely to have MDD (odds ratio, 2.61; 95% confidence interval [CI], 1.11- 6.13; p = 0.03), and ASs with at least one RDP rejection were 1.35 times more likely to develop PTSD for each additional rejection (95% CI, 1.00-1.84; p = 0.05). Reducing the asylum claim rejection rate and granting work rights are likely to reduce the rate of PTSD and MDD in community-based ASs. PMID- 25503785 TI - Social functioning and age across affective and nonaffective psychoses. AB - Both nonaffective and affective psychoses are associated with deficits in social functioning across the course of the illness. However, it is not clear how social functioning varies among diagnostic groups as a function of age. The current study examined the relationship between social functioning and age in schizophrenia (SZ), schizoaffective disorder (SZA), and psychotic bipolar disorder (PBD). We found that individuals with PBD had the highest functioning, whereas individuals with SZ had the poorest. The functioning of individuals with SZA fell in between those of other groups. We also found that older ages were associated with poorer functioning. Although there was not a significant diagnostic group by age interaction, visual inspection of our data suggests a subtly steeper trajectory of decline in PBD. Overall, these results indicate that early interventions targeting social functioning may benefit individuals with either non-affective or affective psychoses to slow a projected decline. PMID- 25503787 TI - Neuroprotective effects of alpha-iso-cubebene against glutamate-induced damage in the HT22 hippocampal neuronal cell line. AB - Since oxidative stress is critically involved in excitotoxic damage, we sought to determine whether the activation of the transcription factors, cAMP-responsive element binding protein (CREB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2, also known as NFE2L2), by alpha-iso-cubebene is involved in its protective effects against glutamate-induced neuronal cell death. Pre-treatment with alpha iso-cubebene significantly attenuated glutamate-induced cytotoxicity in mouse hippocampus-derived neuronal cells. alpha-iso-cubebene also reduced the glutamate induced generation of reactive oxygen species and calcium influx, thus preventing apoptotic cell death. alpha-iso-cubebene inhibited glutamate-induced mitochondrial membrane depolarization and, consequently, inhibited the release of the apoptosis-inducing factor from the mitochondria. Immunoblot anlaysis revealed that the phosphorylation of extracellular signal-regulated kinase (ERK) by glutamate was reduced in the presence of alpha-iso-cubebene. alpha-iso-cubebene activated protein kinase A (PKA), CREB and Nrf2, which mediate the expression of the antioxidant enzymes, heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1), involved in neuroprotection. In addition, alpha-iso-cubebene induced the expression of antioxidant responsive element and CRE transcriptional activity, thus conferring neuroprotection against glutamate-induced oxidative injury. alpha-iso-cubebene also induced the expression of Nrf2-dependent genes encoding HO-1 and NQO1. Furthermore, the knockdown of CREB and Nrf2 by small interfering RNA attenuated the neuroprotective effects of alpha-iso-cubebene. Taken together, our results indicate that alpha-iso-cubebene protects HT22 cells from glutamate-induced oxidative damage through the activation of Nrf2/HO-1/NQO 1, as well as through the PKA and CREB signaling pathways. PMID- 25503786 TI - Analysis of a plant complex resistance gene locus underlying immune-related hybrid incompatibility and its occurrence in nature. AB - Mechanisms underlying speciation in plants include detrimental (incompatible) genetic interactions between parental alleles that incur a fitness cost in hybrids. We reported on recessive hybrid incompatibility between an Arabidopsis thaliana strain from Poland, Landsberg erecta (Ler), and many Central Asian A. thaliana strains. The incompatible interaction is determined by a polymorphic cluster of Toll/interleukin-1 receptor-nucleotide binding-leucine rich repeat (TNL) RPP1 (Recognition of Peronospora parasitica1)-like genes in Ler and alleles of the receptor-like kinase Strubbelig Receptor Family 3 (SRF3) in Central Asian strains Kas-2 or Kond, causing temperature-dependent autoimmunity and loss of growth and reproductive fitness. Here, we genetically dissected the RPP1-like Ler locus to determine contributions of individual RPP1-like Ler (R1-R8) genes to the incompatibility. In a neutral background, expression of most RPP1-like Ler genes, except R3, has no effect on growth or pathogen resistance. Incompatibility involves increased R3 expression and engineered R3 overexpression in a neutral background induces dwarfism and sterility. However, no individual RPP1-like Ler gene is sufficient for incompatibility between Ler and Kas-2 or Kond, suggesting that co-action of at least two RPP1-like members underlies this epistatic interaction. We find that the RPP1-like Ler haplotype is frequent and occurs with other Ler RPP1-like alleles in a local population in Gorzow Wielkopolski (Poland). Only Gorzow individuals carrying the RPP1-like Ler haplotype are incompatible with Kas-2 and Kond, whereas other RPP1-like alleles in the population are compatible. Therefore, the RPP1-like Ler haplotype has been maintained in genetically different individuals at a single site, allowing exploration of forces shaping the evolution of RPP1-like genes at local and regional population scales. PMID- 25503788 TI - Time-resolved compression of a capsule with a cone to high density for fast ignition laser fusion. AB - The advent of high-intensity lasers enables us to recreate and study the behaviour of matter under the extreme densities and pressures that exist in many astrophysical objects. It may also enable us to develop a power source based on laser-driven nuclear fusion. Achieving such conditions usually requires a target that is highly uniform and spherically symmetric. Here we show that it is possible to generate high densities in a so-called fast-ignition target that consists of a thin shell whose spherical symmetry is interrupted by the inclusion of a metal cone. Using picosecond-time-resolved X-ray radiography, we show that we can achieve areal densities in excess of 300 mg cm(-2) with a nanosecond duration compression pulse--the highest areal density ever reported for a cone-in shell target. Such densities are high enough to stop MeV electrons, which is necessary for igniting the fuel with a subsequent picosecond pulse focused into the resulting plasma. PMID- 25503789 TI - Serum and CSF cytokines and matrix metalloproteinases in spinal tuberculosis. AB - AIMS AND OBJECTIVES: Both pro-inflammatory and anti-inflammatory cytokines play key roles in the pathogenesis of various forms of tuberculosis. In this study, we evaluated the role of various cytokines and matrix metalloproteinases (MMPs) in patients with spinal tuberculosis. MATERIALS AND METHODS: In this prospective study, we enrolled 55 histopathologically/microbiologically confirmed patients with spinal tuberculosis. We also included 55 control subjects. Blood and cerebrospinal fluid (CSF) were collected both from cases and controls. Tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL 6, IL-8, IL-10, matrix metalloproteinases MMP-2 and MMP-9 were measured by enzyme linked immunosorbent assay (ELISA). Disability and outcome were measured by modified Barthel Index (MBI). Measured inflammatory parameters were correlated with the outcome after 6 months of follow-up. RESULTS: We observed that serum and CSF cytokines and MMPs were significantly higher in patients with spinal tuberculosis than in controls (p < 0.001). Spearman's rank order correlation test for correlation of baseline MBI (measure of disability) and cytokine/MMP levels showed that baseline MBI had significant negative correlation with serum levels of IFN-gamma (r = -0.517; p < 0.001), IL-1beta (r = -0.355; p = 0.008), IL-6 (r = -0.306; p = 0.023), IL-8 (r = -0.275; p = 0.042), MMP-9 (r = -0.311; p = 0.021) and CSF levels of TNF-alpha (r = -0.327; p = 0.015); whereas baseline MBI had a positive correlation with the serum level of anti-inflammatory cytokine IL-10 (r = 0.327; p = 0.015). Poor outcome, after 6 months, was associated with higher serum TNF-alpha (p = 0.015) and IFN-gamma (p = 0.021) and CSF MMP-9 (p = 0.006) and a lower serum IL-10 (p = 0.018) level. CONCLUSIONS: To conclude, in patients of spinal tuberculosis, poor outcome is associated with higher pro-inflammatory serum TNF-alpha and IFN-gamma, and CSF MMP-9 levels, and a lower anti inflammatory serum IL-10 level. PMID- 25503790 TI - Erratum to: Clinical associations between IL-17 family cytokines and periodontitis and potential differential roles for IL-17A and IL-17E in periodontal immunity. PMID- 25503792 TI - Confronting diminished epistemic privilege and epistemic injustice in pregnancy by challenging a "panoptics of the womb". AB - This paper demonstrates how the problematic kinds of epistemic power that physicians have can diminish the epistemic privilege that pregnant women have over their bodies and can put them in a state of epistemic powerlessness. This result, I argue, constitutes an epistemic injustice for many pregnant women. A reconsideration of how we understand and care for pregnant women and of the physician-patient relationship can provide us with a valuable context and starting point for helping to alleviate the knowledge/power problems that are symptomatic of the current system and structure of medicine. I suggest that we can begin to confront this kind of injustice if medicine adopts a more phenomenological understanding of bodies and if physicians and patients--in this case, pregnant women--become what I call "epistemic peers." PMID- 25503791 TI - Characterization of X chromosome inactivation using integrated analysis of whole exome and mRNA sequencing. AB - In females, X chromosome inactivation (XCI) is an epigenetic, gene dosage compensatory mechanism by inactivation of one copy of X in cells. Random XCI of one of the parental chromosomes results in an approximately equal proportion of cells expressing alleles from either the maternally or paternally inherited active X, and is defined by the XCI ratio. Skewed XCI ratio is suggestive of non random inactivation, which can play an important role in X-linked genetic conditions. Current methods rely on indirect, semi-quantitative DNA methylation based assay to estimate XCI ratio. Here we report a direct approach to estimate XCI ratio by integrated, family-trio based whole-exome and mRNA sequencing using phase-by-transmission of alleles coupled with allele-specific expression analysis. We applied this method to in silico data and to a clinical patient with mild cognitive impairment but no clear diagnosis or understanding molecular mechanism underlying the phenotype. Simulation showed that phased and unphased heterozygous allele expression can be used to estimate XCI ratio. Segregation analysis of the patient's exome uncovered a de novo, interstitial, 1.7 Mb deletion on Xp22.31 that originated on the paternally inherited X and previously been associated with heterogeneous, neurological phenotype. Phased, allelic expression data suggested an 83?20 moderately skewed XCI that favored the expression of the maternally inherited, cytogenetically normal X and suggested that the deleterious affect of the de novo event on the paternal copy may be offset by skewed XCI that favors expression of the wild-type X. This study shows the utility of integrated sequencing approach in XCI ratio estimation. PMID- 25503793 TI - Investigations on dendrimer space reveal solid and liquid tumor growth-inhibition by original phosphorus-based dendrimers and the corresponding monomers and dendrons with ethacrynic acid motifs. AB - The well-known reactive diuretic ethacrynic acid (EA, Edecrin), with low antiproliferative activities, was chemically modified and grafted onto phosphorus dendrimers and the corresponding simple branched phosphorus dendron-like derivatives affording novel nanodevices showing moderate to strong antiproliferative activities against liquid and solid tumor cell lines, respectively. PMID- 25503795 TI - A strategy for screening of high-quality enzyme inhibitors from herbal medicines based on ultrafiltration LC-MS and in silico molecular docking. AB - A novel strategy of ultrafiltration LC-MS and in silico molecular docking was proposed to discover high-quality enzyme inhibitors from herbal medicines. Using this strategy, two compounds were predicted and finally demonstrated as potent xanthine oxidase inhibitors, whose in vitro IC50 values were lower than that of a positive control allopurinol. PMID- 25503794 TI - Vitamin A supplementation in early life enhances the intestinal immune response of rats with gestational vitamin A deficiency by increasing the number of immune cells. AB - Vitamin A is a critical micronutrient for regulating immunity in many organisms. Our previous study demonstrated that gestational or early-life vitamin A deficiency decreases the number of immune cells in offspring. The present study aims to test whether vitamin A supplementation can restore lymphocyte pools in vitamin A-deficient rats and thereby improve the function of their intestinal mucosa; furthermore, the study aimed to identify the best time frame for vitamin A supplementation. Vitamin A-deficient pregnant rats or their offspring were administered a low-dose of vitamin A daily for 7 days starting on gestational day 14 or postnatal day 1, day 14 or day 28. Serum retinol concentrations increased significantly in all four groups that received vitamin A supplementation, as determined by high-performance liquid chromatography. The intestinal levels of secretory immunoglobulin A and polymeric immunoglobulin receptor increased significantly with lipopolysaccharide challenge in the rats that received vitamin A supplementation starting on postnatal day 1. The rats in this group had higher numbers of CD8+ intestinal intraepithelial lymphocytes, CD11C+ dendritic cells in the Peyer's patches and CD4+CD25+ T cells in the spleen compared with the vitamin A-deficient rats; flow cytometric analysis also demonstrated that vitamin A supplementation decreased the number of B cells in the mesenteric lymph nodes. Additionally, vitamin A supplementation during late gestation increased the numbers of CD8+ intestinal intraepithelial lymphocytes and decreased the numbers of B lymphocytes in the mesenteric lymph nodes. However, no significant differences in lymphocyte levels were found between the rats in the other two vitamin A supplement groups and the vitamin A-deficient group. In conclusion, the best recovery of a subset of lymphocytes in the offspring of gestational vitamin A-deficient rats and the greatest improvement in the intestinal mucosal immune response are achieved when vitamin A supplementation occurs during the early postnatal period. PMID- 25503796 TI - Evaluation of back scatter interferometry, a method for detecting protein binding in solution. AB - Back Scatter Interferometry (BSI) has been proposed to be a highly sensitive and versatile refractive index sensor usable for analytical detection of biomarker and protein interactions in solution. However the existing literature on BSI lacks a physical explanation of why protein interactions in general should contribute to the BSI signal. We have established a BSI system to investigate this subject in further detail. We contribute with a thorough analysis of the robustness of the sensor including unwanted contributions to the interferometric signal caused by temperature variation and dissolved gasses. We report a limit of the effective minimum detectability of refractive index at the 10(-7) level. Long term stability was examined by simultaneously monitoring the temperature inside the capillary revealing an average drift of 2.0 * 10(-7) per hour. Finally we show that measurements on protein A incubated with immunoglobulin G do not result in a signal that can be attributed to binding affinities as otherwise claimed in literature. PMID- 25503797 TI - The evolving use of radioiodine therapy in differentiated thyroid cancer. AB - The incidence of differentiated thyroid cancer has increased worldwide over the last three decades, but thyroid cancer-related mortality remains stable. Until recently, the standard treatment for most thyroid cancers has been near-total thyroidectomy followed by radioiodine remnant ablation. Observational data support lower recurrence rates and improved survival after radioiodine ablation in patients with high-risk cancers; however, a similar benefit has not been established for all patients with thyroid cancer. Risk stratification should be used to identify patients who are likely to benefit from radioiodine ablation and guide therapeutic decisions. For most patients who need radioiodine remnant ablation, preparation for therapy with recombinant human thyroid-stimulating hormone stimulation is as effective as thyroid hormone withdrawal. Lower therapeutic doses of radioiodine are recommended for the majority of thyroid remnant ablations. Higher doses are reserved for advanced disease at initial diagnosis, local recurrences that cannot be treated with surgery alone, and distant metastatic disease. PMID- 25503800 TI - Lessons from an aggressive angiomyxoma unrecognized and treated as rectal prolapse. PMID- 25503798 TI - Proteomic analysis of the acidocalcisome, an organelle conserved from bacteria to human cells. AB - Acidocalcisomes are acidic organelles present in a diverse range of organisms from bacteria to human cells. In this study acidocalcisomes were purified from the model organism Trypanosoma brucei, and their protein composition was determined by mass spectrometry. The results, along with those that we previously reported, show that acidocalcisomes are rich in pumps and transporters, involved in phosphate and cation homeostasis, and calcium signaling. We validated the acidocalcisome localization of seven new, putative, acidocalcisome proteins (phosphate transporter, vacuolar H+-ATPase subunits a and d, vacuolar iron transporter, zinc transporter, polyamine transporter, and acid phosphatase), confirmed the presence of six previously characterized acidocalcisome proteins, and validated the localization of five novel proteins to different subcellular compartments by expressing them fused to epitope tags in their endogenous loci or by immunofluorescence microscopy with specific antibodies. Knockdown of several newly identified acidocalcisome proteins by RNA interference (RNAi) revealed that they are essential for the survival of the parasites. These results provide a comprehensive insight into the unique composition of acidocalcisomes of T. brucei, an important eukaryotic pathogen, and direct evidence that acidocalcisomes are especially adapted for the accumulation of polyphosphate. PMID- 25503799 TI - A co-association network analysis of the genetic determination of pig conformation, growth and fatness. AB - BACKGROUND: Several QTLs have been identified for major economically relevant traits in livestock, such as growth and meat quality, revealing the complex genetic architecture of these traits. The use of network approaches considering the interactions of multiple molecules and traits provides useful insights into the molecular underpinnings of complex traits. Here, a network based methodology, named Association Weight Matrix, was applied to study gene interactions and pathways affecting pig conformation, growth and fatness traits. RESULTS: The co association network analysis underpinned three transcription factors, PPARgamma, ELF1, and PRDM16 involved in mesoderm tissue differentiation. Fifty-four genes in the network belonged to growth-related ontologies and 46 of them were common with a similar study for growth in cattle supporting our results. The functional analysis uncovered the lipid metabolism and the corticotrophin and gonadotrophin release hormone pathways among the most important pathways influencing these traits. Our results suggest that the genes and pathways here identified are important determining either the total body weight of the animal and the fat content. For instance, a switch in the mesoderm tissue differentiation may determinate the age-related preferred pathways being in the puberty stage those related with the miogenic and osteogenic lineages; on the contrary, in the maturity stage cells may be more prone to the adipocyte fate. Hence, our results demonstrate that an integrative genomic co-association analysis is a powerful approach for identifying new connections and interactions among genes. CONCLUSIONS: This work provides insights about pathways and key regulators which may be important determining the animal growth, conformation and body proportions and fatness traits. Molecular information concerning genes and pathways here described may be crucial for the improvement of genetic breeding programs applied to pork meat production. PMID- 25503801 TI - Metachronous metastases from colorectal cancer: a population-based study in North East Netherlands. AB - PURPOSE: The main cause of death of colorectal cancer patients is metastatic disease. Approximately 20-25% of the patients present with metastases at time of diagnosis. The clinical course of patients who develop metachronous metastases, however, is less clear. The aims of this study were to describe the incidence, treatment and survival of patients with metachronous metastases from colorectal cancer and to determine risk factors for developing metachronous metastases. METHODS: From the Netherlands Cancer Registry, patients diagnosed with colorectal carcinoma in the period 2002-2003 in North-East Netherlands were selected. Patients were followed for 5 years after diagnosis of the primary tumour. Kaplan Meier method and Cox regression analyses were used to determine predictors for developing metastases and to analyse overall survival. RESULTS: In total, 333 of 1743 (19%) patients developed metachronous metastases. The majority (83%) of these metastases were diagnosed within 3 years, and the most frequent site was the liver. Patients with advanced stage and patients with tumours in the descending colon or in the rectum were more likely to develop metastases. Approximately 10% of all patients underwent intentionally curative treatment for their metastases, with a 5-year survival rate of 60%. Treatment of metastases and pathologic N (pN) status were independent prognostic factors for overall survival. CONCLUSIONS: Site and stage of the primary tumour were predictors for developing metachronous metastases. A limited number of patients with metastatic disease were treated with a curative intent. These patients had a good prognosis. Therefore, focus should be on identifying more patients who could benefit from curative treatment. PMID- 25503802 TI - Gastrointestinal endoscopy in patients aged 75 years and older: risks, complications, and findings--a retrospective study. AB - PURPOSE: Endoscopy of the gastrointestinal tract offers simultaneously diagnostic and therapeutic options and is increasingly performed in elderly patients due to a continuously growth of this population segment. Whereas safety data of diagnostic and interventional endoscopy in patients younger than 65 years are well characterized, only scarce data exist for elderly patients older than 75 years. METHODS: We analyzed outcomes and complications of endoscopic procedures with focus on colonoscopy in patients aged 75 and older at a single tertiary referral center in Germany between 1996 and 2006. RESULTS: A total of 3770 endoscopies (2270 gastroscopies, 735 colonoscopies, 765 ERCP) were performed in 1841 patients with a mean age of 79 years (range 75 to 97 years). Seventy-four percent of all patients suffered from relevant comorbidities. Therapeutic interventions were carried out in 43 % of colonoscopies. Complications were observed in approximately 1 %. CONCLUSION: The observed complication rate in diagnostic and therapeutic endoscopic procedures is not increased in elderly patients compared to the reported complication rates in younger patients. PMID- 25503803 TI - Comparison of minimally invasive and open colorectal resections for patients undergoing simultaneous R0 resection for liver metastases: a propensity score analysis. AB - PURPOSE: The role of minimally invasive colorectal resection for patients undergoing a simultaneous resection for synchronous liver metastases had not been established. This study compared the short- and long-term outcomes between minimally invasive and open colorectal resection for patients undergoing simultaneous resection for liver metastases. METHODS: This study reviewed 101 consecutive patients undergoing simultaneous colorectal resection and R0 resection of synchronous liver metastases between January 2008 and December 2012. In the study, 36 consecutive patients who underwent minimally invasive colorectal resection were matched with 36 patients who had an open approach by propensity scoring. The analyzed variables included patient and tumor characteristics and short-term and long-term outcomes. RESULTS: After propensity score matching, the two groups had similar clinicopathologic variables. No patient undergoing the minimally invasive procedure experienced conversion to the open technique. No postoperative mortality occurred in either group. In the minimally invasive group, the estimated blood loss (P < 0.007), bowel function return time (P < 0.016), and postoperative hospital stay (P < 0.011) were significantly lower than those in the open group, although the operating time was significantly longer (P < 0.001). No significant differences in postoperative complications were observed between the groups. The two groups did not differ significantly in terms of the 5 year overall survival rate (51 vs. 55 %; P = 0.794) and disease-free survival rate (38 vs. 27 %; P = 0.860). CONCLUSION: Minimally invasive colorectal resection with simultaneous resection of liver metastases has an outcome similar to open approach but some short-term advantages. PMID- 25503804 TI - Synthetic retinal analogues modify the spectral and kinetic characteristics of microbial rhodopsin optogenetic tools. AB - Optogenetic tools have become indispensable in neuroscience to stimulate or inhibit excitable cells by light. Channelrhodopsin-2 (ChR2) variants have been established by mutating the opsin backbone or by mining related algal genomes. As an alternative strategy, we surveyed synthetic retinal analogues combined with microbial rhodopsins for functional and spectral properties, capitalizing on assays in C. elegans, HEK cells and larval Drosophila. Compared with all-trans retinal (ATR), Dimethylamino-retinal (DMAR) shifts the action spectra maxima of ChR2 variants H134R and H134R/T159C from 480 to 520 nm. Moreover, DMAR decelerates the photocycle of ChR2(H134R) and (H134R/T159C), thereby reducing the light intensity required for persistent channel activation. In hyperpolarizing archaerhodopsin-3 and Mac, naphthyl-retinal and thiophene-retinal support activity alike ATR, yet at altered peak wavelengths. Our experiments enable applications of retinal analogues in colour tuning and altering photocycle characteristics of optogenetic tools, thereby increasing the operational light sensitivity of existing cell lines or transgenic animals. PMID- 25503805 TI - A genome-wide association study of heparin-induced thrombocytopenia using an electronic medical record. AB - Heparin-induced thrombocytopenia (HIT) is an unpredictable, potentially catastrophic adverse effect of heparin treatment resulting from an immune response to platelet factor 4 (PF4)/heparin complexes. No genome-wide evaluations have been performed to identify potential genetic influences on HIT. Here, we performed a genome-wide association study (GWAS) and candidate gene study using HIT cases and controls identified using electronic medical records (EMRs) coupled to a DNA biobank and attempted to replicate GWAS associations in an independent cohort. We subsequently investigated influences of GWAS-associated single nucleotide polymorphisms (SNPs) on PF4/heparin antibodies in non-heparin treated individuals. In a recessive model, we observed significant SNP associations (odds ratio [OR] 18.52; 95% confidence interval [CI] 6.33-54.23; p=3.18*10(-9)) with HIT near the T-Cell Death-Associated Gene 8 (TDAG8). These SNPs are in linkage disequilibrium with a missense TDAG8 SNP. TDAG8 SNPs trended toward an association with HIT in replication analysis (OR 5.71; 0.47-69.22; p=0.17), and the missense SNP was associated with PF4/heparin antibody levels and positive PF4/heparin antibodies in non-heparin treated patients (OR 3.09; 1.14-8.13; p=0.02). In the candidate gene study, SNPs at HLA-DRA were nominally associated with HIT (OR 0.25; 0.15-0.44; p=2.06*10(-6)). Further study of TDAG8 and HLA-DRA SNPs is warranted to assess their influence on the risk of developing HIT. PMID- 25503807 TI - Tetralogy of Fallot, microcephaly, short stature and brachymesophalangy is associated with hemizygous loss of noncoding MIR17HG and coding GPC5. PMID- 25503808 TI - Outcomes of follicle-stimulating hormone priming and nonpriming in in vitro maturation of oocytes in infertile women with polycystic ovarian syndrome: a single-blinded randomized study. AB - BACKGROUND/AIMS: Follicle-stimulating hormone (FSH) priming has been studied in in vitro matured oocytes for oocyte maturation rate, embryo quality, and pregnancy rate with discouraging results. This study aimed to initiate FSH stimulation later, i.e. on day 6, to prolong natural endometrial priming and promote oocyte maturation. METHODS: Forty polycystic ovarian syndrome (PCOS) patients were enrolled into a single, blinded (investigator), randomized, controlled study, and randomly allocated to group 1 (no FSH priming) or group 2 (day 6 recombinant FSH priming). Oocytes were retrieved after human chorionic gonadotropin injection on day 10. After 27 or 51 h of incubation, only mature oocytes were denuded and fertilized by intracytoplasmic sperm injection. Two day 3 embryos were transferred in most patients. Rates of oocyte maturation, cleavage, and pregnancy were compared. RESULTS: The oocyte maturation rates within 51 h were 62.6 and 72.7% in groups 1 and 2, respectively (p < 0.01). The embryo cleavage rate was significantly higher in group 2 than in group 1 (77.3 vs. 63.6%, p < 0.05). The pregnancy rate was higher in group 1 than in group 2 (50 vs. 30%, p > 0.05). CONCLUSION: FSH priming is beneficial for promotion of the maturation and quality of oocytes, leading to a higher embryo cleavage rate and lower rate of pregnancy loss. PMID- 25503806 TI - Exposure to endosulfan influences sperm competition in Drosophila melanogaster. AB - Dwindling male fertility due to xenobiotics is of global concern. Accordingly, male reproductive toxicity assessment of xenobiotics through semen quality analysis in exposed males, and examining progeny production of their mates is critical. These assays, in part, are biased towards monogamy. Females soliciting multiple male partners (polyandry) is the norm in many species. Polyandry incites sperm competition and allows females to bias sperm use. However, consequences of xenobiotic exposure to the sperm in the light of sperm competition remain to be understood. Therefore, we exposed Drosophila melanogaster males to endosulfan, and evaluated their progeny production as well as the ability of their sperm to counter rival control sperm in the storage organs of females sequentially mated to control/exposed males. Endosulfan (2 MUg/ml) had no significant effect on progeny production and on the expression of certain genes associated with reproduction. However, exposed males performed worse in sperm competition, both as 1(st) and 2(nd) male competitors. These findings indicate that simple non competitive measures of reproductive ability may fail to demonstrate the harmful effects of low-level exposure to xenobiotics on reproduction and advocate consideration of sperm competition, as a parameter, in the reproductive toxicity assessment of xenobiotics to mimic situations prevailing in the nature. PMID- 25503809 TI - Is endoscopic lung volume reduction able to reverse pulmonary hypertension in patients with severe emphysema? PMID- 25503811 TI - Microbiology and antibiotic prophylaxis in rhinoplasty: a review of 363 consecutive cases. AB - IMPORTANCE: A practical technique for reducing infectious complications from rhinoplasty would represent an important surgical advance. OBJECTIVES: To describe the microbial flora of patients undergoing septorhinoplasty and to evaluate the role of preoperative and postoperative antibiotic prophylaxis. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective medical record review of 363 consecutive adult patients who underwent preoperative nasal swab testing and rhinoplasty or septorhinoplasty in a single private practice: 279 women (76.9%) and 84 men (23.1%). The average patient age was 35.9 years (age range, 17-70 years). MAIN OUTCOMES AND MEASURES: Identification of endogenous nasal flora and pathogenic bacteria treated with culture-directed antibiotics; evaluation of comorbidities, perioperative infections, and antibiotic treatments. RESULTS: A total of 174 patients (47.9%) underwent primary rhinoplasty, and 189 (52%) underwent revision rhinoplasty. On preoperative nasal culture, 78.2% of patients had normal flora; 10.7% had Staphylococcus aureus; and 0.28% had methicillin-resistant S aureus (MRSA). In 7.4% of patients, fecal coliforms including Escherichia coli, Enterobacter species, and Citrobacter species were found. Age, sex, smoking, the use of oral contraceptives, or the presence of seasonal allergies did not significantly change the nasal flora or the postoperative infection rate. Patients with adult acne were found to have an increased incidence of colonization with fecal coliforms (43.8%; P < .001). Patients with diabetes were found to have an increased incidence of colonization with S aureus (66.7%; P = .002). The overall infection rate was 3.0% (11 of 363 patients), with 4.0% (7 of 174 patients) seen in primary septorhinoplasties and 2.1% (4 of 189 patients) seen in revision cases. Coliforms accounted for 5 cases (45.5%) of postoperative infections, while S aureus was responsible for 4 cases (36.4%), including 1 case of MRSA. CONCLUSIONS AND RELEVANCE: The results of this study suggest that risk factors alone may not reliably predict the subset of patients in whom antibiotic prophylaxis is indicated. Knowledge of the endogenous nasal flora and the microbiology of common pathogens in patients undergoing septorhinoplasty will help to further reduce the incidence of infectious complications. LEVEL OF EVIDENCE: 3. PMID- 25503810 TI - Bilirubin modulates acetylcholine receptors in rat superior cervical ganglionic neurons in a bidirectional manner. AB - Autonomic dysfunction as a partial contributing factor to cardiovascular instability in jaundiced patients is often associated with increased serum bilirubin levels. Whether increased serum bilirubin levels could directly inhibit sympathetic ganglion transmission by blocking neuronal nicotinic acetylcholine receptors (nAChRs) remains to be elucidated. Conventional patch-clamp recordings were used to study the effect of bilirubin on nAChRs currents from enzymatically dissociated rat superior cervical ganglia (SCG) neurons. The results showed that low concnetrations (0.5 and 2 MUM) of bilirubin enhanced the peak ACh-evoked currents, while high concentrations (3 to 5.5 uM) of bilirubin suppressed the currents with an IC50 of 4 +/- 0.5 MUM. In addition, bilirubin decreased the extent of desensitization of nAChRs in a concentration-dependent manner. This inhibitory effect of bilirubin on nAChRs channel currents was non-competitive and voltage independent. Bilirubin partly improved the inhibitory effect of forskolin on ACh-induced currents without affecting the action of H-89. These data suggest that the dual effects of enhancement and suppression of bilirubin on nAChR function may be ascribed to the action mechanism of positive allosteric modulation and direct blockade. Thus, suppression of sympathetic ganglionic transmission through postganglionic nAChRs inhibition may partially contribute to the adverse cardiovascular effects in jaundiced patients. PMID- 25503813 TI - Isothermal transport properties and majority-type defects of BaCo(0.70)Fe(0.22)Nb(0.08)O(3-delta). AB - (Ba,Sr)(Co,Fe)O3-delta based mixed conducting oxides, e.g. (Ba0.5Sr0.5)(Co1 xFex)O3-delta and Ba(Co0.7Fe0.3-xNbx)O3-delta, are promising candidates for oxygen permeable membranes and SOFC cathodes due to their excellent ambipolar conductivities. Despite these excellent properties, however, their mass/charge transport properties have not been fully characterized and hence, their defect structure has not been clearly elucidated. Until now, the majority types of ionic and electronic defects have been regarded as oxygen vacancies and localized holes. Holes, whether localized or not, are acceptable as majority electronic carriers on the basis of the as-measured total conductivity, which is essentially electronic, and electronic thermopower. On the other hand, the proposal of oxygen vacancies as majority ionic carriers lacks solid evidence. In this work, we document all the isothermal transport properties of Ba(Co0.70Fe0.22Nb0.08)O3 delta in terms of a 2 * 2 Onsager transport coefficient matrix and its steady state electronic thermopower against oxygen activity at elevated temperatures, and determine the valences of Co and Fe via soft X-ray absorption spectroscopy. It turns out that the ionic and electronic defects in majority should be oxygen interstitials and at least two kinds of holes, one free and the other trapped. Furthermore, the lattice molecule should be Ba(Co0.7Fe0.3-xNbx)O2+delta, not Ba(Co0.7Fe0.3-xNbx)O3-delta, to be consistent with all the results observed. PMID- 25503812 TI - Assessment of response to neoadjuvant radiochemotherapy with F-18 FLT and F-18 FDG PET/CT in patients with rectal cancer. AB - OBJECTIVE: The comparison of 2-deoxy-2-[18F]fluoro-D-glucose (F-18 FDG) and 3' deoxy-3'-[18F]fluorothymidine (F-18 FLT) imaging in patients with rectal cancer before and after neoadjuvant radiochemotherapy (RCT) in relation to histopathology and immunohistochemistry obtained from surgery. METHODS: 20 consecutive patients (15 m, 5 f), mean age of 65 +/- 10 years were included into this prospective study with a mean follow-up of 4.1 +/- 0.8 years. RESULTS: Among histopathological responders (n = 8 out of 20), posttreatment F-18 FLT and F-18 FDG scans were negative in 75 % (n = 6) and 38 % (n = 3), respectively. The mean response index (RI) was 61.0 % +/- 14.0 % for F-18 FLT and 58.7 % +/- 14.6 % for F-18 FDG imaging. Peritumoral lymphocytic infiltration (CD3 positive cells) was significantly related to posttreatment SUVmax in F-18 FDG but not F-18 FLT studies. CONCLUSION: A significant decrease of SUVmax in F-18 FDG and F-18 FLT studies could be seen after RCT. Negative posttreatment F-18 FLT studies identified more histopathological responders. PMID- 25503814 TI - Phosphate binding by a novel Zn(II) complex featuring a trans-1,2 diaminocyclohexane ligand. Effective anion recognition in water. AB - In this work we have investigated the binding properties of a new synthetic receptor for phosphate anions that combines metal ion coordination with electrostatic and H-bonding interactions. The described receptor is obtained by assembling an iminodiacetic (IDA) fragment, as a Zn(II) binding site, with a polyamine macrocyclic portion containing two trans-1,2-diaminocyclohexane (DAC) units and a pyrrole ring, as a cationic binding site, into an adaptive structure appropriately spanning the length of di- and tridentate phosphates. Potentiometric measurements together with (1)H and (31)P NMR investigation showed that, in a wide pH range including values of physiological interest, the Zn(II) complex of the receptor binds di- and triphosphates, such as ADP, ATP, pyrophosphate (PP) and triphosphate (TP), far better than monophosphate (MP), and that TP is poorly bound by methyliminodiacetate (MIDA) as a model for the Zn(II) binding site. Besides the excellent selectivity over other phosphates, the affinity for TP is the largest reported to date for Zn(II) complexes in water. PMID- 25503815 TI - Broad implications for respiratory sinus arrhythmia development: associations with childhood symptoms of psychopathology in a community sample. AB - Replicating the group-based developmental trajectory methodology from our prior study (Patriquin, Lorenzi, Scarpa, & Bell. 2014. Developmental Psychobiology, 56, 317-326), the current study examines the development of baseline respiratory sinus arrhythmia (RSA) across a new, larger cohort of typically developing children at 5, 10, 24, 36, and 48 months of age and examines the trajectory relationship with symptoms of childhood psychopathology. Group-based developmental trajectory modeling replicated our prior findings of a two-group model fit: a "High RSA" and "Low RSA" group. The "Low RSA" group, which demonstrated lower baseline RSA across all time points, had significantly more childhood problems at 48 months, namely increased withdrawal, aggressive behavior, pervasive developmental problems, and oppositional defiant problems. All participants for whom there were developmental or autism spectrum concerns (n = 6; based on maternal report at 48 months) were allocated to the Low RSA trajectory group. These results suggest that consistent developmental trajectories of RSA may point to protective factors (i.e., high RSA) against developing symptoms of childhood psychopathology. PMID- 25503816 TI - Intertwining lamellar assembly in porous spherulites composed of two ring-banded poly(ethylene adipate) and poly(butylene adipate). AB - Poly(1,4-butylene adipate) (PBA) and poly(ethylene adipate) (PEA), each with the ability to form ring-banded morphologies at same Tc, were simultaneously crystallized from mixtures of various compositions. Investigations on morphology, phase and thermal behavior were conducted in order to reveal lamellar packing and spherulitic structures in this binary system. As PBA is faster-crystallizing and dominates the crystallization process, it is relatively easy to maintain its ordered ring-banded pattern in a PBA/PEA blend when there is a moderate amount of PBA in the composition (40 wt% or greater). On the other hand, PEA is much slower crystallizing and it has to be in extreme majority (PEA > 95 wt%) in the PBA/PEA mixtures in order to crystallize into ring-banded spherulites of PEA pattern. When PBA composition is between 10 and 40 wt% in the PBA/PEA blend, simultaneous crystallization of PBA and PEA leads to an interpenetrating morphology with an interwoven bird-nest pattern. Porous structures with crevices, owing to the interpenetrating PBA and PEA lamellae, resulted in simultaneous crystallization of these two biodegradable polyesters. PMID- 25503817 TI - Paravertebral Analgesia in Video-Assisted Thoracic Surgery: A New Hybrid Technique of Catheter Placement for Continuous Anesthetic Infusion. AB - Advantages of paravertebral analgesia in thoracotomy include the absence of morphine side effects and the lack of contraindications. We introduce a new technique for paravertebral catheter placement during video-assisted thoracic surgery. The catheter is placed in the same intercostal space as the camera port. Anesthetic is injected to reach the parietal pleura. The catheter is inserted through the needle and pushed until the paravertebral space is reached. Postoperative analgesia is performed by a continuous infusion of local anesthetics. Our technique is safe and easy to perform and avoids opioid use. It works differently from intercostal analgesia and paravertebral blocks. PMID- 25503818 TI - Transsternal thymectomy. AB - Thymectomy is a well-established indication for management of myasthenia gravis and it represents the most effective treatment for thymic tumors. The traditional surgical approach is median sternotomy. More recently, different less-invasive surgical approaches for thymectomy have been proposed as an alternative to open surgery. This article discusses the main technical aspects and results of literature. PMID- 25503819 TI - Effect of temperature on the conformation of natively unfolded protein 4E-BP1 in aqueous and mixed solutions containing trifluoroethanol and hexafluoroisopropanol. AB - Natively unfolded (intrinsically disordered) proteins have attracted growing attention due to their high abundance in nature, involvement in various signalling and regulatory pathways and direct association with many diseases. In the present work the combined effect of temperature and alcohols, trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP), on the natively unfolded 4E-BP1 protein was studied to elucidate the balance between temperature-induced folding and unfolding in intrinsically disordered proteins. It was shown that elevated temperatures induce reversible partial folding of 4E-BP1 both in buffer and in the mixed solutions containing denaturants. In the mixed solutions containing TFE (HFIP) 4E-BP1 adopts a partially folded helical conformation. As the temperature increases, the initial temperature-induced protein folding is replaced by irreversible unfolding/melting only after a certain level of the protein helicity has been reached. Onset unfolding temperature decreases with TFE (HFIP) concentration in solution. It was shown that an increase in the temperature induces two divergent processes in a natively unfolded protein- hydrophobicity-driven folding and unfolding. Balance between these two processes determines thermal behaviour of a protein. The correlation between heat-induced protein unfolding and the amount of helical content in a protein is revealed. Heat-induced secondary structure formation can be a valuable test to characterise minor changes in the conformations of natively unfolded proteins as a result of site-directed mutagenesis. Mutants with an increased propensity to fold into a structured form reveal different temperature behaviour. PMID- 25503820 TI - Central connectivity of the chorda tympani afferent terminals in the rat rostral nucleus of the solitary tract. AB - The rostral nucleus of the solitary tract (rNST) receives gustatory input via chorda tympani (CT) afferents from the anterior two-thirds of the tongue and transmits it to higher brain regions. To help understand how the gustatory information is processed at the 1st relay nucleus of the brain stem, we investigated the central connectivity of the CT afferent terminals in the central subdivision of the rat rNST through retrograde labeling with horseradish peroxidase, immunogold staining for GABA, glycine, and glutamate, and quantitative ultrastructural analysis. Most CT afferents were small myelinated fibers (<5 um(2) in cross-sectional area) and made simple synaptic arrangements with 1-2 postsynaptic dendrites. It suggests that the gustatory signal is relayed to a specific group of neurons with a small degree of synaptic divergence. The volume of the identified synaptic boutons was positively correlated with their mitochondrial volume and active zone area, and also with the number of their postsynaptic dendrites. One-fourth of the boutons received synapses from GABA immunopositive presynaptic profiles, 27 % of which were also glycine immunopositive. These results suggest that the gustatory information mediated by CT afferents to the rNST is processed in a simple and specific manner. They also suggest that the minority of CT afferents are presynaptically modulated by GABA- and/or glycine-mediated mechanism. PMID- 25503821 TI - Volume-sensitive chloride channels are involved in cisplatin treatment of osteosarcoma. AB - Chemotherapy is the most common therapeutic strategy used to treat osteosarcoma. The present study aimed to investigate the effects of functionally activated chloride channels on cisplatin-induced apoptosis of MG-63 human osteosarcoma cells. An MTT assay and flow cytometry were used to detect proliferation and apoptosis of the cells, respectively. Live cell imaging was used to detect volume changes in response to treatment with cisplatin and/or chloride channel blockers. The effects of these treatments on chloride currents were also assayed using the patch-clamp technique. The results of the present study indicate that chloride channel blockers may suppress cisplatin-induced apoptosis. The MG-63 cells cultured with cisplatin demonstrated an apoptotic volume decrease, as well as suppression of cell proliferation; which were reversed by co-treatment with chloride channel blockers. These results suggest that cisplatin may activate chloride channels, and that channel activation is an early signal in the pathways that lead to cisplatin-induced apoptosis and inhibition of proliferation in MG-63 cells. In conclusion, these results indicate that chloride channels have an important role in cisplatin treatment of osteosarcoma. PMID- 25503822 TI - The role of Homer1b/c in neuronal apoptosis following LPS-induced neuroinflammation. AB - Homer, also designated Vesl, is one member of the newly found postsynaptic density scaffold proteins, playing a vital role in maintaining synaptic integrity, regulating intracellular calcium mobilization, and being critical for the regulation of cellular apoptosis. However, its function in the inflamed central nervous system (CNS) is not fully elucidated. Here, we investigated the role of Homer1b/c, a long form of Homer1, in lipopolysaccharide (LPS) induced neuroinflammation in CNS. Western blot analysis indicated that LPS administration significantly increased the expression of Homer1b/c in rat brain. Moreover, double immunofluorescent staining suggested Homer1b/c was mainly distributed in the cytoplasm of neurons and had a close association with cleaved caspase-3 level in neurons in rat brain after LPS injection. In vitro studies indicated that up regulation of Homer1b/c might be related to the subsequent apoptosis in neurons treated by conditioned media (CM), collected from LPS-stimulated mixed glial cultures (MGC). We also found down-regulation of Homer1b/c partly blocked the increase of cleaved caspase-3 and the proportion of Bax/Bcl-2 in neurons induced by MGC-CM. Taken together, these findings suggested that Homer1b/c might promote neuronal apoptosis via the Bax/Bcl-2 dependent pathway during neuroinflammation in CNS, and inhibiting Homer1b/c expression might provide a novel neuroprotective strategy against the inflammation-related neuronal apoptosis. PMID- 25503823 TI - Alteration in 5-HT2C, NMDA receptor and IP3 in cerebral cortex of epileptic rats: restorative role of Bacopa monnieri. AB - Bacopa monnieri is effective in stress management, brain function and a balanced mood. 5-HT2C receptors have been implicated in stress whereas NMDA receptors and mGlu5 play crucial role in memory and cognition. In the present study, we investigated the role of B. monnieri extract in ameliorating pilocarpine induced temporal lobe epilepsy through regulation of 5-HT2C and NMDA receptors in cerebral cortex. Our studies confirmed an increased 5-HT2C receptor function during epilepsy thereby facilitating IP3 release. We also observed an decreased NMDA receptor function with an elevated mGlu5 and GLAST gene expression in epileptic condition indicating the possibility for glutamate mediated excitotoxicity. These alterations lead to impaired behavioural functions as indicated by the Elevated Plus maze test. Carbamazepine and B. monnieri treatments to epileptic rats reversed the alterations in 5-HT2C, NMDA receptor functions and IP3 content thereby effectively managing the neurotransmitter balance in the cerebral cortex. PMID- 25503824 TI - Medication adherence in patients with Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder, after Alzheimer's disease, affecting the elderly worldwide. Current therapy for PD is largely based on prescription of drugs that act as either dopamine precursors, dopamine agonists or agents that inhibit key enzymes in the dopamine catabolic pathways. Most of these drugs are administered in tablet or capsule form and can involve multiple daily doses in complex dosing regimens, which contributes to sub-optimal compliance amongst patients. There is evidence to suggest that non-compliance with medications results in perceived poor response to therapy and may ultimately increase direct and indirect health care costs. Medication compliance in PD assumes a particularly important role, given that PD is a progressive, debilitating condition, and once medication is instituted for ameliorating the symptoms of PD, it is lifelong. We included nine research studies in our review of the medical literature, which report the prevalence of significant medication non-compliance in PD, using standard definitions, varies between 10 and 67%. This variation partly reflects differences in defining what clinically significant medication adherence is, the methods used to estimate the scale of the problem and the underlying population heterogeneity. Nevertheless, medication adherence is related to health costs and to the quality of life of patients affected by PD and, indirectly, their carers. Educating patients and their carers is one method of improving patient adherence to therapy. Simplifying drug regimens can also aid in this effort. PMID- 25503825 TI - Metalinguistic deficits in patients with cerebellar dysfunction: empirical support for the dysmetria of thought theory. AB - The cerebellar cognitive affective syndrome (CCAS) includes disruption of linguistic processing such as verbal fluency, verbal working memory, grammar, and speech perception. We set out to examine linguistic capabilities in patients with cerebellar lesions to determine which domains are spared and which impaired and to evaluate the underlying cognitive structure of these deficits. Forty-four patients with cerebellar disease were compared to 40 healthy controls on the Oral Sentence Production Test (OSPT) which assesses production of sentences with correct syntactic structure and semantic quality. Twenty-five of these cerebellar patients and 25 controls received the Test of Language Competence-Expanded (TLC E) that assesses metalinguistic ability. The OSPT failed to reveal differences between patients and controls. In contrast, all cerebellar patients were impaired on each of the four TLC-E subtests. Differences between isolated cerebellar and complex cerebrocerebellar patients were nonsignificant. These results confirm and extend prior observations of the TLC-E in patients with cerebellar lesions and suggest three separate but related language impairments following cerebellar dysfunction: (1) disruption in automatic adjustment of intact grammatical and semantic abilities to a linguistic context in sentence production, (2) disruption in automatic adjustment to a linguistic context in sentence interpretation, and (3) disruption of cognitive processes essential for linguistic skills, such as analysis and sequential logical reasoning. These findings are consistent with the unifying framework of the universal cerebellar transform and the dysmetria of thought theory and provide new insights into the nature of the cognitive impairments in patients with the CCAS. PMID- 25503826 TI - Fourier transform infrared microspectroscopy monitoring of 5-fluorouracil-induced apoptosis in SW620 colon cancer cells. AB - Colon cancer is associated with a high incidence and a poor prognosis. The aim of the present study was to determine whether Fourier transform infrared (FTIR) microspectroscopy can be used to monitor the chemotherapy drug-induced apoptosis of SW620 colon cancer cells. The 50% inhibitory concentration (IC50) of 5 fluorouracil (5-FU), the main chemotherapeutic agent used for the treatment of colorectal cancer, was determined as the inhibition of growth of the SW620 cells using an MTT assay. Cell starvation and 5-FU treatment synergized to arrest the cells in the G1 and S phases of the cell cycle. FTIR combined with fluorescence activated cell sorting (FACS) analysis were used to analyze the SW620 cells following treatment with 5-FU for 12, 24 and 48 h. The apoptotic cells had several spectral characteristics. The relative peak intensity ratio (I1740/I1460) was significantly increased (P<0.05), the I1740/I1460 ratio, associated with a band of amino acid residues at 1,410 cm-1 was significantly increased at the early and late phases of cell death (P<0.05), the peaks at 1,240 cm-1 increased in wave number, a band at 1,040 cm-1, associated with polysaccharides, appeared at 24 and 48 h and then moved to a higher wave number and the I1040/I1460 ratio increased at the late stage of apoptosis. These results demonstrated that FTIR can be used as a label-free technique to monitor cancer cell apoptosis and to understand the spectral fingerprints of apoptotic cells. This suggested that FTIR spectral features have potential as a powerful tool to monitor cancer cell apoptosis. PMID- 25503827 TI - Characteristics of sudden bath-related death investigated by medical examiners in Tokyo, Japan. AB - BACKGROUND: Sudden bath-related deaths occur frequently in Japan, particularly among elderly people. However, the precise mechanism of bath-related death remains uncertain, and effective prevention strategies have not been established. METHODS: Cases of bath-related deaths (n = 3289) were selected from all cases handled by the Tokyo Medical Examiner's Office from 2009 to 2011 (N = 41 336). The ages and occurrence dates were examined, and major autopsy findings, including toxicological analysis, were evaluated for the autopsied cases (n = 550). RESULTS: Most cases occurred in individuals older than 60 years of age during winter. Analysis of autopsy findings revealed water inhalation signs in many cases (n = 435, 79.1%). Circulatory system diseases constituted more than half of the pathological findings regarding factors that may have contributed significantly to death (n = 300, 54.5%), and cardiac lesions were the most common pathological finding (n = 250, 45.5%). However, approximately one-third of the cases exhibited no remarkable pathological findings (n = 198, 36.0%). A quarter of all cases involved blood ethanol levels that exceeded 0.5 mg/mL (n = 140). CONCLUSIONS: The results suggested that drowning plays an important role in the final process of bath-related death. Circulatory system diseases may be the primary underlying pathology; however, there were variations in the medical histories and pathologies of cases of bath-related death. From a preventive perspective, family members should pay attention to elderly people with circulatory system diseases during bathing, particularly in winter. Additionally, the notion that ill or inebriated individuals should not take baths should be reinforced. PMID- 25503830 TI - The children are our future. PMID- 25503828 TI - Inhibition of i-NOS but not n-NOS protects rat primary cell cultures against MPP(+)-induced neuronal toxicity. AB - Nitrative stress is a key component of the pathogenic process in Parkinson's disease (PD), but the relative roles of constitutive neuronal nitric oxide synthase (n-NOS) and inducible nitric oxide synthase (i-NOS) in glial cells remain unresolved. We have investigated the effects of a range of concentrations of the selective n-NOS inhibitor ARR17477, and the selective i-NOS inhibitor 1400W, on MPP(+)-induced cell death in foetal ventral mesencephalic (VM) dopaminergic cultures. MPP(+) induced a loss of TH-positive neurones accompanied by an increase in immunoreactivity for GFAP and OX-6 as markers of astrocytes and activated microglia, respectively, and induced i-NOS immunoreactivity. Unexpectedly, MPP(+) treatment did not induce 3-NT immunoreactivity in the cultures. ARR17477 and 1400W alone had no effect on the number of TH-positive cells or on the number of GFAP or OX-6 positive cells. ARR17477 did not prevent the MPP(+)-induced decrease in TH-positive neurones and had no effect on the increased number of GFAP- and OX-6-positive cells. By contrast, 1400W caused a concentration-dependent preservation of TH-positive neurones in the presence of MPP(+). It also significantly reduced the number of OX-6-immunoreactive cells and there was a small reduction in GFAP immunoreactivity. The results suggest a major role for i-NOS-mediated nitrative stress in microglia in MPP(+)-induced dopaminergic cell death and this may have important implications for developing neuroprotective strategies for PD. PMID- 25503829 TI - Echogenicity of basal ganglia structures in different Huntington's disease phenotypes. AB - In Huntington's disease (HD), a neurodegenerative-inherited disease, chorea as the typical kind of movement disorder is described. Beside chorea, however, all other kinds of movement disturbances, such as bradykinesia, dystonia, tremor or myoclonus can occur. Aim of the current study was to investigate alterations in the echogenicity of basal ganglia structures in different Huntington's disease phenotypes. 47 patients with manifest and genetically confirmed HD were recruited. All participants underwent a thorough neurological examination. According to a previously described method, classification into predominantly choreatic, mixed or bradykinetic-rigid motor phenotypes was performed depending on subscores of the Unified Huntington's Disease Rating Scale. In addition, findings in juvenile HD were compared to adult HD. Transcranial sonography was performed by investigators blinded to clinical classification. There were no significant differences in basal ganglia echogenicities between the three phenotypes. Size of echogenic area of substantia nigra (SN) correlated positively with CAG repeat and bradykinesia subscore, and negatively with age of onset and chorea subscore. Comparing juvenile and adult HD subtypes, SN hyperechogenicity was significantly more often detectable in the juvenile form (100 vs. 29.3 %, p = 0.002). Regarding echogenicity of caudate or lentiform nuclei, no significant differences were detected. HD patients with the juvenile variant exhibit marked hyperechogenicity of substantia nigra. No significant differences in basal ganglia echogenicities between predominantly choreatic, mixed or bradykinetic rigid motor phenotypes were detected. PMID- 25503831 TI - Are planned home births safe? PMID- 25503832 TI - Transgender men and lactation: what nurses need to know. AB - Research examining needs of postpartum transgender men in relation to lactation and infant feeding is missing from nursing literature. Accordingly, little is known about how perinatal nurses can best support this unique subset of postpartum patients. Case studies presented here reveal that transgender men would appreciate care from nurses who are knowledgeable about transgender individuals and their healthcare needs, but this type of care is not always available. Nurses need more education about how to best support transgender patients and families in order to achieve optimal lactation and infant nutrition in this population. PMID- 25503833 TI - Hydrocolloid to prevent breakdown of nares in preterm infants. AB - PURPOSE: To determine if a double-barrier hydrocolloid dressing prevents trauma to the nares and columella in very low birthweight (VLBW) infants (<1,500 grams) receiving heated humidified high-flow nasal cannula (HHHFNC) oxygen. STUDY DESIGN AND METHODS: Retrospective two-group comparative study design. SAMPLE: Medical records (N = 53) of VLBW infants receiving HHHFNC were reviewed. Control infants (n = 27) did not have a double-barrier hydrocolloid dressing. Intervention infants (n = 26) had a double-barrier hydrocolloid dressing. Groups were similar on sex, race, birthweight, and gestational age. Control infants were significantly older than intervention infants at study entry (4.3 weeks and 1.5 weeks, respectively, p = .001). Skin condition of nares was scored daily ranging from 3 (no breakdown) to 9 (extensive breakdown). Skin scores were abstracted from medical records at baseline then weekly for comparison over time. RESULTS: There were no significant differences in skin scores between groups or over time. Week 1 mean skin score was 3.4 (+/-0.1) in both groups. Mean skin score at week 4 was 3.4 (+/-0.1) in Control infants and 3.1 (+/-0.08) in Intervention infants. CLINICAL IMPLICATIONS: HHHFNC is more frequently being used in infants of extreme prematurity. The dressing may have protected the more immature skin of the intervention infants; however, vigilant nursing observation of the infants' nares during HHHFNC cannot be ruled out. Nurses need adequate education on the consistent application of the hydrocolloid barrier and on documenting skin assessment scores each shift to promote skin protection in this vulnerable population. PMID- 25503834 TI - Clinician perspectives of barriers in perinatal palliative care. AB - PURPOSE: Perinatal palliative care (PPC) is a developing model of care aimed at providing supportive services to families anticipating fetal or neonatal demise. This study measured barriers physicians and advance practice nurses report in providing and referring patients to PPC. STUDY DESIGN AND METHODS: A cross sectional survey design using the Perinatal Palliative Care Perceptions and Barriers Scale (c) was administered using a Web-based tool. Recruitment was completed via email and flyer invitations and list serves. Physicians (n = 66) and advance practice nurses (n = 146) participated. T-test and Mann-Whitney U were used to examine differences in clinician-reported barriers to PPC. RESULTS: Physicians and nurses differ significantly in the barriers they report. Nurses expressed more obstacles at the healthcare systems level reporting difficulty in their ability to garner interdisciplinary support and gain administrative backing. Physicians are more confident in their ability to counsel patients than nurses. Members of both disciplines express similar feelings of distress and helplessness when caring for families expecting a fetal or neonatal demise. They also report a lack of societal support and understanding about PPC. CLINICAL IMPLICATIONS: Cultivating an environment of collaboration and interdisciplinary communication can benefit both caregivers and patients. Nurses have an opportunity to lead and promote PPC endeavors through participating in advantageous partnerships and research. Both disciplines may benefit from interventions directed at increasing their comfort in caring for patients in a palliative setting through targeted education and supportive staff services. PMID- 25503835 TI - Predicting folic acid intake among college students. AB - PURPOSE: Annually in the United States, approximately 3,000 babies are born with neural tube defects (NTDs). Folic acid supplementation can reduce NTDs by 50% to 70%. Despite recommendations for folic acid intake, only 30% of women ages 18 to 24 report folic acid supplementation and 6% have knowledge of when to take folic acid. There is little information regarding lifestyle factors that correlate with consuming folic acid. The purpose was to describe folic acid consumption among college students; and explore the relationship between folic acid intake and the variables of: age, gender, year in college, alcohol and tobacco use, and vitamin supplement intake. STUDY DESIGN AND METHODS: This was a descriptive study with secondary analysis of data from 1,921 college-aged student participants in North Carolina who took part in a pretest/posttest-designed intervention to increase folic acid consumption and knowledge. Surveys included demographic, lifestyle, folic acid knowledge, and consumption questions adapted from the Centers for Disease Control and Prevention questionnaire. Quantitative analyses included descriptive statistics and logistic regression. RESULTS: Of the 1,921 college students, 83.3% reported taking a vitamin supplement, but only 47.6% stated that the vitamin contained folic acid. A relationship was found between age, year in school, gender, and vitamin intake. Lifestyle variables were not significant predictors of folic acid consumption. CLINICAL IMPLICATIONS: Identification of variables associated with folic acid intake, marketing, and education can be focused to increase supplementation levels, and ultimately reduce the number of NTDs. PMID- 25503836 TI - Intermittent auscultation in low-risk labor. PMID- 25503837 TI - Bed sharing. PMID- 25503838 TI - Thinking about a diet? PMID- 25503839 TI - Texting protected health information in healthcare. PMID- 25503840 TI - Meeting the challenge of cystic fibrosis. PMID- 25503842 TI - Electronic health records. PMID- 25503847 TI - Non-hemodynamically significant renal artery stenosis predicts cardiovascular events in persons with ischemic heart disease. AB - BACKGROUND/AIMS: Recently, we reported that small renal arteries, defined by a low reference diameter (RD) or minimal luminal diameter (MD), are independently associated with a low GFR, resistant hypertension, and onset of contrast-induced nephropathy and suggested a post-hoc analysis of CORAL trial based on RD categories. Here we hypothesized that RD and MD are markers of nontraditional cardiovascular risk factors and tested whether low RD and MD could impact the prognosis of patients with ischemic heart disease. METHODS: Prospective cohort study. We used proportional hazards models to analyze the first onset of cardiovascular events in relation with RD, MD, or percentage of renal artery stenosis (RAS) in those with low-to-moderate RAS (10-70%) (n = 181). RESULTS: During the median follow-up of 4.5 (range, 0.1-5) years, 27.8% participants (n = 623; mean age, 64 years; 29% women) experienced a cardiovascular event (35.4% in those with RAS 10-70%). The presence of low-to-moderate RAS was associated with cardiovascular events. In these subjects, those with low MD were associated with a higher risk of cardiovascular events (MD >4.2 mm, HR: 1; MD 3.2-4.2 mm, HR: 1.66, 95% CI: 0.74-3.72, p = 0.22; MD <3.2 mm, HR: 3.72, 95% CI: 1.65-8.40, p = 0.002). When MD was added to a standard risk-factor model, risk prediction improvement was by 4.1%. Results were qualitatively similar if MD was replaced by RD or percentage of stenosis, but with smaller improvement of risk prediction and model fit. CONCLUSIONS: In patients with ischemic heart disease and low-to moderate RAS, MD is a significant predictor of cardiovascular events, improves risk prediction, and may represent a valuable biomarker of cardiovascular disease risk. PMID- 25503845 TI - Systolic hypertension: an increasing clinical challenge in Asia. AB - Systolic hypertension, the predominant form of hypertension in patients aged over 50-60 years, is a growing health issue as the Asian population ages. Elevated systolic blood pressure is mainly caused by arterial stiffening, resulting from age-related vascular changes. Elevated systolic pressure increases the risk of cardiovascular disease, mortality and renal function decline, and this risk may increase at lower systolic pressure levels in Asian than Western subjects. Hence, effective systolic pressure lowering is particularly important in Asians yet blood pressure control remains inadequate despite the availability of numerous antihypertensive medications. Reasons for poor blood pressure control include low awareness of hypertension among health-care professionals and patients, under treatment, and tolerability problems with antihypertensive drugs. Current antihypertensive treatments also lack effects on the underlying vascular pathology of systolic hypertension, so novel drugs that address the pathophysiology of arterial stiffening are needed for optimal management of systolic hypertension and its cardiovascular complications. PMID- 25503848 TI - Compartment fabrication of magneto-responsive Janus microrod particles. AB - Monodispersed magneto-responsive microrod particles of variable magnetic/non magnetic ratios and chemical compositions are created by compartment fabrication in a single poly(dimethylsiloxane) (PDMS) mold with periodic hole arrays. By labeling the two ends with green and red fluorescent dyes separately, we show that the particles can flip freely and reversibly in a confined geometry under the magnetic field, thereby displaying different patterned colors at the air water interface. PMID- 25503846 TI - Pollution profiles and risk assessment of PBDEs and phenolic brominated flame retardants in water environments within a typical electronic waste dismantling region. AB - The aim of this study was to assess the pollution profiles of various typical brominated flame retardants in water and surface sediment near a typical electronic waste dismantling region in southern China. We found that polybrominated diphenyl ethers (PBDEs), 2,4,6-tribromophenol (TBP), pentabromophenol (PeBP), tetrabromobisphenol A (TBBPA), and bisphenol A (BPA) were ubiquitous in the water and sediment samples collected in the study region. In water, Sigma19PBDEs (sum of all 20 PBDE congeners studied except BDE-209, which was below the detection limit) levels ranged from 0.31 to 8.9 * 10(2) ng L( 1). TBP, PeBP, TBBPA, and BPA concentrations in the water samples ranged from not being detectable (nd-under the detection limit) to 3.2 * 10(2) (TBP), from nd to 37 (PeBP), from nd to 9.2 * 10(2) (TBBPA) and from nd-8.6 * 10(2) ng L(-1) (BPA). In sediment, Sigma19PBDEs ranged from nd to 5.6 * 10(3) ng g(-1), while BDE-209 was the predominant congener, with a range of nd to 3.5 * 10(3) ng g(-1). Tri- to hepta-BDE concentrations were significantly (p < 0.01) correlated with each other, except for BDE-71 and BDE-183, and octa- to nona-BDEs concentrations were significantly (p < 0.05) correlated with each other, except for BDE-208. BDE-209 was not significantly correlated with tri- to nona-BDEs. Risk assessments indicated that the water and sediment across the sampling sites posed no estrogenic risk. However, different eco-toxicity risk degrees at three trophic levels did exist at most sampling sites. PMID- 25503849 TI - [Enlargement of keratinized peri-implant mucosa at the time of second stage surgery (re-entry)]. AB - A tightly attached keratinized mucosa around endosseous dental implants is believed to be protective against peri-implant bone loss. Tension caused by buccal frena and mobile non keratinized mucosa is to avoid. This case report documents the optimization of peri-implant mucosal conditions in the upper and lower jaw. At the time of second stage surgery (re-entry) at submucosally osseointegrated dental implants an enlargement of keratinized mucosa and a thickening of soft tissue was obtained administrating a vestibuloplasty combined by a free gingival graft or a vestibuloplasty combined by an apically moved flap. PMID- 25503850 TI - Improving homology modeling of G-protein coupled receptors through multiple template derived conserved inter-residue interactions. AB - Evidenced by the three-rounds of G-protein coupled receptors (GPCR) Dock competitions, improving homology modeling methods of helical transmembrane proteins including the GPCRs, based on templates of low sequence identity, remains an eminent challenge. Current approaches addressing this challenge adopt the philosophy of "modeling first, refinement next". In the present work, we developed an alternative modeling approach through the novel application of available multiple templates. First, conserved inter-residue interactions are derived from each additional template through conservation analysis of each template-target pairwise alignment. Then, these interactions are converted into distance restraints and incorporated in the homology modeling process. This approach was applied to modeling of the human beta2 adrenergic receptor using the bovin rhodopsin and the human protease-activated receptor 1 as templates and improved model quality was demonstrated compared to the homology model generated by standard single-template and multiple-template methods. This method of "refined restraints first, modeling next", provides a fast and complementary way to the current modeling approaches. It allows rational identification and implementation of additional conserved distance restraints extracted from multiple templates and/or experimental data, and has the potential to be applicable to modeling of all helical transmembrane proteins. PMID- 25503851 TI - Methane-rich water induces cucumber adventitious rooting through heme oxygenase1/carbon monoxide and Ca(2+) pathways. AB - KEY MESSAGE: Methane-rich water triggered adventitious rooting by regulating heme oxygenase1/carbon monoxide and calcium pathways in cucumber explants. Heme oxygenase1/carbon monoxide (HO1/CO) and calcium (Ca(2+)) were reported as the downstream signals in auxin-induced cucumber adventitious root (AR) formation. Here, we observed that application of methane-rich water (MRW; 80% saturation) obviously induced AR formation in IAA-depleted cucumber explants. To address the universality, we checked adventitious rooting in soybean and mung bean explants, and found that MRW (50 and 10% saturation, respectively) exhibited the similar inducing results. To further determine if the HO1/CO system participated in MRW induced adventitious rooting, MRW, HO1 inducer hemin, its activity inhibitor zinc protoporphyrin IX (ZnPP), and its catalytic by-products CO, bilirubin, and Fe(2+) were used to detect their effects on cucumber adventitious rooting in IAA depleted explants. Subsequent results showed that MRW-induced adventitious rooting was blocked by ZnPP and further reversed by 20% saturation CO aqueous solution. However, the other two by-products of HO1, bilirubin and Fe(2+), failed to induce AR formation. Above responses were consistent with the MRW-induced increases of HO1 transcript and corresponding protein level. Further molecular evidence indicted that expression of marker genes, including auxin signaling related genes and cell cycle regulatory genes, were modulated by MRW alone but blocked by the cotreatment with ZnPP, the latter of which could be significantly rescued by the addition of CO. By using the Ca(2+)-channel blocker and Ca(2+) chelator, the involvement of Ca(2+) pathway in MRW-induced adventitious rooting was also suggested. Together, our results indicate that MRW might serve as a stimulator of adventitious rooting, which was partially mediated by HO1/CO and Ca(2+) pathways. PMID- 25503853 TI - Phase space determination from measured dose data for intraoperative electron radiation therapy. AB - A procedure to characterize beams of a medical linear accelerator for their use in Monte Carlo (MC) dose calculations for intraoperative electron radiation therapy (IOERT) is presented. The procedure relies on dose measurements in homogeneous media as input, avoiding the need for detailed simulations of the accelerator head. An iterative algorithm (EM-ML) has been employed to extract the relevant details of the phase space (PHSP) of the particles coming from the accelerator, such as energy spectra, spatial distribution and angle of emission of particles. The algorithm can use pre-computed dose volumes in water and/or air, so that the machine-specific tuning with actual data can be performed in a few minutes. To test the procedure, MC simulations of a linear accelerator with typical IOERT applicators and energies, have been performed and taken as reference. A solution PHSP derived from the dose produced by the simulated accelerator has been compared to the reference PHSP. Further, dose delivered by the simulated accelerator for setups not included in the fit of the PHSP were compared to the ones derived from the solution PHSP. The results show that it is possible to derive from dose measurements PHSP accurate for IOERT MC dose estimations. PMID- 25503852 TI - SIRT1 protects against apoptosis by promoting autophagy in degenerative human disc nucleus pulposus cells. AB - SIRT1 could protect degenerative human NP cells against apoptosis, and there were extensive and intimate connection between apoptosis and autophagy. Up to now, the role of autophagy in the process of human IVD degeneration is unclear. We sought to explore the relationship between autophagy and human IVD degeneration and to understand whether autophagy is involved in the protective effect of SIRT1 against apoptosis in NP cells. Our results showed that the autophagosomes number, the mRNA level of LC3 and Beclin-1, the protein expression of LC3-II/I and Beclin 1, decreased in NP from DDD. Resveratrol could increase the protein expression of LC3-II/I and Beclin-1, and reduce apoptosis in degenerative NP cells. In contrast, the protein levels of LC3-II/I and Beclin-1 were down-regulated and apoptosis level was significantly up-regulated in treatment with nicotinamide or SIRT1-siRNA transfection. Further analysis identified that the expression of cleaved Caspase3 and apoptosis incidence significantly increased with the pretreatment of bafilomycin A, whether resveratrol was added or not. These suggested that autophagy may play an important role in IVD degeneration, and SIRT1 protected degenerative human NP cells against apoptosis via promoting autophagy. These findings would aid in the development of novel therapeutic approaches for degenerative disc disease treatment. PMID- 25503854 TI - High dietary diversity supports large group size in Indo-Chinese gray langurs in Wuliangshan, Yunnan, China. AB - Identifying ecological factors underlying primate group size has been a central theme in primate behavioral ecology. The ecological constraints model proposes that increased group size leads to enhanced within-group feeding competition, necessitating increased travel to encounter additional or more productive feeding sites. Over the course of three years, we studied the largest known group (>80 individuals) of Trachypithecus crepusculus (Indo-Chinese gray langur) for 1738 hours during 213 days (including 96 full day follows) in Wuliangshan, China. During this period, group size increased from 81 individuals to over 90 individuals. The group consumed plant parts from 27 +/- 8 (range: 15-51) species per month, and a total 148 plant species during the study. Based on time spent feeding, the diet was similar (54.2% leaves and 32.1% fruit and seeds) to that reported for other colobines. Despite occupying a home range several times larger than other groups of Trachypithecus, we found no evidence of an increase in daily path length with increasing group size, and the group's time budget and daily path length remained relatively constant despite marked monthly changes in dietary pattern (e.g. time spent exploiting fruit and seeds vs. buds and young leaves, vs. mature leaves). These results are inconsistent with many of the predictions of the ecological constraints model. Rather, our data suggest that high dietary diversity and the ability to exploit difficult to digest foods enabled Indo-Chinese gray langurs to reduce opportunities for feeding competition associated with increased group size. PMID- 25503855 TI - RETRACTED ARTICLE: Structure and characterization of cancer pagurus hemocyanin. PMID- 25503857 TI - Serially recurrent osteoid osteoma. AB - Osteoid osteoma is a relatively common, benign, painful tumor of bone. It is widely believed to run a course culminating in spontaneous regression. The tumor can usually be eliminated by excision or ablation, although it may recur locally. Although management has classically been surgical, thermocoagulation via percutaneously delivered radiofrequency energy has demonstrated excellent results, typically resulting in durable response following a single treatment. Here, we present an unusual case of serially recurrent pathologically proven pediatric osteoid osteoma, treated by radiofrequency ablation five times over the course of 11 years. Limitations of RF ablation of osteoid osteoma and possible factors predisposing to incomplete treatment or recurrence are discussed. PMID- 25503859 TI - Usefulness of maternal serum C-reactive protein with vaginal Ureaplasma urealyticum as a marker for prediction of imminent preterm delivery and chorioamnionitis in patients with preterm labor or preterm premature rupture of membranes. AB - AIM: To assess whether maternal serum C-reactive protein (CRP) and genital mycoplasmas measured can help predict imminent preterm delivery or chorioamnionitis in patients with preterm labor (PL) or preterm premature rupture of membranes (PPROM). METHODS: The study group consisted of 165 women with PL or PPROM. Vaginal cultures for genital mycoplasmas and maternal blood for CRP were obtained when they were admitted for the management of PL or PPROM. An elevated level of serum CRP was defined as >=0.8 mg/dL. Histologic evaluation of the placenta was performed after delivery. RESULTS: The prevalence of positive vaginal fluid cultures for Ureaplasma urealyticum (UU) was 63.0%, and elevated maternal serum CRP was 32.7%. No outcome variables were associated with vaginal UU infection in patients with lower CRP levels. However, among women with elevated CRP, the mean gestational age at birth was significantly reduced, and low Apgar score, neonatal intensive care unit admission, histologic chorioamnionitis, and delivery within 7 days of admission were significantly more common in patients with vaginal UU. CONCLUSIONS: Although vaginal UU in PL or PPROM cannot act as the sole predictor of imminent preterm delivery or chorioamnionitis, it can provide predictive information in patients with elevated maternal serum CRP levels. PMID- 25503858 TI - Repair of distal biceps brachii tendon assessed with 3-T magnetic resonance imaging and correlation with functional outcome. AB - OBJECTIVE: Objectives were to study the MRI appearance of the repaired distal biceps tendon (DBT), anatomically reinserted, and to search for a correlation between tendon measurements and functional results. MATERIALS AND METHODS: Twenty five patients (mean age, 49 +/- 4.9 years old) who benefited from 3-T MRI follow up of the elbow after surgical reinsertion of the DBT were retrospectively included and compared to a control group (n = 25; mean age, 48 +/- 10 years old). MRI was performed during the month of clinical follow-up and on average 22 months after surgery. Delayed complications (secondary avulsion, new rupture), intratendinous osteoma, tendinous signal on T1-weighted (T1w) and fat-suppressed proton density-weighted (FS-PDw) images as well as DBT measurements were recorded. The maximum isometric elbow flexion strength (MEFS) and range of motion of the elbow were assessed. RESULTS: Repaired DBT demonstrated a heterogeneous but normally fibrillar structure. Its low T1w signal was less pronounced than that of normal tendons, and the FS-PDW image signal was similar to that of T1w images. MRI detected seven osteomas (Se = 53 % vs. plain radiography), one textiloma and one secondary avulsion. Repaired DBT measurements were significantly correlated with MEFS (dominant arm R2: 0.38; nondominant arm R2: 0.54); this correlation involved the insertion surface (Delta = -75.7 mm(2), p = 0.046), transverse diameter (Delta = -2.6 mm, p = 0.018), anteroposterior diameter at the level of the radial head (Delta = -3.9 mm, p = 0.001) and DBT cross-sectional area (Delta = -50.2 mm(2), p = 0.003). CONCLUSION: The quality of functional outcome after anatomical elbow rehabilitation of DBT correlates with the extent of tendinous hypertrophy during the healing process. PMID- 25503860 TI - Fetal nasal bone length in the second trimester: comparison between population groups from different ethnic origins. AB - OBJECTIVE: To compare normal ranges of ultrasonographically measured fetal nasal bone length in the second trimester between different ethnic groups. METHOD: A prospective, non-interventional study in order to establish normal ranges of fetal nasal bone length in the second trimester in a Greek population was conducted in 1220 singleton fetuses between 18 completed weeks and 23 weeks and 6 days of gestation. A literature search followed in order to identify similar studies in different population groups. Fetal nasal bone length mean values and percentiles from different population groups were compared. RESULTS: Analysis of measurements in the Greek population showed a linear association, i.e., increasing nasal bone length with increasing gestational age from 5.73 mm at 18 weeks to 7.63 mm at 23 weeks. Eleven studies establishing normal ranges of fetal nasal bone length in the second trimester were identified. Comparison of fetal nasal bone length mean values between the 12 population groups showed statistically significant differences (P<0.0001). CONCLUSION: Normal ranges of fetal nasal bone length in the second trimester vary significantly between different ethnic groups. Hence, distinct ethnic nomograms of fetal nasal bone length in the second trimester should be used in a given population rather than an international model. PMID- 25503861 TI - Cardiovascular profile score in 44 fetuses with cervicofacial tumors. AB - BACKGROUND: Cervicofacial tumors are rarely detected by prenatal ultrasound, and prenatal counseling is very difficult as not much information is available about this problem in the literature, other than cases reports. OBJECTIVES: The aim of this study was to know if fetal echocardiography examination is helpful in those cases. MATERIAL AND METHODS: Forty-four fetuses with cervicofacial tumors detected in utero by ultrasonography and referred to our unit were assessed and the cardiovascular profile score (CVPS) based on echocardiography examinations was calculated. The data were analyzed by the standard statistical tests and Pearson's chi2-test (significance level P=0.05). RESULTS: CVPS<8 was diagnosed in 10 fetuses (23%). Structural or functional cardiovascular anomalies were present in 17 fetuses (39%). The statistically significant correlation between the CVPS<8 and the poor outcome was confirmed (P<0.05). CONCLUSION: We recommend fetal echocardiography and CVPS evaluation before counseling in fetuses with cervicofacial tumors as cardiovascular dysfunction diagnosed prenatally may seriously affect survival of the fetus as well as prenatal counseling and need for cardiac treatment. PMID- 25503862 TI - First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China. AB - Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) is an autosomal recessive inborn error of mitochondrial fatty acid beta-oxidation, caused by mutations in the ACADM gene. As it is the most commonly inherited disorder of the mitochondrial fatty acid oxidation in Caucasians, there are no related reports in China diagnosed by molecular genetic testing. We report here the case of a 2-year old female patient who had hepatomegaly and abnormal liver function with a common illness, and who had been healthy before. A marked increase found in the concentration of C8-carnitine with the help of tandem mass spectrometry (MS/MS) profile, as well as the presence of hexanoylglycine and cyclohepta acyl glycinate as shown in the urinary gas chromatography/mass spectrometry (GC/MS) were suggestive of MCADD, a diagnosis that was confirmed by genetic analysis that showed compound heterozygosity for a missense mutation, c.362C>T(p.Thr121Ile), and a 4-bp deletion, c.448-453delCTGA, in the medium-chain acyl-coenzyme A dehydrogenase (MCAD) gene, also named ACADM gene. There are no related reports in China. This report broadens the phenotype and genotype of MCADD in China and underlines the difficulty of diagnosis. PMID- 25503863 TI - Unexpected clinical features in a female patient with proopiomelanocortin (POMC) deficiency. AB - BACKGROUND/AIMS: Loss of function mutations of proopiomelanocortin (POMC) gene results in adrenal insufficiency, early-onset hyperphagic obesity, and red hair. However, neuromotor retardation with POMC deficiency has not been reported before. CASE REPORT: We report a female patient whose initial diagnosis was neurometabolic disease because of motor mental retardation, ataxia, and bilateral hyperintense lesions in the basal ganglia in cranial magnetic resonance imaging, increased lactate-lipid peak in proton magnetic resonance spectroscopy. She was consulted due to rapid weight gain, obesity, and episodes of hypoglycemia and homozygous mutation (c.64delA) in POMC gene was found. CONCLUSION: Severe motor mental retardation and cranial magnetic resonance imagingpathology in patients with POMC deficiency have not been reported previously in the literature. Bilateral hyperintense lesions in the basal ganglia and the increased lactate lipid peak was thought to be the result of recurrent hypoglycemia. PMID- 25503864 TI - Eating behavior, weight problems and eating disorders in 101 long-term survivors of childhood-onset craniopharyngioma. AB - BACKGROUND: As a result of hypothalamic involvement and/or treatment-related hypothalamic damage, up to 75% of childhood craniopharyngioma patients develop hypothalamic obesity. METHODS: Eating behavior was analyzed in 101 survivors of childhood craniopharyngioma, recruited from 1980 to 2001 in the HIT-Endo multicenter study, and in 85 body mass index (BMI)-matched healthy controls using the Inventory for Eating Behavior and Weight Problems (IEG) and the Inventory for Eating Disorders (ESI). RESULTS: Severely obese patients (BMI>8 SD; n=9) presented with pathological eating behavior, more weight problems, and eating disorders, as compared to obese (BMI 3-8 SD; n=44) and normal or overweight patients (BMI<3 SD; n=48). Craniopharyngioma patients with different degrees of obesity showed similar or even less pathological findings as compared to BMI matched normal controls. CONCLUSION: Severe obesity is associated with pathological eating behavior/disorders in craniopharyngioma patients. As these disorders are not disease-specific, risk factors for hypothalamic obesity should be the focus of further craniopharyngioma research. PMID- 25503865 TI - Surgery for pediatric craniopharyngiomas: is less more? AB - Surgery for craniopharyngiomas, especially in childhood and adolescence, has evolved from an era of aggressive strategies - with the primary goal of gross total removal and accepting an impaired functional outcome - to a more individually tailored therapy that avoids immediate treatment-related and long term morbidity. Modern imaging techniques and a wider understanding of hypothalamic risk factors have led to surgical strategies adapted to the localization of these inhomogenously grown pathologies. Whereas purely infradiaphragmatic as well as supradiaphragmatic/infrachiasmatic tumors have a favorably surgical outcome with higher gross total resection rates in experienced hands, lesions within the third ventricle extending beyond the mammillary bodies remain a problem. The same is valid for lesions beyond 3 cm in diameter, more or less independent of their localization. Aside from the traditional microscopic approach via the subfrontal or pterional craniotomy, transsphenoidal approaches and other minimal invasive surgical methods, e.g., catheter implantation into cystic formations of the tumor have become popular. Radiotherapy, with its risks and limitations, can effectively be added to avoid recurrences. Nowadays, surgery as part of an interdisciplinary treatment strategy is still the typical first choice. However, taking the patient's long-term prognosis into considertaion, the surgical complication rates have to be minimized. PMID- 25503866 TI - Bayesian mixed-effects model for the analysis of a series of FRAP images. AB - The binding behavior of molecules in nuclei of living cells can be studied through the analysis of images from fluorescence recovery after photobleaching experiments. However, there is still a lack of methodology for the statistical evaluation of FRAP data, especially for the joint analysis of multiple dynamic images. We propose a hierarchical Bayesian nonlinear model with mixed-effect priors based on local compartment models in order to obtain joint parameter estimates for all nuclei as well as to account for the heterogeneity of the nuclei population. We apply our method to a series of FRAP experiments of DNA methyltransferase 1 tagged to green fluorescent protein expressed in a somatic mouse cell line and compare the results to the application of three different fixed-effects models to the same series of FRAP experiments. With the proposed model, we get estimates of the off-rates of the interactions of the molecules under study together with credible intervals, and additionally gain information about the variability between nuclei. The proposed model is superior to and more robust than the tested fixed-effects models. Therefore, it can be used for the joint analysis of data from FRAP experiments on various similar nuclei. PMID- 25503867 TI - An emphasis on molecular mechanisms of anti-inflammatory effects and glucocorticoid resistance. AB - Glucocorticoids (GC) are universally accepted agents for the treatment of anti inflammatory and immunosuppressive disorders. They are used in the treatment of rheumatic diseases and various inflammatory diseases such as allergy, asthma and sepsis. They bind with GC receptor (GR) and form GC-GR complex with the receptor and exert their actions. On activation the GC-GR complex up-regulates the expression of nucleus anti-inflammatory proteins called as transactivation and down-regulates the expression of cytoplasmic pro-inflammatory proteins called as transrepression. It has been observed that transactivation mechanisms are notorious for side effects and transrepressive mechanisms are identified for beneficial anti-inflammatory effects of GC therapy. GC hampers the function of numerous inflammatory mediators such as cytokines, chemokines, adhesion molecules, arachidonic acid metabolites, release of platelet-activating factor (PAF), inflammatory peptides and enzyme modulation involved in the process of inflammation. The GC resistance is a serious therapeutic problem and limits the therapeutic response of GC in chronic inflammatory patients. It has been observed that the GC resistance can be attributed to cellular microenvironment changes, as a consequence of chronic inflammation. Various other factors responsible for resistance have been identified, including alterations in both GR-dependent and GR-independent signaling pathways of cytokine action, hypoxia, oxidative stress, allergen exposure and serum-derived factors. The present review enumerates various aspects of inflammation such as use of GC for treatment of inflammation and its mechanism of action. Molecular mechanisms of anti-inflammatory action of GC and GC resistance, alternative anti-inflammatory treatments and new strategy for reversing the GC resistance have also been discussed. PMID- 25503868 TI - Gallium(III)- and calcium(II)-catalyzed Meyer-Schuster rearrangements followed by intramolecular aldol condensation or endo-Michael addition. AB - The first gallium- and calcium-catalyzed Meyer-Schuster rearrangements are described. Under substrate control, the incipient conjugated ketones can be trapped intramolecularly by beta-keto esters or amides to yield cyclic products after aldol condensation or endo-Michael addition. An interesting additive effect that promotes the latter tandem process with calcium has been found. PMID- 25503869 TI - Fast printing and in situ morphology observation of organic photovoltaics using slot-die coating. AB - The mini-slot-die coater offers a simple, convenient, materials-efficient route to print bulk-heterojunction (BHJ) organic photovoltaics (OPVs) that show efficiencies similar to spin-coating. Grazing-incidence X-ray diffraction (GIXD) and GI small-angle X-ray scattering (GISAXS) methods are used in real time to characterize the active-layer formation during printing. A polymer-aggregation phase-separation-crystallization mechanism for the evolution of the morphology describes the observations. PMID- 25503870 TI - k-Nearest neighbors optimization-based outlier removal. AB - Datasets of molecular compounds often contain outliers, that is, compounds which are different from the rest of the dataset. Outliers, while often interesting may affect data interpretation, model generation, and decisions making, and therefore, should be removed from the dataset prior to modeling efforts. Here, we describe a new method for the iterative identification and removal of outliers based on a k-nearest neighbors optimization algorithm. We demonstrate for three different datasets that the removal of outliers using the new algorithm provides filtered datasets which are better than those provided by four alternative outlier removal procedures as well as by random compound removal in two important aspects: (1) they better maintain the diversity of the parent datasets; (2) they give rise to quantitative structure activity relationship (QSAR) models with much better prediction statistics. The new algorithm is, therefore, suitable for the pretreatment of datasets prior to QSAR modeling. PMID- 25503882 TI - The measurement of high-density lipoprotein mediated cholesterol efflux from macrophage cells by liquid chromatography tandem mass spectrometry. AB - BACKGROUND: Studies have shown a negative association between macrophage cholesterol efflux and atherosclerotic cardiovascular diseases (CVD). However, the current methods for measuring cholesterol efflux require a radioactive tracer and involve a variety of cell treatments, making the measurement of macrophage cholesterol efflux impractical for use in clinical laboratories. In this study, we developed a non-radioactive and precise LC/MS/MS method for the measurement of high-density lipoprotein (HDL) mediated cholesterol efflux from J774 macrophages. METHODS: J774 cells were seeded on 12-well plates at a density of 1.5*10(5) cells/ml in H-DMEM medium, and when the cells were approximately 80% confluent, they were incubated with H-DMEM medium containing 2% FBS, 0.5 MUg/ml ACAT inhibitor Sandoz 58-035, and 20 MUg/ml [3,4-(13)C]cholesterol for 6 h. After washing and equilibrating the cells, HDL samples were added at a final concentration of 7% and incubated for 8 h. The cells were lysed, and [3,4 (13)C]cholesterol and cholesterol were measured by LC/MS/MS. Cholesterol efflux was expressed as the percent decrease of cell [3,4-(13)C]cholesterol mass during the incubation. RESULTS: When incubated with [3,4-(13)C]cholesterol enriched J774 cells, HDL mediated higher cell cholesterol efflux than influx compared to serum and isolated LDL; therefore, HDL was used as the extracellular acceptor. The results from healthy volunteers showed that the rate of cholesterol efflux was negatively correlated with weight, BMI, blood pressure, and FERHDL and positively correlated with HDL-C, HDL2-C, and apoAI levels. CONCLUSIONS: A LC/MS/MS method for the measurement of HDL mediated cholesterol efflux from macrophage cells has been established. This method is non-radioactive, precise and reliable and is potentially useful for the assessment of HDL function and cardiovascular disease risks. PMID- 25503884 TI - A response to Harris, Gould, and Fujiura: Beyond scoping reviews: a case for mixed-methods research reviews. AB - This article serves as a response to the Work article on scoping literature reviews by Harris et al. [1]. Conceptualizing scoping reviews as an exploratory approach to organizing literature and research findings in a content area that is still developing, we propose a mixed-methods approach to systematic reviews that enables researchers to capture the breadth and depth of existing knowledge, thereby facilitating the transfer of research findings into field practice. PMID- 25503883 TI - [Opioids in chronic low back pain. A systematic review and meta-analysis of efficacy, tolerability and safety in randomized placebo-controlled studies of at least 4 weeks duration]. AB - BACKGROUND: The efficacy and safety of opioid therapy in chronic low back pain (CLBP) is under debate. We updated a recent systematic review on the efficacy and safety of opioids in CLBP. METHODS: We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in CLBP. We included double-blind randomized placebo-controlled studies of at least 4 weeks duration. Using a random effects model, absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. RESULTS: We included 12 RCTs with 17 treatment arms and 4375 participants. Median study duration was 12 (4-16) weeks. Of the 17 treatment arms, seven (41.2 %) used oxycodone; four (23.6 %) tramadol; buprenorphine and oxymorphone were each used in two (11.8 %) and hydromorphone and tapentadol each in one (5.8 %). The results for studies with parallel/cross-over design were as follows (with 95 % confidence interval, CI): opioids were superior to placebo in reducing pain intensity (SMD - 0.29 [- 0.37, - 0.21], p < 0.0001; six studies with 2896 participants). Opioids were superior to placebo in 50 % pain reduction (RD 0.05 [0.01, 0.10], p = 0.01; two studies with 1492 participants; number needed to benefit (NNTB) 19 [95 % CI 10-107]). Opioids were not superior to placebo in reports of much or very much improved pain (RD 0.16 [- 0.01, 0.34], p = 0.07; two studies with 1153 participants). Opioids were superior to placebo in improving physical functioning (SMD - 0.22 [- 0.31, - 0.12], p < 0.0001; four studies with 1895 participants). Patients dropped out less frequently with opioids than with placebo due to lack of efficacy (RD - 0.10 [- 0.16, - 0.04], p = 0.001; five studies with 3168 participants; NNTB 10 [8-13]). Patients dropped out more frequently with opioids than with placebo due to adverse events (RD 0.12 [0.05, 0.19], p = 0.0007; six studies with 2910 participants; number needed to harm (NNTH) 7 [95 % CI 6-8]). There was no significant difference between opioids and placebo in terms of the frequency of serious adverse events or deaths. CONCLUSION: Opioids were superior to placebo in terms of efficacy and inferior in terms of tolerability. Opioids and placebo did not differ in terms of safety during the study period. The conclusion on the safety of opioids compared to placebo is limited by the low number of serious adverse events and deaths. Short-term and intermediate-term opioid therapy may be considered in selected CLBP patients. The English full-text version of this article is freely available at SpringerLink (under "Supplemental"). PMID- 25503885 TI - Enhancing rigor and practice of scoping reviews in social policy research: considerations from a worked example on the Americans with disabilities act. AB - BACKGROUND: There is increasing theoretical consideration about the use of systematic and scoping reviews of evidence in informing disability and rehabilitation research and practice. Indicative of this trend, this journal published a piece by Rumrill, Fitzgerald and Merchant in 2010 explaining the utility and process for conducting reviews of intervention-based research. There is still need to consider how to apply such rigor when conducting more exploratory reviews of heterogeneous research. OBJECTIVES: This article explores the challenges, benefits, and procedures for conducting rigorous exploratory scoping reviews of diverse evidence. METHODS: The article expands upon Rumrill, Fitzgerald and Merchant's framework and considers its application to more heterogeneous evidence on the impact of social policy. RESULTS: A worked example of a scoping review of the Americans with Disabilities Act is provided with a procedural framework for conducting scoping reviews on the effects of a social policy. The need for more nuanced techniques for enhancing rigor became apparent during the review process. CONCLUSIONS: There are multiple methodological steps that can enhance the utility of exploratory scoping reviews. The potential of systematic consideration during the exploratory review process is shown as a viable method to enhance the rigor in reviewing diverse bodies of evidence. PMID- 25503887 TI - Neurological and neurophysiological examinations of workers exposed to arsenic levels exceeding hygiene standards. AB - OBJECTIVES: The assessment of the neurotoxic effect of arsenic (As) and its inorganic compounds is still the subject of interest due to a growing As application in a large array of technologies and the need to constantly verify the principles of prevention and technological parameters. The aim of this study was to determine the status of the nervous system (NS) in workers exposed to As at concentrations exceeding hygiene standards (Threshold Limit Values (TLV) - 10 MUg/m(3), Biological Exposure Index (BEI) - 35 MUg/l) and to analyze the relationship between the NS functional state, species of As in urine and As levels in the workplace air. MATERIAL AND METHODS: The study group comprised 21 men (mean age: 47.43+/-7.59) employed in a copper smelting factory (mean duration of employment: 22.29+/-11.09). The control group comprised 16 men, matched by age and work shifts. Arsenic levels in the workplace air (As-A) ranged from 0.7 to 92.3 MUg/m(3); (M = 25.18+/-28.83). The concentration of total arsenic in urine (As(tot)-U) ranged from 17.35 to 434.68 MUg/l (M = 86.82+/-86.6). RESULTS: Syndrome of peripheral nervous system (PNS) was manifested by extremity fatigue (28.6%), extremity pain (33.3%) and paresthesia in the lower extremities (33.3%), as well as by neuropathy-type mini-symptoms (23.8%). Electroneurographic (ENeG) tests of peroneal nerves showed significantly decreased response amplitude with normal values of motor conduction velocity (MCV). Stimulation of sural nerves revealed a significantly slowed sensory conduction velocity (SCV) and decreased sensory potential amplitude. Neurophysiological parameters and the results of biological and environmental monitoring showed a relationship between As(tot), As(III) (trivalent arsenic), the sum of iAs (As(III)+As(V) (pentavalent arsenic))+MMA (monomethylarsonic acid) concentration in urine and As levels in the air. CONCLUSIONS: The results of the study demonstrate that occupational exposure to inorganic arsenic levels exceeding hygiene standards (TLV, BEI) generates disorders typical of peripheral neuropathy. PMID- 25503888 TI - Anthropometric indicators of obesity in policemen: a systematic review of observational studies. AB - The aim of this paper was to summarize scientific literature on obesity in policemen through a systematic review of observational studies. For this purpose the following electronic databases were selected: Medline by Pubmed, CINAHL, and Scopus; and a manual search of the referenced studies concerning this topic was performed. There were no restrictions with respect to the year or language of the publication. Twenty-three studies were identified and 9 articles, considered as potentially relevant, were included. The labor time, shift and career progression promoted changes in body composition. Most of the policemen taking part in the studies included in this paper were overweight (BMI: 25.2-29.3), obese (body fat >= 25%), had increased waist (90.4-102 cm) and abdominal perimeters (18.9-90.5 cm), and had a higher risk of chronic disease, which is associated with depression and stress development. Interventional studies are needed for the purpose of proposing preventive and rehabilitation programs, which would result in providing physical and mental well-being, improvement of life quality and, especially, prevention of obesity related to police work. PMID- 25503890 TI - The use of Spielberger's State-Trait Personality Inventory (trait anxiety subscale) with naval subaquatic specialists. AB - OBJECTIVES: Panic behavior poses a particular threat to the health and safety of subaquatic occupational specialists. Trait anxiety has previously been identified as a marker of panic behavior under water, and Spielberger's State-Trait Personality Inventory (trait anxiety subscale) has been previously used to measure trait anxiety among subaquatic specialists. Using archived data, the trait anxiety scores of subaquatic specialists were analyzed to meet 3 objectives: 1stly - to develop a trait anxiety profile of subaquatic specialists; 2ndly - to investigate the predictive value of trait anxiety measures upon entering an occupational field; and 3rdly - to establish the reliability of these scores over time. MATERIAL AND METHODS: Archival trait-anxiety data from 322 subjects were analyzed statistically. RESULTS: Analysis of the available scores revealed a highly homogenous as well as a very low trait anxiety profile for the investigated occupational group. Additionally, low trait anxiety was somewhat associated with success during specialist training: fewer candidates with high trait anxiety scores completed their qualification. Moreover, measurement of trait anxiety was stable over time, which suggests that when scores for this occupational group are screened, deviations from previous scores could signify a potential need for referral to an intervention from health professionals. CONCLUSIONS: Using the trait anxiety subscale as part of occupational health surveillance of subaquatic specialists could support prevention of accidents by identifying high-risk candidates during their annual health assessments, and referral for timeous intervention. PMID- 25503891 TI - Work-related depression and associated factors in a shoe manufacturing factory in Haiphong City, Vietnam. AB - OBJECTIVES: To determine the prevalence and associated factors of work-related depression among the employees of a shoe manufacturing factory in Haiphong City, Vietnam. MATERIAL AND METHODS: We carried out this cross-sectional study among 420 workers in 2012 in Le Lai II Shoe Manufacturing Factory in Haiphong City, Vietnam using Karasek's Job Content Questionnaire (JCQ) and the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV) tool for measuring depression. RESULTS: The study results show that a relatively high proportion of workers (20.7%) belongs to the high-strain group based on Karasek's model. The prevalence of work-related depression among workers was relatively high (18.8%). The factors associated with depression at work were high psychological demand (adjusted OR = 3.0, 95% CI: 1.1-8.3), low social support (adjusted OR = 4.7, 95% CI: 1.2-12.8), inadequate work protection materials (OR = 4.1, 95% CI: 2.2-10.1) and work absenteeism (OR = 6.2, 95% CI: 2.5-18.9). CONCLUSIONS: Strengthening the social support network (involving supervisors and co-workers), reducing psychological job demand and assuring work protection materials at the workplace may highly facilitate reducing work-related depression. PMID- 25503892 TI - Effects of work burden, job strain and support on depressive symptoms and burnout among Japanese physicians. AB - OBJECTIVES: Days off, on call, night duty, working hours and job stress can affect physicians' mental health, and support from supervisors and co-workers may have a buffering effect. This study elucidates whether job strain and job factors affect physicians' mental health, and whether support from supervisors and co workers has a protective effect on their mental health. MATERIAL AND METHODS: The subjects included 494 physicians. The Brief Job Stress Questionnaire (BJSQ) was used to evaluate job demand, job control and support. High job strain was defined as a combination of high job demand and low job control. Depressive symptoms were assessed using the Patient Health Questionnaire-9. The Maslach Burnout Inventory General Survey was used to evaluate burnout. Possible confounder adjusted logistic regression analyses were performed to obtain odds ratios for depressive symptoms and burnout. RESULTS: As per the analysis, high job strain had significantly higher odds ratios, and support from co-workers had significant protective odds ratios for depressive symptoms. High job strain and having only 2 4 days off per month (compared to > 8 days off per month) had significantly higher odds ratios, and support from co-workers had significant protective odds ratios for burnout. CONCLUSIONS: High job strain was related to depressive symptoms and burnout, and support from co-workers had a buffering effect on depressive symptoms and burnout. An inadequate number of days off was related to burnout. Assessment of job strain may be a good tool to measure physicians' mental health, and a sufficient number of days off may be needed to prevent burnout. PMID- 25503893 TI - Falling asleep at the wheel among Italian professional drivers (PDs): results from the HiRis PD study. AB - OBJECTIVES: A high percentage of professional drivers (PDs) often report feeling fatigue during their work, and falling asleep at the wheel (FAW) is a major contributing factor to the occurrence of near-miss or actual accidents. The aim of this study is to evaluate the prevalence of FAW among Italian PDs and the effect of fatigue on this occurrence (corrected for the main predictive factors already known). MATERIAL AND METHODS: We performed a cross-sectional questionnaire survey. Data from PDs (N = 497) were used for analyses. Logistic regression analyses were performed to assess the association of reported sudden onset sleep at the wheel with working conditions and general lifestyle factors. RESULTS: Forty-one percent of the interviewees experienced at least 1 episode per month of sudden-onset sleep at the wheel (4.7% per week). Predictive factors of self-reported FAW were: age > 55 years old (odds ratio (OR) = 4.91, confidence interval (CI): 1.79-13.50, p < 0.01), traveling more than 40 thousand miles per year (OR = 1.86, 95% CI: 1.08-3.22, p < 0.05), body mass index >= 30 (OR = 2.16, 95% CI: 1.01-4.64, p < 0.05) and Chalder Fatigue Questionnaire score > 22 (OR = 3.93, 95% CI: 1.90-8.14, p < 0.01). CONCLUSIONS: There are different work and human factors underlying FAW among PDs. The Chalder Fatigue Questionnaire might be useful in measuring fatigue in this group and in detecting PDs at high risk of experiencing FAW. PMID- 25503894 TI - Workplace bullying and post-traumatic stress symptoms among family physicians in Lithuania: an occupation and region specific approach. AB - OBJECTIVES: The study investigated associations between workplace bullying and post-traumatic stress symptoms as compared to and controlled for associations between the latter and other psychosocial stress factors at work and in everyday life. The study employed a representative sample of Lithuanian family physicians, hence investigated a particularly resourceful occupational group in a geographical region earlier found to have a high risk context for exposure to bullying at work. MATERIAL AND METHODS: With a response rate of 89.2%, a total of 323 family physicians filled in an anonymous questionnaire on workplace bullying, post-traumatic symptomatology (IES-R), other psychosocial stressors at work and in everyday life, personal health resources (sense of coherence), behavioral characteristics and demographic variables. The statistical software SPSS 14.0, Windows was used in the analysis. Associations were tested using a multivariate logistic regression analysis. RESULTS: A high prevalence of bullying was found among family physicians in Lithuania, with 13% of them experiencing severe workplace bullying and 17.3% experiencing more occasional incidents of bullying. The prevalence of post-traumatic stress symptoms was also high with 15.8% scoring above the standardized cut-off thresholds for post-traumatic stress disorder. The odds ratio (OR) of severe bullying for post-traumatic stress after adjustment for age and gender was 8.05 (95% confidence intervals (CI): 3.80-17.04). In the fully adjusted model it increased to 13.88 (95% CI: 4.68-41.13) indicating cumulative effects of all the investigated stressors. CONCLUSIONS: Workplace bullying is particularly prevalent among Lithuanian family physicians, as are the symptoms of post-traumatic distress. Strong associations between post-traumatic stress and exposure to severe bullying indicate that bullying is a significant source of mental health. PMID- 25503895 TI - Psychometric properties of the polish version of the Job-related Affective Well being Scale. AB - OBJECTIVES: The aim of this study was to verify psychometric properties of the Polish version of the Job-related Affective Well-being Scale (JAWS). Specifically, theoretical 4-factor structure (based on the dimensions of pleasure and arousal) and reliability of the original - 20-item JAWS (van Katwyk et al., 2000) and the shortened - 12-item (Schaufeli and Van Rhenen, 2006) versions were tested. MATERIAL AND METHODS: Two independent samples were analyzed (police officers, N = 395, and police recruits, N = 202). The Polish version of the original, 20-item, JAWS was used to measure job-related affective states across the past month (van Katwyk et al., 2000). This version of JAWS includes 2 dimensions: valence and arousal, which allow to assess 4 categories of emotions: low-arousal positive emotions, high-arousal positive emotions, low-arousal negative emotions and high-arousal negative emotions. RESULTS: The results of multidimensional scaling analysis showed that the theoretical circumplex model of emotions underlining JAWS was satisfactorily reproduced. Also the hypothesized 4 factor structure of the Polish version of JAWS was confirmed. The 12-item version had better fit with the data than the original, 20-item, version, but the best fit was obtained for the even shorter, 8-item version. This version emerged from a multidimensional scaling of the 12-item version. Reliabilities of the 20- and 12-item versions were good, with lower values for the 8-item JAWS version. CONCLUSIONS: The findings confirmed satisfactory psychometric properties of both Polish versions of the Job-related Affective Well-being Scale. Thus, when both psychometric properties and relevance for cross-cultural comparisons are considered, the 12-item JAWS is recommended as a version of choice. PMID- 25503896 TI - Influence of the long term use of a computer on median, ulnar and radial sensory nerves in the wrist region. AB - OBJECTIVES: Repetitive microtrauma or overuse injuries may often affect upper extremities of the long term computer users. The aim of this study was to compare sensory nerve conduction velocities (SNCV) for median, radial and ulnar nerves in the wrist of computer users with the same parameters in controls who do not use computers regularly. MATERIAL AND METHODS: Twenty one male computer users (age: mean (M) = 28.3 years +/- standard deviation (SD) = 7.5 years) and 21 male control subjects (age: M+/-SD = 24.1+/-4.6 years) were recruited for the study. Limb length and the perimeters of the dominant arm and forearm were measured for each subject. The neurophysiological study consisted of measuring sensory nerve conduction of the median, ulnar and radial nerves. RESULTS: The sensory conduction velocities of both median and ulnar nerves were significantly delayed in the dominant arm of the computer users compared to the controls. In addition, sensory conduction velocity of the median nerve was significantly delayed in the dominant extremity of the computer users compared to their non-dominant extremity. CONCLUSIONS: This study shows that computer users have a tendency toward developing median and ulnar sensory nerve damage in the wrist region. Mechanism of delayed SNCV in the median and ulnar nerves may be due to sustained extension and ulnar deviation of the wrist during computer mouse use and typing. Reduced SNCV changes were more apparent on the dominant side of the median nerve. This may indicate the increased neural deficits related to an increased use of the dominant side. Further investigation is needed to determine how to reduce potential risk factors at this stage in order to prevent development of median or ulnar neuropathy in the long term computer users. PMID- 25503897 TI - [Metastasized renal cell carcinoma. Measurement of plasma levels of the tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib]. AB - BACKGROUND: Several tyrosine kinase inhibitors (TKI) are used in the treatment of metastasized renal cell carcinoma (mRCC). This article presents a feasibility study for the measurement of plasma levels of sunitinib, sorafenib and pazopanib using liquid chromatography tandem mass spectrometry (LC-MS/MS). METHODS: A total of 23 patients suffering from mRCC under treatment with sunitinib (n=16), sorafenib (n=3) and pazopanib (n=4) were included. Plasma samples (100 ul) were separated by liquid chromatographic analysis and the plasma levels of the TKIs determined by tandem mass spectrometry. RESULTS: The plasma levels of sunitinib, sorafenib and pazopanib were measurable and the results reproducible. During storage of the plasma samples for 1 week at 4 degrees C no significant decrease of the initial concentration was found. The highest plasma levels detected were 99 ng/ml for sunitinib, 9.8 ug/ml for sorafenib and 63 ug/ml for pazopanib. We could show variability in plasma levels according to changes in dosage of TKIs or during treatment-free intervals. CONCLUSION: Measurement of TKI plasma levels using LC-MS/MS is feasible. Further clinical studies have to be conducted to examine if there are any threshold levels for the incidence of adverse events or response to treatment. PMID- 25503898 TI - [Bone metastasis by renal cell carcinoma. Importance of calcium and calcium sensing receptor]. AB - Bone tissue is one of the main locations of metastases in renal cell carcinoma (RCC). In bone tissue the concentration of calcium ions is very high. Cells recognize extracellular calcium by the calcium-sensing receptor (CaSR). To investigate the role of calcium in bone metastases, the CaSR was quantified in tumor tissue and primary tumor cells of patients who were free of metastases or developed bone or lung metastases during a time period of 5 years after nephrectomy. In tissue specimens and primary cells of patients developing bone metastases, CaSR expression was clearly enhanced. Functionally, analyses showed a higher sensitivity in bone metastasizing cells concerning proliferation and chemotactical migration. These effects were caused by enhanced activity of the downstream targets of CaSR, namely AKT, PLCg, JNK and p38, analyzed in a phospho kinase array and western blot analysis. The extent to which CaSR is suitable as a new marker for bone-specific metastases from renal cancer must be examined further. PMID- 25503899 TI - [Structure of biobanks for urological research]. AB - Biomedical research plays an important role in the development of novel diagnostic procedures, drugs and treatment strategies with regard to cancerous and chronic inflammatory diseases. Biobanks are essential tools in this process. The complex structures and benefits of biobanks are presented in this article. PMID- 25503900 TI - Metabolic syndrome exacerbates inflammation and bone loss in periodontitis. AB - Clinical studies have shown that metabolic syndrome (MetS) is associated with increased risk of developing periodontitis. However, the underlying mechanisms remain largely unknown. Since it is known that lipopolysaccharide (LPS)-activated toll-like receptor 4 signaling pathways play a crucial role in periodontitis, we hypothesized that MetS enhances LPS-induced periodontal inflammation and alveolar bone loss. In this study, we induced MetS in C57BL/6 mice by feeding them high fat diet (HFD), and we induced periodontitis by periodontal injection of Aggregatibacter actinomycetemcomitans LPS. We found that mice fed a HFD had significantly increased body weight, plasma lipids, insulin, and insulin resistance when compared with mice fed regular chow, indicating that the mice developed MetS. We also found that a HFD markedly increased LPS-induced alveolar bone loss, osteoclastogenesis, and inflammatory infiltration. Analysis of gene expression in periodontal tissue revealed that HFD and LPS injection cooperatively stimulated expression of cytokines that are known to be involved in periodontal tissue inflammation and osteoclastogenesis-such as interleukin 6, monocyte-chemotactic protein 1, receptor activator of nuclear factor kappa-B ligand, and macrophage colony-stimulating factor. To further understand the potential mechanisms involved in MetS-boosted tissue inflammation, our in vitro studies showed that palmitic acid-the most abundant saturated fatty acid (SFA) and the major SFA in the HFD used in our animal study-potently enhanced LPS induced proinflammatory gene expression in macrophages. In sum, this study demonstrated that MetS was associated with increased periodontal inflammation and alveolar bone loss in an LPS-induced periodontitis animal model. This study also suggests that SFA palmitic acid may play an important role in MetS-associated periodontitis by enhancing LPS-induced expression of inflammatory cytokines in macrophages. PMID- 25503902 TI - Clinical endpoint, early detection, and differential diagnosis of postoperative ileus: a systematic review of the literature. AB - BACKGROUND: This systematic review summarizes evidence regarding clinical endpoints, early detection, and differential diagnosis of postoperative ileus (POI). METHODS: Using MEDLINE, EMBASE, Cochrane, and Web-of-Science, we identified 2,084 articles. Risk of bias and level of evidence (LOE) of the included articles were determined, and relevant results were summarized. RESULTS: Eleven articles were included, most of which with substantial risks of bias. Bowel motility studies revealed that defecation together with solid food tolerance is the most representative clinical endpoint of POI (LOE: 2b); other clinical signs (e.g. bowel sounds, passage of flatus) did not correlate with a full recovery of bowel motility. Inflammatory parameters including interleukin (IL)-6, IL-1, and TNF-alpha might assist in an early detection of prolonged POI (LOE: 4). Clinical manifestations (e.g. nausea, vomiting, abdominal distension, bowel sounds, flatus) and X-ray examinations provided limited aid to the differential diagnosis of POI, while CT with Gastrografin had the best specificity and sensitivity (both 100%; LOE: 1c). CONCLUSIONS: Postoperative defecation together with tolerance of solid food intake seems to be the best clinical endpoint of POI. CT has the best differential diagnostic value between POI and other complications. Prospective studies with a high LOE are in great need. PMID- 25503901 TI - Effectiveness of implant therapy analyzed in a Swedish population: early and late implant loss. AB - Treatment outcomes in implant dentistry have been mainly assessed as implant survival rates in small, selected patient groups of specialist or university clinical settings. This study reports on loss of dental implants assessed in a large and randomly selected patient sample. The results were aimed at representing evaluation of effectiveness of implant dentistry. Using the national data register of the Swedish Social Insurance Agency, 4,716 patients were randomly selected. All had been provided with implant-supported restorative therapy in 2003. Patient files of 2,765 patients (11,311 implants) were collected from more than 800 clinicians. Information on patients, treatment procedures, and outcomes related to the implant-supported restorative therapy was extracted from the files. In total, 596 of the 2,765 subjects, provided with 2,367 implants, attended a clinical examination 9 y after therapy. Implant loss that occurred prior to connection of the supraconstruction was scored as an early implant loss, while later occurring loss was considered late implant loss. Early implant loss occurred in 4.4% of patients (1.4% of implants), while 4.2% of the patients who were examined 9 y after therapy presented with late implant loss (2.0% of implants). Overall, 7.6% of the patients had lost at least 1 implant. Multilevel analysis revealed higher odds ratios for early implant loss among smokers and patients with an initial diagnosis of periodontitis. Implants shorter than 10 mm and representing certain brands also showed higher odds ratios for early implant loss. Implant brand also influenced late implant loss. Implant loss is not an uncommon event, and patient and implant characteristics influence outcomes (ClinicalTrials.gov NCT01825772). PMID- 25503903 TI - Conventional versus accelerated collagen cross-linking for keratoconus. AB - : Collagen cross-linking (CXL) is a procedure that primarily aims to increase corneal stiffness. Although used for a variety of conditions, it is most commonly applied to the treatment of keratoconus. Collagen cross-linking involves irradiation of the cornea with ultraviolet A (UVA) irradiation after it has been soaked with riboflavin (vitamin B), a photosensitizer. In conventional treatment, based on the Dresden protocol, a minimum corneal thickness threshold of 400 MUm is recommended and UVA (370 nm) irradiation of 3 mW/cm irradiance is applied for 30 min, resulting in a cumulative dose of 5.4 J/cm. Evidence presented in this review shows that conventional CXL stabilizes the vision and corneal topographic parameters in the majority of treated patients, with only a small failure rate. It has a good safety profile with no endothelial cell loss and a small risk of corneal infiltration and infection. To reduce the treatment duration, accelerated protocols of similar efficacy have been sought. In accelerated protocols, UVA irradiation of higher irradiance, typically 9 mW/cm, is applied for a shorter time, typically 10 min. The evidence, limited to small studies with short follow up, shows that they may also stabilize the vision and the ectasia, with no additional safety concerns highlighted. Randomized controlled studies are, however, required to confirm the encouraging results and noninferiority to conventional treatment. PMID- 25503904 TI - Diffuse Lamellar Keratitis: Confocal Microscopy Features of Delayed-Onset Disease. AB - OBJECTIVE: Diffuse lamellar keratitis is a fairly uncommon complication of laser in situ keratomileusis (LASIK) that usually occurs within 1 week of surgery. It is described as an inflammatory reaction in the lamellar interface characterized by a diffuse, white granular lamellar keratitis. Progression of the keratitis can result in scarring and significant visual loss. We report a case of bilateral diffuse lamellar keratitis (DLK) of delayed onset and look at confocal microscopic features of corneal interface. CASE REPORT: A 35-year-old male patient was referred with visual concerns and red eye. The patient had undergone LASIK procedure for high myopia 3 months previously. A detailed examination revealed a clinical presentation of DLK. A thorough account of the past revealed no pertinent medical history or risk factors for delayed-onset DLK after LASIK. The patient was put on topical antibiotics (ofloxacin, Exocin 3 mg/mL) and topical steroids (prednisolone acetate 1%, Pred Forte). Because of poor response to treatment, an interface washout was carried out and treatment with Pred Forte was continued. This helped in resolution of the condition in both eyes with residual faint, diffuse, corneal haze. Confocal microscopy was carried out before and after interface washout to assess features of DLK at cellular level after a delayed onset. CONCLUSIONS: The presence of inflammatory cells along with interface debris was noted in our case, which is unusual in stage 3 DLK with a delayed presentation as reported in literature. Although it is difficult to confirm without histology the type of inflammatory response seen, it is advocated that delayed presentation should also be treated quite intensively with steroids and any progression should be dealt with lifting up of the flaps to carry out interface washout. PMID- 25503905 TI - No change in anterior chamber dimensions after femtosecond LASIK for hyperopia. AB - OBJECTIVE: To compare the changes in anterior chamber volume (ACV), anterior chamber depth (ACD) and anterior chamber angle (ACA) before and 6 months after femtosecond laser in situ keratomileusis (LASIK) for hyperopia using the Pentacam HR device. METHODS: A total of 24 eyes of 24 consecutive hyperopic patients undergoing femtosecond LASIK were examined preoperatively and 6 months postoperatively. Anterior chamber volume; ACDs in the central, superior, inferior, nasal, and temporal quadrants; and ACA were measured using the Pentacam HR device. Comparisons of preoperative versus postoperative values were performed using paired Student t test. Linear regression analysis was performed to evaluate correlations between ACV change, central ACD change, age, and attempted maximum ablation depth. RESULTS: Preoperative and postoperative mean ACVs were 153.6 and 158.2 MUL, respectively. Preoperative and postoperative mean ACDs were 2.81, 2.28, 2.53, 2.16, and 2.61 mm, and 2.84, 2.31, 2.54, 2.16, and 2.65 mm, respectively. Preoperative and postoperative mean ACAs were 33.3 degrees and 32.0 degrees , respectively. There were not statistically significant differences in ACV, ACDs, and ACA from preoperatively to 6 months after femtosecond LASIK (all P>0.05). The change of central ACD was correlated significantly with age at 6 months postoperatively (R=0.18, P=0.039). CONCLUSIONS: Anterior chamber profiles, including ACV, ACA, and central and peripheral ACDs did not significantly change after femtosecond LASIK for hyperopia. PMID- 25503906 TI - Topical Cyclosporine A 1% for the Treatment of Chronic Follicular Conjunctivitis. AB - OBJECTIVE: To evaluate the use of topical cyclosporine A (CSA) 1% in the treatment of chronic follicular conjunctivitis (CFC). METHODS: Retrospective chart review from 2001 to 2012 identified 12 patients (22 eyes) with CFC (mean +/ standard deviation [SD] age, 50.2 +/- 15.4 years; 75% female; 92% white) treated with CSA. Main outcome measures included inflammation grade, visual acuity, concurrent corticosteroid (CS) therapy, effect on CS taper, and adverse effects. RESULTS: Mean +/- SD follow-up time was 11.7 +/- 9.7 months. Mean +/- SD time from diagnosis to CSA treatment initiation was 2.4 +/- 3.2 months. Mean +/- SD duration of CSA treatment was 5.8 +/- 2.8 months. Four patients (33%) complained of irritation (n = 2), redness (n = 1), itching (n = 1), and burning (n = 1) but none discontinued treatment. Concurrent CSs were tapered off in all patients after a mean +/- SD of 5.0 +/- 2.5 weeks. Mean +/- SD initial vision was 0.078 +/ 0.093 logMAR, whereas vision at final examination was 0.056 +/- 0.081 logMAR (P = 0.02). Mean +/- SD initial inflammation grade of 1.9 +/- 1.0 was significantly reduced to final grade of 0.7 +/- 0.9 (P = 0.0002). Mean +/- SD time to initial inflammation control in 9 patients (75%) was 33.2 +/- 24.5 days. Two patients (17%) switched to oral CSA because of lack of inflammation control. CONCLUSIONS: Topical CSA 1% is an effective and well-tolerated therapy that decreased chronic inflammation and tapered topical CS in patients with CFC. The use of CSA in such patients warrants further investigation. PMID- 25503907 TI - Repeatability and intrasession reproducibility obtained by the Sirius anterior segment analysis system. AB - OBJECTIVE: To analyze repeatability and intrasession reproducibility of anterior segment measurements using the newly developed Sirius Scheimpflug system. METHODS: Three consecutive measurements on 100 eyes of 50 healthy subjects were performed on the same session by the same technician using the Sirius device at the Assuta Optic Laser Center, Tel-Aviv, Israel. For each eye, the following parameters were measured: anterior chamber angle (ACA), anterior chamber volume (ACV), and anterior chamber depth (ACD), thinnest corneal location, keratometry (anterior and posterior), cylinder, and axis. Repeatability was assessed using the coefficient of variation (CV). Intrasession reproducibility was assessed using intraclass correlation coefficient (ICC). RESULTS: Coefficient of variation of 2% and less was observed for ACA, ACD, thinnest corneal location, and anterior keratometry. Intraclass correlation coefficients were high for ACA, ACD, anterior keratometry measurements and moderate for anterior cylinder and axis. Higher CV with relatively low ICC values was noticed with ACV, posterior keratometry measurements, and posterior cylinder, and axis. The last 2 have the highest CV and lowest ICC: 48.79% (range: 37.64%-59.95%) and 0.38%, respectively. CONCLUSIONS: The Sirius Scheimpflug system has a very high repeatability and intrasessional reproducibility when measuring the ACD, ACA, anterior curvature parameters, and the thinnest corneal location. Thus, it can be used with confidence in clinical practice. PMID- 25503908 TI - Tumor necrosis factor-alpha inhibitors as a treatment of corneal hemangiogenesis and lymphangiogenesis. AB - The cornea is normally devoid of blood and lymphatic vessels; however, a number of infectious/inflammatory diseases can induce corneal neovascularization (CNV). Tumor necrosis factor (TNF)-alpha, a well known pro-inflammatory cytokine, acts on the vascular endothelium by promoting vasodilatation, edema, and leukocyte recruitment, which are all commonly associated with the development of CNV. Corneal neovascularization is the second cause of blindness worldwide; hence, pharmacological TNF-alpha inhibition might represent an attractive therapeutic option. Although none of the existing TNF-alpha antagonists has been registered as a CNV inhibitor, three of them (etanercept, adalimumab, and infliximab) have been proposed to control ocular inflammation. More specifically, it has been demonstrated that infliximab is also effective in reducing hemangiogenesis and lymphangiogenesis in different animal models of CNV. In this article, we review the role of TNF-alpha on the ocular surface and, in particular, its specific role in the process of CNV. Moreover, we review existing literature and speculate on the potential role of TNF-alpha inhibitors in the treatment of CNV. PMID- 25503909 TI - Comparing tear film stability prolongation evaluated by Javal-Schiotz keratometer and slitlamp. AB - OBJECTIVE: To innovatively compare the tear film stability assessed noninvasively by Javal-Schiotz keratometer (tear deformation time [TDT]) and invasively by slitlamp (invasive tear breakup time [I-TBUT]). METHODS: Tear deformation time and I-TBUT were assessed in only 1 eye of 100 healthy young participants aged from 18 to 25 years (mean+/-standard deviation=20.49+/-1.80). Healthy ocular surface was considered as inclusive criteria. Nonparametric statistical analysis was performed to compare the TDT with I-TBUT and reveal correlation between them. RESULTS: The TDT values (mean: 22.84+/-20.14 sec) were significantly higher than the I-TBUT (mean: 15.73+/-8.89 sec) data (P=0.027). Neither TDT nor I-TBUT was affected by gender of the subjects. A significant direct correlation was detected between the TDT and I-TBUT data (Spearman rho=0.458, P<0.0001). Neither I-TBUT nor TDT showed a significant relationship with age and sex factors. CONCLUSIONS: Our findings indicated that tear stability prolongation results obtained by TDT technique were significantly higher than the I-TBUT method outcomes. Noninvasive nature, easiness, basal tear film evaluation, availability, inexpensiveness, Fluorescein nonuse, and accessibility in the clinic (no need for para-clinical equipment) are benefits of the TDT technique. Future studies must be aimed at evaluating validity and reliability of the TDT technique on normal and dry eye populations. PMID- 25503910 TI - Distribution of ABO and Rh Blood Groups in Patients With Keratoconus: A Case Control Study. AB - Association of keratoconus (KC) with genetic predisposition and environmental factors has been well documented. However, no single study has investigated the possible relationship between ABO and Rh blood groups and KC. METHODS: A case control study was designed in a university hospital enrolling 214 patients with KC in the case group and equal number of age- and sex-matched healthy subjects in the control group. Primary characteristics, ABO blood group, and Rh factors were compared between the two groups. Topographic findings of KC eyes and the severity of the diseases were investigated according to the distribution of the blood groups. RESULTS: Blood group O and Rh(+) phenotype were most frequent in both groups. There was no significant difference between the two groups in terms of ABO blood groups or Rh factors. Mean keratometery (K), central corneal thickness, thinnest corneal thickness, flat K, steep K, sphere and cylinder, spherical equivalent, and uncorrected visual acuity were all similar between ABO blood groups and Rh(+) and Rh(-) groups. However, the best spectacle-corrected visual acuity (BCVA) had the highest value in AB blood group (0.35 +/- 0.22 logMAR, P=0.005). Moreover, the blood group AB revealed the highest frequency for grade 3 KC, followed by grades 1, 2, and 4 (P=0.003). CONCLUSION: We observed no significant excess of any particular blood group among KC cases compared with healthy subjects. Except BCVA, none of the keratometric or topographic findings was significantly different between blood groups. PMID- 25503911 TI - A comparison of corneal biomechanical properties in patients with psoriasis and healthy subjects. AB - OBJECTIVE: To evaluate the differences in corneal biomechanical properties between healthy subjects and patients with psoriasis using the ocular response analyzer (ORA). METHODS: Fifty-nine eyes of 59 psoriasis patients and 66 healthy individuals were included in the study. Corneal biomechanical parameters were obtained using ORA. Ultrasound pachymetry was used to measure central corneal thickness (CCT). The main parameters assessed were corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated intraocular pressure (IOPg) measurement and corneal-compensated IOP (IOPcc) through ORA. The dry eye evaluation was performed with tear break-up time (TBUT) and Shirmer test. RESULTS: The mean CH values in psoriasis and healthy subject eyes were 10.75+/ 2.9 mm Hg, 11.97+/-3.6 mm Hg, respectively (P=0.047). The mean CRF values were 10.14+/-3.1 mm Hg and 11.61+/-3.3 mm Hg, respectively (P=0.012). The mean CCT were 539.1+/-36 MUm and 536.3+/-28 MUm, respectively (P=0.643). Mean TBUT values were 8.2+/-2.9 sec in psoriasis group and 10.4+/-3.6 sec in healthy subjects (P<0.001). Shirmer test values were less (8.9+/-3.8 mm/5 min) in psoriasis than in healthy subjects (13.1+/-3.6 mm) (P<0.001). CONCLUSIONS: Psoriasis can influence the corneal biomechanical properties. Patients with psoriasis had lower CH and CRF, but higher IOPg and IOPcc values than healthy controls. These corneal biomechanical changes should be considered when determining IOP values. PMID- 25503912 TI - Fungal isolation from disinfectant solutions of contact lens storage cases among asymptomatic users. AB - OBJECTIVES: To investigate the incidence of fungal contamination of store disinfectant solutions contained in contact lens storage cases belonging to asymptomatic contact lens users. METHODS: Asymptomatic contact lens users were asked to bring their storage cases, lenses included, without having opened the lid of the cup after placing lenses inside. The following information was recorded: age, sex, type of refractive error, contact lens material, schedule of wear, and brand of disinfectant solution. Included subjects had to comply with lens handling, cleaning, and replacement instructions given by the manufacturer or their attending optometrist. One sample per cup of contact lens case was collected using a sterile syringe. Samples were cultured on proper media for 96 hr at 35 degrees C. Fungi were identified to species level by standard methodology. RESULTS: A total of 216 samples were collected from 117 contact lens storage cases. All participants were using monthly disposable hydrogel lenses on a daily wear basis. Seven fungal species were isolated from 15 specimens (6.9%) collected from 12 storage cases (10.2%). These included one Fusarium solani, four Aspergillus niger, two Aspergillus fumigatus, five Candida parapsilosis, one Candida tropicalis, one Rhodotorula rubra, and one F. solani in combination with Candida guilliermondii. Disinfectant solutions containing hydrogen peroxide were found to be less effective than various alternative solutions in eliminating fungal species. CONCLUSIONS: The results of this study show that even when contact lens users report compliance for handling, cleaning, and replacement according to the manufacturer's instructions, the potential risk of contact lens related fungal keratitis still remains. PMID- 25503913 TI - A novel lid seal evaluation: the Korb-Blackie light test. AB - PURPOSE: To develop a clinical method to qualitatively evaluate whether a compromised moisture seal is possible even when the lids are apparently closed and to compare these findings with symptoms of ocular discomfort on awakening. METHODS: Patients (n=116) were fully consented and enrolled. The Korb-Blackie lid light evaluation was performed by placing a transilluminator against the relaxed, closed, outer upper eyelids of semi-reclined patients. The amount of visible light emanating from the lid area between the lashes was quantified on a scale of 0 to 3, where 0=no light, 1=minimal, 2=moderate, and 3=severe for temporal, central, and nasal sections of the eyelids. Eye discomfort on awakening was quantified on a scale of 0 to 2 (0=no discomfort, 1=mild, and 2=significant discomfort). RESULTS: Data are presented for right eyes only. The mean age of the patients was 52.6+/-16.8 years. The central lid section had a positive lid-light score (54.3%), significantly more frequently than the nasal (37.9%) or temporal (21.6%) lid sections (P<0.0001). Patients with a positive lid-light evaluation were significantly more likely to have symptoms of discomfort on awakening (P<0.0001). CONCLUSION: Light emanating from between "closed" lids during the Korb-Blackie lid-light evaluation is associated with symptoms of ocular discomfort on awakening. These symptoms of discomfort may be linked to the inability of the lids to achieve an adequate seal to prevent subtle ocular surface desiccation during sleeping. PMID- 25503914 TI - Ocular surface and tear parameters in patients with chronic hepatitis C at initial stages of hepatic fibrosis. AB - PURPOSE: The aim of this study was to evaluate changes in ocular surface and tear function parameters in chronic hepatitis C at initial stages of hepatic fibrosis. METHODS: Thirty-one patients with biopsy-proven chronic hepatitis C and 31 age- and sex-matched healthy control subjects without systemic hepatitis C infection were examined with the Ocular Surface Disease Index (OSDI) questionnaire, Schirmer I, tear film break-up time, and scoring of ocular surface fluorescein and Rose Bengal staining using modified Oxford and van Bijsterveld scoring systems, respectively. RESULTS: All ocular surface parameters, except OSDI and corneal staining scores, were significantly worse in hepatitis C group. The control group had greater OSDI scores than the hepatitis C group, but there was no statistically important difference. In subgroup analysis, progression of hepatic fibrosis was found to be correlated strongly with decreased Schirmer test I, increased OSDI, lid parallel conjunctival folds, conjunctival, and corneal staining scores. CONCLUSION: Patients with chronic hepatitis C were more likely to exhibit severe ocular surface damage and signs of dry eye. PMID- 25503915 TI - Macrophages: Capturing HIV-infected T cells. PMID- 25503916 TI - State laws prohibiting sales to minors and indoor use of electronic nicotine delivery systems--United States, November 2014. AB - Electronic nicotine delivery systems (ENDS), including electronic cigarettes (e cigarettes) and other devices such as electronic hookahs, electronic cigars, and vape pens, are battery-powered devices capable of delivering aerosolized nicotine and additives to the user. Experimentation with and current use of e-cigarettes has risen sharply among youths and adults in the United States. Youth access to and use of ENDS is of particular concern given the potential adverse effects of nicotine on adolescent brain development. Additionally, ENDS use in public indoor areas might passively expose bystanders (e.g., children, pregnant women, and other nontobacco users) to nicotine and other potentially harmful constituents. ENDS use could have the potential to renormalize tobacco use and complicate enforcement of smoke-free policies. State governments can regulate the sales of ENDS and their use in indoor areas where nonusers might be involuntarily exposed to secondhand aerosol. To learn the current status of state laws regulating the sales and use of ENDS, CDC assessed state laws that prohibit ENDS sales to minors and laws that include ENDS use in conventional smoking prohibitions in indoor areas of private worksites, restaurants, and bars. Findings indicate that as of November 30, 2014, 40 states prohibited ENDS sales to minors, but only three states prohibited ENDS use in private worksites, restaurants, and bars. Of the 40 states that prohibited ENDS sales to minors, 21 did not prohibit ENDS use or conventional smoking in private worksites, restaurants, and bars. Three states had no statewide laws prohibiting ENDS sales to minors and no statewide laws prohibiting ENDS use or conventional smoking in private worksites, restaurants, and bars. According to the Surgeon General, ENDS have the potential for public health harm or public health benefit. The possibility of public health benefit from ENDS could arise only if 1) current smokers use these devices to switch completely from combustible tobacco products and 2) the availability and use of combustible tobacco products are rapidly reduced. Therefore, when addressing potential public health harms associated with ENDS, it is important to simultaneously uphold and accelerate strategies found by the Surgeon General to prevent and reduce combustible tobacco use, including tobacco price increases, comprehensive smoke-free laws, high-impact media campaigns, barrier-free cessation treatment and services, and comprehensive statewide tobacco control programs. PMID- 25503917 TI - Estimated influenza illnesses and hospitalizations averted by vaccination--United States, 2013-14 influenza season. AB - The Advisory Committee on Immunization Practices recommends annual influenza vaccination for all persons aged >=6 months to reduce morbidity and mortality caused by influenza in the United States. CDC previously developed a model to estimate that annual influenza vaccination resulted in 1.1-6.6 million fewer cases and 7,700-79,000 fewer hospitalizations per season during the 2005-2013 influenza seasons. For the 2013-14 influenza season, using updated estimates of vaccination coverage, vaccine effectiveness, and influenza hospitalizations, CDC estimates that influenza vaccination prevented approximately 7.2 million illnesses, 3.1 million medically attended illnesses, and 90,000 hospitalizations associated with influenza. Similar to prior seasons, fewer than half of persons aged >=6 months are estimated to have been vaccinated. If influenza vaccination levels had reached the Healthy People 2020 target of 70%, an estimated additional 5.9 million illnesses, 2.3 million medically attended illnesses, and 42,000 hospitalizations associated with influenza might have been averted. For the nation to more fully benefit from influenza vaccines, more effort is needed to reach the Healthy People 2020 target. PMID- 25503918 TI - Incidence of sickle cell trait--United States, 2010. AB - Persons with sickle cell trait (SCT) are heterozygous carriers of an abnormal beta-globin gene that results in the production of an abnormal hemoglobin, Hb S, which can distort red blood cells (http://www.cdc.gov/ncbddd/sicklecell/facts.html). All state newborn screening (NBS) programs have provided universal sickle cell disease (SCD) screening for newborns since 2006. Screening for SCD detects both SCD and SCT. To obtain up-to date measures of the occurrence of SCT among newborns by race/ethnicity and state of birth, data collected by state NBS programs in 2010 were examined. In 2010, the incidence of SCT in participating states was 15.5 per 1,000 newborns overall; 73.1 among black newborns and 6.9 among Hispanic newborns. Incidence by state ranged from 0.8 per 1,000 screened newborns in Montana to 34.1 per 1,000 in Mississippi. Although the occurrence of SCT varies greatly from state-to-state and among different races and ethnicities, every state and racial/ethnic population includes persons living with the condition. The period immediately following NBS is ideal for primary care providers and genetic counselors to begin educating the families of identified persons with SCT about potential health complications and reproductive considerations. PMID- 25503919 TI - Global invasive bacterial vaccine-preventable diseases surveillance--2008-2014. AB - Meningitis and pneumonia are leading causes of morbidity and mortality in children globally infected with Streptococcus pneumoniae (pneumococcus), Neisseria meningitidis, and Haemophilus influenzae causing a large proportion of disease. Vaccines are available to prevent many of the common types of these infections. S. pneumoniae was estimated to have caused 11% of deaths in children aged <5 years globally in the pre-pneumococcal conjugate vaccine (PCV) era. Since 2007, the World Health Organization (WHO) has recommended inclusion of PCV in childhood immunization programs worldwide, especially in countries with high child mortality. As of November 26, 2014, a total of 112 (58%) of all 194 WHO member states and 44 (58%) of the 76 member states ever eligible for support from Gavi, the Vaccine Alliance (Gavi), have introduced PCV. Invasive pneumococcal disease (IPD) surveillance that includes data on serotypes, along with meningitis and pneumonia syndromic surveillance, provides important data to guide decisions to introduce PCV and monitor its impact. PMID- 25503920 TI - Airport exit and entry screening for Ebola--August-November 10, 2014. AB - In response to the largest recognized Ebola virus disease epidemic now occurring in West Africa, the governments of affected countries, CDC, the World Health Organization (WHO), and other international organizations have collaborated to implement strategies to control spread of the virus. One strategy recommended by WHO calls for countries with Ebola transmission to screen all persons exiting the country for "unexplained febrile illness consistent with potential Ebola infection." Exit screening at points of departure is intended to reduce the likelihood of international spread of the virus. To initiate this strategy, CDC, WHO, and other global partners were invited by the ministries of health of Guinea, Liberia, and Sierra Leone to assist them in developing and implementing exit screening procedures. Since the program began in August 2014, an estimated 80,000 travelers, of whom approximately 12,000 were en route to the United States, have departed by air from the three countries with Ebola transmission. Procedures were implemented to deny boarding to ill travelers and persons who reported a high risk for exposure to Ebola; no international air traveler from these countries has been reported as symptomatic with Ebola during travel since these procedures were implemented. PMID- 25503921 TI - Ebola virus disease in health care workers--Sierra Leone, 2014. AB - Health care workers (HCWs) are at increased risk for infection in outbreaks of Ebola virus disease (Ebola). To characterize Ebola in HCWs in Sierra Leone and guide prevention efforts, surveillance data from the national Viral Hemorrhagic Fever database were analyzed. In addition, site visits and interviews with HCWs and health facility administrators were conducted. As of October 31, 2014, a total of 199 (5.2%) of the total of 3,854 laboratory-confirmed Ebola cases reported from Sierra Leone were in HCWs, representing a much higher estimated cumulative incidence of confirmed Ebola in HCWs than in non-HCWs, based on national data on the number of HCW. The peak number of confirmed Ebola cases in HCWs was reported in August (65 cases), and the highest number and percentage of confirmed Ebola cases in HCWs was in Kenema District (65 cases, 12.9% of cases in Kenema), mostly from Kenema General Hospital. Confirmed Ebola cases in HCWs continued to be reported through October and were from 12 of 14 districts in Sierra Leone. A broad range of challenges were reported in implementing infection prevention and control measures. In response, the Ministry of Health and Sanitation and partners are developing standard operating procedures for multiple aspects of infection prevention, including patient isolation and safe burials; recruiting and training staff in infection prevention and control; procuring needed commodities and equipment, including personal protective equipment and vehicles for safe transport of Ebola patients and corpses; renovating and constructing Ebola care facilities designed to reduce risk for nosocomial transmission; monitoring and evaluating infection prevention and control practices; and investigating new cases of Ebola in HCWs as sentinel public health events to identify and address ongoing prevention failures. PMID- 25503922 TI - Rapid assessment of Ebola infection prevention and control needs--six districts, Sierra Leone, October 2014. AB - As of October 31, 2014, the Sierra Leone Ministry of Health and Sanitation had reported 3,854 laboratory-confirmed cases of Ebola virus disease (Ebola) since the outbreak began in May 2014; 199 (5.2%) of these cases were among health care workers. Ebola infection prevention and control (IPC) measures are essential to interrupt Ebola virus transmission and protect the health workforce, a population that is disproportionately affected by Ebola because of its increased risk of exposure yet is essential to patient care required for outbreak control and maintenance of the country's health system at large. To rapidly identify existing IPC resources and high priority outbreak response needs, an assessment by CDC Ebola Response Team members was conducted in six of the 14 districts in Sierra Leone, consisting of health facility observations and structured interviews with key informants in facilities and government district health management offices. Health system gaps were identified in all six districts, including shortages or absence of trained health care staff, personal protective equipment (PPE), safe patient transport, and standardized IPC protocols. Based on rapid assessment findings and key stakeholder input, priority IPC actions were recommended. Progress has since been made in developing standard operating procedures, increasing laboratory and Ebola treatment capacity and training the health workforce. However, further system strengthening is needed. In particular, a successful Ebola outbreak response in Sierra Leone will require an increase in coordinated and comprehensive district-level IPC support to prevent ongoing Ebola virus transmission in household, patient transport, and health facility settings. PMID- 25503923 TI - Clinical inquiries regarding Ebola virus disease received by CDC--United States, July 9-November 15, 2014. AB - Since early 2014, there have been more than 6,000 reported deaths from Ebola virus disease (Ebola), mostly in Guinea, Liberia, and Sierra Leone. On July 9, 2014, CDC activated its Emergency Operations Center for the Ebola outbreak response and formalized the consultation service it had been providing to assist state and local public health officials and health care providers evaluate persons in the United States thought to be at risk for Ebola. During July 9 November 15, CDC responded to clinical inquiries from public health officials and health care providers from 49 states and the District of Columbia regarding 650 persons thought to be at risk. Among these, 118 (18%) had initial signs or symptoms consistent with Ebola and epidemiologic risk factors placing them at risk for infection, thereby meeting the definition of persons under investigation (PUIs). Testing was not always performed for PUIs because alternative diagnoses were made or symptoms resolved. In total, 61 (9%) persons were tested for Ebola virus, and four, all of whom met PUI criteria, had laboratory-confirmed Ebola. Overall, 490 (75%) inquiries concerned persons who had neither traveled to an Ebola-affected country nor had contact with an Ebola patient. Appropriate medical evaluation and treatment for other conditions were noted in some instances to have been delayed while a person was undergoing evaluation for Ebola. Evaluating and managing persons who might have Ebola is one component of the overall approach to domestic surveillance, the goal of which is to rapidly identify and isolate Ebola patients so that they receive appropriate medical care and secondary transmission is prevented. Health care providers should remain vigilant and consult their local and state health departments and CDC when assessing ill travelers from Ebola-affected countries. Most of these persons do not have Ebola; prompt diagnostic assessments, laboratory testing, and provision of appropriate care for other conditions are essential for appropriate patient care and reflect hospital preparedness. PMID- 25503924 TI - Relations between policy for medical teaching and basic need satisfaction in teaching. AB - Policy initiatives that aim to elevate the position of medical teaching to that of medical research could influence the satisfaction of three basic psychological needs related to motivation for medical teaching. To explore relations between the satisfaction of three basic psychological needs towards medical teaching and two policy initiatives for medical teaching: (Junior) Principal Lecturer positions [(J)PL positions] and Subsidized Innovation and Research Projects in Medical Education (SIRPMEs). An online questionnaire was used to collect data about medical teaching in the setting of a university hospital. We adapted the Work-related Basic Need Satisfaction scale (Van den Broeck et al. in J Occup Organ Psychol, 83(4):981-1002, 2010), in order to measure feelings of autonomy, competence, and relatedness in teaching. We examined the relations between (J)PL positions and SIRPMEs and the satisfaction of three basic psychological needs. A total of 767 medical teachers participated. The initiatives appear to be related to different beneficial outcomes in terms of feelings of autonomy, competence, and relatedness in medical teaching. Either a (J)PL position is obtained by teachers who feel competent and related towards medical teaching, or obtaining a (J)PL position makes teachers feel more competent and related towards teaching, or these relations could be interacting. Also, either a SIRPME is obtained by teachers who feel competent and autonomous towards medical teaching, or obtaining a SIRPME makes teachers feel more competent and autonomous towards teaching, or these relations could be interacting. Additional research needs to scrutinize the causal or interacting relations further and to determine optimal conditions for these policy initiatives more specifically. Implications for future research are discussed. PMID- 25503925 TI - Feedback in the brainstem: an excitatory disynaptic pathway for control of whisking. AB - Sensorimotor processing relies on hierarchical neuronal circuits to mediate sensory-driven behaviors. In the mouse vibrissa system, trigeminal brainstem circuits are thought to mediate the first stage of vibrissa scanning control via sensory feedback that provides reflexive protraction in response to stimulation. However, these circuits are not well defined. Here we describe a complete disynaptic sensory receptor-to-muscle circuit for positive feedback in vibrissa movement. We identified a novel region of trigeminal brainstem, spinal trigeminal nucleus pars muralis, which contains a class of vGluT2+ excitatory projection neurons involved in vibrissa motor control. Complementary single- and dual labeling with traditional and virus tracers demonstrate that these neurons both receive primary inputs from vibrissa sensory afferent fibers and send monosynaptic connections to facial nucleus motoneurons that directly innervate vibrissa musculature. These anatomical results suggest a general role of disynaptic architecture in fast positive feedback for motor output that drives active sensation. PMID- 25503926 TI - Shoulder motion during tennis serve: dynamic and radiological evaluation based on motion capture and magnetic resonance imaging. AB - PURPOSE: Rotator cuff and labral lesions in tennis players could be related to posterosuperior internal impingement or subacromial impingement during tennis serve. However, it is unknown which of these impingements are responsible for the lesions found in the tennis player's shoulder. Moreover, there is a lack of validated noninvasive methods and dynamic studies to ascertain impingement during motion. METHODS: Ten intermediate or ex-professional tennis players were motion captured with an optical tracking system while performing tennis serves. The resulting computed motions were applied to patient-specific shoulder joints' 3D models based on magnetic resonance imaging (MRI) data. During motion simulation, impingements were detected and located using computer-assisted techniques. An MRI examination was also performed to evaluate the prevalence of shoulder lesions and to determine their relevance with the simulation findings. RESULTS: Simulation showed that internal impingement was frequently observed compared to subacromial impingement when serving. The computed zones of internal impingement were mainly located in the posterosuperior or superior region of the glenoid. These findings were relevant with respect to radiologically diagnosed damaged zones in the rotator cuff and glenoid labrum. CONCLUSIONS: Tennis players presented frequent radiographic signs of structural lesions that seem to be mainly related to posterosuperior internal impingement due to repetitive abnormal motion contacts. The present study indicates that the practice of tennis serve could lead with time to cartilage/tendon hyper compression, which could be damageable for the glenohumeral joint. PMID- 25503927 TI - Major ligand-induced rearrangement of the heptahelical domain interface in a GPCR dimer. AB - G protein-coupled receptors (GPCRs) are major players in cell communication. Although they form functional monomers, increasing evidence indicates that GPCR dimerization has a critical role in cooperative phenomena that are important for cell signal integration. However, the structural bases of these phenomena remain elusive. Here, using well-characterized receptor dimers, the metabotropic glutamate receptors (mGluRs), we show that structural changes at the dimer interface are linked to receptor activation. We demonstrate that the main dimer interface is formed by transmembrane alpha helix 4 (TM4) and TM5 in the inactive state and by TM6 in the active state. This major change in the dimer interface is required for receptor activity because locking the TM4-TM5 interface prevents activation by agonist, whereas locking the TM6 interface leads to a constitutively active receptor. These data provide important information on the activation mechanism of mGluRs and improve our understanding of the structural basis of the negative cooperativity observed in these GPCR dimers. PMID- 25503929 TI - Doping of single-walled carbon nanotubes controlled via chemical transformation of encapsulated nickelocene. AB - Controlled doping of carbon nanotubes is elemental for their electronic applications. Here we report an approach to tune the polarity and degree of doping of single-walled carbon nanotubes via filling with nickelocene followed by encapsulated reactions. Using Raman, photoemission spectroscopy and transmission electron microscopy, we show that nickelocene molecules transform into nickel carbides, nickel and inner carbon nanotubes with reaction temperatures as low as 250 degrees C. The doping efficiency is determined for each chemical component. Synchronous charge transfer among the molecular components allows bipolar doping of the carbon nanotubes to be achieved in a broad range of +/-0.0012 e(-) per carbon. PMID- 25503928 TI - Squalene hopene cyclases are protonases for stereoselective Bronsted acid catalysis. AB - For many important reactions catalyzed in chemical laboratories, the corresponding enzymes are missing, representing a restriction in biocatalysis. Although nature provides highly developed machineries appropriate to catalyze such reactions, their potential is often ignored. This also applies to Bronsted acid catalysis, a powerful method to promote a myriad of chemical transformations. Here, we report on the unique protonation machinery of a squalene hopene cyclase (SHC). Active site engineering of this highly evolvable enzyme yielded a platform for enzymatic Bronsted acid catalysis in water. This is illustrated by activation of different functional groups (alkenes, epoxides and carbonyls), enabling the highly stereoselective syntheses of various cyclohexanoids while uncoupling SHC from polycyclization chemistry. This work highlights the potential of systematic investigation on nature's catalytic machineries to generate unique catalysts. PMID- 25503930 TI - Sulindac reversal of 15-PGDH-mediated resistance to colon tumor chemoprevention with NSAIDs. AB - Non-steroidal anti-inflammatory drugs prevent colorectal cancer by inhibiting cyclooxygenase (COX) enzymes that synthesize tumor-promoting prostaglandins. 15 hydroxyprostaglandin dehydrogenase (15-PGDH) is a tumor suppressor that degrades tumor-promoting prostaglandins. Murine knockout of 15-PGDH increases susceptibility to azoxymethane-induced colon tumors. It also renders these mice resistant to celecoxib, a selective inhibitor of inducible COX-2 during colon neoplasia. Similarly, humans with low colonic 15-PGDH are also resistant to colon adenoma prevention with celecoxib. Here, we used aspirin and sulindac, which inhibit both COX-1 and COX-2, in order to determine if these broader COX inhibitors can prevent colon tumors in 15-PGDH knockout (KO) mice. Unlike celecoxib, sulindac proved highly effective in colon tumor prevention of 15-PGDH KO mice. Significantly, however, aspirin demonstrated no effect on colon tumor incidence in either 15-PGDH wild-type or KO mice, despite a comparable reduction in colonic mucosal Prostaglandin E2 (PGE2) levels by both sulindac and aspirin. Notably, colon tumor prevention activity by sulindac was accompanied by a marked induction of lymphoid aggregates and proximal colonic inflammatory mass lesions, a side effect seen to a lesser degree with celecoxib, but not with aspirin. These findings suggest that sulindac may be the most effective agent for colon cancer prevention in humans with low 15-PGDH, but its use may also be associated with inflammatory lesions in the colon. PMID- 25503931 TI - Soluble endoglin antagonizes Met signaling in spindle carcinoma cells. AB - Increased levels of soluble endoglin (Sol-Eng) correlate with poor outcome in human cancer. We have previously shown that shedding of membrane endoglin, and concomitant release of Sol-Eng is a late event in chemical mouse skin carcinogenesis associated with the development of undifferentiated spindle cell carcinomas (SpCCs). In this report, we show that mouse skin SpCCs exhibit a high expression of hepatocyte growth factor (HGF) and an elevated ratio of its active tyrosine kinase receptor Met versus total Met levels. We have evaluated the effect of Sol-Eng in spindle carcinoma cells by transfection of a cDNA encoding most of the endoglin ectodomain or by using purified recombinant Sol-Eng. We found that Sol-Eng inhibited both mitogen-activated protein kinase (MAPK) activity and cell growth in vitro and in vivo. Sol-Eng also blocked MAPK activation by transforming growth factor-beta1 (TGF-beta1) and impaired both basal and HGF-induced activation of Met and downstream MAPK. Moreover, Sol-Eng strongly reduced basal and HGF-stimulated spindle cell migration and invasion. Both Sol-Eng and full-length endoglin were shown to interact with Met by coimmunoprecipitation experiments. However, full-length endoglin expressed at the plasma membrane of spindle carcinoma cells had no effect on Met signaling activity, and was unable to inhibit HGF-induced cell migration/invasion. These results point to a paradoxical suppressor role for Sol-Eng in carcinogenesis. PMID- 25503932 TI - MicroRNA-7 expression in colorectal cancer is associated with poor prognosis and regulates cetuximab sensitivity via EGFR regulation. AB - MicroRNA-7 (miR-7) has been reported to be a tumor suppressor in all malignancies including colorectal cancer (CRC). However, its significance for CRC clinical outcomes has not yet been explored. The potential for miR-7 to act as a tumor suppressor by coordinately regulating the epidermal growth factor receptor (EGFR) signaling pathway at several levels was examined. We investigated the tumor inhibitory effect of miR-7 in CRC, with particular focus on the relationship between miR-7 and the EGFR pathway. Quantitative reverse transcription-PCR was used to evaluate miR-7 expression in 105 CRC cases to determine the clinicopathologic significance of this miRNA. The regulation of EGFR by miR-7 was examined with miR-7 precursor-transfected cells. Furthermore, we investigated whether miR-7 suppresses proliferation of CRC cells in combination with cetuximab, a monoclonal antibody against EGFR. Multivariate analysis indicated that low miR-7 expression was an independent prognostic factor for poor survival (P = 0.0430). In vitro assays showed that EGFR and RAF-1 are direct targets of miR-7, which potently suppressed the proliferation of CRC cells, and, interestingly, that the growth inhibitory effect of each of these was enhanced by cetuximab. miR-7 is a meaningful prognostic marker. Furthermore, these data indicate that miR-7 precursor, alone or in combination with cetuximab, may be useful in therapy against CRC. PMID- 25503933 TI - Evaluation of different QuEChERS procedures for the recovery of selected drugs and herbicides from soil using LC coupled with UV and pulsed amperometry for their detection. AB - Seven quick, easy, cheap, effective, rugged and safe (QuEChERS)-based procedures, differing in both the extraction and clean-up steps, were investigated for the recovery of bentazone (BTZ), atrazine (ATZ), carbamazepine (CBZ), phenytoin (PNT) and its metabolite 5-(p-hydroxyphenyl-),5-phenylhydantoin (HPPH) from soil. Target analytes were chosen for their extensive use and/or occurrence in soil, as well as for their medium-high polarity characteristics (log K OW values in the range 0.88-2.80), which have been reported as a critical parameter for the recovery from soil with QuEChERS approaches. Liquid chromatography coupled with UV and pulsed amperometric (PA) detection at a glassy carbon electrode was used as instrumental technique. The recovery data obtained within each tested procedure were discussed for each compound investigated, highlighting different behaviour depending on the specific physicochemical characteristics of the analytes. The optimized QuEChERS conditions consisted of the extraction of analytes with CH3CN:H2O 70:30, 5 % CH3COOH, followed by a dispersive solid-phase extraction (d-SPE) clean-up step with C18 sorbent. This method, in which water is directly added to the soil together with acetonitrile and salts, allowed the rehydration step to be avoided, which can be as long as 30 min. Matrix effects were evaluated for both the detection techniques at different concentration levels, and they were below 24 % for both the detection technique used. The recoveries were evaluated at three concentration levels by a matrix-matched calibration and were in the ranges of 83-113 % (relative standard deviations (RSD) <= 14 %) and 88-109 % (RSD <= 11 %) for UV and PA detection, respectively, highlighting very good performances of the method, even for the more polar analytes. Method detection limits ranged from 4 MUg/kg (BTZ) to 493 MUg/kg (PNT) and from 4 MUg/kg (HPPH) to 11 MUg/kg (BTZ) for UV and PA detection, respectively. The method was finally compared with a microwave-assisted extraction procedure which provided less satisfactory extraction performances than the optimized QuEChERS procedure. PMID- 25503934 TI - Meet the contributors. PMID- 25503935 TI - One-step assay for the quantification of T4 DNA ligase. AB - As one of the most commonly used enzyme in molecular biology, the T4 DNA ligase presents an important tool for the manipulation of DNA. T4 DNA ligase activity measurements are based on the use of radioactivity or rather labor-intense procedures including gel-based analysis. We therefore established a homogeneous T4 DNA ligase assay utilizing a specifically designed fluorescein- and dark quencher-labeled DNA molecule. Upon ligation of both DNA molecules, a quenching occurs and the fluorescence intensity decreases with increasing ligase concentrations. The assay allows a sensitive and precise quantification (CV, 4.6 5.5 %) of T4 DNA ligase activities and showed a high specificity when tested against other ligases of related and different species. Most importantly, this T4 DNA ligase assay requires only one working and incubation step before measurement can take place at room temperature and may therefore offer an interesting alternative to existing, more laborious ligase assays. PMID- 25503936 TI - Analysis of polar triazines and degradation products in waters by in-tube solid phase microextraction and capillary chromatography: an environmentally friendly method. AB - This paper describes a new method for the determination of polar triazines, including some degradation products, which combines online in-tube solid-phase microextraction (IT-SPME) and capillary liquid chromatography with UV-diode array detection (DAD). Different extractive coatings have been evaluated for IT-SPME, a capillary column with a polydimethylsiloxane (PDMS) coating, and the same coating modified with carboxylated single-wall carbon nanotubes (c-SWCNTs) and carboxylated multiwall carbon nanotubes (c-MWCNTs). On the basis of the results obtained, a new method is presented for the identification and determination of triazines in water samples. A careful selection of the eluent composition provides the required selectivity and sensitivity for the quantification of the target analytes, even those highly polar (log K ow <= 2.3). The proposed conditions have been successfully used for the quantitation of the analytes in the 0.25-50.0 MUg L(-1) range. The limits of detection (LODs) are in the 0.02-0.1 MUg L(-1) range, and the intraday and interday relative standard deviation (RSD) coefficients are <=9 and <=17 %, respectively. The reliability of the described method has been tested by analyzing several real water samples. The proposed method can be considered an environmentally friendly and cost-effective alternative for routine monitoring of triazines and their degradation products in waters. PMID- 25503937 TI - GC-C-IRMS in routine doping control practice: 3 years of drug testing data, quality control and evolution of the method. AB - In order to detect the misuse of endogenous anabolic steroids, doping control laboratories require methods that allow differentiation between endogenous steroids and their synthetic copies. Gas chromatography combustion isotope ratio mass spectrometry (GC-C-IRMS) is capable of measuring the carbon isotope ratio of urinary steroids and this allows differentiation between both. GC-C-IRMS and its application to doping control has evolved a lot during the last decade and so have the World Anti-Doping Agency (WADA) technical documents that describe how GC C-IRMS should be applied. Especially the WADA technical document of 2014 introduced a number of obligatory quality controls and a fixed methodology that should be used by all the doping control laboratories. This document imposed more uniform methods between the laboratories in order to decrease the interlaboratory standard deviation and acquire similar results for the analysis of the same urine samples. In this paper, 3 years of drug testing data of our GC-C-IRMS method in routine doping control practice is described, with an emphasis on the new WADA technical document and its implementation. Useful data for other doping control laboratories is presented focussing on general method setup, quality control and data collected from routine samples. The paper concentrates on how IRMS results shift or remain similar by switching to the 2014 WADA technical document and gives insight in a straightforward approach to calculate the measurement uncertainty. PMID- 25503939 TI - Renin-angiotensin system in pain: existing in a double life? AB - Apart from the well-documented role of the renin-angiotensin-aldosterone system (RAAS) in regulating the blood pressure and other related parameters, its role in modulating different physiological/pathological functions, including pain, has also been described. Like its dual role in regulating stress-related anxiety and cognitive functions, its dual role has also been documented in pain modulation in different disease states. Drugs blocking the RAAS activation, viz., renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, AT(1) receptor antagonists and aldosterone antagonists, have been shown to produce beneficial effects in migraine and neuropathic and nociceptive pain. Their beneficial effects have been mainly attributed to inhibition of the inflammatory cascade of reactions by inhibiting the generation of key cytokines, including tumor necrosis factor (TNF)-alpha. On the contrary, clinical as well as preclinical studies have also shown the pain-inducing actions of renin-angiotensin system (RAS) blocking drugs. Furthermore, the pain-relieving actions of angiotensin II (AngII) and pain inducing actions of AT(1) blockers have also been described. The pain-inducing actions of ACE inhibitors have been mainly attributed to interference with metabolism of bradykinin and substance P, while the analgesic actions of AngII have been mainly related to activation of brain localized AT(2) receptors and release of endogenous opioids. The present review describes the dual role of the RAAS in different states of pain. PMID- 25503940 TI - Lumbar degenerative spondylolisthesis is not always unstable: clinicobiomechanical evidence. AB - STUDY DESIGN: A clinicobiomechanical study. OBJECTIVE: To clarify the clinicobiomechanical characteristics of a segment with lumbar degenerative spondylolisthesis (LDS) using an original intraoperative measurement system. SUMMARY OF BACKGROUND DATA: Although radiographical evaluation of LDS is extensively performed, the diagnosis of segmental instability remains controversial. The intraoperative measurement system used in this study is the first clinically available system that performs cyclic flexion-extension displacement of the segment with all ligamentous structures intact and can determine both the stiffness (N/mm) and neutral zone (NZ, [mm/N]). METHODS: Forty eight patients with LDS (males/females = 19/29, 68.5 yr; group D) were compared with 48 patients with lumbar spinal stenosis without LDS (males/females = 33/15, 64.8 yr, group N) in terms of symptoms, radiological, and biomechanical results. Instability was defined as a segment with NZ more than 2 mm. Symptoms (36-Item Short Form Health Survey), radiographical findings (radiographs, magnetic resonance images, computed tomographic scans), stiffness, NZ, and frequency of instability were also compared. Risk factors for instability were analyzed by multivariate logistic regression with a forward stepwise procedure. RESULTS: None of the physical function categories or radiological findings of 36-Item Short Form Health Survey and low back pain (visual analogue scale) differed significantly between the groups. Although NZ was significantly greater in group D (1.97) than in group N (1.73) (P < 0.05), the frequency of instability did not differ significantly between groups. Facet opening (odds ratio, 11.0; P < 0.01) and facet type (odds ratio, 6.0; P < 0.05) were significant risk factors for instability. CONCLUSION: Neither the symptoms nor the frequency of instability differed significantly between groups. The radiological findings of spondylolisthesis did not indicate instability, but facet opening and sagittally oriented facets were indicative of instability. The results of this study demonstrated that LDS is not always unstable in the measurement setting, suggesting that the instability of LDS can stabilize spontaneously during the natural course. LEVEL OF EVIDENCE: N/A. PMID- 25503941 TI - Simplified skeletal maturity scoring system: learning curve and methods to improve reliability. AB - STUDY DESIGN: Retrospective radiographical review by 5 independent observers. OBJECTIVE: To validate the intra- and interobserver reliability of the simplified skeletal maturity scoring (SSMS) system in a large cohort for each stage and for the overall cohort. SUMMARY OF BACKGROUND DATA: The SSMS has been used to successfully predict curve progression in idiopathic scoliosis. METHODS: A total of 275 patients with scoliosis (8-16 yr) with 1 hand radiograph were included from 2005 to 2011. Five participants independently scored images on 2 separate occasions using the SSMS (stage, 1-8). Observers (listed in order of increasing SSMS experience) included orthopedic surgery resident, clinical fellow (CF), research fellow, and senior faculty. Intraobserver agreement between the 2 sets of scores was estimated using the Pearson and Spearman rank correlation coefficients. Interobserver agreement was estimated with the unweighted Fleiss kappa coefficient for the overall cohort and for junior (orthopedic surgery resident, CF, research fellow) versus senior faculty. RESULTS: Intrarater reliability for orthopedic surgery resident, CF, research fellow, senior faculty was 0.956, 0.967, 0.986, 0.991, and 0.998, respectively (Spearman). Intrarater agreement improved with greater familiarity using the SSMS. The inter-rater reliability for junior faculty (kappa = 0.65), senior faculty (kappa = 0.652), and the overall group (kappa = 0.66) indicated agreement between all observers but no improved inter-rater agreement with experience. However, 98% of disagreements occurred only within 1 stage. Stages 2, 3, and 4 accounted for most of the variability; stage 3 was the most commonly scored stage, corresponding to peak growth velocity. CONCLUSION: The SSMS has excellent intraobserver agreement with substantial interobserver agreement. Intraobserver--but not interobserver agreement--improves with familiarity using the SSMS. Expectancy bias may contribute to a higher likelihood of assigning an SSMS 3. Discrepancies when classifying stages 2 to 4 may be resolved by improved descriptions of epiphyseal capping in stages 2 and 3. LEVEL OF EVIDENCE: 2. PMID- 25503943 TI - ADH1B and ADH1C genotype, alcohol consumption and biomarkers of liver function: findings from a Mendelian randomization study in 58,313 European origin Danes. AB - BACKGROUND: The effect of alcohol consumption on liver function is difficult to determine because of reporting bias and potential residual confounding. Our aim was to determine this effect using genetic variants to proxy for the unbiased effect of alcohol. METHODS: We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on alanine aminotransferase (ALT), gamma-glutamyl-transferase (gamma GT), alkaline phosphatase (ALP), bilirubin and prothrombin action. Analyses were undertaken on 58,313 Danes (mean age 56). RESULTS: In both confounder adjusted multivariable and genetic-IV analyses greater alcohol consumption, amongst those who drank any alcohol, was associated with higher ALT [mean difference per doubling of alcohol consumption: 3.4% (95% CI: 3.1, 3.7) from multivariable analyses and 3.7% (-4.5, 11.9) from genetic-IV analyses] and gamma-GT [8.2% (7.8, 8.5) and 6.8% (-2.8, 16.5)]. The point estimates from the two methods were very similar and statistically the results from the two methods were consistent with each other for effects with ALT and gamma-GT (both pdiff>0.3). Results from the multivariable analyses suggested a weak inverse association of alcohol with ALP [ 1.5% (-1 .7, -1.3)], which differed from the strong positive effect found in genetic-IV analyses [11.6% (6.8, 16.4)] (p diff<0.0001). In both multivariable and genetic-IV analyses associations with bilirubin and protrombin action were weak and close to the null. CONCLUSIONS: Our results suggest that greater consumption of alcohol is related to poorer liver function as indicated by higher ALT, gamma-GT and ALP, but not to clotting or bilirubin. PMID- 25503945 TI - Hair 32P measurement for body dose mapping in non-fatal exposures to fast neutrons. AB - Dosimetry bioassay methods are the backbone of a personal dosimetry in criticality accidents. Although methods like hair dosimetry and the use of activation foils (e.g., (32)S) have been employed for decades, capabilities of different techniques, effects of hair type and neutron spectrum on the dose response, sensitivity and uncertainties of different techniques, etc., need more investigations. For this reason, the use of the (32)S(n,p)(32)P reaction and hair samples for estimating non-fatal doses from fast neutrons was studied. The experiments were carried out with the hair samples attached on a RANDO phantom in a Cf-252 neutron field, in the dose range of about 0.05-1.15 Gy. In addition, the adequate post-accident preparation for hair samples including optimum conditioning and timing were investigated. Experimental results prove the good sensitivity and merit of the method for neutron quantification in the mentioned dose range for which other bioassay methods are of poor resolution and sensitivity. A rough estimation of the dose-response curve for Iranian hair was also derived. PMID- 25503944 TI - Hemodynamic forces regulate developmental patterning of atrial conduction. AB - Anomalous action potential conduction through the atrial chambers of the heart can lead to severe cardiac arrhythmia. To date, however, little is known regarding the mechanisms that pattern proper atrial conduction during development. Here we demonstrate that atrial muscle functionally diversifies into at least two heterogeneous subtypes, thin-walled myocardium and rapidly conducting muscle bundles, during a developmental window just following cardiac looping. During this process, atrial muscle bundles become enriched for the fast conduction markers Cx40 and Nav1.5, similar to the precursors of the fast conduction Purkinje fiber network located within the trabeculae of the ventricles. In contrast to the ventricular trabeculae, however, atrial muscle bundles display an increased proliferation rate when compared to the surrounding myocardium. Interestingly, mechanical loading of the embryonic atrial muscle resulted in an induction of Cx40, Nav1.5 and the cell cycle marker Cyclin D1, while decreasing atrial pressure via in vivo ligation of the vitelline blood vessels results in decreased atrial conduction velocity. Taken together, these data establish a novel model for atrial conduction patterning, whereby hemodynamic stretch coordinately induces proliferation and fast conduction marker expression, which in turn promotes the formation of large diameter muscle bundles to serve as preferential routes of conduction. PMID- 25503947 TI - Correction. PMID- 25503946 TI - Above-moderate physical activity reduces both incident and persistent late-life depression in rural Koreans. AB - OBJECTIVE: To investigate the natural course of depressive symptoms among community-dwelling elderly over 5 years. Rates and correlates of the incidence and the persistence of late-life depression were examined. METHODS: A total of 701 elderly people 65 years of age or older without dementia at baseline were included in this study. The association between categorically defined late-life depression (score of >= 8 on the Korean version of the Geriatric Depression Scale Short Form) and possible lifestyle and clinical risk factors, including physical activity assessed with a modified Korean version of the International Physical Activity Questionnaire (IPAQ) and transformed into weekly Metabolic Equivalent Task (MET) values, was longitudinally investigated using multiple logistic regression analyses. Adjustment was done with sociodemographic variables, chronic medical illnesses, and cognitive dysfunction. RESULTS: During the 5-year follow up, 74 (26.5%) of the non-depressed elderly developed depression, whereas 30 (49.2%) of the depressed elderly experienced persistent depression. Above moderate baseline physical activity was independently associated with decreased incidence and persistence rates of late-life depression (adjusted odds ratio (AOR) = 0.44, 95% confidence interval (CI) = 0.22-0.85; AOR = 0.17, 95% CI = 0.03 0.92, respectively), whereas mild physical activity was not. Conversely, poorer executive function also predicted 5-year incident depression (AOR = 0.93, 95% CI = 0.89-0.98) but not persistent depression. CONCLUSION: This study suggests that a minimum of moderate physical activity is related to both emergent and persistent depression in elderly individuals. Research with an extended follow-up period and a shorter inter-assessment interval is needed to confirm this result. PMID- 25503948 TI - Thermodynamic costs of information processing in sensory adaptation. AB - Biological sensory systems react to changes in their surroundings. They are characterized by fast response and slow adaptation to varying environmental cues. Insofar as sensory adaptive systems map environmental changes to changes of their internal degrees of freedom, they can be regarded as computational devices manipulating information. Landauer established that information is ultimately physical, and its manipulation subject to the entropic and energetic bounds of thermodynamics. Thus the fundamental costs of biological sensory adaptation can be elucidated by tracking how the information the system has about its environment is altered. These bounds are particularly relevant for small organisms, which unlike everyday computers, operate at very low energies. In this paper, we establish a general framework for the thermodynamics of information processing in sensing. With it, we quantify how during sensory adaptation information about the past is erased, while information about the present is gathered. This process produces entropy larger than the amount of old information erased and has an energetic cost bounded by the amount of new information written to memory. We apply these principles to the E. coli's chemotaxis pathway during binary ligand concentration changes. In this regime, we quantify the amount of information stored by each methyl group and show that receptors consume energy in the range of the information-theoretic minimum. Our work provides a basis for further inquiries into more complex phenomena, such as gradient sensing and frequency response. PMID- 25503949 TI - Modified Lipoproteins by Acrylamide Showed More Atherogenic Properties and Exposure of Acrylamide Induces Acute Hyperlipidemia and Fatty Liver Changes in Zebrafish. AB - Acrylamide is a well-known potent carcinogen and neurotoxin that, until now, has not been sufficiently investigated with regard to its effects on lipid metabolism. We investigated physiological effects of acrylamide (AA) on lipoprotein metabolism using human macrophages, dermal cells, and zebrafish models. Functional and structural properties of lipoproteins were modified by AA (final concentration of 5-100 mM) with loss of antioxidant ability and multimerization of apoA-I in vitro. AA exacerbated LDL oxidation, degradation, and LDL uptake into macrophages with increased ROS production. In human cells, treatment of AA (1-100 MUM) caused cellular senescence of dermal cells with severe cytotoxicity. Waterborne exposure of zebrafish in cage water containing AA (300 ppm) resulted in acute death within 26 h along with elevation of body weight, blood glucose, triglyceride, and hepatic inflammation. AA exposure caused fat accumulation in liver in a dose-dependent manner. In conclusion, AA affected lipoprotein metabolism to result exacerbation of atherosclerosis. Exposure of zebrafish to AA resulted in acute inflammatory death with hyperlipidemia. PMID- 25503950 TI - Comparative Investigation of Protective Effects of Metyrosine and Metoprolol Against Ketamine Cardiotoxicity in Rats. AB - This study investigated the effect of metyrosine against ketamine-induced cardiotoxicity in rats and compared the results with the effect of metoprolol. In this study, rats were divided into groups A, B and C. In group A, we investigated the effects of a single dose of metyrosine (150 mg/kg) and metoprolol (20 mg/kg) on single dose ketamine (60 mg/kg)-induced cardiotoxicity. In group B, we investigated the effect of metyrosine and metoprolol, which were given together with ketamine for 30 days. In group C, we investigated the effect of metyrosine and metoprolol given 15 days before ketamine and 30 days together with ketamine on ketamine cardiotoxicity. By the end of this process, we evaluated the effects of the levels of oxidant-antioxidant parameters such as MDA, MPO, 8-OHGua, tGSH, and SOD in addition to CK-MB and TP I on cardiotoxicity in rat heart tissue. The experimental results show that metyrosine prevented ketamine cardiotoxicity in groups A, B and C and metoprolol prevented it in only group C. PMID- 25503951 TI - Intercellular adhesion molecule-1 K469E polymorphism and risk of coronary artery disease: a meta-analysis. AB - BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) K469E polymorphism has been implicated in susceptibility to coronary artery disease (CAD). Several studies investigated the association of this polymorphism with CAD in different populations but the results were contradictory. A meta-analysis was conducted to assess the association between ICAM-1 K469E polymorphism and CAD susceptibility. MATERIAL AND METHODS: Databases including PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and Weipu Database were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. A random-effects model was used. RESULTS: Fifteen case-control studies including 3088 cases and 3466 controls were included. Overall, a significant association between ICAM-1 K469E polymorphism and CAD was observed in the dominant model (OR=1.80; 95% CI 1.62-2.01; P<0.00001; Pheterogeneity=0.40). In subgroup analysis by ethnicity, a significant association was found among Asians (OR=1.92; 95% CI 1.51-2.43; P<0.00001; Pheterogeneity=0.98) and among Caucasians (OR=1.64; 95% CI 1.30-2.08; P<0.0001; Pheterogeneity=0.04). In the subgroup analysis by age, a significant association was found among young patients (OR=1.46; 95% CI 1.10-1.93; P=0.008; Pheterogeneity=0.21) and old patients (OR=1.92; 95% CI 1.75-2.10; P<0.00001; Pheterogeneity=0.99). Conclusions Results of this meta-analysis suggest that ICAM 1 K469E polymorphism confers a risk factor of CAD. PMID- 25503952 TI - Kidney disease in Aboriginal Australians: a perspective from the Northern Territory. AB - This article outlines the increasing awareness, service development and research in renal disease in Aboriginal people in Australia's Northern Territory, among whom the rates of renal replacement therapy (RRT) are among the highest in the world. Kidney failure and RRT dominate the intellectual landscape and consume the most professional energy, but the underlying kidney disease has recently swung into view, with increasing awareness of its connection to other chronic diseases and to health profiles and trajectories more broadly. Albuminuria is the marker of the underlying kidney disease and the best treatment target, and glomerulomegaly and focal glomerulosclerosis are the defining histologic features. Risk factors in its multideterminant genesis reflect nutritional and developmental disadvantage and inflammatory/infectious milieu, while the major putative genetic determinants still elude detection. A culture shift of "chronic disease prevention" has been catalyzed in part by the human pain, logistic problems and great costs associated with RRT. Nowadays chronic disease management is the central focus of indigenous primary care, with defined protocols for integrated testing and management of chronic diseases and with government reimbursed service items and free medicines for people in remote areas. Blood pressure, cardiovascular risk and chronic kidney disease (CKD) are all mitigated by good treatment, which centres on renin-angiotensin system blockade and good metabolic control. RRT incidence rates appear to be stabilizing in remote Aboriginal people, and chronic disease deaths rates are falling. However, the profound levels of disadvantage in many remote settings remain appalling, and there is still much to be done, mostly beyond the direct reach of health services. PMID- 25503953 TI - Focal and segmental glomerulosclerosis: clinical and kidney biopsy correlations. AB - BACKGROUND: Primary focal segmental glomerulosclerosis (FSGS) is a common glomerular disease in adults and ranks among the top causes of a primary glomerular disease causing end-stage renal disease (ESRD). Primary FSGS is, however, a diagnosis of exclusion and distinction between primary versus secondary FSGS is not always obvious, resulting in a number of patients with secondary FSGS undergoing unnecessary immunosuppressive therapy. METHODS: We reviewed the Mayo Clinic Renal Pathology Database for patients with a diagnosis of FSGS on native renal biopsy and divided the patients into nephrotic syndrome associated (NS-associated) and non-nephrotic syndrome-associated (NNS-associated) FSGS as a first approximation followed by dividing the lesion according to the degree of foot process effacement (FPE) on electron microscopy (EM) examination. RESULTS: A total of 41 patients with FSGS with complete evaluation were identified. Of these, 18 were classified as having NS and 23 were classified as having NNS. Baseline characteristics (age, gender, body mass index, serum creatinine and hematuria) were not different between the groups. All of the patients with NS showed diffuse FPE ranging from 80 to 100% (mean 96%). On the other hand, of the 23 patients in the NNS group, 22 had segmental FPE and showed patchy effacement, with all cases showing 20-60% FPE (mean of 48%). CONCLUSION: Adult patients presenting with NS, an FSGS lesion on LM, extensive FPE (>=80%) on EM examination and no risk factors associated with secondary FSGS are likely to have primary FSGS. Conversely, the absence of NS in a patient with segmental FPE on EM strongly suggests a secondary FSGS. Dividing FSGS into the presence or absence of NS together with the degree of FPE on EM examination is more helpful as it provides a more practical way to separate patients into cases of primary versus secondary FSGS. PMID- 25503954 TI - Malignant hypertension with thrombotic microangiopathy and persistent acute kidney injury (AKI). AB - Two cases of malignant hypertension presenting with acute kidney injury, thrombocytopenia and hemolytic anemia are presented. In both patients a prolonged duration of renal replacement therapy was required. The plasma levels of ADAMTS13 enzyme were not helpful in delineating the precise pathogenesis in both cases, as the decrements were not severe. We discuss the clinic-pathologic correlation of the biopsy findings and persistence of AKI. PMID- 25503955 TI - Nocturnal mechanical ventilation for chronic hypoventilation in patients with neuromuscular and chest wall disorders. AB - BACKGROUND: Chronic alveolar hypoventilation is a common complication of many neuromuscular and chest wall disorders. Long-term nocturnal mechanical ventilation is commonly used to treat it. This is a 2014 update of a review first published in 2000 and previously updated in 2007. OBJECTIVES: To examine the effects on mortality of nocturnal mechanical ventilation in people with neuromuscular or chest wall disorders. Subsidiary endpoints were to examine the effects of respiratory assistance on improvement of chronic hypoventilation, sleep quality, hospital admissions and quality of life. SEARCH METHODS: We searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE on 10 June 2014. We contacted authors of identified trials and other experts in the field. SELECTION CRITERIA: We searched for quasi-randomised or randomised controlled trials of participants of all ages with neuromuscular or chest wall disorder-related stable chronic hypoventilation of all degrees of severity, receiving any type and any mode of long-term nocturnal mechanical ventilation. The primary outcome measure was one-year mortality and secondary outcomes were unplanned hospital admission, short-term and long-term reversal of hypoventilation-related clinical symptoms and daytime hypercapnia, improvement of lung function and sleep breathing disorders. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology to select studies, extract data and assess the risk of bias in included studies. MAIN RESULTS: The 10 eligible trials included a total of 173 participants. Roughly half of the trials were at low risk of selection, attrition or reporting bias, and almost all were at high risk of performance and detection bias. Four trials reported mortality data in the long term. The pooled risk ratio (RR) of dying was 0.62 (95% confidence interval (CI) 0.42 to 0.91, P value = 0.01) in favour of nocturnal mechanical ventilation compared to spontaneous breathing. There was considerable and significant heterogeneity between the trials, possibly related to differences between the study populations. Information on unplanned hospitalisation was available from two studies. The corresponding pooled RR was 0.25 (95% CI 0.08 to 0.82, P value = 0.02) in favour of nocturnal mechanical ventilation. For most of the outcome measures there was no significant long-term difference between nocturnal mechanical ventilation and no ventilation. Most of the secondary outcomes were not assessed in the eligible trials. Three out of the 10 trials, accounting for 39 participants, two with a cross-over design and one with two parallel groups, compared volume- and pressure-cycled non-invasive mechanical ventilation in the short term. From the only trial (16 participants) on parallel groups, there was no difference in mortality (one death in each arm) between volume- and pressure cycled mechanical ventilation. Data from the two cross-over trials suggested that compared with pressure-cycled ventilation, volume-cycled ventilation was associated with less sleep time spent with an arterial oxygen saturation below 90% (mean difference (MD) 6.83 minutes, 95% CI 4.68 to 8.98, P value = 0.00001) and a lower apnoea-hypopnoea (per sleep hour) index (MD -0.65, 95% CI -0.84 to 0.46, P value = 0.00001). We found no study that compared invasive and non invasive mechanical ventilation or intermittent positive pressure versus negative pressure ventilation. AUTHORS' CONCLUSIONS: Current evidence about the therapeutic benefit of mechanical ventilation is of very low quality, but is consistent, suggesting alleviation of the symptoms of chronic hypoventilation in the short term. In four small studies, survival was prolonged and unplanned hospitalisation was reduced, mainly in participants with motor neuron diseases. With the exception of motor neuron disease and Duchenne muscular dystrophy, for which the natural history supports the survival benefit of mechanical ventilation against no ventilation, further larger randomised trials should assess the long term benefit of different types and modes of nocturnal mechanical ventilation on quality of life, morbidity and mortality, and its cost-benefit ratio in neuromuscular and chest wall diseases. PMID- 25503956 TI - Development and field testing of a miniaturized sampling system for simultaneous sampling of vapours and droplets. AB - The sampling of semi volatiles (SV) in workplaces may lead to different results as measurements may be affected by sampling bias. The new European Standard EN 13936 defines "semi-volatiles" as substances with vapour pressures in the range between 0.001 and 100 Pa at room temperature. EN 13936 regulates the basic requirements for SV compounds that can occur as vapour and particle at the same time. Vapour and particles shall not be sampled separately and particles have to be sampled as inhalable fraction. Following EN 13936, the Institute for Occupational Safety and Health (Institut fur Arbeitsschutz - IFA) has developed a miniaturized droplet-vapour sampler (GGP-Mini) which is designed to sample the inhalable aerosol fraction at low flow rates. The GGP-Mini uses 13 mm filters for particle sampling combined with adsorption tubes for vapour sampling. Laboratory tests were performed on 11 polar and non-polar compounds in a boiling point range from 188 degrees C to 318 degrees C. The substances were spiked directly on the filter followed by aspiration of 40 litres of air. Substances with boiling points below 230 degrees C were almost completely evaporated. Substances with boiling points above 230 degrees C up to 300 degrees C were found on both filter and charcoal tube. Lower-volatile compounds remained almost completely on the filter. For polar substances, the atmospheric humidity had a considerable influence upon the distribution of the liquid and vaporous components. A strong influence of the sampling temperature was found in the range from 0 degrees C to 50 degrees C. Droplet-vapour mixtures of n-hexadecane and diethylene glycol with droplet sizes between 1 MUm and 4 MUm were generated in a flow tube to verify the laboratory results. The aerosol concentrations were analysed on-line with a particle sizer and a flame ionisation detector, while parallel off-line samples were taken with the GGP-Mini. Evaporation losses from filters could be studied by comparing the on-line with off-line measurements. All sampling simulations, both spiking and tests on a droplet aerosol, have shown that the distribution between vapour and droplets is not constant and influenced e. g. by volatility, concentration, temperature and humidity. Only the sum of vapour and droplets constitutes a reproducible result. PMID- 25503957 TI - Anger in the UK Armed Forces: strong association with mental health, childhood antisocial behavior, and combat role. AB - We assessed the strength of the association of several mental health problems, childhood difficulties, and combat role with anger, as well as the contribution of these factors to explain anger assessed by population attributable fraction (PAF). A total of 9885 UK service personnel, some of them deployed to Iraq and Afghanistan, participated in the study. There was a strong or intermediate association between cases and subthreshold cases of symptoms of posttraumatic stress disorder, psychological distress, multiple physical symptoms and alcohol misuse, having a combat role, childhood adversity, and childhood antisocial behavior with anger. The PAF for any mental health problem and combat role and childhood difficulties was 0.64 (95% confidence interval [CI], 0.56-0.70) and increased to 0.77 (95% CI, 0.69-0.83) if subthreshold cases were included. Anger is a frequent component of mental disorders; health care professionals need to be aware of the interference of anger in the management of mental illness and that anger infrequently presents as an isolated phenomenon. PMID- 25503958 TI - Levels of symptom severity and functioning in four different definitions of subthreshold posttraumatic stress disorder in primary care veterans. AB - Four definitions of subthreshold posttraumatic stress disorder (PTSD) were compared in 815 veterans seen in Veterans Affairs Medical Center primary care clinics. We compared PTSD Checklist (PCL) scores and Short Form 36 (SF-36) scores between participants meeting criteria for one of the subthreshold PTSD definitions (based on Schnurr, Marshall, Blanchard, or Stein) to those with and without PTSD. Using regression, those meeting subthreshold criteria by any of the four definitions had lower mental and physical health functioning and higher PCL scores relative to those without PTSD; they also had higher mental health functioning and lower PCL scores relative to those with PTSD. With SF-36 physical functioning scores, only those meeting the Stein definition differed from the group with PTSD. Thus, these definitions appear to distinguish individuals who are qualitatively different from individuals with no PTSD or with PTSD and are nearly equivalent in their ability to discriminate individuals. PMID- 25503959 TI - Acute vs. chronic stressors, multiple suicide attempts, and persistent suicide ideation in US soldiers. AB - This study examined recent-onset (i.e., acute) and persistent (i.e., chronic) life stressors among 54 acutely suicidal US Army Soldiers and examined their relationship to persistence of suicidal crises over time. Soldiers with a history of multiple suicide attempts reported the most severe suicide ideation (F(2,51) = 4.18, p = 0.021) and the greatest number of chronic stressors (F(2,51) = 5.11, p = 0.009). Chronic but not acute stressors were correlated with severity of suicide ideation (r = 0.24, p = 0.026). Participants reporting low-to-average levels of chronic stress resolved suicide ideation during the 6-month follow-up, but participants reporting high levels of chronic stress did not (Wald chi(1) = 4.57, p = 0.032). Soldiers who are multiple attempters report a greater number of chronic stressors. Chronic, but not acute-onset, stressors are associated with more severe and longer-lasting suicidal crises. PMID- 25503961 TI - Scaling of the appendicular skeleton of the giraffe (Giraffa camelopardalis). AB - Giraffes have remarkably long and slender limb bones, but it is unknown how they grow with regard to body mass, sex, and neck length. In this study, we measured the length, mediolateral (ML) diameter, craniocaudal (CC) diameter and circumference of the humerus, radius, metacarpus, femur, tibia, and metatarsus in 10 fetuses, 21 females, and 23 males of known body masses. Allometric exponents were determined and compared. We found the average bone length increased from 340 +/- 50 mm at birth to 700 +/- 120 mm at maturity, while average diameters increased from 30 +/- 3 to 70 +/- 11 mm. Fetal bones increased with positive allometry in length (relative to body mass) and in diameter (relative to body mass and length). In postnatal giraffes bone lengths and diameters increased iso- or negatively allometric relative to increases in body mass, except for the humerus CC diameter which increased with positive allometry. Humerus circumference also increased with positive allometry, that of the radius and tibia isometrically and the femur and metapodials with negative allometry. Relative to increases in bone length, both the humerus and femur widened with positive allometry. In the distal limb bones, ML diameters increased isometrically (radius, metacarpus) or positively allometric (tibia, metatarsus) while the corresponding CC widths increased with negative allometry and isometrically, respectively. Except for the humerus and femur, exponents were not significantly different between corresponding front and hind limb segments. We concluded that the patterns of bone growth in males and females are identical. In fetuses, the growth of the appendicular skeleton is faster than it is after birth which is a pattern opposite to that reported for the neck. Allometric exponents seemed unremarkable compared to the few species described previously, and pointed to the importance of neck elongation rather than leg elongation during evolution. Nevertheless, the front limb bones and especially the humerus may show adaptation to behaviors such as drinking posture. PMID- 25503960 TI - Involvement of the nuclear factor-kappaB signaling pathway in the regulation of CXC chemokine receptor-4 expression in neuroblastoma cells induced by tumor necrosis factor-alpha. AB - Metastasis is a hallmark of malignant neuroblastoma and is the main reason for therapeutic failure and recurrence of the tumor. The CXC chemokine receptor-4 (CXCR4), a Gi protein-coupled receptor for the ligand CXCL12/stromal cell-derived factor-1alpha (SDF-1alpha), is expressed in various types of tumor. This receptor mediates the homing of tumor cells to specific organs that express the ligand, CXCL12, for this receptor and plays an important role in tumor growth, invasion, metastasis and angiogenesis. In the present study, the inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha) upregulated CXCR4 expression in neuroblastoma cells and increased migration to the CXCR4 ligand SDF-1alpha. In addition, this effect was dependent upon NF-kappaB transcriptional activity, as blocking the NF-kappaB pathway with pyrrolidinedithiocarbamic acid ammonium salt suppressed TNF-alpha-induced upregulation of CXCR4 expression and reduced the migration towards the CXCR4 ligand, SDF-1alpha. Treating neuroblastoma cells with TNF-alpha resulted in the activation of nuclear factor-kappa B (NF-kappaB) and subsequently, the translocation of NF-kappaB from the cytoplasm to the nucleus. Using immunohistochemistry, NF-kappaB and CXCR4 were significantly correlated with each other (P=0.0052, Fisher's exact test) in a cohort of neuroblastoma samples (n=80). The present study indicates that the inflammatory cytokine, TNF alpha, partially functions through the NF-kappaB signaling pathway to upregulate CXCR4 expression to foster neuroblastoma cell metastasis. These findings indicate that effective inhibition of neuroblastoma metastasis should be directed against the inflammatory cytokine-induced NF-kappaB/CXCR4/SDF-1alpha signaling pathway. PMID- 25503962 TI - Immunoassay and Nb2 lymphoma bioassay prolactin levels and mammographic density in premenopausal and postmenopausal women the Nurses' Health Studies. AB - Higher circulating prolactin levels have been associated with higher percent mammographic density among postmenopausal women in some, but not all studies. However, few studies have examined associations with dense area and non-dense breast area breast or considered associations with prolactin Nb2 lymphoma cell bioassay levels. We conducted a cross-sectional study among 1,124 premenopausal and 890 postmenopausal women who were controls in breast cancer case-control studies nested in the Nurses' Health Study (NHS) and NHSII. Participants provided blood samples in 1989-1990 (NHS) or 1996-1999 (NHSII) and mammograms were obtained from around the time of blood draw. Multivariable linear models were used to assess the associations between prolactin levels (measured by immunoassay or bioassay) with percent density, dense area, and non-dense area. Among 1,124 premenopausal women, percent density, dense area, and non-dense area were not associated with prolactin immunoassay levels in multivariable models (p trends = 0.10, 0.18, and 0.69, respectively). Among 890 postmenopausal women, those with prolactin immunoassay levels in the highest versus lowest quartile had modestly, though significantly, higher percent density (difference = 3.01 percentage points, 95 % CI 0.22, 5.80) as well as lower non-dense area (p trend = 0.02). Among women with both immunoassay and bioassay levels, there were no consistent differences in the associations with percent density between bioassay and immunoassay levels. Postmenopausal women with prolactin immunoassay levels in the highest quartile had significantly higher percent density as well as lower non dense area compared to those in the lowest quartile. Future studies should examine the underlying biologic mechanisms, particularly for non-dense area. PMID- 25503963 TI - Clinicopathological and prognostic significance of CD24 overexpression in patients with gastric cancer: a meta-analysis. AB - OBJECTIVE: The prognostic significance of CD24 expression for survival in patients with gastric cancer remains controversial. We conducted a meta-analysis to investigate the impact of CD24 expression on clinicopathological features and survival outcomes in gastric cancer. METHODS: A comprehensive literature search of the electronic databases PubMed, Embase, Web of Science and China National Knowledge Infrastructure (CNKI; up to April 8, 2014) was performed for relevant studies using multiple search strategies. Correlations between CD24 expression and clinicopathological features and overall survival (OS) were analyzed. RESULTS: A total of 1,041 patients with gastric cancer from 9 studies were included. The pooled odds ratios (ORs) indicated CD24 expression was associated with tumor depth (OR = 0.45, 95% confidence interval [CI] = 0.32-0.63; P<0.00001), status of lymph nodes (OR = 0.40, 95% CI = 0.25-0.64; P = 0.0001) and tumor node metastasis (TNM) stage (OR = 0.56, 95% CI = 0.41-0.77; P = 0.0003). The pooled hazard ratio (HR) for OS showed overexpression of CD24 reduced OS in gastric cancer (HR = 1.99, 95% CI = 1.29-3.07, P = 0.002). Whereas, combined ORs showed that CD24 expression had no correlation with tumor differentiation or Lauren classifications. CONCLUSION: CD24 overexpression in patients with gastric cancer indicated worse survival outcomes and was associated with common clinicopathological poor prognostic factors. PMID- 25503964 TI - An outbreak of type pi vaccine-derived poliovirus in Sichuan province, China: emergence and circulation in an under-immunized population. AB - BACKGROUND: During August 2011-February 2012, an outbreak of type Pi circulating vaccine-derived poliovirus (cVDPVs) occurred in Sichuan Province, China. METHODS: A field investigation of the outbreak was conducted to characterize outbreak isolates and to guide emergency response. Sequence analysis of poliovirus capsid protein VP1 was performed to determine the viral propagation, and a coverage survey was carried out for risk assessment. RESULTS: One clinical compatible polio case and three VDPV cases were determined in Ngawa County, Ngawa Tibetan and Qiang Autonomous Prefecture, Sichuan Province. Case patients were unimmunized children, 0.8-1 years old. Genetic sequencing showed that the isolates diverged from the VP1 region of the type Pi Sabin strain by 5-12 nucleotides (nt) and shared the same 5 nt VP1 substitutions, which indicate single lineage of cVDPVs. Of the 7 acute flaccid paralysis cases (all>6 months) reported in Ngawa Prefecture in 2011, 4 (57.1%) cases (including 2 polio cases) did not receive oral attenuated poliovirus vaccine. Supplementary immunization activities (SIAs) were conducted in February-May, 2012, and the strain has not been isolated since. CONCLUSION: High coverage of routine immunization should be maintained among children until WPV transmission is globally eradicated. Risk assessments should be conducted regularly to pinpoint high risk areas or subpopulations, with SIAs developed if necessary. PMID- 25503966 TI - Genetic testing and interpretive complexity: a BRCA1 gene mutation example. AB - Diagnosis and interpretation of hereditary breast cancer can be a complex and challenging dilemma. Advances in genetic testing have resulted in guidelines for clinical evaluation and recommendations. Here, we present a case of one family with multiple cases of early-onset breast cancer, some due to a familial BRCA1 mutation but others unrelated to this pathogenic E143X nonsense mutation. In this case report, we highlight the complexities associated with adhering strictly to guidelines and highlight the need for clinical experience in when to deviate from recommended protocols. PMID- 25503965 TI - MORC1 represses transposable elements in the mouse male germline. AB - The Microrchidia (Morc) family of GHKL ATPases are present in a wide variety of prokaryotic and eukaryotic organisms but are of largely unknown function. Genetic screens in Arabidopsis thaliana have identified Morc genes as important repressors of transposons and other DNA-methylated and silent genes. MORC1 deficient mice were previously found to display male-specific germ cell loss and infertility. Here we show that MORC1 is responsible for transposon repression in the male germline in a pattern that is similar to that observed for germ cells deficient for the DNA methyltransferase homologue DNMT3L. Morc1 mutants show highly localized defects in the establishment of DNA methylation at specific classes of transposons, and this is associated with failed transposon silencing at these sites. Our results identify MORC1 as an important new regulator of the epigenetic landscape of male germ cells during the period of global de novo methylation. PMID- 25503967 TI - Self-medication practices and risk factors for self-medication among medical students in Belgrade, Serbia. AB - INTRODUCTION: Self-medication among future health care professionals can represent a serious threat to professionalism in medicine and it has potential to put at risk public trust into this profession. The aim of this research was to investigate prevalence and risk factors for self-medication among population of medical students, because it was previously shown that their attitudes towards pharmacotherapy could affect the way they could prescribe medication in the future. MATERIAL AND METHODS: Research was performed as a cross-sectional study and it included 1296 (84.1%) 1st, 3rd and 6th year students of School of Medicine, University of Belgrade. Students filled out a demographic and self medication questionnaire created for the purpose of this research and the Physical Health Questionnaire - 9 (PHQ-9). Questions about self-medication were related to the period of the previous year. RESULTS: Self-medication was reported by 79.9% students. The most frequently self-prescribed medications were analgesics (55.4%). Independent risk factors for self-medication were possession of home-pharmacies (OR = 5.3, CI 95% 3.89-7.23), lower level of father's education (OR = 1.6, CI 95% 1.18-2.25), consumption of alcoholic beverages (OR = 1.5, CI 95% 1.13-2.08), less than 1 hour spent in physical activity per week (OR = 1.4, CI 95% 1.00-2.02), female gender (OR = 1.4, CI 95% 1.02-1.89), older age (OR = 1.1, CI 95% 1.07-1.21) and higher PHQ-9 score (OR = 1.09, CI 95% 1.05 1.12). CONCLUSIONS: Self-medication is an important issue among population of medical students. Prevalence of self-medication could be controlled through regulatory authorities and further education. PMID- 25503968 TI - Need for a paradigm shift in adult overweight and obesity management - an EASO position statement on a pressing public health, clinical and scientific challenge in Europe. PMID- 25503970 TI - Strictureplasty in Crohn's disease: a new side to side isoperistaltic technique. PMID- 25503969 TI - Oropharyngeal aspiration of Burkholderia mallei and Burkholderia pseudomallei in BALB/c mice. AB - Burkholderia mallei and Burkholderia pseudomallei are potentially lethal pathogens categorized as biothreat agents due, in part, to their ability to be disseminated via aerosol. There are no protective vaccines against these pathogens and treatment options are limited and cumbersome. Since disease severity is greatest when these agents are inhaled, efforts to develop pre- or post-exposure prophylaxis focus largely on inhalation models of infection. Here, we demonstrate a non-invasive and technically simple method for affecting the inhalational challenge of BALB/c mice with B. pseudomallei and B. mallei. In this model, two investigators utilized common laboratory tools such as forceps and a micropipette to conduct and characterize an effective and reproducible inhalational challenge of BALB/c mice with B. mallei and B. pseudomallei. Challenge by oropharyngeal aspiration resulted in acute disease. Additionally, 50% endpoints for B. pseudomallei K96243 and B. mallei ATCC 23344 were nearly identical to published aerosol challenge methods. Furthermore, the pathogens disseminated to all major organs typically targeted by these agents where they proliferated. The pro-inflammatory cytokine production in the proximal and peripheral fluids demonstrated a rapid and robust immune response comparable to previously described murine and human studies. These observations demonstrate that OA is a viable alternative to aerosol exposure. PMID- 25503971 TI - Invited commentary on "Werkgartner G. et al.: Laparoscopic versus open appendectomy for complicated appendicitis in high risk patients". PMID- 25503972 TI - Combination of cyclopamine and tamoxifen promotes survival and migration of mcf-7 breast cancer cells--interaction of hedgehog-gli and estrogen receptor signaling pathways. AB - Hedgehog-Gli (Hh-Gli) signaling pathway is one of the new molecular targets found upregulated in breast tumors. Estrogen receptor alpha (ERalpha) signaling has a key role in the development of hormone-dependent breast cancer. We aimed to investigate the effects of inhibiting both pathways simultaneously on breast cancer cell survival and the potential interactions between these two signaling pathways. ER-positive MCF-7 cells show decreased viability after treatment with cyclopamine, a Hh-Gli pathway inhibitor, as well as after tamoxifen (an ERalpha inhibitor) treatment. Simultaneous treatment with cyclopamine and tamoxifen on the other hand, causes short-term survival of cells, and increased migration. We found upregulated Hh-Gli signaling under these conditions and protein profiling revealed increased expression of proteins involved in cell proliferation and migration. Therefore, even though Hh-Gli signaling seems to be a good potential target for breast cancer therapy, caution must be advised, especially when combining therapies. In addition, we also show a potential direct interaction between the Shh protein and ERalpha in MCF-7 cells. Our data suggest that the Shh protein is able to activate ERalpha independently of the canonical Hh-Gli signaling pathway. Therefore, this may present an additional boost for ER positive cells that express Shh, even in the absence of estrogen. PMID- 25503973 TI - Distinct Leishmania species infecting wild caviomorph rodents (Rodentia: Hystricognathi) from Brazil. AB - BACKGROUND: Caviomorph rodents, some of the oldest Leishmania spp. hosts, are widely dispersed in Brazil. Despite both experimental and field studies having suggested that these rodents are potential reservoirs of Leishmania parasites, not more than 88 specimens were analyzed in the few studies of natural infection. Our hypothesis was that caviomorph rodents are inserted in the transmission cycles of Leishmania in different regions, more so than is currently recognized. METHODOLOGY: We investigated the Leishmania infection in spleen fragments of 373 caviomorph rodents from 20 different species collected in five Brazilian biomes in a period of 13 years. PCR reactions targeting kDNA of Leishmania sp. were used to diagnose infection, while Leishmania species identification was performed by DNA sequencing of the amplified products obtained in the HSP70 (234) targeting. Serology by IFAT was performed on the available serum of these rodents. PRINCIPAL FINDINGS: In 13 caviomorph rodents, DNA sequencing analyses allowed the identification of 4 species of the subgenus L. (Viannia): L. shawi, L. guyanensis, L. naiffi, and L. braziliensis; and 1 species of the subgenus L. (Leishmania): L. infantum. These include the description of parasite species in areas not previously included in their known distribution: L. shawi in Thrichomys inermis from Northeastern Brazil and L. naiffi in T. fosteri from Western Brazil. From the four other positive rodents, two were positive for HSP70 (234) targeting but did not generate sequences that enabled the species identification, and another two were positive only in kDNA targeting. CONCLUSIONS/SIGNIFICANCE: The infection rate demonstrated by the serology (51.3%) points out that the natural Leishmania infection in caviomorph rodents is much higher than that observed in the molecular diagnosis (4.6%), highlighting that, in terms of the host species responsible for maintaining Leishmania species in the wild, our current knowledge represents only the "tip of the iceberg." PMID- 25503975 TI - Factors influencing patients' contract choice with general practitioners in Shanghai: a preliminary study. AB - The general practitioner (GP) system has been widely applied around the world and experimented with in Shanghai, China. To analyze some of the influencing factors on patient-GP contracts, we developed a questionnaire and conducted site investigations in 2011 and 2012 to 1200 patients by random sampling from 6 pilot community health service (CHS) centers in Pudong, Shanghai. The t test, chi(2) test, factor analysis, and logistic regression analysis were used to analyze the data. The factors influencing patients' contract behavior were age (OR = 1.03; 95%CI = 1.02-1.04), education level (OR = 0.83; 95% CI = 0.75-0.93), social interaction of social capital (OR = 1.34; 95% CI = 1.15-1.56), acceptance of first contact in community (OR = 3.25; 95% CI = 2.07-5.12), the year of investigation (OR = 2.58; 95% CI = 1.92-3.47), and the exposure to publicity (OR = 1.60; 95% CI = 1.39-1.85). Elderly patients formed a focus group to sign contracts with GPs. To increase trust in GPs by patients, it is recommended to improve the level of CHSs, strengthen publicity, and cultivate social capital among patients. PMID- 25503938 TI - Synthetic biology for the directed evolution of protein biocatalysts: navigating sequence space intelligently. AB - The amino acid sequence of a protein affects both its structure and its function. Thus, the ability to modify the sequence, and hence the structure and activity, of individual proteins in a systematic way, opens up many opportunities, both scientifically and (as we focus on here) for exploitation in biocatalysis. Modern methods of synthetic biology, whereby increasingly large sequences of DNA can be synthesised de novo, allow an unprecedented ability to engineer proteins with novel functions. However, the number of possible proteins is far too large to test individually, so we need means for navigating the 'search space' of possible protein sequences efficiently and reliably in order to find desirable activities and other properties. Enzymologists distinguish binding (Kd) and catalytic (kcat) steps. In a similar way, judicious strategies have blended design (for binding, specificity and active site modelling) with the more empirical methods of classical directed evolution (DE) for improving kcat (where natural evolution rarely seeks the highest values), especially with regard to residues distant from the active site and where the functional linkages underpinning enzyme dynamics are both unknown and hard to predict. Epistasis (where the 'best' amino acid at one site depends on that or those at others) is a notable feature of directed evolution. The aim of this review is to highlight some of the approaches that are being developed to allow us to use directed evolution to improve enzyme properties, often dramatically. We note that directed evolution differs in a number of ways from natural evolution, including in particular the available mechanisms and the likely selection pressures. Thus, we stress the opportunities afforded by techniques that enable one to map sequence to (structure and) activity in silico, as an effective means of modelling and exploring protein landscapes. Because known landscapes may be assessed and reasoned about as a whole, simultaneously, this offers opportunities for protein improvement not readily available to natural evolution on rapid timescales. Intelligent landscape navigation, informed by sequence-activity relationships and coupled to the emerging methods of synthetic biology, offers scope for the development of novel biocatalysts that are both highly active and robust. PMID- 25503976 TI - Unisexual reproduction drives meiotic recombination and phenotypic and karyotypic plasticity in Cryptococcus neoformans. AB - In fungi, unisexual reproduction, where sexual development is initiated without the presence of two compatible mating type alleles, has been observed in several species that can also undergo traditional bisexual reproduction, including the important human fungal pathogens Cryptococcus neoformans and Candida albicans. While unisexual reproduction has been well characterized qualitatively, detailed quantifications are still lacking for aspects of this process, such as the frequency of recombination during unisexual reproduction, and how this compares with bisexual reproduction. Here, we analyzed meiotic recombination during alpha alpha unisexual and a-alpha bisexual reproduction of C. neoformans. We found that meiotic recombination operates in a similar fashion during both modes of sexual reproduction. Specifically, we observed that in alpha-alpha unisexual reproduction, the numbers of crossovers along the chromosomes during meiosis, recombination frequencies at specific chromosomal regions, as well as meiotic recombination hot and cold spots, are all similar to those observed during a alpha bisexual reproduction. The similarity in meiosis is also reflected by the fact that phenotypic segregation among progeny collected from the two modes of sexual reproduction is also similar, with transgressive segregation being observed in both. Additionally, we found diploid meiotic progeny were also produced at similar frequencies in the two modes of sexual reproduction, and transient chromosomal loss and duplication likely occurs frequently and results in aneuploidy and loss of heterozygosity that can span entire chromosomes. Furthermore, in both alpha-alpha unisexual and a-alpha bisexual reproduction, we observed biased allele inheritance in regions on chromosome 4, suggesting the presence of fragile chromosomal regions that might be vulnerable to mitotic recombination. Interestingly, we also observed a crossover event that occurred within the MAT locus during alpha-alpha unisexual reproduction. Our results provide definitive evidence that alpha-alpha unisexual reproduction is a meiotic process similar to a-alpha bisexual reproduction. PMID- 25503979 TI - Characterization of the uncertainty of divergence time estimation under relaxed molecular clock models using multiple loci. AB - Genetic sequence data provide information about the distances between species or branch lengths in a phylogeny, but not about the absolute divergence times or the evolutionary rates directly. Bayesian methods for dating species divergences estimate times and rates by assigning priors on them. In particular, the prior on times (node ages on the phylogeny) incorporates information in the fossil record to calibrate the molecular tree. Because times and rates are confounded, our posterior time estimates will not approach point values even if an infinite amount of sequence data are used in the analysis. In a previous study we developed a finite-sites theory to characterize the uncertainty in Bayesian divergence time estimation in analysis of large but finite sequence data sets under a strict molecular clock. As most modern clock dating analyses use more than one locus and are conducted under relaxed clock models, here we extend the theory to the case of relaxed clock analysis of data from multiple loci (site partitions). Uncertainty in posterior time estimates is partitioned into three sources: Sampling errors in the estimates of branch lengths in the tree for each locus due to limited sequence length, variation of substitution rates among lineages and among loci, and uncertainty in fossil calibrations. Using a simple but analogous estimation problem involving the multivariate normal distribution, we predict that as the number of loci ([Formula: see text]) goes to infinity, the variance in posterior time estimates decreases and approaches the infinite-data limit at the rate of 1/[Formula: see text], and the limit is independent of the number of sites in the sequence alignment. We then confirmed the predictions by using computer simulation on phylogenies of two or three species, and by analyzing a real genomic data set for six primate species. Our results suggest that with the fossil calibrations fixed, analyzing multiple loci or site partitions is the most effective way for improving the precision of posterior time estimation. However, even if a huge amount of sequence data is analyzed, considerable uncertainty will persist in time estimates. PMID- 25503980 TI - DAG1 mutations associated with asymptomatic hyperCKemia and hypoglycosylation of alpha-dystroglycan. AB - OBJECTIVES: To identify gene mutations in patients with dystroglycanopathy and prove pathogenicity of those mutations using an in vitro cell assay. METHODS: We performed whole-exome sequencing on 20 patients, who were previously diagnosed with dystroglycanopathy by immunohistochemistry and/or Western blot analysis. We also evaluated pathogenicity of identified mutations for phenotypic recovery in a DAG1-knockout haploid human cell line transfected with mutated DAG1 complementary DNA. RESULTS: Using exome sequencing, we identified compound heterozygous missense mutations in DAG1 in a patient with asymptomatic hyperCKemia and pathologically mild muscular dystrophy. Both mutations were in the N-terminal region of alpha-dystroglycan and affected its glycosylation. Mutated DAG1 complementary DNAs failed to rescue the phenotype in DAG1-knockout cells, suggesting that these are pathogenic mutations. CONCLUSION: Novel mutations in DAG1 are associated with asymptomatic hyperCKemia with hypoglycosylation of alpha dystroglycan. The combination of exome sequencing and a phenotype-rescue experiment on a gene-knockout haploid cell line represents a powerful tool for evaluation of these pathogenic mutations. PMID- 25503977 TI - VWF excess and ADAMTS13 deficiency: a unifying pathomechanism linking inflammation to thrombosis in DIC, malaria, and TTP. AB - Absent or severely diminished activity of ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) resulting in the intravascular persistence and accumulation of highly thrombogenic ultra large von Willebrand factor (UL-VWF) multimers is the pathophysiological mechanism underlying thrombotic thrombocytopenic purpura. Reduced VWF-cleaving protease levels, however, are not uniquely restricted to primary thrombotic microangiopathy (TMA), e. g. thrombotic thrombocytopenic purpura, but also occur in other life-threatening thrombocytopenic conditions: severely decreased ADAMTS13 activity is seen in severe sepsis, disseminated intravascular coagulation (DIC) and complicated malarial infection. The clinical relevance of these secondary thrombotic microangiopathies is increasingly recognised, but its therapeutic implications have not yet been determined. The presence of a secondary TMA in certain diseases may define patient groups which possibly could benefit from ADAMTS13 replacement or a VWF-targeting therapy. This short-review focuses on the role of UL-VWF multimers in secondary TMA and discusses the potential of investigational therapies as candidates for the treatment of TTP. In conclusion, prospective clinical trials on the effectiveness of protease replacementin vivo seem reasonable. Carefully selected patients with secondary TMA may benefit from therapies primarily intended for the use in patients with TTP. PMID- 25503981 TI - Alcohol consumption, drinking patterns, and cognitive function in older Eastern European adults. AB - OBJECTIVE: To investigate associations of frequency, quantity, binge, and problem drinking with cognitive function in older Eastern European adults. METHODS: The investigation included 14,575 participants, aged 47 to 78 years at cognitive assessment in 2006-2008 from Novosibirsk (Russia), Krakow (Poland), and 6 Czech towns participating in the HAPIEE (Health, Alcohol, and Psychosocial Factors in Eastern Europe) prospective cohort study. Average response rates were 59% at baseline (2002-2005) and 63% in 2006-2008. Alcohol consumption was assessed at baseline and in 2006-2008. Cognitive tests included immediate and delayed word recall, semantic fluency (animal naming), and letter cancellation. Associations between alcohol indices and cognitive scores were analyzed cross-sectionally (all measures from 2006 to 2008) and prospectively (alcohol and covariates from 2002 to 2005 and cognition from 2006 to 2008). RESULTS: In cross-sectional analyses, nondrinkers had lower cognitive scores and female moderate drinkers had better cognitive performance than light drinkers. Heavy, binge, and problem drinking were not consistently associated with cognitive function. Few associations were replicated in prospective analyses. Participants who stopped drinking during follow-up had worse cognition than stable drinkers; in men, regression coefficients (95% confidence interval) ranged from -0.26 (-0.36, -0.16) for immediate recall to -0.14 (-0.24, -0.04) for fluency. CONCLUSION: Regular and episodic heavy drinking were not consistently associated with cognitive function. Worse cognition in participants who stopped drinking during follow-up suggests that inclusion of less healthy ex-drinkers may partly explain poorer cognition in nondrinkers. PMID- 25503983 TI - Eruptive disseminated superficial basal cell carcinomas 24 years after bone marrow transplantation. AB - Secondary cutaneous malignancies are often reported after treatment of malignant haemopathies using allogeneic bone marrow transplantation (BMT). Within the spectrum of such secondary skin carcinomas, basal cell carcinomas (BCC) appear the most frequent. We report here the case of a 67- year-old male patient who developed 24 years after BMT more than 40 superficial BCC as well as a few nodular BCC. These tumours were mainly found on the lower limbs at sites without sun exposure. The patient was treated with surgical excision of nodular BCC while photodynamic therapy was used for the superficial BCC. No recurrences were reported at 5-year follow-up. To our knowledge, this is the first case of a patient presenting eruptive and non-recurring BCC so long after BMT. Only two similar cases have been reported in other circumstances. There is no clear explanation to this peculiar non-recurrence. We speculate that repair of DNA mutations may have occurred. PMID- 25503978 TI - Constitutive and ligand-induced EGFR signalling triggers distinct and mutually exclusive downstream signalling networks. AB - Epidermal growth factor receptor (EGFR) overexpression plays an important oncogenic role in cancer. Regular EGFR protein levels are increased in cancer cells and the receptor then becomes constitutively active. However, downstream signals generated by constitutively activated EGFR are unknown. Here we report that the overexpressed EGFR oscillates between two distinct and mutually exclusive modes of signalling. Constitutive or non-canonical EGFR signalling activates the transcription factor IRF3 leading to expression of IFI27, IFIT1 and TRAIL. Ligand-mediated activation of EGFR switches off IRF3-dependent transcription, activates canonical extracellular signal-regulated kinase (ERK) and Akt signals, and confers sensitivity to chemotherapy and virus-induced cell death. Mechanistically, the distinct downstream signals result from a switch of EGFR-associated proteins. EGFR constitutively complexes with IRF3 and TBK1 leading to TBK1 and IRF3 phosphorylation. Addition of epidermal growth factor dissociates TBK1, IRF3 and EGFR leading to a loss of IRF3 activity, Shc-EGFR association and ERK activation. Finally, we provide evidence for non-canonical EGFR signalling in glioblastoma. PMID- 25503982 TI - Incidence of polyneuropathy in Utrecht, the Netherlands. AB - OBJECTIVE: Ascertain the incidence of cryptogenic axonal polyneuropathy (CAP) and how this relates to the overall incidence of polyneuropathy. METHODS: Electronic diagnostic registries of all hospital-based neurologic practices in the province of Utrecht (population 1,224,852 = 7.4% of the Dutch population) were consulted in 2010 to identify incident cases with polyneuropathy. Medical files were reviewed to specify the final diagnosis. Age-adjusted incidence rates for the Netherlands were calculated using national age-specific population figures. RESULTS: The overall incidence of polyneuropathy was 77.0/100,000 person-years (95% confidence interval 71.1-82.8) in persons aged 18 years and older. Diabetic polyneuropathy (32%), CAP (26%), toxic polyneuropathy (14%), and immune-mediated polyneuropathy (9%) were the most frequent diagnoses. The incidence of CAP was 31.6/100,000 person-years (95% confidence interval 27.0-36.3) in persons aged 40 years and older. The incidence of polyneuropathy increased with age, as well as the proportion of patients diagnosed with CAP: 12% (40-49 years), 20% (50-59 years), 28% (60-69 years), 32% (70-79 years), and 35% (>=80 years) (chi(2) test, p = 0.005). CONCLUSIONS: The chance of establishing an etiologic diagnosis in patients presenting with a polyneuropathy decreases with age. Given the aging population, polyneuropathy in general and CAP in particular will pose a growing health care problem. PMID- 25503984 TI - Life expectancy and longevity of varanid lizards (Reptilia:Squamata:Varanidae) in North American zoos. AB - In zoos, life expectancy-the average lifespan of individuals within a population, and longevity-the maximum lifespan within a population, can be useful parameters for evaluating captive husbandry and animal welfare. Using life history and demographic data derived from regional studbooks, this study examined life expectancy and longevity in a total of 782 wild-caught (WC) and captive-bred (CB) varanid lizards of seven species maintained in North American zoos since 1926. The average lifespans for WC and CB animals were 6.3 +/- 0.3 and 9.3 +/- 0.4 years, respectively, with CB males living significantly longer than females (P = 0.009). A total of 26.4% of WC and 22.5% of CB animals experienced mortality during their first 2 years in captivity, with mortality during this period greatest among Varanus rudicollis and V. prasinus. A positive correlation was observed between life expectancy and adult body mass in captive-bred individuals (r = 0.981; P = 0.002). Wild-caught females with a history of successful reproduction had a significantly greater average lifespan than non-reproducing females (P < 0.0001). Results from this study suggest that varanids have not been reaching their lifespan capacities in North American zoos. In light of these findings, several husbandry-related factors which may be affecting the welfare and lifespans of varanids in zoos are identified and discussed. This study also highlights the utility of demographic and life history data in captive animal management, and offers a general framework for future herpetological studies of a similar nature. PMID- 25503985 TI - Genetic variants in let-7/Lin28 modulate the risk of oral cavity cancer in a Chinese Han population. AB - Let-7 and Lin28 establish a double-negative feedback loop to affect several biological processes, such as differentiation of stem cell, invasion and metastasis, and tumorigenesis. In this study, we systematically investigated the associations between 6 potentially functional SNPs of let7 and Lin28 genes and the risk of oral cavity cancer with a case-control study including 384 oral cavity cancer cases and 731 controls. We found that the variant allele (T) of rs221636 of Lin28B was significantly associated with a reduced risk of oral cavity cancer [odds ratio (OR) = 0.73, 95% confidence interval (CI) = 0.58-0.92, P = 7.55 * 10(-3) in additive model]. Bioinformatics prediction indicated that rs221636 was located at the binding site of hsa-miR-548p in the 3' UTR of Lin28B. Luciferase activity assay also showed a lower expression level for rs221636 T allele compared with A allele. These findings indicated that rs221236 located at Lin28B may contribute to the risk of oral cavity cancer through the interruption of miRNA binding. PMID- 25503987 TI - Keeping kidneys safe: the pharmacist's role in NSAID avoidance in high-risk patients. AB - OBJECTIVE: To provide information on the role of pharmacists in nonsteroidal anti inflammatory drug (NSAID) avoidance in high-risk patients. SUMMARY: Nonprescription analgesics such as ibuprofen and naproxen are widely used by Americans. These nonsteroidal anti-inflammatory drugs (NSAIDs) are available in large quantities in pharmacies and also in wholesale stores, gas stations, and convenience stores. In addition, more than 111 million people use prescription NSAIDs each year, including many older Americans. NSAIDs may seem innocuous, but they carry a significant risk of disrupting blood flow to the kidneys and thus precipitating acute kidney injury (AKI). Episodes of AKI can lead to costly hospitalizations and long-term consequences such as new-onset chronic kidney disease (CKD) or more rapid progression of existing CKD. Most cases of NSAID induced AKI can be avoided by recognizing high-risk patients and counseling them on appropriate use of these medications. Community pharmacy-based NSAID counseling and education at the point of prescription dispensing or nonprescription purchase could complement and augment NSAID-induced AKI education provided by other members of the health care team to high-risk patients. CONCLUSION: NSAID use is widespread and severely compromises effective renal perfusion in high-risk patients. The community pharmacist can play a pivotal role in NSAID avoidance education to prevent potential episodes of AKI that have long term consequences for patients. PMID- 25503986 TI - Moderate hypoxia induces beta-cell dysfunction with HIF-1-independent gene expression changes. AB - Pancreatic beta-cell failure is central to the development and progression of type 2 diabetes. We recently demonstrated that beta-cells become hypoxic under high glucose conditions due to increased oxygen consumption and that the pancreatic islets of diabetic mice but not those of control mice are moderately hypoxic. However, the impact of moderate hypoxia on beta-cell number and function is unknown. In the present study, moderate hypoxia induced a hypoxic response in MIN6 cells, as evidenced by increased levels of HIF-1alpha protein and target genes. Under these conditions, a selective downregulation of Mafa, Pdx1, Slc2a2, Ndufa5, Kcnj11, Ins1, Wfs1, Foxa2, and Neurod1, which play important roles in beta-cells, was also observed in both MIN6 cells and isolated pancreatic islets. Consistent with the altered expression of these genes, abnormal insulin secretion was detected in hypoxic MIN6 cells. Most of the hypoxia-induced gene downregulation in MIN6 cells was not affected by the suppression of HIF-1alpha, suggesting a HIF-1-independent mechanism. Moderate hypoxia also induced apoptosis in MIN6 cells. These results suggest that hypoxia is a novel stressor of beta cells and that hypoxic stress may play a role in the deterioration of beta-cell function. PMID- 25503989 TI - Zero thermal expansion in NaZn13-type La(Fe,Si)13 compounds. AB - A zero thermal expansion material in a pure form of NaZn13-type La(Fe,Si)13 was fabricated. Through optimizing the chemical composition, an isotropic zero thermal expansion material is achieved. The obtained materials exhibit a low expansion of |alpha| < 1.0 * 10(-6) K(-1) (alpha is the coefficient of linear thermal expansion) over a broad temperature range (15-150 K). The present study indicates that the thermal expansion behavior of the NaZn13-type La(Fe,Si)13 compounds depends mainly on the content of Si element. This new material is desirable in many fields of industry as a reliable and low-cost zero thermal expansion material. PMID- 25503988 TI - IL-28B is a key regulator of B- and T-cell vaccine responses against influenza. AB - Influenza is a major cause of morbidity and mortality in immunosuppressed persons, and vaccination often confers insufficient protection. IL-28B, a member of the interferon (IFN)-lambda family, has variable expression due to single nucleotide polymorphisms (SNPs). While type-I IFNs are well known to modulate adaptive immunity, the impact of IL-28B on B- and T-cell vaccine responses is unclear. Here we demonstrate that the presence of the IL-28B TG/GG genotype (rs8099917, minor-allele) was associated with increased seroconversion following influenza vaccination (OR 1.99 p = 0.038). Also, influenza A (H1N1)-stimulated T- and B-cells from minor-allele carriers showed increased IL-4 production (4-fold) and HLA-DR expression, respectively. In vitro, recombinant IL-28B increased Th1 cytokines (e.g. IFN-gamma), and suppressed Th2-cytokines (e.g. IL-4, IL-5, and IL 13), H1N1-stimulated B-cell proliferation (reduced 70%), and IgG-production (reduced>70%). Since IL-28B inhibited B-cell responses, we designed antagonistic peptides to block the IL-28 receptor alpha-subunit (IL28RA). In vitro, these peptides significantly suppressed binding of IFN-lambdas to IL28RA, increased H1N1-stimulated B-cell activation and IgG-production in samples from healthy volunteers (2-fold) and from transplant patients previously unresponsive to vaccination (1.4-fold). Together, these findings identify IL-28B as a key regulator of the Th1/Th2 balance during influenza vaccination. Blockade of IL28RA offers a novel strategy to augment vaccine responses. PMID- 25503991 TI - Fibroblast growth factor signaling pathway in endothelial cells is activated by BMPER to promote angiogenesis. AB - OBJECTIVE: Previously, we have identified bone morphogenetic protein endothelial cell precursor-derived regulator (BMPER) to increase the angiogenic activity of endothelial cells in a concentration-dependent manner. In this project, we now investigate how BMPER acts in concert with key molecules of angiogenesis to promote blood vessel formation. APPROACH AND RESULTS: To assess the effect of BMPER on angiogenesis-related signaling pathways, we performed an angiogenesis antibody array with BMPER-stimulated endothelial cells. We detected increased basic fibroblast growth factor (bFGF/FGF-2) expression after BMPER stimulation and decreased expression of thrombospondin-1. Additionally, FGF receptor-1 expression, phosphorylation, FGF signaling pathway activity, and cell survival were increased. Consistently, silencing of BMPER by small interfering RNA decreased bFGF and FGF receptor-1 expression and increased thrombospondin-1 expression and cell apoptosis. Next, we investigated the interaction of BMPER and the FGF signaling pathway in endothelial cell function. BMPER stimulation increased endothelial cell angiogenic activity in migration, Matrigel, and spheroid assays. To block FGF signaling, an anti-bFGF antibody was used, which effectively inhibited the proangiogenic BMPER effect. Accordingly, BMPER-silenced endothelial cells under bFGF stimulation showed decreased angiogenic activity compared with bFGF control. We confirmed these findings in vivo by subcutaneous Matrigel injections with and without bFGF in C57BL/6_Bmper(+/-) mice. Aortic ring assays of C57BL/6_Bmper(+/-) mice confirmed a specific effect for bFGF but not for vascular endothelial growth factor. CONCLUSIONS: Taken together, the proangiogenic BMPER effect in endothelial cells is mediated by inhibition of antiangiogenic thrombospondin-1 and enhanced expression and activation of the FGF signaling pathway that is crucial in the promotion of angiogenesis. PMID- 25503990 TI - Inactivation of PI3Kdelta induces vascular injury and promotes aneurysm development by upregulating the AP-1/MMP-12 pathway in macrophages. AB - OBJECTIVE: An aneurysm is an inflammatory vascular condition. Phosphatidylinositol 3-kinases delta is highly expressed in leukocytes, and play a key role in innate immunity. However, the link between phosphatidylinositol 3 kinases delta and aneurysm development has not yet been elucidated. APPROACH AND RESULTS: Carotid ligation unexpectedly induced characteristic aneurysm formation beneath the ligation point in p110delta(D910A/D910A) mice (n=25; P<0.001 versus wild-type). Besides, p110delta inactivation exacerbated CaCl2-induced abdominal aortic aneurysms development. A reverse transcription polymerase chain reaction microarray revealed significant extracellular matrix components degradation and matrix metalloproteinases (MMPs) upregulation in the abdominal aorta of p110delta(D910A/D910A) mice. Similarly, the expression of both collagen I and IV was significantly decreased (n=10; P<0.05 versus wild-type) in carotid artery. Western blot assay confirmed that MMP-12 was significantly upregulated in arteries of p110delta(D910A/D910A) mice (n=10; P<0.01 versus wild-type). In vitro, p110delta inactivation marked increase peritoneal macrophages recruitment and synergistically enhance tumor necrosis factor-alpha-induced recruitment. A specific phosphatidylinositol 3-kinases delta inhibitor (IC87114) or genetic p110delta inactivation upregulated MMP-12 expression and c-Jun phosphorylation (n=6; P<0.05 versus wild-type macrophages). IC87114 also increased activator protein-1 DNA-binding activity (n=6; P<0.001 versus control) and enhanced the effect of tumor necrosis factor-alpha on activator protein-1-binding activity (n=5; P<0.01 versus tumor necrosis factor-alpha treatment groups). Knockdown of c Jun suppressed the effect of the IC87114 and tumor necrosis factor-alpha on MMP 12 mRNA expression (n=5 in each group; P<0.01 versus scrRNA treatment groups). CONCLUSIONS: Our findings demonstrate that p110delta inactivation leads to extracellular matrix degradation in vessels and promotes aneurysm development by inducing macrophages migration and upregulating the activator protein-1/MMP-12 pathway in macrophages. PMID- 25503992 TI - A hybrid method for identification of structural domains. AB - Structural domains in proteins are the basic units to form various proteins. In the protein's evolution and functioning, domains play important roles. But the definition of domain is not yet precisely given, and the update cycle of structural domain databases is long. The automatic algorithms identify domains slowly, while protein entities with great structural complexity are on the rise. Here, we present a method which recognizes the compact and modular segments of polypeptide chains to identify structural domains, and contrast some data sets to illuminate their effect. The method combines support vector machine (SVM) with K means algorithm. It is faster and more stable than most current algorithms and performs better. It also indicates that when proteins are presented as some Alpha carbon atoms in 3D space, it is feasible to identify structural domains by the spatially structural properties. We have developed a web-server, which would be helpful in identification of structural domains (http://vis.sculab.org/~huayongpan/cgi-bin/domainAssignment.cgi). PMID- 25503993 TI - Optimization of attenuation and scatter corrections in sentinel lymph node scintigraphy using SPECT/CT systems. AB - OBJECTIVE: Although SPECT/CT systems have been used for sentinel lymph node (SLN) imaging, few studies have focused on optimization of attenuation correction (AC) and scatter correction (SC). While SLNs could be detected in conventional planar images, they sometimes do not appear in SPECT/CT images. The purpose of this study was to investigate the optimal AC and SC and to improve the detectability of SLNs in examinations using SPECT/CT systems. MATERIALS AND METHODS: The study group consisted of 56 female patients with breast cancer. In SPECT/CT imaging, four kinds of images were created with and without AC and SC; namely, AC-SC-, AC+SC-, AC-SC+ and AC+SC+. Five nuclear medicine physicians interpreted the planar and SPECT/CT images with five grades of confidence levels (1-5). The detection rate was calculated as the number of patients whose average confidence levels of interpretation were more than 4, divided by the total number of patients. RESULTS: The confidence level of interpretation and the detection rate provided by the planar images were 4.76 +/- 0.49 and 94.6 %, respectively. In SPECT/CT imaging, the AC+SC- provided the best detection rate (confidence level of interpretation, 4.81 +/- 0.38; detection rate, 98.2 %), followed by the AC-SC- (4.70 +/- 0.55, 89.3 %), and the AC-SC+ (4.39 +/- 1.2, 78.6 %). The lowest values were obtained for the AC+SC+ (4.36 +/- 1.22, 78.6 %). Regarding the confidence levels of interpretation, significant differences were observed between AC+SC- and AC-SC-, AC+SC- and AC+SC+, AC+SC- and AC-SC+, and between planar images and AC+SC+ (P = 0.0021, 0.0009, 0.0013, and 0.0056, respectively). CONCLUSIONS: When SPECT/CT was used, AC improved the detection of SLNs. SC caused disappearance of a faint SLN in some cases and should not be performed. PMID- 25503994 TI - The efficacy and safety of growth hormone therapy in children with noonan syndrome: a review of the evidence. AB - Noonan syndrome is a genetic disorder associated with short stature. We reviewed 15 studies in which growth hormone (GH) therapy was used in children with Noonan syndrome. Data show consistent increases in mean height standard deviation score (SDS), with first-year changes of up to 1.26 SDS. Among studies reporting adult or near-adult height, GH therapy over 5-7 years resulted in adult height SDS from -0.6 to -2.1, with up to 60% of subjects in some studies achieving adult height within 1 SDS of mid-parental height. GH treatment results in an acceleration of bone age, likely reflecting normalization from the retarded bone age common in Noonan syndrome patients at the start of therapy. BMI is not affected by GH treatment, but favorable changes in fat mass and body composition are achievable. Longer-term studies and observational studies suggest a waning of the effect of GH therapy over time, as is seen in other GH-treated conditions, and early initiation of therapy and prepubertal status are important predictors of response. GH treatment does not appear to be associated with adverse cardiac or metabolic effects, and data on malignancy during GH treatment give no cause for concern, although they are limited. PMID- 25503995 TI - Negligible immunogenicity of induced pluripotent stem cells derived from human skin fibroblasts. AB - Human induced pluripotent stem cells (hiPSCs) have potential applications in cell replacement therapy and regenerative medicine. However, limited information is available regarding the immunologic features of iPSCs. In this study, expression of MHC and T cell co-stimulatory molecules in hiPSCs, and the effects on activation, proliferation and cytokine production in allogeneic human peripheral blood mononuclear cells were examined. We found that no-integrate hiPSCs had no MHC-II and T cell co-stimulatory molecules expressions but had moderate level of MHC-I and HLA-G expressions. In contrast to human skin fibroblasts (HSFs) which significantly induced allogeneic T cell activation and proliferation, hiPSCs failed to induce allogeneic CD45+ lymphocyte and CD8+ T cell activation and proliferation but could induce a low level of allogeneic CD4+ T cell proliferation. Unlike HSFs which induced allogeneic lymphocytes to produce high levels of IFN-gamma, TNF-alpha and IL-17, hiPSCs only induced allogeneic lymphocytes to produce IL-2 and IL-10, and promote IL-10-secreting regulatory T cell (Treg) generation. Our study suggests that the integration-free hiPSCs had low or negligible immunogenicity, which may result from their induction of IL-10 secreting Treg. PMID- 25503996 TI - Calculation and visualization of atomistic mechanical stresses in nanomaterials and biomolecules. AB - Many biomolecules have machine-like functions, and accordingly are discussed in terms of mechanical properties like force and motion. However, the concept of stress, a mechanical property that is of fundamental importance in the study of macroscopic mechanics, is not commonly applied in the biomolecular context. We anticipate that microscopical stress analyses of biomolecules and nanomaterials will provide useful mechanistic insights and help guide molecular design. To enable such applications, we have developed Calculator of Atomistic Mechanical Stress (CAMS), an open-source software package for computing atomic resolution stresses from molecular dynamics (MD) simulations. The software also enables decomposition of stress into contributions from bonded, nonbonded and Generalized Born potential terms. CAMS reads GROMACS topology and trajectory files, which are easily generated from AMBER files as well; and time-varying stresses may be animated and visualized in the VMD viewer. Here, we review relevant theory and present illustrative applications. PMID- 25503997 TI - Beyond broken spines-what the radiologist needs to know about late complications of spinal cord injury. AB - OBJECTIVE: To describe expected imaging findings to assist the emergency room radiologist with recognising complications and pathology unique to the spinal cord injury (SCI) patient population to ensure rapid and accurate diagnosis. METHODS: Pictorial review. RESULTS: We review several imaging findings common to persons with chronic SCI, emphasising imaging in the emergency setting and on CT. CONCLUSION: SCI patients present a unique diagnostic challenge, as they may present with symptoms that are difficult to localise because of abnormal sensation and autonomic instability. Imaging plays an important role in the emergent setting, rapidly differentiating the most commonly encountered complications from less common, unanticipated complications. Radiologists need to be attuned to both the expected findings and potential complications, which may be unique to SCI patients, to ensure accurate diagnosis and treatment in the emergency setting. MAIN MESSAGES: * Medical complications after spinal cord injury are common and associated with significant morbidity. * Radiologists should be aware of complications unique to the SCI population to aid diagnosis. * Due to abnormal sensation, SCI patients often present with symptoms that are difficult to localise. * In the ED, imaging helps to rapidly differentiate common complications from less anticipated ones. PMID- 25503999 TI - Cyclopeptides containing the DEKS motif as conformationally restricted collagen telopeptide analogues: synthesis and conformational analysis. AB - The collagen telopeptides play an important role for lysyl oxidase-mediated crosslinking, a process which is deregulated during tumour progression. The DEKS motif which is located within the N-terminal telopeptide of the alpha1 chain of type I collagen has been suggested to adopt a betaI-turn conformation upon docking to its triple-helical receptor domain, which seems to be critical for lysyl oxidase-catalysed deamination and subsequent crosslinking by Schiff-base formation. Herein, the design and synthesis of cyclic peptides which constrain the DEKS sequence in a beta-turn conformation will be described. Lysine-side chain attachment to 2-chlorotrityl chloride-modified polystyrene resin followed by microwave-assisted solid-phase peptide synthesis and on-resin cyclisation allowed for an efficient access to head-to-tail cyclised DEKS-derived cyclic penta- and hexapeptides. An N(epsilon)-(4-fluorobenzoyl)lysine residue was included in the cyclopeptides to allow their potential radiolabelling with fluorine-18 for PET imaging of lysyl oxidase. Conformational analysis by (1)H NMR and chiroptical (electronic and vibrational CD) spectroscopy together with MD simulations demonstrated that the concomitant incorporation of a D-proline and an additional lysine for potential radiolabel attachment accounts for a reliable induction of the desired betaI-turn structure in the DEKS motif in both DMSO and water as solvents. The stabilised conformation of the cyclohexapeptide is further reflected by its resistance to trypsin-mediated degradation. In addition, the deaminated analogue containing allysine in place of lysine has been synthesised via the corresponding epsilon-hydroxynorleucine containing cyclohexapeptide. Both epsilon-hydroxynorleucine and allysine containing cyclic hexapeptides have been subjected to conformational analysis in the same manner as the lysine-based parent structure. Thus, both a conformationally restricted lysyl oxidase substrate and product have been synthetically accessed, which will enable their potential use for molecular imaging of these important enzymes. PMID- 25503998 TI - Adventitial gene transfer of catalase attenuates angiotensin II-induced vascular remodeling. AB - Vascular adventitia and adventitia-derived reactive oxygen species (ROS) contribute to vascular remodeling following vascular injury. A previous ex vivo study in adventitial fibroblasts showed that catalase, one of most important anti oxide enzymes, was downregulated by angiotensin II (AngII). The aim of the present study was to investigate whether adventitial gene transfer of catalase affects AngII-induced vascular remodeling in vivo. Adenoviruses co-expressing catalase and enhanced green fluorescent protein (eGFP) or expressing eGFP only were applied to the adventitial surface of common carotid arteries of Sprague Dawley rats. Alzet minipumps administering AngII (0.75 mg/kg/day) were then implanted subcutaneously for 14 days. Systolic blood pressure and biological parameters of vascular remodeling were measured in each group. Adventitial fibroblasts were cultured and p38 mitogen-activated protein kinase (MAPK) phosphorylation was measured using western blot analysis. The results showed that adventitial gene transfer of catalase had no effect on AngII-induced systolic blood pressure elevation. However, catalase adenovirus transfection significantly inhibited AngII-induced media hypertrophy compared with that of the control virus (P<0.05). In addition, catalase transfection significantly attenuated AngII induced ROS generation, macrophage infiltration, collagen deposition and adventitial alpha-smooth muscle actin expression. Furthermore, catalase transfection significantly inhibited the AngII-induced increase in p38MAPK phosphorylation. In conclusion, the results of the present study demonstrated that adventitial gene transfer of catalase significantly attenuated AngII-induced vascular remodeling in rats via inhibition of adventitial p38MAPK phosphorylation. PMID- 25504000 TI - Cerebellum and personality traits. AB - Personality traits are multidimensional traits comprising cognitive, emotional, and behavioral characteristics, and a wide array of cerebral structures mediate individual variability. Differences in personality traits covary with brain morphometry in specific brain regions. A cerebellar role in emotional and affective processing and on personality characteristics has been suggested. In a large sample of healthy subjects of both sexes and differently aged, the macro- and micro-structural variations of the cerebellum were correlated with the scores obtained in the Temperament and Character Inventory (TCI) by Cloninger. Cerebellar volumes were associated positively with Novelty Seeking scores and negatively with Harm Avoidance scores. Given the cerebellar contribution in personality traits and emotional processing, we investigated the cerebellar involvement even in alexithymia, construct of personality characterized by impairment in cognitive, emotional, and affective processing. Interestingly, the subjects with high alexithymic traits had larger volumes in the bilateral Crus 1. The cerebellar substrate for some personality dimensions extends the relationship between personality and brain areas to a structure up to now thought to be involved mainly in motor and cognitive functions, much less in emotional processes and even less in personality individual differences. The enlarged volumes of Crus 1 in novelty seekers and alexithymics support the tendency to action featuring both personality constructs. In fact, Novelty Seeking and alexithymia are rooted in behavior and inescapably have a strong action component, resulting in stronger responses in the structures more focused on action and embodiment, as the cerebellum is. PMID- 25504001 TI - Cerebellar cysts in children: a pattern recognition approach. AB - Cerebellar cysts may be seen in selected genetic disorders and acquired anomalies. Here, we review our experience, excluding cystic tumors and parasitic cysts. The pathogenesis is heterogeneous: Cysts may involve/represent normal structures (e.g., Virchow-Robin spaces), be "destructive" (such as in some types of pontocerebellar hypoplasias), "malformative" (such as in some forms of congenital muscular dystrophies and GPR56-related migration disorders), or "disruptive" (such as in some cerebellar dysplasias). The provided checklist may be useful in deciding targeted diagnostic workup. PMID- 25504002 TI - A Randomised Controlled Trial to Evaluate the Effectiveness of Intrathecal Bupivacaine Combined with Different Adjuvants (Fentanyl, Clonidine and Dexmedetomidine) in Caesarean Section. AB - PURPOSE: The purpose of this study was to evaluate comparatively, in women undergoing caesarean section under spinal anesthesia, the effectiveness of hyperbaric bupivacaine combined with 3 different adjuvants (fentanyl, clonidine, and dexmedtomidine) on quality of blockade and maternal and neonatal repercussions. METHOD: 84 patients undergoing elective surgeries under spinal anesthesia were randomized into 4 groups of 21 each, gB, gBF, gBC and gBD. Patients in groups gb, gBF, gBC and gBD were given bupivacaine alone, bupivacaine plus fentanyl (15.0 ug), bupivacaine plus fentanyl plus clonidine (75 ug), and bupivacaine plus dexmedetomidine (10 ug), respectively. Hemodynamic parameters evaluated were the onset and level of sensory block, perioperative analgesia, degree and recovery time of motor block, duration of analgesia, sedation, and maternal-foetal repercussions. RESULTS: The onset of blockade was significantly faster in groups with adjuvants clonidine and dexmedetomidine compared with gB and gBF. Patients in Groups gB and gBF reported pain during the perioperative period. Duration of analgesia was significantly higher in Group gBD and was comparable to gBC and time to motor block recovery was significantly higher in Group gBD. Sedation was significant in Group gBD and gBC. CONCLUSION: Addition of dexmedetomidine and clonidine as adjuvants to hyperbaric bupivacaine provided adequate anesthesia and postoperative analgesia compared to fentanyl adjuvant without causing any significant side effects. PMID- 25504003 TI - In-vitro Activity of Honey and Topical Silver in Wound Care Management. AB - BACKGROUND: With the rise of multidrug resistance among pathogens, especially in wound care management is of great concern. Hence, we designed to study the in vitro activity of topical agents honey and silver against wound infection and compares silver and honey dressings used in wound care. METHODS: 172 isolates from burn and surgical wounds were isolated from patients admitted to Nursing College, Changchun University Of Chinese Medicine, China during 2013-2014 are included in the study. 59 Pseudomonas, 41 E.coli, 28 S aureus, 25 Klebsiella pneumoniae, 11 Proteus, 8 Acinetobacter were isolated. Susceptibility testing for honey and silver nitrate was done using the agar dilution method. 80 patients were divided into 2 groups. Type 1 used Algivon with UMF12 honey coated dressing for 40 patients and the other 40 patients received Type II used Acti-coat silver absorbent dressings. 30 patients received ordinary dressings were included as control group patients. RESULTS: 50/59 (84.7%) Pseudomonas spp, 39 (95.1%) of E.coli and 26/28 (92.9%) S. aureus were sensitive for silver nitrate. K. pneumoniae, Proteus spp and Acinetobacter spp showed 100% sensitivity for silver nitrate by agar dilution method. All the isolates showed 100% sensitivity for honey at concentration. In type I - honey coated dressings consist of 40 patients with 18 (45%) male and 22 (55%) female patients. Type II - silver-coated dressings consist of 40 patients with 24 (60%) females and 16 (40%) male patients. CONCLUSION: This study results showed positive efforts on improvising in wound dressings as a replacement to lower antimicrobial resistance and limit racial use of antibiotics. PMID- 25504004 TI - Tumor recurrence and drug resistance properties of side population cells in high grade ovary cancer. AB - INTRODUCTION: The presence of subset of cancer stem cells (CSCs) called "Side population" (SP) cells has been identified in several solid tumors, responsible for treatment failure especially chemotherapy, and cancer relapse. The present study was aimed to isolate and characterize cancer stem like cells side population cells from high grade ovarian cancer. METHODS: The collected cancer samples were analyzed for presence of SP cells by FACS using Hoechst 33342 exclusion technique. Further the FACS sorted SP and non-SP cells were subjected to analysis of stem cell surface protein expression by western blot and immunocytochemistry, drug resistance and sphere formation assay. RESULTS: By FACS, we have identified 3.7% of cancer stem cell like side population cells in ovarian cancer whose prevalence was reduced to 0.5% upon treatment with verapamil an inhibitor of ABC transporter. Further, these sorted SP cells showed over expression of ABCG2 (ABC transporter), stem cell proteins such as CD144, CD44, EpCAM and antiapoptotic factor Bcl-2. Also the SP cells showed high resistance to chemotherapy drugs, have high survival rate and they are highly potential to form tumor spheres. CONCLUSION: Our data suggest that ovarian cancer contain small sub population of side population cells which shares some characteristics of stem cells. The co-expression of ABC transporters and stem cells surface markers in SP cells may associate with resistance to chemotherapeutic agents, apoptosis and also supports a role for these cells in tumor recurrence, metastasis and invasion. PMID- 25504005 TI - Peroxisome proliferator-activated receptor-gamma agonists for Alzheimer's disease and amnestic mild cognitive impairment: a systematic review and meta-analysis. AB - BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, and close associations between AD and diabetes have been found. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, as newly developed oral hypoglycaemic agents, were evaluated as a possible therapy for AD. AIM: We systematically evaluated the efficacy and safety of PPAR-gamma agonists in the treatment of AD and amnestic mild cognitive impairment (aMCI), the prodromal stage of AD. METHODS: A search of the electronic databases PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure (until July 2014) was conducted, and included randomized controlled trials. Dichotomous data were expressed as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous data were expressed as mean differences (MD) with 95% CIs. The results were pooled using a random-effects model. RESULTS: Nine eligible studies were identified, with 4,327 participants. Using the Alzheimer's Disease Assessment Scale-Cognitive subscale, pioglitazone was found to be efficacious, especially for patients with comorbid diabetes (MD -3.47, 95% CI 4.40 to -2.54). Rosiglitazone was not efficacious, even for apolipoprotein E (APOE) epsilon4 non-carriers (MD -0.31, 95% CI -1.12 to 0.51). There was no increase in any adverse events (AEs) or serious AEs compared with placebo. Peripheral edema was the most frequent AE related to PPAR-gamma agonist treatment (RR 4.14, 95% CI 2.37-7.23). CONCLUSIONS: There is insufficient evidence to support the use of rosiglitazone in aMCI and AD patients in order to improve cognitive performance. Nonetheless, the efficacy of pioglitazone seems to be promising, particularly for patients with comorbid diabetes, however this needs to be further confirmed by well-designed trials with large sample sizes. PPAR gamma agonists such as rosiglitazone and pioglitazone are generally well tolerated in AD and aMCI patients. PMID- 25504006 TI - Genetic diversity of swine influenza viruses in Thai swine farms, 2011-2014. AB - The pig is known as a "mixing vessel" for influenza A viruses. The co-circulation of multiple influenza A subtypes in pig populations can lead to novel reassortant strains. For this study, swine influenza surveillance was conducted from September 2011 to February 2014 on 46 swine farms in Thailand. In total, 78 swine influenza viruses were isolated from 2,821 nasal swabs, and 12 were selected for characterization by whole genome sequencing. Our results showed that the co circulation of swine influenza subtypes H1N1, H3N2, and H1N2 in Thai swine farms was observable throughout the 3 years of surveillance. Furthermore, we repeatedly found reassortant viruses between endemic swine influenza viruses and pandemic H1N1 2009. This observation suggests that there is significant and rapid evolution of swine influenza viruses in swine. Thus, continuous surveillance is critical for monitoring novel reassortant influenza A viruses in Thai swine populations. PMID- 25504007 TI - Subjective memory impairment and cholinergic transmission: a TMS study. AB - Subjective memory impairment (SMI) is being increasingly recognized as a preclinical phase of Alzheimer disease (AD). Short latency afferent inhibition (SAI) is helpful in demonstrating dysfunction of central cholinergic circuits, and was reported to be abnormal in patients with AD and amnestic multiple domain mild cognitive impairment. In this study, we found normal SAI in 20 subjects with SMI. SAI could be a useful biomarker for identifying, among individuals with memory complaints, those in whom cholinergic degeneration has occurred. PMID- 25504009 TI - Role of QuantiFERON-TB Gold antigen-specific IL-1beta in diagnosis of active tuberculosis. AB - The main objective of the study was to evaluate whether in vitro QuantiFERON-TB Gold In-Tube (QFT-GIT) assay antigen-specific IL-1beta, TNF-alpha, IL-2, IL-6, IL 8 and IL-12 (p40) production is associated with active TB. In a cohort of 77 pulmonary TB patients (PTB), 67 healthy household contacts (HHC) and 83 healthy control subjects (HCS), the antigen-specific cytokines levels were determined in supernatants generated from QFT-GIT tubes. Antigen-specific IL-1beta levels were significantly higher in PTB than HHC and HCS. At a fixed cutoff point (1,108 pg/ml), IL-1beta showed positivity of 62.33% in PTB, 22.38% in HHC and 22.89% in HCS. Moreover, antigen-specific IL-1beta assay can differentiate PTB and HHC (believed to be latently infected) (p < 0.0001). Like IL-1beta, significantly higher levels of antigen-specific TNF-alpha were associated with PTB and displayed 43.63% positivity in PTB. The antigen-specific IL-2 levels were associated both with PTB (54.54%) and HHC (48.14%). Other cytokines levels did not differ among the groups. Our results suggest that antigen-specific IL-1beta can be used as a biomarker for active TB diagnosis as well as for differential diagnosis of PTB and LTBI. PMID- 25504010 TI - G31P, CXCR1/2 inhibitor, with cisplatin inhibits the growth of mice hepatocellular carcinoma and mitigates high-dose cisplatin-induced nephrotoxicity. AB - Cisplatin (DDP), a cytotoxic antitumor drug, functions in a dose-dependent manner. However, the pursuit for high-dose therapeutic effects leads to more serious side effects including kidney toxicity. Nephrotoxicity caused due to endothelial cell dysfunction and neutrophils infiltration in kidneys. Interleukin 8 (IL-8) is an ELR+ chemokine binds with CXCR1/2 receptors and its role is primarily in neutrophils recruitment and also involved in invasion, angiogenesis and metastasis of different solid tumors including liver cancer. G31P, a CXCR1/2 antagonist, binds with CXCR1/2 with high affinity, and acts as an anti inflammatory and antitumor agent. In the present study, we examined the antitumor effects of G31P and DDP on mouse liver cancer cells, and the effects exerted by G31P on cisplatin-induced renal injury. In vitro, effects of the G31P and DDP regimen on H22 cell proliferation were investigated by MTT assay. In vivo BALB/c mice were inoculated subcutaneously with 1x106 H22 cells and treated after one week with a high single dose of DDP with and without G31P on alternative days until the experiment was terminated. On the 15th day the mice were sacrificed, dissected and kidney tissues were analyzed using H&E staining. Myeloperoxidase (MPO) activity was assessed and RT-PCR was performed to detect inflammatory cytokines. Solid tumors were weighed for tumor growth and performed pathological examination, immunohistochemistry and western blotting were performed to detect tissue-related protein expressions in tumor tissue. The tumor inhibitory rate of DDP, G31P and DDP+G31P groups was 38.40, 40.74 and 74.80%, respectively, and the general state of mice in the DDP+G31P group was significantly improved as compared to the DDP group. The results indicated that G31P with DDP significantly inhibited the proliferation while the growth of H22 cell carnimona in vitro and in vivo enhanced the efficacy of cisplatin in cancer treatment with reduced side effects on acute renal failure. PMID- 25504008 TI - Aripiprazole increases NAD(P)H-quinone oxidoreductase-1 and heme oxygenase-1 in PC12 cells. AB - We previously showed that aripiprazole increases intracellular NADPH and glucose 6-phosphate dehydrogenase mRNA in PC12 cells. Aripiprazole presumably activates a system that concurrently detoxifies reactive oxygen species and replenishes NADPH. Nrf2, a master transcriptional regulator of redox homeostasis genes, also activates the pentose phosphate pathway, including NADPH production. Therefore, our aim was to determine whether aripiprazole activates Nrf2 in PC12 cells. Aripiprazole increased mRNA expression of Nrf2-dependent genes (NAD(P)H-quinone oxidoreductase-1, Nqo1; heme oxygenase-1, HO1; and glutamate-cysteine ligase catalytic subunit) and protein expression of Nqo1 and HO1 in these cells (p < 0.05). To maintain increased Nrf2 activity, it is necessary to inhibit Nrf2 degradation; this is done by causing Nrf2 to dissociate from Keap1 or beta-TrCP. However, in aripiprazole-treated cells, the relative amount of Nrf2 anchored to Keap1 or beta-TrCP was unaffected and Nrf2 in the nuclear fraction decreased (p < 0.05). Aripiprazole did not affect phosphorylation of Nrf2 at Ser40 and decreased the relative amount of acetylated Nrf2 (p < 0.05). The increase in Nqo1 and HO1 in aripiprazole-treated cells cannot be explained by the canonical Nrf2-degrading pathways. Further experiments are needed to determine the biochemical mechanisms underlying the aripiprazole-induced increase in these enzymes. PMID- 25504011 TI - Molecular characterisation of group IVA (cytosolic) phospholipase A2 in murine osteoblastic MC3T3-E1 cells. AB - Formation of the powerful osteogenic prostaglandin E2 by osteoblasts, a key modulatory event in the paracrine and autocrine regulation of bone cell activity, is preceded by release of the precursor arachidonic acid from phospholipid stores. The main routes of arachidonate liberation may involve phospholipase enzymes such as group IVA phospholipase A2 which is believed to be the main effector in many cell system due to its preference for arachidonate-containing lipids. MC3T3-E1 cells are non-transformed osteoblasts and are widely used as an in vitro model of osteoblast function. In these cells there is still no clarity about the main release pathway of arachidonic acid. Besides cytosolic phospholipase A2, phospholipase C and D pathways may play a key role in arachidonate release. Despite the crucial role of osteoblastic prostgalandin synthesis information on the occurrence of involved enzymes at the molecular level is scarse in MC3T3-E1 cells. We have characterised group IVA phospholipase A2 at the mRNA in these cells as a constitutively expressed enzyme which is cytosolic and translocates to the membrane upon endothelin-1 stimulation. Using immunopurification combined with Western blotting and high-resolution mass spectrometry, the enzyme was also identified at the protein level. Using specific gene silencing we were able to show that osteoblastic cytosolic phospholipase A2 is crucially involved in ET-1-induced prostaglandin formation. PMID- 25504012 TI - Two-week normobaric intermittent-hypoxic exposures stabilize cerebral perfusion during hypocapnia and hypercapnia. AB - The effect of moderately extended, intermittent-hypoxia (IH) on cerebral perfusion during changes in CO2 was unknown. Thus, we assessed the changes in cerebral vascular conductance (CVC) and cerebral tissue oxygenation (ScO2) during experimental hypocapnia and hypercapnia following 14-day normobaric exposures to IH (10% O2). CVC was estimated from the ratio of mean middle cerebral arterial blood flow velocity (transcranial Doppler sonography) to mean arterial pressure (tonometry), and ScO2 in the prefrontal cortex was monitored by near-infrared spectroscopy. Changes in CVC and ScO2 during changes in partial pressure of end tidal CO2 (PETCO2, mass spectrometry) induced by 30-s paced-hyperventilation (hypocapnia) and during 6-min CO2 rebreathing (hypercapnia) were compared before and after 14-day IH exposures in eight young nonsmokers. Repetitive IH exposures reduced the ratio of %DeltaCVC/DeltaPETCO2 during hypocapnia (1.00 +/- 0.13 vs 1.94 +/- 0.35 vs %/mmHg, P = 0.026) and the slope of DeltaCVC/DeltaPETCO2 during hypercapnia (1.79 +/- 0.37 vs 2.97 +/- 0.64 %/mmHg, P = 0.021), but had no significant effect on DeltaScO2/DeltaPETCO2. The ventilatory response to hypercapnia during CO2 rebreathing was significantly diminished following 14-day IH exposures (0.83 +/- 0.07 vs 1.14 +/- 0.09 L/min/mmHg, P = 0.009). We conclude that repetitive normobaric IH exposures significantly diminish variations of cerebral perfusion in response to hypercapnia and hypocapnia without compromising cerebral tissue oxygenation. This IH-induced blunting of cerebral vasoreactivity during CO2 variations helps buffer excessive oscillations of cerebral underperfusion and overperfusion while sustaining cerebral O2 homeostasis. PMID- 25504013 TI - Protective phenotypes of club cells and alveolar macrophages are favored as part of endotoxin-mediated prevention of asthma. AB - Atopic asthma is a chronic allergic disease that involves T-helper type 2 (Th2) inflammation and airway remodeling. Bronchiolar club cells (CC) and alveolar macrophages (AM) are sentinel cells of airway barrier against inhaled injuries, where allergy induces mucous metaplasia of CC and the alternative activation of AM, which compromise host defense mechanisms and amplify Th2-inflammation. As there is evidence that high levels of environmental endotoxin modulates asthma, the goal of this study was to evaluate if the activation of local host defenses by Lipopolysaccharide (LPS) previous to allergy development can contribute to preserving CC and AM protective phenotypes. Endotoxin stimulus before allergen exposition reduced hallmarks of allergic inflammation including eosinophil influx, Interleukin-4 and airway hyperreactivity, while the T-helper type 1 related cytokines IL-12 and Interferon-gamma were enhanced. This response was accompanied by the preservation of the normal CC phenotype and the anti-allergic proteins Club Cell Secretory Protein (CCSP) and Surfactant-D, thereby leading to lower levels of CC metaplasia and preventing the increase of the pro-Th2 cytokine Thymic stromal lymphopoietin. In addition, classically activated alveolar macrophages expressing nitric oxide were promoted over the alternatively activated ones that expressed arginase-1. We verified that LPS induced a long term overexpression of CCSP and the innate immune markers Toll-like receptor 4, and Tumor Necrosis Factor-alpha, changes that were preserved in spite of the allergen challenge. These results demonstrate that LPS pre-exposition modifies the local bronchioalveolar microenvironment by inducing natural anti-allergic mechanisms while reducing local factors that drive Th2 type responses, thus modulating allergic inflammation. PMID- 25504015 TI - Coffee consumption and risk of lung cancer: the ICARE study. PMID- 25504014 TI - Protection of HepG2 cells against acrolein toxicity by 2-cyano-3,12-dioxooleana 1,9-dien-28-imidazolide via glutathione-mediated mechanism. AB - Acrolein is an environmental toxicant, mainly found in smoke released from incomplete combustion of organic matter. Several studies showed that exposure to acrolein can lead to liver damage. The mechanisms involved in acrolein-induced hepatocellular toxicity, however, are not completely understood. This study examined the cytotoxic mechanisms of acrolein on HepG2 cells. Acrolein at pathophysiological concentrations was shown to cause apoptotic cell death and an increase in levels of protein carbonyl and thiobarbituric acid reactive acid substances. Acrolein also rapidly depleted intracellular glutathione (GSH), GSH linked glutathione-S-transferases, and aldose reductase, three critical cellular defenses that detoxify reactive aldehydes. Results further showed that depletion of cellular GSH by acrolein preceded the loss of cell viability. To further determine the role of cellular GSH in acrolein-mediated cytotoxicity, buthionine sulfoximine (BSO) was used to inhibit cellular GSH biosynthesis. It was observed that depletion of cellular GSH by BSO led to a marked potentiation of acrolein mediated cytotoxicity in HepG2 cells. To further assess the contribution of these events to acrolein-induced cytotoxicity, triterpenoid compound 2-cyano-3,12 dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) was used for induction of GSH. Induction of GSH by CDDO-Im afforded cytoprotection against acrolein toxicity in HepG2 cells. Furthermore, BSO significantly inhibited CDDO-Im-mediated induction in cellular GSH levels and also reversed cytoprotective effects of CDDO-Im in HepG2 cells. These results suggest that GSH is a predominant mechanism underlying acrolein-induced cytotoxicity as well as CDDO-Im-mediated cytoprotection. This study may provide understanding on the molecular action of acrolein which may be important to develop novel strategies for the prevention of acrolein-mediated toxicity. PMID- 25504016 TI - The Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES) project--design, population and data harmonization of a large scale, international study. AB - There is a public health demand to prevent health conditions which lead to increased morbidity and mortality among the rapidly-increasing elderly population. Data for the incidence of such conditions exist in cohort studies worldwide, which, however, differ in various aspects. The Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES) project aims at harmonizing data from existing major longitudinal studies for the elderly whilst focussing on cardiovascular diseases, diabetes mellitus, cancer, fractures and cognitive impairment in order to estimate their prevalence, incidence and cause-specific mortality, and identify lifestyle, socioeconomic, and genetic determinants and biomarkers for the incidence of and mortality from these conditions. A survey instrument assessing ageing-related conditions of the elderly will be also developed. Fourteen cohort studies participate in CHANCES with 683,228 elderly (and 150,210 deaths), from 23 European and three non European countries. So far, 287 variables on health conditions and a variety of exposures, including biomarkers and genetic data have been harmonized. Different research hypotheses are investigated with meta-analyses. The results which will be produced can help international organizations, governments and policy-makers to better understand the broader implications and consequences of ageing and thus make informed decisions. PMID- 25504017 TI - The Brighton declaration: the value of non-communicable disease modelling in population health sciences. PMID- 25504018 TI - Cerebral ischemia or intrauterine inflammation promotes differentiation of oligodendroglial precursors in preterm ovine fetuses: possible cellular basis for white matter injury. AB - White matter injury in premature infants is known to be major cause of long-term neurocognitive disability, but the pathogenic mechanism remains unclear, hampering our ability to develop preventions. Periventricular leukomalacia is a severe form of white matter injury. In the present study, we explored the effects of cerebral ischemia and/or intrauterine inflammation on the development of oligodendroglia in the cerebral white matter using chronically instrumented fetal sheep. Each fetus received one of three insults: hemorrhage, inflammation and their combination. In the hemorrhage group, 40% of the fetoplacental blood volume was acutely withdrawn, and 24 hours after removal, the blood was returned to the fetus. The inflammation group received intravenous granulocyte-colony stimulating factor and intra-amniotic endotoxin and thus suffered from necrotizing funisitis and chorioamnionitis. The inflammatory hemorrhage group underwent acute hemorrhage under the inflammatory state. The sham group received no insults. Importantly, periventricular leukomalacia was not detected in the sham and the inflammation groups. Differentiating oligodendroglia at various developmental stages were identified by immunohistochemical analysis with specific antibodies. No difference in the density of oligodendroglial progenitors was detected among the four groups, whereas oligodendroglial precursors were significantly reduced in the three insult groups, compared to sham control. Moreover, the density of immature oligodendroglia was higher in the inflammation group and the inflammatory hemorrhage group, while the density of mature oligodendroglia was highest in the hemorrhage group. We propose that cerebral ischemia or intrauterine inflammation induces the differentiation of oligodendroglial precursors in preterm fetuses, eventually resulting in their exhaustion. PMID- 25504019 TI - A fatal case of infantile malignant osteopetrosis complicated by pulmonary arterial hypertension after hematopoietic stem cell transplantation. AB - Infantile malignant osteopetrosis (IMO) is a rare and fatal autosomal recessive condition characterized by a generalized increased in bone density. Hematopoietic stem cell transplantation (HSCT) is the only effective and rational therapy with achieving long-term disease-free survival. However, complications with HSCT for IMO remain unclear. Here we describe a male infant with IMO, carrying two novel mutations in the T-cell immune regulator 1 (TCIRG1) gene. The TCIRG1 gene encodes the a3 subunit of vacuolar H(+)-ATPase that plays an essential role in the resorptive function of osteoclasts. Direct sequencing of all 20 exons of the TCIRG1 gene revealed a single nucleotide change in exon 11 (c1305 G > T), which causes the substitution of Asp (GAT) for Glu (GAG) at position 435, and a two nucleotide deletion in exon 16 (c1952-1953 del CA), causing a frame-shift mutation. However, the functional consequence of each mutation remains to be determined. Allogeneic HSCT was performed in the patient at the age of nine months. Donor engraftment was achieved, and abnormal bone metabolism and extramedullary hematopoiesis were corrected. Graft-versus-host disease was mild (grade I). However, the patient died of complication of pulmonary arterial hypertension at seven months after the HSCT. Postmortem examination revealed prominent vascular wall thickening of the pulmonary artery and macrophage infiltration to alveoli. It should be noted that a patient with IMO has a risk for pulmonary arterial hypertension, and the evaluation of pulmonary arterial flow should be included in the assessment of each patient with IMO even after HSCT. PMID- 25504020 TI - Intradialytic exercise in hemodialysis patients: a systematic review and meta analysis. AB - BACKGROUND AND OBJECTIVE: Hemodialysis (HD) patients are more inactive, leading to poor functional capacity and quality of life; this may be reversed with intradialytic exercise training. To systematically evaluate the efficacy and safety of intradialytic exercise for HD patients, we conducted a meta-analysis of the published randomized controlled trials. DATA SOURCES AND METHODS: Medline, Embase, and Cochrane Central Register of Controlled Trials were systematically searched up to February, 2014. The reference lists of eligible studies and relevant reviews were also checked. RESULTS: 24 studies of 997 patients were included. Compared with control, intradialytic exercise significantly improve Kt/V (SMD = 0.27, 95% CI 0.01-0.53), peak oxygen consumption (VO(2peak)) (SMD = 0.53, 95% CI 0.30-0.76), and physical performance of physical function of life (SMD = 0.30, 95% CI 0.04-0.55). However, no significant improvements were found in the mental function of life. There was no significant difference with respect to musculoskeletal and cardiovascular complications between the intradialytic exercise groups and control groups. Further subgroup analysis found that, when the trial duration was more than 6 months, the intervention had significant effects on VO(2peak) (SMD = 0.89, 95% CI 0.56-1.22). However, when the trial duration was less than 6 months, the change of VO(2peak) was not significant (SMD = 0.19, 95% CI -0.13 to 0.51). CONCLUSION: Intradialytic exercise can improve Kt/V, VO(2peak), and the physical quality of life, and intradialytic exercise is safe for HD patients. Therefore, we put forward the suggestion that clinical guideline be updated to inform clinicians on the benefits of intradialytic exercise on HD patients. PMID- 25504022 TI - FDG PET/CT diagnostic criteria may need adjustment based on MRI to estimate the presurgical risk of extrapelvic infiltration in patients with uterine endometrial cancer. AB - PURPOSE: The staging of endometrial cancer requires surgery which carries the risk of morbidity. FDG PET/CT combined with anatomical imaging may reduce the number of unnecessary lymphadenectomies by demonstrating the risk of extrapelvic infiltration. The purpose of this study was to optimize FDG PET/CT diagnostic criteria for risk assessment in endometrial cancer after first-line risk triage with MRI. METHODS: The study population comprised 37 patients who underwent curative surgery for the treatment of endometrial cancer. First, the risk of extrapelvic infiltration was triaged using MRI. Second, multiple glucose metabolic profiles of the primary lesion were assessed with FDG PET/CT, and these were correlated with the histopathological risk of extrapelvic infiltration including lymphovascular space invasion (LVSI) and high-grade malignancy (grades 2 and 3). The results of histological correlation were used to adjust FDG PET/CT diagnostic criteria. RESULTS: Presurgical assessment using MRI was positive for deep (>50 %) myometrial invasion in 17 patients. The optimal FDG PET/CT diagnostic criteria vary depending on the results of MRI. Specifically, SUVmax (>=16.0) was used to indicate LVSI risk with an overall diagnostic accuracy of 88.2 % in patients with MRI findings showing myometrial invasion. High-grade malignancy did not correlate with any of metabolic profiles in this patient group. In the remaining patients without myometrial invasion, lesion glycolysis (LG) or metabolic volume were better indicators of LVSI than SUVmax with the same diagnostic accuracy of 80.0 %. In addition, LG (>=26.9) predicted high-grade malignancy with an accuracy of 72.2 %. Using the optimized cut-off criteria for LVSI, glucose metabolic profiling of primary lesions correctly predicted lymph node metastasis with an accuracy of 73.0 %, which was comparable with the accuracy of visual assessment for lymph node metastasis using MRI and FDG PET/CT. CONCLUSION: FDG PET/CT diagnostic criteria may need adjustment based on the anatomical information provided by MRI. The optimized criteria can predict the risk of pathology-proven LVSI correctly in 83.8 % of patients before surgery, and thus would improve presurgical treatment planning. PMID- 25504024 TI - Retrograde cannulation of an occluded lateral vein for cardiac resynchronization therapy: integrating tips and tricks from chronic coronary occlusion intervention. PMID- 25504023 TI - Transverse comparisons between ultrasound and radionuclide parameters in children with presumed antenatally detected pelvi-ureteric junction obstruction. AB - PURPOSE: The main criteria used for deciding on surgery in children with presumed antenatally detected pelviureteric junction obstruction (PPUJO) are the level of hydronephrosis (ultrasonography), the level of differential renal function (DRF) and the quality of renal drainage after a furosemide challenge (renography), the importance of each factor being far from generally agreed. Can we predict, on the basis of ultrasound parameters, the patient in whom radionuclide renography can be avoided? METHODS: We retrospectively analysed the medical charts of 81 consecutive children with presumed unilateral PPUJO detected antenatally. Ultrasound and renographic studies performed at the same time were compared. Anteroposterior pelvic diameter (APD) and calyceal size were both divided into three levels of dilatation. Parenchymal thickness was considered either normal or significantly decreased. Acquisition of renograms under furosemide stimulation provided quantification of DRF, quality of renal drainage and cortical transit. RESULTS: The percentages of patients with low DRF and poor drainage were significantly higher among those with major hydronephrosis, severe calyceal dilatation or parenchymal thinning. Moreover, impaired cortical transit, which is a major risk factor for functional decline, was seen more frequently among those with very severe calyceal dilatation. However, none of the structural parameters obtained by ultrasound examination was able to predict whether the level of renal function or the quality of drainage was normal or abnormal. Alternatively, an APD <30 mm, a calyceal dilatation of <10 mm and a normal parenchymal thickness were associated with a low probability of decreased renal function or poor renal drainage. CONCLUSION: In the management strategy of patients with prenatally detected PPUJO, nuclear medicine examinations may be postponed in those with an APD <30 mm, a calyceal dilatation of <10 mm and a normal parenchymal thickness. On the contrary, precise estimation of DRF and renal cortical transit should be performed in patients with APD >30 mm, major calyceal dilatation and/or parenchymal thinning. PMID- 25504025 TI - A systematic appraisal of field synopses in genetic epidemiology: a HuGE review. AB - Evidence from genetic association studies is accumulating rapidly. Field synopses have recently arisen as an unbiased way of systematically synthesizing this evidence. We performed a systematic review and appraisal of published field synopses in genetic epidemiology and assessed their main findings and methodological characteristics. We identified 61 eligible field synopses, published between January 1, 2007, and October 31, 2013, on 52 outcomes reporting 734 significant associations at the P < 0.05 level. The median odds ratio for these associations was 1.25 (interquartile range, 1.15-1.43). Egger's test was the most common method (n = 30 synopses) of assessing publication bias. Only 12 synopses (20%) used the Venice criteria to evaluate the epidemiologic credibility of their findings (n = 449 variants). Eleven synopses (18%) were accompanied by an online database that has been regularly updated. These synopses received more citations (P = 0.01) and needed a larger research team (P = 0.02) than synopses without an online database. Overall, field synopses are becoming a valuable tool for the identification of common genetic variants, especially when researchers follow relevant methodological guidelines. Our work provides a summary of the current status of the field synopses published to date and may help interested readers efficiently identify the online resources containing the relevant genetic evidence. PMID- 25504026 TI - Mediation analysis with intermediate confounding: structural equation modeling viewed through the causal inference lens. AB - The study of mediation has a long tradition in the social sciences and a relatively more recent one in epidemiology. The first school is linked to path analysis and structural equation models (SEMs), while the second is related mostly to methods developed within the potential outcomes approach to causal inference. By giving model-free definitions of direct and indirect effects and clear assumptions for their identification, the latter school has formalized notions intuitively developed in the former and has greatly increased the flexibility of the models involved. However, through its predominant focus on nonparametric identification, the causal inference approach to effect decomposition via natural effects is limited to settings that exclude intermediate confounders. Such confounders are naturally dealt with (albeit with the caveats of informality and modeling inflexibility) in the SEM framework. Therefore, it seems pertinent to revisit SEMs with intermediate confounders, armed with the formal definitions and (parametric) identification assumptions from causal inference. Here we investigate: 1) how identification assumptions affect the specification of SEMs, 2) whether the more restrictive SEM assumptions can be relaxed, and 3) whether existing sensitivity analyses can be extended to this setting. Data from the Avon Longitudinal Study of Parents and Children (1990 2005) are used for illustration. PMID- 25504028 TI - Is there a link between liraglutide and pancreatitis? A post hoc review of pooled and patient-level data from completed liraglutide type 2 diabetes clinical trials. AB - OBJECTIVE: To report the incidence of pancreatitis in type 2 diabetes trials of liraglutide and details of all pancreatitis cases. RESEARCH DESIGN AND METHODS: Data from Novo Nordisk-sponsored trials with liraglutide (phase 2 and 3; NN2211 identifiers) completed by 19 April 2013 were pooled. All pancreatitis cases were reviewed. RESULTS: Total exposure to liraglutide and active comparators was 5,021 and 1,354 patient-years, respectively (n = 6,345 and 1,846, respectively). Eight cases of acute pancreatitis (AP) with liraglutide and one with any comparator (glimepiride) were found. The incidence of AP was 1.6 cases/1,000 patient-years exposure (PYE) for liraglutide vs. 0.7 cases/1,000 PYE for total active comparators. One of the eight AP cases reported with liraglutide did not meet diagnostic criteria for AP. In six of these eight cases, recognized risk factors for AP were present and/or the onset of AP occurred >6 months after liraglutide initiation. All patients were receiving multiple medications. Four cases of chronic pancreatitis (CP) with liraglutide and none with comparators were found. One of these four cases fulfilled diagnostic criteria for CP; these criteria were not met or information was missing in the remaining three. CONCLUSIONS: Based on the small number of cases observed, the incidences of reported AP and CP were numerically greater with liraglutide than with comparators. Not all cases fulfilled diagnostic criteria, and confounding variables were present in 75% of the AP cases with liraglutide therapy, precluding firm conclusions. PMID- 25504027 TI - Associations of cadmium and lead exposure with leukocyte telomere length: findings from National Health and Nutrition Examination Survey, 1999-2002. AB - Cadmium and lead are ubiquitous environmental contaminants that might increase risks of cardiovascular disease and other aging-related diseases, but their relationships with leukocyte telomere length (LTL), a marker of cellular aging, are poorly understood. In experimental studies, they have been shown to induce telomere shortening, but no epidemiologic study to date has examined their associations with LTL in the general population. We examined associations of blood lead and cadmium (n = 6,796) and urine cadmium (n = 2,093) levels with LTL among a nationally representative sample of US adults from the National Health and Nutrition Examination Survey (1999-2002). The study population geometric mean concentrations were 1.67 ug/dL (95% confidence interval (CI): 1.63, 1.70) for blood lead, 0.44 ug/L (95% CI: 0.42, 0.47) for blood cadmium, and 0.28 ug/L (95% CI: 0.27, 0.30) for urine cadmium. After adjustment for potential confounders, the highest (versus lowest) quartiles of blood and urine cadmium were associated with -5.54% (95% CI: -8.70, -2.37) and -4.50% (95% CI: -8.79, -0.20) shorter LTLs, respectively, with evidence of dose-response relationship (P for trend < 0.05). There was no association between blood lead concentration and LTL. These findings provide further evidence of physiological impacts of cadmium at environmental levels and might provide insight into biological pathways underlying cadmium toxicity and chronic disease risks. PMID- 25504029 TI - The metabolic profile of intrahepatic cholestasis of pregnancy is associated with impaired glucose tolerance, dyslipidemia, and increased fetal growth. AB - OBJECTIVE: Quantification of changes in glucose and lipid concentrations in women with intrahepatic cholestasis of pregnancy (ICP) and uncomplicated pregnancy and study of their influence on fetal growth. RESEARCH DESIGN AND METHODS: A prospective study comparing metabolic outcomes in cholestastic and uncomplicated singleton pregnancies was undertaken at two university hospitals in the U.K. and U.S. from 2011-2014. A total of 26 women with ICP and 27 control pregnancies with no prior history of gestational diabetes mellitus were recruited from outpatient antenatal services and followed until delivery. Alterations in glucose, incretins, cholesterol, and triglycerides were studied using a continuous glucose monitoring (CGM) system and/or a standard glucose tolerance test (GTT) in conjunction with GLP-1 and a fasting lipid profile. Fetal growth was quantified using adjusted birth centiles. RESULTS: Maternal blood glucose concentrations were significantly increased in ICP during ambulatory CGM (P < 0.005) and following a GTT (P < 0.005). ICP is characterized by increased fasting triglycerides (P < 0.005) and reduced HDL cholesterol (P < 0.005), similar to changes observed in metabolic syndrome. The offspring of mothers with ICP had significantly larger customized birth weight centiles, adjusted for ethnicity, sex, and gestational age (P < 0.005). CONCLUSIONS: ICP is associated with impaired glucose tolerance, dyslipidemia, and increased fetal growth. These findings may have implications regarding the future health of affected offspring. PMID- 25504030 TI - PCSK7 genotype modifies effect of a weight-loss diet on 2-year changes of insulin resistance: the POUNDS LOST trial. AB - OBJECTIVE: A common variant rs236918 in the PCSK7 gene has the strongest association with iron homeostasis and is related to insulin resistance. Dietary carbohydrate (CHO) modulates the genetic effect on insulin resistance. We examined whether 2-year weight-loss diets modify the effect of PCSK7 genetic variants on changes in fasting insulin levels and insulin resistance in a randomized, controlled trial. RESEARCH DESIGN AND METHODS: Data were analyzed in the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial, which is a randomized, controlled 2-year weight-loss trial using diets that differed in macronutrient proportions. PCSK7 rs236918 was genotyped in 730 overweight or obese adults (80% whites) in this trial. We assessed the progression in fasting insulin and glucose levels, and insulin resistance by genotypes. RESULTS: During the 6-month weight-loss phase, the PCSK7 rs236918 G allele was significantly associated with greater decreases in fasting insulin levels in the high-dietary CHO group (P for interaction = 0.04), while the interaction for changes in HOMA-insulin resistance (HOMA-IR) (P for interaction = 0.06) did not reach significant levels in white subjects. The G allele was significantly associated with a greater decrease in fasting insulin levels and HOMA-IR in response to high dietary CHO levels (P = 0.02 and P = 0.03, respectively). From 6 months to 2 years (weight-regain phase), the interactions became attenuated due to the regaining of weight (P for interactions = 0.08 and 0.06, respectively). In addition, we observed similar and even stronger results in the whole-study samples from the trial. CONCLUSIONS: Our data suggest that PCSK7 genotypes may interact with dietary CHO intake on changes in insulin sensitivity in the white Americans. PMID- 25504031 TI - Multidetector CT and three-dimensional CT angiography of upper extremity arterial injury. AB - Successful management of upper extremity arterial injury requires fast and accurate diagnosis. The rate of limb preservation depends on the location, severity, and time of ischemia. Indications for diagnostic imaging depend on the mechanism and type of injury, clinical signs, cardiovascular stability, and clinical suspicion. Because of ease of access, speed, and high accuracy for this diagnosis, multidetector computed tomographic (MDCT) angiography is often used as the first line imaging modality. MDCT systems with 64 slice configuration and more afford high temporal and spatial high-resolution, isotropic data acquisition and integration with whole-body trauma MDCT protocols. The use of individual injection timing protocols ensures high diagnostic image quality. Several strategies are available to reduce radiation exposure. Direct MDCT angiography findings of arterial injuries include active extravasation, luminal narrowing, lack of luminal contrast opacification, filling defect, arteriovenous fistula, and pseudoaneurysm. Important descriptors are location and length of defect, degree of luminal narrowing, and presence of distal arterial supply reconstitution. Proximal arterial injuries include the subclavian, axillary, and brachial arteries. Distal arterial injuries include the ulnar and radial arteries, as well as the palmar arterial arches. Concomitant venous injury, musculoskeletal injury, and nerve damage are common. In this exhibit, we outline the role of MDCT angiography in the diagnosis and management of upper extremity arterial injury, discuss strategies for MDCT angiography acquisition and concepts of data visualization, and illustrate various types of injuries. PMID- 25504038 TI - Un-collimated single-photon imaging system for high-sensitivity small animal and plant imaging. AB - In preclinical single-photon emission computed tomography (SPECT) system development the primary objective has been to improve spatial resolution by using novel parallel-hole or multi-pinhole collimator geometries. However, such high resolution systems have relatively poor sensitivity (typically 0.01-0.1%). In contrast, a system that does not use collimators can achieve very high sensitivity. Here we present a high-sensitivity un-collimated detector single photon imaging (UCD-SPI) system for the imaging of both small animals and plants. This scanner consists of two thin, closely spaced, pixelated scintillator detectors that use NaI(Tl), CsI(Na), or BGO. The performance of the system has been characterized by measuring sensitivity, spatial resolution, linearity, detection limits, and uniformity. With (99m)Tc (140 keV) at the center of the field of view (20 mm scintillator separation), the sensitivity was measured to be 31.8% using the NaI(Tl) detectors and 40.2% with CsI(Na). The best spatial resolution (FWHM when the image formed as the geometric mean of the two detector heads, 20 mm scintillator separation) was 19.0 mm for NaI(Tl) and 11.9 mm for CsI(Na) at 140 keV, and 19.5 mm for BGO at 1116 keV, which is somewhat degraded compared to the cm-scale resolution obtained with only one detector head and a close source. The quantitative accuracy of the system's linearity is better than 2% with detection down to activity levels of 100 nCi. Two in vivo animal studies (a renal scan using (99m)Tc MAG-3 and a thyroid scan with (123)I) and one plant study (a (99m)TcO4(-) xylem transport study) highlight the unique capabilities of this UCD-SPI system. From the renal scan, we observe approximately a one thousand fold increase in sensitivity compared to the Siemens Inveon SPECT/CT scanner. UCD SPI is useful for many imaging tasks that do not require excellent spatial resolution, such as high-throughput screening applications, simple radiotracer uptake studies in tumor xenografts, dynamic studies where very good temporal resolution is critical, or in planta imaging of radioisotopes at low concentrations. PMID- 25504039 TI - Parental decision making in male circumcision. AB - PURPOSE: To study which healthcare professionals (HCPs) firstasked parents about their decision regarding circumcision; whether parents felt they were given enough information by their HCP; and what reasons parents cited for their decision. STUDY DESIGN AND METHODS: Bilingual questionnaires were administered to parents and expecting parents of boys (N = 60). Close-ended survey responses were analyzed through factor analysis to ascertain what types of beliefs parents used in their decision making, whether they felt they had enough information, and who first asked them about their decision. RESULTS: Nurses were most likely to be the first HCPs to ask parents about circumcision. Parental personal and cultural beliefs played an equal or more important role in influencing decision making than medical information received. However, some parents noted that there was a lack of access to accurate information regarding risks and benefits of male circumcision. CLINICAL NURSING IMPLICATIONS: Nurses continue to play a critical role in acquisition of knowledge surrounding male circumcision and serve as important liaisons between parents and the proxy consent process. Nurses, as well as other HCPs, should discuss circumcision early in pregnancy so parents have ample time to ask questions, gather information, and make an appropriate decision. PMID- 25504040 TI - Genome dynamics and evolution of Salmonella Typhi strains from the typhoid endemic zones. AB - Typhoid fever poses significant burden on healthcare systems in Southeast Asia and other endemic countries. Several epidemiological and genomic studies have attributed pseudogenisation to be the major driving force for the evolution of Salmonella Typhi although its real potential remains elusive. In the present study, we analyzed genomes of S. Typhi from different parts of Southeast Asia and Oceania, comprising of isolates from outbreak, sporadic and carrier cases. The genomes showed high genetic relatedness with limited opportunity for gene acquisition as evident from pan-genome structure. Given that pseudogenisation is an active process in S. Typhi, we further investigated core and pan-genome profiles of functional and pseudogenes separately. We observed a decline in core functional gene content and a significant increase in accessory pseudogene content. Upon functional classification, genes encoding metabolic functions formed a major constituent of pseudogenes as well as core functional gene clusters with SNPs. Further, an in-depth analysis of accessory pseudogene content revealed the existence of heterogeneous complements of functional and pseudogenes among the strains. In addition, these polymorphic genes were also enriched in metabolism related functions. Thus, the study highlights the existence of heterogeneous strains in a population with varying metabolic potential and that S. Typhi possibly resorts to metabolic fine tuning for its adaptation. PMID- 25504041 TI - The production of coagulation factor VII by adipocytes is enhanced by tumor necrosis factor-alpha or isoproterenol. AB - BACKGROUND: A relationship has been reported between blood concentrations of coagulation factor VII (FVII) and obesity. In addition to its role in coagulation, FVII has been shown to inhibit insulin signals in adipocytes. However, the production of FVII by adipocytes remains unclear. OBJECTIVE: We herein investigated the production and secretion of FVII by adipocytes, especially in relation to obesity-related conditions including adipose inflammation and sympathetic nerve activation. METHODS: C57Bl/6J mice were fed a low- or high-fat diet and the expression of FVII messenger RNA (mRNA) was then examined in adipose tissue. 3T3-L1 cells were used as an adipocyte model for in vitro experiments in which these cells were treated with tumor necrosis factor alpha (TNF-alpha) or isoproterenol. The expression and secretion of FVII were assessed by quantitative real-time PCR, Western blotting and enzyme-linked immunosorbent assays. RESULTS: The expression of FVII mRNA in the adipose tissue of mice fed with high-fat diet was significantly higher than that in mice fed with low-fat diet. Expression of the FVII gene and protein was induced during adipogenesis and maintained in mature adipocytes. The expression and secretion of FVII mRNA were increased in the culture medium of 3T3-L1 adipocytes treated with TNF-alpha, and these effects were blocked when these cells were exposed to inhibitors of mitogen-activated kinases or NF-kappaB activation. The beta adrenoceptor agonist isoproterenol stimulated the secretion of FVII from mature adipocytes via the cyclic AMP/protein kinase A pathway. Blockade of secreted FVII with the anti-FVII antibody did not affect the phosphorylation of Akt in the isoproterenol-stimulated adipocytes. CONCLUSION: Obese adipose tissue produced FVII. The production and secretion of FVII by adipocytes was enhanced by TNF alpha or isoproterenol via different mechanisms. These results indicate that FVII is an adipokine that plays an important role in the pathogenesis of obesity. PMID- 25504043 TI - Tff3 is expressed in neurons and microglial cells. AB - BACKGROUND/AIMS: The trefoil factor family (TFF) peptide TFF3 is typically secreted by mucous epithelia, but is also expressed in the immune system and the brain. It was the aim of this study to determine the cerebral cell types which express Tff3. METHODS: Primary cultures from rat embryonic or neonatal cerebral cortex and hippocampus, respectively, were studied by means of RT-PCR and immunofluorescence. Moreover, Tff3 expression was localized by immunocytochemistry in sections of adult rat cerebellum. RESULTS: Tff3 transcripts were detectable in neural cultures of both the cortex and the hippocampus as well as in glial cell-enriched cultures. Tff3 peptide co-localized with Map2 indicating an expression in neurons in vitro. The neuronal expression was confirmed by immunofluorescence studies of adult rat cerebellum. Furthermore, Tff3 peptide showed also a clear co-localization with Iba-1 in vitro typical of activated microglial cells. CONCLUSION: The neuronal expression of Tff3 is in line with a function of a typical neuropeptide influencing, e.g., fear, memory, depression and motoric skills. The expression in activated microglial cells, which is demonstrated here for the first time, points towards a possible function for Tff3 in immune reactions in the CNS. This opens a plethora of additional possible functions for Tff3 including synaptic plasticity and cognition as well as during neuroinflammatory diseases and psychiatric disorders. PMID- 25504042 TI - Maternal obesity and overnutrition increase oxidative stress in male rat offspring reproductive system and decrease fertility. AB - PURPOSE: Increasing evidence exists that maternal obesity (MO) and overnutrition during pregnancy and lactation have long-lasting consequences for progeny metabolism, cardiovascular and endocrine function. Data on effects of MO on offspring reproduction are limited. We hypothesized that MO during pregnancy and lactation in founder F(0) rat mothers would increase testicular and sperm oxidative stress (OS) and adversely impact male fertility in their F(1) offspring. METHODS: We induced pre-pregnancy MO by feeding F(0) females a high fat diet from weaning through pregnancy and lactation. After weaning, all F(1) rats ate control (C) diet. We determined serum testosterone, malondialdehyde (MDA), reactive oxygen species (ROS) and superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity in F(1) testes and sperm at postnatal days (PNDs) 110, 450 and 650. RESULTS: At PNDs 450 and 650, MO offspring had lower luteinizing hormone while testosterone levels were lower at all ages. Testicular MDA and ROS concentrations and SOD and GPx activity were higher in MO F(1) at all ages. Nitrotyrosine immunostaining was higher at all ages in MO F(1) testes than C F(1). At PNDs 450 and 650, MO F(1) spermatozoa showed higher MDA concentrations and lower SOD and GPx activity with reduced sperm concentration, viability and motility, and more sperm abnormalities. Fertility rate was not affected at PND 110 but was lower in MO F(1) at PNDs 450 and 650. CONCLUSIONS: We conclude that MO during pregnancy and lactation increases F(1) testicular and sperm OS leading to premature aging of reproductive capacity. PMID- 25504045 TI - Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder. AB - We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an ~12-Mbp interval identical by descent (IBD) between the affected individuals on chromosome 3q13.13-21.1 with an LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippocampal neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder. PMID- 25504046 TI - Mendelian genes for Parkinson's disease contribute to the sporadic forms of the disease. AB - Parkinson's disease (PD) can be divided into familial (Mendelian) and sporadic forms. A number of causal genes have been discovered for the Mendelian form, which constitutes 10-20% of the total cases. Genome-wide association studies have successfully uncovered a number of susceptibility loci for sporadic cases but those only explain a small fraction (6-7%) of PD heritability. It has been observed that some genes that confer susceptibility to PD through common risk variants also contain rare causing mutations for the Mendelian forms of the disease. These results suggest a possible functional link between Mendelian and sporadic PD and led us to investigate the role that rare and low-frequency variants could have on the sporadic form. Through a targeting approach, we have resequenced at 49* coverage the exons and regulatory regions of 38 genes (including Mendelian and susceptibility PD genes) in 249 sporadic PD patients and 145 unrelated controls of European origin. Unlike susceptibility genes, Mendelian genes show a clear general enrichment of rare functional variants in PD cases, observed directly as well as with Tajima's D statistic and several collapsing methods. Our findings suggest that rare variation on PD Mendelian genes may have a role in the sporadic forms of the disease. PMID- 25504044 TI - TWEAK/Fn14, a pathway and novel therapeutic target in myotonic dystrophy. AB - Myotonic dystrophy type 1 (DM1), the most prevalent muscular dystrophy in adults, is characterized by progressive muscle wasting and multi-systemic complications. DM1 is the prototype for disorders caused by RNA toxicity. Currently, no therapies exist. Here, we identify that fibroblast growth factor-inducible 14 (Fn14), a member of the tumor necrosis factor receptor super-family, is induced in skeletal muscles and hearts of mouse models of RNA toxicity and in tissues from DM1 patients, and that its expression correlates with severity of muscle pathology. This is associated with downstream signaling through the NF-kappaB pathways. In mice with RNA toxicity, genetic deletion of Fn14 results in reduced muscle pathology and better function. Importantly, blocking TWEAK/Fn14 signaling with an anti-TWEAK antibody likewise improves muscle histopathology and functional outcomes in affected mice. These results reveal new avenues for therapeutic development and provide proof of concept for a novel therapeutic target for which clinically available therapy exists to potentially treat muscular dystrophy in DM1. PMID- 25504047 TI - OXPHOS dysfunction regulates integrin-beta1 modifications and enhances cell motility and migration. AB - Mitochondria are central organelles for cellular metabolism. In cancer cells, mitochondrial oxidative phosphorylation (OXPHOS) dysfunction has been shown to promote migration, invasion, metastization and apoptosis resistance. With the purpose of analysing the effects of OXPHOS dysfunction in cancer cells and the molecular players involved, we generated cybrid cell lines harbouring either wild type (WT) or mutant mitochondrial DNA (mtDNA) [tRNAmut cybrids, which harbour the pathogenic A3243T mutation in the leucine transfer RNA gene (tRNAleu)]. tRNAmut cybrids exhibited lower oxygen consumption and higher glucose consumption and lactate production than WT cybrids. tRNAmut cybrids displayed increased motility and migration capacities, which were associated with altered integrin-beta1 N glycosylation, in particular with higher levels of beta-1,6-N-acetylglucosamine (GlcNAc) branched N-glycans. This integrin-beta1 N-glycosylation pattern was correlated with higher levels of membrane-bound integrin-beta1 and also with increased binding to fibronectin. When cultured in vitro, tRNAmut cybrids presented lower growth rate than WT cybrids, however, when injected in nude mice, tRNAmut cybrids produced larger tumours and showed higher metastatic potential than WT cybrids. We conclude that mtDNA-driven OXPHOS dysfunction correlates with increased motility and migration capacities, through a mechanism that may involve the cross talk between cancer cell mitochondria and the extracellular matrix. PMID- 25504049 TI - A survey of the views of US veterinary teaching faculty to owned cat housing practices. AB - According to the American Pet Products Association, in the USA there are an estimated 86.4 million owned cats, and approximately 40% of these are allowed to roam outdoors. Little has been written about the contribution of owned cats to problems attributed to feral cats, including wildlife predation, spread of zoonotic diseases and overpopulation. A recent study found that 64% of cats have visited the veterinarian within the past year, suggesting frequent opportunity for veterinarians to communicate risks and benefits of indoor vs outdoor living. We conducted the following survey to evaluate current views about this role of veterinarians, by surveying veterinary school faculty (n = 158). Our objectives were to assess (i) the degree to which veterinary teaching faculty believe that the issue of clients maintaining owned cats indoors vs outdoors is appropriate for discussion with students within the veterinary school curriculum; (ii) the degree of agreement and understanding there is among the faculty as to the reasons that clients maintain cats either inside or outside the home; and (iii) the degree to which veterinary faculty believe owned cats that are allowed to go outdoors contribute to various identified problems. The results indicated that many participants believed that the discussion of maintaining cats indoors is relevant to the profession, that it belongs in the veterinary school curriculum, that they understand client motivations, that they feel that more practicing veterinarians should discuss cat housing practices with clients and that cat overpopulation continues to be a significant concern for owned cats being outdoors. Additional ways to help maintain the health and wellbeing of cats that are primarily housed indoors is briefly discussed, including through such means as environmental enrichment or by providing cats access to safe areas while outdoors. PMID- 25504048 TI - Sarcospan integration into laminin-binding adhesion complexes that ameliorate muscular dystrophy requires utrophin and alpha7 integrin. AB - Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in loss of the dystrophin-glycoprotein complex, a laminin receptor that connects the myofiber to its surrounding extracellular matrix. Utrophin, a dystrophin ortholog that is normally localized to the neuromuscular junction, is naturally upregulated in DMD muscle, which partially compensates for the loss of dystrophin. Transgenic overexpression of utrophin causes broad sarcolemma localization of utrophin, restoration of laminin binding and amelioration of disease in the mdx mouse model of DMD. We previously demonstrated that overexpression of sarcospan, a dystrophin- and utrophin-binding protein, ameliorates mdx muscular dystrophy. Sarcospan boosts levels of utrophin to therapeutic levels at the sarcolemma, where attachment to laminin is restored. However, understanding the compensatory mechanism is complicated by concomitant upregulation of alpha7beta1 integrin, which also binds laminin. Similar to the effects of utrophin, transgenic overexpression of alpha7 integrin prevents DMD disease in mice and is accompanied by increased abundance of utrophin around the extra-synaptic sarcolemma. In order to investigate the mechanisms underlying sarcospan 'rescue' of muscular dystrophy, we created double-knockout mice to test the contributions of utrophin or alpha7 integrin. We show that sarcospan-mediated amelioration of muscular dystrophy in DMD mice is dependent on the presence of both utrophin and alpha7beta1 integrin, even when they are individually expressed at therapeutic levels. Furthermore, we found that association of sarcospan into laminin-binding complexes is dependent on utrophin and alpha7beta1 integrin. PMID- 25504050 TI - The pollen- and embryo-specific Arabidopsis DLL promoter bears good potential for application in marker-free Cre/loxP self-excision strategy. AB - KEY MESSAGE: Marker-free transgenic plants can be generated with high efficiency by using the Cre/ lox P self-excision system controlled by the pollen- and embryo specific Arabidopsis DLL promoter. In this work, we aimed to study the feasibility of using the pollen- and embryo-specific DLL promoter of the At4g16160 gene from Arabidopsis thaliana in a Cre/loxP self-excision strategy. A Cre/loxP self-excision cassette controlled by the DLL promoter was introduced into the tobacco genome via Agrobacterium-mediated transformation. No evidence for premature activation of the Cre/loxP system was observed in primary transformants. The efficiency of nptII removal during pollen and embryo development was investigated in transgenic T1 progenies derived from eight self- and four cross-pollinated T0 lines, respectively. Segregation and rooting assays were performed to select recombined T1 plants. Molecular analyses of these plants confirmed the excision event in all analysed T0 lines and marker-free transgenic T1 plants were obtained with efficiency of up to 96.2%. The Arabidopsis DLL promoter appears to be a strong candidate to drive Cre-mediated recombination not only in tobacco as a model plant, but also in other plant species. PMID- 25504052 TI - Correction: Aromatic sulfonate anion-induced pseudorotaxanes: environmentally benign synthesis, selectivity, and structural characterization. AB - Correction for 'Aromatic sulfonate anion-induced pseudorotaxanes: environmentally benign synthesis, selectivity, and structural characterization' by Han-Yuan Gong et al., Chem. Commun., 2015, DOI: . PMID- 25504053 TI - Calculated in situ tear oxygen tension under hybrid contact lenses. AB - OBJECTIVE: We calculated corneal surface oxygen tension under hybrid contact lenses (CLs) by extending existing models of CL oxygen diffusion to the circumstances of hybrid CL designs with tear vaults. METHODS: Theoretical oxygen tensions at the corneal surface, if tear mixing and exchange are excluded, are calculated for hybrid CL (modern, high oxygen-permeable rigid center) designs with a single chamber corneal model using a computer software spreadsheet. Several specific in vivo instances of hybrid CL tear vaults are measured by both slitlamp biomicroscopy and optical coherence tomography (OCT). RESULTS: No significant difference was found between central thickness of hybrid CL rigid portions measured by Vigor gauge and OCT. The amount of central tear vault thickness was found to be significantly greater, however, when interpolated from biomicroscope images (500-1,554 MUm, simulating a poorly fit lens) than from either OCT images (0-91 MUm) or direct measurement through OCT software (0-96 MUm). Using all measurements, excluding any potential contributions from tear exchange or mixing, we predict corneal surface tear pO2 values under several hybrid CLs to range from zero under a lens with an excessive vault to 112 mm Hg under a lens with a minimal vault. CONCLUSIONS: Tear vaults beneath the gas permeable portion of the hybrid CLs of 100 MUm or less resulted in acceptable corneal surface oxygen values. Where tear vaults are greater than about 100 MUm, predicted anterior corneal surface pO2 values are less likely to be adequate for optimal corneal physiology. Any significant tear exchange, however, should increase these values. Although measuring tear thickness, we noted that the photographic biomicroscope and the OCT methods provided inconsistent results, and thus limited the reliability of our primary result. PMID- 25504051 TI - Weather elements, chemical air pollutants and airborne pollen influencing asthma emergency room visits in Szeged, Hungary: performance of two objective weather classifications. AB - Weather classification approaches may be useful tools in modelling the occurrence of respiratory diseases. The aim of the study is to compare the performance of an objectively defined weather classification and the Spatial Synoptic Classification (SSC) in classifying emergency department (ED) visits for acute asthma depending from weather, air pollutants, and airborne pollen variables for Szeged, Hungary, for the 9-year period 1999-2007. The research is performed for three different pollen-related periods of the year and the annual data set. According to age and gender, nine patient categories, eight meteorological variables, seven chemical air pollutants, and two pollen categories were used. In general, partly dry and cold air and partly warm and humid air aggravate substantially the symptoms of asthmatics. Our major findings are consistent with this establishment. Namely, for the objectively defined weather types favourable conditions for asthma ER visits occur when an anticyclonic ridge weather situation happens with near extreme temperature and humidity parameters. Accordingly, the SSC weather types facilitate aggravating asthmatic conditions if warm or cool weather occur with high humidity in both cases. Favourable conditions for asthma attacks are confirmed in the extreme seasons when atmospheric stability contributes to enrichment of air pollutants. The total efficiency of the two classification approaches is similar in spite of the fact that the methodology for derivation of the individual types within the two classification approaches is completely different. PMID- 25504054 TI - Whatever the cost? Information integration in memory-based inferences depends on cognitive effort. AB - One of the most prominent models of probabilistic inferences from memory is the simple recognition heuristic (RH). The RH theory assumes that judgments are based on recognition in isolation, such that other information is ignored. However, some prior research has shown that available knowledge is not generally ignored. In line with the notion of adaptive strategy selection--and, thus, a trade-off between accuracy and effort--we hypothesized that information integration crucially depends on how easily accessible information beyond recognition is, how much confidence decision makers have in this information, and how (cognitively) costly it is to acquire it. In three experiments, we thus manipulated (a) the availability of information beyond recognition, (b) the subjective usefulness of this information, and (c) the cognitive costs associated with acquiring this information. In line with the predictions, we found that RH use decreased substantially, the more easily and confidently information beyond recognition could be integrated, and increased substantially with increasing cognitive costs. PMID- 25504055 TI - Prediction of pancreatic anastomotic failure after pancreatic head resection using preoperative diffusion-weighted MR imaging. AB - PURPOSE: To determine whether the preoperative pancreatic apparent diffusion coefficient (ADC) can be used to predict the development of postoperative pancreatic anastomotic failure (PAF). MATERIALS AND METHODS: We retrospectively examined the cases of 79 patients who underwent pancreatic head resection between January 2010 and October 2013. The patients underwent 1.5-T MR imaging including diffusion-weighted imaging before surgery. The main pancreatic duct diameter (MPD), the pancreatic parenchymal thickness (PT), and the ADC of the pancreatic remnant parenchyma were measured. Two radiologists blinded to the patients' outcomes performed the measurements. The imaging parameters were compared between the patients who developed PAF and those who did not. The cut-off ADC for the development of PAF was calculated with a receiver operating characteristic analysis. RESULTS: The imaging parameters were highly correlated between the two observers. The MPD and PT did not differ significantly among the patients. The mean pancreatic ADCs were significantly higher in the patients with PAF than in those without PAF. An ADC higher than 1.50 * 10(-3) mm(2)/s (Az = 0.719, observer 1) or 1.35 * 10(-3) mm(2)/s (Az = 0.752, observer-2) was optimal for predicting the development of postoperative PAF. CONCLUSION: Measuring the preoperative non tumorous pancreatic ADC may be useful for the prediction of a postoperative PAF. PMID- 25504056 TI - Computed tomography findings of tracheobronchial system diseases: a pictorial essay. AB - The diseases affecting the trachea and main bronchi can be categorized into congenital or acquired abnormalities and also into focal or diffuse diseases. Major congenital bronchial abnormalities cover accessory cardiac bronchus and tracheal bronchus. Tracheobronchial strictures, such as post-intubation and post infectious stenosis and tracheobronchial neoplasms are regarded as focal diseases, whereas tracheobronchomegaly, relapsing polychondritis, tracheobronchopathia osteochondroplastica, amyloidosis, granulomatosis with polyangiitis, tracheobronchomalacia, saber-sheath trachea and tracheobronchitis associated with ulcerative colitis are examples of diffuse diseases. Computed tomography (CT) is the best non-invasive method for evaluation of tracheobronchial lesions. In this pictorial review we aimed to demonstrate CT features of central airway diseases. PMID- 25504058 TI - Clinicians' practices regarding blind versus open weighing among patients with eating disorders. AB - BACKGROUND: Empirically supported treatments for eating disorders, such as cognitive-behavioral therapy and family-based treatment, stress the importance of weighing patients during therapy and using this information as part of treatment. However, weighing practices vary widely across eating disorders professionals, including those that purport to provide empirically supported interventions. OBJECTIVES: To characterize clinicians' practices regarding the decision to share (open weighing) or withhold (blind weighing) weight information with patients, a topic that has received limited prior attention. METHOD: Clinicians (N = 114; 85% female) who regularly treat individuals with an eating disorder completed an online survey to identify factors that might impact their decision to practice blind or open weighing. RESULTS: Approximately half of the clinicians reported generally using open weighing procedures (n = 53; 46.49%). Endorsement of cognitive-behavioral or family-based therapeutic orientation was not significantly associated with open weighing. However, clinicians who endorsed therapeutic modalities that do not specifically encourage open weighing were significantly more likely to engage in blind weighing. Clinicians working with clients with anorexia nervosa were significantly more likely to practice blind weighing, compared to clients with other eating disorder diagnoses, and cognitive or emotional impairment from malnutrition emerged as the strongest predictor of clinicians' decisions to practice blind weighing, controlling for all other variables. DISCUSSION: Development of specific training modules may be useful for improving adherence to empirically supported protocols that recommend open weighing. More importantly, however, our results highlight the need for future treatment studies to identify whether blind or open weighing is beneficial for improving patient outcomes. PMID- 25504057 TI - Phlebotomy treatment for elimination of perfluoroalkyl acids in a highly exposed family: a retrospective case-series. AB - BACKGROUND: Perfluoroalkyl acids (PFAAs) are a family of commonly used synthetic chemicals that have become widespread environmental contaminants. In human serum, perfluorohexane sulfonate (PFHxS), perflurooctane sulfonate (PFOS), and perfluorooctanoate (PFOA) are most frequently detected, in part owing to their long elimination half-lives of between 3.8 yrs (PFOA) and 8.5 yrs (PFHxS). These PFAAs also cross the placenta and have been associated with developmental toxicity, and some are considered likely human carcinogens. Interventions to eliminate PFAAs in highly contaminated individuals would reduce future health risks, but minimal research has been conducted on methods to facilitate accelerated human clearance of these persistent substances. METHODS: Six patients with elevated serum concentrations from a single family were treated by intermittent phlebotomy over a 4-5 year period at intervals similar to, or less frequent than what is done for routine blood donation at Canadian Blood Services. The apparent elimination half-life (HLapp) for PFHxS, PFOS, and PFOA in this treated population was calculated in each patient and compared to the intrinsic elimination half-lives (HLin) from a literature reference population of untreated fluorochemical manufacturing plant retirees (n = 26, age >55 yrs). RESULTS: For all three PFAAs monitored during phlebotomy, HLapp in each of the family members (except the mother, who had a low rate of venesection) was significantly shorter than the geometric mean HL measured in the reference population, and in some cases were even shorter compared to the fastest eliminator in the reference population. CONCLUSION: This study suggests significantly accelerated PFAA clearance with regular phlebotomy treatment, but the small sample size and the lack of controls in this clinical intervention precludes drawing firm conclusions. Given the minimal risks of intermittent phlebotomy, this may be an effective and safe clinical intervention to diminish the body burden of PFAAs in highly exposed people. PMID- 25504060 TI - Tailoring graphene to achieve negative Poisson's ratio properties. AB - Graphene can be made auxetic through the introduction of vacancy defects. This results in the thinnest negative Poisson's ratio material at ambient conditions known so far, an effect achieved via a nanoscale de-wrinkling mechanism that mimics the behavior at the macroscale exhibited by a crumpled sheet of paper when stretched. PMID- 25504059 TI - Two-dimensionality of yeast colony expansion accompanied by pattern formation. AB - Yeasts can form multicellular patterns as they expand on agar plates, a phenotype that requires a functional copy of the FLO11 gene. Although the biochemical and molecular requirements for such patterns have been examined, the mechanisms underlying their formation are not entirely clear. Here we develop quantitative methods to accurately characterize the size, shape, and surface patterns of yeast colonies for various combinations of agar and sugar concentrations. We combine these measurements with mathematical and physical models and find that FLO11 gene constrains cells to grow near the agar surface, causing the formation of larger and more irregular colonies that undergo hierarchical wrinkling. Head-to-head competition assays on agar plates indicate that two-dimensional constraint on the expansion of FLO11 wild type (FLO11) cells confers a fitness advantage over FLO11 knockout (flo11Delta) cells on the agar surface. PMID- 25504061 TI - The effect of chronic peripheral nesfatin-1 application on blood pressure in normal and chronic restraint stressed rats: related with circulating level of blood pressure regulators. AB - Nesfatin is a peptide secreted by peripheral tissues, central and peripheral nervous system. It is involved in the regulation of homeostasis. Although the effects of nesfatin-1 on nutrition have been studied widely in the literature, the mechanisms of nesfatin-1 action and also relations with other physiological parameters are still not clarified well. We aimed to investigate the effect of peripheral chronic nesfatin-1 application on blood pressure regulation in normal and in rats exposed to restraint immobilization stress. In our study, three month old male Wistar rats were used. Rats were divided into 4 groups as Control, Stress, Control+Nesfatin-1, Nesfatin-1+Stress. Angiotensinogen, angiotensin converting enzyme 2, angiotensin II, endothelin-1, endothelial nitric oxide synthase, aldosterone, cortisol, nesfatin-1 levels were determined in plasma samples by ELISA. Our results have shown that chronic peripheral nesfatin-1 administration increases blood pressure in normal and in rats exposed to chronic restraint stress. Effect of nesfatin-1 on circulating level of angiotensinogen, angiotensin converting enzyme 2, angiotensin II, endothelin-1, endothelial nitric oxide synthase, aldosterone and cortisol has been identified. We can conclude that elevated high blood pressure after chronic peripheral nesfatin-1 administration in rats exposed to chronic restraint stress may be related to decreased plasma level of endothelial nitric oxide synthase concentration. PMID- 25504064 TI - [The anniversary year - 60 years of the "Berufsverband der Deutschen Urologen e.V."]. PMID- 25504063 TI - Cholinergic properties of new 7-methoxytacrine-donepezil derivatives. AB - Organophosphorus nerve agents inhibit acetylcholinesterase (AChE) which causes the breakdown of the transmitter acetylcholine (ACh) in the synaptic cleft. Overstimulation of cholinergic receptors (muscarinic and nicotinic) by excessive amounts of ACh causes several health problems and may even cause death. Reversible AChE inhibitors play an important role in prophylaxis against nerve agents. The presented study investigated whether 7-methoxytacrine (7-MEOTA) and 7 MEOTA-donepezil derivatives can act as central and peripheral reversible AChE inhibitors and simultaneously antagonize muscarinic and nicotinic receptors. The possible mechanism of action was studied on cell cultures (patch clamp technique, calcium mobilization assay) and on isolated smooth muscle tissue (contraction study). Furthermore, the kinetics of the compounds were also examined. CNS availability was predicted by determining the passive blood-brain barrier penetration estimated via a modified PAMPA assay. In conclusion, this study provides promising evidence that the new synthesized 7-MEOTA-donepezil derivatives have the desired anticholinergic effect; they can inhibit AChE, and nicotinic and muscarinic receptors in the micromolar range. Furthermore, they seem to penetrate readily into the CNS. However, their real potency and benefit must be verified by in vivo experiments. PMID- 25504067 TI - [GeSRU Residents Congress Calendar 2015: continuing education, networking, career planning]. PMID- 25504068 TI - [Position paper of the "Bundnis JUNGE ARZTE" on the increasing workload in the German health care system]. PMID- 25504062 TI - Emerging evidence for specific neuronal functions of auxiliary calcium channel alpha2delta subunits. AB - In nerve cells the ubiquitous second messenger calcium regulates a variety of vitally important functions including neurotransmitter release, gene regulation, and neuronal plasticity. The entry of calcium into cells is tightly regulated by voltage-gated calcium channels, which consist of a heteromultimeric complex of a pore forming alpha1, and the auxiliary beta and alpha2delta subunits. Four genes (Cacna2d1-4) encode for the extracellular membrane-attached alpha2delta subunits (alpha2delta-1 to alpha2delta-4), out of which three isoforms (alpha2delta-1 to 3) are strongly expressed in the central nervous system. Over the years a wealth of studies has demonstrated the classical role of alpha2delta subunits in channel trafficking and calcium current modulation. Recent studies in specialized neuronal cell systems propose roles of alpha2delta subunits beyond the classical view and implicate alpha2delta subunits as important regulators of synapse formation. These findings are supported by the identification of novel human disease mutations associated with alpha2delta subunits and by the fact that alpha2delta subunits are the target of the anti-epileptic and anti-allodynic drugs gabapentin and pregabalin. Here we review the recently emerging evidence for specific as well as redundant neuronal roles of alpha2delta subunits and discuss the mechanisms for establishing and maintaining specificity. PMID- 25504069 TI - [The life and works of Professor Max Hosel (1906-1971): a pioneer of endoscopic prostate surgery]. AB - In 1949 Max Hosel (1906-1971) founded the largest urological hospital in the world at that time in the former military hospital in Ulm, which at times had over 250 inpatient beds. In the south German region he had at his disposal the most comprehensive endoscopic operation collective and the greatest experience in transurethral resection of the prostate (TUR-P). From 1948 to 1958 he carried out approximately 13,850 prostate resections with an average adenoma weight of 30 g and a mortality rate of <1%. The technical inadequacies of the resection instruments at that time prompted Hosel to develop a new form of resectoscope, namely the type 782. This resectoscope allowed a fast and complete resection of prostatic adenomas due to the improved visual field and better handling (rotating the operational unit) and also made the transurethral resection of larger prostatic adenomas possible. Therefore, in "Ulm and around Ulm" substantially larger prostatic adenomas could be endoscopically treated and open enucleation was not necessary. Prof. Hosel was an international force as a urologist and in Germany was ranked as one of the pioneers in the field of endoscopic prostate surgery. Although he never held the position of a University Chair, in the municipal hospitals in Ulm he accomplished the foundations for the later University Clinic for Urology. PMID- 25504071 TI - Infrared and Raman measurements of halogen bonding in cryogenic solutions. AB - Because they create a weakly interacting environment which, combined with the low temperatures used, leads to small bandwidths and thus facilitates the detection of complex bands only slightly shifted from the monomer modes, solutions in liquefied inert gases have proven to be an ideal medium to study molecular complexes held together by weak and medium-strong C-X...Y (with X=I, Br, Cl and Y=O, N, S, F, Cl, pi,...) halogen bonds. In this chapter, experimental setups for infrared and Raman study of cryosolutions are described, and general methodologies used to examine weakly bound molecular complexes are discussed. The methods are illustrated using data obtained for a variety of halogen-bonded complexes involving, amongst others, the trifluorohalomethanes CF3Cl, CF3Br, and CF3I, and a variety of Lewis bases. The results are compared with theoretical data obtained from ab initio calculations, and with experimental and theoretical data obtained for complexes involving weak C-H proton donors such as CHF3. Preliminary data for mixed proton donor/halogen donors such as CHClF2, CHBrF2 are also discussed. PMID- 25504072 TI - Recent advances in synthesis of P-BH3 compounds. AB - This chapter is dedicated to the main achievements since 2007 regarding the synthesis of BH3-phosphorus complexes. Among this class of compounds, phosphine boranes are the most studied derivatives, mainly as valuable surrogates of phosphines, enabling easy handling and purification. In contrast, metal phosphido boranes have so far only been considered as in situ intermediates in the P functionalization of secondary phosphine-boranes. Thorough investigations of their structures as well as their chemical properties have recently been reported. Besides phosphine-boranes and their phosphides, new families of phosphorus-BH3 complexes, have emerged as useful precursors of new structures in the asymmetric series. New routes toward optically active phosphinous-acid boranes and their esters were developed and applied to the synthesis of enantiopure P-stereogenic secondary and tertiary phosphine-boranes. The stereoselective synthesis of P-stereogenic aminophosphine-boranes, precursors of a new class of chiral ligands, has been reported. Studies dealing with the synthesis and reactivity of phosphonite-boranes were successfully applied to the development of efficient syntheses of functionalized H-phosphinates, compounds difficult to access by other routes. PMID- 25504074 TI - Permeability Imaging as a Biomarker of Leptomeningeal Collateral Flow in Patients with Intracranial Arterial Stenosis. AB - Different methods of angiography are of great clinical utility; however, it still remains unstandardized as which method would be suitable to determine cerebral collateral circulation. Here we compared digital subtraction angiography (DSA), computer tomography angiography (CTA) and dynamic contrast-enhanced T1-weighted imaging magnetic resonance imaging (MRI) findings in seven patients with severe intracranial arterial stenosis, and determine whether volume transfer constant (K(trans)) maps of permeability imaging could be used as the biomarkers of cerebral collateral circulation. We retrospectively reviewed seven adult patients with severe intracranial arterial stenosis or occlusion with a complete parenchymal and vascular imaging work-up. DSA, CTA source imaging (CTA-SI), arterial spin labeling (ASL), and K(trans) maps were used to assess their collateral flow. Cohen's Kappa coefficient was calculated to test the consistency of their collateral scores. A reasonable agreement was found between DSA and K(trans) maps (Kappa = 0.502, P < 0.001) when all 15 regional vascular sites were included, and a better agreement found after exclusion of perforating artery territories (N = 10 sites, Kappa = 0.766, P < 0.001). The agreement between CTA SI and DSA was moderate on all 15 sites (Kappa = 0.413, P < 0.001) and 10 sites (Kappa = 0.329, P < 0.001). The agreement between ASL and DSA was least favorable, no matter for all 15 sites (Kappa = 0.270, P < 0.001) or 10 sites (Kappa = 0.205, P = 0.002). K(trans) maps are useful and promising for leptomeningeal collateral assessment, when compared to CTA-SI or ASL. Further studies are requited for verify its validity in a large registry of patients. PMID- 25504073 TI - Assembling programmable FRET-based photonic networks using designer DNA scaffolds. AB - DNA demonstrates a remarkable capacity for creating designer nanostructures and devices. A growing number of these structures utilize Forster resonance energy transfer (FRET) as part of the device's functionality, readout or characterization, and, as device sophistication increases so do the concomitant FRET requirements. Here we create multi-dye FRET cascades and assess how well DNA can marshal organic dyes into nanoantennae that focus excitonic energy. We evaluate 36 increasingly complex designs including linear, bifurcated, Holliday junction, 8-arm star and dendrimers involving up to five different dyes engaging in four-consecutive FRET steps, while systematically varying fluorophore spacing by Forster distance (R0). Decreasing R0 while augmenting cross-sectional collection area with multiple donors significantly increases terminal exciton delivery efficiency within dendrimers compared with the first linear constructs. Forster modelling confirms that best results are obtained when there are multiple interacting FRET pathways rather than independent channels by which excitons travel from initial donor(s) to final acceptor. PMID- 25504076 TI - STOCK: structure mapper and online coarse-graining kit for molecular simulations. AB - We present a web toolkit STructure mapper and Online Coarse-graining Kit for setting up coarse-grained molecular simulations. The kit consists of two tools: structure mapping and Boltzmann inversion tools. The aim of the first tool is to define a molecular mapping from high, for example, all-atom, to low, that is, coarse-grained, resolution. Using a graphical user interface it generates input files, which are compatible with standard coarse-graining packages, for example, Versatile Object-oriented Toolkit for Coarse-graining Applications and DL_CGMAP. Our second tool generates effective potentials for coarse-grained simulations preserving the structural properties, for example, radial distribution functions, of the underlying higher resolution model. The required distribution functions can be provided by any simulation package. Simulations are performed on a local machine and only the distributions are uploaded to the server. The applicability of the toolkit is validated by mapping atomistic pentane and polyalanine molecules to a coarse-grained representation. Effective potentials are derived for systems of TIP3P (transferable intermolecular potential 3 point) water molecules and salt solution. The presented coarse-graining web toolkit is available at http://stock.cmm.ki.si. PMID- 25504075 TI - Gastropulmonary Route of Infection and the Prevalence of Microaspiration in the Elderly Patients with Ventilator-Associated Pneumonia Verified by Molecular Microbiology-GM-PFGE. AB - Gastropulmonary route of infection was considered to be an important mechanism of ventilator-associated pneumonia (VAP). However there is little evidence to support this assumption. Moreover, the prevalence of microaspiration in elderly ventilated patients was not well understood. To confirm gastropulmonary infection route and investigate the prevalence of microaspiration in elderly ventilated patients using genome macrorestriction-pulsed field gel electrophoresis (GM PFGE). Patients over 60 years old, expected to receive mechanical ventilation longer than 48 h, were prospectively enrolled from October 2009 to January 2012. Clinical data were collected and recorded until they died, developed pneumonia, or were extubated. Samples from gastric fluid, subglottic secretion and lower respiratory tract (LRT) were collected during the follow-up for microbiological examination. To evaluate the homogeneity, GM-PFGE was performed on strains responsible for VAP that had the same biochemical phenotype as those isolated from gastric juice and subglottic secretions sequentially. Among 44 VAP patients, 76 strains were isolated from LRT and considered responsible for VAP. Twenty-two isolates had the same biochemical phenotype with the corresponding gastric isolates. The homology was further confirmed using GM-PFGE in 12 episodes of VAP. Nearly 30% of VAPs were caused by microaspiration based on the analysis of bacterial phenotype or GM-PFGE. In addition, 58.3% patients with gastric colonization developed VAP, especially late-onset VAP (LOP). Gastropulmonary infection route exists in VAP especially LOP in elderly ventilated patients. It is one of the important mechanisms in the development of VAP. PMID- 25504077 TI - Heat stress illness hospitalizations--environmental public health tracking program, 20 States, 2001-2010. AB - PROBLEM/CONDITION: Heat stress illness (HSI), also known as heat-related illness, comprises mild heat edema, heat syncope, heat cramps, heat exhaustion (the most common type of HSI), and heat stroke (the most severe form). CDC's Environmental Public Health Tracking Program receives annual hospitalization discharge data from 23 states that are used to assess and monitor trends of HSI hospitalization over time. REPORTING PERIOD: May-September, 2001-2010. DESCRIPTION OF SYSTEM: The Environmental Public Health Tracking Program is a comprehensive surveillance system implemented in 25 states and one city health department. The core of the system is the Tracking Network, which collects data on environmental hazards, health effects, exposures, and population. The Tracking Network provides nationally consistent environmental and health outcome data that enable federal, state, and local public health agencies to assess trends, explore associations, and generate hypotheses using these data. For HSI surveillance, the Tracking Network uses state-based hospital discharge data. RESULTS: During 2001-2010, approximately 28,000 HSI hospitalizations occurred in 20 states participating in the Tracking Program. Data from three states were not included in this report because of missing data for >=3 years. Two states joined the Tracking Program after the study period and also are not included in this report. The majority of HSI hospitalizations occurred among males and persons aged >=65 years. The highest rates of hospitalizations were in the Midwest and the South. During this period, an overall 2%-5% increase in the rate of HSI hospitalizations occurred in all 20 states compared with the 2001 rate. The correlation between the average number of HSI hospitalizations and the average monthly maximum temperature/heat index was statistically significant (at p<0.0001) in all 20 states. INTERPRETATION: Consistent with previous studies, age and sex were identified as major risk factors for HSI hospitalizations. Certain Tracking states that experienced high temperatures during summer months showed an increase in rate of HSI hospitalizations over the 10-year study period. PUBLIC HEALTH ACTION: HSIs are preventable and an important focus of public health interventions at state and local health departments. Federal, state, and local public health agencies can use data on HSI hospitalizations for surveillance purposes to estimate trends over time and to design targeted intervention to reduce heat stress morbidity among at-risk populations. PMID- 25504079 TI - Abstracts of the UCD School of Medicine & Medical Science, Summer Student Research Awards 2014, 2 October 2014, UCD, Dublin, Ireland. PMID- 25504078 TI - Host genetics predict clinical deterioration in HCV-related cirrhosis. AB - Single nucleotide polymorphisms (SNPs) in the epidermal growth factor (EGF, rs4444903), patatin-like phospholipase domain-containing protein 3 (PNPLA3, rs738409) genes, and near the interleukin-28B (IL28B, rs12979860) gene are linked to treatment response, fibrosis, and hepatocellular carcinoma (HCC) in chronic hepatitis C. Whether these SNPs independently or in combination predict clinical deterioration in hepatitis C virus (HCV)-related cirrhosis is unknown. We genotyped SNPs in EGF, PNPLA3, and IL28B from liver tissue from 169 patients with biopsy-proven HCV cirrhosis. We estimated risk of clinical deterioration, defined as development of ascites, encephalopathy, variceal hemorrhage, HCC, or liver related death using Cox proportional hazards modeling. During a median follow-up of 6.6 years, 66 of 169 patients experienced clinical deterioration. EGF non-AA, PNPLA3 non-CC, and IL28B non-CC genotypes were each associated with increased risk of clinical deterioration in age, sex, and race-adjusted analysis. Only EGF non-AA genotype was independently associated with increased risk of clinical deterioration (hazard ratio [HR] 2.87; 95% confidence interval [CI] 1.31-6.25) after additionally adjusting for bilirubin, albumin, and platelets. Compared to subjects who had 0-1 unfavorable genotypes, the HR for clinical deterioration was 1.79 (95%CI 0.96-3.35) for 2 unfavorable genotypes and 4.03 (95%CI 2.13-7.62) for unfavorable genotypes for all three loci (Ptrend<0.0001). In conclusion, among HCV cirrhotics, EGF non-AA genotype is independently associated with increased risk for clinical deterioration. Specific PNPLA3 and IL28B genotypes also appear to be associated with clinical deterioration. These SNPs have potential to identify patients with HCV-related cirrhosis who require more intensive monitoring for decompensation or future therapies preventing disease progression. PMID- 25504081 TI - Targeting FR-expressing cells in ovarian cancer with Fab-functionalized nanoparticles: a full study to provide the proof of principle from in vitro to in vivo. AB - Efficient targeting in tumor therapies is still an open issue: systemic biodistribution and poor specific accumulation of drugs weaken efficacy of treatments. Engineered nanoparticles are expected to bring benefits by allowing specific delivery of drug to the tumor or acting themselves as localized therapeutic agents. In this study we have targeted epithelial ovarian cancer with inorganic nanoparticles conjugated to a human antibody fragment against the folate receptor over-expressed on cancer cells. The conjugation approach is generally applicable. Indeed several types of nanoparticles (either magnetic or fluorescent) were engineered with the fragment, and their biological activity was preserved as demonstrated by biochemical methods in vitro. In vivo studies with mice bearing orthotopic and subcutaneous tumors were performed. Elemental and histological analyses showed that the conjugated magnetic nanoparticles accumulated specifically and were retained at tumor sites longer than the non conjugated nanoparticles. PMID- 25504080 TI - Pre-treatment whole blood gene expression is associated with 14-week response assessed by dynamic contrast enhanced magnetic resonance imaging in infliximab treated rheumatoid arthritis patients. AB - Approximately 30% of rheumatoid arthritis patients achieve inadequate response to anti-TNF biologics. Attempts to identify molecular biomarkers predicting response have met with mixed success. This may be attributable, in part, to the variable and subjective disease assessment endpoints with large placebo effects typically used to classify patient response. Sixty-one patients with active RA despite methotrexate treatment, and with MRI-documented synovitis, were randomized to receive infliximab or placebo. Blood was collected at baseline and genome-wide transcription in whole blood was measured using microarrays. The primary endpoint in this study was determined by measuring the transfer rate constant (Ktrans) of a gadolinium-based contrast agent from plasma to synovium using MRI. Secondary endpoints included repeated clinical assessments with DAS28(CRP), and assessments of osteitis and synovitis by the RAMRIS method. Infliximab showed greater decrease from baseline in DCE-MRI Ktrans of wrist and MCP at all visits compared with placebo (P<0.001). Statistical analysis was performed to identify genes associated with treatment-specific 14-week change in Ktrans. The 256 genes identified were used to derive a gene signature score by averaging their log expression within each patient. The resulting score correlated with improvement of Ktrans in infliximab-treated patients and with deterioration of Ktrans in placebo-treated subjects. Poor responders showed high expression of activated B cell genes whereas good responders exhibited a gene expression pattern consistent with mobilization of neutrophils and monocytes and high levels of reticulated platelets. This gene signature was significantly associated with clinical response in two previously published whole blood gene expression studies using anti-TNF therapies. These data provide support for the hypothesis that anti-TNF inadequate responders comprise a distinct molecular subtype of RA characterized by differences in pre-treatment blood mRNA expression. They also highlight the importance of placebo controls and robust, objective endpoints in biomarker discovery. TRIAL REGISTRATION: ClinicalTrials.gov NCT01313520. PMID- 25504082 TI - Self-organized ultrathin FePt nanowires produced by glancing-angle ion-beam codeposition on rippled alumina surfaces. AB - Ultradense macroscopic arrays of ferromagnetic alloy nanowires exhibit unique properties that make them attractive both for basic physics studies and for prospective nanodevice applications in various areas. We report here on the production of self-organized equiatomic FePt nanowires produced by glancing-angle ion-beam codeposition on alumina nanoripple patterns at room temperature and subsequent annealing at 600 degrees C. This study demonstrates that periodically aligned FePt nanowires with tunable size (~10-20 nm width and ~0.5-10 nm height) can be successfully grown as a consequence of shadowing effects and low mobility of Fe and Pt on the rippled alumina surface. Moreover, the structure and magnetic properties of the FePt nanowires, which undergo a phase transition from a disordered A1 (soft) structure to a partially ordered L10 (hard) structure, can be modified upon annealing. We show that this behavior can be further exploited to change the effective uniaxial anisotropy of the system, which is determined by a strong interplay between the shape and magnetocrystalline anisotropies of the nanowires. PMID- 25504083 TI - Pregnancy-associated breast cancer in women from Shanghai: risk and prognosis. AB - Breast cancer (BC) has been associated with pregnancy if diagnosed within 5-10 years after delivery (pregnancy-associated BC, PABC). PABC carries a poor prognosis compared to sporadic BC in Western populations. Data are limited regarding PABC in Asian populations, where longer periods of breastfeeding, higher birth rates and a lower median age of BC at diagnosis have been noted, all of which are known to influence prognosis. We used two datasets of women treated for early BC in Shanghai 1990-2012 (n = 10,161 and n = 7,411). For the analysis of BC risk after pregnancy we compared the distribution of pregnancy in our dataset to that in Shanghai using age-specific fertility rates. For disease-free survival (DFS) evaluation, we restricted our data to women <=45 years. Women <30 years had a significantly elevated BC risk within 5 years of completing a pregnancy compared to women who had not been pregnant in the previous 5 years. In women aged 20-24 the relative risk (RR) was 3.33 (P = 0.012), and for women aged 25-29 the RR was 1.76 (P = 0.0074). For women >30, the RR was decreased. Patients with PABC had a higher risk of recurrence or death (hazard ratio (HR) for DFS 1.72, P = 0.019) compared to women with non-PABC by univariable analysis. Age was eliminated from the multivariable model by backward selection, resulting in tumor stage (3 versus 1, HR 3.08, P < .001) and recent pregnancy (HR 1.62, P < 0.05) as significant independent prognosticators. Having had a full-term pregnancy in the previous 5 years was associated with a 62 % increased risk of recurrence. We show that recent full-term pregnancy significantly elevates BC risk in women <30 in Shanghai, and that women diagnosed with PABC have a particularly adverse prognosis. Health care providers and women in Asian populations should be made aware of these results. PMID- 25504086 TI - Piezo-phototronic Boolean logic and computation using photon and strain dual gated nanowire transistors. AB - Using polarization charges created at the metal-cadmium sulfide interface under strain to gate/modulate electrical transport and optoelectronic processes of charge carriers, the piezo-phototronic effect is applied to process mechanical and optical stimuli into electronic controlling signals. The cascade nanowire networks are demonstrated for achieving logic gates, binary computations, and gated D latches to store information carried by these stimuli. PMID- 25504084 TI - Physical and mechanical regulation of macrophage phenotype and function. AB - Macrophages are tissue-resident immune cells that play a critical role in maintaining homeostasis and fighting infection. In addition, these cells are involved in the progression of many pathologies including cancer and atherosclerosis. In response to a variety of microenvironmental stimuli, macrophages can be polarized to achieve a spectrum of functional phenotypes. This review will discuss some emerging evidence in support of macrophage phenotypic regulation by physical and mechanical cues. As alterations in the physical microenvironment often underlie pathophysiological states, an understanding of their effects on macrophage phenotype and function may help provide mechanistic insights into disease pathogenesis. PMID- 25504087 TI - Comparison of Scheimpflug imaging analysis of pellucid marginal corneal degeneration and keratoconus. AB - AIM: To determine and compare various quantitative parameters of pellucid marginal degeneration (PMD) and keratoconus with against-the-rule astigmatism (KC ARA) obtained by elevation-based Scheimpflug imaging and to identify characteristics that can be used to discriminate PMD from KC-ARA. SETTING: Ophthalmology Clinic, Ministry of Health Ankara Training and Research Hospital, Ankara, Turkey. DESIGN: Retrospective case-control study. PATIENTS AND METHODS: Patients with ARA, a butterfly or crab claw pattern in the curvature maps, a kissing bird pattern in the elevation maps and the bell sign in the pachymetric maps were identified, and 60 eyes of 40 patients were chosen for the evaluation. The patients were divided into two groups: the PMD group (29 eyes of 18 patients) and the KC-ARA group (31 eyes of 22 patients). By moving the cursor manually, the pachymetric maps and Scheimpflug images were searched for a thinner location than the automatically identified thinnest location. The coordinates and thickness of this manually identified location were evaluated. RESULTS: In the PMD group, 7 (24.1%) eyes did not have any thinner location than the automatically identified thinnest location on the pachymetric maps and the Scheimpflug images, and in 22 (75.8%) eyes, a thinner location, which was located more peripherally, was found by manual evaluation of the pachymetric maps or Scheimpflug images. In 9 (31.0%) eyes of these 22, the manually identified thinnest locations were visible on pachymetric maps, and in 13 (44.8%) eyes the more peripheral thinnest locations were not visible on pachymetric maps but on Scheimpflug images. In the KC group, no patients had thinner locations than the automatically identified thinnest points on the pachymetric maps and the Scheimpflug images. CONCLUSION: A more peripheral thinner location than the automatically identified thinnest location exists in most of the eyes with PMD. In KC-ARA eyes, a thinner location than the automatically found thinnest point does not exist. Accordingly, a more peripheral thinner point than the identified thinnest point is a very strong indication for PMD. PMID- 25504088 TI - Trends of acute hepatitis B notification rates in eastern China from 2005 to 2013. AB - Zhejiang Province was a high endemicity for hepatitis B disease in the 1990's. A number of measures implemented since then have begun to control and prevent hepatitis B. In 1992, hepatitis B vaccine came on the market. In 2002, hepatitis B vaccine was included in the national Expanded Programme on Immunization (EPI). Between 2007 and 2010, catch-up vaccination was implemented for children under 15. Since 2010, vaccination guidelines for high-risk groups have also been adopted. This study evaluated the impact of these control and prevention strategies on acute hepatitis B notification rates from 2005 through 2013. Data from the National Notifiable Disease Reporting System (NNDRS) revealed a steady downward trend in notification rates of acute hepatitis B. The most dramatic decline occurred among pre-adults, highlighting the benefits of EPI's policy of universal vaccination for children. However, the highest notification rates occurred among young adults of lower socio-economic status. These findings indicate the strong need to vaccinate young adults at risk for HBV infection as well as to collect risk-factor information in the NNDRS for monitoring and following up persons with acute hepatitis B. PMID- 25504089 TI - Experimental assessment of the network properties of the Drosophila circadian clock. AB - Circadian rhythms are conserved across kingdoms and coordinate physiology and behavior for appropriate time-keeping. The neuronal populations that govern circadian rhythms are described in many animal models, and the current challenge is to understand how they interact to control overt rhythms, remaining plastic enough to respond and adapt to a changing environment. In Drosophila melanogaster, the circadian network comprises about 150 neurons, and the main synchronizer is the neuropeptide pigment-dispersing factor (PDF), released by the well-characterized central pacemaker neurons, the small ventral lateral neurons (sLNvs). However, the rules and properties governing the communication and coupling between this central pacemaker and downstream clusters are not fully elucidated. Here we genetically manipulate the speed of the molecular clock specifically in the central pacemaker neurons of Drosophila and provide experimental evidence of their restricted ability to synchronize downstream clusters. We also demonstrate that the sLNv-controlled clusters have an asymmetric entrainment range and were able to experimentally assess it. Our data imply that different clusters are subjected to different coupling strengths, and display independent endogenous periods. Finally, the manipulation employed here establishes a suitable paradigm to test other network properties as well as the cell-autonomous mechanisms running in different circadian-relevant clusters. PMID- 25504090 TI - Protein classification and distribution in osteoarthritic human synovial tissue by matrix-assisted laser desorption ionization mass spectrometry imaging. AB - The remodeling of the synovial membrane, which normally lubricates the joints by producing synovial fluid, is one of the most characteristic events in the pathology of osteoarthritis (OA). The heterogeneity and spatial distribution of proteins in the synovial membrane are poorly studied and we hypothesized that they constitute excellent molecular disease classifiers for the accurate diagnosis of the disease. Matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) allows for the study of the localization and identification of hundreds of different molecules with high sensitivity in very thin tissue sections. In this work, we employed MALDI-MSI in combination with principal component analysis and discriminant analysis to reveal the specific profile and distribution of digested proteins in human normal and OA synovial membranes. Proteins such as hemoglobin subunit alpha 2, hemoglobin subunit beta, actin aortic smooth muscle, biglycan, and fibronectin have been directly identified from human synovial biopsies. In addition, we have determined the location of disease-specific OA markers. Some of them which are located in areas of low inflammation provide valuable information on tissue heterogeneity. Finally, we described the OA molecular protein signatures common to synovial and other articular tissues such as cartilage. For the first time, normal and OA human synovial membranes have been classified by MALDI-MSI, thus offering a new sensitive tool for the study of rheumatic pathologies. PMID- 25504085 TI - Intracellular signaling mechanisms of the melanocortin receptors: current state of the art. AB - The melanocortin system is composed by the agonists adrenocorticotropic hormone and alpha, beta and gamma-melanocyte-stimulating hormone, and two naturally occurring antagonists, agouti and agouti-related protein. These ligands act by interaction with a family of five melanocortin receptors (MCRs), assisted by MCRs accessory proteins (MRAPs). MCRs stimulation activates different signaling pathways that mediate a diverse array of physiological processes, including pigmentation, energy metabolism, inflammation and exocrine secretion. This review focuses on the regulatory mechanisms of MCRs signaling, highlighting the differences among the five receptors. MCRs signal through G-dependent and independent mechanisms and their functional coupling to agonists at the cell surface is regulated by interacting proteins, namely MRAPs and beta-arrestins. The knowledge of the distinct modulation pattern of MCRs signaling and function may be helpful for the future design of novel drugs able to combine specificity, safety and effectiveness in the course of their therapeutic use. PMID- 25504091 TI - Comparison of two exploratory data analysis methods for classification of Phyllanthus chemical fingerprint: unsupervised vs. supervised pattern recognition technologies. AB - In this study, unsupervised and supervised classification methods were compared for comprehensive analysis of the fingerprints of 26 Phyllanthus samples from different geographical regions and species. A total of 63 compounds were identified and tentatively assigned structures for the establishment of fingerprints using high-performance liquid chromatography time-of-flight mass spectrometry (HPLC/TOFMS). Unsupervised and supervised pattern recognition technologies including principal component analysis (PCA), nearest neighbors algorithm (NN), partial least squares discriminant analysis (PLS-DA), and artificial neural network (ANN) were employed. Results showed that Phyllanthus could be correctly classified according to their geographical locations and species through ANN and PLS-DA. Important variables for clusters discrimination were also identified by PCA. Although unsupervised and supervised pattern recognitions have their own disadvantage and application scope, they are effective and reliable for studying fingerprints of traditional Chinese medicines (TCM). These two technologies are complementary and can be superimposed. Our study is the first holistic comparison of supervised and unsupervised pattern recognition technologies in the TCM chemical fingerprinting. They showed advantages in sample classification and data mining, respectively. PMID- 25504092 TI - Does medical students' diagnostic performance improve by observing examples of self-explanation provided by peers or experts? AB - Educational strategies that promote the development of clinical reasoning in students remain scarce. Generating self-explanations (SE) engages students in active learning and has shown to be an effective technique to improve clinical reasoning in clerks. Example-based learning has been shown to support the development of accurate knowledge representations. The purpose of this study was to investigate the effect of combining student's SE and observation of peer's or expert's SE examples on diagnostic performance. Fifty-three third-year medical students were assigned to a peer SE example, an expert SE example or control (no example) group. All participants solved a set of the same four clinical cases (training cases), 1-after SE, 2-after listening to a peer or expert SE example or after a control task, and 3-1 week later. They solved a new set of four different cases (transfer cases) also 1 week later. For training cases, students improved significantly their diagnostic performance overtime but the main effect of group was not significant suggesting that students' SE mainly drives the observed effect. On transfer cases, there was no difference between the three groups (p > .05). Educational implications are discussed and further studies on different types of examples and additional strategies to help students actively process examples are proposed. PMID- 25504094 TI - Aging spine: spine special issue from China. PMID- 25504093 TI - Target risk factors for dementia prevention: a systematic review and Delphi consensus study on the evidence from observational studies. AB - OBJECTIVE: Dementia has a multifactorial etiology, but the importance of individual health and lifestyle related risk factors is often uncertain or based on few studies. The goal of this paper is to identify the major modifiable risk factors for dementia as a first step in developing an effective preventive strategy and promoting healthy late life cognitive functioning. METHODS: A mixed method approach combined findings from a systematic literature review and a Delphi consensus study. The literature search was conducted in PubMed and updated an earlier review by the United States National Institutes of Health from 2010. We reviewed the available evidence from observational epidemiological studies. The online Delphi study asked eight international experts to rank and weigh each risk factor for its importance for dementia prevention. RESULTS: Out of 3127 abstracts, 291 were included in the review. There was good agreement between modifiable risk factors identified in the literature review and risk factors named spontaneously by experts. After triangulation of both methods and re weighting by experts, strongest support was found for depression, (midlife) hypertension, physical inactivity, diabetes, (midlife) obesity, hyperlipidemia, and smoking, while more research is needed for coronary heart disease, renal dysfunction, diet, and cognitive activity. CONCLUSIONS: Findings provide good support for several somatic and lifestyle factors and will be used to inform the design of a new multicenter trial into dementia prevention. PMID- 25504095 TI - A unique meeting pay attention to the interdisciplinary subjects around orthopedics: Jishuitan Orthopaedic Forum. PMID- 25504096 TI - A review of osteoporotic vertebral fracture nonunion management. AB - Osteoporotic vertebral fractures are a frequently encountered clinical problem, and like other fractures, they may develop nonunion that can often go unrecognized. The aim of this study is to review the related articles reporting the osteoporotic vertebral fracture nonunion and discuss the radiological characteristics, diagnosis, and treatment of osteoporotic vertebral fractures. PMID- 25504097 TI - The correlation between ossification of the nuchal ligament and pathological changes of the cervical spine in patients with cervical spondylosis. AB - STUDY DESIGN: A retrospective clinical data analysis. OBJECTIVE: This study was conducted to investigate the correlation between ossification of the nuchal ligament (ONL) and pathological changes of the cervical spine in patients with cervical spondylosis. SUMMARY OF BACKGROUND DATA: ONL can usually be found in cervical spondylosis. Thus, it is important to find the correlation between ONL and pathological changes of the cervical spine in patients with cervical spondylosis. METHODS: The medical records of 100 patients with cervical spondylosis with the local type of ONL (ONL group) and 50 patients with cervical spondylosis only (control group) were reviewed. Data analysis included patients' sex, age, location of ONL, maximum cord compression level, osteophyte height ratio, and grade of cervical intervertebral disc degeneration. Radiological features were evaluated by lateral plain radiography and magnetic resonance imaging. RESULTS: In total, 69.0% of subjects in the ONL group had ONL located at the maximum cord compression level; there was no difference based on sex (P = 0.248). The value of the osteophyte height ratio was higher at the ONL level than at its superior and inferior adjacent segments (P < 0.001). The osteophyte height ratio was also significantly different at the C4-C5 (P < 0.001) and C5-C6 (P = 0.008) levels between the ONL group and the control group. There was a significant difference in distribution of intervertebral disc degeneration grading between the ONL level and superior adjacent segments (P = 0.028), as well as inferior adjacent segments (P = 0.049). The distribution of intervertebral disc degeneration grading at the C5-C6 level between patients whose location of ONL and maximum cord compression level were both at C5-C6 and patients whose maximum cord compression level was at C5-C6 in the control group was also significantly different (P = 0.035). CONCLUSION: The location of ONL commonly corresponds to the most stenotic level of the spinal canal. The location of ONL also correlates with the level of osteophyte formation and intervertebral disc degeneration, indicating that ONL has correspondence to instability-related cervical pathological changes in cervical spondylosis. PMID- 25504098 TI - A comparison between unilateral transverse process-pedicle and bilateral puncture techniques in percutaneous kyphoplasty. AB - STUDY DESIGN: A prospective comparative study. OBJECTIVE: To assess the clinical and radiological outcomes for the treatment of osteoporotic vertebral compression fractures using unilateral transverse process-pedicle and bilateral percutaneous kyphoplasty (PKP). SUMMARY OF BACKGROUND DATA: PKP is a widely used vertebral augmentation procedure for treating painful vertebral compression fractures. A percutaneous bilateral approach is typically used to access the vertebral body. Many previous studies have reported excellent clinical results with PKP. In contrast, numerous complications and problems have also been reported, such as puncture difficulty, cement leakage, and adjacent vertebral fracture. METHODS: This prospective study included 316 patients with single-level lumbar osteoporotic vertebral compression fracture, 224 females and 92 males with a mean age of 71.5 years. Randomized patients underwent PKP using 2 different puncture techniques. The patients were followed up postoperatively and were assessed mainly with regard to clinical and radiological outcomes. Clinical outcomes were evaluated mainly using the visual analogue scale for pain and 36-Item Short Form Health Survey (SF-36) questionnaire for health status. Radiological outcomes were assessed mainly on the basis of radiation dose, bone cement distribution, vertebral body height, and kyphotic angle. RESULTS: Patients were followed up from 12 to 28 months, with an average of 16.8 months. One hundred fifty-eight patients were treated with unilateral method and 151 patients were treated with bilateral method. In the unilateral group, the volume of the injected cement and radiation dose were significantly less than that in the bilateral group. All patients in both groups had significantly less pain after the procedures, compared with their preoperative period pain. No statistically significant differences were observed when visual analogue scale and 36-Item Short Form Health Survey were compared between the groups. Both unilateral and bilateral groups showed insignificant decrease in the kyphotic angle during the follow-ups. The kyphotic angle in the unilateral group improved more significantly than in the bilateral group. In the bilateral group, 16 patients had obvious pain in the puncture sites at 1 month postoperatively caused by facet joint violation. With local block treatment, the pain disappeared in all patients at the last follow up. CONCLUSION: Both bilateral and unilateral PKP are relatively safe and provide effective treatment for patients with painful osteoporotic vertebral compression fracture. However, unilateral PKP received less radiation dose and operation time, it also offered a higher degree of deformity correction and resulted in less complication than bilateral PKP. PMID- 25504099 TI - Krag versus Caudad trajectory technique for pedicle screw insertion in osteoporotic vertebrae: biomechanical comparison and analysis. AB - STUDY DESIGN: To compare in detail the effects of pedicle screw insertion in osteoporotic vertebrae via Krag and Caudad trajectory techniques. OBJECTIVE: To compare the biomechanical stability of 2 pedicle screw fixation techniques and to correlate the stability of the pedicle screw with quantitative computed tomography (QCT). SUMMARY OF BACKGROUND DATA: Pedicle screw fixation is commonly used to facilitate fusion and postoperative rehabilitation. Fixation failure and loosening in the metal-bone interface are frequent, with osteoporosis usually a major factor. Pedicle screw fixation in osteoporotic spines is of particular concern regarding implant failure. Few reports have addressed which fixation method provides better biomechanical strength and thus presents less risk of failure. METHODS: Eleven cadaveric vertebrae were harvested and subjected to dual energy x-ray absorptiometry and QCT to assess bone mineral density. Matched, polyaxial pedicle screws were inserted into the left and right pedicles of each vertebra. Screws were randomly assigned to the Caudad or Krag group by right or left side. They were inserted under 3-dimensional navigation system assistance. Cyclic loading tests were performed (maximum load 250 N, 3 Hz, up to 30,000 cycles) while recording load and displacement. Pullout tests were performed if the cyclic loading test was completed. Stiffness quotients were calculated. RESULTS: Cycle-displacement curves showed more pedicle screw dislodgement in the Krag than the Caudad group (P < 0.01). Initially, stiffness was significantly higher in the Caudad group (P < 0.01), but the difference diminished thereafter. In the Caudad group, bone mineral density measured by QCT was significantly correlated with several biomechanical parameters. CONCLUSION: Pedicle screws inserted in osteoporotic lumbar vertebrae using the Caudad trajectory displayed significantly higher biomechanical strength than those inserted using the Krag trajectory, especially during early fixation. Stability of pedicle screw fixation using the Caudad trajectory technique can be estimated by QCT. PMID- 25504100 TI - Vertebral rotatory subluxation in degenerative scoliosis: facet joint tropism is related. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVE: To identify facet tropism as one of the possible risk factors leading to vertebral rotatory subluxation (VRS). SUMMARY OF BACKGROUND DATA: VRS has been considered as one of the prognostic factors for degenerative scoliosis. Although several risk factors of VRS, including age and Cobb angle, have been investigated, few studies exist that have evaluated the correlation between VRS and anatomical structures of the vertebral column. METHODS: This retrospective study recruited 23 patients diagnosed with degenerative lumbar scoliosis with VRS and 20 patients with degenerative scoliosis without VRS. The lateral translation on coronal radiographs was measured and 5 mm was used as the cutoff value to define rotatory subluxation. Computed tomographic scans for facet joints were made for all lumbar levels. The difference between right and left facet angles was recorded as DeltaFA. Facet tropism was defined as a difference between the bilateral facet angles of more than 10 degrees . RESULTS: In this study, VRS was most commonly found at the L3 L4 level (49%) and, with decreasing frequency at L2-L3 (24%), L4-L5 (20%), and L1 L2 (7%). On the convex side of the main curve, face joints at levels with VRS were more coronally oriented compared with those at levels without VRS (41.64 degrees +/- 11.65 degrees vs. 36.30 degrees +/- 10.99 degrees , P = 0.034). DeltaFA was also significantly different between levels with and without VRS (P = 0.005). A strong correlation was found between DeltaFA and lateral translation, with a coefficient of 0.33 (P < 0.001). In addition, DeltaFA and a larger Cobb angle were found to be significantly associated with VRS based on binary regression analysis, with an odds ratio of 4.68 and 2.14, respectively. CONCLUSION: Facet tropism was more significantly observed at levels with VRS. On the convex side of the main curve, facet joints at levels with VRS were more coronally oriented. A larger Cobb angle and severe facet tropism in degenerative scoliosis should be considered to be related to VRS. PMID- 25504101 TI - An analysis of spinopelvic sagittal alignment after lumbar lordosis reconstruction for degenerative spinal diseases: how much balance can be obtained? AB - STUDY DESIGN: A retrospective and radiological study of degenerative spinal diseases. OBJECTIVE: To explore the changes in spinopelvic sagittal alignment after lumbar instrumentation and fusion of degenerative spinal diseases. SUMMARY OF BACKGROUND DATA: Efforts have been paid to clarify the ideal postoperative sagittal profile for degenerative spinal diseases. However, little has been published about the actual changes of sagittal alignment after lumbar lordosis reconstruction. METHODS: Radiographical analysis of 83 patients with spinal degeneration was performed by measuring sagittal parameters before and after operations. Comparative studies of sagittal parameters between short (1 level) and long (>= 2 level) instrumentation and fusion were performed. Different variances (Delta) of these sagittal parameters before and after operations were calculated and compared. Correlative study and linear regression were performed to establish the relationship between variances. RESULTS: No significant changes were shown in the short-fusion group postoperatively. In the long-fusion group, postoperative lumbar lordosis (LL) and sacral slope (SS) were significantly increased; pelvic tilt (PT), sagittal vertical axis (SVA), pelvic incidence minus lumbar lordosis, and PT/SS were significantly decreased. Different variances of DeltaLL, DeltaSS, DeltaPT, DeltaSVA, Delta(pelvic incidence - LL), and DeltaPT/SS were significantly greater in the long-fusion group than the short-fusion group. Close correlations were mainly shown among DeltaLL, DeltaPT, and DeltaSVA. Linear regression equations could be developed (DeltaPT = -0.185 * DeltaLL - 7.299 and DeltaSVA = -0.152DeltaLL - 1.145). CONCLUSION: In degenerative spinal diseases, long instrumentation and fusion (>= 2 levels) provides more efficient LL reconstruction. PT, SS, and SVA improve corresponding to LL in a linear regression model. Linear regression equations could be developed and used to predict PT and SVA change after long instrumentation and fusion for LL reconstruction. PMID- 25504103 TI - Stereoselective synthesis and physicochemical properties of liquid-crystal compounds possessing a trans-2,5-disubstituted tetrahydropyran ring with negative dielectric anisotropy. AB - Three stereoselective syntheses and the physicochemical properties of trans,trans 5-(4-ethoxy-2,3-difluorophenyl)-2-(4-propylcyclohexyl)tetrahydropyran, which is an important liquid-crystal compound with a large negative dielectric anisotropy (Deltaepsilon=-7.3), are described. The key step in the construction of the trans 2,5-disubstituted tetrahydropyran ring in the first approach involved a benzylic cation mediated intramolecular olefin cyclization of a 2-allyloxy-1-arylethanol derivative. The second method included the Et2 Zn-induced 1,2-aryl shift of a bromohydrin obtained from a hetero-Diels-Alder reaction, followed by stereoselective bromination. The third approach utilized the hetero-Diels-Alder reaction of trans-4-propylcyclohexanecarboxaldehyde and a 2-aryl-3 (trimethylsilyl)oxy-1,3-butadiene, followed by stereoselective protonation. From results obtained by using a quantum chemical calculation method, the reason why the target compound shows a large negative Deltaepsilon value is discussed. PMID- 25504102 TI - Posterolateral transforaminal selective endoscopic diskectomy with thermal annuloplasty for discogenic low back pain: a prospective observational study. AB - STUDY DESIGN: A prospective observational study on 113 patients with 3 years of follow-up. OBJECTIVE: To evaluate the clinical results of therapy for discogenic low back pain (DLBP) with posterolateral transforaminal selective endoscopic diskectomy and thermal annuloplasty (PEDTA). SUMMARY OF BACKGROUND DATA: Currently, various minimally invasive techniques are widely used to treat chronic DLBP with variable clinical outcomes. PEDTA is considered to be a novel, minimally invasive technique for treating chronic DLBP, but the evidence supporting this technique is very limited, and there are no studies demonstrating at least 3 years of follow-up. METHODS: One hundred thirteen consecutive patients with DLBP with positive concordant pain in discography underwent PEDTA from March 2008 to March 2010. These patients included 64 males and 49 females with a mean age of 43.7 years (range, 16-75 yr). The visual analogue scale score, Japanese Orthopedic Association score, and Oswestry Disability Index were evaluated before therapy and each year after surgery. The clinical global outcomes were assessed on the basis of modified MacNab criteria at 3 years after surgery. RESULTS: Ninety-six patients underwent a single-level procedure, and 17 patients underwent multilevel procedures. One hundred one (89.4%) cases were followed up for 3 years. There were no serious complications observed during follow-up. The success rate (excellent and good) was 73.8%. The visual analogue scale score, Japanese Orthopedic Association score and Oswestry Disability Index had significantly improved at each year after surgery (P < 0.01, compared with presurgery). The success rate in patients who underwent a single-level procedure was remarkably higher than that in patients who underwent multilevel procedures (78.2% vs. 50.0%, P = 0.041). CONCLUSION: PEDTA presents a safe and effective treatment for carefully selected groups of patients with DLBP. Better clinical results occurred in patients with single-level discogenic pain. PMID- 25504104 TI - Bilateral osteochondrosis of the distal tibial epiphysis: a case report. AB - Osteochondrosis is a developmental disease characterized by an alteration of endochondral ossification. Genetic causes, repetitive mechanical stresses, vascular abnormalities, hormonal imbalances, and interruption of the blood supply to the epiphyseal cartilage are all described causes of osteochondrosis and the etiology is probably multifactorial. Osteochondrosis can occur in different apophysis and epiphysis in all immature skeletons. Distal tibial epiphysis is rarely involved and most of the time unilaterally. We report on an 11-year-old female with bilateral osteochondrosis on distal tibial epiphysis. Only one other similar case has been described in the literature to date. PMID- 25504106 TI - Vaginal chlorhexidine during labour to prevent early-onset neonatal group B streptococcal infection. AB - BACKGROUND: Although early-onset group B beta-hemolytic streptococcus (GBS) infection is rare, it accounts for approximately 30% of neonatal infections, has a high mortality rate, and is acquired through vertical transmission from colonized mothers. Several trials have demonstrated the efficacy of intrapartum antibiotic prophylaxis (IAP) for preventing early-onset disease (EOD). Vaginal disinfection with chlorhexidine during labour has been proposed as another strategy for preventing GBS EOD in the preterm and term neonate. Chlorhexidine has been found to have no impact on antibiotic resistance, is inexpensive, and applicable to poorly equipped delivery sites. OBJECTIVES: To determine the effectiveness of vaginal disinfection with chlorhexidine during labour in women who are colonized with GBS for preventing early-onset GBS infection in preterm and term neonates. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2014) and reference lists of retrieved studies. SELECTION CRITERIA: Randomized and quasi-randomized trials comparing vaginal disinfection with chlorhexidine (vaginal wash or gel/cream) versus placebo, or no treatment. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the trials for inclusion and risk of bias, extracted the data and checked them for accuracy. MAIN RESULTS: We identified no new trials eligible for inclusion in this update. One study was moved from included to excluded studies from the previous version of the review. Four studies, including 1125 preterm and term infants, met the inclusion criteria and reported on at least one of the outcomes of interest. For the comparison chlorhexidine (vaginal wash or gel) versus placebo or no treatment, two studies (n = 987) were pooled. There was no statistically significant difference in early onset GBS disease (sepsis and/or meningitis) comparing chlorhexidine (vaginal wash or gel/cream) versus placebo or no treatment; risk ratio (RR), 2.32 (95% confidence interval (CI) 0.34 to 15.63); I-squared (I2) = 0% or in GBS pneumonia; RR 0.35 (95% CI 0.01 to 8.6); test for heterogeneity not applicable. The outcome of colonization of the neonate with GBS was reported in three studies (n = 328); RR 0.64 (95% CI 0.40 to 1.01; there was substantial between-study heterogeneity (Chi2 = 3.19; P = 0.20; I2 = 37%). Maternal mild side effects (stinging or local irritation) (three trials, 1066 women) were more commonly seen in women treated with chlorhexidine (RR 8.50 (95% CI 1.60 to 45.28); there was no heterogeneity (Chi2 = 0.01, df = 1 (P = 0.91); I2 = 0%). No side effects were reported among the neonates.For the comparison chlorhexidine vaginal wash verus mechanical washing with placebo or no treatment (one study, n = 79), there was a significant reduction in neonatal colonization with GBS; RR 0.32 (95% CI 0.12 to 0.90). Tests for heterogeneity not applicable. There were no other significant results for this comparison.For the comparison chlorhexidine gel or cream versus placebo or no treatment, there were no statistically significant results for the outcomes reported on.The quality of the trials varied and the overall risk of bias was rated as unclear or high. The quality of the evidence using GRADE was very low for the outcomes of the comparison chlorhexidine (vaginal wash or gel/cream) versus placebo or no treatment. These outcomes included: early-onset GBS disease (sepsis and/or meningitis), GBS pneumonia, neonatal colonization with GBS, neonatal mortality due to early-onset GBS infection and adverse (mild) effects in the mother and the neonate. AUTHORS' CONCLUSIONS: The quality of the four included trials varied as did the risk of bias and the quality of the evidence using GRADE was very low. Vaginal chlorhexidine was not associated with reductions in any of the primary outcomes of early-onset GBS disease (sepsis and/or meningitis) or GBS pneumonia. Vaginal chlorhexidine may reduce GBS colonization of neonates. The intervention was associated with an increased risk of maternal mild adverse effects. The review currently does not support the use of vaginal disinfection with chlorhexidine in labour for preventing early-onset disease. Results should be interpreted with caution as the methodological quality of the studies was poor. As early-onset GBS disease is a rare condition trials with very large sample sizes are needed to assess the effectiveness of vaginal chlorhexidine to reduce its occurrence. In the era of intrapartum antibiotic prophylaxis, such trials may be difficult to justify especially in developed countries. PMID- 25504107 TI - Biomechanical analyses of the human flexor tendon adhesion models in the hand: A cadaveric study. AB - Patients with longstanding trigger finger may develop flexion contracture at the proximal interphalangeal (PIP) joint that persists even after division of the A1 pulley. The purpose of this study was to explore the hypothesis that flexion deformity of the PIP joint in advanced trigger finger is caused by severe adhesion between the flexor digitorum superficialis (FDS) and the flexor digitorum profundus (FDP) tendons. Ten freshly frozen cadaveric hands were used in the experiments. After preparation of the extrinsic flexor, extrinsic extensor, and intrinsic muscle tendons, we applied weights to the flexor tendons and minimal tension to the extrinsic extensor and intrinsic muscle tendons. We then measured the initial flexion angles of the metacarpophalangeal (MCP) and PIP joints. Next, we measured the flexion angles of the MCP and PIP joints as increasing tension was applied to the extrinsic extensor and intrinsic muscle tendons, respectively. We repeated these experiments after constructing flexor tendon adhesion model. The initial flexion angles of the MCP and PIP joints were greater in the adhesion model, as were the average tensions required for full extension of these joints. Our results suggest that adhesion between two flexor tendons contributes to progression of flexion deformity in the PIP joint. PMID- 25504105 TI - Long-Term Gestational Hypoxia Modulates Expression of Key Genes Governing Mitochondrial Function in the Perirenal Adipose of the Late Gestation Sheep Fetus. AB - We previously reported that long-term hypoxia (LTH) increases expression of brown adipose tissue (BAT) genes in the perirenal adipose in the ovine fetus. The mechanisms with which hypoxia mediates the enhanced BAT phenotype are unresolved. This study was designed to examine the effects of LTH on (1) the expression of endothelial cell nitric oxide synthase (eNOS) and (2) indicators of mitochondrial biogenesis (transcription factors mitochondrial transcription factor A (mtTFA), nuclear respiratory factor (NRF) 1, and NRF-2; cytochrome c oxidase (COX) I, II, and IV and mitochondrial DNA content). Pregnant ewes were maintained at high altitude (3820 m) from ~40 to 137 to 140 days of gestation and perirenal adipose was collected from normoxic control and LTH fetuses. There was no effect of LTH on fetal body weight or perirenal adipose mass. Long-term hypoxia increased (P < .05) perirenal eNOS and phospho-eNOS, messenger RNA (mRNA) for NRF1, NRF-2, mtTFA as well as COX-I, COX-II, and COX-IV mRNA. In contrast, mRNA for 2 markers for cellular proliferation (Ki67 and proliferating cell nuclear antigen [PCNA]) was lower in perirenal adipose from LTH fetuses compared to controls (P < .05), while mitochondrial to nuclear DNA ratio did not differ between groups. In conclusion, nitric oxide may function as a mechanism via which LTH enhances the BAT phenotype in fetal sheep prior to birth. Although there is an apparent increase in genes supporting mitochondrial function and adaptive thermogenesis in response to LTH, there does not appear to be an increased mitochondrial biogenesis per se. Such adaptive changes may provide a mechanism for the prominence of the BAT phenotype observed in the late gestation LTH fetus. PMID- 25504108 TI - Downregulation of CXCR4 by SDF-KDEL in SBC-5 cells inhibits their migration in vitro and organ metastasis in vivo. AB - Metastasis is the principal cause of morbidity and mortality in cancer patients. The master genes that govern organ-selective metastasis remain elusive. We compared the expression levels of C-X-C chemokine receptor type 4 (CXCR4) in the human small cell lung cancer (SCLC) cells, SBC-5 and SBC-3, by flow cytometric analysis and found that CXCR4 was expressed at markedly higher levels in the SBC 5 cells which can produce multiple organ metastasis, particularly bone metastasis compared to the SBC-3 cells. Stromal-derived-factor-1 (SDF-1)-CXCR4 has been shown to regulate cell migration and metastasis in a various types of cancer; however, the roles of SDF-1-CXCR4 in the organ-selective metastasis of SCLC in vivo remain to be elucidated. Thus, in this study, we constructed a phenotype of SBC-5 cells in which CXCR4 was knocked out using the intrakine strategy and found that the downregulation of CXCR4 inhibited cell migration and invasion, but did not affect cell proliferation or apoptosis in vitro. In in vivo experiments, the knockout of CXCR4 suppressed the development of metastastic lesions in the lungs, liver and bone, but did not decrease metastasis to the kidneys. Our data demonstrate that CXCR4 is a candidate gene involved in the development of metastastic lesions in specific organs, such as the lungs, bone and liver, which can secrete high concentrations of SDF-1, the sole ligand of CXCR4. Thus, CXCR4 may prove to be a promising target for the prevention and effective treatment of metastastic lesions due to SCLC. PMID- 25504110 TI - Population genetic data of 15 STR loci in Gansu Han population from China. AB - The genetic polymorphisms of 15 autosomal short tandem repeat (STR) loci included in the AmpFISTR SinofilerTM kit were evaluated in 547 healthy unrelated Han individuals from Gansu, China. All of the loci reached the Hardy-Weinberg equilibrium after the Bonferroni correction (p > 0.0033). These loci were examined to determine allele frequencies and forensic statistical parameters. The combined discrimination power and probability of excluding paternity of the 15 STR loci were 0.999999 and 0.995097, respectively. Results suggested that the 15 STR loci are highly polymorphic, which is suitable for forensic personal identification and paternity testing. PMID- 25504109 TI - Once-monthly continuous erythropoietin receptor activator (CERA) for haemoglobin maintenance in haemodialysis patients with chronic renal anaemia. AB - BACKGROUND: This study was conducted to evaluate the efficacy and safety of once monthly continuous erythropoietin receptor activator (CERA) for maintenance of stable haemoglobin (Hb) levels in adult chronic renal anaemia patients on dialysis according to local clinical judgment in Turkey. METHODS: This was a prospective, open-label, single-arm, multi-centre study conducted in 20 centres in Turkey. After a 4-week screening period, eligible patients receiving conventional erythropoiesis-stimulating agents were converted to monthly intravenous CERA and entered a 16-week CERA dose-titration period (DTP) followed by an 8-week efficacy evaluation period (EEP) and a 4-week safety follow-up. The primary endpoint was the proportion of patients whose Hb concentration remained stable within +/-1.0 g/dL of their reference Hb and within the range of 10.0-12.0 g/dL during the EEP. RESULTS: A total of 173 patients were screened, 132 entered the DTP and 84 completed the study. Thirty-nine patients [46.4% (95% confidence interval: 35.5-57.7%)] maintained stable target Hb concentrations. The mean change in time-adjusted average Hb concentration was 0.29 +/- 1.08 g/dL between baseline and the EEP. The mean CERA monthly dose was 112.4 +/- 76.78 ug during the EEP, and the CERA dose was adjusted in 39 patients (36.4%). Eleven patients (8.4%) reported 13 treatment-related adverse events, the most frequent adverse events being infections and infestations, gastrointestinal and vascular disorders. CONCLUSIONS: Once-monthly CERA maintains stable Hb concentrations in chronic renal anaemia patients on dialysis in Turkey. The study results confirm the known efficacy and safety profile of CERA. PMID- 25504112 TI - Erratum to: European adolescent ready-to-eat-cereal (RTEC) consumers have a healthier dietary intake and body composition compared with non-RTEC consumers. PMID- 25504113 TI - Molecular containers. PMID- 25504111 TI - Cinnamaldehyde is the main mediator of cinnamon extract in mast cell inhibition. AB - PURPOSE: In terms of their involvement in allergic and inflammatory conditions, mast cells (MC) can be promising targets for medical agents in therapy. Because of their good compliance and effectiveness, phytochemicals are of great interest as new therapeutic tools in form of nutraceuticals. We found recently that cinnamon extract (CE) inhibits mast cell activation. Here, we analysed the effects of a major compound of CE, cinnamaldehyde (CA), on mast cell activation. METHODS: Release of prestored and de novo synthesised mediators as well as expression of pro-inflammatory cytokines and mast cell-specific proteases were analysed in RBL-2H3 cells or in human mast cells isolated from intestinal tissue (hiMC) treated with CA prior to stimulation by FcepsilonRI crosslinking or IONO/PMA. The results were compared with the corresponding effects of CE. RESULTS: Following treatment with CA, release of beta-hexosaminidase in IgE dependent or IgE-independent activated RBL-2H3 cells was down-regulated in a dose dependent manner to about 10%. In hiMC, release of beta-hexosaminidase was also significantly reduced, and release of LTC4 and CXCL8 was almost completely inhibited by CA. Moreover, IgE-mediated expression of CXCL8, CCL2, CCL3 and CCL4 in hiMC was significantly down-regulated by CA. With the exception of the expression of the mast cell proteases tryptase and chymase, the inhibitory effects of CA were very similar to the effects shown for CE treatment. The reducing effect of CA on mast cell mediators-seen for long- and for short-term incubations-could be related to particular signalling pathways as CA caused a down-regulation in ERK as well as PLCgamma1 phosphorylation. CONCLUSIONS: CA decreases release and expression of pro-inflammatory mast cell mediators. This inhibitory action is similar to the effects observed for CE indicating CA as the main active compound in CE leading to its anti-allergic properties. PMID- 25504114 TI - Sponges with covalently tethered amines for high-efficiency carbon capture. AB - Adsorption using solid amine sorbents is an attractive emerging technology for energy-efficient carbon capture. Current syntheses for solid amine sorbents mainly based on physical impregnation or grafting-to methods (for example, aminosilane-grafting) lead to limited sorbent performance in terms of stability and working capacity, respectively. Here we report a family of solid amine sorbents using a grafting-from synthesis approach and synthesized by cationic polymerization of oxazolines on mesoporous silica. The sorbent with high amount of covalently tethered amines shows fast adsorption rate, high amine efficiency and sorbent capacity well exceeding the highest value reported to date for low temperature carbon dioxide sorbents under simulated flue gas conditions. The demonstrated efficiency of the new amine-immobilization chemistry may open up new avenues in the development of advanced carbon dioxide sorbents, as well as other nitrogen-functionalized systems. PMID- 25504115 TI - Noise monitoring and adverse health effects in residents in different functional areas of Luzhou, China. AB - The purpose of the study was to investigate the noise pollution situation and the resulting adverse effect on residents' health in Luzhou, China, to provide data for noise pollution prevention policies and interventions. Four different functional areas (commercial, construction, residential, and transportation hub areas) were chosen to monitor noise level for 3 months. The survey was performed by questionnaire on the spot on randomly selected individuals; it collected data on the impact of noise on residents' health (quality of sleep, high blood pressure, subjective feeling of nervous system damage, and attention) as well as the knowledge of noise-induced health damage, the degree of adaptation to noise, and their solutions. The noise levels of residential, commercial, transportation, and construction areas exceeded the national standards (P < .001). Sleep quality, prevalence of hypertension, and attention in transportation hub areas were significantly different from those in the other 3 areas (P < .05); only 24.46% of people knew the health hazards associated with noise; 64.57% of residents have adapted to the current noise environment. Most of them have to close the doors and windows to reduce noise. The noise pollution situation in Luzhou, China, is serious, especially the traffic noise pollution. Residents pay less attention to it and adopt single measures to reduce the noise. We should work toward the prevention and control of traffic noise and improve the residents' awareness to reduce the adverse health effects of noise. PMID- 25504116 TI - Snai1 promotes ESC exit from the pluripotency by direct repression of self renewal genes. AB - Although much is known about the pluripotency self-renewal circuitry, the molecular events that lead embryonic stem cells (ESCs) exit from pluripotency and begin differentiation are largely unknown. We found that the zinc finger transcription factor Snai1, involved in gastrulation and epithelial-mesenchymal transition, is already expressed in the inner cell mass of the preimplantation blastocysts. In ESCs, Snai1 does not respond to TGFbeta or BMP4 signaling but it is induced by retinoic acid treatment, which induces the binding, on the Snai1 promoter, of the retinoid receptors RARgamma and RXRalpha, the dissociation of the Polycomb repressor complex 2 which results in the decrease of H3K27me3, and the increase of histone H3K4me3. Snai1 mediates the repression of pluripotency genes by binding directly to the promoters of Nanog, Nr5a2, Tcl1, c-Kit, and Tcfcp2l1. The transient activation of Snai1 in embryoid bodies induces the expression of the markers of all three germ layers. These results suggest that Snai1 is a key factor that triggers ESCs exit from the pluripotency state and initiate their differentiation processes. PMID- 25504117 TI - Chemically powered micro- and nanomotors. AB - Chemically powered micro- and nanomotors are small devices that are self propelled by catalytic reactions in fluids. Taking inspiration from biomotors, scientists are aiming to find the best architecture for self-propulsion, understand the mechanisms of motion, and develop accurate control over the motion. Remotely guided nanomotors can transport cargo to desired targets, drill into biomaterials, sense their environment, mix or pump fluids, and clean polluted water. This Review summarizes the major advances in the growing field of catalytic nanomotors, which started ten years ago. PMID- 25504118 TI - [Colombian National Health Observatory: health knowledge management for informed decision making]. PMID- 25504119 TI - Down syndrome passed from mother to child. AB - Down syndrome is the leading cause of inherited intellectual disability; it is characterized by mental retardation associated to physical growth delay and certain physical traits or features. It is caused by the presence of a third copy of chromosome 21, being this trisomy the most common chromosomal aneuploidy. Women with Down syndrome are less fertile, and pregnancy in these women is rare, although the information on exact statistics of reproduction in these patients is very limited, and they often have difficulties with miscarriage, premature birth, and difficult labor. We report the case of a preterm newborn with Down syndrome passed from her mother; this pregnancy was a result of sexual assault, which is an event that can and should be prevented in this population. PMID- 25504120 TI - [Application of advanced neuroimaging in motor rehabilitation]. AB - INTRODUCTION: Functional magnetic resonance imaging is a noninvasive technique that allows mapping and visualizing of brain connectivity networks. The hemiparesis after a stroke is a good biological model to study changes in brain connectivity. This model can be expanded if information is obtained before and after neurorehabilitation therapy. OBJECTIVE: To present the functional neuroimaging findings in a patient with stroke before and after performing neurorehabilitation therapy. MATERIALS AND METHODS: As part of the neurorehabilitation protocol, resonance imaging was performed before and after treatment with an equipment operating at 1.5 T. Volumetric T1-weighted images, diffusion images for tractography, functional resonance images with the patient at rest and with the patient performing pincer movement with the right hand were obtained. RESULTS: Functional maps before and after therapy were obtained, which are presented together with structural connectivity images obtained by tractography. Clinical changes can be seen accompanied by changes in activation patterns obtained by functional magnetic resonance imaging. CONCLUSION: The versatility of magnetic resonance imaging allows further knowledge of the structural and functional state of the brain generating new possibilities for diagnosis and prognosis in patients undergoing neurorehabilitation therapy. Neurological rehabilitation processes can be quantified and they can reveal certain postlesional neuroplasticity dynamic processes that the central nervous system possesses. PMID- 25504121 TI - Zosteriform cutaneous leishmaniasis due to Leishmania ( Viannia ) panamensis and Leishmania ( Viannia ) braziliensis: report of three cases. AB - In Colombia, zosteriform leishmaniasis is a little-known and infrequent clinical variant of cutaneous leishmaniasis. Its clinical features include one or more plaques made up of papules and pseudo-vesicles, which conform to a lineal pattern, as well as satellite lesions that affect one or more dermatomes, without crossing the median line. We present three zosteriform cutaneous leishmaniasis cases in which Leishmania panamensis and Leishmania braziliensis were identified as the infective species. In light of the fact that the disease occurs infrequently, diagnosis was reached by taking into account epidemiological and clinical suspicion. PMID- 25504122 TI - [Economic burden of methicillin-resistant Staphylococcus aureus bacteremia in critical care patients in hospitals in Bogota]. AB - INTRODUCTION: Resistant infections, especially those involving the bloodstream, are associated with a greater use of resources. Their estimates are variable and depend on the methodology used. Staphylococcus aureus is the main pathogen isolated in blood in our hospitals. There is no consolidated data about economic implications of methicillin-resistant S. aureus infection. OBJECTIVE: To describe the cost of care of methicillin-resistant S. aureus bacteremia in a reference population from nine hospitals in Bogota. Materials y methods: A multicenter cohort study included 204 patients in a 1:1 ratio according to resistance. Direct medical costs were calculated from hospitalization bills, while the bacteremia period was calculated by applying microcosting based on standard fares. RESULTS: We found no significant differences between groups in demographic and clinical characteristics, except for resistance risk factors. Fifty-three percent of patients died during hospitalization. Hospital stay and total invoiced value during hospitalization were significantly higher in the group with methicillin resistant S. aureus bacteremia. For this group, higher costs in ICU stay, antibiotics use, intravenous fluids, laboratory tests and respiratory support were recorded. A crude increase of 31% and an adjusted increase of 70% in care costs associated with methicillin resistance were registered. CONCLUSION: Our study supports decision makers in finding and funding infection prevention programs, especially those infections caused by resistant organisms. PMID- 25504123 TI - [Hepatitis E virus infection in patients with clinical diagnosis of viral hepatitis in Colombia]. AB - INTRODUCTION: Hepatitis E virus (HEV) is an emergent virus of global importance; it is the etiological agent of sporadic cases and outbreaks of hepatitis. The epidemiology of this infection in Colombia is unknown. OBJECTIVE: To determine the seropositivity for hepatitis E virus in Colombia in cases with clinical diagnosis of viral hepatitis. MATERIALS AND METHODS: Serum samples from patients that were sent to the Instituto Nacional de Salud during the period 2005-2010 (group 1) and samples sent to the Laboratorio Departamental de Salud Publica de Antioquia during the 2008-2009 period were included in this study (group 2). Serum samples were analyzed by immunoassay with commercial kits. RESULTS: From the 344 analyzed samples, 8.7% were positive for anti-HEV; the frequency of anti HEV IgM was 1.74% (6/344) and the frequency of anti-HEV IgG was 7.5% (26/344). A difference in frequency of anti-HEV between group 1 (6.3%) and group 2 (1.3%) was observed. The cases were identified in nine departments of Colombia. CONCLUSIONS: This is the first study of hepatitis E virus infection in patients with diagnosis of hepatitis in Colombia. The frequency of anti-HEV described in this population of patients in Colombia is similar to that described in other Latin American countries like Brazil, Peru and Uruguay. Considering the results of this study, it could be necessary to include hepatitis E virus infection serological markers in the differential diagnosis of viral hepatitis in Colombia. PMID- 25504125 TI - [Ultrasound detection of congenital anomalies in 76,155 births in the cities of Bogota and Cali, 2011-2012]. AB - INTRODUCTION: Congenital anomalies affect 2 to 3% of live births in Colombia and they are currently the leading cause of death in children under 1 year of age in Bogota, and the third cause of death in children under 1 year of age in Cali. Congenital anomalies are a major factor contributing to fetal and infant mortality and morbidity in the world. Some congenital anomalies can be detected by obstetric ultrasonography, thus helping to decide on the best way to manage them. OBJECTIVE: To determine the rate of detection of congenital anomalies by obstetric ultrasound and the false positive rate comparing infants born with birth defects in Bogota and Cali treated at health care facilities of different levels of complexity. MATERIALS AND METHODS: We monitored 76,155 births in the cities of Cali and Bogota based on a case-control model following the methodology of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) from January 2011 to December 2012. RESULTS: The rate of malformed infants was 2.08%. The detection rate of diagnosable congenital anomalies was 31.45% among cases that had information about prenatal care. This rate is lower than that reported in the literature. Most of the congenital anomalies detected were of the central nervous system and of the genitourinary system. CONCLUSIONS: The low detection rate highlights the need to improve the quality of ultrasound to have greater sensitivity for adequate prenatal diagnosis that will contribute to the reduction of morbidity and mortality and allow for better care of newborns with malformations. PMID- 25504124 TI - [Atorvastatin-meloxicam association inhibits neuroinflammation and attenuates the cellular damage in cerebral ischemia by arterial embolism]. AB - INTRODUCTION: Stroke is the second leading cause of death and the first cause of disability in the world, with more than 85% of the cases having ischemic origin. OBJECTIVE: To evaluate in an embolism model of stroke the effect of atorvastatin and meloxicam on neurons, astrocytes and microglia. This evaluation was done administering each medication individually and in association. MATERIALS AND METHODS: Wistar rats were subjected to carotid arterial embolism and treatment with meloxicam and atorvastatin at 6, 24, 48 and 72 hours. Using immunohistochemistry, we evaluated the immunoreactivity of COX-2 protein, GFAP and OX-42 in neurons, astrocytes and microglia by densitometric and morphological studies. Data were evaluated by variance analysis and non-parametric multiple comparison. RESULTS: Cerebral ischemia by arterial embolism increased significantly the reactivity of microglia and astrocytes (p<0.001), whereas it was reduced by atorvastatin, meloxicam and their association. Ischemia produced astrocytic shortening, cellular thickening, protoplasmic rupture expansions (clasmatodendrosis) and microglial morphological changes characteristic of various activity stages. In perifocal areas, immunoreactivity of COX-2 was increased and in the ischemic focus it was reduced, while meloxicam and atorvastatin significantly reduced (p<0.001) perifocal immunoreactivity, restoring the marking of cyclooxygenase in the ischemic focus. CONCLUSION: These results suggest that the meloxicam-atorvastatin association attenuates astrocytic and microglial response in the inflammatory process after cerebral ischemia by arterial embolism, reducing neurodegeneration and restoring the morphological and functional balance of nervous tissue . PMID- 25504127 TI - [Physicians' insight about adverse drug reaction to frequently used medication groups in Bogota (Colombia)]. AB - INTRODUCTION: Adverse drug reactions are a public health problem; however, still many prescribers do not seem to recognize the risk associated with the use of medications. OBJECTIVE: To assess the perception of the risk of adverse reactions associated with the groups of drugs most frequently used in clinical practice. MATERIALS AND METHODS: Descriptive study made in 200 physicians with at least 2 years of clinical experience in Bogota, Colombia. The risk of adverse drug reactions associated with the use of medications was assessed using a visual analog scale (0-10 points). RESULTS: The perception of risk was <5 points for 19 of the 31 (61%) therapeutic groups. The therapeutic groups that were related to increased perception of risk were chemotherapy for cancer (median, 8.5, interquartile range: 1.8), insulin (median, 8, interquartile range: 4.8) and anticoagulants (median, 7.5, interquartile range: 4). CONCLUSIONS: Although there is a relationship between the perception of risk and the frequency of adverse drug reactions associated with therapeutic groups of higher score, there is also a strong underestimation of the risk of medicines in common use at hospital and ambulatory level such as NSAID, antihypertensive drugs and oral contraceptives. PMID- 25504126 TI - [Identification and differential expression of the microphthalmia-associated transcription factor in heart and isolated cardiomyocytes from Guinea pigs: possible role in hypertrophy and viability]. AB - INTRODUCTION: The microphthalmia -associated transcription factor ( MITF ) regulates the expression of specific genes and its cardiac expression and function is not known. OBJECTIVES: To identify the expression of MITF in hearts and isolated cardiomyocytes from Guinea pigs, to describe morphological changes associated with mRNA interference of MITF and to evaluate their relative changes in expression in isolated cardiomyocytes under ischemic preconditioning. MATERIALS AND METHODS: The cardiac specific isoform, MITF-H, and relative expression level analysis, was determined by semi-quantitative real time PCR, sequencing and Western blotting. Reduction of mRNA-MITF-H was induced by transduction of specific-MITF-shRNAi interference. The cardiac morphological changes, diameter and number of cardiac fibers were evaluated by direct observation and light microscopy. RESULTS: A cDNA fragment of 281 bp was amplified from heart and isolated ventricular cardiac myocytes. Sequence analysis confirmed the identity of the isoform MITF-H, exon 1. The MITF silencing was associated with an increase in cardiac index (heart weight/body weight vs . 5.46 x 10 -3 vs 4.6 x 10 -3 ) and higher diameter of cardiac fibers (50.2+/-16 u m vs 38,7+/-14,7 u m p<0.05, n=150). In isolated cardiac myocytes under ischemic preconditioning we observed a higher relative expression compared with that measured in myocytes exposed to normoxia and simulated ischemia (eighty and one hundred times, p <0.05, n = 5). Conclusion. The results suggest that MITF-H isoform may be involved in Guinea pig cardiac hypertrophy, response to stress by ischemia and cardiomyocytes survival. PMID- 25504129 TI - [Analysis of mortality caused by tuberculosis in Medellin, Colombia, 2012]. AB - INTRODUCTION: Tuberculosis is a relevant global public health problem. Although reports of the World Health Organization show decrease in overall mortality rates, Colombia and Medellin show no significant decline. OBJECTIVE: To describe the sociodemographic, clinical, diagnosis, and treatment characteristics of patients who died due to tuberculosis in Medellin, Colombia, during 2012. MATERIALS AND METHODS: A descriptive study of tuberculosis deaths reported in the city. RESULTS: 93 deaths were identified, of which 32 were confirmed as directly caused by tuberculosis (34.4%); in 23 deaths (24.7%) tuberculosis was an associated cause. Co-morbidities were found in 34 patients (61.7%), HIV being the most common with 18 cases important(32.7%). Social risk factors such as being homeless, drug addiction or having no fixed address were found in 32 cases (58.1%); and there were deficiencies in the healthcare system in 26 cases (47.2%). No meaningful delay in the onset of anti-tuberculosis treatment was found after the microbiological diagnosis; however, 64% of patients did not adhere to treatment. CONCLUSION: Mortality caused by tuberculosis in Medellin is a relevant problem associated with delays in diagnosis of the disease and lack of adherence to treatment. PMID- 25504128 TI - [Ovitraps evaluation for surveillance and control of Aedes aegypti in two urban settlements of Uraba, Antioquia]. AB - INTRODUCTION: Aedes (Stegomyia) aegypti is the main vector of dengue. Chemical insecticides have been used to control the mosquito and it has developed resistance. It is necessary to evaluate alternative strategies that are efficient, economical and easy to apply, such as ovitraps with Bacillus thuringiesis israeliensis . OBJECTIVE: To evaluate the impact of ovitraps loaded with B. t. israeliensis on traditional indexes, as strategies for surveillance and control of A. aegypti . MATERIALS AND METHODS: We selected eight neighborhoods from the municipalities of Apartado and Carepa. Two neighborhoods in each municipality were chosen for intervention and two for control. The intervention consisted in the installation of ovitraps with B. t. israeliensis in every house. The traps were visited each month between September, 2009, and March, 2010. Traditional indexes were obtained and compared among the neighborhoods. Ovitrap positivity index and egg density index were calculated and we generated density maps. RESULTS: Five hundred and nineteen ovitraps were placed monthly; 3,114 samples were obtained, from which 76.4% were positive. We collected 501,425 eggs. In Apartado, statistically significant differences were observed in the house, container and Breteau indexes. The ovitrap positivity index showed high risk of A. aegypti infestation and traditional indexes showed medium and low risk levels. CONCLUSIONS: Ovitraps had an impact on traditional indexes and proved to be useful strategies for surveillance and control of A. aegypti in Uraba, Antioquia. PMID- 25504130 TI - [Trends in antibiotic resistance in Medellin and municipalities of the Metropolitan Area between 2007 and 2012: Results of six years of surveillance]. AB - INTRODUCTION: Bacterial resistance is a global phenomenon, but it presents geographic and temporal variations; this is the importance of local surveillance programs. OBJECTIVE: To determine trends in antibiotic resistance in hospitals between 2007 and 2012 in Medellin and its Metropolitan Area. MATERIALS AND METHODS: Percentages of antibiotic resistance between 2007 and 2012 in 22 institutions were obtained using WHONET 5.6 program. For interpretation of susceptibility results, CLSI standards of 2009 and 2012 were used. Using the Epi Info 6.04 program a trends analysis of antibiotic resistance was done using the chi-square for linear trend with a confidence level of 95%, a value of p=0.05 was considered significant. RESULTS: In six years of surveillance of antibiotic resistance we found a decrease of oxacillin resistance in Staphylococcus aureus (p=0.0006) and an increase of vancomycin resistance in Enterococcus faecium (p=0.0000). In Escherichia coli and Serratia marcescens an increase of resistance to ceftazidime was found, in contrast to a decrease in Klebsiella pneumoniae (p=0.0000) and Enterobacter cloacae (p=0.058). K. pneumoniae , S. marcescens and E. cloacae showed an increase of carbapenem resistance in contrast to a reduction of carbapenem resistance in Pseudomonas aeruginosa and Acinetobacter baumannii . CONCLUSIONS: The resistance surveillance identified important findings as the emergence of E. faecium resistant to vancomycin and carbapenem-resistant Enterobacteriaceae . It is essential to determine the antibiotic use in the region to establish their influence on the resistance profiles, as well as ensuring the quality of information and microbiological procedures in the microbiology laboratories. PMID- 25504131 TI - [Physical activity levels among Colombian adults: inequalities by gender and socioeconomic status]. AB - INTRODUCTION: Worldwide studies show inequalities in physical activity levels related to socio-demographic characteristics. In Colombia, among the countries in Latin America with the highest inequality, the evidence related to inequalities in physical activity is limited. It is imperative to identify disparities in physical activity in the country, to guide the design of public policies aimed at promoting physical activity. OBJECTIVES: 1) To estimate the prevalence and associated factors of meeting physical activity recommendations; 2) to assess inequalities by gender and socioeconomic status in meeting physical activity recommendations, and 3) to assess the trends in physical activity prevalence within a five-year period. MATERIALS AND METHODS: A secondary analysis of data from the 2010 National Nutrition Survey was conducted. The sample included 27,243 adults. The International Physical Activity Questionnaire was used to measure leisure time and transport domains. Socioeconomic status was measured by the Sisben level. RESULTS: Compared to men, women were less likely to meet physical activity recommendations in all domains. Compared to adults from high socioeconomic-status households, low socioeconomic-status adults had a lower prevalence of meeting physical activity recommendations during leisure time and the highest prevalence of using a bicycle for transport. The factors associated with meeting physical activity recommendations differed by gender and physical activity domain. Household and individual variables explained 13.6% of the inequalities observed by gender, and 23.2% of the inequalities by socioeconomic status. In a five-year period, the prevalence of physical activity in leisure time decreased, while the physical activity of walking for transport increased and biking for transport did not change. CONCLUSIONS: Future interventions to increase physical activity levels in Colombia must consider inequalities by gender and socioeconomic status. Of special concern is the low prevalence of meeting physical activity recommendations during leisure time in both women and in the low socioeconomic status population. PMID- 25504132 TI - [Genotyping and evaluation of infection dynamics in a Colombian isolate of Leptospira santarosai in hamster as an experimental model]. AB - INTRODUCTION: Is necessary to develop models for the study of leptospirosis. OBJECTIVE: To genotype a Colombian strain of Leptospira isolated from a human with Weil's syndrome and to evaluate its infection dynamics in the hamster experimental model. MATERIALS AND METHODS: Genotyping was performed by amplification and sequence analysis of the rrs 16S and lipL32 genes. The median lethal dose was determined in intraperitoneally inoculated hamsters. The patterns of clinical chemistry, the duration of leptospiremia, leptospiruria and pathological findings were studied and compared in the same animal model infected with L. interrogans (Fiocruz L1-130). RESULTS: Molecular typing revealed that the isolate corresponded to the pathogenic species L. santarosai, which was recovered from hamsters' kidneys and lungs and detected by lipL32 PCR from day 3 post infection in these organs. There was a marked increase of C-reactive protein in animals at day 5 post-infection (3.25 mg/dl; normal value: 0.3 mg/dl) with decreases by day 18 (2.60 mg/dl: normal value: 0.8 mg/dl). Biomarkers of urea showed changes consistent with possible renal acute failure (day 5 post infection: 49.01 mg/dl and day 18 post-infection: 53.71 mg/dl). Histopathological changes included interstitial pneumonia with varying degrees of hemorrhage and interstitial nephritis. CONCLUSION: The pathogenic species L. santarosai was identified in Colombia. Its pathogenicity as determined by tropism to lung and kidney was comparable to that of L. interrogans Fiocruz L1-130, well known for its virulence and pulmonar tropism. The biological aspects studied here had never before been evaluated in an autochthonous isolate. PMID- 25504134 TI - [An updated checklist of Phlebotomine sand flies (Diptera: Psychodidae: Phlebotominae) from the Colombian Andean coffee-growing region]. AB - An updated list of phlebotomine sand flies species in coffee growing areas in the Colombian Andean region is presented. Fifty three species were reported from 12 departments. In addition, species distribution in the region was derived from specimens obtained during intensive field work in five departments, from previously published studies and from the taxonomic revision of specimens in the entomological collection of the Programa de Estudio y Control de Enfermedades Tropicales (PECET). The list includes the genera Brumptomyia (2 species), Lutzomyia (50 species) and Warileya (1 species). The updated list contains eleven new records in the region under study, including Lutzomyia panamensis , a species of medical importance not recorded previously in this zone. Eighteen of the species are considered to be anthropophilic, and many of them have been implicated in the transmission of leishmaniasis. PMID- 25504133 TI - [Evaluation of lethal ovitraps as a strategy for Aedes aegypti control]. AB - INTRODUCTION: Dengue fever is a vector-borne viral disease of major public health importance. In the absence of a vaccine, control measures are primarily focused on reducing the mosquito vector. However, these strategies are very expensive, and the use of lethal ovitraps could contribute, in a practical manner, to the design of cost-effective strategies for vector control. OBJECTIVE: To determine the most efficient type of lethal ovitrap for Ae. aegypti vector control by combining different types of insecticides, oviposition substrates and attractant infusions. MATERIALS AND METHODS: The study was conducted in two stages. In the first, 18 different ovitraps resulting from the combination of insecticides (deltamethrin and permethrin), oviposition substrates (towel, dacron and flannel), and attractant infusion (10 and 20% hay infusion, and dechlorinated water) were evaluated in the laboratory. For this evaluation, ovitraps were placed into a mosquito holding cage, and 100 gravid Ae. aegypti females were released. The top six ovitraps were selected based on the higher number of registered eggs, and the lower hatched eggs percentage. In the second, the top six ovitraps were evaluated in field conditions. RESULTS: In laboratory conditions, statistical differences were observed between the 18 ovitraps. The ovitraps with deltamethrin were the most efficient showing the best results. In field conditions, the ovitraps with the highest vector reduction were those combining deltamethrin/towel/10% hay infusion. CONCLUSIONS: The ovitrap combining deltamethrin, towel as oviposition substrate, and 10% hay infusion as attractant was the most efficient Ae. aegypti vector control. PMID- 25504135 TI - N-substituted phenothiazine derivatives: how the stability of the neutral and radical cation forms affects overcharge performance in lithium-ion batteries. AB - Phenothiazine and five N-substituted derivatives were evaluated as electrolyte additives for overcharge protection in LiFePO4 /synthetic graphite lithium-ion batteries. We report on the stability and reactivity of both the neutral and radical-cation forms of these six compounds. While three of the compounds show extensive overcharge protection, the remaining three last for only one to a few cycles. UV/Vis studies of redox shuttle stability in the radical cation form are consistent with the overcharge performance: redox shuttles with spectra that show little change over time exhibit extensive overcharge performance, whereas those with changing spectra have limited overcharge protection. In one case, we determined that a C-N bond cleaves upon oxidation, forming the phenothiazine radical cation and leading to premature overcharge protection failure; in another case, poor solubility appears to limit protection. PMID- 25504136 TI - In vitro assessment of the prebiotic potential of Aloe vera mucilage and its impact on the human microbiota. AB - Aloe vera mucilage is reported to be rich in acemannan that is a polysaccharide with a backbone of beta-(1->4)-D-mannose residues acetylated at the C-2 and C-3 positions and contains some side chains of galactose and arabinose attached to the C-6 carbon. The evaluation of the prebiotic potential of Aloe vera mucilage was carried out by in vitro fermentation using intestinal microbiota from six healthy donors as the inoculum. The prebiotic activity was assessed through the quantification of short chain fatty acids (SCFA) and the evaluation of dynamic bacterial population in mixed faecal cultures by fluorescence in situ hybridization (FISH). Our findings support the possible incorporation of the Aloe vera mucilage in the development of a variety of food products known as prebiotics aimed at improving gastrointestinal health. PMID- 25504137 TI - Polarized and persistent Ca2+ plumes define loci for formation of wall ingrowth papillae in transfer cells. AB - Transfer cell morphology is characterized by a polarized ingrowth wall comprising a uniform wall upon which wall ingrowth papillae develop at right angles into the cytoplasm. The hypothesis that positional information directing construction of wall ingrowth papillae is mediated by Ca(2+) signals generated by spatiotemporal alterations in cytosolic Ca(2+) ([Ca(2+)]cyt) of cells trans-differentiating to a transfer cell morphology was tested. This hypothesis was examined using Vicia faba cotyledons. On transferring cotyledons to culture, their adaxial epidermal cells synchronously trans-differentiate to epidermal transfer cells. A polarized and persistent Ca(2+) signal, generated during epidermal cell trans differentiation, was found to co-localize with the site of ingrowth wall formation. Dampening Ca(2+) signal intensity, by withdrawing extracellular Ca(2+) or blocking Ca(2+) channel activity, inhibited formation of wall ingrowth papillae. Maintenance of Ca(2+) signal polarity and persistence depended upon a rapid turnover (minutes) of cytosolic Ca(2+) by co-operative functioning of plasma membrane Ca(2+)-permeable channels and Ca(2+)-ATPases. Viewed paradermally, and proximal to the cytosol-plasma membrane interface, the Ca(2+) signal was organized into discrete patches that aligned spatially with clusters of Ca(2+)-permeable channels. Mathematical modelling demonstrated that these patches of cytosolic Ca(2+) were consistent with inward-directed plumes of elevated [Ca(2+)]cyt. Plume formation depended upon an alternating distribution of Ca(2+)-permeable channels and Ca(2+)-ATPase clusters. On further inward diffusion, the Ca(2+) plumes coalesced into a uniform Ca(2+) signal. Blocking or dispersing the Ca(2+) plumes inhibited deposition of wall ingrowth papillae, while uniform wall formation remained unaltered. A working model envisages that cytosolic Ca(2+) plumes define the loci at which wall ingrowth papillae are deposited. PMID- 25504139 TI - High-resolution single-molecule fluorescence imaging of zeolite aggregates within real-life fluid catalytic cracking particles. AB - Fluid catalytic cracking (FCC) is a major process in oil refineries to produce gasoline and base chemicals from crude oil fractions. The spatial distribution and acidity of zeolite aggregates embedded within the 50-150 MUm-sized FCC spheres heavily influence their catalytic performance. Single-molecule fluorescence-based imaging methods, namely nanometer accuracy by stochastic chemical reactions (NASCA) and super-resolution optical fluctuation imaging (SOFI) were used to study the catalytic activity of sub-micrometer zeolite ZSM-5 domains within real-life FCC catalyst particles. The formation of fluorescent product molecules taking place at Bronsted acid sites was monitored with single turnover sensitivity and high spatiotemporal resolution, providing detailed insight in dispersion and catalytic activity of zeolite ZSM-5 aggregates. The results point towards substantial differences in turnover frequencies between the zeolite aggregates, revealing significant intraparticle heterogeneities in Bronsted reactivity. PMID- 25504138 TI - Genome-wide conserved non-coding microsatellite (CNMS) marker-based integrative genetical genomics for quantitative dissection of seed weight in chickpea. AB - Phylogenetic footprinting identified 666 genome-wide paralogous and orthologous CNMS (conserved non-coding microsatellite) markers from 5'-untranslated and regulatory regions (URRs) of 603 protein-coding chickpea genes. The (CT)n and (GA)n CNMS carrying CTRMCAMV35S and GAGA8BKN3 regulatory elements, respectively, are abundant in the chickpea genome. The mapped genic CNMS markers with robust amplification efficiencies (94.7%) detected higher intraspecific polymorphic potential (37.6%) among genotypes, implying their immense utility in chickpea breeding and genetic analyses. Seventeen differentially expressed CNMS marker associated genes showing strong preferential and seed tissue/developmental stage specific expression in contrasting genotypes were selected to narrow down the gene targets underlying seed weight quantitative trait loci (QTLs)/eQTLs (expression QTLs) through integrative genetical genomics. The integration of transcript profiling with seed weight QTL/eQTL mapping, molecular haplotyping, and association analyses identified potential molecular tags (GAGA8BKN3 and RAV1AAT regulatory elements and alleles/haplotypes) in the LOB-domain-containing protein- and KANADI protein-encoding transcription factor genes controlling the cis-regulated expression for seed weight in the chickpea. This emphasizes the potential of CNMS marker-based integrative genetical genomics for the quantitative genetic dissection of complex seed weight in chickpea. PMID- 25504140 TI - Effect of intraperitoneal curcumin instillation on postoperative peritoneal adhesions. AB - OBJECTIVE: The aim of this study was to determine the effect of curcumin on adhesion formation in a rat cecum abrasion model. MATERIALS AND METHODS: Thirty Wistar rats were randomized into three groups; the control group received saline, the curcumin group received 10 mg/kg of curcumin after cecal abrasion, and in the sham group the abdominal wall was closed without any abrasion to the cecum. On day 15, adhesions were assessed blindly using a standardized scale, and histopathological samples were taken and examined. RESULTS: There were no incisional hernias or wound dehiscences in any animals of the three groups. A comparison of adhesion scores showed a significant difference between the curcumin (median = 1) and the control group (median = 2; p < 0.05). The grade of inflammation of the curcumin (median = 1) and the sham (median = 0) group was significantly lower than that of the control group (median = 3; p < 0.01 and p < 0.001, respectively). Hydroxyproline levels were significantly lower in the sham (48.3 +/- 11.8 ug/mg) and the curcumin (63.8 +/- 13.9 ug/mg) group compared to the control group (85.7 +/- 22.1 ug/mg; p < 0.05). CONCLUSION: These data suggest that curcumin, administered intraperitoneally, was effective in the prevention of peritoneal adhesion formation. PMID- 25504141 TI - Clinical phenotypes of asthma should link up with disease mechanisms. AB - PURPOSE OF REVIEW: Asthma is a common disease which presents in various clinical forms and levels of severity. The current 'one size fits all' approach to treatment is suboptimal. Using unbiased cluster analysis has identified several asthma phenotypes. Understanding the underlying mechanisms driving these clusters may lead to better patient-orientated medicines. RECENT FINDINGS: Clustering was initially performed on clinical features only, but the addition of biomarkers that characterize sputum and blood cellular profiles has enabled the prediction of responses to targeted therapies. Clusters of severe asthma include those on high-dose corticosteroid treatment associated with severe airflow obstruction and those with discordance between symptoms and sputum eosinophilia. Sputum eosinophilia can predict therapeutic responses to T-helper type 2 cytokine blockade. Further molecular phenotyping or endotyping of asthma will be necessary to determine new treatment strategies. Low T-helper type 2 expression may be predictive of poor therapeutic response to inhaled corticosteroids, but much less is known about this type of asthma. SUMMARY: Phenotype-driven treatment of asthma will be further boosted by the integration of genetic, transcriptomic and proteomic technologies to defining distinct severe asthma phenotypes and biomarkers of therapeutic responses. This will lead towards stratified medicine for asthma. PMID- 25504144 TI - Hole-transport materials with greatly-differing redox potentials give efficient TiO2-[CH3NH3][PbX3] perovskite solar cells. AB - Two diacetylide-triphenylamine hole-transport materials (HTM) with varying redox potential have been applied in planar junction TiO2-[CH3NH3]PbI3-xClx solar cells leading to high power-conversion efficiencies up to 8.8%. More positive oxidation potential of the HTM gives higher VOC and lower JSC illustrating the role of matching energy levels, however both HTMs gave efficient cells despite a difference of 0.44 V in their redox potentials. PMID- 25504143 TI - Randomized test of an implementation intention-based tool to reduce stress induced eating. AB - BACKGROUND: Stress may indirectly contribute to disease (e.g. cardiovascular disease, cancer) by producing deleterious changes to diet. PURPOSE: The purpose of this study was to test the effectiveness of a stress management support (SMS) tool to reduce stress-related unhealthy snacking and to promote stress-related healthy snacking. METHODS: Participants were randomized to complete a SMS tool with instruction to link stressful situations with healthy snack alternatives (experimental) or a SMS tool without a linking instruction (control). On-line daily reports of stressors and snacking were completed for 7 days. RESULTS: Daily stressors were associated with unhealthy snack consumption in the control condition but not in the experimental condition. Participants highly motivated towards healthy eating consumed a greater number of healthy snacks in the experimental condition on stressful days compared to participants in the experimental condition with low and mean levels of motivation. CONCLUSIONS: This tool is an effective, theory driven, intervention that helps to protect against stress-induced high-calorie snack consumption. PMID- 25504145 TI - Medication discrepancies associated with subsequent pharmacist-performed medication reconciliations in an ambulatory clinic. AB - OBJECTIVE: To describe the number of medication discrepancies associated with subsequent medication reconciliations by a clinical pharmacist in an ambulatory family medicine clinic and the proportion of subsequent medication reconciliation visits that were associated with hospital discharge, long-term anticoagulation management, or both. METHODS: Data on medication reconciliations were collected over a 2-year time period in an ambulatory family medicine clinic for patients taking 10 or more medications. RESULTS: Medication reconciliation was performed 752 times for 500 patients. A total of 5,046 discrepancies were identified, with more than one-half deemed clinically important. A mean (+/- SD) of 6.7 +/- 4.6 discrepancies per visit (3.5 +/- 3.2 clinically important) were identified. The findings showed that the distribution of total discrepancies identified by pharmacist-performed medication reconciliation was significantly different over the course of subsequent medication reconciliations. However, the distribution of clinically important discrepancies was not significantly different; important discrepancies were as likely to be found in later reconciliations as in earlier ones. As subsequent medication reconciliation visits were performed, an increasing proportion consisted of post-hospital discharge visits, long-term anticoagulation managed by a clinical pharmacist, or both. CONCLUSION: Patients with a recent hospital discharge, on long-term anticoagulation management, or both, were more likely to have multiple sessions with a clinical pharmacist for medication reconciliation. These findings can help identify patients for whom medication reconciliation is warranted. PMID- 25504142 TI - Direct evidence for BBSome-associated intraflagellar transport reveals distinct properties of native mammalian cilia. AB - Cilia dysfunction underlies a class of human diseases with variable penetrance in different organ systems. Across eukaryotes, intraflagellar transport (IFT) facilitates cilia biogenesis and cargo trafficking, but our understanding of mammalian IFT is insufficient. Here we perform live analysis of cilia ultrastructure, composition and cargo transport in native mammalian tissue using olfactory sensory neurons. Proximal and distal axonemes of these neurons show no bias towards IFT kinesin-2 choice, and Kif17 homodimer is dispensable for distal segment IFT. We identify Bardet-Biedl syndrome proteins (BBSome) as bona fide constituents of IFT in olfactory sensory neurons, and show that they exist in 1:1 stoichiometry with IFT particles. Conversely, subpopulations of peripheral membrane proteins, as well as transmembrane olfactory signalling pathway components, are capable of IFT but with significantly less frequency and/or duration. Our results yield a model for IFT and cargo trafficking in native mammalian cilia and may explain the penetrance of specific ciliopathy phenotypes in olfactory neurons. PMID- 25504147 TI - A common control group - optimising the experiment design to maximise sensitivity. AB - Methods for choosing an appropriate sample size in animal experiments have received much attention in the statistical and biological literature. Due to ethical constraints the number of animals used is always reduced where possible. However, as the number of animals decreases so the risk of obtaining inconclusive results increases. By using a more efficient experimental design we can, for a given number of animals, reduce this risk. In this paper two popular cases are considered, where planned comparisons are made to compare treatments back to control and when researchers plan to make all pairwise comparisons. By using theoretical and empirical techniques we show that for studies where all pairwise comparisons are made the traditional balanced design, as suggested in the literature, maximises sensitivity. For studies that involve planned comparisons of the treatment groups back to the control group, which are inherently more sensitive due to the reduced multiple testing burden, the sensitivity is maximised by increasing the number of animals in the control group while decreasing the number in the treated groups. PMID- 25504146 TI - Temporal dynamics of the ABC transporter response to insecticide treatment: insights from the malaria vector Anopheles stephensi. AB - In insects, ABC transporters have been shown to contribute to defence/resistance to insecticides by reducing toxic concentrations in cells/tissues. Despite the extensive studies about this detoxifying mechanism, the temporal patterns of ABC transporter activation have been poorly investigated. Using the malaria vector Anopheles stephensi as a study system, we investigated the expression profile of ABC genes belonging to different subfamilies in permethrin-treated larvae at different time points (30 min to 48 h). Our results showed that the expression of ABCB and ABCG subfamily genes was upregulated at 1 h after treatment, with the highest expression observed at 6 h. Therefore, future investigations on the temporal dynamics of ABC gene expression will allow a better implementation of insecticide treatment regimens, including the use of specific inhibitors of ABC efflux pumps. PMID- 25504148 TI - Single-cell analysis reveals gene-expression heterogeneity in syntrophic dual culture of Desulfovibrio vulgaris with Methanosarcina barkeri. AB - Microbial syntrophic metabolism has been well accepted as the heart of how methanogenic and other anaerobic microbial communities function. In this work, we applied a single-cell RT-qPCR approach to reveal gene-expression heterogeneity in a model syntrophic system of Desulfovibrio vulgaris and Methanosarcina barkeri, as compared with the D. vulgaris monoculture. Using the optimized primers and single-cell analytical protocol, we quantitatively determine gene-expression levels of 6 selected target genes in each of the 120 single cells of D. vulgaris isolated from its monoculture and dual-culture with M. barkeri. The results demonstrated very significant cell-to-cell gene-expression heterogeneity for the selected D. vulgaris genes in both the monoculture and the syntrophic dual culture. Interestingly, no obvious increase in gene-expression heterogeneity for the selected genes was observed for the syntrophic dual-culture when compared with its monoculture, although the community structure and cell-cell interactions have become more complicated in the syntrophic dual-culture. In addition, the single-cell RT-qPCR analysis also provided further evidence that the gene cluster (DVU0148-DVU0150) may be involved syntrophic metabolism between D. vulgaris and M. barkeri. Finally, the study validated that single-cell RT-qPCR analysis could be a valuable tool in deciphering gene functions and metabolism in mixed-cultured microbial communities. PMID- 25504149 TI - Glioblastoma stem-like cells: at the root of tumor recurrence and a therapeutic target. AB - Glioblastoma is the most common and most aggressive primary brain malignancy. The current initial standard of care consists of maximal safe surgical resection followed by radical radiotherapy and adjuvant temozolomide. Despite optimal therapy, median survival is ~15 months from diagnosis in molecularly unselected patients, and <6 months for patients with recurrent disease. Therefore, clinical treatments are currently palliative, not curative. Collectively, current knowledge suggests that the continued tumor growth and recurrence is in part due to the presence of glioma stem-like cells, which display self-renewal and tumorigenic potential. They differ from their more differentiated progeny, as they are more resistant to current treatments. Recurrent disease may be a consequence of the enhancement and/or gain of stem cell-like characteristics during disease progression, together with preferential death of more differentiated tumor cells during treatment, signifying that the cancer stem cell phenotype is a crucial therapeutic target. The limited knowledge of the characteristics of these cells and their response to current clinical treatments warrants intensive investigation with the aim to improve patient survival and/or develop a cure for this disease. PMID- 25504151 TI - Fontan fenestration closure with Amplatzer Duct Occluder II device. AB - OBJECTIVES: To evaluate Fontan fenestration closure using the Amplatzer Duct Occluder II device (ADO2). BACKGROUND: Fontan fenestration closure is a well established catheter intervention. A range of occlusion devices developed for other interventions have been utilized. Most of these devices, and especially the most commonly used Amplatzer Septal Occluder, are relatively bulky. The ADO2 is a low profile, flexible, and inexpensive device which seems well suited to the Fontan fenestration. METHODS: This study details retrospective review of patients undergoing Fontan fenestration closure with an ADO2 device. Outcome measures included procedural success, pre- and post-procedural differences in oxygen saturation and mean pulmonary artery pressure and complications. RESULTS: Thirteen patients were eligible for inclusion during the 34 month study period. All procedures were technically successful. There was a significant increase in oxygen saturations (Mean=+12%, P<0.01) after fenestration closure but no significant change in mean pulmonary artery pressure (Mean=+0.5 mm Hg, P=0.08). There were no procedural complications. CONCLUSION: Fontan fenestration closure with the ADO2 device is a simple, short, and cost-effective procedure. The ADO2 characteristics recommend it to occlusion of varying sizes and morphologies of Fontan fenestration. PMID- 25504150 TI - Transcriptional profiles of host-pathogen responses to necrotic enteritis and differential regulation of immune genes in two inbreed chicken lines showing disparate disease susceptibility. AB - Necrotic enteritis (NE) is an important intestinal infectious disease of commercial poultry flocks caused by Clostridium perfringens. Using an experimental model of NE involving co-infection with C. perfringens and Eimeria maxima, transcriptome profiling and functional genomics approaches were applied to identify the genetic mechanisms that might regulate the host response to this disease. Microarray hybridization identified 1,049 transcripts whose levels were altered (601 increased, 448 decreased) in intestinal lymphocytes from C. perfringens/E. maxima co-infected Ross chickens compared with uninfected controls. Five biological functions, all related to host immunity and inflammation, and 11 pathways were identified from this dataset. To further elucidate the role of host genetics in NE susceptibility, two inbred chicken lines, ADOL line 6 and line 7 which share an identical B2 major histocompatibility complex haplotype but differ in their susceptibility to virus infection, were compared for clinical symptoms and the expression levels of a panel of immune-related genes during experimental NE. Line 6 chickens were more susceptible to development of experimental NE compared with line 7, as revealed by decreased body weight gain and increased E. maxima oocyst shedding. Of 21 immune-related genes examined, 15 were increased in C. perfringens/E. maxima co infected line 6 vs. line 7 chickens. These results suggest that immune pathways are activated in response to experimental NE infection and that genetic determinants outside of the chicken B complex influence resistance to this disease. PMID- 25504153 TI - Imaging spectrum of renal oncocytomas: a pictorial review with pathologic correlation. AB - OBJECTIVES: The purpose of this pictorial review is to present the imaging spectrum of renal oncocytomas with radiological-pathological correlation. CONCLUSION: The differences in tumour cellularity (high cellularity or low cellularity with abundant stroma) and haemorrhagic/cystic change contribute to a wide spectrum of imaging findings of renal oncocytomas. Imaging findings substantially overlap those of common subtypes of clear cell and non-clear cell renal cell carcinomas. Multifocal renal oncocytomas are not rare, and making the diagnosis of oncocytoma with concomitant renal cell carcinoma is difficult. In addition, renal oncocytomas that demonstrate interval growth or develop in the setting of end-stage renal disease may be mistaken for malignancy. TEACHING POINTS: * High cellular components demonstrate avid arterial enhancement and subsequent washout. * Low cellular components demonstrate gradual subsequent enhancement owing to abundant stroma. * Cystic and hemorrhagic changes may account for lesion heterogeneity in the delayed phase. * Multifocal oncocytomas and oncocytomas coexisting with renal cell carcinoma are not rare. * Renal oncocytomas may demonstrate interval growth. PMID- 25504154 TI - Mycobacterium tuberculosis 19-kDa lipoprotein induces Toll-like receptor 2 dependent peroxisome proliferator-activated receptor gamma expression and promotes inflammatory responses in human macrophages. AB - Mycobacterium tuberculosis (M.tb) enhances its survival in macrophages by suppressing immune responses, in part through its complex cell wall structures. M.tb 19-kDa lipoprotein (P19), a component of the complex cell wall structures of M.tb, is a Toll-like receptor (TLR) agonist, and may induce immune responses through TLR2. Furthermore, the activation of peroxisome proliferator-activated receptor gamma (PPARgamma) is also involved in M.tb-induced immune responses in macrophages. In the present study, specific agonists/antagonists and siRNA were used to investigate the role of PPARgamma in P19-induced immune responses in human macrophages, including TLR2 activation, p38 phosphorylation and cytokine production. In the present study, PPARgamma expression, p38 phosphorylation and cytokine production were upregulated following M.tb H37Rv infection or P19 treatment. By pretreating macrophages with a specific PPARgamma agonist or antagonist, it was demonstrated that phosphorylation and IL-6 production are modulated in macrophages by PPARgamma activity. Following TLR2 knockdown in macrophages, the expression of PPARgamma was significantly decreased in the presence or absence of P19 treatment. Furthermore, p38 phosphorylation and cytokine production were significantly reduced in TLR2 knockdown macrophages following P19 treatment. It was demonstrated in the current study that PPARgamma was induced and activated by M.tb infection and that P19-induced PPARgamma expression, p38 phosphorylation and cytokine production in macrophages are dependent on TLR2. These findings suggest a role for PPARgamma and TLR2 in P19 induced p38 phosphorylation and cytokine production, thereby potentially influencing M.tb pathogenesis. PMID- 25504155 TI - Differentiation of small alkane and alkyl halide constitutional isomers via encapsulation. AB - Previously we have demonstrated that host 1 is capable of hydrocarbon gas separation by selective sequestration of butane from a mixture with propane in the headspace above a solution of the host (C. L. D. Gibb, B. C. Gibb, J. Am. Chem. Soc., 2006, 128, 16498-16499). Expanding on the idea of using this host as a means to affect guest discrimination, we report here on NMR studies of the binding of constitutional isomers of two classes of small molecules: hexanes and chloropentanes. Our results indicate that even with these relatively straightforward classes of molecules, guest binding is complicated. Overall, host 1 displays a preference to bind guests with a X-C(R2)-C(R2)-Me (X = Cl or Me) structure, and more generally, a preference for branched guests rather than highly flexible, unbranched derivatives. The complexity of binding of these isomers is magnified when considering molecular differentiation between pairs of guests. In such cases, different guests demonstrated different propensities to self-sort; some self-sort exclusively, while others show very little propensity to do so. However, whereas the pool of guests reveals some general correlations between binding strength and structure, no obvious relationship between structure and degree of self-sorting was observed. PMID- 25504152 TI - High-throughput characterization of protein-RNA interactions. AB - RNA-binding proteins (RBPs) are important regulators of eukaryotic gene expression. Genomes typically encode dozens to hundreds of proteins containing RNA-binding domains, which collectively recognize diverse RNA sequences and structures. Recent advances in high-throughput methods for assaying the targets of RBPs in vitro and in vivo allow large-scale derivation of RNA-binding motifs as well as determination of RNA-protein interactions in living cells. In parallel, many computational methods have been developed to analyze and interpret these data. The interplay between RNA secondary structure and RBP binding has also been a growing theme. Integrating RNA-protein interaction data with observations of post-transcriptional regulation will enhance our understanding of the roles of these important proteins. PMID- 25504156 TI - Retrospective analysis of long-term adherence to and persistence with DPP-4 inhibitors in US adults with type 2 diabetes mellitus. AB - INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) must remain adherent and persistent on antidiabetic medications to optimize clinical benefits. This analysis compared adherence and persistence among adults initiating dipeptidyl peptidase-4 inhibitors (DPP-4is), sulfonylureas (SUs), and thiazolidinediones (TZDs) and between patients initiating saxagliptin or sitagliptin, two DPP-4is. METHODS: This retrospective cohort study utilized the US MarketScan((r)) (Truven Health Analytics, Ann Arbor, MI, USA) Commercial and Medicare Supplemental health insurance claims databases. Adults aged >=18 years with T2DM who initiated a DPP 4i, SU, or TZD from January 1, 2009 to January 31, 2012 were included. Patients must have been continuously enrolled for >=1 year prior to and >=1 year following initiation. Adherence was measured using proportion of days covered (PDC), with PDC >= 0.80 considered adherent. Persistence was measured as time to discontinuation, defined as last day with drug prior to a 60+ days gap in therapy. Multivariable logistic regression and Cox proportional hazards models compared the outcomes between cohorts, controlling for baseline differences. RESULTS: The sample included 238,372 patients (61,399 DPP-4i, 134,961 SU, 42,012 TZD). During 1-year follow-up, 47.3% of DPP-4i initiators, 41.2% of SU initiators, and 36.7% of TZD initiators were adherent. Adjusted odds of adherence were significantly greater among DPP-4i initiators than SU (adjusted odds ratio [AOR] = 1.678, P < 0.001) and TZD initiators (AOR = 1.605, P < 0.001). During 1 year follow-up, 55.0% of DPP-4i initiators, 47.8% of SU initiators, and 42.9% of TZD initiators did not discontinue therapy. Adjusted hazards of discontinuation were significantly greater for SU (adjusted hazard ratio [AHR] = 1.390, P < 0.001) and TZD initiators (AHR = 1.402, P < 0.001) compared with DPP-4i initiators. Saxagliptin initiators had significantly better adherence (AOR = 1.213, P < 0.001) compared with sitagliptin initiators, and sitagliptin initiators had significantly greater hazard of discontinuation (AHR = 1.159, P < 0.001). Results were similar over a 2-year follow-up. CONCLUSIONS: US adults with T2DM who initiated DPP-4i therapy, particularly saxagliptin, had significantly better adherence and persistence compared with patients who initiated SUs or TZDs. PMID- 25504157 TI - Safety profile of desmopressin tablet for enuresis in a prospective study. AB - INTRODUCTION: This pre-specified sub-study of the desmopressin response in primary nocturnal enuresis study (DRIP study) evaluates the safety profile of the oral desmopressin tablet in children with primary nocturnal enuresis. Endpoints are adverse events and change in body mass index. METHODS: The DRIP study was an open-label, intention-to-treat, phase IV, multi-national study. Overall, 936 patients were screened and 744 children aged 5-15 years with previously untreated primary nocturnal enuresis were eligible to receive the study medication desmopressin once daily as an oral tablet formulation. At each visit, adverse events were questioned and observed signs or symptoms were recorded. RESULTS: Overall, 222 (30%) patients experienced 404 treatment-emergent adverse events. The proportion of patients experiencing treatment-emergent adverse events was similar regardless of patient gender or age. Most treatment-emergent adverse events were experienced in three system organ classes: gastrointestinal disorders; infections and infestations; and respiratory, thoracic and mediastinal disorders and were considered unrelated to the study drug. There was a slight increase in body mass index from screening levels during the study, however, clinically not significant. CONCLUSION: Desmopressin tablet treatment is well tolerated in children with primary nocturnal enuresis, regardless of patient gender or age. FUNDING: The desmopressin response in primary nocturnal enuresis study (DRIP- study) was funded by Ferring. PMID- 25504159 TI - The N-linked glycosylation site at position 158 on the head of hemagglutinin and the virulence of H5N1 avian influenza virus in mice. AB - N-linked glycosylation of the influenza virus hemagglutinin (HA) protein plays crucial roles in HA structure and function, evasion of neutralizing antibodies, and susceptibility to innate soluble antiviral factors. The N-linked glycosylation site at position 158 of highly pathogenic H5N1 virus was previously shown to affect viral receptor-binding preference. H5N1 viruses show heterogeneity with respect to the presence of this glycosylation site. Clade 1 viruses that caused outbreaks in Southeast Asia in 2004 contained this glycosylation site, while the site is absent in the more recent clade 2 viruses. Here, we show that elimination of this glycosylation site increases viral virulence in mice. The mutant lacking the glycosylation site at position 158 showed unaltered growth kinetics in vitro and a comparable level of sensitivity to a major antiviral protein found in respiratory secretions, surfactant protein D (SP-D). PMID- 25504158 TI - C60 fullerene as synergistic agent in tumor-inhibitory Doxorubicin treatment. AB - BACKGROUND: Doxorubicin (Dox) is one of the most potent anticancer drugs, but its successful use is hampered by high toxicity caused mainly by generation of reactive oxygen species. One approach to protect against Dox-dependent chemical insult is combined use of the cytostatic drug with antioxidants. C60 fullerene has a nanostructure with both antioxidant and antitumor potential and may be useful in modulating cell responses to Dox. OBJECTIVE: The aim of this study was to estimate the antitumor effect and antioxidant enzyme activity of combined C60 fullerene and Dox (C60 + Dox) in the liver and heart of mice with Lewis lung carcinoma compared with Dox treatment alone. METHODS: Highly stable pristine C60 fullerene aqueous colloid solution (concentration 1.0 mg/ml, average hydrodynamic diameter of nanoparticles 50 nm) was used in the study and characterized by means of atomic force microscopy (AFM). The in vivo investigation of C60-Dox action was performed via the standard methods of histological and enzyme activity analyses. RESULTS: Dox (total dose 2.5 mg/kg) combined with C60 fullerene (total dose 25 mg/kg) in tumor-bearing animals resulted in tumor growth inhibition, prolongation of life, metastasis inhibition, and increased number of apoptotic tumor cells and was more effective than the corresponding course of Dox treatment alone. C60 fullerene demonstrated a protective effect against superoxide dismutase and glutathione peroxidase inhibition induced by Dox-dependent oxidative insult in the liver and heart. CONCLUSION: Combined treatment with C60 + Dox is considered to be a promising approach for cancer chemotherapy. PMID- 25504160 TI - [Rhabdomyolysis: role of the nephrologist]. AB - Rhabdomyolysis is characterized by skeletal muscle necrosis resulting in release of large amounts of toxic muscle cell components, including electrolytes, myoglobin, and other sarcoplasmic proteins into circulation. Creatinine phosphokinase (CPK) and myoglobin serum levels constitute the diagnostic hallmark. Nowadays, drugs have become one of the most frequent cause of rhabdomyolysis and acute kidney injury (AKI) is a potential life-threatening complication. The mechanisms involved in the development of AKI in rhabdomyolysis are intrarenal vasoconstriction, direct and ischemic tubule injury and tubular obstruction. According to some clinical series, the mortality rate in patients who develop AKI due to rhabdomyolysis is highly variable. The cornerstone in managing this condition is the early, aggressive repletion of fluids. The composition of replacement fluid remains controversial. Saline and sodium bicarbonate, especially in patients with metabolic acidosis, seem to be a reasonable approach. When AKI produces refractory hyperkalemia, acidosis or volume overload, renal replacement therapy is indicated. PMID- 25504161 TI - [Assisted peritoneal dialysis]. AB - Peritoneal dialysis (PD) has a prevalence in Italy that does not exceed 10% of patients in substitution treatment. Among the barriers, which hinder access to DP, the lack of patient autonomy or family support has great importance. In 2012 in Lombardy, the lack of support has prevented 155 new patients to use DP and has forced 17 to stop it. According to the Italian Census of 2012, made by the Peritoneal Dialysis Study Group, Assisted DP involved the 24.5% of patients in 2010. In these cases, the caregiver was a family member in 80.8% of cases, a carer in 12.4%, a homecare nurse in 2.5% and the retirement home staff in 3.9%. In Italy, several regional Governments have sought to encourage home dialysis with economic contributions to the patient or the family. However, so far, none of these interventions has managed to increase the use of DP. In January 2004, we started a program of Assisted PD, using health worker as caregiver, in agreement with ASL Milano and ICP Milano Hospital. In the first 6 months of activity we treated 4 patients, 3 of them had been treated with hemodialysis. We had no critical cases and patients have welcomed this solution. In addition, the costs related to the Assisted PD are lower in comparison with the costs of the hospital hemodialysis. Considering the reliability of the first results, ASL has decided to raise the economic contribution for this activity, allowing us to increase the number of patients to include in Assisted PD. PMID- 25504162 TI - [Parathormone and left ventricular hypertrophy]. AB - In order to examine the relation between secondary hyperparathyroidism (sHPT) and left ventricular hypertrophy (LVH) in hemodialysis (HD) patients, were selected retrospectively 60 of 228 HD patients who had two echocardiography over a 12-16 months period (13.2 1.2 months). Patients were subdivided in three groups (G) according to PTH behaviour: G1 (n = 19), with PTH levels < 300 pg/ml not requiring with vitamin D receptor activators (VDRAs) treatment; G2 (n = 20), with a progressive increase of PTH levels to values > 300 pg/ml that required to start or to increase VDRAs therapy in 18/20 patients during follow-up; G3 (n = 21), with PTH levels > 300 pg/ml and > 50% reduction after VDRAs treatment. Parathormone levels correlated with left ventricular mass index (LVMi; r = 0.714; P < 0.001). Multiple regression analysis indicated that PTH levels were an independent predictor of LVMi (P < 0.001). Patients with baseline PTH levels > 300 pg/ml (n = 27) had higher LVMi with respect to those with PTH < 300 pg/ml (n=33), 197 50 vs 136 30 g/m2 (P < 0.01). In G1 LVMi did not change during follow up. In G2 LVMi increased from 146 26 to 169 35 g/m2 (P=NS). In G3LVMi decreased from 210 44 to 154 42 g/m2 (P < 0.05). Parathyroid hormone seems to play an important role in the genesis and perpetuation of LVH, whereas treatment of sHPT with VDRAs may determine LVH regression or at least slow down its progression. PMID- 25504163 TI - [Colistin: a review]. AB - Colistin (CS) is a polymyxin with bactericidal activity, which is increasingly used in nosocomial infections associated with multidrug-resistant Gram-negative bacteria (MDR-GNB). Intravenous CS is usually administered as a less toxic pro drug, i.e. colistin sodium methanesulfonate (CMS). In water-containing solutions, CMS undergoes a spontaneous hydrolysis to form a complex mixture of partially sulfomethylated derivatives and CS. Pharmacokinetic of CS is dependent on the route of administration, i.e. parenteral, intramuscular, nebulized, intrathecal/intraventricular. Renal toxicity is the most common adverse effect of CS treatment, as the drug is excreted primarily by the kidney and elevated levels of CS may further impair renal function, with a dose-dependent effect. Clinical manifestations of CS associated nephrotoxicity include acute kidney injury, proteinuria and tubular damage. Only few data are currently available on the effects of different renal replacement therapy modalities on CS pharmacokinetics. In patients undergoing the most efficient forms of renal replacement therapies, the extracorporeal clearance of CMS may result in a substantial removal of the antibiotic. Thus, in this setting, the recommended daily doses should be increased. Future studies should better explore CS pharmacokinetics in patients undergoing different modalities of renal replacement therapy. PMID- 25504164 TI - [Cardiac magnetic resonance and uremic cardiomyopathy]. AB - Cardiovascular disease (CV) represents the main risk factor for morbidity and mortality in chronic kidney disease (CKD) patients. Large epidemiological studies have shown direct association between severity of CKD and CV event rates. Although patients with end-stage renal disease (ESRD), including dialysis ones, are at greater CV risk, cardiovascular involvement is already evident at the early stages of CKD. End-stage CKD is characterized conventional atherosclerotic risk factor but they cannot account for CV risk as reflected in high rates of sudden cardiac death, heart failure and myocardial infarction. Non atherosclerotic processes, including left ventricular hypertrophy and fibrosis, mostly account for the excess risk of CV. Employment of cardiac magnetic resonance (CMR) in CKD has brought an improved understanding of the adverse CV changes, known as uremic cardiomyopathy. It is due to ability of cardiac magnetic resonance to provide a comprehensive non - invasive examination of cardiac structure and function, arterial function, myocardial tissue characterization (T1 mapping and inversion recovery imaging), and myocardial metabolic function (spectroscopy). PMID- 25504165 TI - [Metformin- related lactic acidosis]. AB - Lactic acidosis metformin-related is a potentially fatal complication. Reviews show a stable prevalence of this phenomenon, but nephrological experience is required since it is frequently involved in therapeutic management. Here we report the cases of two old patients with severe lactic acidosis and acute renal failure treated with hemodiafiltration. PMID- 25504167 TI - [Where am I?]. PMID- 25504166 TI - [Heroes never die. Tribute to Gabriel Richet]. PMID- 25504168 TI - [Modern approach to parathyroidectomy]. AB - Parathyroid surgery underwent significant innovations in the past 20 years, after both the improvement of the imaging techniques used to localize abnormal parathyroids (ultrasonography and MIBI scintiscan) and the possibility of the intraoperative PTH assay. These two tools, in experienced hands, can correctly differentiate uniglandular (more than 85% of the cases of primary hyperparathyroidism) from multiglandular disease. These technological improvements led to the possibility of limiting the surgical exploration to the single parathyroid responsible for the hyperparathyroidism in the majority of cases, avoiding unnecessary bilateral exploration that might increase both the morbidity of the surgery and its global costs. Furthermore, from a technical point of view, the philosophy of a minimally invasive surgery has also been applied to parathyroidectomy and several techniques have been described which are commonly considered minimally invasive. In this paper, the authors want to summarize their indications to perform a focused parathyroidectomy vs. a more traditional bilateral exploration, their definition of a minimally invasive parathyroidectomy and finally, it is given an overview of the techniques currently used for a parathyroidectomy. PMID- 25504169 TI - [Free light chains reduction on acute kidney injury in multiple myeloma: critical role of high cut-off membranes]. AB - We report our experience with five patients, with dialysis dependent AKI and multiple myeloma (MM). Two of them were already suffering from a mild degree of renal insufficiency, one was on follow-up for smouldering MM and two had a relapse of symptomatic MM. Median concentration of the involved FLC (iFLC) was 15104 mg/L (range 1196-24384). All patients underwent three times per week HCO-HD for 6 hour sessions using Theralite 2100 (median 10, range 6-13 sessions) with one having further twelve sessions of 4 hours using SUPRA device (Bellco). In addition, they followed a bortezomib and dexamethasone regimen according to a bi weekly schedule (3-5 cycles) plus Thalidomide. iFLC concentrations were measured by immunonephelometry in blood at the beginning of each dialysis session. All patients but one, showed a very good partial hematological response. The only exception demonstrated a partial response. iFLCs decreased between 72,8% and 99,7% in a median period of three weeks. After 6 months three patients underwent autologous stem-cell transplantation (ASCT), one of whom repeated the procedure 6 months later. In conclusion, three patients became dialysis independent at the end of the HCO-HD period, one patient became dialysis independent three months later and one remained dialysis dependent. Recovery of renal function in 4 out of 5 patients with a very good hematological response is a consequence of an early and fast removal of the iFLC joined to an efficient therapeutic regimen. PMID- 25504170 TI - [FGF23 and the heart]. AB - The prevalence of chronic kidney disease (CKD) has now reached epidemic proportions and it is very likely that it will continue to rise with the increasing prevalence of juvenile diabetes mellitus, hypertension and aging population. CKD is a risk factor for cardiovascular disease (CVD) and cardiovascular disease can lead to CKD. It is also well known that patients with CKD have a higher risk of death from CVD than of progressing to end-stage renal disease that requires renal replacement therapy. In patients with CKD, there is a higher mortality from sudden cardiac death and congestive heart failure than coronary artery disease, which is not the case in the general population. The high prevalence of congestive heart failure in CKD is due to cardiac remodeling which progresses from concentric remodeling to concentric and eccentric hypertrophy, leading to left ventricular hypertrophy with both systolic and diastolic dysfunction. Recent studies have suggested that, in patients with chronic kidney disease, common traditional risk factors for cardiovascular disease such as hypertension, hyperlipidemia and obesity may not be the main determinants of cardiovascular disease. Among the various non-traditional cardiovascular risk factors present in patients with chronic kidney disease, abnormalities of CKD related mineral and bone disorder, which includes elevated fibroblast growth factor 23 (FGF23) have been one of the most extensively studied. However, after many years of research, the debate over the exact pathways by which FGF23 may lead to increased CVD still continues. FGF23 may have both direct and indirect effects on the cardiovascular system. Better understanding of the most relevant pathophysiologic pathways for FGF23 may lead to therapeutic interventions against cardiovascular disease in patients with CKD. PMID- 25504171 TI - [Doctor's African notebook]. PMID- 25504172 TI - [Lipocalin and kidney transplant]. AB - INTRODUCTION: Kidney transplantation is frequently complicated by delayed graft function (DGF). DGF is associated with more frequent rejection episodes, increased need of post-transplantation biopsies, dialysis sessions and prolonged hospitalization. These complications may have negative impact on long-term survival of transplanted kidney.Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is regarded as acute kidney injury marker.This preliminary study aimed at evaluating whether uNGAL may be early predictor of DGF in kidney transplanted patients. SUBJECTS AND METHODS: Urine samples were collected from renal transplant recipients on day 1 post-transplantation to determine 24/h urinary NGAL and creatinine excretion. On same day, routine blood chemistry was assessed. RESULTS: N. 20 renal transplant recipients were evaluated. DGF was observed in n. 6 patients (DGF-patients). In DGF-patients compared to NO-DGF patients, mean age was higher (586 Vs 5111, p=0.001), while 24/h urine output (5735 Vs 4150 2230 ml/24h; p=0.001) and urinary creatinine excretion (191184 Vs 683660 mg/24h; p=0.001) were lower. No difference was found between DGF- and NO DGF-patients in 24/h urinary NGAL excretion (1,202,20 Vs 2,444,0 mg/24h; p<0.20). In univariate analysis, DGF was inversely associated to 24/h urine output (r2= 0.795, p=0.001) and urinary creatinine excretion (r2=-0.480, p=0.037) and positively to age (r2=0.446, p=0.049). In multivariate analysis 24/h urine output (p=0.014) and 24/h urinary creatinine excretion (p=0.039) were associated to DGF. CONCLUSION: This preliminary study suggests that 24/h urinary NGAL excretion, measured 1 day after kidney transplantation, is not a reliable predictor of DGF. Larger study with longer observation period is mandatory. PMID- 25504173 TI - [An odd diagnosis: "Rolling Stones' Syndrome"]. AB - We present an unusual case of a young patient regularly followed in our Chronic Renal Insufficiency ambulatory with the periodicity of 2-3 visits per year - with stabilization of his residual renal function. The patient came to the emergency department declaring abdominal pain but make a diagnosis turned out to be more complicated than we expected PMID- 25504174 TI - [Evaluation of Italian Journal of Nephrology (GIN) in 2014. Healthcare cost and its future in Italy]. PMID- 25504175 TI - Single case design studies in music therapy: resurrecting experimental evidence in small group and individual music therapy clinical settings. AB - BACKGROUND: The profession would benefit from greater and routine generation of causal evidence pertaining to the impact of music therapy interventions on client outcomes. OBJECTIVE: One way to meet this goal is to revisit the use of Single Case Designs (SCDs) in clinical practice and research endeavors in music therapy. Given the appropriate setting and goals, this design can be accomplished with small sample sizes and it is often appropriate for studying music therapy interventions. METHODS: In this article, we promote and discuss implementation of SCD studies in music therapy settings, review the meaning of internal study validity and by extension the notion of causality, and describe two of the most commonly used SCDs to demonstrate how they can help generate causal evidence to inform the field. RESULTS: In closing, we describe the need for replication and future meta-analysis of SCD studies completed in music therapy settings. CONCLUSIONS: SCD studies are both feasible and appropriate for use in music therapy clinical practice settings, particularly for testing effectiveness of interventions for individuals or small groups. PMID- 25504176 TI - Effects of a dyadic music therapy intervention on parent-child interaction, parent stress, and parent-child relationship in families with emotionally neglected children: a randomized controlled trial. AB - BACKGROUND: Work with families and families at risk within the field of music therapy have been developing for the last decade. To diminish risk for unhealthy child development, families with emotionally neglected children need help to improve their emotional communication and develop healthy parent-child interactions. While some researchers have investigated the effect of music therapy on either the parent or the child, no study has investigated the effect of music therapy on the observed interaction between the parent and child within the field of child protection. OBJECTIVE: The purpose of this study was to investigate the effect of a dyadic music therapy intervention on observed parent child interaction (mutual attunement, nonverbal communication, emotional parental response), self-reported parenting stress, and self-reported parent-child relationship in families at risk and families with emotionally neglected children, ages 5-12 years. METHOD: This was a randomized controlled trial study conducted at a family care center in Denmark. Eighteen parent-child dyads were randomly assigned to receive 10 weekly music therapy sessions with a credentialed music therapist (n = 9) or treatment as usual (n = 9). Observational measures for parent-child interaction, self-reported measures for parenting stress and parent child relationship were completed at baseline and 4 months post-baseline assessment. RESULTS: Results of the study showed that dyads who received music therapy intervention significantly improved their nonverbal communication and mutual attunement. Similarly, parents who participated in dyadic music therapy reported themselves to be significantly less stressed by the mood of the child and to significantly improve their parent-child relationship in terms of being better at talking to and understanding their children than parents who did not receive music therapy. Both groups significantly improved in terms of increased positive and decreased negative emotional parental response, parenting stress and stress in general. There were no significant between group differences in self perceived autonomy, attachment, and parental competence. CONCLUSIONS: The dyadic music therapy intervention examined in this study improved emotional communication between parent and child and interaction after 6 to 10 sessions and can be considered as a viable treatment alternative or supplement for families at risk and families with emotionally neglected children. PMID- 25504177 TI - The effect of musical attention control training (MACT) on attention skills of adolescents with neurodevelopmental delays: a pilot study. AB - BACKGROUND: Given the effect of musical training on the rate and accuracy of processing auditory information, therapeutic uses of music may potentially have remedial benefits for individuals with neurodevelopmental deficits. However, additional studies are needed to establish efficacy of music therapy interventions for attention skills in children/adolescents with neurodevelopmental disabilities including those with Autism Spectrum Disorders (ASD). OBJECTIVE: To establish feasibility and preliminary efficacy of a group music therapy protocol to improve attention skills (sustained, selective, attentional control/switching) in adolescents diagnosed with autism and/or developmental delays. METHODS: This single group pretest/posttest study took place in a private school for high functioning adolescents with neurodevelopmental delays. Nine students (4 males, 5 females), ages 13 to 20, participated in the study. Autism severity was assessed using the CARS2-HF and indicated the following distribution for study participants: severe (n = 3), mild (n = 4), or minimal/no (n = 2) symptoms. We assessed feasibility of implementing a 45-min Musical Attention Control Training (MACT) intervention delivered by a board-certified music therapist eight times over 6 weeks in a school setting. We also examined preliminary efficacy of the MACT to improve attention skills using the Test of Everyday Attention for Children (TEA-Ch). RESULTS: Parental consent rate was 100%. All nine participants successfully completed testing measures and 6 weeks of the intervention. Average participation rate was 97%. Data analysis showed positive trends and improvements on measures of attentional control/switching and selective attention. CONCLUSIONS: The results showed that the intervention and testing measures were feasible to implement and acceptable to the participants who all completed the protocol. Data analysis demonstrated positive trends indicating that more research on the use of music therapy attention training in high-functioning adolescents with neurodevelopmental disabilities is warranted. PMID- 25504178 TI - Recruiting participants for randomized controlled trials of music therapy: a practical illustration. AB - BACKGROUND: Failure to recruit sufficient numbers of participants to randomized controlled trials is a common and serious problem. This problem may be additionally acute in music therapy research. OBJECTIVE: To use the experience of conducting a large randomized controlled trial of music therapy for young people with emotional and behavioral difficulties to illustrate the strategies that can be used to optimize recruitment; to report on the success or otherwise of those strategies; and to draw general conclusions about the most effective approaches. METHODS: Review of the methodological literature, and a narrative account and realist analysis of the recruitment process. RESULTS: The strategies adopted led to the achievement of the recruitment target of 250 subjects, but only with an extension to the recruitment period. In the pre-protocol stage of the research, these strategies included the engagement of non-music therapy clinical investigators, and extensive consultation with clinical stakeholders. In the protocol development and initial recruitment stages, they involved a search of systematic reviews of factors leading to under-recruitment and of interventions to promote recruitment, and the incorporation of their insights into the research protocol and practices. In the latter stages of recruitment, various stakeholders including clinicians, senior managers and participant representatives were consulted in an attempt to uncover the reasons for the low recruitment levels that the research was experiencing. CONCLUSIONS: The primary mechanisms to promote recruitment are education, facilitation, audit and feedback, and time allowed. The primary contextual factors affecting the effectiveness of these mechanisms are professional culture and organizational support. PMID- 25504179 TI - Music therapy career aptitude and generalized self-efficacy in music therapy students. AB - BACKGROUND: While the Music Therapy Career Aptitude Test (MTCAT) provides a measure of student aptitude, measures of perceived self-efficacy may provide additional information about a students' suitability for a music therapy career. OBJECTIVE: As a first step in determining whether future studies examining combined scores from the MTCAT and the Generalized Self-Efficacy (GSE) scale would be useful to help predict academic success in music therapy, we explored the internal reliability of these two measures in a sample of undergraduate students, and the relationship (concurrent validity) of the measures to one another. METHODS: Eighty undergraduate music therapy students (14 male; 66 female) completed the MTCAT and GSE. To determine internal reliability we conducted tests of normality and calculated Cronbach's Coefficient Alpha for each measure. Pearson correlation coefficients were calculated to ascertain the strength of the relationship between the MTCAT and GSE. RESULTS: MTCAT scores were normally distributed and had high internal consistency (Cronbach's alpha = 0.706). GSE scores were not normally distributed, but had high internal consistency (Cronbach's alpha = 0.748). The correlation coefficient analysis revealed that MTCAT and GSE scores were moderately correlated ((r = 0.426, p < 0.0001). CONCLUSION: MTCAT scores can be used to partially determine perceived self-efficacy in undergraduate music therapy students; however, a more complete picture of student suitability for music therapy may be determined by administering the GSE alongside the MTCAT. Future studies are needed to determine whether combined MTCAT and GSE scores can be used to predict student success in an undergraduate music therapy program. PMID- 25504182 TI - Transplant nephrectomy: histologic findings-a single center study. AB - AIMS: To identify the histopathological features of transplant nephrectomy (TN) specimens. METHODS: We performed retrospective analysis of 73 nephrectomies to review the histopathology in detail and correlate the Banff grading characteristics of TN specimens with time post engraftment and clinical features. Retrospective data on donor-specific antibodies (DSA) were also collected. RESULTS: The majority of patients who had TN in less than 3 months posttransplant (n = 20; median time to TN: 4 days) had hemorrhagic infarction; 7 patients (35%) had grade 3 acute rejection (AR). Patients who had TN later than 3 months posttransplant (n = 53; median time to TN: 67 months) had AR, grade 2B (21%) and 3 (43%), coexisting with advanced vascular injury in the form of interstitial hemorrhage, extensive interstitial fibrosis and tubular atrophy (IF/TA) as well as the presence of DSAs. Overall, the majority of patients without DSA pre-TN developed DSA post-TN. CONCLUSIONS: Our data revealed extensive inflammation and ongoing immunologic activity in a subset of patients with a failed graft. Careful and individualized approach based on clinical and laboratory data should guide the decision for transplant nephrectomy. PMID- 25504183 TI - Galanin plays an important role in cancer invasiveness and is associated with poor prognosis in stage II colorectal cancer. AB - Reliable predictors of tumor recurrence for patients with stage II colorectal cancer (CRC) are needed to select patients who should receive adjuvant chemotherapy. Although galanin (GAL) is expressed in several malignant tumors and is associated with cell proliferation and tumor growth, the prognostic value of GAL expression in CRC is poorly understood. We compared GAL expression between 56 patients with stage II and III CRC who developed tumor recurrences and 56 patients who did not. The clinical and prognostic significance of GAL expression was examined using our data and independent public datasets. We also analyzed the influence of GAL expression on the proliferation and invasive activity of CRC cells. Higher expression of GAL was associated with tumor recurrence among the CRC patients (P<0.001). Stage II CRC patients who presented with high expression levels of GAL had significantly poorer prognosis than those with low expression levels of GAL [5-year overall survival: hazard ratio (HR), 7.31; 95% confidence interval (CI), 2.38-24.04; P<0.001; 5-year recurrence-free survival: HR, 3.99; 95% CI, 1.61-9.44; P=0.004], but there was no association between GAL expression and survival in stage III CRC patients. These findings were supported by analysis of two public datasets. Functionally, siRNA-mediated silencing of GAL resulted in a significant decrease in the proliferative and invasive activities of CRC cells. In conclusion, high expression of GAL is associated with poor prognosis of stage II CRC patients and GAL expression may be related to the aggressive behavior of CRC. PMID- 25504184 TI - Pore size and LbL chitosan coating influence mesenchymal stem cell in vitro fibrosis and biomineralization in 3D porous poly(epsilon-caprolactone) scaffolds. AB - Poly(epsilon-caprolactone) (PCL) is a hydrophobic bioplastic under development for bone tissue engineering applications. Limited information is available on the role of internal geometry and cell-surface attachment on osseous integration potential. We tested the hypothesis that human bone marrow mesenchymal stem cells (MSCs) deposit more mineral inside porous 3D PCL scaffolds with fully interconnected 84 or 141 um pores, when the surfaces are coated with chitosan via Layer-by-Layer (LbL)-deposited polyelectrolytes. Freshly trypsinized MSCs were seeded on PCL 3D cylinders using a novel static cold seeding method in 2% serum to optimally populate all depths of the scaffold discs, followed by 10 days of culture in proliferation medium and 21 additional days in osteogenic medium. MSCs were observed by SEM and histology to spread faster and to proliferate more on chitosan-coated pore surfaces. Most pores, with or without chitosan, became filled by collagen networks sparsely populated with fibroblast-like cells. After 21 days of culture in osteogenic medium, sporadic matrix mineralization was detected histologically and by micro-CT in highly cellular surface layers that enveloped all scaffolds and in cell aggregates in 141 um pores near the edges. LbL-chitosan promoted punctate mineral deposition on the surfaces of 84 um pores (p < 0.05 vs. PCL-only) but not the 141 um pores. This study revealed that LbL chitosan coatings are sufficient to promote MSC attachment to PCL but only enhance mineral formation in 84 um pores, suggesting a potential inhibitory role for MSC-derived fibroblasts in osteoblast terminal differentiation. PMID- 25504185 TI - The role of extrahepatic metabolism in the pharmacokinetics of the targeted covalent inhibitors afatinib, ibrutinib, and neratinib. AB - Despite the fact that much progress has been made recently in the development of targeted covalent inhibitors (TCIs), their pharmacokinetics (PK) have not been well characterized in the light of extrahepatic clearance (CLextH) by glutathione (GSH)/glutathione S-transferase (GST)-dependent conjugation attributable to the unique electrophilic structure (e.g., acrylamide moiety) of TCI compounds. In the present study, CLextH values were examined in rat, dog, and monkey to predict the contribution of CLextH to the PK of the TCIs afatinib, ibrutinib, and neratinib in humans. Afatinib and neratinib both underwent extensive conjugation with GSH in buffer and cytosol fractions of liver and kidney, whereas ibrutinib showed much lower reactivity/susceptibility to GSH/GST-dependent conjugation. The CLextH in each species was calculated from the difference between observed total body clearance and predicted hepatic clearance (CLH) in cryopreserved hepatocytes suspended in 100% serum of the corresponding species. The power-based simple allometry relating the CLextH for the unbound compound to animal body weight was applicable across species for afatinib and neratinib (R(2) >= 0.9) but not for ibrutinib (R(2) = 0.04). The predicted AUC after oral administration of afatinib and neratinib agreed reasonably closely with reported values in phase I dose escalation studies. Comparisons of CLextH and CLH predicted that CLextH largely determined the PK of afatinib (>90% as a proportion of total body clearance) and neratinib (~34%) in humans. The present method can serve as one of the tools for the optimization of PK in humans at the discovery stage for the development of TCI candidates. PMID- 25504186 TI - Hierarchal clustering yields insight into multidrug-resistant bacteria isolated from a cattle feedlot wastewater treatment system. AB - Forty-two percent of Escherichia coli and 58% of Enterococcus spp. isolated from cattle feedlot runoff and associated infiltration basin and constructed wetland treatment system were resistant to at least one antibiotic of clinical importance; a high level of multidrug resistance (22% of E. coli and 37% of Enterococcus spp.) was observed. Hierarchical clustering revealed a closely associated resistance cluster among drug-resistant E. coli isolates that included cephalosporins (ceftiofur, cefoxitin, and ceftriaxone), aminoglycosides (gentamycin, kanamycin, and amikacin), and quinolone nalidixic acid; antibiotics from these classes were used at the study site, and cross-resistance may be associated with transferrable multiple-resistance elements. For Enterococcus spp., co-resistance among vancomycin, linezolid, and daptomycin was common; these antibiotics are reserved for complicated clinical infections and have not been approved for animal use. Vancomycin resistance (n = 49) only occurred when isolates were resistant to linezolid, daptomycin, and all four of the MLSB (macrolide-lincosamide-streptogramin B) antibiotics tested (tylosin, erythromycin, lincomycin, and quinipristin/dalfopristin). This suggests that developing co-resistance to MLSB antibiotics along with cyclic lipopeptides and oxazolidinones may result in resistance to vancomycin as well. Effects of the treatment system on antibiotic resistance were pronounced during periods of no rainfall and low flow (long residence time). Increased hydraulic loading (short residence time) under the influence of rain caused antibiotic-resistant bacteria to be flushed through the treatment system. This presents concern for environmental discharge of multidrug-resistant organisms relevant to public health. PMID- 25504187 TI - Selection and screening of microbial consortia for efficient and ecofriendly degradation of plastic garbage collected from urban and rural areas of Bangalore, India. AB - Industrialization and urbanization have led to massive accumulation of plastic garbage all over India. The persistence of plastic in soil and aquatic environment has become ecological threat to the metropolitan city such as Bangalore, India. Present study investigates an ecofriendly, efficient and cost effective approach for plastic waste management by the screening of novel microbial consortia which are capable of degrading plastic polymers. Plastic contaminated soil and water samples were collected from six hot spots of urban and rural areas of Bangalore. The plastic-degrading bacteria were enriched, and degradation ability was determined by zone of clearance method. The percentage of polymer degradation was initially monitored by weight loss method, and the main isolates were characterized by standard microbiology protocols. These isolates were used to form microbial consortia, and the degradation efficiency of the consortia was compared with individual isolate and known strains obtained from the Microbial Type Culture Collection (MTCC) and Gene Bank, India. One of the main enzymes responsible for polymer degradation was identified, and the biodegradation mechanism was hypothesized by bioinformatics studies. From this study, it is evident that the bacteria utilized the plastic polymer as a sole source of carbon and showed 20-50% weight reduction over a period of 120 days. The two main bacteria responsible for the degradation were microbiologically characterized to be Pseudomonas spp. These bacteria could grow optimally at 37 degrees C in pH 9.0 and showed 35-40% of plastic weight reduction over 120 days. These isolates were showed better degradation ability than known strains from MTCC. The current study further revealed that the microbial consortia formulated by combining Psuedomonas spp. showed 40 plastic weight reduction over a period of 90 days. Further, extracellular lipase, one of the main enzymes responsible for polymer degradation, was identified. The computational docking studies suggested that polyethylene glycol and polystyrene present in the plastics might have good interaction towards the microbial lipase with stable binding and interacting forces which probably could be one of the reasons for the degradative mechanisms. PMID- 25504188 TI - Application of 1-(2-pyridylazo)-2-naphthol-modified nanoporous silica as a technique in simultaneous trace monitoring and removal of toxic heavy metals in food and water samples. AB - Solid-phase extraction is one the most useful and efficient techniques for sample preparation, purification, cleanup, preconcentration, and determination of heavy metals at trace levels. In this paper, functionalized MCM-48 nanoporous silica with 1-(2-pyridylazo)-2-naphthol was applied for trace determination of copper, lead, cadmium, and nickel in water and seafood samples. The experimental conditions such as pH, sample and eluent flow rate, type, concentration and volume of the eluent, breakthrough volume, and effect of coexisting ions were optimized for efficient solid-phase extraction of trace heavy metals in different water and seafood samples. The content of solutions containing the mentioned heavy metals was determined by flame atomic absorption spectrometry (FAAS), and the limits of detection were 0.3, 0.4, 0.6, and 0.9 ng mL(-1) for cadmium, copper, nickel, and lead, respectively. Recoveries and precisions were >98.0 and <4%, respectively. The adsorption capacity of the modified nanoporous silica was 178 mg g(-1) for cadmium, 110 mg g(-1) for copper, 98 mg g(-1) for nickel, and 210 mg g(-1) for lead, respectively. The functionalized MCM-48 nanoporous silica with 1-(2-pyridylazo)-2-naphthol was characterized by thermogravimetry analysis (TGA), differential thermal analysis (DTA), transmission electron microscopy (TEM), Fourier transform infrared spectrometry (FT-IR), X-ray diffraction (XRD), elemental analysis (CHN), and N2 adsorption surface area measurement. PMID- 25504189 TI - Variation and correlation of content and leachability of hazardous metals in MSW molten slag. AB - To increase the amount of accessible municipal solid waste molten slag (MSWS) for its use in aggregates such as sand, MSWS must be deemed environmentally safe. Municipal solid waste (MSW) is a heterogeneous waste source used in MSWS and varies in chemical composition. Due to its nature, there is great concern about hazardous metal contamination among users of MSWS. In this study, MSWS samples were obtained weekly for 1 year from a typical incineration ash melting facility for municipal solid waste in Japan. Variation in heavy metal contents and the leachability of MSWS were investigated using two content analysis methods and two leaching tests, respectively. There is a weak correlation between metal content and concentration, and the leachability of metals in slag could not be reduced by decreasing its metal content. No measured values of hazardous metal concentration and metal content exceed the regulation levels stipulated in Japanese Industrial Standards A5031 and A5032, respectively, thereby demonstrating that the slag can be safely utilized as road and concrete aggregates. However, metal concentrations varied widely and differed by greater than 1 order of magnitude and Pb concentrations of several MSWS samples approach the regulation level. Therefore, frequent monitoring of lead leachability of MSWS and storing MSWS for several weeks to obtain a high quality that is more homogeneous in chemical composition are demanded. This study provides fundamental information for controlling the quality of MSWS and the contributing factors for achieving a safe slag recycling system. PMID- 25504190 TI - Background concentrations and reference values for heavy metals in soils of Cuba. AB - The potential threat of heavy metals to human health has led to many studies on permissible levels of these elements in soils. The objective of this study was to establish quality reference values (QRVs) for Cd, Pb, Zn, Cu, Ni, Cr, Fe, Mn, As, Hg, V, Ba, Sb, Ag, Co, and Mo in soils of Cuba. Geochemical associations between trace elements and Fe were also studied, aiming to provide an index for establishing background concentrations of metals in soils. Surface samples of 33 soil profiles from areas of native forest or minimal anthropic influence were collected. Samples were digested (USEPA method 3051A), and the metals were determined by ICP-OES. The natural concentrations of metals in soils of Cuba followed the order Fe > Mn > Ni > Cr > Ba > V > Zn > Cu > Pb > Co > As > Sb > Ag > Cd > Mo > Hg. The QRVs found for Cuban soils were as follows (mg kg(-1)): Ag (1), Ba (111), Cd (0.6), Co (25), Cr (153), Cu (83), Fe (54,055), Mn (1947), Ni (170), Pb (50), Sb (6), V (137), Zn (86), Mo (0.1), As (19), and Hg (0.1). The average natural levels of heavy metals are above the global average, especially for Ni and Cr. The chemical fractionation of soil samples presenting anomalous concentrations of metals showed that Cu, Ni, Cr, Sb, and As have low bioavailability. This suggests that the risk of contamination of agricultural products via plant uptake is low. However, the final decision on the establishment of soil QRVs in Cuba depends on political, economic, and social issues and in-depth risk analyses considering all routes of exposure to these elements. PMID- 25504191 TI - Characterization of wastes from construction and demolition sector. AB - In Republic of Korea, construction and demolition (C&D) waste accounts for 49.9% of the total waste. In the present work, the mineralogical composition, the concentrations of 11 heavy metals, 19 PAH, and 7 polychlorinated biphenyl (PCB) congeners present in the 6 broad category (9 subcategories) of C&D hazardous waste were discussed along with their leaching characteristics. In concrete/mixed cement waste, the concentrations of As, Cr(6+), Hg, and Zn were in the range of 1.76-7.86, ND-1.63, 0.026-0.047, and 110.90-280.17 mg/kg, respectively. The asphalt waste sample A1 possessed relatively high concentrations of phenanthrene, fluoranthene, pyrene, benz(a)anthracene, benzo(a)pyrene, and indeno(1,2,3 cd)pyrene comparing to the other samples and it contains 0.08-0.1% of coal tar. Hazardous nature of the C&D wastes greatly depends on the source of the collection. Zn concentration was above 1000 mg/kg for road asphalt waste samples A4 and A5. Total PCB concentration were high in the soil waste sample S1 (130 MUg/kg) as it was the excavated soil obtained from the premises of an oil station. Leaching of As, Ba, CN(-), and F(-) were observed in most of the C&D waste samples. PMID- 25504192 TI - Estimating the health risks associated with air pollution in Baghdad City, Iraq. AB - Data of total suspended particulate, O3, SO2, NO, NO2, CO, methane, and non methane hydrocarbons gathered from three monitoring stations in Baghdad City for the period from 2009 to 2012 have been analyzed. So an attempt is made to calculate the monthly quality indexes based on US EPA and UK system. Concentrations of most air pollutants in Baghdad City have shown a downward trend in recent years, but they are generally in many instances worse than natural ambient air; thus, all pollutants (except CO) fluctuated between high and below limits certified by Iraqi and international standards. The results show that the average of TSP during 2009-2012 were very high, and they pose concern for Baghdad population. The SO2/CO concentration ratios were less than 1 suggesting that mobile emissions are the primary sources within the study area. It has been observed that the concentrations of the most pollutants are high in summer in comparison to the other seasons. The peak concentrations of pollutants are linked to traffic density, private generators, and chemical processes in the atmosphere. Aside from single air pollutant standards, AQI and API indices enable an additional assessment of the air quality conditions. The application of the UK system suppose low pollution with all pollutants expect TSP. Analysis of AQI values for an average of concentrations CO, NO2, SO2, and O3 are categorized as good to moderate during the study period, while the same index indicated that the TSP located within the three categories (unhealthy, very unhealthy, and hazardous). PMID- 25504193 TI - Youngia erythrocarpa, a newly discovered cadmium hyperaccumulator plant. AB - The farmland weed Youngia erythrocarpa has been found to have the basic characteristics of a cadmium (Cd) hyperaccumulator. This study carried out preliminary and further Cd concentration gradient experiments and field experiment using Y. erythrocarpa to confirm this fact. The results showed that the biomass and resistance coefficient of Y. erythrocarpa decreased, but the root/shoot ratio and the Cd content in roots and shoots increased with the increase in soil Cd concentration. The Cd content in shoots of Y. erythrocarpa exceeded 100 mg/kg when the soil Cd concentration was 25 mg/kg in the two concentration gradient experiments, up to the maxima of 293.25 and 317.87 mg/kg at 100 mg/kg soil Cd. Both the bioconcentration factor of the shoots and the translocation factor exceeded 1 in all Cd treatments. In the field experiment, the total Cd extraction by shoots was 0.934-0.996 mg/m(2) at soil Cd levels of 2.04-2.89 mg/kg. Therefore, Y. erythrocarpa is a Cd hyperaccumulator that could be used to remediate Cd-contaminated farmland soil efficiently. PMID- 25504194 TI - Geospatial quantification and analysis of environmental changes in urbanizing city of Kolkata (India). AB - Over the past five decades, the fragile wetland ecosystem surrounding the city of Kolkata has witnessed extensive changes in the name of urban development. In this study, we elaborate relationships among biophysical parameters and land surface temperature (LST) in Kolkata city and nearby surrounding areas where rapid urbanization has occurred. LST and associated surface physical characteristics were assessed using Landsat images acquired for the years 1989, 2006, and 2010. The satellite data was used to study the spatiotemporal urban footprint and correlation among normalized difference vegetation index (NDVI), normalized difference built-up index (NDBI), normalized difference water index (NDWI) and LST. Land use land cover (LULC) maps prepared using supervised classification had overall accuracy of 90, 88, and 86 % and kappa coefficient of 0.8726, 0.8455, and 0.8212 for 1989, 2006, and 2010, respectively. The spatial expansion as a consequence of increasing urban population is 108.94 km(2) over past two decades. The urban built-up in and around the city extends up to 88.71 km(2) in 1989, 144.64 km(2) in 2006, and 197.65 km(2) in 2010. These changes have attributed in elevating surface temperature in the study region. Analysis of biophysical parameters shows LST and NDBI having a positive correlation, LST and NDVI having negative correlation, while NDBI and NDWI having a perfectly negative correlation. Satellite estimated temperatures of the surface show a warming trend evident from increasing mean surface temperature values from 27.36 degrees C in 1989 to 30.025 degrees C in 2006 and 33.023 degrees C in 2010. The magnitude and extent of the estimates of LST are consistent with the urbanization pattern throughout the city and adjoining areas. PMID- 25504195 TI - Evaluation of passive samplers for the collection of dissolved organic matter in streams. AB - Traditional sampling methods for dissolved organic matter (DOM) in streams limit opportunities for long-term studies due to time and cost constraints. Passive DOM samplers were constructed following a design proposed previously which utilizes diethylaminoethyl (DEAE) cellulose as a sampling medium, and they were deployed throughout a temperate stream network in Indiana. Two deployments of the passive samplers were conducted, during which grab samples were frequently collected for comparison. Differences in DOM quality between sites and sampling methods were assessed using several common optical analyses. The analyses revealed significant differences in optical properties between sampling methods, with the passive samplers preferentially collecting terrestrial, humic-like DOM. We assert that the differences in DOM composition from each sampling method were caused by preferential binding of complex humic compounds to the DEAE cellulose in the passive samplers. Nonetheless, the passive samplers may provide a cost-effective, integrated sample of DOM in situations where the bulk DOM pool is composed mainly of terrestrial, humic-like compounds. PMID- 25504196 TI - The AKR gene family and modifying sex ratios in palms through abiotic stress responsiveness. AB - Sex ratio (SR), the ratio of female inflorescences to total inflorescences, is one of the main yield components of oil palm (Elaeis guineensis Jacq). The SR quantitative trait locus (QTL) was recently identified on linkage (LG) 8 with a phenotype variance explained (PVE) of 11.3 %. The use of both genetic and physical mapping is one strategy for uncovering the genetic basis of the traits. Here, we report the construction of bacterial artificial chromosome (BAC) and fosmid libraries, and their use for physical mapping in oil palm. Combined, the libraries consist of more than 200,000 clones, representing 6.35 genome equivalents. Physical mapping at the SR locus was implemented by incorporating the published oil palm genome sequence and positive BAC/fosmid clones as identified by colony PCR screening. Based on the previously published sequences, the interval (about 184 kb) was comprised of 19 contigs of the known sequences (~117 kb, 64 %). After, combining the 454 pyrosequences of 15 positive clones and the previously published sequences, the known sequences were revealed to cover about 82 % of the interval (~150 kb), and were used for identifying the new markers by designing 35 gene-based and 23 simple sequence repeat (SSR)-amplified primers. As a result, a putative aldo-keto reductase gene (named EgAKR1) was revealed to be a promising candidate for sex ratio determination, via controlling female inflorescence number (11 % of PVE). This was predicted from the two newly identified polymorphic marker loci (mEgSSRsr8-21LB and mEgAKR1-9) designing from EgAKR1. The functions of AKR gene families in other plant species and our promoter analysis suggested that EgAKR1 may contribute to the sex ratio through abiotic stress responsiveness. PMID- 25504197 TI - Upregulation of jasmonate biosynthesis and jasmonate-responsive genes in rice leaves in response to a bacterial pathogen mimic. AB - Xanthomonas oryzae pv. oryzae, the causal agent of bacterial blight of rice, secretes several cell wall degrading enzymes including cellulase (ClsA) and lipase/esterase (LipA). Prior treatment of rice leaves with purified cell wall degrading enzymes such as LipA can confer enhanced resistance against subsequent X. oryzae pv. oryzae infection. To understand LipA-induced rice defense responses, microarray analysis was performed 12 h after enzyme treatment of rice leaves. This reveals that 867 (720 upregulated and 147 downregulated) genes are differentially regulated (>=2-fold). A number of genes involved in defense, stress, signal transduction, and catabolic processes were upregulated while a number of genes involved in photosynthesis and anabolic processes were downregulated. The microarray data also suggested upregulation of jasmonic acid (JA) biosynthetic and JA-responsive genes. Estimation of various phytohormones in LipA-treated rice leaves demonstrated a significant increase in the level of JA Ile (a known active form of JA) while the levels of other phytohormones were not changed significantly with respect to buffer-treated control. This suggests a role for JA-Ile in cell wall damage induced innate immunity. Furthermore, a comparative analysis of ClsA- and LipA-induced rice genes has identified key rice functions that might be involved in elaboration of damage-associated molecular pattern (DAMP)-induced innate immunity. PMID- 25504198 TI - Anthocyanin biosynthesis for cold and freezing stress tolerance and desirable color in Brassica rapa. AB - Flavonoids are divided into several structural classes, including anthocyanins, which provide flower and leaf colors and other derivatives that play diverse roles in plant development and interactions with the environment. This study characterized four anthocyanidin synthase (ANS) genes of Brassica rapa, a structural gene of the anthocyanin biosynthetic pathway, and investigated their association with pigment formation, cold and freezing tolerance in B. rapa. Sequences of these genes were analyzed and compared with similar gene sequences from other species, and a high degree of homology with their respective functions was found. Organ-specific expression analysis revealed that these genes were only expressed in the colored portion of leaves of different lines of B. rapa. Conversely, B. rapa anthocyanidin synthase (BrANS) genes also showed responses to cold and freezing stress treatment in B. rapa. BrANSs were also shown to be regulated by two transcription factors, BrMYB2-2 and BrTT8, contrasting with anthocyanin accumulation and cold stress. Thus, the above results suggest the association of these genes with anthocyanin biosynthesis and cold and freezing stress tolerance and might be useful resources for development of cold-resistant Brassica crops with desirable colors as well. PMID- 25504199 TI - Cord-blood 25-hydroxyvitamin D levels and risk of early-onset neonatal sepsis: a case-control study from a tertiary care center in Turkey. AB - Vitamin D has been linked with immunity, and the immunomodulatory role of this molecule in regulating key elements of the immune system has become an area of intense scientific investigation. We designed a case-control study to investigate whether neonates with early-onset neonatal sepsis (EONS) had lower levels of vitamin D. The primary exposure for the analysis in the study was the cord-blood level of 25-hydroxyvitamin D (25(OH)D). Of the 2571 live births occurring during the 18-month study period, 53 infants were admitted to the neonatal intensive care unit with suspected EONS. After clinical and laboratory confirmation, 40 newborns with EONS and 43 controls were analyzed. Cord-blood 25(OH)D levels of infants in the study group were significantly lower than that of the control group (median 12.6 ng/mL (3.1-78.9) vs. 21 (5-118); p = 0.038, respectively). In multivariate models, a low cord-blood 25(OH)D level (<30 ng/ml) was associated with an increased risk of EONS (OR = 5.6; 95% CI = 1.3-23.5). CONCLUSION: Cord blood 25(OH)D levels of neonates with EONS were significantly lower than that of the healthy controls, and a low level of cord-blood vitamin D was found to be associated with an increased risk of EONS. Further studies are warranted to confirm this association. PMID- 25504200 TI - Reproductive outcomes of women and men born very preterm and/or with a very low birth weight in 1983: a longitudinal cohort study in the Netherlands. AB - The aims of this study were to analyze reproductive outcomes of women and men born very preterm (gestational age <32 weeks) or with a very low birth weight (<1500 g) in 1983 in the Netherlands and to compare their reproductive outcomes with the total population at a similar age of 28 years. Young adults who were born after a pregnancy complicated by very preterm (VP) delivery or with a very low birth weight (VLBW) in the Netherlands in 1983 (Project on Preterm and Small for Gestational Age Infants (POPS) cohort) were invited to complete an online questionnaire at the age of 28. In total, 293 POPS-28 participants (31.6%) completed the questionnaire including 185 female and 108 male participants. Female and male participants who were born VP or with a VLBW had significant reduced reproductive rates compared to the total Dutch population at 28 years of age (female 23.2 vs 31.9% and male 7.4 vs 22.2%). Pregnancies of the female participants were in 14% complicated by preterm delivery in at least one pregnancy. CONCLUSION: This study indicates that women and men born VP or with a VLBW have reduced reproductive rates at the age of 28 compared to the total Dutch population at a similar age. PMID- 25504202 TI - A case of crush syndrome induced by the kneeling seiza position. AB - Crush syndrome results in a characteristic syndrome of rhabdomyolysis with myoglobinuric acute renal failure. The most commonly described crush injury is that which affects victims of natural disasters such as earthquakes. Here, we report a rare case of crush syndrome that was induced by the kneeling seiza position. PMID- 25504201 TI - A rare case of Cushing's syndrome due to bilateral adrenocortical adenomas. AB - We report a rare case of Cushing's syndrome caused by bilateral cortisol secreting adenomas in a 63-year-old man. Our preoperative diagnosis was based on endocrinological results and imaging findings. Laparoscopic adrenalectomy has become a standard technique for adrenal tumors; however, bilateral adrenalectomy results in postoperative adrenal insufficiency, necessitating lifelong steroid replacement. To preserve adrenal function, the left adrenal gland was completely resected, whereas the right adrenal gland was partially resected laparoscopically. Hydrocortisone supplementation was initiated at a dose of 30 mg/day and was slowly tapered. However, symptoms of adrenal insufficiency developed, and adrenal steroid secretion did not respond to exogenous adrenocorticotropic hormone. Bilateral cortisol-secreting tumors rarely cause Cushing's syndrome. The present study comprised few patients, and the utilized surgical procedures (i.e., total/partial adrenalectomy or bilateral total adrenalectomy) were not uniform. Few cases of bilateral adrenal-preserving surgery have been reported. However, our patient developed adrenal insufficiency after the oral cortisone supplementation was tapered. This report demonstrates that partial adrenalectomy does not necessarily preserve normal adrenocortical function. Therefore, careful postoperative observation is necessary for patients undergoing a partial adrenalectomy. PMID- 25504203 TI - Uterine rupture at 26 weeks of pregnancy following laparoscopic salpingectomy with resection of the interstitial portion: a case report. AB - Uterine rupture in pregnancy can occur in patients with a history of uterine surgery such as myomectomy and Cesarean section. Here, we report a case of spontaneous uterine rupture that occurred in the early third trimester in a pregnant woman who had previously undergone laparoscopic removal of the right fallopian tube and interstitial portion for treatment of interstitial pregnancy. The patient presented with sudden onset of abdominal pain at 26 weeks of gestation. Detailed ultrasonography and magnetic resonance imaging led to diagnosis of uterine rupture. In emergency laparotomy, the fetus was delivered by Cesarean section, the placenta and membranes were removed, and the uterus was preserved with closure of the rupture and wound. This case highlights the importance of close follow-up of a pregnant patient who has previously had a uterine incision. The case also raises the question of whether the prevalence of uterine rupture may increase as more patients are treated with laparoscopic surgery of the uterus. PMID- 25504204 TI - What is the most sensitive test for diagnosing carpal tunnel syndrome? AB - OBJECTIVE: To compare sensitivities between 7 principal nerve conduction studies (NCS) for diagnosing carpal tunnel syndrome (CTS). METHOD: In 104 CTS and 64 control hands, following "Standard" NCSs were examined simultaneously: (1) Median sensory NCS; (2) segmental wrist-palm sensory NCS; (3) 4th digit latency difference; (4) 1st digit latency difference and (5) palmar mixed nerve latency difference. As "Guideline" and "Option" NCSs, we also examined: (6) Median motor distal latency and (7) second lumbrical-interossei latency difference (2LILD). Forty-nine CTS hands were divided into a milder subgroup only if action potentials could be recorded using all tests applied; that is, those with any absent potentials were excluded from the subgroup. Sensitivities and specificities were compared to each other. RESULTS: In all CTS hands, the sensitivity of test (1), (2), (3), (4), (5), (6) and (7) was 83, 87, 92, 90, 90, 70 and 92%, respectively. In the milder subgroup, it was 67, 78, 84, 82, 84, 43, and 84% in the same order. There was no statistical difference between Standard tests and 2LILD. Specificities of all tests were over 95%. CONCLUSIONS: All "Standard" tests and 2LILD have high comparable sensitivities. Therefore, 2LILD should be recommended as "Standard" NCS detecting CTS. PMID- 25504205 TI - Clinicopathological analysis of 502 patients with oral squamous cell carcinoma with special interest to distant metastasis. AB - Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. Distant metastasis (DM) especially bone metastasis (BM) may reduce patients' quality of life and affects the clinical outcome. We performed clinicopathological analysis of 502 patients with OSCC undergoing radical surgery in order to evaluate the correlation values of clinicopathological features for OSCC with special interest in DM. DM was found in 54 cases and among them 44 and 25 cases had pulmonary metastasis (PM) and BM, respectively. Advanced T stage, positive N stage, lower histologic grade and higher score YK classification were the independent significant prognostic factors found in our series of 502 cases of OSCC. Positive lymph node was the most important prognostic factors in DM and BM; on the other hand, in PM, it was lower histological grade. All patients with BM except one had vertebral bone metastasis. These characteristics of DM, including BM and PM, of OSCC are useful for understanding the metastatic process of OSCC. PMID- 25504206 TI - Postgraduate education of traditional Japanese (Kampo) medicine: a current survey on the training hospitals in Kanagawa prefecture. AB - OBJECTIVE: There is no precise survey of postgraduate Kampo education in Japan. We aimed to survey the current status of postgraduate Kampo education and to identify major problems and suggest solutions to promote Kampo education during internship. METHODS: The questionnaire, for the 58 training hospitals, including the 4 university hospitals, in Kanagawa prefecture, was mailed to the director of each hospital and the instructors responsible for clinical training. RESULTS: There were 49 responses (84%): 84% of the instructors recognized clinicians' need to prescribe Kampo medicine; 63% thought Kampo education should be introduced into the clinical training; 55% thought a standardized form of education was necessary; 14% had Kampo education programs; 69%, 13%, and 9% of instructors at hospitals without Kampo educational programs noted the lack of Kampo instructors, time, and need to teach Kampo medicine, respectively; 82% had no plans for Kampo education; 44%, 29%, 24%, and 5% of hospitals permitted future Kampo instruction through voluntary study, lectures sponsored by Kampo manufacturers, study sessions with other hospitals, and independent study, respectively. CONCLUSIONS: Kampo education should be introduced into large training hospitals, where qualified Kampo instructors are more easily found, and where many interns and residents work. PMID- 25504207 TI - Clinicopathologic features and clinical outcomes of gastric cancer patients with bone metastasis. AB - OBJECTIVE: We conducted a retrospective analysis to evaluate the clinical manifestations and outcomes of a population of gastric cancer patients with bone metastasis. METHODS: The subjects were 31 gastric cancer patients who were diagnosed with bone metastasis between January 2000 and December 2010. RESULTS: The overall median survival time (MST) was 100 days. The results of a multivariate analysis in relation to overall survival showed that the absence of extraosseous metastasis and having received chemotherapy were favorable prognostic factors. MST was 269 days in the bone metastasis alone group (n = 6) and 65 days in the extraosseous metastasis group (n = 25). We divided the extraosseous metastasis group into two subgroups according to whether the patient had received chemotherapy. Evaluation of the response in the chemotherapy group showed that the subgroup of patients with progressive disease had a significantly longer MST than the no-chemotherapy group (63 days vs. 21 days, p = 0.012). CONCLUSIONS: We concluded that it is useful to divide gastric cancer patients with bone metastasis into two groups according to whether they have extraosseous metastasis. Aggressive chemotherapy should be considered as a means of improving the prognosis of gastric cancer patients with extraosseous metastasis. PMID- 25504210 TI - Layered Perovskite Nanofibers via Electrospinning for Overall Water Splitting. AB - The (111)-layered perovskite materials Ba5 Ta4 O15 , Ba5 Ta2 Nb2 O15 and Ba5 Nb4 O15 are prepared with nanofiber morphology via electrospinning for the first time. The nanofibers are built up from small single crystals, with up to several micrometers length even after calcination. The formation mechanism is investigated in detail, revealing an intermediate formation of amorphous barium carbonate strengthening the nanofiber morphology for high temperature treatment. All nanofiber compounds are able to generate hydrogen without any co-catalyst in photocatalytic reformation of methanol. After photodeposition of Rh-Cr2 O3 co catalysts, the nanofibers show better activity in overall water splitting compared to sol-gel-derived powders. PMID- 25504208 TI - Strategies for combating bacterial biofilm infections. AB - Formation of biofilm is a survival strategy for bacteria and fungi to adapt to their living environment, especially in the hostile environment. Under the protection of biofilm, microbial cells in biofilm become tolerant and resistant to antibiotics and the immune responses, which increases the difficulties for the clinical treatment of biofilm infections. Clinical and laboratory investigations demonstrated a perspicuous correlation between biofilm infection and medical foreign bodies or indwelling devices. Clinical observations and experimental studies indicated clearly that antibiotic treatment alone is in most cases insufficient to eradicate biofilm infections. Therefore, to effectively treat biofilm infections with currently available antibiotics and evaluate the outcomes become important and urgent for clinicians. The review summarizes the latest progress in treatment of clinical biofilm infections and scientific investigations, discusses the diagnosis and treatment of different biofilm infections and introduces the promising laboratory progress, which may contribute to prevention or cure of biofilm infections. We conclude that, an efficient treatment of biofilm infections needs a well-established multidisciplinary collaboration, which includes removal of the infected foreign bodies, selection of biofilm-active, sensitive and well-penetrating antibiotics, systemic or topical antibiotic administration in high dosage and combinations, and administration of anti-quorum sensing or biofilm dispersal agents. PMID- 25504211 TI - Post-activation potentiation: The neural effects of post-activation depression. AB - INTRODUCTION: Our knowledge of the neurophysiology of post-activation potentiation (PAP) is limited. The purpose of this study was to examine the effect of PAP on twitch torque and H-reflex amplitude after a 10-s maximal voluntary contraction (MVC). METHODS: PAP measurements were assessed with the plantarflexors in a relaxed state and during a tonic contraction at 10% MVC. RESULTS: The H-reflex/maximum M-wave ratio (H/M) decreased significantly (P<0.05) and returned to baseline levels after 1 min. The decrement in H/M was depressed when the plantarflexors were active at 10% MVC, and the depression was more obvious in the lateral gastrocnemius than in the soleus muscle. CONCLUSIONS: The inhibition induced immediately after contraction could be attributed to post activation depression. We conclude that PAP after a 10-s MVC cannot be attributed to increased motor neuron excitability through the reflex pathway as assessed by the H-reflex technique. PMID- 25504209 TI - Counter-regulatory phosphatases TNAP and NPP1 temporally regulate tooth root cementogenesis. AB - Cementum is critical for anchoring the insertion of periodontal ligament fibers to the tooth root. Several aspects of cementogenesis remain unclear, including differences between acellular cementum and cellular cementum, and between cementum and bone. Biomineralization is regulated by the ratio of inorganic phosphate (Pi) to mineral inhibitor pyrophosphate (PPi), where local Pi and PPi concentrations are controlled by phosphatases including tissue-nonspecific alkaline phosphatase (TNAP) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (NPP1). The focus of this study was to define the roles of these phosphatases in cementogenesis. TNAP was associated with earliest cementoblasts near forming acellular and cellular cementum. With loss of TNAP in the Alpl null mouse, acellular cementum was inhibited, while cellular cementum production increased, albeit as hypomineralized cementoid. In contrast, NPP1 was detected in cementoblasts after acellular cementum formation, and at low levels around cellular cementum. Loss of NPP1 in the Enpp1 null mouse increased acellular cementum, with little effect on cellular cementum. Developmental patterns were recapitulated in a mouse model for acellular cementum regeneration, with early TNAP expression and later NPP1 expression. In vitro, cementoblasts expressed Alpl gene/protein early, whereas Enpp1 gene/protein expression was significantly induced only under mineralization conditions. These patterns were confirmed in human teeth, including widespread TNAP, and NPP1 restricted to cementoblasts lining acellular cementum. These studies suggest that early TNAP expression creates a low PPi environment promoting acellular cementum initiation, while later NPP1 expression increases PPi, restricting acellular cementum apposition. Alterations in PPi have little effect on cellular cementum formation, though matrix mineralization is affected. PMID- 25504212 TI - Validation of the SCOFF questionnaire for eating disorders in a multiethnic general population sample. AB - INTRODUCTION: This study aimed to validate the SCOFF, an eating disorders (ED) screening questionnaire, in a multiethnic general population sample of adults. METHOD: A two-stage design was employed using the South East London Community Health Study phases I and II data. A total of 1,669 participants were screened using the SCOFF in SELCoHI, and 145 were administrated an ED clinical interview in SELCoHII. We explored the diagnostic validity of the questionnaire restricting to the 145 individuals with the clinical questionnaire. RESULTS: Sensitivity and specificity of the SCOFF were 53.7 and 93.5%, respectively. CONCLUSION: The SCOFF showed good levels of specificity but low sensitivity, resulting in a high percentage of false negatives. Given the low sensitivity found in our sample the SCOFF is likely to be a suboptimal measure for the identification of ED in the community. PMID- 25504213 TI - The challenges for primary caregivers of adolescents with disruptive behavior disorders. AB - Adolescents with disruptive behavior disorders (DBD), including oppositional defiant disorder and conduct disorder, present unique challenges for their families. Although, most empirically supported treatments for DBD are family based, the emphasis is typically on the behavior of the child rather than on the life challenges and resultant distress experienced by the family members. Fifteen families of adolescents with DBD were recruited from a large publicly funded Community Mental Health Center. For this report, data from in-depth interviews with the adolescents' primary caregivers were analyzed by standard content analytic procedures to describe the challenges they experienced living with and caring for the adolescents. The primary caregivers reported that the challenges were overwhelming, demanding, and unrelenting. The two most salient challenges were (a) managing the adolescents' aggressive, defiant, and deceitful behaviors, and (b) interacting frequently with a number of child-serving agencies. A number of clinical implications are drawn from these findings. PMID- 25504214 TI - The duration of hypotension determines the evolution of bacteremia-induced acute kidney injury in the intensive care unit. AB - BACKGROUND: Exploration of the impact of severe hypotension on the evolution of acute kidney injury in septic patients. METHODS AND RESULTS: We reviewed the hemodynamic parameters of 137 adults with septic shock and proven blood stream infection in the ICU. Severe hypotension was defined as a mean arterial blood pressure (MAP) <=65 mmHg. The influence of the duration of severe hypotension on the evolution of acute kidney injury was evaluated according to the RIFLE classification, with day 0 defined as the day of a positive blood stream infection. After bloodstream infection, the probability for a patient to be in Failure was significantly higher than before blood stream infection (OR = 1.94, p = 0.0276). Patients have a significantly higher risk of evolving to Failure if the duration of severe hypotension is longer (OR = 1.02 for each 10 minutes increase in duration of a MAP <65 mmHg, p = 0.0472). A cut-off of at least 51 minutes of severe hypotension (<65 mmHg) or at least 5.5 periods of severe hypotension within 1 day identified patients with increased risk to evolve to Failure. CONCLUSIONS: There is a significant influence of both the duration and the number of periods of severe hypotension on the evolution to Failure. Blood stream infection has a significantly negative effect on the relationship between severe hypotension and Failure. PMID- 25504216 TI - Enhanced performance of dye-sensitized solar cells based on TiO2 nanotube membranes using an optimized annealing profile. AB - We use free-standing TiO2 nanotube membranes that are transferred onto FTO slides in front-side illuminated dye-sensitized solar cells (DSSCs). We investigate the key parameters for solar cell arrangement of self-ordered anodic TiO2 nanotube layers on the FTO substrate, namely the influence of the annealing procedure on the DSSC light conversion efficiency. The results show that using an optimal temperature annealing profile can significantly enhance the DSSC efficiency (in our case eta = 9.8%), as it leads to a markedly lower density of trapping states in the tube oxide, and thus to strongly improved electron transport properties. PMID- 25504215 TI - Sliding of proteins non-specifically bound to DNA: Brownian dynamics studies with coarse-grained protein and DNA models. AB - DNA binding proteins efficiently search for their cognitive sites on long genomic DNA by combining 3D diffusion and 1D diffusion (sliding) along the DNA. Recent experimental results and theoretical analyses revealed that the proteins show a rotation-coupled sliding along DNA helical pitch. Here, we performed Brownian dynamics simulations using newly developed coarse-grained protein and DNA models for evaluating how hydrodynamic interactions between the protein and DNA molecules, binding affinity of the protein to DNA, and DNA fluctuations affect the one dimensional diffusion of the protein on the DNA. Our results indicate that intermolecular hydrodynamic interactions reduce 1D diffusivity by 30%. On the other hand, structural fluctuations of DNA give rise to steric collisions between the CG-proteins and DNA, resulting in faster 1D sliding of the protein. Proteins with low binding affinities consistent with experimental estimates of non-specific DNA binding show hopping along the CG-DNA. This hopping significantly increases sliding speed. These simulation studies provide additional insights into the mechanism of how DNA binding proteins find their target sites on the genome. PMID- 25504218 TI - Oxidized low-density lipoprotein increases bone sialoprotein expression in vascular smooth muscle cells via runt-related transcription factor 2. AB - BACKGROUND: Vascular calcification is a pivotal stage in atherosclerosis. During vascular calcification, vascular smooth muscle cells (VSMCs) synthesize many osteogenic factors such as bone sialoprotein (BSP). Oxidative stress plays a critical role in progression of atherosclerosis and also increases extracellular matrix proteins expression. BSP overexpression has been observed during vascular calcification by oxidative stress. However, the regulatory mechanism of oxidized low-density lipoprotein (oxLDL)-mediated vascular calcification has not yet been fully defined. In this study, we aimed to investigate whether runt-related transcription factor 2 (Runx2) affects the oxLDL-induced BSP expression or not. METHODS: In this experimental study, we cultured VSMCs in F12K media and then treated them with oxLDL. The expression of Runx2 and BSP genes was determined by real-time polymerase chain reaction method. Protein level of each gene was investigated by Western blotting technique. To determine whether Runx2 regulates BSP gene expression at VSMCs induced by oxLDL, we suppressed Runx2 mRNA using siRNA. Transfected cells then were treated with oxLDL and expression of Runx2 and BSP genes was determined again. RESULTS: oxLDL increased Runx2 and BSP expression (4.8 +/- 0.47-fold and 4.91 +/- 0.56-fold, respectively) after 48 hours. Western blotting method confirmed the increased levels of Runx2 and BSP proteins after 48 hours. Runx2 overexpression alone induced BSP expression, whereas knockdown of Runx2 with small interfering siRNA blocked oxLDL-induced BSP expression. CONCLUSIONS: Our results showed that oxLDL-induced BSP expression was dependent on Runx2 expression, suggesting that Runx2 is required for oxLDL-induced BSP expression. PMID- 25504217 TI - The protective effects of parental monitoring and internet restriction on adolescents' risk of online harassment. AB - With many adolescents using the internet to communicate with their peers, online harassment is on the rise among youth. The purpose of this study was to understand how parental monitoring and strategies parents use to regulate children's internet use (i.e., internet restriction) can help reduce online harassment among adolescents. Online survey data were collected from a nationally representative sample of parents and their 12-17 year old adolescents (n = 629; 49 % female). Structural equation modeling was used to test direct and indirect effects of parental monitoring and internet restriction on being a victim of online harassment. Potential mediators included adolescents' frequency of use of social networking websites, time spent on computers outside of school, and internet access in the adolescent's bedroom. Age and gender differences were also explored. Adolescents' reports of parental monitoring and efforts to regulate specific forms of internet use were associated with reduced rates of online harassment. Specifically, the effect of parental monitoring was largely direct and 26 times greater than parental internet restriction. The latter was associated with lower rates of harassment only indirectly by limiting internet access in the adolescent's bedroom. These effects operated similarly for younger and older adolescents and for males and females. Adolescents' perceptions of parental monitoring and awareness can be protective against online harassment. Specific restriction strategies such as regulating internet time and content can also help reduce the risk of online harassment. PMID- 25504219 TI - Survival patterns of lead-exposed workers with end-stage renal disease from Adult Blood Lead Epidemiology and Surveillance program. AB - BACKGROUND: One previous study has shown that patients with end-stage renal disease (ESRD) with higher blood lead levels (BLLs) have shorter survival, in a cohort without occupational exposure where follow-up began an average of 5 years after dialysis (a survivor population). METHODS: The authors studied individuals with at least 1 blood lead test who were part of an occupational lead surveillance program sponsored by the National Institute for Occupational Safety and Health and were diagnosed with ESRD. The authors studied the effect of BLL on survival from time of ESRD diagnosis after adjusting for potential confounders. Cox proportional hazards models were run, in which death was the end point and follow-up time was the time variable. RESULTS: There were 434 ESRD cases with 82% males, 65% white and 31% African American; 51% had 1 blood test, whereas the remainder had a median of 5 tests. The median years of follow-up were 2.7 years with 219 deaths in the cohort. After adjusting for covariates (eg, transplantation status, age at diagnosis, glomerular filtration rate, comorbidities and ethnicity), the authors found no significant association between highest measured BLL and mortality across categories; 0 to <5 MUg/dL (hazard ratio [HR] = 1.00), 5 to <25 MUg/dL (HR = 1.09; 95% confidence interval [CI]: 0.70-1.70), 25 to <40 MUg/dL (HR = 1.28; 95% CI: 0.81-2.02), 40 to <50 MUg/dL (HR = 0.89; 95% CI: 0.48-1.63) and 50+ MUg/dL (HR = 1.09; 95% CI: 0.66 1.81). CONCLUSIONS: The authors found no association between BLL and survival after ESRD diagnosis. The authors' finding differs from earlier findings, possibly because the cohort had higher blood leads (25 versus 10 MUg/dL), follow up began at the time of ESRD diagnosis, and BLLs were measured before ESRD incidence. PMID- 25504220 TI - Role of the endothelium in the metabolic syndrome: IIB or not IIB. PMID- 25504221 TI - Expression of Xanthophyllomyces dendrorhous cytochrome-P450 hydroxylase and reductase in Mucor circinelloides. AB - Carotenoids are natural pigments that act as powerful antioxidants and have various beneficial effects on human and animal health. Mucor circinelloides (Mucoromycotina) is a carotenoid producing zygomycetes fungus, which accumulates beta-carotene as the main carotenoid but also able to produce the hydroxylated derivatives of beta-carotene (i.e. zeaxanthin and beta-cryptoxanthin) in low amount. These xanthophylls, together with the ketolated derivatives of beta carotene (such as canthaxanthin, echinenone and astaxanthin) have better antioxidant activity than beta-carotene. In this study our aim was to modify and enhance the xanthophyll production of the M. circinelloides by expression of heterologous genes responsible for the astaxanthin biosynthesis. The crtS and crtR genes, encoding the cytochrome-P450 hydroxylase and reductase, respectively, of wild-type and astaxanthin overproducing mutant Xanthophyllomyces dendrorhous strains were amplified from cDNA and the nucleotide and the deduced amino acid sequences were compared to each other. Introduction of the crtS on autonomously replicating plasmid in the wild-type M. circinelloides resulted enhanced zeaxanthin and beta-cryptoxanthin accumulation and the presence of canthaxanthin, echinenone and astaxanthin in low amount; the beta-carotene hydroxylase and ketolase activity of the X. dendrorhous cytochrome-P450 hydroxylase in M. circinelloides was verified. Increased canthaxanthin and echinenone production was observed by expression of the gene in a canthaxanthin producing mutant M. circinelloides. Co-expression of the crtR and crtS genes led to increase in the total carotenoid and slight change in xanthophyll accumulation in comparison with transformants harbouring the single crtS gene. PMID- 25504224 TI - Erratum to: Estimation of Some Oxidative Stress Parameters and Blood Pressure After Administration of Endothelin-1 (ET-1) in Rats. PMID- 25504223 TI - Use of enhanced T2 star-weighted angiography (ESWAN) and R2* values to distinguish ovarian cysts due to endometriosis from other causes. AB - PURPOSE: To evaluate the feasibility of enhanced T2 star-weighted angiography (ESWAN) in differentiating endometrial from non-endometrial cysts. METHODS: Forty nine patients with 60 histopathologically proven ovarian cystic lesions underwent pelvic MRI including T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), liver acquisition with volume acceleration, and ESWAN. Ovarian cystic lesions were divided into endometrial cysts (group 1; n = 28), pyosalpinx and hydrosalpinx (group 2; n = 13), and ovarian cystic and cystic-solid tumors (group 3; n = 19). R2* (effective transverse relaxation rate) values were measured and pairwise comparison of the R2* values among the three groups was made using Kruskal-Wallis test. Receiver operating characteristic curves were used to calculate cutoff values and performance of R2* values for distinguishing among groups. T1WI signal intensity and R2* value were also compared using area under curve values. RESULTS: R2* values for group 1 were statistically higher than groups 2 and 3 (15.37, 1.40, and 1.79 Hz, respectively; P < 0.001). The cutoff value for R2* was 7.43 Hz with a sensitivity, specificity, PPV, NPV, and accuracy of 96.43, 87.50, 87.10, 96.55, and 91.67%, respectively. There was no significant difference between the R2* value and T1WI in diagnosing endometrial cysts. CONCLUSIONS: The R2* value provides an effective way to discriminate endometrial cysts from other ovarian cystic lesions. PMID- 25504222 TI - The clinical significance of DC-SIGN and DC-SIGNR, which are novel markers expressed in human colon cancer. AB - BACKGROUND: Colon cancer has always been diagnosed at a late stage, which is associated with poor prognosis. The currently used serum tumor markers CEA and CA19-9 display low sensitivity and specificity and may not have diagnostic value in early stage colon cancer. Thus, there is an urgent need to identify novel serum biomarkers for use in the early detection of colon cancer. METHODS: In this study, the expression of DC-SIGN and DC-SIGNR in serum was detected by enzyme linked immunosorbent assay (ELISA). DC-SIGN and DC-SIGNR expression was detected in cancer tissues by immunohistochemistry (IHC). RESULTS: The level of sDC-SIGN was lower in patients than in the healthy controls, while the level of sDC-SIGNR in patients was higher than in the healthy controls. Both sDC-SIGN and sDC-SIGNR had diagnostic significances for cancer patients, and the combined diagnosis of these two markers was higher than both of them alone. Furthermore, there were significant differences between both sDC-SIGN and sDC-SIGNR in stage I/II patients and the healthy controls. Moreover, high sDC-SIGN level was accompanied with the long survival time. Additionally, DC-SIGNR was negative in the cancer foci and matched normal colon tissues but was weakly positive between the cancer foci. DC-SIGN staining was faint in matched normal colon tissues, strong in the tumor stroma and the invasive margin of colon cancer tissues, and negatively correlated with the sDC-SIGN level in serum from the same patient. Interestingly, the percent survival of patients with a DC-SIGN mean density of>0.001219 (the upper 95% confidence interval of matched normal colon tissues) was higher than for all other patients. CONCLUSION: DC-SIGN and DC-SIGNR are blood-based molecular markers that can potentially be used for the diagnosis of early stage patients. Moreover, expression of DC-SIGN in serum and cancer tissues may affect the survival time for colon cancer patients. PMID- 25504225 TI - Interposition bone block arthrodesis for revision hallux metatarsophalangeal joint surgery: a case series. AB - BACKGROUND: The operative management of failed hallux metatarsophalangeal joint surgery can be difficult. There is often substantial shortening of the first ray. Arthrodesis of the first metatarsophalangeal joint is one treatment option, but results in further shortening of the first ray. METHODS: We present a large retrospective series of patients who had an interposition bone block arthrodesis procedure performed using a nonvascularized tricortical autologous iliac crest bone graft in an attempt to maintain first ray length. Twenty-four patients (25 feet) underwent this salvage procedure over a 10-year period. The mean follow-up period was 62 (range, 11-117) months. RESULTS: Indications included failed hallux valgus surgery, Keller's procedures, various other first metatarsal osteotomies, and failed arthrodesis procedures with shortening of the first ray. All patients had tricortical iliac crest grafts inserted into bony defects of mean length 10.7 (range, 8-15) mm. Fixation was achieved using either multiple wires or a low profile plate. Mean lengthening was 4.4 (range, 0-8) mm. Three feet went on to nonunion requiring further revision surgery and at latest follow-up 2 had united. All patients underwent removal of a stabilizing Kirschner wire. Median patient reported outcome score using the Foot and Ankle Disability Index was 84.6 (range, 37.5-97.1). CONCLUSION: These results suggest this procedure was successful in salvaging failed first ray surgery and prevented further shortening. We believe good results can be achieved, but care must be taken to ensure wound closure without excessive tension to permit wound healing. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 25504226 TI - Deep transverse metatarsal ligament and static stability of lesser metatarsophalangeal joints: a cadaveric study. AB - BACKGROUND: The static support that guides motion around the lesser metatarsophalangeal joints (MTPJs) is complex. Biomechanical studies revealed important roles of both the plantar plane and collateral ligaments. Since part of the plantar plate is attached to the deep transverse metatarsal ligament (DTML), we hypothesized that the transection of the DTML in the intermetatarsal space may substantially reduce the MTPJ stability. METHODS: The second, third, and fourth MTPJ stabilities of 6 fresh-frozen human cadaveric foot specimens were measured under load control. Both dorsiflexion and dorsal subluxation conditions were tested. After the intact condition was assessed, the DTML was sequentially transected such that each MTPJ had a unilateral and then a bilateral DTML transection. Stiffness data were calculated using the loading range in each test condition. Paired Student t tests were performed to test for statistical significance (P value less than .05). RESULTS: In intact specimens, the mean stiffness with dorsiflexion of the second, third, and fourth toes was 0.52 +/- 0.15 N/deg. When the DTML was operatively transected on one side, the dorsiflexion stiffness significantly decreased 17.3% to an average of 0.43 +/- 1.00 N/deg (P < .001). Subsequent transection of the DTML on the other side of each joint resulted in a further significant decrease of 5.8% to an average of 0.40 +/- 0.08 N/deg (P < .001). The mean stiffness with dorsal subluxation of the intact second, third, and fourth toes was 3.55 +/- 0.66 N/mm. When the DTML was operatively transected on one side, the dorsal subluxation stiffness significantly decreased 16.1% to an average of 2.98 +/- 0.64 N/mm (P < .001). Subsequent transection of the DTML on the other side of each joint resulted in a further significance decrease of 7.6% to an average of 2.71 +/- 0.48 N/mm (P = .016). CONCLUSION: The DTML has a significant role in maintaining lesser MTPJ ligament stability. Both unilateral and bilateral DTML transections caused substantial instability of the lesser MTPJ. CLINICAL RELEVANCE: The DTML is part of the natural static restraint to dorsiflexion or dorsal subluxation of the lesser MTPJ. Operative transection, injury, or degeneration of this ligament may predispose the adjacent MTPJ to instability. PMID- 25504227 TI - Stereochemical studies on pheromonal communications. AB - Pheromonal communications are heavily dependent on the stereochemistry of pheromones. Their enantioselective syntheses could establish the absolute configuration of the naturally occurring pheromones, and clarified the unique relationships between absolute configuration and bioactivity. For example, neither the (R)- nor (S)-enantiomer of sulcatol, the aggregation pheromone of an ambrosia beetle, is behaviorally active, while their mixture is bioactive. Recent results as summarized in the present review further illustrate the unique and diverse relationships between stereochemistry and bioactivity of pheromones. PMID- 25504229 TI - Genomic study of ossification of the posterior longitudinal ligament of the spine. AB - Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common disease after the middle age. OPLL frequently causes serious neurological problems due to compression of the spinal cord and/or nerve roots. OPLL occurs in patients with monogenic metabolic diseases including rickets/osteomalacia and hypoparathyroidism; however most of OPLL is idiopathic and is considered as a multi-factorial (polygenic) disease influenced by genetic and environmental factors. Genomic studies for the genetic factors of OPLL have been conducted, mainly in Japan, including linkage and association studies. This paper reviews the recent progress in the genomic study of OPLL and comments on its future direction. PMID- 25504230 TI - Feasibility studies towards future self-sufficient supply of the (99)Mo-(99m)Tc isotopes with Japanese accelerators. AB - In order to establish a self-sufficient supply of (99m)Tc, we studied feasibilities to produce its parent nucleus, (99)Mo, using Japanese accelerators. The daughter nucleus, (99m)Tc, is indispensable for medical diagnosis. (99)Mo has so far been imported from abroad, which is separated from fission products generated in nuclear reactors using enriched (235)U fuel. We investigated (99m)Tc production possibilities based on the following three scenarios: (1) (99)Mo production by the (n, 2n) reaction by spallation neutrons at the J-PARC injector, LINAC; (2) (99)Mo production by the (p, pn) reaction at Ep = 50-80 MeV proton at the RCNP cyclotron; (3) (99m)Tc direct production with a 20 MeV proton beam from the PET cyclotron. Among these three scenarios, scenario (1) is for a scheme on a global scale, scenario (2) works in a local area, and both cases take a long time for negotiations. Scenario (3) is attractive because we can use nearly 50 PET cyclotrons in Japan for (99m)Tc production. We here consider both the advantages and disadvantages among the three scenarios by taking account of the Japanese accelerator situation. PMID- 25504231 TI - Toward the detection of gravitational waves under non-Gaussian noises I. Locally optimal statistic. AB - After reviewing the standard hypothesis test and the matched filter technique to identify gravitational waves under Gaussian noises, we introduce two methods to deal with non-Gaussian stationary noises. We formulate the likelihood ratio function under weakly non-Gaussian noises through the Edgeworth expansion and strongly non-Gaussian noises in terms of a new method we call Gaussian mapping where the observed marginal distribution and the two-body correlation function are fully taken into account. We then apply these two approaches to Student's t distribution which has a larger tails than Gaussian. It is shown that while both methods work well in the case the non-Gaussianity is small, only the latter method works well for highly non-Gaussian case. PMID- 25504228 TI - The molecular basis of myeloid malignancies. AB - Myeloid malignancies consist of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasm (MPN). The latter two diseases have preleukemic features and frequently evolve to AML. As with solid tumors, multiple mutations are required for leukemogenesis. A decade ago, these gene alterations were subdivided into two categories: class I mutations stimulating cell growth or inhibiting apoptosis; and class II mutations that hamper differentiation of hematopoietic cells. In mouse models, class I mutations such as the Bcr-Abl fusion kinase induce MPN by themselves and some class II mutations such as Runx1 mutations induce MDS. Combinations of class I and class II mutations induce AML in a variety of mouse models. Thus, it was postulated that hematopoietic cells whose differentiation is blocked by class II mutations would autonomously proliferate with class I mutations leading to the development of leukemia. Recent progress in high-speed sequencing has enabled efficient identification of novel mutations in a variety of molecules including epigenetic factors, splicing factors, signaling molecules and proteins in the cohesin complex; most of these are not categorized as either class I or class II mutations. The functional consequences of these mutations are now being extensively investigated. In this article, we will review the molecular basis of hematological malignancies, focusing on mouse models and the interfaces between these models and clinical findings, and revisit the classical class I/II hypothesis. PMID- 25504232 TI - Self-beating artificial cells: design of cross-linked polymersomes showing self oscillating motion. AB - Biomimetic cross-linked polymersomes that exhibit a self-beating motion without any on-off switching are developed. The polymersomes are made from a well-defined synthetic thermoresponsive diblock copolymer, and the thermoresponsive segment includes ruthenium catalysts for the oscillatory chemical reaction and vinylidene groups to cross-link the polymersomes. Autonomous volume and shape oscillations of the cross-linked polymersomes are realized following redox changes of the catalysts. PMID- 25504233 TI - ER-poor and HER2-positive: a potential subtype of breast cancer to avoid axillary dissection in node positive patients after neoadjuvant chemo-trastuzumab therapy. AB - PURPOSE: The study was to estimate the likelihood of axillary downstaging and to identify the factors predicting a pathologically node negative status after neoadjuvant chemotherapy (NAC) with or without trastuzumab in HER2-positive breast cancer. METHODS: Patients with HER2-positive, stage IIa-IIIc breast cancer were enrolled. Axillary status was evaluated by palpation and fine needle aspiration (FNA) before NAC. All patients received 4-6 cycles of PCrb (paclitaxel 80 mg/m2 and carboplatin AUC = 2 d1, 8, and 15 of a 28-day cycle, or paclitaxel 175 mg/m2 and carboplatin AUC = 6 every-3-week) and were non-randomly administered trastuzumab (2 mg/kg weekly or 6 mg/kg every-3-week) or not. After NAC, each patient underwent standard axillary lymph node dissection and breast conserving surgery or mastectomy. And some patients received sentinel lymph node biopsy (SLNB) before axillary dissection. RESULTS: Between November-2007 and June 2013, 255 patients were enrolled. Of them, 157 were confirmed as axillary node positive by FNA (group-A) and 98 as axillary node negative either by FNA or impalpable (group-B). After axillary dissection, the overall pathologically node negative rates (pNNR) were 52.9% in group-A and 69.4% in group-B. The ER poor/HER2-positive subtype acquired the highest pNNR (79.6% in group-A and 87.9% in group-B, respectively) and the lowest rate of residual with >=4 nodes involvement (1.9% and 3%, respectively) after PCrb plus trastuzumab. In multivariate analysis, trastuzumab added and ER-poor status were independent factors in predicting a higher pNNR in HER2-positive breast cancer. Forty-six tested patients showed that the ER-poor/HER2-positive subtype acquired a considerable high pNNR and axillary status with SLNB was well macthed with the axillary dissection. CONCLUSIONS: ER-poor/HER2-positive subtype of breast cancer is a potential candidate for undergoing sentinel lymph node biopsy instead of regional node dissection for accurate axillary evaluation after effective downstaging by neoadjuvant chemo-trastuzumab therapy. PMID- 25504235 TI - Influenza vaccination status and attitudes among restaurant employees. AB - CONTEXT: Restaurant employees represent a substantial portion of the US workforce, interact closely with the public, and are at risk for contracting influenza, yet their influenza vaccination rates and attitudes are unknown. OBJECTIVE: Assess influenza vaccination rates and attitudes among Seattle restaurant employees, to identify factors that could enhance the success of a restaurant-based vaccination program. DESIGN: In 2012, we invited employees of Seattle restaurants to complete an anonymous paper survey assessing participant demographics, previous influenza vaccination status, and personal attitudes toward influenza vaccination (using a 5-point scale). SETTING: Sit-down, full service restaurants in or near Seattle, Washington, were eligible if they had no previous history of offering worksite influenza vaccinations and had more than 20 employees who were older than 18 years and spoke either English or Spanish. PARTICIPANTS: We invited staff in all restaurant positions (servers, bussers, kitchen staff, chefs, managers, etc) to complete the survey, which was available in English and Spanish. RESULTS: Of 428 restaurant employees surveyed, 26% reported receiving the seasonal influenza vaccine in 2011-2012 (response rate = 74%). Across 8 attitude statements, participants were most likely to agree that the vaccine is not too expensive (89%), and least likely to agree that it is relevant for their age group (25%), or normative at their workplace (13%). Vaccinated participants reported significantly more positive attitudes than unvaccinated participants, and Hispanics reported significantly more positive attitudes than non-Hispanic whites. CONCLUSIONS: Increasing influenza vaccination rates among restaurant employees could protect a substantial portion of the US workforce, and the public, from influenza. Seattle restaurant employees have low vaccination rates against seasonal influenza. Interventions aimed at increasing vaccination among restaurant employees should highlight the vaccine's relevance and effectiveness for working-age adults. PMID- 25504236 TI - Sexual dysfunction in inflammatory bowel disease. AB - Sexual health is a broad term that encompasses a variety of functions including sexual thoughts, desire, arousal, intercourse, orgasm, and the impact of body image. Sexual dysfunction in individuals with inflammatory bowel disease is multifactorial including the impact of psychosocial factors, disease activity, medical therapies, surgical interventions, body image perceptions and changes, hypogonadism, and pelvic floor disorders. Providers caring for patients with inflammatory bowel disease should be cognizant of these concerns and develop management plans and techniques for earlier diagnosis and treatment. PMID- 25504234 TI - Rare variant testing of imputed data: an analysis pipeline typified. AB - Important methodological advancements in rare variant association testing have been made recently, among them collapsing tests, kernel methods and the variable threshold (VT) technique. Typically, rare variants from a region of interest are tested for association as a group ('bin'). Rare variant studies are already routinely performed as whole-exome sequencing studies. As an alternative approach, we propose a pipeline for rare variant analysis of imputed data and develop respective quality control criteria. We provide suggestions for the choice and construction of analysis bins in whole-genome application and support the analysis with implementations of standard burden tests (COLL, CMAT) in our INTERSNP-RARE software. In addition, three rare variant regression tests (REG, FRACREG and COLLREG) are implemented. All tests are accompanied with the VT approach which optimizes the definition of 'rareness'. We integrate kernel tests as implemented in SKAT/SKAT-O into the suggested strategies. Then, we apply our analysis scheme to a genome-wide association study of Alzheimer's disease. Further, we show that our pipeline leads to valid significance testing procedures with controlled type I error rates. Strong association signals surrounding the known APOE locus demonstrate statistical power. In addition, we highlight several suggestive rare variant association findings for follow-up studies, including genomic regions overlapping MCPH1, MED18 and NOTCH3. In summary, we describe and support a straightforward and cost-efficient rare variant analysis pipeline for imputed data and demonstrate its feasibility and validity. The strategy can complement rare variant studies with next generation sequencing data. PMID- 25504237 TI - [Ebola hemorrhagic fever and the threat it poses to health systems]. PMID- 25504238 TI - [Histoplasmosis of the central nervous system in an immunocompetent patient]. AB - Histoplasmosis is a multifaceted condition caused by the dimorphic fungi Histoplasma capsulatum whose infective spores are inhaled and reach the lungs, the primary organ of infection. The meningeal form, considered one of the most serious manifestations of this mycosis, is usually seen in individuals with impaired cellular immunity such as patients with acquired immunodeficiency syndrome, systemic lupus erythematous or solid organ transplantation, and infants given their immunological immaturity. The most common presentation is self limited and occurs in immunocompetent individuals who have been exposed to high concentrations of conidia and mycelia fragments of the fungi. In those people, the condition is manifested by pulmonary disorders and late dissemination to other organs and systems. We report a case of central nervous system histoplasmosis in an immunocompetent child. PMID- 25504239 TI - [Detection of dengue virus antigen in post-mortem tissues]. AB - The epidemiological situation of dengue has worsened over the last decade. The difficulties in preventing its transmission and the absence of a vaccine or specific treatment have made dengue a serious risk to public health, health centers and research systems at different levels. Currently, most studies on the pathogenesis of dengue infection focus on the T-cell immune response almost exclusively in secondary infections and are aimed at identifying the mechanisms involved in the development of vascular permeability and bleeding events that accompany the infection. This report describes the case of a baby girl less than 45 days of age with clinical signs of severe dengue, whose diagnosis was confirmed by reverse transcription polymerase chain reaction in post-mortem tissue samples and by the ancillary diagnostic use of immunohistochemistry, which detected viral antigens in all organs obtained at autopsy. This case highlights the importance of studying primary infections associated with severe dengue, particularly in children, who are more likely to develop the severe form of the disease without previous infection, and it further stresses the importance of a diagnosis that should not be based solely on the examination of liver tissue samples when studying the pathogenesis of the viral infection. PMID- 25504240 TI - [Cerebrovascular hemorrhage associated with acquired cytomegalovirus infection in an infant]. AB - Cytomegalovirus is the most frequent causative agent of perinatal infection and a major cause of acquired viral infections. This case report aims to show the broad clinical spectrum of the presentation of cytomegalovirus infection. The correct classification of congenital or acquired infection and its prompt treatment can prevent complications and sequelae in severe cases. We report the case of an infant with acquired cytomegalovirus infection, which presented an unusual feature of cerebral hemorrhage. The patient was treated with ganciclovir, with a favorable evolution of the clinical symptoms. Cytomegalovirus infection is common in children, both in its congenital and acquired forms. Acquired infection, as portrayed in this case, is mainly characterized by hematological compromise given by the marked thrombocytopenia, which may rarely result in cases of bleeding in the central nervous system. In this patient, no important clinical implications occurred. In addition, most of the acquired infections are self-limited and require no treatment. PMID- 25504241 TI - [Tuberculous pericarditis]. AB - Tuberculosis remains a major cause of morbidity and mortality worldwide, and the extrapulmonary presentation represents up to 20% of this disease. The pericardial compromise of this disease has been estimated between 1% and 4% of diagnosed patients. This presentation may have a mortality rate as high as 90% without proper treatment and diagnosis, dropping to 12% with timely diagnosis and treatment. We present the case of a 55 year-old female patient hospitalized for two weeks with constitutional symptoms, intermittent fever, dry cough, pleuritic pain and some symptoms of heart failure. The imaging studies (chest x-rays and ultrasound), revealed bilateral pleural effusion: 300 cc on the right side, 1,000 cc on the left side, and 500 cc of pericardial effusion. Direct bacilloscopy of the pleural fluid, the pericardial fluid and the sputum were negative, as well as the C-reactive protein (CRP); however, the Lowenstein-Jensen culture of the pericardial fluid was positive for Mycobacterium tuberculosis . The result of the purified protein derivative (PPD) test showed a 23 mm swelling, and after quadruple therapy her clinical condition rapidly improved until final discharge. Tuberculous pericarditis can be considered as a rare manifestation of tuberculosis, with high morbidity and significant mortality which decrease with effective early diagnosis and treatment. Although several diagnostic criteria for tuberculous pericarditis have been suggested, a definitive diagnosis may suppose several technical challenges. PMID- 25504242 TI - [Burnout : concepts and implications affecting public health]. AB - Burnout was originally described as a mental condition characterized by reduced work performance, impotence, frustration and lack of capability to reach objectives or goals while performing a job. For some authors, burnout is a poorly defined mixture of symptoms and signs, while other professionals think of it as a disease and a potential threat to public health. Worldwide, it has been observed that the most afflicted professionals and technicians are those who work providing services or assistance to other people, especially those dedicated to health care. This paper focuses on the idea that burnout should be considered a disease more than a syndrome. On the other hand, definitions of health and disease have changed with time, as well as theoretical and methodological references about burnout. In addition, burnout remains a condition that is being discussed in various scientific areas, with radically opposing positions; these approaches are discussed in this article. After presenting different conceptions regarding burnout, the essay concludes with an exploration of its implications and the identification of possible treatments, especially for health workers, among whom it is more common depending on their predisposing conditions and environments. PMID- 25504243 TI - Variant in CAPN10 gene and environmental factors show evidence of association with excess weight among young people in a Colombian population. AB - Introduction : Obesity results from interaction between genetic and environmental risk factors. OBJECTIVE: To evaluate the effect of three gene variants and environmental factors on obesity and overweight in young people aged 10 to 18 years in a Colombian population. MATERIALS AND METHODS: A total of 424 subjects were selected and separated into three groups for a cross-sectional study; 100 obese and 112 overweight subjects were matched with 212 normal-weight controls. Associations were evaluated between excess weight and three genetic polymorphisms ( UCP3- rs1800849, FTO -rs17817449, and CAPN10 -rs3842570), as well as the family history, the time spent watching television and playing video games, and the diet. RESULTS: A family history of obesity, the time spent watching television and playing video games, the lack of breastfeeding, a low consumption of cereals, legumes, fruits, vegetables, and a high consumption of fast foods were characteristics typically found in obese individuals compared to controls. A significant association between genotype I/I (SNP19 of CAPN10 ) and excess weight was found even with an active lifestyle. In addition, significant associations between the C/C genotype of the UCP3 gene and the G/G and T/T genotypes of the FTO gene and excess weight were found only in young sedentary individuals. CONCLUSIONS: In this population, inadequate diet and sedentary lifestyle increased the risk of excess weight. Genotype I/I of SNP19 in CAPN10 was significantly associated with excess weight. In contrast, FTO and UCP3 variants exhibited effects only in sedentary environments. PMID- 25504244 TI - [Gene polymorphisms in the dihydrofolate reductase ( dhfr ) and dihydropteroate synthase ( dhps ) genes and structural modelling of the dhps gene in Colombian isolates of Toxoplasma gondii]. AB - INTRODUCTION: There are no reports describing polymorphisms in target genes of anti- Toxoplasma drugs in South American isolates. OBJECTIVE: This study sought to perform cloning and sequencing of the dihydrofolate reductase ( dhfr ) and dihydropteroate-synthase ( dhps ) genes of the reference Rh strain and two Colombian isolates of Toxoplasma gondii . MATERIALS AND METHODS: Two isolates were obtained from the cerebrospinal fluid of HIV-infected patients with cerebral toxoplasmosis. A DNA extraction technique and PCR assay for the dhfr and dhps genes were standardized, and the products of amplification were cloned into Escherichia coli and sequenced. RESULTS: One polymorphism (A " G) was found at position 235 of exon 2 in the dhps gene. In addition, two polymorphisms (G " C) at positions 259 and 260 and one polymorphism (T " G) at position 371 within exon 4 of the dhps gene were detected. In this last exon, a bioinformatic analysis revealed a non-synonymous polymorphism in the coding region that could lead to the substitution of Glu (CAA or CAG) for His (encoded by codons AAU or AAC). A structural model of the T. gondii DHPS protein was calculated, and the results revealed modifications in secondary structure due to mutations. CONCLUSIONS: The methods described in this study can be used as a tool to search for polymorphisms in samples from patients with different clinical manifestations of toxoplasmosis and to examine their relationship with the therapeutic response. PMID- 25504246 TI - [Hearing disorders in elderly people, associated factors and quality of life: SABE Study, Bogota, Colombia]. AB - INTRODUCTION: The aging of the population is a universal epidemiological phenomenon which is not unfamiliar to us and is accompanied by a marked increase of life expectancy. Age-dependent comorbidities, such as hearing disorders, are more prevalent and affect the quality of life in a noticeable manner. OBJECTIVE: To estimate the prevalence of hearing disorders, of the associated factors and their impact on the quality of life of older adults in Bogota. MATERIALS AND METHODS: Data was taken from the Bogota SABE Study, which included 2,000 individuals aged =60 years in a probabilistic cross-sectional study sampled by clusters (with 81.9% coverage). We used the "hearing disorders" variable relating it to socio-demographic variables, as well as to the use of hearing aids, the self-perceived health, the comorbidities, the functionality, the cognition and the quality of life as measured with the Visual Analog Scale of the EuroQol Group (EQ-VAS). RESULTS: We found a prevalence of hearing disorders in 267 individuals (13.5%), of whom 15% used hearing aids. The frequency was higher in individuals aged =75 years (46.1%), in the low socioeconomic level (20.2%) and among illiterate people (19.3%, p<0.05). Regarding comorbidities, we found a higher prevalence in individuals suffering from depression (20.2%, p<0.001), and high blood pressure (15%, p<0.01). The quality of life was worse in individuals with hearing disorders, as measured with the EuroQol EQ-VAS (60.93 +/- 1.38 vs. 71.75 +/- 0.45, p< 0.0001), but it improved among those who used hearing aids as compared to those who did not use them (59.59 +/- 1.52, p<0.01). CONCLUSIONS: Hearing disorders are relevant in elderly individuals and they affect their perceived quality of life in a noticeable manner. In addition, they are associated with other clinical, functional and cognitive problems. Nevertheless, the intervention with hearing aids reverses that perception. PMID- 25504245 TI - [Genotyping of Helicobacter pylori virulence factors vacA and cagA in individuals from two regions in Colombia with opposing risk for gastric cancer]. AB - INTRODUCTION: The overall prevalence of Helicobacter pylori infection is high in Colombia; however, in the country's Andean region, gastric cancer rates far surpass those in coastal areas. Helicobacter pylori genotypes cagA positive and vacA s1 and m1 are associated with an increased risk of gastric cancer. OBJECTIVE: To compare the distribution of H. pylori genotypes associated with virulence in two regions in Colombia with opposing risk for gastric cancer. MATERIALS AND METHODS: Four hundred and one gastric antral biopsies were obtained and analyzed from 401 individuals diagnosed with non-atrophic gastritis, atrophic gastritis and intestinal metaplasia: 256 came from the high-risk area cities of Tunja and Bogota, and 145 from the low-risk area cities of Barranquilla, Santa Marta and Cartagena. Genotyping of virulence genes vacA and cagA was performed by PCR. RESULTS: No difference was observed in the frequency of H. pylori infection between the two areas (77.3% vs 77.9 %, p=non significant, ns). The presence of cagA was higher in the low-risk area (77.9% vs. 69.2 %, p=ns). The vacA s1 allele was also more prevalent in the low-risk area (61.8 % vs 72.0 %, p=ns). The vacA m1 allele was more prevalent in the high-risk area (57.2 % vs 42.8 %, p=ns). The cagA positive s1m1 combination was also more frequent in the low-risk area (48.9% vs 38.9%, p=ns). CONCLUSIONS: The differences in the risk of gastric cancer in these two geographic areas cannot be explained by differences in the prevalence of infection by H. pylori or by differences in the virulence of circulating strains. PMID- 25504247 TI - Social, cultural and economic factors associated with self-medication. AB - INTRODUCTION: Self-medication is an increasingly frequent phenomenon worldwide; some studies suggest that there is a relationship with socio-economic and cultural factors. OBJECTIVE: To determine the prevalence of self-medication and its related factors in a Colombian city. MATERIALS AND METHODS: Cross-sectional descriptive study, in Pereira, Colombia. We selected 414 adults using simple randomization sampling with houses used as the observational unit. The IRIS-AM instrument was used to collect the information required. RESULTS: Four hundred and fourteen (414) people were interviewed, 62.6% were females, and mean age was 44 years; 77.5% of the sample had self-medicated at least once in their life and 31.9% during the last month. The most commonly used medications were: analgesics and antipyretics (44.3%), non-steroidal anti-inflammatory drugs and anti rheumatic medication (36.4%), and anti-histamine medication (8.5%). The most commonly self-medicated symptoms were: headache (55.7%), cold (16.2%) and muscular pain (13.2%). Multivariate analysis revealed an association between self medication throughout life and storing medications at home, and between a high level of education and having a favorable opinion of self-medication. Storing medications at home and recommending them to others were associated with self medication during the previous 30 days. CONCLUSION: Self-medication rates were found to be similar to those reported globally, but there is not an established pattern for this practice. Associations were found between social and demographic variables and self-medication, which require further characterization. Intention to self-medicate has not been well-described in other studies, and may be an important indicator which will contribute to future understanding of this phenomenon. PMID- 25504248 TI - Cell accumulation and antileishmanial effect of exogenous and endogenous protoporphyrin IX after photodynamic treatment. AB - INTRODUCTION: Photodynamic therapy (PDT) using 5-aminolevulinic acid-induced protoporphyrin IX (ALA-PpIX) constitutes an interesting alternative for cutaneous leishmaniasis treatment. OBJECTIVE: To evaluate the production of PpIXbased on the administration of ALA and MAL and the effect of ALA-PDTat cellular level on non-infected and infected THP-1 cells using Leishmania ( Viannia ) panamensis or Leishmania ( Leishmania ) infantum (syn Leishmania chagasi ) parasites. MATERIALS AND METHODS: Protoporphyrin IX (PpIX) production and mitochondrial colocalization were evaluated by confocal microscopy. Cell toxicities were evaluated after treatment with the compounds, followed by light irradiation (597-752 nm) at 2.5 J/cm 2 fluency using a colorimetric MTT assay for THP-1 cells and a standard microscopic analysis of parasites. RESULTS were expressed as compound concentration activity against 50% of cells or parasites (CC 50 or IC 50 ). RESULTS: ALA or MAL induced an endogenous PpIX with a red fluorescence localized mainly in the mitochondria inside human cells. ALA and MAL-PDT induced a similar range of toxicities on THP-1 cells (CC 50 0.16 +/- 0.01 mM and 0.33 +/- 0.019 mM, respectively) without any apparent inhibition of intracellular parasites in the infected cells as compared to untreated controls. Exogenous PpIX-PDT was toxic to THP-1 cells (CC 50 0.00032 +/- 0.00002 mM), L. (L.) infantum (IC 50 0.003 +/- 0.0001 mM) and L. (V.) panamensis (IC 50 0.024 +/- 0.0001 mM) promastigotes. CONCLUSIONS: Despite the effectiveness of exogenous PpIX on promastigotes and the production of PpIX by human infected cells, treatment with ALA or MAL before irradiation was unable to completely destroy L. (L.) infantum or L. (V.) panamensis intracellular amastigotes. PMID- 25504249 TI - [Lymnaea cousini , intermediate host of Fasciola hepatica in the Colombian high tropical Andes, and its new haplotypes confirmed with the mitochondrial marker cytochrome oxidase I]. AB - INTRODUCTION: Fasciolosis is the disease transmitted by vectors with the highest latitudinal, longitudinal, and altitudinal distribution due to the colonizing capacity of the parasite Fasciola hepatica and its intermediate hosts, Lymnaeidae mollusks. These snails are under research due to their epidemiological importance, but their taxonomic identification is difficult given their interspecific phenotypical similarity. For this reason, there is uncertainty regarding Lymnaea cousini -a host of F. hepatica in Colombia- due to the morphological similarity it has with Lymnaea meridensis , recently described for Venezuela. OBJECTIVE: To confirm with the COI marker (ADNmt) the taxonomic status of individuals morphologically identified as L. cousini from Narino, Norte de Santander, and Santander (Colombia), deposited in the Vector Mollusks Collection VHET No. 37 of Universidad de Antioquia. MATERIALS AND METHODS: The amplification of the mitochondrial COI required total DNA extraction of each individual's foot using the DNeasy Blood and Tissue Kit (Qiagen(r)). Products amplified were sent for sequencing to Macrogen Inc., Korea. Twenty seven sequences generated in this research were compared to sequences published in the GenBank, including sequences of the type locality of L. cousini . RESULTS: Two new haplotypes of L. cousini were obtained for Colombia. Specimens from Narino correspond to haplotype A, referenced for Ecuador, and specimens from Santander and Norte de Santander belong to a new haplotype we called haplotype D. CONCLUSION : By using the mitochondrial COI marker, we confirmed that the species under study did correspond to L. cousini . The number of known haplotypes of the species for Colombia has been duplicated and its geographical distribution has been extended to the southwest and northeast of the Colombian high Andean region. PMID- 25504250 TI - [Styrylquinolines-type synthetic compounds with leishmanicidal and cytotoxic activities]. AB - INTRODUCTION: Leishmaniasis is a major public health problem faced by many countries, including Colombia. Its treatment has limitations such as the toxicity of the drugs used, the emergence of resistant strains, and prolonged and expensive treatments. Thus, there is an urgent need to find alternative solutions. OBJECTIVE: To evaluate the leishmanicidal and cytotoxic activities of three 2-styrylquinolines type compounds: 2-[(E)-2-(2,3 diacetyloxyphenyl)ethenyl]quinolin-8-yl-acetate, E1; 2-[(E)-2-(4-acetyloxy-3 methoxyphenyl)ethenyl] quinoline, E2, and 2-[(E)-2-(2,3 diacetyloxyphenyl)ethenyl] quinoline, E3. MATERIALS AND METHODS: The 2 styrylquinolines were obtained by organic synthesis using Perkin-type condensation reaction from 8-hydroxy quinaldine or quinaldine and aromatic aldehydes. The leishmanicidal activity was evaluated on intracellular amastigotes of Leishmania (Viannia) panamensis by flow cytometry. The results were expressed as lethal concentration 50 (LC 50 ) for cytotoxicity and effective concentration 50 (EC 50 ) for leishmanicidal activity, calculated by the Probit method. RESULTS: E3 showed high activity against L. (V) panamensis with a calculated EC 50 value of 1.4 ug/ml, and a selectivity index of 3.9; E1 and E2 showed higher EC 50 values of 5.6 and 68.1 ug/ml, respectively. For cytotoxicity, LC 50 values ranging from 5.4 to 68.1 ug/ml were calculated. E2 was moderately toxic, showing an LC 50 very similar to that of amphotericin B, a substance used as cytotoxic control. CONCLUSION: The styrylquinoline E3 is a promising compound against L. (V) panamensis , as it was able to significantly inhibit amastigotes inside the cell, reducing infection despite its toxicity. PMID- 25504251 TI - [Nasal CPAP versus mechanical ventilation in 28 to 32-week preterm infants with early surfactant administration]. AB - INTRODUCTION: Continuous positive airway pressure (CPAP) is useful in low birth weight infants with respiratory distress, but it is not known if it is a better alternative to mechanical ventilation after early pulmonary surfactant administration. OBJECTIVE: To compare the incidence of adverse events in 28 to 32 week newborns with respiratory distress managed with mechanical ventilation or CPAP after early surfactant administration. MATERIALS AND METHODS: In total, 176 newborns were treated with CPAP and 147 with mechanical ventilation, all with Apgar scores >3 at five minutes and without apnea. RESULTS: The incidence of CPAP failure was 6.5% (95% CI: 11.3-22.8%); 29 patients died: 7 with CPAP (4.0%) and 22 with mechanical ventilation (15.0%, p<0.001). The relative risk of dying with CPAP versus mechanical ventilation was 0.27 (95% CI: 0.12-0.61), but after adjusting for confounding factors, CPAP use did not imply a higher risk of dying (RR=0.60; 95% CI: 0.29-1.24). Mechanical ventilation fatality rate was 5.70 (95% CI: 3.75-8.66) deaths/1,000 days-patient, while with CPAP it was 1.37 (95% CI: 0.65-2.88, p<0.001). Chronic lung disease incidence was lower with CPAP than with mechanical ventilation (RR=0.71; 95% CI: 0.54-0.96), as were intracranial hemorrhage (RR=0.28, 95% CI: 0.09-0.84) and sepsis (RR=0.67; 95%CI: 0.52-0.86), and it was similar for air leaks (RR=2.51; 95% CI: 0.83-7.61) and necrotizing enterocolitis (RR=1.68, 95% CI: 0.59-4.81). CONCLUSION: CPAP exposure of premature infants with respiratory distress syndrome is protective against chronic lung disease, intraventricular hemorrhage and sepsis compared to mechanical ventilation. No differences were observed regarding air leak syndrome or death. PMID- 25504252 TI - [Discriminating concentrations for three insecticides used in public health in a Lutzomyia longipalpis experimental strain from Colombia]. AB - INTRODUCTION: In Colombia, periurban populations of Lutzomyia longipalpis , vector of the causative agent of visceral leishmaniasis in the upper and middle valley of the Magdalena River, may be exposed to insecticide applications with different purposes. Thus, it is important to begin a susceptibility surveillance of this species to insecticides. OBJECTIVE: To determine indicators of susceptibility to three insecticides habitually used in public health, such as malathion, deltamethrin and lambda-cyhalothrin in an experimental strain of L. longipalpis . MATERIALS AND METHODS: We used the method proposed by the Centers for Disease Control and Prevention. Groups of 10 to 15 unfed females were exposed to different concentrations of the insecticides using 250 ml glass bottles as test chambers. Mortality was registered every five minutes for an hour. Diagnostic concentrations and lethal times for each insecticide were calculated. RESULTS: In the evaluated L. longipalpis strain, the diagnostic concentrations and times were 75 ug/ml and 25 minutes for malathion, 10 ug/ml and 35 minutes for deltamethrin, and 15 ug/ml during 30 minutes for lambda-cyhalothrin. CONCLUSIONS: Baseline data over mortality response to three insecticides were established in a susceptibility strain of L. longipalpis vector. These indicators will allow establishing comparisons with populations of L. longipalpis exposed regularly or sporadically to chemical control measures to detect changes in their resistance to these insecticides. PMID- 25504254 TI - A new application area for fullerenes: voltage stabilizers for power cable insulation. AB - Fullerenes are shown to be efficient voltage-stabilizers for polyethylene, i.e., additives that increase the dielectric strength of the insulation material. Such compounds are highly sought-after because their use in power-cable insulation may considerably enhance the transmission efficiency of tomorrow's power grids. On a molal basis, fullerenes are the most efficient voltage stabilizers reported to date. PMID- 25504253 TI - [Oral transmission of Trypanosoma cruzi : a new epidemiological scenario for Chagas' disease in Colombia and other South American countries]. AB - Many cases of infection caused by the oral transmission of Trypanosoma cruzi have been reported during the last decade. These have been due to the contamination of food by faeces from sylvatic triatomines or by leakage from reservoirs in areas where domiciliated vectors have been controlled or where there has been no prior background of domiciliation. The United Nations Food and Agriculture Organization (FAO) and the World Health Organization (WHO) have used epidemiological, clinical and socioeconomic criteria for ranking parasites transmitted by the contamination of food in different areas of the world; T. cruzi was placed tenth in importance amongst a group of 24 parasites in such ranking. Environmental changes such as deforestation and global warming have affected ecotopes and the behaviour of T. cruzi vectors and reservoirs so that these have become displaced to new areas, thereby leading to such new transmission scenario caused by the contamination of food, which requires evaluation in Colombia. The current review deals with the oral transmission of Chagas' disease, emphasising studies aimed at identifying the pertinent risk factors, the triatomine species involved, the physiopathology of oral infection, the parasite's genotypes implicated in this type of transmission in Colombia and other Latin American regions, as well as the need for ongoing epidemiological surveillance and control policies. PMID- 25504256 TI - Surfactant for meconium aspiration syndrome in term and late preterm infants. AB - BACKGROUND: Surfactant replacement therapy has been proven beneficial in the prevention and treatment of neonatal respiratory distress syndrome (RDS). The deficiency of surfactant or surfactant dysfunction may contribute to respiratory failure in a broader group of disorders, including meconium aspiration syndrome (MAS). OBJECTIVES: To evaluate the effect of surfactant administration in the treatment of late preterm and term infants with meconium aspiration syndrome. SEARCH METHODS: We searched The Cochrane Library (Issue 4, 2006), MEDLINE and EMBASE (1985 to December 2006), previous reviews including cross-references, abstracts, conference and symposia proceedings, expert informants, and journal handsearching, without language restrictions. We contacted study authors for additional data.We ran an updated search in November 2014 and searched the following sites for ongoing or recently completed trials: www.clinicaltrials.gov; www.controlled-trials.com; and www.who.int/ictrp. SELECTION CRITERIA: Randomised controlled trials which evaluated the effect of surfactant administration in late preterm and term infants with meconium aspiration syndrome are included in the analyses. DATA COLLECTION AND ANALYSIS: We extracted data on clinical outcomes including mortality, treatment with extracorporeal membrane oxygenation (ECMO), pneumothorax, duration of assisted ventilation, duration of supplemental oxygen, intraventricular haemorrhage (any grade and severe IVH), and chronic lung disease. We conducted data analyses in accordance with the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Four randomised controlled trials met our inclusion criteria. The meta-analysis of four trials (326 infants) showed no statistically significant effect on mortality [typical risk ratio (RR) 0.98, 95% confidence interval (CI) 0.41 to 2.39; typical risk difference (RD) -0.00, 95% CI -0.05 to 0.05]. There was no heterogeneity for this outcome (I2 = 0% for both RR and RD). The risk of requiring extracorporeal membrane oxygenation was significantly reduced in a meta-analysis of two trials (n = 208); [typical RR 0.64, 95% CI 0.46 to 0.91; typical RD -0.17, 95% CI -0.30 to -0.04; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 3 to 25]. There was no heterogeneity for RR (12 = 0%) but moderate heterogeneity for RD (I2 = 50%). One trial (n = 40) reported a statistically significant reduction in the length of hospital stay (mean difference -8 days, 95% CI -14 to -3 days; test for heterogeneity not applicable). There were no statistically significant reductions in any other outcomes studied (duration of assisted ventilation, duration of supplemental oxygen, pneumothorax, pulmonary interstitial emphysema, air leaks, chronic lung disease, need for oxygen at discharge or intraventricular haemorrhage). AUTHORS' CONCLUSIONS: In infants with MAS, surfactant administration may reduce the severity of respiratory illness and decrease the number of infants with progressive respiratory failure requiring support with ECMO. The relative efficacy of surfactant therapy compared to, or in conjunction with, other approaches to treatment including inhaled nitric oxide, liquid ventilation, surfactant lavage and high frequency ventilation remains to be tested. PMID- 25504255 TI - Synthesis and functions of well-defined polymer-drug conjugates as efficient nanocarriers for intravesical chemotherapy of bladder cancer(a). AB - Novel poly(ethylene glycol) and poly(N-(2-hydroxypropyl)methacrylamide) block copolymer (PEG-b-PHPMA) with well-defined composition was synthesized by RAFT polymerization. Folate and doxorubicin (DOX) were quantitatively introduced into the copolymer. The influences of folate content and pH value on folate receptor (FR) mediated cell endocytosis and pH-responsive DOX release were studied. It has been demonstrated that minimum folate content is needed for the enrichment of hydrophobic folate on the hydrophilic part of polymer conjugates. The cytotoxicity of targetable polymer drug conjugates was much higher than that of non-targetable ones and free DOX. It could be concluded that the folate plays a significant role in targeting and internalization of the conjugates against bladder cancer cells. PMID- 25504257 TI - Efficient charge-carrier extraction from Ag2S quantum dots prepared by the SILAR method for utilization of multiple exciton generation. AB - The utilization of electron-hole pairs (EHPs) generated from multiple excitons in quantum dots (QDs) is of great interest toward efficient photovoltaic devices and other optoelectronic devices; however, extraction of charge carriers remains difficult. Herein, we extract photocharges from Ag2S QDs and investigate the dependence of the electric field on the extraction of charges from multiple exciton generation (MEG). Low toxic Ag2S QDs are directly grown on TiO2 mesoporous substrates by employing the successive ionic layer adsorption and reaction (SILAR) method. The contact between QDs is important for the initial charge separation after MEG and for the carrier transport, and the space between neighbor QDs decreases with more SILAR cycles, resulting in better charge extraction. At the optimal electric field for extraction of photocharges, the results suggest that the threshold energy (hnuth) for MEG is 2.41Eg. The results reveal that Ag2S QD is a promising material for efficient extraction of charges from MEG and that QDs prepared by SILAR have an advantageous electrical contact facilitating charge separation and extraction. PMID- 25504258 TI - Group sexual offending by juvenile females. AB - This study examined all group sexual offending cases in the Netherlands between 1995 and 2009 (n = 26) in which at least one juvenile female offender (n = 35) had been adjudicated. Information from court files showed that the majority of juvenile female group sexual offenders have (inter)personal problems and (sexual) abuse experiences. The aims of the offender groups in committing the offense could be categorized in three themes: harassing the victim, sexual gratification, and taking revenge. The reasons why juvenile female offenders participated in a group could be categorized into group dynamics versus instrumental reasons. The findings are contrasted with findings on juvenile male group sexual offenders. Implications of the findings for research and treatment are discussed. PMID- 25504261 TI - Inflammation, adiposity, and atherogenic dyslipidemia in rheumatoid arthritis: is there a paradoxical relationship? AB - Dyslipidemia is highly prevalent in rheumatoid arthritis (RA) and appears to be present very early in the RA disease process, in some studies even before a diagnosis of clinical RA has been made. The association between lipid measures and the risk of cardiovascular disease (CVD) in RA appears to be paradoxical, whereby lower levels of total cholesterol (TC), low-density lipoprotein (LDL-C), and atherogenic ratios are associated with higher CVD risk. This may be due to the lipid-lowering effects of RA-related systemic inflammation. Therefore, standard CVD risk calculators have been shown to underperform in RA. Data also suggest that lipoprotein particle sizes and the apolipoprotein cargo of lipoproteins skew toward atherogenic dyslipidemia in RA and may contribute to the initiation and progression of atherosclerosis. Inflammatory burden in RA may also alter the anti-inflammatory and atheroprotective roles associated with high density lipoprotein cholesterol (HDL-C). Adipose tissue is quantitatively increased in RA patients compared with matched non-RA controls and may be more inflamed and metabolically dysfunctional compared with an otherwise similar non RA patient. In vitro, animal, and a handful of non-RA human, studies suggest that inflamed, metabolically dysfunctional adipose tissue contributes directly to lower HDL-C levels. In turn, lower HDL-C that has been altered functionally by inflammation may lead to expanded adipose mass and further adipose dysfunction and inflammation. In the last part of this review, we speculate how the RA disease state may recapitulate these processes. PMID- 25504260 TI - Challenges for allergy diagnosis in regions with complex pollen exposures. AB - Over the past few decades, significant scientific progress has influenced clinical allergy practice. The biological standardization of extracts was followed by the massive identification and characterization of new allergens and their progressive use as diagnostic tools including allergen micro arrays that facilitate the simultaneous testing of more than 100 allergen components. Specific diagnosis is the basis of allergy practice and is always aiming to select the best therapeutic or avoidance intervention. As a consequence, redundant or irrelevant information might be adding unnecessary cost and complexity to daily clinical practice. A rational use of the different diagnostic alternatives would allow a significant improvement in the diagnosis and treatment of allergic patients, especially for those residing in complex pollen exposure areas. PMID- 25504259 TI - Molecular mechanisms of nasal epithelium in rhinitis and rhinosinusitis. AB - Allergic rhinitis, nonallergic rhinitis, and chronic rhinosinusitis are multifactorial upper airway diseases with high prevalence. Several genetic and environmental factors are proposed to predispose to the pathogenesis of the inflammatory upper airway diseases. Still, the molecular mechanisms leading toward the onset and progression of upper airway diseases are largely unknown. The upper airway epithelium has an important role in sensing the environment and regulating the inhaled air. As such, it links environmental insults to the host immunity. Human sinonasal epithelium serves as an excellent target for observing induced early-phase events, in vivo, and with a systems biological perspective. Actually, increasing number of investigations have provided evidence that altered homeostasis in the sinonasal epithelium might be important in the chronic upper airway inflammation. PMID- 25504262 TI - Sublingual immunotherapy in the treatment of atopic dermatitis: a systematic review using the GRADE system. AB - Controversy exists regarding the role of allergen immunotherapy as a therapeutic intervention for patients with atopic dermatitis and aeroallergen sensitivity. Our aim was to critically appraise the evidence supporting the use of sublingual immunotherapy for patients with atopic dermatitis and aeroallergen sensitivity. We performed a literature search using the terms "sublingual immunotherapy" and "atopic dermatitis" and "sublingual immunotherapy" and "eczema." We used the same terms to search PubMed, Ovid, and Scopus. Our limits were "Humans" and "English." We excluded articles that were not in English. These articles were analyzed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Many studies reported improvement in clinical symptoms of atopic dermatitis. Serious methodological shortcomings were noted including but not limited to lack of control group, lack of randomization, incomplete descriptions of randomization and/or allocation concealment, many enrolled subjects not completing participation, and/or data analysis not by intention to treat. PMID- 25504263 TI - Immune reconstitution inflammatory syndrome associated with biologic therapy. AB - The use of biologics in the treatment of autoimmune disease, cancer, and other immune conditions has revolutionized medical care in these areas. However, there are drawbacks to the use of these medications including increased susceptibility to opportunistic infections. One unforeseen risk once opportunistic infection has occurred with biologic use is the onset of immune reconstitution inflammatory syndrome (IRIS) upon drug withdrawal. Although originally described in human immunodeficiency virus (HIV) patients receiving highly active antiretroviral therapy, it has become clear that IRIS may occur when recovery of immune function follows opportunistic infection in the setting of previous immune compromise/suppression. In this review, we draw attention to this potential pitfall on the use of biologic drugs. PMID- 25504265 TI - Cloning and functional analysis of Delta6-desaturase gene and its upstream region from Mortierella sp. AGED. AB - BACKGROUND: Delta6-desaturase belonging to membrane-bound enzyme is a key enzyme involved in the synthesis of polyunsaturated fatty acids (PUFAs). This study aimed to clone and characterise Delta6-desaturase gene and its upstream regulatory region of Mortierella sp. AGED. RESULTS: Glucose and soybean meal are best for lipid and arachidonic acid accumulation of Mortierella sp. AGED. A 1375 bp Delta6-desaturase gene AGfad6 which contains a 1275-bp open reading frame encoding 424 amino acids without signal peptide was cloned. The putative protein contained three conserved histidine-rich motifs and a conserved cytochrome b5 HPGG (H: Histine, P: Proline, G: Glycine, G: Glycine) motif, with a mass of 48.3 kDa and an isoelectric point of 5.96. AGfad6 was successfully expressed in Pichia pastoris GS115, which exerted the effect on converting linoleic acid to gamma linolenic acid. The 1712-bp upstream region contained basic transcriptional elements including TATA, GC and GATA box, putative target-binding sites for transcription factors such as TATA binding protein, transcription activator, CCAAT-enhancer-binding protein, activator protein 1, alcohol dehydrogenase gene regulator 1 and metabolic regulators p40x in fungi, stress-related elements including GT-1 (light-responsive, salicylic acid-inducible), stress response element, heat stress-responsive element, which might participate in regulation of PUFAs synthesis. CONCLUSION: The present finding could enable us to understand the evolution and regulatory mechanism of Delta6-desaturase gene. PMID- 25504264 TI - Natural killer cells in the development of asthma. AB - Asthma is an immune-mediated disease of the airways characterized by reversible airway obstruction, bronchial eosinophilic inflammation, and airway hyperresponsiveness (AHR). The immune dysregulation in asthma has been attributed to the involvement of diverse immune cells that contribute to the immunopathology of the disease. Natural killer (NK) cells play critical roles in host defense against viruses and various cancers. Accumulating evidence demonstrates additional important roles for these cells in T cell priming, dendritic cell maturation, and the development of inflammation, all of which have the potential to enhance or dampen allergic responses. The ability of NK cells to produce Th2 type cytokines and their pivotal role in combating respiratory infections which cause airway dysfunction in asthmatics further suggest that they may directly contribute to the immunopathogenesis of allergic airway disease. In this review, we examine emerging evidence and discuss the putative roles of NK cells in the sensitization, progression, and resolution of asthma. PMID- 25504266 TI - Relative cerebral blood volume from dynamic susceptibility contrast perfusion in the grading of pediatric primary brain tumors. AB - INTRODUCTION: The aim of this study is to evaluate the utility of relative cerebral blood volume (rCBV) data from dynamic susceptibility contrast (DSC) perfusion in grading pediatric primary brain tumors. METHODS: A retrospective blinded review of 63 pediatric brain tumors with DSC perfusion was performed independently by two neuroradiologists. A diagnosis of low- versus high-grade tumor was obtained from conventional imaging alone. Maximum rCBV (rCBVmax) was measured from manual ROI placement for each reviewer and averaged. Whole-tumor CBV data was obtained from a semi-automated approach. Results from all three analyses were compared to WHO grade. RESULTS: Based on conventional MRI, the two reviewers had a concordance rate of 81% (k = 0.62). Compared to WHO grade, the concordant cases accurately diagnosed high versus low grade in 82%. A positive correlation was demonstrated between manual rCBVmax and tumor grade (r = 0.30, P = 0.015). ROC analysis of rCBVmax (area under curve 0.65, 0.52-0.77, P = 0.03) gave a low-high threshold of 1.38 with sensitivity of 92% (74-99%), specificity of 40% (24-57%), NPV of 88% (62-98%), and PPV of 50% (35-65%) Using this threshold on 12 discordant tumors between evaluators from conventional imaging yielded correct diagnoses in nine patients. Semi-automated analysis demonstrated statistically significant differences between low- and high-grade tumors for multiple metrics including average rCBV (P = 0.027). CONCLUSIONS: Despite significant positive correlation with tumor grade, rCBV from pediatric brain tumors demonstrates limited specificity, but high NPV in excluding high-grade neoplasms. In selective patients whose conventional imaging is nonspecific, an rCBV threshold may have further diagnostic value. PMID- 25504267 TI - Improved implant and postoperative lead performance in CRT-D patients implanted with a quadripolar left ventricular lead. A 6-month follow-up analysis from a multicenter prospective comparative study. AB - PURPOSE: Small single-center comparative studies suggest improved outcomes in cardiac resynchronization therapy (CRT) patients implanted with a quadripolar left ventricular (LV) lead in comparison with non-quadripolar (bipolar) leads. This study represents the first large multicenter prospective registry comparing implant and 6-month postoperative lead performance following CRT-defibrillator (CRT-D) implantation with quadripolar vs. bipolar leads. METHODS: During a 39 month period, 418 consecutive patients having CRT-D implantation attempts with either a quadripolar (n = 230) or bipolar LV lead (n = 188) were enrolled in the registry. The primary outcome of the study was LV lead failure defined as any abnormality, excluding infection, resulting in surgical lead revision or CRT termination. Additionally, operative and follow-up data were analyzed for significant difference between groups. RESULTS: Baseline characteristics of both groups were similar. In 72.9 % of quadripolar leads versus 65.0 % of bipolar leads, the LV lead successfully engaged the predefined ideal target side branch (p = 0.47). Implant duration and fluoroscopy times were significantly shorter when a quadripolar lead was used (p = 0.007 and p = 0.001, respectively). The primary end point occurred in six patients (2.7 %) in the quadripolar group and in 14 patients (8.0 %) in the bipolar group (p = 0.02). Clinically significant phrenic nerve stimulation (PNS) occurred in 4.6 vs. 14.2 % of quadripolar vs. bipolar patients, respectively (p = 0.002); all PNS were resolved noninvasively through programming in the quadripolar group vs. 84 % in bipolar group (p = 0.75). The use of a bipolar lead was associated with a higher risk of surgical LV lead revision (6.3 vs. 2.3 %; p = 0.057) and a higher incidence of dislodgment (5.7 vs. 2.7 %; p = 0.16). CONCLUSIONS: This multicenter study demonstrates that the use of a quadripolar LV lead results in significantly lower rates of lead related problems and reduced procedural and fluoroscopic times for biventricular system implantation. This has important implications for LV pacing lead choice. PMID- 25504269 TI - Catheter ablation of atrial fibrillation in patients with atrial septal defect: long-term follow-up results. AB - INTRODUCTION: Atrial fibrillation (AF) is commonly found in patients with structural heart disease (SHD), including atrial septal defect (ASD). The feasibility and safety of ablation for AF in patients with unrepaired ASD is seldom reported. OBJECTIVES: This study aims to evaluate and compare the long term efficacy of AF ablation in patients with and without ASD. METHODS: From January 2008 to December 2012, 18 consecutive patients were identified with medically refractory AF and an unrepaired ASD under catheter ablation. For each ASD patient, four control subjects were matched from our database. RESULTS: There were no significant differences between groups in terms of age, sex, type of AF, LA diameter, LVIDD, and EF. The mean procedural and fluoroscopy times were not different between the groups (p = NS). After a median follow-up of 20 months, the patients in the ASD group had 44.4 % AF recurrence after a single procedure compared with 34.7 % in the control group (p = 0.11). The mean LA diameter in non recurrent patients was smaller than in recurrent patients (p = 0.03). In univariate Cox proportional hazards analyses, the factor found to have a significant association with arrhythmia recurrences was left atrial diameter (hazard ratio 1.059, 95 % confidence interval 1.002 to 1.120, p = 0.03). CONCLUSIONS: These results indicate that in patients with AF and an ASD amenable to percutaneous closure, a staged approach with radiofrequency ablation of AF preceding closure is a rational strategy. PMID- 25504268 TI - Stand-alone mapping using different transluminal mapping catheters--an accurate and safe way to isolate all pulmonary veins with the cryoballoon? AB - PURPOSE: Cryoballoon isolation of the pulmonary veins (PVI) is an effective and safe method in the treatment of patients with paroxysmal atrial fibrillation (PAF). The circular mapping catheter Achieve(r) (Medtronic Inc., Minneapolis, USA) can be introduced into the pulmonary vein (PV) through the inner lumen of the balloon catheter, allowing online mapping of the PV electrograms during ablation. We prospectively compared the accuracy of this catheter in both available sizes to a standard circular mapping catheter (SCMC) in order to determine bidirectional PV block. METHODS: Patients with symptomatic PAF underwent cryoballoon ablation using either the Achieve(r) 15-mm catheter (group 1, 15 patients) or the Achieve(r) 20 mm (group 2, 15 patients). PV potentials were recorded using Achieve(r) before, during, and after ablation, and exit block was obtained by pacing from inside the PV. Accuracy of PV potential detection was controlled by a SCMC before and after ablation. RESULTS: Rate of PV which could be isolated exclusively using the Achieve(r) as guidewire was 98 % (59/60) in group 1 and 93 % (57/60) in group 2. Online signal recording during ablation was possible in 40 and 60 % of PV (p = 0.037), respectively. Final Achieve(r) diagnosis was accurate in 55/60 (92 %) of the PVs and 12/15 (80 %) of patients in group 1 and 60/60 (100 %) of PV and 15/15 (100 %) of patients in group 2. CONCLUSION: Stand-alone mapping using Achieve(r) 15 mm resulted in a significant lack of diagnostic accuracy. Achieve(r) 20 mm provided excellent diagnostic accuracy comparable to a SCMC and should be preferentially used. PMID- 25504270 TI - Systematic review of the association between climate and hip fractures. AB - This study aims to systematically review epidemiological studies that evaluate the relationship between meteorology and the incidence of hip fracture (HF). After a search in Scopus, PubMed, and Embase, two independent authors assessed the relevance of studies and extracted data for description. From each study, we extracted the geographic and temporal scope, design, study variables (meteorological and related to HF), statistical analysis, and estimated associations. Of a total of 134 works, 20 studies were selected. All use an ecological design but one case-crossover. Most studies have been conducted in northern latitudes. The analysis methodology did not take into account the temporal structure of the data in 10 studies (regression and linear correlations); the rest used Poisson regression (7) and ARIMA model (3). Most studies showed significant positive associations with rainfall, especially in the form of snow: HF relative risk (RR) on days with precipitation vs. days without precipitation that ranged from 1.14 (95 % confidence interval (CI)1.04 to 1.24) to 1.60 (95 % CI 1.06 to 2.41), the temperature, with RR by one degree Celsius decline from 1.012 (95 % CI 1.004 to 1.020) to 1.030 (95 % CI 1.023 to 1.037), and wind (3) RR FC windiest days vs. calm days: 1.32 (95 % CI 1.10 to 1.58) to 1.35 (95 % CI 0.88 to 2.08). This review shows that analytic methods are very heterogeneous and poorly adapted to the temporary nature of the data. Studies confirm a certain seasonality, with more fractures in winter and meaningful relationships with meteorological conditions typical of this season. PMID- 25504273 TI - Transfusion medicine issues pertaining to patients with cancer. PMID- 25504271 TI - Suberin: biosynthesis, regulation, and polymer assembly of a protective extracellular barrier. AB - Suberin is a lipid-phenolic biopolyester deposited in the cell walls of certain boundary tissue layers of plants, such as root endodermis, root and tuber peridermis, and seed coats. Suberin serves as a protective barrier in these tissue layers, controlling, for example, water and ion transport. It is also a stress-induced anti-microbial barrier. The suberin polymer contains a variety of C16-C24 chain-length aliphatics, such as omega-hydroxy fatty acids, alpha,omega dicarboxylic fatty acids, and primary fatty alcohols. Suberin also contains high amounts of glycerol and phenolics, especially ferulic acid. In addition, non covalently linked waxes are likely associated with the suberin polymer. This review focusses on the suberin biosynthetic enzymes identified to date, which include beta-ketoacyl-CoA synthases, fatty acyl reductases, long-chain acyl-CoA synthetases, cytochrome P450 monooxygenases, glycerol 3-phosphate acyltransferases, and phenolic acyltransferases. We also discuss recent advances in our understanding of the transport of suberin components intracellularly and to the cell wall, polymer assembly, and the regulation of suberin deposition. PMID- 25504272 TI - C-Terminally fused affinity Strep-tag II is removed by proteolysis from recombinant human erythropoietin expressed in transgenic tobacco plants. AB - KEY MESSAGE: C -terminally fused Strep -tag II is removed from rhuEPO expressed in tobacco plants. The finding suggests that direct fusion of purification tags at the C -terminus of rhuEPO should be avoided. Asialo-erythropoietin (asialo EPO), a desialylated form of EPO, is a potent tissue-protective agent. Recently, we and others have exploited a low-cost plant-based expression system to produce recombinant human asialo-EPO (asialo-rhuEPO(P)). To facilitate purification from plant extracts, Strep-tag II was engineered at the C-terminus of EPO. Although asialo-rhuEPO(P) was efficiently expressed in transgenic tobacco plants, affinity purification based on Strep -tag II did not result in the recovery of the protein. In this study, we investigated the stability of Strep-tag II tagged asialo-rhuEPO(P) expressed in tobacco plants to understand whether this fused tag is cleaved or inaccessible. Sequencing RT-PCR products confirmed that fused DNA sequences encoding Strep-tag II were properly transcribed, and three-dimensional protein structure model revealed that the tag must be fully accessible. However, Western blot analysis of leaf extracts and purified asialo-rhuEPO(P) revealed that the Strep-tag II was absent on the protein. Additionally, no peptide fragment containing Strep-tag II was identified in the LC-MS/MS analysis of purified protein further supporting that the affinity tag was absent on asialo rhuEPO(P). However, Strep-tag II was detected on asialo-rhuEPO(P) that was retained in the endoplasmic reticulum, suggesting that the Strep-tag II is removed during protein secretion or extraction. These findings together with recent reports that C-terminally fused Strep-tag II or IgG Fc domain are also removed from EPO in tobacco plants, suggest that its C-terminus may be highly susceptible to proteolysis in tobacco plants. Therefore, direct fusion of purification tags at the C-terminus of EPO should be avoided while expressing it in tobacco plants. PMID- 25504274 TI - Safety of the blood supply. AB - BACKGROUND: The transfusion of blood components plays a significant role as supportive therapy in the treatment of patients with cancer. Although blood transfusions help manage complications arising from either the patient's primary condition or associated with therapeutic intervention, their use introduces a new set of risks; therefore, health care professionals must be aware of the potential morbidity introduced by using blood components and endeavor to optimize outcomes by ordering transfusions only when the benefits outweigh the inherent risks. METHODS: This article sought to review the published literature, including the epidemiology of diseases transmissible via transfusion, performance characteristics for assays used for blood donor screening, surveillance activities to detect newly emergent pathogens, and biovigilance activities reported by public health authorities. RESULTS: Effective measures have been implemented to significantly decrease the risk of transmissible diseases associated with transfusion. Reports of viral disease transmitted via transfusion have been nearly eliminated, particularly since the introduction of molecular based detection technology. The transmission of bacteria and parasites still represents a threat to the use of cellular blood components. Transfusion associated human prion disease has not been reported in the United States. Immune mediated reactions due to donor-recipient incompatibility remain a challenge. CONCLUSIONS: Transmissible agents most commonly associated with risks due to transfusion are no longer a major threat; however, a significant challenge remains with regard to addressing the need for quick response mechanisms to manage emerging pathogens with the potential for rapid spread, either unintentionally (eg, globalization) or intentionally (eg, bioterrorism). The use of technology to reduce pathogens holds promise for further increasing the safety profile of blood transfusion. PMID- 25504275 TI - Adverse effects of transfusion. AB - BACKGROUND: Patients with malignancy comprise a unique group for whom transfusions play an important role. Because the need for transfusions may span a long period of time, these patients may be at risk for more adverse events due to transfusion than other patient groups. METHODS: A literature search on PubMed that included original studies and reviews was performed. The results were summarized and complemented by our clinical experience. Long-term complications of transfusions, such as transfusion-associated graft-vs-host disease, alloimmunization, transfusion-related immunomodulation, and iron overload, are discussed. RESULTS: Transfusion-related acute lung injury, transfusion-associated circulatory overload, and hemolytic transfusion reaction are deadly complications from transfusion. These adverse events have nonspecific presentations and may be missed or confused with a patient's underlying condition. Thus, a high level of suspicion and close monitoring of the patient during and following the transfusion is imperative. Common reactions (eg, febrile nonhemolytic transfusion reaction, allergic reaction) are not life threatening, but they may cause discomfort and blood product wastage. CONCLUSIONS: Every transfusion carries risks of immediate and delayed adverse events. Therefore, oncologists should prescribe transfusion for patients with cancer only when absolutely necessary. PMID- 25504276 TI - Clinical effects of red blood cell storage. AB - BACKGROUND: Well-characterized biochemical, structural, and physiological changes occur when red blood cells (RBCs) are stored for a period of time and are collectively called the storage lesion. METHODS: Key study results are summarized and contrasted and new data from recently completed randomized controlled trials will be discussed. RESULTS: It is unclear whether in vitro changes to RBCs that occur during storage are clinically relevant. The clinical effects of RBC storage have been the focus of observational studies in recent years. However, these studies lack any consensus, possibly because of methodological limitations. CONCLUSIONS: The clinical significance of storing RBCs is controversial, although new data from randomized controlled trials of neonates and patients undergoing cardiac surgery suggest that the duration of RBC storage is not associated with adverse clinical outcomes in these patient populations. PMID- 25504277 TI - Transfusion indications for patients with cancer. AB - BACKGROUND: During the last few years, considerable focus has been given to the management of anemia and coagulopathies. This article provides current concepts of red blood cell (RBC) and plasma coagulation factor replacements. METHODS: The literature was reviewed for clinical studies relevant to RBC transfusion indications and outcomes as well as for the uses of coagulation factor replacement products for coagulopathies most likely encountered in patients with cancer. RESULTS: Most patients without complications can be treated with a hemoglobin level of 7 g/dL as an indication for RBC transfusion. However, the effects of disease among patients with cancer may cause fatigue, so transfusions at higher hemoglobin levels may be clinically helpful. Leukoreduced RBCs are recommended as standard therapy for all patients with cancer, most of whom do not develop coagulopathy. Transfusions to correct mild abnormalities are not indicated in this patient population. Data are inconclusive regarding the value of coagulation factor replacement for invasive procedures when the international normalized ratio is below 2. CONCLUSIONS: Indications for RBC transfusion have become more conservative as data and experience have shown that patients can be safely and effectively maintained at lower hemoglobin levels. Coagulation factor replacement is unnecessary for most modest coagulopathies. PMID- 25504278 TI - Platelet transfusion for patients with cancer. AB - BACKGROUND: Platelet transfusion is a critical and often necessary aspect of managing cancer. Low platelet counts frequently lead to bleeding complications; however, the drugs used to combat malignancy commonly lead to decreased production and destruction of the very cell whose function is essential to stop bleeding. The transfusion of allogeneic platelet products helps to promote hemostasis, but alloimmunization may make it difficult to manage other complications associated with cancer. METHODS: The literature relating to platelet transfusion in patients with cancer was reviewed. RESULTS: Platelet storage, dosing, transfusion indications, and transfusion response are essential topics for health care professionals to understand because many patients with cancer will require platelet transfusions during the course of treatment. The workup and differentiation of non-immune-mediated compared with immune-mediated platelet refractoriness are vital because platelet management is different between types of refractoriness. CONCLUSIONS: A combination of appropriate utilization of platelet inventory and laboratory testing coupled with communication between those caring for patients with cancer and those providing blood products is essential for effective patient care. PMID- 25504280 TI - Therapeutic apheresis for patients with cancer. AB - BACKGROUND: Disease complications associated with certain malignancies may be mediated by cells or soluble molecules that traffic in the bloodstream. Because of this, therapeutic apheresis (TA) methodologies have been used to selectively remove or manipulate specific molecules, antibodies, or cellular elements to treat the underlying pathological process. For some disorders, TA is utilized as a rapid-acting and short-term adjunct to conventional chemotherapy or immunotherapy. For others, a series of scheduled treatments is recommended for optimal management. In all cases, the risks, benefits, and costs must be strongly considered. METHODS: The current literature and published guidelines were reviewed to summarize the use of TA in the management of certain complications of cancer. RESULTS: Although TA is relatively safe and useful as a first-line or salvage modality for some disorders, few prospective, randomized clinical trials exist and the majority of evidence is derived from observational studies. Expert based, clinical practice guidelines have been developed to inform hematology/oncology professionals and apheresis physicians about the efficacy and limitations of TA for malignancy-related indications. CONCLUSIONS: Certain oncological conditions respond to TA and consensus guidelines are available to support clinical decision-making. However, well-designed, prospective intervention trials are needed to better define the role of TA for a variety of disorders. PMID- 25504279 TI - Transfusion support issues in hematopoietic stem cell transplantation. AB - BACKGROUND: Patients receiving hematopoietic stem cell transplantation require extensive transfusion support until red blood cell and platelet engraftment occurs. Rare but predictable complications may arise when the transplanted stem cells are incompatible with the native ABO type of the patient. Immediate and delayed hemolysis is often seen. METHODS: A literature review was performed and the results from peer-reviewed papers that contained reproducible findings were integrated. RESULTS: A strong body of clinical evidence has developed around the common complications experienced with ABO-incompatible hematopoietic stem cell transplantation. These complications are discussed and the underlying pathophysiology is explained. General treatment options and guidelines are enumerated. CONCLUSIONS: ABO-incompatible hematopoietic stem cell transplantations are frequently performed. Immune-related hemolysis is a commonly encountered complication; therefore, health care professionals must recognize the signs of immune-mediated hemolysis and understand the various etiologies that may drive the process. PMID- 25504281 TI - Using HLA typing to support patients with cancer. AB - BACKGROUND: The human leukocyte antigen (HLA) system plays a crucial role in immune function, and HLA testing is often needed in the support of patients with cancer. METHODS: We briefly review the published literature to clarify the nomenclature of the HLA system, currently available methods for HLA testing, and commonly used HLA assays. The uses of HLA testing in pharmacogenomics, disease association, platelet transfusion support, and in the management of both solid organ and hematopoietic stem cell transplantation are also reviewed. RESULTS: HLA testing is commonly performed for select patient populations, including patients with cancer and in those requiring solid organ and hematopoietic stem cell transplantation. CONCLUSION: Newer molecular typing methods have helped improve patient outcomes following hematopoietic stem cell transplantation. PMID- 25504282 TI - Mobilization and transplantation patterns of autologous hematopoietic stem cells in multiple myeloma and non-Hodgkin lymphoma. AB - BACKGROUND: The mobilization of hematopoietic stem cells can be a limiting factor for transplantation, yet little is known about how the availability of novel mobilizing agents has affected the practices of oncologists and transplant specialists. METHODS: US-based oncologists (n = 48) and transplant specialists (n = 46) were separately surveyed with a partial overlap of assessed information. RESULTS: More transplant specialists than oncologists believed that the time between referral and first consultation is adequate (89.1% vs 54.2%; P < .001). The presence of comorbidities was the most common reason for patients not being referred for transplantation. Among oncologists, 31.3% avoided cyclophosphamide and 16.7% avoided lenalidomide to prevent mobilization impairment in patients with multiple myeloma (MM). Chemotherapy mobilization for MM was used by 23.9% of transplant specialists due to higher CD34+ yields and by 21.7% due to its anti-MM effect. In non-Hodgkin lymphoma (NHL), 26.1% of transplant specialists used chemotherapy mobilization due to higher CD34+ yields, and 26.1% collected hematopoietic stem cells on the rebound prior to chemotherapy. With regard to plerixafor use in MM, 36.9% of transplant specialists reported that they did not use it, and 28.3% said they reserved it for second mobilization. In NHL, 4.3% of transplant specialists reported not using plerixafor, and 39.1% reserved it for second mobilization. CONCLUSIONS: Educational needs were identified to promote adequate referral for transplantation as well as successful and cost-effective methods for the mobilization of hematopoietic stem cells. PMID- 25504283 TI - Functional health literacy, chemotherapy decisions, and outcomes among a colorectal cancer cohort. AB - BACKGROUND: Functional health literacy is essential for the self-management of chronic diseases and preventive health behaviors. Patients with cancer who have a low level of health literacy may be at greater risk for poor care and poor outcomes. METHODS: We assessed health literacy using the Short Test of Functional Health Literacy in Adults in 347 participants with colorectal cancer who were nested within a prospective observational study of system, health care provider, and participant characteristics influencing cancer outcomes. RESULTS: Having adequate health literacy increased the likelihood that participants with stage 3/4 disease received chemotherapy (odds ratio, 3.29; 95% confidence interval, 1.23-8.80) but had no effect on cancer stage at diagnosis or vital status at last observation during postenrollment follow-up. No difference was seen in health literacy status regarding participant beliefs and preferences about chemotherapy among those with stage 3/4 disease, nor in participant roles in deciding whether to receive chemotherapy. CONCLUSIONS: Patients with lower levels of health literacy were less likely to receive chemotherapy compared with participants with higher levels of health literacy. Therefore, clear communication related to key health care decisions may lead to fewer disparities due to a patient's level of health literacy. PMID- 25504284 TI - Familial gastrointestinal stromal tumor syndrome: report of 2 cases with KIT exon 11 mutation. AB - BACKGROUND: As with cases of sporadic gastrointestinal stromal tumor (GIST), familial GIST syndrome arises from mutations in KIT or PDGFRA. Only a few dozen such families have been described in the literature. METHODS: Cases of 2 individuals from 2 different newly described kindreds with familial GIST syndrome were retrospectively reviewed. Pertinent immunohistochemical stains, including CD117, CD34, DOG1, desmin, and S100, were performed. Samples from each case were sent to outside facilities for molecular analysis. A review of the relevant literature was performed and the number of familial GIST syndrome cases reported was updated through July 2014. RESULTS: In case 1, a woman 40 years of age with a family history of GIST presented with abdominal pain and gastrointestinal bleeding. Biopsy of a gastric mass revealed spindle-cell type GIST. Molecular analysis revealed a heterozygous mutation of p.Asp579del in exon 11 of KIT. The patient was placed on imatinib therapy and an initial positive response was demonstrated by imaging. Disease regression was seen on computed tomography, and several GIST tumors were surgically resected. The patient has had stable disease since surgery. In case 2, an asymptomatic woman 29 years of age presented for screening due to a family history of GIST. One small nodule was noted in her stomach and another was noted in the duodenum; both were surgically resected. The patient recovered well following surgery. The GIST in this patient was noted to have similar histological, immunohistochemical, and molecular findings as case 1. CONCLUSIONS: Imatinib has often been shown to be an effective therapy in both the familial and sporadic forms of GIST. There is no standard protocol for addressing the surveillance of patients with spindle-cell type GIST seen in the setting of familial GIST syndrome and with a p.Asp579del mutation of exon 11 on KIT. PMID- 25504287 TI - Atomic-scale models of early-stage alkali depletion and SiO2-rich gel formation in bioactive glasses. AB - Molecular dynamics simulations of Na(+)/H(+)-exchanged 45S5 Bioglass(r) models reveal that a large fraction of the hydroxyl groups introduced into the proton exchanged, hydrated glass structure do not initially form covalent bonds with Si and P network formers but remain free and stabilised by the modifier metal cations, whereas substantial Si-OH and P-OH bonding is observed only at higher Na(+)/H(+) exchange levels. The strong affinity between free OH groups and modifier cations in the highly fragmented 45S5 glass structure appears to represent the main driving force for this effect. This suggests an alternative direct route for the formation of a repolymerised silica-rich gel in the early stages of the bioactive mechanism, not considered before, which does not require sequential repeated breakings of Si-O-Si bonds and silanol condensations. PMID- 25504285 TI - Current and emerging therapies for bone metastatic castration-resistant prostate cancer. AB - BACKGROUND: A paucity of therapeutic options is available to treat men with metastatic castration-resistant prostate cancer (mCRPC). However, recent developments in our understanding of the disease have resulted in several new therapies that show promise in improving overall survival rates in this patient population. METHODS: Agents approved for use in the United States and those undergoing clinical trials for the treatment of mCRPC are reviewed. Recent contributions to the understanding of prostate biology and bone metastasis are discussed as well as how the underlying mechanisms may represent opportunities for therapeutic intervention. New challenges to delivering effective mCRPC treatment will also be examined. RESULTS: New and emerging treatments that target androgen synthesis and utilization or the microenvironment may improve overall survival rates for men diagnosed with mCRPC. Determining how factors derived from the primary tumor can promote the development of premetastatic niches and how prostate cancer cells parasitize niches in the bone microenvironment, thus remaining dormant and protected from systemic therapy, could yield new therapies to treat mCRPC. Challenges such as intratumoral heterogeneity and patient selection can potentially be circumvented via computational biology approaches. CONCLUSIONS: The emergence of novel treatments for mCRPC, combined with improved patient stratification and optimized therapy sequencing, suggests that significant gains may be made in terms of overall survival rates for men diagnosed with this form of cancer. PMID- 25504286 TI - Genetic data simulators and their applications: an overview. AB - Computer simulations have played an indispensable role in the development and applications of statistical models and methods for genetic studies across multiple disciplines. The need to simulate complex evolutionary scenarios and pseudo-datasets for various studies has fueled the development of dozens of computer programs with varying reliability, performance, and application areas. To help researchers compare and choose the most appropriate simulators for their studies, we have created the genetic simulation resources (GSR) website, which allows authors of simulation software to register their applications and describe them with more than 160 defined attributes. This article summarizes the properties of 93 simulators currently registered at GSR and provides an overview of the development and applications of genetic simulators. Unlike other review articles that address technical issues or compare simulators for particular application areas, we focus on software development, maintenance, and features of simulators, often from a historical perspective. Publications that cite these simulators are used to summarize both the applications of genetic simulations and the utilization of simulators. PMID- 25504288 TI - PHA-4/FOXA-regulated microRNA feed forward loops during Caenorhabditis elegans dietary restriction. AB - Dietary restriction (DR) increases life span and delays the onset of age-related diseases across species. However, the molecular mechanisms have remained relatively unexplored in terms of gene regulation. InC. elegans, a popular model for aging studies, the FOXA transcription factor PHA-4 is a robust genetic regulator of DR, although little is known about how it regulates gene expression. We profiled the transcriptome and miRNAome of an eat-2 mutant, a genetic surrogate of DR, by Next Generation sequencing and find that most of the miRNAs are upregulated in the young-adult worms, none significantly downregulated. Interestingly, PHA-4 can potentially regulate the expression of most of these miRNA genes. Remarkably, many of the PHA-4-regulated genes that are induced during DR are also targets of the PHA-4-upregulated miRNAs, forming a large feed forward gene regulatory network. The genes targeted by the feed-forward loops (FFLs) are enriched for functions related to ubiquitin-mediated decay, lysosomal autophagy, cellular signalling, protein folding etc., processes that play critical roles in DR and longevity. Together our data provides a framework for understanding the complex and unique regulatory network employed during DR, suggesting that PHA-4 employs such FFLs to fine-tune gene expression and instil robustness in the system during energy crisis. PMID- 25504290 TI - Negative effect of combined cysteine and glutathione in soy lecithin-based extender on post-thawed ram spermatozoa. AB - This study was conducted to evaluate the effect of combined cysteine and glutathione in soy lecithin-based semen extender on post-thawed ram sperm quality. A total of 28 ejaculates were collected twice a week (from four rams) during breeding season. In each replicate, semen samples (n = 4, one ejaculate for each ram) were pooled and divided into three equal parts, and each part was diluted with one of following extender: (1) soy lecithin-based extender containing no cysteine and no glutathione (C0-G0), (2) soy lecithin-based extender containing cysteine (5 mM) and glutathione (5 mM) (C5-G5), and (3) soy lecithin-based extender containing cysteine (10 mM) and glutathione (10 mM) (C10 G10). After freeze-thawing process, motility and velocity parameters, plasma membrane integrity and functionality, mitochondrial activity, and apoptosis features of spermatozoa were evaluated. The obtained results showed that total and progressive motility, plasma membrane integrity and functionality, and live post-thawed spermatozoa was lower in C10-G10 extender compared to C0-G0 and C5-G5 extenders (P < 0.05). Also, the percentage of dead spermatozoa was higher in C10 G10 extender compared to C0-G0 extender (P < 0.05). Apoptotic spermatozoa was lower in C10-G10 extender compared to C0-G0 and C5-G5 extenders (P < 0.05). All velocity parameters, exception of BCF, did not different between extenders (P > 0.05). In conclusion, it seems that high concentration of combined cysteine and glutathione in soy lecithin-based semen extender has a detrimental effect of post thawed ram sperm quality. PMID- 25504289 TI - EGF is required for cardiac differentiation of P19CL6 cells through interaction with GATA-4 in a time- and dose-dependent manner. AB - The regulation of cardiac differentiation is critical for maintaining normal cardiac development and function. The precise mechanisms whereby cardiac differentiation is regulated remain uncertain. Here, we have identified a GATA-4 target, EGF, which is essential for cardiogenesis and regulates cardiac differentiation in a dose- and time-dependent manner. Moreover, EGF demonstrates functional interaction with GATA-4 in inducing the cardiac differentiation of P19CL6 cells in a time- and dose-dependent manner. Biochemically, GATA-4 forms a complex with STAT3 to bind to the EGF promoter in response to EGF stimulation and cooperatively activate the EGF promoter. Functionally, the cooperation during EGF activation results in the subsequent activation of cyclin D1 expression, which partly accounts for the lack of additional induction of cardiac differentiation by the GATA-4/STAT3 complex. Thus, we propose a model in which the regulatory cascade of cardiac differentiation involves GATA-4, EGF, and cyclin D1. PMID- 25504294 TI - Gonorrhea treatment practices in the STD Surveillance Network, 2010-2012. AB - BACKGROUND: Replacing oral treatments with ceftriaxone is a central component of public health efforts to slow the emergence of cephalosporin-resistant Neisseria gonorrhoeae in the United States; US gonorrhea treatment guidelines were revised accordingly in 2010. However, current US gonorrhea treatment practices have not been well characterized. METHODS: Six city and state health departments in Cycle II of the STD Surveillance Network (SSuN) contributed data on all gonorrhea cases reported in 101 counties and independent cities. Treatment data were obtained through local public health surveillance and interviews with a random sample of patients. Cases were weighted to adjust for site-specific sample fractions and for differential nonresponse by age, sex, and provider type. RESULTS: From 2010 to 2012, 135,984 gonorrhea cases were reported in participating areas, 15,246 (11.2%) of which were randomly sampled. Of these, 7,851 (51.5%) patients were interviewed. Among patients with complete treatment data, 76.8% received ceftriaxone, 16.4% received an oral cephalosporin, and 6.9% did not receive a cephalosporin; 51.9% of persons were treated with a regimen containing ceftriaxone and either doxycycline or azithromycin. Ceftriaxone treatment increased significantly by year (64.1% of patients in 2010, 79.3% in 2011, 85.4% in 2012; P = 0.0001). Ceftriaxone use varied widely by STD Surveillance Network site (from 44.6% to 95.1% in 2012). CONCLUSIONS: Most persons diagnosed as having gonorrhea between 2010 and 2012 in the United States received ceftriaxone, and its use has increased since the release of the 2010 Centers for Disease Control and Prevention STD Treatment Guidelines. PMID- 25504295 TI - Could home sexually transmitted infection specimen collection with e-prescription be a cost-effective strategy for clinical trials and clinical care? AB - BACKGROUND: Results of a recent demonstration project evaluating feasibility, acceptability, and cost of a Web-based sexually transmitted infection (STI) testing and e-prescription treatment program (eSTI) suggest that this approach could be a feasible alternative to clinic-based testing and treatment, but the results need to be confirmed by a randomized comparative effectiveness trial. METHODS: We modeled a decision tree comparing (1) cost of eSTI screening using a home collection kit and an e-prescription for uncomplicated treatment versus (2) hypothetical costs derived from the literature for referral to standard clinic based STI screening and treatment. Primary outcome was number of STIs detected. Analyses were conducted from the clinical trial perspective and the health care system perspective. RESULTS: The eSTI strategy detected 75 infections, and the clinic referral strategy detected 45 infections. Total cost of eSTI was $94,938 ($1266/STI detected) from the clinical trial perspective and $96,088 ($1281/STI detected) from the health care system perspective. Total cost of clinic referral was $87,367 ($1941/STI detected) from the clinical trial perspective and $71,668 ($1593/STI detected) from the health care system perspective. CONCLUSIONS: Results indicate that eSTI will likely be more cost-effective (lower cost/STI detected) than clinic-based STI screening, both in the context of clinical trials and in routine clinical care. Although our results are promising, they are based on a demonstration project and estimates from other small studies. A comparative effectiveness research trial is needed to determine actual cost and impact of the eSTI system on identification and treatment of new infections and prevention of their sequelae. PMID- 25504296 TI - Trends and patterns of sexual behaviors among adolescents and adults aged 14 to 59 years, United States. AB - BACKGROUND: Evaluation of sexual behaviors is essential to better understand the epidemiology of sexually transmitted infections and their sequelae. METHODS: The National Health and Nutrition Examination Surveys (NHANES) is an ongoing probability sample survey of the US population. Using NHANES sexual behavior data from 1999 to 2012, we performed the following: (1) trend analyses among adults aged 25 to 59 years by 10-year birth cohorts and (2) descriptive analyses among participants aged 14 to 24 years. Sex was defined as vaginal, anal, or oral sex. RESULTS: Among adults aged 25 to 59 years, median age at sexual initiation decreased between the 1940-1949 and 1980-1989 cohorts from 17.9 to 16.2 among females (P trend < 0.001) and from 17.1 to 16.1 among males (P trend < 0.001). Median lifetime partners increased between the 1940-1949 and 1970-1979 cohorts, from 2.6 to 5.3 among females (P trend < 0.001) and from 6.7 to 8.8 among males (P trend < 0.001). The percentage of females reporting ever having a same-sex partner increased from 5.2% to 9.3% between the 1940-1949 and 1970-1979 cohorts (P trend < 0.001). Among participants aged 14 to 24 years, the percentage having had sex increased with age, from 12.5% among females and 13.1% among males at age 14 years to more than 75% at age 19 years for both sexes. Among sexually experienced 14- to 19-year-olds, 45.2% of females and 55.0% of males had at least 3 lifetime partners; 39.4% of females and 48.6% of males had at least 2 partners in the past year. The proportion of females aged 20 to 24 years who reported ever having a same-sex partner was 14.9%. The proportion of participants aged 14-19 or 20-24 years reporting ever having sex did not differ by survey year from 1999 to 2012 for either males or females. CONCLUSIONS: Sexual behaviors changed with successive birth cohorts, with more pronounced changes among females. A substantial proportion of adolescents are sexually active and have multiple partners. These data reinforce existing recommendations for sexual health education and sexually transmitted infection prevention targeting adolescents before sexual debut. PMID- 25504297 TI - Trends in antimicrobial resistance in Neisseria gonorrhoeae isolated from Guangzhou, China, 2000 to 2005 and 2008 to 2013. AB - A total of 1224 Neisseria gonorrhoeae isolates from Guangzhou in 2 periods (2000 2005 and 2008-2013) were subjected to antimicrobial susceptibility testing. The percentage of penicillin- and ciprofloxacin-resistant isolates increased from 71.1% (473/665) to 90.9% (508/559) and 88.9% (591/665) to 98.0% (548/559), respectively. All isolates remain susceptible to spectinomycin and ceftriaxone, with increasing minimum inhibitory concentrations. PMID- 25504298 TI - Test positivity for chlamydia, gonorrhea, and syphilis infection among a cohort of individuals released from jail in Marion County, Indiana. AB - BACKGROUND: Individuals entering jails have high rates of sexually transmitted infections (STI), but there are few data on STI in the postincarceration period. This study aimed to describe rates of chlamydia, gonorrhea, and syphilis infection among individuals released from Marion County (Indianapolis), Indiana jails. METHODS: We conducted a retrospective cohort study of individuals incarcerated in Marion County, Indiana jails from 2003 to 2008 (n = 118,670). We linked county jail and public health data to identify individuals with positive STI test results in the 1 year after release from jail. Rates per 100,000 individuals and Cox proportional hazard analyses were performed for each STI, stratified by demographic, STI, and jail characteristics. RESULTS: We found significantly higher rates of STI in this cohort than in the general population, with rates in the 1 year after release being 2 to 7 times higher for chlamydia, 5 to 24 times higher for gonorrhea, and 19 to 32 times higher for syphilis compared with rates in the general population. Characteristics most associated with increased risk of a positive STI test result among this cohort were younger age for chlamydia and gonorrhea, older age for syphilis, black race for men, being jailed for prostitution for women, history of STI, and history of prior incarceration. CONCLUSIONS: This study found high rates of STIs among a cohort of individuals recently released from jail and identified a number of risk factors. Further study is needed to improve targeted STI testing and treatment among this high-risk population. PMID- 25504300 TI - High prevalence and incidence of asymptomatic sexually transmitted infections during pregnancy and postdelivery in KwaZulu Natal, South Africa. AB - BACKGROUND: We report the prevalence and incidence of 3 treatable sexually transmitted pathogens (Neiserria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis) in women who were HIV infected or at high risk for HIV infection, in pregnancy and postpartum, respectively. METHOD: Vulvovaginal specimens collected at the first antenatal visit and again at 14 weeks postpartum were tested for N. gonorrhoeae, C. trachomatis, and T. vaginalis in the laboratory. Women were routinely tested for HIV-1 with a point-of-care test. RESULTS: Among 1480 women, 32.3% (95% confidence interval, 29.9-34.7) tested positive for any of the sexually transmitted infections (STIs) in pregnancy and 19.2% (95% confidence interval, 16.9-21.5) were positive when retested 14 weeks postpartum (incidence rate, 79.2 per 100 person-years). The prevalence of N. gonorrhoeae and T. vaginalis infections in pregnancy and the incidence rate of any STI at 14 weeks postpartum were significantly higher in HIV-1-infected women (P < 0.0001 amd P = 0.0079). More than 50% of N. gonorrhoeae, T. vaginalis, and C. trachomatis infections in pregnancy were asymptomatic. CONCLUSIONS: The high prevalence of asymptomatic STIs in pregnancy is compelling evidence that demands the development and validation of point-of-care tests for STIs be expedited. In addition, the high incidence of STIs 3 months postpartum suggests that women in this study setting resume unprotected sexual intercourse soon after delivery. PMID- 25504299 TI - Can previous first-line therapies for Neisseria gonorrhoeae be targeted to specific patient subgroups to treat gonorrhea? AB - BACKGROUND: Gonorrhea treatment is challenging because of the emergence of resistance, treatment failure with existing drugs, and the lack of alternative agents. This study investigates the feasibility of targeting previously recommended antimicrobials to specific population subgroups where the prevalence of infection susceptible to these antimicrobials is above the World Health Organization cautionary treatment threshold of 95%. METHODS: Descriptive data from the Gonococcal Resistance to Antimicrobials Surveillance Programme for England and Wales were analyzed to investigate patient characteristics associated with infection with susceptible isolates using univariate and multivariable analyses. RESULTS: Of 6173 isolates from 2007 to 2011, 4684 (82%) were susceptible to penicillin, 3899 (68%) to ciprofloxacin, and 5240 (91%) to cefixime. All subgroups of the MSM population had fewer than 95% of isolates susceptible to penicillin, ciprofloxacin, or cefixime. Higher proportions of isolates from heterosexual patient subgroups were susceptible to these antimicrobials. Multivariable models identified the following associations between patient characteristics and infection with susceptible isolates: patients aged 13 to 24 years (penicillin: 92.3% susceptible adjusted odds ratio and associated 95% confidence interval [aOR CI] 1.84-2.97; ciprofloxacin: 88.3%, aOR CI 2.22-3.39; cefixime: 98.7%, aOR CI 1.29-3.52) patients of black ethnicity (penicillin: 93.9%, aOR CI 2.72-4.91; ciprofloxacin: 92.0%, aOR CI 3.94-6.7; cefixime: 99.1%, aOR CI 1.78-6.4), and patients with concurrent chlamydia (penicillin: 93.9%, aOR CI 1.8-3.22; ciprofloxacin: 91.7%, aOR CI 2.71-4.58; cefixime: 99.0%, aOR CI 1.27-4.54). CONCLUSIONS: This study demonstrated that of the previous first-line therapies, cefixime would be the only antimicrobial suitable for use for infection in heterosexual patients alone. PMID- 25504301 TI - Point-of-care treponemal tests for neurosyphilis diagnosis. AB - BACKGROUND: The laboratory diagnosis of neurosyphilis rests upon identifying cerebrospinal fluid (CSF) abnormalities, including CSF-Venereal Disease Research Laboratory (VDRL) reactivity. The CSF-VDRL may not be available in the parts of the world where neurosyphilis is most common. Treponemal immunochromatographic strip tests (ICSTs) have been developed as point-of-care tests on blood for syphilis diagnosis in resource-limited settings. METHODS: We optimized 3 commercial ICSTs for performance on CSF and tested CSF samples from 217 patients with syphilis. The Syphicheck-WB test (Qualpro Diagnostics, Goa, India; "Syphicheck") was chosen for further study based on agreement with CSF-VDRL test results. We determined CSF-Syphicheck titers for 152 samples. We modified the CSF Syphicheck for point-of-care testing in a US sexually transmitted diseases clinic and compared results on 102 paired centrifuged and uncentrifuged CSF samples obtained in the laboratory to the results obtained at point of care; results of samples diluted 1:4 were compared in a subset. RESULTS: The diagnostic sensitivity of a reactive CSF-Syphicheck (62%-64%) and the diagnostic specificity of a CSF-Syphicheck titer at or above 1:4 (79%-81%) were equivalent to the CSF VDRL (54%-69% sensitivity, 73%-75% specificity) for laboratory and clinical neurosyphilis diagnoses. The CSF-Syphicheck normalized after neurosyphilis therapy similarly to the CSF-VDRL. The modified CSF-Syphicheck performed well at the point of care, albeit with better performance on cell-free compared with uncentrifuged CSF. CONCLUSIONS: Cerebrospinal fluid treponemal ICSTs hold promise for point-of-care neurosyphilis diagnosis in regions where the CSF-VDRL is not available. Further study should address the performance of CSF ICSTs in resource limited settings. PMID- 25504302 TI - The 2 simultaneously published "k" sequence variants of tp0548 locus of Treponema pallidum ssp. pallidum isolates differ: the one published later has to be renamed as "l". PMID- 25504303 TI - Detecting HIV among persons accompanying patients to an infectious diseases clinic. AB - BACKGROUND: Infectious diseases (ID) clinics are locations where members of at risk social networks, including sex partners of HIV-infected patients, make contact with a medical care setting when they accompany HIV-positive patients to appointments. METHODS: We implemented a free point-of-care rapid HIV testing program for anyone accompanying a patient to the University of North Carolina ID clinic. Acceptability of the program among the general clinic population was assessed via an anonymous survey 1 year after program implementation. Basic frequencies of those who underwent and received results of rapid HIV testing, the proportion of positive rapid tests and confirmatory HIV tests performed, and the level of University of North Carolina ID clinic patient satisfaction with the HIV testing program were calculated. RESULTS: Between October 2007 and June 2013, 450 (99.6%) of 452 individuals tested in the program received their results on the same day as testing. Twenty-two individuals (4.9%) tested HIV positive, of which 16 (72.7%) were newly positive, including 3 never previously tested. Excluding previously diagnosed individuals, HIV prevalence was 3.6% (16/446). Among those testing positive by rapid testing, 19 (86.4%) had confirmatory testing and immediately entered into HIV care at the clinic. CONCLUSIONS: The high positivity and confirmatory HIV rates in our program confirm that the provision of rapid HIV testing in an ID clinic capitalizes on missed opportunities among an at-risk population and allows immediate linkage to care. PMID- 25504305 TI - Editorial: Sibling synergy. PMID- 25504304 TI - Dietary glycemic load and cognitive performance in elderly subjects. PMID- 25504306 TI - Over 10-year follow-up of limbic encephalitis associated with anti-LGI1 antibodies. PMID- 25504307 TI - Acute stroke management. PMID- 25504308 TI - The cholinergic basal forebrain in Lewy body dementia and Alzheimer's disease. PMID- 25504310 TI - A method for dynamic nuclear polarization enhancement of membrane proteins. AB - Dynamic nuclear polarization (DNP) magic-angle spinning (MAS) solid-state NMR (ssNMR) spectroscopy has the potential to enhance NMR signals by orders of magnitude and to enable NMR characterization of proteins which are inherently dilute, such as membrane proteins. In this work spin-labeled lipid molecules (SL lipids), when used as polarizing agents, lead to large and relatively homogeneous DNP enhancements throughout the lipid bilayer and to an embedded lung surfactant mimetic peptide, KL4 . Specifically, DNP MAS ssNMR experiments at 600 MHz/395 GHz on KL4 reconstituted in liposomes containing SL-lipids reveal DNP enhancement values over two times larger for KL4 compared to liposome suspensions containing the biradical TOTAPOL. These findings suggest an alternative sample preparation strategy for DNP MAS ssNMR studies of lipid membranes and integral membrane proteins. PMID- 25504311 TI - Differentiation of mesenchymal stem cells into retinal progenitor cells. PMID- 25504309 TI - Body mass index and risk of breast cancer: a nonlinear dose-response meta analysis of prospective studies. AB - The role of Body Mass Index (BMI) for Breast Cancer (BC) remains to be great interest for a long time. However, the precise effect of nonlinear dose-response for BMI and BC risk is still unclear. We conducted a dose-response meta-analysis to quantitatively assess the effect of BMI on BC risk. Twelve prospective studies with 4,699 cases identified among 426,199 participants and 25 studies of 22,809 cases identified among 1,155,110 participants in premenopausal and postmenopausal groups, respectively, were included in this meta-analysis. Significant non-linear dose-response (P < 0.001) association was identified between BMI and BC risk in postmenopausal women. Individuals with BMI of 25, 30, and 35 kg/m(2) yielded relative risks (RRs) of 1.02 [95% confidence interval (CI): 0.98-1.06], 1.12 (95% CI: 1.01-1.24), and 1.26 (95% CI: 1.07-1.50), respectively, when compared to the mean level of the normal BMI range. However, inverse result though not significant was observed in premenopausal women. In conclusion, the results of this meta-analysis highlighted that obesity contributed to increased BC risk in a nonlinear dose-response manner in postmenopausal women, and it is important to realize that body weight control may be a crucial process to reduce BC susceptibility. PMID- 25504312 TI - HIV Risk, Health, and Social Characteristics of Sexual Minority Female Injection Drug Users in Baltimore. AB - Female injection drug users (IDU) who report sex with women are at increased risk for HIV and social instability, but it is important to assess whether these disparities also exist according to sexual minority identity rather than behaviorally defined categories. Within a sample of current IDU in Baltimore, about 17 % of female study participants (n = 307) identified as gay/lesbian/bisexual. In controlled models, sexual minorities were three times as likely to report sex exchange behavior and four times as likely to report a recent STI. Injection risk did not differ significantly, but sexual minority women reported higher prevalence of socio-economic instability, negative health indicators, and fewer network financial, material, and health support resources. There is a need to identify and address socio-economic marginalization, social support, and health issues among female IDUs who identify as lesbian or bisexual. PMID- 25504313 TI - Halogen bond: a long overlooked interaction. AB - Because of their high electronegativity, halogen atoms are typically considered, in most of their derivatives, as sites of high electron density and it is commonly accepted that they can form attractive interactions by functioning as the electron donor site (nucleophilic site). This is the case when they work as hydrogen bond acceptor sites. However, the electron density in covalently bound halogens is anisotropically distributed. There is a region of higher electron density, accounting for the ability of halogens to function as electron donor sites in attractive interactions, and a region of lower electron density where the electrostatic potential is frequently positive (mainly in the heavier halogens). This latter region is responsible for the ability of halogen atoms to function as the electron-acceptor site (electrophilic site) in attractive interactions formed with a variety of lone pair-possessing atoms, anions, and pi systems. This ability is quite general and is shown by a wide diversity of halogenated compounds (e.g., organohalogen derivatives and dihalogens). According to the definition proposed by the International Union of Pure and Applied Chemistry, any attractive interactions wherein the halogen atom is the electrophile is named halogen bond (XB). In this chapter, it is discussed how the practice and the concept of XB developed and a brief history of the interaction is presented. Papers (either from the primary or secondary literature) which have reported major experimental findings in the field or which have given important theoretical contributions for the development of the concept are recollected in order to trace how a unifying and comprehensive categorization emerged encompassing all interactions wherein halogen atoms function as the electrophilic site. PMID- 25504314 TI - Anion Recognition in Solution via Halogen Bonding. AB - An overview of the interactions between anions and electron-deficient, covalently bound halogens is presented. It might be anticipated that species such as halides and oxoanions would be good acceptors of halogen bonds because of their relatively high charge densities and nucleophilicities. The stabilities of the trihalide anions X3 (-) provide a clear indication that this is indeed the case. The thermodynamics of formation of the trihalides, and of analogous complexes between anions and monodentate haloorganics in organic solvent, are discussed in detail. Although the incorporation of multiple interacting groups to achieve high guest affinity has been a key principle of supramolecular chemistry for decades, it is only recently that multidentate halogen bond donors capable of anion recognition have been reported. This contribution highlights the range of architectures that have been employed as the basis for multidentate halogen bond donor design. Examples of selective and high-affinity anion recognition through halogen bonding, including implementations in polar, protic media, are discussed. PMID- 25504315 TI - Cherenkoscopy based patient positioning validation and movement tracking during post-lumpectomy whole breast radiation therapy. AB - To investigate Cherenkov imaging (Cherenkoscopy) based patient positioning and movement tracking during external beam radiation therapy (EBRT). In a phase 1 clinical trial, including 12 patients undergoing post-lumpectomy whole breast irradiation, Cherenkov emission was imaged with a time-gated ICCD camera synchronized to the LINAC pulse output, during different fractions of the treatment. Patients were positioned with the aid of the AlignRT system in the beginning of each treatment session. Inter-fraction setup variation was studied by rigid image registrations between images acquired at individual treatments to the average image from all imaged treatment fractions. The amplitude of respiratory motion was calculated from the registration of each frame of Cherenkov images to the reference. A Canny edge detection algorithm was utilized to highlight the beam field edges and biological features provided by major blood vessels apparent in the images. Real-time Cherenkoscopy can monitor the treatment delivery, patient motion and alignment of the beam edge to the treatment region simultaneously. For all the imaged fractions, the patient positioning discrepancies were within our clinical tolerances (3 mm in shifts and 3 degree in pitch angle rotation), with 4.6% exceeding 3 mm but still within 4 mm in shifts. The average discrepancy of repetitive patient positioning was 1.22 mm in linear shift and 0.34 degrees in rotational pitch, consistent with the accuracy reported by the AlignRT system. The edge detection algorithm enhanced features such as field edges and blood vessels. Patient positioning discrepancies and respiratory motion retrieved from rigid image registration were consistent with the edge enhanced images. Besides positioning discrepancies caused by globally inaccurate setups, edge enhanced blood vessels indicate the existence of deformations within the treatment region, especially for large patients. Real-time Cherenkoscopy imaging during EBRT is a novel imaging tool that can be used for treatment monitoring, patient positioning and motion tracking. PMID- 25504316 TI - Interleukin-10 overexpression improves the function of endothelial progenitor cells stimulated with TNF-alpha through the activation of the STAT3 signaling pathway. AB - Lentivirus vector-interleukin-10 green fluorescent protein (LV-IL-10-GFP) was transfected into endothelial progenitor cells (EPCs) in the present study. The aim was to detect the function of IL-10-modified EPCs and analyze the molecular mechanism. EPCs were cultured and identified by fluorescent labeling with the von Willebrand factor antibody, vascular endothelial growth factor (VEGF) receptor, Ulex europaeus agglutinin-1 and acetylated low-density lipoprotein. Subsequently, EPCs were transfected with LV-IL-10-GFP and lentivirus vector-noncontain-GFP as the control group. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentrations of cytokines in the supernatant with or without tumor necrosis factor-alpha (TNF-alpha). All types of cells were assessed by a tube formation assay, adhesion assay and migration assay induced with or without TNF-alpha. Cell cycle was assessed by flow cytometry. Western blot analysis was applied to detect the expression of proteins in the cells. ELISA analysis showed that the levels of TNF-alpha and IL-8 in the supernatant without TNF-alpha significantly decreased in EPC-LV-IL-10-GFP (P<0.05 for all). By contrast, the levels of IL-10 and VEGF were contrasting in association with these. The concentrations of cytokines in the supernatant with TNF-alpha were consistent to the supernatant without TNF alpha. There was no statistically significant difference in the average number of EPCs undergoing migration, adhesion, total length and cell growth among the EPC, EPC-LV-IL-10-GFP and EPC-LV-NC-GFP groups without TNF-alpha. Further study showed that EPC-LV-IL-10-GFP with TNF-alpha significantly enhanced EPC migration, adhesion and promoted tube formation (P<0.05 for all). Western blot analysis revealed that the expression of VEGF, matrix metallopeptidase-9 and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3) significantly increased in the EPC-LV-IL-10-GFP group. Conversely, STAT-3 expression decreased in the EPC-LV-IL-10-GFP group. The present study suggested that overexpression of IL-10 had no effect on migration, adhesion, tubule formation and cell growth of EPCs without TNF-alpha. Furthermore, in EPCs stimulated with TNF-alpha, the overexpression of IL-10 improved EPC function, including migration, adhesion and tubule formation by activating the STAT3 signal pathway. PMID- 25504317 TI - The reliability and internal consistency of one-shot and flicker change detection for measuring individual differences in visual working memory capacity. AB - We investigated the psychometric properties of the one-shot change detection task for estimating visual working memory (VWM) storage capacity-and also introduced and tested an alternative flicker change detection task for estimating these limits. In three experiments, we found that the one-shot whole-display task returns estimates of VWM storage capacity (K) that are unreliable across set sizes-suggesting that the whole-display task is measuring different things at different set sizes. In two additional experiments, we found that the one-shot single-probe variant shows improvements in the reliability and consistency of K estimates. In another additional experiment, we found that a one-shot whole display-with-click task (requiring target localization) also showed improvements in reliability and consistency. The latter results suggest that the one-shot task can return reliable and consistent estimates of VWM storage capacity (K), and they highlight the possibility that the requirement to localize the changed target is what engenders this enhancement. Through a final series of four experiments, we introduced and tested an alternative flicker change detection method that also requires the observer to localize the changing target and that generates, from response times, an estimate of VWM storage capacity (K). We found that estimates of K from the flicker task correlated with estimates from the traditional one-shot task and also had high reliability and consistency. We highlight the flicker method's ability to estimate executive functions as well as VWM storage capacity, and discuss the potential for measuring multiple abilities with the one-shot and flicker tasks. PMID- 25504318 TI - Myoglobin-catalyzed intermolecular carbene N-H insertion with arylamine substrates. AB - Engineered variants of the heme-containing protein myoglobin can efficiently catalyze the insertion of alpha-diazo esters into the N-H bond of arylamines, featuring a combination of high chemoselectivity, elevated turnover numbers, and broad substrate scope. PMID- 25504319 TI - Insight into factors affecting the presence, degree, and temporal stability of fluorescence intensification on ZnO nanorod ends. AB - We have carried out a combined experimental and simulation study identifying the key physical and optical parameters affecting the presence and degree of fluorescence intensification measured on zinc oxide nanorod (ZnO NR) ends. Previously, we reported on the highly localized, intensified, and prolonged fluorescence signal measured on the NR ends, termed fluorescence intensification on NR ends (FINE). As a step towards understanding the mechanism of FINE, the present study aims to provide insight into the unique optical phenomenon of FINE through experimental and simulation approaches and to elucidate the key factors affecting the occurrence, degree, and temporal stability of FINE. Specifically, we examined the effect of the length, width, and growth orientation of single ZnO NRs on the NR-enhanced biomolecular emission profile after decorating the NR surfaces with different amounts and types of fluorophore-coupled protein molecules. We quantitatively and qualitatively profiled the biomolecular fluorescence signal from individual ZnO NRs as a function of both position along the NR long axis and time. Regardless of the physical dimensions and growth orientations of the NRs, we confirmed the presence of FINE in all ZnO NRs tested by using a range of protein concentrations. We also showed that the manifestation of FINE is not dependent on the spectroscopic signatures of the fluorophores employed. We further observed that the degree of FINE is dependent on the length of the NR with longer NRs showing increased levels of FINE. We also demonstrated that vertically oriented NRs exhibit much stronger fluorescence intensity at the NR ends and a higher level of FINE than the laterally oriented NRs. Additionally, we employed finite-difference time-domain (FDTD) methods to understand the experimental outcomes and to promote our understanding of the mechanism of FINE. Particularly, we utilized the electrodynamic simulations to examine both near field and far-field emission characteristics when considering various scenarios of fluorophore locations, polarizations, spectroscopic characteristics, and NR dimensions. Our efforts may provide deeper insight into the unique optical phenomenon of FINE and further be beneficial to highly miniaturized biodetection favoring the use of single ZnO NRs in low-volume and high-throughput protein assays. PMID- 25504320 TI - Influence of the motion correction algorithm on the quality and interpretability of images of single-source 64-detector coronary CT angiography among patients grouped by heart rate. AB - PURPOSE: We retrospectively investigated the effect of the motion correction algorithm (MCA) on image quality and interpretability by heart rate (HR) in coronary CT angiography (CCTA). MATERIALS AND METHODS: For 105 patients (6 HR groups) undergoing CCTA, 2 readers independently graded the image quality of the 4 major coronary arteries reconstructed with and without MCA at diastole with HR <=64 bpm and at systole and diastole >=65 bpm using a 5-point scale. For each HR group and cardiac phase, we compared per-vessel and per-segment image quality using Wilcoxon signed rank test and percentages of interpretable image quality (scores 3-5) among without MCA at diastole with HR <=64 bpm, as a reference, with MCA at diastole <=69 bpm and at systole 70-79 bpm using the chi-square test. RESULTS: The motion correction algorithm reconstruction provided similar or better image quality and interpretability in all groups, with 96-100 % per-vessel (P = 0.008 for the right coronary artery; otherwise, P > 0.05) and 99 % per segment interpretable image quality (P = 0.0002) at diastole with HR <=69 bpm and at systole 70-79 bpm compared to the reference (88-100 and 97 %, respectively). CONCLUSION: MCA reconstruction preserved image quality and interpretability of CCTA with HR <=79 bpm. PMID- 25504321 TI - A coiled-coil domain acts as a molecular ruler to regulate O-antigen chain length in lipopolysaccharide. AB - Long-chain bacterial polysaccharides have important roles in pathogenicity. In Escherichia coli O9a, a model for ABC transporter-dependent polysaccharide assembly, a large extracellular carbohydrate with a narrow size distribution is polymerized from monosaccharides by a complex of two proteins, WbdA (polymerase) and WbdD (terminating protein). Combining crystallography and small-angle X-ray scattering, we found that the C-terminal domain of WbdD contains an extended coiled-coil that physically separates WbdA from the catalytic domain of WbdD. The effects of insertions and deletions in the coiled-coil region were analyzed in vivo, revealing that polymer size is controlled by varying the length of the coiled-coil domain. Thus, the coiled-coil domain of WbdD functions as a molecular ruler that, along with WbdA:WbdD stoichiometry, controls the chain length of a model bacterial polysaccharide. PMID- 25504322 TI - 5-Formylcytosine alters the structure of the DNA double helix. AB - The modified base 5-formylcytosine (5fC) was recently identified in mammalian DNA and might be considered to be the 'seventh' base of the genome. This nucleotide has been implicated in active demethylation mediated by the base excision repair enzyme thymine DNA glycosylase. Genomics and proteomics studies have suggested an additional role for 5fC in transcription regulation through chromatin remodeling. Here we propose that 5fC might affect these processes through its effect on DNA conformation. Biophysical and structural analysis revealed that 5fC alters the structure of the DNA double helix and leads to a conformation unique among known DNA structures including those comprising other cytosine modifications. The 1.4-A resolution X-ray crystal structure of a DNA dodecamer comprising three 5fCpG sites shows how 5fC changes the geometry of the grooves and base pairs associated with the modified base, leading to helical underwinding. PMID- 25504324 TI - Loneliness in the elderly is associated with the use of psychotropic drugs. AB - OBJECTIVE: The aim of this study was to evaluate the association between loneliness in elderly people with the use of psychotropic drugs. METHODS: A subsample of 3111 participants (ages 55-85) of the large population-based German ESTHER study was included in the study. Loneliness was measured by using a three item questionnaire. Two subgroups were defined according to their degrees of loneliness. Psychotropic drugs were categorized by study doctors. Logistic regression analyses were conducted to determine the association between loneliness subgroups and the use of psychotropic drugs adjusted for psychosocial variables, multimorbidity, depression, anxiety, and somatic symptom severity. RESULTS: Of the participants 14.1% (95%-CI = [12.9; 15.4]) were estimated to have a high degree of loneliness (women > men); 19% (95%-CI = [17.6; 20.4]) of the participants used psychotropic drugs, 8.4% (95%-CI = [7.5; 9.5]) antidepressants. Logistic regression analysis showed that more lonely participants had significantly higher odds for using psychotropic drugs (OR: 1.495; 95%-CI = [1.121; 1.993]). Depression severity, somatic symptom severity, and female gender were also positively associated with the use of psychotropic drugs. CONCLUSION: A high degree of subjective loneliness in the elderly is associated with the use of psychotropic drugs, even after adjustment for somatic and psychological comorbidities and psychosocial variables. PMID- 25504325 TI - Total syntheses and in vivo quantitation of novel neurofuran and dihomo-isofuran derived from docosahexaenoic acid and adrenic acid. AB - Neurofurans (NeuroFs) and dihomo-isofurans (dihomo-IsoFs) are produced in vivo by non-enzymatic free-radical pathways from docosahexaenoic and adrenic acids, respectively. As these metabolites are produced in minute amounts, their analyses in biological samples remain challenging. Syntheses of neurofuran and dihomo isofurans described are based on a pivotal strategy, thanks to an enantiomerically enriched intermediate, which allowed, for the first time, access to both families: the alkenyl and enediol. Owing to this formation, quantitation of specific NeuroF and dihomo-IsoFs in biological samples was attainable. PMID- 25504323 TI - Human cells contain natural double-stranded RNAs with potential regulatory functions. AB - Recent evidence has suggested the existence of sense-antisense transcription in mammals, but the existence of double-stranded RNAs endowed with biological function has remained elusive. Herein we show that hundreds of putative natural double-stranded RNAs (ndsRNAs) are expressed from interspersed genomic locations and respond to cellular cues. We demonstrate that a subset of ndsRNAs localize in the nucleus and, in their double-stranded form, interact with nuclear proteins. Detailed characterization of an ndsRNA (nds-2a) revealed that this molecule displays differential localization throughout the cell cycle and directly interacts with RCC1 and RAN and, through the latter, with the mitotic RANGAP1 SUMO1-RANBP2 complex. Notably, altering nds-2a levels led to postmitotic abnormalities, mitotic catastrophe and cell death, thus supporting a mitosis related role. Altogether, our study reveals a hitherto-unrecognized class of RNAs that potentially participate in major biological processes in human cells. PMID- 25504326 TI - Developmental insights into the pathology of and therapeutic strategies for DM1: Back to the basics. AB - Myotonic Dystrophy type 1 (DM1), the most prevalent adult onset muscular dystrophy, is a trinucleotide repeat expansion disease caused by CTG expansion in the 3'-UTR of DMPK gene. This expansion results in the expression of toxic gain of-function RNA that forms ribonuclear foci and disrupts normal activities of RNA binding proteins belonging to the MBNL and CELF families. Changes in alternative splicing, translation, localization, and mRNA stability due to sequestration of MBNL proteins and up-regulation of CELF1 are key to DM1 pathology. However, recent discoveries indicate that pathogenic mechanisms of DM1 involves many other factors as well, including repeat associated translation, activation of PKC dependent signaling pathway, aberrant polyadenylation, and microRNA deregulation. Expression of the toxic repeat RNA culminates in the developmental remodeling of the transcriptome, which produces fetal isoforms of proteins that are unable to fulfill the physiological requirements of adult tissues. This review will describe advances in the understanding of DM1 pathogenesis as well as current therapeutic developments for DM1. PMID- 25504327 TI - Expression of hepatocyte growth factor and c-Met in non-small-cell lung cancer and association with lymphangiogenesis. AB - Previous experimental studies have demonstrated that hepatocyte growth factor (HGF) and its receptor c-Met serve an important function in lymphangiogenesis, but their biological functions in malignant tumors have remained elusive. The present study aimed to investigate the expression patterns of HGF-alpha and c-Met and their association with vascular endothelial growth factor (VEGF)-C, lymphatic vessel density and lymph node metastasis in non-small-cell lung cancer (NSCLC). In the present study, the lymphatic microvessel density (LMVD) and the expression levels of HGF-alpha, its receptor c-Met and VEGF-C were determined in 113 human NSCLC tissues and 113 normal lung tissue samples, using immunohistochemical staining. As a result, it was determined that the expression levels of HGF-alpha, c-Met and VEGF-C were significantly higher in NSCLC tissues than those in normal lung tissues (HGF-alpha, 67.3 vs. 20.4%, P<0.001; c-Met, 74.3 vs. 23.0%, P<0.001; and VEGF-C, 65.5 vs. 23.9%, P<0.001). HGF-alpha expression was observed to be significantly associated with that of VEGF-C (r=0.234, P=0.012) or c-Met (r=0.648, P<0.001). In addition, there was a positive correlation between the expression levels of VEGF-C and c-Met (r=0.224, P=0.017). In NSCLC tissues, the expression of HGF-alpha, c-Met or VEGF-C was significantly correlated with the LMVD (P=0.045, 0.002 and 0.001, respectively), and lymph node metastasis was more common in HGF-alpha, c-Met or VEGF-C-positive groups (P=0.020, 0.020 and 0.009, respectively). In addition, the HGF-alpha or VEGF-C-positive groups presented shorter survival time periods. In conclusion, the expression of HGF-alpha or c Met was closely correlated with VEGF-C, LMVD and metastases of lymph nodes, indicating that HGF-alpha, c-Met and VEGF-C may perform important and collaborative actions in lymphangiogenesis and lymphatic metastasis of primary NSCLC. PMID- 25504330 TI - Improving long-term weight loss maintenance: can we do it? PMID- 25504332 TI - Evolution of hidden localized flow during glass-to-liquid transition in metallic glass. AB - For glasses, the structural origin of their flow phenomena, such as elastic and plastic deformations especially the microscopic hidden flow before yield and glass-to-liquid transition (GLT), is unclear yet due to the lack of structural information. Here we investigate the evolution of the microscopic localized flow during GLT in a prototypical metallic glass combining with dynamical mechanical relaxations, temperature-dependent tensile experiments and stress relaxation spectra. We show that the unstable and high mobility nano-scale liquid-like regions acting as flow units persist in the glass and can be activated by either temperature or external stress. The activation of such flow units is initially reversible and correlated with beta-relaxation. As the proportion of the flow units reaches a critical percolation value, a mechanical brittle-to-ductile transition or macroscopic GLT happens. A comprehensive picture on the hidden flow as well as its correlation with deformation maps and relaxation spectrum is proposed. PMID- 25504329 TI - Response-dependent dynamics of cell-specific inhibition in cortical networks in vivo. AB - In the visual cortex, inhibitory neurons alter the computations performed by target cells via combination of two fundamental operations, division and subtraction. The origins of these operations have been variously ascribed to differences in neuron classes, synapse location or receptor conductances. Here, by utilizing specific visual stimuli and single optogenetic probe pulses, we show that the function of parvalbumin-expressing and somatostatin-expressing neurons in mice in vivo is governed by the overlap of response timing between these neurons and their targets. In particular, somatostatin-expressing neurons respond at longer latencies to small visual stimuli compared with their target neurons and provide subtractive inhibition. With large visual stimuli, however, they respond at short latencies coincident with their target cells and switch to provide divisive inhibition. These results indicate that inhibition mediated by these neurons is a dynamic property of cortical circuits rather than an immutable property of neuronal classes. PMID- 25504333 TI - Anti-apoptotic and anti-glycative effects of asiatic acid in the brain of D galactose treated mice. AB - Protection of asiatic acid (AA) in mice brain against D-galactose (DG) induced aging was examined. AA at 5, 10 or 20 mg kg(-1) per day was supplied to DG treated mice for 8 weeks. AA intake at 10 or 20 mg kg(-1) per day increased its deposit in brain. DG treatment increased Bax, cleaved caspase-3 protein expression and decreased Bcl-2 expression. AA intake at 10 and 20 mg kg(-1) per day declined Bax, cleaved caspase-3 expression, and retained Bcl-2 expression. DG treatment decreased brain glutathione content and glutathione peroxidase activity; increased brain reactive oxygen species and protein carbonyl levels, and enhanced NAPDH oxidase expression. AA intake at test doses reversed these changes. DG treatment up-regulated the expression of advanced glycation end product (AGE), carboxymethyllysine, receptor of AGE (RAGE), mitogen-activated protein kinases and CD11b as well as increasing the interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha release in the brain. AA intake at 5, 10 and 20 mg kg(-1) per day lowered AGE and carboxymethyllysine expression, and at 10 and 20 mg kg(-1) per day reduced RAGE production. AA intake dose-dependently suppressed p-p38 expression and lowered IL-6 and TNF-alpha levels, and at 10 and 20 mg kg( 1) per day down-regulated p-JNK and CD11b expression. DG treatment declined brain derived neurotropic factor (BDNF) expression and raised glial fibrillary acidic protein (GFAP) expression. AA intake at 20 mg kg(-1) per day retained BDNF expression and at 10 and 20 mg kg(-1) per day reduced GFAP expression. These findings indicated that the supplement of asiatic acid might be beneficial to the prevention or alleviation of brain aging. PMID- 25504334 TI - Transplantation for juvenile myelomonocytic leukemia: a retrospective study of 30 children treated with a regimen of busulfan, fludarabine, and melphalan. AB - We report the outcomes of 30 patients with juvenile myelomonocytic leukemia (JMML) who received unmanipulated hematopoietic stem cell transplantation (HSCT) with oral or intravenous busulfan, fludarabine, and melphalan between 2001 and 2011. Mutations in PTPN11 were detected in 15 patients. Six patients received human leukocyte antigen (HLA)-matched HSCT from related donors, and 24 patients received HSCT from alternative donors, including 13 HLA-mismatched donors. Primary engraftment failed in five patients, all of whom had received allografts from HLA-mismatched donors. HLA-mismatched HSCT resulted in poorer event-free survival than HLA-matched HSCT (28.8 vs. 70.6 %). Three patients died of transplantation-related causes, and eight patients experienced hematological relapse (including five patients who died due to disease progression). Eight patients received a second HSCT, and four of these patients have survived. The 5 year estimated overall survival for all patients was 72.4: 88.9 % for the patients without a mutation in PTPN11 (n = 10) and 58.3 % for the patients with a mutation in PTPN11 (n = 15) (P = 0.092). The conditioning regimen reported in the present study achieved hematological and clinical remission in >50 % of patients with JMML who received HSCT from alternative donors, and may also be effective for JMML patients with PTPN11 mutation. PMID- 25504337 TI - Monte Carlo simulations of the phase separation of a copolymer blend in a thin film. AB - Monte Carlo simulations were carried out to study the phase separation of a copolymer blend comprising an alternating copolymer and/or block copolymer in a thin film, and a phase diagram was constructed with a series of composed recipes. The effects of composition and segregation strength on phase separation were discussed in detail. The chain conformation of the block copolymer and alternating copolymer were investigated with changes of the segregation strength. Our simulations revealed that the segment distribution along the copolymer chain and the segregation strength between coarse-grained beads are two important parameters controlling phase separation and chain conformation in thin films of a copolymer blend. A well-controlled phase separation in the copolymer blend can be used to fabricate novel nanostructures. PMID- 25504338 TI - Ambient temperature synthesis of beta,beta'-fused nickel(II) pyrrolo[1,2 a]pyrazinoporphyrins via a DBSA-catalyzed Pictet-Spengler approach. AB - A facile first synthetic strategy to construct novel pi-extended beta,beta'-fused nickel(II) pyrrolo[1,2-a]pyrazinoporphyrins has been developed via a Pictet Spengler reaction of newly prepared nickel(II) 2-amino-3-(pyrrol-1-yl)-5,10,15,20 tetraphenylporphyrin with various aromatic, aliphatic or heterocyclic aldehydes in the presence of 10 mol% p-dodecylbenzenesulfonic acid (DBSA) as an efficient Bronsted acid catalyst in 1,4-dioxane at 25 degrees C. A variety of these pi extended porphyrin analogues were obtained in moderate to good yields under mild conditions and characterized on the basis of spectral data and single crystal X ray analysis. PMID- 25504336 TI - Abscission of flowers and floral organs is closely associated with alkalization of the cytosol in abscission zone cells. AB - In vivo changes in the cytosolic pH of abscission zone (AZ) cells were visualized using confocal microscopic detection of the fluorescent pH-sensitive and intracellularly trapped dye, 2',7'-bis-(2-carboxyethyl)-5(and-6) carboxyfluorescein (BCECF), driven by its acetoxymethyl ester. A specific and gradual increase in the cytosolic pH of AZ cells was observed during natural abscission of flower organs in Arabidopsis thaliana and wild rocket (Diplotaxis tenuifolia), and during flower pedicel abscission induced by flower removal in tomato (Solanum lycopersicum Mill). The alkalization pattern in the first two species paralleled the acceleration or inhibition of flower organ abscission induced by ethylene or its inhibitor 1-methylcyclopropene (1-MCP), respectively. Similarly, 1-MCP pre-treatment of tomato inflorescence explants abolished the pH increase in AZ cells and pedicel abscission induced by flower removal. Examination of the pH changes in the AZ cells of Arabidopsis mutants defective in both ethylene-induced (ctr1, ein2, eto4) and ethylene-independent (ida, nev7, dab5) abscission pathways confirmed these results. The data indicate that the pH changes in the AZ cells are part of both the ethylene-sensitive and -insensitive abscission pathways, and occur concomitantly with the execution of organ abscission. pH can affect enzymatic activities and/or act as a signal for gene expression. Changes in pH during abscission could occur via regulation of transporters in AZ cells, which might affect cytosolic pH. Indeed, four genes associated with pH regulation, vacuolar H(+)-ATPase, putative high-affinity nitrate transporter, and two GTP-binding proteins, were specifically up-regulated in tomato flower AZ following abscission induction, and 1-MCP reduced or abolished the increased expression. PMID- 25504335 TI - Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis. AB - Systemic sclerosis (SSc) is manifested by fibrosis, vasculopathy and immune dysregulation. So far, a unifying hypothesis underpinning these pathological events remains unknown. Given that SSc is a multifactorial disease caused by both genetic and environmental factors, we focus on the two transcription factors, which modulate the fibrotic reaction and are epigenetically suppressed in SSc dermal fibroblasts, Friend leukaemia integration 1 (Fli1) and Kruppel-like factor 5 (KLF5). In addition to the Fli1 silencing-dependent collagen induction, the simultaneous knockdown of Fli1 and KLF5 synergistically enhances expression of connective tissue growth factor. Notably, mice with double heterozygous deficiency of Klf5 and Fli1 mimicking the epigenetic phenotype of SSc skin spontaneously recapitulate all the three features of SSc, including fibrosis and vasculopathy of the skin and lung, B-cell activation and autoantibody production. These studies implicate the epigenetic downregulation of Fli1 and KLF5 as a central event triggering the pathogenic triad of SSc. PMID- 25504339 TI - Quantitation with chemical tagging reagents in biomarker studies. AB - Isobaric tags for relative and absolute quantitation (iTRAQ), Tandem Mass Tags (TMT) and related chemical tag reagents provide analytical platforms for quantitative proteomics applied to clinical samples. In this Viewpoint article, applications for discovery and targeted modes are discussed with an emphasis on study design and technical considerations in biomarker analysis. The evolution and promise of emerging, related strategies are also discussed. It should be noted that iTRAQ and TMT users contributed to the key debates in the biomarker field, to define strategies for biomarker discovery for identification of clinical biomarkers, and continue to inform design of verification and validation assays via implementation of non-isobaric variants for targeted analyses. PMID- 25504340 TI - Emulsion ripening through molecular exchange at droplet contacts. AB - Two coarsening mechanisms of emulsions are well established: droplet coalescence (fusion of two droplets) and Ostwald ripening (molecular exchange through the continuous phase). Here a third mechanism is identified, contact ripening, which operates through molecular exchange upon droplets collisions. A contrast manipulated small-angle neutron scattering experiment was performed to isolate contact ripening from coalescence and Ostwald ripening. A kinetic study was conducted, using dynamic light scattering and monodisperse nanoemulsions, to obtain the exchange key parameters. Decreasing the concentration or adding ionic repulsions between droplets hinders contact ripening by decreasing the collision frequency. Using long surfactant chains and well-hydrated heads inhibits contact ripening by hindering fluctuations in the film. Contact ripening can be controlled by these parameters, which is essential for both emulsion formulation and delivery of hydrophobic ingredients. PMID- 25504341 TI - The rise of the medical scribe industry: implications for the advancement of electronic health records. PMID- 25504346 TI - Percutaneous left main coronary artery stent for acute myocardial ischemia after repaired ALCAPA. AB - Percutaneous coronary artery stent angioplasty is rare in the pediatric population but can be a life-saving by rapidly reestablishing flow to an obstructed coronary artery. It is a technically challenging and high-risk procedure in infants and further limited by the need for future surgical intervention. We report of an infant with anomalous left coronary artery from the pulmonary artery who underwent acutely successful surgical reimplantation of the left coronary artery onto the ascending aorta. One month later, she developed acute myocardial ischemia and emergent catheterization diagnosed near-total occlusion of the left coronary artery. We implanted a 2.5 mm coronary stent in the left main coronary artery with reestablishment of flow. The patient's left ventricular systolic function recovered within 4 weeks and repeat angiography 3 months later showed complete normalization of the entire left coronary artery system. The patient weighed 3 kg and was < 6 weeks of age at the time of stent implantation which to our knowledge is the smallest and youngest reported patient to undergo coronary stent angioplasty. This case supports the feasibility of this procedure in infants as a temporizing solution to hemodynamic instability from myocardial ischemia due to coronary artery stenosis. The left ventricular systolic function remained normal at 7 months after stent placement and the patient was clinically well from a cardiac perspective. PMID- 25504348 TI - On a charitable mission. AB - Volunteer physicians answered the call over the summer to care for Central American immigrants crossing the border from Mexico into Texas. Nearly 100,000 unaccompanied minors and families flooded into the United States from October 2013 to August 2014. PMID- 25504347 TI - Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin. AB - Poly(ADP-ribose) polymerase (PARP) inhibitors enhance the effect of DNA alkylating agents on BRCA1- and BRCA2-deficient cell lines. The aim of this study was to analyze the effect of the PARP inhibitor nicotinamide (NAM) on breast cancer cells with different BRCA1 expression or function, such as BRCA1-deficient MDA-MB-436 cells, low expression BRCA1 MCF-7 cells, and the BRCA1 wild-type MDA MB-231 cells, to demonstrate its effects as a chemo- or radiosensitizing agent. PARP activity was analyzed in MDA-MB-436, MCF-7 and MDA-MB-231 breast cancer cells subjected or not to NAM. Inhibition of PARP by NAM in the presence of DNA damage was examined by Alexa Fluor 488 immunofluorescence. Crystal violet assays were used to test growth inhibition and the chemo- and radiosensitization effects of NAM were investigated using clonogenic assays. Significant differences among data sets were determined using two-tailed ANOVA and Bonferroni tests. We demonstrated that NAM reduces PARP activity in vitro, and in cells subjected or not to DNA damage, it also reduces the viability of breast cancer cell lines and synergyzes the cytotoxicity of cisplatin in MDA-MB-436 and MCF-7 cells. Downregulation of PARP1 with siRNA led to modest growth inhibition, which was further increased by cisplatin. Nicotinamide also induced radiosensitization in MDA-MB-436 and MDA-MB-231 cells. In conclusion, NAM may be used as a chemo- or radiosensitizing agent regardless of the BRCA1 status in breast cancer. PMID- 25504349 TI - Back to work. AB - Ryan Brannan, new commissioner of the Texas Division of Workers' Compensation, plans to build on the efficiencies created by earlier workers' compensation system reforms, recognizing that one of the best ways to get injured employees back to work is to "get physicians active and involved." PMID- 25504350 TI - Survey results are in. PMID- 25504351 TI - Hand in hand. PMID- 25504352 TI - Equal justice for all. PMID- 25504353 TI - Money over matter? PMID- 25504354 TI - Physician, heal thyself: health maintenance behaviors among physicians. AB - The goal of this article is to assess the need for health maintenance intervention programs directed at physicians and patients. We compared the health maintenance behavior compliance of physicians (as patients) to a control patient population. An online survey was sent to the Texas Tech University Health Sciences Center (TTUHSC) medical school clinical and nonclinical basic science faculties and to the non-TTUHSC clinicians of the local county medical society. The survey included questions regarding basic demographics and recent participation in regular health maintenance strategies including annual checkup, influenza vaccination, colonoscopy, Pap smear, and mammogram. Logistic regressions were conducted to determine if being a physician had a significant association with the likelihood of participating in the health maintenance behavior outcomes listed above. This article shows that physicians are less likely than the general population to adhere to specific health maintenance guidelines: namely, annual checkups, colonoscopies, and mammograms. Pap smear rates did not differ between physicians and a control population, but physicians showed an increased likelihood of receiving an influenza vaccine. PMID- 25504356 TI - Silver nanowires as receiving-radiating nanoantennas in plasmon-enhanced up conversion processes. AB - We demonstrate efficient coupling between plasmons in a single silver nanowire and nanocrystals doped with rare earth ions, alpha-NaYF4:Er(3+)/Yb(3+). Plasmonic interaction results in a sevenfold increase of the up-converted emission of nanocrystals located in the vicinity of the nanowires as well as much faster luminescence decays. The enhancement of the emission can be precisely controlled by the polarization of the excitation laser and is significantly stronger for polarization parallel to the nanowire antennas. Imaging of angular-resolved emission patterns in the Fourier plane reveals plasmon-mediated luminescence, where the up-converted radiation is emitted via the nanowire antennas as leakage radiation. PMID- 25504355 TI - Ethical perspectives on translational pharmacogenetic research involving children. AB - Children represent a special population characterized by dynamic changes which may affect drug safety and efficacy. The interplay of pharmacogenetics with physiological alterations that occur throughout development is an area of increasing research focus. Given the translational nature of pharmacogenetic research, it is possible that pharmacogenetic research results may possess clinically actionable information. The potential long-term implications of pharmacogenetic test results throughout the lifespan of the child, and the potential impact of the results for other members of the family need to be considered. Comprehensive counselling and communication strategies may need to be integrated as part of pharmacogenetic research studies in children. PMID- 25504357 TI - Infantile colic, regurgitation, and constipation: an early traumatic insult in the development of functional gastrointestinal disorders in children? AB - Functional gastrointestinal disorders (FGIDs) are defined as a variable combination of chronic or recurrent gastrointestinal symptoms not explained by structural or biochemical abnormalities. Infantile colic, gastroesophageal reflux, and constipation are the most common FGIDs that lead to referral to a pediatrician during the first 6 months of life and are often responsible for hospitalization, feeding changes, use of drugs, parental anxiety, and loss of parental working days with relevant social consequences. We performed a retrospective study on patients referred for recurrent abdominal pain from January 2002 trough December 2009 to our Pediatric Gastroenterology Outpatient Unit. The population studied was matched with healthy control without history of recurrent abdominal pain, enrolled among pediatricians practicing primary health care. History of infantile colic, regurgitation, and functional constipation was detected respectively in 26.41, 25.31, and 30.16% of children diagnosed with FGIDs compared to 11.34, 12.85, and 11.76% of healthy children. CONCLUSION: According to our data, children with a history of gastrointestinal infantile distress have a higher prevalence of FGIDs years later. PMID- 25504358 TI - High levels of virus replication and an intense inflammatory response contribute to the severe pathology in lymphoid tissues caused by Newcastle disease virus genotype VIId. AB - Some strains of Newcastle disease virus (NDV) genotype VIId cause more-severe tissue damage in lymphoid organs compared to other virulent strains. In this study, we aim to define the mechanism of this distinct pathological manifestation of genotype VII viruses. Pathology, virus replication, and the innate immune response in lymphoid tissues of chickens infected with two genotype VIId NDV strains (JS5/05 and JS3/05), genotype IX NDV F48E8 and genotype IV NDV Herts/33, were compared. Histopathologic examination showed that JS5/05 and JS3/05 produced more-severe lesions in the spleen and thymus, but these four virulent strains caused comparable mild lesions in the bursa. In addition, JS3/05 and JS5/05 replicated at significantly higher levels in the lymphatic organs than F48E8 and Herts/33. A microarray assay performed on the spleens of chickens infected with JS5/05 or Herts/33 revealed that JS5/05 elicited a more potent inflammatory response by increasing the number and expression levels of activated genes. Moreover, cytokine gene expression profiling showed that JS5/05 and JS3/05 induced a stronger cytokine response in lymphoid tissues compared to F48E8 and Herts/33. Taken together, our results indicate that the severe pathology in immune organs caused by genotype VIId NDV strains is associated with high levels of virus replication and an intense inflammatory response. PMID- 25504359 TI - Phylogenetic analysis of infectious pancreatic necrosis virus in Ireland reveals the spread of a virulent genogroup 5 subtype previously associated with imports. AB - Infectious pancreatic necrosis is a significant disease of farmed salmonids resulting in direct economic losses due to high mortality and disease-management costs. Significant outbreaks of the disease occurred in farmed Atlantic salmon in Ireland between 2003 and 2007, associated with imported ova and smolts. As the virus was known to occur in the country since the development of aquaculture in the 1980s, this study examined archived samples to determine whether these older isolates were associated with virulent forms. The study showed that two genotypes of IPNV were present in the 1990s, genotype 3 and genotype 5. A more virulent subtype of the virus first appeared in 2003 associated with clinical outbreaks of IPN, and this subtype is now the most prevalent form of IPNV found in the country. The data also indicated that IPNV in Ireland is more closely related to Scottish and continental European isolates than to Norwegian, Chilean and Australasian genogroup 5 isolates. PMID- 25504360 TI - Epidemical features of HAdV-3 and HAdV-7 in pediatric pneumonia in Chongqing, China. AB - Human adenoviruses (HAdV) of species B, C, and E (HAdV-B, -C, -E) are frequent causative agents of acute respiratory infections worldwide. No specific analysis has been done on the epidemiological and clinical features of HAdV in pediatric pneumonia in China. Nasopharyngeal aspirates were collected from hospitalized children with pneumonia from June 2009 to May 2014. All samples that tested positive for HAdV were typed by sequencing the hexon and fiber genes. From a total of 3089 samples, 208 (6.7 %) were positive for HAdV, identified as belonging to HAdV-B (186, 89.4 %), HAdV-C (9, 4.3 %) and HAdV-E (1, 0.5 %). HAdV 7 (104, 50.0 %) and HAdV-3 (78, 37.5 %) were the two major types, followed by HAdV-1, HAdV-55 and HAdV-14. There were 87 (41.8 %) single HAdV infections, of which 80 % were HAdV-7 infections. Multivariate analysis showed that single infections with HAdV-7 were associated with a higher prevalence of severe pneumonia. Temporal patterns showed that, except for a simultaneous outbreak of HAdV-3 and HAdV-7 during the years 2010-2011, HAdV-7 and HAdV-3 were alternately predominant, and the dominance shifted to HAdV-3 after 2014. Identification of the predominant HAdV genotypes and their epidemical features is useful for determining preventive strategies. HAdV-7 associated severe pneumonia needs to be considered with high priority in clinical practice. PMID- 25504361 TI - The gene expression profile of porcine alveolar macrophages infected with a highly pathogenic porcine reproductive and respiratory syndrome virus indicates overstimulation of the innate immune system by the virus. AB - Since the highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) variant emerged in 2006, it has caused death in more than 20 million pigs in China and other Southeast Asian countries, making it the most destructive swine pathogen currently in existence. To characterize the cellular responses to HP-PRRSV infection, the gene expression profile of porcine alveolar macrophage (PAM) cells, the primary target cells of PRRSV, was analyzed in HP-PRRSV-infected and uninfected PAMs by suppression subtractive hybridization. After confirmation by Southern blot, genes that were differentially expressed in the HP-PRRSV infected and uninfected PAMs were sequenced and annotated. Genes that were upregulated mainly in HP-PRRSV-infected PAM cells were related to immunity and cell signaling. Among the differentially expressed genes, Mx1 and HSP70 protein expression was confirmed by western blotting, and IL-8 expression was confirmed by ELISA. In PAM cells isolated from HP-PRRSV-infected piglets, the differential expression of 21 genes, including IL-16, TGF-beta type 1 receptor, epidermal growth factor, MHC-I SLA, Toll-like receptor, hepatoma-derived growth factor, FTH1, and MHC-II SLA-DRB1, was confirmed by real-time PCR. To our knowledge, this is the first study to demonstrate differential gene expression between HP-PRRSV infected and uninfected PAMs in vivo. The results indicate that HP-PRRSV infection excessively stimulates genes involved in the innate immune response, including proinflammatory cytokines and chemokines. PMID- 25504362 TI - Idiopathic calcium nephrolithiasis: a review of pathogenic mechanisms in the light of genetic studies. AB - BACKGROUND: Calcium nephrolithiasis is a multifactorial disease with a polygenic milieu. Association studies identified genetic polymorphisms potentially implicated in the pathogenesis of calcium nephrolithiasis. The present article reviews the mechanisms of calcium stone formation and the potential contribution of gene polymorphisms to lithogenic mechanisms. SUMMARY: Endoscopy observations suggested that precipitation of calcium-oxalate on the Randall's plaque at the papilla surface may cause idiopathic calcium-oxalate stones. The Randall's plaque is a hydroxyapatite deposit in the interstitium of the kidney medulla, which resembles a soft tissue calcification. Conversely, calcium-phosphate stones may develop from crystalline deposits located at the tip of the Bellini duct. Polymorphisms of eleven genes have been associated with stones in genome-wide association studies and replicated candidate-gene association studies: VDR, SLC34A1, SLC34A4, CLDN14, and CaSR genes coding for proteins regulating tubular phosphate and calcium reabsorption; CaSR, MGP, OPN, PLAU, and UMOD genes coding for proteins preventing calcium salt precipitation; AQP1 gene coding for a water channel in the proximal tubule. The renal activity of the last gene, DGKH, is unknown. Polymorphisms in these genes may predispose to calcium-oxalate and phosphate stones by increasing the risk of calcium-phosphate precipitation in the tubular fluid. Key Messages: Genetic findings suggest that tubular fluid supersaturation with respect to calcium and phosphate predisposes to calcium oxalate stones by triggering cellular mechanisms that lead to the Randall's plaque formation. PMID- 25504364 TI - Ternary Sn-Ti-O based nanostructures as anodes for lithium ion batteries. AB - SnO(x) (x = 0, 1, 2) and TiO(2) are widely considered to be potential anode candidates for next generation lithium ion batteries. In terms of the lithium storage mechanisms, TiO(2) anodes operate on the base of the Li ion intercalation deintercalation, and they typically display long cycling life and high rate capability, arising from the negligible cell volume change during the discharge charge process, while their performance is limited by low specific capacity and low electronic conductivity. SnO(x) anodes rely on the alloying-dealloying reaction with Li ions, and typically exhibit large specific capacity but poor cycling performance, originating from the extremely large volume change and thus the resultant pulverization problems. Making use of their advantages and minimizing the disadvantages, numerous strategies have been developed in the recent years to design composite nanostructured Sn-Ti-O ternary systems. This Review aims to provide rational understanding on their design and the improvement of electrochemical properties of such systems, including SnO(x) -TiO(2) nanocomposites mixing at nanoscale and nanostructured Sn(x) Ti(1-x) O(2) solid solutions doped at the atomic level, as well as their combinations with carbon based nanomaterials. PMID- 25504366 TI - Comparison of proctocolectomy and ileal pouch-anal anastomosis to colectomy and ileorectal anastomosis in familial adenomatous polyposis. AB - Prophylactic surgical options for familial adenomatous polyposis (FAP) are either colectomy and ileorectal anastomosis (IRA) or proctocolectomy and ileal pouch anal anastomosis (IPAA). The aim of this study was to analyse the short-term and long-term outcomes of these two operative techniques. All patients with FAP in Finland have been prospectively recorded in a database since 1963 were retrospectively reviewed in this analysis. Altogether 140 (61%) colectomies with IRA and 88 (39%) proctocolectomies with IPAA have been performed. Complications occurred in 28 (21%) patients after IRA and in 26 (30%) patients after IPAA. There were 15 (11%) severe complications for IRA and 5 (6%) for IPAA. Twenty-one (15%) patients of the IRA group ended up in conventional ileostomy whereas 3 (3.4%) patients of the IPAA group had their ileal reservoir converted to an ileostomy (p = 0.01). Cumulative survival for IRA was lower than for the IPAA (p = 0.03), but if accounting only for operations made after the IPAA era had commenced, there was no significant difference. IPAA was associated with improved long-term survival without an increase in postoperative complications. The risk of death after colectomy and IRA seemed to be predominantly related to the remaining risk of rectal cancer. Therefore, we favour proctocolectomy with IPAA as the prophylactic surgical procedure for FAP with intermediate or severe polyposis. PMID- 25504367 TI - Making the difference: integrating structural variation detection tools. AB - From prokaryotes to eukaryotes, phenotypic variation, adaptation and speciation has been associated with structural variation between genomes of individuals within the same species. Many computer algorithms detecting such variations (callers) have recently been developed, spurred by the advent of the next generation sequencing technology. Such callers mainly exploit split-read mapping or paired-end read mapping. However, as different callers are geared towards different types of structural variation, there is still no single caller that can be considered a community standard; instead, increasingly the various callers are combined in integrated pipelines. In this article, we review a wide range of callers, discuss challenges in the integration step and present a survey of pipelines used in population genomics studies. Based on our findings, we provide general recommendations on how to set-up such pipelines. Finally, we present an outlook on future challenges in structural variation detection. PMID- 25504365 TI - Browning of human adipocytes requires KLF11 and reprogramming of PPARgamma superenhancers. AB - Long-term exposure to peroxisome proliferator-activated receptor gamma (PPARgamma) agonists such as rosiglitazone induces browning of rodent and human adipocytes; however, the transcriptional mechanisms governing this phenotypic switch in adipocytes are largely unknown. Here we show that rosiglitazone-induced browning of human adipocytes activates a comprehensive gene program that leads to increased mitochondrial oxidative capacity. Once induced, this gene program and oxidative capacity are maintained independently of rosiglitazone, suggesting that additional browning factors are activated. Browning triggers reprogramming of PPARgamma binding, leading to the formation of PPARgamma "superenhancers" that are selective for brown-in-white (brite) adipocytes. These are highly associated with key brite-selective genes. Based on such an association, we identified an evolutionarily conserved metabolic regulator, Kruppel-like factor 11 (KLF11), as a novel browning transcription factor in human adipocytes that is required for rosiglitazone-induced browning, including the increase in mitochondrial oxidative capacity. KLF11 is directly induced by PPARgamma and appears to cooperate with PPARgamma in a feed-forward manner to activate and maintain the brite-selective gene program. PMID- 25504368 TI - Effects of raloxifene on bone metabolism in postmenopausal women on chronic hemodialysis. AB - BACKGROUND: Postmenopausal women with end-stage renal failure are at an increased risk of fracture because of the effects of secondary hyperparathyroidism and postmenopausal osteoporosis. In the present study, we investigated the feasibility of using raloxifene to prevent fractures in postmenopausal women with end-stage renal failure on hemodialysis. METHODS: This study was conducted using a multicenter, single-arm, prospective design. Raloxifene was administered to postmenopausal women aged >=50 years who were on maintenance hemodialysis and met any of the following criteria after a 24-week run-in period: an alkaline phosphatase level (bone formation marker) of >=6.18 ukat/L (>=370 U/L), a bone specific alkaline phosphatase (BAP; bone formation marker) level of >=0.59 ukat/L (>=35.4 U/L), or a bone-derived tartrate-resistant acid phosphatase (TRACP-5b; bone resorption marker) level of >=4.2 U/L. RESULTS: A total of 48 individuals were eligible for study inclusion. Of them, 30 individuals participated in this study. The BAP levels were significantly decreased at week 4, but returned to the baseline levels at week 24. Similarly, the TRACP-5b levels were significantly decreased at week 4, but returned to the baseline levels at week 24. The serum calcium value decreased consistently after the start of raloxifene therapy. The intact parathyroid hormone (iPTH) levels were likely increased at week 4. The ratio of BAP to iPTH levels and the ratio of TRACP-5b to iPTH levels both showed significant decreases over time. During the raloxifene therapy, no thrombosis or other drug-related adverse events developed. CONCLUSION: The study results indicated that raloxifene can transiently reduce the levels of bone metabolism markers and might be useful for preventing fractures in postmenopausal women with end-stage renal failure, although raloxifene use over the long term may not have adequate efficacy in the absence of appropriate concomitant active vitamin D therapy. PMID- 25504369 TI - Expression of age-related factors during the development of renal damage in patients with IgA nephropathy. AB - BACKGROUND: Chronic kidney disease patients share clinical and pathological features with the general aging population. Increased oxidative DNA damage, accumulation of cell cycle-arrested cells and decreased Klotho expression are assumed to be age-related factors that are reportedly linked to kidney disease. This study sought to determine the association between these age-related factors and renal damage in patients with IgA nephropathy (IgAN). METHODS: We performed a cross-sectional analysis of 71 patients who were diagnosed with IgAN by renal biopsy. Expression of 8-hydroxydeoxyguanosine (8-OHdG, a marker of oxidative DNA damage), p16 (a marker of cell cycle-arrest) and Klotho (an anti-aging protein) were evaluated by immunohistochemical staining of renal biopsy samples. We correlated the changes in expression of these markers with Lee's pathologic grades and the Oxford classification. We also investigated the independent association between these markers and interstitial fibrosis using multiple linear regression analysis. RESULTS: 8-OHdG and p16 increased but Klotho decreased with progression of pathologic grade. Expression of 8-OHdG and p16 increased with the deterioration of mesangial hypercellularity and segmental glomerulosclerosis. In addition, p16 increased but Klotho decreased with progression of tubular atrophy/interstitial fibrosis. In univariate regression analysis, age, body mass index, systolic blood pressure, urinary protein excretion and expression of 8 OHdG, p16 and Klotho showed significant correlations with interstitial fibrosis. Multivariable regression analyses revealed that aging, increased renal expression of p16 and decreased expression of Klotho were independently correlated with interstitial fibrosis. CONCLUSIONS: The age-related factors might play important roles in the development of IgAN. PMID- 25504372 TI - Development of carrier-based formulation of root endophyte Piriformospora indica and its evaluation on Phaseolus vulgaris L. AB - Endophytic fungi are plant beneficial rhizospheric microorganisms often applied as bioinoculants for enhanced and disease-free crop production. The objectives of the present work were to develop a carrier-based formulation of root endophyte Piriformospora indica as a bioinoculant. Powder formulation of four different carrier materials viz., talcum powder, clay, sawdust and bioboost (organic supplement) were evaluated and a talc-based formulation was optimized for a longer shelf life with respect to microbial concentration, storage temperature and biological activity. Finally the effect of optimized talc formulation on plant productivity was determined. The application dosages were optimized by studies on plant growth parameters of Phaseolus vulgaris L. plants under green house conditions. Five percent formulation (w/w) of talcum powder was observed to be the most stable at 30 degrees C with 10(8) CFU g(-1) and effective for a storage period of 6 months. The application of this optimized formulation resulted in increase of growth parameters of P. vulgaris L. and better adaptation of plants under green house conditions. PMID- 25504371 TI - Elevated Slit2 Activity Impairs VEGF-Induced Angiogenesis and Tumor Neovascularization in EphA2-Deficient Endothelium. AB - Angiogenic remodeling during embryonic development and in adult tissue homeostasis is orchestrated by cooperative signaling between several distinct molecular pathways, which are often exploited by tumors. Indeed, tumors upregulate proangiogenic molecules while simultaneously suppressing angiostatic pathways to recruit blood vessels for growth, survival, and metastatic spread. Understanding how cancers exploit proangiogenic and antiangiogenic signals is a key step in developing new, molecularly targeted antiangiogenic therapies. While EphA2, a receptor tyrosine kinase (RTK), is required for VEGF-induced angiogenesis, the mechanism through which these pathways intersect remains unclear. Slit2 expression is elevated in EphA2-deficient endothelium, and here it is reported that inhibiting Slit activity rescues VEGF-induced angiogenesis in cell culture and in vivo, as well as VEGF-dependent tumor angiogenesis, in EphA2 deficient endothelial cells and animals. Moreover, blocking Slit activity or Slit2 expression in EphA2-deficient endothelial cells restores VEGF-induced activation of Src and Rac, both of which are required for VEGF-mediated angiogenesis. These data suggest that EphA2 suppression of Slit2 expression and Slit angiostatic activity enables VEGF-induced angiogenesis in vitro and in vivo, providing a plausible mechanism for impaired endothelial responses to VEGF in the absence of EphA2 function. IMPLICATIONS: Modulation of angiostatic factor Slit2 by EphA2 receptor regulates endothelial responses to VEGF-mediated angiogenesis and tumor neovascularization. PMID- 25504373 TI - Production and cell surface display of recombinant anthrax protective antigen on the surface layer of attenuated Bacillus anthracis. AB - To investigate the surface display of the anthrax protective antigen (PA) on attenuated Bacillus anthracis, a recombinant B. anthracis strain, named AP429 was constructed by integrating into the chromosome a translational fusion harboring the DNA fragments encoding the cell wall-targeting domain of the S-layer protein EA1 and the anthrax PA. Crerecombinase action at the loxP sites excised the antibiotic marker. Western blot analysis, fluorescence-activated cell sorting and immunofluorescence analysis confirmed that PA was successfully expressed on the S layer of the recombinant antibiotic marker-free strain. Notwithstanding extensive proteolytic degradation of the hybrid protein SLHs-PA, quantitative ELISA revealed that approximately 8.1 * 10(6) molecules of SLHs-PA were gained from each Bacillus cell. Moreover, electron microscopy assay indicated that the typical S-layer structures could be clearly observed from the recombinant strain micrographs. PMID- 25504374 TI - Clinical outcome comparison between TIPS and EBL in patients with cirrhosis and portal vein thrombosis. AB - The aim of this study is to compare the clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) and endoscopic band ligation (EBL) in patients with cirrhosis and portal vein thrombosis (PVT). We retrospectively reviewed the January to September 2010 data from our database and included 25 patients with cirrhosis and PVT who underwent successful TIPS creation. We selected another 25 patients who underwent EBL matching for age, sex, and Child Pugh-Turcotte class. The outcome measures included changes in the PVT status before and after the treatments, the rebleeding rate, and the overall survival. The mean follow-up was 25.1 +/- 8.7 months in the EBL group and 25.6 +/- 8.5 months in the TIPS group (P = 0.85). After treatments, the PVT severity improved in 40% and worsened in 25% of patients who did not undergo TIPS, compared with 87% and none of the patients who underwent TIPS (P < 0.001). Previous splenectomy (OR 0.13, 95% CI 0.02-0.76, P = 0.024) and patency status of TIPS (OR 20.8, 95% CI 3.0-141.8, P = 0.002) were the independent factors associated with PVT disappearance. The 1- and 2-year rebleeding rates were, respectively, 44.6% and 59.0% in the EBL group, and 12.5% and 25.2% in the TIPS group (P = 0.002). The 1- and 2-year survival rates were, respectively, 95.7% and 85.2% in the EBL group, and 96% and 78.7% in the TIPS group (P = 0.203). The MELD score was the only independent predictive factor for survival (HR 1.73, 95% CI 1.27-2.37, P = 0.001). Compared with EBL, TIPS contributed to PVT improvement and reduced the risk of rebleeding without providing a survival benefit for patients with PVT. PMID- 25504375 TI - Duodenal neuroendocrine tumors: retrospective evaluation of CT imaging features and pattern of metastatic disease on dual-phase MDCT with pathologic correlation. AB - PURPOSE: The purpose of the study is to evaluate the CT appearance and pattern of metastatic disease of patients with surgically resected well-differentiated duodenal neuroendocrine tumors who underwent pre-operative dual-phase CT. METHODS: Clinical and pathologic records and CT images of 28 patients (average age 58.0 years) following Whipple procedure were retrospectively reviewed. The size, morphology (polypoid, intraluminal mass or wall thickening, intramural mass), location, CT attenuation in the arterial and venous phases, and the presence of lymph node or liver metastases were recorded. RESULTS: On CT, 19 patients (67.8%) had neuroendocrine tumors manifested as polypoid or intraluminal masses (38 lesions, multiple tumors in 3 patients), 4 patients (14.3%) had tumors manifested as wall thickening or intramural masses, and in 5 patients (17.9%), the primary tumor was not visualized. Lesions not seen at CT were less than 0.8 cm on pathologic diagnosis. The mean size of polypoid tumors on CT was 1.2 cm (range 0.3-3.8 cm); 24 tumors were 1.0 cm or smaller, and 14 tumors were larger than 1.0 cm. Most lesions were hypervascular in the arterial phase (19/23 patients) with an increase in tumor enhancement in the venous phase in 14 patients (60.9%), decrease in enhancement in 7 patients (30.4%), and no change in enhancement in 2 patients (8.7%). Thirteen patients (46.4%) had metastatic disease from carcinoid tumor, most commonly regional enhancing lymphadenopathy. CONCLUSION: Duodenal carcinoid tumors commonly appear as an enhancing mass in either the arterial or venous phases. If a primary tumor is not seen in the duodenum, adjacent enhancing lymphadenopathy can be a clue to the presence of a duodenal carcinoid tumor. PMID- 25504376 TI - Magnetic resonance imaging findings of mucinous borderline ovarian tumors: comparison of intestinal and endocervical subtypes. AB - PURPOSE: The purpose of this study is to compare the MRI features of intestinal and endocervical mucinous borderline ovarian tumors (MBOT). METHODS: Fifty seven and 17 patients with histologically proven intestinal (n = 62) and endocervical (n = 22) MBOT, respectively, underwent preoperative MRI which were reviewed by two radiologists blinded to histology. An array of MRI features and clinical factors (age, cancer antigen 125 [CA-125]) were compared between intestinal and endocervical subtypes using the t test and Chi-square test. Univariate and multivariate logistic regression analyses were performed to evaluate for significant predictors of subtype. RESULTS: There was no significant difference in patient age of intestinal and endocervical MBOT (P = 0.423). CA-125 levels were higher in endocervical MBOT (P = 0.022). Regarding MR features, intestinal MBOT was larger, had more septations, more frequently demonstrated honeycomb loculi, and signal intensity discrepancy while endocervical MBOT was more frequently bilateral with papillary projections (P < 0.05). At multivariate analysis, higher CA-125 (odds ratio [OR] 1.015, P = 0.034) and the presence of papillary projections (OR 11.441, P = 0.024) were the only independent predictive factors of endocervical MBOT. CONCLUSION: Intestinal and endocervical subtypes of MBOT demonstrated significantly different features on MRI. The presence of papillary projection was the only independent MRI feature predictive of endocervical MBOT. PMID- 25504378 TI - Family directed umbilical cord blood banking for acute leukemia: usage rate in hematopoietic stem cell transplantation. AB - Family-directed umbilical cord blood (UCB) collection and banking is indicated in women delivering healthy babies who already have a member of their own family with a disease potentially treatable with an allogeneic hematopoietic stem cell (HSCs) transplantation (HSCT). The rapid availability of UCB is an important issue in HSCs procurement particularly for recipients with acute leukemia who urgently need HSCT. The aims of this study were to assess the usage rate of family UCB collections directed to patients with acute leukemia and to investigate the factors influencing the usage rate. A total of 113 families were enrolled, 118 UCB units were successfully collected and one collection failed due to emergency occurred during delivery. Among these, 7 collections were required for children who were in urgent need of a transplant: three HLA-matched units were successfully transplanted, respectively after 2, 5 and 6 months from collection; three collections resulted HLA-mismatched, while HLA-typing is pending for one unit. The remaining collections were mostly required for potential future use, among these units only one was transplanted in a HLA compatible sibling after 3 years and 4 months from collection. After a median time of storage of 8.5 years (range 0.1-20 years) a total of 4/118 (3.4 %) collection has been transplanted. During this time interval, considering only patients who have had the need of a transplant, the main factor influencing low utilization rate of UCB collections was due to HLA disparity, indeed among typed UCB unit mostly (77 %) resulted HLA mismatched with the intended recipient. PMID- 25504379 TI - Current methods and challenges in the comprehensive characterization of human pluripotent stem cells. AB - Pluripotent stem cells (PSCs) are powerful tools for basic scientific research and promising agents for drug discovery and regenerative medicine. Technological advances have made it increasingly easy to generate PSCs but the various lines generated may differ in their characteristics based on their origin, derivation, number of passages, and culture conditions. In order to confirm the pluripotency, quality, identity, and safety of pluripotent cell lines as they are derived and maintained, it is critical to perform a panel of characterization assays. Functional pluripotency is determined using tests that rely on the expression of specific markers in the undifferentiated and differentiated states; tests for quality, identity and safety are less specialized. This article provides a comprehensive review of current practices in PSC characterization and explores challenges in the field, from the selection of markers to the development of simple and scalable methods. It also delves into emerging trends like the adoption of alternative assays that could be used to supplement or replace traditional methods, specifically the use of in silico assays for determining pluripotency. PMID- 25504380 TI - Cyclometallated platinum(II) complexes of benzylidene-2,6-di-isopropylphenylamine containing bidentate phosphines: synthesis, structural properties and reactivity studies. AB - The reaction of the cyclometallated complex [PtCl(N^C)(dmso)], 1 (N^C represents the cyclometallated Schiff base, benzylidene-2,6-diisopropylphenylamine), with 1,1'-bis(diphenylphosphino)ferrocene, dppf, bis(diphenylphosphino)methane, dppm, or 1,2-bis(diphenylphosphino)ethane, dppe, in a 2 : 1 ratio or an equimolar ratio using acetone as the solvent produced the corresponding binuclear or mononuclear diphosphine platinum complexes. In the case of the mononuclear complexes, the diphosphines act as either a bidentate ligand or a monodentate ligand depending on the size of the bite angle of the diphosphines, while in the case of the binuclear complexes, the diphosphines act as a bridging ligand between the two metal centres. The solid state structures of some of the binuclear as well as mononuclear species are reported. The mononuclear derivatives were found to show different behaviour in solution and in the solid state when compared to the binuclear analogues. This behaviour is also influenced by the nature of the diphosphine ligands employed. PMID- 25504381 TI - Ischemic colitis in five points: an update 2013. AB - BACKGROUND: Ischemic colitis is the most common form of intestinal ischemia. The presence of diarrhea and mild lower gastrointestinal bleeding should guide the diagnosis. Although many laboratory tests and radiographic images may suggest the diagnosis, colonic endoscopic with histological analysis of biopsies is the gold standard for identification of colonic ischemia. aim : The aim of this study was to resume in 5 points: the epidemiology, the clinical features, the diagnostic approach and the management of ischemic colitis in five points. methods: Review of literature. results: Incidence of ischemic colitis was between 3 and 10%. The clinical presentation is predominated by the non gangrenous form associating abdominal pain, tenderness, diarrhea and lower gastrointestinal bleeding. The most frequent causes are represented by systemic hypoperfusion. Laboratory tests can orientate the diagnosis but are unspecific. Radiographic images based on computed tomography or more recently magnetic resonance imaging may suggest the diagnosis, but the confirmation will be given by endoscopic visualization of colonic mucosa with histological analysis of biopsies. Conservative treatment is the most often sufficient to improve colonic lesions. Surgical treatment is reserved for perforations and strictures. CONCLUSION: The incidence of colonic ischemia is difficult to ascertain. The diagnosis is usually made by medical history, examination, and endoscopy which have become the diagnostic procedure of choice. A high index of suspicion and prompt management are essential for optimum outcomes in patients with colonic ischemia. PMID- 25504377 TI - Molecular physiognomies and applications of adipose-derived stem cells. AB - Adipose-derived stromal/stem cells (ASC) are multipotent with abilities to differentiate into multiple lineages including connective tissue and neural cells. Despite unlimited opportunity and needs for human and veterinary regenerative medicine, applications of adipose-derived stromal/stem cells are at present very limited. Furthermore, the fundamental biological factors regulating stemness in ASC and their stable differentiation into other tissue cells are not fully understood. The objective of this review was to provide an update on the current knowledge of the nature and isolation, molecular and epigenetic determinants of the potency, and applications of adipose-derived stromal/stem cells, as well as challenges and future directions. The first quarter of the review focuses on the nature of ASC, namely their definition, origin, isolation and sorting methods and multilineage differentiation potential, often with a comparison to mesenchymal stem cells of bone marrow. Due to the indisputable role of epigenetic regulation on cell identities, epigenetic modifications (DNA methylation, chromatin remodeling and microRNAs) are described broadly in stem cells but with a focus on ASC. The final sections provide insights into the current and potential applications of ASC in human and veterinary regenerative medicine. PMID- 25504382 TI - [The role of biochemical markers of bone turnover in the diagnosis of osteoporosis and predicting fracture risk]. AB - BACKGROUND: Currently, for the diagnosis of osteoporosis, we search risk factors and measure bone mineral density (BMD) by DXA method. However, bone turnover markers, unused still in practice, have shown an interest especially in the prediction of fracture risk. aim: To determine the relationship between bone markers, BMD and osteoporotic fracture. methods: Prospective study of 65 women referred for measure of BMD during the period between May and August 2010. Each patient had a dosage of serum bone formation markers: osteocalcin (OC) and N terminal propeptide of type I collagen (P1NP) and bone resorption markers: serum and urinary C-terminal telopeptide of type I collagen (beta-CTX or CrossLaps) as well as parathyroid hormone and calcium. Risk factors of osteoporosis were identified in each case. results: Our 65 women had a mean age of 58.6 +/- 12.1 years. The majority (83%) were menopausal women. Osteoporosis was found in 52%, osteopenia 26% and normal BMD 22% of cases. An increase in bone turnover markers was correlated with menopause (p = 0. 001 for the OC, p = 0.016 for urinary CTX), a low body mass index (p = 0.015 for OC, p = 0.042 for serum CTX) and osteoporosis (p <0.001 for P1NP, p <0.001 for serum and urinary CTX). Corticosteroid therapy was correlated with a decrease in bone formation markers (p = 0.002 for P1NP). The presence of fracture was only associated with increased urinary CTX (p = 0.05). CONCLUSION: Bone turnover markers increase in menopausal women and in case of low BMD. However, their contribution in the diagnosis of osteoporosis is low. They are rather an interest in the prediction of fracture risk. PMID- 25504383 TI - [Radiation protection in orthopedic surgery at the Charles Nicolle hospital of Tunis]. AB - BACKGROUND: Orthopaedic theatre personnel (OTP) are exposed to ionizing radiation by the use of Image intensification in the operating room. But :The aims of this study are to determine OTP knowledge about ionizing radiation risks and the availability of radiation protection clothes, to propose appropriate corrective measures. methods: This descriptive study was performed during an orthopaedic operating theatre equipped with a mobile Image intensifier unit in Charles Nicolle hospital, in March 2010. We have performed an orthopaedic theatre visit to identify the availability of radiation protection clothes. We used a questionnaire in order to identity OTP knowledge about ionizing radiation. We established a global score of knowledge to classify our population. results: We identified 65 professionals exposed to ionizing radiation. 54 of them (83%) responded to our questionnaire. 65% were men and sex ratio was 0,54. The median of the age was 32 years (23-51). Orthopaedic theatre personnel were 35% surgeons, 32% nurses, 20% superior technicians and 13% service workers. The mean of the Global score of knowledge was 8,4 /20 (3,6 -15,2). The Kruskal-Wallis test showed that this score increases significantly with grade. Because availability of lead aprons, they were worn by 67% of the staff. CONCLUSIONS: In the present study, the results indicate insufficiency in OTP knowledge and in radioprotection tools availability. In order to minimize all unnecessary radiation, attempts should be made to increase orthopaedic theatre personnel knowledge about radiation protection. Safety culture is a referral method to reduce radiation exposure as low as possible. PMID- 25504384 TI - Psychometric properties of the arabic version of the schizotypal personality questionnaire in Tunisian university students. AB - BACKGROUND: The schizotypal personality disorder is considered as a marker of schizophrenia proneness. The schizotypal personality questionnaire (SPQ) is an instrument to help to the diagnosis of schizotypal personality disorder extensively studied in the literature. aim: To assess psychometric properties (reliability and factor structure) of the Arabic version of the SPQ in a sample of Tunisian university students. method: The sample included 490 students (145 males and 345 females; mean age: 20.4 +/- 1.4 years), from the faculty of medicine and the health sciences school of Monastir. Thirty-three students participated in the second assessment of the SPQ three months later. results: Cronbach's (alpha) internal consistency reliability coefficients were 0.92 for the total SPQ and from 0.62 to 0.75 for the SPQ subscales. The test-retest reliability was good with the intraclass correlation coefficients equal to 0.83 for the total SPQ and from 0.67 to 0.87 for the SPQ subscales (P<0.0001). Factor analysis indicated that the three-factor model (positive or cognitive-perceptual, negative or interpersonal, and disorganized) and the four-factor model (cognitive perceptual, paranoid, interpersonal, and disorganized) have provided a good fit to the data, accounting for 70.7% and 77.3% of the total variance of the scale, respectively. CONCLUSION: The results showed that the Arabic version of the SPQ had adequate psychometric properties and confirmed the multidimensional structure of the schizotypal personality in nonclinical populations. PMID- 25504385 TI - [Clinicobiological and morphological profiles of primary sclerosing cholangitis in Tunisia]. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease strongly associated, in the western series, to inflammatory bowel disease (IBD) and particularly to chronic ulcerative colitis. North African data are rare. aim : To study the epidemiological, clinicobiological and morphological profile of PSC in Tunisia. methods: A retrospective multicenter study extended over a period of 14 years (1995-2009), including all patients suffering from PSC, hospitalized in the four participants departments. We collected epidemiological, clinico biological, histopathologic and morphological data for each patient. results: We brought together 33 patients (22 men and 11 women), middle aged 44 years. The disease was symptomatic in 73% of cases. Laboratory tests showed cholestasis (100%) associated with hyperbilirubinemia (72%) and a moderate cytolysis (78%). Morphological analysis of bile ducts by cholangioMRI or endoscopic retrograde cholangio-pancreatography objectified diffuse damage of the biliary tract in 61% of cases. Association with IBD was found in 33% of cases (Crohn's Disease: 27%, chronic ulcerative colitis: 6%). An association with autoimmune hepatitis was found in 6% of cases and primary biliary cirrhosis in 3% of cases. Conclusion : PSC is rare in Tunisia and affects men more often than women. The association with IBD is less frequent than in literature. It concerns essentially Crohn's disease. These data require confirmation by prospective multicenter studies. PMID- 25504386 TI - [Prevalence of height-weight deficit in Tunisian boys of the Northern and Southern regions]. AB - BACKGROUND : Malnutrition is owing to an alimentation regarding quantity and quality food. aim: To examine the different forms of malnutrition among Tunisian boys of the north and south regions, to form an idea about the state of their health and their living conditions. METHODS: Our empirical investigation was carried out on 1082 northern boys and 1016 southern boys, aged from 10 to 14 years including 1057 non pubescent boys and 1041 prepubescent boys. Age, weight and height were recorded for the entire population according to the norms of the standard World Health Organization and the nutritional status of these young was described by two indices: Height for age and body mass index for age. The classification used to describe the build is the Cachera Rolland, RESULTS: Malnutrition are significantly more pronounced among the southern boys than their counterparts in the North. Particularly, short stature (19.2% vs 14.4%) and underweight (28% vs 22.5 %). However, the risk of overweight and obesity is more pronounced among the northern boys. However, the comparison between non pubescent and prepubescent boys shows that the prevalence of stunting increases with age. CONCLUSION: The mechanisms responsible for these inter-individual differences beings regions appear related to living conditions during the first year after birth, particularly, socio-economic status, family size, type of housing, and the education level of parents. PMID- 25504387 TI - [Epidemiology and clinical profile of knee osteoarthrosis in the elderly]. AB - BACKGROUND: Osteoarthris represents one of the most frequent degenerative pathologies. Its prevalence increases with the age as well as the functional consequences which are more considerable at the elderly population. aim : study the epidemiology and clinical features of knee osteoarthritis of older patient. methods: retrospective study made in the department of physical and rehabilitation medicine of the military Tunis hospital, on a sample of 60 patients having osteoarthritis, divided in two groups, the one is constituted by 30 subjects of 65 and more years old, other one of 30 adults aged between 30 and 55 years old. All the patients had a clinical and functional evaluation. results: the comparison between both groups showed a statistically significant difference (P < 0.05) in the following items: the severity of the pain, the bilateral hydarthrosis, the muscular strength of quadriceps, hamstrings and their retraction, the severe reduction of walking perimeter, and the bicompartimental lesion of both knees. CONCLUSION: clinical and sociofunctional features of knee osteoarthritis in the elderly patient require adapted and multidisciplinary management, in order to avoid the potential impact of knee osteoarthritis on the function and quality of life of the patient. PMID- 25504389 TI - [Sub-acute neonatal vomiting]. PMID- 25504388 TI - Thoracoscopic treatment of pulmonary hydatid cyst in children: a report of 25 cases. AB - BACKGROUND: Open surgery is the standard option for the treatment of hydatid pulmonary cysts. Surgeons are able to replicate the principles of conventional surgery using minimally invasive techniques ,in particular thoracoscopy. However, there are few reports about this subject in children. To our knowledge, this is one of the biggest pediatric series ever reported in the literature. aim: the purpose of this study was to determine the best indications of the thoracospic surgery for the treatment of the pulmonary hydatid cysts in children. methods: We report a series of 25 cases with pulmonary hydatid cysts treated using the thoracoscopic approach from 2005 to 2009. We retrospectively analyzed the patients' sex, age, symptoms, biological data, characteristics of hydatid cysts (location, number and size) and the medical treatments. Pulmonary hydatid cyst diagnosis was performed on Chest x-ray, abdominal ultrasound and biological data in all the cases. Tomography was not systematic. All patients underwent video assisted surgery. A conversion to thoracotomy was conducteded in 2 cases. All the patients had a chest tube and received an antibio-prophylaxy , without Albendazol . A concurrent hydatid cyst at the opposite lung or in the peritoneal cavity was treated later. results: There were 25 cases with a sex ratio of 2.1 and a mean age of 8 years. All the patients underwent a video-assisted surgery. A conversion to thoracotomy was performed in 2 cases because hydatid cysts were large (size > 8 cm). The average duration of the procedure was 75 minutes. In the post operative course, one patient presented an air leak which required a prolonged chest drainage for 16 days and a second one was treated for lung infection. In all the other cases, the follow-up was uneventful. CONCLUSION: The thoracoscopic approach for pulmonary hydatid cysts in children is feasible. For better results, it is recommended for cysts smaller than 5 cm. PMID- 25504391 TI - [Pyogenic cyst in childhood]. PMID- 25504390 TI - [A diagnostic trap in urologic emergencies]. PMID- 25504392 TI - [Peripheral neuroectodermal tumor in the abdominopelvic region]. PMID- 25504393 TI - [Osteitis induced by chemotherapy: a case report]. PMID- 25504394 TI - Dorsal elastofibroma: usefulness of MRI imaging. PMID- 25504395 TI - [A confusing paratesticular tumor]. PMID- 25504396 TI - [Thymoma in children, a rare tumor, often with diagnostic difficulty]. PMID- 25504397 TI - [Liver involvement in the course of Rendu-Osler disease]. PMID- 25504398 TI - [Fulminant acute hepatitis B after infliximab treatment in Crohn's disease]. PMID- 25504399 TI - Management of epithelial ovarian tumors in children. PMID- 25504400 TI - Abdominal cystic lymphangioma complicated by mesenteric volvulus: a case report. PMID- 25504401 TI - Getting started in research: systematic reviews and meta-analyses. AB - OBJECTIVES: Systematic reviews are one of the major building blocks of evidence based medicine. This overview is an introduction to conducting systematic reviews and meta-analyses. CONCLUSIONS: Systematic reviews and meta-analyses of randomised controlled trials (RCTs) represent the most robust form of design in the hierarchy of research evidence. In addition, primary data do not have to be collected by the researcher him/herself, and there is no need for approval from an ethics committee. Systematic reviews and meta-analyses are not as daunting as they may appear to be, provided the scope is sufficiently narrow and an appropriate supervisor available. PMID- 25504402 TI - Getting started in research: designing and preparing to conduct a research study. AB - OBJECTIVE: To discuss common pitfalls and useful tips in designing a quantitative research study, the importance and process of ethical approval, and consideration of funding. CONCLUSIONS: Through careful planning, based on formulation of a research question, early career researchers can design and conduct quantitative research projects within the framework of the Scholarly Project or in their own independent projects. PMID- 25504404 TI - Barriers and facilitators to preparing families with premature infants for discharge home from the neonatal unit. Perceptions of health care providers. AB - OBJECTIVE: To explore Colombian health care provider perceptions of barriers and facilitators to preparing families with premature infants for discharge home from the neonatal intensive care unit (NICU). METHODOLOGY: Using a qualitative descriptive design, in-depth semi-structured interviews were conducted with fifteen neonatal health care providers (HCPs) in Colombia. Data were analyzed using qualitative content analysis. RESULTS: Participant responses centered on three main themes: 1) establishment of the parent-infant bond, 2) acquisition of parenting skills, and 3) getting ready for the transition from hospital to home. Barreirs to preparing parents for NICU discharge included obstacles to parental visiting in the NICU, communication barriers, difficulties related to the establishment of successful breastfeeding, insufficient human resources and poor links between hospital and community-based resources. Facilitators included the availability of social aids for vulnerable families, 24-hour telephone access to the neonatal units, tailored educational materials and group sessions, continuing education for staff and the community-based Kangaroo Program available to parents post-discharge. Adolescent mothers, indigenous parent and working fathers were identified as particularly challenging to reach and engage in discharge preparation. CONCLUSION: Neonatal HCPs identified numerous challenges as well as helpful strategies for preparing families for hospital discharge. Additional studies are needed on the experience of neonatal discharge from the perspective of parents of premature infants in Colombia, to help inform optimal interventions for supporting families during the transition from hospital to home. PMID- 25504405 TI - Perception of premature infants' mothers on home visits before and after hospital discharge. AB - OBJECTIVE: To understand the meaning of home visits by neonatal nurses for mothers of premature babies. METHODOLOGY: A qualitative study was conducted with 21 mothers of families participating in a project that supported families of premature infants, born at a university hospital in the city of Londrina, Brazil. Data collection was conducted through semi-structured individual interviews, using a form with the identification data of mothers and an interview script. RESULTS: Three themes were revealed: the home visit as a support to the family, individualized home care, feeling cared for and supported in performing the baby's care. CONCLUSION: The home visit from the perspective of longitudinal care was a powerful resource that promoted the link between families and nurses, decreasing doubts, fears and anxieties of the mother. In addition, home care was provided and adherence to care and treatment was encouraged. PMID- 25504406 TI - Quality of life of elderly. Comparison between urban and rural areas. AB - OBJECTIVE: Comparing the scores of quality of life according to place of residence (urban and rural areas). METHODS: A cross-sectional study involving 2142 elderly in urban area and other 850 in rural area of the municipality of Uberaba (Minas Gerais, Brazil). Instruments used: Olders Americans Resources and Services, World Health Organization Quality of Life--BREF (WHOQOL-BREF) and World Health Organization Quality of Life Assessment for Older Adults (WHOQOL-OLD). RESULTS: We found that in urban area predominated women and men in rural areas. It was common in two areas: 60?70 years old, married marital status, schooling of 4 to 8 years of study and the income of a minimum wage. The elderly residing in the urban area with their children and in rural areas did so with the spouse. In the evaluation of the quality of life, rural elders presented scores significantly higher than the urban area in the domains of physical, psychological, and social relations in the WHOQOL-BREF; and in the facets of autonomy, past, present and future activities, social participation and intimacy of the WHOQOL-OLD. For the latter instrument facets sensory ability and of death and dying the elderly's urban area had higher scores than the rural area. CONCLUSION: The elders of the urban area showed a greater involvement of the quality of life than the residents in the rural area. Nurses who work in primary care should address health strategies according to the specific needs of the urban and rural areas. PMID- 25504407 TI - Care to terminal patients. Perception of nurses from the intensive care unit of a hospital. AB - OBJECTIVE: To identify the perception of nurses with regard to the process of providing care to patients in the context of hospice care. METHOD: Qualitative study using the methodological framework Collective Subject Discourse. A total of 18 nursing professionals of the adult intensive care unit of a public hospital in Sao Paulo, Brazil were interviewed between June and August 2012. RESULTS: The process of providing care to terminal patients is permeated by negative, conflictive and mixed feelings. As regards communication, while the participants acknowledge its importance as a therapeutic resource, they also admit a lack of professional qualification. CONCLUSION: The interviewees have difficulties to deal with care provided to terminal patients. The qualification of these professionals needs to be improved, starting in the undergraduate program. PMID- 25504408 TI - The use of films as a teaching tool for the teaching-learning process in bioethics. AB - OBJECTIVE: Identifying the contribution of using films in the process of teaching learning in bioethics and verifying the facilities and difficulties in using this teaching resource. METHODOLOGY: A qualitative study analyzed from the Bardin referential. Semi-structured interviews were carried out, recorded, and transcribed in full. For definition of the sample was used the criteria of repetition. In total, participated in the study 21 students of Nursing and Biochemistry, members of a Center for Teaching and Research in Bioethics of a public federal university in the city of Divinopolis, Minas Gerais, Brazil. During the analysis of interviews, two thematic categories and two subcategories emerged. RESULTS: In their responses, students indicated the importance of viewing the bioethical problem for the reflection and decision-making in professional practice. Many reported that from the experience in discussions of the films showed, were made changes in the ethical position. CONCLUSION: The use of films as a teaching resource contributes to the process of teaching-learning in bioethics for undergraduate students. The discussions of the films are stimulating and provide a space for reflection and dialogue on bioethical problems that students may encounter in their professional practice. PMID- 25504409 TI - Assessment of stress in the inclusion of nursing students in hospital practice. AB - OBJECTIVE: To verify the presence of stress among undergraduate nursing students in different stages of hospital practice. METHOD: Descriptive, cross-sectional study addressing 86 nursing students in their 6th, 7th, and 9th semesters in 2011. An instrument developed by Costa and Polak for the Assessment of Stress Among Nursing Students was used. It is composed of six domains: performance of practical activities, professional communication, time management, environment, professional training, and theoretical activity. RESULTS: Most participants were women (95%) and the average age was 23 years old. A total of 84% of students passed the program's courses and 91% participated in extracurricular activities. Stressors are present during the entire program but intensify when students are introduced to care practice with an emphasis on the domain of professional training; related stress was high in all the semesters. The scores concerning the practical activity domain were higher only in the 6th semester. There were statistically significant levels at 0.01 and 0.10 in the difference in the averages in the domains of training and time management, respectively, between the semesters. As the students advance in the program, scores obtained in the domains presented by AEEE change. As stress can interfere in the performance and learning of nursing students, coping strategies should be devised to enable them to deal with stress during the program. PMID- 25504410 TI - Exploring the Use of information and communication technologies and social networks among university nursing faculty staff. An opinion survey. AB - OBJECTIVE: This work sought to analyze the use of Information and Communication Technologies (ICTs) and social networks among the university nursing faculty staff in Spain. METHODOLOGY: This was a descriptive, cross-sectional study using a questionnaire on ICT skills designed to comply with the research objective, which was evaluated by experts and which was subjected to exploratory analysis of principal components; the reliability of this instrument measured with Cronbach's alpha was 0.85. The information technology tool used to publish the questionnaire on line was Limesurvey. The sample comprised 165 professors from 25 Nursing Faculties and Schools from universities in Spain. RESULTS: Seventy one percent of the total surveyed used internet services to look for information, 63% used the internet as a means for formation and learning, and 72% used it as a communication platform (e-mail and virtual platforms like Sakai and Moodle). Although 51% of the teaching staff surveyed had more than 120 students registered in their courses, hypothesis testing revealed that the number of students in class is not a determining factor for the teaching staff to have greater interest to update its knowledge in ICTs. Younger professors use new technologies more profusely and the most-valued advantage of using ICTs was quick access to information. Professors perceive that after the Bologna Declaration, which requires modifying their teaching-learning processes through the new teaching methodologies, a drop has been produced in their performance and that of their peers in their area of knowledge. CONCLUSION: The nursing teaching staff is making strong efforts to confront the new challenges posed by ICTs to train the professionals of the 21st century. It is fundamental to pay special attention to improving the university teaching staff's skills in managing ICTs, promoting the implementation of the knowledge acquired. PMID- 25504411 TI - Knowledge, Attitude and Use of Evidence-Based Practice among nurses active on the Internet. AB - OBJECTIVE: to determine the evidence-based practice (EBP) competence of Spanish and Latin-American nurses participating in professional forums on the Internet and estimate the influence of socio-demographic and professional factors on their competence, which was defined as knowledge of, attitude towards, and implementation of EBP. METHODOLOGY: An online survey was administered to a convenience sample of nurses active in Internet forums, comprising validated Spanish versions of the Evidence-Based Practice Questionnaire (EBPQ) and Practice Environment Scale of the Nursing Work Index (PES-NWI) and socio-demographics and professional variables. RESULTS: 314 questionnaires were obtained (76.96%). The mean EBPQ score was 5.02 out of 7 (95%CI, 4.89-5.14). The variables associated with a higher competence in EBP were academic level, (p<03001), professional category (p=0.001), country of work (p<0.001), perception of practice environment (p=0,018) and research activities (p<0,036). CONCLUSIONS: These nurses showed a moderate level of EBP competence. They revealed a positive attitude towards EBP and achieved intermediate scores in both EBP-related skills and knowledge and their implementation. Higher academic levels and professional categories were associated with greater EBP competence. A practice environment perceived to be unfavorable has a negative influence on EBP implementation. PMID- 25504412 TI - Level of involvement of clinical nurses in the evaluation of competence of nursing students. AB - OBJECTIVE: To determine the level of involvement of clinical nurses accredited by the Universitat Jaume I (Spain) as mentors of practice (Reference Nurses) in the evaluation of competence of nursing students. METHODOLGY: Cross-sectional study, in which the "Clinical Practice Assessment Manual'' (CPAM) reported by reference 41 nurses (n=55) were analyzed. Four quality criteria for completion were established: with information at least 80% of the required data, the presence of the signature and final grade in the right place. Verification of learning activities was also conducted. Data collection was performed concurrently reference for nurses and teachers of the subjects in the formative evaluations of clinical clerkship period in the matter "Nursing Care in Healthcare Processes ", from March to June 2013. RESULTS: 63% of CPAM were completed correctly, without reaching the quality threshold established (80%). The absence of the signature is the main criteria of incorrect completion (21%). Nine learning activities do not meet the quality threshold set (80%) (p < 0.05). There are significant differences according to clinical units p < 0.05. From the 30 learning activities evaluated in the CPAM, it can be stated that nine of them do not reach the verification threshold established (80%), therefore it cannot be assumed that these activities had been completed by students and evaluated by the RefN throughout the clinical clerkship period. CONCLUSION: The level of involvement of Reference Nurse cannot be considered adequate, although strategies to encourage involvement through collaboration and training must be developed. PMID- 25504413 TI - Prevalence of prehypertension and associated factors in women. AB - OBJECTIVE: To estimate the prevalence of factors associated with prehypertension among 20 to 59 years old women cared for by primary healthcare units that adopted the Family Health Strategy. METHOD: Cross-sectional study conducted in a city in the interior of Minas Gerais, Brazil. The study's population was composed of 1,773 women with blood pressure below 140/90 mm Hg. The dependent variable was prehypertension (>=120/80 mmHg to <140/90 mmHg). RESULTS: The prevalence of prehypertension was 20.6%. The multivariate analysis showed that overweight or obese women of African descent, 40 years old or older with a family history of hypertension, had an increased risk of presenting prehypertension. CONCLUSION: Although the prevalence found in this study is lower than that reported by other studies, nurses need to implement efforts to prevent and detect prehypertension, especially among high-risk groups. PMID- 25504414 TI - Access to information in qualitative research. A matter of care. AB - In this article attention is focused on access to data; a process that tends to be taken for granted and which in practice takes time and energy from the person who investigates. Access implies a process of contacting key people in institutions; negotiating with them, being invited to obtain data, achieving formal permission, and--finally--constructing relationships with the participants. Access to data is negotiated, trust is constructed in relationships with study participants, and data is obtained. All this constitutes an interactive process in which the person who investigates is revealed as an instrument in obtaining the data. Thus, the appearance, manners, and the way of being of the person who investigates will facilitate access to broad and detailed information. PMID- 25504415 TI - The value of nursing care in the paradigm of chronicity and dependency. New roles and redesigns. AB - The future of Healthcare Systems not only faces financial troubles, but also- perhaps worse, the need to redesign its service offers. It is necessary to work for all the knowledge available to be placed at the service of patients and society, generating much more efficient services and opening to a redesign where nurses lead in new services supported on the strategy of effective care. Additionally, it is hoped that patients assume a responsibility and nurses another: that of accompanying patients during their disease process to become for them a support in their self-care efforts. The new role that must be assumed by community nurses is that of becoming the coaches of chronic patients and of their caregivers so they can reach a situation of equilibrium, between their desires and what they must do, to, thus, assume their responsibility in the self provision of Basic Care. PMID- 25504416 TI - An imagable and photothermal "Abraxane-like" nanodrug for combination cancer therapy to treat subcutaneous and metastatic breast tumors. AB - A new "Abraxane-like" nanotheranostic formulation self-assembled from three clinically approved agents, human serum albumin, paclitaxel, and indocyanine green, is developed. Utilizing such a newly formulated nanodrug, combined photothermal and chemotherapy is conducted under the guidance of imaging, not only effectively eliminating subcutaneous tumors, but also significantly inhibiting the development of metastatic tumors in this proof-of-concept study. PMID- 25504417 TI - Semiconductor polymer dots induce proliferation in human gastric mucosal and adenocarcinoma cells. AB - We investigated the cellular uptake behavior and cell viability of semiconducting polymer dots (Pdots) on human gastric adenocarcinoma (SGC-7901) cells and human gastric mucosal (GES-1) cells. MTT studies indicate the Pdot treatment induces obvious cell proliferation in both types of cell lines. We performed further investigations such as reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) change, which indicate that the cell proliferation is in good agreement with the increase in the ROS and MMP levels. Moreover, expression of protein kinase B (Akt) decreased as the Pdot concentration increases, but the expression of protein dual-phosphorylated Erk (p-Erk) and phosphorylated c-Jun N terminal kinases (p-JNK) were increased. These effects indicated that the Pdots could promote the growth of SGC-7901 cells and GES-1 cells by appropriately regulating the expressions of protein Akt, p-Erk, and p-JNK. PMID- 25504418 TI - Antioxidants for male subfertility. AB - BACKGROUND: Between 30% to 80% of male subfertility cases are considered to be due to the damaging effects of oxidative stress on sperm and 1 man in 20 will be affected by subfertility. Antioxidants are widely available and inexpensive when compared to other fertility treatments and many men are already using these to improve their fertility. It is thought that oral supplementation with antioxidants may improve sperm quality by reducing oxidative stress. Pentoxifylline, a drug that acts like an antioxidant, was also included in this review. OBJECTIVES: This Cochrane review aimed to evaluate the effectiveness and safety of oral supplementation with antioxidants for subfertile male partners in couples seeking fertility assistance. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO and AMED databases (from inception until January 2014); trial registers; sources of unpublished literature and reference lists. An updated search was run in August 2014 when potentially eligible studies were placed in 'Studies awaiting assessment'. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing any type or dose of antioxidant supplement (single or combined) taken by the subfertile male partner of a couple seeking fertility assistance with a placebo, no treatment or another antioxidant. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, extracted the data and assessed the risk of bias of the included studies. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates, adverse events, sperm DNA fragmentation, sperm motility and concentration. Data were combined, where appropriate, to calculate pooled odds ratios (ORs) or mean differences (MD) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I(2) statistic. We assessed the overall quality of the evidence for the main outcomes using GRADE methods. MAIN RESULTS: This updated review included 48 RCTs that compared single and combined antioxidants with placebo, no treatment or another antioxidant in a population of 4179 subfertile men. The duration of the trials ranged from 3 to 26 weeks with follow up ranging from 3 weeks to 2 years. The men were aged from 20 to 52 years. Most of the men enrolled in these trials had low total sperm motility and sperm concentration. One study enrolled men after varicocelectomy, one enrolled men with a varicocoele, and one recruited men with chronic prostatitis. Three trials enrolled men who, as a couple, were undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) and one trial enrolled men who were part of a couple undergoing intrauterine insemination (IUI). Funding sources were stated by 15 trials. Four of these trials stated that funding was from a commercial source and the remaining 11 obtained funding through non-commercial avenues or university grants. Thirty-three trials did not report any funding sources.A limitation of this review was that in a sense we had included two different groups of trials, those that reported on the use of antioxidants and the effect on live birth and clinical pregnancy, and a second group that reported on sperm parameters as their primary outcome and had no intention of reporting the primary outcomes of this review. We included 25 trials reporting on sperm parameters and only three of these reported on live birth or clinical pregnancy. Other limitations included poor reporting of study methods, imprecision, the small number of trials providing usable data, the small sample size of many of the included studies and the lack of adverse events reporting. The evidence was graded as 'very low' to 'low'. The data were current to 31 January 2014.Live birth: antioxidants may have increased live birth rates (OR 4.21, 95% CI 2.08 to 8.51, P< 0.0001, 4 RCTs, 277 men, I(2) = 0%, low quality evidence). This suggests that if the chance of a live birth following placebo or no treatment is assumed to be 5%, the chance following the use of antioxidants is estimated to be between 10% and 31%. However, this result was based on only 44 live births from a total of 277 couples in four small studies.Clinical pregnancy rate: antioxidants may have increased clinical pregnancy rates (OR 3.43, 95% CI 1.92 to 6.11, P < 0.0001, 7 RCTs, 522 men, I(2) = 0%, low quality evidence). This suggests that if the chance of clinical pregnancy following placebo or no treatment is assumed to be 6%, the chance following the use of antioxidants is estimated at between 11% and 28%. However, there were only seven small studies in this analysis and the quality of the evidence was rated as low.Miscarriage: only three trials reported on this outcome and the event rate was very low. There was insufficient evidence to show whether there was a difference in miscarriage rates between the antioxidant and placebo or no treatment groups (OR 1.74, 95% CI 0.40 to 7.60, P = 0.46, 3 RCTs, 247 men, I(2) = 0%, very low quality evidence). The findings suggest that in a population of subfertile men with an expected miscarriage rate of 2%, use of an antioxidant would result in the risk of a miscarriage lying between 1% and 13%.Gastrointestinal upsets: there was insufficient evidence to show whether there was a difference in gastrointestinal upsets when antioxidants were compared to placebo or no treatment as the event rate was very low (OR 1.60, 95% CI 0.47 to 5.50, P = 0.46, 6 RCTs, 429 men, I(2) = 0%).We were unable to draw any conclusions from the antioxidant versus antioxidant comparison as not enough trials compared the same interventions. AUTHORS' CONCLUSIONS: There is low quality evidence from only four small randomised controlled trials suggesting that antioxidant supplementation in subfertile males may improve live birth rates for couples attending fertility clinics. Low quality evidence suggests that clinical pregnancy rates may increase. There is no evidence of increased risk of miscarriage but this is uncertain as the evidence is of very low quality. Data were lacking on other adverse effects. Further large well-designed randomised placebo-controlled trials are needed to clarify these results. PMID- 25504420 TI - Utilisation of potato processing wastewater for microbial lipids and gamma linolenic acid production by oleaginous fungi. AB - BACKGROUND: Microbial lipids are considered as the starting material for production of second-generation biofuels and their polyunsaturated fatty acids are rich sources of neutraceuticals. Exploring cheap feedstock for producing microbial lipids is necessary. The present study examined the potential of microbial lipids and gamma-linolenic acid (GLA) production by two oleaginous fungi, Aspergillus flavus I16-3 and Mucor rouxii, with potato processing wastewater as a low-cost or no-cost nutrient source. RESULTS: Biochemistry and physiology of two oleaginous fungi, A. flavus I16-3 and M. rouxii, on lipid accumulation showed the two fungi grew well and efficiently utilised the starch in wastewater. On average (P < 0.05), 2.8 and 3.6 g L(-1) of lipids were produced by A. flavus I16-3 and M. rouxii, respectively, with maximum GLA yields of 60 and 100 mg L(-1) . Addition of nutrients to raw wastewater significantly improved (P < 0.05) the lipid and GLA yields; 3.5 and 4.2 g L(-1) of lipids, and 100 and 140 mg L(-1) of GLA were produced by A. flavus I16-3 and M. rouxii, respectively. In addition, the wastewater was efficiently treated, with soluble chemical oxygen demand, total soluble nitrogen and total soluble phosphorus removals up to 60% and 90%, 100% and 98%, and 92% and 81% by A. flavus I16-3 and M. rouxii, respectively. CONCLUSION: This study demonstrated an alternative approach to valorise potato processing wastewater to produce microbial lipids and GLA (nutraceuticals). PMID- 25504419 TI - The pharmacodynamics of the p53-Mdm2 targeting drug Nutlin: the role of gene switching noise. AB - In this work we investigate, by means of a computational stochastic model, how tumor cells with wild-type p53 gene respond to the drug Nutlin, an agent that interferes with the Mdm2-mediated p53 regulation. In particular, we show how the stochastic gene-switching controlled by p53 can explain experimental dose response curves, i.e., the observed inter-cell variability of the cell viability under Nutlin action. The proposed model describes in some detail the regulation network of p53, including the negative feedback loop mediated by Mdm2 and the positive loop mediated by PTEN, as well as the reversible inhibition of Mdm2 caused by Nutlin binding. The fate of the individual cell is assumed to be decided by the rising of nuclear-phosphorylated p53 over a certain threshold. We also performed in silico experiments to evaluate the dose-response curve after a single drug dose delivered in mice, or after its fractionated administration. Our results suggest that dose-splitting may be ineffective at low doses and effective at high doses. This complex behavior can be due to the interplay among the existence of a threshold on the p53 level for its cell activity, the nonlinearity of the relationship between the bolus dose and the peak of active p53, and the relatively fast elimination of the drug. PMID- 25504421 TI - Molecular evolution of nitrogen assimilatory enzymes in marine prasinophytes. AB - Nitrogen assimilation is a highly regulated process requiring metabolic coordination of enzymes and pathways in the cytosol, chloroplast, and mitochondria. Previous studies of prasinophyte genomes revealed that genes encoding nitrate and ammonium transporters have a complex evolutionary history involving both vertical and horizontal transmission. Here we examine the evolutionary history of well-conserved nitrogen-assimilating enzymes to determine if a similar complex history is observed. Phylogenetic analyses suggest that genes encoding glutamine synthetase (GS) III in the prasinophytes evolved by horizontal gene transfer from a member of the heterokonts. In contrast, genes encoding GSIIE, a canonical vascular plant and green algal enzyme, were found in the Micromonas genomes but have been lost from Ostreococcus. Phylogenetic analyses placed the Micromonas GSIIs in a larger chlorophyte/vascular plant clade; a similar topology was observed for ferredoxin-dependent nitrite reductase (Fd-NiR), indicating the genes encoding GSII and Fd-NiR in these prasinophytes evolved via vertical transmission. Our results show that genes encoding the nitrogen-assimilating enzymes in Micromonas and Ostreococcus have been differentially lost and as well as recruited from different evolutionary lineages, suggesting that the regulation of nitrogen assimilation in prasinophytes will differ from other green algae. PMID- 25504422 TI - FDG PET imaging for identifying pulmonary hypertension and right heart failure. AB - Pulmonary arterial hypertension (PAH) is a syndrome characterized by lung vascular intimal lesions, smooth muscle layer hypertrophy, perivascular inflammation, and concomitant right ventricular (RV) remodeling which can ultimately lead to the RV function decline known as RV failure (RVF). A key determining factor for RVF development is the RV metabolic state defined by the level of ischemia and glycolysis which constitute a vicious cycle of hypoxia, metabolic shift from glucose oxidation (GO) to glycolysis, increased RV systolic pressure (RVSP), decreased RV output, and further myocardial ischemia. In this context, 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) positron emission tomography (PET) has been used for the measurement of glucose uptake (GU) as an indicator of glucose metabolism in the right heart and pulmonary vasculature. The focus of this review is the application of FDG PET modality for assessing PAH severity and clinical outcome. PMID- 25504423 TI - Modulatory role of intravenous gammaglobulin (IgIV) on the in vitro antibody response to a pneumococcal polysaccharide antigen. AB - INTRODUCTION: Clinical observations in patients with specific antibody deficiency treated for periods of time with IgG infusion have suggested that IgG may have a positive immunoregulatory effect on the production of specific antibodies against pneumococcal polysaccharides. We developed an in vitro model to test the effect of an IgIV preparation on the antibody production in response to a pneumococcal polysaccharide serotype and on the antibody and cytokine production in response to both a protein antigen and a pneumococcal polysaccharide antigen. METHODS: We studied 37 consecutive patients referred to our clinics for evaluation of their recurrent respiratory infections. Subjects were divided into two groups: 22 patients without SAD and 15 patients with SAD. PBMCs were left unstimulated or were stimulated with tetanus toxoid or pneumococcal polysaccharide serotype 19, in the presence of human albumin or IgIV. IgG anti-Pn-19 antibody, IL-4 and IFN gamma concentrations in culture supernatants were determined by ELISA. RESULTS: An increase in IgG anti-Pn-19 antibodies, associated with an increase in IFN gamma and a decrease in IL-4 production was observed in cultures stimulated with pneumococcal polysaccharide in the presence of IgIV when patients were analyzed together. The enhancing effect of IgIV was more significant for both IgG anti Pn19 antibodies and IFN-gamma in patients without SAD. In contrast, IgIV caused a significant decrease in IL-4 secretion in patients with SAD, which was associated with an increase in IgG anti-Pn19 antibodies in 3 of 7 of these patients. CONCLUSIONS: These results suggest that IgIV has some immunomodulatory effect on the in vitro production of IgG anti-Pn19 antibodies and cytokine production in cell cultures stimulated with Pn-19 antigen and that this modulation may be associated with a Th1/Th2 regulatory mechanism. Further studies at a cellular and molecular level are in progress to examine if the differences in the in vitro modulatory response to IgIV in these two groups of patients may point to a functional defect in patients with SAD. PMID- 25504427 TI - Comparison of a flexible versus a rigid breast compression paddle: pain experience, projected breast area, radiation dose and technical image quality. AB - PURPOSE: To compare pain, projected breast area, radiation dose and image quality between flexible (FP) and rigid (RP) breast compression paddles. METHODS: The study was conducted in a Dutch mammographic screening unit (288 women). To compare both paddles one additional image with RP was made, consisting of either a mediolateral-oblique (MLO) or craniocaudal-view (CC). Pain experience was scored using the Numeric Rating Scale (NRS). Projected breast area was estimated using computer software. Radiation dose was estimated using the model by Dance. Image quality was reviewed by three radiologists and three radiographers. RESULTS: There was no difference in pain experience between both paddles (mean difference NRS: 0.08 +/- 0.08, p = 0.32). Mean radiation dose was 4.5 % lower with FP (0.09 +/- 0.01 p = 0.00). On MLO-images, the projected breast area was 0.79 % larger with FP. Paired evaluation of image quality indicated that FP removed fibroglandular tissue from the image area and reduced contrast in the clinically relevant retroglandular area at chest wall side. CONCLUSIONS: Although FP performed slightly better in the projected breast area, it moved breast tissue from the image area at chest wall side. RP showed better contrast, especially in the retroglandular area. We therefore recommend the use of RP for standard MLO and CC views. PMID- 25504428 TI - Prostate cancer staging with extracapsular extension risk scoring using multiparametric MRI: a correlation with histopathology. AB - OBJECTIVES: To evaluate the diagnostic performance of preoperative multiparametric MRI with extracapsular extension (ECE) risk-scoring in the assessment of prostate cancer tumour stage (T-stage) and prediction of ECE at final pathology. MATERIALS AND METHODS: Eighty-seven patients with clinically localised prostate cancer scheduled for radical prostatectomy were prospectively enrolled. Multiparametric MRI was performed prior to prostatectomy, and evaluated according to the ESUR MR prostate guidelines by two different readers. An MRI clinical T-stage (cTMRI), an ECE risk score, and suspicion of ECE based on tumour characteristics and personal opinion were assigned. Histopathological prostatectomy results were standard reference. RESULTS: Histopathology and cTMRI showed a spearman rho correlation of 0.658 (p < 0.001) and a weighted kappa = 0.585 [CI 0.44;0.73](reader A). ECE was present in 31/87 (36 %) patients. ECE risk-scoring showed an AUC of 0.65-0.86 on ROC-curve for both readers, with sensitivity and specificity of 81 % and 78 % at best cutoff level (reader A), respectively. When tumour characteristics were influenced by personal opinion, the sensitivity and specificity for prediction of ECE changed to 61 %-74 % and 77 %-88 % for the readers, respectively. CONCLUSIONS: Multiparametric MRI with ECE risk-scoring is an accurate diagnostic technique in determining prostate cancer clinical tumour stage and ECE at final pathology. KEY POINTS: * Multiparametric MRI is an accurate diagnostic technique for preoperative prostate cancer staging * ECE risk scoring predicts extracapsular tumour extension at final pathology * ECE risk scoring shows an AUC of 0.86 on the ROC-curve * ECE risk scoring shows a moderate inter-reader agreement (K = 0.45) * Multiparametric MRI provides essential knowledge for optimal clinical management. PMID- 25504429 TI - Improved dopamine transporter binding activity after bone marrow mesenchymal stem cell transplantation in a rat model of Parkinson's disease: small animal positron emission tomography study with F-18 FP-CIT. AB - OBJECTIVES: We evaluated the effects of bone marrow-derived mesenchymal stem cells (BMSCs) in a model of Parkinson's disease (PD) using serial F-18 fluoropropylcarbomethoxyiodophenylnortropane (FP-CIT) PET. METHODS: Hemiparkinsonian rats were treated with intravenously injected BMSCs, and animals without stem cell therapy were used as the controls. Serial FP-CIT PET was performed after therapy. The ratio of FP-CIT uptake in the lesion side to uptake in the normal side was measured. The changes in FP-CIT uptake were also analyzed using SPM. Behavioural and histological changes were observed using the rotational test and tyrosine hydroxylase (TH)-reactive cells. RESULTS: FP-CIT uptake ratio was significantly different in the BMSCs treated group (n = 28) at each time point. In contrast, there was no difference in the ratio in control rats (n = 25) at any time point. SPM analysis also revealed that dopamine transporter binding activity was enhanced in the right basal ganglia area in only the BMSC therapy group. In addition, rats that received BMSC therapy also exhibited significantly improved rotational behaviour and preservation of TH positive neurons compared to controls. CONCLUSIONS: The therapeutic effect of intravenously injected BMSCs in a rat model of PD was confirmed by dopamine transporter PET imaging, rotational functional studies, and histopathological evaluation. KEY POINTS: * Mesenchymal stem cells were intravenously injected to treat the PD rats * Dopamine transporter binding activity was improved after stem cell therapy * Stem cell therapy induced functional recovery and preservation of dopaminergic neurons * The effect of stem cells was confirmed by FP-CIT PET. PMID- 25504430 TI - Correlates of healthy fruit and vegetable diet in students in low, middle and high income countries. AB - OBJECTIVES: The aim of this study was to assess the prevalence of fruits and vegetable consumption and associated factors among university students from 26 low, middle and high income countries. METHODS: Using anonymous questionnaires, data were collected in a cross-sectional survey from 17,789 undergraduate university students (mean age 20.8, SD = 2.8) from 27 universities in 26 countries across Asia, Africa and the Americas. RESULTS: Overall, 82.8% of the university students consumed less than the recommended five servings of fruits and/or vegetables. The mean fruit and vegetable consumption varied by country, ranging from <= 2.5 mean daily servings in Jamaica, Philippines and Barbados to >= 3.9 mean daily servings in Mauritius, Tunisia and Ivory Coast. In multivariate logistic regression analysis, sociodemographic factors, psychosocial factors, and behavioural factors (inadequate dietary behaviours, binge drinking and physical inactivity) were associated with low prevalence of fruit and vegetable intake. CONCLUSIONS: Findings stress the need for intervention programmes aiming at increased consumption of fruit and vegetables considering the identified sociodemographic, psychosocial and behavioural risk factors. PMID- 25504431 TI - Wogonin inhibits LPS-induced inflammatory responses in rat dorsal root ganglion neurons via inhibiting TLR4-MyD88-TAK1-mediated NF-kappaB and MAPK signaling pathway. AB - Recent studies showed that the activation of toll-like receptor 4 (TLR4) on dorsal root ganglion (DRG) neurons might underlie neuropathic and inflammatory pain states. This study was undertaken to investigate the effects of wogonin, a flavonoid with potent anti-inflammatory properties on the inflammatory reaction and TLR4 dependent pathways in lipopolysaccharide (LPS)-treated DRG neurons. Our results showed that wogonin not only inhibited the expression and interaction of TLR4, MyD88, and TAK1, but also reduced the activation of nuclear factor kappa B and mitogen-activated protein kinases pathway in LPS-treated DRG neurons. Moreover, wogonin significantly suppressed the release of pro-inflammatory mediators in LPS-induced DRG neurons, including cyclooxygenase-2, inducible nitric oxide synthases, interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha. Our results suggested that pre-treatment with wogonin could attenuate the TLR4-mediated inflammatory response in LPS-induced DRG neurons, thus might be beneficial for the treatment of neuropathic and inflammatory pain. PMID- 25504432 TI - Primary cilia in rat mature Muller glia: downregulation of IFT20 expression reduces sonic hedgehog-mediated proliferation and dedifferentiation potential of Muller glia primary cultures. AB - Primary cilia are specialized organelles that extend from the cell surface and concentrate signal transduction components. In the nervous system, primary cilia associated signals, such as sonic hedgehog (Shh), regulate cell proliferation and neuronal fate. Primary cilia assembly and maintenance require a multi-subunit intraflagellar transport (IFT) protein complex. Defects in primary cilia and IFT proteins are associated to severe pathological phenotypes. In the retina, the study of primary cilia has been mainly restricted to the specialized photoreceptor outer segment. The presence and physiological role of primary cilia in other retinal cells have not been clearly elucidated. Muller cells are the main glia of the retina where they exert distinct functions to maintain homeostasis. In pathological conditions, Muller cells mount a unique regenerative response through the processes of dedifferentiation, proliferation, and differentiation into neuronal lineages. The involvement of IFT proteins or a primary cilium in these processes has not been explored. In this study, we used mature Muller glia primary cultures to reveal the presence of the primary cilia by immunoreactivity to acetylated alpha-tubulin and gamma-tubulin, which localize to the axoneme and ciliar basal body, respectively. We demonstrate that si-RNA mediated downregulation of IFT20 gene expression, a main component of the IFT machinery, blocks Shh-induced Muller cell proliferation. We present evidence that IFT20 ablation impairs the dedifferentiation capacity of Muller cells induced by Shh and by glutamate. Our demonstration that Muller glia expresses IFT20 and harbors primary cilia, and opens new venues of research on the role of primary cilia in the retina. PMID- 25504433 TI - Acidosis promotes invasiveness of breast cancer cells through ROS-AKT-NF-kappaB pathway. AB - It is well known that acidic microenvironment promotes tumorigenesis, however, the underlying mechanism remains largely unknown. In the present study, we show that acidosis promotes invasiveness of breast cancer cells through a series of signaling events. First, our study indicates that NF-kappaB is a key factor for acidosis-induced cell invasion. Acidosis activates NF-kappaB without affecting STAT3 activity; knockdown of NF-kappaB p65 abrogates the acidosis-induced invasion activity. Next, we show that the activation of NF-kappaB is mediated through phosphorylation and degradation of IkappaBalpha; and phosphorylation and nuclear translocation of p65. Upstream to NF-kappaB signaling, AKT is activated under acidic conditions. Moreover, acidosis induces generation of reactive oxygen species (ROS) which can be suppressed by ROS scavengers, reversing the acidosis induced activation of AKT and NF-kappaB, and invasiveness. As a negative regulator of AKT, PTEN is oxidized and inactivated by the acidosis-induced ROS. Finally, inhibition of NADPH oxidase (NOX) suppresses acidosis-induced ROS production, suggesting involvement of NOX in acidosis-induced signaling cascade. Of considerable interest, acidosis-induced ROS production and activation of AKT and NF-kappaB can be only detected in cancer cells, but not in non-malignant cells. Together, these results demonstrate a cancer specific acidosis-induced signaling cascade in breast cancer cells, leading to cell invasion. PMID- 25504434 TI - Early outcome prediction on 18F-fluorocholine PET/CT in metastatic castration resistant prostate cancer patients treated with abiraterone. AB - OBJECTIVE: We investigated the role of 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) in the early evaluation of abiraterone and outcome prediction in patients with metastatic castration resistant prostate cancer (CRPC). PATIENT AND METHODS: Forty-three patients with metastatic CRPC progressing after docetaxel received abiraterone 1,000 mg daily with prednisone 5 mg twice daily. Patients were evaluated monthly for serological PSA response and safety. FCH-PET/CT was done at baseline and after 3 to 6 weeks. Univariate and multivariate Cox regression models addressed potential predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: Declines in PSA level of >=50% were seen in 21 of 43 (49%) patients. Forty-two patients were evaluable for FCH-PET/CT response. FCH-PET/CT bone flare was observed in 4 of 42 (10%) evaluable patients. In univariate analysis, PSA decline and FCH PET/CT response predicted PFS, while PSA decline and FCH-PET/CT (progression vs non progression) predicted OS. In multivariate analysis, only FCH-PET/CT (progression vs nonprogression) remained significant for PFS and OS (p = 0.022 and p = 0.027, respectively). CONCLUSION: Early FCH-PET/CT can predict clinical outcome in CRPC beyond PSA response. These data support further studies on FCH PET/CT for abiraterone monitoring and outcome prediction in patients with CRPC. PMID- 25504435 TI - PRK1/PKN1 controls migration and metastasis of androgen-independent prostate cancer cells. AB - The major threat in prostate cancer is the occurrence of metastases in androgen independent tumor stage, for which no causative cure is available. Here we show that metastatic behavior of androgen-independent prostate tumor cells requires the protein-kinase-C-related kinase (PRK1/PKN1) in vitro and in vivo. PRK1 regulates cell migration and gene expression through its kinase activity, but does not affect cell proliferation. Transcriptome and interactome analyses uncover that PRK1 regulates expression of migration-relevant genes by interacting with the scaffold protein sperm-associated antigen 9 (SPAG9/JIP4). SPAG9 and PRK1 colocalize in human cancer tissue and are required for p38-phosphorylation and cell migration. Accordingly, depletion of either ETS domain-containing protein Elk-1 (ELK1), an effector of p38-signalling or p38 depletion hinders cell migration and changes expression of migration-relevant genes as observed upon PRK1-depletion. Importantly, a PRK1 inhibitor prevents metastases in mice, showing that the PRK1-pathway is a promising target to hamper prostate cancer metastases in vivo. Here we describe a novel mechanism controlling the metastatic behavior of PCa cells and identify PRK1 as a promising therapeutic target to treat androgen-independent metastatic prostate cancer. PMID- 25504436 TI - Reciprocal activation between IL-6/STAT3 and NOX4/Akt signalings promotes proliferation and survival of non-small cell lung cancer cells. AB - Inflammatory cytokines and oxidative stress are two critical mediators in inflammation-associated cancer. Interleukin-6 (IL-6) is one of the most critical tumor-promoting cytokines in non-small cell lung cancer (NSCLC). In our recent study, we confirmed that NADPH oxidase 4 (NOX4), an important source of reactive oxygen species (ROS) production in NSCLC cells, promotes malignant progression of NSCLC. However, whether the crosstalk of NOX4 and IL-6 signalings exists in NSCLC remains undentified. In this study, we show that NOX4 expression is positively correlated with IL-6 expression in NSCLC tissues. Exogenous IL-6 treatment significantly enhances NOX4/ROS/Akt signaling in NSCLC cells. NOX4 also enhances IL-6 production and activates IL-6/STAT3 signaling in NSCLC cells. Specifically, NOX4 is confirmed to functionally interplay with IL-6 to promote NSCLC cell proliferation and survival. The in vivo results were similar to those obtained in vitro. These data indicate a novel NOX4-dependent link among IL-6 in the NSCLC microenvironment, oxidative stress in NSCLC cells and autocrined IL-6 in NSCLC cells. NOX4/Akt and IL-6/STAT3 signalings can reciprocally and positively regulate each other, leading to enhanced NSCLC cell proliferation and survival. Therefore, NOX4 may serve as a promising target against NSCLC alone with IL-6 signaling. PMID- 25504437 TI - miR-125a-5p is a prognostic biomarker that targets HDAC4 to suppress breast tumorigenesis. AB - Identifying stably expressed tumor markers that can be used easily to detect cancer is currently an important area of cancer research. By using miRNA microarray, we identified 20 differentially expressed miRNAs in serum samples of breast cancer patients. Expression of miR-125a-5p was relatively lower in patients with shorter survival compared to long-term survivors. In a cohort of breast cancer patients (N = 300), serum expression of miR-125a-5p was negatively and significantly correlated with tumor grade (P = 0.004), lymph-node status (P = 0.004), and tumor size (P < 0.001). Low miR-125a-5p expression was an independent prognostic marker (OR = 0.421; 95% CI = 0.184 to 0.961; P = 0.04) associated with poor survival rates (P = 0.0062). We show that miR-125a-5p directly inhibits expression of the HDAC4 gene, resulting in tumor suppression in vitro and in vivo. Together these results demonstrate that serum miR-125a-5p level in breast cancer may be a useful prognostic biomarker and offer a novel therapeutic avenue by targeting HDAC4 in breast cancer. PMID- 25504438 TI - DNA methylation transcriptionally regulates the putative tumor cell growth suppressor ZNF677 in non-small cell lung cancers. AB - In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC). By comparing ZNF677 expression in primary tumor (TU) and in the majority of cases also of corresponding non-malignant lung tissue (NL) samples from > 1,000 NSCLC patients, we found tumor-specific downregulation of ZNF677 expression (adjusted p-values < 0.001). We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001). In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression. Moreover, ZNF677 overexpression in NSCLC cells was associated with reduced cell proliferation and cell migration. ZNF677 was identified to regulate expression of many genes mainly involved in growth hormone regulation and interferon signalling. Finally, patients with ZNF677 methylated TUs had a shorter overall survival compared to patients with ZNF677 not methylated TUs (p = 0.013). Overall, our results demonstrate that ZNF677 is trancriptionally regulated by methylation in NSCLCs, suggest that ZNF677 has tumor cell growth suppressing properties in NSCLCs and that ZNF677 methylation might serve as prognostic parameter in these patients. PMID- 25504439 TI - Metformin and trametinib have synergistic effects on cell viability and tumor growth in NRAS mutant cancer. AB - Attempts to directly block the mutant neuroblastoma rat sarcoma oncogene (NRAS) protein, a driving mutation in many cancer types, have been unsuccessful. Current treatments focus on inhibition of different components of NRAS' two main downstream cascades: PI3K/AKT/mTOR and MAPK. Here we test a novel dual therapy combination of metformin and trametinib on a panel of 16 NRAS mutant cell lines, including melanoma cells, melanoma cells with acquired trametinib resistance, lung cancer and neuroblastoma cells. We show that both of the main downstream cascades of NRAS can be blocked by this combination: metformin indirectly inhibits the PI3K/AKT/mTOR pathway and trametinib directly impedes the MAPK pathway. This dual therapy synergistically reduced cell viability in vitro and xenograft tumor growth in vivo. We conclude that metformin and trametinib combinations are effective in preclinical models and may be a possible option for treatment of NRAS mutant cancers. PMID- 25504440 TI - Intrinsic TGF-beta2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance and a slow-cycling state in bone marrow-disseminated tumor cells. AB - Dormant or slow-cycling disseminated tumor cells (DTCs) in bone marrow (BM) are resistant to conventional therapy in various cancers including head and neck squamous cell carcinoma (HNSCC), although the molecular mechanisms remain largely unknown. This study aimed to identify the intrinsic molecular mechanisms underlying drug resistance in BM-DTCs. We used in vivo selection of the human HNSCC cell line HEp3, which mimics non-proliferative BM-DTCs in mice, to establish BM-DTC-derived (BM-HEp3) and lung metastases-derived (Lu-HEp3) sublines. Both sublines had higher migration activity and shortened survival in a murine xenograft model compared with parental (P-HEp3) cells. Slow-cycling BM HEp3 cells had intrinsically enhanced cisplatin resistance compared with Lu-HEp3 cells, which also manifested this resistance but proliferated rapidly. The drug resistance and slow-cycling state of BM-HEp3 cells depended on enhanced positive feedback of the signaling axis of stromal cell-derived factor-1 (SDF-1)-C-X-C chemokine receptor-4 (CXCR4) via their overexpression. Interestingly, BM-DTCs highly expressed transforming growth factor-beta 2 (TGF-beta2) to maintain SDF-1 CXCR4 overexpression. Inhibition of SDF-1-CXCR4 signaling by down-regulating TGF beta2 fully reversed the drug resistance of BM-HEp3 cells via reactivation of cell proliferation. These data suggest that the intrinsic TGF-beta2-triggered SDF 1-CXCR4 signaling axis is crucial for drug resistance dependent on a slow-cycling state in BM-DTCs. PMID- 25504441 TI - The activity regulation of the mitotic centromere-associated kinesin by Polo-like kinase 1. AB - The mitotic centromere-associated kinesin (MCAK), a potent microtubule depolymerase, is involved in regulating microtubule dynamics. The activity and subcellular localization of MCAK are tightly regulated by key mitotic kinases, such as Polo-like kinase 1 (Plk1) by phosphorylating multiple residues in MCAK. Since Plk1 phosphorylates very often different residues of substrates at different stages, we have dissected individual phosphorylation of MCAK by Plk1 and characterized its function in more depth. We have recently shown that S621 in MCAK is the major phosphorylation site of Plk1, which is responsible for regulating MCAK's degradation by promoting the association of MCAK with APC/CCdc20. In the present study, we have addressed another two residues phosphorylated by Plk1, namely S632/S633 in the C-terminus of MCAK. Our data suggest that Plk1 phosphorylates S632/S633 and regulates its catalytic activity in mitosis. This phosphorylation is required for proper spindle assembly during early phases of mitosis. The subsequent dephosphorylation of S632/S633 might be necessary to timely align the chromosomes onto the metaphase plate. Therefore, our studies suggest new mechanisms by which Plk1 regulates MCAK: the degradation of MCAK is controlled by Plk1 phosphorylation on S621, whereas its activity is modulated by Plk1 phosphorylation on S632/S633 in mitosis. PMID- 25504442 TI - Mesenchymal stem cells are resistant to carbon ion radiotherapy. AB - Mesenchymal stem cells (MSCs) participate in regeneration of tissues damaged by ionizing radiation. However, radiation can damage MSCs themselves. Here we show that cellular morphology, adhesion and migration abilities were not measurably altered by photon or carbon ion irradiation. The potential for differentiation was unaffected by either form of radiation, and established MSC surface markers were found to be stably expressed irrespective of radiation treatment. MSCs were able to efficiently repair DNA double strand breaks induced by both high-dose photon and carbon ion radiation. We have shown for the first time that MSCs are relatively resistant to therapeutic carbon ion radiotherapy. Additionally, this form of radiation did not markedly alter the defining stem cell properties or the expression of established surface markers in MSCs. PMID- 25504444 TI - Nuclear magnetic resonance structure elucidation of peptide b2 ions. AB - Tandem mass spectrometry (MS/MS) is powerful for chemical identification but it is still insufficient for explicit ion structure determination. A strategy is introduced to elucidate MS fragment ion structures using NMR spectroscopy for the first time. In our experiments, precursor ions are dissociated at atmospheric pressure and the resulting fragment ions are identified by mass spectrometry but collected outside the mass spectrometer, making the subsequent NMR measurements possible. This new strategy has been applied to determine the chemical structure of the characteristic b2 fragment ion, a subject of longstanding debate in MS based proteomics. PMID- 25504443 TI - Cognitive profile of children and adolescents with anorexia nervosa. AB - OBJECTIVE: Few studies of cognitive functioning in children and adolescents with anorexia nervosa (AN) have been conducted. The aim of this study was to examine the neurocognitive and intelligence profile of this clinical group. METHOD: The study was a matched case-control (N = 188), multi-centre study including children and adolescents with AN (N = 94) and healthy control participants (N = 94). RESULTS: The results suggest that Full Scale Intelligence Quotient (Wechsler Intelligence Scale for Children-III/Wechsler Adult Intelligence Scale-III) in this patient group is close to the normal population mean of 100. Individuals with AN exhibited significantly worse performance in nonverbal intelligence functions (i.e. Wechsler Intelligence Scale for Children-III/Wechsler Adult Intelligence Scale-III, Perceptual Organization Index) and in verbal memory (Test of Memory and Learning-Second Edition, Memory for Stories) and motor speed (Cambridge Neuropsychological Test Automated Battery, Simple and Choice Reaction Time) compared with healthy control participants. No significant difference in set-shifting ability (Cambridge Neuropsychological Test Automated Battery, Intra Extra Dimensional Set Shift and Trail Making Test B) was found. CONCLUSIONS: Inefficiency in nonverbal intelligence functions and in specific cognitive functions was found in this study of children and adolescents with AN. PMID- 25504445 TI - Inhibitory and synergistic effects of natural olive phenols on human platelet aggregation and lipid peroxidation of microsomes from vitamin E-deficient rats. AB - PURPOSE: This study explored the in vitro antioxidant and anti-platelet activities of hydroxytyrosol, hydroxytyrosol acetate, 3,4-dihydroxyphenylglycol and two phenolic olive extracts. These compounds and extracts were obtained from a new industrial process to hydrothermally treat the alperujo (160 degrees C/60 min), a by-product of olive oil extraction. METHODS: The extracts and the purified compounds were obtained chromatographically using both ionic and adsorbent resins. The antioxidant activity was determined by measuring inhibition of human platelet aggregation and inhibition of lipid peroxidation in liver microsomes of vitamin E-deficient rats. RESULTS: The positive effect of the extracts on the inhibition of platelet aggregation is showed, being higher in the case of hydroxytyrosol acetate up to 38%, and for the first time, its synergist effect with hydroxytyrosol has been proved, obtaining more than double of inhibition. The phenolic extracts and the isolated phenols showed good results for inhibiting the lipid oxidation, up to 62 and 25%, respectively. A synergistic effect occurred when the hydroxytyrosol acetate and the 3,4-dihydroxyphenylglycol were supplemented by hydroxytyrosol. CONCLUSION: These results suggest the extract and these compounds obtained from a novel industrial process could be natural alternatives for the prevention of diseases related to cardiovascular disorder or oxidative damage. PMID- 25504446 TI - The influence of the menstrual cycle on energy balance and taste preference in Asian Chinese women. AB - PURPOSE: In Caucasian women, research has shown that energy balance and taste preference change throughout the menstrual cycle. However, the contributory role of the menstrual cycle to obesity and insulin resistance among Asian women remains unclear. We investigate the impact of the menstrual cycle on energy balance and taste preference in Singaporean Chinese females. METHODS: Thirty-one healthy young Chinese female subjects with regular menstrual cycles were recruited. Anthropometrics, body composition, energy intake, resting metabolic rate, premenstrual syndrome (PMS) severity and taste preference to sucrose were assessed during three phases (menses, follicular and luteal), over one (N = 18) to two (N = 13) menstrual cycles. RESULTS: For all subjects (N = 31), we found significant reductions in energy, fat intake (p < 0.05) and taste preference for sucrose (p < 0.05) in the luteal phase compared to early follicular phase as far as Cycle 1 is concerned. No significant differences were observed for carbohydrate and protein intake as well as PMS score. In those evaluated for two full cycles (N = 13), we found that taste preference for sucrose and PMS score were significantly higher in the menstrual phase in Cycle 2 (p < 0.05). No significant differences were observed in energy and macronutrient intake throughout Cycle 2. RMR was similar across the three phases. However, non significant cyclic variations were noted within and between the cycles. CONCLUSION: Cyclic variations in energy intake and expenditure contributed by sensory and behavioural changes occur during the menstrual cycle. Whether this contributes to cyclic weight gain is speculative and remains to be proven. Further research in non-Caucasians spanning more than one menstrual cycle is needed to establish the impact of the menstrual cycle on taste preference and energy balance. PMID- 25504447 TI - Interleaved programming of subthalamic deep brain stimulation to avoid adverse effects and preserve motor benefit in Parkinson's disease. AB - Subthalamic nucleus (STN) deep brain stimulation (DBS) is the most common surgical treatment for managing motor complications in Parkinson's disease (PD). Ultimately, outcomes depend on a variety of factors including lead location, access and expertize in programming and PD medical management. Nevertheless, achieving ideal programming settings can be difficult in certain patients, leading to suboptimal control of symptoms and stimulation-induced side effects, notably dysarthria and dyskinesia. Interleaved stimulation (ILS) is a newer programming technique that attempts to optimize the stimulation field, improving control of symptoms while minimizing stimulation-induced adverse effects. A retrospective chart review was performed on PD patients receiving STN DBS over the past 12 months. Clinical and demographic data were collected from patients identified as having received ILS. The rationale and clinical efficacy of ILS was analyzed. Nine patients received ILS due to incomplete PD symptom control or stimulation-induced side effects after attempting multiple programming options. Appropriate lead location was confirmed with postoperative MRI except in one case. Following ILS, patients reported improvement in symptoms and resolution of side effects, while preserving adequate control in Parkinsonism with a mean improvement in UPDRS-MOTOR scores of 51.2 %. ILS continues to emerge as a safe and effective programming strategy for maximizing symptom control in PD while diminishing stimulation-induced side effects. PMID- 25504448 TI - Erratum to: Autonomic symptoms in idiopathic REM behavior disorder: a multicentre case-control study. PMID- 25504450 TI - Laparoscopic reduction and repair for incarcerated obturator hernia: comparison with open surgery. AB - PURPOSE: Transabdominal preperitoneal (TAPP) repair for obturator hernia (OH) is not well established. Therefore, we evaluated the efficacy of TAPP for OH repair compared with open surgery. METHODS: We retrospectively analyzed patients who underwent surgery for OH at our hospital between 2006 and 2011. Since 2009, we have used TAPP repair for OH instead of open surgery. The clinical results of TAPP repair were compared with those of open surgery performed before 2008. RESULTS: Six patients with OH were treated by TAPP repair; occult contralateral OH was found by laparoscopic exploration in three (50 %) patients and was simultaneously repaired. Bowel incarceration was reduced by water pressure through Nelaton catheter in all but one patient. Bowel resection was performed in two patients after the laparoscopic assessment. For incarcerated OH, five of six cases were repaired using synthetic mesh, and the remaining case was addressed with simple peritoneal closure. Before 2008, six patients with OH underwent open surgery. The background of patients was comparable in the TAPP group and the open surgery group. There were no deaths in either group, but one metachronous contralateral OH occurred in the open surgery group within a short time frame, whereas none occurred in the TAPP group. CONCLUSIONS: TAPP repair, including the inspection of the viability of the incarcerated intestine and protective reduction and assessment of the entire groin area is an effective and minimally invasive strategy for OH patients. PMID- 25504449 TI - Individualized texting for adherence building (iTAB): improving antiretroviral dose timing among HIV-infected persons with co-occurring bipolar disorder. AB - HIV+ persons with co-occurring bipolar disorder (HIV+/BD+) have elevated rates of medication nonadherence. We conducted a 30-day randomized controlled trial of a two-way, text messaging system, iTAB (n = 25), compared to an active comparison (CTRL) (n = 25) to improve antiretroviral (ARV) and psychotropic (PSY) adherence and dose timing. Both groups received medication adherence psychoeducation and daily texts assessing mood. The iTAB group additionally received personalized medication reminder texts. Participants responded to over 90 % of the mood and adherence text messages. Mean adherence, as assessed via electronic monitoring caps, was high and comparable between groups for both ARV (iTAB 86.2 % vs. CTRL 84.8 %; p = 0.95, Cliff's d = 0.01) and PSY (iTAB 78.9 % vs. CTRL 77.3 %; p = 0.43, Cliff's d = -0.13) medications. However, iTAB participants took ARVs significantly closer to their intended dosing time than CTRL participants (iTAB: 27.8 vs. CTRL: 77.0 min from target time; p = 0.02, Cliff's d = 0.37). There was no group difference on PSY dose timing. Text messaging interventions may represent a low-burden approach to improving timeliness of medication-taking behaviors among difficult-to-treat populations. The benefits of improved dose timing for long-term medication adherence require additional investigation. PMID- 25504451 TI - Is it time to rethink our management of dialysis patients undergoing elective ventral hernia repair? Analysis of the ACS NSQIP database. AB - PURPOSE: The number of patients on chronic dialysis is steadily increasing each year. There is little data that describes the outcomes in dialysis patients following elective ventral hernia repair, one of the most common general surgery procedures. Our objective was to compare the mortality and morbidity rates in dialysis versus nondialysis patients following elective ventral hernia repair. METHODS: We analysed the ACS NSQIP database to identify patients that underwent elective ventral hernia repair from 2005 to 2010. Univariate analysis and multivariate logistic regression was performed on all patients included. The main outcome variables were mortality and morbidity, length of hospital stay, and return to the operating room. RESULTS: Following elective ventral hernia repair, dialysis patients were more likely to die within 30 days or experience at least one morbidity. Dialysis patients were more likely to experience an infectious, pulmonary or vascular complication. Patients on dialysis also had a 2-fold greater risk of returning to the operating room within 30 days and stayed in the hospital an average of 1.3 days longer than nondialysis patients. Similar results were found after adjustment for demographics and comorbidities using multivariable logistic regression. CONCLUSION: This is one of the largest studies demonstrating the outcomes of a specific general surgery procedure in dialysis patients. Chronic dialysis prior to elective ventral hernia repair is associated with an increased risk of 30-day mortality, morbidity, and return to the operating room. Dialysis patients are susceptible to infectious, pulmonary, and vascular post-operative complications. PMID- 25504452 TI - Lumbar hernia in South Korea: different from that in foreign literature? AB - PURPOSE: This study aimed to analyze the clinical features of lumbar hernia reported in South Korea and compare these features with those reported in foreign literature. METHODS: From January 1968 through December 2013, 13 cases reported in South Korea were included in the study. The variables compared were age, sex, main symptoms at hospital visit, etiology, location, herniated contents, lateralization, defect size, diagnostic methods, surgical methods, surgical opinions, and recurrence. RESULTS: In the South Korean cases, women outnumbered men (3.3:1) and no significant differences were found in the herniated side (left:right, 1.1:1). In contrast, in the foreign cases, men outnumbered women (3:1) and left-sided hernia was dominant (2:1). Moreover, in most of the foreign cases, patients were aged 50-70 years, whereas in the South Korean cases, none of the patients were in their 50 s. However, no substantial differences were found in etiology, anatomical locations, symptoms, and herniated contents. CONCLUSION: This research revealed that few clinical features of lumbar hernias in South Korea differ from those reported in foreign literature. Thirteen cases were analyzed in the present study, and results obtained from such a small sample size cannot be generalized with certainty. Therefore, more cases should be collected for a definitive analysis. Despite this limitation, this study is important because it is the first attempt to collect and analyze the clinical features of lumbar hernia in South Korea. This study will serve as a basis for future studies investigating the clinical features of lumbar hernia cases in South Korea. PMID- 25504453 TI - Osteotropic polypeptide nanoparticles with dual hydroxyapatite binding properties and controlled cisplatin delivery. AB - PURPOSE: Nanoparticles with prolonged residence time in bone constitute a valuable strategy for bone disease treatments. The aim of this work was to synthesise a simple nanoparticulate system exhibiting both anticancer and hydroxyapatite binding properties for potential bone cancer applications. METHODS: The amphiphilic copolymer poly(gamma-benzyl-glutamate)-block poly(glutamic acid) (PBLG-b-PGlu) was synthetised by ring opening polymerization and nanoparticles were obtained by a simple nanoprecipitation method. Nanoparticles were characterized in terms of cisplatin interaction, association, and release as well as interaction with hydroxyapatite and their cytoxicity was studied in three prostate cancer cell lines. RESULTS: PBLG-b-PGlu nanoparticles of ~50 nm in size were successfully prepared. They could display for the first time dual hydroxyapatite binding and anticancer properties mediated by the PGlu moiety. They could complex cisplatin at a drug loading content of 6.2% (w/w). Cisplatin release was triggered by physiological concentrations of chloride ions according to an almost zero order kinetics during 14 days. Simultaneously, these nanoparticles showed in vitro hydroxyapatite binding. Finally, they were shown to exert a cytotoxic effect in three prostate cancer cell lines that potentially metastasize to bone. CONCLUSIONS: These properties suggest the potential utility of cisplatin-loaded PBLG-b-PGlu nanoparticles as carrier systems for the treatment of bone metastases. PMID- 25504454 TI - MITOsym(r): A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics. AB - PURPOSE: MITOsym, a new mathematical model of hepatocellular respiration and bioenergetics, has been developed in partnership with the DILIsym(r) model with the purpose of translating in vitro compound screening data into predictions of drug induced liver injury (DILI) risk for patients. The combined efforts of these two models should increase the efficiency of evaluating compounds in drug development in addition to enhancing patient care. METHODS: MITOsym includes the basic, essential biochemical pathways associated with hepatocellular respiration and bioenergetics, including mitochondrial oxidative phosphorylation, electron transport chain activity, mitochondrial membrane potential, and glycolysis; also included are dynamic feedback signals based on perturbation of these pathways. The quantitative relationships included in MITOsym are based primarily on published data; additional new experiments were also performed in HepG2 cells to determine the effects on oxygen consumption rate as media glucose concentrations or oligomycin concentrations were varied. The effects of varying concentrations of FCCP on the mitochondrial proton gradient were also measured in HepG2 cells. RESULTS: MITOsym simulates and recapitulates the reported dynamic changes to hepatocellular oxygen consumption rates, extracellular acidification rates, the mitochondrial proton gradient, and ATP concentrations in the presence of classic mitochondrial toxins such as rotenone, FCCP, and oligomycin. CONCLUSIONS: MITOsym can be used to simulate hepatocellular respiration and bioenergetics and provide mechanistic hypotheses to facilitate the translation of in vitro data collection to predictions of in vivo human hepatotoxicity risk for novel compounds. PMID- 25504455 TI - Low pericyte coverage of endometrial microvessels in heavy menstrual bleeding correlates with the microvessel expression of VEGF-A. AB - A prospective clinical study was carried out to investigate whether endometrial microvessels in patients with idiopathic heavy menstrual bleeding (HMB) of endometrial origin (HMB-E) are fragile due to low pericyte coverage. Idiopathic HMB-E is characterized by large endothelial cell gaps related to the microvascular overexpression of vascular endothelial growth factor (VEGF)-A and VEGF receptors 1-3. A total of 10 women with a normal menstrual cycle and a history of HMB of <5 years, and 17 healthy women with a normal menstrual cycle were recruited from the Karolinska University Hospital. Blood samples were obtained for hormone analysis and coagulation tests. Endometrial biopsies were collected in the proliferative or in the secretory phase. Pericyte coverage was assessed using immunohistochemical staining for smooth muscle actin-alpha (SMAalpha) and by image analysis (microvascular density) of endometrial biopsies from 10 patients with HMB-E and 17 healthy ovulating women (control subjects). Previously published data on endothelial cell gap size and the expression of VEGF receptors were used. Although microvascular density did not differ between the patients with HMB-E and the control subjects, the number of SMAalpha-positive microvessels in the proliferative phase was significantly (P=0.005) lower in the patients with HMB-E than in the control subjects. Moreover, the number of SMAalpha-positive microvessels in the control subjects was significantly fewer in the secretory (P=0.04) than in the proliferative phase, whereas this number did not differ among the patients with HMB-E regardless of phase. A significant negative correlation was observed between the number of VEGF-A-positive microvessels and microvessels with pericyte coverage (r=0.8; P=0.04). Finally, the endothelial cell layer was significantly thicker in the patients with HMB-E than in the control subjects. Thus, the upregulation of VEGF-A in idiopathic HMB E is associated with a low pericyte coverage during the proliferative phase of intense angiogenesis, which may confer vessel fragility, possibly leading to excessive blood loss. PMID- 25504456 TI - The role of placekeeping ability in fluid intelligence. AB - The question of what underlies individual differences in general intelligence has never been satisfactorily answered. The purpose of this research was to investigate the role of an executive function that we term placekeeping ability the ability to perform the steps of a complex task in a prescribed order without skipping or repeating steps. Participants completed a newly developed test of placekeeping ability, called the UNRAVEL task. The measure of placekeeping ability from this task (error rate) predicted a measure of fluid intelligence (Raven's Advanced Progressive Matrices score), above and beyond measures of working memory capacity, task switching, and multitasking. An existing model of Raven's performance suggests that placekeeping ability supports the systematic exploration of hypotheses under problem-solving conditions. PMID- 25504457 TI - Addition goes where the big numbers are: evidence for a reversed operational momentum effect. AB - Number processing evokes spatial biases, both when dealing with single digits and in more complex mental calculations. Here we investigated whether these two biases have a common origin, by examining their flexibility. Participants pointed to the locations of arithmetic results on a visually presented line with an inverted, right-to-left number arrangement. We found directionally opposite spatial biases for mental arithmetic and for a parity task administered both before and after the arithmetic task. We discuss implications of this dissociation in our results for the task-dependent cognitive representation of numbers. PMID- 25504458 TI - An empirical test of the independence between declarative and procedural working memory in Oberauer's (2009) theory. AB - It has recently been suggested that working memory could be conceived as two symmetrical subsystems with analogous structure and processing principles: a declarative working memory storing objects of thought available for cognitive operations, and a procedural working memory holding representations of what to do with these objects (Oberauer, Psychology of learning and motivation 51: 45-100, 2009). Within this theoretical framework, the two subsystems are thought to be independent and fueled by their own capacity. The present study tested this hypothesis through two experiments using a complex span task in which participants were asked to maintain consonants for further recall while performing response selection tasks. In line with Oberauer's conception, the load of the procedural working memory was varied by manipulating the number of stimulus-response mappings of the response selection task. Increasing the number of these mappings had a strong detrimental effect on recall performance. Besides contradicting Oberauer's proposal, this finding supports models that assume a resource-sharing between processing and storage in working memory. PMID- 25504459 TI - Selective interference of grasp and space representations with number magnitude and serial order processing. AB - It has been proposed that the metrics of space, time and other magnitudes relevant for action are coupled through a generalized magnitude system that also contribute to number representation. Several studies capitalized on stimulus response compatibility effects to show that numbers map onto left-right representations and grasp representations as a function of their magnitude. However, the tasks typically used do not allow disentangling magnitude from serial order processing. Here, we devised a working memory (WM) task where participants had to remember random sequences of numbers and perform a precision/whole-hand grip (Experiment 1) or a uni-manual left/right button press (Experiment 2) in response to numbers presented during the retention interval. This task does allow differentiating the interference of number magnitude and serial order with each set of responses. Experiment 1 showed that precision grips were initiated faster than whole-hand grips in response to small numbers, irrespective of their serial position in WM. In contrast, Experiment 2 revealed an advantage of right over left button presses as serial position increased, without any influence of number magnitude. These findings demonstrate that grasping and left-right movements overlap with distinct dimensions of number processing. These findings are discussed in the light of different theories explaining the interactions between numbers, space and action. PMID- 25504461 TI - Determination of a refractive index and an extinction coefficient of standard production of CVD-graphene. AB - The refractive index and extinction coefficient of chemical vapour deposition grown graphene are determined by ellipsometry analysis. Graphene films were grown on copper substrates and transferred as both monolayers and bilayers onto SiO2/Si substrates by using standard manufacturing procedures. The chemical nature and thickness of residual debris formed after the transfer process were elucidated using photoelectron spectroscopy. The real layered structure so deduced has been used instead of the nominal one as the input in the ellipsometry analysis of monolayer and bilayer graphene, transferred onto both native and thermal silicon oxide. The effect of these contamination layers on the optical properties of the stacked structure is noticeable both in the visible and the ultraviolet spectral regions, thus masking the graphene optical response. Finally, the use of heat treatment under a nitrogen atmosphere of the graphene-based stacked structures, as a method to reduce the water content of the sample, and its effect on the optical response of both graphene and the residual debris layer are presented. The Lorentz-Drude model proposed for the optical response of graphene fits fairly well the experimental ellipsometric data for all the analysed graphene-based stacked structures. PMID- 25504460 TI - Perceptual and behavioral adjustments after action inhibition. AB - Inhibiting a motor action typically prompts a more cautious action mode, leaning toward accuracy rather than speed. In the present study, we explored whether action inhibition is also accompanied by changes of visual perception. Our participants performed goal-directed hand movements from a start to a target position and then judged the start-target distance. On a proportion of the trials, movement execution had to be stopped before the target position was reached. The results of two experiments revealed smaller start-target distance estimates after interrupted than after unrestricted movements. Moreover, movement amplitudes were decreased in movements that followed interrupted ones. In line with the predictions of action-specific accounts of perception, this outcome indicates that subjective perceptual changes might inform us how to plan future actions. PMID- 25504462 TI - A single institution experience in compliance with universal screening for Lynch syndrome in colorectal cancer. AB - BACKGROUND: Detection of Lynch syndrome has the potential to reduce morbidity and mortality among patients and their family members due to beneficial screening and treatment options. Several institutions have begun to adopt universal rather than risk-stratified screening protocols, but the lack of 100 % compliance rates requires identification of system-level interventions to improve screening practices. OBJECTIVE: We aimed to identify patient, tumor, and system factors associated with lack of screening and identify system-based interventions to improve Lynch syndrome screening. DESIGN AND SETTINGS: This study is a retrospective analysis of Lynch syndrome screening among colorectal cancer patients undergoing surgery in a single healthcare system. PATIENTS: Two hundred and sixty-two patients who underwent surgery for colorectal cancer were studied. MAIN OUTCOME MEASURES: Rate of Lynch syndrome screening. RESULTS: We identified that 75 % of the total cohort was screened for Lynch syndrome. Of patients under the age of 50, 78 % percent were screened. Lower screening rates were found among patients with complete pathologic tumor response and lower pathologic stage of tumor. Higher screening rates were found at the academic hospital and with colorectal surgeons. In multivariable logistic regression analysis, lower screening rates were associated with community hospital location (OR, 0.22; 95 % CI, 0.08-0.56). LIMITATIONS: Results may not be generalizable to different hospital settings. CONCLUSIONS: Several potential system-level interventions were identified to improve screening rates including an emphasis on improved provider communication. PMID- 25504463 TI - SSAT presidential address 2014: here comes Generation Y! PMID- 25504464 TI - Parastomal hernia repair. AB - Parastomal herniation is a common clinical occurrence. Historically, there has been a high recurrence rate after repair, and conservative management is usually recommended for patients with mild symptoms. When operative intervention is warranted, we opt for a laparoscopic mesh sublay over the fascial defect and lateralization of the stoma limb, or the Sugarbaker technique. In patients who are considered poor risk for laparoscopy/laparotomy requiring repair, we perform a fascial onlay with mesh utilizing an anterior circumstomal approach. PMID- 25504465 TI - The effect of bitter melon (Mormordica charantia) in patients with diabetes mellitus: a systematic review and meta-analysis. AB - BACKGROUND: Mormordica charantia (bitter melon) has been investigated for lowering plasma glucose in patients with diabetes mellitus (DM). Previous data has offered inconclusive and inconsistent results about the benefits of bitter melon in patients with DM. Our current project aims to determine whether bitter melon has a favorable effect in lowering plasma glucose in patients with DM. METHODS: We searched PubMed, EMBASE and the Cochrane Library from inception to July 2013 without any language restrictions for randomized controlled trials (RCTs) evaluating bitter melon to no treatment in patients with type 1 or type 2 diabetes. Study selection, data extraction and validity of each article were independently assessed by two investigators. Articles were appraised for proper random sequence generation, allocation concealment, blinding, selective reporting and completeness of outcomes reporting to assess the risk for biases. The glycemic results of each RCT were analyzed to yield weighted mean differences (WMDs) and 95% confidence intervals (CIs). RESULTS: A total of four RCTs, each with 40-66 participants, followed between 4 and 12 weeks were identified in this meta-analysis. Overall risk of bias for each article included was determined to be unclear. In total, 208 participants with type 2 DM (mean age of 56.5 years) were evaluated. Compared with no treatment, bitter melon did not significantly lower A1C (WMD -0.13%, 95% CI -0.41 to 0.16) nor fasting plasma glucose (FPG) 47 (WMD 2.23 mg dl(-1), 95% CI -14.91 to 19.37). CONCLUSIONS: Bitter melon supplementation compared with no treatment did not show significant glycemic improvements on either A1c or FPG.Nutrition & Diabetes advance online publication, 15 December 2014; doi:10.1038/nutd.2014.42. PMID- 25504466 TI - A pilot randomized controlled trial evaluating an integrated treatment of rivastigmine transdermal patch and cognitive stimulation in patients with Alzheimer's disease. AB - OBJECTIVE: To evaluate in a pilot single-blind randomized controlled clinical trial the efficacy of an integrated treatment with rivastigmine transdermal patch (RTP) and cognitive stimulation (CS) in Alzheimer's disease (AD) patients at 6 month follow-up. METHODS: We enrolled 90 patients with an age >=65 years admitted to the outpatient Alzheimer's Evaluation Unit with diagnosis of AD. Patients were randomized to enter in the Group-1 (RTP + CS) or in the Group-2 (RTP). All patients at baseline and after 6 months were evaluated with the following tools: Mini Mental State Examination (MMSE), Clinical Dementia Rating (CDR), Hamilton Rating Scale for Depression (HAM-D), Geriatric Depression Scale (GDS-15), Neuropsychiatric Inventory (NPI), Neuropsychiatric Inventory-Distress (NPI-D), and a standardized Comprehensive Geriatric Assessment, including also activities of daily living (ADL), instrumental activities of daily living (IADL), and the Mini Nutritional Assessment (MNA). Mortality risk was assessed using the Multidimensional Prognostic Index (MPI). RESULTS: At baseline no significant difference was shown between the two groups. After 6 months of follow-up, there were significant differences between Group-1 and Group-2 in: MMSE: +6.39% vs. +2.69%, CDR: +6.92% vs. +1.54%, HDRS-D = -60.7% vs. -45.8%, GDS: -60.9% vs. 7.3%, NPI: -55.2% vs. -32.7%%, NPI-D: -55.1% vs. -18.6%, ADL: +13.88% vs. +5.95%, IADL: +67.59% vs. +18.28%, MNA: +12.02% vs. +5.91%, and MPI: -29.03% vs. -12.90%. CONCLUSION: The integrated treatment of RTP with CS in AD patients for 6 months improved significantly cognition, depressive and neuropsychiatric symptoms, functional status, and mortality risk in comparison with a group of AD patients receiving only RTP. PMID- 25504467 TI - Fine mapping of the Asian soybean rust resistance gene Rpp2 from soybean PI 230970. AB - KEY MESSAGE: Asian soybean rust (ASR) resistance gene Rpp2 has been fine mapped into a 188.1 kb interval on Glyma.Wm82.a2, which contains a series of plant resistance ( R ) genes. Asian soybean rust (ASR), caused by the fungus Phakopsora pachyrihizi Syd. & P. Syd., is a serious disease in major soybean [Glycine max (L.) Merr.] production countries worldwide and causes yield losses up to 75 %. Defining the exact chromosomal position of ASR resistance genes is critical for improving the effectiveness of marker-assisted selection (MAS) for resistance and for cloning these genes. The objective of this study was to fine map the ASR resistance gene Rpp2 from the plant introduction (PI) 230970. Rpp2 was previously mapped within a 12.9-cM interval on soybean chromosome 16. The fine mapping was initiated by identifying recombination events in F2 and F3 plants using simple sequence repeat (SSR) and single nucleotide polymorphism (SNP) markers that flank the gene. Seventeen recombinant plants were identified and then tested with additional genetic markers saturating the gene region to localize the positions of each recombination. The progeny of these selected plants were tested for resistance to ASR and with SSR markers resulting in the mapping of Rpp2 to a 188.1 kb interval on the Williams 82 reference genome (Glyma.Wm82.a2). Twelve genes including ten toll/interleukin-1 receptor (TIR)-nucleotide-binding site (NBS)-leucine-rich repeat (LRR) genes were predicted to exist in this interval on the Glyma.Wm82.a2.v1 gene model map. Eight of these ten genes were homologous to the Arabidopsis TIR-NBS-LRR gene AT5G17680.1. The identified SSR and SNP markers close to Rpp2 and the candidate gene information presented in this study will be significant resources for MAS and gene cloning research. PMID- 25504468 TI - Genetic mapping of QTL for maize weevil resistance in a RIL population of tropical maize. AB - KEY MESSAGE: A tropical RIL maize population was subjected to phenotypic and genotypic analysis for maize weevil resistance during four seasons, and three main genomic areas were detected as main QTLs. The maize weevil (Sitophilus zeamais) (MW) is a common and important pest of stored maize (Zea mays) worldwide, especially in tropical areas. Quantitative trait loci (QTLs) associated with the MW have been analyzed previously in an F2 maize population. In this work, new germplasm-based F6 recombinant inbred line (RIL) families, derived from the cross of Population 84 and Kilima, were analyzed using insect bioassays during four seasons. The parameters analyzed for MW resistance were grain weight losses (GWL), adult progeny (AP), and flour production (FP). Composite interval mapping identified a total of 15 QTLs for MW parameters located on six chromosomes, explaining between 14 and 51 % of phenotypic variation (sigma p (2) ) and 27 and 81 % of genotypic variation (sigma g (2) ). The QTL obtained for GWL was located in bin 2.05, which explained 15 % of sigma p (2) . For AP and FP, the QTLs were located on regions 1.09 and 2.05, explaining 7 and 15 % of sigma p (2) , respectively. Comparative analysis between F2 and F6 families showed similarities in QTL localization; three main regions were co localized in chromosomes 4.08, 10.04, and 10.07, where no resistance-associated genes have been reported previously. These regions could be used for a marker assisted selection in breeding programs for MW resistance in tropical maize. PMID- 25504469 TI - Wiring laccase on covalently modified graphene: carbon nanotube assemblies for the direct bio-electrocatalytic reduction of oxygen. AB - Reduced graphene oxide (RGO) was covalently functionalized by the in situ generation and reduction of anthraquinone diazonium salt. Deposition on multi wall carbon nanotube (MWCNT) electrodes prevents the aggregation of RGO nanosheets and allows the stable deposition of modified graphene, accompanied with excellent electron transfer properties. Laccases were immobilized on the nanostructured electrode by the interaction between the anthraquinone moiety and the laccase hydrophobic pocket located near the T1 copper center. The MWCNT/f-RGO electrode exhibits efficient bioelectrocatalytic oxygen reduction, with current densities of up to 0.9 mA cm(-2) . PMID- 25504470 TI - Mutations in SNRPB, encoding components of the core splicing machinery, cause cerebro-costo-mandibular syndrome. AB - Cerebro-costo-mandibular syndrome (CCMS) is a developmental disorder characterized by the association of Pierre Robin sequence and posterior rib defects. Exome sequencing and Sanger sequencing in five unrelated CCMS patients revealed five heterozygous variants in the small nuclear ribonucleoprotein polypeptides B and B1 (SNRPB) gene. This gene includes three transcripts, namely transcripts 1 and 2, encoding components of the core spliceosomal machinery (SmB' and SmB) and transcript 3 undergoing nonsense-mediated mRNA decay. All variants were located in the premature termination codon (PTC)-introducing alternative exon of transcript 3. Quantitative RT-PCR analysis revealed a significant increase in transcript 3 levels in leukocytes of CCMS individuals compared to controls. We conclude that CCMS is due to heterozygous mutations in SNRPB, enhancing inclusion of a SNRPB PTC-introducing alternative exon, and show that this developmental disease is caused by defects in the splicing machinery. Our finding confirms the report of SNRPB mutations in CCMS patients by Lynch et al. (2014) and further extends the clinical and molecular observations. PMID- 25504471 TI - Roquin binding to target mRNAs involves a winged helix-turn-helix motif. AB - Roquin proteins mediate mRNA deadenylation by recognizing a conserved class of stem-loop RNA degradation motifs via their Roquin domain. Here we present the crystal structure of a Roquin domain, revealing a mostly helical protein fold bearing a winged helix-turn-helix motif. By combining structural, biochemical and mutation analyses, we gain insight into the mode of RNA binding. We show that the winged helix-turn-helix motif is involved in the binding of constitutive decay elements-containing stem-loop mRNAs. Moreover, we provide biochemical evidence that Roquin proteins are additionally able to bind to duplex RNA and have the potential to be functional in different oligomeric states. PMID- 25504472 TI - Initial Experience with the Use of Thrombopoetin Receptor Agonists in Patients with Refractory HIV-Associated Immune Thrombocytopenic Purpura: A Case Series. AB - HIV-associated immune thrombocytopenic purpura (ITP) has decreased in incidence 10-fold since the advent of highly active antiretroviral therapy (HAART). For patients with detectable HIV viral loads, first-line treatment approaches involve optimizing HAART followed by standard ITP options used to treat those without HIV infection. In the general population, the thrombopoetin receptor agonists (TRAs), eltrombopag and romiplostim, are effective when used as salvage ITP therapy. In addition, eltrombopag has been used effectively in patients with thrombocytopenia secondary to hepatitis C--a virus seen commonly in HIV-infected patients, especially in those who also have a history of intravenous drug use. There are, however, few reports or studies of TRAs use in those with HIV infection. Herein, we describe 5 cases of refractory HIV-associated ITP managed with TRAs. Although platelet counts improved for all patients, 2 patients succumbed to thromboembolic complications. Our initial experience, as well as our findings from a Medline review, supports the potential utility of TRA as salvage therapy in the treatment of HIV-related ITP; however, we recommend caution in the use of these agents in those who are at highest risk of thrombosis. Additional studies are needed to determine the efficacy and, more importantly, the safety of TRAs in treatment of HIV-associated ITP. PMID- 25504473 TI - Down syndrome screening information in midwifery practices in the Netherlands: Strategies to integrate biomedical information. AB - The aim of this qualitative study was to analyse counselling with regard to prenatal screening in midwifery consultations in the Netherlands where a national prenatal screening programme has only existed since 2007, after years of social and political debates. The methodology is based on in situ observations of 25 counselling consultations in four midwifery practices in two main cities in the Netherlands. The results of this study show that, since midwives are obliged to offer information on Down syndrome screening to all pregnant women (2007), they have to deal with the communication of medical screening information using biostatistical concepts to explain risks, calculations, probabilities and chromosomal anomalies. In order to avoid the risk of medicalization of their consultation, midwives develop strategies that allow them to integrate this new biomedical discourse while maintaining their low medicalized approach of midwife led care. One of their main strategies is to switch from 'alarming' biomedical messages to 'reassuring words' in order to manage the anxiety induced by the information and to keep the control over their low medicalized consultation. They also tend to distance themselves from the obligation to talk about screening. The way midwives handle these counselling consultations allows them to respect their obligation to propose information, and to remain faithful to their struggle to protect the natural process of pregnancy as well as their professional autonomy. PMID- 25504474 TI - World Health Organization and disease surveillance: Jeopardizing global public health? AB - Health issues now evolve in a global context. Real-time global surveillance, global disease mapping and global risk management characterize what have been termed 'global public health'. It has generated many programmes and policies, notably through the work of the World Health Organization. This globalized form of public health raises, however, some important issues left unchallenged, including its effectiveness, objectivity and legitimacy. The general objective of this article is to underline the impacts of WHO disease surveillance on the practice and theorization of global public health. By using the surveillance structure established by the World Health Organization and reinforced by the 2005 International Health Regulations as a case study, we argue that the policing of 'circulating risks' emerged as a dramatic paradox for global public health policy. This situation severely affects the rationale of health interventions as well as the lives of millions around the world, while travestying the meaning of health, disease and risks. To do so, we use health surveillance data collected by the WHO Disease Outbreak News System in order to map the impacts of global health surveillance on health policy rationale and theory. PMID- 25504475 TI - Presentation of a benign fibroepithelial polyp with frank haematuria: an unusual diagnosis. AB - INTRODUCTION: Fibroepithelial polyps are rare benign lesions which can mimic malignant disease symptomatically and radiologically. They should form part of the differential diagnosis in patients presenting with frank haematuria but they can present a diagnostic dilemma for clinicians. CASE PRESENTATION: This is a case of a 30-year-old female who initially presented with a small palpable urethral lump, thought to be a urethral caruncle by her general practitioner, obstructive voiding and intermittent frank painless haematuria. A rigid cystoscopy identified a polypoid lesion protruding out of the left ureteric orifice. This was resected and pathology showed it to be a fibroepithelial polyp. A post-operative computerized tomography scan showed no hydronephrosis on either side and no lymphadenopathy was identified but the distal left ureter could not be visualised. Further resection with a flexible ureteroscopy confirmed the presence of a benign fibroepithelial polyp and the stalk remnant was ablated with a laser. CONCLUSION: Fibroepithelial polyps mimic malignant disease symptomatically and radiologically and need to be considered in the differential diagnosis of frank haematuria. PMID- 25504476 TI - Socioeconomic influence on orofacial cleft patient care. AB - BACKGROUND: Cleft lip and palate is the most common craniofacial birth defect in the UK. Orofacial clefts have functional and aesthetic implications requiring intensive multi-disciplinary follow-up to optimise development. Failure to attend follow-up is likely to have a negative impact on patient outcomes. The aim of this retrospective audit is to establish if socioeconomic status influences attendance, DNA and cancellation rates in cleft patients. METHODS AND RESULTS: A retrospective audit of 74 orofacial cleft patients born and operated on at the Royal Hospital for Sick Children Glasgow between 2006 and 2007. There was higher rate of DNA in more deprived social groups-21% (SIMD 1) against 10% (SIMD 5). A higher rate of DNA in cleft lip and palate patients was noted. This group of patients showed a marked difference in attendance between SIMD 1 (38%) and SIMD 5 (78%). CONCLUSION: More deprived areas have a higher outpatient DNA rate for cleft patients resulting in suboptimal follow-up. Ultimately, causation of poorer outcomes in this group is likely to be multi-factorial but the financial implication of travelling to multiple clinics should be considered and it may be that resource reallocation is the answer to address the current inequality of health care provision. PMID- 25504477 TI - Targeting endostatin to potentially prevent retinal neovascularization using a hypoxia-responsive Muller glia cell-specific gene therapy. PMID- 25504479 TI - Locally advanced thymic carcinoma with direct pericardial extension and atrial clot diagnosed with endoscopic ultrasound: a case report. PMID- 25504480 TI - Relating the effects of protein type and content in increased-protein cheese pies to consumers' perception of satiating capacity. AB - Since proteins have been shown to have the highest satiation-inducing effects of all the macronutrients, increasing the protein level is one of the main strategies for designing foods with enhanced satiating capacity. However, few studies analyze the effect that protein addition has on the texture and flavor characteristics of the target food item to relate it to the expected satiating capacity it elicits. The present work studied cheese pies with three levels of soy and whey proteins. Since the protein level altered the rheological behavior of the batters before baking and the texture of the baked pies, the feasibility of adding several protein levels for obtaining a range of final products was investigated. A check-all-that-apply questionnaire containing 32 sensory and non sensory characteristics of the samples was given to consumers (n = 131) who also scored the perceived samples' satiating capacity. The results showed that the type and content of protein contributed distinctive sensory characteristics to the samples that could be related to their satiating capacity perception. Harder and drier samples (high protein levels) were perceived as more satiating with less perceptible sweet and milky cheese pie characteristic flavors. Soy contributed an off-flavour. These results will contribute to a better understanding of the interrelation of all these factors, aiding the development of highly palatable solid foods with enhanced satiating capacities. PMID- 25504481 TI - Influence of excited-state absorption on time-resolved luminescence: general formalism and application to the phosphorescence of polycyclic aromatic hydrocarbons. AB - The luminescence decay of a species in an absorbing medium whose optical thickness changes with time, as occurs with triplet-triplet absorption following excitation cut-off, is studied theoretically and experimentally. A general luminescence decay function based on a distribution of optical thicknesses is presented. A simple decay function previously used empirically is shown to result from an exponential distribution of optical thicknesses. The general approach introduced allows the adequate description of the phosphorescence decays of two polycyclic aromatic hydrocarbons, coronene and triphenylene (normal and perdeuterated forms for both molecules), in polymer films in the presence of excited-state absorption. PMID- 25504483 TI - Intermanual transfer effect in young children after training in a complex skill: mechanistic, pseudorandomized, pretest-posttest study. AB - BACKGROUND: Intermanual transfer implies that motor skills learned on one side of the body transfer to the untrained side. This effect was previously noted in adults practicing with a prosthesis simulator. OBJECTIVE: The study objective was to determine whether intermanual transfer is present in children practicing prosthetic handling. DESIGN: A mechanistic, pseudorandomized, pretest-posttest design was used. SETTING: The study was conducted in a primary school in the Netherlands. PARTICIPANTS: The participants were children who were able-bodied (N=48; 25 boys, 23 girls; mean age=5.1 years) and randomly assigned to an experimental group or a control group. INTERVENTION: The experimental group performed 5 training sessions using a prosthesis simulator on the training arm. Before (pretest), immediately after (posttest), and 6 days after (retention test) the training program, their ability to handle the prosthesis with the contralateral (test) arm was measured. The control group only performed the tests. Half of the children performed the tests with the dominant hand, and the other half performed the tests with the nondominant hand. MEASUREMENTS: During the tests, movement time and control of force were measured. RESULTS: An interaction effect of group by test was found for movement time. Post hoc tests revealed significant improvement in the experimental group between the posttest and the retention test. No force control effect was found. LIMITATIONS: Only children who were able-bodied were included. Measurements should have been masked and obtained without tester interference. The fact that 4 children whose results were slower than the mean result discontinued training may have biased the findings. CONCLUSIONS: The intermanual transfer effect was present in 5-year-old children undergoing training in prosthetic handling. After training of one hand, children's movement times for the other, untrained hand improved. This finding may be helpful for training children who are novice users of a prosthesis. PMID- 25504482 TI - Clinical characteristics of patients with cancer referred for outpatient physical therapy. AB - BACKGROUND: Cancer rehabilitation is a developing area, with an increasing number of survivors of cancer in the United States. The increase in survivorship occurs alongside impairments arising directly from cancer or from treatment-related side effects. OBJECTIVE: This study described clinical characteristics of patients with cancer referred for outpatient physical therapy and explored patterns in frequency of impairments between type of cancer and mode of cancer treatment. DESIGN: This was a retrospective chart review of patients with cancer referred to a tertiary care physical therapy clinic over a 2-year period. METHODS: Characteristics such as age, sex, cancer type, mode of treatment, and neuromusculoskeletal impairments were identified. Impairment frequencies were computed based on cancer type and mode of treatment. RESULTS: Data from 418 patients (mean age=57.9 years, SD=14.3; 41.1% female) were examined. Genitourinary cancer (n=169) and breast cancer (n=90) were the most prevalent types of cancer reported in this sample. Impairments in strength (83.6%) and soft tissue (71.3%) were the most common examination findings. Lymphedema was most common in patients with breast cancer, and incontinence was most common in patients with genitourinary cancer. LIMITATIONS: The types of cancer identified in this study may be reflective of this tertiary center and may not generalize to other facilities. Impairment identification during the initial physical therapist evaluation was not performed systematically. CONCLUSION: These data reinforce that physical therapists should screen for lymphedema in patients with breast cancer and incontinence in urogenital cancers. Strength and soft tissue integrity should be evaluated in most patients with cancer. Assessing pain and fatigue levels is recommended for patients who have had radiation therapy. PMID- 25504485 TI - Descriptive data analysis examining how standardized assessments are used to guide post-acute discharge recommendations for rehabilitation services after stroke. AB - BACKGROUND: Use of standardized assessments in acute rehabilitation is continuing to grow, a key objective being to assist clinicians in determining services needed postdischarge. OBJECTIVE: The purpose of this study was to examine how standardized assessment scores from initial acute care physical therapist and occupational therapist evaluations contribute to discharge recommendations for poststroke rehabilitation services. DESIGN: A descriptive analysis was conducted. METHODS: A total of 2,738 records of patients admitted to an acute care hospital with a diagnosis of stroke or transient ischemic attack were identified. Participants received an initial physical therapist and occupational therapist evaluation with standardized assessments and a discharge recommendation of home with no services, home with services, inpatient rehabilitation facility (IRF), or skilled nursing facility (SNF). A K-means clustering algorithm determined if it was feasible to categorize participants into the 4 groups based on their assessment scores. These results were compared with the physical therapist and occupational therapist discharge recommendations to determine if assessment scores guided postacute care recommendations. RESULTS: Participants could be separated into 4 clusters (A, B, C, and D) based on assessment scores. Cluster A was the least impaired, followed by clusters B, C, and D. In cluster A, 50% of the participants were recommended for discharge to home without services, whereas 1% were recommended for discharge to an SNF. Clusters B, C, and D each had a large proportion of individuals recommended for discharge to an IRF (74%-80%). There was a difference in percentage of recommendations across the clusters that was largely driven by the differences between cluster A and clusters B, C, and D. LIMITATIONS: Additional unknown factors may have influenced the discharge recommendations. CONCLUSIONS: Participants poststroke can be classified into meaningful groups based on assessment scores from their initial physical therapist and occupational therapist evaluations. These assessment scores, in part, guide poststroke acute care discharge recommendations. PMID- 25504484 TI - Role of body-worn movement monitor technology for balance and gait rehabilitation. AB - This perspective article will discuss the potential role of body-worn movement monitors for balance and gait assessment and treatment in rehabilitation. Recent advances in inexpensive, wireless sensor technology and smart devices are resulting in an explosion of miniature, portable sensors that can quickly and accurately quantify body motion. Practical and useful movement monitoring systems are now becoming available. It is critical that therapists understand the potential advantages and limitations of such emerging technology. One important advantage of obtaining objective measures of balance and gait from body-worn sensors is impairment-level metrics characterizing how and why functional performance of balance and gait activities are impaired. Therapy can then be focused on the specific physiological reasons for difficulty in walking or balancing during specific tasks. A second advantage of using technology to measure balance and gait behavior is the increased sensitivity of the balance and gait measures to document mild disability and change with rehabilitation. A third advantage of measuring movement, such as postural sway and gait characteristics, with body-worn sensors is the opportunity for immediate biofeedback provided to patients that can focus attention and enhance performance. In the future, body worn sensors may allow therapists to perform telerehabilitation to monitor compliance with home exercise programs and the quality of their natural mobility in the community. Therapists need technological systems that are quick to use and provide actionable information and useful reports for their patients and referring physicians. Therapists should look for systems that provide measures that have been validated with respect to gold standard accuracy and to clinically relevant outcomes such as fall risk and severity of disability. PMID- 25504486 TI - Balance training using an iPhone application in people with familial dysautonomia: three case reports. AB - BACKGROUND AND PURPOSE: Familial dysautonomia (FD) is a rare genetic autosomal recessive disease that impairs vital functions and causes neural and motor deficiency. These motor deficits often are characterized by static and dynamic instability and an ataxic gait. As a result, people with FD are at risk for significant physical impairment and falls and pose unique challenges for delivering rehabilitation exercise. Consequently, there is a need for challenging ways to safely and feasibly deliver active exercise rehabilitation to these individuals. CASE DESCRIPTION: This case report describes 3 people with FD (ages 11, 12, and 22 years) with gait and stability problems who attended rehabilitation exercises augmented by the use of an iPhone application specifically developed for the program. OUTCOMES: The Berg Balance Scale and the Four Square Step Test were conducted prior to training, after training, and after 2 months of follow-up without training. Two patients showed improvements on both measures at the posttest, which were maintained throughout follow-up testing. DISCUSSION: Although greater experience is needed to more fully evaluate the efficiency of the iPhone application used in this program for people with FD, the results of these initial cases are encouraging. Systematically and prospectively tracking motor abilities and other functional outcomes during rehabilitation of individuals with FD who use the suggested application in balance training is recommended in order to provide greater evidence in this area. PMID- 25504487 TI - Daily exercises and education for preventing low back pain in children: cluster randomized controlled trial. AB - BACKGROUND: Children report low back pain (LBP) as young as 8 years. Preventing LBP in children may prevent or delay adult incidence. OBJECTIVES: The purpose of this study was to determine whether education and daily exercise affect LBP episodes in children compared with education alone. DESIGN: This was a prospective, multicenter cluster randomized controlled trial. SETTING: The study was conducted at 7 New Zealand primary schools. PARTICIPANTS: Children (n=708), aged 8 to 11 years, from 7 schools stratified by sample size (36, 114, 151, 168, 113, 45, 83) were randomized and allocated to 2 masked groups: intervention (4 schools, n=469) or control (3 schools, n=239). INTERVENTIONS: Participants in the intervention group were taught 4 spinal movements for daily practice. Both groups participated in education that emphasized "back awareness." MEASUREMENTS: Low back pain history at baseline was assessed. Children reported episodes of LBP during the previous week on trial days 7, 21, 49, 105, 161, and 270. Analysis was at the individual participant level, with adjustment for school clusters. RESULTS: There were no significant differences between groups in the odds of reporting no LBP in the previous week during the study period (odds ratio [OR]=0.72; 95% confidence interval [95% CI]=0.46, 1.14; P=.16). The intervention group reported significantly fewer episodes of LBP (OR=0.54; 95% CI=0.39, 0.74; P<.001) and significantly fewer lifetime first episodes of LBP (n=86 [34%]) compared with the control group (n=58 [47%]) (OR=0.60; 95% CI=0.39, 0.91; P=.02). The odds of an episode of LBP were greater in participants with a history of LBP (OR=4.21; 95% CI=3.07, 5.78; P<.001). Low back pain episodes decreased across the trial period for both groups (OR=0.89; 95% CI=0.84, 0.95; P<.001). Adherence to exercise was poor. LIMITATIONS: Replication in other settings is needed. CONCLUSIONS: Regular exercise and education appear to reduce LBP episodes in children aged 8 to 11 years compared with education alone. PMID- 25504488 TI - Physical activity levels early after lung transplantation. AB - BACKGROUND: Little is known of the early changes in physical activity after lung transplantation. OBJECTIVES: The purposes of this study were: (1) to describe physical activity levels in patients up to 6 months following lung transplantation and (2) to explore predictors of the change in physical activity in that population. DESIGN: This was a prospective cohort study. METHODS: Physical activity (daily steps and time spent in moderate-intensity activity) was measured using an accelerometer before and after transplantation (at hospital discharge, 3 months, and 6 months). Additional functional measurements included submaximal exercise capacity (measured with the 6-Minute Walk Test), quadriceps muscle torque, and health-related quality of life (measured with the Medical Outcomes Study 36-Item Short-Form Health Survey 36 [SF-36] and the St George's Respiratory Questionnaire). RESULTS: Thirty-six lung transplant recipients (18 men, 18 women; mean age=49 years, SD=14) completed posttransplant measurements. Before transplant, daily steps were less than a third of the general population. By 3 months posttransplant, the largest improvement in physical activity had occurred, and level of daily steps reached 55% of the general population. The change in daily steps (pretransplant to 3 months posttransplant) was inversely correlated with pretransplant 6-minute walk distance (r=-.48, P=.007), daily steps (r=-.36, P=.05), and SF-36 physical functioning (SF-36 PF) score (r=-.59, P=.0005). The SF-36 PF was a significant predictor of the change in physical activity, accounting for 35% of the variation in change in daily steps. LIMITATIONS: Only individuals who were ambulatory prior to transplant and discharged from the hospital in less than 3 months were included in the study. CONCLUSIONS: Physical activity levels improve following lung transplantation, particularly in individuals with low self-reported physical functioning. However, the majority of lung transplant recipients remain sedentary between 3 to 6 months following transplant. The role of exercise training, education, and counseling in further improving physical activity levels in lung transplant recipients should be further explored. PMID- 25504489 TI - Interrater Reliability of AM-PAC "6-Clicks" Basic Mobility and Daily Activity Short Forms. AB - BACKGROUND: The interrater reliability of 2 new inpatient functional short-form measures, Activity Measure for Post-Acute Care (AM-PAC) "6-Clicks" basic mobility and daily activity scores, has yet to be established. OBJECTIVE: The purpose of this study was to examine the interrater reliability of AM-PAC "6-Clicks" measures. DESIGN: A prospective observational study was conducted. METHODS: Four pairs of physical therapists rated basic mobility and 4 pairs of occupational therapists rated daily activity of patients in 1 of 4 hospital services. One therapist in a pair was the primary therapist directing the assessment while the other therapist observed. Each therapist was unaware of the other's AM-PAC "6 Clicks" scores. Reliability was assessed with intraclass correlation coefficients (ICCs), Bland-Altman plots, and weighted kappa. RESULTS: The ICCs for the overall reliability of basic mobility and daily activity were .849 (95% confidence interval [CI]=.784, .895) and .783 (95% CI=.696, .847), respectively. The ICCs for the reliability of each pair of raters ranged from .581 (95% CI=.260, .789) to .960 (95% CI=.897, .983) for basic mobility and .316 (95% CI=-.061, .611) to .907 (95% CI=.801, .958) for daily activity. The weighted kappa values for item agreement ranged from .492 (95% CI=.382, .601) to .712 (95% CI=.607, .816) for basic mobility and .251 (95% CI=.057, .445) to .751 (95% CI=.653, .848) for daily activity. Mean differences between raters' scores were near zero. LIMITATIONS: Raters were from one health system. Each pair of raters assessed different patients in different services. CONCLUSIONS: The ICCs for AM-PAC "6-Clicks" total scores were very high. Levels of agreement varied across pairs of raters, from large to nearly perfect for physical therapists and from moderate to nearly perfect for occupational therapists. Levels of agreement for individual item scores ranged from small to very large. PMID- 25504490 TI - Combined clinical and home rehabilitation: case report of an integrated knowledge to-action study in a Dutch rehabilitation stroke unit. AB - BACKGROUND AND PURPOSE: There is growing awareness that the poor uptake of evidence in health care is not a knowledge-transfer problem but rather one of knowledge production. This issue calls for re-examination of the evidence produced and assumptions that underpin existing knowledge-to-action (KTA) activities. Accordingly, it has been advocated that KTA studies should treat research knowledge and local practical knowledge with analytical impartiality. The purpose of this case report is to illustrate the complexities in an evidence informed improvement process of organized stroke care in a local rehabilitation setting. CASE DESCRIPTION: A participatory action approach was used to co-create knowledge and engage local therapists in a 2-way knowledge translation and multidirectional learning process. Evidence regarding rehabilitation stroke units was applied in a straightforward manner, as the setting met the criteria articulated in stroke unit reviews. Evidence on early supported discharge (ESD) could not be directly applied because of differences in target group and implementation environment between the local and reviewed settings. Early supported discharge was tailored to the needs of patients severely affected by stroke admitted to the local rehabilitation stroke unit by combining clinical and home rehabilitation (CCHR). OUTCOMES: Local therapists welcomed CCHR because it helped them make their task-specific training truly context specific. Key barriers to implementation were travel time, logistical problems, partitioning walls between financing streams, and legislative procedures. DISCUSSION: Improving local settings with available evidence is not a straightforward application process but rather a matter of searching, logical reasoning, and creatively working with heterogeneous knowledge sources in partnership with different stakeholders. Multiple organizational levels need to be addressed rather than focusing on therapists as sole site of change. PMID- 25504491 TI - Staged Approach for Rehabilitation Classification: Shoulder Disorders (STAR Shoulder). AB - Shoulder disorders are a common musculoskeletal problem causing pain and functional loss. Traditionally, diagnostic categories are based on a pathoanatomic medical model aimed at identifying the pathologic tissues. However, the pathoanatomic model may not provide diagnostic categories that effectively guide treatment decision making in rehabilitation. An expanded classification system is proposed that includes the pathoanatomic diagnosis and a rehabilitation classification based on tissue irritability and identified impairments. For the rehabilitation classification, 3 levels of irritability are proposed and defined, with corresponding strategies guiding intensity of treatment based on the physical stress theory. Common impairments are identified and are used to guide specific intervention tactics with varying levels of intensity. The proposed system is conceptual and needs to be tested for reliability and validity. This classification system may be useful clinically for guiding rehabilitation intervention and provides a potential method of identifying relevant subgroups in future research studies. Although the system was developed for and applied to shoulder disorders, it may be applicable to classification and rehabilitation of musculoskeletal disorders in other body regions. PMID- 25504492 TI - Recent advances in targeted proteomics for clinical applications. AB - MS-based approaches using targeted methods have been widely adopted by the proteomics community to study clinical questions such as the evaluation of biomarkers. At present, the most widely used targeted MS method is the SRM technique typically performed on a triple quadrupole instrument. However, the high analytical demands for performing clinical studies in combination with the extreme complexity of the samples involved are a serious challenge. The segmentation of the biomarker evaluation workflow has only partially alleviated these issues by differently balancing the analytical requirements and throughput at different stages of the process. The recent introduction of targeted high resolution and accurate-mass analyses on fast sequencing mass spectrometers operated in parallel reaction monitoring (PRM) mode offers new avenues to conduct clinical studies and thus overcome some of the limitations of the triple quadrupole instrument. This article discusses the attributes and specificities of the PRM technique, in terms of experimental design, execution, and data analysis, and the implications for biomarker evaluation. The benefits of PRM on data quality and the impact on the consistency of results are highlighted and the definitive progress on the overall output of clinical studies, including high throughput, is discussed. PMID- 25504494 TI - Detecting cervical cancer progression through extracted intrinsic fluorescence and principal component analysis. AB - Intrinsic fluorescence spectra of the human normal, cervical intraepithelial neoplasia 1 (CIN1), CIN2, and cervical cancer tissue have been extracted by effectively combining the measured polarized fluorescence and polarized elastic scattering spectra. The efficacy of principal component analysis (PCA) to disentangle the collective behavior from smaller correlated clusters in a dimensionally reduced space in conjunction with the intrinsic fluorescence is examined. This combination unambiguously reveals the biochemical changes occurring with the progression of the disease. The differing activities of the dominant fluorophores, collagen, nicotinamide adenine dinucleotide, flavins, and porphyrin of different grades of precancers are clearly identified through a careful examination of the sectorial behavior of the dominant eigenvectors of PCA. To further classify the different grades, the Mahalanobis distance has been calculated using the scores of selected principal components. PMID- 25504495 TI - Specific light-up bioprobe with aggregation-induced emission and activatable photoactivity for the targeted and image-guided photodynamic ablation of cancer cells. AB - Activatable photosensitizers (PSs) have been widely used for the simultaneous fluorescence imaging and photodynamic ablation of cancer cells. However, the ready aggregation of traditional PSs in aqueous media can lead to fluorescence quenching as well as reduced phototoxicity even in the activated form. We have developed a series of PSs that show aggregation-enhanced emission and phototoxicity and thus the exact opposite behavior to that of previously reported PSs. We further developed a dual-targeted enzyme-activatable bioprobe based on the optimized photosensitizer and describe simultaneous light-up fluorescence imaging and activated photodynamic therapy for specific cancer cells. The design of smart probes should thus open new opportunities for targeted and image-guided photodynamic therapy. PMID- 25504496 TI - High Ki-67 expression in involved bone marrow predicts worse clinical outcome in diffuse large B cell lymphoma patients treated with R-CHOP therapy. AB - Approximately 10-25 % of patients with diffuse large B cell lymphoma (DLBCL) at the time of diagnosis exhibit bone marrow involvement (BMI). After introduction of rituximab, immunohistochemistry (IHC) markers lost to prognostic value in DLBCL patients. However, the specimens used have mainly been diagnostic tissues, not bone marrow (BM). It would thus be useful to determine the prognostic value of specific IHC markers of pathologic BM in DLBCL patients with BMI in the rituximab era. In the present study, a total of 580 DLBCL patients were analyzed 67 of whom had BMI. CD10, Bcl-6, MUM-1, Bcl-6 and Ki-67 dyeing on pathologic BM were applied. Bcl-2 positivity was more frequent in discordant BMI (P = 0.039) and high Ki-67 expression was more frequent in concordant BMI (P = 0.016). High Ki-67 expression independently predicted poor prognosis between the negative BMI group and each of the following BMI-positive groups: entire BMI (PFS, P < 0.001; OS, P < 0.001), concordant BMI (PFS, P = 0.024; OS, P = 0.007), and discordant BMI (PFS, P = 0.033; OS, P = 0.026). We found that Ki-67 expression in pathologic BM is a novel significant prognostic parameter of worse prognosis in DLBCL patients with BMI in the rituximab era. PMID- 25504497 TI - A hemi-metallocene chromium catalyst with trimethylaluminum-free methylaluminoxane for the synthesis of disentangled ultra-high molecular weight polyethylene. AB - Recently, it has been shown that by using a single-site catalytic system having titanium as a metallic center, it is possible to tailor the entanglement density in the amorphous region of a semi-crystalline ultra-high molecular weight polyethylene (UHMWPE). This route provides the possibility to make high-modulus, high-strength uniaxially and biaxially drawn tapes and films, without using any solvent during processing. In this publication, it is shown that a single-site catalyst having chromium as metallic center, proposed by Enders and co-workers, can also be tuned to provide control on the entanglement density during synthesis of the UHMWPE. However, to achieve the goal some modifications during the synthesis are required. The synthesized polymers can be processed in the solid state below the equilibrium melting temperature, resulting in uniaxially drawn tapes having tensile strength and modulus greater than 3.5 N/tex and 200 N/tex, respectively. Rheological studies have been performed to follow the increase in entanglement density in melt state with time. PMID- 25504498 TI - Bronchoscopic guidance of endovascular stenting limits airway compression. AB - OBJECTIVE: Bronchial compression as a result of pulmonary artery and aortic arch stenting may cause significant respiratory distress. We set out to limit airway narrowing by endovascular stenting, by using simultaneous flexible bronchoscopy and graduated balloon stent dilatation, or balloon angioplasty to determine maximum safe stent diameter. METHODS: Between August 2010 and August 2013, patients with suspected airway compression by adjacent vascular structures, underwent CT or a 3D rotational angiogram to evaluate the relationship between the airway and the blood vessels. If these studies showed close proximity of the stenosed vessel and the airway, simultaneous bronchoscopy and graduated stent re dilation or graduated balloon angioplasty were performed. RESULTS: Five simultaneous bronchoscopy and interventional catheterization procedures were performed in four patients. Median age/weight was 33 (range 9-49) months and 14 (range 7.6-24) kg, respectively. Three had hypoplastic left heart syndrome, and one had coarctation of the aorta (CoA). All had confirmed or suspected left main stem bronchial compression. In three procedures, serial balloon dilatation of a previously placed stent in the CoA was performed and bronchoscopy was used to determine the safest largest diameter. In the other two procedures, balloon testing with simultaneous bronchoscopy was performed to determine the stent size that would limit compression of the adjacent airway. In all cases, simultaneous bronchoscopy allowed selection of an ideal caliber of the stent that optimized vessel diameter while minimizing compression of the adjacent airway. CONCLUSION: In cases at risk for airway compromise, flexible bronchoscopy is a useful tool to guide endovascular stenting. Maximum safe stent diameter can be determined without risking catastrophic airway compression. PMID- 25504499 TI - Photo quiz. Dyspnea and fever in an allogeneic stem cell recipient. PMID- 25504502 TI - Formation of the accumulative human metabolite and human-specific glutathione conjugate of diclofenac in TK-NOG chimeric mice with humanized livers. AB - 3'-Hydroxy-4'-methoxydiclofenac (VI) is a human-specific metabolite known to accumulate in the plasma of patients after repeated administration of diclofenac sodium. Diclofenac also produces glutathione-conjugated metabolites, some of which are human-specific. In the present study, we investigated whether these metabolites could be generated in humanized chimeric mice produced from TK-NOG mice. After a single oral administration of diclofenac to humanized mice, the unchanged drug in plasma peaked at 0.25 hour and then declined with a half-life (t1/2) of 2.4 hours. 4'-Hydroxydiclofenac (II) and 3'-hydroxydiclofenac also peaked at 0.25 hour and were undetectable within 24 hours. However, VI peaked at 8 hours and declined with a t1/2 of 13 hours. When diclofenac was given once per day, peak and trough levels of VI reached plateau within 3 days. Studies with administration of II suggested VI was generated via II as an intermediate. Among six reported glutathione-conjugated metabolites of diclofenac, M1 (5-hydroxy-4 (glutathion-S-yl)diclofenac) to M6 (2'-(glutathion-S-yl)monoclofenac), we found three dichlorinated conjugates [M1, M2 (4'-hydroxy-3'-(glutathion-S yl)diclofenac), and M3 (5-hydroxy-6-(glutathion-S-yl)diclofenac)], and a single monochlorinated conjugate [M4 (2'-hydroxy-3'-(glutathion-S-yl)monoclofenac) or M5 (4'-hydroxy-2'-(glutathion-S-yl)monoclofenac)], in the bile of humanized chimeric mice. M4 and M5 are positional isomers and have been previously reported as human specific in vitro metabolites likely generated via arene oxide and quinone imine type intermediates, respectively. The biliary monochlorinated metabolite exhibited the same mass spectrum as those of M4 and M5, and we discuss whether this conjugate corresponded to M4 or M5. Overall, humanized TK-NOG chimeric mice were considered to be a functional tool for the study of drug metabolism of diclofenac in humans. PMID- 25504503 TI - Differential expression of cytochrome P450 enzymes from the CYP2C subfamily in the human brain. AB - Cytochrome P450 enzymes from the CYP2C subfamily play a prominent role in the metabolic clearance of many drugs. CYP2C enzymes have also been implicated in the metabolism of arachidonic acid to vasoactive epoxyeicosatrienoic acids. CYP2C8, CYP2C9, and CYP2C19 are expressed in the adult liver at significant levels; however, the expression of CYP2C enzymes in extrahepatic tissues such as the brain is less well characterized. Form-specific antibodies to CYP2C9 and CYP2C19 were prepared by affinity purification of antibodies raised to unique peptides. CYP2C9 and CYP2C19 were located in microsomal fractions of all five human brain regions examined, namely the frontal cortex, hippocampus, basal ganglia, amygdala, and cerebellum. Both CYP2C9 and CYP2C19 were detected predominantly within the neuronal soma but with expression extending down axons and dendrites in certain regions. Finally, a comparison of cortex samples from alcoholics and age-matched controls suggested that CYP2C9 expression was increased in alcoholics. PMID- 25504504 TI - Characterization of phase I metabolism of resibufogenin and evaluation of the metabolic effects on its antitumor activity and toxicity. AB - Resibufogenin (RB), one of the major active compounds of the traditional Chinese medicine Chansu, has displayed great potential as a chemotherapeutic agent in oncology. However, it is a digoxin-like compound that also exhibits extremely cardiotoxic effects. The present study aimed to characterize the metabolic behaviors of RB in humans as well as to evaluate the metabolic effects on its bioactivity and toxicity. The phase I metabolic profile in human liver microsomes was characterized systemically, and the major metabolite was identified as marinobufagenin (5beta-hydroxylresibufogenin, 5-HRB) by liquid chromatography mass spectrometry and nuclear magnetic imaging techniques. Both cytochrome P450 (P450) reaction phenotyping and inhibition assays using P450-selective chemical inhibitors demonstrated that CYP3A4 was mainly involved in RB 5beta-hydroxylation with much higher selectivity than CYP3A5. Kinetic characterization demonstrated that RB 5beta-hydroxylation in both human liver microsomes and human recombinant CYP3A4 obeyed biphasic kinetics and displayed similar apparent kinetic parameters. Furthermore, 5-HRB could significantly induce cell growth inhibition and apoptosis in A549 and H1299 by facilitating apoptosome assembly and caspase activation. Meanwhile, 5-HRB displayed very weak cytotoxicity of human embryonic lung fibroblasts, and in mice there was a greater tolerance to acute toxicity. In summary, CYP3A4 dominantly mediated 5beta-hydroxylation and was found to be a major metabolic pathway of RB in the human liver, whereas its major metabolite (5 HRB) displayed better druglikeness than its parent compound RB. Our findings lay a solid foundation for RB metabolism studies in humans and encourage further research on the bioactive metabolite of RB. PMID- 25504501 TI - Neutrophil extracellular traps: a walk on the wild side of exercise immunology. AB - Intense exercise evokes a rapid and transient increase in circulating cell-free DNA (cf-DNA), a phenomenon that is commonly observed in a variety of acute and chronic inflammatory conditions. While the potential value of cf-DNA for the prediction of disease outcome and therapeutic response is well documented, the release mechanisms and biological relevance of cf-DNA have long remained enigmatic. The discovery of neutrophil extracellular traps (NETs) provided a novel mechanistic explanation for increased cf-DNA levels. Now there is increasing evidence that NETs may contribute to cf-DNA in diverse infectious, non infectious and autoinflammatory conditions, as well as in response to acute exercise. NETs have now been firmly established as a fundamental immune mechanism used by neutrophils to respond to infection and tissue injury. On the other side, aberrant formation of NETs appears to be a driving force in the pathogenesis of autoimmunity and cardiovascular disease. Thus, the emergence of NETs in the 'exercising vasculature' raises important questions considering beneficial effects, as well as occasional adverse effects, of exercise on immune homeostasis. This review gives an overview of the current state of research into the mechanisms of how NETs are released, contribute to host defence and participate in inflammatory disorders. We discuss the impact of exercise-induced NETs, considering a potentially beneficial role in the prevention of lifestyle related diseases, as well as putative detrimental effects that may arise in elite sports. Finally, we propose that exercise-induced cf-DNA responses could be exploited for diagnostic/prognostic purposes to identify individuals who are at increased risk of cardiovascular events or autoimmunity. PMID- 25504505 TI - Stereoselective inhibition of human butyrylcholinesterase by the enantiomers of bambuterol and their intermediates. AB - This work describes the sequential hydrolysis of bambuterol enantiomers and their monocarbamate metabolites (MONO) catalyzed by human butyrylcholinesterase (BChE) as well as the enzyme inhibition resulting from this process. Particular emphasis is given to the contribution given by MONO to the enzyme inhibition because it was not fully characterized in previous works. Bambuterol and MONO enantiomers displayed the same time- and concentration-dependent mechanism of interaction with the enzyme. The hydrolysis kinetics of both bambuterol and MONO was enantioselective, and the (R)-enantiomer of each compound was hydrolyzed fourfold faster than the respective (S)-enantiomer. Even though the enzyme inhibition rates of (R)- and (S)-MONO were much slower than those of their respective bambuterol enantiomers (~15-fold), both MONO enantiomers showed a significant BChE inhibition when physiologically relevant concentrations of enzyme and inhibitors were used (~50% of their respective bambuterol enantiomers). The kinetic constants obtained by testing each single compound were used to model the contribution given by MONO to the enzyme inhibition observed for bambuterol. The hydrolysis of MONO enantiomers enhanced the inhibitory power of bambuterol enantiomers of about 27.5% (R) and 12.5% (S) and extended more than 1 hour the duration of inhibition. The data indicate that MONO contribute significantly to the inhibition of BChE occurring in humans upon administration of normal doses of bambuterol. In addition, the hydrolysis of MONO resulted in the rate-limiting step in the conversion of bambuterol in its pharmacologically active metabolite terbutaline; therefore, MONO concentrations should always be monitored during pharmacokinetic studies of bambuterol. PMID- 25504506 TI - Arsenic trioxide transarterial chemoembolization with and without additional intravenous administration of arsenic trioxide in unresectable hepatocellular carcinoma with lung metastasis: a single-blind, randomized trial. AB - AIM: To evaluate the efficacy and safety of arsenic trioxide transarterial chemoembolization and intravenous administration in unresectable hepatocellular carcinoma with lung metastasis. METHODS: A single-blind, two-parallel group, randomized trial was conducted at three medical centers (Guangzhou, China), including patients with both biopsy-confirmed hepatocellular carcinoma and lung metastasis. The experimental group received arsenic trioxide transarterial chemoembolization and intravenous administration of arsenic trioxide, while the control group only received arsenic trioxide transarterial chemoembolization. We compared overall survival (OS), time to progression (TTP), disease control rate (DCR), and objective response rate (ORR) between the groups. RESULTS: Between April 2013 and June 2014, 139 patients received the allocated intervention, 70 of whom were in the experimental group and 69 of whom were in the control group. No patient was lost to follow-up. The median OS was 7.3 (95 % CI = 6.8-7.8) months in the experimental group and 2.9 (95 % CI = 2.6-3.1) months in the control group (P < 0.001). The median TTP was 2.7 (95 % CI = 1.9-3.3) months in the experimental group and 1.2 (95 % CI = 1.0-1.9) months in the control group (P = 0.023). In the experimental group, the DCR was 72.85 % and the ORR was 7.14 %, while in the control group, the DCR was 7.24 % and the ORR was 0.00 %. DCR and ORR differed significantly between the two groups (P < 0.001 and P = 0.024, respectively). CONCLUSIONS: Arsenic trioxide transarterial chemoembolization and intravenous administration were safe and effective in unresectable hepatocellular carcinoma with lung metastasis. PMID- 25504507 TI - Cytochrome P450 1B1 (CYP1B1) polymorphisms are associated with clinical outcome of docetaxel in non-small cell lung cancer (NSCLC) patients. AB - PURPOSE: Cytochrome P450 1B1 (CYP1B1) is involved in the metabolism of anticancer agents; its overexpression was associated with resistance to docetaxel, a commonly used drug for second-line treatment of NSCLC. Several functional single nucleotide polymorphisms (SNPs) have been associated with CYP1B1 expression and activity. The objective of this study was to retrospectively evaluate the correlation of CYP1B1 SNPs with the outcome of NSCLC patients treated with docetaxel in second or third line. METHODS: Associations between CYP1B1 4326C>G and 4390A>G polymorphisms with response, progression-free survival (PFS) and overall survival (OS) were estimated using Pearson chi(2) test, Kaplan-Meier curves and log-rank test; a multivariate analysis was performed using Cox proportional hazards modeling. RESULTS: A total of 65 advanced NSCLC patients were enrolled into the analysis. Median age was 66 years (range 46-81). Forty nine patients were male; only five were never smokers. Performance status (PS) was 0 in 25 patients, 1 in 28 and 2 in 12. Histology was adenocarcinoma in 28 patients, squamous carcinoma in 22, other NSCLC in the remaining 15. At univariate analysis, stage and CYP1B1 4326C>G SNPs are associated with PFS, while PS and CYP1B1 4326C>G SNPs correlated with OS. In particular, patients with CYP1B1 4326-GG genotype had shorter PFS and OS than patients with other genotypes (PFS 1.80 vs. 2.70 months, p = 0.12; OS 3.63 vs. 9.83 months, p = 0.039). CYP1B1 4326C>G SNPs were also associated with response rate. Multivariate analysis confirmed the independent prognostic/predictive role of CYP1B1 4326C>G SNPs on OS (p = 0.042) with only a trend for PFS (p = 0.083). CONCLUSIONS: CYP1B1 4326C>G polymorphism emerged as possible prognostic/predictive marker of activity and efficacy of docetaxel in NSCLC patients. PMID- 25504508 TI - An efficient plant regeneration and Agrobacterium-mediated genetic transformation of Tagetes erecta. AB - Tagetes erecta, L. an asteraceous plant of industrial and medicinal value, contains important compounds like pyrethrins, thiophenes and lutein, possessing immense potential for insecticidal, nematicidal and nutraceutical activities. Considering the importance and demand for these natural compounds, genetic manipulation of this crop for better productivity of secondary metabolites holds great significance. A rapid and reproducible direct regeneration and genetic transformation system is the prerequisite for genetic manipulation of any crop. This paper elucidates the establishment of an efficient direct regeneration and transformation protocol of T. erecta using Agrobacterium tumefaciens. Investigation of the effects of different types of explants (Hypocotyls, cotyledonary leaves, rachis and leaf sections) and different BAP and GA3 combinations on the regeneration frequency of T. erecta suggested that the best regeneration frequency (66 %) with an average of 5.08 +/- 0.09 shoot buds/explant was observed from hypocotyl explants cultured on media containing 1.5 mg/l BAP and 5 mg/l GA3. The transformation protocol was established using A. tumefaciens strain LBA4404, containing the binary vector pBI121, along with the gusA reporter gene with intron under the transcriptional control of the Cauliflower Mosaic Virus (CaMV) 35S promoter and the neomycin phosphotransferase II (nptII) gene as a kanamycin-resistant plant-selectable marker. Various parameters like optimization of kanamycin concentration (200 mg/l) for selection, standardization of cocultivation time (45 min) and acetosyringone concentration (150 MUM) for obtaining higher transformation frequency were established using hypocotyl explants. The selected putative transgenic shoots were subsequently rooted on the Murashige and Skoog medium and transferred to the green house successfully. The plants were characterised by analysing the gus expression, amplification of 600 bp npt II fragment and Southern blot hybridization using the PCR-amplified gusA fragment as probe. The standardised protocol established during the study will open new vistas for genetic manipulation and introduction of desired genes for genetic improvement of T. erecta. PMID- 25504510 TI - Intravital multiphoton imaging of the selective uptake of water-dispersible quantum dots into sinusoidal liver cells. AB - Although many studies reporting the organ-level biodistribution of nanoparticles (NPs) in animals, very few have addressed the fate of NPs in organs at the cellular level. The liver appears to be the main organ for accumulation of NPs after intravenous injection. In this study, for the first time, the in vivo spatiotemporal disposition of recently developed mercaptosuccinic acid (MSA) capped cadmium telluride/cadmium sulfide (CdTe/CdS) quantum dots (QDs) is explored in rat liver using multiphoton microscopy (MPM) coupled with fluorescence lifetime imaging (FLIM), with subcellular resolution (~1 MUm). With high fluorescence efficiency and largely improved stability in the biological environment, these QDs show a distinct distribution pattern in the liver compared to organic dyes, rhodamine 123 and fluorescein. After intravenous injection, fluorescent molecules are taken up by hepatocytes and excreted into the bile, while negatively charged QDs are retained in the sinusoids and selectively taken up by sinusoidal cells (Kupffer cells and liver sinusoidal endothelial cells), but not by hepatocytes within 3 h. The results could help design NPs targeting the specific types of liver cells and choose the fluorescent markers for appropriate cellular imaging. PMID- 25504509 TI - Disruption of cell-cell contact-mediated notch signaling via hydrogel encapsulation reduces mesenchymal stem cell chondrogenic potential: winner of the Society for Biomaterials Student Award in the Undergraduate Category, Charlotte, NC, April 15 to 18, 2015. AB - Cell-cell contact-mediated Notch signaling is essential for mesenchymal stem cell (MSC) chondrogenesis during development. However, subsequent deactivation of Notch signaling is also required to allow for stem cell chondrogenic progression. Recent literature has shown that Notch signaling can also influence Wnt/beta catenin signaling, critical for MSC differentiation, through perturbations in cell-cell contacts. Traditionally, abundant cell-cell contacts, consistent with development, are emulated in vitro using pellet cultures for chondrogenesis. However, cells are often encapsulated within biomaterials-based scaffolds, such as hydrogels, to improve therapeutic cell localization in vivo. To explore the role of Notch and Wnt/beta-catenin signaling in the context of hydrogel encapsulated MSC chondrogenesis, we compared signaling and differentiation capacity of MSCs in both hydrogels and traditional pellet cultures. We demonstrate that encapsulation within poly(ethylene glycol) hydrogels reduces cell-cell contacts, and both Notch (7.5-fold) and Wnt/beta-catenin (84.7-fold) pathway activation. Finally, we demonstrate that following establishment of cell cell contacts and transient Notch signaling in pellet cultures, followed by Notch signaling deactivation, resulted in a 1.5-fold increase in MSC chondrogenesis. Taken together, these findings support that cellular condensation, and establishment of initial cell-cell contacts is critical for MSC chondrogenesis, and this process is inhibited by hydrogel encapsulation. PMID- 25504511 TI - Influence of mother's depression on her reports of father involvement and child behavioral problems: a latent state-trait approach. AB - Research on father involvement has shown positive effects on child development. Because fathers in high social risk samples may be hard to recruit or retain in studies, the literature often has relied on maternal report of father involvement. A major limitation of this approach is that unobserved traits of the reporting mothers may distort the real associations between father involvement and children's development. Using maternal data from a large, longitudinal sample (N = 704) of low-income, young mothers, we evaluated the degree to which a stable depressive trait affected the link between mother-reported measures of father involvement and child problems. Three waves of maternal depression data were used to fit a latent state-trait model of depression, allowing for separate estimates of occasion-specific symptoms and stable depressive trait. A latent regression analysis which did not control for this trait revealed a link between father involvement and child problems similar in magnitude to the links reported in the literature. However, this association disappeared once we accounted for the effect of maternal depressive trait. Results suggest that studies using maternal reports of both father and child behaviors should control for such confounding effects. We elaborate on these findings in the conclusion and offer suggestions for future research on the role of fathers in child development. PMID- 25504512 TI - The roles of AXIN2 in tumorigenesis and epigenetic regulation. AB - AXIN2, an important regulator in Wnt/beta-catenin signaling pathway, takes part in regulating cell proliferation, cytometaplasia, migration, apoptosis and other important functions, has showed close relations with the development of liver cancer, colon cancer, lung cancer, breast cancer and so on. The epigenetic regulation provides new insights for further exploring the pathogenesis of tumor. In this paper, the roles of AXIN2 in tumorigenesis, AXIN2 methylation, ubiquitination and siRNA/RNA regulation will be reviewed. PMID- 25504513 TI - Effects of categorization method, regression type, and variable distribution on the inflation of Type-I error rate when categorizing a confounding variable. AB - The loss of signal associated with categorizing a continuous variable is well known, and previous studies have demonstrated that this can lead to an inflation of Type-I error when the categorized variable is a confounder in a regression analysis estimating the effect of an exposure on an outcome. However, it is not known how the Type-I error may vary under different circumstances, including logistic versus linear regression, different distributions of the confounder, and different categorization methods. Here, we analytically quantified the effect of categorization and then performed a series of 9600 Monte Carlo simulations to estimate the Type-I error inflation associated with categorization of a confounder under different regression scenarios. We show that Type-I error is unacceptably high (>10% in most scenarios and often 100%). The only exception was when the variable categorized was a continuous mixture proxy for a genuinely dichotomous latent variable, where both the continuous proxy and the categorized variable are error-ridden proxies for the dichotomous latent variable. As expected, error inflation was also higher with larger sample size, fewer categories, and stronger associations between the confounder and the exposure or outcome. We provide online tools that can help researchers estimate the potential error inflation and understand how serious a problem this is. PMID- 25504514 TI - NTPDase2 and the P2Y1 receptor are not required for mammalian eye formation. AB - Eye formation in vertebrates is controlled by a conserved pattern of molecular networks. Homeobox transcription factors are crucially involved in the establishment and maintenance of the retina. A previous study of Masse et al. (Nature, 449: 1058-62, 2007) using morpholino knockdown identified the ectonucleotidase NTPDase2 and the P2Y1 receptor as essential elements for eye formation in embryos of the clawed frog Xenopus laevis. In order to investigate whether a similarly essential mechanism would be active in mammalian eye development, we analyzed mice KO for Entpd2 or P2ry1 as well as double KO for Entpd2/P2ry1. These mice developed normal eyes. In order to identify potential deficits in the molecular identity or in the arrangement of the cellular elements of the retina, we performed an immunohistological analysis using a variety of retinal markers. The analysis of single and double KO mice demonstrated that NTPDase2 and P2Y1 receptors are not required for murine eye formation, as previously shown for eye development in Xenopus laevis. PMID- 25504515 TI - A semiparametric copula method for Cox models with covariate measurement error. AB - We consider measurement error problem in the Cox model, where the underlying association between the true exposure and its surrogate is unknown, but can be estimated from a validation study. Under this framework, one can accommodate general distributional structures for the error-prone covariates, not restricted to a linear additive measurement error model or Gaussian measurement error. The proposed copula-based approach enables us to fit flexible measurement error models, and to be applicable with an internal or external validation study. Large sample properties are derived and finite sample properties are investigated through extensive simulation studies. The methods are applied to a study of physical activity in relation to breast cancer mortality in the Nurses' Health Study. PMID- 25504516 TI - A case of gastric-type adenocarcinoma of the uterine cervix associated with lobular endocervical glandular hyperplasia: radiologic-pathologic correlation. AB - Gastric-type adenocarcinoma (GAS) of the uterine cervix is a recently defined subtype of mucinous adenocarcinoma. GAS is proposed to include minimal deviation adenocarcinoma (MDA) as a very well-differentiated form and has been suggested to arise from lobular endocervical glandular hyperplasia (LEGH). We report the magnetic resonance imaging (MRI) findings of a GAS associated with LEGH. On MRI, the LEGH component was detected as multiple cystic lesions arranged in a "cosmos pattern", while the GAS was depicted as a predominantly solid lesion containing obvious adenocarcinoma and MDA components, which appeared as mass-like and infiltrative components, respectively. The GAS exhibited tiny cysts on three dimensional T2-weighted images, high intensity on diffusion-weighted images mostly due to T2 shine-through effect according to apparent diffusion coefficient (ADC) map, and reticular enhancement on dynamic contrast-enhanced MRI, which reflected numerous dilated glandular structures of the tumor. Low ADC was only observed at the deepest invasion front of the obvious adenocarcinoma component. Our case suggests that the MRI features of GAS vary depending on the tumor's histological components, and it is important to be aware of these imaging features when evaluating LEGH on MRI. PMID- 25504517 TI - A case of testicular seminoma in persistent Mullerian duct syndrome with transverse testicular ectopia. AB - We present a rare case of testicular seminoma in persistent Mullerian duct syndrome (PMDS) with transverse testicular ectopia (TTE). A 42-year-old man noticed scrotal swelling a few weeks earlier and underwent magnetic resonance imaging (MRI) on suspicion of testicular tumor. MRI revealed a normal left testis on the left side of the left scrotum and a heterogeneous mass on the right side within the left scrotum. No right testis was found in the right scrotum. A blind ending tubular structure with thickened wall showed a three-layer appearance on T2-weighted imaging and extended from the prostate through the left inguinal canal to the left scrotum. Findings during surgery suggested right testicular tumor associated with right TTE. The histopathological and immunohistochemical diagnoses of the testicular tumor and blind-ending tubular structure were seminoma and persistent Mullerian duct, respectively. Testicular tumor in PMDS with TTE is rare but may possess a characteristic appearance on imaging. Proper knowledge of these diseases will allow correct preoperative diagnosis. PMID- 25504518 TI - Optimal section thickness for detection of polyps at MR: resolution phantom study. AB - PURPOSE: To determine (1) the sensitivity for detection of small polyps with varying MR slice thicknesses using a resolution phantom; (2) reader confidence in polyp detection; and (3) image acquisition time. METHODS: A resolution phantom was created using a 3D printer. Polyp morphologies were sessile (height = diameter), flat (height = 1/2 diameter of the base), and pedunculated (stalk length = polyp diameter). Polyp diameters were 5, 7, 10, and 12 mm. Images were acquired with section thicknesses of 5, 3, and 1 mm. Images were independently reviewed by 4 board-certified radiologists who were blinded to phantom design and sequences parameters. Readers recorded maximal polyp diameter and confidence level that a polyp was present on a 1-100 point scale. Image acquisition time was also recorded. RESULTS: All polyps were detected by all 4 readers in the 5-mm section thickness series. All polyps were detected by 3 readers in the 3- and 1 mm-section thickness series. The fourth reader identified 11/12 polyps in the 3- and 1-mm-section thickness series. Confidence levels were not statistically significantly different for the different section thicknesses (p = 0.28). Increasing the section thickness from 1 to 5 mm decreased image acquisition time from 3 min 54 s to 41 s. CONCLUSIONS: Five-millimeter-section thickness was adequate for identification of 5-12 mm polyps regardless of shape. Pending further reduction in acquisition time, this prototype sequence holds promise for segmental imaging of the colon with MR colonography. PMID- 25504519 TI - Atropisomeric [(diphosphine)Au2 Cl2 ] complexes and their catalytic activity towards asymmetric cycloisomerisation of 1,6-enynes. AB - X-ray crystal structures of two [(diphosphine)Au2 Cl2 ] complexes (in which diphosphine=P-Phos and xylyl-P-Phos; P-Phos=[2,2',6,6'-Tetramethoxy-4,4' bis(diphenylphosphino)-3,3'-bipyridine]) were determined and compared to the reported structures of similar atropisomeric gold complexes. Correlations between the Au???Au distances and torsional angles for the biaryl series of ligands (MeOBIPHEP, SEGPhos, and P-Phos; BIPHEP=2,2'-bis(diphenylphosphino)-1,1' biphenyl, SEGPhos=[(4,4'-bi-1,3-benzodioxole)-5,5'-diyl]bis[diphenylphosphine]) can be made; these measurements appear to be very dependent upon the phosphorous substituent. Conversely, the same effect was not observed for ligands based on the binaphthyl (BINAP) series. The catalytic activity of these complexes was subsequently assessed in the enantioselective cycloisomerisation of 1,6-enynes and revealed an over-riding electronic effect: more-electron-rich phosphines promote greater enantioselectivity. The possibility of silver acting as a (co )catalyst was ruled out in these reactions. PMID- 25504521 TI - Transparent organic upconversion devices for near-infrared sensing. AB - Transparent organic upconversion devices are shown in a night-vision demonstration of a real object under near-infrared (NIR) illumination in the dark. An extraordinarily high current gain - reflecting the on-off switching effect - greater than 15 000 at a driving voltage of 3 V is demonstrated, indicating the high sensitivity to NIR light and potential of using the proposed upconverter in practical applications. A maximum luminance exceeding 1500 cd m( 2) at 7 V is achieved. Unlike previous studies, where 2D aperture projection is reported, the current study shows 3D images of real objects under NIR illumination in the dark. PMID- 25504522 TI - Glutamine supplementation for young infants with severe gastrointestinal disease. AB - BACKGROUND: Endogenous glutamine biosynthesis may be insufficient to meet the needs of people with severe gastrointestinal disease. Results from studies using experimental animal models of gastrointestinal disease have suggested that glutamine supplementation improves clinical outcomes. This review examines evidence on the effect of glutamine supplementation in young infants with severe gastrointestinal disease. OBJECTIVES: To assess the effect of supplemental glutamine on mortality and morbidity in young infants with severe gastrointestinal disease. SEARCH METHODS: We searcheed the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2014, Issue 8), MEDLINE, EMBASE, and CINAHL (from inception to September 2014), conference proceedings, and reference lists from previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared glutamine supplementation versus no glutamine supplementation in infants up to three months old (corrected for preterm birth if necessary) with severe gastrointestinal disease defined as a congenital or acquired gastrointestinal condition that is likely to necessitate providing parenteral nutrition for at least 24 hours. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and undertook data extraction independently. We analysed the treatment effects in the individual trials and reported the risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference for continuous data, with 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and explored the potential causes of heterogeneity in sensitivity analyses. MAIN RESULTS: We found three trials in which a total of 274 infants participated. The trials were of good methodological quality but were too small to detect clinically important effects of glutamine supplementation. Meta-analyses did not reveal a statistically significant difference in the risk of death before hospital discharge (typical RR 0.79, 95% CI 0.19 to 3.20; typical RD -0.01, 95% CI -0.05 to 0.03) or in the rate of invasive infection (typical RR 1.37, 95% CI 0.89 to 2.11; typical RD 0.08, 95% CI -0.03 to 0.18]). AUTHORS' CONCLUSIONS: The available data from randomised controlled trials do not suggest that glutamine supplementation has any important benefits for young infants with severe gastrointestinal disease. PMID- 25504523 TI - Tissue distribution of heavy metals in heron and egret chicks from Pyeongtaek, Korea. AB - Iron, zinc, manganese, lead and cadmium were measured in the liver, kidney and bone of Grey Heron (Ardea cinerea), Intermediate Egret (Egretta intermedia), Little Egret (Egretta garzetta) and Black-crowned Night Herons (Nycticorax nycticorax) from Korea. Iron, zinc, manganese, lead and cadmium concentrations had species- and tissue- specific accumulation. Lead concentrations in all tissues of Black-crowned Night Heron and cadmium in kidneys of Intermediate Egret chicks were relatively higher than in other species. Iron and manganese in the liver, zinc in the bone, and lead and cadmium in the kidney were relatively higher than other tissues and these results have been reported in other birds. Lead concentrations in all species were at a level associated with acute lead poisoning and cadmium concentrations except for Grey Heron chicks were at a level associated with chronic cadmium exposure. Lead concentrations in livers and bones of heron and egret chicks were within a range considered background level (<6.00 MUg/g dw). But, lead concentrations in kidneys of 12 of 37 heron and egret chicks were at concentrations associated with lethal lead poisoning (6.00-18 MUg/g dw) and 7 of 37 chicks were compatible with death (>18.0 MUg/g dw). For cadmium, all liver and kidney concentrations were at a level considered background for birds (<3.00 MUg/g dw). Essential elements such as iron, zinc and manganese concentrations were within the range observed in other birds. PMID- 25504524 TI - Composition of the volatile fraction of a sample of Brazilian green propolic and its phytotoxic activity. AB - BACKGROUND: Propolis is a resinous material produced by honeybees, containing mainly beeswax and plant material. Despite the wide spectrum of biological activity of propolis, to our knowledge no studies have been carried out about phytotoxic properties of Brazilian propolis and its constituents. The aims of this study were to analyze the chemical composition and to evaluate the phytotoxic activity of the volatile fraction of a sample of Brazilian green propolis. RESULTS: Main constituents are the phenylpropanoid 3-prenylcinnamic acid allyl ester (26.3%) and the sesquiterpene spathulenol (23.4%). Several other sesquiterpenes and phenylpropanoids, in addition to linalool and alpha-terpineol (monoterpenes), were also detected. The activity of solutions of the volatile fraction at 1.0, 0.5 and 0.1% was tested on lettuce seeds and seedlings. The solution at 1% inhibited completely the seed germination and solutions at 0.1 and 0.5% reduced the germination rate index. The solution at 0.5% reduced the growth of the hypocotyl-radicle axis and the development of the cotyledon leaf. CONCLUSIONS: The chemical composition of the volatile fraction of this Brazilian green propolis is different from those previously described, and these results may contribute to a better understanding about the chemical variations in propolis. The volatile fraction of Brazilian green propolis influences both germination of seed lettuce and the growth of its seedlings, showing an phytotoxic potential. PMID- 25504526 TI - MASCC/ESMO/EAPC survey of palliative programs. AB - BACKGROUND: Palliative care program structure is important to integrating palliative services into cancer care. A first step in understanding the structure of palliative care programs is to survey existing programs. METHOD: This data was generated from members of MASCC, the European Society of Medical Oncology (ESMO), and the European Association of Palliative Care (EAPC) who completed the surveys on the website. A survey questionnaire was developed using the survey tool developed by Dr. Hui and colleagues by permission which was modified for the purposes of this study. Findings were described in number and percentages. Inferential statistics involved the Fisher's exact test for factors with two levels, chi-Square test for unordered categorical factors with greater than two levels, Cochran-Armitage trend test for ordered categorical factors, and the Wilcoxon rank sum test for measured factors. RESULTS: Sixty-two program leaders completed the survey. Most programs had been in existence greater than 5 years and were led by oncology trained physicians who had an additional specialty. Most programs had consultative services and outpatient clinics with fewer having inpatient beds and institutionally associated hospices. Most programs provided patient continuity. Patients were generally seen late in the course of illness with the average survival of 23 days when seen as inpatients and 40 days when seen as outpatients. Less than half had palliative care fellowship training programs. Most had research structures in place. DISCUSSION: These findings differ from results reported in a previous survey which may reflect a European palliative care program structure. However, there were similarities which include a high inpatient palliative care unit mortality and short survival of patients seen as outpatients, indicating that referrals to palliative care occur late in the course of cancer. CONCLUSIONS: This study not only differs in some respects to a previous survey of palliative care programs but also confirms the late referral of patients to palliative care. PMID- 25504525 TI - REDD1 functions at the crossroads between the therapeutic and adverse effects of topical glucocorticoids. AB - Cutaneous atrophy is the major adverse effect of topical glucocorticoids; however, its molecular mechanisms are poorly understood. Here, we identify stress inducible mTOR inhibitor REDD1 (regulated in development and DNA damage response 1) as a major molecular target of glucocorticoids, which mediates cutaneous atrophy. In REDD1 knockout (KO) mice, all skin compartments (epidermis, dermis, subcutaneous fat), epidermal stem, and progenitor cells were protected from atrophic effects of glucocorticoids. Moreover, REDD1 knockdown resulted in similar consequences in organotypic raft cultures of primary human keratinocytes. Expression profiling revealed that gene activation by glucocorticoids was strongly altered in REDD1 KO epidermis. In contrast, the down-regulation of genes involved in anti-inflammatory glucocorticoid response was strikingly similar in wild-type and REDD1 KO mice. Integrative bioinformatics analysis of our and published gene array data revealed similar changes of gene expression in epidermis and in muscle undergoing glucocorticoid-dependent and glucocorticoid independent atrophy. Importantly, the lack of REDD1 did not diminish the anti inflammatory effects of glucocorticoids in preclinical model. Our findings suggest that combining steroids with REDD1 inhibitors may yield a novel, safer glucocorticoid-based therapies. PMID- 25504527 TI - Examining the role of subjective and objective burden in carer health-related quality of life: the case of colorectal cancer. AB - PURPOSE: Our aim was to investigate associations between the subjective burden of care and health-related quality of life (both physical and mental) within colorectal cancer patient carers in Ireland, with supplementary analysis of carer objective factors. METHODS: Two hundred twenty-eight colorectal cancer informal carers were sent a postal questionnaire between August 2010 and March 2011 which included the Caregiver Reaction Assessment (CRA) and the SF-12v2. Multiple regression analysis assessed whether five CRA domains (family support, finances, schedule, health and esteem) predicted carer mental or physical health. Between group comparisons investigated differences in these domains across objective factors. RESULTS: One hundred fifty-three carers (82% female) completed the questionnaire (response rate = 68%). Carers' mean physical component summary (PCS) was 48.56 (SD = 10.38) and mean mental component summary (MCS) was 49.22 (SD = 9.7). Five CRA factors explained 30% of variance in the PCS score and 28% of variance in the MCS score. Health burden (beta = -.76, p < .001) and schedule burden (beta = .28, p = .01) were significant predictors of PCS. MCS was significantly predicated by financial burden (beta = -.24, p = .01) and esteem (beta = -.18, p = .03). Younger carers, spouses, those with a comorbid condition and those with no income change had significantly lower PCS. There were no statistically significant group differences for carer mental health. CONCLUSIONS: Our results demonstrate the need to recognise the distinctive aspects of the impact of caring (i.e., physical and mental) on carers and that different domains of subjective carer burden and objective factors impact differently on each of these. This has important implications for those delivering support to carers over the course of the survivorship continuum. PMID- 25504528 TI - Identification of a novel mutation in MAGT1 and progressive multifocal leucoencephalopathy in a 58-year-old man with XMEN disease. AB - XMEN disease (X-linked immunodeficiency with Magnesium defect, Epstein-Barr virus infection and Neoplasia) is a novel primary immune deficiency caused by mutations in MAGT1 and characterised by chronic infection with Epstein-Barr virus (EBV), EBV-driven lymphoma, CD4 T-cell lymphopenia, and dysgammaglobulinemia [1]. Functional studies have demonstrated roles for magnesium as a second messenger in T-cell receptor signalling [1], and for NKG2D expression and consequently NK- and CD8 T-cell cytotoxicity [2]. 7 patients have been described in the literature; the oldest died at 45 years and was diagnosed posthumously [1-3]. We present the case of a 58-year-old Caucasian gentleman with a novel mutation in MAGT1 with the aim of adding to the phenotype of this newly described disease by detailing his clinical course over more than 20 years. PMID- 25504529 TI - Parents' Prenatal Mental Health and Emotional, Behavioral and Social Development in Their Children. AB - This study examines the association between expectant parents' psychological distress and children's development at 36 months old. This is a prospective population study based on the Norwegian Mother and Child Cohort Study, N = 31,663. Logistic regression models were used to assess whether high scores (cutoff >= 2.00) on the symptom checklist-5 in parents predicted higher levels (cutoff >= 90 percentile) of developmental problems in their children. The risk of emotional and behavioral problems were significantly increased in children when both parents were affected by psychological distress during pregnancy, fully adjusted OR 2.35 (95% CI 1.36, 4.07) and OR 2.65 (96% CI 1.564.48), respectively. The risk was higher when mothers reported high level of psychological distress than when only the fathers did, but the risk of emotional difficulties in children was highest when both parents presented high levels of psychological distress, indicating an additive effect of parental psychological distress. PMID- 25504530 TI - An investigation of the factor structure of the beck depression inventory-II in anorexia nervosa. AB - Symptoms of depression frequently co-occur with eating disorders and have been associated with negative outcomes. Self-report measures such as the Beck Depression Inventory-II (BDI-II) are commonly used to assess for the presence of depressive symptoms in eating disorders, but the instrument's factor structure in this population has not been examined. The purposes of this study were to explore the factor structure of the BDI-II in a sample of individuals (N = 437) with anorexia nervosa undergoing inpatient treatment and to examine changes in depressive symptoms on each of the identified factors following a course of treatment for anorexia nervosa in order to provide evidence supporting the construct validity of the measure. Exploratory factor analysis revealed that a three-factor model reflected the best fit for the data. Confirmatory factor analysis was used to validate this model against competing models and the three factor model exhibited strong model fit characteristics. BDI-II scores were significantly reduced on all three factors following inpatient treatment, which supported the construct validity of the scale. The BDI-II appears to be reliable in this population, and the factor structure identified through this analysis may offer predictive utility for identifying individuals who may have more difficulty achieving weight restoration in the context of inpatient treatment. Copyright (c) 2014 John Wiley & Sons, Ltd and Eating Disorders Association. PMID- 25504531 TI - Nitrogen analogues of Thiele's hydrocarbon. AB - A series of bis[N,N-di-(4-methoxylphenyl)amino]arene dications 1(2+) -3(2+) have been synthesized and characterized. Their electronic structures were investigated by various experiments assisted by theoretical calculations. It was found that they are singlets in the ground state and that their diradical character is dependent on the bridging moiety. 3(2+) has a smaller singlet-triplet energy gap and its excited triplet state is thermally readily accessible. The work provides a nitrogen analogue of Thiele's hydrocarbon with considerable diradical character. PMID- 25504520 TI - Genetic and phenotypic intra-species variation in Candida albicans. AB - Candida albicans is a commensal fungus of the human gastrointestinal tract and a prevalent opportunistic pathogen. To examine diversity within this species, extensive genomic and phenotypic analyses were performed on 21 clinical C. albicans isolates. Genomic variation was evident in the form of polymorphisms, copy number variations, chromosomal inversions, subtelomeric hypervariation, loss of heterozygosity (LOH), and whole or partial chromosome aneuploidies. All 21 strains were diploid, although karyotypic changes were present in eight of the 21 isolates, with multiple strains being trisomic for Chromosome 4 or Chromosome 7. Aneuploid strains exhibited a general fitness defect relative to euploid strains when grown under replete conditions. All strains were also heterozygous, yet multiple, distinct LOH tracts were present in each isolate. Higher overall levels of genome heterozygosity correlated with faster growth rates, consistent with increased overall fitness. Genes with the highest rates of amino acid substitutions included many cell wall proteins, implicating fast evolving changes in cell adhesion and host interactions. One clinical isolate, P94015, presented several striking properties including a novel cellular phenotype, an inability to filament, drug resistance, and decreased virulence. Several of these properties were shown to be due to a homozygous nonsense mutation in the EFG1 gene. Furthermore, loss of EFG1 function resulted in increased fitness of P94015 in a commensal model of infection. Our analysis therefore reveals intra-species genetic and phenotypic differences in C. albicans and delineates a natural mutation that alters the balance between commensalism and pathogenicity. PMID- 25504533 TI - Variovorax guangxiensis sp. nov., an aerobic, 1-aminocyclopropane-1-carboxylate deaminase producing bacterium isolated from banana rhizosphere. AB - A 1-aminocyclopropane-1-carboxylate deaminase producing bacterium, designated GXGD002(T), was isolated from the rhizosphere of banana plants cultivated in Guangxi province, China. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain GXGD002(T) is a member of the genus Variovorax. High levels of 16S rRNA gene sequence similarity are found between strain GXGD002(T) and Variovorax paradoxus DSM 30034(T) (99.4 %), Variovorax ginsengisoli KCTC 12583(T) (99.1 %), Variovorax boronicumulans KCTC 22010(T) (99.0 %), Variovorax soli DSM18216(T) (98.7 %), Variovorax defluvii DSM 27259(T) (98.1 %) and Variovorax dokdonensis KCTC 12544(T) (97.4 %) respectively. However, the DNA-DNA hybridization values between strain GXGD002(T) and its closely related species V. paradoxus DSM 30034(T), V. ginsengisoli KCTC 12583(T) and V. boronicumulans KCTC 22010(T) were found to be 40.7, 30.9 and 23.7 %, respectively. The DNA G + C content of strain GXGD002(T) was found to be 67.8 mol%. The major fatty acids of strain GXGD002(T) are C16:0 (20.3 %), C10:0 3OH (18.4 %), C17:0 cyclo (18.9 %), C18:1w7c (12.3 %) and summed feature 3 (13.9 %). The predominant respiratory quinone was identified as ubiquinone-8 (Q-8) and the major polar lipids as phosphatidylethanolamine and phosphatidylglycerol. The results of polyphasic taxonomic study including physiological and biochemical tests, whole-cell SDS PAGE profiles and chemotaxonomic analysis allowed a clear differentiation of strain GXGD002(T) from the other species in the genus Variovorax. Based on these results, a new species, Variovorax guangxiensis, is proposed. The type strain is GXGD002(T) (=DSM 27352(T) = ACCC 05911(T)). PMID- 25504534 TI - Mesh ingrowth with concomitant bacterial infection resulting in inability to explant: a failure of mesh salvage. AB - PURPOSE: Removal is the standard treatment for mesh infection following prosthetic hernia repair. However, certain types of mesh may be less amenable to removal even in the setting of active infection; we present four such cases, all involving the same composite mesh. METHODS: Four high-risk patients underwent Parietex mesh implantation for large ventral wall hernias and developed subsequent Staphylococcus infections with attempted explantation of infected mesh and wound care. RESULTS: There was inability to completely explant mesh in all four cases, leading to chronic purulent wounds and long-term complications. CONCLUSION: While mesh infection is a recognized complication of prosthetic hernia repair, many synthetic meshes form a slimy biofilm and thus can be removed relatively easily. However, the structural qualities of certain types of mesh create ingrowth into tissues even in the setting of infection, resulting in inability to explant with subsequent long-term chronic wound complications. PMID- 25504535 TI - Raman mapping of mannitol/lysozyme particles produced via spray drying and single droplet drying. AB - PURPOSE: This study aimed to investigate the effect of a model protein on the solid state of a commonly used bulk agent in spray-dried formulations. METHODS: A series of lysozyme/mannitol formulations were spray-dried using a lab-scale spray dryer. Further, the surface temperature of drying droplet/particles was monitored using the DRYING KINETICS ANALYZERTM (DKA) with controllable drying conditions mimicking the spray-drying process to estimate the drying kinetics of the lysozyme/mannitol formulations. The mannitol polymorphism and the spatial distribution of lysozyme in the particles were examined using X-ray powder diffractometry (XRPD) and Raman microscopy. Partial Least Squares Discriminant Analysis was used for analyzing the Raman microscopy data. RESULTS: XRPD results indicated that a mixture of beta-mannitol and alpha-mannitol was produced in the spray-drying process which was supported by the Raman analysis, whereas Raman analysis indicated that a mixture of alpha-mannitol and delta-mannitol was detected in the single particles from DKA. In addition Raman mapping indicated that the presence of lysozyme seemed to favor the appearance of alpha-mannitol in the particles from DKA evidenced by close proximity of lysozyme and mannitol in the particles. CONCLUSIONS: It suggested that the presence of lysozyme tend to induce metastable solid state forms upon the drying process. PMID- 25504537 TI - Palmar Crease Pallor. PMID- 25504536 TI - Evidence of Self-correction of Child Sex Ratios in India: A District-Level Analysis of Child Sex Ratios From 1981 to 2011. AB - Sex ratios in India have become increasingly imbalanced over the past decades. We hypothesize that when sex ratios become very uneven, the shortage of girls will increase girls' future value, leading sex ratios to self-correct. Using data on children under 5 from the last four Indian censuses, we examine the relationship between the sex ratio at one point in time and the change in sex ratio over the next 10 years by district. Fixed-effects models show that when accounting for unobserved district-level characteristics--including total fertility rate, infant mortality rate, percentage literate, percentage rural, percentage scheduled caste, percentage scheduled tribe, and a time trend variable--sex ratios are significantly negatively correlated with the change in sex ratio in the successive 10-year period. This suggests that self-corrective forces are at work on imbalanced sex ratios in India. PMID- 25504538 TI - Generation and characterization of tribenuron-methyl herbicide-resistant rapeseed (Brasscia napus) for hybrid seed production using chemically induced male sterility. AB - KEY MESSAGE: Identification and molecular analysis of four tribenuron-methyl resistant mutants in Brassica napus , which would be very useful in hybrid production using a Chemically induced male sterility system. Chemically induced male sterility (CIMS) systems dependent on chemical hybridization agents (CHAs) like tribenuron-methyl (TBM) represent an important approach for practical utilization of heterosis in rapeseed. However, when spraying the female parents with TBM to induce male sterility the male parents must be protected with a shield to avoid injury to the stamens, which would otherwise complicate the seed production protocol and increase the cost of hybrid seed production. Here we report the first proposed application of a herbicide-resistant cultivar in hybrid production, using a CIMS system based on identifying four TBM-resistant mutants in Brassica napus. Genetic analysis indicated that the TBM resistance was controlled by a single dominant nuclear gene. An in vitro enzyme activity assay for acetohydroxyacid synthase (AHAS) suggested that the herbicide resistance is caused by a gain-of-function mutation in a copy of AHAS genes. Comparative sequencing of the mutants and wild type BnaA.AHAS.a coding sequences identified a C-to-T transition at either position 535 or 536 from the translation start site, which resulted in a substitution of proline with serine or leucine at position 197 according to the Arabidopsis thaliana protein sequence. An allele-specific dCAPS marker developed from the C536T variation co-segregated with the herbicide resistance. Transgenic A. thaliana plants expressing BnaA.ahas3.a conferred herbicide resistance, which confirmed that the P197 substitution in BnaA.AHAS.a was responsible for the herbicide resistance. Moreover, the TBM-resistant lines maintain normal male fertility under TBM treatment and can be of practical value in hybrid seed production using CIMS. PMID- 25504539 TI - The sh2-R allele of the maize shrunken-2 locus was caused by a complex chromosomal rearrangement. AB - KEY MESSAGE: The mutant that originally defined the shrunken - 2 locus of maize is shown here to be the product of a complex chromosomal rearrangement. The maize shrunken-2 gene (sh2) encodes the large subunit of the heterotetrameric enzyme, adenosine diphosphate glucose pyrophosphorylases and a rate-limiting enzyme in starch biosynthesis. The sh2 gene was defined approximately 72 years ago by the isolation of a loss-of-function allele conditioning a shrunken, but viable seed. In subsequent years, the realization that this allele, termed zsh2-R or sh2 Reference, causes an extremely high level of sucrose to accumulate in the developing seed led to a revolution in the sweet corn industry. Now, the vast majority of sweet corns grown throughout the world contain this mutant allele. Through initial Southern analysis followed by genomic sequencing, the work reported here shows that this allele arose through a complex set of events involving at least three breaks of chromosome 3 as well as an intra-chromosomal inversion. These findings provide an explanation for some previously reported, unexpected observations concerning rates of recombination within and between genes in this region. PMID- 25504541 TI - Bis(N-confused porphyrin) as a semirigid receptor with a chirality memory: a two way host enantiomerization through point-to-axial chirality transfer. AB - The adduct formation of protonated bis(N-confused porphyrin) (BNCP, 3,3'-bis(meso tetratolyl-2-aza-21-carbaporphyrin) with chiral anions, carboxylic acids, and alcohols was studied in solution by means of (1) H NMR and circular dichroism (CD) spectroscopic analysis and DFT methods. The addition of enantiopure guests to the acidified BNCP resulted in optical activity that vanished after neutralization. Pairs of the (1) H NMR-distinguishable diastereomers were formed when enantiopure guests were applied, although a single form was observed upon the addition of the racemic mixtures in each case. Unidirectional configuration change that led to diastereomeric excess was observed in several instances. Such an excess was memorized by metalation of the adducts with AgBF4 , thus resulting in optically active silver(III) complexes of BNCP with some enantiomeric excess. Absolute configurations of BNCP cations and bis(zinc) and bis(silver(III)) complexes were determined on the basis of time-dependent (TD)-DFT calculations of their CD spectra. It was shown that some of the chiral carboxylates induced opposite directions of enantiomerization of di- and tetracations or di /tetracation and bis(zinc) complexes. The source of the optical activity of the equimolar diastereomeric mixture of adducts is discussed. PMID- 25504542 TI - Inhibition of RAS activation due to a homozygous ezrin variant in patients with profound intellectual disability. AB - Gain-of-function alterations in several components and modulators of the Ras-MAPK pathway lead to dysregulation of the pathway and cause a broad spectrum of autosomal dominant developmental disorders, collectively known as RASopathies. These findings demonstrate the importance of tight multilevel Ras regulation to safeguard signaling output and prevent aberrant activity. We have recently identified ezrin as a novel regulatory element required for Ras activation. Homozygosity mapping and exome sequencing have now revealed the first presumably disease-causing variant in the coding gene EZR in two siblings with a profound intellectual disability. Localization and membrane targeting of the altered ezrin protein appeared normal but molecular modeling suggested protein interaction surfaces to be disturbed. Functional analysis revealed that the altered ezrin protein is no longer able to bind Ras and facilitate its activation. Furthermore, expression of the altered ezrin protein in different cell lines resulted in abnormal cellular processes, including reduced proliferation and neuritogenesis, thus revealing a possible mechanism for its phenotype in humans. To our knowledge, this is the first report of an autosomal recessively inherited loss-of function mutation causing reduced Ras activity and thus extends and complements the pathogenicity spectrum of known Ras-MAPK pathway disturbances. PMID- 25504543 TI - Mid-infrared spectroscopy-based analysis of mammalian cell culture parameters. AB - Within the framework of process analytical technology, infrared spectroscopy (IR) has been used for characterization of biopharmaceutical production processes. Although noninvasive attenuated total reflection (ATR) spectroscopy can be regarded as gold standard within IR-based process analytics, simpler and more cost-effective mid-infrared (MIR) instruments might improve acceptability of this technique for high-level monitoring of small scale experiments as well as for academia where financial restraints impede the use of costly equipment. A simple and straightforward at-line mid-IR instrument was used to monitor cell viability parameters, activity of lactate dehydrogenase (LDH), amount of secreted antibody, and concentration of glutamate and lactate in a Chinese hamster ovary cell culture process, applying multivariate prediction models, including only 25-28 calibration samples per model. Glutamate amount could be predicted with high accuracy (R(2) 0.91 for independent test-set) while antibody concentration achieved good prediction for concentrations >0.4 mg L(-1) . Prediction of LDH activity was accurate except for the low activity regime. The model for lactate monitoring was only moderately good and requires improvements. Relative cell viability between 20 and 95% could be predicted with low error (8.82%) in comparison to reference methods. An initial model for determining the number of nonviable cells displayed only acceptable accuracy and requires further improvement. In contrast, monitoring of viable cell number showed better accuracy than previously published ATR-based results. These results prove the principal suitability of less sophisticated MIR instruments to monitor multiple parameters in biopharmaceutical production with relatively low investments and rather fast calibration procedures. PMID- 25504544 TI - Asthma and COPD proteomics: current approaches and future directions. AB - Although asthma and chronic obstructive pulmonary disease COPD represent the two most common chronic respiratory diseases worldwide, the mechanisms underlying their pathobiology need to be further elucidated. Presently, differentiation of asthma and COPD are largely based on clinical and lung function parameters. However, the complexity of these multifactorial diseases may lead to misclassification and to inappropriate management strategies. Recently, tremendous progress in MS has extended the sensitivity, accuracy, and speed of analysis, enabling the identification of thousands of proteins per experiment. Beyond identification, MS has also greatly implemented quantitation issues allowing to assess qualitative-quantitative differences in protein profiles of different samples, in particular diseased versus normal. Herein, we provide a summary of recent proteomics-based investigations in the field of asthma/COPD, highlighting major issues related to sampling and processing procedures for proteomic analyses of specific airway and parenchymal specimens (induced sputum, exhaled breath condensate, epithelial lining fluid, bronchoalveolar and nasal lavage fluid), as well as blood-derived specimen (plasma and serum). Within such a context, together with current difficulties and limitations mainly due to lack of general standardization in preanalytical sampling procedure, our discussion will focus on the challenges and possible benefits of proteomic studies in phenotypic stratification of asthma and COPD. PMID- 25504545 TI - Micelle-enhanced spectrofluorimetric method for determination of lacidipine in tablet form; application to content uniformity testing. AB - A highly sensitive, simple and rapid spectrofluorimetric method was developed for the determination of lacidipine (LCP) in tablets. The proposed method is based on the investigation of the fluorescence spectral behavior of LCP in both sodium dodecyl sulphate (SDS) and the tween-80 micellar system. In aqueous solutions of acetate buffer (pH 4.5), the fluorescence intensities of LCP were greatly enhanced (ca. 2.4 and 4.3 folds) in the presence of either SDS or tween-80, respectively. The fluorescence intensity was measured at 444 nm after excitation at 277 nm using either SDS or tween-80 as a surfactant. The fluorescence concentration plots were rectilinear over the ranges of 50.0-500.0 ng/ml and 5.0 200.0 ng/ml with lower detection limits of 5.11 and 2.06 ng/ml and lower quantification limits of 17 and 6.87 ng/ml using SDS and tween-80, respectively. The method was successfully applied to the analysis of LCP in commercial tablets and the results were in good agreement with those obtained with the comparison method. Furthermore, content uniformity testing of pharmaceutical tablets was also conducted. PMID- 25504540 TI - Connecting the retina to the brain. AB - The visual system is beautifully crafted to transmit information of the external world to visual processing and cognitive centers in the brain. For visual information to be relayed to the brain, a series of axon pathfinding events must take place to ensure that the axons of retinal ganglion cells, the only neuronal cell type in the retina that sends axons out of the retina, find their way out of the eye to connect with targets in the brain. In the past few decades, the power of molecular and genetic tools, including the generation of genetically manipulated mouse lines, have multiplied our knowledge about the molecular mechanisms involved in the sculpting of the visual system. Here, we review major advances in our understanding of the mechanisms controlling the differentiation of RGCs, guidance of their axons from the retina to the primary visual centers, and the refinement processes essential for the establishment of topographic maps and eye-specific axon segregation. Human disorders, such as albinism and achiasmia, that impair RGC axon growth and guidance and, thus, the establishment of a fully functioning visual system will also be discussed. PMID- 25504547 TI - Bayard Holmes (1852-1924) and Henry Cotton (1869-1933): Surgeon-psychiatrists and their tragic quest to cure schizophrenia. AB - Early 20th-century medicine was dominated by the infectious theory of disease. Some leading physicians believed that infection or the accumulation of toxic substances from bacterial stasis caused a wide range of diseases, including schizophrenia. In the case of schizophrenia, one theory held that intestinal stasis lead to the bacterial production of toxins that affected brain function, resulting in psychotic illness. This theory predicted that clearing the stasis by drainage or by removal of the offending organ would be curative. Bayard Holmes and Henry Cotton, surgeon-psychiatrists, achieved notoriety for their efforts to cure schizophrenia surgically. Their endeavours were not only a failure but resulted in tragedy to their families and to a wider population. Treatment of their own sons also represented a violation of the ethics of their time. This account describes the life and career of Holmes and Cotton and reappraises their work in the light of recent developments. PMID- 25504546 TI - Targeted antithrombotic protein micelles. AB - Activated platelets provide a promising target for imaging inflammatory and thrombotic events along with site-specific delivery of a variety of therapeutic agents. Multifunctional protein micelles bearing targeting and therapeutic proteins were now obtained by one-pot transpeptidation using an evolved sortase A. Conjugation to the corona of a single-chain antibody (scFv), which binds to the ligand-induced binding site (LIBS) of activated GPIIb/IIIa receptors, enabled the efficient detection of thrombi. The inhibition of thrombus formation was subsequently accomplished by incorporating the catalytically active domain of thrombomodulin (TM) onto the micelle corona for the local generation of activated protein C, which inhibits the formation of thrombin. An effective strategy has been developed for the preparation of protein micelles that can be targeted to sites of activated platelets with broad potential for treatment of acute thrombotic events. PMID- 25504548 TI - Injectable, interconnected, high-porosity macroporous biocompatible gelatin scaffolds made by surfactant-free emulsion templating. AB - High-porosity interconnected, thermoresponsive macroporous hydrogels are prepared from oil-in-water high internal phase emulsions (HIPEs) stabilized by gelatin graft-poly(N-isopropylacrylamide). PolyHIPEs are obtained by gelling HIPEs utilizing the thermoresponsiveness of the copolymer components. PolyHIPEs properties can be controlled by varying the aqueous phase composition, internal phase volume ratio, and gelation temperature. PolyHIPEs respond to temperature changes experienced during cell seeding, allowing fibroblasts to spread, proliferate, and penetrate into the scaffold. Encapsulated cells survive ejection of cell-laden hydrogels through a hypodermic needle. This system provides a new strategy for the fabrication of safe injectable biocompatible tissue engineering scaffolds. PMID- 25504549 TI - Vaccination in elite athletes: a call to action to develop guidelines for all infectious diseases. PMID- 25504551 TI - Separation of time-resolved phenomena in surface-enhanced Raman scattering of the photocatalytic reduction of p-nitrothiophenol. AB - Straightforward analysis of chemical processes on the nanoscale is difficult, as the measurement volume is linked to a discrete number of molecules, ruling out any ensemble averaging over rotation and diffusion processes. Raman spectroscopy is sufficiently selective for monitoring chemical changes, but is not sufficiently sensitive to be applied directly. Surface-enhanced Raman spectroscopy (SERS) can be applied for studying reaction kinetics, but adds additional variability in the signal as the enhancement factor is not the same for every location. A novel chemometric method described here separates reaction kinetics from short-term variability, based on the lack of fit in a principal component analysis. We show that it is possible to study effects that occur on different time scales independently without data reduction using the photocatalytic reduction of p-nitrothiophenol as a showcase system. Using this approach a better description of the nanoscale reaction kinetics becomes available, while the short-term variations can be examined separately to examine reorientation and/or diffusion effects. It may even be possible to identify reaction intermediates through this approach. With only a limited number of reactive molecules in the studied volume, an intermediate on a SERS hot spot may temporarily dominate the spectrum. Now such events can be easily separated from the bulk conversion process by making use of this chemometric method. PMID- 25504550 TI - Half-time strategies to enhance second-half performance in team-sports players: a review and recommendations. AB - A number of intermittent team sports require that two consecutive periods of play (lasting for ~30-45 min) are separated by a 10-20 min half-time break. The half time practices employed by team-sports players generally include returning to the changing rooms, temporarily relaxing from the cognitive and physical demands of the first half, rehydration and re-fuelling strategies, addressing injury or equipment concerns, and receiving tactical instruction and coach feedback. However, the typically passive nature of these actions has been associated with physiological changes that impair performance during the second half. Both physical and cognitive performances have been found to decline in the initial stages of subsequent exercise that follows half-time. An increased risk of injury has also been observed during this period. Therefore, half-time provides sports scientists and strength and conditioning coaches with an opportunity to optimise second-half performance. An overview of strategies thought to benefit team-sports athletes is presented; specifically, the efficacy of heat maintenance strategies (including passive and active methods), post-activation potentiation, hormonal priming, and modified hydro-nutritional practices are discussed. A theoretical model of applying these strategies in a manner that compliments current practice is also offered. PMID- 25504553 TI - Inhibiting EGFR clustering and cell proliferation with gold nanoparticles. AB - Gold nanoparticles are functionalized with epidermal growth factor (EGF) molecules and incubated with HeLa cells. These new complexes mechanically interfere with the activation of EGF receptors in a length-dependent manner. Protein-functionalized gold nanoparticles hold great potential for unveiling the fundamental characteristics of cell receptors and for future pharmacological studies on receptor targeting. PMID- 25504555 TI - Growth mixture modeling with non-normal distributions. AB - A limiting feature of previous work on growth mixture modeling is the assumption of normally distributed variables within each latent class. With strongly non normal outcomes, this means that several latent classes are required to capture the observed variable distributions. Being able to relax the assumption of within class normality has the advantage that a non-normal observed distribution does not necessitate using more than one class to fit the distribution. It is valuable to add parameters representing the skewness and the thickness of the tails. A new growth mixture model of this kind is proposed drawing on recent work in a series of papers using the skew-t distribution. The new method is illustrated using the longitudinal development of body mass index in two data sets. The first data set is from the National Longitudinal Survey of Youth covering ages 12-23 years. Here, the development is related to an antecedent measuring socioeconomic background. The second data set is from the Framingham Heart Study covering ages 25-65 years. Here, the development is related to the concurrent event of treatment for hypertension using a joint growth mixture-survival model. PMID- 25504556 TI - Heat-induced mortality and expression of heat shock proteins in Colorado potato beetles treated with imidacloprid. AB - The Colorado potato beetle is an important pest of solanaceous plants in the Northern Hemisphere. Better understanding of its physiological responses to temperature stress and their interactions with still-prevalent chemical control has important implications for the management of this insect. We measured mortality and expression of the Hsp70 heat shock proteins in the Colorado potato beetle larvae exposed to sublethal concentration of the commonly used insecticide imidacloprid, and to supraoptimal temperatures. Both turned out to be significant stress factors, although induction of Hsp70 by imidacloprid observed in the present study was low compared to its induction by the heat. The two factors also interacted with each other. At an extreme temperature of 43 degrees C, exposure to a sublethal dose of imidacloprid resulted in a significant rise in larval mortality, which was not observed at an optimal temperature of 25 degrees C. Heat-stressed larvae also failed to respond to imidacloprid by producing more Hsp70. These findings suggest that when field rates of insecticides become insufficient for killing the exposed beetles under optimal temperature conditions due to the evolution of resistance in beetle populations, they may still reduce the probability of resistant beetles surviving the heat shock created by using propane flamers as a rescue treatment. PMID- 25504554 TI - Purine receptors are required for DHA-mediated neuroprotection against oxygen and glucose deprivation in hippocampal slices. AB - Docosahexaenoic acid (DHA) is important for central nervous system function during pathological states such as ischemia. DHA reduces neuronal injury in experimental brain ischemia; however, the underlying mechanisms are not well understood. In the present study, we investigated the effects of DHA on acute hippocampal slices subjected to experimental ischemia by transient oxygen and glucose deprivation (OGD) and re-oxygenation and the possible involvement of purinergic receptors as the mechanism underlying DHA-mediated neuroprotection. We observed that cellular viability reduction induced by experimental ischemia as well as cell damage and thiobarbituric acid reactive substances (TBARS) production induced by glutamate (10 mM) were prevented by hippocampal slices pretreated with DHA (5 MUM). However, glutamate uptake reduction induced by OGD and re-oxygenation was not prevented by DHA. The beneficial effect of DHA against cellular viability reduction induced by OGD and re-oxygenation was blocked with PPADS (3 MUM), a nonselective P2X1-5 receptor antagonist as well as with a combination of TNP-APT (100 nM) plus brilliant blue (100 nM), which blocked P2X1, P2X3, P2X2/3, and P2X7 receptors, respectively. Moreover, adenosine receptors blockade with A1 receptor antagonist DPCPX (100 nM) or with A2B receptor antagonist alloxazine (100 nM) inhibited DHA-mediated neuroprotection. The addition of an A2A receptor antagonist ZM241385 (50 nM), or A3 receptor antagonist VUF5574 (1 MUM) was ineffective. Taken together, our results indicated that neuroprotective actions of DHA may depend on P2X, A1, and A2B purinergic receptors activation. Our results reinforce the notion that dietary DHA may act as a local purinergic modulator in order to prevent neurodegenerative diseases. PMID- 25504557 TI - Rapid preparative isolation of erythrocentaurin from Enicostemma littorale by medium-pressure liquid chromatography, its estimation by high-pressure thin-layer chromatography, and its alpha-amylase inhibitory activity. AB - Erythrocentaurin is a relatively simple natural product present among the members of Gentianaceae. A preparative method for the isolation of erythrocentaurin from the ethyl acetate fraction of Enicostemma littorale using medium-pressure liquid chromatography has been reported. The method consisted of a simple step gradient from 10 to 20% ethyl acetate in n-hexane. Using a 70 * 460 mm Si60 column, this method is capable of processing 20 g of material in <3 h (purity ~ 97%). The recovery of erythrocentaurin was 87.77%. Estimation of erythrocentaurin in extracts and fractions based on high-pressure thin-layer chromatography was carried out on silica gel 60 F(254) plates with toluene/ethyl acetate/formic acid (80:18:2 v/v/v) as the mobile phase. The densitometric analysis was performed at 230 nm. A well-separated compact band of erythrocentaurin appeared at R(f )0.54 +/- 0.04. The analytical method showed good linearity in the concentration range of 200-1500 ng/band with a correlation coefficient of 0.99417. The limits of detection and quantification were found to be ~60 and ~180 ng/band, respectively. Erythrocentaurin exhibited a concentration-dependent alpha-amylase inhibition (IC(50) 1.67 +/- 0.28 mg/mL). The outcome of the study should be considered for pharmacokinetic and biotransformation studies involving E. littorale. PMID- 25504558 TI - Synergistic doping of fullerene electron transport layer and colloidal quantum dot solids enhances solar cell performance. AB - The spatial location of the predominant source of performance-limiting recombination in today's best colloidal quantum dot (CQD) cells is identified, pinpointing the TiO2:CQD junction; then, a highly n-doped PCBM layer is introduced at the CQD:TiO2 heterointerface. An n-doped PCBM layer is essential to maintain the depletion region and allow for efficient current extraction, thereby producing a record 8.9% in overall power conversion efficiency. PMID- 25504559 TI - Electron spin relaxation times and rapid scan EPR imaging of pH-sensitive amino substituted trityl radicals. AB - Carboxy-substituted trityl (triarylmethyl) radicals are valuable in vivo probes because of their stability, narrow lines, and sensitivity of their spectroscopic properties to oxygen. Amino-substituted trityl radicals have the potential to monitor pH in vivo, and the suitability for this application depends on spectral properties. Electron spin relaxation times T1 and T2 were measured at X-band for the protonated and deprotonated forms of two amino-substituted triarylmethyl radicals. Comparison with relaxation times for carboxy-substituted triarylmethyl radicals shows that T1 exhibits little dependence on protonation or the nature of the substituent, which makes it useful for measuring O2 concentration, independent of pH. Insensitivity of T1 to changes in substituents is consistent with the assignment of the dominant contribution to spin lattice relaxation as a local mode that involves primarily atoms in the carbon and sulfur core. Values of T2 vary substantially with pH and the nature of the aryl group substituent, reflecting a range of dynamic processes. The narrow spectral widths for the amino substituted triarylmethyl radicals facilitate spectral-spatial rapid scan electron paramagnetic resonance imaging, which was demonstrated with a phantom. The dependence of hyperfine splittings patterns on pH is revealed in spectral slices through the image. PMID- 25504560 TI - Effect of in vitro digested cod liver oil of different quality on oxidative, proteomic and inflammatory responses in the yeast Saccharomyces cerevisiae and human monocyte-derived dendritic cells. AB - BACKGROUND: Upon oxidation of the polyunsaturated fatty acids in fish oil, either before ingestion or, as recently shown, during the gastro-intestinal passage, a cascade of potentially cytotoxic peroxidation products, such as malondialdehyde and 4-hydroxy-2-hexenal, can form. In this study, we digested fresh and oxidised cod liver oils in vitro, monitored the levels of lipid peroxidation products and evaluated oxidative, proteomic and inflammatory responses to the two types of digests in the yeast Saccharomyces cerevisiae and human monocyte-derived dendritic cells. RESULTS: Digests of cod liver oil with 22-53 umol L(-1) malondialdehyde and 0.26-3.7 umol L(-1) 4-hydroxy-2-hexenal increased intracellular oxidation and cell energy metabolic activity compared to a digested blank in yeast cells and the influence of digests on mitochondrial protein expression was more pronounced for oxidised cod liver oil than fresh cod liver oil. The four differentially expressed and identified proteins were related to energy metabolism and oxidative stress response. Maturation of dendritic cells was affected in the presence of digested fresh cod liver oil compared to the digested blank, measured as lower CD86 expression. The ratio of secreted cytokines, IL-12p40/IL-10, suggested a pro-inflammatory effect of the digested oils in relation to the blank (1.47-1.67 vs. 1.07). CONCLUSION: Gastro-intestinal digestion of cod liver oil increases the amount of oxidation products and resulting digests affect oxidation in yeast and immunomodulation of dendritic cells. PMID- 25504562 TI - Non-suicidal self-injury in patients with eating disorder: associations with identity formation above and beyond anxiety and depression. AB - In the present study, we investigated the association between non-suicidal self injury (NSSI) and problems in identity formation among patients with eating disorder (ED). NSSI is highly prevalent in ED, and problems with identity formation are characteristic of both NSSI and ED. Few studies, however, have investigated identity formation in patients with ED with and without NSSI while taking into account comorbid psychopathology (e.g. anxiety and depression). Therefore, we investigated the relationships between NSSI characteristics, identity confusion/synthesis, and anxiety/depression in 99 female patients with ED by means of self-report questionnaires. The results showed that 58.6% of the patients with ED engaged in at least one type of NSSI (most frequently cutting), with no significant differences in rates of NSSI or identity problems among ED subtypes. Presence, versatility and automatic negative reinforcement functions of NSSI were each significantly and positively related to identity confusion and negatively related to identity synthesis. Even after controlling for age, anxiety, and depression, lack of identity synthesis remained a significant predictor of NSSI in patients with ED. Given that NSSI may constitute an effort to deal with identity confusion/synthesis in patients with ED, therapists should take this developmental task into account while treating patients with ED with NSSI. PMID- 25504561 TI - Phospholamban as a crucial determinant of the inotropic response of human pluripotent stem cell-derived ventricular cardiomyocytes and engineered 3 dimensional tissue constructs. AB - BACKGROUND: Human (h) embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) serve as a potential unlimited ex vivo source of cardiomyocytes (CMs). However, a well-accepted roadblock has been their immature phenotype. hESC/iPSC-derived ventricular (v) CMs and their engineered cardiac microtissues (hvCMTs) similarly displayed positive chronotropic but null inotropic responses to beta-adrenergic stimulation. Given that phospholamban (PLB) is robustly present in adult but poorly expressed in hESC/iPSC-vCMs and its defined biological role in beta-adrenergic signaling, we investigated the functional consequences of PLB expression in hESC/iPSC-vCMs and hvCMTs. METHODS AND RESULTS: First, we confirmed that PLB protein was differentially expressed in hESC (HES2, H9)- and iPSC-derived and adult vCMs. We then transduced hES2-vCMs with the recombinant adenoviruses (Ad) Ad-PLB or Ad-S16E-PLB to overexpress wild-type PLB or the pseudophosphorylated point-mutated variant, respectively. As anticipated from the inhibitory effect of unphosphorylated PLB on sarco/endoplasmic reticulum Ca2+-ATPase, Ad-PLB transduction significantly attenuated electrically evoked Ca2+ transient amplitude and prolonged the 50% decay time. Importantly, Ad-PLB transduced hES2-vCMs uniquely responded to isoproterenol. Ad-S16E-PLB-transduced hES2-vCMs displayed an intermediate phenotype. The same trends were observed with H9- and iPSC-vCMs. Directionally, similar results were also seen with Ad-PLB transduced and Ad-S16E-transduced hvCMTs. However, Ad-PLB altered neither the global transcriptome nor ICa,L, implicating a PLB-specific effect. CONCLUSIONS: Engineered upregulation of PLB expression in hESC/iPSC-vCMs restores a positive inotropic response to beta-adrenergic stimulation. These results not only provide a better mechanistic understanding of the immaturity of hESC/iPSC-vCMs but will also lead to improved disease models and transplantable prototypes with adult like physiological responses. PMID- 25504563 TI - Total synthesis and biological evaluation of the antibiotic lysocin E and its enantiomeric, epimeric, and N-demethylated analogues. AB - Lysocin E, a macrocyclic peptide, exhibits potent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) through a novel mechanism. The first total synthesis of lysocin E was achieved by applying a full solid-phase strategy. The developed approach also provides rapid access to the enantiomeric, epimeric, and N-demethylated analogues of lysocin E. Significantly, the antibacterial activity of the unnatural enantiomer was comparable to that of the natural isomer, suggesting the absence of chiral recognition in its mode of action. PMID- 25504564 TI - Prediction of renal transporter mediated drug-drug interactions for pemetrexed using physiologically based pharmacokinetic modeling. AB - Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (Vmax) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m(2) of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and the area under the plasma-concentration time curve (AUC0-inf) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen. PMID- 25504566 TI - Genotoxicity of synthetic amorphous silica nanoparticles in rats following short term exposure. Part 1: oral route. AB - Synthetic amorphous silica (SAS) in its nanosized form is now used in food applications although the potential risks for human health have not been evaluated. In this study, genotoxicity and oxidative DNA damage of two pyrogenic (NM-202 and 203) and two precipitated (NM-200 and -201) nanosized SAS were investigated in vivo in rats following oral exposure. Male Sprague Dawley rats were exposed to 5, 10, or 20 mg/kg b.w./day for three days by gavage. DNA strand breaks and oxidative DNA damage were investigated in seven tissues (blood, bone marrow from femur, liver, spleen, kidney, duodenum, and colon) with the alkaline and the (Fpg)-modified comet assays, respectively. Concomitantly, chromosomal damage was investigated in bone marrow and in colon with the micronucleus assay. Additionally, malondialdehyde (MDA), a lipid peroxidation marker, was measured in plasma. When required, a histopathological examination was also conducted. The results showed neither obvious DNA strand breaks nor oxidative damage with the comet assay, irrespective of the dose and the organ investigated. Similarly, no increases in chromosome damage in bone marrow or lipid peroxidation in plasma were detected. However, although the response was not dose-dependent, a weak increase in the percentage of micronucleated cells was observed in the colon of rats treated with the two pyrogenic SAS at the lowest dose (5 mg/kg b.w./day). Additional data are required to confirm this result, considering in particular, the role of agglomeration/aggregation of SAS NMs in their uptake by intestinal cells. PMID- 25504567 TI - Growth of hydrophilic CuS nanowires via DNA-mediated self-assembly process and their use in fabricating smart hybrid films for adjustable chemical release. AB - Facile growth of CuS nanowires through self-assembly and their application as building blocks for near-infrared light-responsive functional films have been demonstrated. It is found that DNA is a key factor in preparing the CuS material with defined nanostructure. An exclusive oriented self-aggregate growth mechanism is proposed for the growth of the nanowires, which might have important implications for preparing advanced, sophisticated nanostructures based on DNA nanotechnology. By employing the hydrophilic CuS nanowire as an optical absorber and thermosensitive nanogel as guest reservoir inside alginate film, a new platform for the release of functional molecules has been set up. In vitro studies have shown that the hybrid film possesses excellent biocompatibility and the release rate of chemical molecules from the film could be controlled with high spatial and temporal precision. Our novel approach and the resulting outstanding combination of properties may advance both the fields of DNA nanotechnology and light-responsive devices. PMID- 25504568 TI - Authors' reply-Re: Shi et al. Protease-activated receptor 2 suppresses lymphangiogenesis and subsequent lymph node metastasis in a murine pancreatic cancer model. J Pathol 2014;234: 398-409. PMID- 25504569 TI - Using community insight to understand physical activity adoption in overweight and obese African American and Hispanic women: a qualitative study. AB - Ecologic models suggest that multiple levels of influencing factors are important for determining physical activity participation and include individual, social, and environmental factors. The purpose of this qualitative study was to use an ecologic framework to gain a deeper understanding of the underlying behavioral mechanisms that influence physical activity adoption among ethnic minority women. Eighteen African American and Hispanic women completed a 1-hour in-depth interview. Verbatim interview transcripts were analyzed for emergent themes using a constant comparison approach. Women were middle-aged (age M = 43.9 +/- 7.3 years), obese (body mass index M = 35.0 +/- 8.9 kg/m(2)), and of high socioeconomic status (88.9% completed some college or more, 41.2% reported income >$82,600/year). Participants discussed individual factors, including the need for confidence, motivation and time, and emphasized the importance of environmental factors, including their physical neighborhood environments and safety of and accessibility to physical activity resources. Women talked about caretaking for others and social support and how these influenced physical activity behavior. The findings from this study highlight the multilevel, interactive complexities that influence physical activity, emphasizing the need for a more sophisticated, ecologic approach for increasing physical activity adoption and maintenance among ethnic minority women. Community insight gleaned from this study may be used to better understand determinants of physical activity and develop multilevel solutions and programs guided by an ecologic framework to increase physical activity in ethnic minority women. PMID- 25504570 TI - Food and Beverage Marketing to Latinos: A Systematic Literature Review. AB - Obesity rates among U.S. adults and children have increased over the past two decades and, although signs of stabilization and decline among certain age groups and geographies are being reported, the prevalence of obesity among Latino adults and children remain high. The Latino population is growing in parallel to these obesity rates and marketers realize they cannot ignore this growing, high spending, media-consuming segment. Studies examining food and beverage marketing strategies tend to discuss minority groups in general but do not account for racial and ethnic differences, reducing our ability to explain existing inequities. This article aimed to identify the food and beverage marketing strategies used to influence food environments for Latinos versus non-Latinos. A systematic literature review and analysis, guided by an established marketing conceptual framework, determined that the food and beverage marketing environment for Latinos is less likely to promote healthy eating and more likely to encourage consumption of low-nutrient, calorie-dense foods and beverages. This analysis also determined that Latinos' food environment and the placement of food retail stores appears to influence their body mass index; however, placement of these stores cannot be generalized, as geographical differences exist. While food and beverage marketing is only one of many sources of influence on food and beverage consumption, these findings reinforce the notion that Latinos are at a disadvantage when it comes to exposure of healthy lifestyle messaging and health promoting food environments. PMID- 25504571 TI - Multiple blocks of intermittent and continuous theta-burst stimulation applied via transcranial magnetic stimulation differently affect sensory responses in rat barrel cortex. AB - KEY POINTS: Theta-burst stimulation (TBS) applied via transcranial magnetic stimulation is able to modulate human cortical excitability. Here we investigated in a rat model how two different forms of TBS, intermittent (iTBS) and continuous (cTBS), affect sensory responses in rat barrel cortex. We found that iTBS but less cTBS promoted late (>18 ms) sensory response components while not affecting the earliest response (8-18 ms). The effect increased with each of the five iTBS blocks applied. cTBS somewhat reduced the early response component after the first block but had a similar effect as iTBS after four to five blocks. We conclude that iTBS primarly modulates the activity of (inhibitory) cortical interneurons while cTBS may first reduce general neuronal excitability with a single block but reverse to iTBS-like effects with application of several blocks. ABSTRACT: Cortical sensory processing varies with cortical state and the balance of inhibition to excitation. Repetitive transcranial magnetic stimulation (rTMS) has been shown to modulate human cortical excitability. In a rat model, we recently showed that intermittent theta-burst stimulation (iTBS) applied to the corpus callosum, to activate primarily supragranular cortical pyramidal cells but fewer subcortical neurons, strongly reduced the cortical expression of parvalbumin (PV), indicating reduced activity of fast-spiking interneurons. Here, we used the well-studied rodent barrel cortex system to test how iTBS and continuous TBS (cTBS) modulate sensory responses evoked by either single or double stimuli applied to the principal (PW) and/or adjacent whisker (AW) in urethane-anaesthetized rats. Compared to sham stimulation, iTBS but not cTBS particularly enhanced late (>18 ms) response components of multi-unit spiking and local field potential responses in layer 4 but not the very early response (<18 ms). Similarly, only iTBS diminished the suppression of the second response evoked by paired PW or AW-PW stimulation at 20 ms intervals. The effects increased with each of the five iTBS blocks applied. With cTBS a mild effect similar to that of iTBS was first evident after 4-5 stimulation blocks. Enhanced cortical c-Fos and zif268 expression but reduced PV and GAD67 expression was found only after iTBS, indicating increased cortical activity due to lowered inhibition. We conclude that iTBS but less cTBS may primarily weaken a late recurrent-type cortical inhibition mediated via a subset of PV+ interneurons, enabling stronger late response components believed to contribute to the perception of sensory events. PMID- 25504572 TI - Noradrenaline upregulates T-type calcium channels in rat pinealocytes. AB - KEY POINTS: The mammalian pineal gland is a neuroendocrine organ that responds to circadian and seasonal rhythms. Its major function is to secrete melatonin as a hormonal night signal in response to nocturnal delivery of noradrenaline from sympathetic neurons. Culturing rat pinealocytes in noradrenaline for 24 h induced a low-voltage activated transient Ca(2+) current whose pharmacology and kinetics corresponded to a CaV3.1 T-type channel. The upregulation of the T-type Ca(2+) current is initiated by beta-adrenergic receptors, cyclic AMP and cyclic AMP dependent protein kinase. Messenger RNA for CaV3.1 T-type channels is significantly elevated by noradrenaline at 8 h and 24 h. The noradrenaline induced T-type channel mediated an increased Ca(2+) entry and supported modest transient electrical responses to depolarizing stimuli, revealing the potential for circadian regulation of pinealocyte electrical excitability and Ca(2+) signalling. ABSTRACT: Our basic hypothesis is that mammalian pinealocytes have cycling electrical excitability and Ca(2+) signalling that may contribute to the circadian rhythm of pineal melatonin secretion. This study asked whether the functional expression of voltage-gated Ca(2+) channels (CaV channels) in rat pinealocytes is changed by culturing them in noradrenaline (NA) as a surrogate for the night signal. Channel activity was assayed as ionic currents under patch clamp and as optical signals from a Ca(2+)-sensitive dye. Channel mRNAs were assayed by quantitative polymerase chain reaction. Cultured without NA, pinealocytes showed only non-inactivating L-type dihydropyridine-sensitive Ca(2+) current. After 24 h in NA, additional low-voltage activated transient Ca(2+) current developed whose pharmacology and kinetics corresponded to a T-type CaV3.1 channel. This change was initiated by beta-adrenergic receptors, cyclic AMP and protein kinase A as revealed by pharmacological experiments. mRNA for CaV3.1 T type channels became significantly elevated, but mRNA for another T-type channel and for the major L-type channel did not change. After only 8 h of NA treatment, the CaV3.1 mRNA was already elevated, but the transient Ca(2+) current was not. Even a 16 h wait without NA following the 8 h NA treatment induced little additional transient current. However, these cells were somehow primed to make transient current as a second NA exposure for only 60 min sufficed to induce large T-type currents. The NA-induced T-type channel mediated an increased Ca(2+) entry during short depolarizations and supported modest transient electrical responses to depolarizing stimuli. Such experiments reveal the potential for circadian regulation of excitability. PMID- 25504573 TI - Chronic activation of CB2 cannabinoid receptors in the hippocampus increases excitatory synaptic transmission. AB - KEY POINTS: The effects of cannabinoids are primarily mediated by two types of cannabinoid receptors, CB1 receptors in the nervous system and CB2 receptors in the immune system. Recent evidence indicates that CB2 receptors are also widely expressed in the brain and involved in neuropsychiatric functions, such as schizophrenia-like behaviours, anxiety, memory, vomiting and pain. The cellular mechanisms by which CB2 receptors regulate neuronal functions are unknown. We show that chronic activation of CB2 receptors in the hippocampus for 7-10 days increases excitatory synaptic transmission, whereas short-term activation of CB2 receptors has little effect on synaptic activity. This study reveals a novel role of CB2 receptors in the brain, which is clearly distinct from that of CB1 receptors, and thus, will help us to understand better the diverse effects of cannabinoids in the nervous system. ABSTRACT: The roles of CB1 cannabinoid receptors in regulating neuronal activity have been extensively characterized. Although early studies show that CB1 receptors are present in the nervous system and CB2 cannabinoid receptors are in the immune system, recent evidence indicates that CB2 receptors are also expressed in the brain. Activation or blockade of CB2 receptors in vivo induces neuropsychiatric effects, but the cellular mechanisms of CB2 receptor function are unclear. The aim of this study is to determine how activation of CB2 receptors present in the hippocampus regulates synaptic function. Here, we show that when organotypic cultures of rodent hippocampal slices were treated with a CB2 receptor agonist (JWH133 or GP1a) for 7-10 days, quantal glutamate release became more frequent and spine density was increased via extracellular signal-regulated kinases. Chronic intraperitoneal injection of JWH133 into mice also increased excitatory synaptic transmission. These effects were blocked by a CB2 receptor antagonist (SR144528) or absent from hippocampal slices of CB2 receptor knock-out mice. This study reveals a novel cellular function of CB2 cannabinoid receptors in the hippocampus and provides insights into how cannabinoid receptor subtypes diversify the roles of cannabinoids in the brain. PMID- 25504574 TI - Anchoring protein AKAP79-mediated PKA phosphorylation of STIM1 determines selective activation of the ARC channel, a store-independent Orai channel. AB - KEY POINTS: Although both the calcium store-dependent CRAC channels and the store independent ARC channels are regulated by the protein STIM1, CRAC channels are regulated by STIM1 in the endoplasmic reticulum, whilst ARC channels are regulated by the STIM1 constitutively resident in the plasma membrane. We now demonstrate that activation of the ARC channels, but not CRAC channels, is uniquely dependent on phosphorylation of a single residue (T389) in the extensive cytosolic domain of STIM1 by protein kinase A. We further demonstrate that the phosphorylation of the T389 residue by protein kinase A is mediated by the association of plasma membrane STIM1 with the scaffolding protein AKAP79. Together, these findings indicate that the phosphorylation status of this single residue in STIM1 represents a key molecular determinant of the relative activities of these two co-existing Ca(2+) entry channels that are known to play critical, but distinct, roles in modulating a variety of physiologically relevant activities. ABSTRACT: The low-conductance, highly calcium-selective channels encoded by the Orai family of proteins represent a major pathway for the agonist induced entry of calcium associated with the generation and modulation of the key intracellular calcium signals that initiate and control a wide variety of physiologically important processes in cells. There are two distinct members of this channel family that co-exist endogenously in many cell types: the store operated Ca(2+) release-activated CRAC channels and the store-independent arachidonic acid-regulated ARC channels. Although the activities of both channels are regulated by the stromal-interacting molecule-1 (STIM1) protein, two distinct pools of this protein are responsible, with the major pool of STIM1 in the endoplasmic reticulum membrane regulating CRAC channel activity, whilst the minor pool of plasma membrane STIM1 regulates ARC channel activity. We now show that a critical feature in determining this selective activation of the two channels is the phosphorylation status of a single threonine residue (T389) within the extensive (~450 residue) cytosolic domain of STIM1. Specifically, protein kinase A (PKA)-mediated phosphorylation of T389 of STIM1 is necessary for effective activation of the ARC channels, whilst phosphorylation of the same residue actually inhibits the ability of STIM1 to activate the CRAC channels. We further demonstrate that the PKA-mediated phosphorylation of T389 occurs at the plasma membrane via the involvement of the anchoring protein AKAP79, which is constitutively associated with the pool of STIM1 in the plasma membrane. The novel mechanism we have described provides a means for the cell to precisely regulate the relative activities of these two channels to independently modulate the resulting intracellular calcium signals in a physiologically relevant manner. PMID- 25504575 TI - Paired associative transcranial alternating current stimulation increases the excitability of corticospinal projections in humans. AB - Many types of non-invasive brain stimulation alter corticospinal excitability (CSE). Paired associative stimulation (PAS) has attracted particular attention as its effects ostensibly adhere to Hebbian principles of neural plasticity. In prototypical form, a single electrical stimulus is directed to a peripheral nerve in close temporal contiguity with transcranial magnetic stimulation delivered to the contralateral primary motor cortex (M1). Repeated pairing of the two discrete stimulus events (i.e. association) over an extended period either increases or decreases the excitability of corticospinal projections from M1, contingent on the interstimulus interval. We studied a novel form of associative stimulation, consisting of brief trains of peripheral afferent stimulation paired with short bursts of high frequency (>=80 Hz) transcranial alternating current stimulation (tACS) over contralateral M1. Elevations in the excitability of corticospinal projections to the forearm were observed for a range of tACS frequency (80, 140 and 250 Hz), current (1, 2 and 3 mA) and duration (500 and 1000 ms) parameters. The effects were at least as reliable as those brought about by PAS or transcranial direct current stimulation. When paired with tACS, muscle tendon vibration also induced elevations of CSE. No such changes were brought about by the tACS or peripheral afferent stimulation alone. In demonstrating that associative effects are expressed when the timing of the peripheral and cortical events is not precisely circumscribed, these findings suggest that multiple cellular pathways may contribute to a long term potentiation-type response. Their relative contributions will differ depending on the nature of the induction protocol that is used. PMID- 25504577 TI - Mutations in CCDC11, which encodes a coiled-coil containing ciliary protein, causes situs inversus due to dysmotility of monocilia in the left-right organizer. AB - In vertebrates, establishment of left-right (LR) asymmetry is dependent on cilia driven fluid flow within the LR organizer. Mutations in CCDC11 disrupt LR asymmetry in humans, but how the gene functions in LR patterning is presently unknown. We describe a patient with situs inversus totalis carrying homozygous loss-of-function mutations in CCDC11. We show that CCDC11 is an axonemal protein in respiratory cilia, but is largely dispensable for their structure and motility. To investigate the role of CCDC11 in LR development, we studied the zebrafish homolog of the gene. Like in human respiratory cilia, loss of Ccdc11 causes minor defects in the motility of zebrafish kidney cilia, although the protein localizes to their axonemes and base. By contrast, Ccdc11 localizes exclusively to the basal bodies of cilia within Kupffer's vesicle, the organ of laterality of teleost fishes, and within the spinal canal. Moreover, the rotational motion of the cilia in these tissues of ccdc11-deficient embryos was strongly impaired. Our findings demonstrate that CCDC11 has a conserved essential function in cilia of the vertebrate LR organizer. To the best of our knowledge, this is the first ciliary component, which has a differential localization and function in different kinds of motile cilia. PMID- 25504576 TI - Differential Effect of Endurance Training on Mitochondrial Protein Damage, Degradation, and Acetylation in the Context of Aging. AB - Acute aerobic exercise increases reactive oxygen species and could potentially damage proteins, but exercise training (ET) enhances mitochondrial respiration irrespective of age. Here, we report a differential impact of ET on protein quality in young and older participants. Using mass spectrometry we measured oxidative damage to skeletal muscle proteins before and after 8 weeks of ET and find that young but not older participants reduced oxidative damage to both total skeletal muscle and mitochondrial proteins. Young participants showed higher total and mitochondrial derived semitryptic peptides and 26S proteasome activity indicating increased protein degradation. ET however, increased the activity of the endogenous antioxidants in older participants. ET also increased skeletal muscle content of the mitochondrial deacetylase SIRT3 in both groups. A reduction in the acetylation of isocitrate dehydrogenase 2 was observed following ET that may counteract the effect of acute oxidative stress. In conclusion aging is associated with an inability to improve skeletal muscle and mitochondrial protein quality in response to ET by increasing degradation of damaged proteins. ET does however increase muscle and mitochondrial antioxidant capacity in older individuals, which provides increased buffering from the acute oxidative effects of exercise. PMID- 25504578 TI - Hop/Sti1 phosphorylation inhibits its co-chaperone function. AB - In eukaryotes, the molecular chaperones Hsp90 and Hsp70 are connected via the co chaperone Sti1/Hop, which allows transfer of clients. Here, we show that the basic functions of yeast Sti1 and human Hop are conserved. These include the simultaneous binding of Hsp90 and Hsp70, the inhibition of the ATPase activity of Hsp90, and the ability to support client activation in vivo. Importantly, we reveal that both Hop and Sti1 are subject to inhibitory phosphorylation, although the sites modified and the influence of regulatory phosphorylation is species specific. Phospho-mimetic variants have a reduced ability to activate clients in vivo and different affinity for Hsp70. Hop is more tightly regulated, as phosphorylation affects also the interaction with Hsp90 and induces structural rearrangements in the core part of the protein. PMID- 25504579 TI - Multiplex detection of enzymatic activity with responsive lanthanide-based luminescent probes. AB - Multiplex analyte detection in complex dynamic systems is desirable for the investigation of cellular communication networks as well as in medical diagnostics. A family of lanthanide-based responsive luminescent probes for multiplex detection is reported. The high modularity of the probe design enabled the rapid assembly of both green and red emitters for a large variety of analytes by the simple exchange of the lanthanide or an analyte-cleavable caging group, respectively. The real-time three-color detection of up to three analytes was demonstrated, thus setting the stage for the non-invasive investigation of interconnected biological processes. PMID- 25504580 TI - Proteomic approaches to the study of malignant lymphoma: analyses on patient samples. AB - We describe the application of proteomic techniques for protein profiling and biomarker discovery in malignant lymphoma. Hematologic malignancies are primarily characterized by their clinical, morphological, immunophenotypical, and molecular genetic features. However, when based on these parameters, apparently identical lymphomas may show distinct clinical courses, suggesting underlying biological heterogeneity. Recent proteomic analyses have identified differences in protein expression both with regard to subclassification of the malignant lymphoma entities, as well as in correlation with clinical outcome. In this review, studies on quantification of differential protein expression in and between malignant lymphoma entities are included. Studies are included that are based on patient samples, that is, serum/plasma or cytological specimens, as well as intact tumor tissues, together with studies that focus on tumor cells alone, or in conjunction with the tumor microenvironment. For biomarker discovery in malignant lymphoma, these approaches are used to uncover the underlying biological mechanisms and identify proteins with potential diagnostic and prognostic utility, either as predictive biomarkers or as novel future treatment targets. PMID- 25504581 TI - Influence of macromolecular precipitants on phase behavior of monoclonal antibodies. AB - For the successful application of protein crystallization as a downstream step, a profound knowledge of protein phase behavior in solutions is needed. Therefore, a systematic screening was conducted to analyze the influence of macromolecular precipitants in the form of polyethylene glycol (PEG). First, the influence of molecular weight and concentration of PEG at different pH-values were investigated and analyzed in three-dimensional (3-D) phase diagrams to find appropriate conditions in terms of a fast kinetic and crystal size for downstream processing. In comparison to the use of salts as precipitant, PEG was more suitable to obtain compact 3-D crystals over a broad range of conditions, whereby the molecular weight of PEG is, besides the pH-value, the most important parameter. Second, osmotic second virial coefficients as parameters for protein interactions are experimentally determined with static light scattering to gain a deep insight view in the phase behavior on a molecular basis. The PEG-protein solutions were analyzed as a pseudo-one-compartment system. As the precipitant is also a macromolecule, the new approach of analyzing cross-interactions between the protein and the macromolecule PEG in form of the osmotic second cross-virial coefficient (B23 ) was applied. Both parameters help to understand the protein phase behavior. However, a predictive description of protein phase behavior for systems consisting of monoclonal antibodies and PEG as precipitant is not possible, as kinetic phenomena and concentration dependencies were not taken into account. PMID- 25504582 TI - Influence of the boron moiety and water on suzuki-miyaura catalyst-transfer condensation polymerization. AB - Although water promotes Suzuki-Miyaura coupling reaction, it also induces side reactions such as deboronation and dehalogenation. Therefore, Suzuki-Miyaura polymerization of triolborate halothiophene monomer 1 with (t) Bu3 PPd(o-tolyl)Br (2) in dry tetrahydrofuran (THF) is investigated. However, the resultant poly(3 hexylthiophene) (P3HT) shows a broad molecular weight distribution and uncontrolled polymer ends. Model reactions of a number of boron reagents 3 with 2,5-dibromothiophene (4) in the presence or absence of water indicate that intramolecular transfer of the catalyst is hardly affected by the boron moiety of 3, whereas it is hindered in the absence of water. Indeed, polymerization of 1 with 2 in H2 O/THF affords P3HT with a narrower molecular weight distribution and controlled tolyl/H ends, as compared to the reaction in dry THF. PMID- 25504583 TI - Assessment of murine brain tissue shrinkage caused by different histological fixatives using magnetic resonance and computed tomography imaging. AB - Especially for neuroscience and the development of new biomarkers, a direct correlation between in vivo imaging and histology is essential. However, this comparison is hampered by deformation and shrinkage of tissue samples caused by fixation, dehydration and paraffin embedding. We used magnetic resonance (MR) imaging and computed tomography (CT) imaging to analyze the degree of shrinkage on murine brains for various fixatives. After in vivo imaging using 7 T MRI, animals were sacrificed and the brains were dissected and immediately placed in different fixatives, respectively: zinc-based fixative, neutral buffered formalin (NBF), paraformaldehyde (PFA), Bouin-Holland fixative and paraformaldehyde-lysine periodate (PLP). The degree of shrinkage based on mouse brain volumes, radiodensity in Hounsfield units (HU), as well as non-linear deformations were obtained. The highest degree of shrinkage was observed for PLP (68.1%, P < 0.001), followed by PFA (60.2%, P<0.001) and NBF (58.6%, P<0.001). The zinc-based fixative revealed a low shrinkage with only 33.5% (P<0.001). Compared to NBF, the zinc-based fixative shows a slightly higher degree of deformations, but is still more homogenous than PFA. Tissue shrinkage can be monitored non-invasively with CT and MR. Zinc-based fixative causes the smallest degree of brain shrinkage and only small deformations and is therefore recommended for in vivo ex vivo comparison studies. PMID- 25504584 TI - Effort-reward imbalance in the school setting: associations with somatic pain and self-rated health. AB - AIMS: According to the workplace theory of effort-reward imbalance (ERI), individuals who perceive a lack of reciprocity between their effort spent at work and the rewards received in turn are at an increased risk of stress-related ill health. It is also assumed that being overcommitted to work is linked to an increased risk of stress-related ill-health. This study applies the effort-reward imbalance model to the school setting. It aims to analyse the associations that effort-reward imbalance and overcommitment share with somatic pain and self-rated health among adolescents. METHODS: Data are from the School Stress and Support Study (TriSSS), involving students in grades 8 and 9 (ages 14-16 years) in two schools in Stockholm, Sweden, during 2010 (n=403). Information on effort-reward imbalance and health outcomes was gathered from self-report questionnaires. An adjusted short version of ERI was used. Factor analysis showed that extrinsic effort, reward and overcommitment constitute three distinct dimensions. The designed measures demonstrated sound psychometric properties both for the full sample and for subgroups. Ordered logistic regressions were conducted. RESULTS: The analyses showed that low reward and higher overcommitment were associated with greater somatic pain and poorer self-rated health. Furthermore, effort reward imbalance was linked with an elevated risk of somatic pain and poorer self rated health. CONCLUSIONS: Students are more likely to experience stress-related ill-health when they perceive an imbalance between their effort and rewards. In addition, high overcommitment is associated with an increased risk of ill-health among students. PMID- 25504585 TI - Socioeconomic inequalities in cause-specific mortality after disability retirement due to different diseases. AB - AIMS: Socioeconomic inequalities in both disability retirement and mortality are large. The aim of this study was to examine socioeconomic differences in cause specific mortality after disability retirement due to different diseases. METHODS: We used administrative register data from various sources linked together by Statistics Finland and included an 11% sample of the Finnish population between the years 1987 and 2007. The data also include an 80% oversample of the deceased during the follow-up. The study included men and women aged 30-64 years at baseline and those who turned 30 during the follow-up. We used Cox regression analysis to examine socioeconomic differences in mortality after disability retirement. RESULTS: Socioeconomic differences in mortality after disability retirement were smaller than in the population in general. However, manual workers had a higher risk of mortality than upper non-manual employees after disability retirement due to mental disorders and cardiovascular diseases, and among men also diseases of the nervous system. After all-cause disability retirement, manual workers ran a higher risk of cardiovascular and alcohol-related death. However, among men who retired due to mental disorders or cardiovascular diseases, differences in social class were found for all causes of death examined. For women, an opposite socioeconomic gradient in mortality after disability retirement from neoplasms was found. Conclusions: The disability retirement process leads to smaller socioeconomic differences in mortality compared with those generally found in the population. This suggests that the disability retirement system is likely to accurately identify chronic health problems with regard to socioeconomic status. PMID- 25504586 TI - Poly(ethylene glycol)-or silicone-modified hyaluronan for contact lens wetting agent applications. AB - Hyaluronan (HA) is a hydrophilic biopolymer that has been explored as a wetting agent in contact lens applications. In this study, HA was modified with siloxy or polyethylene glycol moieties using click chemistry to make it more soluble in monomer solutions used to synthesize model contact lens materials; unmodified HA was not soluble in the same monomer solutions. The water contents of the silicone hydrogels were not increased by the presence of modified HA, nor was there a decrease in the surface contact angle. However, modified HA did lead to a reduction in lysozyme adsorption in some cases. The leaching rate of HA modified with polyethylene glycol from a 78:22 DMA:TRIS(OH) hydrogel was significantly slower than for unmodified HA. PMID- 25504587 TI - IL-33 activates eosinophils of visceral adipose tissue both directly and via innate lymphoid cells. AB - Eosinophils are multifunctional leukocytes involved in allergic reactions as well as adipose tissue regulation. IL-5 is required for eosinophil survival; however, the in vivo mechanisms of eosinophil regulation are not fully understood. A tg mouse model with il5 promoter-driven EGFP expression was established for detecting the IL-5-producing cells in vivo. Il5-egfp tg mice expressed high levels of EGFP in gonadal adipose tissue (GAT) cells. EGFP(+) cells in GAT were mainly group 2 innate lymphoid cells (ILCs). IL-33 preferentially expanded EGFP(+) cells and eosinophils in GAT in vivo. EGFP(+) ILCs were found to upregulate prg2 mRNA expression in GAT eosinophils. These results demonstrate that ILCs activate eosinophils in GAT. The blockage of IL-33Ralpha, on the other hand, did not impair EGFP(+) ILC numbers but did impair eosinophil numbers in vivo. GAT eosinophils expressed IL-33Ralpha and IL-33 expanded eosinophil numbers in CD90(+) cell-depleted mice. IL-33 was further observed to induce the expression of retnla and epx mRNA in eosinophils. These findings demonstrate that IL-33 directly activates eosinophils in GAT, and together with our other findings described above, our findings show that IL-33 has dual pathways via which it activates eosinophils in vivo: a direct activation pathway and a group 2 ILC mediated pathway. PMID- 25504588 TI - Magnetically recoverable efficient demulsifier for water-in-oil emulsions. AB - A magnetically recoverable and efficient demulsifier is shown to demulsify surfactant-stable water-in-oil emulsions rapidly. Ferroferric oxide (Fe3 O4 ) particles are firstly coated by amorphous silicon dioxide (SiO2 ), and further functionalized with a commercial dodecyltrimethoxysilane solution (KH-1231). Owing to their paramagnetic properties, the demulsifier particles can be easily recovered with a magnet. Upon addition of demulsifier to emulsions and subsequent sonification, the supernatant becomes completely transparent and no droplets are observed in the micrographs. It was also demonstrated that this demulsifier is effective for emulsions prepared with a variety of oils. Moreover, magnetically recovered demulsifier can be recycled after simple treatment without any decline of efficiency. This work presents a feasible approach for demulsifying water-in oil emulsions, and has potential value in industry. PMID- 25504589 TI - A supramolecular strategy to leverage the liquid-phase exfoliation of graphene in the presence of surfactants: unraveling the role of the length of fatty acids. AB - Achieving the full control over the production as well as processability of high quality graphene represents a major challenge with potential interest in the field of fabrication of multifunctional devices. The outstanding effort dedicated to tackle this challenge in the last decade revealed that certain organic molecules are capable of leveraging the exfoliation of graphite with different efficiencies. Here, a fundamental understanding on a straightforward supramolecular approach for producing homogenous dispersions of unfunctionalized and non-oxidized graphene nanosheets in four different solvents is attained, namely N-methyl-2-pyrrolidinone, N,N-dimethylformamide, ortho-dichlorobenzene, and 1,2,4-trichlorobenzene. In particular, a comparative study on the liquid phase exfoliation of graphene in the presence of linear alkanes of different lengths terminated by a carboxylic-acid head group is performed. These molecules act as graphene dispersion-stabilizing agents during the exfoliation process. The efficiency of the exfoliation in terms of concentration of exfoliated graphene is found to be proportional to the length of the employed fatty acid. Importantly, a high percentage of single-layer graphene flakes is revealed by high-resolution transmission electron microscopy and Raman spectroscopy analyses. A simple yet effective thermodynamic model is developed to interpret the chain-length dependence of the exfoliation yield. This approach relying on the synergistic effect of a ad-hoc solvent and molecules to promote the exfoliation of graphene in liquid media represents a promising and modular strategy towards the rational design of improved dispersion-stabilizing agents. PMID- 25504590 TI - Biological components and bioelectronic interfaces of water splitting photoelectrodes for solar hydrogen production. AB - Artificial photosynthesis (AP) is inspired by photosynthesis in nature. In AP, solar hydrogen can be produced by water splitting in photoelectrochemical cells (PEC). The necessary photoelectrodes are inorganic semiconductors. Light harvesting proteins and biocatalysts can be coupled with these photoelectrodes and thus form bioelectronic interfaces. We expand this concept toward PEC devices with vital bio-organic components and interfaces, and their integration into the built environment. PMID- 25504591 TI - Low-temperature headspace-trap gas chromatography with mass spectrometry for the determination of trace volatile compounds from the fruit of Lycium barbarum L. AB - The total saccharides content of Lycium barbarum L. is very high, and a high temperature would result in saccharide decomposition and the emergence of a large amount of water. Moreover, the volatile compounds from the fruit of L. barbarum L. are rather low in concentration. Hence, it is difficult for a conventional headspace method to study the volatile compounds from the fruit of L. barbarum L. Since headspace-trap gas chromatography with mass spectrometry is an excellent method for trace analysis, a headspace-trap gas chromatography with mass spectrometry method based on low-temperature (30 degrees C) enrichment and multiple headspace extraction was developed to explore the volatile compounds from the fruit of L. barbarum L. The headspace of the sample was extracted in 17 cycles at 30 degrees C. Each time, the compounds extracted were concentrated in the trap (Tenax TA and Tenax GR, 1:1). Finally, all the volatile compounds were delivered into the gas chromatograph after thermal desorption. With the method described above, a total of 57 compounds were identified. The identification was completed by mass spectral search, retention index, and accurate mass measurement. PMID- 25504592 TI - Shotgun proteomic analysis of Bombyx mori brain: emphasis on regulation of behavior and development of the nervous system. AB - The insect brain plays crucial roles in the regulation of growth and development and in all types of behavior. We used sodium dodecyl sulfate polyacrylamide gel electrophoresis and high-performance liquid chromatography - electron spray ionization tandem mass spectrometry (ESI-MS/MS) shotgun to identify the proteome of the silkworm brain, to investigate its protein composition and to understand their biological functions. A total of 2210 proteins with molecular weights in the range of 5.64-1539.82 kDa and isoelectric points in the range of 3.78-12.55 were identified. These proteins were annotated according to Gene Ontology Annotation into the categories of molecular function, biological process and cellular component. We characterized two categories of proteins: one includes behavior-related proteins involved in the regulation of behaviors, such as locomotion, reproduction and learning; the other consists of proteins related to the development or function of the nervous system. The identified proteins were classified into 283 different pathways according to KEGG analysis, including the PI3K-Akt signaling pathway which plays a crucial role in mediating survival signals in a wide range of neuronal cell types. This extensive protein profile provides a basis for further understanding of the physiological functions in the silkworm brain. PMID- 25504593 TI - Hydrodynamic assembly of conductive nanomesh of single-walled carbon nanotubes using biological glue. AB - A hydrodynamic phenomenon is used to assemble a large-scale conductive nanomesh of single-walled carbon nanotubes (SWNTs) with exceptional control of the nanostructure. This is accomplished by a biological material with nanoscale features and a strong binding affinity toward SWNTs. The biological material also presents a unique glue effect for the assembly. Unprecedented material characteristics are observed for the nanomesh. PMID- 25504594 TI - Trifluoroethanol-containing RP-HPLC mobile phases for the separation of transmembrane peptides human glycophorin-A, integrin alpha-1, and p24: analysis and prevention of potential side reactions due to formic acid. AB - Reversed-phase high-pressure liquid chromatography analysis and purification of three hydrophobic, aggregation-prone peptides, composed mainly of the transmembrane (TM) sequence, were performed using elution systems containing 2,2,2-trifluoroethanol (TFE). The addition of 10-16% TFE to a common mobile phase, such as a water/acetonitrile/propanol (PrOH) or a water/PrOH/formic acid system, markedly improved the chromatographic separation of these peptides. The superior performance of TFE-containing systems in separating peptides over water/PrOH/formic acid systems [Bollhagen R. et al., J. Chromatogr. A, 1995; 711: 181-186.] clearly demonstrated that adding TFE to the mobile phase is one of best methods for TM-peptide purification. Characterization of the potential side reactions using MALDI and ESI-LIT/Orbitrap mass spectrometry indicated that prolonged incubation of peptides in a mixture of TFE-formic acid possibly induces O-formylation of the Ser residue and N-formylation of the N-terminus of peptides. The conditions for selective removal of the formyl groups from TM peptides were also screened. We believe that these results will expand our ability to analyze and prepare hydrophobic, aggregation-prone TM peptides and proteins. PMID- 25504596 TI - Correction for martin and van mooy, fluorometric quantification of polyphosphate in environmental plankton samples: extraction protocols, matrix effects, and nucleic acid interference. PMID- 25504597 TI - Correction for Jacob et al., Prevalence and Relatedness of Escherichia coli O157:H7 Strains in the Feces and on the Hides and Carcasses of U.S. Meat Goats at Slaughter. PMID- 25504599 TI - Multi-frequency, multi-technique pulsed EPR investigation of the copper binding site of murine amyloid beta peptide. AB - Copper-amyloid peptides are proposed to be the cause of Alzheimer's disease, presumably by oxidative stress. However, mice do not produce amyloid plaques and thus do not suffer from Alzheimer's disease. Although much effort has been focused on the structural characterization of the copper- human amyloid peptides, little is known regarding the copper-binding mode in murine amyloid peptides. Thus, we investigated the structure of copper-murine amyloid peptides through multi-frequency, multi-technique pulsed EPR spectroscopy in conjunction with specific isotope labeling. Based on our pulsed EPR results, we found that Ala2, Glu3, His6, and His14 are directly coordinated with the copper ion in murine amyloid beta peptides at pH 8.5. This is the first detailed structural characterization of the copper-binding mode in murine amyloid beta peptides. This work may advance the knowledge required for developing inhibitors of Alzheimer's disease. PMID- 25504600 TI - Ebola and the wisdom of Haygarth. PMID- 25504601 TI - Is the role of instinct important in medicine? PMID- 25504602 TI - We must recognise the actual and opportunity costs of treating immigrants in the NHS. PMID- 25504603 TI - Authors' response to Shin: we must recognise the actual and opportunity costs of treating immigrants in the National Health Service (NHS). PMID- 25504604 TI - A systematic reappraisal of the fifth finger in Renaissance paintings. PMID- 25504605 TI - The representation of women doctors in children's picture books. PMID- 25504606 TI - John Haygarth FRS (1740-1827). PMID- 25504607 TI - John Haygarth's 18th-century 'rules of prevention' for eradicating smallpox. PMID- 25504612 TI - Transcriptional profiling identifies physicochemical properties of nanomaterials that are determinants of the in vivo pulmonary response. AB - We applied transcriptional profiling to elucidate the mechanisms associated with pulmonary responses to titanium dioxide (TiO2 ) nanoparticles (NPs) of different sizes and surface coatings, and to determine if these responses are modified by NP size, surface area, surface modification, and embedding in paint matrices. Adult C57BL/6 mice were exposed via single intratracheal instillations to free forms of TiO2 NPs (10, 20.6, or 38 nm in diameter) with different surface coatings, or TiO2 NPs embedded in paint matrices. Controls were exposed to dispersion medium devoid of NPs. TiO2 NPs were characterized for size, surface area, chemical impurities, and agglomeration state in the exposure medium. Pulmonary transcriptional profiles were generated using microarrays from tissues collected one and 28 d postexposure. Property-specific pathway effects were identified. Pulmonary protein levels of specific inflammatory cytokines and chemokines were confirmed by ELISA. The data were collapsed to 659 differentially expressed genes (P <= 0.05; fold change >= 1.5). Unsupervised hierarchical clustering of these genes revealed that TiO2 NPs clustered mainly by postexposure timepoint followed by particle type. A pathway-based meta-analysis showed that the combination of smaller size, large deposited surface area, and surface amidation contributes to TiO2 NP gene expression response. Embedding of TiO2 NP in paint dampens the overall transcriptional effects. The magnitude of the expression changes associated with pulmonary inflammation differed across all particles; however, the underlying pathway perturbations leading to inflammation were similar, suggesting a generalized mechanism-of-action for all TiO2 NPs. Thus, transcriptional profiling is an effective tool to determine the property specific biological/toxicity responses induced by nanomaterials. PMID- 25504613 TI - Using data-independent, high-resolution mass spectrometry in protein biomarker research: perspectives and clinical applications. AB - In medicine, there is an urgent need for protein biomarkers in a range of applications that includes diagnostics, disease stratification, and therapeutic decisions. One of the main technologies to address this need is MS, used for protein biomarker discovery and, increasingly, also for protein biomarker validation. Currently, data-dependent analysis (also referred to as shotgun proteomics) and targeted MS, exemplified by SRM, are the most frequently used mass spectrometric methods. Recently developed data-independent acquisition techniques combine the strength of shotgun and targeted proteomics, while avoiding some of the limitations of the respective methods. They provide high throughput, accurate quantification, and reproducible measurements within a single experimental setup. Here, we describe and review data-independent acquisition strategies and their recent use in clinically oriented studies. In addition, we also provide a detailed guide for the implementation of SWATH-MS (where SWATH is sequential window acquisition of all theoretical mass spectra) one of the data-independent strategies that have gained wide application of late. PMID- 25504614 TI - Bifunctional N-heterocyclic carbene catalyzed [3+4] annulation of enals and aurones. AB - Bifunctional N-heterocyclic carbenes with a free hydroxy group are demonstrated as efficient catalysts for the [3+4] annulation of enals with aurones to give the corresponding benzofuran-fused epsilon-lactones in good yields with good diastereoselectivities and excellent enantioselectivities. Control experiments reveal that the [3+4] cycloadducts are kinetically favored and could be transformed to the thermodynamically favored [3+2] cycloadducts with a non bifunctional NHC catalyst. PMID- 25504615 TI - Entropic separations of mixtures of aromatics by selective face-to-face molecular stacking in one-dimensional channels of metal-organic frameworks and zeolites. AB - Separation of challenging mixtures using metal-organic frameworks can be achieved by an entropy-driven mechanism, where one of the components can arrange into a "face-to-face" stacking, thus reducing its "footprint" and reaching a higher saturation loading. PMID- 25504616 TI - Surface-initiated anionic polymerization of [1]silaferrocenophanes for the preparation of colloidal preceramic materials. AB - A novel strategy for the preparation of poly(ferrocenylsilane) (PFS) immobilized on the surface of cross-linked polystyrene (PS) nanoparticles is reported. The ferrocene-containing core/shell architectures are shown to be excellent candidates as preceramic polymers yielding spherical ceramic materials consisting of iron silicide (Fe3 Si) and metallic iron after thermal treatment. For this purpose, dimethyl- and hydromethyl[1]silaferrocenophane monomers are polymerized by surface-initiated ring-opening polymerization upon taking advantage of residual vinylic moieties at the PS particle surface. A strategy for selective chain growth from the particle surface is developed without the formation of free PFS homopolymer in solution. The grafted particles are characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS). These particles are excellent precursors for ceramics as studied by thermogravimetric analysis (TGA). The composition of the ceramics is studied using X-ray diffraction (XRD) measurements, while the morphology is probed by scanning electron microscopy (SEM) revealing the original spherical shape of the precursor particles. Obtained ceramic materials- predominantly based on iron silicides-show ferromagnetic behavior as investigated by superconducting quantum interference device (SQUID) magnetization measurements at different temperatures. PMID- 25504617 TI - Effects of flow configuration on bone tissue engineering using human mesenchymal stem cells in 3D chitosan composite scaffolds. AB - Perfusion bioreactor plays important role in supporting 3D bone construct development. Scaffolds of chitosan composites have been studied to support bone tissue regeneration from osteogenic progenitor cells including human mesenchymal stem cells (hMSC). In this study, porous scaffolds of hydroxyapatite (H), chitosan (C), and gelatin (G) were fabricated by phase-separation and press fitted in the perfusion bioreactor system where media flow is configured either parallel or transverse with respect to the scaffolds to investigate the impact of flow configuration on hMSC proliferation and osteogenic differentiation. The in vitro results showed that the interstitial flow in the transverse flow (TF) constructs reduced cell growth during the first week of culture but improved spatial cell distribution and early onset of osteogenic differentiation measured by alkaline phosphatase and expression of osteogenic genes. After 14 days of bioreactor culture, the TF constructs have comparable cell number but higher expression of bone markers genes and proteins compared to the parallel flow constructs. To evaluate ectopic bone formation, the HCG constructs seeded with hMSCs pre-cultured under two flow configurations for 7 days were implanted in CD 1 nude mice. While Masson's Trichrom staining revealed bone formation in both constructs, the TF constructs have improved spatial cell and osteoid distribution throughout the 2.0 mm constructs. The results highlight the divergent effects of media flow over the course of construct development and suggest that the flow configuration is an important parameter regulating the cellular events leading to bone construct formation in the HCG scaffolds. PMID- 25504618 TI - Flexible, scalable, and efficient targeted resequencing on a benchtop sequencer for variant detection in clinical practice. AB - The release of benchtop next-generation sequencing (NGS) instruments has paved the way to implement the technology in clinical setting. The need for flexible, qualitative, and cost-efficient workflows is high. We used singleplex-PCR for highly efficient target enrichment, allowing us to reach the quality standards set in Sanger sequencing-based diagnostics. For the library preparation, a modified NexteraXT protocol was used, followed by sequencing on a MiSeq instrument. With an innovative pooling strategy, high flexibility, scalability, and cost-efficiency were obtained, independent of the availability of commercial kits. The approach was validated for ~250 genes associated with monogenic disorders. An overall sensitivity (>99%) similar to Sanger sequencing was observed in combination with a positive predictive value of >98%. The distribution of coverage was highly uniform, guaranteeing a minimal number of gaps to be filled with alternative methods. ISO15189-accreditation was obtained for the workflow. A major asset of the singleplex PCR-based enrichment is that new targets can be easily implemented. Diagnostic laboratories have validated assays available ensuring that the proposed workflow can easily be adopted. Although our platform was optimized for constitutional variant detection of monogenic disease genes, it is now also used as a model for somatic mutation detection in acquired diseases. PMID- 25504619 TI - Flexible a-Si:H Solar Cells with Spontaneously Formed Parabolic Nanostructures on a Hexagonal-Pyramid Reflector. AB - Flexible amorphous silicon (a-Si:H) solar cells with high photoconversion efficiency (PCE) are demonstrated by embedding hexagonal pyramid nanostructures below a Ag/indium tin oxide (ITO) reflector. The nanostructures constructed by nanoimprint lithography using soft materials allow the top ITO electrode to spontaneously form parabolic nanostructures. Nanoimprint lithography using soft materials is simple, and is conducted at low temperature. The resulting structure has excellent durability under repeated bending, and thus, flexible nanostructures are successfully constructed on flexible a-Si:H solar cells on plastic film. The nanoimprinted pyramid back reflector provides a high angular light scattering with haze reflectance >98% throughout the visible spectrum. The spontaneously formed parabolic nanostructure on the top surface of the a-Si:H solar cells both reduces reflection and scatters incident light into the absorber layer, thereby elongating the optical path length. As a result, the nanopatterned a-Si:H solar cells, fabricated on polyethersulfone (PES) film, exhibit excellent mechanical flexibility and PCE increased by 48% compared with devices on a flat substrate. PMID- 25504620 TI - Putative nicotinic acetylcholine receptor subunits express differentially through the life cycle of codling moth, Cydia pomonella (Lepidoptera: Tortricidae). AB - Nicotinic acetylcholine receptors (nAChRs) are the targets of neonicotinoids and spinosads, two insecticides used in orchards to effectively control codling moth, Cydia pomonella (L.) (Lepidoptera: Tortricidae). Orchardists in Washington State are concerned about the possibility of codling moth field populations developing resistance to these two insecticides. In an effort to help mitigate this issue, we initiated a project to identify and characterize codling moth nAChR subunits expressed in heads. This study had two main goals; (i) identify transcripts from a codling moth head transcriptome that encode for nAChR subunits, and (ii) determine nAChR subunit expression profiles in various life stages of codling moth. From a codling moth head transcriptome, 24 transcripts encoding for 12 putative nAChR subunit classes were identified and verified by PCR amplification, cloning, and sequence determination. Characterization of the deduced protein sequences encoded by putative nAChR transcripts revealed that they share the distinguishing features of the cys-loop ligand-gated ion channel superfamily with 9 alpha-type subunits and 3 beta-type subunits identified. Phylogenetic analysis comparing these protein sequences to those of other insect nAChR subunits supports the identification of these proteins as nAChR subunits. Stage expression studies determined that there is clear differential expression of many of these subunits throughout the codling moth life cycle. The information from this study will be used in the future to monitor for potential target-site resistance mechanisms to neonicotinoids and spinosads in tolerant codling moth populations. PMID- 25504621 TI - Stoichiometric model and flux balance analysis for a mixed culture of Leptospirillum ferriphilum and Ferroplasma acidiphilum. AB - The oxidation process of sulfide minerals in natural environments is achieved by microbial communities from the Archaea and Bacteria domains. A metabolic reconstruction of two dominant species, Leptospirillum ferriphilum and Ferroplasma acidiphilum, which are always found together as a mixed culture in this natural environments, was made. The metabolic model, composed of 152 internal reactions and 29 transport reactions, describes the main interactions between these species, assuming that both use ferrous iron as energy source, and F. acidiphilum takes advantage of the organic compounds secreted by L. ferriphilum for chemomixotrophic growth. A first metabolic model for a mixed culture used in bacterial leaching is proposed in this article, which pretends to represent the characteristics of the mixed culture in a simplified manner. It was evaluated with experimental data through flux balance analysis (FBA) using as objective function the maximization of biomass. The growth yields on ferrous iron obtained for each microorganism are consistent with experimental data, and the flux distribution obtained allows understanding of the metabolic capabilities of both microorganisms growing together in a bioleaching process. The model was used to simulate the growth of F. acidiphilum on different substrates, to determine in silico which compounds maximize cell growth, and which are essential. Knockout simulations were carried out for L. ferriphilum and F. acidiphilum metabolic models, predicting key enzymes of central metabolism. The results of this analysis are consistent with experimental data from literature, showing a robust behavior of the metabolic model. PMID- 25504622 TI - Bio-inspired transition metal-organic hydride conjugates for catalysis of transfer hydrogenation: experiment and theory. AB - Taking inspiration from yeast alcohol dehydrogenase (yADH), a benzimidazolium (BI(+) ) organic hydride-acceptor domain has been coupled with a 1,10 phenanthroline (phen) metal-binding domain to afford a novel multifunctional ligand (L(BI+) ) with hydride-carrier capacity (L(BI+) +H(-) ?L(BI) H). Complexes of the type [Cp*M(L(BI) )Cl][PF6 ]2 (M=Rh, Ir) have been made and fully characterised by cyclic voltammetry, UV/Vis spectroelectrochemistry, and, for the Ir(III) congener, X-ray crystallography. [Cp*Rh(L(BI) )Cl][PF6 ]2 catalyses the transfer hydrogenation of imines by formate ion in very goods yield under conditions where the corresponding [Cp*Ir(L(BI) )Cl][PF6 ] and [Cp*M(phen)Cl][PF6 ] (M=Rh, Ir) complexes are almost inert as catalysts. Possible alternatives for the catalysis pathway are canvassed, and the free energies of intermediates and transition states determined by DFT calculations. The DFT study supports a mechanism involving formate-driven Rh?H formation (90 kJ mol(-1) free-energy barrier), transfer of hydride between the Rh and BI(+) centres to generate a tethered benzimidazoline (BIH) hydride donor, binding of imine substrate at Rh, back-transfer of hydride from the BIH organic hydride donor to the Rh-activated imine substrate (89 kJ mol(-1) barrier), and exergonic protonation of the metal bound amide by formic acid with release of amine product to close the catalytic cycle. Parallels with the mechanism of biological hydride transfer in yADH are discussed. PMID- 25504625 TI - Nuclear remodelling: a consequence of nucleocytoplasmic traffic run amok? PMID- 25504624 TI - Covalent modification of a cysteine residue in the XPB subunit of the general transcription factor TFIIH through single epoxide cleavage of the transcription inhibitor triptolide. AB - Triptolide is a key component of the traditional Chinese medicinal plant Thunder God Vine and has potent anticancer and immunosuppressive activities. It is an irreversible inhibitor of eukaryotic transcription through covalent modification of XPB, a subunit of the general transcription factor TFIIH. Cys342 of XPB was identified as the residue that undergoes covalent modification by the 12,13 epoxide group of triptolide. Mutation of Cys342 of XPB to threonine conferred resistance to triptolide on the mutant protein. Replacement of the endogenous wild-type XPB with the Cys342Thr mutant in a HEK293T cell line rendered it completely resistant to triptolide, thus validating XPB as the physiologically relevant target of triptolide. Together, these results deepen our understanding of the interaction between triptolide and XPB and have implications for the future development of new analogues of triptolide as leads for anticancer and immunosuppressive drugs. PMID- 25504623 TI - Furin-mediated sequential delivery of anticancer cytokine and small-molecule drug shuttled by graphene. AB - A cellular protease (furin)-mediated graphene-based nanosystem is developed for co-delivery of a membrane-associated cytokine (tumor-necrosis-factor-related apoptosis-inducing ligand, TRAIL) and an intracellular-acting small-molecule drug (Doxorubicin, DOX). TRAIL and DOX can be sequentially released toward the plasma membrane and nucleus, respectively. PMID- 25504626 TI - Welcome to Cardiovascular Research in 2015. PMID- 25504627 TI - miR-21-3p regulates cardiac hypertrophic response by targeting histone deacetylase-8. AB - AIMS: Growing evidences indicate that microRNAs (miRNAs) are involved in cardiac hypertrophy development. Multiple miRNAs have been identified as diagnostic and prognostic biomarkers of cardiac hypertrophy, as well as potential therapeutic tools. The present study aimed to investigate the functions and regulatory mechanisms of miR-21-3p in cardiac hypertrophy. METHODS AND RESULTS: Decreased expression of miR-21-3p was observed in cardiac hypertrophy induced by transverse aortic constriction (TAC) and angiotensin (Ang) II infusion in mice. To further explore the role of miR-21-3p in cardiac hypertrophy, rAAV-miR-21-3p was administered intravenously in mice. Overexpression of miR-21-3p markedly suppressed TAC-induced cardiac hypertrophy and also blocked Ang II-induced cardiac hypertrophy as determined by cardiac function measurement and biomarker detection. Furthermore, western blot assays showed that histone deacetylase-8 (HDAC8) was silenced by miR-21-3p, and luciferase reporter assays showed that miR 21-3p binds to the 3' UTR of HDAC8. Moreover, re-expression of HDAC8 attenuated miR-21-3p-mediated suppression of cardiac hypertrophy by enhancing phospho-Akt and phospho-Gsk3beta expression. CONCLUSION: Our data reveal a role of miR-21-3p in regulating HDAC8 expression and Akt/Gsk3beta pathway, and suggest that modulation of miR-21-3p levels may provide a therapeutic approach for cardiac hypertrophy. PMID- 25504628 TI - A weekly alternating diet between caloric restriction and medium fat protects the liver from fatty liver development in middle-aged C57BL/6J mice. AB - SCOPE: We investigated whether a novel dietary intervention consisting of an every-other-week calorie-restricted diet could prevent nonalcoholic fatty liver disease (NAFLD) development induced by a medium-fat (MF) diet. METHODS AND RESULTS: Nine-week-old male C57BL/6J mice received either a (i) control (C), (ii) 30E% calorie restricted (CR), (iii) MF (25E% fat), or (iv) intermittent (INT) diet, a diet alternating weekly between 40E% CR and an ad libitum MF diet until sacrifice at the age of 12 months. The metabolic, morphological, and molecular features of NAFLD were examined. The INT diet resulted in healthy metabolic and morphological features as displayed by the continuous CR diet: glucose tolerant, low hepatic triglyceride content, low plasma alanine aminotransferase. In contrast, the C- and MF-exposed mice with high body weight developed signs of NAFLD. However, the gene expression profiles of INT-exposed mice differed to those of CR-exposed mice and showed to be more similar with those of C- and MF exposed mice with a comparable body weight. CONCLUSIONS: Our study reveals that the INT diet maintains metabolic health and reverses the adverse effects of the MF diet, thus effectively prevents the development of NAFLD in 12-month-old male C57BL/6J mice. PMID- 25504629 TI - Fmoc-Sec(Xan)-OH: synthesis and utility of Fmoc selenocysteine SPPS derivatives with acid-labile sidechain protection. AB - We report here the synthesis of the first selenocysteine SPPS derivatives which bear TFA-labile sidechain protecting groups. New compounds Fmoc-Sec(Xan)-OH and Fmoc-Sec(Trt)-OH are presented as useful and practical alternatives to the traditional Fmoc-Sec-OH derivatives currently available to the peptide chemist. From a bis Fmoc-protected selenocystine precursor, multiple avenues of diselenide reduction were attempted to determine the most effective method for subsequent attachment of the protecting group electrophiles. Our previously reported one-pot reduction methodology was ultimately chosen as the optimal approach toward the synthesis of these novel building blocks, and both were easily obtained in high yield and purity. Fmoc-Sec(Xan)-OH was discovered to be bench-stable for extended timeframes while the corresponding Fmoc-Sec(Trt)-OH derivative appeared to detritylate slowly when not stored at -20 degrees C. Both Sec derivatives were incorporated into single- and multiple-Sec-containing test peptides in order to ascertain the peptides' deprotection behavior and final form upon TFA cleavage. Single-Sec-containing test peptides were always isolated as their corresponding diselenide dimers, while dual-Sec-containing peptide sequences were afforded exclusively as their intramolecular diselenides. PMID- 25504630 TI - The association between influenza vaccination and other preventative health behaviors in a cohort of pregnant women. AB - OBJECTIVES: Although pregnant women are a high-priority group for seasonal influenza vaccination, vaccination rates in this population remain below target levels. Previous studies have identified sociodemographic predictors of vaccine choice, but relationships between preconception heath behaviors and seasonal influenza vaccination are poorly understood. This prospective cohort study followed pregnant women during the 2010-2011 influenza season to determine if certain health behaviors were associated with vaccination status. METHOD: Participants were pregnant women receiving prenatal care from Kaiser Permanente Northwest and Kaiser Permanente Northern California. Women were surveyed about preconception smoking, alcohol consumption, and vitamin/supplement use. Vaccination data were obtained from health plan databases and state immunization records. RESULTS: Data from 1,204 women were included in this analysis. Most participants (1,204; 66.4%) received a seasonal influenza vaccine during the study period. Women vaccinated prior to pregnancy were more likely to use a supplement containing folic acid (80%) or vitamin D (30%) compared with women who were vaccinated during pregnancy (72% and 15%, respectively) or unvaccinated women (62% and 12%, respectively, p < .001). Women vaccinated prior to or during pregnancy were more likely (75%) to have never smoked compared with women who were not vaccinated (70%, p = .005). There were no significant differences in alcohol use or household cigarette smoke exposure by vaccination group. CONCLUSIONS: Women who engaged in specific preconception health behaviors were more likely to receive seasonal influenza vaccination. Failure to participate in these health behaviors could alert health care practitioners to patients' increased risk of remaining unvaccinated during pregnancy. PMID- 25504632 TI - A multicenter phase I study of pazopanib in combination with paclitaxel in first line treatment of patients with advanced solid tumors. AB - This study was designed to evaluate the safety, pharmacokinetics, and clinical activity of pazopanib combined with paclitaxel to determine the recommended phase II dose in the first-line setting in patients with advanced solid tumors. Patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated regimen (MTR) of once daily pazopanib plus paclitaxel administered every 3 weeks at four dose levels (DL1-4). Safety, pharmacokinetics, pharmacogenetics, and disease assessments were performed. Twenty-eight patients received treatment. One patient at DL1 had dose-limiting toxicity (DLT) of elevated hepatic enzymes. After pazopanib discontinuation, liver enzyme concentrations remained high until a concurrent medication, simvastatin, was discontinued. This patient had the defective CYP2C8*3*3 genotype. At DL2, 1 patient had DLT of elevated hepatic enzymes with rash and 1 patient had DLT of rash. The MTR was paclitaxel 150 mg/m(2) plus pazopanib 800 mg. The most common toxicities were alopecia, fatigue, hypertension, nausea, diarrhea, dysgeusia, neutropenia, myalgia, hair color changes, and peripheral neuropathy. Coadministration of pazopanib and paclitaxel resulted in a 38% increase in systemic exposure to paclitaxel, relative to administration of paclitaxel alone, at the MTR. Of the 28 patients treated with the combination, 10 achieved a partial response and 10 achieved stable disease of >=12 weeks. Pazopanib 800 mg daily plus paclitaxel 150 mg/m(2) every 3 weeks was the recommended phase II dose, with a manageable safety profile, and with clinical activity in both melanoma and non-small cell lung cancer that suggest further evaluation of this combination is warranted. PMID- 25504631 TI - Morphological and physiological retinal degeneration induced by intravenous delivery of vitamin A dimers in rabbits. AB - The eye uses vitamin A as a cofactor to sense light and, during this process, some vitamin A molecules dimerize, forming vitamin A dimers. A striking chemical signature of retinas undergoing degeneration in major eye diseases such as age related macular degeneration (AMD) and Stargardt disease is the accumulation of these dimers in the retinal pigment epithelium (RPE) and Bruch's membrane (BM). However, it is not known whether dimers of vitamin A are secondary symptoms or primary insults that drive degeneration. Here, we present a chromatography-free method to prepare gram quantities of the vitamin A dimer, A2E, and show that intravenous administration of A2E to the rabbit results in retinal degeneration. A2E-damaged photoreceptors and RPE cells triggered inflammation, induced remolding of the choroidal vasculature and triggered a decline in the retina's response to light. Data suggest that vitamin A dimers are not bystanders, but can be primary drivers of retinal degeneration. Thus, preventing dimer formation could be a preemptive strategy to address serious forms of blindness. PMID- 25504634 TI - The selective intravenous inhibitor of the MET tyrosine kinase SAR125844 inhibits tumor growth in MET-amplified cancer. AB - Activation of the MET/HGF pathway is common in human cancer and is thought to promote tumor initiation, metastasis, angiogenesis, and resistance to diverse therapies. We report here the pharmacologic characterization of the triazolopyridazine derivative SAR125844, a potent and highly selective inhibitor of the MET receptor tyrosine kinase (RTK), for intravenous administration. SAR125844 displayed nanomolar activity against the wild-type kinase (IC50 value of 4.2 nmol/L) and the M1250T and Y1235D mutants. Broad biochemical profiling revealed that SAR125844 was highly selective for MET kinase. SAR125844 inhibits MET autophosphorylation in cell-based assays in the nanomolar range, and promotes low nanomolar proapoptotic and antiproliferative activities selectively in cell lines with MET gene amplification or pathway addiction. In two MET-amplified human gastric tumor xenograft models, SNU-5 and Hs 746T, intravenous treatment with SAR125844 leads to potent, dose- and time-dependent inhibition of the MET kinase and to significant impact on downstream PI3K/AKT and RAS/MAPK pathways. Long duration of MET kinase inhibition up to 7 days was achieved with a nanosuspension formulation of SAR125844. Daily or every-2-days intravenous treatment of SAR125844 promoted a dose-dependent tumor regression in MET amplified human gastric cancer models at tolerated doses without treatment related body weight loss. Our data demonstrated that SAR125844 is a potent and selective MET kinase inhibitor with a favorable preclinical toxicity profile, supporting its clinical development in patients with MET-amplified and MET pathway-addicted tumors. PMID- 25504633 TI - Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence. AB - Although cisplatin has played a role in "standard-of-care" multimodality therapy for patients with advanced squamous cell carcinoma of the head and neck (HNSCC), the rate of treatment failure remains particularly high for patients receiving cisplatin whose tumors have mutations in the TP53 gene. We found that cisplatin treatment of HNSCC cells with mutant TP53 leads to arrest of cells in the G2 phase of the cell cycle, leading us to hypothesize that the wee-1 kinase inhibitor MK-1775 would abrogate the cisplatin-induced G2 block and thereby sensitize isogenic HNSCC cells with mutant TP53 or lacking p53 expression to cisplatin. We tested this hypothesis using clonogenic survival assays, flow cytometry, and in vivo tumor growth delay experiments with an orthotopic nude mouse model of oral tongue cancer. We also used a novel TP53 mutation classification scheme to identify which TP53 mutations are associated with limited tumor responses to cisplatin treatment. Clonogenic survival analyses indicate that nanomolar concentration of MK-1775 sensitizes HNSCC cells with high risk mutant p53 to cisplatin. Consistent with its ability to chemosensitize, MK 1775 abrogated the cisplatin-induced G2 block in p53-defective cells leading to mitotic arrest associated with a senescence-like phenotype. Furthermore, MK-1775 enhanced the efficacy of cisplatin in vivo in tumors harboring TP53 mutations. These results indicate that HNSCC cells expressing high-risk p53 mutations are significantly sensitized to cisplatin therapy by the selective wee-1 kinase inhibitor, supporting the clinical evaluation of MK-1775 in combination with cisplatin for the treatment of patients with TP53 mutant HNSCC. PMID- 25504635 TI - Evaluation of the in vitro and in vivo efficacy of the JAK inhibitor AZD1480 against JAK-mutated acute lymphoblastic leukemia. AB - Genome-wide studies have identified a high-risk subgroup of pediatric acute lymphoblastic leukemia (ALL) harboring mutations in the Janus kinases (JAK). The purpose of this study was to assess the preclinical efficacy of the JAK1/2 inhibitor AZD1480, both as a single agent and in combination with the MEK inhibitor selumetinib, against JAK-mutated patient-derived xenografts. Patient derived xenografts were established in immunodeficient mice from bone marrow or peripheral blood biopsy specimens, and their gene expression profiles compared with the original patient biopsies by microarray analysis. JAK/STAT and MAPK signaling pathways, and the inhibitory effects of targeted drugs, were interrogated by immunoblotting of phosphoproteins. The antileukemic effects of AZD1480 and selumetinib, alone and in combination, were tested against JAK mutated ALL xenografts both in vitro and in vivo. Xenografts accurately represented the primary disease as determined by gene expression profiling. Cellular phosphoprotein analysis demonstrated that JAK-mutated xenografts exhibited heightened activation status of JAK/STAT and MAPK signaling pathways compared with typical B-cell precursor ALL xenografts, which were inhibited by AZD1480 exposure. However, AZD1480 exhibited modest single-agent in vivo efficacy against JAK-mutated xenografts. Combining AZD1480 with selumetinib resulted in profound synergistic in vitro cell killing, although these results were not translated in vivo despite evidence of target inhibition. Despite validation of target inhibition and the demonstration of profound in vitro synergy between AZD1480 and selumetinib, it is likely that prolonged target inhibition is required to achieve in vivo therapeutic enhancement between JAK and MEK inhibitors in the treatment of JAK-mutated ALL. PMID- 25504636 TI - Glycogen synthase kinase 3beta sustains invasion of glioblastoma via the focal adhesion kinase, Rac1, and c-Jun N-terminal kinase-mediated pathway. AB - The failure of current treatment options for glioblastoma stems from their inability to control tumor cell proliferation and invasion. Biologically targeted therapies offer great hope and one promising target is glycogen synthase kinase 3beta (GSK3beta), implicated in various diseases, including cancer. We previously reported that inhibition of GSK3beta compromises the survival and proliferation of glioblastoma cells, induces their apoptosis, and sensitizes them to temozolomide and radiation. Here, we explore whether GSK3beta also contributes to the highly invasive nature of glioblastoma. The effects of GSK3beta inhibition on migration and invasion of glioblastoma cells were examined by wound-healing and Transwell assays, as well as in a mouse model of glioblastoma. We also investigated changes in cellular microarchitectures, cytoskeletal components, and proteins responsible for cell motility and invasion. Inhibition of GSK3beta attenuated the migration and invasion of glioblastoma cells in vitro and that of tumor cells in a mouse model of glioblastoma. These effects were associated with suppression of the molecular axis involving focal adhesion kinase, guanine nucleotide exchange factors/Rac1 and c-Jun N-terminal kinase. Changes in cellular phenotypes responsible for cell motility and invasion were also observed, including decreased formation of lamellipodia and invadopodium-like microstructures and alterations in the subcellular localization, and activity of Rac1 and F-actin. These changes coincided with decreased expression of matrix metalloproteinases. Our results confirm the potential of GSK3beta as an attractive therapeutic target against glioblastoma invasion, thus highlighting a second role in this tumor type in addition to its involvement in chemo- and radioresistance. PMID- 25504638 TI - Quantitative immunohistochemical assessment of blood and lymphatic microcirculation in cutaneous lichen planus lesions. AB - Latest advances have brought to light the hypothesis that angiogenesis and lymphangiogenesis are tightly connected to some chronic inflammatory diseases. The present study focuses on immunohistochemical assessment of the quantitative changes in the blood and lymphatic microcirculatory bed in common chronic dermatosis - cutaneous lichen planus. Double immunohistochemistry with CD34 and podoplanin antibodies was used to detect blood and lymphatic endothelium, while anti-human VEGF was used for the observation of a key angiogenesis and lymphangiogenesis inducer. Morphometric analysis was performed with QuickPhoto Micro image analysis software. Results confirmed statistically significant enlargement of both the blood and lymphatic microcirculatory beds. Compared to healthy skin, cutaneous lichen planus lesions revealed 1.6 times enlarged blood microcirculatory bed and 1.8 times enlarged lymphatic microcirculatory bed. Vascular endothelial growth factor (VEGF) expression in lesional skin was significantly higher in the epidermis (19.1 times increase) than in the dermis (10.3 times increase). These findings indicate a tight association of angiogenesis and lymphangiogenesis with the pathogenesis of cutaneous lichen planus. PMID- 25504639 TI - "You think it's hard now ... It gets much harder for our children": Youth with autism and their caregiver's perspectives of health care transition services. AB - Adolescents with Autism Spectrum Disorder diagnosis often have complex comorbid physical and mental health conditions. These youth rely heavily on their medical providers and struggle through the often rocky transition out of pediatric care into adulthood and adult-centered care. This study is among the first to qualitatively examine the health care transition experiences of youth with Autism Spectrum Disorder and their caregivers. We conducted four focus groups with youth with Autism Spectrum Disorder (n = 13) and their caregivers (n = 19) and used thematic analysis strategies to identify key themes. Parents' discussions emphasized (a) loss of relationship with provider and lack of support transitioning from pediatric to adult care, (b) providers' lack of knowledge about Autism Spectrum Disorder, and (c) concerns about losing guardianship. Youth emphasized their confusion and anxiety around (a) medical providers' role, especially in the transition to adulthood; and (b) managing their medical lives independently. Our findings are important because they not only improve our understanding of health care transition needs among youth with Autism Spectrum Disorder and their caregivers but demonstrate a sound methodological procedure to facilitate input from youth with Autism Spectrum Disorder. PMID- 25504637 TI - Aging and Functional Health Literacy: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To review the evidence on the association between age and limited health literacy, overall and by health literacy test, and to investigate the mediating role of cognitive function. METHOD: The Embase, MEDLINE, and PsycINFO databases were searched. Eligible studies were conducted in any country or language, included participants aged >=50 years, presented a measure of association between age and health literacy, and were published through September 2013. RESULTS: Seventy analyses in 60 studies were included in the systematic review; 29 of these were included in the meta-analysis. Older age was strongly associated with limited health literacy in analyses that measured health literacy as reading comprehension, reasoning, and numeracy skills (random-effects odds ratio [OR] = 4.20; 95% confidence interval [CI]: 3.13-5.64). By contrast, older age was weakly associated with limited health literacy in studies that measured health literacy as medical vocabulary (random-effects OR = 1.19; 95% CI: 1.03 1.37). Evidence on the mediating role of cognitive function was limited. DISCUSSION: Health literacy tests that utilize a range of fluid cognitive abilities and mirror everyday health tasks frequently observe skill limitations among older adults. Vocabulary-based health literacy skills appear more stable with age. Researchers should select measurement tests wisely when assessing health literacy of older adults. PMID- 25504640 TI - Differences in rates of radiation-induced true and false rib fractures after stereotactic body radiation therapy for Stage I primary lung cancer. AB - The purpose of this study was to analyze the dosimetry and investigate the clinical outcomes of radiation-induced rib fractures (RIRFs) after stereotactic body radiotherapy (SBRT). A total of 126 patients with Stage I primary lung cancer treated with SBRT, who had undergone follow-up computed tomography (CT) at least 12 months after SBRT and who had no previous overlapping radiation exposure were included in the study. We used the Mantel-Haenszel method and multiple logistic regression analysis to compare risk factors. We analyzed D(0.5 cm(3)) (minimum absolute dose received by a 0.5-cm(3) volume) and identified each rib that received a biologically effective dose (BED) (BED3, using the linear quadratic (LQ) formulation assuming an alpha/beta = 3) of at least 50 Gy. Of the 126 patients, 46 (37%) suffered a total of 77 RIRFs. The median interval from SBRT to RIRF detection was 15 months (range, 3-56 months). The 3-year cumulative probabilities were 45% (95% CI, 34-56%) and 3% (95% CI, 0-6%), for Grades 1 and 2 RIRFs, respectively. Multivariate analysis showed that tumor location was a statistically significant risk factor for the development of Grade 1 RIRFs. Of the 77 RIRFs, 71 (92%) developed in the true ribs (ribs 1-7), and the remaining six developed in the false ribs (ribs 8-12). The BED3 associated with 10% and 50% probabilities of RIRF were 55 and 210 Gy to the true ribs and 240 and 260 Gy to the false ribs. We conclude that RIRFs develop more frequently in true ribs than in false ribs. PMID- 25504641 TI - Recurrent selection for wider seedling leaves increases early biomass and leaf area in wheat (Triticum aestivum L.). AB - The breeding of wheat with greater early vigour has potential to increase water- and nutrient-use efficiency, as well as to improve weed competitiveness to raise crop yields profitably. Given that wheat is inherently conservative in its early growth, a sustained breeding effort was initiated to increase genetically seedling leaf area in developing novel high vigour germplasm. A recurrent selection programme was initiated by intercrossing a genetically diverse set of 28 vigorous wheat lines identified globally. These were intercrossed at random and S1:2 progeny with the largest leaf 1 and 2 widths were intermated to develop new populations for assessment of early growth. This procedure was repeated for up to 60 segregating families per cycle across six cycles over 15 years. Thirty random S1:2 progeny were retained from each cycle and seed-increased together to produce seed for early vigour assessment in multiple sowings. The most vigorous wheat seedlings were identified in later cycles, with some lines producing more than double the leaf area and biomass of elite commercial wheat varieties. Phenotypic selection for greater leaf width was associated with a realized significant (P<0.01) linear increase per seedling of 0.41 mm per cycle (+7.1%) for mean leaf width, and correlated linear increases in total leaf area and biomass of 4.48 cm(2) per cycle (+10.3%) and 10.8 mg per cycle (+5.3%), respectively. Genetic gains in widths of leaves 2 (+8.4%) and 3 (+11.5%) were significantly (P<0.01) greater than for leaf 1 (+5.3%). Selection for greater leaf width was associated with linear increases in coleoptile tiller leaf area, small curvilinear increases in leaf 1 length, and reductions in numbers of leaves and mainstem tillers. Genetic variances were large and heritabilities high for leaf width and total leaf area in each cycle, but reduced linearly in size with selection across cycles. Coupling diverse germplasm with a simple, inexpensive, and repeatable selection process has confirmed the value of recurrent selection in developing uniquely vigorous wheat germplasm for use as parents in commercial breeding. PMID- 25504642 TI - Pivoting from Arabidopsis to wheat to understand how agricultural plants integrate responses to biotic stress. AB - In this review, we argue for a research initiative on wheat's responses to biotic stress. One goal is to begin a conversation between the disparate communities of plant pathology and entomology. Another is to understand how responses to a variety of agents of biotic stress are integrated in an important crop. We propose gene-for-gene interactions as the focus of the research initiative. On the parasite's side is an Avirulence (Avr) gene that encodes one of the many effector proteins the parasite applies to the plant to assist with colonization. On the plant's side is a Resistance (R) gene that mediates a surveillance system that detects the Avr protein directly or indirectly and triggers effector triggered plant immunity. Even though arthropods are responsible for a significant proportion of plant biotic stress, they have not been integrated into important models of plant immunity that come from plant pathology. A roadblock has been the absence of molecular evidence for arthropod Avr effectors. Thirty years after this evidence was discovered in a plant pathogen, there is now evidence for arthropods with the cloning of the Hessian fly's vH13 Avr gene. After reviewing the two models of plant immunity, we discuss how arthropods could be incorporated. We end by showing features that make wheat an interesting system for plant immunity, including 479 resistance genes known from agriculture that target viruses, bacteria, fungi, nematodes, insects, and mites. It is not likely that humans will be subsisting on Arabidopsis in the year 2050. It is time to start understanding how agricultural plants integrate responses to biotic stress. PMID- 25504644 TI - Meristem size contributes to the robustness of phyllotaxis in Arabidopsis. AB - Using the plant model Arabidopsis, the relationship between day length, the size of the shoot apical meristem, and the robustness of phyllotactic patterns were analysed. First, it was found that reducing day length leads to an increased meristem size and an increased number of alterations in the final positions of organs along the stem. Most of the phyllotactic defects could be related to an altered tempo of organ emergence, while not affecting the spatial positions of organ initiations at the meristem. A correlation was also found between meristem size and the robustness of phyllotaxis in two accessions (Col-0 and WS-4) and a mutant (clasp-1), independent of growth conditions. A reduced meristem size in clasp-1 was even associated with an increased robustness of the phyllotactic pattern, beyond what is observed in the wild type. Interestingly it was also possible to modulate the robustness of phyllotaxis in these different genotypes by changing day length. To conclude, it is shown first that robustness of the phyllotactic pattern is not maximal in the wild type, suggesting that, beyond its apparent stereotypical order, the robustness of phyllotaxis is regulated. Secondly, a role for day length in the robustness of the phyllotaxis was also identified, thus providing a new example of a link between patterning and environment in plants. Thirdly, the experimental results validate previous model predictions suggesting a contribution of meristem size in the robustness of phyllotaxis via the coupling between the temporal sequence and spatial pattern of organ initiations. PMID- 25504645 TI - Labels, Gender-Role Conflict, Stigma, and Attitudes Toward Seeking Psychological Help in Men. AB - Despite a comparable need, research has indicated that on average men hold more negative attitudes toward psychological help seeking than women. Several researchers have suggested that the gender gap in service use and attitudes could be addressed through efforts to better market psychological services to men; however, a limited number of studies have tested this hypothesis. This study examined whether altering the labels for mental health providers (psychologist or counselor), settings (mental health clinic or counseling center), and treatments (problem or feeling focused) could result in less perceived stigma (social and self) by men. Participants, 165 male college students, were asked to read one of eight randomly assigned vignettes that described a man who was experiencing symptoms of depression and was considering seeking help. The vignettes differed in the labels that were used to describe the help that was being considered. Participants then completed measures assessing the stigma (self and social) associated with the treatment, and their preexisting experience of gender-role conflict and attitudes toward psychological help seeking. In summary, perceived stigma did not depend on the type of label that was used; however, 59% of the variance in attitudes was predicted by self-stigma (uniquely explaining 11%), gender-role conflict (uniquely explaining 10%), and social stigma (uniquely explaining 5%). Specifically, higher levels of gender-role conflict, social stigma, and self-stigma were associated with more negative attitudes toward psychological help seeking. Based on the demographics of the sample, these findings primarily have implications for Caucasian college-educated young adult men. Further limitations with the study and recommendations for future research are discussed. PMID- 25504643 TI - The ethylene response factor Pti5 contributes to potato aphid resistance in tomato independent of ethylene signalling. AB - Ethylene response factors (ERFs) comprise a large family of transcription factors that regulate numerous biological processes including growth, development, and response to environmental stresses. Here, we report that Pti5, an ERF in tomato [Solanum lycopersicum (Linnaeus)] was transcriptionally upregulated in response to the potato aphid Macrosiphum euphorbiae (Thomas), and contributed to plant defences that limited the population growth of this phloem-feeding insect. Virus induced gene silencing of Pti5 enhanced aphid population growth on tomato, both on an aphid-susceptible cultivar and on a near-isogenic genotype that carried the Mi-1.2 resistance (R) gene. These results indicate that Pti5 contributes to basal resistance in susceptible plants and also can synergize with other R gene mediated defences to limit aphid survival and reproduction. Although Pti5 contains the ERF motif, induction of this gene by aphids was independent of ethylene, since the ACC deaminase (ACD) transgene, which inhibits ethylene synthesis, did not diminish the responsiveness of Pti5 to aphid infestation. Furthermore, experiments with inhibitors of ethylene synthesis revealed that Pti5 and ethylene have distinctly different roles in plant responses to aphids. Whereas Pti5 contributed to antibiotic plant defences that limited aphid survival and reproduction on both resistant (Mi-1.2+) and susceptible (Mi-1.2-) genotypes, ethylene signalling promoted aphid infestation on susceptible plants but contributed to antixenotic defences that deterred the early stages of aphid host selection on resistant plants. These findings suggest that the antixenotic defences that inhibit aphid settling and the antibiotic defences that depress fecundity and promote mortality are regulated through different signalling pathways. PMID- 25504646 TI - Barriers to Sexual Expression and Safe Sex Among Mexican Gay Men: A Qualitative Approach. AB - Same-sex sexual practices among men in Mexico City are stigmatized. This article analyzes sexual practices and experiences of gay men in Mexico City and its implications on emotional and sexual health. The concept of sexual practices is used from a public health perspective, and the concept of sexual experiences from a psychological one, intending to understand both physical and emotional discomfort and pleasure in sexual contexts. The aim of this article is to analyze sexual practices and experiences of gay men in Mexico City and its implications on health, particularly emotions that can lead to depression, anxiety, substance abuse, and unsafe sex. Fifteen in-depth interviews were carried out with gay men of three generations who live in Mexico City. The data were analyzed using techniques from grounded theory to identify categories, and critical discourse analysis as an analytical approach to understand how social discourses affect subjectivity, emotions, and practices. Sexual practices and experiences are the result of homoerotic desire, which gender and heteronormative culture encourage to be kept hidden and clandestine. This leads men into risk contexts where practices are hardly negotiated, thus exposing themselves to sexually transmitted infections and abuse. These practices also produce a series of emotions such as guilt, shame, fear, and sadness that may develop into mental health issues such as depression and anxiety. Interventions at all levels must consider homophobic discrimination as part of gay men's daily lives and should be oriented toward decreasing it, to diminish discomforting emotions and reduce the probability of unsafe sex practices. PMID- 25504647 TI - State of the art prediction of HIV-1 protease cleavage sites. AB - MOTIVATION: Understanding the substrate specificity of human immunodeficiency virus (HIV)-1 protease is important when designing effective HIV-1 protease inhibitors. Furthermore, characterizing and predicting the cleavage profile of HIV-1 protease is essential to generate and test hypotheses of how HIV-1 affects proteins of the human host. Currently available tools for predicting cleavage by HIV-1 protease can be improved. RESULTS: The linear support vector machine with orthogonal encoding is shown to be the best predictor for HIV-1 protease cleavage. It is considerably better than current publicly available predictor services. It is also found that schemes using physicochemical properties do not improve over the standard orthogonal encoding scheme. Some issues with the currently available data are discussed. AVAILABILITY AND IMPLEMENTATION: The datasets used, which are the most important part, are available at the UCI Machine Learning Repository. The tools used are all standard and easily available. CONTACT: thorsteinn.rognvaldsson@hh.se. PMID- 25504648 TI - Predicting risk of endovascular device infection in patients with Staphylococcus aureus bacteremia (PREDICT-SAB). AB - BACKGROUND: Prompt recognition of underlying cardiovascular implantable electronic device (CIED) infection in patients presenting with Staphylococcus aureus bacteremia (SAB) is critical for optimal management of these cases. The goal of this study was to identify clinical predictors of CIED infection in patients presenting with SAB and no signs of pocket infection. METHODS AND RESULTS: All cases of SAB in CIED recipients at Mayo Clinic from 2001 to 2011 were retrospectively reviewed. We identified 131 patients with CIED who presented with SAB and had no clinical signs of device pocket infection. Forty-five (34%) of these patients had underlying CIED infection based on clinical or echocardiographic criteria. The presence of a permanent pacemaker rather than an implantable cardioverter-defibrillator (odds ratio, 3.90; 95% confidence interval, 1.65-9.23; P=0.002), >1 device-related procedure (odds ratio, 3.30; 95% confidence interval, 1.23-8.86; P=0.018), and duration of SAB >=4 days (odds ratio, 5.54; 95% confidence interval, 3.32-13.23; P<0.001) were independently associated with an increased risk of CIED infection in a multivariable model. The area under the receiver operating characteristics curve for the multivariable model was 0.79, indicating a good discriminatory capacity to distinguish SAB patients with and without CIED infection. CONCLUSIONS: Among patients presenting with SAB and no signs of pocket infection, the risk of underlying CIED infection can be calculated based on the type of device, number of device-related procedures, and duration of SAB. We propose that patients without any of these high-risk features have a low risk of underlying CIED infection and may be monitored closely without immediate device extraction. Prospective studies are needed to validate this risk prediction model. PMID- 25504649 TI - Primary prevention implantable cardioverter-defibrillators in older racial and ethnic minority patients. AB - BACKGROUND: Racial and ethnic minorities are under-represented in clinical trials of primary prevention implantable cardioverter-defibrillators (ICDs). This analysis investigates the association between primary prevention ICDs and mortality among Medicare, racial/ethnic minority patients. METHODS AND RESULTS: Data from Get With The Guidelines-Heart Failure Registry and National Cardiovascular Data Registry's ICD Registry were used to perform an adjusted comparative effectiveness analysis of primary prevention ICDs in Medicare, racial/ethnic minority patients (nonwhite race or Hispanic ethnicity). Mortality data were obtained from the Medicare denominator file. The relationship of ICD with survival was compared between minority and white non-Hispanic patients. Our analysis included 852 minority patients, 426 ICD and 426 matched non-ICD patients, and 2070 white non-Hispanic patients (1035 ICD and 1035 matched non-ICD patients). Median follow-up was 3.1 years. Median age was 73 years, and median ejection fraction was 23%. Adjusted 3-year mortality rates for minority ICD and non-ICD patients were 44.9% (95% confidence interval [CI], 44.2%-45.7%) and 54.3% (95% CI, 53.4%-55.1%), respectively (adjusted hazard ratio, 0.79; 95% CI, 0.63 0.98; P=0.034). White non-Hispanic patients receiving an ICD had lower adjusted 3 year mortality rates of 47.8% (95% CI, 47.3%-48.3%) compared with 57.3% (95% CI, 56.8%-57.9%) for those with no ICD (adjusted hazard ratio, 0.75; 95% CI, 0.67% 0.83%; P<0.0001). There was no significant interaction between race/ethnicity and lower mortality risk with ICD (P=0.70). CONCLUSIONS: Primary prevention ICDs are associated with lower mortality in nonwhite and Hispanic patients, similar to that seen in white, non-Hispanic patients. These data support a similar approach to ICD patient selection, regardless of race or ethnicity. PMID- 25504650 TI - Cerebral sinovenous thrombosis in neonatal antiphospholipid syndrome: a new entity? AB - Neonatal antiphospholipid syndrome (neonatal APS) seems to be exceedingly rare, as the antiphospholipid antibodies (aPL) related thrombosis in the neonatal period. The pathogenesis of perinatal aPL related thrombosis may be explained both by the transplacental passage of the maternal antibodies and by the production of de novo antibodies by the neonate. However, few cases of neonatal APS are reported in the literature, especially regarding arterial thrombotic events. In particular, only two cases of neonatal aPL related isolated cerebral sinovenous thrombosis (CSVT) are described in the literature. Despite its frequency, CSVT results in significant mortality and morbidity, probably also due to the difficulty in early diagnosis and then in correct managing in the neonatal period. A diagnosis of neonatal APS should be considered in the evaluation of neonates with CSVT, as well as in any case of neonatal thrombosis, to correctly manage the affected neonates and counsel the mother for future pregnancies. PMID- 25504652 TI - Human Connexin43E42K mutation from a sudden infant death victim leads to impaired ventricular activation and neonatal death in mice. AB - BACKGROUND: Sudden infant death syndrome (SIDS) describes the sudden, unexplained death of a baby during its first year of age and is the third leading cause of infant mortality. It is assumed that <=20% of all SIDS cases are because of cardiac arrhythmias resulting from mutations in ion channel proteins. Besides ion channels also cardiac gap junction channels are important for proper conduction of cardiac electric activation. In the mammalian heart Connexin43 (Cx43) is the major gap junction protein expressed in ventricular cardiomyocytes. Recently, a novel Connexin43 loss-of-function mutation (Cx43E42K) was identified in a 2-month old SIDS victim. METHODS AND RESULTS: We have generated Cx43E42K-expressing mice as a model for SIDS. Heterozygous cardiac-restricted Cx43E42K-mutated mice die neonatally without major cardiac morphological defects. Electrocardiographic recordings of embryonic Cx43+/E42K mice reveal severely disturbed ventricular activation, whereas immunohistochemical analyses show normal localization and expression patterns of gap junctional Connexin43 protein in the Cx43E42K-mutated newborn mouse heart. CONCLUSIONS: Because we did not find heterogeneous gap junction loss in Cx43E42K mouse hearts, we conclude that the Cx43E42K gap junction channel creates an arrhythmogenic substrate leading to lethal ventricular arrhythmias. The strong cardiac phenotype of Cx43E42K expressing mice supports the association between the human Cx43E42K mutation and SIDS and indicates that Connexin43 mutations should be considered in future studies when SIDS cases are to be molecularly explained. PMID- 25504651 TI - Toward the design of a catalytic metallodrug: selective cleavage of G-quadruplex telomeric DNA by an anticancer copper-acridine-ATCUN complex. AB - Telomeric DNA represents a novel target for the development of anticancer drugs. By application of a catalytic metallodrug strategy, a copper-acridine-ATCUN complex (CuGGHK-Acr) has been designed that targets G-quadruplex telomeric DNA. Both fluorescence solution assays and gel sequencing demonstrate the CuGGHK-Acr catalyst to selectively bind and cleave the G-quadruplex telomere sequence. The cleavage pathway has been mapped by matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) experiments. CuGGHK-Acr promotes significant inhibition of cancer cell proliferation and shortening of telomere length. Both senescence and apoptosis are induced in the breast cancer cell line MCF7. PMID- 25504654 TI - Gender inequality at home is associated with poorer health for women. AB - BACKGROUND: As more women have joined the work force, the difference in employment rate between men and women has decreased, in Sweden as well as many other countries. Despite this, traditional gender patterns regarding, for example, responsibility for household duties still remain. Women are on sick leave more often than men, and previous studies have indicated that an unequal split of household responsibilities and perceived gender inequality could be associated with negative health outcomes. AIMS: The aim of the present study was to explore whether an unequal distribution of responsibilities in the home was related to various health related outcomes among women. METHODS: A sample consisting of 837 women living in a relationship, and working at least 50% of full time, responded to a questionnaire including information about division of responsibilities at home as well as various psychological and physiological health related outcomes. RESULTS: The results showed that women living in relationships with perceived more unequal distribution of responsibility for house hold duties showed significantly higher levels of perceived stress, fatigue, physical/psychosomatic symptoms, and work family conflict compared with women living in more equal relationships. They also had significantly increased odds for insufficient time for various forms of recovery, which may further contribute to an increased risk of poor health. CONCLUSIONS: Although an increasing employment rate among women is valuable for both society and individuals, it is important to work towards greater gender equality at home to maintain this development without it having a negative effect on women's health and well-being. PMID- 25504655 TI - Associations of physical activity with self-rated health and well-being in middle aged Finnish men. AB - AIMS: We examined the associations of physical activity (PA) frequency with self rated health (SRH), self-rated well-being (SRW) and depressive symptoms, in middle-aged men in Finland. METHODS: The cross-sectional study comprised 665 men (mean age 41 +/- 3 SD years; body mass index (BMI) 26.8 +/- 4.2 SD kg/m(2)), who had completed the screening questionnaire of an intervention for men with cardiovascular risk factors. Their weekly frequency of PA was assessed by a questionnaire, SRH and SRW by visual analog scales (VAS), and depressive symptoms by the Patient Health Questionnaire-2 (PHQ-2). RESULTS: The mean SRH +/- SD (range of scale 0-100) by PA frequency categories was 56.2 +/- 18.5 for PA sometimes or never, 63.8 +/- 16.2 for PA about 1-2 times/week, and 71.1 +/- 15.5 for PA at least 3 times/week. The mean SRW +/- SD (range of scale 0-100) was 59.0 +/- 20.4, 65.6 +/- 17.6, and 68.9 +/- 17.1, respectively. The mean PHQ-2 score +/ SD (range of scale 0-6) by PA categories was 1.83 +/- 1.40 for PA sometimes or never, 1.68 +/- 1.28 for PA about 1-2 times/week, and 1.60 +/- 1.31 for the PA at least 3 times/week group. SRH and SRW improved linearly with increasing PA frequency (both p < 0.001), and the results remained similar after adjustment for BMI, education and smoking status. No association existed between PA frequency and PHQ-2. CONCLUSIONS: More frequent PA was linearly associated with better SRH and SRW, but not with depressive symptoms that were measured by a brief depression screening tool. PMID- 25504653 TI - Late-onset systemic lupus erythematosus in Latin Americans: a distinct subgroup? AB - OBJECTIVE: To examine the characteristics of patients who developed late onset systemic lupus erythematosus (SLE) in the GLADEL (Grupo Latino Americano de Estudio del Lupus) cohort of patients with SLE. METHODS: Patients with SLE of less than two years of disease duration, seen at 34 centers of nine Latin American countries, were included. Late-onset was defined as >50 years of age at time of first SLE-related symptom. Clinical and laboratory manifestations, activity index (SLEDAI), and damage index (SLICC/ACR- DI) were ascertained at time of entry and during the course (cumulative incidence). Features were compared between the two patient groups (<50 and >=50) using descriptive statistics and hypothesis tests. Logistic regression was performed to examine the association of late-onset lupus, adjusting for other variables. RESULTS: Of the 1480 patients included, 102 patients (6.9 %) had late-onset SLE, 87% of which were female. Patients with late-onset SLE had a shorter follow-up (3.6 vs. 4.4 years, p < 0.002) and a longer time to diagnosis (10.1 vs. 5.8 months, p < 0.001) compared to the younger onset group. Malar rash, photosensitivity, and renal involvement were less prevalent while interstitial lung disease, pleural effusions, and sicca symptoms were more frequent in the older age group (p > 0.05). In multivariable analysis, late onset was independently associated with higher odds of ocular (OR = 3.66, 95% CI = 2.15-6.23), pulmonary (OR = 2.04, 95% CI = 1.01-4.11), and cardiovascular (OR = 1.76, 95% CI = 1.04-2.98) involvement and lower odds of cutaneous involvement (OR = 0.41, 95% CI = 0.21-0.80), number of cumulative SLE criteria (OR = 0.79, 95% CI = 0.64-0.97), use of cyclophosphamide (OR = 0.47, 95% CI = 0.24-0.95), and anti-RNP antibodies (OR = 0.43, 95% CI = 0.20-0.91). A Cox regression model revealed a higher risk of dying in older onset than the younger-onset SLE (OR = 2.61, 95% CI = 1.2-5.6). CONCLUSION: Late-onset SLE in Latin Americans had a distinct disease expression compared to the younger-onset group. The disease seems to be mild with lower cumulative SLE criteria, reduced renal/mucocutaneous involvements, and less use of cyclophosphamide. Nevertheless, these patients have a higher risk of death and of ocular, pulmonary, and cardiovascular involvements. PMID- 25504657 TI - Lack of evidence to support use of D-dimer in pregnant women with a suspicion of pulmonary embolism. PMID- 25504656 TI - Water relations traits of C4 grasses depend on phylogenetic lineage, photosynthetic pathway, and habitat water availability. AB - The repeated evolution of C4 photosynthesis in independent lineages has resulted in distinct biogeographical distributions in different phylogenetic lineages and the variants of C4 photosynthesis. However, most previous studies have only considered C3/C4 differences without considering phylogeny, C4 subtype, or habitat characteristics. We hypothesized that independent lineages of C4 grasses have structural and physiological traits that adapt them to environments with differing water availability. We measured 40 traits of 33 species from two major C4 grass lineages in a common glasshouse environment. Chloridoideae species were shorter, with narrower and longer leaves, smaller but denser stomata, and faster curling leaves than Panicoideae species, but overall differences in leaf hydraulic and gas exchange traits between the two lineages were weak. Chloridoideae species had two different ways to reach higher drought resistance potential than Panicoideae; NAD-ME species used water saving, whereas PCK species used osmotic adjustment. These patterns could be explained by the interactions of lineage*C4 subtype and lineage*habitat water availability in affected traits. Specifically, phylogeny tended to have a stronger influence on structural traits, and C4 subtype had more important effects on physiological traits. Although hydraulic traits did not differ consistently between lineages, they showed strong covariation and relationships with leaf structure. Thus, phylogenetic lineage, photosynthetic pathway, and adaptation to habitat water availability act together to influence the leaf water relations traits of C4 grasses. This work expands our understanding of ecophysiology in major C4 grass lineages, with implications for explaining their regional and global distributions in relation to climate. PMID- 25504658 TI - Are you a SCEPTIC? SoCial mEdia Precision & uTility In Conferences. AB - We analysed Twitter feeds at an emergency medicine scientific conference to determine the (1) accuracy of disseminated educational messages and the (2) use in providing rapid feedback to speakers. Most speakers were happy for key messages to be tweeted, and the majority of tweets (34/37) represented these accurately. It is important that speakers and conference organisers consider Twitter use and its potential benefits and disadvantages. PMID- 25504659 TI - Identification of the severe sepsis patient at triage: a prospective analysis of the Australasian Triage Scale. AB - OBJECTIVE: This study aims to investigate the accuracy and validity of the Australasian Triage Scale (ATS) as a tool to identify and manage in a timely manner the deteriorating patient with severe sepsis. METHODS: This was a prospective observational study conducted in five sites of adult patients. Keywords and physiological vital signs data from triage documentation were analysed for the 'identified' status compared with confirmed diagnosis of severe sepsis after admission to the intensive care unit. The primary outcome is the accuracy and validity of the ATS Triage scale categories to identify a prespecified severe sepsis population at triage. Secondary outcome measures included time compliance, antimicrobial administration and mortality prediction. Statistical analysis included parameters of diagnostic performance. Adjusted multivariate logistic regression analysis was applied to mortality prediction. RESULTS: Of 1022 patients meeting the criteria for severe sepsis, 995 were triaged through the emergency department, 164 with shock. Only 53% (n=534) were identified at triage. The overall sensitivity of the ATS to identify severe sepsis was 71%. ATS 3 was the most accurate (likelihood ratio positive, 2.45, positive predictive value 0.73) and ATS 2 the most valid (area under the curve 0.567) category. Identified cases were more likely to survive (OR 0.81, 95% CI 0.697 to 0.94, p<0.007). The strongest bias-adjusted predictors of mortality were circulatory compromise variable (1.78, 95% CI 1.34 to 1.41, p<0.001), lactate >4 (OR 1.63, 95% CI 1.10 to 2.89, p<0.001) and ATS 1 category (OR 1.55, 95% CI 1.09 to 2.35, p<0.005). CONCLUSIONS: The ATS and its categories is a sensitive and moderately accurate and valid tool for identifying severe sepsis in a predetermined group, but lacks clinical efficacy and safety without further education or quality improvement strategies targeted to the identification of severe sepsis. PMID- 25504660 TI - A heteroleptic ferrous complex with mesoionic bis(1,2,3-triazol-5-ylidene) ligands: taming the MLCT excited state of iron(II). AB - Strongly sigma-donating N-heterocyclic carbenes (NHCs) have revived research interest in the catalytic chemistry of iron, and are now also starting to bring the photochemistry and photophysics of this abundant element into a new era. In this work, a heteroleptic Fe(II) complex (1) was synthesized based on sequentially furnishing the Fe(II) center with the benchmark 2,2'-bipyridine (bpy) ligand and the more strongly sigma-donating mesoionic ligand, 4,4' bis(1,2,3-triazol-5-ylidene) (btz). Complex 1 was comprehensively characterized by electrochemistry, static and ultrafast spectroscopy, and quantum chemical calculations and compared to [Fe(bpy)3](PF6)2 and (TBA)2[Fe(bpy)(CN)4]. Heteroleptic complex 1 extends the absorption spectrum towards longer wavelengths compared to a previously synthesized homoleptic Fe(II) NHC complex. The combination of the mesoionic nature of btz and the heteroleptic structure effectively destabilizes the metal-centered (MC) states relative to the triplet metal-to-ligand charge transfer ((3)MLCT) state in 1, rendering it a lifetime of 13 ps, the longest to date of a photochemically stable Fe(II) complex. Deactivation of the (3)MLCT state is proposed to proceed via the (3)MC state that strongly couples with the singlet ground state. PMID- 25504663 TI - Single-anastomosis gastric bypass: better, faster, and safer? AB - BACKGROUND AND AIMS: Metabolic surgery is evolving and safer, but more effective alternatives are constantly sought for. The single-anastomosis gastric bypass was first described in 2001, and although controversial, this operation is gaining fast in popularity worldwide. This review is aiming at a critical evaluation of the procedure in the light of the literature. METHODS: The abstracts of 73 articles were reviewed, and after removal of case studies, duplicates, and irrelevant articles, 10 articles remained for closer review. RESULTS: Several thousand of this operation have been performed for more than 15 years. It is claimed to be an easier, safer, faster, and more effective metabolic operation compared to the standard Roux-en-Y gastric bypass. The proponents of this operation also claim that this operation is easier to revise and reverse, leaving more options compared to the situation after standard bypass in case of failure. However, there is much controversy surrounding this method, mainly concerning the possible harmful and in the long-term even carcinogenic effects of biliopancreaticoduodenal reflux in the gastric pouch. CONCLUSION: The single anastomosis gastric bypass may be an attractive alternative metabolic operation. However, further studies with robust, long-term follow-up are needed. PMID- 25504661 TI - Injectable, high-density collagen gels for annulus fibrosus repair: An in vitro rat tail model. AB - A herniated intervertebral disc often causes back pain when disc tissue is displaced through a damaged annulus fibrosus. Currently, the only methods available for annulus fibrosus repair involve mechanical closure of defect, which does little to address biological healing in the damaged tissue. Collagen hydrogels are injectable and have been used to repair annulus defects in vivo. In this study, high-density collagen hydrogels at 5, 10, and 15 mg/mL were used to repair defects made to intact rat caudal intervertebral discs in vitro. A group of gels at 15 mg/mL were also cross-linked with riboflavin at 0.03 mM, 0.07 mM, or 0.10 mM. These cross-linked, high-density collagen gels maintained their presence in the defect under loading and contributed positively to the mechanical response of damaged discs. Discs exhibited increases to 95% of undamaged effective equilibrium and instantaneous moduli as well as up to fourfold decreases in effective hydraulic permeability from the damaged discs. These data suggest that high-density collagen gels may be effective at restoring mechanical function of injured discs as well as potential vehicles for the delivery of biological agents such as cells or growth factors that may aid in the repair of the annulus fibrosus. PMID- 25504664 TI - Regenerable antioxidants-introduction of chalcogen substituents into tocopherols. AB - To improve the radical-trapping capacity of the natural antioxidants, alkylthio-, alkylseleno-, and alkyltelluro groups were introduced into all vacant aromatic positions in beta-, gamma- and delta-tocopherol. Reaction of the tocopherols with electrophilic chalcogen reagents generated by persulfate oxidation of dialkyl dichalcogenides provided convenient but low-yielding access to many sulfur and selenium derivatives, but failed in the case of tellurium. An approach based on lithiation of the appropriate bromo-tocopherol, insertion of chalcogen into the carbon-lithium bond, air-oxidation to a dichalcogenide, and final borohydride reduction/alkylation turned out to be generally applicable to the synthesis of all chalcogen derivatives. Whereas alkylthio- and alkylseleno analogues were generally poorer quenchers of lipid peroxyl radicals than the corresponding parents, all tellurium compounds showed a substantially improved radical-trapping activity. Introduction of alkyltelluro groups into the tocopherol scaffold also caused a dramatic increase in the regenerability of the antioxidant. In a two phase lipid peroxidation system containing N-acetylcysteine as a water-soluble co antioxidant the inhibition time was up to six-fold higher than that recorded for the natural antioxidants. PMID- 25504666 TI - Metal-Free, room-temperature, radical alkoxycarbonylation of aryldiazonium salts through visible-light photoredox catalysis. AB - The first radical alkoxycarboxylation of aryldiazonium salts using CO gas through visible-light-induced photoredox catalysis (16 W blue LEDs) has been developed. This reaction is entirely metal-free, is carried out at room temperature with a low loading of an organic dye as a photocatalyst (0.5 mol %), and provides a wide range of arylcarboxylic acid esters in high yields. Importantly, this photocatalytic system can be successfully extended to other carboxylation reactions. PMID- 25504667 TI - Baseline CD4(+) T-cell count and cardiovascular risk factors predict the evolution of cognitive performance during 2-year follow-up in HIV-infected patients. AB - BACKGROUND: The aim of our study was to better understand the dynamics between cardiovascular risk factors and immunological parameters in the evolution of cognitive performance in HIV+ patients. METHODS: We conducted a prospective longitudinal study, consecutively enrolling asymptomatic HIV+ subjects during routine outpatient visits at two clinical centres. At baseline and after 2 years, all patients underwent a comprehensive neuropsychological battery. Common carotid intima-media thickness (cIMT) was also measured. RESULTS: A total of 150 patients completed the study (77% males, median age 46 years, 20% with past AIDS-defining events, 95% on cART, 88% with HIV-RNA<50 copies/ml). After a 2-year follow-up, there was no difference in the proportion of patients with cognitive impairment (32% versus 33% at baseline; P=1.00). However, a significantly worse memory performance was observed (z score mean change -0.51, sd 1.05; P=0.001). At multivariate analysis, baseline dyslipidaemia (OR 2.7, 95% CI 1.1, 7.1; P=0.037) showed a significant association with a higher risk of memory impairment at 2 year follow-up, while higher baseline CD4(+) T-cell count (OR 0.80 per 100 cells/MUl higher; 95% CI 0.66, 0.97; P=0.026) was found to be a protective factor, adjusting for the presence of a memory impairment at baseline. When the analysis was restricted to patients who did not change antiretroviral therapy during the study period (n=109), baseline cIMT (OR 14.6 per 0.1 mm higher; 95% CI 1.1, 189.9; P=0.041) also emerged as an independent risk factor for memory impairment at 2-year follow-up. CONCLUSIONS: Immunological parameters and cardiovascular risk factors are independently associated with the evolution of cognitive status in HIV+ patients. PMID- 25504668 TI - Prenatal hormones in first-time expectant parents: Longitudinal changes and within-couple correlations. AB - OBJECTIVES: Expectant mothers experience marked hormone changes throughout the transition to parenthood. Although similar neuroendocrine pathways are thought to support maternal and paternal behavior, much less is known about prenatal hormone changes in expectant fathers, especially in humans. METHODS: We examined longitudinal changes in salivary testosterone, cortisol, estradiol, and progesterone in 29 first-time expectant couples (N = 58). Couples were assessed up to four times throughout the prenatal period, at approximately weeks 12, 20, 28, and 36 of pregnancy. We also examined within-couple correlations in hormones. Data were analyzed using dyadic growth curve modeling. RESULTS: As expected, women showed large prenatal increases in all four hormones. Men showed significant prenatal declines in testosterone and estradiol, but there were no detectable changes in men's cortisol or progesterone. Average levels of cortisol and progesterone were significantly positively correlated within couples. CONCLUSIONS: The current study represents one of the most extensive investigations to date of prenatal hormones in expectant couples. It is also the first study to demonstrate prenatal testosterone changes in expectant fathers and within-couple correlations in progesterone. We discuss implications of these findings for parental behavior and adjustment. PMID- 25504669 TI - A versatile 'click chemistry' route to size-restricted, robust, and functionalizable hydrophilic nanocrystals. AB - A versatile addition-crosslinking route is developed to transfer various hydrophobic nanocrystals into water. By assembling amphiphilic ligands and then crosslinking through 'click chemistry', a monolayer of polymer forms on the nanocrystal surface, leading to excellent stability and limited increase in hydrodynamic diameter. These nanocrystals can also be further functionalized easily for various applications such as catalysis, bioimaging, and medical therapy. PMID- 25504671 TI - Mechanism of versatile catalytic activities of quaternary CuZnFeS nanocrystals designed by a rapid synthesis route. AB - Quaternary alloyed nanocrystals (NCs) composed of earth abundant, environment friendly elements are of interest for energy-harvesting applications. These complex NCs are useful as catalysts for the degradation of multiple refractory organic pollutants as well as nitro-organic reduction at a rapid rate. Here, a remarkably fast (~30 s) and facile synthesis of crystalline quaternary chalcopyrite copper-zinc-iron-sulfide (CZIS) NCs is reported. These NCs show excellent catalytic properties by degrading a number of refractory organic dyes and converting nitro-compounds at a rapid rate. The valence and conduction band information of the newly designed NCs are extracted using scanning tunneling spectroscopy and ultraviolet photoelectron spectroscopy, which reveal energy levels suitable for performing redox chemistry by generating reactive radicals establishing NCs as efficient catalyst with multiple uses. Rapid synthesis of high quality phase-controlled CZIS NCs with robust catalytic activities could be useful for organic waste treatment. PMID- 25504670 TI - Variable transcriptional regulation of the human aldosterone synthase gene causes salt-dependent high blood pressure in transgenic mice. AB - BACKGROUND: Aldosterone, synthesized in the adrenal cortex by the enzyme CYP11B2, induces positive sodium balance and predisposes to hypertension. Various investigators, using genomic DNA analyses, have linked -344T polymorphism in the human CYP11B2 (hCYP11B2) gene to human hypertension. hCYP11B2 gene promoter has 3 single-nucleotide polymorphisms in linkage disequilibrium: T/A at -663, T/C at 470, and C/T at -344. Variants ACT occur together and form the haplotype-I (Hap I), whereas variants TTC constitute Hap-II. We hypothesize that these single nucleotide polymorphisms, when present together, will lead to haplotype-dependent differences in the transcriptional regulation of the hCYP11B2 gene and affect blood pressure regulation. METHODS AND RESULTS: We evaluated differences in tissue expression in vivo and consequential effects on blood pressure stemming from the 2 haplotypes. Novel transgenic mice with the hCYP11B2 gene, targeted to the mouse HPRT locus, with either Hap-II or Hap-I variant are used in this study. Our results show increased adrenal and renal expression of hCYP11B2 in transgenic mice with Hap-I when compared with mice with Hap-II. Importantly, we observed increased baseline blood pressure in Hap-I transgenic mice, an effect accentuated by a high-salt diet. Pathophysiological effects of elevated aldosterone were corroborated by our results showing upregulation of proinflammatory markers in renal tissues from the transgenic mice with Hap-I. CONCLUSIONS: These findings characterize the haplotype-dependent regulation of the hCYP11B2 gene where -344T serves as a reporter polymorphism and show that Hap-I leads to increased expression of hCYP11B2, with permissive effects on blood pressure and inflammatory milieu. PMID- 25504672 TI - Larvicidal activity of the essential oil from Tetradium glabrifolium fruits and its constituents against Aedes albopictus. AB - BACKGROUND: In our screening programme for new agrochemicals from wild plants, the essential oil of Tetradium glabrifolium (Champ. ex Benth.) T.G. Hartley fruits was found to possess strong larvicidal activity against the Asian tiger mosquito, Aedes albopictus L. The essential oil was extracted via hydrodistillation, and the constituents were determined by GC-MS analysis. The active compounds were isolated and identified by bioassay-directed fractionation. RESULTS: GC-MS analyses revealed the presence of 19 components with 2-tridecanone (43.38%), 2-undecanone (24.09%), D-limonene (13.01%), caryophyllene (5.04%) and beta-elemene (4.07%) being the major constituents. Bioactivity-directed chromatographic separation of the oil led to the isolation of 2-tridecanone, 2 undecanone and D-limonene as active compounds. The essential oil of T. glabrifolium exhibited larvicidal activity against the early fourth-instar larvae of A. albopictus, with an LC50 value of 8.20 ug mL(-1). The isolated constituent compounds, 2-tridecanone, 2-undecanone and D-limonene, possessed strong larvicidal activity against the early fourth-instar larvae of A. albopictus, with LC50 values of 2.86, 9.95 and 41.75 ug mL(-1) respectively. CONCLUSION: The findings indicated that the essential oil of T. glabrifolium fruits and the three constituents have an excellent potential for use in control of A. albopictus larvae and could be useful in the search for newer, safer and more effective natural compounds as larvicides. PMID- 25504673 TI - SILAC for biomarker discovery. AB - SILAC has been employed in MS-based proteomics for nearly a decade. This method is based on cells in culture metabolically incorporating isotope-coded essential amino acids and allows the quantification of global protein populations to identify characteristic changes. Variations of this technique developed over the years allow the application of SILAC not only to cell culture derived samples but also to tissues and human specimens, making this powerful technique amenable to clinically relevant samples. In this review, we provide an overview of different SILAC-derived methods and their use in the identification and development of biomarkers. PMID- 25504674 TI - Unlocking the full potential of conducting polymers for high-efficiency organic light-emitting devices. AB - By carefully tuning the thicknesses of low-optical index PEDOT:PSS and high-index ITO layers in organic light-emitting devices (OLEDs), very high optical coupling efficiencies can be obtained through the generation of appropriate microcavity effects. These experiments result in an external quantum efficiency (EQE) of 33.7% for green phosphorescent OLEDs and even higher EQEs of 54.3% can be obtained by adopting an external out-coupling lens. PMID- 25504675 TI - Near-IR phosphorescent ruthenium(II) and iridium(III) perylene bisimide metal complexes. AB - The phosphorescence emission of perylene bisimide derivatives has been rarely reported. Two novel ruthenium(II) and iridium(III) complexes of an azabenz annulated perylene bisimide (ab-PBI), [Ru(bpy)2 (ab-PBI)][PF6 ]2 1 and [Cp*Ir(ab PBI)Cl]PF6 2 are now presented that both show NIR phosphorescence between 750 1000 nm in solution at room temperature. For an NIR emitter, the ruthenium complex 1 displays an unusually high quantum yield (Phip ) of 11 % with a lifetime (taup ) of 4.2 MUs, while iridium complex 2 exhibits Phip <1 % and taup =33 MUs. 1 and 2 are the first PBI-metal complexes in which the spin-orbit coupling is strong enough to facilitate not only the Sn ->Tn intersystem crossing of the PBI dye, but also the radiative T1 ->S0 transition, that is, phosphorescence. PMID- 25504676 TI - A free-blockage controlled release system based on the hydrophobic/hydrophilic conversion of mesoporous silica nanopores. AB - A pH-responsive free-blockage release system was achieved through controlling the hydrophobic/hydrophilic conversion of mesoporous silica nanopores. This system further presented pulsatile release with changing pH values between 4.0 and 7.0 for several cycles. This free-blockage release system could also release antitumor agents to induce cell death after infecting tumor cells and could have the ability of continuous infection to tumor cells with high drug-delivery efficiency and few side effects. PMID- 25504677 TI - Somatic MMR gene mutations as a cause for MSI-H sebaceous neoplasms in Muir-Torre syndrome-like patients. AB - Sebaceous neoplasms are a major clinical feature of Muir-Torre syndrome (MTS) associated with visceral malignancies, especially colorectal and endometrial tumors. The diagnosis of MTS relies largely on the microsatellite instability (MSI) phenotype in tumors, suggesting germline mutations in DNA mismatch repair (MMR) genes responsible for the inherited disease. We hypothesized that in some MSI-H sebaceous tumors, acquired rather than inherited mutations in MMR genes could be involved. Using next-generation sequencing, we screened MMR gene mutations in 18 MSI-H sebaceous tumors. We found mutations in 17 samples (94%). Indeed, 12/17 (71%) were shown to carry acquired somatic mutations and among 12 samples, seven were shown to be associated with additional somatic alterations like loss of heterozygosity or multiple mutations, suggesting somatic second hits. Our findings strongly suggest that somatic MMR deficiency is responsible for a proportion of MSI-H sebaceous tumors. PMID- 25504678 TI - Caesarean section. PMID- 25504679 TI - Manganese increases high mannose glycoform on monoclonal antibody expressed in CHO when glucose is absent or limiting: Implications for use of alternate sugars. AB - Alternate sugars such as galactose and fructose are metabolized at a slower rate than glucose and result in lower accumulation of lactate. While low lactate accumulation is desirable, we report that complete substitution of glucose with these sugars results in an increase in M5 high mannose glycans. Surprisingly, this increase is much higher when the culture is supplemented with manganese: for example, when cells are cultured with galactose, M5 high mannose glycan content increased from 5% at 1 nM Mn(2+) in the basal medium to 32% with 16 uM Mn(2+) supplementation. When galactose is supplemented with glucose maintained at low concentrations, a small reduction in high mannose glycans is seen. In control cultures with glucose, the high mannose content was however <2% in this range of Mn(2+) concentration. By varying Mn(2+) and glucose supplementation levels, with or without galactose, we systematically demonstrate that Mn(2+) concentration and glucose availability, together, significantly affect the high mannose glycan content. To our knowledge, this is the first report that shows that the effect of Mn(2+) on high mannose glycan content depends on glucose availability. At each Mn(2+) supplementation level evaluated, galactosylation percentages were highest for cultures where galactose was supplemented with glucose at non-limiting concentration. PMID- 25504680 TI - Neuropathic pain in a primary care electronic health record database. AB - BACKGROUND: Neuropathic pain (NP) is common in the adult population but is difficult to study in electronic health record (EHR) databases because it is a symptom rather than a pathologic diagnosis. The first step in studying NP in EHR databases is to develop methods for identifying patients with NP. The objectives of this study were to develop estimates of the prevalence of NP among patients in a primary care EHR database and describe these patients' demographic characteristics and health-care utilization. METHODS: This was a retrospective cohort study of de-identified data from a 5-year period (2005-2010) from 23 general practitioners (GPs) in 10 primary care practices in southwestern Ontario, Canada. International Classification of Diseases version 9 (ICD-9) diagnostic codes and medication prescriptions were used to identify patients with certain and probable NP. RESULTS: Different methods produced prevalence estimates ranging from 1.5% (for certain NP in the epidemiologically rigorous period cohort) to 11.2% (for certain NP + probable NP in the more inclusive database cohort). Patients in the NP groups had more GP visits, specialist referrals and analgesic prescriptions than patients without NP. CONCLUSION: This study represents a step towards being able to utilize EHR databases to study NP by proposing methods to identify patients with certain and probable NP in a primary care EHR database. Validation against a gold standard is the next step. PMID- 25504681 TI - Continuous multilayered composite hydrogel as osteochondral substitute. AB - Cartilage is a highly organized avascular soft tissue that assembles from nano-to macro-scale to produce a complex structural network. To mimic cartilage tissue, we developed a stable multilayered composite material, characterized by a tailored gradient of mechanical properties. The optimized procedure implies chemical crosslinking of each layer directly onto the previous one and ensures a drastic reduction of the material discontinuities and brittleness. The multilayered composite was characterized by infrared spectroscopy, differential scanning calorimetry, thermogravimetry, and scanning electron microscopy in order to compare its physico-chemical characteristics with those of cartilage tissue. The rheological behavior of the multilayered composite was similar to that of human cartilage. Finally its cytocompatibility toward chondrocytes and osteoblasts was evaluated. PMID- 25504682 TI - Endoscopic direct vessel closure in carotid artery injury. AB - BACKGROUND: Internal carotid artery (ICA) injury represents one of the most challenging management scenarios for the endoscopic skull base surgeon. Techniques developed through use of an animal model of carotid injury have shown direct vessel closure techniques to be effective in gaining hemostasis and preventing subsequent complications. The aim of this study was to investigate the effectiveness of the novel AnastoClip vessel closure system in ICA injury. METHODS: Nine sheep underwent ICA dissection/isolation followed by the artery placement within a modified "sinus model otorhino neuro trainer" (SIMONT) model. Standardized linear injuries were made and treated endoscopically with the AnastoClip device. Specific outcome measures included attainment of primary hemostasis, procedure time, blood loss, pseudoaneurysm formation and carotid patency on follow-up magnetic resonance imaging (MRI). RESULTS: Primary hemostasis was achieved in all cases. No instances of secondary bleeding. Procedure times averaged 5 minutes and 25 seconds. Average blood loss was 146 mL. All 9 sheep reached the 3-month end point. Eight showed normal carotid flow on MRI, with 1 case of pseudoaneurysm. CONCLUSION: Direct vessel closure is an effective endoscopic technique in ICA injury. It allows for visual confirmation of hemostasis and carotid flow and permits the surgeon to continue with surgery despite the complication. The novel design of the AnastoClip can maintain normal vessel patency as well as accommodate pulsatile flow. PMID- 25504684 TI - Selectively measuring pi back-donation in gold(I) complexes by NMR spectroscopy. AB - Even though the Dewar-Chatt-Duncanson model has been successfully used by chemists since the 1950s, no experimental methodology is yet known to unambiguously estimate the constituents (donation and back-donation) of a metal ligand interaction. It is demonstrated here that one of these components, the metal-to-ligand pi back-donation, can be effectively probed by NMR measurements aimed at determining the rotational barrier of a C-N bond (DeltaHr (?) ) of a nitrogen acyclic carbene ligand. A large series of gold(I) complexes have been synthesized and analyzed, and it was found that the above experimental observables show an accurate correlation with back-donation, as defined theoretically by the appropriate charge displacement originated upon bond formation. The proposed method is potentially of wide applicability for analyzing the ligand effect in metal catalysts and guiding their design. PMID- 25504685 TI - Expression of dopamine transporter in the different cerebral regions of methamphetamine-dependent rats. AB - OBJECTIVES: To observe the expression of the dopamine transporter (DAT) in six cerebral regions of a methamphetamine (MA)-dependent rat, which were frontal cortex, nucleus accumbens septi, striatum, hippocampus, substantia nigra and ventral tegmental area. METHODS: The rats were administrated intraperitoneally with 10 mg/kg/day of MA for 10 days consecutively; the behaviour changes were measured via the conditioned place preference (CPP), and the scores of stereotyped behaviour (SB) were used to confirm animal addiction. Then, the animals were further injected with MA respectively for 1, 2, 4 and 8 weeks to establish different periods of MA-dependent models. The expressions of DAT and DAT messenger RNA in six cerebral regions were detected. RESULTS: The results of CPP and SB scores were significant different when comparing all four experimental groups with the control group (p < 0.05). Comparing between different experimental groups, the expression of DAT mainly decreased and had dynamic changes in the same regions (p < 0.05). Comparing the different regions with each other in the same experimental group, the expression of DAT also had significant difference in several regions p < 0.05). CONCLUSIONS: The expression of DAT mainly decreased and had different in the six cerebral regions at the same MA dependent time period as well as at different time periods in the same cerebral region. It was speculated that DAT might play a crucial role in the mechanism of MA dependence. PMID- 25504686 TI - Role of protein kinase C-eta in cigarette smoke extract-induced apoptosis in MRC 5-cells. AB - Cigarette smoke (CS) is a major risk factor for emphysema, which causes cell death in structural cells of the lung by mechanisms that are still not completely understood. We demonstrated previously that CS extract (CSE) induces caspase activation in MRC-5 human lung fibroblasts, activated protein kinase C-eta (PKC eta), and translocated PKC-eta from the cytosol to the membrane. The objective of this study was to investigate the involvement of PKC-eta activation in a CSE induced extrinsic apoptotic pathway. We determined that CSE increases expression of caspase 3 and 8 cleavage in MRC-5 cells and overexpression of PKC-eta significantly increased expression of caspase 3 and 8 cleavage compared with control LacZ-infected cells. In contrast, dominant negative (dn) PKC-eta inhibited apoptosis in MRC-5 cells exposed to CSE and decreased expression of caspase 3 and 8 compared with control cells. Exposure to 10% CSE for >8 h significantly increased lactate dehydrogenase release in PKC-eta-infected cells compared with LacZ-infected cells. Additionally, PKC-eta-infected cells had an increased number of Hoechst 33342 stained nuclei compared with LacZ-infected cells, while dn PKC-eta-infected cells exhibited fewer morphological changes than LacZ-infected cells under phase-contrast microscopy. In conclusion, PKC-eta activation plays a pro-apoptotic role in CSE-induced extrinsic apoptotic pathway in MRC-5 cells. These results suggest that modulation of PKC-eta may be a useful tool for regulating the extrinsic apoptosis of MRC-5 cells by CSE and may have therapeutic potential in the treatment of CS-induced lung injury. PMID- 25504687 TI - Vitamin U, a novel free radical scavenger, prevents lens injury in rats administered with valproic acid. AB - Valproic acid (2-propyl-pentanoic acid, VPA) is the most widely prescribed antiepileptic drug due to its ability to treat a broad spectrum of seizure types. VPA exhibits various side effects such as organ toxicity, teratogenicity, and visual disturbances. S-Methylmethioninesulfonium is a derivative of the amino acid methionine and it is widely referred to as vitamin U (Vit U). This study was aimed to investigate the effects of Vit U on lens damage parameters of rats exposed to VPA. Female Sprague Dawley rats were divided into four groups. Group I comprised control animals. Group II included control rats supplemented with Vit U (50 mg/kg/day) for 15 days. Group III was given only VPA (500 mg/kg/day) for 15 days. Group IV was given VPA + Vit U (in same dose and time). Vit U was given to rats by gavage and VPA was given intraperitoneally. On the 16th day of experiment, all the animals which were fasted overnight were killed. Lens was taken from animals, homogenized in 0.9% saline to make up to 10% (w/v) homogenate. The homogenates were used for protein, glutathione, lipid peroxidation levels, and antioxidant enzymes activities. Lens lipid peroxidation levels and aldose reductase and sorbitol dehydrogenase activities were increased in VPA group. On the other hand, glutathione levels, superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, and paraoxonase activities were decreased in VPA groups. Treatment with Vit U reversed these effects. This study showed that Vit U exerted antioxidant properties and may prevent lens damage caused by VPA. PMID- 25504688 TI - Serum adiponectin, leptin, and interleukin 6 levels as adipocytokines in children with febrile seizures: The role of adipose tissue in febrile seizures. AB - Proinflammatory and anti-inflammatory cytokines have an important role in the pathogenesis of febrile seizures (FS). Adipocytokines like interleukin 6 (IL-6), leptin, and adiponectin released from adipose tissue play a role in inflammation. This study aimed to assess the probable role of adipose tissue in children with FS. We measured serum IL-6, leptin, and adiponectin levels and evaluated clinical and laboratory findings in children with FS (n = 32) and compared the results with the values of children of the same age with febrile illness without seizures (febrile control, FC; n = 26) and healthy control group (HC; n = 29). The serum levels of white blood cells, C-reactive protein, IL-6, leptin, and adiponectin were found to be significantly higher, while serum hemoglobin (Hb) levels were found to be significantly lower in FS and FC groups than in the HC group (p < 0.001). When we compared the FS with the FC group, the serum Hb levels were significantly lower in the FS group than those in the FC group (p = 0.001). There was no significant difference between the FS and FC group with regard to the serum levels of these adipocytokines (p > 0.05). Our data showed that elevated levels of these adipocytokines as acute phase reactants in FS and FC groups did not contribute to the development of FS. PMID- 25504689 TI - Open duodenal switch for treatment of super obesity--surgical technique. AB - BACKGROUND AND AIMS: Bariatric surgery is increasing worldwide; however, standard techniques, for example, gastric bypass, are often insufficient in super obese patients, body mass index > 50 kg/m(2). Duodenal switch, a more powerful procedure, is often considered technically demanding and is, therefore, underutilized according to some authors. This might result in nonoptimal surgical care for super obese patients, not having the possibility to obtain massive weight loss. MATERIAL AND METHODS: In this report, we present our open duodenal switch technique, which we have found durable in an academic center performing 30 40 cases annually, parallel to other upper abdominal surgery. The present technique, performed through a short upper midline incision, consists of a gastric tube, a 1.5-m alimentary limb, and a 1-m common limb of the distal ileum. CONCLUSION: With correct follow-up to reduce the risk of malnutrition, we encourage the use of duodenal switch and see no rational surgical obstacles. PMID- 25504691 TI - Zero infection. PMID- 25504693 TI - Genomics. Bird genomes give new perches to old friends. PMID- 25504690 TI - Comparison of spike sorting and thresholding of voltage waveforms for intracortical brain-machine interface performance. AB - OBJECTIVE: For intracortical brain-machine interfaces (BMIs), action potential voltage waveforms are often sorted to separate out individual neurons. If these neurons contain independent tuning information, this process could increase BMI performance. However, the sorting of action potentials ('spikes') requires high sampling rates and is computationally expensive. To explicitly define the difference between spike sorting and alternative methods, we quantified BMI decoder performance when using threshold-crossing events versus sorted action potentials. APPROACH: We used data sets from 58 experimental sessions from two rhesus macaques implanted with Utah arrays. Data were recorded while the animals performed a center-out reaching task with seven different angles. For spike sorting, neural signals were sorted into individual units by using a mixture of Gaussians to cluster the first four principal components of the waveforms. For thresholding events, spikes that simply crossed a set threshold were retained. We decoded the data offline using both a Naive Bayes classifier for reaching direction and a linear regression to evaluate hand position. MAIN RESULTS: We found the highest performance for thresholding when placing a threshold between 3 and -4.5 * Vrms. Spike sorted data outperformed thresholded data for one animal but not the other. The mean Naive Bayes classification accuracy for sorted data was 88.5% and changed by 5% on average when data were thresholded. The mean correlation coefficient for sorted data was 0.92, and changed by 0.015 on average when thresholded. SIGNIFICANCE: For prosthetics applications, these results imply that when thresholding is used instead of spike sorting, only a small amount of performance may be lost. The utilization of threshold-crossing events may significantly extend the lifetime of a device because these events are often still detectable once single neurons are no longer isolated. PMID- 25504694 TI - Infectious diseases. The genetics of resistant malaria. PMID- 25504695 TI - Nuclear power. The trouble with tritium. PMID- 25504696 TI - Origin of life. From hell on Earth, life's building blocks. PMID- 25504697 TI - Europe. E.U. to let wary members ban genetically modified crops. PMID- 25504698 TI - Back from the dead. PMID- 25504699 TI - Live wire. PMID- 25504700 TI - Planetary science. Scratching the surface of martian habitability. PMID- 25504701 TI - HIV. Expanding the breadth of an HIV-1 vaccine. PMID- 25504702 TI - Cancer. Cancer by super-enhancer. PMID- 25504683 TI - Influence of edaphic and management factors on the diversity and abundance of ammonia-oxidizing thaumarchaeota and bacteria in soils of bioenergy crop cultivars. AB - Ammonia-oxidizing thaumarcheota (AOA) and ammonia-oxidizing bacteria (AOB) differentially influence soil and atmospheric chemistry, but soil properties that control their distributions are poorly understood. In this study, the ammonia monooxygenase gene (amoA) was used to identify and quantify presumptive AOA and AOB and relate their distributions to soil properties in two experimental fields planted with different varieties of switchgrass (Panicum virgatum), a potential bioenergy feedstock. Differences in ammonia oxidizer diversity were associated primarily with soil properties of the two field sites, with pH displaying significant correlations with both AOA and AOB population structure. Percent nitrogen (%N), carbon to nitrogen ratios (C : N), and pH were also correlated with shifts nitrifier population structure. Nitrosotalea-like and Nitrosospira cluster II populations were more highly represented in acidic soils, whereas populations affiliated with Nitrososphaera and Nitrosospira cluster 3A.1 were relatively more abundant in alkaline soils. AOA were the dominant functional group in all plots based on quantitative polymerase chain reaction and high throughput sequencing analyses. These data suggest that AOA contribute significantly to nitrification rates in carbon and nitrogen rich soils influenced by perennial grasses. PMID- 25504703 TI - Ultrafast dynamics. Electrons take the fast track through silicon. PMID- 25504704 TI - Epidemiology. Mathematical models for emerging disease. PMID- 25504705 TI - Neurodevelopment. Tossed out to save the masses. PMID- 25504706 TI - Genetics. The battle for iron. PMID- 25504707 TI - Recognizing the risks of brain stimulation. PMID- 25504708 TI - Recognizing the risks of brain stimulation--response. PMID- 25504709 TI - Reproducibility in ecological research. PMID- 25504710 TI - Avian genomes. A flock of genomes. Introduction. PMID- 25504711 TI - Valuing collections. PMID- 25504714 TI - Rock mechanics. Superplastic nanofibrous slip zones control seismogenic fault friction. AB - Understanding the internal mechanisms controlling fault friction is crucial for understanding seismogenic slip on active faults. Displacement in such fault zones is frequently localized on highly reflective (mirrorlike) slip surfaces, coated with thin films of nanogranular fault rock. We show that mirror-slip surfaces developed in experimentally simulated calcite faults consist of aligned nanogranular chains or fibers that are ductile at room conditions. These microstructures and associated frictional data suggest a fault-slip mechanism resembling classical Ashby-Verrall superplasticity, capable of producing unstable fault slip. Diffusive mass transfer in nanocrystalline calcite gouge is shown to be fast enough for this mechanism to control seismogenesis in limestone terrains. With nanogranular fault surfaces becoming increasingly recognized in crustal faults, the proposed mechanism may be generally relevant to crustal seismogenesis. PMID- 25504715 TI - Solid state theory. Quantum spin Hall effect in two-dimensional transition metal dichalcogenides. AB - Quantum spin Hall (QSH) effect materials feature edge states that are topologically protected from backscattering. However, the small band gap in materials that have been identified as QSH insulators limits applications. We use first-principles calculations to predict a class of large-gap QSH insulators in two-dimensional transition metal dichalcogenides with 1T' structure, namely, 1T' MX2 with M = (tungsten or molybdenum) and X = (tellurium, selenium, or sulfur). A structural distortion causes an intrinsic band inversion between chalcogenide-p and metal-d bands. Additionally, spin-orbit coupling opens a gap that is tunable by vertical electric field and strain. We propose a topological field effect transistor made of van der Waals heterostructures of 1T'-MX2 and two-dimensional dielectric layers that can be rapidly switched off by electric field through a topological phase transition instead of carrier depletion. PMID- 25504716 TI - Ultrafast dynamics. Attosecond band-gap dynamics in silicon. AB - Electron transfer from valence to conduction band states in semiconductors is the basis of modern electronics. Here, attosecond extreme ultraviolet (XUV) spectroscopy is used to resolve this process in silicon in real time. Electrons injected into the conduction band by few-cycle laser pulses alter the silicon XUV absorption spectrum in sharp steps synchronized with the laser electric field oscillations. The observed ~450-attosecond step rise time provides an upper limit for the carrier-induced band-gap reduction and the electron-electron scattering time in the conduction band. This electronic response is separated from the subsequent band-gap modifications due to lattice motion, which occurs on a time scale of 60 +/- 10 femtoseconds, characteristic of the fastest optical phonon. Quantum dynamical simulations interpret the carrier injection step as light-field induced electron tunneling. PMID- 25504717 TI - Nanolithography. Large-scale nanoshaping of ultrasmooth 3D crystalline metallic structures. AB - We report a low-cost, high-throughput benchtop method that enables thin layers of metal to be shaped with nanoscale precision by generating ultrahigh-strain-rate deformations. Laser shock imprinting can create three-dimensional crystalline metallic structures as small as 10 nanometers with ultrasmooth surfaces at ambient conditions. This technique enables the successful fabrications of large area, uniform nanopatterns with aspect ratios as high as 5 for plasmonic and sensing applications, as well as mechanically strengthened nanostructures and metal-graphene hybrid nanodevices. PMID- 25504718 TI - Membranes. Metal-organic framework nanosheets as building blocks for molecular sieving membranes. AB - Layered metal-organic frameworks would be a diverse source of crystalline sheets with nanometer thickness for molecular sieving if they could be exfoliated, but there is a challenge in retaining the morphological and structural integrity. We report the preparation of 1-nanometer-thick sheets with large lateral area and high crystallinity from layered MOFs. They are used as building blocks for ultrathin molecular sieve membranes, which achieve hydrogen gas (H2) permeance of up to several thousand gas permeation units (GPUs) with H2/CO2 selectivity greater than 200. We found an unusual proportional relationship between H2 permeance and H2 selectivity for the membranes, and achieved a simultaneous increase in both permeance and selectivity by suppressing lamellar stacking of the nanosheets. PMID- 25504712 TI - Comparative genomics reveals insights into avian genome evolution and adaptation. AB - Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits. PMID- 25504713 TI - Whole-genome analyses resolve early branches in the tree of life of modern birds. AB - To better determine the history of modern birds, we performed a genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves using phylogenomic methods created to handle genome-scale data. We recovered a highly resolved tree that confirms previously controversial sister or close relationships. We identified the first divergence in Neoaves, two groups we named Passerea and Columbea, representing independent lineages of diverse and convergently evolved land and water bird species. Among Passerea, we infer the common ancestor of core landbirds to have been an apex predator and confirm independent gains of vocal learning. Among Columbea, we identify pigeons and flamingoes as belonging to sister clades. Even with whole genomes, some of the earliest branches in Neoaves proved challenging to resolve, which was best explained by massive protein-coding sequence convergence and high levels of incomplete lineage sorting that occurred during a rapid radiation after the Cretaceous-Paleogene mass extinction event about 66 million years ago. PMID- 25504719 TI - Pollinator declines. Extinctions of aculeate pollinators in Britain and the role of large-scale agricultural changes. AB - Pollinators are fundamental to maintaining both biodiversity and agricultural productivity, but habitat destruction, loss of flower resources, and increased use of pesticides are causing declines in their abundance and diversity. Using historical records, we assessed the rate of extinction of bee and flower-visiting wasp species in Britain from the mid-19th century to the present. The most rapid phase of extinction appears to be related to changes in agricultural policy and practice beginning in the 1920s, before the agricultural intensification prompted by the Second World War, often cited as the most important driver of biodiversity loss in Britain. Slowing of the extinction rate from the 1960s onward may be due to prior loss of the most sensitive species and/or effective conservation programs. PMID- 25504721 TI - Political science. When contact changes minds: an experiment on transmission of support for gay equality. AB - Can a single conversation change minds on divisive social issues, such as same sex marriage? A randomized placebo-controlled trial assessed whether gay (n = 22) or straight (n = 19) messengers were effective at encouraging voters (n = 972) to support same-sex marriage and whether attitude change persisted and spread to others in voters' social networks. The results, measured by an unrelated panel survey, show that both gay and straight canvassers produced large effects initially, but only gay canvassers' effects persisted in 3-week, 6-week, and 9 month follow-ups. We also find strong evidence of within-household transmission of opinion change, but only in the wake of conversations with gay canvassers. Contact with gay canvassers further caused substantial change in the ratings of gay men and lesbians more generally. These large, persistent, and contagious effects were confirmed by a follow-up experiment. Contact with minorities coupled with discussion of issues pertinent to them is capable of producing a cascade of opinion change. PMID- 25504720 TI - Nutritional immunity. Escape from bacterial iron piracy through rapid evolution of transferrin. AB - Iron sequestration provides an innate defense, termed nutritional immunity, leading pathogens to scavenge iron from hosts. Although the molecular basis of this battle for iron is established, its potential as a force for evolution at host-pathogen interfaces is unknown. We show that the iron transport protein transferrin is engaged in ancient and ongoing evolutionary conflicts with TbpA, a transferrin surface receptor from bacteria. Single substitutions in transferrin at rapidly evolving sites reverse TbpA binding, providing a mechanism to counteract bacterial iron piracy among great apes. Furthermore, the C2 transferrin polymorphism in humans evades TbpA variants from Haemophilus influenzae, revealing a functional basis for standing genetic variation. These findings identify a central role for nutritional immunity in the persistent evolutionary conflicts between primates and bacterial pathogens. PMID- 25504722 TI - Systems biology. Accurate information transmission through dynamic biochemical signaling networks. AB - Stochasticity inherent to biochemical reactions (intrinsic noise) and variability in cellular states (extrinsic noise) degrade information transmitted through signaling networks. We analyzed the ability of temporal signal modulation--that is, dynamics--to reduce noise-induced information loss. In the extracellular signal-regulated kinase (ERK), calcium (Ca(2+)), and nuclear factor kappa-B (NF kappaB) pathways, response dynamics resulted in significantly greater information transmission capacities compared to nondynamic responses. Theoretical analysis demonstrated that signaling dynamics has a key role in overcoming extrinsic noise. Experimental measurements of information transmission in the ERK network under varying signal-to-noise levels confirmed our predictions and showed that signaling dynamics mitigate, and can potentially eliminate, extrinsic noise induced information loss. By curbing the information-degrading effects of cell-to cell variability, dynamic responses substantially increase the accuracy of biochemical signaling networks. PMID- 25504723 TI - Electron microscopy: Ultrastable gold substrates for electron cryomicroscopy. AB - Despite recent advances, the structures of many proteins cannot be determined by electron cryomicroscopy because the individual proteins move during irradiation. This blurs the images so that they cannot be aligned with each other to calculate a three-dimensional density. Much of this movement stems from instabilities in the carbon substrates used to support frozen samples in the microscope. Here we demonstrate a gold specimen support that nearly eliminates substrate motion during irradiation. This increases the subnanometer image contrast such that alpha helices of individual proteins are resolved. With this improvement, we determine the structure of apoferritin, a smooth octahedral shell of alpha helical subunits that is particularly difficult to solve by electron microscopy. This advance in substrate design will enable the solution of currently intractable protein structures. PMID- 25504725 TI - Making science a desirable career. PMID- 25504724 TI - HIV antibodies. Antigen modification regulates competition of broad and narrow neutralizing HIV antibodies. AB - Some HIV-infected individuals develop broadly neutralizing antibodies (bNAbs), whereas most develop antibodies that neutralize only a narrow range of viruses (nNAbs). bNAbs, but not nNAbs, protect animals from experimental infection and are likely a key component of an effective vaccine. nNAbs and bNAbs target the same regions of the viral envelope glycoprotein (Env), but for reasons that remain unclear only nNAbs are elicited by Env immunization. We show that in contrast to germline-reverted (gl) bNAbs, glnNAbs recognized diverse recombinant Envs. Moreover, owing to binding affinity differences, nNAb B cell progenitors had an advantage in becoming activated and internalizing Env compared with bNAb B cell progenitors. We then identified an Env modification strategy that minimized the activation of nNAb B cells targeting epitopes that overlap those of bNAbs. PMID- 25504727 TI - Complex evolutionary trajectories of sex chromosomes across bird taxa. AB - Sex-specific chromosomes, like the W of most female birds and the Y of male mammals, usually have lost most genes owing to a lack of recombination. We analyze newly available genomes of 17 bird species representing the avian phylogenetic range, and find that more than half of them do not have as fully degenerated W chromosomes as that of chicken. We show that avian sex chromosomes harbor tremendous diversity among species in their composition of pseudoautosomal regions and degree of Z/W differentiation. Punctuated events of shared or lineage specific recombination suppression have produced a gradient of "evolutionary strata" along the Z chromosome, which initiates from the putative avian sex determining gene DMRT1 and ends at the pseudoautosomal region. W-linked genes are subject to ongoing functional decay after recombination was suppressed, and the tempo of degeneration slows down in older strata. Overall, we unveil a complex history of avian sex chromosome evolution. PMID- 25504728 TI - Statistical binning enables an accurate coalescent-based estimation of the avian tree. AB - Gene tree incongruence arising from incomplete lineage sorting (ILS) can reduce the accuracy of concatenation-based estimations of species trees. Although coalescent-based species tree estimation methods can have good accuracy in the presence of ILS, they are sensitive to gene tree estimation error. We propose a pipeline that uses bootstrapping to evaluate whether two genes are likely to have the same tree, then it groups genes into sets using a graph-theoretic optimization and estimates a tree on each subset using concatenation, and finally produces an estimated species tree from these trees using the preferred coalescent-based method. Statistical binning improves the accuracy of MP-EST, a popular coalescent-based method, and we use it to produce the first genome-scale coalescent-based avian tree of life. PMID- 25504729 TI - An integrative approach to understanding bird origins. AB - Recent discoveries of spectacular dinosaur fossils overwhelmingly support the hypothesis that birds are descended from maniraptoran theropod dinosaurs, and furthermore, demonstrate that distinctive bird characteristics such as feathers, flight, endothermic physiology, unique strategies for reproduction and growth, and a novel pulmonary system originated among Mesozoic terrestrial dinosaurs. The transition from ground-living to flight-capable theropod dinosaurs now probably represents one of the best-documented major evolutionary transitions in life history. Recent studies in developmental biology and other disciplines provide additional insights into how bird characteristics originated and evolved. The iconic features of extant birds for the most part evolved in a gradual and stepwise fashion throughout archosaur evolution. However, new data also highlight occasional bursts of morphological novelty at certain stages particularly close to the origin of birds and an unavoidable complex, mosaic evolutionary distribution of major bird characteristics on the theropod tree. Research into bird origins provides a premier example of how paleontological and neontological data can interact to reveal the complexity of major innovations, to answer key evolutionary questions, and to lead to new research directions. A better understanding of bird origins requires multifaceted and integrative approaches, yet fossils necessarily provide the final test of any evolutionary model. PMID- 25504730 TI - Evidence for a single loss of mineralized teeth in the common avian ancestor. AB - Edentulism, the absence of teeth, has evolved convergently among vertebrates, including birds, turtles, and several lineages of mammals. Instead of teeth, modern birds (Neornithes) use a horny beak (rhamphotheca) and a muscular gizzard to acquire and process food. We performed comparative genomic analyses representing lineages of nearly all extant bird orders and recovered shared, inactivating mutations within genes expressed in both the enamel and dentin of teeth of other vertebrate species, indicating that the common ancestor of modern birds lacked mineralized teeth. We estimate that tooth loss, or at least the loss of enamel caps that provide the outer layer of mineralized teeth, occurred about 116 million years ago. PMID- 25504734 TI - Functional analysis of FOXE3 mutations causing dominant and recessive ocular anterior segment disease. AB - Mutations in FOXE3 are associated with both recessive and dominant inheritance of severe anterior ocular malformations and glaucoma. However, functional analyses of putative pathogenic mutations have not been performed. We tested the hypothesis that variations in FOXE3 activity underlie the different modes of inheritance and disease phenotype. In band shift assays, three recessive mutants showed loss-of-function, one retained DNA binding activity, whereas two dominant mutants showed altered activity. All six mutants showed reduced transactivation function compared with wild-type, and modeling the heterozygous state resulted in an intermediate level of activity providing no evidence for dominant negative action. Our in vitro data are consistent with loss-of-function below a dosage sensitive threshold as a mechanism of action for recessive mutations, but indicate an altered mutant protein function rather than a haploinsufficient mechanism for dominant mutations. This study provides the first functional evidence demonstrating that FOXE3 mutations identified in patients impair protein function with differential effects. PMID- 25504732 TI - Core and region-enriched networks of behaviorally regulated genes and the singing genome. AB - Songbirds represent an important model organism for elucidating molecular mechanisms that link genes with complex behaviors, in part because they have discrete vocal learning circuits that have parallels with those that mediate human speech. We found that ~10% of the genes in the avian genome were regulated by singing, and we found a striking regional diversity of both basal and singing induced programs in the four key song nuclei of the zebra finch, a vocal learning songbird. The region-enriched patterns were a result of distinct combinations of region-enriched transcription factors (TFs), their binding motifs, and presinging acetylation of histone 3 at lysine 27 (H3K27ac) enhancer activity in the regulatory regions of the associated genes. RNA interference manipulations validated the role of the calcium-response transcription factor (CaRF) in regulating genes preferentially expressed in specific song nuclei in response to singing. Thus, differential combinatorial binding of a small group of activity regulated TFs and predefined epigenetic enhancer activity influences the anatomical diversity of behaviorally regulated gene networks. PMID- 25504733 TI - Convergent transcriptional specializations in the brains of humans and song learning birds. AB - Song-learning birds and humans share independently evolved similarities in brain pathways for vocal learning that are essential for song and speech and are not found in most other species. Comparisons of brain transcriptomes of song-learning birds and humans relative to vocal nonlearners identified convergent gene expression specializations in specific song and speech brain regions of avian vocal learners and humans. The strongest shared profiles relate bird motor and striatal song-learning nuclei, respectively, with human laryngeal motor cortex and parts of the striatum that control speech production and learning. Most of the associated genes function in motor control and brain connectivity. Thus, convergent behavior and neural connectivity for a complex trait are associated with convergent specialized expression of multiple genes. PMID- 25504731 TI - Three crocodilian genomes reveal ancestral patterns of evolution among archosaurs. AB - To provide context for the diversification of archosaurs--the group that includes crocodilians, dinosaurs, and birds--we generated draft genomes of three crocodilians: Alligator mississippiensis (the American alligator), Crocodylus porosus (the saltwater crocodile), and Gavialis gangeticus (the Indian gharial). We observed an exceptionally slow rate of genome evolution within crocodilians at all levels, including nucleotide substitutions, indels, transposable element content and movement, gene family evolution, and chromosomal synteny. When placed within the context of related taxa including birds and turtles, this suggests that the common ancestor of all of these taxa also exhibited slow genome evolution and that the comparatively rapid evolution is derived in birds. The data also provided the opportunity to analyze heterozygosity in crocodilians, which indicates a likely reduction in population size for all three taxa through the Pleistocene. Finally, these data combined with newly published bird genomes allowed us to reconstruct the partial genome of the common ancestor of archosaurs, thereby providing a tool to investigate the genetic starting material of crocodilians, birds, and dinosaurs. PMID- 25504737 TI - High-resolution linkage map and chromosome-scale genome assembly for cassava (Manihot esculenta Crantz) from 10 populations. AB - Cassava (Manihot esculenta Crantz) is a major staple crop in Africa, Asia, and South America, and its starchy roots provide nourishment for 800 million people worldwide. Although native to South America, cassava was brought to Africa 400 500 years ago and is now widely cultivated across sub-Saharan Africa, but it is subject to biotic and abiotic stresses. To assist in the rapid identification of markers for pathogen resistance and crop traits, and to accelerate breeding programs, we generated a framework map for M. esculenta Crantz from reduced representation sequencing [genotyping-by-sequencing (GBS)]. The composite 2412-cM map integrates 10 biparental maps (comprising 3480 meioses) and organizes 22,403 genetic markers on 18 chromosomes, in agreement with the observed karyotype. We used the map to anchor 71.9% of the draft genome assembly and 90.7% of the predicted protein-coding genes. The chromosome-anchored genome sequence will be useful for breeding improvement by assisting in the rapid identification of markers linked to important traits, and in providing a framework for genomic selection-enhanced breeding of this important crop. PMID- 25504736 TI - Multiple QTL for horticultural traits and quantitative resistance to Phytophthora infestans linked on Solanum habrochaites chromosome 11. AB - Previously, a Phytophthora infestans resistance QTL from Solanum habrochaites chromosome 11 was introgressed into cultivated tomato (S. lycopersicum). Fine mapping of this resistance QTL using near-isogenic lines (NILs) revealed some co located QTL with undesirable effects on plant size, canopy density, and fruit size traits. Subsequently, higher-resolution mapping with sub-NILs detected multiple P. infestans resistance QTL within this 9.4-cM region of chromosome 11. In our present study, these same sub-NILs were also evaluated for 17 horticultural traits, including yield, maturity, fruit size and shape, fruit quality, and plant architecture traits in replicated field experiments over 2 years. The horticultural trait QTL originally detected by fine mapping each fractionated into two or more QTL at higher resolution. A total of 34 QTL were detected across all traits, with 14% exhibiting significant QTL * environment interactions (QTL * E). QTL for many traits were co-located, suggesting either pleiotropic effects or tight linkage among genes controlling these traits. Recombination in the pericentromeric region of the introgression between markers TG147 and At4g10050 was suppressed to approximately 29.7 Mbp per cM, relative to the genomewide average of 750 kbp per cM. The genetic architecture of many of the horticultural and P. infestans resistance traits that mapped within this chromosome 11 S. habrochaites region is complex. Complicating factors included fractionation of QTL, pleiotropy or tight linkage of QTL for multiple traits, pericentromeric chromosomal location(s), and/or QTL * E. High-resolution mapping of QTL in this region would be needed to determine which specific target QTL could be useful in breeding cultivated tomato. PMID- 25504738 TI - Synergetic spin crossover and fluorescence in one-dimensional hybrid complexes. AB - Hybrid materials integrated with a variety of physical properties, such as spin crossover (SCO) and fluorescence, may show synergetic effects that find applications in many fields. Herein we demonstrate a promising post-synthetic approach to achieve such materials by grafting fluorophores (1 pyrenecarboxaldehyde and Rhodamine B) on one-dimensional SCO Fe(II) structures. The resulting hybrid materials display expected one-step SCO behavior and fluorescent properties, in particular showing a coupling between the transition temperature of SCO and the temperature where the fluorescent intensity reverses. Consequently, synergetic effect between SCO and fluorescence is incorporated into materials despite different fluorophores. This study provides an effective strategy for the design and development of novel magnetic and optical materials. PMID- 25504735 TI - Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis. AB - Idiopathic scoliosis occurs in 3% of individuals and has an unknown etiology. The objective of this study was to identify rare variants that contribute to the etiology of idiopathic scoliosis by using exome sequencing in a multigenerational family with idiopathic scoliosis. Exome sequencing was completed for three members of this multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. The HSPG2 gene was sequenced in a separate cohort of 100 unrelated individuals affected with idiopathic scoliosis and also was examined in an independent idiopathic scoliosis population. The exome sequencing and subsequent bioinformatics filtering resulted in 16 potentially damaging and rare coding variants. One of these variants, p.Asn786Ser, is located in the HSPG2 gene. The variant p.Asn786Ser also is overrepresented in a larger cohort of idiopathic scoliosis cases compared with a control population (P = 0.024). Furthermore, we identified additional rare HSPG2 variants that are predicted to be damaging in two independent cohorts of individuals with idiopathic scoliosis. The HSPG2 gene encodes for a ubiquitous multifunctional protein within the extracellular matrix in which loss of function mutation are known to result in a musculoskeletal phenotype in both mouse and humans. Based on these results, we conclude that rare variants in the HSPG2 gene potentially contribute to the idiopathic scoliosis phenotype in a subset of patients with idiopathic scoliosis. Further studies must be completed to confirm the effect of the HSPG2 gene on the idiopathic scoliosis phenotype. PMID- 25504739 TI - Extreme confinement of xenon by cryptophane-111 in the solid state. AB - Solids that sorb, capture and/or store the heavier noble gases are of interest because of their potential for transformative rare gas separation/production, storage, or recovery technologies. Herein, we report the isolation, crystal structures, and thermal stabilities of a series of xenon and krypton clathrates of (+/-)-cryptophane-111 (111). One trigonal crystal form, Xe@111?y(solvent), is exceptionally stable, retaining xenon at temperatures of up to about 300 degrees C. The high kinetic stability is attributable not only to the high xenon affinity and cage-like nature of the host, but also to the crystal packing of the clathrate, wherein each window of the molecular container is blocked by the bridges of adjacent containers, effectively imprisoning the noble gas in the solid state. The results highlight the potential of discrete molecule materials exhibiting intrinsic microcavities or zero-dimensional pores. PMID- 25504741 TI - Involvement of the endocannabinoid system in attentional modulation of nociceptive behaviour in rats. AB - BACKGROUND: Distraction is used clinically to relieve and manage pain. It is hypothesized that pain demands attention and that exposure to another attention demanding stimulus causes withdrawal of attention away from painful stimuli, thereby reducing perceived pain. We have recently developed a rat model that provides an opportunity to investigate the neurobiological mechanisms mediating distraction-induced analgesia, as these mechanisms are, at present, poorly understood. Given the well-described role of the endogenous cannabinoid (endocannabinoid; EC) system in the modulation of pain and attentional processing, the present study investigated its role in distraction-induced antinociception in rats. METHODS: Animals received the CB1 receptor antagonist/inverse agonist, rimonabant or vehicle intraperitoneally, 30 min prior to behavioural evaluation. Formalin-evoked nociceptive behaviour was measured in the presence or absence of a novel-object distractor. Liquid chromatography tandem mass spectrometry was used to determine the levels of the endogenous cannabinoids anandamide and 2-arachidonoylglycerol (2-AG) in the ventral hippocampus (vHip). RESULTS: Exposure to a novel object distractor significantly reduced formalin-evoked nociceptive behaviour. The novel object-induced reduction in nociceptive behaviour was attenuated by rimonabant. Novel object exposure was also associated with increased tissue levels of anandamide and 2-AG in the vHip. CONCLUSIONS: These data suggest that the reduction in formalin-evoked nociceptive behaviour that occurs as a result of exposure to a novel object may be mediated by engagement of the EC system, in particular in the vHip. The results provide evidence that the EC system may be an important neural substrate subserving attentional modulation of pain. PMID- 25504742 TI - Trajectory-based co-localization measures for nanoparticle-cell interaction studies. AB - High-resolution live cell microscopy will soon have a fundamental role in understanding bio-nano interactions, providing material that can be exploited using single particle tracking techniques. The present work uses 3D timelapse images obtained with confocal microscopy, to temporally resolve the co localization between polystyrene nanoparticles and lysosomes in live cells through object-based measurements. PMID- 25504744 TI - The effect of the spacer of bis(biurea) ligands on the structure of A2 L3 -type (A=anion) phosphate complexes. AB - By tuning the length and rigidity of the spacer of bis(biurea) ligands L, three structural motifs of the A2 L3 complexes (A represents anion, here orthophosphate PO4 (3-) ), namely helicate, mesocate, and mono-bridged motif, have been assembled by coordination of the ligand to phosphate anion. Crystal structure analysis indicated that in the three complexes, each of the phosphate ions is coordinated by twelve hydrogen bonds from six surrounding urea groups. The anion coordination properties in solution have also been studied. The results further demonstrate the coordination behavior of phosphate ion, which shows strong tendency for coordination saturation and geometrical preference, thus allowing for the assembly of novel anion coordination-based structures as in transition metal complexes. PMID- 25504743 TI - Serum sodium and survival benefit of liver transplantation. AB - Hyponatremia is associated with elevated wait-list mortality among end-stage liver disease candidates for liver transplantation (LT). However, the effect of low serum sodium on the survival benefit of LT has not been examined. We sought to determine whether pretransplant hyponatremia is associated with an altered LT survival benefit. Data were obtained from the Scientific Registry of Transplant Recipients. The study population consisted of adults (age >= 18 years) placed on the waiting list for LT between January 1, 2005 and December 31, 2012 (n = 69,213). The effect of hyponatremia on the survival benefit was assessed via sequential stratification, an extension of Cox regression. Each transplant recipient was matched to appropriate candidates then active on the waiting list with the same Model for End-Stage Liver Disease (MELD) score and in the same donation service area. The focus of the analysis was the interaction between the serum sodium and the MELD score with respect to the survival benefit of LT; this was defined as the covariate-adjusted hazard ratio contrasting post-LT mortality and pre-LT mortality. The LT survival benefit increased significantly with decreasing serum sodium values when the MELD scores were >11. The survival benefit of LT was not affected by serum sodium for patients with MELD scores <= 11. In conclusion, the LT survival benefit (or lack thereof) is independent of serum sodium for patients with MELD scores <= 11. The increase in the survival benefit with decreasing serum sodium among patients with MELD scores > 11 is consistent with recently approved changes to the allocation system incorporating serum sodium. PMID- 25504745 TI - Mimosa-inspired design of a flexible pressure sensor with touch sensitivity. AB - A bio-inspired flexible pressure sensor is generated with high sensitivity (50.17 kPa(-1)), quick responding time (<20 ms), and durable stability (negligible loading-unloading signal changes over 10 000 cycles). Notably, the key resource of surface microstructures upon sensor substrates results from the direct molding of natural mimosa leaves, presenting a simple, environment-friendly and easy scale-up fabrication process for these flexible pressure sensors. PMID- 25504746 TI - Molecularly imprinted hollow sphere array for the sensing of proteins. AB - Mono-dispersed molecularly imprinted hollow spheres (MIHSs) for hemoglobin (Hb) were prepared by employing silica nanospheres as the sacrificial templates. The obtained hollow spheres with uniform particle size of 360 nm in diameter were characterized by transmission electron microscopy. The outstanding affinities of these MIHSs to the target protein were confirmed by adsorption experiment in aqueous solution. Adsorption equilibrium was achieved within 10 min while the binding capacity (Qmax ) of Hb was 8.84 umol g(-1) at pH7.0. Furthermore, the MIHSs were successfully assembled into a closely-packed 3D colloidal array. The molecularly imprinted hollow sphere array (MIHSA) can selectively recognize Hb. As the concentration of Hb increased, the structure color of the MIHSA changed from blue to green, and turn to white finally with maximum red shift for 43 nm. The MIHSA showed promising potential for the naked-eye detection of target Hb. Reflection spectra of the MIHSA in response to different Hb concentrations (0.075 15 umol L(-1) ). PMID- 25504747 TI - Nasal and bronchial response to exercise in children with seasonal allergic rhinitis out of the pollen season. AB - BACKGROUND: Allergic rhinitis is a type I allergic disease of the nasal mucosa, and is characterized by paroxysmal sneezing, watery rhinorrhea, and nasal blockage. In seasonal allergic rhinitis subjects, even subthreshold allergen doses have been found to cause inflammatory cell infiltration in the nasal mucosa. This study aimed to investigate the presence of nasal obstructions and symptoms in seasonal allergic rhinitis subjects by assessing an exercise challenge test (ECT) outside of the pollen season. METHODS: Twenty patients and 20 healthy children who were admitted to the Osmangazi University Medical School Pediatric Allergy Clinic were included in the study in a pollen free season. The total nasal airflow and visual analog scale (for rhinorrhea, nasal congestion, sneezing, and itching) and pulmonary function tests were evaluated before and after each ECT. The nasal airflow and resistance changes were evaluated with anterior rhinomanometry. RESULTS: Eight patients and one healthy child had nasal obstructions after the ECT. There was a significant difference in the exercise induced nasal obstructions between the 2 groups (p = 0.02). Eighteen children with exposure to tobacco smoke in the patient and control groups had lower forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and forced expiratory flow 25% to 75% (FEF25-75 ) values than the children without exposure to tobacco smoke. CONCLUSION: The prevalence of exercise-induced nasal obstruction in children with seasonal rhinitis out of the pollen season is 40%. We showed that minimal persistent inflammation and nasal symptoms can also be diagnosed in rhinitis children in a symptom-free period. PMID- 25504748 TI - Biocompatibility of ferroelectric lithium niobate and the influence of polarization charge on osteoblast proliferation and function. AB - In this work, the influence of substrate surface charge on in vitro osteoblast cell proliferation on ferroelectric lithium niobate (LN) crystal surfaces is investigated. LN has a spontaneous polarization along the z-axis and is thus characterized by positive and negative bound polarization charge at the +z and -z surfaces. Biocompatibility of LN was demonstrated via culturing and fluorescence imaging of MC3T3 osteoblast cells for up to 11 days. The cells showed enhanced proliferation rates and improved osteoblast function through mineral formation on the positively and negatively charged LN surfaces compared to electrostatically neutral x-cut LN and a glass cover slip control. These results highlight the potential of LN as a template for investigating the role of charge on cellular processes. PMID- 25504749 TI - Single-layer transition metal dichalcogenide nanosheet-based nanosensors for rapid, sensitive, and multiplexed detection of DNA. AB - Single-layer transition metal dichalcogenide nanosheets, including MoS2, TiS2, and TaS2, are used as novel sensing platforms for sensitive and selective detection of DNA, based on their high fluorescence-quenching ability and different affinities toward single-stranded DNA and double-stranded DNA. Importantly, for the first time, a single-layer TaS2 nanosheet-based multiplexed DNA sensor is also developed. PMID- 25504750 TI - Real-time model based process monitoring of enzymatic biodiesel production. AB - In this contribution we extend our modelling work on the enzymatic production of biodiesel where we demonstrate the application of a Continuous-Discrete Extended Kalman Filter (a state estimator). The state estimator is used to correct for mismatch between the process data and the process model for Fed-batch production of biodiesel. For the three process runs investigated, using a single tuning parameter, qx = 2 * 10(-2) which represents the uncertainty in the process model, it was possible over the entire course of the reaction to reduce the overall mean and standard deviation of the error between the model and the process data for all of the five measured components (triglycerides, diglycerides, monoglycerides, fatty acid methyl esters, and free fatty acid). The most significant reduction for the three process runs, were for the monoglyceride and free fatty acid concentration. For those components, there was over a ten fold decrease in the overall mean error for the state estimator prediction compared with the predictions from the pure model simulations. It is also shown that the state estimator can be used as a tool for detection of outliers in the measurement data. For the enzymatic biodiesel process, given the infrequent and sometimes uncertain measurements obtained we see the use of the Continuous Discrete Extended Kalman Filter as a viable tool for real time process monitoring. PMID- 25504751 TI - Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma. AB - Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI 587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual gamma-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR). Both GSK216458 and PKI 587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration- and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G2-M cell-cycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC. PMID- 25504752 TI - Identification of LY2510924, a novel cyclic peptide CXCR4 antagonist that exhibits antitumor activities in solid tumor and breast cancer metastatic models. AB - Emerging evidence demonstrates that stromal cell-derived factor 1 (SDF-1) and CXCR4, a chemokine and chemokine receptor pair, play important roles in tumorigenesis. In this report, we describe a small cyclic peptide, LY2510924, which is a potent and selective CXCR4 antagonist currently in phase II clinical studies for cancer. LY2510924 specifically blocked SDF-1 binding to CXCR4 with IC50 value of 0.079 nmol/L, and inhibited SDF-1-induced GTP binding with Kb value of 0.38 nmol/L. In human lymphoma U937 cells expressing endogenous CXCR4, LY2510924 inhibited SDF-1-induced cell migration with IC50 value of 0.26 nmol/L and inhibited SDF-1/CXCR4-mediated intracellular signaling. LY2510924 exhibited a concentration-dependent inhibition of SDF-1-stimulated phospho-ERK and phospho Akt in tumor cells. Biochemical and cellular analyses revealed that LY2510924 had no apparent agonist activity. Pharmacokinetic analyses suggested that LY2510924 had acceptable in vivo stability and a pharmacokinetic profile similar to a typical small-molecular inhibitor in preclinical species. LY2510924 showed dose dependent inhibition of tumor growth in human xenograft models developed with non Hodgkin lymphoma, renal cell carcinoma, lung, and colon cancer cells that express functional CXCR4. In MDA-MB-231, a breast cancer metastatic model, LY2510924 inhibited tumor metastasis by blocking migration/homing process of tumor cells to the lung and by inhibiting cell proliferation after tumor cell homing. Collectively, the preclinical data support further investigation of LY2510924 in clinical studies for cancer. PMID- 25504754 TI - Berberine induces senescence of human glioblastoma cells by downregulating the EGFR-MEK-ERK signaling pathway. AB - Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and has a poor prognosis. We, here, report a potent antitumor effect of berberine, an isoquinoline alkaloid, on GBM. Berberine was found to have an IC50 that is much lower than temozolomide in vitro in U87, U251, and U118 glioblastoma cells. Although previous studies showed that berberine primarily exerts its anticancer effect by inducing cell-cycle arrest, apoptosis, and autophagy, we observed that the antitumor effect of berberine on glioblastoma cells was primarily achieved through induction of cellular senescence. In glioblastoma cells treated with berberine, the level of epidermal growth factor receptor (EGFR) was greatly reduced. Examination of the activities of the kinases downstream of EGFR revealed that the RAF-MEK-ERK signaling pathway was remarkably inhibited, whereas AKT phosphorylation was not altered. Pharmacologic inhibition or RNA interference of EGFR similarly induced cellular senescence of glioblastoma cells. Furthermore, the cellular senescence induced by berberine could be rescued by introduction of a constitutive active MKK. Berberine also potently inhibited the growth of tumor xenografts, which was accompanied by downregulation of EGFR and induction of senescence. Our findings thus revealed a new route by which berberine exerts its anticancer activity. Because EGFR is commonly upregulated in glioblastoma, the demonstration of effective inhibition of EGFR by berberine points to the possibility of using berberine in the treatment of patients with glioblastoma. PMID- 25504753 TI - Targeting BRG1 chromatin remodeler via its bromodomain for enhanced tumor cell radiosensitivity in vitro and in vivo. AB - Radiotherapy treats cancer by inducing DNA double-strand breaks (DSB) in tumor cells using ionizing radiation. However, DNA repair in tumor cells often leads to radioresistance and unsuccessful outcome. Inhibition of DNA repair by targeting repair proteins can increase radiosensitivity of tumor cells. The BRG1 chromatin remodeling enzyme assists DSB repair by stimulating gamma-H2AX formation and BRG1 binding to acetylated histones at DSBs via bromodomain (BRD) is critical for this activity. Here, we show that ectopic expression of BRG1-BRD inhibited gamma-H2AX and DSB repair after irradiation and increased the radiosensitivity in various human cancer cells, including HT29 colon cancer. Dimerization of BRG1-BRD, increasing its chromatin binding affinity, aggravated the defects in gamma-H2AX and DSB repair and further enhanced the radiosensitivity. While little affecting the upstream ATM activation, BRG1-BRD in irradiated HT29 cells inhibited the recruitment of 53BP1 to damaged chromatin, the downstream event of gamma-H2AX, and compromised the G2-M checkpoint and increased apoptosis. Importantly, in a xenograft mouse model, BRG1-BRD increased the radiosensitivity of HT29 tumors, which was further enhanced by dimerization. These data suggest that BRG1-BRD radiosensitizes tumor cells by a dominant negative activity against BRG1, which disrupts gamma-H2AX and its downstream 53BP1 pathways, leading to inefficient DNA repair, G2-M checkpoint defect, and increased apoptosis. This work therefore identifies BRG1-BRD as a novel tumor radiosensitizer and its action mechanism, providing the first example of chromatin remodeler as a target for improving cancer radiotherapy. PMID- 25504755 TI - Long noncoding RNA ANRIL promotes non-small cell lung cancer cell proliferation and inhibits apoptosis by silencing KLF2 and P21 expression. AB - Recent evidence highlights long noncoding RNAs (lncRNA) as crucial regulators of cancer biology that contribute to essential cancer cell functions such as cell proliferation, apoptosis, and metastasis. In non-small cell lung cancer (NSCLC), several lncRNAs' expressions are misregulated and have been nominated as critical actors in NSCLC tumorigenesis. LncRNA ANRIL was first found to be required for the PRC2 recruitment to and silencing of p15(INK4B), the expression of which is induced by the ATM-E2F1 signaling pathway. Our previous study showed that ANRIL was significantly upregulated in gastric cancer, and it could promote cell proliferation and inhibit cell apoptosis by silencing of miR99a and miR449a transcription. However, its clinical significance and potential role in NSCLC is still not documented. In this study, we reported that ANRIL expression was increased in NSCLC tissues, and its expression level was significantly correlated with tumor-node-metastasis stages and tumor size. Moreover, patients with high levels of ANRIL expression had a relatively poor prognosis. In addition, taking advantage of loss-of-function experiments in NSCLC cells, we found that knockdown of ANRIL expression could impair cell proliferation and induce cell apoptosis both in vitro and vivo. Furthermore, we uncover that ANRIL could not repress p15 expression in PC9 cells, but through silencing of KLF2 and P21 transcription. Thus, we conclusively demonstrate that lncRNA ANRIL plays a key role in NSCLC development by associating its expression with survival in patients with NSCLC, providing novel insights on the function of lncRNA-driven tumorigenesis. PMID- 25504756 TI - Sulfono-gamma-AApeptides as a new class of nonnatural helical foldamer. AB - Foldamers offer an attractive opportunity for the design of novel molecules that mimic the structures and functions of proteins and enzymes including biocatalysis and biomolecular recognition. Herein we report a new class of nonnatural helical sulfono-gamma-AApeptide foldamers of varying lengths. The crystal structure of the sulfono-gamma-AApeptide monomer S6 illustrates the intrinsic folding propensity of sulfono-gamma-AApeptides, which likely originates from the bulkiness of tertiary sulfonamide moiety. The two-dimensional solution NMR spectroscopy data for the longest sequence S1 demonstrates a 10/16 right-handed helical structure. Optical analysis using circular dichroism further supports well- defined helical conformation of sulfono-gamma-AApeptides in solution containing as few as five building blocks. Future development of sulfono-gamma AApeptides may lead to new foldamers with discrete functions, enabling expanded application in chemical biology and biomedical sciences. PMID- 25504757 TI - First report of a multidrug-resistant Klebsiella pneumoniae of sequence type 11 causing sepsis in a free-ranging beaver (Castor fiber). AB - Klebsiella pneumoniae of sequence type (ST) 11 is a hyper-epidemic nosocomial clone spreading worldwide among humans and also emerging in pets. In this report, we describe a clinical case of fatal sepsis due to this multidrug-resistant (MDR) pathogen in a Eurasian beaver. The isolate showed resistance to six different classes of antimicrobials including third generation cephalosporins and fluoroquinolones. This is the first report describing the detection of a MDR K. pneumoniae ST11 in a free-ranging animal. Our finding highlights the potential for environmental dissemination of hyper-epidemic clones of K. pneumoniae and possible spread in wildlife and cause epizootics. PMID- 25504758 TI - Chemical stimulation of rat retinal neurons: feasibility of an epiretinal neurotransmitter-based prosthesis. AB - OBJECTIVE: No cure currently exists for photoreceptor degenerative diseases, which cause partial or total blindness in millions of people worldwide. Electrical retinal prostheses have been developed by several groups with the goal of restoring vision lost to these diseases, but electrical stimulation has limitations. It excites both somas and axons, activating retinal pathways nonphysiologically, and limits spatial resolution because of current spread. Chemical stimulation of retinal ganglion cells (RGCs) using the neurotransmitter glutamate has been suggested as an alternative to electrical stimulation with some significant advantages. However, sufficient scientific data to support developing a chemical-based retinal prosthesis is lacking. The goal of this study was to investigate the feasibility of a neurotransmitter-based retinal prosthesis and determine therapeutic stimulation parameters. APPROACH: We injected controlled amounts of glutamate into rat retinas from the epiretinal side ex vivo via micropipettes using a pressure injection system and recorded RGC responses with a multielectrode array. Responsive units were identified using a spike rate threshold of 3 Hz. MAIN RESULTS: We recorded both somal and axonal units and demonstrated successful glutamatergic stimulation across different RGC subtypes. Analyses show that exogenous glutamate acts on RGC synapses similar to endogenous glutamate and, unlike electrical prostheses, stimulates only RGC somata. The spatial spread of glutamate stimulation was ~ 290 MUm from the injection site, comparable to current electrical prostheses. Further, the glutamate injections produced spatially differential responses in OFF, ON, and ON-OFF RGC subtypes, suggesting that differential stimulation of the OFF and ON systems may be possible. A temporal resolution of 3.2 Hz was obtained, which is a rate suitable for spatial vision. SIGNIFICANCE: We provide strong support for the feasibility of an epiretinal neurotransmitter-based retinal prosthesis. Our findings suggest that chemical stimulation of RGCs is a viable alternative to electrical stimulation and could offer distinct advantages such as the selective stimulation of RGC somata. PMID- 25504759 TI - Enhanced skeletal muscle expression of extracellular superoxide dismutase mitigates streptozotocin-induced diabetic cardiomyopathy by reducing oxidative stress and aberrant cell signaling. AB - BACKGROUND: Exercise training enhances extracellular superoxide dismutase (EcSOD) expression in skeletal muscle and elicits positive health outcomes in individuals with diabetes mellitus. The goal of this study was to determine if enhanced skeletal muscle expression of EcSOD is sufficient to mitigate streptozotocin induced diabetic cardiomyopathy. METHODS AND RESULTS: Exercise training promotes EcSOD expression in skeletal muscle and provides protection against diabetic cardiomyopathy; however, it is not known if enhanced expression of EcSOD in skeletal muscle plays a functional role in this protection. Here, we show that skeletal muscle-specific EcSOD transgenic mice are protected from cardiac hypertrophy, fibrosis, and dysfunction under the condition of type 1 diabetes mellitus induced by streptozotocin injection. We also show that both exercise training and muscle-specific transgenic expression of EcSOD result in elevated EcSOD protein in the blood and heart without increased transcription in the heart, suggesting that enhanced expression of EcSOD from skeletal muscle redistributes to the heart. Importantly, cardiac tissue in transgenic mice displayed significantly reduced oxidative stress, aberrant cell signaling, and inflammatory cytokine expression compared with wild-type mice under the same diabetic condition. CONCLUSIONS: Enhanced expression of EcSOD in skeletal muscle is sufficient to mitigate streptozotocin-induced diabetic cardiomyopathy through attenuation of oxidative stress, aberrant cell signaling, and inflammation, suggesting a cross-organ mechanism by which exercise training improves cardiac function in diabetes mellitus. PMID- 25504760 TI - VPAC2 receptor expression in human normal and neoplastic tissues: evaluation of the novel MAB SP235. AB - The vasoactive intestinal peptide receptor 2 (VPAC2) is widely distributed throughout the body and is also overexpressed in a variety of human neoplastic tissues. However, little is known about its precise tissue distribution, regulation and function, which is in part be due to the lack of specific monoclonal anti-VPAC2 antibodies. In this study, we extensively characterised the novel rabbit monoclonal anti-VPAC2 antibody (clone SP235) using transfected cells and mouse, rat and human tissues. SP235 was then subjected to a comparative immunohistochemical study on a series of 167 histological specimens from formalin fixed, paraffin-embedded human tumours and adjacent normal tissues. SP235 detected a broad band migrating at a molecular weight of 50-70 kDa in western blotting analyses of various mouse tissues as well as VPAC2- but not VPAC1 transfected human embryonic kidney 293 cells. SP235 yielded an efficient immunostaining of distinct cell populations in human tissue samples with a predominance of plasma membrane staining, which was completely abolished by preadsorption with its immunising peptide. SP235 immunohistochemistry detected VPAC2 receptors in lymphocytes present in spleen, tonsils, lymph nodes and Peyer's patches, chief cells of gastric mucosa, exocrine and endocrine pancreas, kidney tubules and blood vessels. In addition, VPAC2 was observed in thyroid, gastric and lung carcinomas, pancreatic adenocarcinomas, sarcomas and neuroendocrine tumours. SP235 may prove of great value in the identification of VPAC2 receptors during routine histopathological examination. VPAC2 visualisation with this simple and rapid immunohistochemical method will facilitate identification of candidate tumours for vasoactive intestinal peptide (VIP)-based diagnostics or therapeutic interventions. PMID- 25504762 TI - Benefits and burdens of using a SNP array in pregnancies at increased risk for the common aneuploidies. AB - We present the nature of pathogenic SNP array findings in pregnancies without ultrasound (US) abnormalities and show the additional diagnostic value of SNP array as compared with rapid aneuploidy detection and karyotyping. 1,330 prenatal samples were investigated with a 0.5-Mb SNP array after the exclusion of the most common aneuploidies. In 2.7% (36/1,330) of the cases, pathogenic chromosome aberrations were found; a microscopically detectable abnormality in 0.7% and a submicroscopic aberration in 2%. Our results show that in addition to the age- or screening-related aneuploidy risk, in pregnancies without US abnormalities, there is a risk of 1:148 (9/1,330) for a (sub)microscopic abnormality associated with an early-onset often severe disease, 1:222 (6/1,330) for a submicroscopic aberration causing an early-onset disease, 1:74 (18/1,330) for carrying a susceptibility locus for a neurodevelopmental disorder, and 1:443 (3/1,330) for a late-onset disorder (hereditary neuropathy with liability to pressure palsies in all three cases). These risk figures are important for adequate pretest counseling so that prospective parents can make informed individualized choices between targeted prenatal testing and broad testing with SNP array. Based on our results, we believe if invasive testing is performed, SNP array should be the preferred cytogenetic technique irrespective of the indication. PMID- 25504761 TI - Multitarget drug discovery for Alzheimer's disease: triazinones as BACE-1 and GSK 3beta inhibitors. AB - Cumulative evidence strongly supports that the amyloid and tau hypotheses are not mutually exclusive, but concomitantly contribute to neurodegeneration in Alzheimer's disease (AD). Thus, the development of multitarget drugs which are involved in both pathways might represent a promising therapeutic strategy. Accordingly, reported here in is the discovery of 6-amino-4-phenyl-3,4-dihydro 1,3,5-triazin-2(1H)-ones as the first class of molecules able to simultaneously modulate BACE-1 and GSK-3beta. Notably, one triazinone showed well-balanced in vitro potencies against the two enzymes (IC50 of (18.03+/-0.01) MUM and (14.67+/ 0.78) MUM for BACE-1 and GSK-3beta, respectively). In cell-based assays, it displayed effective neuroprotective and neurogenic activities and no neurotoxicity. It also showed good brain permeability in a preliminary pharmacokinetic assessment in mice. Overall, triazinones might represent a promising starting point towards high quality lead compounds with an AD-modifying potential. PMID- 25504763 TI - Effects of ochratoxin a on mouse oocyte maturation and fertilization, and apoptosis during fetal development. AB - We previously reported that ochratoxin A (OTA), a mycotoxin found in many foods worldwide, causes nephrotoxicity, hepatotoxicity, and immunotoxicity, and is a risk factor for abnormal embryonic development. More specifically, OTA triggers apoptotic processes in the inner cell mass of mouse blastocysts, decreasing cell viability and embryonic development. In the current study, we investigated the deleterious effects of OTA on mouse oocyte maturation, in vitro fertilization (IVF), and subsequent pre- and postimplantation development both in vitro and in vivo. Notably, OTA significantly impaired mouse oocyte maturation, decreased IVF rates, and inhibited subsequent embryonic development in vitro. Preincubation of oocytes with OTA during in vitro maturation increased postimplantation embryonic resorption and decreased mouse fetal weight. In an in vivo animal model, provision of 1-10 MUM OTA in the drinking water or intravenous injection of 1 or 2 mg/kg body weight of OTA decreased oocyte maturation and IVF, and had deleterious effects on early embryonic development. Importantly, preincubation of oocytes with a caspase-3-specific inhibitor effectively blocked these OTA triggered deleterious effects, suggesting that the embryonic injury induced by OTA is mediated via a caspase-dependent apoptotic mechanism. Furthermore, OTA upregulated the levels of p53 and p21 in blastocyst cells derived from OTA pretreated oocytes, indicating that such cells undergo apoptosis via p53-, p21-, and caspase-3-dependent regulatory mechanisms. This could have deleterious effects on embryonic implantation and fetal survival rates, as seen in our animal models. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 724-735, 2016. PMID- 25504764 TI - Superwetting Surfaces under Different Media: Effects of Surface Topography on Wettability. AB - Superwetting surfaces in air, such as superhydrophobic and superoleophobic surfaces that are governed by surface chemical compositions and surface topographies, are one of the most extensively studied topics in this field. However, it is not well-understood how surface topographies affect the behaviors of immiscible liquids and gases under other kinds of media, although it is significant in diverse fields. The main aim of this work is to systematically investigate the wetting behaviors of liquids (water and oil) and gas (air) on silicon surfaces with different topographies (i.e., smooth, micro, nano, and micro-/nanostructures) under various media (i.e., air, water, and oil). The contact angles, as well as contact-angle hysteresis, sliding angles, and adhesive forces, were utilized to evaluate the wettability of these surfaces. As a result, the microstructured surfaces typically exhibit high contact-angle hysteresis, high sliding angles, and high adhesive forces, whereas the micro-/nanostructured surfaces display low contact-angle hysteresis, low sliding angles, and low adhesive forces, even if they have high (>150 degrees ) and similar contact angles. Furthermore, when transferring the same surface from one kind of medium to another, different superwetting states can be reversibly switched. PMID- 25504765 TI - A prospective study of severe irritability in youths: 2- and 4-year follow-up. AB - BACKGROUND: Severe, chronic irritability is receiving increased research attention, and is the cardinal symptom of a new diagnostic category, disruptive mood dysregulation disorder (DMDD). Although data from epidemiological community samples suggest that childhood chronic irritability predicts unipolar depression and anxiety in adulthood, whether these symptoms are stable and cause ongoing clinical impairment is unknown. The present study presents 4-year prospective and longitudinal diagnostic and impairment data on a clinical sample of children selected for symptoms of severe irritability (operationalized as severe mood dysregulation [SMD]). METHODS: Youth meeting criteria for SMD (n = 200) were evaluated at baseline using standard diagnostic methods. Two-year (n = 78) and 4 year (n = 46) follow-up diagnostic and clinical impairment ratings collected at 6 month intervals were completed with those youths enrolled in the study for a sufficient time. RESULTS: Although the number of youth meeting strict categorical SMD criteria declined over time (49 and 40% at 2 and 4 years, respectively), many individuals not meeting full criteria continued to display clinically significant irritability symptoms (2 years: 42%; 4 years: 37%). Impairment due to these irritability symptoms remained consistently in the moderate range on the Clinical Global Impressions Scale. CONCLUSIONS: By the 4-year follow-up, only 40% of youths meet strict SMD criteria; however, most continue to display clinically impairing symptoms and significant impairment warranting psychiatric treatment. These findings provide evidence for the course of irritability, with implications for DMDD. Future research with populations meeting DMDD criteria and followed through the ages of high risk for psychiatric diagnoses is necessary. PMID- 25504770 TI - Personal decision-making processes for living related liver transplantation in children. AB - Living related liver transplantation (LRLT) is a valuable transplant option for children with end-stage liver disease who face long waiting times on regular waiting lists. The subjection of a healthy adult to a potentially life threatening operation can raise issues of freedom of choice, fear, and family conflict for the potential donors. We examined attitudes, fears, and influencing factors in the decision-making process for living liver donation for children in order to identify factors to improve support for living liver donors in the future. In a retrospective, questionnaire-based survey of 93 adults evaluated for living liver donation between 1997 and 2010, 47 of whom actually proceeded to donation, we asked about attitudes, motivation, fears, influencing factors, and well-being during the LRLT evaluation process and during the donation period. Answers were recorded on Likert scales and compared with Pearson's rho correlation and the Mann-Whitney U test as appropriate. Although there was a strong sense of a lack of alternatives among the donors, the majority of the donors felt free in their decision to donate. Donors who were asked to donate for a relative who was not their own child appeared at higher risk of lacking support and of feeling coerced. Family and social support and good and empathic information about the donation process were identified as key factors for donor well-being. In conclusion, potential living liver donors need to have adequate, sufficient, and empathic information, and they need to be provided a supportive framework, including family support, in order to promote their well-being. Care needs to be taken in identifying and counseling potential donors at risk of feeling coerced into donation. PMID- 25504771 TI - Self-report distortions of puffing topography in daily smokers. AB - Under-reporting tobacco consumption is common, although there is lack of evidence whether under-reporting is associated with health risk perception. In this study, smoking topography from 110 smokers was recorded over 24 hours, aiming to capture a representative average of smoking behaviour. Participants significantly under reported the duration of secondary exposure, and there was a significant interaction between self-report distortion type and risk perception. Analysis showed that smokers under-reporting puff number declared perceiving significantly less susceptibility to acquiring airway diseases, which is correlating significantly with the level of under-reporting. The present findings may suggest that under-reporting smoking behaviour has psychological functions beyond achieving social desirability. PMID- 25504772 TI - Clinical assessment of non carious cervical lesion using swept-source optical coherence tomography. AB - Non-carious cervical lesions (NCCLs) involve various forms of tooth loss with different etiologies. This study aimed to utilize swept-source optical coherence tomography (SS-OCT) at 1300 nm wavelength range in vitro and in vivo to evaluate and clarify the mechanism of NCCLs. In the in vitro phase, a dentin attenuation coefficient (MUt ) derived from the SS-OCT signal at NCCL was compared with mineral loss obtained from transverse microradiography (TMR) to determine a MUt threshold to discriminate demineralization of cervical dentin in vivo. In the clinical study, 242 buccal surfaces were investigated in 35 subjects. Presence and dimensions of NCCLs, cervical cracking and the degree of demineralization at the exposed cervical dentin were determined using SS-OCT. Dentin demineralization was observed in 69% of NCCLs. SS-OCT results confirm that dentin mineral loss and occlusal attrition were associated with larger NCCLs, and can be considered as an etiological factor in formation and progress of these lesions. (A) We determined the attenuation coeffcient (MUt ) threshold of SS-OCT signal for the detection of demineralization (1.21) from in vitro study. DEM: demineralized dentin, sound: sound dentin. (B) Using the MUt threshold, we observed NCCLs in vivo to detect the demineralization in cervical dentin. SS-OCT scanning was performed along the red line. (C) SS-OCT image obtained along the red line in B. In SS-OCT, brightness of dentin beneath the NCCL was increased (arrow) compared with intact zone. The cervical dentin was slightly demineralized (MUt : 1.25). e: enamel, d: dentin, g: gingiva. PMID- 25504774 TI - Screening for protein phosphorylation using nanoscale reactions on microdroplet arrays. AB - We present a novel and straightforward screening method to detect protein phosphorylations in complex protein mixtures. A proteolytic digest is separated by a conventional nanoscale liquid chromatography (nano-LC) separation and the eluate is immediately compartmentalized into microdroplets, which are spotted on a microarray MALDI plate. Subsequently, the enzyme alkaline phosphatase is applied to every second microarray spot to remove the phosphate groups from phosphorylated peptides, which results in a mass shift of n*-80 Da. The MALDI-MS scan of the microarray is then evaluated by a software algorithm to automatically identify the phosphorylated peptides by exploiting the characteristic chromatographic peak profile induced by the phosphatase treatment. This screening method does not require extensive MS/MS experiments or peak list evaluation and can be easily extended to other enzymatic or chemical reactions. PMID- 25504775 TI - Synthesis and characterization of a helicene-based imidazolium salt and its application in organic molecular electronics. AB - Herein we demonstrate the synthesis of a helicene-based imidazolium salt. The salt was prepared by starting from racemic 2-methyl[6]helicene, which undergoes radical bromination to yield 2-(bromomethyl)[6]helicene. Subsequent treatment with 1-butylimidazole leads to the corresponding salt 1-butyl-3-(2 methyl[6]helicenyl)-imidazolium bromide. The prepared salt was subsequently characterized by using NMR spectroscopy and X-ray analysis, various optical spectrometric techniques, and computational chemistry tools. Finally, the imidazolium salt was immobilized onto a SiO2 substrate as a crystalline or amorphous deposit. The deposited layers were used for the development of organic molecular semiconductor devices and the construction of a fully reversible humidity sensor. PMID- 25504773 TI - Ectokinases as novel cancer markers and drug targets in cancer therapy. AB - While small-molecule kinase inhibitors became the most prominent anticancer drugs, novel combinatorial strategies need to be developed as the fight against cancer is not yet won. We review emerging literature showing that the release of several ectokinases is significantly upregulated in body fluids from cancer patients and that they leave behind their unique signatures on extracellular matrix (ECM) proteins. Our analysis of proteomic data reveals that fibronectin is heavily phosphorylated in cancer tissues particularly within its growth factor binding sites and on domains that regulate fibrillogenesis. We are thus making the case that cancer is not only a disease of cells but also of the ECM. Targeting extracellular kinases or the extracellular signatures they leave behind might thus create novel opportunities in cancer diagnosis as well as new avenues to interfere with cancer progression and malignancy. PMID- 25504776 TI - Nanocomposite bone scaffolds based on biodegradable polymers and hydroxyapatite. AB - In tissue engineering, development of an osteoconductive construct that integrates with host tissue remains a challenge. In this work, the effect of bone like minerals on maturation of pre-osteoblast cells was investigated using polymer-mineral scaffolds composed of poly(propylene fumarate)-co poly(caprolactone) (PPF-co-PCL) and nano-sized hydroxyapatite (HA). The HA of varying concentrations was added to an injectable formulation of PPF-co-PCL and the change in thermal and mechanical properties of the scaffolds was evaluated. No change in onset of degradation temperature was observed due to the addition of HA, however compressive and tensile moduli of copolymer changed significantly when HA amounts were increased in composite formulation. The change in mechanical properties of copolymer was found to correlate well to HA concentration in the constructs. Electron microscopy revealed mineral nucleation and a change in surface morphology and the presence of calcium and phosphate on surfaces was confirmed using energy dispersive X-ray analysis. To characterize the effect of mineral on attachment and maturation of pre-osteoblasts, W20-17 cells were seeded on HA/copolymer composites. We demonstrated that cells attached more to the surface of HA containing copolymers and their proliferation rate was significantly increased. Thus, these findings suggest that HA/PPF-co-PCL composite scaffolds are capable of inducing maturation of pre-osteoblasts and have the potential for use as scaffold in bone tissue engineering. PMID- 25504777 TI - Pilot study for family-based association analysis of schizophrenia in a Korean population: Analysis for candidate genes positionally on chromosome 18q21. AB - INTRODUCTION: Schizophrenia is the most devastating mental illness that causes severe deterioration in social and occupational functioning. This is a pilot study for family-based association analysis of schizophrenia in a Korean population to search candidate genes functionally relevant and positionally on chromosome 18. METHODS: We have recruited 27 probands (with psychosis) with their parents and siblings whenever possible. We analyzed 20 SNPs (Single Nucleotide Polymorphism) of seven neuronal genes in chromosome 18 for DNA samples that was checked for the data quality and genotype error. For testing of association, we performed family-based association tests analyses with each individual SNP, using the phenotype of psychosis. And then, we performed family-based association tests haplotype analyses with each individual SNP, using the phenotype of psychosis. Finally, we performed linkage disequilibrium analyses for the phenotype of schizophrenia. RESULTS: We found one significant SNPs of one neuronal gene in chromosome 18 (P value < 0.05) for the qualitative phenotype of psychosis (rs1893490:MAPK4). We also found significant haplotypes of four SNPs in mitogen activated protein kinase 4 (MAPK4) gene of chromosome 18 (P value < 0.1) for the phenotype of psychosis (rs1893490-rs3892158-rs3752088-rs3794899). Two SNPS within the MAPK4 gene (rs3794899, rs3794901), plus SNPs within the malic enzyme 2 (rs685533, rs12277), and SMAD4 genes (rs8096092, rs2298617) were in strong linkage disequilibrium with each other (D' > 0.60). DISCUSSION: The present findings provide convergent evidence (fine mapping of a chromosomal locus 18q21 associated with schizophrenia) suggesting that a specific MAPK4 could be a candidate gene for causing a spectrum of schizophrenia phenotype. PMID- 25504778 TI - Reactions of difunctional electrophiles with functionalized aryllithium compounds: remarkable chemoselectivity by flash chemistry. AB - Flash chemistry using flow microreactors enables highly chemoselective reactions of difunctional electrophiles with functionalized aryllithium compounds by virtue of extremely fast micromixing. The approach serves as a powerful method for protecting-group-free synthesis using organolithium compounds and opens a new possibility in the synthesis of polyfunctional organic molecules. PMID- 25504779 TI - An ultrasonically enhanced inclined settler for microalgae harvesting. AB - Microalgae have vast potential as a sustainable and scalable source of biofuels and bioproducts. However, algae dewatering is a critical challenge that must be addressed. Ultrasonic settling has already been exploited for concentrating various biological cells at relatively small batch volumes and/or low throughput. Typically, these designs are operated in batch or semicontinuous mode, wherein the flow is interrupted and the cells are subsequently harvested. These batch techniques are not well suited for scaleup to the throughput levels required for harvesting microalgae from the large-scale cultivation operations necessary for a viable algal biofuel industry. This article introduces a novel device for the acoustic harvesting of microalgae. The design is based on the coupling of the acoustophoretic force, acoustic transparent materials, and inclined settling. A filtration efficiency of 70 +/- 5% and a concentration factor of 11.6 +/- 2.2 were achieved at a flow rate of 25 mL.min(-1) and an energy consumption of 3.6 +/ 0.9 kWh.m(-3) . The effects of the applied power, flow rate, inlet cell concentration, and inclination were explored. It was found that the filtration efficiency of the device is proportional to the power applied. However, the filtration efficiency experienced a plateau at 100 W L(-1) of power density applied. The filtration efficiency also increased with increasing inlet cell concentration and was inversely proportional to the flow rate. It was also found that the optimum settling angle for maximum concentration factor occurred at an angle of 50 +/- 5 degrees . At these optimum conditions, the device had higher filtration efficiency in comparison to other similar devices reported in the previous literature. PMID- 25504781 TI - Distinguishing the strength of electronic coupling for Mo2 -containing mixed valence compounds within the Class III regime. AB - Two, symmetrical, mixed-valence (MV), complex cations-{[Mo2 (DAniF)3 ]2 (MU oxamidate)}(+) (1(+) ) and {Mo2 (DAniF)3 ]2 (MU-dithiooxamidate)}(+) (2(+) ; DAniF=N,N'-di(p-anisyl)formamidinate)-are significantly differentiated in terms of electronic coupling between the two [Mo2 ] units. For 1(+) the intervalence (IV) charge-transfer band in the near-IR spectrum is truncated in half on the low energy side as predicted for MV compounds at the Class II-III limit (2Hab /lambda=1; for which Hab =electronic coupling matrix element and lambda=reorganization energy). In contrast, the very strongly coupled analogue 2(+) , as indicated by 2Hab /lambda=3.5 (> >1), exhibits a higher energy and more symmetrical IV band. As rare examples, this pair of MV species shows distinct optical behaviors for MV systems crossing the Class III region. Optical analysis and DFT calculations are carried out to elucidate the transformation from vibronic to electronic vertical transition. PMID- 25504780 TI - Development and Validation of a Short Version of the Supervisory Relationship Questionnaire. AB - The Supervisory Relationship Questionnaire (SRQ) is one of the few theoretically sound and psychometrically valid questionnaires for measuring the SR within clinical supervision. However, its length can make it difficult to use in clinical practice and research. This study aimed to produce a shorter version of the SRQ (the Short Supervisory Relationship Questionnaire: S-SRQ) that retained its reliability and psychometric validity. The SRQ's 67 items were initially reduced using the criteria of external, internal and face validity. Two hundred and three UK trainee clinical psychologists then completed a series of online questionnaires including the S-SRQ and other clinical supervision measures. A Principal Component Analysis identified three components of the S-SRQ: 'safe base', 'reflective education' and 'structure', and an 18-item version was produced. Analyses revealed that the S-SRQ has high internal reliability, adequate test-retest reliability and good convergent, divergent and predictive validity. Participants also rated the S-SRQ as easy to use and potentially helpful for providing feedback on the SR in supervision. The S-SRQ (three subscales, 18 items) is a valid and reliable measure of the SR from the supervisee perspective. The current findings also support aspects of existing models of the SR. The S-SRQ is a promising measure for use in clinical, training and research settings. Copyright (c) 2014 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: The Short Supervisory Relationship Questionnaire (S-SRQ) is a psychometrically reliable and valid 18-item measure of the supervisory relationship based on the SRQ. Clinically, the measure represents a quick and accessible means for supervisees to assess the quality of their supervisory relationship and discuss this with their supervisors. It can also be used in conjunction with the supervisor-completed Supervisory Relationship Measure to support a dyadic discussion about clinical supervision and the supervisory relationship. PMID- 25504782 TI - Isolation and characterization of biologically active venom protein from sea snake Enhydrina schistosa. AB - The present study is designed to investigate the isolation and characterization of biological and biochemical active venom protein from sea snake, Enhydrina schistosa. The highest purification peaks in ion-exchange chromatography on DEAE cellulose column were obtained for fraction numbers 39-49 when eluted with 0.35 0.45 M NaCl. Eighty per cent purity was obtained in the final stage of purification, and a single protein band of about 44 kDa was visualized in SDS polyacrylamide gel under reducing condition. Purified venom protein expressed as haemolytic, cytotoxicity and proteolytic activities with lethal concentration (LC50 ) at 2.0 MUg/mL. Venom protein exhibits enzymatic activity and hydrolyzed casein and gelatin. Gelatinolytic activity was optimal at pH 5-9. In conclusion, the present results suggested that the sea snake venom might be feasible sources for biologically active substances. Thus, this low molecular weight component of the venom protein could be used in potentially serve biological and pharmaceutical aspects. PMID- 25504783 TI - Toxicity assessment of combined fluoroquinolone and tetracycline exposure in zebrafish (Danio rerio). AB - Fluoroquinolones (FQs) and tetracyclines (TCs), the two beta-diketone antibiotics (DKAs), are two frequently detected pollutants in the environment; however, little data are available on their combined toxicity to zebrafish (Danio rerio). This study reports that toxicologic effects of combined DKA (FQs-TCs) exposure on zebrafish were comparable with or slightly less than those of TCs alone, showing that TCs played a major toxicologic role in the mixtures. The effects of FQs, TCs, and DKAs on malformation rates of zebrafish were dose dependent, with EC50 values of 481.3, 16.4, and 135.1 mg/L, respectively. According to the combined effects of DKAs on zebrafish hatching, mortality, and malformation rates, the interaction between FQs and TCs was shown to be antagonistic based on three assessment methods: Toxic Unit, Additional Index, and Mixture Toxic Index. The 1.56 mg/L TC and 9.38 mg/L DKA treatments resulted in higher zebrafish basal swimming rate compared with the control group at 120 hours postfertilization (hpf). in both light and light-to-dark photoperiod experiments. Under conditions of no obvious abnormality in cardiac development, the heart beats were decreased significantly because of DKA exposure, such as decreasing by ~20% at 150 mg/L DKAs. Transmission electron microscopy observation of myocytes from DKA-exposed hearts displayed prominent interruptions and myofibrillar disorganization of the normal parallel alignment of thick and thin filaments, and partial edematous and dissolved membranes of cell nuclear tissues. At 90 mg/L DKAs, the transcriptional levels of the acta1a, myl7, and gle1b genes, related to heart development and skeletal muscle formation, were significantly changed. This is consistent with the swimming behavior and histopathologic results obtained by transmission electron microscopy. In summary, the toxicity of the combined DKAs to zebrafish was comparable with or less than that of TCs alone and had the ability to impair individual behaviors that are of great importance in the assessment of their ecologic fitness. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 736-750, 2016. PMID- 25504785 TI - Mimicking/extracting structure and functions of natural products: synthetic approaches that address unexplored needs in chemical biology. AB - Natural products are often attractive and challenging targets for synthetic chemists, and many have interesting biological activities. However, synthetic chemists need to be more than simply suppliers of compounds to biologists. Therefore, we have been seeking ways to actively apply organic synthetic methods to chemical biology studies of natural products and their activities. In this personal review, I would like to introduce our work on the development of new biologically active compounds inspired by, or extracted from, the structures of natural products, focusing on enhancement of functional activity and specificity and overcoming various drawbacks of the parent natural products. PMID- 25504784 TI - Particle-based optical sensing of intracellular ions at the example of calcium - what are the experimental pitfalls? AB - Colloidal particles with fluorescence read-out are commonly used as sensors for the quantitative determination of ions. Calcium, for example, is a biologically highly relevant ion in signaling, and thus knowledge of its spatio-temporal distribution inside cells would offer important experimental data. However, the use of particle-based intracellular sensors for ion detection is not straightforward. Important associated problems involve delivery and intracellular location of particle-based fluorophores, crosstalk of the fluorescence read-out with pH, and spectral overlap of the emission spectra of different fluorophores. These potential problems are outlined and discussed here with selected experimental examples. Potential solutions are discussed and form a guideline for particle-based intracellular imaging of ions. PMID- 25504787 TI - On the chemistry of ethanol on basic oxides: revising mechanisms and intermediates in the Lebedev and Guerbet reactions. AB - A common way to convert ethanol into chemicals is by upgrading it over oxide catalysts with basic features; this method makes it possible to obtain important chemicals such as 1-butanol (Guerbet reaction) and 1,3-butadiene (Lebedev reaction). Despite their long history in chemistry, the details of the close inter-relationship of these reactions have yet to be discussed properly. Our present study focuses on reactivity tests, in situ diffuse reflectance infrared Fourier transform spectroscopy, MS analysis, and theoretical modeling. We used MgO as a reference catalyst with pure basic features to explore ethanol conversion from its very early stages. Based on the obtained results, we formulate a new mechanistic theory able to explain not only our results but also most of the scientific literature on Lebedev and Guerbet chemistry. This provides a rational description of the intermediates shared by the two reaction pathways as well as an innovative perspective on the catalyst requirements to direct the reaction pathway toward 1-butanol or butadiene. PMID- 25504788 TI - Highly diastereo- and enantioselective palladium-catalyzed [3+2] cycloaddition of vinyl aziridines and alpha,beta-unsaturated ketones. AB - A palladium-catalyzed asymmetric [3+2] cycloaddition reaction of vinylaziridines with alpha,beta-unsaturated ketones, wherein the alkenes have a single activator, is realized in high diastereo- and enantioselectivity, thus affording 3,4 disubstituted pyrrolidines in high yields with excellent ee values. The introduction of a methyl group at C1 of the vinyl group the vinylaziridines greatly improves the stereochemistry of the reaction. A plausible transition state is proposed. PMID- 25504789 TI - Patients' considerations in the decision-making process of initiating disease modifying antirheumatic drugs. AB - OBJECTIVE: To explore what considerations patients have when deciding about disease-modifying antirheumatic drugs (DMARDs) and what information patients need to participate in the decision-making process. METHODS: In-depth face-to-face interviews were conducted with 32 patients with inflammatory arthritis who recently consulted their rheumatologist and discussed initiating DMARDs. RESULTS: Beliefs in the necessity of DMARDs, either for relief of symptoms or prevention of future joint damage, were reasons to initiate DMARDs. Furthermore, trust in the rheumatologist and the health care system was important in this respect. Patients expressed many concerns about initiating DMARDS. These related to the perceived aggressive and harmful nature of DMARDs, potential (or unknown) side effects, influence on fertility and pregnancy, combination with other medicines, time to benefit, and manner of administration. Participants also worried about the future regarding long-term medication use and drug dependency, and if a medicine proved to be ineffective, about the risks of future treatments and running out of options. To decrease uncertainty, participants wanted to be informed about multiple treatment options, both current and future. They not only wanted clinical information but also information on how the medications could affect their daily lives. CONCLUSION: Health education should inform patients about multiple treatment options, for the present as well as for the future. It should enable patients to compare treatments with regard to both clinical aspects as well as possible consequences for their daily lives. PMID- 25504790 TI - Synthesis and characterization of 5-cyanotetrazolide-based ionic liquids. AB - New salts based on imidazolium, pyrrolidinium, phosphonium, guanidinium, and ammonium cations together with the 5-cyanotetrazolide anion [C2 N5 ](-) are reported. Depending on the nature of cation-anion interactions, characterized by XRD, the ionic liquids (ILs) have a low viscosity and are liquid at room temperature or have higher melting temperatures. Thermogravimetric analysis, cyclic voltammetry, viscosimetry, and impedance spectroscopy display a thermal stability up to 230 degrees C, an electrochemical window of 4.5 V, a viscosity of 25 mPa s at 20 degrees C, and an ionic conductivity of 5.4 mS cm(-1) at 20 degrees C for the IL 1-butyl-1-methylpyrrolidinium 5-cyanotetrazolide [BMPyr][C2 N5 ]. On the basis of these results, the synthesized compounds are promising electrolytes for lithium-ion batteries. PMID- 25504791 TI - Mathematical and computational evolutionary biology (2013). PMID- 25504792 TI - Erratum. PMID- 25504797 TI - Regulation of cancer-related pathways by protein NEDDylation and strategies for the use of NEDD8 inhibitors in the clinic. AB - Post-translational modification of proteins with ubiquitin and ubiquitin-like molecules (UBLs) controls a vast if not every biological process in the cell. It is not surprising that deregulation in ubiquitin and UBL signalling has been implicated in the pathogenesis of many diseases and that these pathways are considered as major targets for therapeutic intervention. In this review, we summarise recent advances in our understanding of the role of the UBL neural precursor cell expressed developmentally downregulated-8 (NEDD8) in cancer related processes and potential strategies for the use of NEDD8 inhibitors as chemotherapeutics. PMID- 25504798 TI - Relationship of serum testosterone levels with cognitive function in chronic antipsychotic-treated male patients with schizophrenia. AB - INTRODUCTION: Some evidence suggests that testosterone might be involved in the cognitive impairments of schizophrenia. We assessed major cognitive domains and serum testosterone levels in male long-term inpatients with schizophrenia. This study aimed to test whether testosterone in serum was abnormal in patients, and whether it was related to the cognitive impairment of schizophrenia. METHODS: Serum testosterone levels in male schizophrenics (n = 80) and normal controls (n = 40) were measured by immunoassay. All patients were assessed for performance on executive functions, sustaining and focusing of attention, memory functions, and verbal fluency using the Digit Cancellation Test (DCT), Semantic Fluency Test, Spatial Span (SS), Trail Making Test, part A (TMT-A), Block Design, and Paced Auditory Serial Addition Test. RESULTS: Serum testosterone levels in schizophrenic patients were similar to control subjects (P > 0.05). We found that serum testosterone levels were significantly correlated with total time taken (in seconds) in the DCT (r = 0.261, P < 0.05) and SS score (r = -0.240, P < 0.05) in schizophrenic patients. Moreover, backward linear regression revealed that testosterone levels significantly predicted performance in DCT (beta = 0.240, P = 0.028) and SS score (beta = -0.207, P = 0.047) in patients. DISCUSSION: Our findings suggest that there is no significant difference in serum testosterone levels between groups, and that serum testosterone levels are associated with the spatial memory and attention deficits in chronic antipsychotic-treated male patients with schizophrenia. PMID- 25504799 TI - Therapeutic potential of cannabinoids in counteracting chemotherapy-induced adverse effects: an exploratory review. AB - Cannabinoids (the active constituents of Cannabis sativa) and their derivatives have got intense attention during recent years because of their extensive pharmacological properties. Cannabinoids first developed as successful agents for alleviating chemotherapy associated nausea and vomiting. Recent investigations revealed that cannabinoids have a wide range of therapeutic effects such as appetite stimulation, inhibition of nausea and emesis, suppression of chemotherapy or radiotherapy-associated bone loss, chemotherapy-induced nephrotoxicity and cardiotoxicity, pain relief, mood amelioration, and last but not the least relief from insomnia. In this exploratory review, we scrutinize the potential of cannabinoids to counteract chemotherapy-induced side effects. Moreover, some novel and yet important pharmacological aspects of cannabinoids such as antitumoral effects will be discussed. PMID- 25504800 TI - Macrophage polarization alters the expression and sulfation pattern of glycosaminoglycans. AB - Macrophages are major cells of inflammatory process and take part in a large number of physiological and pathological processes. According to tissue environment, they can polarize into pro-inflammatory (M1) or alternative (M2) cells. Although many evidences have hinted to a potential role of cell-surface glycosaminoglycans (GAGs) in the functions of macrophages, the effect of M1 or M2 polarization on the biosynthesis of these polysaccharides has not been investigated so far. GAGs are composed of repeat sulfated disaccharide units. Heparan (HS) and chondroitin/dermatan sulfates (CS/DS) are the major GAGs expressed at the cell membrane. They are involved in numerous biological processes, which rely on their ability to selectively interact with a large panel of proteins. More than 20 genes encoding sulfotransferases have been implicated in HS and CS/DS biosynthesis, and the functional repertoire of HS and CS/DS has been related to the expression of these isoenzymes. In this study, we analyzed the expression of sulfotransferases as a response to macrophage polarization. We found that M1 and M2 activation drastically modified the profiles of expression of numerous HS and CS/DS sulfotransferases. This was accompanied by the expression of GAGs with distinct structural features. We then demonstrated that GAGs of M2 macrophages were efficient to present fibroblast growth factor-2 in an assay of tumor cell proliferation, thus indicating that changes in GAG structure may contribute to the functions of polarized macrophages. Altogether, our findings suggest a regulatory mechanism in which fine modifications in GAG biosynthesis may participate to the plasticity of macrophage functions. PMID- 25504801 TI - Atomic-resolution structure of the alpha-galactosyl binding Lyophyllum decastes lectin reveals a new protein family found in both fungi and plants. AB - The crystal structure of the alpha-galactosyl binding Lyophyllum decastes lectin (LDL) was determined to 1.0 A resolution by sulfur single-wavelength anomalous diffraction (SAD). The 10 kDa protein exhibits no sequence similarity to any protein with known structure and adopts a unique lectin fold, where a core of two antiparallel beta-sheets at the heart of the homodimer is connected to the periphery of the structure by intramolecular disulfide bridges. This fold suggests that LDL is secreted, which sets it apart from other mushroom lectins. Structures of complexes between LDL and the ligands alpha-methylgalactoside and globotriose shed light on the binding specificity. Sequence comparison suggests a location and function of LDL and homologous proteins in or at the fungal cell wall. Structural comparison allows the identification of a superfamily of secreted proteins with the LDL fold, which may play a role at the interface between fungi and their environment. PMID- 25504802 TI - Baseline Patient Characteristics Predicting Outcome and Attrition in Cognitive Therapy for Social Phobia: Results from a Large Multicentre Trial. AB - We examined the role of baseline patient characteristics as predictors of outcome (end-state functioning, response and remission) and attrition for cognitive therapy (CT) in social anxiety disorder (SAD). Beyond socio-demographic and clinical variables such as symptom severity and comorbidity status, previously neglected patient characteristics (e.g., personality, self-esteem, shame, interpersonal problems and attachment style) were analysed. METHOD: Data came from the CT arm of a multicentre RCT with n = 244 patients having DSM-IV SAD. CT was conducted according to the manual by Clark and Wells. Severity of SAD was assessed at baseline and end of treatment with the Liebowitz Social Anxiety Scale (LSAS). Multiple linear regression analyses and logistic regression analyses were applied. RESULTS: Up to 37% of the post-treatment variance (LSAS) could be explained by all pre-treatment variables combined. Symptom severity (baseline LSAS) was consistently negatively associated with end-state functioning and remission, but not with response. Number of comorbid diagnoses was negatively associated with end-state functioning and response, but not with remission. Self esteem was positively associated with higher end-state functioning and more shame with better response. Attrition could not be significantly predicted. CONCLUSIONS: The results indicate that the initial probability for treatment success mainly depends on severity of disorder and comorbid conditions while other psychological variables are of minor importance, at least on a nomothetic level. This stands in contrast with efforts to arrive at an empirical-based foundation for differential indication and argues to search for more potent moderators of therapeutic change rather on the process level. KEY PRACTITIONER MESSAGE: Personality, self-esteem, shame, attachment style and interpersonal problems do not or only marginally moderate the effects of interventions in CT of social phobia. Symptom severity and comorbid diagnoses might affect treatment outcome negatively. Beyond these two factors, most patients share a similar likelihood of treatment success when treated according to the manual by Clark and Wells. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25504803 TI - Hydrophobic, electrostatic, and dynamic polymer forces at silicone surfaces modified with long-chain bolaform surfactants. AB - Surfactant self-assembly on surfaces is an effective way to tailor the complex forces at and between hydrophobic-water interfaces. Here, the range of structures and forces that are possible at surfactant-adsorbed hydrophobic surfaces are demonstrated: certain long-chain bolaform surfactants-containing a polydimethylsiloxane (PDMS) mid-block domain and two cationic alpha, omega quarternary ammonium end-groups-readily adsorb onto thin PDMS films and form dynamically fluctuating nanostructures. Through measurements with the surface forces apparatus (SFA), it is found that these soft protruding nanostructures display polymer-like exploration behavior at the PDMS surface and give rise to a long-ranged, temperature- and rate-dependent attractive bridging force (not due to viscous forces) on approach to a hydrophilic bare mica surface. Coulombic interactions between the cationic surfactant end-groups and negatively-charged mica result in a rate-dependent polymer bridging force during separation as the hydrophobic surfactant mid-blocks are pulled out from the PDMS interface, yielding strong adhesion energies. Thus, (i) the versatile array of surfactant structures that may form at hydrophobic surfaces is highlighted, (ii) the need to consider the interaction dynamics of such self-assembled polymer layers is emphasized, and (iii) it is shown that long-chain surfactants can promote robust adhesion in aqueous solutions. PMID- 25504804 TI - Lilium compounds kaempferol and jatropham can modulate cytotoxic and genotoxic effects of radiomimetic zeocin in plants and human lymphocytes In vitro. AB - Organisms are constantly exposed to the detrimental effect of environmental DNA damaging agents. The harmful effects of environmental genotoxins could be decreased in a viable way by antimutagenesis. One of the modern approaches to reduce the mutagenic burden is based on exogenous natural and synthetic compounds that possess protective and antimutagenic potential against genotoxins. The natural compounds kaempferol and jatropham isolated from Lilium candidum were tested with respect to their potential to protect cells against the radiomimetic zeocin, as well as to their cytotoxic and genotoxic activities in two types of experimental eukaryotic test systems: Hordeum vulgare and human lymphocytes in vitro. Mitotic index (MI) was used as an endpoint for cytotoxicity; the frequency of chromosome aberrations (MwA) and the number of induced micronuclei (MN), as endpoints for genotoxicity/clastogenicity. Formation of aberration "hot spots" was also used as an indicator for genotoxicity in H. vulgare. Both kaempferol and jatropham were shown to possess a potential to modulate and decrease the cytotoxic and genotoxic/clastogenic effect of zeocin depending on the experimental design and the test system. Our data could be useful for health research programs, particularly in clarifying the pharmacological potential and activity of natural plant compounds. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 751-764, 2016. PMID- 25504805 TI - NaCS-PDMDAAC immobilized cultivation of recombinant Dictyostelium discoideum for soluble human Fas ligand production. AB - Dictyostelium discoideum is a promising eukaryotic host for the expression of heterologous proteins requiring post-translational modifications. However, the dilute nature of D. discoideum cell culture limits applications for high value proteins production. D. discoideum cells, entrapped in sodium cellulose sulfate/poly-dimethyl-diallyl-ammonium chloride (NaCS-PDMDAAC) capsules were used for biosynthesis of the heterologous protein, soluble human Fas ligand (hFasL). Semi-continuous cultivations with capsules recycling were carried out in shake flasks. Also, a scaled-up cultivation of immobilized D. discoideum for hFasL production in a customized vitreous airlift bioreactor was conducted. The results show that NaCS-PDMDAAC capsules have desirable biophysical properties including biocompatibility with the D. discoideum cells and good mechanical stability throughout the duration of cultivation. A maximum cell density of 2.02 * 10(7) cells mL(-1) (equivalent to a maximum cell density of 2.22 * 10(8) cells mL(-1) in capsules) and a hFasL concentration of 130.40 MUg L(-1) (equivalent to a hFasL concentration of 1434.40 MUg L(-1) in capsules) were obtained in shake flask cultivation with capsules recycling. Also, a maximum cell density of 1.72 * 10(7) cells mL(-1) (equivalent to a maximum cell density of 1.89 * 10(8) cells mL(-1) in capsules) and a hFasL concentration of 106.10 MUg L(-1) (equivalent to a hFasL concentration of 1167.10 MUg L(-1) in capsules) were obtained after ~170 h cultivation in the airlift bioreactor (with a working volume of 200 mL in a 315 mL bioreactor). As the article presents a premier work in the application of NaCS PDMDAAC immobilized D. discoideum cells for the production of hFasL, more work is required to further optimize the system to generate higher cell densities and hFasL titers for large-scale applications. PMID- 25504806 TI - Electrifying white biotechnology: engineering and economic potential of electricity-driven bio-production. AB - The production of fuels and chemicals by electricity-driven bio-production (i.e., using electric energy to drive biosynthesis) holds great promises. However, this electrification of white biotechnology is particularly challenging to achieve because of the different optimal operating conditions of electrochemical and biochemical reactions. In this article, we address the technical parameters and obstacles to be taken into account when engineering microbial bioelectrochemical systems (BES) for bio-production. In addition, BES-based bio-production processes reported in the literature are compared against industrial needs showing that a still large gap has to be closed. Finally, the feasibility of BES bio-production is analysed based on bulk electricity prices. Using the example of lysine production from sucrose, we demonstrate that there is a realistic market potential as cost savings of 8.4 % (in EU) and 18.0 % (in US) could be anticipated, if the necessary yields can be obtained. PMID- 25504807 TI - A hierarchical tin/carbon composite as an anode for lithium-ion batteries with a long cycle life. AB - Tin is a promising anode candidate for next-generation lithium-ion batteries with a high energy density, but suffers from the huge volume change (ca. 260 %) upon lithiation. To address this issue, here we report a new hierarchical tin/carbon composite in which some of the nanosized Sn particles are anchored on the tips of carbon nanotubes (CNTs) that are rooted on the exterior surfaces of micro-sized hollow carbon cubes while other Sn nanoparticles are encapsulated in hollow carbon cubes. Such a hierarchical structure possesses a robust framework with rich voids, which allows Sn to alleviate its mechanical strain without forming cracks and pulverization upon lithiation/de-lithiation. As a result, the Sn/C composite exhibits an excellent cyclic performance, namely, retaining a capacity of 537 mAh g(-1) for around 1000 cycles without obvious decay at a high current density of 3000 mA g(-1) . PMID- 25504808 TI - Dibenzosiloles and 12H-indololo[3,2-d]naphtho[1,2-b][1]siloles: exploration of organic chromophores exhibiting efficient solid-state fluorescence. AB - The construction of a diorganosilylene bridge over a biaryl moiety at the 2,2' positions is a versatile strategy for fine-tuning its HOMO-LUMO energy gap, which is closely linked to the electronic and optical properties of the compounds. Therefore, there is growing interest in the use of silicon-bridged biaryl motifs as key cores of various types of advanced functional materials, such as light emitting, semiconducting, photovoltaic, and sensing materials. To accelerate the advances of materials based on silicon-bridged biaryls, it is essential to create new classes of biaryls and explore their functions and properties. This Personal Account describes recent research on the development of organic chromophores based on functionalized dibenzosiloles and 12H-indololo[3,2-d]naphtho[1,2 b][1]siloles as solid-state emitters. PMID- 25504810 TI - Nanorattles or yolk-shell nanoparticles--what are they, how are they made, and what are they good for? AB - The development of nanotechnology has led to the design of cutting-edge nanomaterials with increasing levels of complexity. Although "traditional" solid, uniform nanoparticles are still the most frequently reported structures, new generations of nanoparticles have been constantly emerging over the last several decades. The outcome of this nano-art extends beyond nanomaterials with alternative compositions and/or morphologies. The current state-of-the-art allows for the design of nanostructures composed of different building blocks that exhibit diverse properties. Furthermore, those properties can be a reflection of either individual features, which are characteristic of a particular building block alone, and/or synergistic effects resulting from interactions between building blocks. Therefore, the unique structures as well as the outstanding properties of nanorattles have attracted increasing attention for possible biomedical and industrial applications. Although these nanoparticles resemble core-shell particles, they have a distinctive feature, which is a presence of a void that provides a homogenous environment for the encapsulated core. In this Review, we give a comprehensive insight into the fabrication of nanorattles. A special emphasis is put on the choice of building blocks as well as the choice of preparation method, because those two aspects further influence properties and thus possible future applications, which will also be discussed. PMID- 25504809 TI - In vivo measurement of localized tibiofemoral cartilage strains in response to dynamic activity. AB - BACKGROUND: Altered local mechanical loading may disrupt normal cartilage homeostasis and play a role in the progression of osteoarthritis. Currently, there are limited data quantifying local cartilage strains in response to dynamic activity in normal or injured knees. PURPOSE/HYPOTHESIS: To directly measure local tibiofemoral cartilage strains in response to a dynamic hopping activity in normal healthy knees. We hypothesized that local regions of cartilage will exhibit significant compressive strains in response to hopping, while overall compartmental averages may not. STUDY DESIGN: Controlled laboratory study. METHODS: Both knees of 8 healthy subjects underwent magnetic resonance imaging before and immediately after a dynamic hopping activity. Images were segmented and then used to create 3-dimensional surface models of bone and cartilage. These pre- and postactivity models were then registered using an iterative closest point technique to enable site-specific measurements of cartilage strain (defined as the normalized change in cartilage thickness before and after activity) on the femur and tibia. RESULTS: Significant strains were observed in both the medial and lateral tibial cartilage, with each compartment averaging a decrease of 5%. However, these strains varied with location within each compartment, reaching a maximum compressive strain of 8% on the medial plateau and 7% on the lateral plateau. No significant averaged compartmental strains were observed in the medial or lateral femoral cartilage. However, local regions of the medial and lateral femoral cartilage experienced significant compressive strains, reaching maximums of 6% and 3%, respectively. CONCLUSION: Local regions of both the femur and tibia experienced significant cartilage strains as a result of dynamic activity. An understanding of changes in cartilage strain distributions may help to elucidate the biomechanical factors contributing to cartilage degeneration after joint injury. CLINICAL RELEVANCE: Site-specific measurements of in vivo cartilage strains are important because altered loading is believed to be a factor contributing to the development and progression of osteoarthritis. Specifically, this methodology and data could be used to evaluate the effects of soft tissue injuries (such as ligament or meniscus tears) on cartilage strains in response to dynamic activities of daily living. PMID- 25504811 TI - Contribution of the subjective components of the disease activity score to the response to biologic treatment in rheumatoid arthritis. AB - OBJECTIVE: A significant proportion of patients with rheumatoid arthritis do not respond adequately to biologic treatment. We hypothesized that lack of response to (biologic) disease-modifying antirheumatic drugs (DMARDs) is high in patients in whom the subjective, patient-reported component of the Disease Activity Score 28 (DAS28) is high at baseline. The primary aim of our present study was to investigate the contribution of the more subjective versus the objective components of the DAS28 to response to biologic agents in RA patients, as well as the changes in this contribution over time. The secondary aim was to examine whether the value of this subjective contribution at baseline affects the response to treatment. METHODS: The DAS28-P (the subjective components of the DAS28 relative to the total DAS28) was calculated. Patients were derived from the computer-assisted Management in Early Rheumatoid Arthritis Trial-II and the Biologicals and Outcome Compared and Predicted in Utrecht Region in Rheumatoid Arthritis Study. Ordinal logistic regression analyses were performed. RESULTS: The DAS28-P score at baseline was not associated with the level of response according to European League Against Rheumatism criteria at 3 months. Overall, a significant reduction in the DAS28-P score was observed 3 months after start of treatment, showing a greater reduction of the combined subjective components in good responders. CONCLUSION: The results reject the hypothesis that the lack of response to biologic DMARDs is especially high in patients in whom the patient reported component of the DAS28 is high at baseline; these subjective components are not linked to treatment response. PMID- 25504812 TI - Association between DRD2 (rs1799732 and rs1801028) and ANKK1 (rs1800497) polymorphisms and schizophrenia: a meta-analysis. AB - The role of dopamine D2 receptor (DRD2) polymorphisms in schizophrenia remains controversial. We performed a meta-analysis to determine whether DRD2 polymorphisms influence the risk of schizophrenia and examined the relationship between rs1799732, rs1801028, and rs1800rs028 an23381d rs1800497 genetic variants and the etiology of schizophrenia. Relevant case-control studies were retrieved by database searches and selected according to established inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. Meta-regression, subgroup analysis, sensitivity analysis, and cumulative meta-analysis were performed. A total of 76 studies with 16096 cases and 18965 controls were included. Specifically, 24 studies with 6075 cases and 6643 controls involved rs1799732, 36 studies with 8043 cases and 10194 controls involved rs1801028 and 16 studies with 1978 cases and 2128 controls involved rs1800497. No significant associations were observed between rs1799732 and rs1800rs732 and rs1800497 and schizophrenia. The rs1801028 locus was associated with schizophrenia, with a pooled OR of 1.221 (95% CI = 1.037-1.438, P = 0.016). This meta-analysis indicates that the rs1801028 locus may be associated with schizophrenia. These data provide possible references for future case control studies related to schizophrenia. PMID- 25504813 TI - Effect of Korean Red Ginseng as an adjuvant treatment for women with residual symptoms of major depression. AB - INTRODUCTION: Around 20% of patients with major depression experience residual symptoms. Ginseng has shown potential antidepressant effects in some animal studies and in patients with stress-related somatic symptoms. Therefore, we investigated the effectiveness and tolerability of Korean Red Ginseng adjuvant treatment in patients with residual symptoms of major depression. METHODS: In this eight-week prospective study, 35 female outpatients aging from 18 to 65 years (45.1 +/- 9.5), who were remitted from major depression with residual symptoms, were given Korean Red Ginseng at doses of 3 g/day. The Depression Residual Symptom Scale (DRSS) and Montgomery-Asberg Depression Rating Scale (MADRS) were administrated to evaluate depressive symptoms. The general severity of symptoms was assessed by a clinician using the Clinical Global Impressions Scale for Severity (CGI-S). The Depression and Somatic Symptom Scale (DSSS) was also used to evaluate somatic symptoms in the subjects. This trial is registered at Clinical.gov, number NCT01496248. RESULTS: Subjects reported significant decrease in depressive symptoms on the DRSS (P < 0.05) and MADRS (P < 0.01) decreased significantly over the eight-week period. The scores on the CGI-S, an objective measurement of symptoms, showed significant improvement in the severity of illness (P < 0.001). Somatic symptoms on the DSSS also attenuated significantly during the study period (P < 0.05). DISCUSSION: These results suggest that Korean Red Ginseng is efficacious as an adjuvant treatment for patients experiencing residual symptoms of major depression. Future placebo controlled research is required to confirm our results. PMID- 25504814 TI - Anti-allergic effect of intranasal administration of type-A procyanidin polyphenols based standardized extract of cinnamon bark in ovalbumin sensitized BALB/c mice. AB - The objective of the present work was to evaluate anti-allergic effects of intranasal administration of type-A procynidines polyphenols (TAPP) based standardized hydroalcoholic extract of Cinnamomum zeylanicum bark (TAPP-CZ) in ovalbumin (OVA)-induced experimental allergic rhinitis (AR) in BALB/c mice. Sixty male BALB/c mice were divided into six groups of ten each (G1-G6). The mice from G1 were nonsensitized and maintained as normal group. Remaining mice (G2-G6) were sensitized with OVA (500 MUL solution, intraperitoneal) on alternate days for 13 days and had twice daily intranasal treatment from day 14-21 as follows: G2 (AR control) received saline, G3 (positive control, XLY) received xylometazoline (0.5 mg/mL, 20 MUL/nostril) and G4-G6 received TAPP-CZ (3, 10 and 30 ug/kg in nostril), respectively. On day 21, mice were challenged with OVA (5 MUL/nostril, 5% solution) and assessments (nasal signs, biochemical and histopathological) were performed. Treatment with TAPP-CZ (10 and 30 ug/kg in nostril) showed significant attenuation in OVA-induced alterations of the nasal (number of nasal rubbing and sneezing), biochemical markers (serum IgE and histamine), haematological, morphological (relative organ weight of spleen and lung) and histopathological (nasal mucosa and spleen) parameters. In conclusion, TAPP-CZ showed anti-allergic efficacy in animal model of AR. PMID- 25504815 TI - Type II intramolecular [5+2] cycloaddition: facile synthesis of highly functionalized bridged ring systems. AB - A type II intramolecular oxidopyrylium-mediated [5+2] cycloaddition reaction allows the efficient and diastereoselective formation of various highly functionalized and synthetically challenging bridged seven-membered ring systems (such as bicyclo[4.4.1]undecane, bicyclo[4.3.1]decane, bicyclo[5.4.1]dodecane, and bicyclo[6.4.1]]tridecane). This simple, thermal, direct transformation has a broad substrate scope and is high yielding, with high functional-group tolerance and unique endo selectivity. The highly strained tricyclic cores of ingenol mebutate (picato) and cyclocitrinol are synthesized efficiently and diastereoselectively using this methodology. PMID- 25504816 TI - 1D copper nanostructures: progress, challenges and opportunities. AB - One-dimensional noble metal nanostructures are important components in modern nanoscience and nanotechnology due to their unique optical, electrical, mechanical, and thermal properties. However, their cost and scalability may become a major bottleneck for real-world applications. Copper, being an earth abundant metallic element, is an ideal candidate for commercial applications. It is critical to develop technologies to produce 1D copper nanostructures with high monodispersity, stability and oxygen-resistance for future low-cost nano-enabled materials and devices. This article covers comprehensively the current progress in 1D copper nanostructures, most predominantly nanorods and nanowires. First, various synthetic methodologies developed so far to generate 1D copper nanostructures are thoroughly described; the methodologies are in conjunction with the discussion of microscopic, spectrophotometric, crystallographic and morphological characterizations. Next, striking electrical, optical, mechanical and thermal properties of 1D copper nanostructures are highlighted. Additionally, the emerging applications of 1D copper nanostructures in flexible electronics, transparent electrodes, low cost solar cells, field emission devices are covered, amongst others. Finally, there is a brief discussion of the remaining challenges and opportunities. PMID- 25504817 TI - The biotechnological potential of subtilisin-like fibrinolytic enzyme from a newly isolated Lactobacillus plantarum KSK-II in blood destaining and antimicrobials. AB - An antimicrobial oxidative- and SDS-stable fibrinolytic alkaline protease designated as KSK-II was produced by Lactobacillus plantarum KSK-II isolated from kishk, a traditional Egyptian food. Maximum enzyme productivity was obtained in medium containing 1% lactose and 0.5% soybean flour as carbon and nitrogen sources, respectively. Purification of enzyme increased its specific activity to 1,140-fold with a recovery of 33% and molecular weight of 43.6 kDa. Enzyme activity was totally lost in the presence of ethylenediaminetetraacetic acid and was restored after addition of Fe(2+) suggesting that KSK-II is a metalloprotease and Fe(2+) acts as cofactor. Enzyme hydrolyzed not only the natural proteins but also synthetic substrates, particularly Suc-Ala-Ala-Pro-Phe-pNA. KSK-II can hydrolyze the Lys-X easier than Arg-X; thus, it was considered as a subtilisin family protease. Its apparent Km , Vmax , and Kcat were 0.41 mM, 6.4 umol mg(-1) min(-1) , and 28.0 s(-1) , respectively. KSK-II is industrially important from the perspectives of its maximal activity at 50 degrees C (stable up to 70 degrees C), ability to function at alkaline pH (10.0), stability at broad pH ranges (7.5 12.0) in addition to its stability toward SDS, H2 O2 , organic solvents, and detergents. We emphasize for the first time the potential of fibrinolytic activity for alkaline proteases used in detergents especially in blood destaining. PMID- 25504818 TI - Electrolytes based on TEMPO-Co tandem redox systems outperform single redox systems in dye-sensitized solar cells. AB - A new TEMPO-Co tandem redox system with TEMPO and Co(bpy)3 (2+/3+) has been investigated for the use in dye-sensitized solar cells (DSSCs). A large open circuit voltage (VOC ) increase, from 862 mV to 965 mV, was observed in the tandem redox system, while the short-circuit current density (JSC ) was maintained. The conversion efficiency was observed to increase from 7.1 % for cells containing the single Co(bpy)3 (2+/3+) redox couple, to 8.4 % for cells containing the TEMPO-Co tandem redox system. The reason for the increase in VOC and overall efficiency is ascribed to the involvement of partial regeneration of the sensitizing dye molecules by TEMPO. This assumption can be verified through the observed much faster regeneration dynamics exhibited in the presence of the tandem system. Using the tandem redox system, the faster recombination problem of the single TEMPO redox couple is resolved and the mass-transport of the metal complex-based electrolyte is also improved. This TEMPO-Co tandem system is so far the most efficient tandem redox electrolyte reported not involving iodine. The current results show a promising future for tandem system as replacements for single redox systems in electrolytes for DSSCs. PMID- 25504819 TI - Ionic liquids as precursors for efficient mesoporous iron-nitrogen-doped oxygen reduction electrocatalysts. AB - A ferrocene-based ionic liquid (Fe-IL) is used as a metal-containing feedstock with a nitrogen-enriched ionic liquid (N-IL) as a compatible nitrogen content modulator to prepare a novel type of non-precious-metal-nitrogen-carbon (M-N-C) catalysts, which feature ordered mesoporous structure consisting of uniform iron oxide nanoparticles embedded into N-enriched carbons. The catalyst Fe(10) @NOMC exhibits comparable catalytic activity but superior long-term stability to 20 wt % Pt/C for ORR with four-electron transfer pathway under alkaline conditions. Such outstanding catalytic performance is ascribed to the populated Fe (Fe3 O4 ) and N (N2) active sites with synergetic chemical coupling as well as the ordered mesoporous structure and high surface area endowed by both the versatile precursors and the synthetic strategy, which also open new avenues for the development of M-N-C catalytic materials. PMID- 25504820 TI - Cleft palate: a clinical review. AB - Orofacial clefts, including cleft palates (CP), are one of the most common birth defects. CP have a multiplicity of effects on the individual and society in terms of economic costs, loss of productivity, psychosocial effects, and increased morbidity and mortality at all stages of life. Embryological development of the palate is well delineated, with developments in the last decade regarding the biomolecular processes involved. Etiology is complex, involving a number of genetic and environmental factors. Various techniques can be employed for the repair of CP, depending on whether the cleft is of the primary or secondary palate, the width of the cleft, whether lengthening of the palate is necessary, and with regard to concerns of disruption of midfacial growth. All surgical techniques have the goals of restoring functional speech, swallowing, and aesthetics. A multidisciplinary team is necessary for the long-term pre- and postoperative care of CP patients to handle complications, associated anomalies, and to optimize function and quality of life. PMID- 25504821 TI - Plasmon-coupled gold nanospheres for two-photon imaging and photoantibacterial activity. AB - Positively charged Au nanospheres are found to form aggregates on the bacterial surface, resulting in significantly enhanced two-photon photoluminescence (TPPL). The enhanced TPPL is successfully utilized to image bacterial cells in the NIR region. In addition, these Au nanospheres effectively eradicate the bacterial cells by laser pulses in the same NIR region due to the photothermal effect. PMID- 25504822 TI - Strongly phosphorescent neutral rhenium(i) isocyanoborato complexes: synthesis, characterization, and photophysical, electrochemical, and computational studies. AB - A new series of neutral isocyanoborato rhenium(I) diimine complexes [Re(CO)3 (N^N)(CNBR3 )], where N^N=bpy, 4,4'-Me2 bpy, phen, 4,7-Me2 phen, 2,9-Me2 phen, 3,4,7,8-Me4 phen; R=C6 F5 , C6 H5 , Cl, 4-ClC6 H4 , 3,5-(CF3 )2 C6 H3 , with various isocyanoborate and diimine ligands of diverse electronic and steric nature have been synthesized and characterized. The X-ray crystal structures of six complexes have also been determined. These complexes displayed intense bluish green to yellow phosphorescence at room temperature in dichloromethane solution. The photophysical and electrochemical properties of these complexes had been investigated. To elucidate the electronic structures and transitions of these complexes, DFT and TD-DFT calculations have been performed, which revealed that the lowest-energy electronic transition associated with these complexes originates from a mixture of MLCT [dpi(Re)->pi*(N^N)] and LLCT [pi(CNBR3 ) >pi*(N^N)] transitions. PMID- 25504823 TI - Comparison of noncontrast MRI magnetization transfer and T2 -Weighted signal intensity ratios for detection of bowel wall fibrosis in a Crohn's disease animal model. AB - PURPOSE: To compare the abilities of magnetization transfer magnetic resonance imaging (MT-MRI) and T2 -weighted signal intensity (T2 WSI) ratios to detect intestinal fibrosis in a Crohn's disease animal model. MATERIALS AND METHODS: Ten rats ("Group 1") received one trinitrobenzenesulfonic acid enema to induce acute colonic inflammation, while 10 additional animals ("Group 2") received multiple enemas to induce colonic inflammation and fibrosis. Gradient recalled-echo MT-MRI (5 and 10 kHz off-resonance) and T2 -weighted spin-echo imaging were performed 2 days after the last enema. MT ratios (MTR) and T2 WSI ratios were calculated in the area of greatest colonic thickening. Bowel wall MTR, bowel wall MTR normalized to paraspinous muscle MTR ("normalized MTR"), and T2 WSI ratios were compared between animal groups using Student's t-test. RESULTS: At 10 kHz off resonance, mean bowel wall MTR for Group 1 was 24.8 +/- 3.1% vs. 30.3 +/- 3.2% for Group 2 (P = 0.001). Mean normalized MTR was 0.45 +/- 0.05 for Group 1 and 0.58 +/- 0.08 for Group 2 (P = 0.0003). At 5 kHz off-resonance, mean bowel wall MTR for Group 1 was 34.7 +/- 5.2% vs. 40.3 +/- 3.6% for Group 2 (P = 0.015). Mean normalized MTR was 0.53 +/- 0.08 for Group 1 and 0.64 +/- 0.07 for Group 2 (P = 0.003). Mean T2 WSI ratio was 5.32 +/- 0.98 for Group 1 and 3.01 +/- 0.66 for group 2 (P < 0.0001). Mean T2 WSI ratio/MTR (10 kHz off-resonance) was 12.06 +/- 2.70 for Group 1 and 5.22 +/- 1.29 for Group 2 (P < 0.0001), with an ROC c statistic of 0.98. CONCLUSION: MTR and T2 WSI ratios detect bowel wall fibrosis in a Crohn's disease animal model. PMID- 25504824 TI - Research in progress-electronic patient records: a new era. AB - Clinical information systems and electronic records are starting to appear in secondary care and herald new potentials for improving health provision and capturing high quality data. In 2006, we set up a program to develop electronic patient records (EPR) for chronic disease using Cystic Fibrosis (CF) as our initial model. Seven years on we are now exploring the real time clinical data to identify risks, trends and outcomes in chronic disease management. We are also working to establish new models of integration and to connect information between the client and all areas of health care. PMID- 25504826 TI - In place of fear: aligning health care planning with system objectives to achieve financial sustainability. AB - The financial sustainability of publicly funded health care systems is a challenge to policymakers in many countries as health care absorbs an ever increasing share of both national wealth and government spending. New technology, aging populations and increasing public expectations of the health care system are often cited as reasons why health care systems need ever increasing funding as well as reasons why universal and comprehensive public systems are unsustainable. However, increases in health care spending are not usually linked to corresponding increases in need for care within populations. Attempts to promote financial sustainability of systems such as limiting the range of services is covered or the groups of population covered may compromise their political sustainability as some groups are left to seek private cover for some or all services. In this paper, an alternative view of financial sustainability is presented which identifies the failure of planning and management of health care to reflect needs for care in populations and to integrate planning and management functions for health care expenditure, health care services and the health care workforce. We present a Health Care Sustainability Framework based on disaggregating the health care expenditure into separate planning components. Unlike other approaches to planning health care expenditure, this framework explicitly incorporates population health needs as a determinant of health care requirements, and provides a diagnostic tool for understanding the sources of expenditure increase. PMID- 25504827 TI - Development of key indicators of hospital resilience: a modified Delphi study. AB - OBJECTIVES: Hospital resilience is an emerging concept, which can be defined as 'a hospital's ability to resist, absorb, and respond to the shock of disasters while maintaining its critical health care functions, and then recover to its original state or adapt to a new one'. Our aim was to develop a comprehensive framework of key indicators of hospital resilience. METHODS: A panel of 33 Chinese experts was invited to participate in a three-round, modified Delphi study to develop a set of potential measures previously derived from a literature review. In the first round, these potential measures were modified to cover the comprehensive domains of hospital resilience. The importance of proposed measures was scored by experts on a five-point Likert scale. Subsequently, the experts reconsidered their voting in light of the previous aggregated results. Agreement on measures was defined as at least 70% of the responders agreeing or strongly agreeing to the inclusion of a measure. RESULTS: A large proportion of preliminary measures (89.5%) were identified as having good potential for assessing hospital resilience. These measures were categorized into eight domains, 17 subdomains, and 43 indicators. The highest rated indicators (mean score) were: equipment for on-site rescue (4.7), plan initiation (4.6), equipment for referral of patients with complex care needs (4.5), the plan execution (4.4), medication management strategies (4.4), emergency medical treatment conditions (4.4), disaster committee (4.4), stock types and quantities for essential medications (4.4), surge capacity of emergency beds (4.4), and mass-casualty triage protocols (4.4). CONCLUSIONS: This framework identifies a comprehensive set of indicators of hospital resilience. It can be used for hospital assessment, as well as informing priority practices to address future disasters better. PMID- 25504825 TI - Complexity and challenges in defining myeloid-derived suppressor cells. AB - Study of myeloid cells endowed with suppressive activity is an active field of research which has particular importance in cancer, in view of the negative regulatory capacity of these cells to the host's immune response. The expansion of these cells, called myeloid-derived suppressor cells (MDSCs), has been documented in many models of tumor-bearing mice and in patients with tumors of various origin, and their presence is associated with disease progression and reduced survival. For this reason, monitoring this type of cell expansion is of clinical importance, and flow cytometry is the technique of choice for their identification. Over the years, it has been demonstrated that MDSCs comprise a group of immature myeloid cells belonging both to monocytic and granulocytic lineages, with several stages of differentiation; their occurrence depends on tumor-derived soluble factors, which guide their expansion and determine their block of differentiation. Because of their heterogeneous composition, accurate phenotyping of these cells requires a multicolor approach, so that the expansion of all MDSC subsets can be appreciated. This review article focuses on identifying MDSCs and discusses problems associated with phenotyping circulating and tumor-associated MDSCs in humans and in mouse models. PMID- 25504829 TI - Obesity and symptoms of depression among adults in selected countries of the Middle East: a systematic review and meta-analysis. AB - Although obesity has been widely recognized for its consequences on physical health, its psychological burden in the adult populations in the Middle East remains unclear. This meta-analysis synthesized data from observational studies to investigate the association between obesity and depression among adult populations in Middle Eastern countries. Five bibliographical electronic databases were searched for studies published up to April 2014. Pooled meta analytic estimates were derived using the random-effect models. Three case control studies and five cross-sectional studies were identified. Meta-analysis showed significant positive associations between obesity and depression across study designs, with an overall effect of odds ratio 1.27 (95% confidence interval 1.11-1.44). The association between obesity and depression was more marked in women than men although that difference was not statistically significant. Other subgroup analysis showed that none of the potential factors including the assessment for obesity or depression, confounder control and study quality had a modification effect on the studied association. Meta-analysis of eight observational studies from five countries in the Middle East suggests an evidence of a positive association between obesity and depression among adult populations, which appeared to be more marked among women. Future research should examine the causal pathways between obesity and depression. PMID- 25504828 TI - A combined analytical solution for chemical exchange saturation transfer and semi solid magnetization transfer. AB - Off-resonant RF irradiation in tissue indirectly lowers the water signal by saturation transfer processes: on the one hand, there are selective chemical exchange saturation transfer (CEST) effects originating from exchanging endogenous protons resonating a few parts per million from water; on the other hand, there is the broad semi-solid magnetization transfer (MT) originating from immobile protons associated with the tissue matrix with kilohertz linewidths. Recently it was shown that endogenous CEST contrasts can be strongly affected by the MT background, so corrections are needed to derive accurate estimates of CEST effects. Herein we show that a full analytical solution of the underlying Bloch McConnell equations for both MT and CEST provides insights into their interaction and suggests a simple means to isolate their effects. The presented analytical solution, based on the eigenspace solution of the Bloch-McConnell equations, extends previous treatments by allowing arbitrary lineshapes for the semi-solid MT effects and simultaneously describing multiple CEST pools in the presence of a large MT pool for arbitrary irradiation. The structure of the model indicates that semi-solid MT and CEST effects basically add up inversely in determining the steady-state Z-spectrum, as previously shown for direct saturation and CEST effects. Implications for existing previous CEST analyses in the presence of a semi-solid MT are studied and discussed. It turns out that, to accurately quantify CEST contrast, a good reference Z-value, the observed longitudinal relaxation rate of water, and the semi-solid MT pool size fraction must all be known. PMID- 25504830 TI - Human herpes virus-8-associated multicentric Castleman's disease in an HIV positive patient presenting with relapsing and remitting hyponatraemia. AB - We report a case of human herpes virus-8-associated multicentric Castleman's disease in an HIV-positive patient with hyponatraemia. A 65-year-old man was admitted with relapsing and remitting fever, scattered skin eruptions and hepatosplenomegaly following combination antiretroviral therapy for his HIV infection. Based on histopathological findings, he was diagnosed as having human herpes virus-8-associated multicentric Castleman's disease and was treated with four-weekly infusions of rituximab. Prior to receiving chemotherapy, we observed several suspected biomarkers of disease activity, positive correlations between plasma human herpes virus-8 viral load and the levels of plasma interleukin-6, C reactive protein and soluble interleukin-2 receptor, and negative correlations between platelet count, albumin levels and especially serum sodium levels. We hypothesize that non-osmotic release of plasma antidiuretic hormone is a cause of hyponatraemia in human herpes virus-8-associated multicentric Castleman's disease and that relapsing and remitting hyponatraemia could be correlated with plasma human herpes virus-8 viral load. PMID- 25504831 TI - High rates of baseline antiretroviral resistance among HIV-infected pregnant women in an HIV referral centre in Rio de Janeiro, Brazil. AB - In order to understand antiretroviral resistance during pregnancy and its impact on HIV vertical transmission, we performed a cross-sectional analysis of 231 HIV infected pregnant women who fulfilled Brazilian guidelines for antiretroviral testing and had antiretroviral genotypic testing performed between April 2010 and October 2012. At entry into prenatal care, the mean CD4 cell count for this cohort of patients was 406 cells/mm(3) (95% CI: 373-438 cells/mm(3)), while the mean HIV RNA was 24,394 copies/ml (95% CI: 18,275-30,513 copies/ml). Thirty-six women (16%) had detectable antiretroviral-resistant mutations. By 34 weeks gestation, 75% had achieved HIV RNA <400 copies/ml. Our logistic regression model showed the odds of harbouring antiretroviral-resistant virus with a baseline CD4 cell count of <200 cells/mm(3) was eight times that of subjects with CD4 cell counts >500 CD4 cells/mm(3) (95% CI 1.5-42.73). Six infants were HIV infected, four born to mothers with detectable viraemia at 34 weeks and two born to mothers who were lost to follow up. Antiretroviral resistance is common in prenatal care but did not increase vertical transmission if viral load was appropriately suppressed. Genotyping should be considered in Brazil in order to assist initiation of appropriate combination antiretroviral therapy during pregnancy to suppress viral load to avoid vertical transmission. PMID- 25504832 TI - A robust microfluidic device for the synthesis and crystal growth of organometallic polymers with highly organized structures. AB - A simple and robust microfluidic device was developed to synthesize organometallic polymers with highly organized structures. The device is compatible with organic solvents. Reactants are loaded into pairs of reservoirs connected by a 15 cm long microchannel prefilled with solvents, thus allowing long-term counter diffusion for self-assembly of organometallic polymers. The process can be monitored, and the resulting crystalline polymers are harvested without damage. The device was used to synthesize three insoluble silver acetylides as single crystals of X-ray diffraction quality. Importantly, for the first time, the single-crystal structure of silver phenylacetylide was determined. The reported approach may have wide applications, such as crystallization of membrane proteins, synthesis and crystal growth of organic, inorganic, and polymeric coordination compounds, whose single crystals cannot be obtained using traditional methods. PMID- 25504833 TI - Viewing the proteome: how to visualize proteomics data? AB - Proteomics has become one of the main approaches for analyzing and understanding biological systems. Yet similar to other high-throughput analysis methods, the presentation of the large amounts of obtained data in easily interpretable ways remains challenging. In this review, we present an overview of the different ways in which proteomics software supports the visualization and interpretation of proteomics data. The unique challenges and current solutions for visualizing the different aspects of proteomics data, from acquired spectra via protein identification and quantification to pathway analysis, are discussed, and examples of the most useful visualization approaches are highlighted. Finally, we offer our ideas about future directions for proteomics data visualization. PMID- 25504834 TI - Exploring spatiotemporal network transitions in task functional MRI. AB - A critical question for cognitive neuroscience regards how transitions between cognitive states emerge from the dynamic activity of functional brain networks. Here we combine a simple data reorganization with spatial independent component analysis (ICA), enabling a spatiotemporal ICA (stICA) which captures the consistent evolution of networks during the onset and offset of a task. The technique was applied to functional magnetic resonance imaging (MRI) (FMRI) datasets involving alternating between rest and task, and to simple synthetic data. Starting and finishing time-points of periods of interest (anchors) were defined at task block onsets and offsets. For each subject, the 10 volumes following each anchor were extracted and concatenated spatially, producing a single 3D sample. Samples for all anchors and subjects were concatenated along the fourth dimension. This 4D dataset was decomposed using ICA into spatiotemporal components. One component exhibited the transition with task onset from a default mode network (DMN) becoming less active to a frontoparietal control network becoming more active. We observed other changes with relevance to understanding network dynamics, for example, the DMN showed a changing spatial distribution, shifting to an anterior/superior pattern of deactivation during task from a posterior/inferior pattern during rest. By anchoring analyses to periods associated with the onsets and offsets of task, our approach reveals novel aspects of the dynamics of network activity accompanying these transitions. Importantly, these findings were observed without specifying a priori either the spatial networks or the task time courses. PMID- 25504835 TI - Islet inflammation in human type 1 diabetes mellitus. AB - Type 1 diabetes mellitus (T1DM) is caused by the selective deletion of pancreatic beta-cells in response to an assault mounted within the pancreas by infiltrating immune cells. However, this apparently clear and focussed annunciation conceals a stark reality in which the cellular and molecular events leading to beta-cell loss remain poorly understood in humans. This reflects the difficulty of studying these processes in living individuals and the fact that, using pathological specimens, islet inflammation has been analysed in fewer than 200 recent-onset cases of T1DM worldwide, over the past century. Nevertheless, insights have been gained and the composition of the islet infiltrate is being disclosed. This is shown to be primarily lymphocytic in nature, with populations of both CD8+ and CD4+ T cells displaying an autoreactivity against specific islet antigenic peptides. The T cells are often accompanied by influent CD20+ B cells, although new data imply that the proportions of these individual cell types vary and that patients fall into at least two distinct categories having either a hyper-immune (CD20Hi) or a pauci-immune (CD20Lo) phenotype. The overall rate of beta-cell decline appears to correlate with these two phenotypes such that hyper-immune patients lose beta-cells more quickly and tend to develop disease at an earlier age than those with the pauci-immune profile. In this article, we review the evidence which underpins our current understanding of the aetiology of T1DM and highlight both the established features as well as areas of on-going ambiguity and debate. PMID- 25504836 TI - Metabolic regulation of mesenchymal stem cell in expansion and therapeutic application. AB - Human mesenchymal or stromal cells (hMSCs) isolated from various adult tissues are primary candidates in cell therapy and tissue regeneration. Despite promising results in preclinical studies, robust therapeutic responses to MSC treatment have not been reproducibly demonstrated in clinical trials. In the translation of MSC-based therapy to clinical application, studies of MSC metabolism have significant implication in optimizing bioprocessing conditions to obtain therapeutically competent hMSC population for clinical application. In addition, understanding the contribution of metabolic cues in directing hMSC fate also provides avenues to potentiate their therapeutic effects by modulating their metabolic properties. This review focuses on MSC metabolism and discusses their unique metabolic features in the context of common metabolic properties shared by stem cells. Recent advances in the fundamental understanding of MSC metabolic characteristics in relation to their in vivo origin and metabolic regulation during proliferation, lineage-specific differentiation, and exposure to in vivo ischemic conditions are summarized. Metabolic strategies in directing MSC fate to enhance their therapeutic potential in tissue engineering and regenerative medicine are discussed. PMID- 25504837 TI - Tumor-Targeting Multifunctional Rattle-Type Theranostic Nanoparticles for MRI/NIRF Bimodal Imaging and Delivery of Hydrophobic Drugs. AB - The development of theranostic systems capable of diagnosis, therapy, and target specificity is considerably significant for accomplishing personalized medicine. Here, a multifunctional rattle-type nanoparticle (MRTN) as an effective biological bimodal imaging and tumor-targeting delivery system is fabricated, and an enhanced loading ability of hydrophobic anticancer drug (paclitaxel) is also realized. The rattle structure with hydrophobic Fe3 O4 as the inner core and mesoporous silica as the shell is obtained by one-step templates removal process, and the size of interstitial hollow space can be easily adjusted. The Fe3 O4 core with hydrophobic poly(tert-butyl acrylate) (PTBA) chains on the surface is not only used as a magnetic resonance imaging (MRI) agent, but contributes to improving hydrophobic drug loading amount. Transferrin (Tf) and a near-infrared fluorescent dye (Cy 7) are successfully modified on the surface of the nanorattle to increase the ability of near-infrared fluorescence (NIRF) imaging and tumor targeting specificity. In vivo studies show the selective accumulation of MRTN in tumor tissues by Tf-receptor-mediated endocytosis. More importantly, paclitaxel loaded MRTN shows sustained release character and higher cytotoxicity than the free paclitaxel. This theranostic nanoparticle as an effective MRI/NIRF bimodal imaging probe and drug delivery system shows great potential in cancer diagnosis and therapy. PMID- 25504838 TI - Methyl N-phenyl carbamate synthesis from aniline and methyl formate: carbon recycling to chemical products. AB - Methyl N-phenyl carbamate was synthesized from aniline by using methyl formate as a green and efficient carbonylating agent. High yields were obtained at milder reaction conditions compared to the conventional CO/CH3 OH route. Studies on the reaction sequence led to suggest an alternative and more efficient route to the carbamate via formanilide as intermediate. PMID- 25504839 TI - Total synthesis of albicidin: a lead structure from Xanthomonas albilineans for potent antibacterial gyrase inhibitors. AB - The peptide antibiotic albicidin, which is synthesized by the plant pathogenic bacterium Xanthomonas albilineans, displays remarkable antibacterial activity against various Gram-positive and Gram-negative microorganisms. The low amounts of albicidin obtainable from the producing organism or through heterologous expression are limiting factors in providing sufficient material for bioactivity profiling and structure-activity studies. Therefore, we developed a convergent total synthesis route toward albicidin. The unexpectedly difficult formation of amide bonds between the aromatic amino acids was achieved through a triphosgene mediated coupling strategy. The herein presented synthesis of albicidin confirms the previously determined chemical structure and underlines the extraordinary antibacterial activity of this compound. The synthetic protocol will provide multigram amounts of albicidin for further profiling of its drug properties. PMID- 25504840 TI - Inflammatory myofibroblastic tumor as a second neoplasm after Wilms tumor. AB - We report two survivors of Wilms tumor (WT) who developed inflammatory myofibroblastic tumor (IMT). The first patient had IMT in the mainstem bronchus 1 year after WT therapy that included vincristine, dactinomycin, doxorubicin (VDA) and whole lung radiation therapy (XRT). The second patient had IMT in the cecum 7 years after WT therapy consisting of VDA and abdominal XRT. The unlikely co occurrence of WT and IMT suggests a genetic link between these tumors or that IMT can arise as a complication of cancer therapy. IMT should be considered in WT survivors who develop secondary tumors, especially at unusual sites. PMID- 25504841 TI - Diffusion tensor imaging and T2 mapping in early denervated skeletal muscle in rats. AB - BACKGROUND: To evaluate the temporal changes of diffusion tensor imaging (DTI) indices, T2 values, and visual signal intensity on various fat suppression techniques in the early state of denervated skeletal muscle in a rat model. METHODS: Institutional Animal Care and Use Committee approval was obtained. Sciatic nerves of eight rats were transected for irreversible neurotmesis model. We examined normal lower leg and denervated muscles at 3 days, 1 week, and 2 weeks on a 3 Tesla MR. fractional anisotropy (FA), mean apparent diffusion coefficient (mADC), and T2 values were measured by using DTI and T2 mapping scan. We subjectively classified the signal intensity change on various fat suppression images into the following three grades: negative, suspicious, and definite change. Wilcoxon-sign rank test and Kruskal-Wallis test were used for the comparison of FA, mADC, T2 values. McNemar's test was used for comparing signal intensity change among fat suppression techniques. RESULTS: FA values of denervated muscles at 3 days (0.35 +/- 0.06), 1 week (0.29 +/- 0.04), and 2 weeks (0.34 +/- 0.05) were significantly (P < 0.05) lower than that in the control group (0.54 +/- 0.17). mADC of denervated muscles decreased without statistically significant (P > 0.05) change. T2 values were significantly increased at 1 week (38.11 +/- 6.42 ms, P = 0.017) and markedly increased at 2 weeks (46.53 +/- 5.17 ms, P = 0.012). The grade of visual signal intensity change on chemical shift selective fat saturation, STIR and IDEAL images were identical in all cases (P = 1.000). CONCLUSION: FA and T2 values can demonstrate the early temporal changes in denervated rat skeletal muscle. PMID- 25504842 TI - Nocturnal risk of gout attacks. AB - OBJECTIVE: Several plausible mechanisms and anecdotal descriptions suggest that gout attacks often occur at night, although there are no scientific data supporting this. We undertook this study to evaluate the hypothesis that gout attacks occur more frequently at night. METHODS: We conducted a case-crossover study to examine the risk of acute gout attacks in relation to the time of the day. Gout patients were prospectively recruited and followed up via the internet for 1 year. Participants were asked about the following information concerning their gout attacks: the date and hour of attack onset, symptoms and signs, medication use, and purported risk factors during the 24- and 48-hour periods prior to the gout attack. We calculated the odds ratios (ORs) of gout attacks (with 95% confidence intervals [95% CIs]) according to three 8-hour time blocks of the day (i.e., 12:00 AM to 7:59 AM, 8:00 AM to 3:59 PM [reference], and 4:00 PM to 11:59 PM) using conditional logistic regression. RESULTS: Our study included 724 gout patients who experienced a total of 1,433 attacks (733, 310, and 390 attacks during the first, second, and third 8-hour time blocks, respectively) over 1 year. The risk of gout flares in the 8-hour overnight time block (12:00 AM to 7:59 AM) was 2.36 times higher than in the daytime (8:00 AM to 3:59 PM) (OR 2.36 [95% CI 2.05-2.73]). The corresponding OR in the evening (4:00 PM to 11:59 PM) was 1.26 (95% CI 1.07-1.48). These associations persisted among those with no alcohol use and in the lowest quintile of purine intake in the 24 hours prior to attack onset. Furthermore, these associations persisted in subgroups according to sex, age group, obesity status, diuretic use, and use of allopurinol, colchicine, and nonsteroidal antiinflammatory drugs. CONCLUSION: These findings provide the first prospective evidence that the risk of gout attacks during the night and early morning is 2.4 times higher than in the daytime. Further, these data support the purported mechanisms and historical descriptions of the nocturnal onset of gout attacks and may have implications for antigout prophylactic measures. PMID- 25504843 TI - Outcomes of arthroscopic Hill-Sachs remplissage and anterior Bankart repair: a retrospective controlled study including ultrasound evaluation of posterior capsulotenodesis and infraspinatus strength assessment. AB - BACKGROUND: Hill-Sachs lesions are compression fractures that result from shoulder dislocation. They involve "engaging" the humeral head on the anterior glenoid rim when the arm is abducted and externally rotated. The defect grows as the number of dislocations increases. HYPOTHESIS: Arthroscopic remplissage and anterior Bankart repair do not significantly affect infraspinatus strength while ensuring healing of the capsulotenodesis. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Sixty-one patients with traumatic anterior shoulder instability treated by arthroscopic Bankart repair and Hill-Sachs remplissage at least 24 months previously were compared with a control group of 40 healthy participants. Preoperative imaging included magnetic resonance imaging for Bankart lesion identification and computed tomography to quantify the humeral head defect. Active range of motion and clinical scores (Walch-Duplay, Constant Murley, and Rowe) were assessed. External rotation (ER) and internal rotation (IR) were measured with arm at the side (ER1 and IR1) and abducted at 90 degrees (ER2 and IR2). Infraspinatus strength was assessed with the scapula free (infraspinatus strength test [IST]) and retracted (infraspinatus scapula retraction test [ISRT]). Infraspinatus tenodesis and posterior capsulodesis healing were evaluated by ultrasound (US). RESULTS: The follow-up median was 39.5 months (range, 24-56 months). One patient experienced a recurrence of instability at 34 months. In the remplissage patients, ER1 was significantly lower in the affected compared with the unaffected shoulder (P < .001). Mean IST and ISRT strength values did not show differences between sides. The mean Constant-Murley score rose from 62.9 +/- 7.1 to 90 +/- 5.2 (P < .0001). The Walch-Duplay and Rowe scores were excellent in 23 (78.6%), good in 6 (17.8%), and poor in 1 patient (both scores). The remplissage group had significantly lower ER1 (P < .001), ER2 (P < .001), and IR2 (P < .01) values compared with the control group. Differences in IST and ISRT between the groups were not significant. Capsulotenodesis healing and filling of the Hill-Sachs defect were confirmed by dynamic US in all subjects. CONCLUSION: Arthroscopic remplissage is a reliable approach to Hill Sachs lesions. The ER and IR restriction does not significantly affect quality of life. Infraspinatus strength recovery is satisfactory even compared with healthy subjects. Ultrasound examination allows accurate evaluation of capsulotenodesis healing. PMID- 25504844 TI - Impact of the oxygen defects and the hydrogen concentration on the surface of tetragonal and monoclinic ZrO2 on the reduction rates of stearic acid on Ni/ZrO2. AB - The role of the specific physicochemical properties of ZrO2 phases on Ni/ZrO2 has been explored with respect to the reduction of stearic acid. Conversion on pure m ZrO2 is 1.3 times more active than on t-ZrO2 , whereas Ni/m-ZrO2 is three times more active than Ni/t-ZrO2 . Although the hydrodeoxygenation of stearic acid can be catalyzed solely by Ni, the synergistic interaction between Ni and the ZrO2 support causes the variations in the reaction rates. Adsorption of the carboxylic acid group on an oxygen vacancy of ZrO2 and the abstraction of the alpha-hydrogen atom with the elimination of the oxygen atom to produce a ketene is the key to enhance the overall rate. The hydrogenated intermediate 1-octadecanol is in turn decarbonylated to heptadecane with identical rates on all catalysts. Decarbonylation of 1-octadecanol is concluded to be limited by the competitive adsorption of reactants and intermediate. The substantially higher adsorption of propionic acid demonstrated by IR spectroscopy and the higher reactivity to O2 exchange reactions with the more active catalyst indicate that the higher concentration of active oxygen defects on m-ZrO2 compared to t-ZrO2 causes the higher activity of Ni/m-ZrO2 . PMID- 25504845 TI - Injuries to staff engaged in foot-and-mouth disease eradication in Japan. AB - BACKGROUND: In April 2010, a large-scale outbreak of foot-and-mouth disease, a highly infectious disease affecting cloven-hoofed animals, was reported in Miyazaki prefecture in Japan. Many staff were dispatched to the epidemic area to undertake containment measures. Various injuries were reported among the dispatched staff. AIMS: To study the characteristics of injuries that occurred during containment measures and to identify the characteristics of those injured. METHODS: We analysed records of injuries that occurred among staff dispatched from national organizations and prefectures other than Miyazaki prefecture. Based on these records, a qualitative analysis was conducted for veterinarians and non veterinarian support staff as each group played a different role during the outbreak. RESULTS: Forty-seven veterinarians and 183 support staff were injured. The injury risk was significantly higher for support staff (13%) than for veterinarians (5%; P < 0.001). The most frequently reported injury resulted from exposure to disinfectant and the next was abrasions caused by friction from protective clothing and rubber boots. Among veterinarians, needlestick accidents were also frequently reported. CONCLUSIONS: Applying a less hazardous disinfectant and improving protective equipment to prevent skin abrasion may be effective in reducing the risk of these injuries among staff conducting containment measures. Reducing injuries among staff in such circumstances will assist effective control measures. PMID- 25504846 TI - Flow cytometry immunophenotypic analysis of Philadelphia-negative myeloproliferative neoplasms: Correlation with histopathologic features. AB - Background: Compared with the proven utility of flow cytometry immunophenotyping (FCI) analysis in the workup of myelodysplastic syndromes (MDS), immunophenotypic alterations in myeloproliferative neoplasms (MPN) have been less studied and the potential utility of FCI is not defined. Methods: Bone marrow (BM) samples of 83 Philadelphia-negative MPN patients were assessed by multicolor FCI including 27 with essential thrombocythemia (ET); 17 polycythemia vera (PV); 33 primary myelofibrosis (PMF) and 6 MPN-unclassifiable (MPN-U). The time interval from initial diagnosis of MPN to FCI analysis was 18 months (0-370). Ninety-five age matched MDS patients with a similar BM blast count were included for comparison. Results: Immunophenotypic alterations, either in CD34+ cells or myelomonocytic cells, were detected in 82 of 83 (99%) MPN cases. FCI abnormalities were more frequently observed in cases with substantial myelofibrosis but not different between PMF and fibrotic stage of ET/PV. Furthermore, FCI abnormalities were more frequent in cases with >=5% BM blasts and/or circulating blasts (p=0.006); as well as cases with an abnormal karyotype (p=0.036); but not associated with morphologic dysplasia or JAK2 mutation status. Comparing with MDS, FCI abnormalities were overall less pronounced in MPN cases (p=0.001). Conclusions: MPNs exhibit frequent immunophenotypic alterations, more pronounced in cases with adverse histopathologic features. These findings illustrate that immunophenotypic alterations are a part of constellational findings in MPN, and correlate progressively with disease stage. The study results also suggest a role of FCI in diagnosis of MPN and monitoring disease over time and after therapy. This article is protected by copyright. All rights reserved. PMID- 25504847 TI - andi: fast and accurate estimation of evolutionary distances between closely related genomes. AB - MOTIVATION: A standard approach to classifying sets of genomes is to calculate their pairwise distances. This is difficult for large samples. We have therefore developed an algorithm for rapidly computing the evolutionary distances between closely related genomes. RESULTS: Our distance measure is based on ungapped local alignments that we anchor through pairs of maximal unique matches of a minimum length. These exact matches can be looked up efficiently using enhanced suffix arrays and our implementation requires approximately only 1 s and 45 MB RAM/Mbase analysed. The pairing of matches distinguishes non-homologous from homologous regions leading to accurate distance estimation. We show this by analysing simulated data and genome samples ranging from 29 Escherichia coli/Shigella genomes to 3085 genomes of Streptococcus pneumoniae. AVAILABILITY AND IMPLEMENTATION: We have implemented the computation of anchor distances in the multithreaded UNIX command-line program andi for ANchor DIstances. C sources and documentation are posted at http://github.com/evolbioinf/andi/ CONTACT: haubold@evolbio.mpg.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25504848 TI - repDNA: a Python package to generate various modes of feature vectors for DNA sequences by incorporating user-defined physicochemical properties and sequence order effects. AB - In order to develop powerful computational predictors for identifying the biological features or attributes of DNAs, one of the most challenging problems is to find a suitable approach to effectively represent the DNA sequences. To facilitate the studies of DNAs and nucleotides, we developed a Python package called representations of DNAs (repDNA) for generating the widely used features reflecting the physicochemical properties and sequence-order effects of DNAs and nucleotides. There are three feature groups composed of 15 features. The first group calculates three nucleic acid composition features describing the local sequence information by means of kmers; the second group calculates six autocorrelation features describing the level of correlation between two oligonucleotides along a DNA sequence in terms of their specific physicochemical properties; the third group calculates six pseudo nucleotide composition features, which can be used to represent a DNA sequence with a discrete model or vector yet still keep considerable sequence-order information via the physicochemical properties of its constituent oligonucleotides. In addition, these features can be easily calculated based on both the built-in and user defined properties via using repDNA. AVAILABILITY AND IMPLEMENTATION: The repDNA Python package is freely accessible to the public at http://bioinformatics.hitsz.edu.cn/repDNA/. CONTACT: bliu@insun.hit.edu.cn or kcchou@gordonlifescience.org SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25504849 TI - MpTheory Java library: a multi-platform Java library for systems biology based on the Metabolic P theory. AB - MpTheory Java library is an open-source project collecting a set of objects and algorithms for modeling observed dynamics by means of the Metabolic P (MP) theory, that is, a mathematical theory introduced in 2004 for modeling biological dynamics. By means of the library, it is possible to model biological systems both at continuous and at discrete time. Moreover, the library comprises a set of regression algorithms for inferring MP models starting from time series of observations. To enhance the modeling experience, beside a pure Java usage, the library can be directly used within the most popular computing environments, such as MATLAB, GNU Octave, Mathematica and R. AVAILABILITY AND IMPLEMENTATION: The library is open-source and licensed under the GNU Lesser General Public License (LGPL) Version 3.0. Source code, binaries and complete documentation are available at http://mptheory.scienze.univr.it. CONTACT: luca.marchetti@univr.it, marchetti@cosbi.eu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25504850 TI - GSDS 2.0: an upgraded gene feature visualization server. AB - : Visualizing genes' structure and annotated features helps biologists to investigate their function and evolution intuitively. The Gene Structure Display Server (GSDS) has been widely used by more than 60 000 users since its first publication in 2007. Here, we reported the upgraded GSDS 2.0 with a newly designed interface, supports for more types of annotation features and formats, as well as an integrated visual editor for editing the generated figure. Moreover, a user-specified phylogenetic tree can be added to facilitate further evolutionary analysis. The full source code is also available for downloading. AVAILABILITY AND IMPLEMENTATION: Web server and source code are freely available at http://gsds.cbi.pku.edu.cn. CONTACT: gaog@mail.cbi.pku.edu.cn or gsds@mail.cbi.pku.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25504851 TI - Flavan-3-ols, anthocyanins, and inflammation. AB - The process of inflammation constitutes a reactive response of the organism to tissue damage and is an important factor making part of a number of degenerative pathologies as insulin resistance, dyslipidemia, and hypertension, all of them comprised in the metabolic syndrome. There is an increasing interest in plant products rich in flavan-3-ols and anthocyanins because of their potential beneficial effects observed in epidemiological studies against inflammatory related diseases. Their anti-inflammatory effects are exerted by modulation of cell redox status and inhibition of signaling pathways as NF-kappaB activation. The effects depend on their concentrations in target tissues and hence the bioavailability pathways followed by each particular compound. In this sense, in vitro studies performed with parental compounds at doses exceeding to those found in vivo may be drawing erroneous conclusions about their real efficacy. Contradictory results have been observed in human intervention trials, which may be ascribed to the type of population studied, length of study, source of flavan 3-ol/anthocyanin, and dose provided. Human studies are required to confirm the positive effects found in vitro and in animal models. Future research should be focused on the understanding of dose/flavonoid intake-response relationship with pharmacokinetic studies, evaluating proper biomarkers of intake. Long-term dietary interventions are necessary to observe effects on markers of late activation as well as the possible preventive effects of these compounds on long term inflammation-related diseases. PMID- 25504852 TI - Lonidamine induces intracellular tumor acidification and ATP depletion in breast, prostate and ovarian cancer xenografts and potentiates response to doxorubicin. AB - We demonstrate that the effects of lonidamine (LND, 100 mg/kg, i.p.) are similar for a number of xenograft models of human cancer including DB-1 melanoma and HCC1806 breast, BT-474 breast, LNCaP prostate and A2870 ovarian carcinomas. Following treatment with LND, each of these tumors exhibits a rapid decrease in intracellular pH, a small decrease in extracellular pH, a concomitant monotonic decrease in nucleoside triphosphate and an increase in inorganic phosphate over a 2-3 h period. We have previously demonstrated that selective intracellular tumor acidification potentiates response of this melanoma model to melphalan (7.5 mg/kg, i.v.), producing an estimated 89% cell kill based on tumor growth delay analysis. We now show that, in both DB-1 melanoma and HCC1806 breast carcinoma, LND potentiates response to doxorubicin, producing 95% cell kill in DB-1 melanoma at 7.5 mg/kg, i.v. doxorubicin and 98% cell kill at 10.0 mg/kg doxorubicin, and producing a 95% cell kill in HCC1806 breast carcinoma at 12.0 mg/kg doxorubicin. Potentiation of doxorubicin may result from cation trapping of the weakly basic anthracycline. Recent experience with the clinical treatment of melanoma and other forms of human cancer suggests that these diseases will probably not be cured by a single therapeutic procedure other than surgery. A multimodality therapeutic approach will be required. As a potent modulator of tumor response to N-mustards and anthracyclines as well as tumor thermo- and radiosensitivity, LND promises to play an important clinical role in the management and possible complete local control of a number of prevalent forms of human cancer. PMID- 25504854 TI - Imaging distributed and massed repetitions of natural scenes: spontaneous retrieval and maintenance. AB - Repetitions that are distributed (spaced) across time prompt enhancement of a memory-related event-related potential, compared to when repetitions are massed (contiguous). Here, we used fMRI to investigate neural enhancement and suppression effects during free viewing of natural scenes that were either novel or repeated four times with massed or distributed repetitions. Distributed repetition was uniquely associated with a repetition enhancement effect in a bilateral posterior parietal cluster that included the precuneus and posterior cingulate and which has previously been implicated in episodic memory retrieval. Unique to massed repetition, conversely, was enhancement in a right dorsolateral prefrontal cluster that has been implicated in short-term maintenance. Repetition suppression effects for both types of spacing were widespread in regions activated during novel picture processing. Taken together, the data are consistent with a hypothesis that distributed repetition prompts spontaneous retrieval of prior occurrences, whereas massed repetition prompts short-term maintenance of the episodic representation, due to contiguous presentation. These processing differences may mediate the classic spacing effect in learning and memory. PMID- 25504855 TI - Intact stable isotope labeled plasma proteins from the SILAC-labeled HepG2 secretome. AB - The plasma proteome remains an attractive biospecimen for MS-based biomarker discovery studies. The success of these efforts relies on the continued development of quantitative MS-based proteomics approaches. Herein we report the use of the SILAC-labeled HepG2 secretome as a source for stable isotope labeled plasma proteins for quantitative LC-MS/MS measurements. The HepG2 liver cancer cell line secretes the major plasma proteins including serum albumin, apolipoproteins, protease inhibitors, coagulation factors, and transporters that represent some of the most abundant proteins in plasma. The SILAC-labeled HepG2 secretome was collected, spiked into human plasma (1:1 total protein), and then processed for LC-MS/MS analysis. A total of 62 and 56 plasma proteins were quantified (heavy:light (H/L) peptide pairs) from undepleted and depleted (serum albumin and IgG), respectively, with log2 H/L = +/- 6. Major plasma proteins quantified included albumin, apolipoproteins (e.g., APOA1, APOA2, APOA4, APOB, APOC3, APOE, APOH, and APOM), protease inhibitors (e.g., A2M and SERPINs), coagulation factors (e.g., Factor V, Factor X, fibrinogen), and transport proteins (e.g., TTR). The average log2 H/L values for shared plasma proteins in both undepleted and depleted plasma samples were 0.43 and 0.44, respectively. This work further expands the SILAC strategy into MS-based biomarker discovery of clinical biospecimens. PMID- 25504857 TI - Decoupling HZSM-5 catalyst activity from deactivation during upgrading of pyrolysis oil vapors. AB - The independent evaluation of catalyst activity and stability during the catalytic pyrolysis of biomass is challenging because of the nature of the reaction system and rapid catalyst deactivation that force the use of excess catalyst. In this contribution we use a modified pyroprobe system in which pulses of pyrolysis vapors are converted over a series of HZSM-5 catalysts in a separate fixed-bed reactor controlled independently. Both the reactor-bed temperature and the Si/Al ratio of the zeolite are varied to evaluate catalyst activity and deactivation rates independently both on a constant surface area and constant acid site basis. Results show that there is an optimum catalyst-bed temperature for the production of aromatics, above which the production of light gases increases and that of aromatics decrease. Zeolites with lower Si/Al ratios give comparable initial rates for aromatics production, but far more rapid catalyst deactivation rates than those with higher Si/Al ratios. PMID- 25504859 TI - Dinitrogen activation upon reduction of a triiron(II) complex. AB - Reaction of a trinuclear iron(II) complex, Fe3 Br3 L (1), with KC8 under N2 leads to dinitrogen activation products (2) from which Fe3 (NH)3 L (2-1; L is a cyclophane bridged by three beta-diketiminate arms) was characterized by X-ray crystallography. (1) H NMR spectra of the protonolysis product of 2 synthesized under (14) N2 and (15) N2 confirm atmospheric N2 reduction, and ammonia is detected by the indophenol assay (yield ~30 %). IR and Mossbauer spectroscopy, and elemental analysis on 2 and 2-1 as well as the tri(amido)triiron(II) 3 and tri(methoxo)triiron 4 congeners support our assignment of the reduction product as containing protonated N-atom bridges. PMID- 25504856 TI - MRI findings of radiation-associated angiosarcoma of the breast (RAS). AB - PURPOSE: To describe the magnetic resonance imaging (MRI) characteristics of radiation-associated breast angiosarcomas (RAS). MATERIALS AND METHODS: In this Institutional Review board (IRB)-approved retrospective study, 57 women were diagnosed with pathologically confirmed RAS during the study period (January 1999 to May 2013). Seventeen women underwent pretreatment breast MRI (prior to surgical resection or chemotherapy), of which 16 studies were available for review. Imaging features, including all available mammograms, ultrasounds, and breast MRIs, of these patients were evaluated by two radiologists independently and correlated with clinical management and outcomes. RESULTS: The median age of patients at original breast cancer diagnosis was 69.3 years (range 42-84 years), with average time from initial radiation therapy to diagnosis of RAS of 7.3 years (range 5.1-9.5 years). Nine women had mammograms (9/16, 56%) and six had breast ultrasound (US) (6/16, 38%) prior to MRI, which demonstrated nonsuspicious findings in 5/9 mammograms and 3/6 ultrasounds. Four patients had distinct intraparenchymal masses on mammogram and MRI. MRI findings included diffuse T2 high signal skin thickening (16/16, 100%). Nearly half (7/16, 44%) of patients had T2 low signal intensity lesions; all lesions rapidly enhanced on postcontrast T1 -weighted imaging. All women underwent surgical resection, with 8/16 (50%) receiving neoadjuvant chemotherapy. Four women died during the study period. CONCLUSION: Clinical, mammographic, and sonographic findings of RAS are nonspecific and may be occult on conventional breast imaging; MRI findings of RAS include rapidly enhancing dermal and intraparenchymal lesions, some of which are low signal on T2 weighted imaging. PMID- 25504858 TI - Space-confined creation of nanoframes in situ on reduced graphene oxide. AB - Nanoframes (NFs) are created in situ on reduced graphene oxide (rGO) through confining the evolutions of precursor nanosheets, such as ZnS(EN)0.5 (EN = ethylenediamine), and nanoparticles within quasi-two-dimensional spaces generated from graphene oxide. The resultant composites of ZnS-NF@rGO exhibit excellent photocurrent responses. This work provides a new strategy to synthesize and modulate nanostructures and nanomaterials for rGO composites. PMID- 25504860 TI - Cross-scale predictive modeling of CHO cell culture growth and metabolites using Raman spectroscopy and multivariate analysis. AB - Multi-component, multi-scale Raman spectroscopy modeling results from a monoclonal antibody producing CHO cell culture process including data from two development scales (3 L, 200 L) and a clinical manufacturing scale environment (2,000 L) are presented. Multivariate analysis principles are a critical component to partial least squares (PLS) modeling but can quickly turn into an overly iterative process, thus a simplified protocol is proposed for addressing necessary steps including spectral preprocessing, spectral region selection, and outlier removal to create models exclusively from cell culture process data without the inclusion of spectral data from chemically defined nutrient solutions or targeted component spiking studies. An array of single-scale and combination scale modeling iterations were generated to evaluate technology capabilities and model scalability. Analysis of prediction errors across models suggests that glucose, lactate, and osmolality are well modeled. Model strength was confirmed via predictive validation and by examining performance similarity across single scale and combination-scale models. Additionally, accurate predictive models were attained in most cases for viable cell density and total cell density; however, these components exhibited some scale-dependencies that hindered model quality in cross-scale predictions where only development data was used in calibration. Glutamate and ammonium models were also able to achieve accurate predictions in most cases. However, there are differences in the absolute concentration ranges of these components across the datasets of individual bioreactor scales. Thus, glutamate and ammonium PLS models were forced to extrapolate in cases where models were derived from small scale data only but used in cross-scale applications predicting against manufacturing scale batches. PMID- 25504861 TI - Catch-up growth during tocilizumab therapy for systemic juvenile idiopathic arthritis: results from a phase III trial. AB - OBJECTIVE: To investigate the impact of tocilizumab treatment on growth and growth-related laboratory parameters in patients with systemic juvenile idiopathic arthritis (JIA) enrolled in a phase III clinical trial. METHODS: Patients with systemic JIA ages 2-17 years (n = 112) received tocilizumab in a 12 week, randomized, placebo-controlled period and a long-term open-label extension. Height velocity and standard deviation (SD) score; levels of insulin-like growth factor 1 (IGF-1), osteocalcin (OC), and C-telopeptide of type I collagen (CTX-I); and Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71) were measured in a post hoc analysis of 83 patients who never received growth hormone and did not reach Tanner stage 5 by the end of the first year of treatment. RESULTS: Patients had stunted growth at baseline (mean height SD score -2.2). During tocilizumab treatment, males (73%) and females (83%) experienced above normal mean height velocities of 6.6 cm/year (P < 0.0001 versus World Health Organization norms). Mean height SD score increases during year 1 (0.29) and year 2 (0.31) were significant (both P < 0.0001). The mean SD score for IGF-1 levels increased significantly (-0.2 for year 1 and -0.1 for year 2 versus -1.0 at baseline; both P < 0.0001). Mean OC and CTX-I levels (both P < 0.0001) and the OC:CTX-I ratio (P = 0.014) significantly increased from baseline to year 2. In multiple regression analysis, first-year height velocity had a significant inverse relationship to JADAS-71 at year 1, age, mean glucocorticoid dosage during the year, and height SD score at baseline. CONCLUSION: Our findings indicate that during treatment with tocilizumab, patients with systemic JIA experience significant catch-up growth, normalization of IGF-1 levels, and bone balance improvement favoring bone formation. PMID- 25504863 TI - Microbial models with data-driven parameters predict stronger soil carbon responses to climate change. AB - Long-term carbon (C) cycle feedbacks to climate depend on the future dynamics of soil organic carbon (SOC). Current models show low predictive accuracy at simulating contemporary SOC pools, which can be improved through parameter estimation. However, major uncertainty remains in global soil responses to climate change, particularly uncertainty in how the activity of soil microbial communities will respond. To date, the role of microbes in SOC dynamics has been implicitly described by decay rate constants in most conventional global carbon cycle models. Explicitly including microbial biomass dynamics into C cycle model formulations has shown potential to improve model predictive performance when assessed against global SOC databases. This study aimed to data-constrained parameters of two soil microbial models, evaluate the improvements in performance of those calibrated models in predicting contemporary carbon stocks, and compare the SOC responses to climate change and their uncertainties between microbial and conventional models. Microbial models with calibrated parameters explained 51% of variability in the observed total SOC, whereas a calibrated conventional model explained 41%. The microbial models, when forced with climate and soil carbon input predictions from the 5th Coupled Model Intercomparison Project (CMIP5), produced stronger soil C responses to 95 years of climate change than any of the 11 CMIP5 models. The calibrated microbial models predicted between 8% (2-pool model) and 11% (4-pool model) soil C losses compared with CMIP5 model projections which ranged from a 7% loss to a 22.6% gain. Lastly, we observed unrealistic oscillatory SOC dynamics in the 2-pool microbial model. The 4-pool model also produced oscillations, but they were less prominent and could be avoided, depending on the parameter values. PMID- 25504864 TI - Dihydrogen catalysis of the reversible formation and cleavage of C-H and N-H bonds of aminopyridinate ligands bound to (eta(5) -C5 Me5 )Ir(III.). AB - This study focuses on a series of cationic complexes of iridium that contain aminopyridinate (Ap) ligands bound to an (eta(5) -C5 Me5 )Ir(III) fragment. The new complexes have the chemical composition [Ir(Ap)(eta(5) -C5 Me5 )](+) , exist in the form of two isomers (1(+) and 2(+) ) and were isolated as salts of the BArF (-) anion (BArF =B[3,5-(CF3 )2 C6 H3 ]4 ). Four Ap ligands that differ in the nature of their bulky aryl substituents at the amido nitrogen atom and pyridinic ring were employed. In the presence of H2 , the electrophilicity of the Ir(III) centre of these complexes allows for a reversible prototropic rearrangement that changes the nature and coordination mode of the aminopyridinate ligand between the well-known kappa(2) -N,N'-bidentate binding in 1(+) and the unprecedented kappa-N,eta(3) -pseudo-allyl-coordination mode in isomers 2(+) through activation of a benzylic C-H bond and formal proton transfer to the amido nitrogen atom. Experimental and computational studies evidence that the overall rearrangement, which entails reversible formation and cleavage of H H, C-H and N-H bonds, is catalysed by dihydrogen under homogeneous conditions. PMID- 25504865 TI - Extraneural metastases of medulloblastoma: desmoplastic variants may have prolonged survival. AB - BACKGROUND: Extraneural metastases from CNS medulloblastoma are rare and poorly described. The purpose of this study is to describe the clinical and radiological characteristics of a large single institution series of patients with medulloblastoma who developed extraneural metastases. PROCEDURE: We retrospectively reviewed a departmental database over a 20 year period for all patients with medulloblastoma who developed extraneural metastases. Chart and imaging reviews were performed, and overall survival (OS) estimated by the Kaplan Meier method. RESULTS: We found 14 patients with medulloblastoma and extraneural metastases. The median age at initial diagnosis was 16.3 years (range, 3.2-44.2), and the most common subtype was desmoplastic (n = 6, 42.9%). After initial gross total resection, most patients received radiation therapy alone (n = 10, 71.4%). Metastases to bone were most common (n = 11, 78.6%) followed by metastases to bone marrow (n = 6, 42.9%), usually to the spine. The median time from initial diagnosis to first extraneural metastasis was 1.5 years (range, 0.2-17.4), and the median OS from extraneural metastasis to death was 3.3 years (range, 0-18). The Kaplan-Meier estimate of 5 year OS from extraneural metastasis diagnosis was 40.0% (95% CI, 20.2-79.2). CONCLUSIONS: Extraneural metastases from medulloblastoma may rarely develop after initial diagnosis to involve bone and bone marrow. We found that desmoplastic variant extraneural tumors had longer survival than nondesmoplastic variants, suggesting that histopathological and more recent molecular subtyping have important roles in determining the prognosis of medulloblastoma patients. PMID- 25504866 TI - Developing a pooled job physical exposure data set from multiple independent studies: an example of a consortium study of carpal tunnel syndrome. AB - BACKGROUND: Six research groups independently conducted prospective studies of carpal tunnel syndrome (CTS) incidence in 54 US workplaces in 10 US States. Physical exposure variables were collected by all research groups at the individual worker level. Data from these research groups were pooled to increase the exposure spectrum and statistical power. OBJECTIVE: This paper provides a detailed description of the characteristics of the pooled physical exposure variables and the source data information from the individual research studies. METHODS: Physical exposure data were inspected and prepared by each of the individual research studies according to detailed instructions provided by an exposure subcommittee of the research consortium. Descriptive analyses were performed on the pooled physical exposure data set. Correlation analyses were performed among exposure variables estimating similar exposure aspects. RESULTS: At baseline, there were a total of 3010 participants in the pooled physical exposure data set. Overall, the pooled data meaningfully increased the spectra of most exposure variables. The increased spectra were due to the wider range in exposure data of different jobs provided by the research studies. The correlations between variables estimating similar exposure aspects showed different patterns among data provided by the research studies. CONCLUSIONS: The increased spectra of the physical exposure variables among the data pooled likely improved the possibility of detecting potential associations between these physical exposure variables and CTS incidence. It is also recognised that methods need to be developed for general use by all researchers for standardisation of physical exposure variable definition, data collection, processing and reduction. PMID- 25504867 TI - Chromosome hydroxymethylation patterns in human zygotes and cleavage-stage embryos. AB - We report the sequential changes in 5-hydroxymethylcytosine (5hmC) patterns in the genome of human preimplantation embryos during DNA methylation reprogramming. We have studied chromosome hydroxymethylation and methylation patterns in triploid zygotes and blastomeres of cleavage-stage embryos. Using indirect immunofluorescence, we have analyzed the localization of 5hmC and its co distribution with 5-methylcytosine (5mC) on the QFH-banded metaphase chromosomes. In zygotes, 5hmC accumulates in both parental chromosome sets, but hydroxymethylation is more intensive in the poorly methylated paternal set. In the maternal set, chromosomes are highly methylated, but contain little 5hmC. Hydroxymethylation is highly region specific in both parental chromosome sets: hydroxymethylated loci correspond to R-bands, but not G-bands, and have well defined borders, which coincide with the R/G-band boundaries. The centromeric regions and heterochromatin at 1q12, 9q12, 16q11.2, and Yq12 contain little 5mC and no 5hmC. We hypothesize that 5hmC may mark structural/functional genome 'units' corresponding to chromosome bands in the newly formed zygotic genome. In addition, we suggest that the hydroxymethylation of R-bands in zygotes can be treated as a new characteristic distinguishing them from G-bands. At cleavages, chromosomes with asymmetrical hydroxymethylation of sister chromatids appear. They decrease in number during cleavages, whereas totally non-hydroxymethylated chromosomes become numerous. Taken together, our findings suggest that, in the zygotic genome, 5hmC is distributed selectively and its pattern is determined by both parental origin of chromosomes and type of chromosome bands - R, G, or C. At cleavages, chromosome hydroxymethylation pattern is dynamically changed due to passive and non-selective overall loss of 5hmC, which coincides with that of 5mC. PMID- 25504868 TI - Effects of maternal n-3 fatty acid supplementation on placental cytokines, pro resolving lipid mediators and their precursors. AB - The aim of this study was to determine whether supplementation with fish oil derived n-3 polyunsaturated fatty acids (n-3 PUFA) during pregnancy modifies placental PUFA composition, the accumulation of specialised pro-resolving lipid mediators (SPMs, specifically resolvins (Rv), protectins (PD) and upstream precursors) and inflammatory gene expression. Placentas were collected from women (n=51) enrolled in a randomised, placebo controlled trial of n-3 PUFA supplementation from 20-week gestation. Lipids were extracted for fatty acid analysis and SPMs were quantitated by mass spectrometry. Gene expression was determined by qRT-PCR. Using multiple regression analysis, data were correlated for placental n-3 PUFA and SPM levels with PUFA levels in maternal and cord blood erythrocytes. Supplementation with n-3 PUFAs increased placental docosahexaenoic acid (DHA) levels, but not eicosapentaenoic acid (EPA) levels (P<0.05), and increased the levels of the SPM precursors 18-hydroxyeicosapentaenoic acid and 17 hydroxydocosahexaenoic acid (17-HDHA) by two- to threefold (P<0.0005). RvD1, 17R RvD1, RvD2 and PD1 were detectable in all placentas, but concentrations were not significantly increased by n-3 PUFA supplementation. Placental DHA levels were positively associated with maternal and cord DHA levels (P<0.005), and with placental 17-HDHA concentrations (P<0.0001). Placental mRNA expression of PTGS2, IL1beta, IL6 and IL10 was unaffected by n-3 PUFA supplementation, but TNFalpha expression was increased by 14-fold (P<0.05). We conclude that n-3 PUFA supplementation in pregnancy i) enhances placental accumulation of DHA and SPM precursors, ii) does not alter placental EPA levels, and iii) has no stimulatory effects on inflammatory gene expression. Further studies are required to ascertain the biological significance of SPMs in the placenta and the potential immunomodulatory effects of elevating placental SPM levels. PMID- 25504869 TI - Investigation of the stallion sperm proteome by mass spectrometry. AB - Stallion spermatozoa continue to present scientific and clinical challenges with regard to the biological mechanisms responsible for their survival and function. In particular, deeper understanding of sperm energy metabolism, defence against oxidative damage and cell-cell interactions should improve fertility assessment and the application of advanced reproductive technologies in the equine species. In this study, we used highly sensitive LC-MS/MS technology and sequence database analysis to identify and characterise the proteome of Percoll-isolated ejaculated equine spermatozoa, with the aim of furthering our understanding of this cell's complex biological machinery. We were able to identify 9883 peptides comprising 1030 proteins, which were subsequently attributed to 975 gene products. Gene ontology analysis for molecular and cellular processes revealed new information about the metabolism, antioxidant defences and receptors of stallion spermatozoa. Mitochondrial proteins and those involved in catabolic processes constituted dominant categories. Several enzymes specific to beta-oxidation of fatty acids were identified, and further experiments were carried out to ascertain their functional significance. Inhibition of carnitine palmitoyl transferase 1, a rate limiting enzyme of beta-oxidation, reduced motility parameters, indicating that beta-oxidation contributes to maintenance of motility in stallion spermatozoa. PMID- 25504870 TI - GATA4 knockdown in MA-10 Leydig cells identifies multiple target genes in the steroidogenic pathway. AB - GATA4 is an essential transcription factor required for the initiation of genital ridge formation, for normal testicular and ovarian differentiation at the time of sex determination, and for male and female fertility in adulthood. In spite of its crucial roles, the genes and/or gene networks that are ultimately regulated by GATA4 in gonadal tissues remain to be fully understood. This is particularly true for the steroidogenic lineages such as Leydig cells of the testis where many in vitro (promoter) studies have provided good circumstantial evidence that GATA4 is a key regulator of Leydig cell gene expression and steroidogenesis, but formal proof is still lacking. We therefore performed a microarray screening analysis of MA-10 Leydig cells in which Gata4 expression was knocked down using an siRNA strategy. Analysis identified several GATA4-regulated pathways including cholesterol synthesis, cholesterol transport, and especially steroidogenesis. A decrease in GATA4 protein was associated with decreased expression of steroidogenic genes previously suspected to be GATA4 targets such as Cyp11a1 and Star. Gata4 knockdown also led to an important decrease in other novel steroidogenic targets including Srd5a1, Gsta3, Hsd3b1, and Hsd3b6, as well as genes known to participate in cholesterol metabolism such as Scarb1, Ldlr, Soat1, Scap, and Cyp51. Consistent with the decreased expression of these genes, a reduction in GATA4 protein compromised the ability of MA-10 cells to produce steroids both basally and under hormone stimulation. These data therefore provide strong evidence that GATA4 is an essential transcription factor that sits atop of the Leydig cell steroidogenic program. PMID- 25504871 TI - Cyclooxygenase and prostaglandins in somatic cell populations of the testis. AB - Prostaglandins (PGs) are synthesized through the action of the rate-limiting enzyme cyclooxygenase (COX) and further specific enzymes. The development of Cox deficient mice in the 1990s gave insights into the reproductive roles of PGs. Female Cox-knockout mice were subfertile or infertile. Interestingly, fertility was not affected in male mice deficient in Cox, suggesting that PGs may not be critical for the functioning of the testis. However, this conclusion has recently been challenged by observations of important roles for PGs in both physiological and pathological processes in the testis. The two key somatic cell types in the testis, Leydig and Sertoli cells, express the inducible isoenzyme COX2 and produce PGs. Testicular COX2 expression in these somatic cells is regulated by hormonal input (FSH, prolactin (PRL), and testosterone) as well as by IL1beta. PGs modulate steroidogenesis in Leydig cells and glucose uptake in Sertoli cells. Hence, the COX2/PG system in Leydig and Sertoli cells acts as a local modulator of testicular activity, and consequently may regulate spermatogenic efficiency. In addition to its expression in Leydig and Sertoli cells, COX2 has been detected in the seminiferous tubule wall, and in testicular macrophages and mast cells of infertile patients. These observations highlight the possible relevance of PGs in testicular inflammation associated with idiopathic infertility. Collectively, these data indicate that the COX2/PG system plays crucial roles not only in testicular physiology (i.e., development, steroidogenesis, and spermatogenesis), but more importantly in the pathogenesis or maintenance of infertility status in the male gonad. Further studies of these actions could lead to new therapeutic approaches to idiopathic male infertility. PMID- 25504872 TI - Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling. AB - Spermatogenesis is a continuous and productive process supported by the self renewal and differentiation of spermatogonial stem cells (SSCs), which arise from undifferentiated precursors known as gonocytes and are strictly controlled in a special 'niche' microenvironment in the seminiferous tubules. Sertoli cells, the only somatic cell type in the tubules, directly interact with SSCs to control their proliferation and differentiation through the secretion of specific factors. Spermatocyte meiosis is another key step of spermatogenesis, which is regulated by Sertoli cells on the luminal side of the blood-testis barrier through paracrine signaling. In this review, we mainly focus on the role of Sertoli cells in the regulation of SSC self-renewal and spermatocyte meiosis, with particular emphasis on paracrine and endocrine-mediated signaling pathways. Sertoli cell growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and fibroblast growth factor 2 (FGF2), as well as Sertoli cell transcription factors, such as ETS variant 5 (ERM; also known as ETV5), nociceptin, neuregulin 1 (NRG1), and androgen receptor (AR), have been identified as the most important upstream factors that regulate SSC self-renewal and spermatocyte meiosis. Other transcription factors and signaling pathways (GDNF RET-GFRA1 signaling, FGF2-MAP2K1 signaling, CXCL12-CXCR4 signaling, CCL9-CCR1 signaling, FSH-nociceptin/OPRL1, retinoic acid/FSH-NRG/ERBB4, and AR/RB ARID4A/ARID4B) are also addressed. PMID- 25504874 TI - Rapid and up-scalable fabrication of free-standing metal oxide nanosheets for high-performance lithium storage. AB - Free-standing alpha-Fe2 O3 nanosheets, SnO2 mesoporous nanosheets and sandwich like polyaniline (PAN)/SnO2 /PAN nanosheets are fabricated at very mild conditions (room temperature or 60 degrees C) via a galvanic replacement method for the first time. These nanosheets show excellent high-rate capability and long term durability as anodes for lithium-ion batteries. PMID- 25504873 TI - Recurrent triploidy due to a failure to complete maternal meiosis II: whole-exome sequencing reveals candidate variants. AB - Triploidy is a relatively common cause of miscarriage; however, recurrent triploidy has rarely been reported. A healthy 34-year-old woman was ascertained because of 18 consecutive miscarriages with triploidy found in all 5 karyotyped losses. Molecular results in a sixth loss were also consistent with triploidy. Genotyping of markers near the centromere on multiple chromosomes suggested that all six triploid conceptuses occurred as a result of failure to complete meiosis II (MII). The proband's mother had also experienced recurrent miscarriage, with a total of 18 miscarriages. Based on the hypothesis that an inherited autosomal dominant maternal predisposition would explain the phenotype, whole-exome sequencing of the proband and her parents was undertaken to identify potential candidate variants. After filtering for quality and rarity, potentially damaging variants shared between the proband and her mother were identified in 47 genes. Variants in genes coding for proteins implicated in oocyte maturation, oocyte activation or polar body extrusion were then prioritized. Eight of the most promising candidate variants were confirmed by Sanger sequencing. These included a novel change in the PLCD4 gene, and a rare variant in the OSBPL5 gene, which have been implicated in oocyte activation upon fertilization and completion of MII. Several variants in genes coding proteins playing a role in oocyte maturation and early embryonic development were also identified. The genes identified may be candidates for the study in other women experiencing recurrent triploidy or recurrent IVF failure. PMID- 25504875 TI - Self-regulation mechanism for charged point defects in hybrid halide perovskites. AB - Hybrid halide perovskites such as methylammonium lead iodide (CH3NH3PbI3) exhibit unusually low free-carrier concentrations despite being processed at low temperatures from solution. We demonstrate, through quantum mechanical calculations, that an origin of this phenomenon is a prevalence of ionic over electronic disorder in stoichiometric materials. Schottky defect formation provides a mechanism to self-regulate the concentration of charge carriers through ionic compensation of charged point defects. The equilibrium charged vacancy concentration is predicted to exceed 0.4% at room temperature. This behavior, which goes against established defect conventions for inorganic semiconductors, has implications for photovoltaic performance. PMID- 25504877 TI - High-resolution localized spatiotemporal encoding correlated spectra under inhomogeneous magnetic fields via asymmetrical gradient encoding/decoding. AB - Applications of conventional localized nuclear magnetic resonance correlated spectroscopy are restrained by long acquisition times and poor performance under inhomogeneous magnetic fields. Here, a method that combines the spatiotemporal encoding technique with the localization technique and implements the encoding and decoding in unison with suitable asymmetrical gradients is proposed to obtain high-resolution localized correlated spectra under inhomogeneous fields in greatly reduced times. Experiments on phantom solutions prove its insensitivity to linear field inhomogeneities along three orthogonal axes. Moreover, this method is applied to adipose study of marrow tissue with resolution improvements. The proposed method may offer promising perspectives for fast analyses of biological tissues. PMID- 25504878 TI - Required role of apoptotic myogenic precursors and toll-like receptor stimulation for the establishment of autoimmune myositis in experimental murine models. AB - OBJECTIVE: Muscle regeneration is a hallmark of the idiopathic inflammatory myopathies (IIMs), a group of autoimmune disorders that are characterized by leukocyte infiltration and dysfunction of the skeletal muscle. Despite detailed studies describing the clinical and histopathologic features of IIMs, the immunopathogenesis of these disorders remains undefined. The aim of this study was to investigate the immunopathologic processes of autoimmune myositis in experimental murine models. METHODS: Expression of the autoantigen histidyl transfer RNA synthetase (HisRS) was analyzed in mice with acutely injured or dystrophic muscles, in inflammatory leukocytes, and in purified satellite cells. Anti-HisRS antibodies and myositis induction were assessed in mice after muscle injury and immunization with apoptotic satellite cells or C2C12 myoblasts, in the presence or absence of the Toll-like receptor 7 (TLR-7) agonist R848. RESULTS: Muscle necrosis, leukocyte infiltration, and myofiber regeneration induced by toxic agents (cardiotoxin or glycerol) or promoted by genetic disruption of the alpha-sarcoglycan/dystrophin complex in mice were uniformly associated with up regulated expression of HisRS. Although regenerating myofibers and purified satellite cells are known to show increased expression of HisRS in these settings, anti-HisRS antibodies were not detectable. However, intramuscular immunization with ultraviolet B-irradiated, HisRS-expressing apoptotic myoblasts in the presence of R848 triggered the production of anti-HisRS IgG antibodies as well as persistent lymphocyte infiltration and prolonged/delayed muscle regeneration. Conversely, intramuscular administration of R848 alone or in combination with living or postapoptotic/necrotic myoblasts failed to generate this myositis phenotype. CONCLUSION: In the presence of TLR/adjuvant signals and underlying muscle injury, apoptotic myogenic precursors expressing high levels of autoantigen can provoke autoantibody formation and lymphocytic infiltration of muscle tissue, effectively replicating the features of IIM. PMID- 25504880 TI - Beyond disease, how biomedical engineering can improve global health. AB - Biomedical engineering tools can be harnessed to address some of the world's most challenging nondisease-focused problems. PMID- 25504881 TI - Visnagin protects against doxorubicin-induced cardiomyopathy through modulation of mitochondrial malate dehydrogenase. AB - Doxorubicin is a highly effective anticancer chemotherapy agent, but its use is limited by its cardiotoxicity. To develop a drug that prevents this toxicity, we established a doxorubicin-induced cardiomyopathy model in zebrafish that recapitulates the cardiomyocyte apoptosis and contractility decline observed in patients. Using this model, we screened 3000 compounds and found that visnagin (VIS) and diphenylurea (DPU) rescue the cardiac performance and circulatory defects caused by doxorubicin in zebrafish. VIS and DPU reduced doxorubicin induced apoptosis in cultured cardiomyocytes and in vivo in zebrafish and mouse hearts. VIS treatment improved cardiac contractility in doxorubicin-treated mice. Further, VIS and DPU did not reduce the chemotherapeutic efficacy of doxorubicin in several cultured tumor lines or in zebrafish and mouse xenograft models. Using affinity chromatography, we found that VIS binds to mitochondrial malate dehydrogenase (MDH2), a key enzyme in the tricarboxylic acid cycle. As with VIS, treatment with the MDH2 inhibitors mebendazole, thyroxine, and iodine prevented doxorubicin cardiotoxicity, as did treatment with malate itself, suggesting that modulation of MDH2 activity is responsible for VIS' cardioprotective effects. Thus, VIS and DPU are potent cardioprotective compounds, and MDH2 is a previously undescribed, druggable target for doxorubicin-induced cardiomyopathy. PMID- 25504882 TI - Protein-releasing polymeric scaffolds induce fibrochondrocytic differentiation of endogenous cells for knee meniscus regeneration in sheep. AB - Regeneration of complex tissues, such as kidney, liver, and cartilage, continues to be a scientific and translational challenge. Survival of ex vivo cultured, transplanted cells in tissue grafts is among one of the key barriers. Meniscus is a complex tissue consisting of collagen fibers and proteoglycans with gradient phenotypes of fibrocartilage and functions to provide congruence of the knee joint, without which the patient is likely to develop arthritis. Endogenous stem/progenitor cells regenerated the knee meniscus upon spatially released human connective tissue growth factor (CTGF) and transforming growth factor-beta3 (TGFbeta3) from a three-dimensional (3D)-printed biomaterial, enabling functional knee recovery. Sequentially applied CTGF and TGFbeta3 were necessary and sufficient to propel mesenchymal stem/progenitor cells, as a heterogeneous population or as single-cell progenies, into fibrochondrocytes that concurrently synthesized procollagens I and IIalpha. When released from microchannels of 3D printed, human meniscus scaffolds, CTGF and TGFbeta3 induced endogenous stem/progenitor cells to differentiate and synthesize zone-specific type I and II collagens. We then replaced sheep meniscus with anatomically correct, 3D-printed scaffolds that incorporated spatially delivered CTGF and TGFbeta3. Endogenous cells regenerated the meniscus with zone-specific matrix phenotypes: primarily type I collagen in the outer zone, and type II collagen in the inner zone, reminiscent of the native meniscus. Spatiotemporally delivered CTGF and TGFbeta3 also restored inhomogeneous mechanical properties in the regenerated sheep meniscus. Survival and directed differentiation of endogenous cells in a tissue defect may have implications in the regeneration of complex (heterogeneous) tissues and organs. PMID- 25504883 TI - Human limbal biopsy-derived stromal stem cells prevent corneal scarring. AB - Conventional allograft therapy for corneal scarring is widespread and successful, but donor tissue is not universally available, and some grafts fail owing to rejection and complications such as endothelial failure. We investigated direct treatment of corneal scarring using autologous stem cells, a therapy that, if successful, could reduce the need for corneal grafts. Mesenchymal cells were expanded from small superficial, clinically replicable limbal biopsies of human cadaveric corneo-scleral rims. Limbal biopsy-derived stromal cells (LBSCs) expanded rapidly in media containing human serum, were highly clonogenic, and could generate spheres expressing stem cell genes (ABCG2, Nestin, NGFR, Oct4, PAX6, and Sox2). Human LBSCs differentiated into keratocytes expressing characteristic marker genes (ALDH3A1, AQP1, KERA, and PTGDS) and organized a thick lamellar stroma-like tissue containing aligned collagen and keratan sulfate proteoglycans when cultured on aligned nanofiber substrata. When engrafted into mouse corneal wounds, LBSCs prevented formation of light-scattering scar tissue containing fibrotic matrix components. The presence of LBSCs induced regeneration of ablated stroma with tissue exhibiting lamellar structure and collagen organization indistinguishable from that of native tissue. Because the limbus can be easily biopsied from either eye of an affected individual and LBSCs capable of corneal stromal remodeling can be expanded under xeno-free autologous conditions, these cells present a potential for autologous stem cell-based treatment of corneal stromal blindness. PMID- 25504884 TI - White matter changes linked to visual recovery after nerve decompression. AB - The relationship between the integrity of white matter tracts and cortical function in the human brain remains poorly understood. We investigate reversible white matter injury, in this case patients with compression of the optic chiasm by pituitary gland tumors, to study the structural and functional changes that attend spontaneous recovery of cortical function and visual abilities after surgical removal of the tumor and subsequent decompression of the nerves. We show that compression of the optic chiasm led to demyelination of the optic tracts, which reversed as quickly as 4 weeks after nerve decompression. Furthermore, variability across patients in the severity of demyelination in the optic tracts predicted visual ability and functional activity in early cortical visual areas. Preoperative measurements of myelination in the optic tracts predicted the magnitude of visual recovery after surgery. These data indicate that rapid regeneration of myelin in the human brain is a component of the normalization of cortical activity, and ultimately the recovery of sensory and cognitive function, after nerve decompression. More generally, our findings demonstrate the use of diffusion tensor imaging as an in vivo measure of myelination in the human brain. PMID- 25504887 TI - Bernardino Ramazzini (1633-1714): a visionary physician, scientist and communicator. PMID- 25504886 TI - Sortase A mediated site-specific immobilization for identification of protein interactions in affinity purification-mass spectrometry experiments. AB - Proteomics approaches using MS in combination with affinity purification have emerged as powerful tools to study protein-protein interactions. Here we make use of the specificity of sortase A transpeptidation reaction to prepare affinity matrices in which a protein bait is covalently linked to the matrix via a short C terminal linker region. As a result of this site-directed immobilization, the bait remains functionally accessible to protein interactions. To apply this approach, we performed SILAC-based pull-down experiments and demonstrate the suitability of the approach. PMID- 25504885 TI - Chronic fetal hypoxia affects axonal maturation in guinea pigs during development: A longitudinal diffusion tensor imaging and T2 mapping study. AB - PURPOSE: To investigate the impact of chronic hypoxia on neonatal brains, and follow developmental alterations and adaptations noninvasively in a guinea pig model. Chronic hypoxemia is the prime cause of fetal brain injury and long-term sequelae such as neurodevelopmental compromise, seizures, and cerebral palsy. MATERIALS AND METHODS: Thirty guinea pigs underwent either normoxic and hypoxemic conditions during the critical stage of brain development (0.7 gestation) and studied prenatally (n = 16) or perinatally (n = 14). Fourteen newborns (7 hypoxia and 7 normoxia group) were scanned longitudinally to characterize physiological and morphological alterations, and axonal myelination and injury using in vivo diffusion tensor imaging (DTI), T2 mapping, and T2 -weighted magnetic resonance imaging (MRI). Sixteen fetuses (8 hypoxia and 8 normoxia) were studied ex vivo to assess hypoxia-induced neuronal injury/loss using Nissl staining and quantitative reverse transcriptase polymerase chain reaction methods. RESULTS: Developmental brains in the hypoxia group showed lower fractional anisotropy in the corpus callosum (-12%, P = 0.02) and lower T2 values in the hippocampus (-16%, P = 0.003) compared with the normoxia group with no differences in the cortex (P > 0.07), indicating vulnerability of the hippocampus and cerebral white matter during early development. Fetal guinea pig brains with chronic hypoxia demonstrated an over 10-fold increase in expression levels of hypoxia index genes such as erythropoietin and HIF-1alpha, and an over 40% reduction in neuronal density, confirming prenatal brain damage. CONCLUSION: In vivo MRI measurement, such as DTI and T2 mapping, provides quantitative parameters to characterize neurodevelopmental abnormalities and to monitor the impact of prenatal insult on the postnatal brain maturation of guinea pigs. PMID- 25504888 TI - Reversible pancytopenia and immunodeficiency in a patient with hereditary folate malabsorption. AB - Mutations in SLC46A1 result in a defect of the proton coupled folate transporter (PCFT) and are the basis of hereditary folate malabsorption (HFM). Patients with HFM frequently present with neurodevelopmental delay and megaloblastic anemia. Some cases may be complicated by additional lymphopenia and immunodeficiency. We report a patient with a new homozygous mutation in the SLC46A1 gene. The boy presented with early-onset pancytopenia and secondary immunodeficiency. We provide clinical and molecular observations that extend the phenotypic description of HFM and highlight diagnostic as well as therapeutic pitfalls in this rare condition. PMID- 25504889 TI - Doped tricalcium phosphate scaffolds by thermal decomposition of naphthalene: Mechanical properties and in vivo osteogenesis in a rabbit femur model. AB - Tricalcium phosphate (TCP) is a bioceramic that is widely used in orthopedic and dental applications. TCP structures show excellent biocompatibility as well as biodegradability. In this study, porous beta-TCP scaffolds were prepared by thermal decomposition of naphthalene. Scaffolds with 57.64% +/- 3.54% density and a maximum pore size around 100 MUm were fabricated via removing 30% naphthalene at 1150 degrees C. The compressive strength for these scaffolds was 32.85 +/- 1.41 MPa. Furthermore, by mixing 1 wt % SrO and 0.5 wt % SiO2 , pore interconnectivity improved, but the compressive strength decreased to 22.40 +/- 2.70 MPa. However, after addition of polycaprolactone coating layers, the compressive strength of doped scaffolds increased to 29.57 +/- 3.77 MPa. Porous scaffolds were implanted in rabbit femur defects to evaluate their biological property. The addition of dopants triggered osteoinduction by enhancing osteoid formation, osteocalcin expression, and bone regeneration, especially at the interface of the scaffold and host bone. This study showed processing flexibility to make interconnected porous scaffolds with different pore size and volume fraction porosity, while maintaining high compressive mechanical strength and excellent bioactivity. Results show that SrO/SiO2 -doped porous TCP scaffolds have excellent potential to be used in bone tissue engineering applications. PMID- 25504891 TI - Trends in the occurrence of new conduction abnormalities after transcatheter aortic valve implantation. AB - OBJECTIVES: The aim of the study was to investigate trends over time in the occurrence of left bundle branch block (LBBB) and permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI) with the Medtronic CoreValve System (MCS) and Edwards SAPIEN Valve (ESV). BACKGROUND: TAVI induced conduction abnormalities (TAVI-CAs) such as LBBB and the need for PPI are frequent postoperative complication. New techniques, procedural refinements, and increased awareness are focused on the reduction of these abnormalities. METHODS: Electrocardiograms of 549 patients without preprocedural LBBB and/or pacemaker were assessed to determine the frequency and nature of TAVI-CAs. To study the effect of experience, patients were subdivided per center into tertiles based on the number of procedures. Univariate and multivariate logistic regression was used to study predictors of TAVI-induced LBBB (TAVI-LBBB) and PPI. RESULTS: TAVI LBBB occurred in 185 patients (33.7%) and significantly decreased over time, from 42.6% to 27.3% (P=0.006). This effect was only significant after implantation of the MCS (59.6% vs. 46.5% vs. 31.1%, P=0.001, ESV: 22.6% vs. 13.1% vs. 24.8%, P=0.11). Between tertiles there was no difference in the frequency of PPI after TAVI (n=73, 13.1% vs. 14.8% vs. 12%, P=0.74). Multivariate analysis revealed that, independent from valve type, depth of implantation was the only significant predictor of TAVI-LBBB (OR [95% C.I.]: 1.16 [1.10-1.24], P<0.001). In case of PPI pre-existing RBBB (OR [95% C.I.]: 7.22 [3.28-15.88], P<0.001) was the only significant predictor. CONCLUSIONS: Over time the frequency of LBBB after TAVI decreased significantly, especially in patients undergoing TAVI with the MCS. Experience and the subsequent reduction in depth of implantation seem responsible for this reduction. Contrary to TAVI-LBBB, the incidence of PPI remained unchanged over time and was not affected by experience. Although experience has led to a decrease in new CAs after TAVI, elucidation of pathophysiologic mechanisms underlying these CAs and subsequent changes in patient stratification, valve design and the procedure are needed to further reduce this complication. PMID- 25504890 TI - Accessing orthographic representations from speech: the role of left ventral occipitotemporal cortex in spelling. AB - The present fMRI study used a spelling task to investigate the hypothesis that the left ventral occipitotemporal cortex (vOT) hosts neuronal representations of whole written words. Such an orthographic word lexicon is posited by cognitive dual-route theories of reading and spelling. In the scanner, participants performed a spelling task in which they had to indicate if a visually presented letter is present in the written form of an auditorily presented word. The main experimental manipulation distinguished between an orthographic word spelling condition in which correct spelling decisions had to be based on orthographic whole-word representations, a word spelling condition in which reliance on orthographic whole-word representations was optional and a phonological pseudoword spelling condition in which no reliance on such representations was possible. To evaluate spelling-specific activations the spelling conditions were contrasted with control conditions that also presented auditory words and pseudowords, but participants had to indicate if a visually presented letter corresponded to the gender of the speaker. We identified a left vOT cluster activated for the critical orthographic word spelling condition relative to both the control condition and the phonological pseudoword spelling condition. Our results suggest that activation of left vOT during spelling can be attributed to the retrieval of orthographic whole-word representations and, thus, support the position that the left vOT potentially represents the neuronal equivalent of the cognitive orthographic word lexicon. PMID- 25504892 TI - Synthesis, culture medium stability, and in vitro and in vivo zebrafish embryo toxicity of metal-organic framework nanoparticles. AB - Metal-organic frameworks (MOFs) are among the most attractive porous materials available today. They have garnered much attention for their potential utility in many different areas such as gas storage, separation, catalysis, and biomedicine. However, very little is known about the possible health or environmental risks of these materials. Here, the results of toxicity studies on sixteen representative uncoated MOF nanoparticles (nanoMOFs), which were assessed for cytotoxicity to HepG2 and MCF7 cells in vitro, and for toxicity to zebrafish embryos in vivo, are reported. Interestingly, there is a strong correlation between their in vitro toxicity and their in vivo toxicity. NanoMOFs were ranked according to their respective in vivo toxicity (in terms of the amount and severity of phenotypic changes observed in the treated zebrafish embryos), which varied widely. Altogether these results show different levels of toxicity of these materials; however, leaching of solubilized metal ions plays a main role. PMID- 25504893 TI - Convergent ecosystem responses to 23-year ambient and manipulated warming link advancing snowmelt and shrub encroachment to transient and long-term climate-soil carbon feedback. AB - Ecosystem responses to climate change can exert positive or negative feedbacks on climate, mediated in part by slow-moving factors such as shifts in vegetation community composition. Long-term experimental manipulations can be used to examine such ecosystem responses, but they also present another opportunity: inferring the extent to which contemporary climate change is responsible for slow changes in ecosystems under ambient conditions. Here, using 23 years of data, we document a shift from nonwoody to woody vegetation and a loss of soil carbon in ambient plots and show that these changes track previously shown similar but faster changes under experimental warming. This allows us to infer that climate change is the cause of the observed shifts in ambient vegetation and soil carbon and that the vegetation responses mediate the observed changes in soil carbon. Our findings demonstrate the realism of an experimental manipulation, allow attribution of a climate cause to observed ambient ecosystem changes, and demonstrate how a combination of long-term study of ambient and experimental responses to warming can identify mechanistic drivers needed for realistic predictions of the conditions under which ecosystems are likely to become carbon sources or sinks over varying timescales. PMID- 25504895 TI - Impact of JIA on parents' work absences. AB - OBJECTIVE: Children with JIA have long-term morbidity and require extensive parental assistance. This study aimed to evaluate the impact of having a child with JIA on parents' missed work time, which can lead to decreased work productivity. METHODS: The Truven Health MarketScan Commercial Database (2000-9) was accessed to identify a cohort of parents having a child with newly diagnosed JIA. For comparison, a cohort of parents having no children with JIA was identified and matched with the preceding cohort. Parents' work absences were analysed using descriptive statistics and multivariable regression. Estimates were weighted to be generalizable to the US employer-sponsored insurance population. RESULTS: The study identified 108 parents having a child with newly diagnosed JIA (mean age 42.5 years), representing an estimated 3335 (weighted) parents nationally. Most of them were from the South (45%), male (71%) and employed in the transportation and utilities industry (58%). The demographic characteristics of the control cohort of parents were generally similar. Children with JIA (mean age 10.6 years) represented an estimated 3528 cases nationally. The mean number of reported missed work-time hours was 281.81 (s.e. 40.50) in a 9 year period for parents having a child with JIA compared with other parents 183.36 (28.55). Work-time loss was significantly related to having a child with JIA, sex and geographical region of residence. Parents having a child with JIA were 2.78 times more likely to report work-time loss [odds ratio (OR) 2.78 (95% CI 1.47, 5.26)] than those having no children with JIA. CONCLUSION: Parents having a child with JIA report significant work-time loss compared with parents with no children having JIA, particularly during the year following the child's diagnosis. PMID- 25504894 TI - Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors. AB - At present, inhibitors of alpha/beta-hydrolase domain 6 (ABHD6) are viewed as a promising approach to treat inflammation and metabolic disorders. This article describes the development of 1,2,5-thiadiazole carbamates as ABHD6 inhibitors. Altogether, 34 compounds were synthesized, and their inhibitory activity was tested using lysates of HEK293 cells transiently expressing human ABHD6 (hABHD6). Among the compound series, 4-morpholino-1,2,5-thiadiazol-3-yl cyclooctyl(methyl)carbamate (JZP-430) potently and irreversibly inhibited hABHD6 (IC50 =44 nM) and showed ~230-fold selectivity over fatty acid amide hydrolase (FAAH) and lysosomal acid lipase (LAL), the main off-targets of related compounds. Additionally, activity-based protein profiling indicated that JZP-430 displays good selectivity among the serine hydrolases of the mouse brain membrane proteome. JZP-430 has been identified as a highly selective, irreversible inhibitor of hABHD6, which may provide a novel approach in the treatment of obesity and type II diabetes. PMID- 25504896 TI - Occurrence of adverse events in patients with JIA receiving biologic agents: long term follow-up in a real-life setting. AB - OBJECTIVE: The aim of this study was to carry out a safety evaluation of biologic agents in patients with JIA and associated uveitis. METHODS: In three tertiary centres in Finland, all adverse events (AEs) in 348 consecutive patients were collected. AEs were classified according to the Common Terminology Criteria for AEs. RESULTS: A total of 1516 patient-years (py) were included: 710 on etanercept, 591 on infliximab, 188 on adalimumab, 8 on rituximab, 5 on anakinra, 6 on tocilizumab, 6 on abatacept and 1 on golimumab. The median follow-up of an individual patient was 51 months (range 1-155). The most common of the 2902 AEs (191/100 py) observed were mild infections, infusion or injection site reactions and alanine aminotransferase elevations. At least one AE occurred in 319 (92%) patients and 121 (35%) had at least one serious AE (SAE). The rate of SAEs was 11.4/100 py on etanercept, 11.8 on infliximab, 10.1 on adalimumab, 15.7 on abatacept, 31.2 on tocilizumab and 87.5 on rituximab, higher than with most anti TNF agents (P = 0.005). No cases of malignant neoplasms or tuberculosis were detected. New-onset uveitis occurred in 9 patients, psoriasis or psoriasiform lesions in 13 and IBD in 6. CONCLUSION: Mild and moderate AEs in patients with JIA treated with biologics were more frequent than previously reported. SAEs were observed in one-third of the patients, but SAEs seldom led to drug discontinuation. PMID- 25504897 TI - Mesenchymal Stem Cells Ameliorate Atherosclerotic Lesions via Restoring Endothelial Function. AB - Transplantation of mesenchymal stem cells (MSCs) is beneficial in myocardial infarction and hind limb ischemia, but its ability to ameliorate atherosclerosis remains unknown. Here, the effects of MSCs on inhibiting endothelial dysfunction and atherosclerosis were investigated in human/mouse endothelial cells treated with oxidized low-density lipoprotein (oxLDL) and in apolipoprotein E-deficient (apoE-/-) mice fed a high-fat diet. Treatment with oxLDL inactivated the Akt/endothelial nitric-oxide synthase (eNOS) pathway, induced eNOS degradation, and inhibited nitric oxide (NO) production in endothelial cells. Coculture with human MSCs reversed the effects of oxLDL on endothelial cells and restored Akt/eNOS activity, eNOS level, and NO production. Reduction of endothelium dependent relaxation and subsequent plaque formation were developed in apoE-/- mice fed a high-fat diet. Systemic infusion with mouse MSCs ameliorated endothelial dysfunction and plaque formation in high-fat diet-fed apoE-/- mice. Interestingly, treatment with interleukin-8 (IL8)/macrophage inflammatory protein 2 (MIP-2) alone induced the similar effects of human/mouse MSCs on oxLDL-treated human/mouse endothelial cells. Neutralization antibodies (Abs) against IL8/MIP-2 also blocked the effects of human/mouse MSCs on oxLDL-treated human/mouse endothelial cells. Consistently, MIP-2 injection alone induced the similar effect of MSCs on the endothelial function in high-fat diet-fed apoE-/- mice. The improvement in endothelial dysfunction by mouse MSCs was also blocked when pretreating MSCs with anti-MIP-2 Abs. In conclusion, MSC transplantation improved endothelial function and plaque formation in high-fat diet-fed apoE-/- mice. Activation of the Akt/eNOS pathway in endothelium by IL8/MIP-2 is involved in the protective effect of MSCs. The study helps support the use and clarify the mechanism of MSCs for ameliorating atherosclerosis. PMID- 25504900 TI - The impact factor of Angewandte Chemie .... AB - What does the Impact Factor tell us? This question is addressed by Peter Glitz in his Editorial, particularly in light of the surprising drop in the 2013 Impact Factor of Angewandte Chemie. An explanation is sought and found. Most importantly the influence of the individual variables that determine the Impact Factor needs to be understood. PMID- 25504898 TI - A systematic review of the association between pleural plaques and changes in lung function. AB - OBJECTIVES: To conduct a systematic review of changes in lung function in relation to presence of pleural plaques in asbestos-exposed populations. METHODS: Database searches of PubMed and Web of Science were supplemented by review of papers' reference lists and journals' tables of contents. Methodological features (eg, consideration of potential confounding by smoking) of identified articles were reviewed by >= two reviewers. Meta-analyses of 20 studies estimated a summary effect of the decrements in per cent predicted (%pred) forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) associated with presence of pleural plaques. RESULTS: Among asbestos-exposed workers, the presence of pleural plaques was associated with statistically significant decrements in FVC (4.09%pred, 95% CI 2.31 to 5.86) and FEV1 (1.99%pred, 95% CI 0.22 to 3.77). Effects of similar magnitude were seen when stratifying by imaging type (X-ray or high-resolution CT) and when excluding studies with potential methodological limitations. Undetected asbestosis was considered as an unlikely explanation of the observed decrements. Several studies provided evidence of an association between size of pleural plaques and degree of pulmonary decrease, and presence of pleural plaques and increased rate or degree of pulmonary impairment. CONCLUSIONS: The presence of pleural plaques is associated with a small, but statistically significant mean difference in FVC and FEV1 in comparison to asbestos-exposed individuals without plaques or other abnormalities. From a public health perspective, small group mean decrements in lung function coupled with an increased rate of decline in lung function of the exposed population may be consequential. PMID- 25504901 TI - Preparation of Pd-Co-based nanocatalysts and their superior applications in formic acid decomposition and methanol oxidation. AB - Formic acid (FA) and methanol, as convenient hydrogen-containing materials, are most widely used for fuel cells. However, using suitable and low-cost catalysts to further improve their energy performance still is a matter of great significance. Herein, PdCo and PdCo@Pd nanocatalysts (NCs) are successfully prepared by the facile method. Pd 3d binding energy decreases due to the presence of Co. Consequently, PdCo@Pd NCs exhibit high catalytic activity and selectivity toward FA dehydrogenation at room temperature. The gas-generation rate at 30 min is 65.4 L h(-1) g(-1) . PdCo/C has the worst catalytic performance in this reaction, despite the fact that it has a high gas-generation rate in the initial 30 min. Furthermore, both PdCo and PdCo@Pd NCs have enhanced electrocatalytic performance toward methanol oxidation. Their maximum currents are 966 and 1205 mA mg(-1) , respectively, which is much higher than monometallic Pd/C. PMID- 25504899 TI - Insulin resistance in rheumatoid arthritis: disease-related indicators and associations with the presence and progression of subclinical atherosclerosis. AB - OBJECTIVE: Systemic inflammation and insulin resistance (IR) are linked, yet the determinants of IR and its impact on atherosclerosis in rheumatoid arthritis (RA) are incompletely understood. The aim of this study was to explore the prevalence of IR in RA and non-RA populations and investigate whether the associations of IR with measures of atherosclerosis differ between these groups. METHODS: IR was quantified using the homeostatic model assessment of IR (HOMA-IR), and was compared between RA patients and demographically matched non-RA controls. Differences in the associations between the HOMA-IR index and the Agatston coronary artery calcium (CAC) score, ultrasound-determined intima-media thickness (IMT) of the common carotid artery (CCA) and internal carotid artery (ICA), and focal plaque in the ICA/carotid bulb were compared according to RA status. RESULTS: Among the 195 RA patients and 198 controls studied, average HOMA-IR levels were higher in the RA group by 31%, and were consistently higher in the RA group regardless of stratification by demographic or cardiometabolic risk factors. While the HOMA-IR index was strongly and significantly associated with C reactive protein (CRP) and interleukin-6 (IL-6) levels in the control group, the association was weaker in the RA group. Among RA patients, higher HOMA-IR levels were associated with rheumatoid factor (RF) seropositivity in men and women, and prednisone use in women only. Before adjustment, higher HOMA-IR levels were associated with all assessed measures of subclinical atherosclerosis in the control group only; associations were diminished and lost statistical significance after adjustment for cardiovascular risk factors. Among the RA patients, neither baseline nor average HOMA-IR levels were significantly associated with change in any of the atherosclerosis measures over an average of 3.2 years of followup. CONCLUSION: Although IR was higher in RA patients than in non-RA controls, higher levels may not independently impart additional risk of atherosclerosis. PMID- 25504902 TI - Compact halo-ligand-conjugated quantum dots for multicolored single-molecule imaging of overcrowding GPCR proteins on cell membranes. AB - To detect single molecules within the optical diffraction limit (< ca. 200 nm), a multicolored imaging technique is developed using Halo-ligand conjugated quantum dots (Halo-QDs; <6 nm in diameter). Using three types of Halo-QDs, multicolored single-molecule fluorescence imaging of GPCR proteins in Dictyostelium cells is achieved. PMID- 25504903 TI - A competing risk analysis of hormone therapy interruption in Asian women with breast cancer. AB - PURPOSE: This study aimed to use a competing risk approach to evaluate the probability of the occurrence of hormone therapy (HT) interruption and to assess its associated predictors in Asian women with breast cancer. METHODS: This retrospective cohort study used the Taiwan Health Insurance Research Database from 2003 to 2011. Reimbursement data for women with newly diagnosed primary breast cancer were extracted. Interruption (gap >= 180 days) and time to first interruption of HT were identified. The probability of interruption was analysed by Kaplan-Meier (KM) method and cumulative incidence competing risk (CICR) method. Competing risk regressions were used to assess the predictors of interruption. RESULTS: The 5-year cumulative incidence of first HT interruption was 14% versus 13% estimated by the KM and the CICR methods, respectively. The estimated incidences from CICR method tended to be around 11% lower than KM method in various HT utilization patterns. Younger (<=50 years) age at diagnosis, switching HT and the presence of HT-related adverse events were identified as predictors of interruption in competing risk regressions. CONCLUSIONS: The competing risk approach provided lower probabilities and estimates when investigating the incidence of first interruption than the standard survival analysis. The competing risk method, which takes into account the competing risks from cancer recurrence and death, should be considered in future analysis. In terms of improving persistence of HT, it is important to focus on patients of younger age at diagnosis, HT switching and experiencing adverse events. PMID- 25504904 TI - Identification of essential steps in laser procedure for twin-twin transfusion syndrome using the Delphi methodology: SILICONE study. AB - OBJECTIVE: To determine, by expert consensus, the essential substeps of fetoscopic laser surgery (FLS) for twin-twin transfusion syndrome (TTTS) that could be used to create an authority-based curriculum for training in this procedure among fetal medicine specialists. METHODS: A Delphi survey was conducted among an international panel of experts (n = 98) in FLS. Experts rated the substeps of FLS on a five-point Likert-type scale to indicate whether they considered them to be essential, and were able to comment on each substep, using a dedicated online platform accessed by the invited tertiary care facilities that specialize in fetal therapy. Responses were returned to the panel until consensus was reached (Cronbach's alpha >= 0.80). All substeps that were rated >= 4 by 80% of the experts were included in the evaluation instrument. RESULTS: After the first iteration of the Delphi procedure, a response rate of 74% (73/98) was reached, and in the second and third iterations response rates of 90% (66/73) and 81% (59/73) were reached, respectively. Among a total of 81 substeps rated in the first round, 21 substeps had to be re-rated in the second round. Finally, from the initial list of substeps, 55 were agreed by experts to be essential. In the third round, the 18 categorized substeps were ranked in order of importance, with 'coagulation of all anastomoses that cross the equator' and 'determination of fetoscope insertion site' as the most important. CONCLUSIONS: A total of 55 substeps of FLS for TTTS were defined by a panel of experts to be essential in the procedure. This list is the first authority-based evidence to be used in the development of a final training model for future fetal surgeons. PMID- 25504906 TI - Thalamic involvement in paroxysmal kinesigenic dyskinesia: a combined structural and diffusion tensor MRI analysis. AB - Alteration of basal ganglia-thalamocortical circuit has been hypothesized to play a role in the pathophysiology underlying paroxysmal kinesigenic dyskinesia (PKD). We investigated macrostructural and microstructural changes in PKD patients using structural and diffusion tensor magnetic resonance imaging (MRI) analyses. Twenty five patients with idiopathic PKD and 25 control subjects were prospectively studied on a 3T magnetic resonance (MR) scanner. Cortical thickness analysis was used to evaluate cortical gray matter (GM) changes, and automated volumetry and shape analysis were used to assess volume changes and shape deformation of the subcortical GM structures, respectively. Tract-based spatial statistics (TBSS) was used to evaluate white matter integrity changes in a whole-brain manner, and region-of-interest (ROI) analysis of diffusion tensor metrics was performed in subcortical GM structures. Compared to controls, PKD patients exhibited a reduction in volume of bilateral thalami and regional shape deformation mainly localized to the anterior and medial aspects of bilateral thalami. TBSS revealed an increase in fractional anisotropy (FA) of bilateral thalami and right anterior thalamic radiation in patients relative to controls. ROI analysis also showed an increase in FA of bilateral thalami in patients compared to controls. We have shown evidence for thalamic abnormalities of volume reduction, regional shape deformation, and increased FA in patients with PKD. Our novel findings of concomitant macrostructural and microstructural abnormalities in the thalamus lend further support to previous observations indicating causal relationship between a preferential lesion in the thalamus and development of PKD, thus providing neuroanatomical basis for the involvement of thalamus within the basal ganglia-thalamocortical pathway in PKD. PMID- 25504905 TI - High-resolution quantitative proteome analysis reveals substantial differences between phagosomes of RAW 264.7 and bone marrow derived macrophages. AB - Macrophages are important immune cells operating at the forefront of innate immunity by taking up foreign particles and microbes through phagocytosis. The RAW 264.7 cell line is commonly used for experiments in the macrophage and phagocytosis field. However, little is known how its functions compare to primary macrophages. Here, we have performed an in-depth proteomics characterization of phagosomes from RAW 264.7 and bone marrow derived macrophages by quantifying more than 2500 phagosomal proteins. Our data indicate that there are significant differences for a large number of proteins including important receptors such as mannose receptor 1 and Siglec-1. Moreover, bone marrow derived macrophages phagosomes mature considerably faster by fusion with endosomes and the lysosome which we validated using fluorogenic phagocytic assays. We provide a valuable resource for researcher in the field and recommend careful use of the RAW 264.7 cell line when studying phagosome functions. All MS data have been deposited in the ProteomeXchange with identifier PXD001293 (http://proteomecentral.proteomexchange.org/dataset/PXD001293). PMID- 25504907 TI - Highly regio- and enantioselective synthesis of N-substituted 2-pyridones: iridium-catalyzed intermolecular asymmetric allylic amination. AB - The first iridium-catalyzed intermolecular asymmetric allylic amination reaction with 2-hydroxypyridines has been developed, thus providing a highly efficient synthesis of enantioenriched N-substituted 2-pyridone derivatives from readily available starting materials. This protocol features a good tolerance of functional groups in both the allylic carbonates and 2-hydroxypyridines, thereby delivering multifunctionalized heterocyclic products with up to 98% yield and 99% ee. PMID- 25504908 TI - Highly enantioselective [3+2] cycloaddition of vinylcyclopropane with nitroalkenes catalyzed by palladium(0) with a chiral bis(tert-amine) ligand. AB - An enantioselective [3+2] cycloaddition of vinyl cyclopropane derived from 1,3 indanedione with nitroalkenes catalyzed by palladium(0) with a chiral bis(tert amine) ligand was developed in high yields with good diastereoselectivities and excellent enantioselectivities. The resulting bis(tert-amine)-palladium complex proved to be a highly efficient catalyst for this cycloaddition. PMID- 25504909 TI - Late coronary BVS malapposition and aneurysm: A Time for Appraisal. AB - Late strut malapposition of currently available stents is a major issue, associated with an increased risk of stent thrombosis. To this day, biovascular scaffolds showed an increased immediate risk of struts malapposition, that however resulted reduced after a few months. Little is known about late acquired struts malapposition of biovascular scaffolds. We here describe two cases that recently occurred in our patients, and we speculate on possible mechanisms for this unexpected and potentially lethal complication. PMID- 25504910 TI - Human pressures predict species' geographic range size better than biological traits. AB - Geographic range size is the manifestation of complex interactions between intrinsic species traits and extrinsic environmental conditions. It is also a fundamental ecological attribute of species and a key extinction risk correlate. Past research has primarily focused on the role of biological and environmental predictors of range size, but macroecological patterns can also be distorted by human activities. Here, we analyse the role of extrinsic (biogeography, habitat state, climate, human pressure) and intrinsic (biology) variables in predicting range size of the world's terrestrial mammals. In particular, our aim is to compare the predictive ability of human pressure vs. species biology. We evaluated the ability of 19 intrinsic and extrinsic variables in predicting range size for 4867 terrestrial mammals. We repeated the analyses after excluding restricted-range species and performed separate analyses for species in different biogeographic realms and taxonomic groups. Our model had high predictive ability and showed that climatic variables and human pressures are the most influential predictors of range size. Interestingly, human pressures predict current geographic range size better than biological traits. These findings were confirmed when repeating the analyses on large-ranged species, individual biogeographic regions and individual taxonomic groups. Climatic and human impacts have determined the extinction of mammal species in the past and are the main factors shaping the present distribution of mammals. These factors also affect other vertebrate groups globally, and their influence on range size may be similar as well. Measuring climatic and human variables can allow to obtain approximate range size estimations for data-deficient and newly discovered species (e.g. hundreds of mammal species worldwide). Our results support the need for a more careful consideration of the role of climate change and human impact - as opposed to species biological characteristics - in shaping species distribution ranges. PMID- 25504911 TI - Heterometallic Sr(II) -M(II) (M=Co, Ni, Zn and Cu) coordination polymers: synthesis, temperature-dependent structural transformation, and luminescent and magnetic properties. AB - The use of pyridine-2,4-dicarboxylic acid (H2 pydc) in the construction of Sr(II) and Sr(II) -M(II) (M=Co, Ni, Zn and Cu) coordination polymers is reported. Eight complexes, that is, [Sr(pydc)H2 O]n (1), [MSr(pydc)2 (H2 O)2 ]n (M=Co (2), Ni (3), Zn (4)), [ZnSr(pydc)2 (H2 O)7 ]n ?4 nH2 O (5), [SrCu(pydc)2 ]n (6), [SrCu(pydc)2 (H2 O)3 ]n ?2 nH2 O (7), and [Cu3 Sr2 (pydc)4 (Hpydc)2 (H2 O)2 ]n (8), have been synthesized via dexterously choosing the appropriate strontium sources and transition metal salts, and rationally controlling the temperature of the reaction systems. Complexes 1, 2 (3, 4), 6, and 8 display four types of 3-D framework structures. Complexes 5 and 7 exhibit a 2-D network and a 1-D chain structure, respectively. The 2-D complex 7 can be reversibly transformed into 3-D compound 6 through temperature-induced solvent-mediated structural transformation. The luminescent property studies indicated that complex 1 shows a strong purple luminescent emission and 4 exhibits a strong violet luminescence emission. The magnetic properties of 2, 3, and 8 were also studied. Antiferromagnetic M(II) ???M(II) interactions were determined for these complexes. PMID- 25504912 TI - Editorial: Fate of fat tissue adipocytes: do they transform into myofibroblasts in scleroderma? PMID- 25504913 TI - Synergistic effect between defect sites and functional groups on the hydrolysis of cellulose over activated carbon. AB - The chemical oxidation of activated carbon by H2 O2 and H2 SO4 is investigated, structural and chemical modifications are characterized, and the materials are used as catalysts for the hydrolysis of cellulose. Treatment with H2 O2 enlarges the pore size and imparts functional groups such as phenols, lactones, and carboxylic acids. H2 SO4 treatment targets the edges of carbon sheets primarily, and this effect is more pronounced with a higher temperature. Adsorption isotherms demonstrate that the adsorption of oligomers on functionalized carbon is dominated by van der Waals forces. The materials treated chemically are active for the hydrolysis of cellulose despite the relative weakness of most of their acid sites. It is proposed that a synergistic effect between defect sites and functional groups enhances the activity by inducing a conformational change in the glucan chains if they are adsorbed at defect sites. This activates the glycosidic bonds for hydrolysis by in-plane functional groups. PMID- 25504914 TI - Characterization of the gene cluster CYP264B1-geoA from Sorangium cellulosum So ce56: biosynthesis of (+)-eremophilene and its hydroxylation. AB - Terpenoids can be found in almost all forms of life; however, the biosynthesis of bacterial terpenoids has not been intensively studied. This study reports the identification and functional characterization of the gene cluster CYP264B1-geoA from Sorangium cellulosum So ce56. Expression of the enzymes and synthesis of their products for NMR analysis and X-ray diffraction were carried out by employing an Escherichia coli whole-cell conversion system that provides the geoA substrate farnesyl pyrophosphate through simultaneous overexpression of the mevalonate pathway genes. The geoA product was identified as a novel sesquiterpene, and assigned NMR signals unambiguously proved that geoA is an (+) eremophilene synthase. The very tight binding of (+)-eremophilene (~0.40 MUM), which is also available in S. cellulosum So ce56, and its oxidation by CYP264B1 suggest that the CYP264B1-geoA gene cluster is required for the biosynthesis of (+)-eremophilene derivatives. PMID- 25504916 TI - Nanopatterned surfaces based on template-assisted multilayer electrodeposition. AB - Selective, template-assisted growth of electrodeposited, layered materials leads to the top-down designable realization of nanopatterned surfaces with a large surface area (>1 cm(2)) comprised of multi-dimensional, multiscale (10 nm-1 MUm) features, without the need of standard nanolithography. This process opens a manufacturable route to functional nanodevices that rely on anisotropic, nanoscale surface structures with controlled dimensions. PMID- 25504915 TI - Factors affecting time to maintenance dose in patients initiating warfarin. AB - PURPOSE: Patients starting warfarin often experience lengthy dose-titration periods, when they are at high risk for bleeding and thromboembolism. However, relatively little is known about why some patients take longer than others to reach maintenance dose. Thus, we sought to identify social, clinical, and genetic factors associated with prolonged time to maintenance dose (TTM). METHODS: We conducted a time-to-event analysis, using a prospective cohort of patients initiating warfarin (N = 390). Additionally, we examined whether changes in post initiation factors were associated with TTM. Finally, we performed a secondary analysis in a subcohort (N = 156) assessing the effect of adherence on TTM. RESULTS: No genetic or post-initiation factors were significantly associated with TTM. However, previous use of warfarin [hazard ratio (HR) = 0.64; 95% confidence interval (CI) 0.46, 0.88], current smoking status (HR = 0.61; 95%CI 0.39, 0.96), fewer than four doctor's visits in the previous year (HR = 0.63 vs 4-12 visits; 95%CI 0.46, 0.88), and worse general health status (HR = 0.63; 95%CI 0.47, 0.84) were significantly associated with longer TTM. Use of illegal injectable drugs (HR = 2.51; 95%CI 1.17, 5.39) was associated with shorter TTM. On secondary analysis, the HR for better adherence and TTM was 1.70 (95%CI 0.88, 3.27). CONCLUSIONS: Time to maintenance dose was associated with pre-existing behavioral factors, health care utilization, and health quality but not clinical comorbidities or genetic factors in patients initiating warfarin. Future studies are needed to determine whether warfarin patients with prolonged TTM would have better outcomes on alternative agents. PMID- 25504917 TI - Exploring analytical proteomics platforms toward the definition of human cardiac stem cells receptome. AB - Human cardiac stem cells (hCSC) express a portfolio of plasma membrane receptors that are involved in the regulatory auto/paracrine feedback loop mechanism of activation of these cells, and consequently contribute to myocardial regeneration. In order to attain a comprehensive description of hCSC receptome and overcoming the inability demonstrated by other technologies applied in receptor identification, mainly due to the transmembrane nature, high hydrophobic character and relative low concentration of these proteins, we have exploited and improved a proteomics workflow. This approach was based on the enrichment of hCSC plasma membrane fraction and addition of prefractionation steps prior to MS analysis. More than 100 plasma membrane receptors were identified. The data reported herein constitute a valuable source of information to further understand cardiac stem cells activation mechanisms and the subsequent cardiac repair process. All MS data have been deposited in the ProteomeXchange with identifier PXD001117 (http://proteomecentral.proteomexchange.org/dataset/PXD001117). PMID- 25504918 TI - Effective connectivity during episodic memory retrieval in schizophrenia participants before and after antipsychotic medication. AB - BACKGROUND: Impairment in episodic memory is one of the most robust findings in schizophrenia. Disruptions of fronto-temporal functional connectivity that could explain some aspects of these deficits have been reported. Recent work has identified abnormal hippocampal function in unmedicated patients with schizophrenia (SZ), such as increased metabolism and glutamate content that are not always seen in medicated SZ. For these reasons, we hypothesized that altered fronto-temporal connectivity might originate from the hippocampus and might be partially restored by antipsychotic medication. METHODS: Granger causality methods were used to evaluate the effective connectivity between frontal and temporal regions in 21 unmedicated SZ and 20 matched healthy controls (HC) during performance of an episodic memory retrieval task. In 16 SZ, effective connectivity between these regions was evaluated before and after 1-week of antipsychotic treatment. RESULTS: In HC, significant effective connectivity originating from the right hippocampus to frontal regions was identified. Compared to HC, unmedicated SZ showed significant altered fronto-temporal effective connectivity, including reduced right hippocampal to right medial frontal connectivity. After 1-week of antipsychotic treatment, connectivity more closely resembled the patterns observed in HC, including increased effective connectivity from the right hippocampus to frontal regions. CONCLUSIONS: These results support the notion that memory disruption in schizophrenia might originate from hippocampal dysfunction and that medication restores some aspects of fronto-temporal dysconnectivity. Patterns of fronto-temporal connectivity could provide valuable biomarkers to identify new treatments for the symptoms of schizophrenia, including memory deficits. PMID- 25504920 TI - Redox-neutral alpha-allylation of amines by combining palladium catalysis and visible-light photoredox catalysis. AB - An unprecedented alpha-allylation of amines was achieved by combining palladium catalysis and visible-light photoredox catalysis. In this dual catalysis process, the catalytic generation of allyl radical from the corresponding pi allylpalladium intermediate was achieved without additional metal reducing reagents (redox-neutral). Various allylation products of amines were obtained in high yields through radical cross-coupling under mild reaction conditions. Moreover, the transformation was applied to the formal synthesis of 8 oxoprotoberberine derivatives which show potential anticancer properties. PMID- 25504919 TI - Reproducibility of first- and second-trimester uterine artery pulsatility index measured by transvaginal and transabdominal ultrasound. AB - OBJECTIVES: To examine and compare the reproducibility of measurement of first- and second-trimester uterine artery pulsatility index (UtA-PI) using transabdominal (TAS) and transvaginal (TVS) ultrasound. METHODS: This was an observational study including women >= 18 years of age, with a singleton pregnancy, in the first trimester (between 11 + 0 and 13 + 6 weeks' gestation) or second trimester (between 20 and 26 weeks' gestation). UtA-PI and angle of insonation were assessed by two observers (one with 15 and the other with 3 years of experience) using both TAS and TVS. The more experienced observer performed two scans alternated by the other observer. The acquisitions were completely independent and the observers were blinded to each other and to their own measurements. Reproducibility of the measurements by TVS and TAS was assessed using the concordance correlation coefficients (CCCs), intraclass correlation coefficients (ICCs) and limits of agreement (LoA). RESULTS: We analyzed data from 97 women in the first trimester and 96 in the second trimester. The mean +/- SD UtA-PI was significantly higher when measured using TVS, compared with TAS, in both the first (1.60 +/- 0.49 vs 1.52 +/- 0.63, respectively; P = 0.03) and second (1.07 +/- 0.33 vs 0.96 +/- 0.32, respectively; P < 0.001) trimesters. The median angle of insonation was significantly lower when using TVS, compared with TAS, in both the first (8.0 degrees (interquartile range (IQR), 2.5-16.3 degrees ) vs 12.5 degrees (IQR, 2.5-20.0 degrees ), respectively; P = 0.04) and second (10.0 degrees (IQR, 4.5-16.5 degrees ) vs 17.5 degrees (IQR, 5.0-27.9 degrees ), respectively; P < 0.001) trimesters. Both ultrasound techniques had similar reproducibility: the intraobserver CCC ranged from 0.93 to 0.95 and the interobserver CCC ranged from 0.81 to 0.86; and the ICCs of both techniques were highly comparable (the intraobserver LoA was approximately +/- 20-30% and the interobserver LoA was approximately +/- 30-40%). CONCLUSIONS: When measuring UtA PI, assessment by TVS provides higher values and better insonation angle compared with TAS. The reproducibility of the ultrasound methods in both first and second trimesters of pregnancy was comparable and should not be considered as good. Future studies examining technical improvements with the aim of increasing the reproducibility of this technique should be encouraged. PMID- 25504921 TI - On the reactivity of tetrakis(trifluoromethyl)cyclopentadienone towards carbon based Lewis bases. AB - The reactivitiy of tetrakis(trifluoromethyl)cyclopentadienone towards different C based Lewis bases, such as N-heterocyclic carbenes (NHC), ylides and isonitriles, are reported. While sterically not hindered carbenes were found to yield kinetic adducts by regiospecific nucleophilic attack at the position adjacent to the carbonyl group of the ketone, bulkier nucleophiles afforded the thermodynamically more stable O-bridged zwitterions. Interestingly, isonitriles were found to dimerize and trimerize under the same reaction conditions, forming bicyclic products that evolve differently depending on the nature of the substituents. PMID- 25504922 TI - Repeated STI and HIV testing among HIV-negative men who have sex with men attending a large STI clinic in Amsterdam: a longitudinal study. AB - OBJECTIVE: In the Netherlands, men who have sex with men (MSM) are advised via informal guidelines to test for STI at least annually. We estimated the proportion of HIV-negative MSM testing repeatedly at 12-month or smaller intervals at a large STI clinic in the Netherlands. In addition, we explored whether repeated testing is related to risk behaviour. DESIGN AND METHODS: Longitudinal data of HIV-negative MSM visiting the Amsterdam STI clinic between 2009 and 2012 were analysed. To estimate the timing of repeated testing, Kaplan Meier methods were used. Determinants for repeated testing (distinguishing testing at 12-month or smaller intervals and less than 12-monthly testing, with single testers as reference group) were identified using multivariate multinomial logistic regression analyses. RESULTS: In total, 19,479 consultations of 9174 HIV negative MSM were identified. Of these MSM, 35% (95% CI 33% to 36%) were estimated to return to the STI clinic within 1 year following baseline consultation. Among 1767 men with at least two consultations and at least 2 years between baseline and last consultation, 43% tested repeatedly at 12-month or smaller intervals in those first 2 years. Repeated testers reported higher sexual risk behaviour (ie, only casual or both casual and steady sex partners, higher numbers of sex partners) at baseline compared with single testers. This effect tended to be slightly stronger for men testing repeatedly at 12-month or smaller intervals. CONCLUSIONS: The proportion of MSM testing for STI annually is low. MSM testing repeatedly had higher baseline levels of risk behaviour. Strategies to motivate MSM to test annually should be explored. PMID- 25504923 TI - Device closure of secundum atrial septal defect in a 4.5 kilogram infant: Novel use of the Amplatzer DuctOccluder II device. AB - Modest secundum atrial septal defects (2 degrees ASD) may cause significant pulmonary over perfusion during infancy, particularly in conjunction with left heart obstructive lesions. Amplatzer Septal Occluders are not ideal in this setting especially given recent concerns regarding device erosion. We report the first use of the Amplatzer Duct Occluder II device (ADO2) to close a 2 degrees ASD in a 4.5 kg infant. PMID- 25504924 TI - Expeditious synthesis of enantiopure, orthogonally protected bis-alpha-amino acids (OPBAAs) and their use in a study of Nod1 stimulation. AB - A convenient approach towards the synthesis of orthogonally protected chiral bis alpha-amino acids (OPBAAs) is described. The key transformations include: (1) a highly stereoselective conjugation (alkylation) of the Schollkopf bis-lactim ethers and oxazolidinyl alkyl halides to build a backbone skeleton; and (2) our orthogonal protection strategy. A series of enantiopure OPBAAs bearing a variety of alkyl chain as a spacer; two stereogenic centers; and three protecting groups were prepared as examples. These versatile molecules were applied to the synthesis of biologically interesting di- or tri-peptide analogues, including chiral iE-meso-DAP and A-iE-meso-DAP, for the study of Nod1 activation in the innate immune response. PMID- 25504925 TI - Associational susceptibility in broccoli: mediated by plant volatiles, impeded by ozone. AB - Plant-emitted volatile organic compounds (VOCs) mediate interactions within a plant community. Typically, receiving a signal from a damaged neighbour enhances the defensive attributes of a receiver plant. The mechanisms underlying plant plant interactions may be divided into active and passive processes, both of which involve transit of VOCs between plants and are vulnerable to environmental perturbation. Numerous studies have documented between-plant interactions, but the specific effects on a receiver plant's interactions with herbivores have received little attention. Moreover, the relative contributions of active and passive processes to plant defence and the effects of environmental pollutants on the processes have been largely unexplored. We used a system comprising Brassica oleracea var. italica (broccoli) and the specialist herbivore Plutella xylostella to test whether plants previously exposed to herbivore-damaged neighbours differed from nonexposed plants in their susceptibility to oviposition. We then investigated the roles of active and passive mechanisms in our observations and whether differences in susceptibility remained under elevated ozone concentrations. Plants exposed to herbivore-damaged neighbours were more susceptible to oviposition than plants exposed to undamaged neighbours, which indicates associational susceptibility. Mechanistically, active and passive volatile-mediated processes occurred in tandem with the passive process - involving adsorption of sesquiterpenes to receiver plants - appearing to structure the oviposition response. Exposure to ozone rapidly degraded the sesquiterpenes and eliminated the associational susceptibility. Plant volatiles have typically been thought to play roles in between-plant interactions and to promote receiver plant defence. Here, we show that receiver plants may also become more susceptible to oviposition and thus more likely to be damaged. Extensive disruption of volatile-mediated interactions by an atmospheric pollutant highlights the need to consider the pervading environment and changes therein when assessing their ecological significance. PMID- 25504926 TI - Modeling the evolution of complex genetic systems: the gene network family tree. AB - In 1994 and 1996, Andreas Wagner introduced a novel model in two papers addressing the evolution of genetic regulatory networks. This work, and a suite of papers that followed using similar models, helped integrate network thinking into biology and motivate research focused on the evolution of genetic networks. The Wagner network has its mathematical roots in the Ising model, a statistical physics model describing the activity of atoms on a lattice, and in neural networks. These models have given rise to two branches of applications, one in physics and biology and one in artificial intelligence and machine learning. Here, we review development along these branches, outline similarities and differences between biological models of genetic regulatory circuits and neural circuits models used in machine learning, and identify ways in which these models can provide novel insights into biological systems. PMID- 25504927 TI - The role of the Pax1/9 gene in the early development of amphioxus pharyngeal gill slits. AB - The pharynx is a major characteristic of chordates. Compared with vertebrates, amphioxus has an advantage for the study of pharynx development, as embryos lack neural crest, and the pharynx is mainly derived from endoderm cells. The Pax1/9 subfamily genes have essential roles in vertebrate pharyngeal patterning, but it is not known if the Pax1/9 gene has similar functions in amphioxus pharynx development. To answer this question, we examined the Pax1/9 gene expression pattern in amphioxus embryos at different developmental stages, and observed morphological changes following Pax1/9 knockdown. RT-qPCR analysis indicated that Pax1/9 expression was initiated during early neurula stage and rapidly peaked during mid-neurula stage. Furthermore, in situ hybridization analysis showed that Pax1/9 transcripts were localized exclusively in the most endodermal region of the developing pharynx in early neurula stage embryos; however, Pax1/9 expression was strikingly down-regulated in the region where gill slits would form from the fusion of endoderm and ectoderm in subsequent developmental stages and was maintained in the border regions between adjacent gill slits. Knockdown of Pax1/9 function using both morpholino and siRNA approaches led to embryonic defects in the first three gill slits, and fusion of the first two gill slits. Moreover, the expression levels of the pharyngeal marker genes Six1/2 and Tbx1/10 were reduced in Pax1/9 knockdown embryos. From these observations, we concluded that the Pax1/9 gene has an important role in the initial differentiation of amphioxus pharyngeal endoderm and in the formation of gill slits, most likely via modulation of Six1/2 and Tbx1/10 expression. PMID- 25504928 TI - Molecular events in adaptive evolution of the hatching strategy of ovoviviparous fishes. AB - Ovoviviparous fish, whose embryonic development and hatching take place in the maternal body, is one of the good model organisms for studying adaptive evolution. Using genome database of the ovoviviparous platy Xiphophorus maculatus, we tried to search hatching enzyme genes (high choriolytic enzyme HCE and low choriolytic enzyme LCE) and egg envelope protein genes (choriogenin H, Hm, and L). Analysis of genes co-localized with them confirmed that shared synteny was found between platy and medaka genome. Both hatching enzyme genes HCE and LCE were pseudogenized in platy. In addition, one of the three choriogenin genes Hm was completely lost from the genome, the other two genes H and L encoded functional proteins. On the other hand, the expression of H and L was very low as compared to oviparous fishes, and the platy egg envelope was extremely thinner. Considering that ovoviviparous fish embryos are protected in the maternal body, an importance of egg envelope for protection of egg/embryo would be reduced in the ovoviviparous fishes. Platy embryos would escape from their thin egg envelope without help of hatching enzymes. In another ovoviviparous fish, black rockfish belonging to different order from the platy, one of the hatching enzyme genes has been reported to be pseudogenized, that is, the embryo of black rockfish can escape from egg envelope by only one hatching enzyme HCE. Adaptive evolution of the hatching strategy of ovoviviparous teleosts may be established by pseudogenization of hatching enzyme genes and/or lowering of expression and/or pseudogenization of hatching enzyme and egg envelope genes. PMID- 25504929 TI - Expression of a retinoic acid receptor (RAR)-like protein in the embryonic and adult nervous system of a protostome species. AB - The vitamin A metabolite, retinoic acid, is an important molecule in nervous system development and regeneration in vertebrates. Retinoic acid signaling in vertebrates is mediated by two classes of nuclear receptors, the retinoid X receptors (RXRs) and the retinoic acid receptors (RARs). Recently, evidence has emerged to suggest that many effects of retinoic acid are conserved between vertebrate and invertebrate nervous systems, even though the RARs were previously thought to be a vertebrate innovation and to not exist in non-chordates. We have cloned a full-length putative RAR from the CNS of the mollusc Lymnaea stagnalis (LymRAR). Immunoreactivity for the RAR protein was found in axons of adult neurons in the central nervous system and in growth cones of regenerating neurons in vitro. A vertebrate RAR antagonist blocked growth cone turning induced by exogenous all-trans retinoic acid, possibly suggesting a role for this receptor in axon guidance. We also provide immunostaining evidence for the presence of RAR protein in the developing, embryonic CNS, where it is also found in axonal processes. Using qPCR, we determined that LymRAR mRNA is detectable in the early veliger stage embryo and that mRNA levels increase significantly during embryonic development. Putative disruption of retinoid signaling in Lymnaea embryos using vertebrate RAR antagonists resulted in abnormal eye and shell development and in some instances completely halted development, resembling the effects of all-trans retinoic acid. This study provides evidence for RAR functioning in a protostome species. PMID- 25504930 TI - Structure and development of male pheromone gland of longicorn beetles and its phylogenetic relationships within the tribe Clytini. AB - The male sex pheromone of the longicorn beetle, Xylotrechus pyrrhoderus pyrrhoderus Bates (Cerambycidae: Tribe Clytini) plays an important role in attracting females. This pheromone is produced by the pheromone gland located in the prothorax. However, the detailed structure and underlying developmental process of this gland are still unknown. We investigated the gland structure by using histological analysis and confirmed that the gland consists of the following parts: gland cell mass, a unique spherical space in the cuticle layer, and ductules connecting the gland cells with the spherical space and conducting canals to the outer opening. The gland structure first appeared male-specific in the late pupal stage, during which the epidermal cells began depositing the exocuticle; the development of the gland was completed after adult emergence. Furthermore, we verified the structural equivalents of the X. p. pyrrhoderus male pheromone gland in 11 species of 2 tribes, Clytini and Anaglyptini. The glands of these insects could be classified into four types on the basis of the absence or presence of the spherical space and the division of the gland cell mass layer. Most noteworthy, all the species with the spherical space and division-type gland were restricted to the Xylotrechus clade, as inferred from the molecular phylogenetic analysis. These results suggest that Clytini and Anaglyptini species share a fundamental process of male pheromone gland development, and that the Japanese Xylotrechus species might have established their current status by developing distinct structural features in the male pheromone gland. PMID- 25504931 TI - Sialic acid-binding immunoglobulin-type lectin H-positive plasmacytoid dendritic cells drive spontaneous lupus-like disease development in B6.Nba2 mice. AB - OBJECTIVE: Patients with systemic lupus erythematosus (SLE) often present with elevated levels of interferon-alpha (IFNalpha) in serum. Plasmacytoid dendritic cells (pDCs) have been suggested to be the primary source of IFNalpha in SLE due to their capacity to produce high levels of IFNalpha. During viral infection, a subset of pDCs expressing sialic acid-binding immunoglobulin-type lectin H (Siglec H) produces the majority of pDC-derived IFNalpha. The aim of this study was to provide evidence that Siglec H-positive pDCs are pathogenic in the IFNalpha-dependent B6.Nba2 mouse model of lupus. METHODS: B6.Nba2 blood dendritic cell antigen 2 (BDCA-2)-diphtheria toxin receptor (DTR)-transgenic (Tg) mice were treated intraperitoneally with DT 3 times weekly starting at 4 weeks or 12 weeks of age and analyzed at 12 weeks and 18 weeks of age, respectively. Lupus-like disease development was measured by the presence of elevated levels of autoantibodies in serum (as determined by enzyme-linked immunosorbent assay), increased expression of IFN-inducible genes (as determined by real-time reverse transcription-polymerase chain reaction), increased IgG immune complex deposition in kidney glomeruli (as determined by immunofluorescence staining), spontaneous lymphocyte activation, and differentiation of B cells into antibody-producing plasma cells (as determined by flow cytometry). RESULTS: B6.Nba2 mice in which Siglec H-positive pDCs were depleted for 6-8 weeks displayed reduced levels of IFNalpha-induced gene transcripts and decreased anti-chromatin autoantibody levels in serum, and significantly fewer activated splenic T cells and B cells, germinal center B cells, follicular helper T cells, and splenic plasma cells. In 18-week-old mice, IgG immune complex deposition in kidney glomeruli was similarly reduced. CONCLUSION: The development of lupus-like disease in congenic B6.Nba2 mice depends on Siglec H-positive pDCs. We suggest that depletion of Siglec H positive pDCs represents a novel cellular target in SLE. PMID- 25504932 TI - Site-directed and global incorporation of orthogonal and isostructural noncanonical amino acids into the ribosomal lasso peptide capistruin. AB - Expansion of the structural diversity of peptide antibiotics was performed through two different methods. Supplementation-based incorporation (SPI) and stop codon suppression (SCS) approaches were used for co-translational incorporation of isostructural and orthogonal noncanonical amino acids (ncAAs) into the lasso peptide capistruin. Two ncAAs were employed for the SPI method and five for the SCS method; each of them probing the incorporation of ncAAs in strategic positions of the molecule. Evaluation of the assembly by HR-ESI-MS proved more successful for the SCS method. Bio-orthogonal chemistry was used for post biosynthetic modification of capistruin congener Cap_Alk10 containing the ncAA Alk (Nepsilon-Alloc-L-lysine) instead of Ala. A second-generation Hoveyda-Grubbs catalyst was used for an in vitro metathesis reaction with Cap_Alk10 and an allyl alcohol, which offers options for post-biosynthetic modifications. The use of synthetic biology allows for the in vivo production of new peptide-based antibiotics from an expanded amino acid repertoire. PMID- 25504933 TI - Striatal shape abnormalities as novel neurodevelopmental endophenotypes in schizophrenia: a longitudinal study. AB - There are varying, often conflicting, reports with respect to altered striatal volume and morphometry in the major psychoses due to the influences of antipsychotic medications on striatal volume. Thus, disassociating disease effects from those of medication become exceedingly difficult. For the first time, using a longitudinally studied sample of structural magnetic resonance images from patients with childhood onset schizophrenia (COS; neurobiologically contiguous with the adult onset form of schizophrenia), their nonpsychotic siblings (COSSIBs), and novel shape mapping algorithms that are volume independent, we report the familial contribution of striatal morphology in schizophrenia. The results of our volumetric analyses demonstrate age-related increases in overall striatal volumes specific only to COS. However, both COS and COSSIBs showed overlapping shape differences in the striatal head, which normalized in COSSIBs by late adolescence. These results mirror previous studies from our group, demonstrating cortical thickness deficits in COS and COSSIBs as these deficits normalize in COSSIBs in the same age range as our striatal findings. Finally, there is a single region of nonoverlapping outward displacement in the dorsal aspect of the caudate body, potentially indicative of a response to medication. Striatal shape may be considered complimentary to volume as an endophenotype, and, in some cases may provide information that is not detectable using standard volumetric techniques. Our striatal shape findings demonstrate the striking localization of abnormalities in striatal the head. The neuroanatomical localization of these findings suggest the presence of abnormalities in the striatal-prefrontal circuits in schizophrenia and resilience mechanisms in COSSIBs with age dependent normalization. PMID- 25504934 TI - Adverse and Advantageous Selection in the Medicare Supplemental Market: A Bayesian Analysis of Prescription drug Expenditure. AB - This paper develops an extended specification of the two-part model, which controls for unobservable self-selection and heterogeneity of health insurance, and analyzes the impact of Medicare supplemental plans on the prescription drug expenditure of the elderly, using a linked data set based on the Medicare Current Beneficiary Survey data for 2003-2004. The econometric analysis is conducted using a Bayesian econometric framework. We estimate the treatment effects for different counterfactuals and find significant evidence of endogeneity in plan choice and the presence of both adverse and advantageous selections in the supplemental insurance market. The average incentive effect is estimated to be $757 (2004 value) or 41% increase per person per year for the elderly enrolled in supplemental plans with drug coverage against the Medicare fee-for-service counterfactual and is $350 or 21% against the supplemental plans without drug coverage counterfactual. The incentive effect varies by different sources of drug coverage: highest for employer-sponsored insurance plans, followed by Medigap and managed medicare plans. PMID- 25504935 TI - Elementary steps of iron catalysis: exploring the links between iron alkyl and iron olefin complexes for their relevance in C-H activation and C-C bond formation. AB - The alkylation of complexes 2 and 7 with Grignard reagents containing beta hydrogen atoms is a process of considerable relevance for the understanding of C H activation as well as C-C bond formation mediated by low-valent iron species. Specifically, reaction of 2 with EtMgBr under an ethylene atmosphere affords the bis-ethylene complex 1 which is an active precatalyst for prototype [2+2+2] cycloaddition reactions and a valuable probe for mechanistic studies. This aspect is illustrated by its conversion into the bis-alkyne complex 6 as an unprecedented representation of a cycloaddition catalyst loaded with two substrates molecules. On the other hand, alkylation of 2 with 1 equivalent of cyclohexylmagnesium bromide furnished the unique iron alkyl species 11 with a 14 electron count, which has no less than four beta-H atoms but is nevertheless stable at low temperature against beta-hydride elimination. In contrast, the exhaustive alkylation of 1 with cyclohexylmagnesium bromide triggers two consecutive C-H activation reactions mediated by a single iron center. The resulting complex has a diene dihydride character in solution (15), whereas its structure in the solid state is more consistent with an eta(3) -allyl iron hydride rendition featuring an additional agostic interaction (14). Finally, the preparation of the cyclopentadienyl iron complex 25 illustrates how an iron mediated C-H activation cascade can be coaxed to induce a stereoselective C?C bond formation. The structures of all relevant new iron complexes in the solid state are presented. PMID- 25504936 TI - Behavioral Health Screening in Pediatric Primary Care: A Pilot Study. AB - This pilot study investigated the effect of the Pediatric Symptom Checklist (PSC) on identification of and physician response to behavioral health (BH) concerns. Researchers reviewed 1211 charts of youth aged 4 to 16 years. Records were compared during baseline and an intervention consisting of implementation of the PSC to determine the rate of BH identification and pediatrician response. Access to PSC data resulted in a trivial difference in BH concerns identified by physicians and did not affect physician responses. This case study demonstrates that simply implementing BH screening in primary care may not result in improved outcomes for these children. PMID- 25504938 TI - United States Physical Therapists' Knowledge About Joint Hypermobility Syndrome Compared with Fibromyalgia and Rheumatoid Arthritis. AB - BACKGROUND: Joint hypermobility syndrome (JHS) is one of the most common inherited connective tissue disorders. It causes significant pain and disability for all age groups, ranging from developmental delay among children to widespread chronic pain in adults. Experts in JHS assert that the condition is under recognized and poorly managed. PURPOSE: The aim of this study was to assess US physical therapists' knowledge about JHS compared with other causes of widespread pain and activity limitations: fibromyalgia, juvenile rheumatoid arthritis and adult rheumatoid arthritis. METHODS: Cross-sectional, Internet-based survey of randomly selected members of the American Physical Therapy Association and descriptive statistics were used to explore physical therapists' knowledge about JHS, fibromyalgia, juvenile rheumatoid arthritis and adult rheumatoid arthritis, and chi square was used to compare knowledge about the different conditions. RESULTS: The response rate was 15.5% (496). Although 36% recognized the Beighton Scale for assessing joint hypermobility, only 26.8% of respondents were familiar with the Brighton Criteria for diagnosing JHS. Few respondents (11-19%) realized that JHS has extra-articular features such as anxiety disorder, fatigue, headache, delayed motor development, easy bruising and sleep disturbance. Physical therapists working in environments most likely to see patients with JHS underestimated the likely prevalence in their patient population. CONCLUSIONS: The results suggest that many physical therapists in the United States are not familiar with the diagnostic criteria, prevalence or common clinical presentation of JHS. PMID- 25504939 TI - First reported use of drug-eluting bioabsorbable vascular scaffold in congenital heart disease. AB - The aim of catheter intervention for vascular stenosis is the restoration of lumen area and optimization of distal blood flow. In pediatric practice, this has traditionally been a compromise between less effective balloon angioplasty and bare metal stent insertion with its attendant limitations of size. Bioabsorbable stents offer short-term relief of stenosis, radial support of the healing lesion, return of endothelial function and crucially, in children, the potential for long term growth. Initial experience, in pediatric practice, with metal-based bioabsorbable stents was relatively disappointing with frequent restenosis secondary to early reabsorption. Design modifications resulting in polymer-based, drug eluting, bioabsorbable vascular scaffolds (BVS) have reportedly overcome some of these faults. We describe the first reported use of a drug eluting BVS in three patients with: (1) A newborn with severe right pulmonary artery (RPA) stensosis post repair of type two common arterial trunk. (2) A child with pulmonary atresia/ventricular septal defect (VSD) and major aorto-pulmonary collateral arteries (MAPCAs), and (3) An infant with severe left pulmonary artery (LPA) stenosis in the setting of an LPA sling. PMID- 25504940 TI - Assessment of ovarian reserve by antral follicle count in ovaries with endometrioma. AB - OBJECTIVE: To evaluate whether the antral follicle count (AFC) is underestimated in the presence of an endometrioma. METHODS: This was a retrospective cohort study assessing all women undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) at our clinic between January 2011 and December 2012 who had both ovaries and unilateral endometrioma. The primary outcome of the study was the difference between AFC and the number of oocytes retrieved per ovary. RESULTS: Within the study period 787 women underwent IVF/ICSI at our clinic. Sixty of these women had at least one endometrioma, but 23 were excluded from the analysis as six had only one ovary and 17 had bilateral endometriomas. Therefore a total of 37 women were included in this study and analysis. Compared with the contralateral ovaries, ovaries with an endometrioma were significantly larger in volume (median, 10.3 (interquartile range (IQR), 4.7 18.9) cm(3) vs median, 3.6 (IQR, 2.7-6.5) cm(3); P < 0.001) and presented a significantly lower AFC (median, 3.0 (IQR, 1.0-6.0) vs median, 5.0 (IQR, 2.0 6.5); P = 0.001). However, the median number of oocytes retrieved was similar (P = 0.60) between ovaries with an endometrioma (2.0 (IQR, 0.5-5.0)) and the contralateral ovaries (2.0 (IQR, 0.0-4.0)). Accordingly, the median difference between AFC and number of oocytes retrieved was significantly smaller (P = 0.005) for ovaries with an endometrioma (0.0 (IQR, -1.0 to 1.5) than for those without (2.0 (IQR, 0.0-4.0)). CONCLUSIONS: Although the AFC is reduced in ovaries with an endometrioma, the number of oocytes retrieved is similar, suggesting that the AFC is underestimated in such ovaries. We believe that this is a consequence of an impaired ability to detect small follicles in the presence of an endometrioma. PMID- 25504942 TI - Direct alcohol fuel cells: toward the power densities of hydrogen-fed proton exchange membrane fuel cells. AB - A 2 MUm thick layer of TiO2 nanotube arrays was prepared on the surface of the Ti fibers of a nonwoven web electrode. After it was doped with Pd nanoparticles (1.5 mgPd cm(-2) ), this anode was employed in a direct alcohol fuel cell. Peak power densities of 210, 170, and 160 mW cm(-2) at 80 degrees C were produced if the cell was fed with 10 wt % aqueous solutions of ethanol, ethylene glycol, and glycerol, respectively, in 2 M aqueous KOH. The Pd loading of the anode was increased to 6 mg cm(-2) by combining four single electrodes to produce a maximum peak power density with ethanol at 80 degrees C of 335 mW cm(-2) . Such high power densities result from a combination of the open 3 D structure of the anode electrode and the high electrochemically active surface area of the Pd catalyst, which promote very fast kinetics for alcohol electro-oxidation. The peak power and current densities obtained with ethanol at 80 degrees C approach the output of H2 -fed proton exchange membrane fuel cells. PMID- 25504943 TI - Oxidative intercalation for monometallic Ni(2+) -Ni(3+) layered double hydroxide and enhanced capacitance in exfoliated nanosheets. AB - Monometallic Ni(2+) -Ni(3+) layered double hydroxide (LDH) is prepared using a simple oxidative intercalation process and may be further exfoliated into positively charged Ni(OH)2 unilamellar sheets. The superior capacitive behavior of the unilamellar sheets stranded in carbon nanotubes (CNTs) networks is achieved because of the complete interfacial charge storage arising from the confined Faradaic reactions at the interfacial region. 3D nanosheet/CNT composites are prepared using an in situ electrostatic assembly of positive charged sheets with CNTs bearing negative charges. The restacking of active nanosheets during electrochemical cycling is effectively prohibited. Consequently, the outstanding specific capacitance and remarkable rate capability of the nanosheet/CNT hybrid electrodes are demonstrated, making them promising candidates for high performance supercapacitors, combining high-energy storage densities with high levels of power delivery. PMID- 25504945 TI - Predatory publishing: what authors, reviewers, and editors need to know. PMID- 25504944 TI - Synergistic approach to elucidate the incorporation of magnesium ions into hydroxyapatite. AB - Although the content of Mg(2+) in hard tissues is very low (typically <=1.5 wt %), its incorporation into synthetic hydroxyapatite (HAp) particles and its role in the mineral's properties are still subject of intensive debate. A combined experimental-computational approach is used to answer many of the open questions. Mg(2+) -enriched HAp particles are prepared using different synthetic approaches and considering different concentrations of Mg(2+) in the reaction medium. The composition, morphology and structure of the resulting particles are investigated using X-ray photoelectron spectroscopy, energy dispersive X-ray spectroscopy, scanning and transmission electron microscopies, FTIR, and wide-angle X-ray diffraction. After this scrutiny, the role of the Mg(2+) in the first nucleation stages, before HAp formation, is investigated using atomistic molecular dynamics simulations. Saturated solutions are simulated with and without the presence of DNA, which has been recently used as a soft template in the biomineralization process. This synergistic investigation provides a complete picture of how Mg(2+) ions affect the mineralization from the first stages onwards. PMID- 25504946 TI - The nature of sleep in 10 bedridden elderly patients with disorders of consciousness in a Japanese hospital. AB - No previous study has satisfactorily clarified the nature of sleep in elderly bedridden people with disorders of consciousness (DOC). The objective of the present study was to clarify the sleep states of 10 elderly bedridden patients with DOC in a Japanese hospital to facilitate provision of evidence-based nursing care and appropriate adjustment of patients' environments. Nocturnal polysomnography recordings were analyzed according to the standard scoring criteria, and the patients' sleep stages and quality were investigated. Of the 10 patients, 9 showed slow wave sleep (SWS), 4 showed very high values for sleep efficiency (96-100%), and in 3 of these patients, the percentage of SWS was >= 20%. Furthermore, three of these four patients had 200 or more changes in sleep stage. Although the mechanism is unknown, the amount of SWS combined with the value of sleep efficiency suggests that the quality of sleep is poor in elderly bedridden patients with DOC. Further study is needed to determine better indicators of good sleep in this population. PMID- 25504947 TI - Impaired autonomic nervous system activity during sleep in family caregivers of ambulatory dementia patients in Japan. AB - The number of dementia patients requiring care is rapidly increasing in Japan. Consequently, a large percentage of family members, including spouses and children of those with dementia, are assuming the role of primary caregiver. Many caregivers develop health problems including sleep disorders. Some report poor quality of sleep even when sleep duration is normal. In the present study, we used actigraphy and heart rate variability spectral analysis to assess autonomic nervous system activity and quality of sleep in family caregivers of people with ambulatory dementia. The 20 caregivers who participated in our study exhibited significantly higher levels of sympathetic nervous system activity during sleep than noncaregivers. This abnormal activity was most prominent during the first half of the sleep period and was not related to overall sleep duration. We propose that relaxation is inhibited during the first half of the sleep period in this caregiver population. This may be due to increased stress, as caregivers of people with ambulatory dementia may worry about their patients waking and wandering at night, potentially injuring themselves. Our findings indicate a need for increased support for caregivers of people with dementia, including the assessment and treatment of sleep disorders. PMID- 25504948 TI - Diurnal fatigue patterns, sleep timing, and mental health outcomes among healthy postpartum women. AB - Postpartum women have frequently interrupted sleep, report high levels of fatigue, and may experience circadian rhythm disruptions. They are also susceptible to mood impairments, anxiety, and stress. The current study explored associations between maternal postpartum daily fatigue patterns, which should vary according to circadian influences and mental health. Seventy-one primiparous, healthy mothers completed multiple daily self-reports of fatigue during postpartum Weeks 2 and 12 and were categorized at each week as having either a rhythmic or random fatigue pattern during the daytime. Wrist actigraphy data were used to calculate sleep midpoints. Surveys assessed chronotype, mood, anxiety, and stress. At postpartum Week 2, there were no differences in mental health measures between fatigue groups. At postpartum Week 12, higher overall fatigue levels were associated with increased anxiety, stress, and mood disruption. However, overall fatigue levels did not differ between fatigue groups. Women with a rhythmic fatigue pattern reported significantly less stress and more vigor than women with a random fatigue pattern. An earlier sleep midpoint was associated with a rhythmic fatigue pattern during postpartum Week 12. These data suggest that, despite similar average daily fatigue levels, having a rhythmic daily pattern of fatigue may be advantageous for mental health outcomes among postpartum women. PMID- 25504949 TI - Effects of exercise on biobehavioral outcomes of fatigue during cancer treatment: results of a feasibility study. AB - Cancer treatment is associated with decreased hemoglobin (Hb) concentration and aerobic fitness (VO2 max), which may contribute to cancer-related fatigue (CRF) and decreased quality of life (QoL). Endurance exercise may attenuate CRF and improve QoL, but the mechanisms have not been thoroughly investigated. Objectives. To (a) determine the feasibility of conducting an exercise intervention among women receiving treatment for breast cancer; (b) examine the effects of exercise on Hb and VO2 max and determine their association with changes in CRF and QoL; and (c) investigate changes in selected inflammatory markers. Methods. Fourteen women receiving chemotherapy for Stages I-II breast cancer were randomly assigned to exercise (n = 7) or usual care (n = 7). Women in the exercise group performed supervised, individualized treadmill exercise 2-3 times/week for the duration of chemotherapy (9-12 weeks). Data were collected 4 times over 15-16 weeks. Results. Recruitment rate was 45.7%. Sixteen women consented and 14 completed the trial, for a retention rate of 87.5%. Adherence to exercise protocol was 95-97%, and completion of data collection was 87.5-100%. Exercise was well tolerated. VO2 max was maintained at prechemotherapy levels in exercisers but declined in the usual-care group (p < .05). Hb decreased (p < .001) in all participants as they progressed through chemotherapy. Exercise did not have significant effects on CRF or QoL. Changes in inflammatory markers favored the exercise group. CONCLUSIONS: Exercise during chemotherapy may protect against chemotherapy-induced decline in VO2 max but not Hb concentration. PMID- 25504950 TI - A reinvestigation of seroconversion rates in hepatits B-vaccinated individuals. AB - The purpose of this study was to examine whether the hepatitis B seroconversion rates in a small sample of subjects reflected that of the published rates, regardless of HIV status, after a hepatitis B vaccination series was completed while following strict vaccine protocols. The study, which had a nonexperimental, correlational cross-sectional design, took place at a community clinic in Laguna Beach, CA. Participants comprised 100, predominantly White, men aged 18-65 years (mean 39.2 years) who were hepatitis B naive, regardless of immune status. After receiving a primary vaccine series for hepatitis B, participants were tested for seroconversion to immune status. Seroconversion to the immune state occurred in 78.6% of the non-immunocompromised, HIV-negative participants (n = 50), who had received the standard three-dose regimen of the vaccine, and in 77% of the immunocompromised, HIV-positive participants (n = 48), who had received the recommended modified three-double-dose regimen. The manufacturer-published rates of seroconversion are 90-100%, depending upon the population. These findings highlight a need for further study to validate or reveal deficits in current vaccine protocols for individuals who are vaccinated against hepatitis B, including health care workers, the immune-compromised and other high-risk populations. PMID- 25504951 TI - Comparison of renal function indicators according to hydration volume in patients receiving intravenous acyclovir with CNS infection. AB - PURPOSE: We aimed to compare the changes in renal function indicators as a function of hydration volume in patients treated with acyclovir for suspected herpes simplex virus (HSV) infection. METHOD: We obtained data from 216 acyclovir treated patients hospitalized between 2007 and 2012 for suspected HSV infection. Intravenous hydration volume and renal function indicators (serum creatinine [sCr], blood urea nitrogen [BUN], glutamate oxaloacetate transferase, glutamate pyruvate transferase, and uric acid levels; estimated glomerular filtration rate [eGFR]; and urine pH) were compared among the patients. The indicators were assessed before acyclovir infusion and after 3 days of acyclovir infusion. RESULTS: Before acyclovir infusion, all the indicators were within normal ranges in all groups (hydration volume lower than 2 L/day, higher than 2 L/day, and without hydration). After acyclovir infusion for 3 days, the groups without hydration and with a volume lower than 2 L/day showed increased sCr (2.22 +/- 0.51 and 1.70 +/- 0.35 mg/dl, respectively), BUN levels (28.33 +/- 0.57 and 22.14 +/- 7.95 mg/dl, respectively), and glutamate oxaloacetate transferase (48.00 +/- 2.65 IU/L, without hydration) and eGFRs lower than the normal range (53.03 +/- 3.05 and 59.66 +/- 10.25 ml/min, respectively; p < .001 for all parameters). The renal function indicators were within normal limits in the group with a hydration volume higher than 2 L/day. CONCLUSIONS: Renal function indicators in acyclovir treated patients varied according to hydration volume. Health care providers should consider whether the hydration volume in each patient receiving intravenous acyclovir is sufficient for preventing nephropathy. PMID- 25504952 TI - Mechanisms of alpha-mangostin-induced antinociception in a rodent model. AB - OBJECTIVE: Elucidate the antinociceptive mechanisms of alpha-mangostin isolated from Garcinia malaccensis Linn. METHODS: Male mice/rats (n = 6/group) were used in this between-group study. To determine alpha-mangostin's antinociceptive profile, animals were given alpha-mangostin orally (3, 30, or 100 mg/kg) 60 min before the start of the abdominal constriction or formalin tests. In the hot plate test, the noxious stimulus was applied before and 60, 90, 120, 150, 180, and 210 min after treatment with test solutions. Positive controls received 100 mg/kg acetylsalicylic acid (ASA; oral) or 5 mg/kg morphine (intraperitoneal injection) for the abdominal constriction and hot plate tests, respectively, and either ASA or morphine for the formalin test. Negative controls received vehicle only. To explore alpha-mangostin's mechanisms of action, we performed (i) the hot plate test with naloxone (5 mg/kg) pretreatment to verify involvement of opioid receptors; (ii) the abdominal constriction test with 20 mg/kg l-arginine, N(G) nitro-l-arginine methyl esters (l-NAME), methylene blue (MB), l-arginine plus l NAME, or l-arginine plus MB or 10 mg/kg glibenclamide pretreatment to verify involvement of the l-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) and K+-ATP pathways; and (iii) the paw-licking test using capsaicin (1.6 MUg capsaicin/paw), glutamate (10 MUmol glutamate/paw), or phorbol 12-myristate 13-acetate (PMA; 0.05 ug/paw) to verify involvement of vanilloid receptors, the glutamatergic system, and protein kinase C (PKC). RESULTS: alpha-mangostin significantly inhibited nociception (p < .05) in all models. Only naloxone, l arginine, methylene blue, PMA, and glibenclamide affected alpha-mangostin antinociception significantly (p < .05). CONCLUSION: alpha-mangostin exhibits peripheral and central antinociception through modulation of opioid and vanilloid receptors, the glutamatergic system, and the l-arginine/NO/cGMP/PKC/K(+)-ATP pathways. PMID- 25504953 TI - Relationship between the pH of enema solutions and intestinal damage in rabbits. AB - Mechanical enemas can lead to intestinal mucosal injuries and bowel barrier damage, presenting as electrolyte disturbances and functional intestinal disorders. Most researchers believe that the mechanism of injury is related to osmolality, volume and temperature of the solution, infusion pressure, and the composition of the enema tube. We hypothesized that the pH of the enema solution may also contribute to intestinal damage. We administered enema solutions--normal saline, soapsuds, or vinegar (neutral, alkaline, or acidic solutions, respectively)--to three groups of rabbits (n = 20 per group). The solutions were standardized for volume and temperature and the soapsuds and vinegar solutions were adjusted to be isotonic with normal saline or deionized water. We also included a control group (n = 20) in which the enema tubes were inserted but no solution was administered. We biopsied 3 sites (rectum and distal and proximal colon). Damage to intestinal mucosa was observed by light microscopy and transmission electron microscopy. In order to explore the detection of damage using noninvasive methods, cyclooxygenase (COX)-2 gene expression was measured in the exfoliated cells gathered from postenema defecation. Epithelial loss, inflammatory reaction, and cellular microstructure damage was increased in the vinegar and soapsuds groups. Also, exfoliated cells in these groups had higher COX-2 expression than the normal saline group. The acidic and alkaline enema solutions thus caused more severe damage to the intestinal mucosa compared to the neutral liquid, supporting our hypothesis. Further, the detection of COX-2 expression shows promise as a noninvasive method for estimating enema-induced damage. PMID- 25504955 TI - The healthy newborn hydration model: a new model for understanding newborn hydration immediately after birth. AB - The normal small volume of breast milk produced in the first 2 days following birth may raise concerns about adequate hydration in breast-fed newborns. These concerns are further magnified when breast-fed infants lose >=7% of their birth weight within 2 days postnatally. Weight loss following birth is presumably mostly water loss that could result in hypohydration and subsequent hypernatremic dehydration. However, excess fluid loss immediately following birth is a normal and necessary process. Furthermore, newborns exposed to excess fluid intake during labor may need to lose >=7% of birth weight in the first 2 days following birth in order to achieve euhydration. Normal newborn fluid loss following birth confounds the use of weight loss as the sole measure of newborn hydration. We thus propose the healthy newborn hydration model that highlights the normalcy of newborn weight loss immediately following birth and the healthy newborn's compensatory mechanisms for preserving adequate hydration. We also recommend the use of serum sodium to measure intravascular osmolarity in addition to monitoring weight loss to obtain a more comprehensive newborn hydration assessment. Research is necessary in healthy newborns to identify relationships among fluids received in utero, newborn weight loss, and hydration, as evaluated with laboratory measures, in the first 2 days following birth. This information will guide clinicians in correctly identifying newborns with inadequate hydration who are in need of supplementary fluids versus newborns with adequate hydration for whom exclusive breast-feeding can be supported and encouraged. PMID- 25504954 TI - A systematic review of genetic influences on coping. AB - Coping refers to the way that an individual manages stress. Coping strategies vary; for example, problem-focused coping is directed at reducing or removing a stressor, while emotion-focused coping is directed more at managing reactions that accompany the stressor. How individuals cope with stress can impact their health, but the physiological effects of coping are not well understood. The field of genetics provides tools that could help illuminate the physiology of coping. This review of the literature was conducted to determine what is currently known about the phenotype of coping from a genetic perspective. PubMed, HubMed, PsychInfo, Medline, Scopus, and Google Scholar databases were used to conduct the search, and reference lists were reviewed to identify additional publications. Only studies that measured coping style or a coping domain specifically, were written in English language, and were human-subject focused were included in the review. We identified 19 studies that met these criteria, and 2 types of genetic studies emerged for the review: heritability (n = 9) and candidate gene association (n = 10) studies. Heritability estimates of .68-.76 support a nonadditive genetic component to coping. Replication of association was found for the serotonin transporter and adrenergic receptor beta 2 genes. In addition to finding evidence supporting a role for genetic variability with coping phenotype, it is worth noting that the review revealed a lack of consistency in instruments used to phenotype coping across studies. PMID- 25504956 TI - Measurement of acute pain in infants: a review of behavioral and physiological variables. AB - BACKGROUND: The use of non-validated pain measurement tools to assess infant pain represents a serious iatrogenic threat to the developing neonatal nervous system. One partial explanation for this practice may be the contradictory empirical data from studies that use newborn pain management tools constructed for infants of different developmental stages or exposed to different environmental stressors. PURPOSE: The purpose of this review is to evaluate the evidence regarding the physiologic and behavioral variables that accurately assess and measure acute pain response in infants. METHODOLOGY: A literature search was conducted using PUBMED and CINAHL and the search terms infant, neonate/neonatal, newborn, pain, assessment, and measurement to identify peer-reviewed studies that examined the validity and reliability of behavioral and physiological variables used for investigation of infant pain. Ten articles were identified for critical review. PRINCIPAL FINDINGS: Strong evidence supports the use of the behavioral variables of facial expressions and body movements and the physiologic variables of heart rate and oxygen saturation to assess acute pain in infants. CONCLUSION: It is incumbent upon researchers and clinical nurses to ensure the validity, reliability, and feasibility of pain measures, so that the outcomes of their investigations and interventions will be developmentally appropriate and effective pain management therapies. PMID- 25504957 TI - Fetal response to live and recorded maternal speech. AB - The purpose of this study was to compare the fetal response to live and recorded maternal speech following a lengthy history of exposure to a passage spoken by the mother. Participants comprised a convenience sample of 21 pregnant women. The women recited an assigned passage (nursery rhyme) twice daily from 28 to 34 weeks' gestational age (GA), and their fetuses were tested at 34 weeks' GA. During testing, fetal heart rate and movement were measured in response to two different formats of the assigned passage: maternal live voicing and a recording of the mother speaking the passage. The fetal cardiac response varied depending upon the format; however, fetal movement did not. A minimal cardiac deceleration occurred in response to live voicing compared to a cardiac acceleration in response to the recorded format. This is the first study to show differences in the fetal cardiac response to a passage spoken live compared to a recording of the passage following a lengthy history of controlled fetal exposure to the multimodal characteristics of maternal speech. Given the differential response to a live voicing compared to a recorded format, future study that incorporates lengthier exposure to the multimodal characteristics of maternal speech may be warranted. PMID- 25504958 TI - Synthesis of heterocycles by formal cycloadditions of isocyanides. AB - Synthetic methodology for the synthesis of heterocycles is of continuous and high interest with applications in materials, catalysis, and medicines. Multicomponent reactions are suitable tools to efficiently generate chemically diverse sets of heterocycles with sufficient structural complexity. Especially isocyanides have proven to be particularly versatile building blocks in these one-pot processes. Due to their electronic structure, isocyanides are able to act sequentially or simultaneously as a nucleophile and an electrophile. Traditionally, isocyanides are therefore frequently used in multicomponent chemistry. In the recent literature, numerous reactions have been reported that involve formal cycloadditions of isocyanides with conjugated heterodienes. This Focus Review aims at mapping this reactivity and at providing insight into the relationship between the various reported reaction partners and the observed reactivity modes. PMID- 25504960 TI - Dual-energy computed tomography molecular imaging of pigmented villonodular synovitis. PMID- 25504959 TI - Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors. AB - OBJECTIVE: Accumulation of myofibroblasts in fibrotic skin is a hallmark of systemic sclerosis (SSc; scleroderma), but the origins of these cells remain unknown. Because loss of intradermal adipose tissue is a consistent feature of cutaneous fibrosis, we sought to examine the hypothesis that myofibroblasts populating fibrotic dermis derive from adipocytic progenitors. METHODS: We performed genetic fate mapping studies to investigate the loss of intradermal adipose tissue and its potential role in fibrosis in mice with bleomycin-induced scleroderma. Modulation of adipocytic phenotypes ex vivo was investigated in adipose tissue-derived cells in culture. RESULTS: A striking loss of intradermal adipose tissue and its replacement with fibrous tissue were consistently observed in mice with bleomycin-induced fibrosis. Loss of adipose tissue and a decline in the expression of canonical adipogenic markers in lesional skin preceded the onset of dermal fibrosis and expression of fibrogenic markers. Ex vivo, subcutaneous adipocytes were driven by transforming growth factor beta to preferentially undergo fibrogenic differentiation. Cell fate mapping studies in mice with the adiponectin promoter-driven Cre recombinase transgenic construct indicated that adiponectin-positive progenitors that are normally confined to the intradermal adipose tissue compartment were distributed throughout the lesional dermis over time, lost their adipocytic markers, and expressed myofibroblast markers in bleomycin-treated mice. CONCLUSION: These observations establish a novel link between intradermal adipose tissue loss and dermal fibrosis and demonstrate that adiponectin-positive intradermal progenitors give rise to dermal myofibroblasts. Adipose tissue loss and adipocyte-myofibroblast transition might be primary events in the pathogenesis of cutaneous fibrosis that represent novel potential targets for therapeutic intervention. PMID- 25504961 TI - Tocilizumab in the treatment of patients with AA amyloidosis secondary to familial Mediterranean fever. PMID- 25504962 TI - Obesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis. AB - OA is a degenerative joint disease characterized by articular cartilage degradation, osteophyte formation, synovitis, and subchondral bone sclerosis. One of OAs main risk factors is obesity. To date, it is not fully understood how obesity results in OA. Historically, this link was ascribed to excessive joint loading as a result of increased body weight. However, the association between obesity and OA in non-weight-bearing joints suggests a more complex aetiology for obesity-induced OA. In the present review, the link between obesity and OA is discussed. First, the historical view of altered joint loading leading to wear and tear of the joint is addressed. Subsequently, the effects of a disturbed lipid metabolism, low-grade inflammation, and adipokines on joint tissues are discussed and linked to OA. Taken together, inflamed adipose tissue and dyslipidaemia play pivotal roles in obesity-induced OA. It becomes increasingly clear that the link between obesity and OA transcends excessive loading. PMID- 25504963 TI - Crystal structure of HydG from Carboxydothermus hydrogenoformans: a trifunctional [FeFe]-hydrogenase maturase. AB - The structure of the radical S-adenosyl-L-methionine (SAM) [FeFe]-hydrogenase maturase HydG involved in CN(-) /CO synthesis is characterized by two internal tunnels connecting its tyrosine-binding pocket with the external medium and the C terminal Fe4 S4 cluster-containing region. A comparison with a tryptophan-bound NosL structure suggests that substrate binding causes the closing of the first tunnel and, along with mutagenesis studies, that tyrosine binds to HydG with its amino group well positioned for H-abstraction by SAM. In this orientation the dehydroglycine (DHG) fragment caused by tyrosine Calpha-Cbeta bond scission can readily migrate through the second tunnel towards the C-terminal domain where both CN(-) and CO are synthesized. Our HydG structure appears to be in a relaxed state with its C-terminal cluster CysX2 CysX22 Cys motif exposed to solvent. A rotation of this domain coupled to Fe4 S4 cluster assembly would bury its putatively reactive unique Fe ion thereby allowing it to interact with DHG. PMID- 25504965 TI - The quality of patient-centred care: haematological cancer survivors' perceptions. AB - OBJECTIVE: Patient-reported outcome measures (PROMs) that assess the quality of patient-centred cancer care have failed to measure all six patient-centredness dimensions endorsed by the Institute of Medicine (IOM). This study is the first to use the Quality of Patient-Centered Cancer Care (QPCCC) measure that covers all six IOM patient-centredness dimensions to examine haematological cancer survivors' perceptions of care and characteristics associated with perceived quality of care. METHODS: Haematological cancer survivors diagnosed in the last 6 years and aged 18-80 years were recruited from two Australian state population based cancer registries. Survivors were mailed the 48-item QPCCC measure. RESULTS: Overall, 545 haematological cancer survivors completed the measure. Areas of care most commonly identified as delivered were hospital staff showing respect to survivors (93%) and making sure the correct treatment was received (93%). Aspects of care most frequently nominated as not delivered were hospital staff helping family and friends (34%) or the survivor (32%) to find other people with similar experiences to talk to. Characteristics associated with survivors perceiving higher quality care was delivered included being employed, having private health insurance, being younger, a Non-Hodgkin lymphoma diagnosis and more recent diagnosis. Being depressed or stressed was associated with perceived lower quality of care. CONCLUSIONS: Provision of peer support programs that allow haematological cancer survivors and families and friends to talk to others in similar situations could be improved. Using PROMs to identify areas where cancer survivors perceive improvements are needed is essential to quality improvement efforts. PMID- 25504966 TI - Hypervalent iodine reagents enable chemoselective deboronative/decarboxylative alkenylation by photoredox catalysis. AB - Chemoselective C(sp(3))-C(sp(2)) coupling reactions under mild reaction conditions are useful for synthesizing alkyl-substituted alkenes having sensitive functional groups. Reported here is a visible-light-induced chemoselective alkenylation through a deboronation/decarboxylation sequence under neutral aqueous reaction conditions at room temperature. This reaction represents the first hypervalent-iodine-enabled radical decarboxylative alkenylation reaction, and a novel benziodoxole-vinyl carboxylic acid reaction intermediate was isolated. This C(sp(3))-C(sp(2)) coupling reaction leads to aryl-and acyl substituted alkenes containing various sensitive functional groups. The excellent chemoselectivity, stable reactants, and neutral aqueous reaction conditions of the reaction suggest future biomolecule applications. PMID- 25504968 TI - Pros and cons .... PMID- 25504964 TI - Functional connectivity associated with gait velocity during walking and walking while-talking in aging: a resting-state fMRI study. AB - Gait decline is common among older adults and is a risk factor for adverse outcomes. Poor gait performance in dual-task conditions, such as walking while performing a secondary cognitive interference task, is associated with increased risk of frailty, disability, and death. Yet, the functional neural substrates that support locomotion are not well established. We examined the functional connectivity associated with gait velocity in single- (normal pace walking) and dual-task (walking while talking) conditions using resting-state functional Magnetic Resonance Imaging (fMRI). We acquired 6 minutes of resting-state fMRI data in 30 cognitively healthy older adults. Independent components analyses were performed to separate resting-state fMRI data into group-level statistically independent spatial components that correlated with gait velocity in single- and dual-task conditions. Gait velocity in both task conditions was associated with similar functional connectivity in sensorimotor, visual, vestibular, and left fronto-parietal cortical areas. Compared to gait velocity in the single-task condition, the networks associated with gait velocity in the dual-task condition were associated with greater functional connectivity in supplementary motor and prefrontal regions. Our findings show that there are partially overlapping functional networks associated with single- and dual-task walking conditions. These initial findings encourage the future use of resting-state fMRI as tool in developing a comprehensive understanding of age-related mobility impairments. PMID- 25504969 TI - Formoterol or salmeterol for asthma--should they be used as monotherapy? PMID- 25504970 TI - Interventions for treating femoral shaft fractures in children and adolescents. AB - BACKGROUND: Fractures of the femoral shaft in children are relatively uncommon but serious injuries that disrupt the lives of children and their carers and can result in significant long-term disability. Treatment involves either surgical fixation, such as intramedullary nailing or external fixation, or conservative treatment involving prolonged immobilisation, often in hospital. OBJECTIVES: To assess the effects (benefits and harms) of interventions for treating femoral shaft fractures in children and adolescents. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (accessed 16 August 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013 Issue 7), MEDLINE (1946 to August Week 1 2013), EMBASE (1980 to 2012 week 9), CINAHL (16 August 2013), clinical trials registries, conference proceedings and reference lists; and contacted trial authors and experts in the field. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing conservative and surgical interventions for diaphyseal fractures of the femur in children under 18 years of age. Our primary outcomes were functional outcome measures, unacceptable malunion, and serious adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently screened and selected trials, assessed risk of bias and extracted data. We assessed the overall quality of the evidence for each outcome for each comparison using the GRADE approach. We pooled data using a fixed-effect model. MAIN RESULTS: We included 10 trials (six randomised and four quasi-randomised) involving a total of 527 children (531 fractures). All trials were at some risk of bias, including performance bias as care provider blinding was not practical, but to a differing extent. Just one trial was at low risk of selection bias. Reflecting both the risk of bias and the imprecision of findings, we judged the quality of evidence to be 'low' for most outcomes, meaning that we are unsure about the estimates of effect. Most trials failed to report on self-assessed function or when children resumed their usual activities. The trials evaluated 10 different comparisons, belonging to three main categories. Surgical versus conservative treatment. Four trials presenting data for 264 children aged 4 to 12 years made this comparison. Low quality evidence (one trial, 101 children) showed children had very similar function assessed using the RAND health status score at two years after surgery (external fixation) compared with conservative treatment (spica cast): mean 69 versus 68. The other three trials did not report on function. There was moderate quality evidence (four trials, 264 children, aged 4 to 12 years, followed up 3 to 24 months) that surgery reduced the risk of malunion (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.15 to 0.59, 4 trials). Assuming an illustrative baseline risk of 115 malunions per 1000 in children treated conservatively, these data equate to 81 fewer (95% CI 47 to 97 fewer) malunions per 1000 in surgically treated children. Conversely, low quality evidence indicated that there were more serious adverse events such as infections after surgery (RR 2.39, 95% CI 1.10 to 5.17, 4 trials). Assuming an illustrative baseline risk of 40 serious adverse events per 1000 for conservative treatment, these data equate to 56 more (95% CI 4 to 167 more) serious adverse events per 1000 children treated surgically. There was low quality evidence (one trial, 101 children) of similar satisfaction levels in children and parents with surgery involving external fixation and plaster cast only. However, there was low quality evidence (one trial, 46 children) that more parents were satisfied with intramedullary nailing than with traction followed by a cast, and that surgery reduced the time taken off from school. Comparisons of different methods of conservative treatment. The three trials in this category made three different comparisons. We are very unsure if unacceptable malunion rates differ between immediate hip spica versus skeletal traction followed by spica in children aged 3 to 10 years followed up for six to eight weeks (RR 4.0, 95% CI 0.5 to 32.9; one trial, 42 children; very low quality evidence). Malunion rates at 5 to 10 years may not differ between traction followed by functional orthosis versus traction followed by spica cast in children aged 5 to 13 years (RR 0.98, 95% CI 0.46 to 2.12; one trial, 43 children; low quality evidence). We are very unsure (very low quality evidence) if either function or serious adverse events (zero events reported) differ between single-leg versus double-leg spica casts (one trial, 52 young children aged two to seven years). Low quality evidence on the same comparison indicates that single-leg casts are less awkward to manage by parents, more comfortable for the child and may require less time off work by the caregiver. Comparisons of different methods of surgical treatment. The three trials in this category made three different comparisons. Very low quality evidence means that we are very unsure if the rates of malunion, serious adverse events, time to return to school or parental satisfaction actually differ in children whose fractures were fixed using elastic stable intramedullary nailing or external fixation (one trial, 19 children). The same applies to the rates of serious adverse events and time to resume full weight bearing in children treated with dynamic versus static external fixation (one trial, 52 children). Very low quality evidence (one trial, 47 children) means that we do not know if malunion, serious adverse events and time to resume weight bearing actually differ between intramedullary nailing versus submuscular plating. However, there could be more difficulties in plate removal subsequently. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine if long-term function differs between surgical and conservative treatment. Surgery results in lower rates of malunion in children aged 4 to 12 years, but may increase the risk of serious adverse events. Elastic stable intramedullary nailing may reduce recovery time. There is insufficient evidence from comparisons of different methods of conservative treatment or of different methods of surgical treatment to draw conclusions on the relative effects of the treatments compared in the included trials. PLAIN LANGUAGE SUMMARY: Different methods of treating fractures of the shaft of the thigh bone in children and adolescents Although uncommon, fractures of the femoral shaft (thigh bone) in children may require prolonged treatment in hospital and sometimes surgery. This can cause significant discomfort and can disrupt the lives of the children and their familles. This review compared different methods of treating these fractures. Surgical treatment comprises different methods of fixing the broken bones, such as internally-placed nails, or pins incorporated into an external frame (external fixation). Non surgical or conservative treatment usually involves different types of plaster casts with or without traction (where a pulling force is applied to the leg). We searched for studies in the medical literature until August 2013. The review includes 10 randomised or quasi-randomised controlled trials that recruited 527 children. Four trials compared different surgical versus non-surgical treatments; three compared different methods of non-surgical treatment and three compared different methods of surgical treatment. Generally we are unsure about the results of these trials because some were at risk of bias, some results were contradictory and usually there was too little evidence to rule out chance findings. Most trials failed to report on self-assessed function or when children resumed their usual activities. Comparing surgical versus non-surgical treatment. Low quality evidence (one trial, 101 children) showed children had similar function at two years after having surgery, involving external fixation, compared with those treated with a plaster cast. The other three trials did not report this outcome. There was moderate quality evidence (four trials, 264 children, aged 4 to 12 years, followed up for 3 to 24 months) that surgery reduced the risk of malunion (the leg is deformed) compared with non-surgical treatment. However, low quality evidence (four trials) indicated that there were more serious adverse events such as infections after surgery. There was low quality evidence (one trial, 101 children) of similar satisfaction levels in children and parents with surgery involving external fixation and plaster cast only. However, there was low quality evidence (one trial, 46 children) that more parents were satisfied with surgery involving an internal nail than with traction followed by a cast and that surgery reduced the time taken off from school. Comparing various non-surgical treatments. Very low quality evidence means that we are very unsure if the rates of malunion differ or not between children treated with immediate plaster casts versus with traction followed by plaster cast (one trial, 42 children), or between children treated with traction followed by either a functional orthosis (a brace or cast that allows some movement) or a cast (one trial, 43 children). We are very unsure if either function or serious adverse events differ between young children (aged two to seven years) immobilised in single-leg versus double leg casts (one trial, 52 children). However, single-leg casts appear to be easier to manage by parents and more comfortable for the child. Comparing various surgical treatments Very low quality evidence means that we are very unsure if the rates of malunion, serious adverse events, time to return to school or parental satisfaction actually differ in children whose fractures were fixed using internal nails or external fixation (one trial, 19 children). (ABSTRACT TRUNCATED) PMID- 25504971 TI - Cochrane in context: Interventions for treating femoral shaft fractures in children and adolescents. PMID- 25504972 TI - Inhaled corticosteroids in children with persistent asthma: effects on growth. AB - BACKGROUND: Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth. OBJECTIVES: To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment). SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases to look for potential relevant unpublished studies. The literature search was conducted in January 2014. SELECTION CRITERIA: Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child. MAIN RESULTS: We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%. Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period. Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi(2) = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 MUg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial. One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 MUg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI 1.90 to -0.50) in adult height compared with those treated with placebo. AUTHORS' CONCLUSIONS: Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma. PLAIN LANGUAGE SUMMARY: Do inhaled corticosteroids reduce growth in children with persistent asthma? Review question: We reviewed the evidence on whether inhaled corticosteroids (ICS) could affect growth in children with persistent asthma, that is, a more severe asthma that requires regular use of medications for control of symptoms. BACKGROUND: Treatment guidelines for asthma recommend ICS as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, parents and physicians always remain concerned about the potential negative effect of ICS on growth. Search date: We searched trials published until January 2014. Study characteristics: We included in this review trials comparing daily use of corticosteroids, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma. KEY RESULTS: Twenty-five trials involving 8471 children with mild to moderate persistent asthma (5128 treated with ICS and 3343 treated with placebo or non-steroidal drugs) were included in this review. Eighty percent of these trials were conducted in more than two different centres and were called multi-centre studies; five were international multi-centre studies conducted in high-income and low-income countries across Africa, Asia Pacifica, Europe and the Americas. Sixty-eight percent were financially supported by pharmaceutical companies. Meta-analysis (a statistical technique that combines the results of several studies and provides a high level of evidence) suggests that children treated daily with ICS may grow approximately half a centimeter per year less than those not treated with these medications during the first year of treatment. The magnitude of ICS-related growth reduction may depend on the type of drug. Growth reduction seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. Evidence provided by this review allows us to conclude that daily use of ICS can cause a small reduction in height in children up to 18 years of age with persistent asthma; this effect seems minor compared with the known benefit of these medications for asthma control. QUALITY OF EVIDENCE: Eleven of 25 trials did not report how they guaranteed that participants had an equal chance of receiving ICS or placebo or non-steroidal drugs. All but six trials did not report how researchers were kept unaware of the treatment assignment list. However, this methodological limitation may not significantly affect the quality of evidence because the results remained almost unchanged when we excluded these trials from the analysis. PMID- 25504973 TI - Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth. AB - BACKGROUND: Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians. OBJECTIVES: To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014. SELECTION CRITERIA: Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation. MAIN RESULTS: Among 22 eligible trials, 17 group comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2 -agonist and generally compared low (50 to 100 MUg) versus low to medium (200 MUg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X(2) = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, bone mass index and skeletal maturation reported with low quality of evidence due to imprecision. AUTHORS' CONCLUSIONS: In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents' and physicians' concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma. PLAIN LANGUAGE SUMMARY: Does altering the dose of inhaled corticosteroids make a difference in growth among children with asthma? BACKGROUND: Asthma guidelines recommend inhaled corticosteroids (ICS) as the first choice of treatment for children with persistent asthma that is not well controlled when only a reliever inhaler is used to treat symptoms. Steroids work by reducing inflammation in the lungs and are known to control underlying symptoms of asthma. However, parents and physicians remain concerned about the potential negative effect of ICS on growth. REVIEW QUESTION: Does altering the dose of inhaled corticosteroids make a difference in the growth of children with asthma? WHAT EVIDENCE DID WE FIND?: We studied whether a difference could be seen in the growth of children with persistent asthma who were using different doses of the same ICS molecule and the same delivery device. We found 22 eligible trials, but only 10 of them measured growth or other measures of interest. Overall, 3394 children included in the review combined 17 group comparisons (i.e. 17 groups of children with mild to moderate asthma using a particular dose and type of steroid in 10 trials). Trials used different ICS molecules (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) either on their own or in combination with a long-acting beta2 -agonist (a drug used to open up the airways) and generally compared low doses of corticosteroids (50 to 100 MUg) with low to medium (200 MUg) doses of corticosteroids (converted in MUg HFA-beclomethasone equivalent) over 12 to 52 weeks. RESULTS: We found a small but statistically significant group difference in growth over 12 months between these different doses clearly favouring the lower dose of ICS. The type of corticosteroid among newer molecules (ciclesonide, fluticasone, mometasone) did not seem to influence the impact on growth over one year. Differences in corticosteroid doses did not seem to affect the change in height, the gain in weight, the gain in bone mass index and the maturation of bones. QUALITY OF THE EVIDENCE: This review is based on a small number of trials that reported data and were conducted on children with mild to moderate asthma. Only 10 of 22 studies measured the few outcomes of interest for this review, and only four comparisons reported growth over 12 months. Our confidence in the quality of evidence is high for this outcome, however it is low to moderate for several other outcomes, depending on the number of trials reporting these outcomes. Moreover, a few outcomes were reported only by a single trial; as these findings have not been confirmed by other trials, we downgraded the evidence for these outcomes to low quality. An insufficient number of trials have compared the effect of a larger difference in dose, for example, between a high dose and a low dose of ICS and of other popular molecules such as budesonide and beclomethasone over a year or longer of treatment. CONCLUSIONS: We report an evidence-based ICS dose-dependent reduction in growth velocity in prepubescent school-aged children with mild to moderate persistent asthma. The choice of ICS molecule (mometasone, ciclesonide or fluticasone) was not found to affect the level of growth velocity response over a year. The effect of corticosteroids on growth was not consistently reported: among 22 eligible trials, only four comparisons reported the effects of corticosteroids on growth over one year. In view of parents' and clinicians' concerns, lack of or incomplete reporting of growth is a matter of concern given the importance of the topic. We recommend that growth be systematically reported in all trials involving children taking ICS for three months or longer. Until further data comparing low versus high ICS dose and trials of longer duration are available, we recommend that the minimal effective ICS dose be used in all children with asthma. PMID- 25504974 TI - Cochrane in context: Inhaled corticosteroids in children with persistent asthma: effects on growth and dose-response effects on growth. PMID- 25504975 TI - A meta-epidemiological study to examine the association between bias and treatment effects in neonatal trials. AB - BACKGROUND: Randomized controlled trials are considered the gold standard for evidence on therapeutic interventions; however, they are susceptible to bias. The objectives of this observational study were to describe the methodological quality of neonatal randomized controlled trials and quantify the bias related to specific methodological and study-level characteristics. METHODS: Twenty-five systematic reviews yielding 208 neonatal trials were included. Two independent reviewers assessed risk of bias (RoB) on seven domains consisting of nine items. For each domain, meta-analyses with at least one high/unclear and one low risk study were included in the analysis. For the primary outcome within each meta analysis a ratio of odds ratios with a 95% confidence interval was generated. The ratio of odds ratios for each meta-analysis were combined using meta-analytic techniques with inverse-variance weighting and a random effects model to obtain a summary ratio of odds ratio. RESULTS: None of the studies had an overall low RoB. Most studies had a low RoB for the domain of incomplete outcome data (89%), while 63%, 55% and 46% of trials had low RoB for sequence generation, other sources of bias, and blinding of outcome assessors, respectively. For all other domains (allocation concealment, blinding of parents and investigators and selective outcome reporting), the majority of trials were assessed as unclear. Selective outcome reporting was rated as unclear RoB for 55% and high for 42% of studies. The only domain that showed a statistically significant association with the treatment effect was selective outcome reporting: trials at unclear/high risk of bias for this domain significantly overestimated the treatment effects compared with those assessed at low risk of bias (ROR = 1.87, 95% confidence interval: 1.26-2.78). CONCLUSIONS: This observational study of a sample of neonatal trials showed that most were at high risk of bias, indicating that there is room for improvement in the design, conduct and reporting of neonatal trials to ensure valid results for the most clinically important outcomes. We did not find an association between most risk of bias domains and effect estimates; however, we found that randomized controlled trials at high risk for selective outcome reporting were associated with overestimates of treatment benefits. These results need to be confirmed in larger samples. PMID- 25504977 TI - Effect of e-learning on quality of cervical-length measurements. AB - OBJECTIVES: To assess the effect of implementation of a newly developed e learning module on the quality of cervical-length measurements. METHODS: With the introduction of cervical-length (CL) measurement in a research setting, a CL measurement e-learning module (CLEM) was developed with the purpose to enhance the knowledge and skills of experienced ultrasonographers. CLEM was designed specifically for ultrasonographers who perform ultrasound in a general obstetrical practice but who do not regularly perform CL measurements. CLEM consists of five theoretical questions and three caliper-placement tests to learn the CL measurement technique. The quality of the CL measurements of CLEM participants was compared with images of non-participants using a CL measurement image score (CIS), defined as the sum of six items which assess the quality of the image. Each CLEM participant submitted five CL images and the images of non CLEM participants were selected randomly from an ultrasound database. RESULTS: The CIS of the CLEM participants (n = 61) were significantly higher than those of non-CLEM participants (n = 23) (164.9 vs 155.6, respectively; P = 0.03). Visualization of the internal os and positioning of the calipers on the internal and external ora were found to have significantly higher CIS among the CLEM participants than among the non-CLEM participants (P = 0.001 and P < 0.001, respectively). CONCLUSIONS: Introducing CLEM may improve the quality of CL measurements obtained by trained and untrained sonographers. PMID- 25504976 TI - Comparison of primary percutaneous coronary intervention in patients with ST elevation myocardial infarction during and prior to availability of an in-house STEMI system: early experience and intermediate outcomes of the HARRT program for achieving routine D2B times <60 minutes. AB - BACKGROUND: Over the last decade, significant advances in ST-elevation myocardial infarction (STEMI) workflow have resulted in most hospitals reporting door-to balloon (D2B) times within the 90 min standard. Few programs have been enacted to systematically attempt to achieve routine D2B within 60 min. We sought to determine whether 24-hr in-house catheterization laboratory coverage via an In House Interventional Team Program (IHIT) could achieve D2B times below 60 min for STEMI and to compare the results to the standard primary percutaneous coronary intervention (PCI) approach. METHODS: An IHIT program was established consisting of an attending interventional cardiologist, and a catheterization laboratory team present in-hospital 24 hr/day. For all consecutive STEMI patients, we compared the standard primary PCI approach during the two years prior to the program (group A) to the initial 20 months of the IHIT program (group B), and repeated this analysis for only CMS-reportable patients. The D2B process was analyzed by calculating workflow intervals. The primary endpoint was D2B process times, and secondary endpoints included in-hospital and 6-month cardiovascular outcomes and resource utilization. RESULTS: An IHIT program for STEMI resulted in significant reductions across all treatment intervals with an overall 57% reduction in D2B time, and an absolute reduction in mean D2B time of 71 min. There were no differences pre- and post-program implementation in regard to individual or composite components of in-hospital cardiovascular outcomes; however at 6 months, there was a reduction in cardiovascular rehospitalization after program implementation (30 vs. 5%, P < 0.01). The IHIT program resulted in a significant reduction in length-of-stay (LOS) (90 +/- 102 vs. 197 +/- 303 hr, P = 0.02), and critical care time (54 +/- 97 vs. 149 +/- 299 hr, P = 0.02). CONCLUSIONS: Availability of an in-house 24-hr STEMI team significantly decreased reperfusion time and led to improved clinical outcomes and a shorter LOS for PCI treated STEMI patients. PMID- 25504978 TI - Nanotentacle-structured magnetic particles for efficient capture of circulating tumor cells. AB - Circulating tumor cells (CTCs) have attracted considerable attention as promising markers for diagnosing and monitoring the cancer status. Despite many technological advances in isolating CTCs, the capture efficiency and purity still remain challenges that limit clinical practice. Here, the construction of "nanotentacle"-structured magnetic particles using M13-bacteriophage and their application for the efficient capturing of CTCs is demonstrated. The M13 bacteriophage to magnetic particles followed by modification with PEG is conjugated, and further tethered monoclonal antibodies against the epidermal receptor 2 (HER2). The use of nanotentacle-structured magnetic particles results in a high capture purity (>45%) and efficiency (>90%), even for a smaller number of cancer cells (~25 cells) in whole blood. Furthermore, the cancer cells captured are shown to maintain a viability of greater than 84%. The approach can be effectively used for capturing CTCs with high efficiency and purity for the diagnosis and monitoring of cancer status. PMID- 25504979 TI - Dynamics of zebrafish fin regeneration using a pulsed SILAC approach. AB - The zebrafish owns remarkable regenerative capacities allowing regeneration of several tissues, including the heart, liver, and brain. To identify protein dynamics during fin regeneration we used a pulsed SILAC approach that enabled us to detect the incorporation of (13) C6 -lysine (Lys6) into newly synthesized proteins. Samples were taken at four different time points from noninjured and regrowing fins and incorporation rates were monitored using a combination of single-shot 4-h gradients and high-resolution tandem MS. We identified more than 5000 labeled proteins during the first 3 weeks of fin regeneration and were able to monitor proteins that are responsible for initializing and restoring the shape of these appendages. The comparison of Lys6 incorporation rates between noninjured and regrowing fins enabled us to identify proteins that are directly involved in regeneration. For example, we observed increased incorporation rates of two actinodin family members at the actinotrichia, which is a hairlike fiber structure at the tip of regrowing fins. Moreover, we used quantitative real-time RNA measurements of several candidate genes, including osteoglycin, si:ch211 288h17.3, and prostaglandin reductase 1 to correlate the mRNA expression to Lys6 incorporation data. This novel pulsed SILAC methodology in fish can be used as a versatile tool to monitor newly synthesized proteins and will help to characterize protein dynamics during regenerative processes in zebrafish beyond fin regeneration. PMID- 25504980 TI - Catalytic hydrodechlorination of benzyl chloride promoted by Rh-N-heterocyclic carbene catalysts. AB - The rhodium(I) complexes [Rh(Cl)(COD)(R-NHC-(CH2 )3 Si(OiPr)3 )] [COD=cyclooctadiene; R=2,6-diisopropylphenyl (1 a); n-butyl (1 b)] are effective catalyst precursors for the homogeneous hydrodechlorination of benzyl chloride using HSiEt3 as hydrogen source. This reaction is selective to the formation of toluene. However, in presence of a stoichiometric amount of potassium tert butoxide (KtBuO) the formation of mixtures containing toluene together with 17-19 mol % of the C--C homocoupling product, namely PhCH2 CH2 Ph, is observed. A mechanism proposal based on experimental insights and theoretical calculations at the DFT level that allows explanation of the experimental findings is included. Moreover, the heterogeneous catalytic system based on catalyst 1 a supported on MCM-41 has been demonstrated to be effective for the solvent-free hydrodechlorination of benzyl chloride using HSiEt3 and HSiMe(OSiMe3 )2 . PMID- 25504981 TI - A large vegetation at the tricuspid valve with gas image. PMID- 25504982 TI - Video-assisted thoracoscopic surgery atrial clipping for atrial fibrillation. AB - The majority of thrombi that arise due to atrial fibrillation occur in the left atrial appendage. Eliminating this cul-de-sac within the left atrium reduces the risk of stroke in these patients. We present a unique case of left atrial appendage occlusion performed via video-assisted thoracoscopic surgery, using an Atriclip to occlude the left atrial appendage in a patient with atrial fibrillation in whom anticoagulation was contraindicated due to a history of recurrent upper gastrointestinal bleeding. PMID- 25504983 TI - Total synthesis of maoecrystal V. AB - Maoecrystal V (1) is a novel diterpenoid, which was originally isolated from the leaves of the Chinese medicinal herb Isodon eriocalyx in 2004 by Sun et al.1 It has been found to be selectively cytotoxic towards HeLa cells, with an IC50 value of 20 ng mL(-1) . Significant research efforts have been devoted to the synthesis of maoecrystal V because of its intriguing biological properties, rarity in nature, and complex structural features. Herein, we describe our recent investigations, which have culminated in the total synthesis of (+/-)-maoecrystal V. The current strategy involved three key steps for the successful construction of the key tetrahydrofuran oxa-bridge skeleton, including a Wessely oxidative dearomatization, a novel intramolecular Diels-Alder reaction, and a Rh(II) catalyzed O - H insertion reaction. PMID- 25504985 TI - pi-Expanded alpha,beta-unsaturated ketones: synthesis, optical properties, and two-photon-induced polymerization. AB - A library of pi-expanded alpha,beta-unsaturated ketones was designed and synthesized. They were prepared by a combination of Wittig reaction, Sonogashira reaction, and aldol condensation. It was further demonstrated that the double aldol condensation can be performed effectively for highly polarized styrene- and diphenylacetylene-derived aldehydes. The strategic placement of two dialkylamino groups at the periphery of D-pi-A-pi-D molecules resulted in dyes with excellent solubility. These ketones absorb light in the region 400-550 nm. Many of them display strong solvatochromism so that the emission ranges from 530-580 nm in toluene to the near-IR region in benzonitrile. Ketones based on cyclobutanone as central moieties display very high fluorescence quantum yields in nonpolar solvents, which decrease drastically in polar media. Photophysical studies of these new functional dyes revealed that they possess an enhanced two-photon absorption cross section when compared with simpler ketone derivatives. Due to strong polarization of the resulting dyes, values of two-photon absorption cross sections on the level of 200-300 GM at 800 nm were achieved, and thanks to that as well as the presence of the keto group, these new two-photon initiators display excellent performance so that the operating region is 5-75 mW in some cases. PMID- 25504987 TI - Why do oncology outpatients who report emotional distress decline help? AB - OBJECTIVE: Many patients who experience distress do not seek help, and little is known about the reasons for this. We explored the reasons for declining help among patients who had significant emotional distress. METHODS: Data were collected through QUICATOUCH screening at an Australian hospital. Oncology outpatients scoring 4 or more on the Distress Thermometer were asked if they would 'like help' with their distress. Those who declined help were asked their reasons. Demographic variables and a clinical measure of anxiety and depression (PSYCH-6) were used to identify factors associated with reasons for declining help. RESULTS: Of 311 patients with significant distress, 221 (71%) declined help. The most common reasons were 'I prefer to manage myself' (n = 99, 46%); 'already receiving help' (n = 52, 24%) and 'my distress is not severe enough' (n = 50, 23%). Younger patients and women were more likely to decline help and were more likely to already be receiving help. Distress score and PSYCH-6 scores were significantly lower among patients who rated their distress as not severe enough to require help. Nevertheless, there were patients who had maximal scores on distress and PSYCH in each group. CONCLUSIONS: Two common patient barriers to help with distress are a preference for self-help and a belief that distress is not sufficiently severe to warrant intervention. These beliefs were held by a sizeable proportion of individuals who reported very high levels of distress. Qualitative research and subsequent interventions for overcoming these barriers are required to obtain the most benefit from distress screening programs. PMID- 25504989 TI - Decarbonylative radical coupling of alpha-aminoacyl tellurides: single-step preparation of gamma-amino and alpha,beta-diamino acids and rapid synthesis of gabapentin and manzacidin A. AB - A new radical-based coupling method has been developed for the single-step generation of various gamma-amino acids and alpha,beta-diamino acids from alpha aminoacyl tellurides. Upon activation by Et3 B and O2 at ambient temperature, alpha-aminoacyl tellurides were readily converted into alpha-amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (-)-manzacidin A. PMID- 25504986 TI - Cerebellar white matter pathways are associated with reading skills in children and adolescents. AB - Reading is a critical life skill in the modern world. The neural basis of reading incorporates a distributed network of cortical areas and their white matter connections. The cerebellum has also been implicated in reading and reading disabilities. However, little is known about the contribution of cerebellar white matter pathways to major component skills of reading. We used diffusion magnetic resonance imaging (dMRI) with tractography to identify the cerebellar peduncles in a group of 9- to 17-year-old children and adolescents born full term (FT, n = 19) or preterm (PT, n = 26). In this cohort, no significant differences were found between fractional anisotropy (FA) measures of the peduncles in the PT and FT groups. FA of the cerebellar peduncles correlated significantly with measures of decoding and reading comprehension in the combined sample of FT and PT subjects. Correlations were negative in the superior and inferior cerebellar peduncles and positive in the middle cerebellar peduncle. Additional analyses revealed that FT and PT groups demonstrated similar patterns of reading associations within the left superior cerebellar peduncle, middle cerebellar peduncle, and left inferior cerebellar peduncle. Partial correlation analyses showed that distinct sub-skills of reading were associated with FA in segments of different cerebellar peduncles. Overall, the present findings are the first to document associations of microstructure of the cerebellar peduncles and the component skills of reading. PMID- 25504990 TI - Engineering high-potency R-spondin adult stem cell growth factors. AB - Secreted R-spondin proteins (RSPOs1-4) function as adult stem cell growth factors by potentiating Wnt signaling. Simultaneous binding of distinct regions of the RSPO Fu1-Fu2 domain module to the extracellular domains (ECDs) of the LGR4 G protein-coupled receptor and the ZNRF3 transmembrane E3 ubiquitin ligase regulates Wnt receptor availability. Here, we examine the molecular basis for the differing signaling strengths of RSPOs1-4 using purified RSPO Fu1-Fu2, LGR4 ECD, and ZNRF3 ECD proteins in Wnt signaling and receptor binding assays, and we engineer novel high-potency RSPOs. RSPO2/3/4 had similar signaling potencies that were stronger than that of RSPO1, whereas RSPO1/2/3 had similar efficacies that were greater than that of RSPO4. The RSPOs bound LGR4 with affinity rank order RSPO4 > RSPO2/3 > RSPO1 and ZNRF3 with affinity rank order RSPO2/3 > > RSPO1 > RSPO4. An RSPO2-4 chimera combining RSPO2 ZNRF3 binding with RSPO4 LGR4 binding was a "Superspondin" that exhibited enhanced ternary complex formation and 10 fold stronger signaling potency than RSPO2 and efficacy equivalent to RSPO2. An RSPO4-1 chimera combining RSPO4 ZNRF3 binding with RSPO1 LGR4 binding was a "Poorspondin" that exhibited signaling potency similar to RSPO1 and efficacy equivalent to RSPO4. Conferring increased ZNRF3 binding upon RSPO4 with amino acid substitutions L56F, I58L, and I63M enhanced its signaling potency and efficacy. Our results reveal the molecular basis for RSPOs1-4 activity differences and suggest that signaling potency is determined by ternary complex formation ability, whereas efficacy depends on ZNRF3 recruitment. High-potency RSPOs may be of value for regenerative medicine and/or therapeutic applications. PMID- 25504991 TI - Impaired lung function is associated with systemic inflammation and macrophage activation. PMID- 25504992 TI - Oronasal mask versus helmet in acute hypercapnic respiratory failure. AB - The choice of the interface for noninvasive ventilation (NIV) is a key factor in NIV success. We hypothesised that a new helmet specifically design to improve performance in hypercapnic patients would be clinically equivalent to a standard oronasal mask. In a multicentre, short-term, physiological, randomised trial in chronic obstructive pulmonary disease patients facing an acute hypercapnic respiratory failure episode, we compared the changes in arterial blood gases (ABGs) and tolerance score obtained using the helmet or mask, and, as secondary end-points, dyspnoea, vital signs, early NIV discontinuation and rate of intubation. 80 patients were randomly assigned to receive NIV either with the helmet (n=39) or mask (n=41), using an intensive care unit ventilator. Compared with baseline, in the first 6 h, NIV improved ABGs, dyspnoea and respiratory rate (p<0.05) in both groups. Changes in ABGs and discomfort were similar with the two groups, while dyspnoea decreased more (p<0.005) using the mask. The rate of intubation and the need for interface change during the whole period of NIV were very low and not different between groups. The new helmet may be a valid alternative to a mask in improving ABGs and achieving a good tolerance during an episode of acute hypercapnic respiratory failure. PMID- 25504993 TI - HFE gene variants and iron-induced oxygen radical generation in idiopathic pulmonary fibrosis. AB - In idiopathic pulmonary fibrosis (IPF), lung accumulation of excessive extracellular iron and macrophage haemosiderin may suggest disordered iron homeostasis leading to recurring microscopic injury and fibrosing damage. The current study population comprised 89 consistent IPF patients and 107 controls. 54 patients and 11 controls underwent bronchoalveolar lavage (BAL). Haemosiderin was assessed by Perls' stain, BAL fluid malondialdehyde (MDA) by high-performance liquid chromatography, BAL cell iron-dependent oxygen radical generation by fluorimetry and the frequency of hereditary haemochromatosis HFE gene variants by reverse dot blot hybridisation. Macrophage haemosiderin, BAL fluid MDA and BAL cell unstimulated iron-dependent oxygen radical generation were all significantly increased above controls (p<0.05). The frequency of C282Y, S65C and H63D HFE allelic variants was markedly higher in IPF compared with controls (40.4% versus 22.4%, OR 2.35, p=0.008) and was associated with higher iron-dependent oxygen radical generation (HFE variant 107.4+/-56.0, HFE wild type (wt) 59.4+/-36.4 and controls 16.7+/-11.8 fluorescence units per 10(5) BAL cells; p=0.028 HFE variant versus HFE wt, p=0.006 HFE wt versus controls). The data suggest iron dysregulation associated with HFE allelic variants may play an important role in increasing susceptibility to environmental exposures, leading to recurring injury and fibrosis in IPF. PMID- 25504994 TI - Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. AB - A randomised, double-blind, phase II, dose escalation trial was conducted to assess the safety, tolerability and pharmacokinetics of the tyrosine kinase inhibitor nintedanib, alone and when added to ongoing pirfenidone therapy, in Japanese patients with idiopathic pulmonary fibrosis. 50 Japanese patients were randomised to receive nintedanib or placebo in one of three cohorts (nintedanib 50 mg twice daily or 100 mg twice daily for 14 days, or 150 mg twice daily for 28 days). Patients receiving pirfenidone at inclusion were stratified to every nintedanib dose group and placebo. Adverse events were reported in nine out of 17 patients receiving nintedanib alone and 10 out of 21 patients receiving nintedanib added to pirfenidone. All adverse events were mild or moderate in intensity. Gastrointestinal disorders were the most common adverse event. Maximum plasma concentration and area under the curve at steady state for nintedanib and its metabolites tended to be lower when nintedanib was added to pirfenidone. Nintedanib had no effect on the pharmacokinetics of pirfenidone. In conclusion, further study is needed to evaluate the safety and tolerability profile of nintedanib when added to pirfenidone in patients with idiopathic pulmonary fibrosis. There was a trend toward lower exposure of nintedanib when it was added to pirfenidone. PMID- 25504996 TI - Right ventricular reserve in a piglet model of chronic pulmonary hypertension. AB - Right ventricular (RV) response to exercise or pharmacological stress is not well documented in pulmonary hypertension (PH). We investigated the relationship between RV reserve and ventricular-arterial coupling. Surgical ligation of the left pulmonary artery was performed in 13 Large White piglets (PH group), thereafter weekly embolisations of the right lower lobe were performed for 5 weeks. A control group of six piglets underwent sham procedures. Right heart catheterisation and echocardiography were performed at week 6. Pressure-volume loops were recorded before and after dobutamine infusion. Induction of experimental PH resulted in a higher mean +/- sd pulmonary artery pressure (34 +/ 9 versus 14 +/- 2 mmHg; p<0.01) and in a lower ventricular-arterial coupling efficiency (0.66 +/- 0.18 versus 1.24 +/- 0.17; p<0.01) compared with controls at 6 weeks. Dobutamine-induced relative changes in RV stroke volume index (SVI) and end-systolic elastance were lower in the PH group (mean +/- SD 47 +/- 5% versus 20 +/- 5%, p<0.01, and 81 +/- 37% versus 32 +/- 14%, p<0.01, respectively). Change in SVI was strongly associated with resting ventricular-arterial coupling (R(2)=0.74; p<0.01). RV reserve was associated with ventricular-arterial coupling in a porcine model of chronic pressure overload. PMID- 25504995 TI - Nebulised budesonide using a novel device in patients with oral steroid-dependent asthma. AB - This phase 2/3 randomised, parallel-group, placebo-controlled trial investigated oral corticosteroid (OCS)-sparing efficacy, safety and tolerability of nebulised budesonide (Bud) administered with a novel computer-controlled, compressor-driven inhalation system (AKITA) as add-on therapy to Global Initiative for Asthma step 5. Patients (18-65 years) with OCS-dependent asthma were randomised (2:1:1:1) to receive 18-week, twice-daily, double-blind treatment with AKITA inhaled corticosteroid (AICS)-Bud 1 mg, AICS-Bud 0.5 mg, AICS-placebo or open-label Bud 1 mg administered by conventional nebuliser (CN-Bud). OCS doses were tapered until week 14. 199 patients started treatment. More AICS-Bud 1 mg (80.0%) than placebo treated (62.5%) patients had daily OCS doses reduced >=50%, with clinical stability to week 18 (one-sided p=0.02; treatment difference: 17.5% (95% CI 0.1 34.9%), two-sided p=0.04). Mean+/-sd forced expiratory volume in 1 s improved (from baseline to week 18) for AICS-Bud 1 mg (239+/-460 mL, p<0.001) and AICS-Bud 0.5 mg (126+/-345 mL, p=0.01) but not placebo (93+/-419 mL, p=0.36) or CN-Bud (137+/-459 mL, p=0.18). Fewer AICS-Bud 1 mg-treated patients experienced asthma exacerbations (7.5%) compared with placebo (17.5%) or CN-Bud (22.5%). All treatments were well tolerated. Budesonide applied with AKITA allowed significant meaningful OCS reduction in OCS-dependent asthma patients while improving pulmonary function and maintaining exacerbation control. PMID- 25504997 TI - Asthma inhaler adherence determinants in adults: systematic review of observational data. AB - Nonadherence to inhaled medication leads to poor asthma control and increased healthcare utilisation. Many studies exploring adherence determinants have been conducted, but summaries of the evidence are scarce. We performed a systematic review of observational research on determinants of asthma inhaler adherence among adults. We searched for articles in English reporting quantitative observational studies on inhaler adherence correlates among adults in developed countries, published in EMBASE, Medline, PsychInfo and PsychArticles in 1990 2014. Two coders independently assessed eligibility and extracted data, and assessed study quality. Results were summarised qualitatively into social and economic, and healthcare-, therapy-, condition- and patient-related factors. The 51 studies included mainly examined patient-related factors and found consistent links between adherence and stronger inhaler-necessity beliefs, and possibly older age. There was limited evidence on the relevance of other determinants, partly due to study heterogeneity regarding the types of determinants examined. Methodological quality varied considerably and studies performed generally poorly on their definitions of variables and measures, risk of bias, sample size and data analysis. A broader adoption of common methodological standards and health behaviour theories is needed before cumulative science on the determinants of adherence to asthma inhalers among adults can develop further. PMID- 25504998 TI - Is parent-child bed-sharing a risk for wheezing and asthma in early childhood? AB - Household crowding can place young children at risk for respiratory infections which subsequently provoke asthma symptoms. However, crowding might also protect against asthma, in accordance with the hygiene hypothesis. We tested if parent infant bed-sharing, an important dimension of household crowding, increases or decreases the risk for asthma. In a population-based prospective cohort (N = 6160) we assessed bed-sharing at 2 and 24 months; wheezing between 1 and 6 years of age; and asthma at 6 years of age. Generalised estimating equation models were used to assess repeated measures of wheezing and asthma. We found no association between bed-sharing in early infancy and wheezing or diagnosis of asthma. By contrast, we found a positive association between bed-sharing in toddlerhood and both wheezing (OR 1.42, 95% CI 1.15-1.74) and asthma (OR 1.57, 95% CI 1.03-2.38). Wheezing was not associated with bed-sharing when using cross-lagged modelling. This study suggests that bed-sharing in toddlerhood is associated with an increased risk of asthma at later ages, and not vice versa. Further studies are needed to explore the underlying causal mechanisms. PMID- 25504999 TI - Rivaroxaban in the treatment of venous thromboembolism and the prevention of recurrences: a practical approach. AB - Anticoagulation therapy is the standard treatment of patients with symptomatic venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism. Until recently, treatment of VTE was based on parenteral or low molecular-weight heparin for initial therapy (5-10 days) and oral vitamin K antagonists for long-term therapy. Those treatments have some limitations, including parenteral administration (heparins), the need for frequent monitoring and dose adjustments, interactions with several medications, and dietary restrictions (vitamin K antagonists). Rivaroxaban is a new oral direct factor Xa inhibitor with a wide therapeutic window, predictable anticoagulant effect, no food interactions, and few drug interactions. Consequently, no periodic monitoring of anticoagulation is needed, and fixed doses can be prescribed. EINSTEIN program demonstrated that rivaroxaban was as effective as and significantly safer than standard therapy for treatment of VTE. Rivaroxaban was recently authorized so doubts exist about how to use it in daily clinical practice. This document aims to clarify common questions formulated by clinicians regarding the use of this new drug. PMID- 25505000 TI - Self-aligned colloidal lithography for controllable and tuneable plasmonic nanogaps. AB - Au nanoparticles (NPs) deposited on a substrate function as ring shaped colloidal shadow masks. Using e-beam evaporation of gold, nanometer sized gaps are formed as a result. The size of these gaps can be accurately tuned by controlling the thickness of the gold deposition, thereby tuning the plasmonic coupling of the NPs with the substrate. The clean cavity produced between the Au NPs and the Au film provides an excellent SERS platform for trace molecule detection. PMID- 25505001 TI - Drug adherence, response and predictors thereof for tocilizumab in patients with rheumatoid arthritis: results from the Swedish biologics register. AB - OBJECTIVE: To evaluate drug adherence, clinical response and predictors thereof for tocilizumab in patients with RA in routine care based on prospectively collected data from the Swedish biologics register, Anti-Rheumatic Therapies in Sweden. METHODS: RA patients who had started with tocilizumab from September 2008 until March 2012 were identified. Cox regression and logistic regression models were used. RESULTS: A total of 530 RA patients were included, of whom 80.6% were female, 64.7% were on concomitant DMARDs, of which 300 were on MTX and 12% were biologic naive. The overall 6 month, 1 and 2 year estimated drug continuations were 79%, 64% and 50%, respectively. In the multivariate analyses, a low initial level of CRP [hazard ratio (HR) 0.76/1 S.D. (95% CI 0.63, 0.91)], high HAQ score [HR 1.23/1 S.D. (95% CI 1.06, 1.44)] and prior exposure to different biologics [HR 1.43 (95% CI 1.12, 1.83)] were predictors for drug termination, whereas concomitant DMARD therapy was not. European League Against Rheumatism (EULAR) good, moderate, and no response were achieved by 184 (46.7%), 133 (33.8%) and 77 (19.5%) patients, respectively. Predictors for EULAR good response vs no response (at 2.5-8 months) were low HAQ [odds ratio (OR) 0.56/1 S.D. (95% CI 0.40, 0.78)], high 28-joint DAS [OR 2.0/1 S.D. (95% CI 1.44, 2.78)] and not being on prednisolone [OR 0.47 (95% CI 0.25, 0.88)] at baseline. CONCLUSION: In this RA cohort treated with tocilizumab, the estimated 1 year drug continuation was 64% and 80% of the patients achieved a EULAR response. Drug discontinuation was not predicted by no concomitant DMARD, but by low CRP, high HAQ and prior exposure to biologics. PMID- 25505002 TI - Effect of component distribution and nanoporosity in CuPt nanotubes on electrocatalysis of the oxygen reduction reaction. AB - Pt-based bimetallic electrocatalysts hold great potential in the oxygen reduction reaction (ORR) in current fuel-cell prototypes. However, they also face challenges from drastic dealloying of less-noble metals and coalescence of small nanoparticles. Porous and structure-ordered nanotubes may hold the potential to improve the stability of bimetallic electrocatalysts. Herein, we report a method to prepare CuPt nanotubes and porous Cu3 Pt intermetallic nanorods through a controlled galvanic replacement reaction and heat treatment process. The effect of the geometric features and compositional segregation on the electrocatalysis of the ORR was clarified. The outstanding performance of the Cu3 Pt/C-700 catalyst in the ORR relative to that of CuPt/C-RT was mainly attributed to the nanoporosity of the catalyst, whereas the enhanced specific activity on CuPt/C-RT after potential cycling was attributed to the interaction between the CuPt alloyed core and the Pt shell in the tube wall. PMID- 25505003 TI - Crystal structures and redox responses coupled with ion recognition of p benzoquinone- and hydroquinone-fused [18]crown-6. AB - The crystal structures and redox properties of p-benzoquinone (BQ)-fused [18]crown-6 1 and bis-BQ-fused [18]crown-6 2 were examined. The anion radicals of these BQ molecules were stabilized by addition of metal ions, through effective electrostatic interactions between the negatively charged BQ moiety and positively charged ion-capturing [18]crown-6 unit. The electrostatic interactions and solvation energy played important roles in determining the magnitudes of anodic redox shifts in the reduction potentials. Regular pi-stacking of BQ units and regular arrays of [18]crown-6 units were observed in crystal 2, in which one dimensional pi-electron columns were separated by ionic channels. The hydroquinone-fused [18]crown-6 molecule 3 and a new BQ- and phenol-fused [18]crown-6 derivative 4 were obtained as single crystals. The molecular conformations of [18]crown-6 in crystal 3 and hydrated crystal 3?H2 O were different from each other. PMID- 25505004 TI - Multifaceted intervention to optimize antibiotic use for intra-abdominal infections. AB - OBJECTIVES: Implementing evidence-based practice guidelines is challenging. We used a multifaceted, continuous educational approach to disseminate an up-to-date internal guideline adapted from published guidelines for management of intra abdominal infections (IAI). PATIENTS AND METHODS: The intervention consisted of continuing educational sessions, internal guideline pocket cards and posters with collaboration among all key stakeholders starting in December 2010. We emphasized risk stratification and the use of ceftriaxone/metronidazole for treatment of low risk IAI, and discouraged the use of fluoroquinolones due to the high local resistance rates. We then compared patients with IAI before the intervention (April-November 2010) to those after implementation of the guideline (April November 2011) in a surgical unit at a tertiary care teaching hospital in Hamilton, Ontario, Canada. Antibiotic use was measured in in-hospital days of antibiotic therapy (DOT) per 1000 patient days (PD). RESULTS: 152 and 145 patients with IAI were included in the pre- and post-intervention periods, respectively. There was a significant reduction in the proportion of patients who received ciprofloxacin therapy from 74% to 34% (OR 0.18, 95% CI 0.11-0.31) and in DOT/1000 PD from 221 to 74 (OR 0.3, 95% CI 0.2-0.3). Also, a reduction in the DOT/1000 PD for piperacillin/tazobactam was seen (from 116 to 67; OR 0.6, 95% CI 0.5-0.7). There was an increase in the use of ceftriaxone from 1.3% to 53% of patients (OR 85, 95% CI 20-515) and from 6 to 92 DOT/1000 PD (OR 17, 95% CI 10 25). This change in practice was sustained over >2 years since the end of the active intervention, as shown in the unit-wide antimicrobial utilization data. CONCLUSIONS: A multifaceted intervention aimed at all key stakeholders resulted in a high adherence to evidence-based treatment guidelines for IAI and has initiated a sustained culture change in prescribing of antibiotics. PMID- 25505005 TI - Subtherapeutic concentrations of first-line anti-TB drugs in South African children treated according to current guidelines: the PHATISA study. AB - OBJECTIVES: There is a paucity of evidence regarding the optimal dosing of anti TB drugs in children. The aim of this study was to identify the pharmacokinetic parameters of first-line anti-TB drugs and the concentrations achieved after implementation of the 2010 WHO-recommended paediatric dosages. METHODS: We conducted a prospective, observational pharmacokinetic study in children 10 years old or younger who were on isoniazid, rifampicin, pyrazinamide and ethambutol therapy in Durban, KwaZulu-Natal, South Africa. Blood was collected at six timepoints over a 24 h period, chosen using optimal sampling theory. The drug concentrations were simultaneously modelled to identify the compartmental pharmacokinetics of each drug in each child, using the ADAPT program. RESULTS: The best six sampling timepoints in children were identified as 0 (pre-dose) and 0.42, 1.76, 3.37, 10.31 and 24 h post-dose. Thirty-one children were recruited and blood was drawn at these timepoints. Rifampicin, ethambutol and pyrazinamide were best described using a one-compartment model, while isoniazid was best described with a two-compartment model. Only 2/31 (6%), 20/31 (65%), 17/31 (55%) and 2/13 (15%) of children attained the WHO 2 h target therapeutic concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol, respectively. Moreover, only 24/31 (77%), 6/31 (19%) and 8/31 (26%) achieved the AUCs associated with an optimal clinical response to rifampicin, pyrazinamide and isoniazid, respectively. No single risk factor was significantly associated with below normal drug levels. CONCLUSIONS: The drug concentrations of all first-line anti TB drugs were markedly below the target therapeutic concentrations in most South African children who received the revised WHO-recommended paediatric weight-based dosages. PMID- 25505006 TI - AtCAST3.0 update: a web-based tool for analysis of transcriptome data by searching similarities in gene expression profiles. AB - In transcriptome experiments, the experimental conditions (e.g. mutants and/or treatments) cause transcriptional changes. Identifying experimental conditions that induce similar or opposite transcriptional changes can be useful to identify experimental conditions that affect the same biological process. AtCAST (http://atpbsmd.yokohama-cu.ac.jp) is a web-based tool to analyze the relationship between experimental conditions among transcriptome data. Users can analyze 'user's transcriptome data' of a new mutant or a new chemical compound whose function remains unknown to generate novel biological hypotheses. This tool also allows for mining of related 'experimental conditions' from the public microarray data, which are pre-included in AtCAST. This tool extracts a set of genes (i.e. module) that show significant transcriptional changes and generates a network graph to present related transcriptome data. The updated AtCAST now contains data on >7,000 microarrays, including experiments on various stresses, mutants and chemical treatments. Gene ontology term enrichment (GOE) analysis is introduced to assist the characterization of transcriptome data. The new AtCAST supports input from multiple platforms, including the 'Arabisopsis gene 1.1 ST array', a new microarray chip from Affymetrix and RNA sequencing (RNA-seq) data obtained using next-generation sequencing (NGS). As a pilot study, we conducted microarray analysis of Arabidopsis under auxin treatment using the new Affymetrix chip, and then analyzed the data in AtCAST. We also analyzed RNA-seq data of the pifq mutant using AtCAST. These new features will facilitate analysis of associations between transcriptome data obtained using different platforms. PMID- 25505008 TI - Congenital cystoid adenomatoid malformation: Surgery in a young child. AB - We present the case of a 3.5-year-old child who presented with recurrent chest infections and fever since birth. Antenatal ultrasonography had shown that she had a congenital cystic malformation of the left lower lobe of her lung. She was initially managed conservatively, and after a couple of years, underwent an uneventful left lower lobectomy via a posterolateral thoracotomy. She did very well after the procedure and her symptoms resolved significantly. PMID- 25505007 TI - MOROKOSHI: transcriptome database in Sorghum bicolor. AB - In transcriptome analysis, accurate annotation of each transcriptional unit and its expression profile is essential. A full-length cDNA (FL-cDNA) collection facilitates the refinement of transcriptional annotation, and accurate transcription start sites help to unravel transcriptional regulation. We constructed a normalized FL-cDNA library from eight growth stages of aerial tissues in Sorghum bicolor and isolated 37,607 clones. These clones were Sanger sequenced from the 5' and/or 3' ends and in total 38,981 high-quality expressed sequence tags (ESTs) were obtained. About one-third of the transcripts of known genes were captured as FL-cDNA clone resources. In addition to these, we also annotated 272 novel genes, 323 antisense transcripts and 1,672 candidate isoforms. These clones are available from the RIKEN Bioresource Center. After obtaining accurate annotation of transcriptional units, we performed expression profile analysis. We carried out spikelet-, seed- and stem-specific RNA sequencing (RNA-Seq) analysis and confirmed the expression of 70.6% of the newly identified genes. We also downloaded 23 sorghum RNA-Seq samples that are publicly available and these are shown on a genome browser together with our original FL cDNA and RNA-Seq data. Using our original and publicly available data, we made an expression profile of each gene and identified the top 20 genes with the most similar expression. In addition, we visualized their relationships in gene co expression networks. Users can access and compare various transcriptome data from S, bicolor at http://sorghum.riken.jp. PMID- 25505009 TI - Singlet-oxygen oxidation of 5-hydroxymethylfurfural in continuous flow. AB - Singlet-oxygen oxidation of 5-hydroxymethylfurfural (5-HMF) was performed in continuous flow mode using rose Bengal as photosensitizer. The resulting butenolide (H(2) MF) was formed selectively in high yield. The procedure proved to be scalable and applicable to related bio-based furfurals. Furthermore, preliminary data show that H(2) MF can be readily isomerized thermally to 5 hydroxy-4-keto-pentenoic acid oligomers. PMID- 25505010 TI - Derivation and characterization of a cytocompatible scaffold from human testis. AB - STUDY QUESTION: Is it possible to derive a scaffold from human testis for the purpose of tissue engineering and regenerative medicine? SUMMARY ANSWER: We developed a method to produce a cytocompatible decellularized testicular matrix (DTM) while maintaining the native tissue-specific characteristics and components. WHAT IS KNOWN ALREADY: The potential benefits of tissue-specific scaffolds consisting of naturally-derived extracellular matrix (ECM) have been demonstrated using a wide variety of animal and human tissue sources. However, so far, testis scaffolds have never been considered for constructive remodelling purposes. STUDY DESIGN, SIZE, DURATION: Human cadaveric testicular tissue was exposed for 24 or 48 h to 1% Triton X-100 and/or 1% sodium dodecyl sulphate (SDS). Acellular samples were used for further scaffold characterization purposes. PARTICIPANTS/MATERIALS, SETTING, METHODS: The extent of decellularization was evaluated by histology. Confirmation of cell removal in DTM was done by a DNA quantification technique. Retention of testicular tissue specific characteristics was evaluated by mass spectrometry, immunohistochemistry, Alcian blue staining and scanning electron microscopy. Soluble toxicity and testicular cell attachment was assessed to check the cytocompatibility of DTM scaffolds. MAIN RESULTS AND THE ROLE OF CHANCE: Histological analysis showed that DTM could be obtained by mechanical agitation in 1% SDS for 24 h. The resulting DTM was found to be clear of cells while retaining the typical three-dimensional structure and the major components of the native tissue scaffold, including collagen type I and IV, fibronectin, laminin and glycosaminoglycans. In addition, using proteomic analysis, we revealed numerous additional ECM proteins in DTM, indicating its complex nature. The mass spectrometry data were deposited to the ProteomeXchange with identifier PXD001524. Importantly, we demonstrated that DTM scaffolds are not cytotoxic, as evidenced by MTT assay not showing an aberrant fibroblast proliferation activity after indirect exposure, and support testicular cell attachment and infiltration. LIMITATIONS, REASONS FOR CAUTION: The functionality of human testicular cells in DTM needs to be investigated. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that the insights into the molecular composition of the testicular ECM provide new clues for the unravelling of its important yet poorly understood role in regulating testicular function, and DTM-based bioscaffolds are promising components for the development of human in vitro spermatogenesis as a treatment for various types of male fertility disorders. PMID- 25505011 TI - Reproductive immunology: the relevance of laboratory research to clinical practice (and vice versa). PMID- 25505013 TI - Alterations in Blood Coagulation and Viscosity Among Young Male Cigarette Smokers of Al-Jouf Region in Saudi Arabia. AB - Hemorheology, a measure of rheological properties of blood, is often correlated with cerebral blood flow and cardiac output; an increased blood viscosity may increase the risk of thrombosis or thromboembolic events. Previous studies have reported a large variation in hemorheological properties of blood among smokers. This prompted us to conduct coagulation experiments to evaluate the effect of cigarette smoking on hematological parameters, like cell counts, and coagulation parameters among young males in Al-Jouf region, Saudi Arabia. The hematological and coagulation parameters were used to relate the changes in viscosity and coagulation to smoking. A total of 321 male participants (126 nonsmokers and 195 smokers) were enrolled into the study as randomized sample. Complete blood count was measured by hematology analyzer, and coagulation tests were performed by coagulation analyzer. Thettest analysis was performed to compare the relationships of variables between the 2 groups. The results confirmed that smoking alters some hematology parameters leading to significant deterioration in blood flow properties. Smoking also increased the hematocrit (HCT), whole blood viscosity (WBV), and plasma viscosity (PV) but decreased the international normalized ratio (INR). The decrease in INR was found to be associated with the increase in WBV, PV, and HCT. Further investigations are necessary to assess the reversibility of such changes in cessation of smoking or other elements of influence. PMID- 25505014 TI - Brimonidine for erythema caused by rosacea. AB - Brimonidine gel (Mirvaso-Galderma) became available in February of this year for the symptomatic treatment of facial erythema associated with rosacea in adults.1 Here, we review the evidence on brimonidine gel and consider its place in the management of erythema associated with rosacea. PMID- 25505015 TI - Faecal microbiota transplantation. AB - The use of faeces for the treatment of gastrointestinal diseases was described in 4th century Chinese medicine for the treatment of severe diarrhoea.1 More recently there has been renewed interest in this unconventional biological therapy, particularly for the treatment of recurrent Clostridium difficile infection (CDI) and to a lesser extent inflammatory bowel diseases (IBD). Faecal microbiota transplantation? (FMT) involves the introduction of enteric bacteria from the faeces of healthy donors in order to restore a healthy balance of bacteria in the gut.2 In March 2014, the National Institute for Health and Care Excellence (NICE) issued guidance on the use of FMT for the treatment of recurrent CDI that has failed to respond to antibiotics and other treatments.2 Here we review the use of FMT in CDI and IBD. PMID- 25505012 TI - Fab fragment glycosylated IgG may play a central role in placental immune evasion. AB - STUDY QUESTION: How does the placenta protect the fetus from immune rejection by the mother? SUMMARY ANSWER: The placenta can produce IgG that is glycosylated at one of its Fab arms (asymmetric IgG; aIgG) which can interact with other antibodies and certain leukocytes to affect local immune reactions at the junction between the two genetically distinct entities. WHAT IS KNOWN ALREADY: The placenta can protect the semi-allogenic fetus from immune rejection by the immune potent mother. aIgG in serum is increased during pregnancy and returns to the normal range after giving birth. aIgG can react to antigens to form immune complexes which do not cause a subsequent immune effector reaction, including fixing complements, inducing cytotoxicity and phagocytosis, and therefore has been called 'blocking antibody'. STUDY DESIGN, SIZE, DURATION: Eighty-eight human placentas, four trophoblast cell lines (TEV-1, JAR, JEG and BeWo), primary culture of human placental trophoblasts and a gene knock-out mouse model were investigated in this study. PARTICIPANTS/MATERIALS, SETTING, METHODS: The general approach included the techniques of cell culture, immunohistochemistry, in situ hybridization, immuno-electron microscopy, western blot, quantitative PCR, protein isolation, glycosylation analysis, enzyme digestion, gene sequencing, mass spectrophotometry, laser-guided microdissection, enzyme-linked immunosorbent assay, pulse chase assay, double and multiple staining to analyze protein and DNA and RNA analysis at the cellular and molecular levels. MAIN RESULTS AND THE ROLE OF CHANCE: Three major discoveries were made: (i) placental trophoblasts and endothelial cells are capable of producing IgG, a significant portion of which is aberrantly glycosylated at one of its Fab arms to form aIgG; (ii) the asymmetrically glycosylated IgG produced by trophoblasts and endothelial cells can react to immunoglobulin molecules of human, rat, mouse, goat and rabbit at the Fc portion; (iii) asymmetrically glycosylated IgG can react to certain leukocytes in the membrane and cytoplasm, while symmetric IgG from the placenta does not have this property. LIMITATIONS, REASONS FOR CAUTION: Most of the experiments were performed in vitro. The proposed mechanism calls for verification in normal and abnormal pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: This study identified a number of new phenomena suggesting that aIgG produced by the placenta would be able to react to detrimental antibodies and leukocytes and interfere with their immune reactions against the placenta and the fetus. This opens a new dimension for further studies on pregnancy physiology and immunology. Should the mechanism proposed here be confirmed, it will have a direct impact on our understanding of the physiology and pathology of human reproduction and offer new possibilities for the treatment of many diseases including spontaneous abortion, infertility and pre-eclampsia. It also sheds light on the mechanism of immune evasion in general including that of cancer. PMID- 25505017 TI - Conventional vascular risk factors: their role in the association between migraine and cardiovascular diseases. AB - INTRODUCTION: Migraine, in particular migraine with aura, has been found to be associated with cardiovascular disease. However, the role of conventional vascular risk factors in the association is still debated. The aim of the present review is to address the association between migraine and conventional cardiovascular risk factors as well as to address their possible role in the association between migraine and cardiovascular disease. METHODS: Data for this review were obtained through searches in multiple sources up to May 2014 using the terms "migraine" OR "headache" in combination with all the vascular risk factors of interest. RESULTS: Data about the possible association between migraine and high blood pressure values are heterogeneous, hindering any final conclusion. Data addressing the possible association between migraine and diabetes mellitus indicate the lack of any association or in some cases a negative association between the two conditions. The body of evidence on the role of dyslipidemia in migraineurs is relatively homogeneous and, with few exceptions, reports an association between migraine and an unfavorable lipid profile; however, the difference in lipid levels between migraineurs and non migraineurs is small and its clinical implication unclear. Regarding obesity, a trend has been observed of increased risk of migraine with increasing obesity, especially in young patients, albeit in the midst of conflicting data. Evidence about the association between cigarette smoking and migraine mostly indicates that migraineurs are more commonly smokers than non-migraineurs. On the other hand, the majority of the available studies report less alcohol use in migraineurs than in non-migraineurs. Finally, many of the available studies suggest a more frequent family history of cardiovascular disease in migraineurs as compared to non-migraineurs. Since most of the studies that supported the association between migraine and cardiovascular disease adjusted the analyses for the presence of several vascular risk factors, they cannot entirely explain this association. CONCLUSIONS: Based on the available reported data, it seems unlikely that the higher risk of cardiovascular disease in migraineurs is mediated by any single vascular risk factor. For this reason the role of specific interactions among risk factors with the contribution of genetic, environmental, personality and psychological factors should be appropriately investigated. PMID- 25505018 TI - The impact of smoking on gender differences in life expectancy: more heterogeneous than often stated. AB - BACKGROUND: Throughout industrialized countries, tobacco consumption is seen as the predominant driver of both the trend and the extent of gender differences in life expectancy. However, several factors raise doubts to this generalization. We hypothesize that the impact of smoking on the gender gap is context-specific and differs between populations. METHODS: We decompose the gender differences in life expectancy into fractions caused by smoking and other non-biological factors for 53 industrialized countries and the period 1955-2009 to assess the significance of smoking among the causes that can be influenced by direct or indirect interference. RESULTS: The trend of the gender gap can indeed be attributed to smoking in most populations of the western world. However, with regard to the overall extent of male excess mortality, smoking is the main driver only in the minority of the studied populations. While the impact of smoking to gender differences in life expectancy declines in all populations, the contribution of other non-biological factors is in most cases higher at the end than at the beginning of the observation period. CONCLUSIONS: Over-generalized statements suggesting that smoking is the main driver of the gender gap in all populations can be misleading. The results of this study demonstrate that-regardless of the prevailing effect of smoking-many populations have still remarkable potentials to further narrow their gender gaps in life expectancy. Although measures to further reduce the prevalence of tobacco consumption must be continued, more attention should be directed to the growing importance of other non-biological factors. PMID- 25505019 TI - Low socioeconomic status and perceptions of social inadequacy and shame: findings from the Dutch SMILE study. AB - BACKGROUND: Based on presumed negative social comparisons in lower socioeconomic status groups, we set out to examine whether notions of 'internalized inferiority' are more common in these groups. METHODS: Dutch Studie naar Medische Informatie en Leefwijzen in Eindhoven (SMILE) data on 1323 participants, aged 58 94 in 2008, were used to estimate odds ratios (ORs) of internalized inferiority by childhood and adulthood socioeconomic indicators. Questionnaires for social inadequacy and shame were used to measure internalized inferiority. RESULTS: Both adulthood low educational level [OR 1.58; 95% confidence interval (CI): 1.04 2.40] and low income level (OR 1.88; 95% CI: 1.23-2.88) had substantial associations with reports of social inadequacy. Recalled childhood poverty was strongly associated with reports of shame (OR 2.20; 95% CI: 1.39-3.48). CONCLUSIONS: The socioeconomic patterning of social inadequacy and shame suggests that notions of internalized inferiority in the individual, psychological makeup might be important in the generation and maintenance of socioeconomic inequalities in health. PMID- 25505020 TI - The extent and distribution of gambling harm in Finland as assessed by the Problem Gambling Severity Index. AB - BACKGROUND: Preventing gambling harm has become a policy priority in many European countries. Adverse consequences related to problem gambling are well known, but few studies have analyzed gambling-related harm in detail in general population samples. We determined the extent and distribution of gambling harm in Finland, as assessed by the Problem Gambling Severity Index (PGSI), and analyzed gambling involvement, demographics and their association with various types of harm. METHODS: A nationwide telephone survey was conducted among 4484 Finns aged 15-74 years in 2011-12. Gambling-related harms were based on the nine-item PGSI. Gambling involvement was measured by gambling frequency and weekly average gambling expenditure. Associations among harms, demographics and gambling involvement were examined in logistic regression. RESULTS: During the previous year, 13% of respondents experienced at least one gambling-related harm (males 18.1%, females 7.2%). The four commonest harms were 'chasing losses' (8.6%), 'escalating gambling to maintain excitement' (3.1%), 'betting more than could afford to lose' (2.8%), and 'feeling guilty' (2.6%). The harm profile in descending order was the same for both genders but differed in prevalence. Young age (<25 years) was associated with increased likelihood of reporting harms. Both monthly and weekly gambling and spending over ?21 per week on gambling were related to the harms. CONCLUSIONS: Our results provide support for the public health approach to gambling: harms were reported even at low gambling frequency expenditure levels. In addition to the high-risk approach, adopting a population level approach to preventing gambling harm could shift the population distribution of harm in a lower direction. PMID- 25505022 TI - Personalized integrative oncology: targeted approaches for optimal outcomes: the 11th International Conference of the Society for Integrative Oncology. AB - The 11th International Conference of the Society for Integrative Oncology (SIO) brought together more than 300 clinicians, researchers, patients, and advocates to hear and interact with world-leading experts about the latest research in the areas of nutrition, exercise, acupuncture, health services research, meditation, and other integrative disciplines. The conference theme, "Personalized Integrative Oncology: Targeted Approaches for Optimal Outcomes," highlighted innovations in personalized medicine and ways this growing field will advance the evolution of individualized integrative cancer care to the next level. This year's conference also featured a clinical track focusing on clinical information for the practicing health care professional. The conference's rigorous schedule included 3 keynotes, 4 plenary sessions, 2 interdisciplinary tumor boards, 5 workshops, 45 concurrent oral sessions, and 106 posters. In addition to the conference theme, keynote and plenary sessions presented topics on stress and cancer, the importance of sleep for cancer patients, epigenetic mechanisms of lifestyle and natural products, recently published Journal of the National Cancer Institute monograph on integrative oncology, SIO's clinical practice guidelines for breast cancer survivors, and a joint session of the American Academy of Hospice and Palliative Medicine and SIO about supportive care and symptom management. This highly successful conference helped further the mission of the SIO to advance evidence-based, comprehensive, integrative health care to improve the lives of people affected by cancer. PMID- 25505023 TI - Life without post-transcriptional addition of G-1: two alternatives for tRNAHis identity in Eukarya. AB - The identity of tRNA(His) is strongly associated with the presence of an additional 5'-guanosine residue (G-1) in all three domains of life. The critical nature of the G-1 residue is underscored by the fact that two entirely distinct mechanisms for its acquisition are observed, with cotranscriptional incorporation observed in Bacteria, while post-transcriptional addition of G-1 occurs in Eukarya. Here, through our investigation of eukaryotes that lack obvious homologs of the post-transcriptional G-1-addition enzyme Thg1, we identify alternative pathways to tRNA(His) identity that controvert these well-established rules. We demonstrate that Trypanosoma brucei, like Acanthamoeba castellanii, lacks the G-1 identity element on tRNA(His) and utilizes a noncanonical G-1-independent histidyl-tRNA synthetase (HisRS). Purified HisRS enzymes from A. castellanii and T. brucei exhibit a mechanism of tRNA(His) recognition that is distinct from canonical G-1-dependent synthetases. Moreover, noncanonical HisRS enzymes genetically complement the loss of THG1 in Saccharomyces cerevisiae, demonstrating the biological relevance of the G-1-independent aminoacylation activity. In contrast, in Caenorhabditis elegans, which is another Thg1 independent eukaryote, the G-1 residue is maintained, but here its acquisition is noncanonical. In this case, the G-1 is encoded and apparently retained after 5' end processing, which has so far only been observed in Bacteria and organelles. Collectively, these observations unearth a widespread and previously unappreciated diversity in eukaryotic tRNA(His) identity mechanisms. PMID- 25505024 TI - Functional importance of Psi38 and Psi39 in distinct tRNAs, amplified for tRNAGln(UUG) by unexpected temperature sensitivity of the s2U modification in yeast. AB - The numerous modifications of tRNA play central roles in controlling tRNA structure and translation. Modifications in and around the anticodon loop often have critical roles in decoding mRNA and in maintaining its reading frame. Residues U38 and U39 in the anticodon stem-loop are frequently modified to pseudouridine (Psi) by members of the widely conserved TruA/Pus3 family of pseudouridylases. We investigate here the cause of the temperature sensitivity of pus3Delta mutants of the yeast Saccharomyces cerevisiae and find that, although Psi38 or Psi39 is found on at least 19 characterized cytoplasmic tRNA species, the temperature sensitivity is primarily due to poor function of tRNA(Gln(UUG)), which normally has Psi38. Further investigation reveals that at elevated temperatures there are substantially reduced levels of the s(2)U moiety of mcm(5)s(2)U34 of tRNA(Gln(UUG)) and the other two cytoplasmic species with mcm(5)s(2)U34, that the reduced s(2)U levels occur in the parent strain BY4741 and in the widely used strain W303, and that reduced levels of the s(2)U moiety are detectable in BY4741 at temperatures as low as 33 degrees C. Additional examination of the role of Psi38,39 provides evidence that Psi38 is important for function of tRNA(Gln(UUG)) at permissive temperature, and indicates that Psi39 is important for the function of tRNA(Trp(CCA)) in trm10Delta pus3Delta mutants and of tRNA(Leu(CAA)) as a UAG nonsense suppressor. These results provide evidence for important roles of both Psi38 and Psi39 in specific tRNAs, and establish that modification of the wobble position is subject to change under relatively mild growth conditions. PMID- 25505025 TI - An evolutionary approach uncovers a diverse response of tRNA 2-thiolation to elevated temperatures in yeast. AB - Chemical modifications of transfer RNA (tRNA) molecules are evolutionarily well conserved and critical for translation and tRNA structure. Little is known how these nucleoside modifications respond to physiological stress. Using mass spectrometry and complementary methods, we defined tRNA modification levels in six yeast species in response to elevated temperatures. We show that 2-thiolation of uridine at position 34 (s(2)U34) is impaired at temperatures exceeding 30 degrees C in the commonly used Saccharomyces cerevisiae laboratory strains S288C and W303, and in Saccharomyces bayanus. Upon stress relief, thiolation levels recover and we find no evidence that modified tRNA or s(2)U34 nucleosides are actively removed. Our results suggest that loss of 2-thiolation follows accumulation of newly synthesized tRNA that lack s(2)U34 modification due to temperature sensitivity of the URM1 pathway in S. cerevisiae and S. bayanus. Furthermore, our analysis of the tRNA modification pattern in selected yeast species revealed two alternative phenotypes. Most strains moderately increase their tRNA modification levels in response to heat, possibly constituting a common adaptation to high temperatures. However, an overall reduction of nucleoside modifications was observed exclusively in S288C. This surprising finding emphasizes the importance of studies that utilize the power of evolutionary biology, and highlights the need for future systematic studies on tRNA modifications in additional model organisms. PMID- 25505026 TI - The need for transparency and efficiency in reimbursement decisions relating to drugs for rare diseases. PMID- 25505028 TI - Peripharyngeal tissue deformation, stress distributions, and hyoid bone movement in response to mandibular advancement. AB - Mandibular advancement (MA) increases upper airway (UA) patency and decreases collapsibility. Furthermore, MA displaces the hyoid bone in a cranial-anterior direction, which may contribute to MA-associated UA improvements via redistribution of peripharyngeal tissue stresses (extraluminal tissue pressure, ETP). In the present study, we examined effects of MA on ETP distributions, deformation of the peripharyngeal tissue surface (UA geometry), and hyoid bone position. We studied 13 supine, anesthetized, tracheostomized, spontaneously breathing adult male New Zealand White rabbits. Graded MA was applied from 0 to ~4.5 mm. ETP was measured at six locations distributed throughout three UA regions: tongue, hyoid, and epiglottis. Axial computed tomography images of the UA (nasal choanae to glottis) were acquired and used to measure lumen geometry (UA length; regional cross-sectional area) and hyoid displacement. MA resulted in nonuniform decreases in ETP (greatest at tongue region), ranging from -0.11 ( 0.15 to -0.06) to -0.82 (-1.09 to -0.54) cmH2O/mm MA [linear mixed-effects model slope (95% confidence interval)], across all sites. UA length decreased by -0.5 ( 0.8 to -0.2) %/mm accompanied by nonuniform increases in cross-sectional area (greatest at hyoid region) ranging from 7.5 (3.6-11.4) to 18.7 (14.9-22.5) %/mm. The hyoid bone was displaced in a cranial-anterior direction by 0.42 (0.36-0.44) mm/mm MA. In summary, MA results in nonuniform changes in peripharyngeal tissue pressure distributions and lumen geometry. Displacement of the hyoid bone with MA may play a pivotal role in redistributing applied MA loads, thus modifying tissue stress/deformation distributions and determining resultant UA geometry outcomes. PMID- 25505029 TI - Muscle-specific deletion of exons 2 and 3 of the IL15RA gene in mice: effects on contractile properties of fast and slow muscles. AB - Interleukin-15 (IL-15) is a putative myokine hypothesized to induce an oxidative skeletal muscle phenotype. The specific IL-15 receptor alpha subunit (IL 15Ralpha) has also been implicated in specifying this contractile phenotype. The purposes of this study were to determine the muscle-specific effects of IL 15Ralpha functional deficiency on skeletal muscle isometric contractile properties, fatigue characteristics, spontaneous cage activity, and circulating IL-15 levels in male and female mice. Muscle creatine kinase (MCK)-driven IL 15Ralpha knockout mice (mIl15ra(fl/fl)/Cre(+)) were generated using the Cre-loxP system. We tested the hypothesis that IL-15Ralpha functional deficiency in skeletal muscle would increase resistance to contraction-induced fatigue, cage activity, and circulating IL-15 levels. There was a significant effect of genotype on the fatigue curves obtained in extensor digitorum longus (EDL) muscles from female mIl15ra(fl/fl)/Cre(+) mice, such that force output was greater during the repeated contraction protocol compared with mIl15ra(fl/fl)/Cre(-) control mice. Muscles from female mIl15ra(fl/fl)/Cre(+) mice also had a twofold greater amount of the mitochondrial genome-specific COXII gene compared with muscles from mIl15ra(fl/fl)/Cre(-) control mice, indicating a greater mitochondrial density in these skeletal muscles. There was a significant effect of genotype on the twitch:tetanus ratio in EDL and soleus muscles from mIl15ra(fl/fl)/Cre(+) mice, such that the ratio was lower in these muscles compared with mIl15ra(fl/fl)/Cre(-) control mice, indicating a pro-oxidative shift in muscle phenotype. However, spontaneous cage activity was not different and IL-15 protein levels were lower in male and female mIl15ra(fl/fl)/Cre(+) mice compared with control. Collectively, these data support a direct effect of muscle IL-15Ralpha deficiency in altering contractile properties and fatigue characteristics in skeletal muscles. PMID- 25505031 TI - Vestibular loss disrupts daily rhythm in rats. AB - Hypergravity disrupts the circadian regulation of temperature (Temp) and locomotor activity (Act) mediated through the vestibular otolithic system in mice. In contrast, we do not know whether the anatomical structures associated with vestibular input are crucial for circadian rhythm regulation at 1 G on Earth. In the present study we observed the effects of bilateral vestibular loss (BVL) on the daily rhythms of Temp and Act in semipigmented rats. Our model of vestibular lesion allowed for selective peripheral hair cell degeneration without any other damage. Rats with BVL exhibited a disruption in their daily rhythms (Temp and Act), which were replaced by a main ultradian period (tau <20 h) for 115.8 +/- 68.6 h after vestibular lesion compared with rats in the control group. Daily rhythms of Temp and Act in rats with BVL recovered within 1 wk, probably counterbalanced by photic and other nonphotic time cues. No correlation was found between Temp and Act daily rhythms after vestibular lesion in rats with BVL, suggesting a direct influence of vestibular input on the suprachiasmatic nucleus. Our findings support the hypothesis that the vestibular system has an influence on daily rhythm homeostasis in semipigmented rats on Earth, and raise the question of whether daily rhythms might be altered due to vestibular pathology in humans. PMID- 25505030 TI - Aging impairs heat loss, but when does it matter? AB - Aging is associated with an attenuated physiological ability to dissipate heat. However, it remains unclear if age-related impairments in heat dissipation only occur above a certain level of heat stress and whether this response is altered by aerobic fitness. Therefore, we examined changes in whole body evaporative heat loss (HE) as determined using whole body direct calorimetry in young (n = 10; 21 +/- 1 yr), untrained middle-aged (n = 10; 48 +/- 5 yr), and older (n = 10; 65 +/- 3 yr) males matched for body surface area. We also studied a group of trained middle-aged males (n = 10; 49 +/- 5 yr) matched for body surface area with all groups and for aerobic fitness with the young group. Participants performed intermittent aerobic exercise (30-min exercise bouts separated by 15-min rest) in the heat (40 degrees C and 15% relative humidity) at progressively greater fixed rates of heat production equal to 300 (Ex1), 400 (Ex2), and 500 (Ex3) W. Results showed that HE was significantly lower in middle-aged untrained (Ex2: 426 +/- 34; and Ex3: 497 +/- 17 W) and older (Ex2: 424 +/- 38; and Ex3: 485 +/- 44 W) compared with young (Ex2: 472 +/- 42; and Ex3: 558 +/- 51 W) and middle-aged trained (474 +/- 21; Ex3: 552 +/- 23 W) males at the end of Ex2 and Ex3 (P < 0.05). No differences among groups were observed during recovery. We conclude that impairments in HE in older and middle-aged untrained males occur at exercise induced heat loads of >=400 W when performed in a hot environment. These impairments in untrained middle-aged males can be minimized through regular aerobic exercise training. PMID- 25505027 TI - The association between complete and partial non-response to psychosocial questions and suicide: the JPHC Study. AB - BACKGROUND: Non-participants to psychosocial studies have been shown to have higher mortality, and mortality differs between partial and complete responders to psychosocial questionnaires. Yet, there is very little information available directly linking survey response status with completing suicide. METHODS: The study population consisted of the participants of the Japanese Public Health Center-based prospective study. Ninety-nine thousand four hundred thirty-nine subjects who returned the 10-year follow-up questionnaire and 31 754 individuals who did not return the questionnaire were included in our analyses. The risk of dying by suicide according to response status was estimated by Cox regression models. RESULTS: There were 358 suicides during 1 128 831 person-years of follow up (mean follow-up time: 8.6 years). Of those who returned the questionnaire, 53.9% were full responders, 42.8% were partial non-responders, and 3.3% were complete non-responders. The risk of suicide was increased for both complete non responders [hazard ratio (HR) = 1.84, 95% confidence interval (CI), 0.51, 6.64] and partial non-responders (HR = 1.36, 95% CI, 0.999, 1.84) to the questionnaire as a whole. The adjusting variables explained around 40% of the risk for complete non-responders whereas they did not explain the increased risk of suicide for partial non-responders. The risk of dying by suicide was significantly increased for partial non-responders to the subscale on coping (HR = 1.36, 95% CI, 1.01, 1.85) and for complete non-responders to questions on sleep (HR = 2.07, 95% CI, 1.03, 4.16). CONCLUSIONS: Partial and complete non-responders have increased suicide risk compared with full responders. More than one non-responder category should therefore be considered when interpreting data pertaining to psychosocial questionnaires in longitudinal studies. PMID- 25505032 TI - Intraabdominal splenosis. PMID- 25505033 TI - Comparison of plant-type phosphoenolpyruvate carboxylases from rice: identification of two plant-specific regulatory regions of the allosteric enzyme. AB - Phosphoenolpyruvate carboxylase (PEPC) is a key enzyme of primary metabolism in bacteria, algae and vascular plants, and it undergoes allosteric regulation by various metabolic effectors. Rice (Oryza sativa) has five plant-type PEPCs, four cytosolic and one chloroplastic. We investigated their kinetic properties using recombinant proteins and found that, like most plant-type PEPCs, rice cytosolic isozymes were activated by glucose 6-phosphate and by alkaline pH. In contrast, no such activation was observed for the chloroplastic isozyme, Osppc4. In addition, Osppc4 showed low affinity for the substrate phosphoenolpyruvate (PEP) and very low sensitivities to allosteric inhibitors aspartate and glutamate. By comparing the isozyme amino acid sequences and three-dimensional structures simulated on the basis of the reported crystal structures, we identified two regions where Osppc4 has unique features that can be expected to affect its kinetic properties. One is the N-terminal extension; replacement of the extension of Osppc2a (cytosolic) with that from Osppc4 reduced the aspartate and glutamate sensitivities to about one-tenth of the wild-type values but left the PEP affinity unaffected. The other is the N-terminal loop, in which a conserved lysine at the N-terminal end is replaced with a glutamate-alanine pair in Osppc4. Replacement of the lysine of Osppc2a with glutamate-alanine lowered the PEP affinity to a quarter of the wild-type level (down to the Osppc4 level), without affecting inhibitor sensitivity. Both the N-terminal extension and the N-terminal loop are specific to plant-type PEPCs, suggesting that plant-type isozymes acquired these regions so that their activity could be regulated properly at the sites where they function. PMID- 25505035 TI - Occipital nerve block for the short-term preventive treatment of migraine: A randomized, double-blinded, placebo-controlled study. AB - BACKGROUND: Occipital nerve (ON) injections with corticosteroids and/or local anesthetics have been employed for the acute and preventive treatment of migraine for decades. However, to date there is no randomized, placebo-controlled evidence to support the use of occipital nerve block (ONB) for the prevention of migraine. OBJECTIVE: The objective of this article is to determine the efficacy of ONB with local anesthetic and corticosteroid for the preventive treatment of migraine. PARTICIPANTS AND METHODS: Patients between 18 and 75 years old with ICHD-II defined episodic (> 1 attack per week) or chronic migraine (modified ICHD-II as patients with > 10 days with consumption of acute medications were permitted into the study) were randomized to receive either 2.5 ml 0.5% bupivacaine plus 0.5 ml (20 mg) methylprednisolone over the ipsilateral (unilateral headache) or bilateral (bilateral headache) ON or 2.75 ml normal saline plus 0.25 ml 1% lidocaine without epinephrine (placebo). Patients completed a one-month headache diary prior to and after the double-blind injection. The primary outcome measure was defined as a 50% or greater reduction in the frequency of days with moderate or severe migraine headache in the four-week post-injection compared to the four week pre-injection baseline period. RESULTS: Thirty-four patients received active and 35 patients received placebo treatment. Because of missing data, the full analysis of 33 patients in the active and 30 patients in the placebo group was analyzed for efficacy. In the active and placebo groups respectively, the mean frequency of at least moderate (mean 9.8 versus 9.5) and severe (3.6 versus 4.3) migraine days and acute medication days (7.9 versus 10.0) were not substantially different at baseline. The percentage of patients with at least a 50% reduction in the frequency of moderate or severe headache days was 30% for both groups (10/30 vs nine of 30, Delta 0.00, 95% CI -0.22 to 0.23). CONCLUSIONS: Greater ONB does not reduce the frequency of moderate to severe migraine days in patients with episodic or chronic migraine compared to placebo.The study was registered with ClinicalTrial.gov (NCT00915473). PMID- 25505036 TI - Late-life migraine accompaniments: A narrative review. AB - BACKGROUND: Migraine is one of the most common chronic neurological disorders. In 1980, C. Miller Fisher described late-life migraine accompaniments as transient neurological episodes in older individuals that mimic transient ischemic attacks. There has not been an update on the underlying nature and etiology of late-life migraine accompanimentsd since the original description. PURPOSE: The purpose of this article is to provide a comprehensive and extensive review of the late-life migraine accompaniments including the epidemiology, clinical characteristics, differential diagnosis, and treatment. METHODS: Literature searches were performed in MEDLINE(r), PubMed, Cochrane Library, and EMBASE databases for publications from 1941 to July 2014. The search terms "Migraine accompaniments," "Late life migraine," "Migraine with aura," "Typical aura without headache," "Migraine equivalents," "Acephalic migraine," "Elderly migraine," and "Transient neurological episodes" were used. CONCLUSION: Late-life onset of migraine with aura is not rare in clinical practice and can occur without headache, especially in elderly individuals. Visual symptoms are the most common presentation, followed respectively by sensory, aphasic, and motor symptoms. Gradual evolution, the march of transient neurological deficits over several minutes and serial progression from one symptom to another in succession are typical clinical features for late-life migraine accompaniments. Transient neurological disturbances in migraine aura can mimic other serious conditions and can be easily misdiagnosed. Careful clinical correlation and appropriate investigations are essential to exclude secondary causes. Treatments are limited and still inconsistent. PMID- 25505034 TI - Plant Omics Data Center: an integrated web repository for interspecies gene expression networks with NLP-based curation. AB - Comprehensive integration of large-scale omics resources such as genomes, transcriptomes and metabolomes will provide deeper insights into broader aspects of molecular biology. For better understanding of plant biology, we aim to construct a next-generation sequencing (NGS)-derived gene expression network (GEN) repository for a broad range of plant species. So far we have incorporated information about 745 high-quality mRNA sequencing (mRNA-Seq) samples from eight plant species (Arabidopsis thaliana, Oryza sativa, Solanum lycopersicum, Sorghum bicolor, Vitis vinifera, Solanum tuberosum, Medicago truncatula and Glycine max) from the public short read archive, digitally profiled the entire set of gene expression profiles, and drawn GENs by using correspondence analysis (CA) to take advantage of gene expression similarities. In order to understand the evolutionary significance of the GENs from multiple species, they were linked according to the orthology of each node (gene) among species. In addition to other gene expression information, functional annotation of the genes will facilitate biological comprehension. Currently we are improving the given gene annotations with natural language processing (NLP) techniques and manual curation. Here we introduce the current status of our analyses and the web database, PODC (Plant Omics Data Center; http://bioinf.mind.meiji.ac.jp/podc/), now open to the public, providing GENs, functional annotations and additional comprehensive omics resources. PMID- 25505037 TI - Cervical screening in HIV-positive women in the East of England: recent CD4 as the predictive risk factor. AB - This study examines the relationship between CD4 count and cervical cytological abnormality in HIV-positive women attending two district general hospital genitourinary medicine clinics in the East of England. It aims to determine whether the rate of cervical cytological abnormalities differs in HIV-positive women with CD4 count >350 cells/ul and those with CD4 count <=350 cells/ul; and to compare the rates of abnormalities with that of the general population. We retrospectively reviewed data from a cross-sectional audit undertaken between December 2010 and December 2011 and analysed them using multivariable statistics. There was a significant association between recent CD4 count <=350 cells/ul and cervical cytological abnormality (p < 0.001). A total of 6.3% of women with recent CD4 counts >350 cells/ul had abnormal cervical smear results, compared with 6.6% of the general population in the screening period 2010-11 and 7.2% of the general population in the screening period 2009-10. In our study population of women with recent CD4 counts >350 cells/ul, the proportions of mild, moderate and severe dysplasia were also similar to national figures. This raises important questions about the cost effectiveness of blanket annual screening for HIV positive women. PMID- 25505038 TI - Desire to father a child and condom use: a study of young black men at risk of sexually transmitted infections. AB - To determine whether men's reported desire to father a child or their perception that someone wanted to have their child was associated with elevated rates of unprotected vaginal sex, we studied a sample of young Black men at high risk of sexually transmitted infection acquisition. Data were collected in clinics treating sexually transmitted infections in three southern U.S. cities. Men 15-23 years of age who identified as Black/African American and reported recent (past two months) penile-vaginal sex were eligible (N = 578). Logistic regression was used to examine whether desire to conceive a child (self and perception of partners' desire) predicted condom use, adjusting for age and whether they had previously impregnated someone. Their own level of desire to conceive a child was not significantly associated with unprotected vaginal sex or the proportion of times a condom was used. However, those who perceived higher level of someone wanting to conceive their child were 1.73 times more likely to report unprotected vaginal sex (P = .006) and 1.62 times more likely to report a lower proportion of times condoms were used (P = .019). Young Black men attending sexually transmitted infection clinics in the USA may forego condom use based on a perceived desire of their partners to become pregnant, putting themselves at risk for sexually transmitted infection acquisition and unplanned pregnancy. Findings provide initial support for the relevance of the idea that perceptions of women partners' desire to conceive may be a critical determinant of condomless sex. PMID- 25505040 TI - Seven years of undiagnosed syphilis: a missed opportunity for mother and child. AB - We report the case of congenital syphilis diagnosed in a 7-year-old child after her 32-year-old mother was investigated for neurosyphilis. Our case illustrates the importance of antenatal syphilis screening and the need for a clear referral and management pathway for women with positive serology to ensure cases such as ours do not occur in the future. PMID- 25505039 TI - Correlates of prevalent HIV infection among adults and adolescents in the Kisumu incidence cohort study, Kisumu, Kenya. AB - We estimated HIV prevalence and identified correlates of HIV infection among 1106 men and women aged 16-34 years residing in Kisumu, Kenya. Demographic, sexual, and other behavioural data were collected using audio computer-assisted self interview in conjunction with a medical examination, real-time parallel rapid HIV testing, and laboratory testing for pregnancy, gonorrhoea, chlamydia, syphilis, and herpes simplex virus type 2. Multivariate logistic regression was used to identify variables associated with prevalent HIV infection by gender. Overall HIV prevalence was 12.1%. HIV prevalence among women (17.1%) was approximately two and-one-half times the prevalence among men (6.6%). Odds of HIV infection in men increased with age (aOR associated with one-year increase in age = 1.21, CI = 1.07-1.35) and were greater among those who were uncircumcised (aOR = 4.42, CI = 1.41-13.89) and those who had an herpes simplex virus type 2-positive (aOR = 3.13, CI = 1.12-8.73) test result. Odds of prevalent HIV infection among women also increased with age (aOR associated with one-year increase in age = 1.16, CI = 1.04-1.29). Women who tested herpes simplex virus type 2 positive had more than three times the odds (aOR = 3.85, CI = 1.38-10.46) of prevalent HIV infection compared with those who tested herpes simplex virus type 2 negative. Tailored sexual health interventions and programs may help mitigate HIV age and gender disparities. PMID- 25505041 TI - Virologic suppression among HIV-infected US Air Force members in a highly structured programme with free access to care. AB - SummaryThe United States Air Force HIV programme has several features that may enhance antiretroviral therapy outcomes, including free access to healthcare and mandatory clinical visits every six months at a single centre. We evaluated viral load suppression (<50 copies/ml) after 12 months of initial antiretroviral therapy, with extension to 18 and 24 months. Active duty Air Force members were categorised by year of antiretroviral therapy initiation: 2000-2005 (n = 95, 36.1%) and 2006-2011 (n = 168, 63.9%). The median months from HIV diagnosis to initial antiretroviral therapy were shorter in the 2000-2005 group (2.4, IQR 1.2 5.9) compared with the 2006-2011 group (12.6, IQR 2.6-29.0; p < 0.001). Viral load suppression was greater in the 2006-2011 group compared with the 2000-2005 group at 12 months (93.2% versus 78.6%, p = 0.002) and 18 months (91.8% versus 80.3%, p = 0.03), and trended higher at 24 months (90.8% versus 82.5%; p = 0.15). Factors associated with viral load suppression at 12 months in multivariate models included antiretroviral therapy initiation during 2006-2011 (OR 5.22, 95% CI 1.50-18.18) and CD4 count at antiretroviral therapy initiation (OR 2.29, 95% CI 1.19-14.43 per 100 cells/ul increase). Structured programmes that minimise traditional barriers to care combined with the use of contemporary antiretroviral therapy regimens can achieve clinic-wide viral load suppression in >90% of patients. PMID- 25505043 TI - Valaciclovir versus aciclovir for the treatment of primary genital herpes simplex: a cost analysis. AB - The current guidelines for the treatment of primary herpes simplex in the Genito urinary department in Sheffield Teaching Hospitals NHS Foundation Trust, recommend valaciclovir as a first-line medication. This is a prodrug of aciclovir, which has been used for many years as a treatment for primary herpes simplex virus. The basis of the recommendation largely relates to valaciclovir being more bioavailable than aciclovir. However, there is no evidence to suggest this has an effect on overall outcome with regard to symptom control and viral shedding. The purpose of the service evaluation was to discover if significant cost savings could be made by changing the prescribing policy to make aciclovir the drug of choice for primary herpes simplex virus. Based on 160 patients receiving valaciclovir (500 mg BD) during April 2013 and March 2014, if they had been treated with aciclovir (400 mg TDS) instead, a saving of L828.80 (66% reduction) could have been made. PMID- 25505042 TI - Human papillomavirus knowledge, vaccine acceptance, and vaccine series completion among female entertainment and sex workers in Phnom Penh, Cambodia: the Young Women's Health Study. AB - Human papillomavirus is a common sexually transmitted infection and the causative agent for cervical cancer, a frequently occurring malignant disease among women in developing countries. We assessed human papillomavirus awareness prior to the delivery of a brief information and education intervention, and human papillomavirus vaccine provision to female entertainment and sex workers (N = 220). At baseline, only 23.6% of women had heard of human papillomavirus. Following the educational intervention, 90% answered all the human papillomavirus knowledge questions correctly. Of 192 participants attending the first quarterly cohort visit where vaccine was offered, 149 (78%) were eligible for vaccination; HIV-positive (n = 32) and pregnant (n = 11) women were excluded. Acceptance of vaccine among eligible women was universal, and 79.2% completed the three-dose vaccination series. Women who reported use of amphetamine-type stimulants had significantly and independently lower odds of vaccine completion (adjusted odds ratio [AOR] 0.24; 95% confidence interval [CI] 0.08, 0.69). New pregnancies also had an impact on vaccine completion: 5.4% (8/149 5.4%) who started the series had to stop due to new pregnancy. Results demonstrate the effectiveness of a simple education intervention designed to increase human papillomavirus knowledge and the feasibility of successful human papillomavirus vaccine in a population that is often difficult to engage in preventive health care. PMID- 25505044 TI - Race/ethnicity, sexual partnerships with men involved with drugs, and sexually transmitted infections among a sample of urban young adult women. AB - In many urban neighbourhoods in the United States, drug markets borne from disadvantage have produced risk for sexually transmitted infections through altered sexual norms and partnerships. Presently, we examined the association of race, sexual partnerships with men involved with drugs, and self-reported sexually transmitted infections among 240 African American and white women aged 18-30 years. Thirty seven per cent reported ever having a sexually transmitted infection. Almost 30% of Whites reported sex with a drug user, compared to 5% of African Americans. Fifty eight per cent of African Americans compared to 31% of Whites reported sex with a drug dealer. On Step 1 of a sequential logistic regression model, race was associated with lifetime sexually transmitted infections (OR = 4.7, 95% CI = 2.61-8.34). Results from the full sequential logistic regression model indicated a significant, but smaller association of race and lifetime sexually transmitted infections (Adjusted OR = 3.5, 95% CI = 1.78-7.02) and an association of sex with a drug dealer and lifetime sexually transmitted infections (Adjusted OR = 2.9, 95% CI = 1.55-5.20). Forming sexual partnerships with drug dealers may place women at increased risk for sexually transmitted infections and explain racial disparities. More research focused on drug dealers as core transmitters is needed. PMID- 25505045 TI - Prevalence of thyroid dysfunction and its correlation with CD4 count in newly diagnosed HIV-positive adults--a cross-sectional study. AB - Prevalence of subclinical hypothyroidism in HIV-positive patients is reported to be high in those with severe immune deficiency. However, there is paucity of literature in newly-diagnosed HIV-positive population. Our aim was to estimate the prevalence of thyroid dysfunction and study its correlation with CD4 count in this population. In this cross-sectional study, patients presenting to the antiretroviral therapy clinic were screened with thyroid function tests, including thyroid stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid peroxidase antibody levels at the time of diagnosis. Two hundred and twenty-five HIV-positive and an equal number of healthy volunteers were enrolled. The mean (SD) CD4 count in the study group was 147.1 (84) and 70.7% had advanced immune deficiency with CD4 count <200 cells/uL. The overall prevalence of thyroid dysfunction was 75.5% in the study group and 16% in the control group. Subclinical hypothyroidism was the commonest abnormality noted in almost 53%. Significant correlation was observed between CD4 count and thyroid stimulating hormone, free triiodothyronine, and free thyroxine levels (r = -0.86, r = 0.77, and r = 0.84, respectively, p < 0.0001 for all). The present study demonstrated high prevalence of thyroid dysfunction in HIV-positive patients. The dysfunction is subclinical in most cases and correlates well with declining CD4 counts. PMID- 25505046 TI - Interferon-gamma gene polymorphism influences the frequency of a Chlamydia trachomatis cervical infection in young women. AB - Cervicitis associated with Chlamydia trachomatis is frequent worldwide, but the factors determining susceptibility to infection remain incompletely determined. We evaluated whether a functional single nucleotide polymorphism at position +874 in the gene coding for interferon gamma (rs2430561) influenced the likelihood of having a cervical C. trachomatis infection. This was a cross-sectional study of 142 sexually-active women attending a general gynaecology service on the outskirts of the city of Fortaleza in northeastern Brazil between August 2011 and August 2012. Endocervical swabs were evaluated for C. trachomatis DNA using hybrid capture. DNA from buccal swabs was utilised for detection of the interferon gamma 874 T/A single nucleotide polymorphism by gene amplification, endonuclease digestion and gel electrophoresis. Nineteen women (13.4%) were positive for C. trachomatis in their cervix. Positivity was 21.7% in women with the A,A genotype versus 7.0% in women with one or two T alleles (p = 0.0227). The variant T allele frequency, associated with elevated interferon gamma production, was 36.2% in women who were negative for C. trachomatis as opposed to 18.4% in women who were positive for a cervical infection with this organism (p = 0.0415). Possession of the T allele at position +874 in the gene coding for interferon gamma is associated with a reduced likelihood of a C. trachomatis cervical infection. PMID- 25505047 TI - HIV knowledge, risk perception and pre-exposure prophylaxis interest among Thai university students. AB - To assess HIV risk perception and pre-exposure prophylaxis (PrEP) interest among university students, an anonymous survey was conducted among students from a large public university in Thailand. There were 641 participants; 118 (18%) were categorised into moderate or high-risk group. Of these 118 participants, 111 (94%) perceived themselves as no or low risk. Despite high levels of knowledge about HIV transmission risks, rates of consistent condom use with vaginal, oral and anal sex were all low (43%, 18% and 33%, respectively). The low rates of consistent condom use were significantly associated with false perception of low HIV risk (P < 0.05). Independent factors associated with the false perception were male gender (P < 0.001), living with a domestic partner (P = 0.004), being homosexual or bisexual (P = 0.02) and being students from a non-medicine faculty (P = 0.04). Of the 641 participants, 211 (33%) were not interested in PrEP. Consistent condom use with oral sex (P = 0.004), consistent condom use with vaginal sex (P = 0.04) and being heterosexual (P = 0.02) were independently associated with no PrEP interest. Our study suggests the need for enhanced interventions to improve HIV risk perception and safe sex practices among the university students. PMID- 25505048 TI - Hemichorea in a patient with HIV-associated central nervous system histoplasmosis. AB - Central nervous system histoplasmosis is a rare opportunistic infection with a heterogeneous clinical presentation. We describe the first case of human immunodeficiency virus-associated cerebral histoplasmosis presenting with hemichorea. The patient recovered after treatment with conventional amphotericin B and itraconazole. PMID- 25505049 TI - Cryptococcal meningoencephalitis relapse after an eight-year delay: an interplay of infection and immune reconstitution. AB - We report a case of a symptomatic relapse of HIV-related cryptococcal meningoencephalitis eight years after the first diagnosis on the background of immune reconstitution. The findings as well as the clinical course suggests a combination of smouldering localised infection and enhanced inflammatory reaction related to immune restoration due to antiretroviral therapy. A combination of antifungal and anti-inflammatory therapy resulted in clinical and radiological improvement. Our case challenges the concept that immune reconstitution inflammatory syndrome and microbiological relapse are dichotomous entities. PMID- 25505050 TI - Biomarkers and pharmaceutical strategies in steroid-induced osteonecrosis of the femoral head: a literature review. AB - The underlying pathology of steroid-induced osteonecrosis of the femoral head (ONFH) is unclear but is known to be multifactorial. It is therefore difficult to find a single predictive biomarker for this disease, and multiple biomarkers are likely to contribute to ONFH progression. Investigation of protein-protein interactions is vital in order to elucidate fully the pathogenesis of this disease, and provide new treatment strategies. This review article discusses the known biomarkers and current treatment strategies for ONFH. PMID- 25505051 TI - Importance of transparency in assessing the feasibility of modeling rare disease. PMID- 25505053 TI - Confirmation and quantification of clenbuterol in horse urine using liquid chromatography tandem mass spectrometry triple quadrupole. AB - Clenbuterol (CLE) is used in horses as a bronchodilator and for its anabolic steroid-like effects. CLE is a Class 3 drug according to current Association of Racing Commissioners International (ARCI) Uniform Classification Guidelines. The Racing Medication and Testing Consortium recommended a urine CLE threshold of 140 pg/mL after careful scientific review of the results of studies describing the disposition of CLE in the horse and this threshold was adopted by the ARCI. Enzyme-linked immunosorbent assay was previously used to screen samples for CLE in Illinois, but could not detect such low concentrations in urine. Thus, a liquid-liquid extraction of CLE from urine followed by quantification by liquid chromatography-tandem mass spectrometry was developed and validated. Method validation included testing stability, ion suppression and enhancement, precision, accuracy and uncertainty. Intra-, interday and total precision and accuracy were calculated for each control and found to be within the +/-15% acceptance range. The Guide to the Expression of Uncertainty in Measurement approach was used to calculate uncertainty, which was 11% at the 95% confidence level. In the past 5 years, only 15 samples were reported as positive for CLE in Illinois. This new method was used in a pilot program to screen and confirm samples received from thoroughbred and harness horses. PMID- 25505052 TI - Examining Intuitive Cancer Risk Perceptions in Haitian-Creole and Spanish Speaking Populations. AB - BACKGROUND: There is a developing emphasis on intuition and affect in the illness risk perception process, yet there have been no available strategies to measure these constructs in non-English speakers. This study examined the comprehensibility and acceptability of translations of cancer risk beliefs in Haitian-Creole and Spanish. METHOD: An established, iterative, team-based translation process was employed. Cognitive interviews (n = 20 in Haitian-Creole speakers; n = 23 in Spanish speakers) were conducted in an inner-city primary care clinic by trained interviewers who were native speakers of each language. Use of an established coding scheme for problematic terms and ambiguous concepts resulted in rewording and dropping items. RESULTS: Most items (90% in the Haitian Creole version; 87% in the Spanish version) were highly comprehensible. DISCUSSION: This work will allow for further research examining health outcomes associated with risk perceptions across diverse, non-English language subgroups, paving the way for targeted risk communication with these populations. PMID- 25505054 TI - Brain tissue: a viable postmortem toxicological specimen. AB - Brain tissue may be a valuable specimen in interpretation of postmortem toxicology. The protected and isolated position of the brain eliminates or at least attenuates many of the interpretive challenges with postmortem blood specimens. This study presents data for 30 drug and drug metabolites in cases submitted to the Sedgwick County Regional Forensic Science Center for autopsy examination from 2007 to 2014. Drug concentration in heart and femoral blood is compared with the drug concentration in brain tissue. There is a positive correlation of blood to brain concentrations, thus providing another tool for the toxicologist or pathologist to utilize in case interpretation. PMID- 25505055 TI - Multiple stressors and multifunctionality: limited effects on an illuminated benthic system. AB - The bulk of experiments that study stressor effects on ecosystem functioning consider only individual functions one at a time, and such narrow focus may well bias our understanding of the overall impact on ecosystem functioning. We used data from six published experiments in which marine illuminated sediment systems were exposed to nutrient enrichment, toxicants, sedimentation and warming, either alone or in combination. Measured functions were primary production, community respiration, inorganic nitrogen and phosphorus fluxes, and autotrophic biomass. We calculated two indices of multifunctionality that simultaneously considered all six functions: (i) a weighted average level of the functions and (ii) the number of functions that simultaneously exceed a critical threshold level. Stressors affected individual functions both positively and negatively, but multifunctionality was generally unaffected by both single and joint stressors. The filtering capacity of coastal illuminated sediment systems thus appears resilient to exposure to moderate levels of multiple stressors, most probably due to the robustness of the benthic microalgal community. We recommend using a multifunctionality approach in future studies on cumulative stressor effects on ecosystem functioning, particularly when considering functions related to ecosystem services. PMID- 25505056 TI - When maths trumps logic: probabilistic judgements in chimpanzees. AB - When searching for hidden food, do chimpanzees take into account both the number of hidden items and the number of potential hiding locations? We presented chimpanzees with two trays, each of them containing a different food/cup ratio and therefore a different likelihood of finding a baited cup among empty alternatives. Subjects' performance was directly influenced by the relative difference (probability ratio (PR)) between the two given probabilities. Interestingly, however, they did not appreciate the special value of a truly safe option (with P = 1.0). Instead, they seemed to 'blindly' rely on the PR between the two options, systematically preferring the more likely one once a certain threshold had been reached. A control condition ruled out the possibility of low level learning explanations for the observed performance. PMID- 25505057 TI - Density-dependent selection closes an eco-evolutionary feedback loop in the stick insect Timema cristinae. AB - Empirical demonstrations of feedbacks between ecology and evolution are rare. Here, we used a field experiment to test the hypothesis that avian predators impose density-dependent selection (DDS) on Timema cristinae stick insects. We transplanted wild-caught T. cristinae to wild bushes at 50 : 50 cryptic : conspicuous morph ratio and manipulated density by transplanting either 24 or 48 individuals. The frequency of the conspicuous morph was reduced by 73% in the low density treatment, but only by 50% in the high-density treatment, supporting a hypothesis of negative DDS. Coupled with previous studies on T. cristinae, which demonstrate that maladaptive gene flow reduces population density, we support an eco-evolutionary feedback loop in this system. Furthermore, our results support the hypothesis that predator satiation is the mechanism driving DDS. We found no effects of T. cristinae density on the abundance or species richness of other arthropods. Eco-evolutionary feedbacks, driven by processes like DDS, can have implications for adaptive divergence and speciation. PMID- 25505058 TI - Comparison of drug detection by three quadrupole time-of-flight mass spectrometry platforms. AB - Urine and plasma specimens fortified with 82 drugs and metabolites were prepared and analyzed by liquid chromatography quadrupole time-of-flight mass spectrometry (QTOF) instrumentation from three different vendors using the instrument manufacturers' methods and workflows for drug screening. No prior knowledge about the compounds included or their concentrations were provided. Samples were prepared and sent for analysis on a TripleTOF((r)) 5600 system, a 6530 QTOF and a Xevo((r)) G2-S QTof. All three platforms performed well with >90% of compounds detected in one set of spiked plasma samples, and 79-88% for a second set of spiked plasma and two sets of spiked urine samples. PMID- 25505059 TI - MicroRNA-mediated transformation by the Kaposi's sarcoma-associated herpesvirus Kaposin locus. AB - The human oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV) expresses a set of ~20 viral microRNAs (miRNAs). miR-K10a stands out among these miRNAs because its entire stem-loop precursor overlaps the coding sequence for the Kaposin (Kap) A/C proteins. The ectopic expression of KapA has been reported to lead to transformation of rodent fibroblasts. However, these experiments inadvertently also introduced miR-K10a, which raises the question whether the transforming activity of the locus could in fact be due to miR-K10a expression. To answer this question, we have uncoupled miR-K10a and KapA expression. Our experiments revealed that miR-K10a alone transformed cells with an efficiency similar to that when it was coexpressed with KapA. Maintenance of the transformed phenotype was conditional upon continued miR-K10a but not KapA protein expression, consistent with its dependence on miRNA-mediated changes in gene expression. Importantly, miR-K10a taps into an evolutionarily conserved network of miR-142-3p targets, several of which are expressed in 3T3 cells and are also known inhibitors of cellular transformation. In summary, our studies of miR-K10a serve as an example of an unsuspected function of an mRNA whose precursor is embedded within a coding transcript. In addition, our identification of conserved miR-K10a targets that limit transformation will point the way to a better understanding of the role of this miRNA in KSHV-associated tumors. IMPORTANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus. The viral Kaposin locus has known oncogenic potential, which has previously been attributed to the encoded KapA protein. Here we show that the virally encoded miR-K10a miRNA, whose precursor overlaps the KapA-coding region, may account for the oncogenic properties of this locus. Our data suggest that miR-K10a mimics the cellular miRNA miR-142-3p and thereby represses several known inhibitors of oncogenic transformation. Our work demonstrates that functional properties attributed to a coding region may in fact be carried out by an embedded noncoding element and sheds light on the functions of viral miR-K10a. PMID- 25505060 TI - Virion-independent transfer of replication-competent hepatitis C virus RNA between permissive cells. AB - In this study, we show that replication-competent subgenomic hepatitis C virus (HCV) RNA can be transferred to permissive Huh7 cells, leading to the establishment of viral RNA replication. Further, we show that these events are mediated by exosomes rather than infectious virus particles. If similar events occur in vivo, this could represent a novel, albeit inefficient, mechanism of viral spread and immune escape. PMID- 25505061 TI - Identification and functional comparison of seven-transmembrane G-protein-coupled BILF1 receptors in recently discovered nonhuman primate lymphocryptoviruses. AB - Coevolution of herpesviruses with their respective host has resulted in a delicate balance between virus-encoded immune evasion mechanisms and host antiviral immunity. BILF1 encoded by human Epstein-Barr virus (EBV) is a 7 transmembrane (7TM) G-protein-coupled receptor (GPCR) with multiple immunomodulatory functions, including attenuation of PKR phosphorylation, activation of G-protein signaling, and downregulation of major histocompatibility complex (MHC) class I surface expression. In this study, we explored the evolutionary and functional relationships between BILF1 receptor family members from EBV and 12 previously uncharacterized nonhuman primate (NHP) lymphocryptoviruses (LCVs). Phylogenetic analysis defined 3 BILF1 clades, corresponding to LCVs of New World monkeys (clade A) or Old World monkeys and great apes (clades B and C). Common functional properties were suggested by a high degree of sequence conservation in functionally important regions of the BILF1 molecules. A subset of BILF1 receptors from EBV and LCVs from NHPs (chimpanzee, orangutan, marmoset, and siamang) were selected for multifunctional analysis. All receptors exhibited constitutive signaling activity via G protein Galphai and induced activation of the NF-kappaB transcription factor. In contrast, only 3 of 5 were able to activate NFAT (nuclear factor of activated T cells); chimpanzee and orangutan BILF1 molecules were unable to activate NFAT. Similarly, although all receptors were internalized, BILF1 from the chimpanzee and orangutan displayed an altered cellular localization pattern with predominant cell surface expression. This study shows how biochemical characterization of functionally important orthologous viral proteins can be used to complement phylogenetic analysis to provide further insight into diverse microbial evolutionary relationships and immune evasion function. IMPORTANCE: Epstein-Barr virus (EBV), known as an oncovirus, is the only human herpesvirus in the genus Lymphocryptovirus (LCV). EBV uses multiple strategies to hijack infected host cells, establish persistent infection in B cells, and evade antiviral immune responses. As part of EBV's immune evasion strategy, the virus encodes a multifunctional 7-transmembrane (7TM) G-protein-coupled receptor (GPCR), EBV BILF1. In addition to multiple immune evasion-associated functions, EBV BILF1 has transforming properties, which are linked to its high constitutive activity. We identified BILF1 receptor orthologues in 12 previously uncharacterized LCVs from nonhuman primates (NHPs) of Old and New World origin. As 7TM receptors are excellent drug targets, our unique insight into the molecular mechanism of action of the BILF1 family and into the evolution of primate LCVs may enable validation of EBV BILF1 as a drug target for EBV-mediated diseases, as well as facilitating the design of drugs targeting EBV BILF1. PMID- 25505062 TI - N-linked glycosylation protects gammaretroviruses against deamination by APOBEC3 proteins. AB - Retroviruses are pathogens with rapid infection cycles that can be a source of disease, genome instability, and tumor development in their hosts. Host intrinsic restriction factors, such as APOBEC3 (A3) proteins, are constitutively expressed and dedicated to interfering with the replication cycle of retroviruses. To survive, propagate, and persist, retroviruses must counteract these restriction factors, often by way of virus genome-encoded accessory proteins. Glycosylated Gag, also called glycosylated Pr80 Gag (gPr80), is a gammaretrovirus genome encoded protein that inhibits the antiretroviral activity of mouse A3 (mA3). Here we show that gPr80 exerts two distinct inhibitory effects on mA3: one that antagonizes deamination-independent restriction and another one that inhibits its deaminase activity. More specifically, we find that the number of N-glycosylated residues in gPr80 inversely correlates with the sensitivity of a gammaretrovirus to deamination by mouse A3 and also, surprisingly, by human A3G. Finally, our work highlights that retroviruses which have successfully integrated into the mouse germ line generally express a gPr80 with fewer glycosylated sites than exogenous retroviruses. This observation supports the suggestion that modulation of A3 deamination intensity could be a desirable attribute for retroviruses to increase genetic diversification and avoid immune detection. Overall, we present here the first description of how gammaretroviruses employ posttranslational modification to antagonize and modulate the activity of a host genome-encoded retroviral restriction factor. IMPORTANCE: APOBEC3 proteins are host factors that have a major role in protecting humans and other mammals against retroviruses. These enzymes hinder their replication and intensely mutate their DNA, thereby inactivating viral progeny and the spread of infection. Here we describe a newly recognized way in which some retroviruses protect themselves against the mutator activity of APOBEC3 proteins. We show that gammaretroviruses expressing an accessory protein called glycosylated Gag, or gPr80, use the host's posttranslational machinery and, more specifically, N-linked glycosylation as a way to modulate their sensitivity to mutations by APOBEC3 proteins. By carefully controlling the amount of mutations caused by APOBEC3 proteins, gammaretroviruses can find a balance that helps them evolve and persist. PMID- 25505063 TI - Hepatitis B virus polymerase disrupts K63-linked ubiquitination of STING to block innate cytosolic DNA-sensing pathways. AB - The cellular innate immune system recognizing pathogen infection is essential for host defense against viruses. In parallel, viruses have developed a variety of strategies to evade the innate immunity. The hepatitis B virus (HBV), a DNA virus that causes chronic hepatitis, has been shown to inhibit RNA helicase RIG-I mediated interferon (IFN) induction. However, it is still unknown whether HBV could affect the host DNA-sensing pathways. Here we report that in transiently HBV-transfected Huh7 cells, the stably HBV-producing cell line HepAD38, and HBV infected HepaRG cells and primary human hepatocytes, HBV markedly interfered with IFN-beta induction and antiviral immunity mediated by the stimulator of interferon genes (STING), which has been identified as a central factor in foreign DNA recognition and antiviral innate immunity. Screening analysis demonstrated that the viral polymerase (Pol), but not other HBV-encoded proteins, was able to inhibit STING-stimulated interferon regulatory factor 3 (IRF3) activation and IFN-beta induction. Moreover, the reverse transcriptase (RT) and the RNase H (RH) domains of Pol were identified to be responsible for the inhibitory effects. Furthermore, Pol was shown to physically associate with STING and dramatically decrease the K63-linked polyubiquitination of STING via its RT domain without altering the expression level of STING. Taken together, these observations suggest that besides its inherent catalytic function, Pol has a role in suppression of IFN-beta production by direct interaction with STING and subsequent disruption of its K63-linked ubiquitination, providing a new mechanism for HBV to counteract the innate DNA-sensing pathways. IMPORTANCE: Although whether and how HBV infection induces the innate immune responses are still controversial, it has become increasingly clear that HBV has developed strategies to counteract the pattern recognition receptor-mediated signaling pathways. Previous studies have shown that type I IFN induction activated by the host RNA sensors could be inhibited by HBV. However, it remains unknown whether HBV as a DNA virus utilizes evasion mechanisms against foreign DNA-elicited antiviral signaling. In recent years, the cytosolic DNA sensor and key adaptor STING has been demonstrated to be essential in multiple foreign DNA-elicited innate immune signalings. Here, for the first time, we report STING as a new target of HBV to antagonize IFN induction and identify the viral polymerase responsible for the inhibitory effect, thus providing an additional molecular mechanism by which HBV evades the innate immunity; this implies that in addition to its inherent catalytic function, HBV polymerase is a multifunctional immunomodulatory protein. PMID- 25505065 TI - Herpes simplex virus 1 gN partners with gM to modulate the viral fusion machinery. AB - Herpes simplex virus 1 (HSV-1) capsids are assembled in the nucleus, where they incorporate the viral genome. They then transit through the two nuclear membranes and are wrapped by a host-derived envelope. In the process, several HSV-1 proteins are targeted to the nuclear membranes, but their roles in viral nuclear egress are unclear. Among them, glycoprotein M (gM), a known modulator of virus induced membrane fusion, is distributed on both the inner and outer nuclear membranes at the early stages of the infection, when no other viral glycoproteins are yet present there. Later on, it is found on perinuclear virions and ultimately redirected to the trans-Golgi network (TGN), where it cycles with the cell surface. In contrast, transfected gM is found only at the TGN and cell surface, hinting at an interaction with other viral proteins. Interestingly, many herpesvirus gM analogs interact with their gN counterparts, which typically alters their intracellular localization. To better understand how HSV-1 gM localization is regulated, we evaluated its ability to bind gN and discovered it does so in both transfected and infected cells, an interaction strongly weakened by the deletion of the gM amino terminus. Functionally, while gN had no impact on gM localization, gM redirected gN from the endoplasmic reticulum (ER) to the TGN. Most interestingly, gN overexpression stimulated the formation of syncytia in the context of an infection by a nonsyncytial strain, indicating that gM and gN not only physically but also functionally interact and that gN modulates gM's activity on membrane fusion. IMPORTANCE: HSV-1 gM is an important modulator of virally induced cell-cell fusion and viral entry, a process that is likely finely modulated in time and space. Until now, little was known of the proteins that regulate gM's activity. In parallel, gM is found in various intracellular locations at different moments, ranging from nuclear membranes, perinuclear virions, the TGN, cell surface, and mature extracellular virions. In transfected cells, however, it is found only on the TGN and cell surface, hinting that its localization is modulated by other viral proteins. The present study identifies HSV-1 gN as a binding partner for gM, in agreement with their analogs in other herpesviruses, but most excitingly shows that gN modulates gM's impact on HSV-1 induced membrane fusion. These findings open up new research avenues on the viral fusion machinery. PMID- 25505064 TI - Timing of galectin-1 exposure differentially modulates Nipah virus entry and syncytium formation in endothelial cells. AB - Nipah virus (NiV) is a deadly emerging enveloped paramyxovirus that primarily targets human endothelial cells. Endothelial cells express the innate immune effector galectin-1 that we have previously shown can bind to specific N-glycans on the NiV envelope fusion glycoprotein (F). NiV-F mediates fusion of infected endothelial cells into syncytia, resulting in endothelial disruption and hemorrhage. Galectin-1 is an endogenous carbohydrate-binding protein that binds to specific glycans on NiV-F to reduce endothelial cell fusion, an effect that may reduce pathophysiologic sequelae of NiV infection. However, galectins play multiple roles in regulating host-pathogen interactions; for example, galectins can promote attachment of HIV to T cells and macrophages and attachment of HSV-1 to keratinocytes but can also inhibit influenza entry into airway epithelial cells. Using live Nipah virus, in the present study, we demonstrate that galectin 1 can enhance NiV attachment to and infection of primary human endothelial cells by bridging glycans on the viral envelope to host cell glycoproteins. In order to exhibit an enhancing effect, galectin-1 must be present during the initial phase of virus attachment; in contrast, addition of galectin-1 postinfection results in reduced production of progeny virus and syncytium formation. Thus, galectin-1 can have dual and opposing effects on NiV infection of human endothelial cells. While various roles for galectin family members in microbial-host interactions have been described, we report opposing effects of the same galectin family member on a specific virus, with the timing of exposure during the viral life cycle determining the outcome. IMPORTANCE: Nipah virus is an emerging pathogen that targets endothelial cells lining blood vessels; the high mortality rate (up to 70%) in Nipah virus infections results from destruction of these cells and resulting catastrophic hemorrhage. Host factors that promote or prevent Nipah virus infection are not well understood. Endogenous human lectins, such as galectin-1, can function as pattern recognition receptors to reduce infection and initiate immune responses; however, lectins can also be exploited by microbes to enhance infection of host cells. We found that galectin-1, which is made by inflamed endothelial cells, can both promote Nipah virus infection of endothelial cells by "bridging" the virus to the cell, as well as reduce production of progeny virus and reduce endothelial cell fusion and damage, depending on timing of galectin-1 exposure. This is the first report of spatiotemporal opposing effects of a host lectin for a virus in one type of host cell. PMID- 25505066 TI - Lentiviral Nef proteins manipulate T cells in a subset-specific manner. AB - The role of the accessory viral Nef protein as a multifunctional manipulator of the host cell that is required for effective replication of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) in vivo is well established. It is unknown, however, whether Nef manipulates all or just specific subsets of CD4(+) T cells, which are the main targets of virus infection and differ substantially in their state of activation and importance for a functional immune system. Here, we analyzed the effect of Nef proteins differing in their T cell receptor (TCR)-CD3 downmodulation function in HIV-infected human lymphoid aggregate cultures and peripheral blood mononuclear cells. We found that Nef efficiently downmodulates TCR-CD3 in naive and memory CD4(+) T cells and protects the latter against apoptosis. In contrast, highly proliferative CD45RA(+) CD45RO(+) CD4(+) T cells were main producers of infectious virus but largely refractory to TCR-CD3 downmodulation. Such T cell subset-specific differences were also observed for Nef-mediated modulation of CD4 but not for enhancement of virion infectivity. Our results indicate that Nef predominantly modulates surface receptors on CD4(+) T cell subsets that are not already fully permissive for viral replication. As a consequence, Nef-mediated downmodulation of TCR-CD3, which distinguishes most primate lentiviruses from HIV type 1 (HIV-1) and its vpu-containing simian precursors, may promote a selective preservation of central memory CD4(+) T cells, which are critical for the maintenance of a functional immune system. IMPORTANCE: The Nef proteins of human and simian immunodeficiency viruses manipulate infected CD4(+) T cells in multiple ways to promote viral replication and immune evasion in vivo. Here, we show that some effects of Nef are subset specific. Downmodulation of CD4 and TCR-CD3 is highly effective in central memory CD4(+) T cells, and the latter Nef function protects this T cell subset against apoptosis. In contrast, highly activated/proliferating CD4(+) T cells are largely refractory to receptor downmodulation but are main producers of infectious HIV-1. Nef-mediated enhancement of virion infectivity, however, was observed in all T cell subsets examined. Our results provide new insights into how primate lentiviruses manipulate their target cells and suggest that the TCR-CD3 downmodulation function of Nef may promote a selective preservation of memory CD4(+) T cells, which are critical for immune function, but has little effect on activated/proliferating CD4(+) T cells, which are the main targets for viral replication. PMID- 25505067 TI - The nucleoprotein of newly emerged H7N9 influenza A virus harbors a unique motif conferring resistance to antiviral human MxA. AB - Interferon-induced Mx proteins show strong antiviral activity against influenza A viruses (IAVs). We recently demonstrated that the viral nucleoprotein (NP) determines resistance of seasonal and pandemic human influenza viruses to Mx, while avian isolates retain Mx sensitivity. We identified a surface-exposed cluster of amino acids in NP of pandemic A/BM/1/1918 (H1N1), comprising isoleucine-100, proline-283, and tyrosine-313, that is essential for reduced Mx sensitivity in cell culture and in vivo. This cluster has been maintained in all descendant seasonal strains, including A/PR/8/34 (PR/8). Accordingly, two substitutions in the NP of PR/8 [PR/8(mut)] to the Mx-sensitive amino acids (P283L and Y313F) led to attenuation in Mx1-positive mice. Serial lung passages of PR/8(mut) in Mx1 mice resulted in a single exchange of tyrosine to asparagine at position 52 in NP (in close proximity to the amino acid cluster at positions 100, 283, and 313), which partially compensates loss of Mx resistance in PR/8(mut). Intriguingly, the NP of the newly emerged avian-origin H7N9 virus also contains an asparagine at position 52 and shows reduced Mx sensitivity. N52Y substitution in NP results in increased sensitivity of the H7N9 virus to human Mx, indicating that this residue is a determinant of Mx resistance in mammals. Our data strengthen the hypothesis that the human Mx protein represents a potent barrier against zoonotic transmission of avian influenza viruses. However, the H7N9 viruses overcome this restriction by harboring an NP that is less sensitive to Mx-mediated host defense. This might contribute to zoonotic transmission of H7N9 and to the severe to fatal outcome of H7N9 infections in humans. IMPORTANCE: The natural host of influenza A viruses (IAVs) are aquatic birds. Occasionally, these viruses cross the species barrier, as in early 2013 when an avian H7N9 virus infected humans in China. Since then, multiple transmissions of H7N9 viruses to humans have occurred, leaving experts puzzled about molecular causes for such efficient crossing of the species barrier compared to other avian influenza viruses. Mx proteins are known restriction factors preventing influenza virus replication. Unfortunately, some viruses (e.g., human IAV) have developed some resistance, which is associated with specific amino acids in their nucleoproteins, the target of Mx function. Here, we demonstrate that the novel H7N9 bird IAV already carries a nucleoprotein that overcomes the inhibition of viral replication by human MxA. This is the first example of an avian IAV that is naturally less sensitive to Mx-mediated inhibition and might explain why H7N9 viruses transmitted efficiently to humans. PMID- 25505068 TI - Characterization of novel transcripts of human papillomavirus type 16 using cap analysis gene expression technology. AB - We have performed cap-analysis gene expression (CAGE) sequencing to identify the regulatory networks that orchestrate genome-wide transcription in human papillomavirus type 16 (HPV16)-positive cervical cell lines of different grades: W12E, SiHa, and CaSki. Additionally, a cervical intraepithelial neoplasia grade 1 (CIN1) lesion was assessed for identifying the transcriptome expression profile. Here we have precisely identified a novel antisense noncoding viral transcript in HPV16. In conclusion, CAGE sequencing should pave the way for understanding a diversity of viral transcript expression. PMID- 25505070 TI - Adaptation of pandemic H2N2 influenza A viruses in humans. AB - The 1957 A/H2N2 influenza virus caused an estimated 2 million fatalities during the pandemic. Since viruses of the H2 subtype continue to infect avian species and pigs, the threat of reintroduction into humans remains. To determine factors involved in the zoonotic origin of the 1957 pandemic, we performed analyses on genetic sequences of 175 newly sequenced human and avian H2N2 virus isolates and all publicly available influenza virus genomes. PMID- 25505069 TI - Kaposi's sarcoma-associated herpesvirus induces Nrf2 activation in latently infected endothelial cells through SQSTM1 phosphorylation and interaction with polyubiquitinated Keap1. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2), the cellular master regulator of the antioxidant response, dissociates from its inhibitor Keap1 when activated by stress signals and participates in the pathogenesis of viral infections and tumorigenesis. Early during de novo infection of endothelial cells, KSHV induces Nrf2 through an intricate mechanism involving reactive oxygen species (ROS) and prostaglandin E2 (PGE2). When we investigated the Nrf2 activity during latent KSHV infection, we observed increased nuclear serine-40-phosphorylated Nrf2 in human KS lesions compared to that in healthy tissues. Using KSHV long-term infected endothelial cells (LTC) as a cellular model for KS, we demonstrated that KSHV infection induces Nrf2 constitutively by extending its half-life, increasing its phosphorylation by protein kinase Czeta (PKCzeta) via the infection-induced cyclooxygenase-2 (COX-2)/PGE2 axis and inducing its nuclear localization. Nrf2 knockdown in LTC decreased expression of antioxidant genes and genes involved in KS pathogenesis such as the NAD(P)H quinone oxidase 1 (NQO1), gamma glutamylcysteine synthase heavy unit (gammaGCSH), the cysteine transporter (xCT), interleukin 6 (IL-6), and vascular endothelial growth factor A (VEGF-A) genes. Nrf2 activation was independent of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1; p62). SQSTM1 levels were elevated in LTC, a consequence of protein accumulation due to decreased autophagy and Nrf2 mediated transcriptional activation. SQSTM1 was phosphorylated on serine-351 and 403, while Keap1 was polyubiquitinated with lysine-63-ubiquitin chains, modifications known to increase their mutual affinity and interaction, leading to Keap1 degradation and Nrf2 activation. The latent KSHV protein Fas-associated death domain-like interleukin-1beta-converting enzyme-inhibitory protein (vFLIP) increased SQSTM1 expression and activated Nrf2. Collectively, these results demonstrate that KSHV induces SQSTM1 to constitutively activate Nrf2, which is involved in the regulation of genes participating in KSHV oncogenesis. IMPORTANCE: The transcription factor Nrf2 is activated by stress signals, including viral infection, and responds by activating the transcription of cytoprotective genes. Recently, Nrf2 has been implicated in oncogenesis and was shown to be activated during de novo KSHV infection of endothelial cells through ROS-dependent pathways. The present study was undertaken to determine the mechanism of Nrf2 activation during prolonged latent infection of endothelial cells, using an endothelial cell line latently infected with KSHV. We show that Nrf2 activation was elevated in KSHV latently infected endothelial cells independently of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1), which was involved in the degradation of the Nrf2 inhibitor Keap1. Furthermore, our results indicated that the KSHV latent protein vFLIP participates in Nrf2 activation. This study suggests that KSHV hijacks the host's autophagic protein SQSTM1 to induce Nrf2 activation, thereby manipulating the infected host gene regulation to promote KS pathogenesis. PMID- 25505071 TI - Phosphatidylserine-specific phospholipase A1 involved in hepatitis C virus assembly through NS2 complex formation. AB - Several members of the phospholipase family have been reported to be involved in hepatitis C virus (HCV) replication. Here, we identified another phospholipase, phosphatidylserine-specific phospholipase A1 (PLA1A), as a host factor involved in HCV assembly. PLA1A was upregulated by HCV infection, and PLA1A knockdown significantly reduced J399EM (genotype 2a) HCV propagation at the assembly step but not the entry, RNA replication, and protein translation steps of the life cycle. Protein localization and interaction analysis further revealed a role of PLA1A in the interaction of NS2-E2 and NS2-NS5A, as the formation of the NS2-E2 and NS2-NS5A complexes was weakened in the absence of PLA1A. In addition, PLA1A stabilized the NS2/NS5A dotted structure during infection. These data suggest that PLA1A plays an important role in bridging the membrane-associated NS2-E2 complex and the NS5A-associated replication complex via its interaction with E2, NS2, and NS5A, which leads to a coordinating interaction between the structural and nonstructural proteins and facilitates viral assembly. IMPORTANCE: Hepatitis C virus (HCV) genomic replication is driven by the replication complex and occurs at the membranous web, while the lipid droplet is the organelle in which virion assembly is initiated. In this study, we identified phosphatidylserine-specific phospholipase A1 (PLA1A), a member of phospholipase A 1 family, as a novel host factor involved in the assembly process of HCV. PLA1A, which is induced by HCV infection at a late infection stage, interacts with HCV E2, NS2, and NS5A proteins and enhances and stabilizes the NS2-E2 and NS2-NS5A complex formation, which is essential for viral assembly. Thus, PLA1A is an important host factor which is involved in the initiation of the viral assembly in close proximity to Core-decorated lipid droplets through bringing together the HCV replication complex and envelope complex. PMID- 25505073 TI - The progressive adaptation of a georgian isolate of African swine fever virus to vero cells leads to a gradual attenuation of virulence in swine corresponding to major modifications of the viral genome. AB - African swine fever virus (ASFV) causes a contagious and often lethal disease of feral and domestic swine. Experimental vaccines derived from naturally occurring, genetically modified, or cell culture-adapted ASFV have been evaluated, but no commercial vaccine is available to control African swine fever (ASF). We report here the genotypic and phenotypic analysis of viruses obtained at different passages during the process of adaptation of a virulent ASFV field isolate from the Republic of Georgia (ASFV-G) to grow in cultured cell lines. ASFV-G was successively passaged 110 times in Vero cells. Viruses obtained at passages 30, 60, 80, and 110 were evaluated in vitro for the ability to replicate in Vero cells and primary swine macrophages cultures and in vivo for assessing virulence in swine. Replication of ASFV-G in Vero cells increased with successive passages, corresponding to a decreased replication in primary swine macrophages cultures. In vivo, progressive loss of virus virulence was observed with increased passages in Vero cells, and complete attenuation of ASFV-G was observed at passage 110. Infection of swine with the fully attenuated virus did not confer protection against challenge with virulent parental ASFV-G. Full-length sequence analysis of each of these viruses revealed significant deletions that gradually accumulated in specific areas at the right and left variable ends of the genome. Mutations that result in amino acid substitutions and frameshift mutations were also observed, though in a rather limited number of genes. The potential importance of these genetic changes in virus adaptation/attenuation is discussed. IMPORTANCE: The main problem in controlling ASF is the lack of vaccines. Attempts to produce vaccines by adaptation of ASFV to cultured cell lines have been made. These attempts led to the production of attenuated viruses that conferred only homologous protection. Specifics regarding adaptation of these isolates to cell cultures have been insufficiently described. Details like the numbers of passages required to obtain attenuated viruses, genetic modifications introduced into the virus genomes along passages, and the extent of attenuation and induced protective efficacy are not readily available. In this study, we assessed the changes that lead to decreased growth in swine macrophages and to attenuation in swine. Loss of virulence, probably associated with limited replication in vivo, may lead to the lack of protective immunity in swine observed after challenge. This report provides valuable information that can be used to further the understanding of ASFV gene function, virus attenuation, and protection against infection. PMID- 25505072 TI - Mutations within the pathogenic region of herpes simplex virus 1 gK signal sequences alter cell surface expression and neurovirulence. AB - To investigate the role of the signal sequences of herpes simplex virus 1 (HSV-1) gK on virus replication and viral pathogenesis, we constructed recombinant viruses with or without mutations within the signal sequences of gK. These recombinant viruses expressed two additional copies of the mutated (MgK) or native (NgK) form of the gK gene in place of the latency-associated transcript with a myc epitope tag to facilitate detection at their 3' ends. The replication of MgK virus was similar to that of NgK both in vitro and in vivo, as well as in the trigeminal ganglia (TG) of latently infected mice. The levels of gB and gK transcripts in the corneas, TG, and brains of infected mice on days 3 and 5 postinfection were markedly virus and time dependent, as well as tissue specific. Mutation in the signal sequence of gK in MgK virus blocked cell surface expression of gK-myc in rabbit skin cells, increased 50% lethal dose, and decreased corneal scarring in ocularly infected mice compared to the NgK or revertant (RgK) virus. MgK and NgK viruses, and not the RgK virus, showed a reduced extent of explant reactivation at the lower dose of ocular infection but not at the higher dose. However, the time of reactivation was not affected by overexpression of the different forms of gK. Taken together, these results strongly suggest that the 8mer peptide (ITAYGLVL) within the signal sequence of gK promotes cell surface expression of gK in infected cells and ocular pathogenesis in infected mice. IMPORTANCE: In this study, we show for the first time that mutations within the signal sequence of gK blocked cell surface expression of inserted recombinant gK in vitro. Furthermore, this blockage in cell surface expression was correlated with higher 50% lethal dose and less corneal scarring in vivo. Thus, these studies point to a key role for the 8mer within the signal sequence of gK in HSV-1-induced pathogenicity. PMID- 25505074 TI - MCL1 enhances the survival of CD8+ memory T Cells after viral infection. AB - Viral infection results in the generation of massive numbers of activated effector CD8(+) T cells that recognize viral components. Most of these are short lived effector T cells (SLECs) that die after clearance of the virus. However, a small proportion of this population survives and forms antigen-specific memory precursor effector cells (MPECs), which ultimately develop into memory cells. These can participate in a recall response upon reexposure to antigen even at protracted times postinfection. Here, antiapoptotic myeloid cell leukemia 1 (MCL1) was found to prolong survival upon T cell stimulation, and mice expressing human MCL1 as a transgene exhibited a skewing in the proportion of CD8(+) T cells, away from SLECs toward MPECs, during the acute phase of vaccinia virus infection. A higher frequency and total number of antigen-specific CD8(+) T cells were observed in MCL1 transgenic mice. These findings show that MCL1 can shape the makeup of the CD8(+) T cell response, promoting the formation of long-term memory. IMPORTANCE: During an immune response to a virus, CD8(+) T cells kill cells infected by the virus, and most die when the infection resolves. However, a small proportion of cells survives and differentiates into long-lived memory cells that confer protection from reinfection by the same virus. This report shows that transgenic expression of an MCL1 protein enhances survival of memory CD8(+) T cells following infection with vaccinia virus. This is important because it shows that MCL1 expression may be an important determinant of the formation of long-term CD8(+) T cell memory. PMID- 25505075 TI - Genetic analysis of the localization of APOBEC3F to human immunodeficiency virus type 1 virion cores. AB - Members of the APOBEC3 family of cytidine deaminases vary in their proportions of a virion-incorporated enzyme that is localized to mature retrovirus cores. We reported previously that APOBEC3F (A3F) was highly localized into mature human immunodeficiency virus type 1 (HIV-1) cores and identified that L306 in the C terminal cytidine deaminase (CD) domain contributed to its core localization (C. Song, L. Sutton, M. Johnson, R. D'Aquila, J. Donahue, J Biol Chem 287:16965 16974, 2012, http://dx.doi.org/10.1074/jbc.M111.310839). We have now determined an additional genetic determinant(s) for A3F localization to HIV-1 cores. We found that one pair of leucines in each of A3F's C-terminal and N-terminal CD domains jointly determined the degree of localization of A3F into HIV-1 virion cores. These are A3F L306/L368 (C-terminal domain) and A3F L122/L184 (N-terminal domain). Alterations to one of these specific leucine residues in either of the two A3F CD domains (A3F L368A, L122A, and L184A) decreased core localization and diminished HIV restriction without changing virion packaging. Furthermore, double mutants in these leucine residues in each of A3F's two CD domains (A3F L368A plus L184A or A3F L368A plus L122A) still were packaged into virions but completely lost core localization and anti-HIV activity. HIV virion core localization of A3F is genetically separable from its virion packaging, and anti-HIV activity requires some core localization. IMPORTANCE: Specific leucine-leucine interactions are identified as necessary for A3F's core localization and anti-HIV activity but not for its packaging into virions. Understanding these signals may lead to novel strategies to enhance core localization that may augment effects of A3F against HIV and perhaps of other A3s against retroviruses, parvoviruses, and hepatitis B virus. PMID- 25505077 TI - Analysis of the early immune response to infection by infectious bursal disease virus in chickens differing in their resistance to the disease. AB - Chicken whole-genome gene expression arrays were used to analyze the host response to infection by infectious bursal disease virus (IBDV). Spleen and bursal tissue were examined from control and infected birds at 2, 3, and 4 days postinfection from two lines that differ in their resistance to IBDV infection. The host response was evaluated over this period, and differences between susceptible and resistant chicken lines were examined. Antiviral genes, including IFNA, IFNG, MX1, IFITM1, IFITM3, and IFITM5, were upregulated in response to infection. Evaluation of this gene expression data allowed us to predict several genes as candidates for involvement in resistance to IBDV. IMPORTANCE: Infectious bursal disease (IBD) is of economic importance to the poultry industry and thus is also important for food security. Vaccines are available, but field strains of the virus are of increasing virulence. There is thus an urgent need to explore new control solutions, one of which would be to breed birds with greater resistance to IBD. This goal is perhaps uniquely achievable with poultry, of all farm animal species, since the genetics of 85% of the 60 billion chickens produced worldwide each year is under the control of essentially two breeding companies. In a comprehensive study, we attempt here to identify global transcriptomic differences in the target organ of the virus between chicken lines that differ in resistance and to predict candidate resistance genes. PMID- 25505076 TI - Prion infection of mouse brain reveals multiple new upregulated genes involved in neuroinflammation or signal transduction. AB - Gliosis is often a preclinical pathological finding in neurodegenerative diseases, including prion diseases, but the mechanisms facilitating gliosis and neuronal damage in these diseases are not understood. To expand our knowledge of the neuroinflammatory response in prion diseases, we assessed the expression of key genes and proteins involved in the inflammatory response and signal transduction in mouse brain at various times after scrapie infection. In brains of scrapie-infected mice at pre- and postclinical stages, we identified 15 previously unreported differentially expressed genes related to inflammation or activation of the STAT signal transduction pathway. Levels for the majority of differentially expressed genes increased with time postinfection. In quantitative immunoblotting experiments of STAT proteins, STAT1alpha, phosphorylated STAT1alpha (pSTAT1alpha), and pSTAT3 were increased between 94 and 131 days postinfection (p.i.) in brains of mice infected with strain 22L. Furthermore, a select group of STAT-associated genes was increased preclinically during scrapie infection, suggesting early activation of the STAT signal transduction pathway. Comparison of inflammatory markers between mice infected with scrapie strains 22L and RML indicated that the inflammatory responses and gene expression profiles in the brains were strikingly similar, even though these scrapie strains infect different brain regions. The endogenous interleukin-1 receptor antagonist (IL 1Ra), an inflammatory marker, was newly identified as increasing preclinically in our model and therefore might influence scrapie pathogenesis in vivo. However, in IL-1Ra-deficient or overexpressor transgenic mice inoculated with scrapie, neither loss nor overexpression of IL-1Ra demonstrated any observable effect on gliosis, protease-resistant prion protein (PrPres) formation, disease tempo, pathology, or expression of the inflammatory genes analyzed. IMPORTANCE: Prion infection leads to PrPres deposition, gliosis, and neuroinflammation in the central nervous system before signs of clinical illness. Using a scrapie mouse model of prion disease to assess various time points postinoculation, we identified 15 unreported genes that were increased in the brains of scrapie infected mice and were associated with inflammation and/or JAK-STAT activation. Comparison of mice infected with two scrapie strains (22L and RML), which have dissimilar neuropathologies, indicated that the inflammatory responses and gene expression profiles in the brains were similar. Genes that increased prior to clinical signs might be involved in controlling scrapie infection or in facilitating damage to host tissues. We tested the possible role of the endogenous IL-1Ra, which was increased at 70 days p.i. In scrapie-infected mice deficient in or overexpressing IL-1Ra, there was no observable effect on gliosis, PrPres formation, disease tempo, pathology, or expression of inflammatory genes analyzed. PMID- 25505079 TI - Expanding the role of the virome: commensalism in the gut. AB - Viruses affect host physiology beyond causing acute disease, thereby giving rise to the concept that the virome is a component of the microbiome. However, the role of the enteric virome is understudied relative to the fast-paced research examining commensal bacteria in the intestine. In this article, I discuss our recent work on murine norovirus indicating that an animal virus in the intestine can provide many of the signals to the host that have been attributed to commensal bacteria. Our findings suggest that the surge in microbiome research should incorporate examination of the enteric virome. PMID- 25505078 TI - Dengue virus induces and requires glycolysis for optimal replication. AB - Viruses rely on host cellular metabolism to provide the energy and biosynthetic building blocks required for their replication. Dengue virus (DENV), a member of the Flaviviridae family, is one of the most important arthropod-borne human pathogens worldwide. We analyzed global intracellular metabolic changes associated with DENV infection of primary human cells. Our metabolic profiling data suggested that central carbon metabolism, particularly glycolysis, is strikingly altered during a time course of DENV infection. Glucose consumption is increased during DENV infection and depriving DENV-infected cells of exogenous glucose had a pronounced impact on viral replication. Furthermore, the expression of both glucose transporter 1 and hexokinase 2, the first enzyme of glycolysis, is upregulated in DENV-infected cells. Pharmacologically inhibiting the glycolytic pathway dramatically reduced DENV RNA synthesis and infectious virion production, revealing a requirement for glycolysis during DENV infection. Thus, these experiments suggest that DENV induces the glycolytic pathway to support efficient viral replication. This study raises the possibility that metabolic inhibitors, such as those that target glycolysis, could be used to treat DENV infection in the future. IMPORTANCE: Approximately 400 million people are infected with dengue virus (DENV) annually, and more than one-third of the global population is at risk of infection. As there are currently no effective vaccines or specific antiviral therapies for DENV, we investigated the impact DENV has on the host cellular metabolome to identify metabolic pathways that are critical for the virus life cycle. We report an essential role for glycolysis during DENV infection. DENV activates the glycolytic pathway, and inhibition of glycolysis significantly blocks infectious DENV production. This study provides further evidence that viral metabolomic analyses can lead to the discovery of novel therapeutic targets to block the replication of medically important human pathogens. PMID- 25505080 TI - Epstein-Barr virus type 2 latently infects T cells, inducing an atypical activation characterized by expression of lymphotactic cytokines. AB - Epstein-Barr virus (EBV) is a well-established B-cell-tropic virus associated with various lymphoproliferative diseases of both B-cell and non-B-cell origin. EBV is associated with a number of T-cell lymphomas; however, in vitro studies utilizing prototypical EBV type 1 (EBV-1) laboratory strains have generally failed to readily infect mature T cells in culture. The difficulties in performing in vitro T-cell experiments have left questions regarding the role of EBV in the pathogenesis of EBV-positive T-cell lymphoproliferative diseases largely unresolved. We report here that the EBV type 2 (EBV-2) strain displays a unique cell tropism for T cells. In remarkable contrast to EBV-1, EBV-2 readily infects primary T cells in vitro, demonstrating a propensity for CD8(+) T cells. EBV-2 infection of purified T cells results in expression of latency genes and ultimately leads to T-cell activation, substantial proliferation, and profound alteration of cytokine expression. The pattern of cytokine production is strikingly skewed toward chemokines with roles in lymphocyte migration, demonstrating that EBV-2 has the ability to modulate normal T-cell processes. Collectively, these novel findings identify a previously unknown cell population potentially utilized by EBV-2 to establish latency and lay the foundation for further studies to elucidate the role of EBV in the pathogenesis of T-cell lymphoproliferative diseases. IMPORTANCE: The ability of EBV to infect T cells is made apparent by its association with a variety of T-cell lymphoproliferative disorders. However, studies to elucidate the pathogenic role of EBV in these diseases have been limited by the inability to conduct in vitro T-cell infection experiments. Here, we report that EBV-2 isolates, compromised in the capacity to immortalize B cells, infect CD3(+) T cells ex vivo and propose a working model of EBV-2 persistence where alteration of T-cell functions resulting from EBV-2 infection enhances the establishment of latency in B cells. If indeed EBV-2 utilizes T cells to establish a persistent infection, this could provide one mechanism for the association of EBV with T-cell lymphomas. The novel finding that EBV-2 infects T cells in culture will provide a model to understand the role EBV plays in the development of T-cell lymphomas. PMID- 25505081 TI - Structural analysis of a rabbit hemorrhagic disease virus binding to histo-blood group antigens. AB - Rabbit hemorrhagic disease virus (RHDV) is a member of the Caliciviridae family (Lagovirus genus). RHDV is highly contagious and attaches to epithelial cells in the digestive or respiratory tract, leading to massive lesions with high mortality rates. A new variant of RHDV (termed RHDVb) recently has emerged, and previously vaccinated rabbits appear to have little protection against this new strain. Similar to human norovirus (Caliciviridae, Norovirus genus), RHDV binds histo-blood group antigens (HBGAs), and this is thought to be important for infection. Here, we report the HBGA binding site on the RHDVb capsid-protruding domain (P domain) using X-ray crystallography. The HBGA binding pocket was located in a negatively charged patch on the side of the P domain and at a dimeric interface. Residues from both monomers contributed to the HBGA binding and involved a network of direct hydrogen bonds and water-mediated interactions. An amino acid sequence alignment of different RHDV strains indicated that the residues directly interacting with the ABH-fucose of the HBGAs (Asp472, Asn474, and Ser479) were highly conserved. This result suggested that different RHDV strains also could bind HBGAs at the equivalent pocket. Moreover, several HBGA binding characteristics between RHDVb and human genogroup II norovirus were similar, which indicated a possible convergent evolution of HBGA binding interactions. Further structural studies with other RHDV strains are needed in order to better understand the HBGA binding mechanisms among the diverse RHDV strains. IMPORTANCE: We identified, for the first time, the HBGA binding site on an RHDVb P domain using X-ray crystallography. Our results showed that RHDVb and human genogroup II noroviruses had similar HBGA binding interactions. Recently, it was discovered that synthetic HBGAs or HBGA-expressing enteric bacteria could enhance human genogroup II norovirus infection in B cells. Considering that RHDVb and genogroup II norovirus similarly interacted with HBGAs, it may be possible that a comparable cell culture system also could work with RHDVb. Taken together, these new findings will extend our understanding of calicivirus HBGA interactions and may help to elucidate the specific roles of HBGAs in calicivirus infections. PMID- 25505083 TI - Caring for tomorrow's workforce: Moral resilience and healthcare ethics education. AB - BACKGROUND: Preparing tomorrow's healthcare workforce for managing the growing complexity of care places high demands on students, educators, and faculties. In the light of worrying data about study-related stress and burnout, understanding how students manage stressors and develop resilience has been identified as a priority topic of research. In addition to study-related stressors, also moral stressors are known to characterize the students' first clinical experiences. OBJECTIVES: However, current debates show that it remains unclear how healthcare ethics education should address them. In order to clarify this issue, this study first develops the notion of moral resilience as a response to moral stressors involving both situations of moral complexity and moral wrongness. Second, it explores the potential of healthcare ethics education in fostering moral resilience. For this purpose, it defines moral resilience operationally as a reduction of moral distress in a given axis of time measured by a validated tool. RESEARCH DESIGN, PARTICIPANTS, AND CONTEXT: The educational transferability was assessed within an explorative, quantitative pre-post interventional study with a purposive sample of 166 nursing students. The educational intervention comprised a lecture introducing the typology of moral stressors. Before and after the lecture, students were presented vignettes depicting morally stressful situations. ETHICAL CONSIDERATIONS: The competent research ethics committee confirmed that no ethical approval was needed. Informed consent was obtained from participants. FINDINGS: Three of four vignettes showed a modest but statistically significant reduction in measured levels of distress after the lecture (p < 0.05, alpha = 5%). DISCUSSION: The study shows the potential of healthcare ethics education in providing students with transformative knowledge that fosters moral resilience. CONCLUSION: In times of global scarcity of educational resources, healthcare ethics education has an important contribution to offer in the promotion of students' mental and physical health by strengthening the knowledge base of moral resilience. This legitimates its costs for societies, faculties, and professional bodies. PMID- 25505082 TI - Functional characterization of nuclear trafficking signals in pseudorabies virus pUL31. AB - The herpesviral nuclear egress complex (NEC), consisting of pUL31 and pUL34 homologs, mediates efficient translocation of newly synthesized capsids from the nucleus to the cytosol. The tail-anchored membrane protein pUL34 is autonomously targeted to the nuclear envelope, while pUL31 is recruited to the inner nuclear membrane (INM) by interaction with pUL34. A nuclear localization signal (NLS) in several pUL31 homologs suggests importin-mediated translocation of the protein. Here we demonstrate that deletion or mutation of the NLS in pseudorabies virus (PrV) pUL31 resulted in exclusively cytosolic localization, indicating active nuclear export. Deletion or mutation of a predicted nuclear export signal (NES) in mutant constructs lacking a functional NLS resulted in diffuse nuclear and cytosolic localization, indicating that both signals are functional. pUL31 molecules lacking the complete NLS or NES were not recruited to the INM by pUL34, while site-specifically mutated proteins formed the NEC and partially complemented the defect of the UL31 deletion mutant. Our data demonstrate that the N terminus of pUL31, encompassing the NLS, is required for efficient nuclear targeting but not for pUL34 interaction, while the C terminus, containing the NES but not necessarily the NES itself, is required for complex formation and efficient budding of viral capsids at the INM. Moreover, pUL31-DeltaNLS displayed a dominant negative effect on wild-type PrV replication, probably by diverting pUL34 to cytoplasmic membranes. IMPORTANCE: The molecular details of nuclear egress of herpesvirus capsids are still enigmatic. Although the key players, homologs of herpes simplex virus pUL34 and pUL31, which interact and form the heterodimeric nuclear egress complex, are well known, the molecular basis of this interaction and the successive budding, vesicle formation, and scission from the INM, as well as capsid release into the cytoplasm, remain largely obscure. Here we show that classical cellular targeting signals for nuclear import and export are important for proper localization and function of the NEC, thus regulating herpesvirus nuclear egress. PMID- 25505084 TI - Effectiveness of narrative pedagogy in developing student nurses' advocacy role. AB - BACKGROUND: The literature and research on nursing ethics and advocacy has shown that generally very few nurses and other clinicians will speak up about an issue they have witnessed regarding a patient advocacy concern and that often advocacy in nursing is not learned until after students have graduated and begun working. OBJECTIVE: To evaluate the effectiveness of narrative pedagogy on the development of advocacy in student nurses, as measured by the Protective Nursing Advocacy Scale. DESIGN: We tested the hypothesis that use of a narrative pedagogy assignment related to ethics would improve student nurse's perception of their advocacy role as measured by the Protective Nursing Advocacy Scale using a quasi experimental nonrandomized study using a pre-test, intervention, post-test design. Data collection occurred during class time from October 2012 to December 2012. The Protective Nursing Advocacy Scale tool was administered to students in class to assess their baseline and was administered again at the completion of the educational intervention to assess whether narrative pedagogy was effective in developing the nursing student's perception of their role as a patient advocate. ETHICAL CONSIDERATIONS: Students were informed that their participation was voluntary and that the data collected would be anonymous and confidential. The survey was not a graded assignment, and students did not receive any incentive to participate. The institutional review board of the college determined the study to be exempt from review. SETTING: School of Nursing at a small liberal arts college in the Northeastern United States. PARTICIPANTS: A consecutive, nonprobability sample of 44 senior-level nursing students enrolled in their final nursing semester was utilized. FINDINGS: Results indicated significant differences in student nurse's perception of their advocacy role related to environment and educational influences following an education intervention using an ethics digital story. CONCLUSION: Using the Protective Nursing Advocacy Scale, we were able to measure the effectiveness of narrative pedagogy on nursing student's perception of the nurse's advocacy role. PMID- 25505085 TI - Identifying cancer-related microRNAs based on gene expression data. AB - MOTIVATION: MicroRNAs (miRNAs) are short non-coding RNAs that play important roles in post-transcriptional regulations as well as other important biological processes. Recently, accumulating evidences indicate that miRNAs are extensively involved in cancer. However, it is a big challenge to identify which miRNAs are related to which cancer considering the complex processes involved in tumors, where one miRNA may target hundreds or even thousands of genes and one gene may regulate multiple miRNAs. Despite integrative analysis of matched gene and miRNA expression data can help identify cancer-associated miRNAs, such kind of data is not commonly available. On the other hand, there are huge amount of gene expression data that are publicly accessible. It will significantly improve the efficiency of characterizing miRNA's function in cancer if we can identify cancer miRNAs directly from gene expression data. RESULTS: We present a novel computational framework to identify the cancer-related miRNAs based solely on gene expression profiles without requiring either miRNA expression data or the matched gene and miRNA expression data. The results on multiple cancer datasets show that our proposed method can effectively identify cancer-related miRNAs with higher precision compared with other popular approaches. Furthermore, some of our novel predictions are validated by both differentially expressed miRNAs and evidences from literature, implying the predictive power of our proposed method. In addition, we construct a cancer-miRNA-pathway network, which can help explain how miRNAs are involved in cancer. AVAILABILITY AND IMPLEMENTATION: The R code and data files for the proposed method are available at http://comp sysbio.org/miR_Path/ CONTACT: liukeq@gmail.com SUPPLEMENTARY INFORMATION: supplementary data are available at Bioinformatics online. PMID- 25505087 TI - Sputnik: ad hoc distributed computation. AB - MOTIVATION: In bioinformatic applications, computationally demanding algorithms are often parallelized to speed up computation. Nevertheless, setting up computational environments for distributed computation is often tedious. Aim of this project were the lightweight ad hoc set up and fault-tolerant computation requiring only a Java runtime, no administrator rights, while utilizing all CPU cores most effectively. RESULTS: The Sputnik framework provides ad hoc distributed computation on the Java Virtual Machine which uses all supplied CPU cores fully. It provides a graphical user interface for deployment setup and a web user interface displaying the current status of current computation jobs. Neither a permanent setup nor administrator privileges are required. We demonstrate the utility of our approach on feature selection of microarray data. AVAILABILITY AND IMPLEMENTATION: The Sputnik framework is available on Github http://github.com/sysbio-bioinf/sputnik under the Eclipse Public License. CONTACT: hkestler@fli-leibniz.de or hans.kestler@uni-ulm.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25505086 TI - Phy-Mer: a novel alignment-free and reference-independent mitochondrial haplogroup classifier. AB - MOTIVATION: All current mitochondrial haplogroup classification tools require variants to be detected from an alignment with the reference sequence and to be properly named according to the canonical nomenclature standards for describing mitochondrial variants, before they can be compared with the haplogroup determining polymorphisms. With the emergence of high-throughput sequencing technologies and hence greater availability of mitochondrial genome sequences, there is a strong need for an automated haplogroup classification tool that is alignment-free and agnostic to reference sequence. RESULTS: We have developed a novel mitochondrial genome haplogroup-defining algorithm using a k-mer approach namely Phy-Mer. Phy-Mer performs equally well as the leading haplogroup classifier, HaploGrep, while avoiding the errors that may occur when preparing variants to required formats and notations. We have further expanded Phy-Mer functionality such that next-generation sequencing data can be used directly as input. AVAILABILITY AND IMPLEMENTATION: Phy-Mer is publicly available under the GNU Affero General Public License v3.0 on GitHub (https://github.com/danielnavarrogomez/phy-mer). CONTACT: Xiaowu_Gai@meei.harvard.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25505088 TI - HYCUD: a computational tool for prediction of effective rotational correlation time in flexible proteins. AB - MOTIVATION: A large fraction of eukaryotic proteins contain unstructured tails or linkers. The presence of flexible regions allows these systems to experience a high level of mobility facilitating their biological function. The complex nature of protein rotation in such flexible modular systems precludes a straightforward application of hydrodynamic methods to calculate their rotational motional properties. We describe the workflow of HYdrodynamic CoUpling of Domains (HYCUD), a program for prediction of effective rotational correlation times in multidomain proteins. The usage of HYCUD is demonstrated by its application to the ribosomal protein L7/L12. Rotational correlation times predicted by HYCUD might be used to detect molecular switch events mediated by disorder-order transitions in interdomain linkers. AVAILABILITY AND IMPLEMENTATION: The source code and documentation are available at www.mpibpc.mpg.de/106144/software. CONTACT: mzwecks@gwdg.de or nare@nmr.mpibpc.mpg.de SUPPLEMENTARY INFORMATION: Supplementary material is available at Bioinformatics online. PMID- 25505089 TI - Response to the comment on 'protein-protein binding affinity prediction from amino acid sequence'. PMID- 25505090 TI - 3Dmol.js: molecular visualization with WebGL. AB - 3Dmol.js is a modern, object-oriented JavaScript library that uses the latest web technologies to provide interactive, hardware-accelerated three-dimensional representations of molecular data without the need to install browser plugins or Java. 3Dmol.js provides a full featured API for developers as well as a straightforward declarative interface that lets users easily share and embed molecular data in websites. AVAILABILITY AND IMPLEMENTATION: 3Dmol.js is distributed under the permissive BSD open source license. Source code and documentation can be found at http://3Dmol.csb.pitt.edu CONTACT: dkoes@pitt.edu. PMID- 25505092 TI - NMRFAM-SPARKY: enhanced software for biomolecular NMR spectroscopy. AB - SPARKY (Goddard and Kneller, SPARKY 3) remains the most popular software program for NMR data analysis, despite the fact that development of the package by its originators ceased in 2001. We have taken over the development of this package and describe NMRFAM-SPARKY, which implements new functions reflecting advances in the biomolecular NMR field. NMRFAM-SPARKY has been repackaged with current versions of Python and Tcl/Tk, which support new tools for NMR peak simulation and graphical assignment determination. These tools, along with chemical shift predictions from the PACSY database, greatly accelerate protein side chain assignments. NMRFAM-SPARKY supports automated data format interconversion for interfacing with a variety of web servers including, PECAN , PINE, TALOS-N, CS Rosetta, SHIFTX2 and PONDEROSA-C/S. AVAILABILITY AND IMPLEMENTATION: The software package, along with binary and source codes, if desired, can be downloaded freely from http://pine.nmrfam.wisc.edu/download_packages.html. Instruction manuals and video tutorials can be found at http://www.nmrfam.wisc.edu/nmrfam-sparky distribution.htm. CONTACT: whlee@nmrfam.wisc.edu or markley@nmrfam.wisc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25505091 TI - JEPEG: a summary statistics based tool for gene-level joint testing of functional variants. AB - MOTIVATION: Gene expression is influenced by variants commonly known as expression quantitative trait loci (eQTL). On the basis of this fact, researchers proposed to use eQTL/functional information univariately for prioritizing single nucleotide polymorphisms (SNPs) signals from genome-wide association studies (GWAS). However, most genes are influenced by multiple eQTLs which, thus, jointly affect any downstream phenotype. Therefore, when compared with the univariate prioritization approach, a joint modeling of eQTL action on phenotypes has the potential to substantially increase signal detection power. Nonetheless, a joint eQTL analysis is impeded by (i) not measuring all eQTLs in a gene and/or (ii) lack of access to individual genotypes. RESULTS: We propose joint effect on phenotype of eQTL/functional SNPs associated with a gene (JEPEG), a novel software tool which uses only GWAS summary statistics to (i) impute the summary statistics at unmeasured eQTLs and (ii) test for the joint effect of all measured and imputed eQTLs in a gene. We illustrate the behavior/performance of the developed tool by analysing the GWAS meta-analysis summary statistics from the Psychiatric Genomics Consortium Stage 1 and the Genetic Consortium for Anorexia Nervosa. CONCLUSIONS: Applied analyses results suggest that JEPEG complements commonly used univariate GWAS tools by: (i) increasing signal detection power via uncovering (a) novel genes or (b) known associated genes in smaller cohorts and (ii) assisting in fine-mapping of challenging regions, e.g. major histocompatibility complex for schizophrenia. AVAILABILITY AND IMPLEMENTATION: JEPEG, its associated database of eQTL SNPs and usage examples are publicly available at http://code.google.com/p/jepeg/. CONTACT: dlee4@vcu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25505093 TI - diXa: a data infrastructure for chemical safety assessment. AB - MOTIVATION: The field of toxicogenomics (the application of '-omics' technologies to risk assessment of compound toxicities) has expanded in the last decade, partly driven by new legislation, aimed at reducing animal testing in chemical risk assessment but mainly as a result of a paradigm change in toxicology towards the use and integration of genome wide data. Many research groups worldwide have generated large amounts of such toxicogenomics data. However, there is no centralized repository for archiving and making these data and associated tools for their analysis easily available. RESULTS: The Data Infrastructure for Chemical Safety Assessment (diXa) is a robust and sustainable infrastructure storing toxicogenomics data. A central data warehouse is connected to a portal with links to chemical information and molecular and phenotype data. diXa is publicly available through a user-friendly web interface. New data can be readily deposited into diXa using guidelines and templates available online. Analysis descriptions and tools for interrogating the data are available via the diXa portal. AVAILABILITY AND IMPLEMENTATION: http://www.dixa-fp7.eu CONTACT: d.hendrickx@maastrichtuniversity.nl; info@dixa-fp7.eu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25505094 TI - Detection of circular permutations within protein structures using CE-CP. AB - MOTIVATION: Circular permutation is an important type of protein rearrangement. Natural circular permutations have implications for protein function, stability and evolution. Artificial circular permutations have also been used for protein studies. However, such relationships are difficult to detect for many sequence and structure comparison algorithms and require special consideration. RESULTS: We developed a new algorithm, called Combinatorial Extension for Circular Permutations (CE-CP), which allows the structural comparison of circularly permuted proteins. CE-CP was designed to be user friendly and is integrated into the RCSB Protein Data Bank. It was tested on two collections of circularly permuted proteins. Pairwise alignments can be visualized both in a desktop application or on the web using Jmol and exported to other programs in a variety of formats. AVAILABILITY AND IMPLEMENTATION: The CE-CP algorithm can be accessed through the RCSB website at http://www.rcsb.org/pdb/workbench/workbench.do. Source code is available under the LGPL 2.1 as part of BioJava 3 (http://biojava.org; http://github.com/biojava/biojava). CONTACT: sbliven@ucsd.edu or info@rcsb.org. PMID- 25505095 TI - Epock: rapid analysis of protein pocket dynamics. AB - SUMMARY: The volume of an internal protein pocket is fundamental to ligand accessibility. Few programs that compute such volumes manage dynamic data from molecular dynamics (MD) simulations. Limited performance often prohibits analysis of large datasets. We present Epock, an efficient command-line tool that calculates pocket volumes from MD trajectories. A plugin for the VMD program provides a graphical user interface to facilitate input creation, run Epock and analyse the results. AVAILABILITY AND IMPLEMENTATION: Epock C++ source code, Python analysis scripts, VMD Tcl plugin, documentation and installation instructions are freely available at http://epock.bitbucket.org. CONTACT: benoist.laurent@gmail.com or baaden@smplinux.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25505097 TI - Nursing students' perceptions of patient dignity. AB - BACKGROUND: Respecting patients' dignity has been described as a fundamental part of nursing care. Many studies have focused on exploring the concept of patients' dignity from the patient and nurse perspective, but knowledge is limited regarding students' nursing perceptions and experiences. OBJECTIVE: To explore the issue of patients' dignity from the perspective of nursing students. RESEARCH DESIGN: A qualitative study was employed with the formation of four focus groups and the participation of nursing students. Data were analysed via a thematic content analysis of the discussions. PARTICIPANTS AND RESEARCH CONTEXT: Thirty four nursing students of a Cyprus University participated in the four focus groups. Each group was homogenous in terms of the year of study and heterogeneous in terms of clinical practice in various wards. ETHICAL CONSIDERATION: The study's protocol was reviewed and approved by the Cyprus National Bioethics Committee. Ethical standards were followed throughout the study. FINDINGS: Several factors that maintain or compromise patients' dignity emerged. These factors were grouped into five themes: (a) patients' preferences, verbal abuse and regarding a patient as a unique person; (b) privacy and confidentiality; (c) loss of autonomy and need for help; (d) discrimination and (e) attribution and reciprocity. DISCUSSION: Different understandings of the perceived concept of dignity and the factors that maintain or compromise patient's dignity were expressed through the eyes and the feelings of nursing students. Students highlighted the importance of promoting patient dignity as an important component of nursing care. CONCLUSION: Nurse educators can use the findings of this study in order to tailor nursing programmes to emphasise the importance of respecting patients' dignity. In addition, nurse ward managers can use the findings as means for persuading nurses to change current behaviour. PMID- 25505098 TI - Moral distress: a review of the argument-based nursing ethics literature. AB - AIM: The aim of this review is to examine the ways in which the concept of moral distress has been delineated and deployed in the argument-based nursing ethics literature. It adds to what we already know about moral distress from reviews of the qualitative and quantitative research. DATA SOURCES: CINAHL, PubMed, Web of Knowledge, EMBASE, Academic Search Complete, PsycInfo, Philosophers' Index and Socindex. REVIEW METHODS: A total of 20 argument-based articles published between January 1984 and December 2013 were analysed. RESULTS: We found that like the empirical literature, most authors in this review draw on Jameton's original definition and describe moral distress in psychological-emotional-physiological terms. They also agree that moral distress is linked to the presence of some kind of constraint on nurses' moral agency, and that it is best understood as a two staged process that can intensify over time. There is also consensus that moral distress has an important normative meaning, although different views concerning the normative meaning of moral distress are expressed. Finally, the authors generally agree that moral distress arises from a number of different sources and that it (mostly) affects negatively on nurses' personal and professional lives and, ultimately, harms patients. However, despite this consensus, many authors take issue with the way in which moral distress is conceptualized and operationalized. Moreover, while some worry that identifying nurses as a group of health professionals whose voices are ignored or marginalized might disempower nurses and encourage them to avoid their moral responsibilities, others take situations involving moral distress as indicative of more fundamental, structural inequities at the heart of contemporary healthcare provision. CONCLUSION: We conclude that research on moral distress in nursing is timely and important because it highlights the specifically moral labour of nurses. However, we suggest that significant concerns about the conceptual fuzziness and operationalization of moral distress also flag the need to proceed with caution. PMID- 25505099 TI - Flushing out smoking: measuring population tobacco use via wastewater analysis. PMID- 25505102 TI - Putative mechanisms mediating tolerance for audiovisual stimulus onset asynchrony. AB - Audiovisual (AV) speech perception is robust to temporal asynchronies between visual and auditory stimuli. We investigated the neural mechanisms that facilitate tolerance for audiovisual stimulus onset asynchrony (AVOA) with EEG. Individuals were presented with AV words that were asynchronous in onsets of voice and mouth movement and judged whether they were synchronous or not. Behaviorally, individuals tolerated (perceived as synchronous) longer AVOAs when mouth movement preceded the speech (V-A) stimuli than when the speech preceded mouth movement (A-V). Neurophysiologically, the P1-N1-P2 auditory evoked potentials (AEPs), time-locked to sound onsets and known to arise in and surrounding the primary auditory cortex (PAC), were smaller for the in-sync than the out-of-sync percepts. Spectral power of oscillatory activity in the beta band (14-30 Hz) following the AEPs was larger during the in-sync than out-of-sync perception for both A-V and V-A conditions. However, alpha power (8-14 Hz), also following AEPs, was larger for the in-sync than out-of-sync percepts only in the V-A condition. These results demonstrate that AVOA tolerance is enhanced by inhibiting low-level auditory activity (e.g., AEPs representing generators in and surrounding PAC) that code for acoustic onsets. By reducing sensitivity to acoustic onsets, visual-to-auditory onset mapping is weakened, allowing for greater AVOA tolerance. In contrast, beta and alpha results suggest the involvement of higher-level neural processes that may code for language cues (phonetic, lexical), selective attention, and binding of AV percepts, allowing for wider neural windows of temporal integration, i.e., greater AVOA tolerance. PMID- 25505105 TI - Visuomotor adaptation to a visual rotation is gravity dependent. AB - Humans perform vertical and horizontal arm motions with different temporal patterns. The specific velocity profiles are chosen by the central nervous system by integrating the gravitational force field to minimize energy expenditure. However, what happens when a visuomotor rotation is applied, so that a motion performed in the horizontal plane is perceived as vertical? We investigated the dynamic of the adaptation of the spatial and temporal properties of a pointing motion during prolonged exposure to a 90 degrees visuomotor rotation, where a horizontal movement was associated with a vertical visual feedback. We found that participants immediately adapted the spatial parameters of motion to the conflicting visual scene in order to keep their arm trajectory straight. In contrast, the initial symmetric velocity profiles specific for a horizontal motion were progressively modified during the conflict exposure, becoming more asymmetric and similar to those appropriate for a vertical motion. Importantly, this visual effect that increased with repetitions was not followed by a consistent aftereffect when the conflicting visual feedback was absent (catch and washout trials). In a control experiment we demonstrated that an intrinsic representation of the temporal structure of perceived vertical motions could provide the error signal allowing for this progressive adaptation of motion timing. These findings suggest that gravity strongly constrains motor learning and the reweighting process between visual and proprioceptive sensory inputs, leading to the selection of a motor plan that is suboptimal in terms of energy expenditure. PMID- 25505104 TI - Informative features of local field potential signals in primary visual cortex during natural image stimulation. AB - The local field potential (LFP) is of growing importance in neurophysiology as a metric of network activity and as a readout signal for use in brain-machine interfaces. However, there are uncertainties regarding the kind and visual field extent of information carried by LFP signals, as well as the specific features of the LFP signal conveying such information, especially under naturalistic conditions. To address these questions, we recorded LFP responses to natural images in V1 of awake and anesthetized macaques using Utah multielectrode arrays. First, we have shown that it is possible to identify presented natural images from the LFP responses they evoke using trained Gabor wavelet (GW) models. Because GW models were devised to explain the spiking responses of V1 cells, this finding suggests that local spiking activity and LFPs (thought to reflect primarily local synaptic activity) carry similar visual information. Second, models trained on scalar metrics, such as the evoked LFP response range, provide robust image identification, supporting the informative nature of even simple LFP features. Third, image identification is robust only for the first 300 ms following image presentation, and image information is not restricted to any of the spectral bands. This suggests that the short-latency broadband LFP response carries most information during natural scene viewing. Finally, best image identification was achieved by GW models incorporating information at the scale of ~ 0.5 degrees in size and trained using four different orientations. This suggests that during natural image viewing, LFPs carry stimulus-specific information at spatial scales corresponding to few orientation columns in macaque V1. PMID- 25505103 TI - Lasting modulation of in vitro oscillatory activity with weak direct current stimulation. AB - Transcranial direct current stimulation (tDCS) is emerging as a versatile tool to affect brain function. While the acute neurophysiological effects of stimulation are well understood, little is know about the long-term effects. One hypothesis is that stimulation modulates ongoing neural activity, which then translates into lasting effects via physiological plasticity. Here we used carbachol-induced gamma oscillations in hippocampal rat slices to establish whether prolonged constant current stimulation has a lasting effect on endogenous neural activity. During 10 min of stimulation, the power and frequency of gamma oscillations, as well as multiunit activity, were modulated in a polarity specific manner. Remarkably, the effects on power and multiunit activity persisted for more than 10 min after stimulation terminated. Using a computational model we propose that altered synaptic efficacy in excitatory and inhibitory pathways could be the source of these lasting effects. Future experimental studies using this novel in vitro preparation may be able to confirm or refute the proposed hypothesis. PMID- 25505106 TI - Cholinergic systems are essential for late-stage maturation and refinement of motor cortical circuits. AB - Previous studies reported that early postnatal cholinergic lesions severely perturb early cortical development, impairing neuronal cortical migration and the formation of cortical dendrites and synapses. These severe effects of early postnatal cholinergic lesions preclude our ability to understand the contribution of cholinergic systems to the later-stage maturation of topographic cortical representations. To study cholinergic mechanisms contributing to the later maturation of motor cortical circuits, we first characterized the temporal course of cortical motor map development and maturation in rats. In this study, we focused our attention on the maturation of cortical motor representations after postnatal day 25 (PND 25), a time after neuronal migration has been accomplished and cortical volume has reached adult size. We found significant maturation of cortical motor representations after this time, including both an expansion of forelimb representations in motor cortex and a shift from proximal to distal forelimb representations to an extent unexplainable by simple volume enlargement of the neocortex. Specific cholinergic lesions placed at PND 24 impaired enlargement of distal forelimb representations in particular and markedly reduced the ability to learn skilled motor tasks as adults. These results identify a novel and essential role for cholinergic systems in the late refinement and maturation of cortical circuits. Dysfunctions in this system may constitute a mechanism of late-onset neurodevelopmental disorders such as Rett syndrome and schizophrenia. PMID- 25505107 TI - Neural correlates of target selection for reaching movements in superior colliculus. AB - We recently demonstrated that inactivation of the primate superior colliculus (SC) causes a deficit in target selection for arm-reaching movements when the reach target is located in the inactivated field (Song JH, Rafal RD, McPeek RM. Proc Natl Acad Sci USA 108: E1433-E1440, 2011). This is consistent with the notion that the SC is part of a general-purpose target selection network beyond eye movements. To understand better the role of SC activity in reach target selection, we examined how individual SC neurons in the intermediate layers discriminate a reach target from distractors. Monkeys reached to touch a color oddball target among distractors while maintaining fixation. We found that many SC neurons robustly discriminate the goal of the reaching movement before the onset of the reach even though no saccade is made. To identify these cells in the context of conventional SC cell classification schemes, we also recorded visual, delay-period, and saccade-related responses in a delayed saccade task. On average, SC cells that discriminated the reach target from distractors showed significantly higher visual and delay-period activity than nondiscriminating cells, but there was no significant difference in saccade-related activity. Whereas a majority of SC neurons that discriminated the reach target showed significant delay-period activity, all nondiscriminating cells lacked such activity. We also found that some cells without delay-period activity did discriminate the reach target from distractors. We conclude that the majority of intermediate-layer SC cells discriminate a reach target from distractors, consistent with the idea that the SC contains a priority map used for effector independent target selection. PMID- 25505108 TI - Parallax-sensitive remapping of visual space in occipito-parietal alpha-band activity during whole-body motion. AB - Despite the constantly changing retinal image due to eye, head, and body movements, we are able to maintain a stable representation of the visual environment. Various studies on retinal image shifts caused by saccades have suggested that occipital and parietal areas correct for these perturbations by a gaze-centered remapping of the neural image. However, such a uniform, rotational, remapping mechanism cannot work during translations when objects shift on the retina in a more complex, depth-dependent fashion due to motion parallax. Here we tested whether the brain's activity patterns show parallax-sensitive remapping of remembered visual space during whole-body motion. Under continuous recording of electroencephalography (EEG), we passively translated human subjects while they had to remember the location of a world-fixed visual target, briefly presented in front of or behind the eyes' fixation point prior to the motion. Using a psychometric approach we assessed the quality of the memory update, which had to be made based on vestibular feedback and other extraretinal motion cues. All subjects showed a variable amount of parallax-sensitive updating errors, i.e., the direction of the errors depended on the depth of the target relative to fixation. The EEG recordings show a neural correlate of this parallax-sensitive remapping in the alpha-band power at occipito-parietal electrodes. At parietal electrodes, the strength of these alpha-band modulations correlated significantly with updating performance. These results suggest that alpha-band oscillatory activity reflects the time-varying updating of gaze-centered spatial information during parallax-sensitive remapping during whole-body motion. PMID- 25505109 TI - Serotonin receptor and KCC2 gene expression in lumbar flexor and extensor motoneurons posttransection with and without passive cycling. AB - Sacrocaudal motoneuron gene expression is altered following a spinal transection. Of interest here is the regulation of serotonin (5-HT) receptors (R), glutamate receptor, metabotropic 1 (mGluR1), and potassium-chloride cotransporter (KCC2), which mediate motoneuron excitability, locomotor recovery, and spasticity posttransection. The examination of these genes in lumbar motoneurons posttransection has not been studied, which is necessary for developing potential pharmacological interventions aimed at restoring locomotion and/or reducing spasticity. Also, if activity is to be used to promote recovery or reduce spasticity postinjury, a further examination of neuromuscular activity on gene expression posttransection is warranted. The purpose of this study was to examine motoneuronal gene expression of 5-HT receptors, KCC2, and mGluR1 at 3 mo following a complete thoracic spinal cord transection, with and without the inclusion of daily passive cycling. Physiological hindlimb extensor and flexor motoneurons were differentially identified with two retrograde fluorescent tracers, allowing for the identification and separate harvesting of extensor and flexor motoneurons with laser capture microdissection and the subsequent examination of mRNA content using quantitative RT-PCR analysis. We demonstrate that posttransection 5-HT1AR, 5-HT2CR, and mGluR1 expression was downregulated, whereas the 5-HT2AR was upregulated. These alterations in gene expression were observed in both flexor and extensor motoneurons, whereas passive cycling influenced gene expression in extensor but not flexor motoneurons. Passive cycling in extensor motoneurons further enhanced 5-HT2AR expression and increased 5-HT7R and KCC2 expression. Our results demonstrate that passive cycling influences serotonin receptor and KCC2 gene expression and that extensor motoneurons compared with flexor motoneurons may be more plastic to activity based interventions posttransection. PMID- 25505111 TI - High-voltage-activated calcium current subtypes in mouse DRG neurons adapt in a subpopulation-specific manner after nerve injury. AB - Changes in ion channel function and expression are characteristic of neuropathic pain. Voltage-gated calcium channels (VGCCs) are integral for neurotransmission and membrane excitability, but relatively little is known about changes in their expression after nerve injury. In this study, we investigate whether peripheral nerve ligation is followed by changes in the density and proportion of high voltage-activated (HVA) VGCC current subtypes in dorsal root ganglion (DRG) neurons, the contribution of presynaptic N-type calcium channels in evoked excitatory postsynaptic currents (EPSCs) recorded from dorsal horn neurons in the spinal cord, and the changes in expression of mRNA encoding VGCC subunits in DRG neurons. Using C57BL/6 mice [8- to 11-wk-old males (n = 91)] for partial sciatic nerve ligation or sham surgery, we performed whole cell patch-clamp recordings on isolated DRG neurons and dorsal horn neurons and measured the expression of all VGCC subunits with RT-PCR in DRG neurons. After nerve injury, the density of P/Q type current was reduced overall in DRG neurons. There was an increase in the percentage of N-type and a decrease in that of P/Q-type current in medium- to large-diameter neurons. No changes were found in the contribution of presynaptic N-type calcium channels in evoked EPSCs recorded from dorsal horn neurons. The alpha2delta-1 subunit was upregulated by 1.7-fold and gamma-3, gamma-2, and beta 4 subunits were all downregulated 1.7-fold in injured neurons compared with sham operated neurons. This comprehensive characterization of HVA VGCC subtypes in mouse DRG neurons after nerve injury revealed changes in N- and P/Q-type current proportions only in medium- to large-diameter neurons. PMID- 25505112 TI - Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses. AB - Lysophosphatidic acid (LPA) is one of the well-characterized, ubiquitous phospholipid molecules. LPA exerts its effect by activating G protein-coupled receptors known as LPA receptors (LPARs). So far, LPAR signaling has been critically implicated during early development stages, including the regulation of synapse formation and the morphology of cortical and hippocampal neurons. In adult brains, LPARs seem to participate in cognitive as well as emotional learning and memory. Recent studies using LPAR1-deficient mice reported impaired performances in a number of behavioral tasks, including the hippocampus-dependent spatial memory and fear conditioning tests. Nevertheless, the effect of LPAR activation in the synaptic transmission of central synapses after the completion of embryonic development has not been investigated. In this study, we took advantage of a novel extracellular agonist for LPARs called gintonin to activate LPARs in adult brain systems. Gintonin, a recently identified active ingredient in ginseng, has been shown to activate LPARs and mobilize Ca(2+) in an artificial cell system. We found that the activation of LPARs by application of gintonin acutely enhanced both excitatory and inhibitory transmission in central synapses, albeit through tentatively distinct mechanisms. Gintonin-mediated LPAR activation primarily resulted in synaptic enhancement and an increase in neuronal excitability in a phospholipase C-dependent manner. Our findings suggest that LPARs are able to directly potentiate synaptic transmission in central synapses when stimulated exogenously. Therefore, LPARs could serve as a useful target to modulate synaptic activity under pathological conditions, including neurodegenerative diseases. PMID- 25505110 TI - Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury. AB - Hyperreflexia and spasticity are chronic complications in spinal cord injury (SCI), with limited options for safe and effective treatment. A central mechanism in spasticity is hyperexcitability of the spinal stretch reflex, which presents symptomatically as a velocity-dependent increase in tonic stretch reflexes and exaggerated tendon jerks. In this study we tested the hypothesis that dendritic spine remodeling within motor reflex pathways in the spinal cord contributes to H reflex dysfunction indicative of spasticity after contusion SCI. Six weeks after SCI in adult Sprague-Dawley rats, we observed changes in dendritic spine morphology on alpha-motor neurons below the level of injury, including increased density, altered spine shape, and redistribution along dendritic branches. These abnormal spine morphologies accompanied the loss of H-reflex rate-dependent depression (RDD) and increased ratio of H-reflex to M-wave responses (H/M ratio). Above the level of injury, spine density decreased compared with below-injury spine profiles and spine distributions were similar to those for uninjured controls. As expected, there was no H-reflex hyperexcitability above the level of injury in forelimb H-reflex testing. Treatment with NSC23766, a Rac1-specific inhibitor, decreased the presence of abnormal dendritic spine profiles below the level of injury, restored RDD of the H-reflex, and decreased H/M ratios in SCI animals. These findings provide evidence for a novel mechanistic relationship between abnormal dendritic spine remodeling in the spinal cord motor system and reflex dysfunction in SCI. PMID- 25505114 TI - Inference of perceptual priors from path dynamics of passive self-motion. AB - The monitoring of one's own spatial orientation depends on the ability to estimate successive self-motion cues accurately. This process has become to be known as path integration. A feature of sequential cue estimation, in general, is that the history of previously experienced stimuli, or priors, biases perception. Here, we investigate how during angular path integration, the prior imparted by the displacement path dynamics affects the translation of vestibular sensations into perceptual estimates. Subjects received successive whole-body yaw rotations and were instructed to report their position within a virtual scene after each rotation. The overall movement trajectory either followed a parabolic path or was devoid of explicit dynamics. In the latter case, estimates were biased toward the average stimulus prior and were well captured by an optimal Bayesian estimator model fit to the data. However, the use of parabolic paths reduced perceptual uncertainty, and a decrease of the average size of bias and thus the weight of the average stimulus prior were observed over time. The produced estimates were, in fact, better accounted for by a model where a prediction of rotation magnitude is inferred from the underlying path dynamics on each trial. Therefore, when passively displaced, we seem to be able to build, over time, from sequential vestibular measurements an internal model of the vehicle's movement dynamics. Our findings suggest that in ecological conditions, vestibular afference can be internally predicted, even when self-motion is not actively generated by the observer, thereby augmenting both the accuracy and precision of displacement perception. PMID- 25505113 TI - Inhibition of anandamide hydrolysis attenuates nociceptor sensitization in a murine model of chemotherapy-induced peripheral neuropathy. AB - Painful neuropathy frequently develops as a consequence of commonly used chemotherapy agents for cancer treatment and is often a dose-limiting side effect. Currently available analgesic treatments are often ineffective on pain induced by neurotoxicity. Although peripheral administration of cannabinoids, endocannabinoids, and inhibitors of endocannabinoid hydrolysis has been effective in reducing hyperalgesia in models of peripheral neuropathy, including chemotherapy-induced peripheral neuropathy (CIPN), few studies have examined cannabinoid effects on responses of nociceptors in vivo. In this study we determined whether inhibition of fatty acid amide hydrolase (FAAH), which slows the breakdown of the endocannabinoid anandamide (AEA), reduced sensitization of nociceptors produced by chemotherapy. Over the course of a week of daily treatments, mice treated with the platinum-based chemotherapy agent cisplatin developed robust mechanical allodynia that coincided with sensitization of cutaneous C-fiber nociceptors as indicated by the development of spontaneous activity and increased responses to mechanical stimulation. Administration of the FAAH inhibitor URB597 into the receptive field of sensitized C-fiber nociceptors decreased spontaneous activity, increased mechanical response thresholds, and decreased evoked responses to mechanical stimuli. Cotreatment with CB1 (AM281) or CB2 (AM630) receptor antagonists showed that the effect of URB597 was mediated primarily by CB1 receptors. These changes following URB597 were associated with an increase in the endocannabinoid anandamide in the skin. Our results suggest that enhanced signaling in the peripheral endocannabinoid system could be utilized to reduce nociceptor sensitization and pain associated with CIPN. PMID- 25505115 TI - Feature attention for binocular disparity in primate area MT depends on tuning strength. AB - Attending to a stimulus modulates the responses of sensory neurons that represent features of that stimulus, a phenomenon named "feature attention." For example, attending to a stimulus containing upward motion enhances the responses of upward preferring direction-selective neurons in the middle temporal area (MT) and suppresses the responses of downward-preferring neurons, even when the attended stimulus is outside of the spatial receptive fields of the recorded neurons (Treue S, Martinez-Trujillo JC. Nature 399: 575-579, 1999). This modulation renders the representation of sensory information across a neuronal population more selective for the features present in the attended stimulus (Martinez Trujillo JC, Treue S. Curr Biol 14: 744-751, 2004). We hypothesized that if feature attention modulates neurons according to their tuning preferences, it should also be sensitive to their tuning strength, which is the magnitude of the difference in responses to preferred and null stimuli. We measured how the effects of feature attention on MT neurons in rhesus monkeys (Macaca mulatta) depended on the relationship between features-in our case, direction of motion and binocular disparity-of the attended stimulus and a neuron's tuning for those features. We found that, as for direction, attention to stimuli containing binocular disparity cues modulated the responses of MT neurons and that the magnitude of the modulation depended on both a neuron's tuning preferences and its tuning strength. Our results suggest that modulation by feature attention may depend not just on which features a neuron represents but also on how well the neuron represents those features. PMID- 25505117 TI - Both ongoing alpha and visually induced gamma oscillations show reliable diversity in their across-site phase-relations. AB - Neural oscillations have emerged as one of the major electrophysiological phenomena investigated in cognitive and systems neuroscience. These oscillations are typically studied with regard to their amplitude, phase, and/or phase coupling. Here we demonstrate the existence of another property that is intrinsic to neural oscillations but has hitherto remained largely unexplored in cognitive and systems neuroscience. This pertains to the notion that these oscillations show reliable diversity in their phase-relations between neighboring recording sites (phase-relation diversity). In contrast to most previous work, we demonstrate that this diversity is restricted neither to low-frequency oscillations nor to periods outside of sensory stimulation. On the basis of magnetoencephalographic (MEG) recordings in humans, we show that this diversity is prominent not only for ongoing alpha oscillations (8-12 Hz) but also for gamma oscillations (50-70 Hz) that are induced by sustained visual stimulation. We further show that this diversity provides a dimension within electrophysiological data that, provided a sufficiently high signal-to-noise ratio, does not covary with changes in amplitude. These observations place phase-relation diversity on the map as a prominent and general property of neural oscillations that, moreover, can be studied with noninvasive methods in healthy human volunteers. This opens important new avenues for investigating how neural oscillations contribute to the neural implementation of cognition and behavior. PMID- 25505116 TI - Painful cutaneous laser stimuli induce event-related gamma-band activity in the lateral thalamus of humans. AB - Although the thalamus is an important module in "pain networks," there are few studies of the effect of experimental pain upon thalamic oscillations. We have now examined the hypothesis that, during a series of painful cutaneous laser stimuli, thalamic signals will show stimulus-related gamma-band spectral activity, which is modulated by attention to vs. distraction from the painful stimulus. When the series of laser stimuli was presented, attention was focused by counting the laser stimuli (count laser task), while distraction was produced by counting backward (count back plus laser task). We have studied the effect of a cutaneous laser on thalamic local field potentials and EEG activity during awake procedures (deep brain stimulation implants) for the treatment of essential tremor. At different delays after the stimulus, three low gamma- (30-50 Hz) and two high gamma-band (70-90 Hz) activations were observed during the two tasks. Greater high-gamma activation was found during the count laser task for the earlier window, while greater high-gamma activation was found during the count back plus laser task for the later window. Thalamic signals were coherent with EEG signals in the beta band, which indicated significant synchrony. Thalamic cross-frequency coupling analysis indicated that the phase of the lower frequency activity (theta to beta) modulated the amplitude of the higher frequency activity (low and high gamma) more strongly during the count laser task than during the count back plus laser task. This modulation might result in multiplexed signals each encoding a different aspect of pain. PMID- 25505119 TI - Selective activation of parvalbumin- or somatostatin-expressing interneurons triggers epileptic seizurelike activity in mouse medial entorhinal cortex. AB - GABAergic interneurons are thought to play a critical role in eliciting interictal spikes (IICs) and triggering ictal discharges in temporal lobe epilepsy, yet the contribution of different interneuronal subtypes to seizure initiation is still largely unknown. Here we took advantage of optogenetic techniques combined with patch-clamp and field recordings to selectively stimulate parvalbumin (PV)- or somatostatin (SOM)-positive interneurons expressing channelrhodopsin-2 (CHR-2) in layers II-III of adult mouse medial entorhinal cortical slices during extracellular perfusion with the proconvulsive compound 4-aminopyridine (4-AP, 100-200 MUM). In control conditions, blue laser photostimulation selectively activated action potential firing in either PV or SOM interneurons and, in both cases, caused a robust GABAA-receptor-mediated inhibition in pyramidal cells (PCs). During perfusion with 4-AP, brief photostimuli (300 ms) activating either PV or SOM interneurons induced patterns of epileptiform activity that closely replicated spontaneously occurring IICs and tonic-clonic ictal discharges. Laser-induced synchronous firing in both interneuronal types elicited large compound GABAergic inhibitory postsynaptic currents (IPSCs) correlating with IICs and preictal spikes. In addition, spontaneous and laser-induced epileptic events were similarly initiated in concurrence with a large increase in extracellular potassium concentration. Finally, interneuron activation was unable to stop or significantly shorten the progression of seizurelike episodes. These results suggest that entorhinal PV and SOM interneurons are nearly equally effective in triggering interictal and ictal discharges that closely resemble human temporal lobe epileptic activity. PMID- 25505118 TI - Modulation of artificial whisking related signals in barrel cortex. AB - Rats use rhythmic whisker movements, called active whisking, to sense the environment, which include whisker protractions followed by retractions at various frequencies. Using a proxy of active whisking in anesthetized rats, called artificial whisking, which is induced by electrically stimulating the facial motor nerve, we characterized the neural responses evoked in the barrel cortex by whisking in air (without contact) and on a surface (with contact). Neural responses were compared between distinct network states consisting of cortical deactivation (synchronized slow oscillations) and activation (desynchronized state) produced by neuromodulation (cholinergic or noradrenergic stimulation in neocortex or thalamus). Here we show that population responses in the barrel cortex consist of a robust signal driven by the onset of the whisker protraction followed by a whisking retraction signal that emerges during low frequency whisking on a surface. The whisking movement onset signal is suppressed by increasing whisking frequency, is controlled by cortical synaptic inhibition, is suppressed during cortical activation states, is little affected by whisking on a surface, and is ubiquitous in ventroposterior medial (VPM) thalamus, barrel cortex, and superior colliculus. The whisking retraction signal codes the duration of the preceding whisker protraction, is present in thalamocortical networks but not in superior colliculus, and is robust during cortical activation; a state associated with natural exploratory whisking. The expression of different whisking signals in forebrain and midbrain may define the sensory processing abilities of those sensorimotor circuits. Whisking related signals in the barrel cortex are controlled by network states that are set by neuromodulators. PMID- 25505121 TI - Vagueness and costs of the pause on gain-of-function (GOF) experiments on pathogens with pandemic potential, including influenza virus. PMID- 25505120 TI - Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates. AB - Nigrostriatal dopamine denervation plays a major role in basal ganglia circuitry disarray and motor abnormalities of Parkinson's disease (PD). Studies in rodent and primate models have revealed that striatal projection neurons, namely, medium spiny neurons (MSNs), increase the firing frequency. However, their activity pattern changes and the effects of dopaminergic stimulation in such conditions are unknown. Using single-cell recordings in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated primates with advanced parkinsonism, we studied MSN activity patterns in the transition to different motor states following levodopa administration. In the "off" state (baseline parkinsonian disability), a burst-firing pattern accompanied by prolonged silences (pauses) was found in 34% of MSNs, and 80% of these exhibited a levodopa response compatible with dopamine D1 receptor activation (direct pathway MSNs). This pattern was highly responsive to levodopa given that bursting/pausing almost disappeared in the "on" state (reversal of parkinsonism after levodopa injection), although this led to higher firing rates. Nonbursty MSNs fired irregularly with marked pausing that increased in the on state in the MSN subset with a levodopa response compatible with dopamine D2 receptor activation (indirect pathway MSNs), although the pause increase was not sustained in some units during the appearance of dyskinesias. Data indicate that the MSN firing pattern in the advanced parkinsonian monkey is altered by bursting and pausing changes and that dopamine differentially and inefficiently regulates these behaviorally correlated patterns in MSN subpopulations. These findings may contribute to understand the impact of striatal dysfunction in the basal ganglia network and its role in motor symptoms of PD. PMID- 25505122 TI - Moratorium on research intended to create novel potential pandemic pathogens. PMID- 25505123 TI - Falling down the rabbit hole: aTRIP toward lexiconic precision in the "gain-of function" debate. PMID- 25505126 TI - mBio addresses the pause in gain-of-function (GOF) experiments involving pathogens with pandemic potential (PPP). PMID- 25505124 TI - Influenza gain-of-function experiments: their role in vaccine virus recommendation and pandemic preparedness. AB - In recent years, controversy has arisen regarding the risks and benefits of certain types of gain-of-function (GOF) studies involving avian influenza viruses. In this article, we provide specific examples of how different types of data, including information garnered from GOF studies, have helped to shape the influenza vaccine production process-from selection of candidate vaccine viruses (CVVs) to the manufacture and stockpiling of safe, high-yield prepandemic vaccines for the global community. The article is not written to support a specific pro- or anti-GOF stance but rather to inform the scientific community about factors involved in vaccine virus selection and the preparation of prepandemic influenza vaccines and the impact that some GOF information has had on this process. PMID- 25505125 TI - Use of highly pathogenic avian influenza A(H5N1) gain-of-function studies for molecular-based surveillance and pandemic preparedness. PMID- 25505127 TI - A proteomic analysis reveals that Snail regulates the expression of the nuclear orphan receptor Nuclear Receptor Subfamily 2 Group F Member 6 (Nr2f6) and interleukin 17 (IL-17) to inhibit adipocyte differentiation. AB - Adipogenesis requires a differentiation program driven by multiple transcription factors, where PPARgamma and C/EBPalpha play a central role. Recent findings indicate that Snail inhibits adipocyte differentiation in 3T3-L1 and murine mesenchymal stem cells (mMSC). An in-depth quantitative SILAC analysis of the nuclear fraction of Snail-induced alterations of 3T3-L1 cells was carried out. In total, 2251 overlapping proteins were simultaneously quantified in forward and reverse experiments. We observed 574 proteins deregulated by Snail1 using a fold change >=1.5, with 111 up- and 463 down-regulated proteins, respectively. Among other proteins, multiple transcription factors such as Trip4, OsmR, Nr2f6, Cbx6, and Prrx1 were down-regulated. Results were validated in 3T3-L1 cells and mMSC cells by Western blot and quantitative PCR. Knock-down experiments in 3T3-L1 cells demonstrated that only Nr2f6 (and Trip4 at minor extent) was required for adipocyte differentiation. Ectopic expression of Nr2f6 reversed the effects of Snail1 and promoted adipogenesis. Because Nr2f6 inhibits the expression of IL-17, we tested the effect of Snail on IL-17 expression. IL-17 and TNFalpha were among the most up-regulated pro-inflammatory cytokines in Snail-transfected 3T3-L1 and mMSC cells. Furthermore, the blocking of IL-17 activity in Snail-transfected cells promoted adipocyte differentiation, reverting Snail inhibition. In summary, Snail inhibits adipogenesis through a down-regulation of Nr2f6, which in turn facilitates the expression of IL-17, an anti-adipogenic cytokine. These results would support a novel and important role for Snail and Nr2f6 in obesity control. PMID- 25505128 TI - Retinal toxicity, in vivo and in vitro, associated with inhibition of nicotinamide phosphoribosyltransferase. AB - Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein with intra- and extra-cellular functions as an enzyme, cytokine, growth factor, and hormone. NAMPT is of interest for oncology, because it catalyzes the rate limiting step in the salvage pathway to generate nicotinamide adenine dinucleotide (NAD), which is considered a universal energy- and signal-carrying molecule involved in cellular energy metabolism and many homeostatic functions. This manuscript describes NAMPT inhibitor-induced retinal toxicity that was identified in rodent safety studies. This toxicity had a rapid onset and progression and initially targeted the photoreceptor and outer nuclear layers. Using in vivo safety and efficacy rodent studies, human and mouse cell line potency data, human and rat retinal pigmented epithelial cell in vitro systems, and rat mRNA expression data of NAMPT, nicotinic acid phosphoribosyltransferase, and nicotinamide mononucleotide adenylyltransferease (NMNAT) in several tissues from rat including retina, we demonstrate that the retinal toxicity is on-target and likely human relevant. We demonstrate that this toxicity is not mitigated by coadministration of nicotinic acid (NA), which can enable NAD production through the NAMPT-independent pathway. Further, modifying the physiochemical properties of NAMPT inhibitors could not sufficiently reduce retinal exposure. Our work highlights opportunities to leverage appropriately designed efficacy studies to identify known and measurable safety findings to screen compounds more rapidly and reduce animal use. It also demonstrates that in vitro systems with the appropriate cell composition and relevant biology and toxicity endpoints can provide tools to investigate mechanism of toxicity and the human translation of nonclinical safety concerns. PMID- 25505129 TI - Carboxylated short single-walled carbon nanotubes but not plain and multi-walled short carbon nanotubes show in vitro genotoxicity. AB - Long carbon nanotubes (CNTs) resemble asbestos fibers due to their high length to diameter ratio and they thus have genotoxic effects. Another parameter that might explain their genotoxic effects is contamination with heavy metal ions. On the other hand, short (1-2 um) CNTs do not resemble asbestos fibers, and, once purified from contaminations, they might be suitable for medical applications. To identify the role of fiber thickness and surface properties on genotoxicity, well characterized short pristine and carboxylated single-walled (SCNTs) and multi walled (MCNTs) CNTs of different diameters were studied for cytotoxicity, the cell's response to oxidative stress (immunoreactivity against hemoxygenase 1 and glutathione levels), and in a hypoxanthine guanine phosphoribosyltransferase (HPRT) assay using V79 chinese hamster fibroblasts and human lung adenocarcinoma A549 cells. DNA repair was demonstrated by measuring immunoreactivity against activated histone H2AX protein. The number of micronuclei as well as the number of multinucleated cells was determined. CNTs acted more cytotoxic in V79 than in A549 cells. Plain and carboxylated thin (<8 nm) SCNTs and MCNTs showed greater cytotoxic potential and carboxylated CNTs showed indication for generating oxidative stress. Multi-walled CNTs did not cause HPRT mutation, micronucleus formation, DNA damage, interference with cell division, and oxidative stress. Carboxylated, but not plain, SCNTs showed indication for in vitro DNA damage according to increase of H2AX-immunoreactive cells and HPRT mutation. Although short CNTs presented a low in vitro genotoxicity, functionalization of short SCNTs can render these particles genotoxic. PMID- 25505131 TI - Constructing predictive models of human running. AB - Running is an essential mode of human locomotion, during which ballistic aerial phases alternate with phases when a single foot contacts the ground. The spring loaded inverted pendulum (SLIP) provides a starting point for modelling running, and generates ground reaction forces that resemble those of the centre of mass (CoM) of a human runner. Here, we show that while SLIP reproduces within-step kinematics of the CoM in three dimensions, it fails to reproduce stability and predict future motions. We construct SLIP control models using data-driven Floquet analysis, and show how these models may be used to obtain predictive models of human running with six additional states comprising the position and velocity of the swing-leg ankle. Our methods are general, and may be applied to any rhythmic physical system. We provide an approach for identifying an event driven linear controller that approximates an observed stabilization strategy, and for producing a reduced-state model which closely recovers the observed dynamics. PMID- 25505130 TI - Collective sensing and collective responses in quorum-sensing bacteria. AB - Bacteria often face fluctuating environments, and in response many species have evolved complex decision-making mechanisms to match their behaviour to the prevailing conditions. Some environmental cues provide direct and reliable information (such as nutrient concentrations) and can be responded to individually. Other environmental parameters are harder to infer and require a collective mechanism of sensing. In addition, some environmental challenges are best faced by a group of cells rather than an individual. In this review, we discuss how bacteria sense and overcome environmental challenges as a group using collective mechanisms of sensing, known as 'quorum sensing' (QS). QS is characterized by the release and detection of small molecules, potentially allowing individuals to infer environmental parameters such as density and mass transfer. While a great deal of the molecular mechanisms of QS have been described, there is still controversy over its functional role. We discuss what QS senses and how, what it controls and why, and how social dilemmas shape its evolution. Finally, there is a growing focus on the use of QS inhibitors as antibacterial chemotherapy. We discuss the claim that such a strategy could overcome the evolution of resistance. By linking existing theoretical approaches to data, we hope this review will spur greater collaboration between experimental and theoretical researchers. PMID- 25505132 TI - Patterns of functional vision loss in glaucoma determined with archetypal analysis. AB - Glaucoma is an optic neuropathy accompanied by vision loss which can be mapped by visual field (VF) testing revealing characteristic patterns related to the retinal nerve fibre layer anatomy. While detailed knowledge about these patterns is important to understand the anatomic and genetic aspects of glaucoma, current classification schemes are typically predominantly derived qualitatively. Here, we classify glaucomatous vision loss quantitatively by statistically learning prototypical patterns on the convex hull of the data space. In contrast to component-based approaches, this method emphasizes distinct aspects of the data and provides patterns that are easier to interpret for clinicians. Based on 13 231 reliable Humphrey VFs from a large clinical glaucoma practice, we identify an optimal solution with 17 glaucomatous vision loss prototypes which fit well with previously described qualitative patterns from a large clinical study. We illustrate relations of our patterns to retinal structure by a previously developed mathematical model. In contrast to the qualitative clinical approaches, our results can serve as a framework to quantify the various subtypes of glaucomatous visual field loss. PMID- 25505133 TI - Boxfish swimming paradox resolved: forces by the flow of water around the body promote manoeuvrability. AB - The shape of the carapace protecting the body of boxfishes has been attributed an important hydrodynamic role in drag reduction and in providing automatic, flow direction realignment and is therefore used in bioinspired design of cars. However, tight swimming-course stabilization is paradoxical given the frequent, high-performance manoeuvring that boxfishes display in their spatially complex, coral reef territories. Here, by performing flow-tank measurements of hydrodynamic drag and yaw moments together with computational fluid dynamics simulations, we reverse several assumptions about the hydrodynamic role of the boxfish carapace. Firstly, despite serving as a model system in aerodynamic design, drag-reduction performance was relatively low compared with more generalized fish morphologies. Secondly, the current theory of course stabilization owing to flow over the boxfish carapace was rejected, as destabilizing moments were found consistently. This solves the boxfish swimming paradox: destabilizing moments enhance manoeuvrability, which is in accordance with the ecological demands for efficient turning and tilting. PMID- 25505134 TI - Modelling the spatial heterogeneity and molecular correlates of lymphocytic infiltration in triple-negative breast cancer. AB - Lymphocytic infiltration is associated with a favourable prognosis and predicts response to chemotherapy in many cancer types, including the aggressive triple negative breast cancer (TNBC). However, it is not well understood owing to the high levels of spatial heterogeneity within tumours, which is difficult to analyse by traditional pathological assessment. This paper describes an unbiased methodology to statistically model the spatial distribution of lymphocytes among tumour cells based on automated analysis of haematoxylin-and-eosin-stained whole tumour section images, which is applied to two independent TNBC cohorts of 181 patients with matched microarray gene expression data. The novelty of the proposed methodology is the fusion of image analysis and statistical modelling for an integrative understanding of intratumour heterogeneity of lymphocytic infiltration. Using this methodology, a quantitative measure of intratumour lymphocyte ratio is developed and found to be significantly associated with disease-specific survival in both TNBC cohorts independent to standard clinical parameters. The proposed image-based measure compares favourably to a number of gene expression signatures of immune infiltration. In addition, heterogeneous immune infiltration at the morphological level is reflected at the molecular scale and correlated with increased expression of CTLA4, the target of ipilimumab. Taken together, these results support the fusion of high-throughput image analysis and statistical modelling to offer reproducible and robust biomarkers for the objective identification of patients with poor prognosis and treatment options. PMID- 25505135 TI - High-frequency dual mode pulsed wave Doppler imaging for monitoring the functional regeneration of adult zebrafish hearts. AB - Adult zebrafish is a well-known small animal model for studying heart regeneration. Although the regeneration of scars made by resecting the ventricular apex has been visualized with histological methods, there is no adequate imaging tool for tracking the functional recovery of the damaged heart. For this reason, high-frequency Doppler echocardiography using dual mode pulsed wave Doppler, which provides both tissue Doppler (TD) and Doppler flow in a same cardiac cycle, is developed with a 30 MHz high-frequency array ultrasound imaging system. Phantom studies show that the Doppler flow mode of the dual mode is capable of measuring the flow velocity from 0.1 to 15 cm s(-1) with high accuracy (p-value = 0.974 > 0.05). In the in vivo study of zebrafish, both TD and Doppler flow signals were simultaneously obtained from the zebrafish heart for the first time, and the synchronized valve motions with the blood flow signals were identified. In the longitudinal study on the zebrafish heart regeneration, the parameters for diagnosing the diastolic dysfunction, for example, E/Em < 10, E/A < 0.14 for wild-type zebrafish, were measured, and the type of diastolic dysfunction caused by the amputation was found to be similar to the restrictive filling. The diastolic function was fully recovered within four weeks post amputation. PMID- 25505136 TI - Magnetic field effects as a result of the radical pair mechanism are unlikely in redox enzymes. AB - Environmental exposure to electromagnetic fields is potentially carcinogenic. The radical pair mechanism is considered the most feasible mechanism of interaction between weak magnetic fields encountered in our environment and biochemical systems. Radicals are abundant in biology, both as free radicals and reaction intermediates in enzyme mechanisms. The catalytic cycles of some flavin-dependent enzymes are either known or potentially involve radical pairs. Here, we have investigated the magnetic field sensitivity of a number of flavoenzymes with important cellular roles. We also investigated the magnetic field sensitivity of a model system involving stepwise reduction of a flavin analogue by a nicotinamide analogue-a reaction known to proceed via a radical pair. Under the experimental conditions used, magnetic field sensitivity was not observed in the reaction kinetics from stopped-flow measurements in any of the systems studied. Although widely implicated in radical pair chemistry, we conclude that thermally driven, flavoenzyme-catalysed reactions are unlikely to be influenced by exposure to external magnetic fields. PMID- 25505137 TI - Single cell profiling of surface carbohydrates on Bacillus cereus. AB - Cell surface carbohydrates are important to various bacterial activities and functions. It is well known that different types of Bacillus display heterogeneity of surface carbohydrate compositions, but detection of their presence, quantitation and estimation of variation at the single cell level have not been previously solved. Here, using atomic force microscopy (AFM)-based recognition force mapping coupled with lectin probes, the specific carbohydrate distributions of N-acetylglucosamine and mannose/glucose were detected, mapped and quantified on single B. cereus surfaces at the nanoscale across the entire cell. Further, the changes of the surface carbohydrate compositions from the vegetative cell to spore were shown. These results demonstrate AFM-based 'recognition force mapping' as a versatile platform to quantitatively detect and spatially map key bacterial surface biomarkers (such as carbohydrate compositions), and monitor in situ changes in surface biochemical properties during intracellular activities at the single cell level. PMID- 25505138 TI - The virtue of innovation: innovation through the lenses of biological evolution. AB - We rehearse the processes of innovation and discovery in general terms, using as our main metaphor the biological concept of an evolutionary fitness landscape. Incremental and disruptive innovations are seen, respectively, as successful searches carried out locally or more widely. They may also be understood as reflecting evolution by mutation (incremental) versus recombination (disruptive). We also bring a platonic view, focusing on virtue and memory. We use 'virtue' as a measure of efforts, including the knowledge required to come up with disruptive and incremental innovations, and 'memory' as a measure of their lifespan, i.e. how long they are remembered. Fostering innovation, in the evolutionary metaphor, means providing the wherewithal to promote novelty, good objective functions that one is trying to optimize, and means to improve one's knowledge of, and ability to navigate, the landscape one is searching. Recombination necessarily implies multi- or inter-disciplinarity. These principles are generic to all kinds of creativity, novel ideas formation and the development of new products and technologies. PMID- 25505139 TI - A nanostructural basis for gloss of avian eggshells. AB - The role of pigments in generating the colour and maculation of birds' eggs is well characterized, whereas the effects of the eggshell's nanostructure on the visual appearance of eggs are little studied. Here, we examined the nanostructural basis of glossiness of tinamou eggs. Tinamou eggs are well known for their glossy appearance, but the underlying mechanism responsible for this optical effect is unclear. Using experimental manipulations in conjunction with angle-resolved spectrophotometry, scanning electron microscopy, atomic force microscopy and chemical analyses, we show that the glossy appearance of tinamou eggshells is produced by an extremely smooth cuticle, composed of calcium carbonate, calcium phosphate and, potentially, organic compounds such as proteins and pigments. Optical calculations corroborate surface smoothness as the main factor producing gloss. Furthermore, we reveal the presence of weak iridescence on eggs of the great tinamou (Tinamus major), an optical effect never previously documented for bird eggs. These data highlight the need for further exploration into the nanostructural mechanisms for the production of colour and other optical effects of avian eggshells. PMID- 25505140 TI - Bacteremia and malaria in Tanzanian children hospitalized for acute febrile illness. AB - We recorded the reason for presentation to a rural hospital in an area endemic for malaria in 909 children between January 2006 and March 2009. Blood smears were examined for Plasmodium falciparum parasites, and blood spots dried on filter paper were prepared for 464 children. A PCR assay utilizing the stored blood spots was developed for Streptococcus pneumoniae (lytA) and Haemophilus influenzae (pal). Malaria was present in 299 children whose blood was tested by polymerase chain reaction (PCR); 19 had lytA and 15 had pal. The overall prevalence of lytA was 25 of the 464 children, while that of pal was 18 children. Fever was present in 369 children of whom 19 had lytA DNA while 11 had pal DNA detected. Of the 95 afebrile children, six had lytA and seven pal. We conclude that there are no clinical features that distinguish malaria alone from bacteremia alone or the presence of both infections. PMID- 25505141 TI - CSB interacts with SNM1A and promotes DNA interstrand crosslink processing. AB - Cockayne syndrome (CS) is a premature aging disorder characterized by photosensitivity, impaired development and multisystem progressive degeneration, and consists of two strict complementation groups, A and B. Using a yeast two hybrid approach, we identified the 5'-3' exonuclease SNM1A as one of four strong interacting partners of CSB. This direct interaction was confirmed using purified recombinant proteins-with CSB able to modulate the exonuclease activity of SNM1A on oligonucleotide substrates in vitro-and the two proteins were shown to exist in a common complex in human cell extracts. CSB and SNM1A were also found, using fluorescently tagged proteins in combination with confocal microscopy and laser microirradiation, to be recruited to localized trioxsalen-induced ICL damage in human cells, with accumulation being suppressed by transcription inhibition. Moreover, SNM1A recruitment was significantly reduced in CSB-deficient cells, suggesting coordination between the two proteins in vivo. CSB-deficient neural cells exhibited increased sensitivity to DNA crosslinking agents, particularly, in a non-cycling, differentiated state, as well as delayed ICL processing as revealed by a modified Comet assay and gamma-H2AX foci persistence. The results indicate that CSB coordinates the resolution of ICLs, possibly in a transcription associated repair mechanism involving SNM1A, and that defects in the process could contribute to the post-mitotic degenerative pathologies associated with CS. PMID- 25505142 TI - Mg2+-dependent conformational changes and product release during DNA-catalyzed RNA ligation monitored by Bimane fluorescence. AB - Among the deoxyribozymes catalyzing the ligation of two RNA substrates, 7S11 generates a branched RNA containing a 2',5'-linkage. We have attached the small fluorogenic probe Bimane to the triphosphate terminated RNA substrate and utilized emission intensity and anisotropy to follow structural rearrangements leading to a catalytically active complex upon addition of Mg(2+). Bimane coupled to synthetic oligonucleotides is quenched by nearby guanines via photoinduced electron transfer. The degree of quenching is sensitive to changes in the base pairing of the residues involved and in their distances to the probe. These phenomena permit the characterization of various sequential processes in the assembly and function of 7S11: binding of Mg(2+) to the triphosphate moiety, release of quenching of the probe by the 5'-terminal G residues of R-RNA as they engage in secondary base-pair interactions, local rearrangement into a distinct active conformation, and continuous release of the Bimane-labeled pyrophosphate during the course of reaction at 37 degrees C. It was possible to assign equilibrium and rate constants and structural interpretations to the sequence of conformational transitions and catalysis, information useful for optimizing the design of next generation deoxyribozymes. The fluorescent signatures, thermodynamic equilibria and catalytic function of numerous mutated (base/substituted) molecules were examined. PMID- 25505143 TI - An archaeal CRISPR type III-B system exhibiting distinctive RNA targeting features and mediating dual RNA and DNA interference. AB - CRISPR-Cas systems provide a small RNA-based mechanism to defend against invasive genetic elements in archaea and bacteria. To investigate the in vivo mechanism of RNA interference by two type III-B systems (Cmr-alpha and Cmr-beta) in Sulfolobus islandicus, a genetic assay was developed using plasmids carrying an artificial mini-CRISPR (AC) locus with a single spacer. After pAC plasmids were introduced into different strains, Northern analyses confirmed that mature crRNAs were produced from the plasmid-borne CRISPR loci, which then guided gene silencing to target gene expression. Spacer mutagenesis identified a trinucleotide sequence in the 3'-region of crRNA that was crucial for RNA interference. Studying mutants lacking Cmr-alpha or Cmr-beta system showed that each Cmr complex exhibited RNA interference. Strikingly, these analyses further revealed that the two Cmr systems displayed distinctive interference features. Whereas Cmr-beta complexes targeted transcripts and could be recycled in RNA cleavage, Cmr-alpha complexes probably targeted nascent RNA transcripts and remained associated with the substrate. Moreover, Cmr-beta exhibited much stronger RNA cleavage activity than Cmr-alpha. Since we previously showed that S. islandicus Cmr-alpha mediated transcription-dependent DNA interference, the Cmr-alpha constitutes the first CRISPR system exhibiting dual targeting of RNA and DNA. PMID- 25505144 TI - Comprehensive discovery of DNA motifs in 349 human cells and tissues reveals new features of motifs. AB - Comprehensive motif discovery under experimental conditions is critical for the global understanding of gene regulation. To generate a nearly complete list of human DNA motifs under given conditions, we employed a novel approach to de novo discover significant co-occurring DNA motifs in 349 human DNase I hypersensitive site datasets. We predicted 845 to 1325 motifs in each dataset, for a total of 2684 non-redundant motifs. These 2684 motifs contained 54.02 to 75.95% of the known motifs in seven large collections including TRANSFAC. In each dataset, we also discovered 43 663 to 2 013 288 motif modules, groups of motifs with their binding sites co-occurring in a significant number of short DNA regions. Compared with known interacting transcription factors in eight resources, the predicted motif modules on average included 84.23% of known interacting motifs. We further showed new features of the predicted motifs, such as motifs enriched in proximal regions rarely overlapped with motifs enriched in distal regions, motifs enriched in 5' distal regions were often enriched in 3' distal regions, etc. Finally, we observed that the 2684 predicted motifs classified the cell or tissue types of the datasets with an accuracy of 81.29%. The resources generated in this study are available at http://server.cs.ucf.edu/predrem/. PMID- 25505147 TI - Corrigendum. PMID- 25505146 TI - Leveraging cross-link modification events in CLIP-seq for motif discovery. AB - High-throughput protein-RNA interaction data generated by CLIP-seq has provided an unprecedented depth of access to the activities of RNA-binding proteins (RBPs), the key players in co- and post-transcriptional regulation of gene expression. Motif discovery forms part of the necessary follow-up data analysis for CLIP-seq, both to refine the exact locations of RBP binding sites, and to characterize them. The specific properties of RBP binding sites, and the CLIP-seq methods, provide additional information not usually present in the classic motif discovery problem: the binding site structure, and cross-linking induced events in reads. We show that CLIP-seq data contains clear secondary structure signals, as well as technology- and RBP-specific cross-link signals. We introduce Zagros, a motif discovery algorithm specifically designed to leverage this information and explore its impact on the quality of recovered motifs. Our results indicate that using both secondary structure and cross-link modifications can greatly improve motif discovery on CLIP-seq data. Further, the motifs we recover provide insight into the balance between sequence- and structure-specificity struck by RBP binding. PMID- 25505145 TI - Roles of PCNA ubiquitination and TLS polymerases kappa and eta in the bypass of methyl methanesulfonate-induced DNA damage. AB - Translesion synthesis (TLS) provides a highly conserved mechanism that enables DNA synthesis on a damaged template. TLS is performed by specialized DNA polymerases of which polymerase (Pol) kappa is important for the cellular response to DNA damage induced by benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), ultraviolet (UV) light and the alkylating agent methyl methanesulfonate (MMS). As TLS polymerases are intrinsically error-prone, tight regulation of their activity is required. One level of control is provided by ubiquitination of the homotrimeric DNA clamp PCNA at lysine residue 164 (PCNA-Ub). We here show that Polkappa can function independently of PCNA modification and that Poleta can function as a backup during TLS of MMS-induced lesions. Compared to cell lines deficient for PCNA modification (Pcna(K164R)) or Polkappa, double mutant cell lines display hypersensitivity to MMS but not to BPDE or UV-C. Double mutant cells also displayed delayed post-replicative TLS, accumulate higher levels of replication stress and delayed S-phase progression. Furthermore, we show that Poleta and Polkappa are redundant in the DNA damage bypass of MMS-induced DNA damage. Taken together, we provide evidence for PCNA-Ub-independent activation of Polkappa and establish Poleta as an important backup polymerase in the absence of Polkappa in response to MMS-induced DNA damage. PMID- 25505148 TI - Influence of environmental information in natural scenes and the effects of motion adaptation on a fly motion-sensitive neuron during simulated flight. AB - Gaining information about the spatial layout of natural scenes is a challenging task that flies need to solve, especially when moving at high velocities. A group of motion sensitive cells in the lobula plate of flies is supposed to represent information about self-motion as well as the environment. Relevant environmental features might be the nearness of structures, influencing retinal velocity during translational self-motion, and the brightness contrast. We recorded the responses of the H1 cell, an individually identifiable lobula plate tangential cell, during stimulation with image sequences, simulating translational motion through natural sceneries with a variety of differing depth structures. A correlation was found between the average nearness of environmental structures within large parts of the cell's receptive field and its response across a variety of scenes, but no correlation was found between the brightness contrast of the stimuli and the cell response. As a consequence of motion adaptation resulting from repeated translation through the environment, the time-dependent response modulations induced by the spatial structure of the environment were increased relatively to the background activity of the cell. These results support the hypothesis that some lobula plate tangential cells do not only serve as sensors of self-motion, but also as a part of a neural system that processes information about the spatial layout of natural scenes. PMID- 25505149 TI - Computer simulations of the mouse spermatogenic cycle. AB - The spermatogenic cycle describes the periodic development of germ cells in the testicular tissue. The temporal-spatial dynamics of the cycle highlight the unique, complex, and interdependent interaction between germ and somatic cells, and are the key to continual sperm production. Although understanding the spermatogenic cycle has important clinical relevance for male fertility and contraception, there are a number of experimental obstacles. For example, the lengthy process cannot be visualized through dynamic imaging, and the precise action of germ cells that leads to the emergence of testicular morphology remains uncharacterized. Here, we report an agent-based model that simulates the mouse spermatogenic cycle on a cross-section of the seminiferous tubule over a time scale of hours to years, while considering feedback regulation, mitotic and meiotic division, differentiation, apoptosis, and movement. The computer model is able to elaborate the germ cell dynamics in a time-lapse movie format, allowing us to trace individual cells as they change state and location. More importantly, the model provides mechanistic understanding of the fundamentals of male fertility, namely how testicular morphology and sperm production are achieved. By manipulating cellular behaviors either individually or collectively in silico, the model predicts causal events for the altered arrangement of germ cells upon genetic or environmental perturbations. This in silico platform can serve as an interactive tool to perform long-term simulation and to identify optimal approaches for infertility treatment and contraceptive development. PMID- 25505150 TI - Testing avian compass calibration: comparative experiments with diurnal and nocturnal passerine migrants in South Sweden. AB - Cue-conflict experiments were performed to study the compass calibration of one predominantly diurnal migrant, the dunnock (Prunella modularis), and two species of nocturnal passerine migrants, the sedge warbler (Acrocephalus schoenobaenus), and the European robin (Erithacus rubecula) during autumn migration in South Sweden. The birds' orientation was recorded in circular cages under natural clear and simulated overcast skies in the local geomagnetic field, and thereafter the birds were exposed to a cue-conflict situation where the horizontal component of the magnetic field (mN) was shifted +90 degrees or -90 degrees at two occasions, one session starting shortly after sunrise and the other ca. 90 min before sunset and lasting for 60 min. The patterns of the degree and angle of skylight polarization were measured by full-sky imaging polarimetry during the cue-conflict exposures and orientation tests. All species showed orientation both under clear and overcast skies that correlated with the expected migratory orientation towards southwest to south. For the European robin the orientation under clear skies was significantly different from that recorded under overcast skies, showing a tendency that the orientation under clear skies was influenced by the position of the Sun at sunset resulting in more westerly orientation. This sun attraction was not observed for the sedge warbler and the dunnock, both orientating south. All species showed similar orientation after the cue-conflict as compared to the preferred orientation recorded before the cue-conflict, with the clearest results in the European robin and thus, the results did not support recalibration of the celestial nor the magnetic compasses as a result of the cue conflict exposure. PMID- 25505151 TI - Morphological, olfactory, and vocal development in big brown bats. AB - Using a within subjects design, we documented morphological, bioacoustical and behavioral developmental changes in big brown bats. Eptesicus fuscus pups are born naked and blind but assume an adult-like appearance by post-natal day (PND) 45 and flight by PND 30. Adult females use spatial memory, acoustic and olfactory cues to reunite with offspring, but it is unclear if pups can recognize maternal scents. We tested the olfactory discrimination abilities of young E. fuscus pups and found they exhibited no odor preferences. Pups also emit distinct vocalizations called isolation calls (i-calls) that facilitate mother-offspring reunions, but how pups shift their vocalizations from i-calls to downward frequency modulated (FM) sweeps used in echolocation remains unclear. Between PND 0-9, pups emitted mainly long duration, tonal i-calls rich in harmonics, but after they switched to short duration, downward FM sweeps with fewer harmonics. Call maximum frequency and repetition rate showed minor changes across development. Signal duration, bandwidth, and number of harmonics decreased, whereas the maximum, minimum and bandwidth of the fundamental, and peak spectral frequency all increased. We recorded vocalizations during prolonged maternal separation and found that isolated pups called longer and at a faster rate, presumably to signal for maternal assistance. To assess how PND 13 pups alter their signals during interactions with humans we compared spontaneous and provoked vocalizations and found that provoked calls were spectrally and temporally more similar to those of younger bats suggesting that pups in distress emit signals that sound like younger bats to promote maternal assistance. PMID- 25505152 TI - Sucrose non-fermenting related kinase enzyme is essential for cardiac metabolism. AB - In this study, we have identified a novel member of the AMPK family, namely Sucrose non-fermenting related kinase (Snrk), that is responsible for maintaining cardiac metabolism in mammals. SNRK is expressed in the heart, and brain, and in cell types such as endothelial cells, smooth muscle cells and cardiomyocytes (CMs). Snrk knockout (KO) mice display enlarged hearts, and die at postnatal day 0. Microarray analysis of embryonic day 17.5 Snrk hearts, and blood profile of neonates display defect in lipid metabolic pathways. SNRK knockdown CMs showed altered phospho-acetyl-coA carboxylase and phospho-AMPK levels similar to global and endothelial conditional KO mouse. Finally, adult cardiac conditional KO mouse displays severe cardiac functional defects and lethality. Our results suggest that Snrk is essential for maintaining cardiac metabolic homeostasis, and shows an autonomous role for SNRK during mammalian development. PMID- 25505153 TI - mzDB: a file format using multiple indexing strategies for the efficient analysis of large LC-MS/MS and SWATH-MS data sets. AB - The analysis and management of MS data, especially those generated by data independent MS acquisition, exemplified by SWATH-MS, pose significant challenges for proteomics bioinformatics. The large size and vast amount of information inherent to these data sets need to be properly structured to enable an efficient and straightforward extraction of the signals used to identify specific target peptides. Standard XML based formats are not well suited to large MS data files, for example, those generated by SWATH-MS, and compromise high-throughput data processing and storing. We developed mzDB, an efficient file format for large MS data sets. It relies on the SQLite software library and consists of a standardized and portable server-less single-file database. An optimized 3D indexing approach is adopted, where the LC-MS coordinates (retention time and m/z), along with the precursor m/z for SWATH-MS data, are used to query the database for data extraction. In comparison with XML formats, mzDB saves ~25% of storage space and improves access times by a factor of twofold up to even 2000 fold, depending on the particular data access. Similarly, mzDB shows also slightly to significantly lower access times in comparison with other formats like mz5. Both C++ and Java implementations, converting raw or XML formats to mzDB and providing access methods, will be released under permissive license. mzDB can be easily accessed by the SQLite C library and its drivers for all major languages, and browsed with existing dedicated GUIs. The mzDB described here can boost existing mass spectrometry data analysis pipelines, offering unprecedented performance in terms of efficiency, portability, compactness, and flexibility. PMID- 25505156 TI - Extent of microcytic anemia among children in a low-income, peri-urban community in the Dominican Republic using different cut-points. AB - Response to anemia in low-resource settings may entail presumptive iron treatment for those with Hemoglobin (Hb) levels falling below certain cut points. This study aimed to inform an anemia screening and treatment service in a low-income community in the Dominican Republic by determining (i) the prevalence of anemia in young children attending this service using different Hb cut points and (ii) the extent of microcytosis using different recommended cut points for the mean corpuscular volume (MCV). Using the WHO recommended cut point of <11.0 g/dl, 69.9% of 292 children would be classified as anemic, while using a more conservative cut point, <10.0 g/dl, 34.6% would be identified. Depending on the Hb cut point and which of two age-based MCV cut points are used, the prevalence of microcytosis within the anemic subsamples ranged from 23.5% to 80.2%. With increasing availability of complete blood counts in low resource settings (vs. Hb only), more sophisticated management algorithms are necessary to guide primary care efforts. PMID- 25505154 TI - Quantitative nuclear proteomics identifies that miR-137-mediated EZH2 reduction regulates resveratrol-induced apoptosis of neuroblastoma cells. AB - Neuroblastoma is the most common pediatric extracranial solid tumor with a broad spectrum of clinical behavior and poor prognosis. Despite intensive multimodal therapy, ongoing clinical trials, and basic science investigations, neuroblastoma remains a complex medical challenge with a long-term survival rate less than 40%. In our study, we found that resveratrol (3, 5, 4'-trihydroxystilbene, RSV), a naturally occurring phytoalexin, possesses an anticancer activity through blocking cell growth and inducing apoptosis in neuroblastoma cell line Neuro-2a (N-2a) cells. Using stable isotope labeling with amino acids in cell culture (SILAC) and quantitative proteomic analysis, we found that 395 proteins were up regulated and 302 proteins were down-regulated in the nucleus of N-2a cells treated with RSV. Among these, the polycomb protein histone methyltransferase EZH2 was reduced significantly, which is aberrantly overexpressed in neuroblastoma and crucial to maintain the malignant phenotype of neuroblastoma by epigenetic repression of multiple tumor suppressor genes. EZH2 reduction further led to decreased H3K27me3 level and reactivation of neuroblastoma tumor suppressor genes CLU and NGFR. Disruption EZH2 expression by RNA interference mediated knockdown or pharmacologic inhibition with DZNep triggered cellular apoptosis in N-2a cells. We found that the up-regulation of miR-137 level was responsible for reduced EZH2 level in tumor suppression induced by RSV. Inhibition of miR-137 expression rescued the cellular apoptosis phenotypes, EZH2 reduction, and CLU and NGFR reactivation, associated with RSV treatment. Taken together, our findings present for the first time, an epigenetic mechanism involving miR-137-mediated EZH2 repression in RSV-induced apoptosis and tumor suppression of neuroblastoma, which would provide a key potential therapeutic target in neuroblastoma treatment. PMID- 25505155 TI - A chemical proteomics approach for global analysis of lysine monomethylome profiling. AB - Methylation of lysine residues on histone proteins is known to play an important role in chromatin structure and function. However, non-histone protein substrates of this modification remain largely unknown. An effective approach for system wide analysis of protein lysine methylation, particularly lysine monomethylation, is lacking. Here we describe a chemical proteomics approach for global screening for monomethyllysine substrates, involving chemical propionylation of monomethylated lysine, affinity enrichment of the modified monomethylated peptides, and HPLC/MS/MS analysis. Using this approach, we identified with high confidence 446 lysine monomethylation sites in 398 proteins, including three previously unknown histone monomethylation marks, representing the largest data set of protein lysine monomethylation described to date. Our data not only confirms previously discovered lysine methylation substrates in the nucleus and spliceosome, but also reveals new substrates associated with diverse biological processes. This method hence offers a powerful approach for dynamic study of protein lysine monomethylation under diverse cellular conditions and in human diseases. PMID- 25505157 TI - Report of the APSAC Task Force on evidence-based service planning guidelines for child welfare. AB - This article presents the American Professional Society on the Abuse of Children (APSAC) Task Force report on the evidence-based service planning (EBSP) approach to child welfare services (CWS) plans and recommendations for practice. The focus of the policy report is on formal psychosocial services. CWS plans prescribe services to promote core child welfare objectives and to benefit children and families. The goal of EBSP is to construct service plans based on the general principles of evidence-based practice and prefer services with empirical support for clinical problems or needs associated with the causes or consequences of child abuse and neglect (CAN). EBSP aims to facilitate an overarching service approach that is collaborative, respectful, and includes services that are most likely to lead to outcomes on both family identified and child welfare mission goals. EBSP emphasizes a focused, assessment-driven, and science-informed approach that both favors plans that are sufficient and avoids overburdening families with compulsory services that address problems which are not directly related to the child welfare CAN referral. PMID- 25505159 TI - Needs and Concerns of Family Caregivers of American Indians, African Americans, and Caucasians With Type 2 Diabetes. AB - Although type 2 diabetes is a chronic illness affecting the entire family, scant literature exists in this area. This study's purpose was to identify needs of family caregivers of persons with type 2 diabetes across cultures. Using a semi structured interview guide with open-ended questions, a convenience sample of 33 family caregivers of American Indians (n = 14), African Americans (n = 11), and Caucasians (n = 8) with type 2 diabetes were interviewed by telephone. Qualitative content analysis was conducted based on five pre-determined categories derived from an existing conceptual model. Results were similar across groups and provided support for the conceptual model with themes emerging within the five pre-determined categories: (a) information about type 2 diabetes, (b) managing emotions and behaviors, (c) physical care, (d) instrumental care, and (e) personal responses to caregiving. No additional themes emerged. Although small and exploratory, findings provide information that may be useful to the future development of culturally based interventions. PMID- 25505160 TI - Henry's voices: the representation of auditory verbal hallucinations in an autobiographical narrative. AB - The book Henry's Demons (2011) recounts the events surrounding Henry Cockburn's diagnosis of schizophrenia from the alternating perspectives of Henry himself and his father Patrick. In this paper, we present a detailed linguistic analysis of Henry's first-person accounts of experiences that could be described as auditory verbal hallucinations. We first provide a typology of Henry's voices, taking into account who or what is presented as speaking, what kinds of utterances they produce and any salient stylistic features of these utterances. We then discuss the linguistically distinctive ways in which Henry represents these voices in his narrative. We focus on the use of Direct Speech as opposed to other forms of speech presentation, the use of the sensory verbs hear and feel and the use of 'non-factive' expressions such as I thought and as if. We show how different linguistic representations may suggest phenomenological differences between the experience of hallucinatory voices and the perception of voices that other people can also hear. We, therefore, propose that linguistic analysis is ideally placed to provide in-depth accounts of the phenomenology of voice hearing and point out the implications of this approach for clinical practice and mental healthcare. PMID- 25505158 TI - Systematically ranking the tightness of membrane association for peripheral membrane proteins (PMPs). AB - Large-scale quantitative evaluation of the tightness of membrane association for nontransmembrane proteins is important for identifying true peripheral membrane proteins with functional significance. Herein, we simultaneously ranked more than 1000 proteins of the photosynthetic model organism Synechocystis sp. PCC 6803 for their relative tightness of membrane association using a proteomic approach. Using multiple precisely ranked and experimentally verified peripheral subunits of photosynthetic protein complexes as the landmarks, we found that proteins involved in two-component signal transduction systems and transporters are overall tightly associated with the membranes, whereas the associations of ribosomal proteins are much weaker. Moreover, we found that hypothetical proteins containing the same domains generally have similar tightness. This work provided a global view of the structural organization of the membrane proteome with respect to divergent functions, and built the foundation for future investigation of the dynamic membrane proteome reorganization in response to different environmental or internal stimuli. PMID- 25505161 TI - Illness perception and adherence to healthy behaviour in Jordanian coronary heart disease patients. AB - BACKGROUND: Patients diagnosed with coronary heart disease are strongly recommended to adopt healthier behaviours and adhere to prescribed medication. Previous research on patients with a wide range of health conditions has explored the role of patients' illness perceptions in explaining coping and health outcomes. However, among coronary heart disease patients, this has not been well examined. OBJECTIVE: The purpose of this study was to explore coronary heart disease patients' illness perception beliefs and investigate whether these beliefs could predict adherence to healthy behaviours. METHODS: A multi-centre cross-sectional study was conducted at four tertiary hospitals in Jordan. A convenience sample of 254 patients (73% response rate), who visited the cardiac clinic for routine review, participated in the study. Participants completed a self-reported questionnaire, which included the Brief Illness Perception Questionnaire, the Godin Leisure Time Activity questionnaire and the Morisky Medication Adherence Scale. RESULTS: Patients reported high levels of disease understanding (coherence) and they were convinced that they were able to control their condition by themselves and/or with appropriate treatment. Male patients perceived lower consequences (p<0.05) and had a better understanding of their illness than female patients (p<0.001). There were significant associations between increasing age and each of timeline (r=0.326, p<0.001), (r=0.146, p<0.024) and coherence (r=-0.166, p<0.010). Adjusted regression analysis showed that exercise adherence was predicted by both a strong perception in personal control (beta 2.66, 95% confidence interval 1.28-4.04), timeline (beta -1.85, 95% confidence interval 0. 8-2.88) and illness coherence (beta 2.12, 95% confidence interval 0.35-3.90). Medication adherence was predicted by perception of personal control and treatment control. Adherence to a low-fat diet regimen was predicted by perception of illness coherence only (odds ratio 12, 95% confidence interval 1.04-1.33). Finally, the majority of patients thought that the cause of their heart problem was related to coronary heart disease risk factors such as obesity and high-fat meals. CONCLUSION: Patients' illness beliefs are candidates for a psycho-educational intervention that should be targeted at improved disease management practices and better adherence to recommended healthy behaviours. PMID- 25505162 TI - Microarrays for identifying binding sites and probing structure of RNAs. AB - Oligonucleotide microarrays are widely used in various biological studies. In this review, application of oligonucleotide microarrays for identifying binding sites and probing structure of RNAs is described. Deep sequencing allows fast determination of DNA and RNA sequence. High-throughput methods for determination of secondary structures of RNAs have also been developed. Those methods, however, do not reveal binding sites for oligonucleotides. In contrast, microarrays directly determine binding sites while also providing structural insights. Microarray mapping can be used over a wide range of experimental conditions, including temperature, pH, various cations at different concentrations and the presence of other molecules. Moreover, it is possible to make universal microarrays suitable for investigations of many different RNAs, and readout of results is rapid. Thus, microarrays are used to provide insight into oligonucleotide sequences potentially able to interfere with biological function. Better understanding of structure-function relationships of RNA can be facilitated by using microarrays to find RNA regions capable to bind oligonucleotides. That information is extremely important to design optimal sequences for antisense oligonucleotides and siRNA because both bind to single stranded regions of target RNAs. PMID- 25505163 TI - A common set of distinct features that characterize noncoding RNAs across multiple species. AB - To find signature features shared by various ncRNA sub-types and characterize novel ncRNAs, we have developed a method, RNAfeature, to investigate >600 sets of genomic and epigenomic data with various evolutionary and biophysical scores. RNAfeature utilizes a fine-tuned intra-species wrapper algorithm that is followed by a novel feature selection strategy across species. It considers long distance effect of certain features (e.g. histone modification at the promoter region). We finally narrow down on 10 informative features (including sequences, structures, expression profiles and epigenetic signals). These features are complementary to each other and as a whole can accurately distinguish canonical ncRNAs from CDSs and UTRs (accuracies: >92% in human, mouse, worm and fly). Moreover, the feature pattern is conserved across multiple species. For instance, the supervised 10 feature model derived from animal species can predict ncRNAs in Arabidopsis (accuracy: 82%). Subsequently, we integrate the 10 features to define a set of noncoding potential scores, which can identify, evaluate and characterize novel noncoding RNAs. The score covers all transcribed regions (including unconserved ncRNAs), without requiring assembly of the full-length transcripts. Importantly, the noncoding potential allows us to identify and characterize potential functional domains with feature patterns similar to canonical ncRNAs (e.g. tRNA, snRNA, miRNA, etc) on ~70% of human long ncRNAs (lncRNAs). PMID- 25505164 TI - An optimized kit-free method for making strand-specific deep sequencing libraries from RNA fragments. AB - Deep sequencing of strand-specific cDNA libraries is now a ubiquitous tool for identifying and quantifying RNAs in diverse sample types. The accuracy of conclusions drawn from these analyses depends on precise and quantitative conversion of the RNA sample into a DNA library suitable for sequencing. Here, we describe an optimized method of preparing strand-specific RNA deep sequencing libraries from small RNAs and variably sized RNA fragments obtained from ribonucleoprotein particle footprinting experiments or fragmentation of long RNAs. Our approach works across a wide range of input amounts (400 pg to 200 ng), is easy to follow and produces a library in 2-3 days at relatively low reagent cost, all while giving the user complete control over every step. Because all enzymatic reactions were optimized and driven to apparent completion, sequence diversity and species abundance in the input sample are well preserved. PMID- 25505166 TI - Thoughts on transcultural nursing and Ebola. PMID- 25505165 TI - Multiple roles of the coding sequence 5' end in gene expression regulation. AB - The codon composition of the coding sequence's (ORF) 5' end first few dozen codons is known to be distinct to that of the rest of the ORF. Various explanations for the unusual codon distribution in this region have been proposed in recent years, and include, among others, novel regulatory mechanisms of translation initiation and elongation. However, due to the fact that many overlapping regulatory signals are suggested to be associated with this relatively short region, its research is challenging. Here, we review the currently known signals that appear in this region, the theories related to the way they regulate translation and affect the organismal fitness, and the debates they provoke. PMID- 25505169 TI - Professing nursing research: the Italian experience. PMID- 25505170 TI - Nursing ethics in times of conflict. PMID- 25505173 TI - Mitochondria-associated endoplasmic reticulum membrane (MAM) regulates steroidogenic activity via steroidogenic acute regulatory protein (StAR)-voltage dependent anion channel 2 (VDAC2) interaction. AB - Steroid hormones are essential for carbohydrate metabolism, stress management, and reproduction and are synthesized from cholesterol in mitochondria of adrenal glands and gonads/ovaries. In acute stress or hormonal stimulation, steroidogenic acute regulatory protein (StAR) transports substrate cholesterol into the mitochondria for steroidogenesis by an unknown mechanism. Here, we report for the first time that StAR interacts with voltage-dependent anion channel 2 (VDAC2) at the mitochondria-associated endoplasmic reticulum membrane (MAM) prior to its translocation to the mitochondrial matrix. In the MAM, StAR interacts with mitochondrial proteins Tom22 and VDAC2. However, Tom22 knockdown by siRNA had no effect on pregnenolone synthesis. In the absence of VDAC2, StAR was expressed but not processed into the mitochondria as a mature 30-kDa protein. VDAC2 interacted with StAR via its C-terminal 20 amino acids and N-terminal amino acids 221-229, regulating the mitochondrial processing of StAR into the mature protein. In the absence of VDAC2, StAR could not enter the mitochondria or interact with MAM associated proteins, and therefore steroidogenesis was inhibited. Furthermore, the N terminus was not essential for StAR activity, and the N-terminal deletion mutant continued to interact with VDAC2. The endoplasmic reticulum-targeting prolactin signal sequence did not affect StAR association with the MAM and thus its mitochondrial targeting. Therefore, VDAC2 controls StAR processing and activity, and MAM is thus a central location for initiating mitochondrial steroidogenesis. PMID- 25505168 TI - Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. AB - Cocaine exhibits prominent abuse liability, and chronic abuse can result in cocaine use disorder with significant morbidity. Major advances have been made in delineating neurobiological mechanisms of cocaine abuse; however, effective medications to treat cocaine use disorder remain to be discovered. The present review will focus on the role of serotonin (5-HT; 5-hydroxytryptamine) neurotransmission in the neuropharmacology of cocaine and related abused stimulants. Extensive research suggests that the primary contribution of 5-HT to cocaine addiction is a consequence of interactions with dopamine (DA) neurotransmission. The literature on the neurobiological and behavioral effects of cocaine is well developed, so the focus of the review will be on cocaine with inferences made about other monoamine uptake inhibitors and releasers based on mechanistic considerations. 5-HT receptors are widely expressed throughout the brain, and several different 5-HT receptor subtypes have been implicated in mediating the effects of endogenous 5-HT on DA. However, the 5-HT2A and 5-HT2C receptors in particular have been implicated as likely candidates for mediating the influence of 5-HT in cocaine abuse as well as to traits (e.g., impulsivity) that contribute to the development of cocaine use disorder and relapse in humans. Lastly, new approaches are proposed to guide targeted development of serotonergic ligands for the treatment of cocaine use disorder. PMID- 25505174 TI - Inhibition of polo-like kinase 1 (Plk1) enhances the antineoplastic activity of metformin in prostate cancer. AB - The widely used anti-diabetic drug metformin has been shown to exert strong antineoplastic actions in numerous tumor types, including prostate cancer (PCa). In this study, we show that BI2536, a specific Plk1 inhibitor, acted synergistically with metformin in inhibiting PCa cell proliferation. Furthermore, we also provide evidence that Plk1 inhibition makes PCa cells carrying WT p53 much more sensitive to low-dose metformin treatment. Mechanistically, we found that co-treatment with BI2536 and metformin induced p53-dependent apoptosis and further activated the p53/Redd-1 pathway. Moreover, we also show that BI2536 treatment inhibited metformin-induced glycolysis and glutamine anaplerosis, both of which are survival responses of cells against mitochondrial poisons. Finally, we confirmed the cell-based observations using both cultured cell-derived and patient-derived xenograft studies. Collectively, our findings support another promising therapeutic strategy by combining two well tolerated drugs against PCa proliferation and the progression of androgen-dependent PCa to the castration resistant stage. PMID- 25505175 TI - The Cdc20-binding Phe box of the spindle checkpoint protein BubR1 maintains the mitotic checkpoint complex during mitosis. AB - The spindle checkpoint ensures accurate chromosome segregation by monitoring kinetochore-microtubule attachment. Unattached or tensionless kinetochores activate the checkpoint and enhance the production of the mitotic checkpoint complex (MCC) consisting of BubR1, Bub3, Mad2, and Cdc20. MCC is a critical checkpoint inhibitor of the anaphase-promoting complex/cyclosome, a ubiquitin ligase required for anaphase onset. The N-terminal region of BubR1 binds to both Cdc20 and Mad2, thus nucleating MCC formation. The middle region of human BubR1 (BubR1M) also interacts with Cdc20, but the nature and function of this interaction are not understood. Here we identify two critical motifs within BubR1M that contribute to Cdc20 binding and anaphase-promoting complex/cyclosome inhibition: a destruction box (D box) and a phenylalanine-containing motif termed the Phe box. A BubR1 mutant lacking these motifs is defective in MCC maintenance in mitotic human cells but is capable of supporting spindle-checkpoint function. Thus, the BubR1M-Cdc20 interaction indirectly contributes to MCC homeostasis. Its apparent dispensability in the spindle checkpoint might be due to functional duality or redundant, competing mechanisms. PMID- 25505176 TI - MDA-9/syntenin is essential for factor VIIa-induced signaling, migration, and metastasis in melanoma cells. AB - Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, is a novel gene that positively regulates cancer cell motility, invasion, and metastasis through distinct biochemical and signaling pathways, but how MDA 9/syntenin is regulated in response to signals with the extracellular environment and promotes tumor progression is unclear. We now demonstrate that MDA-9/syntenin is dramatically up-regulated by a combination of rFVIIa and factor F(X) in malignant melanoma. Induction of MDA-9/syntenin in melanoma was found to occur in a thrombin-independent signaling pathway and involves the PAR-1/c-Src/Rho GTPases Rac1 and Cdc42/c-Jun N-terminal kinase axis resulting in the activation of paxillin, NF-kappaB, and matrix metalloproteinase-2 (MMP-2). MDA-9/syntenin physically interacts with c-Src through its PDZ binding motif following stimulation of melanoma cells with rFVIIa and FX. We also document that induction of this signaling pathway is required for TF.FVIIa.Xa-induced cell migration, invasion, and metastasis by melanoma cells. The present finding uncovers a novel role of MDA-9/syntenin as an important TF.FVIIa.Xa/PAR-1-regulated gene that initiates a signaling circuit essential for cell motility and invasion of metastatic melanoma. In these contexts, targeting TF.FVIIa.Xa and its relevant downstream targets such as MDA-9/syntenin, may represent a novel therapeutic strategy to control the evolution of neoplastic cells. PMID- 25505177 TI - The anoctamin family channel subdued mediates thermal nociception in Drosophila. AB - Calcium-permeable and thermosensitive transient receptor potential (TRP) channels mediate the nociceptive transduction of noxious temperature in Drosophila nociceptors. However, the underlying molecular mechanisms are not completely understood. Here we find that Subdued, a calcium-activated chloride channel of the Drosophila anoctamin family, functions in conjunction with the thermo-TRPs in thermal nociception. Genetic analysis with deletion and the RNAi-mediated reduction of subdued show that subdued is required for thermal nociception in nociceptors. Further genetic analysis of subdued mutant and thermo-TRP mutants show that they interact functionally in thermal nociception. We find that Subdued expressed in heterologous cells mediates a strong chloride conductance in the presence of both heat and calcium ions. Therefore, our analysis suggests that Subdued channels may amplify the nociceptive neuronal firing that is initiated by thermo-TRP channels in response to thermal stimuli. PMID- 25505178 TI - p53 degradation by a coronavirus papain-like protease suppresses type I interferon signaling. AB - Infection by human coronaviruses is usually characterized by rampant viral replication and severe immunopathology in host cells. Recently, the coronavirus papain-like proteases (PLPs) have been identified as suppressors of the innate immune response. However, the molecular mechanism of this inhibition remains unclear. Here, we provide evidence that PLP2, a catalytic domain of the nonstructural protein 3 of human coronavirus NL63 (HCoV-NL63), deubiquitinates and stabilizes the cellular oncoprotein MDM2 and induces the proteasomal degradation of p53. Meanwhile, we identify IRF7 (interferon regulatory factor 7) as a bona fide target gene of p53 to mediate the p53-directed production of type I interferon and the innate immune response. By promoting p53 degradation, PLP2 inhibits the p53-mediated antiviral response and apoptosis to ensure viral growth in infected cells. Thus, our study reveals that coronavirus engages PLPs to escape from the innate antiviral response of the host by inhibiting p53-IRF7 IFNbeta signaling. PMID- 25505179 TI - Molecular interaction between the chaperone Hsc70 and the N-terminal flank of huntingtin exon 1 modulates aggregation. AB - The aggregation of polyglutamine (polyQ)-containing proteins is at the origin of nine neurodegenerative diseases. Molecular chaperones prevent the aggregation of polyQ-containing proteins. The exact mechanism by which they interact with polyQ containing, aggregation-prone proteins and interfere with their assembly is unknown. Here we dissect the mechanism of interaction between a huntingtin exon 1 fragment of increasing polyQ lengths (HttEx1Qn), the aggregation of which is tightly associated with Huntington's disease, and molecular chaperone Hsc70. We show that Hsc70, together with its Hsp40 co-chaperones, inhibits HttEx1Qn aggregation and modifies the structural, seeding, and infectious properties of the resulting fibrils in a polyQ-independent manner. We demonstrate that Hsc70 binds the 17-residue-long N-terminal flank of HttEx1Qn, and we map Hsc70-HttEx1Qn surface interfaces at the residue level. Finally, we show that this interaction competes with homotypic interactions between the N termini of different HttEx1Qn molecules that trigger the aggregation process. Our results lay the foundations of future therapeutic strategies targeting huntingtin aggregation in Huntington disease. PMID- 25505180 TI - The neutral sphingomyelinase pathway regulates packaging of the prion protein into exosomes. AB - Prion diseases are a group of transmissible, fatal neurodegenerative disorders associated with the misfolding of the host-encoded prion protein, PrP(C), into a disease-associated form, PrP(Sc). The transmissible prion agent is principally formed of PrP(Sc) itself and is associated with extracellular vesicles known as exosomes. Exosomes are released from cells both in vitro and in vivo, and have been proposed as a mechanism by which prions spread intercellularly. The biogenesis of exosomes occurs within the endosomal system, through formation of intraluminal vesicles (ILVs), which are subsequently released from cells as exosomes. ILV formation is known to be regulated by the endosomal sorting complexes required for transport (ESCRT) machinery, although an alternative neutral sphingomyelinase (nSMase) pathway has been suggested to also regulate this process. Here, we investigate a role for the nSMase pathway in exosome biogenesis and packaging of PrP into these vesicles. Inhibition of the nSMase pathway using GW4869 revealed a role for the nSMase pathway in both exosome formation and PrP packaging. In agreement, targeted knockdown of nSMase1 and nSMase2 in mouse neurons using lentivirus-mediated RNAi also decreases exosome release, demonstrating the nSMase pathway regulates the biogenesis and release of exosomes. We also demonstrate that PrP(C) packaging is dependent on nSMase2, whereas the packaging of disease-associated PrP(Sc) into exosomes occurs independently of nSMase2. These findings provide further insight into prion transmission and identify a pathway which directly assists exosome-mediated transmission of prions. PMID- 25505181 TI - The H50Q mutation induces a 10-fold decrease in the solubility of alpha synuclein. AB - The conversion of alpha-synuclein from its intrinsically disordered monomeric state into the fibrillar cross-beta aggregates characteristically present in Lewy bodies is largely unknown. The investigation of alpha-synuclein variants causative of familial forms of Parkinson disease can provide unique insights into the conditions that promote or inhibit aggregate formation. It has been shown recently that a newly identified pathogenic mutation of alpha-synuclein, H50Q, aggregates faster than the wild-type. We investigate here its aggregation propensity by using a sequence-based prediction algorithm, NMR chemical shift analysis of secondary structure populations in the monomeric state, and determination of thermodynamic stability of the fibrils. Our data show that the H50Q mutation induces only a small increment in polyproline II structure around the site of the mutation and a slight increase in the overall aggregation propensity. We also find, however, that the H50Q mutation strongly stabilizes alpha-synuclein fibrils by 5.0 +/- 1.0 kJ mol(-1), thus increasing the supersaturation of monomeric alpha-synuclein within the cell, and strongly favors its aggregation process. We further show that wild-type alpha-synuclein can decelerate the aggregation kinetics of the H50Q variant in a dose-dependent manner when coaggregating with it. These last findings suggest that the precise balance of alpha-synuclein synthesized from the wild-type and mutant alleles may influence the natural history and heterogeneous clinical phenotype of Parkinson disease. PMID- 25505182 TI - A novel phosphatidylinositol 4,5-bisphosphate binding domain mediates plasma membrane localization of ExoU and other patatin-like phospholipases. AB - Bacterial toxins require localization to specific intracellular compartments following injection into host cells. In this study, we examined the membrane targeting of a broad family of bacterial proteins, the patatin-like phospholipases. The best characterized member of this family is ExoU, an effector of the Pseudomonas aeruginosa type III secretion system. Upon injection into host cells, ExoU localizes to the plasma membrane, where it uses its phospholipase A2 activity to lyse infected cells. The targeting mechanism of ExoU is poorly characterized, but it was recently found to bind to the phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), a marker for the plasma membrane of eukaryotic cells. We confirmed that the membrane localization domain (MLD) of ExoU had a direct affinity for PI(4,5)P2, and we determined that this binding was required for ExoU localization. Previously uncharacterized ExoU homologs from Pseudomonas fluorescens and Photorhabdus asymbiotica also localized to the plasma membrane and required PI(4,5)P2 for this localization. A conserved arginine within the MLD was critical for interaction of each protein with PI(4,5)P2 and for localization. Furthermore, we determined the crystal structure of the full-length P. fluorescens ExoU and found that it was similar to that of P. aeruginosa ExoU. Each MLD contains a four-helical bundle, with the conserved arginine exposed at its cap to allow for interaction with the negatively charged PI(4,5)P2. Overall, these findings provide a structural explanation for the targeting of patatin-like phospholipases to the plasma membrane and define the MLD of ExoU as a member of a new class of PI(4,5)P2 binding domains. PMID- 25505183 TI - Generation and characterization of ATP analog-specific protein kinase Cdelta. AB - To better study the role of PKCdelta in normal function and disease, we developed an ATP analog-specific (AS) PKCdelta that is sensitive to specific kinase inhibitors and can be used to identify PKCdelta substrates. AS PKCdelta showed nearly 200 times higher affinity (Km) and 150 times higher efficiency (kcat/Km) than wild type (WT) PKCdelta toward N(6)-(benzyl)-ATP. AS PKCdelta was uniquely inhibited by 1-(tert-butyl)-3-(1-naphthyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1NA-PP1) and 1-(tert-butyl)-3-(2-methylbenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4 amine (2MB-PP1) but not by other 4-amino-5-(4-methylphenyl)-7-(t butyl)pyrazolo[3,4-d]pyrimidine (PP1) analogs tested, whereas WT PKCdelta was insensitive to all PP1 analogs. To understand the mechanisms for specificity and affinity of these analogs, we created in silico WT and AS PKCdelta homology models based on the crystal structure of PKCiota. N(6)-(Benzyl)-ATP and ATP showed similar positioning within the purine binding pocket of AS PKCdelta, whereas N(6)-(benzyl)-ATP was displaced from the pocket of WT PKCdelta and was unable to interact with the glycine-rich loop that is required for phosphoryl transfer. The adenine rings of 1NA-PP1 and 2MB-PP1 matched the adenine ring of ATP when docked in AS PKCdelta, and this interaction prevented the potential interaction of ATP with Lys-378, Glu-428, Leu-430, and Phe-633 residues. 1NA-PP1 failed to effectively dock within WT PKCdelta. Other PP1 analogs failed to interact with either AS PKCdelta or WT PKCdelta. These results provide a structural basis for the ability of AS PKCdelta to efficiently and specifically utilize N(6)-(benzyl)-ATP as a phosphate donor and for its selective inhibition by 1NA-PP1 and 2MB-PP1. Such homology modeling could prove useful in designing molecules to target PKCdelta and other kinases to understand their function in cell signaling and to identify unique substrates. PMID- 25505184 TI - Activity of plasma membrane V-ATPases is critical for the invasion of MDA-MB231 breast cancer cells. AB - The vacuolar (H(+))-ATPases (V-ATPases) are a family of ATP-driven proton pumps that couple ATP hydrolysis with translocation of protons across membranes. Previous studies have implicated V-ATPases in cancer cell invasion. It has been proposed that V-ATPases participate in invasion by localizing to the plasma membrane and causing acidification of the extracellular space. To test this hypothesis, we utilized two separate approaches to specifically inhibit plasma membrane V-ATPases. First, we stably transfected highly invasive MDA-MB231 cells with a V5-tagged construct of the membrane-embedded c subunit of the V-ATPase, allowing for extracellular expression of the V5 epitope. We evaluated the effect of addition of a monoclonal antibody directed against the V5 epitope on both V ATPase-mediated proton translocation across the plasma membrane and invasion using an in vitro Matrigel assay. The addition of anti-V5 antibody resulted in acidification of the cytosol and a decrease in V-ATPase-dependent proton flux across the plasma membrane in transfected but not control (untransfected) cells. These results demonstrate that the anti-V5 antibody inhibits activity of plasma membrane V-ATPases in transfected cells. Addition of the anti-V5 antibody also inhibited in vitro invasion of transfected (but not untransfected) cells. Second, we utilized a biotin-conjugated form of the specific V-ATPase inhibitor bafilomycin. When bound to streptavidin, this compound cannot cross the plasma membrane. Addition of this compound to MDA-MB231 cells also inhibited in vitro invasion. These studies suggest that plasma membrane V-ATPases play an important role in invasion of breast cancer cells. PMID- 25505187 TI - Interaction of the Agrobacterium tumefaciens virulence protein VirD2 with histones. AB - Agrobacterium tumefaciens is a Gram-negative soil bacterium that genetically transforms plants and, under laboratory conditions, also transforms non-plant organisms, such as fungi and yeasts. During the transformation process a piece of ssDNA (T-strand) is transferred into the host cells via a type IV secretion system. The VirD2 relaxase protein, which is covalently attached at the 5' end of the T-strand through Tyr29, mediates nuclear entry as it contains a nuclear localization sequence. How the T-strand reaches the chromatin and becomes integrated in the chromosomal DNA is still far from clear. Here, we investigated whether VirD2 binds to histone proteins in the yeast Saccharomyces cerevisiae. Using immobilized GFP-VirD2 and in vitro synthesized His6-tagged S. cerevisiae proteins, interactions between VirD2 and the histones H2A, H2B, H3 and H4 were revealed. In vivo, these interactions were confirmed by bimolecular fluorescence complementation experiments. After co-cultivation of Agrobacterium strains expressing VirD2 tagged with a fragment of the yellow fluorescent protein analogue Venus with yeast strains expressing histone H2A or H2B tagged with the complementary part of Venus, fluorescence was detected in dot-shaped structures in the recipient yeast cells. The results indicated that VirD2 was transferred from Agrobacterium to yeast cells and that it interacted with histones in the host cell, and thus may help direct the T-DNA (transferred DNA) to the chromatin as a prelude to integration into the host chromosomal DNA. PMID- 25505185 TI - Key importance of small RNA binding for the activity of a glycine-tryptophan (GW) motif-containing viral suppressor of RNA silencing. AB - Viruses express viral suppressors of RNA silencing (VSRs) to counteract RNA silencing-based host defenses. Although virtually all stages of the antiviral silencing pathway can be inhibited by VSRs, small RNAs (sRNAs) and Argonaute (AGO) proteins seem to be the most frequent targets. Recently, GW/WG motifs of some VSRs have been proposed to dictate their suppressor function by mediating interaction with AGO(s). Here we have studied the VSR encoded by Pelargonium line pattern virus (family Tombusviridae). The results show that p37, the viral coat protein, blocks RNA silencing. Site-directed mutagenesis of some p37 sequence traits, including a conserved GW motif, allowed generation of suppressor competent and -incompetent molecules and uncoupling of the VSR and particle assembly capacities. The engineered mutants were used to assess the importance of p37 functions for viral infection and the relative contribution of diverse molecular interactions to suppressor activity. Two main conclusions can be drawn: (i) the silencing suppression and encapsidation functions of p37 are both required for systemic Pelargonium line pattern virus infection, and (ii) the suppressor activity of p37 relies on the ability to bind sRNAs rather than on interaction with AGOs. The data also caution against potential misinterpretations of results due to overlap of sequence signals related to distinct protein properties. This is well illustrated by mutation of the GW motif in p37 that concurrently affects nucleolar localization, efficient interaction with AGO1, and sRNA binding capability. These concomitant effects could have been overlooked in other GW motif-containing suppressors, as we exemplify with the orthologous p38 of turnip crinkle virus. PMID- 25505188 TI - Unusual features of the sequences of copies of the 16S-23S rRNA internal transcribed spacer regions of Acinetobacter bereziniae, Acinetobacter guillouiae and Acinetobacter baylyi arise from horizontal gene transfer events. AB - The highly variable nature of the internal transcribed spacer region (ITS) has been claimed to represent an ideal target for designing species-specific probes/primers capable of differentiating between closely related Acinetobacter species. However, several Acinetobacter species contain multiple ITS copies of variable lengths, and these include Acinetobacter bereziniae, Acinetobacter guillouiae and Acinetobacter baylyi. This study shows these length variations result from inter-genomic insertion/deletion events (indels) involving horizontal transfer of ITS fragments of other Acinetobacter species and possibly unrelated bacteria, as shown previously by us. In some instances, indel incorporation results in the loss of probe target sites in the recipient cell ITS. In other cases, some indel sequences contain target sites for probes designed from a single ITS sequence to target other Acinetobacter species. Hence, these can generate false positives. The largest of the indels that remove probe sites is 683 bp (labelled bay/i1-0), and it derives from the horizontal transfer of a complete ITS between A. bereziniae BCRC15423(T) and A. baylyi strain ADP1. As a consequence, ITS sequencing or fingerprinting cannot be used to distinguish between the 683 bp ITS in these two strains. PMID- 25505186 TI - The Bordetella adenylate cyclase repeat-in-toxin (RTX) domain is immunodominant and elicits neutralizing antibodies. AB - The adenylate cyclase toxin (ACT) is a multifunctional virulence factor secreted by Bordetella species. Upon interaction of its C-terminal hemolysin moiety with the cell surface receptor alphaMbeta2 integrin, the N-terminal cyclase domain translocates into the host cell cytosol where it rapidly generates supraphysiological cAMP concentrations, which inhibit host cell anti-bacterial activities. Although ACT has been shown to induce protective immunity in mice, it is not included in any current acellular pertussis vaccines due to protein stability issues and a poor understanding of its role as a protective antigen. Here, we aimed to determine whether any single domain could recapitulate the antibody responses induced by the holo-toxin and to characterize the dominant neutralizing antibody response. We first immunized mice with ACT and screened antibody phage display libraries for binding to purified ACT. The vast majority of unique antibodies identified bound the C-terminal repeat-in-toxin (RTX) domain. Representative antibodies binding two nonoverlapping, neutralizing epitopes in the RTX domain prevented ACT association with J774A.1 macrophages and soluble alphaMbeta2 integrin, suggesting that these antibodies inhibit the ACT receptor interaction. Sera from mice immunized with the RTX domain showed similar neutralizing activity as ACT-immunized mice, indicating that this domain induced an antibody response similar to that induced by ACT. These data demonstrate that RTX can elicit neutralizing antibodies and suggest it may present an alternative to ACT. PMID- 25505189 TI - Streptococcus gordonii comCDE (competence) operon modulates biofilm formation with Candida albicans. AB - Candida albicans is a pleiomorphic fungus that forms mixed species biofilms with Streptococcus gordonii, an early colonizer of oral cavity surfaces. Activation of quorum sensing (QS; intercellular signalling) promotes monospecies biofilm development by these micro-organisms, but the role of QS in mixed species communities is not understood. The comCDE genes in S. gordonii encode a sensor regulator system (ComDE), which is activated by the comC gene product (CSP, competence stimulating peptide) and modulates expression of QS-regulated genes. Dual species biofilms of S. gordonii DeltacomCDE or DeltacomC mutants with C. albicans showed increased biomass compared to biofilms of S. gordonii DL1 wild type with C. albicans. The DeltacomCDE mutant dual species biofilms in particular contained more extracellular DNA (eDNA), and could be dispersed with DNase I or protease treatment. Exogenous CSP complemented the S. gordonii DeltacomC transformation deficiency, as well as the DeltacomC-C. albicans biofilm phenotype. Purified CSP did not affect C. albicans hyphal filament formation but inhibited monospecies biofilm formation by C. albicans. The results suggest that the S. gordonii comCDE QS-system modulates the production of eDNA and the incorporation of C. albicans into dual species biofilms. PMID- 25505190 TI - Handling postpartum haemorrhage- obstetrics between tradition and modernity in post-war Sierra Leone. AB - OBJECTIVES: How traditional birth attendants (TBAs) in post-war Sierra Leone explain, handle and prevent postpartum haemorrhage (PPH) and their potential role in a better management of PPH to reduce maternal mortality in this low resource setting. METHODS: Semi-quantitative interviews about knowledge and measures in PPH and participant observation with 140 Sierra Leonean birth attendants, divided in three groups: (A) TBAs who never attended any official training course (n = 82); (B) TBAs who attended at least one official training course (n = 48); and (C) officially trained birth attendants (n = 10). RESULTS: There are several observable gaps in the knowledge of TBAs about PPH compared to modern obstetrics, however similar procedures exist. Herbal medicine is applied; metaphysical convictions about PPH remain present. Training courses show an impact. Officially trained birth attendants demonstrate knowledge deficiencies and lack resources and infrastructure to manage PPH adequately. CONCLUSIONS: Morbidity and mortality of PPH in Sierra Leone is related to several factors and not solely to the ignorance of TBAs. TBAs still play an important role for many women there. Hence improvement of the formal health sector should be combined with life-saving programmes integrating TBAs in the care for the pregnant, delivering and breastfeeding mothers. PMID- 25505191 TI - Jasmine flower extract lowers prolactin. AB - BACKGROUND: Antipsychotic drugs frequently cause amenorrhoea and galactorrhoea. Jasmine flowers used topically were as effective as oral Bromocriptine in suppressing puerperal lactation. This study aims to evaluate the efficacy and safety of intranasal jasmine flower extract (JFE) to reduce prolactin levels of patients on stable doses of antipsychotic drugs. METHOD: This is a randomized, double blind, crossover clinical trial. An aqueous-ethanol extract of jasmine flowers was prepared and used as nasal drops. A decrease in serum prolactin of >=25 ng/mL was considered a significant response. RESULTS: Ten out of 35 women had a significant drop in the serum prolactin while on the JFE. The non responders to JFE were on higher doses of antipsychotic drugs. The main side effect was a transient and mild burning sensation in the nose. A cost analysis favoured JFE over dopamine agonists. CONCLUSION: JFE contains a prolactin lowering substance which needs further characterisation. PMID- 25505192 TI - Challenges in the management of chronic HBV infection in West Africa: The clinician's perspective. AB - BACKGROUND: Hepatitis B infection has become a public health issue in recent years. Approximately 350 million of the world's population are chronically infected reaching endemic proportions in West Africa. Guidelines for treatment are continuously improving but are becoming more complex. AIM: To determine the challenges hepatologists experience in the management of patients with chronic hepatitis B. METHODS: This was a cross-sectional descriptive study conducted among hepatologists in West Africa during a regional hepatitis conference in 2013. RESULTS: Forty-six hepatologists completed the questionnaire. When evaluating a patient for chronic hepatitis B, the preferred investigations were: LFT (100%); abdominal ultrasound (93.5%); HBeAg (93.5%); HBV DNA (78%); HBsAg measure (22%); HBV genotype (15.2%); and liver biopsy (34.8%). Most had their patients on nucleoside/nucleotide analogue but follow-up visits after 1 year were problematic. CONCLUSION: The majority of hepatologists had good intentions regarding the evaluation of their patients, but only a small percentage of patients are properly investigated. PMID- 25505193 TI - Splenic abscess: Plasmodium vivax with secondary Escherichia coli infection. AB - Splenic abscess is a rare clinical entity as described in literature. The incidence is in the range of 0.14-0.7% and it has a high mortality rate. Hence, it is important to know its clinical presentation and complications, so that it can be treated early. We report a 40-year-old diabetic man who presented with fever with chills and rigor for the last 9 days and heaviness in the left hypochondrium for the last 6 days. He was initially diagnosed as having splenomegaly due to Plasmodium vivax (P. vivax), but was later found to have a splenic abscess due to Escherichia coli (E. coli). This was successfully managed by catheter drainage (CD) and antibiotic treatment. PMID- 25505194 TI - The expression of cysteine-rich secretory protein 2 (CRISP2) and its specific regulator miR-27b in the spermatozoa of patients with asthenozoospermia. AB - Cysteine-rich secretory protein 2 (CRISP2) is an important sperm protein and plays roles in spermatogenesis, modulation of flagellar motility, acrosome reaction, and gamete fusion. Clinical evidence shows a reduced CRISP2 expression in spermatozoa from asthenozoospermic patients, but the molecular mechanism underlying its reduction remains unknown. Herein, we carried out a study focusing on the CRISP2 reduction and its roles in asthenozoospermia. Initially, through analyzing CRISP2 expression and methylation on CRISP2 promoter activity in sperm, we observed a decreased expression of CRISP2 protein rather than its mRNA in the ejaculated spermatozoa from asthenozoospermic patients and no methylation in the CRISP2 promoter, suggesting CRISP2 expression may be regulated in the sperm at the posttranscriptional level. Subsequently, we found that microRNA 27b (miR 27b), predicted as a candidate regulator of CRISP2 using bioinformatics, was highly expressed in the ejaculated spermatozoa from asthenozoospermic patients. Luciferase reporter assay and transfection experiments disclosed that this microRNA could target CRISP2 by specifically binding its 3' untranslated region, suppressing CRISP2 expression. Extended clinical observation further confirmed a highly expressed miR-27b and its obviously negative correlation with CRISP2 protein expression in ejaculated spermatozoa samples from asthenozoospermic patients. Finally, we conducted a retrospective follow-up study to support that either high miR-27b expression or low CRISP2 protein expression was significantly associated with low sperm progressive motility, abnormal morphology, and infertility. Thus, this study provides the first preliminary insight into the mechanism leading to the reduced CRISP2 expression in asthenozoospermia, offering a potential therapeutic target for treating male infertility or for male contraception. PMID- 25505195 TI - Accumulation of electrophilic aldehydes during postovulatory aging of mouse oocytes causes reduced fertility, oxidative stress, and apoptosis. AB - With increasing periods of time following ovulation, the metaphase II (MII)-stage oocyte experiences overproduction of reactive oxygen species and elevated levels of lipid peroxidation that are implicitly linked with functional deficiencies acquired during postovulatory oocyte aging. We have demonstrated that the electrophilic aldehydes 4-hydroxynonenal (4HNE), malondialdehyde, and acrolein are by-products of nonenzymatic lipid peroxidation in the murine MII-stage oocyte, adducting to multiple proteins within the cell. The covalent modification of oocyte proteins by these aldehydes increased with extended periods of time postovulation; the mitochondrial protein succinate dehydrogenase (SDHA) was identified as a primary target for 4HNE adduction. Time- and dose-dependent studies revealed that exposure to elevated levels of electrophilic aldehydes causes mitochondrial reactive oxygen species production, lipid peroxidation, loss of mitochondrial membrane potential, and eventual apoptosis within the MII oocyte, presumably as a consequence of electron transport chain collapse following SDHA adduction. Additionally, we have determined that short-term exposure to low doses of 4HNE dramatically impairs the oocyte's ability to participate in fertilization and support embryonic development; however, this loss of functionality can be prevented by supplementation with the antioxidant penicillamine. In conclusion, this study has revealed that the accumulation of electrophilic aldehydes is linked to postovulatory oocyte aging, causing reduced fertility, oxidative stress, and apoptosis of this highly specialized cell. These data highlight the importance of timely fertilization of the mammalian oocyte postovulation and emphasize the potential advantages associated with antioxidant supplementation of oocyte culture medium in circumstances where reinsemination of oocytes may be desirable (i.e., rescue intracytoplasmic sperm injection), or where in vitro fertilization may be delayed. PMID- 25505196 TI - Involvement of hepatocyte growth factor-induced epithelial-mesenchymal transition in human adenomyosis. AB - Adenomyosis is commonly believed to arise from the basalis endometrium. As an estromedin growth factor, hepatocyte growth factor (HGF) exhibits multiple functions in endometriosis, a disease commonly believed to arise from the functionalis endometrium. Here, we investigated the role of HGF in the occurrence of epithelial-mesenchymal transition (EMT) in adenomyosis. Full-thickness-biopsy specimens from endometrium to myometrium were collected after hysterectomy from women with and without adenomyosis. The relationship between HGF and E-cadherin (epithelial cell marker) and N-cadherin (mesenchymal cell markers) was examined at the gene and protein levels using endometrial epithelial cells (EECs) in culture and tissues by quantitative RT-PCR and immunohistochemistry. The gene and protein expressions of two transcriptional repressors of E-cadherin, SLUG and SNAIL, were examined using Ishikawa cells and in response to HGF and estrogen (E2). HGF down-regulated E-cadherin and up-regulated N-cadherin mRNA expression in EECs, and an inverse relationship in protein expression between HGF and E cadherin was observed in basalis endometria derived from women with diffuse and focal adenomyosis. HGF induced morphological changes of EECs from a cobblestone like appearance to spindle-shaped cells and promoted migration of EECs. Ishikawa cells exhibited up-regulation of SLUG/SNAIL gene expression in response to both HGF and E2 with an additive effect between them. HGF- and E2-promoted SLUG/SNAIL gene expression was significantly abrogated after pretreatment of cells with anti HGF antibody or ICI 182720, an estrogen receptor antagonist. HGF may be involved in gland invagination deep into the myometrium by inducing EMT at the endo myometrial junction in women with adenomyosis. PMID- 25505197 TI - Conjugated linoleic Acid supplementation during pregnancy and lactation reduces maternal high-fat-diet-induced programming of early-onset puberty and hyperlipidemia in female rat offspring. AB - A maternal high-fat (HF) diet during pregnancy and lactation can result in adverse metabolic and reproductive outcomes in female offspring independent of postnatal diet. Interventions during critical windows of developmental plasticity may prevent developmental programming in offspring. The effects of maternal supplementation with the anti-inflammatory lipid conjugated linoleic acid (CLA) on early-onset puberty, metabolic dysfunction, and estrous cycle dysfunction was assessed. Sprague-Dawley rats were randomly assigned to a purified control diet (CD; 10% kcal from fat), CD with CLA (CLA; 10% kcal from fat, 1% CLA), HF (45% kcal from fat) or HF with CLA (HFCLA; 45% kcal from fat, 1% CLA). Diets were fed ad libitum for 10 days prior to time mating and throughout gestation and lactation. Offspring plasma/tissues were taken at Day 24 (prepubertal) or Day 150 (adult). Puberty was assessed from Day 26 and estrous cycle from Day 128. Female offspring from HF mothers had lower birth weights but by Postnatal Day 24 had exhibited catch-up growth concomitant with increased fat mass, hyperleptinemia, and dyslipidemia. Maternal CLA supplementation reversed these effects. Early onset puberty was only observed in HF offspring; this was reversed in HFCLA offspring. In adulthood, despite no evidence of glucose intolerance or altered insulin sensitivity, HF offspring displayed increased fat mass, dyslipidemia, disrupted estrous cyclicity. and hyperleptinemia; this was reversed by maternal CLA supplementation. Data presented in this study demonstrate the importance of diet in women of reproductive age and during pregnancy on reproductive and metabolic parameters in their offspring and that supplementation with CLA during critical windows of development may represent a therapeutic strategy in the prevention of early-life programming of metabolic and reproductive dysfunction. PMID- 25505198 TI - Genome-wide Loci linked to non-obstructive azoospermia susceptibility may be independent of reduced sperm production in males with normozoospermia. AB - Non-obstructive azoospermia (NOA) is a complex, multifactorial disease. Recent genome-wide association studies (GWAS) have identified eight NOA susceptibility loci at genome-wide significance of P < 5.0 * 10(-8) in Han Chinese from southeastern, northern, and central China. To better understand the role of the variants in conferring NOA risk, we selected four GWAS loci (HLA-DRA rs3129878, PRMT6 rs12097821, SOX5 rs10842262, and PEX10 rs2477686) that were reported before 2014 to investigate their association with NOA and their potential effects on sperm production in 1177 Han males from southwest China, including 545 patients with idiopathic NOA and 632 controls with normozoospermia. The results confirmed that the HLA-DRA rs3129878 was an NOA susceptibility locus in the present population. Along with our data, meta-analyses supported the association of the four GWAS-linked loci with NOA, whereas an additive effect of the four loci on NOA susceptibility was not found. Interestingly, the normozoospermic males with the risk genotypes of rs12097821 and rs3129878 + rs10842262 + rs12097821 were observed to have higher total sperm counts relative to non-risk genotypes, suggesting that the risk alleles of the genetic loci may not be via impairing spermatogenic ability to express susceptibility to NOA. These findings may advance our understanding of the role of the NOA susceptibility loci, although the results need to be confirmed in larger samples. PMID- 25505199 TI - Embryo mortality in Isg15-/- mice is exacerbated by environmental stress. AB - The interferon-stimulated gene 15 (Isg15) encodes a ubiquitin-like protein that is induced in the endometrium by pregnancy in mice, humans, and ruminants. Because ISG15 is a component of the innate immune system, we hypothesized that development of the embryo, fetus, and postnatal pup may be impaired in mice lacking Isg15 (Isg15(-/-)) and that this development would be further impaired in response to environmental insults such as hypoxia. The number of implantation sites, resorption sites, dead embryos, and the changes in overall gross morphology of the uterus were evaluated in Isg15(-/-) mice on Days 7.5 and 12.5 postcoitum (dpc). Postnatal development also was monitored from birth to 12 wk of age. On 7.5 dpc, the number of implantation sites and serum progesterone concentrations were similar. However, embryo mortality increased (P < 0.05) in Isg15(-/-) dams by 12.5 dpc, resulting in smaller litter sizes (4.26 +/- 0.21 embryos; n = 83 litters) compared to Isg15(+/+) females (7.78 +/- 0.29 pups; n = 47 litters). Embryo mortality in Isg15(-/-) mice was further exacerbated to 70% when dams were stressed through housing under hypoxic conditions (PB = 445 mmHg; 6.5-12.5 dpc). Transmission electron microscopy revealed lesions in antimesometrial decidua as well as trophoblast cells adjacent to decidual cells on 7.5 dpc. ISG15 was localized to mesometrial decidua on 7.5 dpc. By 12.5 dpc, ISG15 was intensely localized to the labyrinth of the placenta. By 7.5 dpc, uterine natural killer cell migration into the mesometrial pole was diminished by 65% and was less prevalent in Isg15(-/-) compared to Isg15(+/+) deciduum. Postnatal growth rate of offspring that survived to birth from Isg15(-/-) and Isg15(+/+) dams was not different. Embryo mortality occurs in pregnant Isg15(-/-) mice, is exacerbated by environmental insults like maternal hypoxia, and might result from impaired early decidualization, vascular development, and formation of the labyrinth. PMID- 25505201 TI - Elevated body weight gain during the juvenile period alters neuropeptide Y gonadotropin-releasing hormone circuitry in prepubertal heifers. AB - Increased body weight (BW) gain during the juvenile period leads to early maturation of the reproductive neuroendocrine system. We investigated whether a nutritional regimen that advances the onset of puberty leads to alterations in the hypothalamic neuropeptide Y (NPY) circuitry that are permissive for enhanced gonadotropin-releasing hormone (GnRH) secretion. It was hypothesized that NPY mRNA and NPY projections to GnRH and kisspeptin neurons are reduced in heifers that gain BW at an accelerated rate, compared with a lower one, during the juvenile period. Heifers were weaned at approximately 4 mo of age and fed diets to promote relatively low (0.5 kg/day; low gain [LG]) or high (1.0 kg/day; high gain [HG]) rates of BW gain until 8.5 mo of age. Heifers that gained BW at a higher rate exhibited greater circulating concentrations of leptin and reduced overall NPY expression in the arcuate nucleus. The proportion of GnRH neurons in close apposition to NPY fibers and the magnitude of NPY projections to GnRH neurons located in the mediobasal hypothalamus were reduced in HG heifers. However, no differences in NPY projections to kisspeptin neurons in the arcuate nucleus were detected between HG and LG heifers. Results indicate that a reduction in NPY innervation of GnRH neurons, particularly at the level of the mediobasal hypothalamus, occurs in response to elevated BW gain during the juvenile period. This functional plasticity may facilitate early onset of puberty in heifers. PMID- 25505202 TI - Endothelial nitric oxide synthase (eNOS) T-786C, 4a4b, and G894T polymorphisms and male infertility: study for idiopathic asthenozoospermia and meta-analysis. AB - Recent studies on the eNOS gene and male infertility show that expression of eNOS regulates normal spermatogenesis in the testis, and the eNOS gene variants (T 786C, 4a4b, and G894T) are potentially involved in impairment of spermatogenesis and sperm function. Thus, we conducted this association and meta-analysis study to further validate whether variants of those three loci affected the risk of idiopathic asthenozoospermia (AZS) and male infertility. Approximately 340 Chinese idiopathic AZS patients and 342 healthy men were included for this case control study, genotyped by gel electrophoresis analysis or direct sequencing of PCR products. The eNOS mRNA isolated from the semen of patients was further examined by quantitative real-time PCR. Also, a meta-analysis of association between eNOS gene polymorphisms and male infertility was performed. A significant association was identified on allelic level between 4a4b variant and AZS in our study (chi-squared = 7.53, corrected P = 0.018, odds ratio (OR) = 1.808), while there were no significant difference of T-786C and G894T for asthenozoospermia in both genotype and allele distributions. In addition, expression of eNOS was up regulated in patients compared with controls (about 2.4-fold, P < 0.001). Furthermore, the results of the meta-analysis support the conclusion that the T 786C and 4a4b loci were associated with male infertility in both Asian and Caucasian populations. Our study provides genetic evidence for the eNOS gene being a risk factor for idiopathic AZS and male infertility. Considering genetic differences among populations and complex pathogenesis of male infertility, more validating studies using independent samples are suggested in the future. PMID- 25505200 TI - Constitutive activation of transforming growth factor Beta receptor 1 in the mouse uterus impairs uterine morphology and function. AB - Despite increasing evidence pointing to the essential involvement of the transforming growth factor beta (TGFB) superfamily in reproduction, a definitive role of TGFB signaling in the uterus remains to be unveiled. In this study, we generated a gain-of-function mouse model harboring a constitutively active (CA) TGFB receptor 1 (TGFBR1), the expression of which was conditionally induced by the progesterone receptor (Pgr)-Cre recombinase. Overactivation of TGFB signaling was verified by enhanced phosphorylation of SMAD2 and increased expression of TGFB target genes in the uterus. TGFBR1 Pgr-Cre CA mice were sterile. Histological, cellular, and molecular analyses demonstrated that constitutive activation of TGFBR1 in the mouse uterus promoted formation of hypermuscled uteri. Accompanying this phenotype was the upregulation of a battery of smooth muscle genes in the uterus. Furthermore, TGFB ligands activated SMAD2/3 and stimulated the expression of a smooth muscle maker gene, alpha smooth muscle actin (ACTA2), in human uterine smooth muscle cells. Immunofluorescence microscopy identified a marked reduction of uterine glands in TGFBR1 Pgr-Cre CA mice within the endometrial compartment that contained myofibroblast-like cells. Thus, constitutive activation of TGFBR1 in the mouse uterus caused defects in uterine morphology and function, as evidenced by abnormal myometrial structure, dramatically reduced uterine glands, and impaired uterine decidualization. These results underscore the importance of a precisely controlled TGFB signaling system in establishing a uterine microenvironment conducive to normal development and function. PMID- 25505204 TI - Happy anniversary! PMID- 25505203 TI - Biological roles of interferon tau (IFNT) and type I IFN receptors in elongation of the ovine conceptus. AB - Interferon tau (IFNT) is produced by the elongating conceptus in ruminants and is the maternal recognition of the pregnancy signal. Available evidence supports the idea that IFNT acts in a paracrine and autocrine manner to modulate expression of genes in the endometrium and trophectoderm, respectively, which promote conceptus elongation. The actions of IFNT are mediated by the interferon (alpha and beta) receptor (IFNAR), which consists of two subunits, IFNAR1 and IFNAR2. To test the hypothesis that IFNT and its receptor have biological roles in conceptus elongation, an in vivo loss-of-function study was conducted by inhibiting IFNT or IFNAR1/2 mRNA translation in the trophectoderm of the ovine conceptus using morpholino antisense oligonucleotides (MAO) delivered via osmotic pumps from Days 8 to 14 postmating. Elongating, filamentous type conceptuses were recovered from Day 14 ewes receiving a control morpholino or IFNAR MAOs. In contrast, severely growth-retarded and malformed conceptuses were recovered from IFNT MAO-infused ewes. Those conceptuses contained abnormal trophectoderm cells that were apoptotic based on terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analyses. IFNT concentrations were reduced in the uterine lumen of IFNT MAO-infused ewes as was the expression of classical Type I IFN-stimulated genes in the endometrium. IFNT concentrations were also lower in the uterine lumen of IFNAR1/2 MAO-infused ewes. These studies provide in vivo evidence that IFNT is a critical regulator of conceptus elongation and that its embryotrophic actions are primarily mediated by paracrine effects on the endometrium. PMID- 25505205 TI - Hepatitis B virus screening and potential reactivation in patients undergoing treatment for cancer. PMID- 25505206 TI - Progressive multifocal leukoencephalopathy after allogeneic bone marrow transplantation for acute myeloid leukemia. AB - Progressive multifocal leukoencephalopathy (PML) is a rare fatal complication of allogeneic bone marrow transplantation (BMT) resulting from chronic immunosuppression and impaired cellular immunity. This report discusses 2 cases of PML in patients with acute myeloid leukemia after allogeneic BMT. Diagnosis was made based on characteristic brain MRI findings and positive PCR results for John Cunningham virus in the cerebrospinal fluid. Unfortunately, therapeutic options are limited and nearly always result in terminal outcomes. Although immunosuppression is an unavoidable risk of allogeneic BMT, these cases highlight a rare, yet fatal, consequence of prolonged T-cell lymphopenia and impaired cellular immunity after allogeneic BMT in this patient population. PMID- 25505207 TI - Focal takotsubo cardiomyopathy with high-dose interleukin-2 therapy for malignant melanoma. AB - High-dose interleukin-2 (IL-2) is an available treatment option for patients with metastatic melanoma or renal cell carcinoma, and is associated with sustained complete and partial responses in a subset of patients. IL-2, however, is not devoid of toxicities, most of which involve the cardiovascular system and manifest as hypotension, arrhythmias, and cardiomyopathy. This report describes an unusual presentation of takotsubo cardiomyopathy in a postmenopausal woman receiving high-dose IL-2 for metastatic melanoma. PMID- 25505209 TI - Survivorship: tools for transitioning patients with cancer. AB - The number of cancer survivors will be increasing over the next decade. Caring for this burgeoning population will place demands on oncologists and primary care providers to meet the needs of the expected large numbers of new patients as the baby-boom generation ages. Many will live beyond 5 years and possibly for decades after diagnosis. Patients experience many transitions depending on the type and stage of cancer, its treatment, and the long-term or late effects they have from the disease and its treatment. The Institute of Medicine's report, "From Cancer Patient to Cancer Survivor: Lost in Transition," recommends that patients be provided with a summary of their cancer treatment and follow-up care plan (ie, survivorship care plan [SCP]), including recommendations on healthy lifestyle behaviors and resources to promote self-care. This plan should be shared with the patient's other health care providers, including the primary care provider. This will facilitate communication among providers and with the patient, which is a key component to quality care. The American College of Surgeons Commission on Cancer has also made providing SCPs to patients at completion of treatment a quality standard. Barriers to providing SCPs have been identified and include lack of time, reimbursement, and knowledge of late treatment effects and current guidelines. Survivorship guidelines are being developed by professional organizations that may be useful for providers. This article provides some practical tools that address these recommendations to help providers and patients with transitions along the cancer trajectory. PMID- 25505208 TI - Thyroid carcinoma, version 2.2014. AB - These NCCN Guidelines Insights focus on some of the major updates to the 2014 NCCN Guidelines for Thyroid Carcinoma. Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with radioactive iodine. Sorafenib may be considered for select patients with metastatic differentiated thyroid carcinoma, whereas vandetanib or cabozantinib may be recommended for select patients with metastatic medullary thyroid carcinoma. Other kinase inhibitors may be considered for select patients with either type of thyroid carcinoma. A new section on "Principles of Kinase Inhibitor Therapy in Advanced Thyroid Cancer" was added to the NCCN Guidelines to assist with using these novel targeted agents. PMID- 25505210 TI - Comparison of pathologic stage in patients receiving esophagectomy with and without preoperative chemoradiation therapy for esophageal SCC. AB - The prognostic value for the post-chemoradiation therapy (CRT) pathologic stage is uncertain. The purpose of this study was to compare the pathologic stage in patients undergoing esophagectomy with and without preoperative CRT for esophageal squamous cell carcinoma (ESCC). This study retrospectively reviewed the data from 2151 patients with ESCC who underwent esophagectomy with or without preoperative CRT between 2008 and 2011 in Taiwan. Patients were divided into 2 groups. Group A consisted of patients treated with primary surgery without prior treatments (n=1301), and group B consisted of patients receiving preoperative CRT followed by esophagectomy (n=850). In group A, 679 patients received surgery alone, 92 received postoperative chemotherapy, 416 received postoperative chemoradiation therapy, and 114 received postoperative radiation therapy. In group A, the 3-year survival rates by pathologic stage were 82.2% for stage 0, 67.6% for stage I, 50.7% for stage II, 21.5% for stage III, and 14.8% for stage IV (P<.001). In group B, the 3-year survival rates of post-CRT pathologic stages 0, I, II, III, and IV were 59.4%, 46.0%, 40.3%, 19.1%, and 8.2%, respectively (P<.001). In multivariate analysis, the pathologic T, N, and M were all independent prognostic factors in both group A (esophagectomy alone) and B (CRT plus esophagectomy). The current, 7th edition of the esophageal TNM staging system could adequately stratify prognostic groups in patients with squamous cell carcinoma who were treated with preoperative CRT and esophagectomy. PMID- 25505212 TI - Management of anticoagulants in the periprocedural period for patients with cancer. AB - Patients with cancer undergo surgeries and procedures for various purposes, including prophylaxis, diagnosis, staging, cure, debulking, palliation, and reconstruction. The diagnosis of cancer itself, along with the well-established complication of venous thromboembolism (VTE), places these patients at risk for perioperative thromboembolism. It is also well-established that continuing patients on oral anticoagulation therapy during the periprocedural period is associated with an increased risk of bleeding. Rates of periprocedural VTE and major bleeding are significantly higher in patients with cancer, presenting a complex problem for clinicians in terms of periprocedural anticoagulation management. This article reviews the current recommendations regarding periprocedural anticoagulation management in patients with cancer. PMID- 25505211 TI - Analysis of recurrence patterns in acral versus nonacral melanoma: should histologic subtype influence treatment guidelines? AB - Current surgical treatment of primary melanoma is uniform for all histosubtypes, although certain types of melanoma, such as acral lentiginous melanoma (ALM), have a worse prognosis. No study has explored the effectiveness of standard melanoma treatment guidelines for managing ALM compared with nonacral melanoma (NAM). Study subjects were identified from a prospectively enrolled database of patients with primary melanoma at New York University. Patients with ALM were matched to those with NAM (1:3) by gender and melanoma stage, including substage (ALM, 61; NAM, 183). All patients received standard-of-care treatment. Recurrence and survival outcomes in both cohorts were compared. ALM histologic subtype was an independent negative predictor of recurrence-free survival (hazard ratio [HR], 2.24; P=.001) and melanoma-specific survival (HR, 2.58; P=.001) compared with NAM. Recurrence was significantly more common in patients with ALM than in those with NAM (49% vs 30%; P=.007). For tumors less than 2 mm in thickness, a significantly higher recurrence rate was seen with ALM versus NAM (P=.048). No significant difference was seen in recurrence for tumors greater than 2 mm (P=.12). Notably, the rate of locoregional recurrence was nearly double for ALM compared with NAM (P=.001). The data presented herein reveal a high rate of locoregional failure in ALM compared with NAM when controlling for AJCC stage. These results raise the question of whether ALM may require more aggressive surgical treatment than nonacral cutaneous melanomas of equal thickness, particularly in tumors less than 2 mm thick. Larger multicenter trials are necessary for further conclusions. PMID- 25505213 TI - Diet and physical activity in the prevention of colorectal cancer. AB - Diet has been linked to the prevention of colorectal cancer (CRC) and may explain some of the differences in incidence and mortality among various populations. Evidence suggests that a high intake of red and processed meats is associated with an increased risk of CRC. The protective benefits of fiber are unclear, although in some studies fiber is associated with reduced CRC risk. The role of supplements, such as calcium, vitamin D, and folic acid, remains uncertain, and these nutrients cannot be currently recommended for chemoprevention. Obesity and sedentary lifestyle have been associated with an increased risk for colon cancer. Because of the inherent difficulty in studying the effects of specific nutrients, dietary pattern analysis may be a preferable approach to the investigation of the relationship between diet and risk for human diseases. Lifestyle modifications, such as increasing physical activity and consumption of a diet rich in fiber, fruits, vegetables, fish, and poultry and low in red and processed meats, have been advocated for primary prevention of several chronic diseases, and may in fact be beneficial for cancer prevention, particularly CRC. PMID- 25505214 TI - Nanotechnologies in cancer treatment and diagnosis. AB - Despite significant efforts toward research and treatment development, cancer continues to be a major health problem in the United States that is only further enhanced by the heterogeneous nature of the disease. Nanotechnology has evolved as a technology with applications to medicine and the potential to improve clinical outcomes, with its application to cancer garnering much attention recently. In particular, through the generation of novel nanoscale devices and therapeutic platforms, nanotechnologies have emerged as innovative approaches that enable the detection and diagnosis of cancer at its earliest stages, and the delivery of anticancer drugs directly to tumors. This article highlights recent advances in the development of nanotechnologies for cancer therapeutics and diagnostics, and focuses on the potential future of cancer nanotechnology and the challenges this young field faces as it continues to move toward clinical translation. PMID- 25505215 TI - Non-small cell lung cancer, version 1.2015. AB - This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer (NSCLC) focuses on the principles of radiation therapy (RT), which include the following: (1) general principles for early-stage, locally advanced, and advanced/metastatic NSCLC; (2) target volumes, prescription doses, and normal tissue dose constraints for early-stage, locally advanced, and advanced/palliative RT; and (3) RT simulation, planning, and delivery. Treatment recommendations should be made by a multidisciplinary team, including board-certified radiation oncologists who perform lung cancer RT as a prominent part of their practice. PMID- 25505216 TI - The integration of early palliative care with oncology care: the time has come for a new tradition. AB - The past decade has brought forth innovative research that questions the traditional oncology care model for patients with advanced cancer. Through integrating palliative care (PC) early into the disease course for patients with a poor-prognosis cancer, 3 seminal studies showed improvements in outcomes, ranging from quality of life, mood, patient satisfaction, prognostic understanding, health service use, and possibly survival. The results of these paradigm-changing studies generate questions about the mechanisms through which early PC improves patient outcomes and about how best to disseminate early PC models. This article reviews the 3 studies, examines challenges to conducting PC research, and considers future directions in the field. PMID- 25505217 TI - Cancer survivorship: we've only just begun. PMID- 25505219 TI - Cortical Excitability During Passive Action Observation in Hospitalized Adults With Subacute Moderate to Severe Traumatic Brain Injury: A Preliminary TMS Study. AB - Studies indicate that motor functions in patients with traumatic brain injury (TBI) can be improved with action observation. It has been hypothesized that this clinical practice relies on modulation of motor cortical excitability elicited by passive action observation in patients with TBI, a phenomenon shown thus far only in normal controls. The purpose of this work was to test this hypothesis and characterize the modulation of motor cortex excitability during passive action observation in patients with subacute moderate to severe TBI. We measured motor evoked potentials induced by single-pulse transcranial magnetic stimulation to the left primary motor cortex and recorded from the contralateral first dorsal interosseus while 20 participants observed videos of static and moving right index finger. Results were compared with those of 20 age-and gender-matched healthy controls. As expected, greater excitability was elicited during moving than static stimuli in healthy subjects. However, this was not observed in patients with TBI. Modulation of motor excitability during action observation is impaired in patients with TBI depending on motor dysfunction, lesion site, and number of days postinjury. These preliminary results suggest a strategy to identify patients in whom action observation might be a valuable neurorehabilitative strategy. PMID- 25505220 TI - Spaced Noninvasive Brain Stimulation: Prospects for Inducing Long-Lasting Human Cortical Plasticity. AB - Neuroplasticity is critical for learning, memory, and recovery of lost function following neurological damage. Noninvasive brain stimulation (NIBS) techniques can induce neuroplastic changes in the human cortex that are behaviorally relevant, raising the exciting possibility that these techniques might be therapeutically beneficial for neurorehabilitation following brain injury. However, the short duration and instability of induced effects currently limits their usefulness. To date, trials investigating the therapeutic value of neuroplasticity-inducing NIBS have used either single or multiple treatment sessions, typically repeated once-daily for 1 to 2 weeks. Although multiple stimulation sessions are presumed to have cumulative effects on neuroplasticity induction, there is little direct scientific evidence to support this "once daily" approach. In animal models, the repeated application of stimulation protocols spaced using relatively short intervals (typically of the order of minutes) induces long-lasting and stable changes in synaptic efficacy. Likewise, learning through spaced repetition facilitates the establishment of long-term memory. In both cases, the spacing interval is critical in determining the outcome. Emerging evidence in healthy human populations suggests that the within session spacing of NIBS protocols may be an effective approach for significantly prolonging the duration of induced neuroplastic changes. Similar to findings in the animal and learning literature, the interval at which spaced NIBS is applied seems to be a critical factor influencing the neuroplastic response. In this Point of View article, we propose that to truly exploit the therapeutic opportunities provided by NIBS, future clinical trials should consider the optimal spacing interval for repeated applications. PMID- 25505221 TI - Strategy Training Shows Promise for Addressing Disability in the First 6 Months After Stroke. AB - BACKGROUND: Cognitive impairments occur frequently after stroke and contribute to significant disability. Strategy training shows promise but has not been examined in the acute phase of recovery. OBJECTIVE: We conducted a single-blind randomized pilot study estimating the effect of strategy training, relative to reflective listening (attention control), for reducing disability and executive cognitive impairments. METHODS: Thirty participants with acute stroke who were enrolled in inpatient rehabilitation and had cognitive impairments were randomized to receive strategy training (n = 15, 10 sessions as adjunct to usual inpatient rehabilitation) or reflective listening (n = 15, same dose). The Functional Independence Measure assessed disability at baseline, rehabilitation discharge, 3, and 6 months. The Color Word Interference Test of the Delis-Kaplan Executive Function System assessed selected executive cognitive impairments (inhibition, flexibility) at baseline, 3, and 6 months. RESULTS: Changes in Functional Independence Measure scores for the 2 groups over 6 months showed significant effects of group (F1,27 = 9.25, P = .005), time (F3,74 = 96.00, P < .001), and group * time interactions (F3,74 = 4.37, P < .007) after controlling for baseline differences in stroke severity (F1,27 = 6.74, P = .015). Color Word Interference Inhibition scores showed significant effects of group (F1,26 = 6.50, P = .017) and time (F2,34 = 4.74, P = .015), but the group * time interaction was not significant (F2,34 = 2.55, P = .093). Color Word Interference Cognitive Flexibility scores showed significant effects of group (F1,26 = 23.41, P < .001), time (F2,34 = 12.77, P < .001), and group * time interactions (F2,34 = 7.83, P < .002). Interaction effects suggested greater improvements were associated with strategy training. CONCLUSIONS: Strategy training shows promise for addressing disability in the first 6 months after stroke. Lessons from this pilot study may inform future clinical trials. PMID- 25505222 TI - Daily Electrical Muscle Stimulation Enhances Functional Recovery Following Nerve Transection and Repair in Rats. AB - BACKGROUND: Incomplete recovery following surgical reconstruction of damaged peripheral nerves is common. Electrical muscle stimulation (EMS) to improve functional outcomes has not been effective in previous studies. OBJECTIVE: To evaluate the efficacy of a new, clinically translatable EMS paradigm over a 3 month period following nerve transection and immediate repair. METHODS: Rats were divided into 6 groups based on treatment (EMS or no treatment) and duration (1, 2, or 3 months). A tibial nerve transection injury was immediately repaired with 2 epineurial sutures. The right gastrocnemius muscle in all rats was implanted with intramuscular electrodes. In the EMS group, the muscle was electrically stimulated with 600 contractions per day, 5 days a week. Terminal measurements were made after 1, 2, or 3 months. Rats in the 3-month group were assessed weekly using skilled and overground locomotion tests. Neuromuscular junction reinnervation patterns were also examined. RESULTS: Muscles that received daily EMS had significantly greater numbers of reinnervated motor units with smaller average motor unit sizes. The majority of muscle endplates were reinnervated by a single axon arising from a nerve trunk with significantly fewer numbers of terminal sprouts in the EMS group, the numbers being small. Muscle mass and force were unchanged but EMS improved behavioral outcomes. CONCLUSIONS: Our results demonstrated that EMS using a moderate stimulation paradigm immediately following nerve transection and repair enhances electrophysiological and behavioral recovery. PMID- 25505223 TI - Generalizability of the Proportional Recovery Model for the Upper Extremity After an Ischemic Stroke. AB - BACKGROUND AND OBJECTIVE: Spontaneous neurological recovery after stroke is a poorly understood process. The aim of the present article was to test the proportional recovery model for the upper extremity poststroke and to identify clinical characteristics of patients who do not fit this model. METHODS: A change in the Fugl-Meyer Assessment Upper Extremity score (FMA-UE) measured within 72 hours and at 6 months poststroke served to define motor recovery. Recovery on FMA UE was predicted using the proportional recovery model: DeltaFMA-UEpredicted = 0.7.(66 - FMA-UEinitial) + 0.4. Hierarchical cluster analysis on 211 patients was used to separate nonfitters (outliers) from fitters, and differences between these groups were studied using clinical determinants measured within 72 hours poststroke. Subsequent logistic regression analysis served to predict patients who may not fit the model. RESULTS: The majority of patients (~70%; n = 146) showed a fixed proportional upper extremity motor recovery of about 78%; 65 patients had substantially less improvement than predicted. These nonfitters had more severe neurological impairments within 72 hours poststroke (P values <.01). Logistic regression analysis revealed that absence of finger extension, presence of facial palsy, more severe lower extremity paresis, and more severe type of stroke as defined by the Bamford classification were significant predictors of not fitting the proportional recovery model. CONCLUSIONS: These results confirm in an independent sample that stroke patients with mild to moderate initial impairments show an almost fixed proportional upper extremity motor recovery. Patients who will most likely not achieve the predicted amount of recovery were identified using clinical determinants measured within 72 hours poststroke. PMID- 25505225 TI - The value of ADC, T2 signal intensity, and a combination of both parameters to assess Gleason score and primary Gleason grades in patients with known prostate cancer. AB - BACKGROUND: The ability to non-invasively analyze tumor aggressiveness is an important predictor for individual treatment stratification and patient outcome in prostate cancer (PCA). PURPOSE: To evaluate: (i) whether apparent diffusion coefficient (ADC), the T2 signal intensity (SI), and a combination of both parameters allow for an improved discrimination of Gleason Score (GS) >=7 (intermediate and high risk) and GS <7 (low risk) in PCA; and (ii) whether ADC may distinguish between 3 + 4 and 4 + 3 PCA (primary Gleason grades [pGG]). MATERIAL AND METHODS: Prostatectomy specimens of 66 patients (mean age, 63 +/- 5.6 years; 104 PCA foci) with a preceding multiparametric 1.5 T endorectal coil magnetic resonance imaging (MRI) were included. ADC (b values = 0, 100, 400, 800 s/mm(2)), standardized T2 (T2s), and the ADC/T2s ratio were tested for correlation with GS applying multivariate analysis. ADC cutoff values were calculated for prediction of GS and pGG, and logarithm of the odds (LOGIT) was used to express the probability for GS and pGG. Diagnostic accuracy was assessed by ROC analysis. RESULTS: We found an almost linear negative relationship of ADC for GS >=7 (P = 0.002). The effect of ADC for GS >=7 (adjusted odds ratio = 0.995) was almost identical for peripheral and transition zone PCA (P = 0.013 and P < 0.001, respectively). ADC showed an AUC of 78.9% for discrimination between GS <7 and GS >=7. An ADC cutoff of <1.005 * 10(-3 )mm(2)/s indicated a GS >=7 (90.5% sensitivity, 62.5% specificity). Within the group of GS = 7 PCA, an ADC > 0.762 * 10(-3 )mm(2)/s indicated a pGG of 3 (AUC = 69.6%). CONCLUSION: T2s and the ADC/T2s ratio do not provide additional information regarding prediction of GS. ADC values have a good discriminatory power to distinguish tumors with GS >=7 from GS <7 and to predict pGG in GS = 7 PCA. PMID- 25505224 TI - High sensitivity-troponin elevation secondary to non-coronary diagnoses and death and recurrent myocardial infarction: An examination against criteria of causality. AB - BACKGROUND: Myonecrosis provoked by illness unrelated to unstable coronary plaque is common, but uncertainty about a cause-effect relationship with future events challenges the appropriateness of initiating therapies known to be effective in cardiac conditions. We examined the causal relationship between troponin elevation in non-coronary diagnoses and late cardiac events using the Bradford Hills criteria for causality. METHODS AND RESULTS: Patients presenting acutely to South Australian public hospitals receiving at least one troponin between September 2011-September 2012 were included. Diagnoses were classified as coronary, non-coronary cardiac and non-cardiac using the International Classification of Diseases, version 10 Australian Modified, codes. The relationship between peak in-hospital troponin, using a high-sensitivity troponin T assay and adjudicated cardiac and non-cardiac mortality, and subsequent myocardial infarction (MI) was assessed using competing-risk flexible parametric survival models. Troponin results were available for 38,161 patients of whom, 12,645 (33.6%), 3237 (8.5%), and 22,079 (57.9%) patients were discharged with coronary, non-coronary cardiac and non-cardiac diagnoses, respectively. Troponin >14 ng/l was observed in 43.6%. The relationship between troponin and cardiac mortality was stronger among the non-coronary diagnosis group (troponin 1000 ng/l: coronary hazard ratio: 5.1 (95% confidence interval (CI) 4.0-6.6) vs non coronary hazard ratio: 16.3 (95% CI 12.6-22.4)). The temporal hazard for cardiac death was marked within 30 days in both groups. Among non-coronary diagnoses, the hazard for recurrent MI was higher but did not vary with time. CONCLUSIONS: Consistency with causal criteria between secondary myonecrosis and cardiac events suggest the potential benefit for extending cardiac specific interventions to this population if supported in trials appropriately designed to address competing risks. Troponin elevation precipitated by non-coronary events is common and demonstrates an associations with late mortality that are analogous to spontaneous MI resulting from unstable coronary plaque. These observations help inform the design of randomized clinical trials exploring the benefits and risk of therapies with established benefits in other cardiac conditions. Such studies will need to appropriately account for competing risks in this population of patients. PMID- 25505226 TI - Diagnostic accuracy of saline infusion sonography in the evaluation of uterine cavity abnormalities prior to assisted reproductive techniques: a systematic review and meta-analyses. AB - BACKGROUND: The diagnostic accuracy of a 2-D transvaginal scan, which is commonly employed to evaluate the regularity and shape of the uterine cavity in subfertile women, is relatively poor compared with other diagnostic modalities like saline infusion sonography (SIS) or hysteroscopy. SIS is a minimally invasive, cost effective and acceptable diagnostic modality. Therefore the aim of this systematic review was to assess the diagnostic accuracy of SIS in the evaluation of the uterine cavity in subfertile women. METHODS: A systematic review was conducted of diagnostic studies that compared SIS with hysteroscopy. Twenty relevant studies (including 1645 procedures) were identified and a subsequent meta-analysis was performed. Electronic databases were searched for relevant studies and references of relevant studies were cross checked. Validity was assessed and data were extracted independently by two authors. Heterogeneity was examined, studies were plotted in an ROC area and data were pooled. The main outcome measure was the diagnostic accuracy of saline infusion sonography. The pooled sensitivity, specificity, likelihood ratios and the post-test probabilities of saline infusion sonography on the prediction of uterine cavity abnormalities were calculated. RESULTS: The pooled sensitivity of SIS in the detection of all intrauterine abnormalities was 0.88 (95% confidence interval (CI): 0.85-0.90). The pooled specificity was 0.94 (95% CI 0.93-0.96). The positive and negative likelihood ratios were 20.93 (95% CI: 9.06-48.34) and 0.15 (95% CI: 0.10-0.22), respectively. SIS had good accuracy in the detection of all intrauterine abnormalities (area under the summary receiver operating curve (sROC) = 0.97 +/- 0.01). SIS also had a high pooled sensitivity and specificity in the detection of congenital uterine anomalies, 0.85 (95% CI: 0.79-0.90) and 1.00 (95% CI 0.99-1.00), respectively. However the limitations of the review include the heterogeneity amongst the included studies. CONCLUSIONS: SIS is a highly sensitive investigative modality and comparable to the gold standard tool, hysteroscopy in the detection of intrauterine abnormalities in subfertile women. SIS is a highly sensitive and specific test in the diagnosis of uterine polyps, submucous myomas, uterine anomalies and intrauterine adhesions and can be used as a screening tool for subfertile patients prior to IVF treatment. PMID- 25505227 TI - Selenium supplementation and prostate cancer mortality. AB - BACKGROUND: Few studies have evaluated the relation between selenium supplementation after diagnosis and prostate cancer outcomes. METHODS: We prospectively followed 4459 men initially diagnosed with nonmetastatic prostate cancer in the Health Professionals Follow-Up Study from 1988 through 2010 and examined whether selenium supplement use (from selenium-specific supplements and multivitamins) after diagnosis was associated with risk of biochemical recurrence, prostate cancer mortality, and, secondarily, cardiovascular disease mortality and overall mortality, using Cox proportional hazards models. All P values were from two-sided tests. RESULTS: We documented 965 deaths, 226 (23.4%) because of prostate cancer and 267 (27.7%) because of cardiovascular disease, during a median follow-up of 8.9 years. In the biochemical recurrence analysis, we documented 762 recurrences during a median follow-up of 7.8 years. Crude rates per 1000 person-years for prostate cancer death were 5.6 among selenium nonusers and 10.5 among men who consumed 140 or more MUg/day. Crude rates per 1000 person years were 28.2 vs 23.5 for all-cause mortality and 28.4 vs 29.3 for biochemical recurrence, for nonuse vs highest-dose categories, respectively. In multivariable analyses, men who consumed 1 to 24 MUg/day, 25 to 139 MUg/day, and 140 or more MUg/day of supplemental selenium had a 1.18 (95% confidence interval [CI] = 0.73 to 1.91), 1.33 (95% CI = 0.77 to 2.30), and 2.60-fold (95% CI = 1.44 to 4.70) greater risk of prostate cancer mortality compared with nonusers, respectively, P trend = .001. There was no statistically significant association between selenium supplement use and biochemical recurrence, cardiovascular disease mortality, or overall mortality. CONCLUSION: Selenium supplementation of 140 or more MUg/day after diagnosis of nonmetastatic prostate cancer may increase risk of prostate cancer mortality. Caution is warranted regarding usage of such supplements among men with prostate cancer. PMID- 25505229 TI - Learning from history in micronutrient research. PMID- 25505228 TI - Dietary folate intake and breast cancer risk: European prospective investigation into cancer and nutrition. AB - BACKGROUND: There is limited evidence on the association between dietary folate intake and the risk of breast cancer (BC) by hormone receptor expression in the tumors. We investigated the relationship between dietary folate and BC risk using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: A total of 367993 women age 35 to 70 years were recruited in 10 European countries. During a median follow-up of 11.5 years, 11575 women with BC were identified. Dietary folate intake was estimated from country-specific dietary questionnaires. Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk. BC tumors were classified by receptor status. Subgroup analyses were performed by menopausal status and alcohol intake. Intake of other B vitamins was considered. All statistical tests were two-sided. RESULTS: A borderline inverse association was observed between dietary folate and BC risk (hazard ratio comparing top vs bottom quintile [HRQ5-Q1] = 0.92, 95% CI = 0.83 to 1.01, P trend = .037). In premenopausal women, we observed a statistically significant trend towards lower risk in estrogen receptor-negative BC (HRQ5-Q1 = 0.66, 95% CI = 0.45 to 0.96, P trend = .042) and progesterone receptor-negative BC (HRQ5-Q1 = 0.70, 95% CI = 0.51 to 0.97, P trend = .021). No associations were found in postmenopausal women. A 14% reduction in BC risk was observed when comparing the highest with the lowest dietary folate tertiles in women having a high (>12 alcoholic drinks/week) alcohol intake (HRT3-T1 = 0.86, 95% CI = 0.75 to 0.98, P interaction = .035). CONCLUSIONS: Higher dietary folate intake may be associated with a lower risk of sex hormone receptor-negative BC in premenopausal women. PMID- 25505230 TI - Prognostic significance of POLE proofreading mutations in endometrial cancer. AB - BACKGROUND: Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis. METHODS: We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two sided. RESULTS: POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC 1 and-2 and were associated with high tumor grade (P < .001). Women with POLE mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06). CONCLUSION: POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC. PMID- 25505231 TI - Migraine and breast cancer risk: a prospective cohort study and meta-analysis. AB - BACKGROUND: The evidence for an association between migraine and breast cancer risk is inconclusive. While female sex hormones have been proposed as one underlying mechanism, data on sex hormone levels in migraineurs are sparse. METHODS: We prospectively evaluated the association between migraine and breast cancer risk among 115378 Nurses' Health Study II participants using Cox proportional hazards models. Differences in endogenous sex hormone levels according to migraine status were assessed among 2034 premenopausal women using linear regression. We performed a meta-analysis of studies investigating the association between migraine and invasive breast cancer risk published through October 2013. All statistical tests were two-sided. RESULTS: Seventeen thousand six hundred ninety-six women (15.3%) reported a physician's diagnosis of migraine at baseline. Over 20 years of follow-up, 833 in situ and 3091 invasive breast malignancies occurred. Migraine was not associated with total (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.88 to 1.04), in situ (HR = 0.97, 95% CI = 0.82 to 1.15), or invasive breast cancer risk (HR = 0.95, 95% CI = 0.87 to 1.04). Endogenous sex hormone levels did not differ according to migraine status. In the meta-analysis, migraine was associated with a lower risk of breast cancer overall (pooled risk ratio [RR] = 0.84, 95% CI = 0.73 to 0.98). However, this inverse association was apparent only among case-control studies (pooled RR = 0.72, 95% CI = 0.66 to 0.79), and not among cohort studies (pooled RR = 0.98, 95% CI = 0.87 to 1.10). CONCLUSION: In this large cohort study, migraine was not associated with breast cancer risk or differences in endogenous sex hormone levels. While case-control studies suggest an inverse association between migraine and breast cancer risk, prospective cohort studies do not support an association in pooled analyses. PMID- 25505237 TI - Effect of nasopharyngeal carcinoma-derived exosomes on human regulatory T cells. AB - BACKGROUND: Regulatory T cells (Treg) and tumor-exosomes are thought to play a role in preventing the rejection of malignant cells in patients bearing nasopharyngeal carcinoma (NPC). METHODS: Treg recruitment by exosomes derived from NPC cell lines (C15/C17-Exo), exosomes isolated from NPC patients' plasma (Patient-Exo), and CCL20 were tested in vitro using Boyden chamber assays and in vivo using a xenograft SCID mouse model (n = 5), both in the presence and absence of anti-CCL20 monoclonal antibodies (mAb). Impact of these NPC exosomes (NPC-Exo) on Treg phenotype and function was determined using adapted assays (FACS, Q-PCR, ELISA, and MLR). Experiments were performed in comparison with exosomes derived from plasma of healthy donors (HD-Exo). The Student's t test was used for group comparisons. All statistical tests were two-sided. RESULTS: CCL20 allowed the intratumoral recruitment of human Treg. NPC-Exo also facilitated Treg recruitment (3.30 +/- 0.34 fold increase, P < .001), which was statistically significantly inhibited (P < .001) by an anti-CCL20 blocking mAb. NPC-Exo also recruited conventional CD4(+)CD25(-) T cells and mediated their conversion into inhibitory CD4(+)CD25(high) cells. Moreover, NPC-Exo enhanced (P = .0048) the expansion of human Treg, inducing the generation of Tim3(Low) Treg with increased expression of CD25 and FOXP3. Finally, NPC-Exo induced an overexpression of cell markers associated with Treg phenotype, properties and recruitment capacity. For example, GZMB mean fold change was 21.45 +/- 1.75 (P < .001). These results were consistent with a stronger suppression of responder cells' proliferation and the secretion of immunosuppressive cytokines (IL10, TGFB1). CONCLUSION: Interactions between NPC-Exo and Treg represent a newly defined mechanism that may be involved in regulating peripheral tolerance by tumors and in supporting immune evasion in human NPC. PMID- 25505238 TI - Cost-effectiveness of prostate cancer screening: a simulation study based on ERSPC data. AB - BACKGROUND: The results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial showed a statistically significant 29% prostate cancer mortality reduction for the men screened in the intervention arm and a 23% negative impact on the life-years gained because of quality of life. However, alternative prostate-specific antigen (PSA) screening strategies for the population may exist, optimizing the effects on mortality reduction, quality of life, overdiagnosis, and costs. METHODS: Based on data of the ERSPC trial, we predicted the numbers of prostate cancers diagnosed, prostate cancer deaths averted, life-years and quality-adjusted life-years (QALY) gained, and cost effectiveness of 68 screening strategies starting at age 55 years, with a PSA threshold of 3, using microsimulation modeling. The screening strategies varied by age to stop screening and screening interval (one to 14 years or once in a lifetime screens), and therefore number of tests. RESULTS: Screening at short intervals of three years or less was more cost-effective than using longer intervals. Screening at ages 55 to 59 years with two-year intervals had an incremental cost-effectiveness ratio of $73000 per QALY gained and was considered optimal. With this strategy, lifetime prostate cancer mortality reduction was predicted as 13%, and 33% of the screen-detected cancers were overdiagnosed. When better quality of life for the post-treatment period could be achieved, an older age of 65 to 72 years for ending screening was obtained. CONCLUSION: Prostate cancer screening can be cost-effective when it is limited to two or three screens between ages 55 to 59 years. Screening above age 63 years is less cost-effective because of loss of QALYs because of overdiagnosis. PMID- 25505239 TI - Sphingolipid pathway regulates innate immune responses at the fetomaternal interface during pregnancy. AB - For a successful pregnancy, the mother's immune system has to tolerate the semiallogeneic fetus. A deleterious immune attack is avoided by orchestration of cellular, hormonal, and enzymatic factors. However, the precise mechanisms underlying fetomaternal tolerance are not yet completely understood. In this study, we demonstrate that sphingolipid metabolism constitutes a novel signaling pathway that is indispensable for fetomaternal tolerance by regulating innate immune responses at the fetomaternal interface. Perturbation of the sphingolipid pathway by disruption of the sphingosine kinase gene (Sphk) during pregnancy caused unusually high expression of neutrophil chemoattractants, CXCL1 and CXCL2, in the decidua, leading to a massive infiltration of neutrophils into the fetomaternal interface with enhanced oxidative damage, resulting in early fetal death. Sphk-deficient mice also exhibited neutrophilia in the peripheral blood, enhanced generation of granulocytes in the bone marrow, and a decrease in the number of decidual natural killer cells. The blockage of neutrophil influx protected Sphk-deficient mice against pregnancy loss. Notably, a similar result was obtained in human decidual cells, in which Sphk deficiency dramatically increased the secretion of CXCL1 and IL-8. In conclusion, our findings suggest that the sphingolipid metabolic pathway plays a critical role in fetomaternal tolerance by regulating innate immunity at the fetomaternal interface both in mice and humans, and it could provide novel insight into the development of therapeutic strategies to treat idiopathic pregnancy loss in humans. PMID- 25505240 TI - MicroRNA-181b regulates ALX/FPR2 receptor expression and proresolution signaling in human macrophages. AB - Regulatory mechanisms of ALX/FPR2, the lipoxin A4 receptor, expression have considerable relevance in inflammation resolution. Because microRNAs (miRs) are emerging as key players in inflammation resolution, here we examined microRNA mediated regulation of ALX/FPR2 (lipoxin A4 receptor/formyl peptide receptor 2) expression. By matching data from bioinformatic algorithms, we found 27 miRs predicted to bind the 3'-UTR of ALX/FPR2. Among these, we selected miR-181b because of its link with inflammation. Using a luciferase reporter system, we assessed miR-181b binding to ALX/FPR2 3'-UTR. Consistent with this, miR-181b overexpression in human macrophages significantly down-regulated ALX/FPR2 protein levels (-25%), whereas miR-181b knockdown gave a significant increase in ALX/FPR2 (+60%). miR-181b levels decreased during monocyte to macrophage differentiation ( 50%), whereas ALX/FPR2 expression increased significantly (+60%). miR-181b overexpression blunted lipoxin A4 (0.1-10 nm)- and resolvin D1 (0.01-10 nm) stimulated phagocytic activity of macrophages. These results unravel novel regulatory mechanisms of ALX/FPR2 expression and ligand-evoked macrophages proresolution responses mediated by miR-181b, thus uncovering novel components of the endogenous inflammation resolution circuits. PMID- 25505241 TI - The PDZ motif of the alpha1C subunit is not required for surface trafficking and adrenergic modulation of CaV1.2 channel in the heart. AB - Voltage-gated Ca(2+) channels play a key role in initiating muscle excitation contraction coupling, neurotransmitter release, gene expression, and hormone secretion. The association of CaV1.2 with a supramolecular complex impacts trafficking, localization, turnover, and, most importantly, multifaceted regulation of its function in the heart. Several studies hint at an important role for the C terminus of the alpha1C subunit as a hub for multidimensional regulation of CaV1.2 channel trafficking and function. Recent studies have demonstrated an important role for the four-residue PDZ binding motif at the C terminus of alpha1C in interacting with scaffold proteins containing PDZ domains, in the subcellular localization of CaV1.2 in neurons, and in the efficient signaling to cAMP-response element-binding protein in neurons. However, the role of the alpha1C PDZ ligand domain in the heart is not known. To determine whether the alpha1C PDZ motif is critical for CaV1.2 trafficking and function in cardiomyocytes, we generated transgenic mice with inducible expression of an N terminal FLAG epitope-tagged dihydropyridine-resistant alpha1C with the PDZ motif deleted (DeltaPDZ). These mice were crossed with alpha-myosin heavy chain reverse transcriptional transactivator transgenic mice, and the double-transgenic mice were fed doxycycline. The DeltaPDZ channels expressed, trafficked to the membrane, and supported robust excitation-contraction coupling in the presence of nisoldipine, a dihydropyridine Ca(2+) channel blocker, providing functional evidence that they appropriately target to dyads. The DeltaPDZ Ca(2+) channels were appropriately regulated by isoproterenol and forskolin. These data indicate that the alpha1C PDZ motif is not required for surface trafficking, localization to the dyad, or adrenergic stimulation of CaV1.2 in adult cardiomyocytes. PMID- 25505242 TI - Microtubule-associated proteins 1 (MAP1) promote human immunodeficiency virus type I (HIV-1) intracytoplasmic routing to the nucleus. AB - After cell entry, HIV undergoes rapid transport toward the nucleus using microtubules and microfilaments. Neither the cellular cytoplasmic components nor the viral proteins that interact to mediate transport have yet been identified. Using a yeast two-hybrid screen, we identified four cytoskeletal components as putative interaction partners for HIV-1 p24 capsid protein: MAP1A, MAP1S, CKAP1, and WIRE. Depletion of MAP1A/MAP1S in indicator cell lines and primary human macrophages led to a profound reduction in HIV-1 infectivity as a result of impaired retrograde trafficking, demonstrated by a characteristic accumulation of capsids away from the nuclear membrane, and an overall defect in nuclear import. MAP1A/MAP1S did not impact microtubule network integrity or cell morphology but contributed to microtubule stabilization, which was shown previously to facilitate infection. In addition, we found that MAP1 proteins interact with HIV 1 cores both in vitro and in infected cells and that interaction involves MAP1 light chain LC2. Depletion of MAP1 proteins reduced the association of HIV-1 capsids with both dynamic and stable microtubules, suggesting that MAP1 proteins help tether incoming viral capsids to the microtubular network, thus promoting cytoplasmic trafficking. This work shows for the first time that following entry into target cells, HIV-1 interacts with the cytoskeleton via its p24 capsid protein. Moreover, our results support a role for MAP1 proteins in promoting efficient retrograde trafficking of HIV-1 by stimulating the formation of stable microtubules and mediating the association of HIV-1 cores with microtubules. PMID- 25505243 TI - Heart mitochondrial TTP synthesis and the compartmentalization of TMP. AB - The primary pathway of TTP synthesis in the heart requires thymidine salvage by mitochondrial thymidine kinase 2 (TK2). However, the compartmentalization of this pathway and the transport of thymidine nucleotides are not well understood. We investigated the metabolism of [(3)H]thymidine or [(3)H]TMP as precursors of [(3)H]TTP in isolated intact or broken mitochondria from the rat heart. The results demonstrated that [(3)H]thymidine was readily metabolized by the mitochondrial salvage enzymes to TTP in intact mitochondria. The equivalent addition of [(3)H]TMP produced far less [(3)H]TTP than the amount observed with [(3)H]thymidine as the precursor. Using zidovudine to inhibit TK2, the synthesis of [(3)H]TTP from [(3)H]TMP was effectively blocked, demonstrating that synthesis of [(3)H]TTP from [(3)H]TMP arose solely from the dephosphorysynthase pathway that includes deoxyuridine triphosphatelation of [(3)H]TMP to [(3)H]thymidine. To determine the role of the membrane in TMP metabolism, mitochondrial membranes were disrupted by freezing and thawing. In broken mitochondria, [(3)H]thymidine was readily converted to [(3)H]TMP, but further phosphorylation was prevented even though the energy charge was well maintained by addition of oligomycin A, phosphocreatine, and creatine phosphokinase. The failure to synthesize TTP in broken mitochondria was not related to a loss of membrane potential or inhibition of the electron transport chain, as confirmed by addition of carbonyl cyanide 4 (trifluoromethoxy) phenylhydrazone and potassium cyanide, respectively, in intact mitochondria. In summary, these data, taken together, suggest that the thymidine salvage pathway is compartmentalized so that TMP kinase prefers TMP synthesized by TK2 over medium TMP and that this is disrupted in broken mitochondria. PMID- 25505244 TI - Site-directed mutagenesis reveals regions implicated in the stability and fiber formation of human lambda3r light chains. AB - Light chain amyloidosis (AL) is a disease that affects vital organs by the fibrillar aggregation of monoclonal light chains. lambda3r germ line is significantly implicated in this disease. In this work, we contrasted the thermodynamic stability and aggregation propensity of 3mJL2 (nonamyloidogenic) and 3rJL2 (amyloidogenic) lambda3 germ lines. Because of an inherent limitation (extremely low expression), Cys at position 34 of the 3r germ line was replaced by Tyr reaching a good expression yield. A second substitution (W91A) was introduced in 3r to obtain a better template to incorporate additional mutations. Although the single mutant (C34Y) was not fibrillogenic, the second mutation located at CDR3 (W91A) induced fibrillogenesis. We propose, for the first time, that CDR3 (position 91) affects the stability and fiber formation of human lambda3r light chains. Using the double mutant (3rJL2/YA) as template, other variants were constructed to evaluate the importance of those substitutions into the stability and aggregation propensity of lambda3 light chains. A change in position 7 (P7D) boosted 3rJL2/YA fibrillogenic properties. Modification of position 48 (I48M) partially reverted 3rJL2/YA fibril aggregation. Finally, changes at positions 8 (P8S) or 40 (P40S) completely reverted fibril formation. These results confirm the influential roles of N-terminal region (positions 7 and 8) and the loop 40-60 (positions 40 and 48) on AL. X-ray crystallography revealed that the three-dimensional topology of the single and double lambda3r mutants was not significantly altered. This mutagenic approach helped to identify key regions implicated in lambda3 AL. PMID- 25505245 TI - Analysis of mucolipidosis II/III GNPTAB missense mutations identifies domains of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase involved in catalytic function and lysosomal enzyme recognition. AB - UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase tags newly synthesized lysosomal enzymes with mannose 6-phosphate recognition markers, which are required for their targeting to the endolysosomal system. GNPTAB encodes the alpha and beta subunits of GlcNAc-1-phosphotransferase, and mutations in this gene cause the lysosomal storage disorders mucolipidosis II and III alphabeta. Prior investigation of missense mutations in GNPTAB uncovered amino acids in the N-terminal region and within the DMAP domain involved in Golgi retention of GlcNAc-1-phosphotransferase and its ability to specifically recognize lysosomal hydrolases, respectively. Here, we undertook a comprehensive analysis of the remaining missense mutations in GNPTAB reported in mucolipidosis II and III alphabeta patients using cell- and zebrafish-based approaches. We show that the Stealth domain harbors the catalytic site, as some mutations in these regions greatly impaired the activity of the enzyme without affecting its Golgi localization and proteolytic processing. We also demonstrate a role for the Notch repeat 1 in lysosomal hydrolase recognition, as missense mutations in conserved cysteine residues in this domain do not affect the catalytic activity but impair mannose phosphorylation of certain lysosomal hydrolases. Rescue experiments using mRNA bearing Notch repeat 1 mutations in GNPTAB-deficient zebrafish revealed selective effects on hydrolase recognition that differ from the DMAP mutation. Finally, the mutant R587P, located in the spacer between Notch 2 and DMAP, was partially rescued by overexpression of the gamma subunit, suggesting a role for this region in gamma subunit binding. These studies provide new insight into the functions of the different domains of the alpha and beta subunits. PMID- 25505246 TI - MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins. AB - We have previously reported 27 differentially expressed microRNAs (miRNAs) during human monocyte differentiation into immature dendritic cells (imDCs) and mature DCs (mDCs). However, their roles in DC differentiation and function remain largely elusive. Here, we report that microRNA (miR)-146a and miR-146b modulate DC apoptosis and cytokine production. Expression of miR-146a and miR-146b was significantly increased upon monocyte differentiation into imDCs and mDCs. Silencing of miR-146a and/or miR-146b in imDCs and mDCs significantly prevented DC apoptosis, whereas overexpressing miR-146a and/or miR-146b increased DC apoptosis. miR-146a and miR-146b expression in imDCs and mDCs was inversely correlated with TRAF6 and IRAK1 expression. Furthermore, siRNA silencing of TRAF6 and/or IRAK1 in imDCs and mDCs enhanced DC apoptosis. By contrast, lentivirus overexpression of TRAF6 and/or IRAK1 promoted DC survival. Moreover, silencing of miR-146a and miR-146b expression had little effect on DC maturation but enhanced IL-12p70, IL-6, and TNF-alpha production as well as IFN-gamma production by IL 12p70-mediated activation of natural killer cells, whereas miR-146a and miR-146b overexpression in mDCs reduced cytokine production. Silencing of miR-146a and miR 146b in DCs also down-regulated NF-kappaB inhibitor IkappaBalpha and increased Bcl-2 expression. Our results identify a new negative feedback mechanism involving the miR-146a/b-TRAF6/IRAK1-NF-kappaB axis in promoting DC apoptosis. PMID- 25505247 TI - Biophysical studies on interactions and assembly of full-size E3 ubiquitin ligase: suppressor of cytokine signaling 2 (SOCS2)-elongin BC-cullin 5-ring box protein 2 (RBX2). AB - The multisubunit cullin RING E3 ubiquitin ligases (CRLs) target post translationally modified substrates for ubiquitination and proteasomal degradation. The suppressors of cytokine signaling (SOCS) proteins play important roles in inflammatory processes, diabetes, and cancer and therefore represent attractive targets for therapeutic intervention. The SOCS proteins, among their other functions, serve as substrate receptors of CRL5 complexes. A member of the CRL family, SOCS2-EloBC-Cul5-Rbx2 (CRL5(SOCS2)), binds phosphorylated growth hormone receptor as its main substrate. Here, we demonstrate that the components of CRL5(SOCS2) can be specifically pulled from K562 human cell lysates using beads decorated with phosphorylated growth hormone receptor peptides. Subsequently, SOCS2-EloBC and full-length Cul5-Rbx2, recombinantly expressed in Escherichia coli and in Sf21 insect cells, respectively, were used to reconstitute neddylated and unneddylated CRL5(SOCS2) complexes in vitro. Finally, diverse biophysical methods were employed to study the assembly and interactions within the complexes. Unlike other E3 ligases, CRL5(SOCS2) was found to exist in a monomeric state as confirmed by size exclusion chromatography with inline multiangle static light scattering and native MS. Affinities of the protein protein interactions within the multisubunit complex were measured by isothermal titration calorimetry. A structural model for full-size neddylated and unneddylated CRL5(SOCS2) complexes is supported by traveling wave ion mobility mass spectrometry data. PMID- 25505249 TI - The unexpected evolution of basic science studies about cyclic nucleotide action into a treatment for erectile dysfunction. AB - In these Reflections, I describe my perceived role in discoveries made in the cyclic nucleotide field that culminated in the advent of PDE5 inhibitors that treat erectile dysfunction, such as Viagra, Levitra, and Cialis. The discoveries emphasize the critical role of basic science, which often evolves in unpredictable and circuitous paths, in improving human health. PMID- 25505248 TI - Amitriptyline improves motor function via enhanced neurotrophin signaling and mitochondrial functions in the murine N171-82Q Huntington disease model. AB - Huntington disease (HD) is a neurodegenerative disorder characterized by progressive motor impairment and cognitive alterations. Hereditary HD is primarily caused by the expansion of a CAG trinucleotide repeat in the huntingtin (Htt) gene, which results in the production of mutant huntingtin protein (mHTT) with an expanded amino-terminal polyglutamine (poly(Q)) stretch. Besides pathological mHTT aggregation, reduced brain-derived neurotrophic factor (BDNF) levels, impaired neurotrophin signaling, and compromised mitochondrial functions also contribute to the deleterious progressive etiology of HD. As a well tolerated Food and Drug Administration-approved antidepressant, amitriptyline (AMI) has shown efficacy in treating neurodegenerative murine models via potentiation of BDNF levels and amelioration of alterations in neurotrophin signaling pathways. In this study, we observed profound improvements in the motor coordination of AMI-treated N171-82Q HD model mice. The beneficial effects of AMI treatment were associated with its ability to reduce mHTT aggregation, potentiation of the BDNF-TrkB signaling system, and support of mitochondrial integrity and functionality. Our study not only provides preclinical evidence for the therapeutic potency of AMI in treating HD, but it also represents an important example of the usefulness of additional pharmacogenomic profiling of pre-existing drugs for novel therapeutic effects with often intractable pathological scenarios. PMID- 25505250 TI - A role for the adaptor proteins TRAM and TRIF in toll-like receptor 2 signaling. AB - Toll-like receptors (TLRs) are involved in sensing invading microbes by host innate immunity. TLR2 recognizes bacterial lipoproteins/lipopeptides, and lipopolysaccharide activates TLR4. TLR2 and TLR4 signal via the Toll/interleukin 1 receptor adaptors MyD88 and MAL, leading to NF-kappaB activation. TLR4 also utilizes the adaptors TRAM and TRIF, resulting in activation of interferon regulatory factor (IRF) 3. Here, we report a new role for TRAM and TRIF in TLR2 regulation and signaling. Interestingly, we observed that TLR2-mediated induction of the chemokine Ccl5 was impaired in TRAM or TRIF deficient macrophages. Inhibition of endocytosis reduced Ccl5 release, and the data also suggested that TRAM and TLR2 co-localize in early endosomes, supporting the hypothesis that signaling may occur from an intracellular compartment. Ccl5 release following lipoprotein challenge additionally involved the kinase Tbk-1 and Irf3, as well as MyD88 and Irf1. Induction of Interferon-beta and Ccl4 by lipoproteins was also partially impaired in cells lacking TRIF cells. Our results show a novel function of TRAM and TRIF in TLR2-mediated signal transduction, and the findings broaden our understanding of how Toll/interleukin-1 receptor adaptor proteins may participate in signaling downstream from TLR2. PMID- 25505252 TI - Induced phenotype targeted therapy: radiation-induced apoptosis-targeted chemotherapy. AB - BACKGROUND: Tumor heterogeneity and evolutionary complexity may underlie treatment failure in spite of the development of many targeted agents. We suggest a novel strategy termed induced phenotype targeted therapy (IPTT) to simplify complicated targets because of tumor heterogeneity and overcome tumor evolutionary complexity. METHODS: We designed a caspase-3 specific activatable prodrug, DEVD-S-DOX, containing doxorubicin linked to a peptide moiety (DEVD) cleavable by caspase-3 upon apoptosis. To induce apoptosis locally in the tumor, we used a gamma knife, which can irradiate a very small, defined target area. The in vivo antitumor activity of the caspase-3-specific activatable prodrug combined with radiation was investigated in C3H/HeN tumor-bearing mice (n = 5 per group) and analyzed with the Student's t test or Mann-Whitney U test. All statistical tests were two-sided. We confirmed the basic principle using a caspase-sensitive nanoprobe (Apo-NP). RESULTS: A single exposure of radiation was able to induce apoptosis in a small, defined region of the tumor, resulting in expression of caspase-3. Caspase-3 cleaved DEVD and activated the prodrug. The released free DOX further activated DEVD-S-DOX by exerting cytotoxic effects on neighboring tumor or supporting cells, which repetitively induced the expression of caspase-3 and the activation of DEVD-S-DOX. This sequential and repetitive process propagated the induction of apoptosis. This novel therapeutic strategy showed not only high efficacy in inhibiting tumor growth (14-day tumor volume [mm(3)] vs radiation alone: 848.21 +/- 143.24 vs 2511.50 +/- 441.89, P < .01) but also low toxicity to normal cells and tissues. CONCLUSION: Such a phenotype induction strategy represents a conceptually novel approach to overcome tumor heterogeneity and complexity as well as to substantially improve current conventional chemoradiotherapy with fewer sequelae and side effects. PMID- 25505251 TI - A gut microbial metabolite of linoleic acid, 10-hydroxy-cis-12-octadecenoic acid, ameliorates intestinal epithelial barrier impairment partially via GPR40-MEK-ERK pathway. AB - Gut microbial metabolites of polyunsaturated fatty acids have attracted much attention because of their various physiological properties. Dysfunction of tight junction (TJ) in the intestine contributes to the pathogenesis of many disorders such as inflammatory bowel disease. We evaluated the effects of five novel gut microbial metabolites on tumor necrosis factor (TNF)-alpha-induced barrier impairment in Caco-2 cells and dextran sulfate sodium-induced colitis in mice. 10 Hydroxy-cis-12-octadecenoic acid (HYA), a gut microbial metabolite of linoleic acid, suppressed TNF-alpha and dextran sulfate sodium-induced changes in the expression of TJ-related molecules, occludin, zonula occludens-1, and myosin light chain kinase. HYA also suppressed the expression of TNF receptor 2 (TNFR2) mRNA and protein expression in Caco-2 cells and colonic tissue. In addition, HYA suppressed the protein expression of TNFR2 in murine intestinal epithelial cells. Furthermore, HYA significantly up-regulated G protein-coupled receptor (GPR) 40 expression in Caco-2 cells. It also induced [Ca(2+)]i responses in HEK293 cells expressing human GPR40 with higher sensitivity than linoleic acid, its metabolic precursor. The barrier-recovering effects of HYA were abrogated by a GPR40 antagonist and MEK inhibitor in Caco-2 cells. Conversely, 10-hydroxyoctadacanoic acid, which is a gut microbial metabolite of oleic acid and lacks a carbon-carbon double bond at Delta12 position, did not show these TJ-restoring activities and down-regulated GPR40 expression. Therefore, HYA modulates TNFR2 expression, at least partially, via the GPR40-MEK-ERK pathway and may be useful in the treatment of TJ-related disorders such as inflammatory bowel disease. PMID- 25505253 TI - PIM kinase inhibitor AZD1208 for treatment of MYC-driven prostate cancer. AB - BACKGROUND: PIM1 kinase is coexpressed with c-MYC in human prostate cancers (PCs) and dramatically enhances c-MYC-induced tumorigenicity. Here we examine the effects of a novel oral PIM inhibitor, AZD1208, on prostate tumorigenesis and recurrence. METHODS: A mouse c-MYC/Pim1-transduced tissue recombination PC model, Myc-CaP allografts, and human PC xenografts were treated with AZD1208 (n = 5-11 per group). Androgen-sensitive and castrate-resistant prostate cancer (CRPC) models were studied as well as the effects of hypoxia and radiation. RNA sequencing was used to analyze drug-induced gene expression changes. Results were analyzed with chi(2) test. Student's t test and nonparametric Mann-Whitney rank sum U Test. All statistical tests were two-sided. RESULTS: AZD1208 inhibited tumorigenesis in tissue recombinants, Myc-CaP, and human PC xenograft models. PIM inhibition decreased c-MYC/Pim1 graft growth by 54.3 +/- 39% (P < .001), decreased cellular proliferation by 46 +/- 14% (P = .016), and increased apoptosis by 326 +/- 170% (P = .039). AZD1208 suppressed multiple protumorigenic pathways, including the MYC gene program. However, it also downregulated the p53 pathway. Hypoxia and radiation induced PIM1 in prostate cancer cells, and AZD1208 functioned as a radiation sensitizer. Recurrent tumors postcastration responded transiently to either AZD1208 or radiation treatment, and combination treatment resulted in more sustained inhibition of tumor growth. Cell lines established from recurrent, AZD1208-resistant tumors again revealed downregulation of the p53 pathway. Irradiated AZD1208-treated tumors robustly upregulated p53, providing a possible mechanistic explanation for the effectiveness of combination therapy. Finally, an AZD1208-resistant gene signature was found to be associated with biochemical recurrence in PC patients. CONCLUSIONS: PIM inhibition is a potential treatment for MYC-driven prostate cancers including CRPC, and its effectiveness may be enhanced by activators of the p53 pathway, such as radiation. PMID- 25505255 TI - Proteinuria with first-line therapy of metastatic renal cell cancer. AB - BACKGROUND: Vascular endothelial growth factor receptor inhibitors, mammalian target of rapamycin inhibitors, and tyrosine kinase inhibitors are approved for metastatic renal cell cancer. Proteinuria can occur, but there is limited data regarding the incidence, monitoring, and management in metastatic renal cell cancer patients. OBJECTIVE: Our primary objective was to describe the incidence and severity of proteinuria in metastatic renal cell cancer patients treated in the first-line setting with pazopanib, bevacizumab, or everolimus. METHODS: We conducted a retrospective review of patients with metastatic renal cell cancer enrolled from January 2011-April 2013 in a phase II trial. Baseline and toxicity data were extracted from the electronic medical record. Descriptive statistics were used. RESULTS: In all, 129 patients were eligible for analysis. The overall incidence of proteinuria was 81%, with most events being Grade 1 or 2. The incidence of proteinuria was 80% (n = 35) for pazopanib, 64% (n = 25) for bevacizumab, and 96% (n = 44) for everolimus. At peak proteinuria, 80% (n = 28), 64% (n = 16), and 80% (n = 35) of patients on pazopanib, bevacizumab, and everolimus, respectively, were managed with continued monitoring at the same dose. The overall incidence of Grades 3 and 4 events was 24% (n = 6) and found in the bevacizumab group. CONCLUSION: A high incidence of proteinuria with minor severity within each class was demonstrated. It may be reasonable to continue therapy at the same dose for Grade 1 or 2 proteinuria. Treatment modification or discontinuation of therapy may be warranted with Grade 3 or 4 proteinuria. PMID- 25505256 TI - Comparison of 3D C-arm-based registration to conventional pair-point registration regarding navigation accuracy in ENT surgery. AB - OBJECTIVE: Navigation surgery on the skull base requires high navigation accuracy. The registration process is related to the main loss in accuracy. This study compared titanium screw registration with an inbuilt registration process of a 3-dimensional (3D) C-arm. STUDY DESIGN: Experimental phantom study. SETTING: Operating room. SUBJECTS AND METHODS: Four skull models were fabricated with a 3D printer based on the patient's computed tomography (CT) data sets and fitted with an individually customized silicone skin. A 3D-isocentric C-arm fluoroscopic image intensifier system combined with a flat panel detector performed scans of petrous bones (PB) and paranasal sinuses (PS). The navigation accuracy of pair point registration (PPR) with titanium screws was compared with C-arm-based registration. RESULTS: Overall navigation accuracy was 1.53 +/- 0.51 mm after PPR and 1.26 +/- 0.12 mm after C-arm registration (P = .0259). PPR showed the best accuracy results on PS (1.28 +/- 0.69 mm), followed by right PB (1.43 +/- 0.52 mm) and left PB (1.74 +/- 0.69 mm). A significant difference was seen only between PS and left PB (P = .0206). In contrast, C-arm registration revealed significantly lower target registration errors (TREs) on PB (0.99 +/- 0.23 mm right PB, P < .0001; 1.2 +/- 0.35 mm left PB, P = .0412) compared with PS. When comparing both registration modalities, C-arm registration was significantly superior on PB. With respect to specific anatomic locations, C-arm-based registration showed significantly lower TREs on the frontal and lateral skull base than PPR. CONCLUSION: C-arm-based navigation shows higher navigation accuracy on the skull base compared with PPR. As the 3D C-arm allows real-time imaging and real-time navigation, it will be a helpful tool for skull base surgeons. PMID- 25505254 TI - Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. AB - BACKGROUND: The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families. METHODS: Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with chi(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction). RESULTS: Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma. CONCLUSIONS: Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility. PMID- 25505258 TI - Effect of n-butyl-2-cyanoacrylate on the tensile strength and pressure resistance of tracheal anastomoses ex vivo. AB - OBJECTIVES: To investigate the effects of n-butyl-2-cyanoacrylate on tracheal anastomoses in terms of increased tension and intraluminal pressure ex vivo. STUDY DESIGN: Ex vivo experimental study. SETTING: Tertiary referral center (Department of Otolaryngology). SUBJECTS AND METHODS: Thirty sheep tracheas were used. Four cartilage rings were resected from the tracheas that were 20 cm in length. End-to-end anastomoses were performed by using Vicryl only (group 1), Vicryl and n-butyl-2-cyanoacrylate (group 2), and n-butyl-2-cyanoacrylate only (group 3). The amount of force to break off the anastomosis and the amount of intraluminal pressure to arouse air leakage through the anastomosis were measured. RESULTS: The mean force required to break off was 171.9 +/- 29.7 N in group 1, 164.8 +/- 26 N in group 2, and 13.52 +/- 2 N in group 3. The mean force required to break off in group 3 was significantly lower than those in groups 1 and 2 (P = .008 and P = .008, respectively). The mean pressure required to cause air leakage was 49.6 +/- 9.1 mm Hg in group 1, 113 +/- 14.4 mm Hg in group 2, and 15 +/- 4.2 mm Hg in group 3. Group 2 was found to be more resistant to intraluminal pressure than groups 1 and 3 (P = .008 and P = .008, respectively). CONCLUSION: n-Butyl-2-cyanoacrylate had no significant effect on tensile strength. However, its application on the suture line provided extra pressure resistance ex vivo. We believe that further studies need to be conducted to investigate its long-term effects and histological impact on tracheal anastomoses in vivo. PMID- 25505257 TI - Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial. AB - Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for <=64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%. PMID- 25505259 TI - Early versus late tracheostomy: a systematic review and meta-analysis. AB - OBJECTIVE: To investigate whether early tracheostomy leads to improved outcomes compared with late tracheostomy. DATA SOURCES: Ovid MEDLINE (including PubMed), Embase, and the Cochrane Central Register of Controlled Trials. REVIEW METHODS: A systematic search was performed of the above-mentioned databases according to PRISMA guidelines. Data were collected on the following outcomes of interest: hospital mortality, intensive care unit length of stay, length of mechanical ventilation, incidence of pneumonia, laryngotracheal injury, and sedation use. Analysis was performed using the RevMan 5 software (Cochrane Collaboration, Oxford, England). RESULTS: Eleven studies were included for analysis. There was a significant decrease in the intensive care unit length of stay in the early tracheostomy group (weighted mean difference, -9.13 days; 95% confidence interval [CI], -17.55 to -0.70; P = .03). There was no significant difference in hospital mortality (relative risk, 0.84; 95% CI, 0.67 to 1.04; P = .11). A pooled analysis was not performed for the incidence of pneumonia or length of mechanical ventilation, secondary to considerable heterogeneity among the studies. None of the studies reporting laryngotracheal outcomes found a significant difference between the early and late tracheostomy groups, whereas all 3 studies reporting sedation use found a significant decrease in the early tracheostomy group. CONCLUSION: Early tracheostomy performed within 7 days of intubation was associated with a decrease in intensive care unit length of stay. No difference was found in hospital mortality. Insufficient data currently exist to make conclusions about the effect of early tracheostomy on the incidence of pneumonia, length of mechanical ventilation, laryngotracheal injury, or sedation use. PMID- 25505260 TI - Increased expression of toll-like receptors 2 and 4 and related cytokines in persistent allergic rhinitis. AB - OBJECTIVES: Toll-like receptors (TLRs) are the crucial components of host defenses and supposed to play a role in nasal inflammation such as chronic rhinosinusitis and seasonal allergic rhinitis. This study was performed to investigate the expression patterns of TLRs and related cytokines in persistent allergic rhinitis (PER). STUDY DESIGN: Experimental study of human nasal tissue. SETTING: Academic medical center. SUBJECTS AND METHODS: Nasal biopsy specimens were obtained from 21 patients with PER and 21 controls from December 2012 to September 2013. Messenger RNA (mRNA) expression of TLR1-9, interleukin (IL)-1, IL 6, IL-8, IL-12, interferon (IFN)-alpha, and tumor necrosis factor (TNF)-alpha was determined by quantitative reverse transcription polymerase chain reaction. The cellular localizations as well as protein expression of TLR2 and TLR4 were further detected by immunohistochemistry and Western blotting, respectively. RESULTS: TLR1-9 mRNA could be determined in nasal mucosa. Compared with the controls, mRNA expression of only TLR2 and TLR4 was significant higher in patients with PER (P < .05). In addition, mRNA expression of IL-6 and IL-8, but not IL-1, IL-12, IFN-alpha, and TNF-alpha, was upregulated in patients with PER vs control subjects (P < .05). However, these increased cytokines were not correlated with either TLR2 or TLR4 in patients with PER. Protein expression of TLR2 and TLR4 was consistent with mRNA levels (P < .05). The cellular distributions of TLR2 and TLR4 were localized in nasal epithelium, subepithelial glands and capillary endothelial cells, and immune cells. CONCLUSION: TLR2 and TLR4 are increased in patients with PER and may be one of the major contributors to the persistence and aggravation of allergic inflammation in PER. PMID- 25505261 TI - Correlating regional aeroallergen effects on internet search activity. AB - OBJECTIVE: To investigate the correlation between the change in regional aeroallergen levels and Internet search activity related to allergies. STUDY DESIGN: A retrospective time series analysis using a graphical analytical approach and statistical modeling was used. SETTING: Tertiary academic hospital setting. SUBJECTS AND METHODS: There were no specific enrolled subjects. Data from Google Trends were obtained (google.com/trends) for the following search terms: "allergy," "allergies," "pollen," "runny nose," "congestion," and "post nasal drainage." Daily pollen and mold spore count data were obtained for the same period from throughout Texas. Graphical analysis, correlation, and autoregressive integrated moving average (ARIMA) were employed to assess the relationship between aeroallergens on Google search activity. RESULTS: A strong positive correlation was observed between observed pollen counts and search activity for the terms "allergies" (r pollen = 0.798), "allergy" (r pollen = 0.781), and "pollen" (r pollen = 0.849). Symptom term searches were weakly correlated with pollen and mold counts. Also, ARIMA modeling supported the relationships indicated by the correlations. CONCLUSION: Search activities for surrogate terms such as "allergy," "allergies," and "pollen" correlate strongly with observed pollen counts but not mold counts. These data demonstrate the usefulness of Google Trends search data in assessing regional disease burdens and offer insight into how the public seeks information about their own illness. PMID- 25505262 TI - Fancd2 is required for nuclear retention of Foxo3a in hematopoietic stem cell maintenance. AB - Functional maintenance of hematopoietic stem cells (HSCs) is constantly challenged by stresses like DNA damage and oxidative stress. Here we show that the Fanconi anemia protein Fancd2 and stress transcriptional factor Foxo3a cooperate to prevent HSC exhaustion in mice. Deletion of both Fancd2 and Foxo3a led to an initial expansion followed by a progressive decline of bone marrow stem and progenitor cells. Limiting dilution transplantation and competitive repopulating experiments demonstrated a dramatic reduction of competitive repopulating units and progressive decline in hematopoietic repopulating ability of double-knockout (dKO) HSCs. Analysis of the transcriptome of dKO HSCs revealed perturbation of multiple pathways implicated in HSC exhaustion. Fancd2 deficiency strongly promoted cytoplasmic localization of Foxo3a in HSCs, and re-expression of Fancd2 completely restored nuclear Foxo3a localization. By co-expressing a constitutively active CA-FOXO3a and WT or a nonubiquitinated Fancd2 in dKO bone marrow stem/progenitor cells, we demonstrated that Fancd2 was required for nuclear retention of CA-FOXO3a and for maintaining hematopoietic repopulation of the HSCs. Collectively, these results implicate a functional interaction between the Fanconi anemia DNA repair and FOXO3a pathways in HSC maintenance. PMID- 25505263 TI - Prolonged fasting identifies heat shock protein 10 as a Sirtuin 3 substrate: elucidating a new mechanism linking mitochondrial protein acetylation to fatty acid oxidation enzyme folding and function. AB - Although Sirtuin 3 (SIRT3), a mitochondrially enriched deacetylase and activator of fat oxidation, is down-regulated in response to high fat feeding, the rate of fatty acid oxidation and mitochondrial protein acetylation are invariably enhanced in this dietary milieu. These paradoxical data implicate that additional acetylation modification-dependent levels of regulation may be operational under nutrient excess conditions. Because the heat shock protein (Hsp) Hsp10-Hsp60 chaperone complex mediates folding of the fatty acid oxidation enzyme medium chain acyl-CoA dehydrogenase, we tested whether acetylation-dependent mitochondrial protein folding contributes to this regulatory discrepancy. We demonstrate that Hsp10 is a functional SIRT3 substrate and that, in response to prolonged fasting, SIRT3 levels modulate mitochondrial protein folding. Acetyl mutagenesis of Hsp10 lysine 56 alters Hsp10-Hsp60 binding, conformation, and protein folding. Consistent with Hsp10-Hsp60 regulation of fatty acid oxidation enzyme integrity, medium-chain acyl-CoA dehydrogenase activity and fat oxidation are elevated by Hsp10 acetylation. These data identify acetyl modification of Hsp10 as a nutrient-sensing regulatory node controlling mitochondrial protein folding and metabolic function. PMID- 25505264 TI - LDL receptor and ApoE are involved in the clearance of ApoM-associated sphingosine 1-phosphate. AB - Sphingosine 1-phosphate (S1P) is a vasoactive lipid mediator that is speculated to be involved in various aspects of atherosclerosis. About 70% of circulating plasma S1P is carried on HDL, and several pleiotropic properties of HDL have been ascribed to S1P. In the previous study with human subjects, however, LDL cholesterol or apoB, but not HDL cholesterol or apoA-I, had a significant positive correlation with the plasma S1P level, suggesting that the metabolic pathway for LDL might have some roles in the metabolism of S1P. In this study, we analyzed the association between LDL receptor, an important protein in the clearance of LDL, and circulating S1P. We observed that in LDL receptor overexpressing mice, the plasma S1P levels as well as apolipoprotein M (apoM), a carrier of S1P, were decreased and that exogenously administered C17S1P bound to apoM-containing lipoproteins was cleared more rapidly. Unlike the situation in wild-type mice, LDL receptor overexpression in apoE-deficient mice did not reduce the plasma S1P or apoM levels, suggesting that apoE might be a ligand for the LDL receptor during the clearance of these factors. The present findings clarify the novel roles of the LDL receptor and apoE in the clearance of S1P, a multifunctional bioactive phospholipid. PMID- 25505265 TI - Topological analysis of Hedgehog acyltransferase, a multipalmitoylated transmembrane protein. AB - Hedgehog proteins are secreted morphogens that play critical roles in development and disease. During maturation of the proteins through the secretory pathway, they are modified by the addition of N-terminal palmitic acid and C-terminal cholesterol moieties, both of which are critical for their correct function and localization. Hedgehog acyltransferase (HHAT) is the enzyme in the endoplasmic reticulum that palmitoylates Hedgehog proteins, is a member of a small subfamily of membrane-bound O-acyltransferase proteins that acylate secreted proteins, and is an important drug target in cancer. However, little is known about HHAT structure and mode of function. We show that HHAT is comprised of ten transmembrane domains and two reentrant loops with the critical His and Asp residues on opposite sides of the endoplasmic reticulum membrane. We further show that HHAT is palmitoylated on multiple cytosolic cysteines that maintain protein structure within the membrane. Finally, we provide evidence that mutation of the conserved His residue in the hypothesized catalytic domain results in a complete loss of HHAT palmitoylation, providing novel insights into how the protein may function in vivo. PMID- 25505266 TI - Naturally processed non-canonical HLA-A*02:01 presented peptides. AB - Human leukocyte antigen (HLA) class I molecules generally present peptides (p) of 8 to 11 amino acids (aa) in length. Although an increasing number of examples with lengthy (>11 aa) peptides, presented mostly by HLA-B alleles, have been reported. Here we characterize HLA-A*02:01 restricted, in addition to the HLA B*0702 and HLA-B*4402 restricted, lengthy peptides (>11 aa) arising from the B cell ligandome. We analyzed a number of 15-mer peptides presented by HLA-A*02:01, and confirmed pHLA-I formation by HLA folding and thermal stability assays. Surprisingly the binding affinity and stability of the 15-mer epitopes in complex with HLA-A*02:01 were comparable with the values observed for canonical length (8 to 11 aa) HLA-A*02:01-restricted peptides. We solved the structures of two 15-mer epitopes in complex with HLA-A*02:01, within which the peptides adopted distinct super-bulged conformations. Moreover, we demonstrate that T-cells can recognize the 15-mer peptides in the context of HLA-A*02:01, indicating that these 15-mer peptides represent immunogenic ligands. Collectively, our data expand our understanding of longer epitopes in the context of HLA-I, highlighting that they are not limited to the HLA-B family, but can bind the ubiquitous HLA-A*02:01 molecule, and play an important role in T-cell immunity. PMID- 25505267 TI - Helical shape of Helicobacter pylori requires an atypical glutamine as a zinc ligand in the carboxypeptidase Csd4. AB - Peptidoglycan modifying carboxypeptidases (CPs) are important determinants of bacterial cell shape. Here, we report crystal structures of Csd4, a three-domain protein from the human gastric pathogen Helicobacter pylori. The catalytic zinc in Csd4 is coordinated by a rare His-Glu-Gln configuration that is conserved among most Csd4 homologs, which form a distinct subfamily of CPs. Substitution of the glutamine to histidine, the residue found in prototypical zinc carboxypeptidases, resulted in decreased enzyme activity and inhibition by phosphate. Expression of the histidine variant at the native locus in a H. pylori csd4 deletion strain did not restore the wild-type helical morphology. Biochemical assays show that Csd4 can cleave a tripeptide peptidoglycan substrate analog to release m-DAP. Structures of Csd4 with this substrate analog or product bound at the active site reveal determinants of peptidoglycan specificity and the mechanism to cleave an isopeptide bond to release m-DAP. Our data suggest that Csd4 is the archetype of a new CP subfamily with a domain scheme that differs from this large family of peptide-cleaving enzymes. PMID- 25505268 TI - PLK1 inhibition down-regulates polycomb group protein BMI1 via modulation of the miR-200c/141 cluster. AB - The polycomb group protein BMI1 is an important regulator of cancer stem cell (CSC) phenotype and is often overexpressed in cancer cells. Its overexpression leads to increase in CSC fraction and therapy resistance in tumors. BMI1 functions via polycomb repressive complex 1 (PRC1)-mediated gene silencing and also via PRC1-independent transcriptional activities. At present, very little is known about the therapy reagents that can efficiently inhibit BMI1 expression, and the CSC phenotype. Here, we report that the polo-like kinase 1 (PLK1) regulates BMI1 expression, and that its inhibition can efficiently down-regulate BMI1 expression and PRC1 activity, and induce premature senescence in breast cancer cells. We also show that the exogenous BMI1 overexpression mitigates anti oncogenic effects of PLK1 inhibition and overcomes senescence induction by PLK1 inhibitors. We further show that PLK1 inhibition down-regulates BMI1 by upregulating the miRNA-200c/141 cluster, which encodes miR-200c and miR-141, both of which are known to post-transcriptionally downregulate BMI1 expression. Thus, our data suggest that PLK1 inhibitors can be successfully used to inhibit growth of tumors in which PcG protein BMI1 is overexpressed or the PRC1 activity is deregulated. PMID- 25505269 TI - Crystal structure of subunits D and F in complex gives insight into energy transmission of the eukaryotic V-ATPase from Saccharomyces cerevisiae. AB - Eukaryotic V1VO-ATPases hydrolyze ATP in the V1 domain coupled to ion pumping in VO. A unique mode of regulation of V-ATPases is the reversible disassembly of V1 and VO, which reduces ATPase activity and causes silencing of ion conduction. The subunits D and F are proposed to be key in these enzymatic processes. Here, we describe the structures of two conformations of the subunit DF assembly of Saccharomyces cerevisiae (ScDF) V-ATPase at 3.1 A resolution. Subunit D (ScD) consists of a long pair of alpha-helices connected by a short helix ((79)IGYQVQE(85)) as well as a beta-hairpin region, which is flanked by two flexible loops. The long pair of helices is composed of the N-terminal alpha helix and the C-terminal helix, showing structural alterations in the two ScDF structures. The entire subunit F (ScF) consists of an N-terminal domain of four beta-strands (beta1-beta4) connected by four alpha-helices (alpha1-alpha4). alpha1 and beta2 are connected via the loop (26)GQITPETQEK(35), which is unique in eukaryotic V-ATPases. Adjacent to the N-terminal domain is a flexible loop, followed by a C-terminal alpha-helix (alpha5). A perpendicular and extended conformation of helix alpha5 was observed in the two crystal structures and in solution x-ray scattering experiments, respectively. Fitted into the nucleotide bound A3B3 structure of the related A-ATP synthase from Enterococcus hirae, the arrangements of the ScDF molecules reflect their central function in ATPase coupled ion conduction. Furthermore, the flexibility of the terminal helices of both subunits as well as the loop (26)GQITPETQEK(35) provides information about the regulatory step of reversible V1VO disassembly. PMID- 25505272 TI - Multiple venous aneurysms in a patient with hypereosinophilic syndrome. AB - Hypereosinophilic syndrome (HES) is a diverse group of rare disorders, defined by persistent peripheral blood eosinophilia (>1500 per mm(3)), the absence of a primary cause of eosinophilia (such as parasitic or allergic disease), and evidence of eosinophil-mediated end-organ damage. Arterial aneurysms have been previously reported in these patients. This is the first report of a patient with HES and multiple venous aneurysms, causing recurrent pulmonary thromboembolism. Venous aneurysms can represent eosinophil-mediated, potentially fatal end-organ damage in patients with HES. PMID- 25505270 TI - The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension. AB - Pulmonary hypertension (PH) is a complex disorder, spanning several known vascular cell types. Recently, we identified the microRNA-130/301 (miR-130/301) family as a regulator of multiple pro-proliferative pathways in PH, but the true breadth of influence of the miR-130/301 family across cell types in PH may be even more extensive. Here, we employed targeted network theory to identify additional pathogenic pathways regulated by miR-130/301, including those involving vasomotor tone. Guided by these predictions, we demonstrated, via gain- and loss-of-function experimentation in vitro and in vivo, that miR-130/301 specific control of the peroxisome proliferator-activated receptor gamma regulates a panel of vasoactive factors communicating between diseased pulmonary vascular endothelial and smooth muscle cells. Of these, the vasoconstrictive factor endothelin-1 serves as an integral point of communication between the miR 130/301-peroxisome proliferator-activated receptor gamma axis in endothelial cells and contractile function in smooth muscle cells. Thus, resulting from an in silico analysis of the architecture of the PH disease gene network coupled with molecular experimentation in vivo, these findings clarify the expanded role of the miR-130/301 family in the global regulation of PH. They further emphasize the importance of molecular cross-talk among the diverse cellular populations involved in PH. PMID- 25505271 TI - Complex structure and biochemical characterization of the Staphylococcus aureus cyclic diadenylate monophosphate (c-di-AMP)-binding protein PstA, the founding member of a new signal transduction protein family. AB - Signaling nucleotides are integral parts of signal transduction systems allowing bacteria to cope with and rapidly respond to changes in the environment. The Staphylococcus aureus PII-like signal transduction protein PstA was recently identified as a cyclic diadenylate monophosphate (c-di-AMP)-binding protein. Here, we present the crystal structures of the apo- and c-di-AMP-bound PstA protein, which is trimeric in solution as well as in the crystals. The structures combined with detailed bioinformatics analysis revealed that the protein belongs to a new family of proteins with a similar core fold but with distinct features to classical PII proteins, which usually function in nitrogen metabolism pathways in bacteria. The complex structure revealed three identical c-di-AMP-binding sites per trimer with each binding site at a monomer-monomer interface. Although distinctly different from other cyclic-di-nucleotide-binding sites, as the half binding sites are not symmetrical, the complex structure also highlighted common features for c-di-AMP-binding sites. A comparison between the apo and complex structures revealed a series of conformational changes that result in the ordering of two anti-parallel beta-strands that protrude from each monomer and allowed us to propose a mechanism on how the PstA protein functions as a signaling transduction protein. PMID- 25505273 TI - PU.1 opposes IL-7-dependent proliferation of developing B cells with involvement of the direct target gene bruton tyrosine kinase. AB - Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreDeltaPB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19 CreDeltaPB mice. Enriched pro-B cells from CD19-CreDeltaPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreDeltaPB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-CreDeltaPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreDeltaPB pro-B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro-B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells. PMID- 25505274 TI - Transcriptome assessment reveals a dominant role for TLR4 in the activation of human monocytes by the alarmin MRP8. AB - The alarmins myeloid-related protein (MRP)8 and MRP14 are the most prevalent cytoplasmic proteins in phagocytes. When released from activated or necrotic phagocytes, extracellular MRP8/MRP14 promote inflammation in many diseases, including infections, allergies, autoimmune diseases, rheumatoid arthritis, and inflammatory bowel disease. The involvement of TLR4 and the multiligand receptor for advanced glycation end products as receptors during MRP8-mediated effects on inflammation remains controversial. By comparative bioinformatic analysis of genome-wide response patterns of human monocytes to MRP8, endotoxins, and various cytokines, we have developed a model in which TLR4 is the dominant receptor for MRP8-mediated phagocyte activation. The relevance of the TLR4 signaling pathway was experimentally validated using human and murine models of TLR4- and receptor for advanced glycation end products-dependent signaling. Furthermore, our systems biology approach has uncovered an antiapoptotic role for MRP8 in monocytes, which was corroborated by independent functional experiments. Our data confirm the primary importance of the TLR4/MRP8 axis in the activation of human monocytes, representing a novel and attractive target for modulation of the overwhelming innate immune response. PMID- 25505275 TI - Chronic lymphocytic leukemia: a paradigm of innate immune cross-tolerance. AB - Infections are a significant cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The pathogenesis of infections is multifactorial and includes hypogammaglobulinemia, conventional therapy with alkylating drugs, and recently, purine analogs and mAb-associated T cells. Patients without these risk factors also suffer from infections, although the mechanism remains unknown. In a cohort of 70 patients with CLL, we demonstrated that their monocytes were locked into a refractory state and were unable to mount a classic inflammatory response to pathogens. In addition, they exhibited the primary features of endotoxin tolerance, including low cytokine production, high phagocytic activity, and impaired Ag presentation. The involvement of miR-146a in this phenomenon was suspected. We found miR-146a target genes, such as IRAK1 and TRAF6, were manifestly downregulated. Our study provides a new explanation for infections in patients with CLL and describes a cross-tolerance between endotoxins and tumors. PMID- 25505276 TI - HLA-DMA polymorphisms differentially affect MHC class II peptide loading. AB - During the adaptive immune response, MHCII proteins display antigenic peptides on the cell surface of APCs for CD4(+) T cell surveillance. HLA-DM, a nonclassical MHCII protein, acts as a peptide exchange catalyst for MHCII, editing the peptide repertoire. Although they map to the same gene locus, MHCII proteins exhibit a high degree of polymorphism, whereas only low variability has been observed for HLA-DM. As HLA-DM activity directly favors immunodominant peptide presentation, polymorphisms in HLA-DM (DMA or DMB chain) might well be a contributing risk factor for autoimmunity and immune disorders. Our systematic comparison of DMA*0103/DMB*0101 (DMA-G155A and DMA-R184H) with DMA*0101/DMB*0101 in terms of catalyzed peptide exchange and dissociation, as well as direct interaction with several HLA-DR/peptide complexes, reveals an attenuated catalytic activity of DMA*0103/DMB*0101. The G155A substitution dominates the catalytic behavior of DMA*0103/DMB*0101 by decreasing peptide release velocity. Preloaded peptide-MHCII complexes exhibit ~2-fold increase in half-life in the presence of DMA*0103/DMB*0101 when compared with DMA*0101/DMB*0101. We show that this effect leads to a greater persistence of autoimmunity-related Ags in the presence of high-affinity competitor peptide. Our study therefore reveals that HLA-DM polymorphic residues have a considerable impact on HLA-DM catalytic activity. PMID- 25505277 TI - The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity. AB - BAFF and a proliferation-inducing ligand (APRIL), which control B cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF-APRIL receptor TACI, was applied in clinical trials. However, disease activity in multiple sclerosis unexpectedly increased, whereas in systemic lupus erythematosus, atacicept was beneficial. In this study, we show that an endogenous soluble TACI (sTACI) exists in vivo. TACI proteolysis involved shedding by a disintegrin and metalloproteinase 10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by gamma-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B cell survival and NF kappaB activation. We determined sTACI levels in autoimmune diseases with established hyperactivation of the BAFF-APRIL system. sTACI levels were elevated both in the cerebrospinal fluid of the brain-restricted autoimmune disease multiple sclerosis correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease systemic lupus erythematosus correlating with disease activity. Together, we show that TACI is sequentially processed by a disintegrin and metalloproteinase 10 and gamma-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects systemic and compartmentalized B cell accumulation and activation. PMID- 25505279 TI - Chronic lymphocytic leukemia cells express CD38 in response to Th1 cell-derived IFN-gamma by a T-bet-dependent mechanism. AB - Chronic lymphocytic leukemia (CLL) is a B cell malignancy associated with increased levels of inflammatory cytokines. Similarly, expression of CD38 on CLL cells correlates with CLL cell survival and proliferation, but the mechanisms that regulate CD38 expression and inflammatory cytokines remain unclear. We have recently demonstrated that patients have CLL-specific Th cells that support CLL proliferation. In this article, we show that CLL cells attract such Th cells, thereby establishing an Ag-dependent collaboration. Blocking experiments performed in vitro as wells as in vivo, using a xenograft model, revealed that secretion of IFN-gamma was a major mechanism by which CLL-specific Th cells increased CD38 on CLL cells. The expression of the transcription factor T-bet in peripheral blood CLL cells significantly correlated with CD38 expression, and transient transfection of CLL cells with T-bet resulted in T-bet(hi)CD38(hi) cells. Finally, chromatin immunoprecipitation experiments revealed that T-bet can bind to regulatory regions of the CD38 gene. These data suggest that CLL cells attract CLL-specific Th cells and initiate a positive feedback loop with upregulation of T-bet, CD38, and type 1 chemokines allowing further recruitment of Th cells and increased type 1 cytokine secretion. This insight provides a cellular and molecular mechanism that links the inflammatory signature observed in CLL pathogenesis with CD38 expression and aggressive disease and suggests that targeting the IFN-gamma/IFN-gammaR/JAK/STAT/T-bet/CD38 pathway could play a role in the therapy of CLL. PMID- 25505278 TI - CCR2-dependent dendritic cell accumulation in the central nervous system during early effector experimental autoimmune encephalomyelitis is essential for effector T cell restimulation in situ and disease progression. AB - Dendritic cells (DCs)--although absent from the healthy CNS parenchyma--rapidly accumulate within brain and spinal cord tissue during neuroinflammation associated with experimental autoimmune encephalomyelitis (EAE; a mouse model of multiple sclerosis). Yet, although DCs have been appreciated for their role in initiating adaptive immune responses in peripheral lymphoid organ tissues, how DCs infiltrate the CNS and contribute to ongoing neuroinflammation in situ is poorly understood. In this study, we report the following: 1) CD11c(+) bone marrow-derived DCs and CNS-infiltrating DCs express chemokine receptor CCR2; 2) compared with CCR2(+/+) cells, adoptively transferred CCR2(-/-) bone marrow derived DCs or DC precursors do not accumulate in the CNS during EAE, despite abundance in blood; 3) CCR2(-/-) DCs show less accumulation in the inflamed CNS in mixed bone marrow chimeras, when compared with CCR2(+/+) DCs; and 4) ablation of CCR2(+/+) DCs during EAE clinical onset delays progression and attenuates cytokine production by infiltrating T cells. Whereas the role of CCR2 in monocyte migration into the CNS has been implicated previously, the role of CCR2 in DC infiltration into the CNS has never been directly addressed. Our data suggest that CCR2-dependent DC recruitment to the CNS during ongoing neuroinflammation plays a crucial role in effector T cell cytokine production and disease progression, and signify that CNS-DCs and circulating DC precursors might be key therapeutic targets for suppressing ongoing neuroinflammation in CNS autoimmune diseases. PMID- 25505280 TI - Plasmodium suppresses expansion of T cell responses to heterologous infections. AB - Plasmodium remains a major pathogen causing malaria and impairing defense against other infections. Defining how Plasmodium increases susceptibility to heterologous pathogens may lead to interventions that mitigate the severity of coinfections. Previous studies proposed that reduced T cell responses during coinfections are due to diminished recruitment of naive T cells through infection induced decreases in chemokine CCL21. We found that, although Listeria infections reduced expression of CCL21 in murine spleens, lymphocytic choriomeningitis virus (LCMV)-specific T cell responses were not impaired during Listeria + LCMV coinfection, arguing against a major role for this chemokine in coinfection induced T cell suppression. In our experiments, Plasmodium yoelii infection led to a reduced CD8(+) T cell response to a subsequent Listeria infection. We propose an alternative mechanism whereby P. yoelii suppresses Listeria-specific T cell responses. We found that Listeria-specific T cells expanded more slowly and resulted in lower numbers in response to coinfection with P. yoelii. Mathematical modeling and experimentation revealed greater apoptosis of Listeria-specific effector T cells as the main mechanism, because P. yoelii infections did not suppress the recruitment or proliferation rates of Listeria-specific T cells. Our results suggest that P. yoelii infections suppress immunity to Listeria by causing increased apoptosis in Listeria-specific T cells, resulting in a slower expansion rate of T cell responses. PMID- 25505281 TI - Antigen recognition in the islets changes with progression of autoimmune islet infiltration. AB - In type 1 diabetes, the pancreatic islets are an important site for therapeutic intervention because immune infiltration of the islets is well established at diagnosis. Therefore, understanding the events that underlie the continued progression of the autoimmune response and islet destruction is critical. Islet infiltration and destruction is an asynchronous process, making it important to analyze the disease process on a single islet basis. To understand how T cell stimulation evolves through the process of islet infiltration, we analyzed the dynamics of T cell movement and interactions within individual islets of spontaneously autoimmune NOD mice. Using both intravital and explanted two-photon islet imaging, we defined a correlation between increased islet infiltration and increased T cell motility. Early T cell arrest was Ag dependent and due, at least in part, to Ag recognition through sustained interactions with CD11c(+) APCs. As islet infiltration progressed, T cell motility became Ag independent, with a loss of T cell arrest and sustained interactions with CD11c(+) APCs. These studies suggest that the autoimmune T cell response in the islets may be temporarily dampened during the course of islet infiltration and disease progression. PMID- 25505282 TI - Mutation in the CD45 inhibitory wedge modulates integrin activation and leukocyte recruitment during inflammation. AB - Neutrophil recruitment to the site of inflammation plays a pivotal role in host defense. Src family kinases (SFKs) activation is required for integrin and chemokine signaling as well as immune cell function. The receptor-like protein tyrosine phosphatase CD45 positively regulates chemoattractant signaling acting on SFK activity. To further investigate the role of CD45 in neutrophil recruitment and function, we analyzed transgenic mice carrying a single point mutation (CD45E613R), which constitutively activates CD45. By using intravital microscopy experiments, we demonstrated that different steps of the leukocyte recruitment cascade were affected in CD45E613R mutant mice. The rolling velocity of CD45E613R mutant neutrophils was decreased compared with wild-type neutrophils that subsequently resulted in an increased number of adherent cells. The analysis of beta2 integrins LFA-1 and macrophage-1 Ag (Mac-1) showed that in CD45E613R mutant neutrophils LFA-1 adhesiveness was impaired, and avidity was enhanced, whereas Mac-1 adhesiveness was increased. Because of the increased Mac-1 adhesiveness, neutrophil crawling was impaired in CD45E613R mutant compared with wild-type neutrophils. In an Escherichia coli lung infection model, CD45E613R mice displayed a decreased neutrophil recruitment into the alveolar compartment, which resulted in an increased number of CFUs in the lung. Our data demonstrate that the CD45E613R mutation modulates integrin activation and leukocyte recruitment during inflammation. PMID- 25505283 TI - Direct and indirect effects of immune and central nervous system-resident cells on human oligodendrocyte progenitor cell differentiation. AB - In multiple sclerosis, successful remyelination within the injured CNS is largely dependent on the survival and differentiation of oligodendrocyte progenitor cells. During inflammatory injury, oligodendrocytes and oligodendrocyte progenitor cells within lesion sites are exposed to secreted products derived from both infiltrating immune cell subsets and CNS-resident cells. Such products may be considered either proinflammatory or anti-inflammatory and have the potential to contribute to both injury and repair processes. Within the CNS, astrocytes also contribute significantly to oligodendrocyte biology during development and following inflammatory injury. The overall objective of the current study was to determine how functionally distinct proinflammatory and anti inflammatory human immune cell subsets, implicated in multiple sclerosis, can directly and/or indirectly (via astrocytes) impact human oligodendrocyte progenitor cell survival and differentiation. Proinflammatory T cell (Th1/Th17) and M1-polarized myeloid cell supernatants had a direct cytotoxic effect on human A2B5(+) neural progenitors, resulting in decreased O4(+) and GalC(+) oligodendrocyte lineage cells. Astrocyte-conditioned media collected from astrocytes pre-exposed to the same proinflammatory supernatants also resulted in decreased oligodendrocyte progenitor cell differentiation without an apparent increase in cell death and was mediated through astrocyte-derived CXCL10, yet this decrease in differentiation was not observed in the more differentiated oligodendrocytes. Th2 and M2 macrophage or microglia supernatants had neither a direct nor an indirect impact on oligodendrocyte progenitor cell differentiation. We conclude that proinflammatory immune cell responses can directly and indirectly (through astrocytes) impact the fate of immature oligodendrocyte lineage cells, with oligodendrocyte progenitor cells more vulnerable to injury compared with mature oligodendrocytes. PMID- 25505285 TI - Severe neutrophil-dominated inflammation and enhanced myelopoiesis in IL-33 overexpressing CMV/IL33 mice. AB - IL-33 is a cytokine of the IL-1 family, which signals through the ST2 receptor. Previous studies emphasized a role for IL-33 in shaping innate and adaptive immune responses. IL-33 was also reported to modulate myelopoiesis and myeloid cell activity. In this article, we describe IL-33-overexpressing CMV/IL33 and LysM/IL33 mice, which display an inflammatory phenotype associated with growth retardation and paw swelling. The phenotype of CMV/IL33 mice is dependent on activation of the ST2 receptor and is characterized by extensive neutrophil infiltration into different organs, including the paws. Local or systemic levels of proinflammatory mediators such as IL-1beta, Cxcl-1, G-CSF, and IL-6 are increased. CMV/IL-33 mice also suffer from anemia, thrombocytosis, and a marked dysregulation of myelopoiesis, leading to an important increase in myeloid cell production or accumulation in bone marrow (BM), spleen, and peripheral blood. Consistently, recombinant IL-33 induced proliferation of myeloid lineage cells in BM-derived granulocyte cultures, whereas IL-33 knockout mice exhibited minor deficiencies in spleen and BM myeloid cell populations. Our observations reveal a neutrophil-dominated inflammatory phenotype in IL-33-overexpressing CMV/IL33 and LysM/IL33 mice, and highlight important regulatory effects of IL-33 on myelopoiesis in vitro and in vivo, where excessive IL-33 signaling can translate into the occurrence of a myeloproliferative disorder. PMID- 25505284 TI - IL-17A-mediated protection against Acanthamoeba keratitis. AB - Acanthamoeba keratitis (AK) is a very painful and vision-impairing infection of the cornea that is difficult to treat. Although past studies have indicated a critical role of neutrophils and macrophages in AK, the relative contribution of the proinflammatory cytokine, IL-17A, that is essential for migration, activation, and function of these cells into the cornea is poorly defined. Moreover, the role of the adaptive immune response, particularly the contribution of CD4(+) T cell subsets, Th17 and regulatory T cells , in AK is yet to be understood. In this report, using a mouse corneal intrastromal injection-induced AK model, we show that Acanthamoeba infection induces a strong CD4(+) T effector and regulatory T cell response in the cornea and local draining lymph nodes. We also demonstrate that corneal Acanthamoeba infection induces IL-17A expression and that IL-17A is critical for host protection against severe AK pathology. Accordingly, IL-17A neutralization in Acanthamoeba-infected wild-type mice or Acanthamoeba infection of mice lacking IL-17A resulted in a significantly increased corneal AK pathology, increased migration of inflammatory cells at the site of inflammation, and a significant increase in the effector CD4(+) T cell response in draining lymph nodes. Thus, in sharp contrast with other corneal infections such as herpes and Pseudomonas aeruginosa keratitis where IL-17A exacerbates corneal pathology and inflammation, the findings presented in this article suggest that IL-17A production after Acanthamoeba infection plays an important role in host protection against invading parasites. PMID- 25505287 TI - Corrigendum: Improving upon the efficiency of complete case analysis when covariates are MNAR (10.1093/biostatistics/kxu023). PMID- 25505286 TI - Cutting edge: IL-1alpha is a crucial danger signal triggering acute myocardial inflammation during myocardial infarction. AB - Myocardial infarction (MI) induces a sterile inflammatory response that contributes to adverse cardiac remodeling. The initiating mechanisms of this response remain incompletely defined. We found that necrotic cardiomyocytes released a heat-labile proinflammatory signal activating MAPKs and NF-kappaB in cardiac fibroblasts, with secondary production of cytokines. This response was abolished in Myd88(-/-) fibroblasts but was unaffected in nlrp3-deficient fibroblasts. Despite MyD88 dependency, the response was TLR independent, as explored in TLR reporter cells, pointing to a contribution of the IL-1 pathway. Indeed, necrotic cardiomyocytes released IL-1alpha, but not IL-1beta, and the immune activation of cardiac fibroblasts was abrogated by an IL-1R antagonist and an IL-1alpha-blocking Ab. Moreover, immune responses triggered by necrotic Il1a( /-) cardiomyocytes were markedly reduced. In vivo, mice exposed to MI released IL 1alpha in the plasma, and postischemic inflammation was attenuated in Il1a(-/-) mice. Thus, our findings identify IL-1alpha as a crucial early danger signal triggering post-MI inflammation. PMID- 25505288 TI - Proton beam radiotherapy of diffuse iris melanoma in 54 patients. AB - BACKGROUND: Treatment modalities in iris melanoma include excision, plaque radiotherapy, photon or proton beam therapy and enucleation. In extensive tumours and diffuse seeding, radiotherapy remains as an alternative to enucleation. METHODS: This study is a retrospective, consecutive, interventional, single institutional case series. 54 patients with a diffuse and non-resectable iris melanoma diagnosed from September 1998 to June 2012 were included. A 68 megaelectron volt proton beam was used to treat the anterior segment with a total dose of 4*12.5 cobalt grey equivalent. The cases were evaluated for local tumour control, eye retention, functional outcome and local complications after treatment. RESULTS: During a mean follow-up of 62.7 months (median 54.8 months, range 5.5-159.6 months), local tumour control was achieved in 96.3% of the patients. Cataract and glaucoma were the main complications developing after irradiation in 42.6% and 55.6%, respectively. In 34 of 44 patients (77.3%) who underwent cataract removal, a visual acuity of 20/40 or better following surgery was preserved. Enucleation was performed in three patients. The reason was suspected tumour recurrence in one and glaucoma in two. Hepatic metastasis occurred in one patient. CONCLUSIONS: As an alternative to enucleation, whole anterior segment fractionated proton beam radiotherapy offered excellent local tumour control in diffuse iris melanoma. Given the limited alternatives, the rate of complications appears acceptable and visual function could be preserved in the majority of the patients during follow-up. PMID- 25505289 TI - A single amino acid change in inhibitory killer cell Ig-like receptor results in constitutive receptor self-association and phosphorylation. AB - Signaling by immunoreceptors is often initiated by phosphorylation of cytosolic tyrosines, which then recruit effector molecules. In the case of MHC class I specific inhibitory receptors, phosphorylation of cytosolic tyrosine residues within ITIMs results in recruitment of a protein tyrosine phosphatase that blocks activation signals. Recent work showed that signaling by an HLA-C-specific killer cell Ig-like receptor (KIR) is independent of signaling by activation receptors. It is not known how ITIM phosphorylation is initiated and regulated. In this article, we show that substitution of His-36 in the first Ig domain of KIR2DL1 with alanine (KIR2DL1-H36A) resulted in constitutive KIR2DL1 self-association and phosphorylation, as well as recruitment of tyrosine phosphatase SHP-1. Furthermore, substitution of His-36 with a similar bulky amino acid, phenylalanine, maintained the receptor in its unphosphorylated state, suggesting that steric hindrance by the His-36 side chain prevents constitutive KIR2DL1 self association and ITIM phosphorylation. The equally strong phosphorylation of KIR2DL1 and KIR2DL1-H36A after inhibition of tyrosine phosphatase by pervanadate suggested that KIR2DL1-H36A is selectively protected from dephosphorylation. We propose that KIR phosphorylation is controlled by the accessibility of ITIM to tyrosine phosphatases and that KIR binding to HLA-C must override the hindrance that His-36 puts on KIR2DL1 self-association. Expression of KIR2DL1-H36A on NK cells led to stronger inhibition of lysis of HLA-C(+) target cells than did expression of wild-type KIR2DL1. These results revealed that ITIM phosphorylation is controlled by self-association of KIR and that His-36 serves as a gatekeeper to prevent unregulated signaling through KIR2DL1. PMID- 25505290 TI - CCR6-dependent positioning of memory B cells is essential for their ability to mount a recall response to antigen. AB - Chemokine-dependent localization of specific B cell subsets within the immune microarchitecture is essential to ensure successful cognate interactions. Although cognate interactions between T cells and memory B cells (B(mem)) are essential for the secondary humoral immune responses, the chemokine response patterns of B(mem) cells are largely unknown. In contrast to naive B cells, this study shows that Ag-specific B(mem) cells have heightened expression of CCR6 and a selective chemotactic response to the CCR6 ligand, CCL20. Although CCR6 appears be nonessential for the initial clonal expansion and maintenance of B(mem), CCR6 is essential for the ability of B(mem) to respond to a recall response to their cognate Ag. This dependency was deemed intrinsic by studies in CCR6-deficient mice and in bone marrow chimeric mice where CCR6 deficiency was limited to the B cell lineage. Finally, the mis-positioning of CCR6-deficient B(mem) was revealed by immunohistological analysis with an altered distribution of CCR6-deficient B(mem) from the marginal and perifollicular to the follicular/germinal center area. PMID- 25505291 TI - TGF-beta1, but not bone morphogenetic proteins, activates Smad1/5 pathway in primary human macrophages and induces expression of proatherogenic genes. AB - Macrophages are responsible for the control of inflammation and healing, and their malfunction results in cardiometabolic disorders. TGF-beta is a pleiotropic growth factor with dual (protective and detrimental) roles in atherogenesis. We have previously shown that in human macrophages, TGF-beta1 activates Smad2/3 signaling and induces a complex gene expression program. However, activated genes were not limited to known Smad2/3-dependent ones, which prompted us to study TGF beta1-induced signaling in macrophages in detail. Analysis of Id3 regulatory sequences revealed a novel enhancer, located between +4517 and 4662 bp, but the luciferase reporter assay demonstrated that this enhancer is not Smad2/3 dependent. Because Id3 expression is regulated by Smad1/5 in endothelial cells, we analyzed activation of Smad1/5 in macrophages. We demonstrate here for the first time, to our knowledge, that TGF-beta1, but not BMPs, activates Smad1/5 in macrophages. We show that an ALK5/ALK1 heterodimer is responsible for the induction of Smad1/5 signaling by TGF-beta1 in mature human macrophages. Activation of Smad1/5 by TGF-beta1 induces not only Id3, but also HAMP and PLAUR, which contribute to atherosclerotic plaque vulnerability. We suggest that the balance between Smad1/5- and Smad2/3-dependent signaling defines the outcome of the effect of TGF-beta on atherosclerosis where Smad1/5 is responsible for proatherogenic effects, whereas Smad2/3 regulate atheroprotective effects of TGF beta. PMID- 25505293 TI - A functional polymorphism of Ptpn22 is associated with type 1 diabetes in the BioBreeding rat. AB - The R620W variant of PTPN22 is one of the major genetic risk factors for several autoimmune disorders including type 1 diabetes (T1D) in humans. In the BioBreeding T1D-prone (BBDP) rat, a single nucleotide polymorphism in Ptpn22 results in an A629T substitution immediately C-terminal to the aliphatic residues central to the Ptpn22-C-terminal Src kinase interaction. This variant exhibits a 50% decrease in C-terminal Src kinase binding affinity and contributes to T cell hyperresponsiveness. Examination of BBDP sublines congenic for the Iddm26.2 locus that includes Ptpn22 has not only shown an expansion of activated CD4(+)25(+) T lymphocytes in animals homozygous for the BBDP allele, consistent with enhanced TCR-mediated signaling, but also a decrease in their proportion of peripheral Foxp3(+) regulatory T cells. Furthermore, clinical assessment of both an F2(BBDP * ACI.1u.Lyp) cohort and Iddm26.2 congenic BBDP sublines has revealed an association of Ptpn22 with T1D. Specifically, in both cases, T1D risk is significantly greater in BBDP Ptpn22 homozygous and heterozygous animals. These findings are consistent with a role for rat Ptpn22 allelic variation within Iddm26.2 in the regulation of T cell responses, and subsequently the risk for development of T1D. PMID- 25505292 TI - Profiling T cell activation using single-molecule fluorescence in situ hybridization and flow cytometry. AB - Flow cytometric characterization of Ag-specific T cells typically relies on detection of protein analytes. Shifting the analysis to detection of RNA would provide several significant advantages, which we illustrate by developing a new host immunity-based platform for detection of infections. Cytokine mRNAs synthesized in response to ex vivo stimulation with pathogen-specific Ags are detected in T cells with single-molecule fluorescence in situ hybridization followed by flow cytometry. Background from pre-existing in vivo analytes is lower for RNAs than for proteins, allowing greater sensitivity for detection of low-frequency cells. Moreover, mRNA analysis reveals kinetic differences in cytokine expression that are not apparent at the protein level but provide novel insights into gene expression programs expected to define different T cell subsets. The utility of probing immunological memory of infections is demonstrated by detecting T cells that recognize mycobacterial and viral Ags in donors exposed to the respective pathogens. PMID- 25505294 TI - The effects of cytokines on spontaneous hepatitis B surface antigen seroconversion in chronic hepatitis B virus infection. AB - We examined the role of human cytokines in the natural course of hepatitis B surface Ag (HBsAg) seroconversion in chronic hepatitis B virus (HBV) infection. The clinical course of spontaneous HBsAg seroconversion was assessed in 296 chronically HBV-infected patients. Single nucleotide polymorphisms (SNPs) in IL 1beta, IL-2, IL-4, IL-10, IL-12beta, IL-13, IL-27, and IFN-gamma genes were examined in 296 chronically HBV-infected patients and another 193 HBV recoverers. The HBsAg a determinant sequence of chronically HBV-infected subjects with and without HBsAg seroconversion was also analyzed. The start of the immune-clearance phase (serum alanine aminotransferase levels > 30 IU/l) before the age of 48 mo and hepatitis B e Ag (HBeAg) seroconversion before the age of 10 y predicted spontaneous HBsAg seroconversion in chronically HBV-infected patients (odds ratios 17.7 and 5.0; p < 0.001 and p < 0.002, respectively). The A-allele of IL 10 SNP rs1800872 was associated with higher IL-10 serum levels, and the G-allele of IL-12beta SNP rs3212217 was associated with sustained high serum IL-12p70 levels during the immune-clearance phase. Both were predictors of spontaneous HBsAg seroconversion and HBV recovery (odds ratios 4.0 and 26.3; p = 0.002 and p < 0.001, respectively). Spontaneous HBsAg seroconversion was not related to sex, HBV genotype, or HBsAg a determinant mutation. The start of immune-clearance phase, age at HBeAg seroconversion, and serum IL-10 and IL-12 levels are associated with the course of the immune-clearance phase in chronic HBV infection, and are predictive of spontaneous HBsAg seroconversion and HBV recovery. PMID- 25505295 TI - Norovirus Infection and Disease in an Ecuadorian Birth Cohort: Association of Certain Norovirus Genotypes With Host FUT2 Secretor Status. AB - BACKGROUND: Although norovirus is the most common cause of gastroenteritis, there are few data on the community incidence of infection/disease or the patterns of acquired immunity or innate resistance to norovirus. METHODS: We followed a community-based birth cohort of 194 children in Ecuador with the aim to estimate (1) the incidence of norovirus gastroenteritis from birth to age 3 years, (2) the protective effect of norovirus infection against subsequent infection/disease, and (3) the association of infection and disease with FUT2 secretor status. RESULTS: Over the 3-year period, we detected a mean of 2.26 diarrheal episodes per child (range, 0-12 episodes). Norovirus was detected in 260 samples (18%) but was not found more frequently in diarrheal samples (79 of 438 [18%]), compared with diarrhea-free samples (181 of 1016 [18%]; P = .919). A total of 66% of children had at least 1 norovirus infection during the first 3 years of life, and 40% of children had 2 infections. Previous norovirus infections were not associated with the risk of subsequent infection. All genogroup II, genotype 4 (GII.4) infections were among secretor-positive children (P < .001), but higher rates of non-GII.4 infections were found in secretor-negative children (relative risk, 0.56; P = .029). CONCLUSIONS: GII.4 infections were uniquely detected in secretor-positive children, while non-GII.4 infections were more often found in secretor-negative children. PMID- 25505296 TI - Modeling options to manage type 1 wild poliovirus imported into Israel in 2013. AB - BACKGROUND: After 25 years without poliomyelitis cases caused by circulating wild poliovirus (WPV) in Israel, sewage sampling detected WPV type 1 (WPV1) in April 2013, despite high vaccination coverage with only inactivated poliovirus vaccine (IPV) since 2005. METHODS: We used a differential equation-based model to simulate the dynamics of poliovirus transmission and population immunity in Israel due to past exposure to WPV and use of oral poliovirus vaccine (OPV) in addition to IPV. We explored the influences of various immunization options to stop imported WPV1 circulation in Israel. RESULTS: We successfully modeled the potential for WPVs to circulate without detected cases in Israel. Maintaining a sequential IPV/OPV schedule instead of switching to an IPV-only schedule in 2005 would have kept population immunity high enough in Israel to prevent WPV1 circulation. The Israeli response to WPV1 detection prevented paralytic cases; a more rapid response might have interrupted transmission more quickly. CONCLUSIONS: IPV-based protection alone might not provide sufficient population immunity to prevent poliovirus transmission after an importation. As countries transition to IPV in immunization schedules, they may need to actively manage population immunity and consider continued use of OPV, to avoid the potential circulation of imported live polioviruses before globally coordinated cessation of OPV use. PMID- 25505297 TI - Brucella Intracellular Life Relies on the Transmembrane Protein CD98 Heavy Chain. AB - Brucella are intracellular bacterial pathogens that use a type IV secretion system (T4SS) to escape host defenses and create a niche in which they can multiply. Although the importance of Brucella T4SS is clear, little is known about its interactions with host cell structures. In this study, we identified the eukaryotic protein CD98hc as a partner for Brucella T4SS subunit VirB2. This transmembrane glycoprotein is involved in amino acid transport, modulation of integrin signaling, and cell-to-cell fusion. Knockdown of CD98hc expression in HeLa cells demonstrated that it is essential for Brucella infection. Using knockout dermal fibroblasts, we confirmed its role for Brucella but found that it is not required for Salmonella infection. CD98hc transiently accumulates around the bacteria during the early phases of infection and is required for both optimal bacterial uptake and intracellular multiplication of Brucella. These results provide new insights into the complex interplay between Brucella and its host. PMID- 25505299 TI - The Recombinant BCG DeltaureC::hly Vaccine Targets the AIM2 Inflammasome to Induce Autophagy and Inflammation. AB - BACKGROUND: The recombinant BCG DeltaureC::hly (rBCG) vaccine candidate induces improved protection against tuberculosis over parental BCG (pBCG) in preclinical studies and has successfully completed a phase 2a clinical trial. However, the mechanisms responsible for the superior vaccine efficacy of rBCG are still incompletely understood. Here, we investigated the underlying biological mechanisms elicited by the rBCG vaccine candidate relevant to its protective efficacy. METHODS: THP-1 macrophages were infected with pBCG or rBCG, and inflammasome activation and autophagy were evaluated. In addition, mice were vaccinated with pBCG or rBCG, and gene expression in the draining lymph nodes was analyzed by microarray at day 1 after vaccination. RESULTS: BCG-derived DNA was detected in the cytosol of rBCG-infected macrophages. rBCG infection was associated with enhanced absent in melanoma 2 (AIM2) inflammasome activation, increased activation of caspases and production of interleukin (IL)-1beta and IL 18, as well as induction of AIM2-dependent and stimulator of interferon genes (STING)-dependent autophagy. Similarly, mice vaccinated with rBCG showed early increased expression of Il-1beta, Il-18, and Tmem173 (transmembrane protein 173; also known as STING). CONCLUSIONS: rBCG stimulates AIM2 inflammasome activation and autophagy, suggesting that these cell-autonomous functions should be exploited for improved vaccine design. PMID- 25505298 TI - Meningococcal carriage among Georgia and Maryland high school students. AB - BACKGROUND: Meningococcal disease incidence in the United States is at an all time low. In a previous study of Georgia high school students, meningococcal carriage prevalence was 7%. The purpose of this study was to measure the impact of a meningococcal conjugate vaccine on serogroup Y meningococcal carriage and to define the dynamics of carriage in high school students. METHODS: This was a prospective cohort study at 8 high schools, 4 each in Maryland and Georgia, during a school year. Students at participating schools received quadrivalent meningococcal conjugate vaccine that uses diphtheria toxoid as the protein carrier (MCV4-DT). In each state, 2 high schools were randomly assigned for MCV4 DT receipt by students at the beginning of the study, and 2 were randomly assigned for MCV4-DT receipt at the end. Oropharyngeal swab cultures for meningococcal carriage were performed 3 times during the school year. RESULTS: Among 3311 students, the prevalence of meningococcal carriage was 3.21%-4.01%. Phenotypically nongroupable strains accounted for 88% of carriage isolates. There were only 5 observed acquisitions of serogroup Y strains during the study; therefore, the impact of MCV4-DT on meningococcal carriage could not be determined. CONCLUSIONS: Meningococcal carriage rates in US high school students were lower than expected, and the vast majority of strains did not express capsule. These findings may help explain the historically low incidence of meningococcal disease in the United States. PMID- 25505300 TI - Live attenuated influenza virus increases pneumococcal translocation and persistence within the middle ear. AB - BACKGROUND: Infection with influenza A virus (IAV) increases susceptibility to respiratory bacterial infections, resulting in increased bacterial carriage and complications such acute otitis media, pneumonia, bacteremia, and meningitis. Recently, vaccination with live attenuated influenza virus (LAIV) was reported to enhance subclinical bacterial colonization within the nasopharynx, similar to IAV. Although LAIV does not predispose to bacterial pneumonia, whether it may alter bacterial transmigration toward the middle ear, where it could have clinically relevant implications, has not been investigated. METHODS: BALB/c mice received LAIV or phosphate-buffered saline 1 or 7 days before or during pneumococcal colonization with either of 2 clinical isolates, 19F or 7F. Middle ear bacterial titers were monitored daily via in vivo imaging. RESULTS: LAIV increased bacterial transmigration to and persistence within the middle ear. When colonization followed LAIV inoculation, a minimum LAIV incubation period of 4 days was required before bacterial transmigration commenced. CONCLUSIONS: While LAIV vaccination is safe and effective at reducing IAV and coinfection with influenza virus and bacteria, LAIV may increase bacterial transmigration to the middle ear and could thus increase the risk of clinically relevant acute otitis media. These data warrant further investigations into interactions between live attenuated viruses and naturally colonizing bacterial pathogens. PMID- 25505306 TI - A rigid and bioabsorbable material for anterior chest wall reconstruction in a canine model. AB - OBJECTIVES: The optimal material for anterior chest wall reconstruction following chest wall resection remains controversial. The aim of this experimental study was to evaluate short-term, morphological and histological outcomes of anterior chest wall reconstruction with a rigid and bioabsorbable material in a canine model. METHODS: Twenty adult beagle dogs underwent anterior chest wall resection. In the experimental group (n = 10), the anterior chest wall was reconstructed with a rigid and bioabsorbable material composed of poly-L-lactide acid matrix (60 wt%) and uncalcined and unsintered hydroxyapatite particles (40 wt%), whereas in the control group it was (n = 10) reconstructed with dual polypropylene mesh sheets. Short-term complication rates were compared with a chi(2) test. Postoperative sternal deviations were evaluated with sternal alignment angles using computed tomography and multiplanar reconstruction and were compared with Mann-Whitney U-test immediately after reconstruction, and at 1, 3, 6, 9 and 12 months postoperatively. Histological findings of the regenerated chest wall tissue were obtained after staining with haematoxylin and eosin and Elastica van Gieson (EVG) and compared at 3, 6, 9 and 12 months. RESULTS: There was not a significant difference in the short-term postoperative complication rate (P = 0.53) and the complication rate was 20% (wound infection, n = 1 and lethal mediastinitis, n = 1) in the control group and 10% (wound infection, n = 1) in the experimental group. The postoperative sternal deviation was significantly less remarkable at 1 month (123.3 +/- 32.2 degrees vs 159.4 +/- 19.7 degrees , P = 0.027), 3 months (109.8 +/- 34.7 degrees vs 150.9 +/- 34.2 degrees , P = 0.039) and 12 months (61 +/- 15.6 degrees vs 170.3 +/- 6.6 degrees , P = 0.046) in the experimental group than in the control group, whereas no significant difference was noted immediately after reconstruction (165.7 +/- 6.4 degrees vs 168.4 +/- 9.1 degrees , P = 0.50). Histological findings showed dense connective tissue in the regenerated chest wall in both groups and showed chondroblasts in the regenerated chest wall tissue at 3 and 6 months only in the experimental group. CONCLUSIONS: Our results suggest that anterior chest wall reconstruction with a rigid and bioabsorbable material is feasible and may be a valuable alternative to reconstruction with a non-rigid and non-absorbable material. PMID- 25505308 TI - A role for orbitofrontal cortex in reward-modulated conflict adaptation. PMID- 25505301 TI - Regulation of Helicobacter pylori Virulence Within the Context of Iron Deficiency. AB - Helicobacter pylori strains that harbor the oncoprotein CagA increase gastric cancer risk, and this risk is augmented under iron-deficient conditions. We demonstrate here that iron depletion induces coccoid morphology in strains lacking cagA. To evaluate the stability of augmented H. pylori virulence phenotypes stimulated by low-iron conditions, H. pylori isolated from iron depleted conditions in vivo were serially passaged in vitro. Long-term passage decreased the ability of hypervirulent strains to translocate CagA or induce interleukin 8, indicating that hypervirulent phenotypes stimulated by low-level iron conditions are reversible. Therefore, rectifying iron deficiency may attenuate disease among H. pylori-infected persons with no response to antibiotics. PMID- 25505309 TI - Modality-spanning deficits in attention-deficit/hyperactivity disorder in functional networks, gray matter, and white matter. AB - Previous neuroimaging investigations in attention-deficit/hyperactivity disorder (ADHD) have separately identified distributed structural and functional deficits, but interconnections between these deficits have not been explored. To unite these modalities in a common model, we used joint independent component analysis, a multivariate, multimodal method that identifies cohesive components that span modalities. Based on recent network models of ADHD, we hypothesized that altered relationships between large-scale networks, in particular, default mode network (DMN) and task-positive networks (TPNs), would co-occur with structural abnormalities in cognitive regulation regions. For 756 human participants in the ADHD-200 sample, we produced gray and white matter volume maps with voxel-based morphometry, as well as whole-brain functional connectomes. Joint independent component analysis was performed, and the resulting transmodal components were tested for differential expression in ADHD versus healthy controls. Four components showed greater expression in ADHD. Consistent with our a priori hypothesis, we observed reduced DMN-TPN segregation co-occurring with structural abnormalities in dorsolateral prefrontal cortex and anterior cingulate cortex, two important cognitive control regions. We also observed altered intranetwork connectivity in DMN, dorsal attention network, and visual network, with co occurring distributed structural deficits. There was strong evidence of spatial correspondence across modalities: For all four components, the impact of the respective component on gray matter at a region strongly predicted the impact on functional connectivity at that region. Overall, our results demonstrate that ADHD involves multiple, cohesive modality spanning deficits, each one of which exhibits strong spatial overlap in the pattern of structural and functional alterations. PMID- 25505311 TI - Odorant concentration differentiator for intermittent olfactory signals. AB - Animals need to discriminate differences in spatiotemporally distributed sensory signals in terms of quality as well as quantity for generating adaptive behavior. Olfactory signals characterized by odor identity and concentration are intermittently distributed in the environment. From these intervals of stimulation, animals process odorant concentration to localize partners or food sources. Although concentration-response characteristics in olfactory neurons have traditionally been investigated using single stimulus pulses, their behavior under intermittent stimulus regimens remains largely elusive. Using the silkmoth (Bombyx mori) pheromone processing system, a simple and behaviorally well-defined model for olfaction, we investigated the neuronal representation of odorant concentration upon intermittent stimulation in the naturally occurring range. To the first stimulus in a series, the responses of antennal lobe (AL) projection neurons (PNs) showed a concentration dependence as previously shown in many olfactory systems. However, PN response amplitudes dynamically changed upon exposure to intermittent stimuli of the same odorant concentration and settled to a constant, largely concentration-independent level. As a result, PN responses emphasized odorant concentration changes rather than encoding absolute concentration in pulse trains of stimuli. Olfactory receptor neurons did not contribute to this response transformation which was due to long-lasting inhibition affecting PNs in the AL. Simulations confirmed that inhibition also provides advantages when stimuli have naturalistic properties. The primary olfactory center thus functions as an odorant concentration differentiator to efficiently detect concentration changes, thereby improving odorant source orientation over a wide concentration range. PMID- 25505310 TI - Optogenetic excitation of central amygdala amplifies and narrows incentive motivation to pursue one reward above another. AB - Choosing one reward above another is important for achieving adaptive life goals. Yet hijacked into excessive intensity in disorders such as addiction, single minded pursuit becomes maladaptive. Here, we report that optogenetic channelrhodopsin stimulation of neurons in central nucleus of amygdala (CeA), paired with earning a particular sucrose reward in rats, amplified and narrowed incentive motivation to that single reward target. Therefore, CeA rats chose and intensely pursued only the laser-paired sucrose reward while ignoring an equally good sucrose alternative. In contrast, reward-paired stimulation of basolateral amygdala did not hijack choice. In a separate measure of incentive motivation, CeA stimulation also increased the progressive ratio breakpoint or level of effort exerted to obtain sucrose reward. However, CeA stimulation by itself failed to support behavioral self-stimulation in the absence of any paired external food reward, suggesting that CeA photo-excitation specifically transformed the value of its external reward (rather than adding an internal reinforcement state). Nor did CeA stimulation by itself induce any aversive state that motivated escape. Finally, CeA stimulation also failed to enhance 'liking' reactions elicited by sucrose taste and did not simply increase the general motivation to eat. This pattern suggests that CeA photo-excitation specifically enhances and narrows incentive motivation to pursue an associated external reward at the expense of another comparable reward. PMID- 25505313 TI - Cognitive enhancement or cognitive cost: trait-specific outcomes of brain stimulation in the case of mathematics anxiety. AB - The surge in noninvasive brain stimulation studies investigating cognitive enhancement has neglected the effect of interindividual differences, such as traits, on stimulation outcomes. Using the case of mathematics anxiety in a sample of healthy human participants in a placebo-controlled, double-blind, crossover experiment, we show that identical transcranial direct current stimulation (tDCS) exerts opposite behavioral and physiological effects depending on individual trait levels. Mathematics anxiety is the negative emotional response elicited by numerical tasks, impairing mathematical achievement. tDCS was applied to the dorsolateral prefrontal cortex, a frequent target for modulating emotional regulation. It improved reaction times on simple arithmetic decisions and decreased cortisol concentrations (a biomarker of stress) in high mathematics anxiety individuals. In contrast, tDCS impaired reaction times for low mathematics anxiety individuals and prevented a decrease in cortisol concentration compared with sham stimulation. Both groups showed a tDCS-induced side effect-impaired executive control in a flanker task-a cognitive function subserved by the stimulated region. These behavioral and physiological double dissociations have implications for brain stimulation research by highlighting the role of individual traits in experimental findings. Brain stimulation clearly does not produce uniform benefits, even applied in the same configuration during the same tasks, but may interact with traits to produce markedly opposed outcomes. PMID- 25505312 TI - Neuronal transgene expression in dominant-negative SNARE mice. AB - Experimental advances in the study of neuroglia signaling have been greatly accelerated by the generation of transgenic mouse models. In particular, an elegant manipulation that interferes with astrocyte vesicular release of gliotransmitters via overexpression of a dominant-negative domain of vesicular SNARE (dnSNARE) has led to documented astrocytic involvement in processes that were traditionally considered strictly neuronal, including the sleep-wake cycle, LTP, cognition, cortical slow waves, depression, and pain. A key premise leading to these conclusions was that expression of the dnSNARE was specific to astrocytes. Inconsistent with this premise, we report here widespread expression of the dnSNARE transgene in cortical neurons. We further demonstrate that the activity of cortical neurons is reversibly suppressed in dnSNARE mice. These findings highlight the need for independent validation of astrocytic functions identified in dnSNARE mice and thus question critical evidence that astrocytes contribute to neurotransmission through SNARE-dependent vesicular release of gliotransmitters. PMID- 25505314 TI - Voltage imaging of waking mouse cortex reveals emergence of critical neuronal dynamics. AB - Complex cognitive processes require neuronal activity to be coordinated across multiple scales, ranging from local microcircuits to cortex-wide networks. However, multiscale cortical dynamics are not well understood because few experimental approaches have provided sufficient support for hypotheses involving multiscale interactions. To address these limitations, we used, in experiments involving mice, genetically encoded voltage indicator imaging, which measures cortex-wide electrical activity at high spatiotemporal resolution. Here we show that, as mice recovered from anesthesia, scale-invariant spatiotemporal patterns of neuronal activity gradually emerge. We show for the first time that this scale invariant activity spans four orders of magnitude in awake mice. In contrast, we found that the cortical dynamics of anesthetized mice were not scale invariant. Our results bridge empirical evidence from disparate scales and support theoretical predictions that the awake cortex operates in a dynamical regime known as criticality. The criticality hypothesis predicts that small-scale cortical dynamics are governed by the same principles as those governing larger scale dynamics. Importantly, these scale-invariant principles also optimize certain aspects of information processing. Our results suggest that during the emergence from anesthesia, criticality arises as information processing demands increase. We expect that, as measurement tools advance toward larger scales and greater resolution, the multiscale framework offered by criticality will continue to provide quantitative predictions and insight on how neurons, microcircuits, and large-scale networks are dynamically coordinated in the brain. PMID- 25505316 TI - Controlling NMDA receptor subunit composition using ectopic retention signals. AB - Ligand-gated ion channels (LGICs) mediate fast synaptic transmission in the CNS. Typically, these membrane proteins are multimeric complexes associating several homologous subunits around a central pore. Because of the large repertoire of subunits within each family, LGICs exist in vivo as multiple subtypes that differ in subunit composition and functional properties. Establishing the specific properties of individual receptor subtypes remains a major goal in the field of neuroscience and molecular pharmacology. However, isolating specific receptor subtype in recombinant systems can be problematic because of the mixture of receptor populations. This is the case for NMDA receptors (NMDARs), a large family of tetrameric glutamate-gated ion channels that play key roles in brain physiology and pathology. A significant fraction of native NMDARs are triheteromers composed of two GluN1 subunits and two different GluN2 subunits (GluN2A-D). We developed a method based on dual retention signals adapted from G protein-coupled GABA-B receptors allowing exclusive cell surface expression of triheteromeric rat NMDARs while coexpressed diheteromeric receptors (which contain a single type of GluN2 subunit) are retained intracellularly. Using this approach, we determined the functional properties of GluN1/GluN2A/GluN2B triheteromers, one of the most abundant NMDAR subtypes in the adult forebrain, revealing their unique gating and pharmacological attributes. We envision applicability of the retention signal approach for the study of a variety of heteromeric glutamate-gated ion channel receptors with defined subunit composition. PMID- 25505315 TI - Compartment-specific modulation of GABAergic synaptic transmission by TRPV1 channels in the dentate gyrus. AB - The transient receptor potential TRPV1 or vanilloid receptor is a nonselective ligand-gated channel highly expressed in primary sensory neurons where it mediates nociception. TRPV1 is also expressed in the brain where its activation depresses excitatory synaptic transmission. Whether TRPV1 also regulates inhibitory synapses in the brain is unclear. Here, using a combination of pharmacology, electrophysiology, and an in vivo knockdown strategy, we report that TRPV1 activation by capsaicin or by the endocannabinoid anandamide depresses somatic, but not dendritic inhibitory transmission in both rat and mouse dentate gyrus. The effect on somatic inhibition was absent in TRPV1 knock-out mice and was also eliminated by two different TRPV1 shRNAs expressed in dentate granule cells, strongly supporting a functional role for TRPV1 in modulating GABAergic synaptic function. Moreover, TRPV1-mediated depression occurs independently of GABA release, requires postsynaptic Ca(2+) rise and activation of calcineurin, and is likely due to clathrin-dependent internalization of GABA receptors. Altogether, these findings reveal a novel form of compartment-specific regulation whereby TRPV1 channels can modify synaptic function in the brain. PMID- 25505317 TI - Synaptic strength is bidirectionally controlled by opposing activity-dependent regulation of Nedd4-1 and USP8. AB - The trafficking of AMPA receptors (AMPARs) to and from synapses is crucial for synaptic plasticity. Previous work has demonstrated that AMPARs undergo activity dependent ubiquitination by the E3 ubiquitin ligase Nedd4-1, which promotes their internalization and degradation in lysosomes. Here, we define the molecular mechanisms involved in ubiquitination and deubiquitination of AMPARs. We report that Nedd4-1 is rapidly redistributed to dendritic spines in response to AMPAR activation and not in response to NMDA receptor (NMDAR) activation in cultured rat neurons. In contrast, NMDAR activation directly antagonizes Nedd4-1 function by promoting the deubiquitination of AMPARs. We show that NMDAR activation causes the rapid dephosphorylation and activation of the deubiquitinating enzyme (DUB) USP8. Surface AMPAR levels and synaptic strength are inversely regulated by Nedd4 1 and USP8. Strikingly, we show that homeostatic downscaling of synaptic strength is accompanied by an increase and decrease in Nedd4-1 and USP8 protein levels, respectively. Furthermore, we show that Nedd4-1 is required for homeostatic loss of surface AMPARs and downscaling of synaptic strength. This study provides the first mechanistic evidence for rapid and opposing activity-dependent control of a ubiquitin ligase and DUB at mammalian CNS synapses. We propose that the dynamic regulation of these opposing forces is critical in maintaining synapses and scaling them during homeostatic plasticity. PMID- 25505319 TI - Initial investigation of the effects of an experimentally learned schema on spatial associative memory in humans. AB - Networks of interconnected neocortical representations of prior knowledge, "schemas," facilitate memory for congruent information. This facilitation is thought to be mediated by augmented encoding and accelerated consolidation. However, it is less clear how schema affects retrieval. Rodent and human studies to date suggest that schema-related memories are differently retrieved. However, these studies differ substantially as most human studies implement pre experimental world-knowledge as schemas and tested item or nonspatial associative memory, whereas animal studies have used intraexperimental schemas based on item location associations within a complex spatial layout that, in humans, could engage more strategic retrieval processes. Here, we developed a paradigm conceptually linked to rodent studies to examine the effects of an experimentally learned spatial associative schema on learning and retrieval of new object location associations and to investigate the neural mechanisms underlying schema related retrieval. Extending previous findings, we show that retrieval of schema defining associations is related to activity along anterior and posterior midline structures and angular gyrus. The existence of such spatial associative schema resulted in more accurate learning and retrieval of new, related associations, and increased time allocated to retrieve these associations. This retrieval was associated with right dorsolateral prefrontal and lateral parietal activity, as well as interactions between the right dorsolateral prefrontal cortex and medial and lateral parietal regions, and between the medial prefrontal cortex and posterior midline regions, supporting the hypothesis that retrieval of new, schema-related object-location associations in humans also involves augmented monitoring and systematic search processes. PMID- 25505318 TI - An RNA binding protein promotes axonal integrity in peripheral neurons by destabilizing REST. AB - The RE1 Silencing Transcription Factor (REST) acts as a governor of the mature neuronal phenotype by repressing a large consortium of neuronal genes in non neuronal cells. In the developing nervous system, REST is present in progenitors and downregulated at terminal differentiation to promote acquisition of mature neuronal phenotypes. Paradoxically, REST is still detected in some regions of the adult nervous system, but how REST levels are regulated, and whether REST can still repress neuronal genes, is not known. Here, we report that homeostatic levels of REST are maintained in mature peripheral neurons by a constitutive post transcriptional mechanism. Specifically, using a three-hybrid genetic screen, we identify the RNA binding protein, ZFP36L2, associated previously only with female fertility and hematopoiesis, and show that it regulates REST mRNA stability. Dorsal root ganglia in Zfp36l2 knock-out mice, or wild-type ganglia expressing ZFP36L2 shRNA, show higher steady-state levels of Rest mRNA and protein, and extend thin and disintegrating axons. This phenotype is due, at least in part, to abnormally elevated REST levels in the ganglia because the axonal phenotype is attenuated by acute knockdown of REST in Zfp36l2 KO DRG explants. The higher REST levels result in lower levels of target genes, indicating that REST can still fine-tune gene expression through repression. Thus, REST levels are titrated in mature peripheral neurons, in part through a ZFP36L2-mediated post transcriptional mechanism, with consequences for axonal integrity. PMID- 25505320 TI - Preictal activity of subicular, CA1, and dentate gyrus principal neurons in the dorsal hippocampus before spontaneous seizures in a rat model of temporal lobe epilepsy. AB - Previous studies suggest that spontaneous seizures in patients with temporal lobe epilepsy might be preceded by increased action potential firing of hippocampal neurons. Preictal activity is potentially important because it might provide new opportunities for predicting when a seizure is about to occur and insight into how spontaneous seizures are generated. We evaluated local field potentials and unit activity of single, putative excitatory neurons in the subiculum, CA1, CA3, and dentate gyrus of the dorsal hippocampus in epileptic pilocarpine-treated rats as they experienced spontaneous seizures. Average action potential firing rates of neurons in the subiculum, CA1, and dentate gyrus, but not CA3, increased significantly and progressively beginning 2-4 min before locally recorded spontaneous seizures. In the subiculum, CA1, and dentate gyrus, but not CA3, 41 57% of neurons displayed increased preictal activity with significant consistency across multiple seizures. Much of the increased preictal firing of neurons in the subiculum and CA1 correlated with preictal theta activity, whereas preictal firing of neurons in the dentate gyrus was independent of theta. In addition, some CA1 and dentate gyrus neurons displayed reduced firing rates preictally. These results reveal that different hippocampal subregions exhibit differences in the extent and potential underlying mechanisms of preictal activity. The finding of robust and significantly consistent preictal activity of subicular, CA1, and dentate neurons in the dorsal hippocampus, despite the likelihood that many seizures initiated in other brain regions, suggests the existence of a broader neuronal network whose activity changes minutes before spontaneous seizures initiate. PMID- 25505321 TI - Synaptic calcium regulation in hair cells of the chicken basilar papilla. AB - Cholinergic inhibition of hair cells occurs by activation of calcium-dependent potassium channels. A near-membrane postsynaptic cistern has been proposed to serve as a store from which calcium is released to supplement influx through the ionotropic ACh receptor. However, the time and voltage dependence of acetylcholine (ACh)-evoked potassium currents reveal a more complex relationship between calcium entry and release from stores. The present work uses voltage steps to regulate calcium influx during the application of ACh to hair cells in the chicken basilar papilla. When calcium influx was terminated at positive membrane potential, the ACh-evoked potassium current decayed exponentially over ~100 ms. However, at negative membrane potentials, this current exhibited a secondary rise in amplitude that could be eliminated by dihydropyridine block of the voltage-gated calcium channels of the hair cell. Calcium entering through voltage-gated channels may transit through the postsynaptic cistern, since ryanodine and sarcoendoplasmic reticulum calcium-ATPase blockers altered the time course and magnitude of this secondary, voltage-dependent contribution to ACh evoked potassium current. Serial section electron microscopy showed that efferent and afferent synaptic structures are juxtaposed, supporting the possibility that voltage-gated influx at afferent ribbon synapses influences calcium homeostasis during long-lasting cholinergic inhibition. In contrast, spontaneous postsynaptic currents ("minis") resulting from stochastic efferent release of ACh were made briefer by ryanodine, supporting the hypothesis that the synaptic cistern serves primarily as a calcium barrier and sink during low-level synaptic activity. Hypolemmal cisterns such as that at the efferent synapse of the hair cell can play a dynamic role in segregating near-membrane calcium for short-term and long term signaling. PMID- 25505323 TI - Hypoxia inducible factor-1alpha (HIF-1alpha) is required for neural stem cell maintenance and vascular stability in the adult mouse SVZ. AB - HIF-1alpha is a hypoxia-inducible protein that regulates many cell and molecular processes, including those involved in angiogenesis and stem cell maintenance. Prior studies demonstrated constitutive HIF-1alpha stabilization in neural stem cells (NSCs) of the adult mouse SVZ, but its role there has not been elucidated. Here, we tested the hypothesis that HIF-1alpha plays an essential role in the maintenance of adult NSCs and stabilization of the SVZ vascular niche using conditional, tamoxifen-inducible Hif1a knock-out mice. We generated nestin CreER(T2)/R26R-YFP/Hif1a(fl/fl) triple transgenic mice, to enable tamoxifen inducible Hif1a gene inactivation in nestin-expressing NSCs within the adult SVZ. Hif1a gene deletion resulted in a significant loss of YFP(+) NSCs within the SVZ by 45 d post recombination, which was preceded by significant regression of the SVZ vasculature at 14 d, and concomitant decrease of VEGF expression by NSCs. Loss of YFP(+) NSCs following Hif1a gene inactivation in vivo was likely an indirect consequence of vascular regression, since YFP(+) neurosphere formation over serial passage was unaffected. These results identify NSC-encoded HIF-1alpha as an essential factor in the maintenance of the adult SVZ, and demonstrate that NSCs within the SVZ maintain the integrity of their vascular niche through HIF 1alpha-mediated signaling mechanisms. PMID- 25505322 TI - Live imaging of endogenous PSD-95 using ENABLED: a conditional strategy to fluorescently label endogenous proteins. AB - Stoichiometric labeling of endogenous synaptic proteins for high-contrast live cell imaging in brain tissue remains challenging. Here, we describe a conditional mouse genetic strategy termed endogenous labeling via exon duplication (ENABLED), which can be used to fluorescently label endogenous proteins with near ideal properties in all neurons, a sparse subset of neurons, or specific neuronal subtypes. We used this method to label the postsynaptic density protein PSD-95 with mVenus without overexpression side effects. We demonstrated that mVenus tagged PSD-95 is functionally equivalent to wild-type PSD-95 and that PSD-95 is present in nearly all dendritic spines in CA1 neurons. Within spines, while PSD 95 exhibited low mobility under basal conditions, its levels could be regulated by chronic changes in neuronal activity. Notably, labeled PSD-95 also allowed us to visualize and unambiguously examine otherwise-unidentifiable excitatory shaft synapses in aspiny neurons, such as parvalbumin-positive interneurons and dopaminergic neurons. Our results demonstrate that the ENABLED strategy provides a valuable new approach to study the dynamics of endogenous synaptic proteins in vivo. PMID- 25505324 TI - Utility-based early modulation of processing distracting stimulus information. AB - Humans are selective information processors who efficiently prevent goal inappropriate stimulus information to gain control over their actions. Nonetheless, stimuli, which are both unnecessary for solving a current task and liable to cue an incorrect response (i.e., "distractors"), frequently modulate task performance, even when consistently paired with a physical feature that makes them easily discernible from target stimuli. Current models of cognitive control assume adjustment of the processing of distractor information based on the overall distractor utility (e.g., predictive value regarding the appropriate response, likelihood to elicit conflict with target processing). Although studies on distractor interference have supported the notion of utility-based processing adjustment, previous evidence is inconclusive regarding the specificity of this adjustment for distractor information and the stage(s) of processing affected. To assess the processing of distractors during sensory-perceptual phases we applied EEG recording in a stimulus identification task, involving successive distractor target presentation, and manipulated the overall distractor utility. Behavioral measures replicated previously found utility modulations of distractor interference. Crucially, distractor-evoked visual potentials (i.e., posterior N1) were more pronounced in high-utility than low-utility conditions. This effect generalized to distractors unrelated to the utility manipulation, providing evidence for item-unspecific adjustment of early distractor processing to the experienced utility of distractor information. PMID- 25505325 TI - GLOBIN-5-dependent O2 responses are regulated by PDL-1/PrBP that targets prenylated soluble guanylate cyclases to dendritic endings. AB - Aerobic animals constantly monitor and adapt to changes in O2 levels. The molecular mechanisms involved in sensing O2 are, however, incompletely understood. Previous studies showed that a hexacoordinated globin called GLB-5 tunes the dynamic range of O2-sensing neurons in natural C. elegans isolates, but is defective in the N2 lab reference strain (McGrath et al., 2009; Persson et al., 2009). GLB-5 enables a sharp behavioral switch when O2 changes between 21 and 17%. Here, we show that GLB-5 also confers rapid behavioral and cellular recovery from exposure to hypoxia. Hypoxia reconfigures O2-evoked Ca(2+) responses in the URX O2 sensors, and GLB-5 enables rapid recovery of these responses upon re-oxygenation. Forward genetic screens indicate that GLB-5's effects on O2 sensing require PDL-1, the C. elegans ortholog of mammalian PrBP/PDE6delta protein. In mammals, PDE6delta regulates the traffic and activity of prenylated proteins (Zhang et al., 2004; Norton et al., 2005). PDL-1 promotes localization of GCY-33 and GCY-35, atypical soluble guanylate cyclases that act as O2 sensors, to the dendritic endings of URX and BAG neurons, where they colocalize with GLB-5. Both GCY-33 and GCY-35 are predicted to be prenylated. Dendritic localization is not essential for GCY-35 to function as an O2 sensor, but disrupting pdl-1 alters the URX neuron's O2 response properties. Functional GLB-5 can restore dendritic localization of GCY-33 in pdl-1 mutants, suggesting GCY-33 and GLB-5 are in a complex. Our data suggest GLB-5 and the soluble guanylate cyclases operate in close proximity to sculpt O2 responses. PMID- 25505326 TI - GABAergic projections from the medial septum selectively inhibit interneurons in the medial entorhinal cortex. AB - The medial septum (MS) is required for theta rhythmic oscillations and grid cell firing in the medial entorhinal cortex (MEC). While GABAergic, glutamatergic, and cholinergic neurons project from the MS to the MEC, their synaptic targets are unknown. To investigate whether MS neurons innervate specific layers and cell types in the MEC, we expressed channelrhodopsin-2 in mouse MS neurons and used patch-clamp recording in brain slices to determine the response to light activation of identified cells in the MEC. Following activation of MS axons, we observed fast monosynaptic GABAergic IPSPs in the majority (>60%) of fast-spiking (FS) and low-threshold-spiking (LTS) interneurons in all layers of the MEC, but in only 1.5% of nonstellate principal cells (NSPCs) and in no stellate cells. We also observed fast glutamatergic responses to MS activation in a minority (<5%) of NSPCs, FS, and LTS interneurons. During stimulation of MS inputs at theta frequency (10 Hz), the amplitude of GABAergic IPSPs was maintained, and spike output from LTS and FS interneurons was entrained at low (25-60 Hz) and high (60 180 Hz) gamma frequencies, respectively. By demonstrating cell type-specific targeting of the GABAergic projection from the MS to the MEC, our results support the idea that the MS controls theta frequency activity in the MEC through coordination of inhibitory circuits. PMID- 25505328 TI - Alternative splicing coupled nonsense-mediated decay generates neuronal cell type specific expression of SLM proteins. AB - The unique physiological and morphological properties of neuronal populations are crucial for the appropriate functioning of neuronal circuits. Alternative splicing represents an attractive mechanism for generating cell type-specific molecular repertoires that steer neuronal development and function. However, the mechanisms that link neuronal identity to alternative splicing programs are poorly understood. We report that cell type-specific, mutually exclusive expression of two alternative splicing regulators, SLM1 and SLM2, in the mouse hippocampus is achieved by a cross-repression mechanism. Deletion of SLM2 in vivo modifies alternative splicing of its paralog Slm1 and stabilizes its mRNA, resulting in expression of SLM1 in previously SLM2-expressing cells. Despite this ectopic upregulation of SLM1, loss of SLM2 severely disrupts the alternative splicing regulation of Nrxn1, Nrxn2, and Nrxn3, highlighting that the two SLM paralogs have partially divergent functions. Our study uncovers a hierarchical, SLM2-dependent mechanism for establishing cell type-specific expression of neuronal splicing regulators in vivo. PMID- 25505327 TI - Human subthalamic nucleus in movement error detection and its evaluation during visuomotor adaptation. AB - Monitoring and evaluating movement errors to guide subsequent movements is a critical feature of normal motor control. Previously, we showed that the postmovement increase in electroencephalographic (EEG) beta power over the sensorimotor cortex reflects neural processes that evaluate motor errors consistent with Bayesian inference (Tan et al., 2014). Whether such neural processes are limited to this cortical region or involve the basal ganglia is unclear. Here, we recorded EEG over the cortex and local field potential (LFP) activity in the subthalamic nucleus (STN) from electrodes implanted in patients with Parkinson's disease, while they moved a joystick-controlled cursor to visual targets displayed on a computer screen. After movement offsets, we found increased beta activity in both local STN LFP and sensorimotor cortical EEG and in the coupling between the two, which was affected by both error magnitude and its contextual saliency. The postmovement increase in the coupling between STN and cortex was dominated by information flow from sensorimotor cortex to STN. However, an information drive appeared from STN to sensorimotor cortex in the first phase of the adaptation, when a constant rotation was applied between joystick inputs and cursor outputs. The strength of the STN to cortex drive correlated with the degree of adaption achieved across subjects. These results suggest that oscillatory activity in the beta band may dynamically couple the sensorimotor cortex and basal ganglia after movements. In particular, beta activity driven from the STN to cortex indicates task-relevant movement errors, information that may be important in modifying subsequent motor responses. PMID- 25505329 TI - Hippocampal metaplasticity is required for the formation of temporal associative memories. AB - Metaplasticity regulates the threshold for modification of synaptic strength and is an important regulator of learning rules; however, it is not known whether these cellular mechanisms for homeostatic regulation of synapses contribute to particular forms of learning. Conditional ablation of mGluR5 in CA1 pyramidal neurons resulted in the inability of low-frequency trains of afferent activation to prime synapses for subsequent theta burst potentiation. Priming-induced metaplasticity requires mGluR5-mediated mobilization of endocannabinoids during the priming train to induce long-term depression of inhibition (I-LTD). Mice lacking priming-induced plasticity had no deficit in spatial reference memory tasks, but were impaired in an associative task with a temporal component. Conversely, enhancing endocannabinoid signaling facilitated temporal associative memory acquisition and, after training animals in these tasks, ex vivo I-LTD was partially occluded and theta burst LTP was enhanced. Together, these results suggest a link between metaplasticity mechanisms in the hippocampus and the formation of temporal associative memories. PMID- 25505331 TI - Antigen dependently activated cluster of differentiation 8-positive T cells cause perforin-mediated neurotoxicity in experimental stroke. AB - Neuroinflammation plays a key role in secondary brain damage after stroke. Although deleterious effects of proinflammatory cytokines are well characterized, direct cytotoxic effects of invading immune cells on the ischemic brain and the importance of their antigen-dependent activation are essentially unknown. Here we examined the effects of adaptive and innate immune cells-cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells-that share the direct perforin-mediated cytotoxic pathway on outcome after cerebral ischemia in mice. Although CTLs and NK cells both invaded the ischemic brain, only brain-infiltrating CTLs but not NK cells were more activated than their splenic counterparts. Depletion of CTLs decreased infarct volumes and behavioral deficit in two ischemia models, whereas NK cell depletion had no effect. Correspondingly, adoptive CTL transfer from wild type into Rag1 knock-out mice increased infarct size. Adoptive CTL transfer from perforin knock-out or interferon-gamma knock-out mice into Rag1 knock-out mice revealed that CTL neurotoxicity was mediated by perforin. Accordingly, CTLs isolated from wild-type or interferon-gamma knock-out but not from perforin knock out mice induced neuronal cell death in vitro. CTLs derived from ovalbumin specific T-cell receptor transgenic mice were not activated and infiltrated less into the ischemic brain compared with wild-type CTLs. Their transfer did not increase the infarct size of Rag1 knock-out mice, indicating antigen-dependent activation as an essential component of CTL neurotoxicity. Our findings underscore the importance of antigen-dependent, direct cytotoxic immune responses in stroke and suggest modulation of CTLs and their effector pathways as a potential new strategy for stroke therapy. PMID- 25505330 TI - D1-dependent 4 Hz oscillations and ramping activity in rodent medial frontal cortex during interval timing. AB - Organizing behavior in time is a fundamental process that is highly conserved across species. Here we study the neural basis of timing processes. First, we found that rodents had a burst of stimulus-triggered 4 Hz oscillations in the medial frontal cortex (MFC) during interval timing tasks. Second, rodents with focally disrupted MFC D1 dopamine receptor (D1DR) signaling had impaired interval timing performance and weaker stimulus-triggered oscillations. Prior work has demonstrated that MFC neurons ramp during interval timing, suggesting that they underlie temporal integration. We found that MFC D1DR blockade strongly attenuated ramping activity of MFC neurons that correlated with behavior. These macro- and micro-level phenomena were linked, as we observed that MFC neurons with strong ramping activity tended to be coherent with stimulus-triggered 4 Hz oscillations, and this relationship was diminished with MFC D1DR blockade. These data provide evidence demonstrating how D1DR signaling controls the temporal organization of mammalian behavior. PMID- 25505332 TI - The neural representation of interaural time differences in gerbils is transformed from midbrain to cortex. AB - Interaural time differences (ITDs) are the dominant cue for the localization of low-frequency sounds. While much is known about the processing of ITDs in the auditory brainstem and midbrain, there have been relatively few studies of ITD processing in auditory cortex. In this study, we compared the neural representation of ITDs in the inferior colliculus (IC) and primary auditory cortex (A1) of gerbils. Our IC results were largely consistent with previous studies, with most cells responding maximally to ITDs that correspond to the contralateral edge of the physiological range. In A1, however, we found that preferred ITDs were distributed evenly throughout the physiological range without any contralateral bias. This difference in the distribution of preferred ITDs in IC and A1 had a major impact on the coding of ITDs at the population level: while a labeled-line decoder that considered the tuning of individual cells performed well on both IC and A1 responses, a two-channel decoder based on the overall activity in each hemisphere performed poorly on A1 responses relative to either labeled-line decoding of A1 responses or two-channel decoding of IC responses. These results suggest that the neural representation of ITDs in gerbils is transformed from IC to A1 and have important implications for how spatial location may be combined with other acoustic features for the analysis of complex auditory scenes. PMID- 25505334 TI - Independent premotor encoding of the sequence and structure of birdsong in avian cortex. AB - How the brain coordinates rapid sequences of learned behavior, such as human speech, remains a fundamental problem in neuroscience. Birdsong is a model of such behavior, which is learned and controlled by a neural circuit that spans avian cortex, basal ganglia, and thalamus. The songs of adult male zebra finches (Taeniopygia guttata), produced as rapid sequences of vocal gestures (syllables), are encoded by the cortical premotor region HVC (proper name). While the motor encoding of song within HVC has traditionally been viewed as unitary and distributed, we used an ablation technique to ask whether the sequence and structure of song are processed independently within HVC. Results revealed a functional topography across the medial-lateral axis of HVC. Bilateral ablation of medial HVC induced a positive disruption of song (increase in atypical syllable sequences), whereas bilateral ablation of lateral HVC induced a negative disruption (omission of individual syllables). Bilateral ablation of central HVC either had no effect on song or induced syllable omission, similar to lateral HVC ablation. We then investigated HVC connectivity and found parallel afferent and efferent pathways that transit medial and lateral HVC and converge at vocal motor cortex. In light of recent evidence that syntactic and lexical components of human speech are processed independently by neighboring regions of cortex (Menenti et al., 2012), our demonstration of anatomically distinct pathways that differentially process the sequence and structure of birdsong in parallel suggests that the vertebrate brain relies on a common approach to encode rapid sequences of vocal gestures. PMID- 25505335 TI - Antibody-derived in vivo imaging of tau pathology. AB - Antibodies or their derivatives as imaging probes for pathological tau protein have great potential, but have not been well studied. In particular, smaller, single-chain-variable antibody fragments (scFv's) are attractive for detecting tau lesions in live subjects. Here, we generated libraries of scFv's and identified numerous phospho-tau-selective scFv's. Peripheral injection of one of these scFv's consistently resulted in a strong in vivo brain signal in transgenic tauopathy mice, but not in wild-type or amyloid-beta plaque mice. The parent tau antibody provided similar results, albeit with a weaker signal intensity. The imaging signal correlated very well with colocalization of the probe with intraneuronal tau aggregates. Both were associated with markers of endosomes, autophagosomes, and lysosomes, suggesting their interaction in these degradation pathways. Such specific antibody-derived imaging probes have great potential as diagnostic markers for Alzheimer's disease and related tauopathies. PMID- 25505333 TI - The LIM homeodomain factor Lhx2 is required for hypothalamic tanycyte specification and differentiation. AB - Hypothalamic tanycytes, a radial glial-like ependymal cell population that expresses numerous genes selectively enriched in embryonic hypothalamic progenitors and adult neural stem cells, have recently been observed to serve as a source of adult-born neurons in the mammalian brain. The genetic mechanisms that regulate the specification and maintenance of tanycyte identity are unknown, but are critical for understanding how these cells can act as adult neural progenitor cells. We observe that LIM (Lin-11, Isl-1, Mec-3)-homeodomain gene Lhx2 is selectively expressed in hypothalamic progenitor cells and tanycytes. To test the function of Lhx2 in tanycyte development, we used an intersectional genetic strategy to conditionally delete Lhx2 in posteroventral hypothalamic neuroepithelium, both embryonically and postnatally. We observed that tanycyte development was severely disrupted when Lhx2 function was ablated during embryonic development. Lhx2-deficient tanycytes lost expression of tanycyte specific genes, such as Rax, while also displaying ectopic expression of genes specific to cuboid ependymal cells, such as Rarres2. Ultrastructural analysis revealed that mutant tanycytes exhibited a hybrid identity, retaining radial morphology while becoming multiciliated. In contrast, postnatal loss of function of Lhx2 resulted only in loss of expression of tanycyte-specific genes. Using chromatin immunoprecipitation, we further showed that Lhx2 directly regulated expression of Rax, an essential homeodomain factor for tanycyte development. This study identifies Lhx2 as a key intrinsic regulator of tanycyte differentiation, sustaining Rax-dependent activation of tanycyte-specific genes while also inhibiting expression of ependymal cell-specific genes. These findings provide key insights into the transcriptional regulatory network specifying this still poorly characterized cell type. PMID- 25505336 TI - Sex differences in the brain's dopamine signature of cigarette smoking. AB - Cigarette smoking is a major public health danger. Women and men smoke for different reasons and cessation treatments, such as the nicotine patch, are preferentially beneficial to men. The biological substrates of these sex differences are unknown. Earlier PET studies reported conflicting findings but were each hampered by experimental and/or analytical limitations. Our new image analysis technique, lp-ntPET (Normandin et al., 2012; Morris et al., 2013; Kim et al., 2014), has been optimized for capturing brief (lasting only minutes) and highly localized dopaminergic events in dynamic PET data. We coupled our analysis technique with high-resolution brain scanning and high-frequency motion correction to create the optimal experiment for capturing and characterizing the effects of smoking on the mesolimbic dopamine system in humans. Our main finding is that male smokers smoking in the PET scanner activate dopamine in the right ventral striatum during smoking but female smokers do not. This finding-men activating more ventrally than women-is consistent with the established notion that men smoke for the reinforcing drug effect of cigarettes whereas women smoke for other reasons, such as mood regulation and cue reactivity. lp-ntPET analysis produces a novel multidimensional endpoint: voxel-level temporal patterns of neurotransmitter release ("DA movies") in individual subjects. By examining these endpoints quantitatively, we demonstrate that the timing of dopaminergic responses to cigarette smoking differs between men and women. Men respond consistently and rapidly in the ventral striatum whereas women respond faster in a discrete subregion of the dorsal putamen. PMID- 25505338 TI - Unraveling mechanisms underlying partial agonism in 5-HT3A receptors. AB - Partial agonists have emerged as attractive therapeutic molecules. 2-Me-5HT and tryptamine have been defined as partial agonists of 5-HT3 receptors on the basis of macroscopic measurements. Because several mechanisms may limit maximal responses, we took advantage of the high-conductance form of the mouse serotonin type 3A (5-HT3A) receptor to understand their molecular actions. Individual 5-HT bound receptors activate in long episodes of high open probability, consisting of groups of openings in quick succession. The activation pattern is similar for 2 Me-5HT only at very low concentrations since profound channel blockade takes place within the activating concentration range. In contrast, activation episodes are significantly briefer in the presence of tryptamine. Generation of a full activation scheme reveals that the fully occupied receptor overcomes transitions to closed preopen states (primed states) before opening. Reduced priming explains the partial agonism of tryptamine. In contrast, 2-Me-5HT is not a genuine partial agonist since priming is not dramatically affected and its low apparent efficacy is mainly due to channel blockade. The analysis also shows that the first priming step is the rate-limiting step and partial agonists require an increased number of priming steps for activation. Molecular docking suggests that interactions are similar for 5-HT and 2-Me-5HT but slightly different for tryptamine. Our study contributes to understanding 5-HT3A receptor activation, extends the novel concept of partial agonism within the Cys-loop family, reveals novel aspects of partial agonism, and unmasks molecular actions of classically defined partial agonists. Unraveling mechanisms underlying partial responses has implications in the design of therapeutic compounds. PMID- 25505337 TI - Dopamine modulates the neural representation of subjective value of food in hungry subjects. AB - Although there is a rich literature on the role of dopamine in value learning, much less is known about its role in using established value estimations to shape decision-making. Here we investigated the effect of dopaminergic modulation on value-based decision-making for food items in fasted healthy human participants. The Becker-deGroot-Marschak auction, which assesses subjective value, was examined in conjunction with pharmacological fMRI using a dopaminergic agonist and an antagonist. We found that dopamine enhanced the neural response to value in the inferior parietal gyrus/intraparietal sulcus, and that this effect predominated toward the end of the valuation process when an action was needed to record the value. Our results suggest that dopamine is involved in acting upon the decision, providing additional insight to the mechanisms underlying impaired decision-making in healthy individuals and clinical populations with reduced dopamine levels. PMID- 25505340 TI - Slow oscillations during sleep coordinate interregional communication in cortical networks. AB - Large-amplitude sleep slow oscillations group faster neuronal oscillations and are of functional relevance for memory performance. However, relatively little is known about the impact of slow oscillations on functionally coupled networks. Here, we provide a comprehensive view on how human slow oscillatory dynamics influence various measures of brain processing. We demonstrate that slow oscillations coordinate interregional cortical communication, as assessed by phase synchrony in the sleep spindle frequency range and cross-frequency coupling between spindle and beta activity. Furthermore, we show that the organizing role of slow oscillations is restricted to circumscribed topographical areas. These findings add importantly to our basic understanding of the orchestrating role of slow oscillations. In addition, they are of considerable relevance for accounts of sleep-dependent memory reprocessing and consolidation. PMID- 25505339 TI - Human scalp potentials reflect a mixture of decision-related signals during perceptual choices. AB - Single-unit animal studies have consistently reported decision-related activity mirroring a process of temporal accumulation of sensory evidence to a fixed internal decision boundary. To date, our understanding of how response patterns seen in single-unit data manifest themselves at the macroscopic level of brain activity obtained from human neuroimaging data remains limited. Here, we use single-trial analysis of human electroencephalography data to show that population responses on the scalp can capture choice-predictive activity that builds up gradually over time with a rate proportional to the amount of sensory evidence, consistent with the properties of a drift-diffusion-like process as characterized by computational modeling. Interestingly, at time of choice, scalp potentials continue to appear parametrically modulated by the amount of sensory evidence rather than converging to a fixed decision boundary as predicted by our model. We show that trial-to-trial fluctuations in these response-locked signals exert independent leverage on behavior compared with the rate of evidence accumulation earlier in the trial. These results suggest that in addition to accumulator signals, population responses on the scalp reflect the influence of other decision-related signals that continue to covary with the amount of evidence at time of choice. PMID- 25505341 TI - Activity-dependent upregulation of presynaptic kainate receptors at immature CA3 CA1 synapses. AB - Presynaptic kainate-type glutamate receptors (KARs) regulate glutamate release probability and short-term plasticity in various areas of the brain. Here we show that long-term depression (LTD) in the area CA1 of neonatal rodent hippocampus is associated with an upregulation of tonic inhibitory KAR activity, which contributes to synaptic depression and causes a pronounced increase in short-term facilitation of transmission. This increased KAR function was mediated by high affinity receptors and required activation of NMDA receptors, nitric oxide (NO) synthetase, and postsynaptic calcium signaling. In contrast, KAR activity was irreversibly downregulated in response to induction of long-term potentiation in a manner that depended on activation of the TrkB-receptor of BDNF. Both tonic KAR activity and its plasticity were restricted to early stages of synapse development and were lost in parallel with maturation of the network due to ongoing BDNF-TrkB signaling. These data show that presynaptic KARs are targets for activity-dependent modulation via diffusible messengers NO and BDNF, which enhance and depress tonic KAR activity at immature synapses, respectively. The plasticity of presynaptic KARs in the developing network allows nascent synapses to shape their response to incoming activity. In particular, upregulation of KAR function after LTD allows the synapse to preferentially pass high-frequency afferent activity. This can provide a potential rescue from synapse elimination by uncorrelated activity and also increase the computational dynamics of the developing CA3-CA1 circuitry. PMID- 25505342 TI - Short- and long-term effects of brain death on post-transplant graft function in a rodent model. AB - OBJECTIVES: Heart transplantation has become the most effective treatment for end stage heart failure. Donors after brain death (BD) are currently the only reliable source for cardiac transplants. However, haemodynamic instability and cardiac dysfunction have been demonstrated in brain-dead donors and this could therefore also affect post-transplant graft function. We studied the effects of BD on cardiac function and its short-term (1 h) or long-term (5 h) impacts on graft function. METHODS: In Lewis rats, BD was induced by inflation of a subdurally placed balloon catheter (n = 7). Sham-operated rats served as controls (n = 9). We continuously assessed cardiac function by left ventricular (LV) pressure-volume analysis. Then, 1 or 5 h after BD or sham operation, hearts were perfused with a cold preservation solution (Custodiol), then explanted, stored at 4 degrees C in Custodiol and heterotopically transplanted. We evaluated graft function 1.5 h after transplantation. RESULTS: BD was associated with decreased left ventricular contractility (ejection fraction: 37 +/- 6 vs 57 +/- 5%; maximum rate of rise of LV pressure dP/dtmax: 4770 +/- 197 vs 7604 +/- 348 mmHg/s; dP/dtmax-end-diastolic volume: 60 +/- 7 vs 74 +/- 2 mmHg/s; slope Emax of the end systolic pressure-volume relationship: 2.4 +/- 0.1 vs 4.4 +/- 0.3 mmHg/ul; preload recruitable stroke work: 47 +/- 9 vs 78 +/- 3 mmHg; P <0.05) and relaxation (maximum rate of fall of left ventricular pressure dP/dtmin: -6638 +/- 722 vs -11 285 +/- 539 mmHg/s; time constant of left ventricular pressure decay Tau: 12.6 +/- 0.7 vs 10.5 +/- 0.4 ms; end-diastolic pressure-volume relationship: 0.22 +/- 0.05 vs 0.09 +/- 0.03 mmHg/ul, P <0.05) 45 min after its initiation and for the rest of 5 h compared with controls. Moreover, after transplantation, graft systolic and diastolic functions were impaired in the 5-h brain-dead group, while they were identical in the 1-h brain-dead group compared with the corresponding controls. CONCLUSIONS: We established a well-characterized in vivo rat model to examine the influence of BD on cardiac function using a miniaturized technology for pressure-volume analysis. These results demonstrate that impaired donor cardiac function after short-term BD is reversible after transplantation and long-term BD renders hearts more susceptible to ischaemia/reperfusion injury. PMID- 25505344 TI - Proposal to consistently apply the International Code of Nomenclature of Prokaryotes (ICNP) to names of the oxygenic photosynthetic bacteria (cyanobacteria), including those validly published under the International Code of Botanical Nomenclature (ICBN)/International Code of Nomenclature for algae, fungi and plants (ICN), and proposal to change Principle 2 of the ICNP. AB - This taxonomic note was motivated by the recent proposal [Oren & Garrity (2014) Int J Syst Evol Microbiol 64, 309-310] to exclude the oxygenic photosynthetic bacteria (cyanobacteria) from the wording of General Consideration 5 of the International Code of Nomenclature of Prokaryotes (ICNP), which entails unilateral coverage of these prokaryotes by the International Code of Nomenclature for algae, fungi, and plants (ICN; formerly the International Code of Botanical Nomenclature, ICBN). On the basis of key viewpoints, approaches and rules in the systematics, taxonomy and nomenclature of prokaryotes it is reciprocally proposed to apply the ICNP to names of cyanobacteria including those validly published under the ICBN/ICN. For this purpose, a change to Principle 2 of the ICNP is proposed to enable validation of cyanobacterial names published under the ICBN/ICN rules. PMID- 25505343 TI - Alicyclobacillus dauci sp. nov., a slightly thermophilic, acidophilic bacterium isolated from a spoiled mixed vegetable and fruit juice product. AB - A novel, moderately thermophilic, acidophilic, Gram-variable, rod-shaped, endospore-forming bacterium was isolated from a spoiled mixed vegetable and fruit juice product that had the off-flavour of guaiacol. The bacterium, strain 4F(T), grew aerobically at 20-50 degrees C (optimum 40 degrees C) and pH 3.0-6.0 (optimum pH 4.0) and produced acid from glycerol, d-galactose and d-glucose. It contained menaquinone-7 (MK-7) as the major isoprenoid quinone and the DNA G+C content was 49.6 mol%. The predominant cellular fatty acids of strain 4F(T) were omega-alicyclic (omega-cyclohexane fatty acids), which are characteristic of the genus Alicyclobacillus. Phylogenetic analyses based on 16S rRNA gene sequences showed that the strain belongs to the Alicyclobacillus cluster, and is related most closely to the type strains of Alicyclobacillus acidoterrestris (97.4 % similarity) and Alicyclobacillus fastidiosus (97.3 %). Strain 4F(T) produced guaiacol from vanillic acid. It can be distinguished from related species by its acid production type and guaiacol production. On the basis of phenotypic characteristics, phylogenetic analysis and DNA-DNA relatedness values, it can be concluded that the strain represents a novel species of the genus Alicyclobacillus, for which the name Alicyclobacillus dauci sp. nov. is proposed; the type strain is 4F(T) ( = DSM 28700(T) = NBRC 108949(T) = NRIC 0938(T)). PMID- 25505345 TI - Anoxybacter fermentans gen. nov., sp. nov., a piezophilic, thermophilic, anaerobic, fermentative bacterium isolated from a deep-sea hydrothermal vent. AB - A novel piezophilic, thermophilic, anaerobic, fermentative bacterial strain, designated strain DY22613(T), was isolated from a deep-sea hydrothermal sulfide deposit at the East Pacific Rise (GPS position: 102.6 degrees W 3.1 degrees S). Cells of strain DY22613(T) were long, motile rods (10 to 20 um in length and 0.5 um in width) with peritrichous flagella and were Gram-stain-negative. Growth was recorded at 44-72 degrees C (optimum 60-62 degrees C) and at hydrostatic pressures of 0.1-55 MPa (optimum 20 MPa). The pH range for growth was from pH 5.0 to 9.0 with an optimum at pH 7.0. Growth was observed in the presence of 1 to 8 % (w/v) sea salts and 0.65 to 5.2 % (w/v) NaCl, with optimum salt concentrations at 3.5 % for sea salts and at 2.3 % for NaCl. Under optimal growth conditions, the shortest generation time observed was 27 min (60 degrees C, 20 MPa). Strain DY22613(T) was heterotrophic, able to utilize complex organic compounds, amino acids, sugars and organic acids including peptone, tryptone, beef extract, yeast extract, alanine, glutamine, methionine, phenylalanine, serine, threonine, fructose, fucose, galactose, gentiobiose, glucose, mannose, melibiose, palatinose, rhamnose, turanose, pyruvate, lactic acid, methyl ester, erythritol, galacturonic acid and glucosaminic acid. Strain DY22613(T) was able to reduce Fe(III) compounds, including Fe(III) oxyhydroxide (pH 7.0), amorphous iron(III) oxide (pH 9.0), goethite (alpha-FeOOH, pH 12.0), Fe(III) citrate and elementary sulfur. Products of fermentation were butyrate, acetate and hydrogen. Main cellular fatty acids were iso-C15 : 0, iso-C14 : 0 3-OH and C14 : 0. The genomic DNA G+C content of strain DY22613(T) was 36.7 mol%. Based on 16S rRNA gene sequence analysis, the strain forms a novel lineage within the class Clostridia and clusters with the order Haloanaerobiales (86.92 % 16S rRNA gene sequence similarity). The phylogenetic data suggest that the lineage represents at least a novel genus and species, for which the name Anoxybacter fermentans gen. nov., sp. nov. is proposed. The type strain is DY22613(T) ( = JCM 19466(T) = DSM 28033(T) = MCCC 1A06456(T)). PMID- 25505346 TI - Bacillus polymachus sp. nov., with a broad range of antibacterial activity, isolated from forest topsoil samples by using a modified culture method. AB - A new, modified culture method that utilizes a transwell plate with a 0.4 um pore size microporous membrane was developed. This system allows only trace nutrients from the soil into the liquid culture through the microporous membrane. The method is a more powerful tool for the discovery of novel species from soils than are traditional methods. Such newly identified species could potentially produce useful metabolites. A bacterial strain, T515(T), was isolated using this modified culture method. Growth of strain T515(T) occurred at pH 4-9 in a temperature range between 20 degrees C and 40 degrees C and in the presence of 0-2 % (w/v) NaCl on R2A agar. Colonies on the agar plates were tiny, white, and convex after 5 days incubation at 28 degrees C. Comparative analysis of the nearly full length 16S rRNA gene sequence of strain T515(T) revealed close pairwise similarity with species of the genus Bacillus, and strain T515(T) was most closely related to Bacillus panaciterrae Gsoil 1517(T) (96.7 %) and Bacillus funiculus NAF001(T) (96.0 %). The major quinone of strain T515(T) was menaquinone 7 (MK-7) and the major fatty acids were iso-C15 : 0 (45.5 %), anteiso-C15 : 0 (23.2 %) and C16 : 0 (10.9 %). The predominant polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Strain T515(T) was sensitive to streptomycin and tetracycline, but resistant to rifampicin (0.125 ug ml(-1)), ampicillin (0.5 ug ml(-1)) and chloramphenicol (1 ug ml(-1)). The strain showed antimicrobial activities against the six strains tested: Bacillus subtilis KEMB 51201-001, Staphylococcus aureus KEMB 4659, Pseudomonas aeruginosa KACC 10185, Staphylococcus epidermidis KACC 13234, Paenibacillus larvae KACC 14031 and Escherichia coli KEMB 212-234. Based on these results, strain T515(T) represents a novel species of the genus Bacillus with the proposed name, Bacillus polymachus sp. nov. The type strain is T515(T) ( = KEMB 9005-168(T) = KACC 18242(T) = NBRC 110614(T)). PMID- 25505347 TI - Strains of Yersinia wautersii should continue to be classified as the 'Korean Group' of the Yersinia pseudotuberculosis complex and not as a separate species. PMID- 25505348 TI - Effects of 3D microwell culture on initial fate specification in human embryonic stem cells. AB - Several studies have demonstrated that 3D culture systems influence human embryonic stem cell (hESC) phenotypes and fate choices. However, the effect that these microenvironmental changes have on signaling pathways governing hESC behaviors is not well understood. Here, we have used a 3D microwell array to investigate differences in activation of developmental pathways between 2D and 3D cultures of both undifferentiated hESCs and hESCs undergoing initial differentiation in embryoid bodies (EBs). We observed increased induction into mesoderm and endoderm and differences in expression of genes from multiple signaling pathways that regulate development, including Wnt/beta-catenin, TGF beta superfamily, Notch and FGF during EB-mediated differentiation, in 3D microwells as compared with the 2D substrates. In undifferentiated hESCs, we also observed differences in epithelial-mesenchymal transition phenotypes and the TGFbeta/BMP pathway between cultures in 3D and 2D. These results illustrate that 3D culture influences multiple pathways that may regulate the differentiation trajectories of hESCs. PMID- 25505349 TI - GRID-ENABLED TREATMENT PLANNING FOR PROTON THERAPY USING MONTE CARLO SIMULATIONS. AB - Grid computing is an emerging technology that enables computational tasks to be accomplished in a collaborative approach by using a distributed network of computers. The grid approach is especially important for computationally intensive problems that are not tractable with a single computer or even with a small cluster of computers, e.g., radiation transport calculations for cancer therapy. The objective of this work was to extend a Monte Carlo (MC) transport code used for proton radiotherapy to utilize grid computing techniques and demonstrate its promise in reducing runtime from days to minutes. As proof of concept we created the Medical Grid between Texas Tech University and Rice University. Preliminary computational experiments were carried out in the GEANT4 simulation environment for transport of 25 *106 200 MeV protons in a prostate cancer treatment plan. The simulation speedup was approximately linear; deviations were attributed to the spectrum of parallel runtimes and communication overhead due to Medical Grid computing. The results indicate that ~3 * 105 to 5 * 105 proton events with processor core would result in 65 to 83% efficiency. Extrapolation of our results indicates that about 103 processor cores of the class used here would reduce the MC simulation runtime from 18.3 days to ~1 h. PMID- 25505350 TI - URBAN REVITALIZATION AND SEATTLE CRIME, 1982-2000. AB - This study examines the relationship between crime and processes of urban revitalization, or gentrification. Drawing on recent urban demography research, we hypothesize that gentrification progressed rapidly in many American cities over the last decade of the 20th century, and that these changes had implications for area crime rates. Criminological theories hold competing hypotheses for the connections between gentrification and crime, and quantitative studies of this link remain infrequent and limited. Using two measures of gentrification and longitudinal tract-level demographic and crime data for the city of Seattle, we find that many of Seattle's downtown tracts underwent rapid revitalization during the 1990's, and that these areas 1) saw reductions in crime relative to similar tracts that did not gentrify, and 2) were areas with higher-than-average crime at the beginning of the decade. Moreover, using a within-tract longitudinal design, we find that yearly housing investments in the 1980's showed a modest positive association with crime change, while yearly investments in the 1990's showed the opposite pattern. Our findings suggest a curvilinear gentrification-crime relationship, whereby gentrification in its earlier stages is associated with small increases in crime, but gentrification in its more consolidated form is associated with modest crime declines. Implications of these results for criminological theory, urban development, and broader crime patterns are discussed. PMID- 25505352 TI - Effect of Cane Technique on Obstacle Detection with the Long Cane. PMID- 25505351 TI - Preparation of 1-Monoacylglycerols via the Suzuki-Miyaura Reaction: 2,3 Dihydroxypropyl (Z)-tetradec-7-enoate. PMID- 25505354 TI - A cross-validation deletion-substitution-addition model selection algorithm: Application to marginal structural models. AB - The cross-validation deletion-substitution-addition (cvDSA) algorithm is based on data-adaptive estimation methodology to select and estimate marginal structural models (MSMs) for point treatment studies as well as models for conditional means where the outcome is continuous or binary. The algorithm builds and selects models based on user-defined criteria for model selection, and utilizes a loss function-based estimation procedure to distinguish between different model fits. In addition, the algorithm selects models based on cross-validation methodology to avoid "over-fitting" data. The cvDSA routine is an R software package available for download. An alternative R-package (DSA) based on the same principles as the cvDSA routine (i.e., cross-validation, loss function), but one that is faster and with additional refinements for selection and estimation of conditional means, is also available for download. Analyses of real and simulated data were conducted to demonstrate the use of these algorithms, and to compare MSMs where the causal effects were assumed (i.e., investigator-defined), with MSMs selected by the cvDSA. The package was used also to select models for the nuisance parameter (treatment) model to estimate the MSM parameters with inverse probability of treatment weight (IPTW) estimation. Other estimation procedures (i.e., G-computation and double robust IPTW) are available also with the package. PMID- 25505353 TI - Identification and nomenclature of the genus Penicillium. AB - Penicillium is a diverse genus occurring worldwide and its species play important roles as decomposers of organic materials and cause destructive rots in the food industry where they produce a wide range of mycotoxins. Other species are considered enzyme factories or are common indoor air allergens. Although DNA sequences are essential for robust identification of Penicillium species, there is currently no comprehensive, verified reference database for the genus. To coincide with the move to one fungus one name in the International Code of Nomenclature for algae, fungi and plants, the generic concept of Penicillium was re-defined to accommodate species from other genera, such as Chromocleista, Eladia, Eupenicillium, Torulomyces and Thysanophora, which together comprise a large monophyletic clade. As a result of this, and the many new species described in recent years, it was necessary to update the list of accepted species in Penicillium. The genus currently contains 354 accepted species, including new combinations for Aspergillus crystallinus, A. malodoratus and A. paradoxus, which belong to Penicillium section Paradoxa. To add to the taxonomic value of the list, we also provide information on each accepted species MycoBank number, living ex-type strains and provide GenBank accession numbers to ITS, beta tubulin, calmodulin and RPB2 sequences, thereby supplying a verified set of sequences for each species of the genus. In addition to the nomenclatural list, we recommend a standard working method for species descriptions and identifications to be adopted by laboratories working on this genus. PMID- 25505355 TI - It is Who You Know That Counts: Intergroup Contact and Judgments about Race-Based Exclusion. AB - Intergroup contact and evaluations about race-based exclusion were assessed for majority and minority students in fourth, seventh, and tenth grades (N = 685). Students were presented with scenarios depicting cross-race relations in contexts of dyadic friendship, parental discomfort, and peer group disapproval. Participants reporting higher levels of intergroup contact gave higher ratings of wrongfulness of exclusion and lower frequency estimations of race-based exclusion than did participants reporting lower levels of such contact. Intergroup contact also predicted students' attributions of motives in two out of three scenarios. Findings are discussed in terms of the extant literature on peer relations, moral reasoning, and intergroup contact. PMID- 25505356 TI - Matching species traits to projected threats and opportunities from climate change. AB - AIM: Climate change can lead to decreased climatic suitability within species' distributions, increased fragmentation of climatically suitable space, and/or emergence of newly suitable areas outside present distributions. Each of these extrinsic threats and opportunities potentially interacts with specific intrinsic traits of species, yet this specificity is seldom considered in risk assessments. We present an analytical framework for examining projections of climate change induced threats and opportunities with reference to traits that are likely to mediate species' responses, and illustrate the applicability of the framework. LOCATION: Sub-Saharan Africa. METHODS: We applied the framework to 195 sub Saharan African amphibians with both available bioclimatic envelope model projections for the mid-21st century and trait data. Excluded were 500 narrow ranging species mainly from montane areas. For each of projected losses, increased fragmentation and gains of climate space, we selected potential response-mediating traits and examined the spatial overlap with vulnerability due to these traits. We examined the overlap for all species, and individually for groups of species with different combinations of threats and opportunities. RESULTS: In the Congo Basin and arid Southern Africa, projected losses for wide ranging amphibians were compounded by sensitivity to climatic variation, and expected gains were precluded by poor dispersal ability. The spatial overlap between exposure and vulnerability was more pronounced for species projected to have their climate space contracting in situ or shifting to distant geographical areas. Our results exclude the potential exposure of narrow-ranging species to shrinking climates in the African tropical mountains. MAIN CONCLUSIONS: We illustrate the application of a framework combining spatial projections of climate change exposure with traits that are likely to mediate species' responses. Although the proposed framework carries several assumptions that require further scrutiny, its application adds a degree of realism to familiar assessments that consider all species to be equally affected by climate change induced threats and opportunities. PMID- 25505357 TI - Love thy neighbour or opposites attract? Patterns of spatial segregation and association among crested penguin populations during winter. AB - AIM: Competition for food among populations of closely related species and conspecifics that occur in both sympatry and parapatry can be reduced by interspecific and intraspecific spatial segregation. According to predictions of niche partitioning, segregation is expected to occur at habitat boundaries among congeners and within habitats among conspecifics, while negative relationships in the density of species or populations will occur in areas of overlap. We tested these predictions by modelling the winter distributions of two crested penguin species from three colonies in the south-western Atlantic. LOCATION: Penguins were tracked from two large colonies on the Falkland Islands and one in South Georgia, from where they dispersed through the South Atlantic, Southern Ocean and south-eastern Pacific. METHODS: Forty macaroni penguins (Eudyptes chrysolophus) from South Georgia and 82 southern rockhopper penguins (Eudyptes chrysocome chrysocome) from two colonies in the Falkland Islands were equipped with global location sensors which log time and light, allowing positions to be estimated twice-daily, from April to August in 2011. Positions were gridded and converted into maps of penguin density. Metrics of overlap were calculated and density was related to remote-sensed oceanographic variables and competitor density using generalized additive models. RESULTS: Macaroni penguins from western South Georgia and southern rockhopper penguins from Steeple Jason Island, Falkland Islands, were spatially segregated by differences in their habitat preferences thus supporting our first prediction regarding interspecific segregation. However, southern rockhopper penguins from Beauchene Island showed a marked spatial overlap with macaroni penguins as the two had similar habitat preferences and strong mutual associations when controlling for habitat. Contrary to our predictions relating to intraspecific segregation, southern rockhopper penguins from Beauchene Island and Steeple Jason Island were segregated by differences in habitat selection. MAIN CONCLUSIONS: Morphological differentiation probably allows macaroni penguins from South Georgia and southern rockhopper penguins from Beauchene Island to coexist in areas of spatial overlap, whereas segregation of the two Falkland rockhopper penguin populations may have arisen from two distinct lineages retaining cultural fidelity to ancestral wintering areas. PMID- 25505359 TI - Attuning Assessment to the Client: Recent Advances in Theory and Methodology. PMID- 25505358 TI - Gradient Models in Molecular Biophysics: Progress, Challenges, Opportunities. AB - In the interest of developing a bridge between researchers modeling materials and those modeling biological molecules, we survey recent progress in developing nonlocal-dielectric continuum models for studying the behavior of proteins and nucleic acids. As in other areas of science, continuum models are essential tools when atomistic simulations (e.g. molecular dynamics) are too expensive. Because biological molecules are essentially all nanoscale systems, the standard continuum model, involving local dielectric response, has basically always been dubious at best. The advanced continuum theories discussed here aim to remedy these shortcomings by adding features such as nonlocal dielectric response, and nonlinearities resulting from dielectric saturation. We begin by describing the central role of electrostatic interactions in biology at the molecular scale, and motivate the development of computationally tractable continuum models using applications in science and engineering. For context, we highlight some of the most important challenges that remain and survey the diverse theoretical formalisms for their treatment, highlighting the rigorous statistical mechanics that support the use and improvement of continuum models. We then address the development and implementation of nonlocal dielectric models, an approach pioneered by Dogonadze, Kornyshev, and their collaborators almost forty years ago. The simplest of these models is just a scalar form of gradient elasticity, and here we use ideas from gradient-based modeling to extend the electrostatic model to include additional length scales. The paper concludes with a discussion of open questions for model development, highlighting the many opportunities for the materials community to leverage its physical, mathematical, and computational expertise to help solve one of the most challenging questions in molecular biology and biophysics. PMID- 25505360 TI - INTRAFAMILIAL AND MIDPARENTAL-CHILD CORRELATIONS AND HERITABILITY ESTIMATES OF ANTHROPOMETRIC MEASUREMENTS IN PRADER-WILLI SYNDROME FAMILIES. AB - To determine the effects of familial background on anthropometric dimensions in Prader-Willi syndrome (PWS), we measured weight; height; sitting height; longitude and breadth of the head, hands, and feet; head, arm, and calf circumferences; and triceps and subscapular skinfolds in 28 individuals with the syndrome and their natural parents. Midparental-child correlations were significant for height and foot length, with heritability estimates of 0.52 and 0.68, respectively. Significant mother-child correlations were found for weight, height, foot length, and minimal frontal diameter for the total group; in addition, hand length and breadth, and calf and arm circumferences were significant for the patients age 12.5 years or under. These data provide evidence for maternal effects on several physical characteristics in PWS, particularly in younger patients. PMID- 25505361 TI - AMINO ACID LEVELS IN PRADER-WILLI SYNDROME AND OBESE INDIVIDUALS. AB - To determine if certain features (e.g., hypopigmentation) seen in persons with Prader-Willi syndrome (PWS) may be reflected in abnormalities of amino acid metabolism, fasting plasma amino acid levels were measured from 25 patients and compared with those in 17 obese individuals. Thirteen of the patients with PWS were previously identified by high-resolution analysis to have chromosome 15q deletion, while 12 had normal chromosomes. Compared with reference plasma levels, several amino acid levels were elevated in both patients and obese individuals. Aspartic acid, taurine, and glutamic acid levels were elevated (>2 Z score) in 44% of the patients with PWS but were increased in only one obese individual. The average phenylalanine and tyrosine levels were not different in the two groups. Significant differences in taurine, cystine, glutamic acid, citrulline, and aspartic acid levels were found. There was no correlation with age, degree of obesity (percentage of ideal body weight), and the degree of elevation of amino acids in either patients with PWS or obese individuals. Similarly, the degree of obesity in those with PWS was not associated with chromosome status. Several amino acid concentrations were abnormal in patients compared with our laboratory reference ranges, but many of these abnormalities were also present in obese individuals. Whether the amino acid changes simply reflect the altered eating habits of obese individuals or whether the altered profile may play a role in appetite or energy regulation is not known. PMID- 25505362 TI - FASTING PLASMA LIPID, GLUCOSE, AND INSULIN LEVELS IN PRADER-WILLI SYNDROME AND OBESE INDIVIDUALS. AB - Plasma lipid, glucose, and insulin levels were measured from 26 patients with Prader-Willi syndrome (16 with the chromosome 15q deletion and 10 with normal chromosomes) and 32 obese, normal individuals. The average percentage of ideal body weight (IBW) for the former group was 175.6 +/- 68.0, compared to 150.3 +/- 43.8 for the latter. Fasting plasma lipid, glucose, and insulin levels were not significantly different between the two groups. No significant correlations were found among the three measurements in patients with PWS (deletion or nondeletion) or obese individuals and either age or percentage of IBW. Both insulin and glucose levels were higher in the PWS group, while only insulin levels were higher in the obese group compared with normative laboratory standards. Our study supports previously reported lipid, glucose, and insulin data in PWS and obesity. PMID- 25505363 TI - NORMATIVE STANDARDS AND PATTERNING OF FAT AND MUSCLE IN WHITE AND BLACK NEWBORN INFANTS. AB - Due to the lack of normative data in newborns, we report fat and muscle patterning, and standards for the sums of fat and muscle areas and muscle circumferences for arm, forearm, thigh, and calf in white and black newborn infants that may have clinical application in the assessment of body composition in newborns. Significant differences were found between white males and white females in fatness patterning: white female newborns were larger for all 21 variables except height. Statistically significant differences (t test; p < 0.05) existed for five skinfold measurements (forearm, subscapular, suprailiac, thigh, medial calf), three limb fat areas (forearm, thigh, calf), and the sums of the skinfolds and fat areas despite similar limb circumferences. Black female newborns were larger than black males for five of the eight skinfolds (with a significant difference observed in medial calf skinfold), for all of the limb fat areas, and for the sums of the skinfolds and fat areas. Despite their larger skinfolds and fat areas, black females had smaller circumferences. No sex-related trends or significantly different variables were observed in the muscle patterning of white infants. Differences in muscle patterning were observed between black males and black females, with males having larger values for all 14 variables. Statistically significant differences were found between white and black infants, with white newborns having greater height, medial calf skinfold, and calf fat area. PMID- 25505365 TI - How to Spot Bias in Research. PMID- 25505364 TI - Technologies and Challenges in Proteomic Analysis of Protein S-acylation. AB - Protein S-acylation (also called palmitoylation) is a pervasive post translational modification that plays critical roles in regulating protein trafficking, localization, stability, activity, and complex formation. The past decade has witnessed tremendous advances in the study of protein S-acylation, largely owing to the development of novel S-acylproteomics technologies. In this review, we summarize current S-acylproteomics approaches, critically review published S-acylproteomics studies, and envision future directions for the burgeoning S-acylproteomics field. Emerging S-acylproteomics technologies promise to shed new light on this distinct post-translational modification and facilitate the discovery of new disease mechanisms, biomarkers, and therapeutic targets. PMID- 25505366 TI - Teacher's Corner: Latent Curve Models and Latent Change Score Models Estimated in R. AB - In recent years the use of the Latent Curve Model (LCM) among researchers in social sciences has increased noticeably, probably thanks to contemporary software developments and to the availability of specialized literature. Extensions of the LCM, like the the Latent Change Score Model (LCSM), have also increased in popularity. At the same time, the R statistical language and environment, which is open source and runs on several operating systems, is becoming a leading software for applied statistics. We show how to estimate both the LCM and LCSM with the sem, lavaan, and OpenMx packages of the R software. We also illustrate how to read in, summarize, and plot data prior to analyses. Examples are provided on data previously illustrated by Ferrer, Hamagami, & McArdle, 2004. The data and all scripts used here are available on the first author's website. PMID- 25505367 TI - Resource Use in Small Island States: Material Flows in Iceland and Trinidad and Tobago, 1961-2008. AB - Iceland and Trinidad and Tobago are small open, high-income island economies with very specific resource-use patterns. This article presents a material flow analysis (MFA) for the two countries covering a time period of nearly five decades. Both countries have a narrow domestic resource base, their economy being largely based on the exploitation of one or two key resources for export production. In the case of Trinidad and Tobago, the physical economy is dominated by oil and natural gas extraction and petrochemical industries, whereas Iceland's economy for centuries has been based on fisheries. More recently, abundant hydropower and geothermal heat were the basis for the establishment of large export-oriented metal processing industries, which fully depend on imported raw materials and make use of domestic renewable electricity. Both countries are highly dependent on these natural resources and vulnerable to overexploitation and price developments. We show how the export-oriented industries lead to high and growing levels of per capita material and energy use and carbon dioxide emissions resulting from large amounts of processing wastes and energy consumption in production processes. The example of small open economies with an industrial production system focused on few, but abundant, key resources and of comparatively low complexity provides interesting insights of how resource endowment paired with availability or absence of infrastructure and specific institutional arrangements drives domestic resource-use patterns. This also contributes to a better understanding and interpretation of MFA indicators, such as domestic material consumption. PMID- 25505368 TI - Accounting for the Material Stock of Nations. AB - National material stock (MS) accounts have been a neglected field of analysis in industrial ecology, possibly because of the difficulty in establishing such accounts. In this research, we propose a novel method to model national MS based on historical material flow data. This enables us to avoid the laborious data work involved with bottom-up accounts for stocks and to arrive at plausible levels of stock accumulation for nations. We apply the method for the United States and Japan to establish a proof of concept for two very different cases of industrial development. Looking at a period of 75 years (1930-2005), we find that per capita MS has been much higher in the United States for the entire period, but that Japan has experienced much higher growth rates throughout, in line with Japan's late industrial development. By 2005, however, both Japan and the United States arrive at a very similar level of national MS of 310 to 375 tonnes per capita, respectively. This research provides new insight into the relationship between MS and flows in national economies and enables us to extend the debate about material efficiency from a narrow perspective of throughput to a broader perspective of stocks. PMID- 25505369 TI - Impact of Abuse History on Adolescent African-American Women's Current HIV/STD associated Behaviors and Psychosocial Mediators of HIV/STD Risk. AB - This study examined if relationship power, sex refusal self-efficacy, and/or fear of condom negotiation mediated the relationship between abuse history and consistent condom use (CCU) among African-American female adolescents (n=593). Participants with an abuse history (58%) were less likely to report CCU (p=.003). Women with an abuse history reported less relationship power (p=.006) and self efficacy for refusing sex (p<.001), and more fear of condom negotiation (p=.003), none of which independently or jointly mediated the association between abuse and CCU. Notably, history of abuse was associated with CCU across mediator models (p=.037 to p=.067), despite inclusion of psychosocial mediators. This study demonstrates the importance of understanding adolescents' condom use behaviors within the context of their life experiences, especially past abuse history. PMID- 25505370 TI - Resolving the Antarctic contribution to sea-level rise: a hierarchical modelling framework. AB - Determining the Antarctic contribution to sea-level rise from observational data is a complex problem. The number of physical processes involved (such as ice dynamics and surface climate) exceeds the number of observables, some of which have very poor spatial definition. This has led, in general, to solutions that utilise strong prior assumptions or physically based deterministic models to simplify the problem. Here, we present a new approach for estimating the Antarctic contribution, which only incorporates descriptive aspects of the physically based models in the analysis and in a statistical manner. By combining physical insights with modern spatial statistical modelling techniques, we are able to provide probability distributions on all processes deemed to play a role in both the observed data and the contribution to sea-level rise. Specifically, we use stochastic partial differential equations and their relation to geostatistical fields to capture our physical understanding and employ a Gaussian Markov random field approach for efficient computation. The method, an instantiation of Bayesian hierarchical modelling, naturally incorporates uncertainty in order to reveal credible intervals on all estimated quantities. The estimated sea-level rise contribution using this approach corroborates those found using a statistically independent method. (c) 2013 The Authors. Environmetrics Published by John Wiley & Sons, Ltd. PMID- 25505371 TI - Total Synthesis of (+/-)-Paroxetine by Diastereoconvergent Cobalt-Catalysed Arylation. AB - A total synthesis of paroxetine is reported, with a diastereoselective and diastereoconvergent cobalt-catalysed sp3-sp2 coupling reaction involving a 3 substituted 4-bromo-N-Boc-piperidine (Boc = tert-butoxycarbonyl) substrate as a key step. A 9:1 diastereoselectivity was obtained, while a control experiment involving a conformationally locked 3-substituted 4-bromo-tert-butyl cyclohexane ring proceeded with essentially complete stereoselectivity. PMID- 25505373 TI - Recent Advances in Computational Epidemiology. PMID- 25505372 TI - Activation of EGFR-PI3K-AKT signaling is required for Mycoplasma hyorhinis promoted gastric cancer cell migration. AB - Persistent infection of Mycoplasma hyorhinis (M. hyorhinis) was associated with gastric cancer cell migration and invasion, but the mechanisms were not well understood. Herein, we found that M. hyorhinis activated phosphoinositide 3 kinase (PI3K)-AKT signaling axis in gastric cancer cell lines. Epidermal growth factor receptor (EGFR) was upstream of PI3K-AKT signaling in the context of M. hyorhinis infection, because phosphorylation of AKT Serine 473 was almost completely attenuated by the EGFR inhibitor AG1478 or by EGFR knockdown. Phosphorylation of AKT S473 induced by M. hyorhinis infection was also abolished by PI3K inhibitor wortmannin. Furthermore, we found that p37, a membrane protein of M. hyorhinis, could also promote M. hyorhinis-induced PI3K-AKT signaling activation and cell migration. In addition, pre-treatment with AG1478 or wortmannin significantly inhibited cell migration induced by M. hyorhinis infection or p37 treatment. In conclusion, EGFR-PI3K-AKT signaling plays an important role in M. hyorhinis-promoted cell migration in gastric cancer cells, thus providing a clue to the pathogenesis of M. hyorhinis in gastric cancer. PMID- 25505374 TI - Dependence of NMR noise line shapes on tuning, matching, and transmission line properties. AB - The tuning and matching conditions of rf circuits, as well as the properties of the transmission lines connecting these to the preamplifier, have direct consequences for NMR probe sensitivity and as for the optimum delivery of rf power to the sample. In addition, tuning/matching conditions influence radiation damping effects, which manifest themselves as fast signal flip-back and line broadening effects, and can lead to concentration-dependent frequency shifts. Previous studies have also shown that the appearance of spin-noise and absorbed circuit noise signals heavily depended on tuning settings. Consequently, all these phenomena are linked together. The mutual connections and interdependences of these effects are highlighted and reviewed here. PMID- 25505375 TI - High Throughput Screening of Dynamic Silk-Elastin-Like Protein Biomaterials. AB - The need for dynamic, elastomeric polymeric biomaterials remains high, with few options with tunable control of mechanical properties, and environmental responses. Yet the diversity of these types of protein polymers pursued for biomaterials-related needs remains limited. Robust high-throughput synthesis and characterization methods will address the need to expand options for protein polymers for a range of applications. To address this need, a combinatorial library approach with high throughput screening is used to select specific examples of dynamic protein silk-elastin-like polypeptides (SELPs) with unique stimuli responsive features, including tensile strength, and adhesion. Using this approach 64 different SELPs with different sequences and molecular weights are selected out of over 2,000 recombinant E. coli colonies. New understanding of sequence-function relationships with this family of proteins is gained through this combinatorial-screening approach and can provide a guide to future library designs. Further, this approach yields new families of SELPs to match specific material functions. PMID- 25505376 TI - Lactate oxidation at the mitochondria: a lactate-malate-aspartate shuttle at work. AB - Lactate, the conjugate base of lactic acid occurring in aqueous biological fluids, has been derided as a "dead-end" waste product of anaerobic metabolism. Catalyzed by the near-equilibrium enzyme lactate dehydrogenase (LDH), the reduction of pyruvate to lactate is thought to serve to regenerate the NAD(+) necessary for continued glycolytic flux. Reaction kinetics for LDH imply that lactate oxidation is rarely favored in the tissues of its own production. However, a substantial body of research directly contradicts any notion that LDH invariably operates unidirectionally in vivo. In the current Perspective, a model is forwarded in which the continuous formation and oxidation of lactate serves as a mitochondrial electron shuttle, whereby lactate generated in the cytosol of the cell is oxidized at the mitochondria of the same cell. From this perspective, an intracellular lactate shuttle operates much like the malate-aspartate shuttle (MAS); it is also proposed that the two shuttles are necessarily interconnected in a lactate-MAS. Among the requisite features of such a model, significant compartmentalization of LDH, much like the creatine kinase of the phosphocreatine shuttle, would facilitate net cellular lactate oxidation in a variety of cell types. PMID- 25505377 TI - Sitting and standing intention can be decoded from scalp EEG recorded prior to movement execution. AB - Low frequency signals recorded from non-invasive electroencephalography (EEG), in particular movement-related cortical potentials (MRPs), are associated with preparation and execution of movement and thus present a target for use in brain machine interfaces. We investigated the ability to decode movement intent from delta-band (0.1-4 Hz) EEG recorded immediately before movement execution in healthy volunteers. We used data from epochs starting 1.5 s before movement onset to classify future movements into one of three classes: stand-up, sit-down, or quiet. We assessed classification accuracy in both externally triggered and self paced paradigms. Movement onset was determined from electromyography (EMG) recordings synchronized with EEG signals. We employed an artifact subspace reconstruction (ASR) algorithm to eliminate high amplitude noise before building our time-embedded EEG features. We applied local Fisher's discriminant analysis to reduce the dimensionality of our spatio-temporal features and subsequently used a Gaussian mixture model classifier for our three class problem. Our results demonstrate significantly better than chance classification accuracy (chance level = 33.3%) for the self-initiated (78.0 +/- 2.6%) and triggered (74.7 +/- 5.7%) paradigms. Surprisingly, we found no significant difference in classification accuracy between the self-paced and cued paradigms when using the full set of non-peripheral electrodes. However, accuracy was significantly increased for self-paced movements when only electrodes over the primary motor area were used. Overall, this study demonstrates that delta-band EEG recorded immediately before movement carries discriminative information regarding movement type. Our results suggest that EEG-based classifiers could improve lower-limb neuroprostheses and neurorehabilitation techniques by providing earlier detection of movement intent, which could be used in robot-assisted strategies for motor training and recovery of function. PMID- 25505378 TI - Racing to learn: statistical inference and learning in a single spiking neuron with adaptive kernels. AB - This paper describes the Synapto-dendritic Kernel Adapting Neuron (SKAN), a simple spiking neuron model that performs statistical inference and unsupervised learning of spatiotemporal spike patterns. SKAN is the first proposed neuron model to investigate the effects of dynamic synapto-dendritic kernels and demonstrate their computational power even at the single neuron scale. The rule set defining the neuron is simple: there are no complex mathematical operations such as normalization, exponentiation or even multiplication. The functionalities of SKAN emerge from the real-time interaction of simple additive and binary processes. Like a biological neuron, SKAN is robust to signal and parameter noise, and can utilize both in its operations. At the network scale neurons are locked in a race with each other with the fastest neuron to spike effectively "hiding" its learnt pattern from its neighbors. The robustness to noise, high speed, and simple building blocks not only make SKAN an interesting neuron model in computational neuroscience, but also make it ideal for implementation in digital and analog neuromorphic systems which is demonstrated through an implementation in a Field Programmable Gate Array (FPGA). Matlab, Python, and Verilog implementations of SKAN are available at: http://www.uws.edu.au/bioelectronics_neuroscience/bens/reproducible_research. PMID- 25505379 TI - Contribution of glycogen in supporting axon conduction in the peripheral and central nervous systems: the role of lactate. AB - The role of glycogen in the central nervous system is intimately linked with the glycolytic pathway. Glycogen is synthesized from glucose, the primary substrate for glycolysis, and degraded to glucose-6-phosphate. The metabolic cost of shunting glucose via glycogen exceeds that of simple phosphorylation of glucose to glucose-6-phosphate by hexokinase; thus, there must be a metabolic advantage in utilizing this shunt pathway. The dogmatic view of glycogen as a storage depot persists, based on initial descriptions of glycogen supporting neural function in the face of aglycemia. The variable latency to conduction failure, dependent upon tissue glycogen levels, provided convincing evidence of the role played by glycogen in supporting neural function. Glycogen is located predominantly in astrocytes in the central nervous system, thus for glycogen to benefit neural elements, intercellular metabolic communication must exist in the form of astrocyte to neuron substrate transfer. Experimental evidence supports a model where glycogen is metabolized to lactate in astrocytes, with cellular expression of monocarboxylate transporters and enzymes appropriately located for lactate shuttling between astrocytes and neural elements, where lactate acts as a substrate for oxidative metabolism. Biosensor recordings have demonstrated a significant steady concentration of lactate present on the periphery of both central white matter and peripheral nerve under unstimulated baseline conditions, indicating continuous cellular efflux of lactate to the interstitium. The existence of this lactate pool argues we must reexamine the "on demand" shuttling of lactate between cellular elements, and suggests continuous lactate efflux surplus to immediate neural requirements. PMID- 25505381 TI - Genetically encoded Ca(2+) indicators; expanded affinity range, color hue and compatibility with optogenetics. PMID- 25505382 TI - Pannexin 2 protein expression is not restricted to the CNS. AB - Pannexins (Panx) are proteins homologous to the invertebrate gap junction proteins called innexins (Inx) and are traditionally described as transmembrane channels connecting the intracellular and extracellular compartments. Three distinct Panx paralogs (Panx1, Panx2 and Panx3) have been identified in vertebrates but previous reports on Panx expression and functionality focused primarily on Panx1 and Panx3 proteins. Several gene expression studies reported that Panx2 transcript is largely restricted to the central nervous system (CNS) hence suggesting that Panx2 might serve an important role in the CNS. However, the lack of suitable antibodies prevented the creation of a comprehensive map of Panx2 protein expression and Panx2 protein localization profile is currently mostly inferred from the distribution of its transcript. In this study, we characterized novel commercial monoclonal antibodies and surveyed Panx2 expression and distribution at the mRNA and protein level by real-time qPCR, Western blotting and immunofluorescence. Panx2 protein levels were readily detected in every tissue examined, even when transcriptional analysis predicted very low Panx2 protein expression. Furthermore, our results indicate that Panx2 transcriptional activity is a poor predictor of Panx2 protein abundance and does not correlate with Panx2 protein levels. Despite showing disproportionately high transcript levels, the CNS expressed less Panx2 protein than any other tissues analyzed. Additionally, we showed that Panx2 protein does not localize at the plasma membrane like other gap junction proteins but remains confined within cytoplasmic compartments. Overall, our results demonstrate that the endogenous expression of Panx2 protein is not restricted to the CNS and is more ubiquitous than initially predicted. PMID- 25505380 TI - Menstrual cycle influence on cognitive function and emotion processing-from a reproductive perspective. AB - The menstrual cycle has attracted research interest ever since the 1930s. For many researchers the menstrual cycle is an excellent model of ovarian steroid influence on emotion, behavior, and cognition. Over the past years methodological improvements in menstrual cycle studies have been noted, and this review summarizes the findings of methodologically sound menstrual cycle studies in healthy women. Whereas the predominant hypotheses of the cognitive field state that sexually dimorphic cognitive skills that favor men are improved during menstrual cycle phases with low estrogen and that cognitive skills that favor women are improved during cycle phases with increased estrogen and/or progesterone, this review has not found sufficient evidence to support any of these hypotheses. Mental rotation has gained specific interest in this aspect, but a meta-analysis yielded a standardized mean difference in error rate of 1.61 (95% CI -0.35 to 3.57), suggesting, at present, no favor of an early follicular phase improvement in mental rotation performance. Besides the sexually dimorphic cognitive skills, studies exploring menstrual cycle effects on tasks that probe prefrontal cortex function, for instance verbal or spatial working memory, have also been reviewed. While studies thus far are few, results at hand suggest improved performance at times of high estradiol levels. Menstrual cycle studies on emotional processing, on the other hand, tap into the emotional disorders of the luteal phase, and may be of relevance for women with premenstrual disorders. Although evidence at present is limited, it is suggested that emotion recognition, consolidation of emotional memories, and fear extinction is modulated by the menstrual cycle in women. With the use of functional magnetic resonance imaging, several studies report changes in brain reactivity across the menstrual cycle, most notably increased amygdala reactivity in the luteal phase. Thus, to the extent that behavioral changes have been demonstrated over the course of the menstrual cycle, the best evidence suggests that differences in sexually dimorphic tasks are small and difficult to replicate. However, emotion related changes are more consistently found, and are better associated with progesterone than with estradiol such that high progesterone levels are associated with increased amygdala reactivity and increased emotional memory. PMID- 25505383 TI - The truth in complexes: perspectives on ion channel signaling nexuses in the nervous system. PMID- 25505386 TI - VGLUT3 does not synergize GABA/glycine release during functional refinement of an inhibitory auditory circuit. AB - The vesicular glutamate transporter 3 (VGLUT3) is expressed at several locations not normally associated with glutamate release. Although the function of this protein has been generally elusive, when expressed in non-glutamatergic synaptic terminals, VGLUT3 can not only allow glutamate co-transmission but also synergize the action of non-glutamate vesicular transporters. Interestingly, in the immature glycinergic projection between the medial nucleus of the trapezoid body (MNTB) and the lateral superior olive (LSO) of auditory brainstem, the transient early expression of VGLUT3 is required for normal developmental refinement. It has however been unknown whether the primary function of VGLUT3 in development of these inhibitory synapses is to enable glutamate release or to promote loading of inhibitory neurotransmitter through vesicular synergy. Using tissue from young mice in which Vglut3 had been genetically deleted, we evaluated inhibitory neurotransmission in the MNTB-LSO pathway. Our results show, in contrast to what has been seen at adult synapses, that VGLUT3 expression has little or no effect on vesicular synergy at the immature glycinergic synapse of brainstem. This finding supports the model that the primary function of increased VGLUT3 expression in the immature auditory brainstem is to enable glutamate release in a developing inhibitory circuit. PMID- 25505385 TI - Single dendrite-targeting interneurons generate branch-specific inhibition. AB - Microcircuits composed of dendrite-targeting inhibitory interneurons and pyramidal cells (PCs) are fundamental elements of cortical networks, however, the impact of individual interneurons on pyramidal dendrites is unclear. Here, we combine paired recordings and calcium imaging to determine the spatial domain over which single dendrite-targeting interneurons influence PCs in olfactory cortex. We show that a major action of individual interneurons is to inhibit dendrites in a branch-specific fashion. PMID- 25505384 TI - Prolonged, brain-wide expression of nuclear-localized GCaMP3 for functional circuit mapping. AB - Larval zebrafish offer the potential for large-scale optical imaging of neural activity throughout the central nervous system; however, several barriers challenge their utility. First, ~panneuronal probe expression has to date only been demonstrated at early larval stages up to 7 days post-fertilization (dpf), precluding imaging at later time points when circuits are more mature. Second, nuclear exclusion of genetically-encoded calcium indicators (GECIs) limits the resolution of functional fluorescence signals collected during imaging. Here, we report the creation of transgenic zebrafish strains exhibiting robust, nuclearly targeted expression of GCaMP3 across the brain up to at least 14 dpf utilizing a previously described optimized Gal4-UAS system. We confirmed both nuclear targeting and functionality of the modified probe in vitro and measured its kinetics in response to action potentials (APs). We then demonstrated in vivo functionality of nuclear-localized GCaMP3 in transgenic zebrafish strains by identifying eye position-sensitive fluorescence fluctuations in caudal hindbrain neurons during spontaneous eye movements. Our methodological approach will facilitate studies of larval zebrafish circuitry by both improving resolution of functional Ca(2+) signals and by allowing brain-wide expression of improved GECIs, or potentially any probe, further into development. PMID- 25505387 TI - Quantitative relationships in delphinid neocortex. AB - Possessing large brains and complex behavioral patterns, cetaceans are believed to be highly intelligent. Their brains, which are the largest in the Animal Kingdom and have enormous gyrification compared with terrestrial mammals, have long been of scientific interest. Few studies, however, report total number of brain cells in cetaceans, and even fewer have used unbiased counting methods. In this study, using stereological methods, we estimated the total number of cells in the neocortex of the long-finned pilot whale (Globicephala melas) brain. For the first time, we show that a species of dolphin has more neocortical neurons than any mammal studied to date including humans. These cell numbers are compared across various mammals with different brain sizes, and the function of possessing many neurons is discussed. We found that the long-finned pilot whale neocortex has approximately 37.2 * 10(9) neurons, which is almost twice as many as humans, and 127 * 10(9) glial cells. Thus, the absolute number of neurons in the human neocortex is not correlated with the superior cognitive abilities of humans (at least compared to cetaceans) as has previously been hypothesized. However, as neuron density in long-finned pilot whales is lower than that in humans, their higher cell number appears to be due to their larger brain. Accordingly, our findings make an important contribution to the ongoing debate over quantitative relationships in the mammalian brain. PMID- 25505388 TI - Signaling mechanisms and behavioral function of the mouse basal vomeronasal neuroepithelium. AB - The vomeronasal organ (VNO) is a sensory organ that is found in most terrestrial vertebrates and that is principally implicated in the detection of pheromones. The VNO contains specialized sensory neurons organized in a pseudostratified neuroepithelium that recognize chemical signals involved in initiating innate behavioral responses. In rodents, the VNO neuroepithelium is segregated into two distinct zones, apical and basal. The molecular mechanisms involved in ligand detection by apical and basal VNO sensory neurons differ extensively. These two VNO subsystems express different subfamilies of vomeronasal receptors and signaling molecules, detect distinct chemosignals, and project to separate regions of the accessory olfactory bulb (AOB). The roles that these olfactory subdivisions play in the control of specific olfactory-mediated behaviors are largely unclear. However, analysis of mutant mouse lines for signal transduction components together with identification of defined chemosensory ligands has revealed a fundamental role of the basal part of the mouse VNO in mediating a wide range of instinctive behaviors, such as aggression, predator avoidance, and sexual attraction. Here we will compare the divergent functions and synergies between the olfactory subsystems and consider new insights in how higher neural circuits are defined for the initiation of instinctive behaviors. PMID- 25505389 TI - Automated computation of arbor densities: a step toward identifying neuronal cell types. AB - The shape and position of a neuron convey information regarding its molecular and functional identity. The identification of cell types from structure, a classic method, relies on the time-consuming step of arbor tracing. However, as genetic tools and imaging methods make data-driven approaches to neuronal circuit analysis feasible, the need for automated processing increases. Here, we first establish that mouse retinal ganglion cell types can be as precise about distributing their arbor volumes across the inner plexiform layer as they are about distributing the skeletons of the arbors. Then, we describe an automated approach to computing the spatial distribution of the dendritic arbors, or arbor density, with respect to a global depth coordinate based on this observation. Our method involves three-dimensional reconstruction of neuronal arbors by a supervised machine learning algorithm, post-processing of the enhanced stacks to remove somata and isolate the neuron of interest, and registration of neurons to each other using automatically detected arbors of the starburst amacrine interneurons as fiducial markers. In principle, this method could be generalizable to other structures of the CNS, provided that they allow sparse labeling of the cells and contain a reliable axis of spatial reference. PMID- 25505391 TI - Problems with theories that equate consciousness with information or information processing. PMID- 25505390 TI - Hierarchical processing in the prefrontal cortex in a variety of cognitive domains. AB - This review scrutinizes several findings on human hierarchical processing within the prefrontal cortex (PFC) in diverse cognitive domains. Converging evidence from previous studies has shown that the PFC, specifically, BA44, may function as the essential region for hierarchical processing across the domains. In language fMRI studies, BA 44 was significantly activated for the hierarchical processing of center-embedded sentences and this pattern of activations was also observed in artificial grammar. The same pattern was observed in the visuo-spatial domain where BA44 was actively involved in the processing of hierarchy for the visual symbol. Musical syntax, which is the rule-based arrangement of musical sets, has also been construed as hierarchical processing as in the language domain such that the activation in BA44 was observed in a chord sequence paradigm. P600 ERP was also engendered during the processing of musical hierarchy. Along with a longstanding idea that a human's number faculty is developed as a "by-product of language faculty", BA44 was closely involved in hierarchical processing in mental arithmetic. This review extended its discussion of hierarchical "processing" to hierarchical "behavior", that is, human action which has been referred to as being hierarchically composed. Several lesion and TMS studies supported the involvement of BA44 for hierarchical processing in the action domain. Lastly, the hierarchical organization of cognitive controls was discussed within the PFC, forming a cascade of top-down hierarchical processes operating along a posterior to-anterior axis of the lateral PFC including BA44 within the network. It is proposed that PFC is actively involved in different forms of hierarchical processing and specifically BA44 may play an integral role in the process. Taking levels of proficiency and subcortical areas into consideration may provide further insight into the functional role of BA44 for hierarchical processing. PMID- 25505392 TI - Real-time fMRI brain-computer interface: development of a "motivational feedback" subsystem for the regulation of visual cue reactivity. AB - Here we present a novel neurofeedback subsystem for the presentation of motivationally relevant visual feedback during the self-regulation of functional brain activation. Our "motivational neurofeedback" approach uses functional magnetic resonance imaging (fMRI) signals elicited by visual cues (pictures) and related to motivational processes such as craving or hunger. The visual feedback subsystem provides simultaneous feedback through these images as their size corresponds to the magnitude of fMRI signal change from a target brain area. During self-regulation of cue-evoked brain responses, decreases and increases in picture size thus provide real motivational consequences in terms of cue approach vs. cue avoidance, which increases face validity of the approach in applied settings. Further, the outlined approach comprises of neurofeedback (regulation) and "mirror" runs that allow to control for non-specific and task-unrelated effects, such as habituation or neural adaptation. The approach was implemented in the Python programming language. Pilot data from 10 volunteers showed that participants were able to successfully down-regulate individually defined target areas, demonstrating feasibility of the approach. The newly developed visual feedback subsystem can be integrated into protocols for imaging-based brain computer interfaces (BCI) and may facilitate neurofeedback research and applications into healthy and dysfunctional motivational processes, such as food craving or addiction. PMID- 25505393 TI - Enhancing inferential abilities in adolescence: new hope for students in poverty. AB - The ability to extrapolate essential gist through the analysis and synthesis of information, prediction of potential outcomes, abstraction of ideas, and integration of relationships with world knowledge is critical for higher-order learning. The present study investigated the efficacy of cognitive training to elicit improvements in gist reasoning and fact recall ability in 556 public middle school students (grades seven and eight), vs. a sample of 357 middle school students who served as a comparison group, to determine if changes in gist reasoning and fact recall were demonstrated without cognitive training. The results showed that, in general, cognitive training increased gist reasoning and fact recall abilities in students from families in poverty as well as students from families living above poverty. However, the magnitude of gains in gist reasoning varied as a function of gender and grade level. Our primary findings were that seventh and eighth grade girls and eighth grade boys showed significant increases in gist reasoning after training regardless of socioeconomic status (SES). There were no significant increases in gist reasoning or fact recall ability for the 357 middle school students who served as a comparison group. We postulate that cognitive training in middle school is efficacious for improving gist reasoning ability and fact recall in students from all socioeconomic levels. PMID- 25505394 TI - Finding the answer in space: the mental whiteboard hypothesis on serial order in working memory. AB - Various prominent models on serial order coding in working memory (WM) build on the notion that serial order is achieved by binding the various items to-be maintained to fixed position markers. Despite being relatively successful in accounting for empirical observations and some recent neuro-imaging support, these models were largely formulated on theoretical grounds and few specifications have been provided with respect to the cognitive and/or neural nature of these position markers. Here we outline a hypothesis on a novel candidate mechanism to substantiate the notion of serial position markers. Specifically, we propose that serial order WM is grounded in the spatial attention system: (I) The position markers that provide multi-item WM with a serial context should be understood as coordinates within an internal, spatially defined system; (II) internal spatial attention is involved in searching through the resulting serial order representation; and (III) retrieval corresponds to selection by spatial attention. We sketch the available empirical support and discuss how the hypothesis may provide a parsimonious framework from which to understand a broad range of observations across behavioral, neural and neuropsychological domains. Finally, we pinpoint what we believe are major questions for future research inspired by the hypothesis. PMID- 25505395 TI - The contribution of proprioceptive information to postural control in elderly and patients with Parkinson's disease with a history of falls. AB - Proprioceptive deficits negatively affect postural control but their precise contribution to postural instability in Parkinson's disease (PD) is unclear. We investigated if proprioceptive manipulations differentially affect balance, measured by force plates, during quiet standing in 13 PD patients and 13 age matched controls with a history of falls. Perceived limits of stability (LoS) were derived from the differences between maximal center of pressure (CoP) displacement in anterior-posterior (AP) and medio-lateral (ML) direction during a maximal leaning task. Task conditions comprised standing with eyes open (EO) and eyes closed (EC): (1) on a stable surface; (2) an unstable surface; and (3) with Achilles tendon vibration. CoP displacements were calculated as a percentage of their respective LoS. Perceived LoS did not differ between groups. PD patients showed greater ML CoP displacement than elderly fallers (EF) across all conditions (p = 0.043) and tended to have higher postural sway in relation to the LoS (p = 0.050). Both groups performed worse on an unstable surface and during tendon vibration compared to standing on a stable surface with EO and even more so with EC. Both PD and EF had more AP sway in all conditions with EC compared to EO (p < 0.001) and showed increased CoP displacements when relying on proprioception only compared to standing with normal sensory input. This implies a similar role of the proprioceptive system in postural control in fallers with and without PD. PD fallers showed higher ML sway after sensory manipulations, as a result of which these values approached their perceived LoS more closely than in EF. We conclude that despite a similar fall history, PD patients showed more ML instability than EF, irrespective of sensory manipulation, but had a similar reliance on ankle proprioception. Hence, we recommend that rehabilitation and fall prevention for PD should focus on motor rather than on sensory aspects. PMID- 25505396 TI - Slow cortical potential neurofeedback and self-management training in outpatient care for children with ADHD: study protocol and first preliminary results of a randomized controlled trial. AB - BACKGROUND: Treatment for children with attention deficit/hyperactivity disorder (ADHD) today is predominantly pharmacological. While it is the most common treatment, it might not always be the most appropriate one. Moreover, long term effects remain unclear. Behavior therapy (BT) and non-pharmacological treatments such as neurofeedback (NF) are promising alternatives, though there are no routine outpatient care/effectiveness studies yet that have included children with medication or changes in medication. METHODS/DESIGN: This paper presents the protocol of a randomized controlled trial to compare the effectiveness of a Slow Cortical Potential (SCP) NF protocol with self-management (SM) in a high frequent outpatient care setting. Both groups (NF/SM) receive a total of 30 high frequent therapy sessions. Additionally, 6 sessions are reserved for comorbid problems. The primary outcome measure is the reduction of ADHD core symptoms according to parent and teacher ratings. PRELIMINARY RESULTS: Untill now 58 children were included in the study (48 males), with a mean age of 8.42 (1.34) years, and a mean IQ of 110 (13.37). Conners-3 parent and teacher ratings were used to estimate core symptom change. Since the study is still ongoing, and children are in different study stages, pre-post and follow-up results are not yet available for all children included. Preliminary results suggest overall good pre-post effects, though. For parent and teacher ratings an ANOVA with repeated measures yielded overall satisfying pre-post effects (eta (2) 0.175-0.513). Differences between groups (NF vs. SM) could not yet be established (p = 0.81). DISCUSSION: This is the first randomized controlled trial to test the effectiveness of a NF protocol in a high frequent outpatient care setting that does not exclude children on or with changes in medication. First preliminary results show positive effects. The rationale for the trial, the design, and the strengths and limitations of the study are discussed. TRIAL REGISTRATION: This trial is registered in www.clinicaltrials.gov as NCT01879644. PMID- 25505397 TI - Effect of perceived intimacy on social decision-making in patients with schizophrenia. AB - Social dysfunctions including emotional perception and social decision-making are common in patients with schizophrenia. The aim of this study was to determine the level of intimacy formation and the effect of intimacy on social decision in patients with schizophrenia using virtual reality tasks, which simulate complicated social situations. Twenty-seven patients with schizophrenia and 30 healthy controls performed the 2 virtual social tasks: the intimacy task and the social decision task. The first one was to estimate repeatedly how intimate participants felt with each avatar after listening to what avatars said. The second one was to decide whether or not participants accepted the requests of easy, medium, or hard difficulty by the intimate or distant avatars. During the intimacy task, the intimacy rating scores for intimate avatars were not significantly different between groups, but those for distant avatars were significantly higher in patients than in controls. During the social decision task, the difference in the acceptance rate between intimate and distant avatars was significantly smaller in patients than in controls. In detail, a significant group difference in the acceptance rate was found only for the hard requests, but not for the easy and medium difficulty requests. These results suggest that patients with schizophrenia have a deficit in emotional perception and social decision-making. Various factors such as a peculiarity of emotional deficits, motivational deficits, concreteness, and paranoid tendency may contribute to these abnormalities. PMID- 25505398 TI - What can body ownership illusions tell us about minimal phenomenal selfhood? PMID- 25505399 TI - Fetal autonomic brain age scores, segmented heart rate variability analysis, and traditional short term variability. AB - Disturbances of fetal autonomic brain development can be evaluated from fetal heart rate patterns (HRP) reflecting the activity of the autonomic nervous system. Although HRP analysis from cardiotocographic (CTG) recordings is established for fetal surveillance, temporal resolution is low. Fetal magnetocardiography (MCG), however, provides stable continuous recordings at a higher temporal resolution combined with a more precise heart rate variability (HRV) analysis. A direct comparison of CTG and MCG based HRV analysis is pending. The aims of the present study are: (i) to compare the fetal maturation age predicting value of the MCG based fetal Autonomic Brain Age Score (fABAS) approach with that of CTG based Dawes-Redman methodology; and (ii) to elaborate fABAS methodology by segmentation according to fetal behavioral states and HRP. We investigated MCG recordings from 418 normal fetuses, aged between 21 and 40 weeks of gestation. In linear regression models we obtained an age predicting value of CTG compatible short term variability (STV) of R (2) = 0.200 (coefficient of determination) in contrast to MCG/fABAS related multivariate models with R (2) = 0.648 in 30 min recordings, R (2) = 0.610 in active sleep segments of 10 min, and R (2) = 0.626 in quiet sleep segments of 10 min. Additionally segmented analysis under particular exclusion of accelerations (AC) and decelerations (DC) in quiet sleep resulted in a novel multivariate model with R (2) = 0.706. According to our results, fMCG based fABAS may provide a promising tool for the estimation of fetal autonomic brain age. Beside other traditional and novel HRV indices as possible indicators of developmental disturbances, the establishment of a fABAS score normogram may represent a specific reference. The present results are intended to contribute to further exploration and validation using independent data sets and multicenter research structures. PMID- 25505400 TI - Multiple tasks and neuroimaging modalities increase the likelihood of detecting covert awareness in patients with disorders of consciousness. AB - Minimal or inconsistent behavioral responses to command make it challenging to accurately diagnose the level of awareness of a patient with a Disorder of consciousness (DOC). By identifying markers of mental imagery being covertly performed to command, functional neuroimaging (fMRI), electroencephalography (EEG) has shown that some of these patients are aware despite their lack of behavioral responsiveness. We report the findings of behavioral, fMRI, and EEG approaches to detecting command-following in a group of patients with DOC. From an initial sample of 14 patients, complete data across all tasks was obtained in six cases. Behavioral evaluations were performed with the Coma Recovery Scale Revised. Both fMRI and EEG evaluations involved the completion of previously validated mental imagery tasks-i.e., motor imagery (EEG and fMRI) and spatial navigation imagery (fMRI). One patient exhibited statistically significant evidence of motor imagery in both the fMRI and EEG tasks, despite being unable to follow commands behaviorally. Two behaviorally non-responsive patients produced appropriate activation during the spatial navigation fMRI task. However, neither of these patients successfully completed the motor imagery tasks, likely due to specific motor area damage in at least one of these cases. A further patient demonstrated command following only in the EEG motor imagery task, and two patients did not demonstrate command following in any of the behavioral, EEG, or fMRI assessments. Due to the heterogeneity of etiology and pathology in this group, DOC patients vary in terms of their suitability for some forms of neuroimaging, the preservation of specific neural structures, and the cognitive resources that may be available to them. Assessments of a range of cognitive abilities supported by spatially-distinct brain regions and indexed by multiple neural signatures are therefore required in order to accurately characterize a patient's level of residual cognition and awareness. PMID- 25505401 TI - Increased putamen volume in adults with autism spectrum disorder. AB - Basal ganglia (BG) abnormalities are implicated in the pathophysiology of autism spectrum disorder (ASD). However, studies measuring the volume of the entire BG in individuals with ASD have reported discrepant findings, and no study conducted volume measurement of the entire substructures of the BG (the caudate, putamen, nucleus accumbens, and globus pallidus) in individuals with ASD. We delineated the BG substructures and measured their volumes in 29 adults with ASD without intellectual disabilities and 29 age- and gender-matched typically developed adult controls. We acquired T1-weighted anatomical images and performed semiautomated delineation and volume measurements of the above-mentioned subregions. Total cerebral volumes, sex, and ages were partialed out. Compared with controls, the putamen was significantly larger in the ASD group. The increased volume of the putamen found in high-functioning adults with ASD suggests that structural or histological abnormalities of the putamen may underlie the pathologies of ASD, such as repetitive and stereotyped behaviors and impaired social interactions. PMID- 25505403 TI - Removing spatial responses reveals spatial concepts-even in a culture with mixed reading habits. PMID- 25505402 TI - Proprioceptive rehabilitation of upper limb dysfunction in movement disorders: a clinical perspective. AB - Movement disorders (MDs) are frequently associated with sensory abnormalities. In particular, proprioceptive deficits have been largely documented in both hypokinetic (Parkinson's disease) and hyperkinetic conditions (dystonia), suggesting a possible role in their pathophysiology. Proprioceptive feedback is a fundamental component of sensorimotor integration allowing effective planning and execution of voluntary movements. Rehabilitation has become an essential element in the management of patients with MDs, and there is a strong rationale to include proprioceptive training in rehabilitation protocols focused on mobility problems of the upper limbs. Proprioceptive training is aimed at improving the integration of proprioceptive signals using "task-intrinsic" or "augmented feedback." This perspective article reviews the available evidence on the effects of proprioceptive stimulation in improving upper limb mobility in patients with MDs and highlights the emerging innovative approaches targeted to maximizing the benefits of exercise by means of enhanced proprioception. PMID- 25505405 TI - Multi-dimensional classification of GABAergic interneurons with Bayesian network modeled label uncertainty. AB - Interneuron classification is an important and long-debated topic in neuroscience. A recent study provided a data set of digitally reconstructed interneurons classified by 42 leading neuroscientists according to a pragmatic classification scheme composed of five categorical variables, namely, of the interneuron type and four features of axonal morphology. From this data set we now learned a model which can classify interneurons, on the basis of their axonal morphometric parameters, into these five descriptive variables simultaneously. Because of differences in opinion among the neuroscientists, especially regarding neuronal type, for many interneurons we lacked a unique, agreed-upon classification, which we could use to guide model learning. Instead, we guided model learning with a probability distribution over the neuronal type and the axonal features, obtained, for each interneuron, from the neuroscientists' classification choices. We conveniently encoded such probability distributions with Bayesian networks, calling them label Bayesian networks (LBNs), and developed a method to predict them. This method predicts an LBN by forming a probabilistic consensus among the LBNs of the interneurons most similar to the one being classified. We used 18 axonal morphometric parameters as predictor variables, 13 of which we introduce in this paper as quantitative counterparts to the categorical axonal features. We were able to accurately predict interneuronal LBNs. Furthermore, when extracting crisp (i.e., non-probabilistic) predictions from the predicted LBNs, our method outperformed related work on interneuron classification. Our results indicate that our method is adequate for multi dimensional classification of interneurons with probabilistic labels. Moreover, the introduced morphometric parameters are good predictors of interneuron type and the four features of axonal morphology and thus may serve as objective counterparts to the subjective, categorical axonal features. PMID- 25505404 TI - A biologically plausible learning rule for the Infomax on recurrent neural networks. AB - A fundamental issue in neuroscience is to understand how neuronal circuits in the cerebral cortex play their functional roles through their characteristic firing activity. Several characteristics of spontaneous and sensory-evoked cortical activity have been reproduced by Infomax learning of neural networks in computational studies. There are, however, still few models of the underlying learning mechanisms that allow cortical circuits to maximize information and produce the characteristics of spontaneous and sensory-evoked cortical activity. In the present article, we derive a biologically plausible learning rule for the maximization of information retained through time in dynamics of simple recurrent neural networks. Applying the derived learning rule in a numerical simulation, we reproduce the characteristics of spontaneous and sensory-evoked cortical activity: cell-assembly-like repeats of precise firing sequences, neuronal avalanches, spontaneous replays of learned firing sequences and orientation selectivity observed in the primary visual cortex. We further discuss the similarity between the derived learning rule and the spike timing-dependent plasticity of cortical neurons. PMID- 25505407 TI - Temporal precision in population-but not individual neuron-dynamics reveals rapid experience-dependent plasticity in the rat barrel cortex. AB - Cortical reorganization following sensory deprivation is characterized by alterations in the connectivity between neurons encoding spared and deprived cortical inputs. The extent to which this alteration depends on Spike Timing Dependent Plasticity (STDP), however, is largely unknown. We quantified changes in the functional connectivity between layer V neurons in the vibrissal primary somatosensory cortex (vSI) (barrel cortex) of rats following sensory deprivation. One week after chronic implantation of a microelectrode array in vSI, sensory evoked activity resulting from mechanical deflections of individual whiskers was recorded (control data) after which two whiskers on the contralateral side were paired by sparing them while trimming all other whiskers on the rat's mystacial pad. The rats' environment was then enriched by placing novel objects in the cages to encourage exploratory behavior with the spared whiskers. Sensory-evoked activity in response to individual stimulation of spared whiskers and adjacent re grown whiskers was then recorded under anesthesia 1-2 days and 6-7 days post trimming (plasticity data). We analyzed spike trains within 100 ms of stimulus onset and confirmed previously published reports documenting changes in receptive field sizes in the spared whisker barrels. We analyzed the same data using Dynamic Bayesian Networks (DBNs) to infer the functional connectivity between the recorded neurons. We found that DBNs inferred from population responses to stimulation of each of the spared whiskers exhibited graded increase in similarity that was proportional to the pairing duration. A significant early increase in network similarity in the spared-whisker barrels was detected 1-2 days post pairing, but not when single neuron responses were examined during the same period. These results suggest that rapid reorganization of cortical neurons following sensory deprivation may be mediated by an STDP mechanism. PMID- 25505406 TI - Lateral and feedforward inhibition suppress asynchronous activity in a large, biophysically-detailed computational model of the striatal network. AB - Striatal medium spiny neurons (MSNs) receive lateral inhibitory projections from other MSNs and feedforward inhibitory projections from fast-spiking, parvalbumin containing striatal interneurons (FSIs). The functional roles of these connections are unknown, and difficult to study in an experimental preparation. We therefore investigated the functionality of both lateral (MSN-MSN) and feedforward (FSI-MSN) inhibition using a large-scale computational model of the striatal network. The model consists of 2744 MSNs comprised of 189 compartments each and 121 FSIs comprised of 148 compartments each, with dendrites explicitly represented and almost all known ionic currents included and strictly constrained by biological data as appropriate. Our analysis of the model indicates that both lateral inhibition and feedforward inhibition function at the population level to limit non-ensemble MSN spiking while preserving ensemble MSN spiking. Specifically, lateral inhibition enables large ensembles of MSNs firing synchronously to strongly suppress non-ensemble MSNs over a short time-scale (10 30 ms). Feedforward inhibition enables FSIs to strongly inhibit weakly activated, non-ensemble MSNs while moderately inhibiting activated ensemble MSNs. Importantly, FSIs appear to more effectively inhibit MSNs when FSIs fire asynchronously. Both types of inhibition would increase the signal-to-noise ratio of responding MSN ensembles and contribute to the formation and dissolution of MSN ensembles in the striatal network. PMID- 25505408 TI - Spatial component analysis of MRI data for Alzheimer's disease diagnosis: a Bayesian network approach. AB - This work presents a spatial-component (SC) based approach to aid the diagnosis of Alzheimer's disease (AD) using magnetic resonance images. In this approach, the whole brain image is subdivided in regions or spatial components, and a Bayesian network is used to model the dependencies between affected regions of AD. The structure of relations between affected regions allows to detect neurodegeneration with an estimated performance of 88% on more than 400 subjects and predict neurodegeneration with 80% accuracy, supporting the conclusion that modeling the dependencies between components increases the recognition of different patterns of brain degeneration in AD. PMID- 25505411 TI - Brain structure across the lifespan: the influence of stress and mood. AB - Normal brain aging is an inevitable and heterogeneous process characterized by a selective pattern of structural changes. Such heterogeneity arises as a consequence of cumulative effects over the lifespan, including stress and mood effects, which drive different micro- and macro-structural alterations in the brain. Investigating these differences in healthy age-related changes is a major challenge for the comprehension of the cognitive status. Herein we addressed the impact of normal aging, stress, mood, and their interplay in the brain gray and white matter (WM) structure. We showed the critical impact of age in the WM volume and how stress and mood influence brain volumetry across the lifespan. Moreover, we found a more profound effect of the interaction of aging/stress/mood on structures located in the left hemisphere. These findings help to clarify some divergent results associated with the aging decline and to enlighten the association between abnormal volumetric alterations and several states that may lead to psychiatric disorders. PMID- 25505412 TI - Motor and cognitive changes in normal aging. PMID- 25505410 TI - Variations in brain DNA. AB - It is assumed that DNA sequences are conserved in the diverse cell types present in a multicellular organism like the human being. Thus, in order to compare the sequences in the genome of DNA from different individuals, nucleic acid is commonly isolated from a single tissue. In this regard, blood cells are widely used for this purpose because of their availability. Thus blood DNA has been used to study genetic familiar diseases that affect other tissues and organs, such as the liver, heart, and brain. While this approach is valid for the identification of familial diseases in which mutations are present in parental germinal cells and, therefore, in all the cells of a given organism, it is not suitable to identify sporadic diseases in which mutations might occur in specific somatic cells. This review addresses somatic DNA variations in different tissues or cells (mainly in the brain) of single individuals and discusses whether the dogma of DNA invariance between cell types is indeed correct. We will also discuss how single nucleotide somatic variations arise, focusing on the presence of specific DNA mutations in the brain. PMID- 25505413 TI - The acute effects of exercise on cortical excitation and psychosocial outcomes in men treated for prostate cancer: a randomized controlled trial. AB - PURPOSE: Regular exercise improves psychological well-being in men treated for prostate cancer (PCa). For this population and among cancer survivors in general, the effect of a single bout of exercise on self-report or objective measures of psychological well-being has not been examined. We examined the acute effect of a single bout of exercise on the cortical silent period (CSP) and on self-reported mood in men that have received treatment for PCa. METHODS: Thirty-six PCa survivors were randomly assigned to 60 min of low to moderate intensity exercise or to a control condition. Outcomes were assessed immediately before and after either the exercise or the control condition. RESULTS: No significant between group differences were observed in CSP or mood were observed following the exercise session or control conditions. Participants with higher scores of trait anxiety had significantly shorter CSP at baseline, as well as those receiving androgen deprivation therapy. Age and baseline CSP had a low-moderate, but significant negative correlation. Changes in CSP following the exercise condition were strongly negatively correlated with changes in self-reported vigor. CONCLUSION: While we did not observe any acute effect of exercise on the CSP in this population, the associations between CSP and trait anxiety, age, and vigor are novel findings requiring further examination. IMPLICATIONS FOR CANCER SURVIVORS: Exercise did not acutely affect our participants in measures of psychological well-being. Additional mechanisms to explain the chronic psychosocial benefits of exercise previously observed in men with PCa require further exploration. Clinicaltrials.gov Identifier: NCT01715064 (http://clinicaltrials.gov/show/NCT01715064). PMID- 25505409 TI - Synaptic plasticity, neural circuits, and the emerging role of altered short-term information processing in schizophrenia. AB - Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons and thus modifies the likelihood that action potentials in a presynaptic neuron will lead to an action potential in a postsynaptic neuron. As such, synaptic plasticity and pathological changes in synaptic plasticity impact the synaptic computation which controls the information flow through the neural microcircuits responsible for the complex information processing necessary to drive adaptive behaviors. As current theories of neuropsychiatric disease suggest that distinct dysfunctions in neural circuit performance may critically underlie the unique symptoms of these diseases, pathological alterations in synaptic plasticity mechanisms may be fundamental to the disease process. Here we consider mechanisms of both short-term and long-term plasticity of synaptic transmission and their possible roles in information processing by neural microcircuits in both health and disease. As paradigms of neuropsychiatric diseases with strongly implicated risk genes, we discuss the findings in schizophrenia and autism and consider the alterations in synaptic plasticity and network function observed in both human studies and genetic mouse models of these diseases. Together these studies have begun to point toward a likely dominant role of short-term synaptic plasticity alterations in schizophrenia while dysfunction in autism spectrum disorders (ASDs) may be due to a combination of both short-term and long-term synaptic plasticity alterations. PMID- 25505415 TI - Applications of linking PBPK and PD models to predict the impact of genotypic variability, formulation differences, differences in target binding capacity and target site drug concentrations on drug responses and variability. AB - This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-rich physiologically based pharmacokinetic (PBPK) models with pharmacodynamics (PDs) models. Four distinct applications that were developed and tested are presented here. PBPK models were developed for metoprolol using different CYP2D6 genotypes based on in vitro data. Application of the models for prediction of phenotypic differences in the pharmacokinetics (PKs) and PD compared favorably with clinical data, demonstrating that these differences can be predicted prior to the availability of such data from clinical trials. In the second case, PK and PD data for an immediate release formulation of nifedipine together with in vitro dissolution data for a controlled release (CR) formulation were used to predict the PK and PD of the CR. This approach can be useful to pharmaceutical scientists during formulation development. The operational model of agonism was used in the third application to describe the hypnotic effects of triazolam, and this was successfully extrapolated to zolpidem by changing only the drug related parameters from in vitro experiments. This PBPK modeling approach can be useful to developmental scientists who which to compare several drug candidates in the same therapeutic class. Finally, differences in QTc prolongation due to quinidine in Caucasian and Korean females were successfully predicted by the model using free heart concentrations as an input to the PD models. This PBPK linked PD model was used to demonstrate a higher sensitivity to free heart concentrations of quinidine in Caucasian females, thereby providing a mechanistic understanding of a clinical observation. In general, permutations of certain conditions which potentially change PK and hence PD may not be amenable to the conduct of clinical studies but linking PBPK with PD provides an alternative method of investigating the potential impact of PK changes on PD. PMID- 25505416 TI - Structural plasticity in mesencephalic dopaminergic neurons produced by drugs of abuse: critical role of BDNF and dopamine. AB - Mesencephalic dopaminergic neurons were suggested to be a critical physiopathology substrate for addiction disorders. Among neuroadaptive processes to addictive drugs, structural plasticity has attracted attention. While structural plasticity occurs at both pre- and post-synaptic levels in the mesolimbic dopaminergic system, the present review focuses only on dopaminergic neurons. Exposures to addictive drugs determine two opposite structural responses, hypothrophic plasticity produced by opioids and cannabinoids (in particular during the early withdrawal phase) and hypertrophic plasticity, mostly driven by psychostimulants and nicotine. In vitro and in vivo studies identified BDNF and extracellular dopamine as two critical factors in determining structural plasticity, the two molecules sharing similar intracellular pathways involved in cell soma and dendrite growth, the MEK-ERK1/2 and the PI3K-Akt-mTOR, via preferential activation of TrkB and dopamine D3 receptors, respectively. At present information regarding specific structural changes associated to the various stages of the addiction cycle is incomplete. Encouraging neuroimaging data in humans indirectly support the preclinical evidence of hypotrophic and hypertrophic effects, suggesting a possible differential engagement of dopamine neurons in parallel and partially converging circuits controlling motivation, stress, and emotions. PMID- 25505414 TI - GABAA receptor drugs and neuronal plasticity in reward and aversion: focus on the ventral tegmental area. AB - GABAA receptors are the main fast inhibitory neurotransmitter receptors in the mammalian brain, and targets for many clinically important drugs widely used in the treatment of anxiety disorders, insomnia and in anesthesia. Nonetheless, there are significant risks associated with the long-term use of these drugs particularly related to development of tolerance and addiction. Addictive mechanisms of GABAA receptor drugs are poorly known, but recent findings suggest that those drugs may induce aberrant neuroadaptations in the brain reward circuitry. Recently, benzodiazepines, acting on synaptic GABAA receptors, and modulators of extrasynaptic GABAA receptors (THIP and neurosteroids) have been found to induce plasticity in the ventral tegmental area (VTA) dopamine neurons and their main target projections. Furthermore, depending whether synaptic or extrasynaptic GABAA receptor populations are activated, the behavioral outcome of repeated administration seems to correlate with rewarding or aversive behavioral responses, respectively. The VTA dopamine neurons project to forebrain centers such as the nucleus accumbens and medial prefrontal cortex, and receive afferent projections from these brain regions and especially from the extended amygdala and lateral habenula, forming the major part of the reward and aversion circuitry. Both synaptic and extrasynaptic GABAA drugs inhibit the VTA GABAergic interneurons, thus activating the VTA DA neurons by disinhibition and this way inducing glutamatergic synaptic plasticity. However, the GABAA drugs failed to alter synaptic spine numbers as studied from Golgi-Cox-stained VTA dendrites. Since the GABAergic drugs are known to depress the brain metabolism and gene expression, their likely way of inducing neuroplasticity in mature neurons is by disinhibiting the principal neurons, which remains to be rigorously tested for a number of clinically important anxiolytics, sedatives and anesthetics in different parts of the circuitry. PMID- 25505417 TI - Central role of carotid body chemoreceptors in disordered breathing and cardiorenal dysfunction in chronic heart failure. AB - Oscillatory breathing (OB) patterns are observed in pre-term infants, patients with cardio-renal impairment, and in otherwise healthy humans exposed to high altitude. Enhanced carotid body (CB) chemoreflex sensitivity is common to all of these populations and is thought to contribute to these abnormal patterns by destabilizing the respiratory control system. OB patterns in chronic heart failure (CHF) patients are associated with greater levels of tonic and chemoreflex-evoked sympathetic nerve activity (SNA), which is associated with greater morbidity and poor prognosis. Enhanced chemoreflex drive may contribute to tonic elevations in SNA by strengthening the relationship between respiratory and sympathetic neural outflow. Elimination of CB afferents in experimental models of CHF has been shown to reduce OB, respiratory-sympathetic coupling, and renal SNA, and to improve autonomic balance in the heart. The CB chemoreceptors may play an important role in progression of CHF by contributing to respiratory instability and OB, which in turn further exacerbates tonic and chemoreflex evoked increases in SNA to the heart and kidney. PMID- 25505419 TI - Role of sinoatrial node architecture in maintaining a balanced source-sink relationship and synchronous cardiac pacemaking. AB - Normal heart rhythm (sinus rhythm) depends on regular activity of the sinoatrial node (SAN), a heterogeneous collection of specialized myocytes in the right atrium. SAN cells, in general, possess a unique electrophysiological profile that promotes spontaneous electrical activity (automaticity). However, while automaticity is required for normal pacemaking, it is not necessarily sufficient. Less appreciated is the importance of the elaborate structure of the SAN complex for proper pacemaker function. Here, we review the important structural features of the SAN with a focus on how these elements help manage a precarious balance between electrical charge generated by the SAN ("source") and the charge needed to excite the surrounding atrial tissue ("sink"). We also discuss how compromised "source-sink" balance due, for example to fibrosis, may promote SAN dysfunction, characterized by slow and/or asynchronous pacemaker activity and even failure, in the setting of cardiovascular disease (e.g., heart failure, atrial fibrillation). Finally, we discuss implications of the "source-sink" balance in the SAN complex for cell and gene therapies aimed at creating a biological pacemaker as replacement or bridge to conventional electronic pacemakers. PMID- 25505420 TI - Impact of nutrient excess and endothelial nitric oxide synthase on the plasma metabolite profile in mice. AB - An increase in calorie consumption is associated with the recent rise in obesity prevalence. However, our current understanding of the effects of nutrient excess on major metabolic pathways appears insufficient to develop safe and effective metabolic interventions to prevent obesity. Hence, we sought to identify systemic metabolic changes caused by nutrient excess and to determine how endothelial nitric oxide synthase (eNOS)-which has anti-obesogenic properties-affects systemic metabolism by measuring plasma metabolites. Wild-type (WT) and eNOS transgenic (eNOS-TG) mice were placed on low fat or high fat diets for 6 weeks, and plasma metabolites were measured using an unbiased metabolomic approach. High fat feeding in WT mice led to significant increases in fat mass, which was associated with significantly lower plasma levels of 1,5-anhydroglucitol, lysophospholipids, 3-dehydrocarnitine, and bile acids, as well as branched chain amino acids (BCAAs) and their metabolites. Plasma levels of several lipids including sphingomyelins, stearoylcarnitine, dihomo-linoleate and metabolites associated with oxidative stress were increased by high fat diet. In comparison with low fat-fed WT mice, eNOS-TG mice showed lower levels of several free fatty acids, but in contrast, the levels of bile acids, amino acids, and BCAA catabolites were increased. When placed on a high fat diet, eNOS overexpressing mice showed remarkably higher levels of plasma bile acids and elevated levels of plasma BCAAs and their catabolites compared with WT mice. Treatment with GW4064, an inhibitor of bile acid synthesis, decreased plasma bile acid levels but was not sufficient to reverse the anti-obesogenic effects of eNOS overexpression. These findings reveal unique metabolic changes in response to high fat diet and eNOS overexpression and suggest that the anti-obesity effects of eNOS are likely independent of changes in the bile acid pool. PMID- 25505421 TI - Specific and quantitative labeling of biomolecules using click chemistry. AB - Specific and highly efficient fluorescent labeling techniques for biomolecules, especially for proteins, are required for the quantitative analyses of bio phenomena and for subsequent systems biology. Although expression of exogenous proteins fused with fluorescent tags, such as green fluorescent protein, is the most widely used method for quantitative bio-analysis, the following problems need to be considered carefully: (1) precise stoichiometric control in living cells is difficult, and (2) the bulkiness of the fluorescent tags restricts analysis of the inherent physical and biological properties of the proteins. Therefore, novel techniques to specifically and stoichiometrically label intrinsic proteins or other biomolecules in living cells should be developed. Click chemistry reactions (e.g., Huisgen cycloaddition and Staudinger ligation) are the most promising approaches for this purpose, because these chemical reactions have following advantages: (1) bioorthogonal reactions; (2) mild reaction conditions suitable for fragile biomolecules, cells, and tissues; (3) extremely high reaction ratio; (4) small size of the functional groups for the cross-coupling reactions; (5) stable covalent bonding; and (6) simple metabolic labeling procedures in living cells, using various biomolecular analogs. Diverse quantitative biological studies have been carried out using this technology (e.g., quantification of novel synthesized proteins and observation of post translational modifications). In this review, I explain the basics of chemical probing with click chemistry, and discuss its recent applications in the field of quantitative biology. Furthermore, I discuss the capability, significance, and future of the chemical probing of proteins, with an emphasis on the use of click chemistry in the field of the quantitative biology. PMID- 25505422 TI - Cerebral oxygenation in health and disease. PMID- 25505423 TI - Effect of acute hypobaric hypoxia on the endothelial glycocalyx and digital reactive hyperemia in humans. AB - INTRODUCTION: Hypoxia is associated with increased capillary permeability. This study tested whether acute hypobaric hypoxia involves degradation of the endothelial glycocalyx. METHODS: We exposed 12 subjects to acute hypobaric hypoxia (equivalent to 4500 m for 2-4 h) and measured venous blood concentrations of biomarkers reflecting endothelial and glycocalyx degradation (catecholamines, syndecan-1, soluble CD40 ligand, protein C, soluble thrombomodulin, tissue-type plasminogen activators, histone-complexed DNA fragments, and nitrite/nitrate). Endothelial function was assessed by the hyperemic response to brachial artery occlusion by peripheral arterial tonometry. RESULTS: Compared with normoxic baseline levels, hypoxia increased concentrations of syndecan-1 from 22 (95% confidence interval: 17-27) to 25 (19-30) ng/ml (p < 0.02) and protein C from 76 (70-83)% to 81 (74-88)% (p < 0.02). Nitrite/nitrate decreased from 23 (18-27) MUM at baseline to 19 (14-24) MUM and 18 (14-21) MUM in hypoxia and recovery, respectively (p < 0.05). Other biomarkers remained unchanged. The post occlusion/pre-occlusion ratio (reactive hyperemia index, RHI) decreased from 1.80 (1.52-2.07) in normoxia to 1.62 (1.28-1.96) after 2-4 h of hypobaric hypoxia and thereafter increased to 2.43 (1.99-2.86) during normoxic recovery (p < 0.01). CONCLUSIONS: The increase in syndecan-1 and protein C suggests that acute hypobaric hypoxia produces a minor degree of glycocalyx degradation and overall cellular damage. After hypoxia RHI rebounded to higher than baseline levels suggesting improved endothelial functionality. PMID- 25505425 TI - Stable schizophrenia patients learn equally well as age-matched controls and better than elderly controls in two sensorimotor rotary pursuit tasks. AB - OBJECTIVE: To compare sensorimotor performance and learning in stable schizophrenia patients, healthy age- and sex-matched controls and elderly controls on two variations of the rotary pursuit: circle pursuit (true motor learning) and figure pursuit (motor and sequence learning). METHOD: In the circle pursuit, a target circle, rotating with increasing speed along a predictable circular path on the computer screen, must be followed by a cursor controlled by a pen on a writing tablet. In the eight-trial figure pursuit, subjects learn to draw a complex figure by pursuing the target circle that moves along an invisible trajectory between and around several goals. Tasks were administered thrice (day 1, day 2, day 7) to 30 patients with stable schizophrenia (S), 30 healthy age- and sex-matched controls (C), and 30 elderly participants (>65 years; E) and recorded with a digitizing tablet and pressure-sensitive pen. The outcome measure accuracy (% of time that cursor is within the target) was used to assess performance. RESULTS: We observed significant group differences in accuracy, both in circle and figure pursuit tasks (E < S < C, p < 0.01). Strong learning effects were found in each group. Learning curves were similar in circle pursuit but differed between groups in figure pursuit. When corrected for group differences in starting level, the learning gains over the three sessions of schizophrenia patients and age-matched controls were equal and both were larger than those of the elderly controls. CONCLUSION: Despite the reduced sensorimotor performance that was found in the schizophrenia patients, their sensorimotor learning seems to be preserved. The relevance of this finding for the evaluation of procedural learning in schizophrenia is discussed. The better performance and learning rate of the patients compared to the elderly controls was unexpected and deserves further study. PMID- 25505418 TI - The impact of age-related dysregulation of the angiotensin system on mitochondrial redox balance. AB - Aging is associated with the accumulation of various deleterious changes in cells. According to the free radical and mitochondrial theory of aging, mitochondria initiate most of the deleterious changes in aging and govern life span. The failure of mitochondrial reduction-oxidation (redox) homeostasis and the formation of excessive free radicals are tightly linked to dysregulation in the Renin Angiotensin System (RAS). A main rate-controlling step in RAS is renin, an enzyme that hydrolyzes angiotensinogen to generate angiotensin I. Angiotensin I is further converted to Angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II binds with equal affinity to two main angiotensin receptors type 1 (AT1R) and type 2 (AT2R). The binding of Ang II to AT1R activates NADPH oxidase, which leads to increased generation of cytoplasmic reactive oxygen species (ROS). This Ang II-AT1R-NADPH-ROS signal triggers the opening of mitochondrial KATP channels and mitochondrial ROS production in a positive feedback loop. Furthermore, RAS has been implicated in the decrease of many of ROS scavenging enzymes, thereby leading to detrimental levels of free radicals in the cell. AT2R is less understood, but evidence supports an anti-oxidative and mitochondria-protective function for AT2R. The overlap between age related changes in RAS and mitochondria, and the consequences of this overlap on age related diseases are quite complex. RAS dysregulation has been implicated in many pathological conditions due to its contribution to mitochondrial dysfunction. Decreased age-related, renal and cardiac mitochondrial dysfunction was seen in patients treated with angiotensin receptor blockers. The aim of this review is to: (a) report the most recent information elucidating the role of RAS in mitochondrial redox hemostasis and (b) discuss the effect of age-related activation of RAS on generation of free radicals. PMID- 25505426 TI - Patients' Perspectives on Stigma of Mental Illness (an Egyptian Study in a Private Hospital). AB - The present study is concerned with the stigma of mental illness. It examines the subjective element of the experience of stigma among a sample of in-patients with different mental disorders. The sample was taken from consecutive admissions of in-patients meeting International Classification of Diseases, 10th revision (ICD 10) criteria for mental disorders who had capacity to decide on participation in the study and were willing to respond to the structured interview. The study was undertaken in an Egyptian private psychiatric hospital. The structured clinical interview included aspects of the emotional, behavioral, and cognitive effects of having a psychiatric diagnosis on in-patients with various diagnostic labels in an Egyptian psychiatric hospital. It also studied whether this effect changes with specific disorders, total duration of illness, or sociodemographic variables as gender, age, or educational level. The study illustrated the core items of stigmatization attached to the diagnosis of mental illness (1), which more than half of the participants responded affirmatively. The study aimed to explore the most prevailing aspects of stigma or social disadvantage; hoping that this may offer a preliminary guide for clinicians to address these issues in their practice. PMID- 25505427 TI - Role of respiration in mind-body practices: concepts from contemporary science and traditional yoga texts. PMID- 25505424 TI - Cerebellar-motor dysfunction in schizophrenia and psychosis-risk: the importance of regional cerebellar analysis approaches. AB - Motor abnormalities in individuals with schizophrenia and those at-risk for psychosis are well documented. An accumulating body of work has also highlighted motor abnormalities related to cerebellar dysfunction in schizophrenia including eye-blink conditioning, timing, postural control, and motor learning. We have also recently found evidence for motor dysfunction in individuals at ultra high risk for psychosis (1-3). This is particularly relevant as the cerebellum is thought to be central to the cognitive dysmetria model of schizophrenia, and these overt motor signs may point to more general cerebellar dysfunction in the etiology of psychotic disorders. While studies have provided evidence indicative of motor cerebellar dysfunction in at-risk populations and in schizophrenia, findings with respect to the cerebellum have been mixed. One factor potentially contributing to these mixed results is the whole-structure approach taken when investigating the cerebellum. In non-human primates, there are distinct closed loop circuits between the cerebellum, thalamus, and brain with motor and non motor cortical regions. Recent human neuroimaging has supported this finding and indicates that there is a cerebellar functional topography (4), and this information is being missed with whole-structure approaches. Here, we review cerebellar-motor dysfunction in individuals with schizophrenia and those at-risk for psychosis. We also discuss cerebellar abnormalities in psychosis, and the cerebellar functional topography. Because of the segregated functional regions of the cerebellum, we propose that it is important to look at the structure regionally in order to better understand its role in motor dysfunction in these populations. This is analogous to approaches taken with the basal ganglia, where each region is considered separately. Such an approach is necessary to better understand cerebellar pathophysiology on a macro-structural level with respect to the pathogenesis of psychosis. PMID- 25505428 TI - Cannabis use and anxiety: is stress the missing piece of the puzzle? AB - OBJECTIVE: Comorbidity between anxiety and cannabis use is common yet the nature of the association between these conditions is not clear. Four theories were assessed, and a fifth hypothesis tested to determine if the misattribution of stress symptomology plays a role in the association between state-anxiety and cannabis. METHODS: Three-hundred-sixteen participants ranging in age from 18 to 71 years completed a short online questionnaire asking about their history of cannabis use and symptoms of stress and anxiety. RESULTS: Past and current cannabis users reported higher incidence of lifetime anxiety than participants who had never used cannabis; however, these groups did not differ in state anxiety, stress, or age of onset of anxiety. State-anxiety and stress were not associated with frequency of cannabis use, but reported use to self-medicate for anxiety was positively associated with all three. Path analyses indicated two different associations between anxiety and cannabis use, pre-existing and high state-anxiety was associated with (i) higher average levels of intoxication and, in turn, acute anxiety responses to cannabis use; (ii) frequency of cannabis use via the mediating effects of stress and self-medication. CONCLUSION: None of the theories was fully supported by the findings. However, as cannabis users reporting self-medication for anxiety were found to be self-medicating stress symptomology, there was some support for the stress-misattribution hypothesis. With reported self-medication for anxiety being the strongest predictor of frequency of use, it is suggested that researchers, clinicians, and cannabis users pay greater attention to the overlap between stress and anxiety symptomology and the possible misinterpretation of these related but distinct conditions. PMID- 25505429 TI - Pre-treatment amygdala volume predicts electroconvulsive therapy response. AB - BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for patients with severe depression. Knowledge on factors predicting therapeutic response may help to identify patients who will benefit most from the intervention. Based on the neuroplasticity hypothesis, volumes of the amygdala and hippocampus are possible candidates for predicting treatment outcome. Therefore, this prospective cohort study examines the predictive value of amygdala and hippocampal volumes for the effectiveness of ECT. METHODS: Prior to ECT, 53 severely unipolar depressed patients [mean age 57 +/- 14 years; 40% (n = 21) male] received structural magnetic resonance imaging (MRI) at 1.5 T. Normalized amygdala and hippocampal volumes were calculated based on automatic segmentation by FreeSurfer (FS). Regression analyses were used to test if the normalized volumes could predict the response to a course of ECT based on the Montgomery-Asberg Depression Rating Scale (MADRS) scores. RESULTS: A larger amygdala volume independently and significantly predicted a lower post-ECT MADRS score (beta = -0.347, P = 0.013). The left amygdala volume had greater predictive value for treatment outcome relative to the right amygdala volume. Hippocampal volume had no independent predictive value. CONCLUSION: A larger pre-treatment amygdala volume predicted more effective ECT, independent of other known predictors. Almost all patients continued their medication during the study, which might have influenced the course of treatment in ways that were not taken into account. PMID- 25505430 TI - Cognitive programs: software for attention's executive. AB - What are the computational tasks that an executive controller for visual attention must solve? This question is posed in the context of the Selective Tuning model of attention. The range of required computations go beyond top-down bias signals or region-of-interest determinations, and must deal with overt and covert fixations, process timing and synchronization, information routing, memory, matching control to task, spatial localization, priming, and coordination of bottom-up with top-down information. During task execution, results must be monitored to ensure the expected results. This description includes the kinds of elements that are common in the control of any kind of complex machine or system. We seek a mechanistic integration of the above, in other words, algorithms that accomplish control. Such algorithms operate on representations, transforming a representation of one kind into another, which then forms the input to yet another algorithm. Cognitive Programs (CPs) are hypothesized to capture exactly such representational transformations via stepwise sequences of operations. CPs, an updated and modernized offspring of Ullman's Visual Routines, impose an algorithmic structure to the set of attentional functions and play a role in the overall shaping of attentional modulation of the visual system so that it provides its best performance. This requires that we consider the visual system as a dynamic, yet general-purpose processor tuned to the task and input of the moment. This differs dramatically from the almost universal cognitive and computational views, which regard vision as a passively observing module to which simple questions about percepts can be posed, regardless of task. Differing from Visual Routines, CPs explicitly involve the critical elements of Visual Task Executive (vTE), Visual Attention Executive (vAE), and Visual Working Memory (vWM). Cognitive Programs provide the software that directs the actions of the Selective Tuning model of visual attention. PMID- 25505431 TI - Ever-present threats from information technology: the Cyber-Paranoia and Fear Scale. AB - Delusions involving technology, and specifically the internet, are increasingly common, and fear-reality statistics suggest computer-related fears are very widespread. These fears form a continuum from the widely understandable and realistic to the unrealistic, and frankly paranoid. The present study investigated the validity of this construct in a non-clinical population by constructing a novel self-report measure. The new Cyber-Paranoia and Fear Scale aims to measure the perception of information technology-related threats originating from or enabled by computers, smartphones, social networks, and digital surveillance. Psychometric properties of the new Cyber-Paranoia and Fear Scale are reported alongside an established measure of suspiciousness and paranoia in 181 participants including a sub-group of fifty information technology professionals. Exploratory factor analysis suggested the presence of two, related, dimensions that we term cyber-paranoia and cyber-fear. Both sub scales were internally consistent and produced a normal distribution of scores. The relationships of the sub-scales with age, gender, trait paranoia, digital literacy, and digital inclusion are supportive of construct validity. The distinctiveness of 'cyber-paranoia' from general trait paranoia appears to mirror the clinical distinctiveness of 'internet' and other technology-fuelled delusions. Knowledge provision to increase technological proficiency and awareness may bring about a reduction in cyber-paranoia. PMID- 25505432 TI - Causal beliefs about depression in different cultural groups-what do cognitive psychological theories of causal learning and reasoning predict? AB - Cognitive psychological research focuses on causal learning and reasoning while cognitive anthropological and social science research tend to focus on systems of beliefs. Our aim was to explore how these two types of research can inform each other. Cognitive psychological theories (causal model theory and causal Bayes nets) were used to derive predictions for systems of causal beliefs. These predictions were then applied to lay theories of depression as a specific test case. A systematic literature review on causal beliefs about depression was conducted, including original, quantitative research. Thirty-six studies investigating 13 non-Western and 32 Western cultural groups were analyzed by classifying assumed causes and preferred forms of treatment into common categories. Relations between beliefs and treatment preferences were assessed. Substantial agreement between cultural groups was found with respect to the impact of observable causes. Stress was generally rated as most important. Less agreement resulted for hidden, especially supernatural causes. Causal beliefs were clearly related to treatment preferences in Western groups, while evidence was mostly lacking for non-Western groups. Overall predictions were supported, but there were considerable methodological limitations. Pointers to future research, which may combine studies on causal beliefs with experimental paradigms on causal reasoning, are given. PMID- 25505433 TI - Evidence for the role of German final devoicing in pre-attentive speech processing: a mismatch negativity study. AB - Results of a mismatch negativity experiment are reported in which the pre attentive relevance of the German phonological alternation of final devoicing (FD) is shown in two ways. The experiment employs pseudowords. (1) A deviant [vus] paired with standard /vuze/ did not show a mismatch effect for the voicing change in /z/ versus [s] because the two can be related by FD. When standard and deviant were reversed, the two could not be related by FD and a mismatch effect for the voicing difference occurred. (2) An ill-formed deviant that violates FD, *[vuz], triggered mismatch effects that were plausibly attributed to its ill formedness. The results show that a syllable-related process like FD is already taken into account by the processing system in early pre-attentive processing. PMID- 25505434 TI - Individual aptitude in Mandarin lexical tone perception predicts effectiveness of high-variability training. AB - Although the high-variability training method can enhance learning of non-native speech categories, this can depend on individuals' aptitude. The current study asked how general the effects of perceptual aptitude are by testing whether they occur with training materials spoken by native speakers and whether they depend on the nature of the to-be-learned material. Forty-five native Dutch listeners took part in a 5-day training procedure in which they identified bisyllabic Mandarin pseudowords (e.g., asa) pronounced with different lexical tone combinations. The training materials were presented to different groups of listeners at three levels of variability: low (many repetitions of a limited set of words recorded by a single speaker), medium (fewer repetitions of a more variable set of words recorded by three speakers), and high (similar to medium but with five speakers). Overall, variability did not influence learning performance, but this was due to an interaction with individuals' perceptual aptitude: increasing variability hindered improvements in performance for low aptitude perceivers while it helped improvements in performance for high-aptitude perceivers. These results show that the previously observed interaction between individuals' aptitude and effects of degree of variability extends to natural tokens of Mandarin speech. This interaction was not found, however, in a closely matched study in which native Dutch listeners were trained on the Japanese geminate/singleton consonant contrast. This may indicate that the effectiveness of high-variability training depends not only on individuals' aptitude in speech perception but also on the nature of the categories being acquired. PMID- 25505435 TI - Nonverbal synchrony and affect in dyadic interactions. AB - In an experiment on dyadic social interaction, we invited participants to verbal interactions in cooperative, competitive, and 'fun task' conditions. We focused on the link between interactants' affectivity and their nonverbal synchrony, and explored which further variables contributed to affectivity: interactants' personality traits, sex, and the prescribed interaction tasks. Nonverbal synchrony was quantified by the coordination of interactants' body movement, using an automated video-analysis algorithm (motion energy analysis). Traits were assessed with standard questionnaires of personality, attachment, interactional style, psychopathology, and interpersonal reactivity. We included 168 previously unacquainted individuals who were randomly allocated to same-sex dyads (84 females, 84 males, mean age 27.8 years). Dyads discussed four topics of general interest drawn from an urn of eight topics, and finally engaged in a fun interaction. Each interaction lasted 5 min. In between interactions, participants repeatedly assessed their affect. Using hierarchical linear modeling, we found moderate to strong effect sizes for synchrony to occur, especially in competitive and fun task conditions. Positive affect was associated positively with synchrony, negative affect was associated negatively. As for causal direction, data supported the interpretation that synchrony entailed affect rather than vice versa. The link between nonverbal synchrony and affect was strongest in female dyads. The findings extend previous reports of synchrony and mimicry associated with emotion in relationships and suggest a possible mechanism of the synchrony affect correlation. PMID- 25505437 TI - Expert analogy use in a naturalistic setting. AB - The use of analogy is an important component of human cognition. The type of analogy we produce and communicate depends heavily on a number of factors, such as the setting, the level of domain expertise present, and the speaker's goal or intent. In this observational study, we recorded economics experts during scientific discussion and examined the categorical distance and structural depth of the analogies they produced. We also sought to characterize the purpose of the analogies that were generated. Our results supported previous conclusions about the infrequency of superficial similarity in subject-generated analogs, but also showed that distance and depth characteristics were more evenly balanced than in previous observational studies. This finding was likely due to the nature of the goals of the participants, as well as the broader nature of their expertise. An analysis of analogical purpose indicated that the generation of concrete source examples of more general target concepts was most prevalent. We also noted frequent instances of analogies intended to form visual images of source concepts. Other common purposes for analogies were the addition of colorful speech, inclusion (i.e., subsumption) of a target into a source concept, or differentiation between source and target concepts. We found no association between depth and either of the other two characteristics, but our findings suggest a relationship between purpose and distance; i.e., that visual imagery typically entailed an outside-domain source whereas exemplification was most frequently accomplished using within-domain analogies. Overall, we observed a rich and diverse set of spontaneously produced analogical comparisons. The high degree of expertise within the observed group along with the richly comparative nature of the economics discipline likely contributed to this analogical abundance. PMID- 25505438 TI - A possible neurophysiological correlate of audiovisual binding and unbinding in speech perception. AB - Audiovisual (AV) speech integration of auditory and visual streams generally ends up in a fusion into a single percept. One classical example is the McGurk effect in which incongruent auditory and visual speech signals may lead to a fused percept different from either visual or auditory inputs. In a previous set of experiments, we showed that if a McGurk stimulus is preceded by an incongruent AV context (composed of incongruent auditory and visual speech materials) the amount of McGurk fusion is largely decreased. We interpreted this result in the framework of a two-stage "binding and fusion" model of AV speech perception, with an early AV binding stage controlling the fusion/decision process and likely to produce "unbinding" with less fusion if the context is incoherent. In order to provide further electrophysiological evidence for this binding/unbinding stage, early auditory evoked N1/P2 responses were here compared during auditory, congruent and incongruent AV speech perception, according to either prior coherent or incoherent AV contexts. Following the coherent context, in line with previous electroencephalographic/magnetoencephalographic studies, visual information in the congruent AV condition was found to modify auditory evoked potentials, with a latency decrease of P2 responses compared to the auditory condition. Importantly, both P2 amplitude and latency in the congruent AV condition increased from the coherent to the incoherent context. Although potential contamination by visual responses from the visual cortex cannot be discarded, our results might provide a possible neurophysiological correlate of early binding/unbinding process applied on AV interactions. PMID- 25505439 TI - The role of visual awareness for conflict adaptation in the masked priming task: comparing block-wise adaptation with trial-by-trial adaptation. AB - This study investigated the role of participants' visual awareness in the block wise and the trial-by-trial adaptations. We employed a subliminal response compatibility task in which a prime arrow was briefly presented before the target arrow, and the participants were requested to indicate the direction of the target arrow. The direction of the prime and direction of the target were either the same (compatible trial) or different (incompatible trial). To examine block wise adaptation, two blocks were conducted, i.e., the Neutral block (50% compatible and 50% incompatible trials) and the Incompatible block (10% compatible and 90% incompatible trials). The results showed the existence of the block-wise adaptation without participants' visual awareness. The compatibility effect on both response time and error rate (ER) was smaller in the Incompatible block than in the Neutral block. Moreover, a separate data analysis based on the preceding trial type revealed that the trial-by-trial adaptation of cognitive control was observed only in the ER. These results suggest the different role of visual awareness in the block-wise and trial-by-trial adaptations. PMID- 25505441 TI - The benefits of mystery in nature on attention: assessing the impacts of presentation duration. AB - Although research has provided prodigious evidence in support of the cognitive benefits that natural settings have over urban settings, all nature is not equal. Within nature, natural settings that contain mystery are often among the most preferred nature scenes. With the prospect of acquiring new information, scenes of this type could more effectively elicit a person's sense of fascination, enabling that person to rest the more effortful forms of attention. The present study examined the direct cognitive benefits that mystery in nature has on attention. Settings of this sort presumably evoke a form of attention that is undemanding or effortless. In order to investigate that notion, participants (n = 144) completed a Recognition Memory Task (RMT) that evaluated recognition performance based on the presence of mystery and presentation duration (300 ms, 1 s, 5 s, and 10 s). Results revealed that with additional viewing time, images perceived high in mystery achieved greater improvements in recognition performance when compared to those images perceived low in mystery. Tests for mediation showed that the effect mystery had on recognition performance occurred through perceptions of fascination. Implications of these and other findings are discussed in the context of Attention Restoration Theory. PMID- 25505436 TI - Globularity and language-readiness: generating new predictions by expanding the set of genes of interest. AB - This study builds on the hypothesis put forth in Boeckx and Benitez-Burraco (2014), according to which the developmental changes expressed at the levels of brain morphology and neural connectivity that resulted in a more globular braincase in our species were crucial to understand the origins of our language ready brain. Specifically, this paper explores the links between two well-known 'language-related' genes like FOXP2 and ROBO1 implicated in vocal learning and the initial set of genes of interest put forth in Boeckx and Benitez-Burraco (2014), with RUNX2 as focal point. Relying on the existing literature, we uncover potential molecular links that could be of interest to future experimental inquiries into the biological foundations of language and the testing of our initial hypothesis. Our discussion could also be relevant for clinical linguistics and for the interpretation of results from paleogenomics. PMID- 25505440 TI - Cognition and emotional decision-making in chronic low back pain: an ERPs study during Iowa gambling task. AB - Previous reports documented abnormalities in cognitive functions and decision making (DM) in patients with chronic pain, but these changes are not consistent across studies. Reasons for these discordant findings might include the presence of confounders, variability in chronic pain conditions, and the use of different cognitive tests. The present study was aimed to add evidence in this field, by exploring the cognitive profile of a specific type of chronic pain, i.e., chronic low back pain (cLBP). Twenty four cLBP patients and 24 healthy controls underwent a neuropsychological battery and we focused on emotional DM abilities by means of Iowa gambling task (IGT). During IGT, behavioral responses and the electroencephalogram (EEG) were recorded in 12 patients and 12 controls. Event related potentials (ERPs) were averaged offline from EEG epochs locked to the feedback presentation (4000 ms duration, from 2000 ms before to 2000 ms after the feedback onset) separately for wins and losses and the feedback-related negativity (FRN) and P300 peak-to-peak amplitudes were calculated. Among cognitive measures, cLBP patients scored lower than controls in the modified card sorting test (MCST) and the score in this test was significantly influenced by pain duration and intensity. Behavioral IGT results documented worse performance and the absence of a learning process during the test in cLBP patients compared to controls, with no effect of pain characteristics. ERPs findings documented abnormal feedback processing in patients during IGT. cLBP patients showed poor performance in the MCST and the IGT. Abnormal feedback processing may be secondary to impingement of chronic pain in brain areas involved in DM or suggest the presence of a predisposing factor related to pain chronification. These abnormalities might contribute to the impairment in the work and family settings that often cLBP patients report. PMID- 25505442 TI - When in doubt follow your nose-a wayfinding strategy. AB - Route selection is governed by various strategies which often allow minimizing the required memory capacity. Previous research showed that navigators primarily remember information at route decision points and at route turns, rather than at intersections which required straight walking. However, when actually navigating the route or indicating directional decisions, navigators make fewer errors when they are required to walk straight. This tradeoff between location memory and route decisions accuracy was interpreted as a "when in doubt follow your nose" strategy which allows navigators to only memorize turns and walk straight by default, thus considerably reducing the number of intersections to memorize. These findings were based on newly learned routes. In the present study, we show that such an asymmetry in route memory also prevails for planning routes within highly familiar environments. Participants planned route sequences between locations in their city of residency by pressing arrow keys on a keyboard. They tended to ignore straight walking intersections, but they ignored turns much less so. However, for reported intersections participants were quicker at indicating straight walking than turning. Together with results described in the literature, these findings suggest that a "when in doubt follow your nose strategy" is applied also within highly familiar spaces and might originate from limited working memory capacity during planning a route. PMID- 25505444 TI - The technique of endovascular intracranial revascularization. AB - Intracranial atherosclerosis was traditionally believed to carry a risk of stroke of 8% to 22% per annum. The annualized stroke rate in the recent stenting and aggressive medical management for preventing stroke in intracranial stenosis (SAMMPRIS) trial medical management arm was 12.2%. This trial was halted due to excessive periprocedural events in the stent arm. This stroke rate is still unacceptably, high and a treatment strategy is still needed. SAMMPRIS has no bearing on angioplasty alone. Angioplasty alone has always been our primary intervention for intracranial atherosclerosis and remains so to this day due to its relative simplicity, low complication rate, and efficacy. We have, however, made adjustments to our patient management regimen based on the results of SAMMPRIS. This paper outlines our current patient selection, procedural technique, and post-procedure management. The complications we have encountered while developing our technique are described along with how to avoid them and how to manage them. Our most recent results (since previous publications) are also discussed. PMID- 25505443 TI - Activity-Based Therapies for Repair of the Corticospinal System Injured during Development. AB - This review presents the mechanistic underpinnings of corticospinal tract (CST) development, derived from animal models, and applies what has been learned to inform neural activity-based strategies for CST repair. We first discuss that, in normal development, early bilateral CST projections are later refined into a dense crossed CST projection, with maintenance of sparse ipsilateral projections. Using a novel mouse genetic model, we show that promoting the ipsilateral CST projection produces mirror movements, common in hemiplegic cerebral palsy (CP), suggesting that ipsilateral CST projections become maladaptive when they become abnormally dense and strong. We next discuss how animal studies support a developmental "competition rule" whereby more active/used connections are more competitive and overtake less active/used connections. Based on this rule, after unilateral injury the damaged CST is less able to compete for spinal synaptic connections than the uninjured CST. This can lead to a progressive loss of the injured hemisphere's contralateral projection and a reactive gain of the undamaged hemisphere's ipsilateral CST. Knowledge of the pathophysiology of the developing CST after injury informs interventional strategies. In an animal model of hemiplegic CP, promoting injured system activity or decreasing the uninjured system's activity immediately after the period of a developmental injury both increase the synaptic competitiveness of the damaged system, contributing to significant CST repair and motor recovery. However, delayed intervention, despite significant CST repair, fails to restore skilled movements, stressing the need to consider repair strategies for other neural systems, including the rubrospinal and spinal interneuronal systems. Our interventional approaches harness neural activity-dependent processes and are highly effective in restoring function. These approaches are minimally invasive and are poised for translation to the human. PMID- 25505445 TI - New Perception of Mitochondrial Regulatory Pathway in Parkinsonism - Ubiquitin, PINK1, and Parkin. PMID- 25505446 TI - Predictors of cardiovascular autonomic neuropathy in patients with type 1 diabetes. AB - Cardiovascular disease (CVD) is the leading cause of mortality in patients with type 1 diabetes (T1D). The cardiovascular autonomic neuropathy (CAN), although considered as an independent risk factor for CVD, remains underdiagnosed. The aim of this paper was to determine the prevalence, predictors of CAN in patients with T1D and its association with other chronic complications of diabetes. Patients with T1D underwent a clinical-epidemiological survey, had blood and urinary samples collected, performed ophthalmoscopic and clinical neurological examination and cardiovascular reflex tests. One hundred and fifty one patients with T1D, 53.6% female, 45.7% Caucasian, mean age of 33.4 +/- 13 years, diabetes duration of 16.3 +/- 9.5 years, and glycated hemoglobin levels of 9.1 +/- 2% were evaluated. The prevalence of CAN in the studied population was 30.5%. CAN was associated with age (p = 0.01), diabetes duration (p = 0.036), hypertension (p = 0.001), resting heart rate (HR) (p = 0.000), HbA1c (p = 0.048), urea (p = 0.000), creatinine (p = 0.008), glomerular filtration rate (p = 0.000), urinary albumin concentration (p = 0.000), LDL (p = 0.048), free T4 (p = 0.023), hemoglobin (p = 0.01) and presence of retinopathy (p = 0.000), nephropathy (p = 0.000) and diabetic neuropathy (p = 0.000), the following symptoms syncope (p = 0.000), post prandial nausea (p = 0.042), early satiety (p = 0.031), sexual dysfunction (p = 0.049), and gustatory sweating (p = 0.018). In logistic regression model, it was observed that only resting HR, diabetic neuropathy, and retinopathy were independent associated with CAN. In conclusion, CAN is a common chronic complication of T1D affecting about 30% of the studied population and is associated with the presence of other chronic complications. Indicators of CAN included age, diabetes duration, hypertension, resting HR, diabetic neuropathy and retinopathy, and symptoms suggestive of autonomic neuropathy. This study confirms the importance of systematic and early screening for CAN. PMID- 25505447 TI - Disruption of O-GlcNAc Cycling in C. elegans Perturbs Nucleotide Sugar Pools and Complex Glycans. AB - The carbohydrate modification of serine and threonine residues with O-linked beta N-acetylglucosamine (O-GlcNAc) is ubiquitous and governs cellular processes ranging from cell signaling to apoptosis. The O-GlcNAc modification along with other carbohydrate modifications, including N-linked and O-linked glycans, glycolipids, and sugar polymers, all require the use of the nucleotide sugar UDP GlcNAc, the end product of the hexosamine biosynthetic pathway (HBP). In this paper, we describe the biochemical consequences resulting from perturbation of the O-GlcNAc pathway in C. elegans lacking O-GlcNAc transferase and O-GlcNAcase activities. In ogt-1 null animals, steady-state levels of UDP-GlcNAc/UDP-GalNAc and UDP-glucose were substantially elevated. Transcripts of genes encoding for key members in the HBP (gfat-2, gna-2, C36A4.4) and trehalose metabolism (tre-1, tre-2, tps-2) were elevated in ogt-1 null animals. While there is no evidence to suggest changes in the profile of N-linked glycans in the ogt-1 and oga-1 mutants, glycans insensitive to PNGase digestion (including O-linked glycans, glycolipids, and glycopolymers) were altered in these strains. Our data support that changes in O-GlcNAcylation alters nucleotide sugar production, overall glycan composition, and transcription of genes encoding glycan processing enzymes. These data along with our previous findings that disruption in O-GlcNAc cycling alters macronutrient storage underscores the noteworthy influence this posttranslational modification plays in nutrient sensing. PMID- 25505449 TI - Multiple sulfur isotope signatures of sulfite and thiosulfate reduction by the model dissimilatory sulfate-reducer, Desulfovibrio alaskensis str. G20. AB - Dissimilatory sulfate reduction serves as a key metabolic carbon remineralization process in anoxic marine environments. Sulfate reducing microorganisms can impart a wide range in mass-dependent sulfur isotopic fractionation. As such, the presence and relative activity of these organisms is identifiable from geological materials. By extension, sulfur isotope records are used to infer the redox balance of marine sedimentary environments, and the oxidation state of Earth's oceans and atmosphere. However, recent work suggests that our understanding of microbial sulfate reduction (MSRs) may be missing complexity associated with the presence and role of key chemical intermediates in the reductive process. This study provides a test of proposed metabolic models of sulfate reduction by growing an axenic culture of the well-studied MSRs, Desulfovibrio alaskensis strain G20, under electron donor limited conditions on the terminal electron acceptors sulfate, sulfite or thiosulfate, and tracking the multiple S isotopic consequences of each condition set. The dissimilatory reduction of thiosulfate and sulfite produce unique minor isotope effects, as compared to the reduction of sulfate. Further, these experiments reveal a complex biochemistry associated with sulfite reduction. That is, under high sulfite concentrations, sulfur is shuttled to an intermediate pool of thiosulfate. Site-specific isotope fractionation (within thiosulfate) is very large ((34)epsilon ~ 300/00) while terminal product sulfide carries only a small fractionation from the initial sulfite ((34)epsilon < 100/00): a signature similar in magnitude to sulfate and thiosulfate reduction. Together these findings show that microbial sulfate reduction (MSR) is highly sensitive to the concentration of environmentally important sulfur-cycle intermediates (sulfite and thiosulfate), especially when thiosulfate and the large site-specific isotope effects are involved. PMID- 25505451 TI - In situ examination of Lactobacillus brevis after exposure to an oxidizing disinfectant. AB - Beer is a hostile environment for most microorganisms, but some lactic acid bacteria can grow in this environment. This is primarily because these organisms have developed the ability to grow in the presence of hops. It has been speculated that hop resistance is inversely correlated to resistance against oxidation, and this would have great impact on the use of various disinfectants in the brewing industry. In this study, we cultivated bacteria under aerobic and anaerobic conditions, and then investigated the in situ outgrowth of individual cells into microcolonies on de Man Rogosa Sharpe (MRS) agar after exposure to the oxidizing agent peracetic acid (PAA). An automated microscope stage allowed us to analyse a much larger number of cells over extended periods of incubation. After PAA treatment, the lag time increased markedly, and extensive variation in morphology, MUmax as well as stress resistance was observed between and within the tested Lactobacillus brevis strains. The results suggest that aerobic cultivation increased the oxidative stress tolerance in Lactobacillus brevis. The results also show that dead cells are randomly distributed in a microcolony and the majority of non-growing individual cells do not stain with a membrane impermanent dye (Propidium iodide), which indicates that PAA may not destroy the plasma membrane. In conclusion, the developed microscopic analysis of individual cells on MRS agar can provides faster results and more details of cell physiology compared to the traditional CFU method. PMID- 25505450 TI - Microbial diversity in a Venezuelan orthoquartzite cave is dominated by the Chloroflexi (Class Ktedonobacterales) and Thaumarchaeota Group I.1c. AB - The majority of caves are formed within limestone rock and hence our understanding of cave microbiology comes from carbonate-buffered systems. In this paper, we describe the microbial diversity of Roraima Sur Cave (RSC), an orthoquartzite (SiO4) cave within Roraima Tepui, Venezuela. The cave contains a high level of microbial activity when compared with other cave systems, as determined by an ATP-based luminescence assay and cell counting. Molecular phylogenetic analysis of microbial diversity within the cave demonstrates the dominance of Actinomycetales and Alphaproteobacteria in endolithic bacterial communities close to the entrance, while communities from deeper in the cave are dominated (82-84%) by a unique clade of Ktedonobacterales within the Chloroflexi. While members of this phylum are commonly found in caves, this is the first identification of members of the Class Ktedonobacterales. An assessment of archaeal species demonstrates the dominance of phylotypes from the Thaumarchaeota Group I.1c (100%), which have previously been associated with acidic environments. While the Thaumarchaeota have been seen in numerous cave systems, the dominance of Group I.1c in RSC is unique and a departure from the traditional archaeal community structure. Geochemical analysis of the cave environment suggests that water entering the cave, rather than the nutrient-limited orthoquartzite rock, provides the carbon and energy necessary for microbial community growth and subsistence, while the poor buffering capacity of quartzite or the low pH of the environment may be selecting for this unusual community structure. Together these data suggest that pH, imparted by the geochemistry of the host rock, can play as important a role in niche-differentiation in caves as in other environmental systems. PMID- 25505448 TI - Thyroid hormone and leptin in the testis. AB - Leptin is primarily expressed in white adipose tissue; however, it is expressed in the hypothalamus and reproductive tissues as well. Leptin acts by activating the leptin receptors (Ob-Rs). Additionally, the regulation of several neuroendocrine and reproductive functions, including the inhibition of glucocorticoids and enhancement of thyroxine and sex hormone concentrations in human beings and mice are leptin functions. It has been suggested that thyroid hormones (TH) could directly regulate leptin expression. Additionally, hypothyroidism compromises the intracellular integration of leptin signaling specifically in the arcuate nucleus. Two TH receptor isoforms are expressed in the testis, TRa and TRb, with TRa being the predominant one that is present in all stages of development. The effects of TH involve the proliferation and differentiation of Sertoli and Leydig cells during development, spermatogenesis, and steroidogenesis. In this context, TH disorders are associated with sexual dysfunction. An endocrine and/or direct paracrine effect of leptin on the gonads inhibits testosterone production in Leydig cells. Further studies are necessary to clarify the effects of both hormones in the testis during hypothyroidism. The goal of this review is to highlight the current knowledge regarding leptin and TH in the testis. PMID- 25505452 TI - S-layer and cytoplasmic membrane - exceptions from the typical archaeal cell wall with a focus on double membranes. AB - The common idea of typical cell wall architecture in archaea consists of a pseudo crystalline proteinaceous surface layer (S-layer), situated upon the cytoplasmic membrane. This is true for the majority of described archaea, hitherto. Within the crenarchaea, the S-layer often represents the only cell wall component, but there are various exceptions from this wall architecture. Beside (glycosylated) S layers in (hyper)thermophilic cren- and euryarchaea as well as halophilic archaea, one can find a great variety of other cell wall structures like proteoglycan-like S-layers (Halobacteria), glutaminylglycan (Natronococci), methanochondroitin (Methanosarcina) or double layered cell walls with pseudomurein (Methanothermus and Methanopyrus). The presence of an outermost cellular membrane in the crenarchaeal species Ignicoccus hospitalis already gave indications for an outer membrane similar to Gram-negative bacteria. Although there is just limited data concerning their biochemistry and ultrastructure, recent studies on the euryarchaeal methanogen Methanomassiliicoccus luminyensis, cells of the ARMAN group, and the SM1 euryarchaeon delivered further examples for this exceptional cell envelope type consisting of two membranes. PMID- 25505453 TI - Leishmanicidal activities of Artemisia annua leaf essential oil against Visceral Leishmaniasis. AB - Visceral leishmaniasis (VL), the second-most dreaded parasitic disease after malaria, is currently endemic in 88 countries. Dramatic increases in the rates of infection, drug resistance, and non-availability of safe vaccines have highlighted the need for identification of novel and inexpensive anti-leishmanial agents from natural sources. In this study, we showed the leishmanicidal effect of essential oil from Artemisia annua leaves (AALEO) against Leishmania donovani in vitro and in vivo. AALEO was extracted by hydrodistillation and characterized by GC-MS, the most abundant compounds were found to be camphor (52.06 %) followed by beta-caryophyllene (10.95 %). AALEO exhibited significant leishmanicidal activity against L. donovani, with 50 % inhibitory concentration of 14.63 +/- 1.49 MUg ml(-1) and 7.3 +/- 1.85 MUg ml(-1), respectively, against the promastigotes and intracellular amastigotes. The effect was mediated through programmed cell death as confirmed by externalization of phosphatidylserine, DNA nicking by TdT-mediated dUTP nick-end labeling assay, dyskinetoplastidy, cell cycle arrest at sub-G0-G1 phase, loss of mitochondrial membrane potential and reactive oxygen species generation in promastigotes and nitric oxide generation in ex vivo model. AALEO presented no cytotoxic effects against mammalian macrophages even at 200 MUg ml(-1). Intra-peritoneal administration of AALEO (200 mg/ kg.b.w.) to infected BALB/c mice reduced the parasite burden by almost 90% in the liver and spleen with significant reduction in weight. There was no hepato- or nephro-toxicity as demonstrated by normal levels of serum enzymes. The promising antileishmanial activity shown by camphor-rich AALEO may provide a new lead in the treatment of VL. PMID- 25505455 TI - Intra- and inter-species interactions in microbial communities. PMID- 25505454 TI - Triggering receptor expressed on myeloid cells-1 (TREM-1): a new player in antiviral immunity? AB - The triggering receptor expressed on myeloid cells (TREM) family of protein receptors is rapidly emerging as a critical regulator of a diverse array of cellular functions, including amplification of inflammation. Although the ligand(s) for TREM have not yet been fully identified, circumstantial evidence indicates that danger- and pathogen-associated molecular patterns (DAMPs and PAMPs) can induce cytokine production via TREM-1 activation. The discovery of novel functions of TREM, such as regulation of T-cell proliferation and activation of antigen-presenting cells, suggests a larger role of TREM proteins in modulation of host immune responses to microbial pathogens, such as bacteria and fungi. However, the significance of TREM signaling in innate immunity to virus infections and the underlying mechanisms remain largely unclear. The nature and intensity of innate immune responses, specifically production of type I interferon and inflammatory cytokines is a crucial event in dictating recovery vs. adverse outcomes from virus infections. In this review, we highlight the emerging roles of TREM-1, including synergy with classical pathogen recognition receptors. Based on the literature using viral PAMPs and other infectious disease models, we further discuss how TREM-1 may influence host-virus interactions and viral pathogenesis. A deeper conceptual understanding of the mechanisms associated with pathogenic and/or protective functions of TREM-1 in antiviral immunity is essential to develop novel therapeutic strategies for the control of virus infection by modulating innate immune signaling. PMID- 25505456 TI - The influence of human settlement on the distribution and diversity of iron oxidizing bacteria belonging to the Gallionellaceae in tropical streams. AB - Among the neutrophilic iron-oxidizing bacteria (FeOB), Gallionella is one of the most abundant genera in freshwater environments. By applying qPCR and DGGE based on 16S rRNA gene-directed primers targeting Gallionellaceae, we delineated the composition and abundance of the Gallionellaceae-related FeOB community in streams differentially affected by metal mining, and explored the relationships between these community characteristics and environmental variables. The sampling design included streams historically impacted by mining activity and a non impacted stream. The sediment and water samples harbored a distinct community represented by Gallionella, Sideroxydans, and Thiobacillus species. Sequences affiliated with Gallionella were exclusively observed in sediments impacted by mining activities, suggesting an adaptation of this genus to these environments. In contrast, Sideroxydans-related sequences were found in all sediments including the mining impacted locations. The highest and lowest relative frequencies of Gallionellaceae-related FeOB were associated with the lowest and highest concentrations of Fe, respectively. The data enclosed here clearly show distinct species-specific ecological niches, with Gallionella species dominating in sediments impacted by anthropogenic activities over Sideroxydans species. PMID- 25505457 TI - Sodium houttuyfonate affects production of N-acyl homoserine lactone and quorum sensing-regulated genes expression in Pseudomonas aeruginosa. AB - Quorum sensing (QS) is a means of cell-to-cell communication that uses diffusible signaling molecules that are sensed by the population to determine population density, thus allowing co-ordinate gene regulation in response to population density. In Pseudomonas aeruginosa, production of the QS signaling molecule, N acyl homoserine lactone (AHL), co-ordinates expression of key factors of pathogenesis, including biofilm formation and toxin secretion. It is predicted that the inhibition of AHL sensing would provide an effective clinical treatment to reduce the expression of virulence factors and increase the effectiveness of antimicrobial agents. We previously demonstrated that sodium houttuyfonate (SH), commonly used in traditional Chinese medicine to treat infectious diseases, can effectively inhibit QS-regulated processes, including biofilm formation. Here, using a model system, we demonstrate that SH causes the dose-dependent inhibition of AHL production, through down-regulation of the AHL biosynthesis gene, lasI. Addition of SH also resulted in down-regulation of expression of the AHL sensor and transcriptional regulator, LasR, and inhibited the production of the QS regulated virulence factors, pyocyanin and LasA. These results suggest that the antimicrobial activity of SH may be due to its ability to disrupt QS in P. aeruginosa. PMID- 25505458 TI - Natural microbial communities supporting the transfer of the IncP-1beta plasmid pB10 exhibit a higher initial content of plasmids from the same incompatibility group. AB - Antibiotic resistance gene transfer mediated by plasmids is a matter of concern for public health, but permissive environments supporting plasmid dissemination are still quite difficult to identify. Lately, we have reported a molecular approach based on quantitative PCR (qPCR) to monitor the fate of the IncP-1beta plasmid pB10 in natural microbial communities maintained in microcosms. Such plasmid transfer experiments were carried out with 13 different environmental matrices, and demonstrated that the transfer of the conjugative-proficient plasmid pB10 in complex environments is relatively rare and is strongly matrix dependent. An attempt to link the microbial community structure and the matrix permissiveness showed that TTGE analysis is not resolutive enough to point out common features among comparable communities supporting pB10 transfer. However, an estimation of the IncP-1alpha/IncP-1beta plasmids abundance by qPCR demonstrated that pB10 transfer tends to be supported by environmental matrices exhibiting a higher content of IncP-1 plasmids. We suggest that the relative abundance of IncP-1 plasmids in a given microbial community reflects its permissiveness to the transfer of plasmids belonging to the same incompatibility group, which prevails over transfer limitation due to a phenomenon known as superinfection immunity. PMID- 25505459 TI - Cellulolytic potential under environmental changes in microbial communities from grassland litter. AB - In many ecosystems, global changes are likely to profoundly affect microorganisms. In Southern California, changes in precipitation and nitrogen deposition may influence the composition and functional potential of microbial communities and their resulting ability to degrade plant material. To test whether such environmental changes impact the distribution of functional groups involved in leaf litter degradation, we determined how the genomic diversity of microbial communities in a semi-arid grassland ecosystem changed under reduced precipitation or increased N deposition. We monitored communities seasonally over a period of 2 years to place environmental change responses into the context of natural variation. Fungal and bacterial communities displayed strong seasonal patterns, Fungi being mostly detected during the dry season whereas Bacteria were common during wet periods. Most putative cellulose degraders were associated with 33 bacterial genera and predicted to constitute 18% of the microbial community. Precipitation reduction reduced bacterial abundance and cellulolytic potential whereas nitrogen addition did not affect the cellulolytic potential of the microbial community. Finally, we detected a strong correlation between the frequencies of genera of putative cellulose degraders and cellulase genes. Thus, microbial taxonomic composition was predictive of cellulolytic potential. This work provides a framework for how environmental changes affect microorganisms responsible for plant litter deconstruction. PMID- 25505460 TI - Biosynthesis of archaeal membrane ether lipids. AB - A vital function of the cell membrane in all living organism is to maintain the membrane permeability barrier and fluidity. The composition of the phospholipid bilayer is distinct in archaea when compared to bacteria and eukarya. In archaea, isoprenoid hydrocarbon side chains are linked via an ether bond to the sn glycerol-1-phosphate backbone. In bacteria and eukarya on the other hand, fatty acid side chains are linked via an ester bond to the sn-glycerol-3-phosphate backbone. The polar head groups are globally shared in the three domains of life. The unique membrane lipids of archaea have been implicated not only in the survival and adaptation of the organisms to extreme environments but also to form the basis of the membrane composition of the last universal common ancestor (LUCA). In nature, a diverse range of archaeal lipids is found, the most common are the diether (or archaeol) and the tetraether (or caldarchaeol) lipids that form a monolayer. Variations in chain length, cyclization and other modifications lead to diversification of these lipids. The biosynthesis of these lipids is not yet well understood however progress in the last decade has led to a comprehensive understanding of the biosynthesis of archaeol. This review describes the current knowledge of the biosynthetic pathway of archaeal ether lipids; insights on the stability and robustness of archaeal lipid membranes; and evolutionary aspects of the lipid divide and the LUCA. It examines recent advances made in the field of pathway reconstruction in bacteria. PMID- 25505461 TI - D701N mutation in the PB2 protein contributes to the pathogenicity of H5N1 avian influenza viruses but not transmissibility in guinea pigs. AB - H5N1 highly pathogenic avian influenza virus (HPAIV) of clade 2.3.2 has been circulating in waterfowl in Southern China since 2003. Our previous studies showed that certain H5N1 HPAIV isolates within clade 2.3.2 from Southern China had high pathogenicity in different birds. Guinea pigs have been successfully used as models to evaluate the transmissibility of AIVs and other species of influenza viruses in mammalian hosts. However, few studies have reported pathogenicity and transmissibility of H5N1 HPAIVs of this clade in guinea pigs. In this study, we selected an H5N1 HPAIV isolate, A/duck/Guangdong/357/2008, to investigate the pathogenicity and transmissibility of the virus in guinea pigs. The virus had high pathogenicity in mice; additionally, it only replicated in some tissues of the guinea pigs without production of clinical signs, but was transmissible among guinea pigs. Interestingly, virus isolates from co-caged guinea pigs had the D701N mutation in the PB2 protein. These mutant viruses showed higher pathogenicity in mice and higher replication capability in guinea pigs but did not demonstrate enhanced the transmissibility among guinea pigs. These findings indicate the transmission of the H5N1 virus between mammals could induce virus mutations, and the mutant viruses might have higher pathogenicity in mammals without higher transmissibility. Therefore, the continued evaluation of the pathogenicity and transmissibility of avian influenza virus (AIVs) in mammals is critical to the understanding of the evolutionary characteristics of AIVs and the emergence of potential pandemic strains. PMID- 25505463 TI - Impact of spatial distribution on the development of mutualism in microbes. AB - The evolution of mutualism is one of the long-standing puzzles in evolutionary biology. Why would an individual contribute to the group at the expense of its own fitness? Individual bacterial cells cooperate by secreting products that are beneficial for the community, but costly to produce. It has been shown that cooperation is critical for microbial communities, most notably in biofilms, however, the degree of cooperation strongly depends on the culturing conditions. Spatial community structure provides a solution how cooperation might develop and remain stable. This perspective paper discusses recent progresses on experiments that use microbes to understand the role of spatial distribution on the stability of intraspecific cooperation from an evolutionary point of view and also highlights the effect of mutualism on spatial segregation. Recent publications in this area will be highlighted, which suggest that while mechanisms that allow assortment help to maintain cooperative traits, strong mutualism actually promotes population intermixing. Microbes provide simple and suitable systems to examine the features that define population organization and mutualism. PMID- 25505464 TI - Archaeal S-layer glycoproteins: post-translational modification in the face of extremes. AB - Corresponding to the sole or basic component of the surface (S)-layer surrounding the archaeal cell in most known cases, S-layer glycoproteins are in direct contact with the harsh environments that characterize niches where Archaea can thrive. Accordingly, early work examining archaeal S-layer glycoproteins focused on identifying those properties that allow members of this group of proteins to maintain their structural integrity in the face of extremes of temperature, pH, and salinity, as well as other physical challenges. However, with expansion of the list of archaeal strains serving as model systems, as well as growth in the number of molecular tools available for the manipulation of these strains, studies on archaeal S-layer glycoproteins are currently more likely to consider the various post-translational modifications these polypeptides undergo. For instance, archaeal S-layer glycoproteins can undergo proteolytic cleavage, both N and O-glycosylation, lipid-modification and oligomerization. In this mini review, recent findings related to the post-translational modification of archaeal S-layer glycoproteins are considered. PMID- 25505462 TI - Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria. AB - Polymyxins are polycationic antimicrobial peptides that are currently the last resort antibiotics for the treatment of multidrug-resistant, Gram-negative bacterial infections. The reintroduction of polymyxins for antimicrobial therapy has been followed by an increase in reports of resistance among Gram-negative bacteria. Some bacteria, such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii, develop resistance to polymyxins in a process referred to as acquired resistance, whereas other bacteria, such as Proteus spp., Serratia spp., and Burkholderia spp., are naturally resistant to these drugs. Reports of polymyxin resistance in clinical isolates have recently increased, including acquired and intrinsically resistant pathogens. This increase is considered a serious issue, prompting concern due to the low number of currently available effective antibiotics. This review summarizes current knowledge concerning the different strategies bacteria employ to resist the activities of polymyxins. Gram-negative bacteria employ several strategies to protect themselves from polymyxin antibiotics (polymyxin B and colistin), including a variety of lipopolysaccharide (LPS) modifications, such as modifications of lipid A with phosphoethanolamine and 4-amino-4-deoxy-L-arabinose, in addition to the use of efflux pumps, the formation of capsules and overexpression of the outer membrane protein OprH, which are all effectively regulated at the molecular level. The increased understanding of these mechanisms is extremely vital and timely to facilitate studies of antimicrobial peptides and find new potential drugs targeting clinically relevant Gram-negative bacteria. PMID- 25505465 TI - Ubiquitination as an efficient molecular strategy employed in salmonella infection. AB - The ubiquitin modification has various functions in the host innate immune system in response to the bacterial infection. To counteract the host immunity, Salmonella can specifically target ubiquitin pathways by its effector proteins. In this review, we describe the multiple facets of ubiquitin function during infection with Salmonella enterica Typhimurium and hypothesize how these studies on the host-pathogen interactions can help to understand the general function of the ubiquitination pathway in the host cell. PMID- 25505467 TI - Multiple Receptor-Ligand Interactions Direct Tissue-Resident gammadelta T Cell Activation. AB - gammadelta T cells represent a major T cell population in epithelial tissues, such as skin, intestine, and lung, where they function in maintenance of the epithelium and provide a crucial first line defense against environmental and pathogenic insults. Despite their importance, the molecular mechanisms directing their activation and function have remained elusive. Epithelial-resident gammadelta T cells function through constant communication with neighboring cells, either via direct cell-to-cell contact or cell-to-matrix interactions. These intimate relationships allow gammadelta T cells to facilitate the maintenance of epithelial homeostasis, tissue repair following injury, inflammation, and protection from malignancy. Recent studies have identified a number of molecules involved in these complex interactions, under both homeostatic conditions, as well as following perturbation of these barrier tissues. These interactions are crucial to the timely production of cytokines, chemokines, growth factors, and extracellular matrix proteins for restoration of homeostasis. In this review, we discuss recent advances in understanding the mechanisms directing epithelial-T cell crosstalk and the distinct roles played by individual receptor-ligand pairs of cell surface molecules in this process. PMID- 25505466 TI - Depletion of tumor-associated macrophages slows the growth of chemically induced mouse lung adenocarcinomas. AB - Chronic inflammation is a risk factor for lung cancer, and low-dose aspirin intake reduces lung cancer risk. However, the roles that specific inflammatory cells and their products play in lung carcinogenesis have yet to be fully elucidated. In mice, alveolar macrophage numbers increase as lung tumors progress, and pulmonary macrophage programing changes within 2 weeks of carcinogen exposure. To examine how macrophages specifically affect lung tumor progression, they were depleted in mice bearing urethane-induced lung tumors using clodronate-encapsulated liposomes. Alveolar macrophage populations decreased to <=50% of control levels after 4-6 weeks of liposomal clodronate treatment. Tumor burden decreased by 50% compared to vehicle treated mice, and tumor cell proliferation, as measured by Ki67 staining, was also attenuated. Pulmonary fluid levels of insulin-like growth factor-I, CXCL1, IL-6, and CCL2 diminished with clodronate liposome treatment. Tumor-associated macrophages expressed markers of both M1 and M2 programing in vehicle and clodronate liposome treated mice. Mice lacking CCR2 (the receptor for macrophage chemotactic factor CCL2) had comparable numbers of alveolar macrophages and showed no difference in tumor growth rates when compared to similarly treated wild-type mice suggesting that while CCL2 may recruit macrophages to lung tumor microenvironments, redundant pathways can compensate when CCL2/CCR2 signaling is inactivated. Depletion of pulmonary macrophages rather than inhibition of their recruitment may be an advantageous strategy for attenuating lung cancer progression. PMID- 25505469 TI - Targeting Dendritic Cells as a Good Alternative to Combat Leishmania spp. PMID- 25505468 TI - TH1/TH2 paradigm extended: macrophage polarization as an unappreciated pathogen driven escape mechanism? AB - The classical view of the Th1/Th2 paradigm posits that the pathogen nature, infectious cycle, and persistence represent key parameters controlling the choice of effector mechanisms operating during an immune response. Thus, efficient Th1 responses are triggered by replicating intracellular pathogens, while Th2 responses would control helminth infection and promote tissue repair during the resolution phase of an infectious event. However, this vision does not account for a growing body of data describing how pathogens exploit the polarization of the host immune response to their own benefit. Recently, the study of macrophages has illustrated a novel aspect of this arm race between pathogens and the immune system, and the central role of macrophages in homeostasis, repair and defense of all tissues is now fully appreciated. Like T lymphocytes, macrophages differentiate into distinct effectors including classically (M1) and alternatively (M2) activated macrophages. Interestingly, in addition to represent immune effectors, M1/M2 cells have been shown to represent potential reservoir cells to a wide range of intracellular pathogens. Subversion of macrophage cell metabolism by microbes appears as a recently uncovered immune escape strategy. Upon infection, several microbial agents have been shown to activate host metabolic pathways leading to the production of nutrients necessary to their long term persistence in host. The purpose of this review is to summarize and discuss the strategies employed by pathogens to manipulate macrophage differentiation, and in particular their basic cell metabolism, to favor their own growth while avoiding immune control. PMID- 25505470 TI - Longitudinal study on health-related quality of life in a cohort of 96 patients with common variable immune deficiencies. AB - Health-related quality of life (HRQoL) in common variable immunodeficiency diseases (CVID) was evaluated by different tools, which were mainly used to compare different schedules of immunoglobulins administration in cross-sectional or short-term longitudinal studies. We assessed the HRQoL and psychological status of CVID patients in a longitudinal study over a 6-year period by a generic, non-disease-specific instrument (SF-36), and by a General Health Questionnaire (GHQ-12) for the risk of depression/anxiety. At baseline, 96 patients were enrolled. After 1 year, a second assessment was performed on 92 patients and, after 6 years, a third assessment was performed on 66 patients. Eighteen patients died during the study time. HRQoL was low, with mental health scales less affected than physical scales. A decline in the score on SF-36 scales was observed between the first and the third assessment for the Physical Functioning, Body Pain, General Health, Social Functioning, and Role-Emotional scales. The General Health scale showed a lower score in these patients, when compared to patients with other chronic diseases. Approximately one-third of the patients were at risk of anxiety/depression at all observation times, a percentage that reached two thirds of the patients, considering only the group of females. Over the 6 years of the study, the health condition of 11/66 patients worsened, passing from "GHQ-negative" to "GHQ-positive"; their score on SF-36 scales also decreased. A decrement of one point in each of the Physical Functioning, Vitality, Social Functioning, and Mental Health SF-36 scales increased the risk of developing anxiety/depression from three to five percent. A negative variation of the Physical Functioning score increased the risk of psychological distress. In a survival analysis with dichotomized variables, Physical Functioning scores <50 were associated with a relative risk (RR) of 4.4, whereas Social Functioning scores <37.5 were associated with a RR of 10.0. In our study, it was the clinical condition, as opposed to the different treatment strategies with immunoglobulins, which had a major role on the deterioration of HRQoL. Moreover, in a quality-of-life evaluation, disorders such as anxiety/depression should be assessed, as they yet often go unrecognized. Our results might be helpful in the interpretation of currently available data on quality of life in CVID patients. PMID- 25505471 TI - M1/M2 macrophage polarity in normal and complicated pregnancy. AB - Tissue macrophages play an important role in all stages of pregnancy, including uterine stromal remodeling (decidualization) before embryo implantation, parturition, and post-partum uterine involution. The activation state and function of utero-placental macrophages are largely dependent on the local tissue microenvironment. Thus, macrophages are involved in a variety of activities such as regulation of immune cell activities, placental cell invasion, angiogenesis, and tissue remodeling. Disruption of the uterine microenvironment, particularly during the early stages of pregnancy (decidualization, implantation, and placentation) can have profound effects on macrophage activity and subsequently impact pregnancy outcome. In this review, we will provide an overview of the temporal and spatial regulation of utero-placental macrophage activation during normal pregnancy in human beings and rodents with a focus on more recent findings. We will also discuss the role of M1/M2 dysregulation within the intrauterine environment during adverse pregnancy outcomes. PMID- 25505472 TI - Tumor-Infiltrating gammadelta T Lymphocytes: Pathogenic Role, Clinical Significance, and Differential Programing in the Tumor Microenvironment. AB - There is increasing clinical evidence indicating that the immune system may either promote or inhibit tumor progression. Several studies have demonstrated that tumors undergoing remission are largely infiltrated by T lymphocytes [tumor infiltrating lymphocytes (TILs)], but on the other hand, several studies have shown that tumors may be infiltrated by TILs endowed with suppressive features, suggesting that TILs are rather associated with tumor progression and unfavorable prognosis. gammadelta T lymphocytes are an important component of TILs that may contribute to tumor immunosurveillance, as also suggested by promising reports from several small phase-I clinical trials. Typically, gammadelta T lymphocytes perform effector functions involved in anti-tumor immune responses (cytotoxicity, production of IFN-gamma and TNF-alpha, and dendritic cell maturation), but under appropriate conditions they may divert from the typical Th1-like phenotype and polarize to Th2, Th17, and Treg cells thus acquiring the capability to inhibit anti-tumor immune responses and promote tumor growth. Recent studies have shown a high frequency of gammadelta T lymphocytes infiltrating different types of cancer, but the nature of this association and the exact mechanisms underlying it remain uncertain and whether or not the presence of tumor-infiltrating gammadelta T lymphocytes is a definite prognostic factor remains controversial. In this paper, we will review studies of tumor-infiltrating gammadelta T lymphocytes from patients with different types of cancer, and we will discuss their clinical relevance. Moreover, we will also discuss on the complex interplay between cancer, tumor stroma, and gammadelta T lymphocytes as a major determinant of the final outcome of the gammadelta T lymphocyte response. Finally, we propose that targeting gammadelta T lymphocyte polarization and skewing their phenotype to adapt to the microenvironment might hold great promise for the treatment of cancer. PMID- 25505473 TI - Linking stomatal traits and expression of slow anion channel genes HvSLAH1 and HvSLAC1 with grain yield for increasing salinity tolerance in barley. AB - Soil salinity is an environmental and agricultural problem in many parts of the world. One of the keys to breeding barley for adaptation to salinity lies in a better understanding of the genetic control of stomatal regulation. We have employed a range of physiological (stomata assay, gas exchange, phylogenetic analysis, QTL analysis), and molecular techniques (RT-PCR and qPCR) to investigate stomatal behavior and genotypic variation in barley cultivars and a genetic population in four experimental trials. A set of relatively efficient and reliable methods were developed for the characterization of stomatal behavior of a large number of varieties and genetic lines. Furthermore, we found a large genetic variation of gas exchange and stomatal traits in barley in response to salinity stress. Salt-tolerant cultivar CM72 showed significantly larger stomatal aperture under 200 mM NaCl treatment than that of salt-sensitive cultivar Gairdner. Stomatal traits such as aperture width/length were found to significantly correlate with grain yield under salt treatment. Phenotypic characterization and QTL analysis of a segregating double haploid population of the CM72/Gairdner resulted in the identification of significant stomatal traits related QTLs for salt tolerance. Moreover, expression analysis of the slow anion channel genes HvSLAH1 and HvSLAC1 demonstrated that their up-regulation is linked to higher barley grain yield in the field. PMID- 25505474 TI - The past, present and future of breeding rust resistant wheat. AB - Two classes of genes are used for breeding rust resistant wheat. The first class, called R (for resistance) genes, are pathogen race specific in their action, effective at all plant growth stages and probably mostly encode immune receptors of the nucleotide binding leucine rich repeat (NB-LRR) class. The second class is called adult plant resistance genes (APR) because resistance is usually functional only in adult plants, and, in contrast to most R genes, the levels of resistance conferred by single APR genes are only partial and allow considerable disease development. Some but not all APR genes provide resistance to all isolates of a rust pathogen species and a subclass of these provides resistance to several fungal pathogen species. Initial indications are that APR genes encode a more heterogeneous range of proteins than R proteins. Two APR genes, Lr34 and Yr36, have been cloned from wheat and their products are an ABC transporter and a protein kinase, respectively. Lr34 and Sr2 have provided long lasting and widely used (durable) partial resistance and are mainly used in conjunction with other R and APR genes to obtain adequate rust resistance. We caution that some APR genes indeed include race specific, weak R genes which may be of the NB-LRR class. A research priority to better inform rust resistance breeding is to characterize further APR genes in wheat and to understand how they function and how they interact when multiple APR and R genes are stacked in a single genotype by conventional and GM breeding. An important message is do not be complacent about the general durability of all APR genes. PMID- 25505475 TI - The roles of ethylene and transcription factors in the regulation of onset of leaf senescence. AB - Leaf senescence is the last stage of leaf development and is accompanied by cell death. In contrast to senescence in individual organisms that leads to death, leaf senescence is associated with dynamic processes that include the translocation of nutrients from old leaves to newly developing or storage tissues within the same plant. The onset of leaf senescence is largely regulated by age and internal and external stimuli, which include the plant hormone ethylene. Earlier studies have documented the important role of ethylene in the regulation of leaf senescence. The production of ethylene coincides with the onset of leaf senescence, whereas the application of ethylene to plants induces precocious leaf senescence. Recently, many studies have described the components of ethylene signaling and biosynthetic pathways that are involved in modulating the onset of leaf senescence. Particularly, transcription factors (TFs) integrate ethylene signals with those from environmental and developmental factors to accelerate or delay leaf senescence. This review aims to discuss the regulatory cascade involving ethylene and TFs in the regulation of onset of leaf senescence. PMID- 25505476 TI - Canga biodiversity, a matter of mining. AB - Brazilian name canga refers to the ecosystems associated with superficial iron crusts typical for the Brazilian state of Minas Gerais (MG) and some parts of Amazon (Flona de Carajas). Iron stone is associated with mountain plateaux and so, in addition to high metal concentrations (particularly iron and manganese), canga ecosystems, as other rock outcrops, are characterized by isolation and environmental harshness. Canga inselbergs, all together, occupy no more than 200 km(2) of area spread over thousands of km(2) of the Iron Quadrangle (MG) and the Flona de Carajas, resulting in considerable beta biodiversity. Moreover, the presence of different microhabitats within the iron crust is associated with high alpha biodiversity. Hundreds of angiosperm species have been reported so far across remote canga inselbergs and different micro-habitats. Among these are endemics such as the cactus Arthrocereus glaziovii and the medicinal plant Pilocarpus microphyllus. Canga is also home to iron and manganese metallophytes; species that evolved to tolerate high metal concentrations. These are particularly interesting to study metal homeostasis as both iron and manganese are essential plant micro-elements. Besides being models for metal metabolism, metallophytes can be used for bio-remediation of metal contaminated sites, and as such are considered among priority species for canga restoration. "Biodiversity mining" is not the only mining business attracted to canga. Open cast iron mining generates as much as 5-6% of Brazilian gross domestic product and dialog between mining companies, government, society, and ecologists, enforced by legal regulation, is ongoing to find compromise for canga protection, and where mining is unavoidable for ecosystem restoration. Environmental factors that shaped canga vegetation, canga biodiversity, physiological mechanisms to play a role, and ways to protect and restore canga will be reviewed. PMID- 25505477 TI - Comparative analysis of ABCB1 reveals novel structural and functional conservation between monocots and dicots. AB - Phytohormone auxin plays a critical role in modulating plant architecture by creating a gradient regulated via its transporters such as ATP-binding cassette (ABC) B1. Except for Arabidopsis and maize, where it was shown to interrupt auxin transport, ABCB1's presence, structure and function in crop species is not known. Here we describe the structural and putative functional organization of ABCB1 among monocots relative to that of dicots. Identified from various plant species following specific and stringent criteria, ZmABCB1's "true" orthologs sequence identity ranged from 56-90% at the DNA and 75-91% at the predicted amino acid (aa) level. Relative to ZmABCB1, the size of genomic copies ranged from -27 to +1.5% and aa from -7.7 to +0.6%. With the average gene size being similar (5.8 kb in monocots and 5.7 kb in dicots), dicots have about triple the number of introns with an average size of 194 bp (total 1743 bp) compared to 556 bp (total 1667 bp) in monocots. The intron-exon junctions across species were however conserved. N termini of the predicted proteins were highly variable: in monocots due to mismatches and small deletions of 1-13 aa compared to large, species-specific deletions of up to 77 aa in dicots. The species-, family- and group- specific conserved motifs were identified in the N-terminus and linker region of protein, possibly responsible for the specific functions. The near-identical conserved motifs of Nucleotide Binding Domains (NBDs) in two halves of the protein showed subtle aa changes possibly favoring ATP binding to the N-terminus. Predicted 3-D protein structures showed remarkable similarity with each other and for the residues involved in auxin binding. PMID- 25505478 TI - Plant natriuretic peptides induce proteins diagnostic for an adaptive response to stress. AB - In plants, structural and physiological evidence has suggested the presence of biologically active natriuretic peptides (PNPs). PNPs are secreted into the apoplast, are systemically mobile and elicit a range of responses signaling via cGMP. The PNP-dependent responses include tissue specific modifications of cation transport and changes in stomatal conductance and the photosynthetic rate. PNP also has a critical role in host defense responses. Surprisingly, PNP-homologs are produced by several plant pathogens during host colonization suppressing host defense responses. Here we show that a synthetic peptide representing the biologically active fragment of the Arabidopsis thaliana PNP (AtPNP-A) induces the production of reactive oxygen species in suspension-cultured A. thaliana (Col 0) cells. To identify proteins whose expression changes in an AtPNP-A dependent manner, we undertook a quantitative proteomic approach, employing tandem mass tag (TMT) labeling, to reveal temporal responses of suspension-cultured cells to 1 nM and 10 pM PNP at two different time-points post-treatment. Both concentrations yield a distinct differential proteome signature. Since only the higher (1 nM) concentration induces a ROS response, we conclude that the proteome response at the lower concentration reflects a ROS independent response. Furthermore, treatment with 1 nM PNP results in an over-representation of the gene ontology (GO) terms "oxidation-reduction process," "translation" and "response to salt stress" and this is consistent with a role of AtPNP-A in the adaptation to environmental stress conditions. PMID- 25505479 TI - AtSIG6 and other members of the sigma gene family jointly but differentially determine plastid target gene expression in Arabidopsis thaliana. AB - Plants contain a nuclear gene family for plastid sigma factors, i.e., proteins that associate with the "bacterial-type" organellar RNA polymerase and confer the ability for correct promoter binding and transcription initiation. Questions that are still unresolved relate to the "division of labor" among members of the sigma family, both in terms of their range of target genes and their temporal and spatial activity during development. Clues to the in vivo role of individual sigma genes have mainly come from studies of sigma knockout lines. Despite its obvious strengths, however, this strategy does not necessarily trace-down causal relationships between mutant phenotype and a single sigma gene, if other family members act in a redundant and/or compensatory manner. We made efforts to reduce the complexity by genetic crosses of Arabidopsis single mutants (with focus on a chlorophyll-deficient sig6 line) to generate double knockout lines. The latter typically had a similar visible phenotype as the parental lines, but tended to be more strongly affected in the transcript patterns of both plastid and sigma genes. Because triple mutants were lethal under our growth conditions, we exploited a strategy of transformation of single and double mutants with RNAi constructs that contained sequences from the unconserved sigma region (UCR). These RNAi/knockout lines phenotypically resembled their parental lines, but were even more strongly affected in their plastid transcript patterns. Expression patterns of sigma genes revealed both similarities and differences compared to the parental lines, with transcripts at reduced or unchanged amounts and others that were found to be present in higher (perhaps compensatory) amounts. Together, our results reveal considerable flexibility of gene activity at the levels of both sigma and plastid gene expression. A (still viable) "basal state" seems to be reached, if 2-3 of the 6 Arabidopsis sigma genes are functionally compromised. PMID- 25505481 TI - Transfer cells. PMID- 25505480 TI - Regulation of inflorescence architecture by cytokinins. AB - In flowering plants, the arrangement of flowers on a stem becomes an inflorescence, and a huge variety of inflorescence architecture occurs in nature. Inflorescence architecture also affects crop yield. In simple inflorescences, flowers form on a main stem; by contrast, in compound inflorescences, flowers form on branched stems and the branching pattern defines the architecture of the inflorescence. In this review, we highlight recent findings on the regulation of inflorescence architecture by cytokinin plant hormones. Results in rice (Oryza sativa) and Arabidopsis thaliana show that although these two species have distinct inflorescence architectures, cytokinins have a common effect on inflorescence branching. Based on these studies, we discuss how cytokinins regulate distinct types of inflorescence architecture through their effect on meristem activities. PMID- 25505482 TI - Stochastic processes in gravitropism. AB - In this short review we focus on the role of noise in gravitropism of plants - the reorientation of plants according to the direction of gravity. We briefly introduce the conventional picture of static gravisensing in cells specialized in sensing. This model hinges on the sedimentation of statoliths (high in density and mass relative to other organelles) to the lowest part of the sensing cell. We then present experimental observations that cannot currently be understood within this framework. Lastly we introduce some current alternative models and directions that attempt to incorporate and interpret these experimental observations, including: (i) dynamic sensing, where gravisensing is suggested to be enhanced by stochastic events due to thermal and mechanical noise. These events both effectively lower the threshold of response, and lead to small distance sedimentation, allowing amplification, and integration of the signal. (ii) The role of the cytoskeleton in signal-to-noise modulation and (iii) in signal transduction. In closing, we discuss directions that seem to either not have been explored, or that are still poorly understood. PMID- 25505484 TI - Validation of a multiplex reverse transcription and pre-amplification method using TaqMan((r)) MicroRNA assays. AB - Since the discovery of microRNAs (miRNAs), different approaches have been developed to label, amplify and quantify miRNAs. The TaqMan((r)) technology, provided by Applied Biosystems (ABIs), uses a stem-loop reverse transcription primer system to reverse transcribe the RNA and amplify the cDNA. This method is widely used to identify global differences between the expression of 100s of miRNAs across comparative samples. This technique also allows the quantification of the expression of targeted miRNAs to validate observations determined by whole genome screening or to analyze few specific miRNAs on a large number of samples. Here, we describe the validation of a method published by ABIs on their web site allowing to reverse transcribe and pre-amplify multiple miRNAs and snoRNAs simultaneously. The validation of this protocol was performed on human muscle and plasma samples. Fast and cost efficient, this method achieves an easy and convenient way to screen a relatively large number of miRNAs in parallel. PMID- 25505485 TI - Optimizing the creation of base populations for aquaculture breeding programs using phenotypic and genomic data and its consequences on genetic progress. AB - The success of an aquaculture breeding program critically depends on the way in which the base population of breeders is constructed since all the genetic variability for the traits included originally in the breeding goal as well as those to be included in the future is contained in the initial founders. Traditionally, base populations were created from a number of wild strains by sampling equal numbers from each strain. However, for some aquaculture species improved strains are already available and, therefore, mean phenotypic values for economically important traits can be used as a criterion to optimize the sampling when creating base populations. Also, the increasing availability of genome-wide genotype information in aquaculture species could help to refine the estimation of relationships within and between candidate strains and, thus, to optimize the percentage of individuals to be sampled from each strain. This study explores the advantages of using phenotypic and genome-wide information when constructing base populations for aquaculture breeding programs in terms of initial and subsequent trait performance and genetic diversity level. Results show that a compromise solution between diversity and performance can be found when creating base populations. Up to 6% higher levels of phenotypic performance can be achieved at the same level of global diversity in the base population by optimizing the selection of breeders instead of sampling equal numbers from each strain. The higher performance observed in the base population persisted during 10 generations of phenotypic selection applied in the subsequent breeding program. PMID- 25505483 TI - Methods to address poultry robustness and welfare issues through breeding and associated ethical considerations. AB - As consumers and society in general become more aware of ethical and moral dilemmas associated with intensive rearing systems, pressure is put on the animal and poultry industries to adopt alternative forms of housing. This presents challenges especially regarding managing competitive social interactions between animals. However, selective breeding programs are rapidly advancing, enhanced by both genomics and new quantitative genetic theory that offer potential solutions by improving adaptation of the bird to existing and proposed production environments. The outcomes of adaptation could lead to improvement of animal welfare by increasing fitness of the animal for the given environments, which might lead to increased contentment and decreased distress of birds in those systems. Genomic selection, based on dense genetic markers, will allow for more rapid improvement of traits that are expensive or difficult to measure, or have a low heritability, such as pecking, cannibalism, robustness, mortality, leg score, bone strength, disease resistance, and thus has the potential to address many poultry welfare concerns. Recently selection programs to include social effects, known as associative or indirect genetic effects (IGEs), have received much attention. Group, kin, multi-level, and multi-trait selection including IGEs have all been shown to be highly effective in reducing mortality while increasing productivity of poultry layers and reduce or eliminate the need for beak trimming. Multi-level selection was shown to increases robustness as indicated by the greater ability of birds to cope with stressors. Kin selection has been shown to be easy to implement and improve both productivity and animal well-being. Management practices and rearing conditions employed for domestic animal production will continue to change based on ethical and scientific results. However, the animal breeding tools necessary to provide an animal that is best adapted to these changing conditions are readily available and should be used, which will ultimately lead to the best possible outcomes for all impacted. PMID- 25505487 TI - Dysregulation of antiviral helicase pathways in systemic lupus erythematosus. AB - In the autoimmune disease systemic lupus erythematosus (SLE), our normal antiviral defenses are inappropriately activated, resulting in over-activity of the type I interferon (IFN) pathway. This increased activity of the type I IFN pathway is an important primary pathogenic factor in the disease. Emerging evidence has implicated the antiviral helicases in this process. The antiviral helicases normally function as nucleic acid receptors in viral immunity. Genetic variations in antiviral helicase genes have been associated with SLE, supporting the idea that helicase pathways are involved in the primary pathogenesis of SLE. Studies have documented functional consequences of these genetic variations within the type I IFN pathway in human cell lines and SLE patients. In this review, we summarize the function of helicases in the anti-viral immune response, and how this response is dysregulated in SLE patients. In particular, we will focus on known functional genetic polymorphisms in the IFIH1 (MDA5) and mitochondrial antiviral signaling protein genes which have been implicated in human SLE. These data provide fascinating evidence for dysregulation of helicase mediated innate immunity in SLE, and may support novel therapeutic strategies in the disease. PMID- 25505488 TI - Sensing deep extreme environments: the receptor cell types, brain centers, and multi-layer neural packaging of hydrothermal vent endemic worms. AB - INTRODUCTION: Deep-sea alvinellid worm species endemic to hydrothermal vents, such as Alvinella and Paralvinella, are considered to be among the most thermotolerant animals known with their adaptability to toxic heavy metals, and tolerance of highly reductive and oxidative stressful environments. Despite the number of recent studies focused on their overall transcriptomic, proteomic, and metabolic stabilities, little is known regarding their sensory receptor cells and electrically active neuro-processing centers, and how these can tolerate and function in such harsh conditions. RESULTS: We examined the extra- and intracellular organizations of the epidermal ciliated sensory cells and their higher centers in the central nervous system through immunocytochemical, ultrastructural, and neurotracing analyses. We observed that these cells were rich in mitochondria and possessed many electron-dense granules, and identified specialized glial cells and serial myelin-like repeats in the head sensory systems of Paralvinella hessleri. Additionally, we identified the major epidermal sensory pathways, in which a pair of distinct mushroom bodies-like or small interneuron clusters was observed. These sensory learning and memory systems are commonly found in insects and annelids, but the alvinellid inputs are unlikely derived from the sensory ciliary cells of the dorsal head regions. CONCLUSIONS: Our evidence provides insight into the cellular and system-wide adaptive structure used to sense, process, and combat the deep-sea hydrothermal vent environment. The alvinellid sensory cells exhibit characteristics of annelid ciliary types, and among the most unique features were the head sensory inputs and structure of the neural cell bodies of the brain, which were surrounded by multiple membranes. We speculated that such enhanced protection is required for the production of normal electrical signals, and to avoid the breakdown of the membrane surrounding metabolically fragile neurons from oxidative stress. Such pivotal acquisition is not broadly found in the all body parts, suggesting the head sensory inputs are specific, and these heterogenetic protection mechanisms may be present in alvinellid worms. PMID- 25505489 TI - Medical patients' treatment decision making capacity: a report from a general hospital in Greece. AB - This study aimed to assess the decision-making capacity for treatment of patients hospitalized in an internal medicine ward of a General Hospital in Greece, and to examine the views of treating physicians regarding patients' capacity. All consecutive admissions to an internal medicine ward within a month were evaluated. A total of 134 patients were approached and 78 patients were interviewed with the MacArthur Competence Assessment Tool for Treatment (MacCAT T) and the Mini Mental State Examination (MMSE) questionnaire. Sixty-eight out of 134 patients (50.7%) were incompetent to decide upon their treatment. The majority of them (n=56, 41.8%) were obviously incapable because they were unconscious, or had such marked impairment that they could not give their own names, and the rest (n=12, 8.9%) were rated as incompetent according to their performance in the MacCAT-T. Neurological disorders, old age and altered cognitive function according to MMSE were negatively correlated with decision making capacity. Physicians sometimes failed to recognize patients' incapacity. Rates of decision-making incapacity for treatment in medical inpatients are high, and incapacity may go unrecognized by treating physicians. Combined patient evaluation with the use of the MacCAT-T and MMSE, could be useful for the determination of incapable patients. PMID- 25505486 TI - Genetics and genomics of disease resistance in salmonid species. AB - Infectious and parasitic diseases generate large economic losses in salmon farming. A feasible and sustainable alternative to prevent disease outbreaks may be represented by genetic improvement for disease resistance. To include disease resistance into the breeding goal, prior knowledge of the levels of genetic variation for these traits is required. Furthermore, the information from the genetic architecture and molecular factors involved in resistance against diseases may be used to accelerate the genetic progress for these traits. In this regard, marker assisted selection and genomic selection are approaches which incorporate molecular information to increase the accuracy when predicting the genetic merit of selection candidates. In this article we review and discuss key aspects related to disease resistance in salmonid species, from both a genetic and genomic perspective, with emphasis in the applicability of disease resistance traits into breeding programs in salmonids. PMID- 25505490 TI - Occupational accident and disease claims, work-related stress and job satisfaction of physiotherapists. AB - INTRODUCTION: Physiotherapists are exposed to diverse occupational demands. Until now, little has been known about the interaction between occupational stress and the job satisfaction of physiotherapists. This paper aims to examine their work related stress and job satisfaction. It will analyse accidents at work and occupational diseases of physiotherapists along with work-related physical and psychosocial stress and job satisfaction. METHOD: We analysed routine data of the German Institute for Statutory Accident Insurance and Prevention in the Health and Welfare Services (BGW) on accidents at work and occurring en route to/from work as well as occupational diseases of physiotherapists. Work-related stress and job satisfaction were examined in a cross-sectional survey using a standard questionnaire to be completed by subjects themselves. RESULTS: Between 2007 and 2011, 1,229 cases of occupational disease were reported to the BGW. The majority of reports involved skin diseases (73%). Stumbles and falls were the most frequent causes of accidents at work (42.9%). Eighty-five physiotherapists all over Germany took part in the survey. They experience high quantitative demands at work. The main physical demands consist of a torso posture between 45 degrees and 90 degrees and high hand activity. Of the 85 subjects, 51% suffer from complaints of the musculoskeletal system in the neck and thoracic spine area and 24% have skin diseases. Most physiotherapists (88%) are satisfied with their work overall. This is aided by a high degree of influence on their work and breaks, by practical application of skills and expert knowledge, high regard for their profession, varied work and a good atmosphere at work. Reservations tend to be about statutory regulations and the social benefits provided by the German healthcare system. CONCLUSION: Overall, despite high demands and stress relating to the adequacy of resources, the majority of physiotherapists surveyed seem to be satisfied with their job. The main focus of action to promote the health of physiotherapists should be on preventing skin disease, problems of the musculoskeletal system and accidents caused by stumbles and falls. PMID- 25505491 TI - Joint Attention and Vocabulary Development: A Critical Look. AB - Joint attention - parents' and children's coordinated attention to each other and to a third object or event - is believed to play a causal and critical role in early word learning. However, joint attention, as conventionally defined and measured, relies only on overt indicators of attention, is studied predominantly in the visual modality, and varies by culture. Moreover, word learning can occur without joint attention in typical development, in autistic development, and in Williams syndrome, and joint attention can occur without commensurate word learning in Down syndrome. Thus, the assumption that joint attention is a necessary and sufficient precursor to vocabulary learning is not universally supported. PMID- 25505492 TI - Cancer survivors' views of lymphoedema management. AB - BACKGROUND: Many clinicians recognise the importance of the patient's role in treating and managing lymphoedema and that optimal outcomes depend on patients' compliance to treatment, or a prescribed daily lymphoedema care regimen. Such a widespread belief can be called a 'compliance paradigm'. AIMS: To ascertain whether breast cancer survivors with lymphoedema have the same concept of compliance as clinicians to characterise their experiences. METHODS: Using a descriptive phenomenological method, 34 participants were recruited and 102 interviews completed. RESULTS: The findings of the study reveal that, from the perspective of breast cancer survivors, managing lymphoedema is broader than compliance to treatment. The women actively structured their lives to make lymphoedema management feasible by incorporating it into a daily routine. The study offers an alternative insight into the compliance approach to lymphoedema management and it is important for researchers and clinicians to be aware that breast cancer survivors do not consider compliance to treatment as part of their daily lymphoedema care. CONCLUSIONS: In research and practice, it may be more appropriate to assess the presence or absence of breast cancer survivors' intentions, effective and ineffective strategies, and barriers to effective strategies. PMID- 25505493 TI - Microbial sequencing to improve individual and population health. AB - Recent advances in sequencing technologies are changing the face of infectious disease investigation and control. Personalized anti-infective therapies and surveillance of emergent pathogen outbreaks are just two examples of the potential benefits of merging the fields of genomics and infectious diseases. PMID- 25505496 TI - Osteocompatibility of biofilm inhibitors. AB - The demand for infection prevention therapies has led to the discovery of several biofilm inhibitors. These inhibiting signals are released by bacteria, fungi, or marine organisms to signal biofilm dispersal or disruption in Gram-positive, Gram negative, and fungal microorganisms. The purpose of this study was to test the biocompatibility of five different naturally-produced biofilm chemical dispersal and inhibition signals with osteoblast-like cells: D-amino acids (D-AA), lysostaphin (LS), farnesol, cis-2-decenoic acid (C2DA), and desformyl flustrabromine (dFBr). In this preliminary study, compatibility of these anti biofilm agents with differentiating osteoblasts was examined over a 21 days period at levels above and below concentrations active against bacterial biofilm. Anti-biofilm compounds listed above were serially diluted in osteogenic media and added to cultures of MC3T3 cells. Cell viability and cytotoxicity, after exposure to each anti-biofilm agent, were measured using a DNA assay. Differentiation characteristics of osteoblasts were determined qualitatively by observing staining of mineral deposits and quantitatively with an alkaline phosphatase assay. D-AA, LS, and C2DA were all biocompatible within the reported biofilm inhibitory concentration ranges and supported osteoblast differentiation. Farnesol and dFBr induced cytotoxic responses within the reported biofilm inhibitory concentration range and low doses of dFBr were found to inhibit osteoblast differentiation. At high concentrations, such as those that may be present after local delivery, many of these biofilm inhibitors can have effects on cellular viability and osteoblast function. Concentrations at which negative effects on osteoblasts occur should serve as upper limits for delivery to orthopaedic trauma sites and guide development of these potential therapeutics for orthopaedics. PMID- 25505497 TI - Spinal Cord Injury without Radiographic Abnormality (SCIWORA) - Clinical and Radiological Aspects. AB - The acronym SCIWORA (Spinal Cord Injury Without Radiographic Abnormality) was first developed and introduced by Pang and Wilberger who used it to define "clinical symptoms of traumatic myelopathy with no radiographic or computed tomographic features of spinal fracture or instability". SCIWORA is a clinical radiological condition that mostly affects children. SCIWORA lesions are found mainly in the cervical spine but can also be seen, although much less frequently, in the thoracic or lumbar spine. Based on reports from different authors, SCIWORA is responsible for 6 to 19% and 9% to 14% of spinal injuries in children and adults, respectively. Underlying degenerative changes, including spondylosis or spinal canal stenosis, are typically present in adult patients. The level of spinal cord injury corresponds to the location of these changes. With recent advances in neuroimaging techniques, especially in magnetic resonance imaging, and with increasing availability of MRI as a diagnostic tool, the overall detection rate of SCIWORA has significantly improved. PMID- 25505495 TI - Protein dynamics and the allosteric transitions of pentameric receptor channels. AB - The recent application of molecular dynamics (MD) methodology to investigate the allosteric transitions of the acetylcholine receptor and its prokaryotic and eukaryotic pentameric homologs has yielded new insights into the mechanisms of signal transduction by these receptors. Combined with available data on X-ray structures, MD techniques enable description of the dynamics of the conformational change at the atomic level, intra-molecular propagation of this signal transduction mechanism as a concerted stepwise process at physiological timescales and the control of this process by allosteric modulators, thereby offering new perspectives for drug design. PMID- 25505498 TI - Evaluating Variables as Unbiased Proxies for Other Measures: Assessing the Step Test Exercise Prescription as a Proxy for the Maximal, High-intensity Peak Oxygen Consumption in Older Adults. AB - To assess validity of a low-intensity measure of fitness (X) in a population of older adults as a proxy measure for the original, high-intensity measure (Y), we used ordinary least square regression with the new, potential proxy measure (X) as the sole explanatory variable for Y. A perfect proxy measure would be unbiased (i.e., result in a regression line with a y-intercept of zero and a slope of one) with no error (variance equal to zero). We evaluated the properties of potential biases of proxy measures. A two degree-of-freedom approach using a contrast matrix in the setting of simple linear ordinary least squares regression was compared to a one degree-of-freedom paired t test alternative approach. We found that substantial improvements in power could be gained through use of the two degree-of-freedom approach in many settings, while scenarios where no linear bias was present there could be modest gains from the paired t test approach. In general, the advantages of the two degree-of-freedom approach outweighed the benefits of the one degree-of-freedom approach. Using the two degree-of-freedom approach, we assessed the data from our motivating example and found that the low intensity fitness measure was biased, and thus was not a good proxy for the original, high-intensity measure of fitness in older adults. PMID- 25505499 TI - EFFECT OF BREASTFEEDING ON GASTROINTESTINAL INFECTION IN INFANTS: A TARGETED MAXIMUM LIKELIHOOD APPROACH FOR CLUSTERED LONGITUDINAL DATA. AB - The PROmotion of Breastfeeding Intervention Trial (PROBIT) cluster-randomized a program encouraging breastfeeding to new mothers in hospital centers. The original studies indicated that this intervention successfully increased duration of breastfeeding and lowered rates of gastrointestinal tract infections in newborns. Additional scientific and popular interest lies in determining the causal effect of longer breastfeeding on gastrointestinal infection. In this study, we estimate the expected infection count under various lengths of breastfeeding in order to estimate the effect of breastfeeding duration on infection. Due to the presence of baseline and time-dependent confounding, specialized "causal" estimation methods are required. We demonstrate the double robust method of Targeted Maximum Likelihood Estimation (TMLE) in the context of this application and review some related methods and the adjustments required to account for clustering. We compare TMLE (implemented both parametrically and using a data-adaptive algorithm) to other causal methods for this example. In addition, we conduct a simulation study to determine (1) the effectiveness of controlling for clustering indicators when cluster-specific confounders are unmeasured and (2) the importance of using data-adaptive TMLE. PMID- 25505494 TI - The path to visualization of walking myosin V by high-speed atomic force microscopy. AB - The quest for understanding the mechanism of myosin-based motility started with studies on muscle contraction. From numerous studies, the basic frameworks for this mechanism were constructed and brilliant hypotheses were put forward. However, the argument about the most crucial issue of how the actin-myosin interaction generates contractile force and shortening has not been definitive. To increase the "directness of measurement", in vitro motility assays and single molecule optical techniques were created and used. Consequently, detailed knowledge of the motility of muscle myosin evolved, which resulted in provoking more arguments to a higher level. In parallel with technical progress, advances in cell biology led to the discovery of many classes of myosins. Myosin V was discovered to be a processive motor, unlike myosin II. The processivity reduced experimental difficulties because it allowed continuous tracing of the motor action of single myosin V molecules. Extensive studies of myosin V were expected to resolve arguments and build a consensus but did not necessarily do so. The directness of measurement was further enhanced by the recent advent of high-speed atomic force microscopy capable of directly visualizing biological molecules in action at high spatiotemporal resolution. This microscopy clearly visualized myosin V molecules walking on actin filaments and at last provided irrefutable evidence for the swinging lever-arm motion propelling the molecules. However, a peculiar foot stomp behavior also appeared in the AFM movie, raising new questions of the chemo-mechanical coupling in this motor and myosin motors in general. This article reviews these changes in the research of myosin motility and proposes new ideas to resolve the newly raised questions. PMID- 25505500 TI - Applying Public Health Frameworks to Advance the Promotion of Mental Health Among Asian American Children. AB - Asian American (ASA) children experience high rates of mental health problems. Although there is a pressing need to utilize population approaches, emerging frameworks from the fields of public and population health have not been applied to ASA children. This paper addresses this gap by first discussing applications of the National Prevention Strategy (NPS), a population strategy developed from the Social Determinants of Health perspective, to guide ASA prevention work. Next, we provide a practical example to illustrate how the NPS can be applied to prevention program design (using ParentCorps as an example) and dissemination and implementation processes to broadly address ASA children's mental health needs. Finally, we present preliminary data on the feasibility of applying this population strategy to ASA families and a framework for researchers who are considering disseminating and implementing evidence-based programs to ASA or ethnic minority pediatric populations. PMID- 25505501 TI - Image-based Analysis to Study Plant Infection with Human Pathogens. AB - Our growing awareness that contaminated plants, fresh fruits and vegetables are responsible for a significant proportion of food poisoning with pathogenic microorganisms indorses the demand to understand the interactions between plants and human pathogens. Today we understand that those pathogens do not merely survive on or within plants, they actively infect plant organisms by suppressing their immune system. Studies on the infection process and disease development used mainly physiological, genetic, and molecular approaches, and image-based analysis provides yet another method for this toolbox. Employed as an observational tool, it bears the potential for objective and high throughput approaches, and together with other methods it will be very likely a part of data fusion approaches in the near future. PMID- 25505502 TI - Cell-based Models To Investigate Tau Aggregation. AB - Accumulation of abnormal tau aggregates in neuron is an important pathological signature in multiple neurodegenerative disorders including Alzheimer's disease. Tau is a neuron specific microtubule-associated protein that regulates microtubule stability, which is critical for axonal outgrowth and synaptic plasticity. In a pathological condition, tau dissociates from microtubules and forms insoluble aggregates called neurofibrillary tangles (NFTs). The accumulation of NFTs in neuron directly correlates with microtubule dysfunction and neuronal degeneration. Due to the pathophysiological importance of tau, great efforts have been made to understand tau aggregation processes and find therapeutics to halt or reverse the processes. However, progress has been slow due to the lack of a suitable method for monitoring tau aggregation. In this mini review, we will review the conventional methods for studying tau aggregation, and introduce recent cell-based sensor approaches that allow monitoring tau aggregation in living cells. PMID- 25505505 TI - Quality of life, anxiety and depression in Turkish women prior to receiving assisted reproductive techniques. AB - BACKGROUND: This study evaluated the quality of life and anxiety-depression levels of patients prior to receiving assisted reproductive techniques. MATERIALS AND METHODS: This cross-sectional research was conducted in the In-Vitro Fertilization Unit of a private University's Faculty of Medicine, Department of Obstetrics and Gynecology. Study participants consisted of 160 individuals diagnosed as infertile whose treatment plans were determined, as well as 160 reportedly healthy fertile individuals (n=320). Each participant completed the Patient Identification Form, Beck Anxiety Inventory, Beck Depression Inventory and Quality of Life Scale questionaires. RESULTS: The results of this study indicate a higher prevalence of depression and anxiety in the infertile group (p<0.05). Also, quality of life scores were found to be lower in the infertile group (p<0.05). CONCLUSION: Individuals who experience infertility need psychological support in order to overcome the psycho-social difficulties they experience. It is essential to have studies that stress the importance of integrating psychological and emotional support into clinical practice. PMID- 25505504 TI - Evolutionary genomics and population structure of Entamoeba histolytica. AB - Amoebiasis caused by the gastrointestinal parasite Entamoeba histolytica has diverse disease outcomes. Study of genome and evolution of this fascinating parasite will help us to understand the basis of its virulence and explain why, when and how it causes diseases. In this review, we have summarized current knowledge regarding evolutionary genomics of E. histolytica and discussed their association with parasite phenotypes and its differential pathogenic behavior. How genetic diversity reveals parasite population structure has also been discussed. Queries concerning their evolution and population structure which were required to be addressed have also been highlighted. This significantly large amount of genomic data will improve our knowledge about this pathogenic species of Entamoeba. PMID- 25505503 TI - Stochastic simulation in systems biology. AB - Natural systems are, almost by definition, heterogeneous: this can be either a boon or an obstacle to be overcome, depending on the situation. Traditionally, when constructing mathematical models of these systems, heterogeneity has typically been ignored, despite its critical role. However, in recent years, stochastic computational methods have become commonplace in science. They are able to appropriately account for heterogeneity; indeed, they are based around the premise that systems inherently contain at least one source of heterogeneity (namely, intrinsic heterogeneity). In this mini-review, we give a brief introduction to theoretical modelling and simulation in systems biology and discuss the three different sources of heterogeneity in natural systems. Our main topic is an overview of stochastic simulation methods in systems biology. There are many different types of stochastic methods. We focus on one group that has become especially popular in systems biology, biochemistry, chemistry and physics. These discrete-state stochastic methods do not follow individuals over time; rather they track only total populations. They also assume that the volume of interest is spatially homogeneous. We give an overview of these methods, with a discussion of the advantages and disadvantages of each, and suggest when each is more appropriate to use. We also include references to software implementations of them, so that beginners can quickly start using stochastic methods for practical problems of interest. PMID- 25505506 TI - Comparison of Intracytoplasmic Sperm Injection Outcomes between Oligozoospermic, Obstructive Azoospermic and Non-Obstructive Azoospermic Patients. AB - BACKGROUND: To determine the differences in sperm quality and results of intracytoplasmic sperm injection (ICSI) cycles between three groups of male factor infertile couples: oligozoospermic, obstructive azoospermic and non obstructive azoospermic. MATERIALS AND METHODS: In this prospective cohort study, 628 male factor infertile couples who underwent ICSI cycles from April 2004 to March 2006 were enrolled. Three hundred fourteen oligozoospermic patients (group I), 180 obstructive azoospermic patients (group II) and 134 non-obstructive azoospermic patients (group III) were included. Fertilization, cleavage, implantation and clinical pregnancy, early abortion rates were assessed. Chisquare and analysis of variances with Post Hoc (Tukey test) were used for data analysis. RESULTS: Fertilization rates were significantly different in the three groups (group I: 66.6%; group II: 51.8%; group III: 47.7%; p=0.004). There were differences in the implantation rates (I: 19.5%; II: 17.6%; III: 6.4%; p=0.001). The cleavage rates were found to be 55.1% (group I), 47.5% (group II), 45.5%(group III), respectively. The clinical pregnancy rate was the lowest in the third group (I: 37.6%; II: 28.9%; III: 13.4%; p=0.001). There was no significant difference in early abortion rates between the three groups: (I: 10.7%; II: 9.8%; III: 8%; p=0.776). CONCLUSION: It can be concluded that patients with oligozoospermia may benefit the most from ICSI treatment. ICSI cycles which use spermatozoa from non-obstructive azoospermic patients have a lower chance for successful outcome. The results of this study suggest, in cases of failure to achieve pregnancy after 1 or 2 cycles in non-obstructive azoospermic patients, embryo donation would be a better alternative. PMID- 25505507 TI - Biological and histopathological investigations of moclobemide on injured ovarian tissue following induction of ischemia-reperfusion in rats. AB - BACKGROUND: The effects of moclobemide on damaged ovarian tissue induced by ischemia- reperfusion and damaged contralateral ovarian tissue were investigated in rats, biochemically and histologically. MATERIALS AND METHODS: In this experimental study, 40 rats were equally divided into four groups: 10 mg/kg moclobemide, 20 mg/kg moclobemide, ischemia/reperfusion control, and intact control groups. A 2-2.5-cm-long vertical incision was made in the lower abdomen of each rat in order to reach the ovaries, after which a vascular clip was placed on the lower side of the right ovary of each animal in the two treatment groups and the ischemia-reperfusion control group, but not in the healthy (intact control) animal group. The purpose of this procedure was to create ischemia over the course of three hours, then the clips were unclamped to provide reperfusion for the next two hours. At the end of the two hours of reperfusion, all the animals were killed by high-dose anaesthesia and their ovaries were taken and subjected to histological and biochemical (malondialdehyde, nitric oxide, glutathione) studies. RESULTS: The obtained results showed that moclobemide suppressed nitric oxide and malondialdehyde production in the ischemia reperfusion damage area, and prevented the decrease in endogenous antioxidant levels (glutathione) in the rat ovarian tissue. Moclobemide also prevented infiltration of leukocytes to the ovarian tissue. These results showed that moclobemide protected ovarian tissue against ischemiareperfusion injury. CONCLUSION: This study shows that moclobemide represses malondialdehyde and nitric oxide production in the rat ovarian tissue subjected to ischemia reperfusion injury and keeps the endogenous antioxidant glutathione level from decreasing. Moclobemide also inhibits leukocytic migration into ovarian tissue following ischemia-reperfusion injury. From these results, it is suggested that moclobemide can be used in the treatment of ovarian ischemia-reperfusion injury. PMID- 25505508 TI - Hysteroscopic findings in patients with a history of two implantation failures following in vitro fertilization. AB - BACKGROUND: This study was designed to evaluate the incidence of uterine pathologies in infertile women with a history of two implantation failures after in vitro fertilization (IVF) and estimate the effect of hysteroscopic correction on achieving a pregnancy in these patients. MATERIALS AND METHODS: The retrospective study population included 238 infertile women attended the outpatient infertility clinic between November 2007 and December 2008. Patients with at least two previous IVF failures were eligible for this study. All patients had normal findings on hysterosalpingography performed prior their first attempt for IVF. Standard transvaginal ultrasonography and diagnostic hysteroscopy were performed in patients before the subsequent IVF attempt. RESULTS: Out of 238 patients with previous IVF failure who underwent hysteroscopic evaluation, 158 patients (66.4%) showed normal uterine cavity. Abnormal cavity was found in 80 patients (33.6%). We found polyp as the most common abnormality (19.7%) in the patients with previous history of IVF failure. The pregnancy rate was similar between IVF failure patients who treated by hysteroscopy for a detected uterine abnormality (24.6%) and similar patients with normal uterine cavity (21.2%) in hysteroscopic examinations. CONCLUSION: The intrauterine lesions diagnosed by hysteroscopy in patients with previous IVF failure ranges from 0.8%-19.7%. Correction of abnormalities such as myoma and polyp showed good outcome, similar to that achieved in patients with a normal hysteroscopy. PMID- 25505509 TI - Enhanced ovarian folliclular development by metformin does not correlate with pregnancy rate: a randomized trial. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common, complex endocrine disorder for women of productive age. A high incidence of ovulation failure in women with PCOS is related to insulin resistance. Some studies have assessed the effects of hyperinsulinemia and insulin resistance in relationship with insulin sensitizing agents such as Metformin (Met). These medicines have been suggested new scope for ovulation stimulation enhancement with Clomiphene Citrate (CC) in PCOs women. The aim of this study is to compare the effectiveness of adding Met to CC in women with PCOS. MATERIALS AND METHODS: This multicenter, single-blind, randomized controlled trial study was performed on 334 PCOS patients from 2007 to 2009. Patients were randomly divided into two groups and ovulation induction was performed with either CC alone or CC + Met. The treatment was continued for three cycles, then the mature follicle and pregnancy rates were evaluated. RESULTS: In the CC + Met group, 68% had at least one dominant follicle in the first cycle that was significant (p<0.001), and 31.7% had one in the second cycle. In the CC group 54.5% in the first cycle, 31.7% second cycle, and 6.9% ovulated in the third cycle. The pregnancy rate was 28.7% in CC + Met group and 24.6% in the CC group, with no significant differences between the two groups. CONCLUSION: Adding Met to CC is significant for ovulation, but it does not enhance the pregnancy rate (Registration Number: IRCT138904174306N1). PMID- 25505510 TI - Admissibility Investigation and Validation of Infertility Distress Scale (IDS) in Iranian Infertile Women. AB - BACKGROUND: Psychological stress has a profound effect on infertility and its treatment. The aim of this study was to develop a specific scale to determine distress levels among Iranian infertile women. MATERIALS AND METHODS: In this cross-sectional study the samples included 300 women (145 fertile and 155 infertile) who completed the Infertility Distress Scale (IDS) form. Data was analysed using correlation method and main component analysis. RESULTS: These results show that all 21 items had a high correlation with the overall scale. Cronbach's alpha value was 0.91 for the entire list. Factor analysis results with 5 element extraction could identify 88% of overall variance with a special value higher than 1. CONCLUSION: According to results, the IDS questionnaire has enough admissibility and va- lidity in the measurement of the infertility distress scale in Iranian infertile women. PMID- 25505511 TI - A low-cost efficient multiplex PCR for prenatal sex determination in bovine fetus using free fetal DNA in maternal plasma. AB - BACKGROUND: In order to establish a reliable non-invasive method for sex determination in a bovine fetus in a routine setting, the possibility of identifying specific sequence in the fetal X and Y-chromosomes has been evaluated in maternal plasma using conventional multiplex polymerase chain reaction (PCR) analysis. The aim of this study was to provide a rapid and reliable method for sexing bovine fetuses. MATERIALS AND METHODS: In this experimental study, peripheral blood samples were taken from 38 pregnant heifers with 8 to 38 weeks of gestation. DNA template was extracted by phenol-chloroform method from 350 ul maternal plasma. Two primer pairs for bovine amelogenin gene (bAML) and BC1.2 were used to amplify fragments from X and Y chromosomes. A multiplex PCR reaction has been optimized for amplification of 467 bp and 341 bp fragments from X and Y bAML gene and a 190 bp fragment from BC1.2 related to Y chromosome. RESULTS: The 467 bp fragment was observed in all 38 samples. Both 341 and 190 bp fragments were detected only in 24 plasma samples from male calves. The sensitivity and specificity of test were 100% with no false negative or false positive results. CONCLUSION: The results showed that phenol-chloroform method is a simple and suitable method for isolation of fetal DNA in maternal plasma. The multiplex PCR method is an available non-invasive approach which is cost efficient and reliable for sexing bovine fetuses. PMID- 25505512 TI - Effects of prenatal lipopolysaccharide exposure on reproductive activities and serum concentrations of pituitary-gonadal hormones in mice offspring. AB - BACKGROUND: Maternal infection during pregnancy is a risk factor for some behavioral problems with neurodevelopmental origin. This study aimed to evaluate the effects of exposure of pregnant mice to the bacterial lipopolysaccharide (LPS) on sexual behaviour and serum level of pituitary-gonadal hormones of offspring in adulthood. MATERIALS AND METHODS: In this Expremental study, pregnant NMRI mice (n=7/group) were treated with intra-peritoneal administration of LPS (1, 5 and 10 ug/kg) at day 10 of gestation. Induction of the pro inflammatory cytokines, Tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and interleukin-6 (IL-6) were measured in maternal serum 2 hours following the maternal LPS challenge. Behavior in the adult male offspring reproductive activity was investigated using receptive female mice. Concentrations of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in adult offspring serum were measured using the enzyme-linked immunosorbent assay (ELISA) method (at postnatal day 60, n=10/group). RESULTS: One-way ANOVA showed that LPS administration induces a significant increase in TNF-alpha, IL-1beta and IL-6 levels of maternal serum. Prenatal LPS exposure reduces sexual behavior and serum concentration of LH and testosterone in adult male offspring. CONCLUSION: The overall results suggest that prenatal exposure to LPS increases pro- inflammatory cytokine levels, affects development of neuroendocrine systems and results in the inhibition of reproductive behaviors and reactivity of hypothalamic-pituitary-gonadal (HPG) axis in adult male offspring. PMID- 25505513 TI - Intraperitoneal dexamethasone as a new method for relieving postoperative shoulder pain after gynecologic laparoscopy. AB - BACKGROUND: In this study, we tried to show the efficacy of Intraperitoneal dexamethasone on relieving shoulder pain after gynecologic laparoscopy. MATERIALS AND METHODS: In this double-blind randomized clinical trial, 63 patients who were candidates for gynecologic laparoscopy were included. At the end of the procedure patients randomly received 16 mg dexamethasone (n=31) or placebo (n=32) intraperitoneally. Visual analogue scale (VAS) was used for clinical evaluation of pain severity during 24 hours after laparoscopy . A physician, who was not aware whether patients were treated with drug or placebo, evaluated the patients. RESULTS: The severity of pain in the dexamethasone group within 0, 2, 4, 8, 12, 24 hours after procedure was significantly less than in the placebo group (p<0.001). The average consumption of opioids as analgesic/ sedative in the placebo group was more than the dexamethasone group (p=0.025). CONCLUSION: Findings of this study show that the prescription of 16 mg of dexametha- sone (single dose) in the peritoneal cavity may significantly reduce the severity of pain after Laparoscopy in comparison with placebo and may decrease the need for narcotics as pain relief (Registration Number: IRCT201105306640N1). PMID- 25505514 TI - The Effect of Flutamide on Ovulation Induction in PCOS Patients. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a disorder that affects various body organs and requires comprehensive long term evaluation and management. The aim of this study was to evaluate effect of Flutamide on ovulation induction in PCOS patients. MATERIALS AND METHODS: This prospective study applied triple blind method, a simple convenience sampling method, to induce ovulations of the ninety six PCOS patients. Patients were divided into two groups; group A included 53 subjects (received Flutamide + Clomiphene Citrate) and group B included 43 subjects (received placebo + Clomiphene Citrate). Ultrasound was carried to determine the size of follicles and growth rate of them during follicular phase of the menstrual cycle. Also, progesterone levels were measured on days 19 and 21 of the menstrual cycle. RESULTS: In this study, ninety six PCOS patients, in two treatment and control groups, were evaluated regarding to body mass index (BMI), cycle irregularity, age and number of dominant follicles, duration of stimulation, endocrine profile and score of hirsutism. The obtained results revealed no significant differences between two groups. CONCLUSION: Flutamide does not affect ovulation improvement in PCOS patients undergoing induction (Registration Number: IRCT 201105081141N10). PMID- 25505515 TI - Spatiotemporal changes in Cx30 and Cx43 expression during neuronal differentiation of P19 EC and NT2/D1 cells. AB - While connexins (Cxs) are thought to be involved in differentiation, their expression and role has yet to be fully elucidated. We investigated the temporal expression of Cx30, Cx36 and Cx43 in two in vitro models of neuronal differentiation: human NT2/D1 and murine P19 cells, and the spatial localisation of Cx30 and Cx43 in these models. A temporal Cx43 downregulation was confirmed in both cell lines during RA-induced neuronal differentiation using RT-PCR (P < 0.05) preceding an increase in neuronal doublecortin protein. RT-PCR showed Cx36 was upregulated twofold in NT2/D1 cells (P < 0.05) and sixfold in P19 cells (P < 0.001) during neuronal differentiation. Cx30 exhibited a transient peak in expression midway through the timecourse of differentiation increasing threefold in NT2/D1 cells (P < 0.001) and eightfold in P19 cells (P < 0.01). Qualitative immunocytochemistry was used to examine spatiotemporal patterns of Cx protein distribution alongside neuronal differentiation markers. The temporal immunolabelling pattern was similar to that seen using RT-PCR. Cx43 was observed intracellularly and on cell surfaces, while Cx30 was seen as puncta. Spatially Cx43 was seen on doublecortin-negative cells, which may indicate Cx43 downregulation is requisite for differentiation in these models. Conversely, Cx30 puncta were observed on doublecortin-positive and -negative cells in NT2/D1 cells and examination of the Cx30 peak showed puncta also localized to nestin-positive cells, with few puncta on MAP2-positive cells. In P19 cells Cx30 was localized on clusters of cells surrounded by MAP2- and doublecortin-positive processes. The expression pattern of Cx30 indicates a role in neuronal differentiation; the nature of that role warrants future investigation. PMID- 25505516 TI - Do informed consent documents for chiropractic clinical research studies meet readability level recommendations and contain required elements: a descriptive study. AB - BACKGROUND: Informed consent documents (ICD) in research are designed to educate research participants about the nature of the research project in which he or she may participate. United States (US) law requires the documents to contain specific elements present and be written in a way that is understandable to research participants. The purpose of this research is to determine if ICDs from randomized controlled trials conducted at chiropractic colleges meet recommended readability standards and contain the 13 content items required by US law. METHODS: This study was approved by Palmer College of Chiropractic's IRB #2012-12 3-T and was conducted between December 3, 2012 and February 14, 2013. We contacted the research directors of five chiropractic colleges that have received federal funding supporting their clinical research. A total of 13 informed consent documents from four chiropractic colleges were analyzed using the Flesch Kincaid measurement. We assigned a grade-level readability score to the document based on the average of three separate grade level scores conducted on the three largest uninterrupted blocks of text. Content of the 13 ICDs was assessed using a 13-element checklist. A point was given for every element present in the document, giving a score range of "0, no elements are present", to "13, all elements are present." RESULTS: The mean Flesch-Kincaid grade level readability was 10.8 (range 7.2 -14.0). Our sample had a mean readability score 2.8 grade levels above the generally-accepted US average reading level. Content varied among the 13 informed consent forms, ranging from only nine elements present in one document to all 13 required in five documents. Additionally, we collated the risks presented in each document. CONCLUSION: These results strongly suggest that chiropractic clinical researchers are not developing ICDs at a readability level congruent with the national average acceptable level. The low number of elements in some of the informed consent documents raises concern that not all research participants were fully informed when given the informed consent, and it may suggest that some documents may not be in compliance with federal requirements. Risk varies among institutions and even within institutions for the same intervention. PMID- 25505517 TI - Benefits and costs of ecological restoration: Rapid assessment of changing ecosystem service values at a U.K. wetland. AB - Restoration of degraded land is recognized by the international community as an important way of enhancing both biodiversity and ecosystem services, but more information is needed about its costs and benefits. In Cambridgeshire, U.K., a long-term initiative to convert drained, intensively farmed arable land to a wetland habitat mosaic is driven by a desire both to prevent biodiversity loss from the nationally important Wicken Fen National Nature Reserve (Wicken Fen NNR) and to increase the provision of ecosystem services. We evaluated the changes in ecosystem service delivery resulting from this land conversion, using a new Toolkit for Ecosystem Service Site-based Assessment (TESSA) to estimate biophysical and monetary values of ecosystem services provided by the restored wetland mosaic compared with the former arable land. Overall results suggest that restoration is associated with a net gain to society as a whole of $199 ha(-1)y( 1), for a one-off investment in restoration of $2320 ha(-1). Restoration has led to an estimated loss of arable production of $2040 ha(-1)y(-1), but estimated gains of $671 ha(-1)y(-1) in nature-based recreation, $120 ha(-1)y(-1) from grazing, $48 ha(-1)y(-1) from flood protection, and a reduction in greenhouse gas (GHG) emissions worth an estimated $72 ha(-1)y(-1). Management costs have also declined by an estimated $1325 ha(-1)y(-1). Despite uncertainties associated with all measured values and the conservative assumptions used, we conclude that there was a substantial gain to society as a whole from this land-use conversion. The beneficiaries also changed from local arable farmers under arable production to graziers, countryside users from towns and villages, and the global community, under restoration. We emphasize that the values reported here are not necessarily transferable to other sites. PMID- 25505519 TI - Rapid evolutionary adaptation to elevated salt concentrations in pathogenic freshwater bacteria Serratia marcescens. AB - Rapid evolutionary adaptions to new and previously detrimental environmental conditions can increase the risk of invasion by novel pathogens. We tested this hypothesis with a 133-day-long evolutionary experiment studying the evolution of the pathogenic Serratia marcescens bacterium at salinity niche boundary and in fluctuating conditions. We found that S. marcescens evolved at harsh (80 g/L) and extreme (100 g/L) salt conditions had clearly improved salt tolerance than those evolved in the other three treatments (ancestral conditions, nonsaline conditions, and fluctuating salt conditions). Evolutionary theories suggest that fastest evolutionary changes could be observed in intermediate selection pressures. Therefore, we originally hypothesized that extreme conditions, such as our 100 g/L salinity treatment, could lead to slower adaptation due to low population sizes. However, no evolutionary differences were observed between populations evolved in harsh and extreme conditions. This suggests that in the study presented here, low population sizes did not prevent evolution in the long run. On the whole, the adaptive potential observed here could be important for the transition of pathogenic S. marcescens bacteria from human-impacted freshwater environments, such as wastewater treatment plants, to marine habitats, where they are known to infect and kill corals (e.g., through white pox disease). PMID- 25505521 TI - CO2 efflux from subterranean nests of ant communities in a seasonal tropical forest, Thailand. AB - Many ant species construct subterranean nests. The presence of their nests may explain soil respiration "hot spots", an important factor in the high CO2 efflux from tropical forests. However, no studies have directly measured CO2 efflux from ant nests. We established 61 experimental plots containing 13 subterranean ant species to evaluate the CO2 efflux from subterranean ant nests in a tropical seasonal forest, Thailand. We examined differences in nest CO2 efflux among ant species. We determined the effects of environmental factors on nest CO2 efflux and calculated an index of nest structure. The mean CO2 efflux from nests was significantly higher than those from the surrounding soil in the wet and dry seasons. The CO2 efflux was species-specific, showing significant differences among the 13 ant species. The soil moisture content significantly affected nest CO2 efflux, but there was no clear relationship between nest CO2 efflux and nest soil temperature. The diameter of the nest entrance hole affected CO2 efflux. However, there was no significant difference in CO2 efflux rates between single hole and multiple-hole nests. Our results suggest that in a tropical forest ecosystem the increase in CO2 efflux from subterranean ant nests is caused by species-specific activity of ants, the nest soil environment, and nest structure. PMID- 25505520 TI - The design and function of birds' nests. AB - All birds construct nests in which to lay eggs and/or raise offspring. Traditionally, it was thought that natural selection and the requirement to minimize the risk of predation determined the design of completed nests. However, it is becoming increasingly apparent that sexual selection also influences nest design. This is an important development as while species such as bowerbirds build structures that are extended phenotypic signals whose sole purpose is to attract a mate, nests contain eggs and/or offspring, thereby suggesting a direct trade-off between the conflicting requirements of natural and sexual selection. Nest design also varies adaptively in order to both minimize the detrimental effects of parasites and to create a suitable microclimate for parents and developing offspring in relation to predictable variation in environmental conditions. Our understanding of the design and function of birds' nests has increased considerably in recent years, and the evidence suggests that nests have four nonmutually exclusive functions. Consequently, we conclude that the design of birds' nests is far more sophisticated than previously realized and that nests are multifunctional structures that have important fitness consequences for the builder/s. PMID- 25505518 TI - Effective population size does not predict codon usage bias in mammals. AB - Synonymous codons are not used at equal frequency throughout the genome, a phenomenon termed codon usage bias (CUB). It is often assumed that interspecific variation in the intensity of CUB is related to species differences in effective population sizes (N e), with selection on CUB operating less efficiently in species with small N e. Here, we specifically ask whether variation in N e predicts differences in CUB in mammals and report two main findings. First, across 41 mammalian genomes, CUB was not correlated with two indirect proxies of N e (body mass and generation time), even though there was statistically significant evidence of selection shaping CUB across all species. Interestingly, autosomal genes showed higher codon usage bias compared to X-linked genes, and high-recombination genes showed higher codon usage bias compared to low recombination genes, suggesting intraspecific variation in N e predicts variation in CUB. Second, across six mammalian species with genetic estimates of N e (human, chimpanzee, rabbit, and three mouse species: Mus musculus, M. domesticus, and M. castaneus), N e and CUB were weakly and inconsistently correlated. At least in mammals, interspecific divergence in N e does not strongly predict variation in CUB. One hypothesis is that each species responds to a unique distribution of selection coefficients, confounding any straightforward link between N e and CUB. PMID- 25505522 TI - Integrating environmental, molecular, and morphological data to unravel an ice age radiation of arctic-alpine Campanula in western North America. AB - Many arctic-alpine plant genera have undergone speciation during the Quaternary. The bases for these radiations have been ascribed to geographic isolation, abiotic and biotic differences between populations, and/or hybridization and polyploidization. The Cordilleran Campanula L. (Campanulaceae Juss.), a monophyletic clade of mostly endemic arctic-alpine taxa from western North America, experienced a recent and rapid radiation. We set out to unravel the factors that likely influenced speciation in this group. To do so, we integrated environmental, genetic, and morphological datasets, tested biogeographic hypotheses, and analyzed the potential consequences of the various factors on the evolutionary history of the clade. We created paleodistribution models to identify potential Pleistocene refugia for the clade and estimated niche space for individual taxa using geographic and climatic data. Using 11 nuclear loci, we reconstructed a species tree and tested biogeographic hypotheses derived from the paleodistribution models. Finally, we tested 28 morphological characters, including floral, vegetative, and seed characteristics, for their capacity to differentiate taxa. Our results show that the combined effect of Quaternary climatic variation, isolation among differing environments in the mountains in western North America, and biotic factors influencing floral morphology contributed to speciation in this group during the mid-Pleistocene. Furthermore, our biogeographic analyses uncovered asynchronous consequences of interglacial and glacial periods for the timing of refugial isolation within the southern and northwestern mountains, respectively. These findings have broad implications for understanding the processes promoting speciation in arctic-alpine plants and the rise of numerous endemic taxa across the region. PMID- 25505523 TI - Diversity of honey stores and their impact on pathogenic bacteria of the honeybee, Apis mellifera. AB - Honeybee colonies offer an excellent environment for microbial pathogen development. The highest virulent, colony killing, bacterial agents are Paenibacillus larvae causing American foulbrood (AFB), and European foulbrood (EFB) associated bacteria. Besides the innate immune defense, honeybees evolved behavioral defenses to combat infections. Foraging of antimicrobial plant compounds plays a key role for this "social immunity" behavior. Secondary plant metabolites in floral nectar are known for their antimicrobial effects. Yet, these compounds are highly plant specific, and the effects on bee health will depend on the floral origin of the honey produced. As worker bees not only feed themselves, but also the larvae and other colony members, honey is a prime candidate acting as self-medication agent in honeybee colonies to prevent or decrease infections. Here, we test eight AFB and EFB bacterial strains and the growth inhibitory activity of three honey types. Using a high-throughput cell growth assay, we show that all honeys have high growth inhibitory activity and the two monofloral honeys appeared to be strain specific. The specificity of the monofloral honeys and the strong antimicrobial potential of the polyfloral honey suggest that the diversity of honeys in the honey stores of a colony may be highly adaptive for its "social immunity" against the highly diverse suite of pathogens encountered in nature. This ecological diversity may therefore operate similar to the well-known effects of host genetic variance in the arms race between host and parasite. PMID- 25505524 TI - Allometric scaling relationship between above- and below-ground biomass within and across five woody seedlings. AB - Allometric biomass allocation theory predicts that leaf biomass (M L ) scaled isometrically with stem (M S ) and root (M R ) biomass, and thus above-ground biomass (leaf and stem) (M A ) and root (M R ) scaled nearly isometrically with below-ground biomass (root) for tree seedlings across a wide diversity of taxa. Furthermore, prior studies also imply that scaling constant should vary with species. However, litter is known about whether such invariant isometric scaling exponents hold for intraspecific biomass allocation, and how variation in scaling constants influences the interspecific scaling relationship between above- and below-ground biomass. Biomass data of seedlings from five evergreen species were examined to test scaling relationships among biomass components across and within species. Model Type II regression was used to compare the numerical values of scaling exponents and constants among leaf, stem, root, and above- to below ground biomass. The results indicated that M L and M S scaled in an isometric or a nearly isometric manner with M R , as well as M A to M R for five woody species. Significant variation was observed in the Y-intercepts of the biomass scaling curves, resulting in the divergence for intraspecific scaling and interspecific scaling relationships for M L versus M S and M L versus M R , but not for M S versus M R and M A versus M R . We conclude, therefore, that a nearly isometric scaling relationship of M A versus M R holds true within each of the studied woody species and across them irrespective the negative scaling relationship between leaf and stem. PMID- 25505525 TI - Intraspecific competition reduces niche width in experimental populations. AB - Intraspecific competition is believed to drive niche expansion, because otherwise suboptimal resources can provide a refuge from competition for preferred resources. Competitive niche expansion is well supported by empirical observations, experiments, and theory, and is often invoked to explain phenotypic diversification within populations, some forms of speciation, and adaptive radiation. However, some foraging models predict the opposite outcome, and it therefore remains unclear whether competition will promote or inhibit niche expansion. We conducted experiments to test whether competition changes the fitness landscape to favor niche expansion, and if competition indeed drives niche expansion as expected. Using Tribolium castaneum flour beetles fed either wheat (their ancestral resource), corn (a novel resource) or mixtures of both resources, we show that fitness is maximized on a mixed diet. Next, we show that at higher population density, the optimal diet shifts toward greater use of corn, favoring niche expansion. In stark contrast, when beetles were given a choice of resources, we found that competition caused niche contraction onto the ancestral resource. This presents a puzzling mismatch between how competition alters the fitness landscape, versus competition's effects on resource use. We discuss several explanations for this mismatch, highlighting potential reasons why optimality models might be misleading. PMID- 25505526 TI - Sexual size dimorphism is not associated with the evolution of parental care in frogs. AB - Sex differences in parental care are thought to arise from differential selection on the sexes. Sexual dimorphism, including sexual size dimorphism (SSD), is often used as a proxy for sexual selection on males. Some studies have found an association between male-biased SSD (i.e., males larger than females) and the loss of paternal care. While the relationship between sexual selection on males and parental care evolution has been studied extensively, the relationship between female-biased SSD (i.e., females larger than males) and the evolution of parental care has received very little attention. Thus, we have little knowledge of whether female-biased SSD coevolves with parental care. In species displaying female-biased SSD, we might expect dimorphism to be associated with the evolution of paternal care or perhaps the loss of maternal care. Here, drawing on data for 99 extant frog species, we use comparative methods to evaluate how parental care and female-biased SSD have evolved over time. Generally, we find no significant correlation between the evolution of parental care and female-biased SSD in frogs. This suggests that differential selection on body size between the sexes is unlikely to have driven the evolution of parental care in these clades and questions whether we should expect sexual dimorphism to exhibit a general relationship with the evolution of sex differences in parental care. PMID- 25505527 TI - Sex-specific winter distribution in a sexually dimorphic shorebird is explained by resource partitioning. AB - Sexual size dimorphism (SSD) implies correlated differences in energetic requirements and feeding opportunities, such that sexes will face different trade offs in habitat selection. In seasonal migrants, this could result in a differential spatial distribution across the wintering range. To identify the ecological causes of sexual spatial segregation, we studied a sexually dimorphic shorebird, the bar-tailed godwit Limosa lapponica, in which females have a larger body and a longer bill than males. With respect to the trade-offs that these migratory shorebirds experience in their choice of wintering area, northern and colder wintering sites have the benefit of being closer to the Arctic breeding grounds. According to Bergmann's rule, the larger females should incur lower energetic costs per unit of body mass over males, helping them to winter in the cold. However, as the sexes have rather different bill lengths, differences in sex-specific wintering sites could also be due to the vertical distribution of their buried prey, that is, resource partitioning. Here, in a comparison between six main intertidal wintering areas across the entire winter range of the lapponica subspecies in northwest Europe, we show that the percentage of females between sites was not correlated with the cost of wintering, but was positively correlated with the biomass in the bottom layer and negatively with the biomass in the top layer. We conclude that resource partitioning, rather than relative expenditure advantages, best explains the differential spatial distribution of male and female bar-tailed godwits across northwest Europe. PMID- 25505528 TI - Determinants of bird species richness, endemism, and island network roles in Wallacea and the West Indies: is geography sufficient or does current and historical climate matter? AB - Island biogeography has greatly contributed to our understanding of the processes determining species' distributions. Previous research has focused on the effects of island geography (i.e., island area, elevation, and isolation) and current climate as drivers of island species richness and endemism. Here, we evaluate the potential additional effects of historical climate on breeding land bird richness and endemism in Wallacea and the West Indies. Furthermore, on the basis of species distributions, we identify island biogeographical network roles and examine their association with geography, current and historical climate, and bird richness/endemism. We found that island geography, especially island area but also isolation and elevation, largely explained the variation in island species richness and endemism. Current and historical climate only added marginally to our understanding of the distribution of species on islands, and this was idiosyncratic to each archipelago. In the West Indies, endemic richness was slightly reduced on islands with historically unstable climates; weak support for the opposite was found in Wallacea. In both archipelagos, large islands with many endemics and situated far from other large islands had high importance for the linkage within modules, indicating that these islands potentially act as speciation pumps and source islands for surrounding smaller islands within the module and, thus, define the biogeographical modules. Large islands situated far from the mainland and/or with a high number of nonendemics acted as links between modules. Additionally, in Wallacea, but not in the West Indies, climatically unstable islands tended to interlink biogeographical modules. The weak and idiosyncratic effect of historical climate on island richness, endemism, and network roles indicates that historical climate had little effects on extinction immigration dynamics. This is in contrast to the strong effect of historical climate observed on the mainland, possibly because surrounding oceans buffer against strong climate oscillations and because geography is a strong determinant of island richness, endemism and network roles. PMID- 25505531 TI - Responses to drought stress among sex morphs of Oxyria sinensis (Polygonaceae), a subdioecious perennial herb native to the East Himalayas. AB - It is generally accepted that dioecious plants occur more frequently in dry and nutrient-poor habitats, suggesting that abiotic stress factors could contribute to evolution of dioecy from hermaphrodite. Therefore, experimental investigations on the responses of subdioecious species, a special sexual system comprising male, female, and hermaphrodite plants, to abiotic stress factors could quantify the contribution of selective pressure on the evolution of dioecy. In this study, we evaluated the physiological responses of different sex morphs of Oxyria sinensis Hemsley, a perennial herb native to the East Himalayas, to drought stress. Male, female, and hermaphrodite plants of O. sinensis were subjected to low, moderate, and high drought stress conditions in a glasshouse. Generally, with increasing water stress, the values of most measured variables slightly decreased, whereas water-use efficiency slightly increased. Furthermore, there were no significant differences in most of the measured parameters among the sex morphs under each drought stress treatment, indicating that O. sinensis might be well-adapted to drought stress conditions as its typical habitat is the dry and hot habitats of xerothermic river valleys. However, nitrogen-use efficiency was significantly higher in male and female plants than in hermaphrodite plants under high drought stress conditions, suggesting that that nitrogen-use efficiency under conditions of drought stress might have contributed to the evolution of dioecy from the hermaphrodite to some degree. PMID- 25505530 TI - The application of eDNA for monitoring of the Great Crested Newt in the UK. AB - Current ecological surveys for great crested newts are time-consuming and expensive and can only be carried out within a short survey window. Additional survey methods which would facilitate the detection of rare or protected species such as the great crested newt (Triturus cristatus) would be extremely advantageous. Environmental DNA (eDNA) analysis has been utilized for the detection of great crested newts in Denmark. Here, the same methodology has been applied to water samples taken from UK ponds concurrently with conventional field surveying techniques. Our eDNA analysis exhibited an 84% success rate with a kappa coefficient of agreement between field and eDNA surveys of 0.86. One pond determined to be negative for great crested newt by field survey was positive by eDNA analysis, revealing the potential for improved detection rates using this methodology. Analysis of water samples collected in late summer indicates that eDNA analysis could be used to detect great crested newt after the optimal survey window for current field techniques had passed. Consequently, eDNA analysis could augment currently stipulated techniques for great crested newt surveying as a relatively quick and inexpensive tool for collecting great crested newt presence and distribution data within the UK instead of or prior to full field surveys. PMID- 25505532 TI - Community assembly rules affect the diversity of expanding communities. AB - Despite centuries of interest in species range limits, few studies have taken a whole community into consideration. Actually, multiple species may simultaneously respond to environmental changes, for example, global warming, leading a series of dynamical communities toward the advancing front. We investigated multiple species range expansions through the analysis of a two-species dispersion model and simulations of multiple species assemblages regulated by neutral and fecundity-survival trade-offs (FSTs), respectively, and found that species assemblages regulated by different mechanisms would initiate different expanding patterns in geographic ranges in response to environmental changes. The neutral model generally predicts a higher biodiversity near the core of an expanding range, and a lower community similarity compared with a FST model. Without considering the evolution of life history traits, an assortment of the reproduction ability happens at the advancing front under FSTs at the expense of a higher death rate or lower competitive ability. These results emphasize the importance of community assembly rules to the biodiversity maintenance of range expanding communities. PMID- 25505533 TI - Host-specific thermal profiles affect fitness of a widespread pathogen. AB - Host behavior can interact with environmental context to influence outcomes of pathogen exposure and the impact of disease on species and populations. Determining whether the thermal behaviors of individual species influence susceptibility to disease can help enhance our ability to explain and predict how and when disease outbreaks are likely to occur. The widespread disease chytridiomycosis (caused by the fungal pathogen Batrachochytrium dendrobatidis, Bd) often has species-specific impacts on amphibian communities; some host species are asymptomatic, whereas others experience mass mortalities and population extirpation. We determined whether the average natural thermal regimes experienced by sympatric frog species in nature, in and of themselves, can account for differences in vulnerability to disease. We did this by growing Bd under temperatures mimicking those experienced by frogs in the wild. At low and high elevations, the rainforest frogs Litoria nannotis, L. rheocola, and L. serrata maintained mean thermal regimes within the optimal range for pathogen growth (15-25 degrees C). Thermal regimes for L. serrata, which has recovered from Bd-related declines, resulted in slower pathogen growth than the cooler and less variable thermal regimes for the other two species, which have experienced more long-lasting declines. For L. rheocola and L. serrata, pathogen growth was faster in thermal regimes corresponding to high elevations than in those corresponding to low elevations, where temperatures were warmer. For L. nannotis, which prefers moist and thermally stable microenvironments, pathogen growth was fastest for low-elevation thermal regimes. All of the thermal regimes we tested resulted in pathogen growth rates equivalent to, or significantly faster than, rates expected from constant-temperature experiments. The effects of host body temperature on Bd can explain many of the broad ecological patterns of population declines in our focal species, via direct effects on pathogen fitness. Understanding the functional response of pathogens to conditions experienced by the host is important for determining the ecological drivers of disease outbreaks. PMID- 25505534 TI - Plant-derived differences in the composition of aphid honeydew and their effects on colonies of aphid-tending ants. AB - In plant-ant-hemipteran interactions, ants visit plants to consume the honeydew produced by phloem-feeding hemipterans. If genetically based differences in plant phloem chemistry change the chemical composition of hemipteran honeydew, then the plant's genetic constitution could have indirect effects on ants via the hemipterans. If such effects change ant behavior, they could feed back to affect the plant itself. We compared the chemical composition of honeydews produced by Aphis nerii aphid clones on two milkweed congeners, Asclepias curassavica and Asclepias incarnata, and we measured the responses of experimental Linepithema humile ant colonies to these honeydews. The compositions of secondary metabolites, sugars, and amino acids differed significantly in the honeydews from the two plant species. Ant colonies feeding on honeydew derived from A. incarnata recruited in higher numbers to artificial diet, maintained higher queen and worker dry weight, and sustained marginally more workers than ants feeding on honeydew derived from A. curassavica. Ants feeding on honeydew from A. incarnata were also more exploratory in behavioral assays than ants feeding from A. curassavica. Despite performing better when feeding on the A. incarnata honeydew, ant workers marginally preferred honeydew from A. curassavica to honeydew from A. incarnata when given a choice. Our results demonstrate that plant congeners can exert strong indirect effects on ant colonies by means of plant-species-specific differences in aphid honeydew chemistry. Moreover, these effects changed ant behavior and thus could feed back to affect plant performance in the field. PMID- 25505535 TI - Variability in sperm form and function in the context of sperm competition risk in two Tupinambis lizards. AB - In polyandrous species, sperm morphometry and sperm velocity are under strong sexual selection. Although several hypotheses have been proposed to explain the role of sperm competition in sperm trait variation, this aspect is still poorly understood. It has been suggested that an increase in sperm competition pressure could reduce sperm size variation or produce a diversity of sperm to maximize male fertilization success. We aim at elucidating the variability of sperm morphometric traits and velocity in two Tupinambis lizards in the context of sperm competition risk. Sperm traits showed substantial variation at all levels examined: between species, among males within species, and within the ejaculate of individual males. Sperm velocity was found to be positively correlated with flagellum: midpiece ratio, with relatively longer flagella associated with faster sperm. Our results document high variability in sperm form and function in lizards. PMID- 25505536 TI - Extensive variation in chromosome number and genome size in sexual and parthenogenetic species of the jumping-bristletail genus Machilis (Archaeognatha). AB - Parthenogenesis in animals is often associated with polyploidy and restriction to extreme habitats or recently deglaciated areas. It has been hypothesized that benefits conferred by asexual reproduction and polyploidy are essential for colonizing these habitats. However, while evolutionary routes to parthenogenesis are manifold, study systems including polyploids are scarce in arthropods. The jumping-bristletail genus Machilis (Insecta: Archaeognatha) includes both sexual and parthenogenetic species, and recently, the occurrence of polyploidy has been postulated. Here, we applied flow cytometry, karyotyping, and mitochondrial DNA sequencing to three sexual and five putatively parthenogenetic Eastern-Alpine Machilis species to investigate whether (1) parthenogenesis originated once or multiply and (2) whether parthenogenesis is strictly associated with polyploidy. The mitochondrial phylogeny revealed that parthenogenesis evolved at least five times independently among Eastern-Alpine representatives of this genus. One parthenogenetic species was exclusively triploid, while a second consisted of both diploid and triploid populations. The three other parthenogenetic species and all sexual species were diploid. Our results thus indicate that polyploidy can co-occur with parthenogenesis, but that it was not mandatory for the emergence of parthenogenesis in Machilis. Overall, we found a weak negative correlation of monoploid genome size (Cx) and chromosome base number (x), and this connection is stronger among parthenogenetic species alone. Likewise, monoploid genome size decreased with elevation, and we therefore hypothesize that genome downsizing could have been crucial for the persistence of alpine Machilis species. Finally, we discuss the evolutionary consequences of intraspecific chromosomal rearrangements and the presence of B chromosomes. In doing so, we highlight the potential of Alpine Machilis species for research on chromosomal and genome-size alterations during speciation. PMID- 25505537 TI - A metagenomics-based approach to the top-down effect on the detritivore food web: a salamanders influence on fungal communities within a deciduous forest. AB - The flow of energy within an ecosystem can be considered either top-down, where predators influence consumers, or bottom-up, where producers influence consumers. Plethodon cinereus (Red-backed Salamander) is a terrestrial keystone predator who feeds on invertebrates within the ecosystem. We investigated the impact of the removal of P. cinereus on the detritivore food web in an upland deciduous forest in northwest Ohio, U.S.A. A total of eight aluminum enclosures, each containing a single P. cinereus under a small log, were constructed in the deciduous forest. On Day 1 of the experiment, four salamanders were evicted from four of the eight enclosures. Organic matter and soil were collected from the center of each enclosure at Day 1 and Day 21. From each sample, DNA was extracted, fungal specific amplification performed, and 454 pyrosequencing was used to sequence the nuclear ribosomal internal transcribed spacer (ITS2) region and partial ribosomal large subunit (LSU). Changes in overall fungal community composition or species diversity were not statistically significant between treatments. Statistically significant shifts in the most abundant taxonomic groups of fungi were documented in presence but not absence enclosures. We concluded that P. cinereus does not affect the overall composition or diversity of fungal communities, but does have an impact on specific groups of fungi. This study used a metagenomics-based approach to investigate a missing link among a keystone predator, P. cinereus, invertebrates, and fungal communities, all of which are critical in the detritivore food web. PMID- 25505538 TI - Estimates of direct and indirect effects for early juvenile survival in captive populations maintained for conservation purposes: the case of Cuvier's gazelle. AB - Together with the avoidance of any negative impact of inbreeding, preservation of genetic variability for life-history traits that could undergo future selective pressure is a major issue in endangered species management programmes. However, most of these programmes ignore that, apart from the direct action of genes on such traits, parents, as contributors of offspring environment, can influence offspring performance through indirect parental effects (when parental genotype and phenotype exerts environmental influences on offspring phenotype independently of additive genetic effects). Using quantitative genetic models, we estimated the additive genetic variance for juvenile survival in a population of the endangered Cuvier's gazelle kept in captivity since 1975. The dataset analyzed included performance recording for 700 calves and a total pedigree of 740 individuals. Results indicated that in this population juvenile survival harbors significant additive genetic variance. The estimates of heritability obtained were in general moderate (0.115-0.457) and not affected by the inclusion of inbreeding in the models. Maternal genetic contribution to juvenile survival seems to be of major importance in this gazelle's population as well. Indirect genetic and indirect environmental effects assigned to mothers (i.e., maternal genetic and maternal permanent environmental effects) roughly explain a quarter of the total variance estimated for the trait analyzed. These findings have major evolutionary consequences for the species as show that offspring phenotypes can evolve strictly through changes in the environment provided by mothers. They are also relevant for the captive breeding programme of the species. To take into account, the contribution that mothers have on offspring phenotype through indirect genetic effects when designing pairing strategies might serve to identify those females with better ability to recruit, and, additionally, to predict reliable responses to selection in the captive population. PMID- 25505540 TI - Variable detours in long-distance migration across ecological barriers and their relation to habitat availability at ground. AB - Migration detours, the spatial deviation from the shortest route, are a widespread phenomenon in migratory species, especially if barriers must be crossed. Moving longer distances causes additional efforts in energy and time, and to be adaptive, this should be counterbalanced by favorable condition en route. We compared migration patterns of nightingales that travelled along different flyways from their European breeding sites to the African nonbreeding sites. We tested for deviations from shortest routes and related the observed and expected routes to the habitat availability at ground during autumn and spring migration. All individuals flew detours of varying extent. Detours were largest and seasonally consistent in western flyway birds, whereas birds on the central and eastern flyways showed less detours during autumn migration, but large detours during spring migration (eastern flyway birds). Neither migration durations nor the time of arrival at destination were related to the lengths of detours. Arrival at the breeding site was nearly synchronous in birds flying different detours. Flying detours increased the potential availability of suitable broad-scale habitats en route only along the western flyway. Habitat availability on observed routes remained similar or even decreased for individuals flying detours on the central or the eastern flyway as compared to shortest routes. Thus, broad-scale habitat distribution may partially explain detour performance, but the weak detour-habitat association along central and eastern flyways suggests that other factors shape detour extent regionally. Prime candidate factors are the distribution of small suitable habitat patches at local scale as well as winds specific for the region and altitude. PMID- 25505539 TI - Genetic connectivity among swarming sites in the wide ranging and recently declining little brown bat (Myotis lucifugus). AB - Characterizing movement dynamics and spatial aspects of gene flow within a species permits inference on population structuring. As patterns of structuring are products of historical and current demographics and gene flow, assessment of structure through time can yield an understanding of evolutionary dynamics acting on populations that are necessary to inform management. Recent dramatic population declines in hibernating bats in eastern North America from white-nose syndrome have prompted the need for information on movement dynamics for multiple bat species. We characterized population genetic structure of the little brown bat, Myotis lucifugus, at swarming sites in southeastern Canada using 9 nuclear microsatellites and a 292-bp region of the mitochondrial genome. Analyses of F ST, PhiST, and Bayesian clustering (STRUCTURE) found weak levels of genetic structure among swarming sites for the nuclear and mitochondrial genome (Global F ST = 0.001, P < 0.05, Global PhiST = 0.045, P < 0.01, STRUCTURE K = 1) suggesting high contemporary gene flow. Hierarchical AMOVA also suggests little structuring at a regional (provincial) level. Metrics of nuclear genetic structure were not found to differ between males and females suggesting weak asymmetries in gene flow between the sexes. However, a greater degree of mitochondrial structuring does support male-biased dispersal long term. Demographic analyses were consistent with past population growth and suggest a population expansion occurred from approximately 1250 to 12,500 BP, following Pleistocene deglaciation in the region. Our study suggests high gene flow and thus a high degree of connectivity among bats that visit swarming sites whereby mainland areas of the region may be best considered as one large gene pool for management and conservation. PMID- 25505541 TI - Expression of major photosynthetic and salt-resistance genes in invasive reed lineages grown under elevated CO2 and temperature. AB - It is important to investigate the molecular causes of the variation in ecologically important traits to fully understand phenotypic responses to climate change. In the Mississippi River Delta, two distinct, sympatric invasive lineages of common reed (Phragmites australis) are known to differ in several ecophysiological characteristics and are expected to become more salt resistant due to increasing atmospheric CO2 and temperature. We investigated whether different patterns of gene expression can explain their ecophysiological differences and increased vigor under future climatic conditions. We compared the transcript abundance of photosynthetic genes of the Calvin cycle (Rubisco small subunit, RbcS; Phosphoglycerate kinase, PGK; Phosphoribulokinase, PRK), genes related with salt transport (Na(+)/H(+) antiporter, PhaNHA) and oxidative stress response genes (Manganese Superoxide dismutase, MnSOD; Glutathione peroxidase, GPX), and the total aboveground biomass production between two genotypes representing the two lineages. The two genotypes (Delta-type, Mediterranean lineage, and EU-type, Eurasian lineage) were grown under an ambient and a future climate scenario with simultaneously elevated CO2 and temperature, and under two different soil salinities (00/00 or 200/00). We found neither differences in the aboveground biomass production nor the transcript abundances of the two genotypes, but soil salinity significantly affected all the investigated parameters, often interacting with the climatic conditions. At 200/00 salinity, most genes were higher expressed in the future than in the ambient climatic conditions. Higher transcription of the genes suggests higher abundance of the protein they code for, and consequently increased photosynthate production, improved stress responses, and salt exclusion. Therefore, the higher expression of these genes most likely contributed to the significantly ameliorated salinity impact on the aboveground biomass production of both P. australis genotypes under elevated temperature and CO2. Although transcript abundances did not explain differences between the lineages, they correlated with the increased vigor of both lineages under anticipated future climatic conditions. PMID- 25505542 TI - Effects of ice and floods on vegetation in streams in cold regions: implications for climate change. AB - Riparian zones support some of the most dynamic and species-rich plant communities in cold regions. A common conception among plant ecologists is that flooding during the season when plants are dormant generally has little effect on the survival and production of riparian vegetation. We show that winter floods may also be of fundamental importance for the composition of riverine vegetation. We investigated the effects of ice formation on riparian and in-stream vegetation in northern Sweden using a combination of experiments and observations in 25 reaches, spanning a gradient from ice-free to ice-rich reaches. The ice-rich reaches were characterized by high production of frazil and anchor ice. In a couple of experiments, we exposed riparian vegetation to experimentally induced winter flooding, which reduced the dominant dwarf-shrub cover and led to colonization of a species-rich forb-dominated vegetation. In another experiment, natural winter floods caused by anchor-ice formation removed plant mimics both in the in-stream and in the riparian zone, further supporting the result that anchor ice maintains dynamic plant communities. With a warmer winter climate, ice induced winter floods may first increase in frequency because of more frequent shifts between freezing and thawing during winter, but further warming and shortening of the winter might make them less common than today. If ice-induced winter floods become reduced in number because of a warming climate, an important disturbance agent for riparian and in-stream vegetation will be removed, leading to reduced species richness in streams and rivers in cold regions. Given that such regions are expected to have more plant species in the future because of immigration from the south, the distribution of species richness among habitats can be expected to show novel patterns. PMID- 25505543 TI - A grass-fire cycle eliminates an obligate-seeding tree in a tropical savanna. AB - A grass-fire cycle in Australian tropical savannas has been postulated as driving the regional decline of the obligate-seeding conifer Callitris intratropica and other fire-sensitive components of the regional flora and fauna, due to proliferation of flammable native grasses. We tested the hypothesis that a high biomass invasive savanna grass drives a positive feedback process where intense fires destroy fire-sensitive trees, and the reduction in canopy cover facilitates further invasion by grass. We undertook an observational and experimental study using, as a model system, a plantation of C. intratropica that has been invaded by an African grass, gamba (Andropogon gayanus) in the Northern Territory, Australia. We found that high grass biomass was associated with reduced canopy cover and restriction of foliage to the upper canopy of surviving stems, and mortality of adult trees was very high (>50%) even in areas with low fuel loads (1 t.ha(-1)). Experimental fires, with fuel loads >10 t.ha(-1), typical of the grass-invasion front, caused significant mortality due to complete crown scorch. Lower fuel loads cause reduced canopy cover through defoliation of the lower canopy. These results help explain how increases in grass biomass are coupled with the decline of C. intratropica throughout northern Australia by causing a switch from litter and sparse perennial grass fuels, and hence low-intensity surface fires, to heavy annual grass fuel loads that sustain fires that burn into the midstorey. This study demonstrates that changes in fuel type can alter fire regimes with substantial knock-on effects on the biota. PMID- 25505544 TI - Honeybee nutrition is linked to landscape composition. AB - Declines in insect pollinators in Europe have been linked to changes in land use. Pollinator nutrition is dependent on floral resources (i.e., nectar and pollen), which are linked to landscape composition. Here, we present a stratified analysis of the nutritional composition of beebread in managed honeybee hives with a view to examining potential sources of variation in its nutritional composition. Specifically, we tested the hypothesis that beebread composition correlates with local land use and therefore available floral resources. The results demonstrated that the starch, lipid, and moisture contents of beebread are all highly conserved across hives, whereas levels of protein and nonreducing sugar increased as the year progressed, reducing sugars, however, decreased during the first half of the year and then increased toward the end. Local land use around hives was quantified using data from the Countryside Survey 2007 Land Cover Map. Bee-bread protein content was negatively correlated with increasing levels of arable and horticultural farmland surrounding hives and positively correlated with the cover of natural grasslands and broadleaf woodlands. Reducing sugar content was also positively correlated with the amount of broad-leaved woodland in a 3 Km2 radius from the hives. Previous studies on a range of invertebrates, including honeybees, indicate that dietary protein intake may have a major impact on correlates of fitness, including longevity and immune function. The finding that beebread protein content correlates with land use suggests that landscape composition may impact on insect pollinator well-being and provides a link between landscape and the nutritional ecology of socially foraging insects in a way not previously considered. PMID- 25505546 TI - Effect of left atrial and ventricular abnormalities on renal transplant recipient outcome-a single-center study. AB - BACKGROUND: Premature cardiovascular (CV) death is the commonest cause of death in renal transplant recipients. Abnormalities of left ventricular (LV) structure (collectively termed uremic cardiomyopathy) and left atrial (LA) dilation, a marker of fluid status and diastolic function, are risk factors for reduced survival in patients with end stage renal disease (ESRD). In the present analysis, we studied the impact of pre-transplant LA and LV abnormalities on survival after successful renal transplantation (RT). METHODS: One hundred nineteen renal transplant recipients (first transplant, deceased donors) underwent cardiovascular MRI (CMR) as part of CV screening prior to inclusion on the waiting list. Data regarding transplant function and patient survival after transplantation were collected. RESULTS: Median post-transplant follow-up was 4.3 years (interquartile range (IQR) 1.9, 6.2). During the post-transplant period, 13 patients returned to dialysis after graft failure and 23 patients died with a functioning graft. Survival analyses, censoring for patients returning to dialysis, showed that pre-transplant LV hypertrophy and elevated LA volume were significantly associated with reduced survival after transplantation. Multivariate Cox regression analyses demonstrated that longer waiting time, poorer transplant function, presence of LV hypertrophy and higher LA volume on screening CMR and female sex were independent predictors of death in patients with a functioning transplant. CONCLUSIONS: Presence of LVH and higher LA volume are significant, independent predictors of death in patients who are wait-listed and proceed with renal transplantation. PMID- 25505547 TI - B-cell subpopulations in children: National reference values. AB - Peripheral B-lymphocytes undergo a series of changes during the first few years of life. Encounters with foreign antigens lead to maturation and differentiation. Several primary antibody deficiencies (PADs) affecting B-cell development are associated with abnormalities in the composition and/or differentiation of B-cell compartments. The most recent international classifications of primary immunodeficiencies (PIDs) and common variable immunodeficiencies (CVID) have highlighted the importance of B-cell immunophenotyping and age-specific reference intervals for diagnostic purposes. We established national reference values for memory B-cell subpopulations, on the basis of CD27 and surface IgD expression in the peripheral blood of 242 healthy children. We report here the absolute counts and percentages of naive, switched and non-switched memory B-cells for seven age groups, from neonates to adults. We found that the naive B-cells percentage declined between the ages of 6 months and 8 years, after which it remained stable at about 70-80%. Memory B-cells are already present at birth and their numbers increase throughout childhood, stabilizing between the ages of 12 and 18 years. The definition of reference intervals for pediatric B-cell levels should facilitate the screening and diagnosis of various B-cell immunodeficiencies. This multicenter study, providing national reference values, should thus facilitate immunological diagnosis in children. PMID- 25505548 TI - Early life environmental predictors of asthma age-of-onset. AB - Prevention strategies that delay the onset of asthma may improve clinical outcomes. To identify early life environmental exposures associated with asthma age-of-onset and potential genetic modifiers of these exposures, we studied 1085 subjects with physician-diagnosed asthma and disease onset at or after age two. Subjects reported retrospectively on their exposure to 17 environmental factors before the age of two. The presence of individual or combinations of these early life exposures was then tested for association with variation in asthma age-of onset. For exposures significantly associated with age-of-onset, we tested if 26 single nucleotide polymorphisms (SNP) with an established association with allergic disease significantly modified the effect of the exposure. Five environmental exposures were significantly associated with variation in asthma age-of-onset after correction for multiple testing: carpet at home (P = 6 * 10( 5)), a serious chest illness (P = 10(-4)), father a cigarette smoker (P = 6 * 10( 4)) and direct exposure to father's smoking (P = 3 * 10(-4)). Individuals with early childhood asthma onset, between the ages of two and six, were 1.4-fold (CI 1.1-1.9) more likely to report having lived in a house with carpet and 2.1-fold (CI 1.3-3.5) more likely to report suffering a serious chest illness before the age of two, than asthmatics with later disease onset. We further found these individual risks to increase to 3.2-fold (CI 1.7-6.0) if carpet exposure and suffering a serious chest illness co-occurred before age two. Paternal smoking exposures were less likely to be reported by asthmatics with early when compared to later disease onset (OR 0.5, CI 0.3-0.7). There were no significant SNP interactions with these environmental exposures after correction for multiple testing. Our results suggest that disease onset in individuals at a high-risk of developing asthma can potentially be delayed by avoiding exposure to carpet at home and preventing serious chest illnesses during the first 2 years of life. PMID- 25505549 TI - VEGF-C improves regeneration and lymphatic reconnection of transplanted autologous lymph node fragments: An animal model for secondary lymphedema treatment. AB - Secondary lymphedema occurs after for example breast cancer surgery and radiation in 20-50% of the patients. Due to the poor outcomes of surgical treatments in the past, the therapy often remains symptomatic. However, avascular transplantation of autologous lymph node fragments (LN-Tx) combined with postoperative injections of vascular endothelial growth factor-C (VEGF-C) emerges as a potential surgical therapy. In this study, adult rats underwent LN-Tx to investigate the following parameters of VEGF-C application: time point, location and dosage. Furthermore, the influences of VEGF-C on lymphatic reconnection and transplant regeneration were analyzed. The reconnection was investigated using intradermally injected blue dye and the regeneration was evaluated histologically using hematoxylin eosin (H&E) staining and immunohistochemistry. The higher dosage enhanced the reconnection rates significantly and showed a statistical tendency of improving regeneration. An application on early postoperative days and the injection into the medial thigh improved the reconnection significantly. However, these variables did not affect the regeneration statistically. This study confirms that LN-Tx combined with lymphatic growth factor VEGF-C is a possible approach in the therapy of secondary lymphedema and shows the important role of VEGF-C application parameters. PMID- 25505550 TI - Advantages of Foxp3(+) regulatory T cell depletion using DEREG mice. AB - Several mechanisms enable immunological self-tolerance. Regulatory T cells (Tregs) are a specialized T cell subset that prevents autoimmunity and excessive immune responses, but can also mediate detrimental tolerance to tumors and pathogens in a Foxp3-dependent manner. Genetic tools exploiting the foxp3 locus including bacterial artificial chromosome (BAC)-transgenic DEREG mice have provided essential information on Treg biology and the potential therapeutic modulation of tolerance. In DEREG mice, Foxp3(+) Tregs selectively express eGFP and diphtheria toxin (DT) receptor, allowing for the specific depletion of Tregs through DT administration. We here provide a detailed overview about important considerations such as DT toxicity, which affects any mouse strain treated with DT, and Treg rebound after depletion. Additionally, we point out the specific advantages of BAC-transgenic DEREG mice including their suitability to study organ-specific autoimmunity such as type I diabetes. Moreover, we discuss recent insights into the role of Tregs in viral infections. In summary, DEREG mice are an important tool to study Treg-mediated tolerance and its therapeutic circumvention. PMID- 25505551 TI - Immunomodulation of human intestinal T cells by the synthetic CD80 antagonist RhuDex(r). AB - Deregulated activation of mucosal lamina propria T cells plays a central role in the pathogenesis of intestinal inflammation. One of the means to attenuate T cell activation is by blocking the CD28/CD80 co-stimulatory pathway. Here we investigate RhuDex(r), a small molecule that binds to human CD80, for its effects on the activation of lamina propria T cells employing a gut-culture model of inflammation. To this end, lamina propria leukocytes (LPL) and peripheral blood lymphocytes (PBL) were stimulated either through the CD3/T-cell-receptor complex or the CD2-receptor (CD2) employing agonistic monoclonal antibodies. Co stimulatory signals were provided by CD80/CD86 present on lamina propria myeloid cells or LPS-activated peripheral blood monocytes. Results show that RhuDex(r) caused a profound reduction of LPL and PBL proliferation, while Abatacept (CTLA-4 Ig) inhibited LPL proliferation to a small degree, and had no effect on PBL proliferation. Furthermore, Abatacept significantly inhibited IL-2, TNF-alpha, and IFN-gamma release from LPL, primarily produced by CD4(+) T cells, where IL-2 blockage was surprisingly strong, suggesting a down-regulating effect on regulatory T cells. In contrast, in the presence of RhuDex(r), secretion of IL 17, again mostly by CD4(+) T cells, and IFN-gamma was inhibited in LPL and PBL, yet IL-2 remained unaffected. Thus, RhuDex(r) efficiently inhibited lamina propria and peripheral blood T-cell activation in this pre-clinical study making it a promising drug candidate for the treatment of intestinal inflammation. PMID- 25505552 TI - MHC-Ig induces memory T cell formation in vivo and inhibits tumour growth. AB - Induction of a T cell mediated immune response is critical for the eradication of viral infections and tumours. Soluble peptide-loaded major histocompatibility complex-Ig ((pep-)MHC-Ig) have been shown to bind their cognate ligands, T cell receptor, with high affinity, and are successfully used to visualize antigen specific T cells. Furthermore, immobilized (pep-)MHC-Ig can activate and expand antigen-specific T cells in vitro and in vivo. In this study, we investigate the use of (pep-)MHC-Ig as a potential strategy to modulate antigen specific T cell immune responses in vivo. (SIY-)K(b)-Ig immunization, together with the pre activation by an anti-CD40 monoclonal antibody, is able to stimulate a strong expansion of adoptively transferred 2C transgenic T cells and the formation of long term antigen-specific memory T cells. In addition, mechanistic studies show that the (pep-)MHC-Ig molecules directly activate T cells in vivo without requiring uptake and reprocessing by antigen-presenting cells. Furthermore, B6 mice immunized with (pep-)MHC-Ig molecules inhibit tumour growth in a B16-SIY melanoma prevention model. Thus, soluble (pep-)MHC-Ig molecules represent a powerful tool for active immunotherapy. PMID- 25505555 TI - alpha1D-Adrenoceptors are responsible for the high sensitivity and the slow time course of noradrenaline-mediated contraction in conductance arteries. AB - The objective of this study was to determine whether the different time-course characteristics of alpha1-adrenoceptor-mediated contraction in arteries can be related to the subtypes involved. Contractile responses to noradrenaline (NA) were compared with inositol phosphate accumulation and extracellular signal regulated kinase (ERK)1/2 phosphorylation after alpha1-agonist stimuli in the same vessels in the presence or absence of alpha1-antagonists in rat or in alpha1 subtype knockout (KO) mice. Aorta, where alpha1D-AR is the main functional subtype, had higher sensitivity to NA (in respect of inositol phosphate [IP], pERK1/2, and contractile response) than tail artery, where the alpha1A adrenoceptor subtype is predominant. Furthermore, the contraction in aorta exhibited a slower decay after agonist removal and this was consistent in all strains harboring alpha1D-adrenoceptors (from rat, alpha1B-KO, and wild-type [WT] mice) but was not observed in the absence of the alpha1D-adrenoceptor signal (alpha1D-adrenoceptor blocked rat aorta or aorta from alpha1D-KO). IP formation paralleled alpha1-adrenoceptor-mediated contraction (agonist present or postagonist) in aorta and tail artery. High sensitivity to agonist and persistence of response after agonist removal is a property of alpha1D adrenoceptors. Therefore, the preponderance of this subtype in noninnervated conductance arteries such as aorta allows responsiveness to circulating catecholamines and prevents abrupt changes in vessel caliber when the stimulus fluctuates. Conversely, in innervated distributing arteries, high local concentrations of NA are required to activate alpha1A-adrenoceptors for a response that is rapid but short lived allowing fine adjustment of the contractile tone by perivascular sympathetic nerves. PMID- 25505553 TI - Genetic determinants in the development of sensitization to environmental allergens in early childhood. AB - Sensitization to environmental allergens remains one of the strongest risk factors for asthma, and there is likely a genetic basis. We sought to identify genetic determinants for the development of allergic sensitization to environmental allergens, particularly cockroach allergen, in early childhood. A total of 631 children with the information about genotypic data on 895 single nucleotide polymorphisms (SNPs) in 179 candidate genes were selected from an existing dataset (Boston Birth Cohort). Genetic analysis was performed for allergic sensitizations among all subjects and sub-population, Black/African, respectively. Eight SNPs in seven genes showed significant association with allergic sensitization with P < 0.05, including two top SNPs, rs7851969 in JAK2 (P = 0.003) and rs11739089 in CNOT6 (P = 0.008). When analyses were specifically performed for cockroach sensitization, 16 SNPs in 13 genes showed P < 0.05, including five genes with SNPs at P < 0.01 (JAK1, JAK3, IL5RA, FCER1A, and ADAM33). Particularly, haplotype analyses demonstrated that multiple-haplotypes in FCER1A were significantly associated with cockroach sensitization with the strongest association for a 2-marker haplotype (rs6665683T-rs12136904T, P = 0.001). Furthermore, SNP rs6665683 was marginally associated with the levels of cockroach allergen specific IgE. When a similar analysis was performed for house dust mite, four SNPs in three genes (JAK2, MAML1, and NOD1) had P < 0.01. Of these, JAK2 appeared to be an only gene showing association across the sensitizations we analyzed. Some of findings were further validated when analysis was limited to black population. Our study identified several loci that may confer the susceptibility to allergic sensitization, and suggested that sensitization to allergens may depend on their unique loci. PMID- 25505556 TI - Glucuronidation of drugs in humanized UDP-glucuronosyltransferase 1 mice: Similarity with glucuronidation in human liver microsomes. AB - Uridine 5'-diphosphate-glucuronosyltransferases (UGTs) are phase II drug metabolizing enzymes that catalyze glucuronidation of various endogenous and exogenous substrates. Among 19 functional human UGTs, UGT1A family enzymes largely contribute to the metabolism of clinically used drugs. While the UGT1A locus is conserved in mammals such as humans, mice, and rats, species differences in drug glucuronidation have been reported. Recently, humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) have been developed. To evaluate the usefulness of hUGT1 mice to predict human glucuronidation of drugs, UGT activities, and inhibitory effects on UGTs were examined in liver microsomes of hUGT1 mice as well as in those of wild-type mice and humans. Furosemide acyl-glucuronidation was sigmoidal and best fitted to the Hill equation in hUGT1 mice and human liver microsomes, while it was fitted to the substrate inhibition equation in mouse liver microsomes. Kinetic parameters of furosemide glucuronidation were very similar between hUGT1 mice and human liver microsomes. The kinetics of S-naproxen acyl-glucuronidation and inhibitory effects of compounds on furosemide glucuronidation in hUGT1 liver microsomes were also slightly, but similar to those in human liver microsomes, rather than in wild-type mice. While wild-type mice lack imipramine and trifluoperazine N-glucuronidation potential, hUGT1 mice showed comparable N glucuronidation activity to that of humans. Our data indicate that hUGT1 mice are promising tools to predict not only in vivo human drug glucuronidation but also potential drug-drug interactions. PMID- 25505557 TI - Evaluation of AMG 076, a potent and selective MCHR1 antagonist, in rodent and primate obesity models. AB - Melanin-concentrating hormone (MCH) regulates food intake through activation of the receptor, MCHR1. We have identified AMG 076 as an orally bioavailable potent and selective small molecule antagonist of MCHR1. In mouse models of obesity, AMG 076 caused a reduction in body weight gain in wild-type (MCHR1+/+) but not in knockout (MCHR1-/-) mice. The body weight reduction was associated with decreases in food intake and increases in energy expenditure. Importantly, we show that these MCHR1-dependent effects of AMG 076 were also reflected in improved metabolic phenotypes, increased glucose tolerance and insulin sensitivity. Preliminary data on effects of AMG 076 in obese cynomolgus monkeys are also presented. PMID- 25505558 TI - Green fluorescent protein fused to peptide agonists of two dissimilar G protein coupled receptors: novel ligands of the bradykinin B2 (rhodopsin family) receptor and parathyroid hormone PTH1 (secretin family) receptor. AB - We hypothesized that peptide hormone sequences that stimulate and internalize G protein-coupled receptors (GPCRs) could be prolonged with a functional protein cargo. To verify this, we have selected two widely different pairs of peptide hormones and GPCRs that nevertheless share agonist-induced arrestin-mediated internalization. For the parathyroid hormone (PTH) PTH1 receptor (PTH1R) and the bradykinin (BK) B2 receptor (B2R), we have designed fusion proteins of the agonists PTH1-34 and maximakinin (MK, a BK homologue) with the enhanced green fluorescent protein (EGFP), thus producing candidate high molecular weight ligands. According to docking models of each hormone to its receptor, EGFP was fused either at the N-terminus (MK) or C-terminus (PTH1-34) of the ligand; the last construction is also secretable due to inclusion of the preproinsulin signal peptide and has been produced as a conditioned medium. EGFP-MK has been produced as a lysate of transfected cells. Using an enzyme-linked immunosorbent assay (ELISA) for GFP, average concentrations of 1.5 and 1670 nmol/L, respectively, of ligand were found in these preparations. The functional properties and potential of these analogs for imaging receptor-expressing cells were examined. Microscopic and cytofluorometric evidence of specific binding and internalization of both fusion proteins was obtained using recipient HEK 293a cells that expressed the cognate recombinant receptor. Endosomal colocalization studies were conducted (Rab5, Rab7, beta-arrestin1). Evidence of agonist signaling was obtained (expression of c-Fos, cyclic AMP responsive element (CRE) reporter gene for PTH1 34-EGFP). The constructs PTH1-34-EGFP and EGFP-MK represent bona fide agonists that support the feasibility of transporting protein cargoes inside cells using GPCRs. PMID- 25505559 TI - Expression pattern of human ATP-binding cassette transporters in skin. AB - ATP-binding cassette (ABC) transporters transport a variety of substrates across cellular membranes coupled with hydrolysis of ATP. Currently 49 ABC transporters consisting of seven subfamilies, ABCA, ABCB, ABCC, ABCD, ABCE, ABCF, and ABCG, have been identified in humans and they are extensively expressed in various tissues. Skin can develop a number of drug-induced toxicities' such as Stevens Johnson syndrome and psoriasis. Concentration of drugs in the skin cells is associated with the development of adverse drug reactions. ABC transporters play important roles in absorption and disposition of drugs in the cells; however, the expression pattern of human ABC transporters in the skin has not been determined. In this study, the expression patterns of 48 human ABC transporters were determined in the human skin as well as in the liver and small intestine. Most of the ABCA, ABCB, ABCC, ABCD, ABCE, and ABCF family members were highly or moderately expressed in the skin, while ABCG family members were slightly expressed in the skin. Significant interindividual variability was also observed in the expression levels of those ATP transporters in the skin, except for ABCA5 and ABCF1, which were found to be expressed in all of the human skin samples tested in this study. In conclusion, this is the first study to identify the expression pattern of the whole human ABC family of transporters in the skin. The interindividual variability in the expression levels of ABC transporters in the human skin might be associated with drug-induced skin diseases. PMID- 25505560 TI - Cilostazol prevents retinal ischemic damage partly via inhibition of tumor necrosis factor-alpha-induced nuclear factor-kappa B/activator protein-1 signaling pathway. AB - Cilostazol is a specific inhibitor of phosphodiesterase III and is widely used to treat ischemic symptoms of peripheral vascular disease. We evaluated the protective effects of cilostazol in a murine model of ocular ischemic syndrome in which retinal ischemia was induced by 5-h unilateral ligation of both the pterygopalatine artery (PPA) and the external carotid artery (ECA) in anesthetized mice. The effects of cilostazol (30 mg/kg, p.o.) on ischemia/reperfusion (I/R)-induced retinal damage were examined by histological, retinal vascular permeability, and electrophysiological analyses. Using immunoblotting, the protective mechanism for cilostazol was evaluated by examining antiinflammatory effects of cilostazol on the expression of tumor necrosis factors-alpha (TNF-alpha) and tight junction proteins (ZO-1 and claudin 5), and the phosphorylations of nuclear factor-kappa B (NF-kappaB) and c-Jun. The histological analysis revealed that I/R decreased the cell number in the ganglion cell layer (GCL) and the thicknesses of the inner plexiform layer (IPL) and inner nuclear layer (INL), and that cilostazol attenuated these decreases. Additionally, cilostazol prevented the hyperpermeability of blood vessels. Electroretinogram (ERG) measurements revealed that cilostazol prevented the I/R induced reductions in a-, b-, and oscillatory potential (OP) wave amplitudes seen at 5 days after I/R. Cilostazol inhibited the increased expression of TNF-alpha and the phosphorylation levels of NF-kappaB and c-Jun in the retina after I/R. In addition, cilostazol prevented TNF-alpha-induced reduction of ZO-1 and claudin-5 expression in human retinal microvascular endothelial cells (HRMECs). These findings indicate that cilostazol may prevent I/R-induced retinal damage partly through inhibition of TNF-alpha-induced NF-kappaB/AP-1 signaling pathway. PMID- 25505561 TI - Effects of D-amino acid oxidase inhibition on memory performance and long-term potentiation in vivo. AB - N-methyl-d-aspartate receptor (NMDAR) activation can initiate changes in synaptic strength, evident as long-term potentiation (LTP), and is a key molecular correlate of memory formation. Inhibition of d-amino acid oxidase (DAAO) may increase NMDAR activity by regulating d-serine concentrations, but which neuronal and behavioral effects are influenced by DAAO inhibition remain elusive. In anesthetized rats, extracellular field excitatory postsynaptic potentials (fEPSPs) were recorded before and after a theta frequency burst stimulation (TBS) of the Schaffer collateral pathway of the CA1 region in the hippocampus. Memory performance was assessed after training with tests of contextual fear conditioning (FC, mice) and novel object recognition (NOR, rats). Oral administration of 3, 10, and 30 mg/kg 4H-furo[3,2-b]pyrrole-5-carboxylic acid (SUN) produced dose-related and steady increases of cerebellum d-serine in rats and mice, indicative of lasting inhibition of central DAAO. SUN administered 2 h prior to training improved contextual fear conditioning in mice and novel object recognition memory in rats when tested 24 h after training. In anesthetized rats, LTP was established proportional to the number of TBS trains. d-cycloserine (DCS) was used to identify a submaximal level of LTP (5* TBS) that responded to NMDA receptor activation; SUN administered at 10 mg/kg 3-4 h prior to testing similarly increased in vivo LTP levels compared to vehicle control animals. Interestingly, in vivo administration of DCS also increased brain d-serine concentrations. These results indicate that DAAO inhibition increased NMDAR related synaptic plasticity during phases of post training memory consolidation to improve memory performance in hippocampal-dependent behavioral tests. PMID- 25505563 TI - Enantioselectivity in the cytochrome P450-dependent conversion of tegafur to 5 fluorouracil in human liver microsomes. AB - Tegafur (FT) is a prodrug of 5-fluorouracil (5-FU) used in cancer chemotherapy, and the bioactivation of FT to 5-FU is mainly catalyzed by cytochrome P450 (CYP) in hepatic microsomes. FT has a chiral center and is a racemate consisting of the enantiomers, R- and S-FT. In the present study, we clarified the enantioselectivity in the conversion of FT to 5-FU and identified human CYP isoforms involved in the metabolism of its enantiomers using human hepatic preparations and recombinant CYP isoforms. Although 5-FU was generated from both FT enantiomers, R-FT was a preferred substrate than S-FT, because of the considerably higher intrinsic clearance for 5-FU formation from R-FT in liver. Eadie-Hofstee plots in microsomes showed that the conversions of R- and S-FT to 5 FU followed biphasic and monophasic kinetics, respectively. Based on the evaluation using cDNA-expressed enzymes, CYP2A6 showed the highest activity for 5 FU formation from R-FT with the K m value similar to that of the high-affinity component in microsomes. Also, CYP2A6 was the most effective catalyst for S-FT. Inhibition studies using CYP-selective inhibitors and anti-CYP antibodies demonstrated that CYP2A6 mainly contributed to the enantioselective metabolism of FT, and were almost in accordance with the relative percentage contribution of each CYP isoform to the metabolism of FT estimated using relative activity factor methods. These results suggest that the enantioselectivity in the bioactivation of FT to 5-FU in humans is mainly due to the large difference of the catalytic activity of CYP2A6 between R- and S-FT. PMID- 25505562 TI - Methamphetamine causes acute hyperthermia-dependent liver damage. AB - Methamphetamine-induced neurotoxicity has been correlated with damage to the liver but this damage has not been extensively characterized. Moreover, the mechanism by which the drug contributes to liver damage is unknown. This study characterizes the hepatocellular toxicity of methamphetamine and examines if hyperthermia contributes to this liver damage. Livers from methamphetamine treated rats were examined using electron microscopy and hematoxylin and eosin staining. Methamphetamine increased glycogen stores, mitochondrial aggregation, microvesicular lipid, and hydropic change. These changes were diffuse throughout the hepatic lobule, as evidenced by a lack of hematoxylin and eosin staining. To confirm if these changes were indicative of damage, serum aspartate and alanine aminotransferase were measured. The functional significance of methamphetamine induced liver damage was also examined by measuring plasma ammonia. To examine the contribution of hyperthermia to this damage, methamphetamine-treated rats were cooled during and after drug treatment by cooling their external environment. Serum aspartate and alanine aminotransferase, as well as plasma ammonia were increased concurrently with these morphologic changes and were prevented when methamphetamine-induced hyperthermia was blocked. These findings support that methamphetamine produces changes in hepatocellular morphology and damage persisting for at least 24 h after drug exposure. At this same time point, methamphetamine treatment significantly increases plasma ammonia concentrations, consistent with impaired ammonia metabolism and functional liver damage. Methamphetamine-induced hyperthermia contributes significantly to the persistent liver damage and increases in peripheral ammonia produced by the drug. PMID- 25505565 TI - Antitumor activity of (R,R')-4-methoxy-1-naphthylfenoterol in a rat C6 glioma xenograft model in the mouse. AB - (R,R')-4-methoxy-1-naphthylfenoterol (MNF) inhibits cancer cell proliferation in vitro through cell-type specific modulation of beta2-adrenergic receptor and/or cannabinoid receptor function. Here, we report an investigation into antitumor activity of MNF in rat C6 glioma cells. The potent antiproliferative action of MNF in these cells (IC50 of ~1 nmol/L) was refractory to pharmacological inhibition of beta2-adrenergic receptor while a synthetic inverse agonist of cannabinoid receptor 1 significantly blocked MNF activity. The antitumor activity of MNF was then assessed in a C6 glioblastoma xenograft model in mice. Three days after subcutaneous implantation of C6 cells into the lower flank of nude mice, these animals were subjected to i.p. injections of saline or MNF (2 mg/kg) for 19 days and tumor volumes were measured over the course of the experiment. Gene expression analysis, quantitative RT-PCR and immunoblot assays were performed on the tumors after treatment. Significant reduction in mean tumor volumes was observed in mice receiving MNF when compared with the saline-treated group. We identified clusters in expression of genes involved in cellular proliferation, as well as molecular markers for glioblastoma that were significantly downregulated in tumors of MNF-treated mice as compared to saline-injected controls. The efficacy of MNF against C6 glioma cell proliferation in vivo and in vitro was accompanied by marked reduction in the expression of cell cycle regulator proteins. This study is the first demonstration of MNF-dependent chemoprevention of a glioblastoma xenograft model and may offer a potential mechanism for its anticancer action in vivo. PMID- 25505566 TI - Differential analysis of transient increases of serum cTnI in response to handling in rats. AB - Serum cardiac troponins are the key biomarkers of myocardial necrosis in humans and in preclinical species. The use of ultrasensitive assays for serum cardiac troponin I (cTnI) as a biomarker in safety studies is hampered by interindividual differences. In this study, we investigated the effect of handling procedures on serum cTnI and explored modeling and simulation approaches to mitigate the impact of these interindividual differences. Femoral-catheterized male Crl:WI(Han) rats (n = 16/group) were left undisturbed in their cages with no handling; subjected to 5 min of isoflurane/O2 anesthesia (A); or placed into a rodent restrainer followed by simulated tail vein injection (RR). Serum cTnI concentrations were assessed over a 24-h period using an ultrasensitive assay, and the study was repeated for confirmation. The mean serum cTnI concentration pre-procedure was 4.2 pg/mL, and remained stable throughout the duration of the study in the rats submitted to the A procedure. Serum cTnI concentrations increased transiently after the RR procedure with a median time to maximum concentration (T max), of 1 and 2 h and a mean maximum value concentration (C max), of 53.0 and 7.2 pg/mL in the initial and repeat studies, respectively. A population pharmacodynamic model identified interindividual, procedure- and study-specific effects on serum cTnI concentrations in rats. It is concluded that a modeling and simulation approach more appropriately describes and statistically analyzes the data obtained with this ultrasensitive assays. PMID- 25505567 TI - Modeling of age-dependent amyloid accumulation and gamma-secretase inhibition of soluble and insoluble Abeta in a transgenic mouse model of amyloid deposition. AB - According to the "amyloid hypothesis," accumulation of amyloid beta (Abeta) peptides in the brain is linked to the development of Alzheimer's disease. The aims of this investigation were to develop a model for the age-dependent amyloid accumulation and to quantify the age- and treatment-duration-dependent efficacy of the gamma-secretase inhibitor MRK-560 in the Tg2576 transgenic mouse model of amyloid deposition. Soluble and insoluble Abeta40 and Abeta42 brain concentrations were compiled from multiple naive, vehicle, and MRK-560-treated animals. The age of Tg2576 mice in the studies ranged between 3.5 and 26 months. Single doses of MRK-560 inhibited soluble Abeta40 levels in animals up to 9 months old. In contrast, MRK-560 did not cause significant acute effects on soluble Abeta40 levels in animals older than 13 months. Absolute levels of Abeta variants increased exponentially over age and reached a plateau at ~20 months. In the final model, it was assumed that MRK-560 inhibited the Abeta production rate with an Abeta level-dependent IC50.The age-dependent increase in Abeta levels was best described by a logistic model that stimulated the production rate of soluble Abeta. The increase in insoluble Abeta was defined as a function of soluble Abeta by using a scaling factor and a different turnover rate. The turnover half-life for insoluble Abeta was estimated at 30 days, explaining that at least a 4-week treatment in young animals was required to demonstrate a reduction in insoluble Abeta. Taken together, the derived knowledge could be exploited for an improved design of new experiments in Tg2576 mice. PMID- 25505568 TI - The arylpiperazine derivatives N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1 piperazinehexanamide and N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide exert a long-lasting inhibition of human serotonin 5-HT7 receptor binding and cAMP signaling. AB - We performed a detailed in vitro pharmacological characterization of two arylpiperazine derivatives, compound N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1 piperazinehexanamide (LP-211) previously identified as a high-affinity brain penetrant ligand for 5-hydroxytryptamine (serotonin) type 7 (5-HT7) receptors, and its analog N-benzyl-4-(2-diphenyl)-1-piperazinehexanamide (MEL-9). Both ligands exhibited competitive displacement of [(3)H]-(2R)-1-[(3 hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine ([(3)H]-SB 269970) radioligand binding and insurmountable antagonism of 5 carboxamidotryptamine (5-CT)-stimulated cyclic adenosine monophosphate (cAMP) signaling in human embryonic kidney (HEK293) cells stably expressing human 5-HT7 receptors. They also inhibited forskolin-stimulated adenylate cyclase activity in 5-HT7-expressing HEK293 cells but not in the parental cell line. The compounds elicited long-lasting (at least 24 h) concentration-dependent inhibition of radioligand binding at 5-HT7-binding sites in whole-cell radioligand binding assays, after pretreatment of the cells with the compounds and subsequent compound removal. In cAMP assays, pretreatment of cells with the compounds rendered 5-HT7 receptors unresponsive to 5-CT and also rendered 5-HT7-expressing HEK293 cells unresponsive to forskolin. Compound 1-(2-biphenyl)piperazine (RA-7), a known active metabolite of LP-211 present in vivo, was able to partially inhibit 5-HT7 radioligand binding in a long-lasting irreversible manner. Hence, LP-211 and MEL-9 were identified as high-affinity long-acting inhibitors of human 5-HT7 receptor binding and function in cell lines. The detailed in vitro characterization of these two pharmacological tools targeting 5-HT7 receptors may benefit the study of 5-HT7 receptor function and it may lead to the development of novel selective pharmacological tools with defined functional properties at 5 HT7 receptors. PMID- 25505569 TI - Methotrexate and a spleen tyrosine kinase inhibitor cooperate to inhibit responses to peripheral blood B cells in rheumatoid arthritis. AB - BACKGROUND: Selective disruption of the spleen tyrosine kinase (Syk) represents a novel strategy to control B-cell functional responses by inhibition of B-cell antigen receptor (BCR) signaling. PRT062607 (P505-15) is a highly selective small molecule Syk inhibitor that potently suppresses B-cell function in human and rodent blood, and reduces inflammation in rodent models of rheumatoid arthritis (RA). AIMS: In this study, we sought to determine the potency of Syk inhibition by PRT062607 in whole blood from RA patients, and elucidate covariates that affect the potency of immune-regulation by this compound. MATERIALS AND METHODS: Whole blood was collected from 30 patients diagnosed with RA as part of a single center outpatient study. Disease severity, serum protein markers of inflammation, and co-medications were related to each other, and to PRT062607 activity in ex vivo Syk-mediated immune function assays. RESULTS: We report here that PRT062607 exhibited greater potency in suppressing BCR mediated B-cell functional responses in whole blood from RA patients who received stable methotrexate (MTX) therapy. We demonstrate that the B-cell functional response to BCR ligation is influenced by cytokines and JAK/STAT signaling. DISCUSSION: MTX is a known cytokine modulating agent, and this mechanism may act in concert with PRT062607 to control B-cell function. CONCLUSION: These data have important implications for the co administration of Syk inhibitors and MTX for the treatment of RA. PMID- 25505570 TI - In vitro metabolism and metabolic effects of ajulemic acid, a synthetic cannabinoid agonist. AB - Ajulemic acid is a synthetic analog of Delta(8)-THC-11-oic acid, the terminal metabolite of Delta(8)-THC. Unlike Delta(9)-THC, the psychoactive principle of Cannabis, it shows potent anti-inflammatory action and has minimal CNS cannabimimetic activity. Its in vitro metabolism by hepatocytes from rats, dogs, cynomolgus monkeys and humans was studied and the results are reported here. Five metabolites, M1 to M5, were observed in human hepatocyte incubations. One metabolite, M5, a glucuronide, was observed in the chromatogram of canine hepatocyte incubations. In monkey hepatocyte incubations, M5 was observed in the chromatograms of both the 120 and 240 min samples, trace metabolite M1 (side chain hydroxyl) was observed in the 120 min samples, and trace metabolite M4 (side-chain dehydrogenation) was observed in the 240 min samples. No metabolites were found in the rat hepatocyte incubations. Unchanged amounts of ajulemic acid detected after the 2-h incubation were 103%, 90%, 86%, and 83% for rat, dog, monkey, and human hepatocytes, respectively. Additional studies were done to ascertain if ajulemic acid can inhibit the activities of five principal human cytochrome P450 isozymes; CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5. In contrast to the phytocannabinoids Delta(9)-THC and CBD, no significant inhibition of cytochrome activity was observed. These data further support the conclusions reached in earlier reports on ajulemic acid's high margin of safety and suggest that it undergoes minimal metabolism and is not likely to interfere with the normal metabolism of drugs or endogenous substances. PMID- 25505571 TI - Antagonism of human CC-chemokine receptor 4 can be achieved through three distinct binding sites on the receptor. AB - Chemokine receptor antagonists appear to access two distinct binding sites on different members of this receptor family. One class of CCR4 antagonists has been suggested to bind to a site accessible from the cytoplasm while a second class did not bind to this site. In this report, we demonstrate that antagonists representing a variety of structural classes bind to two distinct allosteric sites on CCR4. The effects of pairs of low-molecular weight and/or chemokine CCR4 antagonists were evaluated on CCL17- and CCL22-induced responses of human CCR4(+) T cells. This provided an initial grouping of the antagonists into sets which appeared to bind to distinct binding sites. Binding studies were then performed with radioligands from each set to confirm these groupings. Some novel receptor theory was developed to allow the interpretation of the effects of the antagonist combinations. The theory indicates that, generally, the concentration-ratio of a pair of competing allosteric modulators is maximally the sum of their individual effects while that of two modulators acting at different sites is likely to be greater than their sum. The low-molecular weight antagonists could be grouped into two sets on the basis of the functional and binding experiments. The antagonistic chemokines formed a third set whose behaviour was consistent with that of simple competitive antagonists. These studies indicate that there are two allosteric regulatory sites on CCR4. PMID- 25505573 TI - Nigramide J is a novel potent inverse agonist of the human constitutive androstane receptor. AB - The constitutive androstane receptor (CAR, NR1I3) is very important for drug development and for understanding pharmacokinetic drug-drug interactions. We screened by mammalian one hybrid assay among natural compounds to discover novel ligands of human constitutive androstane receptor (hCAR). hCAR transcriptional activity was measured by luciferase assay and mRNA levels of CYP2B6 and CYP3A4 in HepTR-hCAR cells and human primary hepatocytes were measured by real-time RT-PCR. Nigramide J (NJ) whose efficacy is comparable to those of hitherto known inverse agonists such as clotrimazole, PK11195, and ethinylestradiol. NJ is a naturally occurring cyclohexane-type amide alkaloid that was isolated from the roots of Piper nigrum. The suppressive effect of NJ on the CAR-dependent transcriptional activity was found to be species specific, in the descending order of hCAR, rat CAR, and mouse CAR. The unliganded hCAR-dependent transactivation of reporter and endogenous genes was suppressed by NJ at concentrations higher than 5 MUmol/L. The ligand-binding cavity of hCAR was shared by NJ and CITCO, because they were competitive in the binding to hCAR. NJ interfered with the interaction of hCAR with coactivator SRC-1, but not with its interaction with the corepressor NCoR1. Furthermore, NJ is agonist of human pregnane X receptor (hPXR). NJ is a dual ligand of hCAR and hPXR, being an agonist of hPXR and an inverse agonist of hCAR. PMID- 25505574 TI - Mapping the sevoflurane-binding sites of calmodulin. AB - General anesthetics, with sevoflurane (SF) being the first choice inhalational anesthetic agent, provide reversible, broad depressor effects on the nervous system yet have a narrow margin of safety. As characterization of low-affinity binding interactions of volatile substances is exceptionally challenging with the existing methods, none of the numerous cellular targets proposed as chief protagonists in anesthesia could yet be confirmed. The recognition that most critical functions modulated by volatile anesthetics are under the control of intracellular Ca(2+) concentration, which in turn is primarily regulated by calmodulin (CaM), motivated us for characterization of the SF-CaM interaction. Solution NMR (Nuclear Magnetic Resonance) spectroscopy was used to identify SF binding sites using chemical shift displacement, NOESY and heteronuclear Overhauser enhancement spectroscopy (HOESY) experiments. Binding affinities were measured using ITC (isothermal titration calorimetry). SF binds to both lobes of (Ca(2+))4-CaM with low mmol/L affinity whereas no interaction was observed in the absence of Ca(2+). SF does not affect the calcium binding of CaM. The structurally closely related SF and isoflurane are shown to bind to the same clefts. The SF-binding clefts overlap with the binding sites of physiologically relevant ion channels and bioactive small molecules, but the binding affinity suggests it could only interfere with very weak CaM targets. PMID- 25505575 TI - The utility of serum biomarkers to detect myocardial alterations induced by Imatinib in rats. AB - BACKGROUND: Imatinib (Imb) is a tyrosine kinase inhibitor with cardiotoxic activity (decreases in left ventricular function and congestive heart failure) in patients. Currently, clinical diagnosis of Imb cardiotoxicity relies primarily on evaluation of left ventricular function, Imb also induces cardiac lesions in rats. AIMS: This study, in rats, sought to determine whether monitoring biochemical markers would be a sensitive means to detect Imb-induced changes in cardiomyocyte morphology. MATERIALS AND METHODS: Groups of male Sprague-Dawley rats were dosed orally with 50, 100, 200 mg kg(-1) Imb or water daily for 28 days. Tissues and blood samples were collected 24 h after the last dosing. Cardiac biomarkers such as cardiac troponin I (cTnI), cardiac troponin T (cTnT), and fatty acid binding protein 3 (FABP3) were monitored by the Erenna, Elecsys, and Meso Scale immunoassay systems. RESULTS: Imb caused microscopic myocardial lesions (myofibrillar loss, cytoplasmic vacuolization, and necrosis) at all doses as determined by unbiased histopathology analysis. The severity of the alterations was dose-related with mean lesion scores (based on a scale of 0-3) of 1.2 (50 mg kg(-1)), 2.1 (100 mg kg(-1)) and 2.9 (200 mg kg(-1)). However, the increases in cTnI, cTnT, and FABP3 levels were noted primarily in high-dose Imb treated animals. DISCUSSION AND CONCLUSION: The occurrence of myocardial alterations in animals without consistent changes in cardiac troponin and FABP3 concentrations raises questions regarding the utility of these biomarkers as early indicators of Imb-induced cardiotoxicity. Due to limited numbers of animals the reasons for this discrepancy could not be determined. PMID- 25505577 TI - Database search of spontaneous reports and pharmacological investigations on the sulfonylureas and glinides-induced atrophy in skeletal muscle. AB - The ATP-sensitive K(+) (KATP) channel is an emerging pathway in the skeletal muscle atrophy which is a comorbidity condition in diabetes. The "in vitro" effects of the sulfonylureas and glinides were evaluated on the protein content/muscle weight, fibers viability, mitochondrial succinic dehydrogenases (SDH) activity, and channel currents in oxidative soleus (SOL), glycolitic/oxidative flexor digitorum brevis (FDB), and glycolitic extensor digitorum longus (EDL) muscle fibers of mice using biochemical and cell-counting Kit-8 assay, image analysis, and patch-clamp techniques. The sulfonylureas were: tolbutamide, glibenclamide, and glimepiride; the glinides were: repaglinide and nateglinide. Food and Drug Administration-Adverse Effects Reporting System (FDA AERS) database searching of atrophy-related signals associated with the use of these drugs in humans has been performed. The drugs after 24 h of incubation time reduced the protein content/muscle weight and fibers viability more effectively in FDB and SOL than in the EDL. The order of efficacy of the drugs in reducing the protein content in FDB was: repaglinide (EC50 = 5.21 * 10(-6)) >= glibenclamide(EC50 = 8.84 * 10(-6)) > glimepiride(EC50 = 2.93 * 10(-5)) > tolbutamide(EC50 = 1.07 * 10(-4)) > nateglinide(EC50 = 1.61 * 10(-4)) and it was: repaglinide(7.15 * 10(-5)) >= glibenclamide(EC50 = 9.10 * 10(-5)) > nateglinide(EC50 = 1.80 * 10(-4)) >= tolbutamide(EC50 = 2.19 * 10(-4)) > glimepiride(EC50=-) in SOL. The drug-induced atrophy can be explained by the KATP channel block and by the enhancement of the mitochondrial SDH activity. In an 8 month period, muscle atrophy was found in 0.27% of the glibenclamide reports in humans and in 0.022% of the other not sulfonylureas and glinides drugs. No reports of atrophy were found for the other sulfonylureas and glinides in the FDA AERS. Glibenclamide induces atrophy in animal experiments and in human patients. Glimepiride shows less potential for inducing atrophy. PMID- 25505576 TI - XG-102 administered to healthy male volunteers as a single intravenous infusion: a randomized, double-blind, placebo-controlled, dose-escalating study. AB - The aim of the study is to evaluate the safety, tolerability and pharmacokinetics (PK) of the JNK inhibitor XG-102 in a randomized, double blind, placebo controlled, sequential ascending dose parallel group Phase 1 Study. Three groups of male subjects received as randomly assigned ascending single XG-102 doses (10, 40, and 80 MUg/kg; 6 subjects per dose) or placebo (2 subjects per dose) as an intravenous (IV) infusion over 60 min. Safety and tolerability were assessed by physical examination, vital signs, electrocardiography, eye examination, clinical laboratory tests and adverse events (AEs). PK was analyzed using noncompartmental methods. All reported AEs were mild to moderate and neither their number nor their distribution by System Organ Class suggest a dose relationship. Only headache and fatigue were considered probably or possibly study drug related. Headache frequency was similar for active and placebo, consequently this was not considered to be drug related but probably to study conditions. The other examinations did not show clinically relevant deviations or trends suggesting a XG-102 relationship. Geometric mean half-life was similar among doses, ranging from 0.36 to 0.65 h. Geometric mean XG-102 AUC0-last increased more than linearly with dose, 90% confidence intervals (CIs) did not overlap for the two highest doses. Geometric mean dose normalized C max values suggest a more than linear increase with dose but 90% CIs overlap. It may be concluded that XG-102 single IV doses of 10-80 MUg/kg administered over 1 h to healthy male subjects were safe and well tolerated. PMID- 25505579 TI - From the dual function lead AP2238 to AP2469, a multi-target-directed ligand for the treatment of Alzheimer's disease. AB - The development of drugs with different pharmacological properties appears to be an innovative therapeutic approach for Alzheimer's disease. In this article, we describe a simple structural modification of AP2238, a first dual function lead, in particular the introduction of the catechol moiety performed in order to search for multi-target ligands. The new compound AP2469 retains anti acetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme (BACE)1 activities compared to the reference, and is also able to inhibit Abeta 42 self-aggregation, Abeta 42 oligomer-binding to cell membrane and subsequently reactive oxygen species formation in both neuronal and microglial cells. The ability of AP2469 to interfere with Abeta 42 oligomer-binding to neuron and microglial cell membrane gives this molecule both neuroprotective and anti-inflammatory properties. These findings, together with its strong chain breaking antioxidant performance, make AP2469 a potential drug able to modify the course of the disease. PMID- 25505581 TI - Selective antinociceptive effects of a combination of the N-methyl-D-aspartate receptor peptide antagonist [Ser(1)]histogranin and morphine in rat models of pain. AB - Numerous rather than a few analgesic endogenous neuropeptides are likely to work in concert in vivo in ameliorating pain. Identification of effective neuropeptide combinations would also facilitate the development of gene or cell-based analgesics. In this study, opioid peptides endomorphin-1 (EM-1) and endomorphin-2 (EM-2) and the peptide histogranin analogue [Ser(1)]histogranin (SHG), which possess activity as an N-methyl-d-aspartate (NMDA) receptor antagonist, were intrathecally (i.t.) injected alone and in combination in rat models of acute and persistent pain. None of the peptides when injected alone altered hind paw responses of uninjured rats to acute noxious stimulation. EM-1 and EM-2 showed divergent efficacies in the persistent pain models. For example, EM-1 injected alone was antinociceptive in rats with neuropathic pain, whereas EM-2 demonstrated no efficacy. Demonstration of synergism was also divergent across the models. For example, while SHG combined with EM-1 did not alter the efficacy of EM-1 in rats with neuropathic pain, SHG significantly increased the efficacy of EM-1 in the formalin test. By contrast, the potency and efficacy of the peptides alone and combinations were much less than those of the reference analgesic morphine. Furthermore, morphine combined with the clinically used NMDA receptor antagonist ketamine showed synergism across a broad range of pain states. While the current set of neuropeptides could serve as a basis for analgesic therapeutics, there could be other neuropeptides with greater efficacy and potency and broader therapeutic application. PMID- 25505580 TI - The potent and selective alpha4beta2*/alpha6*-nicotinic acetylcholine receptor partial agonist 2-[5-[5-((S)Azetidin-2-ylmethoxy)-3-pyridinyl]-3 isoxazolyl]ethanol demonstrates antidepressive-like behavior in animal models and a favorable ADME-tox profile. AB - Preclinical and clinical studies demonstrated that the inhibition of cholinergic supersensitivity through nicotinic antagonists and partial agonists can be used successfully to treat depressed patients, especially those who are poor responders to selective serotonin reuptake inhibitors (SSRIs). In our effort to develop novel antidepressant drugs, LF-3-88 was identified as a potent nicotinic acetylcholine receptor (nAChR) partial agonist with subnanomolar to nanomolar affinities for beta2-containing nAChRs (alpha2beta2, alpha3beta2, alpha4beta2, and alpha4beta2*) and superior selectivity away from alpha3beta4 - (K i > 10(4) nmol/L) and alpha7-nAChRs (K i > 10(4) nmol/L) as well as 51 other central nervous system (CNS)-related neurotransmitter receptors and transporters. Functional activities at different nAChR subtypes were characterized utilizing (86)Rb(+) ion efflux assays, two-electrode voltage-clamp (TEVC) recording in oocytes, and whole-cell current recording measurements. In mouse models, administration of LF-3-88 resulted in antidepressive-like behavioral signatures 15 min post injection in the SmartCube(r) test (5 and 10 mg/kg, i.p.; about 45 min session), decreased immobility in the forced swim test (1-3 mg/kg, i.p.; 1-10 mg/kg, p.o.; 30 min pretreatment, 6-min trial), and decreased latency to approach food in the novelty-suppressed feeding test after 29 days chronic administration once daily (5 mg/kg but not 10 mg/kg, p.o.; 15-min trial). In addition, LF-3-88 exhibited a favorable profile in pharmacokinetic/ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) assays. This compound was also shown to cause no mortality in wild-type Balb/CJ mice when tested at 300 mg/kg. These results further support the potential of potent and selective nicotinic partial agonists for use in the treatment of depression. PMID- 25505582 TI - A clinical therapeutic protein drug-drug interaction study: coadministration of denosumab and midazolam in postmenopausal women with osteoporosis. AB - Drug-disease interactions involving therapeutic proteins that target cytokines and potentially impact cytochrome P450 (CYP) enzymes have been of increased interest to drug regulatory agencies and industry sponsors in recent years. This parallel-group open-label study evaluated the effects of the monoclonal antibody denosumab, an inhibitor of the cytokine RANKL, on the pharmacokinetics of the probe CYP3A4 substrate midazolam in postmenopausal women with osteoporosis. The pharmacokinetics of a 2 mg oral dose of midazolam was evaluated on days 1 and 16. Subjects in Group A received a 60 mg subcutaneous dose of denosumab on day 2, 2 weeks before the second midazolam dose, while subjects in Group B did not. For Group A (n = 17), point estimates for the ratio of least square means for midazolam exposures based on maximum observed plasma concentration (C max) and areas under the plasma concentration-time curve (AUCs) on day 16 versus day 1 ranged from 1.02 to 1.04 and 90% confidence intervals were within 0.80-1.25. No period effect was observed for Group B (n = 8). Midazolam and denosumab coadministration was safe and well tolerated. Inhibition of the cytokine RANKL by denosumab does not affect CYP3A4 in postmenopausal women with osteoporosis and will not alter the pharmacokinetics of drugs metabolized by this enzyme. These results are consistent with data suggesting that RANKL does not impact markers of inflammation and represent the first clinical data demonstrating a lack of effect on CYP3A4 of a therapeutic protein that is a cytokine modulator. PMID- 25505583 TI - Effects of repeated dosing with mechanistically distinct antinociceptive ligands in a rat model of neuropathic spinal cord injury pain. AB - A lack of efficacy of some analgesic drugs has been previously described in rats with neuropathic spinal cord injury (SCI) pain. It has been suggested that repeated dosing in these animals over time may eventually lead to efficacy. However, it is also possible that efficacy may diminish over time with repeated dosing. This study evaluated the efficacy of various drugs upon repeated dosing over time in a rat model of SCI pain. Four weeks following an acute spinal cord compression at the mid-thoracic level, rats developed decreased hind paw withdrawal threshold, suggestive of below level neuropathic hypersensitivity. Either cannabinoid (CB) receptor agonist CP 55,940, the anticonvulsant carbamazepine or gabapentin, the antidepressant amitriptyline or vehicle was administered over a period of 7 days. Neither carbamazepine nor amitriptyline demonstrated efficacy either after a single or repeated dosing. Beginning with a 50% efficacious dose of gabapentin, the effect of gabapentin in SCI rats neither increased nor decreased over the treatment period. The antinociceptive effect of CP 55,940 was maintained for the entire treatment period, which was mediated by CB1 but not CB2 receptors. The current data suggest that sustained antinociception can be obtained with some drugs in rats with neuropathic SCI pain. Furthermore, the current data do not substantiate the notion that repeated treatment with initially ineffective drugs will eventually lead to efficacy; treatments that are not acutely effective are unlikely to demonstrate clinical efficacy. PMID- 25505584 TI - Species differences in sinusoidal and canalicular efflux transport of mycophenolic acid 7-O-glucuronide in sandwich-cultured hepatocytes. AB - Metabolism and sinusoidal/canalicular efflux of mycophenolic acid (MPA) was investigated using sandwich-cultured hepatocytes (SCHs). After applying MPA to SCHs from humans, wild-type rats, and multidrug resistance-associated protein (Mrp) 2-deficient rats, the MPA metabolites 7-O-glucuronide (MPAG) and acyl glucuronide (AcMPAG) were detected in the intracellular compartment of the SCHs. Sinusoidal efflux of MPAG was detected in all SCH preparations including Mrp2 deficient rat SCHs, whereas canalicular efflux of MPAG was observed in wild-type rat and human SCHs but not in Mrp2-deficient rat SCHs. The ratio of canalicular efflux to net (canalicular plus sinusoidal) efflux was 37 +/- 8% in wild-type rat SCHs, while the ratio in human SCHs was significantly lower (20 +/- 2%, P < 0.05), indicating species differences in the direction of hepatic MPAG transport. This 20% ratio in human SCHs corresponds to a high sinusoidal MPAG efflux (80%) that can in part account for the urine-dominated recovery of MPAG in humans. Both sinusoidal and canalicular MPAG efflux in rat SCHs shows a good correspondence to urinary and biliary recovery of MPAG after MPA dosing. The sinusoidal efflux of AcMPAG in human SCHs was detected from one out of three donors, suggesting donor to-donor variation. In conclusion, this study demonstrates the predictive value of SCHs for elucidating the interplay of metabolism and efflux transport, in addition to demonstrating a species difference between rat and human in sinusoidal and canalicular efflux of MPAG. PMID- 25505585 TI - Intestinal absorption of the antiepileptic drug substance vigabatrin is altered by infant formula in vitro and in vivo. AB - Vigabatrin is an antiepileptic drug substance mainly used in pediatric treatment of infantile spasms. The main source of nutrition for infants is breast milk and/or infant formula. Our hypothesis was that infant formula may affect the intestinal absorption of vigabatrin. The aim was therefore to investigate the potential effect of coadministration of infant formula with vigabatrin on the oral absorption in vitro and in vivo. The effect of vigabatrin given with an infant formula on the oral uptake and transepithelial transport was investigated in vitro in Caco-2 cells. In vivo effects of infant formula and selected amino acids on the pharmacokinetic profile of vigabatrin was investigated after oral coadministration to male Sprague-Dawley rats using acetaminophen as a marker for gastric emptying. The presence of infant formula significantly reduced the uptake rate and permeability of vigabatrin in Caco-2 cells. Oral coadministration of vigabatrin and infant formula significantly reduced C max and prolonged t max of vigabatrin absorption. Ligands for the proton-coupled amino acid transporter PAT1, sarcosine, and proline/l-tryptophan had similar effects on the pharmacokinetic profile of vigabatrin. The infant formula decreased the rate of gastric emptying. Here we provide experimental evidence for an in vivo role of PAT1 in the intestinal absorption of vigabatrin. The effect of infant formula on the oral absorption of vigabatrin was found to be due to delayed gastric emptying, however, it seems reasonable that infant formula may also directly affect the intestinal absorption rate of vigabatrin possibly via PAT1. PMID- 25505586 TI - Orthovanadate-induced vasocontraction is mediated by the activation of Rho-kinase through Src-dependent transactivation of epidermal growth factor receptor. AB - Orthovanadate (OVA), a protein tyrosine phosphatase (PTPase) inhibitor, exerts contractile effects on smooth muscle in a Rho-kinase-dependent manner, but the precise mechanisms are not elucidated. The aim of this study was to determine the potential roles of Src and epidermal growth factor receptor (EGFR) in the OVA induced contraction of rat aortas and the phosphorylation of myosin phosphatase target subunit 1 (MYPT1; an index of Rho-kinase activity) in vascular smooth muscle cells (VSMCs). Aortic contraction by OVA was significantly blocked not only by Rho kinase inhibitors Y-27632 [R-[+]-trans-N-[4-pyridyl]-4-[1-aminoethyl] cyclohexanecarboxamide] and hydroxyfasudil [1-(1-hydroxy-5 isoquinolinesulfonyl)homopiperazine] but also by Src inhibitors PP2 [4-amino-3-(4 chlorophenyl)-1-(t-butyl)-1H-pyrazolo[3,4-d]pyrimidine] and Src inhibitor No. 5 [4-(3'-methoxy-6'-chloro-anilino)-6-methoxy-7(morpholino-3-propoxy)-quinazoline], and the EGFR inhibitors AG1478 [4-(3-chloroanilino)-6,7-dimethoxyquinazoline] and EGFR inhibitor 1 [cyclopropanecarboxylic acid-(3-(6-(3-trifluoromethyl phenylamino)-pyrimidin-4-ylamino)-phenyl)-amide]. OVA induced rapid increases in the phosphorylation of MYPT1 (Thr-853), Src (Tyr-416), and EGFR (Tyr-1173) in VSMCs, and Src inhibitors abolished these effects. OVA-induced Src phosphorylation was abrogated by Src inhibitors, but not affected by inhibitors of EGFR and Rho-kinase. Inhibitors of Src and EGFR, but not Rho-kinase, also blocked OVA-induced EGFR phosphorylation. Furthermore, a metalloproteinase inhibitor TAPI-0 [N-(R)-[2-(hydroxyaminocarbonyl) methyl]-4-methylpentanoyl-l naphthylalanyl-l-alanine amide] and an inhibitor of heparin-binding EGF (CRM 197) not only abrogated the OVA-induced aortic contraction, but also OVA-induced EGFR and MYPT1 phosphorylation, suggesting the involvement of EGFR transactivation. OVA also induced EGFR phosphorylation at Tyr-845, one of residues phosphorylated by Src. These results suggest that OVA-induced vasocontraction is mediated by the Rho-kinase-dependent inactivation of myosin light-chain phosphatase via signaling downstream of Src-induced transactivation of EGFR. PMID- 25505588 TI - Discrepancies in listed adverse drug reactions in pharmaceutical product information supplied by the regulatory authorities in Denmark and the USA. AB - Pharmaceutical product information (PI) supplied by the regulatory authorities serves as a source of information on safe and effective use of drugs. The objectives of this study were to qualitatively and quantitatively compare PIs for selected drugs marketed in both Denmark and the USA with respect to consistency and discrepancy of listed adverse drug reaction (ADR) information. We compared individual ADRs listed in PIs from Denmark and the USA with respect to type and frequency. Consistency was defined as match of ADRs and of ADR frequency or match could not be ruled out. Discrepancies were defined as ADRs listed only in one country or listed with different frequencies. We analyzed PIs for 40 separate drugs from ten therapeutic groups and assigned the 4003 identified ADRs to System Organ Classes (Medical Dictionary for Regulatory Activities [MedDRA] terminology). Less than half of listed ADRs (n = 1874; 47%) showed consistency. Discrepancies (n = 2129; 53%) were split into ADRs listed only in the USA (n = 1558; 39%), ADRs listed only in Denmark (n = 325; 8%) and ADRs listed with different frequencies (n = 246; 6%). The majority of listed ADRs were of the type "gastrointestinal disorders" and "nervous system disorders". Our results show great differences in PIs for drugs approved in both Denmark and the USA illuminating concerns about the credibility of the publicly available PIs. The results also represent an argument for further harmonization across borders to improve consistency between authority-supplied information. PMID- 25505589 TI - NL-103, a novel dual-targeted inhibitor of histone deacetylases and hedgehog pathway, effectively overcomes vismodegib resistance conferred by Smo mutations. AB - Misregulation of hedgehog (Hh) signaling has been implicated in the pathogenesis of basal cell carcinoma (BCC) and medulloblastoma. Vismodegib, an orally bioavailable Hh signal pathway inhibitor targeting Smo, has been approved for the treatment of advanced BCC. However, acquired drug resistance to vismodegib induced by point mutation in Smo is emerging as a major problem to vismodegib treatment. In this study, we designed and synthesized a novel chimeric compound NL-103, which comprises structural elements of Hh pathway inhibitor vismodegib, and histone deacetylase (HDAC) inhibitor vorinostat. NL-103 simultaneously and significantly inhibited both HDACs and Hh pathway. Importantly, NL-103, as well as vorinostat, effectively overcame vismodegib resistance induced by Smoothened point mutations. Moreover, NL-103 and vorinostat, but not vismodegib, significantly downregulated the expression of Gli2 which plays an important role in Hh pathway. These results indicate that HDAC inhibitory activity is essential for NL-103 to overcome vismodegib resistance and that dual inhibition of HDAC and Hh signaling pathway may be a rational strategy for overcoming vismodegib resistance. Our findings suggest that NL-103 may be a promising compound for clinical development as a more effective Hh pathway inhibitor. PMID- 25505590 TI - Identification of metabolic pathways and enzyme systems involved in the in vitro human hepatic metabolism of dronedarone, a potent new oral antiarrhythmic drug. AB - The in vitro metabolism of dronedarone and its major metabolites has been studied in human liver microsomes and cryopreserved hepatocytes in primary culture through the use of specific or total cytochrome P450 (CYP) and monoamine oxidase (MAO) inhibitors. The identification of the main metabolites and enzymes participating in their metabolism was also elucidated by using rhCYP, rhMAO, flavin monooxygenases (rhFMO) and UDP-glucuronosyltransferases (rhUGT) and liquid chromatography/tandem mass spectrometry (LC/MS-MS) analysis. Dronedarone was extensively metabolized in human hepatocytes with a metabolic clearance being almost completely inhibited (98 +/- 2%) by 1-aminobenzotriazole. Ketoconazole also inhibited dronedarone metabolism by 89 +/- 7%, demonstrating the crucial role of CYP3A in its metabolism. CYP3A isoforms mostly contributed to N debutylation while hydroxylation on the butyl-benzofuran moiety was catalyzed by CYP2D6. However, hydroxylation on the dibutylamine moiety did not appear to be CYP-dependent. N-debutyl-dronedarone was less rapidly metabolized than dronedarone, the major metabolic pathway being catalyzed by MAO-A to form propanoic acid-dronedarone and phenol-dronedarone. Propanoic acid-dronedarone was metabolized at a similar rate to that of N-debutyl-dronedarone and was predominantly hydroxylated by CYP2C8 and CYP1A1. Phenol-dronedarone was extensively glucuronidated while C-dealkyl-dronedarone was metabolized at a slow rate. The evaluation of the systemic clearance of each metabolic process together with the identification of both the major metabolites and predominant enzyme systems and isoforms involved in the formation and subsequent metabolism of these metabolites has enhanced the overall understanding of metabolism of dronedarone in humans. PMID- 25505591 TI - Dexmedetomidine preconditioning ameliorates kidney ischemia-reperfusion injury. AB - Kidney ischemia-reperfusion (I/R) injury is a common cause of acute kidney injury. We tested whether dexmedetomidine (Dex), an alpha2 adrenoceptor (alpha2 AR) agonist, protects against kidney I/R injury. Sprague-Dawley rats were divided into four groups: (1) Sham-operated group; (2) I/R group (40 min ischemia followed by 24 h reperfusion); (3) I/R group + Dex (1 MUg/kg i.v. 60 min before the surgery), (4) I/R group + Dex (10 MUg/kg). The effects of Dex postconditiong (Dex 1 or 10 MUg/kg i.v. after reperfusion) as well as the effects of peripheral alpha2-AR agonism with fadolmidine were also examined. Hemodynamic effects were monitored, renal function measured, and acute tubular damage along with monocyte/macrophage infiltration scored. Kidney protein kinase B, toll like receptor 4, light chain 3B, p38 mitogen-activated protein kinase (p38 MAPK), sirtuin 1, adenosine monophosphate kinase (AMPK), and endothelial nitric oxide synthase (eNOS) expressions were measured, and kidney transciptome profiles analyzed. Dex preconditioning, but not postconditioning, attenuated I/R injury induced renal dysfunction, acute tubular necrosis and inflammatory response. Neither pre- nor postconditioning with fadolmidine protected kidneys. Dex decreased blood pressure more than fadolmidine, ameliorated I/R-induced impairment of autophagy and increased renal p38 and eNOS expressions. Dex downregulated 245 and upregulated 61 genes representing 17 enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, in particular, integrin pathway and CD44. Ingenuity analysis revealed inhibition of Rac and nuclear factor (erythroid-derived 2)-like 2 pathways, whereas aryl hydrocarbon receptor (AHR) pathway was activated. Dex preconditioning ameliorates kidney I/R injury and inflammatory response, at least in part, through p38-CD44-pathway and possibly also through ischemic preconditioning. PMID- 25505592 TI - Hydroxyethyl starch as an effective methotrexate carrier in anticancer therapy. AB - At present, effective anticancer therapy remains one of the most challenging tasks facing the scientific community. A major limitation to most conventional low-molecular weight anticancer chemotherapeutics is their unfavourable uptake by healthy tissue, fast metabolism and lack of tumour cell selectivity. One way to solve this problem is the application of hybrid nanoparticles containing widely known therapeutic substances. This study was performed with the aim of investigating the potential of use hydroxyethyl starch (HES) as a high-molecular weight carrier for anticancer drug (methotrexate, MTX). HES-MTX conjugates were characterized in terms of MTX content, hydrodynamic size, zeta potential, and drug release kinetics. In vitro biological characteristics were determined using different cancer cell lines. The antitumor effect in vivo was tested in NOD/SCID mice subcutaneously inoculated with MV-4-11 human leukaemia cells and CDF1 mice intraperitoneally inoculated with P388 murine leukaemia cells. The in vivo experiments revealed the considerably higher antitumor efficacy of HES-MTX conjugates in comparison to unconjugated drug. The results presented in this article demonstrate that the application of HES as an anticancer drug carrier can improve the treatment efficacy and have significant implications for the future design and implementation of drug-carrier conjugates. The study should help create new opportunities in the design of HES-based innovative drug-carrier conjugates. PMID- 25505594 TI - Assessment of the effect of potential antifibrotic compounds on total and alphaVbeta6 integrin-mediated TGF-beta activation. AB - Transforming growth factor-beta (TGF-beta) plays an important role in the development of tissue fibrosis, and molecules inhibiting this pathway are attractive therapeutic targets for fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). Activation of TGF-beta is the rate-limiting step in TGF-beta bioavailability, and activation by the alphaVbeta6 integrin is important in fibrosis of the lung, liver, and kidney. Activation of TGF-beta by alphaVbeta6 requires direct cell-cell contact and measurable release of active TGF-beta in extracellular fluid compartments does not reflect tissue specific activation. The aim of this study was to determine the effect of antifibrotic compounds on both total, and specific alphaVbeta6 integrin-mediated TGF-beta activity. Using a transformed mink lung cell (TMLC) TGF-beta reporter, the effects of potential antifibrotic therapies including an activin-like kinase (Alk5) inhibitor, Dexamethasone, Pirfenidone, N-acetylcysteine (NAC), and BIBF1120 were assessed. Effects due to alphaVbeta6 integrin-mediated TGF-beta activity were measured using reporter cells cocultured with cells expressing alphaVbeta6 integrins. These high-throughput studies were validated using a phosphorylated Smad2 Enzyme Linked Immunosorbent Assay. Alk5 inhibitors are potent inhibitors of TGF-beta activity, whereas the novel antifibrotics, Pirfenidone, BIBF1120, and NAC are only moderate inhibitors, and Dexamethasone does not specifically affect TGF betaactivity, but inhibits TGF-beta-induced gene expression. None of the current small molecular inhibitors inhibit alphaVbeta6-mediated TGF-beta activity. These results demonstrate the potential of this high-throughput assay of alphaVbeta6 specific TGF-beta activity and illustrate that currently available antifibrotics have limited effects on alphaVbeta6 integrin-mediated TGF-beta activity. PMID- 25505595 TI - The in vivo efficacy and side effect pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long-acting beta 2-adrenoceptor agonist in preclinical animal species. AB - Bronchodilators are a central therapy for symptom relief in respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma, with inhaled beta 2-adrenoceptor agonists and anticholinergics being the primary treatments available. The present studies evaluated the in vivo pharmacology of (R)-6-[[3 [[4-[5-[[2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino]pent-1 ynyl]phenyl]carbamoyl]phenyl]sulfonyl]-4-[(3-methoxyphenyl)amino]-8 methylquinoline-3-carboxamide (GS-5759), a novel bifunctional compound with both phosphodiesterase 4 (PDE4) inhibitor and long-acting beta 2-adrenoceptor agonist (LABA) activity, which has been optimized for inhalation delivery. GS-5759 dose dependently inhibited pulmonary neutrophilia in a lipopolysaccharide (LPS) aerosol challenge model of inflammation in rats with an ED50 <= 10 MUg/kg. GS 5759 was also a potent bronchodilator with an ED50 of 0.09 MUg/kg in guinea pigs and 3.4 MUg/kg in dogs after methylcholine (MCh) and ragweed challenges respectively. In cynomolgus monkeys, GS-5759 was dosed as a fine-particle dry powder and was efficacious in the same dose range in both MCh and LPS challenge models, with an ED50 = 70 MUg/kg for bronchodilation and ED50 = 4.9 MUg/kg for inhibition of LPS-induced pulmonary neutrophilia. In models to determine therapeutic index (T.I.), efficacy for bronchodilation was evaluated against increased heart rate and GS-5759 had a T.I. of 700 in guinea pigs and >31 in dogs. In a ferret model of emesis, no emesis was seen at doses several orders of magnitude greater than the ED50 observed in the rat LPS inflammation model. GS 5759 is a bifunctional molecule developed for the treatment of COPD, which has both bronchodilator and anti-inflammatory activity and has the potential for combination as a triple therapy with a second compound, within a single inhalation device. PMID- 25505596 TI - Methyllycaconitine- and scopolamine-induced cognitive dysfunction: differential reversal effect by cognition-enhancing drugs. AB - There is a growing body of evidence pointing to the pivotal role of alpha-7 nicotinic acetylcholine receptor (alpha7 nAchR) dysfunction in cognitive disorders such as Alzheimer's disease or schizophrenia. This study was undertaken to establish and characterize an in vivo model for cognitive disorder secondary to the blockade of alpha7 nAChR by its specific antagonist, methyllycaconitine (MLA). The results show that MLA elicited cognitive dysfunction as assessed by reduced spontaneous alternation of mice in the T-maze. The maximal effect of MLA produced 25-30% reduction in the spontaneous alternation of mice, a level comparable with that induced by the muscarinic antagonism of scopolamine. Donepezil and galantamine fully reversed both MLA and scopolamine-induced cognitive dysfunction. However, the ED50 of donepezil and galantamine was significantly shifted to the left in the MLA- compared to scopolamine-treated mice (0.0005 and 0.002 mg/kg for donepezil; 0.0003 and 0.7 mg/kg for galantamine). Moreover, memantine elicited marked reversion of cognitive dysfunction (up to 70%) in MLA-treated mice while only a weak reversal effect at high dose of memantine (less than 20%) was observed in scopolamine-treated mice. The above findings indicate that MLA-induced cognitive dysfunction in the mouse is highly sensitive and more responsive to the current procognitive drugs than the traditional scopolamine-based assay. Thus, it can be of value for the preclinical screening and profiling of cognition-enhancing drugs. PMID- 25505597 TI - Characterization of a novel brain barrier ex vivo insect-based P-glycoprotein screening model. AB - In earlier studies insects were proposed as suitable models for vertebrate blood brain barrier (BBB) permeability prediction and useful in early drug discovery. Here we provide transcriptome and functional data demonstrating the presence of a P-glycoprotein (Pgp) efflux transporter in the brain barrier of the desert locust (Schistocerca gregaria). In an in vivo study on the locust, we found an increased uptake of the two well-known Pgp substrates, rhodamine 123 and loperamide after co-administration with the Pgp inhibitors cyclosporine A or verapamil. Furthermore, ex vivo studies on isolated locust brains demonstrated differences in permeation of high and low permeability compounds. The vertebrate Pgp inhibitor verapamil did not affect the uptake of passively diffusing compounds but significantly increased the brain uptake of Pgp substrates in the ex vivo model. In addition, studies at 2 degrees C and 30 degrees C showed differences in brain uptake between Pgp-effluxed and passively diffusing compounds. The transcriptome data show a high degree of sequence identity of the locust Pgp transporter protein sequences to the human Pgp sequence (37%), as well as the presence of conserved domains. As in vertebrates, the locust brain-barrier function is morphologically confined to one specific cell layer and by using a whole-brain ex vivo drug exposure technique our locust model may retain the major cues that maintain and modulate the physiological function of the brain barrier. We show that the locust model has the potential to act as a robust and convenient model for assessing BBB permeability in early drug discovery. PMID- 25505598 TI - Investigating the potential role of TRPA1 in locomotion and cardiovascular control during hypertension. AB - Radiotelemetry was used to investigate the in vivo cardiovascular and activity phenotype of both TRPA1 (transient receptor potential ankyrin 1) wild-type (WT) and TRPA1 knockout (KO) mice. After baseline recording, experimental hypertension was induced using angiotensin II infusion (1.1 mg(-1) kg(-1) a day, for 14 days). TRPA1 WT and KO mice showed similar morphological and functional cardiovascular parameters, including similar basal blood pressure (BP), heart rate, size, and function. Similar hypertension was also displayed in response to angiotensin II (156 +/- 7 and 165 +/- 11 mmHg, systolic BP +/- SEM, n = 5-6). TRPA1 KO mice showed increased hypertensive hypertrophy (heart weight:tibia length: 7.3 +/- 1.6 mg mm(-1) vs. 8.8 +/- 1.7 mg mm(-1)) and presented with blunted interleukin 6 (IL 6) production compared with hypertensive WT mice (151 +/- 24 vs. 89 +/- 16 pg mL( 1)). TRPA1 expression in dorsal root ganglion (DRG) neurones was upregulated during hypertension (163% of baseline expression). Investigations utilizing the TRPA1 agonist cinnamaldehyde (CA) on mesenteric arterioles isolated from naive mice suggested a lack of TRPA1-dependent vasoreactivity in this vascular bed; a site with notable ability to alter total peripheral resistance. However, mesenteric arterioles isolated from TRPA1 KO hypertensive mice displayed significantly reduced ability to relax in response to nitric oxide (NO) (P < 0.05). Unexpectedly, naive TRPA1 KO mice also displayed physical hyperactivity traits at baseline, which was exacerbated during hypertension. In conclusion, our study provides a novel cardiovascular characterization of TRPA1 KO mice in a model of hypertension. Results suggest that TRPA1 has a limited role in global cardiovascular control, but we demonstrate an unexpected capacity for TRPA1 to regulate physical activity. PMID- 25505599 TI - Gene expression analysis of membrane transporters and drug-metabolizing enzymes in the lung of healthy and COPD subjects. AB - This study describes for the first time the expression levels of genes encoding membrane transporters and drug-metabolizing enzymes in the lungs of ex-smoking patients with chronic obstructive pulmonary disease (COPD). Membrane transporters and drug-metabolizing enzymes are key determinants of drug uptake, metabolism, and elimination for systemically administered as well as inhaled drugs, with consequent influence on clinical efficacy and patient safety. In this study, while no difference in gene expression was found between healthy and COPD subjects, we identified a significant regional difference in mRNA expression of both membrane transporters and drug-metabolizing enzymes between central and peripheral tissue in both healthy and COPD subjects. The majority of the differentially expressed genes were higher expressed in the central airways such as the transporters SLC2A1 (GLUT1), SLC28A3 (CNT3), and SLC22A4 (OCTN1) and the drug-metabolizing enzymes GSTZ1, GSTO2, and CYP2F1. Together, this increased knowledge of local pharmacokinetics in diseased and normal lung may improve modeling of clinical outcomes of new chemical entities intended for inhalation therapy delivered to COPD patients. In addition, based on the similarities between COPD and healthy subjects regarding gene expression of membrane transporters and drug-metabolizing enzymes, our results suggest that clinical pharmacological studies in healthy volunteers could be a valid model of COPD patients regarding drug disposition of inhaled drugs in terms of drug metabolism and drug transporters. PMID- 25505600 TI - Inhibition of Let-7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice. AB - The members of lethal-7 (Let-7) microRNA (miRNA) family are involved in regulation of cell differentiation and reprogramming of somatic cells into induced pluripotent stem cells. However, their function in the heart is not known. In this study, we examined the effect of inhibiting the function of Let-7c miRNA on the progression of postinfarction left ventricular (LV) remodeling in mice. Myocardial infarction was induced with permanent ligation of left anterior descending coronary artery with a 4-week follow-up period. Let-7c miRNA was inhibited with a specific antagomir administered intravenously. The inhibition of Let-7c miRNA downregulated the levels of mature Let-7c miRNA and its other closely related members of Let-7 family in the heart and resulted in increased expression of pluripotency-associated genes Oct4 and Sox2 in cardiac fibroblasts in vitro and in adult mouse heart in vivo. Importantly, Let-7c inhibitor prevented the deterioration of cardiac function postinfarction, as demonstrated by preserved LV ejection fraction and elevated cardiac output. Improvement in cardiac function by Let-7c inhibitor postinfarction was associated with decreased apoptosis, reduced fibrosis, and reduction in the number of discoidin domain receptor 2-positive fibroblasts, while the number of c-kit(+) cardiac stem cells and Ki-67(+) proliferating cells remained unaltered. In conclusion, inhibition of Let-7 miRNA may be beneficial for the prevention of postinfarction LV remodeling and progression of heart failure. PMID- 25505601 TI - PDE10A inhibitors stimulate or suppress motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways. AB - The enzyme phosphodiesterase 10A (PDE10A) regulates the activity of striatal, medium spiny neurons (MSNs), which are divided into a behaviorally stimulating, Gs-coupled D1 receptor-expressing "direct" pathway and a behaviorally suppressant, Gi-coupled D2 receptor-expressing "indirect" pathway. Activating both pathways, PDE10A inhibitors (PDE10AIs) combine functional characteristics of D2 antagonists and D1 agonists. While the effects of PDE10AIs on spontaneous and stimulated behavior have been extensively reported, the present study investigates their effects on suppressed behavior under various conditions of reduced dopaminergic neurotransmission: blockade of D1 receptors with SCH-23390, blockade of D2 receptors with haloperidol, or depletion of dopamine with RO-4 1284 or reserpine. In rats, PDE10AIs displayed relatively low cataleptic activity per se. After blocking D1 receptors, however, they induced pronounced catalepsy at low doses close to those required for inhibition of apomorphine-induced behavior; slightly higher doses resulted in behavioral stimulant effects, counteracting the catalepsy. PDE10AIs also counteracted catalepsy and related behaviors induced by D2 receptor blockade or dopamine depletion; catalepsy was replaced by behavioral stimulant effects under the latter but not the former condition. Similar interactions were observed at the level of locomotion in mice. At doses close to those inhibiting d-amphetamine-induced hyperlocomotion, PDE10AIs reversed hypolocomotion induced by D1 receptor blockade or dopamine depletion but not hypolocomotion induced by D2 receptor blockade. It is concluded that PDE10AIs stimulate or inhibit motor behavior dependent on the relative activation state of the direct and indirect striatal output pathways. PMID- 25505604 TI - Extensive protein interactions involving cytochrome P450 3A4: a possible contributor to the formation of a metabolosome. AB - Cytochrome P450 (CYP) 3A4 is a membrane protein that catalyzes hydroxylation of endogenous and exogenous substrates. Protein-protein interaction is a crucial factor that regulates the function of enzymes. However, protein-protein interactions involving human CYPs have not been fully understood. In this study, extensive protein-protein interactions involving CYP3A4 were determined by a shotgun analysis of immunoprecipitate utilizing anti-CYP3A4 antibody. Our shotgun analysis revealed that 149 proteins were immunoprecipitated with anti-CYP3A4 antibody in human liver microsomes. We further determined that 51 proteins of 149 proteins were specifically immunoprecipitated with the anti-CYP3A4 antibody. Our analysis demonstrated that other CYP isoforms are interacting with CYP3A4, which is in agreement with previous findings. Based on our current and previous findings, we propose that drug-metabolizing enzymes such as CYP3A4 and UDP glucuronosyltransferase 2B7 form a metabolosome, which is a functional unit of metabolism consisting of multiple metabolism-related proteins. PMID- 25505603 TI - Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake. AB - After synthesis and release from cells, prostaglandin E2 (PGE2) undergoes reuptake by the prostaglandin transporter (PGT), followed by cytoplasmic oxidation. Although genetic inactivation of PGT in mice and humans results in distinctive phenotypes, and although experiments in localized environments show that manipulating PGT alters downstream cellular events, a direct mechanistic link between PGT activity and PGE2 (EP) receptor activation has not been made. Toward this end, we created two reconstituted systems to examine the effect of PGT expression on PGE2 signaling via two of its receptors (EP1 and EP4). In human embryonic kidney cells engineered to express the EP1 receptor, exogenous PGE2 induced a dose-dependent increase in cytoplasmic Ca(2+). When PGT was expressed at the plasma membrane, the PGE2 dose-response curve was right-shifted, consistent with reduction in cell surface PGE2 availability; a potent PGT inhibitor acutely reversed this shift. When bradykinin was used to induce endogenous PGE2 release, PGT expression similarly induced a reduction in Ca(2+) responses. In separate experiments using Madin-Darby Canine Kidney cells engineered to express the PGE2 receptor EP4, bradykinin again induced autocrine PGE2 signaling, as judged by an abrupt increase in intracellular cAMP. As in the EP1 experiments, expression of PGT at the plasma membrane caused a reduction in bradykinin-induced cAMP accumulation. Pharmacological concentrations of exogenous PGE2 induced EP4 receptor desensitization, an effect that was mitigated by PGT. Thus, at an autocrine/paracrine level, plasma membrane PGT regulates PGE2 signaling by decreasing ligand availability at cell surface receptors. PMID- 25505606 TI - Metabolism and disposition of MM-433593, a selective FAAH-1 inhibitor, in monkeys. AB - MM-433593 is a highly potent and selective inhibitor of fatty acid amide hydrolase-1 (FAAH-1) with potential utility as an orally administered treatment of pain, inflammation, and other disorders. In this study, we investigated the metabolism and pharmacokinetics of MM-433593 in monkeys, and compared plasma and urine metabolites of this compound to the in vitro metabolites produced by monkey hepatocytes. Intravenous administration of MM-433593 to cynomolgus monkeys produced a rapid distribution phase and slower elimination phase with a mean systemic clearance rate of 8-11 mL/min/kg. Absolute oral bioavailability was determined to be 14-21% with maximum plasma concentrations reached ~3 h (T max) following a 10 mg/kg oral dose. The average terminal half-life of MM-433593 was 17-20 h, and there were no qualitative sex differences in the metabolite profile of MM-433593. The major site of metabolism was oxidation of the methyl group at the five position of the indole ring, which was confirmed by chromatography and mass spectrometry comparison to a synthesized authentic standard. This metabolite was further oxidized to the corresponding carboxylic acid and/or conjugated with sulfate, glucuronide, or glutathione. In all, 18 metabolites were found in plasma and urine. In vitro incubations of MM-433593 with monkey hepatocytes yielded 13 metabolites, all of which were found in vivo, indicating a good correlation between the in vitro and in vivo metabolism data. A comprehensive pathway for the metabolism of MM-433593 is proposed, including a plausible, five-step biotransformation for the formation of N-acetylcysteine conjugate metabolite (M18) from the hydroxylated parent (M5). PMID- 25505605 TI - Azithromycin inhibits nuclear factor-kappaB activation during lung inflammation: an in vivo imaging study. AB - We studied in vivo the potential involvement of nuclear factor-kappaB (NF-kappaB) pathway in the molecular mechanism of the anti-inflammatory and immunomodulatory activity of azithromycin in the lung. Mice transiently transfected with the luciferase gene under the control of a NF-kappaB responsive element were used to assess in vivo NF-kappaB activation by bioluminescence imaging. Bioluminescence as well as inflammatory cells and concentrations of proinflammatory cytokines in bronchoalveolar lavage fluids, were monitored in an acute model of pulmonary inflammation resulting from intratracheal instillation of lipopolysaccharide. Lipopolysaccharide (LPS) instillation induced a marked increase in lung bioluminescence in mice transiently transfected with the luciferase gene under the control of an NF-kappaB responsive element, with significant luciferase expression in resident cells such as endothelial and epithelial cells, as assessed by duoplex immunofluorescence staining. Activation of NF-kappaB and inflammatory cell lung infiltration linearly correlated when different doses of bortezomib were used to inhibit NF-kappaB activation. Pretreatment with azithromycin significantly decreased lung bioluminescence and airways cell infiltration induced by LPS, also reducing proinflammatory cytokines concentrations in bronchoalveolar lavages and inhibiting NF-kappaB nuclear translocation. The results obtained using a novel approach to monitor NF-kappaB activation, provided, for the first time, in vivo evidence that azithromycin treatment results in pulmonary anti-inflammatory activity associated with the inhibition of NF-kappaB activation in the lung. PMID- 25505607 TI - Effect of perampanel, a novel AMPA antagonist, on benzodiazepine-resistant status epilepticus in a lithium-pilocarpine rat model. AB - This study assessed the efficacy of diazepam, and the alpha-amino-3-hydroxy-5 methyl-4-isoxazole-propionic acid (AMPA) receptor antagonists perampanel and GYKI52466 in a lithium-pilocarpine status epilepticus (SE) model. SE was induced in rats using lithium chloride, scopolamine methyl bromide, and pilocarpine. Diazepam 10, 20, or 40 mg kg(-1), or perampanel 1, 2.5, 5, or 8 mg kg(-1) were administered intravenously at 10 or 30 min after seizure onset, and GYKI52466 50 mg kg(-1), or combinations of diazepam 2.5-5 mg kg(-1) and perampanel 0.5-1 mg kg(-1), were administered intravenously at 30 min after seizure onset. Diazepam 20 mg kg(-1) terminated seizures (based on electroencephalography and assessment of behavioral seizures) in 2/6 rats at 10 min and 0/6 rats at 30 min (ED50: 10 min, 30 mg kg(-1); 30 min, not determined). Perampanel 8 mg kg(-1) terminated seizures in 6/6 rats at both 10 and 30 min (ED50: 10 min 1.7 mg kg(-1); 30 min, 5.1 mg kg(-1)). GYKI52466 50 mg kg(-1) terminated seizures in 2/4 rats at 30 min. Co-administration of diazepam 5 mg kg(-1) and perampanel 1 mg kg(-1) terminated seizures in 9/9 rats at 30 min. In conclusion, perampanel and GYKI52466 provided efficacy in a lithium-pilocarpine SE model at 30 min after seizure onset, when SE was refractory to diazepam, supporting the therapeutic potential of AMPA receptor antagonists for refractory SE. The perampanel dose required to terminate seizures was reduced by combination with diazepam, suggesting synergy. PMID- 25505608 TI - Survival benefit of ghrelin in the heart failure due to dilated cardiomyopathy. AB - Although ghrelin has been demonstrated to improve cardiac function in heart failure, its therapeutic efficacy on the life expectancy remains unknown. We aim to examine whether ghrelin can improve the life survival in heart failure using a mouse model of inherited dilated cardiomyopathy (DCM) caused by a deletion mutation DeltaK210 in cardiac troponin T (cTnT). From 30 days of age, ghrelin (150 MUg/kg) was administered subcutaneously to DCM mice once daily, control mice received saline only. The survival rates were compared between the two groups for 30 days. After 30-day treatment, functional and morphological measurements were conducted. Ghrelin-treated DCM mice had significantly prolonged life spans compared with saline-treated control DCM mice. Echocardiography showed that ghrelin reduced left ventricular (LV) end-diastolic dimensions and increased LV ejection fraction. Moreover, histoanatomical data revealed that ghrelin decreased the heart-to-body weight ratio, prevented cardiac remodeling and fibrosis, and markedly decreased the expression of brain natriuretic peptide. Telemetry recording and heart rate variability analysis showed that ghrelin suppressed the excessive cardiac sympathetic nerve activity (CSNA) and recovered the cardiac parasympathetic nerve activity. These results suggest that ghrelin has therapeutic benefits for survival as well as for the cardiac function and remodeling in heart failure probably through suppression of CSNA and recovery of cardiac parasympathetic nerve activity. PMID- 25505610 TI - Involvement of S1P1 receptor pathway in angiogenic effects of a novel adenosine like nucleic acid analog COA-Cl in cultured human vascular endothelial cells. AB - COA-Cl (2Cl-C.OXT-A) is a recently developed adenosine-like nucleic acid analog that promotes angiogenesis via the mitogen-activated protein (MAP) kinases ERK1/2. Endothelial S1P1 receptor plays indispensable roles in developmental angiogenesis. In this study, we examined the functions of S1P1 in COA-Cl-induced angiogenic responses. Antagonists for S1P1, W146, and VPC23019, substantially but still partly inhibited the effects of COA-Cl with regard to ERK1/2 activation and tube formation in cultured human umbilical vein endothelial cells (HUVEC). Antagonists for adenosine A1 receptor and purinergic P2Y1 receptor were without effect. Genetic knockdown of S1P1 with siRNA, but not that of S1P3, attenuated COA-Cl-elicited ERK1/2 responses. The signaling properties of COA-Cl showed significant similarities to those of sphingosine 1-phosphate, an endogenous S1P1 ligand, in that both induced responses sensitive to pertussis toxin (Galpha i/o inhibitor), 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), (calcium chelator), and PP2 (c-Src tyrosine kinase inhibitor). COA-Cl elevated intracellular Ca(2+) concentration and induced tyrosine phosphorylation of p130Cas, a substrate of c-Src, in HUVEC. COA-Cl displaced [(3)H]S1P in a radioligand-binding competition assay in chem-1 cells overexpressing S1P1. However, COA-Cl activated ERK1/2 in CHO-K1 cells that lack functional S1P1 receptor, suggesting the presence of additional yet-to-be-defined COA-Cl target in these cells. The results thus suggest the major contribution of S1P1 in the angiogenic effects of COA-Cl. However, other mechanism such as that seen in CHO-K1 cells may also be partly involved. Collectively, these findings may lead to refinement of the design of this nucleic acid analog and ultimately to development of small molecule-based therapeutic angiogenesis. PMID- 25505609 TI - Intranasal NAP (davunetide) decreases tau hyperphosphorylation and moderately improves behavioral deficits in mice overexpressing alpha-synuclein. AB - Genome-wide association studies have identified strong associations between the risk of developing Parkinson's disease (PD) and polymorphisms in the genes encoding alpha-synuclein and the microtubule-associated protein tau. However, the contribution of tau and its phosphorylated form (p-tau) to alpha-synuclein induced pathology and neuronal dysfunction remains controversial. We have assessed the effects of NAP (davunetide), an eight-amino acid peptide that decreases tau hyperphosphorylation, in mice overexpressing wild-type human alpha synuclein (Thy1-aSyn mice), a model that recapitulates aspects of PD. We found that the p-tau/tau level increased in a subcortical tissue block that includes the striatum and brain stem, and in the cerebellum of the Thy1-aSyn mice compared to nontransgenic controls. Intermittent intranasal NAP administration at 2 MUg/mouse per day, 5 days a week, for 24 weeks, starting at 4 weeks of age, significantly decreased the ratio of p-tau/tau levels in the subcortical region while a higher dose of 15 MUg/mouse per day induced a decrease in p-tau/tau levels in the cerebellum. Both NAP doses reduced hyperactivity, improved habituation to a novel environment, and reduced olfactory deficits in the Thy1 aSyn mice, but neither dose improved the severe deficits of motor coordination observed on the challenging beam and pole, contrasting with previous data obtained with continuous daily administration of the drug. The data reveal novel effects of NAP on brain p-tau/tau and behavioral outcomes in this model of synucleinopathy and suggest that sustained exposure to NAP may be necessary for maximal benefits. PMID- 25505613 TI - Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer. AB - In a personalized treatment designed for a patient with pancreatic cancer resistant to other treatments, the success of Mitomycin C (MMC) has been highlighted. This was revealed in a murine xenograft tumor model encompassing pancreatic adenocarcinoma cells extracted from the patient. The patient was found to exhibit a biallelic inactivation of the PALB2 gene, involved in DNA repair in addition to another mutation in the TSC2 gene that induces susceptibility of the tumor to therapeutic targets of the PI3K-mTOR pathway. The aim of the study was to apply metabolomics to elucidate the modes of action of each therapy, suggesting why MMC was so successful in this patient and why it could be a more popular choice in future pancreatic cancer treatment. The effectiveness of MMC compared to rapamycin (RM), another relevant therapeutic agent has been evaluated through liquid- and gas-chromatography mass spectrometry-based metabolomic analyses of the xenograft tumors. The relative concentrations of many metabolites in the xenograft tumors were found to be increased by MMC relative to other treatments (RM and a combination of both), including a number that are involved in central carbon metabolism (CCM). Metabolic fingerprinting revealed statistically significantly altered pathways including, but not restricted to, the pentose phosphate pathway, glycolysis, TCA cycle, purine metabolism, fatty acid biosynthesis, in addition to many significant lipid and amino acid alterations. Given the genetic background of the patient, it was expected that the combined therapy would be most effective; however, the most effective was MMC alone. It is proposed that the effectiveness of MMC is owed to its direct effect on CCM, a vital region of tumor metabolism. PMID- 25505612 TI - Mefloquine, an anti-malaria agent, causes reactive oxygen species-dependent cell death in mast cells via a secretory granule-mediated pathway. AB - Mast cells are known to have a detrimental impact on a variety of pathological conditions. There is therefore an urgent need of developing strategies that limit their harmful effects. The aim of this study was to accomplish this by developing a means of inducing mast cell apoptosis. The strategy was to identify novel compounds that induce mast cell apoptosis by permeabilization of their secretory lysosomes (granules). As a candidate, we assessed mefloquine, an anti-malarial drug that has been proposed to have lysosome-permeabilizing activity. Mefloquine was added to mast cells and administered in vivo, followed by assessment of the extent and mechanisms of mast cell death. Mefloquine was cytotoxic to murine and human mast cells. Mefloquine induced apoptotic cell death of wild-type mast cells whereas cells lacking the granule compounds serglycin proteoglycan or tryptase were shown to undergo necrotic cell death, the latter finding indicating a role of the mast cell granules in mefloquine-induced cell death. In support of this, mefloquine was shown to cause compromised granule integrity and to induce leakage of granule components into the cytosol. Mefloquine-induced cell death was refractory to caspase inhibitors but was completely abrogated by reactive oxygen species inhibition. These findings identify mefloquine as a novel anti-mast cell agent, which induces mast cell death through a granule-mediated pathway. Mefloquine may thus become useful in therapy aiming at limiting harmful effects of mast cells. PMID- 25505614 TI - Isobenzofuranone derivatives exhibit antileishmanial effect by inhibiting type II DNA topoisomerase and inducing host response. AB - Leishmania, a protozoan parasite, causes a wide range of human diseases ranging from the localized self-healing cutaneous lesions to fatal visceral leishmaniasis. Toxicity of traditional first line drugs and emergence of drug resistant strains have worsened the situation. DNA topoisomerase II in kinetoplastid protozoan parasites are of immense interest as drug target because they take part in replication of unusual kinetoplast DNA network. In this study, we have taken target-based therapeutic approaches to combat leishmaniasis. Two isobenzofuranone compounds, viz., (1) 3,5-bis(4-chlorophenyl)-7 hydroxyisobenzofuran-1(3H)-one (JVPH3) and (2) (4-bromo)-3'-hydroxy-5'-(4 bromophenyl)-benzophenone(JVPH4) were synthesized chemically and characterized by NMR and mass spectrometry analysis. Activity of type II DNA topoisomerase of leishmania (LdTOPII) was monitored by decatenation assay and plasmid cleavage assay. The antiparasitic activity of these compounds was checked in experimental BALB/c mice model of visceral leishmaniasis. Isobenzofuranone derivatives exhibited potent antileishmanial effect on both antimony (Sb) sensitive and resistant parasites. Treatment with isobenzofuranone derivatives on promastigotes caused induction of reactive oxygen species (ROS)-mediated apoptosis like cell death in leishmania. Both the compounds inhibited the decatenation activity of LdTOPII but have no effect on bi-subunit topoisomerase IB. Treatment of LdTOPII with isobenzofuranone derivatives did not stabilize cleavage complex formation both in vitro and in vivo. Moreover, treatment with isobenzofuranone derivatives on Leishmania donovani-infected mice resulted in clearance of parasites in liver and spleen by induction of Th1 cytokines. Taken together, our data suggest that these compounds can be exploited as potential antileishmanial agents targeted to DNA topoisomerase II of the parasite. PMID- 25505615 TI - Detection of morphine-3-sulfate and morphine-6-sulfate in human urine and plasma, and formation in liver cytosol. AB - Morphine is still the mainstay in treatment of severe pain and is metabolized in the liver mainly by glucuronidation, partly to the pharmacologically active morphine-6-glucuronide (M6G). The sulfation pathway has attracted much less attention but may also form active metabolites. The aim of the present study was to study two sulfate metabolites of morphine in humans. Urine and plasma from newborns, adult heroin addicts, and terminal cancer patients was analyzed for the presence of morphine-3-sulfate (M3S) and morphine-6-sulfate (M6S) by a new liquid chromatography - tandem mass spectrometry (LC-MS/MS) method. In addition, morphine sulfation was studied in vitro in human liver cytosol preparations. M3S was present in urine and plasma from all study groups although at lower concentrations than morphine-3-glucuronide (M3G). The plasma M3S/M3G ratio was 30 times higher in newborns than in adults indicating that the relative sulfation is more important at early stage of life. M6S was measurable in only one plasma sample from a newborn patient, and in one of the urine sample from the drug testing group. The incubation of morphine with liver cytosol extracts resulted in approximately equal rate of formation of both M3S and M6S. In conclusion, sulfation of morphine is catalyzed in human liver but this minor metabolic pathway probably lacks clinical significance. The M6S metabolite is formed at a low rate, making it undetectable in most individuals. PMID- 25505616 TI - Development of a 'patient information leaflet' for use following assessment of patients with reported or suspected paracetamol overdose in the UK. AB - The aim of this study was to design an information leaflet for patients with paracetamol overdose based on Medicines and Healthcare products Regulatory Agency guidance and to assess its readability. A two-sided one page information leaflet was designed for patients being discharged from hospital after a paracetamol overdose. Patients presenting with an acute paracetamol overdose, irrespective of whether they were treated or not, were recruited to read the leaflet and then answer a brief structured questionnaire based on the leaflet. The readability of the information leaflet was assessed using the Flesch reading ease score. Thirty patients (15 male, 12 female, 3 not recorded; mean age 38 +/- 13.0 years) were recruited, wherein 100% of patients reported the language used was understandable, 96.6% knew which symptoms would require urgent medical review after discharge and 100% of patients knew the liver was affected by paracetamol. The Flesch reading ease score was 67.6 (out of a maximum of 100), equivalent to a UK reading age of 10-11years old. Our information leaflet for all patients being discharged after paracetamol overdose was well received by patients, provided them with the required knowledge and had an appropriate reading age based on UK literacy rates. We would recommend that this leaflet could be used as a template on a national level, localized to individual hospitals, to improve patient knowledge of paracetamol toxicity, and facilitate early medical review in the event of deterioration following discharge from the hospital. PMID- 25505617 TI - Analysis of FK506, timcodar (VX-853) and FKBP51 and FKBP52 chaperones in control of glucocorticoid receptor activity and phosphorylation. AB - The immunosuppressive ligand FK506 and the FK506-binding protein FKBP52 are stimulatory to glucocorticoid receptor (GR) activity. Here, we explore the underlying mechanism by comparing GR activity and phosphorylation status in response to FK506 and the novel nonimmunosuppressive ligand timcodar (VX-853) and in the presence and absence of FKBP52 and the closely related protein FKBP51. Using mouse embryonic fibroblast cells (MEFs) deficient knockout (KO) in FKBP51 or FKBP52, we show decreased GR activity at endogenous genes in 52KO cells, but increased activity in 51KO cells. In 52KO cells, elevated phosphorylation occurred at inhibitory serine 212 and decreased phosphorylation at the stimulatory S220 residue. In contrast, 51KO cells showed increased GR phosphorylation at the stimulatory residues S220 and S234. In wild-type (WT) MEF cells, timcodar, like FK506, potentiated dexamethasone-induced GR transcriptional activity at two endogenous genes. Using 52KO and 51KO MEF cells, FK506 potentiated GR activity in 51KO cells but could not do so in 52KO cells, suggesting FKBP52 as the major target of FK506 action. Like FK506, timcodar potentiated GR in 51KO cells, but it also increased GR activity in 52KO cells. Knock-down of FKBP51 in the 52KO cells showed that the latter effect of timcodar required FKBP51. Thus, timcodar appears to have a dual specificity for FKBP51 and FKBP52. This work demonstrates phosphorylation as an important mechanism in FKBP control of GR and identifies the first nonimmunosuppressive macrolide capable of targeting GR action. PMID- 25505618 TI - Use of a novel rapid and resource-efficient cassette dosing approach to determine the pharmacokinetics and CNS distribution of small molecule 7-transmembrane receptor allosteric modulators in rat. AB - Approaches to efficiently and accurately define the pharmacokinetics (PK) of large sets of small molecules in rodents have been previously described. Likewise, a variety of methods for determining brain tissue distribution (BTD) have been reported for use in the discovery of therapeutics targeting the central nervous system (CNS). Herein we describe a novel cassette approach to efficiently obtain concurrent PK and BTD data from a dose of up to five compounds in one rat over 24 h. In conjunction with fraction unbound (fu) data obtained in plasma and brain homogenate, this approach serves as an efficient means to determine compound unbound brain:unbound plasma partition coefficients (K p,uu), thereby providing insight to compounds bearing poor permeability and/or active transporter activity impacting their permeation of the blood-brain barrier (BBB). This integrated approach was utilized in a lead optimization effort towards the discovery of CNS-penetrant allosteric modulators of a seven-transmembrane (7TM) receptor target. Rat PK and brain distribution was rapidly obtained for 70 compounds and correlated to data obtained from in vitro assessments. Two compounds that were evaluated in cassette and discrete studies, displayed agreement in PK (compound 1: cassette CLp = 1.6 mL min(-1) kg(-1), discrete CLp = 1.6 mL min(-1) kg(-1); compound 2: cassette CLp = 11 mL min(-1) kg(-1), discrete CLp = 8.1 mL min(-1) kg(-1)) and BTD (compound 1: cassette K p = 0.11, discrete K p = 0.09; compound 2: cassette K p < 0.05, discrete K p = 0.04). The resulting data were used to guide medicinal chemistry efforts and to enable the progression of optimized compounds to in vivo pharmacodynamic assessments. PMID- 25505619 TI - Nordihydroguaiaretic acid activates hTRPA1 and modulates behavioral responses to noxious cold in mice. AB - Nordihydroguaiaretic acid (NDGA) is a major biologically active component of the creosote bush, Larrea tridentate, widely used in unregulated therapies. NDGA is a lipoxygenase inhibitor while a derivative, terameprocol, has been trialed as a chemotherapeutic agent. When investigating fatty acid activation of the human transient receptor potential cation channel subfamily A, member 1 (hTRPA1), we found that NDGA activated the channel. Here we investigate the actions of NDGA and terameprocol at hTRPA1 and the consequences of this for noxious cold sensitivity in mice. hTRPA1 was stably expressed in HEK 293 cells (HEK 293-TRPA1) and channel activity examined by measuring changes in intracellular calcium ([Ca]i) using a fluorescent dye and activation of membrane currents using patch clamp electrophysiology. The effects of local NDGA and terameprocol application on acetone-induced paw flinching were examined in mice. NDGA (pEC50 of 5.4 +/- 0.1, maximum change in fluorescence of 385 +/- 30%) and terameprocol (pEC50 4.5 +/- 0.2, maximum 550 +/- 75%) increased [Ca]i in HEK 293-hTRPA1 cells. NDGA also induced an increase in membrane conductance in HEK 293-hTRPA1 cells. These effects were prevented by the TRPA1 antagonist HC-030031, and were dependent on the presence of Cys621, Cys 641, and Cys 665 in hTRPA1. Neither NDGA nor terameprocol alone produced spontaneous pain behaviors in mice after hind paw injection, but both enhanced responses to acetone. NDGA and terameprocol are efficacious activators of TRPA1. NDGA should be used with care to probe lipoxygenase involvement in nociception while TRPA1 activity should be considered when considering use of these drugs in humans. PMID- 25505623 TI - The ongoing need for local services for people with complex mental health problems. AB - Despite developments in mental healthcare over recent decades, there remains a group of people with very complex needs who require lengthy admissions and high levels of support in the community on discharge. This is the group that mental health rehabilitation services focus on. In the context of contemporary mental health services that minimise in-patient lengths of stay, the needs of this group must not be overlooked. Providing a local, 'whole system, integrated rehabilitation care pathway' requires intelligent commissioning in order to avoid the social exclusion of this group to the 'virtual asylum' of out-of-area placements. PMID- 25505620 TI - Selective IAP inhibition results in sensitization of unstimulated but not CD40 stimulated chronic lymphocytic leukaemia cells to TRAIL-induced apoptosis. AB - Despite recent advances in therapy, chronic lymphocytic leukaemia (CLL) remains incurable and new treatment strategies are therefore urgently required. Inhibitor of apoptosis proteins (IAPs) are over-expressed in CLL, suggesting both a role in disease pathogenesis and the potential for therapeutic targeting. To explore these questions, we evaluated the effects on primary CLL cells of AZD5582, a novel potent and selective inhibitor of IAPs. AZD5582 at nanomolar concentrations induced extensive degradation of cIAP-1 and cIAP-2, but minimally of X chromosome linked IAP (XIAP). However, these effects of AZD5582 produced little or no direct cytotoxicity, nor did they sensitize CLL cells to p53-dependent killing by fludarabine or p53-independent killing by dexamethasone. In contrast, AZD5582 significantly enhanced apoptosis induced by the death receptor (DR) agonist tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Importantly, killing by TRAIL plus AZD5582 was independent of adverse prognostic features including TP53 deletion which is strongly associated with chemoresistance in CLL. Coculture experiments involving transfected mouse fibroblasts expressing human CD40L (CD154) to mimic the effect of T cells at sites of tissue involvement showed that CD40 stimulation almost completely prevented the killing of CLL cells by TRAIL plus AZD5582 despite up-regulating TRAIL receptors 1 and 2. In conclusion, our findings confirm the rate-limiting, upstream involvement of IAPs in the extrinsic but not intrinsic apoptotic pathway of CLL cells and suggest that drug combinations that simultaneously activate DRs and inhibit IAPs may have therapeutic potential in patients with CLL who have failed T-cell-depleting chemotherapy. PMID- 25505621 TI - Modulation of CYP3a expression and activity in mice models of type 1 and type 2 diabetes. AB - CYP3A4, the most abundant cytochrome P450 enzyme in the human liver and small intestine, is responsible for the metabolism of about 50% of all marketed drugs. Numerous pathophysiological factors, such as diabetes and obesity, were shown to affect CYP3A activity. Evidences suggest that drug disposition is altered in type 1 (T1D) and type 2 diabetes (T2D). The objective was to evaluate the effect of T1D and T2D on hepatic and intestinal CYP3a drug-metabolizing activity/expression in mice. Hepatic and intestinal microsomes were prepared from streptozotocin induced T1D, db/db T2D and control mice. Domperidone was selected as a probe substrate for CYP3a and formation of five of its metabolites was evaluated using high performance liquid chromatography. Hepatic CYP3a protein and mRNA expression were assessed by Western blot and reverse-transcription quantitative polymerase chain reaction respectively. Hepatic microsomal CYP3a activity was significantly increased in both T1D and T2D groups versus control group. Intestinal CYP3a activity was also significantly increased in both T1D and T2D groups. Moreover, significant increases of both hepatic CYP3a mRNAs and protein expression were observed in both T1D and T2D groups versus control group. Additional experiments with testosterone further validated the increased activity of CYP3a under the effect of both T1D and T2D. Although differences exist in the pathophysiological insults associated with T1D and T2D, our results suggest that these two distinct diseases may have the same modulating effect on the regulation of CYP3a, ultimately leading to variability in drug response, ranging from lack of effect to life-threatening toxicity. PMID- 25505624 TI - Patient engagement and problematic behaviours in nurse-staffed residential rehabilitation units. AB - Aims and method To build on previous research findings by examining engagement and problematic behaviours of patients in 10 residential rehabilitation units. Two measures were completed on patients in community rehabilitation, longer-term complex care and high-dependency units (109 patients in total). Data were analysed and categorised into higher-engagement ratings across the domains of engagement and behaviour over the past 6 months and lifetime in terms of presence of the behaviour and likelihood of resulting harm. Results Data were available for 73% of patients. All aspects of engagement were consistently low for all units, with highest levels in community rehabilitation units. Levels of problematic behaviours were similar across all units. Socially inappropriate behaviours and failure to complete everyday activities were evident for over half of all patients and higher for lifetime prevalence. Verbal aggression was at significantly lower levels in community units. Lifetime behaviours likely to lead to harm were much more evident in high-dependency units. Clinical implications Despite some benefits of this type of care, patients continue to present challenges in engagement and problematic behaviours that require new approaches and a change in focus. PMID- 25505625 TI - Hope, happiness and home treatment: a study into patient satisfaction with being treated at home. AB - Aims and method This study investigates patient satisfaction and levels of hope after receiving treatment from a home treatment team. It studies whether distributing questionnaires during the last visit increases the response rate, and explores whether patient satisfaction and levels of hope are associated with particular elements of the care received. Results Patients who answered the questionnaire tended to be satisfied. When forms were distributed during the last visit, the response rate increased to at least 64%. People with negative views were more likely to return the form by post. Patient satisfaction and levels of hope were associated with most elements of received care, and the resolution of problems was predictive of both satisfaction and increased hope in logistic regression. Clinical implications The distribution of service evaluation questionnaires during the last visit increased the response rate considerably. This study suggests that in order to improve services, it is important to focus on whether patients think their problems have been resolved. PMID- 25505626 TI - Demographic and clinical characteristics of UK military veterans attending a psychological therapies service. AB - Aims and method To investigate the demographic and clinical characteristics of subgroups of UK veterans attending a dedicated psychological therapies service following the Improving Access to Psychological Therapies (IAPT) treatment model. Veterans accessing a newly established service in the north-west were categorised into three groups: early service leavers, those with a physical disability, and substance and/or alcohol misusers. Anxiety, depression and social functioning were measured pre- and post-treatment. Results Veterans vary in their demographic and clinical characteristics as well as in treatment efficacy, as measured by the post-treatment scores on probable depression and anxiety. Therapy appears to be most effective in early service leavers, whereas veterans with a physical disability or a substance or alcohol misuse problem tend not to do as well in terms of symptoms of depression or anxiety. Clinical implications This study highlights the importance of targeting different veteran subgroups for dedicated psychological therapy. PMID- 25505627 TI - Does a home treatment acute relapse prevention strategy reduce admissions for people with mania in bipolar affective disorder? AB - Aims and method To assess whether a home treatment team acute relapse prevention (ARP) strategy reduces admissions to hospital with mania. A retrospective design was used to analyse records for manic admissions since 2002. The number and length of admissions and detentions pre- and post-ARP were determined and rates of admissions and detentions calculated from this. Results We found reductions in admission and detention rates following the introduction of the ARP: 0.3 fewer admissions per person per year (95% bootstrap CI 0.09-0.62) and 0.25 fewer detentions per person per year (95% bootstrap CI 0.0-0.48). Wilcoxon signed-rank tests gave P<0.0001. Clinical implications A person-centred care plan such as the ARP which enables quick action in response to relapse-warning signs of mania appears to reduce rates of admission to hospital. The ARP could be used anywhere in the UK and fits with current mental health policy. PMID- 25505629 TI - Sustainable psychiatry in the UK. AB - Demands on our mental health services are growing as financial pressures increase. In addition, there are regular changes to service design and commissioning. The current political mantra is 'more and more, of better quality, for less and less, please'. We suggest that mental health services need to actively respond to these constraints and that clinical transformation is needed to move towards a more sustainable system of healthcare. Emphasis on prevention, patient empowerment and leaner, greener services is required alongside more extensive use of technologies. Focusing on these areas will make mental health services more responsive to the challenges we face and serve to future-proof psychiatry in the UK. Services need to be delivered to provide maximum benefit to the health of our patients, but also to our society and the environment. PMID- 25505628 TI - Systematic computerised cardiovascular health screening for people with severe mental illness. AB - Aims and method People with severe mental illness (SMI) die relatively young, with mortality rates four times higher than average, mainly from natural causes, including heart disease. We developed a computer-based physical health screening template for use with primary care information systems and evaluated its introduction across a whole city against standards recommended by the National Institute for Health and Care Excellence for physical health and cardiovascular risk screening. Results A significant proportion of SMI patients were excluded from the SMI register and only a third of people on the register had an annual physical health check recorded. The screening template was taken up by 75% of GP practices and was associated with better quality screening than usual care, doubling the rate of cardiovascular risk recording and the early detection of high cardiovascular risk. Clinical implications A computerised annual physical health screening template can be introduced to clinical information systems to improve quality of care. PMID- 25505631 TI - Does a cluster always equal a cluster? Geographical variation of cluster populations. AB - Aims and method To provide information regarding the extent to which the process of clustering using the mental health clustering tool captures the complexity of patient need across different geographical areas. Investigation was undertaken via a 'deep dive' into patient notes, with data collected on patients allocated to cluster 5, 8 or 13 in three different London boroughs. Results There is evidence for within-cluster differences between patients in different London boroughs in terms of various complexity factors. Further findings in relation to accuracy of clustering suggest some area-specific patterns in terms of clustering practice, raising the possibility that clinicians have different scoring thresholds in different areas. Clinical implications Complexity factors can affect resource use and therefore cost of service provision. In the case of a national tariff, providers of care to more complex patients may be placed at greater financial risk. It is therefore likely that some form of tariff adjustments will need to be introduced so as not to disadvantage patients and clinicians practising in areas of greater complexity. PMID- 25505630 TI - Embedding the Mental Capacity Act 2005 in clinical practice: an audit review. AB - Aims and method An audit cycle assessed compliance of healthcare professionals within Oxleas NHS Foundation Trust with the statutory requirements of the Mental Capacity Act 2005 in patient care. Each stage involved a retrospective review of relevant patient electronic records. The additional purpose of the audit was to make recommendations to improve compliance with the requirement of the Act by healthcare professionals and improve patient understanding of its provisions. Results The audit cycle demonstrated some improvement in clinical practice as well as the need for further efforts at raising the understanding and compliance of clinicians and the public with provisions of the Act. Clinical Implications Healthcare professionals need further understanding of the provisions of the Act and their responsibilities. There is also the need to enhance public awareness to provisions of the Act in relation to their decision-making autonomy. Stakeholders need to put strategies in place for these to be achieved. PMID- 25505632 TI - Do regulated resident working hours affect medical graduate education? Trends in the American psychiatry board pass rates pre- and post-2003 duty hours regulations. AB - Aims and method To assess trends of the American Board of Psychiatry and Neurology examination pass rates before and after the 2003 duty hours regulations (DHR). We obtained the pass rates for part I and II for years 2000-2010. Data were divided pre-DHR (2000-2003) and post-DHR (2007-2010). Results During the pre DHR period, first- and multiple-attempt group pass rates were 80.7% and 39.0% which changed in the post-DHR period to 89.7% and 39.1% respectively. Similarly for the part II exam, the pre-DHR first- and multiple-attempt group pass rates were 60.2% and 43.5% respectively, which increased to 78.7% and 53.8%, among the post-DHR group. Overall, there was a significant increase in the first-attempt candidates pass rates for parts I and II, whereas multiple-attempt candidates did not benefit as strongly. Clinical implications The results suggest that the 2003 DHR may have had a positive impact on examination-based medical knowledge in psychiatry. PMID- 25505633 TI - Profile: dr simon sinclair. PMID- 25505634 TI - More support from mental health trusts needed to enable exposure to psychiatry for secondary school pupils. PMID- 25505635 TI - Availability of work experience placements in psychiatry: the real picture. PMID- 25505636 TI - Mainstream media today: the contemporary challenge in rebranding modern psychiatry. PMID- 25505637 TI - More case reports in child psychiatry needed. PMID- 25505638 TI - A proactive and acceptable clinic solution for patients with medically unexplained symptoms. PMID- 25505639 TI - Insulin coma therapy: let's be factual. PMID- 25505640 TI - Response to review of Play: Experiential Methodologies. PMID- 25505642 TI - Subclinical Indication of Linkage Between Markers of Skeletal and Cardiovascular Properties. AB - Little is known about early coincidental changes in bone and vascular properties, particularly in the context of skeletal anabolism (puberty) versus relative equilibrium (young adulthood). We aimed to determine if subclinical markers of vascular function were associated with bone mineral content (BMC) and to evaluate the contribution of systemic factors in healthy females ages 14-42 years. Endothelial function was assessed by flow mediated dilatation (FMD), arterial stiffness by pulse wave velocity (PWV) and augmentation index (AIx), blood pressure (BP) by sphygmomanometer, BMC by DXA, and systemic factors by fasting blood draw. General linear models controlled for age, race and height indicated a positive association between systolic BP (SBP) and BMC independent of systemic factors. When stratified by age using 19 years as a cut-point, there was an inverse relationship between AIx75 in adolescents with insulin (P<0.10) or inflammatory markers (P<0.10) in statistical models. Conversely, there was a positive relationship between BMC and both PWV and AIx75 in young adults (P<0.05). The link between bone and the vasculature may be life stage-dependent. In the context of a less dynamic microenvironment in young adult females, metabolic factors appear to moderate less of an effect of hemodynamic properties on the skeleton relative to adolescents. PMID- 25505643 TI - An Evidence-Based Approach to the Evaluation, Diagnostic Assessment and Treatment of Fecal Incontinence in Women. AB - Fecal incontinence (FI) is a debilitating disorder which negatively impacts quality of life. The etiology is often multifactorial and although most women with FI are able to be treated, many remain untreated because a significant proportion of women do not report their symptoms and seek care. The evaluation and treatment of FI can be also hindered by a lack of understanding of the mechanisms and current options. This article provides a review on the evidence based evaluation and management for FI. PMID- 25505644 TI - Distributive Conjugal Transfer: New Insights into Horizontal Gene Transfer and Genetic Exchange in Mycobacteria. AB - The last decade has seen an explosion in the application of genomic tools across all biological disciplines. This is also true for mycobacteria, where whole genome sequences are now available for pathogens and non-pathogens alike. Genomes within the Mycobacterium tuberculosis Complex (MTBC) bear the hallmarks of horizontal gene transfer (HGT). Conjugation is the form of HGT with the highest potential capacity and evolutionary influence. Donor and recipient strains of Mycobacterium smegmatis actively conjugate upon co-culturing in biofilms and on solid media. Whole genome sequencing of the transconjugant progeny demonstrated the incredible scale and range of genomic variation that conjugation generates. Transconjugant genomes are complex mosaics of the parental strains. Some transconjugant genomes are up to one-quarter donor-derived, distributed over 30 segments. Transferred segments range from ~50 bp to ~225,000 bp in length, and are exchanged with their recipient orthologs all around the genome. This unpredictable genome-wide infusion of DNA sequences is called Distributive Conjugal Transfer (DCT), to distinguish it from traditional oriT-based conjugation. The mosaicism generated in a single transfer event resembles that seen from meiotic recombination in sexually reproducing organisms, and contrasts with traditional models of HGT. This similarity allowed the application of a GWAS like approach to map the donor genes that confer a donor mating identity phenotype. The mating identity genes map to the esx1 locus, expanding the central role of ESX-1 function in conjugation. The potential for DCT to instantaneously blend genomes will affect how we view mycobacterial evolution, and provide new tools for the facile manipulation of mycobacterial genomes. PMID- 25505646 TI - In silico pharmacology: drug design and discovery's gate to the future. PMID- 25505645 TI - Behavioural asymmetries on the greyscales task: The influence of native reading direction. AB - Reliable leftward attentional and perceptual biases demonstrated in a variety of visuospatial tasks have been found to deviate from the left in research examining the influence of scanning habits. The aim of the current research was to examine the influence of native script direction on pseudoneglect during the greyscales task in a representative sample of native right-to-left readers. Fifty-four native left-to-right readers and 43 right-to-left readers completed the greyscales task, which required judging the darker of two left-right mirrored brightness gradients. Native left-to-right readers demonstrated a left response bias on the greyscales task, whereas right-to-left readers failed to demonstrate a bias, however, both groups responded more quickly when making leftward choices. The research suggests that the strength of attentional biases are influenced by behavioural biases, such as scanning habits, and neural and anatomical asymmetries in the right parietal and frontal cortices. Thus, to improve the clinical utility of the greyscales task for diagnosing neglect, right-to-left readers should be examined to fully understand the normal range of biases displayed by neurologically healthy individuals. PMID- 25505647 TI - Agonist and antagonist binding to the nuclear vitamin D receptor: dynamics, mutation effects and functional implications. AB - PURPOSE: The thermodynamically favored complex between the nuclear vitamin D receptor (VDR) and 1alpha,25(OH)2-vitamin D3 (1,25D3) triggers a shift in equilibrium to favor VDR binding to DNA, heterodimerization with the nuclear retinoid x receptor (RXR) and subsequent regulation of gene transcription. The key amino acids and structural requirements governing VDR binding to nuclear coactivators (NCoA) are well defined. Yet very little is understood about the internal changes in amino acid flexibility underpinning the control of ligand affinity, helix 12 conformation and function. Herein, we use molecular dynamics (MD) to study how the backbone and side-chain flexibility of the VDR differs when a) complexed to 1alpha,25(OH)2-vitamin D3 (1,25D3, agonist) and (23S),25-dehydro 1alpha(OH)-vitamin D3-26,23-lactone (MK, antagonist); b) residues that form hydrogen bonds with the C25-OH (H305 and H397) of 1,25D3 are mutated to phenylalanine; c) helix 12 conformation is changed and ligand is removed; and d) x-ray water near the C1- and C3-OH groups of 1,25D3 are present or replaced with explicit solvent. METHODS: We performed molecular dynamic simulations on the apo- and holo-VDRs and used T-Analyst to monitor the changes in the backbone and side chain flexibility of residues that form regions of the VDR ligand binding pocket (LBP), NCoA surface and control helix 12 conformation. RESULTS: The VDR-1,25D3 and VDR-MK MD simulations demonstrate that 1,25D3 and MK induce highly similar changes in backbone and side-chain flexibility in residues that form the LBP. MK however did increase the backbone and side-chain flexibility of L404 and R274 respectively. MK also induced expansion of the VDR charge clamp (i.e. NCoA surface) and weakened the intramolecular interaction between H305---V418 (helix 12) and TYR401 (helix 11). In VDR_FF, MK induced a generally more rigid LBP and stronger interaction between F397 and F422 than 1,25D3, and reduced the flexibility of the R274 side-chain. Lastly the VDR MD simulations indicate that R274 can sample multiple conformations in the presence of ligand. When the R274 is extended, the beta-OH group of 1,25D3 lies proximal to the backbone carbonyl oxygen of R274 and the side-chain forms H-bonds with hinge domain residues. This differs from the x-ray, kinked geometry, where the side-chain forms an H-bond with the 1alpha-OH group. Furthermore, 1,25D3, but not MK was observed to stabilize the x-ray geometry of R274 during the > 30 ns MD runs. CONCLUSIONS: The MD methodology applied herein provides an in silico foundation to be expanded upon to better understand the intrinsic flexibility of the VDR and better understand key side-chain and backbone movements involved in the bimolecular interaction between the VDR and its' ligands. PMID- 25505648 TI - Hybrid phenylthiazole and 1,3,5-triazine target cytosolic leucyl-tRNA synthetase for antifungal action as revealed by molecular docking studies. AB - BACKGROUND: Leucyl-tRNA synthetase (LeuRS) is one of the essential enzymes belonging to the family of aminoacyl-tRNA synthetases (aaRSs), which executes the translation of genetic code by catalyzing the specific attachment of amino acids to their cognate tRNAs. This process is very crucial for survival of micro organism and thus the inhibition of LeuRS offered a novel and lucrative target for developing new antimicrobials. FINDINGS: Docking studies using hybrid phenylthiazole-1,3,5-triazine derivatives revealed that these molecules acted as probable inhibitors of candida albicans cytosolic leucyl-tRNA synthetase. CONCLUSION: The conjugates of phenylthiazole and 1,3,5-triazine can act as lead molecules towards the development of potential leucyl-tRNA synthetase inhibitors on the basis of molecular docking runs, which contribute to the possible mechanism of antifungal activity of these analogues. PMID- 25505649 TI - Use of a physiologically-based pharmacokinetic model to simulate artemether dose adjustment for overcoming the drug-drug interaction with efavirenz. AB - PURPOSE: To treat malaria, HIV-infected patients normally receive artemether (80 mg twice daily) concurrently with antiretroviral therapy and drug-drug interactions can potentially occur. Artemether is a substrate of CYP3A4 and CYP2B6, antiretrovirals such as efavirenz induce these enzymes and have the potential to reduce artemether pharmacokinetic exposure. The aim of this study was to develop an in vitro in vivo extrapolation (IVIVE) approach to model the interaction between efavirenz and artemether. Artemether dose adjustments were then simulated in order to predict optimal dosing in co-infected patients and inform future interaction study design. METHODS: In vitro data describing the chemical properties, absorption, distribution, metabolism and elimination of efavirenz and artemether were obtained from published literature and included in a physiologically based pharmacokinetic model (PBPK) to predict drug disposition simulating virtual clinical trials. Administration of efavirenz and artemether, alone or in combination, were simulated to mirror previous clinical studies and facilitate validation of the model and realistic interpretation of the simulation. Efavirenz (600 mg once daily) was administered to 50 virtual subjects for 14 days. This was followed by concomitant administration of artemether (80 mg eight hourly) for the first two doses and 80 mg (twice daily) for another two days. RESULTS: Simulated pharmacokinetics and the drug-drug interaction were in concordance with available clinical data. Efavirenz induced first pass metabolism and hepatic clearance, reducing artemether Cmax by 60% and AUC by 80%. Dose increases of artemether, to correct for the interaction, were simulated and a dose of 240 mg was predicted to be sufficient to overcome the interaction and allow therapeutic plasma concentrations of artemether. CONCLUSIONS: The model presented here provides a rational platform to inform the design for a clinical drug interaction study that may save time and resource while the optimal dose is determined empirically. Wider application of IVIVE could help researchers gain a better understanding of the molecular mechanisms underpinning variability in drug disposition. PMID- 25505650 TI - Computational pharmacokinetics at a crossroads. AB - This first special issue of In Silico Pharmacology focuses on computational pharmacokinetics since they are an important part of integrated applications in computational pharmacology. The important topics of model structure, model parameterization, improved organ description, and modeling of drug-drug interactions are covered. They are actually at the crossroads between several emerging disciplines which will shape the future of therapeutic treatments and public health. PMID- 25505651 TI - Using Bayesian-PBPK modeling for assessment of inter-individual variability and subgroup stratification. AB - PURPOSE: Inter-individual variability in clinical endpoints and occurrence of potentially severe adverse effects represent an enormous challenge in drug development at all phases of (pre-)clinical research. To ensure patient safety it is important to identify adverse events or critical subgroups within the population as early as possible. Hence, a comprehensive understanding of the processes governing pharmacokinetics and pharmacodynamics is of utmost importance. In this paper we combine Bayesian statistics with detailed mechanistic physiologically-based pharmacokinetic (PBPK) models. On the example of pravastatin we demonstrate that this combination provides a powerful tool to investigate inter-individual variability in groups of patients and to identify clinically relevant homogenous subgroups in an unsupervised approach. Since PBPK models allow the identification of physiological, drug-specific and genotype specific knowledge separately, our approach supports knowledge-based extrapolation to other drugs or populations. METHODS: PBPK models are based on generic distribution models and extensive collections of physiological parameters and allow a mechanistic investigation of drug distribution and drug action. To systematically account for parameter variability within patient populations, a Bayesian-PBPK approach is developed rigorously quantifying the probability of a parameter given the amount of information contained in the measured data. Since these parameter distributions are high-dimensional, a Markov chain Monte Carlo algorithm is used, where the physiological and drug-specific parameters are considered in separate blocks. RESULTS: Considering pravastatin pharmacokinetics as an application example, Bayesian-PBPK is used to investigate inter-individual variability in a cohort of 10 patients. Correlation analyses infer structural information about the PBPK model. Moreover, homogeneous subpopulations are identified a posteriori by examining the parameter distributions, which can even be assigned to a polymorphism in the hepatic organ anion transporter OATP1B1. CONCLUSIONS: The presented Bayesian-PBPK approach systematically characterizes inter-individual variability within a population by updating prior knowledge about physiological parameters with new experimental data. Moreover, clinically relevant homogeneous subpopulations can be mechanistically identified. The large scale PBPK model separates physiological and drug-specific knowledge which allows, in combination with Bayesian approaches, the iterative assessment of specific populations by integrating information from several drugs. PMID- 25505654 TI - The simcyp population based simulator: architecture, implementation, and quality assurance. AB - Developing a user-friendly platform that can handle a vast number of complex physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models both for conventional small molecules and larger biologic drugs is a substantial challenge. Over the last decade the Simcyp Population Based Simulator has gained popularity in major pharmaceutical companies (70% of top 40 - in term of R&D spending). Under the Simcyp Consortium guidance, it has evolved from a simple drug-drug interaction tool to a sophisticated and comprehensive Model Based Drug Development (MBDD) platform that covers a broad range of applications spanning from early drug discovery to late drug development. This article provides an update on the latest architectural and implementation developments within the Simulator. Interconnection between peripheral modules, the dynamic model building process and compound and population data handling are all described. The Simcyp Data Management (SDM) system, which contains the system and drug databases, can help with implementing quality standards by seamless integration and tracking of any changes. This also helps with internal approval procedures, validation and auto-testing of the new implemented models and algorithms, an area of high interest to regulatory bodies. PMID- 25505653 TI - Modeling bioavailability to organs protected by biological barriers. AB - Computational pharmacokinetic (PK) modeling gives access to drug concentration vs. time profiles in target organs and allows better interpretation of clinical observations of therapeutic or toxic effects. Physiologically-based PK (PBPK) models in particular, based on mechanistic descriptions of the body anatomy and physiology, may also help to extrapolate in vitro or animal data to human. Once in the systemic circulation, a chemical has access to the microvasculature of every organ or tissue. However, its penetration in the brain, retina, thymus, spinal cord, testis, placenta,... may be limited or even fully prevented by dynamic physiological blood-tissue barriers. Those barriers are both physical (involving tight junctions between adjacent cells) and biochemical (involving metabolizing enzymes and transporters). On those cases, correct mechanistic characterization of the passage (or not) of molecules through the barrier can be crucial for improved PBPK modeling and prediction. In parallel, attempts to understand and quantitatively characterize the processes involved in drug penetration of physiological barriers have led to the development of several in vitro experimental models. Data from such assays are very useful to calibrate PBPK models. We review here those in vitro and computational models, highlighting the challenges and perspectives for in vitro and computational models to better assess drug availability to target tissues. PMID- 25505655 TI - A framework incorporating the impact of exposure scenarios and application conditions on risk assessment of chemicals applied to skin. AB - PURPOSE: 1. To develop a framework for exposure calculation via the dermal route to meet the needs of 21st century toxicity testing and refine current approaches; 2. To demonstrate the impact of exposure scenario and application conditions on the plasma concentration following dermal exposure. METHOD: A workflow connecting a dynamic skin penetration model with a generic whole-body physiologically-based pharmacokinetic (PBPK) model was developed. The impact of modifying exposure scenarios and application conditions on the simulated steady-state plasma concentration and exposure conversion factor was investigated for 9 chemicals tested previously in dermal animal studies which did not consider kinetics in their experimental designs. RESULTS: By simulating the animal study scenarios and exposure conditions, we showed that 7 studies were conducted with finite dose exposures, 1 with both finite and infinite dose exposures (in these 8 studies, an increase in the animal dose resulted in an increase in the simulated steady-state plasma concentrations (C p,ss)), while 1 study was conducted with infinite dose exposures only (an increase in the animal dose resulted in identical C p,ss). Steady-state plasma concentrations were up to 30-fold higher following an infinite dose scenario vs. a finite dose scenario, and up to 40-fold higher with occlusion vs. without. Depending on the chemical, the presence of water as a vehicle increased or decreased the steady-state plasma concentration, the largest difference being a factor of 16. CONCLUSIONS: The workflow linking Kasting's model of skin penetration and whole-body PBPK enables estimation of plasma concentrations for various applied doses, exposure scenarios and application conditions. Consequently, it provides a quantitative, mechanistic tool to refine dermal exposure calculations methodology for further use in risk assessment. PMID- 25505656 TI - Inhibition of VEGF: a novel mechanism to control angiogenesis by Withania somnifera's key metabolite Withaferin A. AB - PURPOSE: Angiogenesis, or new blood vessel formation from existing one, plays both beneficial and detrimental roles in living organisms in different aspects. Vascular endothelial growth factor (VEGF), a signal protein, well established as key regulator of vasculogenesis and angiogenesis. VEGF ensures oxygen supply to the tissues when blood supply is not adequate, or tissue environment is in hypoxic condition. Limited expression of VEGF is necessary, but if it is over expressed, then it can lead to serious disease like cancer. Cancers that have ability to express VEGF are more efficient to grow and metastasize because solid cancers cannot grow larger than a limited size without adequate blood and oxygen supply. Anti-VEGF drugs are already available in the market to control angiogenesis, but they are often associated with severe side-effects like fetal bleeding and proteinuria in the large number of patients. To avoid such side effects, new insight is required to find potential compounds as anti-VEGF from natural sources. In the present investigation, molecular docking studies were carried out to find the potentiality of Withaferin A, a key metabolite of Withania somnifera, as an inhibitor of VEGF. METHODS: Molecular Docking studies were performed in DockingServer and SwissDock. Bevacizumab, a commercial anti VEGF drug, was used as reference to compare the activity of Withaferin A. X-ray crystallographic structure of VEGF, was retrieved from Protein Data Bank (PDB), and used as drug target protein. Structure of Withaferin A and Bevacizumab was obtained from PubChem and ZINC databases. Molecular visualization was performed using UCSF Chimera. RESULTS: Withaferin A showed favorable binding with VEGF with low binding energy in comparison to Bevacizumab. Molecular Docking studies also revealed potential protein-ligand interactions for both Withaferin A and Bevacizumab. CONCLUSIONS: Conclusively our results strongly suggest that Withaferin A is a potent anti-VEGF agent as ascertained by its potential interaction with VEGF. This scientific hypothesis might provide a better insight to control angiogenesis as well as to control solid cancer growth and metastasis. PMID- 25505658 TI - New measurement criteria for studying alcohol drinking and relapse in rodents. AB - PURPOSE: Relapse to alcohol use is considered as one of the central features distinguishing dependence from controlled alcohol consumption. Relapse-like drinking in rodents is a transient episode of heavy drinking that follows a period of abstinence. This behaviour is called the alcohol deprivation effect (ADE). Not all animals develop behavioural changes that resemble relapse-like drinking behaviour. The purpose of our study was to develop a generalized quantitative criterion by which animals could be separated into two groups depending on their behaviour during a relapse-like situation (ADE vs. no-ADE). METHODS: An automated drinkometer system was used for data collection. This system measures fluid consumption by means of high-precision sensors attached to the drinking bottles in the home cage of the rat. We used a four bottle free choice paradigm with water 5, 10, and 20% ethanol solutions. For data analysis we developed a new measure of alcohol intake that quantifies net alcohol intake in relation to net consumption of water. This new measure is called water-penalized net ethanol intake. RESULTS: The new measure is more robust than commonly used measurements, such as alcohol preference and intake. It allows the comparison of alcohol intake between different groups of animals and different setups using an arbitrary number of bottles. Based on this new measure we developed a method to automatically select the threshold for the presence of ADE in individual animals. CONCLUSIONS: Separating animals by their behavior during relapse-like situation could be used as one of the criteria for identification of alcohol addicted and non-addicted rats. A classification into presenting ADE or not is also essential to test the effectiveness of newly developed therapeutic drugs. PMID- 25505652 TI - Ethanol-induced alterations of amino acids measured by in vivo microdialysis in rats: a meta-analysis. AB - PURPOSE: In recent years in vivo microdialysis has become an important method in research studies investigating the alterations of neurotransmitters in the extracellular fluid of the brain. Based on the major involvement of glutamate and gamma-aminobutyric acid (GABA) in mediating a variety of alcohol effects in the mammalian brain, numerous microdialysis studies have focused on the dynamical behavior of these systems in response to alcohol. METHODS: Here we performed multiple meta-analyses on published datasets from the rat brain: (i) we studied basal extracellular concentrations of glutamate and GABA in brain regions that belong to a neurocircuitry involved in neuropsychiatric diseases, especially in alcoholism (Noori et al., Addict Biol 17:827-864, 2012); (ii) we examined the effect of acute ethanol administration on glutamate and GABA levels within this network and (iii) we studied alcohol withdrawal-induced alterations in glutamate and GABA levels within this neurocircuitry. RESULTS: For extraction of basal concentrations of these neurotransmitters, datasets of 6932 rats were analyzed and the absolute basal glutamate and GABA levels were estimated for 18 different brain sites. In response to different doses of acute ethanol administration, datasets of 529 rats were analyzed and a non-linear dose response (glutamate and GABA release) relationship was observed in several brain sites. Specifically, glutamate in the nucleus accumbens shows a decreasing logarithmic dose response curve. Finally, regression analysis of 11 published reports employing brain microdialysis experiments in 104 alcohol-dependent rats reveals very consistent augmented extracellular glutamate and GABA levels in various brain sites that correlate with the intensity of the withdrawal response were identified. CONCLUSIONS: In summary, our results provide standardized basal values for future experimental and in silico studies on neurotransmitter release in the rat brain and may be helpful to understand the effect of ethanol on neurotransmitter release. Furthermore, this study illustrates the benefit of meta-analyses using the generalization of a wide range of preclinical data. PMID- 25505657 TI - In silico drug metabolism and pharmacokinetic profiles of natural products from medicinal plants in the Congo basin. AB - PURPOSE: Drug metabolism and pharmacokinetics (DMPK) assessment has come to occupy a place of interest during the early stages of drug discovery today. The use of computer modelling to predict the DMPK and toxicity properties of a natural product library derived from medicinal plants from Central Africa (named ConMedNP). Material from some of the plant sources are currently employed in African Traditional Medicine. METHODS: Computer-based methods are slowly gaining ground in this area and are often used as preliminary criteria for the elimination of compounds likely to present uninteresting pharmacokinetic profiles and unacceptable levels of toxicity from the list of potential drug candidates, hence cutting down the cost of discovery of a drug. In the present study, we present an in silico assessment of the DMPK and toxicity profile of a natural product library containing ~3,200 compounds, derived from 379 species of medicinal plants from 10 countries in the Congo Basin forests and savannas, which have been published in the literature. In this analysis, we have used 46 computed physico-chemical properties or molecular descriptors to predict the absorption, distribution, metabolism and elimination and toxicity (ADMET) of the compounds. RESULTS: This survey demonstrated that about 45% of the compounds within the ConMedNP compound library are compliant, having properties which fall within the range of ADME properties of 95% of currently known drugs, while about 69% of the compounds have <= 2 violations. Moreover, about 73% of the compounds within the corresponding "drug-like" subset showed compliance. CONCLUSIONS: In addition to the verified levels of "drug-likeness", diversity and the wide range of measured biological activities, the compounds from medicinal plants in Central Africa show interesting DMPK profiles and hence could represent an important starting point for hit/lead discovery. PMID- 25505659 TI - Comparison of gene expression profiles in the blood, hippocampus and prefrontal cortex of rats. AB - BACKGROUND: The comparability of gene expression between blood and brain tissues is a central issue in neuropsychiatric research where the analysis of molecular mechanisms in the brain is of high importance for the understanding of the diseases and the discovery of biomarkers. However, the accessibility of brain tissue is limited. Therefore, knowledge about how easily accessible peripheral tissue, e. g. blood, is comparable to and reflects gene expression of brain regions will help to advance neuropsychiatric research. DESCRIPTION: Gene expression in the blood, hippocampus (HC) and prefrontal cortex (PFC) of genetically identical rats was compared using a genome-wide Affymetrix gene expression microarray covering 29,215 expressed genes. A total of 56.8% of 15,717 expressed genes were co-expressed in blood and at least one brain tissue, while 55.3% of all genes were co-expressed in all three tissues simultaneously. The overlapping genes included a set of genes of relevance to neuropsychiatric diseases, in particular bipolar disorder, schizophrenia and alcohol addiction. These genes included CLOCK, COMT, FAAH, NPY, NR3C1, NRGN, PBRM1, TCF4, and SYNE. CONCLUSIONS: This study provides baseline data on absolute gene expression and differences between gene expression in the blood, HC and PFC brain tissue of genetically identical rats. The present data represents a valuable resource for future studies as it might be used for first information on gene expression levels of genes of interest in blood and brain under baseline conditions. Limitations of our study comprise possible contamination of brain tissue with blood and the non-detection of genes with very low expression levels. Genes that are more highly expressed in the brain than in the blood are of particular interest since changes in their expression, e.g. due to disease status, or treatment, are likely to be detected in an experiment. In contrast, genes with higher expression in the blood than in the brain are less informative since their higher baseline levels could superimpose variation in brain. PMID- 25505661 TI - Drug-target and disease networks: polypharmacology in the post-genomic era. AB - With the growing understanding of complex diseases, the focus of drug discovery has shifted away from the well-accepted "one target, one drug" model, to a new "multi-target, multi-drug" model, aimed at systemically modulating multiple targets. Identification of the interaction between drugs and target proteins plays an important role in genomic drug discovery, in order to discover new drugs or novel targets for existing drugs. Due to the laborious and costly experimental process of drug-target interaction prediction, in silico prediction could be an efficient way of providing useful information in supporting experimental interaction data. An important notion that has emerged in post-genomic drug discovery is that the large-scale integration of genomic, proteomic, signaling and metabolomic data can allow us to construct complex networks of the cell that would provide us with a new framework for understanding the molecular basis of physiological or pathophysiological states. An emerging paradigm of polypharmacology in the post-genomic era is that drug, target and disease spaces can be correlated to study the effect of drugs on different spaces and their interrelationships can be exploited for designing drugs or cocktails which can effectively target one or more disease states. The future goal, therefore, is to create a computational platform that integrates genome-scale metabolic pathway, protein-protein interaction networks, gene transcriptional analysis in order to build a comprehensive network for multi-target multi-drug discovery. PMID- 25505663 TI - Computational neuroscience in research for depression. AB - Depression is a common and hazardous mental disorder, which has been pathophysiologically associated with alterations of neurocircuitries involving medial prefrontal cortex, hippocampus and thalamus. Recent progress in computational neuroscience, particularly in the field of in silico psychopharmacology suggests the increasing potential of mathematical modeling in providing insights on the dynamics of these neuronal networks, which in turn may lead to further develop and clarify the present models of the pathophysiology of depression. Moreover, computational approaches provide well-defined non-invasive frameworks for investigation of the clinically common poly-pharmacological treatment strategies, which take us one step closer to the development of novel agents that will potentially result in diagnostic and prognostic indicators to be used in individualized treatment strategies. PMID- 25505660 TI - Graph analysis of beta2 adrenergic receptor structures: a "social network" of GPCR residues. AB - PURPOSE: G protein-coupled receptors (GPCRs) are a superfamily of membrane proteins of vast pharmaceutical interest. Here, we describe a graph theory-based analysis of the structure of the beta2 adrenergic receptor (beta2 AR), a prototypical GPCR. In particular, we illustrate the network of direct and indirect interactions that link each amino acid residue to any other residue of the receptor. METHODS: Networks of interconnected amino acid residues in proteins are analogous to social networks of interconnected people. Hence, they can be studied through the same analysis tools typically employed to analyze social networks - or networks in general - to reveal patterns of connectivity, influential members, and dynamicity. We focused on the analysis of closeness centrality, which is a measure of the overall connectivity distance of the member of a network to all other members. RESULTS: The residues endowed with the highest closeness-centrality are located in the middle of the seven transmembrane domains (TMs). In particular, they are mostly located in the middle of TM2, TM3, TM6 or TM7, while fewer of them are located in the middle of TM1, TM4 or TM5. At the cytosolic end of TM6, the centrality detected for the active structure is markedly lower than that detected for the corresponding residues in the inactive structures. Moreover, several residues acquire centrality when the structures are analyzed in the presence of ligands. Strikingly, there is little overlap between the residues that acquire centrality in the presence of the ligand in the blocker bound structures and the agonist-bound structures. CONCLUSIONS: Our results reflect the fact that the receptor resembles a bow tie, with a rather tight knot of closely interconnected residues and two ends that fan out in two opposite directions: one toward the extracellular space, which hosts the ligand binding cavity, and one toward the cytosol, which hosts the G protein binding cavity. Moreover, they underscore how interaction network is by the conformational rearrangements concomitant with the activation of the receptor and by the presence of agonists or blockers. PMID- 25505662 TI - Convergent functional genomics in addiction research - a translational approach to study candidate genes and gene networks. AB - Convergent functional genomics (CFG) is a translational methodology that integrates in a Bayesian fashion multiple lines of evidence from studies in human and animal models to get a better understanding of the genetics of a disease or pathological behavior. Here the integration of data sets that derive from forward genetics in animals and genetic association studies including genome wide association studies (GWAS) in humans is described for addictive behavior. The aim of forward genetics in animals and association studies in humans is to identify mutations (e.g. SNPs) that produce a certain phenotype; i.e. "from phenotype to genotype". Most powerful in terms of forward genetics is combined quantitative trait loci (QTL) analysis and gene expression profiling in recombinant inbreed rodent lines or genetically selected animals for a specific phenotype, e.g. high vs. low drug consumption. By Bayesian scoring genomic information from forward genetics in animals is then combined with human GWAS data on a similar addiction relevant phenotype. This integrative approach generates a robust candidate gene list that has to be functionally validated by means of reverse genetics in animals; i.e. "from genotype to phenotype". It is proposed that studying addiction relevant phenotypes and endophenotypes by this CFG approach will allow a better determination of the genetics of addictive behavior. PMID- 25505665 TI - The Camerino symposium series (1978-2013): a privileged observatory of receptorology development. AB - The organizers of the Camerino Receptor Symposia survey the development of receptorology. They trace the course from the first Symposium in 1978, which laid the foundation for Pirenzepine, the first selective muscarinic antagonist, to the 2010 Symposium, which highlighted the utility of functional simple domain antibodies (nanobodies) as novel G Protein-Coupled Receptor (GPCR) modulators. This 30-year period sees the acceptance of terms such as G-protein, auto- and heteroreceptors, site-directed mutagenesis, chimeric receptors, constitutive activity, inverse agonism, and orphan receptors. GPCRs are finally a reality and Langley and Ehrlich, if they returned to their laboratories, would be proud of how their intuitions have been realized. PMID- 25505664 TI - G protein-coupled receptors: computer-aided ligand discovery and computational structural analyses in the 2010s. AB - G protein-coupled receptors, or GPCRs, are a large superfamily of proteins found on the plasma membrane of cells. They are involved in most physiological and pathophysiological functions and constitute the target of the majority of marketed drugs. Although these receptors have been historically elusive to attempts of structural determination, GPCR crystallography is now in full blossom, opening the way to structure-based drug discovery and enabling homology modeling. This thematic issue of the journal In Silico Pharmacology, which illustrates how the expanding body of structural knowledge is fostering complex computational analyses of the structure-function relationships of the receptors and their interactions with their ligands, stems from the 31st Camerino-Cyprus Noordwijkerhout Symposium held in Italy, in May 2013, at the University of Camerino. Specifically, it originates from a session of the symposium entitled "Structure-Based Discovery of Ligands of G Protein-Coupled Receptors: Finally a Reality", and features a mix of research articles and reviews on the application of computational modeling to the analysis of the structure of GPCRs and the interactions of the receptors with their ligands. PMID- 25505666 TI - Simulation and comparative analysis of binding modes of nucleoside and non nucleoside agonists at the A2B adenosine receptor. AB - PURPOSE: A2B receptor agonists are studied as possible therapeutic tools for a variety of pathological conditions. Unfortunately, medicinal chemistry efforts have led to the development of a limited number of potent agonists of this receptor, in most cases with a low or no selectivity versus the other adenosine receptor subtypes. Among the developed molecules, two structural families of compounds have been identified based on nucleoside and non-nucleoside (pyridine) scaffolds. The aim of this work is to analyse the binding mode of these molecules at 3D models of the human A2B receptor to identify possible common interaction features and the key receptor residues involved in ligand interaction. METHODS: The A2B receptor models are built by using two recently published crystal structures of the human A2A receptor in complex with two different agonists. The developed models are used as targets for molecular docking studies of nucleoside and non-nucleoside agonists. The generated docking conformations are subjected to energy minimization and rescoring by using three different scoring functions. Further analysis of top-score conformations are performed with a tool evaluating the interaction energy between the ligand and the binding site residues. RESULTS: Results suggest a set of common interaction points between the two structural families of agonists and the receptor binding site, as evidenced by the superimposition of docking conformations and by analysis of interaction energy with the receptor residues. CONCLUSIONS: The obtained results show that there is a conserved pattern of interaction between the A2B receptor and its agonists. These information and can provide useful data to support the design and the development of A2B receptor agonists belonging to nucleoside or non-nucleoside structural families. PMID- 25505667 TI - Implementing the "Best Template Searching" tool into Adenosiland platform. AB - BACKGROUND: Adenosine receptors (ARs) belong to the G protein-coupled receptors (GCPRs) family. The recent release of X-ray structures of the human A2A AR (h A2A AR ) in complex with agonists and antagonists has increased the application of structure-based drug design approaches to this class of receptors. Among them, homology modeling represents the method of choice to gather structural information on the other receptor subtypes, namely A1, A2B, and A3 ARs. With the aim of helping users in the selection of either a template to build its own models or ARs homology models publicly available on our platform, we implemented our web-resource dedicated to ARs, Adenosiland, with the "Best Template Searching" facility. This tool is freely accessible at the following web address: http://mms.dsfarm.unipd.it/Adenosiland/ligand.php. FINDINGS: The template suggestions and homology models provided by the "Best Template Searching" tool are guided by the similarity of a query structure (putative or known ARs ligand) with all ligands co-crystallized with hA2A AR subtype. The tool computes several similarity indexes and sort the outcoming results according to the index selected by the user. CONCLUSIONS: We have implemented our web-resource dedicated to ARs Adenosiland with the "Best Template Searching" facility, a tool to guide template and models selection for hARs modelling. The underlying idea of our new facility, that is the selection of a template (or models built upon a template) whose co crystallized ligand shares the highest similarity with the query structure, can be easily extended to other GPCRs. PMID- 25505668 TI - Editorial: a new journal in bipolar disorders. PMID- 25505669 TI - European Network of Bipolar Research Expert Centre (ENBREC): a network to foster research and promote innovative care. AB - Bipolar disorders rank as one of the most disabling illnesses in working age adults worldwide. Despite this, the quality of care offered to patients with this disorder is suboptimal, largely due to limitations in our understanding of the pathology. Improving this scenario requires the development of a critical mass of expertise and multicentre collaborative projects. Within the framework of the European FP7 programme, we developed a European Network of Bipolar Research Expert Centres (ENBREC) designed specifically to facilitate EU-wide studies. ENBREC provides an integrated support structure facilitating research on disease mechanisms and clinical outcomes across six European countries (France, Germany, Italy, Norway, Spain and the UK). The centres are adopting a standardised clinical assessment that explores multiple aspects of bipolar disorder through a structured evaluation designed to inform clinical decision-making as well as being applicable to research. Reliable, established measures have been prioritised, and instruments have been translated and validated when necessary. An electronic healthcare record and monitoring system (e-ENBREC(c)) has been developed to collate the data. Protocols to conduct multicentre clinical observational studies and joint studies on cognitive function, biomarkers, genetics, and neuroimaging are in progress; a pilot study has been completed on strategies for routine implementation of psycho-education. The network demonstrates 'proof of principle' that expert centres across Europe can collaborate on a wide range of basic science and clinical programmes using shared protocols. This paper is to describe the network and how it aims to improve the quality and effectiveness of research in a neglected priority area. PMID- 25505671 TI - Aripiprazole as augmentation therapy in bipolar patients with current minor or subsyndromal mood symptoms. AB - BACKGROUND: This study aims to evaluate the effectiveness of aripiprazole augmentation of maintenance treatment for bipolar disorder in patients with minor or subsyndromal mood episodes while on a stable dose of a mood stabiliser and/or antidepressant. METHODS: All subjects had a diagnosis of bipolar I or II disorder (Diagnostic and Statistical Manual of Mental Disorders-4th Edition, Text Revision). Open-label aripiprazole was given over 8 weeks initially. The starting dose was 5 to 15 mg/day with a mean final dose of 11.5 mg (+/-4.6). Patients were assessed at weeks 0, 2, 4 and 8 with the Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS) and Clinical Global Impression of Severity (CGI-S). RESULTS AND DISCUSSION: Seventeen of 20 (85%) patients completed week 4, while 14 (70%) patients completed 8 weeks. For intention-to treat data, there was a significant decrease in MADRS scores over the course of treatment, with a reduction of 6.40 points at endpoint (p < 0.0005). Improvement from baseline was significant at week 2 and remained through to week 8. Similarly, CGI-S scores significantly decreased over the course of study, but not YMRS scores. Aripiprazole was shown to be a modestly effective augmentation therapy for depressive symptoms in bipolar I and II in this small open-label study. PMID- 25505670 TI - Cortical thinning in young psychosis and bipolar patients correlate with common neurocognitive deficits. AB - BACKGROUND: People in midlife with established psychosis or bipolar disorder exhibit patterns of cortical thinning across several brain regions. It is unclear whether these patterns are indicative of a continuously active pathological process, residual effects of an earlier illness phase or pre-illness onset developmental risk factors. Here, we investigated whether cortical thinning is evident in younger patients in the early phase of psychosis or bipolar disorder and the relationship between cortical thinning and neurocognitive performance in young people. METHODS: Magnetic resonance imaging was obtained from a sample of young patients with psychosis (n = 40; mean age 23.5 years), bipolar disorder (n = 73; mean age 21.9 years) or controls (n = 49; mean age 24.2 years). Group differences in cortical thickness were assessed using statistical difference maps, and regions of cortical thinning were correlated with medication dosage and performance on neurocognitive tasks. As initial comparisons using multiple corrections found no differences between the groups, follow-up analysis with a significance threshold of p < 0.001 was performed. RESULTS AND DISCUSSION: As distinct from reported findings in older subjects, young patients with psychosis have less extensive thinning in parietal-temporal areas and do not demonstrate significant thinning in the insula or dorsal lateral prefrontal cortex. Young patients with bipolar disorder exhibit cortical thinning in regions more consistent with those previously reported in paediatric bipolar patients. Although there were some differences in the regions of cortical thinning between the two groups, the shared regions of cortical thinning were correlated with neurocognitive deficits in visual sustained attention, semantic verbal fluency and verbal learning and memory that are commonly reported in young people with either psychosis or bipolar disorder. PMID- 25505672 TI - Drug treatment patterns in bipolar disorder: analysis of long-term self-reported data. AB - BACKGROUND: The objective of this study is to investigate drug treatment patterns in bipolar disorder using daily data from patients who received treatment as usual. METHODS: Patients self-reported the drugs taken daily for about 6 months. Daily drug use and drug combinations were determined for each patient, both by the specific drugs and by medication class. The drug load was calculated for all drugs taken within a medication class. RESULTS AND DISCUSSION: Four hundred fifty patients returned a total of 99,895 days of data (mean 222.0 days). The most frequently taken drugs were mood stabilizers. Of the 450 patients, 353 (78.4%) took a stable drug combination for >=50% of days. The majority of patients were taking polypharmacy, including 75% of those with a stable combination. Only a small number of drugs were commonly taken within each medication class, but there were a large number of unique drug combinations: 52 by medication class and 231 by specific drugs. Eighty percent of patients with a stable combination were taking three or less drugs daily. Patients without a stable combination took drugs but made frequent changes. Taking more than one drug within a medication class greatly increased the drug load. To summarize, (1) patients were more likely to take a mood stabilizer than any other drug; (2) although most patients were taking polypharmacy, there were no predominant drug regimens even among those taking a stable combination; and (3) most patients with a stable combination take a relatively small number of drugs daily. The wide variation in drug regimens and numerous possible drug combinations suggest that more evidence is needed to optimize treatment of bipolar disorder. PMID- 25505673 TI - Biological rhythm disturbance in remitted bipolar patients. AB - BACKGROUND: Biological rhythm disturbance is common in bipolar patients and seems to affect the course and prognosis of the illness negatively. The main aim of the current study was to assess biological rhythms in remitted bipolar patients. We also assessed whether there was an association between clinical variables or functioning and biological rhythms in remitted bipolar participants. METHODS: The Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) was used to assess biological rhythm disturbance. It is an 18-item interviewer-administered instrument which allows us to investigate the main areas related to circadian rhythm disturbance (sleep/social, activities, and eating pattern) in bipolar disorder. RESULTS AND DISCUSSION: Bipolar patients (n = 107) experienced greater biological rhythm alterations than the control group (n = 100) (BRIAN total scores 35.36 +/- 7.11 vs. 32.48 +/- 6.10, t = 6.912, p = 0.002, Cohen's d = 0.43, r = 0.21). In particular, patients were more impaired than the control group with regard to sleep/social (14.67 +/- 4.14 vs. 13.49 +/- 2.91, t = 10.61, p = 0.018, Cohen's d = 0.33, r = 0.16) and activity (8.49 +/- 2.51 vs. 7.07 +/- 2.13, t = 3.90, p = 0.001, Cohen's d = 0.61, r = 0.29) domains. Furthermore, a significant correlation was found between biological rhythms with residual depressive symptoms (r = 0.459, p < 0.001) and functioning (r = 0.432, p < 0.001). These findings suggest a potential link between biological rhythms and the pathophysiology of bipolar disorder. It highlights the importance of novel instruments (e.g., BRIAN) which allow us to assess biological rhythm disturbance in psychiatry. Finally, specific psychosocial interventions focused on lifestyle regularity may be considered as a supplemental treatment of bipolar illness episodes. PMID- 25505674 TI - Do current screening recommendations allow for early detection of lithium-induced hyperparathyroidism in patients with bipolar disorder? AB - BACKGROUND: Current screening recommendations for early detection of lithium associated hyperparathyroidism propose an exclusive measurement of serum albumin adjusted calcium (Aac) concentration as a single first step. However, longitudinal data in patients with recurrent affective disorders suggest that increases in serum intact parathyroid hormone (iPTH) levels in lithium-treated patients may not necessarily be accompanied by a parallel increase in the concentration of Aac. If true, patients with an isolated increase in iPTH concentration above the reference range might be missed following current screening recommendations. Therefore, this study set out to examine key parameters of calcium metabolism, including iPTH and 25-hydroxycholecalciferol concentrations in patients with bipolar disorder that was or was not managed with lithium. METHODS: Sixty patients with bipolar disorder according to DSM-IV were enrolled, 30 of whom had received long-term lithium treatment (lithium group), whereas the other 30 patients were on psychopharmacological treatment not including lithium (non-lithium group) at the time of the study. Owing to exclusion criteria (e.g., lithium < 6 months, laboratory results indicative of secondary hyperparathyroidism), 23 bipolar patients composed the final lithium group, whereas 28 patients remained in the non-lithium group for statistical analyses. RESULTS: Patients in the lithium group showed a significantly higher concentration of iPTH compared to the non-lithium group (p < 0.05). Similarly, Aac concentrations were significantly increased in the lithium group compared to the non-lithium group (p < 0.05). However, in a multivariate linear regression model, group affiliation only predicted iPTH concentration (p < 0.05). In line with this, none of the four patients in the lithium group with an iPTH concentration above the reference range had an Aac concentration above the reference range. DISCUSSION: This study suggests that the biochemical characteristics between primary hyperparathyroidism and lithium-induced hyperparathyroidism differ substantially with regard to regulation of calcium homeostasis. As such, current screening practice does not reliably detect iPTH concentrations above the reference range. Therefore, further research is needed to elucidate the consequences of an isolated iPTH concentration above the reference range in order to develop the most appropriate screening tools for hyperparathyroidism in lithium-treated patients with bipolar disorder. PMID- 25505675 TI - The association of glycogen synthase kinase-3beta (GSK-3beta) gene polymorphism with kidney function in long-term lithium-treated bipolar patients. AB - BACKGROUND: Most bipolar patients experience a reduction in urinary concentrating ability within a few weeks of starting lithium treatment. This phenomenon may be connected with the effect of lithium on the glycogen synthase kinase-3beta (GSK 3beta) present in the renal tubules. The GSK-3beta gene is located on chromosome 3q13 and possesses a functional -50 C/T polymorphism. In the present study, we estimated this polymorphism in a group of long-term lithium-treated patients and assessed its association with various parameters of kidney function, including novel markers of kidney injury such as serum neutrophil gelatinase-associated lipocalin (NGAL) and urinary beta2-microglobulin (beta2-MG). METHODS: The study comprised 78 patients with bipolar mood disorder (25 males, 53 females), aged 36 to 82 (60 +/- 11) years. The mean duration of bipolar illness was 6 to 50 (24 +/- 10) years, and the patients have been receiving lithium for 5 to 38 (16 +/- 9) years. All the patients had the following features, regarded as the phenotypes of kidney functions measured: urine examination for specific gravity evaluation, serum creatinine concentration, and estimated glomerular filtration rate (eGFR) evaluation, as well as the serum concentrations of NGAL and urinary beta2-MG. Genotyping of GSK-3beta gene -50 C/T polymorphism was done by polymerase chain reaction analysis. RESULTS AND DISCUSSION: Thirty-four patients (6 males, 28 females) had the T/T genotype, 37 patients (16 males, 21 females) had the T/C genotype, and 7 patients (3 males, 4 females) had the C/C genotype. Patients homozygous for C allele had significantly higher urine specific gravities (1.019 +/- 0.008) compared to the remaining genotypes (1.013 +/- 0.007) (p = 0.035), with no influence of the duration of lithium treatment. Other parameters of kidney function (serum creatinine, eGFR, serum NGAL, and urinary beta2-MG levels) were not different between genotypes and, again, were not affected by the duration of lithium treatment. There was no correlation between urine specific gravity and other kidney function parameters. The results of our study indicate that the GSK-3beta genotype may be connected with lithium-induced impairment of renal concentrating ability in long-term lithium-treated bipolar patients. Limitations of the study include small size of the sample, small number of C/C genotype patients, and a lack of multiple testing analysis of genotypic differences in various measures of kidney function. PMID- 25505676 TI - Bipolar disorder and socioeconomic status: what is the nature of this relationship? AB - BACKGROUND: In psychiatric literature stretching over a century, there have been glaring discrepancies in the findings describing the relationship between bipolar disorder (BD) and socioeconomic status (SES). Early studies indicated an overall association between manic-depressive illness and higher social class. However, recent epidemiologic studies have failed to find an association between BD and SES. Instead, they report a similar distribution of BD among social classes and educational levels, and in one particular study, a lower family income was reported. The determinants of SES are complex, and the early findings are now interpreted as having been incorrect and stemming from past methodological weaknesses. METHODS: For this analysis we explored the relationship between SES and BD in a sample of patients who had participated in prior clinical and therapeutic studies. These patients met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for BD, required long-term stabilizing treatment, and were assessed in terms of their response to lithium stabilization and a number of other clinical characteristics in accordance with research protocol. Good response to lithium stabilization (LiR) served as a proxy for identifying a subtype of manic-depressive illness, the classical form of BD. Non responders to stabilizing lithium (LiNR) were considered belonging to other subtypes of bipolar spectrum disorder. The SES of the parents was measured upon entry into treatment using the Hollingshead SES scale, which despite its limitations has been used in psychiatry most widely to determine SES. The groups of LiR and LiNR were compared statistically in terms of SES. The influence of bipolar subtype and gender on SES was investigated. RESULTS AND DISCUSSION: A significantly higher SES was associated with the lithium-responsive form (LiR) of BD when compared with patients continuing to relapse despite adequate lithium treatment (representing other types of bipolar spectrum). Our observation suggests that the discrepant literature findings about SES and BD may be better explained by the change in diagnostic practices: early studies describing a positive relationship included mostly classical manic-depressive disorder, while the patients in recent studies have been diagnosed according to much broader criteria, reflecting the era of bipolar spectrum disorder. PMID- 25505677 TI - Quetiapine monotherapy in bipolar II depression: combined data from four large, randomized studies. AB - BACKGROUND: Despite being present in up to 1% of the population, few controlled trials have examined the efficacy of treatments for bipolar II depression. Pooled data are presented from four placebo-controlled studies (BOLDER I [5077US/0049] and II [D1447C00135]; EMBOLDEN I [D1447C00001] and II [D1447C00134]) that evaluated the efficacy of quetiapine monotherapy for depressive episodes in patients with bipolar II disorder. METHODS: All studies included an 8-week, double-blind treatment phase in which patients were randomly assigned to treatment with quetiapine 300 mg/day, quetiapine 600 mg/day, or placebo. Outcome measures included the change from baseline in MADRS total score at week 8, effect sizes, and MADRS response and remission rates. RESULTS AND DISCUSSION: Improvements in mean MADRS total scores from baseline to week 8 were significantly greater with quetiapine 300 and 600 mg/day (-15.58 [n = 283] and 14.88 [n = 289]; p < 0.001) compared with placebo (-11.61 [n = 204]). The MADRS effect sizes were 0.44 for quetiapine 300 mg/day and 0.47 for 600 mg/day (p < 0.001 vs placebo). Significantly higher proportions of patients receiving quetiapine, at both doses, than placebo-treated patients achieved response and remission at week 8 (p < 0.01). Common adverse events associated with quetiapine (both doses) included dry mouth, somnolence, sedation, dizziness, and headache. Rates of mania and hypomania were similar for quetiapine and placebo. Quetiapine monotherapy demonstrated significant efficacy compared with placebo and was generally well tolerated in the treatment of bipolar II depression. PMID- 25505679 TI - Bipolar disorders in DSM-5: strengths, problems and perspectives. AB - The diagnostic classification of mood disorders by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) had two major shortcomings: an underdiagnosis of bipolar disorders and a large proportion of treated patients had to be allocated to the vague NOS groups 'not otherwise specified'. Several new subthreshold groups of depression, bipolar disorders and mixed states are now operationally defined in DSM-5. In addition, hypomanic and manic episodes occurring during antidepressant treatments are, under certain conditions, accepted as criteria for bipolar disorders. The diagnosis of bipolarity now requires, as entry criterion A, not only the presence of elated or irritable mood but also the association of these symptoms with increased energy/activity. This restriction will unfortunately change the diagnoses of some patients from DSM-IV bipolar I and II disorders to subdiagnostic bipolar syndromes. Nonetheless, overall, DSM-5 is a step in the right direction, specifying more subdiagnostic categories with an improved dimensional approach to severity. DSM-5 may also have an impact on patient selection for placebo-controlled drug trials with antidepressants. PMID- 25505678 TI - Stability of lithium treatment in bipolar disorder - long-term follow-up of 346 patients. AB - BACKGROUND: The purpose of this study was to investigate the effectiveness and stability of long-term lithium treatment in a prospective, international, multicenter cohort of bipolar patients in a naturalistic setting. METHODS: Patients were selected according to DSM IV criteria for bipolar disorder and required long-term treatment. They were prospectively followed and documented in five centers belonging to the International Group for the Study of Lithium Treated Patients. This was a prospective cohort study without a comparison group. Lithium treatment was administered in a naturalistic and specialized outpatient setting. All patients underwent a comprehensive psychiatric examination, which included the use of standard rating scales, as well as an evaluation of clinical course based on the morbidity index (MI). Wald tests were used to assess the significance of fixed effects and covariates when analyzing the relationship between depressive, manic, and total morbidity index and several characteristics of illness course. RESULTS AND DISCUSSION: A total of 346 patients with bipolar disorder I or II were followed for a mean period of 10.0 years (standard deviation (SD) 6.2, range 1 to 20). The morbidity index remained stable over time: the mean MI was 0.125 (SD 0.299) in year 1 and 0.110 (SD 0.267) in year 20. The MI was not associated with the duration of lithium treatment, the number or frequency of episodes prior to treatment, or latency from the onset of bipolar disorder to the start of lithium treatment. The drop-out rate was high over the study period. Our findings suggest that long-term response to lithium maintenance treatment remains stable over time. PMID- 25505681 TI - Diagnosing bipolar disorders in DSM-5. PMID- 25505680 TI - Impulsivity, anxiety, and alcohol misuse in bipolar disorder comorbid with eating disorders. AB - BACKGROUND: Eating disorders (ED) are noted to occur with bipolar disorder (BD), but relationships between additional comorbidities, clinical correlates, and personality factors common to both remain largely unknown. METHODS: Using data from the Prechter Longitudinal Study of Bipolar Disorder, we measured the prevalence and demographic factors of comorbid ED with BD, presence of additional comorbidity of anxiety and substance use disorders, psychosis, suicide attempts, mixed symptoms, childhood abuse, impact of NEO-Personality Inventory (NEO-PI) personality factors, and mood outcome in 354 patients with BD. We analyzed the prevalence of ED using both broad and narrow criteria. RESULTS AND DISCUSSION: ED was more common in the Prechter BD sample than the general population, with the majority of those with ED being female. Anxiety disorders, alcohol abuse/dependence, and NEO-PI N5 impulsiveness were independently associated with ED in a multivariable linear regression analysis. BD age at onset was earlier in the ED group than that in the non-ED group and was earlier than the average onset of ED. Anxiety occurred before ED and alcohol use disorders after both BD and ED. Childhood trauma was associated with ED. Impulsivity and anxiety associated with BD may fuel ED and put patients at risk for other impulsivity-related disorders such as alcohol use disorders. ED was associated with more severe and variable moods and more frequent depression. Patients with BD should be regularly screened for ED, anxiety disorders, and alcohol use disorders, and comorbidity should be promptly addressed. PMID- 25505682 TI - Bipolar disorder with comorbid anxiety disorders: impact of comorbidity on treatment outcome in cognitive-behavioral therapy and psychoeducation. AB - BACKGROUND: Comorbid anxiety disorders are extremely prevalent in bipolar disorder (BD) and have substantial impact on the course of illness. Limited evidence regarding treatment factors has led to a renewal of research efforts examining both the impact of treatments on comorbid anxiety and the impact of comorbid anxiety on treatments. The current study examines the impact of comorbid anxiety disorders on response to two psychosocial interventions for BD. METHODS: A sample of 204 patients with BD took part in the study. Of them, 41.7% had a comorbid anxiety disorder. All participants received either individual cognitive behavioral therapy or group psychoeducation for BD. Evaluations included complete pretreatment and 18-month follow-up assessments of mood and anxiety symptoms, functioning, medication compliance, dysfunctional attitudes, and coping style. Outcome was compared based on the presence or absence of a comorbid anxiety disorder. RESULTS AND DISCUSSION: The participants with comorbid anxiety disorders ranked more severe than those without on several measures. Despite more severe illness characteristics, the magnitude of their treatment gains was equivalent or superior to that of the participants without anxiety disorders on a variety of outcome measures. Although the treatments did not specifically target the anxiety disorder, the participants made significant improvements in anxiety symptoms. Despite greater illness severity, patients with comorbid anxiety disorders can make substantial gains from psychosocial interventions targeting BD. Even in the presence of an anxiety disorder, they are able to attend to the content of the psychosocial treatments and apply it to better manage their condition. The presence of a comorbid anxiety disorder should not be considered a deterrent to offering BD-focused psychosocial treatments. PMID- 25505684 TI - Hypercalcemia in patients with bipolar disorder treated with lithium: a cross sectional study. AB - BACKGROUND: Lithium-induced hyperparathyroidism (LIH) is a relative underrecognized complication of long-term lithium treatment. Hypercalcemia may be the first, but often overlooked, sign of LIH. Symptoms of LIH can be similar to the underlying psychiatric illness, which may cause a significant doctor's delay in diagnosing LIH. The aim of this study was to determine the prevalence of hypercalcemia in a cohort of psychiatric patients. METHODS: In this cross sectional study, we collected data from 314 patients treated with lithium in an outpatient clinic for bipolar disorder. Patients with bipolar disorder from the same clinics, who had never been treated with lithium and of whom serum calcium levels were available, were included as controls (n = 15). Patient characteristics and laboratory results were collected during the period of June 2010 till June 2011. RESULTS: The mean serum calcium level was 2.49 (SD 0.11) mmol/l. The point prevalence of hypercalcemia (>2.60 mmol/l) was 15.6%. In a comparable group of psychiatric patients not using lithium, the mean serum calcium level was 2.37 mmol/l, and none of these patients had hypercalcemia (p = 0.001). The duration of lithium treatment was the only significant predictor for the development of hypercalcemia (p = 0.002). DISCUSSION: The prevalence of hypercalcemia in lithium-treated patients was significantly higher than that in non-lithium treated controls and correlated to the cumulative time lithium was used in this cross-sectional study. We recommend that serum calcium levels should be routinely tested in patients using lithium for timely detection of LIH or hypercalcemia due to other causes. PMID- 25505685 TI - Evaluating depressive symptoms in hypomanic and manic episodes using a structured diagnostic tool: validation of a new Mini International Neuropsychiatric Interview (M.I.N.I.) module for the DSM-5 'With Mixed Features' specifier. AB - BACKGROUND: The Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), includes a new 'With Mixed Features' specifier for mood episodes. In (hypo-)manic episodes, the specifier is given if three or more depressive symptoms are present nearly every day during the episode. A new module of the Mini International Neuropsychiatric Interview (M.I.N.I.) has been developed as a patient-completed questionnaire to evaluate the DSM-5 specifier for (hypo-)manic episodes. The objective of this study was to validate this new module. METHODS: In Phase I, patients with a manic episode in the past 6 months completed the module and were asked whether the wording was clear, understandable, relevant and specific. Based on their feedback, the module was refined and finalised. In Phase II, psychiatrists each invited five patients to complete the module. The psychiatrists completed record forms for these five patients, which included their diagnoses, made according to DSM-5 criteria during clinical interviewing. The module was validated by comparing depressive symptoms reported by the patients themselves using the M.I.N.I. module with those evaluated by their psychiatrist using DSM-5 criteria during clinical interviewing. RESULTS AND DISCUSSION: In Phase I, a few changes were made to the M.I.N.I. module based on feedback from 20 patients (60% of whom had mixed features). In Phase II, 23 psychiatrists completed record forms for 115 patients, 99 (86.1%) of whom completed the M.I.N.I. module. Agreement between psychiatrists' DSM-5 diagnoses and patients' M.I.N.I. responses was substantial (Cohen's kappa coefficient, 0.60). The overall sensitivity of the M.I.N.I. was 0.91 and its specificity was 0.70. Sensitivity ranged from 0.63 for psychomotor retardation to 0.90 for suicidal thoughts. Specificity ranged from 0.63 for diminished interest/pleasure to 0.90 for suicidal thoughts. The module's positive and negative predictive values were 0.72 and 0.90, respectively. In summary, the M.I.N.I. module demonstrated good concurrent validity with psychiatrists' evaluation of DSM-5 mixed features in manic patients, accurately detecting mixed features with limited risk of over-diagnosis. Due to its simplicity, the M.I.N.I. module could be incorporated into routine psychiatric evaluation of patients with manic episodes. It could also provide a valuable standardised tool for clinical and epidemiological research. PMID- 25505683 TI - Sleep quality during euthymia in bipolar disorder: the role of clinical features, personality traits, and stressful life events. AB - BACKGROUND: Poor sleep quality is known to precede the onset of mood episodes and to be associated with poor treatment outcomes in bipolar disorder (BD). We sought to identify modifiable factors that correlate with poor sleep quality in BD independent of residual mood symptoms. METHODS: A retrospective analysis was conducted to assess the association between the Pittsburgh Sleep Quality Index and clinical variables of interest in euthymic patients with DSM-IV BD (n = 119) and healthy controls (HC; n = 136) participating in the Prechter Longitudinal Study of Bipolar Disorder. Multivariable linear regression models were constructed to investigate the relationship between sleep quality and demographic and clinical variables in BD and HC participants. A unified model determined independent predictors of sleep quality. RESULTS AND DISCUSSION: Euthymic participants with BD and HC differed in all domains. The best fitting unified multivariable model of poor sleep quality in euthymic participants with BD included rapid cycling (beta = .20, p = .03), neuroticism (beta = .28, p = 2 * 10(-3)), and stressful life events (beta = .20, p = .02). Poor sleep quality often persists during euthymia and can be a target for treatment. Clinicians should remain vigilant for treating subjective sleep complaints independent of residual mood symptoms in those sensitive to poor sleep quality, including individuals with high neuroticism, rapid cycling, and recent stressful life events. Modifiable factors associated with sleep quality should be targeted directly with psychosocial or somatic treatment. Sleep quality may be a useful outcome measure in BD treatment studies. PMID- 25505686 TI - Searching the internet for health information about bipolar disorder: some cautionary issues. AB - Adults routinely use the Internet as a source of health information. Patients with bipolar disorder and caregivers should be encouraged to increase their knowledge of this complex illness, including through the Internet. However, patients, caregivers, and physicians should be aware of potential perils when searching the Internet for health information, including loss of privacy, quality of web site content, and Internet scams. This review summarizes these cautionary issues. The digital divide remains and includes a lack of technical skills and competency in searching and appraising web sites, in addition to limited access to the Internet. Physicians should provide patients with a list of trustworthy web sites and a brief printed handout on concerns related to searching the Internet. More studies of the use of the Internet by patients with bipolar disorder are needed. PMID- 25505687 TI - Distress and disability in young adults presenting to clinical services with mood disorders. AB - BACKGROUND: Distress and/or dysfunction are well established as key reasons for help-seeking. We explore the characteristics of groups defined by high or low distress or disability in young people with unipolar depression (UP) or bipolar disorder (BD). METHODS: Individuals aged 12 to 25 years presenting to youth mental health services for the first time with a primary diagnosis of UP or BD were assessed using the Kessler Psychological Distress Scale (Kessler-10) and the Work and Social Adjustment Scale (WSAS). Four groups with high or low distress or impairment were defined (according to scores above or below the group medians for the Kessler-10 and WSAS). Multinomial logistic regression (MNLR) was used to examine how cases with high levels of distress and disability (reference group) differed from the other three groups. RESULTS AND DISCUSSION: The sample comprised 1,746 cases (90% UP, 56% female) with a median age of 17.5 years. Median scores on the Kessler-10 and WSAS were both high (30 and 20, respectively) and were significantly inter-correlated (r = 0.62); the high impairment/distress group was the largest sub-group (39% of cases). The MNLR analysis demonstrated that younger age was associated with lower impairment groups (irrespective of distress level), whilst male gender was associated with lower distress (irrespective of impairment). Compared to the low impairment/distress cases, the high impairment/distress group was significantly more likely to use cannabis and/or alcohol. Age, substance use and possibly gender are probably better predictors of distress/impairment sub-group than mood disorder sub-type in youth. PMID- 25505688 TI - Occurrence of bipolar spectrum disorder and comorbidities in women with eating disorders. AB - BACKGROUND: Eating disorder (ED) patients often have comorbidities with other psychiatric disorders, especially with mood disorders. Although recent studies suggest an intimate relationship between ED and bipolar disorder (BD), the study on a broader bipolar spectrum definition has not been done in this population. We aimed to study the occurrence of bipolar spectrum (BS) and comorbidities in eating disorder patients of a tertiary service provider. METHODS: Sixty-nine female patients diagnosed with anorexia nervosa, bulimia nervosa, or eating disorder not otherwise specified were evaluated. The assessment comprised the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), clinical criteria for diagnosis of the Zurich bipolar spectrum. Mann-Whitney tests compared means of continuous variables. The association between categorical variables and the groups was described using contingency tables and analyzed using the chi-square or Fisher's exact test. The level of significance alpha was set at 5%. RESULTS: The results showed that 68.1% of patients had comorbidity with bipolar spectrum, and this was associated with higher family income, proportion of married people, and comorbidity with substance use. The ED with BS group showed higher rates of substance use comorbidity (40.4%) than the ED without BS group (13.6%). DISCUSSION: These results showed that the bipolar spectrum is a common comorbidity in patients with eating disorders and is associated with correlates of clinical importance, notably the comorbidity with substance use. Due to the pattern of similarity between the groups with and without comorbid bipolar spectrum in relation to various outcomes evaluated, the identification of comorbidity can be difficult. However, the precise diagnosis and careful identification of clinical correlates may contribute to future advances in treating these conditions. Further studies are necessary to evaluate the association of other clinical correlates and its possible causal association. PMID- 25505690 TI - Behavioral addictions in euthymic patients with bipolar I disorder: a comparison to controls. AB - BACKGROUND: Bipolar disorder may be associated with a hypersensitive behavioral approach system and therefore to increased reward sensitivity. The objective of this study is to explore the interrelationships between bipolar disorder, behavioral addictions, and personality/temperament traits in a group of euthymic outpatients with bipolar I disorder and in a group of comparison subjects. METHODS: Fifty clinically stable patients and 50 comparison subjects matched for age, sex, and educational level were administered the Temperament and Character Inventory-140 and the Behavioral Addiction Scale. RESULTS: The patient group scored significantly higher than comparison subjects for two benign behavioral addictions (music, shopping) as well as for smoking. Comparison subjects scored higher on two harmful behavioral addictions (drugs, alcohol). Novelty Seeking was positively correlated with harmful addictions, and Cooperativeness was negatively correlated with harmful addictions, in both groups. DISCUSSION: The hypersensitive behavioral approach system model of bipolar disorder would predict higher levels of various addictions in bipolar patients as compared to controls. In this study, this was true for three behavioral addictions, whereas controls showed higher levels of behavioral addiction to drugs and alcohol. This may be because the patients in this study are stable, have received considerable psychoeducation, and are relatively adherent to their medication recommendations. Temperament and character traits may play roles both as risk and protective factors regarding behavioral addictions. PMID- 25505689 TI - Antidepressant dosage taken by patients with bipolar disorder: factors associated with irregularity. AB - BACKGROUND: This study analyzed regularity in the daily dosage of antidepressants taken by patients with bipolar disorder and identified the factors associated with irregularity. METHODS: Daily self-reported medication dosage taken and mood ratings were available from 144 patients who received treatment as usual. All 144 patients took the same antidepressant for at least 100 days. One hundred eleven of these patients were also taking a mood stabilizer. Approximate entropy (ApEn) was used to measure serial regularity in daily dosage. Regularity is the tendency that values within a time series remain the same on incremental comparisons. Drug holidays (missing three or more consecutive days) were also determined. Generalized estimating equations (GEE) were used to estimate if any demographic or clinical variables were associated with regularity. RESULTS: Although the mean percent of days missing doses was only 18.6%, there was a wide range of regularity in the daily antidepressant dosage. Drug holidays were common, occurring in 41% of the analyses. Factors significantly associated with irregularity were as follows: total number of psychotropic medications (p = 0.005), pill burden (p = 0.005), and depression (p = 0.015). Neither the percent of days missing doses nor the drug holidays were associated with any demographic or clinical factors. For patients taking both antidepressants and mood stabilizers, there was no significant difference in regularity in daily dosage between these drugs. DISCUSSION: There can be considerable irregularity in daily dosage despite a low percent of days missing doses. Medication regimen complexity and depressed mood are associated with increased irregularity. Daily regularity in drug dosage may be more dependent on the individual than on the specific drug. Research on the clinical impact of irregularity in daily dosage of antidepressants is needed. PMID- 25505692 TI - Using theatre to address mental illness stigma: a knowledge translation study in bipolar disorder. AB - BACKGROUND: Reduction of the stigma of mental illness is an international priority; arts- and contact-based approaches represent a promising mode of intervention. This project was designed to explore the impact of a one-woman theatrical performance on attitudes towards bipolar disorder (BD) on people with BD and healthcare providers. METHODS: A playwright and actress who lives with BD developed a stage performance - 'That's Just Crazy Talk' - targeting stigmatizing attitudes towards BD. Prospective, longitudinal and sequential mixed methods were used to assess the impact of the performance on people with BD (n = 80) and healthcare providers (n = 84). Qualitative interviews were conducted with 33 participants (14 people with BD and 19 healthcare providers). RESULTS AND DISCUSSION: Quantitatively, healthcare providers showed significantly improved attitudes immediately post-performance, but this change was not maintained over time; people with BD showed little quantitative change. Qualitatively, both people with BD and BD healthcare providers showed enduring and broadly positive changes. A theatrical presentation designed to reduce stigma produced immediate impact on healthcare providers quantitatively and significant qualitative impact on people with BD and healthcare providers. Additionally, the utility of using mixed-method approaches in mental health research was demonstrated. PMID- 25505691 TI - Quantitative leukocyte BDNF promoter methylation analysis in bipolar disorder. AB - BACKGROUND: Bipolar disorder (BD) is a complex psychiatric phenotype with a high heritability and a multifactorial etiology. Multisite collaborative efforts using genome-wide association studies (GWAS) have identified only a portion of DNA sequence-based risk factors in BD. In addition to predisposing DNA sequence variants, epigenetic misregulation may play an etiological role in BD and account for monozygotic twin discordance, parental origin effects, and fluctuating course of BD. In this study, we investigated DNA methylation of the brain-derived neurotrophic factor (BDNF) gene in BD. METHODS: Fifty participants with BD were compared to the same number of age- and sex-matched controls for DNA methylation differences at BDNF promoters 3 and 5. DNA methylation reads were obtained using a mass spectrophotometer for 64 cytosine-guanine (CpG) sites in 36 CpG 'units' across three amplicons of BDNF promoters 3 and 5. RESULTS AND DISCUSSION: Methylation fractions differed between BD participants and controls for 11 of 36 CpG units. Five CpG units, mostly in promoter 5, remained significant after false discovery rate correction (FDR) (p values <= 0.004) with medium to large effect sizes (Cohen's d >= 0.61). Several of the significant CpGs overlapped with or were immediately adjacent to transcription factor binding sites (TFBSs) - including two of the FDR-significant CpG units in promoter 5. For the CpGs in promoter 3, there was a positive and significant correlation between age at sample collection and DNA methylation fraction (rho = 0.56, p = 2.8 *10(-5)) in BD cases, but not in controls. Statistically significant differences in mean methylation fraction at 5/36 CpG units (after FDR), some at or immediately adjacent to TFBSs, suggest possible relevance for the current findings to BD etiopathogenesis. The positive correlation between age and methylation seen in promoter 3 is consistent with age-related decline in BDNF expression previously reported. Future studies should provide more exhaustive epigenetic study of the BDNF locus to better characterize the relationship between BDNF methylation differences and BD. PMID- 25505693 TI - Lithium as add-on to quetiapine XR in adult patients with acute mania: a 6-week, multicenter, double-blind, randomized, placebo-controlled study. AB - Quetiapine extended release (XR) and lithium are treatments with proven efficacy in acute mania. This randomized study evaluated the efficacy and safety of lithium or placebo as add-on to quetiapine XR in adult patients with manic or mixed symptoms of bipolar I disorder. In this 6-week, double-blind study (Trial D144AC00003), adult patients with DSM-IV-TR-diagnosed bipolar I disorder (current episode manic or mixed), a Young Mania Rating Scale (YMRS) total score >=20, and score >=4 on two of four core YMRS items were administered quetiapine XR (400 to 800 mg/day) and randomly assigned to receive add-on lithium (600 to 1,800 mg/day) or placebo. The primary efficacy end point was change in the YMRS total score from baseline to day 43, analyzed using a mixed-model for repeated measures (MMRM) approach. Secondary efficacy and safety end points were also measured. Rating scales were administered by trained staff. Three hundred fifty-six patients treated with quetiapine XR were randomized to add-on lithium (n = 173) or placebo (n = 183). Two hundred ninety-one patients (81.7%) completed the study. At day 43, least squares mean change in YMRS total score was -22.8 for add on lithium and -20.1 for add-on placebo, a statistically significant treatment group difference of -2.69 (p < 0.001). On secondary measures, add-on lithium was associated with significant improvements in response, remission, illness severity, and overall illness versus add-on placebo (p < 0.05). The number needed to treat was 9.1 for response and 7.9 for remission for add-on lithium compared with add-on placebo. Lithium in combination with quetiapine XR was generally well tolerated, with a similar profile to quetiapine XR in combination with placebo. The addition of lithium to quetiapine XR therapy was associated with significantly greater efficacy than placebo as add-on and was generally well tolerated in patients with acute bipolar I mania. This study was registered under Clinicaltrials.gov Identifier NCT00931723. PMID- 25505694 TI - Second generation tyrosine kinase inhibitors for the treatment of metastatic non small-cell lung cancer. AB - BACKGRUOND: Since their first description, activating epidermal growth factor receptor (EGFR) mutations identify a distinct clinical entity of patients with non-small-cell lung cancer (NSCLC). FINDINGS: New targeted therapies for molecularly selected NSCLC are changing the natural history of the disease, with results superior to standard chemotherapy as demonstrated in large phase III studies with first generation EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, after an initial response, all patients inevitably progress and several mechanisms including a secondary mutation in exon 20 of the EGFR gene (T790M) or MET or HER2 amplifications are responsible for acquired resistance (AR). In clinical practice few options are available for patients with AR, and several new agents or strategies are currently under investigation, including second generation TKIs. CONCLUSIONS: Aim of the present review is to present available data on new EGFR-TKIs and to discuss how these agents could overcome AR to erlotinib or gefitinib. PMID- 25505696 TI - Diagnosis and management of interstitial lung disease. AB - The complex tasks of making a confident diagnosis of a specific form of interstitial lung disease (ILD) and formulating a patient-centered, personalized management plan in an attempt to achieve remission or stabilization of the disease process can pose formidable challenges to clinicians. When patients are evaluated for suspected ILD, an accurate diagnosis of the specific form of ILD that a patient has developed must be made to provide the patient with useful prognostic information and to formulate an appropriate management plan that can relieve symptoms and restore or significantly improve quality of life. A well performed patient history and physical examination provides invaluable information that can be combined with appropriate laboratory testing, imaging, and, if needed, tissue biopsy to reach a confident ILD diagnosis, and high resolution computed tomography (HRCT) of the thorax is usually a key component of the diagnostic evaluation. If treatment is indicated, many forms of ILD can respond significantly to immunosuppressive anti-inflammatory therapies. However, ILD accompanied by extensive fibrosis may be difficult to treat, and the identification of an effective pharmacologic therapy for idiopathic pulmonary fibrosis (IPF) has remained elusive despite the completion of many phase 3 clinical trials over the past decade. Nonetheless, patients with IPF or advanced forms of non-IPF ILD can benefit significantly from detection and treatment of various co-morbid conditions that are often found in patients (especially the elderly patient), and supportive care (oxygen therapy, pulmonary rehabilitation) can have a beneficial impact on quality of life and symptom palliation. Finally, lung transplantation is an option for patients with progressive, advanced disease that does not respond to other therapies, but only a relatively small subset of patients with end-stage ILD are able to meet wait listing requirements and eventually undergo successful lung transplantation. PMID- 25505695 TI - The expanding role of aerosols in systemic drug delivery, gene therapy and vaccination: an update. AB - Until the late 1990s, aerosol therapy consisted of beta2-adrenergic agonists, anti-cholinergics, steroidal and non-steroidal agents, mucolytics and antibiotics that were used to treat patients with asthma, COPD and cystic fibrosis. Since then, inhalation therapy has matured to include drugs that: (1) are designed to treat diseases outside the lung and whose target is the systemic circulation (systemic drug delivery); (2) deliver nucleic acids that lead to permanent expression of a gene construct, or protein coding sequence, in a population of cells (gene therapy); and (3) provide needle-free immunization against disease (aerosolized vaccination). During the evolution of these advanced applications, it was also necessary to develop new devices that provided increased dosing efficiency and less loss during delivery. This review will present an update on the success of each of these new applications and their devices. The early promise of aerosolized systemic drug delivery and its outlook for future success will be highlighted. In addition, the challenges to aerosolized gene therapy and the need for appropriate gene vectors will be discussed. Finally, progress in the development of aerosolized vaccination will be presented. The continued expansion of the role of aerosol therapy in the future will depend on: (1) improving the bioavailability of systemically delivered drugs; (2) developing gene therapy vectors that can efficiently penetrate the mucus barrier and cell membrane, navigate the cell cytoplasm and efficiently transfer DNA material to the cell nucleus; (3) improving delivery of gene vectors and vaccines to infants; and (4) developing formulations that are safe for acute and chronic administrations. PMID- 25505697 TI - Epidemiology of bronchial asthma and asthma control assessment in Henan Province, China. AB - BACKGROUND: Prevalence of bronchial asthma, asthma treatment assessment, and estimation of the control level among asthma patients in Henan Province, China are reported in this paper. METHODS: We selected 10 among the 109 cities and districts in Henan province using a multistage stratified cluster random sampling method. A total of 500 households from each city and district were chosen. Approximately 20,000 residents from a total of 5,000 households were randomly selected to answer a questionnaire recommended by the China Asthma Alliance. Asthma patients were asked to answer a detailed questionnaire using the symptom based guidelines to assess the levels of disease control. RESULTS: The overall prevalence of asthma was 0.73% +/- 0.12%. Urban and rural residents had asthma prevalence rates of 1.1% +/- 0.23% (88/7,924) and 0.48% +/- 0.12% (57/11,792), respectively. Among the asthma patients, only 33.8% (52) received regular medication, 25% (13) used oral glucocorticoids, and 71.1% (37) used oral theophylline. The classified control levels of patients were as follows: 33.1% controlled, 49.7% partially controlled, and 17.2% uncontrolled. A total of 38.5% and 27.5% of regularly and irregularly treated asthma patients reached controlled level, respectively. The two groups significantly differed in asthma control level. CONCLUSION: Asthma prevalence is low in Henan Province, China. Urban residents have higher prevalence of asthma than rural residents do. Patients with asthma receive insufficient medication, resulting in suboptimal asthma control. Improvement in diagnosis and treatment of asthma patients is urgently needed. PMID- 25505698 TI - Secretion properties, clearance, and therapy in airway disease. AB - Chronic airway diseases like cystic fibrosis, chronic bronchitis, asthma, diffuse panbronchiolitis, and bronchiectasis are all associated with chronic inflammation. The airway mucosa responds to infection and inflammation in part by surface mucous (goblet) cell and submucosal gland hyperplasia and hypertrophy with mucus hypersecretion. Products of inflammation including neutrophil derived DNA and filamentous actin, effete cells, bacteria, and cell debris all contribute to mucus purulence and, when this is expectorated it is called sputum. Mucus is usually cleared by ciliary movement, and sputum is cleared by cough. These airway diseases each are associated with the production of mucus and sputum with characteristic composition, polymer structure, and biophysical properties. These properties change with the progress of the disease making it possible to use sputum analysis to identify the potential cause and severity of airway diseases. This information has also been important for the development of effective mucoactive therapy to promote airway hygiene. PMID- 25505699 TI - Inhibition of beta-catenin/p300 interaction proximalizes mouse embryonic lung epithelium. AB - BACKGROUND: Wnt/beta-catenin signaling has been suggested to regulate proximal distal determination of embryonic lung epithelium based upon genetically modified mouse models. The previously identified and characterized small molecule inhibitor IQ1 can pharmacologically decrease the interaction between beta-catenin and its transcriptional coactivator p300, thereby enhancing the beta-catenin/CBP interaction. Inhibition of the beta-catenin/p300 interaction by IQ1 blocks the differentiation of embryonic stem cells and epicardial progenitor cells; however, whether differential coactivator usage by beta-catenin plays a role in proximal distal determination of lung epithelium is unknown. METHODS: We examined the effects of inhibiting the beta-catenin/p300 interaction with IQ1 on lung branching morphogenesis in mouse embryos in utero and mouse embryonic lung organ culture ex vivo. The phenotype of IQ1 treated lungs was analyzed by epithelial staining, histology, quantitative PCR and in situ hybridization. RESULTS: Inhibition of the beta-catenin/p300 interaction by IQ1 disrupted the distal branching of mouse lung epithelium both in utero and ex vivo. IQ1 proximalized lung epithelium with decreased expression of the genes Bmp4 and Fgf10, hallmarks of distal lung determination, and increased expression of the proximal genes Sox2 and Scgb1a1 (CC10) as shown by quantitative PCR and in situ hybridization. The disruption of branching was reversible ex vivo as branching was reinitiated after removal of IQ1 from the media. CONCLUSIONS: The results demonstrate that the beta catenin/p300 interaction plays a critical role in proximal-distal determination of the epithelium in mouse lung branching morphogenesis and beta-catenin/p300 inhibition pharmacologically proximalizes lung epithelium. PMID- 25505700 TI - Systematic review of cadaveric studies on anatomic posterior cruciate ligament reconstruction: the landmarks in anatomic posterior cruciate ligament reconstruction. AB - Recently, several new techniques for anatomic posterior cruciate ligament reconstruction (PCLR) have emerged and are believed to restore the normal anatomy of the posterior cruciate ligament more accurately. Despite the latest trend, the optimal methods for anatomic PCLR remain controversial. The purpose of this research is to review surgical techniques for PCLR in cadaver studies and suggest consistent and reproducible technical criteria. For the review of the literature, MEDLINE and EMBASE were screened for articles on anatomic PCLR. Only basic science studies on PCLR performed on human cadavers and written in English were included. Seventeen studies were included in this systematic review. Only the tunnel positions, graft types, and surgical techniques were reported in the majority of the studies. There were many variations of the reported tunnel positions, graft types, and surgical techniques among the studies. In most studies, surgical techniques for consistent and reproducible anatomic PCLR were not explained clearly. Therefore, high level medical research should be encouraged in order to establish standard surgical techniques for anatomic PCLR. PMID- 25505702 TI - Effects of tourniquet use on quadriceps function and pain in total knee arthroplasty. AB - PURPOSE: A pneumatic tourniquet is commonly used in total knee arthroplasty (TKA) to improve surgical field visualisation but may result in quadriceps muscle ischaemia. We performed this study to analyse the effect of the tourniquet on recovery following TKA. MATERIALS AND METHODS: A prospective randomised single blinded trial was undertaken to examine the effect of the tourniquet on post operative pain, swelling, blood loss, quadriceps function and outcome following TKA. Twenty patients with osteoarthritis of the knee were randomised to tourniquet or no tourniquet groups. Quadriceps function was assessed using surface electromyography (EMG) during active knee extension. RESULTS: The no tourniquet group had significantly less pain in the early post-operative period compared to the tourniquet group. There was no difference in Oxford knee score, range of motion, or thigh and knee swelling up to 12 months post-operatively. Quadriceps function, measured by surface EMG, was compromised for the first six months post-surgery by tourniquet use. The radiological cement mantle at the bone prosthesis interface at 12-month follow-up was not affected by the absence of a tourniquet. CONCLUSIONS: We believe that it is safe and beneficial for our patients to routinely perform TKA without a tourniquet. PMID- 25505703 TI - Comparison of Precision between Optical and Electromagnetic Navigation Systems in Total Knee Arthroplasty. AB - PURPOSE: The purpose of this study is to compare and analyze the precision of optical and electromagnetic navigation systems in total knee arthroplasty (TKA). MATERIALS AND METHODS: We retrospectively reviewed 60 patients who underwent TKA using an optical navigation system and 60 patients who underwent TKA using an electromagnetic navigation system from June 2010 to March 2012. The mechanical axis that was measured on preoperative radiographs and by the intraoperative navigation systems were compared between the groups. The postoperative positions of the femoral and tibial components in the sagittal and coronal plane were assessed. RESULTS: The difference of the mechanical axis measured on the preoperative radiograph and by the intraoperative navigation systems was 0.6 degrees more varus in the electromagnetic navigation system group than in the optical navigation system group, but showed no statistically significant difference between the two groups (p>0.05). The positions of the femoral and tibial components in the sagittal and coronal planes on the postoperative radiographs also showed no statistically significant difference between the two groups (p>0.05). CONCLUSIONS: In TKA, both optical and electromagnetic navigation systems showed high accuracy and reproducibility, and the measurements from the postoperative radiographs showed no significant difference between the two groups. PMID- 25505701 TI - Continuous Improvements of a Clinical Pathway Increased Its Feasibility and Improved Care Providers' Perception in TKA. AB - PURPOSE: We aimed to determine 1) whether dropout rate decreased and 2) whether health care providers' perceptions were changed with continued improvements of contents of clinical pathway (CP) for total knee arthroplasty (TKA). MATERIALS AND METHODS: This retrospective study included two separate analyses of patients and health care providers. In the analysis of patients, dropout rates and reasons were evaluated in two cohorts of patients who underwent TKA with CP applied at two different time periods (384 patients from 2009 to 2010 and 242 patients from 2012 to 2013). Contents of CP were continuously improved during the 3-year interval. Self-administered questionnaire surveys targeted to health care providers were carried out twice (2010 and 2013) and compared. RESULTS: Dropout rate decreased from 19.1% in the first time period to 10.4% in the second time period. Although overall satisfaction of care providers was high at both time points, doctors had more favorable perceptions than nurses; most positive changes of perception were noted in nurses. The health care providers' perceptions for potential concerns of CP were improved while the perceptions for potential benefits and satisfaction were maintained. CONCLUSIONS: Continuously improved CP has increased feasibility for TKA patients and reduced health care providers' concern about its value. We propose that CP can be implemented and actively used to improve the outcomes and efficacy of patient care for TKA, regardless of the rotation of care providers. PMID- 25505704 TI - Perioperative Risk Assessment in Patients Aged 75 Years or Older: Comparison between Bilateral and Unilateral Total Knee Arthroplasty. AB - PURPOSE: The purpose of this study is to evaluate the risk of sequential bilateral total knee arthroplasty (TKA) under 1 anesthesia in patients 75 years or older. MATERIALS AND METHODS: Patients aged 75 years or older who underwent sequential bilateral TKA (bilateral group, n=159) and unilateral TKA (unilateral group, n=159) between 2002 and 2012 were selected. All patients were evaluated for underlying medical diseases, such as cardiac, pulmonary, and renal problems, and high-risk patients were recommended to postpone the surgery. We compared the underlying diseases, major postoperative complications, and the length of hospital stay between bilateral and unilateral groups. RESULTS: The prevalence of underlying diseases of the bilateral group was 74.8% and major complications occurred in 6 patients (3.8%). The prevalence of underlying diseases of the unilateral group was 52.4% and complications were observed in 4 patients (2.4%). Although the complication rate of the bilateral group was slightly higher than that of the unilateral group, the difference was not statistically meaningful (p=0.204). The length of hospital stay was 21.9 days for the bilateral group and 24.9 days for the unilateral group. CONCLUSIONS: There was no significant difference in postoperative complications between groups. The result shows that bilateral TKA can be relatively safe compared with unilateral TKA in patients 75 years or older. However, careful selection of low-risk patients is advised. PMID- 25505705 TI - Proposed Methods for Real-Time Measurement of Posterior Condylar Angle during TKA. AB - PURPOSE: Conventional instruments are known to result in high numbers of outliers in restoring femoral component rotation primarily due to fixed degree of external rotation resection relative to the posterior condylar line (PCL). Outliers can be reduced by determining the patient specific posterior condylar angle (PCA) preoperatively or intraoperatively. There is a paucity of methods that can be used during surgery for determining the PCA. We propose two simple, real-time methods to determine the PCA and hence to measure the axial anatomical variation during surgery. MATERIALS AND METHODS: The study was conducted using axial computed tomography (CT) scans of the knees of 26 patients. The commercial software K-PACS and our proposed two methods (trigonometric and protractor) were used to measure the angle between the transepicondylar axis and PCL, i.e., PCA. Statistical comparison between the mean angles obtained by K-PACS and our methods were done. RESULTS: The three methods resulted in similar PCAs. The mean PCA measured by the three methods were similar. The mean PCA value measured by the K PACS, trigonometric method and protractor method was 6.27 degrees (range, 0 degrees to 12 degrees ), 6.23 degrees (range, 0 degrees to 11.11 degrees ) and 6.31 degrees (range, 0 degrees to 12 degrees ), respectively. There were significant correlations between the K-PACS measured PCA and trigonometrically or protractor measured PCA. CONCLUSIONS: Our novel, simple, easily reproducible, real-time and radiation-free PCA measurement methods obviate the need for preoperative CT scan for identification of patient specific PCA. PMID- 25505706 TI - Efficacy of intra-articular injection of thrombin-based hemostatic agent in the control of bleeding after primary total knee arthroplasty. AB - PURPOSE: To evaluate the hemostatic effect of intraarticular injection of a thrombin-based hemostatic agent in total knee arthroplasty (TKA). MATERIALS AND METHODS: We performed a prospective randomized controlled trial on the use of a thrombin-based hemostatic agent in patients undergoing unilateral TKA. A total of 100 TKA patients were enrolled, with 50 patients randomized into the study group and the other 50 patients into the controlled group. Drain output, hemoglobin level, total red blood cell loss for 24 hours after surgery, transfusion rates, and complications were assessed. RESULTS: Postoperative drain output was 525 mL in the study group and 667 mL in the control group (p=0.01). Nine patients in the study group and eighteen in the control group received blood transfusion (p=0.043). But, there was no significant difference between two groups in terms of hemoglobin level change and total red blood cell loss (p>0.05). CONCLUSIONS: The thrombin-based hemostatic agent demonstrated efficacy in reducing drain output and blood transfusion rates. Thus, we believe the use of a thrombin-based hemostatic agent should be considered as an option in orthopedic surgery that involves massive bleeding. PMID- 25505707 TI - Comparison of the Modified Transtibial Technique, Anteromedial Portal Technique and Outside-in Technique in ACL Reconstruction. AB - PURPOSE: To compare clinical and radiographic results of anterior cruciate ligament (ACL) reconstruction using modified transtibial technique (mTT), anteromedial (AM) portal technique and outside-in (OI) technique. MATERIALS AND METHODS: From March 2007 to December 2012, ACL reconstruction was performed using the mTT, AM portal technique and OI technique in 20 patients each. Anteroposterior and rotational stability were assessed using the GNRB arthrometer and pivot-shift test. Femoral tunnel obliquity was measured on the anteroposterior and lateral radiographs. RESULTS: Tegner score, Lysholm score, International Knee Documentation Committee score, pivot-shift test were improved at final follow-up in all three groups. However, statistical difference was not shown. Side-to-side difference in GNRB arthrometer was average of 1.4 mm, 1.0 mm and 0.9 mm in mTT, AM and OI group, showing the signicant difference between mTT and AM/OI groups (p<0.001). The mean femoral tunnel obliquity was 56.4 degrees in the mTT group, 39.4 degrees in the AM group and 33.6 degrees in the OI group, showing significant intergroup difference (p<0.001). It showed the significant difference among three groups (p<0.001). CONCLUSIONS: Clinical results were improved in all three groups. Femoral tunnel obliquity in AM and OI were more horizontal on the coronal plane. They are thought to have more benefits in oblique positioning of the grafted ACL in rotational stability; however, there was no significant difference among three techniques in pivot-shift test to assess the rotational stability in this study. PMID- 25505708 TI - Localized pigmented villonodular synovitis of the proximal tibiofibular joint. AB - Pigmented villonodular synovitis (PVNS) is a rare disease. It is a benign neoplastic process typically affecting young to middle-aged adults and most commonly involving the knee, hip, and shoulder joints. The symptoms include diffuse pain and swelling with discomfort. We report a rare case of localized PVNS originating at the proximal tibiofibular joint in a 39-year-old female patient with radiologic changes for short duration of time. The clinical history, plain radiographs, magnetic resonance imaging, and pathologic findings of the reported patient were reviewed. Complete surgical excision was performed and there was no evidence of recurrence after one-year follow-up. PMID- 25505709 TI - Baker's Cyst Filled with Hematoma at the Lower Calf. AB - Baker's cyst is a distension of the gastrocnemius-semimembranosus bursa of the knee, which communicates with the posterior portion of the joint capsule. Baker's cyst is commonly located in the inferomedial or superficial layers of the knee joint and rarely extends laterally or proximally. Complications of Baker's cysts are dissection, rupture, pseudothrombophlebitis, leg ischemia, nerve entrapment, and compartment syndrome. However, hematomas in the Baker's cyst have not been reported in Korea. We report a rare case of hematoma in the Baker's cyst with subfascial extension into the calf. The hematoma was demonstrated by magnetic resonance imaging and removed by mass excision. PMID- 25505710 TI - Endoscopic submucosal dissection for gastric neoplasm at an outpatient clinic: efficacy and safety. PMID- 25505711 TI - Diagnosis of immunoglobulin g4-related sclerosing cholangitis. PMID- 25505712 TI - Prevention strategies for gastric cancer: a global perspective. AB - Despite the substantial burden of gastric cancer worldwide, population strategies for primary prevention have not been introduced in any country. Recognizing the causal role of Helicobacter pylori infection, there is increasing interest in population-based programs to eradicate the infection to prevent gastric cancer. Nonetheless, the paucity of available evidence on feasibility and effectiveness has prevented implementation of this approach. There are very few secondary prevention programs based on screening with endoscopy or radiography, notably in the Republic of Korea and Japan, two of the countries with the highest incidence rates of gastric cancer. In Korea, where the organized screening program is in place, survival rate of gastric cancer is as high as 67%. More research is needed to quantify the specific contribution of the screening program to observed declines in mortality rates. Gastric cancer screening is unlikely to be feasible in many Low-Middle Income Countries where the gastric cancer burden is high. Prevention strategies are still under development and the optimal approach may differ depending on local conditions and societal values. The present review gives an overview of the etiology and burden of the disease, and possible prevention strategies for countries and regions confronted with a significant burden of disease. PMID- 25505713 TI - Screening for gastric cancer: the usefulness of endoscopy. AB - Gastric cancer screening is common in countries with high prevalence rates of gastric cancer. However, data supporting the effectiveness of gastric cancer screening are lacking. Thus, the aim of this review was to examine the current evidence on gastric cancer screening. Herein, we reviewed radiographic and endoscopic tests as methods of gastric cancer screening. Previous cohort studies and case-control studies have demonstrated reduced gastric cancer mortality in study populations that had undergone gastric cancer screening with radiographic tests. Recently, a case-control study in Japan reported a 30% reduction in gastric cancer mortality when screening was undertaken via endoscopy. Also, endoscopic screening for gastric cancer exhibited higher sensitivity and specificity than radiographic screening. Moreover, most cost-effectiveness analyses on the best strategy for detecting early gastric cancer have generally concluded that endoscopy is more cost-effective than radiographic testing. Although data on the impact of endoscopy screening programs on gastric cancer mortality are limited, recent study results suggest that gastric cancer screening by endoscopy in average-risk populations performs better than radiography screening. Further evaluation of the impact of these screening methods should take into account cost and any associated reduction in gastric cancer mortality. PMID- 25505715 TI - Colon cancer screening with image-enhanced endoscopy. AB - Colorectal cancer (CRC) is a major cause of cancer mortality worldwide, and this has led to an increased use of screening colonoscopy. This screening has resulted in long-term risk reduction in asymptomatic individuals. However, endoscopists may fail to detect advanced adenomas or colon cancer during screening. The reasons that adenomas or cancers are missed are thought to be associated with the location of the lesions or the skills of the endoscopist. To address the limitations of white light endoscopy (WLE) for adenoma detection, advanced endoscopic images have recently been used. Image-enhanced endoscopies (IEEs), including the use of topical dyes, optical filtering, and ultramagnification, allow for gastrointestinal lesion analysis. Many studies have compared the adenoma detection rate (ADR) obtained by using WLE and IEE, but with different results. IEE can be used to help the endoscopist to improve their ADR in screening colonoscopy. This review examines the possible roles of image-enhanced colonoscopy in CRC screening. PMID- 25505714 TI - Endoscopic gastric cancer screening and surveillance in high-risk groups. AB - Gastric cancer remains a major cancer problem world-wide and future incidence will likely increase due to rapidly aging population demographics. Population based screening is being undertaken in Korea and Japan, where gastric cancer incidence rates are high, and seems to be effective in reducing mortality from gastric cancer. However, such strategies are difficult to implement in countries with a low incidence or limited resources. Thus, screening strategies should be directed towards high-risk population subgroups. Gastric cancer has a relatively long mean sojourn time, and prognosis of early-stage disease is excellent. In general population, screening at 2-year interval in Korea seems to be effective for early-stage diagnosis. In subjects with atrophic gastritis or intestinal metaplasia, surveillance is recommended at 1 to 3 years intervals according to European and Japanese recommendation. Screening intervals for family members with sporadic gastric cancer has not yet been adequately evaluated, but 1-year interval is recommended for hereditary diffuse gastric cancer family-members. Gastric cancer patients treated by endoscopic resection are the highest-risk group, and 1-year interval surveillance can detect most metachronous gastric cancers at an early stage. Future gastric cancer surveillance strategies using endoscopy should be guided by risk-stratification assessment, and further refinement of optimal surveillance intervals is needed. PMID- 25505716 TI - Colon cancer screening and surveillance in inflammatory bowel disease. AB - Patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Accordingly, the duration and anatomic extent of the disease have been known to affect the development of IBD-related CRC. When CRC occurs in patients with IBD, unlike in sporadic CRC, it is difficult to detect the lesions because of mucosal changes caused by inflammation. In addition, the tumor types vary with ill-circumscribed lesions, and the cancer is difficult to diagnose and remedy at an early stage. For the diagnosis of CRC in patients with IBD, screening endoscopy is recommended 8 to 10 years after the IBD diagnosis, and surveillance colonoscopy is recommended every 1 to 2 years thereafter. The recent development of targeted biopsies using chromoendoscopy and relatively newer endoscopic techniques helps in the early diagnosis of CRC in patients with IBD. A total proctocolectomy is advisable when high-grade dysplasia or multifocal low-grade dysplasia is confirmed by screening endoscopy or surveillance colonoscopy or if a nonadenoma-like dysplasia-associated lesion or mass is detected. Currently, pharmacotherapies are being extensively studied as a way to prevent IBD-related CRC. PMID- 25505717 TI - Stricture occurring after endoscopic submucosal dissection for esophageal and gastric tumors. AB - Endoscopic submucosal dissection (ESD) is a widely accepted treatment for early gastric and esophageal cancer. Compared to endoscopic mucosal resection, ESD has the advantage of enabling en bloc removal of tumors regardless of their size. However, ESD can result in a large artificial ulcer, which may lead to a considerable deformity. Circumferential mucosal defects of more than three fourths the esophageal circumference, long longitudinal mucosal defects (>30 mm), and lesions in the upper esophagus are significant risk factors for the development of post-ESD strictures of the esophagus. In the stomach, a circumferential mucosal defects more than three-fourths in extent and longitudinal mucosal defects >5 cm are risk factors of post-ESD stricture. If scheduled early, regular endoscopic balloon dilation is effective in controlling and preventing post-ESD stricture. Moreover, intralesional steroid injections or oral steroids can achieve remission of dysphagia or reduce the need for repeated endoscopic balloon dilation. However, further study is needed to improve the prevention of stricture formation. PMID- 25505718 TI - Lymph Node Metastases in Esophageal Carcinoma: An Endoscopist's View. AB - One of the most important prognostic factors in esophageal carcinoma is lymph node metastasis, and in particular, the number of affected lymph nodes, which influences long-term outcomes. The esophageal lymphatic system is connected longitudinally and transversally; thus, the pattern of lymph node metastases is very complex. Early esophageal cancer frequently exhibits skipped metastasis, and minimal surgery using sentinel node navigation cannot be performed. In Korea, most esophageal cancer cases are squamous cell carcinoma (SCC), although the incidence of adenocarcinoma has started to increase recently. Most previous reports have failed to differentiate between SCC and adenocarcinoma, despite the fact that the Union for International Cancer Control (7th edition) and American Joint Committee on Cancer staging systems both consider these separately because they differ in cause, biology, lymph node metastasis, and outcome. Endoscopic tumor resection is an effective and safe treatment for lesions with no associated lymph node metastasis. Esophageal mucosal cancer confined to the lamina propria is an absolute indication for endoscopic resection, and a lesion that has invaded the muscularis mucosae can be cured by local resection if invasion to the lymphatic system has not occurred. PMID- 25505719 TI - Comparison of clinical outcomes associated with pull-type and introducer-type percutaneous endoscopic gastrostomies. AB - BACKGROUND/AIMS: Percutaneous endoscopic gastrostomy (PEG) is a method of providing enteral nutrition using endoscopy. The PEG techniques differ according to the insertion method, and include the pull type, push type, and introducer type. The aim of this study was to compare the clinical outcomes associated with the pull-type and introducer-type PEG insertion techniques, which included the adverse events, at our tertiary care center in Korea. METHODS: We retrospectively reviewed 141 cases that had undergone PEG insertion at our center from January 2009 to June 2012. The indications for PEG insertion and the acute and chronic complications caused by each type of PEG insertion were analyzed. RESULTS: The indications for PEG insertion in our cohort included neurologic disease (58.7%), malignancy (21.7%), and other indications (19.6%). Successful PEG insertions were performed on 136 cases (96.5%), and there were no PEG-associated deaths. Bleeding was the most frequent acute complication (12.8%), and wound problems were the most frequent chronic complications (8.8%). There were no statistically significant differences between the pull-type and introducer-type PEG insertion techniques in relation to complication rates in our study population. CONCLUSIONS: PEG insertion is considered a safe procedure. The pull-type and introducer-type PEG insertion techniques produce comparable outcomes, and physicians may choose either of these approaches according to the circumstances. PMID- 25505720 TI - Gastric endoscopic submucosal dissection is safe for day patients. AB - BACKGROUND/AIMS: Although the advantages of endoscopic submucosal dissection (ESD) are well established, there are important limitations that relate to its higher cost and higher rate of complications compared with endoscopic mucosal resection. This study assessed the therapeutic safety and efficacy of ESD in the treatment of small gastric dysplasia and early gastric cancer (EGC) located within the antrum in an outpatient setting, and it compared the results with those from patients admitted to hospital for ESD treatment. METHODS: This study was a retrospective analysis of a prospectively maintained database. We reviewed consecutive patients with EGC or gastric dysplasia who underwent ESD between October 2007 and May 2008. The lesions were smaller than 2 cm and were located in the antrum. We analyzed 105 lesions in 105 patients. The patients were assigned to two groups according to each patient's preference. RESULTS: The overall rates of complete resection were 98.1% in the inpatients group and 94.3% in the outpatients group. Immediate bleeding occurred in four inpatients, which included one patient in the outpatient group. Delayed bleeding occurred in one inpatient within 24 hours of the procedure. Macroperforations did not occur in either group. A microperforation was found in one outpatient. CONCLUSIONS: The safety and efficacy of ESD used to treat small gastric tumors in the antrum in an outpatient setting appeared to be similar to the safety and efficacy of ESD used to treat patients who were admitted to the hospital. PMID- 25505721 TI - Endoscopic Submucosal Dissection Using a Novel Versatile Knife: An Animal Feasibility Study (with Video). AB - BACKGROUND/AIMS: In order to reduce the procedure time and the number of accessory changes during endoscopic submucosal dissection (ESD), we developed a novel versatile knife, which has the combined advantages of several conventional knives. The aim of this study was to compare the efficacy, safety, and histological quality of ESD performed using this novel versatile knife and a combination of several conventional knives. METHODS: This was an in vivo animal study comparing two different modalities of ESD in mini-pigs. Completion time of each resection was documented, and the resected specimens were retrieved and evaluated for completeness. To assess the quality control of the procedures and adverse events, detailed histopathological examinations were performed. RESULTS: A total of 18 specimens were dissected by ESD safely and easily (nine specimens using the new versatile knife; nine specimens by mixing conventional knives). All resections were completed as en bloc resections. There was no significant difference in procedure time between the 2 modalities (456 seconds vs. 355 seconds, p=0.258) and cutting speed (1.983 mm(2)/sec vs. 1.57 mm(2)/sec, p=1.000). The rate of adverse events and histological quality did not statistically differ between the modalities. CONCLUSIONS: ESD with a versatile knife appeared to be an easy, safe, and technically efficient method. PMID- 25505722 TI - IgG4 Levels in Bile for Distinguishing IgG4-Associated Cholangiopathy from Other Biliary Disorders: A Single Blinded Pilot Study. AB - BACKGROUND/AIMS: Immunoglobulin G4 (IgG4)-associated cholangiopathy (IAC) is an inflammatory disease and may mimic primary sclerosing cholangitis (PSC), cholangiocarcinoma (CCA), or pancreatic cancer on cholangiography. We investigated whether IgG4 levels in bile aspirated during endoscopic retrograde cholangiopancreatography (ERCP) can distinguish IAC from PSC, CCA, and pancreatic cancer. METHODS: Bile was aspirated directly from the common bile duct during ERCP in patients with IAC prior to steroid therapy. For control purposes, bile was obtained from patients with PSC, CCA, pancreatic cancer, and benign biliary conditions (sphincter of oddi dysfunction/choledocholithiasis). RESULTS: Biliary IgG4 levels were measured in 54 patients. The median bile IgG4 levels were markedly elevated in patients with IAC (5.5 mg/dL; interquartile range [IQR], 5.1 to 15.6) as compared to patients with benign biliary conditions (0 mg/dL; IQR, 0 to 0.1; p=0.003). The median biliary IgG4 levels in PSC, CCA, and pancreatic cancer were 1.2 (IQR, 0.2 to 3.8), 0.9 (IQR, 0.2 to 3.4), and 0.2 mg/dL (IQR, 0.1 to 0.8), respectively. A cutoff value of 3.8 mg/dL distinguished IAC from PSC and CCA patients with 100% and 76.9% sensitivity and specificity, respectively. CONCLUSIONS: The results of this pilot study suggest that measurement of biliary IgG4 levels may have clinical value in distinguishing patients with IAC from biliary disorders that can mimic IAC. PMID- 25505723 TI - Esophgeal Perforation and Bilateral Empyema Following Endoscopic EsophyX Transoral Incisionless Fundoplication. AB - Transoral incisionless fundoplication (TIF) has been used for endoscopic treatment of gastroesophageal reflux disease (GERD). TIF using the EsophyX device system (EndoGastric Solutions) was designed to create a full-thickness valve at the gastroesophageal junction through the insertion of multiple fasteners; it improves GERD, reduces proton pump inhibitor use, and improves quality of life. Although TIF is effective in select patients, a significant subset of patients undergoing TIF develop persistent or recurrent GERD symptoms and may need antireflux surgery to control the GERD symptoms. We now report a 48-year-old man with chronic GERD unresponsive to medical management. He underwent TIF complicated by esophageal perforation and developed mediastinitis, left pneumothorax, bilateral pleural effusions, and acute respiratory failure. He required chest tube placement and bilateral decortication for treatment of nonresolving empyemas. Additional postmarketing studies are required to assess the safety, efficacy, and clinical outcomes of this novel procedure, and patients undergoing this procedure need close postprocedural follow-up. PMID- 25505724 TI - Successful treatment of a gastric plasmacytoma using a combination of endoscopic submucosal dissection and oral thalidomide. AB - We report a rare case of a gastric plasmacytoma treated with endoscopic resection and oral thalidomide therapy. A 70-year-old man was admitted to our hospital with indigestion. He had no specific medical history and unremarkable laboratory results. Gastroendoscopic findings revealed a focal, erythematous, flat elevated lesion in the anterior wall of the stomach antrum. A biopsy revealed atypical lymphocytes. Endoscopic submucosal dissection (ESD) with an insulation-tipped knife was performed 45 days after diagnosis. Radiological and hematological evaluations, including a bone marrow biopsy, were performed and showed no involvement of other organs. The patient was diagnosed with extramedullary gastric plasmacytoma. Follow-up gastroendoscopy was performed three times during a 2-year period and showed nonspecific ESD scarring. The patient's condition was found to be stable. PMID- 25505725 TI - Endoscopic diagnosis of duodenal stenosis in a 5-month-old male infant. AB - Duodenal stenosis and duodenal atresia are well-known gastrointestinal anomalies in patients with Down syndrome. Although duodenal atresia presents early and classically with vomiting in the immediate neonatal period, the presentation of duodenal stenosis can be significantly more subtle and the diagnosis delayed. Here, we describe the case of a 5-month-old male infant with Down syndrome and delayed presentation of high-grade duodenal stenosis diagnosed endoscopically. Pediatric gastroenterologists should include duodenal stenosis in the differential diagnosis of older infants and children with vomiting and should be familiar with the endoscopic appearance of this lesion. PMID- 25505726 TI - Gastric squamous papilloma in a 52-year-old female patient. AB - A papilloma is a benign epithelial lesion characterized by finger-like projections of tissue lined by an overgrowth of squamous cells and a core of connective tissue. We report a case of squamous papilloma on the cardia in a 52 year-old asymptomatic female. Endoscopy showed a 1-cm sized is polyp with hyperemic change originating from the cardia adjacent to the esophagogastric junction, the biopsy of which suggested a diagnosis of squamous papilloma. Endoscopic mucosal resection was performed to obtain a definite diagnosis and the polyp was completely removed. The histological result was compatible with squamous papilloma, and its surrounding tissues showed foveolar epithelium, which suggested a stomach origin. This is the first report of endoscopic resection of a gastric squamous papilloma. Squamous papilloma should be considered in the differential diagnosis of a gastric polyp, especially one in the cardia. As the prognostic value of a squamous papilloma is not well known, we recommend endoscopic resection to treat a gastric squamous papilloma, when possible. PMID- 25505727 TI - Polypoid arteriovenous malformation presenting with jejunojejunal intussusceptions in an adult. AB - Jejunal polypoid arteriovenous malformations (AVMs) and jejunojejunal intussusceptions are both rare. Here, we present the case of a 61-year-old woman who suffered intermittent episodes of abdominal pain over the course of 13 years. A computed tomography scan of her abdomen and pelvis revealed a distal jejunojejunal intussusception. A suspected low density mass was observed at the tip of the intussusception. Treatment comprised laparoscopic small bowel resection with end-to-end jejunostomy. The final diagnosis was a polypoid AVM measuring 5*3.5*3 cm. We suggest that polypoid AVM should be considered as a differential diagnosis in patients presenting with small intestinal neoplasms. PMID- 25505728 TI - Acute pancreatitis due to a duodenal ulcer. AB - Duodenal ulcers and acute pancreatitis are two of the most commonly encountered gastrointestinal diseases among the general population. However, duodenal ulcer induced pancreatitis is very rarely reported worldwide. This report elaborates on a distinct medical treatment that contributes to partial or complete treatment of acute pancreatitis induced by a duodenal ulcer scar. PMID- 25505729 TI - Pro: propofol in endoscopy. PMID- 25505730 TI - Planning national radiotherapy services. AB - Countries, states, and island nations often need forward planning of their radiotherapy services driven by different motives. Countries without radiotherapy services sponsor patients to receive radiotherapy abroad. They often engage professionals for a feasibility study in order to establish whether it would be more cost-beneficial to establish a radiotherapy facility. Countries where radiotherapy services have developed without any central planning, find themselves in situations where many of the available centers are private and thus inaccessible for a majority of patients with limited resources. Government may decide to plan ahead when a significant exodus of cancer patients travel to another country for treatment, thus exposing the failure of the country to provide this medical service for its citizens. In developed countries, the trigger has been the existence of highly visible waiting lists for radiotherapy revealing a shortage of radiotherapy equipment. This paper suggests that there should be a systematic and comprehensive process of long-term planning of radiotherapy services at the national level, taking into account the regulatory infrastructure for radiation protection, planning of centers, equipment, staff, education programs, quality assurance, and sustainability aspects. Realistic budgetary and cost considerations must also be part of the project proposal or business plan. PMID- 25505731 TI - Stereotactic Body Radiation Therapy for Prostate Cancer: Review of Experience of a Multicenter Phase I/II Dose-Escalation Study. AB - INTRODUCTION: Stereotactic body radiation therapy (SBRT) is an area of active investigation for treatment of prostate cancer. In our phase I dose-escalation study, maximum-tolerated dose (MTD) was not reached, and subsequently phase II study has been completed. The purpose of this article is to review our experiences of dose-escalated SBRT for localized prostate cancer. METHODS AND MATERIALS: Patients enrolled to phase I/II study from 2006 to 2011 were reviewed. Prescription dose groups were 45, 47.5, and 50 Gray (Gy) in five fractions over 2.5 weeks. Toxicity and quality of life questionnaire data were collected and analyzed. Descriptive statistics were obtained in the form of means, medians, and ranges for the continuous variables, and frequencies and percentages for the categoric variables. RESULTS: Ninety-one patients were enrolled from five institutions. Median follow-up for prostate specific antigen (PSA) evaluation was 42 months. PSA control remains at 99%. While the MTD was not reached in the phase I study, excess high grade rectal toxicity (10.6%) was noted in the phase II study. The 13 patients treated to 50 Gy in the phase I study that did not have high grade rectal toxicity, in retrospect met these parameters and have not had further events on longer follow-up. CONCLUSION: Prostate specific antigen control rate, even for patients with intermediate risk, is thus far excellent at these dose levels. This study provides a platform for exploration of SBRT based clinical trials aimed at optimizing outcome for intermediate and high risk patients. High grade toxicities specifically related to the rectum were observed in a small but meaningful minority at the highest dose level. Dose constraints based on physiologic parameters have been defined to mitigate this risk, and strategies to minimize rectal exposure to such doses are being explored. PMID- 25505732 TI - Virtual HDR CyberKnife SBRT for Localized Prostatic Carcinoma: 5-Year Disease Free Survival and Toxicity Observations. AB - PURPOSE: Prostate stereotactic body radiotherapy (SBRT) may substantially recapitulate the dose distribution of high-dose-rate (HDR) brachytherapy, representing an externally delivered "Virtual HDR" treatment method. Herein, we present 5-year outcomes from a cohort of consecutively treated virtual HDR SBRT prostate cancer patients. METHODS: Seventy-nine patients were treated from 2006 to 2009, 40 low-risk, and 39 intermediate-risk, under IRB-approved clinical trial, to 38 Gy in four fractions. The planning target volume (PTV) included prostate plus a 2-mm volume expansion in all directions, with selective use of a 5-mm prostate-to-PTV expansion and proximal seminal vesicle coverage in intermediate-risk patients, to better cover potential extraprostatic disease; rectal PTV margin reduced to zero in all cases. The prescription dose covered >95% of the PTV (V100 >=95%), with a minimum 150% PTV dose escalation to create "HDR-like" PTV dose distribution. RESULTS: Median pre-SBRT PSA level of 5.6 ng/mL decreased to 0.05 ng/mL 5 years out and 0.02 ng/mL 6 years out. At least one PSA bounce was seen in 55 patients (70%) but only 3 of them subsequently relapsed, biochemical-relapse-free survival was 100 and 92% for low-risk and intermediate risk patients, respectively, by ASTRO definition (98 and 92% by Phoenix definition). Local relapse did not occur, distant metastasis-free survival was 100 and 95% by risk-group, and disease-specific survival was 100%. Acute and late grade 2 GU toxicity incidence was 10 and 9%, respectively; with 6% late grade 3 GU toxicity. Acute urinary retention did not occur. Acute and late grade 2 GI toxicity was 0 and 1%, respectively, with no grade 3 or higher toxicity. Of patient's potent pre-SBRT, 65% remained so at 5 years. CONCLUSION: Virtual HDR prostate SBRT creates a very low PSA nadir, a high rate of 5-year disease-free survival and an acceptable toxicity incidence, with results closely resembling those reported post-HDR brachytherapy. PMID- 25505733 TI - Promising Targets and Current Clinical Trials in Metastatic Non-Squamous NSCLC. AB - Lung adenocarcinoma is the most common subtype of lung cancer today. With the discovery of epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and effective targeted therapy, personalized medicine has become a reality for patients with lung adenocarcinoma. Here, we review potential additional targets and novel therapies of interest in lung adenocarcinoma including targets within the cell surface (receptor tyrosine kinases EGFR, human epidermal growth factor receptor 2, RET, ROS1, mesenchymal epidermal transition, TRK), targets in intracellular signal transduction (ALK, RAS-RAF-MEK, PI3K-AKT-PTEN, WNT), nuclear targets such as poly-ADP ribose polymerase, heat shock protein 90, and histone deacetylase, and selected pathways in the tumor environment. With the evolving ability to identify specific molecular aberrations in patient tumors in routine practice, our ability to further personalize therapy in lung adenocarcinoma is rapidly expanding. PMID- 25505735 TI - Harnessing oncolytic virus-mediated anti-tumor immunity. PMID- 25505734 TI - A Phase II Study of Stereotactic Body Radiation Therapy for Low-Intermediate-High Risk Prostate Cancer Using Helical Tomotherapy: Dose-Volumetric Parameters Predicting Early Toxicity. AB - Endpoint: To assess early urinary (GU) and rectal (GI) toxicities after helical tomotherapy Stereotactic body radiation therapy (SBRT), and to determine their predictive factors. METHODS: Since May 2012, 45 prostate cancer patients were treated with eight fractions of 5.48 (low risk, 29%) or 5.65 Gy (intermediate high risk, 71%) on alternative days over 2.5 weeks. The exclusion criteria were Gleason score 9-10, PSA >40 ng/mL, cT3b-4, IPSS >=20, and history of acute urinary retention. During the follow-up, a set of potential prognostic factors was correlated with urinary or rectal toxicity. RESULTS: The median follow-up was 13.8 months (2-25 months). There were no grade >=3 toxicities. Acute grade 2 GU complications were found in a 22.7% of men, but in 2.3% of patients at 1 month, 0% at 6 months, and 0% at 12 months. The correspondent figures for grade 2 GI toxicities were 20.4% (acute), 2.3% (1 month), 3.6% (6 months), and 5% (12 months). Acute GI toxicity was significantly correlated with the rectal volume (>15 cm(3)) receiving 28 Gy, only when expressed as absolute volume. The age (>72 years old) was a predictor of GI toxicity after 1 month of treatment. No correlation was found, however, between urinary toxicity and the other analyzed variables. IPSS increased significantly at the time of the last fraction and within the first month, returning to the baseline at sixth month. Urinary-related quality of life (IPSS question 8 score), it was not significantly worsen during radiotherapy returning to the baseline levels 1 month after the treatment. At 12 months follow-up patient's perception of their urinary function improved significantly in comparison with the baseline. CONCLUSION: Our scheme of eight fractions on alternative days delivered using helical tomotherapy is well tolerated. We recommend using actual volume instead of percentual volume in the treatment planning, and not to exceed 15 cm(3) of rectal volume receiving >=25 Gy in order to diminish acute GI toxicity. PMID- 25505736 TI - Human cytomegalovirus antigens in malignant gliomas as targets for adoptive cellular therapy. AB - Malignant gliomas are the most common primary brain tumor in adults, with over 12,000 new cases diagnosed in the United States each year. Over the last decade, investigators have reliably identified human cytomegalovirus (HCMV) proteins, nucleic acids, and virions in most high-grade gliomas, including glioblastoma (GBM). This discovery is significant because HCMV gene products can be targeted by immune-based therapies. In this review, we describe the current level of understanding regarding the presence and role in pathogenesis of HCMV in GBM. We describe our success detecting and expanding HCMV-specific cytotoxic T lymphocytes to kill GBM cells and explain how these cells can be used as a platform for enhanced cellular therapies. We discuss alternative approaches that capitalize on HCMV infection to treat patients with HCMV-positive tumors. Adoptive cellular therapy for HCMV-positive GBM has been tried in a small number of patients with some benefit, but we reason why, to date, these approaches generally fail to generate long-term remission or cure. We conjecture how cellular therapy for GBM can be improved and describe the barriers that must be overcome to cure these patients. PMID- 25505737 TI - Differential Gene Expression Landscape of Co-Existing Cervical Pre-Cancer Lesions Using RNA-seq. AB - Genetic changes occurring in different stages of pre-cancer lesions reflect causal events initiating and promoting the progression to cancer. Co-existing pre cancerous lesions including low- and high-grade squamous intraepithelial lesion (LGSIL and HGSIL), and adjacent "normal" cervical epithelium from six formalin fixed paraffin-embedded samples were selected. Tissues from these 18 samples were isolated using laser-capture microdissection, RNA was extracted and sequenced. RNA-sequencing generated 2.4 billion raw reads in 18 samples, of which ~50.1% mapped to known and annotated genes in the human genome. There were 40 genes up regulated and 3 down-regulated (normal to LGSIL) in at least one-third of the sample pairs (same direction and FDR p < 0.05) including S100A7 and KLK6. Previous studies have shown that S110A7 and KLK7 are up-regulated in several other cancers, whereas CCL18, CFTR, and SLC6A14, also differentially expressed in two samples, are up-regulated specifically in cervical cancer. These differentially expressed genes in normal to LGSIL progression were enriched in pathways related to epithelial cell differentiation, keratinocyte differentiation, peptidase, and extracellular activities. In progression from LGSIL to HGSIL, two genes were up-regulated and five down-regulated in at least two samples. Further investigations using co-existing samples, which account for all internal confounders, will provide insights to better understand progression of cervical pre-cancer. PMID- 25505740 TI - Doctoral and post-doctoral research - a priority of the Romanian postgraduate education system. PMID- 25505738 TI - The Multifaceted Mechanism of Leptin Signaling within Tumor Microenvironment in Driving Breast Cancer Growth and Progression. AB - Adipokines represent likely candidates to mediate the increased breast cancer risk and the enhanced progression associated with obesity. Other contributors to obesity-related cancer progression are insulin/IGF-1 pathways and hormones. Among these, the adipokine leptin is the most intensively studied in both metabolism in general and in cancer due to the fact that leptin levels increase in proportion of fat mass. Leptin is primarily synthesized from adipocytes but it is also produced by other cells including fibroblasts. In this latter case, it has been well demonstrated how cancer-associated fibroblasts express leptin receptor and secrete leptin, which sustains a short autocrine loop and is able to target tumor epithelial cells enhancing breast cancer cell motility and invasiveness. In addition, it has been reported that leptin may induce breast cancer to undergo a transition from epithelial to spindle-like mesenchymal morphology, activating the signaling pathways devoted to the EMT. Thus, it emerges how leptin may play a crucial role in mediating malignant cell and tumor microenvironment interactions. Here, we present an overview of the role of leptin in breast cancer, covering the following topics: (1) leptin as an amplifier of estrogen signaling in tumor epithelial cells contributing to the promotion of carcinogenesis; (2) leptin as a crucial player in mediating tumor-stroma interaction and influencing EMT-linked mechanisms, that may sustain breast cancer growth and progression; (3) leptin and leptin receptor targeting as novel therapeutic strategies for breast cancer treatment. PMID- 25505739 TI - Molecular determinants of staphylococcal biofilm dispersal and structuring. AB - Staphylococci are frequently implicated in human infections, and continue to pose a therapeutic dilemma due to their ability to form deeply seated microbial communities, known as biofilms, on the surfaces of implanted medical devices and host tissues. Biofilm development has been proposed to occur in three stages: (1) attachment, (2) proliferation/structuring, and (3) detachment/dispersal. Although research within the last several decades has implicated multiple molecules in the roles as effectors of staphylococcal biofilm proliferation/structuring and detachment/dispersal, to date, only phenol soluble modulins (PSMs) have been consistently demonstrated to serve in this role under both in vitro and in vivo settings. PSMs are regulated directly through a density-dependent manner by the accessory gene regulator (Agr) system. They disrupt the non-covalent forces holding the biofilm extracellular matrix together, which is necessary for the formation of channels, a process essential for the delivery of nutrients to deeper biofilm layers, and for dispersal/dissemination of clusters of biofilm to distal organs in acute infection. Given their relevance in both acute and chronic biofilm-associated infections, the Agr system and the psm genes hold promise as potential therapeutic targets. PMID- 25505741 TI - Human parasitic protozoa in drinking water sources in rural Zimbabwe and their link to HIV infection. AB - OBJECTIVE: We aimed to perform a risk assessment in a rural setting, where drinking water is obtained from both protected and unprotected deep or shallow wells, boreholes and springs. Water is consumed untreated and this poses a risk of acquiring waterborne infections that may cause diarrhea. METHODS: The study included 113 study participants who volunteered in Chiweshe rural community (Musarara village) in Mashonaland Central Province in Zimbabwe. There were 34 (30%) males and 79 (70%) females with ages ranging from 2 to 89 years. HIV counseling was carried out at the communal meeting and testing was done at home visits. Stool and drinking water samples were collected from 104 subjects. Routine laboratory methods were used to examine for parasitic infections. RESULTS: Only 29 (25.7%) of participants were confirmed HIV positive using 2 rapid serology tests; eighty-four (74.3%) were negative. Diarrheic stool samples were observed in 17 (16.3%) participants and of these 5 (29.4%) were HIV seropositive. Several parasites were isolated from stool samples: G. duodenalis 6 (5.7%), E. histolytica/dispar 19 (18.2%), C. parvum, 8 (7.6%) and C. cayetanensis 23 (22.1%). Eleven out of 30 (36.6%) water bodies had protozoan parasites: G. duodenalis 2 (6.6%), E. histolytica 4 (13.3%), C. parvum 1 (3.3%), C. cayetanensis 3 (10%), E. coli 1 (3.3%). CONCLUSION: The water sources were being used without treatment and were shown to pose a risk for acquiring diarrheagenic protozoan parasites. PMID- 25505742 TI - Experimental approach for bacteriophage susceptibility testing of planktonic and sessile bacterial populations - Study protocol. AB - INTRODUCTION: Antimicrobial resistance is a growing threat for all clinical branches. This phenomenon poses important challenges in controlling infectious diseases. However, multidrug resistance is not the only issue, as bacteria that are otherwise susceptible to common antibiotics express other patterns for evading antibiotherapy, for example they can aggregate within a self-produced matrix to form biofilm. METHODS: We intend to perform a prospective laboratory study of the germs isolated from different samples collected from patients admitted with infectious pathology in reference hospitals in Romania. We will perform antibiotic resistance testing as well as phage testing, both on solid and liquid growth medium, for Staphylococcus spp., Enterococcus spp., and Pseudomonas spp. We intend to collect data for 150 patients with different infections with these identified pathogens. Phage susceptibility testing will be performed using 5 types of strain-specific bacteriophage mixtures: PYO, INTESTI, STAPHYLOCOCCAL (Eliava BioPreparations, Tbilisi, Georgia), PHAGYO, PHAGESTI (JSC "Biochimpharm", Tbilisi, Georgia). For phage-susceptible strains, we will evaluate biofilm formation in the presence of phages, as well as phage effect on already formed biofilm. EXPECTED RESULTS: Through this study, we intend to provide the first set of results on bacteriophage-susceptibility of bacteria isolated from patients with hard to treat infections, from reference hospitals in Romania. By evaluating a large number of bacterial strains we aim to predict and project biofilm kinetics, while adding binary phage dilutions at key timepoints during biofilm formation. ACKNOWLEDGMENTS: POSDRU/159/1.5/S/141531; Carol Davila University of Medicine and Pharmacy, Young Researchers Grant no. 28341/2013. PMID- 25505743 TI - Utility of contact tracing in reducing the magnitude of Ebola disease. PMID- 25505745 TI - The Cell Survival of F10B16 Melanoma and 4T1 Breast Adenocarcinoma Irradiated to Gamma Radiation Using the MTT Assay Based on Two Different Calculation Methods. AB - BACKGROUND: various MTT assay methods are proposed to obtain the cell survival parameters. OBJECTIVE: determining the survival curve characteristics of two cancerous cells of interest based on a common and a novel MTT assay method after exposing them to ionizing radiation. METHODS: a common and a novel MTT assay method were used and compared for obtaining the F10B16 melanoma and 4T1 breast adenocarcinoma survivals after exposing them to ionizing radiation from a Co-60 machine. To obtain the survival parameters of the cells based on the common method, the cells were inoculated in 96-well plates. After irradiating the plates, the MTT assay was performed over the following days for a period of 8 days. Thereafter, the survival fraction was calculated from a simple equation for every day from which the best day was selected. To acquire the cells' survival parameters based on the novel method, extensive experiments were performed on a large number of samples. Then, the MTT assay was done in every day following various experimental treatments to acquire the exponential growth. Finally, the cells' survivals were determined by measuring the space between relevant growing curves. RESULTS: at low doses (<4Gy) the two MTT assay methods indicated the same results. However, at higher doses there were significant differences among the findings. CONCLUSION: both of the MTT methods indicated that the cells' responses are dependent on the dose levels used. Although the implementation of the common MTT assay method is simpler, the novel method seems to show more precise and reliable results at all levels of radiation doses. PMID- 25505744 TI - Auricular or body acupuncture: which one is more effective in reducing abdominal fat mass in Iranian men with obesity: a randomized clinical trial. AB - BACKGROUND: The prevalence of abdominal obesity is on the rise worldwide. Previous studies have indicated the higher diagnostic value of body fat distribution pattern compared with general body in abdominal obesity assessments. Several non-pharmacological methods have been suggested for obesity management, of which acupuncture has gained a great deal of research interest with promising results. This study aimed to comparatively evaluate the effects of conventional auricular and body electroacupuncture on abdominal fat mass in obese men. METHODS: The volunteers were randomly divided into four groups, including 2 interventions and 2 controls. This study was conducted on 80 obese volunteer men with Body Mass Index (BMI) range of 30-40 kg/m2.The intervention groups including real body electroacupuncture (A), real auricular acupuncture (C) and the control groups containing sham body electroacupuncture (B), and sham auricular acupuncture (D). All groups were in combination with a low-calorie diet for 6 weeks. BMI, Trunk Fat Mass (TFM), Waist Circumference (WC), and Hip Circumference (HC) were measured pre- and post-intervention. RESULTS: In group A, respectively a significant reduction was shown in BMI (P < 0.005), TFM (P < 0.005), WC (P < 0.05, P < 0.005) and HC (P < 0.005) when compared with controls (Groups B and D). Interestingly, group C had significant decreases in BMI (P < 0.005), TFM (P < 0.01, P < 0.005), WC (P < 0.005) and HC (P < 0.001) after comparison with the sham. Likewise, WC (P < 0.05) and HC (P < 0.05) were significantly reduced post- intervention when compared with two treatment groups. CONCLUSIONS: In our study, acupuncture treatment (body or auricular) seemed to have an effect on reducing BMI, TFM, WC and HC. Comparison of the two types of treatment (body and auricular acupuncture) suggests that the two types of acupuncture had similar effects on reducing BMI and TFM, but body electroacupuncture is more effective in reducing WC and auricular in HC. It seems that both auricular and body electro-acupuncture combined with a low-calorie diet are efficient, simple and painless methods to reduce respectively the HC and WC fat in obese men, compared with conventional techniques. TRIAL REGISTRATION: IRCT201201127117N2. PMID- 25505746 TI - Effect of Gold Nanoparticle on Percentage Depth Dose Enhancement On Megavoltage Energy in MAGICA Polymer Gel Dosimeter. AB - BACKGROUND: Radiation-sensitive polymer gels are among the most promising three dimensional dose verification tools and tissue-like phantom developed to date. OBJECTIVE: The aim of this study is an investigating of percentage depth dose enhancement within the gel medium with used of conformal distribution gold nanoparticle as contrast agents by high atomic number material. METHODS: In this work the normoxic polymer gel dosimeter MAGICA tissue-equivalence was first theoretically verified using MCNPX Monte Carlo code and experimentally by percentage depth dose curves within the gel medium. Then gold nanoparticles (GNPs) of 50nm diameter with different concentrations of 0.1mM, 0.2mM, and 0.4mM were embedded in MAGICA gel and irradiated by 18MV photon beam. RESULTS: Experimental results have shown dose increase of 10%, 2% and 4% in 0.1mM, 0.2mM and 0.4mM concentrations, respectively. Simulation results had good agreement in the optimum concentration of 0.1mM. The largest error between experimental and simulation results was equal to 9.28% stood for 0.4mM concentration. CONCLUSION: The results showed that the optimum concentration of gold nanoparticles to achieve maximum absorbed dose in both experimental and simulation was 0.1 mM and so it can be used for clinical studies. PMID- 25505747 TI - Modeling the Circle of Willis Using Electrical Analogy Method under both Normal and Pathological Circumstances. AB - BACKGROUND AND OBJECTIVE: The circle of Willis (COW) supports adequate blood supply to the brain. The cardiovascular system, in the current study, is modeled using an equivalent electronic system focusing on the COW. METHODS: In our previous study we used 42 compartments to model whole cardiovascular system. In the current study, nevertheless, we extended our model by using 63 compartments to model whole CS. Each cardiovascular artery is modeled using electrical elements, including resistor, capacitor, and inductor. The MATLAB Simulink software is used to obtain the left and right ventricles pressure as well as pressure distribution at efferent arteries of the circle of Willis. Firstly, the normal operation of the system is shown and then the stenosis of cerebral arteries is induced in the circuit and, consequently, the effects are studied. RESULTS: In the normal condition, the difference between pressure distribution of right and left efferent arteries (left and right ACA-A2, left and right MCA, left and right PCA-P2) is calculated to indicate the effect of anatomical difference between left and right sides of supplying arteries of the COW. In stenosis cases, the effect of internal carotid artery occlusion on efferent arteries pressure is investigated. The modeling results are verified by comparing to the clinical observation reported in the literature. CONCLUSION: We believe the presented model is a useful tool for representing the normal operation of the cardiovascular system and study of the pathologies. PMID- 25505748 TI - Ultra-sensitive optical biosensor based on whispering gallery modes: The effect of buffer solutions refractive index on their sensitivity and performance. AB - BACKGROUND: Whispering gallery modes (WGM) biosensors are ultrasensitive systems that can measure amount of adsorbed layer onto the micro-cavity surface. They have many applications including protein, peptide growth, DNA and bacteria detection, molecular properties measurements and specific interaction and drug table recognitions due to their high sensitivity, compact size and label free sensing mechanism. OBJECTIVE: In this paper we investigate the effect of buffer solution on detection of specific biomolecules in WGM biosensors through its refractive index change. METHODS: The propagation of electromagnetic waves in a dielectric microsphere is analyzed by solving Maxwell's equations through proper boundary condition to find a concise relation for micro-cavity resonance shift. RESULTS: Analysis of the buffer solution's refractive index effects on detection of BSA by WGM biosensors are presented and it was shown that even a very small change in the refractive index of buffer solution can affect the biosensor wavelength shift and the sensitivity of biosensors. CONCLUSION: This study opens up a discussion in biosensor sensitivity based on true and reliable performance of the buffer solution through its accurate determination of refractive index and behavior. To avoid expensive methods of enhancing sensitivity, one can improve the sensitivity of WGM biosensor to some extent, by means of using proper buffer solution. PMID- 25505751 TI - Development of a Brain Computer Interface (BCI) Speller System Based on SSVEP Signals. AB - BCI is one of the most intriguing technologies among other HCI systems, mostly because of its capability of recording brain activities. Spelling BCIs, which help paralyzed people to maintain communication, are one of the striking topics in the field of BCI. In this scientific a spelling BCI system with high transfer rate and accuracy that uses SSVEP signals is proposed. In addition, we suggested that LED light sources can provide proper signals for speller BCIs and they can be used in future. PMID- 25505749 TI - Autoregulation of blood flow: Vessel diameter changes in response to different temperatures. AB - Autoregulation of blood flow is a marvelous phenomenon balancing blood supply and tissue demand. Although many chemically-based explanations for this phenomenon have been proposed and some of them are commonly used today, biomechanical aspects of this phenomenon was neglected. The biomechanical aspect provides insights to us to model vessel diameter changes more precisely and comprehensively. One important aspect of autoregulation phenomenon is temperature changes of the tissue resulted from tissue metabolism. We hypothesize that temperature changes can affect the mechanical properties of the vessel wall leading to vessel diameter changes during autoregulation. Mechanical modeling of vessel diameter changes can also be useful to explain other phenomena in which the vessel diameter changes in response to temperature alterations. Through the mechanical modeling of any vessel, the analysis of temperature-induced changes in vessel diameter can be done more precisely. PMID- 25505750 TI - Systemic targeted alpha radiotherapy for cancer. AB - BACKGROUND: The fundamental principles of internal targeted alpha therapy forcancer were established many decades ago.The high linear energy transfer (LET) ofalpha radiation to the targeted cancer cellscauses double strand breaks in DNA. Atthe same time, the short range radiation spares adjacent normal tissues. This targeted approach complements conventional external beam radiotherapy and chemotherapy. Such therapies fail on several fronts, such as lack of control of some primary cancers (e.g. glioblastoma multiforme) and to inhibit the development of lethal metastaticcancer after successful treatment of the primary cancer. OBJECTIVE: This review charts the developing role of systemic high LET, internalradiation therapy. METHOD: Targeted alpha therapy is a rapidly advancing experimental therapy thatholds promise to deliver high cytotoxicity to targeted cancer cells. Initially thoughtto be indicated for leukemia and micrometastases, there is now evidence that solidtumors can also be regressed. RESULTS: Alpha therapy may be molecular or physiological in its targeting. Alphaemitting radioisotopes such as Bi-212, Bi-213, At-211 and Ac-225 are used to labelmonoclonal antibodies or proteins that target specific cancer cells. Alternatively, Radium-233 is used for palliative therapy of breast and prostate cancers because of its bone seeking properties. CONCLUSION: Preclinical studies and clinical trials of alpha therapy are discussedfor leukemia, lymphoma, melanoma, glioblastoma multiforme, bone metastases, ovarian cancer, pancreatic cancer and other cancers. PMID- 25505752 TI - The endothelial permeability increased by low voltage and high frequency electroporation. AB - Propose: Standard electroporation and electrochemotherapy caused the endothelial cell permeability and reduction in tumor blood flow. The effects of low voltage and high frequency electroporation on the endothelial cells permeability and viability were expected. Therefore, the propose of present study was to evaluate the effect of electroporation with bleomycin or alone on viability and permeabilization of human Embryo microvascular endothelial (HUVEC) cell line. MATERIAL AND METHODS: The HUVEC cells were exposed to 4000 electric pulsed with 100us duration, 50-150 v/cm with increment of 10 v/cm in 4, 5 and 6 kHz frequency (33 experimental groups) and then uptake and viability reduction was measured in each group. RESULTS: The results of this study demonstrated that electric pulses alone reduce the cell viability and with bleomycin significantly increases the toxicity to endothelial cells. CONCLUSION: Our data indicated that low voltage, high frequency ECT is highly cytotoxic for a HUVEC cell offers a possible effect of antivascular actions of this kind of electrochemotherapy. PMID- 25505753 TI - Designing an Algorithm for Cancerous Tissue Segmentation Using Adaptive K-means Cluttering and Discrete Wavelet Transform. AB - BACKGROUND: Breast cancer is currently one of the leading causes of death among women worldwide. The diagnosis and separation of cancerous tumors in mammographic images require accuracy, experience and time, and it has always posed itself as a major challenge to the radiologists and physicians. OBJECTIVE: This paper proposes a new algorithm which draws on discrete wavelet transform and adaptive K means techniques to transmute the medical images implement the tumor estimation and detect breast cancer tumors in mammograms in early stages. It also allows the rapid processing of the input data. METHOD: In the first step, after designing a filter, the discrete wavelet transform is applied to the input images and the approximate coefficients of scaling components are constructed. Then, the different parts of image are classified in continuous spectrum. In the next step, by using adaptive K-means algorithm for initializing and smart choice of clusters' number, the appropriate threshold is selected. Finally, the suspicious cancerous mass is separated by implementing the image processing techniques. RESULTS: We Received 120 mammographic images in LJPEG format, which had been scanned in Gray-Scale with 50 microns size, 3% noise and 20% INU from clinical data taken from two medical databases (mini-MIAS and DDSM). The proposed algorithm detected tumors at an acceptable level with an average accuracy of 92.32% and sensitivity of 90.24%. Also, the Kappa coefficient was approximately 0.85, which proved the suitable reliability of the system performance. CONCLUSION: The exact positioning of the cancerous tumors allows the radiologist to determine the stage of disease progression and suggest an appropriate treatment in accordance with the tumor growth. The low PPV and high NPV of the system is a warranty of the system and both clinical specialists and patients can trust its output. PMID- 25505754 TI - Nanomaterial containing wall paints can increase radon concentration in houses located in radon prone areas. AB - BACKGROUND: Nowadays, extensive technological advancements have made it possible to use nanopaints which show exciting properties. In IR Iran excessive radon levels (up to 3700 Bq m-3) have been reported in homes located in radon prone areas. Over the past decades, concerns have been raised about the risk posed by residential radon exposure. OBJECTIVE: This study aims at investigating the effect of using nanomaterial containing wall paints on radon concentration in homes. METHODS: Two wooden model houses were used in this study. Soil samples from Ramsar high background radiation areas were used for simulating the situation of a typical house in radon-prone areas. Conventional water-soluble wall paint was used for painting the walls of the 1st house model; while the 2nd house model was painted with the same wall paint with montmorillonitenanoclay. RESULTS: Three days after sealing the house models, radon level was measured by using a portable radon survey meter. The mean radon level inside the 1st house model (conventional paint) was 515.3 +/- 17.8 Bq/m(3) while the mean radon concentration in the 2nd house model (nano-painted house model) was 570.8 +/- 18.5 Bq/m(3). The difference between these means was statistically significant (P<0.001). CONCLUSION: To the best of our knowledge, this study is the first investigation on the effect of nano-material containing wall paints on indoor radon concentrations. It can be concluded that nano-material-containing wall paints should not be used in houses with wooden walls located in radon prone areas. Although the mechanism of this effect is not clearly known, decreased porosity in nano-paints might be a key factor in increasing the radon concentration in homes. PMID- 25505756 TI - Message from the IOMP President, Dr. Kin Yin Cheung and the Chairman of the IOMP Education and Training Committee, Prof. John Damilakis on November 7, 2013: "International Day of Medical Physics". PMID- 25505755 TI - Exposure to mobile phone radiation opens new horizons in Alzheimer's disease treatment. AB - Alzheimer's disease, the most common type of dementia and a progressive neurodegenerative disease, occurs when the nerve cells in the brain die. Although there are medications that can help delay the development of Alzheimer's disease, there is currently no cure for this disease. Exposure to ionizing and non ionizing radiation may cause adverse health effects such as cancer. Looking at the other side of the coin, there are reports indicating stimulatory or beneficial effects after exposure to cell phone radiofrequency radiation. Mortazavi et al. have previously reported some beneficial cognitive effects such as decreased reaction time after human short-term exposure to cell phone radiation or occupational exposure to radar microwave radiation. On the other hand, some recent reports have indicated that RF radiation may have a role in protecting against cognitive impairment in Alzheimer's disease. Although the majority of these data come from animal studies that cannot be easily extrapolated to humans, it can be concluded that this memory enhancing approach may open new horizons in treatment of cognitive impairment in Alzheimer disease. PMID- 25505757 TI - An Automated MR Image Segmentation System Using Multi-layer Perceptron Neural Network. AB - BACKGROUND: Brain tissue segmentation for delineation of 3D anatomical structures from magnetic resonance (MR) images can be used for neuro-degenerative disorders, characterizing morphological differences between subjects based on volumetric analysis of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF), but only if the obtained segmentation results are correct. Due to image artifacts such as noise, low contrast and intensity non-uniformity, there are some classification errors in the results of image segmentation. OBJECTIVE: An automated algorithm based on multi-layer perceptron neural networks (MLPNN) is presented for segmenting MR images. The system is to identify two tissues of WM and GM in human brain 2D structural MR images. A given 2D image is processed to enhance image intensity and to remove extra cerebral tissue. Thereafter, each pixel of the image under study is represented using 13 features (8 statistical and 5 non- statistical features) and is classified using a MLPNN into one of the three classes WM and GM or unknown. RESULTS: The developed MR image segmentation algorithm was evaluated using 20 real images. Training using only one image, the system showed robust performance when tested using the remaining 19 images. The average Jaccard similarity index and Dice similarity metric for the GM and WM tissues were estimated to be 75.7 %, 86.0% for GM, and 67.8% and 80.7%for WM, respectively. CONCLUSION: The obtained performances are encouraging and show that the presented method may assist with segmentation of 2D MR images especially where categorizing WM and GM is of interest. PMID- 25505758 TI - Effectiveness Evaluation of Skin Covers against Intravascular Brachytherapy Sources Using VARSKIN3 Code. AB - BACKGROUND AND OBJECTIVE: The most common intravascular brachytherapy sources include (32)P, (188)Re, (106)Rh and (90)Sr/(90)Y. In this research, skin absorbed dose for different covering materials in dealing with these sources were evaluated and the best covering material for skin protection and reduction of absorbed dose by radiation staff was recognized and recommended. METHOD: Four materials including polyethylene, cotton and two different kinds of plastic were proposed as skin covers and skin absorbed dose at different depths for each kind of the materials was calculated separately using the VARSKIN3 code. RESULTS: The results suggested that for all sources, skin absorbed dose was minimized when using polyethylene. Considering this material as skin cover, maximum and minimum doses at skin surface were related to (90)Sr/(90)Y and (106)Rh, respectively. CONCLUSION: polyethylene was found the most effective cover in reducing skin dose and protecting the skin. Furthermore, proper agreement between the results of VARSKIN3 and other experimental measurements indicated that VRASKIN3 is a powerful tool for skin dose calculations when working with beta emitter sources. Therefore, it can be utilized in dealing with the issue of radiation protection. PMID- 25505759 TI - A Comparison of Skin Dose Delivered with MammoSite and Multicatheter Breast Brachytherapy. AB - BACKGROUND: Accelerated partial breast irradiation via interstitial balloon brachytherapy is a fast and effective treatment method for certain early stage breast cancers however skin, chest wall and Lung doses are correlated with toxicity in patients treated with breast brachytherapy. OBJECTIVE: To investigate the percentage of the dose received by critical organ (skin), thermoluminescence detector was used in MammoSite brachytherpy and the ability to control skin dose between MammoSite and MultiCatheter brachytherapy was compared with each other. METHOD: Dosimetry is carried out using a female-equivalent mathematical chest phantom and Ir-192 source for brachytherapy application. RESULTS: Our initial results has shown good agreement with surface doses between those calculated from the treatment planning results and those measured by the thermoluminescence detector. The mean skin dose for the experimental dosimetry in MammoSite was 2.3 Gy (56.76% of prescription dose). CONCLUSION: The results show that the MultiCatheter method is associated with significantly lower mean skin and chest wall dose than is the MammoSite. The MultiCatheter technique is quite flexible and can be applied to any size of breast or lumpectomy cavity, But in MammoSite technique, verification of balloon symmetry, balloon/cavity conformance and overlying skin thickness is essential to assure target coverage and toxicity avoidance. PMID- 25505760 TI - Comparative Measurements of Radon Concentration in Soil Using Passive and Active Methods in High Level Natural Radiation Area (HLNRA) of Ramsar. AB - BACKGROUND: Radon and its daughters are amongst the most important sources of natural exposure in the world. Soil is one of the significant sources of radon/thoron due to both radium and thorium so that the emanated thoron from it may cause increased uncertainties in radon measurements. Recently, a diffusion chamber has been designed and optimized for passive discriminative measurements of radon/thoron concentrations in soil. OBJECTIVE: In order to evaluate the capability of the passive method, some comparative measurements (with active methods) have been performed. METHOD: The method is based upon measurements by a diffusion chamber, including two Lexan polycarbonate SSNTDs, which can discriminate the emanated radon/thorn from the soil by delay method. The comparative measurements have been done in ten selected points of HLNRA of Ramsar in Iran. The linear regression and correlation between the results of two methods have been studied. RESULTS: The results show that the radon concentrations are within the range of 12.1 to 165 kBq/m(3) values. The correlation between the results of active and passive methods was measured by 0.99 value. As well, the thoron concentrations have been measured between 1.9 to 29.5 kBq/m(3) values at the points. CONCLUSION: The sensitivity as well as the strong correlation with active measurements shows that the new low-cost passive method is appropriate for accurate seasonal measurements of radon and thoron concentration in soil. PMID- 25505762 TI - Numerical investigation of angulation effects in stenosed renal arteries. AB - BACKGROUND: Numerical study of angulation effects of renal arteries on blood flow has been of great interest for many researchers. Objective : This paper aims at numerically determining the angulation effects of stenosed renal arteries on blood flow velocity and renal mass flow. METHOD: An anatomically realistic model of abdominal aorta and renal arteries is reconstructed from CT-scan images and used to conduct numerical simulation of pulsatile non-Newtonian blood flow incorporating fluid-structure interaction. The renal arteries in the realistic model have left and right branch angles of 53 and 45, respectively. Atrapezium shape stenosis is considered in the entrance of right renal artery. Two other branch angles, i.e. 90 and 135, are also considered for right renal artery to study the angulation effects. RESULTS: Comparison between models with right renal branch angles of 45, 90 and 135 reveals that high curvature of streamlines in the entrance of the renal artery with the angle of 135 causes the flow velocity and renal mass flow to be less than those of 45and 90. CONCLUSION: It is concluded that large renal branch angles cause the arteries to be unable to deliver blood in the requisite amounts to kidney. Kidney responds to counteract low blood flow by activating the renin-angiotension system which leads to severe hypertension. PMID- 25505761 TI - A hybrid classifier for characterizing motor unit action potentials in diagnosing neuromuscular disorders. AB - BACKGROUND: The time and frequency features of motor unit action potentials (MUAPs) extracted from electromyographic (EMG) signal provide discriminative information for diagnosis and treatment of neuromuscular disorders. However, the results of conventional automatic diagnosis methods using MUAP features is not convincing yet. OBJECTIVE: The main goal in designing a MUAP characterization system is obtaining high classification accuracy to be used in clinical decision system. For this aim, in this study, a robust classifier is proposed to improve MUAP classification performance in estimating the class label (myopathic, neuropathic and normal) of a given MUAP. METHOD: The proposed scheme employs both time and time-frequency features of a MUAP along with an ensemble of support vector machines (SVMs) classifiers in hybrid serial/parallel architecture. Time domain features includes phase, turn, peak to peak amplitude, area, and duration of the MUAP. Time-frequency features are discrete wavelet transform coefficients of the MUAP. RESULTS: Evaluation results of the developed system using EMG signals of 23 subjects (7 with myopathic, 8 with neuropathic and 8 with no diseases) showed that the system estimated the class label of MUAPs extracted from these signals with average of accuracy of 91% which is at least 5% higher than the accuracy of two previously presented methods. CONCLUSION: Using different optimized subsets of features along with the presented hybrid classifier results in a classification accuracy that is encouraging to be used in clinical applications for MUAP characterization. PMID- 25505763 TI - Production of a Novel Mineral-based Sun Lotion for Protecting the Skin from Biohazards of Electromagnetic Radiation in the UV Region. AB - BACKGROUND: Sun protection materials have been one of the major concerns in pharmaceutical in-dustry since almost one century ago. Various materials have been found to have such an effect but there are still many unknown substances that have not been discovered. Objective : To introduce a novel mineral-based sun lotion with considerable UV absorption properties compared to commercially available sunscreens. METHOD: UV absorption properties of transparent plas-tic sheets covered by a uniform cream layer of different mineral-based sun lotions and a commercially available sun lotion were tested. RESULTS: Sun lotions containing specific proportion of bentonite and zeolite minerals were capable of absorbing the highest level of UV light com-pared to that of the commercially available sun lotion. CONCLUSION: Mineral-based sun lotions can be considered as cost effective alternatives for current commercial sunscreens. PMID- 25505764 TI - Quantitative Comparison of SPM, FSL, and Brainsuite for Brain MR Image Segmentation. AB - BACKGROUND: Accurate brain tissue segmentation from magnetic resonance (MR) images is an important step in analysis of cerebral images. There are software packages which are used for brain segmentation. These packages usually contain a set of skull stripping, intensity non-uniformity (bias) correction and segmentation routines. Thus, assessment of the quality of the segmented gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) is needed for the neuroimaging applications. METHODS: In this paper, performance evaluation of three widely used brain segmentation software packages SPM8, FSL and Brainsuite is presented. Segmentation with SPM8 has been performed in three frameworks: i) default segmentation, ii) SPM8 New-segmentation and iii) modified version using hidden Markov random field as implemented in SPM8-VBM toolbox. RESULTS: The accuracy of the segmented GM, WM and CSF and the robustness of the tools against changes of image quality has been assessed using Brainweb simulated MR images and IBSR real MR images. The calculated similarity between the segmented tissues using different tools and corresponding ground truth shows variations in segmentation results. CONCLUSION: A few studies has investigated GM, WM and CSF segmentation. In these studies, the skull stripping and bias correction are performed separately and they just evaluated the segmentation. Thus, in this study, assessment of complete segmentation framework consisting of pre-processing and segmentation of these packages is performed. The obtained results can assist the users in choosing an appropriate segmentation software package for the neuroimaging application of interest. PMID- 25505765 TI - Continuous and Cuffless Blood Pressure Monitoring Based on ECG and SpO2 Signals ByUsing Microsoft Visual C Sharp. AB - BACKGROUND: One of the main problems especially in operating room and monitoring devices is measurement of Blood Pressure (BP) by sphygmomanometer cuff. Objective :In this study we designed a new method to measure BP changes continuously for detecting information between cuff inflation times by using vital signals in monitoring devices. This will be achieved by extraction of the time difference between each cardiac cycle and a relative pulse wave. METHODS: Finger pulse and ECG signals in lead I were recorded by a monitoring device. The output of monitoring device wasinserted in a computer by serial network communication. A software interface (Microsoft Visual C#.NET ) was used to display and process the signals in the computer. Time difference between each cardiac cycle and pulse signal was calculated throughout R wave detection in ECG and peak of pulse signal by the software. The relation between time difference in two waves and BP was determined then the coefficients of equation were obtained in different physical situations. The results of estimating BP were compared with the results of sphygmomanometer method and the error rate was calculated. RESULTS: In this study, 25 subjects participated among them 15 were male and 10 were female. The results showed that BP was linearly related to time difference. Average of coefficient correlation was 0.9+/-0.03 for systolic and 0.82+/-0.04 for diastolic blood pressure. The highest error percentage was calculated 8% for male and 11% for female group. Significant difference was observed between the different physical situation and arm movement changes. The relationship between time difference and age was estimated in a linear relationship with a correlation coefficient of 0.76. CONCLUSION: By determining linear relation values with high accuracy, BP can be measured with insignificant error. Therefore it can be suggested as a new method to measure the blood pressure continuously. PMID- 25505766 TI - Removing ECG Artifact from the Surface EMG Signal Using Adaptive Subtraction Technique. AB - BACKGROUND: The electrocardiogram artifact is a major contamination in the electromyogram signals when electromyogram signal is recorded from upper trunk muscles and because of that the contaminated electromyogram is not useful. Objective : Removing electrocardiogram contamination from electromyogram signals. METHODS: In this paper, the clean electromyogram signal, electrocardiogram artifact and electrocardiogram signal were recorded from leg muscles, the pectoralis major muscle of the left side and V4, respectively. After the pre processing, contaminated electromyogram signal is simulated with a combination of clean electromyogram and electrocardiogram artifact. Then, contaminated electromyogram is cleaned using adaptive subtraction method. This method contains some steps; (1) QRS detection, (2) formation of electrocardiogram template by averaging the electrocardiogram complexes, (3) using low pass filter to remove undesirable artifacts, (4) subtraction. RESULTS: Performance of our method is evaluated using qualitative criteria, power spectrum density and coherence and quantitative criteria signal to noise ratio, relative error and cross correlation. The result of signal to noise ratio, relative error and cross correlation is equal to 10.493, 0.04 and %97 respectively. Finally, there is a comparison between proposed method and some existing methods. CONCLUSION: The result indicates that adaptive subtraction method is somewhat effective to remove electrocardiogram artifact from contaminated electromyogram signal and has an acceptable result. PMID- 25505767 TI - Subjective Symptoms Related to GSM Radiation from Mobile Phone Base Stations: a cross-sectional study. PMID- 25505768 TI - Comment to the Letter to the Editor: Subjective Symptoms Related to GSM Radiation from Mobile Phone Base Stations: A Cross-sectional Study in Reply to the Comments by Seyed Mohammad Javad Mortazavi. PMID- 25505769 TI - Evaluation of Effective Sources in Uncertainty Measurements of Personal Dosimetry by a Harshaw TLD System. AB - BACKGROUND: The accurate results of the individual doses in personal dosimety which are reported by the service providers in personal dosimetry are very important. There are national / international criteria for acceptable dosimetry system performance. Objective : In this research, the sources of uncertainties are identified, measured and calculated in a personal dosimetry system by TLD. METHOD: These sources are included; inhomogeneity of TLDs sensitivity, variability of TLD readings due to limited sensitivity and background, energy dependence, directional dependence, non-linearity of the response, fading, dependent on ambient temperature / humidity and calibration errors, which may affect on the dose responses. Some parameters which influence on the above sources of uncertainty are studied for Harshaw TLD-100 cards dosimeters as well as the hot gas Harshaw 6600 TLD reader system. RESULTS: The individual uncertainties of each sources was measured less than 6.7% in 68% confidence level. The total uncertainty was calculated 17.5% with 95% confidence level. CONCLUSION: The TLD-100 personal dosimeters as well as the Harshaw TLD-100 reader 6600 system show the total uncertainty value which is less than that of admissible value of 42% for personal dosimetry services. PMID- 25505770 TI - Modeling time resolved light propagation inside a realistic human head model. AB - BACKGROUND: Near infrared spectroscopy imaging is one of the new techniques used for investigating structural and functionality of different body tissues. This is done by injecting light into the medium and measuring the photon intensity at the surface of the tissue. METHODS: In this paper the different medical applications, various imaging and simulation techniques of NIRS imaging is described. Each method is introduced and discussed. Then, the optimized model is prepared for numerical simulations. In this paper, the finite element method is used for solving the diffusion equation numerically. RESULTS: Diffusion equation was solved for realistic human head model using finite element approach for a point light source and time resolved case. The photon intensity distribution in different head layers has been shown and the intensity orientation via the CSF layer has been illustrated. CONCLUSION: Simulating the photon transformation inside the tissue is essential for investigating the NIRS imaging technique. The finite element approach is a fast and accurate method for simulating this fact. The time resolved approach of this technique could illustrate the photon migration and intensity orientation in the tissue for time dependent light sources in tissues. PMID- 25505771 TI - Designing and constructing blood flow monitoring system to predict pressure ulcers on heel. AB - BACKGROUND: A pressure ulcer is a complication related to the need for the care and treatment of primarily disabled and elderly people. With the decrease of the blood flow caused by the pressure loaded, ulcers are formed and the tissue will be wasted with the passage of time. OBJECTIVE: The aim of this study was to construct blood flow monitoring system on the heel tissue which was under external pressure in order to evaluate the tissue treatment in the ulcer. METHODS: To measure the blood flow changes, three infrared optical transmitters were used at the distances of 5, 10, and 15 mm to the receiver. Blood flow changes in heels were assessed in pressures 0, 30, and 60 mmHg. The time features were extracted for analysis from the recorded signal by MATLAB software. Changes of the time features under different pressures were evaluated at the three distances by ANOVA in SPSS software. The level of significance was considered at 0.05. RESULTS: In this study, 15 subjects, including both male and female, with the mean age of 54+/-7 participated. The results showed that the signal amplitude, power and absolute signal decreased significantly when pressure on the tissue increased in different layers (p<0.05). Heart rate only decreased significantly in pressures more than 30 mmHg (p=0.02). In pressures more than 30 mmHg, in addition to a decrease in the time features, the pattern of blood flow signal changed and it wasn't the same as no-load signal. CONCLUSION: By detecting the time features, we can reach an early diagnosis to prognosticate the degeneration of the tissue under pressure and it can be recommended as a method to predict bedsores in the heel. PMID- 25505772 TI - Introducing the RadBioStat Educational Software: Computer-Assisted Teaching of the Random Nature of Cell Killing. AB - The interaction of radiation with cells and tissues has a random nature. Therefore, understanding the random nature of cell killing that is determined by Poisson distribution statistics is an essential point in education of radiation biology. RadBioStat is a newly developed educational MATLAB-based software designed for computer-assisted learning of the target theory in radiation biology. Although its potential applications is developing rapidly, currently RadBioStat software can be a useful tool in computer-assisted education of radiobiological models such as single target single hit, multiple target single hit and multiple target multiple hit. Scholars' feedback is valuable to the producers of this software and help them continuously improve this product, add new features and increase its desirability and functionality. PMID- 25505773 TI - Editorial. PMID- 25505774 TI - Comparison of the light charged particles on scatter radiation dose in thyroid hadron therapy. AB - BACKGROUND: Hadron therapy is a novel technique of cancer radiation therapy which employs charged particles beams, (1)H and light ions in particular. Due to their physical and radiobiological properties, they allow one to obtain a more conformal treatment, sparing better the healthy tissues located in proximity of the tumor and allowing a higher control of the disease. Objective : As it is well known, these light particles can interact with nuclei in the tissue, and produce the different secondary particles such as neutron and photon. These particles can damage specially the critical organs behind of thyroid gland. METHODS: In this research, we simulated neck geometry by MCNPX code and calculated the light particles dose at distance of 2.14 cm in thyroid gland, for different particles beam: (1)H, (2)H, (3)He, and (4)He. Thyroid treatment is important because the spine and vertebrae is situated right behind to the thyroid gland on the posterior side. RESULTS: The results show that (2)H has the most total flux for photon and neutron, 1.944E-3 and 1.7666E-2, respectively. Whereas (1)H and (3)He have best conditions, 8.88609E-4 and 1.35431E-3 for photon, 4.90506E-4 and 4.34057E-3 for neutron, respectively. The same calculation has obtained for energy depositions for these particles. CONCLUSION: In this research, we investigated that which of these light particles can deliver the maximum dose to the normal tissues and the minimum dose to the tumor. By comparing these results for the mentioned light particles, we find out (1)H and (3)He is the best therapy choices for thyroid glands whereas (2)H is the worst. PMID- 25505776 TI - Dynamics and regulation of locomotion of a human swing leg as a double-pendulum considering self-impact joint constraint. AB - BACKGROUND: Despite some successful dynamic simulation of self-impact double pendulum (SIDP)-as humanoid robots legs or arms- studies, there is limited information available about the control of one leg locomotion. OBJECTIVE: The main goal of this research is to improve the reliability of the mammalians leg locomotion and building more elaborated models close to the natural movements, by modeling the swing leg as a SIDP. This paper also presents the control design for a SIDP by a nonlinear model-based control method. To achieve this goal, the available data of normal human gait will be taken as the desired trajectories of the hip and knee joints. METHOD: The model is characterized by the constraint that occurs at the knee joint (the lower joint of the model) in both dynamic modeling and control design. Since the system dynamics is nonlinear, the MIMO Input-Output Feedback Linearization method will be employed for control purposes. RESULTS: The first constraint in forward impact simulation happens at 0.5 rad where the speed of the upper link is increased to 2.5 rad/sec. and the speed of the lower link is reduced to -5 rad/sec. The subsequent constraints occur rather moderately. In the case of both backward and forward constraints simulation, the backward impact occurs at -0.5 rad and the speeds of the upper and lower links increase to 2.2 and 1.5 rad/sec., respectively. CONCLUSION: The designed controller performed suitably well and regulated the system accurately. PMID- 25505775 TI - Design and fabrication of helmholtz coils to study the effects of pulsed electromagnetic fields on the healing process in periodontitis: preliminary animal results. AB - BACKGROUND: Effects of electromagnetic fields on healing have been investigated for centuries. Substantial data indicate that exposure to electromagnetic field can lead to enhanced healing in both soft and hard tissues. Helmholtz coils are devices that generate pulsed electromagnetic fields (PEMF). Objective : In this work, a pair of Helmholtz coils for enhancing the healing process in periodontitis was designed and fabricated. METHOD: An identical pair of square Helmholtz coils generated the 50 Hz magnetic field. This device was made up of two parallel coaxial circular coils (100 turns in each loop, wound in series) which were separated from each other by a distance equal to the radius of one coil (12.5 cm). The windings of our Helmholtz coil was made of standard 0.95mm wire to provide the maximum possible current. The coil was powered by a function generator. RESULTS: The Helmholtz Coils generated a uniform magnetic field between its coils. The magnetic field strength at the center of the space between two coils was 97.6 MUT. Preliminary biological studies performed on rats show that exposure of laboratory animals to pulsed electromagnetic fields enhanced the healing of periodontitis. CONCLUSION: Exposure to PEMFs can lead to stimulatory physiological effects on cells and tissues such as enhanced healing of periodontitis. PMID- 25505777 TI - Quantification the effect of ageing on characteristics of the photoplethysmogram using an optimized windkessel model. AB - BACKGROUND: With increasing age, some changes appeared in specifications of vessels which including dimensions and elasticity in theirs. The changes in parameters such as resistance, inertance and compliance vessels appear and eventually changes in the environmental pulse releases are in circulation. These changes clearly appear in specification of photoplethysmogram particularly in the size and position signals second peak is observed. AIM AND SCOPE: The aim of study was to Circulatory system modeling using windkessel electrical model for evalution blood flow and Its matching with the photoplethysmogram's signal for investigate the reasons for changes of Characteristics of the Photoplethysmogram. The first purpose of this paper is to examine the age-related parameters in the Photoplethysmogram's signal and finally the diagnosis of cardiovascular disease using the model and photoplethysmogram's signal. METHODS: In this study we followed some of these effects to the circulatory system by using the windkessel electrical model. The algorithm in this project appeared by optimization with the matrix coefficients of state space windkessel electrical model. Optimize of the coefficients matching with the output of the model and the photoplethysmogram's signal. Photoplethysmogram's signals from 50 healthy subjects with the age range of 20 to 50 years, shows that outputs the model and photoplethysmogram's signal in terms of error rate and cross-correlation algorithm in a fully automate, was consistent. Wavelength of the Photoplethysmogram's signals were 950 nm and The sampling rate was set at 50 Hz. RESULTS: Simulation results show that aging reduces the signal amplitude and delay of the second peak occurs. These changes were seen as reduce the rate of compliance and increase the rate of resistance and inertance windkessel electrical model of circulation. CONCLUSION: The high accuracy of the results led to being able to identify the age range and some cardiac arrhythmias in individuals. All the simulations were done in matlab software environment. PMID- 25505778 TI - Electromagnetic Radiofrequency Radiation Emitted from GSM Mobile Phones Decreases the Accuracy of Home Blood Glucose Monitors. AB - Mobile phones are two-way radios that emit electromagnetic radiation in microwave range. As the number of mobile phone users has reached 6 billion, the bioeffects of exposure to mobile phone radiation and mobile phone electromagnetic interference with electronic equipment have received more attention, globally. As self-monitoring of blood glucose can be a beneficial part of diabetes control, home blood glucose testing kits are very popular. The main goal of this study was to investigate if radiofrequency radiation emitted from a common GSM mobile phone can alter the accuracy of home blood glucose monitors. Forty five female nondiabetic students aged 17-20 years old participated in this study. For Control EMF group (30 students), blood glucose concentration for each individual was measured in presence and absence of radiofrequency radiation emitted by a common GSM mobile phone (HTC touch, Diamond 2) while the phone was ringing. For Control- Repeat group (15 students), two repeated measurements were performed for each participant in the absence of electromagnetic fields. The magnitude of the changes between glucose levels in two repeated measurements (|DeltaC|) in Control Repeat group was 1.07 +/- 0.88 mg/dl while this magnitude for Control-EMF group was 7.53 +/- 4.76 mg/dl (P < 0.001, two-tailed test). To the best of our knowledge, this is the first study to assess the electromagnetic interference in home blood glucose monitors. It can be concluded that electromagnetic interference from mobile phones has an adverse effect on the accuracy of home blood glucose monitors. We suggest that mobile phones should be used at least 50 cm away from home blood glucose monitors. PMID- 25505779 TI - Impact of ventilatory modes on the breathing variability in mechanically ventilated infants. AB - OBJECTIVES: Reduction of breathing variability is associated with adverse outcome. During mechanical ventilation, the variability of ventilatory pressure is dependent on the ventilatory mode. During neurally adjusted ventilatory assist (NAVA), the support is proportional to electrical activity of the diaphragm (EAdi), which reflects the respiratory center output. The variability of EAdi is, therefore, translated into a similar variability in pressures. Contrastingly, conventional ventilatory modes deliver less variable pressures. The impact of the mode on the patient's own respiratory drive is less clear. This study aims to compare the impact of NAVA, pressure-controlled ventilation (PCV), and pressure support ventilation (PSV) on the respiratory drive patterns in infants. We hypothesized that on NAVA, EAdi variability resembles most of the endogenous respiratory drive pattern seen in a control group. METHODS: Electrical activity of the diaphragm was continuously recorded in 10 infants ventilated successively on NAVA (5 h), PCV (30 min), and PSV (30 min). During the last 10 min of each period, the EAdi variability pattern was assessed using non-rhythmic to rhythmic (NRR) index. These variability profiles were compared to the pattern of a control group of 11 spontaneously breathing and non-intubated infants. RESULTS: In control infants, NRR was higher as compared to mechanically ventilated infants (p < 0.001), and NRR pattern was relatively stable over time. While the temporal stability of NRR was similar in NAVA and controls, the NRR profile was less stable during PCV. PSV exhibited an intermediary pattern. PERSPECTIVES: Mechanical ventilation impacts the breathing variability in infants. NAVA produces EAdi pattern resembling most that of control infants. NRR can be used to characterize respiratory variability in infants. Larger prospective studies are necessary to understand the differential impact of the ventilatory modes on the cardio-respiratory variability and to study their impact on clinical outcomes. PMID- 25505780 TI - Spaced scenario demonstrations improve knowledge and confidence in pediatric acute illness management. AB - OBJECTIVES: Nationally accredited simulation courses such as advance pediatric life support and pediatric advance life support are recommended for health care professionals (HCPs) at two yearly intervals as a minimum requirement, despite literature evidence suggesting rapid decline in knowledge shortly after course completion. The objective of this study was to evaluate an observation-based, educational intervention program aimed at improving previously acquired knowledge and confidence in managing critical illnesses. METHODS: A prospective cohort longitudinal study was conducted over a 6-month period. Participants were assessed with a knowledge based questionnaire immediately prior to and after observing 12 fortnightly critical illness scenario demonstrations (CISDs). The outcome measure was performance on questionnaires. Regression analysis was used to adjust for potential confounders. Questionnaire practice effect was evaluated on 30 independent HCPs not exposed to the CISDs. RESULTS: Fifty-four HCPs (40 doctors and 14 nurses) participated in the study. All participants had previously attended nationally accredited simulation courses with a mean time since last attendance of 1.8 +/- 0.4 years. The median number of attendances at CISD was 6 (2-12). The mean questionnaire scores at baseline (17.2/25) were significantly lower than the mean post intervention questionnaire scores (20.3/25), p = 0.003. The HCPs self-rated confidence in managing CISD was 6.5 times higher at the end of the program in the intervention group (p = 0.002) than at baseline. There was no practice effect for questionnaires demonstrated in the independent sample. CONCLUSION: The educational intervention program significantly improved the knowledge and confidence of the participants in managing pediatric critical illnesses. The CISD program provides an inexpensive, practical, and time effective method of facilitating knowledge acquisition and retention. Despite the distinctively different approach, this study has shown the effectiveness of the participant being an observer to enhance pediatric resuscitation skills. PMID- 25505781 TI - Predicting tick presence by environmental risk mapping. AB - Public health statistics recorded an increasing trend in the incidence of tick bites and erythema migrans (EM) in the Netherlands. We investigated whether the disease incidence could be predicted by a spatially explicit categorization model, based on environmental factors and a training set of tick absence-presence data. Presence and absence of Ixodes ricinus were determined by the blanket dragging method at numerous sites spread over the Netherlands. The probability of tick presence on a 1 km by 1 km square grid was estimated from the field data using a satellite-based methodology. Expert elicitation was conducted to provide a Bayesian prior per landscape type. We applied a linear model to test for a linear relationship between incidence of EM consultations by general practitioners in the Netherlands and the estimated probability of tick presence. Ticks were present at 252 distinct sampling coordinates and absent at 425. Tick presence was estimated for 54% of the total land cover. Our model has predictive power for tick presence in the Netherlands, tick-bite incidence per municipality correlated significantly with the average probability of tick presence per grid. The estimated intercept of the linear model was positive and significant. This indicates that a significant fraction of the tick-bite consultations could be attributed to the I. ricinus population outside the resident municipality. PMID- 25505782 TI - Quality Assurance of Teleconsultations in a Store-and-Forward Telemedicine Network - Obtaining Patient Follow-up Data and User Feedback. AB - User surveys in telemedicine networks confirm that follow-up data are essential, both for the specialists who provide advice and for those running the system. We have examined the feasibility of a method for obtaining follow-up data automatically in a store-and-forward network. We distinguish between follow-up, which is information about the progress of a patient and is based on outcomes, and user feedback, which is more general information about the telemedicine system itself, including user satisfaction and the benefits resulting from the use of telemedicine. In the present study, we were able to obtain both kinds of information using a single questionnaire. During a 9-month pilot trial in the Medecins Sans Frontieres telemedicine network, an email request for information was sent automatically by the telemedicine system to each referrer exactly 21 days after the initial submission of the case. A total of 201 requests for information were issued by the system and these elicited 41 responses from referrers (a response rate of 20%). The responses were largely positive. For example, 95% of referrers found the advice helpful, 90% said that it clarified their diagnosis, 94% said that it assisted with management of the patient, and 95% said that the telemedicine response was of educational benefit to them. Analysis of the characteristics of the referrers who did not respond, and their cases, did not suggest anything different about them in comparison with referrers who did respond. We were not able to identify obvious factors associated with a failure to respond. Obtaining data by automatic request is feasible. It provides useful information for specialists and for those running the network. Since obtaining follow-up data is essential to best practice, one proposal to improve the response rate is to simplify the automatic requests so that only patient follow-up information is asked for, and to restrict user feedback requests to the cases being assessed each month by the quality assurance panel. PMID- 25505784 TI - Optimization of thermoelectric performance of SrSi2-based alloys via the modification in band structure and phonon-point-defect scattering. AB - Thermoelectric properties of alkaline-earth-metal disilicides are strongly dependent on their electronic band structure in the vicinity of the Fermi level. In particular, the strontium disilicide, SrSi2 with a narrow band gap of about few tens of meV is composed of non-toxic, naturally abundant elements, and its thermoelectric properties are very sensitive to the substitution/alloying with third elements. In this article, we summarize the thermoelectric performance of substituted and Sr-deficient/Sr-rich SrSi2 alloys to realize the high thermoelectric figure-of-merit (ZT) for practical applications in the electronic and thermoelectric aspects, and also to explore the alternative routes to further improve its ZT value. PMID- 25505785 TI - Variation in the expression of ergot alkaloids between individual tillers of perennial ryegrass. AB - Epichloe fungal endophytes of cool season grasses are well-known to produce a range of alkaloids of benefit to the host. Some of these compounds are advantageous to agriculture due to qualities that promote pasture persistence (e.g., the loline class of alkaloids confer insect protection) while others are detrimental to the well-being of grazing livestock. The ergot alkaloids (e.g., ergovaline), produced in ryegrass and tall fescue associations, causes poor animal health in farming regions in many countries around the world and further study is required to improve our knowledge on this class of compounds. Here we present the application of a quantitative LC-MS/MS (liquid chromatography coupled to mass spectrometry) method measuring eight ergot alkaloids (chanoclavine, agroclavine, elymoclavine, lysergol, lysergic acid, ergine, lysergyl-alanine, ergovaline) produced by endophyte infected grasses, to monitor levels in individual tillers from multiple plants of a single cultivar of perennial ryegrass (Lolium perenne cv. "Grasslands Samson") infected with a common toxic endophyte strain (Epichloe festucae var. lolii). Monitoring the expression in individual tillers allows an estimation of the variability within a plant (between tillers) as well as between plants. The study showed that there is significant variation in the concentration of the ergot alkaloids between tillers of a single plant, at or exceeding the level of variation observed between individual plants of a population. This result emphasizes the fundamental importance of robust experimental design and sampling procedures when alkaloid expression assessment is required and these need to be rigorously tailored to the hypothesis being tested. PMID- 25505786 TI - Concepts, challenges, and successes in modeling thermodynamics of metabolism. AB - The modeling of the chemical reactions involved in metabolism is a daunting task. Ideally, the modeling of metabolism would use kinetic simulations, but these simulations require knowledge of the thousands of rate constants involved in the reactions. The measurement of rate constants is very labor intensive, and hence rate constants for most enzymatic reactions are not available. Consequently, constraint-based flux modeling has been the method of choice because it does not require the use of the rate constants of the law of mass action. However, this convenience also limits the predictive power of constraint-based approaches in that the law of mass action is used only as a constraint, making it difficult to predict metabolite levels or energy requirements of pathways. An alternative to both of these approaches is to model metabolism using simulations of states rather than simulations of reactions, in which the state is defined as the set of all metabolite counts or concentrations. While kinetic simulations model reactions based on the likelihood of the reaction derived from the law of mass action, states are modeled based on likelihood ratios of mass action. Both approaches provide information on the energy requirements of metabolic reactions and pathways. However, modeling states rather than reactions has the advantage that the parameters needed to model states (chemical potentials) are much easier to determine than the parameters needed to model reactions (rate constants). Herein, we discuss recent results, assumptions, and issues in using simulations of state to model metabolism. PMID- 25505787 TI - Obsolescence and intervention: on synthetic-biological entities. PMID- 25505791 TI - Validity and Efficacy of Screening Algorithms for Assessing Deep Brain Stimulation Candidacy in Parkinson Disease. AB - BACKGROUND: Deep Brain Stimulation (DBS) for Parkinson disease (PD) may be underutilized because of limited access to care (most DBS surgeries are performed at specialized centers) or over-referral of poor candidates, leading to inequitable utilization of limited evaluative resources. There is a pressing need for a widely employable screening algorithm to aid in the evaluation of PD candidates for DBS. OBJECTIVE: To compare the validity and efficacy of two published screening algorithms, the Florida Surgical Questionnaire for PD and Stimulus, to predict candidacy for DBS. METHODS: We reviewed the clinical data at our DBS center for 147 consecutive PD DBS referrals between 9/1/2007 and 12/31/2011. Florida Surgical Questionnaire and Stimulus scores were applied retrospectively through a chart review of the Movement Disorder neurologist's initial clinical evaluation. The validity and accuracy of these two algorithms in predicting candidacy for DBS was compared to the decision to offer DBS surgery by our multidisciplinary DBS team. RESULTS: Of the 130 consecutive PD referrals who presented for initial evaluation, 50 were offered DBS after a standardized multidisciplinary evaluation. The Stimulus scale was a superior screening tool for predicting PD DBS candidacy in these referrals [Area under the Receiver operating curve = 0.8088] compared to the Florida Surgical Questionnaire for PD [Area under the Receiver operating curve = 0.6285]. CONCLUSION: In this single center study, Stimulus was a more appropriate screening measure than the Florida Surgical Questionnaire for PD to assess DBS candidacy for PD. PMID- 25505783 TI - Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking. AB - Cancer is one of the most common diseases afflicting people globally. New therapeutic approaches are needed due to the complexity of cancer as a disease. Many current treatments are very toxic and have modest efficacy at best. Increased understanding of tumor biology and immunology has allowed the development of specific immunotherapies with minimal toxicity. It is important to highlight the performance of monoclonal antibodies, immune adjuvants, vaccines and cell-based treatments. Although these approaches have shown varying degrees of clinical efficacy, they illustrate the potential to develop new strategies. Targeted immunotherapy is being explored to overcome the heterogeneity of malignant cells and the immune suppression induced by both the tumor and its microenvironment. Nanodelivery strategies seek to minimize systemic exposure to target therapy to malignant tissue and cells. Intracellular penetration has been examined through the use of functionalized particulates. These nano-particulate associated medicines are being developed for use in imaging, diagnostics and cancer targeting. Although nano-particulates are inherently complex medicines, the ability to confer, at least in principle, different types of functionality allows for the plausible consideration these nanodelivery strategies can be exploited for use as combination medicines. The development of targeted nanodelivery systems in which therapeutic and imaging agents are merged into a single platform is an attractive strategy. Currently, several nanoplatform-based formulations, such as polymeric nanoparticles, micelles, liposomes and dendrimers are in preclinical and clinical stages of development. Herein, nanodelivery strategies presently investigated for cancer immunotherapy, cancer targeting mechanisms and nanocarrier functionalization methods will be described. We also intend to discuss the emerging nano-based approaches suitable to be used as imaging techniques and as cancer treatment options. PMID- 25505792 TI - The launch of the Translational Perioperative and Pain Medicine. PMID- 25505793 TI - ODVBA-C: Optimally-Discriminative Voxel-Based Analysis of Continuous Variables. AB - In this paper, we propose a new method that utilizes a novel spatially adaptive scheme for detection of multivariate neuroimaging patterns relating to a continuous subject-level variable, aiming to effectively determine the optimal spatially adaptive filtering of neuroimaging data from the persepective of finding relationships between imaging and continues (e.g. clinical and cognitive) variables. Analyses employ local pattern analysis using regularized least square regression with nonnegativity constraints within a spatial neighborhood around each voxel. Within each neighborhood, we determine the optimal regression coefficients that relate local patterns to the continuous variable of interest. As each voxel belongs to multiple overlapping neighborhoods, the statistic for a given voxel is determined by combining weights from all neighborhoods to which the voxel participates. Finally, nonparametric permutation testing is used to obtain a voxelwise significance map. Using both simulated and real fMRI data, we demonstrate the effectiveness of the proposed method. PMID- 25505790 TI - Reversal of Neuronal Atrophy: Role of Cellular Immunity in Neuroplasticity and Aging. AB - Emerging evidence indicates that neuroimmunological changes in the brain can modify intrinsic brain processes that are involved in regulating neuroplasticity. Increasing evidence suggests that in some forms of motor neuron injury, many neurons do not die, but reside in an atrophic state for an extended period of time. In mice, facial motor neurons in the brain undergo a protracted period of degeneration or atrophy following resection of their peripheral axons. Reinjuring the proximal nerve stump of the chronically resected facial nerve stimulates a robust reversal of motor neuron atrophy which results in marked increases in both the number and size of injured motor neurons in the facial motor nucleus. In this brief review, we describe research from our lab which indicates that the reversal of atrophy in this injury model is dependent on normal cellular immunity. The role of T cells in this unique form of neuroplasticity following injury and in brain aging, are discussed. The potential role of yet undiscover intrinsic actions of recombination activating genes in the brain are considered. Further research using the facial nerve reinjury model could identify molecular signals involved in neuroplasticity, and lead to new ways to stimulate neuroregenerative processes in neurotrauma and other forms of brain insult and disease. PMID- 25505789 TI - The neural crest lineage as a driver of disease heterogeneity in Tuberous Sclerosis Complex and Lymphangioleiomyomatosis. AB - Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease, best characterized by the formation of proliferative nodules that express smooth muscle and melanocytic antigens within the lung parenchyma, leading to progressive destruction of lung tissue and function. The pathological basis of LAM is associated with Tuberous Sclerosis Complex (TSC), a multi-system disorder marked by low-grade tumors in the brain, kidneys, heart, eyes, lung and skin, arising from inherited or spontaneous germ-line mutations in either of the TSC1 or TSC2 genes. LAM can develop either in a patient with TSC (TSC-LAM) or spontaneously (S LAM), and it is clear that the majority of LAM lesions of both forms are characterized by an inactivating mutation in either TSC1 or TSC2, as in TSC. Despite this genetic commonality, there is considerable heterogeneity in the tumor spectrum of TSC and LAM patients, the basis for which is currently unknown. There is extensive clinical evidence to suggest that the cell of origin for LAM, as well as many of the TSC-associated tumors, is a neural crest cell, a highly migratory cell type with extensive multi-lineage potential. Here we explore the hypothesis that the types of tumors that develop and the tissues that are affected in TSC and LAM are dictated by the developmental timing of TSC gene mutations, which determines the identities of the affected cell types and the size of downstream populations that acquire a mutation. We further discuss the evidence to support a neural crest origin for LAM and TSC tumors, and propose approaches for generating humanized models of TSC and LAM that will allow cell of origin theories to be experimentally tested. Identifying the cell of origin and developing appropriate humanized models is necessary to truly understand LAM and TSC pathology and to establish effective and long-lasting therapeutic approaches for these patients. PMID- 25505794 TI - Molecular Events in Late Stages of HIV-1 Replication. PMID- 25505795 TI - Navigation for the Blind through Audio-Based Virtual Environments. AB - We present the design, development and an initial study changes and adaptations related to navigation that take place in the brain, by incorporating an Audio Based Environments Simulator (AbES) within a neuroimaging environment. This virtual environment enables a blind user to navigate through a virtual representation of a real space in order to train his/her orientation and mobility skills. Our initial results suggest that this kind of virtual environment could be highly efficient as a testing, training and rehabilitation platform for learning and navigation. PMID- 25505788 TI - Developments in the tools and methodologies of synthetic biology. AB - Synthetic biology is principally concerned with the rational design and engineering of biologically based parts, devices, or systems. However, biological systems are generally complex and unpredictable, and are therefore, intrinsically difficult to engineer. In order to address these fundamental challenges, synthetic biology is aiming to unify a "body of knowledge" from several foundational scientific fields, within the context of a set of engineering principles. This shift in perspective is enabling synthetic biologists to address complexity, such that robust biological systems can be designed, assembled, and tested as part of a biological design cycle. The design cycle takes a forward design approach in which a biological system is specified, modeled, analyzed, assembled, and its functionality tested. At each stage of the design cycle, an expanding repertoire of tools is being developed. In this review, we highlight several of these tools in terms of their applications and benefits to the synthetic biology community. PMID- 25505796 TI - Enhancing Navigation Skills through Audio Gaming. AB - We present the design, development and initial cognitive evaluation of an Audio based Environment Simulator (AbES). This software allows a blind user to navigate through a virtual representation of a real space for the purposes of training orientation and mobility skills. Our findings indicate that users feel satisfied and self-confident when interacting with the audio-based interface, and the embedded sounds allow them to correctly orient themselves and navigate within the virtual world. Furthermore, users are able to transfer spatial information acquired through virtual interactions into real world navigation and problem solving tasks. PMID- 25505797 TI - Enhancing Orientation and Mobility Skills in Learners who are Blind through Video gaming. AB - In this work we present the results of the cognitive impact evaluation regarding the use of Audiopolis, an audio and/or haptic-based videogame. The software has been designed, developed and evaluated for the purpose of developing orientation and mobility (O&M) skills in blind users. The videogame was evaluated through cognitive tasks performed by a sample of 12 learners. The results demonstrated that the use of Audiopolis had a positive impact on the development and use of O&M skills in school-aged blind learners. PMID- 25505798 TI - Prolonged Exposure for Guilt and Shame in a Veteran of Operation Iraqi Freedom. AB - Morally injurious events appear capable of producing posttraumatic stress disorder (PTSD), even though they may not involve actual or perceived life-threat or a response of fear, horror, or helplessness. Researchers have questioned whether exposure therapies can address these events. The current report presents evidence of the effectiveness of this treatment approach for addressing posttraumatic symptoms related to a morally injurious event through an illustrative case of an Operation Iraqi Freedom veteran with PTSD characterized by symptoms of guilt and shame. The veteran was successfully treated with nine sessions of prolonged exposure therapy, reporting minimal PTSD symptoms one week post-treatment and at a six-month follow-up assessment. Implications for the treatment of veterans with significant guilt and shame using exposure-based therapies, and with respect to the recent changes to the diagnostic criteria for PTSD, are discussed. PMID- 25505799 TI - VARIETIES OF VIOLENT BEHAVOR. AB - There is an implicit assumption of homogeneity across violent behaviors and offenders in the criminology literature. Arguing against this assumption, I draw on three distinct literatures [child abuse and neglect (CAN) and violence, violence and post-traumatic stress disorder (PTSD), and CAN and PTSD] to provide a rationale for an examination of varieties of violent behaviors. I use data from my prospective cohort design study of the long-term consequences of CAN to define three varieties of violent offenders using age of documented cases of CAN, onset of PTSD, and first violent arrest in a temporally correct manner [CAN -> to violence, CAN -> PTSD -> violence (PTSD first), and CAN -> violence -> PTSD (violence first)], and a fourth variety, violence only. The results illustrate meaningful heterogeneity in violent behavior and different developmental patterns and characteristics. There are three major implications: First, programs and policies that target violence need to recognize the heterogeneity and move away from a "one-size-fits-all" approach. Second, violence prevention policies and programs that target abused and neglected children are warranted, given the prominent role of CAN in the backgrounds of these violent offenders. Third, criminologists and others interested in violence need to attend to the role of PTSD, which is present in about one fifth (21 percent) of these violent offenders, and not relegate the study of these offenders to the psychiatric and psychological literatures. PMID- 25505801 TI - Does Expressing Your Emotions Raise or Lower Your Blood Pressure? The Answer Depends on Cultural Context. AB - Emotion-expressive behavior is often - but not always -- inversely related to physiological responding. To test the hypothesis that cultural context moderates the relationship between expressivity and physiological responding, we had Asian American and European American women engage in face-to-face conversations about a distressing film in same-ethnicity dyads. Blood pressure was measured continuously and emotional expressivity was rated from videotapes. Results indicated that emotion-expressive behavior was inversely related to blood pressure in European American dyads, but the reverse was true in Asian American dyads who showed a trend towards a positive association. These results suggest that the links between emotion-expressive behavior and physiological responding may depend upon cultural context. One possible explanation for this effect may be that cultural contexts shape the meaning individuals give to emotional expressions that occur during social interactions. PMID- 25505800 TI - Neonatal body condition, immune responsiveness, and hematocrit predict longevity in a wild bird population. AB - Measures of body condition, immune function, and hematological health are widely used in ecological studies of vertebrate populations, predicated on the assumption that these traits are linked to fitness. However, compelling evidence that these traits actually predict long-term survival and reproductive success among individuals in the wild is lacking. Here, we show that body condition (i.e., size-adjusted body mass) and cutaneous immune responsiveness to phytohaemagglutinin (PHA) injection among neonates positively predict recruitment and subsequent longevity in a wild, migratory population of house wrens (Troglodytes aedon). However, neonates with intermediate hematocrit had the highest recruitment and longevity. Neonates with the highest PHA responsiveness and intermediate hematocrit prior to independence eventually produced the most offspring during their lifetime breeding on the study site. Importantly, the effects of PHA responsiveness and hematocrit were revealed while controlling for variation in body condition, sex, and environmental variation. Thus, our data demonstrate that body condition, cutaneous immune responsiveness, and hematocrit as a neonate are associated with individual fitness. Although hematocrit's effect is more complex than traditionally thought, our results suggest a previously underappreciated role for this trait in influencing survival in the wild. PMID- 25505802 TI - Private Financial Transfers, Family Income, and the Great Recession. AB - Using longitudinal data from the Fragile Families and Child Wellbeing Study (N = 4,701; 1998-2010), the authors studied whether the unemployment rate was associated with private financial transfers (PFTs) among urban families with young children and whether family income moderated these associations. They found that an increase in the unemployment rate was associated with greater PFT receipt and that family income moderated the association. Poor and near-poor mothers experienced increases in PFT receipt when unemployment rates were high, whereas mothers with incomes between 2 and 3 times the poverty threshold experienced decreases. Simulations estimating the impact of the Great Recession suggest that moving from 5% to 10% unemployment is associated with a 9-percentage-point increase in the predicted probability of receiving a PFT for the sample as a whole, with greater increases in predicted probabilities among poor and near poor mothers. PMID- 25505803 TI - Renegotiating intimate relationships with men: how HIV shapes attitudes and experiences of marriage for South African women living with HIV: 'Now in my life, everything I do, looking at my health' AB - This paper explores marriage attitudes and practices among Xhosa-speaking women living with HIV (WLHIV) in Cape Town, South Africa. It reports on a study that assessed the fertility intentions of a cohort of people living with HIV, aimed at informing an HIV care intervention. It draws on qualitative data generated from 30 successive interviews with WHLIV in wave 1, 23 interviews in wave 2 and 20 follow-up interviews in wave 3. Gender inequality, marriage and HIV are strongly intertwined. Broader layers of South Africa's history, politics and socio economic and cultural contexts have consequences for the fluidity in intimate relations, marriage and motherhood for WLHIV. Key and conflicting themes emerge that impact on marriage and motherhood. Firstly, marriage is the 'last on a list of priorities' for WLHIV, who wish to further their children's education, to work, to earn money, and to achieve this rapidly because of their HIV-positive status. We demonstrate that the pressure women face in marriage to bear children creates a different attitude to and experience of marriage for WLHIV. Some WLHIV wish to avoid marriage due to its accompanying pressure to have children. Other WLHIV experience difficulties securing intimacy. WLHIV may find it easier to seek partners who are also living with HIV. A partner living with HIV is perceived as sharing similar fertility goals. In this study, HIV accentuates existing issues and highlights new ones for WLHIV negotiating intimacy. The findings contribute to the existing knowledge base regarding the fluidity of marriage and fertility intentions within the dynamic context of living with HIV. These are likely to have broader relevance in currently rapidly urbanising and economically developing countries with high HIV prevalence in southern Africa. PMID- 25505804 TI - Entrepreneurial training for girls empowerment in Lesotho: A process evaluation of a model programme. AB - A Girls Empowerment Programme held in 2010 in Lesotho, Sub-Saharan Africa, focused on HIV/AIDS risk reduction and prevention, life skills and entrepreneurial training (income-generating activities). Entrepreneurial training was a crucial part of equipping the camp attendees with basic skills to help them develop sustainable livelihoods. Such skills and financial independence are essential to enable rural girls to complete their secondary schooling (in a fee based educational system) and to pursue a career, as well as to further help them be less susceptible to transactional sex and its significant risks. The results of a brief process evaluation with some nested supporting data showed considerable improvement in the girls' knowledge about income-generating activities. In addition, almost half of the camp attendees participated in further entrepreneurial training and about half of these girls went on to develop small businesses. Replication of this model of camp training is recommended and being explored in other African countries. PMID- 25505805 TI - Numerical computation of the optimal vector field: Exemplified by a fishery model. AB - Numerous optimal control models analyzed in economics are formulated as discounted infinite time horizon problems, where the defining functions are nonlinear as well in the states as in the controls. As a consequence solutions can often only be found numerically. Moreover, the long run optimal solutions are mostly limit sets like equilibria or limit cycles. Using these specific solutions a BVP approach together with a continuation technique is used to calculate the parameter dependent dynamic structure of the optimal vector field. We use a one dimensional optimal control model of a fishery to exemplify the numerical techniques. But these methods are applicable to a much wider class of optimal control problems with a moderate number of state and control variables. PMID- 25505807 TI - How Are Children and Families Faring a Decade After Welfare Reform? Evidence from Five Non-Experimental Panel Studies. AB - Not applicable. PMID- 25505806 TI - Escaping paradise: Larval export from Hawaii in an Indo-Pacific reef fish, the Yellow Tang (Zebrasoma flavescens). AB - The depauperate marine ecosystems of the Hawaiian Archipelago share a high proportion of species with the southern and western Pacific, indicating historical and/or ongoing connections across the large oceanic expanse separating Hawaii from its nearest neighbors. The rate and direction of these interactions are, however, unknown. While previous biogeographic studies have consistently described Hawaii as a diversity sink, prevailing currents likely offer opportunities for larval export. To assess interactions between the remote reefs of the Hawaiian Archipelago and the species rich communities of the Central and West Pacific, we surveyed 14 nuclear microsatellite loci (nDNA; n = 857) and a 614 bp segment of mitochondrial cytochrome b (mtDNA; n = 654) in the Yellow Tang (Zebrasoma flavescens). Concordant frequency shifts in both nDNA and mtDNA reveal significant population differentiation among three West Pacific sites and Hawaii (nDNA F' CT = 0.116, mtDNA phi CT = 0.098, P < 0.001). SAMOVA analyses of microsatellite data additionally indicate fine scale differentiation within the 2600 km Hawaiian Archipelago (F' SC = 0.026; P < 0.001), with implications for management of this heavily-exploited aquarium fish. Mismatch analyses indicate the oldest contemporary populations are in the Hawaiian Archipelago (circa 318,000 y), with younger populations in the West Pacific (91,000 - 175,000 y). Estimates of Yellow Tang historical demography contradict expectations of Hawaii as a population sink, and instead indicate asymmetrical gene flow, with Hawaii exporting rather than importing Yellow Tang larvae. PMID- 25505808 TI - Family Economic Well-Being Following the 1996 Welfare Reform: Trend Data from Five Non-Experimental Panel Studies. AB - This analysis summarizes trends in family economic well-being from five non experimental, longitudinal welfare-to-work studies launched following the passage of the Personal Responsibility and Work Opportunity Reconciliation Act of 1996 (PRWORA). The studies include a sizable group of parents and other caregivers who received TANF at the point of sample selection or shortly thereafter, and share a wide range of similar measures of economic well-being. This analysis provides descriptive information on how these families are faring over time. Our results confirm what has been found by previous studies. Many families remain dependent on public benefits, and are either poor or near-poor, despite gains in some indicators of economic well-being. We caution that these aggregate statistics may mask important heterogeneity among families. PMID- 25505811 TI - Reply to Bile acids in Non-Alcoholic Steato-Hepatitis: inserting nuclear receptors into the circle. PMID- 25505809 TI - Welfare, Work, and Health Care Access Predictors of Low-Income Children's Physical Health Outcomes. AB - This analysis examines whether young children's (N= 494) general physical health is associated with parental employment, welfare receipt, and health care access within a low-income population transitioning from welfare to work. A latent physical health measure derived from survey and medical chart data is used to capture children's poor health, and parental ratings of child health are used to identify excellent health. Controlling for a host of factors associated with children's health outcomes, results show that children of caregivers who are unemployed and off welfare have better health than children of caregivers who are working and off welfare. Children whose caregivers are unemployed and on welfare, or combining work and welfare, have health outcomes similar to children of caregivers who are working and off welfare. Health care access characteristics, such as gaps in health insurance coverage, source of primary care setting, and type of health insurance are associated with children's general physical health. Implications of these results for state TANF programs are discussed. PMID- 25505810 TI - Effects of context and word class on lexical retrieval in Chinese speakers with anomic aphasia. AB - BACKGROUND: Differences in processing nouns and verbs have been investigated intensely in psycholinguistics and neuropsychology in past decades. However, the majority of studies examining retrieval of these word classes have involved tasks of single word stimuli or responses. While the results have provided rich information for addressing issues about grammatical class distinctions, it is unclear whether they have adequate ecological validity for understanding lexical retrieval in connected speech which characterizes daily verbal communication. Previous investigations comparing retrieval of nouns and verbs in single word production and connected speech have reported either discrepant performance between the two contexts with presence of word class dissociation in picture naming but absence in connected speech, or null effects of word class. In addition, word finding difficulties have been found to be less severe in connected speech than picture naming. However, these studies have failed to match target stimuli of the two word classes and between tasks on psycholinguistic variables known to affect performance in response latency and/or accuracy. AIMS: The present study compared lexical retrieval of nouns and verbs in picture naming and connected speech from picture description, procedural description, and story telling among 19 Chinese speakers with anomic aphasia and their age, gender, and education matched healthy controls, to understand the influence of grammatical class on word production across speech contexts when target items were balanced for confounding variables between word classes and tasks. METHODS & PROCEDURES: Elicitation of responses followed the protocol of the AphasiaBank consortium (http://talkbank.org/AphasiaBank/). Target words for confrontation naming were based on well-established naming tests, while those for narrative were drawn from a large database of normal speakers. Selected nouns and verbs in the two contexts were matched for age-of-acquisition (AoA) and familiarity. Influence of imageability was removed through statistical control. OUTCOMES & RESULTS: When AoA and familiarity were balanced, nouns were retrieved better than verbs, and performance was higher in picture naming than connected speech. When imageability was further controlled for, only the effect of task remained significant. CONCLUSIONS: The absence of word class effects when confounding variables are controlled for is similar to many previous reports; however, the pattern of better word retrieval in naming is rare but compatible with the account that processing demands are higher in narrative than naming. The overall findings have strongly suggested the importance of including connected speech tasks in any language assessment and evaluation of language rehabilitation of individuals with aphasia. PMID- 25505812 TI - Examining the comorbidity of language disorders and ADHD. AB - In the companion papers this issue we presented the value of research on comorbidity, particularly in complex developmental disorders where the identification of etiology is challenging. As we will document below, Language Impairment (SLI) and Attention Deficit Hyperactivity Disorder (ADHD) have been shown to co-occur in a number of studies, and this phenomenon is commonplace in the experience of many clinicians. Given this, we must ask whether the overlap between SLI and ADHD can aid our understanding of these disorders, particularly with regard to the basis for comorbidity. As we review the literature, we will consider the models of comorbidity that were outlined in the Introduction to this issue. Finally, we present original data on SLI and ADHD from a population-based sample of children that have studied over the last two decades in the State of Iowa. PMID- 25505813 TI - MicroRNA expression profiling in PBMCs: a potential diagnostic biomarker of chronic hepatitis C. AB - The expression levels of miR-16, miR-193b, miR-199a, miR-222, and miR-324 in PBMCs were significantly higher in CHC patients compared with healthy controls and significantly different between CHC patients with HCV genotype 1 (GT-1) and non-genotype-1 (non-GT-1). Multivariate logistic regression analysis also showed that patients with high expression levels of the six target miRNAs had an approximately 7.202-fold risk of CHC compared with those with low expression levels of the target miRNAs. We concluded that the expression levels of miR-16, miR-193b, miR-199a, miR-222, and miR-324 target miRNAs in PBMCs of CHC may act as significant risk biomarkers for the development of CHC. PMID- 25505814 TI - Pleural fluid mesothelin as an adjunct to the diagnosis of pleural malignant mesothelioma. AB - RATIONALE: The diagnosis of pleural malignant mesothelioma (MM) by effusion cytology may be difficult and is currently controversial. Effusion mesothelin levels are increased in patients with MM but the clinical role of this test is uncertain. OBJECTIVES: To determine the clinical value of measuring mesothelin levels in pleural effusion supernatant to aid diagnosis of MM. METHODS AND MEASUREMENTS: Pleural effusion samples were collected prospectively from 1331 consecutive patients. Mesothelin levels were determined by commercial ELISA in effusions and their relationship to concurrent pathology reporting and final clinical diagnosis was determined. RESULTS: 2156 pleural effusion samples from 1331 individuals were analysed. The final clinical diagnosis was 183 MM, 436 non MM malignancy, and 712 nonmalignant effusions. Effusion mesothelin had a sensitivity of 67% for MM at 95% specificity. Mesothelin was elevated in over 47% of MM cases in effusions obtained before definitive diagnosis of MM was established. In the setting of inconclusive effusion cytology, effusion mesothelin had a positive predictive value of 79% for MM and 94% for malignancy. CONCLUSIONS: A mesothelin-positive pleural effusion, irrespective of the identification of malignant cells, indicates the likely presence of malignancy and adds weight to the clinical rationale for further investigation to establish a malignant diagnosis. PMID- 25505816 TI - Nonlinear Susceptibility Magnitude Imaging of Magnetic Nanoparticles. AB - This study demonstrates a method for improving the resolution of susceptibility magnitude imaging (SMI) using spatial information that arises from the nonlinear magnetization characteristics of magnetic nanoparticles (mNPs). In this proof-of concept study of nonlinear SMI, a pair of drive coils and several permanent magnets generate applied magnetic fields and a coil is used as a magnetic field sensor. Sinusoidal alternating current (AC) in the drive coils results in linear mNP magnetization responses at primary frequencies, and nonlinear responses at harmonic frequencies and intermodulation frequencies. The spatial information content of the nonlinear responses is evaluated by reconstructing tomographic images with sequentially increasing voxel counts using the combined linear and nonlinear data. Using the linear data alone it is not possible to accurately reconstruct more than 2 voxels with a pair of drive coils and a single sensor. However, nonlinear SMI is found to accurately reconstruct 12 voxels (R2 = 0.99, CNR = 84.9) using the same physical configuration. Several time-multiplexing methods are then explored to determine if additional spatial information can be obtained by varying the amplitude, phase and frequency of the applied magnetic fields from the two drive coils. Asynchronous phase modulation, amplitude modulation, intermodulation phase modulation, and frequency modulation all resulted in accurate reconstruction of 6 voxels (R2 > 0.9) indicating that time multiplexing is a valid approach to further increase the resolution of nonlinear SMI. The spatial information content of nonlinear mNP responses and the potential for resolution enhancement with time multiplexing demonstrate the concept and advantages of nonlinear SMI. PMID- 25505815 TI - Neutrophil-to-lymphocyte ratio as a predictor of response to peginterferon plus ribavirin therapy for chronic hepatitis C. AB - We aimed to determine whether neutrophil-to-lymphocyte ratio (NLR) could be a predictor of antiviral response in chronic hepatitis C patients. A total of 602 consecutive patients (genotype 1, n = 263; genotype 2, n = 297; others/unknown, n = 42) receiving response-guided therapy with peginterferon plus ribavirin were recruited. NLR was related to clinical and virological features and to treatment outcome. Rapid virological response (RVR) and sustained virological response (SVR) were achieved in 436 (73%) and 458 (76%) of the patients, respectively. Higher NLR (>=1.42) was found to be associated with higher prevalence of DM (P = 0.039) and higher hepatitis C viral load (P = 0.002) and white cell count (P < 0.001). NLR was significantly lower in patients with RVR and SVR compared to those without (P = 0.032 and 0.034, resp.). However, NLR was not an independent factor by multivariate analysis. In the subgroup analysis, higher NLR (>=1.42) (odds ratio, 0.494, P = 0.038) was an independent poor predictor of SVR in genotype 2 patients but was not in genotype 1 patients. In conclusion, NLR is a simple and easily accessible marker to predict response to peginterferon plus ribavirin therapy for chronic hepatitis C genotype 2. PMID- 25505818 TI - Vowels as Islands of Reliability. AB - Vowel nuclei of syllables appear to provide a relatively stable (although not stationary) frame of reference for judging consonant events. We offer evidence that reliable consonant identification demands prior or simultaneous evaluation of this "vocalic frame." Listeners were presented a list of /bVs/, /dVs/, and /gVs/ syllables and were instructed to press a response key immediately upon recognizing a particular initial consonant target. Three groups of subjects monitored for /b/, /d/, and /g/, respectively. The test syllables contained 10 English vowels varying substantially in intrinsic duration. Response times to the initial consonants correlated positively with the duration of the following vowels, even when the effect of consonant-vowel formant transition duration was partialed out. The results suggest that consonant recognition is vowel dependent and, specifically, that a certain amount or proportion of the vowel formant trajectory must be evaluated before consonants can be reliably identified. PMID- 25505817 TI - Clinical Strategies for Integrating Medication Interventions Into Behavioral Treatment for Adolescent ADHD: The Medication Integration Protocol. AB - Attention-Deficit/Hyperactivity Disorder (ADHD) is highly prevalent among adolescents enrolled in behavioral health services but remains undertreated in this age group. Also the first-line treatment for adolescent ADHD, stimulant medication, is underutilized in routine practice. This article briefly describes three behavioral interventions designed to promote stronger integration of medication interventions into treatment planning for adolescent ADHD: family ADHD psychoeducation, family-based medication decision-making, and behavior therapist leadership in coordinating medication integration. It then introduces the Medication Integration Protocol (MIP), which incorporates all three interventions into a five-task protocol: ADHD Assessment and Medication Consult; ADHD Psychoeducation and Client Acceptance; ADHD Symptoms and Family Relations; ADHD Medication and Family Decision-Making; and Medication Management and Integration Planning. The article concludes by highlighting what behavior therapists should know about best practices for medication integration across diverse settings and populations: integrating medication interventions into primary care, managing medication priorities and polypharmacy issues for adolescents with multiple diagnoses, providing ADHD medications to adolescent substance users, and the compatibility of MIP intervention strategies with everyday practice conditions. PMID- 25505819 TI - Building and Accessing Clausal Representations: The Advantage of First Mention versus the Advantage of Clause Recency. AB - We investigated two seemingly contradictory phenomena: the Advantage of the First Mentioned Participant (participants mentioned first in a sentence are more accessible than participants mentioned second) and the Advantage of the Most Recent Clause (concepts mentioned in the most recent clause are more accessible than concepts mentioned in an earlier clause). We resolved this contradiction by measuring how quickly comprehenders accessed participants mentioned in the first versus second clauses of two-clause sentences. Our data supported the following hypotheses: Comprehenders represent each clause of a two-clause sentence in its own mental substructure. Comprehenders have greatest access to information in the substructure that they are currently developing; that is, they have greatest access to the most recent clause. However, at some point, the first clause becomes more accessible because the substructure representing the first clause of a two-clause sentence serves as a foundation for the whole sentence-level representation. PMID- 25505820 TI - Risk Factors Associated with Reoperation for Bleeding following Liver Transplantation. AB - Introduction. This study's objective was to identify risk factors associated with reoperation for bleeding following liver transplantation (LTx). Methods. A retrospective study was performed at a single institution between 2001 and 2012. Operative reports were used to identify patients who underwent reoperation for bleeding within 2 weeks following LTx (operations for nonbleeding etiologies were excluded). Results. Reoperation for bleeding was observed in 101/928 (10.8%) of LTx patients. The following characteristics were associated with reoperation on multivariable analysis: recipient MELD score (OR 1.06/MELD unit, 95% CI 1.03, 1.09), number of platelets transfused (OR 0.73/platelet unit, 95% CI 0.58, 0.91), and aminocaproic acid utilization (OR 0.46, 95% CI 0.27, 0.80). LTx patients who underwent reoperation for bleeding had a longer ICU stay (5 days +/- 7 versus 2 days +/- 3, P < 0.001) and hospitalization (18 days +/- 9 versus 10 days +/- 18, P < 0.001). The risk of death increased in patients who underwent reoperation for bleeding (HR 1.89, 95% CI 1.26, 2.85). Conclusion. Reoperation for bleeding following LTx was associated with increased resource utilization and recipient mortality. A lower threshold for intraoperative platelet transfusion and antifibrinolytics, especially in patients with high lab-MELD score, may decrease the incidence of reoperation for bleeding following LTx. PMID- 25505821 TI - Primary leiomyoma of the liver: a review of a rare tumour. AB - Context. Primary leiomyoma of the liver is a rare tumour with uncertain pathogenesis with similar presentation with other tumours of the liver. Little is known about its clinical course. Objectives. To review the literature for case reports of primary leiomyoma of the liver. Methods. Extensive literature search was carried out for case reports of primary leiomyoma of the liver. Results. A total of 36 cases of primary leiomyoma of the liver were reviewed. The mean age of presentation is 43 years with slight female sex affectation; females accounted for 55.6% of the cases reported in the literature. The average size of the tumour is 8.7 cm. 34.4% of the cases reviewed were incidental finding with the mean follow-up time of 33 months with most cases reporting no evidence of disease. Conclusions. Primary leiomyoma of the liver is very rare tumour with complex pathogenesis which remains largely unknown. Imaging of the tumour does not allow for a tissue specific diagnosis; hence histological review of the tissue specimen and immunohistochemical stains are imperative for diagnosis. Surgical resection is both diagnostic and curative. The diagnosis of primary leiomyoma of the liver should be considered as a differential in the management of liver tumours. PMID- 25505822 TI - Establishing 'quality of life' parameters using behavioural guidelines for humane euthanasia of captive non-human primates. AB - Chronic pain and distress are universally accepted conditions that may adversely affect an animal's quality of life (QOL) and lead to the humane euthanasia of an animal. At most research institutions and zoological parks in the USA, a veterinarian, who has physically examined the animal and reviewed the clinical records, ultimately decides when an animal has reached a humane endpoint. To aid in the difficult process of interpreting pain and distress, we have developed specific behavioural guidelines, in addition to standard clinical information, to help define unique characteristics and traits of primates to assess and promote discussion of an individual primate's QOL, and thereby, to assist in the decision making process regarding euthanasia. These guidelines advocate the creation of a QOL team when the animal is diagnosed with a life-threatening or debilitating chronic condition, or at the time the animal is entered into a terminal study. The team compiles a list of characteristics unique to that individual animal by utilising a questionnaire and a behavioural ethogram. This list enables the team to quantitatively assess any deviations from the established normal behavioural repertoire of that individual. Concurrently, the QOL team determines the number of behavioural deviations that are needed to trigger an immediate discussion of the necessity for humane euthanasia of the animal. The team remains intact once created, and revisits the animal's condition as frequently as deemed necessary. This process improves animal welfare by continuing the quest to optimally define QOL for captive primates, and potentially for all captive animals. PMID- 25505825 TI - Reaching for Relevance. PMID- 25505826 TI - The Eye of the Beholder. PMID- 25505828 TI - The True Meaning of Research Participation. PMID- 25505827 TI - Neural Diversity. PMID- 25505823 TI - Mushrooms: a potential natural source of anti-inflammatory compounds for medical applications. AB - For centuries, macrofungi have been used as food and medicine in different parts of the world. This is mainly attributed to their nutritional value as a potential source of carbohydrates, proteins, amino acids, and minerals. In addition, they also include many bioactive metabolites which make mushrooms and truffles common components in folk medicine, especially in Africa, the Middle East, China, and Japan. The reported medicinal effects of mushrooms include anti-inflammatory effects, with anti-inflammatory compounds of mushrooms comprising a highly diversified group in terms of their chemical structure. They include polysaccharides, terpenoids, phenolic compounds, and many other low molecular weight molecules. The aims of this review are to report the different types of bioactive metabolites and their relevant producers, as well as the different mechanisms of action of mushroom compounds as potent anti-inflammatory agents. PMID- 25505829 TI - Structured Set Intra Prediction With Discriminative Learning in a Max-Margin Markov Network for High Efficiency Video Coding. AB - This paper proposes a novel model on intra coding for High Efficiency Video Coding (HEVC), which simultaneously predicts blocks of pixels with optimal rate distortion. It utilizes the spatial statistical correlation for the optimal prediction based on 2-D contexts, in addition to formulating the data-driven structural interdependences to make the prediction error coherent with the probability distribution, which is desirable for successful transform and coding. The structured set prediction model incorporates a max-margin Markov network (M3N) to regulate and optimize multiple block predictions. The model parameters are learned by discriminating the actual pixel value from other possible estimates to maximize the margin (i.e., decision boundary bandwidth). Compared to existing methods that focus on minimizing prediction error, the M3N-based model adaptively maintains the coherence for a set of predictions. Specifically, the proposed model concurrently optimizes a set of predictions by associating the loss for individual blocks to the joint distribution of succeeding discrete cosine transform coefficients. When the sample size grows, the prediction error is asymptotically upper bounded by the training error under the decomposable loss function. As an internal step, we optimize the underlying Markov network structure to find states that achieve the maximal energy using expectation propagation. For validation, we integrate the proposed model into HEVC for optimal mode selection on rate-distortion optimization. The proposed prediction model obtains up to 2.85% bit rate reduction and achieves better visual quality in comparison to the HEVC intra coding. PMID- 25505831 TI - Sexual Abuse is Associated with Negative Health Consequences among High-risk Men who have Sex with Men. AB - This study evaluated whether a history of sexual abuse could differentiate negative health consequences among men who have sex with men (MSM; N=148) enrolled in a risk counseling program. Over half (51.4%) reported an experience of sexual abuse. A history of sexual abuse was associated with increased psychological distress, increased rates of alcohol (AOR = 2.91; p < .01) and/or drug abuse (AOR = 2; p < .01) treatment, increased risk of housing instability (AOR = 2.13; p < .05), and increased risk for suicidality (AOR = 4.3; p < .001). Findings demonstrate that screening for sexual abuse may be useful in determining the service needs of high-risk MSM. PMID- 25505832 TI - Synthesis and Crystallographic Study of N'-(1-benzylpiperidin-4 yl)acetohydrazide. AB - As part of a study into new Fentanyl-derived opioid compounds with potent analgesic activity and reduced side effects the starting material title compound, C14H21N3O (1), was synthesized and characterized by NMR spectroscopy and single crystal X-ray diffraction. The crystal structure is monoclinic Cc with unit cell parameters a = 14.1480(3) A, b = 14.1720(4) A, c = 27.6701(7) A, beta = 96.956(1) degrees , alpha = gamma = 90 degrees . The compound has crystallized with four crystallographically unique molecules in the asymmetric unit; each molecule has a very similar conformation and an analysis of the structure shows that although all four unique molecules overlay very well there is no evidence of pseudo symmetry which would relate the molecules in the higher symmetry space group C2/c. The crystal packing consists of two separate hydrogen bonded chains which are linked together to form a thick 2D structure in the ab plane. PMID- 25505833 TI - The lactase persistence genotype is a protective factor for the metabolic syndrome. AB - The Metabolic Syndrome (MetS) is defined as a pattern of metabolic disturbances, which include central obesity, insulin resistance and hyperglycemia, dyslipidemia, and hypertension. Milk has been promoted as a healthy beverage that can improve the management of MetS. Most human adults, however, down-regulate the production of intestinal lactase after weaning. Lactase encoded by the LCT gene is necessary for lactose digestion. The -13910C > T SNP (rs4988235) is responsible for the lactase persistence phenotype in European populations. We herein investigated whether the lactase persistence genotype is also associated with the MetS in subjects from a Brazilian population of European descent. This study consisted of 334 individuals (average age of 41 years) genotyped by PCR based methods for the -13910C > T SNP. Clinical data were assessed and the genotypes were tested for their independent contribution to the MetS using chi square tests and multiple logistic regression analysis. Univariate analyses showed that hypertension and MetS prevalence were higher in individuals with the lactase non-persistence genotype than in lactase persistence subjects. Furthermore, lactase persistence was associated with a lower risk for MetS (OR = 0.467; 95% CI 0.264-0.824; p = 0.009). These results suggest that LCT genotypes can be a valuable tool for the management of MetS treatment. PMID- 25505830 TI - Reefs and islands of the Chagos Archipelago, Indian Ocean: why it is the world's largest no-take marine protected area. AB - The Chagos Archipelago was designated a no-take marine protected area (MPA) in 2010; it covers 550 000 km2, with more than 60 000 km2 shallow limestone platform and reefs. This has doubled the global cover of such MPAs.It contains 25-50% of the Indian Ocean reef area remaining in excellent condition, as well as the world's largest contiguous undamaged reef area. It has suffered from warming episodes, but after the most severe mortality event of 1998, coral cover was restored after 10 years.Coral reef fishes are orders of magnitude more abundant than in other Indian Ocean locations, regardless of whether the latter are fished or protected.Coral diseases are extremely low, and no invasive marine species are known.Genetically, Chagos marine species are part of the Western Indian Ocean, and Chagos serves as a 'stepping-stone' in the ocean.The no-take MPA extends to the 200 nm boundary, and. includes 86 unfished seamounts and 243 deep knolls as well as encompassing important pelagic species.On the larger islands, native plants, coconut crabs, bird and turtle colonies were largely destroyed in plantation times, but several smaller islands are in relatively undamaged state.There are now 10 'important bird areas', coconut crab density is high and numbers of green and hawksbill turtles are recovering.Diego Garcia atoll contains a military facility; this atoll contains one Ramsar site and several 'strict nature reserves'. Pollutant monitoring shows it to be the least polluted inhabited atoll in the world. Today, strict environmental regulations are enforced.Shoreline erosion is significant in many places. Its economic cost in the inhabited part of Diego Garcia is very high, but all islands are vulnerable.Chagos is ideally situated for several monitoring programmes, and use is increasingly being made of the archipelago for this purpose. PMID- 25505835 TI - Frequency of the allelic variant c.1150T > C in exon 10 of the fibroblast growth factor receptor 3 (FGFR3) gene is not increased in patients with pathogenic mutations and related chondrodysplasia phenotypes. AB - Mutations in the FGFR3 gene cause the phenotypic spectrum of FGFR3 chondrodysplasias ranging from lethal forms to the milder phenotype seen in hypochondroplasia (Hch). The p.N540K mutation in the FGFR3 gene occurs in ~70% of individuals with Hch, and nearly 30% of individuals with the Hch phenotype have no mutations in the FGFR3, which suggests genetic heterogeneity. The identification of a severe case of Hch associated with the typical mutation c.1620C > A and the occurrence of a c.1150T > C change that resulted in a p.F384L in exon 10, together with the suspicion that this second change could be a modulator of the phenotype, prompted us to investigate this hypothesis in a cohort of patients. An analysis of 48 patients with FGFR3 chondrodysplasia phenotypes and 330 healthy (control) individuals revealed no significant difference in the frequency of the C allele at the c.1150 position (p = 0.34). One patient carrying the combination 'pathogenic mutation plus the allelic variant c.1150T > C' had a typical achondroplasia (Ach) phenotype. In addition, three other patients with atypical phenotypes showed no association with the allelic variant. Together, these results do not support the hypothesis of a modulatory role for the c.1150T > C change in the FGFR3 gene. PMID- 25505834 TI - c.G2114A MYH9 mutation (DFNA17) causes non-syndromic autosomal dominant hearing loss in a Brazilian family. AB - We studied a family presenting 10 individuals affected by autosomal dominant deafness in all frequencies and three individuals affected by high frequency hearing loss. Genomic scanning using the 50k Affymetrix microarray technology yielded a Lod Score of 2.1 in chromosome 14 and a Lod Score of 1.9 in chromosome 22. Mapping refinement using microsatellites placed the chromosome 14 candidate region between markers D14S288 and D14S276 (8.85 cM) and the chromosome 22 near marker D22S283. Exome sequencing identified two candidate variants to explain hearing loss in chromosome 14 [PTGDR - c.G894A:p.R298R and PTGER2 - c.T247G:p.C83G], and one in chromosome 22 [MYH9, c.G2114A:p.R705H]. Pedigree segregation analysis allowed exclusion of the PTGDR and PTGER2 variants as the cause of deafness. However, the MYH9 variant segregated with the phenotype in all affected members, except the three individuals with different phenotype. This gene has been previously described as mutated in autosomal dominant hereditary hearing loss and corresponds to DFNA17. The mutation identified in our study is the same described in the prior report. Thus, although linkage studies suggested a candidate gene in chromosome 14, we concluded that the mutation in chromosome 22 better explains the hearing loss phenotype in the Brazilian family. PMID- 25505836 TI - Lack of an association between SNPs within the cholinergic receptor genes and smoking behavior in a Czech post-MONICA study. AB - Smoking has a significant heritable component of approximately 30-60%. Recent genome wide association studies have identified single nucleotide polymorphisms (SNPs) within the nicotinic cholinergic receptor subunits 3 (rs578776), 5 (rs16969968) and beta3 (rs6474412), which are associated with nicotine dependence in Western European populations. To analyze the association in a Czech population, we genotyped 1,191 males and 1,368 females (post-MONICA study). The WHO protocol was used to examine smoking status and the number of cigarettes smoked per day. There were 32.1% current and 27.6% past smokers among the males and 22.5% current and 13.8% past smokers among the females. We have not confirmed the original results: the SNPs rs16969968 (p = 0.07), rs578776 (p = 0.16) and rs6474412 (p = 0.76) were not associated with smoking status (never-smokers vs. ever-smokers) in the entire population, if a codominant model of analysis was used. This result was valid for both the male and female subpopulations if analyzed separately and adjusted for age. Finally, in ever-smokers, the number of cigarettes smoked per day was also independent of different genotypes, regardless of which polymorphism (and gender) was analyzed (the lowest p value was 0.49). The association between the cholinergic receptors-nicotinic subunits (-3, -5 and beta3), and smoking behavior may be population-dependent. PMID- 25505837 TI - Comparison of breeding value prediction for two traits in a Nellore-Angus crossbred population using different Bayesian modeling methodologies. AB - The objectives of this study were to 1) compare four models for breeding value prediction using genomic or pedigree information and 2) evaluate the impact of fixed effects that account for family structure. Comparisons were made in a Nellore-Angus population comprising F2, F3 and half-siblings to embryo transfer F2 calves with records for overall temperament at weaning (TEMP; n = 769) and Warner-Bratzler shear force (WBSF; n = 387). After quality control, there were 34,913 whole genome SNP markers remaining. Bayesian methods employed were BayesB (pi = 0.995 or 0.997 for WBSF or TEMP, respectively) and BayesC (pi = 0 and pi), where pi is the ideal proportion of markers not included. Direct genomic values (DGV) from single trait Bayesian analyses were compared to conventional pedigree based animal model breeding values. Numerically, BayesC procedures (using pi) had the highest accuracy of all models for WBSF and TEMP (rhogg = 0.843 and 0.923, respectively), but BayesB had the least bias (regression of performance on prediction closest to 1, betay,x = 2.886 and 1.755, respectively). Accounting for family structure decreased accuracy and increased bias in prediction of DGV indicating a detrimental impact when used in these prediction methods that simultaneously fit many markers. PMID- 25505838 TI - Chromosomal diversity in three species of electric fish (Apteronotidae, Gymnotiformes) from the Amazon Basin. AB - Cytogenetic studies were carried out on samples of Parapteronotus hasemani, Sternarchogiton preto and Sternarchorhamphus muelleri (Apteronotidae, Gymnotiformes) from the Amazon basin. The first two species exhibited both a 2n = 52 karyotype, but differed in their karyotypic formulae, distribution of constitutive heterochromatin, and chromosomal location of the NOR. The third species, Sternarchorhamphus muelleri, was found to have a 2n = 32 karyotype. In all three species the DAPI and chromomycin A3 staining results were consistent with the C-banding results and nucleolar organizer region (NOR) localization. The 18S rDNA probe confirmed that there was only one pair of ribosomal DNA cistron bearers per species. The telomeric probe did not reveal interstitial telomeric sequences (ITS). The karyotypic differences among these species can be used for taxonomic identification. These data will be useful in future studies of these fishes and help understanding the phylogenetic relationships and chromosomal evolution of the Apteronotidae. PMID- 25505839 TI - Genetic identification of bucktooth parrotfish Sparisoma radians (Valenciennes, 1840) (Labridae, Scarinae) by chromosomal and molecular markers. AB - Parrotfishes (Labridae, Scarinae) comprise a large marine fish group of difficult identification, particularly during juvenile phase when the typical morphology and coloration of adults are absent. Therefore, the goal of this study was to test cytogenetic markers and DNA barcoding in the identification of bucktooth parrtotfish Sparisoma radians from the northeastern coast of Brazil. Sequencing of cytochrome c oxidase subunit I (COI) confirmed all studied samples as S. radians, and all showed high similarity (99-100%) with Caribbean populations. The karyotype of this species was divergent from most marine Perciformes, being composed of 2n = 46 chromosomes. These consisted of a large number of metacentric and submetacentric pairs with small amounts of heterochromatin and GC-rich single nucleolar organizer regions (NORs) not syntenic to 5S rDNA clusters. These are the first data about DNA barcoding in parrotfish from the Brazilian province and the first refined chromosomal analysis in Scarinae, providing useful data to a reliable genetic identification of S. radians. PMID- 25505840 TI - Comparative proteomic analysis of indica and japonica rice varieties. AB - Indica and japonica are two main subspecies of Asian cultivated rice (Oryza sativa L.) that differ clearly in morphological and agronomic traits, in physiological and biochemical characteristics and in their genomic structure. However, the proteins and genes responsible for these differences remain poorly characterized. In this study, proteomic tools, including two-dimensional electrophoresis and mass spectrometry, were used to globally identify proteins that differed between two sequenced rice varieties (93-11 and Nipponbare). In all, 47 proteins that differed significantly between 93-11 and Nipponbare were identified using mass spectrometry and database searches. Interestingly, seven proteins were expressed only in Nipponbare and one protein was expressed specifically in 93-11; these differences were confirmed by quantitative real-time PCR and proteomic analysis of other indica and japonica rice varieties. This is the first report to successfully demonstrate differences in the protein composition of indica and japonica rice varieties and to identify candidate proteins and genes for future investigation of their roles in the differentiation of indica and japonica rice. PMID- 25505841 TI - DNA barcoding in Atlantic Forest plants: What is the best marker for Sapotaceae species identification? AB - The Atlantic Forest is a phytogeographic domain with a high rate of endemism and large species diversity. The Sapotaceae is a botanical family for which species identification in the Atlantic Forest is difficult. An approach that facilitates species identification in the Sapotaceae is urgently needed because this family includes threatened species and valuable timber species. In this context, DNA barcoding could provide an important tool for identifying species in the Atlantic Forest. In this work, we evaluated four plant barcode markers (matK, rbcL, trnH psbA and the nuclear ribosomal internal transcribed spacer region - ITS) in 80 samples from 26 species of Sapotaceae that occur in the Atlantic Forest. ITS yielded the highest average interspecific distance (0.122), followed by trnH-psbA (0.019), matK (0.008) and rbcL (0.002). For species discrimination, ITS provided the best results, followed by matK, trnH-psbA and rbcL. Furthermore, the combined analysis of two, three or four markers did not result in higher rates of discrimination than obtained with ITS alone. These results indicate that the ITS region is the best option for molecular identification of Sapotaceae species from the Atlantic Forest. PMID- 25505842 TI - Identification of novel and conserved microRNAs in Coffea canephora and Coffea arabica. AB - As microRNAs (miRNAs) are important regulators of many biological processes, a series of small RNAomes from plants have been produced in the last decade. However, miRNA data from several groups of plants are still lacking, including some economically important crops. Here microRNAs from Coffea canephora leaves were profiled and 58 unique sequences belonging to 33 families were found, including two novel microRNAs that have never been described before in plants. Some of the microRNA sequences were also identified in Coffea arabica that, together with C. canephora, correspond to the two major sources of coffee production in the world. The targets of almost all miRNAs were also predicted on coffee expressed sequences. This is the first report of novel miRNAs in the genus Coffea, and also the first in the plant order Gentianales. The data obtained establishes the basis for the understanding of the complex miRNA-target network on those two important crops. PMID- 25505843 TI - Analysis of the ergosterol biosynthesis pathway cloning, molecular characterization and phylogeny of lanosterol 14 alpha-demethylase (ERG11) gene of Moniliophthora perniciosa. AB - The phytopathogenic fungus Moniliophthora perniciosa (Stahel) Aime & Philips Mora, causal agent of witches' broom disease of cocoa, causes countless damage to cocoa production in Brazil. Molecular studies have attempted to identify genes that play important roles in fungal survival and virulence. In this study, sequences deposited in the M. perniciosa Genome Sequencing Project database were analyzed to identify potential biological targets. For the first time, the ergosterol biosynthetic pathway in M. perniciosa was studied and the lanosterol 14alpha-demethylase gene (ERG11) that encodes the main enzyme of this pathway and is a target for fungicides was cloned, characterized molecularly and its phylogeny analyzed. ERG11 genomic DNA and cDNA were characterized and sequence analysis of the ERG11 protein identified highly conserved domains typical of this enzyme, such as SRS1, SRS4, EXXR and the heme-binding region (HBR). Comparison of the protein sequences and phylogenetic analysis revealed that the M. perniciosa enzyme was most closely related to that of Coprinopsis cinerea. PMID- 25505844 TI - Clustering of water bodies in unpolluted and polluted environments based on Escherichia coli phylogroup abundance using a simple interaction database. AB - Different types of water bodies, including lakes, streams, and coastal marine waters, are often susceptible to fecal contamination from a range of point and nonpoint sources, and have been evaluated using fecal indicator microorganisms. The most commonly used fecal indicator is Escherichia coli, but traditional cultivation methods do not allow discrimination of the source of pollution. The use of triplex PCR offers an approach that is fast and inexpensive, and here enabled the identification of phylogroups. The phylogenetic distribution of E. coli subgroups isolated from water samples revealed higher frequencies of subgroups A1 and B23 in rivers impacted by human pollution sources, while subgroups D1 and D2 were associated with pristine sites, and subgroup B1 with domesticated animal sources, suggesting their use as a first screening for pollution source identification. A simple classification is also proposed based on phylogenetic subgroup distribution using the w-clique metric, enabling differentiation of polluted and unpolluted sites. PMID- 25505845 TI - Chromosomal damage and apoptosis analysis in exfoliated oral epithelial cells from mouthwash and alcohol users. AB - Chromosomal damage and apoptosis were analyzed in users of mouthwash and/or alcoholic beverages, using the micronucleus test on exfoliated oral mucosa cells. Samples from four groups of 20 individuals each were analyzed: three exposed groups (EG1, EG2 and EG3) and a control group (CG). EG1 comprised mouthwash users; EG2 comprised drinkers, and EG3 users of both mouthwashes and alcoholic beverages. Cell material was collected by gently scraping the insides of the cheeks. Then the cells were fixed in a methanol/acetic acid (3:1) solution and stained and counterstained, respectively, with Schiff reactive and fast green. Endpoints were computed on 2,000 cells in a blind test. Statistical analysis showed that chromosomal damage and apoptosis were significantly higher in individuals of groups EG1 and EG3 than in controls (p < 0.005 and p < 0.001, respectively). No significant difference in chromosomal damage and apoptosis was observed between the exposed groups. In EG2, only the occurrence of apoptosis was significantly higher than in the controls. These results suggest that mouthwashes alone or in association with alcoholic drinks induce genotoxic effects, manifested as chromosomal damage and apoptosis. They also suggest that alcoholic drinks are effective for stimulating the process of apoptosis. However, these data need to be confirmed in larger samples. PMID- 25505846 TI - Targeted disruption of the mouse testis-enriched gene Znf230 does not affect spermatogenesis or fertility. AB - The mouse testis-enriched Znf230 gene, which encodes a type of RING finger protein, is present primarily in the nuclei of spermatogonia, the acrosome and the tail of spermatozoa. To investigate the role of Znf230 in spermatogenesis, we generated Znf230-deficient mice by disrupting Znf230 exon-5 and exon-6 using homologous recombination. The homozygous Znf230-knockout (KO) mice did not exhibit Znf230 mRNA expression and Znf230 protein production. Znf230 KO mice exhibited no obvious impairment in body growth or fertility. Male Znf230 KO mice had integral reproductive systems and mature sperm that were regular in number and shape. The developmental stages of male germ cells of Znf230 KO mice were also normal. We further examined variations in the transcriptomes of testicular tissue between Znf230 KO and wild-type mice through microarray analysis. The results showed that the mRNA level of one unclassified transcript 4921513I08Rik was increased and that the mRNA levels of three other transcripts, i.e., 4930448A20Rik, 4931431B13Rik and potassium channel tetramerisation domain containing 14(Kctd14), were reduced more than two-fold in Znf230 KO mice compared with wild-type mice. Using our current examination techniques, these findings suggested that Znf230 deficiency in mice may not affect growth, fertility or spermatogenesis. PMID- 25505848 TI - Compact Orientation-Independent Differential Interference Contrast (OI-DIC) Microscope Designed for High Resolution and High Sensitivity Mapping of Optical Path and Optical Path Gradient. PMID- 25505847 TI - PCI-24781 down-regulates EZH2 expression and then promotes glioma apoptosis by suppressing the PIK3K/Akt/mTOR pathway. AB - PCI-24781 is a novel histone deacetylase inhibitor that inhibits tumor proliferation and promotes cell apoptosis. However, it is unclear whether PCI 24781 inhibits Enhancer of Zeste 2 (EZH2) expression in malignant gliomas. In this work, three glioma cell lines were incubated with various concentrations of PCI-24781 (0, 0.25, 0.5, 1, 2.5 and 5 MUM) and analyzed for cell proliferation by the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium] assay and colony formation, and cell cycle and apoptosis were assessed by flow cytometry. The expression of EZH2 and apoptosis related proteins was assessed by western blotting. Malignant glioma cells were also transfected with EZH2 siRNA to examine how PCI-24781 suppresses tumor cells. EZH2 was highly expressed in the three glioma cell lines. Incubation with PCI 24781 reduced cell proliferation and increased cell apoptosis by down-regulating EZH2 in a concentration-dependent manner. These effects were simulated by EZH2 siRNA. In addition, PCI-24781 or EZH2 siRNA accelerated cell apoptosis by down regulating the expression of AKT, mTOR, p70 ribosomal protein S6 kinase (p70s6k), glycogen synthase kinase 3A and B (GSK3a/b) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). These data suggest that PCI-24781 may be a promising therapeutic agent for treating gliomas by down-regulating EZH2 which promotes cell apoptosis by suppressing the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of the rapamycin (mTOR) pathway. PMID- 25505849 TI - Experimental study on the regulation of erlotinib-induced radiosensitization with an anti-c-MET monoclonal antibody. AB - PURPOSE: Erlotinib is a novel therapeutic agent for cancer treatment. This study was performed to investigate the role of c-MET-PI3K-AKT pathway in the regulation of erlotinib-induced radiosensitization. METHODS: A973 lung adenocarcinoma cells treated with 6 Gy of radiation were incubated in the presence of erlotinib. The apoptotic rate after 24 hours, the colony-formating rate after 14 days, and changes in the c-MET expression levels after 14 days of irradiation were examined. Surviving fractions in different treatment groups (blank control, radiation alone, erlotinib alone, anti-c-MET monoclonal antibody alone, combined erlotinib and radiation, and combined erlotinib and radiation with anti-c-MET monoclonal antibody groups) were determined, the survival curves were plotted, and the sensitizer enhancement ratio was calculated using colony formation assays. Expressions of c-MET, p-c-MET, PI3K, AKT, and p-AKT in cells in different treatment groups were examined by Western blot analysis. RESULTS: The apoptotic rate in the combined erlotinib and radiation group was higher than those in single treatment groups; however, the colony-forming rate remained approximately 2.04 +/- 1.02%. The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib. The expression of c-Met, p-c MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET. CONCLUSIONS: Upregulated activity of the c-MET-PI3K-AKT pathway was found to be important for cell survival under combined the treatment with erlotinib and radiation. The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib. PMID- 25505850 TI - Proteomic analysis of seed storage proteins in wild rice species of the Oryza genus. AB - BACKGROUND: The total protein contents of rice seeds are significantly higher in the three wild rice species (Oryza rufipogon Grill., Oryza officinalis Wall. and Oryza meyeriana Baill.) than in the cultivated rice (Oryza sativa L.). However, there is still no report regarding a systematic proteomic analysis of seed proteins in the wild rice species. Also, the relationship between the contents of seed total proteins and rice nutritional quality has not been thoroughly investigated. RESULTS: The total seed protein contents, especially the glutelin contents, of the three wild rice species were higher than those of the two cultivated rice materials. Based on the protein banding patterns of SDS-PAGE, O. rufipogon was similar to the two cultivated rice materials, followed by O. officinalis, while O. meyeriana exhibited notable differences. Interestingly, O. meyeriana had high contents of glutelin and low contents of prolamine, and lacked 26 kDa globulin band and appeared a new 28 kDa protein band. However, for O. officinali a 16 kDa protein band was absent and a row of unique 32 kDa proteins appeared. In addition, we found that 13 kDa prolamine band disappeared while special 14 kDa and 12 kDa protein bands were present in O. officinalis. Two dimensional gel electrophoresis (2-DE) analysis revealed remarkable differences in protein profiles of the wild rice species and the two cultivated rice materials. Also, the numbers of detected protein spots of the three wild rice species were significantly higher than those of two cultivated rice. A total of 35 differential protein spots were found for glutelin acidic subunits, glutelin precursors and glutelin basic subunits in wild rice species. Among those, 18 protein spots were specific and 17 major spots were elevated. Six differential protein spots for glutelin acidic subunits were identified, including a glutelin type-A 2 precursor and five hypothetical proteins. CONCLUSION: This was the first report on proteomic analysis of the three wild rice species. Overall results suggest that there were many new types of glutelin subunits and precursor in the three wild rice species. Hence, wild rice species are important genetic resources for improving nutritional quality to rice. PMID- 25505851 TI - Identity Distress among Youth Exposed to Natural Disasters: Associations with Level of Exposure, Posttraumatic Stress, and Internalizing Problems. AB - Identity distress involves intense or prolonged upset or worry about personal identity issues including long-term goals, career choice, friendships, sexual orientation and behavior, religion, values and beliefs, and group loyalties. Research suggests that trauma exposure and subsequent PTSD symptoms may negatively impact identity development and psychological adjustment. However, little is known about their specific associations with identity distress and internalizing problems among disaster-exposed adolescents. The purpose of this study was to examine these relationships in a sample of 325 adolescents (60% female; 89% African American) who experienced a major natural disaster and its aftermath. The results indicated that identity distress was positively associated with age, hurricane exposure, PTSD symptoms, and internalizing problems. Linear regression analyses also showed that identity distress was uniquely associated with internalizing symptoms and that there was an indirect effect of hurricane exposure on identity distress via PTSD symptoms. Finally, PTSD symptoms moderated the link between identity distress and internalizing symptoms, with a significant positive slope found for youth with more PTSD symptoms. Findings were generally consistent with previous work and predictions, and add to the extant knowledge about identity distress by providing data on the linkages between disaster exposure, posttraumatic stress and internalizing problems in adolescents. PMID- 25505852 TI - Opioid use remits, depression remains. PMID- 25505855 TI - The Meteoric Rise of the Signaling Molecule Cyclic di-GMP. AB - During the past decade, research on c-di-GMP expanded greatly, uncovering several roles it plays among bacteria. PMID- 25505854 TI - Effects of 28 days of beta-alanine and creatine supplementation on muscle carnosine, body composition and exercise performance in recreationally active females. AB - BACKGROUND: The purpose of this study was to examine the short-term and chronic effects of beta-ALA supplementation with and without creatine monohydrate on body composition, aerobic and anaerobic exercise performance, and muscle carnosine and creatine levels in college-aged recreationally active females. METHODS: Thirty two females were randomized in a double-blind, placebo-controlled manner into one of four supplementation groups: beta-ALA only (BA, n = 8), creatine only (CRE, n = 8), beta-ALA and creatine combined (BAC, n = 9) and placebo (PLA, n = 7). Participants supplemented for four weeks included a loading phase for the creatine for week 1 of 0.3 g/kg of body weight and a maintenance phase for weeks 2-4 of 0.1 g/kg of body weight, with or without a continuous dose of beta-ALA of 0.1 g/kg of body weight with doses rounded to the nearest 800 mg capsule providing an average of 6.1 +/- 0.7 g/day of beta-ALA. Participants reported for testing at baseline, day 7 and day 28. Testing sessions consisted of obtaining a resting muscle biopsy of the vastus lateralis, body composition measurements, performing a graded exercise test on the cycle ergometer for VO2peak with lactate threshold determination, and multiple Wingate anaerobic capacity tests. RESULTS: Although mean changes were consistent with prior studies and large effect sizes were noted, no significant differences were observed among groups in changes in muscle carnosine levels (BA 35.3 +/- 45; BAC 42.5 +/- 99; CRE 0.72 +/- 27; PLA 13.9 +/- 44%, p = 0.59). Similarly, although changes in muscle phosphagen levels after one week of supplementation were consistent with prior reports and large effect sizes were seen, no statistically significant effects were observed among groups in changes in muscle phosphagen levels and the impact of CRE supplementation appeared to diminish during the maintenance phase. Additionally, significant time * group * Wingate interactions were observed among groups for repeated sprint peak power normalized to bodyweight (p = 0.02) and rate of fatigue (p = 0.04). CONCLUSIONS: Results of the present study did not reveal any consistent additive benefits of BA and CRE supplementation in recreationally active women. PMID- 25505856 TI - Absolute quantification of endogenous angiotensin II levels in human plasma using ESI-LC-MS/MS. AB - BACKGROUND: Angiotensin II acts as a peptide hormone and component of renin angiotensin- system (RAS) regulating the blood pressure, and seems to be involved in renal and vascular disorders. There is no reliable quantification method for angiotensin II available until now and the angiotensin II plasma levels described in the literature are correspondingly strongly divergent. Therefore, we developed and validated a sensitive, selective and reliable LC-ESI-MS/MS method for absolute quantification of angiotensin II concentration in human plasma based on the AQUA strategy. METHODS: Plasma samples were extracted using MAX Oasis cartridges and were subjected to a further immunoaffinity-purification using immobilized anti-angiotensin II antibodies in order to isolate endogenous angiotensin II. Stable isotope ((13)C- and (15) N-) labeled angiotensin II was used as an internal standard. The fractionated samples were analysed using LC-ESI MS/MS. RESULTS: The calibration curve was established in plasma in the concentration range 6-240 pM (r(2) > 0.999). The developed and validated method was successfully applied for quantification of endogenous angiotensin II in human plasma of healthy volunteers and chronic kidney disease (CKD-5D) patients. The mean plasma angiotensin II levels were found to be 18.4 +/- 3.3 pM in healthy subjects and 64.5 +/- 32.4 pM in CKD-5D patients (each n =9). CONCLUSION: The LC ESI-MS/MS-based method for quantification of angiotensin II levels in human plasma was successfully evaluated within the study. This method is applicable for clinical applications aiming at the validation of the impact of highly physiologically and pathophysiologically active angiotensin II. PMID- 25505857 TI - Metal-Free Preparation of Cycloalkyl Aryl Sulfides via Di-tert-butyl Peroxide Promoted Oxidative C(sp3)[BOND]H Bond Thiolation of Cycloalkanes. AB - A concise thiolation of C(sp3)-H bond of cycloalkanes with diaryl disulfides in the presence of oxidant of di-tert-butylperoxide (DTBP) has been developed. This reaction without using any of metal catalyst, tolerates varieties of disulfides and cycloalkanes substrates, giving good to excellent chemical yields, which provides a useful approach to cycloalkyl aryl sulfides from unactivated cycloalkanes. PMID- 25505858 TI - Chronic Venous Insufficiency: prevalence and effect of compression stockings. AB - INTRODUCTION: Chronic venous insufficiency (CVI) is a common disease affecting mainly lower limbs and significantly influencing the quality of life. This study aims to estimate the prevalence of CVI in the Qassim Region and test the effectiveness of compression stockings as an intervention option. METHODS: A cross sectional study was conducted to assess the prevalence of CVI among patients visiting primary health care (PHC) centers in the Qassim Region. CVI patients were diagnosed and classified using the clinical, etiologic, anatomical, and pathophysiological (CEAP) scale. They were randomly divided into two groups, one using compression stockings and the other standard medical therapy. A clinical follow up was done using multiple scale system including CEAP scale. Data analysis was performed using SPSS. RESULTS: Among the 226 screened patients, 138 (61.1%) were diagnosed as having CVI (69% female and 45% male, p<0.001). Compared to the baseline, both the clinical and venous scores for CVI at the follow-up were significantly lower among patients using compression stockings, p=0.002 and p=0.003, respectively. Regression analysis suggested that, after controlling for age, sex and body mass index, compliance was the main factor responsible for a significant reduction in the clinical score among CVI patients. CONCLUSIONS: Chronic venous insufficiency is very common in the Qassim Region. Compression stockings are highly effective in improving clinical symptoms and signs of CVI. TRIAL REGISTRATION: This study is registered at www.clinicaltrials.gov(NCT02050061). PMID- 25505859 TI - Lipoprotein (a) and atherogenic indices in Sudanese patients with type 2 diabetes. AB - BACKGROUND & AIMS: Type 2 diabetes is associated with significant cardiac morbidity and mortality with a more than threefold increased risk of coronary artery disease (CAD). We aimed to assess the serum concentrations of lipoprotein (a) and lipid profile indexes as predictors for CAD in Sudanese type 2 diabetics compared to healthy subjects. MATERIALS & METHODS: This case-control study was conducted at Jabir Abu-Aliz Specialized Center, Khartoum State, Sudan. After overnight fasting, 4 ml blood samples were collected in plain vials through venous puncture from each subject. Lipid profile parameters were estimated by standard laboratory procedures. Serum lipoprotein (a) was measured by immunoturbidimetric method. Statistical analyses were performed using SPSS software (version 17). RESULTS: Compared to healthy controls, type 2 diabetics showed significantly higher serum lipids and lipoprotein fractions. The mean values of lipoprotein (a), TC: HDL-C (5.55+/-.8 vs. 3.89+/-.6) and LDL-C: HDL-C (3.80+/-0.7 vs. 2.32+/-0.5) were significantly increased in patients. Lipoprotein (a) was significantly correlated with TG (p=.025), HDL-C (inversely, p<.001), VLDL-C (p= .025), and TC: HDL-C ratio (p= 016). Moreover, LDL-C: HDL-C ratio and TC were the most common risk factors distributed among the study patients (80% and 71.4% respectively). CONCLUSION: Diabetic patients characterized by higher ratios of TC: HDL -C and LDL: HDL and Lipoprotein (a) compared to healthy controls. The evaluation of these lipid indices in diabetics, beside the routine lipid profile analysis, may be a crucial helpful step in the prevention of coronary artery disease since these atherogenic factors can be reduced by lifestyle modifications. PMID- 25505860 TI - Profile of epilepsy in a regional hospital in Al qassim, saudi arabia. AB - INTRODUCTION: Epilepsy is a diverse set of chronic neurological disorders characterized by seizures. It is one of the most common of the serious neurological disorders. About 3% of people will be diagnosed with epilepsy at some time in their lives. OBJECTIVES: We aimed to address the commonest types of seizures, their aetiologies, EEG and neuroimaging results and prognosis of patients presented to neurology services of the King Fahad Specialist Hospital- AlQassim (KFSH). METHODOLOGY: In this retrospective epidemiological study we investigated the medical records of patients with epilepsy, who attended the neurology services of KFSH, during the study period (26/10/2011-26/4/2012). RESULTS: The study included 341 patients; 189 (55.4%) males and 152 (44.6%) females. Their ages ranged between 12 and 85 years (mean +/- SD = 31+/-16.9). The majority of patients had Generalised Tonic Clonic Seizures (76.2%), followed by Complex Partial Seizures (7.6%). 73% of our patients had idiopathic epilepsy. The commonest causes for symptomatic epilepsy were Cerebro Vascular Accidents and Head trauma. Hemiplegia, mental retardation and psychiatric illness were the commonest comorbidity. 69.3% of patients had controlled seizures. Patients with idiopathic epilepsy were significantly controlled than patients with symptomatic epilepsy (P=0.01), and those using one Anti Epileptic Drug were significantly controlled compared to patients using polytherapy (P=0.0001) there was no significant relation between controlled seizure and duration of illness or hospitalization or EEG changes. CONCLUSION: Seizure types, aetiology, drug therapy, Comorbidities and outcome in a tertiary care hospital in Saudi Arabia are similar to previous local and international studies. 35.3% of patients were hospitalized, higher rates than previous studies. Seizure control was better in generalized seizures and idiopathic epilepsy compared to complex partial seizures or partial seizures with secondary generalization and symptomatic epilepsy. PMID- 25505861 TI - Histopathological Studies on Rabbits Infected by Bacteria Causing Infectious Keratitis in Human through Eye Inoculation. AB - AIM: This study aimed to investigate the pathogenic effect of bacteria causing infectious keratitis among patients through experimental study conducted on rabbits' eyes with the aid of histopathology as eye infection is a common disease in developing countries that may complicate to loss of vision. METHODOLOGY: 100 swab samples were collected from human infected eyes, at Qassim region during 2012, for the isolation of Pseudomonas aeruginosa and Staphylococcus aureus. The isolated pathogenic bacteria were tested to various antibiotics using some selected antibiotics discs through agar-well diffusion method. Then, experimental study conducted on 27 rabbits. The rabbits were divided randomly into three equal groups, each containing 9 rabbits. Rabbits of group (1) served as control group (Negative Control) and their eyes were inoculated with the buffer only. Rabbits of group (2) were inoculated through eyes with the isolated Pseudomonas aeruginosa. Rabbits of group (3) were inoculated through eyes with the isolated Staphylococcus aureus. RESULTS: Out of 100 collected swab samples from human infected eyes, Pseudomonas aeruginosa and Staphylococcus aureus were isolated with a total percentage of 25.21% and 15.65%; respectively and used in this study. Both bacterial isolates were sensitive to Gentamicin and Cefuroxime. Clinically, experimentally infected rabbits by Pseudomonas aeruginosa, revealed varying degree corneal abrasions, corneal abscess and dense corneal opacity. Histopathologically, at 3(rd) day post-infection (PI), the cornea revealed polymorpho-nuclear cells infiltration with loss of the outer epithelial lining. At 7(th) day PI, neutrophils were seen in the stroma. At 15(th) day PI, proliferation of fibroblasts and new vascularisation were seen in the stroma. Clinically, rabbits experimentally infected with Staphylococcus aureus, revealed corneal ulcers and focal abscesses. Histopathologically, at 3(rd) and 7(th) day PI, the cornea revealed edema and infiltration of leukocytes. At 15(th) day PI, hyperplasia of corneal epithelium and proliferation of keratocytes were evident. The liver and kidneys of experimented rabbits revealed no remarkable histopathological alterations along the period of experiment. CONCLUSION: Pseudomonas aeruginosa and Staphylococcus aureus are common eye infection in human, both induced severe lesions in the eyes of rabbits that could interfere with vision, therefore, strict measures to control these infections in human is recommended. PMID- 25505862 TI - Extrinsic stain removal with a toothpowder: A randomized controlled trial. AB - OBJECTIVES: The efficacy of a commercially available toothpowder was compared with toothpaste in removing extrinsic dental stains. METHODS: In this single blind, randomized controlled trial, 77 volunteers were included from a residential professional college. All study subjects (control toothpaste users and test toothpowder users) plaque control measures. All study subjects were instructed to rinse with 5 ml 0.12% chlorhexidine mouthwash for 1 minute, twice and one cup of double tea bag solution three times daily for three weeks. Subjects were randomized into test (n=36) and control (n=36) groups. Toothpaste (control) and toothpowder (test) was used for two weeks to see the effects on removing stains on the labial surfaces of 12 anterior teeth. For measuring dental extrinsic stains Lobene Stain Index (SI) was used. RESULTS: The amount of stain following the use of toothpaste and toothpowder was more controlled with the experimental toothpowder. For all sites combined, there was evidence that the experimental toothpowder was significantly superior to toothpaste in reducing stain area (p<.001), stain intensity (p<.001) and composite/product (area * intensity) (p<.001). CONCLUSION: Stain removing efficacy of toothpowder was significantly higher as compared with toothpaste. A toothpowder may be expected to be of benefit in controlling and removing extrinsic dental staining. PMID- 25505863 TI - The Effect of Systemic Delivery of Aminoguanidine versus Doxycycline on the Resorptive Phase of Alveolar Bone Following modified Widman Flap in Diabetic Rats: A Histopathological and Scanning Electron Microscope (SEM) study. AB - OBJECTIVES: Aminoguanidine (guanylhydrazinehydrochloride) is a drug that prevents many of the classical systemic complications of diabetes including diabetic osteopenia through its inhibitory activity on the accumulation of advanced glycation end -products (AGEs). The aim of the present study was to evaluate the effectiveness of aminoguanidine versus doxycycline in reducing alveolar bone resorption following mucoperiosteal flap in diabetic rats, using the conventional histopathology and scanning electron microscope (SEM). METHODS: Twenty-seven male albino rats were used in this study. Periodontal defects were induced experimentally on lower anterior teeth. All rats were subjected to induction of diabetes, by IV injection of the pancreatic B-cells toxin alloxan monohydrate. After eight weeks following the establishment of periodontal defects in all rats, the ligation was removed and 3 rats were scarified as negative control (group 1). The remaining animals were divided into three group based on treatment applied following mucoperiosteal flap surgery. Group 2 received saline treatment only, group 3 received doxycycline periostat (1.5 mg/kg/day) for 3 weeks, and group 4 received aminoguanidine (7.3 mmol/kg) for 3 weeks. The fasting glucose level was measured weekly post operatively. After 21 days all rats were sacrificed. Three anterior parts of the mandible of each group was prepared for histopathological examination and two parts were prepared for SEM. RESULTS: Aminoguanidine treated group (group 4) showed statistically significant increased new bone formation, higher number of osteoblasts and decrease osteoclasts number, resorptive lacunae and existing inflammatory cell infiltration as compared to positive control group (group 2) (P<0.05). Doxycycline was also effective in reducing bone loss as documental by histopathological study. CONCLUSION: The present study showed that aminoguanidine was significantly effective in reducing alveolar bone loss and can modify the detrimental effects of diabetes in alveolar bone resorption. PMID- 25505864 TI - Pain Assessment and Management in Critically ill Intubated Patients in Jordan: A Prospective Study. AB - OBJECTIVES: The purpose of this study was to describe: (1) pain indicators used by nurses and physicians to assess pain, (2) pain management interventions (pharmacological and non-pharmacological) used by nurses, and (3) indicators used by nurses to verify pain intervention effectiveness. METHODOLOGY: A total of 301 medical records of currently admitted patients from six different ICUs in Jordan were reviewed using a data collection instrument developed by Gelinas et al. (2004) Pain-related indicators were classified into non-observable (patient's self-reports of pain) and observable (physiological and behavioral) categories. RESULTS: Only 105 (35%) of a total 301 reviewed medical records contained pain assessment data. From these medical records, 15 pain episodes were collected altogether. Observable indicators documented 98% of the 115 pain episodes. Patients' self-reports of pain were documented only 1.7% of the time. In 78% and 46% of the 115 pain episodes, pharmacological and nonpharmacological interventions for pain management were documented, respectively. Only 37% of the pain episodes were reassessed with self- report (1%) and observable indicators (36%) to determine the effectiveness of the interventions. CONCLUSION: Pain documentation for assessment, management, and reassessment was lacking and needs improvement. PMID- 25505865 TI - The effect of chemical disinfectants on the color of a porcelain shade guide. AB - OBJECTIVE: To evaluate the effect of long term utilization of chemical disinfectants on the color of porcelain shade guides. METHODOLOGY: three chemical disinfectants were used in this study: Minuten spray, Lysol ICQuaternary Disinfectant Cleaner (QDC), and Lysol IC Ready to Use Disinfectant Cleaner (RDC). Simulation of disinfecting cycles for one year, two years, and three years were done on Vita 3D master shade guide. Color differences were determined by visual inspection and analyzing DeltaE. RESULTS: DeltaE values were significantly below the perceptible (DeltaE=1) and the clinically acceptable (DeltaE=3.7) thresholds. CONCLUSIONS: Simulated utilization of Minuten Spray, Lysol IC (QDC), and Lysol (RDC) disinfectants for up to three years didn't cause a clinically significant difference in the color of VITA Toothguide 3D-Master Shade Guide. PMID- 25505866 TI - Umbilical pilonidal sinus. AB - Pilonidal sinuses are commonly encountered, but their occurrence in the umbilical area is rare. The author presents one such case of an umbilical pilonidal sinus in an obese male patient that presented with recurrent episodes of umbilical discharge. The condition was treated with sinus excision and umbilical reconstruction. There was no recurrence of the disease until one year of follow up. PMID- 25505867 TI - Congenital central hypoventilation syndrome with PHOX2B mutation in Saudi Arabia: a- single center experience. PMID- 25505868 TI - Role of intermittent fasting on improving health and reducing diseases. PMID- 25505853 TI - Composition, roles, and regulation of cullin-based ubiquitin e3 ligases. AB - Due to their sessile nature, plants depend on flexible regulatory systems that allow them to adequately regulate developmental and physiological processes in context with environmental cues. The ubiquitin proteasome pathway, which targets a great number of proteins for degradation, is cellular tool that provides the necessary flexibility to accomplish this task. Ubiquitin E3 ligases provide the needed specificity to the pathway by selectively binding to particular substrates and facilitating their ubiquitylation. The largest group of E3 ligases known in plants is represented by CULLIN-REALLY INTERESTING NEW GENE (RING) E3 ligases (CRLs). In recent years, a great amount of knowledge has been generated to reveal the critical roles of these enzymes across all aspects of plant life. This review provides an overview of the different classes of CRLs in plants, their specific complex compositions, the variety of biological processes they control, and the regulatory steps that can affect their activities. PMID- 25505869 TI - Asymmetry of cerebral gray and white matter and structural volumes in relation to sex hormones and chromosomes. AB - Whilst many studies show sex differences in cerebral asymmetry, their mechanisms are still unknown. This report describes the potential impact of sex hormones and sex chromosomes by comparing MR data from 39 male and 47 female controls and 33 men with an extra X-chromosome (47,XXY). METHODS: Regional asymmetry in gray and white matter volumes (GMV and WMV) was calculated using voxel based moprhometry (SPM5), by contrasting the unflipped and flipped individual GMV and WMV images. In addition, structural volumes were calculated for the thalamus, caudate, putamen, amygdala, and hippocampus, using the FreeSurfer software. Effects of plasma testosterone and estrogen on the GMV and WMV, as well on the right/left ratios of the subcortical volumes were tested by multi-regression analysis. RESULTS: All three groups showed a leftward asymmetry in the motor cortex and the planum temporale, and a rightward asymmetry of the middle occipital cortex. Both asymmetries were more pronounced in 46,XY males than 46,XX females and 47,XXY males, and were positively correlated with testosterone levels. There was also a rightward asymmetry of the vermis and leftward GMV asymmetry in the cerebellar hemispheres in all groups. Notably, cerebellar asymmetries were larger in 46,XX females and 47,XXY males, but were not related to sex hormone levels. No asymmetry differences between 46,XX females and 47,XXY males, and no overall effects of brain size were detected. CONCLUSION: The asymmetry in the planum temporale area and the occipital cortex seem related to processes associated with testosterone, whereas the observed cerebellar asymmetries suggest a link with X chromosome escapee genes. Sex differences in cerebral asymmetry are moderated by sex hormones and X-chromosome genes, in a regionally differentiated manner. PMID- 25505870 TI - Engineering a genetically-encoded SHG chromophore by electrostatic targeting to the membrane. AB - Although second harmonic generation (SHG) microscopy provides unique imaging advantages for voltage imaging and other biological applications, genetically encoded SHG chromophores remain relatively unexplored. SHG only arises from non centrosymmetric media, so an anisotropic arrangement of chromophores is essential to provide strong SHG signals. Here, inspired by the mechanism by which K-Ras4B associates with plasma membranes, we sought to achieve asymmetric arrangements of chromophores at the membrane-cytoplasm interface using the fluorescent protein mVenus. After adding a farnesylation motif to the C-terminus of mVenus, nine amino acids composing its beta-barrel surface were replaced by lysine, forming an electrostatic patch. This protein (mVe9Knus-CVIM) was efficiently targeted to the plasma membrane in a geometrically defined manner and exhibited SHG in HEK293 cells. In agreement with its design, mVe9Knus-CVIM hyperpolarizability was oriented at a small angle (~7.3 degrees ) from the membrane normal. Genetically encoded SHG chromophores could serve as a molecular platform for imaging membrane potential. PMID- 25505871 TI - Molecular magnetic resonance imaging of brain-immune interactions. AB - Although the blood-brain barrier (BBB) was thought to protect the brain from the effects of the immune system, immune cells can nevertheless migrate from the blood to the brain, either as a cause or as a consequence of central nervous system (CNS) diseases, thus contributing to their evolution and outcome. Accordingly, as the interface between the CNS and the peripheral immune system, the BBB is critical during neuroinflammatory processes. In particular, endothelial cells are involved in the brain response to systemic or local inflammatory stimuli by regulating the cellular movement between the circulation and the brain parenchyma. While neuropathological conditions differ in etiology and in the way in which the inflammatory response is mounted and resolved, cellular mechanisms of neuroinflammation are probably similar. Accordingly, neuroinflammation is a hallmark and a decisive player of many CNS diseases. Thus, molecular magnetic resonance imaging (MRI) of inflammatory processes is a central theme of research in several neurological disorders focusing on a set of molecules expressed by endothelial cells, such as adhesion molecules (VCAM-1, ICAM-1, P-selectin, E-selectin, ...), which emerge as therapeutic targets and biomarkers for neurological diseases. In this review, we will present the most recent advances in the field of preclinical molecular MRI. Moreover, we will discuss the possible translation of molecular MRI to the clinical setting with a particular emphasis on myeloperoxidase imaging, autologous cell tracking, and targeted iron oxide particles (USPIO, MPIO). PMID- 25505874 TI - Capture of microtubule plus-ends at the actin cortex promotes axophilic neuronal migration by enhancing microtubule tension in the leading process. AB - Microtubules are a critical part of neuronal polarity and leading process extension, thus microtubule movement plays an important role in neuronal migration. However, the dynamics of microtubules during the forward movement of the nucleus into the leading process (nucleokinesis) is unclear and may be dependent on the cell type and mode of migration used. In particular, little is known about cytoskeletal changes during axophilic migration, commonly used in anteroposterior neuronal migration. We recently showed that leading process actin flow in migrating GnRH neurons is controlled by a signaling cascade involving IP3 receptors, CaMKK, AMPK, and RhoA. In the present study, microtubule dynamics were examined in GnRH neurons. Failure of the migration of these cells leads to the neuroendocrine disorder Kallmann Syndrome. Microtubules translocated forward along the leading process shaft during migration, but reversed direction and moved toward the nucleus when migration stalled. Blocking calcium release through IP3 receptors halted migration and induced the same reversal of microtubule translocation, while blocking cortical actin flow prevented microtubules from translocating toward the distal leading process. Super-resolution imaging revealed that microtubule plus-end tips are captured at the actin cortex through calcium-dependent mechanisms. This work shows that cortical actin flow draws the microtubule network forward through calcium-dependent capture in order to promote nucleokinesis, revealing a novel mechanism engaged by migrating neurons to facilitate movement. PMID- 25505872 TI - ER to synapse trafficking of NMDA receptors. AB - Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. There are three distinct subtypes of ionotropic glutamate receptors (GluRs) that have been identified including 2-amino-3-(5-methyl-3-oxo 1,2-oxazol-4-yl)propanoic acid receptors (AMPARs), N-methyl-D-aspartate receptors (NMDARs) and kainate receptors. The most common GluRs in mature synapses are AMPARs that mediate the fast excitatory neurotransmission and NMDARs that mediate the slow excitatory neurotransmission. There have been large numbers of recent reports studying how a single neuron regulates synaptic numbers and types of AMPARs and NMDARs. Our current research is centered primarily on NMDARs and, therefore, we will focus in this review on recent knowledge of molecular mechanisms occurring (1) early in the biosynthetic pathway of NMDARs, (2) in the transport of NMDARs after their release from the endoplasmic reticulum (ER); and (3) at the plasma membrane including excitatory synapses. Because a growing body of evidence also indicates that abnormalities in NMDAR functioning are associated with a number of human psychiatric and neurological diseases, this review together with other chapters in this issue may help to enhance research and to gain further knowledge of normal synaptic physiology as well as of the etiology of many human brain diseases. PMID- 25505876 TI - Inducible forebrain-specific ablation of the transcription factor Creb during adulthood induces anxiety but no spatial/contextual learning deficits. AB - The cyclic AMP (cAMP)-response element binding protein (CREB) is an activity dependent transcription factor playing a role in synaptic plasticity, learning and memory, and emotional behavior. However, the impact of Creb ablation on rodent behavior is vague as e.g., memory performance of different Creb mutant mice depends on the specific type of mutation per se but additionally on the background and learning protocol differences. Here we present the first targeted ablation of CREB induced during adulthood selectively in principal forebrain neurons in a pure background strain of C57BL/6 mice. All hippocampal principal neurons exhibited lack of CREB expression. Mutant mice showed a severe anxiety phenotype in the openfield and novel object exploration test as well as in the Dark-Light Box Test, but unaltered hippocampus-dependent long-term memory in the Morris water maze and in context dependent fear conditioning. On the molecular level, CREB ablation led to CREM up regulation in the hippocampus and frontal cortex which may at least in part compensate for the loss of CREB. BDNF, a postulated CREB target gene, was down regulated in the frontal lobe but not in the hippocampus; neurogenesis remained unaltered. Our data indicate that in the adult mouse forebrain the late onset of CREB ablation can, in case of memory functionality, be compensated for and is not essential for memory consolidation and retrieval during adulthood. In contrast, the presence of CREB protein during adulthood seems to be pivotal for the regulation of emotional behavior. PMID- 25505875 TI - The role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity. AB - In the mammalian central nervous system, excitatory glutamatergic synapses harness neurotransmission that is mediated by ion flow through alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs, which are enriched in the postsynaptic membrane on dendritic spines, are highly dynamic, and shuttle in and out of synapses in an activity-dependent manner. Changes in their number, subunit composition, phosphorylation state, and accessory proteins can all regulate AMPARs and thus modify synaptic strength and support cellular forms of learning. Furthermore, dysregulation of AMPAR plasticity has been implicated in various pathological states and has important consequences for mental health. Here we focus on the mechanisms that control AMPAR plasticity, drawing particularly from the extensive studies on hippocampal synapses, and highlight recent advances in the field along with considerations for future directions. PMID- 25505877 TI - Incoordination between spikes and LFPs in Abeta1-42-mediated memory deficits in rats. AB - Alzheimer's disease (AD) is a neurodegenerative disease that gradually induces cognitive deficits. Impairments of working memory have been typically observed in AD. It is well known that spikes and local field potentials (LFPs) as well as the coordination between them encode information in normal brain function. However, the abnormal coordination between spikes and LFPs in the cognitive deficits of AD has remained largely unexplored. As amyloid-beta peptide (Abeta) is a causative factor for the cognitive impairments of AD, developing a mechanistic understanding of the contribution of Abeta to cognitive impairments may yield important insights into the pathophysiology of AD. In the present study, we simultaneously recorded spikes and LFPs from multiple electrodes implanted in the prefrontal cortex of rats (control and intra-hippocampal Abeta injection group) that performed a Y-maze working memory task. The information changes in spikes and LFPs during the task were assessed by calculation of entropy. Then the coordination between spikes and LFPs was estimated by the correlation of LFP entropy and spike entropy. Compared with the control group, the Abeta group showed significantly weaker coordination between spikes and LFPs. Our results indicate that the incoordination between spikes and LFPs may provide a potential mechanism for the cognitive deficits in working memory of AD. PMID- 25505873 TI - Neurogenesis in the embryonic and adult brain: same regulators, different roles. AB - Neurogenesis persists in adult mammals in specific brain areas, known as neurogenic niches. Adult neurogenesis is highly dynamic and is modulated by multiple physiological stimuli and pathological states. There is a strong interest in understanding how this process is regulated, particularly since active neuronal production has been demonstrated in both the hippocampus and the subventricular zone (SVZ) of adult humans. The molecular mechanisms that control neurogenesis have been extensively studied during embryonic development. Therefore, we have a broad knowledge of the intrinsic factors and extracellular signaling pathways driving proliferation and differentiation of embryonic neural precursors. Many of these factors also play important roles during adult neurogenesis, but essential differences exist in the biological responses of neural precursors in the embryonic and adult contexts. Because adult neural stem cells (NSCs) are normally found in a quiescent state, regulatory pathways can affect adult neurogenesis in ways that have no clear counterpart during embryogenesis. BMP signaling, for instance, regulates NSC behavior both during embryonic and adult neurogenesis. However, this pathway maintains stem cell proliferation in the embryo, while it promotes quiescence to prevent stem cell exhaustion in the adult brain. In this review, we will compare and contrast the functions of transcription factors (TFs) and other regulatory molecules in the embryonic brain and in adult neurogenic regions of the adult brain in the mouse, with a special focus on the hippocampal niche and on the regulation of the balance between quiescence and activation of adult NSCs in this region. PMID- 25505878 TI - Fast mental states decoding in mixed reality. AB - The combination of Brain-Computer Interface (BCI) technology, allowing online monitoring and decoding of brain activity, with virtual and mixed reality (MR) systems may help to shape and guide implicit and explicit learning using ecological scenarios. Real-time information of ongoing brain states acquired through BCI might be exploited for controlling data presentation in virtual environments. Brain states discrimination during mixed reality experience is thus critical for adapting specific data features to contingent brain activity. In this study we recorded electroencephalographic (EEG) data while participants experienced MR scenarios implemented through the eXperience Induction Machine (XIM). The XIM is a novel framework modeling the integration of a sensing system that evaluates and measures physiological and psychological states with a number of actuators and effectors that coherently reacts to the user's actions. We then assessed continuous EEG-based discrimination of spatial navigation, reading and calculation performed in MR, using linear discriminant analysis (LDA) and support vector machine (SVM) classifiers. Dynamic single trial classification showed high accuracy of LDA and SVM classifiers in detecting multiple brain states as well as in differentiating between high and low mental workload, using a 5 s time-window shifting every 200 ms. Our results indicate overall better performance of LDA with respect to SVM and suggest applicability of our approach in a BCI-controlled MR scenario. Ultimately, successful prediction of brain states might be used to drive adaptation of data representation in order to boost information processing in MR. PMID- 25505879 TI - Auditory-motor entrainment and phonological skills: precise auditory timing hypothesis (PATH). AB - Phonological skills are enhanced by music training, but the mechanisms enabling this cross-domain enhancement remain unknown. To explain this cross-domain transfer, we propose a precise auditory timing hypothesis (PATH) whereby entrainment practice is the core mechanism underlying enhanced phonological abilities in musicians. Both rhythmic synchronization and language skills such as consonant discrimination, detection of word and phrase boundaries, and conversational turn-taking rely on the perception of extremely fine-grained timing details in sound. Auditory-motor timing is an acoustic feature which meets all five of the pre-conditions necessary for cross-domain enhancement to occur (Patel, 2011, 2012, 2014). There is overlap between the neural networks that process timing in the context of both music and language. Entrainment to music demands more precise timing sensitivity than does language processing. Moreover, auditory-motor timing integration captures the emotion of the trainee, is repeatedly practiced, and demands focused attention. The PATH predicts that musical training emphasizing entrainment will be particularly effective in enhancing phonological skills. PMID- 25505880 TI - Combined action observation and imagery facilitates corticospinal excitability. AB - Observation and imagery of movement both activate similar brain regions to those involved in movement execution. As such, both are recommended as techniques for aiding the recovery of motor function following stroke. Traditionally, action observation and movement imagery (MI) have been considered as independent intervention techniques. Researchers have however begun to consider the possibility of combining the two techniques into a single intervention strategy. This study investigated the effect of combined action observation and MI on corticospinal excitability, in comparison to either observation or imagery alone. Single-pulse transcranial magnetic stimulation (TMS) was delivered to the hand representation of the left motor cortex during combined action observation and MI, passive observation (PO), or MI of right index finger abduction-adduction movements or control conditions. Motor evoked potentials (MEPs) were recorded from the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles of the right hand. The combined action observation and MI condition produced MEPs of larger amplitude than were obtained during PO and control conditions. This effect was only present in the FDI muscle, indicating the facilitation of corticospinal excitability during the combined condition was specific to the muscles involved in the observed/imagined task. These findings have implications for stroke rehabilitation, where combined action observation and MI interventions may prove to be more effective than observation or imagery alone. PMID- 25505881 TI - A Comparative Analysis of Speed Profile Models for Ankle Pointing Movements: Evidence that Lower and Upper Extremity Discrete Movements are Controlled by a Single Invariant Strategy. AB - Little is known about whether our knowledge of how the central nervous system controls the upper extremities (UE), can generalize, and to what extent to the lower limbs. Our continuous efforts to design the ideal adaptive robotic therapy for the lower limbs of stroke patients and children with cerebral palsy highlighted the importance of analyzing and modeling the kinematics of the lower limbs, in general, and those of the ankle joints, in particular. We recruited 15 young healthy adults that performed in total 1,386 visually evoked, visually guided, and target-directed discrete pointing movements with their ankle in dorsal-plantar and inversion-eversion directions. Using a non-linear, least squares error-minimization procedure, we estimated the parameters for 19 models, which were initially designed to capture the dynamics of upper limb movements of various complexity. We validated our models based on their ability to reconstruct the experimental data. Our results suggest a remarkable similarity between the top-performing models that described the speed profiles of ankle pointing movements and the ones previously found for the UE both during arm reaching and wrist pointing movements. Among the top performers were the support-bounded lognormal and the beta models that have a neurophysiological basis and have been successfully used in upper extremity studies with normal subjects and patients. Our findings suggest that the same model can be applied to different "human" hardware, perhaps revealing a key invariant in human motor control. These findings have a great potential to enhance our rehabilitation efforts in any population with lower extremity deficits by, for example, assessing the level of motor impairment and improvement as well as informing the design of control algorithms for therapeutic ankle robots. PMID- 25505882 TI - Coordinated reset stimulation in a large-scale model of the STN-GPe circuit. AB - Synchronization of populations of neurons is a hallmark of several brain diseases. Coordinated reset (CR) stimulation is a model-based stimulation technique which specifically counteracts abnormal synchrony by desynchronization. Electrical CR stimulation, e.g., for the treatment of Parkinson's disease (PD), is administered via depth electrodes. In order to get a deeper understanding of this technique, we extended the top-down approach of previous studies and constructed a large-scale computational model of the respective brain areas. Furthermore, we took into account the spatial anatomical properties of the simulated brain structures and incorporated a detailed numerical representation of 2 . 10(4) simulated neurons. We simulated the subthalamic nucleus (STN) and the globus pallidus externus (GPe). Connections within the STN were governed by spike-timing dependent plasticity (STDP). In this way, we modeled the physiological and pathological activity of the considered brain structures. In particular, we investigated how plasticity could be exploited and how the model could be shifted from strongly synchronized (pathological) activity to strongly desynchronized (healthy) activity of the neuronal populations via CR stimulation of the STN neurons. Furthermore, we investigated the impact of specific stimulation parameters especially the electrode position on the stimulation outcome. Our model provides a step forward toward a biophysically realistic model of the brain areas relevant to the emergence of pathological neuronal activity in PD. Furthermore, our model constitutes a test bench for the optimization of both stimulation parameters and novel electrode geometries for efficient CR stimulation. PMID- 25505883 TI - In vivo magnetic resonance imaging of the human limbic white matter. AB - The limbic system mediates memory, behavior, and emotional output in the human brain, and is implicated in the pathology of Alzheimer's disease and a wide spectrum of related neurological disorders. In vivo magnetic resonance imaging (MRI) of structural components comprising the limbic system and their interconnections via white matter pathways in the human brain has helped define current understanding of the limbic model based on the classical circuit proposed by Papez. MRI techniques, including diffusion MR imaging, provide a non-invasive method to characterize white matter tracts of the limbic system, and investigate pathological changes that affect these pathways in clinical settings. This review focuses on delineation of the anatomy of major limbic tracts in the human brain, namely, the cingulum, the fornix and fimbria, and the stria terminalis, based on in vivo MRI contrasts. The detailed morphology and intricate trajectories of these pathways that can be identified using relaxometry-based and diffusion weighted MRI provide an important anatomical reference for evaluation of clinical disorders commonly associated with limbic pathology. PMID- 25505884 TI - The neuron-astrocyte-microglia triad in a rat model of chronic cerebral hypoperfusion: protective effect of dipyridamole. AB - Chronic cerebral hypoperfusion during aging may cause progressive neurodegeneration as ischemic conditions persist. Proper functioning of the interplay between neurons and glia is fundamental for the functional organization of the brain. The aim of our research was to study the pathophysiological mechanisms, and particularly the derangement of the interplay between neurons and astrocytes-microglia with the formation of "triads," in a model of chronic cerebral hypoperfusion induced by the two-vessel occlusion (2VO) in adult Wistar rats (n = 15). The protective effect of dipyridamole given during the early phases after 2VO (4 mg/kg/day i.v., the first 7 days after 2VO) was verified (n = 15). Sham-operated rats (n = 15) were used as controls. Immunofluorescent triple staining of neurons (NeuN), astrocytes (GFAP), and microglia (IBA1) was performed 90 days after 2VO. We found significantly higher amount of "ectopic" neurons, neuronal debris and apoptotic neurons in CA1 Str. Radiatum and Str. Pyramidale of 2VO rats. In CA1 Str. Radiatum of 2VO rats the amount of astrocytes (cells/mm(2)) did not increase. In some instances several astrocytes surrounded ectopic neurons and formed a "micro scar" around them. Astrocyte branches could infiltrate the cell body of ectopic neurons, and, together with activated microglia cells formed the "triads." In the triad, significantly more numerous in CA1 Str. Radiatum of 2VO than in sham rats, astrocytes and microglia cooperated in the phagocytosis of ectopic neurons. These events might be common mechanisms underlying many neurodegenerative processes. The frequency to which they appear might depend upon, or might be the cause of, the burden and severity of neurodegeneration. Dypiridamole significantly reverted all the above described events. The protective effect of chronic administration of dipyridamole might be a consequence of its vasodilatory, antioxidant and anti-inflammatory role during the early phases after 2VO. PMID- 25505886 TI - Glutathione revisited: a better scavenger than previously thought. AB - Glutathione (GSH) is the classical example of a scavenging antioxidant. It forms the first line of defense and efficiently scavenges reactive species, e.g., hypochlorous acid (HOCl), before they inflict damage to biomolecules. Scavenging antioxidant activity is best established in competition assays (that closely mimics molecular mechanism of the biological effect). In this type of assay, the antioxidant competes with a molecule that functions as an easy read-out detector for a reactive species. It is generally assumed that the scavenging antioxidant activity reflects the reaction rate constant of the antioxidant with the reactive species (ka). However, critical appraisal of several competition assays of GSH with HOCl as reactive species, reveals that ka does not determine the scavenging antioxidant activity. Assays using acetylcholine esterase, alpha1-antiprotease, methionine, and albumin as detector are compared. The total number of molecules of the reactive species scavenged by GSH plus that by partially oxidized forms of the GSH, reflect the scavenging activity of GSH. The contribution of the partially oxidized forms of GSH depends on the reactivity of the competing molecule. In several assays the partially oxidized forms of GSH have a substantial contribution to the scavenging activity of GSH. In contrast to the prevailing perception, not the reaction rate but rather the total number of molecules of the reactive species scavenged reflects the true scavenging activity of an antioxidant like GSH. PMID- 25505885 TI - Improving the safety of cell therapy products by suicide gene transfer. AB - Adoptive T-cell therapy can involve donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation, the administration of tumor infiltrating lymphocyte expanded ex-vivo, or more recently the use of T cell receptor or chimeric antigen receptor redirected T cells. However, cellular therapies can pose significant risks, including graft-vs.-host-disease and other on and off target effects, and therefore strategies need to be implemented to permanently reverse any sign of toxicity. A suicide gene is a genetically encoded molecule that allows selective destruction of adoptively transferred cells. Suicide gene addition to cellular therapeutic products can lead to selective ablation of gene modified cells, preventing collateral damage to contiguous cells and/or tissues. The "ideal" suicide gene would ensure the safety of gene modified cellular applications by granting irreversible elimination of "all" and "only" the cells responsible for the unwanted toxicity. This review presents the suicide gene safety systems reported to date, with a focus on the state-of-the-art and potential applications regarding two of the most extensively validated suicide genes, including the clinical setting: herpes-simplex-thymidine-kinase and inducible-caspase-9. PMID- 25505887 TI - Pharmacokinetic non-interaction analysis in a fixed-dose formulation in combination of atorvastatin and ezetimibe. AB - Recent clinical research has shown that atorvastatin (ATO) in combination with cholesterol absorption inhibitor ezetimibe (EZE) significantly reduces LDL-C level in patients with hypercholesterolemia, showing a superior lipid-lowering efficacy compared to statin alone. With no information currently available on the interaction between the two drugs, a pharmacokinetic study was conducted to investigate the influence of EZE on ATO and conversely when the two drugs were coadministered. The purpose of this study was to investigate the presence of differences in the pharmacokinetic profiles of capsules containing ATO 80 mg, EZE 10 mg or the combination of both 80/10 mg administered to healthy Mexican volunteers. This was a randomized, three-period, six-sequences crossover study. 36 eligible subjects aged between 20 to 50 years were included. Blood samples were collected up to 96 h after dosing, and pharmacokinetic parameters were obtained by non-compartmental analysis. Adverse events were evaluated based on subject interviews and physical examinations. Area under the concentration-time curve (AUC) and maximum plasma drug concentration (Cmax) were measured for each drug alone or together and tested for bioequivalence-based hypothesis. The estimation computed (90% confidence intervals) for AUC and Cmax, were 96.04% (85.88-107.42%) and 97.04% (82.36-114.35%), respectively for ATO-EZE combination versus ATO alone, while 84.42% (77.19-92.32%) and 95.60% (82.43-110.88%), respectively, for ATO-EZE combination versus EZE alone were estimated. These results suggest that ATO and EZE have no relevant pharmacokinetic drug-drug interaction. PMID- 25505889 TI - Toward an expansion of an enactive ethics with the help of care ethics. PMID- 25505888 TI - Molecular mechanism of the intramembrane cleavage of the beta-carboxyl terminal fragment of amyloid precursor protein by gamma-secretase. AB - Amyloid beta-protein (Abeta) plays a central role in the pathogenesis of Alzheimer's disease, the most common age-associated neurodegenerative disorder. Abeta is generated through intramembrane proteolysis of the beta-carboxyl terminal fragment (betaCTF) of beta-amyloid precursor protein (APP) by gamma secretase. The initial cleavage by gamma-secretase occurs in the membrane/cytoplasm boundary of the betaCTF, liberating the APP intracellular domain (AICD). The remaining betaCTFs, which are truncated at the C-terminus (longer Abetas), are then cropped sequentially in a stepwise manner, predominantly at three residue intervals, to generate Abeta. There are two major Abeta product lines which generate Abeta40 and Abeta42 with concomitant release of three and two tripeptides, respectively. Additionally, many alternative cleavages occur, releasing peptides with three to six residues. These modulate the Abeta product lines and define the species and quantity of Abeta generated. Here, we review our current understanding of the intramembrane cleavage of the betaCTF by gamma-secretase, which may contribute to the future goal of developing an efficient therapeutic strategy for Alzheimer's disease. PMID- 25505890 TI - The effects of positive versus negative impact reflection on change in job performance and work-life conflict. AB - Research on task significance and relational job design suggests that information from beneficiaries of one's work fosters perceptions of impact, and thus improved work outcomes. This paper presents results from a longitudinal field experiment examining the effect of another strategy for fostering perceptions of impact - engaging employees in regular reflection about how their work benefits others. With a sample of professionals from multiple organizations, this longitudinal study examined the effect on job performance and work-life conflict of both positive and negative impact reflection. Results show that negative impact reflection had a pronounced negative effect on job performance, but no effect on work-life conflict. Positive impact reflection had a weak positive effect on work life conflict, but no significant effect on job performance. The direction of effects seen in the no intervention condition mirrored that of the negative impact reflection condition, suggesting a possible buffering effect for positive impact reflection. This research provides empirical and theoretical contributions to the literatures on relational job design and task significance. PMID- 25505891 TI - Color-discrimination threshold determination using pseudoisochromatic test plates. AB - We produced a set of pseudoisochromatic plates for determining individual color difference thresholds to assess test performance and test properties, and analyzed the results. We report a high test validity and classification ability for the deficiency type and severity level [comparable to that of the fourth edition of the Hardy-Rand-Rittler (HRR) test]. We discuss changes of the acceptable chromatic shifts from the protan and deutan confusion lines along the CIE xy diagram, and the high correlation of individual color-difference thresholds and the red-green discrimination index. Color vision was tested using an Oculus HMC anomaloscope, a Farnsworth D15, and an HRR test on 273 schoolchildren, and 57 other subjects with previously diagnosed red-green color vision deficiency. PMID- 25505892 TI - Automatic attraction of visual attention by supraletter features of former target strings. AB - Observers were trained to search for a particular horizontal string of three capital letters presented among similar strings consisting of exactly the same letters in different orders. The training was followed by a test in which the observers searched for a new target that was identical to one of the former distractors. The new distractor set consisted of the remaining former distractors plus the former target. On each trial, three letter strings were displayed, which included the target string with a probability of 0.5. In Experiment 1, the strings were centered at different locations on the circumference of an imaginary circle around the fixation point. The training phase of Experiment 2 was similar, but in the test phase of the experiment, the strings were located in a vertical array centered on fixation, and in target-present arrays, the target always appeared at fixation. In both experiments, performance (d') degraded on trials in which former targets were present, suggesting that the former targets automatically drew processing resources away from the current targets. Apparently, the two experiments showed automatic attraction of visual attention by supraletter features of former target strings. PMID- 25505893 TI - Major depressive disorder with melancholia displays robust alterations in resting state heart rate and its variability: implications for future morbidity and mortality. AB - BACKGROUND: Major depressive disorder (MDD) is associated with increased heart rate and reductions in its variability (heart rate variability, HRV) - markers of future morbidity and mortality - yet prior studies have reported contradictory effects. We hypothesized that increases in heart rate and reductions in HRV would be more robust in melancholia relative to controls, than in patients with non melancholia. METHODS: A total of 72 patients with a primary diagnosis of MDD (age M: 36.26, SE: 1.34; 42 females) and 94 controls (age M: 35.69, SE: 1.16; 52 females) were included in this study. Heart rate and measures of its variability (HRV) were calculated from two 2-min electrocardiogram recordings during resting state. Propensity score matching controlled imbalance on potential confounds between patients with melancholia (n = 40) and non-melancholia (n = 32) including age, gender, disorder severity, and comorbid anxiety disorders. RESULTS: MDD patients with melancholia displayed significantly increased heart rate and lower resting-state HRV (including the square root of the mean squared differences between successive N-N intervals, the absolute power of high frequency and standard deviation of the Poincare plot perpendicular to the line of identity measures of HRV) relative to controls, findings associated with a moderate effect size (Cohens d's = 0.56-0.58). Patients with melancholia also displayed an increased heart rate relative to those with non-melancholia (Cohen's d = 0.20). CONCLUSION: MDD patients with melancholia - but not non-melancholia - display robust increases in heart rate and decreases in HRV. These findings may underpin a variety of behavioral impairments in patients with melancholia including somatic symptoms, cognitive impairment, reduced responsiveness to the environment, and over the longer-term, morbidity and mortality. PMID- 25505895 TI - Corrigendum: sexual dimorphism in the effects of exercise on metabolism of lipids to support resting metabolism. PMID- 25505894 TI - Localization of interictal epileptiform activity using magnetoencephalography with synthetic aperture magnetometry in patients with a vagus nerve stimulator. AB - Magnetoencephalography (MEG) provides useful and non-redundant information in the evaluation of patients with epilepsy, and in particular, during the pre-surgical evaluation of pharmaco-resistant epilepsy. Vagus nerve stimulation (VNS) is a common treatment for pharmaco-resistant epilepsy. However, interpretation of MEG recordings from patients with a VNS is challenging due to the severe magnetic artifacts produced by the VNS. We used synthetic aperture magnetometry (g2) [SAM(g2)], an adaptive beamformer that maps the excessive kurtosis, to map interictal spikes to the coregistered MRI image, despite the presence of contaminating VNS artifact. We present a series of eight patients with a VNS who underwent MEG recording. Localization of interictal epileptiform activity by SAM(g2) is compared to invasive electrophysiologic monitoring and other localizing approaches. While the raw MEG recordings were uninterpretable, analysis of the recordings with SAM(g2) identified foci of peak kurtosis and source signal activity that was unaffected by the VNS artifact. SAM(g2) analysis of MEG recordings in patients with a VNS produces interpretable results and expands the use of MEG for the pre-surgical evaluation of epilepsy. PMID- 25505896 TI - Genomic analyses of bacterial porin-cytochrome gene clusters. AB - The porin-cytochrome (Pcc) protein complex is responsible for trans-outer membrane electron transfer during extracellular reduction of Fe(III) by the dissimilatory metal-reducing bacterium Geobacter sulfurreducens PCA. The identified and characterized Pcc complex of G. sulfurreducens PCA consists of a porin-like outer-membrane protein, a periplasmic 8-heme c-type cytochrome (c-Cyt) and an outer-membrane 12-heme c-Cyt, and the genes encoding the Pcc proteins are clustered in the same regions of genome (i.e., the pcc gene clusters) of G. sulfurreducens PCA. A survey of additionally microbial genomes has identified the pcc gene clusters in all sequenced Geobacter spp. and other bacteria from six different phyla, including Anaeromyxobacter dehalogenans 2CP-1, A. dehalogenans 2CP-C, Anaeromyxobacter sp. K, Candidatus Kuenenia stuttgartiensis, Denitrovibrio acetiphilus DSM 12809, Desulfurispirillum indicum S5, Desulfurivibrio alkaliphilus AHT2, Desulfurobacterium thermolithotrophum DSM 11699, Desulfuromonas acetoxidans DSM 684, Ignavibacterium album JCM 16511, and Thermovibrio ammonificans HB-1. The numbers of genes in the pcc gene clusters vary, ranging from two to nine. Similar to the metal-reducing (Mtr) gene clusters of other Fe(III)-reducing bacteria, such as Shewanella spp., additional genes that encode putative c-Cyts with predicted cellular localizations at the cytoplasmic membrane, periplasm and outer membrane often associate with the pcc gene clusters. This suggests that the Pcc-associated c-Cyts may be part of the pathways for extracellular electron transfer reactions. The presence of pcc gene clusters in the microorganisms that do not reduce solid-phase Fe(III) and Mn(IV) oxides, such as D. alkaliphilus AHT2 and I. album JCM 16511, also suggests that some of the pcc gene clusters may be involved in extracellular electron transfer reactions with the substrates other than Fe(III) and Mn(IV) oxides. PMID- 25505897 TI - Purinergic and calcium signaling in macrophage function and plasticity. AB - In addition to a fundamental role in cellular bioenergetics, the purine nucleotide adenosine triphosphate (ATP) plays a crucial role in the extracellular space as a signaling molecule. ATP and its metabolites serve as ligands for a family of receptors that are collectively referred to as purinergic receptors. These receptors were first described and characterized in the nervous system but it soon became evident that they are expressed ubiquitously. In the immune system, purinergic signals regulate the migration and activation of immune cells and they may also orchestrate the resolution of inflammation (1, 2). The intracellular signal transduction initiated by purinergic receptors is strongly coupled to Ca(2+)-signaling, and co-ordination of these pathways plays a critical role in innate immunity. In this review, we provide an overview of purinergic and Ca(2+)-signaling in the context of macrophage phenotypic polarization and discuss the implications on macrophage function in physiological and pathological conditions. PMID- 25505898 TI - Exploring preterm birth as a polymicrobial disease: an overview of the uterine microbiome. AB - Infection is a leading cause of preterm birth (PTB). A focus of many studies over the past decade has been to characterize microorganisms present in the uterine cavity and document any association with negative pregnancy outcome. A range of techniques have been used to achieve this, including microbiological culture and targeted polymerase chain reaction assays, and more recently, microbiome-level analyses involving either conserved, phylogenetically informative genes such as the bacterial 16S rRNA gene or whole shotgun metagenomic sequencing. These studies have contributed vast amounts of data toward characterization of the uterine microbiome, specifically that present in the amniotic fluid, fetal membranes, and placenta. However, an overwhelming emphasis has been placed on the bacterial microbiome, with far less data produced on the viral and fungal/yeast microbiomes. With numerous studies now referring to PTB as a polymicrobial condition, there is the need to investigate the role of viruses and fungi/yeasts in more detail and in particular, look for associations between colonization with these microorganisms and bacteria in the same samples. Although the major pathway by which microorganisms are believed to colonize the uterine cavity is vertical ascension from the vagina, numerous studies are now emerging suggesting hematogenous transfer of oral microbiota to the uterine cavity. Evidence of this has been produced in mouse models and although DNA-based evidence in humans appears convincing in some aspects, use of methodologies that only detect viable cells as opposed to lysed cells and extracellular DNA are needed to clarify this. Such techniques as RNA analyses and viability polymerase chain reaction are likely to play key roles in the clinical translation of future microbiome-based data, particularly in confined environments such as the uterus, as detection of viable cells plays a key role in diagnosis and treatment of infection. PMID- 25505899 TI - Human leukocyte antigen typing using a knowledge base coupled with a high throughput oligonucleotide probe array analysis. AB - Human leukocyte antigens (HLA) are important biomarkers because multiple diseases, drug toxicity, and vaccine responses reveal strong HLA associations. Current clinical HLA typing is an elimination process requiring serial testing. We present an alternative in situ synthesized DNA-based microarray method that contains hundreds of thousands of probes representing a complete overlapping set covering 1,610 clinically relevant HLA class I alleles accompanied by computational tools for assigning HLA type to 4-digit resolution. Our proof-of concept experiment included 21 blood samples, 18 cell lines, and multiple controls. The method is accurate, robust, and amenable to automation. Typing errors were restricted to homozygous samples or those with very closely related alleles from the same locus, but readily resolved by targeted DNA sequencing validation of flagged samples. High-throughput HLA typing technologies that are effective, yet inexpensive, can be used to analyze the world's populations, benefiting both global public health and personalized health care. PMID- 25505900 TI - The Role of microRNAs in Bovine Infection and Immunity. AB - MicroRNAs (miRNAs) are a class of small, non-coding RNAs that are recognized as critical regulators of immune gene expression during infection. Many immunologically significant human miRNAs have been found to be conserved in agriculturally important species, including cattle. Discovering how bovine miRNAs mediate the immune defense during infection is critical to understanding the etiology of the most prevalent bovine diseases. Here, we review current knowledge of miRNAs in the bovine genome, and discuss the advances in understanding of miRNAs as regulators of immune cell function, and bovine immune response activation, regulation, and resolution. Finally, we consider the future perspectives on miRNAs in bovine viral disease, their role as potential biomarkers and in therapy. PMID- 25505901 TI - Interpreting sperm DNA damage in a diverse range of mammalian sperm by means of the two-tailed comet assay. AB - Key ConceptsThe two-dimensional Two-Tailed Comet assay (TT-comet) protocol is a valuable technique to differentiate between single-stranded (SSBs) and double stranded DNA breaks (DSBs) on the same sperm cell.Protein lysis inherent with the TT-comet protocol accounts for differences in sperm protamine composition at a species-specific level to produce reliable visualization of sperm DNA damage.Alkaline treatment may break the sugar-phosphate backbone in abasic sites or at sites with deoxyribose damage, transforming these lesions into DNA breaks that are also converted into ssDNA. These lesions are known as Alkali Labile Sites "ALSs."DBD-FISH permits the in situ visualization of DNA breaks, abasic sites or alkaline-sensitive DNA regions.The alkaline comet single assay reveals that all mammalian species display constitutive ALS related with the requirement of the sperm to undergo transient changes in DNA structure linked with chromatin packing.Sperm DNA damage is associated with fertilization failure, impaired pre and post- embryo implantation and poor pregnancy outcome.The TT is a valuable tool for identifying SSBs or DSBs in sperm cells with DNA fragmentation and can be therefore used for the purposes of fertility assessment. Sperm DNA damage is associated with fertilization failure, impaired pre-and post- embryo implantation and poor pregnancy outcome. A series of methodologies to assess DNA damage in spermatozoa have been developed but most are unable to differentiate between single-stranded DNA breaks (SSBs) and double-stranded DNA breaks (DSBs) on the same sperm cell. The two-dimensional Two-Tailed Comet assay (TT-comet) protocol highlighted in this review overcomes this limitation and emphasizes the importance in accounting for the difference in sperm protamine composition at a species-specific level for the appropriate preparation of the assay. The TT-comet is a modification of the original comet assay that uses a two dimensional electrophoresis to allow for the simultaneous evaluation of DSBs and SSBs in mammalian spermatozoa. Here we have compiled a retrospective overview of how the TT-comet assay has been used to investigate the structure and function of sperm DNA across a diverse range of mammalian species (eutheria, metatheria, and prototheria). When conducted as part of the TT-comet assay, we illustrate (a) how the alkaline comet single assay has been used to help understand the constitutive and transient changes in DNA structure associated with chromatin packing, (b) the capacity of the TT-comet to differentiate between the presence of SSBs and DSBs (c) and the possible implications of SSBs or DSBs for the assessment of infertility. PMID- 25505903 TI - A Comparative Study of Contemporary Color Tongue Image Extraction Methods Based on HSI. AB - Tongue image with coating is of important clinical diagnostic meaning, but traditional tongue image extraction method is not competent for extraction of tongue image with thick coating. In this paper, a novel method is suggested, which applies multiobjective greedy rules and makes fusion of color and space information in order to extract tongue image accurately. A comparative study of several contemporary tongue image extraction methods is also made from the aspects of accuracy and efficiency. As the experimental results show, geodesic active contour is quite slow and not accurate, the other 3 methods achieve fairly good segmentation results except in the case of the tongue with thick coating, our method achieves ideal segmentation results whatever types of tongue images are, and efficiency of our method is acceptable for the application of quantitative check of tongue image. PMID- 25505902 TI - From early lessons to new frontiers: the worm as a treasure trove of small RNA biology. AB - In the past 20 years, the tiny soil nematode Caenorhabditis elegans has provided critical insights into our understanding of the breadth of small RNA-mediated gene regulatory activities. The first microRNA was identified in C. elegans in 1993, and the understanding that dsRNA was the driving force behind RNA-mediated gene silencing came from experiments performed in C. elegans in 1998. Likewise, early genetic screens in C. elegans for factors involved in RNA interference pointed to conserved mechanisms for small RNA-mediated gene silencing pathways, placing the worm squarely among the founding fathers of a now extensive field of molecular biology. Today, the worm continues to be at the forefront of ground breaking insight into small RNA-mediated biology. Recent studies have revealed with increasing mechanistic clarity that C. elegans possesses an extensive nuclear small RNA regulatory network that encompasses not only gene silencing but also gene activating roles. Further, a portrait is emerging whereby small RNA pathways play key roles in integrating responses to environmental stimuli and transmitting epigenetic information about such responses from one generation to the next. Here we discuss endogenous small RNA pathways in C. elegans and the insight worm biology has provided into the mechanisms employed by these pathways. We touch on the increasingly spectacular diversity of small RNA biogenesis and function, and discuss the relevance of lessons learned in the worm for human biology. PMID- 25505904 TI - Factors Influencing Cecal Intubation Time during Retrograde Approach Single Balloon Enteroscopy. AB - Background and Aim. The predisposing factors for prolonged cecal intubation time (CIT) during colonoscopy have been well identified. However, the factors influencing CIT during retrograde SBE have not been addressed. The aim of this study was to determine the factors influencing CIT during retrograde SBE. Methods. We investigated patients who underwent retrograde SBE at a medical center from January 2011 to March 2014. The medical charts and SBE reports were reviewed. The patients' characteristics and procedure-associated data were recorded. These data were analyzed with univariate analysis as well as multivariate logistic regression analysis to identify the possible predisposing factors. Results. We enrolled 66 patients into this study. The median CIT was 17.4 minutes. With univariate analysis, there was no statistical difference in age, sex, BMI, or history of abdominal surgery, except for bowel preparation (P = 0.021). Multivariate logistic regression analysis showed that inadequate bowel preparation (odds ratio 30.2, 95% confidence interval 4.63-196.54; P < 0.001) was the independent predisposing factors for prolonged CIT during retrograde SBE. Conclusions. For experienced endoscopist, inadequate bowel preparation was the independent predisposing factor for prolonged CIT during retrograde SBE. PMID- 25505906 TI - Health-related quality of life of rural clients seeking telepsychology services. AB - Sixty million US residents live in rural areas, but health policies and interventions developed from an urban mindset often fail to address the significant barriers to health experienced by these local communities. Telepsychology, or psychological services delivered by distance via technology, is an emerging treatment modality with special implications for underserved rural areas. This study found that a sample of rural residents seeking telepsychology services (n = 94) had low health-related quality of life (HRQOL), often due to cooccurring physical and mental health diagnoses including high rates of depression. However, a brief telepsychology treatment delivered to rural clients (n = 40) was associated with an improvement in mental health-related quality of life (d = 0.70, P < .001). These results indicate that despite the complex health needs of these underserved communities, telepsychology interventions may help offset the disparities in health service access in rural areas. PMID- 25505905 TI - Liver fibrosis and protection mechanisms action of medicinal plants targeting apoptosis of hepatocytes and hepatic stellate cells. AB - Following chronic liver injury, hepatocytes undergo apoptosis leading to activation of hepatic stellate cells (HSC). Consequently, activated HSC proliferate and produce excessive extracellular matrix, responsible for the scar formation. The pandemic trend of obesity, combined with the high incidence of alcohol intake and viral hepatitis infections, highlights the urgent need to find accessible antifibrotic therapies. Treatment strategies should take into account the versatility of its pathogenesis and act on all the cell lines involved to reduce liver fibrosis. Medicinal plants are achieving popularity as antifibrotic agents, supported by their safety, cost-effectiveness, and versatility. This review will describe the role of hepatocytes and HSC in the pathogenesis of liver fibrosis and detail the mechanisms of modulation of apoptosis of both cell lines by twelve known hepatoprotective plants in order to reduce liver fibrosis. PMID- 25505907 TI - Conditioned Medium Reconditions Hippocampal Neurons against Kainic Acid Induced Excitotoxicity: An In Vitro Study. AB - Stem cell therapy is gaining attention as a promising treatment option for neurodegenerative diseases. The functional efficacy of grafted cells is a matter of debate and the recent consensus is that the cellular and functional recoveries might be due to "by-stander" effects of grafted cells. In the present study, we investigated the neuroprotective effect of conditioned medium (CM) derived from human embryonic kidney (HEK) cells in a kainic acid (KA) induced hippocampal degeneration model system in in vitro condition. Hippocampal cell line was exposed to KA (200 uM) for 24 hrs (lesion group) whereas, in the treatment group, hippocampal cell line was exposed to KA in combination with HEK-CM (KA + HEK-CM). We observed that KA exposure to cells resulted in significant neuronal loss. Interestingly, HEK-CM cotreatment completely attenuated the excitotoxic effects of KA. In HEK-CM cotreatment group, the cell viability was ~85-95% as opposed to 47% in KA alone group. Further investigation demonstrated that treatment with HEK CM stimulated the endogenous cell survival factors like brain derived neurotrophic factors (BDNF) and antiapoptotic factor Bcl-2, revealing the possible mechanism of neuroprotection. Our results suggest that HEK-CM protects hippocampal neurons against excitotoxicity by stimulating the host's endogenous cell survival mechanisms. PMID- 25505908 TI - Ameliorating Effects of Iron and Zinc on Vigna mungo L. Treated with Tannery Effluent. AB - Different dilutions, that is, 25, 50, 75, and 100%, of tannery effluent (TE) were chosen for the present study to assess the phytotoxic effects on Vigna mungo L. For amelioration purposes, different levels and combinations of iron and zinc were supplied to the plants along with 50% TE that is chosen on the basis of prior test under Petri dish culture. Cytotoxic and biochemical analysis and plant tolerance index (PTI) of plant were observed. Mitotic index deceased with increase in effluent concentration whereas abnormality % was increased. The pigments (chlorophyll a, total, and carotenoids) were decreased with increasing treatment levels of TE at both growth stages. However, carotenoid content increased significantly at all dilution levels of TE after first growth stage. Chlorophyll b was increased significantly after 35 days of growth but decreased after 70 days. The protein contents were also significantly decreased with increase in all TE treatments and increased significantly in zinc recovery treatments. Activities of catalase and peroxidase enzymes were significantly affected and increased significantly with effluent treatments. PTI showed an enhanced tolerance capacity of plant with treatment of iron and zinc. A negative correlation was found (r = -0.97) between plant height and different dilutions of effluent whereas it was positively correlated (r = 0.95) with iron and zinc treatments. The study represents the ameliorative effect of iron and zinc for phytotoxic damage in V. mungo caused by tannery effluent. PMID- 25505909 TI - Ovarian and adrenal androgens and their link to high human chorionic gonadotropin levels: a prospective controlled study. AB - Background. Although the association between human chorionic gonadotropin (hCG) and hyperandrogenism was identified more than 40 years ago, relevant questions remain unanswered. Design and Methods. We conducted a prospective, longitudinal, and controlled study in 23 women with a diagnosis of a complete hydatidiform mole (HM). Results. All participants completed the study. Before HM evacuation mean hCG was markedly higher in the cases than in the control group (P <= 0.001). Free testosterone (T) and dehydroepiandrosterone sulfate (DHEA-S) were found to be higher in the cases (2.78 +/- 1.24 pg/mL and 231.50 +/- 127.20 MU/dL) when compared to the control group (1.50 +/- 0.75 pg/mL and 133.59 +/- 60.69 MU/dL) (P = 0.0001 and 0.001), respectively. There was a strong correlation between hCG and free T/total T/DHEA-S concentrations (r = 0.78; P <= 0.001, r = 0.74; P <= 0.001, and r = 0.71; P <= 0.001), respectively. In the cases group 48 hours after HM evacuation, hCG levels were found to be significantly lower when compared to initial levels (P = 0.001) and free T and DHEA-S declined significantly (P = 0.0002 and 0.009). Conclusion. Before uterus evacuation, hCG, free T, and DHEA-S levels were significantly higher when compared with controls finding a strong correlation between hCG and free T/DHEA-S levels. Forty-eight hours after HM treatment hCG levels declined and the difference was lost. A novel finding of our study is that in cases, besides free T, DHEA-S was also found to be significantly higher and both the ovaries and adrenal glands appear to be the sites of this androgen overproduction. PMID- 25505911 TI - Coexistence of Histologically Confirmed Hashimoto's Thyroiditis with Different Stages of Papillary Thyroid Carcinoma in a Consecutive Chinese Cohort. AB - Purpose. To determine the relationship between Hashimoto's thyroiditis (HT) and all stages of papillary thyroid carcinoma (PTC) with or without local lymph node metastasis (LNM). Methods. We conducted a retrospective study of thyroidectomies from 2008-2013 in First Affiliated Hospital of Nanjing Medical University. We categorized patients according to the presence of histopathologically proven HT. The prevalence of mPTC (maximum diameter <= 10 mm) and crPTC (clinical relevant PTC) and local LNM rates were compared. Results. We evaluated 6,432 consecutive thyroidectomies. In total, 1,328 specimens were confirmed as HT. The prevalence of PTC in this HT cohort was 43.8%, significantly higher than non-HT group. After adjustment of gender and age, the prevalence of PTC was still higher in HT group. HT was a risk factor for PTC in multivariate analysis with odds ratio 2.725 (95% CI, 2.390-3.109) (P < 0.001). However, no correlation was found between HT and LNM of PTC. Conclusion. HT was associated with an increased prevalence of all stages of PTC, independent of tumor size, gender, and age. In contrast, locally advanced disease defined by LNM was unrelated to HT. These data suggest an association of HT with low risk PTC and a potential protective immunologic effect from further disease progression. PMID- 25505912 TI - Conservative approach in patients with pemphigus gingival vulgaris: a pilot study of five cases. AB - Objectives. The aim of this pilot study was to describe the clinical efficacy of a conservative oral hygiene protocol in patients affected by gingival pemphigus vulgaris (PV) applied in a case series. Methods. Subjects suffering from PV with gingival localisation and slightly responsive to conventional treatment with systemic corticosteroids and immunosuppressive drugs were selected among individuals treated in the Unit of Oral Medicine Section of the University of Turin. Five subjects received nonsurgical periodontal therapy, over a 7-day period, including oral hygiene instructions; patients were instructed about domiciliary oral hygiene maintenance and instructions were reinforced at each visit and personalised if necessary. Clinical outcome variables were recorded at baseline (before starting) and 16 weeks after intervention, including full mouth plaque score (FMPS), bleeding scores (FMBS), probing pocket depth (PPD), oral pemphigus clinical score (OPCS), and patient related outcomes (visual analogue score of pain). Results. Five patients were treated and, after finishing the proposed therapy protocol, a statistical significant reduction was observed for FMBS (P = 0.043) and OPCS (P = 0.038). Conclusions. Professional oral hygiene procedures with nonsurgical therapy are related to an improvement of gingival status and a decrease of gingival bleeding in patients affected by PV with specific gingival localization. PMID- 25505910 TI - Angiogenesis in pituitary adenomas: human studies and new mutant mouse models. AB - The role of angiogenesis in pituitary tumor development has been questioned, as pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to noninvasive and microprolactinomas. Many growth factors and their receptors are involved in pituitary tumor development. For example, VEGF, FGF-2, FGFR1, and PTTG, which give a particular vascular phenotype, are modified in human and experimental pituitary adenomas of different histotypes. In particular, vascular endothelial growth factor, VEGF, the central mediator of angiogenesis in endocrine glands, was encountered in experimental and human pituitary tumors at different levels of expression and, in particular, was higher in dopamine agonist resistant prolactinomas. Furthermore, several anti-VEGF techniques lowered tumor burden in human and experimental pituitary adenomas. Therefore, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF, making permeable pituitary endothelia, might contribute to adequate temporal vascular supply and mechanisms other than endothelial cell proliferation. The study of angiogenic factor expression in aggressive prolactinomas with resistance to dopamine agonists will yield important data in the search of therapeutical alternatives. PMID- 25505913 TI - Defining Boundaries for Ecosystem-Based Management: A Multispecies Case Study of Marine Connectivity across the Hawaiian Archipelago. AB - Determining the geographic scale at which to apply ecosystem-based management (EBM) has proven to be an obstacle for many marine conservation programs. Generalizations based on geographic proximity, taxonomy, or life history characteristics provide little predictive power in determining overall patterns of connectivity, and therefore offer little in terms of delineating boundaries for marine spatial management areas. Here, we provide a case study of 27 taxonomically and ecologically diverse species (including reef fishes, marine mammals, gastropods, echinoderms, cnidarians, crustaceans, and an elasmobranch) that reveal four concordant barriers to dispersal within the Hawaiian Archipelago which are not detected in single-species exemplar studies. We contend that this multispecies approach to determine concordant patterns of connectivity is an objective and logical way in which to define the minimum number of management units and that EBM in the Hawaiian Archipelago requires at least five spatially managed regions. PMID- 25505914 TI - Not All Larvae Stay Close to Home: Insights into Marine Population Connectivity with a Focus on the Brown Surgeonfish (Acanthurus nigrofuscus). AB - Recent reports of localized larval recruitment in predominately small-range fishes are countered by studies that show high genetic connectivity across large oceanic distances. This discrepancy may result from the different timescales over which genetic and demographic processes operate or rather may indicate regular long-distance dispersal in some species. Here, we contribute an analysis of mtDNA cytochrome b diversity in the widely distributed Brown Surgeonfish (Acanthurus nigrofuscus; N = 560), which revealed significant genetic structure only at the extremes of the range (PhiCT = 0.452; P < .001). Collections from Hawaii to the Eastern Indian Ocean comprise one large, undifferentiated population. This pattern of limited genetic subdivision across reefs of the central Indo-Pacific has been observed in a number of large-range reef fishes. Conversely, small-range fishes are often deeply structured over the same area. These findings demonstrate population connectivity differences among species at biogeographic and evolutionary timescales, which likely translates into differences in dispersal ability at ecological and demographic timescales. While interspecific differences in population connectivity complicate the design of management strategies, the integration of multiscale connectivity patterns into marine resource planning will help ensure long-term ecosystem stability by preserving functionally diverse communities. PMID- 25505915 TI - An updated systematic review and meta-analysis of the obstetric consequences of female genital mutilation/cutting. AB - In our recent systematic review in Obstetrics and Gynecology International of the association between FGM/C and obstetric harm we concluded that FGM/C significantly increases the risk of delivery complications. The findings were based on unadjusted effect estimates from both prospective and retrospective studies. To accommodate requests by critics, we aimed to validate these results through additional analyses based on adjusted estimates from prospective studies. We judged that 7 of the 28 studies included in our original systematic review were prospective. Statistical adjustments for measured confounding factors were made in eight studies, including three prospective studies. The adjusted confounders differed across studies in number and type. Results from meta analyses based on adjusted estimates, with or without data from retrospective studies, consistently pointed in the same direction as our earlier findings. There were only small differences in the sizes or the level of statistical significance. Using GRADE, we assessed that our confidence in the effect estimates was very low or low for all outcomes. The adjusted estimates generally show similar obstetric harms from FGM/C as unadjusted estimates do. Thus, the current analyses confirm the findings from our previous systematic review. There are sufficient grounds to conclude that FGM/C, with respect to obstetric circumstances, involves harm. PMID- 25505916 TI - Management of varicella gangrenosa: a life-threatening condition from chickenpox. AB - Varicella gangrenosa, in which gangrenous ulceration of the skin and/or deeper tissues is seen, is a rare but alarming complication of Varicella infection. An early surgical intervention is generally advised, especially in case of sepsis and/or the presence of large necrotic lesions. We describe a case of a previously healthy 12-month-old boy presenting with sepsis due to Varicella gangrenosa. He presented with moderate lesions of moist gangrene. We treated our patient initially with antibiotics (ceftriaxone and metronidazole) and later on flucloxacillin and antiviral therapy (acyclovir) whereupon his condition rapidly improved and all skin lesions healed entirely. This report highlights the possibility of conservative treatment and emphasizes the significance of acyclovir in the management of chickenpox complicated by moist gangrene due to bacterial superinfection. PMID- 25505917 TI - Argon laser photoablation for postburn conjunctival pigmentation. AB - We report a case of an ocular burn injury from boiling water which resulted in conjunctival pigmentation, 1 week following injury. For cosmetic purposes, 2 sessions of argon laser photoablation were performed. One month after laser treatment, conjunctival pigmentation had been successfully removed and the patient was very satisfied with the results. Argon laser photoablation may be an effective way to remove postburn conjunctival pigmentation. PMID- 25505918 TI - Comparison on the Effects and Safety of Tualang Honey and Tribestan in Sperm Parameters, Erectile Function, and Hormonal Profiles among Oligospermic Males. AB - Introduction. This study aims to evaluate the effectiveness of Tualang honey on sperm parameters, erectile function, and hormonal and safety profiles. Methodology. A randomized control trial was done using Tualang honey (20 grams) and Tribestan (750 mg) over a period of 12 weeks. Sperm parameters including sperm concentration, motility, and morphology were analyzed and erectile function was assessed using IIEF-5 questionnaire. Hormonal profiles of testosterone, FSH, and LH were studied. The volunteers were randomized into two groups and the outcomes were analyzed using SPSS version 18. Results. A total of 66 participants were involved. A significant increment of mean sperm concentration (P < 0.001), motility (P = 0.015) and morphology (P = 0.008) was seen in Tualang honey group. In Tribestan group, a significant increment of mean sperm concentration (P = 0.007), and morphology (P = 0.009) was seen. No significant differences of sperm concentration, motility, and morphology were seen between Tualang honey and Tribestan group and similar results were also seen in erectile function and hormonal profile. All safety profiles were normal and no adverse event was reported. Conclusion. Tualang honey effect among oligospermic males was comparable with Tribestan in improving sperm concentration, motility, and morphology. The usage of Tualang honey was also safe with no reported adverse event. PMID- 25505919 TI - Antibiotic Use in Children with Acute Respiratory or Ear Infections: Prospective Observational Comparison of Anthroposophic and Conventional Treatment under Routine Primary Care Conditions. AB - Children with acute respiratory or ear infections (RTI/OM) are often unnecessarily prescribed antibiotics. Antibiotic resistance is a major public health problem and antibiotic prescription for RTI/OM should be reduced. Anthroposophic treatment of RTI/OM includes anthroposophic medications, nonmedication therapy and if necessary also antibiotics. This secondary analysis from an observational study comprised 529 children <18 years from Europe (AT, DE, NL, and UK) or USA, whose caregivers had chosen to consult physicians offering anthroposophic (A-) or conventional (C-) treatment for RTI/OM. During the 28-day follow-up antibiotics were prescribed to 5.5% of A-patients and 25.6% of C patients (P < 0.001); unadjusted odds ratio for nonprescription in A- versus C patients 6.58 (95%-CI 3.45-12.56); after adjustment for demographics and morbidity 6.33 (3.17-12.64). Antibiotic prescription rates in recent observational studies with similar patients in similar settings, ranged from 31.0% to 84.1%. Compared to C-patients, A-patients also had much lower use of analgesics, somewhat quicker symptom resolution, and higher caregiver satisfaction. Adverse drug reactions were infrequent (2.3% in both groups) and not serious. Limitation was that results apply to children of caregivers who consult A-physicians. One cannot infer to what extent antibiotics might be avoided in children who usually receive C-treatment, if they were offered A treatment. PMID- 25505920 TI - Effect of Uncaria tomentosa Extract on Apoptosis Triggered by Oxaliplatin Exposure on HT29 Cells. AB - Background/Aim. The use of herbal products as a supplement to minimize the effects of chemotherapy for cancer treatment requires further attention with respect to the activity and toxicity of chemotherapy. Uncaria tomentosa extract, which contains oxindole alkaloids, is one of these herbal products. The objective of this study was to evaluate whether Uncaria tomentosa extract modulates apoptosis induced by chemotherapy exposure. Materials and Methods. Colorectal adenocarcinoma cells (HT29 cells) were grown in the presence of oxaliplatin and/or Uncaria tomentosa extract. Results. The hydroalcoholic extract of Uncaria tomentosa enhanced chemotherapy-induced apoptosis, with an increase in the percentage of Annexin positive cells, an increase in caspase activities, and an increase of DNA fragments in culture of the neoplastic cells. Moreover, antioxidant activity may be related to apoptosis. Conclusion. Uncaria tomentosa extract has a role for cancer patients as a complementary therapy. Further studies evaluating these beneficial effects with other chemotherapy drugs are recommended. PMID- 25505921 TI - Preparative Purification of Linarin Extracts from Dendranthema indicum Flowers and Evaluation of Its Antihypertensive Effect. AB - Background. Preliminary research showed that linarin (LIN) might have a relationship with the antihypertensive effect of Dendranthema indicum flowers. However, the preparative method for LIN enriched extract from Dendranthema indicum flowers was not clear and its antihypertensive effect was not confirmed. In this study, we designed a series of experiments to develop an efficient method for purification of LIN extracts and confirm the possibility of LIN extracts to be an antihypertensive drug. Materials and Methods. HPLC-VWD/DAD were used in the process of developing purification method. The antihypertensive effect of LIN extracts was tested by CODA Mouse & Rat Tail-Cuff Blood Pressure System; western blot and biochemical analysis were used to investigate mechanism and toxicity. Results. The content and recovery of LIN reached 55.68 +/- 2.08% and 66.65 +/- 1.73%, respectively, through solid-liquid extraction. The composition of product was stable through the analysis of fingerprint. Chronic administration of LIN extracts reduced blood pressure obviously which had a relationship with the inhibition of renin-angiotensin system (RAS) in kidney and the function indexes of kidney and liver had no variations. Conclusions. The preparation method was simple, low-cost, and stable, and it was fit for industrial application. The LIN prepared by this method had the potential to be an antihypertensive drug. PMID- 25505922 TI - Gyejigachulbu-Tang Relieves Oxaliplatin-Induced Neuropathic Cold and Mechanical Hypersensitivity in Rats via the Suppression of Spinal Glial Activation. AB - Activation of spinal glial cells plays a crucial role in the pathogenesis of neuropathic pain. An administration of oxaliplatin, an important anticancer drug, often induces acute neuropathic cold hypersensitivity and/or mechanical hypersensitivity in patients. Gyejigachulbu-tang (GBT), a herbal formula comprising Cinnamomi Cortex, Paeoniae Radix, Atractylodis Lanceae Rhizoma, Zizyphi Fructus, Glycyrrhizae Radix, Zingiberis Rhizoma, and Aconiti Tuber, has been used in East Asia to treat various pain symptoms, especially in cold patients. This study investigated whether and how GBT alleviates oxaliplatin induced cold and mechanical hypersensitivity in rats. The behavioral signs of cold and mechanical hypersensitivity were evaluated by a tail immersion test in cold water (4 degrees C) and a von Frey hair test, respectively. The significant cold and mechanical hypersensitivity were observed 3 days after an oxaliplatin injection (6 mg/kg, i.p.). Daily oral administration of GBT (200, 400, and 600 mg/kg) for 5 days markedly attenuated cold and mechanical hypersensitivity. Immunoreactivities of glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker) in the spinal dorsal horn were significantly increased by an oxaliplatin injection, which were restored by GBT administration. These results indicate that GBT relieves oxaliplatin-induced cold and mechanical hypersensitivity in rats possibly through the suppression of spinal glial activation. PMID- 25505923 TI - Antifungal Activity of Decyl Gallate against Several Species of Pathogenic Fungi. AB - This work aims to demonstrate that the gallic acid structure modification to the decyl gallate (G14) compound contributed to increase the antifungal activity against several species of pathogenic fungi, mainly, Candida spp., Cryptococcus spp., Paracoccidioides spp., and Histoplasma capsulatum, according to standardized microdilution method described by Clinical Laboratory Standard Institute (CLSI) documents. Moreover this compound has a particularly good selectivity index value, which makes it an excellent candidate for broad-spectrum antifungal prototype and encourages the continuation of subsequent studies for the discovery of its mechanism of action. PMID- 25505924 TI - Protective effect of shen-fu injection on neuronal mitochondrial function in a porcine model of prolonged cardiac arrest. AB - Background. Shen-Fu injection (SFI) following cardiac arrest exhibits neurological effects, but its effect on neurological dysfunction is unclear. This study sought to investigate the protective effect of SFI on nerve cells in a porcine model of cardiac arrest. Methods. After eight minutes of untreated ventricular fibrillation (VF) and 2 minutes of basic life support, 24 pigs were randomized and divided into three cardiopulmonary resuscitation groups, which received central venous injection of either Shen-Fu (SFI group; 1.0 ml/kg), epinephrine (EP group; 0.02 mg/kg), or saline (SA group). Surviving pigs were sacrificed at 24 h after ROSC and brains were removed for analysis for morphologic changes of mitochondria by electron microscopy, for mitochondrial transmembrane potential (MTP) by flow cytometry, and for opening of the mitochondrial permeability transition pore (MPTP) by mitochondrial light scattering. Results. Compared with the EP and SA groups, SFI treatment reduced opening of MPTP, showing higher MMP. In addition, animals treated with SFI showed slight cerebral ultrastructure damage under the electron microscopy. Conclusion. Shen-Fu injection alleviated brain injury, improved neurological ultrastructure, stabilized membrane potential, and inhibited opening of MPTP. Therefore, SFI could significantly attenuate postresuscitation cerebral ischemia and reperfusion injury by modulating mitochondrial dysfunction of nerve cells. PMID- 25505925 TI - Pien Tze Huang Overcomes Multidrug Resistance and Epithelial-Mesenchymal Transition in Human Colorectal Carcinoma Cells via Suppression of TGF-beta Pathway. AB - The traditional Chinese medicine formula Pien Tze Huang (PZH) has long been used as a folk remedy for cancer. To elucidate the mode of action of PZH against cancer, in the present study we used a 5-FU resistant human colorectal carcinoma cell line (HCT-8/5-FU) to evaluate the effects of PZH on multidrug resistance (MDR) and epithelial-mesenchymal transition (EMT) as well as the activation of TGF-beta pathway. We found that PZH dose-dependently inhibited the viability of HCT-8/5-FU cells which were insensitive to treatment of 5-FU and ADM, demonstrating the ability of PZH to overcome chemoresistance. Furthermore, PZH increased the intercellular accumulation of Rhodamine-123 and downregulated the expression of ABCG2 in HCT-8/5-FU cells. In addition, drug resistance induced the process of EMT in HCT-8 cells as evidenced by EMT-related morphological changes and alteration in the expression of EMT-regulatory factors, which however was neutralized by PZH treatment. Moreover, PZH inhibited MDR/EMT-enhanced migration and invasion capabilities of HCT-8 cells in a dose-dependent manner and suppressed MDR-induced activation of TGF-beta signaling in HCT-8/5-FU cells. Taken together, our study suggests that PZH can effectively overcome MDR and inhibit EMT in human colorectal carcinoma cells via suppression of the TGF-beta pathway. PMID- 25505926 TI - Protective effect of tea polyphenol ophthalmic gel on lens epithelial cells in rabbits with silicone oil tamponade after vitrectomy. AB - Purpose. The aim of this study was to investigate the effect of tea polyphenols (TP) ophthalmic gel on lens epithelial cells (LECs) in rabbits with silicone oil tamponade after vitrectomy. Methods. In this study, unilateral vitrectomy with silicone oil tamponade was performed using 2-month-old New Zealand white rabbits (n = 72); meanwhile, age-matched nonoperated rabbits (n = 18) were used as controls. The TP ophthalmic gel was administered topically in the surgical eyes till they were sacrificed. On days 45 and 90 after operation, the levels of reactive oxygen species (ROS), mitochondrial membrane potential (DeltaPsim), and apoptosis of LECs were analyzed, respectively. Meanwhile, caspase-3 mRNA and protein levels were also determined. Results. The results indicate that the levels of ROS and apoptosis were elevated for LECs in rabbits after operation, whereas DeltaPsim was decreased. Caspase-3 was apparently increased at both mRNA and protein levels. Treatment of TP ophthalmic gel could reduce the generation of ROS, maintain DeltaPsim, inhibit the overexpression of caspase-3, and thus decrease the apoptosis of LECs of rabbits after operation. Conclusions. TP ophthalmic gel can efficiently inhibit caspase-3 overexpression, reduce the apoptosis of LECs, and prevent LECs from damage. Our result provides a new approach to prevent the development of complicated cataract after vitrectomy. PMID- 25505927 TI - The Metabolism of Polysaccharide from Atractylodes macrocephala Koidz and Its Effect on Intestinal Microflora. AB - An active polysaccharide from the rhizome of Atractylodes macrocephala Koidz (PAM) was identified to improve and adjust disordered intestinal flora. High performance gel permeation chromatography (HPGPC) and gas chromatography-mass spectrometry (GC-MS) were employed to identify the components of PAM as rhamnose, glucose, mannose, xylose, and galactose at a ratio of 0.03 : 0.25 : 0.15 : 0.41 : 0.15. PAM metabolized in gastrointestinal tract when incubated with artificial gastric and intestinal juices. Anaerobic incubation of PAM on intestinal flora confirmed that PAM promoted the ability of intestinal bacteria to digest reducing sugar. Based on the Shannon index and similarity coefficient index of enterobacterial repetitive intergenic consensus-PCR (ERIC-PCR) fingerprinting of the total intestinal bacteria DNA, we concluded that PAM can significantly improve disordered intestinal flora and may be used as an oral adjuvant to regulate intestinal flora. PMID- 25505928 TI - SENIEUR status of the originating cell donor negates certain 'anti immunosenescence' effects of ebselen and N-acetyl cysteine in human T cell clone cultures. AB - BACKGROUND: Damage to T cells of the immune system by reactive oxygen species may result in altered cell function or cell death and thereby potentially impact upon the efficacy of a subsequent immune response. Here, we assess the impact of the antioxidants Ebselen and N-acetyl cysteine on a range of biological markers in human T cells derived from a SENIEUR status donor. In addition, the impact of these antioxidants on different MAP kinase pathways in T cells from donors of different ages was also examined. METHODS: T cell clones were derived from healthy 26, 45 and SENIEUR status 80 year old people and the impact of titrated concentrations of Ebselen or N-acetyl cysteine on their proliferation and in vitro lifespan, GSH:GSSG ratio as well as levels of oxidative DNA damage and on MAP kinase signaling pathways was examined. RESULTS: In this investigation neither Ebselen nor N-acetyl cysteine supplementation had any impact on the biological endpoints examined in the T cells derived from the SENIEUR status 80 year old donor. This is in contrast to the anti-immunosenescent effects of these antioxidants on T cells from donors of 26 or 45 years of age. The analysis of MAP kinases showed that pro-apoptotic pathways become activated in T cells with increasing in vitro age and that Ebselen or N-acetyl cysteine could decrease activation (phosphorylation) in T cells from 26 or 45 year old donors, but not from the SENIEUR status 80 year old donor. CONCLUSIONS: The results of this investigation demonstrate that the biological phenotype of SENIEUR status derived human T cells negates the anti-immunosenescence effects of Ebselen and also N acetyl cysteine. The results highlight the importance of pre-antioxidant intervention evaluation to determine risk-benefit. PMID- 25505929 TI - The role of platelet gel in osteoarticular injuries of young and old patients. AB - BACKGROUND: The use of autologous platelet gel in orthopedics is effective in accelerating the healing process of osteochondral, muscle, tendon and ligament lesions. The aim of our study was to verify whether the variability in response to infiltration with platelet gel was dependent on the underlying disease treated, sex and age of the patients. During four years, 140 patients have been treated for musculoskeletal injuries by infiltration of gel platelet and lysate platelet obtained from autologous thrombin, with echo-ultrasound guided. The response to treatment was assessed at different time points T0, T1, T2 with respect to pain estimation (VAS), joint mobility (ROM scale) and echo-ultrasound evaluation. This data collection has allowed classifying the response to treated lesions in three categories: NR (no response), PR (partial response), CR (complete response). RESULTS: The data here reported showed that the ability to physical recovery response is evident in tendon injuries, while the large joints injuries gave a poor response. Almost all patients showed a significant pain relief after the first infiltration, but in terms of echo-ultrasound evaluation and tissue repair, only the muscle and tendon injuries showed hyperechoic areas, signs or evidences of repair. Concerning the correlation between response to infiltration with platelet gel and gender/age of the patients, the clinical results appear not influenced by the age and the gender of the patient. DISCUSSION: Our data indicate that, pain relief and ability to physical recovery of muscles, tendons and ligaments depend on tissue repair clearly visible by echo ultrasound evaluation. On the other hand tissue repair seems not occur in the large joints (hip and knee) where arthritis and /or corrosion of articular cartilage cannot be repaired and the only relief is exclusively linked to the reduction of periarticular inflammation (reduction of the inflammatory leakage and signs). PMID- 25505930 TI - Standardization of the NEO-PI-3 in the Greek general population. AB - BACKGROUND: The revised NEO Personality Inventory (NEO-PI-3) includes 240 items corresponding to the Big Five personality traits (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience) and subordinate dimensions (facets). It is suitable for use with adolescents and adults (12 years or older). The aim of the current study was to validate the Greek translation of the NEO-PI-3 in the general Greek population. MATERIAL AND METHODS: The study sample included 734 subjects from the general Greek population of whom 59.4% were females and 40.6% males aged 40.80 +/- 11.48. The NEO-PI-3 was translated into Greek and back-translated into English, and the accuracy of the translation was confirmed and established. The statistical analysis included descriptive statistics, confirmatory factorial analysis (CFA), the calculation of Cronbach's alpha, and the calculation of Pearson product-moment correlations. Sociodemographics groups were compared by ANOVA. RESULTS: Most facets had Cronbach's alpha above 0.60. Confirmatory factor analysis showed acceptable loading of the facets on their own hypothesized factors and very good estimations of Cronbach's alphas for the hypothesized factors, so it was partially supportive of the five-factor structure of the NEO-PI-3.The factors extracted with Procrustes rotation analysis can be considered reasonably homologous to the factors of the American normative sample. Correlations between dimensions were as expected and similar to those reported in the literature. DISCUSSION: The literature suggests that overall, the psychometric properties of NEO-PI-3 scales have been found to generalize across ages, cultures, and methods of measurement. In accord with this, the results of the current study confirm the reliability of the Greek translation and adaptation of the NEO-PI-3. The inventory has comparable psychometric properties in its Greek version in comparison to the original and other national translations, and it is suitable for clinical as well as research use. PMID- 25505931 TI - The Impact of Peplau's Therapeutic Communication Model on Anxiety and Depression in Patients Candidate for Coronary Artery Bypass. AB - BACKGROUND AND OBJECTIVE: Anxiety and depression are among the psychological disorders in heart surgeries. Establishing a simple communication is essential to reduce anxiety and depression. Hence, the objective of the present studywas to examine the impact of Peplau therapeutic communication model on anxiety and depression in patients, who were candidate for coronary artery bypass in Al-Zahra Heart Hospital, Shiraz during 2012-2013. METHODS: This is a clinical trial in which 74 patients were randomly divided into intervention and control groups, each consisted of 37 patients. Anxiety and depression levels were assessed before, and two and four months after intervention using the Hospital Anxiety and Depression Scale (HADS). Seven therapeutic communication sessions were held in four stages. Data were analyzed with the SPSS (version 16) using analysis of covariance. RESULTS: The mean anxiety and depression levels decreased in the intervention group after the therapeutic communication (p<0.01). Anxiety scores in the intervention group before and after intervention were 10.23 and 9.38, respectively. While the corresponding scores in the control group were 10.26 and 11.62, respectively. Depression scores in the intervention group before and after intervention were 11 and 9.13, respectively. The corresponding scores in the control group were 11.30 and 12.08, respectively. CONCLUSION: The results demonstrated the positive role of therapeutic communication in reducing anxiety and depression of the patients. Therefore, the therapeutic communication is recommended as a simple, cost effective and efficient method in this area. PMID- 25505932 TI - Engineering of an endogenous hexose transporter into a specific D-xylose transporter facilitates glucose-xylose co-consumption in Saccharomyces cerevisiae. AB - BACKGROUND: Engineering of Saccharomyces cerevisiae for the simultaneous utilization of hexose and pentose sugars is vital for cost-efficient cellulosic bioethanol production. This yeast lacks specific pentose transporters and depends on endogenous hexose transporters for low affinity pentose uptake. Consequently, engineered xylose-fermenting yeast strains first utilize D-glucose before D xylose can be transported and metabolized. RESULTS: We have used an evolutionary engineering approach that depends on a quadruple hexokinase deletion xylose fermenting S. cerevisiae strain to select for growth on D-xylose in the presence of high D-glucose concentrations. This resulted in D-glucose-tolerant growth of the yeast of D-xylose. This could be attributed to mutations at N367 in the endogenous chimeric Hxt36 transporter, causing a defect in D-glucose transport while still allowing specific uptake of D-xylose. The Hxt36-N367A variant transports D-xylose with a high rate and improved affinity, enabling the efficient co-consumption of D-glucose and D-xylose. CONCLUSIONS: Engineering of yeast endogenous hexose transporters provides an effective strategy to construct glucose-insensitive xylose transporters that are well integrated in the carbon metabolism regulatory network, and that can be used for efficient lignocellulosic bioethanol production. PMID- 25505933 TI - Molecular-cytogenetic analysis of Aegilops triuncialis and identification of its chromosomes in the background of wheat. AB - BACKGROUND: Species belonging to the genus Aegilops L. are an important source of genetic material for expanding genetic variability of wheat. Ae. triuncialis is an allotetraploid in this genus which was originated from hybridization of Ae. umbellulata and Ae. markgrafii (Greuter) Hammer. Although the Ae. triuncialis karyotype was thoroughly examined by conventional chromosome staining and Giemsa C-banding, it is still poorly characterized using FISH markers. The objective of this study was to test the fluorescence in situ hybridization (FISH) patterns of Ae. triuncialis (2n = 4x = 28, C(t)C(t)U(t)U(t)) chromosomes using different repetitive sequences and to compare the produced patterns to the chromosomes of its diploid ancestors, with the aim of establishing a generalized Ae. triuncialis idiogram and detection of Aegilops chromosomes in the background of wheat. RESULTS: The probes pSc119.2-1, pTa535-1, pAs1-1, (CTT)10 and the 45S rDNA clone from wheat (pTa71) were hybridized to chromosomes of Ae. triuncialis and compared with its diploid progenitors (Ae. umbellulata Zhuk., 2n = 2x = 14, UU and Ae. markgrafii (Greuter) Hammer, 2n = 2x = 14, CC) and Ae. cylindrica Host. (2n = 4x = 28, D(c)D(c)C(c)C(c)), another tetraploid species containing the C-genome. Ae. cylindrica was further analyzed by genomic in situ hybridization (GISH) using C genome probe in order to identify any possible translocation. CONCLUSIONS: In general, FISH patterns of the U(t)- and C(t)-genome chromosomes of Ae. triuncialis were similar to those of U- and C-genome chromosomes of the diploid progenitor species Ae. umbellulata and Ae. markgrafii respectively, although some differences were observed. Two major 45S rDNA loci were revealed in the short arm of chromosomes A and C, of the C(t) genome which correspond to homoeologous groups 1 and 5 respectively. Minor 45S rDNA loci were mapped on the short arm of chromosomes 1U(t) and 5U(t). GISH analysis revealed three different non reciprocal homologous or heterologous translocations between C(c) and D(c) chromosomes in all studied accessions of Ae. cylindrica. PMID- 25505934 TI - YMAP: a pipeline for visualization of copy number variation and loss of heterozygosity in eukaryotic pathogens. AB - The design of effective antimicrobial therapies for serious eukaryotic pathogens requires a clear understanding of their highly variable genomes. To facilitate analysis of copy number variations, single nucleotide polymorphisms and loss of heterozygosity events in these pathogens, we developed a pipeline for analyzing diverse genome-scale datasets from microarray, deep sequencing, and restriction site associated DNA sequence experiments for clinical and laboratory strains of Candida albicans, the most prevalent human fungal pathogen. The YMAP pipeline (http://lovelace.cs.umn.edu/Ymap/) automatically illustrates genome-wide information in a single intuitive figure and is readily modified for the analysis of other pathogens with small genomes. PMID- 25505936 TI - Antioxidant function of steen solution. PMID- 25505935 TI - Evaluation of neonatal streptozotocin induced diabetic rat model for the development of cataract. AB - Type 2 diabetes (T2D) generally follows prediabetes (PD) conditions such as impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). Although studies reported an association of IGT or IFG with cataract, the experimental basis for PD associated cataract is not known. Hence, we evaluated neonatal streptozotocin (nSTZ) induced rat model to study PD associated cataractogenesis by injecting STZ to two-day old rats. While majority (70%) of nSTZ injected pups developed IGT (nSTZ-PD) by two months but not cataract even after seven months, remaining (30%) nSTZ rats developed hyperglycemia (nSTZ-D) by two months and mature cataract by seven months. Lens biochemical analysis indicated increased oxidative stress as indicated by increased SOD activity, lipid peroxidation, and protein carbonyl levels in nSTZ-D cataractous lens. There was also increased polyol pathway as assessed by aldose reductase activity and sorbitol levels. Though nSTZ-PD animals have not shown any signs of lenticular opacity, insolubilization of proteins along with enhanced polyol pathway was observed in the lens. Further there was increased oxidative stress in lens of IGT animals. These results suggest that oxidative stress along with increased polyol pathway might play a role in IGT-associated lens abnormalities. In conclusion, nSTZ-PD rat model could aid to investigate IGT-associated lens abnormalities. PMID- 25505937 TI - Protective effects of gelam honey against oxidative damage in young and aged rats. AB - Aging is characterized by progressive decline in physiological and body function due to increase in oxidative damage. Gelam honey has been accounted to have high phenolic and nonphenolic content to attenuate oxidative damage. This study was to determine the effect of local gelam honey on oxidative damage of aged rats. Twenty-four male Spraque-Dawley rats were divided into young (2 months) and aged (19 months) groups. Each group was further divided into control (fed with plain water) and supplemented with 2.5 mg/kg body weight of gelam honey for 8 months. DNA damage level was determined by comet assay and plasma malondialdehyde (MDA) by high performance liquid chromatography (HPLC). The activity of blood and cardiac antioxidant enzymes was determined by spectrophotometer. The DNA damage and MDA level were reduced in both gelam honey supplemented groups. Gelam honey increases erythrocytes CAT and cardiac SOD activities in young and cardiac CAT activity in young and aged groups. The DNA damage was increased in the aged group compared to young group, but reduced at the end of the study. The decline of oxidative damage in rats supplemented with gelam honey might be through the modulation of antioxidant enzyme activities. PMID- 25505938 TI - Introduction to the Arizona Sky Island Arthropod Project (ASAP): Systematics, Biogeography, Ecology, and Population Genetics of Arthropods of the Madrean Sky Islands. AB - The Arizona Sky Island Arthropod Project (ASAP) is a new multi-disciplinary research program at the University of Arizona that combines systematics, biogeography, ecology, and population genetics to study origins and patterns of arthropod diversity along elevation gradients and among mountain ranges in the Madrean Sky Island Region. Arthropods represent taxonomically and ecologically diverse organisms that drive key ecosystem processes in this mountain archipelago. Using data from museum specimens and specimens we obtain during long term collecting and monitoring programs, ASAP will document arthropod species across Arizona's Sky Islands to address a number of fundamental questions about arthropods of this region. Baseline data will be used to determine climatic boundaries for target species, which will then be integrated with climatological models to predict future changes in arthropod communities and distributions in the wake of rapid climate change. ASAP also makes use of the natural laboratory provided by the Sky Islands to investigate ecological and genetic factors that influence diversification and patterns of community assembly. Here, we introduce the project, outline overarching goals, and describe preliminary data from the first year of sampling ground-dwelling beetles and ants in the Santa Catalina Mountains. PMID- 25505939 TI - Mediation effects of a culturally generic substance use prevention program for Asian American adolescents. AB - In this paper, we examined the mediation effects of a family-based substance use prevention program on a sample of Asian American families. These families were randomized into an intervention arm or a non-intervention control arm. Using path models, we assessed the effect of the intervention on adolescent girls' substance use outcomes at 2-year follow-up through family relationships and adolescent self efficacy pathways. Bias-corrected bootstrapping strategy was employed to assess the significance of the mediation effect by evaluating the 95% confidence interval of the standardized coefficient. The results show that receiving the intervention exerted a positive effect on girls' family relationships at 1-year follow-up. Such an improvement was associated with girls' increased self efficacy, which in turn led to girls' decreased alcohol use, marijuana use, and future intention to use substances at 2-year follow-up. Considering the diverse cultural backgrounds, as well as languages, nationalities, and acculturation levels under the umbrella term "Asian Americans", we demonstrate that a universal web-based intervention that tackles the theoretical- and empirical-based risk and protective factors can be effective for Asian Americans. Despite its generic nature, our program may provide relevant tools for Asian American parents in assisting their adolescent children to navigate through the developmental stage and ultimately, resist substance use. PMID- 25505940 TI - The Effect of Short Term Vitamin D Supplementation on the Inflammatory and Oxidative Mediators of Arterial Stiffness. AB - BACKGROUND: Vitamin D deficiency has been implicated as a potential risk factor for cardiovascular disease. The high rate of vitamin D deficiency (<30 ng/ml) exhibited by African Americans may account for some of the excess prevalence of cardiovascular morbidity and mortality in this vulnerable US population. Vitamin D supplementation may reduce the risk of cardiovascular disease by ameliorating the onset and progression of arterial stiffness, a strong predictor of cardiovascular mortality, usually assessed by pulse wave velocity and augmentation index. Very few prospective studies have evaluated the effect of vitamin D supplementation on the inflammatory and oxidative stress mediators of arterial stiffness. METHOD: In a double blind randomized placebo controlled study we evaluated the effect of a monthly dose of 100,000IU of vitamin D3 for three months on the level of serum 25(OH)D, intact parathyroid hormone (PTH), urinary isoprostane, adipocyte cytokine expression and arterial stiffness among 130 overweight and obese (BMI > 25) African Americans with elevated blood pressure (130 - 150/85 - 100 mmHg) and low serum vitamin D level (10 - 25 ng/ml). RESULTS: There was a significant increase in the serum 25(OH)D levels to a mean level of 34.5 ng/ml (SD = 7.1) with the intervention (p < 0.001). The increase in 25(OH)D levels was associated with a significant decrease in the serum level of intact PTH (p = 0.02), mean urinary isoprostane (p = 0.02) and adipocyte cytokine expression. Although the increase in the 25(OH)D levels was not associated with any significant change in the Pulse Wave Velocity (PWV) in the overall study sample, it was associated with a significant decrease in the augmentation index among the participants with the highest tertile of urinary isoprostane (p = 0.007). CONCLUSION: We concluded that vitamin D supplementation increased serum 25(OH)D levels, decreased intact PTH level and the levels of select inflammatory and oxidative stress mediators of arterial stiffness. Longer term prospective studies are warranted to evaluate the effect of high dose vitamin D supplementation on arterial stiffness. PMID- 25505941 TI - Is B-mode ultrasound alone a sufficient screening tool for carotid stenosis? A pilot study. AB - BACKGROUND: Carotid ultrasound is performed solely in hospital ultrasound departments or outpatient labs, using both B- and Doppler modes. We hypothesize that B-mode without Doppler can be used to classify patients as having carotid stenosis (CS) above or below 50%. Our objective is to determine the frequency with which a CS >50% is found using Doppler when no such stenosis was visible using B-mode. METHODS: This was a retrospective study of 100 patients referred to the stroke clinic and 100 patients referred for carotid endarterectomy (CEA). All patients had an elective carotid ultrasound done at Health Sciences North. The ultrasound reports were mixed together and blinded. Investigators determined if there was a CS of greater or less than 50% based on the carotid diagram. These results were compared to the degree of CS found on Doppler. RESULTS: In the CEA group, there were 198 ultrasounds, with 153 showing a CS of >50%. Only one case of CS >50% was missed by B-mode. In the clinic group, 32 of 192 ultrasounds showed a CS of >50%. None were missed by B-mode. B-mode had a sensitivity and negative predictive value of 100% and a specificity of 65%. CONCLUSION: This study supports the theory that it may be possible to use B-mode ultrasound without Doppler to reliably determine if there is CS above or below 50%. Further research is required before carotid ultrasound using B-mode alone can be recommended. PMID- 25505942 TI - Diversity-Oriented Synthesis for Novel, Selective and Drug-like Inhibitors for a Phosphatase from Mycobacterium Tuberculosis. AB - Mycobacterium protein tyrosine phosphatase B (mPTPB) is a potential drug target of Tuberculosis (TB). Small molecule inhibitors of mPTPB could be a treatment to overcome emerging TB drug resistance. Using a Diversity-Oriented Synthesis (DOS) strategy, we successfully developed a salicylic acid based and drug-like mPTPB inhibitor with an IC50 of 2 MUM and >20-fold specificity over many human PTPs, making it an excellent lead molecule for anti-TB drug discovery. In addition, DOS generated bicyclic salicylic acids are also promising starting points for acquiring inhibitors targeting other PTPs. PMID- 25505943 TI - Optimization of the anti-cancer activity of phosphatidylinositol-3 kinase pathway inhibitor PITENIN-1: switching a thiourea with 1,2,3-triazole. AB - We previously reported encouraging in vitro and in vivoanti-cancer activity of N ((3-chloro-2-hydroxy-5-nitrophenyl)carbamothioyl)benzamide (termed PITENIN-1). In the current work, we describe the structure-activity relationship study of PIT-1 series, based on the replacement of central thiourea unit with a 1,2,3-triazole, which leads to increased liver microsomal stability, drug likeness and toxicity towards cancer cells. PMID- 25469233 TI - Immunofluorescent visualization of mouse interneuron subtypes. AB - The activity of excitatory neurons is controlled by a highly diverse population of inhibitory interneurons. These cells show a high level of physiological, morphological and neurochemical heterogeneity, and play highly specific roles in neuronal circuits. In the mammalian hippocampus, these are divided into 21 different subtypes of GABAergic interneurons based on their expression of different markers, morphology and their electrophysiological properties. Ideally, all can be marked using an antibody directed against the inhibitory neurotransmitter GABA, but parvalbumin, calbindin, somatostatin, and calretinin are also commonly used as markers to narrow down the specific interneuron subtype. Here, we describe a journey to find the necessary immunological reagents for studying GABAergic interneurons of the mouse hippocampus. Based on web searches there are several hundreds of different antibodies on the market directed against these four markers. Searches in the literature databases allowed us to narrow it down to a subset of antibodies most commonly used in publications. However, in our hands the most cited ones did not work for immunofluorescence stainings of formaldehyde fixed tissue sections and cultured hippocampal neurons, and we had to immunostain our way through thirteen different commercial antibodies before finally finding a suitable antibody for each of the four markers. The antibodies were evaluated based on signal-to-noise ratios as well as if positive cells were found in layers of the hippocampus where they have previously been described. Additionally, the antibodies were also tested on sections from mouse spinal cord with similar criteria for specificity of the antibodies. Using the antibodies with a high rating on pAbmAbs, an antibody review database, stainings with high signal-to-noise ratios and location of the immunostained cells in accordance with the literature could be obtained, making these antibodies suitable choices for studying the GABAergic system. PMID- 25505945 TI - Acetate metabolism in cancer cells. PMID- 25505946 TI - A new ICB sister journal focuses on clinical and translational immunology. PMID- 25505947 TI - Monocyte-derived macrophages do not explain susceptibility to pulmonary non tuberculous mycobacterial disease. AB - Pulmonary infections with non-tuberculous mycobacteria (NTM) affect a subset of older individuals (mostly women) with no known immunological defects. As NTMs are intracellular pathogens, it is important to establish whether NTM disease is associated with defective production of Th1 cytokines or poor responses by host macrophage/monocytes. We have shown that patients display vigorous production of interferon gamma (IFNgamma) when CD4 T cells are stimulated with mycobacterial antigens. This implicated the macrophage response to IFNgamma. Blood monocytes are poorly representative of lung macrophages, so monocyte-derived macrophages (MDMs) were created and then stimulated with lipomannan (a Toll-like receptor (TLR)2 agonist), lipopolysaccharide (LPS; a TLR4 agonist) or recombinant human IFNgamma. MDMs from NTM patients, their offspring and healthy donors expressed similar amounts of IFNgammaR1, and cellular responses to IFNgamma were similar, so there is no evidence of a genetic defect in this pathway. MDMs from NTM patients produced less interleukin-6 in response to LPS (P<0.01) than cells from controls, but other cytokine responses were normal. This warrants further study. PMID- 25505948 TI - IL-21 Modulates Activation of NKT Cells in Patients with Stage IV Malignant Melanoma. AB - Interleukin-21 (IL-21) is a common gamma-chain cytokine produced by T helper and natural killer T (NKT) cells. It has been shown to regulate the response of various lymphocyte subsets including NK, NKT, T and B cells. Owing to its potent anti-tumor function in preclinical studies and its ability to induce cytotoxicity and interferon-gamma (IFN-gamma) production in NK and CD8 T cells, recombinant IL 21 (rIL-21) was fast-tracked into early-phase clinical trials of patients with various malignancies. In a phase 2a trial of patients with metastatic melanoma, we analyzed the frequency and function of NKT cells in patients receiving rIL-21. NKT cells were present at a low frequency, but their levels were relatively stable in patients administered rIL-21. Unlike our observations in NK and CD8 T cells, rIL-21 appeared to reduce IFN-gamma and TNF production by NKT cells, whereas it enhanced IL-4 production. It also modulated the expression of cell surface markers, specifically on CD4(-) NKT cells. In addition, an increase in CD3(+)CD56(+) NKT-like cells was observed over the course of rIL-21 administration. These results highlight that IL-21 is a potent regulator of NKT cell function in vivo. PMID- 25505949 TI - Pollen-induced antigen presentation by mesenchymal stem cells and T cells from allergic rhinitis. AB - Mesenchymal stem cells (MSCs) are promising cellular suppressor of inflammation. This function of MSCs is partly due to their licensing by inflammatory mediators. In cases with reduced inflammation, MSCs could become immune-enhancer cells. MSCs can suppress the inflammatory response of antigen-challenged lymphocytes from allergic asthma. Although allergic rhinitis (AR) is also an inflammatory response, it is unclear if MSCs can exert similar suppression. This study investigated the immune effects (suppressor vs enhancer) of MSCs on allergen stimulated lymphocytes from AR subjects (grass or weed allergy). In contrast to subjects with allergic asthma, MSCs caused a significant (P<0.05) increase in the proliferation of antigen-challenged lymphocytes from AR subjects. The increase in lymphocyte proliferation was caused by the MSCs presenting the allergens to CD4(+) T cells (antigen-presenting cells (APCs)). This correlated with increased production of inflammatory cytokines from T cells, and increased expressions of major histocompatibility complex (MHC)-II and CD86 on MSCs. The specificity of APC function was demonstrated in APC assay using MSCs that were knocked down for the master regulator of MHC-II transcription, CIITA. The difference in the effects of MSCs on allergic asthma and AR could not be explained by the sensitivity to the allergen, based on skin tests. Thus, we deduced that the contrasting immune effects of MSCs for antigen-challenged lymphocytes on AR and allergic asthma could be disease specific. It is possible that the enhanced inflammation from asthma might be required to license the MSCs to become suppressor cells. This study underscores the need for robust preclinical studies to effectively translate MSCs for any inflammatory disorder. PMID- 25505950 TI - Bacterial lipodipeptide, Lipid 654, is a microbiome-associated biomarker for multiple sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disease of unknown etiology. Infectious agents have been suggested to have a role as environmental factors in MS, but this concept remains controversial. Recently, gastrointestinal commensal bacteria have been implicated in the pathogenesis of autoimmune diseases, but mechanisms underlying the relationship of human systemic autoimmunity with the commensal microbiome have yet to be identified. Consistent with the lack of understanding of pathogenic mechanisms and relevant environmental factors in MS, no blood biomarkers have been identified that distinguish MS patients from healthy individuals. We recently identified a unique gastrointestinal and oral bacteria derived lipodipeptide, Lipid 654, which is produced by commensal bacteria and functions as a human and mouse Toll-like receptor 2 ligand. Using multiple reaction-monitoring mass spectrometry, a critical approach in targeted lipidomics, we now report that Lipid 654 can be recovered in the serum of healthy individuals. Most interestingly, we find that Lipid 654 is expressed at significantly lower levels in the serum of patients with MS compared with both healthy individuals and patients with Alzheimer's disease. These results thus identify for the first time a potential mechanism relating the gastrointestinal and oral commensal microbiome to a human systemic autoimmune disease. In addition, these results also identify a potential etiologic environmental factor and novel clinically relevant serum biomarker for MS. PMID- 25505951 TI - Maternal and infant infections stimulate a rapid leukocyte response in breastmilk. AB - Breastmilk protects infants against infections; however, specific responses of breastmilk immune factors to different infections of either the mother or the infant are not well understood. Here, we examined the baseline range of breastmilk leukocytes and immunomodulatory biomolecules in healthy mother/infant dyads and how they are influenced by infections of the dyad. Consistent with a greater immunological need in the early postpartum period, colostrum contained considerable numbers of leukocytes (13-70% out of total cells) and high levels of immunoglobulins and lactoferrin. Within the first 1-2 weeks postpartum, leukocyte numbers decreased significantly to a low baseline level in mature breastmilk (0 2%) (P<0.001). This baseline level was maintained throughout lactation unless the mother and/or her infant became infected, when leukocyte numbers significantly increased up to 94% leukocytes out of total cells (P<0.001). Upon recovery from the infection, baseline values were restored. The strong leukocyte response to infection was accompanied by a more variable humoral immune response. Exclusive breastfeeding was associated with a greater baseline level of leukocytes in mature breastmilk. Collectively, our results suggest a strong association between the health status of the mother/infant dyad and breastmilk leukocyte levels. This could be used as a diagnostic tool for assessment of the health status of the lactating breast as well as the breastfeeding mother and infant. PMID- 25505952 TI - Interleukin-6: a new therapeutic target in systemic sclerosis? AB - Interleukin-6 (IL-6) is a classic pro-inflammatory cytokine critical in mounting an effective immune response. It is secreted by a wide array of cell types; however, its effector cells are more restricted, owing to the fact that very few cells, except lymphocytes and hepatocytes, express the functional membrane IL-6 receptor thus reducing the number of IL-6-responsive cells. Trans-signalling, the shedding of the membrane-bound form of the IL-6 receptor into the local microenvironment, greatly increases the range of cells that can respond. IL-6 has been demonstrated to have a pivotal role in the pathogenesis of rheumatoid arthritis, Castleman's disease and Crohn's disease exemplified by the use of an anti-IL-6 biological therapy. However, IL-6 is also associated with the autoimmune disease systemic sclerosis (SSc) and has been shown to be directly fibrotic. Elevated levels of IL-6 are found in SSc patients and this correlates with skin thickness, suggesting a causal effect. This review focuses on the role of IL-6 in SSc, a chronic autoimmune disease with fibrosis. In particular, we will examine the evidence base of the role of IL-6 in fibrosis in this condition, especially the downstream effector pathways. We will then argue why molecular targeting of IL-6 is a promising therapeutic target in this fibrosing disease. PMID- 25505953 TI - The delicate balance of melanoma immunotherapy. AB - The strategy of immune modulation for the treatment of cancer is being refined with the introduction of multiple new therapeutic agents into the clinic. Melanoma is a disease where many of these agents have demonstrated efficacy. The mechanisms of action of these agents exploit the counter-regulatory mechanisms of the immune response. However, these agents are also associated with immune related adverse events (IRAEs), which represent tissue-specific inflammatory responses. These IRAEs highlight the delicate balance of immunologic homeostasis and, with some interventions, may occur more frequently in patients who sustain a therapeutic response. This review will discuss melanoma immunogenicity and immunotherapy. Furthermore, the spectrum and distinction between a reversible immune adverse event and autoimmunity will be highlighted. PMID- 25505954 TI - Invariant natural killer T-cell neutralization is a possible novel therapy for human eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disorder that needs a potential therapeutic strategy. We earlier showed that iNKT cell deficient mice are protected from allergen-induced EoE. Therefore, we now tested the hypothesis that iNKT cells are induced in the human EoE and is a novel possible target for the treatment of human EoE. Accordingly, we examine number of iNKT cells and eosinophils and expression of iNKT-associated cell surface receptors and chemokines by performing immunofluorescence, qPCR and ELISA in the esophageal biopsies and blood samples of normal subjects (comparison control) and EoE patients. Herein, we show that iNKT cell number, their receptor subcomponents Valpha24 and Vbeta11 expression, and associated chemokine CXCL16 levels (or expression) are induced significantly in EoE patients compared with normal individuals. In addition, we show that CXCL16 levels (or expression) correlate with the mRNA levels of Valpha24 receptor but not well with esophageal eosinophilia in human EoE. Of note, we show that in vivo activation of iNKT cells is sufficient to induce EoE in mice. Furthermore, we show that anti-mCD1d- and anti-hValpha24Jalpha18-neutralizing antibody treatment protects allergen-induced experimental EoE. Taken together, we have shown first time that iNKT cells have a critical pathogenic role in human and experimental EoE. iNKT cell neutralization by humanized anti-CD1d and anti-Valpha24Jalpha18 antibodies might be a novel and potential therapy for human EoE. PMID- 25505956 TI - EV71 vaccine, an invaluable gift for children. AB - Enterovirus 71 (EV71) is a major pathogen for severe hand, foot and mouth disease (HFMD). Development of vaccines against EV71 would be the most effective approach to prevent the EV71 outbreak. Research and development (R&D) of EV71 vaccine was carried out in several Asian countries. Currently three companies in mainland China have completed Phase III clinical trials of inactivated EV71 whole-virus vaccines, whereas the other two companies have completed Phase I clinical trials separately in Taiwan and in Singapore. Results from those clinical trials have indicated high safety and immunogenicity of EV71 vaccine. Protective efficacies were over 90% on EV71-associated HFMD and over 80% on other EV71-associated diseases. In this paper, we summarize the results from three EV71 vaccine Phase III clinical trials and discuss the challenges of incorporating EV71 vaccine into Expanded Program on Immunization (EPI) in countries with EV71 epidemics. PMID- 25505955 TI - Epstein-Barr virus and multiple sclerosis: potential opportunities for immunotherapy. AB - Multiple sclerosis (MS) is a common chronic inflammatory demyelinating disease of the central nervous system (CNS) causing progressive disability. Many observations implicate Epstein-Barr virus (EBV) in the pathogenesis of MS, namely universal EBV seropositivity, high anti-EBV antibody levels, alterations in EBV specific CD8(+) T-cell immunity, increased spontaneous EBV-induced transformation of peripheral blood B cells, increased shedding of EBV from saliva and accumulation of EBV-infected B cells and plasma cells in the brain. Several mechanisms have been postulated to explain the role of EBV in the development of MS including cross-reactivity between EBV and CNS antigens, bystander damage to the CNS by EBV-specific CD8(+) T cells, activation of innate immunity by EBV encoded small RNA molecules in the CNS, expression of alphaB-crystallin in EBV infected B cells leading to a CD4(+) T-cell response against oligodendrocyte derived alphaB-crystallin and EBV infection of autoreactive B cells, which produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells in the CNS. The rapidly accumulating evidence for a pathogenic role of EBV in MS provides ground for optimism that it might be possible to prevent and cure MS by effectively controlling EBV infection through vaccination, antiviral drugs or treatment with EBV-specific cytotoxic CD8(+) T cells. Adoptive immunotherapy with in vitro-expanded autologous EBV-specific CD8(+) T cells directed against viral latent proteins was recently used to treat a patient with secondary progressive MS. Following the therapy, there was clinical improvement, decreased disease activity on magnetic resonance imaging and reduced intrathecal immunoglobulin production. PMID- 25505957 TI - Post-traumatic stress disorder: revisiting adrenergics, glucocorticoids, immune system effects and homeostasis. AB - This review focuses on post-traumatic stress disorder (PTSD). Several sequelae of PTSD are partially attributed to glucocorticoid-induced neuronal loss in the hippocampus and amygdala. Glucocorticoids and adrenergic agents cause both immediate and late sequelae and are considered from the perspective of their actions on the expression of cytokines as well as some of their physiological and psychological effects. A shift in immune system balance from Th1 to Th2 dominance is thought to result from the actions of both molecular groups. The secretion of glucocorticoids and adrenergic agents is commonly induced by trauma or stress, and synergy between these two parallel but separate pathways can produce long- and short-term sequelae in individuals with PTSD. Potential therapies are suggested, and older therapies that involve the early effects of adrenergics or glucocorticoids are reviewed for their control of acute symptoms. These therapies may also be useful for acute flashback therapy. Timely and more precise glucocorticoid and adrenergic control is recommended for maintaining these molecular groups within acceptable homeostatic limits and thus managing immune and brain sequelae. Psychotherapy should supplement the above therapeutic measures; however, psychotherapy is not the focus of this paper. Instead, this review focuses on the probable molecular basis of PTSD. Integrating historical findings regarding glucocorticoids and adrenergic agents into current research and clinical applications returns the focus to potentially life-changing treatments. Autologous adoptive immune therapy may also offer utility. This paper reports clinical and translational research that connects and challenges separate fields of study, current and classical, in an attempt to better understand and ameliorate the effects of PTSD. PMID- 25505958 TI - Interferon-alpha, immune activation and immune dysfunction in treated HIV infection. AB - Type I interferons (IFNs) exert anti-viral effects through the induction of numerous IFN-stimulated genes and an immunomodulatory effect on innate and adaptive immune responses. This is beneficial in controlling virus infections but prolonged IFN-alpha activity in persistent virus infections, such as HIV infection, may contribute to immune activation and have a detrimental effect on the function of monocytes and T and B lymphocytes. Activation of monocytes, associated with increased IFN-alpha activity, contributes to atherosclerotic vascular disease, brain disease and other 'age-related diseases' in HIV patients treated with long-term antiretroviral therapy (ART). In HIV patients receiving ART, the anti-viral effects of IFN-alpha therapy have the potential to contribute to eradication of HIV infection while IFN-alpha inhibitor therapy is under investigation for the treatment of immune activation. The management of HIV patients receiving ART will be improved by understanding more about the opposing effects of IFN-alpha on HIV infection and disease and by developing methods to assess IFN-alpha activity in clinical practice. PMID- 25505959 TI - Accelerating immune reconstitution after hematopoietic stem cell transplantation. AB - Viral infections remain a significant cause of morbidity and mortality after hematopoietic stem cell transplantation. Pharmacologic agents are effective against some pathogens, but they are costly and can be associated with significant toxicities. Thus, many groups have investigated adoptive T-cell transfer as a means of hastening immune reconstitution and preventing and treating viral infections. This review discusses the immunotherapeutic strategies that have been explored. PMID- 25505960 TI - Clinical immune-monitoring strategies for predicting infection risk in solid organ transplantation. AB - Infectious complications remain a leading cause of morbidity and mortality after solid organ transplantation (SOT), and largely depend on the net state of immunosuppression achieved with current regimens. Cytomegalovirus (CMV) is a major opportunistic viral pathogen in this setting. The application of strategies of immunological monitoring in SOT recipients would allow tailoring of immunosuppression and prophylaxis practices according to the individual's actual risk of infection. Immune monitoring may be pathogen-specific or nonspecific. Nonspecific immune monitoring may rely on either the quantification of peripheral blood biomarkers that reflect the status of a given arm of the immune response (serum immunoglobulins and complement factors, lymphocyte sub-populations, soluble form of CD30), or on the functional assessment of T-cell responsiveness (release of intracellular adenosine triphosphate following a mitogenic stimulus). In addition, various methods are currently available for monitoring pathogen specific responses, such as CMV-specific T-cell-mediated immune response, based on interferon-gamma release assays, intracellular cytokine staining or main histocompatibility complex-tetramer technology. This review summarizes the clinical evidence to date supporting the use of these approaches to the post transplant immune status, as well as their potential limitations. Intervention studies based on validated strategies for immune monitoring still need to be performed. PMID- 25505961 TI - Vaccines to prevent leishmaniasis. AB - Leishmaniasis is a parasitic disease that encompasses a range of clinical manifestations affecting people in tropical and subtropical regions of the world. Epidemiological and experimental data indicate that protection from disease can be achieved in most people. In addition, we know how the host immune system must respond to infection in order to control parasite growth. However, there is still no vaccine for use in humans. Here, we review our understanding of host immunity following Leishmania infection and also discuss recent advances in the development of vaccines to prevent leishmaniasis, highlighting a new promising approach that targets the parasite hemoglobin receptor. PMID- 25505962 TI - Human placenta-derived adherent cells induce tolerogenic immune responses. AB - Human placenta-derived adherent cells (PDAC cells) are a culture expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory and anti-inflammatory properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. To elucidate the mechanisms underlying the immunoregulatory properties of PDAC cells, we investigated their effects on immune cell populations, including T cells and dendritic cells (DC) in vitro and in vivo. PDAC cells suppressed T-cell proliferation in an OT-II T-cell adoptive transfer model, reduced the severity of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis and ameliorated inflammation in a delayed type hypersensitivity response model. In vitro, PDAC cells suppressed T-cell proliferation and inhibited Th1 and Th17 differentiation. Analysis of tissues derived from PDAC cell-treated animals revealed diminished CD86 expression on splenic DC, suggesting that they can also modulate DC populations. Furthermore, PDAC cells modulate the differentiation and maturation of mouse bone marrow-derived DC. Similarly, human DC differentiated from CD14(+) monocytes in the presence of PDAC cells acquired a tolerogenic phenotype. These tolerogenic DC failed to induce allogeneic T-cell proliferation and differentiation toward Th1, but skewed T-cell differentiation toward Th2. Inhibition of cyclo-oxygenase-2 activity resulted in a significant, but not complete, abrogation of PDAC cells' effects on DC phenotype and function, implying a role for prostaglandin E2 in PDAC-mediated immunomodulation. This study identifies modulation of DC differentiation toward immune tolerance as a key mechanism underlying the immunomodulatory activities of PDAC cells. PMID- 25505963 TI - Prognosis in autoimmune and infectious disease: new insights from genetics. AB - A well-recognised feature of autoimmune and infectious diseases is that their clinical course and eventual outcome can vary substantially between affected individuals. This variability in disease prognosis critically determines patient well-being, and yet is relatively poorly understood and largely understudied-with many investigators opting instead to study what causes disease development in the first place. Better understanding of what determines prognosis could provide unique insights into disease biology, potentially revealing new therapeutic targets, and will also be essential if prognosis-based 'personalised medicine' is ever to become a reality. Here, we highlight the previously under-appreciated role that genetics has in determining prognosis in autoimmune and infectious disease, and the common role that FOXO3 has been shown to have as a modulator of inflammatory responses, and thereby of outcome, across several distinct diseases. PMID- 25505964 TI - Clinical application of genetically modified T cells in cancer therapy. AB - Immunotherapies are emerging as highly promising approaches for the treatment of cancer. In these approaches, a variety of materials are used to boost immunity against malignant cells. A key component of many of these approaches is functional tumor-specific T cells, but the existence and activity of sufficient T cells in the immune repertoire is not always the case. Recent methods of generating tumor-specific T cells include the genetic modification of patient lymphocytes with receptors to endow them with tumor specificity. These T cells are then expanded in vitro followed by infusion of the patient in adoptive cell transfer protocols. Genes used to modify T cells include those encoding T-cell receptors and chimeric antigen receptors. In this review, we provide an introduction to the field of genetic engineering of T cells followed by details of their use against cancer in the clinic. PMID- 25505965 TI - Adoptive T-cell therapy: adverse events and safety switches. AB - The potential of adoptive T-cell therapy in effecting complete and durable responses has been demonstrated in a number of malignant and infectious diseases. Ongoing progress in T-cell engineering has given cause for optimism in the broader clinical applicability of this approach. However, the development of more potent T cells is checked by safety concerns, highlighted by the occurrence of on target and off-target toxicities that, although uncommon, have been fatal on occasions. Timely pharmacological intervention is effective in the management of a majority of adverse events but adoptively transferred T cells can persist long term, along with any unwanted effects. A recently validated cellular safety switch, inducible caspase 9 (iCasp9), has the potential to mitigate the risks of T-cell therapy by enabling the elimination of transferred T cells if required. In haematopoietic stem cell transplantation, iCasp9-modified donor T cells can be rapidly eliminated in the event of graft-versus-host disease. This review presents an overview of the risks associated with modern T-cell therapy and the development, clinical results and potential future application of the iCasp9 safety switch. PMID- 25505966 TI - Increase in DNA vaccine efficacy by virosome delivery and co-expression of a cytolytic protein. AB - The potential of DNA vaccines has not been realised due to suboptimal delivery, poor antigen expression and the lack of localised inflammation, essential for antigen presentation and an effective immune response to the immunogen. Initially, we examined the delivery of a DNA vaccine encoding a model antigen, luciferase (LUC), to the respiratory tract of mice by encapsulation in a virosome. Virosomes that incorporated influenza virus haemagglutinin effectively delivered DNA to cells in the mouse respiratory tract and resulted in antigen expression and systemic and mucosal immune responses to the immunogen after an intranasal (IN) prime/intradermal (ID) boost regimen, whereas a multidose ID regimen only generated systemic immunity. We also examined systemic immune responses to LUC after ID vaccination with a DNA vaccine, which also encoded one of the several cytolytic or toxic proteins. Although the herpes simplex virus thymidine kinase, in the presence of the prodrug, ganciclovir, resulted in cell death, this failed to increase the humoral or cell-mediated immune responses. In contrast, the co-expression of LUC with the rotavirus non-structural protein 4 (NSP4) protein or a mutant form of mouse perforin, proteins which are directly cytolytic, resulted in increased LUC-specific humoral and cell-mediated immunity. On the other hand, co-expression of LUC with diphtheria toxin subunit A or overexpression of perforin or NSP4 resulted in a lower level of immunity. In summary, the efficacy of DNA vaccines can be improved by targeted IN delivery of DNA or by the induction of cell death in vaccine-targeted cells after ID delivery. PMID- 25505967 TI - Site-specific host gene modification by zinc finger nucleases: pointing the way to drug free control of HIV-1? AB - Anti-retroviral therapy (ART) for human immunodeficiency virus-1 (HIV-1) infection has transformed its clinical course with spectacular reductions in morbidity and mortality, turning this once fatal diagnosis into a manageable chronic infection. However, ART has its limitations. Current ART does not eliminate the virus. Interruption of therapy results in rapid rebound of the virus, and such rebounds are associated with excess morbidity and mortality. This means that therapy once started is for life. This raises the issues of drug resistance due to suboptimal compliance, cumulative toxicities and mounting costs. Efforts to control the virus through novel interventions, particularly through cell or gene therapy have had a resurgence of interest as a single patient was apparently cured by an allogeneic stem cell transplantation from a donor who carried homozygous mutations that disable expression of the HIV-1 co receptor CCR5. This paper reviews the state of play of gene therapy for HIV infection in the context of a recent paper showing the safety and feasibility of an approach that involves the ex vivo disruption of the ccr5 gene in autologous CD4 T cells using a virally delivered zinc finger nuclease, before their expansion and reinfusion. Although there are still considerable challenges, this approach may point towards a future drug free therapy for HIV-1 infection. PMID- 25505968 TI - Stem memory T cells (TSCM)-their role in cancer and HIV immunotherapies. AB - Stem memory T cells (TSCM) have been described in mice, non-human primates and in humans, constituting approximately 2-4% of the total CD4(+) and CD8(+) T-cell population in the periphery. TSCM represent the earliest and long-lasting developmental stage of memory T cells, displaying stem cell-like properties, and exhibiting a gene profile between naive and central memory T cells. Their self renewal capacity and long-term survival has sparked interest in the cancer and human immunodeficiency virus (HIV) fields. How and when the formation of TSCM occurs during the immune response to pathogens and the therapeutic potential of these cells are currently being investigated. This review will explore the potential role of TSCM to be used as, or targeted by, immunotherapies and vaccines for treatment of cancer and HIV. PMID- 25505969 TI - Dendritic cell immunotherapy: clinical outcomes. AB - The use of tumour-associated antigens for cancer immunotherapy studies is exacerbated by tolerance to these self-antigens. Tolerance may be broken by using ex vivo monocyte-derived dendritic cells (DCs) pulsed with self-antigens. Targeting tumour-associated antigens directly to DCs in vivo is an alternative and simpler strategy. The identification of cell surface receptors on DCs, and targeting antigens to DC receptors, has become a popular approach for inducing effective immune responses against cancer antigens. Many years ago, we demonstrated that targeting the mannose receptor on macrophages using the carbohydrate mannan to DCs led to appropriate immune responses and tumour protection in animal models. We conducted Phase I, I/II and II, clinical trials demonstrating the effectiveness of oxidised mannan-MUC1 in patients with adenocarcinomas. Here we summarise DC targeting approaches and their efficacy in human clinical trials. PMID- 25505970 TI - Improved mouse models to assess tumour immunity and irAEs after combination cancer immunotherapies. AB - The current excitement surrounding cancer immunotherapy stems particularly from clinical data involving agents mediating immune checkpoint receptor blockade, which have induced unprecedented efficacy against a range of tumours compared with previous immunotherapeutic approaches. However, an important consideration in targeting checkpoint receptors has been the emergence of associated toxicities termed immune-related adverse events (irAEs). In light of the clinical benefits observed after co-blockade of checkpoint receptors and data from preclinical mouse models, there is now a strong rationale to combine different checkpoint receptors together, with other immunotherapies or more conventional therapies to assess if clinical benefits to cancer patients can be further improved. However, one may predict the frequency and severity of irAEs will increase with combinations, which may result in premature therapy cessation, thus limiting the realization of such an approach. In addition, there is a limit to how many different combination therapies that can be tested in a timely manner given the legal, regulatory and budgetary issues associated with conducting clinical trials. Thus, there is a need to develop preclinical mouse models that more accurately inform us as to which immunotherapies might combine best to provide the optimal therapeutic index (maximal anti-tumour efficacy and low level irAEs) in different cancer settings. In this review we will discuss the irAEs observed in patients after checkpoint blockade and discuss which mouse models of cancer can be appropriate to assess the development of tumour immunity and irAEs following combination cancer immunotherapies. PMID- 25505971 TI - Synovial fluid myeloid dendritic cells display important differences compared to monocyte-derived dendritic cells prepared in vitro. AB - The object of this study was to characterise synovial fluid dendritic cells (SFDCs) with regard to morphology, phenotype and responses to 1,25hydroxy cholecalciferol (1,25D) and lipopolysaccharide (LPS), and to compare these characteristics with those of peripheral blood (PB) monocyte-derived DCs (MDDCs). SF was aspirated from knees with inflammatory effusions. PB samples were obtained contemporaneously. SFDCs were separated by flow cytometry. Morphology was determined on cytosmears. Expression of accessory molecules, cytokines and prostaglandin synthases mRNA was quantified by reverse transcription PCR. Analyses were performed on freshly prepared DCs and after incubation with 1,25D and LPS, separately and in combination. SFDCs and MDDCs displayed broadly similar morphology. Expression of accessory molecules, cytokines, cyclooxygenase-2 (COX 2) and prostaglandin E-synthase (PGES) was similar. SFDCs, but not MDDCs, expressed prostaglandin D-synthase (PGDS). PGDS was lost on incubation with SFDCs, but was induced by 1,25D in MDDCs. LPS in the presence or absence of 1,25D, induced interleukin 23 (IL23), IL1beta and tumour necrosis factor-alpha in SFDCs and MDDCs, with SFDC showing stronger expression of these cytokines. 1,25D in combination with LPS induced PGES and enhanced LPS induction of IL6 in SFDCs and MDDCs. LPS reduced 1,25D-induced expression of PGDS in MDDCs. SFDCs and MDDCs display similar basal characteristics but differ in PGDS expression and responsiveness to LPS and 1,25D. MDDCs have limitations as a model of SFDCs which have differentiated in vivo. PMID- 25505972 TI - Grouping of large populations into few CTL immune 'response-types' from influenza H1N1 genome analysis. AB - Despite extensive work on influenza, a number of questions still remain open about why individuals are differently susceptible to the disease and why only some strains lead to epidemics. Here we study the effect of human leukocyte antigen (HLA) genotype heterogeneity on possible cytotoxic T-lymphocyte (CTL) response to 186 influenza H1N1 genomes. To enable such analysis, we reconstruct HLA genotypes in different populations using a probabilistic method. We find that epidemic strains in general correlate with poor CTL response in populations. Our analysis shows that large populations can be classified into a small number of groups called response-types, specific to a given viral strain. Individuals of a response-type are expected to exhibit similar CTL responses. Extent of CTL responses varies significantly across different populations and increases with increase in genetic heterogeneity. Overall, our analysis presents a conceptual advance towards understanding how genetic heterogeneity influences disease susceptibility in individuals and in populations. We also obtain lists of top ranking epitopes and proteins, ranked on the basis of conservation, antigenic cross-reactivity and population coverage, which provide ready short-lists for rational vaccine design. Our method is fairly generic and has the potential to be applied for studying other viruses. PMID- 25505973 TI - Designer antigens for elicitation of broadly neutralizing antibodies against HIV. AB - Broadly neutralizing antibodies (bNAbs) are a consistent protective immune correlate in human immunodeficiency virus (HIV) patients as well as in passive immunotherapy studies. The inability to elicit bNAbs is the core reason underlining the repeated failures in traditional HIV vaccine research. Rare monoclonal bNAbs against HIV, however, have been produced. The significance of producing and studying more monoclonal bNAbs against HIV is underlined by its capability of defining critical epitopes for antigen designs aimed at the development of a serum-neutralizing HIV vaccine. In this regard, traditional antigen preparations have failed. There is a need to clearly advocate the concept, and systematic study, of more sophisticated 'designer antigens' (DAGs), which carry epitopes that can lead to the elicitation of bNAbs. Using an extremely efficient cell-to-cell HIV infection model for the preparation of HIV prefusion intermediates, we have investigated a novel and systematic approach to produce (not screen for) potential bNAbs against HIV. We have established the concept and the experimental system for producing formaldehyde-fixed HIV DAGs that carry temperature-arrested prefusion intermediates. These prefusion intermediates are structures on the cell surface after viral attachment and receptor engagement but before fully functional viral entry. Using defined HIV prefusion DAGs, we have produced monoclonal antibodies (mAbs) specific to novel epitopes on HIV prefusion intermediates. These mAbs do not react with the static/native surface HIV or cellular antigens, but react with the DAGs. This is a paradigm shift from the current mainstream approach of screening elite patients' bNAbs. PMID- 25505974 TI - Visual outcomes and patient satisfaction after refractive lens exchange with a single-piece diffractive multifocal intraocular lens. AB - Purpose. To report visual outcomes and patient satisfaction after unilateral or bilateral refractive lens exchange (RLE) with a single-piece bifocal diffractive multifocal intraocular lens (MIOL). Methods. All patients underwent RLE with the ZMB00 MIOL (Abbott Medical Optics). Patient charts were reviewed to evaluate the distance, intermediate, and near visual acuity (VA), contrast sensitivity, extent of visual symptoms (0-5), satisfaction (1-5), and rate of spectacle independence between unilateral and bilateral RLE group. Results. Forty-seven eyes of 28 patients were included. No intraoperative complications developed. Mean monocular uncorrected VA at distance, intermediate (67 cm), and near (30 cm) were 0.01 +/- 0.12 (standard deviation), 0.27 +/- 0.18, and 0.15 +/- 0.11, respectively. No eyes lost >1 line of corrected distance VA. Monocular contrast sensitivity remained at normal level. Median scores of halos, night glare, and starbursts for 27 patients were 2.0, 3.0, and 0.0, respectively. Median score of satisfaction was 4.0. There were no differences in visual symptom scores or satisfaction between unilateral and bilateral group (P > 0.05). Eighty percent of 25 patients reported total spectacle freedom, with similar rate between bilateral (82%) and unilateral group (75%) (P = 1.000). Conclusions. RLE with the bifocal diffractive MIOL was safe in presbyopic patients and resulted in a high rate of spectacle independence. PMID- 25505975 TI - Vitreous hemorrhage in pediatric age group. AB - Purpose. To identify and study causes of vitreous hemorrhage (VH) in pediatric age group and to investigate factors predicting visual and anatomical outcomes. Procedure. A retrospective review of patients aged 16 years or less with the diagnosis of vitreous hemorrhage from January 2005 until December 2010. Results. A total number of 230 patients (240 eyes) were identified. Traumatic vitreous hemorrhage accounted for 82.5%. In cases of accidental trauma, final visual acuity of 20/200 was significantly associated with visual acuity of >=20/200 at presentation and the absence of retinal detachment at last follow-up. Patients with nontraumatic vitreous hemorrhage were significantly younger with higher rates of enucleation/evisceration/exenteration and retinal detachment at last follow-up compared to traumatic cases. Conclusion. Trauma is the most common cause of VH in pediatric age group. In this group, initial visual acuity was the most important predictor for visual outcome, and the presence of retinal detachment is a negative predictor for final good visual outcome. The outcome is significantly worse in nontraumatic cases compared to traumatic cases. PMID- 25505976 TI - Intravitreal Aflibercept Outcomes in Patients with Persistent Macular Exudate Previously Treated with Bevacizumab and/or Ranibizumab for Neovascular Age Related Macular Degeneration. AB - Purpose. To assess whether intravitreal aflibercept (2.0 mg) can effectively reduce persistent macular exudate and enhance visual acuity in ranibizumab (0.5 mg) and/or bevacizumab (1.25 mg) treatment resistant patients with neovascular age-related macular degeneration. Methods. This retrospective study included 47 treatment resistant eyes from 47 patients switched to intravitreal aflibercept injections after receiving a minimum of 3 injections with either ranibizumab or bevacizumab. Snellen visual acuity and optical coherence tomography were assessed just prior to the first injection (baseline) and prior to the fourth injection (final). Additionally, anatomical regions of persistent macular exudate were tracked to determine if these areas yielded varying responses to aflibercept. Results. At baseline, patients had received an average of 11.3 injections with any prior anti-VEGF drug (SD 5.96). For whole group analysis, baseline and final central retinal thickness were 370.57 um and 295.7 um (P <= .001), respectively. Baseline and final retinal fluid volumes were 4.81 mm(3) and 4.37 mm(3) (P <= .001), respectively. Baseline and final logMAR were 0.56 and 0.53 (P = 0.301), respectively. Anatomic location of persistent exudate did not appreciably alter treatment outcome. Conclusion. Central retinal thickness and total retinal fluid volume were reduced in ranibizumab and/or bevacizumab treatment resistant patients following three aflibercept injections. No appreciable change in visual acuity was noted. PMID- 25505977 TI - Analysis of femtosecond laser assisted capsulotomy cutting edges and manual capsulorhexis using environmental scanning electron microscopy. AB - Purpose. To investigate the structure and irregularity of the capsulotomy cutting edges created by two femtosecond (FS) laser platforms in comparison with manual continuous circular capsulorhexis (CCC) using environmental scanning electron microscopy (eSEM). Methods. Ten anterior capsulotomies were obtained using two different FS laser cataract platforms (LenSx, n = 5, and Victus, n = 5). In addition, five manual CCC (n = 5) were obtained using a rhexis forceps. The specimens were imaged by eSEM (FEI Quanta 400, OR, USA). Objective metrics, which included the arithmetic mean deviation of the surface (Sa) and the root-mean square deviation of the surface (Sq), were used to evaluate the irregularity of both the FS laser capsulotomies and the manual CCC cutting edges. Results. Several microirregularities were shown across the FS laser capsulotomy cutting edges. The edges of manually torn capsules were shown, by comparison of Sa and Sq values, to be smoother (P < 0.05) than the FS laser capsulotomy edges. Conclusions. Work is needed to understand whether the FS laser capsulotomy edge microirregularities, not seen in manual CCC, may act as focal points for the concentration of stress that would increase the risk of capsular tear during phacoemulsification as recently reported in the literature. PMID- 25505978 TI - Effect on intraocular pressure of switching from latanoprost and travoprost monotherapy to timolol fixed combinations in patients with normal-tension glaucoma. AB - Purpose. To evaluate the effect on intraocular pressure (IOP) of switching from latanoprost and travoprost monotherapy to timolol fixed combinations in Japanese patients with normal-tension glaucoma (NTG). Methods. 27 NTG patients (54 eyes) were compared IOP, superficial punctuate keratitis (SPK) scores, and conjunctival injection scores in eyes treated with prostaglandin (PG) or PG analog/beta blocker (PG/b) fixed-combination 6 months after the change in therapy. Results. The mean baseline intraocular pressure was 17.4 +/- 1.59 mmHg in eyes receiving PG therapy only and 17.4 +/- 1.69 mmHg in eyes switched to PG/b. Switching to fixed combination therapy from PG monotherapy, the mean IOP was 13.1 +/- 1.79 mmHg (P < 0.001) (-24.71% reduction from baseline) at 6 months. The mean conjunctival injection score was 0.69 for eyes on PG monotherapy and 0.56 for eyes on fixed combination therapy (P = 0.028). The mean SPK scores were 0.46 and 0.53. This difference was not statistically significant (P = 0.463). Conclusions. Switching from PG monotherapy to PG/b fixed combination therapy for NTG resulted in a greater intraocular pressure reduction than PG alone without increasing the number of instillations. PMID- 25505979 TI - Spectral domain optical coherence tomographic findings of bietti crystalline dystrophy. AB - We analyzed the OCT features of 24 eyes of 12 patients with Bietti crystalline dystrophy (BCD) with the Heidelberg HRA2-OCT. Seventeen of 24 eyes were in intermediate stage of the disease and seven in advanced stage of the disease at the time of latest OCT examination performed in 2014. Outer retinal tubulations and retinal hyperreflective dots were present in 20 of 24 eyes. The remaining four eyes had advanced disease with very thin retina. Appearance of bright plaque on top of RPE-Bruch membrane was present in all eyes. Choroidal hyperreflective spots were noted in 19 of 24 eyes. The remaining five eyes had advanced disease stage with very thin choroid. Mean central macular thickness was 163.08 MUm +/- 62.52 for all eyes (170.35 MUm +/- 56.46 in eyes with intermediate disease and 145.42 MUm +/- 77.2 in eyes with advanced disease). Mean subfoveal choroidal thickness was 95.37 MUm +/- 55.93 for the study eyes (116.47 +/- 46.92 MUm in eyes with intermediate disease and 44.14 MUm +/- 42.43 in eyes with advanced disease). Choroidal hyperreflective spots were noted in 21 of 24 eyes (87.5%). SD OCT shows the disease progression in retinal and choroidal layers delicately in eyes with BCD and expands our knowledge about the ongoing disease process. PMID- 25505980 TI - Serum leptin levels in treatment-naive patients with clinically isolated syndrome or relapsing-remitting multiple sclerosis. AB - Several studies have investigated leptin levels in patients with multiple sclerosis (MS) with somewhat conflicting results. They have all focused on patients with established relapsing-remitting (RR) MS but have not specifically looked at patients with clinically isolated syndrome (CIS) suggestive of MS, in the early stages of disease. In this study, serum leptin levels were measured in 89 treatment-naive patients with CIS (53 patients) or RRMS (36 patients) and 73 controls searching for differences between the groups and for associations with several disease parameters. The expected significant sexual dimorphism in leptin levels (higher levels in females) was observed in both MS patients and controls. Increased leptin levels were found in female patients with RRMS compared to female controls (P = .003) and female CIS patients (P = .001). Female CIS patients had comparable levels to controls. Leptin levels correlated positively to disease duration, but not to EDSS, in female patients with RRMS. The results of the present study do not indicate involvement of leptin in the early stages of MS. Normal leptin levels in patients with CIS suggest that leptin does not have a pathogenic role. The ratio leptin/BMI increases during disease course in female MS patients in a time-dependent and disability-independent manner. PMID- 25505981 TI - The influence of antiobesity media content on intention to eat healthily and exercise: a test of the ordered protection motivation theory. AB - This study extended the ordered protection motivation framework to determine whether exposure and attention to antiobesity media content increases people's appraisals of threat and their ability to cope with it. It also assesses whether these cognitive processes, in turn, affected people's intention to abide by the practices recommended to prevent obesity. The results of a national online survey using a nonprobability sample indicate that attention to mediated obesity and related information significantly increased people's intention to exercise as well as their overall coping appraisals (the perceived effectiveness of the recommended behaviors and their ability to perform them). Likewise, increased threat and coping appraisals were both found to significantly influence people's intention to exercise and diet. Coping (rather than threat) appraisals more strongly predicted behavioral intent. Following the attitude-behavior literature, behavioral intention was used as the most proximate predictor of actual behavior (i.e., stronger intentions increase the likelihood of behavior change). PMID- 25505982 TI - Effects of high phosphorus diet on bone metabolism-related gene expression in young and aged mice. AB - In this study, the effects of high phosphorus (P) diet on bone metabolism-related gene expression were investigated in young and aged mice. Twelve- and 80-week-old ddY male mice were divided into two groups, respectively, and fed a control diet containing 0.3% P or a high P diet containing 1.2% P. After 4 weeks of treatment, serum parathyroid hormone (PTH) concentration was significantly higher in the high P groups than in the control groups in both young and aged mice and was significantly higher in aged mice than in young mice fed the high P diet. High P diet significantly increased receptor activator of NF-kappaB ligand (RANKL) mRNA in the femur of both young and aged mice and significantly increased the RANKL/osteoprotegerin (OPG) mRNA ratio only in aged mice. High P diet significantly increased mRNA expression of transient receptor potential vanilloid type 6, calbindin-D9k, and plasma membrane Ca(2+)-ATPase 1b in the duodenum of both young and aged mice. These results suggest that high P diet increased RANKL mRNA expression in the femur and calcium absorption-related gene expression in the duodenum regardless of age. Furthermore, the high P diet-induced increase in PTH secretion might increase the RANKL/OPG mRNA ratio in aged mice. PMID- 25505983 TI - Effects of canned pineapple consumption on nutritional status, immunomodulation, and physical health of selected school children. AB - This randomized, controlled trial examined the effects of canned pineapple consumption on immunomodulation, nutritional status, and physical health of ninety-eight (98) school children with mean age of 8.44 +/- 0.20. The study participants were divided into three groups: Group A (33) includes subjects who were not given canned pineapple, Group B (33) includes those who were given 140 g, and Group C (32) includes those given 280 g of canned pineapple for nine weeks. Each major group was further divided into two groups: normal (N) and underweight (U) based on 2007 WHO Growth Reference Standards. Sociodemographic, anthropometric, physical examination, dietary intake, hemoglobin level, and immunological data were analyzed. Results showed a decrease in incidence of viral and bacterial infections for both Group B and Group C (normal and underweight) after canned pineapple consumption. Granulocyte production increased by 0.77 26.61% for normal weight subjects and 14.95-34.55% for underweight. CD16+56 count augmented by 20.44-22.13% for normal weight and 3.57-15.89% for underweight subjects. Thus, intake of both one can (140 g) and two cans (280 g) of canned pineapple may shorten the duration and incidence of infection and may increase the production of granulocytes and CD16+56, but intake of two cans (280 g) demonstrated higher granulocyte and CD16+56 production. This trial is registered with Philippine Health Research Registry: PHRR140826-000225. PMID- 25505984 TI - Rapid Screening of Psychological Well-Being of Patients with Chronic Illness: Reliability and Validity Test on WHO-5 and PHQ-9 Scales. AB - This study intended to test the reliability and validity of two simple psychological screening scales, the World Health Organization Well-being Index (WHO-5) and the 9-item Patient Health Questionnaire (PHQ-9), in patients with chronic illness in Taiwan and to understand the psychological well-being of patients with chronic illness (e.g., metabolic syndrome) in Taiwan and the incidences of psychological problems that follow. The research design of this study was a descriptive cross-sectional study. The sample comprised 310 patients with metabolic syndrome (MS), aged 20 years or more, from the outpatient clinic of a municipal hospital in Taiwan. This study used questionnaires to collect basic information, including physiological indices, WHO-5 and PHQ-9 that were used. "Hospital Anxiety and Depression scale (HADS)," and "World Health Organization Quality of Life-Short-form Version for Taiwan (WHOQOL)". Results are as follows: (1) compared to PHQ-9, the reliability and validity of WHO-5 are better for screening the psychological well-being of patients with chronic illness. (2) The features of WHO-5 are high sensitivity, briefness, and ease-of use. The incidence of depression in patients with metabolic syndrome was approximately 1.0-6.5%, which is significantly lower than that of western countries. PMID- 25505985 TI - Mental Health Promotion in School: Schoolchildren's and Families' Viewpoint. AB - While developing mental health work in schools, it is very important to consider the viewpoint of pupils. Parents can also give remarkable information on their children's viewpoint. The purpose of this study was to produce a description of the concepts used by schoolchildren aged 12-16 years and their families associated with promoting mental health in schools. The research material comprised interviews with schoolchildren and mothers, and verbal answers from the school well-being profile survey (n = 426). The analysis was conducted by applying the grounded theory method as introduced by Strauss. The study was conducted in a Finnish comprehensive school. PMID- 25505986 TI - How public health nurses identify and intervene in child maltreatment based on the national clinical guideline. AB - Objectives. To describe how Finnish public health nurses identify and intervene in child maltreatment and how they implement the National Clinical Guideline in their work. Design and Sample. Cross-sectional survey of 367 public health nurses in Finland. Measures. A web-based questionnaire developed based on the content areas of the guideline: identifying, intervening, and implementing. Results. The respondents reported they identify child maltreatment moderately (mean 3.38), intervene in it better (4.15), and implement the guideline moderately (3.43, scale between 1 and 6). Those with experience of working with maltreated children reported they identify them better (P < 0.001), intervene better (P < 0.001), and implement the guideline better (P < 0.001) than those with no experience. This difference was also found for those who were aware of the guideline, had read it, and participated in training on child maltreatment, as compared to those who were not aware of the guideline, had not read it, or had not participated in such training. Conclusions. The public health nurses worked quite well with children who had experienced maltreatment and families. However, the results point out several developmental targets for increasing training on child maltreatment, for devising recommendations for child maltreatment, and for applying these recommendations systematically in practice. PMID- 25505987 TI - Extensive Genetic Diversity among Clinical Isolates of Mycobacterium tuberculosis in Central Province of Iran. AB - Human tuberculosis caused by Mycobacterium tuberculosis (Mtb) remains a significant disease in many countries. According to Iran's borders with Afghanistan and Pakistan, which are among the 22 high burden countries around the world, this study was conducted to analyze the current molecular epidemiology of tuberculosis and survey genetic diversity of Mtb strains in Markazi Province in center of Iran. In this experimental study, 75 sputum specimens and one gastric lavage from all smear-positive TB patients admitted to the public hospitals across the Markazi Province were cultured on specific mycobacterial culture media. Genomic DNA was digested by PvuII and transferred to positively charged nylon membrane by southern blotting method and hybridization by PGRS and DR probes. Genotyping of the isolates by PGRS-RFLP and DR-RFLP displayed a wide range of genetic diversity as 25 and 26 genotypes were identified, respectively. Generally speaking, despite the relatively limited number of isolates in the study, high age of patients and also large heterogeneity found in the setting are both in opposition to active circulation of Mtb strains between patients under study either Iranian or Afghan nationals. Thus, it seems that reactivation of latent infection has had the main role in the spread of tuberculosis. PMID- 25505988 TI - Latex hypersensitivity among allergic Egyptian children: relation to parental/self reports. AB - BACKGROUND: Latex allergy is one of the major health concerns and allergic reactions to latex may be serious and fatal. PURPOSE: In this study, we sought to determine the frequency of latex hypersensitivity in a group of allergic Egyptian infants and children and its relation to the history provided by the patients or caregivers. METHODS: We consecutively enrolled 400 patients with physician diagnosed allergic diseases. The study measurements included clinical evaluation for the site and duration of allergy, history suggestive of latex allergy, family history of allergy, and skin prick testing (SPT) using a commercial latex extract. RESULTS: The study revealed that 16/400 (4%) patients had positive SPT; 11 of them only had positive history of sensitivity to latex. Positive latex SPT was reported in 3.4% (11/326) of patients with bronchial asthma, 5.9% (7/118) of patients with skin allergy, and 4.5% (2/44) of patients with allergic rhinitis. SPT was positive in 7.4% (4/54) of patients with concomitant respiratory and skin allergy. Latex SPT was more specific than sensitive (97.69% and 77.77%, resp.) with a negative predictive value of 99.47%. CONCLUSION: Although underrecognized, latex is an important allergen in the pediatric age group with a sensitization frequency of 4% among allergic children. It was observed to be especially associated with multiple allergic diseases coexisting in the same patient. Pediatric allergologists should educate their patients on latex allergy and encourage the use of latex-free products. PMID- 25505989 TI - Computational study of estrogen receptor-alpha antagonist with three-dimensional quantitative structure-activity relationship, support vector regression, and linear regression methods. AB - Human estrogen receptor (ER) isoforms, ERalpha and ERbeta, have long been an important focus in the field of biology. To better understand the structural features associated with the binding of ERalpha ligands to ERalpha and modulate their function, several QSAR models, including CoMFA, CoMSIA, SVR, and LR methods, have been employed to predict the inhibitory activity of 68 raloxifene derivatives. In the SVR and LR modeling, 11 descriptors were selected through feature ranking and sequential feature addition/deletion to generate equations to predict the inhibitory activity toward ERalpha. Among four descriptors that constantly appear in various generated equations, two agree with CoMFA and CoMSIA steric fields and another two can be correlated to a calculated electrostatic potential of ERalpha. PMID- 25505991 TI - Synthesis, Physicochemical Properties, and Antimicrobial Studies of Iron (III) Complexes of Ciprofloxacin, Cloxacillin, and Amoxicillin. AB - Iron (III) complexes of ciprofloxacin, amoxicillin, and cloxacillin were synthesized and their aqueous solubility profiles, relative stabilities, and antimicrobial properties were evaluated. The complexes showed improved aqueous solubility when compared to the corresponding ligands. Relative thermal and acid stabilities were determined spectrophotometrically and the results showed that the complexes have enhanced thermal and acid stabilities when compared to the pure ligands. Antimicrobial studies showed that the complexes have decreased activities against most of the tested microorganisms. Ciprofloxacin complex, however, showed almost the same activity as the corresponding ligand. Job's method of continuous variation suggested 1 : 2 metals to ligand stoichiometry for ciprofloxacin complex but 1 : 1 for cloxacillin complex. PMID- 25505990 TI - Synthesis Antimicrobial and Anticancer Evaluation of 1-Aryl-5-(o-methoxyphenyl)-2 S-benzyl Isothiobiurets. AB - A series of S-benzyl aryl thiourea were condensed with o-Methoxy phenyl isocyanate to yield respective isothiobiuret derivatives. The newly synthesized compounds were characterized by (1)H-NMR, IR, and Mass Spectral studies and tested for biological activities. PMID- 25505992 TI - Peritoneal Dialysis as a First versus Second Option after Previous Haemodialysis: A Very Long-Term Assessment. AB - For renal replacement therapy, overall survival is more important than the choice of currently available individual therapy. Objectives. To compare patients and technique survival on peritoneal dialysis as first treatment (PDF) versus after previous haemodialysis (HDPD) and other indicators of follow-up. Methods. We prospectively studied 110 incident patients, during the period from August 4, 1993, to June 30, 2012, for patients and technique survival (Kaplan-Meier) (log rank P < 0.05). Results. Groups: (A) PDF: 37 patients, 24 females, age: 52.2 +/- 14.9 years old, time at risk: 2123 patient-months (p/m), mean: 57 +/- 42 months; (B) HDPD: 73 patients, 42 females, age: 52.45 +/- 14.7 years old, time in haemodialysis: 3569.2 (p/m), range: 3-216 months, mean: 49 +/- 45 months, time at risk in PD: 3700 (p/m), mean: 51 +/- 49 months. Patients' survival: (A) PDF: 100%, 76.6%, 65.6%, and 19.7%; (B) HDPD: 95.4%, 65.6%, 43%, and 43% at 12, 60, 120, and 144 months, respectively, P = 0.34. TECHNIQUE: (A) PDF: 100%, 90%, 59.8%, and 24%; (B) HDPD: 94%, 75%, 32%, and 32% at 12, 60, 120, and 144 months, respectively, P = 0.40. Conclusions. Comparable patient and technique survival were observed. Peritoneal dialysis enables a greater extension of renal replacement therapy for patients with serious difficulties continuing with haemodialysis. PMID- 25505993 TI - Soluble fas and the -670 polymorphism of fas in lupus nephritis. AB - This study was performed to clarify the role of soluble Fas (sFas) in lupus nephritis (LN) and establish a potential relationship between LN and the -670 polymorphism of Fas in 67 patients with systemic lupus erythematosus (SLE), including a subset of 24 LN patients with proteinuria. Additionally, a group of 54 healthy subjects (HS) was included. The allelic frequency of the -670 polymorphism of Fas was determined using PCR-RFLP analysis, and sFas levels were assessed by ELISA. Additionally, the WT-1 protein level in urine was measured. The Fas receptor was determined in biopsies by immunohistochemistry (IHC) and in situ hybridization (FISH) and apoptotic features by TUNEL. Results. The -670 Fas polymorphism showed that the G allele was associated with increased SLE susceptibility, with an odds ratio (OR) of 1.86. The sFas was significantly higher in LN patients with the G/G genotype, and this subgroup exhibited correlations between the sFas level and proteinuria and increased urinary WT-1 levels. LN group shows increased expression of Fas and apoptotic features. In conclusion, our results indicate that the G allele of the -670 polymorphism of Fas is associated with genetic susceptibility in SLE patients with elevated levels of sFas in LN with proteinuria. PMID- 25505995 TI - Design and evaluation of polyox and pluronic controlled gastroretentive delivery of troxipide. AB - Objective. Objective of the present work was to develop site-specific gastroretentive drug delivery of Troxipide using polymers Pluronic F127 and Polyox 205 WSR. Troxipide is a novel gastroprotective agent with antiulcer, anti inflammatory, and mucus secreting properties with elimination half-life of 7.4 hrs. Troxipide inhibits H. pylori-derived urease. It is mainly absorbed from stomach. Methods. 3(2) factorial design was applied to study the effect of independent variable. Effects of concentration of polymer on dependant variables as swelling index, hardness, and % drug release were studied. Pluronic F127 and Polyox 205 WSR were used as rate controlled polymer. Sodium bicarbonate and citric acid were used as effervescent-generating agent. Results. From the factorial batches, it was observed that formulation F5 (19% Pluronic F127 and 80% Polyox 205 WSR) showed optimum controlled drug release (98.60% +/- 1.82) for 10 hrs with ability to float >12 hrs. Optimized formulation characterized by FTIR and DSC studies confirmed no chemical interactions between drug and polymer. Gastroretention for 6 hrs for optimized formulations was confirmed by in vivo X ray placebo study. Conclusion. Results demonstrated feasibility of Troxipide in the development of gastroretentive site-specific drug delivery. PMID- 25505996 TI - An extremely rare reason for failure of left sided pacemaker implantation. AB - We reported a case of isolated anomaly of the left brachiocephalic vein which is diagnosed during a permanent pacemaker implantation. It is a very rare anomaly and makes the left sided pacemaker implantation impossible. PMID- 25505997 TI - Endodontic management of a maxillary molar with three mesiobuccal canals. AB - It is imperative that the clinician should have comprehensive knowledge about the normal anatomy and its variations of the teeth as the deviations from the usual are very common. An increased awareness of unusual anatomy and a better understanding of the root canal system guide the clinician in accurate diagnosis and treatment of such variations in order to achieve a successful endodontic outcome. The maxillary first molar has been shown to have a wide variation in respect to the number of canals specifically noted in the mesiobuccal root. The current case report shows the successful management of a maxillary molar in which the mesiobuccal root had three canals. PMID- 25505998 TI - Hypochondroplasia, Acanthosis Nigricans, and Insulin Resistance in a Child with FGFR3 Mutation: Is It Just an Association? AB - FGFR3 mutations cause wide spectrum of disorders ranging from skeletal dysplasias (hypochondroplasia, achondroplasia, and thanatophoric dysplasia), benign skin tumors (epidermal nevi, seborrhaeic keratosis, and acanthosis nigricans), and epithelial malignancies (multiple myeloma and prostate and bladder carcinoma). Hypochondroplasia is the most common type of short-limb dwarfism in children resulting from fibroblast growth factor receptor 3 (FGFR3) mutation. Acanthosis nigricans might be seen in severe skeletal dysplasia, including thanatophoric dysplasia and SADDAN syndrome, without a biochemical evidence of hyperinsulinemia. Insulin insensitivity and acanthosis nigricans are uncommonly seen in hypochondroplasia patients with FGFR3 mutations which may represent a new association. We aim to describe the association of hypochondroplasia, acanthosis nigricans, and insulin resistance in a child harboring FGFR3 mutation. To our knowledge, this is the first case report associating the p.N540 with acanthosis nigricans and the second to describe hyperinsulinemia in hypochondroplasia. This finding demonstrates the possible coexistence of insulin insensitivity and acanthosis nigricans in hypochondroplasia patients. PMID- 25506000 TI - Biliary cystadenoma: an unusual cause of acute pancreatitis and indication for mesohepatectomy. AB - The classic presentation of cystic hepatobiliary lesions is usually nonspecific and often identified incidentally. Here we describe the case of a patient presenting with acute pancreatitis resulting from a large centrally located biliary cystadenoma compressing the pancreas. Determination of the origin of the cystic lesion was difficult on imaging studies. Due to the difficult location of the lesion, a complete surgical resection was achieved with mesohepatectomy and the suspected diagnosis confirmed by pathology. The patient continues to do well 2 years post-op with no signs of recurrence. PMID- 25505999 TI - Treatment of a gastric lactobezoar with N-acetylcysteine. AB - Lactobezoars are a rare finding with potentially serious sequelae in pediatric patients with feeding intolerance. Aggressive treatment may be preferred to traditional treatments to avoid complications in medically complex patients. In our patient, N-acetylcysteine lavage was a safe and effective alternative that resulted in rapid resolution of his feeding intolerance. PMID- 25506001 TI - Partial Gene Deletions of PMP22 Causing Hereditary Neuropathy with Liability to Pressure Palsies. AB - Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal neuropathy that is commonly caused by a reciprocal 1.5 Mb deletion on chromosome 17p11.2, at the site of the peripheral myelin protein 22 (PMP22) gene. Other patients with similar phenotypes have been shown to harbor point mutations or small deletions, although there is some clinical variation across these patients. In this report, we describe a case of HNPP with copy number changes in exon or promoter regions of PMP22. Multiplex ligation-dependent probe analysis revealed an exon 1b deletion in the patient, who had been diagnosed with HNPP in the first decade of life using molecular analysis. PMID- 25506002 TI - Systemic lupus erythematosus with hepatosplenic granuloma: a rare case. AB - Background. Systemic lupus erythematosus (SLE) is an autoimmune disease which is known to present with a wide variety of clinical manifestations. Case Report. A 15-year-old male presented with complaints of moderate grade fever and generalized body swelling. There was no history of cough, weight loss, joint pain, oral ulcerations, skin rash, photosensitivity, loss of hair, pain abdomen, jaundice, or any significant illness in the past. Contrast enhanced computerized tomography of the abdomen revealed hypodense lesions in both liver and spleen (without contrast enhancement), suggestive of granulomas along with few retroperitoneal and mesenteric lymph nodes. On the basis of immunological tests and renal biopsy report, SLE with hepatosplenic granulomatosis diagnosis was made. He was given pulse methylprednisolone 500 mg, for 3 days and he showed dramatic improvement clinically. Conclusion. Hepatic and splenic granulomas are not common in SLE, but this should be kept in differential diagnosis. PMID- 25505994 TI - mTOR Signaling in Protein Translation Regulation: Implications in Cancer Genesis and Therapeutic Interventions. AB - mTOR is a central nutrient sensor that signals a cell to grow and proliferate. Through distinct protein complexes it regulates different levels of available cellular energy substrates required for cell growth. One of the important functions of the complex is to maintain available amino acid pool by regulating protein translation. Dysregulation of mTOR pathway leads to aberrant protein translation which manifests into various pathological states. Our review focuses on the role mTOR signaling plays in protein translation and its physiological role. It also throws some light on available data that show translation dysregulation as a cause of pathological complexities like cancer and the available drugs that target the pathway for cancer treatment. PMID- 25506003 TI - Aeromonas hydrophila Sepsis Associated with Consumption of Raw Oysters. AB - Introduction. Aeromonas hydrophila is a gram negative bacillus that is native to aquatic environments that is increasingly reported in humans. This case is remarkable for A. hydrophila with an initial presentation of acute pancreatitis. Case Presentation. A 61-year-old male presented to the emergency department with nausea, vomiting, and abdominal pain for two days. His past medical history was significant for alcohol abuse. Initial laboratory examination showed an elevated white blood cell count, elevated lipase, and elevated liver function tests (LFT). Computer tomography (CT) showed peripancreatic inflammatory changes and retroperitoneal free fluid, suggestive of acute pancreatitis. The patient was treated with intravenous (IV) fluids and IV meropenem. After two days, the patient developed sepsis and respiratory failure and was intubated. Blood cultures were positive for Aeromonas hydrophila sensitive to ciprofloxacin which was added to his treatment. Additionally, it was discovered that this patient had recently vacationed in Florida where he consumed raw oysters. He was discharged home on the eighth day of the hospital admission. Conclusion. This is a rare case of A. hydrophila sepsis in an elderly patient with acute pancreatitis and a history of consumption of raw oysters. This case suggests that A. hydrophila can cause disseminated infection in immunocompetent individuals. PMID- 25506004 TI - Necrotizing Soft Tissue Infection Occurring after Exposure to Mycobacterium marinum. AB - Cutaneous infections caused by Mycobacterium marinum have been attributed to aquarium or fish exposure after a break in the skin barrier. In most instances, the upper limbs and fingers account for a majority of the infection sites. While previous cases of necrotizing soft tissue infections related to M. marinum have been documented, the importance of our presenting case is to illustrate the aggressive nature of M. marinum resulting in a persistent necrotizing soft tissue infection of a finger that required multiple aggressive wound debridements, followed by an amputation of the affected extremity, in order to hasten recovery. PMID- 25506005 TI - Successfully treated calcific uremic arteriolopathy: two cases of a high anion gap metabolic acidosis with intravenous sodium thiosulfate. AB - Calcific uremic arteriolopathy (CUA) is a rare and potentially fatal disorder of calcification involving subcutaneous small vessels and fat in patients with renal insufficiency. We describe the successful use of intravenous sodium thiosulfate (STS) for the treatment of CUA in two patients. The first case was complicated by the development of a severe anion gap metabolic acidosis, which was accompanied by a seizure. Both patients had complete wound healing within five months. Although STS should be considered in the treatment of CUA, little is known about pharmacokinetics and additional studies are required to determine dosing strategies to minimize severe potential side effects. PMID- 25506006 TI - Primary neuroendocrine tumor in brain. AB - The incidence of brain metastases for neuroendocrine tumor (NET) is reportedly 1.5~5%, and the origin is usually pulmonary. A 77-year-old man presented to our hospital with headache and disturbance of specific skilled motor activities. Computed tomography (CT) showed a massive neoplastic lesion originating in the left temporal and parietal lobes that caused a mass edematous effect. Grossly, total resection of the tumor was achieved. Histological examination revealed much nuclear atypia and mitotic figures. Staining for CD56, chromogranin A, and synaptophysin was positive, indicating NET. The MIB-1 index was 37%. Histopathologically, the tumor was diagnosed as NET. After surgery, gastroscopy and colonoscopy were performed, but the origin was not seen. After discharge, CT and FDG-PET (fluoro-2-deoxy-d-glucose positron emission tomography) were performed every 3 months. Two years later we have not determined the origin of the tumor. It is possible that the brain is the primary site of this NET. To our knowledge, this is the first reported case of this phenomenon. PMID- 25506007 TI - Late isolated central nervous system relapse from ovarian serous adenocarcinoma: a case report and literature review. AB - Central nervous system involvement by ovarian serous adenocarcinoma is rare. We report a case of a 60-year-old woman that developed brain metastasis as isolated site of relapse 4.5 years after a complete resection and adjuvant chemotherapy for a stage Ic disease. She proceeded to a craniotomy with resection of the lesion and, subsequently, to a whole brain radiotherapy. Nineteen months later, she developed carcinomatous meningitis as isolated site of recurrence. Patient was submitted to intrathecal chemotherapy with methotrexate; however, she died from progressive neurologic involvement disease few weeks later. PMID- 25506008 TI - Recognizing presentations of pemphigoid gestationis: a case study. AB - Introduction. Pemphigoid gestationis (PG) is an autoimmune blistering disease that occurs in approximately 1 in 50,000 pregnancies. Failing to recognize PG may lead to inadequate maternal treatment and possible neonatal complications. Case Report. At 18 weeks of gestation, a 36-year-old otherwise healthy Caucasian G4P1 presented with pruritic papules on her anterior thighs, initially treated with topical steroids. At 31 weeks of gestation, she was switched to oral steroids after her rash and pruritus worsened. The patient had an uncomplicated SVD of a healthy female infant at 37 weeks of gestation and was immediately tapered off steroid treatment, resulting in a severe postpartum flare of her disease. Discussion. This case was similar to reported cases of pruritic urticarial papules followed by blisters; however, this patient had palm, sole, and mucous membrane involvement, which is rare. Biopsy for direct immunofluorescence or ELISA is the preferred test for diagnosis. Previous case reports describe severe postdelivery flares that require higher steroid doses. Obstetrical providers need to be familiar with this disease although it is rare, as this condition can be easily confused with other dermatoses of pregnancy. Adequate treatment is imperative for the physical and psychological well-being of the mother and infant. PMID- 25506009 TI - Management of posterior reversible syndrome in preeclamptic women. AB - Posterior reversible encephalopathy syndrome (PRES) is a neurological syndrome associated with a number of conditions including preeclampsia. It is characterized by seizures, alteration of consciousness, visual disturbances, and symmetric white matter abnormalities, typically in the posterior parietooccipital regions of the cerebral hemispheres, at computed tomography (CT) and magnetic resonance (MRI). We report three new cases of PRES in preeclamptic patients and describe the management of these patients. We present a brief review of other cases in the literature, with particular attention to the anesthetic management. PMID- 25506010 TI - Vaginal evisceration: an unexpected complication of conization. AB - Background. Large loop excision of the transformation zone (LLETZ) is routinely performed for the management of high grade intracervical neoplasia (CIN). Several uncommon complications have been described, including postoperative peritonitis, pseudoaneurysm of uterine artery, and bowel fistula. We report a unique case of postoperative vaginal evisceration and the subsequent management. Case. A 73 years-old woman underwent LLETZ for high grade CIN. On postoperative day 3, she was admitted for small bowel evisceration through the vagina. Surgical management was based on combined laparoscopic and transvaginal approach and consisted in bowel inspection and reinstatement, peritoneal washing, and dehiscence repair. Conclusions. Vaginal evisceration is a rare but potentially serious complication of pelvic surgery. This case report is to make clinicians aware of such complication following LLETZ and its management. PMID- 25506011 TI - Metastatic Basal cell carcinoma accompanying gorlin syndrome. AB - Gorlin-Goltz syndrome or basal cell nevus syndrome is an autosomal dominant syndrome characterized by skeletal anomalies, numerous cysts observed in the jaw, and multiple basal cell carcinoma of the skin, which may be accompanied by falx cerebri calcification. Basal cell carcinoma is the most commonly skin tumor with slow clinical course and low metastatic potential. Its concomitance with Gorlin syndrome, resulting from a mutation in a tumor suppressor gene, may substantially change morbidity and mortality. A 66-year-old male patient with a history of recurrent basal cell carcinoma was presented with exophthalmus in the left eye and the lesions localized in the left lateral orbita and left zygomatic area. His physical examination revealed hearing loss, gapped teeth, highly arched palate, and frontal prominence. Left orbital mass, cystic masses at frontal and ethmoidal sinuses, and multiple pulmonary nodules were detected at CT scans. Basal cell carcinoma was diagnosed from biopsy of ethmoid sinus. Based on the clinical and typical radiological characteristics (falx cerebri calcification, bifid costa, and odontogenic cysts), the patient was diagnosed with metastatic skin basal cell carcinoma accompanied by Gorlin syndrome. Our case is a basal cell carcinoma with aggressive course accompanying a rarely seen syndrome. PMID- 25506012 TI - Familial pancreatic cancer: the case for prophylactic pancreatectomy in lieu of serial screening and shared decision making. AB - At-risk family members with familial pancreatic cancer (FCaP) face uncertainty regarding the individual risk of developing pancreatic cancer (CaP) and whether to choose serial screening or prophylactic pancreatectomy to avoid CaP. We treated 2 at-risk siblings with a history of FCaP, congenital hepatic fibrosis (CHF), and jaundice secondary to a bile duct stricture. In one, a pancreaticoduodenal resection was done and in the second a total pancreatectomy. Malignancy was not present, but extensive pancreatic intraepithelial neoplasia (PanIn) 2 was present throughout both pancreata. The clinical course and literature review are presented along with the previously unreported association of CHF and CaP. PMID- 25506013 TI - Two cases of suprachoroidal hemorrhage after implantation of an ex-press miniature glaucoma device and an intraocular lens. AB - Suprachoroidal hemorrhage is a rare complication of ophthalmic surgery in general and of glaucoma filtration procedures in particular. We present herein two cases of suprachoroidal hemorrhage in aphakic patients after simultaneous implantation of an Ex-Press miniature glaucoma device and an intraocular lens. Although a rare complication, we have now seen two cases develop in previously aphakic patients when we have attempted to place an Ex-Press miniature glaucoma device in conjunction with placement of a secondary intraocular lens. These two cases suggest that greater caution is warranted when attempting to surgically implant an express mini shut in the aphakic patient. PMID- 25506014 TI - Fourth primary malignant tumor in a patient with possible li-fraumeni syndrome: synchronous diagnosis of postirradiation sarcoma, cutaneous relapse of a previous soft tissue sarcoma, and lung adenocarcinoma. AB - We present a 46-year-old female patient who is diagnosed with synchronous postirradiation sarcoma, cutaneous relapse of a previous soft tissue sarcoma, and lung adenocarcinoma. More than one malignant tumor at the same time with an accompanying relapse of a previous malignant tumor is a rare entity. A relatively young patient diagnosed with adenocarcinoma of the urethra before age 40, which is an unusual tumor for that age, later three more different malignant tumors being diagnosed, two of which are synchronous, causes the suspicion of Li Fraumeni syndrome. PMID- 25506015 TI - Two patients with osteochondral injury of the weight-bearing portion of the lateral femoral condyle associated with lateral dislocation of the patella. AB - Complications of patellar dislocation include osteochondral injury of the lateral femoral condyle and patella. Most cases of osteochondral injury occur in the anterior region, which is the non-weight-bearing portion of the lateral femoral condyle. We describe two patients with osteochondral injury of the weight-bearing surface of the lateral femoral condyle associated with lateral dislocation of the patella. The patients were 18- and 11-year-old females. Osteochondral injury occurred on the weight-bearing surface distal to the lateral femoral condyle. The presence of a free osteochondral fragment and osteochondral injury of the lateral femoral condyle was confirmed on MRI and reconstruction CT scan. Treatment consisted of osteochondral fragment fixation or microfracture, as well as patellar stabilization. Osteochondral injury was present in the weight-bearing portion of the lateral femoral condyle in both patients, suggesting that the injury was caused by friction between the patella and lateral femoral condyle when the patella was dislocated or reduced at about 90 degrees flexion of the knee joint. These findings indicate that patellar dislocation may occur and osteochondral injury may extend to the weight-bearing portion of the femur even in deep flexion, when the patella is stabilized on the bones of the femoral groove. PMID- 25506016 TI - Bilateral simultaneous femoral neck fracture mimicking abdominal pain in a cerebral palsy patient. AB - Simultaneous bilateral femoral neck fractures are unusual lesions, generally associated with an underlying condition which causes impaired bone mineralization, triggered by an increased bone stress. We present a 24-year-old cerebral palsy patient, who was previously evaluated in another institution due to inability to walk, interpreted as abdominal pain. No alteration in blood analysis or abdominal X-rays was found. As no response to treatment was observed, a new abdominal X-ray was taken, which incidentally depicted bilateral medial femoral neck fracture. He was referred to our practice after a resection arthroplasty was offered in another institution. After admission, bilateral one stage THA was performed. Several reports emphasize bone disease as a major precipitating factor, and there is an increased incidence of hip fractures in chronic epilepsy, renal osteodystrophy, and chronic steroid use. Femoral head resection has been proven to be effective in immobilized patients, whereas this was not a reasonable option in this patient who presented walking ability. Despite the treatment election, primary care physicians should be aware of and alert to the possibility of fractures in patients with neurological disorders and calcium metabolism alterations. Late diagnosis of orthopedic injuries in this type of patients may lead to permanent disability. PMID- 25506017 TI - Chronologic presentation of a severe case of progressive hemifacial atrophy (parry-romberg syndrome) with the loss of an eye. AB - Progressive hemifacial atrophy, also known as Parry-Romberg syndrome, is a slowly advancing degenerative disease that mostly affects the cutaneous, subcutaneous fatty tissue, muscle tissue, and bone structures on one side of the face. We describe the chronological progression of this very rare syndrome from early childhood until adulthood in a patient who developed severe atrophy and lost one eye. We also discuss the aetiology and pathophysiology of this syndrome. PMID- 25506018 TI - Psychogenic nonepileptic spells in chronic epilepsy patients with moderate cognitive impairment: the need for video EEG monitoring for adequate diagnosis. AB - The objective of our study was to emphasize the importance of intensive video EEG monitoring in patients with a well-established diagnosis of epilepsy with moderate cognitive impairment. The idea was to diagnose new onset frequent atypical events prompting the need for frequent emergency room and clinic visits and hospital admissions. Retrospective chart reviews were conducted on patients with chronic epilepsy with moderate cognitive impairment who had an increased incidence of new onset episodes different from the baseline seizures. Data were acquired from electronic medical records. The hospital's Institutional Review Board gave approval for this retrospective analysis of patient records. We retrospectively analyzed data from three patients with an established diagnosis of epilepsy. Extensive chart reviews were performed with emphasis on type and duration of epilepsy and description of baseline seizures and description of new events. There were two men and one woman with moderate cognitive impairment. One subject had generalized epilepsy and other two had temporal lobe epilepsy. The patients were on an average of two to three antiepileptic medicines. The duration of follow-up in our neurology clinic ranged from 9 months to 5 years. The occurrence of increased frequency of these atypical events as described by the caregivers, despite therapeutic anticonvulsant levels, prompted the need for 5 day intensive video EEG monitoring. New atypical spells were documented in all three patients and the brain waves were normal during those episodes. The diagnosis of pseudoseizures was made based on the data acquired during the epilepsy monitoring unit stay. Our data analysis showed that intensive video EEG monitoring is an important tool to evaluate change in frequency and description of seizures even in cognitively impaired patients with an established diagnosis of epilepsy for adequate seizure management. PMID- 25506019 TI - Delayed recurrence of atypical pulmonary carcinoid cluster: a rare occurrence. AB - Carcinoid is one of the most common tumors of the gastrointestinal tract followed by the tracheobronchial tree. Bronchial carcinoid compromises 20% of total carcinoid and accounts for 1-5% of pulmonary malignancies. Carcinoid can be typical or atypical, with atypical carcinoid compromises 10% of the carcinoid tumors. Carcinoid usually presents as peripheral lung lesion or solitary endobronchial abnormality. Rarely it can present as multiple endobronchial lesion. We hereby present a rare case of an elderly gentleman who had undergone resection of right middle and lower lobe of lung for atypical carcinoid. Seven years later he presented with cough. CT scan of chest revealed right hilar mass. Flexible bronchoscopy revealed numerous endobronchial polypoid lesions in the tracheobronchial tree. Recurrent atypical carcinoid was then confirmed on biopsy. PMID- 25506020 TI - An unusual case of pulmonary nocardiosis in immunocompetent patient. AB - Pulmonary nocardiosis is a subacute or chronic necrotizing pneumonia caused by aerobic actinomycetes of the genus Nocardia and rare in immune-competent patients. A 35-year-old male, who had treated with antituberculosis drugs, presented with cough, dyspnea, and expectoration with episodes of hemoptysis with purulent sputum. The diagnosis of nocardiosis was made by microscopic examination of the surgically resected portion of the lung and revealed filamentous Gram positive bacteria. PMID- 25506021 TI - Renal sinus fat invasion and tumoral thrombosis of the inferior vena cava-renal vein: only confined to renal cell carcinoma. AB - Epithelioid angiomyolipoma (E-AML), accounting for 8% of renal angiomyolipoma, is usually associated with tuberous sclerosis (TS) and demonstrates aggressive behavior. E-AML is macroscopically seen as a large infiltrative necrotic tumor with occasional extension into renal vein and/or inferior vena cava. However, without history of TS, renal sinus and venous invasion E-AML would be a challenging diagnosis, which may lead radiologists to misinterpret it as a renal cell carcinoma (RCC). In this case presentation, we aimed to report cross sectional imaging findings of two cases diagnosed as E-AML and pathological correlation of these aforementioned masses mimicking RCC. PMID- 25506022 TI - A Rare Case of Neuromyelitis Optica Spectrum Disorder in Patient with Sjogren's Syndrome. AB - We report a 48-year-old female with the history of Sjogren's syndrome who presented with 3-week history of tingling, numbness, and shooting back, waist, and bilateral leg pain and numbness in the pelvic region with urinary and bowel incontinence. Physical examination was remarkable for reduced motor power in both lower extremities with spasticity. Sensory deficit was noted at the T6 level. Laboratory investigation revealed elevated ESR and CRP and positive serum antiaquaporin-4 IgG. Thoracic and lumbar magnetic resonance imaging revealed abnormal patchy areas, leptomeningeal enhancement through the thoracic cord extending from T3 through T6 levels, without evidence of cord compression. Impression of neuromyelitis optica spectrum disorder was made and patient was treated with methylprednisolone intravenously followed by tapering oral prednisone. Neurological symptoms gradually improved with resolution of bowel and urinary incontinence. In a patient with Sjogren's syndrome who presents with neurological complaints, the possibility of neuromyelitis optica or neuromyelitis optica spectrum disorder should be considered. Awareness of the possibility of CNS disease is important due to the serious nature of CNS complications, some of which are treatable with immunosuppressants. Our patient with Sjogren's syndrome who presented with myelopathy benefited from early recognition and institution of appropriate therapy. PMID- 25506023 TI - Ascites as the presenting symptom of multiple myeloma in a scleroderma patient. AB - Several reports have demonstrated associations between scleroderma and cancer and between multiple myeloma and autoimmune diseases. Few papers have also reported the concurrence of scleroderma and multiple myeloma. We report a case of multiple myeloma that developed in a male patient after 28 years of fulfilling a diagnosis of scleroderma. The main presenting feature of multiple myeloma was ascites, solely explained by the increased vascular permeability that occurs in this disease. PMID- 25506024 TI - Posterior reversible encephalopathy syndrome in a patient with systemic lupus erythematosus/systemic sclerosis overlap syndrome. AB - Posterior reversible encephalopathy syndrome is a clinicoradiologic entity associated with diverse medical conditions. It is very important to properly recognize this condition because early diagnosis and treatment usually result in its complete resolution, whereas a delay in giving an adequate therapy may lead to permanent neurologic sequelae. A case of posterior reversible encephalopathy syndrome in a female patient with an overlap syndrome of systemic lupus erythematosus and systemic sclerosis is presented here. PMID- 25506026 TI - A Rare Presentation of Maydl's Hernia. AB - We present a case of an unsual type of obstructed indirect inguinal hernia with impending strangulation. The operative findings revealed a sliding Maydl's hernia with an ischemic inner ileal loop and an adherent inflamed appendix. This case highlights the importance of intraoperative examination of the intra-abdominal bowel loops proximal to the hernia sac of an incarcerated, obstructed, or strangulated hernia. PMID- 25506025 TI - Solitary cecal diverticulitis: an unusual cause of acute right iliac fossa pain-a case report and review of the literature. AB - Solitary cecal diverticulitis is a rare cause of acute abdominal pain in the Western world. Its clinical presentation, in most cases, mimics acute appendicitis. A 38-year-old Caucasian man presented with acute abdomen and clinical signs of acute appendicitis. Laparotomy was performed and revealed an inflammatory, solitary diverticulum of the cecum. A typical appendectomy was performed and a catheter was inserted for draining percutaneously the inflamed diverticulum of the cecum. The patient had an uneventful recovery and was discharged on the 4th postoperative day. This frequently misdiagnosed condition, in most cases, is being suspected and identified intraoperatively as acute appendicitis. The aim of this study is to review the available different surgical management options and to present an alternative therapeutic approach that may be valuable under specific circumstances. PMID- 25506027 TI - Giant subcutaneous leiomyosarcoma of anterior abdominal wall. AB - Subcutaneous leiomyosarcomas are rare tumors accounting for 1% to 2% of all superficial soft tissue malignancies. Although they may arise anywhere in the body, they most frequently occur in the lower extremities. The incidence of subcutaneous LMS affecting the anterior abdominal wall is very rare. We herein report the case of a patient with a giant subcutaneous leiomyosarcoma arising in the anterior abdominal wall. It was diagnosed by histopathology and immunohistochemistry and treated accordingly. PMID- 25506028 TI - Transvaginal appendectomy in morbidly obese patient. AB - Introduction. Laparoscopic appendectomy has significant benefits in obese patients. However, morbid obesity can be accepted as an exclusion criterion for natural orifice transluminal endoscopic surgery (NOTES). Here, we present a transvaginal appendectomy in a 66-year-old morbidly obese (BMI 36 kg/m(2), ASA III) patient. Case and Technique. Acute appendicitis was suspected based on history, physical examination, laboratory tests, and ultrasound findings. During laparoscopic surgery, a 5 mm trocar was inserted through the umbilicus and a 5 mm telescope was placed. A 12 mm trocar and a 5 mm grasper were inserted separately through the posterior fornix of the vagina under laparoscopic guidance. The appendix was divided with an endoscopic stapler through the transvaginal 12 mm trocar and removed from the same trocar. The operating time was 75 minutes with minimal blood loss (<10 mL). The patient was discharged 16 hours after surgery uneventfully and she did not require any analgesic administration. Conclusion. To the best of our knowledge, this is the first clinical case that focuses on the transvaginal appendectomy at morbid obesity. We can say that morbid obesity does not constitute an obstacle for treatment of acute appendicitis by transvaginal endoscopic surgery. PMID- 25506029 TI - Mucinous adenocarcinoma arising in chronic perianal fistula: good results with neoadjuvant chemoradiotherapy followed by surgery. AB - Chronic perianal fistulas are a common clinical condition. However, their evolution to adenocarcinoma is rare. We report the case of a 48-year-old man with perianal chronic fistulas, who developed two perianal ulcerated lesions near the external orifices of the fistulas, which extended proximally as a pararectal tumor. No intestinal lesion was seen at endoscopic examination. Histopathological biopsy indicated mucinous adenocarcinoma. Staging was performed by pelvic magnetic resonance imaging (MRI) and thoracoabdominal CT scan. The patient underwent a laparoscopic colostomy followed by neoadjuvant chemoradiotherapy and then laparoscopic abdominoperineal resection followed by adjuvant therapy. We have seen a favorable outcome with no recurrence at 3 years of follow-up. PMID- 25506030 TI - Fournier's Gangrene as a Postoperative Complication of Inguinal Hernia Repair. AB - Fournier's gangrene is the necrotizing fasciitis of perianal, genitourinary, and perineal regions. Herein, we present a case of scrotal Fournier's gangrene as a postoperative complication of inguinal hernia repair. A 51-year-old male with giant indirect hernia is presented. Patient underwent inguinal hernia repair, and after an unproblematic recovery period, he was discharged. He applied to our outpatient clinic on the fifth day with swollen and painful scrotum and it turned out to be Fournier's gangrene. Polypropylene mesh was not infected. Patient recovered and was discharged after repeated debridements. Basic principles in treatment of Fournier's gangrene are comprised of initial resuscitation, broad spectrum antibiotics therapy, and early aggressive debridement. In the management of presented case, aggressive debridement was made right after diagnosis and broad-spectrum antibiotics were given to the hemodynamically stable patient. In these circumstances, the important question is whether we could prevent occurrence of Fournier's gangrene. PMID- 25506031 TI - Necrotising myositis, the deadly impersonator. AB - We report two cases of patients with necrotising myositis who presented initially with limb pain and swelling on a background of respiratory complaints. Patient 1, a previously well 38-year-old female, underwent various investigations in the emergency department for excessive lower limb pain and a skin rash. Patient 2, a 61-year-old female with a background of rheumatoid arthritis and hypertension, presented to accident and emergency feeling generally unwell and was treated for presumed respiratory sepsis. Both deteriorated rapidly and were referred to the plastic surgery team with soft tissue necrosis, impending multiorgan failure and toxaemia. Large areas of necrotic muscle and skin were debrided, which grew group A streptococci, Streptococcus pyogenes. Patient 1 had a high above knee amputation of the left leg with extensive debridement of the right. Despite aggressive surgical intervention and microbiological input with intensive care support, patient 2 died. These two cases highlight the importance of early diagnosis and prompt surgical and pharmacological intervention in managing this life-threatening disease. Pain is the primary symptom with skin changes being a late and subtle sign in a septic patient. The Laboratory Risk Indicator for Necrotising Fasciitis (LRINEC) may be of use if there is concern to aid diagnosis of this life-threatening disease. PMID- 25506032 TI - Single-incision laparoscopic surgery for intersigmoid hernia. AB - Intersigmoid hernia is a rare form of internal hernia. Here, we report a case of intersigmoid hernia and provide a brief review of the 62 cases involving the mesosigmoid reported in Japan from 2000 to 2013. In the current case, a 26-year old man with no previous history of abdominal surgery presented with abdominal pain and vomiting. Abdominal computed tomography revealed an extensively dilated small bowel and a closed loop of small bowel in the mesosigmoid. The patient was diagnosed with an intestinal obstruction due to an incarcerated internal hernia involving the mesosigmoid. There was no blood flow obstruction at the incarcerated bowel. An elective single-incision laparoscopic surgery was performed after decompression of the bowel using ileus tube. As the ileum herniated into the intersigmoid fossa, the patient was diagnosed with an intersigmoid hernia. The incarcerated small bowel was reduced in order to make it viable, and the hernial defect was closed with interrupted sutures. The patient had an uneventful recovery and was discharged on postoperative day five. PMID- 25506033 TI - Successful outcome of triangle tilt as revision surgery in a pediatric obstetric brachial plexus patient with multiple previous operations. AB - Introduction. Obstetric brachial plexus injury (OBPI) occurs during the process of labor and childbirth. OBPI has been reported to be associated with shoulder dystocia, macrosomia, and breech delivery. Its occurrence in uncomplicated delivery is possible as well. Case Presentation. The patient in the present report is a 6.5-year-old girl, who suffered a severe brachial plexus injury at birth and had many reconstructive surgical procedures at an outside brachial plexus center before presenting to us. Discussion. The traditional surgical treatments by other surgical groups were unsuccessful and therefore the patient came to our clinic for further treatment. She had triangle tilt surgery with us, as a salvage procedure. Conclusion. The OBPI patient in this study clearly showed noticeable clinical and functional improvements after triangle tilt surgical management. The posture of the arm at rest was greatly improved to a more normal position, and hand to mouth movement was improved as well. Triangle tilt surgery should be conducted as a first choice treatment for medial rotation contracture of the shoulder in OBPI patients. PMID- 25506034 TI - Transitional cell carcinoma in orthotopic ileal neobladder. AB - Urothelial carcinoma developing in orthotopic ileal neobladder is an extremely rare entity. Fewer than 10 cases have been reported in the literature describing urothelial carcinoma recurrence in orthotopic ileal neobladder. We report a case of transitional cell carcinoma recurrence in orthotopic ileal neobladder after 11 years of surgery. PMID- 25506035 TI - Hormonal treatment for severe hydronephrosis caused by bladder endometriosis. AB - The incidence of endometriosis cases involving the urinary system has recently increased, and the bladder is a specific zone where endometriosis is most commonly seen in the urinary system. In the case presented here, a patient presented to the emergency department with the complaint of side pain and was examined and diagnosed with severe hydronephrosis and bladder endometriosis was determined in the etiology. After the patient was pathologically diagnosed, Levonorgestrel-Releasing Intrauterine System (LNG-IUS) was administered to the uterine cavity. At the 12-month follow-up, endometriosis was not observed in the cystoscopy and symptoms had completely regressed. Hydronephrosis may be observed after exposure of the ureter, and silent renal function loss may develop in patients suffering from endometriosis with bladder involvement. For patients with moderate or severe hydronephrosis associated with bladder endometriosis, LNG-IUS application may be separately and successfully used after conservative surgery. PMID- 25506036 TI - Anticholinesterase and Antioxidative Properties of Aqueous Extract of Cola acuminata Seed In Vitro. AB - Background. Cola acuminata seed, a commonly used stimulant in Nigeria, has been reportedly used for the management of neurodegenerative diseases in folklore without scientific basis. This study sought to investigate the anticholinesterase and antioxidant properties of aqueous extracts from C. acuminata seed in vitro. Methodology. The aqueous extract of C. acuminata seed was prepared (w/v) and its effect on acetylcholinesterase (AChE) and butyrylcholinesterase activities, as well as some prooxidant (FeSO4, sodium nitroprusside (SNP), and quinolinic acid (QA)) induced lipid peroxidation in rat brain in vitro, was investigated. Results. The results revealed that C. acuminata seed extract inhibited AChE (IC50 = 14.6 MUg/mL) and BChE (IC50 = 96.2 MUg/mL) activities in a dose-dependent manner. Furthermore, incubation of rat's brain homogenates with some prooxidants caused a significant increase P < 0.05 in the brain malondialdehyde (MDA) content and inhibited MDA production dose-dependently and also exhibited further antioxidant properties as typified by their high radicals scavenging and Fe(2+) chelating abilities. Conclusion. Inhibition of AChE and BChE activities has been the primary treatment method for mild Alzheimer's disease (AD). Therefore, one possible mechanism through which the seed exerts its neuroprotective properties is by inhibiting cholinesterase activities as well as preventing oxidative-stress induced neurodegeneration. However, this is a preliminary study with possible physiological implications. PMID- 25506037 TI - A syntenic region conserved from fish to Mammalian x chromosome. AB - Sex chromosomes bearing the sex-determining gene initiate development along the male or female pathway, no matter which sex is determined by XY male or ZW female heterogamety. Sex chromosomes originate from ancient autosomes but evolved rapidly after the acquisition of sex-determining factors which are highly divergent between species. In the heterogametic male system (XY system), the X chromosome is relatively evolutionary silent and maintains most of its ancestral genes, in contrast to its Y counterpart that has evolved rapidly and degenerated. Sex in a teleost fish, the Nile tilapia (Oreochromis niloticus), is determined genetically via an XY system, in which an unpaired region is present in the largest chromosome pair. We defined the differences in DNA contents present in this chromosome with a two-color comparative genomic hybridization (CGH) and the random amplified polymorphic DNA (RAPD) approach in XY males. We further identified a syntenic segment within this region that is well conserved in several teleosts. Through comparative genome analysis, this syntenic segment was also shown to be present in mammalian X chromosomes, suggesting a common ancestral origin of vertebrate sex chromosomes. PMID- 25506038 TI - Bone mineral density in gravida: effect of pregnancies and breast-feeding in women of differing ages and parity. AB - Changes of bone during pregnancy and during lactation evaluated by bone mineral density (BMD) may have implications for risk of osteoporosis and fractures. We studied BMD in women of differing ages, parity, and lactation histories immediately postpartum for BMD, T-scores, and Z-scores. Institutional Review Board approval was received. All women while still in hospital postpartum were asked to participate. BMD was performed by dual-energy X-ray absorptiometry (DXA) machine at femoral neck (FN) and lumbar spine (LS) by a single technician. Of 132 participants, 73 (55.3%) were <=30 years; 27 (20.5%) were primiparous; 36 (27.3%) were grand multiparous; 35 (26.5%) never breast fed. Mean FN T-scores and Z scores were higher than respective mean LS scores, but all means were within the normal limits. Mean LS T-scores and Z-scores were highest in the grand multiparas. There were only 2 (1.5%) outliers with low Z-scores. We conclude that, in a large cohort of Israeli women with BMD parameters assessed by DXA within two days postpartum, mean T-scores and Z-scores at both the LS and FN were within normal limits regardless of age (20-46 years), parity (1-13 viable births), and history of either no or prolonged months of lactation (up to 11.25 years). PMID- 25506040 TI - Parkinson's disease: low-dose haloperidol increases dopamine receptor sensitivity and clinical response. AB - Background. It is known that ultra-low doses of haloperidol can cause dopamine supersensitivity of dopamine D2 receptors and related behaviour in animals. Objective. The objective was to determine whether a daily ultra-low dose of 40 micrograms of haloperidol could enhance the clinical action of levodopa in Parkinson's disease patients. Method. While continuing their daily treatment with levodopa, 16 patients with Parkinson's disease were followed weekly for six weeks. They received an add-on daily dose of 40 micrograms of haloperidol for the first two weeks only. The SPES/SCOPA scale (short scale for assessment of motor impairments and disabilities in Parkinson's disease) was administered before treatment and weekly throughout the trial. Results. The results showed a mean decrease in SPES/SCOPA scores after one week of the add-on treatment. Conclusion. SCOPA scores decreased after the addition of low-dose haloperidol to the standard daily levodopa dose. This finding is consistent with an increase in sensitivity of dopamine D2 receptors induced by haloperidol. Such treatment for Parkinson's disease may possibly permit the levodopa dose to be reduced and, thus, delay the onset of levodopa side effects. PMID- 25506039 TI - Role of Different Pfcrt and Pfmdr-1 Mutations in Conferring Resistance to Antimalaria Drugs in Plasmodium falciparum. AB - Emergence of drugs resistant strains of Plasmodium falciparum has augmented the scourge of malaria in endemic areas. Antimalaria drugs act on different intracellular targets. The majority of them interfere with digestive vacuoles (DVs) while others affect other organelles, namely, apicoplast and mitochondria. Prevention of drug accumulation or access into the target site is one of the mechanisms that plasmodium adopts to develop resistance. Plasmodia are endowed with series of transporters that shuffle drugs away from the target site, namely, pfmdr (Plasmodium falciparum multidrug resistance transporter) and pfcrt (Plasmodium falciparum chloroquine resistance transporter) which exist in DV membrane and are considered as putative markers of CQ resistance. They are homologues to human P-glycoproteins (P-gh or multidrug resistance system) and members of drug metabolite transporter (DMT) family, respectively. The former mediates drifting of xenobiotics towards the DV while the latter chucks them outside. Resistance to drugs whose target site of action is intravacuolar develops when the transporters expel them outside the DVs and vice versa for those whose target is extravacuolar. In this review, we are going to summarize the possible pfcrt and pfmdr mutation and their role in changing plasmodium sensitivity to different anti-Plasmodium drugs. PMID- 25506041 TI - Is the MDS-UPDRS a Good Screening Tool for Detecting Sleep Problems and Daytime Sleepiness in Parkinson's Disease? AB - Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale (MDS UPDRS) has separate items for measuring sleep problems (item 1.7) and daytime sleepiness (1.8). The aim of our study was to evaluate the screening sensitivity and specificity of these items to the PD Sleep Scale 2nd version (PDSS-2) and Epworth Sleepiness Scale (ESS). In this nationwide, cross-sectional study 460 PD patients were enrolled. Spearman's rank correlation coefficients were calculated between the individual items, domains, and the total score of PDSS-2 and item 1.7 of MDS-UPDRS. Similarly, the items and the total score of ESS were contrasted to item 1.8 of MDS-UPDRS. After developing generalized ordinal logistic regression models, the transformed and observed scores were compared by Lin's Concordance Correlation Coefficient. Only item 3 difficulties staying asleep and the "disturbed sleep" domain of PDSS-2 showed high correlation with "sleep problems" item 1.7 of the MDS-UPDRS. Total score of PDSS-2 had moderate correlation with this MDS-UPRDS item. The total score of ESS showed the strongest, but still moderate, correlation with "daytime sleepiness" item 1.8 of MDS-UPDRS. As intended, the MDS-UPDRS serves as an effective screening tool for both sleep problems and daytime sleepiness and identifies subjects whose disabilities need further investigation. PMID- 25506042 TI - 18FDG-PET/CT Definition of Clinical Target Volume for Robotic Stereotactic Body Radiosurgery Treatment of Metastatic Gynecologic Malignancies. AB - The objective of the current article was to evaluate 2-[18F]fluoro-2-deoxy-D glucose 18F-FDG) as measured by positron emission tomography for delineation of abdominopelvic gross tumor volumes (GTV) for stereotactic body radiosurgery treatment (SBRT) of metastatic gynecologic cancers. A retrospective review of SBRT was conducted in 27 women with stage IV gynecologic cancers recurring in para-aortic lymph nodes. Robotic SBRT involved 2400 cGy in 3 consecutive 800 cGy daily fractions prescribed to a 3.0 mm expanded planning tumor volume (PTV) defined by both CT-based and 18F-FDG-based GTVs. In this study, 18F-FDG-based GTVs led to significantly larger PTVs in all 27 women, than if they had been based on CT GTVs alone (P < 0.001). Enlarged PTVs may have resulted from the breathing-induced target motion during the time of 18F-FDG image acquisition smearing 18F-FDG signal over a greater anatomic dimension. Ultimately, SBRT target local control, based on the RECIST 1.1 criteria, was 96% (26 of 27), and associated with minor reversible toxicity. The use of 18F-FDG to define SBRT target volumes warrants further interrogation in SBRT clinical trials. PMID- 25506044 TI - Another case of "shopping bag" tremor: a difficult to classify action tremor. AB - This letter was written in response to: Zesiewicz T, Vu T, Carranza MA, et al. Unusual wrist tremor: unilateral isometric tremor? Tremor Other Hyperkinet Mov. 2014; 4: http://tremorjournal.org/article/view/194. PMID- 25506045 TI - A Behavior Genetic Analysis of Pleasant Events, Depressive Symptoms, and Their Covariation. AB - Although pleasant events figure prominently in behavioral models of depression, little is known regarding characteristics that may predispose people to engage in pleasant events and derive pleasure from these events. The present study was conducted to evaluate genetic and environmental influences on the experience of pleasant events, depressive symptoms, and their covariation in a sample of 148 twin pairs. A multivariate twin modeling approach was used to examine the genetic and environmental covariance of pleasant events and depressive symptoms. Results indicated that the experience of pleasant events was moderately heritable and that the same genetic factors influence both the experience of pleasant events and depressive symptoms. These findings suggest that genetic factors may give rise to dispositional tendencies to experience both pleasant events and depression. PMID- 25506043 TI - Pathophysiology and treatment of alien hand syndrome. AB - BACKGROUND: Alien hand syndrome (AHS) is a disorder of involuntary, yet purposeful, hand movements that may be accompanied by agnosia, aphasia, weakness, or sensory loss. We herein review the most reported cases, current understanding of the pathophysiology, and treatments. METHODS: We performed a PubMed search in July of 2014 using the phrases "alien hand syndrome," "alien hand syndrome pathophysiology," "alien hand syndrome treatment," and "anarchic hand syndrome." The search yielded 141 papers (reviews, case reports, case series, and clinical studies), of which we reviewed 109. Non-English reports without English abstracts were excluded. RESULTS: Accumulating evidence indicates that there are three AHS variants: frontal, callosal, and posterior. Patients may demonstrate symptoms of multiple types; there is a lack of correlation between phenomenology and neuroimaging findings. Most pathologic and functional imaging studies suggest network disruption causing loss of inhibition as the likely cause. Successful interventions include botulinum toxin injections, clonazepam, visuospatial coaching techniques, distracting the affected hand, and cognitive behavioral therapy. DISCUSSION: The available literature suggests that overlap between AHS subtypes is common. The evidence for effective treatments remains anecdotal, and, given the rarity of AHS, the possibility of performing randomized, placebo controlled trials seems unlikely. As with many other interventions for movement disorders, identifying the specific functional impairments caused by AHS may provide the best guidance towards individualized supportive care. PMID- 25506047 TI - Public health learning - purposeful, progressive, global by design. PMID- 25506046 TI - Practice-Based Approach to Assessing and Treating Non-Adherence in Pediatric Regimens. AB - With advances in medical care, youth with chronic illness have the potential for higher quality of life; however, these treatments often come with cost (i.e., burden, financial) that can result in non-adherence. Pediatric non-adherence, on average, is approximately 50% across chronic health conditions. Research has identified effective, evidence-based assessment measures and intervention strategies to promote regimen adherence in youth. Yet, these measures and strategies typically are designed for clinical trials and thus may not be feasible or practical in typical clinic settings. As the field of adherence assessment and intervention expands, it will be important to devise evidence based tools that are pragmatic and can be translated easily into practice. To guide this future direction, the goals of this paper are to review evidence-based adherence assessment and intervention strategies that can be used with youth and families in clinical practice, to illustrate the complexities of addressing adherence concerns in routine practice, and to discuss the challenges of disseminating and implementing evidence-based strategies in the real world. PMID- 25506048 TI - Comparison of two methods - regression predictive model and intake shift model - for adjusting self-reported dietary recall of total energy intake of populations. AB - Daily dietary intake data derived from self-reported dietary recall surveys are widely considered inaccurate. In this study, methods were developed for adjusting these dietary recalls to more plausible values. In a simulation model of two National Health and Nutrition Examination Surveys (NHANES), NHANES I and NHANES 2007-2008, a predicted one-third of raw data fell outside a range of physiologically plausible bounds for dietary intake (designated a 33% failure rate baseline). To explore the nature and magnitude of this bias, primary data obtained from an observational study were used to derive models that predicted more plausible dietary intake. Two models were then applied for correcting dietary recall bias in the NHANES datasets: (a) a linear regression to model percent under-reporting as a function of subject characteristics and (b) a shift of dietary intake reports to align with experimental data on energy expenditure. After adjustment, the failure rates improved to <2% with the regression model and 4-9% with the intake shift model - both substantial improvements over the raw data. Both methods gave more reliable estimates of plausible dietary intake based on dietary recall and have the potential for more far-reaching application in correction of self-reported exposures. PMID- 25506049 TI - Male Role Norms, Knowledge, Attitudes, and Perceptions of Colorectal Cancer Screening among Young Adult African American Men. AB - Racial disparities in health among African American men (AAM) in the United States are extensive. In contrast to their White counterparts, AAM have more illnesses and die younger. AAM have colorectal cancer (CRC) incidence and mortality rates 25% and 50% higher, respectively, than White men. Due to CRC's younger age at presentation and high incidence among AAM, CRC screening (CRCS) is warranted at the age of 45 rather than 50, but little is known about younger AAM's views of CRCS. Employing survey design, the purpose of the study was to describe the male role norms (MRN), knowledge, attitudes, perceived subjective norms, and perceived barriers associated with screening for CRC among a non random sample of 157 young adult AAM (ages 19-45). Sixty-seven percent of the study sample received a passing knowledge score (85% or better), yet no significant differences were found among the three educational levels (i.e., low, medium, high). More negative attitudes toward CRCS correlated with the participants' strong perceptions of barriers, but no extremely negative or positive MRN and perceived subjective norms were found. The factors significantly associated with attitudes were family history of cancer (unsure), work status, and perceived barriers. Findings from this study provide a solid basis for developing structured health education interventions that address the salient factors shaping young adult AAM's view of CRC and early detection screening behaviors. PMID- 25506050 TI - Biomolecular corona on nanoparticles: a survey of recent literature and its implications in targeted drug delivery. AB - Achieving controlled cellular responses of nanoparticles (NP) is critical for the successful development and translation of NP-based drug delivery systems. However, precise control over the physicochemical and biological properties of NPs could become convoluted, diminished, or completely lost as a result of the adsorption of biomolecules to their surfaces. Characterization of the formation of the "biomolecular" corona has thus received increased attention due to its impact on NP and protein structure as well as its negative effect on NP-based targeted drug delivery. This review presents a concise survey of the recent literature concerning the importance of the NP-biomolecule corona and how it can be utilized to improve the in vivo efficacy of targeted delivery systems. PMID- 25506051 TI - Development and validation of a statistical shape modeling-based finite element model of the cervical spine under low-level multiple direction loading conditions. AB - Cervical spinal injuries are a significant concern in all trauma injuries. Recent military conflicts have demonstrated the substantial risk of spinal injury for the modern warfighter. Finite element models used to investigate injury mechanisms often fail to examine the effects of variation in geometry or material properties on mechanical behavior. The goals of this study were to model geometric variation for a set of cervical spines, to extend this model to a parametric finite element model, and, as a first step, to validate the parametric model against experimental data for low-loading conditions. Individual finite element models were created using cervical spine (C3-T1) computed tomography data for five male cadavers. Statistical shape modeling (SSM) was used to generate a parametric finite element model incorporating variability of spine geometry, and soft-tissue material property variation was also included. The probabilistic loading response of the parametric model was determined under flexion-extension, axial rotation, and lateral bending and validated by comparison to experimental data. Based on qualitative and quantitative comparison of the experimental loading response and model simulations, we suggest that the model performs adequately under relatively low-level loading conditions in multiple loading directions. In conclusion, SSM methods coupled with finite element analyses within a probabilistic framework, along with the ability to statistically validate the overall model performance, provide innovative and important steps toward describing the differences in vertebral morphology, spinal curvature, and variation in material properties. We suggest that these methods, with additional investigation and validation under injurious loading conditions, will lead to understanding and mitigating the risks of injury in the spine and other musculoskeletal structures. PMID- 25506052 TI - The Virtual Patient Simulator of Deep Brain Stimulation in the Obsessive Compulsive Disorder Based on Connectome and 7 Tesla MRI Data. AB - We present work in progress on the virtual patient model for patients with Deep Brain Stimulation (DBS) implants based on Connectome and 7 Tesla Magnetic Resonance Imaging (MRI) data. Virtual patients are realistic computerized models of patients that allow medical-device companies to test new products earlier, helping the devices get to market more quickly and cheaply according to the Food and Drug Administration. We envision that the proposed new virtual patient simulator will enable radio frequency power dosimetry on patients with the DBS implant undergoing MRI. Future patients with DBS implants may profit from the proposed virtual patient by allowing for a MRI investigation instead of more invasive Computed Tomography (CT) scans. The virtual patient will be flexible and morphable to relate to neurological and psychiatric conditions such as Obsessive Compulsive Disorder (OCD), which benefit from DBS. PMID- 25506053 TI - Genetic polymorphisms of interleukin-1 alpha and the vitamin d receptor in mexican mestizo patients with intervertebral disc degeneration. AB - Intervertebral disc degeneration (IDD) is the most common diagnosis in patients with back pain, a leading cause of musculoskeletal disability worldwide. Several conditions, such as occupational activities, gender, age, and obesity, have been associated with IDD. However, the development of this disease has strong genetic determinants. In this study, we explore the possible association between rs1800587 (c.-949C>T) of interleukin-1 alpha (IL1A) and rs2228570 (c.2T>V) and rs731236 (c.1056T>C) of vitamin D receptor (VDR) gene polymorphisms and the development of IDD in northwestern Mexican Mestizo population. Gene polymorphisms were analyzed by polymerase chain reaction followed by restriction fragment length polymorphism, in two groups matched by age and gender: patients with symptomatic lumbar IDD (n = 100) and subjects with normal lumbar-spine MRI-scans (n = 100). Distribution of the mutated alleles in patients and controls was 27.0% versus 28.0% (P = 0.455) for T of rs1800587 (IL1A); 53.0% versus 58.0% (P = 0.183) for V of rs2228570 (VDR); and 18.0% versus 21.0% (P = 0.262) for C of rs731236 (VDR). Our results showed no association between the studied polymorphisms and IDD in this population. This is the first report on the contribution of gene polymorphisms on IDD in a Mexican population. PMID- 25506054 TI - Chronic kidney disease requiring healthcare services: a new approach to evaluate epidemiology of renal disease. AB - BACKGROUND: Screening-based CKD estimates may not provide a sufficient insight into the impact of CKD on the use of healthcare resources in clinical practice. The aim of this study was to evaluate the epidemiology of "medicalized" CKD, that is, CKD requiring healthcare services, in an outpatient setting. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This is a retrospective, longitudinal population based study conducted in a large general practice setting in Southern Italy (Caserta) using a healthcare database. Over 2006-2011, all patients with a CKD diagnosis, either through CKD-related indications of use associated with drug prescriptions or through CKD-related hospital discharge diagnoses/procedures, were identified using this database. The prevalence of "medicalized" CKD in the general population of Caserta was estimated by age, gender, and calendar year. RESULTS: Overall, 1,989 (1.3%) patients with a diagnosis of CKD were identified from 2006-2011 in the Caserta general population. The one year prevalence increased from 0.9% in 2006 to 1.6% in 2011, which is much lower compared to previous screening-based studies. The prevalence was slightly higher in males and increased significantly with advancing age (in 2011, 0.2% in <=44 years old versus 9.2% in >80 years old). CONCLUSIONS: The findings of this study suggest that, in the general population, the prevalence of "medicalized" CKD is lower compared to the screening-based CKD prevalence. PMID- 25506055 TI - Neuroprotective effects of geniposide in SH-SY5Y cells and primary hippocampal neurons exposed to Abeta42. AB - Our former studies have suggested that TongLuoJiuNao (TLJN) is clinically efficacious in the treatment of dementia and improving learning and memory in AD models. When Abeta aggregated with oligomer, it is known to be able to induce cellular toxicity as well as cognitive impairment. We tested the possibility that TLJN affects the formation of Abeta oligomers. In our experiment, TLJN improved cell viability, inhibited LDH release, and promoted the outgrowth of neurites of neurons treated with Abeta. Geniposide, the main component of TLJN, could increase the cell viability of SY5Y-APP695sw cells. The cytotoxicity of pretreated Abeta with geniposide was decreased in a dose-dependent manner. SDS PAGE and Western blotting showed that geniposide and TLJN stimulated Abeta oligomer assembly. Compared with the control, more and longer fibrils of Abeta in the presence of geniposide were observed under electron microscope though the fibrils became less sensitive to thioflavin T staining. In sum, geniposide is able to protect neurons from Abeta-induced damage by remodeling Abeta. PMID- 25506056 TI - Kinematic analysis of healthy hips during weight-bearing activities by 3D-to-2D model-to-image registration technique. AB - Dynamic hip kinematics during weight-bearing activities were analyzed for six healthy subjects. Continuous X-ray images of gait, chair-rising, squatting, and twisting were taken using a flat panel X-ray detector. Digitally reconstructed radiographic images were used for 3D-to-2D model-to-image registration technique. The root-mean-square errors associated with tracking the pelvis and femur were less than 0.3 mm and 0.3 degrees for translations and rotations. For gait, chair rising, and squatting, the maximum hip flexion angles averaged 29.6 degrees , 81.3 degrees , and 102.4 degrees , respectively. The pelvis was tilted anteriorly around 4.4 degrees on average during full gait cycle. For chair-rising and squatting, the maximum absolute value of anterior/posterior pelvic tilt averaged 12.4 degrees /11.7 degrees and 10.7 degrees /10.8 degrees , respectively. Hip flexion peaked on the way of movement due to further anterior pelvic tilt during both chair-rising and squatting. For twisting, the maximum absolute value of hip internal/external rotation averaged 29.2 degrees /30.7 degrees . This study revealed activity dependent kinematics of healthy hip joints with coordinated pelvic and femoral dynamic movements. Kinematics' data during activities of daily living may provide important insight as to the evaluating kinematics of pathological and reconstructed hips. PMID- 25506058 TI - Anticipating the impact of insurance expansion on inpatient urological surgery. AB - PURPOSE: The Affordable Care Act (ACA) is expected to provide coverage for nearly twenty-five million previously uninsured individuals. Because the potential impact of the ACA for urological care remains unknown, we estimated the impact of insurance expansion on the utilization of inpatient urological surgeries using Massachusetts (MA) healthcare reform as a natural experiment. METHODS: We identified nonelderly patients who underwent inpatient urological surgery from 2003 through 2010 using inpatient databases from MA and two control states. Using July 2007 as the transition point between pre- and post-reform periods, we performed a difference-indifferences (DID) analysis to estimate the effect of insurance expansion on overall and procedure-specific rates of inpatient urological surgery. We also performed subgroup analyses according to race, income and insurance status. RESULTS: We identified 1.4 million surgeries performed during the study interval. We observed no change in the overall rate of inpatient urological surgery for the MA population as a whole, but an increase in the rate of inpatient urological surgery for non-white and low income patients. Our DID analysis confirmed these results (all 1.0%, p=0.668; non-whites 9.9%, p=0.006; low income 6.6%, p=0.041). At a procedure level, insurance expansion caused increased rates of inpatient BPH procedures, but had no effect on rates of prostatectomy, cystectomy, nephrectomy, pyeloplasty or PCNL. CONCLUSIONS: Insurance expansion in Massachusetts increased the overall rate of inpatient urological surgery only for non-whites and low income patients. These data inform key stakeholders about the potential impact of national insurance expansion for a large segment of urological care. PMID- 25506057 TI - Different resting-state functional connectivity alterations in smokers and nonsmokers with Internet gaming addiction. AB - This study investigated changes in resting-state functional connectivity (rsFC) of posterior cingulate cortex (PCC) in smokers and nonsmokers with Internet gaming addiction (IGA). Twenty-nine smokers with IGA, 22 nonsmokers with IGA, and 30 healthy controls (HC group) underwent a resting-state fMRI scan. PCC connectivity was determined in all subjects by investigating synchronized low frequency fMRI signal fluctuations using a temporal correlation method. Compared with the nonsmokers with IGA, the smokers with IGA exhibited decreased rsFC with PCC in the right rectus gyrus. Left middle frontal gyrus exhibited increased rsFC. The PCC connectivity with the right rectus gyrus was found to be negatively correlated with the CIAS scores in the smokers with IGA before correction. Our results suggested that smokers with IGA had functional changes in brain areas related to motivation and executive function compared with the nonsmokers with IGA. PMID- 25506059 TI - HIV and Re-Incarceration: Time for a Comprehensive Approach. PMID- 25506060 TI - A PREVIOUSLY UNKNOWN UNIQUE CHALLENGE FOR INHIBITORS OF SYK ATP-BINDING SITE: ROLE OF SYK AS A CELL CYCLE CHECKPOINT REGULATOR. AB - The identification of SYK as a molecular target in B-lineage leukemia/lymphoma cells prompted the development of SYK inhibitors as a new class of anti-cancer drug candidates. Here we report that induction of the SYK gene expression in human cells causes a significant down-regulation of evolutionarily conserved genes associated with mitosis and cell cycle progression providing unprecedented evidence that SYK is a master regulator of cell cycle regulatory checkpoint genes in human cells. We further show that SYK regulates the G2 checkpoint by physically associating with and inhibiting the dual-specificity phosphatase CDC25C via phosporylation of its S216 residue. SYK depletion by RNA interference or treatment with the chemical SYK inhibitor prevented nocodazole-treated human cell lines from activating the G2 checkpoint via CDC25C S216-phoshorylation and resulted in polyploidy. Our study provides genetic and biochemical evidence that spleen tyrosine kinase (SYK) has a unique role in the activation of the G2 checkpoint in both nonlymphohematopoietic and B-lineage lymphoid cells. This previously unknown role of SYK as a cell cycle checkpoint regulator represents an unforeseen and significant challenge for inhibitors of SYK ATP binding site. PMID- 25506062 TI - Damage identification of piles based on vibration characteristics. AB - A method of damage identification of piles was established by using vibration characteristics. The approach focused on the application of the element strain energy and sensitive modals. A damage identification equation of piles was deduced using the structural vibration equation. The equation contained three major factors: change rate of element modal strain energy, damage factor of pile, and sensitivity factor of modal damage. The sensitive modals of damage identification were selected by using sensitivity factor of modal damage firstly. Subsequently, the indexes for early-warning of pile damage were established by applying the change rate of strain energy. Then the technology of computational analysis of wavelet transform was used to damage identification for pile. The identification of small damage of pile was completely achieved, including the location of damage and the extent of damage. In the process of identifying the extent of damage of pile, the equation of damage identification was used in many times. Finally, a stadium project was used as an example to demonstrate the effectiveness of the proposed method of damage identification for piles. The correctness and practicability of the proposed method were verified by comparing the results of damage identification with that of low strain test. The research provided a new way for damage identification of piles. PMID- 25506061 TI - Hydrogen supplementation of preservation solution improves viability of osteochondral grafts. AB - Allogenic osteochondral tissue (OCT) is used for the treatment of large cartilage defects. Typically, OCTs collected during the disease-screening period are preserved at 4 degrees C; however, the gradual reduction in cell viability during cold preservation adversely affects transplantation outcomes. Therefore, improved storage methods that maintain the cell viability of OCTs are needed to increase the availability of high-quality OCTs and improve treatment outcomes. Here, we evaluated whether long-term hydrogen delivery to preservation solution improved the viability of rat OCTs during cold preservation. Hydrogen-supplemented Dulbecco's Modified Eagles Medium (DMEM) and University of Wisconsin (UW) solution both significantly improved the cell viability of OCTs during preservation at 4 degrees C for 21 days compared to nonsupplemented media. However, the long-term cold preservation of OCTs in DMEM containing hydrogen was associated with the most optimal maintenance of chondrocytes with respect to viability and morphology. Our findings demonstrate that OCTs preserved in DMEM supplemented with hydrogen are a promising material for the repair of large cartilage defects in the clinical setting. PMID- 25506063 TI - Strength and durability performance of alkali-activated rice husk ash geopolymer mortar. AB - This paper describes the experimental investigation carried out to develop the geopolymer concrete based on alkali-activated rice husk ash (RHA) by sodium hydroxide with sodium silicate. Effect on method of curing and concentration of NaOH on compressive strength as well as the optimum mix proportion of geopolymer mortar was investigated. It is possible to achieve compressive strengths of 31 N/mm(2) and 45 N/mm(2), respectively for the 10 M alkali-activated geopolymer mortar after 7 and 28 days of casting when cured for 24 hours at 60 degrees C. Results indicated that the increase in curing period and concentration of alkali activator increased the compressive strength. Durability studies were carried out in acid and sulfate media such as H2SO4, HCl, Na2SO4, and MgSO4 environments and found that geopolymer concrete showed very less weight loss when compared to steam-cured mortar specimens. In addition, fluorescent optical microscopy and X ray diffraction (XRD) studies have shown the formation of new peaks and enhanced the polymerization reaction which is responsible for strength development and hence RHA has great potential as a substitute for ordinary Portland cement concrete. PMID- 25506064 TI - Age changes of jaws and soft tissue profile. AB - Age-related changes of jaws and soft tissue profile are important both for orthodontists and general dentists. Mouth profile is the area which is manipulated during dental treatment. These changes should be planned in accordance with other components of facial profile to achieve ultimate aim of structural balance, functional efficacy, and esthetic harmony. Through this paper, the authors wish to discuss age changes of the hard and soft tissues of human face which would help not only the orthodontists but also oral surgeons, prosthodontists, pedodontists, and general dentists. PMID- 25506065 TI - The effect of anthelmintic treatment on coccidia oocyst shedding in a wild mammal host with intermittent cestode infection. AB - While hosts are routinely exploited by a community of parasite species, the principles governing host responses towards parasites are unclear. Identifying the health outcomes of coinfections involving helminth macroparasites and microparasites is one area of importance for public and domestic animal health. For instance, it is controversial how deworming programmes affect incidence and severity of such important microparasite diseases as malaria. One problem is that most study systems involve domestic and laboratory animals with conditions hardly comparable to those of free-living animals. Here, we study the effect of anthelmintic treatment on coccidia infection intensity in wild Alpine marmots, M. marmota. Our results lend support to the hypothesis that helminth infection has a positive effect on concurrent microparasite infection. However, our work also points to the fact that within-host interactions between helminths and microparasites are context-dependent and can turn to negative ones once helminth burdens increase. Our study suggests that coccidia benefit from intermittent helminth infection in marmots due to the protective effects of helminth infection only during the early phase of the host's active season. Also, the marmot's response towards coccidia infection appears optimal only under no helminth infection when the host immune response towards coccidia would not be compromised, thereby pointing to the importance of regular intestinal helminth elimination by marmots just before hibernation. PMID- 25506067 TI - Research on optimal policy of single-period inventory management with two suppliers. AB - We study a single-period inventory control problem with two independent suppliers. With the first supplier, the buyer incurs a high variable cost but negligible fixed cost; with the second supplier, the buyer incurs a lower variable cost but a positive fixed cost. At the same time, the ordering quantity is limited. We develop the optimal inventory control policy when the holding and shortage cost function is convex. We also conduct some numerical experiments to explore the effects of the fixed setup cost K and the ordering capacity Q on the optimal control policy. PMID- 25506068 TI - Effects of plant size, temperature, and light intensity on flowering of Phalaenopsis hybrids in Mediterranean greenhouses. AB - Mediterranean greenhouses for cultivation of Phalaenopsis orchids reproduce the warm, humid, and shaded environment of tropical underbrush. Heating represents the highest production cost, due to the high thermal requirements and the long unproductive phase of juvenility, in which plants attain the critical size for flowering. Our researches aimed to investigate the effect of plant size, temperature, and light intensity, during the phase of flower induction, on flowering of modern genotypes selected for Mediterranean greenhouses. Three experiments were carried out to compare (i) plant size: reduced size versus size considered optimal for flowering (hybrids "Sogo Yukidian," "Chain Xen Diamond," and "Pinlong"); (ii) temperature: moderate reduction of temperature versus standard thermal regime (hybrid "Premium"); (iii) light intensity: supplemental lighting versus reference light intensity (hybrid "Premium"). The premature exposure of plants to the inductive treatment delayed the beginning of flowering and reduced the flower stem quality, in all the tested hybrids. In "Premium," the lower temperature did not affect flowering earliness and commercial quality of flower stems compared to the standard regime, whereas it promoted stem branching. In the same hybrid, supplemental lighting anticipated flowering and promoted the emission of the second stem and the stem branching, compared to the reference light regime. PMID- 25506066 TI - Protective effects of aqueous extract of Solanum nigrum Linn. leaves in rat models of oral mucositis. AB - Oral mucositis is one of the most debilitating side effects in patient undergoing chemotherapy or chemoradiotherapy. Leaves of the plant Solanum nigrum are used in folklore medicine to treat oral ulcers in India. However, no pharmacological investigation has been carried out till date. Aqueous extract of Solanum nigrum leaves (AESN) was prepared and subjected to various phytochemical screening. HPLC analysis of the ethyl acetate fraction was carried out. The aqueous extract (100 and 200 mg/kg) was further evaluated for its protective effect on two rat models: (a) busulfan plus infrared radiation (chemoradiotherapy) induced oral mucositis and (b) methotrexate (chemotherapy) induced oral mucositis. Various parameters including body weight change, food intake, and mortality were measured. AESN showed protective effect in both models of oral mucositis; however, the higher dose was more effective in chemotherapy induced oral mucositis. A reduction in oral mucositis score (P < 0.05) was observed in the treatment groups. Significant (P < 0.05) improvement in food intake was also observed in AESN treated groups. Aqueous extract of Solanum nigrum leaves has protective effect on chemotherapy and chemoradiotherapy induced oral mucositis in rats. PMID- 25506069 TI - The surface structure and thermal properties of novel polymer composite films based on partially phosphorylated poly(vinyl alcohol) with aluminum phosphate. AB - Partially phosphorylated polyvinyl alcohol (PPVA) with aluminum phosphate (ALPO4) composites was synthesized by solution casting technique to produce (PPVA)(100-y) - (ALPO4)(y) (y = 0, 1, and 2). The surface structure and thermal properties of the films were characterized using Fourier transform infrared (FTIR) spectroscopy and thermogravimetric analysis (TGA). The results showed that the films have higher thermal stability with strong bonding between PPVA and ALPO4. PMID- 25506070 TI - Production and structural characterization of Lactobacillus helveticus derived biosurfactant. AB - A probiotic strain of lactobacilli was isolated from traditional soft Churpi cheese of Yak milk and found positive for biosurfactant production. Lactobacilli reduced the surface tension of phosphate buffer saline (PBS) from 72.0 to 39.5 mNm(-1) pH 7.2 and its critical micelle concentration (CMC) was found to be 2.5 mg mL(-1). Low cost production of Lactobacilli derived biosurfactant was carried out at lab scale fermenter which yields 0.8 mg mL(-1) biosurfactant. The biosurfactant was found least phytotoxic and cytotoxic as compared to the rhamnolipid and sodium dodecyl sulphate (SDS) at different concentration. Structural attributes of biosurfactant were determined by FTIR, NMR ((1)H and (13)C), UPLC-MS, and fatty acid analysis by GCMS which confirmed the presence of glycolipid type of biosurfactant closely similar to xylolipids. Biosurfactant is mainly constituted by lipid and sugar fractions. The present study outcomes provide valuable information on structural characterization of the biosurfactant produced by L. helveticus MRTL91. These findings are encouraging for the application of Lactobacilli derived biosurfactant as nontoxic surface active agents in the emerging field of biomedical applications. PMID- 25506071 TI - Alteration of loperamide-induced prostate relaxation in high-fat diet-fed rats. AB - OBJECTIVE: To investigate the change of loperamide-induced prostate relaxation in rats fed with high-fat diet (HFD). MATERIALS AND METHODS: Adult male Wistar rats were divided into 2 groups: (1) control rats fed with normal chow and (2) rats fed with HFD for 6 months. The prostate was removed for histology study. Isolated prostate strips were hung in organ bath and precontracted with 1 MUmol/L phenylephrine or 50 mmol/L KCl. The relaxation responses to loperamide 0.1 to 10 MUmol/L were recorded. Western blotting analyses were performed for prostate MU opioid receptors (MOR) and ATP-sensitive potassium (K(ATP)) channel proteins: sulfonylurea receptor (SUR) and inwardly rectifying potassium channel (Kir) 6.2 subunits. RESULTS: Body weight, prostate weight, plasma levels of glucose, insulin, triglyceride, and cholesterol, as well as systolic blood pressure, were significantly increased in the HFD rats. Histology showed prostatic hyperplasia in the HFD rat prostate. Prostatic relaxation induced by loperamide was markedly reduced in HFD when compared to the control. Protein expressions of MOR, SUR, and Kir 6.2 were decreased in HFD-fed rats. CONCLUSION: Loperamide-induced prostate relaxation is decreased in HFD rats due to reduced MOR and K(ATP) channel expressions. PMID- 25506072 TI - Distribution of phenolic compounds and antioxidative activities of rice kernel and their relationships with agronomic practice. AB - The phenolic and antioxidant activity of ethanolic extract of two Japonica rice cultivars, Taikeng no. 16 (medium and slender grain) and Kaohsiung no. 139 (short and round grain), grown under organic and conventional farming were examined. Analyses shows that Kaohsiung no. 139 contains the highest amount of secondary metabolites and continuous farming can increase its production. Results also suggest that phenolic content under different agronomic practices, has not shown significant differences but organically grown rice has proven to be better in higher accumulation of other secondary metabolites (2,2-diphenyl-1-picrylhydrazyl (DPPH), flavonoid content, and ferrous chelating capacity). In nutshell, genetic traits and environment have significant effect on phenolic compounds and the least variation reported under agronomic practices. PMID- 25506073 TI - Low power adder based auditory filter architecture. AB - Cochlea devices are powered up with the help of batteries and they should possess long working life to avoid replacing of devices at regular interval of years. Hence the devices with low power consumptions are required. In cochlea devices there are numerous filters, each responsible for frequency variant signals, which helps in identifying speech signals of different audible range. In this paper, multiplierless lookup table (LUT) based auditory filter is implemented. Power aware adder architectures are utilized to add the output samples of the LUT, available at every clock cycle. The design is developed and modeled using Verilog HDL, simulated using Mentor Graphics Model-Sim Simulator, and synthesized using Synopsys Design Compiler tool. The design was mapped to TSMC 65 nm technological node. The standard ASIC design methodology has been adapted to carry out the power analysis. The proposed FIR filter architecture has reduced the leakage power by 15% and increased its performance by 2.76%. PMID- 25506074 TI - The airport gate assignment problem: a survey. AB - The airport gate assignment problem (AGAP) is one of the most important problems operations managers face daily. Many researches have been done to solve this problem and tackle its complexity. The objective of the task is assigning each flight (aircraft) to an available gate while maximizing both conveniences to passengers and the operational efficiency of airport. This objective requires a solution that provides the ability to change and update the gate assignment data on a real time basis. In this paper, we survey the state of the art of these problems and the various methods to obtain the solution. Our survey covers both theoretical and real AGAP with the description of mathematical formulations and resolution methods such as exact algorithms, heuristic algorithms, and metaheuristic algorithms. We also provide a research trend that can inspire researchers about new problems in this area. PMID- 25506075 TI - Healthcare waste management: qualitative and quantitative appraisal of nurses in a tertiary care hospital of India. AB - BACKGROUND: The nurse's role in healthcare waste management is crucial. OBJECTIVES: (1) To appraise nurses quantitatively and qualitatively regarding healthcare waste management; (2) to elicit the determinants of knowledge and attitudes of healthcare waste management. METHOD: A cross-sectional study was undertaken at a tertiary care hospital of Mangalore, India. Self-administered pretested questionnaire and "nonparticipatory observation" were used for quantitative and qualitative appraisals. Percentage knowledge score was calculated based on their total knowledge score. Nurses' knowledge was categorized as excellent (>70%), good (50-70%), and poor (<50%). Chi square test was applied to judge the association of study variables with their attitudes and knowledge. RESULTS: Out of 100 nurses 47 had excellent knowledge (>70% score). Most (86%) expressed the need of refresher training. No study variable displayed significant association (P > 0.05) with knowledge. Apt segregation practices were followed except in casualty. Patients and entourages misinterpreted the colored containers. CONCLUSION: Nurses' knowledge and healthcare waste management practices were not satisfactory. There is a need of refresher trainings at optimum intervals to ensure sustainability and further improvement. Educating patients and their entourages and display of segregation information board in local language are recommended. PMID- 25506076 TI - Cone-like rectification properties of cGMP-gated channels in transmutated retinal photoreceptors of nocturnal geckoes. AB - Photoreceptors of nocturnal geckoes are scotopic, with rod-shaped outer segments, and sensitivities to light similar to the one of retinal rods from other species of lower vertebrates. However, these cells are not rods, but they originated from cones of ancestral diurnal geckoes with pure-cone retinas, after being forced to adapt to a nocturnal behavior. Several interesting adaptations of these rod-like cones have been studied to date; molecular biology and functional studies confirmed that several proteins of the phototransductive cascade display structural and functional properties that indicate their origin from cones rather than from rods. In this paper, we investigate, with whole cell voltage clamp in the photoreceptor detached outer segment preparation, the voltage rectification properties of cGMP-gated channels in three species, Gekko gecko, Tarentola mauritanica, and Hemidactylus frenatus. We show that the current-voltage properties in the physiological voltage range are reminiscent of the ones of cGMP gated channels from cones rather than from rods of other cold-blooded vertebrates. The origin and the relevance of the mechanisms investigated are discussed. PMID- 25506078 TI - Team Training (Training at Own Facility) versus Individual Surgeon's Training (Training at Trainer's Facility) When Implementing a New Surgical Technique: Example from the ONSTEP Inguinal Hernia Repair. AB - Background. When implementing a new surgical technique, the best method for didactic learning has not been settled. There are basically two scenarios: the trainee goes to the teacher's clinic and learns the new technique hands-on, or the teacher goes to the trainee's clinic and performs the teaching there. Methods. An informal literature review was conducted to provide a basis for discussing pros and cons. We also wanted to discuss how many surgeons can be trained in a day and the importance of the demand for a new surgical procedure to ensure a high adoption rate and finally to apply these issues on a discussion of barriers for adoption of the new ONSTEP technique for inguinal hernia repair after initial training. Results and Conclusions. The optimal training method would include moving the teacher to the trainee's department to obtain team training effects simultaneous with surgical technical training of the trainee surgeon. The training should also include a theoretical presentation and discussion along with the practical training. Importantly, the training visit should probably be followed by a scheduled visit to clear misunderstandings and fine-tune the technique after an initial self-learning period. PMID- 25506077 TI - Visual perception during mirror-gazing at one's own face in patients with depression. AB - In normal observers, gazing at one's own face in the mirror for a few minutes, at a low illumination level, produces the apparition of strange faces. Observers see distortions of their own faces, but they often see hallucinations like monsters, archetypical faces, faces of relatives and deceased, and animals. In this research, patients with depression were compared to healthy controls with respect to strange-face apparitions. The experiment was a 7-minute mirror-gazing test (MGT) under low illumination. When the MGT ended, the experimenter assessed patients and controls with a specifically designed questionnaire and interviewed them, asking them to describe strange-face apparitions. Apparitions of strange faces in the mirror were very reduced in depression patients compared to healthy controls. Depression patients compared to healthy controls showed shorter duration of apparitions; minor number of strange faces; lower self-evaluation rating of apparition strength; lower self-evaluation rating of provoked emotion. These decreases in depression may be produced by deficits of facial expression and facial recognition of emotions, which are involved in the relationship between the patient (or the patient's ego) and his face image (or the patient's bodily self) that is reflected in the mirror. PMID- 25506079 TI - An Analysis of Scalable GPU-Based Ray-Guided Volume Rendering. AB - Volume rendering continues to be a critical method for analyzing large-scale scalar fields, in disciplines as diverse as biomedical engineering and computational fluid dynamics. Commodity desktop hardware has struggled to keep pace with data size increases, challenging modern visualization software to deliver responsive interactions for O(N3) algorithms such as volume rendering. We target the data type common in these domains: regularly-structured data. In this work, we demonstrate that the major limitation of most volume rendering approaches is their inability to switch the data sampling rate (and thus data size) quickly. Using a volume renderer inspired by recent work, we demonstrate that the actual amount of visualizable data for a scene is typically bound considerably lower than the memory available on a commodity GPU. Our instrumented renderer is used to investigate design decisions typically swept under the rug in volume rendering literature. The renderer is freely available, with binaries for all major platforms as well as full source code, to encourage reproduction and comparison with future research. PMID- 25506080 TI - A cost-effective, case-control study on the association between breast cancer and pregnancy through web mining. AB - We report a case-control, breast cancer epidemiological study through mining people stories from the Internet. The aim of the study is to test whether mining openly available, personal stories from the Internet can be a cost-effective way for reliable epidemiological discoveries. As a case study, we focus on the association between breast cancer risk and pregnancy, which is clearly established through controlled clinical survey studies. Specifically, we mined 30,000 online obituary articles. Replicating a case-control study design, our web mining based approach confirmed the general trends reported by traditional epidemiological studies. Our web mining study demonstrates promising preliminary evidence that online content mining can be a cost-effective way for epidemiological knowledge discovery. PMID- 25506081 TI - New Challenges to Social Measurement. PMID- 25506082 TI - DYNAMICS AND STAGNATION IN THE MALTHUSIAN EPOCH. AB - This paper examines the central hypothesis of the influential Malthusian theory, according to which improvements in the technological environment during the pre industrial era had generated only temporary gains in income per capita, eventually leading to a larger, but not significantly richer, population. Exploiting exogenous sources of cross-country variations in land productivity and the level of technological advancement the analysis demonstrates that, in accordance with the theory, technological superiority and higher land productivity had significant positive effects on population density but insignificant effects on the standard of living, during the time period 1-1500 CE. PMID- 25506083 TI - The 'Out of Africa' Hypothesis, Human Genetic Diversity, and Comparative Economic Development. AB - This research argues that deep-rooted factors, determined tens of thousands of years ago, had a significant effect on the course of economic development from the dawn of human civilization to the contemporary era. It advances and empirically establishes the hypothesis that, in the course of the exodus of Homo sapiens out of Africa, variation in migratory distance from the cradle of humankind to various settlements across the globe affected genetic diversity and has had a long-lasting effect on the pattern of comparative economic development that is not captured by geographical, institutional, and cultural factors. In particular, the level of genetic diversity within a society is found to have a hump-shaped effect on development outcomes in both the pre-colonial and the modern era, reflecting the trade-off between the beneficial and the detrimental effects of diversity on productivity. While the intermediate level of genetic diversity prevalent among Asian and European populations has been conducive for development, the high degree of diversity among African populations and the low degree of diversity among Native American populations have been a detrimental force in the development of these regions. PMID- 25506084 TI - GENETIC DIVERSITY AND THE ORIGINS OF CULTURAL FRAGMENTATION. AB - Despite the importance attributed to the effects of diversity on the stability and prosperity of nations, the origins of the uneven distribution of ethnic and cultural fragmentation across countries have been underexplored. Building on the role of deeply-rooted biogeographical forces in comparative development, this research empirically demonstrates that genetic diversity, predominantly determined during the prehistoric "out of Africa" migration of humans, is an underlying cause of various existing manifestations of ethnolinguistic heterogeneity. Further exploration of this uncharted territory may revolutionize the understanding of the effects of deeply-rooted factors on economic development and the composition of human capital across the globe. PMID- 25506085 TI - Simultaneous detection of major blackleg and soft rot bacterial pathogens in potato by multiplex polymerase chain reaction. AB - A multiplex polymerase chain reaction (PCR) assay for simultaneous, fast and reliable detection of the main soft rot and blackleg potato pathogens in Europe has been developed. It utilises three pairs of primers and enables detection of three groups of pectinolytic bacteria frequently found in potato, namely: Pectobacterium atrosepticum, Pectobacterium carotovorum subsp. carotovorum together with Pectobacterium wasabiae and Dickeya spp. in a multiplex PCR assay. In studies with axenic cultures of bacteria, the multiplex assay was specific as it gave positive results only with strains of the target species and negative results with 18 non-target species of bacteria that can possibly coexist with pectinolytic bacteria in a potato ecosystem. The developed assay could detect as little as 0.01 ng uL-1 of Dickeya sp. genomic DNA, and down to 0.1 ng uL-1 of P. atrosepticum and P. carotovorum subsp. carotovorum genomic DNA in vitro. In the presence of competitor genomic DNA, isolated from Pseudomonas fluorescens cells, the sensitivity of the multiplex PCR decreased tenfold for P. atrosepticum and Dickeya sp., while no change was observed for P. carotovorum subsp. carotovorum and P. wasabiae. In spiked potato haulm and tuber samples, the threshold level for target bacteria was 101 cfu mL-1 plant extract (102 cfu g-1 plant tissue), 102 cfu mL-1 plant extract (103 cfu g-1 plant tissue), 103 cfu mL-1 plant extract (104 cfu g-1 plant tissue), for Dickeya spp., P. atrosepticum and P. carotovorum subsp. carotovorum/P. wasabiae, respectively. Most of all, this assay allowed reliable detection and identification of soft rot and blackleg pathogens in naturally infected symptomatic and asymptomatic potato stem and progeny tuber samples collected from potato fields all over Poland. PMID- 25506087 TI - Effects of Classroom Practices on Reading Comprehension, Engagement, and Motivations for Adolescents. AB - We investigated the roles of classroom supports for multiple motivations and engagement in students' informational text comprehension, motivation, and engagement. A composite of classroom contextual variables consisting of instructional support for choice, importance, collaboration, and competence, accompanied by cognitive scaffolding for informational text comprehension, was provided in four-week instructional units for 615 grade 7 students. These classroom motivational-engagement supports were implemented within integrated literacy/history instruction in the Concept-Oriented Reading Instruction (CORI) framework. CORI increased informational text comprehension compared with traditional instruction (TI) in a switching replications experimental design. Students' perceptions of the motivational-engagement supports were associated with increases in students' intrinsic motivation, value, perceived competence, and increased positive engagement (dedication) more markedly in CORI than in TI, according to multiple regression analyses. Results extended the evidence for the effectiveness of CORI to literacy/history subject matter and informational text comprehension among middle school students. The experimental effects in classroom contexts confirmed effects from task-specific, situated experimental studies in the literature. PMID- 25506086 TI - Interactive effects of landscape history and current management on dispersal trait diversity in grassland plant communities. AB - Plant communities and their ecosystem functions are expected to be more resilient to future habitat fragmentation and deterioration if the species comprising the communities have a wide range of dispersal and persistence strategies. However, the extent to which the diversity of dispersal and persistence traits in plant communities is determined by the current and historical characteristics of sites and their surrounding landscape has yet to be explored.Using quantitative information on long-distance seed dispersal potential by wind and animals (dispersal in space) and on species' persistence/longevity (dispersal in time), we (i) compared levels of dispersal and persistence trait diversity (functional richness, FRic, and functional divergence, FDiv) in seminatural grassland plant communities with those expected by chance, and (ii) quantified the extent to which trait diversity was explained by current and historical landscape structure and local management history - taking into account spatial and phylogenetic autocorrel.Null model analysis revealed that more grassland communities than expected had a level of trait diversity that was lower or higher than predicted, given the level of species richness. Both the range (FRic) and divergence (FDiv) of dispersal and persistence trait values increased with grassland age. FDiv was mainly explained by the interaction between current grazing intensity and the amount of grassland habitat in the surrounding landscape in 1938.Synthesis. The study suggests that the variability of dispersal and persistence traits in grassland plant communities is driven by deterministic assembly processes, with both history and current management (and their interactions), playing a major role as determinants of trait diversity. While a long continuity of grazing management is likely to have promoted the diversity of dispersal and persistence traits in present-day grasslands, communities in sites that are well grazed at the present day, and were also surrounded by large amounts of grassland in the past, showed the highest diversity of dispersal and persistence strategies. Our results indicate that the historical context of a site within a landscape will influence the extent to which current grazing management is able to maintain a diversity of dispersal and persistence strategies and buffer communities (and their associated functions) against continuing habitat fragmentation. PMID- 25506088 TI - Assessing the heterogeneity of treatment effects via potential outcomes of individual patients. AB - There is growing interest in understanding the heterogeneity of treatment effects (HTE), which has important implications in treatment evaluation and selection. The standard approach to assessing HTE (i.e. subgroup analyses based on known effect modifiers) is informative about the heterogeneity between subpopulations but not within. It is arguably more informative to assess HTE in terms of individual treatment effects, which can be defined by using potential outcomes. However, estimation of HTE based on potential outcomes is challenged by the lack of complete identifiability. The paper proposes methods to deal with the identifiability problem by using relevant information in baseline covariates and repeated measurements. If a set of covariates is sufficient for explaining the dependence between potential outcomes, the joint distribution of potential outcomes and hence all measures of HTE will then be identified under a conditional independence assumption. Possible violations of this assumption can be addressed by including a random effect to account for residual dependence or by specifying the conditional dependence structure directly. The methods proposed are shown to reduce effectively the uncertainty about HTE in a trial of human immunodeficiency virus. PMID- 25506089 TI - Job Authority and Breast Cancer. AB - Using the 1957-2011 data from the Wisconsin Longitudinal Study, I integrate the gender relations theory, a life course perspective, and a biosocial stress perspective to explore the effect of women's job authority in 1975 (at age 36) and 1993 (at age 54) on breast cancer incidence up to 2011. Findings indicate that women with the authority to hire, fire, and influence others' pay had a significantly higher risk of a breast cancer diagnosis over the next 30 years compared to housewives and employed women with no job authority. Because job authority conferred the highest risk of breast cancer for women who also spent more hours dealing with people at work in 1975, I suggest that the assertion of job authority by women in the 1970s involved stressful interpersonal experiences, such as social isolation and negative social interactions, that may have increased the risk of breast cancer via prolonged dysregulation of the glucocorticoid system and exposure of breast tissue to the adverse effects of chronically elevated cortisol. This study contributes to sociology by emphasizing gendered biosocial pathways through which women's occupational experiences become embodied and drive forward physiological repercussions. PMID- 25506090 TI - EEG/ERP Measures of Emotion-cognition Integration during Development. PMID- 25506091 TI - Multicultural desires? Parental negotiation of multiculture and difference in choosing secondary schools for their children. AB - This paper considers the ways in which parents talk about choosing secondary schools in three areas of Greater Manchester. It argues that this can be a moment when parents are considering their own attitudes to, and shaping their children's experiences of, multiculture. Multiculture is taken as the everyday experience of living with difference. The paper argues that multiculture needs to be understood as shaped not only by racialized, ethnic or religious difference (as it is commonly understood) but also by other differences which parents may consider important, particularly class and approaches to parenting. We stress the need to examine what parents say about schooling in the context in which they are talking, which is shaped by local areas and the experiences of their children in primary schools. Based on interviews with an ethnically mixed groups of parents from different schools, we show how perceptions of the racialized and class demographics of schools can influence parents' choice of secondary schools. The paper also argues that attention needs to be paid to the ways in which terms such as 'multicultural' and 'mix' are applied uniformly to very different contexts, be they particular schools or local areas, suggesting there is a paucity of language in Britain when talking about multiculture. PMID- 25506093 TI - Response to Letter by Tsuda Regarding Article, "Vitamin D Deficiency Is Associated With Subclinical Carotid Atherosclerosis: The Northern Manhattan Study" PMID- 25506092 TI - Stagnating Life Expectancies and Future Prospects in an Age of Uncertainty* AB - OBJECTIVE: This article provides a timely assessment of U.S. life expectancy given recent stalls in the growth of length of life, the continuing drop in international rankings of life expectancy for the U.S., and during a period of growing social and economic insecurity. METHODS: Time series analysis is used on over 70 years of data from the Human Mortality Database to forecast future life expectancy to the year 2055. RESULTS: The results show limited improvements in U.S. life expectancy at birth, less than 3 years on average, for both men and women. CONCLUSIONS: Even in uncertain times, it is important to look forward in preparing for the needs of future populations. The results presented here underscore the relevance of policy and health initiatives aimed at improving the nation's health and reveal important insight into possible limits to mortality improvement over the next five decades. PMID- 25506094 TI - Enantioselective Synthesis of the Tricyclic Core of FR901483 Featuring a Rh Catalyzed [2+2+2] Cycloaddition. AB - An efficient approach to the tricyclic framework of FR901483 is described. The sequence features a [3, 3]-sigmatropic rearrangement of a cyanate into an isocyanate, followed by its subsequent asymmetric rhodium-catalyzed [2+2+2] cycloaddition with a terminal alkyne for the synthesis of the indolizidine core. The aza-tricyclic core is completed using an intramolecular benzoin reaction to close the last ring of the natural product. Through a model study of the key cycloaddition, we evaluated the impact of different substituents on the tether of the alkenyl isocyanate. PMID- 25506095 TI - Rapid synthesis of 1,7-bis(t-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane (DO2A-t-Bu ester). AB - A three-step route was used to synthesize 1,7-bis(t-butoxycarbonylmethyl) 1,4,7,10-tetraazacyclododecane (DO2A-t-Bu ester) from 1,4,7,10 tetraazacyclododecane (cyclen). The overall time of reaction was reduced from a combined ~56 h to 2.3 h with an overall yield comparable to previously reported methods. PMID- 25506096 TI - Silver-Mediated Synthesis of Indolizines via Oxidative C-H functionalization and 5- endo-dig cyclization. AB - An efficient strategy for the synthesis of indolizines from readily available starting materials via oxidative C-H functionalization and 5-endo-dig cyclization in one step has been demonstrated. This protocol represents wide substrate scope, high functional group tolerance and selectivity. The structure of the product was confirmed by the X-ray crystallographic studies. The Ag2CO3 required of this tandem reaction can be recycled and reused after undergoing oxidative reaction. PMID- 25506097 TI - Evaluating the performance of parallel subsurface simulators: An illustrative example with PFLOTRAN. AB - [1] To better inform the subsurface scientist on the expected performance of parallel simulators, this work investigates performance of the reactive multiphase flow and multicomponent biogeochemical transport code PFLOTRAN as it is applied to several realistic modeling scenarios run on the Jaguar supercomputer. After a brief introduction to the code's parallel layout and code design, PFLOTRAN's parallel performance (measured through strong and weak scalability analyses) is evaluated in the context of conceptual model layout, software and algorithmic design, and known hardware limitations. PFLOTRAN scales well (with regard to strong scaling) for three realistic problem scenarios: (1) in situ leaching of copper from a mineral ore deposit within a 5-spot flow regime, (2) transient flow and solute transport within a regional doublet, and (3) a real-world problem involving uranium surface complexation within a heterogeneous and extremely dynamic variably saturated flow field. Weak scalability is discussed in detail for the regional doublet problem, and several difficulties with its interpretation are noted. PMID- 25506098 TI - Storage dynamics in hydropedological units control hillslope connectivity, runoff generation, and the evolution of catchment transit time distributions. AB - : We examined the storage dynamics and isotopic composition of soil water over 12 months in three hydropedological units in order to understand runoff generation in a montane catchment. The units form classic catena sequences from freely draining podzols on steep upper hillslopes through peaty gleys in shallower lower slopes to deeper peats in the riparian zone. The peaty gleys and peats remained saturated throughout the year, while the podzols showed distinct wetting and drying cycles. In this region, most precipitation events are <10 mm in magnitude, and storm runoff is mainly generated from the peats and peaty gleys, with runoff coefficients (RCs) typically <10%. In larger events the podzolic soils become strongly connected to the saturated areas, and RCs can exceed 40%. Isotopic variations in precipitation are significantly damped in the organic-rich soil surface horizons due to mixing with larger volumes of stored water. This damping is accentuated in the deeper soil profile and groundwater. Consequently, the isotopic composition of stream water is also damped, but the dynamics strongly reflect those of the near-surface waters in the riparian peats. "pre-event" water typically accounts for >80% of flow, even in large events, reflecting the displacement of water from the riparian soils that has been stored in the catchment for >2 years. These riparian areas are the key zone where different source waters mix. Our study is novel in showing that they act as "isostats," not only regulating the isotopic composition of stream water, but also integrating the transit time distribution for the catchment. KEY POINTS: Hillslope connectivity is controlled by small storage changes in soil unitsDifferent catchment source waters mix in large riparian wetland storageIsotopes show riparian wetlands set the catchment transit time distribution. PMID- 25506099 TI - Floodplain ecohydrology: Climatic, anthropogenic, and local physical controls on partitioning of water sources to riparian trees. AB - : Seasonal and annual partitioning of water within river floodplains has important implications for ecohydrologic links between the water cycle and tree growth. Climatic and hydrologic shifts alter water distribution between floodplain storage reservoirs (e.g., vadose, phreatic), affecting water availability to tree roots. Water partitioning is also dependent on the physical conditions that control tree rooting depth (e.g., gravel layers that impede root growth), the sources of contributing water, the rate of water drainage, and water residence times within particular storage reservoirs. We employ instrumental climate records alongside oxygen isotopes within tree rings and regional source waters, as well as topographic data and soil depth measurements, to infer the water sources used over several decades by two co-occurring tree species within a riparian floodplain along the Rhone River in France. We find that water partitioning to riparian trees is influenced by annual (wet versus dry years) and seasonal (spring snowmelt versus spring rainfall) fluctuations in climate. This influence depends strongly on local (tree level) conditions including floodplain surface elevation and subsurface gravel layer elevation. The latter represents the upper limit of the phreatic zone and therefore controls access to shallow groundwater. The difference between them, the thickness of the vadose zone, controls total soil moisture retention capacity. These factors thus modulate the climatic influence on tree ring isotopes. Additionally, we identified growth signatures and tree ring isotope changes associated with recent restoration of minimum streamflows in the Rhone, which made new phreatic water sources available to some trees in otherwise dry years. KEY POINTS: Water shifts due to climatic fluctuations between floodplain storage reservoirsAnthropogenic changes to hydrology directly impact water available to treesEcohydrologic approaches to integration of hydrology afford new possibilities. PMID- 25506101 TI - Coping with Natural Hazards in a Conservation Context: Resource-Use Decisions of Maasai Households During Recent and Historical Droughts. AB - Analyzing people's decisions can reveal key variables that affect their behaviors. Despite the demonstrated utility of this approach, it has not been applied to livelihood decisions in the context of conservation initiatives. We used ethnographic decision modeling in combination with qualitative comparative analysis (QCA) to examine the herding decisions of Maasai households living near Tarangire National Park (TNP) during recent and historical droughts. The effects of the establishment of TNP on herding practices during drought were different than anticipated based on the size and reliability of several prominent resource areas that are now within the park. We found little evidence of people relying on these swamps and rivers for watering cattle during historical droughts; rather, these sites were more commonly used as grazing areas for small stock and wet season grazing areas for cattle to avoid disease carried by calving wildebeest. Yet during the 2009 drought, many herders moved their livestock - especially cattle from outside of the study area - toward TNP in search of grazing. Our analysis of herding decisions demonstrates that resource-use decisions are complex and incorporate a variety of information beyond the size or reliability of a given resource area, including contextual factors (e.g., disease, conflict, grazing) and household factors (e.g., social capital, labor, herd size). More broadly, this research illustrates that pairing decision modeling with QCA is a structured approach to identifying these factors and understanding how opportunities, constraints, and perceptions influence how people respond to changes in resource access. PMID- 25506100 TI - The Architecture of the Pollen Hoarding Syndrome in Honey Bees: Implications for Understanding Social Evolution, Behavioral Syndromes, and Selective Breeding. AB - Social evolution has influenced every aspect of contemporary honey bee biology, but the details are difficult to reconstruct. The reproductive ground plan hypothesis of social evolution proposes that central regulators of the gonotropic cycle of solitary insects have been coopted to coordinate social complexity in honey bees, such as the division of labor among workers. The predicted trait associations between reproductive physiology and social behavior have been identified in the context of the pollen hoarding syndrome, a larger suite of interrelated traits. The genetic architecture of this syndrome is characterized by a partially overlapping genetic architecture with several consistent, pleiotropic QTL. Despite these central QTL and an integrated hormonal regulation, separate aspects of the pollen hoarding syndrome may evolve independently due to peripheral QTL and additionally segregating genetic variance. The characterization of the pollen hoarding syndrome has also demonstrated that this syndrome involves many non-behavioral traits, which may be the case for numerous "behavioral" syndromes. Furthermore, the genetic architecture of the pollen hoarding syndrome has implications for breeding programs for improving honey health and other desirable traits: If these traits are comparable to the pollen hoarding syndrome, consistent pleiotropic QTL will enable marker assisted selection, while sufficient additional genetic variation may permit the dissociation of trade-offs for efficient multiple trait selection. PMID- 25506102 TI - Evidence That Loss-of-Function Filaggrin Gene Mutations Evolved in Northern Europeans to Favor Intracutaneous Vitamin D3 Production. AB - Skin pigmentation lightened progressively to a variable extent, as modern humans emigrated out of Africa, but extreme lightening occurred only in northern Europeans. Yet, loss of pigmentation alone cannot suffice to sustain cutaneous vitamin D3 (VD3) formation at the high latitudes of northern Europe. We hypothesized that loss-of-function mutations in the epidermal structural protein, filaggrin (FLG), could have evolved to sustain adequate VD3 status. Loss of FLG results in reduced generation of trans-urocanic acid, the principal endogenous ultraviolet-B (UV-B) filter in lightly-pigmented individuals. Accordingly, we identified a higher prevalence of FLG mutations in northern European populations when compared to more southern European, Asian and African populations that correlates significantly with differences in circulating 25-OH-VD3 levels in these same populations. By allowing additional UV-B penetration and intracutaneous VD3 formation, the latitude-dependent gradient in FLG mutations, likely together with other concurrent mutations in VD3 metabolic pathways, provide a non-pigment-based mechanism that sustains higher levels of circulating VD3 in northern Europeans. At the time that FLG mutations evolved, xerosis due to FLG deficiency was a lesser price to pay for enhanced VD3 production. Yet, the increase in FLG mutations has inadvertently contributed to an epidemic of atopic diseases that has emerged in recent decades. PMID- 25506103 TI - A Chemical Engineer's Perspective on Health and Disease. AB - Chemical process systems engineering considers complex supply chains which are coupled networks of dynamically interacting systems. The quest to optimize the supply chain while meeting robustness and flexibility constraints in the face of ever changing environments necessitated the development of theoretical and computational tools for the analysis, synthesis and design of such complex engineered architectures. However, it was realized early on that optimality is a complex characteristic required to achieve proper balance between multiple, often competing, objectives. As we begin to unravel life's intricate complexities, we realize that that living systems share similar structural and dynamic characteristics; hence much can be learned about biological complexity from engineered systems. In this article, we draw analogies between concepts in process systems engineering and conceptual models of health and disease; establish connections between these concepts and physiologic modeling; and describe how these mirror onto the physiological counterparts of engineered systems. PMID- 25506105 TI - ? AB - This study investigates the phonological acquisition of Brazilian Portuguese (BP) by a group of 24 bimodal bilingual hearing children, who have unrestricted access to Brazilian Sign Language (Libras), and a group of 6 deaf children, who use cochlear implants (CI), with restricted or unrestricted access to Libras. The children's phonological system of BP was assessed through the Naming Task (Part A) of the ABFW - Children Language Test (ANDRADE et al. 2004). The results revealed that the hearing children and the deaf child who use CI, all with full access to Libras, showed expected (normal) phonological acquisition considering their age groups. We consider that the early acquisition and unrestricted access to Libras may have determined these children's performance in the oral tests. PMID- 25506104 TI - Quantitative Analysis of Robustness of Dynamic Response and Signal Transfer in Insulin mediated PI3K/AKT Pathway. AB - Robustness is a critical feature of signaling pathways ensuring signal propagation with high fidelity in the event of perturbations. Here we present a detailed quantitative analysis of robustness in insulin mediated PI3K/AKT pathway, a critical signaling pathway maintaining self-renewal in human embryonic stem cells. Using global sensitivity analysis, we identified robustness promoting mechanisms that ensure (1) maintenance of a first order or overshoot dynamics of self-renewal molecule, p-AKT and (2) robust transfer of signals from oscillatory insulin stimulus to p-AKT in the presence of noise. Our results indicate that negative feedback controls the robustness to most perturbations. Faithful transfer of signal from the stimulating ligand to p-AKT occurs even in the presence of noise, albeit with signal attenuation and high frequency cut-off. Negative feedback contributes to signal attenuation, while positive regulators upstream of PIP3 contribute to signal amplification. These results establish precise mechanisms to modulate self-renewal molecules like p-AKT. PMID- 25506106 TI - Autism: Common, heritable, but not harmful. AB - We assert that one of the examples used by Keller & Miller (K&M), namely, autism, is indeed common, and heritable, but we question whether it is harmful. We provide a brief review of cognitive science literature in which autistics perform superiorly to non-autistics in perceptual, reasoning, and comprehension tasks; however, these superiorities are often occluded and are instead described as dysfunctions. PMID- 25506107 TI - Implications of the Flynn Effect for Age-Cognition Relations. AB - Many studies have documented that cognitive performance is often higher among people of the same age who are tested in more recent years, and it is sometimes suggested that this phenomenon will distort the relations between age and cognition in cross-sectional studies. This possibility was examined with data from two large projects involving adults across a wide age range. The results indicated that there were similar time-of-measurement increases in cognitive scores at different ages, which were accompanied by nearly constant cross sectional age differences, but positively inflated estimates of longitudinal age differences. It is proposed that when the Flynn Effect is of comparable magnitude in adults of different ages, longitudinal comparisons of age-cognition relations are more subject to distortion than cross-sectional comparisons. PMID- 25506108 TI - Causal Inference for fMRI Time Series Data with Systematic Errors of Measurement in a Balanced On/Off Study of Social Evaluative Threat. AB - Functional magnetic resonance imaging (fMRI) has facilitated major advances in understanding human brain function. Neuroscientists are interested in using fMRI to study the effects of external stimuli on brain activity and causal relationships among brain regions, but have not stated what is meant by causation or defined the effects they purport to estimate. Building on Rubin's causal model, we construct a framework for causal inference using blood oxygenation level dependent (BOLD) fMRI time series data. In the usual statistical literature on causal inference, potential outcomes, assumed to be measured without systematic error, are used to define unit and average causal effects. However, in general the potential BOLD responses are measured with stimulus dependent systematic error. Thus we define unit and average causal effects that are free of systematic error. In contrast to the usual case of a randomized experiment where adjustment for intermediate outcomes leads to biased estimates of treatment effects (Rosenbaum, 1984), here the failure to adjust for task dependent systematic error leads to biased estimates. We therefore adjust for systematic error using measured "noise covariates" , using a linear mixed model to estimate the effects and the systematic error. Our results are important for neuroscientists, who typically do not adjust for systematic error. They should also prove useful to researchers in other areas where responses are measured with error and in fields where large amounts of data are collected on relatively few subjects. To illustrate our approach, we re-analyze data from a social evaluative threat task, comparing the findings with results that ignore systematic error. PMID- 25506109 TI - A Markov Random Field Groupwise Registration Framework for Face Recognition. AB - In this paper, we propose a new framework for tackling face recognition problem. The face recognition problem is formulated as groupwise deformable image registration and feature matching problem. The main contributions of the proposed method lie in the following aspects: (1) Each pixel in a facial image is represented by an anatomical signature obtained from its corresponding most salient scale local region determined by the survival exponential entropy (SEE) information theoretic measure. (2) Based on the anatomical signature calculated from each pixel, a novel Markov random field based groupwise registration framework is proposed to formulate the face recognition problem as a feature guided deformable image registration problem. The similarity between different facial images are measured on the nonlinear Riemannian manifold based on the deformable transformations. (3) The proposed method does not suffer from the generalizability problem which exists commonly in learning based algorithms. The proposed method has been extensively evaluated on four publicly available databases: FERET, CAS-PEAL-R1, FRGC ver 2.0, and the LFW. It is also compared with several state-of-the-art face recognition approaches, and experimental results demonstrate that the proposed method consistently achieves the highest recognition rates among all the methods under comparison. PMID- 25506110 TI - The educational homogamy gap between married and cohabiting couples in Latin America. AB - The explosive expansion of non-marital cohabitation in Latin America since the 1970s has led to the narrowing of the gap in educational homogamy between married and cohabiting couples (what we call "homogamy gap") as shown by our analysis of 29 census samples encompassing eight countries: Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Mexico and Panama (N = 2,295,160 young couples). Most research on the homogamy gap is limited to a single decade and a small group of developed countries (the United States, Canada, and Europe). We take a historical and cross-national perspective and expand the research to a range of developing countries, where since early colonial times traditional forms of cohabitation among the poor, uneducated sectors of society have coexisted with marriage, although to widely varying degrees from country to country. In recent decades, cohabitation is emerging in all sectors of society. We find that among married couples educational homogamy continues to be higher than for those who cohabit, but in recent decades the difference has narrowed substantially in all countries. We argue that assortative mating between cohabiting and married couples tend to be similar when the contexts in which they are formed are also increasingly similar. PMID- 25506111 TI - Exploring Child Mortality Risks Associated with Diverse Patterns of Maternal Migration in Haiti. AB - Internal migration is a salient dimension of adulthood in Haiti, particularly among women. Despite the prevalence of migration in Haiti, it remains unknown whether Haitian women's diverse patterns of migration influence their children's health and survival. In this paper, we introduce the concept of lateral (i.e., rural-to-rural, urban-to-urban) versus nonlateral (i.e., rural-to-urban, urban-to rural) migration to describe how some patterns of mothers' internal migration may be associated with particularly high mortality among children. We use the 2006 Haitian Demographic and Health Survey to estimate a series of discrete-time hazard models among 7,409 rural children and 3,864 urban children. We find that, compared with their peers with nonmigrant mothers, children born to lateral migrants generally experience lower mortality whereas those born to nonlateral migrants generally experience higher mortality. Although there are important distinctions across Haiti's rural and urban contexts, these associations remain net of socioeconomic factors, suggesting they are not entirely attributable to migrant selection. Considering the timing of maternal migration uncovers even more variation in the child health implications of maternal migration; however, the results counter the standard disruption and adaptation perspective. Although future work is needed to identify the processes underlying the differential risk of child mortality across lateral versus nonlateral migrants, the study demonstrates that looking beyond rural-to-urban migration and considering the timing of maternal migration can provide a fuller, more complex understanding of migration's association with child health. PMID- 25506112 TI - Domain selection for the varying coefficient model via local polynomial regression. AB - In this article, we consider the varying coefficient model, which allows the relationship between the predictors and response to vary across the domain of interest, such as time. In applications, it is possible that certain predictors only affect the response in particular regions and not everywhere. This corresponds to identifying the domain where the varying coefficient is nonzero. Towards this goal, local polynomial smoothing and penalized regression are incorporated into one framework. Asymptotic properties of our penalized estimators are provided. Specifically, the estimators enjoy the oracle properties in the sense that they have the same bias and asymptotic variance as the local polynomial estimators as if the sparsity is known as a priori. The choice of appropriate bandwidth and computational algorithms are discussed. The proposed method is examined via simulations and a real data example. PMID- 25506113 TI - A New Time Calibration Method for Switched-capacitor-array-based Waveform Samplers. AB - We have developed a new time calibration method for the DRS4 waveform sampler that enables us to precisely measure the non-uniform sampling interval inherent in the switched-capacitor cells of the DRS4. The method uses the proportionality between the differential amplitude and sampling interval of adjacent switched capacitor cells responding to a sawtooth-shape pulse. In the experiment, a sawtooth-shape pulse with a 40 ns period generated by a Tektronix AWG7102 is fed to a DRS4 evaluation board for calibrating the sampling intervals of all 1024 cells individually. The electronic time resolution of the DRS4 evaluation board with the new time calibration is measured to be ~2.4 ps RMS by using two simultaneous Gaussian pulses with 2.35 ns full-width at half-maximum and applying a Gaussian fit. The time resolution dependencies on the time difference with the new time calibration are measured and compared to results obtained by another method. The new method could be applicable for other switched-capacitor-array technology-based waveform samplers for precise time calibration. PMID- 25506114 TI - Chinese sex differences in intelligence: Some new evidence. AB - Sex differences on the WISC-R in Chinese children were examined in a sample of 788 aged 12 years. Boys obtained a higher mean full scale IQ than girls of 3.75 IQ points, a higher performance IQ of 4.20 IQ points, and a higher verbal IQ of 2.40 IQ points. Boys obtained significantly higher means on the information, picture arrangement, picture completion, block design, and object assembly subtests, while girls obtained a significantly higher mean on coding. The results were in general similar to the sex differences in the United States standardisation sample of the WISC-R. Boys showed greater variability than girls. PMID- 25506115 TI - Closed-loop optimization of chromatography column sizing strategies in biopharmaceutical manufacture. AB - BACKGROUND: This paper considers a real-world optimization problem involving the identification of cost-effective equipment sizing strategies for the sequence of chromatography steps employed to purify biopharmaceuticals. Tackling this problem requires solving a combinatorial optimization problem subject to multiple constraints, uncertain parameters, and time-consuming fitness evaluations. RESULTS: An industrially-relevant case study is used to illustrate that evolutionary algorithms can identify chromatography sizing strategies with significant improvements in performance criteria related to process cost, time and product waste over the base case. The results demonstrate also that evolutionary algorithms perform best when infeasible solutions are repaired intelligently, the population size is set appropriately, and elitism is combined with a low number of Monte Carlo trials (needed to account for uncertainty). Adopting this setup turns out to be more important for scenarios where less time is available for the purification process. Finally, a data-visualization tool is employed to illustrate how user preferences can be accounted for when it comes to selecting a sizing strategy to be implemented in a real industrial setting. CONCLUSION: This work demonstrates that closed-loop evolutionary optimization, when tuned properly and combined with a detailed manufacturing cost model, acts as a powerful decisional tool for the identification of cost-effective purification strategies. (c) 2013 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 25506116 TI - Effects of Topiramate on Smoking in Patients with Schizoaffective Disorder, Bipolar Type: Response to Khazaal and Zullino. PMID- 25506117 TI - Diagnosis of ADHD and its Behavioral, Neurologic and Genetic Roots. AB - Attention-Deficit/Hyperactivity Disorder (ADHD) is a common developmental disorder often associated with other developmental disorders including speech, language, and reading disorders. Here we review the principal features of ADHD and current diagnostic standards for the disorder. We outline the ADHD subtypes, which are based upon the dimensions of inattention and hyperactivity. These serve as the phenotype for ADHD. Current nomenclature implies a deficit in the cognitive construct of attention, and this has taken researchers on an extended inquiry into several potential endophenotypes underlying ADHD, in particular executive function and its subcomponents. We review this literature and then delve into the neurobiology of ADHD. This research has suggested to us that the corticostriatal system is a strong candidate system in the etiology of ADHD, in part because of the dopaminergic system, which is known to play a role in the disorder. We present this system as an important contributor to the comorbidty of ADHD with other developmental disorders, especially language disorder. PMID- 25506118 TI - MATERNAL DEPRESSIVE SYMPTOMS IN CHILDHOOD AND OPENNESS TO EXPERIENCE IN ADULTHOOD. AB - We examined the role of maternal depressive symptoms reported during childhood as a predictor of an important personality trait, Openness to Experience (O), in middle adulthood. Participants were 95 adults (38 previously malnourished, 57 control, mean age 42.1 years) who had been followed longitudinally since childhood by the Barbados Nutrition Study. Maternal depressive symptoms had been measured when the participants were 5-11 years of age by the General Adjustment and Morale Scale; O was measured in adulthood by the Revised NEO-Personality Inventory (NEO-PI-R). Multiple regression analyses, adjusted for childhood household standard of living, showed a significant main effect on O of maternal depressive symptoms (p < 0.01). Maternal depression also attenuated the significant effect of childhood malnutrition by 14%. Maternal depressive symptoms in childhood may therefore play a causal role in adult personality, in particular Openness to Experience, with implications for creativity. PMID- 25506119 TI - Residual salivary secretion ability may be a useful marker for differential diagnosis in autoimmune diseases. AB - BACKGROUND: We have elucidated decreased resting salivary flow in approximately 60% of patients with autoimmune diseases not complicated by Sjogren syndrome (SjS). In this study, salivary stimulation tests using capsaicin were performed to examine residual salivary secretion ability in patients with autoimmune diseases. MATERIALS AND METHODS: Fifty-eight patients were divided into three groups: patients with primary or secondary SjS (SjS group), patients with systemic sclerosis not complicated by SjS (SSc group), and patients with other autoimmune diseases (non-SjS/non-SSc group). Simple filter paper and filter paper containing capsaicin were used to evaluate salivary flow rates. RESULTS: Resting salivary flow rates were significantly lower in the SjS and SSc groups than in the non-SjS/non-SSc group but did not differ significantly between the SjS and SSc groups. Capsaicin-stimulated salivary flow rates were significantly lower in the SjS and SSc groups than in the non-SjS/non-SSc group, but not significantly different between the SjS and SSc groups. In the non-SjS/non-SSc group, salivary flow rates increased after capsaicin stimulation to the threshold level for determination of salivary gland dysfunction, whereas no improvement was observed in the SjS and SSc groups. CONCLUSION: Residual salivary secretion ability may be a useful marker for differential diagnosis in autoimmune diseases. PMID- 25506121 TI - Artifact Patterns in Continuous Noninvasive Monitoring of Patients. PMID- 25506122 TI - LEARNING TEMPORAL RULES TO FORECAST INSTABILITY IN INTENSIVE CARE PATIENTS. PMID- 25506120 TI - The use of humoral responses as a marker of CMV burden in HIV patients on ART requires consideration of T-cell recovery and persistent B-cell activation. AB - OBJECTIVES: Elevated humoral responses to cytomegalovirus (CMV) associate with increased risk of cardiovascular disease (CVD) in HIV patients on antiretroviral therapy (ART). To better understand the persistence of CMV humoral responses in relation to CVD, we determined trends in CMV antibody levels over the first 10 years on ART. DESIGN: We describe longitudinal analyses of plasma from 13 HIV patients commencing ART with <210 CD4 T-cells/uL and 27 controls. Antibodies reactive with CMV (fibroblast lysate, gB and IE-1 antigens), EBV-VCA, and HIVgp41 were quantitated. B-cell activation was assessed via total IgG and sBAFF. Inflammation was assessed via sTNF-RI and sCD14. RESULTS: Amongst CMV seropositive HIV patients, levels of antibody reactive with CMV (P = 0.03) and EBV-VCA (P = 0.02) peaked after 1 year on ART. Levels of total IgG, sCD14, and sTNF-RI declined to approximate those in controls after 10 years, but sBAFF (P = 0.0002), EBV-VCA (P = 0.001), and CMV (P = 0.0004) antibodies remained elevated. A strong correlation between sBAFF and CMVgB antibody was seen at 10 years (R = 0.93, P = 0.0009) and verified in a second cohort. CONCLUSIONS: CMV antibody titres peak on ART and remain high. A correlation between CMV antibody and sBAFF suggests a role for HIV-induced B-cell pathology that may affect its use as a marker of CMV burden. PMID- 25506123 TI - Benchmarking Student Diversity at Public Universities in the United States: Accounting for State Population Composition. AB - Regions rely at least partially on the internal production of a qualified workforce in order to maintain their economic competitiveness. Increasingly, at least from a university or corporate point of view, a qualified workforce is viewed as one that is racially and ethnically diverse. However, the conceptualization and measurement of ethnic and racial diversity in higher education appears to be often based on normative values rather than solid benchmarks, making any regional comparisons or goals difficult to specify. Ideally, at least as a starting point, public state universities would, while attempting to increase overall student diversity, benchmark their progress against the state population composition. This paper combines enrollment data from the National Center for Education Statistics (NCES) with U.S. Census Bureau population estimates data to provide a point of comparison for state universities. The paper has two goals: first a university-level comparison of diversity scores, as measured by the interaction index and, second, an analysis of how university student population composition compares to that of the population the university was originally intended to serve - the state population. PMID- 25506125 TI - China's Land Market Auctions: Evidence of Corruption? AB - This paper studies the urban land market in China in 2003-2007. In China, all urban land is owned by the state. Leasehold use rights for land for (re)development are sold by city governments and are a key source of city revenue. Leasehold sales are viewed as a major venue for corruption, prompting a number of reforms over the years. Reforms now require all leasehold rights be sold at public auction. There are two main types of auction: regular English auction and an unusual type which we call a "two stage auction". The latter type of auction seems more subject to corruption, and to side deals between potential bidders and the auctioneer. Absent corruption, theory suggests that two stage auctions would most likely maximize sales revenue for properties which are likely to have relatively few bidders, or are "cold", which would suggest negative selection on property unobservables into such auctions. However, if such auctions are more corruptible, that could involve positive selection as city officials divert hotter properties to a more corruptible auction form. The paper finds that, overall, sales prices are lower for two stage auctions, and there is strong evidence of positive selection. The price difference is explained primarily by the fact that two stage auctions typically have just one bidder, or no competition despite the vibrant land market in Chinese cities. PMID- 25506124 TI - Practical understanding of hemostasis and approach to the bleeding patient in the OR. PMID- 25506126 TI - Too real for comfort? Uncanny responses to computer generated faces. AB - As virtual humans approach photorealistic perfection, they risk making real humans uncomfortable. This intriguing phenomenon, known as the uncanny valley, is well known but not well understood. In an effort to demystify the causes of the uncanny valley, this paper proposes several perceptual, cognitive, and social mechanisms that have already helped address riddles like empathy, mate selection, threat avoidance, cognitive dissonance, and psychological defenses. In the four studies described herein, a computer generated human character's facial proportions, skin texture, and level of detail were varied to examine their effect on perceived eeriness, human likeness, and attractiveness. In Study I, texture photorealism and polygon count increased human likeness. In Study II, texture photorealism heightened the accuracy of human judgments of ideal facial proportions. In Study III, atypical facial proportions were shown to be more disturbing on photorealistic faces than on other faces. In Study IV, a mismatch in the size and texture of the eyes and face was especially prone to make a character eerie. These results contest the depiction of the uncanny valley as a simple relation between comfort level and human likeness. This paper concludes by introducing a set of design principles for bridging the uncanny valley. PMID- 25506128 TI - Mining the Home Environment. AB - Individuals spend a majority of their time in their home or workplace and for many, these places are our sanctuaries. As society and technology advance there is a growing interest in improving the intelligence of the environments in which we live and work. By filling home environments with sensors and collecting data during daily routines, researchers can gain insights on human daily behavior and the impact of behavior on the residents and their environments. In this article we provide an overview of the data mining opportunities and challenges that smart environments provide for researchers and offer some suggestions for future work in this area. PMID- 25506129 TI - Tunable dual-emitting shell-crosslinked nano-objects as single-component ratiometric pH-sensing materials. AB - Dual-emitting photonic nano-objects that can sense changes in the environmental pH are designed based on shell-crosslinked micelles assembled from amphiphilic block copolymers and crosslinked with pH-insensitive chromophores. The chromophoric crosslinkers are tetra-functionalized pyrazine molecules that bear a set of terminal aliphatic amine groups and a set of anilino amine groups, which demonstrate morphology-dependent reactivities towards the poly(acrylic acid) shell domain of the nano-objects. The extent to which the anilino amine groups react with the nano-object shell is shown to affect the hypsochromic shift (blue shift). The ratio of fluorescence intensity at 496 nm over that of 560 nm is dependent upon the solution pH. We report, herein, observations on the pH sensitive dual-emission photophysical properties of rod-shaped or spherical nano objects, whose shell domains offer two distinct platforms for amidation reactions to occur-through formation of activated esters upon addition of carbodiimide or pre-installation of activated ester groups. We demonstrate that physical manipulations (changes in morphology or particle dimensions) or chemical manipulations of the crosslinking reaction (the order of installation of activated esters) lead to fine tuning of dual-emission over ca. 60 nm in a physiologically relevant pH range. Rod-shaped shell-crosslinked nanostructures with poly(p-hydroxystyrene) core show blue-shift as a function of increasing pH while spherical shell-crosslinked nanostructures with polystyrene core and poly(ethylene oxide) corona exhibit blue-shift as a function of decreasing pH. PMID- 25506127 TI - Language experience enhances early cortical pitch-dependent responses. AB - Pitch processing at cortical and subcortical stages of processing is shaped by language experience. We recently demonstrated that specific components of the cortical pitch response (CPR) index the more rapidly-changing portions of the high rising Tone 2 of Mandarin Chinese, in addition to marking pitch onset and sound offset. In this study, we examine how language experience (Mandarin vs. English) shapes the processing of different temporal attributes of pitch reflected in the CPR components using stimuli representative of within-category variants of Tone 2. Results showed that the magnitude of CPR components (Na-Pb and Pb-Nb) and the correlation between these two components and pitch acceleration were stronger for the Chinese listeners compared to English listeners for stimuli that fell within the range of Tone 2 citation forms. Discriminant function analysis revealed that the Na-Pb component was more than twice as important as Pb-Nb in grouping listeners by language affiliation. In addition, a stronger stimulus-dependent, rightward asymmetry was observed for the Chinese group at the temporal, but not frontal, electrode sites. This finding may reflect selective recruitment of experience-dependent, pitch-specific mechanisms in right auditory cortex to extract more complex, time-varying pitch patterns. Taken together, these findings suggest that long-term language experience shapes early sensory level processing of pitch in the auditory cortex, and that the sensitivity of the CPR may vary depending on the relative linguistic importance of specific temporal attributes of dynamic pitch. PMID- 25506130 TI - Large displacement vertical translational actuator based on piezoelectric thin films. AB - A novel vertical translational microactuator based on thin-film piezoelectric actuation is presented, using a set of four compound bend-up/bend-down unimorphs to produce translational motion of a moving platform or stage. The actuation material is a chemical-solution deposited lead-zirconate-titanate (PZT) thin film. Prototype designs have shown as much as 120 MUm of static displacement, with 80-90 MUm displacements being typical, using four 920 MUm long by 70 MUm legs. Analytical models are presented that accurately describe nonlinear behavior in both static and dynamic operation of prototype stages when the dependence of piezoelectric coefficients on voltage is known. Resonance of the system is observed at a frequency of 200 Hz. The large displacement and high bandwidth of the actuators at low-voltage and low-power levels should make them useful to a variety of optical applications, including endoscopic microscopy. PMID- 25506131 TI - A three-degree-of-freedom thin-film PZT-actuated microactuator with large out-of plane displacement. AB - A novel three degree-of-freedom microactuator based on thin-film lead-zirconate titanate (PZT) is described with its detailed structural model. Its central rectangular-shaped mirror platform, also referred to as the stage, is actuated by four symmetric PZT bending legs such that each leg provides vertical translation for one corner of the stage. It has been developed to support real-time in vivo vertical cross-sectional imaging with a dual axes confocal endomicroscope for early cancer detection, having large displacements in three axes (z, thetax, thetay) and a relatively high bandwidth in the z-axis direction. Prototype microactuators closely meet the performance requirements for this application; in the out-of-plane (z-axis) direction, it has shown more than 177 MUm of displacement and about 84 Hz of structural natural frequency, when two diagonal legs are actuated at 14V. With all four legs, another prototype of the same design with lighter stage mass has achieved more than 430 MUm of out-of-plane displacement at 15V and about 200 Hz of bandwidth. The former design has shown approximately 6.4 degrees and 2.9 degrees of stage tilting about the x-axis and y-axis, respectively, at 14V. This paper also presents a modeling technique that uses experimental data to account for the effects of fabrication uncertainties in residual stress and structural dimensions. The presented model predicts the static motion of the stage within an average absolute error of 14.6 MUm, which approaches the desired imaging resolution, 5 MUm, and also reasonably anticipates the structural dynamic behavior of the stage. The refined model will support development of a future trajectory tracking controller for the system. PMID- 25506132 TI - Optimized Treatment of Fibromyalgia Using System Identification and Hybrid Model Predictive Control. AB - The term adaptive intervention is used in behavioral health to describe individually-tailored strategies for preventing and treating chronic, relapsing disorders. This paper describes a system identification approach for developing dynamical models from clinical data, and subsequently, a hybrid model predictive control scheme for assigning dosages of naltrexone as treatment for fibromyalgia, a chronic pain condition. A simulation study that includes conditions of significant plant-model mismatch demonstrates the benefits of hybrid predictive control as a decision framework for optimized adaptive interventions. This work provides insights on the design of novel personalized interventions for chronic pain and related conditions in behavioral health. PMID- 25506133 TI - Tribute to one of the foundational fathers of Indian endodontics and operative dentistry. PMID- 25506134 TI - Root canal centering ability of rotary cutting nickel titanium instruments: A meta-analysis. AB - AIM: To systematically review articles on canal centering ability of endodontic rotary cutting Nickel-Titanium (Ni-Ti) instruments and subject results to meta analysis. MATERIALS AND METHODS: A comprehensive search was initiated on canal centering ability of different rotary cutting Ni-Ti files such as Protaper, Hero Shaper, K3, Mtwo, Race, Wave One by selecting articles published in peer reviewed journals during 1991-2013 using "Pub Med" database. Inclusion and exclusion criteria were established. A data was created by tabulating: Author name, publication year, sample size, number of experimental groups, methods to evaluate canal centering ability, instrument cross section, taper, tip design, rake angle, mean and standard deviation. The data generated was subjected to meta-analysis. RESULTS: Maximum studies were found to be conducted on mesiobuccal canal of mandibular 1(st) molar with curvature ranging from 15-60 degrees . The difference in canal centering ability of different rotary cutting Ni-Ti instruments was not statistically significant. CONCLUSION: All endodontic rotary cutting Ni-Ti instruments are capable of producing centered preparations. Protaper depicted the best centering ability. Computed tomography is an effective method of evaluating canal centering ability. PMID- 25506135 TI - Endodontic-periodontal microsurgery for combined endodontic-periodontal lesions: An overview. AB - Endodontic and periodontal microsurgery has surpassed the success rates for traditional endodontic and periodontal surgical procedures. Excellent healing results are being attributed to both the techniques, when employed, for isolated endodontic or periodontal defects. Combined endodontic-periodontal lesions have been referred to as a true challenge, requiring not only endodontic microsurgical management but also concurrent bone grafting and membrane barriers techniques. The prevention of epithelial downgrowth and regeneration of periodontal cementum, fiber, and bone seals the fate of these cases. Achieving primary closure with submergence of grafts has a positive effect on GTR outcome. New techniques of periodontal microsurgery, such as minimally invasive papilla preserving flaps with passive internal mattress suturing, have managed to obtain 90% primary flap closure over grafted sites. Root surface treatment and conditioning has also shown to be beneficial for GTR. Endodontic microsurgery for the combined lesion has not integrated these advances yet. These advances, along with a recently suggested treatment strategy, are ushering in the level next in management of the combined lesions. This article offers an overview of the combined lesion, the disease, its classification, treatment strategy, regenerative tools, microsurgical recommendations, and outcome studies. PMID- 25506136 TI - Effect of single dose pretreatment analgesia with three different analgesics on postoperative endodontic pain: A randomized clinical trial. AB - INTRODUCTION: One of the aims of root canal treatment is to prevent or eliminate pain. Postoperative endodontic pain control continues to be a significant challenge. AIM: To compare and evaluate the effect of single oral dose of 100 mg of tapentadol, 400 mg of etodolac, or 10 mg of ketorolac as a pretreatment analgesic for the prevention and control of postoperative endodontic pain in patients with symptomatic irreversible pulpitis. The incidence of side effects was recorded as secondary outcome. MATERIALS AND METHODS: Sixty emergency patients with moderate to severe pain, diagnosed with symptomatic irreversible pulpitis were randomly allocated (1:1:1) to any of the three groups; tapentadol, etodolac, or ketorolac. Medications were administered 30 min before beginning of the endodontic treatment. Patients recorded pain intensity on 10 cm visual analog scale (VAS) after treatment, for upto 24 h. RESULTS: At 24 h, mean +/-standard deviation (SD) of VAS scores (in cm) for tapentadol, etodolac, and ketorolac were 0.89 +/- 0.83, 2.68 +/- 2.29, and 0.42 +/- 0.69, respectively. Kruskal-Wallis (K W) test showed significant difference among the three groups (P = 0.001). Mann Whitney test showed significantly lower VAS scores in tapentadol and ketorolac than etodolac group (P = 0.013 and 0.001, respectively). CONCLUSIONS: Single oral dose of 10 mg of ketorolac and 100mg of tapentadol as a pretreatment analgesic significantly reduced postoperative endodontic pain in patients with symptomatic irreversible pulpitis when compared to 400 mg of etodolac. PMID- 25506137 TI - Anesthetic efficacy of the supplemental X-tip intraosseous injection using 4% articaine with 1:100,000 adrenaline in patients with irreversible pulpitis: An in vivo study. AB - INTRODUCTION: Pain management remains the utmost important qualifying criteria in minimizing patient agony and establishing a strong dentist-patient rapport. Symptomatic irreversible pulpitis is a painful condition necessitating immediate attention and supplemental anesthetic techniques are often resorted to in addition to conventional inferior alveolar nerve block. AIM: The purpose of the study was to evaluate the anesthetic efficacy of X-tip intraosseous injection in patients with symptomatic irreversible pulpitis, in mandibular posterior teeth, using 4% Articaine with 1:100,000 adrenaline as local anesthetic, when the conventional inferior alveolar nerve block proved ineffective. MATERIALS AND METHODS: X-tip system was used to administer 1.7 ml of 4% articaine with 1:100,000 adrenaline in 30 patients diagnosed with irreversible pulpitis of mandibular posterior teeth with moderate to severe pain on endodontic access after administration of an inferior alveolar nerve block. RESULTS: The results of the study showed that 25 X-tip injections (83.33%) were successful and 5 X-tip injections (16.66%) were unsuccessful. CONCLUSION: When the inferior alveolar nerve block fails to provide adequate pulpal anesthesia, X-tip system using 4% articaine with 1:100,000 adrenaline was successful in achieving pulpal anesthesia in patients with irreversible pulpitis. PMID- 25506138 TI - In vitro investigations into the etiology of mineral trioxide tooth staining. AB - AIM: To investigate the role of bismuth oxide, a constituent of contemporary mineral trioxide aggregate (MTA) materials, and its response to various solutions that may contribute to the potential discoloration that occurs following MTA applications within the scope of endodontics. SETTING AND DESIGN: Laboratory assessment of chemical reactions with white ProRoot((r)) MTA and white Portland cement (WPC). MATERIALS AND METHODS: Set specimens and freshly mixed specimens of white ProRoot((r)) MTA and white ProRoot((r)) MTA powder, along with specimens of WPC were exposed to distilled water, phosphate buffered saline (PBS), 10% formalin, hydroxyethylmethacrylate (HEMA), sodium hypochlorite, sodium hydroxide (NaOH) base, and hydrochloric acid (HCl) acid. Specimens were visually inspected periodically for color changes. RESULTS: All forms of ProRoot MTA showed discoloration when exposed to 10% formalin within 30 min, as opposed to WPC, and were completely blackened at 4 days. Bismuth oxide alone and with calcium oxide also turned black within 30 min after exposure to 10% formalin. No discoloration was seen when exposed to the other solutions. CONCLUSIONS: Exposing MTA in various forms to a variety of liquids has determined that bismuth oxidein combination with other chemical moieties is the prime cause of staining observed by clinicians. PMID- 25506139 TI - The assessment of surface roughness and microleakage of eroded tooth-colored dental restorative materials. AB - OBJECTIVES: To investigate the effect of acidic solution on surface roughness and microleakage of tooth-colored restorative materials. MATERIALS AND METHODS: A 160 box-shaped cavities were prepared on the buccal surfaces of 160 human molars, and assigned to four groups: Group A restored with KetacTM Molar Easymix, Group B with Fuji IITM LC, Group C with KetacTM N100, and Group D with FiltekTM Z250, and subdivided into study and control groups (n = 20). Study groups were immersed in lemon juice (pH = 2.79) for 24 h, whilst controlgroups in deionized distilled water. All samples were immersed in 2% methylene blue dye, sectioned into two equal halves for surface roughness, and microleakage tests. Data were analyzed using Mann-Whitney and Kruskal-Wallis tests at P < 0.05. RESULTS: There was a significant difference in surface roughness of KetacTM Molar, Fuji IITM LC, and KetacTM N100. No significant difference was found in microleakage of KetacTM Molar and Fuji IITM LC; however, there were significant differences in the gingival margin of KetacTM N100, and the occlusal margin of FiltekTM Z250. CONCLUSIONS: All glass ionomer cements were eroded after exposure to the acidic drink. FiltekTM Z250 and KetacTM Molar Easymix showed more microleakage. All materials showed more microleakage at the gingival margins. PMID- 25506140 TI - A comparative in vitro efficacy of conventional rotatory and chemomechanical caries removal: Influence on cariogenic flora, microhardness, and residual composition. AB - BACKGROUND: Chemomechanical caries removal system is part of the minimal invasive dentistry; the aim of the study was to compare the amount of bacteria after caries removal with chemomechanical system and conventional rotatory instruments and to test the Vickers microhardness and micro-RAMAN analysis of residual dentin after excavation. MATERIALS AND METHODS: Molars were induced for demineralization, confirmed with DIAGNOdent; Streptococcus mutans were inoculated into the cavities and filled. Caries removal was performed with rotatory instruments and chemomechanical system; surviving bacteria were cultured for 24 and 48 hours at 37 degrees C. Vickers microhardness and micro-RAMAN analysis were tested after excavation. Data were analyzed with Wilcoxon, continuity correction, odds ratio, ANOVA post hoc Tukey test, and Spearman correlation. RESULTS: Demineralization was significantly detectable at 240 hours of incubation; conventional rotatory instruments and chemomechanical caries removal were effective in 19.4%-22.6% and 25.8%-32.3%, respectively. Vickers microhardness of chemomechanical system was higher (P < 0.0001) than conventional rotatory instruments and comparable to healthy dentin. Micro-RAMAN analysis showed that healthy dentin is correlated to chemomechanical system (R (2) = 0.683, P < 0.00001) and drilling with burs (R (2) = 0.139, P < 0.00001). CONCLUSION: The chemomechanical system is effective for caries elimination, comparable to conventional rotatory instruments; the remaining Vickers microhardness and composition surface tissue are similar to healthy dentin. PMID- 25506141 TI - Comparative evaluation of human pulp tissue dissolution by different concentrations of chlorine dioxide, calcium hypochlorite and sodium hypochlorite: An in vitro study. AB - INTRODUCTION: Irrigation plays an indispensable role in removal of tissue remnants and debris from the complicated root canal system. This study compared the human pulp tissue dissolution by different concentrations of chlorine dioxide, calcium hypochlorite and sodium hypochlorite. MATERIALS AND METHODS: Pulp tissue was standardized to a weight of 9 mg for each sample. In all,60 samples obtained were divided into 6 groups according to the irrigating solution used- 2.5% sodium hypochlorite (NaOCl), 5.25% NaOCl, 5% calcium hypochlorite (Ca(OCl)2), 10% Ca(OCl)2, 5%chlorine dioxide (ClO2) and 13% ClO2. Pulp tissue was placed in each test tube carrying irrigants of measured volume (5ml) according to their specified subgroup time interval: 30 minutes (Subgroup A) and 60 minutes (Subgroup B). The solution from each sample test tube was filtered and was left for drying overnight. The residual weight was calculated by filtration method. RESULTS: Mean tissue dissolution increases with increase in time period. Results showed 5.25% NaOCl to be most effective at both time intervals followed by 2.5% NaOCl at 60 minutes, 10%Ca(OCl)2 and 13% ClO2 at 60 minutes. Least amount of tissue dissolving ability was demonstrated by 5% Ca(OCl)2 and 5% ClO2 at 30 minutes. Distilled water showed no pulp tissue dissolution. CONCLUSION: Withinthe limitations of the study, NaOCl most efficiently dissolved the pulp tissue at both concentrations and at both time intervals. Mean tissue dissolution by Ca(OCl)2 and ClO2 gradually increased with time and with their increase in concentration. PMID- 25506142 TI - Dentine microhardness changes following conventional and alternate irrigation regimens: An in vitro study. AB - AIM: To compare the changes in microhardness of root dentin caused by two novel irrigation regimens with conventional irrigation. MATERIALS AND METHODS: Forty extracted human permanent incisor teeth were selected. Decoronated roots were separated longitudinally to get 80 specimens that were embedded in autopolymerizing acrylic resin and grounded flat with silicon carbide abrasive papers. Of these, 60 root segments without any cracks or defects were selected and divided into four groups according to the irrigation regimen used (n = 15). Group I: 5% sodium hypochlorite (NaOCl) + 17% ethylenediaminetetraacetic acid (EDTA) + 0.2% chlorhexidine digluconate (CHX) (conventional). Group II: 6% Morinda Citrifolia Juice + 17% EDTA (MCJ). Group III: 5% NaOCl + Q Mix 2 in 1 (QMix). Group IV: Distilled water (control). Irrigation regimens were performed for 5 minutes. Dentin microhardness was measured with a Vickers indenter under a 200-g load and a 20-s dwell time at the midroot level of root dentin. The data were analyzed using Kruskal Wallis test and Dunn's multiple comparison tests. RESULTS: A significant difference was seen in the median values of the four groups. The control group showed the least reduction in microhardness when comparison with the other groups. Except for Group III (Q Mix), the other groups that were tested (MCJ and conventional regimens) showed statistically significant difference from the control group. CONCLUSION: Within the limitation of this study, it was concluded that NaOCl + Q Mix were least detrimental to root dentin microhardness when compared with MCJ and conventional irrigation regimens. PMID- 25506143 TI - The comparison of the effects of different whitening toothpastes on the micro hardness of a nano hybrid composite resin. AB - AIM: The aim of this study was to compare the micro hardness of a nanohybrid composite resin after brushing with two herbal and one non-herbal whitening toothpastes. MATERIALS AND METHODS: We divided Eighty disk-shaped specimens of a nanohybrid composite (Tetric N Ceram, Ivoclar Vivadent, Asia) into 4 groups of 20 specimens each: Groups A, B, C, and D. Group A was control, Group B was brushed with Colgate total advanced whitening (Colgate-Palmolive (India) Limited), Group C with Salt and Lemon, Dabur (Dabur International Limited, Dubai, UAE), and Group D with HiOra Shine, Himalaya (The Himalaya Drug Company, India). The specimens were polished using medium, fine, and superfine discs (Sof-lex, 3M, ESPE, USA) and subsequently placed at 37 degrees C in distilled water. They were brushed for 2 minutes twice daily with a soft motorized toothbrush (Colgate 360 sonic power battery-operated tooth brush, Colgate Palmolive, India) for 30 days. The samples were rinsed under running water to remove the toothpaste and stored in distilled water at 37 degrees C until the readout was taken on the Vickers's hardness tester for microhardness. RESULTS: The results revealed that the difference among the groups was statistically significant (P < 0.001). Tukey's test showed that reduction in microhardness for Group B was significantly higher than that for Group C and Group D (P < 0.001). CONCLUSION: Within the limitations of this study, non-herbal whitening toothpaste had a greater impact on the microhardness of nanohybrid resin composite than herbal whitening toothpastes. PMID- 25506144 TI - Investigate the correlation between clinical sign and symptoms and the presence of P. gingivalis, T. denticola, and T. forsythia individually or as a "Red complex" by a multiplex PCR method. AB - AIM: The aim of this study was to investigate the correlation between endodontic clinical signs and symptoms and the presence of Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia or their association by Multiplex polymerase chain reaction assay. MATERIALS AND METHODS: Microbial samples were taken from 30 cases with necrotic pulp tissues in primary infections. DNA was extracted from the samples, which were analyzed for the presence of three endodontic pathogens by using species-specific primers. RESULTS: P. gingivalis, T. denticola, T. forsythia, and Red Complex were present in 11, 17, 4, and 2 canals, respectively. Clinical and statistically significant relationships were found between T. forsythia and mobility and between T. denticola and swelling. (P < 0.05). Presence of other Red complex bacteria shows clinical association with presence of signs and symptoms but no statistically significant relationship. CONCLUSION: The high prevalence of P. gingivalis, T. denticola, and T. forsythia in the examined samples suggests that these bacteria are related to the etiology of symptomatic periradicular diseases. PMID- 25506145 TI - Comparison of canal transportation and centering ability of rotary protaper, one shape system and wave one system using cone beam computed tomography: An in vitro study. AB - AIM: The aim of the present study was to compare the canal transportation and centering ability of Rotary ProTaper, One Shape and Wave One systems using cone beam computed tomography (CBCT) in curved root canals to find better instrumentation technique for maintaining root canal geometry. MATERIALS AND METHODS: Total 30 freshly extracted premolars having curved root canals with at least 10 degrees of curvature were divided into three groups of 10 teeth each. All teeth were scanned by CBCT to determine the root canal shape before instrumentation. In Group 1, the canals were prepared with Rotary ProTaper files, in Group 2 the canals were prepared with One Shape files and in Group 3 canals were prepared with Wave One files. After preparation, post-instrumentation scan was performed. Pre-instrumentation and post-instrumentation images were obtained at three levels, 3 mm apical, 3 mm coronal and 8 mm apical above the apical foramen were compared using CBCT software. Amount of transportation and centering ability were assessed. The three groups were statistically compared with analysis of variance and Tukey honestly significant. RESULTS: All instruments maintained the original canal curvature with significant differences between the different files. Data suggested that Wave One files presented the best outcomes for both the variables evaluated. Wave One files caused lesser transportation and remained better centered in the canal than One Shape and Rotary ProTaper files. CONCLUSION: The canal preparation with Wave One files showed lesser transportation and better centering ability than One Shape and ProTaper. PMID- 25506147 TI - Disinfection of gutta-percha cones using three reagents and their residual effects. AB - AIMS AND OBJECTIVES: The purpose of this study was to compare the efficacy of 5.25% sodium hypochlorite, 2% chlorehexidine and MTAD in disinfecting gutta percha cones and to analyze the surface topography of gutta-percha cones after the rapid chemical disinfection procedure. MATERIALS AND METHODS: Gutta-percha cones were immersed in suspensions of Enterococcus faecalis and Staphylococcus aureus separately. The cones were then immersed in 5.25% NaOCl, 2% CHX and MTAD for 30 seconds, 1 minute and 5 minutes separately. The disinfected cones were then incubated in thioglycollate media for 7 days. The thioglycolate media was sub-cultured and colony forming units were counted. For topographical examination of gutta-percha cones, the cones were immersed in respective solutions for one minute and allowed to air dry for 30 minutes after rinsing or without rinsing the cones with distilled water. The topography of the cones were then analyzed under SEM. Data was statistically analyzed using one way anova. RESULTS: MTAD was found to be the most effective disinfecting solution. The topographical examination of GP cones found some deposits after the disinfection procedure in every group. These deposits were removed when the GP cones were rinsed with distilled water. CONCLUSIONS: MTAD possesses superior bactericidal activity when compared with NaOCl and CHX and a final rinse with distilled water is essential after the disinfection procedure. PMID- 25506146 TI - Comparison of marginal adaptation of mineral trioxide aggregate, glass ionomer cement and intermediate restorative material as root-end filling materials, using scanning electron microscope: An in vitro study. AB - AIM: The present study compares the marginal adaption of Mineral Trioxide Aggregate (MTA), Glass Ionomer Cement (GIC) and Intermediate Restorative Material (IRM) as root-end filling materials in extracted human teeth using Scanning Electron Microscope (SEM). MATERIALS AND METHODS: Thirty single rooted human teeth were obturated with Gutta-percha after cleaning and shaping. Apical 3 mm of roots were resected and retrofilled with MTA, GIC and IRM. One millimeter transverse section of the retrofilled area was used to study the marginal adaptation of the restorative material with the dentin. Mounted specimens were examined using SEM at approximately 15 Kv and 10(-6) Torr under high vacuum condition. At 2000 X magnification, the gap size at the material-tooth interface was recorded at 2 points in microns. STATISTICAL ANALYSIS: One way ANOVA Analysis of the data from the experimental group was carried out with gap size as the dependent variable, and material as independent variable. RESULTS: The lowest mean value of gap size was recorded in MTA group (0.722 +/- 0.438 MUm) and the largest mean gap in GIC group (1.778 +/- 0.697 MUm). CONCLUSION: MTA showed least gap size when compared to IRM and GIC suggesting a better marginal adaptation. PMID- 25506148 TI - Influence of cervical preflaring using different rotary instruments on the accuracy of apical file size determination: A comparative in-vitro study. AB - AIM: To investigate the influence of cervical preflaring using different rotary instruments on apical file size determination. MATERIALS AND METHODS: Extracted human molar teeth were randomly divided in to eight groups (N = 10): Control group (CG); LA Axxess group (LA); HyFLex group (HF); GatesGlidden group (GG); ProTaper group (PT); Race group(RC); FlexMaster group (FM); and K3 group (K3). Patency was maintained and working length was established under magnification. All instruments were used according to manufacturer's instructions. Steriomicroscopic images were taken to determine the discrepancies in diameters. ProPlus software (USA) was used to determine the diameter of the root canal. ANOVA test and Post Hoc Tests-Bonferroni Multiple Comparisons were used for statistical analysis. RESULTS: Canals preflared with LA Axxess burs showed the best results. Control group that is, the canals with no cervical preflaring showed the maximum discrepancy between the initial apical file diameter and apical canal diameter. CONCLUSION: Cervical preflaring plays an important role in reducing the discrepancy between initial apical file diameter and apical canal diameter. PMID- 25506149 TI - Evaluation of the apical sealing ability of bioceramic sealer, AH plus & epiphany: An in vitro study. AB - OBJECTIVE: This in vitro study evaluated and compared the microleakage of three sealers; Endosequence bioceramic (BC) sealer, AH Plus and Epiphany. MATERIALS AND METHODS: Study was done on 75 extracted human single rooted permanent teeth, which were decoronated and the root canals were instrumented. The specimens were randomly divided into three groups (n = 25) and obturated by continuous wave condensation technique. Group A: using Endosequence BC, Group B: using AH Plus sealer, Group C: using Resilon Epiphany system. Microleakage was evaluated using dye penetration method. Teeth were split longitudinally and then horizontally markings were made at 2, 4 and 6 mm from the apex. Dye penetration evaluation was done under stereomicroscope (30X magnification). RESULTS: The dye penetration in Group B was more than in Group A and C in both vertical and horizontal directions, suggesting that newly introduced BC sealer and Epiphany sealer sealed the root canal better compared to AH Plus Sealer. CONCLUSION: Newer root canal sealers seal the root canal better but cannot totally eliminate leakage. PMID- 25506152 TI - "Internal root resorption: An endodontic challenge": A case series. AB - Management of internal root resorption is a challenge to the endodontists. It may occur in cases with chronic pulpal inflammation, following caries or due to trauma in the form of an accidental blow. Most cases of internal root resorption are seen in anterior teeth, due to their susceptibility to trauma. However, it may be seen in posterior teeth, most likely because of carious involvement of the pulp. Early diagnosis, removal of the cause, proper treatment of the resorbed root is mandatory for successful treatment outcome. This paper is an attempt to summarize the knowledge on internal root resorption and present various cases, which were successfully managed with different treatment modalities. PMID- 25506150 TI - Influence of root canal curvature on the accuracy of an electronic apex locator: An in vitro study. AB - OBJECTIVE: This study investigated whether the canal curvature has an influence on the accuracy of Electronic Apex Locator. MATERIALS AND METHODS: Sixty mandibular posterior teeth were decoronated. A number (No.) 10 file was inserted into the mesiobuccal canal and radiographs were taken to determine the degree of curvature by Schneider's method. Samples were divided into three groups of mild (<20 degrees ), moderate (20-36 degrees ) and severe curvature (>36 degrees ). After enlarging the orifice, the actual canal length was determined by introducing a file until the tip emerged through the major foramen when observed under 20X magnification. The teeth were embedded in an alginate model and the Root ZX was used to determine the electronic length. The data was analyzed by Kruskal-Wallis test followed by Mann-Whitney test. RESULTS: The difference in measurement of Actual and Electronic working length was statistically significant between group 1 and 2 (P < 0.05) as well as between group 1 and group 3 (P < 0.05) with group 1 showing the lowest difference. CONCLUSION: Considering +/- 0.5 mm as tolerance limit for accuracy, the device was 95% accurate for the mild curvature group and 80% accurate for moderate and severe groups. PMID- 25506151 TI - Management of a rare combination of avulsion and intrusive luxation: A case report. AB - In traumatic dental injury, concomitant occurrence of avulsion and intrusive luxation is exceptional. This is because the vectors of forces responsible for both avulsive and intrusive injuries are in different directions. The present case report reviews the management of a rare combination of avulsion in right maxillary lateral incisor (tooth #12) and intrusive luxation in right maxillary central incisor (tooth #11) in a 22-year-old Asian male. Clinical and radiographic evaluation was done at 12-month follow-up. Various treatment modalities and complications associated with both avulsion and intrusion are also discussed in the paper. PMID- 25506153 TI - Treatment of combined endodontic: periodontic lesion by sealing of palato radicular groove using biodentine. AB - INTRODUCTION: Palatoradicular groove is a developmental anomaly which is predominantly found in maxillary lateral incisors. It provides a susceptible alcove for the progression of localised periodontal inflammation which can further cause pulpal involvement. This case report describes the successful treatment of a large periodontic - endodontic lesion usingnon surgical endodontic therapy and biodentine for the sealing of the palatoradicular groove. PMID- 25506154 TI - Influence of trial design, heterogeneity and regulatory environment on the results of clinical trials: An appraisal in the context of recent trials on acute stroke intervention. AB - The outcome of randomized controlled trials can vary depending on the eligibility criteria of the patients entering into the trial, as well as the heterogeneity of the eligible population and/or the interventions. If the subject population and/or interventions are heterogeneous, the final outcome of the trial depends on the degree of concordance of effects of the subgroups of interventions on the subgroups of the subject population. The considerations that go into the calculation of sample size and determination of the study stopping rules also would affect the nature of the outcome of the study. In this paper we try to examine these phenomena with respect to the recent trials on endovascular therapy in acute ischemic stroke. PMID- 25506155 TI - Bobbling head in a young subject. AB - Bobble-head Doll Syndrome is a rare and unique movement disorder found in children. Clinically, it is characterized by a to and fro or side to side movement of the head at the frequency of 2 to 3 Hz. It is mostly associated with cystic lesions around the third ventricle, choroid plexus papilloma, aqueductal stenosis and other rare disorders. An eleven year old child presented in the outpatient department with continuous to and fro movement of the head and declining vision for the last one month. MRI Scan showed a large contrast enhanced lesion in the region of the third ventricle along with gross hydrocephalus. Ventriculo-peritoneal shunt was inserted and the movements of the head disappeared completely. Bobble-head doll syndrome is a rare condition and therefore this case is presented and the literature reviewed. PMID- 25506157 TI - Next-generation sequencing and genetic diagnosis of Charcot-Marie-Tooth disease. AB - Over 70 different Charcot-Marie-Tooth disease (CMT)-associated genes have now been discovered and their number is growing. Conventional genetic testing for all CMT genes is cumbersome, expensive, and impractical in an individual patient. Next-generation sequencing (NGS) technology allows cost-effective sequencing of large scale DNA, even entire exome (coding sequences) or whole genome and thus, NGS platform can be employed to effectively target a large number or all CMT related genes for accurate diagnosis. This overview discusses how NGS can be strategically used for genetic diagnosis in patients with CMT or unexplained neuropathy. A comment is made to combine simple clinical and electrophysiological algorithm to assign patients to major CMT subtypes and then employ NGS to screen for all known mutations in the subtype-specific CMT gene panel. PMID- 25506156 TI - Neuropsychological deficits in temporal lobe epilepsy: A comprehensive review. AB - Temporal lobe epilepsy (TLE) is the most prevalent form of complex partial seizures with temporal lobe origin of electrical abnormality. Studies have shown that recurrent seizures affect all aspects of cognitive functioning, including memory, language, praxis, executive functions, and social judgment, among several others. In this article, we will review these cognitive impairments along with their neuropathological correlates in a comprehensive manner. We will see that neuropsychological deficits are prevalent in TLE. Much of the effort has been laid on memory due to the notion that temporal lobe brain structures involved in TLE play a central role in consolidating information into memory. It seems that damage to the mesial structure of the temporal lobe, particularly the amygdale and hippocampus, has the main role in these memory difficulties and the neurobiological plausibility of the role of the temporal lobe in different aspects of memory. Here, we will cover the sub-domains of working memory and episodic memory deficits. This is we will further proceed to evaluate the evidences of executive function deficits in TLE and will see that set-shifting among other EFs is specifically affected in TLE as is social cognition. Finally, critical components of language related deficits are also found in the form of word-finding difficulties. To conclude, TLE affects several of cognitive function domains, but the etiopathogenesis of all these dysfunctions remain elusive. Further well-designed studies are needed for a better understanding of these disorders. PMID- 25506159 TI - Posterior quadrant disconnection for refractory epilepsy: A case series. AB - OBJECTIVE: To analyze the surgical outcome and safety of posterior quadrant disconnection in medically refractory epilepsy arising from the posterior head region from a level IV tertiary care center over a period of three years. MATERIALS AND METHODS: Seven consecutive patients who underwent posterior quadrant disconnection for refractory epilepsy were analyzed. RESULTS: We analyzed the data of seven (n = 7) consecutive posterior quadrant epilepsy patients who underwent posterior quadrant disconnection with a mean age of 8.5 years over the last three years of which 4 were male and 3 females. All patients underwent extensive pre-surgical evaluation including detailed history, examination, prolonged video EEG recordings, neuropsychological testing, MRI brain, DTI, PET scan (n = 6), fMRI (n = 4), WADA test (n = 1) and invasive recording (n = 1), Of seven patients four had left sided pathology and three had right sided pathology. All patients except one underwent pure disconnection and one underwent partial resection. CONCLUSION: Posterior quadrant disconnection is effective surgical procedure for medically refractory epilepsy arising from the posterior quadrant in carefully selected patients without morbidity or functional disability across various age groups especially in children. In our series, all seven patient had good seizure outcome and none had functional disabilities. PMID- 25506158 TI - Clinical profile and genetic correlation of patients with spinocerebellar ataxia: A study from a tertiary care centre in Eastern India. AB - BACKGROUND: Progressive cerebellar ataxia inherited by autosomal dominant transmission is known as Spino Cerebellar Ataxia (SCA). AIMS AND OBJECTIVES: To look for various clinical profile and molecular genetics of patients with SCAs and their phenotype-genotype correlation of patients with SCAs. MATERIALS AND METHODS: This was a cross-sectional study conducted at Bangur Institute of Neurosciences, Kolkata from June 2010 to April 2013. We selected patients from the neurogenetic clinic of our institute and performed genetic test for SCA 1, 2, 3, 6 and 12. The diagnosis was based on suggestive clinical features and positive genetic study, done by polymerase chain reaction. RESULTS: 83 patients were tested for trineucleotide repeats and turned out 45 positive for the mentioned SCAs. We found 13(28.9%) SCA-1, 18(40%) SCA-2, 7(15.6%) SCA-3, 6(13.3) SCA-6 and 1(2.2%) SCA-12 patients. Half of the remaining 38 patients had positive family history. The mean age of onset were 38.46 years in SCA-1, 29.55 years in SCA-2, 38.43 years in SCA-3, 47.33 years in SCA-6. Slow saccades were observed in 7(53.8%) SCA-1, 17(94.4%) SCA-2, 4(57.1%) SCA-3, 3(50%) SCA-6 patients. Hyporeflexia was noticed in 5(27.8%) SCA-2 patients. Pyramidal tract involvement was found in 8(61.5%) SCA-1, 4(22.2%) SCA-2, 4(57.1%) SCA-3 and 1(16.7%) SCA-6 patients. CONCLUSION: Our study showed SCA-2 is the most common variety of SCA and genotypic-phenotypic correlation was observed in SCA-1,2,6 and 12 patients. PMID- 25506161 TI - What patients do to counteract the symptoms of Willis-Ekbom disease (RLS/WED): Effect of gender and severity of illness. AB - OBJECTIVES: This study was carried out to assess different counteracting strategies used by patients with idiopathic Willis-Ekbom disease (RLS/WED). Whether these strategies were influenced by gender or disease severity was also assessed. MATERIALS AND METHODS: A total of 173 patients of idiopathic RLS/WED were included in this study. Their demographic data was recorded. Details regarding the RLS/WED and strategies that they used to counteract the symptoms were asked. The severity of RLS/WED was measured with the help of the Hindi version of international restless legs syndrome severity rating scale. They were asked to provide the details regarding the relief obtained from all the strategies they used on three-point scale: no relief, some relief, and complete relief. RESULTS: Of the patients, 72% were females. Mean age of the subjects in this study was 39.6 +/- 12.6 years, and male subjects were older than females. Four common strategies were reported by the patients to counter the sensations of RLS/WED: moving legs while in bed (85.5%), asking somebody to massage their legs or massaging legs themselves (76.9%), walking (53.2%), and tying a cloth/rope tightly on the legs (39.3%). Of all the patients who moved their legs, 6.7% did not experience any relief, 64.2% reported some relief, and 28.4% reported complete relief. Similarly, of all the patients who used "walking" to counteract symptoms, 50% reported complete relief, 44.5% reported some relief, and the rest did not experience any relief. Many of these patients reported that massage and tying a cloth/rope on legs brought greater relief than any of these strategies. Tying cloth on the leg was more common among females as compared to males (45.9% females vs. 23.5% males; chi(2) = 7.54; P = 0.006), while patients with moderately severe to severe RLS/WED reported "moving legs in bed" (79.3% in mild to moderate RLS/WED; 91.8% in severe to very severe RLS; chi(2) = 5.36; P = 0.02). CONCLUSION: Patients with RLS/WED use a variety of strategies to counteract symptoms. These strategies may be influenced by gender, disease severity, and cultural practices. PMID- 25506160 TI - Low plasma antioxidant status in patients with epilepsy and the role of antiepileptic drugs on oxidative stress. AB - BACKGROUND: Oxidative stress has been implicated in various disorders including epilepsy. We studied the antioxidant status in patients with epilepsy and aimed at determining whether there was any difference in the antioxidant levels between patients and controls, patients who are not on antiepileptic drugs (AEDs), and on treatment, between individual AEDs and patients on monotherapy and polytherapy. MATERIALS AND METHODS: Antioxidant levels like catalase, glutathione peroxidase (GPx), vitamin E, glutathione (GSH), thiol group (SH), uric acid, and total antioxidant capacity (TAC) were compared between 100 patients with epilepsy and equal number of controls. Twenty-five patients who were not on AEDs were compared with patients on AEDs and the control group. Patients were divided into monotherapy and polytherapy group and antioxidant status was compared between the two groups and between individual drugs. RESULTS: Catalase, SH, vitamin E, and TAC were significantly low in patients with epilepsy than those in the control group (P < 0.001). GSH and uric acid did not show any difference; GPx in patients was significantly higher than those in the control group There were no differences in the antioxidant levels between the treated and the untreated groups; however, it was lower in untreated patients than controls (P < 0.001), suggesting that AEDs do not modify the oxidative stress. Patients on Valproate (VPA) showed higher catalase and GPx levels. Catalase was higher in the monotherapy than polytherapy group (P < 0.04). CONCLUSION: Our study found significantly low levels of antioxidant in patients as compared to controls. AED did not influence the antioxidant status suggesting that seizures induce oxidative stress. PMID- 25506163 TI - Sleep disturbances in drug naive Parkinson's disease (PD) patients and effect of levodopa on sleep. AB - CONTEXT: Parkinson's disease (PD) is associated with sleep disturbances, attributed to the neurodegenerative process and therapeutic drugs. Studies have found levodopa to increase wakefulness in some patients while increasing sleepiness in others. AIMS: To confirm sleep disturbances in drug naive PD patients and understand the impact of levodopa on their sleep. MATERIALS AND METHODS: Twenty-three drug naive PD patients and 31 age-gender matched controls were compared using the Parkinson's Disease Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS). A polysomnogram objectively compared sleep quality. Of the 23 patients, the 12 initiated on levodopa were reassessed subjectively and through polysomnography after 2 months of therapy. STATISTICAL ANALYSIS: Data was expressed as mean +/- standard deviation, median, and range. Continuous variables were analyzed by Student's T test for normally distributed data and Mann-Whitney U test for skewed data. Discrete variables were compared by Chi Square tests (Pearson Chi square Test or Fisher's Exact Test). Wilcoxon signed ranks test was applied in the analysis of paired data pre- and post-levodopa. A P value < 0.05 was considered as statistically significant. Statistical analysis of the data was done using the Statistical Package for the Social Sciences (SPSS) version 12. RESULTS: Drug naive PD patients had lower PDSS scores than controls. The sleep architecture changes observed on polysomnogram were reduced NREM Stage III and REM sleep and increased sleep latency and wake after sleep onset time. Following levodopa, improved sleep efficiency with reduced sleep latency and wake after sleep onset time was noted, coupled with improved PDSS scores. However, NREM Stage III and REM sleep duration did not increase. DISCUSSION: PD patients take longer to fall asleep and have difficulty in sleep maintenance. Sleep maintenance is affected by nocturia, REM behavioral disorder, nocturnal cramps, akinesia, and tremors, as observed in PDSS scores. Levodopa improves sleep efficiency by improving motor scores without altering sleep architecture. CONCLUSIONS: Poor sleep quality and sleep architecture changes occur secondary to the neurodegenerative process in PD patients. Though levodopa improves sleep quality by reducing rigidity and tremor, it does not reverse sleep architecture changes. PMID- 25506162 TI - Magnitude of peripheral neuropathy in cirrhosis of liver patients from central rural India. AB - CONTEXT: Cirrhosis of liver is an important cause of morbidity and mortality and if associated with peripheral neuropathy (PN) it also poses a huge financial, psychological burden for the patients and their families. AIM: The aim of the present study was to study the magnitude of PN among subjects with cirrhosis of liver presenting to tertiary care teaching hospital in central rural India. SETTINGS AND DESIGN: A cross-sectional study was performed in a tertiary care teaching hospital. MATERIALS AND METHODS: In all patients of cirrhosis of liver irrespective of etiology, aged 15 and above, undergone clinical assessment for peripheral nervous systems damage and confirmed by nerve conduction studies. STATISTICAL ANALYSIS USED: We used chi square test to study associations. P value <=0.05 was considered as significant. Crude odds ratios were computed to assess the strength of association between independent variables and dependent variables along with their 95% confidence intervals. RESULTS: We included 207 of cirrhosis of liver patients admitted in medicine department from November 2010 through November 2013. Nearly 83% patients were male and 63.2% patients were under the age of 45 years. Common features in these patients were ascites (71%) splenomegaly (63.3%) pedal edema (61.4%) icterus (46.4%) tingling (44.9%) gastrointestinal bleeding(39.1%), ataxia (26.6%), numbness(26.6%), distal motor weakness (21.7%) and paresthesia(20.8%). Among the manifestation of peripheral nerve involvement, loss of ankle reflex was the most common feature in 51.7%, followed by loss of temperature sense 29.5%, loss of vibration sense 20.8%, loss of touch 16.4%, loss of position sense 14.5% and loss of pain in 6.3% of the patients. Peripheral neuropathy was found in 53.6% [95% CI: 46.58- 60.56] study subjects on electrophysiological study. CONCLUSIONS: Analysis of electrophysiological study shows that the PN is very common in study subjects with cirrhosis of liver, especially in male subjects, during the middle age group. PMID- 25506164 TI - A pilot study on utility of Malayalam version of Addenbrooke's Cognitive Examination in detection of amnestic mild cognitive impairment: A critical insight into utility of learning and recall measures. AB - AIMS: This pilot study sought to determine whether the Malayalam adaptation of Addenbrooke's Cognitive Examination (M-ACE) can effectively identify patients with amnestic mild cognitive impairment (a-MCI) and the impact of measures of learning and free recall. MATERIALS AND METHODS: A cohort of 23 patients with a MCI aged between 55-80 years diagnosed as per current criteria and 23 group matched cognitively normal healthy controls (CNHC) were studied. The measures of acquisition and delayed recall were the Rey Auditory Verbal Learning Test (RAVLT) and Wechsler Memory Scale (WMS)-III (verbal and visual subsets) and Delayed Matching-to-sample Test (DMS)-48. Test scores of M-ACE registration and recall scores were included. To examine the differences in test performances between the groups, we compared the number of subjects with test scores less than 1.5 standard deviation (SD) of the control scores. Comparisons between a-MCI and controls were drawn using Fisher's exact test and Mann-Whitney U tests. RESULTS: M-ACE registration component ascertained on a 24-point scale failed to demonstrate any differences between a-MCI and controls (P = 0.665) as opposed to recall judged on a cumulative 10-point scale (P = 0.001). Significant differences were noted in RAVLT list learning (P < 0.001) and list recall (P = 0.003), WMS III paragraph learning (P <0.001) and recall (P = 0.007), visual learning (P = 0.004) and recall (P = 0.001). CONCLUSIONS: M-ACE recall scores are an effective screening tool to identify patients with suspected a-MCI. Both word list and paragraph learning and recall components have been found to be sensitive to concretely identify a-MCI and impairment on at least 2 tests should be considered in the diagnostic criteria of MCI rather than rely on a single screening battery. PMID- 25506165 TI - Chronic meningitis in systemic lupus erythematosus: An unusual etiology. AB - Chronic aseptic meningitis is a rare manifestation of systemic lupus erythematosus (SLE). Apart from immunological causes and drugs, the aseptic meningitis group can include some unidentified viral infections that cannot be detected by routine microbiological testing. It is imperative to do complete cerebrospinal fluid (CSF) workup before implicating the symptoms to disease activity or drugs, as untreated infections cause significant mortality in SLE. We present a case of young female with SLE who presented with chronic meningitis of an uncommon etiology. PMID- 25506166 TI - Langerhans cell histiocytosis of atlantoaxial joint in a middle-aged man presenting with deafness as first symptom and soft-tissue mass at neck showing excellent response to radiotherapy alone: Report of an extremely rare and unusual clinical condition and review of literature. AB - Langerhans cell histiocytosis (LCH) is a disorder of clonal proliferation of dendritic cell mainly occurring in children. Spine involvement is rare. This usually presents with pain and torticollis when neck is involved. Histopathology with immunohistochemistry is confirmatory. Local curative therapy with excision or curettage is used for localized disease. Radiotherapy is usually reserved for selected cases. Systemic chemotherapy is the treatment of choice for widespread systemic disease. In this article, we present an unusual presentation of atlantoaxial LCH with mastoid involvement resulting in hearing loss as the first symptom and quadruparesis in a middle aged male patient, which was also associated with soft-tissue mass at the nape of the neck and deafness. The patient was treated with radical radiotherapy, which provided excellent response to the disease. Involvement of atlantoaxial joint and temporal bone associated with soft-tissue mass neck and deafness in a middle-aged man is an extremely rare clinical situation. PMID- 25506167 TI - Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME): Probable first family from India. AB - Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME) is an extremely rare syndrome characterized by familial occurrence of postural and action-induced tremors of the hands but showing electrophysiologic findings of cortical reflex myoclonus. Patients also have cognitive decline and tonic-clonic seizures, often precipitated by sleep deprivation or photic stimulation. We describe probably the first family from India of this ill-defined syndrome. PMID- 25506168 TI - Importance of acylcarnitine profile analysis for disorders of lipid metabolism in adolescent patients with recurrent rhabdomyolysis: Report of two cases. AB - Metabolic myopathies due to disorders of lipid metabolism are a heterogeneous group of diseases. Newborns may present with hypotonia and convulsions, while progressive proximal muscle weakness or recurrent episodes of muscle weakness accompanied by rhabdomyolysis/myoglobinuria may be seen in older ages. There is little knowledge on detection of disorders of lipid metabolism by acylcarnitine profile (ACP) analysis by tandem mass spectrometry outside the neonatal period particularly in cases with recurrent rhabdomyolysis first presenting in adolescence and adulthood. Two adolescent female cases presented with episodes of rhabdomyolysis and muscle weakness. A 13-year-old patient had five episodes of rhabdomyolysis triggered by infections. Tandem mass spectrometry was normal. A 16 year-old female patient was hospitalized eight times due to recurrent rhabdomyolysis. Increased levels of C14:2, C14:1, and C14 were determined in tandem mass spectrometry. Final diagnoses were carnitine palmitoyltransferase II (CPT II) deficiency and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Increased serum levels of long-chain acylcarnitine can guide to the diagnosis of lipid metabolism disorders. Serum ACP should be performed before enzyme assay and genetic studies. PMID- 25506169 TI - A case of congenital myopathy masquerading as paroxysmal dyskinesia. AB - Gastroesophageal reflux (GER) disease is a significant comorbidity of neuromuscular disorders. It may present as paroxysmal dyskinesia, an entity known as Sandifer syndrome. A 6-week-old neonate presented with very frequent paroxysms of generalized stiffening and opisthotonic posture since day 22 of life. These were initially diagnosed as seizures and he was started on multiple antiepileptics which did not show any response. After a normal video electroencephalogram (VEEG) was documented, possibility of dyskinesia was kept. However, when he did not respond to symptomatic therapy, Sandifer syndrome was thought of and GER scan was done, which revealed severe GER. After his symptoms got reduced to some extent, a detailed clinical examination revealed abnormal facies with flaccid quadriparesis. Muscle biopsy confirmed the diagnosis of a specific congenital myopathy. On antireflux measures, those episodic paroxysms reduced to some extent. Partial response to therapy in GER should prompt search for an underlying secondary etiology. PMID- 25506170 TI - Crohns disease with central nervous system vasculitis causing subarachnoid hemorrhage due to aneurysm and cerebral ischemic stroke. AB - Cerebral vasculitis secondary to Crohn's disease (CD) seems to be a very rare phenomenon. We report a 39-year-old male who presented with headache, vomiting, and left-sided weakness in the known case of CD. Cross-sectional imaging (computed tomography and magnetic resonance imaging,) showed right gangliocapsular acute infarct with supraclinoid cistern subarachnoid hemorrhage (SAH). Cerebral digital substraction angiography (DSA) showed dilatation and narrowing of right distal internal carotid artery (ICA). Left ICA was chronically occluded. His inflammatory markers were significantly raised. Imaging features are suggestive of cerebral vasculitis. Arterial and venous infarcts due to thrombosis are known in CD. Our case presented with acute subarachnoid hemorrhage in supraclinoid cistern due to rupture of tiny aneurysm of perforator arteries causing SAH and infarction in right basal ganglia. Patient was treated conservatively with immunosuppression along with medical management of SAH. PMID- 25506171 TI - Candida tropicalis brain abscess in a neonate: An emerging nosocomial menace. AB - Fungi are a relatively uncommon cause of brain abscess in neonates and early infancy. They are usually associated with predisposing factors like prematurity, low birth weight, use of broad-spectrum antibiotics, and prolonged stay in the intensive care unit. Candida tropicalis (C. tropicalis) is rapidly emerging as a nosocomial threat in the neonatal intensive care settings. This case report describes a neonate with C. tropicalis brain abscess who was diagnosed early and managed aggressively with a favorable outcome. Inadvertent use of intravenous antibiotics can have serious complications such as invasive fungal infection. Correct microbiological diagnosis is the key to successful treatment of deep seated pyogenic infection. Fungal etiology should always be studied in relevant clinical settings. PMID- 25506172 TI - Endovascular treatment of vein of Galen dural arteriovenous fistula presenting as dementia. AB - Dural arteriovenous fistula (DAVF) is an important cause of neurological dysfunction that is often misdiagnosed, especially in elderly population. Galenic DAVFs are a subtype of the rare falcotentorial DAVFs with a high risk of hemorrhage and aggressive clinical course. In most cases, DAVFs present with pulsatile tinnitus, headache, or orbital symptoms such as chemosis and proptosis. We report a patient with DAVF of Vein of Galen presented with progressive dementia, treated by Onyx embolisation and had good clinical outcome. PMID- 25506173 TI - Intravenous thrombolysis in a patient with left atrial myxoma with acute ischemic stroke. AB - Intravenous thrombolysis (IVT) is an accepted therapy in patients with acute ischemic stroke presenting within 3-4.5 hours of symptom onset. Selection of the patient for thrombolysis depends on the careful assessment for the risk of post thrombolysis symptomatic haemorrhage (6.2-8.9%) which may be fatal. Atrial myxomas which are the commonest tumors of the heart are associated with stroke due to tumor/clot embolism. There are very few case reports of IVT and its outcome in patients with atrial myxoma with stroke. Some have reported successful thrombolysis, while others have reported intracerebral bleeding. In this report we describe our experience of IVT in atrial myxoma patient with ischemic stroke and review the relevant literature. PMID- 25506174 TI - Molecular analysis of PRRT2 gene in a case of paroxysmal kinesigenic dyskinesia patient. AB - Paroxysmal kinesigenic dyskinesia (PKD) is an abnormal involuntary movement that is episodic or intermittent, with sudden onset, and the attacks are induced by sudden movement. Mutations in proline-rich transmembrane protein 2 (PRRT2) gene have been implicated in the cause of this disorder. This study presents a case of PKD on the basis of clinical findings supported and evidences obtained through a mutational analysis. Sequencing of all the exons of PRRT2 gene revealed a frameshift mutation (p.R217Pfs*8) in exon 2 and a novel transition mutation (c.244C > T) in 5'-untranslated region (UTR). Though mutations in PRRT2 gene are well-established in PKD, this study for the first time presents a novel transition mutation in the exon 2 region. PMID- 25506175 TI - Factors predicting poor outcome in patients with fulminant Guillaine-Barre syndrome. AB - This paper describes three patients with acute fulminant Guillain-Barriota Syndrome (GBS) with electrophysiologically inexcitable peripheral nerves not responding to two courses of intravenous immunoglobulin. Their clinical profile is compared with two other GBS patients having similar severity of disease but with demyelinative features, managed similarly during the same period. Patients who failed to respond were elderly with a mean age of 60 years, had prodromal diarrhea, rapid progression of muscle weakness requiring mechanical ventilation within 24 hours, dense weakness of all four limbs with cardiovascular autonomic symptoms and inexcitable peripheral nerves. The remaining two who recovered well were relatively younger with a mean age of 50 years, had no prodromal diarrhea, required ventilatory support by fourth day of illness, no cardiovascular autonomic symptoms and demyelinative neuropathy. PMID- 25506176 TI - Pure psychiatric presentation in a patient with Fahr's disease. PMID- 25506177 TI - Linear nevus sebaceous syndrome. PMID- 25506178 TI - Hot water epilepsy: Phenotype and single photon emission computed tomography observations. AB - We studied the anatomical correlates of reflex hot water epilepsy (HWE) using multimodality investigations viz. magnetic resonance imaging (MRI), electroencephalography (EEG), and single photon emission computed tomography (SPECT). Five men (mean age: 27.0 ? 5.8 years) with HWE were subjected to MRI of brain, video-EEG studies, and SPECT scan. These were correlated with phenotypic presentations. Seizures could be precipitated in three patients with pouring of hot water over the head and semiology of seizures was suggestive of temporal lobe epilepsy. Ictal SPECT showed hyperperfusion in: left medial temporal - one, left lateral temporal - one, and right parietal - one. Interictal SPECT was normal in all five patients and did not help in localization. MRI and interictal EEG was normal in all the patients. The clinical and SPECT studies suggested temporal lobe as the seizure onset zone in some of the patients with HWE. PMID- 25506179 TI - Sleep disorders in children with cerebral palsy and its correlation with sleep disturbance in primary caregivers and other associated factors. AB - AIMS: To observe prevalence of sleep disturbance (SD) in cerebral palsy (CP) children in a specific age-group and its correlation with SD in primary caregivers and other associated factors. MATERIALS AND METHODS: This was a prospective cross-sectional study. SD assessed using Sleep Disturbance Scale for Children (SDSC) in CP children and Pittsburgh Sleep Quality Index (PSQI) in caregivers. Fifty cases of clinically diagnosed CP [27 females, mean age: 107.9 ? 29.5 months (range: 78-180 months)] fulfilling criteria were included. RESULTS: Eighteen (36%) children had pathological sleep total score (TS) and Disorders of Initiating and Maintaining Sleep (DIMS) was the commonest SD (n = 25, 50%). All primary caregivers were mothers. Twenty-five (50%) mothers had SD on PSQI scale. DIMS, Disorders of Excessive Somnolence (DES), and TS had significant correlation with PSQI (P < 0.05). Disorders of Arousal (DA) and TS had significant correlation with seizures (P < 0.05) in CP children. Bed-sharing had significant correlation with SD in caregivers (P < 0.001) but not with CP children. No significant correlation was observed between SD in CP and gross motor function (Gross Motor Function Classification System), use of orthoses, and dental caries. INTERPRETATION: Children with CP have underreported significant SD, which negatively impacts caregiver's sleep also. Seizure disorders and medications contribute significantly to SD. PMID- 25506180 TI - Isolated vision loss and disappearing lesions as the manifestation of subacute sclerosing panencephalitis. PMID- 25506181 TI - Parinaud's syndrome: A rare presentation of lung carcinoma with solitary pineal metastasis. PMID- 25506182 TI - Efficacy and safety of methylcobalamin, alpha lipoic acid and pregabalin combination versus pregabalin monotherapy in improving pain and nerve conduction velocity in type 2 diabetes associated impaired peripheral neuropathic condition. [MAINTAIN]: Results of a pilot study. PMID- 25506183 TI - Conducting randomized controlled trials in clinical settings of a pilot study. PMID- 25506184 TI - Multiple strategies for resilient livelihoods in communal areas of South Africa. AB - Livestock farming in communal areas is an activity pursued by rural households as one of a range of livelihood strategies aimed at spreading risk. The cash and non cash benefits derived from livestock, as well as the wide range of secondary resources harvested from communal rangelands, make an important contribution to livelihood diversification, and hence, resilience. Rural development policy should therefore not focus narrowly on commercialisation of livestock production in communal areas. Rather, it should take a multi-faceted approach to building livelihood resilience while providing pathways for households to escape poverty through enhancing the multiple benefits of livestock, adding value to secondary rangeland resources, and expanding the rural non-farm economy. PMID- 25506185 TI - Familias: Preparando la Nueva Generacion: A Randomized Control Trial Testing the Effects on Positive Parenting Practices. AB - OBJECTIVES: This article reports the effects of a culturally grounded parenting intervention to strengthen positive parenting practices. METHOD: The intervention was designed and tested with primarily Mexican origin parents in a large urban setting of the southwestern United States using an ecodevelopmental approach. Parents (N = 393) were randomly assigned three treatment conditions: (1) a parenting and youth intervention, (2) a youth only intervention, or (3) a control group. A measurement model for positive parenting was first evaluated using confirmatory factor analysis, followed by structural equation modeling to estimate the effects of the intervention on positive parenting (i.e., baseline to follow-up). RESULTS: As hypothesized, parents in the intervention group reported higher rates of positive parenting compared to parents in youth-only condition. CONCLUSION: The results are promising and add to growing evidence that interventions tailored to the cultural characteristics and environments of parents and their children can strengthen positive parenting. PMID- 25506186 TI - Adolescent Pathways to Co-Occurring Problem Behavior: The Effects of Peer Delinquency and Peer Substance Use. AB - Delinquency and substance use are more likely to co-occur in adolescence compared to earlier and later developmental periods. The present study examined developmental pathways to co-occurring problem behavior from 6th-10th grade (N=2,002), testing how peer delinquency and substance use were linked to transitioning between abstaining, delinquency, substance use, and co-occurring problem behavior. Developmentally, most youth transition from abstinence to delinquent behavior, and then escalate to co-occurring problem behavior. Once co occurring problem behavior onsets, remitting to single problem behavior or abstinence is unlikely. The impact of peers on problem behavior are domain specific when individuals transition from abstaining to a single problem behavior, but are more general with respect to escalation of and desistance from problem behavior. PMID- 25506187 TI - Large Stroke Vertical PZT Microactuator With High-Speed Rotational Scanning. AB - A thin-film piezoelectric microactuator using a novel combination of active vertical translational scanning and passive resonant rotational scanning is presented. Thin-film lead-zirconate-titanate unimorph bending beams surrounding a central platform provide nearly 200-MUm displacement at 18 V with bandwidth greater than 200 Hz. Inside the platform, a mirror mount, or mirror surface, supported by silicon dioxide spring beams can be excited to resonance by low voltage; high-frequency excitation of the outer PZT beams. Over +/-5.5 degrees mechanical resonance is obtained at 3.8 kHz and +/-2 V. The combination of large translational vertical displacements and high-speed rotational scanning is intended to support real-time cross-sectional imaging in a dual axes confocal endomicroscope. PMID- 25506188 TI - Modeling and Simulation of a Parametrically Resonant Micromirror With Duty-Cycled Excitation. AB - High frequency large scanning angle electrostatically actuated microelectromechanical systems (MEMS) mirrors are used in a variety of applications involving fast optical scanning. A 1-D parametrically resonant torsional micromirror for use in biomedical imaging is analyzed here with respect to operation by duty-cycled square waves. Duty-cycled square wave excitation can have significant advantages for practical mirror regulation and/or control. The mirror's nonlinear dynamics under such excitation is analyzed in a Hill's equation form. This form is used to predict stability regions (the voltage frequency relationship) of parametric resonance behavior over large scanning angles using iterative approximations for nonlinear capacitance behavior of the mirror. Numerical simulations are also performed to obtain the mirror's frequency response over several voltages for various duty cycles. Frequency sweeps, stability results, and duty cycle trends from both analytical and simulation methods are compared with experimental results. Both analytical models and simulations show good agreement with experimental results over the range of duty cycled excitations tested. This paper discusses the implications of changing amplitude and phase with duty cycle for robust open-loop operation and future closed-loop operating strategies. PMID- 25506189 TI - Fertility Intentions, Career Considerations and Subsequent Births: The Moderating Effects of Women's Work Hours. AB - Prior research indicates a negative relationship between women's labor force participation and fertility at the individual level in the United States, but little is known about the reasons for this relationship beyond work hours. We employed discrete event history models using panel data from the National Survey of Families and Households (N = 2,411) and found that the importance of career considerations mediates the work hours/fertility relationship. Further, fertility intentions and the importance of career considerations were more predictive of birth outcomes as women's work hours increase. Ultimately, our findings challenge the assumption that working more hours is the direct cause for employed women having fewer children and highlight the importance of career and fertility preferences in fertility outcomes. PMID- 25506190 TI - Arrhythmogenic Cardiomyopathy - New Insights into Disease Mechanisms and Drug Discovery. AB - Arrhythmogenic cardiomyopathy (ACM) is a primary myocardial disorder characterized by the early appearance of ventricular arrhythmias often out of proportion to the degree of ventricular remodeling and dysfunction. ACM typically presents in adolescence or early adulthood. It accounts for 10% of sudden cardiac deaths in individuals under the age of 18 years. Although there has been significant progress in recognizing the genetic determinants of ACM, how specific gene mutations cause the disease remains poorly understood. Here, we review insights gained from studying the human disease as well as in vivo and in vitro experimental models. These observations have advanced our understanding of the molecular mechanisms underlying the pathogenesis of ACM and may lead to development of new mechanism-based therapies. PMID- 25506191 TI - Enantiopure Cryptophane-129Xe Nuclear Magnetic Resonance Biosensors Targeting Carbonic Anhydrase. AB - The (+) and (-) enantiomers for a cryptophane-7-bond-linker-benzenesulfonamide biosensor (C7B) were synthesized and their chirality confirmed by electronic circular dichroism (ECD) spectroscopy. Biosensor binding to carbonic anhydrase II (CAII) was characterized for both enantiomers by hyperpolarized (hp) 129Xe NMR spectroscopy. Our previous study of the racemic (+/-) C7B biosensor-CAII complex [Chambers, et al., J. Am. Chem. Soc. 2009, 131, 563-569], identified two "bound" 129Xe@C7B peaks by hp 129Xe NMR (at 71 and 67 ppm, relative to "free" biosensor at 64 ppm), which led to the initial hypothesis that (+) and (-) enantiomers produce diastereomeric peaks when coordinated to Zn2+ at the chiral CAII active site. Unexpectedly, the single enantiomers complexed with CAII also identified two "bound" 129Xe@C7B peaks: (+) 72, 68 ppm and (-) 68, 67 ppm. These results are consistent with X-ray crystallographic evidence for benzenesulfonamide inhibitors occupying a second site near the CAII surface. As illustrated by our studies of this model protein-ligand interaction, hp 129Xe NMR spectroscopy can be useful for identifying supramolecular assemblies in solution. PMID- 25506192 TI - Maternal Relationship Insecurity and Depressive Symptoms as Moderators of Home Visiting Impacts on Child Outcomes. AB - The purpose of this study was to determine the extent to which maternal relationship insecurity and severe depressive symptoms moderate home visiting impacts on developmental and behavioral outcomes in 2-year old children. In an experimental trial of the Healthy Families Alaska home visiting program, families (N = 249) were randomly assigned to home visiting (n = 126) or community services as usual (n = 123). Maternal severe depressive symptoms (CES-D >= 24) and relationship insecurity were measured using the Center for Epidemiologic Studies Depression Scale and the Attachment Style Questionnaire at baseline. Child cognitive and psychomotor development and behavior problems were measured with the Bayley Scales of Infant Development and the Child Behavior Checklist at follow-up. The results revealed that home visiting significantly impacted three outcomes- child cognitive development, internalizing behavior, and externalizing behavior. Home visiting impacts were limited to subgroups defined by maternal depressive symptoms and relationship insecurity. Home visiting improved cognitive development (B = 6.02, p < .03), and decreased internalizing behavior (B = -3.83, p = .02) and externalizing behavior problems (B = -3.74, p = .03) in children of mothers with either severe depressive symptoms or high levels of discomfort with trust at baseline, but not both. Family engagement in home visiting seems to play a role in mediating these moderating effects. These findings reflect the importance of screening for maternal relationship insecurity and depressive symptoms to distinguish family subgroups likely to benefit from home visiting from those for whom an enhanced service model might be needed. PMID- 25506194 TI - Light-Sharing Interface for dMiCE Detectors using Sub-Surface Laser Engraving. AB - We have previously reported on dMiCE, a method of resolving depth or interaction (DOI) in a pair of discrete crystals by encoding light sharing properties as a function of depth in the interface of this crystal-element pair. A challenge for this method is the cost and repeatability of interface treatment for a crystal pair. In this work, we report our preliminary results on using sub-surface laser engraving (SSLE) as a means of forming this depth-dependent interface in a dMiCE detector. A surplus first-generation SSLE system was used to create a partially reflective layer 100-microns thick at the boundary between two halves of a 1.4-by 2.9-by-20 mm^3 LYSO crystal. The boundary of these paired crystal elements was positioned between two 3-mm wide Geiger-Muller avalanche photodiodes from Hamamatsu. The responses of these two photodetectors were acquired for an ensemble of 511-keV photons collimated to interact at a fixed depth in just one crystal element. Interaction position was then varied to measure detector response as a function of depth, which was then used to maximum-likelihood positions events. Despite use of sub-optimal SSLE processing we found an average DOI resolution of 3.4 mm for front-sided readout and 3.9 mm for back-sided readout. We expect DOI resolution can be improved significantly by optimizing the SSLE process and pattern. PMID- 25506193 TI - Familial Interstitial Pneumonia (FIP). PMID- 25506196 TI - Supervised classification by filter methods and recursive feature elimination predicts risk of radiotherapy-related fatigue in patients with prostate cancer. AB - BACKGROUND: Fatigue is a common side effect of cancer (CA) treatment. We used a novel analytical method to identify and validate a specific gene cluster that is predictive of fatigue risk in prostate cancer patients (PCP) treated with radiotherapy (RT). METHODS: A total of 44 PCP were categorized into high-fatigue (HF) and low-fatigue (LF) cohorts based on fatigue score change from baseline to RT completion. Fold-change differential and Fisher's linear discriminant analyses (LDA) from 27 subjects with gene expression data at baseline and RT completion generated a reduced base of most discriminatory genes (learning phase). A nearest neighbor risk (k-NN) prediction model was developed based on small-scale prognostic signatures. The predictive model validity was tested in another 17 subjects using baseline gene expression data (validation phase). RESULT: The model generated in the learning phase predicted HF classification at RT completion in the validation phase with 76.5% accuracy. CONCLUSION: The results suggest that a novel analytical algorithm that incorporates fold-change differential analysis, LDA, and a k-NN may have applicability in predicting regimen-related toxicity in cancer patients with high reliability, if we take into account these results and the limited amount of data that we had at disposal. It is expected that the accuracy will be improved by increasing data sampling in the learning phase. PMID- 25506195 TI - Health information technology in oncology practice: a literature review. AB - The adoption and implementation of information technology are dramatically remodeling healthcare services all over the world, resulting in an unstoppable and sometimes overwhelming process. After the introduction of the main elements of electronic health records and a description of what every cancer-care professional should be familiar with, we present a narrative review focusing on the current use of computerized clinical information and decision systems in oncology practice. Following a detailed analysis of the many coveted goals that oncologists have reached while embracing informatics progress, the authors suggest how to overcome the main obstacles for a complete physicians' engagement and for a full information technology adoption, and try to forecast what the future holds. PMID- 25506197 TI - FocalCall: An R Package for the Annotation of Focal Copy Number Aberrations. AB - In order to identify somatic focal copy number aberrations (CNAs) in cancer specimens and to distinguish them from germ-line copy number variations (CNVs), we developed the software package FocalCall. FocalCall enables user-defined size cutoffs to recognize focal aberrations and builds on established array comparative genomic hybridization segmentation and calling algorithms. To distinguish CNAs from CNVs, the algorithm uses matched patient normal signals as references or, if this is not available, a list with known CNVs in a population. Furthermore, FocalCall differentiates between homozygous and heterozygous deletions as well as between gains and amplifications and is applicable to high resolution array and sequencing data. PMID- 25506198 TI - Trial prospector: matching patients with cancer research studies using an automated and scalable approach. AB - Cancer is responsible for approximately 7.6 million deaths per year worldwide. A 2012 survey in the United Kingdom found dramatic improvement in survival rates for childhood cancer because of increased participation in clinical trials. Unfortunately, overall patient participation in cancer clinical studies is low. A key logistical barrier to patient and physician participation is the time required for identification of appropriate clinical trials for individual patients. We introduce the Trial Prospector tool that supports end-to-end management of cancer clinical trial recruitment workflow with (a) structured entry of trial eligibility criteria, (b) automated extraction of patient data from multiple sources, (c) a scalable matching algorithm, and (d) interactive user interface (UI) for physicians with both matching results and a detailed explanation of causes for ineligibility of available trials. We report the results from deployment of Trial Prospector at the National Cancer Institute (NCI)-designated Case Comprehensive Cancer Center (Case CCC) with 1,367 clinical trial eligibility evaluations performed with 100% accuracy. PMID- 25506199 TI - A pan-cancer analysis of alternative splicing events reveals novel tumor associated splice variants of matriptase. AB - High-throughput transcriptome sequencing allows identification of cancer-related changes that occur at the stages of transcription, pre-messenger RNA (mRNA), and splicing. In the current study, we devised a pipeline to predict novel alternative splicing (AS) variants from high-throughput transcriptome sequencing data and applied it to large sets of tumor transcriptomes from The Cancer Genome Atlas (TCGA). We identified two novel tumor-associated splice variants of matriptase, a known cancer-associated gene, in the transcriptome data from epithelial-derived tumors but not normal tissue. Most notably, these variants were found in 69% of lung squamous cell carcinoma (LUSC) samples studied. We confirmed the expression of matriptase AS transcripts using quantitative reverse transcription PCR (qRT-PCR) in an orthogonal panel of tumor tissues and cell lines. Furthermore, flow cytometric analysis confirmed surface expression of matriptase splice variants in chinese hamster ovary (CHO) cells transiently transfected with cDNA encoding the novel transcripts. Our findings further implicate matriptase in contributing to oncogenic processes and suggest potential novel therapeutic uses for matriptase splice variants. PMID- 25506201 TI - Isolated posterior capsular rupture following blunt head trauma. AB - Closed-globe traumatic cataract is not uncommon in males in the pediatric age group. However, there is a relative paucity of literature on isolated posterior lens capsule rupture associated with closed-globe traumatic cataract. We report a case of a 6-year-old boy who presented with white cataract 1 day after blunt trauma to the forehead associated with posterior capsular rupture that was detected by B-scan ultrasonography preoperatively. No stigmata of trauma outside the posterior capsule could be detected by slit-lamp exam, funduscopy, and optical coherence tomography. Phacoemulsification with posterior chamber intraocular lens implant was performed 24 hours after trauma, with the patient achieving 6/6 visual acuity 1 week and 6 months after surgery. Our case is unique, being the youngest (amblyogenic age) to be reported, with prompt surgical intervention, and with no signs of trauma outside the posterior capsule. PMID- 25506200 TI - Computational Construction of Antibody-Drug Conjugates Using Surface Lysines as the Antibody Conjugation Site and a Non-cleavable Linker. AB - Antibody-drug conjugates (ADCs) constitute a category of anticancer targeted therapy that has gathered great interest during the last few years because of their potential to kill cancer cells while causing significantly fewer side effects than traditional chemotherapy. In this paper, a process of computational construction of ADCs is described, using the surface lysines of an antibody and a non-covalent linker molecule, as well as a cytotoxic substance, as files in Protein Data Bank format. Also, aspects related to the function, properties, and development of ADCs are discussed. PMID- 25506202 TI - Utility of Heidelberg retinal tomography as a screening tool for analyzing retinal nerve fiber layer defects. AB - CONTEXT: Although Heidelberg retinal tomography (HRT)-generated topographic images have been studied extensively for the detection of retinal nerve fiber layer (RNFL) defects, little is known about the role of HRT-generated surface reflectivity images in the detection of RNFL defects in either patients with glaucoma or glaucoma suspects. AIMS: To evaluate the effectiveness of HRT version II (HRT II) optic nerve reflectivity images in uncovering RNFL defects in an outpatient population evaluated for glaucoma. STUDY DESIGN/MATERIALS AND METHODS: In 102 consecutive eyes from 60 patients evaluated for glaucoma in an academic based practice, HRT II optic nerve images were prospectively imaged and compared with clinical optic nerve exam techniques to see if HRT II was able to detect RNFL defects overlooked in clinical practice. RESULTS: Nine eyes (8.8%) were found to have RNFL defects recognized by screening with HRT II. Of these nine eyes, eight (88.9%) were recognized to demonstrate RNFL defects by conventional examination techniques. One additional eye had an RNFL defect seen on physical exam that was not detected by HRT. CONCLUSION: In academic practice, HRT II may be helpful in complementing conventional exam techniques in the recognition and documentation of acquired RNFL loss. PMID- 25506203 TI - Evaluation of actual retinal images produced by misaligned aspheric intraocular lenses in a model eye. AB - PURPOSE: To examine the effect of misalignment (decentration and tilt) of intraocular lenses (IOLs) on retinal image quality using a water-immersed model eye with corneal spherical aberration adjusted to the values found in normal human eyes (spherical aberration 0.25 MUm; pupil diameter 6 mm). METHODS: Three types of IOL holders were prepared. The first was without decentration or tilt, the second had a decentration of 0.5 mm, and the third had a tilt of 5.0 degrees . One spherical IOL and three aspherical IOLs, each with a power of +20 D, were set in the holders and their optical properties (wave front aberration, defocused modulation transfer function, defocused point spread function, and Landolt ring simulations) were compared. RESULTS: Coma aberrations generated by misaligned IOLs were related to the spherical aberration corrective power of the IOLs. Landolt ring simulations show that the depth of focus increased as spherical aberration increased and that the retinal image quality was degraded by increases in coma aberration. CONCLUSION: Coma aberration was generated by IOLs with a large degree of spherical aberration correction, leading to reduced retinal image quality when the IOL was misaligned. This suggests that, in a clinical setting, the quality of vision might be improved by reducing the degree of coma aberration using IOLs that retain, or minimally correct, spherical aberration. PMID- 25506204 TI - Hyperopic correction: clinical validation with epithelium-on and epithelium-off protocols, using variable fluence and topographically customized collagen corneal crosslinking. AB - PURPOSE: To report novel application of topographically-customized collagen crosslinking aiming to achieve hyperopic refractive changes. Two approaches were evaluated, one based on epithelium-off and one based on epithelium-on (transepithelial). METHODS: A peripheral annular-shaped topographically customizable design was employed for high-fluence ultraviolet (UV)-A irradiation aiming to achieve hyperopic refractive changes. A total of ten eyes were involved in this study. In group-A (five eyes), a customizable ring pattern was employed to debride the epithelium by excimer laser ablation, while in group-B (also five eyes), the epithelium remained intact. In both groups, specially formulated riboflavin solutions were applied. Visual acuity, cornea clarity, keratometry, topography, and pachymetry with a multitude of modalities, as well as endothelial cell counts were evaluated. RESULTS: One year postoperatively, the following changes have been noted: in group-A, average uncorrected distance visual acuity changed from 20/63 to 20/40. A mean hyperopic refractive increase of +0.75 D was achieved. There was some mild reduction in the epithelial thickness. In group-B, average uncorrected distance visual acuity changed from 20/70 to 20/50. A mean hyperopic refractive increase of +0.85 D was achieved. Epithelial thickness returned to slightly reduced levels (compared to baseline) in group-A, whereas to slightly increased levels in group-B. CONCLUSION: We introduce herein the novel application of a topographically-customizable collagen crosslinking to achieve a hyperopic refractive effect. This novel technique may be applied either with epithelial removal, offering a more stable result or with a non-ablative and non incisional approach, offering a minimally invasive alternative. PMID- 25506205 TI - Ocular surface squamous neoplasia in HIV-positive and HIV-negative patients and response to 5-fluorouracil in Angola. AB - BACKGROUND: Ocular surface squamous neoplasia (OSSN) is becoming increasingly prevalent and aggressive in Sub-Saharan Africa. It is a phenomenon linked with human immunodeficiency virus (HIV) infection, although association rates in Angola are currently unknown. A topical treatment that is effective in HIV positive and HIV-negative individuals may be preferable to surgery in some contexts. We aimed to estimate the proportion of OSSN associated with HIV in Angola and to report on the success of topical 5-fluorouracil as a primary treatment in HIV-positive and HIV-negative patients. METHODS: Photographs of OSSNs taken at presentation and following treatment with 5-fluorouracil in patients presenting to Boa Vista Eye Clinic, Angola, between October 2011 and July 2013 were grouped into HIV-positive and HIV-negative groups and analyzed to compare presenting features and treatment response. Eighty-one OSSNs were analyzed for clinical features and 24 met the inclusion criteria for analysis of treatment response. RESULTS: Eighty-two patients presented with OSSN between October 2011 and July 2013. Twenty-one (26%) were HIV-positive and typically had OSSNs that exhibited more pathological features than those in HIV-negative patients. Twenty-four (29%) patients met the inclusion criteria for analysis of treatment response; of these, 26 (91%) OSSNs in both groups displayed at least partial resolution after one treatment course. In the HIV-positive group, five of eight patients displayed complete resolution, two showed partial resolution, and one failed. In the HIV-negative group, five of 16 showed complete resolution, ten of 16 had partial resolution, and one failed. CONCLUSION: Individuals presenting with OSSN in Angola are more likely to have HIV infection compared with the general population. Regardless of HIV status, 5-fluorouracil drops can be an effective strategy for management of OSSN without incurring the costs and risks of surgery in the developing world setting. PMID- 25506206 TI - Comparison study of OCT, HRT and VF findings among normal controls and patients with pseudoexfoliation, with or without increased IOP. AB - PURPOSE: To compare and evaluate optic nerve head (ONH) and retinal nerve fiber layer (RNFL) measurements obtained with the optical coherence tomography (OCT) and the Heidelberg retina tomography (HRT) to visual field (VF) parameters in normal and in patients with pseudoexfoliation with or without increased intraocular pressure (IOP). METHODS: A total of 96 subjects were included in our study aged between 65 years and 78 years. The normal group consisted of 28 subjects (14 men and 14 women). Out of the total number of patients, 68 patients who showed pseudoexfoliation (21 men and 47 women) were divided into two groups. Of these, the first group had pseudoexfoliation with increased IOP and the second group showed deposits of pseudoexfoliative material without an increase in IOP. The normal controls were randomly chosen and restricted to those without any glaucomatous optic disc damages, VF defects, and an IOP <15 mmHg. All subjects were prospectively included for repeated measurements of IOP, OCT, HRT, and VFs during the same visit by the same examiner and all measurements were repeated every 3 months. RESULTS: Mean RNFL thickness measured by OCT was larger in the normal controls than in the other two groups (98.04 MUm (first group) vs 75.42 MUm and 97.02 MUm (second group), P<0.05). Four-quadrant RNFL thickness measurements were significantly different between the normal and the group 1 (P<0.05) but not with the group 2 (P>0.05). Rim area had a mean difference of 0.44, whereas cup-to-disc ratio (C/D) showed a mean difference of 0.31, thus being significantly different between the normal and the two groups (all P<0.05). The median of the mean deviation parameter of VFs was -0.28 for the normal vs 0.32 and -0.18 for the other two groups, whereas pattern standard deviation median difference was 0.89 for the normal and 1.32 and 1.20 for the other two groups, respectively (P<0.05). CONCLUSION: Both OCT and HRT showed early ONH and RNFL changes in their parameters and did not correlate with the normal findings of the automated perimetry. PMID- 25506207 TI - Clinical course of focal choroidal excavation in Vogt-Koyanagi-Harada disease. AB - We describe focal choroidal excavation (FCE) in a case of Vogt-Koyanagi-Harada (VKH) disease and compare the findings with different chorioretinal conditions. A 55-year-old man was diagnosed with VKH based on panuveitis and exudative retinal detachments. Spectral-domain optical coherence tomography demonstrated a dome shaped protrusion with a nonconforming pattern at the fovea, which had been detected as a conforming pattern 1 year before the onset. The FCE pattern returned into a conforming pattern following corticosteroid therapy. These findings suggest that the natively existent FCE could be affected by pathophysiological changes of VKH as well as other chorioretinal conditions. PMID- 25506208 TI - Inner retinal damage after exposure to green diode laser during a laser show. AB - Here we report two cases of retinal damage after exposure to a 510 nm laser diode during a laser show. The first patient was a 20-year-old female who presented with decreased visual acuity in her right eye after visiting a dance party with a diode laser show (wavelength 510 nm, power 2 mW), although she did not directly see the light. Retinal examination revealed a sub-internal limiting membrane hemorrhage and a small laser burn. The second patient was a 20-year-old female who visited for decreased vision in her left eye. She described similar events as the first patient. An exposure to green diode laser can result in retinal damage. It is strongly recommended that certified personnel operate laser devices used in indoor laser shows under strict regulation. PMID- 25506210 TI - Care pathways for dementia: current perspectives. AB - Uncertainty appears to typify the experience of living with dementia. With an uncertain illness trajectory and unpredictable levels of deterioration and stability in symptoms, people with a diagnosis of dementia may live with uncertainty and anxiety and find it hard to make plans or decisions for their future. People with memory problems and caregivers seeking a diagnosis of dementia may also potentially find themselves navigating a labyrinth-like maze of services, practitioners, assessments, and memory tests, with limited understanding of test scores and little information about what support is available. In this context of uncertainty, the apparent clarity and certainty of a "dementia care pathway" may be attractive. However, the term "dementia care pathway" has multiple and overlapping meanings, which can potentially give rise to further confusion if these are ill-defined or a false consensus is presumed. This review distinguishes four meanings: 1) a mechanism for the management and containment of uncertainty and confusion, useful for the professional as well as the person with dementia; 2) a manual for sequencing care activities; 3) a guide to consumers, indicating eligibility for care activities, or a guide to self management for dementia dyads, indicating the appropriateness of care activities; and 4) a manual for "walking with" the person. Examples of these approaches are presented from UK dementia services with illustrations of existing care pathways and associated time points, specifically focusing on: 1) early symptom identification and first service encounters, 2) assessment process, 3) diagnostic disclosure, 4) postdiagnostic support, and 5) appropriate interventions. We review the evidence around these themes, as well as discuss service pathways and referral routes used by some services in England and internationally. We conclude that the attraction of the term "care pathway" is seductive, but caution is needed in taking shared understandings for granted. PMID- 25506209 TI - Multikinase inhibitors use in differentiated thyroid carcinoma. AB - Thyroid cancer is the most common endocrine malignancy, and its incidence is increasing. Standard therapy for most patients with localized differentiated thyroid cancer (DTC) includes surgery, radioactive iodine, and thyroid hormone replacement. A minority of thyroid cancer patients requires systemic therapy for metastatic disease. Patients with metastatic DTC do not usually benefit from traditional cytotoxic chemotherapy. In this review, we describe newly developed small-molecule tyrosine kinase inhibitors (TKIs) that are being actively tested and used in the management of advanced thyroid cancer. The use of TKIs as a form of molecular targeted therapy is evolving based on understanding of the pathways involved in DTC. Disrupting tumor vascular supply by targeting vascular endothelial growth factor receptor signaling is the most commonly used approach to treat advanced/metastatic DTC. Other mechanisms include targeting BRAF, MAPK/ERK kinase, or mammalian target of rapamycin signaling. Although TKIs appear to have superior efficacy compared to cytotoxic chemotherapy, they can cause substantial adverse effects; symptomatic management of adverse effects, dose adjustment, or cessation of therapy may be required. PMID- 25506211 TI - Efficacy and tolerability of Ginkgo biloba extract EGb 761(r) in dementia: a systematic review and meta-analysis of randomized placebo-controlled trials. AB - The objective of this systematic review was to evaluate current evidence for the efficacy of Ginkgo biloba extract EGb 761((r)) in dementia. Seven of 15 randomized, placebo-controlled trials in patients with dementia identified by database searches met all our selection criteria and were included in the meta analysis. In these trials, patients were treated with 120 mg or 240 mg per day of the defined extract EGb 761 or placebo. Efficacy was assessed using validated tests and rating scales for the cognitive domain, the functional domain (activities of daily living), and global assessment. Tolerability was evaluated by risk differences based on incidences of adverse events and premature discontinuation rates. Of 2,684 outpatients randomized to receive treatment for 22-26 weeks, 2,625 represented the full analysis sets (1,396 for EGb 761 and 1,229 for placebo). Standardized mean differences for change in cognition (-0.52; 95% confidence interval [CI] -0.98, -0.05; P=0.03), activities of daily living ( 0.44; 95% CI -0.68, -0.19; P<0.001), and global rating (-0.52; 95% CI -0.92, 0.12; P=0.01) significantly favored EGb 761 compared with placebo. Statistically significant superiority of EGb 761 over placebo was confirmed by responder analyses as well as for patients suffering from dementia with neuropsychiatric symptoms. Treatment-associated risks in terms of relative risks of adverse events and premature withdrawal rates did not differ noticeably between the two treatment groups. In conclusion, meta-analyses confirmed the efficacy and good tolerability of Ginkgo biloba extract EGb 761 in patients with dementia. PMID- 25506212 TI - Olive oil in the prevention and treatment of osteoporosis after artificial menopause. AB - PURPOSE: The goal of this study was to investigate the anti-osteoporosis effect of extra virgin olive oil (EVOO) in vivo, and explore its antioxidant, anti inflammatory properties in Sprague Dawley rats and its anticancer properties in patients. MATERIALS AND METHODS: A total of 120 healthy female Sprague Dawley rats aged 6 months were divided into four groups: 1) sham-operated control (Sham group, n=30); 2) ovariectomized (OVX group, n=30); 3) ovariectomized rats supplemented with EVOO (OVX + Olive, n=30); 4) ovariectomized rats supplemented with estrogen (OVX + E2, n=30). EVOO and estrogen were administered by oral gavage at a dose of 1 mL/100 g weight on a daily basis for 12 consecutive weeks. Twelve weeks later blood samples were obtained to detect the levels of calcium, alkaline phosphatase, phosphorus, interleukin-6 (IL-6), malonyldialdehyde (MDA), and nitrate content. Dual energy X-ray absorptiometer measured bone mineral density (BMD) of ovariectomized Sprague Dawley rats that had been fed olive oil for 3 months. Blood samples from patients, who regularly consumed olive oil over a 1 year period were also used to measure carbohydrate antigen 125, carcino embryonic antigen, alpha-fetoprotein, and carbohydrate antigen 19-9 levels. BMD of lumbar spine and left femur was also evaluated by dual energy X-ray absorptiometry. RESULTS: Animal experiments showed that EVOO significantly increased BMD and decreased phosphatase, alkaline phosphatase, IL-6, MDA, and nitrate levels. However, it had no significant effect on the Ca(2+) level. In clinical follow-up, EVOO also improved patient BMD levels on L3, L4, and left femoral neck, and reduced carbohydrate antigen 125, alpha-fetoprotein, and carcino-embryonic antigen levels. But it had no significant effect on the carbohydrate antigen 19-9 level. CONCLUSION: EVOO illustrated significant anti osteoporosis, antioxidant, anti-inflammatory, and anticancer properties in vivo. However, further studies are required to determine the active component(s) responsible for these effects. PMID- 25506213 TI - Noninvasive detection of macrophages in atherosclerotic lesions by computed tomography enhanced with PEGylated gold nanoparticles. AB - Macrophages are becoming increasingly significant in the progression of atherosclerosis (AS). Molecular imaging of macrophages may improve the detection and characterization of AS. In this study, dendrimer-entrapped gold nanoparticles (Au DENPs) with polyethylene glycol (PEG) and fluorescein isothiocyanate (FI) coatings were designed, tested, and applied as contrast agents for the enhanced computed tomography (CT) imaging of macrophages in atherosclerotic lesions. Cell counting kit-8 assay, fluorescence microscopy, silver staining, and transmission electron microscopy revealed that the FI-functionalized Au DENPs are noncytotoxic at high concentrations (3.0 MUM) and can be efficiently taken up by murine macrophages in vitro. These nanoparticles were administered to apolipoprotein E knockout mice as AS models, which demonstrated that the macrophage burden in atherosclerotic areas can be tracked noninvasively and dynamically three dimensionally in live animals using micro-CT. Our findings suggest that the designed PEGylated gold nanoparticles are promising biocompatible nanoprobes for the CT imaging of macrophages in atherosclerotic lesions and will provide new insights into the pathophysiology of AS and other concerned inflammatory diseases. PMID- 25506214 TI - Induction of mucosal immune responses and protection of cattle against direct contact challenge by intranasal delivery with foot-and-mouth disease virus antigen mediated by nanoparticles. AB - The aim of this study was to enhance specific mucosal, systemic, and cell mediated immunity and to induce earlier onset of protection against direct contact challenge in cattle by intranasal delivery of a nanoparticle-based nasal vaccine against type A foot-and-mouth disease (FMD). In this study, two kinds of nanoparticle-based nasal vaccines against type A FMD were designed: (1) chitosan coated poly(lactic-co-glycolic acid) (PLGA) loaded with plasmid DNA (Chi-PLGA DNA) and (2) chitosan-trehalose and inactivated foot-and-mouth disease virus (FMDV) (Chi-Tre-Inactivated). Cattle were immunized by an intranasal route with nanoparticles and then challenged for 48 hours by direct contact with two infected donor cattle per pen. Donors were inoculated intradermally in the tongue 48 hours before challenge, with 0.2 mL cattle-passaged FMDV. Serological and mucosal antibody responses were evaluated, and virus excretion and the number of contact infections were quantified. FMDV-specific secretory immunoglobulin (Ig)A (sIgA) antibodies in nasal washes were initially detected at 4 days postvaccination (dpv) with two kinds of nanoparticles. The highest levels of sIgA expression were observed in nasal washes, at 10 dpv, from animals with Chi-PLGA DNA nanoparticles, followed by animals immunized once by intranasal route with a double dose of Chi-Tre-Inactivated nanoparticles and animals immunized by intranasal route three times with Chi-Tre-Inactivated nanoparticles (P<0.05). FMDV-specific IgA antibodies in serum showed a similar pattern. All animals immunized by intranasal route developed low levels of detectable IgG in serum at 10 dpv. Following stimulation with FMDV, the highest levels of proliferation were observed in splenocytes harvested from Chi-PLGA-DNA-immunized animals, followed by proliferation of cells harvested from Chi-Tre-Inactivated nanoparticle immunized animals (P<0.05). Higher protection rates were associated with the highest sIgA antibody responses induced in the Chi-PLGA-DNA nanoparticle immunized group. Only one animal was clinically affected with mild signs after 7 days of contact challenge, after a delay of 2-3 days compared with the clinically affected negative-control group. Of the five animals directly challenged that were vaccinated by intranasal route with a double dose of Chi-Tre-Inactivated, four were clinically infected; however, the degree of severity of disease in this group was lower than in control cattle. The number of viral RNA copies in nasal swabs from the vaccinated, severely infected group was significantly higher than in swabs from the vaccinated, clinically protected group. These data suggested that intranasal delivery of Chi-PLGA-DNA nanoparticles resulted in higher levels of mucosal, systemic, and cell-mediated immunity than did of Chi-Tre-Inactivated nanoparticles. In conclusion, although intranasal delivery with FMDV antigen mediated by nanoparticles did not provide complete clinical protection, it reduced disease severity and virus excretion and delayed clinical symptoms. Chi PLGA-DNA nanoparticle vaccines have potential as a nasal delivery system for vaccines. PMID- 25506215 TI - Rapid and quantitative detection of C-reactive protein using quantum dots and immunochromatographic test strips. AB - BACKGROUND: Rapid immunochromatographic tests can detect disease markers in 10-15 minutes, which facilitates clinical diagnosis and treatment programs. However, most immunochromatographic tests employ gold nanoparticles as reporters, and these have only moderate sensitivity and act as qualitative methods for analyzing high biomarker concentrations. METHODS: In this study, we introduce quantum dots (QDs) as fluorescent probes and immunochromatographic strips to develop quantitative fluorescence point-of-care tests (QF-POCT) to analyze C-reactive protein (CRP) levels. Goat anti-rabbit IgG and rabbit IgG were used as control antibodies, and mouse monoclonal CRP antibody pairs were used for disease marker detection. One monoclonal CRP antibody was conjugated with QDs and served as a signal antibody, and the other monoclonal CRP antibody was dispensed onto the nitrocellulose membrane and served as a capturing antibody. In the presence of CRP, the fluorescence intensity of the monoclonal antibody-CRP-monoclonal antibody sandwich complex captured on the nitrocellulose membrane was determined using the fluorescence strip reader. RESULTS: QF-POCT assays could quantitatively analyze the concentration of CRP in 15 minutes had a detection limit of 0.25 mg/L, and had a wide detection linearity range (0.5-300 mg/L). The intra-assay and interassay coefficients of variation were 8.95% and 9.86% at 0.5 mg/L, 6.47% and 8.66% at 10 mg/L, and 6.81% and 9.10% at 60 mg/L, respectively. In a comparison between clinical samples, the results of this QD-based assay of CRP levels were significantly correlated with those of an Immulite 2000 assay (R=0.993, P<0.001). CONCLUSION: Our results demonstrated that the QD-based immunochromatographic test is a rapid, sensitive, accurate, and quantitative method for the detection of disease biomarkers. PMID- 25506216 TI - Similar healthy osteoclast and osteoblast activity on nanocrystalline hydroxyapatite and nanoparticles of tri-calcium phosphate compared to natural bone. AB - While there have been numerous studies to determine osteoblast (bone forming cell) functions on nanocrystalline compared to micron crystalline ceramics, there have been few studies which have examined osteoclast activity (including tartrate resistant acid phosphatase, formation of resorption pits, size of resorption pits, and receptor activator of nuclear factor kappaB [RANK]). This is despite the fact that osteoclasts are an important part of maintaining healthy bone since they resorb bone during the bone remodeling process. Moreover, while it is now well documented that bone formation is enhanced on nanoceramics compared to micron ceramics, some have pondered whether osteoblast functions (such as osteoprotegerin and RANK ligand [RANKL]) are normal (ie, non-diseased) on such materials compared to natural bone. For these reasons, the objective of the present in vitro study was to determine various functions of osteoclasts and osteoblasts on nanocrystalline and micron crystalline hydroxyapatite as well as tri-calcium phosphate materials and compare such results to cortical and cancellous bone. Results showed for the first time similar osteoclast activity (including tartrate-resistant acid phosphatase, formation of resorption pits, size of resorption pits, and RANK) and osteoblast activity (osteoprotegerin and RANKL) on nanocrystalline hydroxyapatite compared to natural bone, whereas osteoclast and osteoblast functions on micron crystalline versions of these ceramics were much different than natural bone. In this manner, this study provides additional evidence that nanocrystalline calcium phosphates can serve as suitable synthetic analogs to natural bone to improve numerous orthopedic applications. It also provides the first data of healthy osteoclast and osteoblast functions on nanocrystalline calcium phosphates compared to natural bone. PMID- 25506217 TI - Fluorescence tomographic imaging of sentinel lymph node using near-infrared emitting bioreducible dextran nanogels. AB - Sentinel lymph node (SLN) mapping is a critical procedure for SLN biopsy and its diagnosis as tumor metastasis in clinical practice. However, SLN mapping agents used in the clinic frequently cause side effects and complications in the patients. Here, we report the development of a near-infrared (NIR) emitting polymeric nanogel with hydrodynamic diameter of ~28 nm - which is the optimal size for SLN uptake - for noninvasive fluorescence mapping of SLN in a mouse. This polymeric nanogel was obtained by coupling Cy7, an NIR dye, to the self assembled nanogel from disulfide-linked dextran-deoxycholic acid conjugate with the dextran of 10 kDa, denoted as Dex-Cy7. Fluorescence imaging analysis showed that Dex-Cy7 nanogels had an enhanced photostability when compared to Cy7 alone. After intradermal injection of Dex-Cy7 nanogel into the front paw of a mouse, the nanogels were able to migrate into the mouse's axillary lymph node, exhibiting longer retention time and higher fluorescence intensity in the node when compared to Cy7 alone. An immunohistofluorescence assay revealed that the nanogels were localized in the central region of lymph node and that the uptake was largely by the macrophages. In vitro and in vivo toxicity results indicated that the dextran based nanogels were of low cytotoxicity at a polymer concentration up to 1,000 MUg/mL and harmless to normal liver and kidney organs in mice at an intravenous dose of 1.25 mg/kg. The results of this study suggest that NIR-emitting polymeric nanogels based on bioreducible dextran-deoxycholic acid conjugates show high potential as fluorescence nanoprobes for safe and noninvasive SLN mapping. PMID- 25506218 TI - Immunoliposome co-delivery of bufalin and anti-CD40 antibody adjuvant induces synergetic therapeutic efficacy against melanoma. AB - Liposomes constitute one of the most popular nanocarriers for improving the delivery and efficacy of agents in cancer patients. The purpose of this study was to design and evaluate immunoliposome co-delivery of bufalin and anti-CD40 to induce synergetic therapeutic efficacy while eliminating systemic side effects. Bufalin liposomes (BFL) conjugated with anti-CD40 antibody (anti-CD40-BFL) showed enhanced cytotoxicity compared with bufalin alone. In a mouse B16 melanoma model, intravenous injection of anti-CD40-BFL achieved smaller tumor volume than did treatment with BFL (average: 117 mm(3) versus 270 mm(3), respectively); the enhanced therapeutic efficacy through a caspase-dependent pathway induced apoptosis, which was confirmed using terminal deoxynucleotidyl transferase mediated dUTP-Fluorescein nick end labeling and Western blot assay. Meanwhile, anti-CD40-BFL elicited unapparent body-weight changes and a significant reduction in serum levels of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interferon-gamma, and hepatic enzyme alanine transaminase, suggesting minimized systemic side effects. This may be attributed to the mechanism by which liposomes are retained within the tumor site for an extended period of time, which is supported by the following biodistribution and flow cytometric analyses. Taken together, the results demonstrated a highly promising strategy for liposomal vehicle transport of anti-CD40 plus bufalin that can be used to enhance antitumor effects via synergetic systemic immunity while blocking systemic toxicity. PMID- 25506219 TI - In vitro antioxidant activity and in vivo antifatigue effect of layered double hydroxide nanoparticles as delivery vehicles for folic acid. AB - Folic acid antioxidants were successfully intercalated into layered double hydroxides (LDH) nanoparticles according to a previous method with minor modification. The resultant folic acid-LDH constructs were then characterized by X-ray powder diffraction and transmission electron microscopy. The in vitro antioxidant activities, cytotoxicity effect, and in vivo antifatigue were examined by a series of assays. The results showed that folic acid-LDH antioxidant system can scavenge 1,1-diphenyl-2-picrylhydrazyl and hydroxyl free radicals and chelate pro-oxidative Cu(2+). The in vitro cytotoxicity assays indicated that folic acid-LDH antioxidant system had no significant cytotoxic effect or obvious toxicity to normal cells. It also prolonged the forced swimming time of the mice by 32% and 51% compared to folic acid and control groups, respectively. It had an obvious effect on decreasing the blood urea nitrogen and blood lactic acid, while increasing muscle and hepatic glycogen levels. Therefore, folic acid-LDH might be used as a novel antioxidant and antifatigue nutritional supplement. PMID- 25506220 TI - Increasing dependency of older people in nursing homes is associated with need for dental treatments. AB - To determine relationships between the need for dental treatments of institutionalized elderly people and cognitive impairment and the general level of care needed. Two hundred and sixty-eight residents of long-term care facilities in Germany were included in this study. Age, sex, diseases, number of frequently taken drugs, and location of the long-term care facility of the participants were recorded. For each participant, the need for care was assessed by use of the Barthel index (BI). Cognitive impairment was evaluated by use of the mini-mental state examination (MMSE). To assess dental treatment needs, the revised oral assessment guide (ROAG) was applied for different oral health conditions, which were rated "healthy" or "treatment needed". Spearman correlations were performed to evaluate associations between BI and MMSE and dental treatment needs. Statistical analysis revealed significant associations of BI (P<0.001) and MMSE (P=0.015) with the ROAG score. Increasing dependency and decreasing cognitive ability worsen oral health and increase the need for dental treatment. PMID- 25506221 TI - The clinical psychologist and the management of inpatient pain: a small case series. AB - Recent research has confirmed that between 25% and 33% of all hospitalized patients experience unacceptable levels of pain. Studies further indicate that this reduces patient satisfaction levels, lengthens hospital stays, and increases cost. Hospitals are aiming to discharge patients earlier, and this can interfere with adequate pain management. Therefore, the pain service at Chelsea and Westminster Hospital has adapted to this changing model of care. An increasing body of evidence demonstrates that psychological factors are key components of patients' pain experiences in both acute and chronic pain. Therefore, it is reasonable to suggest a clinical psychologist should be involved in inpatient pain management. This small study discusses three cases that highlight how patient care could be improved by including a clinical psychologist as part of the inpatient pain team. Two cases particularly highlight the active role of the psychologist in the diagnosis and management of common conditions such as fear and anxiety, along with other psychiatric comorbidities. The management therefore employed an eclectic approach adapted from chronic pain and comprising of behavioral, cognitive behavioral, and dialectical behavioral therapeutic techniques blended with brief counseling. The third case exemplifies the importance of nurse-patient interactions and the quality of nurse-patient relationships on patient outcomes. Here, the psychologist helped to optimize communication and to resolve a difficult and potentially risk-laden situation. This small case series discusses the benefits derived from the involvement of a clinical psychologist in the management of inpatient pain, and therefore illustrates the need for novel initiatives for inpatient pain services. However, future research is warranted to validate this approach. PMID- 25506222 TI - Complications of the endovascular management of acute ischemic stroke. AB - Acute ischemic stroke is a significant source of morbidity and mortality across the globe. Currently, the only US Food and Drug Administration approved medical treatment of acute ischemic stroke is intravascular (IV) alteplase. While IV thrombolysis has been shown to decrease morbidity and mortality from acute ischemic stroke, it is limited in both its efficacy in certain types of stroke, as well as in its generalizability. It has been shown that time to revascularization is one of the most important predictors of outcomes in acute ischemic stroke, and thus clinicians have turned to endovascular options in efforts to improve outcomes from stroke. Direct intra-arterial thrombolysis was one of the first of such efforts to improve efficacy rates and increase the timeline for thrombolytic therapy. More recently, investigators and clinicians have turned to newer endovascular options in attempts to further improve recanalization rates. Many different endovascular techniques have been employed and are growing exponentially in use. Examples include stenting, as well as mechanical thrombectomy with both older-generation devices and newer stent retrieval technology. While the majority of the literature focuses on the effectiveness of different techniques, such as recanalization rates and major overall outcomes such as death and disability, there is very little literature on the complications of the different techniques. The purpose of this article is to review the different forms of endovascular treatment of acute ischemic stroke and their associated complications. PMID- 25506223 TI - Doxorubicin-conjugated bacteriophages carrying anti-MHC class I chain-related A for targeted cancer therapy in vitro. AB - BACKGROUND: Cancer therapy by systemic administration of anticancer drugs, besides the effectiveness shown on cancer cells, demonstrated the side effects and cytotoxicity on normal cells. The targeted drug-carrying nanoparticles may decrease the required drug concentration at the site and the distribution of drugs to normal tissues. Overexpression of major histocompatibility complex class I chain-related A (MICA) in cancer is useful as a targeted molecule for the delivery of doxorubicin to MICA-expressing cell lines. METHODS: The application of 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide (EDC) chemistry was employed to conjugate the major coat protein of bacteriophages carrying anti-MICA and doxorubicin in a mildly acid condition. Doxorubicin (Dox) on phages was determined by double fluorescence of phage particles stained by M13-fluorescein isothiocyanate (FITC) and drug autofluorescence by flow cytometry. The ability of anti-MICA on phages to bind MICA after doxorubicin conjugation was evaluated by indirect enzyme-linked immunosorbent assay. One cervical cancer and four cholangiocarcinoma cell lines expressing MICA were used as models to evaluate targeting activity by cell cytotoxicity test. RESULTS: Flow cytometry and indirect enzyme-linked immunosorbent assay demonstrated that most of the phages (82%) could be conjugated with doxorubicin, and the Dox-carrying phage-displaying anti-MICA (Dox-phage) remained the binding activity against MICA. Dox-phage was more efficient than free drugs in killing all the cell lines tested. The half maximal inhibitory concentration (IC50) values of Dox-phage were lower than those of free drugs at approximately 1.6-6 times depending on MICA expressions and the cell lines tested. CONCLUSION: Evidently, the application of 1-ethyl-3-[3 dimethylaminopropyl] carbodiimide chemistry is effective to conjugate doxorubicin and major coat protein of bacteriophages without destroying binding activity of MICA antibodies. Dox-carrying bacteriophages targeting MICA have been successfully developed and may enable a broad range of applications in cancer targeting chemotherapy. PMID- 25506224 TI - EGF and EGFR genetic polymorphisms predict prognosis in locally advanced pharyngolaryngeal squamous cell carcinoma patients receiving postoperative concurrent chemoradiotherapy. AB - BACKGROUND: Epidermal growth factor (EGF) and its receptor (EGFR) are part of an important signaling pathway that is involved in the pathogenesis of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that EGF/EGFR genetic polymorphisms might have a prognostic impact on disease-free survival and overall survival (OS) in locally advanced SCCHN. MATERIALS AND METHODS: The patient group included a consecutive cohort of 180 patients with locally advanced SCCHN who underwent postoperative concurrent chemoradiotherapy between 2002 and 2010. DNA from formalin-fixed, paraffin-embedded tumor tissues was genotyped for the single nucleotide polymorphism (SNP) of EGF A61G A>G, EGFR R521K G>A and G-216T. The log rank test was applied to evaluate the impact of SNPs on the outcomes. Survival was estimated using the Kaplan-Meier statistical method. RESULTS: We demonstrated that EGF/EGFR SNPs might predict prognosis in patients with primary pharyngolaryngeal tumors, but not in those with oral cavity tumors. In pharyngolaryngeal tumor subgroup, EGF61 G/G genotype led to worse 5 year OS rate when compared to G/A or A/A genotypes (13.3% versus 34.3% versus 50.0%, P=0.017). The 5 year OS of patients with EGFR R521K G/G (11.1%) and G/A (15.9%) were lower than the A/A (62.5%) genotype (P=0.054). Patients carrying one or two unfavorable alleles had worse 5 year OS than those without unfavorable allele (not available versus 20% versus 71.4%, P=0.002). Multivariate analysis revealed that the highest risk of death was associated with the coexistence of two unfavorable genotypes (hazard ratio 25.7, 95% confidence interval =3.4-193.4; P=0.002). CONCLUSION: In this study, we were able to demonstrate that the EGF A61G and EGFR R521K genetic polymorphisms might be important prognostic factors in patients with locally advanced primary pharyngolaryngeal squamous cell carcinoma who underwent postoperative concurrent chemoradiotherapy. PMID- 25506225 TI - Role of urokinase plasminogen activator and plasminogen activator inhibitor mRNA expression as prognostic factors in molecular subtypes of breast cancer. AB - BACKGROUND: Protein levels of urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) determined by enzyme-linked immunosorbent assay from fresh frozen tumor tissue have been evaluated as prognostic factors in prospectively randomized trials in breast cancer. However, the role of uPA and PAI-1 in the context of breast cancer subtypes and for mRNA expression of these factors is less clear. METHODS: We evaluated uPA and PAI-1 mRNA expression using the Affymetrix HG-U 133A array within molecular subgroups of breast cancer in cohorts of patients with systemic treatment (cohort A, n=362) and without systemic treatment (cohort B, n=200). We validated mRNA expression in a cohort of HER2 positive breast cancer patients (cohort C, n=290). Luminal, triple-negative, and HER2-positive subcohorts were defined by ESR1 and ERBB2 mRNA expression using predefined cutoffs. RESULTS: In the entire cohort A, elevated PAI-1 but not uPA mRNA expression was associated with shorter disease-free survival (P=0.007 for PAI and 0.069 for uPA). Regarding different molecular subgroups, 67% (n=244) of tumors were luminal, 14% (n=49) were HER2-positive, and 19% (n=69) were triple negative. Elevated PAI-1 mRNA expression was associated with shorter disease-free survival only in the HER2-positive subgroup (P=0.031). The same disease-free survival results were found for uPA in HER2-positive patients (P=0.011). In contrast, no association between either marker and survival was observed in the luminal or triple-negative subgroups. In the HER2-positive validation cohort C, elevated uPA and PAI-1 mRNA expression also showed strong associations with shorter disease-free survival (P=0.014 for PAI-1, P<0.001 for uPA). CONCLUSION: In this study, the prognostic impact of uPA and PAI-1 expression was mainly observed in patients with HER2-positive tumors. PMID- 25506226 TI - Microtubule inhibitor-based antibody-drug conjugates for cancer therapy. AB - The specificity of monoclonal antibodies represents a potential therapeutic advantage, but their use as single agents in oncology has proven limited to date. The development of antibody-drug conjugates (ADCs) takes advantage of the specificity of the monoclonal antibody and potent cytotoxic effect of chemotherapy, leading to enhanced cytotoxicity in target cells and limiting toxicity to normal tissue. Microtubules represent a validated oncologic target in a range of tumor types, with a number of anti-microtubule targeting cytotoxic drugs approved for cancer use. The systemic use of potent microtubule-binding agents is limited by their effects in normal cells, which leads to toxicity including myelosuppression and peripheral neuropathy. Linking these agents to monoclonal antibodies may limit toxicity to normal tissues and increase drug concentration in target tissues, also allowing the use of more potent agents which would be too toxic to administer in their unbound form. Two such ADCs have been approved for clinical use and many others are in development. Here we review the characteristics of each of the ADC components that have led to efficacious therapies and discuss some of the tubulin inhibitor-based ADCs in development for cancer therapy. PMID- 25506227 TI - Angiogenesis and antiangiogenic agents in cervical cancer. AB - Standard treatment of cervical cancer (CC) consists of surgery in the early stages and of chemoradiation in locally advanced disease. Metastatic CC has a poor prognosis and is usually treated with palliative platinum-based chemotherapy. Current chemotherapeutic regimens are associated with significant adverse effects and only limited activity, making identification of active and tolerable novel targeted agents a high priority. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer. The dominant role of angiogenesis in CC seems to be directly related to human papillomavirus-related inhibition of p53 and stabilization of hypoxia-inducible factor-1alpha. Both of these mechanisms are able to increase expression of vascular endothelial growth factor (VEGF). Activation of VEGF promotes endothelial cell proliferation and migration, favoring formation of new blood vessels and increasing permeability of existing blood vessels. Since bevacizumab, a recombinant humanized monoclonal antibody binding to all isoforms of VEGF, has been demonstrated to significantly improve survival in gynecologic cancer, some recent clinical research has explored the possibility of using novel therapies directed toward inhibition of angiogenesis in CC too. Here we review the main results from studies concerning the use of antiangiogenic drugs that are being investigated for the treatment of CC. PMID- 25506230 TI - Rituximab therapy in a patient with low grade B-cell lymphoproliferative disease and concomitant acquired angioedema. AB - Acquired angioedema is often associated with significant morbidity. An underlying lymphatic malignancy, autoimmune disorder, adenocarcinoma, or other malignancy may be present. Screening for these disorders should occur in all patients with acquired angioedema as treatment may result in resolution of angioedema. PMID- 25506228 TI - From regenerative dentistry to regenerative medicine: progress, challenges, and potential applications of oral stem cells. AB - Adult mesenchymal stem cells (MSCs) and epithelial stem cells play essential roles in tissue repair and self-healing. Oral MSCs and epithelial stem cells can be isolated from adult human oral tissues, for example, teeth, periodontal ligament, and gingiva. Cocultivated adult oral epithelial stem cells and MSCs could represent some developmental events, such as epithelial invagination and tubular structure formation, signifying their potentials for tissue regeneration. Oral epithelial stem cells have been used in regenerative medicine over 1 decade. They are able to form a stratified cell sheet under three-dimensional culture conditions. Both experimental and clinical data indicate that the cell sheets can not only safely and effectively reconstruct the damaged cornea in humans, but also repair esophageal ulcer in animal models. Oral MSCs include dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHED), stem cells from apical papilla (SCAP), periodontal ligament stem cells (PDLSCs), and mesenchymal stem cells from gingiva (GMSCs). They are widely applied in both regenerative dentistry and medicine. DPSCs, SHED, and SCAP are able to form dentin-pulp complex when being transplanted into immunodeficient animals. They have been experimentally used for the regeneration of dental pulp, neuron, bone muscle and blood vessels in animal models and have shown promising results. PDLSCs and GMSCs are demonstrated to be ideal cell sources for repairing the damaged tissues of periodontal, muscle, and tendon. Despite the abovementioned applications of oral stem cells, only a few human clinical trials are now underway to use them for the treatment of certain diseases. Since clinical use is the end goal, their true regenerative power and safety need to be further examined. PMID- 25506229 TI - Some aspects of allogeneic stem cell transplantation in patients with myelodysplastic syndrome: advances and controversy. AB - Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid disorders. MDS remains a disease of elderly patients; moreover, the incidence of high risk MDS is proportionally greater in elderly patients, with increased frequency of secondary acute myeloid leukemia, as well as adverse cytogenetic abnormalities. Allogeneic stem cell transplantation is a therapeutic approach with known curative potential for patients with MDS that allows the achievement of long-term disease control. Numerous controversies still exist regarding transplantation in MDS: timing of transplantation, disease status at transplantation and comorbidity, conditioning intensity, pretransplant therapy, and stem cell source. Various transplant modalities of different intensities and alternative donor sources are now in use. Current advances in transplant technology are allowing the consideration of older patients. This should result in a greater number of older patients benefiting from this potentially curative treatment modality. Despite advances in transplantation technology, there is still considerable morbidity and mortality associated with this approach. Nevertheless, with the introduction of reduced-intensity conditioning and thereby reduced early mortality, transplant numbers in MDS patients have significantly increased. Moreover, recent new developments with innovative drugs, including hypomethylating agents, have extended the therapeutic alternatives for MDS patients. Hypomethylating agents allow the delay of allogeneic stem cell transplantation by serving as an effective and well-tolerated means to reduce disease burden. PMID- 25506231 TI - Seriousness, preventability, and burden impact of reported adverse drug reactions in Lombardy emergency departments: a retrospective 2-year characterization. AB - OBJECTIVE: The purpose of this study was to determine the prevalence of adverse drug reactions (ADRs) reported in emergency departments (EDs) and carry out a thorough characterization of these to assess preventability, seriousness that required hospitalization, subsequent 30-day mortality, and economic burden. METHODS: This was a retrospective cohort study of data from an active pharmacovigilance project at 32 EDs in the Lombardy region collected between January 1, 2010 and December 31, 2011. Demographic, clinical, and pharmacological data on patients admitted to EDs were collected by trained and qualified monitors, and deterministic record linkage was performed to estimate hospitalizations. Pharmacoeconomic analyses were based on Diagnosis-Related Group reimbursement. RESULTS: 8,862 ADRs collected with an overall prevalence rate of 3.5 per 1,000 visits. Of all ADRs, 42% were probably/definitely preventable and 46.4% were serious, 15% required hospitalization, and 1.5% resulted in death. The System Organ Classes most frequently associated with ADRs were: skin and subcutaneous tissue, gastrointestinal, respiratory thoracic and mediastinal, and nervous system disorders. The most common Anatomical Therapeutic Chemical classes involved in admissions were J (anti-infectives and immunomodulating agents), B (blood and blood-forming organs), and N (nervous system). Older age, yellow and red triage, higher number of concomitantly taken drugs, and previous attendance in ED for the same ADR were significantly associated with an increased risk of hospitalization. The total cost associated with ADR management was ?5,184,270, with a mean cost per patient of ?585. Fifty-eight percent of the economic burden was defined as probably/definitely preventable. CONCLUSION: ADRs are a serious health/economic issue in EDs. This assessment provides a thorough estimation of their seriousness, preventability, and burden impact in a large population from a representative European region. PMID- 25506232 TI - Level, pattern, and determinants of polypharmacy and inappropriate use of medications by village doctors in a rural area of Bangladesh. AB - OBJECTIVE: Village doctors, informal health care providers practicing modern medicine, are dominant health care providers in rural Bangladesh. Given their role, it is important to examine their prescription pattern and inappropriate use of medication. METHODS: These cross-sectional study data were collected through surveys of patients seen by village doctors during 2008 and 2010 at Chakaria, a typical rural area of Bangladesh. Categorization of appropriate, inappropriate, and harmful prescriptions by disease conditions was based on guidelines defined by the World Health Organization (WHO), the United Nations Children's Fund (UNICEF), and the Government of Bangladesh. Analytical categorization of polypharmacy was defined when five or more medications were prescribed for a patient at a single visit. FINDINGS: A total of 2,587 prescriptions were written by village doctors during the survey periods. Among the prescriptions were appropriate (10%), inappropriate (8%), combination of appropriate and inappropriate (63%), and harmful medications (19%). Village doctors with more than high school education were 53% less likely (odds ratio [OR]: 0.47, 95% confidence interval [CI]: 0.26-0.86) to give polypharmacy prescriptions than those with less than high school education. While exploring determinants of prescribing inappropriate and harmful medications, this study found that polypharmacy prescriptions were six times more likely [OR: 6.00, 95% CI: 3.88 9.29] to have harmful medications than prescriptions with <5 medications. CONCLUSION: Village doctors' training and supervision may improve the quality of services and establish accountability for the benefit of the rural population. PMID- 25506234 TI - Mechanism linking diabetes mellitus and obesity. AB - Body mass index has a strong relationship to diabetes and insulin resistance. In obese individuals, the amount of nonesterified fatty acids, glycerol, hormones, cytokines, proinflammatory markers, and other substances that are involved in the development of insulin resistance, is increased. The pathogenesis in the development of diabetes is based on the fact that the beta-islet cells of the pancreas are impaired, causing a lack of control of blood glucose. The development of diabetes becomes more inevitable if the failure of beta-islet cells of the pancreas is accompanied by insulin resistance. Weight gain and body mass are central to the formation and rising incidence of type 1 and type 2 diabetes. This literature review will demonstrate the facts that link obesity with insulin resistance and pancreatic beta-cell dysfunction. In conclusion, new approaches in managing and preventing diabetes in obese individuals must be studied and investigated based on the facts. PMID- 25506233 TI - Different strategies and cost-effectiveness in the treatment of primary open angle glaucoma. AB - Glaucoma is the second highest cause of blindness worldwide with an estimated half of the glaucoma population unaware of their disease. To date, intraocular pressure is the most important modifiable risk factor and lowering it has been proven to reduce progression of visual field loss associated with glaucoma. Different strategies are available to lower intraocular pressure and include medical, laser, or surgical treatment in the form of topical or systemic medications, argon or selective laser trabeculoplasty, and glaucoma drainage surgery such as trabeculectomy, deep sclerectomy, or other drainage devices. The effectiveness of these treatments has been well documented however their cost effectiveness between the developed world and third world remains unclear. PMID- 25506235 TI - Inhibiting TNF-alpha signaling does not attenuate induction of endotoxin tolerance. AB - Tumor necrosis factor-alpha (TNF-alpha) is a central mediator of inflammatory responses elicited by Toll-like receptor agonists, such as the Gram-negative bacterial outer membrane antigen lipopolysaccharide (LPS). TNF-alpha is responsible for altering vascular permeability and activating infiltrating inflammatory cells, such as monocytes and neutrophils. Interestingly, TNF-alpha has also demonstrated the ability to induce tolerance to subsequent challenges with TNF-alpha or LPS in monocyte and macrophage cell populations. Tolerance is characterized by the inability to mount a typical inflammatory response during subsequent challenges following the initial exposure to an inflammatory mediator such as LPS. The ability of TNF-alpha to induce a tolerant-like state with regard to LPS is most likely a regulatory mechanism to prevent excessive inflammation. We hypothesized that the induction of tolerance or the degree of tolerance is dependent upon the production of TNF-alpha during the primary response to LPS. To investigate TNF-alpha-dependent tolerance, human monocytic THP-1 cells were treated with TNF-alpha-neutralizing antibodies or antagonistic TNF-alpha receptor antibodies before primary LPS stimulation and then monitored for the production of TNF-alpha during the primary and challenge stimulation. During the primary stimulation, anti-TNF-alpha treatment effectively attenuated the production of TNF-alpha and interleukin-1beta; however, this reduced production did not impact the induction of endotoxin tolerance. These results demonstrate that interfering with TNF-alpha signaling attenuates production of inflammatory cytokines without affecting the induction of tolerance. PMID- 25506236 TI - New insights into the genetic basis of infertility. AB - Infertility is a disease of the reproductive system characterized by inability to achieve pregnancy after 12 or more months of regular unprotected sexual intercourse. A variety of factors, including ovulation defects, spermatogenic failure, parental age, obesity, and infections have been linked with infertility, in addition to specific karyotypes and genotypes. The study of genes associated with infertility in rodent models has expanded the field of translational genetics in identifying the underlying cause of human infertility problems. Many intriguing aspects of the molecular basis of infertility in humans remain poorly understood; however, application of genetic knowledge in this field looks promising. The growing literature on the genetics of human infertility disorders deserves attention and a critical concise summary is required. This paper provides information obtained from a systematic analysis of the literature related to current research into the genetics of infertility affecting both sexes. PMID- 25506239 TI - Analysis of the presence or absence of atrophy of the subgenual and subcallosal cingulate cortices using voxel-based morphometry on MRI is useful to select prescriptions for patients with depressive symptoms. AB - OBJECTIVE: We objectively evaluated the presence or absence of atrophy of the subgenual anterior cingulate cortex (sgACC) and the subcallosal anterior cingulate cortex (scACC), using new voxel-based morphometry (VBM) software employing Statistical Parametric Mapping software v8 and diffeomorphic anatomic registration through an exponentiated lie algebra. We prepared a database covering young-mature adulthood and investigated the clinical usefulness of the evaluation. SUBJECTS AND METHODS: One hundred seven patients with major depressive disorder (MDD), 74 patients with bipolar disorder (BD), and 240 healthy control subjects underwent 1.5T magnetic resonance imaging scanning. Using new VBM software and databases covering young-mature adults and the elderly, target volumes of interest were set in the sgACC and scACC, four indicators (severity, extent, ratio, and whole-brain extent) were determined, and the presence or absence of atrophy of the sgACC and scACC was evaluated on the basis of the indicators. In addition, the relationships between the presence or absence of atrophy of the sgACC and scACC and performance of diagnosing MDD and BD and therapeutic drugs were investigated. RESULTS: It was clarified that the disease is likely to be MDD when atrophy is detected in the sgACC, and likely to be BD when no atrophy is detected in the sgACC but is detected in the scACC. Regarding the relationship with therapeutic drugs, it was clarified that, when atrophy is detected in both the sgACC and the scACC, concomitant administration of mood stabilizers and atypical antipsychotics acting as dopamine-system stabilizers is necessary in many cases. CONCLUSION: VBM on magnetic resonance imaging enabled automatic analysis of atrophy in the sgACC and scACC, and findings obtained by this procedure are useful not only for differentiation of MDD and BD patients but also for selection of prescriptions. PMID- 25506237 TI - Splicing modulation therapy in the treatment of genetic diseases. AB - Antisense-mediated splicing modulation is a tool that can be exploited in several ways to provide a potential therapy for rare genetic diseases. This approach is currently being tested in clinical trials for Duchenne muscular dystrophy and spinal muscular atrophy. The present review outlines the versatility of the approach to correct cryptic splicing, modulate alternative splicing, restore the open reading frame, and induce protein knockdown, providing examples of each. Finally, we outline a possible path forward toward the clinical application of this approach for a wide variety of inherited rare diseases. PMID- 25506238 TI - Evaluating the benefits of home-based peritoneal dialysis. AB - Peritoneal dialysis (PD) is an effective renal replacement strategy for patients suffering from end-stage renal disease. PD offers patient survival comparable to or better than in-center hemodialysis while preserving residual kidney function, empowering patient autonomy, and reducing financial burden to payors. The majority of patients suffering from kidney failure are eligible for PD. In patients with cardiorenal syndrome and uncontrolled fluid status, PD is of particular benefit, decreasing hospitalization rates and duration. This review discusses the benefits of chronic PD, performed by the patient or a caregiver at home. Recognition of the benefits of PD is a cornerstone in stimulating the use of this treatment strategy. PMID- 25506240 TI - Effect of acetylsalicylic acid on thalassemia with pulmonary arterial hypertension. AB - OBJECTIVE: To compare pulmonary artery systolic pressure (PASP) between thalassemic patients with pulmonary arterial hypertension (PAH) for whom acetylsalicylic acid (ASA) was and was not prescribed after 1 year. METHODS: A retrospective cohort study was conducted at the hematological outpatient clinic at Chiang Rai Hospital, Chiang Rai, Thailand. All new cases of thalassemia with PAH from January 2007 to January 2012 were studied at the first month and at 12 months. The patients were classified into two groups. In one group, ASA 81 mg daily was prescribed for 1 year, whereas in another group no ASA was prescribed, due to its contraindications, which included bleeding, gastrointestinal side effects, and thrombocytopenia. PASP, estimated by a Doppler echocardiography, was measured by the same cardiologist. Propensity score adjustment was used to control confounding variables by indication and contraindication. Multivariable regression analysis was used to evaluate the effects of ASA. RESULTS: Of the 63 thalassemia patients with PAH, there were 47 (74.6%) in the ASA group and 16 (25.4%) in the no ASA group. ASA, as compared with no ASA, did not significantly reduce PASP (adjusted difference -0.95; 95% confidence interval -16.99 to 15.10; P=0.906). CONCLUSION: Low-dose ASA may not have a beneficial effect on PASP after 1 year of treatment of PAH in thalassemia. PMID- 25506241 TI - Effects and tolerability of betahistine in patients with vestibular vertigo: results from the Romanian contingent of the OSVaLD study. AB - BACKGROUND AND METHODS: An efficacy population of 245 patients with vertigo of peripheral vestibular origin was recruited in Romania as part of a 3-month multinational, post-marketing surveillance study of open-label betahistine 48 mg/day (OSVaLD). Endpoints were changes in the Dizziness Handicap Index (primary endpoint), Medical Outcome Study Short-Form 36 (SF-36v2((r))), and the Hospital Anxiety and Depression Scale. RESULTS: During treatment, the total Dizziness Handicap Index score improved by 41 points (on a 100-point scale). Statistically significant improvements of 12-14 points were recorded in all three domains of the Dizziness Handicap Index scale (P<0.0001). Betahistine therapy was also accompanied by progressive improvements in mean Hospital Anxiety and Depression anxiety and depression scores (P<0.0001) and significant improvements in both the physical and mental component summary of the SF-36v2 (P<0.0001). Betahistine was well tolerated, with only one suspected adverse drug reaction recorded in the Romanian safety population (n=259). CONCLUSION: Betahistine 48 mg/day was associated with improvements in multiple measures of health-related quality of life and had a good tolerability profile in these Romanian patients with recurrent peripheral vestibular vertigo. PMID- 25506244 TI - Survival benefit of adjuvant radiotherapy in stage III and IV bladder cancer: results of 170 patients. AB - BACKGROUND: Radical cystectomy (RC) with or without neoadjuvant chemotherapy is the standard treatment for muscle-invasive bladder cancers. However, the locoregional recurrence rate is still significantly higher for locally advanced cases post-RC. The underuse of postoperative radiotherapy (PORT) in such cases after RC is related mainly to a lack of proven survival benefit. Here we are reporting our long-term Egyptian experience with bladder cancer patients treated with up-front RC with or without conformal PORT. PATIENTS AND METHODS: This retrospective study included 170 locally advanced bladder cancer (T3-T4, N0/N1, M0) patients who had RC performed with or without PORT at Damietta Cancer Institute during the period of 1998-2006. The treatment outcomes and toxicity profile of PORT were evaluated and compared with those of a non-PORT group of patients. RESULTS: Ninety-two patients received PORT; 78 did not. At median follow-up of 47 months (range, 17-77 months), 33% locoregional recurrences were seen in the PORT group versus 55% in the non-PORT group (P<0.001). The overall distant metastasis rate in the whole group was 39%, with no difference between the two groups. The 5-year disease-free survival for the whole group of patients was 53%+/-11%, which was significantly affected by additional PORT, and 65%+/-13% compared with 40%+/-9% for the non-PORT group (P=0.04). The pathological subtypes did not affect 5-year disease-free survival significantly (P=0.9). The 5-year overall survival was 44%+/-10%. Using multivariate analysis, PORT, stage, and extravesical extension (positive surgical margins) were found to be important prognostic factors for locoregional control. Stage and lymph node status were important prognosticators for distant metastasis control. CONCLUSION: PORT was found to be a safe and effective tool in decreasing local recurrence rates and improving disease-free survival. PMID- 25506242 TI - Provocative diskography: safety and predictive value in the outcome of spinal fusion or pain intervention for chronic low-back pain. AB - There is still no clear definition of diskogenic low-back pain and no consensus on a generally agreed test, such as provocative diskography (PD), to diagnose painful disk degeneration, and probably more importantly, to predict the outcome of therapy intended to reduce pain that is presumed to be diskogenic in nature. Nevertheless, PD is the most specific procedure to diagnose diskogenic low-back pain. Its accuracy, however, is rather low or at best unknown. Although rare, the most prevalent complication, postdiskography diskitis, can be devastating for the individual patient, so all measures, like strict sterile conditions and antibiotic prophylaxis, should be taken to avoid this complication. It is advised to perform the procedure in a pressure-controlled way with a constant low flow, and optionally computed tomography imaging. PD should not be performed in morphologically normal disks. A standardized execution of the test should be established in order to perform high-quality studies to determine its accuracy to lead to meaningful interventions, and find best practices for diagnosis and treatment of diskogenic back pain. Possibly, PD may have detrimental effects on the disk, causing early degeneration, although it is unknown whether this will be related to clinical symptoms. Especially with these possible adverse side effects in mind, the risk-benefit ratio with the lack of clear benefits from treatments provided, and possible complications of disk puncture, the rationale for PD is questionable, which should be stressed to patients in the process of shared decision making. Diskography as a stand-alone test is not recommended in clinical decision making for patients with chronic low-back pain. PMID- 25506245 TI - Aspirin overutilization for the primary prevention of cardiovascular disease. AB - BACKGROUND: Aspirin is commonly used for the primary prevention of cardiovascular disease (CVD) in the US. Previous research has observed significant levels of inappropriate aspirin use for primary CVD prevention in some European populations, but the degree to which aspirin is overutilized in the US remains unknown. This study examined the association between regular aspirin use and demographic/clinical factors in a population-based sample of adults without a clinical indication for aspirin for primary prevention. METHODS: A cross sectional analysis was performed using 2010-2012 data from individuals aged 30-79 years in the Marshfield Epidemiologic Study Area (WI, USA). Regular aspirin users included those who took aspirin at least every other day. RESULTS: There were 16,922 individuals who were not clinically indicated for aspirin therapy for primary CVD prevention. Of these, 19% were regular aspirin users. In the final adjusted model, participants who were older, male, lived in northern Wisconsin, had more frequent medical visits, and had greater body mass index had significantly higher odds of regular aspirin use (P<0.001 for all). Race/ethnicity, health insurance, smoking, blood pressure, and lipid levels had negligible influence on aspirin use. A sensitivity analysis found a significant interaction between age and number of medical visits, indicating progressively more aspirin use in older age groups who visited their provider frequently. CONCLUSION: There was evidence of aspirin overutilization in this US population without CVD. Older age and more frequent provider visits were the strongest predictors of inappropriate aspirin use. Obesity was the only significant clinical factor, suggesting misalignment between perceived aspirin benefits and cardiovascular risks in this subgroup of patients. Prospective studies that examine cardiac and bleeding events associated with regular aspirin use among obese samples (without CVD) are needed to refine clinical guidelines in this area. PMID- 25506243 TI - Proinflammatory cytokines and DHEA-S in women with fibromyalgia: impact of psychological distress and menopausal status. AB - Though fibromyalgia is not traditionally considered an inflammatory disorder, evidence for elevated inflammatory processes has been noted in this disorder in multiple studies. Support for inflammatory markers in fibromyalgia has been somewhat equivocal to date, potentially due to inattention to salient patient characteristics that may affect inflammation, such as psychiatric distress and aging milestones like menopause. The current study examined the relationships between proinflammatory cytokines and hormone levels, pain intensity, and psychological distress in a sample of 34 premenopausal and postmenopausal women with fibromyalgia. Our results indicated significant relationships between interleukin-8 and ratings of pain catastrophizing (r=0.555, P<0.05), pain anxiety (r=0.559, P<0.05), and depression (r=0.551, P<0.05) for postmenopausal women but not premenopausal women (r,0.20 in all cases). Consistent with previous studies, ratios of interleukin-6 to interleukin-10 were significantly lower in individuals with greater levels of depressive symptoms (r=-0.239, P<0.05). Contrary to previous research, however, dehydroepiandrosterone sulfate did not correlate with pain intensity or psychological or biological variables. The results of the current study highlight the importance of psychological functioning and milestones of aging in the examination of inflammatory processes in fibromyalgia. PMID- 25506246 TI - Self-reported health following percutaneous coronary intervention: results from a cohort followed for 3 years with multiple measurements. AB - OBJECTIVE: Improvements in the treatment of coronary heart disease have increased the number of patients living with a chronic heart disease. Patient-reported outcomes are required to adequately describe prognosis. We report self-rated health in a population-based cohort of patients with coronary heart disease treated with percutaneous coronary intervention (PCI). METHODS: Over 3 years, we followed 1,726 patients under 65 years treated with PCI with eight repetitive questionnaires. With the use of multiple imputation, we described the course of self-rated health using the short form 12-item survey's mental component summary (MCS) and physical component summary (PCS) and analyzed adjusted differences by sex, age, educational level, indication for PCI, and left ventricular ejection fraction along with an analysis of decrease in health status. RESULTS: MCS scores increased during follow-up, while PCS scores were stable over time. Men rated higher in MCS and PCS than women, and older patients rated higher in MCS than younger. Other differences were negligible. Younger age was identified as a risk factor for marked decrease in mental health over time. CONCLUSION: In a complete population-based cohort of PCI patients with multiple measurements, we found improvements in mental, but not physical health over time. Demographic differences in health were larger than disease-related differences. PMID- 25506248 TI - Minimally invasive veneers: current state of the art. AB - Ceramic veneers are considered a conservative solution for patients requiring improvement of the shape, color, or position of their anterior teeth. Ceramic veneers have been extensively and successfully used to mask intrinsic staining, to give the appearance of straightening, and to correct minor malformations of anterior teeth without the removal of substantial amounts of sound tooth substance. The current literature was reviewed to search for the most important parameters determining the long-term success and correct application of ceramic veneers. PMID- 25506247 TI - Bias in identification of the best treatment in a Bayesian network meta-analysis for binary outcome: a simulation study. AB - Network meta-analysis (NMA) has emerged as a useful analytical tool allowing comparison of multiple treatments based on direct and indirect evidence. Commonly, a hierarchical Bayesian NMA model is used, which allows rank probabilities (the probability that each treatment is best, second best, and so on) to be calculated for decision making. However, the statistical properties of rank probabilities are not well understood. This study investigates how rank probabilities are affected by various factors such as unequal number of studies per comparison in the network, the sample size of individual studies, the network configuration, and effect sizes between treatments. In order to explore these factors, a simulation study of four treatments (three equally effective treatments and one less effective reference) was conducted. The simulation illustrated that estimates of rank probabilities are highly sensitive to both the number of studies per comparison and the overall network configuration. An unequal number of studies per comparison resulted in biased estimates of treatment rank probabilities for every network considered. The rank probability for the treatment that was included in the fewest number of studies was biased upward. Conversely, the rank of the treatment included in the most number of studies was consistently underestimated. When the simulation was altered to include three equally effective treatments and one superior treatment, the hierarchical Bayesian NMA model correctly identified the most effective treatment, regardless of all factors varied. The results of this study offer important insight into the ability of NMA models to rank treatments accurately under several scenarios. The authors recommend that health researchers use rank probabilities cautiously in making important decisions. PMID- 25506249 TI - Does the presence of coexisting diseases modulate the effectiveness of a low-dose estrogen/progestin, ethinylestradiol/drospirenone combination tablet in dysmenorrhea? Reanalysis of two randomized studies in Japanese women. AB - BACKGROUND: The purpose of this study was to investigate the effectiveness of a combination of ethinylestradiol (EE) and 0.02 mg/drospirenone (DRSP) 3 mg in Japanese women with dysmenorrhea and in particular to determine whether or not the presence of specific coexisting organic diseases (eg, endometriosis, uterine fibroids, uterine adenomyosis) has an impact on treatment. METHODS AND RESULTS: Four hundred and ten patients with dysmenorrhea aged 20 years or older (315 without coexisting organic disease, 28 with endometriosis, 37 with uterine fibroids, and 46 with uterine adenomyosis [some patients had multiple coexisting organic diseases]) were enrolled and treated with EE/DRSP in either a 16-week comparator study or a 52-week long-term safety study. Evaluations included changes in total dysmenorrhea score, visual analog scale for dysmenorrhea, severity of symptoms, hormone levels, endometrial thickness, and safety outcomes. In both studies, the total dysmenorrhea score was significantly (P<0.001) decreased from baseline during treatment with EE/DRSP. Time-dependent changes in visual analog score for dysmenorrhea and alleviation of symptoms, such as lower abdominal pain, low back pain (lumbago), headache, and nausea/vomiting, were similar in all patient groups with and without any specific coexisting organic diseases. These improvements with EE/DRSP were observed for both short-term (16 weeks) and long-term (52 weeks) use. These effects were associated with suppressed increases in serum estradiol and progesterone levels and decreased endometrial thickness. The safety profile of EE/DRSP was similar in all patients, irrespective of the presence of coexisting organic diseases. CONCLUSION: EE/DRSP may be prescribed for patients with dysmenorrhea irrespective of the presence of any specific coexisting organic diseases. PMID- 25506250 TI - Enantiomer-selective pharmacokinetics, oral bioavailability, and sex effects of various alpha-lipoic acid dosage forms. AB - The present study aimed to examine the enantiomer-selective pharmacokinetics (PK), relative bioavailability (Frel), and sex effects of various oral dosage forms of racemic alpha-lipoic acid (ALA). In an open-label, randomized, four period, four-sequence crossover study, 24 healthy adult subjects (12 males and 12 females) received single doses of 600 mg of ALA in fasted state at four different occasions as follows: three 200 mg tablets (T 200); two 300 mg tablets (T 300); one 600 mg tablet (T 600); and a racemic ALA solution (OS). All tablet formulations (Thioctacid HR) were considered test treatments, while the OS (Thioctacid, 600 T) served as the reference treatment. Serial blood samples were collected over 8 hours postdose to quantify R-(+)- and S-(-)-ALA enantiomer plasma concentrations for the PK evaluation. The maximum observed plasma concentration (Cmax) and total exposure (area under the curve [AUC]0-t) were compared between treatments by analysis of variance. Weight-normalized Cmax and the AUC data of male and female study subjects were applied to examine the presence of sex effects. All treatments displayed rapid absorption of both enantiomers with median time to maximum concentration (tmax) values ranging from 0.33-0.5 hours. The Frel of all tablet formulations was comparable, with R-(+) enantiomer Cmax test/reference ratios ranging from 36% (T 600) to 43% (T 200), and R-(+)-enantiomer AUC test/reference ratios ranging from 64% (T 600) to 79% (T 300), indicating a favorable Frel of all tablet formulations, especially in terms of the total extent of absorption (AUC). An examination of weight-normalized female/male Cmax and AUC sex ratios for both ALA enantiomers indicated the absence of a significant sex effect for Cmax, as well as 20%-26% and 25%-32% higher R-(+)- and S-(-)-ALA enantiomer AUC outcomes in females when compared to males. The observed modest sex effect was comparable for both ALA enantiomers and across all formulations, and it did not appear to require a dose adjustment in clinical practice. PMID- 25506252 TI - Inpatient hospital costs and length of stay for the treatment of affective and somatoform disorders - evidence from Germany. AB - INTRODUCTION: Diagnosis related costs analyses are the subject of science and research and are of great relevance and importance for decision makers in the hospital and for funding bodies, but also for international health policy. Up to now, standardized costs analyses with valid costs data have not been available for inpatient care of patients with affective and somatoform disorders. BACKGROUND: This clinical picture presents a major challenge for the provision of outpatient and inpatient care. An interdisciplinary approach in an inpatient setting can be beneficial for already "chronified" patients with severe forms of progression. Because of its structural and procedural demands, this type of care is associated with a greater expenditure of resources. METHODS: Costs data from the years 2008 to 2012 were analyzed for a total of 17,424 hospitalized patients in more than 200 different hospitals in Germany. The study compared the costs of treating patients with the main diagnosis affective and somatoform disorders using standardized interdisciplinary therapy, with the costs of conventional therapy. RESULTS: Interdisciplinary patient care is characterized by a high proportion of the costs derived from the structural and procedural implementation and the medical and nursing care. For interdisciplinary therapy with a mean period of hospitalization of 15.2 days, over 60% of the total costs were incurred by the personnel and material costs of the medical and non-medical infrastructure. The outlay is considerably greater than would be incurred by a conventional therapeutic approach without interdisciplinary therapy. DISCUSSION AND CONCLUSION: For the first time, detailed diagnosis-related costs data are published which were generated by consistent, standardized cost unit accounting. An interdisciplinary, holistic approach to the clinical picture results in a significant increase in costs for the hospitals. PMID- 25506251 TI - Metabolic syndrome in chronic hepatitis C infection: does it still matter in the era of directly acting antiviral therapy? AB - Metabolic syndrome is prevalent in patients with hepatitis C virus (HCV) infection. Given the pandemic spread of HCV infection and metabolic syndrome, the burden of their interaction is a major public health issue. The presence of metabolic syndrome accelerates the progression of liver disease in patients with HCV infection. New drug development in HCV has seen an unprecedented rise in the last year, which resulted in better efficacy, better tolerance, and a shorter treatment duration. This review describes the underlying mechanisms and clinical effects of metabolic syndrome in HCV infection, as well as their importance in the era of new directly acting antiviral therapy. PMID- 25506253 TI - Pulsing blue light through closed eyelids: effects on acute melatonin suppression and phase shifting of dim light melatonin onset. AB - Circadian rhythm disturbances parallel the increased prevalence of sleep disorders in older adults. Light therapies that specifically target regulation of the circadian system in principle could be used to treat sleep disorders in this population. Current recommendations for light treatment require the patients to sit in front of a bright light box for at least 1 hour daily, perhaps limiting their willingness to comply. Light applied through closed eyelids during sleep might not only be efficacious for changing circadian phase but also lead to better compliance because patients would receive light treatment while sleeping. Reported here are the results of two studies investigating the impact of a train of 480 nm (blue) light pulses presented to the retina through closed eyelids on melatonin suppression (laboratory study) and on delaying circadian phase (field study). Both studies employed a sleep mask that provided narrowband blue light pulses of 2-second duration every 30 seconds from arrays of light-emitting diodes. The results of the laboratory study demonstrated that the blue light pulses significantly suppressed melatonin by an amount similar to that previously shown in the same protocol at half the frequency (ie, one 2-second pulse every minute for 1 hour). The results of the field study demonstrated that blue light pulses given early in the sleep episode significantly delayed circadian phase in older adults; these results are the first to demonstrate the efficacy and practicality of light treatment by a sleep mask aimed at adjusting circadian phase in a home setting. PMID- 25506255 TI - Developing a Measure of Traffic Calming Associated with Elementary School Students' Active Transport. AB - The objective of this study is to develop a measure of traffic calming with nationally available GIS data from NAVTEQ and to validate the traffic calming index with the percentage of children reported by school administrators as walking or biking to school, using data from a nationally representative sample of elementary schools in 2006-2010. Specific models, with and without correlated errors, examined associations of objective GIS measures of the built environment, nationally available from NAVTEQ, with the latent construct of traffic calming. The best fit model for the latent traffic calming construct was determined to be a five factor model including objective measures of intersection density, count of medians/dividers, count of low mobility streets, count of roundabouts, and count of on-street parking availability, with no correlated errors among items. This construct also proved to be a good fit for the full measurement model when the outcome measure of percentage of students walking or biking to school was added to the model. The traffic calming measure was strongly, significantly, and positively correlated with the percentage of students reported as walking or biking to school. Applicability of results to public health and transportation policies and practices are discussed. PMID- 25506256 TI - Strong rules for discarding predictors in lasso-type problems. AB - We consider rules for discarding predictors in lasso regression and related problems, for computational efficiency. El Ghaoui and his colleagues have propose 'SAFE' rules, based on univariate inner products between each predictor and the outcome, which guarantee that a coefficient will be 0 in the solution vector. This provides a reduction in the number of variables that need to be entered into the optimization. We propose strong rules that are very simple and yet screen out far more predictors than the SAFE rules. This great practical improvement comes at a price: the strong rules are not foolproof and can mistakenly discard active predictors, i.e. predictors that have non-zero coefficients in the solution. We therefore combine them with simple checks of the Karush-Kuhn-Tucker conditions to ensure that the exact solution to the convex problem is delivered. Of course, any (approximate) screening method can be combined with the Karush-Kuhn-Tucker, conditions to ensure the exact solution; the strength of the strong rules lies in the fact that, in practice, they discard a very large number of the inactive predictors and almost never commit mistakes. We also derive conditions under which they are foolproof. Strong rules provide substantial savings in computational time for a variety of statistical optimization problems. PMID- 25506254 TI - Learning lessons from operational research in infectious diseases: can the same model be used for noncommunicable diseases in developing countries? AB - About three-quarters of global deaths from noncommunicable diseases (NCDs) occur in developing countries. Nearly a third of these deaths occur before the age of 60 years. These deaths are projected to increase, fueled by such factors as urbanization, nutrition transition, lifestyle changes, and aging. Despite this burden, there is a paucity of research on NCDs, due to the higher priority given to infectious disease research. Less than 10% of research on cardiovascular diseases comes from developing countries. This paper assesses what lessons from operational research on infectious diseases could be applied to NCDs. The lessons are drawn from the priority setting for research, integration of research into programs and routine service delivery, the use of routine data, rapid-assessment survey methods, modeling, chemoprophylaxis, and the translational process of findings into policy and practice. With the lines between infectious diseases and NCDs becoming blurred, it is justifiable to integrate the programs for the two disease groups wherever possible, eg, screening for diabetes in tuberculosis. Applying these lessons will require increased political will, research capacity, ownership, use of local expertise, and research funding. PMID- 25506257 TI - Association mapping for root architectural traits in durum wheat seedlings as related to agronomic performance. AB - Association mapping provides useful insights on the genetic architecture of quantitative traits across a large number of unrelated genotypes, which in turn allows an informed choice of the lines to be crossed for a more accurate characterization of major QTLs in a biparental genetic background. In this study, seedlings of 183 durum wheat elite accessions were evaluated in order to identify QTLs for root system architecture (RSA). The QTLs identified were compared with QTLs detected for grain yield and its component traits, plant height and peduncle length measured in a previous study where the same accessions were evaluated in 15 field trials with a broad range of soil moisture availability and productivity (Maccaferri et al. in J Exp Bot 62:409-438, 2011). The following RSA features were investigated in seedlings at the four-leaf stage: seminal root angle, primary root length, total root length, average root length, root number and shoot length. Highly significant differences among accessions were detected for all traits. The highest repeatability (h2 = 0.72) was observed for seminal root angle. Out of the 48 QTLs detected for RSA, 15 overlapped with QTLs for agronomic traits and/or grain yield in two or more environments. The congruency of the effects of RSA traits and agronomic traits was evaluated. Seminal root angle and root number appear the most promising traits for further studies on the adaptive role of RSA plasticity on field performance in environments differing for water availability. Our results provide novel insights on the genetic control of RSA and its implications on field performance of durum wheat. PMID- 25506258 TI - Crossbreeding of transgenic flax plants overproducing flavonoids and glucosyltransferase results in progeny with improved antifungal and antioxidative properties. AB - Flavonoids are a large group of secondary plant metabolites with many important functions; they play a role in fruit, flower and seed pigmentation and are involved in multiple protective mechanisms. They are very active natural antioxidants, acting as antimicrobial compounds in defense against pathogens, and they protect the plant against various stress factors, including excessive solar radiation and temperature. They are also an animal deterrent. Flax is already a very useful crop plant with nutritional and biomedical applications. With increased phenylpropanoid content, flax plants could be used in the production of improved dietary supplements and antimicrobial agents. The main aim of this study was to engineer a flax variety with increased flavonoid content by crossing two transgenic flax varieties that have heightened flavonoid levels. A mother plant that over expresses genes encoding the flavonoid biosynthesis pathway enzymes chalcone synthase, chalcone isomerase and dihydroflavonol reductase was crossed with plants overexpressing the glucosyltransferase (GT) gene. It was expected that the progeny would display better properties thanks to the simultaneous increases in flavonoid synthesis and stability. In comparison to the control and parental plants, plants of the selected flax lines were found to have increased contents of flavonoids and other phenylpropanoids, including phenolic acids, in their stems and seeds. A significant increase in the secoisolariciresinol diglucoside content was found in the seeds. The antioxidative properties of extracts from W92 * GT crossbreed plants were higher than the control (non transgenic) and parental plants. These results correlated with the increase in the susceptibility of the crossbreeds to Fusarium infection. The increased flavonoid content did not cause any negative phenotypic changes or reduce the yield of seeds. PMID- 25506259 TI - Using instrumental variables to estimate a Cox's proportional hazards regression subject to additive confounding. AB - The estimation of treatment effects is one of the primary goals of statistics in medicine. Estimation based on observational studies is subject to confounding. Statistical methods for controlling bias due to confounding include regression adjustment, propensity scores and inverse probability weighted estimators. These methods require that all confounders are recorded in the data. The method of instrumental variables (IVs) can eliminate bias in observational studies even in the absence of information on confounders. We propose a method for integrating IVs within the framework of Cox's proportional hazards model and demonstrate the conditions under which it recovers the causal effect of treatment. The methodology is based on the approximate orthogonality of an instrument with unobserved confounders among those at risk. We derive an estimator as the solution to an estimating equation that resembles the score equation of the partial likelihood in much the same way as the traditional IV estimator resembles the normal equations. To justify this IV estimator for a Cox model we perform simulations to evaluate its operating characteristics. Finally, we apply the estimator to an observational study of the effect of coronary catheterization on survival. PMID- 25506260 TI - Changes in intracranial pressure gradients between the cerebral hemispheres in patients with intracerebral hematomas in one cerebral hemisphere. AB - BACKGROUND: Intracranial-pressure (ICP) monitoring is useful for patients with increased ICP following hemorrhagic stroke. In this study, the changes in pressure gradients between the two cerebral hemispheres were investigated after hemorrhagic stroke of one side, and after a craniotomy. METHODS: Twenty-four patients with acute cerebral hemorrhages and intracerebral hematomas who exhibited mass effect and midline shift to the contralateral side on computed tomography were selected for this study. After admission, both sides of the cranium were drilled, and optical fiber sensors were implanted to monitor the brain parenchyma pressure (BPP) in both cerebral hemispheres. All patients underwent surgical hematoma evacuations. The preoperative and postoperative BPP data from both cerebral hemispheres were collected at various time points and compared pairwise. RESULTS: There were statistically significant differences (P < 0.01) in the preoperative BPP values between the two hemispheres at three different time points. Differences in the BPP values between the two hemispheres at the time of surgery, and 24 and 48 h after surgery, were not statistically significant (P > 0.05). The posteroperative BPPs of both hemispheres were statistically significantly lower than preoperative recordings. CONCLUSIONS: BPP sensors should be applied to the injured cerebral hemisphere, because this becomes the source of increased ICP. Hematoma evacuation surgery effectively decreases ICP and eliminates pressure gradients between the two cerebral hemispheres, consequently enabling brain shift correction. PMID- 25506261 TI - Practice of percutaneous needle autopsy; a descriptive study reporting experiences from Uganda. AB - BACKGROUND: Percutaneous needle autopsy can overcome a number of barriers that limit the use of complete autopsies. We performed blind-and ultrasound guided needle autopsies in HIV-infected adults in Uganda. In this study we describe in detail the methods we used, the ability of both procedures to obtain sufficient tissue for further examination and the learning curve of the operators over time. METHODS: If written informed consent was granted from the next of kin, we first performed a blind needle autopsy, puncturing brain, heart, lungs, liver, spleen and kidneys using predefined surface marking points. We then performed an ultrasound guided needle autopsy puncturing heart, liver, spleen and kidneys. The number of attempts, expected success and duration of the procedure were noted. A pathologist read the slides and indicated if the target tissue was present and of sufficient quality for pathological review. We report the predicted and true success rates, compare the yield of blind to ultrasound guided needle biopsies and evaluate the failure rate over time. RESULTS: Two operators performed 96 blind needle autopsies and 95 ultrasound guided needle autopsies. For blind needle biopsies true success rates varied from 56-99% and predicted success rates from 89-99%. For ultrasound guided needle biopsies true success rates varied from 72-100% and predicted success rates from 84-98%. Ultrasound guidance led to a significantly higher success rate in heart and left kidney. A learning curve was observed over time with decreasing failure rates with increasing experience and a shorter duration of the needle autopsy. CONCLUSION: Needle autopsy can successfully obtain tissue for further pathological review in the vast majority of cases, with a decrease in failure rate with increasing experience of the operator. The benefit of ultrasound guidance will depend on the population, the disease and organ of interest and the local circumstances. Our results justify further evaluation of needle autopsies as a method to establish a cause of death. PMID- 25506264 TI - Sex work and modes of self-employment in the informal economy: diverse business practices and constraints to effective working. AB - This article draws on research with adult sex workers in indoor settings in Great Britain to explore diverse forms of self-employment, employment relationships and small business development, set within the context of changes to the wider economy. It considers how external constraints such as the legal context, social stigma and dominant policy discourses can impact on sex workers' autonomy and actively work against their safety and wellbeing. The article argues that broad policy and legal approaches which fail to recognise the complexity of sex work constrain sex workers' opportunities for business development and improvement of their working circumstances. It suggests the need for recognition of sex work as legitimate labour, as a prerequisite for policy changes to support sex workers and pave the way for improved working conditions, not only in managed settings but also facilitating collective arrangements and independent lone working. PMID- 25506263 TI - Perioperative nursing in public university hospitals: an ethnography. AB - BACKGROUND: In recent years, perioperative nursing has received ongoing attention as part of an interprofessional collaboration. Perioperative nursing is constantly faced with new challenges and opportunities that necessitate continual updates of nursing knowledge and technical skills. In light of the longstanding relationship between nursing and technology, it is interesting that few studies with this focus have been performed. Therefore, our research question was: What is the content of perioperative nursing and how do nurses facilitate the interaction between nursing care and technology in highly specialized operating rooms in public university hospitals? METHODS: An ethnography involving participant observations and interviews was conducted during a 9-month study period. The participants comprised 24 nurses from 9 different operating wards at 2 university hospitals in different regions of Denmark. RESULTS: Patients were addressed as either human beings or objects. Likewise, the participants' technical skills were observed and described as either technical flair or a lack of technical skills/technophobia. The different ways in which the technical skills were handled and the different ways in which the patients were viewed contributed to the development of three levels of interaction between technology and nursing care: the interaction, declining interaction, and failing interaction levels. CONCLUSION: Nursing practice at the interaction level is characterized by flexibility and excellence, while practice at the declining interaction level is characterized by inflexibility and rigidity. Nursing practice at the failing interaction level is characterized by staff members working in isolation with limited collaboration with other staff members in operating rooms. Considering that the declining and failing interaction levels are characterized by inflexibility, rigidity, and isolation in nursing practice, nurses at these two levels must develop and improve their qualifications to reach a level of flexible, excellent interaction. Nurse leaders must therefore refocus their skills on proficiency in perioperative nursing. PMID- 25506262 TI - Nurses' lifestyle behaviours, health priorities and barriers to living a healthy lifestyle: a qualitative descriptive study. AB - BACKGROUND: Nurses have an increased risk for non-communicable diseases (NCDs), along with a high prevalence of obesity, poor eating habits and insufficient physical activity. The aim of this study was to determine the health concerns, health priorities and barriers to living a healthy lifestyle among nurses and hospital management staff from public hospitals in the Western Cape Metropole, South Africa. METHODS: Participants were purposively sampled (n = 103), and included management personnel (n = 9), night shift (n = 57) and day-shift nurses (n = 36). Twelve focus groups (FGDs) were conducted with nursing staff to obtain insight into nurses' health concerns, lifestyle behaviours and worksite health promotion programmes (WHPPs). Seven key informant interviews (KII) were conducted with management personnel, to gain their perspective on health promotion in the worksite. Thematic analysis was used to analyse the data with the assistance of Atlas.ti Qualitative Data Analysis Software. RESULTS: Night shift nurses frequently identified weight gain and living with NCDs such as hypertension as their main health concerns. Being overweight was perceived to have a negative impact on work performance. All nurses identified backache and exposure to tuberculosis (TB) as occupation-related health concerns, and both management and nurses frequently reported a stressful working environment. Nurses frequently mentioned lack of time to prepare healthy meals due to long working hours and being overtired from work. The hospital environment was perceived to have a negative influence on the nurses' lifestyle behaviours, including food service that offered predominantly unhealthy foods. The most commonly delivered WHPPs included independent counselling services, an online employee wellness programme offered by the Department of Health and wellness days in which clinical measures, such as blood glucose were measured. Nurses identified a preference for WHPPs that provided access to fitness facilities or support groups. CONCLUSIONS: Public hospitals are a stressful work environment and shift work places an additional strain on nurses. The risk of NCDs and exposure to infectious disease remains a concern in this working population. Our findings highlight the need for WHPPs that support nurses in managing stress and transforming the work environment to facilitate healthy lifestyles. PMID- 25506265 TI - Upregulation of death receptor 5 and activation of caspase 8/3 play a critical role in ergosterol peroxide induced apoptosis in DU 145 prostate cancer cells. AB - BACKGROUND: Though ergosterol peroxide (EP) derived from Neungyi mushrooms (Sarcodon aspratus) was known to have cytotoxic, apoptotic, anti-inflammatory and antimycobacterial effects, the underlying molecular mechanism of EP still remains unclear. Thus, in the present study, the apoptotic mechanism of EP was elucidated in DU 145 prostate cancer cells. METHODS: Cell viability of prostate cancer cells was measured by MTT assay. To see whether EP induces the apoptosis, FACS, western blot and TUNEL assay were performed. To determine the role of Death receptor (DR) 5 molecules in EP-induced apoptosis in DU 145 prostate cancer cells, the silencing of DR 5 was performed by using siRNAs. RESULTS: EP showed significant cytotoxicity against DU 145, PC 3, M2182 prostate cancer cells. Also, EP effectively increased the sub G1 population and terminal deoxynucleotidyl transferase DUTP nick end labeling (TUNEL) positive cells in DU 145 prostate cancer cells. Furthermore, western blotting revealed that EP cleaved poly (ADP ribose) polymerase (PARP) and caspase 8/3, attenuated the expression of fluorescence loss in photobleaching (FLIP), Bcl-XL and Bcl-2 as well as activated Bax, Fas-associated death domain (FADD) and DR 5 in a concentration dependent manner in DU 145 prostate cancer cells. Conversely, caspase 8 inhibitor Z-IETD FMK blocked the apoptotic ability of EP to cleave PARP and an increase of sub G1 population in DU 145 prostate cancer cells. Likewise, the silencing of DR 5 suppressed the cleavages of PARP induced by EP in DU 145 prostate cancer cells. CONCLUSION: Overall, our findings suggest that ergosterol peroxide induces apoptosis via activation of death receptor 5 and caspase 8/3 in DU 145 prostate cancer cells as a cancer chemopreventive agent or dietary factor. PMID- 25506268 TI - Efficacy and safety of novel oral anticoagulants in clinical practice: a report from three centers in Sweden. AB - INTRODUCTION: In clinical trials new oral anticoagulants (NOAC) have proved to be as effective as warfarin for thromboprophylaxis in atrial fibrillation. The aim of this study was to evaluate the efficacy and safety of these drugs in clinical practise. METHODS AND RESULTS: All patients treated with new oral anticoagulants at Skane University hospital and Halland County Hospital Halmstad between 2009 and September 2013 was identified in the Swedish national quality registry for atrial fibrillation and anticoagulation (AuriculA). Medical records were reviewed to identify thromboembolism and major bleeding and compared to a warfarin cohort with a time in therapeutic range (TTR) of 76%. There were 826 patients, mean age 70.6, follow up 591 years, with atrial fibrillation treated with NOAC. Dabigatran was the initial drug in 79% of the cohort. The incidences of ischemic stroke/ TIA and major bleeding were 1.9 (95% CI; 1.0-3.2) and 2.0 (95% CI; 1.1-3.5) per 100 patient-years respectively. The corresponding incidences for warfarin were 1.5 (95% CI; 1.0-2.2) and 2.5 (95% CI; 1.8-3.3), with no statistical significance between the groups. Two subdural hematomas occurred 0.4 (95% CI; 0.06-1.1) per 100 patient-years. Mean age of patients with complications was 77.9 (+/-5.9) and 69.3 (+/-11.3) for those without (p < 0.001). The discontinuation rate was 6.5% and 1.7% was due to dyspepsia for dabigatran, lower than the RE-LY trial. CONCLUSION: This study, largely based on dabigatran shows that treatment is efficient and safe in everyday clinical practice and not significantly different compared to a warfarin cohort with tight anticoagulation control. PMID- 25506267 TI - Treatment options for venous thromboembolism: lessons learnt from clinical trials. AB - Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is a common condition associated with a significant clinical and economic burden. Anticoagulant therapy is the mainstay of treatment for VTE, having been shown to reduce the risk of death in patients with pulmonary embolism, and recurrence or extension of thrombi in patients with deep vein thrombosis during the initial treatment period. Long-term anticoagulation is indicated in some individuals with VTE, depending on individual risk of VTE recurrence and anticoagulant-related bleeding. Management of VTE in clinical practice is often complex because patients' characteristics and treatment needs may differ considerably from those encountered in clinical trials. Current guidelines recommend the use of either low molecular weight heparins or fondaparinux overlapping with and followed by a vitamin K antagonist for the initial treatment of VTE, with the vitamin K antagonist continued when long-term anticoagulation is required. These traditional anticoagulants have practical limitations that have led to the development of direct oral anticoagulants that directly target either Factor Xa or thrombin and are administered at a fixed dose without the need for routine coagulation monitoring. This review discusses practical considerations for hospital physicians and haematologists in the management of VTE treatment, including the potential for the direct oral anticoagulants to simplify treatment. PMID- 25506266 TI - Reducing inequities in colorectal cancer screening in North America. AB - Colorectal cancer (CRC) is an important cause of mortality and morbidity in North America. Screening using a fecal occult blood test, flexible sigmoidoscopy, or colonoscopy reduces CRC mortality through the detection and treatment of precancerous polyps and early stage CRC. Although CRC screening participation has increased in recent years, large inequities still exist. Minorities, new immigrants, and those with lower levels of education or income are much less likely to be screened. This review provides an overview of the commonly used tests for CRC screening, disparities in CRC screening, and promising methods at the individual, provider, and system levels to reduce these disparities. Overall, to achieve high CRC participation rates and reduce the burden of CRC in the population, a multi-faceted approach that uses strategies at all levels to reduce CRC screening disparities is urgently required. PMID- 25506269 TI - Hypothermia: effects on platelet function and hemostasis. AB - Mild therapeutic hypothermia is considered standard care in the treatment of patients resuscitated from cardiac arrest. With increasingly more frequent concomitant use of platelet-inhibiting drugs, clinicians must be cognizant of the ramifications of hypothermia on platelet function as part of hemostasis. The effects of hypothermia on platelet function have been studied for more than 50 years, but the results are inconsistent and may be related to the circumstances during which hypothermia is achieved. This review summarizes current knowledge of platelet function during hypothermia and the impact on hemostasis. PMID- 25506271 TI - MRI Dynamic Range: Theory and Measurement. PMID- 25506270 TI - The back squat: A proposed assessment of functional deficits and technical factors that limit performance. AB - Fundamental movement competency is essential for participation in physical activity and for mitigating the risk of injury, which are both key elements of health throughout life. The squat movement pattern is arguably one of the most primal and critical fundamental movements necessary to improve sport performance, to reduce injury risk and to support lifelong physical activity. Based on current evidence, this first (1 of 2) report deconstructs the technical performance of the back squat as a foundation training exercise and presents a novel dynamic screening tool that incorporates identification techniques for functional deficits that limit squat performance and injury resilience. The follow-up report will outline targeted corrective methodology for each of the functional deficits presented in the assessment tool. PMID- 25506273 TI - Dominican Immigrants and Discrimination in a New Destination: The Case of Reading, Pennsylvania* AB - The last decade has witnessed the diversification of immigrant destinations in the United States. Although the literature on this phenomenon is burgeoning, research on the experiences of smaller immigrant groups in new destinations is underdeveloped. This is especially the case for those from the Dominican Republic, a group that is expanding beyond the traditional gateway cities of the Northeast. Using a survey of Dominican immigrants in Reading, Pennsylvania, this study has two objectives. The first objective is to describe the prevalence of experiences with institutional and interpersonal discrimination. The second objective is to determine the extent to which these experiences are structured around racial markers (i.e. skin tone), forms of capital, forms of incorporation, and exposure to the U.S. Our results show that a substantial minority of Dominican immigrants claims to have been treated unfairly, primarily because of their "race and ethnicity." In addition, experiences with some types of discrimination are positively associated with skin tone (i.e., darkness) and several factors that are identified in models of assimilation. PMID- 25506274 TI - An Examination of the Geography of Population Composition and Change in the United States, 2000-2010: Insights from Geographical Indices and a Shift-Share Analysis. PMID- 25506272 TI - Maternal Disrupted Communication During Face-to-Face Interaction at 4 months: Relation to Maternal and Infant Cortisol Among at-Risk Families. AB - The study evaluated the association between maternal disrupted communication and the reactivity and regulation of the psychobiology of the stress response in infancy. Mothers and infants were recruited via the National Health Service from the 20% most economically impoverished data zones in a suburban region of Scotland. Mothers (N = 63; M age = 25.9) and their 4-month-old infants (35 boys, 28 girls) were videotaped interacting for 8 min, including a still-face procedure as a stress inducer and a 5-min coded recovery period. Saliva samples were collected from the dyads prior to, during, and after the still-face procedure and later assayed for cortisol. Level of disruption in maternal communication with the infant was coded from the 5-min videotaped interaction during the recovery period which followed the still-face procedure. Severely disrupted maternal communication was associated with lower levels of maternal cortisol and a greater divergence between mothers' and infants' cortisol levels. Results point to low maternal cortisol as a possible mechanism contributing to the mother's difficulty in sensitively attuning to her infant's cues, which in turn has implications for the infant's reactivity to and recovery from a mild stressor in early infancy. PMID- 25506275 TI - 'Poisonous, filthy, loathsome, damnable stuff': the rhetorical ecology of vaccination concern. AB - In this article, we analyze newspaper articles and advertisements mentioning vaccination from 1915 to 1922 and refer to historical studies of vaccination practices and attitudes in the early 20th century in order to assess historical continuities and discontinuities in vaccination concern. In the Progressive Era period, there were a number of themes or features that resonated with contemporary issues and circumstances: 1) fears of vaccine contamination; 2) distrust of medical professionals; 3) resistance to compulsory vaccination; and 4) the local nature of vaccination concern. Such observations help scholars and practitioners understand vaccine skepticism as longstanding, locally situated, and linked to the sociocultural contexts in which vaccination occurs and is mandated for particular segments of the population. A rhetorical approach offers a way to understand how discourses are engaged and mobilized for particular purposes in historical contexts. Historically situating vaccine hesitancy and addressing its articulation with a particular rhetorical ecology offers scholars and practitioners a robust understanding of vaccination concerns that can, and should, influence current approaches to vaccination skepticism. PMID- 25506276 TI - Understanding vaccines: a public imperative. AB - Though once a discovery greatly celebrated by the nation, the vaccine has come under fire in recent decades from skeptics, critics, and a movement set into motion by fraudulent scientists and fueled by frustrated parents looking for answers to the autism conundrum. There is enough denialist resistance to vaccination to bring upon renewed fear of young children and infants becoming infected with diseases, the threats of which had been functionally eradicated from the United States. In more recent years, the surge in independent online journalism and blogging has invited many to rapidly share their opinions with millions of readers and, importantly, has appeared to open the door for opinion to be portrayed as fact. As a result, many parents are inundated with horror stories of vaccine dangers, all designed to eat away at them emotionally while the medical and scientific communities have mounted their characteristic response by sharing the facts, the data, and all of the reliable peer-reviewed and well cited research to show that vaccines are safe and effective. It has become clear to me that facts are no match for emotion, but perhaps an understanding behind vaccine methodology will help parents overcome these fears of vaccinating. By helping those who doubt vaccines better understand what vaccines really are and how they work in such an incredibly engineered fashion, we may have a stronger weapon than we realize in battling the emotional arsenal that comes from the fear and skepticism of vaccinating. PMID- 25506277 TI - Healthy bodies, toxic medicines: college students and the rhetorics of flu vaccination. AB - This article examines flu vaccination beliefs and practices produced during a survey of undergraduate students in Spring 2012 (IRB#10-732). This research uses the methods of rhetorical analysis - or the study of persuasive features and arguments used in language - to examine statements respondents made regarding flu and flu vaccine. In these responses, students generated unique categories of arguments about the perceived dangers of flu vaccination, including the assertion that vaccines cause disease (including illnesses and conditions other than flu), that vaccines are toxic medicines, and that vaccines carry unknown, population wide risks that are inadequately acknowledged. This study provides insight into vaccination beliefs and rationales among a population at risk of flu (college students) and suggests that further study of this population may yield important keys to addressing flu vaccine concerns as expressed by college students. Rhetorical analysis also offers a useful set of methods to understanding vaccination beliefs and practices, adding to existing methods of study and analysis of vaccination practices and beliefs in medicine and public health. PMID- 25506278 TI - Improving influenza vaccination coverage in the pediatric asthma population: the case for combined methodologies. AB - The Advisory Committee on Immunization Practices recommends annual influenza vaccine for pediatric asthma patients. Despite considerable risk for influenza complications in pediatric asthma patients, including hospitalization and death, influenza vaccination among children with asthma remains low, especially among low-income pediatric asthma patients. Multiple interventions have been attempted to increase immunization in the pediatric asthma population, including recall and reminders, parent/patient education, and physician education. More recently, information technology methods have been employed, including electronic alerts and computerized physician order entry/clinical decision support interventions. Each of these interventions, as well as a recent legislative intervention, has evidence of effectiveness, but none achieved the Healthy People 2020 vaccination goals of 80 percent for this population. This goal may be achievable with a combination of these methodologies and strategies that increase access to care for underserved patients. PMID- 25506279 TI - Pediatric infectious disease epidemiology: prevention trumps treatment: an interview with Marietta Vazquez, MD. PMID- 25506281 TI - Reducing outbreaks: using international governmental risk pools to fund research and development of infectious disease medicines and vaccines. AB - The deadliest Ebola outbreak the world has ever seen is currently ravaging West Africa, despite the concerted efforts of the World Health Organization and many national governments. The current picture is troubling, but not altogether unexpected. Ebola was initially identified in 1976, and since that time, few drugs have been developed to combat it. The same is true for myriad other dangerous infectious diseases to which the world is currently susceptible. One proposal that might prevent outbreaks of this scale and magnitude from recurring would be to have the World Health Organization (WHO) and its technical partners assess which of its member states are at high risk for a disease, either directly or indirectly, and facilitate the creation of international governmental risk pools of those member states. Risk pools would offer open-indexed grant contracts to fund vaccine and drug development for a particular disease, and pharmaceutical companies could browse the index to apply for these grants. If the risk-pool states and a particular company sign a contract, a mutually agreed upon amount of the vaccine or drug would be produced at a below-market purchase price for those states. In return, the company would keep any patents or intellectual property rights for the developed vaccines or drugs. Risk-pool countries that did not use their vaccine or drug could resell that supply on secondary markets to other countries outside of the risk pool. This arrangement will increase the supply of tested drug and vaccine candidates available for combatting unexpected outbreaks of any previously discovered major infectious disease in the future. PMID- 25506280 TI - Multilevel factors influencing hepatitis B screening and vaccination among Vietnamese Americans in Atlanta, Georgia. AB - Chronic hepatitis B virus (HBV) infection may lead to liver cirrhosis, chronic liver disease, and liver cancer. Immunization rates are suboptimal among Asian Americans/Pacific Islanders (AAPIs), who remain disproportionately affected by these illnesses. We investigated socioecological factors affecting HBV prevention among 316 Vietnamese Americans in Atlanta, Georgia. Social and community support of HBV vaccination was associated with screening (OR=1.69, 95% CI [1.21,2.38]), vaccination (OR=1.89, [1.27,2.81]), and intent to vaccinate (OR=1.77, [1.13,2.78]). Misconceptions decreased screening likelihood (OR=0.67, [0.46,0.99]) and vaccination (OR=0.55, [0.35,0.86]). Those able to pay for medical treatment (OR=1.23, [1.01,1.50]) were also more likely immunized, and greater transportation access (OR=1.42, [1.07,1.87]) was associated with greater intention to vaccinate. Multi-level factors facilitated HBV vaccination in this population. Tailored, culturally appropriate communication strategies will positively influence immunization uptake. PMID- 25506282 TI - Anti-cancer vaccines - a one-hit wonder? AB - Immunization against common bacterial and viral diseases has helped prevent millions of deaths worldwide. More recently, the concept of vaccination has been developed into a potentially novel strategy to treat and prevent cancer formation, progression, and spread. Over the past few years, a handful of anti cancer vaccines have been licensed and approved for use in clinical practice, thus providing a breakthrough in the field. However, the path has not always been easy, with many hurdles that have had to be overcome in order to reach this point. Nevertheless, with more anti-cancer vaccines currently in development, there is still hope that they can eventually become routine tools used in the treatment and prevention of cancer in the future. This review will discuss in detail both types of anti-cancer vaccine presently used in clinical practice - therapeutic and preventive - before considering some of the more promising anti cancer vaccines that are currently in development. Finally, the issue of side effects and the debate surrounding the overall cost-effectiveness of anti-cancer vaccines will be examined. PMID- 25506284 TI - Vaccine development: how scientific collaboration and communication help prevent the spread of disease: an interview with Erol Fikrig, MD. PMID- 25506285 TI - Renal sympathetic denervation in the treatment of resistant hypertension. AB - Arterial hypertension (HTN) is a major health problem worldwide. Treatment resistant hypertension (trHTN) is defined as the failure to achieve target blood pressure despite the concomitant use of maximally tolerated doses of three different antihypertensive medications, including a diuretic. trHTN is associated with considerable morbidity and mortality. Renal sympathetic denervation (RDn) is available and implemented abroad as a strategy for the treatment of trHTN and is currently under clinical investigation in the United States. Selective renal sympathectomy via an endovascular approach effectively decreases renal sympathetic nerve hyperactivity leading to a decrease in blood pressure. The Symplicity catheter, currently under investigation in the United States, is a 6 French compatible system advanced under fluoroscopic guidance via percutaneous access of the common femoral artery to the distal lumen of each of the main renal arteries. Radiofrequency (RF) energy is then applied to the endoluminal surface of the renal arteries via an electrode located at the tip of the catheter. Two clinical trials (Symplicity HTN 1 and Symplicity HTN 2) have shown the efficacy of RDn with a post-procedure decline of 27/17 mmHg at 12 months and 32/12 mmHg at 6 months, respectively, with few minor adverse events. Symplicity HTN-3 study is a, multi-center, prospective, single-blind, randomized, controlled study currently under way and will provide further insights about the safety and efficacy of renal denervation in patients with trHTN. PMID- 25506283 TI - Optimizing dendritic cell-based approaches for cancer immunotherapy. AB - Dendritic cells (DC) are professional antigen-presenting cells uniquely suited for cancer immunotherapy. They induce primary immune responses, potentiate the effector functions of previously primed T-lymphocytes, and orchestrate communication between innate and adaptive immunity. The remarkable diversity of cytokine activation regimens, DC maturation states, and antigen-loading strategies employed in current DC-based vaccine design reflect an evolving, but incomplete, understanding of optimal DC immunobiology. In the clinical realm, existing DC-based cancer immunotherapy efforts have yielded encouraging but inconsistent results. Despite recent U.S. Federal and Drug Administration (FDA) approval of DC-based sipuleucel-T for metastatic castration-resistant prostate cancer, clinically effective DC immunotherapy as monotherapy for a majority of tumors remains a distant goal. Recent work has identified strategies that may allow for more potent "next-generation" DC vaccines. Additionally, multimodality approaches incorporating DC-based immunotherapy may improve clinical outcomes. PMID- 25506286 TI - Anorectal human papillomavirus: current concepts. AB - Increased anorectal human papillomavirus (HPV) infection is related to the recent trends in sexual behavior in both homosexual and heterosexual groups and prevalence of infection with human immunodeficiency virus (HIV). Clinical presentation and natural history depend on the serotype involved. HPV 6 and 11 are found in the benign wart. Local control can be achieved with a wide selection of surgical and topical techniques. HPV 16, 18, and 31 are found in dysplastic lesions and have the potential to progress to invasive anal squamous cell carcinoma. Recognition and early management of dysplastic lesions is crucial to prevent the morbidity and mortality associated with anal cancer. While low-grade lesions can be closely observed, high-grade lesions should be eradicated. Different strategies can be used to eradicate the disease while preserving anorectal function. Studies on the efficacy of vaccination on anorectal HPV showed promising results in select population groups and led to the recent expansion of current vaccination recommendations. PMID- 25506288 TI - Heart block and acute kidney injury due to hyperparathyroidism-induced hypercalcemic crisis. AB - We describe a patient who presented with multi-system organ failure due to extreme hypercalcemia (serum calcium 19.8 mg/dL), resulting from primary hyperparathyroidism. He was found to have a 4.8 cm solitary atypical parathyroid adenoma. His course was complicated by complete heart block, acute kidney injury, and significant neurocognitive disturbances. Relevant literature was reviewed and discussed. Hyperparathyroidism-induced hypercalcemic crisis (HIHC) is a rare presentation of primary hyperparathyroidism and only a small minority of these patients develop significant cardiac and renal complications. In cases of HIHC, a multidisciplinary effort can facilitate rapid treatment of life-threatening hypercalcemia and definitive treatment by surgical resection. As such, temporary transvenous cardiac pacing and renal replacement therapy can provide a life saving bridge to definitive parathyroidectomy in cases of HIHC. PMID- 25506289 TI - Lateralizing sensorimotor deficits in a case of pseudopheochromocytoma. AB - Pseudopheochromocytoma is a poorly understood, rare cause of severe paroxysmal hypertension that mimics the symptomatology of pheochromocytoma in the absence of biochemical evidence of this tumor. Symptoms such as headache, nausea, sweating, and palpitations during hypertensive episodes have been described. In this paper, we describe previously unreported findings of lateralizing sensorimotor deficits in a patient with pseudopheochromocytoma. These changes presented during a hypertensive episode and were concerning for stroke but were not accompanied by acute radiologic abnormalities. The deficits improved over 1.5 weeks as blood pressure stabilized with beta-blockade. We also review relevant literature on the clinical features, pathophysiology, and management of pseudopheochromocytoma. PMID- 25506287 TI - The controversy surrounding bone morphogenetic proteins in the spine: a review of current research. AB - Bone morphogenetic proteins have been in use in spinal surgery since 2002. These proteins are members of the TGF-beta superfamily and guide mesenchymal stem cells to differentiate into osteoblasts to form bone in targeted tissues. Since the first commercial BMP became available in 2002, a host of research has supported BMPs and they have been rapidly incorporated in spinal surgeries in the United States. However, recent controversy has arisen surrounding the ethical conduct of the research supporting the use of BMPs. Yale University Open Data Access (YODA) recently teamed up with Medtronic to offer a meta-analysis of the effectiveness of BMPs in spinal surgery. This review focuses on the history of BMPs and examines the YODA research to guide spine surgeons in their use of BMP in spinal surgery. PMID- 25506290 TI - A comprehensive, simulation-based approach to teaching clinical skills: the medical students' perspective. AB - The purpose of this study was to determine if third-year medical students participating in a mandatory 12-week simulation course perceived improvement in decision-making, communication, and teamwork skills. Students participated in or observed 24 acute emergency scenarios. At 4-week intervals, students completed 0 10 point Likert scale questionnaires evaluating the curriculum and role of team leader. Linear contrasts were used to examine changes in outcomes. P-values were Bonferroni-corrected for multiple pairwise comparisons. Student evaluations (n = 96) demonstrated increases from week 4 to 12 in educational value (p = 0.006), decision-making (p < 0.001), communication (p = 0.02), teamwork (p = 0.01), confidence in management (p < 0.001), and translation to clinical experience (p < 0.001). Regarding the team leader role, students reported a decrease in stress (p = 0.001) and increase in ability to facilitate team function (p < 0.001) and awareness of team building (p = <0.001). Ratings demonstrate a positive impact of simulation on both clinical management skills and team leadership skills. A simulation curriculum can enhance the ability to manage acute clinical problems and translates well to the clinical experience. These positive perceptions increase as the exposure to simulation increases. PMID- 25506291 TI - On Medicaid and the Affordable Care Act in Connecticut: the problem with subspecialty services. AB - BACKGROUND: Medicaid is the federal program, administered by states, for health care for the poor. The Affordable Care Act (ACA) has added a large number of new recipients to this program. HYPOTHESIS: Medicaid programs in some, if not many, states do not provide patients uniform access to subspecialty care guaranteed by the federal statutes. Insofar as the ACA does not address this pre-existing "sub specialty gap" and more patients are now covered by Medicaid under the ACA, the gap is likely to increase and may contribute to disparities of health care access and outcomes. METHODS: A brief description of previous studies demonstrating or suggesting a subspecialty gap in Medicaid services is accompanied by perspectives of the authors, using published literature - most notably the Denver, Colorado health care system - to propose various solutions that may be deployed to address gaps in subspecialty coverage. RESULTS: All published studies describing the Medicaid subspecialty gap are qualitative, survey designs. There are no authoritative objective data regarding the exact prevalence of gaps for each subspecialty in each state. However, surveys of caregivers suggest that gaps were prevalent in the United States prior to initiation of the ACA. Even fewer papers have addressed solutions (in light of the paucity of data describing the magnitude of the problem), and proposed solutions remain speculative and not grounded in objective data. CONCLUSIONS: There is reason to believe that a substantial proportion of U.S. citizens - those who are guaranteed a full complement of health services through Medicaid - have difficult or no access to some subspecialty services, many of which other citizens take for granted. This problem deserves greater attention to verify its existence, quantify its magnitude, and develop solutions. PMID- 25506293 TI - Letter to the editor. PMID- 25506292 TI - The future is now: frontiers on display at Yale-NAVBO cardiovascular inflammation and remodeling symposium 2014. AB - Earlier this year, 200 researchers from across the globe gathered at the Omni New Haven Hotel at Yale University in New Haven, Connecticut, for 3 days of talks from 30 of the leading pioneers in modern cardiovascular medicine. From May 8 to 10, 2014, scientists discussed and dissected topics ranging from the clinical treatment of atherosclerosis to the molecular biology of leukocyte-endothelial cell interactions. With other sessions exploring vascular malformation and aneurysm, hypertension, the endothelial-mesenchymal transition (endo-MT), and the role of metabolism in cardiovascular disease, conference participants gained striking insights into rapid advances and ongoing challenges in the field of cardiovascular inflammation and remodeling. PMID- 25506294 TI - Strategic Authenticity and Voice: New Ways of Seeing and Being Seen as Young Mothers through Digital Storytelling. PMID- 25506295 TI - Modeling Scalable Pattern Generation in DNA Reaction Networks. AB - We have developed a theoretical framework for developing patterns in multiple dimensions using controllable diffusion and designed reactions implemented in DNA. This includes so-called strand displacement reactions in which one single stranded DNA hybridizes to a hemi-duplex DNA and displaces another single stranded DNA, reversibly or irreversibly. These reactions can be designed to proceed with designed rate and molecular specificity. By also controlling diffusion by partial complementarity to a stationary, cross-linked DNA, we can generate predictable patterns. We demonstrate this with several simulations showing deterministic, predictable shapes in space. PMID- 25506296 TI - Alcohol Control and Foster Care. AB - Parental alcohol consumption is often associated with an increased likelihood of child abuse. As consumption is related to price, the purpose of this paper is to investigate the propensity for increases in the full price of alcohol to influence entry rates and the length of time spent in foster care. Using alcoholic beverage prices and a measure of availability in combination with data on foster care cases, we find that higher alcohol prices are not effective in reducing foster care entry rates; however, once in foster care, the duration of stay may be shortened by higher prices and reduced availability. PMID- 25506297 TI - In-vitro Antiproliferative Activity of New Tetrahydroisoquinolines (THIQs) on Ishikawa Cells and their 3D Pharmacophore Models. AB - The antiproliferative activities of new substituted tetrahydroisoquinolines (THIQs) are described. Their cytotoxicities against Ishikawa human endometrial cell line were determined after 72 h drug expose employing Celtiter-Glo assay at concentrations ranging from 0.01 to 100,000 nM. The antiproliferative activities of the compounds understudy were compared to tamoxifen (TAM). In-vitro results indicated that most of the compounds showed better activity than TAM. The most active compounds obtained in this study were 1, 2, 3 and 22 whose IC50 values are 1.41, 0.91, 0.74 and 0.36 MUM respectively. This study helped us to evaluate the risk of developing endometrial cancer in the design of non-steroid estrogen receptor modulators with no agonistic effects on uterus. In-silico pharmacophore hypotheses were generated using GALAHAD and PHASE and the best models with a probable bioactive conformation(s) for these compounds were proposed. These conformations and the alignments of the molecular structures give us an insight in designing compounds with better biological activity. PMID- 25506298 TI - Phytophthora species, new threats to the plant health in Korea. AB - Given the lack of a resistant genetic pool in host plants, the introduction of exotic invasive pathogens can result in epidemics that affect a specific ecosystem and economy. Plant quarantine, which is designed to protect endemic plant resources, is a highly invaluable safeguard that should keep biosecurity with increasing international trade and global transportation. A total of 34 species of plant pathogens including Phytophthora infestans were documented as introduced from other countries into Korea from 1900 to 2010. The genus Phytophthora, classified in oomycetes, includes more than 120 species that are mostly recognized worldwide as highly invasive plant pathogens. After 2000, over 50 new species of Phytophthora were identified internationally as plant pathogens occurring in crops and forest trees. In Korea, Phytophthora is also one of the most serious plant pathogens. To date, 22 species (about one-fifth of known species) of the genus have been identified and reported as plant pathogens in the country. The likelihood of new exotic Phytophthora species being introduced into Korea continues to increase, thus necessitating intensive plant quarantine inspections. As new potential threats to plant health in Korea, six Phytophthora species, namely, P. alni, P. inundata, P. kernoviae, P. pinifolia, P. quercina, and P. ramorum, are discussed in this review with focus on history, disease, biology, management, and plant quarantine issues. PMID- 25506299 TI - Transcriptome Analysis of Early Responsive Genes in Rice during Magnaporthe oryzae Infection. AB - Rice blast disease caused by Magnaporthe oryzae is one of the most serious diseases of cultivated rice (Oryza sativa L.) in most rice-growing regions of the world. In order to investigate early response genes in rice, we utilized the transcriptome analysis approach using a 300 K tilling microarray to rice leaves infected with compatible and incompatible M. oryzae strains. Prior to the microarray experiment, total RNA was validated by measuring the differential expression of rice defense-related marker genes (chitinase 2, barwin, PBZ1, and PR-10) by RT-PCR, and phytoalexins (sakuranetin and momilactone A) with HPLC. Microarray analysis revealed that 231 genes were up-regulated (>2 fold change, p < 0.05) in the incompatible interaction compared to the compatible one. Highly expressed genes were functionally characterized into metabolic processes and oxidation-reduction categories. The oxidative stress response was induced in both early and later infection stages. Biotic stress overview from MapMan analysis revealed that the phytohormone ethylene as well as signaling molecules jasmonic acid and salicylic acid is important for defense gene regulation. WRKY and Myb transcription factors were also involved in signal transduction processes. Additionally, receptor-like kinases were more likely associated with the defense response, and their expression patterns were validated by RT-PCR. Our results suggest that candidate genes, including receptor-like protein kinases, may play a key role in disease resistance against M. oryzae attack. PMID- 25506300 TI - Comparative Analysis of Defense Responses in Chocolate Spot-Resistant and Susceptible Faba Bean (Vicia faba) Cultivars Following Infection by the Necrotrophic Fungus Botrytis fabae. AB - In this study, resistance responses were investigated during the interaction of Botrytis fabae with two faba bean cultivars expressing different levels of resistance against this pathogen, Nubaria (resistant) and Giza 40 (susceptible). Disease severity was assessed on leaves using a rating scale from 1 to 9. Accumulation levels of reactive oxygen species (ROS), lipid peroxidation and antioxidant enzymes (superoxide dismutase, catalase and ascorbate peroxidase) were measured in leaf tissues at different times of infection. The expression profiles of two pathogenesis-related proteins (PRPs) encoded by the genes PR-1 and beta-1,3-glucanase were also investigated using reverse transcription RT-PCR analysis. The accumulation of these defense responses was induced significantly in both cultivars upon infection with B. fabae compared with un-inoculated controls. The resistant cultivar showed weaker necrotic symptom expression, less ROS accumulation, a lower rate of lipid peroxidation and higher activity of the enzymatic ROS scavenging system compared with susceptible cultivar. Interestingly, ROS accumulated rapidly in the resistant leaf tissues and peaked during the early stages of infection, whereas accumulation was stronger and more intense in the susceptible tissues in later stages. Moreover, the response of the resistant cultivar to infection was earlier and stronger, exhibiting high transcript accumulation of the PR genes. These results indicated that the induction of oxidant/antioxidant responses and the accumulation of PRPs are part of the faba bean defense mechanism against the necrotrophic fungus B. fabae with a different intensity and timing of induction, depending on the resistance levels. PMID- 25506301 TI - Analysis of in planta Expressed Orphan Genes in the Rice Blast Fungus Magnaporthe oryzae. AB - Genomes contain a large number of unique genes which have not been found in other species. Although the origin of such "orphan" genes remains unclear, they are thought to be involved in species-specific adaptive processes. Here, we analyzed seven orphan genes (MoSPC1 to MoSPC7) prioritized based on in planta expressed sequence tag data in the rice blast fungus, Magnaporthe oryzae. Expression analysis using qRT-PCR confirmed the expression of four genes (MoSPC1, MoSPC2, MoSPC3 and MoSPC7) during plant infection. However, individual deletion mutants of these four genes did not differ from the wild-type strain for all phenotypes examined, including pathogenicity. The length, GC contents, codon adaptation index and expression during mycelial growth of the four genes suggest that these genes formed during the evolutionary history of M. oryzae. Synteny analyses using closely related fungal species corroborated the notion that these genes evolved de novo in the M. oryzae genome. In this report, we discuss our inability to detect phenotypic changes in the four deletion mutants. Based on these results, the four orphan genes may be products of de novo gene birth processes, and their adaptive potential is in the course of being tested for retention or extinction through natural selection. PMID- 25506302 TI - Isolation and Characterization of the Colletotrichum acutatum ABC Transporter CaABC1. AB - Fungi tolerate exposure to various abiotic stresses, including cytotoxic compounds and fungicides, via their ATP-driven efflux pumps belonging to ATP binding cassette (ABC) transporters. To clarify the molecular basis of interaction between the fungus and various abiotic stresses including fungicides, we constructed a cDNA library from germinated conidia of Colletotrichum acutatum, a major anthracnose pathogen of pepper (Capsicum annum L.). Over 1,000 cDNA clones were sequenced, of which single clone exhibited significant nucleotide sequence homology to ABC transporter genes. We isolated three fosmid clones containing the C. acutatum ABC1 (CaABC1) gene in full-length from genomic DNA library screening. The CaABC1 gene consists of 4,059 bp transcript, predicting a 1,353-aa protein. The gene contains the typical ABC signature and Walker A and B motifs. The 5'-flanking region contains a CAAT motif, a TATA box, and a Kozak region. Phylogenetic and structural analysis suggested that the CaABC1 is a typical ABC transporter gene highly conserved in various fungal species, as well as in Chromista, Metazoans, and Viridiplantae. We also found that CaABC1 was up regulated during conidiation and a minimal medium condition. Moreover, CaABC1 was induced in iprobenfos, kresoxim-methyl, thiophanate-methyl, and hygromycin B. These results demonstrate that CaABC1 is necessary for conidiation, abiotic stress, and various fungicide resistances. These results will provide the basis for further study on the function of ABC transporter genes in C. acutatum. PMID- 25506304 TI - Characterization of the Maize Stalk Rot Pathogens Fusarium subglutinans and F. temperatum and the Effect of Fungicides on Their Mycelial Growth and Colony Formation. AB - Maize is a socioeconomically important crop in many countries. Recently, a high incidence of stalk rot disease has been reported in several maize fields in Gangwon province. In this report, we show that maize stalk rot is associated with the fungal pathogens Fusarium subglutinans and F. temperatum. Since no fungicides are available to control these pathogens on maize plants, we selected six fungicides (tebuconazole, difenoconazole, fluquinconazole, azoxystrobin, prochloraz and kresoxim-methyl) and examined their effectiveness against the two pathogens. The in vitro antifungal effects of the six fungicides on mycelial growth and colony formation were investigated. Based on the inhibition of mycelial growth, the most toxic fungicide was tebuconazole with 50% effective concentrations (EC50) of <0.1 MUg/ml and EC90 values of 0.9 MUg/ml for both pathogens, while the least toxic fungicide was azoxystrobin with EC50 values of 0.7 and 0.5 MUg/ml for F. subglutinans and F. temperatum, respectively, and EC90 values of >3,000 MUg/ml for both pathogens. Based on the inhibition of colony formation by the two pathogens, kresoxim-methyl was the most toxic fungicide with complete inhibition of colony formation at concentrations of 0.1 and 0.01 MUg/ml for F. subglutinans and F. temperatum, respectively, whereas azoxystrobin was the least toxic fungicide with complete inhibition of colony formation at concentrations >3,000 MUg/ml for both pathogens. PMID- 25506303 TI - Evidence for Genetic Similarity of Vegetative Compatibility Groupings in Sclerotinia homoeocarpa. AB - Vegetative compatibility groups (VCGs) are determined for many fungi to test for the ability of fungal isolates to undergo heterokaryon formation. In several fungal plant pathogens, isolates belonging to a VCG have been shown to share significantly higher genetic similarity than those of different VCGs. In this study we sought to examine the relationship between VCG and genetic similarity of an important cool season turfgrass pathogen, Sclerotinia homoeocarpa. Twenty-two S. homoeocarpa isolates from the Midwest and Eastern US, which were previously characterized in several studies, were all evaluated for VCG using an improved nit mutant assay. These isolates were also genotyped using 19 microsatellites developed from partial genome sequence of S. homoeocarpa. Additionally, partial sequences of mitochondrial genes cytochrome oxidase II and mitochondrial small subunit (mtSSU) rRNA, and the atp6-rns intergenic spacer, were generated for isolates from each nit mutant VCG to determine if mitochondrial haplotypes differed among VCGs. Of the 22 isolates screened, 15 were amenable to the nit mutant VCG assay and were grouped into six VCGs. The 19 microsatellites gave 57 alleles for this set. Unweighted pair group methods with arithmetic mean (UPGMA) tree of binary microsatellite data were used to produce a dendrogram of the isolate genotypes based on microsatellite alleles, which showed high genetic similarity of nit mutant VCGs. Analysis of molecular variance of microsatellite data demonstrates that the current nit mutant VCGs explain the microsatellite genotypic variation among isolates better than the previous nit mutant VCGs or the conventionally determined VCGs. Mitochondrial sequences were identical among all isolates, suggesting that this marker type may not be informative for US populations of S. homoeocarpa. PMID- 25506305 TI - Detection of Multiple Potato Viruses in the Field Suggests Synergistic Interactions among Potato Viruses in Pakistan. AB - Viral diseases have been a major limiting factor threating sustainable potato (Solanum tuberosum L.) production in Pakistan. Surveys were conducted to serologically quantify the incidence of RNA viruses infecting potato; Potato virus X (PVX), Potato virus Y (PVY), Potato virus S (PVS), Potato virus A (PVA), Potato virus M (PVM) and Potato leaf roll virus (PLRV) in two major potato cultivars (Desiree and Cardinal). The results suggest the prevalence of multiple viruses in all surveyed areas with PVY, PVS and PVX dominantly widespread with infection levels of up to 50% in some regions. Co-infections were detected with the highest incidence (15.5%) for PVX and PVS. Additionally the data showed a positive correlation between co-infecting viruses with significant increase in absorbance value (virus titre) for at least one of the virus in an infected plant and suggested a synergistic interaction. To test this hypothesis, glasshouse grown potato plants were challenged with multiple viruses and analyzed for systemic infections and symptomology studies. The results obtained conclude that multiple viral infections dramatically increase disease epidemics as compared to single infection and an effective resistance strategy in targeting multiple RNA viruses is required to save potato crop. PMID- 25506306 TI - The current incidence of viral disease in korean sweet potatoes and development of multiplex rt-PCR assays for simultaneous detection of eight sweet potato viruses. AB - Sweet potato is grown extensively from tropical to temperate regions and is an important food crop worldwide. In this study, we established detection methods for 17 major sweet potato viruses using single and multiplex RT-PCR assays. To investigate the current incidence of viral diseases, we collected 154 samples of various sweet potato cultivars showing virus-like symptoms from 40 fields in 10 Korean regions, and analyzed them by RT-PCR using specific primers for each of the 17 viruses. Of the 17 possible viruses, we detected eight in our samples. Sweet potato feathery mottle virus (SPFMV) and sweet potato virus C (SPVC) were most commonly detected, infecting approximately 87% and 85% of samples, respectively. Furthermore, Sweet potato symptomless virus 1 (SPSMV-1), Sweet potato virus G (SPVG), Sweet potato leaf curl virus (SPLCV), Sweet potato virus 2 ( SPV2), Sweet potato chlorotic fleck virus (SPCFV), and Sweet potato latent virus (SPLV) were detected in 67%, 58%, 47%, 41%, 31%, and 20% of samples, respectively. This study presents the first documented occurrence of four viruses (SPVC, SPV2, SPCFV, and SPSMV-1) in Korea. Based on the results of our survey, we developed multiplex RT-PCR assays for simple and simultaneous detection of the eight sweet potato viruses we recorded. PMID- 25506307 TI - Transcriptome Analysis of the Barley-Rhynchosporium secalis Interaction. AB - Leaf scald caused by the infection of Rhynchosporium secalis, is a worldwide crop disease resulting in significant loss of barley yield. In this study, a systematic sequencing of expressed sequence tags (ESTs) was chosen to obtain a global picture of the assembly of genes involved in pathogenesis. To identify a large number of plant ESTs, which are induced at different time points, an amplified fragment length polymorphism (AFLP) display of complementary DNA (cDNA) was utilized. Transcriptional changes of 140 ESTs were observed, of which 19 have no previously described function. Functional annotation of the transcripts revealed a variety of infection-induced host genes encoding classical pathogenesis-related (PR) or genes that play a role in the signal transduction pathway. The expression analyses by a semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) revealed that Rar1 and Rpg4 are defense inducible genes, and were consistent with the cDNA-AFLP data in their expression patterns. Hence, the here presented transcriptomic approach provides novel global catalogue of genes not currently represented in the EST databases. PMID- 25506308 TI - Development of a Selective Medium for the Fungal Pathogen Cylindrocarpon destructans Using Radicicol. AB - The soil-borne ascomycete fungus Cylindrocarpon destructans causes ginseng root rot disease and produces various secondary metabolites such as brefeldin A and radicicol. The slow growth of this fungus compared with other plant pathogenic and saprophytic fungi in soil disturbs isolation of this fungus from soil and infected ginseng. In this study, we developed a selective medium for C. destructans using radicicol produced by this fungus. Supplementing 50 mg/L of radicicol to medium inhibited the mycelia growth of other fungi including Botrytis cinerea, Rhizoctonia solani and Alternaria panax, but did not affect the growth of C. destructans. In addition, conidia germination of other fungal species except for C. destructans was inhibited in submerged culture supplemented with radicicol. This medium provides a very efficient tool for isolating C. destructans and also can be used as an enrichment medium for this fungus. PMID- 25506309 TI - Simple Method to Produce in vitro Pyrenophora tritici-repentis Teleomorph. AB - A fungus Pyrenophora tritici-repentis induces tan spot of wheat which is a foliar disease that causes yield loss to wheat crops worldwide. In this study, a new, simple and non-costly technique was performed to produce the sexual stage of this fungus in culture, within 9 weeks using wheat straw. This protocol will be helpful to researchers studying the biology of sexual stage development, disease epidemiology and genetics of this fungus. PMID- 25506310 TI - Development of a PCR Diagnostic System for Iris yellow spot tospovirus in Quarantine. AB - Iris yellow spot virus (IYSV) is a plant pathogenic virus which has been reported to continuously occur in onion bulbs, allium field crops, seed crops, lisianthus, and irises. In South Korea, IYSV is a "controlled" virus that has not been reported, and inspection is performed when crops of the genus Iris are imported into South Korea. In this study, reverse-transcription polymerase chain reaction (RT-PCR) and nested PCR inspection methods, which can detect IYSV, from imported crops of the genus Iris at quarantine sites, were developed. In addition, a modified positive plasmid, which can be used as a positive control during inspection, was developed. This modified plasmid can facilitate a more accurate inspection by enabling the examination of a laboratory contamination in an inspection system. The inspection methods that were developed in this study are expected to contribute, through the prompt and accurate inspection of IYSV at quarantine sites to the plant quarantine in South Korea. PMID- 25506311 TI - Survey of Cherry necrotic rusty mottle virus and Cherry green ring mottle virus incidence in Korea by Duplex RT-PCR. AB - The incidence of Cherry necrotic rusty mottle virus (CNRMV) and Cherry green ring mottle virus (CGRMV) have recently been occurred in Korea, posing a problem for sweet cherry cultivation. Since infected trees have symptomless leaves or ring like spots on the pericarp, it is difficult to identify a viral infection. In this study, the incidence of CNRMV and CGRMV in sweet cherry in Gyeongbuk province was surveyed using a newly developed duplex reverse transcriptase polymerase chain reaction (RT-PCR) method that can detect both viruses in a single reaction. CNRMV and CGRMV co-infection rates were 29.6%, 53.6%, and 17.6%, respectively, in samples collected from three different sites (Daegu, Gyeongju and Gyeongsan) in Gyeongbuk province during 2012 and 2013. This duplex RT-PCR method offers a simple, rapid, and effective way of identifying CNRMV and CGRMV simultaneously in sweet cherry trees, which can aid in the management of viral infections that could undermine yield. PMID- 25506312 TI - Control of Meloidogyne incognita Using Mixtures of Organic Acids. AB - This study sought to control the root-knot nematode (RKN) Meloidogyne incognita using benign organo-chemicals. Second-stage juveniles (J2) of RKN were exposed to dilutions (1.0%, 0.5%, 0.2%, and 0.1%) of acetic acid (AA), lactic acid (LA), and their mixtures (MX). The nematode bodies were disrupted severely and moderately by vacuolations in 0.5% of MX and single organic acids, respectively, suggesting toxicity of MX may be higher than AA and LA. The mortality of J2 was 100% at all concentrations of AA and MX and only at 1.0% and 0.5% of LA, which lowered slightly at 0.2% and greatly at 0.1% of LA. This suggests the nematicidal activity of MX may be mostly derived from AA together with supplementary LA toxicity. MX was applied to chili pepper plants inoculated with about 1,000 J2, for which root-knot gall formations and plant growths were examined 4 weeks after inoculation. The root gall formation was completely inhibited by 0.5% MX and standard and double concentrations of fosthiazate; and inhibited 92.9% and 57.1% by 0.2% and 0.1% MX, respectively. Shoot height, shoot weight, and root weight were not significantly (P <= 0.05) different among all treatments and the untreated and non-inoculated controls. All of these results suggest that the mixture of the organic acids may have a potential to be developed as an eco friendly nematode control agent that needs to be supported by the more nematode control experiments in fields. PMID- 25506313 TI - [Key Concepts for Understanding Vulnerable Populations: A Conversation Between Alejandro Moreno Olmedo and Philippe Bourgois.] PMID- 25506314 TI - DNA Hybridization-Mediated Liposome Fusion at the Aqueous Liquid Crystal Interface. AB - The prominence of receptor-mediated bilayer fusion in cellular biology motivates development of biomimetic strategies for studying fusogenic mechanisms. An approach is reported here for monitoring receptor-mediated fusion that exploits the unique physical and optical properties of liquid crystals (LC). PEG functionalized lipids are used to create an interfacial environment capable of inhibiting spontaneous liposome fusion with an aqueous/LC interface. Then, DNA hybridization between oligonucleotides within bulk phase liposomes and a PEG lipid monolayer at an aqueous/LC interface is exploited to induce receptor mediated liposome fusion. These hybridization events induce strain within the liposome bilayer, promote lipid mixing with the LC interface, and consequently create an interfacial environment favoring re-orientation of the LC to a homeotropic (perpendicular) state. Furthermore, the bi-functionality of aptamers is exploited to modulate DNA hybridization-mediated liposome fusion by regulating the availability of the appropriate ligand (i.e., thrombin). Here, a LC-based approach for monitoring receptor (i.e., DNA hybridization)-mediated liposome fusion is demonstrated, liposome properties that dictate fusion dynamics are explored, and an example of how this approach may be used in a biosensing scheme is provided. PMID- 25506315 TI - Estimation of effective connectivity via data-driven neural modeling. AB - This research introduces a new method for functional brain imaging via a process of model inversion. By estimating parameters of a computational model, we are able to track effective connectivity and mean membrane potential dynamics that cannot be directly measured using electrophysiological measurements alone. The ability to track the hidden aspects of neurophysiology will have a profound impact on the way we understand and treat epilepsy. For example, under the assumption the model captures the key features of the cortical circuits of interest, the framework will provide insights into seizure initiation and termination on a patient-specific basis. It will enable investigation into the effect a particular drug has on specific neural populations and connectivity structures using minimally invasive measurements. The method is based on approximating brain networks using an interconnected neural population model. The neural population model is based on a neural mass model that describes the functional activity of the brain, capturing the mesoscopic biophysics and anatomical structure. The model is made subject-specific by estimating the strength of intra-cortical connections within a region and inter-cortical connections between regions using a novel Kalman filtering method. We demonstrate through simulation how the framework can be used to track the mechanisms involved in seizure initiation and termination. PMID- 25506317 TI - The cerebellum: from development to structural complexity and motor learning. PMID- 25506316 TI - The role of GABA in the regulation of GnRH neurons. AB - Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for the central regulation of reproduction. Gamma-amino butyric acid (GABA) has long been implicated as one of the major players in the regulation of GnRH neurons. Although GABA is typically an inhibitory neurotransmitter in the mature adult central nervous system, most mature GnRH neurons show the unusual characteristic of being excited by GABA. While many reports have provided much insight into the contribution of GABA to the activity of GnRH neurons, the precise physiological role of the excitatory action of GABA on GnRH neurons remains elusive. This brief review presents the current knowledge of the role of GABA signaling in GnRH neuronal activity. We also discuss the modulation of GABA signaling by neurotransmitters and neuromodulators and the functional consequence of GABAergic inputs to GnRH neurons in both the physiology and pathology of reproduction. PMID- 25506318 TI - Medial prefrontal cortex dopamine controls the persistent storage of aversive memories. AB - Medial prefrontal cortex (mPFC) is essential for initial memory processing and expression but its involvement in persistent memory storage has seldom been studied. Using the hippocampus dependent inhibitory avoidance learning task and the hippocampus-independent conditioned taste aversion paradigm together with specific dopamine receptor agonists and antagonists we found that persistence but not formation of long-term aversive memories requires dopamine D1/D5 receptors activation in mPFC immediately after training and, depending on the task, between 6 and 12 h later. Our results indicate that besides its well-known participation in retrieval and early consolidation, mPFC also modulates the endurance of long lasting aversive memories regardless of whether formation of the aversive mnemonic trace requires the participation of the hippocampus. PMID- 25506319 TI - Noradrenergic blockade of memory reconsolidation: a failure to reduce conditioned fear responding. AB - Upon recall, a memory can enter a labile state in which it requires new protein synthesis to restabilize. This two-phased reconsolidation process raises the prospect to directly target excessive fear memory as opposed to the formation of inhibitory memory following extinction training. In our previous studies, we convincingly demonstrated that 40 mg propranolol HCl administration before or after memory reactivation eliminated the emotional expression of fear memory indexed by the fear potentiated startle reflex. To apply this procedure in clinical practice it is important to understand the optimal and boundary conditions of this procedure. As part of a large project aimed at unraveling putative boundary conditions of disrupting reconsolidation of associative fear memory with propranolol HCl, we again tested our memory reconsolidation procedure. Participants (N = 44) underwent a three-day differential fear conditioning procedure. Twenty-four hours after fear acquisition, participants received 40 mg propranolol HCl prior to memory reactivation. The next day, participants were subjected to extinction training and reinstatement testing. In sharp contrast to our previous findings, propranolol HCl before memory reactivation did not attenuate the startle fear response. Remarkably, the startle fear response even persisted during extinction training and did not show the usually observed gradual decline in conditioned physiological responding (startle potentiation and skin conductance) upon repeated unreinforced trials. We discuss these unexpected findings and propose some potential explanations. It remains, however, unclear why we observed a resistance to reduce conditioned fear responding by either disrupting reconsolidation or extinction training. The present results underscore that the success of human fear conditioning research may depend on subtle manipulations and instructions. PMID- 25506320 TI - Impairments of working memory in schizophrenia and bipolar disorder: the effect of history of psychotic symptoms and different aspects of cognitive task demands. AB - Comparisons of cognitive impairments between schizophrenia (SZ) and bipolar disorder (BPD) have produced mixed results. We applied different working memory (WM) measures (Digit Span Forward and Backward, Short-delay and Long-delay CPT AX, N-back) to patients with SZ (n = 23), psychotic BPD (n = 19) and non psychotic BPD (n = 24), as well as to healthy controls (HC) (n = 18) in order to compare the level of WM impairments across the groups. With respect to the less demanding WM measures (Digit Span Forward and Backward, Short-delay CPT-AX), there were no between group differences in cognitive performance; however, with respect to the more demanding WM measures (Long-delay CPT-AX, N-back), we observed that the groups with psychosis (SZ, psychotic BPD) did not differ from one another, but performed poorer than the group without a history of psychosis (non-psychotic BPD). A history of psychotic symptoms may influence cognitive performance with respect to WM delay and load effects as measured by Long-delay CPT-AX and N-back tests, respectively. We observed a positive correlation of WM performance with antipsychotic treatment and a negative correlation with depressive symptoms in BPD and with negative symptoms in SZ subgroup. Our study suggests that WM dysfunctions are more closely related to a history of psychosis than to the diagnostic categories of SZ and BPD described by psychiatric classification systems. PMID- 25506322 TI - Sleep spindling and fluid intelligence across adolescent development: sex matters. AB - Evidence supports the intricate relationship between sleep electroencephalogram (EEG) spindling and cognitive abilities in children and adults. Although sleep EEG changes during adolescence index fundamental brain reorganization, a detailed analysis of sleep spindling and the spindle-intelligence relationship was not yet provided for adolescents. Therefore, adolescent development of sleep spindle oscillations were studied in a home polysomnographic study focusing on the effects of chronological age and developmentally acquired overall mental efficiency (fluid IQ) with sex as a potential modulating factor. Subjects were 24 healthy adolescents (12 males) with an age range of 15-22 years (mean: 18 years) and fluid IQ of 91-126 (mean: 104.12, Raven Progressive Matrices Test). Slow spindles (SSs) and fast spindles (FSs) were analyzed in 21 EEG derivations by using the individual adjustment method (IAM). A significant age-dependent increase in average FS density (r = 0.57; p = 0.005) was found. Moreover, fluid IQ correlated with FS density (r = 0.43; p = 0.04) and amplitude (r = 0.41; p = 0.049). The latter effects were entirely driven by particularly reliable FS-IQ correlations in females [r = 0.80 (p = 0.002) and r = 0.67 (p = 0.012), for density and amplitude, respectively]. Region-specific analyses revealed that these correlations peak in the fronto-central regions. The control of the age dependence of FS measures and IQ scores did not considerably reduce the spindle IQ correlations with respect to FS density. The only positive spindle-index of fluid IQ in males turned out to be the frequency of FSs (r = 0.60, p = 0.04). Increases in FS density during adolescence may index reshaped structural connectivity related to white matter maturation in the late developing human brain. The continued development over this age range of cognitive functions is indexed by specific measures of sleep spindling unraveling gender differences in adolescent brain maturation and perhaps cognitive strategy. PMID- 25506321 TI - Schizophrenia and cortical blindness: protective effects and implications for language. AB - The repeatedly noted absence of case-reports of individuals with schizophrenia and congenital/early developed blindness has led several authors to argue that the latter can confer protective effects against the former. In this work, we present a number of relevant case-reports from different syndromes that show comorbidity of congenital and early blindness with schizophrenia. On the basis of these reports, we argue that a distinction between different types of blindness in terms of the origin of the visual deficit, cortical or peripheral, is crucial for understanding the observed patterns of comorbidity. We discuss the genetic underpinnings and the brain structures involved in schizophrenia and blindness, with insights from language processing, laying emphasis on the three structures that particularly stand out: the occipital cortex, the lateral geniculate nucleus (LGN), and the pulvinar. Last, we build on previous literature on the nature of the protective effects in order to offer novel insights into the nature of the protection mechanism from the perspective of the brain structures involved in each type of blindness. PMID- 25506323 TI - Binocular advantage for prehension movements performed in visually enriched environments requiring visual search. AB - The purpose of this study was to examine the role of binocular vision during a prehension task performed in a visually enriched environment where the target object was surrounded by distractors/obstacles. Fifteen adults reached and grasped for a cylindrical peg while eye movements and upper limb kinematics were recorded. The complexity of the visual environment was manipulated by varying the number of distractors and by varying the saliency of the target. Gaze behavior (i.e., the latency of the primary gaze shift and frequency of gaze shifts prior to reach initiation) was comparable between viewing conditions. In contrast, a binocular advantage was evident in performance accuracy. Specifically, participants picked up the wrong object twice as often during monocular viewing when the complexity of the environment increased. Reach performance was more efficient during binocular viewing, which was demonstrated by shorter reach reaction time and overall movement time. Reaching movements during the approach phase had higher peak velocity during binocular viewing. During monocular viewing reach trajectories exhibited a direction bias during the acceleration phase, which was leftward during left eye viewing and rightward during right eye viewing. This bias can be explained by the presence of esophoria in the covered eye. The grasping interval was also extended by ~20% during monocular viewing; however, the duration of the return phase after the target was picked up was comparable across viewing conditions. In conclusion, binocular vision provides important input for planning and execution of prehension movements in visually enriched environments. Binocular advantage was evident, regardless of set size or target saliency, indicating that adults plan their movements more cautiously during monocular viewing, even in relatively simple environments with a highly salient target. Nevertheless, in visually-normal adults monocular input provides sufficient information to engage in online control to correct the initial errors in movement planning. PMID- 25506325 TI - A neuromorphic system for video object recognition. AB - Automated video object recognition is a topic of emerging importance in both defense and civilian applications. This work describes an accurate and low-power neuromorphic architecture and system for real-time automated video object recognition. Our system, Neuormorphic Visual Understanding of Scenes (NEOVUS), is inspired by computational neuroscience models of feed-forward object detection and classification pipelines for processing visual data. The NEOVUS architecture is inspired by the ventral (what) and dorsal (where) streams of the mammalian visual pathway and integrates retinal processing, object detection based on form and motion modeling, and object classification based on convolutional neural networks. The object recognition performance and energy use of the NEOVUS was evaluated by the Defense Advanced Research Projects Agency (DARPA) under the Neovision2 program using three urban area video datasets collected from a mix of stationary and moving platforms. These datasets are challenging and include a large number of objects of different types in cluttered scenes, with varying illumination and occlusion conditions. In a systematic evaluation of five different teams by DARPA on these datasets, the NEOVUS demonstrated the best performance with high object recognition accuracy and the lowest energy consumption. Its energy use was three orders of magnitude lower than two independent state of the art baseline computer vision systems. The dynamic power requirement for the complete system mapped to commercial off-the-shelf (COTS) hardware that includes a 5.6 Megapixel color camera processed by object detection and classification algorithms at 30 frames per second was measured at 21.7 Watts (W), for an effective energy consumption of 5.45 nanoJoules (nJ) per bit of incoming video. These unprecedented results show that the NEOVUS has the potential to revolutionize automated video object recognition toward enabling practical low-power and mobile video processing applications. PMID- 25506326 TI - Finding minimal action sequences with a simple evaluation of actions. AB - Animals are able to discover the minimal number of actions that achieves an outcome (the minimal action sequence). In most accounts of this, actions are associated with a measure of behavior that is higher for actions that lead to the outcome with a shorter action sequence, and learning mechanisms find the actions associated with the highest measure. In this sense, previous accounts focus on more than the simple binary signal of "was the outcome achieved?"; they focus on "how well was the outcome achieved?" However, such mechanisms may not govern all types of behavioral development. In particular, in the process of action discovery (Redgrave and Gurney, 2006), actions are reinforced if they simply lead to a salient outcome because biological reinforcement signals occur too quickly to evaluate the consequences of an action beyond an indication of the outcome's occurrence. Thus, action discovery mechanisms focus on the simple evaluation of "was the outcome achieved?" and not "how well was the outcome achieved?" Notwithstanding this impoverishment of information, can the process of action discovery find the minimal action sequence? We address this question by implementing computational mechanisms, referred to in this paper as no-cost learning rules, in which each action that leads to the outcome is associated with the same measure of behavior. No-cost rules focus on "was the outcome achieved?" and are consistent with action discovery. No-cost rules discover the minimal action sequence in simulated tasks and execute it for a substantial amount of time. Extensive training, however, results in extraneous actions, suggesting that a separate process (which has been proposed in action discovery) must attenuate learning if no-cost rules participate in behavioral development. We describe how no-cost rules develop behavior, what happens when attenuation is disrupted, and relate the new mechanisms to wider computational and biological context. PMID- 25506324 TI - Insights from the supplementary motor area syndrome in balancing movement initiation and inhibition. AB - The supplementary motor area (SMA) syndrome is a characteristic neurosurgical syndrome that can occur after unilateral resection of the SMA. Clinical symptoms may vary from none to a global akinesia, predominantly on the contralateral side, with preserved muscle strength and mutism. A remarkable feature is that these symptoms completely resolve within weeks to months, leaving only a disturbance in alternating bimanual movements. In this review we give an overview of the old and new insights from the SMA syndrome and extrapolate these findings to seemingly unrelated diseases and symptoms such as Parkinson's disease (PD) and tics. Furthermore, we integrate findings from lesion, stimulation and functional imaging studies to provide insight in the motor function of the SMA. PMID- 25506327 TI - Discovery of GPCR ligands for probing signal transduction pathways. AB - G protein-coupled receptors (GPCRs) are seven integral transmembrane proteins that are the primary targets of almost 30% of approved drugs and continue to represent a major focus of pharmaceutical research. All of GPCR targeted medicines were discovered by classical medicinal chemistry approaches. After the first GPCR crystal structures were determined, the docking screens using these structures lead to discovery of more novel and potent ligands. There are over 360 pharmaceutically relevant GPCRs in the human genome and to date about only 30 of structures have been determined. For these reasons, computational techniques such as homology modeling and molecular dynamics simulations have proven their usefulness to explore the structure and function of GPCRs. Furthermore, structure based drug design and in silico screening (High Throughput Docking) are still the most common computational procedures in GPCRs drug discovery. Moreover, ligand based methods such as three-dimensional quantitative structure-selectivity relationships, are the ideal molecular modeling approaches to rationalize the activity of tested GPCR ligands and identify novel GPCR ligands. In this review, we discuss the most recent advances for the computational approaches to effectively guide selectivity and affinity of ligands. We also describe novel approaches in medicinal chemistry, such as the development of biased agonists, allosteric modulators, and bivalent ligands for class A GPCRs. Furthermore, we highlight some knockout mice models in discovering biased signaling selectivity. PMID- 25506330 TI - "No level up!": no effects of video game specialization and expertise on cognitive performance. AB - Previous research into the effects of action video gaming on cognition has suggested that long term exposure to this type of game might lead to an enhancement of cognitive skills that transfer to non-gaming cognitive tasks. However, these results have been controversial. The aim of the current study was to test the presence of positive cognitive transfer from action video games to two cognitive tasks. More specifically, this study investigated the effects that participants' expertise and genre specialization have on cognitive improvements in one task unrelated to video gaming (a flanker task) and one related task (change detection task with both control and genre-specific images). This study was unique in three ways. Firstly, it analyzed a continuum of expertise levels, which has yet to be investigated in research into the cognitive benefits of video gaming. Secondly, it explored genre-specific skill developments on these tasks by comparing Action and Strategy video game players (VGPs). Thirdly, it used a very tight experiment design, including the experimenter being blind to expertise level and genre specialization of the participant. Ninety-two university students aged between 18 and 30 (M = 21.25) were recruited through opportunistic sampling and were grouped by video game specialization and expertise level. While the results of the flanker task were consistent with previous research (i.e., effect of congruence), there was no effect of expertise, and the action gamers failed to outperform the strategy gamers. Additionally, contrary to expectation, there was no interaction between genre specialization and image type in the change detection task, again demonstrating no expertise effect. The lack of effects for game specialization and expertise goes against previous research on the positive effects of action video gaming on other cognitive tasks. PMID- 25506331 TI - Reading component skills in dyslexia: word recognition, comprehension and processing speed. AB - The cognitive model of reading comprehension (RC) posits that RC is a result of the interaction between decoding and linguistic comprehension. Recently, the notion of decoding skill was expanded to include word recognition. In addition, some studies suggest that other skills could be integrated into this model, like processing speed, and have consistently indicated that this skill influences and is an important predictor of the main components of the model, such as vocabulary for comprehension and phonological awareness of word recognition. The following study evaluated the components of the RC model and predictive skills in children and adolescents with dyslexia. 40 children and adolescents (8-13 years) were divided in a Dyslexic Group (DG; 18 children, MA = 10.78, SD = 1.66) and control group (CG 22 children, MA = 10.59, SD = 1.86). All were students from the 2nd to 8th grade of elementary school and groups were equivalent in school grade, age, gender, and IQ. Oral and RC, word recognition, processing speed, picture naming, receptive vocabulary, and phonological awareness were assessed. There were no group differences regarding the accuracy in oral and RC, phonological awareness, naming, and vocabulary scores. DG performed worse than the CG in word recognition (general score and orthographic confusion items) and were slower in naming. Results corroborated the literature regarding word recognition and processing speed deficits in dyslexia. However, dyslexics can achieve normal scores on RC test. Data supports the importance of delimitation of different reading strategies embedded in the word recognition component. The role of processing speed in reading problems remain unclear. PMID- 25506328 TI - Biological redundancy of endogenous GPCR ligands in the gut and the potential for endogenous functional selectivity. AB - This review focuses on the existence and function of multiple endogenous agonists of the somatostatin and opioid receptors with an emphasis on their expression in the gastrointestinal tract. These agonists generally arise from the proteolytic cleavage of prepropeptides during peptide maturation or from degradation of peptides by extracellular or intracellular endopeptidases. In other examples, endogenous peptide agonists for the same G protein-coupled receptors can be products of distinct genes but contain high sequence homology. This apparent biological redundancy has recently been challenged by the realization that different ligands may engender distinct receptor conformations linked to different intracellular signaling profiles and, as such the existence of distinct ligands may underlie mechanisms to finely tune physiological responses. We propose that further characterization of signaling pathways activated by these endogenous ligands will provide invaluable insight into the mechanisms governing biased agonism. Moreover, these ligands may prove useful in the design of novel therapeutic tools to target distinct signaling pathways, thereby favoring desirable effects and limiting detrimental on-target effects. Finally we will discuss the limitations of this area of research and we will highlight the difficulties that need to be addressed when examining endogenous bias in tissues and in animals. PMID- 25506329 TI - Hyperactivity and Motoric Activity in ADHD: Characterization, Assessment, and Intervention. AB - The aim of the present literature review is threefold. (1) We will review theories, models, and studies on symptomatic hyperactivity and motoric activity in attention-deficit/hyperactivity disorder (ADHD). (2) Another focus will be on assessment methods that have been proven to be effective in the detection of hyperactivity and motoric activity in children, adolescents, and adults with and without ADHD and emerging areas of research in the field of ADHD. We will compare subjective methods (i.e., rating scales) and objective methods (i.e., accelerometers). (3) Finally, physical activity intervention studies aiming at a modification of activity and overactive behavior will be summarized that seem to be promising candidates for alleviating hyperactivity symptoms in children, adolescents, and adults with ADHD. PMID- 25506333 TI - The implication of the coefficient of centrality for assessing the meaning of the mean. PMID- 25506334 TI - If times change, should we throw away the hearthstone? Exploring (Dis) continuities in autonomy and decision-making in the lives of Ghanaian women. AB - This paper attempts to investigate continuities and discontinuities between traditional and modern representations of womanhood and female gender roles focusing primarily on family and work settings. Using approaches informed by Sociology, Cultural Psychology, and African Studies, the paper explores traditional views of womanhood encapsulated in (and also transmitted intergenerationally) through proverbs. This customary perspective is contrasted with the results of the Everyday Lives Survey from the Pathways of Women's Empowerment Ghana project. The survey investigated the nature of everyday life- education, work, decision making, access to institutions, and autonomy in relationships-in six hundred (600) adult women in both rural and urban communities in three regions of Ghana. We argue that although the times are changing, there have only been modest disruptions in the lives of Ghanaian women as far as issues of autonomy and decision-making in are concerned. PMID- 25506332 TI - Crossmodal effect of music and odor pleasantness on olfactory quality perception. AB - Previous research has demonstrated that ratings of the perceived pleasantness and quality of odors can be modulated by auditory stimuli presented at around the same time. Here, we extend these results by assessing whether the hedonic congruence between odor and sound stimuli can modulate the perception of odor intensity, pleasantness, and quality in untrained participants. Unexpectedly, our results reveal that broadband white noise, which was rated as unpleasant in a follow-up experiment, actually had a more pronounced effect on participants' odor ratings than either the consonant or dissonant musical selections. In particular, participants rated the six smells used as being less pleasant and less sweet when they happened to be listening to white noise, as compared to any one of the other music conditions. What is more, these results also add evidence to support the existence of a close relationship between an odor's hedonic character and the perception of odor quality. So, for example, independent of the sound condition, pleasant odors were rated as sweeter, less dry, and brighter than the unpleasant odors. These results are discussed in terms of their implications for the understanding of crossmodal correspondences between olfactory and auditory stimuli. PMID- 25506335 TI - The uniquely predictive power of evolutionary approaches to mind and behavior. PMID- 25506336 TI - Transferring control demands across incidental learning tasks - stronger sequence usage in serial reaction task after shortcut option in letter string checking. AB - After incidentally learning about a hidden regularity, participants can either continue to solve the task as instructed or, alternatively, apply a shortcut. Past research suggests that the amount of conflict implied by adopting a shortcut seems to bias the decision for vs. against continuing instruction-coherent task processing. We explored whether this decision might transfer from one incidental learning task to the next. Theories that conceptualize strategy change in incidental learning as a learning-plus-decision phenomenon suggest that high demands to adhere to instruction-coherent task processing in Task 1 will impede shortcut usage in Task 2, whereas low control demands will foster it. We sequentially applied two established incidental learning tasks differing in stimuli, responses and hidden regularity (the alphabet verification task followed by the serial reaction task, SRT). While some participants experienced a complete redundancy in the task material of the alphabet verification task (low demands to adhere to instructions), for others the redundancy was only partial. Thus, shortcut application would have led to errors (high demands to follow instructions). The low control demand condition showed the strongest usage of the fixed and repeating sequence of responses in the SRT. The transfer results are in line with the learning-plus-decision view of strategy change in incidental learning, rather than with resource theories of self-control. PMID- 25506337 TI - Mental imagery interventions reduce subsequent food intake only when self regulatory resources are available. AB - Research has shown that imagining food consumption leads to food-specific habituation effects. In the present research, we replicated these effects and further examined whether the depletion of self-regulatory resources would reduce the habituation effects of imagined food consumption. Since self-regulatory resources have been shown to reduce habituation effects during the perception of emotional stimuli, we expected a reduction in habituation effects from imagined food consumption when self-regulatory resources were depleted. In Study 1, we replicated habituation effects as a response to imagining gummy bear consumption with a high (36) and medium number (18) of repetitions in a camouflaged taste test. Participants imagining gummy bear intake showed decreased food intake compared with participants who imagined putting a coin into a laundry machine. The number of repetitions did not significantly moderate the observed habituation effect. In Study 2, we investigated whether self-regulatory depletion would impede habituation effects evoked by the imagination of walnut consumption. Participants in a depleted state did not show a reduction in food intake after imagining walnut intake compared with participants in a non-depleted state. We discuss directions for future research and processes that might underlie the observed moderating effect of self-regulatory resources. PMID- 25506338 TI - Clinical features in patients with long-lasting macrophagic myofasciitis. AB - Macrophagic myofasciitis (MMF) is an emerging condition characterized by specific muscle lesions assessing abnormal long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients usually are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and marked cognitive deficits, not related to pain, fatigue, or depression. Clinical features usually correspond to that observed in chronic fatigue syndrome/myalgic encephalomyelitis. Representative features of MMF associated cognitive dysfunction include dysexecutive syndrome, visual memory impairment, and left ear extinction at dichotic listening test. Most patients fulfill criteria for non-amnestic/dysexecutive mild cognitive impairment, even if some cognitive deficits appear unusually severe. Cognitive dysfunction seems stable over time despite marked fluctuations. Evoked potentials may show abnormalities in keeping with central nervous system involvement, with a neurophysiological pattern suggestive of demyelination. Brain perfusion SPECT shows a pattern of diffuse cortical and subcortical abnormalities, with hypoperfusions correlating with cognitive deficiencies. The combination of musculoskeletal pain, chronic fatigue, and cognitive disturbance generates chronic disability with possible social exclusion. Classical therapeutic approaches are usually unsatisfactory making patient care difficult. PMID- 25506339 TI - Structural Differences in Gray Matter between Glider Pilots and Non-Pilots. A Voxel-Based Morphometry Study. AB - Glider flying is a unique skill that requires pilots to control an aircraft at high speeds in three dimensions and amidst frequent full-body rotations. In the present study, we investigated the neural correlates of flying a glider using voxel-based morphometry. The comparison between gray matter densities of 15 glider pilots and a control group of 15 non-pilots exhibited significant gray matter density increases in left ventral premotor cortex, anterior cingulate cortex, and the supplementary eye field. We posit that the identified regions might be associated with cognitive and motor processes related to flying, such as joystick control, visuo-vestibular interaction, and oculomotor control. PMID- 25506341 TI - Mechanistic insights into filamentous phage integration in Vibrio cholerae. AB - Vibrio cholerae, the etiological agent of acute diarrhoeal disease cholera, harbors large numbers of lysogenic filamentous phages, contribute significantly to the host pathogenesis and provide fitness factors to the pathogen that help the bacterium to survive in natural environment. Most of the vibriophage genomes are not equipped with integrase and thus exploit two host-encoded tyrosine recombinases, XerC and XerD, for lysogenic conversion. Integration is site specific and it occurs at dimer resolution site (dif) of either one or both chromosomes of V. cholerae. Each dif sequence contains two recombinase-binding sequences flanking a central region. The integration follows a sequential strand exchanges between dif and attP sites within a DNA-protein complex consisting of one pair of each recombinase and two DNA fragments. During entire process of recombination, both the DNA components and recombinases of the synaptic complex keep transiently interconnected. Within the context of synaptic complex, both of the actuated enzymes mediate cleavage of phosphodiester bonds. First cleavage generates a phosphotyrosyl-linked recombinase-DNA complex at the recombinase binding sequence and free 5'-hydroxyl end at the first base of the central region. Following the cleavage, the exposed bases with 5'-hydroxyl ends of the central region of dif and attP sites melt from their complementary strands and react with the recombinase-DNA phosphotyrosyl linkage of their recombining partner. Subsequent ligation between dif and attP strands requires complementary base pair interactions at the site of phosphodiester bond formation. Integration mechanism is mostly influenced by the compatibility of dif and attP sequences. dif sites are highly conserved across bacterial phyla. Different phage genomes have different attP sequences; therefore they rely on different mechanisms for integration. Here, I review our current understanding of integration mechanisms used by the vibriophages. PMID- 25506343 TI - Investigating microbial activities of electrode-associated microorganisms in real time. AB - Electrode-associated microbial biofilms are essential to the function of bioelectrochemical systems (BESs). These systems exist in a number of different configurations but all rely on electroactive microorganisms utilizing an electrode as either an electron acceptor or an electron donor to catalyze biological processes. Investigations of the structure and function of electrode associated biofilms are critical to further the understanding of how microbial communities are able to reduce and oxidize electrodes. The community structure of electrode-reducing biofilms is diverse and often dominated by Geobacter spp. whereas electrode-oxidizing biofilms are often dominated by other microorganisms. The application of a wide range of tools, such as high-throughput sequencing and metagenomic data analyses, provide insight into the structure and possible function of microbial communities on electrode surfaces. However, the development and application of techniques that monitor gene expression profiles in real-time are required for a more definite spatial and temporal understanding of the diversity and biological activities of these dynamic communities. This mini review summarizes the key gene expression techniques used in BESs research, which have led to a better understanding of population dynamics, cell-cell communication and molecule-surface interactions in mixed and pure BES communities. PMID- 25506342 TI - Nitrogen regulation of fungal secondary metabolism in fungi. AB - Fungi occupy diverse environments where they are constantly challenged by stressors such as extreme pH, temperature, UV exposure, and nutrient deprivation. Nitrogen is an essential requirement for growth, and the ability to metabolize a wide variety of nitrogen sources enables fungi to colonize different environmental niches and survive nutrient limitations. Favored nitrogen sources, particularly ammonium and glutamine, are used preferentially, while the expression of genes required for the use of various secondary nitrogen sources is subject to a regulatory mechanism called nitrogen metabolite repression. Studies on gene regulation in response to nitrogen availability were carried out first in Saccharomyces cerevisiae, Aspergillus nidulans, and Neurospora crassa. These studies revealed that fungi respond to changes in nitrogen availability with physiological and morphological alterations and activation of differentiation processes. In all fungal species studied, the major GATA transcription factor AreA and its co-repressor Nmr are central players of the nitrogen regulatory network. In addition to growth and development, the quality and quantity of nitrogen also affects the formation of a broad range of secondary metabolites (SMs). Recent studies, mainly on species of the genus Fusarium, revealed that AreA does not only regulate a large set of nitrogen catabolic genes, but can also be involved in regulating production of SMs. Furthermore, several other regulators, e.g., a second GATA transcription factor, AreB, that was proposed to negatively control nitrogen catabolic genes by competing with AreA for binding to GATA elements, was shown to act as activator of some nitrogen-repressed as well as nitrogen-induced SM gene clusters. This review highlights our latest understanding of canonical (AreA-dependent) and non-canonical nitrogen regulation mechanisms by which fungi may regulate biosynthesis of certain SMs in response to nitrogen availability. PMID- 25506344 TI - Progression to AIDS in SIV-Infected Rhesus Macaques is Associated with Distinct KIR and MHC class I Polymorphisms and NK Cell Dysfunction. AB - Killer cell immunoglobulin-like receptors (KIR) regulate the activity of natural killer (NK) cells and have been shown to be associated with susceptibility to a number of human infectious diseases. Here, we analyzed NK cell function and genetic associations in a cohort of 52 rhesus macaques experimentally infected with SIVmac and subsequently stratified into high viral load (HVL) and low viral load (LVL) plasma viral loads at set point. This stratification coincided with fast (HVL) and slow (LVL) disease progression indicated by the disease course and critical clinical parameters including CD4+ T cell counts. HVL animals revealed sustained proliferation of NK cells but distinct loss of peripheral blood NK cell numbers and lytic function. Genetic analyses revealed that KIR genes 3DL05, 3DS05, and 3DL10 as well as 3DSW08, 3DLW03, and 3DSW09 are correlated, most likely due to underlying haplotypes. SIV-infection outcome associated with presence of transcripts for two inhibitory KIR genes (KIR3DL02, KIR3DL10) and three activating KIR genes (KIR3DSW08, KIR3DS02, KIR3DS05). Presence of KIR3DL02 and KIR3DSW08 was associated with LVL outcome, whereas presence of KIR3DS02 was associated with HVL outcome. Furthermore, we identified epistasis between KIR and MHC class I alleles as the transcript presence of the correlated genes KIR3DL05, KIR3DS05, and KIR3DL10 increased HVL risk when Mamu-B*012 transcripts were also present or when Mamu-A1*001 transcripts were absent. These genetic associations were mirrored by changes in the numbers, the level of proliferation, and lytic capabilities of NK cells as well as overall survival time and gastro-intestinal tissue viral load. PMID- 25506340 TI - Natriuretic hormones in brain function. AB - Natriuretic hormones (NH) include three groups of compounds: the natriuretic peptides (ANP, BNP and CNP), the gastrointestinal peptides (guanylin and uroguanylin), and endogenous cardiac steroids. These substances induce the kidney to excrete sodium and therefore participate in the regulation of sodium and water homeostasis, blood volume, and blood pressure (BP). In addition to their peripheral functions, these hormones act as neurotransmitters or neuromodulators in the brain. In this review, the established information on the biosynthesis, release and function of NH is discussed, with particular focus on their role in brain function. The available literature on the expression patterns of each of the NH and their receptors in the brain is summarized, followed by the evidence for their roles in modulating brain function. Although numerous open questions exist regarding this issue, the available data support the notion that NH participate in the central regulation of BP, neuroprotection, satiety, and various psychiatric conditions, including anxiety, addiction, and depressive disorders. In addition, the interactions between the different NH in the periphery and the brain are discussed. PMID- 25506345 TI - The definition of lymphocyte activating factor: giving a helping hand to serendipity. PMID- 25506346 TI - Molecular mechanisms that influence the macrophage m1-m2 polarization balance. AB - As an essential component of innate immunity, macrophages have multiple functions in both inhibiting or promoting cell proliferation and tissue repair. Diversity and plasticity are hallmarks of macrophages. Classical M1 and alternative M2 activation of macrophages, mirroring the Th1-Th2 polarization of T cells, represent two extremes of a dynamic changing state of macrophage activation. M1 type macrophages release cytokines that inhibit the proliferation of surrounding cells and damage contiguous tissue, and M2-type macrophages release cytokines that promote the proliferation of contiguous cells and tissue repair. M1-M2 polarization of macrophage is a tightly controlled process entailing a set of signaling pathways, transcriptional and posttranscriptional regulatory networks. An imbalance of macrophage M1-M2 polarization is often associated with various diseases or inflammatory conditions. Therefore, identification of the molecules associated with the dynamic changes of macrophage polarization and understanding their interactions is crucial for elucidating the molecular basis of disease progression and designing novel macrophage-mediated therapeutic strategies. PMID- 25506347 TI - A novel conserved mechanism for plant NLR protein pairs: the "integrated decoy" hypothesis. AB - Plant immunity is often triggered by the specific recognition of pathogen effectors by intracellular nucleotide-binding, leucine-rich repeat receptors (NLR). Plant NLRs contain an N-terminal signaling domain that is mostly represented by either a Toll-interleukin1 receptor (TIR) domain or a coiled coil (CC) domain. In many cases, single NLR proteins are sufficient for both effector recognition and signaling activation. However, many paired NLRs have now been identified where both proteins are required to confer resistance to pathogens. Recent detailed studies on the Arabidopsis thaliana TIR-NLR pair RRS1 and RPS4 and on the rice CC-NLR pair RGA4 and RGA5 have revealed for the first time how such protein pairs function together. In both cases, the paired partners interact physically to form a hetero-complex receptor in which each partner plays distinct roles in effector recognition or signaling activation, highlighting a conserved mode of action of NLR pairs across both monocotyledonous and dicotyledonous plants. We also describe an "integrated decoy" model for the function of these receptor complexes. In this model, a plant protein targeted by an effector has been duplicated and fused to one member of the NLR pair, where it acts as a bait to trigger defense signaling by the second NLR upon effector binding. This mechanism may be common to many other plant NLR pairs. PMID- 25506348 TI - Genome wide transcriptome analysis reveals ABA mediated response in Arabidopsis during gold (AuCl(-) 4) treatment. AB - The unique physico-chemical properties of gold nanoparticles (AuNPs) find manifold applications in diagnostics, medicine and catalysis. Chemical synthesis produces reactive AuNPs and generates hazardous by-products. Alternatively, plants can be utilized to produce AuNPs in an eco-friendly manner. To better control the biosynthesis of AuNPs, we need to first understand the detailed molecular response induced by AuCl(-) 4 In this study, we carried out global transcriptome analysis in root tissue of Arabidopsis grown for 12- h in presence of gold solution (HAuCl4) using the novel unbiased Affymetrix exon array. Transcriptomics analysis revealed differential regulation of a total of 704 genes and 4900 exons. Of these, 492 and 212 genes were up- and downregulated, respectively. The validation of the expressed key genes, such as glutathione-S transferases, auxin responsive genes, cytochrome P450 82C2, methyl transferases, transducin (G protein beta subunit), ERF transcription factor, ABC, and MATE transporters, was carried out through quantitative RT-PCR. These key genes demonstrated specific induction under AuCl4(-) treatment relative to other heavy metals, suggesting a unique plant-gold interaction. GO enrichment analysis reveals the upregulation of processes like oxidative stress, glutathione binding, metal binding, transport, and plant hormonal responses. Changes predicted in biochemical pathways indicated major modulation in glutathione mediated detoxification, flavones and derivatives, and plant hormone biosynthesis. Motif search analysis identified a highly significant enriched motif, ACGT, which is an abscisic acid responsive core element (ABRE), suggesting the possibility of ABA- mediated signaling. Identification of abscisic acid response element (ABRE) points to the operation of a predominant signaling mechanism in response to AuCl( ) 4 exposure. Overall, this study presents a useful picture of plant-gold interaction with an identification of candidate genes involved in nanogold synthesis. PMID- 25506349 TI - Metabolic trade-offs between biomass synthesis and photosynthate export at different light intensities in a genome-scale metabolic model of rice. AB - Previously we have used a genome scale model of rice metabolism to describe how metabolism reconfigures at different light intensities in an expanding leaf of rice. Although this established that the metabolism of the leaf was adequately represented, in the model, the scenario was not that of the typical function of the leaf-to provide material for the rest of the plant. Here we extend our analysis to explore the transition to a source leaf as export of photosynthate increases at the expense of making leaf biomass precursors, again as a function of light intensity. In particular we investigate whether, when the leaf is making a smaller range of compounds for export to the phloem, the same changes occur in the interactions between mitochondrial and chloroplast metabolism as seen in biomass synthesis for growth when light intensity increases. Our results show that the same changes occur qualitatively, though there are slight quantitative differences reflecting differences in the energy and redox requirements for the different metabolic outputs. PMID- 25506350 TI - Transcript abundance on its own cannot be used to infer fluxes in central metabolism. AB - An attempt has been made to define the extent to which metabolic flux in central plant metabolism is reflected by changes in the transcriptome and metabolome, based on an analysis of in vitro cultured immature embryos of two oilseed rape (Brassica napus) accessions which contrast for seed lipid accumulation. Metabolic flux analysis (MFA) was used to constrain a flux balance metabolic model which included 671 biochemical and transport reactions within the central metabolism. This highly confident flux information was eventually used for comparative analysis of flux vs. transcript (metabolite). Metabolite profiling succeeded in identifying 79 intermediates within the central metabolism, some of which differed quantitatively between the two accessions and displayed a significant shift corresponding to flux. An RNA-Seq based transcriptome analysis revealed a large number of genes which were differentially transcribed in the two accessions, including some enzymes/proteins active in major metabolic pathways. With a few exceptions, differential activity in the major pathways (glycolysis, TCA cycle, amino acid, and fatty acid synthesis) was not reflected in contrasting abundances of the relevant transcripts. The conclusion was that transcript abundance on its own cannot be used to infer metabolic activity/fluxes in central plant metabolism. This limitation needs to be borne in mind in evaluating transcriptome data and designing metabolic engineering experiments. PMID- 25506351 TI - Transgenic plants expressing omega-ACTX-Hv1a and snowdrop lectin (GNA) fusion protein show enhanced resistance to aphids. AB - Recombinant fusion proteins containing arthropod toxins have been developed as a new class of biopesticides. The recombinant fusion protein Hv1a/GNA, containing the spider venom toxin omega-ACTX-Hv1a linked to snowdrop lectin (GNA) was shown to reduce survival of the peach-potato aphid Myzus persicae when delivered in artificial diet, with survival <10% after 8 days exposure to fusion protein at 1 mg/ml. Although the fusion protein was rapidly degraded by proteases in the insect, Hv1a/GNA oral toxicity to M. persicae was significantly greater than GNA alone. A construct encoding the fusion protein, including the GNA leader sequence, under control of the constitutive CaMV 35S promoter was transformed into Arabidopsis; the resulting plants contained intact fusion protein in leaf tissues at an estimated level of 25.6 +/- 4.1 ng/mg FW. Transgenic Arabidopsis expressing Hv1a/GNA induced up to 40% mortality of M. persicae after 7 days exposure in detached leaf bioassays, demonstrating that transgenic plants can deliver fusion proteins to aphids. Grain aphids (Sitobion avenae) were more susceptible than M. persicae to the Hv1a/GNA fusion protein in artificial diet bioassays (LC50 = 0.73 mg/ml after 2 days against LC50 = 1.81 mg/ml for M. persicae), as they were not able to hydrolyze the fusion protein as readily as M. persicae. Expression of this fusion protein in suitable host plants for the grain aphid is likely to confer higher levels of resistance than that shown with the M. persicae/Arabidopsis model system. PMID- 25506352 TI - Peptides and small molecules of the plant-pathogen apoplastic arena. AB - Plants reside within an environment rich in potential pathogens. Survival in the presence of such threats requires both effective perception of, and appropriate responses to, pathogenic attack. While plants lack an adaptive immune system, they have a highly developed and responsive innate immune system able to detect and inhibit the growth of the vast majority of potential pathogens. Many of the critical interactions that characterize the relationship between plants and pathogens are played out in the intercellular apoplastic space. The initial perception of pathogen invasion is often achieved through specific plant receptor like kinases that recognize conserved molecular patterns presented by the pathogen or respond to the molecular debris caused by cellular damage. The perception of either microbial or damage signals by these receptors initiates a response that includes the production of peptides and small molecules to enhance cellular integrity and inhibit pathogen growth. In this review, we discuss the roles of apoplastic peptides and small molecules in modulating plant-pathogen interactions. PMID- 25506354 TI - To move or to evolve: contrasting patterns of intercontinental connectivity and climatic niche evolution in "Terebinthaceae" (Anacardiaceae and Burseraceae). AB - Many angiosperm families are distributed pantropically, yet for any given continent little is known about which lineages are ancient residents or recent arrivals. Here we use a comprehensive sampling of the pantropical sister pair Anacardiaceae and Burseraceae to assess the relative importance of continental vicariance, long-distance dispersal and niche-conservatism in generating its distinctive pattern of diversity over time. Each family has approximately the same number of species and identical stem age, yet Anacardiaceae display a broader range of fruit morphologies and dispersal strategies and include species that can withstand freezing temperatures, whereas Burseraceae do not. We found that nuclear and chloroplast data yielded a highly supported phylogenetic reconstruction that supports current taxonomic concepts and time-calibrated biogeographic reconstructions that are broadly congruent with the fossil record. We conclude that the most recent common ancestor of these families was widespread and likely distributed in the Northern Hemisphere during the Cretaceous and that vicariance between Eastern and Western Hemispheres coincided with the initial divergence of the families. The tempo of diversification of the families is strikingly different. Anacardiaceae steadily accumulated lineages starting in the Late Cretaceous-Paleocene while the majority of Burseraceae diversification occurred in the Miocene. Multiple dispersal- and vicariance-based intercontinental colonization events are inferred for both families throughout the past 100 million years. However, Anacardiaceae have shifted climatic niches frequently during this time, while Burseraceae have experienced very few shifts between dry and wet climates and only in the tropics. Thus, we conclude that both Anacardiaceae and Burseraceae move easily but that Anacardiaceae have adapted more often, either due to more varied selective pressures or greater intrinsic lability. PMID- 25506353 TI - Epithelial cells as alternative human biomatrices for comet assay. AB - The comet assay is a valuable experimental tool aimed at mapping DNA damage in human cells in vivo for environmental and occupational monitoring, as well as for therapeutic purposes, such as storage prior to transplant, during tissue engineering, and in experimental ex vivo assays. Furthermore, due to its great versatility, the comet assay allows to explore the use of alternative cell types to assess DNA damage, such as epithelial cells. Epithelial cells, as specialized components of many organs, have the potential to serve as biomatrices that can be used to evaluate genotoxicity and may also serve as early effect biomarkers. Furthermore, 80% of solid cancers are of epithelial origin, which points to the importance of studying DNA damage in these tissues. Indeed, studies including comet assay in epithelial cells have either clear clinical applications (lens and corneal epithelial cells) or examine genotoxicity within human biomonitoring and in vitro studies. We here review improvements in determining DNA damage using the comet assay by employing lens, corneal, tear duct, buccal, and nasal epithelial cells. For some of these tissues invasive sampling procedures are needed. Desquamated epithelial cells must be obtained and dissociated prior to examination using the comet assay, and such procedures may induce varying amounts of DNA damage. Buccal epithelial cells require lysis enriched with proteinase K to obtain free nucleosomes. Over a 30 year period, the comet assay in epithelial cells has been little employed, however its use indicates that it could be an extraordinary tool not only for risk assessment, but also for diagnosis, prognosis of treatments and diseases. PMID- 25506355 TI - Even modest prediction accuracy of genomic models can have large clinical utility. AB - Whole Genome Prediction (WGP) jointly fits thousands of SNPs into a regression model to yield estimates for the contribution of markers to the overall variance of a particular trait, and for their associations with that trait. To date, WGP has offered only modest prediction accuracy, but in some cases even modest prediction accuracy may be useful. We provide an illustration of this using a theoretical simulation that used WGP to predict weight loss after bariatric surgery with moderate accuracy (R (2) = 0.07) to assess the clinical utility of WGP despite these limitations. Prevention of Type 2 Diabetes (T2DM) post-surgery was considered the major outcome. Treating only patients above predefined threshold of predicted weight loss in our simulation, in the realistic context of finite resources for the surgery, significantly reduced lifetime risk of T2DM in the treatable population by selecting those most likely to succeed. Thus, our example illustrates how WGP may be clinically useful in some situations, and even with moderate accuracy, may provide a clear path for turning personalized medicine from theory to reality. PMID- 25506357 TI - Coronary Plaque Boundary Enhancement in IVUS Image by Using a Modified Perona Malik Diffusion Filter. AB - We propose a modified Perona-Malik diffusion (PMD) filter to enhance a coronary plaque boundary by considering the conditions peculiar to an intravascular ultrasound (IVUS) image. The IVUS image is commonly used for a diagnosis of acute coronary syndrome (ACS). The IVUS image is however very grainy due to heavy speckle noise. When the normal PMD filter is applied for speckle noise reduction in the IVUS image, the coronary plaque boundary becomes vague. For this problem, we propose a modified PMD filter which is designed in special reference to the coronary plaque boundary detection. It can then not only reduce the speckle noise but also enhance clearly the coronary plaque boundary. After applying the modified PMD filter to the IVUS image, the coronary plaque boundaries are successfully detected further by applying the Takagi-Sugeno fuzzy model. The accuracy of the proposed method has been confirmed numerically by the experiments. PMID- 25506358 TI - A novel adjustment method for shearer traction speed through integration of T-S cloud inference network and improved PSO. AB - In order to efficiently and accurately adjust the shearer traction speed, a novel approach based on Takagi-Sugeno (T-S) cloud inference network (CIN) and improved particle swarm optimization (IPSO) is proposed. The T-S CIN is built through the combination of cloud model and T-S fuzzy neural network. Moreover, the IPSO algorithm employs parameter automation adjustment strategy and velocity resetting to significantly improve the performance of basic PSO algorithm in global search and fine-tuning of the solutions, and the flowchart of proposed approach is designed. Furthermore, some simulation examples are carried out and comparison results indicate that the proposed method is feasible, efficient, and is outperforming others. Finally, an industrial application example of coal mining face is demonstrated to specify the effect of proposed system. PMID- 25506356 TI - IRF4 and IRF8: Governing the virtues of B Lymphocytes. AB - Interferon Regulatory Factor 4 (IRF4) and IRF8 are critical regulators of immune system development and function. In B lymphocytes, IRF4 and IRF8 have been shown to control important events during their development and maturation including pre B cell differentiation, induction of B cell tolerance pathways, marginal zone B cell development, germinal center reaction and plasma cell differentiation. Mechanistically, IRF4 and IRF8 are found to function redundantly to control certain stages of B cell development, but in other stages, they function nonredundantly to play distinct roles in B cell biology. In line with their essential roles in B cell development, deregulated expressions of IRF4 and IRF8 have been associated to the pathogenesis of several B cell malignancies and diseases. Recent studies have elucidated diverse transcriptional networks regulated by IRF4 and IRF8 at distinct B cell developmental stages and related malignancies. In this review we will discuss the recent advances for the roles of IRF4 and IRF8 during B cell development and associated diseases. PMID- 25506359 TI - Determinants of Weight Loss prior to Diagnosis in Inflammatory Bowel Disease: A Retrospective Observational Study. AB - Aims. To identify prevalence, severity, and environmental determinants of weight loss in inflammatory bowel disease (IBD) patients just prior to time of formal diagnosis. Methodology. IBD patients attending outpatient clinic were questioned about weight loss prior to diagnosis and other environmental and demographic variables. The percentage BMI loss was calculated for each subject and factors associated with weight loss were determined. Results. Four hundred and ninety four subjects were recruited (237 cases of Crohn's disease (CD) and 257 cases of ulcerative colitis (UC)). Overall, 57% of subjects with CD and 51% of subjects with UC experienced significant weight loss prior to diagnosis (>5% BMI loss). Younger age at diagnosis and history of previous IBD surgery were significantly associated with both lower BMI at diagnosis and increased weight loss prior to diagnosis. In CD patients, increasing age at diagnosis was inversely associated with weight loss prior to diagnosis. Ileal disease was a risk factor of weight loss, whereas prior appendectomy was associated with reduced risk of weight loss. Conclusions. Weight loss is a significant problem for many IBD patients at presentation, especially in younger age and CD with ileal involvement. Appendectomy is associated with diminished weight loss. PMID- 25506360 TI - Lower urinary tract dysfunction in pelvic gynecologic cancer: the role of urodynamics. AB - The exact incidence of lower urinary tract dysfunction is not known and its pathogenesis is not completely understood. Advances in urodynamic assessment and widespread availability of a standardized technique have facilitated its exploration prior to and subsequent to the surgical management of patients with gynecologic pelvic cancer. We performed a PubMed and Medline literature search using the following keywords: bladder dysfunction, urinary dysfunction, and urodynamics and all these terms in combination with radical hysterectomy in order to analyze the role of urodynamics in patients with pelvic gynecologic cancer in the preoperative as well as in the early and late postoperative settings. PMID- 25506361 TI - Retrospective Analysis of Cushing's Disease with or without Hyperprolactinemia. AB - Objective. We compared the characteristics of patients with Cushing's disease alone with those of patients with Cushing's disease and hyperprolactinemia. Methods. Eighty-four patients were enrolled between 2002 and 2011, in a hospital in China. Clinical, endocrinological, and histopathological data, MRI scans, and surgical outcomes were reviewed throughout the follow-up period. Results. Patients with Cushing's disease and hyperprolactinemia had a younger age at diagnosis (30.28 +/- 14.23 versus 36.08 +/- 10.91 years; P = 0.037) and a larger adenoma maximal diameter (2.44 +/- 1.32 versus 1.44 +/- 1.05 cm; P < 0.001) than patients with Cushing's disease alone. Menstrual disorders (P = 0.027) and visual field defects (P = 0.021) were more common and progressive obesity (P = 0.009) and hypertension (P < 0.001) were less common in patients with Cushing's disease and hyperprolactinemia. The rate of normalization of hormonal levels was lower (41.7% versus 91.7%; P < 0.001) and the recurrence rate was higher (36.1% versus 8.3%; P < 0.001) in patients with Cushing's disease and hyperprolactinemia. Conclusions. Careful long-term follow-up is needed of patients with Cushing's disease and hyperprolactinemia. PMID- 25506362 TI - Assessment of the Contamination of Some Foodstuffs by Escherichia coli O157 in Benin, West Africa. AB - Escherichia coli O157 is a pathogenic bacterium causing haemorrhagic colitis. It represents a serious public health problem in Northern America and Europe, which can plague Africa. Most cases of mentioned poisoning were related to contaminated meat products and vegetables. The present work aimed to estimate the prevalence of E. coli O157 in meat and vegetables in Benin. For this purpose, 6 lots of faeces samples from pigs and 8 from cattle were collected at the farms on the outskirts of Cotonou. Similarly, 20 samples of carcasses, 20 samples of intestines and stomach, and 20 surfaces samples of slaughtering equipment were taken. Vegetables and environment materials in gardens have also been sampled for 84 samples. Bacteriological analyses revealed a percentage of contamination of 50% for pig faeces and 25% for cattle ones. All the meats from stalling parks have been contaminated by this bacterium. For vegetables, 14.6% of samples were contaminated by E. coli O157. The presence of this pathovar in animal breeding and slaughtering environment and in the gardens shows that Benin is not aware of the risks of foodborne illness associated with the consumption of contaminated products. Therefore, it urges including that germ in a systematic search during safety control of food products in Benin. PMID- 25506363 TI - Vitamin D Levels Are Associated with Expression of SLE, but Not Flare Frequency. AB - This study explores links between vitamin D deficiency (25(OH)D = 50 nmol/L) and serological autoimmunity (ANA > 1 : 80) and frequency of self-reported flares (SRF) in participants with clinical autoimmunity (SLE). 25(OH)D levels of 121 females were quantified and compared. The cohort consisted of 80 ACR defined SLE patients and 41 age and sex matched controls. Association analysis of log2 (25(OH)D) levels and ANA 80 positivity was undertaken via two-sample t-tests and regression models. Significant differences were found for 25(OH)D levels (mean: control 74 nmol/L (29.5 ng/ml); SLE 58 nmol/L (23.1 ng/ml), P = 0.04), 25(OH)D deficiency (P = 0.02). Regression models indicate that, for a twofold rise in 25(OH)D level, the odds ratio (OR) for ANA-positivity drops to 36% of the baseline OR. No link was found between SRF-days and 25(OH)D levels. Our results support links between vitamin D deficiency and expression of serological autoimmunity and clinical autoimmunity (SLE). However, no demonstrable association between 25(OH)D and SRF was confirmed, suggesting independent influences of other flare-inducing factors. Results indicate that SLE patients have high risk of 25(OH)D deficiency and therefore supplementation with regular monitoring should be considered as part of patient management. PMID- 25506364 TI - Effects of glossopharyngeal insufflation in ankylosing spondylitis: a pilot study. AB - In Ankylosing Spondylitis (AS), thoracic range of motion is often greatly limited. The objective of the study was to describe the effects of 12 weeks of Glossopharyngeal Insufflation (GI) training in patients with AS. Dynamic spirometry included vital capacity, forced expiratory volume, and peak expiratory flow. Thoracic and lumbar range of motion was assessed by tragus-to-wall distance, modified Schober test, and tape measure. Disease activity, activity limitation, and health perception were assessed using the BAS-Indices, and tension in the thoracic region during GI was assessed using the Borg CR-10 scale. Adherence to training was recorded in an activity log, along with any remarks on the training. Ten patients were recruited and six male patients fulfilled the study protocol. Three patients were able to learn GI by exceeding their maximal vital capacity with 5% using GI. A significant increase in thoracic range of motion both on costae IV (P = 0.04) and at the level of the xiphoid process (P = 0.04) was seen. Thus, patients with AS can practice GI, it is safe if maximal exertion is avoided, and patients with some mobility in the chest can increase their lung function substantially by performing GI during 12 weeks. PMID- 25506365 TI - Malignant granular cell tumor of the back: a case report and review of the literature. AB - Malignant granular cell tumors are rare, intensely aggressive entities. This paper presents a case of a large rapidly recurrent malignant granular cell tumor with regional and distal metastases on the back of a 54-year-old Cuban man. The primary tumor recurred within six months of the original wide local excision and with satellite lesions apparent at twelve months, and the mass was diagnosed using the histological criteria established by Fanburg-Smith et al. for malignant granular cell tumors. By fifteen months, right axillary lymphadenopathy, multiple satellite lesions, pulmonary nodules, and distant metastasis in the right thigh were present. At sixteen months, wide local excision of recurrent mass and local satellite masses along with right axillary dissection and placement of Integra with subsequent split-thickness skin graft were performed by surgical oncology and plastic surgery teams. The surgical specimen measured 32.0 * 13.5 * 5.5 cm, containing multiple homogeneous masses with the largest mass 22.0 * 9.0 * 4.6 cm. Following surgery, patient was started on Pazopanib 800 mg/day based on phase III randomized trial data in the treatment of soft tissue sarcomas showing this as a potential novel therapy for malignant granular cell tumors. PMID- 25506366 TI - Diagnostic Difficulties in Woman with Crohn's Disease, Ascites, and Elevated Value of Serum CA125 Antigen. AB - Variety of symptoms and atypical clinical course of Crohn's disease (CD) often create the need for additional diagnostic procedures. In the described case of woman with CD, there was a suspicion of coexistence of ovarian cancer. This issue is particularly important in patients treated with immunosuppressants and biological agents. The discussion focused on the usefulness of CA125 (cancer antigen 125, mucin 16) serum level estimation in clinical practice and draws attention to the possible reasons for the increase of its value which is not associated to ovarian cancer. PMID- 25506369 TI - The Big Census Data Revolution: IPUMS-International. Trans-Border Access to Decades of Census Samples for Three-Fourths of the World and more. AB - Over the past decade a revolution has occurred in the dissemination and analysis of census microdata. This paper discusses the IPUMS-International initiative to liberate census data for researchers world-wide without cost. As of June 2013, academic researchers and policy makers may access, 234 anonymized samples representing 74 countries and totaling over one-half billion person records. The database expands with the addition of 20-30 samples each year. Data are downloadable as extracts from the project website: www.ipums.org/international. To facilitate good use, both metadata and microdata are integrated. The analysis of 450 citations in the project bibliography reveals patterns in publications by country and topic. PMID- 25506367 TI - Differentiation of equine mesenchymal stromal cells into cells of neural lineage: potential for clinical applications. AB - Mesenchymal stromal cells (MSCs) are able to differentiate into extramesodermal lineages, including neurons. Positive outcomes were obtained after transplantation of neurally induced MSCs in laboratory animals after nerve injury, but this is unknown in horses. Our objectives were to test the ability of equine MSCs to differentiate into cells of neural lineage in vitro, to assess differences in morphology and lineage-specific protein expression, and to investigate if horse age and cell passage number affected the ability to achieve differentiation. Bone marrow-derived MSCs were obtained from young and adult horses. Following demonstration of stemness, MSCs were neurally induced and microscopically assessed at different time points. Results showed that commercially available nitrogen-coated tissue culture plates supported proliferation and differentiation. Morphological changes were immediate and all the cells displayed a neural crest-like cell phenotype. Expression of neural progenitor proteins, was assessed via western blot or immunofluorescence. In our study, MSCs generated from young and middle-aged horses did not show differences in their ability to undergo differentiation. The effect of cell passage number, however, is inconsistent and further experiments are needed. Ongoing work is aimed at transdifferentiating these cells into Schwann cells for transplantation into a peripheral nerve injury model in horses. PMID- 25506368 TI - Geographical Differences in the Population-Based Cross-Sectional Growth Curve and Age at Peak Height Velocity with respect to the Prevalence Rate of Overweight in Japanese Children. AB - The School Health Examination Survey is a nationwide examination carried out annually in Japan, and the results are entered into a prefectural-level physical measurement database. We used this database to determine the geographical differences in a population-based cross-sectional growth curve and investigated the association between age at peak height velocity (PHV) and the prevalence rate of overweight in children among Japanese prefectures. Mean prefectural-level age at PHV was estimated by the cubic spline-fitting procedure using cross-sectional whole-year prefectural mean height data (5-17 years, 2006-2013), and 8-year (2006 2013) means of the standardized prevalence rates of overweight children and other anatomical data (8-year standardized weight and height) were recalculated. Mean prefectural age at PHV was more strongly correlated with the mean prefectural prevalence rate of overweight (age 5-8 years) than with other weights or heights in both sexes. On the basis of these findings and their confirmation by multiple regression analysis, the prevalence rate of overweight was selected as a primary factor to explain the geographical difference in age at PHV. These findings suggest that childhood overweight is a dominant factor responsible for the observed geographical differences in onset of puberty in Japan. PMID- 25506370 TI - Clinicopathologic and survival characteristics of malignant pleural mesothelioma registered in hospital cancer registry. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but fatal thoracic tumor, which in the majority of patients is caused by prolonged exposure to asbestos fibers. We aimed at presenting clinicopathological and treatment outcomes of 60 patients of MPM registered in our hospital cancer registry. MATERIALS AND METHODS: Demographic characteristics of patients, exposure to asbestos, smoking habit, their clinicopathologic characteristics and survival analysis were described. RESULTS: Sixty patients had MPM. Forty patients (66.7%) were men. The mean age of patients was 55.8+/-11 years. Chest pain and dyspnea were the most prevalent symptoms (31.7%, and 30%, respectively). Thirty-six (61.7%) patients reported asbestos exposure. The median survival and Progression free survival (PFS) were 10.5 months (0.95CI=9.22-11.78) and 7.57 months (0.95CI=5.68-9.45), respectively. In multivariate analysis, exposure to asbestos and epithelioid subtype significantly extended the survival time. Bilateral involvement, high blood level of LDH and platelet count >=400,000 significantly shortened the overall survival. CONCLUSION: MPM is still an important health problem in Iran. Given the aforementioned results, developing a national program to eliminate asbestos-related diseases according to the world health organization (WHO) recommendation is necessary. PMID- 25506371 TI - Efficacy of Dressing with Absorbent Foam versus Dressing with Gauze in Prevention of Tracheostomy Site Infection. AB - BACKGROUND: Tracheostomy site infection can cause numerous problems. Absorbent foam dressing may be able to prevent proliferation of infectious microorganisms by absorbing the tracheostomy stoma exudate. This study aimed to compare the efficacy of absorbent foam with gauze dressing for prevention of tracheostomy site infection. MATERIALS AND METHODS: In this double-blind randomized clinical trial, 80 patients (18 to 60 years) hospitalized in the intensive care unit (ICU) due to severe head injury were randomly divided into two groups and early tracheostomy was done for them during the first 2 days. In the first group, gauze was used as tracheostomy site dressing, while in the second, absorbent foam, was placed. Tracheostomy site was checked daily for any sign of infection and samples were taken from the stoma for culture in case of presence of any sign of infection. RESULTS: Of a total of 80, 11 had tracheostomy site infection (13.75%), including 7 (17.5%) in the gauze group and 4 (10%) in the foam group. The difference in this regard between the two groups was not significant (P=0.051). Also, the dominant strains in the culture of gauze group were hospital acquired Gram-negative bacteria (particularly Acinetobacter), while in the foam group, Gram-positives and more commonly Staphylococcus epidermidis were found. CONCLUSION: Absorbent foam dressing is not superior to gauze dressings for prevention of tracheostomy site infection. PMID- 25506372 TI - Lean body mass can predict lung function in underweight and normal weight sedentary female young adults. AB - BACKGROUND: A previous cross-sectional study found reduced lung function among over weight and obese students in Zanjan city. However, there is no reliable evidence about the respiratory function of underweight and normal weight students. The objective of this study was to evaluate lung function and develop prediction equations in underweight and normal weight female young adults residing in Soltanieh city near Zanjan. MATERIALS AND METHODS: A cross sectional study was conducted on underweight (n=29, mean age=16+/-0.84 years) and normal weight (n=38, mean age=15.9+/-0.86 years) sedentary female young adults. Fat mass (FM) was measured by Omron Body Fat Monitor FB-3002. Lean body mass (LBM), waist to hip ratio (WHR), body mass index (BMI) and waist circumference (WC) were calculated. Maximum oxygen uptake was calculated using Queen's College step test. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were recorded, using Spirolab III spirometer. Independent t test, Pearson's correlation test and stepwise linear regression analysis were used for data analysis. RESULTS: FVC and FEV1 were significantly lower than the reference values in both groups (P<0.05). LBM was significantly correlated with FVC and FEV1 in underweight and normal weight groups (P<0.05). Regression equations were derived to predict FVC and FEV1 using LBM. CONCLUSION: This study suggests that dynamic lung functions are poor in underweight and normal weight sedentary female young adults residing in Soltanieh city and LBM plays a significant role in their lung function. PMID- 25506373 TI - Spirometry values for detecting a restrictive pattern in occupational health settings. AB - BACKGROUND: Pulmonary function tests are valuable measures for diagnosis and management of respiratory diseases. In the field of occupational medicine, spirometry is commonly performed, and in a considerable number of spirometries during occupational health evaluations, restrictive pattern is observed without any respiratory symptoms and may necessitate referral of the subject for body plethysmography, which is an expensive test. In this study, we evaluated the diagnostic accuracy of spirometry for detection of restrictive lung pattern in an occupational setting. MATERIALS AND METHODS: In a cross-sectional study from 2008 to 2012, 1224 subjects were selected and entered in the study out of 1,486 individuals referred for annual spirometry. Selected subjects underwent spirometry and body plethysmography. Subjects were divided into two groups of restrictive and non-restrictive patterns and then sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of spirometry for detection of restrictive lung pattern were calculated using total lung capacity measured by plethysmography as the gold standard. Receiver operating characteristic (ROC) curves were used as well. RESULTS: Spirometry showed sensitivity, specificity, PPV and NPV of 97.75%, 73.04%, 73.72% and 97.67% for FVC< lower limit of normal (LLN) and 98.68%, 78.00%, 77.31% and 98.83% for FVC< LLN along with FEV1/FVC>= LLN, respectively. According to the ROC curve, the best cut-off point for FVC for detection of restrictive lung pattern was 70%. CONCLUSION: This study showed that spirometry is a useful method in occupational health evaluations to rule out restrictive lung patterns with acceptable accuracy; however, it is not an accurate tool for detection of restrictive lung pattern in an occupational setting. Simultaneous use of FVC and FEV1/FVC for detection of restriction increases the predictive value of spirometry. PMID- 25506374 TI - Relationship of occupational and non-occupational stress with smoking in automotive industry workers. AB - BACKGROUND: Tobacco use is the second cause of death and first cause of preventable mortality worldwide. Smoking in the workplace is particularly concerning. Smoking-free workplaces decrease the risk of exposure of non-smoking personnel to cigarette smoke. Recent studies have mostly focused on the effect of daily or non-occupational stressors (in comparison with occupational stress) on prevalence of smoking. Occupational stress is often evaluated in workplaces for smoking cessation or control programs, but the role of non-occupational stressors is often disregarded in this respect. MATERIALS AND METHODS: This cross-sectional study was conducted in an automobile manufacturing company. The response of automotive industry workers to parts of the validated, reliable, Farsi version of Musculoskeletal Intervention Center (MUSIC)-Norrtalje questionnaire was evaluated. A total of 3,536 factory workers participated in this study. Data were analyzed using SPSS and P<0.05 was considered statistically significant. RESULTS: The correlation of smoking with demographic factors, occupational stressors and life events was evaluated. The results of logistic regression analysis showed that even after adjusting for the confounding factors, cigarette smoking was significantly correlated with age, sex, level of education, job control and life events (P<0.05). CONCLUSION: The results showed that of occupational and non occupational stressors, only job control was correlated with cigarette smoking. Non-occupational stressors had greater effect on cigarette smoking. Consideration of both non-occupational and occupational stressors can enhance the success of smoking control programs. On the other hand, a combination of smoking control and stress (occupational and non-occupational) control programs can be more effective than smoking cessation interventions alone. PMID- 25506375 TI - Sleep-disordered breathing as presenting manifestation of Chiari type I malformation: a case report. AB - Chiari Type I malformation (CM-I) is a rare disorder with displaced cerebellar tonsils through foramen magnum. Here we present a 30-year-old man with severe central and obstructive sleep apneas as presenting manifestations of CM-I. The patient underwent neurosurgery and the follow-up polysomnography revealed the resolution of central apnea while obstructive apnea remained unchanged. Central sleep apnea (CSA) could be associated with an underlying pathology; thus, further investigation is recommended in affected subjects. PMID- 25506376 TI - Primary composite lymphoma of the lung: a case report. AB - Herein, we report a rare case of primary lung lymphoma in a 61 year-old woman with a history of 6-month nonspecific symptoms like dry cough, fever, chills and weight loss. She was admitted to a hospital and received broad-spectrum antibiotics but discharged without full recovery. In her second hospital admission, a bronchoscopic evaluation and transbronchial biopsy were performed, which were not diagnostic. Finally, an open lung biopsy was done. Immunohistochemical (IHC) staining of the specimen suggested pulmonary Hodgkin lymphoma. Because of disease recurrence, a second bronchoscopy was performed and endobronchial biopsy revealed transformation to anaplastic lymphoma. In the second recurrence, we decided to reevaluate the last biopsy specimens in greater details. Finally, after conduction of several staining patterns, the diagnosis of primary composite lymphoma of the lung was made. PMID- 25506377 TI - Supraglottic Hemangioma as a Rare Cause of Recurrent Hemoptysis: A New Treatment Modality with Argon Plasma Coagulation (APC). AB - Adult laryngeal hemangiomas are rare and mainly involve the supraglottic region. Most common symptoms include dysphagia, dysphonia, shortness of breath and occasionally recurrent bleeding which sometimes cause a diagnostic dilemma for pulmonologists and head and neck surgeons. There is no consensus about the most appropriate treatment modality for laryngeal hemangiomas. We present a case of supraglottic hemangioma in an adult female, which was diagnosed by fiberoptic bronchoscopy and coagulated by Argon plasma coagulation (APC) with no complication. PMID- 25506378 TI - The unintended implications of blurring the line between research and clinical care in a genomic age. AB - While the development of next-generation sequencing technology has had a paradigm changing impact on biomedical research, there is likely to be a gap between discovery of therapeutic benefits in research and actual adoption of the new technology into clinical practice. This gap can create pressure on the research enterprise to provide individualized care more typical of the clinic setting because it is uniquely accessible in research. This blurring of the line between research and clinical care is understandable, and perhaps even inevitable. But even if the gap is only transitory, such a blurring can have lasting implications, both by expanding obligations imposed on researchers, but also by challenging long-held ethical views. We explore this idea, focusing on how the dissolving distinction between research and clinical care has influenced the vigorous debate around how researchers should manage genetic findings (sometimes separated into primary and incidental or secondary findings) resulting from research. PMID- 25506379 TI - Recent advances in personalized lung cancer medicine. AB - The identification of molecular subtypes of non-small-cell lung cancer has transformed the clinical management of this disease. This is best exemplified by the clinical success of targeting the EGFR or ALK with tyrosine kinase inhibitors in the front-line setting. Our ability to further improve patient outcomes with biomarker-based targeted therapies will depend on a more comprehensive genetic platform that can rationally interrogate the cancer genome of an individual patient. Novel technologies, including multiplex genotyping and next-generation sequencing are rapidly evolving and will soon challenge the oncologist with a wealth of genetic information for each patient. Although there are many barriers to overcome, the integration of these genetic platforms into clinical care has the potential to transform the management of lung cancer through improved molecular categorization, patient stratification, and drug development, thereby, improving clinical outcomes through personalized lung cancer medicine. PMID- 25506380 TI - Efficacy and safety of clearing heat and detoxifying injection in the treatment of influenza: a randomized, double-blinded, placebo-controlled trial. AB - Objective. To evaluate the efficacy and safety of CHDI in the treatment of influenza infection. Method. A randomized double-blind, double dummy trial was conducted. Influenza patients with a positive influenza A rapid test diagnosis were randomized to receive CHDI or oseltamivir. Primary outcome was assessed by the median fever alleviation time and clearance time, and secondary outcome was total scores of influenza symptoms. Results. One hundred thirty-nine participants were screened and 34 had a RT-PCR laboratory confirmation of influenza virus infection. Fever alleviation time was 2.5 and 5 hours in CHDI and oseltamivir, respectively, and fever clearance time was 32.5 and 49 hours. The HR of fever alleviation and clearance time shows no significant difference between two groups. Total scores of influenza symptoms descended significantly in both groups after treatment and descended more in CHDI than oseltamivir on day 2. Similar to total symptoms severity score, fever severity score descend more significantly in CHDI than oseltamivir on day 2, and there were no differences on other symptoms. Conclusions. CHDI have a similar effect to oseltamivir in reducing the duration of influenza illness. CHDI was well tolerated, with no serious adverse events noted during the study period. PMID- 25506381 TI - The Effect of Optimally Timed Osteopathic Manipulative Treatment on Length of Hospital Stay in Moderate and Late Preterm Infants: Results from a RCT. AB - Introduction. Little research has been conducted looking at the effects of osteopathic manipulative treatment (OMT) on preterm infants. Aim of the Study. This study hypothesized that osteopathic care is effective in reducing length of hospital stay and that early OMT produces the most pronounced benefit, compared to moderately early and late OMT. A secondary outcome was to estimate hospital cost savings by the use of OMT. Methods. 110 newborns ranging from 32- to 37-week gestation were randomized to receive either OMT or usual pediatric care. Early, moderately early, and late OMT were defined as <4, <9, and <14 days from birth, respectively. Result. Hospital stay was shorter in infants receiving late OMT ( 2.03; 95% CI -3.15, -0.91; P < 0.01) than controls. Subgroup analysis of infants receiving early and moderately early OMT resulted in shorter LOS (early OMT: 4.16; -6.05, -2.27; P < 0.001; moderately early OMT: -3.12; -4.36, -1.89; P < 0.001). Costs analysis showed that OMT significantly produced a net saving of ?740 (-1309.54, -170.33; P = 0.01) per newborn per LOS. Conclusions. This study shows evidence that the sooner OMT is provided, the shorter their hospital stay is. There is also a positive association of OMT with overall reduction in cost of care. PMID- 25506382 TI - Effects of anethole in nociception experimental models. AB - This study investigated the antinociceptive activity of anethole (anethole 1 methoxy-4-benzene (1-propenyl)), major compound of the essential oil of star anise (Illicium verum), in different experimental models of nociception. The animals were pretreated with anethole (62.5, 125, 250, and 500 mg/kg) one hour before the experiments. To eliminate a possible sedative effect of anethole, the open field test was conducted. Anethole (62.5, 125, 250, and 500 mg/kg) showed an antinociceptive effect in the writhing model induced by acetic acid, in the second phase of the formalin test (125 and 250 mg/kg) in the test of glutamate (62.5, 125, and 250 mg/kg), and expresses pain induced by ACF (250 mg/kg). In contrast, anethole was not able to increase the latency time on the hot plate and decrease the number of flinches during the initial phase of the formalin test in any of the doses tested. It was also demonstrated that anethole has no association with sedative effects. Therefore, these data showed that anethole, at all used doses, has no sedative effect and has an antinociceptive effect. This effect may be due to a decrease in the production/release of inflammatory mediators. PMID- 25506383 TI - Sodium hydrosulfide relieves neuropathic pain in chronic constriction injured rats. AB - Aberrant neuronal activity in injured peripheral nerves is believed to be an important factor in the development of neuropathic pain (NPP). Channel protein pCREB of that activity has been shown to mitigate the onset of associated molecular events in the nervous system, and sodium hydrosulfide (NaHS) could inhibit the expression of pCREB. However, whether NaHS could relieve the pain, it needs further experimental research. Furthermore, the clinical potential that NaHS was used to relieve pain was limited so it would be required. To address these issues, the rats of sciatic nerve chronic constriction injury (CCI) were given intraperitoneal injection of NaHS containing hydrogen sulfide (H2S). The experimental results showed that NaHS inhibited the reduction of paw withdrawal thermal latency (PWTL), mechanical withdrawal threshold (MWT), and the level of pCREB in CCI rats in a dose-dependent manner and they were greatly decreased in NaHSM group (P < 0.05). NaHS alleviates chronic neuropathic pain by inhibiting expression of pCREB in the spinal cord of Sprague-Dawley rats. PMID- 25506384 TI - Anatomo-Functional Correlation between Head Zones and Acupuncture Channels and Points: A Comparative Analysis from the Perspective of Neural Therapy. AB - Background. Neural therapy and traditional Chinese medicine (TCM) are part of complementary and alternative medicine in western world. Both of them share characteristics in diagnosis and therapeutics in search of changes in tenderness, pain, and skin stiffness related to visceral disease, as well as therapeutic procedures with specific stimuli on the skin that generate local, segmental, or remote reactions. Head zones explain segmental viscerocutaneous relations in neural therapy; however, interference fields and remote reactions after infiltration of local anesthetic go beyond this segmental distribution. Methods. This descriptive research required review and analysis of texts of Henry Head and traditional Chinese medicine. Results. Anatomical and functional relationships were found between Head zones in body, and head and neck with 14 acupuncture channels and their points. Anatomical areas of strong correlations were found: Head zones of heart and lung with heart and pericardium channels; Head zones of genitals with bladder and kidney channels. Strong functional relations between all Head zones, channels, and acupoints were found when following the pattern of segmental dermatomes; 235 acupuncture points were found in concordance. PMID- 25506385 TI - Atypical endometrial cells and atypical glandular cells favor endometrial origin in Papanicolaou cervicovaginal tests: Correlation with histologic follow-up and abnormal clinical presentations. AB - The 2001 Bethesda system recommends further classifying atypical glandular cells (AGCs) as either endocervical or endometrial origin. Numerous studies have investigated the clinical significance of AGC. In this study, we investigated the incidence of clinically significant lesions among women with liquid-based Papanicolaou cervicovaginal (Pap) interpretations of atypical endometrial cells (AEMs) or AGC favor endometrial origin (AGC-EM). More importantly, we correlated patients of AEM or AGC-EM with their clinical presentations to determine if AEM/AGC-EM combined with abnormal vaginal bleeding is associated with a higher incidence of significant endometrial pathology. All liquid-based Pap tests with an interpretation of AEM and AGC-EM from July, 2004 through June, 2009 were retrieved from the database. Women with an interpretation of atypical endocervical cells, AGC, favor endocervical origin or AGC, favor neoplastic were not included in the study. The most severe subsequent histologic diagnoses were recorded for each patient. During this 5-year period, we accessioned 332,470 Pap tests of which 169 (0.05%) were interpreted as either AEM or AGC-EM. Of the 169 patients, 133 had histologic follow-up within the health care system. The patients ranged in age from 21 to 71 years old (mean 49.7). On follow-up histology, 27 (20.3%) had neoplastic/preneoplastic uterine lesions. Among them, 20 patients were diagnosed with adenocarcinoma (18 endometrial, 1 endocervical, and 1 metastatic colorectal), 3 with atypical endometrial hyperplasia, and 4 with endometrial hyperplasia without atypia. All patients with significant endometrial pathology, except one, were over 40 years old, and 22 of 25 patients reported abnormal vaginal bleeding at the time of endometrial biopsy or curettage. This study represents a large series of women with liquid-based Pap test interpretations of AEM and AGC-EM with clinical follow-up. Significant preneoplastic or neoplastic endometrial lesions were identified in 20.3% of patients. Patients with Pap test interpretations of AEM or AGC-EM and the clinical presentation of abnormal vaginal bleeding should be followed closely. PMID- 25506386 TI - Fine-needle aspiration cytology of pilomatrixoma: A short series of three cases. AB - Pilomatrixoma (PMX) (pilomatricoma, calcifying epithelioma of Malherbe) is a benign tumor with differentiation toward the hair matrix cells and is common in head and neck region. It is most commonly seen in the first two decades of life and presents as a subcutaneous, small, asymptomatic firm solitary nodule. Fine needle aspiration cytology (FNAC) has been described as an important preoperative diagnostic investigation though on cytology the diagnosis of PMX is sometimes difficult and misdiagnosed. We describe two patients with gradually increasing asymptomatic swelling on pinna and middle finger. FNAC was done and a diagnosis of PMX was given, further confirmed by histopathological examination. The present cases highlight the importance of FNAC in considering PMX as differential diagnosis of dermal or subcutaneous nodules in locations other than head and neck. Cytopathologists who play an important role in the preliminary diagnosis should keep in mind the variability of the cellular composition of these types of lesions to avoid misdiagnosis. PMID- 25506387 TI - Nano-imaging enabled via self-assembly. AB - Imaging object details with length scales below approximately 200 nm has been historically difficult for conventional microscope objective lenses because of their inability to resolve features smaller than one-half the optical wavelength. Here we review some of the recent approaches to surpass this limit by harnessing self-assembly as a fabrication mechanism. Self-assembly can be used to form individual nano- and micro-lenses, as well as to form extended arrays of such lenses. These lenses have been shown to enable imaging with resolutions as small as 50 nm half-pitch using visible light, which is well below the Abbe diffraction limit. Furthermore, self-assembled nano-lenses can be used to boost contrast and signal levels from small nano-particles, enabling them to be detected relative to background noise. Finally, alternative nano-imaging applications of self-assembly are discussed, including three-dimensional imaging, enhanced coupling from light emitting diodes, and the fabrication of contrast agents such as quantum dots and nanoparticles. PMID- 25506388 TI - Potential lung nodules identification for characterization by variable multistep threshold and shape indices from CT images. AB - Computed tomography (CT) is an important imaging modality. Physicians, surgeons, and oncologists prefer CT scan for diagnosis of lung cancer. However, some nodules are missed in CT scan. Computer aided diagnosis methods are useful for radiologists for detection of these nodules and early diagnosis of lung cancer. Early detection of malignant nodule is helpful for treatment. Computer aided diagnosis of lung cancer involves lung segmentation, potential nodules identification, features extraction from the potential nodules, and classification of the nodules. In this paper, we are presenting an automatic method for detection and segmentation of lung nodules from CT scan for subsequent features extraction and classification. Contribution of the work is the detection and segmentation of small sized nodules, low and high contrast nodules, nodules attached with vasculature, nodules attached to pleura membrane, and nodules in close vicinity of the diaphragm and lung wall in one-go. The particular techniques of the method are multistep threshold for the nodule detection and shape index threshold for false positive reduction. We used 60 CT scans of "Lung Image Database Consortium-Image Database Resource Initiative" taken by GE medical systems LightSpeed16 scanner as dataset and correctly detected 92% nodules. The results are reproducible. PMID- 25506390 TI - Women at work with breast cancer-related lymphoedema. AB - BACKGROUND: Little attention has been given to the impact of lymphoedema on breast cancer survivors' work experience. AIMS: To describe the experience of work of breast cancer survivors with lymphoedema. METHODS: A descriptive phenomenological method was used. Sixty-six in-depth interviews were completed with 22 participants in the United States. RESULTS: Three essential themes illuminating the meaning of working for breast cancer survivors with lymphoedema emerged, namely: having a visible sign of disability or a need for help; having physical limitations that made some women handicapped, while others felt inconvenienced; and, finally, some women had constant worries while others felt fortunate. CONCLUSIONS: Women endured emotional distress at work. Women whose jobs required heavy lifting and constant use of the affected limb, suffered profoundly from the physical and functional impact of having lymphoedema. Future research should focus on interventions that help employers to understand breast cancer survivors with lymphoedema and improve their working conditions. PMID- 25506389 TI - Novel harmonic regularization approach for variable selection in Cox's proportional hazards model. AB - Variable selection is an important issue in regression and a number of variable selection methods have been proposed involving nonconvex penalty functions. In this paper, we investigate a novel harmonic regularization method, which can approximate nonconvex Lq (1/2 < q < 1) regularizations, to select key risk factors in the Cox's proportional hazards model using microarray gene expression data. The harmonic regularization method can be efficiently solved using our proposed direct path seeking approach, which can produce solutions that closely approximate those for the convex loss function and the nonconvex regularization. Simulation results based on the artificial datasets and four real microarray gene expression datasets, such as real diffuse large B-cell lymphoma (DCBCL), the lung cancer, and the AML datasets, show that the harmonic regularization method can be more accurate for variable selection than existing Lasso series methods. PMID- 25506391 TI - A comparative multidimensional LC-MS proteomic analysis reveals mechanisms for furan aldehyde detoxification in Thermoanaerobacter pseudethanolicus 39E. AB - BACKGROUND: Chemical and physical pretreatment of lignocellulosic biomass improves substrate reactivity for increased microbial biofuel production, but also restricts growth via the release of furan aldehydes, such as furfural and 5 hydroxymethylfurfural (5-HMF). The physiological effects of these inhibitors on thermophilic, fermentative bacteria are important to understand; especially as cellulolytic strains are being developed for consolidated bioprocessing (CBP) of lignocellulosic feedstocks. Identifying mechanisms for detoxification of aldehydes in naturally resistant strains, such as Thermoanaerobacter spp., may also enable improvements in candidate CBP microorganisms. RESULTS: Thermoanaerobacter pseudethanolicus 39E, an anaerobic, saccharolytic thermophile, was found to grow readily in the presence of 30 mM furfural and 20 mM 5-HMF and reduce these aldehydes to their respective alcohols in situ. The proteomes of T. pseudethanolicus 39E grown in the presence or absence of 15 mM furfural were compared to identify upregulated enzymes potentially responsible for the observed reduction. A total of 225 proteins were differentially regulated in response to the 15 mM furfural treatment with 152 upregulated versus 73 downregulated. Only 87 proteins exhibited a twofold or greater change in abundance in either direction. Of these, 54 were upregulated in the presence of furfural and 33 were downregulated. Two oxidoreductases were upregulated at least twofold by furfural and were targeted for further investigation. Teth39_1597 encodes a predicted butanol dehydrogenase (BdhA) and Teth39_1598, a predicted aldo/keto reductase (AKR). Both genes were cloned from T. pseudethanolicus 39E, with the respective enzymes overexpressed in E. coli and specific activities determined against a variety of aldehydes. Overexpressed BdhA showed significant activity with all aldehydes tested, including furfural and 5-HMF, using NADPH as the cofactor. Cell extracts with AKR also showed activity with NADPH, but only with four-carbon butyraldehyde and isobutyraldehyde. CONCLUSIONS: T. pseudethanolicus 39E displays intrinsic tolerance to the common pretreatment inhibitors furfural and 5-HMF. Multidimensional proteomic analysis was used as an effective tool to identify putative mechanisms for detoxification of furfural and 5-HMF. T. pseudethanolicus was found to upregulate an NADPH-dependent alcohol dehydrogenase 6.8-fold in response to furfural. In vitro enzyme assays confirmed the reduction of furfural and 5-HMF to their respective alcohols. PMID- 25506392 TI - Physical activity and sleep: Day-to-day associations among individuals with and without Bipolar Disorder. AB - OBJECTIVE: To evaluate the relative role of psychopathology in the relationship between physical activity and sleep, the present study investigated the day-to day relationship between physical activity and sleep in individuals without a psychiatric disorder and individuals with bipolar disorder using a longitudinal, naturalistic design. METHOD: Participants in two groups-a healthy group with no psychiatric illness (N=36) and an inter-episode bipolar disorder group (N=32)- were studied over a two-month period. Physical health was assessed by the SF-36. Daily subjective and objective measures of physical activity and sleep were collected. A total of 6,670 physical activity measurements and 6,548 sleep measurements were logged. RESULTS: The bipolar disorder group exhibited poorer physical health on the SF-36 and more sleep disturbance relative to the healthy group. No group differences were found in physical activity, nor in models examining the relationship between physical activity and sleep. Hierarchical linear models indicated that for every standard deviation increase in sleep disturbance (i.e., increased total wake time), there was a three percent decrease in subsequent day physical activity, in both the healthy and bipolar groups. Increased physical activity was associated with improved sleep for participants who reported greater average sleep disturbance. CONCLUSIONS: The results for all participants in the study suggest that reduced physical activity and sleep difficulties may be mutually maintaining processes, particularly for individuals who suffer from poor sleep. Findings also raise the potential importance of targeting physical activity and sleep concurrently in interventions aimed at improving physical and mental health. PMID- 25506393 TI - Interstitial 287 kb deletion of 4p16.3 including FGFRL1 gene associated with language impairment and overgrowth. AB - We report a male patient with developmental delay carrying an interstitial 4p16.3 deletion of 287 kb, disclosed by oligo array-CGH and inherited from his father with a similar but milder phenotype. This deletion is distal to the Wolf Hirschhorn syndrome critical regions, but includes the FGFRL1 gene proposed to be a plausible candidate for part of the craniofacial characteristics of Wolf Hirschhorn syndrome patients. However, the proband lacks the typical facial appearance of the syndrome, but exhibits overgrowth, dysfunction of temporomandibular articulation and a bicuspid aortic valve. Given the pattern of expression of the fibroblast growth factor receptor-like 1 and its involvement in bone and cartilage formation as well as in heart valve morphogenesis, we discuss the impact of its haploinsufficiency in the phenotype. PMID- 25506394 TI - Cytogenetically normal uterine leiomyomas without MED12-mutations - a source to identify unknown mechanisms of the development of uterine smooth muscle tumors. AB - BACKGROUND: Recent findings on genetic changes in uterine leiomyomas suggest these benign tumors being a heterogeneous group of diseases in terms of molecular pathogenesis with those showing karyotype alterations as well as those characterized only by cytogenetically invisible mutations of mediator subcomplex 12 (MED12). Herein, five uterine leiomyomas (UL) with an apparently normal karyotype that lacked MED12-mutations were investigated by copy number variation arrays along with their matching myometrium to search for small genomic imbalances. RESULTS: Of five tumors one showed chromothripsis-like phenomena with numerous gains and losses of small segments mainly clustered to five chromosomal regions i.e. 2p14-2pter, 2q33.1-2q37.3, 5q31.3-5qter,11q14.1-11qter, and 18p11.21 18q2.3. Apparently, these cells had escaped detection by classical cytogenetics. Histologically, the tumor presented as a cellular leiomyoma with extended hyalinization. Of the remaining four tumors, one had a small intragenic deletion of the HMGA2 gene that was lacking in the corresponding myometrium. The other three tumors did not show relevant copy number alterations at all. CONCLUSIONS: Overall, the results suggest that leiomyomas with an apparently normal karyotype based on classical cytogenetics and lacking MED12 mutations represent a heterogeneous group of diseases. While the HMGA2 deletion detected in one of the tumors likely represents the driver mutation and, due to its size, has escaped detection by classical cytogenetics, the extended genomic imbalances detected in one of the other cases cannot be overlooked by this method suggesting an inability of the affected cells to divide in vitro. Of particular interest in that case is the occurrence of so-called "chromothripsis" or "firestorms" without involvement of the loci of common chromosomal rearrangements in UL, as e.g. 12q14 ~ 15 and 6p21. While chromothripsis was initially described as a hallmark of malignancy, the etiology and significance of this phenomenon in benign tumors still remain obscure. In uterine smooth muscle tumors, these changes per se do not indicate malignancy. PMID- 25506395 TI - A de novo 2.9 Mb interstitial deletion at 13q12.11 in a child with developmental delay accompanied by mild dysmorphic characteristics. AB - BACKGROUND: Proximal deletions in the 13q12.11 region are very rare. Much larger deletions including this region have been described and are associated with complex phenotypes of mental retardation, developmental delay and various others anomalies. RESULTS: We report on a 3-year-old girl with a rare 2.9 Mb interstitial deletion at 13q12.11 due to a de novo unbalanced t(13;14) translocation. She had mild mental retardation and relatively mild dysmorphic features such as microcephaly, flat nasal bridge, moderate micrognathia and clinodactyly of 5(th) finger. Molecular karyotyping revealed a deletion on the long arm of chromosome 13 as involving sub-bands 13q12.11, a deletion of about 2.9 Mb. DISCUSSION: The clinical application of array-CGH has made it possible to detect submicroscopical genomic rearrangements that are associated with varying phenotypes.The description of more patients with deletions of the 13q12.11 region will allow a more precise genotype-phenotype correlation. PMID- 25506396 TI - Subtelomeric multiplex ligation-dependent probe amplification as a supplement for rapid prenatal detection of fetal chromosomal aberrations. AB - BACKGROUND: Pregnant women with high-risk indications are highly suspected of fetal chromosomal aberrations. To determine whether Multiplex Ligation-dependent Probe Amplification (MLPA) using subtelomeric probe mixes (P036-E2 and P070-B2) is a reliable method for rapid detection of fetal chromosomal aberrations. The subtelomeric MLPA probe mixes were used to evaluate 50 blood samples from healthy individuals. 168 amniocytes and 182 umbilical cord blood samples from high-risk fetuses were analyzed using the same subtelomeric MLPA probe sets. Karyotyping was also performed in all cases of high-risk pregnancies, and single nucleotide polymorphism array analysis was used to confirm submicroscopic and ambiguous results from MLPA/karyotyping. RESULTS: Subtelomeric MLPA analysis of normal samples showed normal result in all cases by use of P036-E2 probe mix, while P070 B2 probe mix gave normal results for all but one case. In one normal control case P070-B2 produced a duplicated signal of probe for 13q34. In the high-risk group, totally 44 chromosomal abnormalities were found by karyotyping and MLPA, including 23 aneuploidies and 21 rearrangements or mosaics. MLPA detected all 23 aneuploidies, 12 rearrangements and 1 mosaic. Importantly, MLPA revealed 4 chromosomal translocations, 2 small supernumerary marker chromosomes (sSMCs), and 3 subtelomeric imbalances that were not well characterized or not detectable by karyotyping. However, MLPA showed negetive results for the remaining 8 rearrangements or mosaics, including 3 low mosaic aneuploidies, 1 inherited sSMC, and 4 paracentric inversions. CONCLUSIONS: Results suggest that combined use of subtelomeric MLPA and karyotyping may be an alternative method for using karyotype analyses alone in rapid detection of aneuploidies, rearrangements, and sSMCs. PMID- 25506397 TI - The use of semi-quantitative ultrasound elastosonography in combination with conventional ultrasonography and contrast-enhanced ultrasonography in the assessment of malignancy risk of thyroid nodules with indeterminate cytology. AB - BACKGROUND: The pre-surgical selection of thyroid nodules with indeterminate cytology (Thy 3 according to British Thyroid Association) after fine-needle aspiration biopsy (FNAB) is currently required in order to reduce unnecessary total thyroidectomy. The objective of our study was to use a surgical series of Thy 3 nodules to evaluate the predictive role of ultrasound elastosonography (USE) and contrast-enhanced ultrasonography (CEUS) in pre-surgical diagnoses of malignancy. SUBJECTS AND METHODS: We enrolled 63 patients with Thy 3 nodules in which cytological-histological correlation was available. The ELX 2/1 strain index was obtained by means of semi-quantitative USE, which was performed before surgery in addition to conventional ultrasonography (US) and contrast-enhanced US (CEUS) on the Thy 3 nodules. The ELX 2/1 strain index, a five-item US score and both peak (P) index and time to peak (TTP) index from CEUS were correlated with the histological results. After surgical diagnosis, the data were analysed by using a receiver-operating characteristic (ROC) curve. RESULTS: Histology was benign in 50 and malignant in 13 Thy 3 nodules. No difference in maximal diameter was noted between benign (22.8 +/- 1.6 mm) and malignant (18.9 +/- 2.9 mm) nodules. Significant correlations were found between histology and cumulative US findings (p=0.005), ELX 2/1 index (p=0.002), P index (p=0.01) and TTP index (p=0.02). On analysing data from US, USE and CEUS, significant ROC areas under the curve were observed (p<0.0001). A cut-off value was set for US (>2), ELX 2/1 (>0.95), P index (<0.99) and TTP index (>0.98) scores. The diagnostic power of the cumulative pre-surgical analysis of Thy 3 nodules with US, USE and CEUS, considering the experimental cut-off points obtained from the ROC curves was: sensitivity 64%, specificity 92%, PPV 75% and accuracy 84%. CONCLUSION: The ELX 2/1 index in conjunction with the US score can be useful in orienting surgical strategies in Thy 3 nodules. The information added by CEUS is less sensitive than that provided by US and USE. The use of a cut-off based on histology can reduce thyroidectomy. Observation should be the first choice when not all instrumental results are suspect. PMID- 25506398 TI - Serum macrophage migration inhibitory factor levels in Hashimoto's thyroiditis; a case control study. AB - OBJECTIVE: The cell-mediated immune process by CD4+ and CD8+ lymphocyte subsets of T-cells has a major role in the pathogenesis of Hashimoto's thyroiditis (HT). However, the exact mechanisms of initiation and progression of thyroid autoimmunity have not been completely clarified yet. Macrophage migration inhibitory factor (MIF) is commonly recognized as playing vital roles in various autoimmune diseases. Ee aimed to investigate serum MIF levels in subjects with HT and correlate them with the level of thyroid hormones and autoantibodies. MATERIALS AND METHODS: This study included 93 patients with untreated Hashimoto's thyroiditis and 53 healthy controls. We measured serum levels of TSH, free T4 (FT4), free T3 (FT3), anti-thyroglobulin autoantibody (TGAb) and anti-thyroid peroxidase autoantibody (TPOAb) in all patients and thyroid ultrasonography was performed. The concentration of MIF was measured using enzyme-linked immunosorbent assay (ELISA) method. RESULTS: We enrolled 93 patients with HT (mean age; 31.3 +/- 11.1 years), and 53 healthy control group (mean age; 29.3 +/- 8.5 years) in the current study. The patient group consisted of 52 with euthyroid autoimmune thyroiditis, 31 with subclinical hypothyroidism and 10 with overt hypothyroidism. Serum levels of MIF were higher in patients with overt hypothyroidism (6300.9 +/- 2504.3 pg/ml) than the euthyroid patients (3955.2 +/- 3013.6 pg/ml) (p = 0.036). CONCLUSION: MIF increases in overt hypothyroidism due to the Hashimoto's thyroiditis. Further investigations are needed to explore the role of MIF in pathogenesis of Hashimoto's thyroiditis. PMID- 25506399 TI - Nucleosomes are enriched at the boundaries of hypomethylated regions (HMRs) in mouse dermal fibroblasts and keratinocytes. AB - BACKGROUND: The interplay between epigenetic modifications and chromatin structure are integral to our understanding of genome function. Methylation of cytosine (5mC) at CG dinucleotides, traditionally associated with transcriptional repression, is the most highly studied chemical modification of DNA, occurring at over 70% of all CG dinucleotides in the genome. Hypomethylated regions (HMRs) often occur in CG islands (CGIs), however, they also occur outside of CGIs and function as cell-type specific enhancers. During the process of differentiation, reorganization of chromatin and nucleosome arrangement at regulatory regions is thought to occur in order for the establishment of cell-type specific transcriptional programs. However, the specifics regarding the organization of nucleosomes at HMRs and the potential mechanisms regulating nucleosome occupancy in these regions are unknown. Here, we have investigated nucleosome organization around hypomethylated regions (HMRs) identified in two mouse primary cells. RESULTS: Microccocal nuclease (MNase) digested mononucleosomes from primary cultures of new-born female mouse dermal fibroblasts and keratinocytes were mapped and compared to the HMRs obtained from single base-pair resolution methylomes. In both cell types, we find that nucleosomes are enriched at HMR boundaries. In contrast to the nucleosomes found at boundaries of HMRs in CGIs, HMRs outside of CGIs are calculated to be preferentially bound by nucleosomes, with phased nucleosomes propagating into the methylated region. Nucleosomes are enriched at the tissue-specific HMRs (TS-HMR) boundaries in both cell types suggesting that nucleosome organization surrounding HMR boundaries is independent of methylation status. In addition, we find potential transcription factor (TF) binding sites (E-box motifs) enriched in non-CGI TS-HMR boundaries. CONCLUSIONS: Our results show that intrinsic nucleosome occupancy score (INOS) positively correlate with the nucleosome organization surrounding non-CGI TS-HMRs, suggesting that DNA sequence plays a role in the establishment of HMRs in the genome. Since nucleosomes impact all processes involving the genome, our results provide a link between epigenetic modifications, chromatin structure, and regulatory function. PMID- 25506400 TI - Reliable estimation of prediction errors for QSAR models under model uncertainty using double cross-validation. AB - BACKGROUND: Generally, QSAR modelling requires both model selection and validation since there is no a priori knowledge about the optimal QSAR model. Prediction errors (PE) are frequently used to select and to assess the models under study. Reliable estimation of prediction errors is challenging - especially under model uncertainty - and requires independent test objects. These test objects must not be involved in model building nor in model selection. Double cross-validation, sometimes also termed nested cross-validation, offers an attractive possibility to generate test data and to select QSAR models since it uses the data very efficiently. Nevertheless, there is a controversy in the literature with respect to the reliability of double cross-validation under model uncertainty. Moreover, systematic studies investigating the adequate parameterization of double cross-validation are still missing. Here, the cross validation design in the inner loop and the influence of the test set size in the outer loop is systematically studied for regression models in combination with variable selection. METHODS: Simulated and real data are analysed with double cross-validation to identify important factors for the resulting model quality. For the simulated data, a bias-variance decomposition is provided. RESULTS: The prediction errors of QSAR/QSPR regression models in combination with variable selection depend to a large degree on the parameterization of double cross validation. While the parameters for the inner loop of double cross-validation mainly influence bias and variance of the resulting models, the parameters for the outer loop mainly influence the variability of the resulting prediction error estimate. CONCLUSIONS: Double cross-validation reliably and unbiasedly estimates prediction errors under model uncertainty for regression models. As compared to a single test set, double cross-validation provided a more realistic picture of model quality and should be preferred over a single test set. PMID- 25506401 TI - Influence of acute hyperlipidemia to adipocyte-derived hormones in lean normotensive and subjects with metabolic syndrome. AB - BACKGROUND: Adipocyte-derived factors and regulators likely contribute to the metabolic syndrome (MetS) in patients with central obesity. This study was undertaken to assess the contribution of leptin, adiponectin, and acylation stimulating protein (ASP-C3ades/ARG) to hemodynamic (blood pressure [BP]) and metabolic (insulin, glucose, lipids) features of MetS. METHODS: In this study, leptin, adiponectin, and C3ades/ARG were measured at baseline and in response to an infusion of Intralipid((r)) and heparin in 12 lean healthy controls and 12 patients with MetS. RESULTS: Baseline plasma leptin (27.6 +/- 6.2 vs. 10.9 +/- 3.8 ng/mL, p < 0.01) and plasma C3ades/ARG (273 +/- 79 vs 198 +/- 57 mg/dL, p < 0.05) were higher in the MetS than control group, whereas baseline plasma adiponectin was higher in the control than MetS group (9.9 +/- 1.9 vs. 5.4 +/- 0.6 g/mL). Plasma leptin correlated with body mass index (BMI), systolic and diastolic BP (r = 0.53-0.77, p < 0.01). Conversely, adiponectin correlated inversely with insulin, glucose, waist circumference, and insulin sensitivity (r = 0.48-0.51, p <= 0.02). Plasma triglycerides increased similarly in MetS and control groups after 4-hours of Intralipid and heparin. C3ades/ARG increased only in lean volunteers. The decrease in triglycerides 1-hour post-infusion was lower in the MetS than control group (-116 +/- 33 vs. -282 +/- 81 mg/dL, p = 0.01) and correlated inversely with the change in C3ades/ARG. CONCLUSION: These data suggest that leptin is more closely associated with hemodynamic (BP) aspects of MetS, whereas adiponectin and C3ades/ARG are more closely associated with metabolic components. PMID- 25506402 TI - Tn5 transposition in Escherichia coli is repressed by Hfq and activated by over expression of the small non-coding RNA SgrS. AB - BACKGROUND: Hfq functions in post-transcriptional gene regulation in a wide range of bacteria, usually by promoting base pairing of mRNAs with trans-encoded sRNAs. It was previously shown that Hfq down-regulates Tn10 transposition by inhibiting IS10 transposase expression at the post-transcriptional level. This provided the first example of Hfq playing a role in DNA transposition and led us to ask if a related transposon, Tn5, is similarly regulated. RESULTS: We show that Hfq strongly suppresses Tn5 transposition in Escherichia coli by inhibiting IS50 transposase expression. However, in contrast to the situation for Tn10, Hfq primarily inhibits IS50 transposase transcription. As Hfq does not typically function directly in transcription, we searched for a transcription factor that also down-regulated IS50 transposase transcription and is itself under Hfq control. We show that Crp (cyclic AMP receptor protein) fits these criteria as: (1) disruption of the crp gene led to an increase in IS50 transposase expression and the magnitude of this increase was comparable to that observed for an hfq disruption; and (2) Crp expression decreased in hfq (-) . We also demonstrate that IS50 transposase expression and Tn5 transposition are induced by over expression of the sRNA SgrS and link this response to glucose limitation. CONCLUSIONS: Tn5 transposition is negatively regulated by Hfq primarily through inhibition of IS50 transposase transcription. Preliminary results support the possibility that this regulation is mediated through Crp. We also provide evidence that glucose limitation activates IS50 transposase transcription and transposition. PMID- 25506403 TI - Prevalence and Characteristics of School Services for High School Students with Attention-Deficit/Hyperactivity Disorder. AB - This study examines the prevalence and characteristics of services reported by school staff for 543 high school students participating in the 8 year follow-up of the multi-site Multimodal Treatment study of ADHD (MTA). Overall, 51.6% of students with a history of attention-deficit/hyperactivity disorder (ADHD) were receiving services through an Individualized Educational Plan (IEP) or a 504 plan, a rate higher than expected for this age group. Less than 5% of these had 504 plans; 35.5% attended special education classes. Very few services (except tutoring) were provided outside of an IEP or 504 plan. Almost all students with services received some type of academic intervention, whereas only half received any behavioral support or learning strategy. Less than one-fourth of interventions appear to be evidence-based. Students receiving services showed greater academic and behavioral needs than those not receiving services. Services varied based upon type of school, with the greatest number of interventions provided to students attending schools that only serve those with disabilities. Original MTA treatment randomization was unrelated to services, but cumulative stimulant medication and greater severity predicted more service receipt. Results highlight a need for accommodations with greater evidence of efficacy and for increased services for students who develop academic difficulties in high school. PMID- 25506404 TI - Polymeric Nanoparticles to Combat Squamous Cell Carcinomas in Patients with Dystrophic Epidermolysis Bullosa. AB - Skin cancer is the leading cause of malignancy in the United States, with Basal Cell Carcinoma, Squamous Cell Carcinoma , and Melanoma being the three most common diagnoses, respectively. Squamous Cell Carcinoma (SCC) is a particular concern for patients suffering from Dystrophic Epidermolysis Bullosa (DEB), a disease that affects the production and function of collagen VII, a protein that forms the anchoring fibrils which bind the epidermis to the dermis. Patients with DEB suffer from chronic blistering and wounds that have impaired healing capabilities, often leading to the development of SCC and eventual mortality. Nanomedicine is playing an increasing role in the delivery of effective therapeutics to combat a wide range of diseases, including the imaging and treatment of SCC. In this review, we discuss the role of nanoparticles in the treatment of SCC with an emphasis on PLGA nanoparticles and SCCs found in patients suffering from DEB, and address recent patents that are pertinent to the development of novel nanomedical therapeutics. PMID- 25506405 TI - Intellectual Disabilities and Neglectful Parenting: Preliminary Findings on the Role of Cognition in Parenting Risk. AB - Parents with intellectual disabilities (PID) are over-represented in the child protective services (CPS) system. This study examined a more nuanced view of the role of cognition in parenting risk. Its goal was to validate a social information processing (SIP) model of child neglect that draws on social cognition research and advances in neuroscience. Mothers who had CPS child neglect cases were compared with mothers with no CPS involvement on a set of SIP factors. Mothers with low IQs were oversampled. As predicted, the Neglect group had significantly greater SIP problems than the Comparison mothers. SIP problems were associated with direct measures of neglect (e.g., cognitive stimulation provided children, home hygiene, belief regarding causes of child injuries). Further, for the direct measures that were most closely linked to CPS Neglect Status, IQ did not add significant predictive capacity beyond SIP factors in preliminary model testing. Implications for intervention with PID discussed. PMID- 25506406 TI - Propane-d6 Heterogeneously Hyperpolarized by Parahydrogen. AB - Long-lived spin states of hyperpolarized propane-d6 gas were demonstrated following pairwise addition of parahydrogen gas to propene-d6 using heterogeneous parahydrogen-induced polarization (HET-PHIP). Hyperpolarized molecules were synthesized using Rh/TiO2 solid catalyst with 1.6 nm Rh nanoparticles. Hyperpolarized (PH ~ 1%) propane-d6 was detected at high magnetic field (9.4 T) spectroscopically and by high-resolution 3D gradient-echo MRI (4.7 T) as the gas flowed through the radiofrequency coil with a spatial and temporal resolution of 0.5 * 0.5 * 0.5 mm3 and 17.7 s, respectively. Stopped-flow hyperpolarized propane d6 gas was also detected at 0.0475 T with an observed nuclear spin polarization of PH ~ 0.1% and a relatively long lifetime with T1,eff = 6.0 +/- 0.3 s. Importantly, it was shown that the hyperpolarized protons of the deuterated product obtained via pairwise parahydrogen addition could be detected directly at low magnetic field. Importantly, the relatively long low-field T1,eff of HP propane-d6 gas is not susceptible to paramagnetic impurities as tested by exposure to ~0.2 atm oxygen. This long lifetime and nontoxic nature of propane gas could be useful for bioimaging applications including potentially pulmonary low-field MRI. The feasibility of high-resolution low-field 2D gradient-echo MRI was demonstrated with 0.88 * 0.88 mm2 spatial and ~0.7 s temporal resolution, respectively, at 0.0475 T. PMID- 25506407 TI - High-Temperature Magnetism as a Probe for Structural and Compositional Uniformity in Ligand-Capped Magnetite Nanoparticles. AB - To investigate magnetostructural relationships in colloidal magnetite (Fe3O4) nanoparticles (NPs) at high temperature (300-900 K), we measured the temperature dependence of magnetization (M) of oleate-capped magnetite NPs ca. 20 nm in size. Magnetometry revealed an unusual irreversible high-temperature dependence of M for these NPs, with dip and loop features observed during heating-cooling cycles. Detailed characterizations of as-synthesized and annealed Fe3O4 NPs as well as reference ligand-free Fe3O4 NPs indicate that both types of features in M(T) are related to thermal decomposition of the capping ligands. The ligand decomposition upon the initial heating induces a reduction of Fe3+ to Fe2+ and the associated dip in M, leading to more structurally and compositionally uniform magnetite NPs. Having lost the protective ligands, the NPs continually sinter during subsequent heating cycles, resulting in divergent M curves featuring loops. The increase in M with sintering proceeds not only through elimination of a magnetically dead layer on the particle surface, as a result of a decrease in specific surface area with increasing size, but also through an uncommonly invoked effect resulting from a significant change in Fe3+/Fe2+ ratio with heat treatment. The interpretation of irreversible features in M(T) indicates that reversible M(T) behavior, conversely, can be expected only for ligand-free, structurally and compositionally uniform magnetite NPs, suggesting a general applicability of high temperature M(T) measurements as an analytical method for probing the structure and composition of magnetic nanomaterials. PMID- 25506409 TI - D-Glucose-Induced Cytotoxic, Genotoxic, and Apoptotic Effects on Human Breast Adenocarcinoma (MCF-7) Cells. AB - INTRODUCTION: Glucose is a simple sugar that plays an important role in energy production in biological systems. However, it has been linked to many long-term health problems including the risk of heart disease and stroke, erectile dysfunction in men and pregnancy complications in women, and damage to the kidneys, nerves, eye and vision. Also, the underlying mechanisms of diabetic complications are poorly understood. METHODS: In the present study, D-glucose induced cytotoxic, genotoxic, and apoptotic effects were studied using MCF-7 cells as an in vitro test model. Cell viability was determined by MTT assay. Genotoxic damage was tested by the means of alkaline single cell gel electrophoresis (Comet) assay. Cell apoptosis was measured by flow cytometry assessment (Annexin-V/PI assay). RESULTS: The results of MTT assay indicated that D-glucose significantly reduces the viability of MCF-7 cells in a dose and time dependent manner. Similar trend was obtained with the trypan blue exclusion test. Data obtained from the Comet assay indicated that D-glucose causes DNA damage in MCF-7 cells in a dose-dependent manner. The flow cytometry assessment (Annexin V FITC/PI) showed a strong dose-response relationship between D-glucose exposure and annexin V positive MCF-7 cells undergoing early apoptosis. CONCLUSION: Taking together, these data provide clear evidence that D-glucose induces cytotoxic, genotoxic, and apoptotic effects on MCF-7 cells. This finding represents the basis for further studies addressing the pathophysiological mechanisms of action of glucose overdose. PMID- 25506410 TI - Parenting Behaviors of Mothers with Borderline Personality Disorder: A Call to Action. PMID- 25506408 TI - Quantitative Analysis of Aortic Valve Stenosis and Aortic Root Dimensions by Three-Dimensional Echocardiography in Patients Scheduled for Transcutaneous Aortic Valve Implantation. AB - Accurate assessment of the aortic valve area (AVA) and evaluation of the aortic root are important for clinical decision-making in patients being considered for transcatheter aortic valve implantation (TAVI). Real-time three-dimensional transesophageal echocardiography (RT3D-TEE) provides accurate and reliable quantitative assessment of aortic valve stenosis and the aortic root. We performed two-dimensional transthoracic echocardiography (2D-TTE), real-time 2D transesophageal echocardiography (RT2D-TEE) and RT3D-TEE in 71 consecutive patients referred for TAVI. RT3D-TEE multiplanar reconstruction was used to measure aortic root parameters, including left ventricular outflow tract (LVOT) diameter and area, aortic annulus diameter, aortic annulus area, and AVA. RT3D TEE methods for planimetry and the LVOT-derived continuity equation for the estimation of AVA showed a good correlation. As iatrogenic coronary ostium occlusion is a potentially life-threatening complication, we evaluated the distances from the aortic annulus to the coronary ostia using RT3D-TEE. Based on our findings, we conclude that the geometry of the aortic root and aortic valve can be reliably and feasibly evaluated using RT3D-TEE, which is important for protecting against potential complications of TAVI, such as underestimation of the size of the aortic annulus that can result in aortic regurgitation and dislocation of the valve, or overestimation can lead to annulus rupture. PMID- 25506411 TI - Survival of post-treatment canine-to-canine lingual retainers with fiber reinforced composite resin: a retrospective study. AB - The aim of the study is to evaluate the long term results of ribbond retainer after orthodontic treatment. One hundred and thirty patients who were orthodontically treated satisfied the inclusion criteria of having received a semipermanent retention were treated with FRC lingual retainers (Ribbond ((r))). It was performed a follow up evaluation after 2 years average from the retainer application and any complication or failure was recorded. Data from 119 remaining patients that met the inclusion criteria were analyzed and no instances of loosening were observed. It may be concluded that orthodontic canine-to-canine FRC retainers provide aneffective means of retaining realigned anterior teeth for at least two years. PMID- 25506412 TI - A multimedia oral health promoting project in primary schools in central Italy. AB - AIM: The purpose of the study Project was to test the effectiveness of a multimedia game designed in order to attract the attention of primary school children to oral health basic concepts and use the instrument to assess students' knowledge. MATERIALS AND METHODS: An originally designed multimedia game on oral health was administered in the computer class rooms, before (T0) and after (T1) an educational stage, to third (8-9 years) and fifth graders (10-11 years) of primary schools in urban and rural areas of two provinces of medium-small cities in Center Italy (Terni and Latina). Considered variables were: age, gender, school time schedule (only antemeridian, extended schedule). The statistical test used was the non-parametric Wilcox on signed-rank test. RESULTS: Response rate was 90.6% (due to absence on the due date). 1,300 students were involved. Overall, the average of the correct answers was 40.7% before oral health lessons and 59.2% after. An improving trend of correct answers was recorded from T0 to T1, significantly (p < 0.05) among: fifth graders (+ 17.5%), extended school time schedulers (+18.1%) and females (+18.9%). The results, however, show poor global oral health knowledge, being total percentage of correct answers below 60%. CONCLUSIONS: The results stress the importance of the school environment as access to health promotion for all socio-economic classes. The multimedia educational approach has proved a valuable and updated tool to attract the attention of digital native children. PMID- 25506414 TI - Atomic force microscopy study of enamel remineralization. AB - AIM: The aim of the present in vitro study was the evaluation of two products: a CPP-ACP paste (GC Tooth Mousse, GC Corp.) and a desensitizing toothpaste (Colgate Sensitive Pro Relief, Colgate-Palmolive) on preventing enamel erosion produced by a soft drink (Coca Cola) by using Atomic Force Microscopy (AFM). METHODS: Thirty enamel specimens were assigned to 6 groups of 5 specimens each. 1: intact enamel, 2: enamel + soft drink, 3: intact enamel + Colgate Sensitive Pro Relief, 4: enamel + soft drink + Colgate Sensitive Pro Relief, 5: intact enamel + GC Tooth Mousse, 6: enamel + soft drink + GC Tooth Mousse. The surface of each specimen was imaged by AFM. The root mean-square roughness (Rrms) was obtained from the AFM images and the differences in the averaged values among the groups were analyzed by ANOVA test. RESULTS: Comparing groups 4 and 6 (soft drink + toothpastes) with group 2 (eroded enamel) a statistical difference (P<0.05) was registered, suggesting effectiveness in protecting enamel against erosion of the products investigated. CONCLUSIONS: The use of new formulation toothpastes can prevent enamel demineralization. PMID- 25506415 TI - Histological evaluation of a biomimetic material in bone regeneration after one year from graft. AB - AIM: The use of substitute materials is one of the solutions used in periodontology for the reconstruction of intrabony defects. Advances in scientific research gave rise to a new generation of biomaterials of synthetic origin stoichiometrically unstable and therefore really absorbable. Our research is directed precisely towards a biomaterial synthesis, Engipore(r) (Finceramica, Faenza, Italy) which is a bone substitute of the latest hydroxyapatite-based generation, that possesses chemical and morphological properties similar to those of natural bone in the treatment of infrabony periodontal defects. Aim of this study was to evaluate the efficacy of Engipore(r) in the treatment of intrabony periodontal defects. METHODS: The study was conducted on 100 parodontopatics patients, which had gingival pockets of at least infrabonies 8/10 mm. The histological evaluation was performed with samples after one year from the graft. RESULTS: The histological samples collected after one year showed an abundant new bone formation, with mature lamellar bone tissue surrounding the residual particles of Engipore(r) that appear completely osteointegrated. The surrounding connective tissue shows no signs of inflammation. CONCLUSIONS: The results obtained in our research demonstrated that, after a proper selection of patients and lesions, and applying an adequate surgical technique, this type of biomaterial in the treatment of periodontal defects acts in an optimal manner as a filler inducing the formation of new bone as evidenced by histological examinations. PMID- 25506413 TI - Root canal obturation: experimental study on the thermafil system related to different irrigation protocols. AB - AIM: The aim of this study was to stress the ability of a specific obturation technique (thermafil technique) to seal root canal system in presence or absence of smear layer. METHODOLOGY: Sixteen monoradicular teeth, extracted for periodontal reasons, were collected for this study. All specimens were prepared with nickel-titanium rotary files, and then divided into two groups: for each group was applied a different kind of irrigation method, verifying the effectiveness in removing the smear layer, thus rendering the dentinal tubules more permeable for penetration of softened gutta-percha. Thermafil system was used to fill the root canals, and then all the specimens were observed under scanning electron microscope (SEM). RESULTS: The results showed that the Group which followed irrigation only with sodium hypochlorite exhibited significantly less gutta-percha tags when compared to the second Group, which was irrigated with sodium hypochlorite and EDTA. CONCLUSION: The thermafil systems have a very good quality of compression and fluency that permit to gain a good seal of endodontic space; furthermore it allows the penetration of gutta-percha with the formation of numerous of gutta-percha tags inside the dentinal tubules above all when smear layer is reduced or eliminated. PMID- 25506416 TI - Nano-hydroxyapatite and its applications in preventive, restorative and regenerative dentistry: a review of literature. AB - This study aims to critically summarize the literature about nano-hydroxyapatite. The purpose of this work is to analyze the benefits of using nano-hydroxyapatite in dentistry, especially for its preventive, restorative and regenerative applications. We also provide an overview of new dental materials, still experimental, which contain the nano-hydroxyapatite in its nano-crystalline form. Hydroxyapatite is one of the most studied biomaterials in the medical field for its proven biocompatibility and for being the main constituent of the mineral part of bone and teeth. In terms of restorative and preventive dentistry, nano hydroxyapatite has significant remineralizing effects on initial enamel lesions, certainly superior to conventional fluoride, and good results on the sensitivity of the teeth. The nano-HA has also been used as an additive material, in order to improve already existing and widely used dental materials, in the restorative field (experimental addition to conventional glass ionomer cements, that has led to significant improvements in their mechanical properties). Because of its unique properties, such as the ability to chemically bond to bone, to not induce toxicity or inflammation and to stimulate bone growth through a direct action on osteoblasts, nano-HA has been widely used in periodontology and in oral and maxillofacial surgery. Its use in oral implantology, however, is a widely used practice established for years, as this substance has excellent osteoinductive capacity and improves bone-to-implant integration. PMID- 25506417 TI - High-resolution chromosomal microarray analysis of early-stage human embryonic stem cells reveals an association between X chromosome instability and skewed X inactivation. AB - X chromosome inactivation (XCI) is a dosage compensation mechanism that silences the majority of genes on one X chromosome in each female cell via a random process. Skewed XCI is relevant to many diseases, but the mechanism leading to it remains unclear. Human embryonic stem cells (hESCs) derived from the inner cell mass (ICM) of blastocyst-stage embryos have provided an excellent model system for understanding XCI initiation and maintenance. Here, we derived hESC lines with random or skewed XCI patterns from poor-quality embryos and investigated the genome-wide copy number variation (CNV) and loss of heterozygosity (LOH) patterns at the early passages of these two groups of hESC lines. It was found that the average size of CNVs on the X chromosomes in the skewed group is twice as much as that in the random group. Moreover, the LOH regions of the skewed group covered the gene locus of either XIST or XACT, which are master long non-coding RNA (lncRNA) effectors of XCI in human pluripotent stem cells. In conclusion, our work has established an experimentally tractable hESC model for study of skewed XCI and revealed an association between X chromosome instability and skewed XCI. PMID- 25506419 TI - Self-organization of signal transduction. AB - We propose a model of parameter learning for signal transduction, where the objective function is defined by signal transmission efficiency. We apply this to learn kinetic rates as a form of evolutionary learning, and look for parameters which satisfy the objective. This is a novel approach compared to the usual technique of adjusting parameters only on the basis of experimental data. The resulting model is self-organizing, i.e. perturbations in protein concentrations or changes in extracellular signaling will automatically lead to adaptation. We systematically perturb protein concentrations and observe the response of the system. We find compensatory or co-regulation of protein expression levels. In a novel experiment, we alter the distribution of extracellular signaling, and observe adaptation based on optimizing signal transmission. We also discuss the relationship between signaling with and without transients. Signaling by transients may involve maximization of signal transmission efficiency for the peak response, but a minimization in steady-state responses. With an appropriate objective function, this can also be achieved by concentration adjustment. Self organizing systems may be predictive of unwanted drug interference effects, since they aim to mimic complex cellular adaptation in a unified way. PMID- 25506418 TI - Ouabain inhibition of Na/K-ATPase across the retina prevents signed refractive compensation to lens-induced defocus, but not default ocular growth in young chicks. AB - PURPOSE: The relevance of retinal integrity and energy pathways to ocular growth and induction of refractive errors has seldom been investigated. Thus, we used ouabain to target the channels that are essential for the maintenance of membrane potentials in cells, sodium potassium ATPase (Na/K-ATPase), to examine refractive compensation and ocular growth in response to lens-induced defocus in the chick. METHODS: A single intravitreal injection of 1 mM ouabain in dimethyl sulfoxide (DMSO) carrier or DMSO alone was followed by monocular defocus with positive or negative 10 D lens (or no lens) from post-hatching days 5-9 under 12/12 hr light/dark conditions. Biometry and dark-adapted flash and electroretinography (ERG) were conducted on day 9, followed by immunohistological analyses. RESULTS: Ouabain inhibited differential ocular growth and refractive compensation to signed defocus compared to DMSO. By 4-days post-ouabain injection all components of the typical ERG responses to light had been eliminated, and widespread histological damage was apparent, though some 'default state' ocular growth was measurable. Immunohistochemistry demonstrated reduction in the specialized water channel Aquaporin 4 (AQP4) expression and increased evidence of caspase 3 expression (a cell death associated protein) in ouabain-treated eyes compared with DMSO alone. CONCLUSION: The current study demonstrates that blockade of photoreceptor and inner retinal responses to light onset and offset by ouabain inhibits differential refractive compensation to optical blur, but does not prevent ocular growth. PMID- 25506420 TI - The electrostatic profile of consecutive Cbeta atoms applied to protein structure quality assessment. AB - The structure of a protein provides insight into its physiological interactions with other components of the cellular soup. Methods that predict putative structures from sequences typically yield multiple, closely-ranked possibilities. A critical component in the process is the model quality assessing program (MQAP), which selects the best candidate from this pool of structures. Here, we present a novel MQAP based on the physical properties of sidechain atoms. We propose a method for assessing the quality of protein structures based on the electrostatic potential difference (EPD) of Cbeta atoms in consecutive residues. We demonstrate that the EPDs of Cbeta atoms on consecutive residues provide unique signatures of the amino acid types. The EPD of Cbeta atoms are learnt from a set of 1000 non-homologous protein structures with a resolution cuto of 1.6 A obtained from the PISCES database. Based on the Boltzmann hypothesis that lower energy conformations are proportionately sampled more, and on Annsen's thermodynamic hypothesis that the native structure of a protein is the minimum free energy state, we hypothesize that the deviation of observed EPD values from the mean values obtained in the learning phase is minimized in the native structure. We achieved an average specificity of 0.91, 0.94 and 0.93 on hg_structal, 4state_reduced and ig_structal decoy sets, respectively, taken from the Decoys 'R' Us database. The source code and manual is made available at https://github.com/sanchak/mqap and permanently available on 10.5281/zenodo.7134. PMID- 25506421 TI - The impact of high density receptor clusters on VEGF signaling. AB - Vascular endothelial growth factor (VEGF) signaling is involved in the process of blood vessel development and maintenance. Signaling is initiated by binding of the bivalent VEGF ligand to the membrane-bound receptors (VEGFR), which in turn stimulates receptor dimerization. Herein, we discuss experimental evidence that VEGF receptors localize in caveloae and other regions of the plasma membrane, and for other receptors, it has been shown that receptor clustering has an impact on dimerization and thus also on signaling. Overall, receptor clustering is part of a complex ecosystem of interactions and how receptor clustering impacts dimerization is not well understood. To address these questions, we have formulated the simplest possible model. We have postulated the existence of a single high affinity region in the cell membrane, which acts as a transient trap for receptors. We have defined an ODE model by introducing high- and low-density receptor variables and introduce the corresponding reactions from a realistic model of VEGF signal initiation. Finally, we use the model to investigate the relation between the degree of VEGFR concentration, ligand availability, and signaling. In conclusion, our simulation results provide a deeper understanding of the role of receptor clustering in cell signaling. PMID- 25506423 TI - Socioeconomic barriers to rhegmatogenous detachment surgery in Brazil. AB - Purpose. To verify access barriers patients with retinal detachment face to arrive at a reference center and to evaluate patients' knowledge about the disease. Methods. Transversal study that applied a questioner to 65 patients of the Clinical Hospital of the University of Sao Paulo with retinal detachment between February and August of 2010. Results. Reasons for not performing the surgery in other services were as follows: 47% were referred because there was not vitreoretinal surgeon at original service; 27% could not afford the surgery, had no health insurance, or had no coverage at health insurance plan for the procedure. Time between the first symptom and the arrival at our service was as follows: 18 patients arrived in up to 7 days; 35 between 8 and 30 days; 8 between 31 and 90 days; 5 in more than 90 days. Reasons for delay were as follows: 70% did not know how serious the pathology was; 56% thought that it had spontaneous cure; 16% did not have money to pay for ophthalmic evaluation, 10% did not know where to go and 24% for other reasons. Conclusion. Educational programs about disease and measures to optimize the referral to specialized services are needed to accelerate the treatment of patients with rhegmatogenous retinal detachment. PMID- 25506422 TI - A Comparison of Methods for RNA-Seq Differential Expression Analysis and a New Empirical Bayes Approach. AB - Transcriptome-based biosensors are expected to have a large impact on the future of biotechnology. However, a central aspect of transcriptomics is differential expression analysis, where, currently, deep RNA sequencing (RNA-seq) has the potential to replace the microarray as the standard assay for RNA quantification. Our contributions here to RNA-seq differential expression analysis are two-fold. First, given the high cost of an RNA-seq run, biological replicates are rare, and therefore, information sharing across genes to obtain variance estimates is crucial. To handle such information sharing in a rigorous manner, we propose an hierarchical, empirical Bayes approach (R-EBSeq) that combines the Cufflinks model for generating relative transcript abundance measurements, known as FPKM (fragments per kilobase of transcript length per million mapped reads) with the EBArrays framework, which was previously developed for empirical Bayes analysis of microarray data. A desirable feature of R-EBSeq is easy-to-implement analysis of more than pairwise comparisons, as we illustrate with experimental data. Secondly, we develop the standard RNA-seq test data set, on the level of reads, where 79 transcripts are artificially differentially expressed and, therefore, explicitly known. This test data set allows us to compare the performance, in terms of the true discovery rate, of R-EBSeq to three other widely used RNAseq data analysis packages: Cuffdiff, DEseq and BaySeq. Our analysis indicates that DESeq identifies the first half of the differentially expressed transcripts well, but then is outperformed by Cuffdiff and R-EBSeq. Cuffdiff and R-EBSeq are the two top performers. Thus, R-EBSeq offers good performance, while allowing flexible and rigorous comparison of multiple biological conditions. PMID- 25506424 TI - The perception of family function by adolescents with epilepsy in a rural nigerian community. AB - The family plays a significant role in epilepsy management in sub-Saharan Africa and how this role is perceived by persons with epilepsy could influence epilepsy outcomes. The objective of the study was to assess perception of family function by adolescents with epilepsy (AWE). The sociodemographic and epilepsy characteristics of AWE in a rural Nigerian community were assessed and the Family APGAR tool was used in assessing their perception of satisfaction with family functioning. Adolescents (n = 1708) constituted 26% of the community's population and 18 (10.5/1000) had epilepsy. The AWE age range was 11-19 years (mean 16.7 +/- 2.6 years) with a male preponderance (15, 83.3%). The family was the only source of care. Family dysfunction (Family APGAR Score <7) was indicated by 15 (83.3%) of the AWE. The strongest perception of family function was in adaptability while the weakest was with growth. The indication of family dysfunction was significant (P<0.05) in the older (age 14-19 years) AWE when compared with the younger AWE (11-13 years) in the study. Most of the AWE indicated living in a dysfunctional family setting. The study highlights the need to address the role of the family in the provision of comprehensive epilepsy care. PMID- 25506425 TI - Laparoscopic versus Open Surgery for Colorectal Cancer: A Retrospective Analysis of 163 Patients in a Single Institution. AB - Background. The present study aimed to compare the clinical outcomes of laparoscopic versus open surgery for colorectal cancers. Materials and Methods. The medical records from a total of 163 patients who underwent surgery for colorectal cancers were retrospectively analyzed. Patient's demographic data, operative details and postoperative early outcomes, outpatient follow-up, pathologic results, and stages of the cancer were reviewed from the database. Results. The patients who underwent laparoscopic surgery showed significant advantages due to the minimally invasive nature of the surgery compared with those who underwent open surgery, namely, less blood loss, faster postoperative recovery, and shorter postoperative hospital stay (P < 0.05). However, laparoscopic surgery for colorectal cancer resulted in a longer operative time compared with open surgery (P < 0.05). There were no statistically significant differences between groups for medical complications (P > 0.05). Open surgery resulted in more incisional infections and postoperative ileus compared with laparoscopic surgery (P < 0.05). There were no differences in the pathologic parameters between two groups (P < 0.05). Conclusions. These findings indicated that laparoscopic surgery for colorectal cancer had the clear advantages of a minimally invasive surgery and relative disadvantage with longer surgery time and exhibited similar pathologic parameters compared with open surgery. PMID- 25506426 TI - Abdominoplasty improves quality of life, psychological distress, and eating disorder symptoms: a prospective study. AB - Background. Only some studies provide sufficient data regarding the effects of nonpostbariatric (aesthetic) abdominoplasty on various aspects of quality of life. Nevertheless, when considering the effects on eating habits, publications are lacking. Therefore we decided to assess the effects of nonpostbariatric abdominoplasty on eating disorder symptoms, psychological distress, and quality of life. Materials and Methods. 64 consecutive women underwent nonpostbariatric abdominoplasty. Three outcome measures were completed: the Eating Disorder Inventory (EDI), Raitasalo's modification of the Beck Depression Inventory (RBDI), and the 15D general quality of life questionnaire. Results. The mean age at baseline was 42 years and the mean body mass index (BMI) 26.4. Fifty-three (83%) women completed all the outcome measures with a mean follow-up time of 5 months. A significant improvement from baseline to follow-up was noted in women's overall quality of life, body satisfaction, effectiveness, sexual functioning, and self-esteem. The women were significantly less depressive and had significantly less drive for thinness as well as bulimia, and their overall risk of developing an eating disorder also decreased significantly. Conclusions. Abdominoplasty results in significantly improved quality of life, body satisfaction, effectiveness, sexual functioning, self-esteem, and mental health. The risk of developing an eating disorder is decreased significantly. This trial is registered with Clinicaltrials.gov NCT02151799. PMID- 25506427 TI - Adverse reactions to antituberculosis drugs in Iranian tuberculosis patients. AB - Background. Antituberculosis multidrug regimens have been associated with increased incidence of adverse drug reactions (ADRs). This study aimed to determine the incidence and associated factors of ADRs due to antituberculosis therapy. Methods. This is a retrospective cross-sectional study on tuberculosis patients who were treated in tuberculosis clinics in Markazi province in Iran. The information contained in the medical files was extracted and entered into the questionnaire. Data was descriptively analyzed by using statistical package for social sciences (SPSS 18). Results. A total of 940 TB patients of 1240 patients' medical records available in 10 medical offices were included in this study. Of the 563 ADRs found in this study, 82.4% were considered minor reactions and 17.6% were major reactions. No death from antituberculosis ADR was observed. We found that the risk of major ADRs was higher in females (P value = 0.0241), age >50 y (P value = 0.0223), coinfection with HIV (P value = 0.0323), smoking (P value = 0.002), retreatment TB (P value = 0.0203), and comorbidities (P value = 0.0005). Conclusions. This study showed that severe side effects of anti-TB drugs are common in patients who have risk factors of ADRs and they should be followed up by close monitoring. PMID- 25506428 TI - Differentiation of human breast-milk stem cells to neural stem cells and neurons. AB - Objectives. Human breast milk contains a heterogeneous population of cells that have the potential to provide a noninvasive source of cells for cell therapy in many neurodegenerative diseases without any ethical concern. The objectives of this study were to differentiate the breast milk-derived stem cells (BMDSC) toward neural stem cells and then into the neurons and neuroglia. Materials and Methods. To do this, the BMDSC were isolated from human breast milk and cultured in Dulbecco's modified Eagle medium/F12 (DMEM/F12) containing fibroblast growth factor (bFGF). The cells were then characterized by evaluation of the embryonic and stem cell markers. Then, the cells were exposed to culture medium containing 1% B27 and 2% N2 for 7-10 days followed by medium supplemented with B27, N2, bFGF 10 ug/mL, and endothelial growth factor (EGF) 20 ug/mL. Then, the sphere-forming assay was performed. The spheres were then differentiated into three neural lineages by withdrawing growth factor in the presence of 5% FBS (fetal bovine serum). The immunofluorescence was done for beta-tubulin III, O4, and GFAP (glial fibrillary acidic protein). Results. The results indicated that the cells expressed both embryonic and mesenchymal stem cell (MSC) markers. They also showed neurospheres formation that was nestin-positive. The cells were also differentiated into all three neural lineages. Conclusion. The BMDSC can behave in the same way with neural stem cells. They were differentiated into oligodendrocytes, and astrocytes as well as neurons. PMID- 25506431 TI - Comparison of colour duplex ultrasound with computed tomography to measure the maximum abdominal aortic aneurysmal diameter. AB - Introduction. Maximum diameter of an abdominal aortic aneurysm (AAA) is the main indication for surgery. This study compared colour duplex ultrasound (CDU) and computed tomography (CT) in assessing AAA diameter. Patients and Methods. Patients were included if they had both scans performed within 90 days. Pearson's correlation coefficient, paired t-test, and limits of agreement (LOA) were calculated for the whole group. Subgroup analysis of small (<5.0 cm), medium (5.0 6.5 cm), and large (>6.5 cm) aneurysms was performed. A P value of <0.05 was considered statistically significant. Results. 389 patients were included, giving 130 pairs of tests for comparison. Excellent correlation was in the whole group (r = 0.95) and in the subgroups (r = 0.94; 0.69; 0.96, resp.). Small LOA between the two imaging modalities was found in all subgroups. Conclusion. Small aneurysms can be accurately measured using CDU. CDU is preferable for small AAAs, but cannot supplant CT for planning aortic intervention. PMID- 25506430 TI - A prospective study of villous capillary lesions in complicated pregnancies. AB - The vascularity of placental tissue is dependent on various factors of which fetomaternal hypoxia plays a major role. Hypoxia can be of different types and each type influences the vascularity of the villi, especially terminal villi, in its own way. In this study, we attempted to identify villous vascular changes in a group of term placentae from mothers with diseases complicating pregnancy. Chorangiosis was the most frequently identified lesion while chorangioma was found in only 2 cases. There were no cases of chorangiomatosis. A few cases had normal villous vasculature. Maternal diseases have a major role in disrupting the placental vasculogenesis and angiogenesis by creating a hypoxic environment that may affect the fetus adversely. Hence, such conditions need to be identified early in pregnancy and managed appropriately as it is possible to maintain a normal vasculature and prevent neonatal mortality and morbidity if prompt intervention is done. PMID- 25506429 TI - Relevance of chronic lyme disease to family medicine as a complex multidimensional chronic disease construct: a systematic review. AB - Lyme disease has become a global public health problem and a prototype of an emerging infection. Both treatment-refractory infection and symptoms that are related to Borrelia burgdorferi infection remain subject to controversy. Because of the absence of solid evidence on prevalence, causes, diagnostic criteria, tools and treatment options, the role of autoimmunity to residual or persisting antigens, and the role of a toxin or other bacterial-associated products that are responsible for the symptoms and signs, chronic Lyme disease (CLD) remains a relatively poorly understood chronic disease construct. The role and performance of family medicine in the detection, integrative treatment, and follow-up of CLD are not well studied either. The purpose of this paper is to describe insights into the complexity of CLD as a multidimensional chronic disease construct and its relevance to family medicine by means of a systematic literature review. PMID- 25506433 TI - Cheating the CHA2DS2-VASc Score: Thromboembolism in Apical Hypertrophic Cardiomyopathy. AB - Atrial fibrillation increases the risk of systemic thromboembolism in general and stroke in particular. Not all patients who develop atrial fibrillation are at significantly heightened risk of thromboembolic complications, however, with the development of risk scoring systems aiding clinicians in determining whether formal anticoagulation is mandated. The most commonly used contemporary scoring systems-CHADS2 and CHA2DS2-VASc-provide a reliable means of assessing stroke risk, but certain cardiac conditions are associated with an increased incidence of thromboembolism without impacting on these risk scores. Hypertrophic cardiomyopathy, with its apical variant, is such a condition. We present a case of a patient with apical hypertrophic cardiomyopathy and atrial fibrillation who suffered dire thromboembolic consequences despite a reassuringly low CHA2DS2-VASc score and suggest that this scoring system is modified to incorporate the thromboembolic risk inherent to certain cardiomyopathies irrespective of impairment of left ventricular systolic dysfunction or clinical heart failure. PMID- 25506432 TI - Glucagon-like peptide-1 as predictor of body mass index and dentate gyrus neurogenesis: neuroplasticity and the metabolic milieu. AB - Glucagon-like peptide-1 (GLP-1) regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1), and body mass index (BMI) in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP 1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge-high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues. PMID- 25506434 TI - Hypertriglyceridemia induced pancreatitis (chylomicronemia syndrome) treated with supportive care. AB - Hypertriglyceridemia is a rare cause of pancreatitis. In treatment pancreatic rest, lifestyle changes, medications (fibrates, n-3 polyunsaturated fatty acids, and nicotinic acid) are essential. Many experimental treatment modalities have been reported as insulin and heparin infusion and plasmapheresis. In this study we present the hypertriglyceridemia-induced pancreatitis treated with supportive care. PMID- 25506435 TI - Extensive presentation of central ossifying fibroma treated with conservative surgical excision. AB - Central ossifying fibroma is a benign slow-growing tumor of mesenchymal origin and it tends to occur in the second and third decades of life, with predilection for women and for the mandibular premolar and molar areas. Clinically, it is a large asymptomatic tumor of aggressive appearance, with possible tooth displacement. Occasionally treated by curettage enucleation, this conservative surgical excision is showing a recurrence rate extremely low. The objective of this study was to report a case of a 44-year-old woman, presenting a very large ossifying fibroma in the mandible, which was successfully treated with curettage, and to conduct a brief literature review of this lesion, focusing on the histology, clinical behavior, and management of these uncommon lesions. PMID- 25506436 TI - Central odontogenic fibroma of simple type. AB - Central odontogenic fibroma (COF) is an extremely rare benign tumor that accounts for 0.1% of all odontogenic tumors. It is a lesion associated with the crown of an unerupted tooth resembling dentigerous cyst. In this report, a 10-year-old male patient is presented, who was diagnosed with central odontogenic fibroma of simple type from clinical, radiological, and histopathological findings. PMID- 25506437 TI - Interdisciplinary management of an isolated intrabony defect. AB - The treatment of intrabony defects is a real challenge in molar teeth as it is chronic, slowly progressing disease which needs timely intervention. Periodontal inflammation associated with intrabony defect is not a separate entity as it secondarily affects the pulp causing retrograde pulpitis. However, treatment of these lesions will be complicated due to extensive bone loss. The tooth was endodontically treated followed by periodontal surgery to eliminate the deep periodontal pocket and promote bone fill in osseous defect. PepGen P-15 composited with platelet rich plasma was utilized for enhancing bone formation. The combination of these graft materials provides synergistic effect on bone regeneration. PMID- 25506438 TI - A rare interstitial duplication of 8q22.1-8q24.3 associated with syndromic bilateral cleft lip/palate. AB - We present a rare case of 8q interstitial duplication derived from maternal balanced translocations in a patient with bilateral cleft lip and palate in syndromic form associated with other congenital malformations. G-banding cytogenetic analysis revealed a chromosomal abnormality in the form of the karyotype 46,XX der(22)t(8;22)(q22.1;p11.1)mat. Chromosome microarray analysis evidenced a 49 Mb duplicated segment of chromosome 8q with no pathogenic imbalances on chromosome 22. Two siblings also carry the balanced translocation. We have compared this case with other "pure" trisomies of 8q patients reported in the literature and with genome wide association studies recently published. This work highlights the involvement of chromosome 8q in orofacial clefts. PMID- 25506439 TI - A Case of Odontogenic Infection by Streptococcus constellatus Leading to Systemic Infection in a Cogan's Syndrome Patient. AB - Odontogenic infection in immunocompromised patients tends to extend systemically beyond the oral cavity. Our case report presents a patient with sepsis due to a Streptococcus constellatus (S. constellatus) odontogenic infection in a 64-year old-immunocompromised woman with Cogan's syndrome. She had been suffering from chronic mandibular osteomyelitis which was thought to have been caused by dental caries and/or chronic periodontitis with furcation involvement of the left mandibular first molar. We suspect that the acute symptoms of the chronic osteomyelitis due to S. constellatus led to the systemic infection. This infection could be accelerated by the use of a corticosteroid and an alendronate. This is the first report which represents the potential association between odontogenic infection and Cogan's syndrome. PMID- 25506440 TI - Successful treatment of disseminated subcutaneous panniculitis-like T-cell lymphoma with single agent oral cyclosporine as a first line therapy. AB - Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a rare cutaneous neoplasm of mature cytotoxic T-cells. Currently there are no standardized therapies for SPTL; however good responses have been seen with chemotherapy regimens generally employed for B-cell lymphomas. Cyclosporine, an immunosuppressant, has shown good responses in relapsed/refractory SPTL; however its use in first line setting is not well established. We, herein, describe a 22 year-old girl with disseminated SPTL who attained complete clinical remission with single agent oral cyclosporine used as a first line therapy. PMID- 25506441 TI - Vascular malformation and common keratinocytic nevus of the soft type: phacomatosis pigmentovascularis revisited. AB - Phacomatosis pigmentovascularis is a rare syndrome characterized by the coexistence of a pigmented nevus and a cutaneous vascular malformation. We report a 5-year-old boy with all the typical findings of phacomatosis pigmentovascularis type Ia. Although its existence according to the traditional classification has been questioned, this case represents a very rare association of a capillary vascular malformation and a common keratinocytic nevus of the soft type. PMID- 25506442 TI - A new case of 13q12.2q13.1 microdeletion syndrome contributes to phenotype delineation. AB - A recently described genetic disorder has been associated with 13q12.3 microdeletion spanning three genes, namely, KATNAL1, LINC00426, and HMGB1. Here, we report a new case with similar clinical features that we have followed from birth to 5 years old. The child carried a complex rearrangement with a double translocation: 46,XX,t(7;13)(p15;q14),t(11;15)(q23;q22). Array-CGH identified a de novo microdeletion at 13q12.2q13.1 spanning 3-3.4 Mb and overlapping 13q12.3 critical region. Clinical features resembling those reported in the literature confirm the existence of a distinct 13q12.3 microdeletion syndrome and provide further evidence that is useful to characterize its phenotypic expression during the 5 years of development. PMID- 25506443 TI - Oral lesion as unusual first manifestation of multiple myeloma: case reports and review of the literature. AB - Extramedullary plasmacytoma (EMP) and solitary bone plasmacytoma (SBP) represent a disease continuum through a multistage process of cell differentiation, survival, proliferation, and dissemination, strictly related to multiple myeloma (MM), the second most common hematological malignancy. Herein, we report two cases of recurrent oral plasmacytoma progressed to MM, in which the first clinical sign of a more widespread disease was limited to the mouth. Based on our experience, we recommend a strict workup for the differential diagnosis between EMP, SBP, and MM for patients with oral plasmacytoma, including radiological exam of the skeleton, magnetic resonance imaging (MRI) of the bone, and positive emission tomography (FDG-PET). MRI and possibly PET can all be used to more sensitively detect EM plasmacytoma sites. PMID- 25506444 TI - Kerstersia gyiorum Isolated from a Bronchoalveolar Lavage in a Patient with a Chronic Tracheostomy. AB - The use of the matrix-assisted laser desorption ionization-time of flight (MALDI TOF) mass spectrometry (MS) generates rapid microbial identification. We are presenting a case of a 63-year-old woman with a medical history of chronic tracheostomy admitted for hypotension and fevers to illustrate the clinical implication of MALDI-TOF MS on bacterial identification. Kerstersia gyiorum was identified from the bronchoalveolar lavage isolate. Kerstersia gyiorum has been isolated from human sputum samples, and may be a previously unrecognized colonizer of the upper respiratory tract. Thus, patients with long-term tracheotomies or who are chronically aspirating may be at risk of lower respiratory infection with this organism. Increased use of MALDI-TOF MS in the clinical setting may increase reporting of this atypical isolate. PMID- 25506445 TI - Successful treatment of infectious endocarditis associated glomerulonephritis mimicking c3 glomerulonephritis in a case with no previous cardiac disease. AB - We report a 42-year-old man with subacute infectious endocarditis (IE) with septic pulmonary embolism, presenting rapidly progressive glomerulonephritis and positive proteinase 3-anti-neutrophil cytoplasmic antibody (PR3-ANCA). He had no previous history of heart disease. Renal histology revealed diffuse endocapillary proliferative glomerulonephritis with complement 3- (C3-) dominant staining and subendothelial electron dense deposit, mimicking C3 glomerulonephritis. Successful treatment of IE with valve plastic surgery gradually ameliorated hypocomplementemia and renal failure; thus C3 glomerulonephritis-like lesion in this case was classified as postinfectious glomerulonephritis. IE associated glomerulonephritis is relatively rare, especially in cases with no previous history of valvular disease of the heart like our case. This case also reemphasizes the broad differential diagnosis of renal involvement in IE. PMID- 25506446 TI - ANCA Associated Vasculitis and Renal Failure Related to Propylthiouracil and Hyperthyroidism Induced Cholestasis in the Same Case. AB - Introduction. Liver involvement due to hyperthyroidism and also ANCA positive vasculitis related renal failure cases were reported separately several times before. However, to our knowledge, these two complications together in the same case had never been observed before. Case Presentation. The case of an ANCA positive 71-year-old Caucasian male with renal failure and lung involvement, subclinical hyperthyroidism, and intrahepatic cholestatic jaundice was presented in this paper. After exclusion of all of the other possibilities, cholestatic hepatitis was explained by subclinical hyperthyroidism; renal failure and lung involvement were interpreted as ANCA related vasculitis which might be a side effect of propylthiouracil use. Conclusion. The coexistence of these rare conditions in the same patient deserves emphasis and it is worth reporting. This case demonstrates that following the clinical course of the patient is essential after prescribing any medications to see whether any complication occurs or not. If the complications of this case were noticed earlier, it would be possible to treat and to prevent the permanent damages. PMID- 25506447 TI - PML-IRIS during Fingolimod Diagnosed after Natalizumab Discontinuation. AB - Background. Natalizumab treatment is frequently discontinued and replaced by alternative medication in multiple sclerosis (MS) patients having a high risk of progressive multifocal leukoencephalopathy (PML). Case Presentation. We report a PML case that was missed on magnetic resonance imaging (MRI) at the time Natalizumab treatment was discontinued. The patient subsequently developed a PML immune reconstitution inflammatory syndrome after the initiation of Fingolimod treatment, suggesting that immune reconstitution may occur even during Fingolimod induced lymphopenia. Conclusion. This report highlights the need for strict drug surveillance using MRI of Natalizumab-associated MS patients at the time of drug discontinuation and beyond. This is important with respect to pharmacovigilance purposes not only for Natalizumab, but also for alternative drugs used after Natalizumab discontinuation. PMID- 25506448 TI - Menkes disease presenting with epilepsia partialis continua. AB - Aim. We aim to describe a female patient with Menkes disease who presented with epilepsia partialis continua. Case Presentation. Seventeen-months-old Saudi infant was presented with repetitive seizures and was diagnosed to have epilepsia partialis continua. Discussion. Menkes disease (OMIM: 309400) is considered a rare, X-linked recessive neurodegenerative disorder resulting from a mutation in the gene coding for the copper transporting ATPase (ATP7A). Affected individuals usually present with kinky hair, skeletal changes, prolonged jaundice, hypothermia, developmental regression, decreased tone, spasticity, weakness, and therapy resistant seizures. Conclusion. Raising awareness of abnormal presentation of this rare disease may help in the control of seizures through subcutaneous copper supplementation. PMID- 25506449 TI - Rescue of primary incomplete microkeratome flap with secondary femtosecond laser flap in LASIK. AB - For laser-assisted in situ keratomileusis (LASIK) retreatments with a previous unsuccessful mechanical microkeratome-assisted surgery, some surgical protocols have been described as feasible, such as relifting of the flap or the creation of a new flap and even the change to a surface ablation procedure (photorefractive keratectomy (PRK)). This case shows the use of femtosecond technology for the creation of a secondary flap to perform LASIK in a cornea with a primary incomplete flap obtained with a mechanical microkeratome. As we were unable to characterize the interface of the first partial lamellar cut, a thick flap was planned and created using a femtosecond laser platform. As the primary cut was very thick in the nasal quadrant, a piece of loose corneal tissue appeared during flap lifting which was fitted in its position and not removed. Despite this condition and considering the regularity of the new femtosecond laser cut, the treatment was uneventful. This case report shows the relevance of a detailed corneal analysis with an advanced imaging technique before performing a secondary flap in a cornea with a primary incomplete flap. The femtosecond laser technology seems to be an excellent tool to manage such cases successfully. PMID- 25506450 TI - Intravitreal Ranibizumab for Stage IV Proliferative Sickle Cell Retinopathy: A First Case Report. AB - Purpose. To present the case of a 27-year-old male patient with stage IV proliferative sickle cell retinopathy, treated with one intravitreal injection of ranibizumab, showing regression of the neovascularization and no recurrence at the 9-month follow-up. Methods. A 27-year-old male patient presented with blurred vision and floaters in the right eye since three days. His best corrected visual acuity was 6/18. Ophthalmological examination and fluorescein angiography revealed proliferative sickle cell retinopathy stage IV with vitreous hemorrhage and sea fan neovascularization, as well as ischemic areas at the temporal periphery. Results. The patient was treated with one intravitreal injection of ranibizumab, presenting improvement in the visual acuity from 6/18 to 6/6, resolution of vitreous hemorrhage, and regression of the neovascularization. Additionally, he underwent scatter laser photocoagulation at the ischemic areas. At the 9-month follow-up there was no recurrence, while no adverse effects were noticed. Conclusions. Intravitreal ranibizumab may be a useful adjunct to laser photocoagulation in the management of proliferative sickle cell retinopathy and may permit some patients to avoid pars plana vitrectomy for vitreous hemorrhage. PMID- 25506451 TI - Central retinal vein occlusion in a patient with retinal vasculitis and Crohn's disease. AB - The authors report a rare case of a 47-year-old woman with Crohn's disease (CD) who presented with retinal vasculitis and central retinal vein occlusion (CRVO) during remission. The patient complained of sudden painless visual loss in her left eye (OS). Ophthalmologic evaluation revealed a best corrected visual acuity (BCVA) of 20/20 in the right eye and hand movements in OS. Ophthalmoscopy and fluorescein angiography of OS showed signs of nonischemic CRVO and extensive vasculitis. She was treated with oral prednisolone, mercaptopurine, and intravitreal bevacizumab in OS. After 1 month of treatment, VA of OS improved to 5/10 and after 1 year it was 10/10 with complete resolution of retinal vasculitis and nonischemic CRVO. PMID- 25506452 TI - An Unusual Metallic Foreign Body inside the Knee Medial Femoral Condyle. AB - Foreign bodies in the knee joint are uncommon, particularly those not related to surgical procedures. In this paper, we present a case of an intraosseous metallic foreign body situated in the medial femoral condyle for one year, causing pain, which was removed with complete resolution of the symptoms. PMID- 25506453 TI - Calcific tendonitis of the longus colli muscle: a noninfectious cause of retropharyngeal fluid collection. AB - Calcific tendonitis of the longus colli (CTLC) muscle is an underrecognized cause of spontaneous acute or subacute neck pain, dysphagia, or odynophagia. Imaging may reveal a retropharyngeal fluid collection leading to the presumed diagnosis of retropharyngeal abscess. Recognition of this uncommon presentation is important to prevent unnecessary surgical incision and drainage. A 44-year-old otherwise healthy male presented with a 2-week history of progressive neck pain, stiffness, and odynophagia. A noncontrast CT scan of the cervical spine revealed a retropharyngeal fluid collection with a small area of calcification anterior to C2. There was a presumed diagnosis of retropharyngeal abscess. The patient was afebrile with normal vital signs. Flexible nasolaryngoscopy was unremarkable. C reactive protein was elevated but all other bloodwork was normal with no evidence of an infective process. A CT scan was repeated with IV contrast showing no enhancement around the fluid collection. A diagnosis of CTLC was made. The patient was successfully managed with a short course of intravenous steroids and oral NSAIDs with complete resolution of symptoms. Clinically CTLC can mimic more serious disease processes. Identifying pathognomonic imaging findings often confirms the diagnosis. Awareness of this condition by the otolaryngologist will ensure proper patient management and avoidance of unnecessary procedures. PMID- 25506454 TI - Residual fistula of fourth branchial arch anomalies and recurrent left-side cervical abscess: clinical case and review of the literature. AB - Congenital fourth branchial arch anomalies are uncommon entities. Most of these anomalies are diagnosed in childhood. The majority of cases occur on the left side. The clinical presentation of these anomalies varies with age. A respiratory distress is the usual clinical presentation in neonates, cervical cutaneous fistulas in late childhood or acute suppurative thyroiditis. Multiples diagnostic options have been described with different modalities of treatment. The majority of cases of fourth branchial arch anomalies are described only in case reports. We report a clinical case of recurrent cervical abscess in a young woman due to a residual fistula of fourth branchial arch. PMID- 25506455 TI - A challenge for diagnosing acute liver injury with concomitant/sequential exposure to multiple drugs: can causality assessment scales be utilized to identify the offending drug? AB - Drug-induced hepatotoxicity most commonly manifests as an acute hepatitis syndrome and remains the leading cause of drug-induced death/mortality and the primary reason for withdrawal of drugs from the pharmaceutical market. We report a case of acute liver injury in a 12-year-old Hispanic boy, who received a series of five antibiotics (amoxicillin, ceftriaxone, vancomycin, ampicillin/sulbactam, and clindamycin) for cervical lymphadenitis/retropharyngeal cellulitis. Histopathology of the liver biopsy specimen revealed acute cholestatic hepatitis. All known causes of acute liver injury were appropriately excluded and (only) drug-induced liver injury was left as a cause of his cholestasis. Liver-specific causality assessment scales such as Council for the International Organization of Medical Sciences/Roussel Uclaf Causality Assessment Method scoring system (CIOMS/RUCAM), Maria and Victorino scale, and Digestive Disease Week-Japan were applied to seek the most likely offending drug. Although clindamycin is the most likely cause by clinical diagnosis, none of causality assessment scales aid in the diagnosis. PMID- 25506456 TI - Atypical CT Findings in Plexiform Ameloblastoma. AB - Ameloblastoma is an uncommon epithelial odontogenic neoplasm that is nonmineralized, locally aggressive, and, in most cases, benign. Most ameloblastomas develop in the molar-ramus region of the mandible with 70% of them arising in the molar-ramus area. Radiologically they are unilocular or multilocular radiolucency with a honeycomb or soap bubble appearance. The radiographic appearance of ameloblastoma can vary according to the type of tumor. CT is usually helpful in determining the contours of the lesion, its contents, and its extension into soft and hard tissues. Through this case we would bring to light some of the unusual CT findings which include the destruction of the surrounding structures by the lesion which appeared to be normal routine lesion when viewed clinically. PMID- 25506457 TI - IgG4-Related Disease: A Multispecialty Condition. AB - IgG4-related disease (IgG4-RD) is a recently recognized group of conditions, characterized by tumor-like swelling of involved organs, lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, variable degrees of fibrosis, and elevated serum IgG4 concentrations. Currently IgG4-RD is recognized as a systemic condition that can affect several organs and tissues. Herein we report the case of a 34-year-old male patient who was admitted to our hospital with diffuse abdominal pain, weight loss, and painful stiffness in his neck. He had a history of tumoral mass of the left maxillary region, right palpebral ptosis with protrusion of the eyeball, and chronic dry cough for about 6 years. Laboratory tests revealed polyclonal hypergammaglobulinemia and increased serum IgG4 levels. Immunohistochemical staining of the maxillary biopsy was compatible with IgG4-RD. He had an excellent response to corticosteroid therapy. This case highlights that IgG4-RD should be included in the differential diagnosis with multisystem diseases. PMID- 25506458 TI - Rescue ALPPS: Intraoperative Conversion to ALPPS during Synchronous Resection of Rectal Cancer and Liver Metastasis. AB - Future liver remnant (FLR) is the most important deciding factor in planning for liver resection. Portal vein embolization (PVE) was first introduced in the 1980s to induce liver hypertrophy, enabling removal of multiple/bilobar tumors. PVE was later combined with sequential hepatectomies with the aim of allowing the liver remnant to hypertrophy (15-20%) between procedures. However, the interval between the two procedures (3-8 weeks) put patients at risk for disease progression. With portal vein ligation alone or when combined with sequential hepatectomy, there is also a risk for inadequate liver hypertrophy because of intrahepatic portal collaterals leading to a high (19-30%) dropout rate. The ALPPS procedure (associating liver partition and portal vein ligation for staged hepatectomy) was recently developed as a feasible means to perform extensive/bilobar liver resections. It produces rapid, enormous hypertrophy of the remnant, making previously unresectable lesions resectable. Indications for ALPPS include any extensive liver resection with inadequate FLR. Here we present a novel indication for ALPPS as a rescue when inadequate FLR was faced intraoperatively, during a simultaneous resection of rectal primary and liver metastasis. PMID- 25506460 TI - Replacement of Vena Cava up to the Right Atrium during Living Donor Liver Transplantation for Echinococcus alveolaris. AB - Management of advanced stage of Echinococcus alveolaris is a very difficult procedure. Surgical treatment like resection and liver transplantation is accepted procedure nowadays. Here we presented a case report of Echinococcus alveolaris which invaded the inferior vena cava up to the right atrium and surrounding tissues. This patient underwent living donor liver transplantation with replacement of inferior vena cava up to the right atrium with cryopreserved cadaveric aortic graft. This procedure is very difficult but it is a life-saving chance for patients in advanced cases of Echinococcus alveolaris. PMID- 25506459 TI - Giant mature primary retroperitoneal teratoma in a young adult: report of a rare case and literature review. AB - Teratomas are neoplasms of the embryonic tissues that typically arise in the gonadal and sacrococcygeal regions of adults and children. Primary adult retroperitoneal teratomas are rare and demand challenging management options. We report a case of a unilateral primary retroperitoneal mature cystic teratoma mimicking an adrenal mass in a 28-year-old female patient. Complete resection of the mass was performed by a laparotomy approach. Because of the risk of malignancy, follow-up radiographic studies were performed to ensure the oncologic efficacy of resection. The patient remains free of recurrence to date. PMID- 25506461 TI - Laparoscopic nephrectomy, ex vivo partial nephrectomy, and autotransplantation for the treatment of complex renal masses. AB - In the contemporary era of minimally invasive surgery, very few T1/T2 renal lesions are not amenable to nephron-sparing surgery. However, centrally located lesions continue to pose a clinical dilemma. We sought to describe our local experience with three cases of laparoscopic nephrectomy, ex vivo partial nephrectomy, and autotransplantation. Laparoscopic donor nephrectomy was performed followed by immediate renal cooling and perfusion with isotonic solution. Back-table partial nephrectomy, renorrhaphy, and autotransplantation were then performed. Mean warm ischemia (WIT) and cold ischemic times (CIT) were 2 and 39 minutes, respectively. Average blood loss was 267 mL. All patients preserved their renal function postoperatively. Final pathology confirmed pT1, clear cell renal cell carcinoma with negative margins in all. All are disease free at up to 39 months follow-up with stable renal function. In conclusion, the described approach remains a viable option for the treatment of complex renal masses preserving oncological control and renal function. PMID- 25506462 TI - Correlates and Consequences of Opioid Misuse among High-Risk Young Adults. AB - Background. Prescription opioids are the most frequently misused class of prescription drug among young adults aged 18-25, yet trajectories of opioid misuse and escalation are understudied. We sought to model opioid misuse patterns and relationships between opioid misuse, sociodemographic factors, and other substance uses. Methods. Participants were 575 young adults age 16-25 who had misused opioids in the last 90 days. Latent class analysis was performed with models based on years of misuse, recency of misuse, and alternate modes of administration within the past 12 months, 3 months, and 30 days. Results. Four latent classes emerged that were differentially associated with heroin, cocaine, and methamphetamine use, tranquilizer misuse, daily opioid misuse, and opioid withdrawal. Alternate modes of administering opioids were associated with increased risk for these outcomes. Sociodemographic factors, homelessness, prescription history, and history of parental drug use were significantly associated with riskier opioid misuse trajectories. Conclusion. Young adults who reported more debilitating experiences as children and adolescents misused opioids longer and engaged in higher risk alternate modes of administering opioids. Data on decisions both to use and to alter a drug's form can be combined to describe patterns of misuse over time and predict important risk behaviors. PMID- 25506463 TI - Balloon Occlusion Types in the Treatment of Coronary Perforation during Percutaneous Coronary Intervention. AB - Coronary artery perforation is an uncommon complication in patients with coronary heart disease undergoing percutaneous coronary intervention. However, pericardial tamponade following coronary artery perforation may be lethal, and prompt treatment is crucial in managing such patients. Balloon occlusion and the reversal of anticoagulant activity are the common methods used to prevent cardiac tamponade by reducing the amount of bleeding. Herein, we discuss the pros and cons of currently used occlusion types for coronary perforation. Optimal balloon occlusion methods should reduce the amount of bleeding and ameliorate subsequent myocardial ischemia injury, even during cardiac surgery. PMID- 25506464 TI - Mother-to-Children Plasmodium falciparum Asymptomatic Malaria Transmission at Saint Camille Medical Centre in Ouagadougou, Burkina Faso. AB - Background. Malaria's prevalence during pregnancy varies widely in parts of sub Saharan Africa, including Burkina Faso. The objective of this study was to evaluate the incidence of mother-to-child malaria transmission during childbirth at St. Camille Medical Centre in the city of Ouagadougou. Methods. Two hundred and thirty-eight (238) women and their newborns were included in the study. Women consenting to participate in this study responded to a questionnaire that identified their demographic characteristics. Asymptomatic malaria infection was assessed by rapid detection test Acon (Acon Malaria Pf, San Diego, USA) and by microscopic examination of Giemsa-stained thick and thin smears from peripheral, placental, and umbilical cord blood. Birth weights were recorded and the biological analyses of mothers and newborns' blood were also performed. Results. The utilization of long-lasting insecticidal nets (LLINs) and intermittent preventive treatment with sulfadoxine-pyrimethamine (SP) were 86.6% and 84.4%, respectively. The parasitic infection rates of 9.5%, 8.9%, and 2.8% were recorded, respectively, for the peripheral, placental, and umbilical cord blood. Placental infection was strongly associated with the presence of parasites in the maternal peripheral blood and a parasite density of >1000 parasites/uL. Conclusion. The prevalence of congenital malaria was reduced but was associated with a high rate of mother-to-child malaria transmission. PMID- 25506465 TI - Low Prevalence of Pfcrt Resistance Alleles among Patients with Uncomplicated Falciparum Malaria in Niger Six Years after Chloroquine Withdrawal. AB - Chloroquine (CQ) resistance is widespread in Africa, but few data are available for Niger. Pfcrt haplotypes (aa 56-118) and ex vivo responses to CQ and amodiaquine were characterized for 26 isolates collected in South Niger from children under 15 years of age suffering from uncomplicated falciparum malaria, six years after the introduction of artemisinin-based combinations and the withdrawal of CQ. The wild-type Pfcrt haplotype CVMNK was found in 22 of the 26 isolates, with CVIET sequences observed in only three of the samples. We also describe for the first time a new CVINT haplotype. The ex vivo responses were better for CVMNK than for CVIET parasites. Pfcrt sequence data were compared with those obtained for 26 additional parasitized blood samples collected in Gabon, from an area of CQ resistance used as a control. Our findings suggest that there has been a significant decline in CQ-resistant genotypes since the previous estimates for Niger were obtained. No such decline in molecular resistance to CQ was observed in the subset of samples collected in similar conditions from Gabon. These results have important implications for public health and support the policy implemented in Niger since 2005, which aims to increase the efficacy and availability of antimalarial drugs whilst controlling the spread of resistance. PMID- 25506467 TI - Virulence Genes Content and Antimicrobial Resistance in Escherichia coli from Broiler Chickens. AB - A total of 121 E. coli strains were isolated from broiler chickens (96 extraintestinal pathogenic (ExPEC) strains from diseased broiler chickens and 25 avian fecal E. coli (AFEC) from healthy ones). Ten of the isolates (6 from diseased chickens and 4 from healthy birds) were serogrouped and 25 were examined for 4 virulence markers (tsh, papC, colV, and iss genes) as well as for their antimicrobial resistance. Five strains were nontypable and the rest were serotyped as follows: O86:K61 (2/5), O78:K80 (1/5), and O128:K67 (1/5) were recovered from diseased chickens, while O111:K58 strain (1/4) was isolated from healthy ones. The iss gene was found in 72.2% of the examined ExPEC strains in contrast to zero percentages (0%) in the AFEC strains, which may serve as a good marker for distinguishing APEC and its knocking out may help in creation of candidate vaccine that may prove sucess in elimination of infections in broiler chickens. Antimicrobial resistance patterns revealed a complete resistance to gentamicin, pefloxacin, amoxicillin, and enrofloxacin among examined strains followed by varying degrees of resistance for the rest of tested agents. The highest resistance was recorded against norfloxacin, in 24 isolates (96%), in contrast to the lowest resistance was recorded against colistin sulphate, in 14 strains (56%). These findings suggest the need for the prudent use of antimicrobials with broiler chickens and act as a warrant for the possibility of avian sources to transmit these resistant isolates to humans. PMID- 25506466 TI - Recurrent Falls in People with Parkinson's Disease without Cognitive Impairment: Focusing on Modifiable Risk Factors. AB - Falls can be considered a disabling feature in Parkinson's disease. We aimed to identify risk factors for falling, testing simultaneously the ability of disease specific and balance-related measures. We evaluated 171 patients, collecting demographic and clinical data, including standardized assessments with the Unified Parkinson's Disease Rating Scale (UPDRS), activities of daily living (ADL) and motor sections, modified Hoehn and Yahr Scale, Schwab and England, eight-item Parkinson's Disease Questionnaire, Activities-specific Balance Confidence Scale, Falls Efficacy Scale-International (FES-I), Berg Balance Scale, Dynamic Gait Index, Functional Reach, and Timed Up and Go. ROC curves were constructed to determine the cutoff scores for all measures. Variables with P < 0.1 entered a logistic regression model. The prevalence of recurrent falls was 30% (95% CI 24%-38%). In multivariate analysis, independent risk factors for recurrent falls were (P < 0.05) levodopa equivalent dose (OR = 1.283 per 100 mg increase; 95% CI = 1.092-1.507), UPDRS-ADL > 16 points (OR = 10.0; 95% CI = 3.6 28.3), FES-I > 30 points (OR = 6.0; 95% CI = 1.6-22.6), and Berg <= 48 points (OR = 3.9; 95% CI = 1.2-12.7).We encourage the utilization of these modifiable risk factors in the screening of fall risk. PMID- 25506468 TI - Temporal Bacteriostatic Effect and Growth Factor Loss in Equine Platelet Components and Plasma Cultured with Methicillin-Sensitive and Methicillin Resistant Staphylococcus aureus: A Comparative In Vitro Study. AB - The aims were (1) to evaluate the bacteriostatic effect of platelet-rich plasma (PRP), platelet-rich gel (PRG), leukocyte-poor plasma (LPP), leukocyte-poor gel (LPG), plasma, and heat-inactivated plasma (IP) on both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) over a period of 24 h; (2) to determine and to compare the concentrations and degradation over time of platelet factor 4 (PF-4), transforming growth factor beta 1 (TGF-beta 1), and platelet-derived growth factor isoform BB (PDGF-BB); and (3) to identify any correlations between MSSA and MRSA growth and either the cellular, PF-4, TGF-beta 1, or PDGF-BB concentrations in the blood components. PRP and its byproducts from 18 horses were obtained by the tube method. All blood components were cultured with either MSSA or MRSA. Bacterial growth, PF-4, TGF beta 1, and PDGF-BB were determined at 6 h and 24 h. At six hours, bacterial growth was significantly inhibited by all blood components, with the exception of IP. MSSA was more sensitive to the treatments than MRSA. At 24 hours, bacterial growth was significantly higher in IP. MRSA bacterial growth was significantly higher in PRP, LPP, and plasma when compared to MSSA. Growth factor concentrations were not significantly affected by bacteria. PMID- 25506469 TI - Molecular detection, phylogenetic analysis, and identification of transcription motifs in feline leukemia virus from naturally infected cats in malaysia. AB - A nested PCR assay was used to determine the viral RNA and proviral DNA status of naturally infected cats. Selected samples that were FeLV-positive by PCR were subjected to sequencing, phylogenetic analysis, and motifs search. Of the 39 samples that were positive for FeLV p27 antigen, 87.2% (34/39) were confirmed positive with nested PCR. FeLV proviral DNA was detected in 38 (97.3%) of p27 antigen negative samples. Malaysian FeLV isolates are found to be highly similar with a homology of 91% to 100%. Phylogenetic analysis revealed that Malaysian FeLV isolates divided into two clusters, with a majority (86.2%) sharing similarity with FeLV-K01803 and fewer isolates (13.8%) with FeLV-GM1 strain. Different enhancer motifs including NF-GMa, Krox-20/WT1I-del2, BAF1, AP-2, TBP, TFIIF-beta, TRF, and TFIID are found to occur either in single, duplicate, triplicate, or sets of 5 in different positions within the U3-LTR-gag region. The present result confirms the occurrence of FeLV viral RNA and provirus DNA in naturally infected cats. Malaysian FeLV isolates are highly similar, and a majority of them are closely related to a UK isolate. This study provides the first molecular based information on FeLV in Malaysia. Additionally, different enhancer motifs likely associated with FeLV related pathogenesis have been identified. PMID- 25506470 TI - Quantification of anandamide, oleoylethanolamide and palmitoylethanolamide in rodent brain tissue using high performance liquid chromatography-electrospray mass spectroscopy. AB - Reported concentrations for endocannabinoids and related lipids in biological tissues can vary greatly; therefore, methods used to quantify these compounds need to be validated. This report describes a method to quantify anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) from rodent brain tissue. Analytes were extracted using acetonitrile without further sample clean up, resolved on a C18 reverse-phase column using a gradient mobile phase and detected using electrospray ionization in positive selected ion monitoring mode on a single quadrupole mass spectrometer. The method produced high recovery rates for AEA, OEA and PEA, ranging from 98.1% to 106.2%, 98.5% to 102.2% and 85.4% to 89.5%, respectively. The method resulted in adequate sensitivity with a lower limit of quantification for AEA, OEA and PEA of 1.4 ng/mL, 0.6 ng/mL and 0.5 ng/mL, respectively. The method was reproducible as intraday and interday accuracies and precisions were under 15%. This method was suitable for quantifying AEA, OEA and PEA from rat brain following pharmacological inhibition of fatty acid amide hydrolase. PMID- 25506471 TI - The heterodimeric structure of heterogeneous nuclear ribonucleoprotein C1/C2 dictates 1,25-dihydroxyvitamin D-directed transcriptional events in osteoblasts. AB - Heterogeneous nuclear ribonucleoprotein (hnRNP) C plays a key role in RNA processing. More recently hnRNP C has also been shown to function as a DNA binding protein exerting a dominant-negative effect on transcriptional responses to the vitamin D hormone,1,25-dihydroxyvitamin D (1,25(OH)2D), via interaction in cis with vitamin D response elements (VDREs). The physiologically active form of human hnRNPC is a tetramer of hnRNPC1 (huC1) and C2 (huC2) subunits known to be critical for specific RNA binding activity in vivo, yet the requirement for heterodimerization of huC1 and C2 in DNA binding and downstream action is not well understood. While over-expression of either huC1 or huC2 alone in mouse osteoblastic cells did not suppress 1,25(OH)2D-induced transcription, over expression of huC1 and huC2 in combination using a bone-specific polycistronic vector successfully suppressed 1,25(OH)2D-mediated induction of osteoblast target gene expression. Over-expression of either huC1 or huC2 in human osteoblasts was sufficient to confer suppression of 1,25(OH)2D-mediated transcription, indicating the ability of transfected huC1 and huC2 to successfully engage as heterodimerization partners with endogenously expressed huC1 and huC2. The failure of the chimeric combination of mouse and human hnRNPCs to impair 1,25(OH)2D-driven gene expression in mouse cells was structurally predicted, owing to the absence of the last helix in the leucine zipper (LZ) heterodimerization domain of hnRNPC gene product in lower species, including the mouse. These results confirm that species-specific heterodimerization of hnRNPC1 and hnRNPC2 is a necessary prerequisite for DNA binding and down-regulation of 1,25(OH)2D-VDR-VDRE-directed gene transactivation in osteoblasts. PMID- 25506473 TI - Gene susceptibility in Iranian asthmatic patients: a narrative review. AB - As environmental factors are important in the development of asthma, genetic factors could have a critical role in the expression of the disease. Hence, we carried out a systematic review to assess the susceptible genes for asthma in Iranian population. We conducted a literature search by using the electronic database PubMed, Biological Abstracts Web of Science, Current Contents Connect, Cinahl, ScienceDirect, Scopus, IranMedex, and Scientific Information Database to identify articles that evaluated the association between genetic variants and the risk of asthma in Iranian population (until April 30, 2012). The search terms were used include: Asthma and gene in combination with Iran for international database. The following criteria were used for selecting literatures in this review: The study should evaluate the association between gene polymorphism and risk of asthma in Iranian population, and the study should be a case-control design with normal subject as ac control group that published in a journal. Finally, 14 case-control studies were extracted from local and international database. In this study, we reviewed 38 polymorphisms in 19 genes. Polymorphism in interleukin-13 (IL-13), IL-10, IL-1, IL-2, IL-12, E-Selectin, S128R and Exon 9 Vitamin D Receptor were susceptible for asthma and polymorphism in chemokine receptor 5, transforming growth factor-a (TGF-a), Intron 8 of the Vitamin D Receptor, angiotensin-converting enzyme gene, IL-6 and interferon-c were not susceptible for asthma in Iranian population. Polymorphism in IL-4, tumor necrosis factor-alpha and TGF-b had inconsistent findings. This systematic review indicated that three polymorphisms (IL-13, IL-10, and IL-1) are associated with risk of asthma in Iranian population. PMID- 25506472 TI - Hepatitis B vaccination and associated oral manifestations: a non-systematic review of literature and case reports. AB - Hepatitis B vaccine has been administered in children and adults routinely to reduce the incidence of the disease. Even though, hepatitis B vaccine is considered as highly safe, some adverse reactions have been reported. A literature search was carried out in PubMed, accessed via the National Library of Medicine PubMed interface, searching used the following keywords: Hepatitis B vaccine and complications from 1980 to 2014. A total of 1147 articles were obtained out of which articles, which discuss the complications occurring orally or occurring elsewhere in the body, which have the potential to manifest orally after hepatitis B vaccination were selected. A total of 82 articles were identified which included 58 case series or case reports, 15 review articles, 4 cross sectional studies, 3 prospective cohort studies, one retrospective cohort study and a case control study. After reviewing the literature, we observed that complications seen after Hepatitis B vaccination are sudden infant death syndrome, multiple sclerosis, chronic fatigue syndrome, idiopathic thrombocytopenic purpura, vasculititis optic neuritis, anaphylaxis, systemic lupus erytymatosus, lichen planus and neuro-muscular disorder. Of these complications, some are manifested orally or have the potential to manifest orally. Although, most of the complications are self-limiting, some are very serious conditions, which require hospitalization with immediate medical attention. PMID- 25506475 TI - Periodontal Status and Some Variables among Pregnant Women in a Nigeria Tertiary Institution. AB - BACKGROUND: Gingival changes during pregnancy have been well-documented. The prevalence of gingivitis in pregnant women has reportedly ranged from 30% to 100%. Increase in both the rate of estrogen metabolism and synthesis of prostaglandins by the gingiva contributed to the gingival changes observed during pregnancy. In effect increased prevalence of dental caries, gingivitis, periodontitis and tooth mobility may be encountered in pregnancy. AIM: The purpose of the study was to determine the association of some variables and the periodontal status in a sample of pregnant women attending the Ante Natal Clinic (ANC) of Lagos State University Teaching Hospital (LASUTH), Ikeja, Lagos. SUBJECTS AND METHODS: Women at various stages of pregnancy, attending the ANC of LASUTH, constituted the target population. The questionnaire was administered on each patient followed by dental examinations. Periodontal status was assessed using the community periodontal index (CPI) of treatment needs. Oral hygiene status was evaluated according to Green and Vermilion simplified oral hygiene index (OHI-S). RESULTS: The association between the CPI scores; OHI-S scores and variables such as trimester and dental visits were statistically significant. CONCLUSION: This study indicated that the gestational age of pregnancy and dental visits have a definite impact on the periodontal status. Oral health education should be included as an integral part of antenatal care to increase the women awareness. This would improve the mothers' dental care-seeking behavior. PMID- 25506474 TI - Methylenetetrahydrofolate Reductase A1298C Polymorphism and Breast Cancer Risk: A Meta-analysis of 33 Studies. AB - Methylenetetrahydrofolate reductase (MTHFR) enzyme is essential for DNA synthesis and DNA methylation, and its gene polymorphisms have been implicated as risk factors for birth defects, neurological disorders, and different types of cancers. Several studies have investigated the association between the MTHFR A1298C polymorphism and breast cancer (BC) risk, but the results were inconclusive. To assess the risk associated with MTHFR A1298C polymorphism, a comprehensive meta-analysis was performed. PubMed, Google Scholar, Elsevier and Springer Link databases were searched for case-control studies relating the association between MTHFR A1298C polymorphism and BC risk and estimated summary odds ratios (ORs) with confidence intervals (CIs) for assessment. Up to January 2014, 33 case-control studies involving 15,919 BC patients and 19,700 controls were included in the present meta-analysis. The results showed that the A1298C polymorphism was not associated with BC risk in all the five genetic models (C vs. A allele (allele contrast): OR = 0.99, 95% confidence interval (CI): 0.93 1.05; AC versus AA (heterozygote/codominant): OR = 0.97, 95% CI: 0.89-1.04; CC versus AA (homozygote): OR = 0.99, 95% CI: 0.91-1.06; CC + AC versus AA (dominant model): OR = 0.97, 95% CI: 0.90-1.05; and CC versus AC + AA (recessive model): OR = 0.99, 95% CI: 0.91-1.07). The present meta-analysis did not support any association between the MTHFR A1298C polymorphism and BC risk. PMID- 25506476 TI - Re-evaluation of the first phenytoin paste healing effects on oral biopsy ulcers. AB - BACKGROUND: Until now, several formulations of topical phenytoin have been used to promote wound healing. AIM: This study was aimed at re-evaluating the effects of a newly formulated phenytoin mucoadhesive paste on wound healing after oral biopsy. SUBJECTS AND METHODS: In a double-blind clinical trial, 35 consecutive patients with oral lichenoid or lichen planus lesions were randomized into two groups. After incisional biopsy, patients applied simple, or 1% phenytoin paste at least three times a day (after each meal), for 4 days. They were evaluated every other day for size of wound closure, severity of pain, and diameter of the inflammatory halo. This study was approved by Medical Ethics committee of Shahid Beheshti University of Medical Sciences, Tehran, Iran. Statistical analysis was performed using Mann-Whitney U test and Ordinal Logistic Regression. RESULTS: Of 35 patients, 17 (10 [10/17, 59%]) men, 7 (7/17, 41%) women, mean age: 40 (4.11) were in phenytoin group, and 18 (9 [9/9, 50%]) men, 9 (9/9, 50%) women, mean age: 43.1 (5.15) were in placebo group. There were no significant differences between both study groups in terms of age and sex (male/female ratio) (P = 0.76, P = 0.88). As all biopsies were done by means of punch number 8, the incisions were of 10 mm length. After second and third appointments, it was observed that patients in the treatment group showed quicker wound closure and less pain compared to control group significantly (P < 0.05). Although not significant, patients treated with phenytoin paste had smaller inflammatory halo than controls. CONCLUSION: Applying 1% phenytoin mucoadhesive paste on oral biopsy incisions resulted in accelerated wound healing and decrease in pain. PMID- 25506477 TI - Antimicrobial Synergic Effect of Allicin and Silver Nanoparticles on Skin Infection Caused by Methicillin-Resistant Staphylococcus aureus spp. AB - BACKGROUND: Today, the commonly used antibiotics may more and more frequently be ineffective against multiple pathogens, due to the selection of resistant microbial strains. As a result, an effort to find a new approach for solving this issue has been considered. AIM: The aim of this study is to investigate antimicrobial properties of allicin, silver nanoparticles (Ag NPs) and their combination again skin infection caused by methicillin-resistant Staphylococcus aureus (MRSA) strains in an animal model. MATERIALS AND METHODS: In vivo, the effects of allicin, Ag NPs and their combination were investigated on mice in which the skin infection was caused by MRSA strains. In animals, S. aureus colony forming units (CFU)/mL were counted the 4(th) day after treatment. In vitro, minimum inhibitory concentration (MIC) of bacterial growth and minimum bactericidal concentration (MBC) of allicin, Ag NPs and their combination were determined by microdilution technique. RESULTS: The results of in vitro assays showed that MIC of allicin and Ag NPs were 2.2 mg/mL and 5.6 mg/mL, respectively, and MBC of allicin and Ag NPs were 3.1 ppm and 7.5 ppm, respectively. However, MIC and MBC of allicin and Ag NPs together on MRSA strains were 0.4 mg/mL and 1.1 ppm, respectively. The results of in vivo tests on skin infection showed that bacteria counted for control, Ag NPs, allicin and their combination were 377 * 108, 80 * 106, 43 * 105, and 0 CFU/mL, respectively. CONCLUSION: The obtained results clearly indicated (for the first time, to the best of our knowledge) that allicin and Ag NPs, when used in combination, exhibited a synergistic activity. Therefore, the present results can be of interest in the future to improve the treatment of skin infections caused by MRSA strains. PMID- 25506478 TI - Do stages of dentistry training affect anxiety provoking situations? AB - BACKGROUND: Undetected and unaddressed anxiety negatively affects performance in clinical learning environments. AIM: The aim was to investigate the anxiety provoking situations in clinical dental care delivery among students of preclinical and clinical years and house officers. SUBJECTS AND METHODS: A 38 item modified Moss and McManus clinical anxiety questionnaire, general health questionnaire-12 (GHQ-12) and the Zung self-rating anxiety scale were the data collection tools. RESULTS: Of the 84 recruited, 79 completed the study giving 94.0% (79/84) response rate. The median age of the participants was 25 years with 50.6% (40/79) being 20-25 years. Gender distribution revealed that males constituted 60.8% (48/79) of the participants. House officers constituted 29.1% (23/79), clinical students 36.7% (29/79), and preclinical students 34.2 (27/79) of the participants. The top anxiety provoking situations using the modified Moss and McManus clinical anxiety questionnaire were extracting wrong tooth 3.24 (1.06), inability to pass examination 3.32 (1.01), achieving examination requirement 3.19 (1.01), fracturing a tooth 3.08 (0.98) and accidental pulp exposure 2.96 (1.04). Getting diagnosis wrong, help in faint episode, not developing radiograph properly and coping with children were the anxiety provoking situations that showed statistically significant difference in the 3 studied training stages of dentistry. Bonferroni post-hoc analysis significant difference was in the preclinical and clinical students' pair for getting diagnosis wrong, not developing radiograph properly and coping with children while house officers/clinical students and house officers/preclinical students' pairs were for help in faint episode. Overall, 2.5% (2/79) had severe, 69.6% (55/79) moderate, 26.6% (21/79) mild clinical anxiety while 1 (1.3%) of the participants expressed no clinical anxiety. CONCLUSION: Data from this study revealed that the clinical anxiety of moderate severity was prevalent among the studied dental healthcare students. The anxiety-provoking situations were also found to be majorly similar in preclinical, clinical and post-graduation clinical stages of dental training stages in Nigeria. PMID- 25506479 TI - Cross-sectional studies published in Indian journal of community medicine: evaluation of adherence to strengthening the reporting of observational studies in epidemiology statement. AB - BACKGROUND: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement is a set of recommendations about what should be included in a more accurate and complete description of observational studies. AIM: The aim was to assess the quality of reporting of cross-sectional studies by evaluating the extent to which they adhere to the STROBE statement. MATERIALS AND METHODS: This study has a cross-sectional design. All the articles published as original articles in Indian Journal of Community Medicine from January 2010 to September 2011 were downloaded from the journal website. A total of 96 articles were downloaded out of which 80 were found to have a cross-sectional design. Variables were: (1) Percentage of STROBE items included in a report and (2) percentage of articles reporting each item in the STROBE checklist. Data analysis was done by descriptive statistics using frequencies and percentages. RESULTS: A total of 80 articles were evaluated. About 46% (37/80) articles reported 12-15 items of the STROBE checklist. Bias, nonparticipants and reasons for nonparticipation, other analyses done, generalizability, and source of funding were reported by < 25% of studies. The most frequently reported items of the checklist were summary of what was done and what was found in the abstract, background/rationale, objectives, setting, outcome data, key results in discussion, interpretation of results. None of the articles reported all items of the STROBE checklist. CONCLUSION: This study reveals that the quality of reporting cross-sectional studies in Indian Journal of Community Medicine is not satisfactory and there is room for improvement. PMID- 25506480 TI - Estimated probability of stroke among medical outpatients in enugu South East Nigeria. AB - BACKGROUND: Stroke is a growing noncommunicable disease in Africa and accounts for a substantial number of medical and neurological admissions in Nigerian hospitals. The prevalence of some risk factors for stroke such as hypertension and diabetes are high and growing among Africans. AIM: The aim was to investigate the distribution of stroke risk factors and estimate the 10-year probability of stroke among patients attending the out-patient clinics in the two biggest hospitals in Enugu South East Nigeria. SUBJECTS AND METHODS: Consecutive consenting patients attending out-patient clinics at University of Nigeria Teaching Hospital and Enugu state University of Science and Technology Teaching Hospital all in Enugu were enrolled. Risk factors for stroke were evaluated using a series of laboratory tests, medical history and physical examinations. The 10 year probability of stroke was determined by applying the Framingham stroke risk equation. Statistical analysis was performed with the use of the SPSS 17.0 software package (SPSS Inc., Chicago, IL, USA). RESULTS: A total of 165 patients were evaluated. Of these 94 were male and 71 were female. The most common risk factors were left ventricular hypertrophy 70.3% (116/165) and raised systolic blood pressure 52.7% (87/165). The mean age of patients was 66.1 (8.1) years. The mean 10-year probability of stroke was 18.1 (14.6) (19.7 [14.9] in men and 14.5 [14.6] women) and was higher in older age groups. CONCLUSION: The 10-year probability of stroke in Nigerians attending medical outpatient Clinic in SE Nigeria may be high. Aggressive interventions are needed to reduce risk factors and the probability of stroke risks especially in men in SE Nigeria. PMID- 25506481 TI - Toothache and self-medication practices: a study of patients attending a niger delta tertiary hospital in Nigeria. AB - BACKGROUND: There is evidence that self-medication practices among dental patients with toothache are common, and despite the adverse clinical consequences, there is a paucity of literature on it, and only few programs are available for its control. AIM: The aim was to assess the self-medication practices among adult dental patients suffering from toothache. SUBJECTS AND METHODS: An instrument adapted from modified form of 117-item self-report questionnaire based on world Health Organization guidelines for students' substance use survey and open-ended questionnaire was administered to adult patients attending the Dental and Maxillofacial Surgery Clinic of this Health Institution for a period of 6 months. RESULTS: The results show that 80.6% (287/356) subjects indulged in self-medication practices. Majority of the patients 42.9% (123/287) were in the 2-4(th) decades of life, whereas the male: female ratio was 1.3:1. The most commonly abused medications/substance was analgesics/non-steroidal anti-inflammatory drug (243/287; 24.5%), antibiotics (233/287; 23.5%), "touch and go" (187/287; 18.8%). The practice of self medication cut across all social strata, P < 0.01 (significant) and only 3.8% (11/287) subjects admitted knowledge of the dosage and side-effects of the used medications/substances. The toothache not being serious initially (112/287; 22.5%) and time constraints to attend dental clinic (93/287; 18.7%) were the major reasons for self-medication. CONCLUSION: This study suggests that the practice of self-medication is common among adult dental patients with toothache in Nigeria. This should be reduced to the barest minimum by dental health education, upgrading of dental health facilities, and enforcement of drug control mechanisms. PMID- 25506482 TI - Evaluation of five formulae for estimating body surface area of nigerian children. AB - BACKGROUND: Physiological functions are often assessed by standardizing for body surface area (BSA) to avoid excessive variation in calculations in pediatric practice. AIM: To explore the suitability of existing formulae for estimating the BSA of Nigerian children. SUBJECTS AND METHODS: This cross-sectional study involved healthy children in a Local Government Area, Oyo State, Nigeria. The BSAs of 2745 children were calculated using the formulae by Boyd, Mosteller, Gehan and George, Haycock, and Dubois-DuBois, and the sixth arithmetic mean of these five formulae (mean-BSA) was performed. The outcome of interest was agreement between estimated BSA and mean-BSA for each method. The performance of each BSA estimation method was compared using bias, root mean square error and Bland-Altman plots of agreement. RESULTS: The study participants comprised of 1229 males and 1246 females with mean (standard deviation) ages of 6.3 (3.0) years and 6.6 (3.1) years respectively (P = 0.01). Reference values for BSA estimates by gender were proposed each age group. Furthermore, BSA estimates from Boyd's and Mosteller's formulae were most similar to the mean-BSA with mathematically perfect correlations. The degree of deviation of BSA estimates from DuBois was largest with a remarkable increase at ages <6 years. CONCLUSION: Formulae by Boyd and Mosteller are the best BSA estimate for Nigerian children among the existing formulae. PMID- 25506483 TI - The comparison of parents' educational level on the breastfeeding status between turkman and non-turkman ethnic groups in the north of iran. AB - BACKGROUND: Mother's milk plays an important role in infant's health, and World Health Organization (WHO) recommends infants should be breastfed for 2 years or up. AIM: The main objective of this study was to evaluate the breastfeeding status based on parents' educational level with comparison between Turkman and non-Turkman ethnic groups in the North of Iran in 2010. SUBJECTS AND METHODS: This is a descriptive, cross-sectional study, which was carried out on 6519 subjects (3897 = non-Turkman and 2622 = Turkman) in urban and rural areas. Data have been collected through interviewing with primary school children's mothers. The schools and students were selected using multi-cluster random sampling methods. Breastfeeding was defined based on WHO predominant definition. RESULTS: Of all mothers, 5.8% (377/6519) breastfed for 6 months, 34.8% (2265/6519) for 7 18 months, 57.4% (3745/6519) for 18-24 months and 2% (132/6519) didn't breastfeed their infants. Breastfeeding prevalence at 19-24 months in Turkman ethnic group (64.7%; 1696/2622) was significantly more than in non-Turkman ethnic group (52.6%; 2049/3897) (P < 0.01) besides early weaning prevalence (at 6 months) in Turkman group was significantly less than in non-Turkman group (4.7%; 123/2622 vs. 6.5%; 254/3897) (P < 0.01). Odds ratio for weaning before 6 months in non Turkman mothers were 0.563 (0.365-0.786, confidence interval [CI] 95%) in 1-12 years schooling and 0.665 (0.486-0.910, CI: 95%) in uneducated groups compared to college educated. This ratio in Turkman fathers was 3.413 (1.726-6.746, CI: 95%) in 1-12 years schooling compared with college educated. CONCLUSION: The duration of breastfeeding was longer among Turkman compared with non-Turkman mothers, and longer duration of breastfeeding was associated with higher educational level in the Turkman but not in the non-Turkman mothers. PMID- 25506484 TI - Emergency Contraception: Awareness, Perception and Practice among Female Undergraduates in Imo State University, Southeastern Nigeria. AB - BACKGROUND: Limited knowledge and practice of contraception is a global public health problem. Unintended pregnancies are the primary cause of induced abortion. When safe abortions are not available, as in Nigeria with restricted abortion laws, abortion can contribute significantly to maternal mortality and morbidity. Adequate information on the awareness and the use of emergency contraception is necessary for planning interventions in groups vulnerable to unwanted pregnancy. AIM: The aim of the following study is to access the awareness, perception and practice of emergency contraception among female undergraduates in Imo State University, South Eastern Nigeria. SUBJECTS AND METHODS: A questionnaire based cross-sectional survey using female undergraduates selected randomly from Imo State University, Owerri. RESULTS: A total of 700 students participated in the study. Awareness of emergency contraception was very high (85.1%) (596/700). The awareness was significantly higher amongst students in health related faculties than in the non-health related faculties (P = 0.01). The main sources of information were through friends (43.1%) (317/700) and lectures (22.1%) (192/700). High dose progestogen (postinor-2) was the most commonly known type of emergency contraception (70.8%) (422/596). Only 58.1% (346/596) of those who were aware of emergency contraception approved of their use. The major reasons given by the 41.9% (250/596) who disapproved of their use were religious reasons (50.4%) (126/250) and that they were harmful to health (49.2%) (123/250). Two third (67%) (46 9/700) of the students were sexually active and only 39.9% (187/469) of them used emergency contraception. High dose progestogen (postinor 2) was again the most commonly used method (70.8%) (422/596). The most common situation in which emergency contraception was used was following unprotected sexual intercourse (45.5%) (85/144). Only 34.6% (206/596) of those who were aware of emergency contraception identified correctly the appropriate time interval for its effectiveness. CONCLUSION: Although the awareness of emergency contraception was high amongst female undergraduates, the attitude and practice are still poor. The inclusion of reproductive health education as part of the undergraduate school curriculum might help to change students' attitude toward emergency contraceptives. PMID- 25506485 TI - Clinical and laboratory features of pertussis in hospitalized infants with confirmed versus probable pertussis cases. AB - BACKGROUND: The clinical presentations of pertussis infection have considerable variation. Many infections and illnesses can cause prolonged repetitive paroxysmal cough that could be confused with Bordetella pertussis infection. AIM: This retrospective study was designed to compare the clinico-laboratory findings between two groups of hospitalized infants with confirmed, and those who have clinical pertussis disease; to identify the possible additional diagnostic clues "for the diagnosis of confirmed pertussis disease". SUBJECTS AND METHODS: The study population consisted of infants <=12 months of age with clinical diagnosis of pertussis that fulfilled the World Health Organization definition for pertussis or those diagnosed by physicians. Clinico-laboratory findings were compared between two groups of patients (confirmed vs. clinical cases). RESULTS: From a total of 118 infants admitted with a clinical diagnosis of pertussis, 16% (19/118) were confirmed by laboratory to have confirmed pertussis. Twelve of 19 (63%) and 71.99% of confirmed and clinical cases were younger than 6 months of age, respectively. For most patients, the duration of symptoms before hospitalization was <14 days. There were no significant differences between two groups of patients for paroxysmal cough and facial discoloration. However, whoop and apnea were more common among confirmed pertussis cases: P = 0.01, and P = 0.02, respectively. Leukocytosis (>=16,000/ml) (P = 0.01) and lymphocytosis (>=11,000) (P = 0.02) were reported significantly more frequently in confirmed pertussis cases. CONCLUSION: Given the unavailability of a highly sensitive diagnostic test, in every afebrile patient with paroxysmal cough lasting for >=7 days associated with whoop and/or apnea, particularly if accompanied by leukocytosis/lymphocytosis, pertussis disease should be considered. In this situation, prompt administration of empiric treatment for cases, and providing control measures to prevent infection transmission to contacts are recommended. PMID- 25506486 TI - Comparison of some risk factors for diabetes across different social groups: a cross-sectional study. AB - BACKGROUND: In fast, developing economies such as India, the population is undergoing rapid social transition, which can increase the risk profile for diabetes. Market forces promoting lifestyles such as sedentary habits, alcohol and tobacco use, which earlier were more prevalent among affluent urban populations are now trickling into the urban poor and rural populations. AIM: The aim of the present research was to compare the prevalence of risk factors for diabetes among three distinct social groups-the urban affluent, the urban poor and the rural poor. SUBJECTS AND METHODS: A total of 775 adult population over 18 years and belonging to both genders were surveyed for prevalence of some of the risk factors for diabetes such as physical inactivity, obesity, alcohol, and tobacco use. The sample comprised of three distinct social groups as follows; 125 medical students representing the affluent, 400 subjects from urban slums, and 250 subjects from rural areas. Obesity was measured by body mass index (BMI) while central obesity was ascertained by waist hip ratio (WHR). Alcohol and tobacco use were elicited by interview. RESULTS: The overall response rate was 88.52% (686/775). Medical students were more sedentary with mean hours spent each day sitting or reclining at 10.47 (3.25) h, compared to corresponding figures of 6.34 (3.1) h and 7.49 (3.74) h for the rural and urban slum residents respectively (P < 0.001). However, all types of leisure time physical activities were significantly more among the medical students compared to the other groups (P < 0.001). BMI was significantly highest among the rural population with mean of 24.22 (4.17) kg/m(2) when compared to the other groups, (P < 0.001). Villagers also had higher WHR and had a higher proportion of persons above the WHR cut-off for gender (P < 0.001). Experimentation with alcohol was more prevalent among the medical students while the urban slum residents were more frequent and heavy drinkers. Smoking was most prevalent among the medical students, while smokeless tobacco use was more among the other groups. CONCLUSIONS: Physical inactivity, obesity, including central obesity, alcohol and tobacco use were found in various degrees in the study samples. An important finding was that both obesity and central obesity ascertained by BMI and WHR respectively were highest among the rural population implying the impact of social change on diabetic risk factors. PMID- 25506488 TI - Prevalence and predictors of episiotomy among women at first birth in enugu, South-East Nigeria. AB - BACKGROUND: Women having their first birth have a higher risk of episiotomies. Therefore, the study of the procedure in this group of at risk women will assist in solving some of its associated controversies. AIM: The aim was to determine the prevalence, predictors, and outcomes of episiotomy among primigravid women in Enugu, Nigeria. MATERIALS AND METHODS: The study was a retrospective cross sectional review of labor ward records of women that had their first delivery at the University of Nigeria Teaching Hospital (UNTH) Enugu, over a 5-year of April 204 to March 2009. Only women that had a vaginal delivery were included in the study. Mann-Whitney U-test (continuous data) and Chi-square test (categorical data) were used for data analysis. RESULTS: Prevalence of episiotomy in the study was 62.1% (411/662). The episiotomy rate for booked women (65.6%, 376/573) was significantly higher than that of unbooked women (39.3%, 35/89), (prevalence ratio = 1.67 [95% confidence interval: 1.28, 2.17]). The birth weights of babies delivered in the episiotomy group (median = 3.2 kg [interquartile range (IQR): 2.9-3.5]) was statistically higher than those of women who did not receive episiotomy (median, 3.1 kg [IQR: 2.7-3.4]), (Z = -3.415, P = 0.001). Proportion of newborns with low 1(st) min Apgar scores in the episiotomy group (21.7%, 89/411) was significantly lower than the no episiotomy group (15.1%, 38/251) (P = 0.04). CONCLUSION: Prevalence of episiotomy among women that had their first births in the UNTH, Enugu was high, and the predictors included booked status of women, higher gestational age at delivery, and larger neonatal birth weight. More efforts should be made to reduce episiotomy rate in the hospital. PMID- 25506487 TI - Determinants of Patient's Adherence to Hypertension Medications: Application of Health Belief Model Among Rural Patients. AB - BACKGROUND: Hypertension is a major health problem in developing and developed countries, and its increasing epidemy is a serious warning to take more attention to this silent disease. AIM: This study was aimed to determine the factors of adherence to hypertension medication based on health belief model (HBM). SUBJECTS AND METHODS: A cross-sectional study was conducted in a rural area of the Ardabil city in 2013. This study was carried out using a pre-structured and validated questionnaire. The questionnaire included information on demographic characteristics, lifestyle habits, HBM constructs and adherence to hypertension medication (Morisky 4-Item Self-Report Measure of Medication-taking Behavior [Morisky Medication Adherence Scale]). Data were analyzed with the use of SPSS version 18. P < 0.05 was considered as statistically significant. RESULTS: A total of 671 hypertensive patients participated in the study (169 were males and 502 were females). The prevalence of adherence was 24% (161/671)% in the study population. Respondents with regular physical activity and nonsmokers were more adherent to hypertension medication when compared to respondents with sedentary lifestyle and smoking (P < 0.01). Based on HBM constructs, the respondents who perceived high susceptibility, severity, benefit had better adherence compared to moderate and low susceptibility, severity, and benefit. CONCLUSION: The prevalence of adherence to hypertension management was low in study population, this due to inadequate perceived susceptibility, perceived, severity, perceived benefit and poor lifestyle factors. Improving adherence in hypertension patients need to recognize the value and importance of patient perceptions medications. PMID- 25506489 TI - A study of triple negative breast cancer at a tertiary cancer care center in southern India. AB - BACKGROUND: Triple negative breast cancers (TNBCs) are a diverse and heterogeneous group of tumors that by definition lack estrogen and progesterone receptors and amplification of the HER-2 gene. The majority of the tumors classified as TNBCs are highly malignant, patients are usually young and only a subgroup of patients responds to conventional chemotherapy with a favorable prognosis. Various studies have been reported in western literature on TNBCs, all highlighting the poor prognosis of this subtype. However, extensive data from India is lacking. AIM: The aim of this study was to analyze the epidemiological and clinical profile of TNBCs at our institute. MATERIALS AND METHODS: This was the retrospective study carried out in Tertiary Cancer Care Center in South India. Case files of all breast cancer patients were reviewed from the hospital database registered in 1 year and TNBC patients were selected for the study. Patient's characteristic, treatment, and histological features were analyzed. RESULTS: A total of 322 patients were registered during the period of 1 year and 26% (84/322) of total patients were TNBC. Median age of presentation was 44.5 years. About 94% (79/84) of patients had first full-term delivery before the age of 30 years. The most common presenting symptom was left sided breast lump. Locally advanced and early breast cancer (EBC) was 51% (43/84) and 42% (36/84), respectively. Metastatic breast cancer was seen in five patients. The highest numbers of patients were node negative disease (36.9%) [31/84], followed by N1 30.95% (26/84). Most of the patients had high-grade tumor. 94% (34/36) of cases of EBC had undergone upfront modified radical mastectomy. Invasive ductal carcinoma was the predominant histology except one who had medullary carcinoma. Twenty-four patients received neoadjuvant chemotherapy (NACT). There was no pathological complete remission, but all patients responded to NACT. Metastatic disease was seen in five patients. All patients had bone metastasis. CONCLUSIONS: TNBCs are highly aggressive subtype, with high grade with limited treatment options and very poor prognosis. Incidence is more in our country than the western literature. Even in our country also the incidence is varies in different region. TNBCs are significantly associated with young aged patients. There was a lack of association between tumor size and lymph node positivity. PMID- 25506490 TI - Indications and risk factors for complications of lower third molar surgery in a nigerian teaching hospital. AB - BACKGROUND: The surgical extraction of impacted third molars is a common oral surgical procedure, and it is often associated with complications such as sensory nerve damage, dry socket, pain, swelling, trismus, infection and hemorrhage. AIM: The aim of this study was to determine the surgical indications and risk factors for complications of third molar surgery at a Nigerian teaching hospital. MATERIALS AND METHODS: Medical records of patients referred to the Oral Surgery Clinic of our institution for surgical extraction of their impacted mandibular third molars from January 2008 to December 2010 were retrospectively examined. Information on patients' demography, types of impaction, operative parameters and complications were obtained and analyzed using Statistical Package for Social Sciences (SPSS Version 13), Chicago, IL, USA. A P < 0.0.5 was considered significant. RESULTS: A total of 330 impacted teeth were extracted from 250 patients. Male comprises (104/250 [41.6%]) and female (146/250 [58.4%]). The mesioangular (176/330 [53.4%]) and distoangular (73/330 [22.1%]) impactions were the commonest types. Recurrent pericoronitis (154/330 [46.7%]) was the most common indication for extraction. The complications were delayed healing (19/330 [5.8%]), alveolar, osteitis (9/330 [2.7%]) and injury to alveolar nerve (2/330 [0.6%]). Cigarette smoking (P < 0.001), Oral contraceptives use (P = 0.01), age of the patient (P = 0.03) and the surgeon's experience (P = 0.04) were found to be significantly associated with the development of alveolar osteitis; nerves injuries were significantly associated with the raising of a lingual flap (P < 0.001) and the technique of surgery (P <= 0.001). CONCLUSION: The age of the patient, cigarette smoking and oral contraceptive use at the time of surgery are some of the factors affecting outcome in third molar surgery. PMID- 25506491 TI - An evaluation of dental prosthetic status and prosthetic needs among eunuchs (trans genders) residing in bhopal city, madhya pradesh, India: a cross-sectional study. AB - BACKGROUND: Eunuchs are considered as the most vulnerable, frustrated, and insecure community. The accessibility to medical and dental facilities for the eunuchs is nearly nonexistent. Due to these reasons, they might be at a high risk of developing severe dental problems like tooth loss. AIM: The present cross sectional study aimed to evaluate the dental prosthetic status and prosthetic needs among eunuchs residing in Bhopal city, Madhya Pradesh, India. SUBJECTS AND METHODS: On the basis of convenient nonprobability snowball sampling technique, all the self-identified eunuchs residing in the city of Bhopal along with a matched control consisting of cross section of the general population residing in the same locality was examined to evaluate the prosthetic status and prosthetic needs of the population. All the obtained data were entered into a personal computer on Microsoft excel sheet and analyzed using the software; Statistical Package for Social Science version 20. Data comparison was done by applying Chi square test. RESULTS: A total of 639 subjects comprised of 207 eunuchs, 218 males and 214 females. Among all participants, 2.8% (18/639) were having prosthesis. The overall prosthetic status among males was 3.2% (7/218) followed by 2.9% (6/207) eunuchs and 2.3% (5/214) females. However, need for multi-unit and combination of one and more unit prosthesis for upper and lower jaws was higher in males compared to females and eunuchs, but the difference was not statistically significant. CONCLUSION: The findings of this study clearly demonstrate a high unmet need for prosthetic care among the population surveyed. PMID- 25506492 TI - Attitude of expectant mothers on the use of ultrasound in pregnancy in a tertiary institution in South East of Nigeria. AB - BACKGROUND: With the world-wide availability of ultrasound services even in the developing countries, routine ultrasonography in pregnancy remains a controversial issue. However, in this era of reproductive health right and evidence-based medicine, the views of women need to be ascertained. AIMS: The aim is to assess the attitude of antenatal women toward sonography in pregnancy. SUBJECTS AND METHODS: A descriptive self-administered questionnaire-based cross sectional study using 208 women that booked for antenatal care from January 1, 2009 to June 30, 2009 at the University of Nigeria Teaching Hospital, Enugu. RESULTS: The number of respondents who had ultrasonography in their previous pregnancies was 58.7% (122/208). Although many reasons were given for personal ultrasound requests, 19.7% (24/122) of the women who had obstetric scan in their previous pregnancies thought it was a normal booking test done for every pregnant woman. When compared with other booking investigations, 60.1% (125/208), mainly civil servants .expressed the views that ultrasound in pregnancy is costly, while 24.4% (59/208) felt it is cheap, 9.1% (19/208) said it is very costly, while the remaining 2.4% (5/208) thought it is not affordable. Apart from visualizing the images of their babies, 17.8% (37/208) of the cases wanted to know the sexes of their babies while 15.4% (32/208) was for determination of fetal position. Out of 110, 52.9% (110/208) were of the opinion that women can decide when to request for sonography. CONCLUSION: The attitude of Nigerian women to sonography is good. Majority of them request ultrasound for fetal observation and gender determination. PMID- 25506493 TI - Seroprevalence of Human Immunodeficiency Virus, Hepatitis B, Hepatitis C, Syphilis, and Co-infections among Antenatal Women in a Tertiary Institution in South East, Nigeria. AB - BACKGROUND: Sexually transmitted infections and human immunodeficiency virus (HIV)/AIDS are a major public health concern owing to both their prevalence and propensity to affect offspring through vertical transmission. AIM: The aim was to determine the seroprevalence of HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis, and co-infections among antenatal women in Enugu, South-East Nigeria. MATERIALS AND METHODS: A retrospective study of antenatal women at the University of Nigeria Teaching Hospital, Enugu, South-East Nigeria from 1(st) May 2006 to 30(th) April 2008. A pretested data extraction form was used to obtain data on sociodemographic variables and screening test results from the antenatal records. The analysis was done with SPSS version 17 (Chicago, IL, USA). RESULTS: A total of 1239 antenatal records was used for the study. The seroprevalence of HIV, HBV, HCV, and syphilis among the antenatal women were 12.4% (154/1239), 3.4% (42/1239) 2.6 (32/1239) 0.08% (1/1239), respectively. The HIV/HBV and HIV/HCV co infection prevalence rates were 0.24% (3/1239), 0.16% (2/1239), respectively. There was no HBC and HCV co-infection among both HIV positive and negative antenatal women. There was no statistically significant difference in HBV and HCV infection between the HIV positive and negative antenatal women. The only woman that was seropositive for syphilis was also positive to HIV. CONCLUSION: The seroprevalence of HIV, HBV, HCV, and syphilis is still a challenge in Enugu. Community health education is necessary to reduce the prevalence of this infection among the most productive and economically viable age bracket. PMID- 25506495 TI - Chronic cutaneous draining sinus of dental origin. AB - Extra oral sinus of odontogenic origin occurs when the purulent by-products of dental pulp necrosis spread along the path of least resistance from the root apex to the skin on the face. Patients presenting with cutaneous sinus usually visit a general physician or dermatologist first, as the lesion can mimic various dermatologic pathologies, ranging from an infected sebaceous cysts to a basal cell carcinoma. Despite systemic antibiotics, symptoms often persist causing further confusion, and at times leading to unnecessary surgical interventions. The location of this sinus in the head and neck region should lead the physician to seek a dental opinion in order to avoid misdiagnosis. PMID- 25506494 TI - Occupational cow horn eye injuries in ibadan, Nigeria. AB - This case series aims to describe the clinical features, management, and outcome of occupational eye injuries caused by cow horns and to recommend possible preventive measures. A review of patients with cow horn inflicted eye injuries seen at the University College Hospital, Ibadan between January 2006, and December 2011 was conducted. Three patients were identified, and their charts were reviewed for demographic information, mechanism of injury, initial and final visual acuity, surgeries performed, as well as anatomic and visual outcome. The three patients were males and were aged 45, 22, and 49 years, respectively. They were all involved in cattle-related jobs, and they all had unilateral open-globe injuries with corneoscleral lacerations. Presenting visual acuity was nil light perception in the injured eyes. The contralateral eyes were all normal. Two of the patients required evisceration of the eye, while the third patient underwent repair of lacerations. Visual improvement was not achieved in any of the patients. Cow horn eye injuries may be quite severe and could result in loss of the eye with monocular blindness. Careful attention must be paid to prevent such injuries. Cattle rearers and dealers should wear safety goggles, and proper restraint of the animals is advocated. PMID- 25506496 TI - Primary tubercular chorioretinitis. AB - The aim of this report is to emphasize that corticosteroids should not be prescribed when the etiological factors remain unidentified. A 34-year-old male visited our ophthalmology clinic suffering from blurred vision. Behcet's disease had been diagnosed 5 years prior, and the patient was taking an oral immunosuppressant and a systemic corticosteroid. Vitreous cell count and foci of chorioretinitis (apparently confined to the ocular fundus) were evident. A vitreous sample was subjected to polymerase chain reaction, which resulted in the identification of and Mycobacterium tuberculosis. Treatment with a combination of four anti-tuberculosis drugs was commenced. During the follow-up, the vitritis disappeared, and the foci of active chorioretinitis improved. Systemic and Sub Tenon corticosteroid treatment should not be prescribed until vitreous and anterior chamber fluid samples have been evaluated in patients with uveitis. Some microbes are not detected on routine examination. PMID- 25506497 TI - Acute osteomyelitis as cause of late sepsis in a nigerian neonate. AB - Neonatal osteomyelitis (NO) is said to be rare and uncommonly reported in the sub region. Although this may be true, either because the cases are under-diagnosed, unreported or under-reported. The diagnosis is clinical and supported with blood culture or the aspiration of pus with radiological findings. We report a case of a neonate with acute osteomyelitis of the right femur, diagnosed at 10(th) day of life, which was confirmed with blood culture and radiogram findings of the right upper thigh of the baby. To the best of our knowledge, this is the first documented reported case of NO from the south-eastern Nigeria. It is imperative to recognize the clinical presentation necessary to raise the suspicion of NO and other focal infection in the newborn. With thorough examination and selected investigation the focus of infection in the neonate can be detected. PMID- 25506498 TI - Unusual complications of incisional hernia. AB - Incisional hernia represents a breakdown or loss of continuity of a fascial closure. These hernias are of particular concern not only for the high recurrence rates among them but also for the challenges that follow their repair. It is known to occur in 11-23% of laparotomies. This paper presents two unusual complications of incisional hernia managed by the authors. One ruptured incisional hernia with evisceration of gut and a case of incarcerated gravid uterus in a woman in labour. The case records of the two patients with unusual complications of incisional hernia were pooled and presented to highlight the clinical presentation and management options of this condition. The patient with ruptured hernia and eviscerated gut presented immediately and was resuscitated and the hernia repaired with polypropylene mesh. The patient with incarcerated uterus had caesarean section and mesh repair of the hernia. Incisional hernia can present with unusual complications. The management is very challenging. Good knowledge and skills are required to deal with this condition. PMID- 25506500 TI - Clinical genetics and pathobiology of ciliary chondrodysplasias. AB - Ciliary chondrodysplasias represent a heterogenous group of rare, nearly exclusively autosomal recessively inherited developmental conditions. While the skeletal phenotype, mainly affecting limbs, ribs and sometimes the craniofacial skeleton, is predominant, extraskeletal disease affecting the kidneys, liver, heart, eyes and other organs and tissues is observed inconsistently. Significant lethality, resulting from cardiorespiratory failure due to thoracic constriction as well as from renal and hepatic insufficiency or primary cardiac failure due to congenital heart disease, is observed with these conditions. The underlying genetic defects as well as developmental biology and cell biology work undertaken using animal model systems, suggest that these rare conditions result from ciliary malfunction. The skeletal phenotype is believed to result from imbalances in the hedgehog signaling pathway that normally occurs in functional cilia in chondrocytes. Although phenotypes have been historically distinguished based on clinical features into short-rib polydactyly syndrome, Jeune asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, Sensenbrenner syndrome (cranioectodermal dysplasia), oral-facial-digital syndrome and Ellis-van Creveld syndrome, recent research suggests that there is significant genetic as well as phenotypic overlap between the conditions. This review discusses ciliary chondrodysplasias from phenotypic hallmarks to clinical management and summarizes progress in identification of the underlying molecular mechanisms as well as potential future therapeutic perspectives. PMID- 25506499 TI - Any defining role of mast cell or mast cell density in oral squamous cell carcinoma? PMID- 25506501 TI - An Automatic Approach for Satisfying Dose-Volume Constraints in Linear Fluence Map Optimization for IMPT. AB - Prescriptions for radiation therapy are given in terms of dose-volume constraints (DVCs). Solving the fluence map optimization (FMO) problem while satisfying DVCs often requires a tedious trial-and-error for selecting appropriate dose control parameters on various organs. In this paper, we propose an iterative approach to satisfy DVCs using a multi-objective linear programming (LP) model for solving beamlet intensities. This algorithm, starting from arbitrary initial parameter values, gradually updates the values through an iterative solution process toward optimal solution. This method finds appropriate parameter values through the trade-off between OAR sparing and target coverage to improve the solution. We compared the plan quality and the satisfaction of the DVCs by the proposed algorithm with two nonlinear approaches: a nonlinear FMO model solved by using the L-BFGS algorithm and another approach solved by a commercial treatment planning system (Eclipse 8.9). We retrospectively selected from our institutional database five patients with lung cancer and one patient with prostate cancer for this study. Numerical results show that our approach successfully improved target coverage to meet the DVCs, while trying to keep corresponding OAR DVCs satisfied. The LBFGS algorithm for solving the nonlinear FMO model successfully satisfied the DVCs in three out of five test cases. However, there is no recourse in the nonlinear FMO model for correcting unsatisfied DVCs other than manually changing some parameter values through trial and error to derive a solution that more closely meets the DVC requirements. The LP-based heuristic algorithm outperformed the current treatment planning system in terms of DVC satisfaction. A major strength of the LP-based heuristic approach is that it is not sensitive to the starting condition. PMID- 25506502 TI - Dyadic Patterns of Intimate Partner Violence in Early Marriage. AB - OBJECTIVE: Research examining dyadic patterns of intimate partner violence (IPV) often focuses on static conceptions based on whether either the husband or wife has exhibited any violence. This study examined the dyadic patterns of IPV empirically and traced how these groups change over time. METHOD: Couples (N=634) were assessed with respect to IPV and relationship satisfaction at the time of marriage, and at their first and second anniversaries. Cluster analysis was conducted on Total Aggression, Differential Aggression, and the Aggression Ratio prior to marriage for couples with any violence. RESULTS: This analysis revealed 5 clusters; Very High-Husband to Wife, (High:H>W); Very High-Wife to Husband (High-W>H); Low to Moderate, Husband to Wife (Low:H>W); Low to Moderate, Wife to Husband (Low-W>H); Low to Moderate, Both Aggressive (Low:H=W). The majority (57%) of the aggressive couples were classified in the gender asymmetric groups. Most asymmetric clusters became symmetric over time, but the High:H>W cluster became more asymmetric. By the 2nd anniversary, all clusters were characterized by higher injuries experienced by wives than by husbands. CONCLUSION: These results demonstrate that a considerable amount of IPV that is typically classified as "bidirectional" is gender asymmetric and that these asymmetric patterns tend to converge into more symmetric patterns over time. PMID- 25506503 TI - Vestibular schwannoma or tanycytic ependymoma: Immunohistologic staining reveals. AB - BACKGROUND: The cerebellopontine angle (CPA) is a common location for primary tumors, most often vestibular schwannomas, and also meningiomas, dermoids, and a host of other neoplasms. Our case report illustrates how radiologic and histopathologic presentations of an unusual variant of ependymal neoplasm can be diagnostically challenging and how accurate diagnosis can affect treatment protocols. CASE HISTORY: Our patient had a CPA mass that was a variant of ependymoma known as tanycytic ependymoma that mimicked vestibular schwannoma radiologically and during intraoperative pathologic examination. Diagnosis as a World Health Organization (WHO) grade II tanycytic ependymoma was supported by its appearance on evaluation of the permanent sections, its diffuse immunoreactivity for glial fibrillary acidic protein (GFAP), and the perinuclear dot-and-ring-like staining for epithelial membrane antigen (EMA). CONCLUSIONS: Our patient's CPA mass initially believed to be a vestibular schwannoma on preoperative evaluation, surgical appearance, and intraoperative pathologic consultation was then correctly diagnosed as a WHO grade II tanycytic ependymoma on permanent histologic sections with the assistance of immunohistochemical stains, including EMA. After this definitive diagnosis, our patient's adjuvant treatment was adjusted. Earlier diagnosis could have provided guidance for goals of resection and prompt initiation of adjuvant treatment. PMID- 25506505 TI - Honoring the past: A prologue for the future of neuroscience nursing. PMID- 25506504 TI - Endoscopic biopsy of brain tumors: Does the technique matter? AB - BACKGROUND: Endoscopic biopsy of brain tumors is an important part of the armamentarium of management of intra- and periventricular tumors that is generally considered an acceptable and, in some situations, a preferred method for tissue sampling. The diagnostic yield of the procedure has been variably reported. Technical aspects of the procedure should undoubtedly reflect on its success rate and accuracy. Such impact on diagnostic yield of endoscopic brain biopsy is infrequently discussed in the literature. METHODS: A search of the medical literature was conducted for publications on endoscopic brain biopsy. These reports were analyzed regarding the various technical aspects. RESULTS: In the 43 publications analyzed, lenscopes were exclusively used in 22 reports and a tissue diagnosis was possible in 362 out of 387 endoscopic biopsies with a diagnostic yield of 93.54%. Only fiberscopes were used in 8 reports and a tissue diagnosis was possible in 100 out of 132 endoscopic biopsies with a diagnostic yield of 75.76%. The diagnostic yield in the mixed and unspecified groups was 88.95 and 88.04%, respectively. Very few details on the histopathological methods and tumor molecular genetics could be found. CONCLUSION: Endoscopic biopsy of brain tumors has a higher diagnostic yield when lenscopes are used. Neuronavigation seems to add to the diagnostic accuracy of the procedure. Studies detailing molecular genetic features of biopsied tumors are necessary in the future. PMID- 25506506 TI - Case Report: Ehlers-Danlos Syndrome in an adolescent presenting with Chronic Daily Headache. AB - BACKGROUND: Classic Ehlers-Danlos syndrome (EDS) is a connective tissue disorder characterized by skin hyperextensibility, skin fragility as well as joint hypermobility. EDS has been associated with psychiatric disorders, fatigue, dizziness, musculoskeletal pain, and stomach pain that are common complaints associated with adolescent chronic daily headache (CDH). This case report discusses an adolescent who presents with CDH and is subsequently diagnosed with EDS based upon the presenting symptoms for headache including syncope and chronic musculoskeletal pain as well as a history of hypermobility. CASE DESCRIPTION: A 15-year-old female presented to an outpatient headache clinic with a 10-year history of headache, which had become daily over the past 3 months and awakened her in the middle of the night. Past history also revealed chronic musculoskeletal pain, syncope, fatigue, and hypermobility of joints. Subsequent referral to a geneticist confirmed mild classic EDS. CONCLUSION: Along with the major manifestation of EDS, other signs and symptoms that characterize this disorder include musculoskeletal pain, fatigue, dizziness/vertigo, depression, and anxiety, which are often associated with CDH in adolescents. Clinicians treating CDH need to be aware of the major clinical manifestations of EDS as well as the other signs and symptoms that characterize both of these chronic pain disorders. An understanding of this syndrome will lead not only to a diagnosis of EDS but also initiation of a treatment plan specific for an adolescent with CDH and EDS. PMID- 25506508 TI - Understanding paroxysmal sympathetic hyperactivity after traumatic brain injury. AB - BACKGROUND: Paroxysmal sympathetic hyperactivity (PSH) is a condition occurring in a small percentage of patients with severe traumatic brain injury (TBI). It is characterized by a constellation of symptoms associated with excessive adrenergic output, including tachycardia, hypertension, tachypnea, and diaphoresis. Diagnosis is one of exclusion and, therefore, is often delayed. Treatment is aimed at minimizing triggers and pharmacologic management of symptoms. METHODS: A literature review using medline and cinahl was conducted to identify articles related to PSH. Search terms included paroxysmal sympathetic hyperactivity, autonomic storming, diencephalic seizures, and sympathetic storming. Reference lists of pertinent articles were also reviewed and these additional papers were included. RESULTS: The literature indicates that the understanding of PSH following TBI is in its infancy. The majority of information is based on small case series. The review revealed treatments that may be useful in treating PSH. CONCLUSIONS: Nurses play a critical role in the identification of at-risk patients, symptom complexes, and in the education of family. Early detection and treatment is likely to decrease overall morbidity and facilitate recovery. Further research is needed to establish screening tools and treatment algorithms for PSH. PMID- 25506509 TI - Neuroscience nursing interactive patient vignette. PMID- 25506507 TI - Neonatal pain: What's age got to do with it? AB - BACKGROUND: The neurobiology of neonatal pain processing, especially in preterm infants, differs significantly from older infants, children, adolescence, and adults. Research suggests that strong painful procedures or repeated mild procedures may permanently modify individual pain processing. Acute injuries at critical developmental periods are risk factors for persistent altered neurodevelopment. The purpose of this narrative review is to present the seminal and current literature describing the unique physiological aspects of neonatal pain processing. METHODS: Articles describing the structures and physiological processes that influence neonatal pain were identified from electronic databases Medline, PubMed, and CINAHL. RESULTS: The representation of neonatal pain physiology is described in three processes: Local peripheral nervous system processes, referred to as transduction; spinal cord processing, referred to as transmission and modulation; and supraspinal processing and integration or perception of pain. The consequences of undermanaged pain in preterm infants and neonates are discussed. CONCLUSION: Although the process and pain responses in neonates bear some similarity to processes and pain responses in older infants, children, adolescence, and adults; there are some pain processes and responses that are unique to neonates rendering them at risk for inadequate pain treatment. Moreover, exposure to repeated painful stimuli contributes to adverse long-term physiologic and behavioral sequelae. With the emergence of studies showing that painful experiences are capable of rewiring the adult brain, it is imperative that we treat neonatal pain effectively. PMID- 25506510 TI - A Within-Subject Normal-Mixture Model with Mixed-Effects for Analyzing Heart Rate Variability. AB - Data on heart rate variability (HRV) have been used extensively to indirectly assess the autonomic control of the heart. The distributions of HRV measures, such as the RR-interval, are not necessarily normally distributed and current methodology does not typically incorporate this characteristic. In this article, a mixed-effects modeling approach under the assumption of a two-component normal mixture distribution for the within-subject observations has been proposed. Estimation of the parameters of the model was performed through an application of the EM algorithm, which is different from the traditional EM application for the normal-mixture methods. An application of this method was illustrated and the results from a simulation study were discussed. Differences among other methods were also reviewed. PMID- 25506512 TI - Commitment across the Transition to Parenthood among Married and Cohabiting Couples. AB - Commitment has long been hypothesized to increase across the transition to parenthood, even though much research has found that relationship functioning declines during this period. We examined change in interpersonal commitment, measured as personal dedication and relationship confidence, and constraint commitment, measured as felt constraint, across the transition to parenthood. We tested for marital status differences in the change in commitment across the transition among three groups: cohabitation, marriage preceded by cohabitation, and direct marriage. Data came from the New Parents Project, a community sample of 173 married and cohabiting couples. Difference-in-difference estimates indicated that cohabiting fathers, in comparison to married fathers, dropped further in personal dedication and relationship confidence and increased more in felt constraint across the transition to parenthood. No significant differences across the transition were found between cohabiting and married mothers. Further research on the transition to parenthood among unmarried couples is suggested. PMID- 25506513 TI - TB Vaccines: The (Human) Challenge Ahead. PMID- 25506511 TI - Genetic Syndromes and Genes Involved in the Development of the Female Reproductive Tract: A Possible Role for Gene Therapy. AB - Mullerian and vaginal anomalies are congenital malformations of the female reproductive tract resulting from alterations in the normal developmental pathway of the uterus, cervix, fallopian tubes, and vagina. The most common of the Mullerian anomalies affect the uterus and may adversely impact reproductive outcomes highlighting the importance of gaining understanding of the genetic mechanisms that govern normal and abnormal development of the female reproductive tract. Modern molecular genetics with study of knock out animal models as well as several genetic syndromes featuring abnormalities of the female reproductive tract have identified candidate genes significant to this developmental pathway. Further emphasizing the importance of understanding female reproductive tract development, recent evidence has demonstrated expression of embryologically significant genes in the endometrium of adult mice and humans. This recent work suggests that these genes not only play a role in the proper structural development of the female reproductive tract but also may persist in adults to regulate proper function of the endometrium of the uterus. As endometrial function is critical for successful implantation and pregnancy maintenance, these recent data suggest a target for gene therapy. Future research will be needed to determine if gene therapy may improve reproductive outcomes for patients with demonstrated deficient endometrial expression related to abnormal gene expression. PMID- 25506514 TI - A protocol for evaluation of Rett Syndrome symptom improvement by metabolic modulators in Mecp2-mutant mice. AB - Mouse models recapitulate many symptoms of Rett Syndrome, an X-linked disorder caused by mutations in methyl-CpG-binding protein 2 (MECP2). The study of Mecp2 null male mice has provided insight into pathogenesis of the disorder; most recently, dysregulation of cholesterol and lipid metabolism. Perisymptomatic treatment with statin drugs successfully mitigates the effects of this metabolic syndrome, increases longevity and improves motor function. Described here is a metabolic drug screening protocol and timeline for symptom evaluation in Mecp2 mutant mice. Specifically, mice are treated twice weekly with a compound of interest alongside subjective health assessments, bi-weekly body composition measurements and blood chemistries. Throughout treatment, behavioral phenotyping tests are carried out at specific time points. This protocol is highly adaptable to other neurological diseases; however, the time for completion depends on the specific mutant model under study. The protocol highlights the use of several different CPMo protocols to carry out testing in a preclinical model. PMID- 25506517 TI - Reduced locomotor activity correlates with increased severity of arthritis in a mouse model of antibody-induced arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and progressive cartilage and bone destruction that leads to a substantial loss of general functions and/or a decline in physical activities such as walking speed in humans. The K/BxN serum transfer arthritis in mice shares many immunological and pathological features with human RA. Very few studies are available in mice that investigate the changes in physical activity in relation to arthritis development. In this study we investigate the effect of arthritis on the locomotor activity of mice during K/BxN sera transfer arthritis. METHODS: Arthritis was induced in Balb/c mice by injecting intraperitoneally with 200ul of K/BxN sera; Balb/c mice injected with phosphate buffered saline (PBS) served as control. Progress of arthritis was estimated by daily measurements of joint thickness. Each mouse's locomotor activity (travel distance and travel time) was assessed every day for duration of 20 minute period using the SmartCageTM platform. Data were analyzed using the SmartCageTM analysis software (CageScoreTM). RESULTS: Arthritic Balb/c mice showed a reduction in distance covered and travel speed when compared to arthritis-free, control Balb/c mice. Maximum decline in locomotor activity was observed during the peak period of the disease and correlated to the increase in joint thickness in the arthritic mice. CONCLUSION: This report demonstrates that measuring locomotor activity of mice during progression of K/BxN sera-induced arthritis using the SmartCageTM platform offers a quantitative method to assess physical activity in mice during arthritis. PMID- 25506518 TI - The process of EDC-NHS Cross-linking of reconstituted collagen fibres increases collagen fibrillar order and alignment. AB - We describe the production of collagen fibre bundles through a multi-strand, semi continuous extrusion process. Cross-linking using an EDC (1-ethyl-3-(3 dimethylaminopropyl)carbodiimide), NHS (N-hydroxysuccinimide) combination was considered. Atomic Force Microscopy (AFM) and Raman spectroscopy focused on how cross-linking affected the collagen fibrillar structure. In the cross-linked fibres, a clear fibrillar structure comparable to native collagen was observed which was not observed in the non-cross-linked fibre. The amide III doublet in the Raman spectra provided additional evidence of alignment in the cross-linked fibres. Raman spectroscopy also indicated no residual polyethylene glycol (from the fibre forming buffer) or water in any of the fibres. PMID- 25506515 TI - Emerging Concepts in Breast Cancer Risk Prediction. AB - Developing improved methods for breast cancer risk prediction could facilitate the targeting of interventions to women at highest risk, thereby reducing mortality, while sparing low-risk women the costs and inconvenience of unnecessary testing and procedures. However, currently available risk assessment tools fall short of achieving accurate individual risk prediction, precluding implementation of this approach. Improving these tools will require the identification of new methods of assessing risk and increasing the accuracy of existing risk indicators. We review four emerging topics that may have importance for breast cancer risk assessment: etiological heterogeneity, genetic susceptibility, mammographic breast density and assessment of breast involution. PMID- 25506519 TI - Gene prediction and annotation in Penstemon (Plantaginaceae): A workflow for marker development from extremely low-coverage genome sequencing. AB - PREMISE OF THE STUDY: Penstemon (Plantaginaceae) is a large and diverse genus endemic to North America. However, determining the phylogenetic relationships among its 280 species has been difficult due to its recent evolutionary radiation. The development of a large, multilocus data set can help to resolve this challenge. * METHODS: Using both previously sequenced genomic libraries and our own low-coverage whole-genome shotgun sequencing libraries, we used the MAKER2 Annotation Pipeline to identify gene regions for the development of sequencing loci from six extremely low-coverage Penstemon genomes (~0.005* 0.007*). We also compared this approach to BLAST searches, and conducted analyses to characterize sequence divergence across the species sequenced. * RESULTS: Annotations and gene predictions were successfully added to more than 10,000 contigs for potential use in downstream primer design. Primers were then designed for chloroplast, mitochondrial, and nuclear loci from these annotated sequences. MAKER2 identified longer gene regions in all six Penstemon genomes when compared with BLASTN and BLASTX searches. The average level of sequence divergence among the six species was 7.14%. * DISCUSSION: Combining bioinformatics tools into a workflow that produces annotations can be useful for creating potential phylogenetic markers from thousands of sequences even when genome coverage is extremely low and reference data are only available from distant relatives. Furthermore, the output from MAKER2 contains information about important gene features, such as exon boundaries, and can be easily integrated with visualization tools to facilitate the process of marker development. PMID- 25506520 TI - A review of the prevalence, utility, and caveats of using chloroplast simple sequence repeats for studies of plant biology. AB - Microsatellites occur in all plant genomes and provide useful markers for studies of genetic diversity and structure. Chloroplast microsatellites (cpSSRs) are frequently targeted because they are more easily isolated than nuclear microsatellites. Here, we quantified the frequency and uses of cpSSRs based on a literature review of over 400 studies published 1995-2013. These markers are an important and economical tool for plant biologists and continue to be used alongside modern genomics approaches to study genetic diversity and structure, evolutionary history, and hybridization in native and agricultural species. Studies using species-specific primers reported a greater number of polymorphic loci than those employing universal primers. A major disadvantage to cpSSRs is fragment size homoplasy; therefore, we documented its occurrence at several cpSSR loci within and between species of Acmispon (Fabaceae). Based on our empirical data set, we recommend targeted sequencing of a subset of samples combined with fragment genotyping as a cost-efficient, data-rich approach to the use of cpSSRs and as a test of homoplasy. The availability of genomic resources for plants aids in the development of primers for new study systems, thereby enhancing the utility of cpSSRs across plant biology. PMID- 25506522 TI - Characterization of fungus-specific microsatellite markers in the lichen-forming fungus Parmelina carporrhizans (Parmeliaceae). AB - PREMISE OF THE STUDY: Microsatellite loci were developed to study the lichen forming fungus Parmelina (Parmeliaceae) in different habitats of western Europe and the Mediterranean for baseline studies to understand the effects of climate change on its distribution. * METHODS AND RESULTS: We cultured P. carporrhizans from ascospores for genomic sequencing with Illumina HiSeq. We successfully developed 11 polymorphic microsatellite markers and associated primer sets and assessed them with 30 individuals from two of the Canary Islands. The average number of alleles per locus was 8.8. Nei's unbiased gene diversity of these loci ranged from 0.53 to 0.91 in the tested populations. Amplification in two closely related species (P. tiliacea, P. cryptotiliacea) yielded only limited success. * CONCLUSIONS: The new microsatellite markers will allow the study of genetic diversity and population structure in P. carporrhizans. We propose eight markers to combine in two multiplex reactions for further studies on a larger set of populations. PMID- 25506521 TI - Geneious! Simplified genome skimming methods for phylogenetic systematic studies: A case study in Oreocarya (Boraginaceae). AB - PREMISE OF THE STUDY: As systematists grapple with how to best harness the power of next-generation sequencing (NGS), a deluge of review papers, methods, and analytical tools make choosing the right method difficult. Oreocarya (Boraginaceae), a genus of 63 species, is a good example of a group lacking both species-level resolution and genomic resources. The use of Geneious removes bioinformatic barriers and makes NGS genome skimming accessible to even the least tech-savvy systematists. * METHODS: A combination of de novo and reference-guided assemblies was used to process 100-bp single-end Illumina HiSeq 2000 reads. A subset of 25 taxa was used to test the suitability of genome skimming for future systematic studies in recalcitrant lineages like Oreocarya. * RESULTS: The nuclear ribosomal cistron, the plastome, and 12 mitochondrial genes were recovered from all 25 taxa. All data processing and phylogenomic analyses were performed in Geneious. We report possible future multiplexing levels and published low-copy nuclear genes represented within de novo contigs. * DISCUSSION: Genome skimming represents a much-improved primary data collection over PCR+Sanger sequencing when chloroplast DNA (cpDNA), nuclear ribosomal DNA (nrDNA), and mitochondrial DNA (mtDNA) are the target sequences. This study details methods that plant systematists can employ to study their own taxa of interest. PMID- 25506523 TI - Development and characterization of nuclear microsatellite markers in the endophytic fungus Epichloe festucae (Clavicipitaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed for the endophytic fungus Epichloe festucae, which is symbiotic with Festuca rubra, to study the population genetics of the species and to compare population structures between E. festucae and its host F. rubra. * METHODS AND RESULTS: We developed 14 polymorphic markers using the unplaced genomic scaffold sequences of E. festucae from GenBank. The number of alleles per locus (A) varied from four to 16, and unbiased haploid diversity (h) was 0.717 in eight populations located in the Faroe Islands, Finland, and Spain. The Spanish populations possessed a higher number of alleles and haploid diversity (on average A = 5.1 and h = 0.591, respectively) compared to northern populations (on average A = 1.5 and h = 0.199, respectively). * CONCLUSIONS: These polymorphic markers will be used by grass breeders for uses including the improvement of commercial turfgrass cultivars, and by population geneticists to study different species of the Epichloe genus. PMID- 25506524 TI - Development and characterization of chloroplast microsatellite markers in a fine leaved fescue, Festuca rubra (Poaceae). AB - PREMISE OF THE STUDY: Chloroplast microsatellite markers were developed for Festuca rubra to examine its population genetic characteristics, taxonomy, and coevolution with its endophyte Epichloe festucae. * METHODS AND RESULTS: Thirteen polymorphic markers were identified from the chloroplast genome of a F. ovina accession and intergenic chloroplast sequences of F. rubra accessions. They amplified a total of 65 alleles in a sample of 93 individuals of F. rubra originating from six different populations located in the Faroe Islands, Finland, Greenland, Norway, and Spain. * CONCLUSIONS: The developed microsatellite primer pairs can be used by researchers in population genetic and taxonomic studies, and by plant breeders in breeding programs on grasses. PMID- 25506525 TI - Development of polymorphic genic-SSR markers by cDNA library sequencing in boxwood, Buxus spp. (Buxaceae). AB - PREMISE OF THE STUDY: Genic microsatellites or simple sequence repeat (genic SSR) markers were developed in boxwood (Buxus taxa) for genetic diversity analysis, identification of taxa, and to facilitate breeding. * METHODS AND RESULTS: cDNA libraries were developed from mRNA extracted from leaves of Buxus sempervirens 'Vardar Valley' and sequenced using the Illumina MiSeq system. Approximately 11.9 million base pairs of sequence data were examined and 845 genic-SSRs were identified, including 469 dinucleotide, 360 trinucleotide, seven tetranucleotide, one pentanucleotide, and eight hexanucleotide repeats. Primer pairs were designed for 71 selectively chosen genic-SSRs containing trinucleotide repeat motifs and were used to amplify the corresponding loci in 18 diverse boxwood accessions. Twenty-three primer pairs amplified polymorphic loci, with two to 10 alleles per locus. * CONCLUSIONS: These novel polymorphic genic-SSR markers will aid in evaluating genetic diversity of boxwood germplasm and allow verification of hybrids and cultivars for breeding programs. PMID- 25506527 TI - SERI Surgical Scaffold as an Adjunct for Circumferential Abdominoplasty and Lower Body Lift. AB - SUMMARY: Patients who have undergone massive weight loss typically have poor quality skin and fascia and thus are prone to experiencing recurrent skin laxity, bulges, and poor scarring after body contouring efforts, even in the hands of experienced surgeons. Moreover, this challenging patient population often has nutritional deficiencies and concomitant medical problems, which may lead to delayed or suboptimal wound healing. A silk-derived biological scaffold (SBS) and its facilitation of autogenous tissue generation may be viewed as a qualitative reinforcement of the superficial fascial system. Therefore, it may help support and stabilize a superficial fascial system that has been weakened by obesity and other factors. When employed in body lifting for patients with massive weight loss who desire long-lasting aesthetic results, it may represent a paradigm shift that has the potential to solve at least some issues that plague this patient population. In the present case of circumferential abdominoplasty and lower body lift, this silk-based bioresorbable scaffold was implanted in one side of the patient's body but not the other. Throughout the 7-month follow-up period, the patient and her husband (who were blinded as to which side received the SBS) and the author consistently observed more favorable results for the SBS side, which included greater postoperative comfort, better shape, higher buttock position, less recurrent laxity, and less descent of the scar. PMID- 25506526 TI - Intracranial volume in 15 children with bilateral coronal craniosynostosis. AB - BACKGROUND: Intracranial volume (ICV) growth in patients with bilateral coronal craniosynostosis (BCS) is not well described. It is therefore important to evaluate the consequences of cranial surgery in children with this condition. The aim of the present study was to evaluate ICVs in patients operated on for BCS. METHODS: A consecutive series of patients with BCS were operated on using spring assisted cranioplasty, with computed tomography scans in 0.6-mm slices, were included. A MATLAB-based computer program capable of measuring ICV was used. Patients were compared with an age- and gender-matched control group of healthy children. Student's t test was used for statistical analysis. RESULTS: Fifteen patients (7 girls and 8 boys) with 43 computed tomography scans were identified. The diagnoses were 13 syndromic BCS (3 Apert, 1 Crouzon, 6 Muenke, and 3 Saethre Chotzen) and 2 nonsyndromic BCS. The mean preoperative volume at the age of 5 months (n = 15) was 887 mL (range, 687-1082). Mean volume at follow-up at the age of 3 years (n = 13) was 1369 mL (range, 1196-1616). In comparison, the mean ICVs for controls at the ages of 5 months (n = 30) and 3 years (n = 26) were 854 mL and 1358 mL, respectively. The differences were not statistically significant (P > 0.05). CONCLUSIONS: Patients with BCS were operated on with spring-assisted cranioplasty seem to maintain their age-related ICV at 3 years of age when compared to normal children. PMID- 25506528 TI - Aggressive metastatic chordoma in the wrist. PMID- 25506530 TI - Tissue expander capsule for abdominal wall in autologous breast reconstruction. AB - SUMMARY: Adjuvant treatment planning can change after breast cancer resection and definitive pathological examination. Radiation therapy is often chosen as a supplementary treatment. Rectus abdominis-based muscle flaps are one of the main choices when breast reconstruction plans must be changed from implant-based to autologous methods. We herein report a case in which the patient's own tissue expander capsule was used to repair an abdominal wall defect after muscle-sparing transverse rectus abdominis myocutaneous flap reconstruction. PMID- 25506531 TI - Technical tips to trim the stump of a nonspurting recipient artery. PMID- 25506529 TI - Clinical application of a silk fibroin protein biologic scaffold for abdominal wall fascial reinforcement. AB - BACKGROUND: Preclinical studies have demonstrated that macroporous silk fibroin protein scaffolds are capable of promoting physiologically durable supportive tissue, which favors application of these engineered tissues for clinical implantation. The safety and effectiveness of a long-lasting, transitory, 510(k) cleared purified silk fibroin biologic scaffold (SBS) are investigated for soft tissue support and repair of the abdominal wall. METHODS: We conducted a multicenter retrospective review of all consecutive patients who underwent abdominal wall soft-tissue reinforcement with an SBS device between 2011 and 2013. Indications, comorbid conditions, surgical technique, complications, and outcomes were evaluated. RESULTS: We reviewed the records of 172 consecutive patients who received an SBS for soft-tissue support. Of those, 77 patients underwent abdominal wall fascial repair, with a mean follow-up of 18.4 +/- 7.5 months. Procedures using an SBS included reinforcement of an abdominal-based flap donor site (31.2%), ventral hernia repair (53.2%), and abdominoplasty (15.6%). The overall complication rate was 6.5%, consisting of 2 wound dehiscences, 1 with device exposure, 1 seroma, 1 infection with explantation, and a perioperative bulge requiring reoperation. There were no reports of hernia. CONCLUSIONS: Postoperative complication rates after 18 months were low, and most surgical complications were managed nonoperatively on an outpatient basis without mesh removal. To our knowledge, this is the only series to report on a long-lasting, transitory SBS for abdominal wall repair and reinforcement. Procedure-specific outcome studies are warranted to delineate optimal patient selection and define potential device characteristic advantages. PMID- 25506532 TI - Soft, Brown Rupture: Clinical Signs and Symptoms Associated with Ruptured PIP Breast Implants. AB - BACKGROUND: Preoperative signs and symptoms of patients with Poly Implant Prothese (PIP) implants could be predictive of device failure. Based on clinical observation and intraoperative findings 4 hypotheses were raised: (1) Preoperative clinical signs including acquired asymmetry, breast enlargement, fullness of the lower pole, decreased mound projection, and change in breast consistency could be indicative of implant rupture. (2) Device failure correlates with a low preoperative Baker grade of capsule. (3) Brown-stained implants are more prone to implant failure. (4) The brown gel could be indicative of iodine ingression through a substandard elastomer shell. METHODS: Preoperative clinical signs were compared with intraoperative findings for 27 patients undergoing PIP implant explantation. RESULTS: Acquired asymmetry (P = 0.0003), breast enlargement (P = 0.0002), fuller lower pole (P < 0.0001), and loss of lateral projection (P < 0.0001) were all significantly predictive of device failure. Capsule Baker grade was lower preoperatively for ruptured implants. The lack of palpable and visible preoperative capsular contracture could be secondary to the elastic nature of the capsular tissue found. Brown implants failed significantly more often than white implants. Analysis of brown gel revealed the presence of iodine, suggesting povidone iodine ingression at implantation. CONCLUSIONS: Preoperative signs can be predictive of PIP implant failure. Brown-stained implants are more prone to rupture. The presence of iodine in the gel suggests unacceptable permeability of the shell early in the implant's life span. A noninvasive screening test to detect brown implants in situ could help identify implants at risk of failure in those who elect to keep their implants. PMID- 25506533 TI - Novel Polypropylene Barbed Threads for Midface Lift-"REEBORN Lifting". PMID- 25506535 TI - Lymphoepithelioma-like Carcinoma of the Skin: A Case with Perineural Invasion. AB - SUMMARY: Lymphoepithelioma-like carcinoma of the skin is a rare, low malignant cutaneous neoplasm. We report a case of an elderly woman with lymphoepithelioma like carcinoma of the skin in the forehead. The tumor was mistaken first as actinic keratosis and later as metastatic squamous cell carcinoma. A histological reassessment showed lymphoepithelioma-like carcinoma of the skin with perineural invasion, which is rare and considered more aggressive. The patient therefore received adjuvant radiotherapy after the recommended wide excision. Lymphoepithelioma-like carcinoma of the skin is a variant of squamous cell carcinoma, and histologically, it resembles the more aggressive lymphoepithelioma of the nasopharynx. The later is Epstein-Barr positive, whereas lymphoepithelioma like carcinoma normally is not. Lymphoepithelioma-like carcinoma is an important diagnosis to know and the disease is discussed. PMID- 25506536 TI - A Novel Approach to the Management of Margin-positive DCIS in Nipple-sparing Mastectomy. AB - SUMMARY: Nipple-sparing mastectomy (NSM) is gaining acceptance as an oncologically sound and cosmetically superior mastectomy technique. Debate exists over the management of positive margins near the nipple-areola complex. This case report presents a novel approach to the management of margin-positive ductal carcinoma in situ in NSM. A 50-year-old white female with invasive ductal carcinoma underwent NSM. Intraoperative pathology indicated the presence of DCIS positive retroareolar margins. Revision through a direct vertical nipple incision allowed for adequate surgical revision and pathologic evaluation of the retroareolar breast tissue while maintaining the nipple-areola skin and primary mastectomy incision. This novel approach ensures negative margins, allows superior cosmetic outcome, and improves patient autonomy in decision making. The technique may translate to NSM patients with positive retroareolar margins or false-negative margins. PMID- 25506537 TI - Microcystic adnexal carcinoma: reconstruction of a large centrofacial defect. AB - SUMMARY: We report a rare case of a large facial microcystic adnexal carcinoma in an elderly patient who underwent several rounds of excision. The patient was left with a large facial defect and remaining positive margins. The decision was made to stop further excision and proceed with reconstructive surgery. We show that the patient's function and quality of life were not impeded despite reconstruction in light of positive margins for tumor. We believe that this case will draw the surgeon's attention to the possibility of palliative reconstruction in the treatment of a patient with large debilitating facial defects after microcystic adnexal carcinoma excision. PMID- 25506534 TI - Plastic surgery and the breast: a citation analysis of the literature. AB - BACKGROUND: A large proportion of the plastic surgery literature is dedicated to the breast. It is one of the most common topics in our specialty, yet it is unclear which articles have been the most influential. The purpose of this study was to identify the top 100 most-cited articles on breast in the plastic surgery literature and examine the characteristics of each individual article. METHODS: Using an electronic database through the Web of Science, we were able to determine the 6 journals that contributed to the 100 most-cited articles on breast in the plastic surgery literature. RESULTS: Each article was examined individually looking at characteristics such as subject matter, article type, country of origin, institution, authorship, and year of publication. Plastic and Reconstructive Surgery contributed the most articles to the top 100 with 81 articles including the most-cited article which has been referenced 673 times to date. The United States produced 73% of the top 100 articles, and the most prolific institution was the University of Texas M. D. Anderson Cancer Center with 15 articles. CONCLUSIONS: This study has identified the most influential articles on breast in the plastic surgery literature over the past 68 years and highlighted many important scientific breakthroughs and landmarks that have occurred during this time. PMID- 25506539 TI - Modification of the Nuss Procedure: The Single-incision Technique. AB - SUMMARY: The Nuss procedure is a prevalent minimally invasive surgery for pectus excavatum. Although the Nuss procedure has the advantage of leaving less obtrusive scars, the standard technique requires at least 3 skin incisions to insert several instruments. We experienced 7 cases of the modified Nuss procedure using a single incision during a 7-year period. To facilitate passing of the bar, a traction guide was created according to our unique method. There was no need for a bar stabilizer, and no severe intraoperative complications occurred. All patients exhibited satisfactory short-term results; however, 1 patient suffered from bar rotation and required repeat surgery for fixation. Two patients underwent bar removal via the same single incision without any difficulties. PMID- 25506538 TI - A Multi-institutional Analysis of Insurance Status as a Predictor of Morbidity Following Breast Reconstruction. AB - BACKGROUND: Although recent literature suggests that patients with Medicaid and Medicare are more likely than those with private insurance to experience complications following a variety of procedures, there has been limited evaluation of insurance-based disparities in reconstructive surgery outcomes. Using a large, multi-institutional database, we sought to evaluate the potential impact of insurance status on complications following breast reconstruction. METHODS: We identified all breast reconstructive cases in the 2008 to 2011 Tracking Operations and Outcomes for Plastic Surgeons clinical registry. Propensity scores were calculated for each case, and insurance cohorts were matched with regard to demographic and clinical characteristics. Outcomes of interest included 15 medical and 13 surgical complications. RESULTS: Propensity score matching yielded 493 matched patients for evaluation of Medicaid and 670 matched patients for evaluation of Medicare. Overall complication rates did not significantly differ between patients with Medicaid or Medicare and those with private insurance (P = 0.167 and P = 0.861, respectively). Risk-adjusted multivariate regressions corroborated this finding, demonstrating that Medicaid and Medicare insurance status does not independently predict surgical site infection, seroma, hematoma, explantation, or wound dehiscence (all P > 0.05). Medicaid insurance status significantly predicted flap failure (odds ratio = 3.315, P = 0.027). CONCLUSIONS: This study is the first to investigate the differential effects of payer status on outcomes following breast reconstruction. Our results suggest that Medicaid and Medicare insurance status does not independently predict increased overall complication rates following breast reconstruction. This finding underscores the commitment of the plastic surgery community to providing consistent care for patients, irrespective of insurance status. PMID- 25506540 TI - Breast total male breast reconstruction with fat grafting. AB - SUMMARY: Cancer of a male breast represents less than 1% of all breast cancer. As with to female patients, mastectomy in men creates a substantial emotional burden. Breast reconstruction may improve the patient's psychological well-being, compliance with adjuvant treatments, and overall outcome. However, due to the unique anatomy of the male breast, standard reconstructive strategies using anatomic or prosthetic modalities are not entirely applicable. We describe a case of a 68-year-old male patient who underwent successful unilateral breast reconstruction solely with fat grafting technique. PMID- 25506541 TI - Metatarsal reconstruction with a fibular osteocutaneous flap: a novel approach utilizing virtual surgical planning. AB - SUMMARY: Craniofacial reconstruction remains the main application for virtual surgical planning (VSP). We present a case in which this technology was applied to reconstruct a bony defect of the first metatarsal bone from a gunshot injury. VSP was used to facilitate a 1-stage reconstruction with a fibular osteocutaneous flap. A template of the reconstructed bone was designed based on the virtual mirror-image, noninjured bone. Prefabricated cutting guides facilitated precise shaping of the vascularized bone accounting for location of perforators. Successful reconstruction of the metatarsal bone was achieved with excellent functional outcomes. We believe that VSP can be a valuable tool in reconstruction of metatarsal bones by facilitating precise intraoperative shaping and anatomic orientation of the vascularized flap and reducing flap ischemia and operative time. PMID- 25506542 TI - Application of microautologous fat transplantation in the correction of sunken upper eyelid. AB - BACKGROUND: Although fat grafting has been clinically applied by surgeons in esthetic and reconstructive surgery, it has widely evolved in processes such as harvesting, processing, and placement of fat, using the fat-grafting procedure, which dates back over 100 years. Surgeons frequently use fat grafting to recontour, augment, or fill soft-tissue defects, facial wrinkles, or skin problems such as depressions or scars. However, fat grafting has not been thoroughly understood and has not been conclusively standardized to ensure superior clinical results. METHODS: This study was intended to determine the role of microautologous fat transplantation (MAFT) under evidence-based medicine, particularly in accurate delivery of small fat parcels. The research method involved the conceptualization of MAFT and the development of an innovative surgical instrument for fat placement. Clinically, 168 patients with sunken upper eyelids with multiple folds underwent this procedure. RESULTS: The major findings suggested that MAFT exhibits promising clinical results and offers a superior guideline for fat placement. Details of the technique and theoretical implications are also discussed. CONCLUSIONS: The therapeutic effects of MAFT and the long-term clinical results of patients with sunken upper eyelids with multiple folds indicated satisfactory outcomes. Based on the results, MAFT offers an alternative option to surgeons for performing fat grafting and provides a more favorable option for the benefit and welfare of patients by reducing the potential complications. PMID- 25506543 TI - Lifecourse Socioeconomic Position and Racial Disparities in BMI Trajectories among Black and White Women: Exploring Cohort Effects in the Americans Changing Lives' Study. AB - INTRODUCTION: Few studies have analyzed the cohort effects of lifecourse socioeconomic position (SEP) on racial disparities in body mass index (BMI) trajectories. We assessed the contribution of lifecourse SEP on racial differences in BMI trajectories among two different age cohorts of women. METHODS: Four waves of the Americans' Changing Lives' study (1986-2002) were used to compute BMI trajectories for 2194 Black and White women. Multivariable associations of lifecourse SEP variables (father's education, perceived childhood family status, education, income, wealth and financial security) with Wave 1(W1) BMI and BMI change were assessed using mixed models. RESULTS: Black women had higher W1 BMI than White women in both cohorts (women <40 years in 1986 (+2.6 kg/m2 (95%CI: +1.71, +3.53)) and women>=40 in 1986 (+2.68 kg/m2 (95%CI:+2.12,3.24))); Black women in the younger cohort had a higher change in BMI (+0.73 kg/m2/year (95%CI:+0.17,+1.29)). High education was associated with lower W1 BMI in both cohorts (-1.34 (95%CI:-2.53,-0.15) and -1.08 kg/m2 (95%CI: 0.50,-1.65), respectively). Among the younger cohort, high income was associated with lower W1 BMI (-0.78kg/m2/unit log income (95%CI:-1.32,-0.25)) while among the older cohort, high father's education (-0.78 kg/m2 (95%CI:-0.06,-1.50)) and higher wealth (-0.26 kg/m2(95%CI:-0.43,-0.08))were associated with low W1 BMI. Racial disparities in W1 BMI were attenuated by 20-25% while those for BMI change remained unexplained on adjustment for lifecourse SEP. CONCLUSION: In this large population-based dataset, results suggest that the contribution of lifecourse SEP to racial disparities in BMI may be established early in adulthood. PMID- 25506546 TI - Economic development and gender inequality in cognition: a comparison of China and India, and of SAGE and the HRS sister studies. AB - This paper examines cognition measures by age and gender from two types of studies in China and India. It finds that despite some notable differences in samples and measures, a general strong association of cognition in older ages with education emerges as a potential explanation for gender gaps and cohort differences. Female disadvantage in cognition is greater in India, both before and after controlling for education. The process of rural-urban migration draws more cognitively able women to cities in China but not in India. The advent of modern longitudinal studies of aging in these developing countries holds great promise for future work. PMID- 25506545 TI - Using Acceptance and Commitment Therapy to Increase Self-Compassion: A Randomized Controlled Trial. AB - Self-compassion has been shown to be related to several types of psychopathology, including traumatic stress, and has been shown to improve in response to various kinds of interventions. Current conceptualizations of self-compassion fit well with the psychological flexibility model, which underlies acceptance and commitment therapy (ACT). However, there has been no research on ACT interventions specifically aimed at self-compassion. This randomized trial therefore compared a 6-hour ACT-based workshop targeting self-compassion to a wait-list control. From pretreatment to 2-month follow-up, ACT was significantly superior to the control condition in self-compassion, general psychological distress, and anxiety. Process analyses revealed psychological flexibility to be a significant mediator of changes in self-compassion, general psychological distress, depression, anxiety, and stress. Exploratory moderation analyses revealed the intervention to be of more benefit in terms of depression, anxiety, and stress to those with greater trauma history. PMID- 25506544 TI - The Inheritance of Tourette Disorder: A review. AB - Georges Gilles de la Tourette, in describing the syndrome that now bears his name, observed that the condition aggregated within families. Over the last three decades, numerous studies have confirmed this observation, and demonstrated that familial clustering is due in part to genetic factors. Recent studies are beginning to provide clues about the underlying genetic mechanisms important for the manifestation of some cases of Tourette Disorder (TD). Evidence has come from different study designs, such as nuclear families, twins, multigenerational families, and case-control samples, together examining the broad spectrum of genetic variation including cytogenetic abnormalities, copy number variants, genome-wide association of common variants, and sequencing studies targeting rare and/or de novo variation. Each of these classes of genetic variation holds promise for identifying the causative genes and biological pathways contributing to this paradigmatic neuropsychiatric disorder. PMID- 25506548 TI - GLP-1 receptor agonism ameliorates hepatic VLDL overproduction and de novo lipogenesis in insulin resistance. AB - BACKGROUND/OBJECTIVES: Fasting dyslipidemia is commonly observed in insulin resistant states and mechanistically linked to hepatic overproduction of very low density lipoprotein (VLDL). Recently, the incretin hormone glucagon-like peptide 1 (GLP-1) has been implicated in ameliorating dyslipidemia associated with insulin resistance and reducing hepatic lipid stores. Given that hepatic VLDL production is a key determinant of circulating lipid levels, we investigated the role of both peripheral and central GLP-1 receptor (GLP-1R) agonism in regulation of VLDL production. METHODS: The fructose-fed Syrian golden hamster was employed as a model of diet-induced insulin resistance and VLDL overproduction. Hamsters were treated with the GLP-1R agonist exendin-4 by intraperitoneal (ip) injection for peripheral studies or by intracerebroventricular (ICV) administration into the 3rd ventricle for central studies. Peripheral studies were repeated in vagotomised hamsters. RESULTS: Short term (7-10 day) peripheral exendin-4 enhanced satiety and also prevented fructose-induced fasting dyslipidemia and hyperinsulinemia. These changes were accompanied by decreased fasting plasma glucose levels, reduced hepatic lipid content and decreased levels of VLDL-TG and -apoB100 in plasma. The observed changes in fasting dyslipidemia could be partially explained by reduced respiratory exchange ratio (RER) thereby indicating a switch in energy utilization from carbohydrate to lipid. Additionally, exendin-4 reduced mRNA markers associated with hepatic de novo lipogenesis and inflammation. Despite these observations, GLP-1R activity could not be detected in primary hamster hepatocytes, thus leading to the investigation of a potential brain-liver axis functioning to regulate lipid metabolism. Short term (4 day) central administration of exendin-4 decreased body weight and food consumption and further prevented fructose-induced hypertriglyceridemia. Additionally, the peripheral lipid-lowering effects of exendin-4 were negated in vagotomised hamsters implicating the involvement of parasympathetic signaling. CONCLUSION: Exendin-4 prevents fructose-induced dyslipidemia and hepatic VLDL overproduction in insulin resistance through an indirect mechanism involving altered energy utilization, decreased hepatic lipid synthesis and also requires an intact parasympathetic signaling pathway. PMID- 25506547 TI - Embryonic development of the hypothalamic feeding circuitry: Transcriptional, nutritional, and hormonal influences. AB - BACKGROUND: Embryonic neurogenesis and differentiation in the hypothalamic feeding circuitry is under the control of a variety of diffused morphogens and intrinsic transcription factors, leading to the unique structural and functional characteristics of each nucleus. SCOPE OF REVIEW: The transcriptional regulation of the development of feeding neuroendocrine systems during the period of embryonic neurogenesis and differentiation will be reviewed here, with a special emphasis on genetic and environmental manipulations that yield an adverse metabolic phenotype. MAJOR CONCLUSIONS: Emerging data suggest that developmental mechanisms can be perturbed not only by genetic manipulation, but also by manipulations to maternal nutrition during the gestational period, leading to long-lasting behavioral, neurobiological, and metabolic consequences. Leptin is neurotrophic in the embryonic brain, and given that it varies in proportion to maternal energy balance, may mediate these effects through an interaction with the mechanisms of hypothalamic development. PMID- 25506551 TI - Vagal plasticity the key to obesity. PMID- 25506549 TI - The omega6-fatty acid, arachidonic acid, regulates the conversion of white to brite adipocyte through a prostaglandin/calcium mediated pathway. AB - OBJECTIVE: Brite adipocytes are inducible energy-dissipating cells expressing UCP1 which appear within white adipose tissue of healthy adult individuals. Recruitment of these cells represents a potential strategy to fight obesity and associated diseases. METHODS/RESULTS: Using human Multipotent Adipose-Derived Stem cells, able to convert into brite adipocytes, we show that arachidonic acid strongly inhibits brite adipocyte formation via a cyclooxygenase pathway leading to secretion of PGE2 and PGF2alpha. Both prostaglandins induce an oscillatory Ca(++) signaling coupled to ERK pathway and trigger a decrease in UCP1 expression and in oxygen consumption without altering mitochondriogenesis. In mice fed a standard diet supplemented with omega6 arachidonic acid, PGF2alpha and PGE2 amounts are increased in subcutaneous white adipose tissue and associated with a decrease in the recruitment of brite adipocytes. CONCLUSION: Our results suggest that dietary excess of omega6 polyunsaturated fatty acids present in Western diets, may also favor obesity by preventing the "browning" process to take place. PMID- 25506550 TI - Defective insulin secretory response to intravenous glucose in C57Bl/6J compared to C57Bl/6N mice. AB - OBJECTIVE: The C57Bl/6J (Bl/6J) mouse is the most widely used strain in metabolic research. This strain carries a mutation in nicotinamide nucleotide transhydrogenase (Nnt), a mitochondrial enzyme involved in NADPH production, which has been suggested to lead to glucose intolerance and beta-cell dysfunction. However, recent reports comparing Bl/6J to Bl/6N (carrying the wild type Nnt allele) under normal diet have led to conflicting results using glucose tolerance tests. Thus, we assessed glucose-stimulated insulin secretion (GSIS), insulin sensitivity, clearance and central glucose-induced insulin secretion in Bl/6J and N mice using gold-standard methodologies. METHODS: GSIS was measured using complementary tests (oral and intravenous glucose tolerance tests) and hyperglycemic clamps. Whole-body insulin sensitivity was assessed using euglycemic-hyperinsulinemic clamps. Neurally-mediated insulin secretion was measured during central hyperglycemia. RESULTS: Bl/6J mice have impaired GSIS compared to Bl/6N when glucose is administered intravenously during both a tolerance test and hyperglycemic clamp, but not in response to oral glucose. First and second phases of GSIS are altered without changes in whole body insulin sensitivity, insulin clearance, beta-cell mass or central response to glucose, thereby demonstrating defective beta-cell function in Bl/6J mice. CONCLUSIONS: The Bl/6J mouse strain displays impaired insulin secretion. These results have important implications for choosing the appropriate test to assess beta-cell function and background strain in genetically modified mouse models. PMID- 25506552 TI - Prognostic gene signature profiles of hepatitis C-related early-stage liver cirrhosis. AB - The rate of hepatitis C virus (HCV) related liver cirrhosis and subsequent cancer development is increasing and raising the risk of related mortality and morbidity. To address this issue, we aimed to develop a prognostic index that can be used to stratify patients for risk of disease progression. This index was developed in part by using a gene signature test implemented in a clinically applicable digital transcript counting platform (NanoString nCounter system). A cohort of 145 U.S. patients with HCV-related early-stage cirrhosis was analyzed by using the assay. This dataset (GEO accession number GPL17230) provides information of expression levels of the prognostic genes in the cohort. PMID- 25506553 TI - Cell-type specific transcriptomic profiling to dissect mechanisms of differential dendritogenesis. AB - The establishment, maintenance and modulation of cell-type specific neural architectures is critically important to the formation of functional neural networks. At the neuroanatomical level, differential patterns of dendritic arborization directly impact neural function and connectivity, however the molecular mechanisms underlying the specification of distinct dendrite morphologies remains incompletely understood. To address this question, we analyzed global gene expression from purified populations of wild-type class I and class IV Drosophila melanogaster dendritic arborization (da) sensory neurons compared to wild-type whole larval RNA using oligo DNA microarray expression profiling. Herein we present detailed experimental methods and bioinformatic analyses to correspond with our data reported in the Gene Expression Omnibus under accession number GSE46154. We further provide R code to facilitate data accession, perform quality controls, and conduct bioinformatic analyses relevant to this dataset. Our cell-type specific gene expression datasets provide a valuable resource for guiding further investigations designed to explore the molecular mechanisms underlying differential patterns of neuronal patterning. PMID- 25506554 TI - Variations in active transport behavior among different neighborhoods and across adult lifestages. AB - OBJECTIVE: Built environment characteristics are closely related to transport behavior, but observed variations could be due to residents own choice of neighborhood called residential self-selection. The aim of this study was to investigate differences in neighborhood walkability and residential self selection across life stages in relation to active transport behavior. METHODS: The IPEN walkability index, which consists of four built environment characteristics, was used to define 16 high and low walkable neighborhoods in Aarhus, Denmark (250.000 inhabitants). Transport behavior was assessed using the IPAQ questionnaire. Life stages were categorized in three groups according to age and parental status. A factor analysis was conducted to investigate patterns of self-selection. Multivariable logistic regression analyses were carried out to evaluate the association between walkability and transport behavior i.e. walking, cycling and motorized transport adjusted for residential self-selection and life stages. RESULTS: A total of 642 adults aged 20-65 years completed the questionnaire. The highest rated self-selection preference across all groups was a safe and secure neighborhood followed by getting around easily on foot and by bicycle. Three self-selection factors were detected, and varied across the life stages. In the multivariable models high neighborhood walkability was associated with less motorized transport (OR 0.33 95%CI 0.18-0.58), more walking (OR 1.65 95%CI 1.03-2.65) and cycling (OR 1.50 95% CI 1.01-2.23). Self-selection and life stage were also associated with transport behavior, and attenuated the association with walkability. CONCLUSION: This study supports the hypothesis that some variation in transport behavior can be explained by life stages and self selection, but the association between living in a more walkable neighborhood and active transport is still significant after adjusting for these factors. Life stage significantly moderated the association between neighborhood walkability and cycling for transport, and household income significantly moderated the association between neighborhood walkability and walking for transport. Getting around easily by bicycle and on foot was the highest rated self-selection factor second only to perceived neighborhood safety. PMID- 25506555 TI - Sexually transmitted infections in women: A correlation of clinical and laboratory diagnosis in cases of vaginal discharge syndrome. AB - AIMS: This study compares the clinical and laboratory diagnosis of vaginal discharge syndrome. SETTINGS AND DESIGN: This cross-sectional study was carried out at the gynaecology outpatient department of a tertiary care hospital in Gujarat, India. MATERIAL AND METHODS: Total of 180 females diagnosed as vaginal discharge or cervicitis based on syndromic approach and were recruited for the study. Their clinical profile was noted and they were investigated for bacterial vaginosis, trichomoniasis, candidiasis, gonorrhoea and chlamydia infection. RESULTS: Lower abdominal pain (35%) followed by burning micturition (23.9%) were the common associated complaints. Bacterial vaginosis was the most common clinical diagnosis, while trichomoniasis was least common. Upon laboratory investigation, 35.6% of cases of vaginal discharge and 12% of cases of cervicitis tested positive. Percentage of cases confirmed by laboratory investigation was 50, 27.8 and 41.7 for bacterial vaginosis, trichomoniasis and candidiasis respectively. CONCLUSION: Among all the females diagnosed as vaginal discharge syndrome, a very small percentage actually turned out to be positive upon laboratory testing. PMID- 25506556 TI - Acrokeratosis verruciformis of Hopf in family. AB - Acrokeratosis verruciformis of Hopf (AKV) is a rare disorder of keratinization inherited in an autosomal dominant fashion. A 15-year-old female presented with numerous skin-colored papular lesions over the neck as well as dorsa of the hands and feet of 7 years duration. Similar lesions were noted in her mother. Six other members of her family showed similar lesions with similar site of involvement. Presence of characteristic warty papules and histopathology led to diagnosis of a rare condition of acrokeratosis verruciformis. PMID- 25506557 TI - Berardinelli-Seip congenital lipodystrophy in two siblings. AB - Berardinelli-Seip congenital lipodystrophy (BSCL) is a very rare autosomal recessive disorder characterized by various dermatological and systemic manifestations such as lipoatrophy, hypertriglyceridemia, hepatomegaly, acanthosis nigricans, and acromegaloid features. BSCL type 2 is more common and severe, with onset in the neonatal period or in early infancy. The locus for BSCL2 has been identified on chromosome 11q13. Early recognition and differentiation from other congenital generalized lipodystrophies help in the initiation of appropriate preventive and therapeutic measures such as lifestyle modification and pharmacotherapy that helps postpone the onset of metabolic syndrome. We report BSCL type 2 in two siblings with several cutaneous manifestations like acanthosis nigricans, hypertrichosis, prominent subcutaneous veins, and increased lanugo hair. PMID- 25506558 TI - Segmental vitiligo with segmental morphea: An autoimmune link? AB - An 18-year old girl with segmental vitiligo involving the left side of the trunk and left upper limb with segmental morphea involving the right side of trunk and right upper limb without any deeper involvement is illustrated. There was no history of preceding drug intake, vaccination, trauma, radiation therapy, infection, or hormonal therapy. Family history of stable vitiligo in her brother and a history of type II diabetes mellitus in the father were elicited. Screening for autoimmune diseases and antithyroid antibody was negative. An autoimmune link explaining the co-occurrence has been proposed. Cutaneous mosiacism could explain the presence of both the pathologies in a segmental distribution. PMID- 25506559 TI - Metastatic basal cell carcinoma to the lungs: Case report and review of literature. AB - Basal cell carcinoma is the most common form of skin cancer and it rarely metastasizes. The prevalence of metastatic basal cell carcinoma (MBCC) varies between 0.0028% and 0.55% of all cases. Over 250 MBCC have been reported in the literature. We present a case with large recurrent basal cell carcinoma of the face with radiological and histopathological findings indicating the presence of metastasis to the lungs. PMID- 25506560 TI - Chilblain lupus erythematosus in an adolescent girl. AB - Chilblain Lupus Erythematosus (CHLE) is a rare form of cutaneous lupus erythematosus (LE), more frequently seen in middle aged females. It is characterized by erythematous to violaceous plaques over the acral areas induced by exposure to cold or drop in temperature unlike lesions of lupus erythematosus that worsen with sun exposure. Here, we present a case of chilblain lupus erythematosus in an adolescent girl with few unique features not previously reported. PMID- 25506561 TI - Rowell syndrome. AB - Rowell syndrome is a rare disease consisting of erythema multiforme-like lesions associated with lupus erythematosus. The syndrome occurs mostly in middle-aged women. The authors describe the syndrome in a 15-year-old boy who responded well to systemic steroids and hydroxychloroquine. PMID- 25506562 TI - Nodular colloid degeneration of the skin: Report of three cases with review and update. AB - Nodular colloid degeneration (NCD) is a rare dermatological disorder and uncommon type of colloid milium. The degeneration may be related to sun exposure. In this report, three cases, all presenting as multiple plaques and nodules over the nose and the face are depicted. Histologically, these nodular masses were homogeneous, with eosinophilic-cleaved materials expanding the papillary dermis and extending into the deep dermis. Periodic acid Schiff (PAS), crystal violet, and methyl violet stains highlight the colloid material. All the three cases were finally diagnosed as NCD. NCD could be considered in any case with facial nodules and a long history of sun exposure. We suggest the long-term sun exposure as an etiologic factor; thus sun protection would be the most preventive and available treatment. PMID- 25506563 TI - Unilateral nevoid acanthosis nigricans: Uncommon variant of a common disease. AB - Acanthosis nigricans (AN) is a fairly common dermatosis characterized by hyperpigmented velvety plaques, having a predilection for the intertriginous areas. We herein present a case of unilateral nevoid acanthosis nigricans over the left lateral chest, in an adult male. The rarity of documentation of this entity in the world literature prompted us to report the case. PMID- 25506564 TI - Congenital candidiasis. AB - Congenital candidiasis (CC) is a rare disease with less than 100 cases being reported in the literature. It presents within six days of life with manifestations ranging from localized skin disease to systemic involvement in the form of respiratory distress, sepsis, and death. We report a neonate who presented with diffuse pustular eruption on erythematous background involving face, trunk, and palms within 24 h after birth. Candida albicans was identified in 10% potassium hydroxide (KOH) smear and culture from the pustules. Intravenous fluconazole and topical ketoconazole were given and the condition improved completely in two weeks. CC is rare and needs to be differentiated from other conditions presenting with pustular lesions at birth in order to avoid complications. Early diagnosis and prompt treatment of this condition is important as untreated cases carry a mortality rate of 8-40%. PMID- 25506565 TI - Unusual presentation of severe pompholyx. PMID- 25506566 TI - Marjolin's ulcer: A rare report. PMID- 25506567 TI - Hypersensitivity reaction to scorpion antivenom. PMID- 25506568 TI - Keraunographic tattoo. PMID- 25506569 TI - Buschke-Lowenstein tumor in a patient with decompensated cirrhosis. PMID- 25506570 TI - Multiple papulonodular lesions located over the nasolabial sulcus. PMID- 25506571 TI - Uremic frost. PMID- 25506572 TI - Tendinous xanthoma with familial hypercholesterolemia. PMID- 25506573 TI - Epidemiological pattern of psoriasis, vitiligo and atopic dermatitis in India: Hospital-based point prevalence. AB - BACKGROUND: The knowledge of the prevalence of common dermatoses will be useful for optimum use of valuable resources of the country. AIM: The aim of the study is to determine the pattern and prevalence of psoriasis, vitiligo and atopic dermatitis (AD) in India. MATERIALS AND METHODS: This was a hospital-based study conducted on a single day in one medical college each in four zones of India. RESULTS: The point prevalence of dermatological cases was 9.25%. The point prevalence of psoriasis, vitiligo and AD were 8%, 9.98% and 6.75% respectively. Chronic plaque type psoriasis was the most common (50%) clinical pattern. The most common site of involvement of psoriasis was the palms. Stable type of vitiligo was common which accounted for 65.21%. Lower lip was involved in 75% of mucosal vitiligo. Lower limbs were the most common site of onset of vitiligo. AD was most prevalent in the first decade (40.7%). Personal history of atopy was present in (59.5%) patients. Dry skin was present in 92.5% of patients. CONCLUSIONS: Our data correlates with previous hospital-based prevalence studies of psoriasis, vitiligo and AD. PMID- 25506574 TI - Molluscuoid lesions over the body. PMID- 25506575 TI - Pityriasis amiantacea. PMID- 25506576 TI - Idiopathic congenital true leukonychia totalis. PMID- 25506577 TI - Half and half nail. PMID- 25506578 TI - Ehlers-Danlos syndrome. AB - Ehlers-Danlos syndrome (EDS) is a generalized disorder of one element of connective tissue manifesting clinically by fragility and hyperelasticity of the skin and joint laxity. It is a hereditary disorder, the inheritance being usually autosomal dominant with low penetrance. Autosomal recessive and X-linked recessive varieties are also known. First described by Hippocrates in 4(th) century B.C., the various clinical types with variable penetrance have been described lately. The number of cases EDS reported in the literature is very meagre. With the available information only about six publications of classic EDS in siblings had been reported in Indian literature. PMID- 25506579 TI - Role of hormones and blood lipids in the pathogenesis of acne vulgaris in non obese, non-hirsute females. AB - CONTEXT: Acne vulgaris (AV) is a common disease affecting all ages and ethnic groups. Androgens, skin and serum lipids, inflammatory signaling and regulatory neuropeptides seem to be involved in this multi-factorial process. AIM: The aim of this work was to determine hormonal levels and lipid profile in non-obese, non hirsute females with AV. SUBJECTS AND METHODS: A total of 60 non-obese, non hirsute female cases with different grades of AV and 60 age- and gender-matched healthy volunteers were included. Measurement of serum total and free testosterone, sex hormone binding globulin (SHBG), estradiol and progesterone and blood lipids was done during the luteal phase of the menstrual cycle. RESULTS: Total testosterone, free testosterone (FT) and progesterone levels were significantly higher (P < 0.001 for all) while estradiol levels (P < 0.001) and SHBG (P < 0.01) were significantly lower in cases than controls. Total cholesterol and low density lipoprotein cholesterol (LDL-C) levels were significantly higher (P < 0.001 for both) while high density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 (ApoA-1) levels were significantly lower (P < 0.001 for both) in cases than controls. Higher values of FT (P = 0.03) and SHBG (P = 0.02) and lower values of estradiol (P = 0.04) levels were significantly in favor of severe acne. Higher values of cholesterol (P < 0.001) and LDL-C (P = 0.03) and lower values of HDL-C (P = 0.01) and ApoA-1 (P = 0.02) levels were significantly associated with severe acne. CONCLUSION: Changes in hormone levels and lipid profile in non-obese and non-hirsute females with AV should be considered in disease pathogenesis and in treatment prescription of these patients. PMID- 25506580 TI - Nocturnal enuresis: A topic review and institution experience. AB - The objective is to provide a review of nocturnal enuresis (NE), including its epidemiology, etiology, pathophysiology, evaluation, and current management. We also set to provide further insight on the treatment of this condition from the experience derived from patients cared for at our tertiary-care institution. NE affects approximately 15% of all children at 5-year-old, affecting boys more frequently than girls. At our large university tertiary pediatric urology center, NE and incontinence, in general, is one the most common chief complaints prompting urologic care. In this review, we examine the condition in detail, highlighting specific goals of the initial evaluation and treatment. We contrast the commonly implemented treatment recommendations, available from the literature with strategies we have found valuable from our extensive experience in treating patients with this disorder. Using current urologic reference textbooks, book chapters, Medline, journal articles and reviews describing the many aspects of NE were reviewed in order to describe NE and the current practices at our institution. Although, this is not a systematic literature review, it includes relevant available research, institutional experience and urological expert opinion and current practices at a tertiary state health facility. The treatment of NE remains a challenge for many pediatricians and pediatric urologists. This likely stems from the multiple possible etiologies of the disorder. We have established a treatment algorithm at our institution, which we have found successful in the majority of our patients. This consists of starting patients on urotherapy, then offering both the enuresis alarm device and medication therapy as first line treatments, and finally adding anticholingerics for combination therapy. Our hope is with further research the treatment of NE will continue to improve. PMID- 25506581 TI - The impact of protocol assignment for older adolescents with hodgkin lymphoma. AB - BACKGROUND AND PURPOSE: Hodgkin lymphoma (HL) treatment has evolved to reduce or avoid radiotherapy (RT) dose and volume and minimize the potential for late effects. Some older adolescents are treated on adult protocols. The purpose of this study is to examine the protocol assignment of older adolescents and its impact on radiation dose to relevant thoracic structures. MATERIALS AND METHODS: Cooperative group data were reviewed and 12 adolescents were randomly selected from a pediatric HL protocol. Treatment plans were generated per one pediatric and two adult protocols. Dose volume histograms for heart, lung, and breast allowed comparison of radiation dose to these sites across these three protocols. RESULTS: A total of 15.2% of adolescents were treated on adult HL protocols and received significantly higher radiation dosage to heart and lung compared to pediatric HL protocols. Adolescents treated on either pediatric or adult protocols received similar RT dose to breast. CONCLUSION: Older adolescents treated on adult HL protocols received higher RT dose to thoracic structures except breast. Level of nodal involvement may impact overall RT dose to breast. The impact of varying field design and RT dose on survival, local, and late effects needs further study for this vulnerable age group. Adolescents, young adults, Hodgkin lymphoma, RT, clinical trials. PMID- 25506583 TI - Physical principles demonstrate that the biceps femoris muscle relative to the other hamstring muscles exerts the most force: implications for hamstring muscle strain injuries. AB - Of the hamstring muscle group the biceps femoris muscle is the most commonly injured muscle in sports requiring interval sprinting. The reason for this observation is unknown. The objective of this study was to calculate the forces of all three hamstring muscles, relative to each other, during a lengthening contraction to assess for any differences that may help explain the biceps femoris predilection for injury during interval sprinting. To calculate the displacement of each individual hamstring muscle previously performed studies on cadaveric anatomical data and hamstring kinematics during sprinting were used. From these displacement calculations for each individual hamstring muscle physical principles were then used to deduce the proportion of force exerted by each individual hamstring muscle during a lengthening muscle contraction. These deductions demonstrate that the biceps femoris muscle is required to exert proportionally more force in a lengthening muscle contraction relative to the semimembranosus and semitendinosus muscles primarily as a consequence of having to lengthen over a greater distance within the same time frame. It is hypothesized that this property maybe a factor in the known observation of the increased susceptibility of the biceps femoris muscle to injury during repeated sprints where recurrent higher force is required. PMID- 25506585 TI - alpha-Amylase inhibitory activity of some traditionally used medicinal species of Labiatae. AB - BACKGROUND: Natural alpha-amylase inhibitors of herbal origin are an attractive therapeutic approach to control post-prandial hyperglycemia via reducing the glucose release from starch and delaying carbohydrate absorption. These compounds are able to inhibit the activity of the carbohydrate hydrolyzing enzymes in the small intestine and potentially useful in control of diabetes. The enlarged Lamiaceae (Labiatae) family contains about 6,900 to 7,200 species worldwide and many species of this family possess medicinal properties and have been used traditionally for treatment of chronic illnesses including diabetes. METHODS: In the present study particular species of Labiatae family from the genera, Phlomis, Satureja, Salvia, Scutellarua, Stachys and Hymenocrater, which are growing wildly in Iran, selected to evaluate for possible in vitro alpha-amylase inhibitory activity, compared to acarbose as a positive control. RESULTS: The inhibitory activities of all the herbal extracts were varied from 1.9 to 18.6 (IC50, MUg/mL). Additionally, the ethyl acetate extract of P. bruguieri (IC50 = 1.9 MUg/mL) and the butanol extract of P. persica (IC50 = 3.6 MUg/mL) exhibited the lowest IC50 values among all the species as the most potent herbal extracts, while the inhibitory activity of S. sahendica and S. macrosiphon (ethyl acetate extracts) as well as P. caucasica (butanol extract) on alpha-amylase enzyme was observed as weak and did not reach at least to the 50% of the enzyme inhibition level. CONCLUSIONS: Taking together, P. bruguieri and P. persica among the Phlomis species can be the promising sources of alpha-amylase inhibitors. However, P. rigida, S. bizantina and H. bituminosus that exhibited moderate activity can be stand on second level of interest. PMID- 25506586 TI - Current and Future Role of the Gastroenterologist in GI Cancer Management. AB - With advances in technology, advances in the understanding of biology of cancer, and the advent of improved and novel therapies, the role of the gastroenterologist has been modified greatly over the past 2 decades, and continues to be shaped by the knowledge, skill, and opportunity to capitalize on the unique position that gastroenterologists hold in the patient care continuum. The gastroenterologist is evolving from a "pure" diagnostician to an endoscopic surgeon, a geneticist, a nutritionist, an immunologist and chemotherapist, and palliative care physician. PMID- 25506584 TI - Metabolic syndrome in premenopausal and postmenopausal women with type 2 diabetes: loss of protective effects of premenopausal status. AB - BACKGROUND: Diabetes is probably responsible for worsening of metabolic syndrome (MetS)components. The aim of the present study was to compare the components of MetS between premenopausal and postmenopausal women with type 2 diabetes (T2DM). METHOD: In this cross sectional study, we studied 639 women with T2DM that were divided in pre-menopausal (n = 221) and post-menopausal (n = 418) group. They were selected from participants of a diabetes clinic and assessed for MetS and its components. All MetS components were evaluated to follow age and duration of diabetes adjusted according to the ATP III criteria. RESULTS: The mean ages of pre-menopausal and post-menopausal were 43.33 +/- 0.47 and 60.35 +/- 0.38 years, respectively. MetS was defined for 88.3% of total subjects (87.5% and 87.7% in pre-menopausal and post-menopausal women with T2DM respectively). Systolic blood pressure (SBP) and waist circumference (WC) were significantly higher in post menopausal women with T2DM in comparison with pre-menopausal ones. There were no significant differences in triglyceride (T.G) level, diastolic blood pressure (DBP) and high density lipoprotein cholesterol (HDL-C) between the two groups. Myocardial infarction (MI) occurred in 1% total subjects (1.3% and 1.8%) in pre menopausal and post-menopausal women with T2DM, respectively (p = 0.21). CONCLUSION: Worsening of MetS and its components except for SBP and waist circumference has been shown in pre-menopausal women with T2DM similar to post menopausal ones. The observed differences may be explained by increasing age. With respect to increasing of myocardial infarction in premenopausal subjects, we suggest that diabetes can abolish the protective effects of premenopausal status for MetS and MI. PMID- 25506587 TI - Trypanosoma cruzi, the Causal Agent of Chagas Disease: Boundaries between Wild and Domestic Cycles in Venezuela. AB - Trypanosoma cruzi the etiological agent of American Trypanosomiasis or Chagas disease (ChD) is transmitted by triatomines vectors between mammals including man. T. cruzi has existed for circa 150 Ma in the Americas and nearly 10 million people are currently infected. The overlap between wild and domestic ecotopes where T. cruzi circulates is increasing. Host-parasite interactions have been determined by infection patterns in these cycles, all under natural or laboratorial conditions. This mini-review describes specific parasite niches, such as plant communities or biological corridors between domestic and wild landscapes, in order to help identify risk factors for ChD and define the boundaries between wild and domestic transmission cycles, with an emphasis on research undertaken in Venezuela. PMID- 25506582 TI - Combinations of immunotherapy and radiation in cancer therapy. AB - The immune system has the ability to recognize and specifically reject tumors, and tumors only become clinically apparent once they have evaded immune destruction by creating an immunosuppressive tumor microenvironment. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor specific T-cells, acting as an in situ tumor vaccine; however, RT alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement RT to help overcome tumor-induced immune suppression, as demonstrated in pre-clinical tumor models. Here, we provide the rationale for combinations of different immunotherapies and RT, and review the pre-clinical and emerging clinical evidence for these combinations in the treatment of cancer. PMID- 25506588 TI - Hierarchical Stochastic Simulation Algorithm for SBML Models of Genetic Circuits. AB - This paper describes a hierarchical stochastic simulation algorithm, which has been implemented within iBioSim, a tool used to model, analyze, and visualize genetic circuits. Many biological analysis tools flatten out hierarchy before simulation, but there are many disadvantages associated with this approach. First, the memory required to represent the model can quickly expand in the process. Second, the flattening process is computationally expensive. Finally, when modeling a dynamic cellular population within iBioSim, inlining the hierarchy of the model is inefficient since models must grow dynamically over time. This paper discusses a new approach to handle hierarchy on the fly to make the tool faster and more memory-efficient. This approach yields significant performance improvements as compared to the former flat analysis method. PMID- 25506590 TI - Automated Cough Assessment on a Mobile Platform. AB - The development of an Automated System for Asthma Monitoring (ADAM) is described. This consists of a consumer electronics mobile platform running a custom application. The application acquires an audio signal from an external user-worn microphone connected to the device analog-to-digital converter (microphone input). This signal is processed to determine the presence or absence of cough sounds. Symptom tallies and raw audio waveforms are recorded and made easily accessible for later review by a healthcare provider. The symptom detection algorithm is based upon standard speech recognition and machine learning paradigms and consists of an audio feature extraction step followed by a Hidden Markov Model based Viterbi decoder that has been trained on a large database of audio examples from a variety of subjects. Multiple Hidden Markov Model topologies and orders are studied. Performance of the recognizer is presented in terms of the sensitivity and the rate of false alarm as determined in a cross validation test. PMID- 25506589 TI - Super-resolution imaging of C-type lectin spatial rearrangement within the dendritic cell plasma membrane at fungal microbe contact sites. AB - Dendritic cells express DC-SIGN and CD206, C-type lectins (CTLs) that bind a variety of pathogens and may facilitate pathogen uptake for subsequent antigen presentation. Both proteins form punctate membrane nanodomains (~80 nm) on naive cells. We analyzed the spatiotemporal distribution of CTLs following host-fungal particle contact using confocal microscopy and three distinct methods of cluster identification and measurement of receptor clusters in super-resolution datasets: DBSCAN, Pair Correlation and a custom implementation of the Getis spatial statistic. Quantitative analysis of confocal and super-resolution images demonstrated that CTL nanodomains become concentrated in the contact site relative to non-contact membrane after the first hour of exposure and established that this recruitment is sustained out to 4 h. DC-SIGN nanodomains in fungal contact sites exhibit a 70% area increase and a 38% decrease in interdomain separation. Contact site CD206 nanodomains possess 90% greater area and 42% lower interdomain separation relative to non-contact regions. Contact site CTL clusters appear as disk-shaped domains of approximately 150-175 nm in diameter. The increase in length scale of CTL nanostructure in contact sites suggests that the smaller nanodomains on resting membranes may merge during fungal recognition, or that they become packed closely enough to achieve sub-resolution inter-domain edge separations of <30 nm. This study provides evidence of local receptor spatial rearrangements on the nanoscale that occur in the plasma membrane upon pathogen binding and may direct important signaling interactions required to recognize and respond to the presence of a relatively large pathogen. PMID- 25506592 TI - The significance of body mass index in calculating the cut-off points for low muscle mass in the elderly: methodological issues. AB - OBJECTIVES: Cut-off points (COPs) for appendicular lean mass (ALM) index, essential to define low muscle mass (LMM) in the elderly, have never been officially defined for Poland. The aim of the study was to establish them. Additionally, the significance of body mass index (BMI) for correctly defining the COPs in a young, healthy reference group was assessed. METHODS: The study was composed of reference group (n = 1113) and the elderly group (n = 200). In all subjects, body composition was assessed by bioimpedance analysis, and ALM index was calculated. Next, COPs (kg/m(2)) were set up for the whole reference group and for particular subgroups with different BMIs separately. They were used to diagnose sarcopenia in the elderly. RESULTS: COP for all young females was 5.37 (COP-F), while it was equal to 5.52 (COP-F2) when only those with a recommended BMI (18.50-24.99 kg/m(2)) were taken into consideration. For males, it was 7.32 and 7.29, respectively. Only 7% of elderly females had LMM based on COP-F and 15% had LMM based on COP-F2 (P < 0.05); for males, the percentages were 18% and 16%, respectively. CONCLUSIONS: COPs for LMM for Poland are 5.52 kg/m(2) (females) and 7.29 kg/m(2) (males). The reference group BMI is an important factor in establishing COPs for low muscle mass. PMID- 25506593 TI - 3D dynamic culture of rabbit articular chondrocytes encapsulated in alginate gel beads using spinner flasks for cartilage tissue regeneration. AB - Cell-based therapy using chondrocytes for cartilage repair suffers from chondrocyte dedifferentiation. In the present study, the effects of an integrated three-dimensional and dynamic culture on rabbit articular chondrocytes were investigated. Cells (passages 1 and 4) were encapsulated in alginate gel beads and cultured in spinner flasks in chondrogenic and chondrocyte growth media. Subcutaneous implantation of the cell-laden beads was performed to evaluate the ectopic chondrogenesis. It was found that cells remained viable after 35 days in the three-dimensional dynamic culture. Passage 1 cells demonstrated a proliferative growth in both media. Passage 4 cells showed a gradual reduction in DNA content in growth medium, which was attenuated in chondrogenic medium. Deposition of glycosaminoglycans (GAG) was found in all cultures. While passage 1 cells generally produced higher amounts of GAG than passage 4 cells, GAG/DNA became similar on day 35 for both cells in growth media. Interestingly, GAG/DNA in growth medium was greater than that in chondrogenic medium for both cells. Based on GAG quantification and gene expression analysis, encapsulated passage 1 cells cultured in growth medium displayed the best ectopic chondrogenesis. Taken together, the three-dimensional and dynamic culture for chondrocytes holds great potential in cartilage regeneration. PMID- 25506591 TI - Contribution of Crk adaptor proteins to host cell and bacteria interactions. AB - The Crk adaptor family of proteins comprises the alternatively spliced CrkI and CrkII isoforms, as well as the paralog Crk-like (CrkL) protein, which is encoded by a different gene. Initially thought to be involved in signaling during apoptosis and cell adhesion, this ubiquitously expressed family of proteins is now known to play essential roles in integrating signals from a wide range of stimuli. In this review, we describe the structure and function of the different Crk proteins. We then focus on the emerging roles of Crk adaptors during Enterobacteriaceae pathogenesis, with special emphasis on the important human pathogens Salmonella, Shigella, Yersinia, and enteropathogenic Escherichia coli. Throughout, we remark on opportunities for future research into this intriguing family of proteins. PMID- 25506594 TI - CR TKA UHMWPE wear tested after artificial aging of the vitamin E treated gliding component by simulating daily patient activities. AB - The wear behaviour of total knee arthroplasty (TKA) is dominated by two wear mechanisms: the abrasive wear and the delamination of the gliding components, where the second is strongly linked to aging processes and stress concentration in the material. The addition of vitamin E to the bulk material is a potential way to reduce the aging processes. This study evaluates the wear behaviour and delamination susceptibility of the gliding components of a vitamin E blended, ultra-high molecular weight polyethylene (UHMWPE) cruciate retaining (CR) total knee arthroplasty. Daily activities such as level walking, ascending and descending stairs, bending of the knee, and sitting and rising from a chair were simulated with a data set received from an instrumented knee prosthesis. After 5 million test cycles no structural failure of the gliding components was observed. The wear rate was with 5.62 +/- 0.53 mg/million cycles falling within the limit of previous reports for established wear test methods. PMID- 25506598 TI - The Rite of Relocation: Social and Material Transformations in the Midwest US. AB - Concerns of appropriate housing may arise in older adulthood. Some older adults may make life work in the place we call home; others take steps to voluntarily relocate in anticipation of health and other needs. While moving at any age can be challenging, moving from one's home in later life also represents multiple reflections: past, present and future selves, control of one's space and relinquishing the care of one's space to another person or corporation, family support and family fissures, and the body's capacities and limitations. Moving is examined as a moment where regimes of value are negotiated through competing semiotic ideologies and at times social roles are transformed. Ethnographic fieldwork occurred from January 2009-May 2012 in the Midwest United States. This paper presents experiences of relocation of material and social role transformation as older adults make this housing, and writ large, life transition. PMID- 25506595 TI - Coapplication of lidocaine and membrane-impermeable lidocaine derivative QX-222 produces divergent effects on evoked and spontaneous nociceptive behaviors in mice. AB - The present study was aimed at investigating the analgesic properties of a combination of lidocaine and QX-222 and its effects on evoked pain behavior (complete Freund's adjuvant-induced allodynia and hyperalgesia in inflammatory condition) and spontaneous pain behavior (formalin-induced acute pain) in mice. Drugs were injected adjacent to sciatic nerve or into plantar. Motor function, thermal withdrawal latency, mechanical withdrawal threshold, and licking/biting were evaluated by behavioral tests. A combination of lidocaine and QX-222 adjacent sciatic nerve injection produced the long-lasting sensory-specific nerve block, and intraplantar injection inhibited spontaneous pain in the formalin treated mice but did not detectably attenuated hyperalgesia and allodynia in the complete Freund's adjuvant- (CFA-) treated mice. Our results suggest that a combination of lidocaine and QX-222 achieves a long-lasting differential block (sensory selective) and produces divergent effects on evoked and spontaneous pain behaviors in mice. PMID- 25506596 TI - Vasculotoxic and Proinflammatory Effects of Plasma Heme: Cell Signaling and Cytoprotective Responses. AB - The proinfammatory vasculotoxic effects of intravascular hemolysis are modulated by plasma hemoglobin and heme clearance via the haptoglobin/CD163 system and the hemopexin/CD91 system, respectively, and detoxification through the heme oxygenase/ferritin system. However, sudden or excessive hemolysis can overwhelm these protective systems leading to heme interacting with cells of the vasculature. Heme presents a damage-associated molecular pattern to the innate immune system. Heme is an extracellular inflammatory signaling molecule with strict binding specificity for TLR4 on monocyte/macrophages, endothelial, and other cells. The resulting TLR4 signaling cascade rapidly leads to intracellular oxidative stress and an inflammatory response. Heme also induces a cytoprotective response that includes Nrf2 responsive genes such as heme oxygenase-1, ferritin, haptoglobin, hemopexin, and other antioxidant response genes. It is the balance between the pro-inflammatory/vasculotoxic effects of plasma hemoglobin/heme and the cytoprotective responses that ultimately determines the pathophysiologic outcome in patients. PMID- 25506599 TI - Frailty Attenuates the Impact of Metformin on Reducing Mortality in Older Adults with Type 2 Diabetes. AB - OBJECTIVE: To determine whether the protective effect of metformin against death is modified by frailty status in older adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a cohort study during October 1, 1999-September 30, 2006 among veterans aged 65-89 years old with type 2 diabetes but without history of liver, renal diseases, or cancers, who had sulfonylureas or metformin as the sole antidiabetic drug for >=180 days. The Cox proportional hazard model was used to compare hazard rates of all-cause mortality between the metformin and sulfonylurea users adjusting for the propensity score of metformin use and covariates: age, race/ethnicity, diabetes duration, Charlson comorbidity score, statin use, smoking status, BMI, LDL, and HbA1c. RESULTS: In this cohort of 2,415 veterans, 307 (12.7%) were metformin users, 2,108 (87.3%) were sulfonylurea users, the mean age was 73.7+/-5.2 years, the mean study period was 5.6+/-2.3 years, the mean HbA1c at baseline was 6.7+/-1.0%, 23% had diabetes for >=10 years, and 43.6% (N=1,048) died during the study period. For patients with and without frailty, the adjusted hazard ratio (HR) of death for metformin vs. sulfonylurea use were 0.92 (95% CI=0.90-1.31, p-value=0.19) and 0.69 (95% CI = 0.60-0.79, p-value<0.001), respectively. Logistic regression analyses showed that metformin (vs. sulfonylurea) was significantly associated with a decreased odds of frailty (OR: 0.66, 95% CI: 0.61-0.71, p-value <.0001). CONCLUSION: Our study suggests that metformin could potentially promote longevity via preventing frailty in older adults with type 2 diabetes. PMID- 25506600 TI - Pancreatic and Islet Development and Function: The Role of Thyroid Hormone. AB - A gradually expanding body of literature suggests that Thyroid Hormone (TH) and Thyroid Hormone Receptors (TRs) play a contributing role in pancreatic and islet cell development, maturation, and function. Studies using a variety of model systems capable of exploiting species-specific developmental paradigms have revealed the contribution of TH to cellular differentiation, lineage decisions, and endocrine cell specification. Moreover, in vitro and in vivo evidence suggests that TH is involved in islet beta cell proliferation and maturation; however, the signaling pathway(s) connected with this function of TH/TR are not well understood. The purpose of this review is to discuss the current literature that has defined the effects of TH and TRs on pancreatic and islet cell development and function, describe the impact of hyper- and hypothyroidism on whole body metabolism, and highlight future and potential applications of TH in novel therapeutic strategies for diabetes. PMID- 25506602 TI - Behavioral control blunts reactions to contemporaneous and future adverse events: medial prefrontal cortex plasticity and a corticostriatal network. AB - It has been known for many years that the ability to exert behavioral control over an adverse event blunts the behavioral and neurochemical impact of the event. More recently, it has become clear that the experience of behavioral control over adverse events also produces enduring changes that reduce the effects of subsequent negative events, even if they are uncontrollable and quite different from the original event controlled. This review focuses on the mechanism by which control both limits the impact of the stressor being experienced and produces enduring, trans-situational "immunization". The evidence will suggest that control is detected by a corticostriatal circuit involving the ventral medial prefrontal cortex (mPFC) and the posterior dorsomedial striatum (DMS). Once control is detected, other mPFC neurons that project to stress responsive brainstem (dorsal raphe nucleus, DRN) and limbic (amygdala) structures exert top-down inhibitory control over the activation of these structures that is produced by the adverse event. These structures, such as the DRN and amygdala, in turn regulate the proximate mediators of the behavioral and physiological responses produced by adverse events, and so control blunts these responses. Importantly, the joint occurrence of control and adverse events seems to produce enduring plastic changes in the top-down inhibitory mPFC system such that this system is now activated by later adverse events even if they are uncontrollable, thereby reducing the impact of these events. Other issues are discussed that include a) whether other processes such as safety signals and exercise, that lead to resistance/resilience, also use the mPFC circuitry or do so in other ways; b) whether control has similar effects and neural mediation in humans, and c) the relationship of this work to clinical phenomena. PMID- 25506601 TI - Recognizing Resilience: Learning from the Effects of Stress on the Brain. AB - As the central organ of stress and adaptation to stressors, the brain plays a pivotal role in behavioral and physiological responses that may lead to successful adaptation or to pathophysiology and mental and physical disease. In this context, resilience can be defined as "achieving a positive outcome in the face of adversity". Underlying this deceptively simple statement are several questions; first, to what extent is this ability limited to those environments that have shaped the individual or can it be more flexible; second, when in the life course does the brain develop capacity for flexibility for adapting positively to new challenges; and third, can such flexibility be instated in individuals where early life experiences have limited that capacity? Brain architecture continues to show plasticity throughout adult life and studies of gene expression and epigenetic regulation reveal a dynamic and ever-changing brain. The goal is to recognize those biological changes that underlie flexible adaptability, and to recognize gene pathways, epigenetic factors and structural changes that indicate lack of resilience leading to negative outcomes, particularly when the individual is challenged by new circumstances. Early life experiences determine individual differences in such capabilities via epigenetic pathways and laying down of brain architecture that determine the later capacity for flexible adaptation or the lack thereof. Reactivation of such plasticity in individuals lacking such resilience is a new challenge for research and practical application. Finally, sex differences in the plasticity of the brain are often overlooked and must be more fully investigated. PMID- 25506606 TI - Saccharomyces cerevisiae mixed culture of blackberry (Rubus ulmifolius L.) juice: synergism in the aroma compounds production. AB - Blackberry (Rubus sp.) juice was fermented using four different strains of Saccharomyces cerevisiae (Vitilevure-CM4457, Enoferm-T306, ICV-K1, and Greroche Rhona-L3574) recognized because of their use in the wine industry. A medium alcoholic graduation spirit (<6 degrees GL) with potential to be produced at an industrial scale was obtained. Alcoholic fermentations were performed at 28 degrees C, 200 rpm, and noncontrolled pH. The synergistic effect on the aromatic compounds production during fermentation in mixed culture was compared with those obtained by monoculture and physic mixture of spirits produced in monoculture. The aromatic composition was determined by HS-SPME-GC. The differences in aromatic profile principally rely on the proportions in aromatic compounds and not on the number of those compounds. The multivariance analysis, principal component analysis (PCA), and factorial discriminant analysis (DFA) permit to demonstrate the synergism between the strains. PMID- 25506603 TI - Endogenous Opioids: The Downside of Opposing Stress. AB - Our dynamic environment regularly exposes us to potentially life-threatening challenges or stressors. To answer these challenges and maintain homeostasis, the stress response, an innate coordinated engagement of central and peripheral neural systems is initiated. Although essential for survival, the inappropriate initiation of the stress response or its continuation after the stressor is terminated has pathological consequences that have been linked to diverse neuropsychiatric and medical diseases. Substantial individual variability exists in the pathological consequences of stressors. A theme of this Special Issue is that elucidating the basis of individual differences in resilience or its flipside, vulnerability, will greatly advance our ability to prevent and treat stress-related diseases. This can be approached by studying individual differences in "pro-stress" mediators such as corticosteroids or the hypothalamic orchestrator of the stress response, corticotropin-releasing factor. More recently, the recognition of endogenous neuromodulators with "anti-stress" activity that have opposing actions or that restrain stress-response systems suggests additional bases for individual differences in stress pathology. These "anti-stress" neuromodulators offer alternative strategies for manipulating the stress response and its pathological consequences. This review uses the major brain norepinephrine system as a model stress-response system to demonstrate how co-regulation by opposing pro-stress (corticotropin-releasing factor) and anti stress (enkephalin) neuromodulators must be fine-tuned to produce an adaptive response to stress. The clinical consequences of tipping this fine-tuned balance in the direction of either the pro- or anti-stress systems are emphasized. Finally, that each system provides multiple points at which individual differences could confer stress vulnerability or resilience is discussed. PMID- 25506607 TI - Production, characterization of tannase from Penicillium montanense URM 6286 under SSF using agroindustrial wastes, and application in the clarification of grape juice (Vitis vinifera L.). AB - Tannase is an enzyme that hydrolyzes esters and lateral bonds of tannins, such as tannic acid, releasing glucose and gallic acid and stands out in the clarification of wines and juices. Fungi of the genera Aspergillus and Penicillium are excellent producers of this enzyme. The search for fungi that produce high levels of tannase as well as new substrates for the enzyme production by the SSF is required. The objectives of this study were to evaluate the production of tannase by Aspergillus and Penicillium species through SSF using leaves and agroindustrial waste barbados cherry and mangaba fruit as substrate, select the best producer, optimize production, characterize the crude enzyme extract, and apply it the clarification of grape juice. Selecting the best producer was performed by planning Placket-Burman and RSM. P. montanense showed highest activity with 41.64 U/mL after 72 h of fermentation residue using barbados cherry, with 3.5% tannic acid and 70% moisture. The enzyme showed the highest activity at pH 9.0 and 50 degrees C. The tannase of P. montanense was stable over a wide pH range and temperature and, when applied to grape juice, showed higher efficiency by reducing 46% of the tannin content after incubation 120 m. PMID- 25506605 TI - Peripheral and Central Mechanisms of Stress Resilience. AB - Viable new treatments for depression and anxiety have been slow to emerge, likely owing to the complex and incompletely understood etiology of these disorders. A budding area of research with great therapeutic promise involves the study of resilience, the adaptive maintenance of normal physiology and behavior despite exposure to marked psychological stress. This phenomenon, documented in both humans and animal models, involves coordinated biological mechanisms in numerous bodily systems, both peripheral and central. In this review, we provide an overview of resilience mechanisms throughout the body, discussing current research in animal models investigating the roles of the neuroendocrine, immune, and central nervous systems in behavioral resilience to stress. PMID- 25506604 TI - Targeting the Neuropeptide Y System in Stress-related Psychiatric Disorders. AB - Repeated, extreme, or traumatic stressors can elicit pathological effects leading to many negative physical and psychological outcomes. Stressors can precipitate the onset of psychiatric diseases, or exacerbate pre-existing disorders including various anxiety and mood disorders. As stressors can negatively impact human psychiatric health, it is essential to identify neurochemicals that may confer protection from the negative sequelae of repeated or extreme stress exposure. Elucidating the neurobiological underpinnings of stress resilience will enhance our ability to promote resilience to, or recovery from, stress-related psychiatric disease. Herein, we will review the evidence for neuropeptide Y as an endogenous mediator of resilience and its potential relevance for the treatment of stress-related psychiatric diseases. PMID- 25506609 TI - Supernumerary teeth in Nepalese children. AB - OBJECTIVE: The objectives of the present study were to investigate the prevalence and characteristics of supernumerary teeth in a patient sample of Nepalese children. STUDY DESIGN: A survey was performed on 2684 patients (1829 females and 1035 males) ranging in age from 6 to 14 for the presence of supernumerary teeth. For each patient with supernumerary teeth the demographic variables (age and sex), number, location, eruption status, and morphology were recorded. Descriptive statistics were performed. RESULTS: Supernumerary teeth were detected in 46 subjects (1.6%), of which 26 were males and 20 were females with a male : female ratio of 1.3 : 1. The most commonly found supernumerary tooth was mesiodens followed by maxillary premolars, maxillary lateral incisor, and mandibular lateral incisor. Of the 55 supernumerary teeth examined, 58.18% (n = 32) had conical morphology, followed by tuberculate (30.90%, n = 17) and supplemental (10.90%, n = 6) forms. The majority of the supernumerary teeth were erupted (56.36%, n = 31). CONCLUSION: The prevalence of supernumerary teeth in Nepalese children was found to be 1.6%, the most frequent type being mesiodens. Conical morphology was found to be the most common form of supernumerary tooth. PMID- 25506608 TI - Ammonia diffusion through Nalophan double bags: effect of concentration gradient reduction. AB - The ammonia loss through Nalophan bags has been studied. The losses observed for storage conditions and times as allowed by the reference standard for dynamic olfactometry (EN 13725:2003) indicate that odour concentration values due to the presence of small molecules may be significantly underestimated if samples are not analysed immediately after sampling. A diffusion model was used in order to study diffusion through the bag. The study discusses the effect of concentration gradient (DeltaC) across the polymeric membrane of the analyte. The DeltaC was controlled by using a setup bag called "double bags." Experimental data show a reduction of ammonia percentage losses due to the effect of the external multibarrier. The expedient of the double bag loaded with the same gas mixture allows a reduced diffusion of ammonia into the inner bag. Comparing the inner bag losses with those of the single bag stored in the same conditions (T, P, u) and with equal geometrical characteristics (S/V, z), it was observed that the inner bag of the double bag displays a 16% loss while the single bag displays a 37% loss. Acting on the DeltaC it is possible to achieve a gross reduction of 57% in the ammonia leakage due to diffusion. PMID- 25506611 TI - Performance analysis for wireless networks: an analytical approach by multifarious Sym Teredo. AB - IPv4-IPv6 transition rolls out numerous challenges to the world of Internet as the Internet is drifting from IPv4 to IPv6. IETF recommends few transition techniques which includes dual stack and translation and tunneling. By means of tunneling the IPv6 packets over IPv4 UDP, Teredo maintains IPv4/IPv6 dual stack node in isolated IPv4 networks behindhand network address translation (NAT). However, the proposed tunneling protocol works with the symmetric and asymmetric NATs. In order to make a Teredo support several symmetric NATs along with several asymmetric NATs, we propose multifarious Sym Teredo (MTS), which is an extension of Teredo with a capability of navigating through several symmetric NATs. The work preserves the Teredo architecture and also offers a backward compatibility with the original Teredo protocol. PMID- 25506610 TI - The effect of different types of walking on dual-task performance and task prioritization among community-dwelling older adults. AB - BACKGROUND: The ability to safely conduct different types of walking concurrently with a cognitive task (i.e., dual task) is crucial for daily life. The contribution of different walking types to dual-task performance has not yet been determined, nor is there agreement on the strategies that older adults use to divide their attention between two tasks (task prioritization). OBJECTIVES: To compare the effect of walking in three different directions (forward, backward, and sideways) on dual-task performance and to explore the strategies of older adults to allocate their attention in response to different motor task demands. DESIGN: A cross-sectional study. SUBJECTS: Thirty-two (22 female) community dwelling older adults (aged 72.7+/-5.7 years). METHODS: Subjects randomly conducted single and dual task: walking to three directions separately, cognitive tasks separately, and combination of the two. RESULTS: Walking forward was the least demanding task, during single (FW < BW, SW) (P < .001) and dual tasks (FW < BW < SW) (P < .001). The calculation of DTC revealed the same pattern (P < .001). DTC of the cognitive tasks was not significantly different among the three walking types. CONCLUSIONS: The decline mainly in the motor performance during dual task indicates that participants prioritized the cognitive task. These findings challenge the "posture first" paradigm for task prioritization. PMID- 25506612 TI - Critical product features' identification using an opinion analyzer. AB - The increasing use and ubiquity of the Internet facilitate dissemination of word of-mouth through blogs, online forums, newsgroups, and consumer's reviews. Online consumer's reviews present tremendous opportunities and challenges for consumers and marketers. One of the challenges is to develop interactive marketing practices for making connections with target consumers that capitalize consumer to-consumer communications for generating product adoption. Opinion mining is employed in marketing to help consumers and enterprises in the analysis of online consumers' reviews by highlighting the strengths and weaknesses of the products. This paper describes an opinion mining system based on novel review and feature ranking methods to empower consumers and enterprises for identifying critical product features from enormous consumers' reviews. Consumers and business analysts are the main target group for the proposed system who want to explore consumers' feedback for determining purchase decisions and enterprise strategies. We evaluate the proposed system on real dataset. Results show that integration of review and feature-ranking methods improves the decision making processes significantly. PMID- 25506613 TI - Suicidal ideation and associated factors among adolescents in northeastern Brazil. AB - This study aimed to identify the prevalence and factors associated with suicidal ideation among Brazilian adolescents. The instrument designed for the research was used considering three models with outcomes that identified the following: (a) adolescent had considered suicide, (b) adolescents have planned suicide, and (c) adolescents have attempted suicide. Logistic Regression was used in all models with significance level of 5%. An association between being female and suicidal ideation (OR = 2.18, CI 95% 1.60 to 2.97), suicide planning (OR = 1.80, CI 95% = 1.26-2.56), and suicide attempt (OR = 2.91, CI 95% 1.79 to 4.75) was found. Violent behavior/involvement in fights was associated with thinking about suicide (OR = 2.00, CI 95% = 1.43 to 2.81), suicide planning (OR = 1.65, CI 95% = 1.10-2.46), and suicide attempt (OR = 2.35, CI 95% = 1.49 to 3.70). For cigarette consumption, association was found with suicide ideation (OR = 1.62, CI 95% 1.03 to 2.55), planning (OR = 1.88, CI 95% = 1.15 to 3.08), and attempt (OR = 2.35, CI 95% 1.37 to 4.03). For alcohol consumption, association was found with suicide ideation (OR = 1.93, CI 95% 1.47 to 2.54), planning (OR = 2.22, CI 95% 1.61 to 3.08), and attempt (OR = 1.73, CI 95% 1.15 to 2.59). It was concluded that suicidal ideation was associated with female sex, involvement in fights, and illicit drug use. PMID- 25506614 TI - Detection, characterization, and molecular typing of human Mycoplasma spp. from major hospitals in Cairo, Egypt. AB - Mycoplasmas are fastidious slow growing organisms lacking a cell wall and mostly isolated from the mucosal surfaces of the respiratory and genitourinary tracts. There is a dearth of information regarding clinical Mycoplasma spp. isolates among Egyptian patients. A total of 170 samples were collected from patients and apparently healthy personnel in local public hospitals in Cairo, Egypt. Isolation of Mycoplasma spp. was carried out using appropriate culture media and further identification was carried out by biochemical tests followed by serotyping using specific antisera. Confirmation was done by PCR for detection of different Mycoplasma spp. using genus-specific primers targeting 16S ribosomal RNA gene. Characterization of the antibiotic resistance and sensitivity pattern against different antimicrobials was carried out using disc diffusion test. The results indicated the presence of six Mycoplasma spp. in 22.94% of the samples. Mycoplasmas were detected more frequently in throat swabs than sputum. Mycoplasma pneumoniae was highly sensitive to macrolides and quinolones but less sensitive to aminoglycosides and tetracyclines. Molecular techniques were found to be of more rapid, highly sensitive, able to detect nonviable organisms, and cost effective. These results shed light on difficulties of Mycoplasma detection and the superiority of molecular techniques over culture. PMID- 25506615 TI - Facile synthesis of pyrazole- and benzotriazole-containing selenoethers. AB - Azole-containing selenoethers, 1,5-bis(3,5-dimethylpyrazol-1-yl)-3-selena pentane and 1,3-bis(1,2,3-benzotriazol-1-yl)-2-selena propane were prepared by the reaction of corresponding tosylate or chloride with sodium selenide generated in situ from elemental selenium and sodium formaldehydesulfoxylate (rongalite). PMID- 25506616 TI - Virtual visits in home health care for older adults. AB - BACKGROUND: This review identifies the content of virtual visits in community nursing services to older adults and explores the manner in which service users and the nurses use virtual visits. DESIGN: An integrative literature review. METHOD: Data collection comprised a literature search in three databases: Cinahl, Medline, and PubMed. In addition, a manual search of reference lists and expert consultation were performed. A total of 12 articles met the inclusion criteria. The articles were reviewed in terms of study characteristics, service content and utilization, and patient and health care provider experience. RESULTS: Our review shows that in most studies the service is delivered on a daily basis and in combination with in-person visits. The findings suggest that older home-dwelling patients can benefit from virtual visits in terms of enhanced social inclusion and medication compliance. Service users and their nurses found virtual visits satisfactory and suitable for care delivery in home care to the elderly. Evidence for cost-saving benefits of virtual visits was not found. CONCLUSIONS: The findings can inform the planning of virtual visits in home health care as a complementary service to in-person visits, in order to meet the increasingly complex needs of older adults living at home. PMID- 25506617 TI - Clinical trials of immunogene therapy for spontaneous tumors in companion animals. AB - Despite the important progress obtained in the treatment of some pets' malignancies, new treatments need to be developed. Being critical in cancer control and progression, the immune system's appropriate modulation may provide effective therapeutic options. In this review we summarize the outcomes of published immunogene therapy veterinary clinical trials reported by many research centers. A variety of tumors such as canine melanoma, soft tissue sarcomas, osteosarcoma and lymphoma, feline fibrosarcoma, and equine melanoma were subjected to different treatment approaches. Both viral and mainly nonviral vectors were used to deliver gene products as cytokines, xenogeneic tumor associated antigens, specific ligands, and proapoptotic regulatory factors. In some cases autologous, allogenic, or xenogeneic transgenic cytokine producing cells were assayed. In general terms, minor or no adverse collateral effects appeared during this kind of therapies and treated patients usually displayed a better course of the disease (longer survival, delayed or suppressed recurrence or metastatic spread, and improvement of the quality of life). This suggests the utility of these methodologies as standard adjuvant treatments. The encouraging outcomes obtained in companion animals support their ready application in veterinary clinical oncology and serve as preclinical proof of concept and safety assay for future human gene therapy trials. PMID- 25506618 TI - Does motor training of the nonparetic side influences balance and function in chronic stroke? A pilot RCT. AB - BACKGROUND: Balance and functional abilities are controlled by both sides of the body. The role of nonparetic side has never been explored for such skills. OBJECTIVE: The objective of the present study was to examine the effect of a motor therapy program primarily involving the nonparetic side on balance and function in chronic stroke. METHOD: A randomized controlled, double blinded trial was conducted on 39 poststroke hemiparetic subjects (21, men; mean age, 42 years; mean poststroke duration, 13 months). They were randomly divided into the experimental group (n = 20) and control group (n = 19). The participants received either motor therapy focusing on the nonparetic side along with the conventional program or conventional program alone for 8 weeks (3 session/week, 60 minutes each). The balance ability was assessed using Berg Balance Scale (BBS) and Functional Reach Test (FRT) while the functional performance was measured by Barthel Index (BI). RESULT: After intervention, the experimental group exhibited significant (P < 0.05) change on BBS (5.65 versus 2.52) and BI (12.75 versus 2.16) scores in comparison to the control group. CONCLUSION: The motor therapy program incorporating the nonparetic side along with the affected side was found to be effective in enhancing balance and function in stroke. PMID- 25506620 TI - Evaluation of selected honey and one of its phenolic constituent eugenol against L1210 lymphoid leukemia. AB - People affected with leukemia are on the rise and several strategies were employed to thwart this deadly disease. Recent decade of research focuses on phenolic constituents as a tool for combating various inflammatory, cancer, and cardiac diseases. Our research showed honey and its phenolic constituents as crusaders against cancer. In this work, we explored the antileukemic activity of selected honey and one of its phenolic constituent eugenol against L1210 leukemia animal model. Results of this experiment showed that the selected honey samples as well as eugenol after intraperitoneal injection could not increase the median survival time (MST) of animals. Further, there was only slight marginal increase in the %T/C values of honey and eugenol treated groups. The number of phenolics present in the honey may not be a prime factor to promote antileukemic effect since there was no difference in the MST of two different honeys tested. This study limits the use of selected honey and eugenol against leukemia animal model. PMID- 25506619 TI - Antinociceptive and anti-inflammatory activities of Bridelia retusa methanolic fruit extract in experimental animals. AB - Antinociceptive and anti-inflammatory potentials of methanolic extract of Bridelia retusa fruit (BRME) were evaluated against different animal models in rodents. Antinociceptive effects of BRME were assessed in mice using the acetic acid-induced writhing and formalin test. Anti-inflammatory effects of BRME in three different doses, namely, 100, 200, and 400 mg/kg, were evaluated by utilizing different animal models representing various changes associated with inflammation, namely, carrageenan-induced paw oedema, histamine and serotonin induced paw oedema, arachidonic acid-induced paw oedema, formalin-induced paw oedema, TPA-induced ear oedema, acetic acid-induced vascular permeability, total WBC count in paw fluid, and myeloperoxidase assay. Also BRME was phytochemically evaluated using chromatographic method. The BRME did not exhibit any signs of toxicity up to a dose of 2000 mg/kg. The extract showed statistical significant inhibition of induced nociception and inflammation in dose dependent manner. The higher dose of extract significantly inhibited pain and inflammation against control (P < 0.001). HPLC results revealed the presence of gallic acid and ellagic acid as phytoconstituents in BRME and it was proven as anti-inflammatory agents. The present study scientifically demonstrated the antinociceptive and anti-inflammatory potential of fruit of B. retusa methanolic extract. These effects may be attributed to the presence of polyphenolic phytoconstituents in the extract. PMID- 25506621 TI - Coefficient bounds for some families of starlike and convex functions of reciprocal order. AB - The aim of the present paper is to investigate coefficient estimates, Fekete Szego inequality, and upper bound of third Hankel determinant for some families of starlike and convex functions of reciprocal order. PMID- 25506622 TI - Mixed-Effects Shape Models for Estimating Longitudinal Changes in Anatomy. AB - In this paper, we propose a new method for longitudinal shape analysis that fits a linear mixed-effects model, while simultaneously optimizing correspondences on a set of anatomical shapes. Shape changes are modeled in a hierarchical fashion, with the global population trend as a fixed effect and individual trends as random effects. The statistical significance of the estimated trends are evaluated using specifically designed permutation tests. We also develop a permutation test based on the Hotelling T2 statistic to compare the average shapes trends between two populations. We demonstrate the benefits of our method on a synthetic example of longitudinal tori and data from a developmental neuroimaging study. PMID- 25506624 TI - Associations between showering behaviours following physical education, physical activity and fitness in English schoolchildren. AB - We aimed to describe the frequency of showering after physical education (PE) in English high-school pupils. We examined differences in physical activity (PA) and cardiorespiratory fitness according to showering behaviours and examined predictors of showering. We measured PA and cardiorespiratory fitness of n = 3921 pupils (11-16 years, 53.5% males) from eight high schools. Pupils self-reported showering behaviour and parental PA levels. We calculated deprivation and distance travelled to school from their home postcode. Overall, 53% of boys and 68% of girls said they never shower after PE. Pupils who did not shower after PE were less physically active and engaged in fewer team sports. Girls who did not shower also had lower cardiorespiratory fitness than those who did. Showering behaviour varied greatly by school, so we adjusted for clustering at the school level. Pupils were more likely to shower if they were active with their parents [odds ratio (OR) = 1.72; 95% CI: 1.43, 2.07] and less likely to shower if they were from deprived areas (OR = 0.68; 95% CI: 0.52, 0.88). Showering after PE is relatively rare in English schoolchildren, particularly girls. While we cannot infer causality regarding the relationships found here, the low rates of showering and the lower PA and cardiorespiratory fitness (in girls) observed in schoolchildren who do not shower suggest research is needed to determine whether showering is a barrier to being physically active during PE. PMID- 25506625 TI - Synthesis of chromeno[2,3-b]indol-11(6H)-one via PhI(OAc)2-mediated intramolecular oxidative C(sp(2))-N(H2) bond formation. AB - Various chromeno[2,3-b]indol-11(6H)-ones were conveniently constructed via phenyliodine(III) diacetate (PIDA)-mediated intramolecular oxidative annulation. This method, while realizing a direct oxidative C-N bond formation between an aromatic ring and a pendent free-NH2 moiety, features a metal-free protocol, mild reaction conditions, simple workup, and the ready availability of the starting substrates. PMID- 25506626 TI - Bacterial protoplast-derived nanovesicles as vaccine delivery system against bacterial infection. AB - The notion that widespread infectious diseases could be best managed by developing potent, adjuvant-free vaccines has resulted in the use of various biological immune-stimulating components as new vaccine candidates. Recently, extracellular vesicles, also known as exosomes and microvesicles in mammalian cells and outer membrane vesicles in Gram-negative bacteria, have gained attention for the next generation vaccine. However, the more invasive and effective the vaccine is in delivery, the more risk it holds for severe immune toxicity. Here, in optimizing the current vaccine delivery system, we designed bacterial protoplast-derived nanovesicles (PDNVs), depleted of toxic outer membrane components to generate a universal adjuvant-free vaccine delivery system. These PDNVs exhibited significantly higher productivity and safety than the currently used vaccine delivery vehicles and induced strong antigen-specific humoral and cellular immune responses. Moreover, immunization with PDNVs loaded with bacterial antigens conferred effective protection against bacterial sepsis in mice. These nonliving nanovesicles derived from bacterial protoplast open up a new avenue for the creation of next generation, adjuvant-free, less toxic vaccines to be used to prevent infectious diseases. PMID- 25506627 TI - Fluorogenic squaraine dimers with polarity-sensitive folding as bright far-red probes for background-free bioimaging. AB - Polarity-sensitive fluorogenic dyes raised considerable attention because they can turn on their fluorescence after binding to biological targets, allowing background-free imaging. However, their brightness is limited, and they do not operate in the far-red region. Here, we present a new concept of fluorogenic dye based on a squaraine dimer that unfolds on changing environment from aqueous to organic and thus turns on its fluorescence. In aqueous media, all three newly synthesized dimers displayed a short wavelength band characteristic of an H aggregate that was practically nonfluorescent, whereas in organic media, they displayed a strong fluorescence similar to that of the squaraine monomer. For the best dimer, which contained a pegylated squaraine core, we obtained a very high turn-on response (organic vs aqueous) up to 82-fold. Time-resolved studies confirmed the presence of nonfluorescent intramolecular H-aggregates that increased with the water content. To apply these fluorogenic dimers for targeted imaging, we grafted them to carbetocin, a ligand of the oxytocin G protein coupled receptor. A strong receptor-specific signal was observed for all three conjugates at nanomolar concentrations. The probe derived from the core-pegylated squaraine showed the highest specificity to the target receptor together with minimal nonspecific binding to serum and lipid membranes. The obtained dimers can be considered as the brightest polarity-sensitive fluorogenic molecules reported to date, having ~660,000 M(-1) cm(-1) extinction coefficient and up to 40% quantum yield, whereas far-red operation region enables both in vitro and in vivo applications. The proposed concept can be extended to other dye families and other membrane receptors, opening the route to new ultrabright fluorogenic dyes. PMID- 25506628 TI - High-throughput platform assay technology for the discovery of pre-microrna selective small molecule probes. AB - MicroRNAs (miRNA) play critical roles in human development and disease. As such, the targeting of miRNAs is considered attractive as a novel therapeutic strategy. A major bottleneck toward this goal, however, has been the identification of small molecule probes that are specific for select RNAs and methods that will facilitate such discovery efforts. Using pre-microRNAs as proof-of-concept, herein we report a conceptually new and innovative approach for assaying RNA small molecule interactions. Through this platform assay technology, which we term catalytic enzyme-linked click chemistry assay or cat-ELCCA, we have designed a method that can be implemented in high throughput, is virtually free of false readouts, and is general for all nucleic acids. Through cat-ELCCA, we envision the discovery of selective small molecule ligands for disease-relevant miRNAs to promote the field of RNA-targeted drug discovery and further our understanding of the role of miRNAs in cellular biology. PMID- 25506629 TI - Positive Surgical Margin Trends in Patients with Pathologic T3 Prostate Cancer Treated with Robot-Assisted Radical Prostatectomy. AB - INTRODUCTION: We analyzed the trends of positive surgical margin (PSM) location in patients who had pT3 disease at robot-assisted radical prostatectomy (RARP). We aimed to describe our changing incidence of PSMs in the largest series to date of patients with pT3 disease who were treated by RARP. METHODS: A single institution, single-surgeon review was performed of all patients who underwent RARP from 2005 to 2011. Perioperative data were collected for all patients with pT3 prostate cancer from a prospectively maintained RARP database. The PSM incidence and rates were stratified by location. The PSM rates per location were trended over time. RESULTS: In total, 2478 consecutive patients underwent RARP between July 2005 and December 2011. Of these patients, 555 were found to have pT3 disease. The PSM rate for patients with pT3 disease was 47%. The PSM rate for patients with pT3a and pT3B disease was 42.8% and 60.6%, respectively. Over the duration of this study, the PSM rate in patients with pT3 disease decreased significantly from 70.6% in 2005 to 32.3% in 2011 (p=0.002). The apical PSM rate showed the greatest decrease during this period going from 52.9% in 2005 to 5.2% in 2011 (p=0.018). CONCLUSION: We present the largest series to date involving the treatment of locally advanced prostate cancer initially managed with RARP. Our findings suggest that patients with locally advanced prostate cancer can be treated with RARP with acceptable positive margin rates. Overall PSM rates improved nearly 40% over the 6.5-year period of this study. PMID- 25506630 TI - Frontal brain deactivation during a non-verbal cognitive judgement bias test in sheep. AB - Animal welfare concerns have raised an interest in animal affective states. These states also play an important role in the proximate control of behaviour. Due to their potential to modulate short-term emotional reactions, one specific focus is on long-term affective states, that is, mood. These states can be assessed by using non-verbal cognitive judgement bias paradigms. Here, we conducted a spatial variant of such a test on 24 focal animals that were kept under either unpredictable, stimulus-poor or predictable, stimulus-rich housing conditions to induce differential mood states. Based on functional near-infrared spectroscopy, we measured haemodynamic frontal brain reactions during 10 s in which the sheep could observe the configuration of the cognitive judgement bias trial before indicating their assessment based on the go/no-go reaction. We used (generalised) mixed-effects models to evaluate the data. Sheep from the unpredictable, stimulus poor housing conditions took longer and were less likely to reach the learning criterion and reacted slightly more optimistically in the cognitive judgement bias test than sheep from the predictable, stimulus-rich housing conditions. A frontal cortical increase in deoxy-haemoglobin [HHb] and a decrease in oxy haemoglobin [O2Hb] were observed during the visual assessment of the test situation by the sheep, indicating a frontal cortical brain deactivation. This deactivation was more pronounced with the negativity of the test situation, which was reflected by the provenance of the sheep from the unpredictable, stimulus poor housing conditions, the proximity of the cue to the negatively reinforced cue location, or the absence of a go reaction in the trial. It seems that (1) sheep from the unpredictable, stimulus-poor in comparison to sheep from the predictable, stimulus-rich housing conditions dealt less easily with the test conditions rich in stimuli, that (2) long-term housing conditions seemingly did not influence mood--which may be related to the difficulty of tracking a constant long-term state in the brain--and that (3) visual assessment of an emotional stimulus leads to frontal brain deactivation in sheep, specifically if that stimulus is negative. PMID- 25506632 TI - Comparative long-term toxicity of Libby amphibole and amosite asbestos in rats after single or multiple intratracheal exposures. AB - In former mine workers of Libby, MT, exposure to amphibole-containing vermiculite was linked to increased rates of asbestosis, lung cancer, and mesothelioma. Although many studies showed adverse effects following exposure to Libby amphibole (LA; a mixture of winchite, richterite, and tremolite), little is known regarding the relative toxicity of LA compared to regulated asbestos, or regarding the risks associated with acute high-dose exposures relative to repeated low-dose exposures. In this study, pulmonary function, inflammation, and pathology were assessed after single or multiple intratracheal (IT) exposures of LA or a well-characterized amosite (AM) control fiber with equivalent fiber characteristics. Male F344 rats were exposed to an equivalent total mass dose (0.15, 0.5, 1.5, or 5 mg/rat) of LA or AM administered either as a single IT instillation, or as multiple IT instillations given every other week over a 13-wk period, and necropsied up to 20 mo after the initial IT. When comparing the two fiber types, in both studies LA resulted in greater acute neutrophilic inflammation and cellular toxicity than equal doses of AM, but long-term histopathological changes were approximately equivalent between fibers, suggesting that LA is at least as toxic as AM. In addition, although no dose response relationship was discerned, mesothelioma or lung carcinomas were found after exposure to low and high dose levels of LA or AM in both studies. Conversely, when comparing studies, an equal mass dose given over multiple exposures instead of a single bolus resulted in greater chronic pathological changes in lung at lower doses, despite the initially weaker acute inflammatory response. Overall, these results suggest that there is a possibility of greater long-term pathological changes with repeated lower LA dose exposures, which more accurately simulates chronic environmental exposures. PMID- 25506631 TI - Longevity and determinants of protective humoral immunity after pandemic influenza infection. AB - RATIONALE: Antibodies to influenza hemagglutinin are the primary correlate of protection against infection. The strength and persistence of this immune response influences viral evolution and consequently the nature of influenza epidemics. However, the durability and immune determinants of induction of humoral immunity after primary influenza infection remain unclear. OBJECTIVES: The spread of a novel H1N1 (A[H1N1]pdm09) virus in 2009 through an unexposed population offered a natural experiment to assess the nature and longevity of humoral immunity after a single primary influenza infection. METHODS: We followed A(H1N1)pdm09-seronegative adults through two influenza seasons (2009-2011) as they developed A(H1N1)pdm09 influenza infection or were vaccinated. Antibodies to A(H1N1)pdm09 virus were measured by hemagglutination-inhibition assay in individuals with paired serum samples collected preinfection and postinfection or vaccination to assess durability of humoral immunity. Preexisting A(H1N1)pdm09 specific multicytokine-secreting CD4 and CD8 T cells were quantified by multiparameter flow cytometry to test the hypothesis that higher frequencies of CD4(+) T-cell responses predict stronger antibody induction after infection or vaccination. MEASUREMENTS AND MAIN RESULTS: Antibodies induced by natural infection persisted at constant high titer for a minimum of approximately 15 months. Contrary to our initial hypothesis, the fold increase in A(H1N1)pdm09 specific antibody titer after infection was inversely correlated to the frequency of preexisting circulating A(H1N1)pdm09-specific CD4(+)IL-2(+)IFN-gamma(-)TNF alpha(-) T cells (r = -0.4122; P = 0.03). CONCLUSIONS: The longevity of protective humoral immunity after influenza infection has important implications for influenza transmission dynamics and vaccination policy, and identification of its predictive cellular immune correlate could guide vaccine development and evaluation. PMID- 25506633 TI - Effects of intravenous benzo[a]pyrene dose administration on levels of exposure biomarkers, DNA adducts, and gene expression in rats. AB - The effects of benzo[a]pyrene (BaP) administration on biomarkers of exposure and early effects were studied in male Sprague-Dawley rats intravenously injected with doses of 0.4, 4, 10, or 40 MUmol BaP/kg . Blood, tissues, and excreta were collected 8 and 24 h posttreatment. BaP and several of its metabolites were simultaneously measured in blood, tissues and excreta by ultra-high-performance liquid chromatography (UHPLC)/fluorescence. DNA adducts of BaP diol epoxide (BaPDE) in lungs were quantified using an ultrasensitive immunoassay with chemiluminescence detection. Expression of selected genes in lungs of treated rats (lung RNA) compared to control rats was also assessed by quantitative real time polymerase chain reaction. There was a dose-dependent increase in blood, tissue, and excreted levels of BaP metabolites. At 8 and 24 h postinjection, BaP and hydroxyBaP were found in higher concentrations in blood and tissues compared to other analytes. However, diolBaP were excreted in greater amounts in urine and apparently more rapidly than hydroxyBaP. Mean percentages (+/- SD) of injected dose excreted in urine as 4,5-diolBaP during the 0-8 h and 0-24 h period posttreatment were 0.16 +/- 0.027% and 0.14 +/- 0.083%, respectively. Corresponding values for 3-OHBaP were 0.0045 +/- 0.0009% and 0.026 +/- 0.014%. BaP-diones were not detectable in blood, tissues, and excreta; 7,8-diolBaP and BaPtetrol were found to be minor metabolites. There was also a dose-dependent increase in DNA adduct formation in lung. Analysis of gene expression further showed a modulation of Cyp1a1, Cyp1b1, Nqo1, Nrf2, Fos, and Ahr expression at 10- and 40-MUmol/kg doses, but not at the lower doses. This study provided a better assessment of the influence of absorbed BaP doses on biological levels of diolBaP and OHBaP exposure biomarkers and association of the latter with early biological alterations, such as DNA adducts and gene expression. PMID- 25506634 TI - Determination of adsorption affinity of nanoparticles for interleukin-8 secreted from A549 cells by in vitro cell-free and cell-based assays. AB - The evaluation of the potential of nanoparticles (NP) for adsorbing biomolecules and use of control approaches are important for accurate presentation of in vitro analytical data. In this study, seven types of NP including carbon black (CB), cerium dioxide (CeO2), copper oxide (CuO), indium trioxide (In2O3), nickel oxide (NiO), silicon dioxide (SiO2), and titanium dioxide (TiO2) were used for determining the adsorption ability of interleukin-8 (IL-8) under either (1) a cell-free condition where NP were incubated with supernatant of A549 cells, or (2) a cell-based condition, where cells were treated with NP. Under the cell-free condition, CB and TiO2 NP showed a high adsorption affinity for IL-8 in supernatants of both lipopolysaccharide (LPS)-stimulated and unstimulated A549 cells. In contrast, SiO2 and In2O3 NP displayed a relatively low adsorption affinity. Further, IL-8 adsorption was markedly reduced when NP were predispersed in fetal bovine serum. The results obtained under cell-based conditions using both stimulated and unstimulated cells were consistent with those of the cell free condition. Data indicate that adsorption of IL-8 onto NP surface is variable depending on type of NP, preparation method of NP, and cellular inflammatory state. Thus, the cell-free adsorption assay may be utilized for reliable interpretation of data produced by in vitro cell-based methodology. PMID- 25506635 TI - Factors influencing stable isotopes and growth of algae in oil sands aquatic reclamation. AB - Previous studies reported (15)N enrichment of biota in reclamation wetlands that contain oil sands processed material (e.g., processed water and tailings); however, there is little information on the factors controlling (15)N enrichment in these systems. In this microcosm study, the aim was to examine stable C and N isotopes and growth (chlorophyll a [chl a] and dry weight) of algae as a function of exposure to different sources and concentrations of water-soluble fractions (WSF) derived from tailings. Two sources of tailings including mature fine tailings (MFT) and consolidated tailings (CT) and peat-mineral overburden were utilized to generate separate WSF that differed in water quality. In general, there was (15)N enrichment of filamentous algae along the increasing gradient of WSF/nutrient concentrations in both CT and peat microcosms, and among the different sources, algae were more (15)N enriched in CT WSF than in peat WSF. Growth of filamentous algae was inhibited at higher WSF concentrations, possibly due to reduced light availability at elevated levels of fine clay particles in MFT microcosms and colored dissolved organic carbon (DOC) in peat microcosms. Filamentous algae displayed lower biomass and (15)N depletion in 100% peat WSF. This study indicated that both the quality (source) and quantity of WSF affected algal growth and directly and/or indirectly influenced delta(15)N of algae. The distinct (15)N enrichment of primary producers derived from tailings suggest that stable N isotopes might be useful to trace exposure to oil sands processed material in biota that utilize these resources in reclaimed systems constructed with tailings or natural systems that receive tailings dyke seepage. PMID- 25506636 TI - Engaged patients, engaged partnerships: singles and partners dealing with an acute cardiac event. AB - A few studies examine patients' (and partners') individual and relational functioning after an acute cardiac event and no research focuses on the individual and relational factors associated with the patient's engagement in his/her disease management. The present study aimed at exploring these variables in male and female patients as well as their partners. We pursued our objectives by taking advantage of a dyadic research design that involved both partners in the data collection, when present, and by including women patients in the sample. Findings showed that patients in a couple, compared to single patients, perceive that their illness had less serious consequences for their life and they were more engaged in their health care; that patients and partners showed comparable levels of distress; and that less depressed, more confident, and better informed patients were more likely to actively engage in their treatment. Findings are discussed in light of their implications for clinical practice. PMID- 25506637 TI - Genotoxicity assessment of TiO2 nanoparticles in the teleost Danio rerio. AB - Titanium dioxide nanoparticles (TiO2 NPs), widely used in paints, pharmaceutical preparations and in many consumer products, have been shown to induce cytotoxicity, genotoxicity and carcinogenic responses both in vitro and in vivo. Numerous studies have shown the potential impact of nanoparticles on a series of aquatic organisms and their toxicity has been linked to their dissolution, surface properties and size. In vitro studies have raised concerns about the toxicity of TiO2 NPs, but there are very limited data on ecotoxicity to aquatic life. This in vivo study aimed to describe the genotoxicity of TiO2 NPs in the zebrafish Danio rerio. After 2 weeks of adaptation, groups of zebrafish were exposed to TiO2 NPs (1 and 10MUg/L) for 5, 7, 14, 21 and 28 days. The genotoxic potential of TiO2 NPs was assessed by the Comet assay, the Diffusion assay and RAPD-PCR technique. The use of multi-biomarkers has become an important aspect of ecotoxicology to evaluate environmental quality through a wide panel of biological responses triggered by contaminants. The highest genotoxic effect was observed at the maximum concentrations of nanoparticles (10MUg/L) with all three tests at 14 and 21 days of exposure. The results suggests the presence of mechanisms that can reduce the n-TiO2 genotoxicity. Future studies are necessary to analyze the DNA repairing capacity in zebrafish cells and so verify the role of the antioxidant defence system in modulating the response to exposure to n TiO2 in fish. PMID- 25506638 TI - Effects of aging on pointing movements under restricted visual feedback conditions. AB - The goal of this study was to investigate the effects of aging on pointing movements under restricted visual feedback of hand movement and target location. Fifteen young subjects and fifteen elderly subjects performed pointing movements under four restricted visual feedback conditions that included full visual feedback of hand movement and target location (FV), no visual feedback of hand movement and target location condition (NV), no visual feedback of hand movement (NM) and no visual feedback of target location (NT). This study suggested that Fitts' law applied for pointing movements of the elderly adults under different visual restriction conditions. Moreover, significant main effect of aging on movement times has been found in all four tasks. The peripheral and central changes may be the key factors for these different characteristics. Furthermore, no significant main effects of age on the mean accuracy rate under condition of restricted visual feedback were found. The present study suggested that the elderly subjects made a very similar use of the available sensory information as young subjects under restricted visual feedback conditions. In addition, during the pointing movement, information about the hand's movement was more useful than information about the target location for young and elderly subjects. PMID- 25506639 TI - Management of soft tissue irritation around exposed zygomatic implant in a hemimaxillectomy patient: a technical report. AB - Patients missing portions or all of the maxillary alveolar bone who are restored with zygomatic implants frequently have threads exposed that can be a mucosal irritant. If such irritation is reported, covering the threads with a highly polished titanium sleeve is recommended. The technique of placing said custom sleeve is described. This adjunctive treatment method has eliminated mucosal irritation. PMID- 25506640 TI - Crestal bone remodeling around implants placed using a short drilling protocol. AB - PURPOSE: The aim of the study was to examine the influence of a short drilling protocol on peri-implant crestal bone levels. MATERIALS AND METHODS: Forty implants were placed in the posterior mandibles of 20 patients. The implants (diameter, 4.2 mm; length, 10 to 11.5 mm) were inserted in pairs: one implant was inserted using the standard drilling protocol (five drills in sequence), while the other was inserted using the short drilling protocol sequence (three drills). All implants received healing abutments and were restored with single-unit restorations after 3 months of healing. Analysis of crestal bone level was based on radiographs taken at insertion and at 3, 6, and 12 months after insertion. The results were analyzed using software Image J 1.46r (National Institutes of Health). Crestal bone level was measured in millimeters at the distal aspect of each implant. RESULTS: None of the implants in either group was lost during the 12-month follow-up period, and all patients completed the follow-up examination. The drilling time for the insertion of one implant with the short drilling protocol was 1.03 +/- 3.63 minutes compared to 1.57 +/- 2.88 minutes for the standard protocol. The mean values of crestal bone loss at 12 months were 0.94 +/ 0.43 mm for implants placed using the standard protocol and 0.90 +/- 0.33 mm for implants placed using the short drilling protocol. No statistically significant differences were noted. CONCLUSION: Using the short drilling protocol reduced the surgery time by approximately 50% and did not affect crestal bone remodeling during the first year postinsertion. PMID- 25506642 TI - Long-Term Results of Mandibular Reconstruction of Continuity Defects with Fibula Free Flap and Implant-Borne Dental Rehabilitation. AB - Purpose: This study evaluated the retrospective outcomes of implant-borne dental rehabilitation in patients with mandibular defects reconstructed with a fibula free flap. Materials and Methods: Patients with segmental mandibular defects were enrolled in this cohort study. Defects in these patients were caused by oral neoplasm, trauma, and osteoradionecrosis. The patients were treated with a fibula free flap procedure and dental implant-borne prostheses between 1988 and 2010. Clinical and radiographic data were evaluated; Kaplan-Meier survival analysis and Poisson regression analysis were used to evaluate implant survival parameters. The statistical significance (alpha = .05) of the results was determined. Results: Seventy-four patients were selected in this study. All patients were available for continuous follow-up. Nine patients (12.1%) developed fibular graft complications postoperatively: 3 in donor sites and 6 in recipient sites. One hundred ninety-two implants were inserted, and 18 implants failed (9.3%). Overall implant survival in patients was 90.1%, 83.1%, and 69.3% after 5, 10, and 20 years, respectively. In 152 implants, probing depth (PD) ranged from 2 to 3 mm. In 31 implants, PD was greater than 5 mm. In 9 implants, PD was greater than 7 mm. The highest implant failure rates were expected for men (odds ratio [OR] = 2.948; 95% confidence interval [CI], 1.10 to 7.85; P = .031), patients receiving primary fibula free flap reconstruction (OR = 3.696; 95% CI,1.16 to 11.73; P = .027), and patients receiving radiotherapy (OR = 5.269; 95% CI, 1.40 to 19.7; P = .014). Conclusion: Fibula free flap procedures and implant-borne prostheses proved to be reliable approaches for rehabilitation of mandibular defects and oral function. The overall postoperative fibula free flap and peri-implant complication rates proved to be low. Regular follow-up visits and proper oral hygiene maintenance contributed to the long-term successful treatments. PMID- 25506641 TI - Implant therapy in a surgical specialty clinic: an analysis of patients, indications, surgical procedures, risk factors, and early failures. AB - PURPOSE: The aim of this study was to analyze the patient pool referred to a specialty clinic for implant surgery over a 3-year period. MATERIALS AND METHODS: All patients receiving dental implants between 2008 and 2010 at the Department of Oral Surgery and Stomatology were included in the study. As primary outcome parameters, the patients were analyzed according to the following criteria: age, sex, systemic diseases, and indication for therapy. For the inserted implants, the type of surgical procedure, the types of implants placed, postsurgical complications, and early failures were recorded. A logistic regression analysis was performed to identify possible local and systemic risk factors for complications. As a secondary outcome, data regarding demographics and surgical procedures were compared with the findings of a historic study group (2002 to 2004). RESULTS: A total of 1,568 patients (792 women and 776 men; mean age, 52.6 years) received 2,279 implants. The most frequent indication was a single-tooth gap (52.8%). Augmentative procedures were performed in 60% of the cases. Tissue level implants (72.1%) were more frequently used than bone-level implants (27.9%). Regarding dimensions of the implants, a diameter of 4.1 mm (59.7%) and a length of 10 mm (55.0%) were most often utilized. An early failure rate of 0.6% was recorded (13 implants). Patients were older and received more implants in the maxilla, and the complexity of surgical interventions had increased when compared to the patient pool of 2002 to 2004. CONCLUSION: Implant therapy performed in a surgical specialty clinic utilizing strict patient selection and evidence-based surgical protocols showed a very low early failure rate of 0.6%. PMID- 25506643 TI - Assessment of the effect of chemical agents used in dentistry on the removal of Porphyromonas gingivalis and Escherichia coli from sandblasted acid-etched titanium dental implants: an in vitro study. AB - PURPOSE: The aim of this study was to evaluate the capability of chemicals to decontaminate Escherichia coli (E coli) or Porphyromonas gingivalis (P gingivalis) from sandblasted acid-etched (SAE) titanium dental implants. MATERIALS AND METHODS: SAE titanium dental implants were contaminated with E coli or P gingivalis and incubated in a sterile bacterial culture media under aerobic and anaerobic conditions, respectively. The implants were treated with 10 different conditions: calcium hydroxide [Ca(OH)2] paste for 1 minute and saline irrigation for 1 minute; Ca(OH)2 paste for 1 minute and 0.2% chlorhexidine digluconate (CHXD) irrigation for 1 minute; 0.2% CHXD for 1 minute; Dakin's solution for 1 minute; tetracycline hydrochloride (T-HCl) as a 1 g per 20 mL solution for 1, 2, and 3 minutes; and T-HCl paste for 1, 2, and 3 minutes. All implants were irrigated with 1 mL of saline solution and incubated under aerobic and anaerobic conditions for 24 hours or 48 hours for E coli- and P gingivalis contaminated implants, respectively. The control group was submitted to all procedures except for the chemical treatments. Aliquots were removed, and turbidity was measured by spectrophotometry. The level of bacterial growth in control cultures was considered to have a decontamination percentage (DC%) of 0. RESULTS: Spectrophotometric analysis showed that all chemical treatments resulted in significantly higher DC% compared to controls for SAE implants contaminated with E coli (P < .05) or P gingivalis (P < .05). For the P gingivalis experiments, SAE implants treated with Ca(OH)2 paste and saline solution had a lower DC% (39.3%) than those in the other treatment groups. In the E coli experiments, DC% was significantly lower for SAE implants treated with Ca(OH)2 paste and saline solution (48.7%), Dakin's solution (92.7%), or T-HCl paste for 1 minute (96.6%) than those in the other groups. CONCLUSION: The DC% of SAE implants contaminated with E coli or P gingivalis by means of chemicals commonly used in dentistry is high, with the exception of Ca(OH)2 paste burnished for 1 minute and then irrigated with saline solution for 1 minute. PMID- 25506644 TI - The influence of momentary retention forces on patient satisfaction and quality of life of two-implant-retained mandibular overdenture wearers. AB - PURPOSE: The purpose of this study was to assess the influence of momentary retention forces on patient satisfaction and quality of life of two-implant retained mandibular overdenture wearers. MATERIALS AND METHODS: Edentulous patients who had been rehabilitated with two-implant-supported mandibular overdentures with single attachments and maxillary complete dentures at a university clinic were included in this study. The overdenture attachments were either ball or locator attachments. All the patients completed the Turkish version of the Oral Health Impact Profile-14 (OHIP-14) and the visual analog scale (VAS) satisfaction questionnaires. Momentary retention forces of the overdentures were measured using a custom-made dynamic testing machine. RESULTS: Fifty-five patients were included in this study. No statistically significant association was detected between momentary retention forces and VAS scores (P > .05), but higher retention forces presented significantly better quality of life scores in the social disability and handicap domains of OHIP-14 (P < .05). CONCLUSION: Within the limitations of this clinical study, it may be presumed that although higher instant retention force of an implant-retained overdenture provides better quality of life, it does not affect patient satisfaction. PMID- 25506645 TI - Evaluation of the three-dimensional accuracy of implant impression techniques in two simulated clinical conditions by optical scanning. AB - PURPOSE: The success of an implant-supported prosthesis is dependent on the passive fit of its framework fabricated on a precise cast. The aim of this in vitro study was to digitally compare the three-dimensional accuracy of implant impression techniques in partially and completely edentulous conditions. MATERIALS AND METHODS: The master model simulated two clinical conditions. The first condition was a partially edentulous mandibular arch with an anterior edentulous space (D condition). Two implant analogs were inserted in bilateral canine sites. After elimination of the teeth, the model was converted to a completely edentulous condition (E condition). Three different impression techniques were performed (open splinted [OS], open unsplinted [OU], closed [C]) for each condition. Six groups of casts (DOS, DOU, DC, EOS, EOU, EC) (n = 8), totaling 48 casts, were made. Two scan bodies were secured onto the master edentulous model and onto each test cast and digitized by an optical scanning system. The related scans were superimposed, and the mean discrepancy for each cast was determined. RESULTS: The statistical analysis showed no significant difference in the accuracy of casts as a function of model status (P = .78, analysis of variance [ANOVA] test), impression technique (P = .57, ANOVA test), or as the combination of both (P = .29, ANOVA test). The distribution of data was normal (Kolmogorov-Smirnov test). CONCLUSION: Model status (dentate or edentulous) and impression technique did not influence the precision of the casts. There is no difference among any of the impression techniques in either simulated clinical condition. PMID- 25506646 TI - Effect of insertion method and postinsertion time interval prior to force application on the removal torque of orthodontic miniscrews. AB - PURPOSE: Success of orthodontic miniscrews in providing stable anchorage is dependent on their stability. The purpose of this study was to assess the effect of insertion method and postinsertion time interval on the removal torque of miniscrews as an indicator of their stability. MATERIALS AND METHODS: Seventy-two miniscrews (Jeil Medical) were inserted into the femoral bones of three male German Shepherd dogs and assigned to nine groups of eight miniscrews. Three insertion methods, including hand-driven, motor-driven with 5.0-Ncm insertion torque, and motor-driven with 20.0-Ncm insertion torque, were tested. Three time intervals of 0, 2, and 6 weeks between miniscrew insertion and removal were tested as well. Removal torque values were measured in newton centimeters by a removal torque tester (IMADA). Data were analyzed by one-way analysis of variance (ANOVA) followed by the Bonferroni post hoc test at a .05 level of significance. RESULTS: A miniscrew survival rate of 93% was observed in this study. The highest mean value of removal torque among the three postinsertion intervals (2.4 +/- 0.59 Ncm) was obtained immediately after miniscrew insertion with a statistically significant difference from the other two time intervals (P < .001). Insertion were observed in this regard (P = .46). CONCLUSION: The stability of miniscrews was not affected by the insertion method. However, of the postinsertion time intervals, the highest removal torque values were obtained immediately after insertion. PMID- 25506648 TI - Synthesis and characterization of TiO2 loaded cashew nut shell activated carbon and photocatalytic activity on BG and MB dyes under sunlight radiation. AB - Synthesis of titanium dioxide (TiO2) nanoparticles and TiO2 loaded cashew nut shell activated carbon (TiO2/CNSAC) had been undertaken using sol-gel method and their application in BG and MB dyes removal under sunlight radiation has been investigated. The synthesized photocatalysts were characterized by X-ray diffraction analysis (XRD), Fourier infra-red spectroscopy (FT-IR), UV-Vis diffuse reflectance spectroscopy (DRS) and scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX). The various experimental parameters like amount of catalyst, contact time for efficient dyes degradation of BG and MB were concerned in this study. Activity measurements performed under solar irradiation has shown good results for the photodegradation of BG and MB in aqueous solution. It was concluded that the higher photocatalytic activity in TiO2/CNSAC was due to parameters like band-gap, number of hydroxyl groups, surface area and porosity of the catalyst. The kinetic data were also described by the pseudo-first-order and pseudo-second-order kinetic models. PMID- 25506647 TI - Load limit of mini-implants with reduced abutment height based on fatigue fracture resistance: experimental and finite element study. AB - PURPOSE: The primary objective of this study was to investigate the fracture resistance of experimental mini-implants with a reduced abutment height. The secondary objective was to assess the effects of implant diameter and bone level on the load limit, using finite element simulations. MATERIALS AND METHODS: Two Ti-6A1-4V 1.8-mm-diameter implants were subjected to monotonic bending testing and fatigue tests incorporating 5 x 10(6) cycles (ISO 14801): a commercially available implant (c18), and an experimental implant with a reduced abutment height (e18). The load limit was estimated using the finite element models based on the maximum stress at failure in the experiments. For simulations, implants with increased diameters of 2.1 and 2.4 mm were also modeled, and the load limit was estimated for all models in a bone model. RESULTS: In the bending test, e18 revealed a higher mean load at yield stress than c18, and this was attributed to the reduced height of the former. An endurance limit of 140 N was detected for both c18 and e18 in the fatigue test, while the load limit of e18 was higher than that of c18. The estimated load limit increased as the implant diameter or the bone level increased, with the highest value of 510 N observed at a diameter of 2.4 mm. CONCLUSION: A higher load limit was evident in the experimental mini implant with a reduced abutment height. The simulations indicated that the load limit increased with increased implant diameter and higher bone levels. PMID- 25506649 TI - Cellular injury evidenced by impedance technology and infrared microspectroscopy. AB - Fourier Transform Infrared (FTIR) spectroscopy is finding increasing biological application, for example in the analysis of diseased tissues and cells, cell cycle studies and investigating the mechanisms of action of anticancer drugs. Cancer treatment studies routinely define the types of cell-drug responses as either total cell destruction by the drug (all cells die), moderate damage (cell deterioration where some cells survive) or reversible cell cycle arrest (cytostasis). In this study the loss of viability and related chemical stress experienced by cells treated with the medicinal plant, Plectranthus ciliatus, was investigated using real time cell electronic sensing (RT-CES) technology and FTIR microspectroscopy. The use of plants as medicines is well established and ethnobotany has proven that crude extracts can serve as treatments against various ailments. The aim of this study was to determine whether FTIR microspectroscopy would successfully distinguish between different types of cellular injury induced by a potentially anticancerous plant extract. Cervical adenocarcinoma (HeLa) cells were treated with a crude extract of Pciliatus and cells monitored using RT-CES to characterize the type of cellular responses induced. Cell populations were then investigated using FTIR microspectroscopy and statistically analysed using One-way Analysis of Variance (ANOVA) and Principal Component Analysis (PCA). The plant extract and a cancer drug control (actinomycin D) induced concentration dependent cellular responses ranging from nontoxic, cytostatic or cytotoxic. Thirteen spectral peaks (915cm(-)(1), 933cm( )(1), 989cm(-)(1), 1192cm(-)(1), 1369cm(-)(1), 1437cm(-)(1), 1450cm(-)(1), 1546cm(-)(1), 1634cm(-)(1), 1679cm(-)(1) 1772cm(-)(1), 2874cm(-)(1) and 2962cm( )(1)) associated with cytotoxicity were significantly (p value<0.05, one way ANOVA, Tukey test, Bonferroni) altered, while two of the bands were also indicative of early stress related responses. In PCA, poor separation between nontoxic and cytostatic responses was evident while clear separation was linked to cytotoxicity. RT-CES detected morphological changes as indicators of cell injury and could distinguish between viable, cytostatic and cytotoxic responses. FTIR microspectroscopy confirmed that cytostatic cells were viable and could still recover while also describing early cellular stress related responses on a molecular level. PMID- 25506650 TI - Synthesis and characterization of PVK/AgNPs nanocomposites prepared by laser ablation. AB - Nanocomposites of Poly (n-vinylcarbazole) PVK/Ag nanoparticles were prepared by laser ablation of a silver plate in aqueous solution of chlorobenzene. The influences of laser parameters such as; time of irradiation, source power and wavelength (photon energy) on structural, morphological and optical properties have been investigated using X-ray diffraction (XRD), Transmission electron microscopy (TEM), Ultraviolet-visible (UV-Vis) and Photoluminescence (PL). A correlation between the investigated properties has been discussed. XRD, TEM and PL indicated that the complexation between AgNPs and PVK in the composite system is possible. Only the reflection peak at 2theta=38 degrees of AgNPs appeared in the composite nanoparticles while the other reflection peaks were destroyed. The nanoparticles shape and size distribution were evaluated from TEM images. TEM analysis revealed a lower average particle size at long laser irradiation time 40min and short laser wavelength 532nm together with high laser power 570mW. From UV-Visible spectra the values of absorption coefficient, absorption edge and energy tail were calculated. The reduction of band tail value with increasing the laser ablation parameters confirms the decrease of the disorder in such composite system. The PL and UV-Vis. spectra confirm that nanocomposite samples showed quantum confinement effect. PMID- 25506651 TI - Experimental and theoretical investigations on N,N'-diphenylguanidinium dihydrogen phosphite - a semi-organic nonlinear optical material. AB - Single crystal of N,N'-diphenylguanidinium dihydrogen phosphite (DPGP) was grown by a slow evaporation technique and was characterized by single crystal X-ray diffraction and powder X-ray diffraction to confirm the structure and crystalline nature of DPGP crystal. UV-vis spectral study revealed that the DPGP crystal is optically transparent. The chemical bonding and presence of various functional groups were confirmed by the FT-IR and FT-Raman spectral studies. The thermal behavior of DPGP crystal was analyzed by simultaneous TG-DTA studies. The laser induced surface damage threshold study was carried out for the grown crystal using Nd:YAG laser. The second harmonic generation (SHG) nonlinearity of the grown crystalline sample was measured by the Kurtz and Perry powder technique. The quantum chemical analyses were performed by density functional theory (DFT) using B3LYP/6-31G (d,p) basis set. PMID- 25506652 TI - Rhodamine functionalized magnetic core-shell nanocomposite: an emission "Off-On" sensing system for mercury ion detection and extraction. AB - This paper reported a core-shell structured composite with superparamagnetic ferroferric oxide as the inner core and silica molecular sieve as the outer shell. A rhodamine based sensing dye was covalently grafted into the highly ordered tunnels of silica molecular sieve, so that mercury ion sensing and extraction could be achieved from this composite. This probe loaded core-shell structure was characterized by electron microscopy images, X-ray diffraction patterns, infrared spectra, thermogravimetry and N2 adsorption/desorption measurement. This composite showed increased emission with increasing mercury ion concentration, along with high sensitivity and good selectivity. Linear response and good regenerating performance were also observed from this composite. PMID- 25506653 TI - Health-related social control among older men with depressive symptomatology. AB - OBJECTIVES: Social control attempts, or attempts by social network members to influence a person's behavior, significantly predict men's health behaviors and psychological well-being. Despite the fact that depression is associated with compromised interpersonal functioning and poor health behaviors, the association between social control processes and depression has not been studied. Thus, this pilot study explored differential vulnerability to spouses' social control attempts among older, male primary care patients with varying levels of depression symptom severity and the degree to which these attempts predicted patients' behavioral and affective responses. METHOD: Participants included 88 older men referred by their primary care providers for a behavioral health assessment at a Veterans Affairs Medical Center. Data on sociodemographics, depressive symptomatology, health behaviors, spouses' positive and negative social control attempts, and patients' behavioral and affective responses to attempts were collected by telephone. RESULTS: The sample was primarily Caucasian (mean age = 65.3 (SD = 8.1) years). Patients' higher depressive symptoms were significantly associated with positive and negative affective responses to their spouses' social control attempts. The frequency of control attempts and patients' behavioral responses, however, were unrelated to patients' depressive symptoms. Multiple regression models revealed that while spouses' control attempts were unrelated to patients' positive behavioral responses, more frequent negative attempts predicted greater negative behavioral responses (e.g., ignoring spouses' attempts). Moreover, negative control attempts predicted greater negative affective responses (e.g., resentment, sadness). CONCLUSION: The findings highlight the value of identifying effective social control strategies that maximize positive behavioral change, emotional responses, and health outcomes among older men with depressive symptoms. PMID- 25506655 TI - Vision, spatial cognition and intellectual disability. AB - Vision is the most synthetic sensory channel and it provides specific information about the relative position of distant landmarks during visual exploration. In this paper we propose that visual exploration, as assessed by the recording of eye movements, offers an original method to analyze spatial cognition and to reveal alternative adaptation strategies in people with intellectual disabilities (ID). Our general assumption is that eye movement exploration may simultaneously reveal whether, why, and how, compensatory strategies point to specific difficulties related to neurological symptoms. An understanding of these strategies will also help in the development of optimal rehabilitation procedures. PMID- 25506654 TI - Effects of providing domain specific progress monitoring and feedback to therapists and patients on outcome. AB - OBJECTIVE: Progress monitoring and feedback reduces the number of patients deteriorating in psychotherapy. The current study examined the effects of providing treatment progress information to therapists and patients using individual feedback of both wellbeing and affective psychological distress compared to feedback of wellbeing alone. METHOD: The sample comprised 845 consecutive psychiatric day-hospital admissions using a historical cohort design. The effects of monitoring and feedback of wellbeing in Cohort 1 were compared against the effects of monitoring and feedback of both wellbeing and affective psychological distress in Cohort 2. RESULTS: Patients who were "not-on-track" in Cohort 2 demonstrated significantly greater improvement for affective psychological distress than those from Cohort 1. CONCLUSIONS: These findings suggest that providing feedback from multiple sources enhances patient outcomes in comparison to single source feedback. PMID- 25506656 TI - Task instructions determine the visuospatial and verbal-spatial nature of number space associations. AB - Evidence for number-space associations comes from the spatial-numerical association of response codes (SNARC) effect, consisting in faster reaction times to small/large digits with the left/right hand, respectively. Two different proposals are commonly discussed concerning the cognitive origin of the SNARC effect: the visuospatial account and the verbal-spatial account. Recent studies have provided evidence for the relative dominance of verbal-spatial over visuospatial coding mechanisms, when both mechanisms were directly contrasted in a magnitude comparison task. However, in these studies, participants were potentially biased towards verbal-spatial number processing by task instructions based on verbal-spatial labels. To overcome this confound and to investigate whether verbal-spatial coding mechanisms are predominantly activated irrespective of task instructions, we completed the previously used paradigm by adding a spatial instruction condition. In line with earlier findings, we could confirm the predominance of verbal-spatial number coding under verbal task instructions. However, in the spatial instruction condition, both verbal-spatial and visuospatial mechanisms were activated to an equal extent. Hence, these findings clearly indicate that the cognitive origin of number-space associations does not always predominantly rely on verbal-spatial processing mechanisms, but that the spatial code associated with numbers is context dependent. PMID- 25506657 TI - Analysis of complex reacting mixtures by time-resolved 2D NMR. AB - Nuclear magnetic resonance (NMR) spectroscopy is a versatile tool for chemical analysis. Besides the most straightforward application to study a stable sample containing a single compound, NMR has been also used for the analysis of mixtures. In particular, the analyzed mixtures can undergo changes caused by chemical reactions. The multidimensional NMR techniques are especially effective in a case of samples containing many components. Unfortunately, they are usually too lengthy to be applied in time-resolved experiments performed to study mentioned changes in a series of spectral "snapshots." Recently, time-resolved nonuniform sampling (NUS) has been proposed as a straightforward solution to the problem. In this paper, we discuss the features of time-resolved NUS and give practical recommendations regarding the temporal resolution and use of the time pseudodimension to resolve the components. The theoretical considerations are exemplified by the application in challenging cases of fermenting samples of wheat flour and milk. PMID- 25506658 TI - Effect of splinting in accuracy of two implant impression techniques. AB - Because there is no consensus in the literature about the need for a splint between copings, the aim of this study was to evaluate, in vitro, the accuracy of 2 impression techniques for implant-supported prostheses. A master cast was fabricated with four parallel implant abutment analogs and a passive framework. Two groups with 5 casts each were formed: Group 1 (squared impression copings with no splint: S) and Group 2 (splinted squared impression copings, using metal drill burs and Pattern resin: SS). The impression material used was polyvinyl siloxane with open trays for standard preparation of the casts. For each cast, the framework was positioned, and a titanium screw was tightened with 10 N.cm torque in analog A, after which measurements of the abutment-framework interface gaps were performed at analogs C and D. This process was repeated for analog D. These measurements were analyzed using software. A one-way analysis of variance (ANOVA) with a confidence interval of 95% was used to analyze the data. Significant differences were detected between S and SS in relation to the master cast (P <= 0.05). The median values of the abutment-framework interface gaps were as follows: master cast: 39.64 MUm; squared impression copings with no splint: 205.86 MUm; splinted squared impression copings: 99.19 MUm. Under the limitations of this study, the technique presented for Group 2 produces better results compared with the technique used for Group 1. PMID- 25506659 TI - Retentiveness of various luting agents used with implant-supported prosthesis: an in vitro study. AB - Desired retrievability of cemented implant-supported fixed prosthesis makes the retentive strength of cementing agents an important consideration. The aim of the study was to evaluate the retentiveness of purposely designed implant cement and compare its retentiveness with dental cements that are commonly used with implant systems. Ten implant analogs were embedded in auto-polymerizing acrylic resin blocks and titanium abutments were attached to them. Fifty standardized copings were waxed directly on the abutment and casted. The cements used were: (1) resin bonded zinc oxide eugenol cement, (2) purposely designed implant cement, (3) zinc phosphate cement, (4) zinc polycarboxylate cement, and (5) glass ionomer cement. After cementation, each sample was subjected to a pull-out test using universal testing machine and loads required to remove the crowns were recorded. The mean values and standard deviations of cement failure loads were analyzed using ANOVA and Bonferroni test. The mean values (+/- SD) of loads at failure (n = 10) for various cements were as follows (N): resin-bonded zinc oxide eugenol cement 394.62 (+/- 9.76), Premier implant cement 333.86 (+/- 18.91), zinc phosphate cement 629.30 (+/- 20.65), zinc polycarboxylate cement 810.08 (+/- 11.52), and glass ionomer cement 750.17 (+/- 13.78). The results do not suggest that one cement type is better than another, but they do provide a ranking order of the cements regarding their ability to retain the prosthesis and facilitate easy retrievability. PMID- 25506660 TI - Role of rhBMP-2 and rhBMP-7 in the metabolism and differentiation of osteoblast like cells cultured on chemically modified titanium surfaces. AB - This study analyzed the role of recombinant human bone morphogenetic protein 2 (rhBMP-2) and recombinant human bone morphogenetic protein 7 (rhBMP-7) in the adhesion and differentiation of rat osteoblast-like (osteo-1) cells cultured on chemically modified titanium surfaces. Osteo-1 cells were cultured on chemically modified (modified sandblasted and acid-etched) titanium surfaces in 3 different types of medium: control, medium supplemented with 20 ng/mL rhBMP-2, and medium supplemented with 20 ng/mL rhBMP-7. The following parameters were evaluated: cell adhesion after 24 hours; total protein content; collagen content and alkaline phosphatase (AP) activity after 7, 14, and 21 days; and calcified nodule formation after 21 days. The addition of rhBMP-2 or rhBMP-7 did not influence cell adhesion (P = .1175). Cell differentiation was influenced by rhBMP-2, as demonstrated by a significant increase in collagen content after 7 days of culture (P < .0001) and a significant decrease in AP activity after 21 days (P < .0001). The addition of rhBMP-7 only influenced AP activity, and a significant increase was observed after 21 days (P < .0001). Within the limitations of the study, we conclude that the presence of rhBMP-2 or rhBMP-7 did not influence cell adhesion to chemically modified titanium surfaces but provided an additional stimulus during the differentiation of rat osteo-1 cells cultured on this type of surface. PMID- 25506661 TI - Flapless alveolar ridge preservation utilizing the "socket-plug" technique: clinical technique and review of the literature. AB - It has been documented that after every extraction of one or more teeth, the alveolar bone of the respective region undergoes resorption and atrophy. Therefore, ridge preservation techniques are often employed after tooth extraction to limit this phenomenon. The benefits of a flapless procedure include maintenance of the buccal keratinized gingiva, prevention of alterations to the gingival contours, and migration of the mucogingival junction that are often experienced after raising a flap. The purpose of this article is to review the literature concerning flapless ridge preservation techniques with the aid of collagen plugs for occlusion of the socket. The term "socket-plug" technique is introduced to describe these techniques. The basic steps of the "socket-plug" technique consist of atraumatic tooth extraction, placement of the appropriate biomaterials in the extraction site, preservation of soft tissue architecture employing a flapless technique, and placement and stabilization of the collagen plug. A case example is presented that illustrates the steps used in this technique. PMID- 25506663 TI - Retrieval of a separated implant screwdriver fragment. PMID- 25506662 TI - Full-mouth rehabilitation of a patient with ectodermal dysplasia with dental implants. AB - Oral findings in patients with ectodermal dysplasia (ED) include complete or partial hypodontia, anodontia, loss of vertical dimension of occlusion, protuberant lips, malformed and widely spaced conical-shaped teeth, and underdeveloped alveolar ridges. These patients present a substantial challenge in dental treatment. This case report presents oral rehabilitation of a 22-year-old male patient diagnosed with ED using an implant tooth-supported telescopic partial denture at the mandible and a tooth-supported telescopic partial denture at the maxilla. Implants in the mandible were placed at the sites of the right and left lateral incisor teeth. Following implant placement, the remaining buccal bone dehiscence was filled with deproteinized bovine bone graft and covered with resorbable membrane. To manage the vestibular insufficiency and to increase the keratinized mucosa in maxilla, bilateral acellular dermal matrix allograft was used on the right and left buccal aspects. The treatment described here improved the patient's functional and esthetic status while significantly restoring his oral health and self-esteem. PMID- 25506664 TI - Replacement of an implant and prosthesis in the premaxilla due to a malposition and prosthetic failure: a clinical case letter. PMID- 25506665 TI - A new restorative technique for the perishing implant due to abutment screw fracture. PMID- 25506666 TI - Fit of CAD/CAM implant frameworks: a comprehensive review. AB - Computer-aided design and computer-aided manufacturing (CAD/CAM) is a strongly emerging prosthesis fabrication method for implant dentistry. Currently, CAD/CAM allows the construction of implant frameworks from different materials. This review evaluates the literature pertaining to the precision fit of fixed implant frameworks fabricated by CAD/CAM. Following a comprehensive electronic search through PubMed (MEDLINE), 14 relevant articles were identified. The results indicate that the precision fit of CAD/CAM frameworks exceeded the fit of the 1 piece cast frameworks and laser-welded frameworks. A similar fit was observed for CAD/CAM frameworks and bonding of the framework body to prefabricated cylinders. The influence of CAD/CAM materials on the fit of a framework is minimal. PMID- 25506667 TI - Spontaneous water oxidation at hematite (alpha-Fe2O3) crystal faces. AB - Hematite (alpha-Fe2O3) persists as a promising candidate for photoelectrochemical water splitting, but a slow oxygen evolution reaction (OER) at its surfaces remains a limitation. Here we extend a series of studies that examine pH dependent surface potentials and electron-transfer properties of effectively perfect low-index crystal faces of hematite in contact with simple electrolyte. Zero-resistance amperometry (ZRA) was performed in a two electrode configuration to quantify spontaneous dark current between hematite crystal face pairs (001)/(012), (001)/(113), and (012)/(113) at pH 3. Exponentially decaying currents initially of up to 200 nA were reported between faces over 4 min experiments. Fourth-order ZRA kinetics indicated rate limitation by the OER for current that flows between (001)/(012) and (001)/(113) face pairs, with the (012) and (113) faces serving as the anodes when paired with (001). The cathodic partner reaction is reductive dissolution of the (001) face, converting surface Fe(3+) to solubilized aqueous Fe(2+), at a rate maintained by the OER at the anode. In contrast, OER rate limitation does not manifest for the (012)/(113) pair. The uniqueness of the (001) face is established in terms of a faster intrinsic ability to accept the protons required for the reductive dissolution reaction. OER rate limitation inversely may thus arise from sluggish kinetics of hematite surfaces to dispense with the protons that accompany the four-electron OER. The results are explained in terms of semiquantitative energy band diagrams. The finding may be useful as a consideration for tailoring the design of polycrystalline hematite photoanodes that present multiple terminations to the interface with electrolyte. PMID- 25506668 TI - Conformation dynamics and polarization effect of alpha,alpha-trehalose in a vacuum and in aqueous and salt solutions. AB - Conformational changes of alpha,alpha-trehalose in a vacuum, water, and 0-20 wt % NaCl solutions were investigated by means of molecular dynamics (MD) simulations at different levels of density function theory (DFT) and with fixed-charge nonpolarizable and variable-charge force fields (FFs), respectively. The relative thermodynamic stability of trehalose is enhanced by the formation of intercycle and/or intracycle hydrogen bonds, but some thermodynamically unfavorable structures can be sampled in the DFT-based ab initio MD simulation. The polarization effects of polar trehalose molecule in aqueous and NaCl solutions were studied by a series of MD simulations with both the conventional nonpolarizable and polarizable force field models. In the polarizable model, the partial charges of trehalose were updated every 2 ps using DFT calculations and fused with the other FF parameters for the energy calculation and MD simulation. Around the trehalose, water molecules located in an asymmetry model and trehalose have a stronger tendency to bind with water molecules than Na(+) and Cl(-) ions. When the trehalose concentration is increased from 3.26 to 6.31 wt % in salt aqueous solution, the two trehalose molecules periodically approach each other in a nearly anhydrate state and leave a way to keep the favorable hydration structure with the mean trehalose-trehalose distance of 8.6 A. The similarity between the solvated dimer packing styles (shoulder-by-shoulder or head-to-head) and crystal stacking can be used to make an extrapolation to higher sugar concentrations and to rationalize the bioprotection function of trehalose in high salt concentration. PMID- 25506669 TI - Analysis of inflammatory cells and mediators in skin wound biopsies to determine wound age in living subjects in forensic medicine. AB - OBJECTIVE: In forensic medicine it is important to determine the age of skin wounds in living subjects. The aim of this study was to assess whether analysis of inflammatory cells and inflammatory mediators in skin biopsies of wounds from living subjects could improve wound age determination. METHODS: Biopsies (n=101), representing the superficial border area of a skin wound, were taken from skin injuries of known wound age (range: 4.5 hours to 25 days) of living subjects. All biopsies were analyzed for 3 inflammatory cell markers (MPO, CD45 and CD68) and 4 inflammatory mediators (MIP-1, IL-8, CML and vitronectin). For quantification, biopsies were subdivided in 4 different timeframes: 0.2-2 days, 2-4 days, 4-10 days and 10-25 days old wounds. Subsequently, a probability scoring system was developed. RESULTS: MPO, CD45, MIP-1, IL-8 (inflammatory cell markers) and N(epsilon)-(carboxymethyl)lysine (CML) positivity were maximal in wounds of 0.2-2 days old and then decreased in time. Remarkably, CD45, CD68 and CML showed a minor but non-significant increase again in 10-25 days old wounds. MPO and CD68 positivity was significantly lower in 4-25 days old wounds compared to 0.2-4 days old wounds. MPO positivity was also significantly lower in 10-25 days old wounds compared to 0.2-10 days old wounds. For CD45, MIP-1, IL-8 and CML no significant differences between the age groups were found. In case of vitronectin positivity in the extravasate or when the number of MIP-1 or IL-8-positive cells was more than 10 cells/mm(2) the probability that a wound was more than 10 days old was 0%. A probability scoring system of all analyzed markers can be used to calculate individual wound age probabilities in biopsies of skin wounds of living subjects. CONCLUSIONS: We have developed a probability scoring system of inflammatory cells and mediators that can be used to determine wound age in skin biopsies of living subjects. PMID- 25506671 TI - Isolation and characterization of a novel arenavirus harbored by Rodents and Shrews in Zhejiang province, China. AB - To determine the biodiversity of arenaviruses in China, we captured and screened rodents and shrews in Wenzhou city, Zhejiang province, a locality where hemorrhagic fever diseases are endemic in humans. Accordingly, arenaviruses were detected in 42 of 351 rodents from eight species, and in 12 of 272 Asian house shrews (Suncus murinus), by RT-PCR targeting the L segment. From these, a single arenavirus was successfully isolated in cell culture. The virion particles exhibited a typical arenavirus morphology under transmission electron microscopy. Comparison of the S and L segment sequences revealed high levels of nucleotide (>32.2% and >39.6%) and amino acid (>28.8% and >43.8%) sequence differences from known arenaviruses, suggesting that it represents a novel arenavirus, which we designated Wenzhou virus (WENV). Phylogenetic analysis revealed that all WENV strains harbored by both rodents and Asian house shrews formed a distinct lineage most closely related to Old World arenaviruses. PMID- 25506672 TI - Low uptake of HIV testing and no HIV positivity in stable serodiscordant heterosexual partners of long-term treated HIV-infected Thais. AB - The objective of this study was to characterize HIV-serodiscordant heterosexual couples and to evaluate acceptance for HIV testing and HIV prevalence in nonindex partners. We conducted a cross-sectional study with quantitative and qualitative components. Two cohorts of 1767 HIV-positive people were screened to identify heterosexual HIV-serodiscordant couples. HIV-positive partners (index) were administered a questionnaire; CD4, viral load (VL), and antiretroviral therapy (ART) history were gathered from clinical records. HIV-negative/unknown status partners (nonindex) were invited for a similar questionnaire and HIV testing. In depth interviews with three HIV-serodiscordant couples were conducted. Two hundred and ninety-seven index partners agreed to enroll in this study. The median duration of the relationship was 10 years, and 81% were sexually active. All but two index partners were on ART, and 98% had VL < 1000 copies/mL. Only 111 (37%) nonindex partners came for HIV testing, and all of them tested HIV negative. In addition, only 41% of nonindex partners had HIV testing in the last one year. The main reasons for the nonindex partners not to come for HIV testing were "no interest" (n = 117, 63%) and "nondisclosure of HIV status" (n = 46, 25%). The latter was substantiated and explained by the qualitative outcome of this study, suggesting relation to stigma against HIV-positive people. Our results support the WHO recommendation for starting ART for treatment and prevention in HIV-serodiscordant couples at any CD4 count. Furthermore, we recommend the dissemination of data showing that no HIV transmission in heterosexual couples through sex practice has been observed provided VL is suppressed. This could be a powerful tool for effective fight against stigma and self-stigma in people living with HIV. PMID- 25506670 TI - Mutations within A 35 amino acid region of P6 influence self-association, inclusion body formation, and Caulimovirus infectivity. AB - Cauliflower mosaic virus gene VI product (P6) is an essential protein that forms cytoplasmic, inclusion bodies (IBs). P6 contains four regions involved in self association, termed D1-D4. D3 binds to D1, along with D4 and contains a spacer region (termed D3b) between two RNA-binding domains. Here we show D3b binds full length P6 along with D1 and D4. Full-length P6s harboring single amino acid substitutions within D3b showed reduced binding to both D1 and D4. Full-length P6s containing D3b mutations and fused with green fluorescent protein formed inclusion-like bodies (IL-Bs) when expressed in Nicotiana benthamiana leaves. However, mutant P6s with reduced binding to D1 and D4, showed smaller IL-Bs, than wild type. Likewise, viruses containing these mutations showed a decrease in inoculated leaf viral DNA levels and reduced efficiency of systemic infection. These data suggest that mutations influencing P6 self-association alter IB formation and reduce virus infection. PMID- 25506673 TI - Enhancing fluorescence in vivo imaging using inorganic nanoprobes. AB - Fluorescence imaging is a versatile tool for biological and preclinical studies with steady improvements in performance thanks to instrumentation and probe developments. The sensitive detection and imaging of deep targets in vivo is especially challenging due to the diffusion and absorption of light by the tissues and to the emission of autofluorescence from intrinsic chromophores. Fluorescent inorganic nanoparticles present interesting optical properties that may significantly differ from organic dyes. In this short review, we present recent developments in the design of these nanoprobes and their use for new in vivo fluorescence modalities which provide enhanced imaging capabilities. PMID- 25506674 TI - Frequency of cholinergic and caudate nucleus dopaminergic deficits across the predemented cognitive spectrum of Parkinson disease and evidence of interaction effects. AB - IMPORTANCE: Little is known about the relative contributions of multisystem degenerative processes across the spectrum of predemented cognitive decline in Parkinson disease (PD). OBJECTIVE: To investigate the relative frequency of caudate nucleus dopaminergic and forebrain cholinergic deficits across a spectrum of cognitively impaired patients with PD to explore their relative, individual, and combined contributions to cognitive impairment in PD. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study at an academic movement disorders clinic that included a predominantly nondemented cohort of 143 patients with PD. The mean (SD) age of patients was 65.5 (7.4) years and the mean (SD) Hoehn and Yahr stage was 2.4 (0.6). MAIN OUTCOMES AND MEASURES: Binary classification of carbon 11-labeled [11C]PMP acetylcholinesterase and caudate nucleus [11C]DTBZ monoaminergic positron-emission tomography imaging based on normative data. The frequency of significant degenerative processes based on normative values was determined for consecutive intervals of cognitive impairment, ranging from no or minimal (z > -0.5) to more severe (z <= -2) cognitive impairment. RESULTS: Across the spectrum from minimal (z > -0.5) to more severe (z <= -2) global cognitive impairment scores, caudate nucleus dopaminergic denervation was relatively frequent in individuals with minimal or no cognitive changes (51.1%) and increased in patients with more severe cognitive impairments (chi2 = 12.8; P = .01). Cortical cholinergic denervation frequency increased monotonically with increasing cognitive impairment from 24.7% (z > -0.5) to 85.7% (z <= -2); chi2 = 23.2; P = .001). Eighty-seven percent of patients with neocortical cholinergic deficits had caudate nucleus dopaminergic deficits. Multiple regression analysis (F = 7.51; P < .001) showed both independent cognitive predictions for caudate nucleus dopaminergic (F = 7.25; P = .008) and cortical cholinergic (F = 7.50; P = .007) degenerations as well as interaction effects (F = 5.40; P = .02). CONCLUSIONS AND RELEVANCE: Cortical cholinergic denervation is a major neurodegeneration associated with progressive declines across the spectrum of cognitive impairment in PD and typically occurs in the context of significant caudate nucleus dopaminergic denervation. Our findings imply that dopaminergic and cholinergic degenerations exhibit both independent and interactive contributions to cognitive impairment in PD. PMID- 25506676 TI - Problematic consequences of using standard errors rather than standard deviations reply. PMID- 25506675 TI - Multivalency in the inhibition of oxidative protein folding by arsenic(III) species. AB - The renewed use of arsenicals as chemotherapeutics has rekindled interest in the biochemistry of As(III) species. In this work, simple bis- and tris-arsenical derivatives were synthesized with the aim of exploiting the chelate effect in the inhibition of thiol-disulfide oxidoreductases (here, Quiescin sulfhydryl oxidase, QSOX, and protein disulfide isomerase, PDI) that utilize two or more CxxC motifs in the catalysis of oxidative protein folding. Coupling 4-aminophenylarsenoxide (APAO) to acid chloride or anhydride derivatives yielded two bis-arsenical prototypes, BA-1 and BA-2, and a tris-arsenical, TA-1. Unlike the monoarsenical, APAO, these new reagents proved to be strong inhibitors of oxidative protein folding in the presence of a realistic intracellular concentration of competing monothiol (here, 5 mM reduced glutathione, GSH). However, this inhibition does not reflect direct inactivation of QSOX or PDI, but avid binding of MVAs to the reduced unfolded protein substrates themselves. Titrations of reduced riboflavin binding protein with MVAs show that all 18 protein -SH groups can be captured by these arsenicals. With reduced RNase, addition of substoichiometric levels of MVAs is accompanied by the formation of Congo Red- and Thioflavin T-positive fibrillar aggregates. Even with Kd values of ~50 nM, MVAs are ineffective inhibitors of PDI in the presence of millimolar levels of competing GSH. These results underscore the difficulties of designing effective and specific arsenical inhibitors for folded enzymes and proteins. Some of the cellular effects of arsenicals likely reflect their propensity to associate very tightly and nonspecifically to conformationally mobile cysteine-rich regions of proteins, thereby interfering with folding and/or function. PMID- 25506677 TI - Improving the mining soil quality for a vegetation cover after addition of sewage sludges: inorganic ions and low-molecular-weight organic acids in the soil solution. AB - We assessed the effects of applying stabilized sewage sludge (SSL) and composted sewage sludge (CLV), at 5 and 10% to an acid mining soil. Limed soil (NCL) amended or not with SSL and CLV was incubated for 47 days. We studied the cations and organic and inorganic anions in the soil solution by means of ion chromatography. Liming led to big increases in Ca(2+) and SO4(2-) and to significant decreases in K(+), Mg(2+), NH4(+) and NO3(-). Addition of both organic amendments increased some cations (NH4(+), K(+), Mg(2+), Na(+)) and anions (Cl(-), NO3(-) only with CLV and PO4(3-) only with SSL) and provided a greater amount of low-molecular-weight organic acids (LMWOAs) (SSL more than CLV). Incubation led to decreases in all cations, particularly remarkable for Ca(2+) and Mg(2+) in SSL-10. A decrease in NH4(+) was associated with variations in NO2(-) and NO3(-) resulting from nitrification reactions. During incubation the LMWOAs content tended to decrease similarly to the cations, especially in SSL 10. Chemometric tools revealed a clear discrimination between SSL, CLV and NCL. Furthermore, treatment effects depended upon dose, mainly in SSL. Amendment nature and dose affect the quality of a mining soil and improve conditions for plant establishment. PMID- 25506678 TI - Feeling old vs being old: associations between self-perceived age and mortality. PMID- 25506679 TI - False-positive test results in a patient with severe hepatitis: a teachable moment-the risk of treating the numbers. PMID- 25506681 TI - The shape of the plasma glucose curve during an oral glucose tolerance test as an indicator of Beta cell function and insulin sensitivity in end-pubertal obese girls. AB - It is hypothesized that the shape of the glucose curve during an oral glucose tolerance test is an early indicator of the risk for developing type 2 diabetes mellitus. In this study, we aimed to examine the shape of plasma glucose response curves and study their relationship with insulin sensitivity, insulin secretion and components of the metabolic syndrome in end-pubertal obese girls. Eighty-one end-pubertal obese girls [median (range) age: 14.4 (11.2-18.0) years; BMI: 34.6 (25.4-50.8) kg/m(2)] who underwent a 2-h oral glucose tolerance test were classified according to the shape of the glucose curve. Four shape types of the plasma glucose response curve were observed: 28 (34.6%) monophasic, 30 (37.0%) biphasic, 14 (17.3%) triphasic, and 9 (11.1%) unclassified. Patients with a monophasic shape had a higher area under the curve for glucose (p = 0.008), a lower early-phase insulin secretion (p = 0.005), and a poorer beta cell function relative to insulin sensitivity as reflected by the oral disposition index (p = 0.022) compared to the bi- and triphasic shape types. In addition, the triglyceride level and TG/HDL-C ratio was higher in patients with a monophasic shape compared to those with a biphasic shape (p = 0.040 and p = 0.048, respectively). In conclusion, end-pubertal obese girls with a monophasic plasma glucose curve are at increased risk for insulin resistance, which can contribute to the development of type 2 diabetes mellitus and cardiovascular diseases. PMID- 25506680 TI - Household interventions for preventing domestic lead exposure in children. AB - BACKGROUND: Lead poisoning is associated with physical, cognitive and neurobehavioural impairment in children and trials have tested many household interventions to prevent lead exposure. This is an update of the original review by the same authors first published in 2008. OBJECTIVES: To determine the effectiveness of household interventions in preventing or reducing lead exposure in children as measured by reductions in blood lead levels and/or improvements in cognitive development. SEARCH METHODS: We identified trials through electronic searches of CENTRAL (2012, Issue 1), MEDLINE (1948 to January Week 1 2012), EMBASE (1980 to Week 2 2012), CINAHL (1937 to January 2012), PsycINFO (1887 to January Week 2 2012), ERIC (1966 to January 2012), Sociological Abstracts (1952 to January 2012), Science Citation Index (1970 to 20 January 2012), ZETOC (20 January 2012), LILACS (20 January 2012), Dissertation Abstracts (late 1960s to January 2012), ClinicalTrials.gov (19 January 2012), Current Controlled Trials (19 January 2012), Australian New Zealand Clinical Trials Registry (19 January 2012) and the National Research Register Archive. We also contacted experts to find unpublished studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of household educational or environmental interventions to prevent lead exposure in children where at least one standardised outcome measure was reported. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed all eligible studies for inclusion, assessed risk of bias and extracted data. We contacted trialists to obtain missing information. MAIN RESULTS: We included 14 studies (involving 2656 children). All studies reported blood lead level outcomes and none reported on cognitive or neurobehavioural outcomes. We put studies into subgroups according to their intervention type. We performed meta-analysis of both continuous and dichotomous data for subgroups where appropriate. Educational interventions were not effective in reducing blood lead levels (continuous: mean difference (MD) 0.02, 95% confidence interval (CI) -0.09 to 0.12, I(2) = 0 (log transformed); dichotomous >= 10ug/dL (>= 0.48 umol/L): relative risk (RR) 1.02, 95% CI 0.79 to 1.30, I(2)=0; dichotomous >= 15ug/dL (>= 0.72 umol/L): RR 0.60, 95% CI 0.33 to 1.09, I(2) = 0). Meta-analysis for the dust control subgroup also found no evidence of effectiveness (continuous: MD -0.15, 95% CI -0.42 to 0.11, I(2) = 0.9 (log transformed); dichotomous >= 10ug/dL (>= 0.48 umol/L): RR 0.93, 95% CI 0.73 to 1.18, I(2) =0; dichotomous >= 15ug/dL (>= 0.72 umol/L): RR 0.86, 95% CI 0.35 to 2.07, I(2) = 0.56). When meta-analysis for the dust control subgroup was adjusted for clustering, no statistical significant benefit was incurred. The studies using soil abatement (removal and replacement) and combination intervention groups were not able to be meta-analysed due to substantial differences between studies. AUTHORS' CONCLUSIONS: Based on current knowledge, household educational or dust control interventions are ineffective in reducing blood lead levels in children as a population health measure. There is currently insufficient evidence to draw conclusions about the effectiveness of soil abatement or combination interventions.Further trials are required to establish the most effective intervention for prevention of lead exposure. Key elements of these trials should include strategies to reduce multiple sources of lead exposure simultaneously using empirical dust clearance levels. It is also necessary for trials to be carried out in developing countries and in differing socioeconomic groups in developed countries. PMID- 25506682 TI - The role of non-placental signals in the adaptation of islets to pregnancy. AB - It is well established that the maternal beta-cell mass increases during pregnancy in both humans and rodents to compensate insulin resistance and increased metabolic demand, and rapidly returns to normal levels post-partum. However, the mechanisms underlying this adaptation are not well understood. It is established that this process is driven partly by placental signals, but the contribution of non-placental signals is still unclear. This study aimed to differentiate between the role of placental and non-placental signals in regulating the beta-cell mass and glucose homeostasis during and after pregnancy. Pseudopregnant, pregnant and lactating mice were used to study the effects of maternal hormones on beta-cell function during early pregnancy, mid-to-late pregnancy and post-partum, respectively. Pseudopregnant mice, with circulating hormone levels mirroring those during pregnancy but lacking placental signals, had significantly increased beta-cell proliferation compared to non-pregnant controls but no change in glucose homeostasis, suggesting a role for non placental hormones in increasing beta-cell mass. The rate of beta-cell proliferation rate dropped immediately after parturition, but lactating mice still had a significantly higher rate of beta-cell proliferation compared to non lactating post-partum mice, suggesting that lactation-related hormones play a role in the controlled involution of beta-cell mass post-partum. These results implicate a role for both non-placental and placental signals in regulating beta cell mass during and after pregnancy. PMID- 25506683 TI - Xenotransplantation of porcine islet cells as a potential option for the treatment of type 1 diabetes in the future. AB - Solid organ and cell transplantation, including pancreatic islets constitute the treatment of choice for chronic terminal diseases. However, the clinical use of allogeneic transplantation is limited by the growing shortage of human organs. This has prompted us to initiate a unique multi-center and multi-team effort to promote translational research in xenotransplantation to bring xenotransplantation to the clinical setting. Supported by the German Research Foundation, an interdisciplinary group of surgeons, internal medicine doctors, diabetologists, material sciences experts, immunologists, cell biologists, virologists, veterinarians, and geneticists have established a collaborative research center (CRC) focusing on the biology of xenogeneic cell, tissue, and organ transplantation. A major strength of this consortium is the inclusion of members of the regulatory bodies, including the Paul-Ehrlich Institute (PEI), infection specialists from the Robert Koch Institute and PEI, veterinarians from the German Primate Center, and representatives of influential ethical and religious institutions. A major goal of this consortium is to promote islet xenotransplantation, based on the extensive expertise and experience of the existing clinical islet transplantation program. Besides comprehensive approaches to understand and prevent inflammation-mediated islet xenotransplant dysfunction [immediate blood-mediated inflammatory reaction (IBMIR)], we also take advantage of the availability of and experience with islet macroencapsulation, with the goal to improve graft survival and function. This consortium harbors a unique group of scientists with complementary expertise under a cohesive program aiming at developing new therapeutic approaches for islet replacement and solid organ xenotransplantation. PMID- 25506684 TI - Terahertz time-domain and low-frequency Raman spectroscopy of organic materials. AB - With the ongoing proliferation of terahertz time-domain instrumentation from semiconductor physics into applied spectroscopy over the past decade, measurements at terahertz frequencies (1 THz = 10(12) Hz = 33 cm(-1)) have attracted a sustained growing interest, in particular the investigation of hydrogen-bonding interactions in organic materials. More recently, the availability of Raman spectrometers that are readily able to measure in the equivalent spectral region very close to the elastic scattering background has also grown significantly. This development has led to renewed efforts in performing spectroscopy at the interface between dielectric relaxation phenomena and vibrational spectroscopy. In this review, we briefly outline the underlying technology, the physical phenomena governing the light-matter interaction at terahertz frequencies, recent examples of spectroscopic studies, and the current state of the art in assigning spectral features to vibrational modes based on computational techniques. PMID- 25506685 TI - Adipose tissue-derived mesenchymal stem cells induce expansion of interleukin-10 producing regulatory B cells and ameliorate autoimmunity in a murine model of systemic lupus erythematosus. AB - Mesenchymal stem cells (MSCs) are multipotent cells characterized by immunomodulatory properties and are therefore considered a promising tool for the treatment of autoimmune diseases. One functional B-cell subset, regulatory B cells (Bregs), has recently been shown to restrain excessive inflammatory responses in autoimmune diseases. In the present study, we investigated the impact of human adipose-derived MSCs on Bregs and their therapeutic effect in an animal model of systemic lupus erythematosus (SLE). Coculture of human adipose derived MSCs with splenocytes from C57BL/6 mice expanded the population of interleukin-10-producing B cells (B10 B cells). In vivo treatment with human adipose-derived MSCs reduced serum anti-double-stranded antibody levels and improved renal pathology of lupus mice (Roquin(san/san) mice). MSCs decreased ICOS(+)CD44(+) follicular helper T cells, Th1 cells and Th17 cells, in spleens of Roquin(san/san) mice. In contrast, MSCs increased Foxp3-expressing regulatory T cells. MSCs also decreased the size and number of germinal centers and effector B cells. As expected, in vivo treatment with MSCs expanded the population of Bregs in spleens of Roquin(san/san) mice. Our results indicate that human adipose derived MSCs induce the expansion of Bregs and ameliorate autoimmunity in a murine model of SLE. These findings suggest that human adipose-derived MSCs may be a promising therapeutic strategy targeting B-cell-mediated autoimmune diseases such as SLE. PMID- 25506686 TI - Terahertz time-domain spectroscopy and quantitative analysis of metal gluconates. AB - A series of metal gluconates (Na(+), K(+), Mg(2+), Ca(2+), Fe(2+), Cu(2+), and Zn(2+)) were investigated by terahertz (THz) time-domain spectroscopy. The absorption coefficients and refractive indices of the samples were obtained in the frequency range of 0.5-2.6 THz. The gluconates showed distinct THz characteristic fingerprints, and the dissimilarities reflect their different structures, hydrogen-bond networks, and molecular interactions. In addition, some common features were observed among these gluconates, and the similarities probably come from the similar carbohydrate anion group. The X-ray powder diffraction measurements of these metal gluconates were performed, and the copper(II) gluconate was found to be amorphous, corresponding to the monotonic increase feature in the THz absorption spectrum. The results suggest that THz spectroscopy is sensitive to molecular structure and physical form. Binary and ternary mixtures of different gluconates were quantitatively analyzed based on the Beer-Lambert law. A chemical map of a tablet containing calcium D-gluconate monohydrate and alpha-lactose in the polyethylene host was obtained by THz imaging. The study shows that THz technology is a useful tool in pharmaceutical research and quality control applications. PMID- 25506687 TI - DFO enhances the targeting of CD34-positive cells and improves neovascularization. AB - Desferrioxamine (DFO), an iron chelator, mimicked hypoxia by inhibiting HIF 1alpha degradation and upregulated angiogenic factors. In this experiment, we elucidated the effect of DFO on CD34-positive cell migration and neovascularization. CD34-positive cells were cultured in media with DFO or an inhibitor and subjected to in vitro tubule formation and the expression of factors. Nude mice were randomly divided into five groups of 12: control, CD34, CD34-DFO, CD34-DFO-AMD (AMD3100, CXCR4 inhibitor), and CD34-DFO-LY (LY294002, the PI3K inhibitor) groups. Limb perfusion and in vivo imaging was evaluated by laser speckle imaging (LSI) and bioluminescence imaging (BLI). Capillary density was examined 14 days after surgery, and the relevant mechanism was also explored. In vitro, DFO significantly increased the tube formation and expression of angiogenic factors in CD34-positive cells, which were blocked by the PI3K inhibitor, LY294002. DFO enhanced blood flow, the function of the ischemic hindlimb, and the levels of VEGF. Further, p-eNOS and p-Akt increased in response to the ischemia. BLI showed that DFO increased the number of CD34-positive cells targeted to the ischemic sites. Immunohistofluorescence revealed that the capillary density in the ischemic hindlimb was significantly higher in the DFO treatment group compared with the other groups. However, all of these effects were diminished by LY294002. DFO treatment enhanced CD34-positive cell targeting and improved neovascularization via the PI3K/Akt signal transduction pathway in an ischemic hindlimb. PMID- 25506688 TI - Spectral and dynamic characteristics of helium plasma emission and its effect on a laser-ablated target emission in a double-pulse laser-induced breakdown spectroscopy (LIBS) experiment. AB - A systematic study has been performed on the spectral characteristics of the full spectrum of He emission lines and their time-dependent behaviors measured from the He gas plasmas generated by a nanosecond neodymium-doped yttrium aluminum garnet laser. It is shown that among the major emission lines observed, the triplet He(I) 587.6 nm emission line stands out as the most prominent and long lasting line, associated with de-excitation of the metastable triplet (S = 1) excited state (1s(1) 3d(1)). The role of this metastable excited state is manifested in the intensity enhancement and prolonged life time of the Cu emission with narrow full width half-maximum, as demonstrated in an orthogonal double-pulse experiment using a picosecond laser for the target ablation and a nanosecond laser for the prior generation of the ambient He gas plasma. These desirable emission features are in dire contrast to the characteristics of emission spectra observed with N2 ambient gas having no metastable excited state, which exhibit an initial Stark broadening effect and rapid intensity diminution typical to thermal shock wave-induced emission. The aforementioned He metastable excited state is therefore responsible for the demonstrated favorable features. The advantage of using He ambient gas in the double-pulse setup is further confirmed by the emission spectra measured from a variety of samples. The results of this study have thus shown the potential of extending the existing laser induced breakdown spectroscopy application to high-sensitivity and high resolution spectrochemical analysis of wide-ranging samples with minimal destructive effect on the sample surface. PMID- 25506689 TI - T cell epitope mapping of the e-protein of West Nile virus in BALB/c mice. AB - West Nile virus (WNV) is a zoonotic virus, which is transmitted by mosquitoes. It is the causative agent of the disease syndrome called West Nile fever. In some human cases, a WNV infection can be associated with severe neurological symptoms. The immune response to WNV is multifactorial and includes both humoral and cellular immunity. T-cell epitope mapping of the WNV envelope (E) protein has been performed in C57BL/6 mice, but not in BALB/c mice. Therefore, we performed in BALB/c mice a T-cell epitope mapping using a series of peptides spanning the WNV envelope (E) protein. To this end, the WNV-E specific T cell repertoire was first expanded by vaccinating BALB/c mice with a DNA vaccine that generates subviral particles that resemble West Nile virus. Furthermore, the WNV structural protein was expressed in Escherichia coli as a series of overlapping 20-mer peptides fused to a carrier-protein. Cytokine-based ELISPOT assays using these purified peptides revealed positive WNV-specific T cell responses to peptides within the different domains of the E-protein. PMID- 25506690 TI - STIM1 positively regulates the Ca2+ release activity of the inositol 1,4,5 trisphosphate receptor in bovine aortic endothelial cells. AB - The endothelium is actively involved in many functions of the cardiovascular system, such as the modulation of arterial pressure and the maintenance of blood flow. These functions require a great versatility of the intracellular Ca2+ signaling that resides in the fact that different signals can be encoded by varying the frequency and the amplitude of the Ca2+ response. Cells use both extracellular and intracellular Ca2+ pools to modulate the intracellular Ca2+ concentration. In non-excitable cells, the inositol 1,4,5-trisphosphate receptor (IP3R), located on the endoplasmic reticulum (ER), is responsible for the release of Ca2+ from the intracellular store. The proteins STIM1 and STIM2 are also located on the ER and they are involved in the activation of a store-operated Ca2+ entry (SOCE). Due to their Ca2+ sensor property and their close proximity with IP3Rs on the ER, STIMs could modulate the activity of IP3R. In this study, we showed that STIM1 and STIM2 are expressed in bovine aortic endothelial cells and they both interact with IP3R. While STIM2 appears to play a minor role, STIM1 plays an important role in the regulation of agonist-induced Ca2+ mobilization in BAECs by a positive effect on both the SOCE and the IP3R-dependent Ca2+ release. PMID- 25506691 TI - Urinary excretion of fatty acid-binding protein 4 is associated with albuminuria and renal dysfunction. AB - BACKGROUND: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) is expressed in not only adipocytes and macrophages but also peritubular capillaries in the normal kidney. We recently demonstrated that ectopic expression of FABP4, but not FABP1 known as liver FABP (L-FABP), in the glomerulus is associated with progression of proteinuria and renal dysfunction. However, urinary excretion of FABP4 has not been investigated. METHODS: Subjects who participated in the Tanno-Sobetsu Study, a study with a population-based cohort design, in 2011 (n = 392, male/female: 166/226) were enrolled. Urinary FABP4 (U-FABP4) and urinary albumin-to-creatinine ratio (UACR) were measured. Change in estimated glomerular filtration rate (eGFR) was followed up one year later. RESULTS: In 93 (23.7%) of the 392 subjects, U FABP4 level was below the sensitivity of the assay. Subjects with undetectable U FABP4 were younger and had lower UACR and higher eGFR levels than subjects with measurable U-FABP4. U-FABP4 level was positively correlated with age, systolic blood pressure and levels of serum FABP4 (S-FABP4), triglycerides, hemoglobin A1c (HbA1c), urinary FABP1 (U-FABP1) and UACR (r = 0.360, p<0.001). Age, S-FABP4, U FABP1 and UACR were independent predictors of U-FABP4. On the other hand, systolic blood pressure, HbA1c and U-FABP4 were independently correlated with UACR. Reduction in eGFR after one year was significantly larger in a group with the highest tertile of baseline U-FABP4 than a group with the lowest tertile. CONCLUSIONS: Urinary FABP4 level is independently correlated with level of albuminuria and possibly predicts yearly decline of eGFR. U-FABP4 would be a novel biomarker of glomerular damage. PMID- 25506692 TI - A survey of management practices that influence performance and welfare of dairy calves reared in southern Brazil. AB - Here we report dairy calf management practices used by 242 smallholder family farmers in the South of Brazil. Data were collected via a semi-structured questionnaire with farmers, inspection of the production environment and an in depth interview with a sample of 26 farmers. Herds had an average of 22.3 lactating cows and an average milk production of 12.7 L/cow/day. Calves were dehorned in 98% of the farms, with a hot iron in 95%. Male calves were castrated in 71% of the farms; methods were surgery (68%), emasculator (29%), or rubber rings (3%). No pain control was used for these interventions. In 51% of the farms all newborn male calves were reared, sold or donated to others; in 35% all newborn males were killed on the farm. Calves were separated from the dam up to 12 h after birth in 78% of the farms, and left to nurse colostrum from the dam without intervention in 55% of the farms. The typical amount of milk fed to calves was 4 L/day until a median age of 75 days. In 40% of the farms milk was provided in a bucket, in 49% with bottles, and in 11% calves suckled from a cow. Solid feeding in the milk-feeding period started at a median age of 10 days. Calves were housed individually in 70% of the farms; in 81% of the farms calves were housed in indoor pens, in 6% in outdoor hutches and in 13% they were kept on pasture. Diarrhoea was reported as the main cause of calf mortality in 71% of the farms. Farmers kept no records of calf disease, mortality, or use of medicines. Changing the scenario identified in this survey is essential to support the sustainable development of dairy production, an activity of great economic and social relevance for the region. PMID- 25506693 TI - Sheets of vertically aligned BaTiO3 nanotubes reduce cell proliferation but not viability of NIH-3T3 cells. AB - All biomaterials initiate a tissue response when implanted in living tissues. Ultimately this reaction causes fibrous encapsulation and hence isolation of the material, leading to failure of the intended therapeutic effect of the implant. There has been extensive bioengineering research aimed at overcoming or delaying the onset of encapsulation. Nanotechnology has the potential to address this problem by virtue of the ability of some nanomaterials to modulate interactions with cells, thereby inducing specific biological responses to implanted foreign materials. To this effect in the present study, we have characterised the growth of fibroblasts on nano-structured sheets constituted by BaTiO3, a material extensively used in biomedical applications. We found that sheets of vertically aligned BaTiO3 nanotubes inhibit cell cycle progression - without impairing cell viability - of NIH-3T3 fibroblast cells. We postulate that the 3D organization of the material surface acts by increasing the availability of adhesion sites, promoting cell attachment and inhibition of cell proliferation. This finding could be of relevance for biomedical applications designed to prevent or minimize fibrous encasement by uncontrolled proliferation of fibroblastic cells with loss of material-tissue interface underpinning long-term function of implants. PMID- 25506694 TI - Rural poor economies and foreign investors: an opportunity or a risk? AB - In the current age of commercial and financial openness, remote and poor local economies are becoming increasingly exposed to inflows of external capital. The new investors - enjoying lower credit constraints than local dwellers - might play a propulsive role in local development. At the same time, inflows of external capital can have negative impacts on local natural resource-dependent activities. We analyze a two-sector model where both sectors damage the environment, but only that of domestic producers relies on natural resources. We assess under which conditions the coexistence of the two sectors is compatible with sustainability, defined as convergence to a stationary state characterized by a positive stock of the natural resource. Moreover, we find that capital inflows can be stimulated by an increase in the pollution intensity of incoming activities, but also in the pollution intensity of the domestic sector; in both cases, capital inflows generate environmental degradation and a decrease in welfare for the local population. Finally, we show that a reduction in the cost of capital for external investors and the consequent capital inflows have the effect to increase wages, local investments and welfare of the local populations only if the environmental impact of the external sector is relatively low with respect to that of local activities. Otherwise, an unexpected scenario characterized by a reduction in domestic capital accumulation and the impoverishment of local agents can occur. PMID- 25506696 TI - Functional invertebrate prey groups reflect dietary responses to phenology and farming activity and pest control services in three sympatric species of aerially foraging insectivorous birds. AB - Farming activity severely impacts the invertebrate food resources of farmland birds, with direct mortality to populations of above-ground arthropods thorough mechanical damage during crop harvests. In this study we assessed the effects of phenological periods, including the timing of harvest, on the composition and biomass of prey consumed by three species of aerial insectivorous birds. Common Swifts Apus apus, Barn Swallows Hirundo rustica and House Martins Delichon urbica breed sympatrically and most of their diet is obtained from agricultural sources of invertebrate prey, especially from oil-seed rape crops. We categorized invertebrate prey into six functional groups, including oil-seed rape pests; pests of other arable crops; other crop-provisioned taxa; coprophilous taxa; and taxa living in non-crop and mixed crop/non-crop habitats. Seasonality impacted functional groups differently, but the general direction of change (increase/decrease) of all groups was consistent as indexed by prey composition of the three aerial insectivores studied here. After the oil-seed rape crop harvest (mid July), all three species exhibited a dietary shift from oil-seed rape insect pests to other aerial invertebrate prey groups. However, Common Switfts also consumed a relative large quantity of oil-seed rape insect pests in the late summer (August), suggesting that they could reduce pest insect emigration beyond the host plant/crop. Since these aerially foraging insectivorous birds operate in specific conditions and feed on specific pest resources unavailable to foliage/ground foraging avian predators, our results suggest that in some crops like oil-seed rape cultivations, the potential integration of the insectivory of aerial foraging birds into pest management schemes might provide economic benefits. We advise further research into the origin of airborne insects and the role of aerial insectivores as agents of the biological control of crop insect pests, especially the determination of depredation rates and the cascading effects of insectivory on crop damage and yield. PMID- 25506695 TI - Targeting SR proteins improves SMN expression in spinal muscular atrophy cells. AB - Spinal muscular atrophy (SMA) is one of the most common inherited causes of pediatric mortality. SMA is caused by deletions or mutations in the survival of motor neuron 1 (SMN1) gene, which results in SMN protein deficiency. Humans have a centromeric copy of the survival of motor neuron gene, SMN2, which is nearly identical to SMN1. However, SMN2 cannot compensate for the loss of SMN1 because SMN2 has a single-nucleotide difference in exon 7, which negatively affects splicing of the exon. As a result, most mRNA produced from SMN2 lacks exon 7. SMN2 mRNA lacking exon 7 encodes a truncated protein with reduced functionality. Improving SMN2 exon 7 inclusion is a goal of many SMA therapeutic strategies. The identification of regulators of exon 7 inclusion may provide additional therapeutic targets or improve the design of existing strategies. Although a number of regulators of exon 7 inclusion have been identified, the function of most splicing proteins in exon 7 inclusion is unknown. Here, we test the role of SR proteins and hnRNP proteins in SMN2 exon 7 inclusion. Knockdown and overexpression studies reveal that SRSF1, SRSF2, SRSF3, SRSF4, SRSF5, SRSF6, SRSF7, SRSF11, hnRNPA1/B1 and hnRNP U can inhibit exon 7 inclusion. Depletion of two of the most potent inhibitors of exon 7 inclusion, SRSF2 or SRSF3, in cell lines derived from SMA patients, increased SMN2 exon 7 inclusion and SMN protein. Our results identify novel regulators of SMN2 exon 7 inclusion, revealing potential targets for SMA therapeutics. PMID- 25506699 TI - Apoptotic efficacy of etomoxir in human acute myeloid leukemia cells. Cooperation with arsenic trioxide and glycolytic inhibitors, and regulation by oxidative stress and protein kinase activities. AB - Fatty acid synthesis and oxidation are frequently exacerbated in leukemia cells, and may therefore represent a target for therapeutic intervention. In this work we analyzed the apoptotic and chemo-sensitizing action of the fatty acid oxidation inhibitor etomoxir in human acute myeloid leukemia cells. Etomoxir caused negligible lethality at concentrations up to 100 uM, but efficaciously cooperated to cause apoptosis with the anti-leukemic agent arsenic trioxide (ATO, Trisenox), and with lower efficacy with other anti-tumour drugs (etoposide, cisplatin), in HL60 cells. Etomoxir-ATO cooperation was also observed in NB4 human acute promyelocytic cells, but not in normal (non-tumour) mitogen stimulated human peripheral blood lymphocytes. Biochemical determinations in HL60 cells indicated that etomoxir (25-200 uM) dose-dependently inhibited mitochondrial respiration while slightly stimulating glycolysis, and only caused marginal alterations in total ATP content and adenine nucleotide pool distribution. In addition, etomoxir caused oxidative stress (increase in intracellular reactive oxygen species accumulation, decrease in reduced glutathione content), as well as pro-apoptotic LKB-1/AMPK pathway activation, all of which may in part explain the chemo-sensitizing capacity of the drug. Etomoxir also cooperated with glycolytic inhibitors (2-deoxy-D-glucose, lonidamine) to induce apoptosis in HL60 cells, but not in NB4 cells. The combined etomoxir plus 2-deoxy-D-glucose treatment did not increase oxidative stress, caused moderate decrease in net ATP content, increased the AMP/ATP ratio with concomitant drop in energy charge, and caused defensive Akt and ERK kinase activation. Apoptosis generation by etomoxir plus 2-deoxy-D-glucose was further increased by co incubation with ATO, which is apparently explained by the capacity of ATO to attenuate Akt and ERK activation. In summary, co-treatment with etomoxir may represent an interesting strategy to increase the apoptotic efficacy of ATO and (with some limitations) 2-deoxy-D-glucose which, although clinically important anti-tumour agents, exhibit low efficacy in monotherapy. PMID- 25506701 TI - Planning study of flattening filter free beams for volumetric modulated arc therapy in squamous cell carcinoma of the scalp. AB - PURPOSE: Flattening filter free (FFF) beams show the potential for a higher dose rate and lower peripheral dose. We investigated the planning study of FFF beams with their role for volumetric modulated arc therapy (VMAT) in squamous cell carcinoma of the scalp. METHODS AND MATERIALS: One patient with squamous cell carcinoma which had involvement of entire scalp was subjected to VMAT using TrueBeam linear accelerator. As it was a rare skin malignancy, CT data of 7 patients with brain tumors were also included in this study, and their entire scalps were outlined as target volumes. Three VMAT plans were employed with RapidArc form: two half-field full-arcs VMAT using 6 MV standard beams (HFF-VMAT FF), eight half-field quarter-arcs VMAT using 6 MV standard beams (HFQ-VMAT-FF), and HFQ-VMAT using FFF beams (HFQ-VMAT-FFF). Prescribed dose was 25 * 2 Gy (50 Gy). Plan quality and efficiency were assessed for all plans. RESULTS: There were no statistically significant differences among the three VMAT plans in target volume coverage, conformity, and homogeneity. For HFQ-VMAT-FF plans, there was a significant decrease by 12.6% in the mean dose to the brain compared with HFF VMAT-FF. By the use of FFF beams, the mean dose to brain in HFQ-VMAT-FFF plans was further decreased by 7.4% compared with HFQ-VMAT-FF. Beam delivery times were similar for each technique. CONCLUSIONS: The HFQ-VMAT-FF plans showed the superiority in dose distributions compared with HFF-VMAT-FF. HFQ-VMAT-FFF plans might provide further normal tissue sparing, particularly in the brain, showing their potential for radiation therapy in squamous cell carcinoma of the scalp. PMID- 25506703 TI - Mapping interdisciplinary fields: efficiencies, gaps and redundancies in HIV/AIDS research. AB - While interdisciplinarity continues to increase in popularity among funders and other scientific organizations, its potential to promote scientific advances remains under-examined. For HIV/AIDS research, we examine the dynamics of disciplinary integration (or lack thereof) providing insight into a field's knowledge base and those questions that remain unresolved. Drawing on the complete histories of two interdisciplinary journals, we construct bibliographic coupling networks based on overlapping citations to identify segregation into research clusters and estimate topic models of research content. We then compare how readily those bibliographic coupling clusters account for the structuring of topics covered within the field as it evolves over two decades. These comparisons challenge one-dimensional and/or cross-sectional approaches to interdisciplinarity. Some topics are increasingly coordinated across disciplinary boundaries (e.g., vaccine development); others remain relatively segmented into disconnected disciplinary domains for the full period (e.g., drug resistance). This divergence indicates heterogeneity in interdisciplinarity and emphasizes the need for critical approaches to studying the organization of science. PMID- 25506700 TI - Post diagnosis diet quality and colorectal cancer survival in women. AB - BACKGROUND: Dietary factors are known to influence colorectal cancer (CRC) risk, however, their association with CRC survival is unclear. Therefore, we prospectively examined the association between diet quality scores, dietary patterns and colorectal cancer (CRC) survival. METHODS: 1201 women diagnosed with stage I-III CRC between 1986 and 2008, were followed through 2010. Diet was assessed via a food frequency questionnaire administered at least 6 months after diagnosis. We computed the Alternate Healthy Eating Index-2010 (AHEI-2010), alternate Mediterranean Diet score (aMED) and Dietary Approaches to Stop Hypertension score (DASH) and derived two dietary patterns, Western (unhealthy) and prudent (healthy), by principal component analysis for each woman. RESULTS: During follow-up, we documented 435 deaths, including 162 from CRC. After adjusting for potential confounders, only a higher AHEI-2010 score was significantly associated with lower overall mortality (HR comparing extreme quintiles = 0.71, 95% CI 0.52-0.98, p trend = 0.01) as well as borderline significantly with lower risk of CRC mortality by the trend test (HR Q5 vs Q1 = 0.72, 95% CI = 0.43-1.21, p trend = 0.07). When AHEI-2010 components were examined separately, inverse associations for overall mortality were primarily accounted for by moderate alcohol intake (HR comparing abstainers vs 5-15 g/d = 1.30, 95%CI = 1.05-1.61) and lower intake of sugar sweetened beverages and fruit juices combined (HR for each additional serving = 1.11, 95% CI = 1.01-1.23). No other diet quality score or dietary pattern was associated with overall or CRC specific mortality. CONCLUSION: Higher AHEI-2010 score may be associated with lower overall mortality, moderate alcohol consumption and lower consumption of sugar sweetened beverages and juices combined appeared to account for most of the observed associations. PMID- 25506704 TI - Standardization of Procedures for the Preparation of (177)Lu- and (90)Y-labeled DOTA-Rituximab Based on the Freeze-dried Kit Formulation. AB - Rituximab when radiolabelled with (177)Lu or (90)Y has been investigated for the treatment of patients with Non-Hodgkin's Lymphoma. In this study, we optimized the preparation of antibody conjugates with chelating agent in the freeze-dried kit. It shortens procedures needed for the successful radiolabeling with lutetium 177 and yttrium-90 and assures reproducible labelling yields. Various molar ratios of Rituximab:DOTA (from 1:5 to 1:100) were used at the conjugation step and different purification method to remove unbound DOTA were investigated (size exclusion chromatography, dialysis, ultrafiltration). The final monoclonal antibody concentration was quantified by Bradford method, and the number of DOTA molecules was determined by radiolabeling assay using (64)Cu. The specific activity of (177)Lu-DOTA-Rituximab and (90)Y-DOTA-Rituximab were optimized using various amounts of radiometal. Quality control (SE-HPLC, ITLC) and stability study were performed. An average of 4.2 +/- 0.8 p-SCN-Bz-DOTA molecules could be randomly conjugated to a single molecule of Rituximab. The ultrafiltration system was the most efficient for purification and resulted in the highest recovery efficiency (77.2%). At optimized conditions the (177)Lu-DOTARituximab and (90)Y DOTA-Rituximab were obtained with radiochemical purity >99% and specific activity ca. 600 MBq/mg. The radioimmunoconjugates were stable in human serum and 0.9% NaCl. After 72 h of incubation the radiochemical purity of (177)Lu-DOTA-Rituximab decreased to 94% but it was still more than 88% for (90)Y-DOTA-Rituximab. The radioimmunoconjugate showed stability after six months storage at 2 - 8(0)C, as a lyophilized formulation. Our study shows that Rituximab-DOTA can be efficiently radiolabeled with (177)Lu and (90)Y via p-SCN-Bn-DOTA using a freezedried kit. PMID- 25506702 TI - Effects of anti-angiogenesis on glioblastoma growth and migration: model to clinical predictions. AB - Glioblastoma multiforme (GBM) causes significant neurological morbidity and short survival times. Brain invasion by GBM is associated with poor prognosis. Recent clinical trials of bevacizumab in newly-diagnosed GBM found no beneficial effects on overall survival times; however, the baseline health-related quality of life and performance status were maintained longer in the bevacizumab group and the glucocorticoid requirement was lower. Here, we construct a clinical-scale model of GBM whose predictions uncover a new pattern of recurrence in 11/70 bevacizumab treated patients. The findings support an exception to the Folkman hypothesis: GBM grows in the absence of angiogenesis by a cycle of proliferation and brain invasion that expands necrosis. Furthermore, necrosis is positively correlated with brain invasion in 26 newly-diagnosed GBM. The unintuitive results explain the unusual clinical effects of bevacizumab and suggest new hypotheses on the dynamic clinical effects of migration by active transport, a mechanism of hypoxia driven brain invasion. PMID- 25506705 TI - Monitoring Kidney Function in Neuroendocrine Tumor Patients Treated with (90)Y DOTATOC: Associations with Risk Factors. AB - Peptide receptor radionuclide therapy (PRRT) is an established treatment for progressive neuroendocrine tumours with nephrotoxicity as the limiting factor. It is therefore important to monitor kidney function changes after PRRT treatment. We aimed to investigate kidney function by different methods and during a 4-hour and a 24-hour amino acid (AA) infusion protocol. We measured the Glomerular Filtration Rate (GFR) in 28 patients before and 3, 6, 12, and 18 months after (90)YDOTATOC therapy. We used standardized (51)Cr-EDTA plasma clearance (Cr-GFR) and estimated GFR (eGFR) by the simplified 4 variable Modification of Diet in Renal Disease based on serum creatinine values. Further, we determined GFR in 15 patients treated with a 4-hour infusion of AA compared to 13 patients with a 24 hour infusion at 3, 6, 12 and 18 months after therapy. Pre-existing risk factors associated with kidney failure were seen in 82% of the patients. We observed a significant reduction in Cr-GFR up to 12 months after PRRT (mean loss 27 ml/min/1.73 m(2) (32%)). The eGFR continuously overestimated the Cr-GFR with a bias of 8%. There was no significant difference between the two AA protocols, however, the 24-hour AA protocol tended to reduce mean Cr-GFR loss 12 months post therapy. Pre-existing risk factors for kidney failure were highly prevalent in this patient cohort, and kidney function after PRRT treatment is best monitored by (51)Cr-EDTA plasma clearance. Further, the use of a 24-hour AA kidney protection protocol seems to reduce the loss of kidney function in these patients. PMID- 25506708 TI - We can see the (risks of UV) light. PMID- 25506706 TI - Avidity of anti-circumsporozoite antibodies following vaccination with RTS,S/AS01E in young children. AB - BACKGROUND: The nature of protective immune responses elicited by immunization with the candidate malaria vaccine RTS,S is still incompletely understood. Antibody levels correlate with protection against malaria infection, but considerable variation in outcome is unexplained (e.g., children may experience malaria despite high anti-circumsporozoite [CS] titers). METHODS AND FINDINGS: We measured the avidity index (AI) of the anti-CS antibodies raised in subgroup of 5 17 month old children in Kenya who were vaccinated with three doses of RTS,S/AS01E between March and August 2007. We evaluated the association between the AI and the subsequent risk of clinical malaria. We selected 19 cases (i.e., with clinical malaria) and 42 controls (i.e., without clinical malaria), matching for anti-CS antibody levels and malaria exposure. We assessed their sera collected 1 month after the third dose of the vaccine, in March 2008 (range 4-10 months after the third vaccine), and at 12 months after the third vaccine dose. The mean AI was 45.2 (95% CI: 42.4 to 48.1), 45.3 (95% CI: 41.4 to 49.1) and 46.2 (95% CI; 43.2 to 49.3) at 1 month, in March 2008 (4-10 months), and at 12 months after the third vaccination, respectively (p = 0.9 by ANOVA test for variation over time). The AI was not associated with protection from clinical malaria (OR = 0.90; 95% CI: 0.49 to 1.66; p = 0.74). The AI was higher in children with high malaria exposure, as measured using the weighted local prevalence of malaria, compared to those with low malaria exposure at 1 month post dose 3 (p = 0.035). CONCLUSION: Our data suggest that in RTS,S/AS01E-vaccinated children residing in malaria endemic countries, the avidity of anti-circumsporozoite antibodies, as measured using an elution ELISA method, was not associated with protection from clinical malaria. Prior natural malaria exposure might have primed the response to RTS,S/AS01E vaccination. PMID- 25506709 TI - Synthesis of 2-amino-1,3,4-oxadiazoles and 2-amino-1,3,4-thiadiazoles via sequential condensation and I2-mediated oxidative C-O/C-S bond formation. AB - 2-Amino-substituted 1,3,4-oxadiazoles and 1,3,4-thiadiazoles were synthesized via condensation of semicarbazide/thiosemicarbazide and the corresponding aldehydes followed by I2-mediated oxidative C-O/C-S bond formation. This transition-metal free sequential synthesis process is compatible with aromatic, aliphatic, and cinnamic aldehydes, providing facile access to a variety of diazole derivatives bearing a 2-amino substituent in an efficient and scalable fashion. PMID- 25506707 TI - HSPD1 interacts with IRF3 to facilitate interferon-beta induction. AB - The production of IFN- I (IFN-alpha/beta) is one of the earliest and most important host-protective responses. Interferon regulatory factor 3 (IRF3) is a critical transcriptional factor in the IFN-beta signaling pathway. Although significant progress has been achieved in the regulation of IRF3, the process may be more complicated than previously considered. In the present study, heat shock protein 60 (HSP60, HSPD1) was identified as a novel IRF3-interacting protein. Overexpression of HSPD1 facilitated the phosphorylation and dimerization of IRF3 and enhanced IFN-beta induction induced by SeV infection. In contrast, knockdown of endogenous HSPD1 significantly inhibited the signaling pathway. Furthermore, HSPD1 enhanced activation of the IFN-beta promoter mediated by RIG-I, MDA-5, MAVS, TBK1 and IKKepsilon but not IRF3/5D, a mock phosphorylated form of IRF3. The present study indicated that HSPD1 interacted with IRF3 and it contributed to the induction of IFN-beta. PMID- 25506710 TI - Strain-driven mound formation of substrate under epitaxial nanoparticles. AB - We observe the growth of crystalline SiC nanoparticles on Si(001) at 900 degrees C using in situ electron microscopy. Following nucleation and growth of the SiC, there is a massive migration of Si, forming a crystalline Si mound underneath each nanoparticle that lifts it 4-5 nm above the initial growth surface. The volume of the Si mounds is roughly five to seven times the volume of the SiC nanoparticles. We propose that relaxation of strain drives the mound formation. This new mechanism for relieving interfacial strain, which involves a dramatic restructuring of the substrate, is in striking contrast to the familiar scenario in which only the deposited material restructures to relieve strain. PMID- 25506711 TI - Cu(II) galvanic reduction and deposition onto iron nano- and microparticles: resulting morphologies and growth mechanisms. AB - The galvanic reduction of heavy metal ions by zerovalent iron nanoparticles is a key process occurring extensively in wastewater remediation, as well as for the synthesis of materials, including catalysts. In this work, we studied the growth of copper species on nano- and micrometer-sized iron particles and investigated the morphologies of the resulting structures. The growth proceeds via sacrificial oxidation of iron particles and reduction of Cu(2+) cations from aqueous solutions. Based on the results of transmission and scanning electron microscopy (TEM and SEM), coupled with energy-dispersive X-ray spectroscopy (EDX), electron energy loss spectroscopy (EELS), and X-ray photoelectron spectroscopy (XPS), we proposed two growth mechanisms for the morphologies seen for the copper exposed nano- and microiron particles at varying copper/iron ratios. We observed that, in low Cu/Fe ratios (<=1/100), copper particles decorated the oxide shell of the iron nano/microparticles, while in higher Cu/Fe ratios (>=1/10), Cu-rich hollow structures were formed. Iron microparticles also led to the formation of interesting Cu-fern structures. This study provides insight into the fate of particles used in remediation, as well as recommendations for the synthesis of well-defined materials tailored for precise applications. PMID- 25506712 TI - Simple and improved approaches to long-lasting, hydrophilic silicones derived from commercially available precursors. AB - Three types of commercially derived methylsilicone materials, Sylgard-184, Q(V)Q(H) (an MQ-based silicone containing no dimethylsiloxane, D units), and D(V)D(H) (a D-based silicone with no additives), were judiciously chosen to study the conditions under which long-lasting hydrophilicity after oxygen plasma treatment can be obtained. A 30 s plasma treatment time under controlled conditions was found to be optimal in terms of achieving the lowest initial advancing and receding contact angles of theta(A)/theta(R) = 10 degrees /5 degrees with undetectable surface damage. Vacuum treatment, a necessary step prior to plasma ignition that has been overlooked in previous studies, as well as room temperature curing were explored as means to remove low molecular weight species. For thin films (a few micrometers), 40 min vacuum treatment was sufficient to achieve low dynamic contact angles of theta(A)/theta(R) = 51-56 degrees /38-43 degrees on all three types of silicones measured more than 30 days after the plasma treatments. These values indicate superior hydrophilicity relative to what has been reported. The small and slow rise in contact angle over time is likely caused by the intrinsic nature of the silicone materials, i.e., surface reorientation of hydrophilic functional groups to the bulk and condensation of surface silanol groups, and is thus unavoidable. For thick films (~1 mm), room temperature curing in addition to vacuum treatment was required to reduce hydrophobic recovery and to achieve long-lasting hydrophilicity. The final contact angles for thick samples were slightly higher than the corresponding thin film samples due to the greater "reservoir" depth and migration length for mobile species. In particular, Sylgard exhibited inferior performance among the thick samples, and we attribute this to the additives in its commercial formulation. Furthermore, unlike polydimethylsiloxane-based silicones, Q(V)Q(H) does not contain equilibration products of the Dn-type; its thin films perform as well as those of Sylgard and D(V)D(H). Silicones without D units are promising materials with intrinsically low hydrophobic recovery characteristics and long-lasting hydrophilicity after oxygen plasma treatment. PMID- 25506713 TI - Poly(2-ethyl-2-oxazoline)-doxorubicin conjugate-based dual endosomal pH-sensitive micelles with enhanced antitumor efficacy. AB - Dual endosomal pH-sensitive micelles were designed and fabricated to deliver doxorubicin (DOX) for treating breast cancer based on a poly(2-ethyl-2-oxazoline) (PEOz)-DOX (PEOz-hyd-DOX) conjugate. PEOz-hyd-DOX was successfully synthesized by connecting DOX to PEOz via an acid cleavable hydrazone linker and self-assembled into nanosized micelles, which further physically encapsulated DOX. The conjugate and DOX-loaded conjugate micelles displayed faster release of DOX at pH 5.0 than at pH 7.4. This pH-dependent release behavior might assist the quick diffusion of DOX from acidic endosomes or lysosomes and the intracellular transfer into the nucleus after internalization, which was confirmed by confocal laser scanning microscopy images. As expected, PEOz-hyd-DOX conjugate and DOX-loaded conjugate micelles maintained cytotoxicity of DOX. In addition, the dual endosomal pH sensitive micelles were found to substantially enhance antitumor efficacy and reduce side effects compared with free DOX. Therefore, PEOz-hyd-DOX conjugate based micelles might be potential drug delivery vehicles of DOX for safe and effective breast cancer therapy. PMID- 25506714 TI - Correction to "Structure and Stability of Phospholipid Bilayers Hydrated by a Room-Temperature Ionic Liquid/Water Solution: A Neutron Reflectometry Study". PMID- 25506715 TI - Resonance Raman spectroscopy reveals pH-dependent active site structural changes of lactoperoxidase compound 0 and its ferryl heme O-O bond cleavage products. AB - The first step in the enzymatic cycle of mammalian peroxidases, including lactoperoxidase (LPO), is binding of hydrogen peroxide to the ferric resting state to form a ferric-hydroperoxo intermediate designated as Compound 0, the residual proton temporarily associating with the distal pocket His109 residue. Upon delivery of this "stored" proton to the hydroperoxo fragment, it rapidly undergoes O-O bond cleavage, thereby thwarting efforts to trap it using rapid mixing methods. Fortunately, as shown herein, both the peroxo and the hydroperoxo (Compound 0) forms of LPO can be trapped by cryoradiolysis, with acquisition of their resonance Raman (rR) spectra now permitting structural characterization of their key Fe-O-O fragments. Studies were conducted under both acidic and alkaline conditions, revealing pH-dependent differences in relative populations of these intermediates. Furthermore, upon annealing, the low pH samples convert to two forms of a ferryl heme O-O bond-cleavage product, whose nu(Fe?O) frequencies reflect substantially different Fe?O bond strengths. In the process of conducting these studies, rR structural characterization of the dioxygen adduct of LPO, commonly called Compound III, has also been completed, demonstrating a substantial difference in the strengths of the Fe-O linkage of the Fe-O-O fragment under acidic and alkaline conditions, an effect most reasonably attributed to a corresponding weakening of the trans-axial histidyl imidazole linkage at lower pH. Collectively, these new results provide important insight into the impact of pH on the disposition of the key Fe-O-O and Fe?O fragments of intermediates that arise in the enzymatic cycles of LPO, other mammalian peroxidases, and related proteins. PMID- 25506716 TI - Application of blind source separation to real-time dissolution dynamic nuclear polarization. AB - The use of a blind source separation (BSS) algorithm is demonstrated for the analysis of time series of nuclear magnetic resonance (NMR) spectra. This type of data is obtained commonly from experiments, where analytes are hyperpolarized using dissolution dynamic nuclear polarization (D-DNP), both in in vivo and in vitro contexts. High signal gains in D-DNP enable rapid measurement of data sets characterizing the time evolution of chemical or metabolic processes. BSS is based on an algorithm that can be applied to separate the different components contributing to the NMR signal and determine the time dependence of the signals from these components. This algorithm requires minimal prior knowledge of the data, notably, no reference spectra need to be provided, and can therefore be applied rapidly. In a time-resolved measurement of the enzymatic conversion of hyperpolarized oxaloacetate to malate, the two signal components are separated into computed source spectra that closely resemble the spectra of the individual compounds. An improvement in the signal-to-noise ratio of the computed source spectra is found compared to the original spectra, presumably resulting from the presence of each signal more than once in the time series. The reconstruction of the original spectra yields the time evolution of the contributions from the two sources, which also corresponds closely to the time evolution of integrated signal intensities from the original spectra. BSS may therefore be an approach for the efficient identification of components and estimation of kinetics in D DNP experiments, which can be applied at a high level of automation. PMID- 25506717 TI - Mesoporous organosilica nanoparticles containing superacid and click functionalities leading to cooperativity in biocidal coatings. AB - A superior degree of functionality in materials can be expected, if two or more operational entities are related in a cooperative form. It is obvious that, for this purpose, one is seeking materials with complex design comprising bi- or multiple functional groups complementing each other. In the current paper, it is demonstrated that periodically ordered mesoporous organosilicas (PMOs) based on co-condensation of sol-gel precursors with bridging phenyl derivatives RF1,2C6H3[Si(O(iso)Pr)3]2 allow for rich opportunities in providing high-surface area materials with such a special chemical architecture. PMOs containing high density of thiol (? RF1) and sulfonic acid units (? RF2) were prepared as mesoporous nanoparticles via an aerosol-assisted gas-phase method and were tested for biocidal applications. Each of the mentioned organic groups fulfills several tasks at once. The selective functionalization of thiols located at the surface of the particles using click chemistry leads to durable grafting on different substrates like glass or stainless steel, and the intraparticle -SH groups are important regarding the uptake of metal ions like Ag(+) and for immobilization of Ag(0) nanoparticles inside the pores as an enduring reservoir for antibacterial force. The superacidic sulfonic acid groups exhibit a strong and instantaneous biocidal acitivity, and they are important for adjusting the Ag(+) release rate. Biological studies involving inhibitory investigation tests (MIC), fluorescence microscopy (life/dead staining), and bacterial adhesion tests with Pseudomonas aeruginosa show that the organobifunctional materials present much better performance against biofilm formation compared to materials containing only one of the above-mentioned groups. PMID- 25506718 TI - (+/-)-Quassidines I and J, two pairs of cytotoxic bis-beta-carboline alkaloid enantiomers from Picrasma quassioides. AB - (+/-)-Quassidines I (1) and J (2), two pairs of new bis-beta-carboline alkaloid enantiomers, were isolated from the stems of Picrasma quassioides. Their structures were determined by the analysis of spectroscopic data, including HRESIMS and 2D NMR, and confirmed by single-crystal X-ray diffraction analysis. The racemic mixtures of 1 and 2 were resolved into two pairs of enantiomers, (+) S-1a and (-)-R-1b and (+)-S-2a and (-)-R-2b, by HPLC using a chiral Daicel IB-3 column, respectively, which represents the first successful example to resolve bis-beta-carboline racemic mixtures. The absolute configurations of the two pairs of enantiomers were determined by comparison between the calculated and experimental ECD spectra. The cytotoxicity evaluation revealed that (+)-S-1a and (+)-S-2a showed more potent cytotoxicity against human cervical HeLa and gastric MKN-28 cancer cell lines with IC50 values of 4.03-6.30 MUM than their enantiomers with IC50 values of 9.64-12.3 MUM; however, the two (+)-S-quassidines showed similar activities to their enantiomers against the mouse melanoma B-16 cancer cell line. PMID- 25506720 TI - Conformal nanopatterning of extracellular matrix proteins onto topographically complex surfaces. AB - Our Patterning on Topography (PoT) printing technique enables fibronectin, laminin and other proteins to be applied to biomaterial surfaces in complex geometries that are inaccessible using traditional soft lithography techniques. Engineering combinatorial surfaces that integrate topographical and biochemical micropatterns enhances control of the biotic-abiotic interface. Here, we used this method to understand cardiomyocyte response to competing physical and chemical cues in the microenvironment. PMID- 25506721 TI - Not all players are equally motivated: The role of narcissism. AB - Research on motivational climates consistently demonstrates that mastery-focused climates are associated with positive outcomes and ego-involving performance climates lead to maladaptive outcomes. However, the role of personality within such a framework has been largely ignored. To redress this imbalance, we examined the potential role of narcissism in moderating the effects of different motivational climates on leader-inspired extra effort in training. Training is where rugby players spend most of their rugby time and we were keen to examine the combination of personality and climate that might maximise the yield of such training environments. Female rugby players (n = 126) from 15 clubs completed measures of narcissism, motivational climate and effort. Moderated regression analyses revealed that narcissism moderated the relationship between motivational climate and effort. Increases in either performance or mastery climates were associated with increases in effort for narcissists; no such relationship was revealed for low narcissists. The findings demonstrate the importance of considering personality within rugby training environments, as it is clear that not every player will respond the same way to specific training conditions. Coaches who understand this and are able to tailor individualised motivational climates will likely gain the greatest benefits from their different players. PMID- 25506719 TI - Fast native-SAD phasing for routine macromolecular structure determination. AB - We describe a data collection method that uses a single crystal to solve X-ray structures by native SAD (single-wavelength anomalous diffraction). We solved the structures of 11 real-life examples, including a human membrane protein, a protein-DNA complex and a 266-kDa multiprotein-ligand complex, using this method. The data collection strategy is suitable for routine structure determination and can be implemented at most macromolecular crystallography synchrotron beamlines. PMID- 25506722 TI - Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans. AB - HLA-DRB1 is a sarcoidosis risk gene, and the *03:01 allele is strongly associated with disease resolution in European sarcoidosis cases. Whereas the HLA-DRB1 variation is associated with sarcoidosis susceptibility in African Americans, DRB1 risk alleles are not as well defined, and associations with disease resolution have not been studied. Associations between genotyped and imputed HLA DRB1 alleles and disease susceptibility/resolution were evaluated in a sample of 1,277 African-American patients with sarcoidosis and 1,467 control subjects. In silico binding assays were performed to assess the functional significance of the associated alleles. Increased disease susceptibility was associated with the HLA DRB1 alleles *12:01 (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.65 2.69; P = 3.2 * 10(-9)) and *11:01 (OR, 1.69; 95% CI, 1.42-2.01; P = 3.0 * 10( 9)). The strongest protective association was found with *03:01 (OR, 0.56; 95% CI, 0.44-0.73; P = 1.0 * 10(-5)). The African-derived allele *03:02 was associated with decreased risk of persistent radiographic disease (OR, 0.52; 95% CI, 0.37-0.72; P = 1.3 * 10(-4)), a finding consistent across the three component studies comprising the analytic sample. The DRB1*03:01 association with disease persistence was dependent upon local ancestry, with carriers of at least one European allele at DRB1 at a decreased risk of persistent disease (OR, 0.36; 95% CI, 0.14-0.94; P = 0.037). Results of in silico binding analyses showed that DRB1*03:01 consistently demonstrated the highest binding affinities for six bacterial peptides previously found in sarcoidosis granulomas, whereas *12:01 displayed the lowest binding affinities. This study has identified DRB1*03:01 and *03:02 as novel alleles associated with disease susceptibility and course in African Americans. Further investigation of DRB1*03 alleles may uncover immunologic factors that favor sarcoidosis protection and resolution among African Americans. PMID- 25506725 TI - The dismantling of Calliobothrium (Cestoda: Tetraphyllidea) with erection of Symcallio n. gen. and description of two new species. AB - This paper aims to resolve the dual composition of the triakid shark-hosted tetraphyllidean genus Calliobothrium--an issue that has been recognized for over a decade. As it stands, this genus includes a number of large species with laciniate proglottids, most of which bear 3 suckers at the anterior margin of each bothridium, but it also includes a number of species that lack proglottid laciniations and bear only a single sucker per bothridium, most of which are relatively small. Discovery of 2 new species, 1 of each form, parasitizing the whitespot smoothhound shark, Mustelus palumbes, off South Africa, prompted the first molecular analysis of the genus. Bayesian inference and maximum likelihood analyses of 28S rDNA (D1-D3) sequence data generated for specimens of both new species as well as of 2 known species of the laciniate form (Calliobothrium australis and Calliobothrium cf. verticillatum) and 3 known species of the non laciniate form (Calliobothrium violae, Calliobothrium riseri, and Calliobothrium barbarae) confirmed the reciprocal monophyly of the 2 clades, supporting establishment of a new genus. Because the type of Calliobothrium, C. verticillatum, is of the laciniate form, Symcallio n. gen., with Symcallio peteri n. gen., n. sp., from M. palumbes described as its type, is established to house members of the non-laciniate clade. The 11 described species consistent with this form are transferred to the new genus. A new species of the laciniate clade, Calliobothrium euzeti n. sp., is described from M. palumbes, and a revised diagnosis of Calliobothrium is presented. PMID- 25506724 TI - Smoking, internalized heterosexism, and HIV disease management among male couples. AB - High rates of cigarette smoking have been observed among HIV-positive individuals. Smoking has been linked to HIV-related medical complications and non AIDS defining cancers and negatively impacts on immune function and virologic control. Although internalized heterosexism has been related to smoking behaviors, little is known about associations between partners' reports of smoking, internalized heterosexism, and HIV medication management in male couples with HIV. A sample of 266 male couples completed baseline assessments for a cohort study examining relationship factors and HIV treatment. A computer-based survey assessed self-reported smoking behaviors, alcohol use, internalized heterosexism, and antiretroviral therapy (ART) adherence. HIV-positive men also provided blood samples to assess viral load. Approximately 30% of the sample reported that they are currently smoking cigarettes. After adjusting for demographic characteristics, men in a primary relationship with a partner who reported currently smoking had more than five-fold greater odds of reporting smoking. Higher levels of internalized heterosexism and financial hardship were each independently associated with greater odds of reporting smoking. Among HIV positive men on ART (n = 371), having a partner who reported smoking was associated with almost three-fold greater odds of having a detectable viral load. Our findings add new support to the evidence of romantic partners influencing each other's health behaviors, and demonstrate an association between smoking and disease management within male couples. Future research should explore the interpersonal and social contexts of smoking in order to develop interventions that meet the unique needs of male couples. PMID- 25506726 TI - 25 years of systemic therapies research: progress and promise. AB - OBJECTIVE: In this article we describe and assess the state of the science on systemic psychotherapies. In the quarter century since the first issue of Psychotherapy Research was published, considerable progress has been made. There is an increasingly solid evidence base for systemic treatments, which includes a wide range of approaches to working conjointly with couples and families. Moreover, there are exciting new developments that hold promise for explicating the dynamic processes of therapeutic change in couple and family systems. METHOD: We begin by explaining how we view "systemic therapies" as different from individual approaches and then summarize what we have learned in the past 25 years about this set of treatments, how we have learned it, and what we have yet to learn. RESULTS AND CONCLUSIONS: We consider current trends in research on outcomes and change process mechanisms, and end with speculations about what lies ahead in the interrelated domains of systemic research and practice. PMID- 25506727 TI - Small molecules for immunomodulation in cancer: a review. AB - Small-molecule cytotoxic agents are already in use for cancer immunotherapy in the form of antibody conjugates containing these molecules linked covalently to antibodies or their fragments with the goal of targeting specific surface components of tumor cells. However, there are also reports of small molecules that act as antagonists to surface enzyme-linked receptors and receptors that interact with the tumor microenvironment, or that even inhibit metabolic enzymes. Such molecules have been shown to directly inhibit the signaling initiated by the respective ligands binding to their receptors, to recruit antibodies and other immunomodulatory molecules, or to promote or inhibit the proliferation of different immune cells to target specific types of cancer cells. This review will discuss immune response modifiers such as imiquimod, antibody-recruiting molecules that target prostate cancer, integrin receptor antagonists, indoleamine 2,3-dioxygenase inhibitors, emodin, RORgammat antagonists, ephrin receptor antagonists, membrane-bound carbonic anhydrase IX (CAIX) inhibitors, and selected protein kinase inhibitors. These small molecules can open up new ways to treat many types of cancers and possibly even other diseases that arise from immune dysregulation. Finally, the review will briefly discuss some additional targets that are being pursued to modify immune system responses in the tumor microenvironment. PMID- 25506728 TI - [Sense and nonsense of ophthalmological eponyms]. PMID- 25506723 TI - Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca(2+) regulation in airway smooth muscle (ASM). AB - Airway inflammation is a key aspect of diseases such as asthma. Several inflammatory cytokines (e.g., TNFalpha and IL-13) increase cytosolic Ca(2+) ([Ca(2+)]cyt) responses to agonist stimulation and Ca(2+) sensitivity of force generation, thereby enhancing airway smooth muscle (ASM) contractility (hyper reactive state). Inflammation also induces ASM proliferation and remodeling (synthetic state). In normal ASM, the transient elevation of [Ca(2+)]cyt induced by agonists leads to a transient increase in mitochondrial Ca(2+) ([Ca(2+)]mito) that may be important in matching ATP production with ATP consumption. In human ASM (hASM) exposed to TNFalpha and IL-13, the transient increase in [Ca(2+)]mito is blunted despite enhanced [Ca(2+)]cyt responses. We also found that TNFalpha and IL-13 induce reactive oxidant species (ROS) formation and endoplasmic/sarcoplasmic reticulum (ER/SR) stress (unfolded protein response) in hASM. ER/SR stress in hASM is associated with disruption of mitochondrial coupling with the ER/SR membrane, which relates to reduced mitofusin 2 (Mfn2) expression. Thus, in hASM it appears that TNFalpha and IL-13 result in ROS formation leading to ER/SR stress, reduced Mfn2 expression, disruption of mitochondrion-ER/SR coupling, decreased mitochondrial Ca(2+) buffering, mitochondrial fragmentation, and increased cell proliferation. PMID- 25506729 TI - Dependence of Raman and resonance Raman intensities on sample self-absorption. AB - Resonance Raman cross sections are generally larger than normal or preresonance Raman cross sections. Thus, higher Raman intensities are expected for resonance excitation, especially for backscattering measurements. However, self absorption decreases the observed Raman intensities. In the work here we examine the effect of self absorption on the observed preresonance and resonance Raman intensities. For the simplest case where a single electronic transition dominates the Raman scattering, and where the resonance enhancement scales with the square of the molar absorptivity of the absorption band, theory predicts that for close to resonance excitation the observed Raman intensities monotonically increase as resonance is approached. In the case that an impurity absorbs, the observed Raman intensities may decrease as excitation moves close to resonance for particular conditions of impurity absorption band widths and frequency offsets. Impurity absorption also causes decreases in observed Raman intensities for the more slowly increasing preresonance excitation. PMID- 25506730 TI - Regional implantation of autologous adipose tissue-derived cells induces a prompt healing of long-lasting indolent digital ulcers in patients with systemic sclerosis. AB - Digital ulcers (DUs) are a rather frequent and invalidating complication in systemic sclerosis (SSc), often showing a very slow or null tendency to heal, in spite of the commonly used systemic and local therapeutic procedures. Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. In the present study, we have tentatively treated long-lasting and poorly responsive to traditional therapy SSc-related DUs by implantation of autologous adipose tissue-derived cell (ATDC) fractions. Fifteen patients with SSc having a long lasting DU in only one fingertip who were unresponsive to intensive systemic and local treatment were enrolled in the study. The grafting procedure consisted of the injection, at the basis of the corresponding finger, of 0.5-1 ml of autologous ATDC fractions, separated by centrifugation of adipose tissue collected through liposuction from subcutaneous abdominal fat. Time to heal after the procedure was the primary end point of the study, while reduction of pain intensity and of analgesic consumption represented a secondary end point. Furthermore, the posttherapy variation of the number of capillaries, observed in the nailfold video capillaroscopy (NVC) exam and of the resistivity in the digit arteries, measured by high-resolution echocolor-Doppler, were also taken into account. A rather fast healing of the DUs was reached in all of the enrolled patients (mean time to healing 4.23 weeks; range 2-7 weeks). A significant reduction of pain intensity was observed after a few weeks (p < 0.001), while the number of capillaries was significantly increased at 3- and 6-month NVC assessment (p < 0.0001 in both cases). Finally, a significant after-treatment reduction of digit artery resistivity was also recorded (p < 0.0001). Even with the limitations related to the small number of patients included and to the open label design of the study, the observed strongly favorable outcome suggests that local grafting with ATDCs could represent a promising option for the treatment of SSc-related DUs unresponsive to more consolidated therapies. PMID- 25506731 TI - Indoor tanning-related injuries treated in a national sample of US hospital emergency departments. PMID- 25506732 TI - Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation positive cohort. AB - IMPORTANCE: Numerically, the most important genetic risk factor for the development of Parkinson disease (PD) is the presence of a glucocerebrosidase gene (GBA) mutation. OBJECTIVE: To evaluate longitudinally and clinically a GBA mutation-positive cohort and the evolution of the prodromal features of PD. DESIGN, SETTING, AND PARTICIPANTS: Participants in a study of the etiology and prodrome of PD were reevaluated in this clinic-based 2-year follow-up report. Patients with type 1 Gaucher disease (GD) and heterozygous GBA mutation carriers were recruited in 2010 from the Lysosomal Storage Disorder Unit at the Royal Free Hospital, London, England. Thirty patients who previously received a diagnosis of type 1 GD, 28 heterozygous GBA mutation carriers, and 26 genetically unrelated controls were included. Exclusion criteria included a diagnosis of PD or dementia for both the patients with GD and the GBA mutation carriers and any existing neurological disease for the controls. MAIN OUTCOMES AND MEASURES: Assessment was performed for clinical markers using standardized scales for hyposmia, rapid eye movement sleep behavior disorder, depression, autonomic dysfunction, cognitive function, and parkinsonian motor signs (using the Unified Parkinson's Disease Rating Scale motor subscale [UPDRS part III]). RESULTS: Over 2 years, depression scores were significantly worse for heterozygous carriers (mean baseline, 0.65; mean follow-up, 2.88; P = .01), rapid eye movement sleep behavior disorder scores were significantly worse for patients with GD (mean baseline, 0.93; mean follow up, 2.93; P < .001) and heterozygotes (mean baseline, 0.10; mean follow-up, 2.30; P < .001), and UPDRS part III scores were significantly worse for patients with GD (mean baseline, 4.29; mean follow-up, 7.82; P < .001) and heterozygotes (mean baseline, 1.97; mean follow-up, 4.50; P < .001). For controls, there was a small but significant deterioration in the UPDRS part II (activities of daily living) score (mean baseline, 0.00; mean follow-up, 0.58; P = .006). At 2 years, olfactory and cognitive assessment scores were lower in patients with GD and heterozygotes compared with controls, but they did not differ significantly from baseline. When the results from the patients with GD and the heterozygotes were combined, a significant deterioration from baseline was observed, as reflected in the Rapid Eye Movement Sleep Behaviour Disorder Questionnaire (mean baseline, 0.51; mean follow-up, 2.63; P < .001), Beck Depression Inventory (mean baseline, 1.72; mean follow-up, 4.44; P = .002), and UPDRS part II (mean baseline, 0.88; mean follow-up, 2.01; P < .001) and part III scores (mean baseline, 3.09; mean follow-up, 6.10; P < .001) (all P < .01), and at 2 years, significant differences in University of Pennsylvania Smell Identification Test, Unified Multiple System Atrophy Rating Scale, Mini-Mental State Examination, Montreal Cognitive Assessment, and UPDRS part II and part III scores were observed between patients with GD/heterozygotes and controls (all P < .05). CONCLUSIONS AND RELEVANCE: This study indicates that, as a group, GBA mutation-positive individuals show a deterioration in clinical markers consistent with the prodrome of PD. Within this group of individual, 10% appear to be evolving at a more rapid rate. PMID- 25506735 TI - Application of portable fluorescence spectrophotometry for integrity testing of recycled water dual distribution systems. AB - Water utilities supplying recycled water to households via a "third-pipe" or "dual reticulation" system have a need for a rapid, portable method to detect cross-connections within potable water reticulation networks. This study evaluates portable fluorimetry as a technique for cross-connection detection in the field. For the first time, an investigation of a full-scale dual reticulation water-recycling network has been carried out to identify cross-connections using a portable fluorimeter. We determined that this can be carried out with a 3 mL water sample, and unlike methods that are currently in use for cross-connection detection, can be achieved quickly without disruption to water flow or availability within the network. It was also revealed that fluorescence trigger values could be established with high levels of confidence by sampling less than 2.5% of the network. Fluorescence analysis was also able to uncover a single, real cross-connection event. As such, this paper is a fundamental demonstration of fluorescence as a reliable, highly portable technique for cross-connection detection within dual reticulation water recycling networks and further establishes the abilities of fluorescence devices as valuable field instruments for water quality monitoring. PMID- 25506736 TI - Proactive outreach strategies to connect smokers with tobacco cessation treatment. PMID- 25506737 TI - Gas-phase reactions of CF(+) with molecules of interstellar relevance. AB - We have studied the gas-phase reactions of CF(+) with 24 neutral species. Reaction rate constants and product branching fractions are measured at 298 K using a flowing afterglow-selected ion flow tube. Experimental work is supported by computational chemistry calculations to provide insight into the reactivity of classes of neutral molecules. Reactions of CF(+) with small triatomic species and oxygen-containing organic molecules produce the stable molecule CO. The product branching fractions are discussed, and the potential energy surfaces for a few representative reactions are examined. CF(+) is highly reactive with complex molecules and will likely be destroyed in dense environments in the interstellar medium. However, the lack of reactivity with small diatomic molecules will likely enable its survival in diffuse regions. PMID- 25506733 TI - Comparative effectiveness of intravenous vs oral antibiotics for postdischarge treatment of acute osteomyelitis in children. AB - IMPORTANCE: Postdischarge treatment of acute osteomyelitis in children requires weeks of antibiotic therapy, which can be administered orally or intravenously via a peripherally inserted central catheter (PICC). The catheters carry a risk for serious complications, but limited evidence exists on the effectiveness of oral therapy. OBJECTIVE: To compare the effectiveness and adverse outcomes of postdischarge antibiotic therapy administered via the PICC or the oral route. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective cohort study comparing PICC and oral therapy for the treatment of acute osteomyelitis. Among children hospitalized from January 1, 2009, through December 31, 2012, at 36 participating children's hospitals, we used discharge codes to identify potentially eligible participants. Results of medical record review confirmed eligibility and defined treatment group allocation and study outcomes. We used within- and across-hospital propensity score-based full matching to adjust for confounding by indication. INTERVENTIONS: Postdischarge administration of antibiotics via the PICC or the oral route. MAIN OUTCOMES AND MEASURES: The primary outcome was treatment failure. Secondary outcomes included adverse drug reaction, PICC line complication, and a composite of all 3 end points. RESULTS: Among 2060 children and adolescents (hereinafter referred to as children) with osteomyelitis, 1005 received oral antibiotics at discharge, whereas 1055 received PICC-administered antibiotics. The proportion of children treated via the PICC route varied across hospitals from 0 to 100%. In the across-hospital (risk difference, 0.3% [95% CI, -0.1% to 2.5%]) and within-hospital (risk difference, 0.6% [95% CI, -0.2% to 3.0%]) matched analyses, children treated with antibiotics via the oral route (reference group) did not experience more treatment failures than those treated with antibiotics via the PICC route. Rates of adverse drug reaction were low (<4% in both groups) but slightly greater in the PICC group in across-hospital (risk difference, 1.7% [95% CI, 0.1%-3.3%]) and within-hospital (risk difference, 2.1% [95% CI, 0.3%-3.8%]) matched analyses. Among the children in the PICC group, 158 (15.0%) had a PICC complication that required an emergency department visit (n = 96), a rehospitalization (n = 38), or both (n = 24). As a result, the PICC group had a much higher risk of requiring a return visit to the emergency department or for hospitalization for any adverse outcome in across hospital (risk difference, 14.6% [95% CI, 11.3%-17.9%]) and within-hospital (risk difference, 14.0% [95% CI, 10.5%-17.6%]) matched analyses. CONCLUSIONS AND RELEVANCE: Given the magnitude and seriousness of PICC complications, clinicians should reconsider the practice of treating otherwise healthy children with acute osteomyelitis with prolonged intravenous antibiotics after hospital discharge when an equally effective oral alternative exists. PMID- 25506738 TI - Mimicry of sputtered i-ZnO thin films using chemical bath deposition for solution processed solar cells. AB - Solution processing provides a versatile and inexpensive means to prepare functional materials with specifically designed properties. The current challenge is to mimic the structural, optical, and/or chemical properties of thin films fabricated by vacuum-based techniques using solution-based approaches. In this work we focus on ZnO to show that thin films grown using a simple, aqueous-based, chemical bath deposition (CBD) method can mimic the properties of sputtered coatings, provided that the kinetic and thermodynamic reaction parameters are carefully tuned. The role of these parameters toward growing highly oriented and dense ZnO thin films is fully elucidated through detailed microscopic and spectroscopic investigations. The prepared samples exhibit bulk-like optical properties, are intrinsic in their electronic characteristics, and possess negligible organic contaminants, especially when compared to ZnO layers deposited by sol-gel or from nanocrystal inks. The efficacy of our CBD-grown ZnO thin films is demonstrated through the effective replacement of sputtered ZnO buffer layers within high efficiency solution processed Cu2ZnSnS4xSe4(1-x) solar cells. PMID- 25506739 TI - Combining total internal reflection sum frequency spectroscopy spectral imaging and confocal fluorescence microscopy. AB - Understanding surface and interfacial lateral organization in material and biological systems is critical in nearly every field of science. The continued development of tools and techniques viable for elucidation of interfacial and surface information is therefore necessary to address new questions and further current investigations. Sum frequency spectroscopy (SFS) is a label-free, nonlinear optical technique with inherent surface specificity that can yield critical organizational information on interfacial species. Unfortunately, SFS provides no spatial information on a surface; small scale heterogeneities that may exist are averaged over the large areas typically probed. Over the past decade, this has begun to be addressed with the advent of SFS microscopy. Here we detail the construction and function of a total internal reflection (TIR) SFS spectral and confocal fluorescence imaging microscope directly amenable to surface investigations. This instrument combines, for the first time, sample scanning TIR-SFS imaging with confocal fluorescence microscopy. PMID- 25506740 TI - Access to large cyclic peptides by a one-pot two-peptide segment ligation/cyclization process. AB - The use of the N-acetoacetyl protecting group for N-terminal cysteine residue enabled creation of an efficient and mild one-pot native chemical ligation/SEA ligation sequence giving access to large cyclic peptides. PMID- 25506741 TI - Solid-state synthesis and characterization of sigma-alkane complexes, [Rh(L2)(eta(2),eta(2)-C7H12)][BAr(F)4] (L2 = bidentate chelating phosphine). AB - The use of solid/gas and single-crystal to single-crystal synthetic routes is reported for the synthesis and characterization of a number of sigma-alkane complexes: [Rh(R2P(CH2)nPR2)(eta(2),eta(2)-C7H12)][BAr(F)4]; R = Cy, n = 2; R = (i)Pr, n = 2,3; Ar = 3,5-C6H3(CF3)2. These norbornane adducts are formed by simple hydrogenation of the corresponding norbornadiene precursor in the solid state. For R = Cy (n = 2), the resulting complex is remarkably stable (months at 298 K), allowing for full characterization using single-crystal X-ray diffraction. The solid-state structure shows no disorder, and the structural metrics can be accurately determined, while the (1)H chemical shifts of the Rh...H-C motif can be determined using solid-state NMR spectroscopy. DFT calculations show that the bonding between the metal fragment and the alkane can be best characterized as a three-center, two-electron interaction, of which sigmaCH -> Rh donation is the major component. The other alkane complexes exhibit solid-state (31)P NMR data consistent with their formation, but they are now much less persistent at 298 K and ultimately give the corresponding zwitterions in which [BAr(F)4](-) coordinates and NBA is lost. The solid-state structures, as determined by X-ray crystallography, for all these [BAr(F)4](-) adducts are reported. DFT calculations suggest that the molecular zwitterions within these structures are all significantly more stable than their corresponding sigma alkane cations, suggesting that the solid-state motif has a strong influence on their observed relative stabilities. PMID- 25506742 TI - 2,4-Dithiothymine as a potent UVA chemotherapeutic agent. AB - Substitution of both oxygen atoms in the exocyclic carbonyl groups of the thymine chromophore by sulfur atoms results in a remarkable redshift of its absorption spectrum from an absorption maximum at 267 nm in thymidine to 363 nm in 2,4 dithiothymine (DeltaE = 9905 cm(-1)). A single sulfur substitution of a carbonyl group in the thymine chromophore at position 2 or 4 results in a significantly smaller redshift in the absorption maximum, which depends sensitively on the position at which the sulfur atom is substituted, varying from 275 nm in 2 thiothymine to 335 nm in 4-thiothymidine. Femtosecond transient absorption spectroscopy reveals that excitation of 2,4-dithiothymine at 335 or 360 nm leads to the ultrafast population of the triplet state, with an intersystem crossing lifetime of 180 +/- 40 fs-the shortest intersystem crossing lifetime of any DNA base derivative studied so far in aqueous solution. Surprisingly, the degree and position at which the sulfur atom is substituted have important effects on the magnitude of the intersystem crossing rate constant, showing a 1.2-, 3.2-, and 4.2-fold rate increases for 2-thiothymine, 4-thiothymidine, and 2,4 dithiothymine, respectively, relative to that of thymidine, whereas the triplet yield increases 60-fold to near unity, independent of the site of sulfur atom substitution. While the natural thymine monomers owe their high degree of photostability to ultrafast internal conversion to the ground state and low triplet yields, the near-unity triplet yields in the thiothymine series account for their potent photosensitization properties. Nanosecond time-resolved luminescence spectroscopy shows that 4-thiothymidine and 2,4-dithiothymine are efficient singlet oxygen generators, with singlet oxygen quantum yields of 0.42 +/- 0.02 and 0.46 +/- 0.02, respectively, in O2-saturated acetonitrile solution. Taken together, these photophysical measurements strongly suggest that 2,4 dithiothymine can act as a more effective UVA chemotherapeutic agent than the currently used 4-thiothymidine, especially in deeper-tissue chemotherapeutic applications. PMID- 25506743 TI - Study of the exhaled acetone in type 1 diabetes using quantum cascade laser spectroscopy. AB - The acetone concentration exhaled in the breath of three type 1 diabetes patients (two minors and one adult) and one healthy volunteer is studied using a quantum cascade laser-based spectroscopic system. Using the acetone signature between 1150 and 1250 cm(-1) and a multiline fitting method, the concentration variations on the order of parts per billion by volume were measured. Blood glucose and ketone concentrations in blood measurements were performed simultaneously to study their relation with acetone in exhaled breath. We focus on personalized studies to better understand the role of acetone in diabetes. For each volunteer, we performed a series of measurements over a period of time, including overnight fastings of 11 +/- 1 h and during ketosis-hyperglycemia events for the minors. Our results highlight the importance of performing personalized studies because the response of the minors to the presence of ketosis was consistent but unique for each individual. Also, our results emphasize the need for performing more studies with T1D minors, because the acetone concentration in the breath of the minors differs, with respect to those reported in the literature, which are based on adults. PMID- 25506744 TI - Vibrational excitation induced proton transfer in hydrated Nafion membranes. AB - We study the energy relaxation and structural relaxation dynamics of hydrated protons in Nafion membranes at different hydration levels using femtosecond infrared transient absorption spectroscopy. At low hydration levels we observe that the excitation of the proton vibration of an Eigen-like proton hydration structure leads to a structural relaxation process in which the Eigen-like structure evolves to a Zundel-like proton hydration structure. This reorganization leads to a transfer of the proton charge and closely follows the mechanism of infrared-induced adiabatic proton transfer that has been proposed by S. Hammes-Schiffer, J. T. Hynes, and others. At high hydration levels, the spectral dynamics are dominated by vibrational energy relaxation and subsequent cooling of the proton hydration structures and the surrounding water molecules. Using a kinetic analysis of the transient spectral data, we determine the rates of proton transfer, vibrational energy relaxation, and cooling as a function of hydration level. We find that infrared-induced proton transfer occurs at all hydration levels but becomes less observable at high hydration levels due to the increasingly dominant influence of the vibrational energy relaxation. PMID- 25506745 TI - Symmetry breaking and electrical frustration during tip-induced polarization switching in the nonpolar cut of lithium niobate single crystals. AB - Polarization switching in ferroelectric materials is governed by a delicate interplay between bulk polarization dynamics and screening processes at surfaces and domain walls. Here we explore the mechanism of tip-induced polarization switching at nonpolar cuts of uniaxial ferroelectrics. In this case, the in-plane component of the polarization vector switches, allowing for detailed observations of the resultant domain morphologies. We observe a surprising variability of resultant domain morphologies stemming from a fundamental instability of the formed charged domain wall and associated electric frustration. In particular, we demonstrate that controlling the vertical tip position allows the polarity of the switching to be controlled. This represents a very unusual form of symmetry breaking where mechanical motion in the vertical direction controls the lateral domain growth. The implication of these studies for ferroelectric devices and domain wall electronics are discussed. PMID- 25506746 TI - Transgenerational effects of two antidepressants (sertraline and venlafaxine) on Daphnia magna life history traits. AB - The low levels of antidepressants detected in surface waters currently raise concern about their potential long-term risks to nontarget aquatic organisms. We investigated the transgenerational effects of sertraline, a selective serotonin reuptake inhibitor, and venlafaxine, a serotonin-norepinephrine reuptake inhibitor, on the life traits of Daphnia magna over two generations under environmentally realistic concentrations. We also studied the reversibility of the effect using recovery experiments. We assessed daphnid survival, growth, and reproduction over 21 days and evidenced detectable effects of the antidepressants. Sertraline increased the F0-daphnid fecundity whereas it decreased the offspring number of F1-daphnids. Transfer to clean medium caused negative effects on the offspring of daphnids exposed to 0.3 MUg L(-1), but improved the fecundity of offspring of daphnids exposed to 100 MUg L(-1). Venlafaxine exposure decreased the offspring number of F0-daphnids and resulted in drug tolerance in the F1 generation. Sertraline, unlike venlafaxine, may turn out to be a true environmental threat due to its accumulation in algae and the physiological weakness observed over generations. These effects across generations point out to the need to perform multigeneration tests to assess the environmental risk of pharmaceuticals in nontarget organisms. PMID- 25506747 TI - Physiopathology of kainate receptors in epilepsy. AB - Kainate receptors (KARs) are tetrameric ionotropic glutamate receptors composed of the combinations of five subunits GluK1-GluK5. KARs are structurally related to AMPA receptors but they serve quite distinct functions by regulating the activity of synaptic circuits at presynaptic and postsynaptic sites, through either ionotropic or metabotropic actions. Although kainate is a potent neurotoxin known to induce acute seizures through activation of KARs, the actual role of KARs in the clinically-relevant chronic phase of temporal lobe epilepsy (TLE) has long been elusive. Recent evidences have described pathophysiological mechanisms of heteromeric GluK2/GluK5 KARs in generating recurrent seizures in chronic epilepsy. The role of the other major subunit GluK1 in epileptogenic activity is still a matter of debate. This review will present the current knowledge on the subtype-specific pharmacology of KARs and highlight recent results linking KARs to epileptic conditions. PMID- 25506748 TI - Metabotropic glutamate receptors as drug targets: what's new? AB - The question in the title: 'what's new?' has two facets. First, are 'clinical' expectations met with success? Second, is the number of CNS disorders targeted by mGlu drugs still increasing? The answer to the first question is 'no', because development program with promising drugs in the treatment of schizophrenia, Parkinson's disease, and Fragile X syndrome have been discontinued. Nonetheless, we continue to be optimistic because there is still the concrete hope that some of these drugs are beneficial in targeted subpopulations of patients. The answer to the second question is 'yes', because mGlu ligands are promising targets for 'new' disorders such as type-1 spinocerebellar ataxia and absence epilepsy. In addition, the increasing availability of pharmacological tools may push mGlu7 and mGlu8 receptors into the clinical scenario. After almost 30 years from their discovery, mGlu receptors are still alive. PMID- 25506749 TI - A simulation approach for change-points on phylogenetic trees. AB - We observe n sequences at each of m sites and assume that they have evolved from an ancestral sequence that forms the root of a binary tree of known topology and branch lengths, but the sequence states at internal nodes are unknown. The topology of the tree and branch lengths are the same for all sites, but the parameters of the evolutionary model can vary over sites. We assume a piecewise constant model for these parameters, with an unknown number of change-points and hence a transdimensional parameter space over which we seek to perform Bayesian inference. We propose two novel ideas to deal with the computational challenges of such inference. Firstly, we approximate the model based on the time machine principle: the top nodes of the binary tree (near the root) are replaced by an approximation of the true distribution; as more nodes are removed from the top of the tree, the cost of computing the likelihood is reduced linearly in n. The approach introduces a bias, which we investigate empirically. Secondly, we develop a particle marginal Metropolis-Hastings (PMMH) algorithm, that employs a sequential Monte Carlo (SMC) sampler and can use the first idea. Our time-machine PMMH algorithm copes well with one of the bottle-necks of standard computational algorithms: the transdimensional nature of the posterior distribution. The algorithm is implemented on simulated and real data examples, and we empirically demonstrate its potential to outperform competing methods based on approximate Bayesian computation (ABC) techniques. PMID- 25506750 TI - Impact of microbial count distributions on human health risk estimates. AB - Quantitative microbiological risk assessment (QMRA) is influenced by the choice of the probability distribution used to describe pathogen concentrations, as this may eventually have a large effect on the distribution of doses at exposure. When fitting a probability distribution to microbial enumeration data, several factors may have an impact on the accuracy of that fit. Analysis of the best statistical fits of different distributions alone does not provide a clear indication of the impact in terms of risk estimates. Thus, in this study we focus on the impact of fitting microbial distributions on risk estimates, at two different concentration scenarios and at a range of prevalence levels. By using five different parametric distributions, we investigate whether different characteristics of a good fit are crucial for an accurate risk estimate. Among the factors studied are the importance of accounting for the Poisson randomness in counts, the difference between treating "true" zeroes as such or as censored below a limit of quantification (LOQ) and the importance of making the correct assumption about the underlying distribution of concentrations. By running a simulation experiment with zero-inflated Poisson-lognormal distributed data and an existing QMRA model from retail to consumer level, it was possible to assess the difference between expected risk and the risk estimated with using a lognormal, a zero-inflated lognormal, a Poisson-gamma, a zero-inflated Poisson-gamma and a zero-inflated Poisson-lognormal distribution. We show that the impact of the choice of different probability distributions to describe concentrations at retail on risk estimates is dependent both on concentration and prevalence levels. We also show that the use of an LOQ should be done consciously, especially when zero-inflation is not used. In general, zero-inflation does not necessarily improve the absolute risk estimation, but performance of zero-inflated distributions in QMRA tends to be more robust to changes in prevalence and concentration levels, and to the use of an LOQ to interpret zero values, compared to that of their non-zero-inflated counterparts. PMID- 25506751 TI - Drone warfare. PMID- 25506752 TI - Cognitive dissonance induction in everyday life: An fMRI study. AB - This functional magnetic resonance imaging (fMRI) study explored the neural substrates of cognitive dissonance during dissonance "induction." A novel task was developed based on the results of a separate item selection study (n = 125). Items were designed to generate dissonance by prompting participants to reflect on everyday personal experiences that were inconsistent with values they had expressed support for. One experimental condition (dissonance) and three control conditions (justification, consonance, and non-self-related inconsistency) were used for comparison. Items of all four types were presented to each participant (n = 14) in a randomized design. The fMRI analysis used a whole-brain approach focusing on the moments dissonance was induced. Results showed that in comparison with the control conditions the dissonance experience led to higher levels of activation in several brain regions. Specifically dissonance was associated with increased neural activation in key brain regions including the anterior cingulate cortex (ACC), anterior insula, inferior frontal gyrus, and precuneus. This supports current perspectives that emphasize the role of anterior cingulate and insula in dissonance processing. Less extensive activation in the prefrontal cortex than in some previous studies is consistent with this study's emphasis on dissonance induction, rather than reduction. This article also contains a short review and comparison with other fMRI studies of cognitive dissonance. PMID- 25506753 TI - Enhanced ERPs to visual stimuli in unaffected male siblings of ASD children. AB - Autism spectrum disorders are characterized by deficits in social and communication abilities. While unaffected relatives lack severe deficits, milder impairments have been reported in some first-degree relatives. The present study sought to verify whether mild deficits in face perception are evident among the unaffected younger siblings of children with ASD. Children between 6-9 years of age completed a face-recognition task and a passive viewing ERP task with face and house stimuli. Sixteen children were typically developing with no family history of ASD, and 17 were unaffected children with an older sibling with ASD. Findings indicate that, while unaffected siblings are comparable to controls in their face-recognition abilities, unaffected male siblings in particular show relatively enhanced P100 and P100-N170 peak-to-peak amplitude responses to faces and houses. Enhanced ERPs among unaffected male siblings is discussed in relation to potential differences in neural network recruitment during visual and face processing. PMID- 25506754 TI - Knowledge, attitudes, and practices regarding antiretroviral management, reproductive health, sexually transmitted infections, and sexual risk behavior among perinatally HIV-infected youth in Thailand. AB - More than 30% of perinatally HIV-infected children in Thailand are 12 years and older. As these youth become sexually active, there is a risk that they will transmit HIV to their partners. Data on the knowledge, attitudes, and practices (KAP) of HIV-infected youth in Thailand are limited. Therefore, we assessed the KAP of perinatally HIV-infected youth and youth reporting sexual risk behaviors receiving care at two tertiary care hospitals in Bangkok, Thailand and living in an orphanage in Lopburi, Thailand. From October 2010 to July 2011, 197 HIV infected youth completed an audio computer-assisted self-interview to assess their KAP regarding antiretroviral (ARV) management, reproductive health, sexual risk behaviors, and sexually transmitted infections (STIs). A majority of youth in this study correctly answered questions about HIV transmission and prevention and the importance of taking ARVs regularly. More than half of the youth in this study demonstrated a lack of family planning, reproductive health, and STI knowledge. Girls had more appropriate attitudes toward safe sex and risk behaviors than boys. Although only 5% of the youth reported that they had engaged in sexual intercourse, about a third reported sexual risk behaviors (e.g., having or kissing boy/girlfriend or consuming an alcoholic beverage). We found low condom use and other family planning practices, increasing the risk of HIV and/or STI transmission to sexual partners. Additional resources are needed to improve reproductive health knowledge and reduce risk behavior among HIV-infected youth in Thailand. PMID- 25506755 TI - Is the BPRS-5 subscale of the psychotic depression assessment scale a reliable screening tool for psychotic depression?: Results from the CRESCEND study. AB - BACKGROUND: The detection of psychotic depression (PD) among patients with depressive disorders is important for both treatment and monitoring. Therefore, in continuation of our previous work, this study aimed to test the ability of the five-item Brief Psychiatric Rating Scale (BPRS-5) of the Psychotic Depression Assessment Scale (PDAS) in separating patients with psychotic depression from those with non-psychotic depression (non-PD) and to compare this discriminative validity to that of other item sets. METHODS: A receiver operating characteristics curve was used to identify the optimal cut-off score of the BPRS 5 subscale for sensitive and specific distinction between PD and non-PD in a sample of 494 patients with depressive disorders (53 with PD and 441 with non PD). RESULTS: Using an optimal cut-off score of 1, the sensitivity and the specificity of the BPRS-5 subscale in detecting PD were 71.2% and 87.2%, respectively. The BPRS-5 outperformed other item sets of the PDAS and the positive symptom subscale of the BPRS in identifying patients with PD. LIMITATIONS: The inter-rater reliability of the PDAS and the BPRS-5 subscale was not evaluated in this study. CONCLUSIONS: The BPRS-5 subscale can be regarded as a more sensitive screening method for PD compared to other item sets from the PDAS and the BPRS. Hence, from a screening perspective, a positive score on any of the five symptoms of the BPRS-5 subscale (hallucinatory behavior, unusual thought content, suspiciousness, blunted affect, and emotional withdrawal) is indicative of PD, and should lead to more thorough diagnostic assessment. PMID- 25506756 TI - A new measure of multimorbid illness and treatment representations: the example of diabetes and depression. AB - BACKGROUND: Depression is two to three times more common in people with diabetes than in the general population. Although multimorbid diabetes and depression is associated with poor health outcome, existing research has focused on patients' understanding and management of each condition in isolation. This study describes the development and validation of the Diabetes and Depression Representation and Management Questionnaire (DDRMQ), a measure of understanding, management and medication beliefs in people with diabetes and depression. METHODS: In Study 1, DDRMQ items were developed through further analysis of an earlier qualitative study and refined through 18 cognitive interviews. In Study 2, 334 adults with diabetes and depression from general practices, diabetes clinics and support groups completed the DDRMQ, demographic questions and validating measures. RESULTS: Factor analysis of the DDRMQ using principal axis factoring resulted in a 35 item scale organised into ten subscales. The modified measure had adequate internal and test-retest reliability. Initial evidence of construct validity was also demonstrated. LIMITATIONS: Low participant response rates and the high percentage of well-educated white participants limit the generalisability of results. As Study 2 was cross-sectional, future research is needed to establish if different ways of thinking about and managing diabetes and depression can predict patient outcome. CONCLUSIONS: The DDRMQ is the first measure of patient understanding, management and medication beliefs in people with established diagnoses of both diabetes and depression. The DDRMQ will facilitate an increased awareness of the patient experience of diabetes and depression and help inform patient centred care and intervention development for people with multiple conditions. PMID- 25506758 TI - History. PMID- 25506757 TI - The association between arterial properties and blood pressure in children. AB - Elevated blood pressure (BP) in adults is associated with increased arterial stiffness and thickness; however, its effect on arterial health in a pediatric population is less understood. The purpose of this study was to identify the relationship between childhood BP and arterial markers of arteriosclerotic progression. The study consisted of 106 children across a wide range of BP values divided into 2 BP groups: high BP (HBP; >= 95th percentile; n = 21) and normal BP (NBP; < 90th percentile; n = 85) based on consistent automated BP measures taken at 2 time points. The laboratory examination involved systemic pulse wave velocity (PWV), common carotid artery (CCA) intima media thickness (IMT) and distensibility, as well as body mass index (BMI) and pubertal maturation. BMI and heart rate, as well as PWV (HBP: n = 15 and NBP: n = 56), were higher in the HBP group (p < 0.001) with no difference between groups for both CCA distensibility and IMT (HBP: n = 21 and NBP: n = 83). Multivariate linear regression revealed that BP group (p = 0.003) was an independent predictor of PWV after controlling for age, sex, BMI, heart rate, and maturation. Our findings demonstrate a higher systemic PWV with no difference in CCA IMT or distensibility in children with elevated BP. Hence, markers of cardiovascular disease risk are augmented in healthy children with elevated BP. PMID- 25506759 TI - Fast Clustered Radial Basis Function Network as an adaptive predictive controller. AB - This paper presents a novel artificial neural network with the Radial Basis Function (RBF) as an activation function of neurons and clustered neurons in the hidden layer which has a high learning speed, thus it is called Fast Clustered Radial Basis Function Network (FCRBFN). The weights of the network are determined by solving a number of linear equation systems. In addition, new training data can be given to the network on-line and the re-training is done at high speed using the Least Squares method. In order to test the validity of the FCRBFN, it is applied to 4 classical regression applications, and also used to build the functional adaptive predictive controller. Experimental results show that, compared with other methods, the FCRBFN with a small amount of hidden neurons could achieve good or better regression precision and generalization, as well as adaptive ability at a much faster learning speed. PMID- 25506761 TI - Action spectra for validation of pathogen disinfection in medium-pressure ultraviolet (UV) systems. AB - Ultraviolet (UV) reactors used for disinfecting water and wastewater must be validated and monitored over time. The validation process requires understanding the photochemical properties of the pathogens of concern and the challenge microorganisms used to represent them. Specifically for polychromatic UV systems, the organisms' dose responses to UV light and their sensitivity across the UV spectrum must be known. This research measured the UV spectral sensitivity, called action spectra, of Cryptosporidium parvum, and MS2, T1UV, Q Beta, T7, and T7m Coliphages, as well as Bacillus pumilus spores. A tunable laser from the National Institute of Standards and Technology was used to isolate single UV wavelengths at 10 nm intervals between 210 and 290 nm. Above 240 nm, all bacteria and viruses tested exhibited a relative peak sensitivity between 260 and 270 nm. Of the coliphage, MS2 exhibited the highest relative sensitivity below 240 nm, relative to its sensitivity at 254 nm, followed by Q Beta, T1UV, T7m and T7 coliphage. B. pumilus spores were more sensitive to UV light at 220 nm than any of the coliphage. These spectra are required for calculating action spectra correction factors for medium pressure UV system validation, for matching appropriate challenge microorganisms to pathogens, and for improving UV dose monitoring. Additionally, understanding the dose response of these organisms at multiple wavelengths can improve polychromatic UV dose calculations and enable prediction of pathogen inactivation from wavelength-specific disinfection technologies such as UV light emitting diodes (LEDs). PMID- 25506760 TI - Effects of weaning on total and free iodothyronines in lambs. AB - BACKGROUND: Weaning is a crucial period in the management of lambs, resulting in physiological and mental challenges, that may have prolonged effects on lamb's health and welfare. HYPOTHESIS/OBJECTIVES: To evaluate the effect of weaning on total and free triiodothyronine (T3, fT3) and thyroxine (T4, fT4) concentrations in serum of lambs by enzyme immunoassay. Animal and methods: The study was performed on two groups of 17 clinically healthy Comisana cross-bred lambs (7 males and 10 females) with or without weaning at 10 weeks of age. Serum samples were collected at the age of 8 weeks, 24 h and 2 weeks after weaning in the experimental group and at similar times in the non-weaned control group. Enzyme immunoassay was performed. Statistical analysis was done by one-way analysis of variance. RESULTS: Compared to control animals, weaned animals showed significantly decreased T3 and elevated T4 concentrations two weeks after weaning with higher concentrations in both males and females in contrast to 24 h after weaning. Body weight (BW) was significantly restored in both females (11% increase) and males (6%) two weeks after weaning as compared to 24 h after weaning. No gender effects were shown for total and free iodothyronine changes. Significant positive correlations were observed between BW and T4 concentrations in both females (r = 0.692) and males (r = 0.856), fT3 concentrations in males (r = 0.968) and fT4 concentrations in females (r = 0.862). CONCLUSION AND CLINICAL IMPORTANCE: Total iodothyronines could represent an indicator of their different metabolic activity with their magnitude altered two weeks following weaning. PMID- 25506764 TI - Filtration of triazine herbicides by polymer-clay sorbents: coupling an experimental mechanistic approach with empirical modeling. AB - Triazine herbicides detected in surface and groundwater pose environmental and health risks. Removal of triazine herbicides (simazine, atrazine and terbuthylazine) by polymer-clay composites was studied and modeled. Their binding by a poly 4-vinyl pyridine co styrene-montmorillonite (HPVP-CoS-MMT) composite was especially high due to specific interactions between the herbicides and polymer, mainly hydrogen bonds and pi-pi stacking. The binding kinetics to the composite was in the order of simazine > atrazine > terbuthylazine, which was in accord with their equilibrium Langmuir binding coefficients; 44,000, 17,500 and 16,500 M(-1), respectively, which correlated with herbicide accessibility to form specific interaction with the polymer. Simazine binding kinetics to the composite was significantly faster than to granulated activated carbon (GAC), reaching 93% vs 38% of the maximal adsorption within 10 min, respectively. Herbicide filtration by composite columns was adequately fitted by a model which considers convection and employs Langmuir formalism for kinetics of adsorption/desorption. Filtration of simazine (10 MUg L(-1)) by composite columns (40 cm long, which included 26 g composite mixed with sand 1:40 (weight ratio)), was well predicted by the model with nearly 120 L purified, i.e., effluent concentrations were below regulation limit (3 MUg L(-1)). Effluent concentrations from GAC columns exceeded the limit after filtering 5 L. Experimental results and model predictions suggest that while GAC has a high capacity for simazine binding, the composite has higher affinity towards the herbicide and its adsorption is faster, which yields more efficient filtration by composite columns. PMID- 25506762 TI - Ammonia-oxidizing microbial communities in reactors with efficient nitrification at low-dissolved oxygen. AB - Ammonia-oxidizing microbial communities involved in ammonia oxidation under low dissolved oxygen (DO) conditions (<0.3 mg/L) were investigated using chemostat reactors. One lab-scale reactor (NS_LowDO) was seeded with sludge from a full scale wastewater treatment plant (WWTP) not adapted to low-DO nitrification, while a second reactor (JP_LowDO) was seeded with sludge from a full-scale WWTP already achieving low-DO nitrifiaction. The experimental evidence from quantitative PCR, rDNA tag pyrosequencing, and fluorescence in situ hybridization (FISH) suggested that ammonia-oxidizing bacteria (AOB) in the Nitrosomonas genus were responsible for low-DO nitrification in the NS_LowDO reactor, whereas in the JP_LowDO reactor nitrification was not associated with any known ammonia oxidizing prokaryote. Neither reactor had a significant population of ammonia oxidizing archaea (AOA) or anaerobic ammonium oxidation (anammox) organisms. Organisms isolated from JP_LowDO were capable of autotrophic and heterotrophic ammonia utilization, albeit without stoichiometric accumulation of nitrite or nitrate. Based on the experimental evidence we propose that Pseudomonas, Xanthomonadaceae, Rhodococcus, and Sphingomonas are involved in nitrification under low-DO conditions. PMID- 25506765 TI - Differential effects of social stress on laboratory-based decision-making are related to both impulsive personality traits and gender. AB - Urgency is the tendency to make impulsive decisions under extreme positive or negative emotional states. Stress, gender and impulsive personality traits are all known to influence decision-making, but no studies have examined the interplay of all of these factors. We exposed 78 men and women to a stress or a non-stress condition, and then administered the Balloon Analogue Risk Task. We found that stress effects varied as a function of gender and urgency traits. Under stress, women low in negative urgency and men high in negative urgency made fewer risky decisions. Positive urgency yielded a similar pattern. Thus, decisions under stress depend on a complex interplay between gender and impulsive personality traits. These findings have implications for clinical disorders, such as substance use disorders, in which there are known deficits in decision-making and high levels of impulsive traits. PMID- 25506763 TI - Bioelectrogenic role of anoxic microbial anode in the treatment of chemical wastewater: microbial dynamics with bioelectro-characterization. AB - A membrane-less anoxic bioelectrochemical treatment (AxBET) system was evaluated to study the influence of bioelectrogenic activity during the treatment of chemical wastewater (CW). Increment in power generation was observed with increase in substrate loading (61-204 mW/m(2)) indicating the ability of anodic bacteria in BET system to utilize the complex chemicals as the sole carbon source. Derivative analysis of voltammograms depicted by positive and negative peak potentials which relate to the extracellular electron transport sites (EETs) that presumably play a significant role in electron transfer. These self-driven redox mediators varied with respect to the substrate load. The microbial population was dominated by anaerobic microorganisms which are commonly involved in effluent treatment plants during the initial phase of operation. A gradual shift in the microbial community was observed towards enrichment of electrogenically active bacteria belonging to phyla viz., Firmicutes and Proteobacteria after prolonged operation. Shannon Index and principal component analysis correlated with the microbial profile studies. The feasibility of self driven bioremediation of chemical wastewater in an AxBET system demonstrated bioelectricity production along with multipollutant removal simultaneously. PMID- 25506767 TI - The methylation status of plant genomic DNA influences PCR efficiency. AB - During the polymerase chain reaction (PCR), which is a versatile and widely used method, certain DNA sequences are rapidly amplified through thermocycling. Although there are numerous protocols of PCR optimization for different applications, little is known about the effect of DNA modifications, such as DNA methylation, on PCR efficiency. Recent studies show that cytosine methylation alters DNA mechanical properties and suggest that DNA methylation may directly or indirectly influence the effectiveness of DNA amplification during PCR. In the present study, using plant DNA, we found that highly methylated plant DNA genomic regions were amplified with lower efficiencies compared to that for the regions methylated at a lower level. The correlation was observed when amplifying stilbene synthase (STS1, STS10) genes of Vitis amurensis, the Actin2 gene of Arabidopsis thaliana, the internal transcribed spacer (AtITS), and tRNAPro of A. thaliana. The level of DNA methylation within the analyzed DNA regions has been analyzed with bisulfite sequencing. The obtained data show that efficient PCRs of highly methylated plant DNA regions can be hampered. Proteinase K treatment of the plant DNA prior to PCR and using HotTaq DNA polymerase improved amplification of the highly methylated plant DNA regions. We suggest that increased DNA denaturation temperatures of the highly methylated DNA and contamination with DNA binding proteins contribute to the hampered PCR amplification of highly methylated DNA. The data show that it is necessary to use current DNA purification protocols and commercial kits with caution to ensure appropriate PCR product yield and prevent bias toward unmethylated DNA amplification in PCRs. PMID- 25506766 TI - Comparative proteomic analysis of tobacco expressing cyanobacterial flavodoxin and its wild type under drought stress. AB - Tobacco plants expressing cyanobacterial flavodoxin (Fld) show enhanced tolerance to a wide range of abiotic stresses including drought, temperature and UV. The mechanisms of adaptation to stress conditions under Fld expression are largely unknown. Here, we applied comparative proteomic analysis to uncover the changes in the proteome profile of Fld-expressing plants in response to drought stress. Using high-resolution two-dimensional gel electrophoresis, we were able to detect 930 protein spots and compare their abundance. We found changes up to 1.5 fold for 52 spots under drought in transgenic and/or wild type plants. Using combined MALDI-TOF/TOF and ESI-Q/TOF analysis 39 (24 in wild type, 11 in transgenic, and 4 in both) drought-responsive proteins (DRPs) could be identified. The majority of DRPs are known to be involved in photosynthesis, carbohydrate and energy metabolism, amino acid and protein synthesis and processing, and oxidative stress responses. Among candidate DRPs, the abundance of remurin, ferredoxin-NADP reductase, chloroplast manganese stabilizing protein-II, phosphoglycerate mutase, and glutathione S-transferase decreased in drought stressed Fld-tobacco while S formylglutathione hydrolase and pyridoxine biosynthesis protein abundance increased. In wild type plants, drought caused a reduction of proteins related to carbohydrate metabolism. These results suggest that the stress tolerance conferred by Fld expression is strongly related to control mechanisms regarding carbohydrate and energy metabolism as well as oxidative stress responses. PMID- 25506768 TI - Protein profiling and tps23 induction in different maize lines in response to methyl jasmonate treatment and Diabrotica virgifera infestation. AB - Plant responses to herbivore insects involve direct and indirect defense with the production of signal molecules including jasmonic acid (JA) and its derivatives (e.g. methyl jasmonate, MeJA). In maize (Zea mays), root feeding by Diabrotica virgifera larvae activates an indirect defense mechanism, through enthomopathogenic nematodes that are recruited after Terpene Synthase 23 (tps23) upregulation and (E)-beta-caryophyllene root emission. In order to gain insight into the correlation between JA signaling and response to Diabrotica attack, we analyzed tps23 expression and protein profiles in maize roots in response to MeJA treatment and insect infestation. Similar to herbivore feeding, MeJA treatment was found to increase tps23 transcript accumulation, with consistent variations for both treatments in maize lines differing in (E)-beta-caryophyllene production. Analysis of root protein profiles showed specific alterations leading to the identification of three proteins that were induced by MeJA treatment. We focused on a peroxidase-like protein (Px-like) showing that the corresponding transcripts accumulated in all tested lines. Results show that exogenous application of MeJA upregulates tps23 expression and specifically alters protein patterns in maize roots. Parallel effects on tps23 transcript accumulation were observed upon hormone exposure and insect infestation in different maize lines. In contrast, Px-like transcript profiling showed differences between treatments. These results support the possible involvement of MeJA in mediating the upregulation of tps23 in response to Diabrotica attack. PMID- 25506769 TI - Molecular cloning and characterization of a Mlo gene in rubber tree (Hevea brasiliensis). AB - Mlo gene encodes a plant-specific seven-transmembrane domain protein involved in a variety of cellular processes. In this study, a novel Mlo gene from rubber tree (Hevea brasiliensis), designated HbMlo1, was cloned by RT-PCR in rubber tree. The ORF of HbMlo1 was 1551bp in length, encoding a putative protein of 516 amino acids. HbMlo1 was a typical Mlo protein with seven-transmembrane domain. Sequence comparison between HbMlo1 and other Mlo proteins demonstrated that HbMlo1 shared the highest similarity with the Cucumis melo CmMlo1 and Arabidopsis thaliana AtMlo1 with 75.1% and 71.3% sequence identity, respectively. Phylogenetic analysis revealed that HbMlo1, CmMlo1, AtMlo1, AtMlo13, and AtMlo15 formed into the phylogenetic clade II with 100% bootstrap support value. HbMlo1 transcript exhibited tissue specificity, and it was preferentially expressed in leaf. Furthermore, the amount of HbMlo1 transcript was significantly induced by various phytohormones (including ethephon, methyl jasmonate, salicylic acid, abscisic acid, indole-3-acetic acid, and gibberellic acid), H2O2, and wounding treatments. Under drought stress, HbMlo1 exhibited a complex pattern of regulation. However, HbMlo1 expression did not significantly change during powdery mildew infection. These results suggested that HbMlo1 might play a role in phytohormone signaling and abiotic stress response processes in rubber tree. PMID- 25506772 TI - Mechanism and significance of global coherence in scalp EEG. AB - What distinguishes animals from robots is the neurodynamics of intention. The mechanism is the action-perception cycle that creates and applies knowledge. Knowledge is the condensed, categorized information brains accumulate over lifetimes of experience. Vertebrate intention emerged in the Ordovician period as a tool to prowl first olfactory environments, then environments of other modalities. Action necessitates remembering space-time trajectories. Hence the sensory, motor, and hippocampal cortices interact intimately. Brains create the contextual richness of relevant knowledge almost instantly by exploiting the capacity of cortical neuropil to transit between a gas-like phase with sparse, random firing and a liquid-liked phase of high-energy, narrow band oscillation synchronized widely. They express remembrances in spatial patterns of amplitude modulation (AM) of beta and gamma waves. PMID- 25506770 TI - Peroxidase 4 is involved in syringyl lignin formation in Arabidopsis thaliana. AB - Syringyl lignins result from the oxidative polymerization of sinapyl alcohol in a reaction mediated by syringyl (basic) peroxidases. Several peroxidases have been identified in the genome of Arabidopsis thaliana as close homologues to ZePrx, the best characterized basic peroxidase so far, but none of these has been directly involved in lignification. We have used a knock-out mutant of AtPrx4, the closest homologue to ZePrx, to study the involvement of this basic peroxidase in the physiology of the plant under both long- and short-day light conditions. Our results suggest that AtPrx4 is involved in cell wall lignification, especially in syringyl monomer formation. The disruption of AtPrx4 causes a decrease in syringyl units proportion, but only when light conditions are optimal. Moreover, the effect of AtPrx4 disruption is age-dependent, and it is only significant when the elongation process of the stem has ceased and lignification becomes active. In conclusion, AtPrx4 emerges as a basic peroxidase regulated by day length with an important role in lignification. PMID- 25506773 TI - Evaluation of the attentional capacities and working memory of early and late blind persons. AB - Although attentional processes and working memory seem to be significantly involved in the daily activities (particularly during navigating) of persons who are blind and who use these abilities to compensate for their lack of vision, few studies have investigated these mechanisms in this population. The aim of this study is to evaluate the selective, sustained and divided attention, attentional inhibition and switching and working memory of blind persons. Early blind, late blind and sighted participants completed neuropsychological tests that were designed or adapted to be achievable in the absence of vision. The results revealed that the early blind participants outperformed the sighted ones in selective, sustained and divided attention and working memory tests, and the late blind participants outperformed the sighted participants in selective, sustained and divided attention. However, no differences were found between the blind groups and the sighted group in the attentional inhibition and switching tests. Furthermore, no differences were found between the early and late blind participants in this set of tests. These results suggest that early and late blind persons can compensate for the lack of vision by an enhancement of the attentional and working memory capacities. PMID- 25506771 TI - Proactive tobacco cessation outreach to smokers of low socioeconomic status: a randomized clinical trial. AB - IMPORTANCE: Widening socioeconomic disparities in mortality in the United States are largely explained by slower declines in tobacco use among smokers of low socioeconomic status (SES) than among those of higher SES, which points to the need for targeted tobacco cessation interventions. Documentation of smoking status in electronic health records (EHRs) provides the tools for health systems to proactively offer tobacco treatment to socioeconomically disadvantaged smokers. OBJECTIVE: To evaluate a proactive tobacco cessation strategy that addresses sociocontextual mediators of tobacco use for low-SES smokers. DESIGN, SETTING, AND PARTICIPANTS: This prospective, randomized clinical trial included low-SES adult smokers who described their race and/or ethnicity as black, Hispanic, or white and received primary care at 1 of 13 practices in the greater Boston area (intervention group, n = 399; control group, n = 308). INTERVENTIONS: We analyzed EHRs to identify potentially eligible participants and then used interactive voice response (IVR) techniques to reach out to them. Consenting patients were randomized to either receive usual care from their own health care team or enter an intervention program that included (1) telephone-based motivational counseling, (2) free nicotine replacement therapy (NRT) for 6 weeks, (3) access to community-based referrals to address sociocontextual mediators of tobacco use, and (4) integration of all these components into their normal health care through the EHR system. MAIN OUTCOMES AND MEASURES: Self-reported past-7-day tobacco abstinence 9 months after randomization ("quitting"), assessed by automated caller or blinded study staff. RESULTS: The intervention group had a higher quit rate than the usual care group (17.8% vs 8.1%; odds ratio, 2.5; 95% CI, 1.5-4.0; number needed to treat, 10). We examined whether use of intervention components was associated with quitting among individuals in the intervention group: individuals who participated in the telephone counseling were more likely to quit than those who did not (21.2% vs 10.4%; P < .001). There was no difference in quitting by use of NRT. Quitting did not differ by a request for a community referral, but individuals who used their referral were more likely to quit than those who did not (43.6% vs 15.3%; P < .001). CONCLUSIONS AND RELEVANCE: Proactive, IVR-facilitated outreach enables engagement with low-SES smokers. Providing counseling, NRT, and access to community-based resources to address sociocontextual mediators among smokers reached in this setting is effective. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01156610. PMID- 25506774 TI - Structure emerges faster during cultural transmission in children than in adults. AB - How does children's limited processing capacity affect cultural transmission of complex information? We show that over the course of iterated reproduction of two dimensional random dot patterns transmission accuracy increased to a similar extent in 5- to 8-year-old children and adults whereas algorithmic complexity decreased faster in children. Thus, children require more structure to render complex inputs learnable. In line with the Less-Is-More hypothesis, we interpret this as evidence that children's processing limitations affecting working memory capacity and executive control constrain the ability to represent and generate complexity, which, in turn, facilitates emergence of structure. This underscores the importance of investigating the role of children in the transmission of complex cultural traits. PMID- 25506775 TI - It is there whether you hear it or not: syntactic representation of missing arguments. AB - Many languages allow arguments to be omitted when they are recoverable from the context, but how do people comprehend sentences with a missing argument? We contrast a syntactically-represented account whereby people postulate a syntactic representation for the missing argument, with a syntactically-non-represented account whereby people do not postulate any syntactic representation for it. We report two structural priming experiments in Mandarin Chinese that showed that comprehension of a dative sentence with a missing direct-object argument primed the production of a full-form dative sentence (relative to an intransitive) and that it behaved similarly to a corresponding full-form dative sentence. The results suggest that people construct the same constituent structure for missing argument sentences and full-form sentences, in accord with the syntactically represented account. We discuss the implications for syntactic representations in language processing. PMID- 25506776 TI - Space-time interdependence: evidence against asymmetric mapping between time and space. AB - Time and space are intimately related, but what is the real nature of this relationship? Is time mapped metaphorically onto space such that effects are always asymmetric (i.e., space affects time more than time affects space)? Or do the two domains share a common representational format and have the ability to influence each other in a flexible manner (i.e., time can sometimes affect space more than vice versa)? In three experiments, we examined whether spatial representations from haptic perception, a modality of relatively low spatial acuity, would lead the effect of time on space to be substantially stronger than the effect of space on time. Participants touched (but could not see) physical sticks while listening to an auditory note, and then reproduced either the length of the stick or the duration of the note. Judgements of length were affected by concurrent stimulus duration, but not vice versa. When participants were allowed to see as well as touch the sticks, however, the higher acuity of visuohaptic perception caused the effects to converge so length and duration influenced each other to a similar extent. These findings run counter to the spatial metaphor account of time, and rather support the spatial representation account in which time and space share a common representational format and the directionality of space-time interaction depends on the perceptual acuity of the modality used to perceive space. PMID- 25506777 TI - Human umbilical cord blood cells and diabetes mellitus: recent advances. AB - Stem cell therapy for patients with diabetes is an area of great interest to both scientists and clinicians. Human umbilical cord blood cells (HUCBCs) are being increasingly used as a source of stem cells for cell-based therapy for diabetes because these cells can differentiate into pancreatic islet beta-cells. Administration of HUCBCs has been shown to lower blood glucose levels in diabetic animal models. The use of autologous HUCBC transfusion in type 1 diabetic children has not shown any benefit. However, "Stem Cell Educator" therapy has shown promise in long term lowering of blood glucose levels in both type 1 and type 2 diabetic patients. In this review, we will briefly discuss recent advances in HUCBC therapy in the treatment of diabetes and some of its complications. PMID- 25506779 TI - Counterion and substrate effects on barrier heights of the hydrolytic kinetic resolution of terminal epoxides catalyzed by Co(III)-salen. AB - Density functional theory (DFT) has been applied to the proposed rate-limiting step of the hydrolytic kinetic resolution (HKR) of terminal epoxides as catalyzed by Co-salen-X (X = counterion) in order to resolve questions surrounding the mechanism. The present results indicate that the bimetallic mechanism proposed by Jacobsen shows nonadditive, cooperative catalysis with a larger reduction in barrier height than the sum of the barrier height reductions from the two monometallic reaction pathways. We computed barrier heights for the reaction using several counterions (chloride, acetate, tosylate, and hydroxide). For the three counterions that are experimentally active (chloride, acetate, and tosylate) the barrier heights are 35, 38, and 34 kJ mol(-1), respectively, while for hydroxide it is 48 kJ mol(-1). The similarity of the barrier heights for chloride, acetate, and tosylate is in agreement with their similar peak reaction rates. The finding that Co-salen-X with these counterions leads to rather different overall reaction profiles suggests that they have quite different rates of reaction with epoxide to form the activated Co-salen-OH required for the bimetallic mechanism. Co-salen-OH is inactive as the sole catalyst for HKR, and this inactivity is ascribed to its larger barrier height for the ring-opening step, rather than to any inability to activate epoxide. Barrier heights were also computed using propylene oxide, 1-hexene oxide, and epichlorohydrin; propylene oxide and 1-hexene oxide have similar barrier heights, 35.5 and 33.2 kJ mol(-1), respectively, and epichlorohydrin has a significantly lower barrier height of 18.8 kJ mol(-1), which is qualitatively consistent with experiments showing faster reactions for epicholorohydrin than propylene oxide when catalyzed by Co salen-OAc. PMID- 25506778 TI - Marital discord, past depression, and metabolic responses to high-fat meals: Interpersonal pathways to obesity. AB - BACKGROUND: Longitudinal studies have implicated both marital distress and depression in the development of the metabolic syndrome, a risk factor for diabetes and cardiovascular disease. This study addressed the impact of hostile marital interactions and a mood disorder history on obesity-related metabolic responses to high-fat meals. METHODS: This double-blind, randomized crossover study included serial assessments of resting energy expenditure (REE), fat and carbohydrate oxidation, triglycerides, insulin, glucose, interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) before and after two high-fat meals. During two separate 9.5h visits, 43 healthy married couples, ages 24-61 (mean=38.22), received either a high saturated fat meal or a high oleic sunflower oil meal, both 930kcal and 60g fat. The Structured Diagnostic Interview for DSM IV assessed mood disorder history. Couples discussed a marital disagreement during both visits; behavioral coding of these interactions provided data on hostile marital behaviors. RESULTS: Men and women who displayed more hostile behaviors and who also had a mood disorder history had significantly lower post meal REE, higher insulin, and higher peak triglyceride responses than other participants, with nonsignificant effects for fat and carbohydrate oxidation. Participants with a mood disorder history had a steeper rise in postprandial IL-6 and glucose than those without a past history. Higher levels of hostile behaviors were associated with higher post-meal TNF-alpha. The two meals did not differ on any outcome assessed. CONCLUSIONS: People spend about 18 of every 24h in a postprandial state, and dining with one's partner is a common daily event. Among subjects with a mood disorder history, the cumulative 6.75-h difference between high and low hostile behaviors translates into 128kcal, a difference that could add 7.6pounds/year. Our findings illustrate novel pathways through which chronic marital stress and a mood disorder history synergistically heighten the risk for obesity, metabolic syndrome, and cardiovascular disease. PMID- 25506780 TI - Nonalcoholic fatty liver disease: a challenge for pediatricians. AB - Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and is considered the most common form of chronic liver disease in children. Several factors contribute to NAFLD development, including race/ethnicity, genetic factors, environmental exposures, and alterations in the gut microbiome. The histologic spectrum of NAFLD ranges from simple steatosis to the more aggressive nonalcoholic steatohepatitis (NASH). Fibrosis and eventually cirrhosis can develop from NAFLD during childhood. Diagnosing advanced disease is challenging and may require a liver biopsy, highlighting the urgent need for reliable, noninvasive markers of disease severity. The mainstay of treatment for NAFLD remains lifestyle modifications and weight loss. Probiotics and omega-3 fatty acids may ameliorate disease progression. Recent data have suggested that vitamin E may be considered as a NASH-specific therapy in children, and there are several ongoing human studies evaluating different therapeutic targets for NAFLD. We provide an up-to-date review of the risk factors, diagnosis, and treatment to manage this common disease in children. PMID- 25506782 TI - In vivo study of lipid accumulation in the microalgae marine diatom Thalassiosira pseudonana using Raman spectroscopy. AB - An in vivo non-invasive quantitative analysis technique was introduced for evaluating the fat composition of living marine diatoms by using Raman spectroscopy in conjunction with a chemometric method. This technique enabled the observation of real-time variations in individual lipids in diatom cells without specific treatment or fat extraction. A confocal Raman spectroscope was used to measure the marine centric diatom Thalassiosira (T.) pseudonana that was cultured under six stress conditions, and the spectral data of accumulated fatty acids were obtained. A model-based chemometrics technique, ordinary least square was then used to extract specific signals from Raman spectra obtained for a mixture of fatty acids. The levels of four major lipid moieties from diatoms were extracted simultaneously, including myristic acid, palmitic acid, palmitoleic acid, and eicosapentaenoic acid from the Raman spectra. These results indicate that Raman spectroscopy in conjunction with a chemometrics method is reliable for the quantitative determination of the lipid composition accumulated in the cells of marine diatoms. PMID- 25506781 TI - Antibodies to aquaporin 4, myelin-oligodendrocyte glycoprotein, and the glycine receptor alpha1 subunit in patients with isolated optic neuritis. AB - IMPORTANCE: In patients with isolated optic neuritis (ON), the presence of antibodies to aquaporin 4 (AQP4) has diagnostic and prognostic value. In the same clinical setting, the significance of antibodies to myelin-oligodendrocyte glycoprotein (MOG) or the glycine receptor alpha1 subunit (GlyR) is unclear. OBJECTIVES: To investigate the frequency of antibodies to AQP4, MOG, and GlyR in patients with unilateral or bilateral, severe, or recurrent isolated ON and to determine their clinical and prognostic correlates. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case-control study from November 1, 2005, through May 30, 2014 with the detection of autoantibodies in a neuroimmunology referral center. We included 51 patients with ON but without clinical and magnetic resonance imaging findings outside the optic nerves and 142 controls (30 healthy individuals, 48 patients with neuromyelitis optica, and 64 patients with multiple sclerosis). MAIN OUTCOMES AND MEASURES: Clinicoimmunologic analysis. We determined the presence of antibodies to AQP4, MOG, and GlyR using cell-based assays. RESULTS: The median age of the patients at the onset of ON symptoms was 28 (range, 5-65) years; 36 patients (71%) were female. Antibodies were identified in 23 patients (45%), including MOG in 10 patients, AQP4 in 6 patients, and GlyR in 7 patients (concurrent with MOG in 3 and concurrent with AQP4 in 1). Patients with AQP4 antibodies (median visual score, 3.5 [range, 1-9]) had a worse visual outcome than patients with MOG antibodies alone (median visual score, 0 [range, 0 5]; P = .007), patients with seronegative findings (n = 28) (median visual score, 1.0 [range, 0-14]; P = .08), and patients with GlyR antibodies alone (n = 3) (median visual score, 0 [range, 0-2]; P = .10).The median age of the 7 patients with GlyR antibodies was 27 (range, 11-38) years; 5 (71%) of these were female. Among the 3 patients with GlyR antibodies alone, 1 patient had monophasic ON, 1 had recurrent isolated ON, and 1 had conversion to multiple sclerosis. The 3 patients with GlyR antibodies concurrent with MOG antibodies had recurrent isolated ON, and the patient with concurrent AQP4 antibodies had conversion to neuromyelitis optica. Of the 48 controls with neuromyelitis optica, 37 (77%) had AQP4 antibodies, 4 (8%) had MOG antibodies, 2 (4%) had AQP4 antibodies concurrent with MOG antibodies, and 5 (10%) were seronegative. Of the 64 controls with multiple sclerosis, 5 (8%) had GlyR antibodies. CONCLUSIONS AND RELEVANCE: Forty five percent of patients with unilateral or bilateral, severe, or recurrent isolated ON had antibodies to MOG, AQP4, or GlyR. Patients with AQP4 antibodies had the poorest visual outcomes, whereas patients with MOG antibodies had a better outcome that was similar to that of patients with seronegative findings. The significance of GlyR antibodies in the setting of ON is unclear and deserves further study. PMID- 25506783 TI - Outpatient antibiotic therapy for acute osteomyelitis in children: balancing safety and efficacy. PMID- 25506784 TI - Effect of public disclosure on antibiotic prescription rate for upper respiratory tract infections. PMID- 25506785 TI - Direct observation of guanine radical cation deprotonation in G-quadruplex DNA. AB - Although numerous studies have been devoted to the charge transfer through double stranded DNA (dsDNA), one of the major problems that hinder their potential applications in molecular electronics is the fast deprotonation of guanine cation (G(+*)) to form a neutral radical that can cause the termination of hole transfer. It is thus of critical importance to explore other DNA structures, among which G-quadruplexes are an emerging topic. By nanosecond laser flash photolysis, we report here the direct observation and findings of the unusual deprotonation behavior (loss of amino proton N2-H instead of imino proton N1-H) and slower (1-2 orders of magnitude) deprotonation rate of G(+*) within G quadruplexes, compared to the case in the free base dG or dsDNA. Four G quadruplexes AG3(T2AG3)3, (G4T4G4)2, (TG4T)4, and G2T2G2TGTG2T2G2 (TBA) are measured systematically to examine the relationship of deprotonation with the hydrogen-bonding surroundings. Combined with in depth kinetic isotope experiments and pKa analysis, mechanistic insights have been further achieved, showing that it should be the non-hydrogen-bonded free proton to be released during deprotonation in G-quadruplexes, which is the N2-H exposed to solvent for G bases in G-quartets or the free N1-H for G base in the loop. The slower N2-H deprotonation rate can thus ensure less interruption of the hole transfer. The unique deprotonation features observed here for G-quadruplexes open possibilities for their interesting applications as molecular electronic devices, while the elucidated mechanisms can provide illuminations for the rational design of G quadruplex structures toward such applications and enrich the fundamental understandings of DNA radical chemistry. PMID- 25506786 TI - Allosteric reversion of Haemophilus influenzae beta-carbonic anhydrase via a proline shift. AB - Haemophilus influenzae beta-carbonic anhydrase (HICA) has been reverse-engineered in the allosteric site region to resemble the nonallosteric Pisum sativum enzyme in order to identify critical features of allostery and intersusbunit communication. Three variants (W39V/G41A, P48S/A49P, and W39V/G41A/P48S/A49P) were identified, through a comparison with a crystal structure of nonallosteric P. sativum beta-carbonic anhydrase (PSCA, PDB 1EKJ ), to potentially revert HICA to a nonallosteric enzyme. The W39V/G41A and P48S/A49P mutations decreased the apparent kcat/Km proton dependence from 4 to 2 and 1, respectively, increasing the overall maximal kcat/Km to 16 +/- 2 MUM(-1) s(-1) (380% of wild type) and 17 +/- 3 MUM(-1) s(-1) (405% of wild type). The pKa values of the metal-bound water molecule based on the pH-rate profile kinetics (8.32 +/- 0.04 for W39V/G41A and 8.3 +/- 0.1 for P48S/A49P) were also slightly higher than that for the wild-type enzyme (7.74 +/- 0.04). The P48S/A49P variant has lost all pH-rate cooperativity. The W39V/G41A/P48S/A49P variant's kinetics were unusual and were fit with a log linear function with a slope 0.9 +/- 0.2. The crystal structure of the W39V/G41A variant revealed an active site very similar to the T-state wild-type oligomer with bicarbonate trapped in the escort site. By contrast, the X-ray crystal structure of a proline shift variant (P48S/A49P) reveals that it has adopted an active site conformation nearly identical to that of nonallosteric beta-carbonic anhydrase (R-state) for one chain, including a tight association with the dimer exchanged N-terminal helices; the second chain in the asymmetric unit is associated in a biologically relevant oligomer, but it adopts a T-state conformation that is not capped by dimer-exchanged N-terminal helices. The hybrid R/T nature of HICA P48S/A49P structurally recapitulates the interruption of pH rate cooperativity observed for this variant. Comparison of the conformations of the R and T chains of P48S/A49P suggests a new hypothesis to explain HICA allosteric communication that is mediated by the N-terminal helices and anion binding at the dimer interface. PMID- 25506788 TI - Effects of water concentration on the free volume of amino acid ionic liquids investigated by molecular dynamics simulations. AB - Amino acid ionic liquids (AAILs) are gaining attention because of their potential in CO2 capture technology. Molecular dynamics simulations of AAILs tetramethylammonium glycinate ([N1111][Gly]), tetrabutylammonium glycinate ([N4444][Gly]), and 1,1,1-trimethylhydrazinium glycinate ([aN111][Gly]) and their corresponding mixtures with water were performed to investigate the effect of water concentration on the cation-anion interactions. The water content significantly influenced the free volume (FV) and fractional free volume (FFV) of the AAILs that varied with the hydrophobic and hydrophilic nature of the ion pairs. Under dry conditions, the FFV increased with increasing cation molecular sizes, indicative of proportional adsorption of any inert gases, such as N2, as consistent with experimental observations. Furthermore, the polarity of the cation played an important role in FFV and hence the diffusion of the AAILs. Density functional theory calculations suggested that hydrophilic [aN111][Gly] featured stronger interactions in the presence of water, whereas the hydrophobic IL showed weaker interactions. The carboxylate group of glycinate displayed stronger interactions with water than the cation. The computational study provided qualitative insight into the role of FV of the AAILs on CO2 and N2 absorption and suggests that [aN111][Gly] has CO2 adsorption capacity in the presence of water superior to that of other studied AAILs. PMID- 25506787 TI - Genetically encoded molecular biosensors to image histone methylation in living animals. AB - Post-translational addition of methyl groups to the amino terminal tails of histone proteins regulates cellular gene expression at various stages of development and the pathogenesis of cellular diseases, including cancer. Several enzymes that modulate these post-translational modifications of histones are promising targets for development of small molecule drugs. However, there is no promising real-time histone methylation detection tool currently available to screen and validate potential small molecule histone methylation modulators in small animal models. With this in mind, we developed genetically encoded molecular biosensors based on the split-enzyme complementation approach for in vitro and in vivo imaging of lysine 9 (H3-K9 sensor) and lysine 27 (H3-K27 sensor) methylation marks of histone 3. These methylation sensors were validated in vitro in HEK293T, HepG2, and HeLa cells. The efficiency of the histone methylation sensor was assessed by employing methyltransferase inhibitors (Bix01294 and UNC0638), demethylase inhibitor (JIB-04), and siRNA silencing at the endogenous histone K9-methyltransferase enzyme level. Furthermore, noninvasive bioluminescence imaging of histone methylation sensors confirmed the potential of these sensors in monitoring histone methylation status in response to histone methyltransferase inhibitors in living animals. Experimental results confirmed that the developed H3-K9 and H3-K27 sensors are specific and sensitive to image the drug-induced histone methylation changes in living animals. These novel histone methylation sensors can facilitate the in vitro screening and in vivo characterization of new histone methyltransferase inhibitors and accelerate the pace of introduction of epigenetic therapies into the clinic. PMID- 25506789 TI - In vivo tracking and fate of intra-articularly injected superparamagnetic iron oxide particle-labeled multipotent stromal cells in an ovine model of osteoarthritis. AB - In this study, superparamagnetic iron oxide (SPIO) particle-labeled mesenchymal stromal cells (MSCs) were injected intra-articularly into osteoarthritic knee joints. Their fate and distribution were evaluated using magnetic resonance imaging (MRI) and macroscopic and histologic postmortem examination. Osteoarthritis was induced in 12 sheep by bilateral meniscectomy. After 6 weeks, one knee joint received 10 * 10(6) SPIO-labeled MSCs (Molday Ion Rhodamine B). Contralateral knees received a control injection of a) PBS, b) SPIO in PBS, c) 10 * 10(6) nonvital SPIO-labeled MSCs in PBS, or d) no injection. MR images were acquired immediately after injection and 1, 4, 8, and 12 weeks thereafter using a 0.5-T unit and a T2* sequence. Signal intensity of synovial fluid and synovial lining was assessed semiquantitatively using a scoring system. Viable SPIO labeled MSCs produced a strong hypointense signal in the synovial fluid immediately after injection, but normal signal intensity of the synovial fluid was observed 1 week later. Synovial lining maintained its hypointensity throughout the study period. Nonvital SPIO-labeled MSCs induced hypointense signals of the synovial fluid; synovial lining appeared weak and inconsistently hypointense in the following weeks. Pure SPIO produced a strong hyperintense signal in the synovial fluid at the time of injection only. Histologically, in all knee joints receiving viable SPIO-labeled MSCs, SPIO particles were detected (Prussian blue) within the synovial lining, dorsal fat pad, and neomeniscus tissue, but not in osteochondral samples. Few SPIO particles were detected in joints injected with nonvital SPIO-labeled MSCs. Immunohistologically, no increased cell death (TUNEL) was observed in the area of detected SPIO particles, but we did observe potential chondrogenic cell differentiation (Safranin O or S100beta). We conclude that viable SPIO-labeled MSCs remain detectable within the joint for 12 weeks and attach themselves to some but not all diseased joint structures. PMID- 25506790 TI - Rapid, nondestructive denim fiber bundle characterization using luminescence hyperspectral image analysis. AB - An investigation into the performance of luminescence-based hyperspectral imaging (LHSI) for denim fiber bundle discrimination has been conducted. We also explore the potential of nitromethane (CH3NO2) -based quenching to improve discrimination, and we determine the quenching mechanism. The luminescence spectra (450-850 nm) and images from the denim fiber bundles were obtained with excitation at 325 or 405 nm. LHSI data were recorded in less than 5 s and subsequently assessed by principal component analysis or rendered as red, green, blue (RGB) component histograms. The results show that LHSI data can be used to rapidly and uniquely discriminate between all the fiber bundle types studied in this research. These non-destructive techniques eliminate extensive sample preparation and allow for rapid hyperspectral image collection, analysis, and assessment. The quenching data also revealed that the dye molecules within the individual fiber bundles exhibit dramatically different accessibilities to CH3NO2. PMID- 25506791 TI - In situ ultrafast 2D NMR spectroelectrochemistry for real-time monitoring of redox reactions. AB - The in situ implementation of an electrochemical cell (EC) inside a nuclear magnetic resonance (NMR) spectrometer is extremely powerful to study redox reactions in real time and identify unstable reaction intermediates. Unfortunately, the implementation of an electrochemical device near the sensitive volume of an NMR probe significantly affects the quality of the NMR signal, inducing significant line broadening resulting in peak overlap and partial loss of the multiplet structures. Two-dimensional (2D) NMR spectroscopy allows one to bypass signal overlapping by spreading the peaks along two orthogonal dimensions, while providing precious information in terms of structural elucidation. Nevertheless, the acquisition of 2D NMR data suffers from long acquisition durations which are incompatible with fast redox processes taking place in solution. Here, we present a new approach to deal with this issue, consisting of coupling EC-NMR with ultrafast 2D spectroscopy, capable of recording 2D spectra much faster than conventional 2D NMR. This approach is applied to the real-time monitoring of a model reaction. Fast correlation spectroscopy (COSY) spectra are recorded every 3 min in the course of the 80 min reaction, leading to the unambiguous identification of one reaction intermediate and two reaction products. The evolution of 2D NMR peak volumes in the course of time provides further insight into the mechanism of this reaction involving an unstable intermediate. This study demonstrates the feasibility and the relevance of coupling in situ spectroelectrochemistry with ultrafast 2D spectroscopy to monitor real-time electrochemical reactions in the NMR tube. PMID- 25506792 TI - A qualitative study of the reactions of young adults with epilepsy to SUDEP disclosure, perceptions of risks, views on the timing of disclosure, and behavioural change. AB - OBJECTIVE: We examined young adults' responses to information about sudden unexpected death in epilepsy (SUDEP). METHOD: Consecutive patients attending a specialist epilepsy clinic, aged 16-30years, with a Hospital Anxiety and Depression Scale (HADS) score of <11, and who had been told about SUDEP at least 2weeks previously, were invited to the study. Semistructured in-depth interviews were conducted by an experienced qualitative interviewer until data saturation was achieved. An inductive thematic analysis of the data was conducted, facilitated by the use of the qualitative data analysis software (NVivo). The study was approved by the South East Scotland Research Ethics Committee. RESULTS: Twenty-seven patients (15 females) aged 18-29years were interviewed. All said that they were satisfied with the information that they had received about SUDEP. However, at the interview, their understanding of SUDEP was often limited and incorrect. Many were not aware of their own SUDEP risk status. Twenty-two (81%) said that everyone should be told about SUDEP. Most thought that disclosure should happen at the time of the diagnosis or soon after, preferably in a face-to face consultation; clinician judgment on timing was highlighted. Few reported seeking further information on SUDEP for themselves beyond the initial consultation. Most were either untroubled by the initial disclosure of SUDEP or reported initial anxiety that was not long-lasting. A minority reported changing their behavior, for example, improving medication adherence, but most reported no change. The majority expressed a fatalistic view of SUDEP as something outside of their control. SIGNIFICANCE: Our results suggest that clinicians can be more confident that most of their young adult patients want to know about SUDEP, want to be told early, and do not have long-lasting anxiety due to its disclosure. Getting information on SUDEP will not, on its own, increase medication adherence in most patients. Methods to increase patient understanding of SUDEP are needed. PMID- 25506793 TI - Impaired picture recognition in transient epileptic amnesia. AB - Transient epileptic amnesia (TEA) is an epileptic syndrome characterized by recurrent, brief episodes of amnesia. Transient epileptic amnesia is often associated with the rapid decline in recall of new information over hours to days (accelerated long-term forgetting - 'ALF'). It remains unknown how recognition memory is affected in TEA over time. Here, we report a systematic study of picture recognition in patients with TEA over the course of one week. Sixteen patients with TEA and 16 matched controls were presented with 300 photos of everyday life scenes. Yes/no picture recognition was tested 5min, 2.5h, 7.5h, 24h, and 1week after picture presentation using a subset of target pictures as well as similar and different foils. Picture recognition was impaired in the patient group at all test times, including the 5-minute test, but it declined normally over the course of 1week. This impairment was associated predominantly with an increased false alarm rate, especially for similar foils. High performance on a control test indicates that this impairment was not associated with perceptual or discrimination deficits. Our findings suggest that, at least in some TEA patients with ALF in verbal recall, picture recognition does not decline more rapidly than in controls over 1week. However, our findings of an early picture recognition deficit suggest that new visual memories are impoverished after minutes in TEA. This could be the result of deficient encoding or impaired early consolidation. The early picture recognition deficit observed could reflect either the early stages of the process that leads to ALF or a separable deficit of anterograde memory in TEA. Lastly, our study suggests that at least some patients with TEA are prone to falsely recognizing new everyday visual information that they have not in fact seen previously. This deficit, alongside their ALF in free recall, likely affects everyday memory performance. PMID- 25506794 TI - Urokinase-type plasminogen activator deficiency has little effect on seizure susceptibility and acquired epilepsy phenotype but reduces spontaneous exploration in mice. AB - Urokinase-type plasminogen activator (uPA), a serine protease, converts plasminogen to plasmin. Activation of plasmin leads to degradation of the extracellular matrix, which is critical for tissue recovery, angiogenesis, cell migration, and axonal and synaptic plasticity. We hypothesized that uPA deficiency would cause an abnormal neurophenotype and would lead to exacerbated epileptogenesis after brain injury. Wild-type (Wt) and uPA-/- mice underwent a battery of neurologic behavioral tests evaluating general reactivity, spontaneous exploratory activity, motor coordination, pain threshold, fear and anxiety, and memory. We placed particular emphasis on the effect of uPA deficiency on seizure susceptibility, including the response to convulsants (pentylenetetrazol, kainate, or pilocarpine) and kainate-induced epileptogenesis and epilepsy. The uPA-/- mice showed no motor or sensory impairment compared with the Wt mice. Hippocampus-dependent spatial memory also remained intact. The uPA-/- mice, however, exhibited reduced exploratory activity and an enhanced response to a tone stimulus (p<0.05 compared with the Wt mice). The urokinase-type plasminogen activator deficient mice showed no increase in spontaneous or evoked epileptiform electrographic activity. Rather, the response to pilocarpine administration was reduced compared with the Wt mice (p<0.05). Also, the epileptogenesis and the epilepsy phenotype after intrahippocampal kainate injection were similar to those in the Wt mice. Taken together, uPA deficiency led to diminished interest in the environmental surroundings and enhanced emotional reactivity to unexpected aversive stimuli. Urokinase-type plasminogen activator deficiency was not associated with enhanced seizure susceptibility or worsened poststatus epilepticus epilepsy phenotype. PMID- 25506795 TI - Copper-catalyzed synthesis of substituted quinolines via C-N coupling/condensation from ortho-acylanilines and alkenyl iodides. AB - An efficient cascade copper-catalyzed intermolecular Ullmann-type C-N coupling/enamine condensation reaction is described, in which ortho-acylanilines and alkenyl iodides converted to multisubstituted quinolines in good to excellent yields. PMID- 25506797 TI - Corrigendum. PMID- 25506796 TI - SIPRI Yearbook 2013: armaments, disarmament and international security. PMID- 25506798 TI - Improving survival of probiotic bacteria using bacterial poly-gamma-glutamic acid. AB - A major hurdle in producing a useful probiotic food product is bacterial survival during storage and ingestion. The aim of this study was to test the effect of gamma-PGA immobilisation on the survival of probiotic bacteria when stored in acidic fruit juice. Fruit juices provide an alternative means of probiotic delivery, especially to lactose intolerant individuals. In addition, the survival of gamma-PGA-immobilised cells in simulated gastric juice was also assessed. Bifidobacteria strains (Bifidobacteria longum, Bifidobacteria breve), immobilised on 2.5% gamma-PGA, survived significantly better (P<0.05) in orange and pomegranate juice for 39 and 11 days respectively, compared to free cells. However, cells survived significantly better (P<0.05) when stored in orange juice compared to pomegranate juice. Moreover, both strains, when protected with 2.5% gamma-PGA, survived in simulated gastric juice (pH2.0) with a marginal reduction (<0.47 log CFU/ml) or no significant reduction in viable cells after 4h, whereas free cells died within 2h. In conclusion, this research indicates that gamma-PGA can be used to protect Bifidobacteria cells in fruit juice, and could also help improve the survival of cells as they pass through the harsh conditions of the gastrointestinal tract (GIT). Following our previous report on the use of gamma PGA as a cryoprotectant for probiotic bacteria, this research further suggests that gamma-PGA could be used to improve probiotic survival during the various stages of preparation, storage and ingestion of probiotic cells. PMID- 25506800 TI - Analytical characterization of label-free immunosensor subsystems based on multi walled carbon nanotube array-modified gold interface. AB - In the present work, we report characterization studies of antigen(Ag)-antibody (Ab) interaction based on the multi-walled carbon nanotube array-modified gold electrode for label-free electrochemical immunosensor. -COOH functionalization of MWCNT was suggested by FTIR spectroscopy. Images from atomic force microscopy (AFM) and RAMAN spectroscopy confirmed the interaction of Ab on the gold interface based on the MWCNT array. A cyclic voltammetric study exhibited a linear response in phosphate buffered saline (PBS) solution including 1mM K3Fe (CN) 6 at pH 7.4 with PSA concentrations over a range of 2 to 40 ngmL(-1), and a calculated detection limit of 0.56 ngmL(-1). PMID- 25506799 TI - Opt-out HIV testing in prison: informed and voluntary? AB - HIV testing in prison settings has been identified as an important mechanism to detect cases among high-risk, underserved populations. Several public health organizations recommend that testing across health-care settings, including prisons, be delivered in an opt-out manner. However, implementation of opt-out testing within prisons may pose challenges in delivering testing that is informed and understood to be voluntary. In a large state prison system with a policy of voluntary opt-out HIV testing, we randomly sampled adult prisoners in each of seven intake prisons within two weeks after their opportunity to be HIV tested. We surveyed prisoners' perception of HIV testing as voluntary or mandatory and used multivariable statistical models to identify factors associated with their perception. We also linked survey responses to lab records to determine if prisoners' test status (tested or not) matched their desired and perceived test status. Thirty-eight percent (359/936) perceived testing as voluntary. The perception that testing was mandatory was positively associated with age less than 25 years (adjusted relative risk [aRR]: 1.45, 95% confidence interval [CI]: 1.24, 1.71) and preference that testing be mandatory (aRR: 1.81, 95% CI: 1.41, 2.31) but negatively associated with entry into one of the intake prisons (aRR: 0.41 95% CI: 0.27, 0.63). Eighty-nine percent of prisoners wanted to be tested, 85% were tested according to their wishes, and 82% correctly understood whether or not they were tested. Most prisoners wanted to be HIV tested and were aware that they had been tested, but less than 40% understood testing to be voluntary. Prisoners' understanding of the voluntary nature of testing varied by intake prison and by a few individual-level factors. Testing procedures should ensure that opt-out testing is informed and understood to be voluntary by prisoners and other vulnerable populations. PMID- 25506801 TI - Bioluminescent cell-based NAD(P)/NAD(P)H assays for rapid dinucleotide measurement and inhibitor screening. AB - Abstract The central role of nicotinamide adenine dinucleotides in cellular energy metabolism and signaling makes them important nodes that link the metabolic state of cells with energy homeostasis and gene regulation. In this study, we describe the implementation of cell-based bioluminescence assays for rapid and sensitive measurement of those important redox cofactors. We show that the sensitivity of the assays (limit of detection ~0.5 nM) enables the selective detection of total amounts of nonphosphorylated or phosphorylated dinucleotides directly in cell lysates. The total amount of NAD+NADH or NADP+NADPH levels can be detected in as low as 300 or 600 cells/well, respectively. The signal remains linear up to 5,000 cells/well with the maximum signal-to-background ratios ranging from 100 to 200 for NAD+NADH and from 50 to 100 for NADP+NADPH detection. The assays are robust (Z' value >0.7) and the inhibitor response curves generated using a known NAD biosynthetic pathway inhibitor FK866 correlate well with the reported data. More importantly, by multiplexing the dinucleotide detection assays with a fluorescent nonmetabolic cell viability assay, we show that dinucleotide levels can be decreased dramatically (>80%) by FK866 treatment before changes in cell viability are detected. The utility of the assays to identify modulators of intracellular nicotinamide adenine dinucleotide levels was further confirmed using an oncology active compound library, where novel dinucleotide regulating compounds were identified. For example, the histone deacetylase inhibitor entinostat was a potent inhibitor of cellular nicotinamide adenine dinucleotides, whereas the selective estrogen receptor modulator raloxifene unexpectedly caused a twofold increase in cellular nicotinamide adenine dinucleotide levels. PMID- 25506802 TI - A zebrafish in vivo phenotypic assay to identify 3-aminothiophene-2-carboxylic acid-based angiogenesis inhibitors. AB - Abstract Small molecules that inhibit angiogenesis are attractive drug candidates for cancer, retinopathies, and age-related macular degeneration. In vivo, phenotypic screening in zebrafish (Danio rerio) emerges as a powerful methodology to identify and optimize novel compounds with pharmacological activity. Zebrafish provides several advantages for in vivo phenotypic screens especially for angiogenesis, since it develops rapidly, externally, and does not rely on a functional cardiovascular system to survive for several days during development. In this study, we utilize a transgenic line that allows the noninvasive monitoring of angiogenesis at a cellular level. The inhibition of angiogenesis can be observed under a fluorescent stereoscope and quantified. To exemplify the versatility and robustness of the zebrafish screen, we have employed a series of 60 novel compounds that were designed based on a potent VEGFR2 inhibitor. Herein, we report their structure-based design, synthesis, and in vivo zebrafish screening for optimal activity, toxicity, and off-target effects, which revealed six reversible inhibitors of angiogenesis. PMID- 25506803 TI - High-content high-throughput assays for characterizing the viability and morphology of human iPSC-derived neuronal cultures. AB - Abstract Development of quantitative high-throughput in vitro assays that enable assessment of viability and morphological changes in neuronal cells is an active area of investigation in drug discovery and environmental chemical safety assessment. High-content imaging is an emerging and efficient tool for generating multidimensional quantitative cellular readouts; in addition, human induced pluripotent stem cell (iPSC)-derived neurons are a promising in vitro model system that emulates both the functionality and behavior of mature neurons, and they are available in quantities sufficient for screening workflows. The goal of this study was to develop high-content imaging and analysis methods to assess multiple phenotypes in human iPSC-derived neuronal cells. Specifically, we optimized cell culture, staining, and imaging protocols in a 384-well assay format and improved laboratory workflow by designing a one-step procedure to reduce assay time and minimize cell disturbance. Phenotypic readouts include quantitative characterization of neurite outgrowth and branching, cell number and viability, as well as measures of adverse effects on mitochondrial integrity and membrane potential. To verify the robustness of the workflow, we tested a series of compounds that are established toxicants. We report concentration-response effects of selected test compounds on human iPSC-derived neuronal cells and illustrate how the proposed methods may be used for high-content high-throughput compound toxicity screening and safety evaluation of drugs and environmental chemicals. PMID- 25506804 TI - Two-stage hybrid repair of Kommerell diverticulum with supra-aortic debranching. AB - OBJECTIVES: The surgical treatment of Kommerell diverticula is associated with high mortality and morbidity rates. In the mid-2000s, hybrid aortic arch repair was developed, and the procedure has since been used to repair Kommerell diverticula. In the present study, we focused on the postoperative outcomes of two-stage hybrid repair of Kommerell diverticula that required supra-aortic debranching (type I hybrid arch repair). METHODS: From August 2010 to July 2013, a total of four patients (aged 73.5 +/- 9.5 years) underwent two-stage hybrid repair (type I hybrid arch repair) for Kommerell diverticula, and their cases were retrospectively studied. All four patients had right aortic arches and aberrant left subclavian arteries. The repair procedure consisted of two stages: (1) debranching of the supra-aortic vessels via a median sternotomy; (2) exclusion of the Kommerell diverticulum by performing thoracic endovascular repair via a femoral approach and coil embolization of the orifice of the aberrant subclavian artery. RESULTS: There were no in-hospital deaths. One patient developed an acute kidney injury and required hemodialysis on postoperative day 2, although his renal function recovered within 48 hours. No strokes, paraplegia, or early aortic events were observed in our series. The mean follow-up period was 19.5 months (range, 5-47 months). All patients remained free from aortic events and endoleaks during the follow-up period. CONCLUSION: The early and mid-term outcomes of hybrid repair for Kommerell diverticula that require supra-aortic debranching, which are less invasive and do not involve hypothermic circulatory arrest, are acceptable. However, this procedure requires the insertion of an endograft into the ascending aorta, and careful and long-term follow-up is required to confirm its efficacy. PMID- 25506806 TI - Borrelia burgdorferi seeks vectors. PMID- 25506805 TI - Functionalization of lignin through ATRP grafting of poly(2-dimethylaminoethyl methacrylate) for gene delivery. AB - The biomass kraft lignin was modified into lignin-based macroinitiators (LnMI) through esterification of the alcohol and phenol functional groups on lignin backbone with 2-bromo-isobutyric bromide under mild condition. Then a series of cationic amphiphilic lignin-based graft copolymers were synthesized by atom transfer radical polymerization (ATRP) of 2-(dimethylamino)ethyl methacrylate (DMAEMA) starting from the lignin-based macroinitiators. These copolymers, denoted as LnPDMAEMA, had a hyperbranched structure with a hydrophobic backbone of lignin and multiple cationic hydrophilic arms of PDMAEMA. The LnPDMAEMA copolymers were characterized by (1)H NMR and elemental analysis (EA), and studied in terms of their DNA binding capability, formation of nanoparticles with plasmid DNA (pDNA), cytotoxicity, and gene transfection in cultured cells. It was found that all the copolymers could efficiently compact pDNA into nanoparticles with sizes ranging from 100 to 200 nm at N/P ratios of 5 or higher. The cytotoxicity of these copolymers depends greatly on the chain length of PDMAEMA arms, the longer the PAMAEMA chain the higher the cytotoxicity. Luciferase assay was used to study the in vitro gene transfection for the LnPDMAEMA copolymers in different cell lines. The gene transfection efficiency of these copolymers was dependent on the grafted PDMAEMA chain length and N/P ratio. Generally, the transfection efficiency decreased with the increase of PAMAEMA length at N/P ratio of 20 or higher. It is very interesting that one of the LnPDMAEMA copolymers with very short arm length (degree of average DMAEMA units=5.5) showed excellent in vitro transfection efficiency that was comparable or even higher than that of branched PEI (25K). These novel biomass-based LnPDMAEMA hyperbranched copolymers can be a promising nonviral gene vectors for future gene delivery application. PMID- 25506807 TI - In vitro dopaminergic neurotoxicity of pesticides: a link with neurodegeneration? AB - Around the globe, chemical compounds are used to treat or repel pests and plagues that pose a threat to food and feed production. From epidemiological studies, it is known that there is a link between exposure to certain chemical classes of these so-called pesticides and the prevalence of neurodegenerative disorders such as Parkinson's disease in humans. However, which particular compound(s) account for this link or what underlying mechanisms are involved is still largely unresolved. The degenerative process in Parkinson's disease is largely limited to the dopaminergic neurons in the basal ganglia. Cellular mechanisms that are implicated in parkinsonian neurodegeneration include mitochondrial dysfunction, oxidative stress, disturbance of intracellular calcium homeostasis and endoplasmic reticulum (ER) stress. A major characteristic that distinguishes the dopaminergic neurons in the basal ganglia from other dopaminergic neurons is a particular reliance on intracellular calcium for spontaneous activity. Considering the energy consuming nature of maintenance of the intracellular calcium homeostasis and its involvement in life and death of a neuron, this may explain the specific vulnerability of this neuronal population. Despite a large variation in primary mechanism of action it has been demonstrated that pesticides from different classes disturb intracellular calcium homeostasis, thus interfering with intracellular calcium signalling. This relates to altered dopaminergic signalling, disturbed protein homeostasis and increased oxidative stress. Therefore, effects of (mixtures of) pesticides on the intracellular calcium homeostasis may play a role in the development of Parkinson's disease in humans. Although human exposure to pesticides via e.g. food often occurs in complex mixtures, (human) risk assessment is largely based on the assessment of single compounds. The discovery of common modes of action across different classes of pesticides therefore underpins the urgency of development of new models and approaches in risk assessment. PMID- 25506808 TI - Rumination and multi-modal emotional reactivity. AB - Rumination, a cognitive process that involves passively and repetitively focusing on negative feelings and their consequences, has been linked to negative emotional outcomes. Previous research suggests that rumination may lead to deleterious outcomes through prolonging emotional reactivity; however, evidence supporting the link between rumination and reactivity has been mixed. In the present study, we examined the relationship between state and trait rumination and multi-modal emotional reactivity (i.e., hypothalamic-pituitary-adrenal axis, autonomic nervous system, subjective experience). Fifty undergraduates participated in a social evaluative laboratory stressor. They also reported on their general tendency to ruminate and their use of rumination in response to this particular laboratory stressor. State, but not trait, rumination was associated with increases in cortisol and negative affect. Findings underscore the importance of multi-modal assessment of emotional reactivity and suggest important implications for rumination following a stressor. PMID- 25506809 TI - Synthesis and anticancer activity of some novel indolo[3,2-b]andrographolide derivatives as apoptosis-inducing agents. AB - A series of novel indolo[3,2-b]andrographolide derivatives were designed, synthesized and screened in vitro against three human cancer cell lines MCF7 (human breast cancer), HCT116 (human colon cancer), and DU145 (human prostate cancer). Fourteen compounds 6b, 6e, 6i, 6j, 6l, 6m, 6n, 12a, 12b, 13a, 13b, 15a, 17a, and 17b exhibited better anti-cancer activities than andrographolide for all three human cancer lines, with compound 6l displaying best activity with IC50 values of 1.85, 1.22 and 1.24 MUM against MCF7, HCT116 and DU145 respectively. Preliminary anti-cancer mechanistic investigation was performed in terms of the cell cycle arrest and cell apoptosis assays of compound 6l against HCT116 using flow cytometry, and the results suggested that compound 6l inhibited tumor proliferation through inducing early and late cellular apoptosis in a concentration-dependent manner and causing cell cycle arrest in the S-phase. PMID- 25506810 TI - Synthesis of indazole motifs and their medicinal importance: an overview. AB - Indazoles is an important class of heterocyclic compounds having a wide range of biological and pharmaceutical applications. There is enormous potential in the synthesis of novel heterocyclic systems to be used as building blocks for the next generation of pharmaceuticals as anti-bacterial, anti-depressant and anti inflammatory. Fused aromatic 1H and 2H-indazoles are well recognized for anti hypertensive and anti-cancer properties. The present review focuses on novel routes of their synthesis and various biological activities. PMID- 25506811 TI - Leishmanicidal activity of polysaccharides and their oxovanadium(IV/V) complexes. AB - The parasites of the genus Leishmania cause a range of leishmaniasis diseases, whose treatment is impaired due to intramacrophage parasites living in the mammalian host. Immunostimulation has been considered an important strategy to leishmaniasis treatment. The immunomodulatory effects of the polysaccharides arabinogalactan (ARAGAL), galactomannan (GMPOLY), and xyloglucan (XGJ), as well as their oxovanadium (IV/V) complexes (ARAGAL:VO, GMPOLY:VO, and XGJ:VO) were evaluated on peritoneal macrophages. At 25 MUg/mL of GMPOLY:VO and of XGJ:VO, and 10 MUg/mL of ARAGAL:VO, nitric oxide (NO) production by the macrophages was not altered compared with the control group. All polymers increased the production of interleukins 1 beta and 6 (IL-1beta and IL-6), but the oxovanadium complexes were more potent activators of these mediators. ARAGAL:VO 10 MUg/mL, GMPOLY:VO and XGJ:VO 25 MUg/mL led to an increase of 562%, 1054%, and 523% for IL-1beta, respectively. For IL-6 at the same concentration, the levels increased by 539% and 794% for ARAGAL:VO and GMPOLY:VO, respectively. Polysaccharides and their oxovanadium complexes exhibited important leishmanicidal effects on amastigotes of Leishmania (L.) amazonensis. The native and complexed polymers reduced the growth of promastigote-form Leishmania by ~60%. This effect was reached at concentrations 12 times lower than that observed for Glucantime (300 MUg/mL promoted an inhibition of ~60%). The 50% inhibitory concentration (IC50) values for the complexes were determined. XGJ:VO showed the lowest IC50 value (6.2 MUg/mL; 0.07 MUg/mL of vanadium), which for ARAGAL:VO was 6.5 MUg/mL (0.21 MUg/mL of vanadium) and 7.3 MUg/mL (0.06 MUg/mL of vanadium) for GMPOLY:VO. The upregulation of IL-1beta and IL-6 release and downregulation of NO production by macrophages and the important leishmanicidal effect are essential to stablish their potential use against this pathology. PMID- 25506812 TI - Sex Differences in Workplace Satisfaction and Engagement of Academic Pathologists: Opportunities to Enhance Faculty Diversity. AB - CONTEXT: There is attrition of women across professorial ranks in academic pathology. Women are underrepresented as leaders; 15.4% of academic pathology departments are chaired by women, according to the Association of American Medical Colleges (AAMC). OBJECTIVE: To identify areas for targeted interventions that can advance academic and leadership development of women faculty by examining (1) sex differences in career satisfaction in US medical school pathology departments participating in the AAMC's Faculty Forward Engagement Survey, and (2) findings from a survey of the Association of Pathology Chairs (APC). DESIGN: The AAMC Faculty Forward Engagement Survey data are from 14 US medical schools participating in the 2011-2012 survey. Pathologists' response rate was 66% (461 of 697). To investigate sex differences, t tests and chi(2) analyses were used. The APC survey, administered to academic department chairs, had a 55% response rate (104 of 189). RESULTS: According to the Faculty Forward Engagement Survey, women report more time in patient care and less time in research. Women consider formal mentorship, feedback, and career advancement more important than men do and are less satisfied with communication and governance. The APC survey shows that 20% to 40% of nonchair department leaders are women. More than half of chairs report satisfaction with the sex diversity of their departmental leaders. CONCLUSION: Opportunities exist for department chairs and professional organizations to create targeted interventions to support career satisfaction, recruitment, retention, and career and leadership development for women in academic pathology. Although chairs report satisfaction with diversity within department leadership, responses of women faculty indicate there is work to be done to grow more women leaders. PMID- 25506813 TI - Interventions for treating painful nipples among breastfeeding women. AB - BACKGROUND: Leading health authorities all recommend exclusive breastfeeding to six months' postpartum. While most women initiate breastfeeding, many discontinue due to difficulties encountered rather than maternal choice. One common breastfeeding difficulty is painful nipples. Research has identified poor infant positioning or latch as a common cause of painful nipples. While many different interventions designed to reduce nipple pain in breastfeeding women have been evaluated, it is unclear which intervention is the most effective treatment. An understanding of nipple pain and treatment options are needed to improve breastfeeding duration and exclusivity rates and to address systematically one of the most frequent difficulties encountered by breastfeeding women. OBJECTIVES: To assess the effects of all interventions in the resolution or reduction of nipple pain and the impact of the interventions on other outcomes such as nipple trauma, nipple infections, breast mastitis, breastfeeding duration, breastfeeding exclusivity, and maternal satisfaction. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2014) and scanned secondary references. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials designed to evaluate any intervention for treating nipple pain among breastfeeding women. Trials using a cluster-randomised design were eligible for inclusion. Cross-over trials were not eligible for inclusion. The following interventions were eligible for inclusion compared with each other or usual care (i.e. education only): pharmacological (e.g. antifungal creams); non pharmacological topical treatments (e.g. lanolin); dressings (e.g. hydrogel dressings); nipple protection devices (e.g. breast shells), phototherapy, and expressed breast milk. Nipple pain in women who are feeding with expressed breast milk (i.e. women of infants in neonatal units) is associated with other methods of removing milk from the mother's breast such as manual expression and various types of breast pumps. Nipple pain and subsequent treatment is different in this unique maternal population and thus we excluded women solely feeding with expressed breast milk from this review. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data, evaluated methodological quality, and checked data for accuracy. We sought additional information from several trial researchers. MAIN RESULTS: We included four trials of good methodological quality involving 656 women in the review. The four included trials evaluated five different interventions including glycerine pads, lanolin with breast shells, lanolin alone, expressed breast milk, and an all purpose nipple ointment. All studies included education to position the infant at the breast correctly as part of routine postpartum care to both treatment and control groups.Pooled data existed only for the comparison of lanolin versus usual care. We did not pool data for other outcomes due to either heterogeneity in outcome measures or differing interventions.There was no evidence that glycerine gel dressings or breast shells with lanolin significantly improved nipple pain. One trial found no clear differences in nipple pain (at one to three days, four to five days, or six to seven days' post-treatment) between women who applied lanolin or nothing to their nipples. In contrast, the same trial found that women who applied expressed breast milk had significantly lower perceptions of nipple pain following four to five days of treatment than women who applied lanolin. However, this beneficial effect was not maintained after six to seven days of treatment. There were no group differences in nipple pain perceptions at any assessment between women who applied expressed breast milk and women who applied nothing. Women who applied an "all-purpose nipple ointment", in comparison to women who applied lanolin, had no improvement in nipple pain after seven days of treatment. There was insufficient evidence that glycerine gel dressings, lanolin with breast shells, lanolin alone, expressed breast milk, or all-purpose nipple ointment improved maternal perceptions of nipple pain.Overall, there was insufficient evidence to recommend any intervention for the treatment of nipple pain. However, one important finding was that regardless of the treatment used, for most women nipple pain reduced to mild levels after approximately seven to 10 days' postpartum. The provision of anticipatory guidance regarding usual time to pain reduction may be a useful strategy in assisting women to continue to breastfeed and to do so exclusively. The overall quality of the evidence for the primary outcome of nipple pain as assessed using GRADE was of low quality, mainly because single studies with few participants contributed data for analysis. AUTHORS' CONCLUSIONS: There was insufficient evidence that glycerine gel dressings, breast shells with lanolin, lanolin alone, or the all-purpose nipple ointment significantly improved maternal perceptions of nipple pain. The results from these four trials of good methodological quality suggested that applying nothing or just expressed breast milk may be equally or more beneficial in the short-term experience of nipple pain than the application of an ointment such as lanolin.The quality of the evidence for this review did not lead to robust conclusions regarding the objectives assessed. We included only four trials, incorporating 656 women, in the review and all four trials compared varying interventions, participants, study outcome measures, and standards of usual care. The methodological quality of the included studies was good but the overall quality of the evidence for the primary outcome of nipple pain was of low quality, mainly because single studies with few participants contributed data for analysis. PMID- 25506814 TI - Broadband spin echoes and broadband SIFTER in EPR. AB - Applications of broadband pulses for EPR have been reported for FID, echo detection and inversion pulses recently. Here we present a broadband Hahn, stimulated and refocused echo sequence derived from adiabatic pulses. The formation of echoes is accomplished by using variable chirp rates and pulse lengths. In all three broadband echo experiments the complete spectral shape of a nitroxide (about 70 Gauss at X-band frequency) could be recovered by Fourier transformation of the quadrature detected echo signals. Such broadband echoes provide an exciting opportunity to optimize pulse sequences where a full excitation of the spectrum is mandatory for an optimum performance. We applied our pulses to the SIFTER (single frequency technique for refocusing dipolar couplings) experiment, a solid echo based pulse sequence to measure the dipolar coupling between two unpaired electron spins. By employing our broadband Hahn echo sequence on a nitroxide biradical we could achieve an artifact free dipolar evolution time trace in the SIFTER experiment with 95% modulation depth at X-band frequency and of 10% modulation depth at Q-band frequency. PMID- 25506815 TI - Conditional rotations of heteronuclear coupled spins. AB - We present a new pulse sequence that conditionally excites I spin magnetization only in the presence of a nonzero heteronuclear coupling to an S spin. The pulse sequence, referred to as the reverse INEPT pathway selective pulse or RIPSP, generates a pure I spin rotation by an angle that depends upon the heteronuclear coupling constant in InS spin systems. Experimental demonstrations are shown in (13)C labeled chloroform, dichloromethane, and toluene samples and in unlabeled 2,3-dibromopropionic acid and brucine samples. PMID- 25506816 TI - Monoamine oxidase inhibitory activity of 2-aryl-4H-chromen-4-ones. AB - A series of twenty 2-aryl-4H-chromen-4-one (flavones) derivatives (3a-3s) were synthesized and tested for hMAO inhibitory activity. Fifteen compounds (3a, 3c, 3e-3h, 3j-3p, 3r, 3s) were found to be selective towards MAO-B, while 3d was selective towards MAO-A, and 3b, 3i and 3q were non-selective. Experimental Selectivity Index for MAO-B ranges from 2.0 (3g, 3p) to 30.0 (3j). Compound 3j, which is carrying 3,4-di-OMeC6H3 groups at R position on the molecule, was found to be potent MAO-B inhibitor amongst the fifteen with Ki value for MAO-B of 0.16+/-0.01 MUM comparable to that of standard drug, Selegiline (Ki for MAO-B is 0.16+/-0.01 MUM). Compound 3j also appeared as the most selective MAO-B inhibitor according to its best selectivity index (30.0), which is comparable to that of Selegiline (SIMAO-B=35.0). Molecular docking and molecular dynamics simulation studies were carried out using Autodock-4.0 and Amber12 to understand the molecular level interaction and energy relation of MAO isoforms with selective inhibitors (3d and 3j). Simulation results are in good agreement with the experimental results. Leads identified may further be explored to develop potent isoform specific inhibitors of MAO. PMID- 25506817 TI - Combination of biochar amendment and mycoremediation for polycyclic aromatic hydrocarbons immobilization and biodegradation in creosote-contaminated soil. AB - Soils impregnated with creosote contain high concentrations of polycyclic aromatic hydrocarbons (PAH). To bioremediate these soils and avoid PAH spread, different bioremediation strategies were tested, based on natural attenuation, biochar application, wheat straw biostimulation, Pleurotus ostreatus mycoremediation, and the novel sequential application of biochar for 21 days and P. ostreatus 21 days more. Soil was sampled after 21 and 42 days after the remediation application. The efficiency and effectiveness of each remediation treatment were assessed according to PAH degradation and immobilization, fungal and bacterial development, soil eco-toxicity and legal considerations. Natural attenuation and biochar treatments did not achieve adequate PAH removal and soil eco-toxicity reduction. Biostimulation showed the highest bacterial development but low PAH degradation rate. Mycoremediation achieved the best PAH degradation rate and the lowest bioavailable fraction and soil eco-toxicity. This bioremediation strategy achieved PAH concentrations below Spanish legislation for contaminated soils (RD 9/2005). Sequential application of biochar and P. ostreatus was the second treatment most effective for PAH biodegradation and immobilization. However, the activity of P. ostreatus was increased by previous biochar application and PAH degradation efficiency was increased. Therefore, the combined strategy for PAH degradation have high potential to increase remediation efficiency. PMID- 25506818 TI - Responses to stress in patients with psychotic disorders compared to persons with varying levels of vulnerability to psychosis, persons with depression and healthy controls. AB - BACKGROUND AND OBJECTIVES: An experimental design was used to test whether self reported, psychophysiological and symptomatic stress-responses increase as a function of the underlying vulnerability to psychosis as proposed by vulnerability-stress-models. METHODS: Stress-responses of participants with psychotic disorders (PSY, n = 35) were compared to those of participants with attenuated positive symptoms (AS, n = 29), first-degree relatives of persons with psychotic disorders (REL, n = 26), healthy controls (HC, n = 28) and controls with depression (DEP, n = 30). Using a repeated measures design, participants were assigned to a noise stressor, a social stressor and a no stress condition in random order. Stress-responses were assessed via self-report, salivary cortisol levels, heart rate and skin conductance levels. State-paranoia and depression were assessed with clinical scales. RESULTS: PSY reported to be significantly more stressed than HC, AS and REL across all conditions which went along with increased heart rate and decreased overall cortisol release. In contrast, AS showed elevated levels of cortisol. PSY showed a stronger response of self reported stress to the noise condition compared to the no stress condition than HC, but no stronger response than the other samples. Furthermore, the stressors did not trigger stronger psychophysiological responses or symptom-increases in PSY. LIMITATIONS: The social stressor was brief and not individualized and did not have an effect on cortisol. CONCLUSIONS: The findings support the notion that subjective stress-responsiveness increases with vulnerability, but not the assumption that symptoms arise directly as a function of stress and vulnerability. Also, the generally high levels of arousal seem to be more relevant to psychosis than the responsiveness to specific stressors. PMID- 25506819 TI - A urinary catheter left in place for slightly too long: a teachable moment. PMID- 25506820 TI - Beyond the experience: Detection of metamemorial regularities. AB - We examined the mechanisms involved in the development of the easily learned, easily remembered (ELER) heuristic in three groups of young children (4-5 years, 6-7 years, and 8-9 years). A trial-to-acquisition procedure was used to evaluate how much these children's judgment of learning depended on the ELER heuristic. Moreover, a new experimental paradigm, composed of six phases-a pretest, four training phases, and a posttest-was employed to implicitly influence the validity of the ELER association that underlies this metacognitive rule. Results revealed that the ELER heuristic develops early (4-5years), but its use is reduced after implicit training. Furthermore, executive monitoring was found to account for the smaller changes observed in older children (8-9 years) after training. From a developmental perspective, these findings present a coherent picture of children's learning of metacognitive heuristics, wherein early automatic and implicit learning is later followed by effortful control. PMID- 25506821 TI - Consequences of poly(vinyl chloride) presence on the thermochemical process of lignocellulosic biomass in CO2 by thermogravimetric analysis. AB - The thermochemical processes of lignocellulosic biomass and its mixtures with poly(vinyl chloride) (PVC) fractions were investigated by thermogravimetric analysis in CO2 atmosphere. Superposition property was assumed to examine whether and/or to what extent interactions occurred during the mixture decomposition. Results showed that interactions existed, of which the intensities changed with reaction stage, heating rate and PVC quantity, and they actively behaved toward the decomposition in most cases. With PVC presence, lignocellulosic biomass turned from three-stage to four-stage decomposition process where the reactions occurred at lower temperatures with heightened intensity, especially in the first stage. The measured activation energies calculated by Ozawa-Flynn-Wall and Vyazovkin methods were of minor difference <5 kJ/mol, and comparing them between materials in each stage confirmed the results of interaction impact. This work provides a theoretical basis bringing about the possibilities of recycling CO2 into a reaction medium of thermo-treatment of lignocellulosic material with PVC contaminants. PMID- 25506822 TI - VAAPA: a web platform for visualization and analysis of alternative polyadenylation. AB - Polyadenylation [poly(A)] is an essential process during the maturation of most mRNAs in eukaryotes. Alternative polyadenylation (APA) as an important layer of gene expression regulation has been increasingly recognized in various species. Here, a web platform for visualization and analysis of alternative polyadenylation (VAAPA) was developed. This platform can visualize the distribution of poly(A) sites and poly(A) clusters of a gene or a section of a chromosome. It can also highlight genes with switched APA sites among different conditions. VAAPA is an easy-to-use web-based tool that provides functions of poly(A) site query, data uploading, downloading, and APA sites visualization. It was designed in a multi-tier architecture and developed based on Smart GWT (Google Web Toolkit) using Java as the development language. VAAPA will be a valuable addition to the community for the comprehensive study of APA, not only by making the high quality poly(A) site data more accessible, but also by providing users with numerous valuable functions for poly(A) site analysis and visualization. PMID- 25506823 TI - Improved HIV awareness and perceived empowerment to negotiate safe sex among married women in Ethiopia between 2005 and 2011. AB - INTRODUCTION: The HIV prevalence rate in Ethiopia for married (or cohabiting) women is 3 times that found amongst women who have never been married. While marriage used to be seen as a protective factor against HIV, evidence suggests that this is no longer necessarily the case. This study analyses the trend and socio-demographic determinants of HIV awareness and safe sex negotiation among married women in Ethiopia between 2005 and 2011. METHODS: Data from Ethiopian Demographic and Health Surveys conducted in 2005 and in 2011 were analysed. Socio demographic variables as well as 'survey year' were selected to assess their interaction with selected HIV awareness and safe sex negotiation indicators. Multivariable regression analyses were performed. Odds ratios and confidence intervals were computed. RESULTS: A significant increase in knowledge of HIV and ability to negotiate safer sex occurred between 2005 and 2011 reflecting a positive trend in gender empowerment amongst married Ethiopian women. Some of these advancements were striking, for instance respondents were 3.6 times more likely to have "Heard of AIDS" in 2011 than in 2005. HIV awareness and safer sex negotiation were significantly associated with higher education, higher socioeconomic status, those who had heard of HIV, those of the Orthodox Christian faith, and (to some extent) those living in rural areas. CONCLUSION: HIV awareness has increased significantly in Ethiopia over the last decade but married women are still disproportionately susceptible to HIV. Community programmes, already effective in Ethiopia, also need to target this vulnerable sub-group of women. PMID- 25506824 TI - Metabolism of skin-absorbed resveratrol into its glucuronized form in mouse skin. AB - Resveratrol (RESV) is a plant polyphenol, which is thought to have beneficial metabolic effects in laboratory animals as well as in humans. Following oral administration, RESV is immediately catabolized, resulting in low bioavailability. This study compared RESV metabolites and their tissue distribution after oral uptake and skin absorption. Metabolomic analysis of various mouse tissues revealed that RESV can be absorbed and metabolized through skin. We detected sulfated and glucuronidated RESV metabolites, as well as dihydroresveratrol. These metabolites are thought to have lower pharmacological activity than RESV. Similar quantities of most RESV metabolites were observed 4 h after oral or skin administration, except that glucuronidated RESV metabolites were more abundant in skin after topical RESV application than after oral administration. This result is consistent with our finding of glucuronidated RESV metabolites in cultured skin cells. RESV applied to mouse ears significantly suppressed inflammation in the TPA inflammation model. The skin absorption route could be a complementary, potent way to achieve therapeutic effects with RESV. PMID- 25506825 TI - Psychological distress and coping amongst higher education students: a mixed method enquiry. AB - BACKGROUND: Psychological distress among higher education students is of global concern. Students on programmes with practicum components such as nursing and teacher education are exposed to additional stressors which may further increase their risk for psychological distress. The ways in which these students cope with distress has potential consequences for their health and academic performance. An in-depth understanding of how nursing/midwifery and teacher education students experience psychological distress and coping is necessary to enable higher education providers to adequately support these students. METHODS: This mixed method study was employed to establish self-reported psychological distress (General Health Questionnaire), coping processes (Ways of Coping Questionnaire) and lifestyle behaviour (Lifestyle Behaviour Questionnaire) of a total sample (n = 1557) of undergraduate nursing/midwifery and teacher education students in one university in Ireland. Individual interviews (n = 59) provided an in-depth understanding of students experiences of psychological distress and coping. RESULTS: A significant percentage (41.9%) of respondents was psychologically distressed. The factors which contributed to their distress, included study, financial, living and social pressures. Students used varied coping strategies including seeking social support, problem solving and escape avoidance. The positive relationship between elevated psychological distress and escape avoidance behaviours including substance use (alcohol, tobacco and cannabis) and unhealthy diet is of particular concern. Statistically significant relationships were identified between "escape-avoidance" and gender, age, marital status, place of residence, programme/year of study and lifestyle behaviours such as diet, substance use and physical inactivity. CONCLUSION: The paper adds to existing research by illuminating the psychological distress experienced by undergraduate nursing/midwifery and teacher education students. It also identifies their distress, maladaptive coping and the relationship to their lifestyle behaviours. The findings can inform strategies to minimise student distress and maladaptive coping during college and in future professional years. PMID- 25506826 TI - IM-TORNADO: a tool for comparison of 16S reads from paired-end libraries. AB - MOTIVATION: 16S rDNA hypervariable tag sequencing has become the de facto method for accessing microbial diversity. Illumina paired-end sequencing, which produces two separate reads for each DNA fragment, has become the platform of choice for this application. However, when the two reads do not overlap, existing computational pipelines analyze data from read separately and underutilize the information contained in the paired-end reads. RESULTS: We created a workflow known as Illinois Mayo Taxon Organization from RNA Dataset Operations (IM TORNADO) for processing non-overlapping reads while retaining maximal information content. Using synthetic mock datasets, we show that the use of both reads produced answers with greater correlation to those from full length 16S rDNA when looking at taxonomy, phylogeny, and beta-diversity. AVAILABILITY AND IMPLEMENTATION: IM-TORNADO is freely available at http://sourceforge.net/projects/imtornado and produces BIOM format output for cross compatibility with other pipelines such as QIIME, mothur, and phyloseq. PMID- 25506827 TI - Master Settlement Agreement (MSA) spending and tobacco control efforts. AB - We investigate whether the distributions to the states from the Tobacco Master Settlement Agreement (MSA) in 1998 is associated with stronger tobacco control efforts. We use state level data from 50 states and the District of Columbia from four time periods post MSA (1999, 2002, 2004, and 2006) for the analysis. Using fixed effect regression models, we estimate the relationship between MSA disbursements and a new aggregate measure of strength of state tobacco control known as the Strength of Tobacco Control (SoTC) Index. Results show an increase of $1 in the annual per capita MSA disbursement to a state is associated with a decrease of -0.316 in the SoTC mean value, indicating higher MSA payments were associated with weaker tobacco control measures within states. In order to achieve the initial objectives of the MSA payments, policy makers should focus on utilizing MSA payments strictly on tobacco control activities across states. PMID- 25506828 TI - Hepatic farnesoid X-receptor isoforms alpha2 and alpha4 differentially modulate bile salt and lipoprotein metabolism in mice. AB - The nuclear receptor FXR acts as an intracellular bile salt sensor that regulates synthesis and transport of bile salts within their enterohepatic circulation. In addition, FXR is involved in control of a variety of crucial metabolic pathways. Four FXR splice variants are known, i.e. FXRalpha1-4. Although these isoforms show differences in spatial and temporal expression patterns as well as in transcriptional activity, the physiological relevance hereof has remained elusive. We have evaluated specific roles of hepatic FXRalpha2 and FXRalpha4 by stably expressing these isoforms using liver-specific self-complementary adeno associated viral vectors in total body FXR knock-out mice. The hepatic gene expression profile of the FXR knock-out mice was largely normalized by both isoforms. Yet, differential effects were also apparent; FXRalpha2 was more effective in reducing elevated HDL levels and transrepressed hepatic expression of Cyp8b1, the regulator of cholate synthesis. The latter coincided with a switch in hydrophobicity of the bile salt pool. Furthermore, FXRalpha2-transduction caused an increased neutral sterol excretion compared to FXRalpha4 without affecting intestinal cholesterol absorption. Our data show, for the first time, that hepatic FXRalpha2 and FXRalpha4 differentially modulate bile salt and lipoprotein metabolism in mice. PMID- 25506829 TI - Functional analysis of the Brassica napus L. phytoene synthase (PSY) gene family. AB - Phytoene synthase (PSY) has been shown to catalyze the first committed and rate limiting step of carotenogenesis in several crop species, including Brassica napus L. Due to its pivotal role, PSY has been a prime target for breeding and metabolic engineering the carotenoid content of seeds, tubers, fruits and flowers. In Arabidopsis thaliana, PSY is encoded by a single copy gene but small PSY gene families have been described in monocot and dicotyledonous species. We have recently shown that PSY genes have been retained in a triplicated state in the A- and C-Brassica genomes, with each paralogue mapping to syntenic locations in each of the three "Arabidopsis-like" subgenomes. Most importantly, we have shown that in B. napus all six members are expressed, exhibiting overlapping redundancy and signs of subfunctionalization among photosynthetic and non photosynthetic tissues. The question of whether this large PSY family actually encodes six functional enzymes remained to be answered. Therefore, the objectives of this study were to: (i) isolate, characterize and compare the complete protein coding sequences (CDS) of the six B. napus PSY genes; (ii) model their predicted tridimensional enzyme structures; (iii) test their phytoene synthase activity in a heterologous complementation system and (iv) evaluate their individual expression patterns during seed development. This study further confirmed that the six B. napus PSY genes encode proteins with high sequence identity, which have evolved under functional constraint. Structural modeling demonstrated that they share similar tridimensional protein structures with a putative PSY active site. Significantly, all six B. napus PSY enzymes were found to be functional. Taking into account the specific patterns of expression exhibited by these PSY genes during seed development and recent knowledge of PSY suborganellar localization, the selection of transgene candidates for metabolic engineering the carotenoid content of oilseeds is discussed. PMID- 25506830 TI - Factors associated with death during tuberculosis treatment of patients co infected with HIV at the Yaounde Central Hospital, Cameroon: an 8-year hospital based retrospective cohort study (2006-2013). AB - BACKGROUND: Contributors to fatal outcomes in TB/HIV co-infected patients actively undergoing TB treatment are poorly characterized. The aim was to assess factors associated with death in TB/HIV co-infected patients during the initial 6 months of TB treatment. METHODS: We conducted a hospital-based retrospective cohort study from January 2006 to December 2013 at the Yaounde Central Hospital, Cameroon. We reviewed medical records to identify hospitalized co-infected TB/HIV patients aged 15 years and older. Death was defined as any death occurring during TB treatment, as per the World Health Organization's recommendations. We conducted logistic regression analysis to identify factors associated with a fatal outcome. Magnitudes of associations were expressed by adjusted odds ratio (aOR) with 95% confidence interval. RESULTS: The 337 patients enrolled had a mean age of 39.3 (standard deviation 10.3) years and 54.3% were female. TB treatment outcomes were distributed as follows: 205 (60.8%) treatment success, 99 (29.4%) deaths, 18 (5.3%) not evaluated, 14 (4.2%) lost to follow-up, and 1 (0.3%) failed. After exclusion of patients lost to follow-up and not evaluated, death in TB/HIV co-infected patients during TB treatment was associated with a TB diagnosis made before 2010 (aOR = 2.50 [1.31-4.78]; p = 0.006), the presence of other AIDS-defining diseases (aOR = 2.73 [1.27-5.86]; p = 0.010), non-AIDS comorbidities (aOR = 3.35 [1.37-8.21]; p = 0.008), not receiving cotrimoxazole prophylaxis (aOR = 3.61 [1.71-7.63]; p = 0.001), not receiving antiretroviral therapy (aOR = 2.45 [1.18-5.08]; p = 0.016), and CD4 cells count <50 cells/mm3 (aOR = 16.43 [1.05-258.04]; p = 0.047). CONCLUSIONS: The TB treatment success rate among TB/HIV co-infected patients in our setting is low. Mortality was high among TB/HIV co-infected patients during TB treatment and is strongly associated with clinical and biological factors, highlighting the urgent need for specific interventions focused on enhancing patient outcomes. PMID- 25506832 TI - Identifying and validating a combined mRNA and microRNA signature in response to imatinib treatment in a chronic myeloid leukemia cell line. AB - Imatinib, a targeted tyrosine kinase inhibitor, is the gold standard for managing chronic myeloid leukemia (CML). Despite its wide application, imatinib resistance occurs in 20-30% of individuals with CML. Multiple potential biomarkers have been identified to predict imatinib response; however, the majority of them remain externally uncorroborated. In this study, we set out to systematically identify gene/microRNA (miRNA) whose expression changes are related to imatinib response. Through a Gene Expression Omnibus search, we identified two genome-wide expression datasets that contain expression changes in response to imatinib treatment in a CML cell line (K562): one for mRNA and the other for miRNA. Significantly differentially expressed transcripts/miRNAs post imatinib treatment were identified from both datasets. Three additional filtering criteria were applied 1) miRbase/miRanda predictive algorithm; 2) opposite direction of imatinib effect for genes and miRNAs; and 3) literature support. These criteria narrowed our candidate gene-miRNA to a single pair: IL8 and miR-493-5p. Using PCR we confirmed the significant up-regulation and down-regulation of miR-493-5p and IL8 by imatinib treatment, respectively in K562 cells. In addition, IL8 expression was significantly down-regulated in K562 cells 24 hours after miR-493 5p mimic transfection (p = 0.002). Furthermore, we demonstrated significant cellular growth inhibition after IL8 inhibition through either gene silencing or by over-expression of miR-493-5p (p = 0.0005 and p = 0.001 respectively). The IL8 inhibition also further sensitized K562 cells to imatinib cytotoxicity (p < 0.0001). Our study combined expression changes in transcriptome and miRNA after imatinib exposure to identify a potential gene-miRNA pair that is a critical target in imatinib response. Experimental validation supports the relationships between IL8 and miR-493-5p and between this gene-miRNA pair and imatinib sensitivity in a CML cell line. Our data suggests integrative analysis of multiple omic level data may provide new insight into biomarker discovery as well as mechanisms of imatinib resistance. PMID- 25506833 TI - Monitoring brain tumor vascular heamodynamic following anti-angiogenic therapy with advanced magnetic resonance imaging in mice. AB - Advanced MR imaging methods have an essential role in classification, grading, follow-up and therapeutic management in patients with brain tumors. With the introduction of new therapeutic options, the challenge for better tissue characterization and diagnosis increase, calling for new reliable non-invasive imaging methods. In the current study we evaluated the added value of a combined protocol of blood oxygen level dependent (BOLD) imaging during hyperoxic challenge (termed hemodynamic response imaging (HRI)) in an orthotopic mouse model for glioblastoma under anti-angiogenic treatment with B20-4.1.1, an anti VEGF antibody. In glioblastoma tumors, the elevated HRI indicated progressive angiogenesis as further confirmed by histology. In the current glioblastoma model, B20-treatment caused delayed tumor progression with no significant changes in HRI yet with slightly reduced tumor vascularity as indicated by histology. Furthermore, fewer apoptotic cells and higher proliferation index were detected in the B20-treated tumors compared to control-treated tumors. In conclusion, HRI provides an easy, safe and contrast agent free method for the assessment of the brain hemodynamic function, an additionally important clinical information. PMID- 25506836 TI - Neuroinvasion of the highly pathogenic influenza virus H7N1 is caused by disruption of the blood brain barrier in an avian model. AB - Influenza A virus (IAV) causes central nervous system (CNS) lesions in avian and mammalian species, including humans. However, the mechanism used by IAV to invade the brain has not been determined. In the current work, we used chickens infected with a highly pathogenic avian influenza (HPAI) virus as a model to elucidate the mechanism of entry of IAV into the brain. The permeability of the BBB was evaluated in fifteen-day-old H7N1-infected and non-infected chickens using three different methods: (i) detecting Evans blue (EB) extravasation into the brain, (ii) determining the leakage of the serum protein immunoglobulin Y (IgY) into the brain and (iii) assessing the stability of the tight-junction (TJ) proteins zonula occludens-1 and claudin-1 in the chicken brain at 6, 12, 18, 24, 36 and 48 hours post-inoculation (hpi). The onset of the induced viremia was evaluated by quantitative real time RT-PCR (RT-qPCR) at the same time points. Viral RNA was detected from 18 hpi onward in blood samples, whereas IAV antigen was detected at 24 hpi in brain tissue samples. EB and IgY extravasation and loss of integrity of the TJs associated with the presence of viral antigen was first observed at 36 and 48 hpi in the telencephalic pallium and cerebellum. Our data suggest that the mechanism of entry of the H7N1 HPAI into the brain includes infection of the endothelial cells at early stages (24 hpi) with subsequent disruption of the TJs of the BBB and leakage of virus and serum proteins into the adjacent neuroparenchyma. PMID- 25506835 TI - Intranasal administration of recombinant TRAIL down-regulates CXCL-1/KC in an ovalbumin-induced airway inflammation murine model. AB - Ovalbumin (OVA)-sensitized BALB/c mice were i.n. instilled with recombinant TNF related apoptosis inducing ligand (TRAIL) 24 hours before OVA challenge. The total number of leukocytes and the levels of the chemokine CXCL-1/KC significantly increased in the bronchoalveolar lavage (BAL) fluids of allergic animals with respect to control littermates, but not in the BAL of mice i.n. pretreated with recombinant TRAIL before OVA challenge. In particular, TRAIL pretreatment significantly reduced the BAL percentage of both eosinophils and neutrophils. On the other hand, when TRAIL was administrated simultaneously to OVA challenge its effect on BAL infiltration was attenuated. Overall, the results show that the i.n. pretreatment with TRAIL down-modulated allergic airway inflammation. PMID- 25506837 TI - Antibody and plasmablast response to 13-valent pneumococcal conjugate vaccine in chronic lymphocytic leukemia patients--preliminary report. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) leads to significant immune system dysfunction. The predominant clinical presentation in 50% of patients involves recurrent, often severe, infections. Infections are also the most common (60-80%) cause of deaths in CLL patients. The scope of infections varies with the clinical stage of the disease. Treatment-naive patients typically present with respiratory tract infections caused by encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenzae. Since 2012, the 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended in the United States and some EU countries for pneumococcal infection prevention in patients with CLL (besides the long-standing standard, 23-valent pneumococcal polysaccharide vaccine, PPV23). The aim of this study was to compare the immune response to PCV13 in 24 previously untreated CLL patients and healthy subjects. METHODS: Both groups were evaluated for: the levels of specific pneumococcal antibodies, the levels of IgG and IgG subclasses and selected peripheral blood lymphocyte subpopulations including the frequency of plasmablasts before and after immunization. RESULTS: Adequate response to vaccination, defined as an at least two-fold increase in specific pneumococcal antibody titers versus pre-vaccination baseline titers, was found in 58.3% of CLL patients and 100% of healthy subjects. Both the CLL group and the control group demonstrated a statistically significant increase in the IgG2 subclass levels following vaccination (P = 0.0301). After vaccination, the frequency of plasmablasts was significantly lower (P<0.0001) in CLL patients in comparison to that in controls. Patients who responded to vaccination had lower clinical stage of CLL as well as higher total IgG, and IgG2 subclass levels. No significant vaccine-related side effects were observed. CONCLUSIONS: PCV13 vaccination in CLL patients is safe and induces an effective immune response in a considerable proportion of patients. To achieve an optimal vaccination response, the administration of PCV13 is recommended as soon as possible following CLL diagnosis. PMID- 25506838 TI - Neuroprotective mechanism of BNG-1 against focal cerebral ischemia: a neuroimaging and neurotrophin study. AB - BNG-1 is a herb complex used in traditional Chinese medicine to treat stroke. In this study, we attempted to identify the neuroprotective mechanism of BNG-1 by using neuroimaging and neurotrophin analyses of a stroke animal model. Rats were treated with either saline or BNG-1 for 7 d after 60-min middle cerebral artery occlusion by filament model. The temporal change of magnetic resonance (MR) imaging of brain was studied using a 7 Tesla MR imaging (MRI) system and the temporal expressions of neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) in brain were analyzed before operation and at 4 h, 2 d, and 7 d after operation. Compared with the saline group, the BNG-1 group exhibited a smaller infarction volume in the cerebral cortex in T2 image from as early as 4 h to 7 d, less edema in the cortex in diffusion weighted image from 2 to 7 d, earlier reduction of postischemic hyperperfusion in both the cortex and striatum in perfusion image at 4 h, and earlier normalization of the ischemic pattern in the striatum in susceptibility weighted image at 2 d. NT-3 and BDNF levels were higher in the BNG-1 group than the saline group at 7 d. We concluded that the protective effect of BNG-1 against cerebral ischemic injury might act through improving cerebral hemodynamics and recovering neurotrophin generation. PMID- 25506839 TI - Low-temperature synthesis of anatase TiO2 nanoparticles with tunable surface charges for enhancing photocatalytic activity. AB - In this work, the positively or negatively charged anatase TiO2 nanoparticles were synthesized via a low temperature precipitation-peptization process (LTPPP) in the presence of poly(ethyleneimine) (PEI) and poly(sodium4- styrenesulfonate) (PSS). X-ray diffraction (XRD) pattern and high-resolution transmission electron microscope (HRTEM) confirmed the anatase crystalline phase. The charges of the prepared TiO2, PEI-TiO2 and PSS-TiO2 nanoparticles were investigated by zeta potentials. The results showed that the zeta potentials of PEI-TiO2 nanoparticles can be tuned from +39.47 mV to +95.46 mV, and that of PSS-TiO2 nanoparticles can be adjusted from -56.63 mV to -119.32 mV. In comparison with TiO2, PSS-TiO2 exhibited dramatic adsorption and degradation of dye molecules, while the PEI modified TiO2 nanoparticles showed lower photocatalytic activity. The photocatalytic performances of these charged nanoparticles were elucidated by the results of UV-vis diffuse reflectance spectra (DRS) and the photoluminescence (PL) spectra, which indicated that the PSS-TiO2 nanoparticles showed a lower recombination rate of electron-hole pairs than TiO2 and PEI-TiO2. PMID- 25506841 TI - Non-healing gastro-duodenal ulcer: A rare presentation of primary abdominal tuberculosis. AB - INTRODUCTION: We present a case of primary gastrointestinal tuberculosis that has culminated in ulcer formation, in the absence of pulmonary involvement in an immunocompetent patient. PRESENTATION OF CASE: A 28-year-old Asian male presented to casualty with a 1-week history of epigastric cramping abdominal pain and several episodes of non-bilious vomiting. The patient deteriorated clinically, becoming more cachectic and given his unexplained weight loss, an oesophageal gastro-duodenal endoscopic imaging confirmed a duodenal ulcer. The biopsy of the non-healing ulcer was the hallmark of the disease, revealing evidence of granulomatous inflammation consistent with tuberculosis bacilli. DISCUSSION: Gastrointestinal tuberculosis with ulceration is rare with respect to the oesophagus, stomach and duodenum. This case proves to be unique, as our patient had experienced primary isolated gastric tuberculosis in the absence of pulmonary tuberculosis in a healthy individual. Immunohistochemical staining, histopathology and radiological investigations have demonstrated their importance in confirming abdominal tuberculosis and the extent of bowel involvement. CONCLUSION: This case has illustrated the difficulties associated with a prompt diagnosis of an unusual case of primary duodenal tuberculosis from chronic peptic ulcer disease in an immunocompetent patient. PMID- 25506842 TI - Intra-abdominal removal of a displaced hip prosthesis. AB - INTRODUCTION: Intra-pelvic displacement of hip prostheses is an uncommon complication following arthroplasty surgery but can have significant detrimental effects on the patient. We present a case of a displaced hip prosthesis into the pelvic cavity and highlight the importance of pre-operative planning and investigation as well as choosing a suitable surgical approach. PRESENTATION OF CASE: A 69 year old lady with developmental dysplasia of the hips was found to have displacement of her prosthesis into the pelvis on day three following complex uncemented total hip replacement. A subsequent combined procedure between vascular and orthopaedic surgeons was carried out, including access via a laparotomy incision to allow vision and control of the iliac vessels before removal of the prosthesis. The hip was reconstructed during the same operation using a cup cage construct, reinforced with plate fixation of the posterior column of the pelvis. DISCUSSION: Intra-pelvic displacement of hip prostheses is rare and morbidity and mortality can be significant. Pre-operative imaging modalities such as CT scanning should be used to carefully delineate the anatomy. A retro-peritoneal approach has been reported, but we used a trans-abdominal approach in this case to permit greater vision and control of pelvic structures due to the significant medial displacement of the prosthesis. CONCLUSION: Intra abdominal removal of a displaced hip prosthesis is rarely performed but allows for visualisation and careful control of the pelvic structures without damaging further the pelvic wall. We recommend this approach should be performed in conjunction with a vascular surgeon. PMID- 25506843 TI - Spontaneous rupture of the liver in a patient admitted for subarachnoid hemorrhage. AB - INTRODUCTION: Spontaneous rupture of the liver is a rare event often associated with the presence of malignant liver disease or occurring in the context of a HELLP syndrome. We present a case of spontaneous rupture of the liver in a patient admitted to our Intensive Care Department with hemoperitoneum in the aftermath of recent surgical clipping of a cerebral aneurysm. PRESENTATION OF CASE: We report a 50-year-old woman who was transferred from the Bolzano Hospital Department of Neurosurgery to the Intensive Care Unit with anemia and the occurrence of major abdominal pain. DISCUSSION: Spontaneous hepatic rupture remains a rare event, associated more often than not with pregnancy or traumatic events. The treatment of hemorrhage due to spontaneous rupture of the liver includes, in addition to serial monitoring of hemoglobin values, in cases of unstable patients, embolization, hepatic resection and packing. CONCLUSION: The case described here shows that spontaneous rupture of the liver may be due to indefinable causes and that its treatment remains complex and multidisciplinary. PMID- 25506840 TI - High-throughput sequencing of microRNA transcriptome and expression assay in the sturgeon, Acipenser schrenckii. AB - Sturgeons are considered as living fossils and have very high evolutionary, economical and conservation values. The multiploidy of sturgeon that has been caused by chromosome duplication may lead to the emergence of new microRNAs (miRNAs) involved in the ploidy and physiological processes. In the present study, we performed the first sturgeon miRNAs analysis by RNA-seq high-throughput sequencing combined with expression assay of microarray and real-time PCR, and aimed to discover the sturgeon-specific miRNAs, confirm the expressed pattern of miRNAs and illustrate the potential role of miRNAs-targets on sturgeon biological processes. A total of 103 miRNAs were identified, including 58 miRNAs with strongly detected signals (signal >500 and P<=0.01), which were detected by microarray. Real-time PCR assay supported the expression pattern obtained by microarray. Moreover, co-expression of 21 miRNAs in all five tissues and tissue specific expression of 16 miRNAs implied the crucial and particular function of them in sturgeon physiological processes. Target gene prediction, especially the enriched functional gene groups (369 GO terms) and pathways (37 KEGG) regulated by 58 miRNAs (P<0.05), illustrated the interaction of miRNAs and putative mRNAs, and also the potential mechanism involved in these biological processes. Our new findings of sturgeon miRNAs expand the public database of transcriptome information for this species, contribute to our understanding of sturgeon biology, and also provide invaluable data that may be applied in sturgeon breeding. PMID- 25506844 TI - Ancient Schwannoma of superficial peroneal nerve presenting as intermittent leg pain: A case report. AB - INTRODUCTION: Schwannomas are benign, encapsulated, slow-growing and usually solitary tumors originating from Schwann cells of the peripheral nerve sheath. Schwannomas of the superficial peroneal nerves are very rare, and therefore scarcely documented in the literature. The authors report a case of a diagnosed superficial fibular nerve sheath tumor with an unreported clinical presentation. PRESENTATION OF CASE: A 52-year-old Caucasian female arrived to our Orthopedics Department complaining of pain and numbness of the lateral aspect of her left leg. These symptoms were present for a year and were more evident at the end of the day, or after a long time in the orthostatic position. No evidence of other medical illnesses was found. There was no record of prior traumatic events related to that limb. Diagnosis of a benign peripheral nerve tumor was achieved and the patient was treated by surgical excision of the lesion. DISCUSSION: The intermittent symptomatology presentation on this case suggest a mechanical compression etiology, allied to classical pain and paresthesia often exhibited by this kind of the tumor. An intracompartimental pressure elevation could explain why the symptoms disclosed an episodic pattern, due to a constricted, inclosed nerve. CONCLUSION: We describe a rare case of a patient with an unusual superficial peroneal nerve Schwannoma clinical presentation. Literature on this topic is scarce and, therefore, this case report intends to add further data about this kind of lesion. PMID- 25506845 TI - Bilateral complete ureteral duplication with calculi obstructing both limbs of left double ureter. AB - INTRODUCTION: A woman with bilateral complete ureteral duplication with stones simultaneously obstructing both limbs of the left double ureter is presented. A search of the English medical literature suggests that this is the first reported case. Based on the initial difficulty accessing the stones via ureteroscopy we make recommendations regarding how this rare problem should be approached if encountered. PRESENTATION OF CASE: A 37-year old woman with left-sided flank pain was discovered on CT scan to have bilateral complete ureteral duplication and three stones obstructing both limbs of the left double ureter. Ureteroscopy was initially unsuccessful due to the very small calibre and unyielding nature of the ureters and both ureteral limbs were stented. Repeat ureteroscopy was easily achieved after pre-stenting and the impacted stones were completely cleared with intracorporeal laser lithotripsy. DISCUSSION: The smaller calibre of both double ureters and their presence in a common adventitial sheath distally, made initial attempts at ureteroscopy difficult. Stenting both limbs increased ureteral compliance, passively dilated both ureters and allowed for improved manoeuvrability and retrograde passage of the ureteroscope. Based on the experience with this first reported case it is recommended that pre-stenting should be routinely performed prior to any attempt at ureteroscopy in cases of stones complicating completely duplicated ureters. CONCLUSION: We report the first recorded case of bilateral complete ureteral duplication with stones simultaneously obstructing both limbs of the double ureter and recommend that routine pre-stenting be done prior to ureteroscopy to allow easy uncomplicated retrograde passage of the ureteroscope. PMID- 25506846 TI - Small bowel intussusception secondary to metastatic melanoma 15 years after complete excision of the primary tumor. AB - INTRODUCTION: Primary intestinal melanoma is a rare entity, however the gastrointestinal tract, and particularly the small bowel, is a common site of recurrence from cutaneous melanoma. PRESENTATION OF CASE We report the case of a 48 year old woman with small bowel intussusception secondary to metastatic cutaneous melanoma, 15 years after excision of the primary tumor. The patient underwent an emergency small bowel resection with negative margins on final pathology. DISCUSSION: Surgical resection is a palliative, yet necessary, procedure in the setting of small bowel obstruction due to intussusception secondary to intestinal metastatic melanoma. In case of bowel metastasis, presenting symptoms are nonspecific and do not provide significant clues to the differential diagnosis of the underlying disease. In some patients, complete surgical resection of early diagnosed bowel metastases is associated with prolonged survival. Systemic chemotherapy in these patients does not provide survival benefit. CONCLUSION: The occurrence of bowel relapse after very long disease free interval, while highly unlikely in most tumors, should always be considered in the differential diagnosis of patients with previous history of cutaneous malignant melanoma presenting with gastrointestinal symptoms. PMID- 25506848 TI - Mantle cell lymphoma presenting as acute appendicitis. AB - INTRODUCTION: Most cases of appendicitis associated with lymphoma reported in literature are in patients with Burkitt's or large B-cell lymphoma. Mantle cell lymphoma only makes up 4% of all lymphoma cases in the U.S. We report a case of a patient with mantle cell lymphoma presenting with acute appendicitis. PRESENTATION OF CASE: A 75 year old male with a history of left cervical lymphadenopathy biopsied to be mantle cell lymphoma presented with right lower abdomen pain for 3 days. An outpatient CT scan revealed acute appendicitis. Laparoscopic appendectomy was performed without any complication. The histologic examination showed mantle cell lymphoma occluding the lumen of appendix. DISCUSSION: Typically, appendicitis is caused by obstruction of the lumen of appendix by fecalith or lymphoma. A previously reported case of a patient with mantle cell lymphoma who developed appendicitis received chemotherapy before appendectomy. The author could not determine how mantle cell lymphoma contributed to appendicitis because the lumen of appendix was not occluded by the lymphoma, likely from cytoreduction from chemotherapy. We have a patient with mantle cell lymphoma before the patient received chemotherapy who presented with appendicitis. The appendiceal specimen shows the lumen filled with mantle cell lymphoma. CONCLUSION: This is a rare case of mantle cell lymphoma causing obstruction of appendiceal lumen and subsequently appendicitis, unaffected by chemotherapy. PMID- 25506847 TI - Inferior gluteal artery pseudoaneurysm related to intramuscular injection. AB - INTRODUCTION: Gluteal artery pseudoaneurysms are rare, yet the most common in cases involving the superior gluteal artery. Pseudoaneurysms of the inferior gluteal artery are uncommon and are often related to blunt or penetrating trauma, infections and fractures of the pelvis. PRESENTATION OF CASE: The authors present a case of pseudoaneurysm of the inferior gluteal artery related to an iatrogenic injury due to intramuscular injection of medication, which was treated with selective embolization of the artery during angiography. DISCUSSION: The most common manifestation of an inferior gluteal artery pseudoaneurysm is the presence of a painful mass in the buttock that may or may not be associated with neurological symptoms due to compression of the sciatic nerve. Ultrasound with color Doppler and computerized tomography with multi-detectors are useful non invasive tools for diagnosis. However, both diagnosis and therapy are facilitated by catheter angiography. CONCLUSION: This case cautions that although pseudoaneurysms are rare, pseudoaneurysms of the inferior gluteal artery require a high index of suspicion and careful physical examination by the physician in order to avoid misdiagnosis. It also illustrates the usefulness of a minimally invasive modality for treatment of these lesions. PMID- 25506849 TI - Repeated recurrence of a gastric gastrointestinal stromal tumor on the chest wall after initial curative resection: Report of a case. AB - INTRODUCTION: Extra-abdominal recurrence or metastasis of a gastrointestinal stromal tumor (GIST) is very rare. Chest wall recurrence of a resected gastric GIST is extremely rare. PRESENTATION OF CASE: A 64-year-old Japanese man had undergone proximal gastrectomy for a gastric submucosal tumor 11 years previously. The histopathological diagnosis was GIST (size, 8cm). He did not receive adjuvant therapy, and underwent imaging evaluations every 6 months for the first 5 years after surgery and then annually. He was admitted to our hospital because of a lump on his right anterior chest wall 7 years after curative resection. We resected the tumor, and histopathologic findings revealed metastatic GIST. Four years after metastasectomy, another lump appeared at a different location on the right anterior chest wall. The patient was diagnosed with a second recurrence of gastric GIST and began adjuvant treatment with imatinib after second resection. He has remained alive without tumor recurrence for 2 years. DISCUSSION: Most recurrences were predominantly found in the intra abdominal cavity, either locally or involving the liver or peritoneum. Extra abdominal recurrence was much less common. Although we assume that the recurrent tumor of our patient was derived from his gastric GIST, based on the histopathological examinations and clinical course, it is possible that the recurrent tumor of our case was an "extragastrointestinal GIST". CONCLUSION: Because extra-abdominal recurrence can occur many years after curative resection, continued, careful whole-body follow-up is required for patients with high-risk GIST. PMID- 25506850 TI - Development of pneumoperitoneum after CPR. AB - INTRODUCTION: Chest compressions are performed routinely and have several well known complications, however one of the rare complications is pneumoperitoneum caused by air entry through a perforation of the viscus. The exact cause of the perforation is not always clear. Furthermore, this rarely reported condition does not have clear management guidelines. PRESENTATION OF CASE: We present an uncommon complication of pneumoperitoneum following successful resuscitation possibly caused by the presence of an orogastric tube at the time of compressions in a 79 year old Hispanic male. Following chest compressions, a distended and tympanic abdomen was noted and air seen under the diaphragm in X-ray imaging. DISCUSSION: A review of previous case reports along with etiology and evaluation of risk factors is presented. CONCLUSION: Although the exact cause of pneumoperitoneum cannot be confirmed, emergency personnel should be aware of the risk factors associated with viscus perforation during chest compressions. PMID- 25506851 TI - Type IV paraesophageal hernia as a cause of ileus: Report of a case. AB - INTRODUCTION: Type IV paraesophageal hernias (PEHs) have been rarely reported in the literature. Transverse colon is the most common viscus to herniate in this category. PRESENTATION OF CASE: Herein we present a case with an emergent admission of a 66 year old man with type IV PEH with small intestine into the hernia sac. DISCUSSION: The diagnosis of PEHs can be challenging due to their extremely low incidence and the non-specific symptoms and can be easily missed from the initial differential diagnosis. CONCLUSION: In this case, the hernia was diagnosed early and managed successfully with an immediate laparotomy. PMID- 25506852 TI - Leiomyosarcoma of the small bowel: Report of a case and review of the literature. AB - INTRODUCTION: Leiomyosarcoma of the small bowel is an extremely rare form of gastrointestinal malignancy. Small bowel tumours are usually asymptomatic at the early stages, and difficult to visualise by upper and lower endoscopy. PRESENTATION OF CASE: An 83-year-old gentleman presented in surgical outpatient clinic with chronic anaemia, abdominal discomfort and a single episode of malaena. Initial OGD and colonoscopy were both unremarkable. Subsequent CT revealed a mass in the right iliac fossa of likely small bowel origin, leading to an urgent laparotomy and resection with primary anastomosis. Histopathology showed a high grade leiomyosarcoma with no signs of metastasis and confirmatory immunological staining. Post-surgery follow up remains unremarkable. DISCUSSION: Leiomyosarcomas of the small bowel are extremely rare entities, particularly following the advent of robust immunohistological diagnostic methods allowing differentiation from GISTs. As small bowel tumours are often not visualised by upper and lower endoscopy, further investigations to visualise the small bowel are crucial, generally in the form of magnetic resonance enterography, CT colonography or wireless capsule endoscopy. CONCLUSION: The treatment of such tumours remains predominantly centred around surgical resection, and prognosis is dependent on tumour size and histological staging. PMID- 25506854 TI - The importance of purpose: moving beyond consent in the societal use of personal health information. AB - BACKGROUND: Adoption of electronic health record systems has increased the availability of patient-level electronic health information. OBJECTIVE: To examine public support for secondary uses of electronic health information under different consent arrangements. DESIGN: National experimental survey to examine perceptions of uses of electronic health information according to patient consent (obtained vs. not obtained), use (research vs. marketing), and framing of the findings (abstract description without results vs. specific results). SETTING: Nationally representative survey. PARTICIPANTS: 3064 African American, Hispanic, and non-Hispanic white persons (response rate, 65%). MEASUREMENTS: Appropriateness of health information use described in vignettes on a scale of 1 (not at all appropriate) to 10 (very appropriate). RESULTS: Mean ratings ranged from a low of 3.81 for a marketing use when consent was not obtained and specific results were presented to a high of 7.06 for a research use when consent was obtained and specific results were presented. Participants rated scenarios in which consent was obtained as more appropriate than when consent was not obtained (difference, 1.01 [95% CI, 0.69 to 1.34]; P<0.001). Participants rated scenarios in which the use was marketing as less appropriate than when the use was research (difference, -2.03 [CI, -2.27 to -1.78]; P<0.001). Unconsented research uses were rated as more appropriate than consented marketing uses (5.65 vs. 4.52; difference, 1.13 [CI, 0.87 to 1.39]). LIMITATIONS: Participants rated hypothetical scenarios. Results could be vulnerable to nonresponse bias despite the high response rate. CONCLUSION: Although approaches to health information sharing emphasize consent, public opinion also emphasizes purpose, which suggests a need to focus more attention on the social value of information use. PRIMARY FUNDING SOURCE: National Human Genome Research Institute. PMID- 25506853 TI - Racial disparities in colon cancer survival: a matched cohort study. AB - BACKGROUND: Differences in colon cancer survival by race are a recognized problem among Medicare beneficiaries. OBJECTIVE: To determine to what extent the racial disparity in survival is due to disparity in presentation characteristics at diagnosis or disparity in subsequent treatment. DESIGN: Black patients with colon cancer were matched with 3 groups of white patients: a "demographic characteristics" match controlling for age, sex, diagnosis year, and Survey, Epidemiology, and End Results (SEER) site; a "presentation" match controlling for demographic characteristics plus comorbid conditions and tumor characteristics, including stage and grade; and a "treatment" match, including presentation variables plus details of surgery, radiation, and chemotherapy. SETTING: 16 U.S. SEER sites. PATIENTS: 7677 black patients aged 65 years or older diagnosed between 1991 and 2005 in the SEER-Medicare database and 3 sets of 7677 matched white patients, followed until 31 December 2009. MEASUREMENTS: 5-year survival. RESULTS: The absolute difference in 5-year survival between black and white patients was 9.9% (95% CI, 8.3% to 11.4%; P<0.001) in the demographic characteristics match. This disparity remained unchanged between 1991 and 2005. After matching for presentation characteristics, the difference decreased to 4.9% (CI, 3.6% to 6.1%; P<0.001). After additional matching for treatment, this difference decreased to 4.3% (CI, 2.9% to 5.5%; P<0.001). The disparity in survival attributed to treatment differences made up only an absolute 0.6% of the overall 9.9% survival disparity. LIMITATION: An observational study limited to elderly Medicare fee-for-service beneficiaries living in selected geographic areas. CONCLUSION: Racial disparities in colon cancer survival did not decrease among patients diagnosed between 1991 and 2005. This persistent disparity seemed to be more related to presentation characteristics at diagnosis than to subsequent treatment differences. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality and National Science Foundation. PMID- 25506857 TI - Corporate research ethics: whose responsibility? PMID- 25506858 TI - Updating research oversight for the 21st century. PMID- 25506859 TI - What wasn't taught. PMID- 25506855 TI - Association between emphysema-like lung on cardiac computed tomography and mortality in persons without airflow obstruction: a cohort study. AB - BACKGROUND: Low lung function is known to predict mortality in the general population, but the prognostic significance of emphysema on computed tomography (CT) in persons without chronic obstructive pulmonary disease (COPD) is uncertain. OBJECTIVE: To determine whether greater emphysema-like lung on CT is associated with all-cause mortality among persons in the general population without airflow obstruction or COPD. DESIGN: Prospective cohort study. SETTING: Population-based, multiethnic sample from 6 U.S. communities. PARTICIPANTS: 2965 participants aged 45 to 84 years without airflow obstruction on spirometry. MEASUREMENTS: Emphysema-like lung was defined as the number of lung voxels with attenuation less than -950 Hounsfield units on cardiac CT and was adjusted for the number of total imaged lung voxels. RESULTS: Among 2965 participants, 50.9% of whom had never smoked, there were 186 deaths over a median of 6.2 years. Greater emphysema-like lung was independently associated with increased mortality (adjusted hazard ratio per one-half interquartile range, 1.14 [95% CI, 1.04 to 1.24]; P=0.004) after adjustment for potential confounders, including cardiovascular risk factors and FEV1. Generalized additive models supported a linear association between emphysema-like lung and mortality without evidence for a threshold. The association was of greatest magnitude among smokers, although multiplicative interaction terms did not support effect modification by smoking status. LIMITATIONS: Cardiac CT scans did not include lung apices. The number of deaths was limited among subgroup analyses. CONCLUSION: Emphysema-like lung on CT was associated with all-cause mortality among persons without airflow obstruction or COPD in a general population sample, particularly among smokers. Recognition of the independent prognostic significance of emphysema on CT among patients without COPD on spirometry is warranted. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute. PMID- 25506860 TI - HIV infection and subclinical coronary atherosclerosis. PMID- 25506861 TI - HIV infection and subclinical coronary atherosclerosis. PMID- 25506862 TI - Screening pelvic examinations in asymptomatic, average-risk adult women. PMID- 25506863 TI - Screening pelvic examinations in asymptomatic, average-risk adult women. PMID- 25506864 TI - Screening pelvic examination in adult women. PMID- 25506865 TI - Screening pelvic examination in adult women. PMID- 25506866 TI - Screening pelvic examination in adult women. PMID- 25506867 TI - Screening for and prevalence of hepatitis B virus infection among high-risk veterans under the care of the U.S. Department of Veterans Affairs: a case report. PMID- 25506869 TI - Web Exclusives. The consult guys--balancing the medication portfolio 5 years after a heart attack. PMID- 25506870 TI - In heart failure, automatic implant-based telemonitoring reduced a composite of cardiac events and mortality. PMID- 25506871 TI - Review: vitamin K antagonists increase risk for subdural hematoma compared with other antithrombotics. PMID- 25506872 TI - In catheter ablation of AF, continuing vs interrupting warfarin reduced periprocedural thromboembolic events. PMID- 25506873 TI - QBleed predicted risk for gastrointestinal and intracranial bleeding. PMID- 25506874 TI - Invitation for flexible sigmoidoscopy screening reduced colorectal cancer and colorectal cancer mortality. PMID- 25506875 TI - Neither ondansetron nor metoclopramide reduced nausea and vomiting in the emergency department. PMID- 25506876 TI - In acute calculous cholecystitis, antibiotics after cholecystectomy did not reduce infection. PMID- 25506877 TI - Pooled RCTs: BP-lowering drugs reduced major CV events; absolute reductions were greater with higher baseline risk. PMID- 25506878 TI - Review: in adult outpatients, nurse-managed protocols improve hemoglobin A1c levels and blood pressure. PMID- 25506879 TI - Review: diet and exercise counseling improve intermediate health outcomes in persons with CV risk factors. PMID- 25506881 TI - Review: bDMARDs are linked to increased risk for infection compared with conventional synthetic DMARDs in RA. PMID- 25506880 TI - Review: bDMARDs plus conventional synthetic DMARDs have greater efficacy than either alone in RA. PMID- 25506882 TI - Massive CAG repeat expansion and somatic instability in maternally transmitted infantile spinocerebellar ataxia type 7. AB - IMPORTANCE: We report the first case to date of maternally transmitted infantile spinocerebellar ataxia type 7 (SCA7), in which a tract of (CAG)45 expands to lengths as large as (CAG)92-250. OBSERVATIONS: A 38-year-old woman with classic SCA7 (and a son, who died at age 3 years) had pronounced cerebellar atrophy and a renal biopsy specimen that showed focal segmental glomerulosclerosis with abnormal podocytes containing cytoplasmic inclusions. Polymerase chain reaction amplification across the SCA7 repeat tract assessed expansion levels in tissues of the affected son. High levels of somatic CAG instability were observed in blood, kidney, and skeletal muscle. This transmitted expansion is considerably larger than previously reported maternal transmission expansions of 5 to 10 gained repeats. CONCLUSIONS AND RELEVANCE: We document the first intertissue CAG instability reported to date in patients with SCA7, similar to SCA7 mouse models. Infantile SCA7, which is often paternally transmitted, can rarely arise by maternal transmission, which has implications for diagnosis and counseling among families of patients with SCA7. PMID- 25506883 TI - Problematic consequences of using standard errors rather than standard deviations: calculation of effect sizes. PMID- 25506884 TI - Liquid sampling-atmospheric pressure glow discharge as a secondary excitation source for laser ablation-generated aerosols: parametric dependence and robustness to particle loading. AB - Liquid sampling-atmospheric pressure glow discharge (LS-APGD) microplasma is being developed as a secondary vaporization-excitation source for the optical emission analysis of laser ablation (LA)-generated particle populations. The practicalities of this coupling are evaluated by determining the influence of source parameters on the emission response and the plasma's robustness upon LA introduction of easily ionized elements (EIEs). The influence of discharge current (45-70 mA), LA carrier gas flow rate (0.1-0.8 L min(-1)), and electrode separation distance (0.5-3.5 mm) was studied by measuring Cu emission lines after ablation of a brass sample. Best emission responses were observed for high discharge currents, low He carrier gas flow rates, and relatively small (<1.5 mm) electrode gaps. Plasma robustness and spectroscopic matrix effects were studied by monitoring Mg(II) : Mg(I) intensity ratios and N2-derived plasma rotational temperatures after the ablation of Sr- and Ca-containing pellets. Plasma robustness investigations showed that the plasma is not appreciably affected by the particle loadings, with the microplasma being slightly more ionizing in the case of Ca introduction. In neither case did the concentration of the concomitant element change the robustness values, implying a high level of robustness. Introduction of the LA particles results in slight increases in the rotational temperatures (~10% relative), with Ca-containing particles having a greater effect than Sr-containing particles. The observed variation of 9% in the plasma rotational temperature is in the same order of magnitude as the short-term reproducibility determined by the proposed LA-LS-APGD system. The determined rotational temperatures ranged from 1047 to 1212 K upon introducing various amounts of Ca and Sr. The relative immunity to LA particle-induced matrix effects is attributed to the relatively long residence times and high power densities (>10 W mm(-3)) of the LS-APGD microplasma. PMID- 25506885 TI - Stem Cell Therapy for Corneal Regeneration Medicine and Contemporary Nanomedicine for Corneal Disorders. AB - The ocular surface is the outermost part of the visual system that faces many extrinsic or intrinsic threats, such as chemical burn, infectious pathogens, thermal injury, Stevens-Johnson syndrome, ocular pemphegoid, and other autoimmune diseases. The cornea plays an important role in conducting light into the eyes and protecting intraocular structures. Several ocular surface diseases will lead to the neovascularization or conjunctivalization of corneal epithelium, leaving opacified optical media. It is believed that some corneal limbal cells may present stem cell-like properties and are capable of regenerating corneal epithelium. Therefore, cultivation of limbal cells and reconstruction of the ocular surface with these limbal cell grafts have attracted tremendous interest in the past few years. Currently, stem cells are found to potentiate regenerative medicine by their capability of differentiation into multiple lineage cells. Among these, the most common cell sources for clinical use are embryonic, adult, and induced stem cells. Different stem cells have varied specific advantages and limitations for in vivo and in vitro expansion. Other than ocular surface diseases, culture and transplantation of corneal endothelial cells is another major issue for corneal decompensation and awaits further studies to find out comprehensive solutions dealing with nonregenerative corneal endothelium. Recently, studies of in vitro endothelium culture and rho-associated kinase (ROCK) inhibitor have gained encouraging results. Some clinical trials have already been finished and achieved remarkable vision recovery. Finally, nanotechnology has shown great improvement in ocular drug delivery systems during the past two decades. Strategies to reconstruct the ocular surface could combine with nanoparticles to facilitate wound healing, drug delivery, and even neovascularization inhibition. In this review article, we summarized the major advances of corneal limbal stem cells, limbal stem cell deficiency, corneal endothelial cell culture/transplantation, and application of nanotechnology on ocular surface reconstruction. We also illustrated potential applications of current knowledge for the future treatment of ocular surface diseases. PMID- 25506887 TI - Pattern recognition-assisted infrared library searching of automotive clear coats. AB - Pattern recognition techniques have been developed to search the infrared (IR) spectral libraries of the paint data query (PDQ) database to differentiate between similar but nonidentical IR clear coat paint spectra. The library search system consists of two separate but interrelated components: search prefilters to reduce the size of the IR library to a specific assembly plant or plants corresponding to the unknown paint sample and a cross-correlation searching algorithm to identify IR spectra most similar to the unknown in the subset of spectra identified by the prefilters. To develop search prefilters with the necessary degree of accuracy, IR spectra from the PDQ database were preprocessed using wavelets to enhance subtle but significant features in the data. Wavelet coefficients characteristic of the assembly plant of the vehicle were identified using a genetic algorithm for pattern recognition and feature selection. A search algorithm was then used to cross-correlate the unknown with each IR spectrum in the subset of library spectra identified by the search prefilters. Each cross correlated IR spectrum was simultaneously compared to an autocorrelated IR spectrum of the unknown using several spectral windows that span different regions of the cross-correlated and autocorrelated data from the midpoint. The top five hits identified in each search window are compiled, and a histogram is computed that summarizes the frequency of occurrence for each selected library sample. The five library samples with the highest frequency of occurrence are selected as potential hits. Even in challenging trials where the clear coat paint samples evaluated were all the same make (e.g., General Motors) within a limited production year range, the model of the automobile from which the unknown paint sample was obtained could be identified from its IR spectrum. PMID- 25506889 TI - Targeting Epithelial-to-Mesenchymal Transition for Cancer Therapy. PMID- 25506890 TI - Cancer/testis antigens trigger epithelial-mesenchymal transition and genesis of cancer stem-like cells. AB - Malignant tumors aberrantly overexpress various embryonic genes and proto oncogenes, including a variety of cancer-testis antigens (CTAs). CTAs belong to a class of testis-derived proteins which are only expressed in germ cells in the male testis, and the expression of CTA genes is entirely silenced in the adult somatic tissues. They are, however, aberrantly overexpressed in a variety of malignant tumor tissues. Emerging evidence shows that a number of CTAs promote epithelialmesenchymal transition (EMT) and genesis of cancer stem like cells, escalating tumorigenesis, invasion, and metastasis. The can cer-testis antigens, such as SSX, MAGE-D4B, CAGE, piwil2, and CT45A1, upregulate EMT and metastatic genes, promoting EMT and tumor dissemination. In addition, certain members of CTAs, including Piwil2, DNAJB8, CT45A1, MAGE-A, GAGE, and SPANX, are implicated in the initiation or maintenance, of cancer stem-like cells, promoting tumorigenesis and malignant progression. Clinically CTAs are closely associated with poor prognosis in cancer patients. Intriguely, CTAs are strongly immunogenic and normally restricted to the male testis after birth, however, these proteins are aberrantly overexpressed in cancer stem-like cells and in a variety of cancers, suggesting their target potential for cancer immunotherapy, as diagnostic biomarkers, and as targets for novel anticancer drug discovery. Thus, the targeting of tumorigenic CTAs is a promising strategy to eradicate cancer stem-like cells and inhibit tumorigenesis for effective cancer treatment. PMID- 25506888 TI - Diofenolan induces male offspring production through binding to the juvenile hormone receptor in Daphnia magna. AB - Juvenile hormone (JH) and JH agonists have been reported to induce male offspring production in various daphnid species including Daphnia magna. We recently established a short-term in vivo screening assay to detect chemicals having male offspring induction activity in adult D. magna. Diofenolan has been developed as a JH agonist for insect pest control, but its male offspring induction activity in daphnids has not been investigated yet. In this study, we found that the insect growth regulator (IGR) diofenolan exhibited a potent male offspring induction activity at low ng/L to MUg/L concentrations, as demonstrated by the short-term in vivo screening assay and the recently developed TG211 ANNEX 7 test protocol. A two-hybrid assay performed using the D. magna JH receptor confirmed that diofenolan had a strong JH activity. Global whole body transcriptome analysis of D. magna exposed to 10 ng/L diofenolan showed an up-regulation of JH responsive genes and modulation of several genes involved in the ecdysone receptor signaling pathway. These results clearly demonstrate that diofenolan has strong JH activity and male offspring induction activity, and that a combination of modified standardized regulatory testing protocols and rapid in vitro and in vivo screening assays are able to identify potential endocrine disruptors in D. magna. The observation that diofenolan modulates multiple endocrine signaling pathways in D. magna suggests that further investigation of potential interference with growth, development and reproduction is warranted. PMID- 25506893 TI - Epigenetic regulation of epithelial-mesenchymal transition by hypoxia in cancer: targets and therapy. AB - Intratumoral hypoxia followed by stabilization/activation of hypoxia-inducible factor 1 (HIF-1) and its downstream transcriptional factors, is one of the most important mechanisms inducing epithelial-mesenchymal transition (EMT), which has been widely accepted as a crucial step to generate early stage of tumor metastasis. Accumulating evidence suggests that epigenetic mechanisms play important roles in hypoxia-induced EMT and metastasis. These epigenetic regulations are mediated by various players including chromatin modifiers, transcriptional co-regulators, microRNAs, etc. In this review, we discuss how his tone-modifying enzymes and transcriptional co-regulators regulate EMT under hypoxic conditions. Developed or potential anticancer agents targeting epigenetic molecules regulating hypoxia-induced EMT are also discussed. PMID- 25506891 TI - Twist-BRD4 complex: potential drug target for basal-like breast cancer. AB - As an important basic helix-loop-helix (bHLH) transcription factor, Twist associates with several physiological processes such as mesodermal development, and pathological processes such as Saethre-Chotzen syndrome. During cancer progression, Twist induces epithelial-mesenchymal transition (EMT), potentiating cancer cell invasion and metastasis. Although many studies have revealed its multiple biological roles, it remained unclear how Twist transcriptionally activates targeted genes. Recently we discovered tip60-mediated Twist di acetylation in the ''histone H4-mimic'' GK-X-GK motif. The di-acetylated Twist recruits BRD4 and related transcriptional components to super-enhancer of its targeted genes during progression of basal-like breast cancer (BLBC). Here, we review this new advance of regulation and functional mechanism of Twist. PMID- 25506892 TI - Vitamin D receptor signaling and pancreatic cancer cell EMT. AB - Pancreatic ductal adenocarcinoma (PDAC) still remains one of the most fatal human malignant tumors. Long-term survival rate is still extremely pathetic even for patients who receive surgery. Epithelial-to-mesenchymal transition (EMT), which is a physiologic process of morphological as well as genetic changes in carcinoma cells, plays a vital role in aggressiveness of PDAC. Meanwhile EMT is also the reason why pancreatic cancer cells achieve such huge metastatic potentials. Many tumor microenvironmental factors such as cytokines, growth factors, as well as chemotherapeutic agents may induce EMT. Our study provides evidence regarding effects of EMT on pancreatic cancer progression, focusing on the correlation between EMT and other pathways which are crucial to tumor progression, especially vitamin D receptor signaling pathway. Research on signal pathways resulting in EMT inactivation during these disease processes may offer innovative ideas on plasticity of cellular phenotypes as well as possible therapeutic interventions. PMID- 25506894 TI - The functions of F-box proteins in regulating the epithelial to mesenchymal transition. AB - Epithelial to mesenchymal transition (EMT) has been unraveled to regulate the tumor invasion and metastasis processes. In this review, in order to better understand the regulatory mechanisms of EMT, we describe that F-box proteins could be critically involved in regulating the EMT process in human cancers. Specifically, we discuss how these F-box proteins directly control the stability of EMT regulators such as E-cadherin, beta-catenin, Twist, Slug, Snail and ZEB. Moreover, we summary mechanistically how the F-box proteins govern EMT progression through regulation of EMT inducers including Notch, NF-kappaB, Akt, Hedgehog, mTOR, and HIF-1alpha. Therefore, targeting these F-box proteins could be useful for treating human cancers. PMID- 25506898 TI - The epithelial-mesenchymal transition and cancer stem cells: functional and mechanistic links. AB - The epithelial-mesenchymal transition (EMT) is a highly conserved cellular process that transforms epithelial cells into mesenchymal cells; EMT is involved in normal embryogenesis and tissue repair and contributes to tumor progression, including tumor metastasis, therapy resistance and disease recurrence. Cancer stem cells (CSCs) represent a fraction of undifferentiated cancer cells that exhibit stem cell-like features. They have the ability to self-renew and can seed new tumors. Thus, CSCs might represent the cellular resource that causes metastases and accounts for therapy resistance. Recent studies have highlighted a link between EMT and CSC formation. EMT is relevant to the acquisition and maintenance of stem cell-like characteristics and is sufficient to endow differentiated normal and cancer cells with stem cell properties. Moreover, CSCs often exhibit EMT properties. This reciprocal relationship between EMT and CSCs might have many implications in tumor progression. In this paper, we review current studies related to EMT and CSCs in tumor progression and therapeutic resistance, with a special focus on the common characteristics and links between these processes, and explore the importance of these links in the development of improved antitumor therapies. PMID- 25506897 TI - Glioblastoma multiforme formation and EMT: role of FoxM1 transcription factor. AB - Glioblastoma multiforme (GBM) is one of the most malignant cancers in human brain. The prognosis of GBM is extremely poor because it is resistant to radiotherapy and chemotherapy. Improving understanding of the tumor biology brings some new hope to the treatment of GBM. In this review, we discuss the evidence that FoxM1 promotes the development and progression of GBM by regulating key factors involved in cell proliferation, epithelial to mesenchymal transition (EMT), invasion, angiogenesis and upregulating Wnt/beta-catenin signalling. Our recent experimental findings are also summarized to prove that FoxM1 is a novel therapeutic target against GBM. PMID- 25506896 TI - Role of epithelial mesenchymal transition in prostate tumorigenesis. AB - Globally, the cancer associated deaths are generally attributed to the spread of cancerous cells or their features to the nearby or distant secondary organs by a process known as metastasis. Among other factors, the metastatic dissemination of cancer cells is attributed to the reactivation of an evolutionary conserved developmental program known as epithelial to mesenchymal transition (EMT). During EMT, fully differentiated epithelial cells undergo a series of dramatic changes in their morphology, along with loss of cell to cell contact and matrix remodeling into less differentiated and invasive mesenchymal cells. Many studies provide evidence for the existence of EMT like states in prostate cancer (PCa) and suggest its possible involvement in PCa progression and metastasis. At the same time, the lack of conclusive evidence regarding the presence of full EMT in human PCa samples has somewhat dampened the interest in the field. However, ongoing EMT research provides new perspectives and unveils the enormous potential of this field in tailoring new therapeutic regimens for PCa management. This review summarizes the role of many transcription factors and other molecules that drive EMT during prostate tumorigenesis. PMID- 25506899 TI - Pancreatic cancer metastasis: are we being pre-EMTed? AB - Pancreatic cancer, often considered a metastatic disease at the time of clinical diagnosis due to lack of any reliable early diagnostic marker(s), is refractory to conventional chemo- and radiotherapy and has a dismal 5-year survival rate of only 6%. Although surgical removal of the primary tumor is considered to be curative, the 5-year survival rate is no more than 20% even in patients with clear resection margins (R0). The recurrence of local and metastatic disease (primarily liver metastasis) post resection is considered to be the leading cause of mortality in these patients. In addition, instances of metastatic disease without any local recurrence post resection have also been observed. Cancer metastasis is the primary cause of mortality in cancer patients and is classically viewed as a late event during the progression of the disease, which is supported by the genetic studies used to understand the evolution of pancreatic cancer. However, this view has recently been challenged by studies using mathematical modeling and genetically labeled mouse models of pancreatic cancer to understand the dynamics of tumor cell dissemination and epithelial to mesenchymal transition (EMT) of tumor cells well before the primary tumor is formed. Given that EMT is a hallmark process that initiates the metastatic seeding of cancer cells and the dismal prognosis of pancreatic cancer patients even after efficient removal of the primary tumor (99.9%), an early dissemination hypothesis of cancer cells cannot be undermined. In this review, we will discuss the current views regarding pancreatic cancer metastasis with particular emphasis on the epithelial to mesenchymal transition, its influence on the selection of patients for surgical resection and the therapeutic intervention. PMID- 25506900 TI - A fluorescent aptasensor for H5N1 influenza virus detection based-on the core shell nanoparticles metal-enhanced fluorescence (MEF). AB - A fluorescent aptasensor system has been designed for the sensitive detection of recombinant hemagglutinin (rHA) protein of the H5N1 influenza virus in human serum. Guanine-richen anti-rHA aptamers by SELEX were immobilized on the surface of the Ag@SiO2 nanoparticles which performed as a metal-enhanced fluorescence (MEF) sensing platform. Thiazole orange (TO) was used as fluorescent tag which reported to the G-quadruplex secondary structural induced by aptamer-rHA binding event. In the absence of rHA protein, TO was free in the solution with almost no fluorescence emission. When rHA protein was added to the solution, the aptamer strand bound rHA protein to form a stable G-quadruplex complex, which can bind TO and excite the fluorescence emission of TO. Moreover, the excited-state TO captured by the G-quadruplex complex was forced to the surface of the Ag@SiO2 nanoparticles and could experience a surface plasmon resonance enhancement which can be transformed into more efficient fluorescence emission signals, therefore, the fluorescence signal of TO can be amplified largely. This system does not require covalent labeling with fluorophores to the aptamer and the background noise is very low. The detection of rHA protein of the H5N1 influenza virus could be operated both in aqueous buffer and human serum with the detection limit of 2 and 3.5ng/mL respectively. More important, the whole detection process can be finished in a PE tube within 30min, which makes it suitable as a self-contained diagnostic kit for H5N1 influenza virus point-of-care (POC) diagnostic. PMID- 25506895 TI - Epithelial-mesenchymal plasticity of breast cancer stem cells: implications for metastasis and therapeutic resistance. AB - Over the past several decades the traditional view of cancer being a homogeneous mass of rapid proliferating malignant cells is being replaced by a model of ever increasing complexity, which points out that cancers are complex tissues composed of multiple cell types. A large variety of immune and other host cells constitute the tumor microenvironment, which supports the growth and progression of the tumor where individual cancer cells evolve with increasing phenotypic and genetic heterogeneity. Furthermore, it has also become clear that, in addition to this cellular and genetic heterogeneity, most tumors exhibit a hierarchical organization composed of tumor cells displaying divergent lineage markers and at the apex of this hierarchy are cells capable of self-renewal. These "cancer stem cells" not only drive tumor growth, but also mediate metastasis and contribute to treatment resistance. Besides displaying remarkable genetic and phenotypic heterogeneity, cancer stem cells maintain plasticity to transition between mesenchymal-like (EMT) and epithelial-like (MET) states in a process regulated by the tumor microenvironment. These stem cell state transitions may play a fundamental role in the process of tumor metastasis. In this review, we will discuss emerging knowledge regarding the plasticity of cancer stem cells and the role that this plasticity plays in tumor metastasis. We also discuss the implications of these findings for the development of cancer stem cell targeted therapeutics. PMID- 25506901 TI - Highly selective manganese-doped zinc sulfide quantum dots based label free phosphorescent sensor for phosphopeptides in presence of zirconium (IV). AB - We report a room-temperature phosphorescence (RTP) sensor for phosphopeptides based on zirconium (IV)-modulated mercaptopropionic acid (MPA)-capped Mn-doped ZnS quantum dots (QDs). This sensor incorporates the advantages of the well-known Zr(4+)-phosphopeptide affinity pair and the RTP properties of doped QDs. The RTP of Mn-doped ZnS QDs capped with MPA can be effectively quenched by Zr(4+). The high affinity of phosphopeptides to Zr(4+) enables the dissociation of the ion from the surface of MPA-capped ZnS QDs, thereby forming a stable complex with phosphopeptides in the solution, and recovering the RTP of the QDs. The Zr(4+) induced RTP quenching and subsequent phosphopeptide-induced RTP recovery for MPA capped ZnS QDs provide a solid basis for the present RTP sensor based on QDs for the detection of phosphopeptides. The detection limit for phosphopeptides is 0.9ngmL(-1), the relative standard deviations is 2.5%, and the recovery of urine and serum samples with phosphopeptides addition rangs from 96% to 105% at optimal conditions. The proposed method was successfully applied to biological fluids and obtained satisfactory results. PMID- 25506902 TI - A highly sensitive quartz crystal microbalance immunosensor based on magnetic bead-supported bienzymes catalyzed mass enhancement strategy. AB - A highly sensitive quartz crystal microbalance (QCM) immunosensor based on magnetic bead-supported bienzyme catalyzed mass enhanced strategy was developed for the detection of human immunoglobulin G (hIgG) protein. The high sensitive detection was achieved by increasing the deposited mass on the QCM crystal through the enhanced precipitation of 4-chloro-1-naphthol (CN) using higher amounts of horseradish peroxidase (HRP) and glucose oxidase (GOx) bienzymes attached on the magnetic beads (MB). The protein A (PA) and capture antibody (monoclonal anti-human IgG antibody produced in mouse, Ab1)-based QCM probe and the detection antibody (anti-human IgG antibody produced in goat, Ab2)-based MB/HRP/GOx bienzymatic bioconjugates were characterized using scanning electron microscope, transmission electron microscope, cyclic voltammetry, and electrochemical impedance spectroscopy techniques. Under the optimized experimental condition, the linear range and the detection limit of hIgG immunosensor were determined to be 5.0pg/mL-20.0ng/mL and 5.0+/-0.18pg/mL, respectively. The applicability of the present hIgG immunosensor was examined in hIgG spiked human serum samples and excellent recoveries of hIgG were obtained. PMID- 25506904 TI - Size characterization of dissolved metals and organic matter in source waters to streams in developed landscapes. AB - Individual and mixed water samples from wastewater treatment plant effluents, stormwater runoff, streams from developed areas were characterized with respect to organic matter concentration and spectral properties and metal concentration and size distribution. In addition, asymmetric flow-field flow fractionation coupled to inductively coupled plasma mass spectrometry was used to measure concentration, size distribution and association of metals in the colloidal size range. Results reveal that Fe, Cu, Zn and Pb in the colloidal size range were mainly associated with the less than 5 nm, or less than 10 kDa size range. Cu was most strongly associated with organic matter, while Zn and Pb were mixed between Fe and organic matter. Effluent showed higher binding capacity for metals, while stormwater, even with higher organic matter concentrations showed more exchangeable metals. Upon mixing of source waters, colloidal metal concentrations and size distributions were conserved. PMID- 25506905 TI - Avoidance behavior in chronic pain research: a cold case revisited. AB - In chronic musculoskeletal pain, avoidance behavior is a prominent behavioral characteristic that can manifest itself in various ways. It is also considered a crucial component in the development and maintenance of chronic pain-related disability, supposedly fueled by pain-related fear and catastrophic beliefs. Despite the frequent occurrence of avoidance behavior and its potential impact on quality of life, relatively little research has been dedicated to the nature of avoidance in chronic pain and its assessment, leaving its underlying mechanisms poorly understood. In the current paper, we stipulate some of the existing parallels between chronic pain research and more basic fear and anxiety research inspired by modern learning theories. After a brief introduction, we discuss avoidance theories that are likely apt to be applied to chronic pain, including avoidance as a response that can affect fear responding, and the role of avoidant decision making and motivational context. Finally, we will outline how these theories may impact clinical treatment. PMID- 25506903 TI - Highly sensitive fluorescence assay of DNA methyltransferase activity by methylation-sensitive cleavage-based primer generation exponential isothermal amplification-induced G-quadruplex formation. AB - Site-specific identification of DNA methylation and assay of MTase activity are imperative for determining specific cancer types, provide insights into the mechanism of gene repression, and develop novel drugs to treat methylation related diseases. Herein, we developed a highly sensitive fluorescence assay of DNA methyltransferase by methylation-sensitive cleavage-based primer generation exponential isothermal amplification (PG-EXPA) coupled with supramolecular fluorescent Zinc(II)-protoporphyrin IX (ZnPPIX)/G-quadruplex. In the presence of DNA adenine methylation (Dam) MTase, the methylation-responsive sequence of hairpin probe is methylated and cleaved by the methylation-sensitive restriction endonuclease Dpn I. The cleaved hairpin probe then functions as a signal primer to initiate the exponential isothermal amplification reaction (EXPAR) by hybridizing with a unimolecular DNA containing three functional domains as the amplification template, producing a large number of G-quadruplex nanostructures by utilizing polymerases and nicking enzymes as mechanical activators. The G quadruplex nanostructures act as host for ZnPPIX that lead to supramolecular complexes ZnPPIX/G-quadruplex, which provides optical labels for amplified fluorescence detection of Dam MTase. While in the absence of Dam MTase, neither methylation/cleavage nor PG-EXPA reaction can be initiated and no fluorescence signal is observed. The proposed method exhibits a wide dynamic range from 0.0002 to 20U/mL and an extremely low detection limit of 8.6*10(-5)U/mL, which is superior to most conventional approaches for the MTase assay. Owing to the specific site recognition of MTase toward its substrate, the proposed sensing system was able to readily discriminate Dam MTase from other MTase such as M.SssI and even detect the target in a complex biological matrix. Furthermore, the application of the proposed sensing strategy for screening Dam MTase inhibitors was also demonstrated with satisfactory results. This novel method not only provides a promising platform for monitoring activity and inhibition of DNA MTases, but also shows great potentials in biological process researches, drugs discovery and clinical diagnostics. PMID- 25506906 TI - Assessing risks to adults and preschool children posed by PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) during a biomass burning episode in Northern Thailand. AB - To investigate the potential cancer risk resulting from biomass burning, polycyclic aromatic hydrocarbons (PAHs) bound to fine particles (PM2.5) were assessed in nine administrative northern provinces (NNP) of Thailand, before (N I) and after (N-II) a haze episode. The average values of Sigma 3,4-ring PAHs and B[a] P Equivalent concentrations in world urban cities were significantly (p<0.05) much higher than those in samples collected from northern provinces during both sampling periods. Application of diagnostic binary ratios of PAHs underlined the predominant contribution of vehicular exhaust to PM2.5-bound PAH levels in NNP areas, even in the middle of the agricultural waste burning period. The proximity of N-I and N-II values in three-dimensional (3D) principal component analysis (PCA) plots also supports this conclusion. Although the excess cancer risk in NNP areas is much lower than those of other urban area and industrialized cities, there are nevertheless some concerns relating to adverse health impacts on preschool children due to non-dietary exposure to PAHs in home environments. PMID- 25506907 TI - Analysis of phthalate esters in soils near an electronics manufacturing facility and from a non-industrialized area by gas purge microsyringe extraction and gas chromatography. AB - Here, a novel technique is described for the extraction and quantitative determination of six phthalate esters (PAEs) from soils by gas purge microsyringe extraction and gas chromatography. Recovery of PAEs ranged from 81.4% to 120.3%, and the relative standard deviation (n=6) ranged from 5.3% to 10.5%. Soil samples were collected from roadsides, farmlands, residential areas, and non-cultivated areas in a non-industrialized region, and from the same land-use types within 1 km of an electronics manufacturing facility (n=142). Total PAEs varied from 2.21 to 157.62 mg kg(-1) in non-industrialized areas and from 8.63 to 171.64 mg kg(-1) in the electronics manufacturing area. PAE concentrations in the non industrialized area were highest in farmland, followed (in decreasing order) by roadsides, residential areas, and non-cultivated soil. In the electronics manufacturing area, PAE concentrations were highest in roadside soils, followed by residential areas, farmland, and non-cultivated soils. Concentrations of dimethyl phthalate (DMP), diethyl phthalate (DEP), and di-n-butyl phthalate (DnBP) differed significantly (P<0.01) between the industrial and non industrialized areas. Principal component analysis indicated that the strongest explanatory factor was related to DMP and DnBP in non-industrialized soils and to butyl benzyl phthalate (BBP) and DMP in soils near the electronics manufacturing facility. Congener-specific analysis confirmed that diethylhexyl phthalate (DEHP) was a predictive indication both in the non-industrialized area (r(2)=0.944, P<0.01) and the industrialized area (r(2)=0.860, P<0.01). The higher PAE contents in soils near the electronics manufacturing facility are of concern, considering the large quantities of electronic wastes generated with ongoing industrialization. PMID- 25506908 TI - Weight-of-evidence approach in assessment of ecotoxicological risks of acid sulphate soils in the Baltic Sea river estuaries. AB - Acidity and leaching of metals from acid sulphate soils (ASSs) impair the water quality of receiving surface waters. The largest ASS areas in Europe are found in the coasts of the northern Baltic Sea. We used weight-of-evidence (WoE) approach to assess potential risks in 14 estuary sites affected by ASS in the Gulf of Finland, northern Baltic Sea. The assessment was based on exposure and effect profiles utilizing sediment and water metal concentrations and concurrent pH variation, sediment toxicity tests using the luminescent bacterium Vibrio fischeri and the midge Chironomus riparius, and the ecological status of benthic macroinvertebrate communities. Sediment metal concentrations were compared to national sediment quality criteria/guidelines, and water metal concentrations to environmental quality standards (EQSs). Hazard quotients (HQs) were established for maximum aluminium, cadmium and zinc concentrations at low pH based on applicable US EPA toxicity database. Sediment metal concentrations were clearly elevated in most of the studied estuaries. The EQS of cadmium (0.1 MUg/l) was exceeded in 3 estuaries out of 14. The pH-minima were below the national threshold value (5.5) between good and satisfactory water quality in 10 estuaries. V. fischeri bioluminescence indicated toxicity of the sediments but toxic response was not observed in the C. riparius emergence test. Benthic invertebrate communities were deteriorated in 6 out of 14 sites based on the benthic invertebrate quality index. The overall ecotoxicological risk was assessed as low in five, moderate in three and high in five of the estuary sites. The risk assessment utilizing the WoE approach indicated that harmful effects of ASSs are likely to occur in the Baltic Sea river estuaries located at the ASS hotspot area. PMID- 25506909 TI - Impacts of global change on the concentrations and dilution of combined sewer overflows in a drinking water source. AB - This study presents an analysis of climate change impacts on a large river located in Quebec (Canada) used as a drinking water source. Combined sewer overflow (CSO) effluents are the primary source of fecal contamination of the river. An analysis of river flowrates was conducted using historical data and predicted flows from a future climate scenario. A spatio-temporal analysis of water quality trends with regard to fecal contamination was performed and the effects of changing flowrates on the dilution of fecal contaminants were analyzed. Along the river, there was a significant spatial trend for increasing fecal pollution downstream of CSO outfalls. Escherichia coli concentrations (upper 95th percentile) increased linearly from 2002 to 2012 at one drinking water treatment plant intake. Two critical periods in the current climate were identified for the drinking water intakes considering both potential contaminant loads and flowrates: local spring snowmelt that precedes river peak flow and extra-tropical storm events that occur during low flows. Regionally, climate change is expected to increase the intensity of the impacts of hydrological conditions on water quality in the studied basin. Based on climate projections, it is expected that spring snowmelt will occur earlier and extreme spring flowrates will increase and low flows will generally decrease. High and low flows are major factors related to the potential degradation of water quality of the river. However, the observed degradation of water quality over the past 10 years suggests that urban development and population growth may have played a greater role than climate. However, climate change impacts will likely be observed over a longer period. Source water protection plans should consider climate change impacts on the dilution of contaminants in addition to local land uses changes in order to maintain or improve water quality. PMID- 25506910 TI - Ultrastructural visualization of the Mesenchymal-to-Epithelial Transition during reprogramming of human fibroblasts to induced pluripotent stem cells. AB - The Mesenchymal-to-Epithelial Transition (MET) has been recognized as a crucial step for successful reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs). Thus, it has been demonstrated, that the efficiency of reprogramming can be enhanced by promoting an epithelial expression program in cells, with a concomitant repression of key mesenchymal genes. However, a detailed characterization of the epithelial transition associated with the acquisition of a pluripotent phenotype is still lacking to this date. Here, we integrate a panel of morphological approaches with gene expression analyses to visualize the dynamics of episomal reprogramming of human fibroblasts to iPSCs. We provide the first ultrastructural analysis of human fibroblasts at various stages of episomal iPSC reprogramming, as well as the first real-time live cell visualization of a MET occurring during reprogramming. The results indicate that the MET manifests itself approximately 6-12days after electroporation, in synchrony with the upregulation of early pluripotency markers, and resembles a reversal of the Epithelial-to-Mesenchymal Transition (EMT) which takes place during mammalian gastrulation. PMID- 25506911 TI - Protoporphyrins enhance oligomerization and enzymatic activity of HtrA1 serine protease. AB - High temperature requirement protein A1 (HtrA1), a secreted serine protease of the HtrA family, is associated with a multitude of human diseases. However, the exact functions of HtrA1 in these diseases remain poorly understood. We seek to unravel the mechanisms of HtrA1 by elucidating its interactions with chemical or biological modulators. To this end, we screened a small molecule library of 500 bioactive compounds to identify those that alter the formation of extracellular HtrA1 complexes in the cell culture medium. An initial characterization of two novel hits from this screen showed that protoporphyrin IX (PPP-IX), a precursor in the heme biosynthetic pathway, and its metalloporphyrin (MPP) derivatives fostered the oligomerization of HtrA1 by binding to the protease domain. As a result of the interaction with MPPs, the proteolytic activity of HtrA1 against Fibulin-5, a specific HtrA1 substrate in age-related macular degeneration (AMD), was increased. This physical interaction could be abolished by the missense mutations of HtrA1 found in patients with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Furthermore, knockdown of HtrA1 attenuated apoptosis induced by PPP-IX. These results suggest that PPP-IX, or its derivatives, and HtrA1 may function as co factors whereby porphyrins enhance oligomerization and the protease activity of HtrA1, while active HtrA1 elevates the pro-apoptotic actions of porphyrin derivatives. Further analysis of this interplay may shed insights into the pathogenesis of diseases such as AMD, CARASIL and protoporphyria, as well as effective therapeutic development. PMID- 25506912 TI - Uveal melanoma cells utilize a novel route for transendothelial migration. AB - Uveal melanoma arises in the eye, and it spreads to distant organs in almost half of patients, leading to a fatal outcome. To metastasize, uveal melanoma cells must transmigrate into and out of the microvasculature, crossing the monolayer of endothelial cells that separates the vessel lumen from surrounding tissues. We investigated how human uveal melanoma cells cross the endothelial cell monolayer, using a cultured cell system with primary human endothelial cell monolayers on hydrogel substrates. We found that uveal melanoma cells transmigrate by a novel and unexpected mechanism. Uveal melanoma cells intercalate into the endothelial cell monolayer and flatten out, assuming a shape and geometry similar to those of endothelial cells in the monolayer. After an extended period of time in the intercalated state, the uveal melanoma cells round up and migrate underneath the monolayer. VCAM is present on endothelial cells, and anti-VCAM antibodies slowed the process of intercalation. Depletion of BAP1, a known suppressor of metastasis in patients, increased the amount of transmigration of uveal melanoma cells in transwell assays; but BAP1 depletion did not affect the rate of intercalation, based on movies of living cells. Our results reveal a novel route of transendothelial migration for uveal melanoma cells, and they provide insight into the mechanism by which loss of BAP1 promotes metastasis. PMID- 25506913 TI - Acoustic telemetry reveals large-scale migration patterns of walleye in Lake Huron. AB - Fish migration in large freshwater lacustrine systems such as the Laurentian Great Lakes is not well understood. The walleye (Sander vitreus) is an economically and ecologically important native fish species throughout the Great Lakes. In Lake Huron walleye has recently undergone a population expansion as a result of recovery of the primary stock, stemming from changing food web dynamics. During 2011 and 2012, we used acoustic telemetry to document the timing and spatial scale of walleye migration in Lake Huron and Saginaw Bay. Spawning walleye (n = 199) collected from a tributary of Saginaw Bay were implanted with acoustic tags and their migrations were documented using acoustic receivers (n = 140) deployed throughout U.S. nearshore waters of Lake Huron. Three migration pathways were described using multistate mark-recapture models. Models were evaluated using the Akaike Information Criterion. Fish sex did not influence migratory behavior but did affect migration rate and walleye were detected on all acoustic receiver lines. Most (95%) tagged fish migrated downstream from the riverine tagging and release location to Saginaw Bay, and 37% of these fish emigrated from Saginaw Bay into Lake Huron. Remarkably, 8% of walleye that emigrated from Saginaw Bay were detected at the acoustic receiver line located farthest from the release location more than 350 km away. Most (64%) walleye returned to the Saginaw River in 2012, presumably for spawning. Our findings reveal that fish from this stock use virtually the entirety of U.S. nearshore waters of Lake Huron. PMID- 25506914 TI - Age-related longitudinal changes in metabolic energy expenditure during walking in boys with Duchenne muscular dystrophy. AB - OBJECTIVE: The aim of this study was to evaluate age-related changes in metabolic walking energy expenditure in ambulant boys affected by Duchenne muscular dystrophy over a follow-up period of 12 months. METHODS: At baseline (T1) and 12 months later (T2), metabolic walking energy expenditure was assessed during a 6 minute walk test at comfortable speed in 14 ambulant boys with Duchenne (age range: 6.0-12.5 years, mean 8.2). Outcome measures derived from the assessment included the 6-minute comfortable walking distance (m) and net-nondimensional energy cost relative to speed-matched control cost (SMC-EC, %). Statistical comparisons were made using a two-way repeated measures ANOVA (factors: time (T1 versus T2) and age (<8 years of age (yoa) versus >=8 yoa)). RESULTS: Over the course of the study, a significant decrease of -28m (-8.2%, p = 0.043) was noted in the walked distance at comfortable speed. Besides, SMC-EC increased with 4.4%, although this change was not significant (p = 0.452). Regarding age groups, boys below 8 yoa showed a smaller annual decrease in the walked distance (-15 m) compared to boys above 8 yoa (-37 m). SMC-EC increased with 10% in the older boys, while in the younger boys it decreased (-2.1%). The main effect of age group on walking distance and SMC-EC however was not significant (p>0.158), and also there were no interaction effects (p>0.248). CONCLUSIONS: The results of our small study suggest that the natural course of walking performance in ambulant boys with Duchenne is characterized by a decrease in comfortable walking distance and an increase in walking energy cost. The rate of energy cost seems to increase with age, while walking distance decreases, which is opposite from the trend in typically developing children. PMID- 25506915 TI - A subpopulation of circulating endothelial cells express CD109 and is enriched in the blood of cancer patients. AB - BACKGROUND: The endothelium is not a homogeneous organ. Endothelial cell heterogeneity has been described at the level of cell morphology, function, gene expression, and antigen composition. As a consequence of the genetic, transcriptome and surrounding environment diversity, endothelial cells from different vascular beds have differentiated functions and phenotype. Detection of circulating endothelial cells (CECs) by flow cytometry is an approach widely used in cancer patients, and their number, viability and kinetic is a promising tool to stratify patient receiving anti-angiogenic treatment. METHODOLOGY/PRINCIPAL FINDINGS: Currently CECs are identified as positive for a nuclear binding antigen (DNA+), negative for the pan leukocyte marker CD45, and positive for CD31 and CD146. Following an approach recently validated in our laboratory, we investigated the expression of CD109 on CECs from the peripheral blood of healthy subject and cancer patients. The endothelial nature of these cells was validated by RT-PCR for the presence of m-RNA level of CDH5 (Ve-Cadherin) and CLDN5 (Claudin5), two endothelial specific transcripts. Before treatment, significantly higher levels of CD109+ CECs and viable CD109+CECs were found in breast cancer patients and glioblastoma patients compared to healthy controls, and their number significantly decreased after treatment. Higher levels of endothelial specific transcripts expressed in developing endothelial cells CLEC14a, TMEM204, ARHGEF15, GPR116, were observed in sorted CD109+CECs when compared to sorted CD146+CECs, suggesting that these genes can play an important role not only during embryogenesis but also in adult angiogenesis. Interestingly, mRNA levels of TEM8 (identified as Antrax Toxin Receptor1, Antrax1) were expressed in CD109+CECs+ but not in CD146+CECs. CONCLUSION: Taken together our results suggest that CD109 represent a rare population of circulating tumor endothelial cells, that play a potentially useful prognostic role in patients with glioblastoma. The role of CD109 expression in cancer vessel-specific endothelial cells deserves to be further investigated by gene expression studies. PMID- 25506916 TI - Applying multivariate clustering techniques to health data: the 4 types of healthcare utilization in the Paris metropolitan area. AB - BACKGROUND: Cost containment policies and the need to satisfy patients' health needs and care expectations provide major challenges to healthcare systems. Identification of homogeneous groups in terms of healthcare utilisation could lead to a better understanding of how to adjust healthcare provision to society and patient needs. METHODS: This study used data from the third wave of the SIRS cohort study, a representative, population-based, socio-epidemiological study set up in 2005 in the Paris metropolitan area, France. The data were analysed using a cross-sectional design. In 2010, 3000 individuals were interviewed in their homes. Non-conventional multivariate clustering techniques were used to determine homogeneous user groups in data. Multinomial models assessed a wide range of potential associations between user characteristics and their pattern of healthcare utilisation. RESULTS: We identified four distinct patterns of healthcare use. Patterns of consumption and the socio-demographic characteristics of users differed qualitatively and quantitatively between these four profiles. Extensive and intensive use by older, wealthier and unhealthier people contrasted with narrow and parsimonious use by younger, socially deprived people and immigrants. Rare, intermittent use by young healthy men contrasted with regular targeted use by healthy and wealthy women. CONCLUSION: The use of an original technique of massive multivariate analysis allowed us to characterise different types of healthcare users, both in terms of resource utilisation and socio demographic variables. This method would merit replication in different populations and healthcare systems. PMID- 25506917 TI - Mesothelin expression in triple negative breast carcinomas correlates significantly with basal-like phenotype, distant metastases and decreased survival. AB - Mesothelin is a cell surface associated antigen expressed on mesothelial cells and in some malignant neoplasms. Mesothelin-targeted therapies are in phase I/II clinical trials. The clinicopathologic and prognostic significance of mesothelin expression in triple negative breast carcinomas (TNBC) has not been fully assessed. We evaluated the expression of mesothelin and of basal markers in tissue microarrays of 226 TNBC and 88 non-TNBC and assessed the clinicopathologic features of mesothelin-expressing breast carcinomas. Furthermore, we investigated the impact of mesothelin expression on the disease-free and overall survival of patients with TNBC. We found that mesothelin expression is significantly more frequent in TNBC than in non-TNBC (36% vs 16%, respectively; p = 0.0006), and is significantly correlated with immunoreactivity for basal keratins, but not for EGFR. Mesothelin-positive and mesothelin-negative TNBC were not significantly different by patients' race, tumor size, histologic grade, tumor subtype, lymphovascular invasion and lymph node metastases. Patients with mesothelin positive TNBC were older than patients with mesothelin-negative TNBC, developed more distant metastases with a shorter interval, and had significantly lower overall and disease-free survival. Based on our results, patients with mesothelin positive TNBC could benefit from mesothelin-targeted therapies. PMID- 25506918 TI - In vivo selection of resistant E. coli after ingestion of milk with added drug residues. AB - Antimicrobial resistance represents a major global threat to modern medicine. In vitro studies have shown that very low concentrations of drugs, as frequently identified in the environment, and in foods and water for human and animal consumption, can select for resistant bacteria. However, limited information is currently available on the in vivo impact of ingested drug residues. The objective of our study was to evaluate the effect of feeding preweaned calves milk containing antimicrobial drug residues (below the minimum inhibitory concentration), similar to concentrations detected in milk commonly fed to dairy calves, on selection of resistant fecal E. coli in calves from birth to weaning. At birth, thirty calves were randomly assigned to a controlled feeding trial where: 15 calves were fed raw milk with no drug residues (NR), and 15 calves were fed raw milk with drug residues (DR) by adding ceftiofur, penicillin, ampicillin, and oxytetracycline at final concentrations in the milk of 0.1, 0.005, 0.01, and 0.3 ug/ml, respectively. Fecal samples were rectally collected from each calf once a week starting at birth prior to the first feeding in the trial (pre treatment) until 6 weeks of age. A significantly greater proportion of E. coli resistant to ampicillin, cefoxitin, ceftiofur, streptomycin and tetracycline was observed in DR calves when compared to NR calves. Additionally, isolates from DR calves had a significant decrease in susceptibility to ceftriaxone and ceftiofur when compared to isolates from NR calves. A greater proportion of E. coli isolates from calves in the DR group were resistant to 3 or more antimicrobial drugs when compared to calves in the ND group. These findings highlight the role that low concentrations of antimicrobial drugs have on the evolution and selection of resistance to multiple antimicrobial drugs in vivo. PMID- 25506921 TI - Maximal standard dose of parenteral iron for hemodialysis patients: an MRI-based decision tree learning analysis. AB - BACKGROUND AND OBJECTIVES: Iron overload used to be considered rare among hemodialysis patients after the advent of erythropoesis-stimulating agents, but recent MRI studies have challenged this view. The aim of this study, based on decision-tree learning and on MRI determination of hepatic iron content, was to identify a noxious pattern of parenteral iron administration in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: We performed a prospective cross-sectional study from 31 January 2005 to 31 August 2013 in the dialysis centre of a French community-based private hospital. A cohort of 199 fit hemodialysis patients free of overt inflammation and malnutrition were treated for anemia with parenteral iron-sucrose and an erythropoesis-stimulating agent (darbepoetin), in keeping with current clinical guidelines. Patients had blinded measurements of hepatic iron stores by means of T1 and T2* contrast MRI, without gadolinium, together with CHi-squared Automatic Interaction Detection (CHAID) analysis. RESULTS: The CHAID algorithm first split the patients according to their monthly infused iron dose, with a single cutoff of 250 mg/month. In the node comprising the 88 hemodialysis patients who received more than 250 mg/month of IV iron, 78 patients had iron overload on MRI (88.6%, 95% CI: 80% to 93%). The odds ratio for hepatic iron overload on MRI was 3.9 (95% CI: 1.81 to 8.4) with >250 mg/month of IV iron as compared to <250 mg/month. Age, gender (female sex) and the hepcidin level also influenced liver iron content on MRI. CONCLUSIONS: The standard maximal amount of iron infused per month should be lowered to 250 mg in order to lessen the risk of dialysis iron overload and to allow safer use of parenteral iron products. PMID- 25506919 TI - Agrin and perlecan mediate tumorigenic processes in oral squamous cell carcinoma. AB - Oral squamous cell carcinoma is the most common type of cancer in the oral cavity, representing more than 90% of all oral cancers. The characterization of altered molecules in oral cancer is essential to understand molecular mechanisms underlying tumor progression as well as to contribute to cancer biomarker and therapeutic target discovery. Proteoglycans are key molecular effectors of cell surface and pericellular microenvironments, performing multiple functions in cancer. Two of the major basement membrane proteoglycans, agrin and perlecan, were investigated in this study regarding their role in oral cancer. Using real time quantitative PCR (qRT-PCR), we showed that agrin and perlecan are highly expressed in oral squamous cell carcinoma. Interestingly, cell lines originated from distinct sites showed different expression of agrin and perlecan. Enzymatically targeting chondroitin sulfate modification by chondroitinase, oral squamous carcinoma cell line had a reduced ability to adhere to extracellular matrix proteins and increased sensibility to cisplatin. Additionally, knockdown of agrin and perlecan promoted a decrease on cell migration and adhesion, and on resistance of cells to cisplatin. Our study showed, for the first time, a negative regulation on oral cancer-associated events by either targeting chondroitin sulfate content or agrin and perlecan levels. PMID- 25506922 TI - Subcellular metabolite and lipid analysis of Xenopus laevis eggs by LAESI mass spectrometry. AB - Xenopus laevis eggs are used as a biological model system for studying fertilization and early embryonic development in vertebrates. Most methods used for their molecular analysis require elaborate sample preparation including separate protocols for the water soluble and lipid components. In this study, laser ablation electrospray ionization (LAESI), an ambient ionization technique, was used for direct mass spectrometric analysis of X. laevis eggs and early stage embryos up to five cleavage cycles. Single unfertilized and fertilized eggs, their animal and vegetal poles, and embryos through the 32-cell stage were analyzed. Fifty two small metabolite ions, including glutathione, GABA and amino acids, as well as numerous lipids including 14 fatty acids, 13 lysophosphatidylcholines, 36 phosphatidylcholines and 29 triacylglycerols were putatively identified. Additionally, some proteins, for example thymosin beta4 (Xen), were also detected. On the subcellular level, the lipid profiles were found to differ between the animal and vegetal poles of the eggs. Radial profiling revealed profound compositional differences between the jelly coat vitelline/plasma membrane and egg cytoplasm. Changes in the metabolic profile of the egg following fertilization, e.g., the decline of polyamine content with the development of the embryo were observed using LAESI-MS. This approach enables the exploration of metabolic and lipid changes during the early stages of embryogenesis. PMID- 25506924 TI - Aberrant expression of shared master-key genes contributes to the immunopathogenesis in patients with juvenile spondyloarthritis. AB - Association of juvenile spondyloarthritis (jSpA) with the HLA-B27 genotype is well established, but there is little knowledge of other genetic factors with a role in the development of the disease. To date, only a few studies have tried to find those associated genes by obtaining expression profiles, but with inconsistent results due to various patient selection criteria and methodology. The aim of the present study was to identify and confirm gene signatures and novel biomarkers in highly homogeneous cohorts of untreated and treated patients diagnosed with jSpA and other forms of juvenile idiopathic arthritis (JIA) according to ILAR criteria. For the purposes of the research, total RNA was isolated from whole blood of 45 children with jSpA and known HLA genotype, 11 children with oligo- and polyarticular forms of JIA, as well as 12 age and sex matched control participants without diagnosis of inflammatory disease. DNA microarray gene expression was performed in 11 patients with jSpA and in four healthy controls, along with bioinformatical analysis of retrieved data. Carefully selected differentially expressed genes where analyzed by qRT-PCR in all participants of the study. Microarray results and bioinformatical analysis revealed 745 differentially expressed genes involved in various inflammatory processes, while qRT-PCR analysis of selected genes confirmed data universality and specificity of expression profiles in jSpA patients. The present study indicates that jSpA could be a polygenic disease with a possible malfunction in antigen recognition and activation of immunological response, migration of inflammatory cells and regulation of the immune system. Among genes involved in these processes TLR4, NLRP3, CXCR4 and PTPN12 showed almost consistent expression in study patients diagnosed with jSpA. Those genes and their products could therefore potentially be used as novel biomarkers, possibly predictive of disease prognosis and response to therapy, or even as a target for new therapeutic approaches. PMID- 25506926 TI - Temporal changes in population structure of a marine planktonic diatom. AB - A prevailing question in phytoplankton research addresses changes of genetic diversity in the face of huge population sizes and apparently unlimited dispersal capabilities. We investigated population genetic structure of the pennate planktonic marine diatom Pseudo-nitzschia multistriata at the LTER station MareChiara in the Gulf of Naples (Italy) over four consecutive years and explored possible changes over seasons and from year to year. A total of 525 strains were genotyped using seven microsatellite markers, for a genotypic diversity of 75.05%, comparable to that found in other Pseudo-nitzschia species. Evidence from Bayesian clustering analysis (BA) identified two genetically distinct clusters, here interpreted as populations, and several strains that could not be assigned with >= 90% probability to either population, here interpreted as putative hybrids. Principal Component Analysis (PCA) recovered these two clusters in distinct clouds with most of the putative hybrids located in-between. Relative proportions of the two populations and the putative hybrids remained similar within years, but changed radically between 2008 and 2009 and between 2010 and 2011, when the 2008-population apparently became the dominant one again. Strains from the two populations are inter-fertile, and so is their offspring. Inclusion of genotypes of parental strains and their offspring shows that the majority of the latter could not be assigned to any of the two parental populations. Therefore, field strains classified by BA as the putative hybrids could be biological hybrids. We hypothesize that P. multistriata population dynamics in the Gulf of Naples follows a meta-population-like model, including establishment of populations by cell inocula at the beginning of each growth season and remixing and dispersal governed by moving and mildly turbulent water masses. PMID- 25506925 TI - Functional interaction between cyclooxygenase-2 and p53 in response to an endogenous electrophile. AB - Cyclooxygenase-2 (Cox-2) is rapidly expressed by various stimuli and plays a key role in conversion of free arachidonic acid to prostaglandins. We have previously identified 4-hydroxy-2-nonenal (HNE), a lipid peroxidation-derived electrophile, as the potent Cox-2 inducer in rat epithelial RL34 cells and revealed that the HNE-induced Cox-2 expression resulted from the stabilization of Cox-2 mRNA that is mediated by the p38 mitogen-activated protein kinase signaling pathway. In the present study, we investigated an alternative regulatory mechanism of Cox-2 expression mediated by a transcription factor p53. In addition, to characterize the causal role for Cox-2, we examined the effects of Cox-2 overexpression in RL34 cells. To examine whether the HNE-induced Cox-2 expression was mechanistically linked to the p53 expression, we analyzed changes in Cox-2 and p53 expression levels in response to HNE and observed that the Cox-2 levels were inversely correlated with the p53 levels. Down-regulation of p53 followed by the activation of a transcription factor Sp1 was suggested to be involved in the HNE induced Cox-2 gene expression. To characterize the effect of Cox-2 expression in the cells, we established the Cox-2-overexpressing derivatives of RL34 cells by stable transfection with Cox-2 cDNA. An oligonucleotide microarray analysis revealed a dramatic down-regulation of the proteasome subunit RC1 in the Cox-2 overexpressed cells compared to the empty-vector transfected control cells. Consistent with the Cox-2-mediated down-regulation of proteasome, a moderate reduction of the proteasome activities was observed. This proteasome dysfunction mediated by the Cox-2 overproduction was associated with the enhanced accumulation of p53 and ubiquitinated proteins, leading to the enhanced sensitivity toward electrophiles. These results suggest the existence of a causal link between Cox-2 and p53, which may represent a toxic mechanism of electrophilic lipid peroxidation products. PMID- 25506928 TI - Preparation, pharmacokinetics, biodistribution, antitumor efficacy and safety of Lx2-32c-containing liposome. AB - Lx2-32c is a novel taxane that has been demonstrated to have robust antitumor activity against different types of tumors including several paclitaxel-resistant neoplasms. Since the delivery vehicles for taxane, which include cremophor EL, are all associated with severe toxic effects, liposome-based Lx2-32c has been developed. In the present study, the pharmacokinetics, biodistribution, antitumor efficacy and safety characteristics of liposome-based Lx2-32c were explored and compared with those of cremophor-based Lx2-32c. The results showed that liposome based Lx2-32c displayed similar antitumor effects to cremophor-based Lx2-32c, but with significantly lower bone marrow toxicity and cardiotoxicity, especially with regard to the low ratio of hypersensitivity reaction. In comparing these two delivery modalities, targeting was superior using the Lx2-32c liposome formulation; it achieved significantly higher uptake in tumor than in bone marrow and heart. Our data thus suggested that the Lx2-32c liposome was a novel alternative formulation with comparable antitumor efficacy and a superior safety profiles to cremophor-based Lx2-32c, which might be related to the improved pharmacokinetic and biodistribution characteristics. In conclusion, the Lx2-32c liposome could be a promising alternative formulation for further development. PMID- 25506927 TI - MTO1-deficient mouse model mirrors the human phenotype showing complex I defect and cardiomyopathy. AB - Recently, mutations in the mitochondrial translation optimization factor 1 gene (MTO1) were identified as causative in children with hypertrophic cardiomyopathy, lactic acidosis and respiratory chain defect. Here, we describe an MTO1-deficient mouse model generated by gene trap mutagenesis that mirrors the human phenotype remarkably well. As in patients, the most prominent signs and symptoms were cardiovascular and included bradycardia and cardiomyopathy. In addition, the mutant mice showed a marked worsening of arrhythmias during induction and reversal of anaesthesia. The detailed morphological and biochemical workup of murine hearts indicated that the myocardial damage was due to complex I deficiency and mitochondrial dysfunction. In contrast, neurological examination was largely normal in Mto1-deficient mice. A translational consequence of this mouse model may be to caution against anaesthesia-related cardiac arrhythmias which may be fatal in patients. PMID- 25506929 TI - Mitochondrial COI and 16sRNA evidence for a single species hypothesis of E. vitis, J. formosana and E. onukii in East Asia. AB - Tea green leafhopper is one of the most damaging tea pests in main tea production regions of East Asia. For lack of recognized morphological characters, the dominant species of tea green leafhoppers in Mainland China, Taiwan and Japan have always been named as Empoasca vitis Gothe, Jacobiasca formosana Paoli and Empoasca onukii MATSUDA, respectively. Furthermore, nothing is known about the genetic relationships among them. In this study, we collected six populations from Mainland China, four populations from Japan and one population from Taiwan, and examined the genetic distances in the COI and 16sRNA regions of mtDNA among them. The results showed that the genetic distances based on single gene or the combined sequences among eleven leafhopper populations were 0.3-1.2%, which were all less than the species boundary of 2%. Moreover, there were at least two haplotypes shared by two distinct populations from different regions. The phylogenetic analysis based on single gene or combined sets also supported that tea green leafhoppers from Mainland China, Taiwan and Japan were closely related to each other, and there were at least two specimens from different regions clustered ahead of those from the same region. Therefore, we propose that the view of recognizing the dominant species of tea green leafhoppers in three adjacent tea production regions of East Asia as different species is unreliable or questionable and suggest that they are a single species. PMID- 25506931 TI - A new apparatus for standardized rat kidney biopsy. AB - Survival biopsies are frequently applied in rat kidney disease models, but several drawbacks such as surgical kidney trauma, bleeding risk and variable loss of kidney tissue are still unsolved. Therefore, we developed an easy-to-use core biopsy instrument and evaluated whether two consecutive kidney biopsies within the same kidney can be carried out in a standardized manner. On day 0, 18 Lewis rats underwent a right nephrectomy and 9 of these rats a subsequent first biopsy of the left kidney (Bx group). 9 control rats had a sham biopsy of the left kidney (Ctrl group). On day 7, a second kidney biopsy/sham biopsy was performed. On day 42, all animals were sacrificed and their kidneys were removed for histology. Biopsy cylinders contained 57+/-28 glomeruli per transversal section, representing an adequate sample size. PAS staining showed that the biopsy depth was limited to the renal cortex whereas surgical tissue damage was limited to the area immediately adjacent to the taken biopsy cylinder. On day 42, the reduction of functional renal mass after two biopsies was only 5.2% and no differences of body weight, blood pressure, proteinuria, serum creatinine, glomerulosclerosis, interstitial fibrosis or number of ED-1 positive macrophages were found between both groups. In summary, our apparatus offers a safe method to perform repetitive kidney biopsies with minimal trauma and sufficient sample size and quality even in experimental disease models restricted to one single kidney. PMID- 25506932 TI - Evodiamine induces G2/M arrest and apoptosis via mitochondrial and endoplasmic reticulum pathways in H446 and H1688 human small-cell lung cancer cells. AB - The goal of this study was to evaluate the ability of EVO to decrease cell viability and promote cell cycle arrest and apoptosis in small cell lung cancer (SCLC) cells. Lung cancer has the highest incidence and mortality rates among all cancers. Chemotherapy is the primary treatment for SCLC; however, the drugs that are currently used for SCLC are less effective than those used for non-small cell lung cancer (NSCLC). Therefore, it is necessary to develop new drugs to treat SCLC. In this study, the effects of evodiamine (EVO) on cell growth, cell cycle arrest and apoptosis were investigated in the human SCLC cell lines NCI-H446 and NCI-H1688. The results represent the first report that EVO can significantly inhibit the viability of both H446 and H1688 cells in dose- and time-dependent manners. EVO induced cell cycle arrest at G2/M phase, induced apoptosis by up regulating the expression of caspase-12 and cytochrome C protein, and induced the expression of Bax mRNA and by down-regulating of the expression of Bcl-2 mRNA in both H446 and H1688 cells. However, there was no effect on the protein expression of caspase-8. Taken together, the inhibitory effects of EVO on the growth of H446 and H1688 cells might be attributable to G2/M arrest and subsequent apoptosis, through mitochondria-dependent and endoplasmic reticulum stress-induced pathways (intrinsic caspase-dependent pathways) but not through the death receptor-induced pathway (extrinsic caspase-dependent pathway). Our findings suggest that EVO is a promising novel and potent antitumor drug candidate for SCLC. Furthermore, the cell cycle, the mitochondria and the ER stress pathways are rational targets for the future development of an EVO delivery system to treat SCLC. PMID- 25506933 TI - Healthy dietary interventions and lipoprotein (a) plasma levels: results from the Omni Heart Trial. AB - BACKGROUND: Increased lipoprotein(a) [Lp(a)] levels are associated with atherosclerotic cardiovascular disease. Studies of dietary interventions on changes in Lp(a) are sparse. We aimed to compare the effects of three healthy dietary interventions differing in macronutrient content on Lp(a) concentration. METHODS: Secondary analysis of a randomized, 3-period crossover feeding study including 155 (89 blacks; 66 whites) individuals. Participants were given DASH type healthy diets rich in carbohydrates [Carb], in protein [Prot] or in unsaturated fat [Unsat Fat] for 6 weeks each. Plasma Lp(a) concentration was assessed at baseline and after each diet. RESULTS: Compared to baseline, all interventional diets increased mean Lp(a) by 2 to 5 mg/dl. Unsat Fat increased Lp(a) less than Prot with a difference of 1.0 mg/dl (95% CI, -0.5, 2.5; p = 0.196) in whites and 3.7 mg/dl (95% CI, 2.4, 5.0; p < 0.001) in blacks (p-value between races = 0.008); Unsat Fat increased Lp(a) less than Carb with a difference of -0.6 mg/dl, 95% CI, -2.1, 0.9; p = 0.441) in whites and -1.5 mg/dl (95% CI, -0.2, -2.8; p = 0.021) in blacks (p-value between races = 0.354). Prot increased Lp(a) more than Carb with a difference of 0.4 mg/dl (95% CI, -1.1, 1.9; p = 0.597) in whites and 2.2 mg/dl (95%CI, 0.9, 3.5; p = 0.001) in blacks (p value between races = 0.082). CONCLUSION: Diets high in unsaturated fat increased Lp(a) levels less than diets rich in carbohydrate or protein with greater changes in blacks than whites. Our results suggest that substitutions with dietary mono- and polyunsaturated fatty acids in healthy diets may be preferable over protein or carbohydrates with regards to Lp(a). TRIAL REGISTRATION: Clinicaltrials.gov NCT00051350. PMID- 25506934 TI - Dietary habits in patients with ischemic stroke: a case-control study. AB - BACKGROUND AND AIMS: Diet appears to have some role in stroke development. The objective of our study was to describe the dietary habits in patients admitted with acute ischemic stroke and compare selected dietary components with healthy controls. Adherence to healthy diet behaviors was also assessed. METHODS: A case control study of consecutive patients with acute ischemic stroke admitted to the Neurology Department of Hospital del Mar from 2007 to 2010. Patients were matched by age and sex with control subjects. A previously validated nutritional survey was administered to patients and controls. Demographic data, vascular risk factors, caloric intake and dietary nutrients were evaluated. Intention to follow a healthy diet was also assessed in both groups. RESULTS: A total of 300 acute ischemic stroke patients and 300 controls with evaluation of dietary habits. No differences were observed in vascular risk factors, except smoking habit, diabetes and ischemic heart disease. Stroke patients reported a higher caloric intake: 2444.8(1736.8-3244.5) vs 2208.7(1753.1-2860.7) Kcal, p = 0.001. After adjusting for energy intake, patients had higher intake of proteins (p<0.001; OR 1.02), total cholesterol (p = 0.001; OR 1.04), and breaded foods (p = 0.001; OR 1.94) and lower consumption of probiotic yogurt (p = 0.002; OR 0.88). Compared to patients, control participants indicated greater intention to eat vegetables (p = 0.002; OR 1.5) and whole foods (p = 0.000; OR 2.4) and reduce their intake of salt (p = 0.002; OR 1.7), fat (p = 0.000; OR 3.7) and sweets (p = 0.004; OR 1.7) than patients. CONCLUSION: We observed different dietary patterns between stroke patients and controls. Stroke patients have a higher caloric intake and are less concerned about maintaining healthy nutritional habits. PMID- 25506935 TI - An integrative computational approach for prioritization of genomic variants. AB - An essential step in the discovery of molecular mechanisms contributing to disease phenotypes and efficient experimental planning is the development of weighted hypotheses that estimate the functional effects of sequence variants discovered by high-throughput genomics. With the increasing specialization of the bioinformatics resources, creating analytical workflows that seamlessly integrate data and bioinformatics tools developed by multiple groups becomes inevitable. Here we present a case study of a use of the distributed analytical environment integrating four complementary specialized resources, namely the Lynx platform, VISTA RViewer, the Developmental Brain Disorders Database (DBDB), and the RaptorX server, for the identification of high-confidence candidate genes contributing to pathogenesis of spina bifida. The analysis resulted in prediction and validation of deleterious mutations in the SLC19A placental transporter in mothers of the affected children that causes narrowing of the outlet channel and therefore leads to the reduced folate permeation rate. The described approach also enabled correct identification of several genes, previously shown to contribute to pathogenesis of spina bifida, and suggestion of additional genes for experimental validations. The study demonstrates that the seamless integration of bioinformatics resources enables fast and efficient prioritization and characterization of genomic factors and molecular networks contributing to the phenotypes of interest. PMID- 25506937 TI - On cross-sectional associations of leukocyte telomere length with cardiac systolic, diastolic and vascular function: the Asklepios study. AB - BACKGROUND: Systemic telomere length has been associated with measures of diastolic function, vascular stiffness and left ventricular mass mainly in smaller, patient-specific settings and not in a general population. In this study we describe the applicability of these findings in a large, representative population. METHODS AND RESULTS: Peripheral blood leukocyte telomere length (PBL TL) was measured using telomere restriction fragment analysis in the young to middle-aged (>2500 volunteers, ~35 to 55 years old) Asklepios study population, free from overt cardiovascular disease. Subjects underwent extensive echocardiographic, hemodynamic and biochemical phenotyping. After adjusting for relevant confounders (age, sex, systolic blood pressure, heart rate, body mass index and use of antihypertensive drugs) we found no associations between PBL TL and left ventricular mass index (P = 0.943), ejection fraction (P = 0.933), peak systolic septal annular motion (P = 0.238), pulse wave velocity (P = 0.971) or pulse pressure (P = 0.999). In contrast, our data showed positive associations between PBL TL and parameters of LV filling: the transmitral flow early (E) to late (A) velocity ratio (E/A-ratio; P<0.001), the ratio of early (e') to late (a') mitral annular velocities (e'/a'-ratio; P = 0.012) and isovolumic relaxation time (P = 0.015). Interestingly, these associations were stronger in women than in men and were driven by associations between PBL TL and the late diastolic components (A and a'). CONCLUSIONS: In a generally healthy, young to middle-aged population, PBL TL is not related to LV mass or systolic function, but might be associated with an altered LV filling pattern, especially in women. PMID- 25506938 TI - Nutrients differentially regulate nucleobindin-2/nesfatin-1 in vitro in cultured stomach ghrelinoma (MGN3-1) cells and in vivo in male mice. AB - Nesfatin-1 is secreted, meal-responsive anorexigenic peptide encoded in the precursor nucleobindin-2 [NUCB2]. Circulating nesfatin-1 increases post prandially, but the dietary components that modulate NUCB2/nesfatin-1 remain unknown. We hypothesized that carbohydrate, fat and protein differentially regulate tissue specific expression of nesfatin-1. NUCB2, prohormone convertases and nesfatin-1 were detected in mouse stomach ghrelinoma [MGN3-1] cells. NUCB2 mRNA and protein were also detected in mouse liver, and small and large intestines. MGN3-1 cells were treated with glucose, fatty acids or amino acids. Male C57BL/6 mice were chronically fed high fat, high carbohydrate and high protein diets for 17 weeks. Quantitative PCR and nesfatin-1 assays were used to determine nesfatin-1 at mRNA and protein levels. Glucose stimulated NUCB2 mRNA expression in MGN3-1 cells. L-Tryptophan also increased NUCB2 mRNA expression and ghrelin mRNA expression, and nesfatin-1 secretion. Oleic acid inhibited NUCB2 mRNA expression, while ghrelin mRNA expression and secretion was enhanced. NUCB2 mRNA expression was significantly lower in the liver of mice fed a high protein diet compared to mice fed other diets. Chronic intake of high fat diet caused a significant reduction in NUCB2 mRNA in the stomach, while high protein and high fat diet caused similar suppression of NUCB2 mRNA in the large intestine. No differences in serum nesfatin-1 levels were found in mice at 7 a.m, at the commencement of the light phase. High carbohydrate diet fed mice showed significantly elevated nesfatin-1 levels at 1 p.m. Serum nesfatin-1 was significantly lower in mice fed high fat, protein or carbohydrate compared to the controls at 7 p.m, just prior to the dark phase. Mice that received a bolus of high fat had significantly elevated nesfatin-1/NUCB2 at all time points tested post-gavage, compared to control mice and mice fed other diets. Our results for the first time indicate that nesfatin-1 is modulated by nutrients. PMID- 25506936 TI - The antipsychotic olanzapine interacts with the gut microbiome to cause weight gain in mouse. AB - The second-generation antipsychotic olanzapine is effective in reducing psychotic symptoms but can cause extreme weight gain in human patients. We investigated the role of the gut microbiota in this adverse drug effect using a mouse model. First, we used germ-free C57BL/6J mice to demonstrate that gut bacteria are necessary and sufficient for weight gain caused by oral delivery of olanzapine. Second, we surveyed fecal microbiota before, during, and after treatment and found that olanzapine potentiated a shift towards an "obesogenic" bacterial profile. Finally, we demonstrated that olanzapine has antimicrobial activity in vitro against resident enteric bacterial strains. These results collectively provide strong evidence for a mechanism underlying olanzapine-induced weight gain in mouse and a hypothesis for clinical translation in human patients. PMID- 25506939 TI - Computational analysis and mapping of novel open reading frames in influenza A viruses. AB - The influenza A virus contains 8 segmented genomic RNAs and was considered to encode 10 viral proteins until investigators identified the 11th viral protein, PB1-F2, which uses an alternative reading frame of the PB1 gene. The recently identified PB1-N40, PA-N155 and PA-N182 influenza A proteins have shown the potential for using a leaking ribosomal scanning mechanism to generate novel open reading frames (ORFs). These novel ORFs provide examples of the manner in which the influenza A virus expands its coding capacity by using overlapping reading frames. In this study, we performed a computational search, based on a ribosome scanning mechanism, on all influenza A coding sequences to identify possible forward-reading ORFs that could be translated into novel viral proteins. We specified that the translated products had a prevalence >=5% to eliminate sporadic ORFs. A total of 1,982 ORFs were thus identified and presented in terms of their locations, lengths and Kozak sequence strengths. We further provided an abridged list of ORFs by requiring every candidate an upstream start codon (within the upstream third of the primary transcript), a strong Kozak consensus sequence and high prevalence (>=95% and >=50% for in-frame and alternative-frame ORFs, respectively). The PB1-F2, PB1-N40, PA-N155 and PA-N182 proteins all fulfilled our filtering criteria. Subject to these three stringent settings, we additionally named 16 novel ORFs for all influenza A genomes except for HA and NA, for which 43 HA and 11 NA ORFs from their respective subtypes were also recognized. PMID- 25506941 TI - Amino alcohol- (NPS-2143) and quinazolinone-derived calcilytics (ATF936 and AXT914) differentially mitigate excessive signalling of calcium-sensing receptor mutants causing Bartter syndrome Type 5 and autosomal dominant hypocalcemia. AB - INTRODUCTION: Activating calcium sensing receptor (CaSR) mutations cause autosomal dominant hypocalcemia (ADH) characterized by low serum calcium, inappropriately low PTH and relative hypercalciuria. Four activating CaSR mutations cause additional renal wasting of sodium, chloride and other salts, a condition called Bartter syndrome (BS) type 5. Until today there is no specific medical treatment for BS type 5 and ADH. We investigated the effects of different allosteric CaSR antagonists (calcilytics) on activating CaSR mutants. METHODS: All 4 known mutations causing BS type 5 and five ADH mutations were expressed in HEK 293T cells and receptor signalling was studied by measurement of intracellular free calcium in response to extracellular calcium ([Ca2+]o). To investigate the effect of calcilytics, cells were stimulated with 3 mM [Ca2+]o in the presence or absence of NPS-2143, ATF936 or AXT914. RESULTS: All BS type 5 and ADH mutants showed enhanced signalling activity to [Ca2+]o with left shifted dose response curves. In contrast to the amino alcohol NPS-2143, which was only partially effective, the quinazolinone calcilytics ATF936 and AXT914 significantly mitigated excessive cytosolic calcium signalling of all BS type 5 and ADH mutants studied. When these mutants were co-expressed with wild-type CaSR to approximate heterozygosity in patients, ATF936 and AXT914 were also effective on all mutants. CONCLUSION: The calcilytics ATF936 and AXT914 are capable of attenuating enhanced cytosolic calcium signalling activity of CaSR mutations causing BS type 5 and ADH. Quinazolinone calcilytics might therefore offer a novel treatment option for patients with activating CaSR mutations. PMID- 25506943 TI - Identification of neonatal white matter on DTI: influence of more inclusive thresholds for atlas segmentation. AB - PURPOSE: Semi-automated diffusion tensor imaging (DTI) analysis of white matter (WM) microstructure offers a clinically feasible technique to assess neonatal brain development and provide early prognosis, but is limited by variable methods and insufficient evidence regarding optimal parameters. The purpose of this research was to investigate the influence of threshold values on semi-automated, atlas-based brain segmentation in very-low-birth-weight (VLBW) preterm infants at near-term age. MATERIALS AND METHODS: DTI scans were analyzed from 45 VLBW preterm neonates at near-term-age with no brain abnormalities evident on MRI. Brain regions were selected with a neonatal brain atlas and threshold values: trace <0.006 mm2/s, fractional anisotropy (FA)>0.15, FA>0.20, and FA>0.25. Relative regional volumes, FA, axial diffusivity (AD), and radial diffusivity (RD) were compared for twelve WM regions. RESULTS: Near-term brain regions demonstrated differential effects from segmentation with the three FA thresholds. Regional DTI values and volumes selected in the PLIC, CereP, and RLC varied the least with the application of different FA thresholds. Overall, application of higher FA thresholds significantly reduced brain region volume selected, increased variability, and resulted in higher FA and lower RD values. The lower threshold FA>0.15 selected 78+/-21% of original volumes segmented by the atlas, compared to 38+/-12% using threshold FA>0.25. CONCLUSION: Results indicate substantial and differential effects of atlas-based DTI threshold parameters on regional volume and diffusion scalars. A lower, more inclusive FA threshold than typically applied for adults is suggested for consistent analysis of WM regions in neonates. PMID- 25506944 TI - Comparison of modic changes in the lumbar and cervical spine, in 3167 patients with and without spinal pain. AB - BACKGROUND CONTEXT: There are few comparisons of Modic changes (MCs) in the lumbar and cervical spine. PURPOSE: Compare the prevalence of MCs in the lumbar and cervical spine, and determine how MC prevalence depends on spinal pain, age, disc degeneration, spinal level, and the presence or absence of kyphosis. STUDY DESIGN: Retrospective clinical survey. MATERIALS AND METHODS: Magnetic resonance images (MRIs) were compared from five patient groups: 1. 1223 patients with low back pain/radiculopathy only; 2. 1023 patients with neck pain/radiculopathy only; 3. 497 patients with concurrent low-back and neck symptoms; 4. 304 asymptomatic subjects with lumbar MRIs; and 5. 120 asymptomatic subjects with cervical MRIs. RESULTS: The prevalence of MCs was higher in those with spinal pain than in those without, both in the lumbar spine (21.0% vs 10.5%) and cervical spine (8.8% vs 3.3%). Type II MCs were most common and Type III were least common in all groups. The prevalence of lumbar MCs in people with back pain was little affected by the presence of concurrent neck pain, and the same was true for the prevalence of cervical MCs in people with neck pain with or without concurrent back pain. When symptomatic patients were reclassified into two groups (back pain, neck pain), the prevalence of lumbar MCs in people with back pain was greater than that of cervical MCs in people with neck pain. The prevalence of lumbar and cervical MCs increased with age, disc degeneration, (descending) spinal level, and increased kyphosis. CONCLUSIONS: There is a significantly higher prevalence of MCs in patients with back and neck pain. The reported association with increased kyphosis (flat back) is novel. PMID- 25506945 TI - Light-promoted rhodopsin expression and starvation survival in the marine dinoflagellate Oxyrrhis marina. AB - The discovery of microbial rhodopsins in marine proteobacteria changed the dogma that photosynthesis is the only pathway to use the solar energy for biological utilization in the marine environment. Although homologs of these rhodopsins have been identified in dinoflagellates, the diversity of the encoding genes and their physiological roles remain unexplored. As an initial step toward addressing the gap, we conducted high-throughput transcriptome sequencing on Oxyrrhis marina to retrieve rhodopsin transcripts, rapid amplification of cDNA ends to isolate full length cDNAs of dominant representatives, and quantitative reverse-transcription PCR to investigate their expression under varying conditions. Our phylogenetic analyses showed that O. marina contained both the proton-pumping type (PR) and sensory type (SR) rhodopsins, and the transcriptome data showed that the PR type dominated over the SR type. We compared rhodopsin gene expression for cultures kept under light: dark cycle and continuous darkness in a time course of 24 days without feeding. Although both types of rhodopsin were expressed under the two conditions, the expression levels of PR were much higher than SR, consistent with the transcriptomic data. Furthermore, relative to cultures kept in the dark, rhodopsin expression levels and cell survival rate were both higher in cultures grown in the light. This is the first report of light-dependent promotion of starvation survival and concomitant promotion of PR expression in a eukaryote. While direct evidence needs to come from functional test on rhodopsins in vitro or gene knockout/knockdown experiments, our results suggest that the proton pumping rhodopsin might be responsible for the light-enhanced survival of O. marina, as previously demonstrated in bacteria. PMID- 25506976 TI - Contemporary immunology: placing the controversies in abeyance. PMID- 25506975 TI - Authors' reply. PMID- 25506987 TI - Keys to success for buyers. PMID- 25506986 TI - Keys to success for owners. PMID- 25506946 TI - Expression and activity of acid-sensing ion channels in the mouse anterior pituitary. AB - Acid sensing ion channels (ASICs) are proton-gated cation channels that are expressed in the nervous system and play an important role in fear learning and memory. The function of ASICs in the pituitary, an endocrine gland that contributes to emotions, is unknown. We sought to investigate which ASIC subunits were present in the pituitary and found mRNA expression for all ASIC isoforms, including ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3 and ASIC4. We also observed acid evoked ASIC-like currents in isolated anterior pituitary cells that were absent in mice lacking ASIC1a. The biophysical properties and the responses to PcTx1, amiloride, Ca2+ and Zn2+ suggested that ASIC currents were mediated predominantly by heteromultimeric channels that contained ASIC1a and ASIC2a or ASIC2b. ASIC currents were also sensitive to FMRFamide (Phe-Met-Arg-Phe amide), suggesting that FMRFamide-like compounds might endogenously regulate pituitary ASICs. To determine whether ASICs might regulate pituitary cell function, we applied low pH and found that it increased the intracellular Ca2+ concentration. These data suggest that ASIC channels are present and functionally active in anterior pituitary cells and may therefore influence their function. PMID- 25506989 TI - Exhibition gains momentum. PMID- 25506988 TI - Novel program matching retirees with new owners. PMID- 25506990 TI - New Auxiliary president pays forward her appreciation. PMID- 25506991 TI - Targeted feral cat sterilization yields lower euthanasia rates. PMID- 25506992 TI - Animals can be considered crime victims in Oregon. PMID- 25506993 TI - Study finds Listeria in raw pet foods. PMID- 25506994 TI - FDA warns makers of unapproved 'tear stain' products. PMID- 25506995 TI - Arizona veterinary program secures funding. PMID- 25506996 TI - The authors respond. PMID- 25507172 TI - [Why do patients discontinue their drugs?]. AB - BACKGROUND: Preventing or treating an illness just as avoiding its complications depend on the proper continuity of the intake of medication. Patients who discontinue their drugs unilaterally could call the resuIt of treatment into question. METHODS: Practising doctors who have the patients' trust asked, whether patients had discontinued their drugsandwhytheydidso. RESULTS: 250 patients from 19 doctors' offices admitted having discontinued, 54.8% of them because of adverse drug reactions, and 45.2% because of other reasons. Most of the adverse drug reactions were listed in the prescribing information, but there were also adverse events, which were not listet, and which could have a signal effect. Patients named a lot of different reasons for discontinuation not related to adverse drug reactions. The reasons were comprehensible and possibly could be avoided. CONCLUSION: Physicians should call attention to possible adverse events and should show up a benefit-risk profile. Reasons for discontinuation different from adverse drug reactions require physicians' efforts, but also help from family members, pharmacist, health insurance and health authority. PMID- 25507173 TI - [The Oncologic and Palliative Network Landshut: a problem-solving approach to oncological and palliative care in structurally weak rural areas, with special emphasis on outpatient and inpatient networking]. AB - The Oncologic and Palliative Network Landshut is a problem-solving approach to structurally weak rural areas to improve an a dequate care of critically ill patients, especially by a close involvement of outpatient and inpatient care providers. These networks not only improve the medical and nursing care of patients, but can also be cost-effective. PMID- 25507177 TI - [In Process Citation]. PMID- 25507176 TI - [Relevance of strong-acting opioids from a medical practitioner's point of view. Results of a cross-sectional survey of 4,283 opioid prescribing physicians]. PMID- 25507175 TI - [Daytime flexible application of Insulin degludec in patients with type 1 diabetes or type 2 diabetes]. AB - BACKGROUND: Insulin degludec (IDeg) is a basal insulin with a stable, flat action profile and an even distribution of the blood glucose lowering effect over 24 hou rs. The terminal half-life of IDeg is about 25 hours, which reflects a mean prolongation by factor 2 compared to Insulin glargin (lGlar).This may enable for a more flexible daytime dosing versus up to now available basal insulins. METHOD: Two open, randomized, treat-to-target studies enrolled patients with type 1 diabetes (n =493) or type 2 diabetes (n = 687). Both phase 3 studies compared a daytime flexible dosing of IDeg (IDeg-flex) with IDeg at the evening meal (IDeg evening) and IDler at a fixed daytime. In the IDeg-flex-group dosing intervals were predefined with variations between 8 and 40 hours. RESULTS: In patients with type 1 diabetes IDeg-flex proved to be non-inferior with respect to reduction of HbA1C (-0.40%) versus IDeg-evening (-0.41%) and IGlar (-0.58%) after 26 weeks. In addition, nocturnal hypoglycemic events were reduced by 40% (p < 0.01) with IDeg flex versus IGlar. In patients with type 2 diabetes reduction of HbA1C with ID)eg flex (-1.28%) was non-inferior to IDeg-evening (-1.07%) and IGlar (-1.26%), respectively, whereas rates for hypoglycemia were comparable. CONCLUSION: Patients with diabetes mellitus are enabled to dose a basal insulin flexibly when needed (minimum interval of 8 hours afterthe last injection is necessary). Impacts of this treatment option on quality of life and adherence and outcomes should be examined in observational trials. PMID- 25507178 TI - [In Process Citation]. PMID- 25507179 TI - [In Process Citation]. PMID- 25507180 TI - [In Process Citation]. PMID- 25507181 TI - [In Process Citation]. PMID- 25507182 TI - [In Process Citation]. PMID- 25507183 TI - [In Process Citation]. PMID- 25507184 TI - [In Process Citation]. PMID- 25507185 TI - [In Process Citation]. PMID- 25507186 TI - [In Process Citation]. PMID- 25507187 TI - [In Process Citation]. PMID- 25507188 TI - [In Process Citation]. PMID- 25507190 TI - [In Process Citation]. PMID- 25507191 TI - [In Process Citation]. PMID- 25507189 TI - [In Process Citation]. PMID- 25507192 TI - [In Process Citation]. PMID- 25507193 TI - [In Process Citation]. PMID- 25507195 TI - [In Process Citation]. PMID- 25507194 TI - [In Process Citation]. PMID- 25507196 TI - [In Process Citation]. PMID- 25507197 TI - [In Process Citation]. PMID- 25507198 TI - [In Process Citation]. PMID- 25507200 TI - [In Process Citation]. PMID- 25507199 TI - [In Process Citation]. PMID- 25507201 TI - [Surgical treatment of degenerative hip disease: when to preserve the joint, when to replace it]. PMID- 25507202 TI - [Joint preserving surgical treatment of degenerative hip diseases]. PMID- 25507204 TI - [Scrotal calcinosis]. PMID- 25507203 TI - [Surgical treatment of degenerative hip disease--joint replacement]. PMID- 25507206 TI - [How to unravel hyperaldosteronism in clinical practice]. PMID- 25507205 TI - [Calcific tendinitis of the shoulder: operative and nonoperative treatment options]. PMID- 25507207 TI - [Emergency checklist: rectal bleeding]. PMID- 25507209 TI - [In Process Citation]. PMID- 25507208 TI - [In Process Citation]. PMID- 25507210 TI - [In Process Citation]. PMID- 25507256 TI - [Cognitive behavioral treatment of obesity--psychosomatic approach of lifestyle modification]. PMID- 25507218 TI - [How deaf people cope in routine and emergency situations - suggested paths for thought and action]. AB - Oeaf people have unique characteristics and needs. There is a limited amount of research regarding the needs of deaf people, and no studies were found concerning deaf people in emergency situations. The absence of the sense of hearing in deaf people is only one component of the complexity of their world. Many factors contribute to this complexity, but the most striking is the means of communication between the deaf and the hearing person and vice versa. Changes during emergency situations present a challenge for hearing individuals, and even more so, for deaf people. Deaf individuals experience difficulty in obtaining and transmitting information, accessing care and more. These difficulties often result in the dependency of the deaf person on others. The State of Israel enacted laws targeted to facilitate the access of individuals with disabilities in general, and deaf people in particular, to public services. In emergencies, the Home Front Command and the Ministry of Social Welfare distribute pagers to the deaf population, as a device to communicate warning alerts. However, these devices do not fulfil the need for accessible care, bi-directional flow of information, and additional needs that arise during times of emergency. The deaf population is a cultural minority, whose needs in emergency situations are unknown. Familiarity with the deaf population is the first step towards improving treatment and communication that are apt for this population. This paper reviews what is known in the literature about this topic and presents an attempt to bridge the gap of knowledge and barriers to communication between the deaf population and PMID- 25507257 TI - Localization of S100A2, S100A4, S100A6, S100A7, and S100P in the human hair follicle. AB - The hair follicle is a highly differentiated structure. In this study, we examined immunohistological localization of S100A2, S100A4, S100A6, S100A7, and S100P using specific monoclonal antibodies. S100A2 was strongly expressed in the entire outer-root sheath (ORS), but more weakly in cuticle and medulla in the bulb. S100A6, S100A7, and S100P were expressed in the innermost cells of ORS. The cuticular area was weakly positive for S100A2, S100A6, S100A7, and S100P. S100A4 was expressed in dendritic Langerhans cells and melanocytes. Sebaceous cells were variably immunopositive for S100A2, S100A6, and S100A7. A subset of dermal papilla cells expressed S100A4 and S100A6. None of the antibodies labeled the inner-root sheath. The distinct spatiostructural distributions of the S100 family proteins suggest that each protein is differentially involved in the physiological function of normal hair follicles. PMID- 25507333 TI - Quality of life, perceptions of change, and psychological well-being of the elderly population in small rural towns in the Midwest. AB - This study examines the quality of life of the elderly residents of two rural Nebraska towns, both having experienced a large increase in population. The study examines how the residents' perception of changes in the community affect their view of quality of life, and identifies determinants of psychological well-being for these elderly residents. The results are compared to the non-elderly residents of these two communities for purposes of contrast. A face-to-face survey of the residents addressed physical, social/cultural, economic, and service issues. Both correlation and regression were used to analyze the data. The quality of life of the elderly residents in our study, in terms of satisfaction with the various components of general well-being--home and neighborhood, accessibility and adequacy of services (including transportation), health and safety--were very positive or satisfactory; this applies equally to the non-elderly population, with the exception of access to public transportation. PMID- 25507334 TI - Nursing home residents and celebrities: a tale of morality. AB - In contemporary Western societies, characterized by global aging and an omnipresent celebrity culture, little is known about the role of celebrities for older adults. This study bridges gerontology and celebrity studies to explore a social role that celebrities can fulfill for nursing home residents: triggering moral discussions. This potential role is examined in four focus groups with 27 nursing home residents in Flanders (Belgium). Here, 20 celebrity pictures are employed to evoke moral discussions, with a focus on adultery and homosexuality. These discussions are subjected to a framing analysis. Results show that celebrities can trigger moral discussions among the nursing home residents. The residents' adultery and homosexuality frames show that they mostly retain dominant values from their youth, often combining them with contemporary dominant values. Further, the residents' frames prove to be relativistic, which can be linked to their multitude of life experiences and complex emotional skills. PMID- 25507335 TI - Men's experiences of grandfatherhood: a welcome surprise. AB - The present-day involvement of men in many facets of childrearing stands in contrast to previous eras when men accepted that the major task of fathering was to provide a secure income to support the family. This imperative often required long hours away from the family. However, when men whose contact with children has been limited due to work and cultural constraints retire, their newly acquired lifestyle may bring fresh opportunities for involvement with grandchildren. An important question therefore concerns the impact of caring for young children on men's perceptions of their role as grandfathers. This interview study explores the experiences of 19 Australian grandfathers. The analysis found themes that relate to relationships and change, as well as themes concerning core beliefs and existential questions. The findings demonstrate the potential for insight into family relationships and personal growth in older age when studying the topic of grandparenting and caring from the male perspective. PMID- 25507336 TI - The experience of being an old never-married single: a life course perspective. AB - PURPOSE OF THE STUDY: To explore the aging experience of the "over 60" group of singles who have never been married and have no children. How they experience their aging process in terms of their singlehood and vice versa. DESIGN AND METHODS: A qualitative-phenomenological approach was adopted. In-depth semi structured interviews were conducted with 16 participants aged 60 to 87. RESULTS: Four major themes emerged: (a) "How come I stayed single?" (b) Between loneliness, aloneness and solitude. (c) "I have to take care of myself in old age." (d) The self behind prejudices and stereotypes. IMPLICATIONS: As the normative expectation is to live with partners, children, and grandchildren, they need to account for their alternative choice and give meaning to being a never married single. This meaning is expressed by constructing their self-dentity and accepting their way of life. PMID- 25507396 TI - Diana Edwards (nee Montgomery). PMID- 25507408 TI - The new rules for coffee and wine drinkers: Healthful? In moderation, perhaps. In vast quantities? Dream on. PMID- 25507487 TI - Reforming our organization. PMID- 25507411 TI - Medicare program; revisions to payment policies under the Physician Fee Schedule, Clinical Laboratory Fee Schedule, access to identifiable data for the Center for Medicare and Medicaid Innovation Models & other revisions to Part B for CY 2015. Final rule with comment period. AB - This major final rule with comment period addresses changes to the physician fee schedule, and other Medicare Part B payment policies to ensure that our payment systems are updated to reflect changes in medical practice and the relative value of services, as well as changes in the statute. See the Table of Contents for a listing of the specific issues addressed in this rule. PMID- 25507865 TI - Movement disorders. PMID- 25508102 TI - [Review of: "Problems of studying adventitious and synanthropic floras of Russia and countries of the near abroad: materials of IV International Scientific Conference"]. PMID- 25508092 TI - [Music therapy and "brain music": state of the art, problems and perspectives]. AB - Recent literature on the problem of interaction between music and the brain is reviewed and summarized. Mechanisms and effects of two most popular music therapy applications are picked out, including music listening and music making. Special attention is paid to relatively new line of investigations that is called "music of the brain" and deals with transformation of bioelectric processes of human organism into music. Unresolved questions of music therapy are identified and some promising lines of future investigations are delineated. PMID- 25508154 TI - [In Process Citation]. PMID- 25508143 TI - Tissue-specific DNase l-sensitive sites of the maize P gene and their changes upon epimutation. AB - map has been developed of nuclease-hypersensitive sites of P-rr, the standard allele of the P-locus of Zea mays L. Using a traditional DNase I assay, eight such sites have been found that are specific for the expressing tissue and span a region of more than 25 kb of the P-locus, making it one of the largest plant genes yet described. The maps of the standard allele have also been compared with the recently described moderately stable P-pr allele, which arose from epimutation. Six of the eight sites exhibit the same tissue-specificity in P-pr plants, while two stay repressed as in non-expressing tissues of plants with the standard allele. Interestingly, the two repressed sites coincide with two hypermethylated restriction sites that have previously been correlated with the expression potential of the P-pr allele. On the other hand, four of the DNase I sites, coinciding with CpG islands that were not hypermethylated by the epimutation, also showed no differences in their sensitivity to DNase I between the standard allele and the P-pr allele. This suggests that the epimutation affects both site-specific methylation changes and a specific local chromatin structure of the P gene involved in its regulation. PMID- 25508155 TI - [In Process Citation]. PMID- 25508157 TI - [In Process Citation]. PMID- 25508156 TI - [In Process Citation]. PMID- 25508158 TI - [In Process Citation]. PMID- 25508159 TI - [In Process Citation]. PMID- 25508160 TI - [In Process Citation]. PMID- 25508161 TI - [In Process Citation]. PMID- 25508162 TI - [In Process Citation]. PMID- 25508163 TI - [In Process Citation]. PMID- 25508165 TI - [In Process Citation]. PMID- 25508164 TI - [In Process Citation]. PMID- 25508166 TI - [In Process Citation]. PMID- 25508167 TI - [In Process Citation]. PMID- 25508168 TI - [In Process Citation]. PMID- 25508170 TI - [In Process Citation]. PMID- 25508169 TI - [In Process Citation]. PMID- 25508171 TI - [In Process Citation]. PMID- 25508173 TI - [Spider-bust, varicosis, crural ulcer - problems of the legs]. PMID- 25508172 TI - [In Process Citation]. PMID- 25508174 TI - [Diagnostic and therapy of varicose veins]. PMID- 25508175 TI - [Therapy of chronic crural ulcers from the perspective of a surgeon]. PMID- 25508176 TI - [Therapy of osteoporotic fractures - new therapeutic options]. PMID- 25508177 TI - [Community acquired pneumonia in general practice]. PMID- 25508178 TI - [Uncontrolled blood pressure despite my numerous pills]. PMID- 25508179 TI - [Complications of catheter ablation of atrial fibrillation]. PMID- 25508180 TI - [Gestational diabetes and pregnancy]. PMID- 25508181 TI - [In Process Citation]. PMID- 25508182 TI - [In Process Citation]. PMID- 25508453 TI - Calcium and vitamin D supply in Polish population--facts and myths. PMID- 25508452 TI - [In Process Citation]. PMID- 25508454 TI - Rehabilitation in the case of total right leg paresis caused by disc herniation- case report. PMID- 25508457 TI - SubodhMitra--the forgotten hero in the Indian radiotherapy. PMID- 25508458 TI - Debate. PMID- 25508460 TI - How the rise of the millenial generation could mean changes in the way veterinarians do business. PMID- 25508459 TI - Making sense of the Medicare physician payment data release: uses, limitations, and potential. AB - In April 2014, the Centers for Medicare and Medicaid Services released a data file containing information on Medicare payments made to physicians and other providers. Though an important achievement in promoting greater health system transparency, limitations in the data have hindered key users, including consumers, payers, and providers, from discerning meaningful information from the file. This brief outlines the significance of the data release, the limitations of the dataset, the current uses of the information, and proposals for rendering the file more meaningful for public use. PMID- 25508461 TI - Finding a way forward with nonprofit service providers. PMID- 25508462 TI - Changing the rules for pharmacy. PMID- 25508464 TI - Guidance addresses relocation of dogs, cats for adoption. PMID- 25508463 TI - Committee seeks autonomy in accrediting veterinary technology programs. PMID- 25508466 TI - Study may show how bluetongue virus survives winter. PMID- 25508465 TI - DEA expands options for controlled substances disposal. PMID- 25508467 TI - FDA may allow more conditional drug approvals. PMID- 25508468 TI - All hydrocodone products now schedule II drugs. PMID- 25508469 TI - H3N1 poses risks for people, pigs. PMID- 25508470 TI - KSU and St. Jude partner on one-health study of swine flu viruses. PMID- 25508471 TI - APHIS finalizes restrictions on dog importation. PMID- 25508472 TI - Students win grand prize for pet care innovation. PMID- 25508473 TI - Certificate programs promote diversity in veterinary medicine. PMID- 25508474 TI - New foundation to support specialists. PMID- 25508475 TI - [In Process Citation]. PMID- 25508476 TI - [In Process Citation]. PMID- 25508477 TI - [In Process Citation]. PMID- 25508478 TI - [In Process Citation]. PMID- 25508609 TI - Commentary to "100 most cited articles in fracture surgery". PMID- 25508610 TI - Commentary to "patient-specific imaging and missed tumors: a catastrophic outcome". PMID- 25508605 TI - [The effect of R(+) limonene on beta - adrenerg signaling: the significance of oxidative stress index]. AB - Reactive oxygen intermediers (ROI) play a role in the signal transduction of beta adrenergic receptors. We investigated whether an antioxidant (limonene) can reduce the beta-mimetic effect of terbutaline in beta-2-adrenergic receptor (beta2-AR)-regulated smooth muscles. Tissue samples were collected from nonpregnant (trachea) and 22-day-pregnant (myometrium and cervix) rats. Tissue contractility was investigated in an isolated organ bath. In separate groups of animals, the tracheal and uterine beta2-AR activities were upregulated by 17-beta estradiol valerate (E2) and progesterone (P4), respectively. The total oxidant (TOS) and total antioxidant status (TAS) were also measured. The oxidative stress index (OSI) was defined as the ratio ofTOS and TAS. Terbutaline (10(-10) - 10(-5) M) decreased the spontaneous contractions in the nontreated and the P4-pretreated myometria. The concentration-response curves for terbutaline in the presence of 10-3 M limonene were shifted to the left, but the maximum inhibitory effect was unchanged. Terbutaline (10(-6) M) increased the cervical resistance both in the nontreated and in the P4-treated samples, while limonene reduced this action only in the P4-treated cervices. Terbutaline (10(-9) - 10(-4) M) reduced the tracheal tones both in the nontreated and in the E2-treated tissues, while limonene reduced these effects. The OSI was highest in the trachea and lowest in the pregnant myometrium. Limonene has various influence on terbutaline induced effects in certain tissues. Higher OSI value means, that the antioxidants have greater role in the beta-adrenergic signalmechanism. We assume that the significance of ROI in the signalling process of the beta2-ARs are divergent in the various tissues. Our results suggest that the antiasthmatic effect of beta mimetics may worsen during parallel limonene administration. PMID- 25508777 TI - Control of genes for conjugative transfer of plasmids and other mobile elements. AB - Conjugative transfer is a primary means of spread of mobile genetic elements (plasmids and transposons) between bacteria.It leads to the dissemination and evolution of the genes (such as those conferring resistance to antibiotics) which are carried by the plasmid. Expression of the plasmid genes needed for conjugative transfer is tightly regulated so as to minimise the burden on the host. For plasmids such as those belonging to the IncP group this results in downregulation of the transfer genes once all bacteria have a functional conjugative apparatus. For F-like plasmids (apart from F itself which is a derepressed mutant) tight control results in very few bacteria having a conjugative apparatus. Chance encounters between the rare transfer-proficient bacteria and a potential recipient initiate a cascade of transfer which can continue until all potential recipients have acquired the plasmid. Other systems express their transfer genes in response to specific stimuli. For the pheromone responsive plasmids of Enterococcus it is small peptide signals from potential recipients which trigger the conjugative transfer genes. For the Ti plasmids of Agrobacterium it is the presence of wounded plants which are susceptible to infection which stimulates T-DNA transfer to plants. Transfer and integration of T-DNA induces production of opines which the plasmid-positive bacteria can utilise. They multiply and when they reach an appropriate density their plasmid transfer system is switched on to allow transfer of the Ti plasmid to other bacteria. Finally some conjugative transfer systems are induced by the antibiotics to which the elements confer resistance. Understanding these control circuits may help to modify management of microbial communities where plasmid transfer is either desirable or undesirable. z 1998 Published by Elsevier Science B.V. PMID- 25508778 TI - Space-resolved 3 m normal incidence spectrometer for edge impurity diagnostics in the large helical device. AB - A space-resolved vacuum ultraviolet (VUV) spectroscopy using a 3 m normal incidence spectrometer has been developed to measure the impurity profile in the edge ergodic layer composed of stochastic magnetic field by which the edge plasma in the large helical device (LHD) is uniquely characterized. It vertically measures the spatial profile of VUV lines emitted from impurities in the wavelength range of 300-3200 A. The wavelength interval, Deltalambda, which can be measured in a single discharge, is about 37 A. A spectral resolution of 0.153 A, which results from an entrance slit width of the spectrometer of 20 MUm, is adopted. The vertical observation range, DeltaZ, can be switched by taking a convex mirror in and out, which enables both the edge profile measurement focused on the ergodic layer and the full profile measurement covering an entire vertical size of the LHD plasma, e.g., 165 <= DeltaZ <= 200 mm and 1000 <= DeltaZ <= 1250 mm for the R(ax)=3.6 m configuration, respectively, which shows a slight wavelength dependence. Precise calibrations on the line dispersion, spectral resolution, vertical range of the observable region, and the spatial resolution have been performed with a unique method. As a preliminary result, the ion temperature profile is obtained for CIV at 1548.20 A in the second order (denoted as 1548.20 * 2 A) in high-density helium discharges in addition to the emission profile with a time resolution of 100 ms in a multitrack CCD operation mode. The poloidal flow in the ergodic layer based on the Doppler-shift measurement of CIV at 1548.20 * 2 A is also observed in high-density hydrogen discharges. PMID- 25508783 TI - Depth of the biomass maximum affects the rules of resource competition in a water column. AB - The theory of resource competition in spatially extended systems with resources and biomass fluxes is far from trivial. Here, we analyze the competition between two phytoplankton species for light and a nutrient in a weakly mixed water column. We develop a general framework for such an analysis and show that the competition outcome can be largely understood from a single parameter, the slope of the invasion threshold in the plane of resources. Using this approach, we show that the competition outcome crucially depends on the depth of the biomass maximum. Under eutrophic conditions, when the phytoplankton production peaks on the surface, species composition depends on the ratio of resource supplies, and the competition outcome follows the "classic" rule: coexistence is possible if each competitor has the greatest effect on its most limiting resource. By contrast, in oligotrophic systems, characterized by deep biomass maxima, the absolute level of resource supplies drives species composition, and coexistence becomes more feasible if each competitor mostly consumes its least limiting resource. Finally, when the production peaks in the subsurface, good nutrient competitors are favored. Our findings are supported by empirical data. PMID- 25508816 TI - She will givebirth easily: therapeutic approaches to childbirth in 1st millennium BCE cuneiform sources. AB - This article offers, in the first place, an overview on women's healthcare in relation to childbirth in ancient Mesopotamia, as an introduction that helps to evaluate the meaning of the 7th century Assur text BAM 248 within therapeutic cuneiform texts on childbirth. We proceed to analyse the variety of therapeutic approaches to childbirth present in BAM 248, which brings together various healing devices to help a woman give birth quickly and safely. We analyse the text in its entirety as an example of intersection between different medical approaches to childbirth, given the number of differences in the complexity of remedies, in the materia medica employed, in the methods of preparation and application, even in the technical knowledge required and also, most probably, in the social origin and/or use of the remedies in question. PMID- 25508824 TI - [Boundaries and integrity in the "Social Contract for Spanish Science", 1907 1939]. AB - This article analyzes the relationship between science and politics in Spain in the early 20th century from the perspective of the Social Contract for Science. The article shows that a genuine social contract for science was instituted in Spain during this period, although some boundary and integrity problems emerged. These problems are analyzed, showing that the boundary problems were a product of the conservative viewpoint on the relationship between science and politics, while the integrity problems involved the activation of networks of influence in the awarding of scholarships to study abroad. Finally, the analysis reveals that these problems did not invalidate the Spanish social contract for science. PMID- 25508825 TI - Beyond anesthetic properties: the effects of isoflurane on brain cell death, neurogenesis, and long-term neurocognitive function. AB - Anesthetic drugs cause brain cell death and long-term neurocognitive dysfunction in neonatal rats. Recently, human data also suggest that anesthesia early in life may cause cognitive impairment. The connection between cell death and neurocognitive decline is uncertain. It is conceivable that mechanisms other than brain cell death contribute to neurocognitive outcome of neonatal anesthesia. In a series of experiments, we demonstrate that isoflurane exposure causes significant hypercarbia in postnatal day 7 rats and that exposure to isoflurane or carbon dioxide for 4 h provoked brain cell death. However, 1 h of isoflurane exposure was not sufficient to cause brain cell death. Moreover, only 4 h of isoflurane exposure, but not 1 or 2 h of exposure or 4 h of carbon dioxide, led to impaired hippocampal function,questioning the association between anesthesia induced brain cell death and neurocognitive dysfunction. Neurogenesis both in the developing and adult dentate gyrus is important for hippocampal function, specifically learning and memory. gamma-Amino-butyric-acid regulates proliferation and neuronal differentiation both in the developing and the adult brain. Inhaled anesthetics are gamma-amino-butyric-acid-ergic and may therefore affect neurogenesis, which could be an alternative mechanism mediating anesthesia induced neurocognitive decline in immature rats. Understanding the mechanism will help guide clinical trials aiming to define the scope of the problem in humans and may lead to preventive and therapeutic strategies. PMID- 25508848 TI - Increases in generative concern among older adults following reminders of mortality. AB - According to terror management theory, people are motivated to protect themselves from the potential for anxiety resulting from awareness of mortality. It was hypothesized that increased concern for future generations, and the symbolic immortality this produces, may be particularly important to older adults when awareness of their mortality is increased. In two studies, older and younger adults' generative concern was examined following mortality or control primes. As hypothesized, older adults' generative concern and preference for pro-social over pro-self generativity were greater following reminders of mortality, whereas neither effect was observed among younger adults. For both studies, age differences were only observed when mortality salience was heightened; older and younger adults' generative concern did not differ in control conditions. Results provide support for the hypothesis that younger and older adults differ in their responses to increased awareness of mortality and suggest that older adults respond to death reminders by adopting a more pro-social generative orientation. PMID- 25508849 TI - Remoteness modulates the effects of emotional valence on the neural network of autobiographical memory in older females. AB - To better understand the effects of emotional valence on autobiographical memory (AM), the present study compared behavioral performance and neural activation in positive and negative AMs at different levels of remoteness (the time-interval between encoding and retrieving) in a sample of Chinese older females. The behavioral results revealed that older females held a positivity bias in emotional AM in the form of an obvious trend of higher level of vividness when retrieving positive AMs compared with negative AMs. At the neural level, a de lateralized neural network, covering the core AM system and the affect processing system, was found to be associated with emotional AM. Within the network, increased activation of a prefrontal cortex/anterior cingulate cortex (PFC/ACC) control system was found when processing negative recent AMs compared with positive recent AMs; increased activation of the somatosensory area was found with positive remote AMs compared with negative remote AMs. On the basis of these results, we suggest that the positivity bias of the older adults in recent AMs may be due to the use of an emotion regulation or control system (involving PFC/ACC) against negative AMs; in contrast, for remote AMs, the positivity bias may be due to better access to the positive remote memory details than the negative remote memory details. PMID- 25508850 TI - The influence of sexual attitudes on mid- to late-life sexual well-being: age, not gender, as a salient factor. AB - The influence of sexual attitudes on sexual activity and expression has been relatively understudied in older populations. In the current study, we sought to understand the role sexual attitudes have on sexual well-being among middle-aged and young-old adults. Using a diverse sample of participants over the age of 45 (N = 384), a path model was analyzed to determine whether sexual attitudes contributed to sexual well-being. The model was then compared by gender. Results indicated: a) only age-relative sexual attitudes significantly contributed to sexual well-being; and b) the model was equally robust for both men and women, even though women held slightly more positive age-relative sexual attitudes than men. Therefore, among middle-aged and young-old adults, sexual well-being may be reduced by harboring negative ageist sexual attitudes. Efforts should be made to reduce stigma surrounding continued sexual activity and expression among the aged. PMID- 25508981 TI - [Abstracts of the Joint XII Congress of the International Association of Morphologists and the VII Congress of the All-Russian Scientific Medical Association of Anatomists, Histologists and Embryologists, May 28-31, 2014, Tiumen, Russia]. PMID- 25508851 TI - Risk factors related to cognitive functioning: a cross-national comparison of U.S. and Korean older adults. AB - The purpose of this study was to conduct a cross-national comparison of factors related to cognitive functioning in later life in a U.S. and Korean sample. The study sample was comprised of subjects from the HRS (N = 10,175) and the KLoSA (N = 3,550). Separate multivariate regression models were employed to examine the impact of socio-demographic, health, and health behaviors on cognitive functioning among older adults. Regression results showed that age, gender, education, wealth, self-rated health, ADL, IADL, stroke, and poor eyesight were significantly associated with cognitive functioning in both countries. However, depression, high blood pressure, diabetes, and drinking were significantly associated with cognition only among Americans, while marital status and poor hearing were significantly associated with cognition only among Koreans. In addition, gender-specific models suggested several socio-economic and health factors had significantly different effects by gender in both countries. Cross national comparative research identified similar risk factors, suggesting robust associations. Unique factors related to cognitive functioning in U.S. and Korean older adults highlight the important role of societal influences on cognitive outcomes. PMID- 25508982 TI - Abstracts of the 44th European Contact Lens and Ocular Surface Congress (ECLSO), October 10-11, 2014, Dubrovnik, Croatia. PMID- 25508983 TI - Abstracts of the annual congress of the Italian Association of Anatomy and Pathology, October 22-25, 2014, Firenze, Italy. PMID- 25508984 TI - Abstracts of the 69th Annual Conference of the Association of Physicians of India, February 20-23, 2014, Ludhiana, Punjab, India. PMID- 25508991 TI - They deal with diagnosis of gastrointestinal pathologies, mechanical ventilation, and modeling of biomedical processes. PMID- 25508990 TI - MT-45: a new, dangerous legal high. PMID- 25509055 TI - Enhancing the well-being of veterans using extended group-based nature recreation experiences. AB - Physical and mental health issues associated with military service persist as challenges for many veterans. This study draws on existing research showing the value of engaging in nature-based recreation to examine the effects of such experiences on veterans specifically. Four organizations, offering 12 different programs each lasting 4-7 d, were included in the study. Ninety-eight veterans were recruited and surveyed 1 wk before, 1 wk after, and approximately 1 mo after participating in these extended group-based outdoor experiences. In addition to background information, the survey instrument assessed changes in psychological well-being, social functioning, and life outlook. The results showed significant improvements in each of these domains 1 wk after the outdoor experience. Some improvements persisted over the next month, but to a lesser degree. The positive changes were particularly strong for veterans who initially reported more severe ongoing health issues. Overall, the findings suggest that extended group-based nature recreation experiences that bring veterans together can have significant positive effects on veterans struggling with serious health problems. PMID- 25509056 TI - Glasgow Coma Scale scores, early opioids, and 4-year psychological outcomes among combat amputees. AB - Morphine and fentanyl are frequently used for analgesia after trauma, but there is debate over the advantages and disadvantages of these opioids. Among combat amputees, intravenous (IV) morphine (vs IV fentanyl) after injury was associated with reduced likelihood of posttraumatic stress disorder (PTSD). The previous results were based on military health diagnoses over 2 yr postinjury. The present study followed psychological diagnoses of patients with amputation for 4 yr using military and Department of Veterans Affairs health data. In-theater combat casualty records (n = 145) documented Glasgow Coma Scale (GCS) scores and/or morphine, fentanyl, or no opioid treatment within hours of injury. We found that (1) GCS scores were not significantly associated with PTSD; (2) longitudinal modeling using four (yearly) time points showed significantly reduced odds of PTSD for patients treated with morphine (vs fentanyl) across years (adjusted odds ratio = 0.40; 95% confidence interval = 0.17-0.94); (3) reduced PTSD prevalence for morphine (vs IV fentanyl; morphine = 25%, fentanyl = 59%, p < 0.05) was significant, specifically among patients with traumatic brain injury during the first 2 yr postinjury; and (4) PTSD prevalence, but not other disorders (e.g., mood), increased between year 1 (PTSD = 18%) and years 2 through 4 postinjury (PTSD range = 30%-32%). PMID- 25509057 TI - Effect of low-intensity direct current on expression of vascular endothelial growth factor and nitric oxide in diabetic foot ulcers. AB - This study investigated the effect of low-intensity cathodal direct current on the release of plasma vascular endothelial growth factor (VEGF) and nitric oxide (NO) in diabetic foot ulceration. Twenty type 2 diabetic patients with foot ulceration and thirteen age-matched healthy subjects were enrolled. Patients were randomly assigned to electrical stimulation (ES) (n = 10) or sham ES (placebo, n = 10) groups. The ES group received cathodal direct current (1.48 +/- 0.98 mA) for 1 h/d,3 d/wk for 4 wk (12 sessions). Blood samples were collected for VEGF and NO measurement in the first and last treatment sessions before and after intervention. Wound surface area and skin temperature were measured at the 1st, 6th, and 12th sessions. VEGF significantly increased in the ES group compared with the placebo group after the 1st (106.61 +/- 79.50 and 40.88 +/- 26.20, respectively) and 12th sessions (109.28 +/- 67.30 and 34.79 +/- 13.20, respectively). NO level also increased significantly in the ES group compared with the placebo group after the 12th session (44.21 +/- 14.00 and 35.25 +/ 11.00, respectively). The increase of skin temperature was significantly higher in the ES group than the placebo group. Application of low-intensity ES increases the expression of VEGF and NO, which may lead to improved blood flow and tissue temperature and, consequently, wound healing in diabetic foot ulceration. PMID- 25509058 TI - Extraction of spatial information for low-bandwidth telerehabilitation applications. AB - Telemedicine applications, based on two-dimensional (2D) video conferencing technology, have been around for the past 15 to 20 yr. They have been demonstrated to be acceptable for face-to-face consultations and useful for visual examination of wounds and abrasions. However, certain telerehabilitation assessments need the use of spatial information in order to accurately assess the patient's condition and sending three-dimensional video data over low-bandwidth networks is extremely challenging. This article proposes an innovative way of extracting the key spatial information from the patient's movement during telerehabilitation assessment based on 2D video and then presenting the extracted data by using graph plots alongside the video to help physicians in assessments with minimum burden on existing video data transfer. Some common rehabilitation scenarios are chosen for illustrations, and experiments are conducted based on skeletal tracking and color detection algorithms using the Microsoft Kinect sensor. Extracted data are analyzed in detail and their usability discussed. PMID- 25509060 TI - Content and format of labeling for human prescription drug and biological products; requirements for pregnancy and lactation labeling. Final rule. AB - The Food and Drug Administration (FDA) is amending its regulations governing the content and format of the "Pregnancy," "Labor and delivery," and "Nursing mothers" subsections of the "Use in Specific Populations" section of the labeling for human prescription drug and biological products. The final rule requires the removal of the pregnancy categories A, B, C, D, and X from all human prescription drug and biological product labeling. For human prescription drug and biological products subject to the Agency's 2006 Physician Labeling Rule, the final rule requires that the labeling include a summary of the risks of using a drug during pregnancy and lactation, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy and lactation. The final rule eliminates the "Labor and delivery" subsection because information about labor and delivery is included in the "Pregnancy" subsection. The final rule requires that the labeling include relevant information about pregnancy testing, contraception, and infertility for health care providers prescribing for females and males of reproductive potential. The final rule creates a consistent format for providing information about the risks and benefits of prescription drug and/or biological product use during pregnancy and lactation and by females and males of reproductive potential. These revisions will facilitate prescriber counseling for these populations. PMID- 25509059 TI - Intrinsic transient tracheal occlusion training and myogenic remodeling of rodent parasternal intercostal fibers. AB - It is recognized that diaphragm muscle plasticity occurs with mechanical overloads, yet less is known about synergistic parasternal intercostal muscle fiber remodeling. We conducted overload training with intrinsic transient tracheal occlusion (ITTO) exercises in conscious animals. We hypothesized that ITTO would yield significant fiber hypertrophy and myogenic activation that would parallel diaphragm fiber remodeling. Sprague-Dawley rats underwent placement of a tracheal cuff and were randomly assigned to receive daily 10 min sessions of conscious ITTO or observation (sham) over 2 wk. After training, fiber morphology, myosin heavy chain (MHC) isoform composition, cross-sectional area, proportion of Pax7-positive nuclei, and presence of embryonic MHC (eMHC) were quantified. Type IIx/b fibers were 20% larger after ITTO training than with sham training (ITTO: 4,431 +/- 676 MUm2, sham: 3,689 +/- 400 MUm2, p < 0.05), and type I fibers were more prevalent after ITTO (p < 0.01). Expression of Pax7 was increased in ITTO parasternals and diaphragm (p < 0.05). In contrast, the proportion of eMHC positive fibers was increased only in ITTO parasternals (1.2% [3.4%-0.6%], sham: 0% [0.6%-0%], p < 0.05). Although diaphragm and parasternal type II fibers hypertrophy to a similar degree, myogenic remodeling appears to differ between the two muscles. PMID- 25509061 TI - Medicare program; requirements for the Medicare incentive reward program and provider enrollment. Final rule. AB - This final rule implements various provider enrollment requirements. These include: Expanding the instances in which a felony conviction can serve as a basis for denial or revocation of a provider or supplier's enrollment; if certain criteria are met, enabling us to deny enrollment if the enrolling provider, supplier, or owner thereof had an ownership relationship with a previously enrolled provider or supplier that had a Medicare debt; enabling us to revoke Medicare billing privileges if we determine that the provider or supplier has a pattern or practice of submitting claims that fail to meet Medicare requirements; and limiting the ability of ambulance suppliers to "backbill" for services performed prior to enrollment. PMID- 25509062 TI - [Species composition and community structure of a spruce-fir forest and a larch forest on the northern slope of Changbai Mountains, Northeast China]. AB - Spruce-fir forest is the best protected forest vegetation, while larch forest is intrazonal vegetation on the northern slope of Changbai Mountains. To further understand their species composition and community structure, we established a 4 hm2 forest permanent plot in each of these two forests in 2010. All free-standing plant species with DBH (diameter at breast height) >= 1 cm were mapped, tagged, and identified to species. The results showed that there were 9257 stems belonging to 8640 genotype individuals, 22 species, 6 genera and 12 families in the spruce-fir forest plot, while 4060 stems belonging to 3696 genotype individuals, 22 species, 8 genera and 16 families in the larch forest plot. Species composition in the two plots was very similar. Most of the species belonged to the Changbai Mountains plant flora. The analysis of species' importance values showed that there were dominant species in both communities. The spruce-fir forest was dominated by Abies nephrolepis and Larix olgensis, whose importance values accounted for 38.7% and 23.9% of the sum of importance values over all species in the plot, respectively. The larch forest was dominated solely by L. olgensis, whose importance value accounted for 61.9% of the sum of importance values over all species in the plot. Both forests were in good condition of regeneration and showed a reversed 'J' type in tree size distributions, at community level. However, different species showed different shapes in size distribution in the two forests. A. nephrolepis showed a reversed 'J' type size distribution in the spruce-fir forest, while L. olgensis with DBH >= 10 cm showed a hump-shaped distribution in the larch forest. Spatial distribution patterns of the main species changed differently with size class and spatial scales. Common species had different spatial distribution patterns in the two plots. PMID- 25509063 TI - [Effects of snow patches on the release of N and P during foliar litter decomposition in an alpine forest of western Sichuan China]. AB - A field experiment using litterbags was conducted in an alpine forest of western Sichuan in order to understand the effects of snow patches on the dynamics of N and P during decomposition of six representative species foliar litter in different periods of winter. Net N immobilization during foliar litter decomposition was observed in the whole snow cover season regardless of species. In contrast, P mainly released from foliar litter in the snow cover season, with a rapid rate of P release in the snow melt stage. Thick and moderate snow patches showed higher P release rates, but lower N release rates of foliar litter. The rate of N release was negatively related to daily mean temperature regardless of species, but the rate of P release was positively related to daily mean temperature with the exception of fir needle-litter. The decrease of snow cover in the scenario of global warming could inhibit P release but promote N release from foliar litter decomposition in winter in the alpine forest. PMID- 25509064 TI - [Ecosystem carbon exchange in Artemisia ordosica shrubland of Ordos Plateau in two different precipitation years]. AB - Characteristics of ecosystem carbon exchange and its impact factors in Artemisia ordosica shrubland in 2011 (low precipitation) and 2012 (high precipitation), Ordos Plateau, were studied using eddy covariance methods. The results showed that the diurnal dynamics of ecosystem carbon exchange could be expressed as single-peak and double-peak curves in the two different precipitation years. In 2011, three carbon absorption peaks and three carbon release peaks of ecosystem carbon exchange presented in the growing season. In 2012, four carbon absorption peaks and one carbon release peak appeared in the growing season. The A. ordosica shrubland was a net carbon sink from June to September and a carbon source in October in 2011. In 2012, A. ordosica shrubland was a net carbon sink in the whole growing season. The amount of carbon fixed by A. ordosica shrubland in the growing season in 2012 was 268.90 mg CO2 x m(-2) x s(-1) higher than that in 2011. The ecosystem carbon exchange of A. ordosica shrubland was controlled by PAR (photosynthetically active radiation) on the day scale, and affected by both abiotic (precipitation and soil water content) and biotic (aboveground net primary, productivity) factors on the growing season scale. PMID- 25509065 TI - [Response of fine root decomposition to simulated nitrogen deposition in Pleioblastus amarus plantation, rainy area of West China]. AB - As an important contributor to carbon (C) flux in the global C cycle, fine root litter decomposition in forests has the potential to be affected by the elevated nitrogen (N) deposition observed globally. From November 2007 to January 2013, a field experiment involving monthly simulated deposition of N in a Pleioblastus amarus plantation was conducted in the Rainy Area of West China. Four levels of nitrogen deposition were included as control (0 g N x m(-2) x a(-1)), low nitrogen (5 g N x m(-2) x a(-1)), medium nitrogen (15 g N x m(-2) x a(-1)) and high nitrogen (30 g N x m(-2) x a(-1)). After 3 years of simulated N deposition experiment (January 2011) , a two-year fine root decomposition experiment was conducted in the simulated N deposition plots using litterbag method, under monthly experimental N deposition. The decomposition rates of fine roots were fast first and then slow. Mass loss of fine roots in the first year of decomposition was up to 60%, and the change of the remaining mass was very slow in the second year. The time of 50% and 95% mass loss of fine roots was 1.20 and 5.17 years, respectively, under the conditions of no addition N input. In general, decomposition rates were underestimated using negative exponential model. Simulated N deposition significantly inhibited the decomposition of fine roots. The remaining mass in the high nitrogen treatment was 51.0% higher than that in the control, after two years of decomposition. Simulated N deposition increased C, P and K contents in the remaining mass of litter. Compared with the control, soil pH decreased significantly in the medium and high nitrogen treatments, soil organic C, total N, ammonium and nitrate contents and fine root biomass of P. amarus increased significantly in the high nitrogen treatment after simulated N deposition for 4. 5 years. Key words: nitrogen deposition; fine root decomposition; Pleioblastus amarus. PMID- 25509066 TI - [Effects of simulating acid rain on photosynthesis and chlorophyll fluorescence parameters of Quercus glauca Quercus glauca]. AB - At three levels of simulated acid rainfall intensities with pH values of 2.5 (severe), 40 (medium) and 5.6 (light) respectively, the responses of chlorophyll fluorescence and photosynthetic parameters of Quercus glauca seedlings were studied in three acid rainfall treatments, i. e. only the aboveground of seedlings exposed to acid rain (T1), both of the seedlings and soil exposed to acid rain (T2), only the soil exposed to acid rain (T3) compared with blank control (CK). Under the severe acid rainfall, T1 significantly inhibited chlorophyll synthesis, and thus reduced the primary photochemical efficiency of PS II ( F(v)/F(m)), potential activity of PS II (F(v)/F(o)) , apparent quantum (Y), net photosynthetic rate (P(n)), and transpiration rate (T(r)), but increased the light compensation point (LCP) and dark respiration rate (R(d)) of Q. glauca seedlings. T2 inhibited, but T3 played a little enhancement on the aforementioned parameters of Q. glauca seedlings. Under the conditions of medium and light acid rainfall intensities, the above parameters in the three treatments were higher than that of CK, except with lower R(d). The chlorophyll fluorescence and photosynthetic parameters showed a similar tendency in the three treatments, i. e. T2>T3 >T1. It indicated that T1 had the strongest inhibition on seedlings in condition of the severe acid rainfall, while T2 had the most dramatic facilitating effect on seedlings under the medium and light acid rainfall. Intensity of acid rainfall had significant influences on SPAD, F(v)/F(m), F(v)/F(o), Y, P(n), T(r), and maximum photosynthetic rate (A(max)), whereas treatments of acid rainfall affected SPAD, F(v)/F(m), Y, P(n), T(r), A(max) and light saturation point (LSP). The interaction of acid rainfall intensities and treatments played significant effects on SPAD, F(v)/F(m), Y, P(n) and A(max). PMID- 25509067 TI - [Rainfall redistribution traits of three main forest types in Dagangshan Mountains of Jiangxi Province, China]. AB - The redistribution processes of rainfall due to the canopy were studied on three typical forest types (Chinese fir forest, evergreen broad-leaved forest and Phyllostachys pubescens forest) in Dagangshan Mountains of Jiangxi Province. The results showed that from April to June, 2012, the total precipitation was 531.6 mm, with the maximum single rainfall of 61.7 mm. The rainfall in this area was mainly light and moderate. During the research period, the total throughfall of P. pubescens forest was the greatest, and that of evergreen broad-leaved forest was the smallest. The throughfall of P. pubescens and Chinese fir forest were almost equal at the same rainfall intensity. However, the throughfall of evergreen broad-leaved forest was smaller than those of the other two types of forest at the same high rainfall intensity. Throughfall presented a distinct spatial variability within each forest. Stemflow of Chinese fir forest, evergreen broad-leaved forest and P. pubescens forest were 1.4%, 8.9% and 8.8%, respectively. There were significant differences (P < 0.01) in stemflow between the Chinese fir forest and the other two types of forests. In addition, the moisture degree of forests before a rain event greatly influenced the quantity of the stemflow. The effect was strongest in the Chinese fir plantation and weakest in the P. pubescens forest. The proportion of interception to rainfall was in a descending order of 30.5%, 25.5% and 19.2% for the Chinese fir forest, the evergreen broad-leaved forest and the P. pubescens forest, respectively. The Chinese fir forest had the obviously greater interception rate than the other two types of forests under usual rainfall in the study area. PMID- 25509068 TI - [Comparison on concentrations and quality of dissolved organic matter in throughfall and stemflow in a secondary forest of Castanopsis carlesii and Cunninghamia lanceolata plantation]. AB - In this paper, monthly variation of dissolved organic matter (DOM) concentrations as well as humification and aromaticity indices in throughfall and stemflow from secondary broadleaved Castanopsis carlesii (BF) forest and Cunninghamia lanceolata plantation (CP) were measured. The DOC concentrations in throughfall were significantly higher with greater variation in BF than in CP. The concentrations of DOC in throughfall were averagely 7.2 and 3.2 times of those in rainfall in BF and CP forests, respectively. The DOC concentrations of stemflow in CP were averagely 2.5 times as much as those in BF, and the DOC concentrations in stemflow tended to be greater in dry season than in rain season for the two forests. A significantly negative relationship was' found between the DOC concentrations in stemflow and the amounts of stemflow for both BF and CP. Moreover, the humification and aromaticity indices of DOM in throughfall in BF was significantly greater than in CP. In contrast, the humification and aromaticity indices of DOM from stemflow of CP were significantly greater than those of BF. This result indicated that the structure of DOM from throughfall was more complex in BF than in CP, and the structure of DOM from stemflow was vice versa. These results indicated that DOM in stemflow and throughfall showed significant variations in quantity and quality between BF and CP and may greatly impact the accumulation of soil organic carbon. PMID- 25509069 TI - [Trunk sap flow dynamic changes in response to the slopes of plantation of Toona ciliata var. pubescens]. AB - The sap flow and environmental factors, including temperature, water content and water potential of soil, were continuously measured by using an auto-data collection system at the upper and lower slopes of Toona ciliata var. pubescens plantation in July to October, 2012 to investigate the relationships between the sap flow and environmental factors. The results showed that, the trunk sap flow velocity of the two positions both presented a typical single-peak curve, with high values in the daytime and low values in the nighttime. The average sap flow of the lower slope was significantly higher than that of the upper slope. Soil temperature of the upper slope was significantly higher than that of the lower slope, and soil water content and water potential were vice versa. Soil water content and water potential were the leading environmental factors affecting the trunk sap flow velocity at the lower slope, while soil temperature and water potential were the main environmental factors at the upper slope. PMID- 25509070 TI - [Carbon storage of forest stands in Shandong Province estimated by forestry inventory data]. AB - Based on the 7th forestry inventory data of Shandong Province, this paper estimated the carbon storage and carbon density of forest stands, and analyzed their distribution characteristics according to dominant tree species, age groups and forest category using the volume-derived biomass method and average-biomass method. In 2007, the total carbon storage of the forest stands was 25. 27 Tg, of which the coniferous forests, mixed conifer broad-leaved forests, and broad leaved forests accounted for 8.6%, 2.0% and 89.4%, respectively. The carbon storage of forest age groups followed the sequence of young forests > middle-aged forests > mature forests > near-mature forests > over-mature forests. The carbon storage of young forests and middle-aged forests accounted for 69.3% of the total carbon storage. Timber forest, non-timber product forest and protection forests accounted for 37.1%, 36.3% and 24.8% of the total carbon storage, respectively. The average carbon density of forest stands in Shandong Province was 10.59 t x hm(-2), which was lower than the national average level. This phenomenon was attributed to the imperfect structure of forest types and age groups, i. e., the notably higher percentage of timber forests and non-timber product forest and the excessively higher percentage of young forests and middle-aged forest than mature forests. PMID- 25509071 TI - [Diversity and classification system of weed community in Harbin City, China]. AB - To analyze the causes of weed community diversity and their strategies of adaption to the high heterogeneity of urban habitats, weed communities in the central urban area of Harbin, China were studied, and a classification system was established for the weed communities. There were 175 weed species, belonging to 128 genera and 38 families. The heterogeneous urban habitats and species' temporal niche differentiation resulted in the highly diversified weed communities. The high proportions of mono-species dominance and annual species dominance communities were their response to the unstable urban habitats under human disturbances with high intensities and frequencies. A four-level classification system was established in terms of plant species and habitat conditions. Within this system, the identified 1763 weed communities could be categorized into two types of life form, 5 types of dormancy form, 22 community groups, and 119 dominance communities. PMID- 25509072 TI - [Decomposition of herbaceous species in reservoir riparian region of Three Gorges Reservoir under flooding condition]. AB - A total of 10 annuals and perennials of herbaceous species were investigated in reservoir riparian region of Three Gorges Reservoir. The correlations between the plants' nutrient release rate and the substrate composition and structural matter were studied under flooding condition. The decomposition rates of different species differed substantially, with the maximum of Alternanthera philoxeroides (decomposition rate constant k = 0.0228 d(-1)) and the minimum of Microstegium vimineum (k = 0.0029 d(-1)). There was no significant difference in k between annuals and perennials. There was no significant difference in nitrogen and phosphorus contents between annuals and perennials. Paspalum paspaloides and Bidens pilosa released more nutrients into the water than the other species. A. philoxeroides had a higher potential to release nitrogen while it had little effect on water phosphorus compared with the other species. Total N, P contents in the water were negatively correlated with the plants' decomposition rate, initial C content, C:N ratio, lignin:N ratio, and positively correlated with initial contents of K, Ca and N in plants. PMID- 25509073 TI - [Exploration of a quantitative methodology to characterize the retention of PM2.5 and other atmospheric particulate matter by plant leaves: taking Populus tomentosa as an example]. AB - Taking Populus tomentosa as an example, a methodology called elution-weighing particle size-analysis (EWPA) was proposed to evaluate quantitatively the ability of retaining fine particulate matter (PM2.5, diameter d <= 2.5 MUm) and atmospheric particulate matter by plant leaves using laser particle size analyzer and balance. This method achieved a direct, accurate measurement with superior operability about the quality and particle size distribution of atmospheric particulate matter retained by plant leaves. First, a pre-experiment was taken to test the stability of the method. After cleaning, centrifugation and drying, the particulate matter was collected and weighed, and then its particle size distribution was analyzed by laser particle size analyzer. Finally, the mass of particulate matter retained by unit area of leaf and stand was translated from the leaf area and leaf area index. This method was applied to a P. tomentosa stand which had not experienced rain for 27 days in Beijing Olympic Forest Park. The results showed that the average particle size of the atmospheric particulate matter retained by P. tomentosa was 17.8 MUm, and the volume percentages of the retained PM2.5, inhalable particulate matter (PM10, d <= 10 MUm) and total suspended particle (TSP, d <= 100 MUm) were 13.7%, 47.2%, and 99.9%, respectively. The masses of PM2.5, PM10, TSP and total particulate matter were 8.88 x 10(-6), 30.6 x 10(-6), 64.7 x 10(-6) and 64.8 x 10(-6) g x cm(-2) respectively. The retention quantities of PM2.5, PM10, TSP and total particulate matter by the P. tomentosa stand were 0.963, 3.32, 7.01 and 7.02 kg x hm(-2), respectively. PMID- 25509074 TI - [Effects of environmental factors at different altitudes on leaves and fruit quality of Fuji apple]. AB - To inquire the different performances of the leaves and fruit quality of Fuji apple tress at various altitudes and their responses to the environmental factors, indices including leaf morphology, anatomy, delta13 C, and fruit quality of the Fuji apple trees at respective altitudes of 1375 m, 1575 m and 1715 m were investigated and their responses to environmental factors were determined following stepwise regression analysis. The results showed that 6 factors like the warmth index, Bailey's index, photosynthetically active radiation (PAR), coldness index, ultraviolet B and the annual precipitation dominantly affected the characteristic parameters of leaves and fruit. Elevation increase was matched by the decreasing warmth index, rising Bailey' s index, intenser PAR, higher coldness index, stronger ultraviolet B and heavier annual precipitation; meanwhile, the leaf structure and fruit quality parameters also displayed evident trends of change accordingly, namely, leaf parameters like leaf thickness, cuticle thickness, ratio of palisade and spongy, maximum conduit diameter, delta13C and nitrogen content per unit area increased gradually, and oppositely, leaf length-width ratio, specific leaf area, stoma length-width ratio and ratio of upper and lower epidermis to the leaf thickness decreased gradually; similarly, fruit parameters such as fruit shape index, fruit hardness, sugar-acid ratio, total color and the a/b-value ascended while the titratable acid and the hue angle descended. With increasing the altitude, the photosynthetic rate and water use efficiency of leaves were enhanced, and the fruit sugar-acid ratio climbed and the fruit flavor and color improved. Therefore, it could be safely concluded that within the altitude range between 1375 and 1715 m, environmental factors at a higher altitude favored Fuji apple growth. PMID- 25509075 TI - [Effects of drought and waterlogging on carbohydrate contents of cotton boll and its relationship with boll biomass accumulation at the flowering and bolling stage]. AB - Cotton cultivar NuCOTN 33B was planted in isolated pools treated with drought or waterlogging for 7 or 14 d to explore their effects on cotton boll carbohydrate content and its relationship with the biomass accumulation. The results showed that the drought treatment reduced the carbohydrate content of cotton boll shell on middle fruit branches, but had a weak effect on cotton boll shells on lower fruit branches. Soluble sugar, starch and sucrose contents of cotton boll shell on upper fruit branches under the drought condition and on whole plant branches under waterlogging treatment changed similarly, namely, the soluble sugar and starch content increased, while the sucrose content went down firstly and then increased later, which indicated that the exportation of sucrose from boll shell was inhibited and became worse with the increase of waterlogging duration. Compared with the boll shell, the carbohydrate contents of cotton seed were less affected by the drought and waterlogging treatments at the flowering and bolling stage. Under the treatments of drought and 7 d-waterlogging, the biomass accumulation of cotton bolls on the middle fruit branches initiated earlier but lasted less days, and the maximum speed at lower and upper fruit branches reduced, while the treatment of waterlogging for 14 d caused the decline of maximum speed of biomass accumulation of bolls on whole branches. On the other side, the correlation analysis showed the significant positive relationships among the boll biomass, the maximum speed and the contents of soluble sugar and sucrose in the boll shell respectively. In conclusion, the treatment of drought and waterlogging at the flowering and bolling stage retarded the outward transportation of sucrose from cotton bolls, changed the boll biomass accumulation characteristics, and therefore were detected as the important cause of cotton boll total biomass reduction. PMID- 25509076 TI - [Effects of irrigation and planting patterns on photosynthetic characteristics of flag leaf and yield at late growth stages of winter wheat]. AB - High-yield winter wheat cultivar Jimai 22 was used to study effects of irrigation and planting patterns on water consumption characteristics and photosynthetic characteristics of winter wheat in field from 2009 to 2011. Three different planting patterns (uniform row, wide-narrow row and furrow) and four irrigation schedules (W0, no irrigation; W1, irrigation at jointing stage; W2, irrigations at jointing and anthesis stages; W3, irrigation at jointing, anthesis and milking stages. Each irrigation rate was 60 mm) were designed in the experiment. Results showed that, with the increasing of irrigation amount, flag leaf area, net photosynthesis rate, maximum photochemical efficiency and actual light transformation efficiency at late growth stages of winter wheat increased. Compared with W0 treatment, the other irrigation treatments had higher grain yields, but lower water use efficiencies. Under the same irrigation condition, the flag leaf net photosynthesis, maximum photochemical efficiency and actual light transformation efficiency were much higher in furrow pattern. Grain yields of winter wheat under furrow pattern and W2 treatment were significantly higher than that of the other treatments. Taking grain yield and WUE into consideration, furrow pattern combined with irrigation at jointing and anthesis stages might be the optimal water-saving and planting mode for the winter wheat production in North China Plain. PMID- 25509077 TI - [Effect of reduced N application on soil N residue and N loss in maize-soybean relay strip intercropping system]. AB - A field experiment was conducted in 2012, including three planting pattern (maize soybean relay strip intercropping, mono-cultured maize and soybean) and three nitrogen application level [0 kg N x hm(-2), 180 kg N x hm(-2) (reduced N) and 240 kg N x hm(-2) (normal N)]. Fields were assigned to different treatments in a randomized block design with three replicates. The objective of this work was to analyze the effects of planting patterns and nitrogen application rates on plant N uptake, soil N residue and N loss. After fertilization applications, NH4(+)-N and NO3(-)-N levels increased in the soil of intercropped maize but decreased in the soil of intercropped soybean. Compared with mono-crops, the soil N residue and loss of intercropped soybean were reduced, while those of intercropped maize were increased and decreased, respectively. With the reduced rate of N application, N residue rate, N loss rate and ammonia volatilization loss rate of the maize-soybean intercropping relay strip system were decreased by 17.7%, 21.5% and 0.4% compared to mono-cultured maize, but increased by 2.0%, 19.8% and 0.1% compared to mono-cultured soybean, respectively. Likewise, the reduced N application resulted in reductions in N residue, N loss, and the N loss via ammonia volatilization in the maize-soybean relay strip intercropping system compared with the conventional rate of N application adopted by local farmers, and the N residue rate, N loss rate and ammonia volatilization loss rate reduced by 12.0%, 15.4% and 1.2%, respectively. PMID- 25509078 TI - [Effects of different tillage methods on phospholipid fatty acids and enzyme activities in calcareous cinnamon soil]. AB - In order to study changes of physical and chemical characteristics and microbial activities in soil under different tillage methods, effects of four tillage methods, rotary tillage (RT), subsoil tillage (ST), conventional tillage (CT) with corn straw returned to soil, and rotary tillage with no corn straw returned to soil (CK), on phospholipid fatty acids (PLFA) characteristics and hydrolase enzymes activities in calcareous cinnamon soil were investigated. The results showed that soil hydrolase enzymes activities, nutrient contents, microbial diversity varied greatly with the different tillage methods. Returning corn straw to soil increased the kinds, amount of soil total PLFAs, bacteria PLFAs and actonomycetes PLFAs, while decreased the fungi PLFAs, indicating that fungi was more adaptable than bacteria to an infertile environment. ST and CT resulted in higher amounts of total PLFAs, which were 74.7% and 53.3% higher than that of CK, indicating they were more beneficial to the growth of plants. They could also improve soil physical and chemical properties, increase alk-phosphatase, protease and urease activities, which would provide a favorable soil condition for high and stable crop yields. PMID- 25509079 TI - [Effects of biochar addition into soils in semiarid land on water infiltration under the condition of the same bulk density]. AB - Making clear the effects of biochar addition on soil water infiltration process can provide the scientific basis for the evaluation of the influence of biochar application on soil hydrology in semi-arid region. In this paper, through the soil column simulation method in laboratory, the effects of biochar of three sizes (1-2 mm, 0.25-1 mm and <= 0.25 mm) at 4 doses (10, 50, 100 and 150 g x kg( 1)) on the cumulative infiltration, the permeability and the stable infiltration rate of two different soils (anthrosol and aeolian sandy soil) were studied. The results showed that the infiltration capacity of the anthrosol was obviously increased compared to the control, however, the one in the aeolian sandy soil was decreased due to the biochar addition. At 100 minutes after infiltration starting, the averaged cumulative infiltration was increased by 25.1% in the anthrosol with comparison to the control. Contrarily, the averaged cumulative infiltration was decreased by 11.1% in the aeolian sandy soil at 15 minutes after infiltration starting. When the dose was the same, biochar with different particle sizes improved the infiltration for the anthrosol, but for the different dose treatments, the particle size of biochar which showed the greatest improvement was different. As for the aeolian sandy soil, the infiltration increased at the dose of 10 g x kg(-1) after the addition of biochar with different particle sizes, while decreased at the higher dose of 50, 100 and 150 g x kg(-1). The cumulative infiltration of the aeolian sandy soil was decreased with the increase in addition amount of biochar with the same particle size, while it was not so for the anthrosol. The determination coefficient fitted by the Philip infiltration model ranged from 0.965 to 0.999, suggesting this model was suitable for the simulation of soil water infiltration process after biochar application. Statistical analysis of main effects showed that the biochar particle size, the biochar addition amount, and the interactive effect had statistically significant effect on the soil permeability and stable infiltration rate in the two soils. In conclusion, the biochar had different effects on the soils with different textures, moreover, there was a positive correlation relationship between the impact and the addition amount. PMID- 25509080 TI - [Controlling effects of dual mulching on soil moisture in an apple orchard]. AB - To investigate the controlling effects of dual mulching on soil moisture in an apple orchard on the Weibei rainfed highland, soil moisture in the 0-600 cm soil profile of the apple orchard was measured under four mulching treatments (plastic film plus straw, plastic film and straw mulches, as well as a non-mulching control) , and meanwhile the apple yield and branch growth increment were analyzed statistically. Results showed that the dual mulching treatment had the best effect on soil moisture conservation, and the soil water storage in such a soil profile was 6.7% higher than the control treatment. Long-term dual mulching could effectively alleviate soil desiccation occurring in deep soil layer in the region, and the monthly averaged soil water storage in stable layer (240-600 cm) was 64.22 mm higher than that of the control treatment. Both plastic film plus straw and plastic film mulches were able to reduce the temporal fluctuation of soil moisture in shallow soil (0-60 cm) and enhance the temporal stability of soil moisture in the layer. Compared with the single mulching treatments, the dual mulching treatment could effectively decrease the vertical variation of soil moisture in the profile and improve the stability of the vertical soil moisture distribution. The apple yield under the dual mulching treatment was evidently increased by 48.2%, as compared with the control treatment. All the analyses showed that dual mulching had more advantages in controlling soil moisture and improving apple yield than single mulching. PMID- 25509081 TI - [Effects of scale-like pit and mulching measures on soil moisture of dryland jujube orchard in North Shaanxi Province, China]. AB - Soil moisture is a key factor affecting jujube growth in the semiarid Northern Shaanxi Province. The impacts of different engineering and mulching measures on soil moisture were investigated via in situ measurements in a typical dryland jujube orchard. The results showed that the mean soil moistures (0-180 cm) of scale-like pit + branch mulching, scale-like scale + straw mulching, and soil moisture of scale-like pit with no mulching were increased by 14.2%, 9.4%, and 4.8% than control, respectively. Different measures, especially for the scale like pit + branch mulching, significantly increased the soil moisture in the soil surface (0-20 cm) and the main root zone layer (20-100 cm) during the jujube growth stage. Individual precipitation events had great impacts on soil moisture in the 0-100 cm, while its effect on soil moisture in deep layers was not apparent. There was no significant difference among the soil moistures in different soil depths of scale-like pit with no mulching when compared with the control under high, medium, and low soil humidity conditions. This study indicated that using the clipped jujube branches as mulching could both save materials cost and achieve the goal of reserving more water in dryland jujube orchard in north Shaanxi Province. PMID- 25509082 TI - [Comparison of three daily global solar radiation models]. AB - Three daily global solar radiation estimation models ( A-P model, Thornton Running model and model provided by Liu Ke-qun et al.) were analyzed and compared using data of 13 weather stations from 1982 to 2012 from three northeastern provinces and eastern Inner Mongolia. After cross-validation analysis, the result showed that mean absolute error (MAE) for each model was 1.71, 2.83 and 1.68 MJ x m(-2) x d(-1) respectively, showing that A-P model and model provided by Liu Ke qun et al. which used percentage of sunshine had an advantage over Thornton Running model which didn't use percentage of sunshine. Model provided by Liu Ke qun et al. played a good effect on the situation of non-sunshine, and its MAE and bias percentage were 18.5% and 33.8% smaller than those of A-P model, respectively. High precision results could be obtained by using the simple linear model of A-P. A-P model, Thornton-Running model and model provided by Liu Ke-qun et al. overvalued daily global solar radiation by 12.2%, 19.2% and 9.9% respectively. MAE for each station varied little with the spatial change of location, and annual MAE decreased with the advance of years. The reason for this might be that the change of observation accuracy caused by the replacement of radiation instrument in 1993. MAEs for rainy days, non-sunshine days and warm seasons of the three models were greater than those for days without rain, sunshine days and cold seasons respectively, showing that different methods should be used for different weather conditions on estimating solar radiation with meteorological elements. PMID- 25509083 TI - [Optimization of application parameters of soil seed bank in vegetation recovery via response surface methodology]. AB - The thickness of surface soil, the covering thickness and the number of adding arbor seeds are all important factors to be considered in the application of soil seed bank (SSB) for vegetation recovery. To determine the optimal conditions, the Box-Behnken central composite design with three parameters and three levels was conducted and Design-Expert was used for response surface optimization. Finally, the optimal model and optimal level of each parameter were selected. The quadratic model was more suitable for response surface optimization (P < 0.0001), indicating the model had good statistical significance which could express ideal relations between all the independent variable and dependent variable. For the optimum condition, the thickness of surface soil was 4.3 cm, the covering thickness was 2 cm, and the number of adding arbor seeds was 224 ind x m(-2), under which the number of germinated seedlings could be reached up to 6222 plants x m(-2). During the process of seed germination, significant interactions between the thickness of surface soil and the covering thickness, as well as the thickness of surface soil and the number of adding arbor seeds were found, but the relationship between the covering thickness and the number of adding arbor seeds was relatively unremarkable. Among all the parameters, the thickness of surface soil was the most important one, which had the steepest curve and the largest standardized coefficient. PMID- 25509084 TI - [Assessing dynamic patterns of forest fragmentation based on a landscape mosaic indicator: a case study of Oregon State, USA]. AB - Effectively assessing landscape pattern characteristics and predicting their dynamics have been a basic prerequisite for more reasonably regulating and managing forest landscape, and maintaining landscape security patterns. In this study, based on three U. S. National Land Cover Databases (1992, 2001 and 2006), the landscape mosaic indicator in combination with the Markov model was adopted to analyze forest fragmentation patterns and changes in the characteristics of spatial interactions between forests and other land use types in Oregon State, USA. The results showed that conversion from the development-dominated type D to the single development type DD in landscape mosaic model had the highest transition probability 0.319, indicating that urbanization has been the major force responsible for the change of regional landscape patterns. In the forest security model, the highest rates of forest loss occurred in agriculture and the developed landscape mosaic type (ad), showing that in the development and agriculture dominated landscapes, encroaching upon forests was at the highest likelihood. The areal percentage of forest over the total study area was less than 50% when reaching a steady-state distribution, with an accelerating rate of forest fragmentation, and the landscape spatial distribution tended to be a mixed landscape pattern. The Kappa coefficient between the simulated values and the observed values from the 2006 landscape mosaic model was estimated at 0.82, indicating this model had a high precision. However, the accuracy of the forest security model was poor, with a Kappa coefficient of 0.21. PMID- 25509085 TI - [Landscape connectivity of waterbody network in the new reclamation region of Lianyungang based on effective distance model]. AB - Landscape connectivity is an important indicator to measure effectiveness of landscape ecological services. Waterbody connectivity in Lianyun New City, the new reclamation region of Lianyungang, was investigated based on GIS technology and effective distance model. The results showed that the total connectivity of waterbodies was poor in Lanyun New City. Connectivity of patches was related to characteristics of ecological process, ecological services value and spatial arrangement. The higher the ecosystem services value of patches was, the greater its contribution to the overall water landscape connectivity was. Some patches with long strip structure played a key role to improve the landscape connectivity. By classifying the importance of connectivity and functional groups of waterbody patches, planning of waterbodies in Lianyun New City conformed to the theory of non-substitutable pattern developed by Forman. Waterbody patches with corresponding functions should be considered with priority when planning and building a new city. The present study demonstrated that connectivity of patches should be an important factor to be considered in ecological landscape planning. Construction of ecological corridors should not only take the number of ecological landscapes into consideration, but also pay attention to spatial arrangement of landscapes in order to improve the overall landscape connectivity. PMID- 25509086 TI - [Effects of bamboo charcoal on the growth of Trifolium repens and soil bacterial community structure]. AB - The effects of addition rates (0, 3% and 9%) and particle sizes (0.05, 0.05-1.0 and 1.0-2.0 mm) of bamboo charcoal on the growth of Trifolium repens and soil microbial community structure were investigated. The results showed that bamboo charcoal addition greatly promoted the early growth of T. repens, with the 9% charcoal addition rate being slightly better than the 3% charcoal addition rate. The effects of different particle sizes of bamboo charcoal on the growth of T. repens were not different significantly. Growth promotion declined with time during 120 days after sowing, and disappeared completely after 5 months. DGGE analysis of the bacterial 16S rDNA V3 fragment indicated that bamboo charcoal altered the soil bacterial community structure. The amount and Shannon diversity index of bacteria in the bamboo charcoal addition treatments increased compared with CK. The quantitative analysis showed that the amount of bacteria in the treatment with bamboo charcoal of fine particle (D < 0.05 mm) at the 9% addition rate was significantly higher than in the other treatments. The fine bamboo charcoal had a great effect on soil bacteria amount compared with the charcoal of other sizes at the same addition rate. PMID- 25509087 TI - [Effects of long-term tillage measurements on soil aggregate characteristic and microbial diversity]. AB - Soil aggregate stability and microbial diversity play important roles in nutrient recycling in soil-crop systems. This study investigated the impacts of different soil tillage systems on soil aggregation and soil microbial diversity based on a 15-year long-term experiment on loess soil in Henan Province of China. Treatments included reduced tillage (RT), no-tillage (NT), sub-soiling with mulch (SM), wheat-peanut two crops (TC), and conventional tillage (CT). Soil aggregates were separated by wet sieving method, and soil microbial (bacterial, archaeal and fungal) diversity was examined by using the techniques of denaturing gradient gel electrophoresis (PCR-DGGE) analysis. The results showed that water-stable macroaggregates concent (R0.25) and the mean mass diameter (MWD) in the surface soil significantly increased under NT, SM and TC, R0.25 increased by 21.5%, 29.5% and 69.2%, and MWD increased by 18.0%, 12.2% and 50.4%, respectively, as compared with CT. Tillage practices caused changes in bacterial, archaeal and fungal community compositions. With NT, SM and TC, the bacterial, archaeal and fungal Shannon indices increased by 0.3%, 0.3%, and 0.6%, and 20.2%, 40.5%, and 49.1%, and 23.7%, 19.5%, and 25.8%, respectively, as compared with CT. Both bacterial and archaeal Shannon indices were significantly correlated with the indices of R0.25 and MWD, while the fungal Shannon index was not significantly correlated with these two indices. In conclusion, conservation tillage, including NT and SM, and crop rotation, including TC, improved soil aggregation and soil microbial diversity. PMID- 25509088 TI - [Microbial activity and functional diversity in rhizosphere of cucumber under different subsurface drip irrigation scheduling]. AB - The effects of subsurface drip irrigation scheduling on microbial activity and functional diversity in rhizosphere of cucumber in solar greenhouse were studied in this paper. The results showed that the soil microbial biomass C and N, basal respiration, metabolic quotient and values of AWCD, Shannon and McIntosh indexes were increased at first and then decreased with the increase of irrigation water amount. The values of microbial C and N, basal respiration and metabolic quotient in I2 treatments were significantly higher than those in I1 treatments at the 0.8E(p) irrigation level. The numbers of bacteria, actinomyces and nitrogen fixing bacteria, and the activities of urease, phosphatase, sucrase, catalase and polyhenoloxidase were significantly higher in the 0.8E(p) treatment than in the other treatments. The numbers of bacteria and nitrogen-fixing bacteria, the activities of urease, phosphatase and sucrase in I2 treatments were significantly higher than in I1 treatment, the actinomyces number and activities of catalase and polyhenoloxidase had no significant difference between I1 and I2 treatments, however, the fungi number in I2 treatments were significantly lower than in I2 treaments at the 0.8E(p) irrigation level. The microbial activity and functional diversity in rhizosphere of cucumber were strengthened in the I20.8E(p) treatment, meanwhile, the soil microflora was improved and the soil enzymes activities were enhanced, therefore, the cucumber growth was promoted as well. PMID- 25509089 TI - [Allelopathic effects of phenolic compounds of melon root exudates on Fusarium oxysporum f. sp. melonis]. AB - In this study, the phenolic compounds of melon root exudates were identified by HPLC and seven phenolic compounds including gallic acid, phthalic acid, syringic acid, salicylic acid, ferulic acid, benzoic acid and cinnamic acid were observed. The laboratory experiment showed that ferulic acid, benzoic acid and cinnamic acid of 0.1 and 0.25 mmol x L(-1) could significantly promote the germination of Fusarium oxysporum f. sp. melonis spore while salicylic acid inhibited the spore germination to some degree. Syringic acid and ferulic acid significantly promoted the mycelium growth at the late stage of incubation. The pot experiments demonstrated that cinnamic acid, benzoic acid and ferulic acid enhanced melon infection at concentrations of 0.5, 0.1 and 0.5 mmol x L(-1). PMID- 25509090 TI - [Responses of soil nematode communities to long-term application of inorganic fertilizers in upland red soil]. AB - Soil biota plays a key role in ecosystem functioning of red soil. Based on the long-term inorganic fertilization field experiment (25-year) in an upland red soil, the impacts of different inorganic fertilization managements, including NPK (nitrogen, phosphorus and potassium fertilizers), NPKCaS (NPK plus gypsum fertilizers), NP (nitrogen and phosphorus fertilizers), NK (nitrogen and potassium fertilizers) and PK (phosphorus and potassium fertilizers), on the assemblage of soil nematodes during the growing period of peanut were investigated. Significant differences among the treatments were observed for total nematode abundance, trophic groups and ecological indices (P < 0.01). The total nematode abundance decreased in the order of PK > NPKCaS > NPK > NP > NK. The total number of nematodes was significantly higher in NPKCaS and PK than in NPK, NP and NK except in May. Plant parasitic nematodes were the dominant trophic group in all treatments excepted in NPKCaS, and their proportion ranged between 38% and 65%. The dominant trophic group in NPKCaS was bacterivores and represented 42.1%. Furthermore, the higher values of maturity index, Wasilewska index and structure index in NPKCaS indicated that the combined application of NPK and gypsum could remarkably relieve soil acidification, resulting in a more mature and stable soil food web structure. While, that of the NK had the opposite effect. In conclusion, our study suggested that the application of both gypsum and phosphate is an effective practice to improve soil quality. Moreover, the analysis of nematode assemblage is relevant to reflect the impact of different inorganic fertilizer on the red soil ecosystem. PMID- 25509091 TI - [NO3-/NO2- inhibits sulfate-reducing activity of the enrichment culture of sulfate-reducing prokaryotes from an off-shore oil reservoir at Bohai Bay, China]. AB - Long-term injection of sulfate-rich water into oil reservoirs stimulates the proliferation of sulfate-reducing prokaryotes (SRP) therein and results in production of a great amount of H2S, leading to souring in oil reservoirs and related environmental problems. In this study, we first, using modified API RP 38 medium, enriched SRP present in production water from a producing well at Bohai Bay, China, and then examined the inhibitory effects of nitrate or nitrite on sulfate reduction activity of the SRP. Results showed that the enriched SRP culture exhibited a high sulfate reduction activity as indicated by a sulfate reducing rate of 10.4 mmol SO4(2-) x d(-1) x g(-1) dry cell. In presence of 0.4, 0.8, 1.8, and 4.2 mmol x L(-1) nitrate, sulfate reduction was inhibited for 5, 9, 20, and over 35 days, respectively. With the addition of 0.6, 0.9, 1.4, 2.6 and 4.6 mmol x L(-1) of nitrite, the inhibitory period lasted 3, 12, 22, and over 39 days, respectively. The SRP enrichment culture could dissimilatorily reduce nitrate to ammonium. When sulfate, nitrate and nitrite coexisted, nitrate or nitrite was preferentially used over sulfate as electron acceptor by the enriched SRP. This competitive use of electron acceptor and the strong inhibitory effect of nitrite possibly accounted for the suppression of nitrate and nitrite on the sulfate-reducing activity of the enriched SRP cultures from offshore oil reservoir at Bohai Bay. PMID- 25509092 TI - [Chemical characteristics of the rhizosphere soil of water spinach cultivars differing in Cd accumulation]. AB - A rhizobox experiment was conducted to investigate the chemical characteristics of the rhizosphere soils of two water spinach cultivars differing in Cd accumulation, QLQ (a low-Cd cultivar) and T308 (a high-Cd cultivar). The results showed that the diethylenetriamine pentacetate acid extractable Cd (DTPA-Cd) concentration in the rhizos-phere soil of QLQ was significantly higher than that of T308 (P < 0.05). pH and Eh in the rhizosphere soil of QLQ were significantly higher than those of T308 (P < 0.05), while EC was opposite. Contents of organic matter and dissolved organic matter (DOM) in the rhizosphere soil of QLQ were both higher than those of T308. In contaminated soil, the composition and concentration of low molecular weight organic acids in the rhizosphere between the two cultivars were both different. Acetic, propionic, citric and fumaric acids were detected in the rhizosphere soil of T308, and only citric and fumaric acids were detected in that of QLQ. The total concentration of low molecular weight organic acids in the rhizosphere soil of QLQ (1.93 nmol x g(-1) DM) was lower than that of T308 (15.11 nmol x g(-1) DM) (P < 0.01). Compared with the high-Cd cultivar (T308), the chemical characteristics of the rhizosphere soil of the low-Cd cultivar (QLQ) were obviously distinct, i. e., the relatively higher content of organic matter, the lower content of low molecular weight organic acids with a specific composition, less acidification of soil, and a lower ability in reduction, correspondingly lowering the mobility of Cd in soil and reducing Cd accumulation by plant. PMID- 25509093 TI - [Effects of silicon on the ultrastructures of wheat radical cells under copper stress]. AB - To explore the alleviation effect of silicon on wheat growth under copper stress, cultivar Aikang 58 was chosen as the experimental material. The growth, root activities and root tip ultrastructures of wheat seedlings, which were cultured in Hoagland nutrient solution with five different treatments (control, 15 mg x L( 1) Cu2+, 30 mg x L(-1) Cu2+, 15 mg x L(-1) Cu2+ and 50 mg x L(-1) silicon, 30 mg x L(-1) Cu2+ and 50 mg x L(-1) silicon), were fully analyzed. The results showed that root length, plant height and root activities of wheat seedlings were significantly restrained under the copper treatments compared with the control (P < 0.01), while these restraining effects were alleviated after adding silicon to copper-stress Hoagland nutrient solution. Under copper stress, the cell wall and cell membrane of wheat seedling root tips suffered to varying degrees of destruction, which caused the increase of intercellular space and the disappearance of some organelles. After adding silicon, the cell structure was maintained intact, although some cells and organelles were still slightly deformed compared with the control. In conclusion, exogenous silicon could alleviate the copper stress damages on wheat seedlings and cellular components to some extent. PMID- 25509094 TI - [Treatment effect of biological filtration and vegetable floating-bed combined system on greenhouse turtle breeding wastewater]. AB - Unorganized discharge of greenhouse turtle breeding wastewater has brought several negative influences on the ecological environment in the rural area of Yangtze River Delta. Biological filtration and vegetable floating-bed combined system is a potential ecological method for greenhouse turtle breeding wastewater treatment. In order to explore the feasibility of this system and evaluate the contribution of vegetable uptake of nitrogen (N) and phosphorus (P) in treating greenhouse turtle breeding wastewater, three types of vegetables, including Ipomoea aquatica, lettuce and celery were selected in this study. Results showed the combined system had a high capacity in simultaneous removal of organic matter, N and P. The removal efficiencies of COD, NH4(+)-N, TN and TP from the wastewater reached up to 93.2%-95.6%, 97.2%-99.6%, 73.9%-93.1% and 74.9%-90.0%, respectively. System with I. aquatica had the highest efficiencies in N and P removal, followed by lettuce and celery. However, plant uptake was not the primary pathway for TN arid TP removal in the combined system. The vegetable uptake of N and P accounted for only 9.1%-25.0% of TN and TP removal from the wastewater while the effect of microorganisms would be dominant for N and P removal. In addition, the highest amounts of N and P uptake in I. aquatica were closely related with the biomass of plant. Results from the study indicated that the biological filtration and vegetable floating-bed combined system was an effective approach to treating greenhouse turtle breeding wastewater in China. PMID- 25509095 TI - [Spatial-temporal and environmental effects of catch rate on Antarctic krill fishery in the South Georgia Island in the austral winter season based on the fine scale data]. AB - The waters around the South Georgia Island is one of the main fishing ground of Antarctic krill fishery and many predators such as sea seal and whale inhabited this island target Antarctic krill as a food source. So it is very important for further understanding Antarctic ecosystem to conduct the research on abundance fluctuation of Antarctic krill resource around this island. Consequently, based on the fine scale fishery data collected in the winter 2013, using the generalized additive model (GAM), the present study analyzed the relationship between environmental factors and the catch rate of Antarctic krill. The results showed the model could explain 32.0% of the accumulation of deviance of the catch rate. The variable that provided the maximum contribution was ten-day with a contribution rate of 21.4% and followed by the latitude (4.4%). Generally, the catch rate decreased from the first 10 days of July to September. Higher catch rates occurred in the eastern fishing ground, particularly the central-eastern part of survey area, and lower catch rates presented in the northern part. The mean catch rate deceased with the increasing change rate of bathymetry. The oceanographic condition with wind scale below 4 was suitable for fishing operation and associated with the higher catch rate, but the wind direction did not significantly affect the catch rate. The mean catch rate increased with the increasing sea surface temperature within 0.5 to 2.0 degrees C. PMID- 25509096 TI - [Effects of microalgal diets on juvenile growth and survival of the ark shell, Scapharca broughtonii]. AB - Under hatchery conditions (temperature, 23.5-24.0 degrees C; salinity, 29.5 30.0), effects of microalgal diets on growth and survival of the juvenile ark shell, Scapharca broughtonii, were investigated for 24 days by feeding with diets made of single or combinatory use of four different microalgae, Isochrysis galbana, Chlorella sp., Chaetoceros muelleri and Nitzschia closterium. The results showed that the survival rates were over 95% in all diet groups with no significant difference among them. When feeding with single microalgae, the best feeding effects on growth were observed in I. galbana, while the worst effects occurred in Chlorella sp. When feeding with various combinations of microalgae, the optimal effects on shell length and specific growth rate were observed in diets containing I. galbana compared to the other diets. The diet composed of I. galbana and Chlorella sp. (1:1) provided the best effects for S. broughtonii juveniles, resulting in a specific growth rate of 5.6% x d(-1) in shell length and 6.4% x d(-1) in shell height. These results should be valuable to direct the technique optimization of artificial breeding for the hatchery production of S. broughtonii seeds. PMID- 25509097 TI - [Trace elements in the statoliths of neon flying squid, Ommastrephes bartramii in the Northwest Pacific Ocean]. AB - Statolith is one of the most important hard tissues of cephalopods which is widely used in the research of fisheries ecology including population structure, life history reconstruction and so on. Trace elements of 18 statoliths of neon flying squid Ommastrephes bartramii collected in the Northwest Pacific Ocean in 2007 by Chinese jigging fishing fleets were analyzed by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The results indicated that the statoliths of O. bartramii mainly contained 55 elements, and calcium (Ca), strontium (Sr), sodium (Na), phosphorus (P), potassium (K), silicon (Si), magnesium (Mg), boron (B), iron (Fe), barium (Ba) were the 10 most abundant elements. The analysis of variance showed that there was no significant difference in each element distribution between different sexual squid except for P, Si and B. Significant differences existed in the contents of Sr and Na but no significant difference was found in the contents of Ca, P, K, Si, Mg, B, Fe and Ba between different hatching populations. There were significant differences in the contents of Ca, Sr, Na, P, Mg and Ba, but no significant difference was found in the contents of K, Fe, B and Si in the statoliths among different growth zones. This study presented Sr and Na could be the best two trace elements used in the research on the population structure and life history reconstruction for O. bartramii. PMID- 25509098 TI - [Preliminary assessment of habitat of juvenile Collichthys lucidus in the Yangtze estuary]. AB - To evaluate the choice preference of fish habitat in the Yangtze estuary, juvenile Collichthys lucidus which is the dominant species in spring was selected. The 4 indicator factors, including abundance of Pseudograpsus albus, salinity, substrate type and water depth, were selected from 19 environmental factors. Then, the indices of the habitat suitability curves of the 4 indicator factors were established, and the HSI of juvenile C. lucidus at each site was calculated. The results indicated that HSI was almost more than 0.5 in North Branch, and less than 0.2 in South Branch. It showed that the North Branch of Yangtze estuary was the main nursery area of C. lucidus. The most suitable growth sector was the area with salinity more than 14, mean grain size of substrate less than 29 MUm and water depth 2 to 5 m, which was consistent with the distribution of HSI. The study demonstrated that biological factors could be characterized by the response of juvenile C. lucidus to the environment. Chemical oxygen demand, ammonium nitrogen, total phosphorus and volatile phenol did not have significant correlation with the fish abundance, with which nitrite nitrogen, nitrate nitrogen and total nitrogen had significant positive correlation. It suggested that the eutrophication of the survey area had not damaged the habitat of C. lucidus. However, copper ion and cadmium ion had significant negative correlation with the fish abundance, which indicated that the heavy metal pollution had harmed the growth and distribution of juvenile C. lucidus. It was inferred that the heavy metal pollution was the restrictive factor influencing the fish habitat in Yangtze estuary. PMID- 25509099 TI - [Circadian rhythm of emergence and reproduction of Micromelalopha troglodyta (Lepidoptera: Notodontidae)]. AB - Micromelalopha troglodyta (Graeser) is one of serious defoliators of poplars. In order to explore the occurrence regularity of emergence and reproductive behavior of M. troglodyte, which could provide references to the application of ecological control techniques, the circadian rhythms of emergence, calling, mating and oviposition were studied at (27 +/- 1) degrees C and (60 +/- 10)% RH under a 14L:10D photoperiod. The results showed that the emergence peak of the female occurred at the 7th day of the pupal stage, while the male at 8th day. As for the circadian rhythm during 24 hours, most individuals of both sexes emerged from the 6th hour of the photophase to the 2th hour of the scotophase. The 11th hour after initiation of the photophase was the emergence peak of female, while that of the male was 1 hour later. Female M. troglodyte after emergence did not call until the scotophase. The calling percentage reached the peak at the 6th-7th hour of the scotophase which increased with age of 1-3 days and reached 69.8% at the 3rd day, and then went down gradually. In the cage of only a pair of female and male, adults started mating after the 5th hour of the scotophase, and reached peak at the 7th-8th hour. But in the cage of multiple pairs of adult moths, they started mating after 0.5 hour of the scotophase, and the peak was 1.5 hours later than one pair's. Eggs laid by females at the age of 1 to 3 days accounted for 68.4% of their total lifetime fecundity, and then the oviposition gradually reduced with the age. PMID- 25509100 TI - [Research progress in chemical communication among insect-resistant genetically modified plants, insect pests and natural enemies]. AB - Semiochemicals released by plants or insects play an important role in the communication among plants, phytophagous insects and their natural enemies. They thus form a chemical information network which regulates intra- and inter specific behaviors and sustains the composition and structure of plant and insect communities. The application of insect-resistant genetically modified (IRGM) crops may affect the chemical communication within and among the tritrophic levels, and thus cause disturbances to the biotic community structure and the stability of the farmland ecosystem. This has raised concerns about the environmental safety of IRGM crops and triggered research worldwide. In the current article we provided a brief summary of the chemical communication among plants, herbivores and natural enemies; analyzed the potential of IRGM crops to affect the chemical communication between plants and arthropods and the related mechanisms; and discussed the current research progress and the future prospects in this field. We hope that this will promote the research in this field by Chinese scientists and increase our understanding of the potential effects of growing of IRGM crops on the arthropod community structure. PMID- 25509101 TI - [Review on farmer's climate change perception and adaptation]. AB - As the most serious challenge that the humankind is facing, climate change has been strengthened vulnerability in many countries and regions, and how to scientifically adapt to climate change has become the global issue of common concern to the international community today. The impact of climate change on farming people depending on the nature resource is especially remarkable, and understanding farmers' adaptation mechanism and process is very important to effectively make the adaptation policy. As the basis of understanding the human response action, public perception has provided a new perspective to verify the farmers' adaptation mechanism and process about climate change. Based on the recent theoretical and empirical developments of farmers' perception and adaptation, the impact of climate change on the farmers' livelihood was analyzed, and the main adaptation obstacles which the farmers faced in response to climate change were summarized systematically. Then, we analyzed the relationship between the farmers' climate change perception and adaptation, illuminated the key cognitive elements in the process of the farmers' climate change adaptation and introduced the framework to analyze the relationship between the farmers' climate change perception and adaptation. At last, this review put forward the key questions which should be considered in study on the relationship between the farmers' climate change perception and adaptation. PMID- 25509102 TI - [On the nervous system of a parasitic cnidarian Polypodium hydriforme]. AB - Nerve cells in a parasitic cnidarian Polypodium hydriforme at the parasitic and free-living stages of the life cycle have been localized immunocytochemically using antibodies to FMRF-amide, and their ultrastructure has been described. Ganglion cells form a net under epidermis consisting of bi- and tripolar neurons which cross the mesoglea and usually contact muscle cells and cnidocytes. Fusiform sensory and neurosecretory cells, especially characteristic to sensory tentacles, are interspersed among epidermal cells. All three types of nerve cells have dense cored vesicles about 80-120 nm in diameter. The sensory cells demonstrate a sensory flagellum-like immobile structure. Neurosecretory and sensory cells form septate junctions with epidermal cells. Ganglion cells show gap junctions between them. A centriole encircled by a fragment of nuclear envelope which is a marker of ectodermal lineage cells in Polypodium has been described in the cytoplasm of a sensory cell, thus proving the ectodermal nature of the nervous system. PMID- 25509103 TI - [Migration rate of rabbit bone marrow stromal cells and rabbit dermal fibroblasts in different gels and activity of their MMPs]. AB - This paper presents the results of the study of rabbit bone marrow stromal cells (BMSC) and rabbit dermal fibroblasts (DF) migration rates to collagen type I and fibrin gels. It has been shown that DF exhibit greater migration activity in collagen gel, whereas BMSC show a higher migration activity in fibrin gels. By studying the activity of matrix metalloproteinases (MMPs) synthesized by cells during cultivation in gels, it has been found for both cell types that the activity of MMP-9 is increased in fibrin gels and activity of MMP-2 is increased in collagen gels. Different speed of the migration of cells may be due to the properties of the cells, the activity of MMP synthesized by the cells and the influence of the microenvironment (collagen or fibrin) on the process of synthesis. PMID- 25509104 TI - [A comparative analysis of colorectal carcinoma cell lines that differ in metastatic potential]. AB - In the current work we make an attempt to compare cancer cells of one origin, but differing in the expression of CEA protein, a clinical marker of metastatic carcinomas, presumably one of the key factors in metastatic activity. We have explored the morphology of cell colonies in vitro, expression patterns of epithelial markers, the ability of these cells to form tumors and metastases in vivo, and evaluated their stem compartment with the aid of a suicidal genetic construct sensitive to the embryonic stem cell marker, Oct4. PMID- 25509105 TI - [Structural and functional peculiarities of lymphocytes from patients with lymphoblastic leukemia]. AB - New data on the structure and properties of the cell surface of lymphocytes from the blood of patients with CLL, ALL and ALL at remission stage has been obtained using AFM technologies. It's been shown that, despite the presence of immature lymphocytes in the blood flow of patients with CLL and ALL, the mechanical properties and geometrical parameters of the cells are different. Lymphocytes of CLL patients had an increased volume and higher stiffness, while the cells from the blood of patients with ALL and ALL in remission had decreased stiffness, which allowed the cells to spread on the substrate, thereby the volumes increased due to their reduced height and increased diameter. Identified structural and functional peculiarities of white blood cells from the patients with leukemia can be used for prognosis of the cancer progression. PMID- 25509106 TI - [Analysis of the inflammatory processes in the diffuse thickening of the intima of human aorta]. AB - It is generally recognized that the accumulation of lipids and immuno inflammatory cells are early signs of atherosclerosis. In the present study, we have investigated the relationship between the deposition of lipids, of immuno inflammatory cells and the expression of HLA-DR molecules (a marker of immune activation), the molecules of the class II of major histocompatibility complex (MHC) in diffuse thickening of the intima (DIT). Lipids, including triglycerides, cholesterol esters, free cholesterol and phospholipids were studied by chromatography, Oil Red O histochemisty, as well as by electron microscopic analysis. Immuno-inflammatory cells and the expression of HLA-DR were investigated by immunohistochemistry in consecutive section of the same tissue samples. It has been shown that the lipids were unevenly distributed in DIT. In juxtaluminal sublayer, lipids were detected both in the cytoplasm of intimal cells and extracellularly. In the juxtamedial musculoelastic sublayer of the intima, lipids were present predominantly along elastic fibers. The positive correlation between the presence of lipids and the expression of HLA-DR was revealed (r = 0.79; P < 0.001). Also, a positive correlation was found between the deposition of lipids and the number of immune-inflammatory cells, although correlations was different for different sublayers of the intima. In particular, the correlation between the deposition of lipids and immune-inflammatory cells in the juxtaluminal sublayer of the intima was higher (r = 0.99; P < 0.001) than in the juxtamedial musculoelastic layer (r = 0.28; P < 0.001). These data support the hypothesis that postulates that the accumulation of lipids in the intima is a key factor in the initiation of inflammatory reactions. At the pre atherosclerotic stage of the development of this disease, earlier pathological processes associated with lipid-dependent activation of immune cells occur mainly in the juxtaluminal portion of the intima. PMID- 25509107 TI - [Drosophila melanogaster imaginal discs mitotic anomalies induced by tumor supressor dlg silencing construction]. AB - Mitosis, cytokinesis and nuclear texture of wing imaginal discs cells silenced by UAS-RNAi-dlg construct induced by 1096-Ga 14 driver were studied. The silencing construct contains coding region of dlg gene and the complementary region. Further, this RNA hairpin (Dietzl et al., 2007) is processed by endogenous protein Dicer and the resulting RNA fragments silence mRNA dlg. Tumor suppressor gene dlg is encoding for 21 transcripts. The construct UAS-RNAi-dlg inactivates 14 transcripts--RE, RH, RQ, RS, RG, RD, RL, RB, RK, RR, RT, RN, RA, RP--and does not silenced the other 7 (RO, RF, RI, RU, RJ, RC, RM). This permits to study functions of proteins containg guanilate-kinase domain IPR008145 at C-end of the protein. The most important consequences of the silencing are abnormal mitotic exit and the formation of binuclear cells. Quantitative fluorescence measurements of anti-H3-p histone and DAPI signals showed phase-specific changes in nuclear texture. The inactivation of cellular cortex polarization is the most likely target of dlg inactivation in mitosis. PMID- 25509108 TI - [Effect of hydrostatic pressure on structural organization of the maize root cells]. AB - We analyzed the effect of hydrostatic pressure at 24 MPa level on the growth and organization of corn seedlings cells. At pressure value of 2 MPa, we observed the clarification of the mitochondrial matrix, clusterization of endoplasmic reticulum elements with formation of ergastorplasm sites and the increasing number of small vacuoles in the cytoplasm. We detected the accumulation of vesicles with electron-dense content on the trans side of dictyosomes, which indicates a change in the endomembranous system traffic. The reduction of electronic density of tonoplast was accompanied by a reduction of osmiophilic inclusions in the vacuoles. Increasing the pressure up to 4 MPa showed the emergence of destructive alterations in the tonoplast. None of the variants showed any violation of plasmalemma integrity, as confirmed by coloring with Evans blue. When we reset the hydrostatic pressure to atmospheric pressure, the frequency of structural distortions of the tonoplast membrane was proportional to the pressure difference: the minimum was at reset from 2 to 0 MPa and the maximum was at reset from 4 to 0 MPa. Thus, it has been concluded, that the endomembraneous system is among the targets of pressure effect on the plant cells. PMID- 25509109 TI - [The STAT5 signaling in the expression of alpha-subunit of interleukin-2 receptor in human blood lymphocytes]. AB - The comparative study of the STAT3 and STAT5 activity (as assessed by tyrosine phosphorylation level) and the expression of a alpha-subunit of interleukin-2 receptor (as examined by cytophotometric evaluation of the number of CD25+ cells) during the phytohemagglutinin (PHA)-induced proliferation of human blood lymphocytes (HBL) have been made. It has been revealed that the level of STAT3 phosphorylation is high in both res ting and competent HBL and remains unchanged in the presence of PHA or interleukin-2 (IL-2). In contrast to STAT3, phosphorylation of STAT5 was not seen in both resting and competent HBL. We observed phosphorylation of STAT5 no earlier than 5 h after PHA stimulation and the maximum phosphorylation was detected following 24 h. Exogenous IL-2 induced high level of STAT5 phosphorylation in the competent HBL as early as at 30 min and this level of STAT5 phosphorylation kept in the next 24-48 h. The correlation between alterations in tyrosine phosphorylation level of STAT5 and the expression of CD25 has been established. WHI-P131, an inhibitor of JAK3 kinase, prevents STAT5 activation, cell surface expression of CD25 and lymphocyte proliferation. It has been concluded that JAK3/STAT5 signaling via IL-2 receptor is necessary to maintain the long-term expression of the high-affinity alphabetagamma(c)-receptor of IL-2 and optimal proliferation of HBL. PMID- 25509110 TI - [Ability of the influenza viruses and their envelope proteins to stimulates endothelial cells apoptosis in vitro]. AB - The ability of the modern epidemic strains of influenza virus type A (subtypes H5N1, H3N2, H1N1pdm) and their surface proteins, hemagglutinin (HA) and neuraminidase to cause the activation of the cellular protein caspase-3 and stimulate the emergence of phosphatidylserine on the membrane of human endothelial cell line EAhy926 has been studied. It was questioned how the viruses and their surface proteins that were studied cause the activation of caspase-3 after 0.5 h of exposure that recorded immunogistotsitohimicheski. The test viruses and neuraminidase (concentration 10 MUg/ml) led to the appearance of phosphatidylserine on the cell membrane in a time interval of 2-8 h from the beginning of the treatment, which was recorded by flow cytometry. The death of endothelial cells when exposed to the HA (in a concentration of 50 MUg/ml) and in the same time frame was not accompanied by the appearance of phosphatidylserine. The specific feature of apoptotic cell death during the reproduction of the virus are described, as well as the effects of viral proteins. PMID- 25509111 TI - [Karyotypes of four species of chironomids (Diptera, Chironomidae) from Northern Italy]. AB - Karyotypes of 4 chironomid species were studied: Cryptochironomus obreptans Walker, Criptochironomus sp., Chironomus plumosus Linnaeus and Stictochironomus rosenscholdi Zetterstedt. All these species belong to the subfamily Chironominae. Each species is characterized by the specific karyotype structure. The first species in the list has 2n = 4, while the other 3 species have 2n = 8. PMID- 25509112 TI - [Endoplasmic reticulum: membrane contact sites]. AB - The review of modern data about a functional purpose of membrane contact sites (MCSs) of endoplasmic reticulum is presented. Traffic problems of lipids and calcium in MCSs are discussed. The sufficient condition for giving MCSs of certain functional is not received till now; the problem of the "anchors" providing contact of two membranes, definitively is not solved. The question of ability of MCSs to realize free diffusion of any small molecules (presumably to 1.5 kDa) and ions between compartments is discussed. PMID- 25509113 TI - [Effect of type I collagen and fibronectin on cell morphology of human MSCs in vitro]. AB - Limited knowledge about behaviour of stem cells in culture seems to be one of the reasons for problems in their successful introduction to applied medicine. To address this issue we have studied in vitro interaction of human mesenchymal stromal cells (MSCs) with various substrates (plastic, type I collagen, fibronectin, and mixtures of these proteins at various ratios) during the 16-18 h after cell plating. Several cell morphology features such as Area, Perimeter, spreading coefficient, polarization coefficient were determined. It has been shown that MSCs respond specifically to the substrate and can be classified into several groups according to the parameters studied. Collagen preferably fibronectin have opposite effects on polarization and spreading of the cells. Collagen preferably enhances polarization of the cells, whereas fibronectin stimulates proportional spreading of cells. Effect of collagen-fibronectin mixture on the cells cannot be considered as a simple additive effect. We assume that variation in the ratio of these proteins in the extracellular matrix might be one of the possible ways to influence the morphology of stem cells when they are induced to differentiate. PMID- 25509114 TI - [The influence of substrate from extracellular matrix proteins on karyotypic variability of the Indian muntjac skin fibroblast two cell lines]. AB - The effect of cell culture conditions on numerical and structural karyotypic variability was investigated in two Indian muntjac skin fibroblast "markerless" cell lines, M and MT. The cells cultivated on the substrate consisting of extracellular matrix proteins (ECM), synthesized by human mesenchymal stem cells (SC5-MSC). The character of cell distribution for chromosome number of cell line M changed after cultivation for 1 and 4 days as compared to control cells, which were cultured on hydrophilic surface without ECM-coating. These changes involve a significant decrease in frequency of cells with modal numbers of chromosomes and an increase in frequency of cells with lower chromosome numbers. Many new types of additional structural variants of the karyotype (SVK) appear. MT cell line, differing from M line in the number of homologous chromosomes, demonstrated similar with M line the character of cell distribution for chromosome number only for 1 day after cultivating on the ECM-substrate, but not after 4 days in the same culture conditions, no difference from the control cells was observed. The observed alterations seem to be due to disturbances in correct chromosome segregation process, which were caused by abrupt shift in the cell culture conditions. The analysis of the structural karyotypic variability revealed significant increase in frequency of chromosomal aberrations in M cell line for 1 and 4 days in culture on the ECM-substrate as compared to the control cells. The frequency of dicentric chromosomes (telomeric associations) was increased and constituted more than 50% of all chromosome aberrations. No increase in frequency of chromosome aberrations was observed for MT cells cultured in the same conditions. The obtained results show that the cell lines of the same origin but of different karyotypic structure react to substrate in a different way. In contrast to M line, in MT line a fast normalization of numerical karyotypic characteristics and no enhancement of structural karyotypic variability takes place. This provides a possibility to cultivate MT cell on the given protein substrate maintaining a balanced karyotypic structure characteristic of MT cell line. PMID- 25509115 TI - [Reaction of population of pulmonary mast cells in rat bronchial asthma under the effect of beta-adrenoreceptor antagonists]. AB - Multifunctional granular mast cells (MCs) are among targets in bronchial asthma (BA) therapy. We studied pulmonary MC population in a rat model of BA under the effect of beta-adrenoreceptor antagonists and of the latter combined with the standard therapy (glucocorticoid budesonide + beta2-adrenergic agonist salbutamol). MCs of different degrees of maturity were identified on paraffin section of lung stained with Alcian blue and Safranin. MC density in the lung of rats with BA increased 1.9 times. Alcian blue-positive immature cells predominated in the lungs of both intact rats and rats with BA. In response to pharmacological agents, the mean MC densities were reduced in 2-2.7 times in all the variants of experiments and were close to the norm. It allows us to suppose that MCs migration from the outside was suppressed and, in consequence of the decline of MC densities, the release of the mediators involved in the progression of BA may be diminished. PMID- 25509116 TI - [Interpopulation defferences in parameters of hemocyte DNA-comets of snail Lymnaea stagnalis from regions with the different environmental load]. AB - The research of hemocytes of snail Lymnaea stagnalis from regions with different environmental load has been carried out by means of DNA-comet assay. Significant interpopulation distinctions in parameters of hemocytes DNA comets, and also significant differences of sensitivity of hemocyte genetic matherial in snails form different ecological zones to the influence of external damaging factors (in particular, heavy metals) have been revealed by means of the software analysis of hemocyte DNA-comet images. Since the two populations of mollusks are characterized by high genetic identity, the different levels of proliferative processes in hemocytes of snail Lymnaea stagnalis from different ecological zones (that we revealed using the comet assay) may act as an indicator of the intensity of damaging effects and environmental quality. PMID- 25509117 TI - [Characteristics of primary cell culture from neonatal thyroid grand of pigs: folliculogenesis, hormone and growth]. AB - In the study, comprehensive assessment of proliferative and hormonal activity of primary cell cultures derived from neonatal pig thyroid has been carried out for the first time. We have evaluated the basal and TSH-stimulated secretion of thyroxine and morphological features of culture, depending on the initial state of the material placed in culture: in the form of single cells or follicular conglomerates. Folliculogenesis and formation of dome structures were observed in culture spontaneous and under chronic TSH stimulation. The ability of the cells to expression of beta-III-tubulin during prolonged cultivation in the presence of NGF has been demonstrated in the study. PMID- 25509118 TI - [Line class retroposon is the component of the DNA polymorphic fragments pattern of trematode Himasthla elongata parthenitae]. AB - We have determined that S-SAP method (Sequence specific amplification polymorphism) reveals clonal variability in the genomes of larvae of flatworm Himasthla elongata (Trematoda, Echinostomatidae). Being parthenogenetic the larvae were previously considered to be genetically homogeneous. Cloning and sequencing of a -500 bp conservative fragment (B1) from the fragments' pattern has been performed. Sequence analysis of B1 has shown that this fragment has maximum homology with LINE elements from CR1 family of Hydra and sparrow. In situ hybridization (FISH) has detected dispersed distribution of B1. Several other fragments cloned from the same lane of agarose electrophoresis correspond to conservative domain of reverse transcriptase (RT) from CR1 family. Thus, we have shown that 1) cercariae of trematode H. elongata have clonal variability; 2) the S-SAP method allows to obtaining patterns of fragment distribution characteristic of individual cercariae; 3) conservative domain of RT of CR1 family participates in the pattern of polymorphic fragments generation. Identification of the CR1 transcripts in cercariae of H. elongata transcriptome is the aim of the future work. Cloning of the variable fragments from the fragments' pattern is in progress. PMID- 25509119 TI - [Effect of polychromatic visible light combined with infrared radiation on tumorigenicity of murine hepatoma cells and their sensitivity to lytic activity of natural killers]. AB - Tumorigenicity of murine hepatoma cells (MH22a) and their sensitivity to lysis by natural killers (NKs) have been studied after exposure to polychromatic visible and infrared light (VIS-IR, 480-3400 nm, 40 mW/cm2), similar to the terrestrial solar spectrum without its minor UV component, in order to elucidate the involvement of this important environmental and physiotherapeutic factor in regulation of the anti-tumor defense system. The MH22 cells were in vitro exposed to VIS-IR light and their sensitivity to lytic activity of NKs was evaluated. We found that sensitivity of MH22a cells to lysis by NKs after exposure to VIS-IR light at a dose of 4.8 J/cm2 increased 1.5-2 times, while it did not change after exposure to a dose of 9.6 J/cm2 at all ratios (1 : 5-1 : 50) of the number of NKs (effectors) to that of hepatoma cells (targets). The increase in the sensitivity of hepatoma cells to NKs was accompanied by structural changes of cell surface: the capability of supramembraneous glycoproteins (glycocalix) to sorb the vital dye alcian blue (AB) was significantly lower as compared with the unexposed cells of control group. However, no changes in AB sorption was revealed in hepatoma cells exposed to the light at a dose 9.6 J/cm2. Tumorigenicity of photo irradiated MH22a cells has been studied in the in vivo experiments. Light-exposed (4.8 and 9.6 J/cm2) and intact hepatoma cells were transplanted into syngenic mice C3HA. Tumor volumes 25 days after transplantation proved to be smaller after exposure to the light at both doses than in the control group (4-4.5 times and 2.5-4 times, respectively), which correlated with the increase in the sensitivity to lisys by NKs and decrease in the AB sorption only after light exposure at dose 4.8 J/cm2. Using the flow cytometry method we could show that VIS-IR light at the applied doses did not interfere with the distribution of hepatoma cells over the cycle phases and thus deceleration of the tumor growth was not associated with cytostatic effect of VIS-IR light. To evaluate effect of polychromatic light on the growth of the preformed tumors, the 5-day course of daily light exposures of tumor bearing mice C3HA was carried out in 10 days after subcutaneous transplantation of 2 x 10(5) cells of syngene hepatoma when the tumors had developed in 100% animals. Like in the case of transplantation of the light exposed cells, irradiation of the tumor bearing mice at doses 4.8-9.6 J/cm2 resulted in deceleration of tumor growth (2.1-2.9 and 2.2 times respectively) for 4 weeks as compared with non-irradiated mice. PMID- 25509120 TI - [A method of the mesa trimming with glass knives for the obtaining the large series of ultrathin sections]. AB - Ultrastructural analysis of tissue based on 3D reconstruction from serial ultrathin sections is one of the most adequate methods in the research of spatial organization of biological objects. Sample preparation technique for 3D reconstruction includes two technically the most difficult procedures: an obtaining of a stable ribbon of serial sections and the mounting of the ribbon onto a grid coated with support film. Both special approaches and technical tools for mounting of the ribbon onto the film have been proposed and well appreciated. Much attention has been paid to obtaining the large and stable ribbon of serial section but this mainly concerned the selection of epoxy embedding media. The critical condition for the obtaining the straight and stable ribbon is the precise parallelism of leading (bottom) and trailing (top) edges of the mesa falling onto the cutting edge. The trimming of mesa with dry diamond knife for cryoultratomy allows fulfilling this rule. In the given report, a method for obtaining parallel edges of mesa by means of two forms of glass knives is offered. PMID- 25509121 TI - [The role of different E3 ubiquitin ligases in regulation of the P53 tumor suppressor protein]. AB - Ubiquitin-dependent proteasomal degradation is one of the major pathways of non lysosomal protein degradation in the cell. The ubiquitination process involves several enzymatic reactions and includes the following enzymes: E1--activating, E2--conjugating, and the third--E3--ligating enzymes. E3 ligases determine the specificity of ubiquitination reaction, i. e. what target protein will be subjected to the covalent modification by ubiquitins. The p53b tumor suppressor protein is one of the most intensively studied over the past several decades. Regulation of its activity is a complex and multi-level process that involves many factors. Ubiquitination is one of the major post-translational modifications of p53, and plays a fundamental role in the control of p53 function, its amount, activity and subcellular localization. This review is focused on p53-specific E3 ubiquitin ligases that are potential targets for cancer therapy using small molecule inhibitors. PMID- 25509122 TI - [The structures of plant trophic tract: plastid stromules and cell wall plasmodesmata]. AB - Plastid stromules and cell wall plasmodesmata are special structures of plant cell. They were discovered with time difference in one and half hundred years: stromules--at the beginning of XXI century, plasmodesmata--at the end of XIX century. The former and latter are, correspondingly, the intra- and intercellular fragments of endoplasmic reticulum which is a network for the photosynthate distribution along plant body. Discovery methods and history, structural similarity and differences, succession of functional interpretation are discussed. The origin of both is connected with photosynthesis and photosynthate export. Their tubular structure and transport function are similar. The impulsive mobility of both is under control of the acto-myosin cytoskeleton. Temperature regime of formation and functioning is also the same. Photosynthesis is possible at 0 degrees C and even below. The structures of exporting network, stromules and plasmodesmata, are not formed up to 10 degrees C, and the numbers of both increase sharply at temperature 20 degrees C due to increasing cytoskeleton plasticity. Structural and functional continuity of stromules and plasmodesmata are postulated as the mobile trophic tract of vascular plants. PMID- 25509123 TI - [Investigation of transcriptional regulation of Oct4 (POU5F1) gene with distal enhancer]. AB - Investigations of transcriptional regulation of Oct4 gene in mouse embryonic stem cells have revealed an important cis-element--the distal enhancer (DE). DE consists of two functionally significant elements--DEa and DEb. Both elements are necessary to complete the DE-mediated expression of Oct4 gene in pluripotent cells. The most likely candidates for the binding site DEb are Oct4 itself in complex with Sox2 protein. It remains unclear which transcriptional proteins bind to the DEa site and what is the mechanism of the co-operation between the DEa and the DEb. Through the use of using the EMSA and chromatographic fractionation of proteins from extracts of mouse embryonic stem cells and mouse tissues, were isolated proteins specifically interacting with the sequence DEa Oct4 gene. PMID- 25509124 TI - [Li/Na exchange and Li active transport in human lymphoid cells U937 cultured in lithium media]. AB - Lithium transport across the cell membrane is interesting in the light of general cell physiology and becau- se of its alteration during numerous human diseases. The mechanism of Li4 transfer has been studied mainly in erythrocytes with a slow kinetics of ion exchange and therefore under the unbalanced ion distribution. Prolife- rating cultured cells with a rapid ion exchange have not been used practically in study of Li4 transport. In pre- sent paper, the kinetics of Li4 uptake and exit as well as its balanced distribution across the plasma membrane of U937 cells were studied at minimal external Li+ concentrations and after the whole replacement of external Na+ for Li+. It has been found that a steady state Li+ distribution is attained at a high rate similar to that for Na+ and Cl- and that Li+/Na+ discrimination under the balanced ion distribution at 1-10 mM external Li+ keeps on 3 and drops to 1 following blocking of the Na,K-ATPase pump by ouabain. About of 80% of the total Li+ flux across the plasma membrane under the balanced Li+ distribution at 5 mM external Li+ accounts for the equiva- lent Li+/Li+ exchange. The most part of the Li+ flux into the cell down the electrochemical gradient is a flux through channels and its small part may account for the NC and NKCC cotransport influxes. The downhill Li+ influxes are balanced by the uphill Li+ efflux involved in Li+/Na+ exchange. The Na+ flux involved in the countertransport with the Li+ accounts for about 0.5% of the total Na+ flux across the plasma membrane. The study of Li+ transport is an important approach to understand the mechanism of the equivalent Li+/Li+/Na+/Na+ exchange because no blockers of this mode of ion transfer are known and it cannot be revealed by electrophysiological methods. Cells treated with the medium where Na+ is replaced for Li+ are recommended as an object for studying cells without the Na,K-ATPase pump and with very low intracellular Na+ and K+ concentration. PMID- 25509125 TI - [Extracellular matrix dependence of the cardiomyocyte contractile apparatus organization]. AB - In the process of cardiomyocyte culturing, their contractile apparatus undergoes reorganization involving the convertation of typical myofibrils into non-muscle type structures and subsequent restoration of the initial organization. The causes and mechanisms of the rearrangements described are unknown. In this study, we have shown that cultivation of cardiomyocytes on the individual extracellular matrix proteins, as well as on the matrix produced either by cardiac fibroblasts or by similar cardiomyocyte, reduses the time when the contractile apparatus is in a rearranged state, whereas soluble factors of the conditioned culture do not affect obviously these rearrangements. Using method of extracellular matrix isolation adapted for cardiomyocytes, we have shown that cardiomyocytes in culture produce their own extracellular matrix, which differs from the extracellular matrix of cardiac fibroblasts and varies with the culturing time. PMID- 25509126 TI - [Functional properties of smooth muscle cells in ascending aortic aneurysm]. AB - Thoracic aortic aneurism (TAA) develops as a result of complex series of events that dynamically alter the structure and composition of the aortic vascular extracellular matrix (ECM). The main elements that alter the composition of aortic wall are smooth muscle cells (SMC). The purpose of the present work was to study alteration of smooth muscle cell functions derived from the patients with TAA and from healthy donors. As it is supposed that TAA associated with bicuspid aortic valve (BAV) and with tricuspid aortic valve (TAV) differ in their pathogenesis, we compared the SMC and tissues samples from BAV-, TAV-patients and healthy donors. We compared TAA patients' derived tissues and SMC to healthy donors' ones in several parameters: SMC growth, migration and apoptotic dynamics; metalloproteinase MMP2 and MMP9 activity (zymography) and elastin, collagen and fibrillin content (Western blot) in both tissue samples and cultured SMC. Proliferation ability of both BAV and TAV SMC was decreased comparing to donors cells; migration ability in scratch tests was increased in TAV-derived SMC comparing to donor cells. BAV-cells migration ability was not changed comparing to donor-SMC. Elastin content was decreased in TAA SMC comparing to donor cells whereas the content of fibrillin and collagen was not altered. At the same time elastin and collagen protein level was significantly higher in tissue samples of TAA patients comparing to donor-derived samples. SMS proliferation and migration ability is differently affected in TAV and BAV-associated TAA that supports the idea of different nature of these two groups of TAA. Also our data show that SMC functional properties are altered in TAA patients and these alterations could play a significant role in the disease pathogenesis. PMID- 25509127 TI - [Comparative antioxidant action on the level of reactive oxygen species in normal and transformed fibroblasts]. AB - We studied the changes in the level of reactive oxygen species (ROS) in normal (3T3) and transformed (3T3-SV40) murine fibroblasts under the antioxidant action for 15 min using fluorescent probe carbo- xy-H2DCFDA. We have shown that N acetylcysteine (NAC) decreased ROS level in both cellular types. Another antioxidant, alpha-lipoic acid (ALA), and its reduced form, dihydrolipoic acid (DHLA), caused the prooxidant effects. Both ALA and DHLA in the concentration range of 0.1-1.25 mM increased ROS level in dose dependent manner in both cellular types. The ability of ALA and DHLA to activate hydrogen peroxide production is discussed. PMID- 25509128 TI - [Regulation of adenylyl cyclase activity in the rat testes by acylated derivatives of peptide 562-572 of luteinizing hormone receptor]. AB - One of directions of the search of hormonal signaling systems regulators is the development of peptides that correspond to the cytoplasmic regions of G-protein coupled receptors (GPCR). Modification of the pepti- des with hydrophobic radicals increases their efficiency and selectivity. But currently is not studied as the acti- vity of the peptide depends on the localization of the hydrophobic radicals, their number and the chemical natu- re. The aim of this work was the synthesis of modified by fatty acid radicals derivatives of peptide 562-572 corresponding to the C-terminal region of luteinizing hormone receptor (LHR), and the study of regulatory ef- fects of the acylated LHR-peptides on the basal and hormone-stimulated activity of adenylyl cyclase (AC) in the rat tissues. To elucidate the effect of localization of hydrophobic radicals and their number the modification of peptide 562-572 only at the N- or C-terminus or at both ends was carried out. To study the effect of hydrop- hobicity the residues ofpalmitic (Pal) and decanoic (Dec) acids were selected. Using a solid phase strategy we have synthesized unmodified peptide NDTKIAKK-Nle-A562-572-KA (1) and five of its acylated analogues, such as N[K(Dec)]DTKIAKK-Nle-A562-572-KA (2), NKDTKIAKK-Nle A562-572-[K(Dec)]A (3), N[K(Dec)] DTKIAKK-Nle-A562-572-[K(Dec)]A (4), N[K(Pal)]DTKIAKK-Nle-A562-572-KA (5), and NKDTKIAKK-Nle- A562--572-[K(Pal)]A (6). Peptide 6 modified with palmitate at the C-terminus to a large extent increased the ba- sal AC activity and reduced AC stimulating effect of human chorionic gonadotropin (hCG) in the testes of rats, peptides 3 and 4 modified with decanoate at the C-terminus were less effective, but exceeded in activity the un- modified peptide 1, while peptides 2 and 5 acylated at the N-terminus were little active. The action of peptides was characterized by the tissue and the receptor specificity. Thus, the modification of LHR-peptide 562-572 with fatty acid radicals at the C-terminus increases its regulatory effect on the functional activity of the adenyla- te cyclase system in the rat testes, indicating promising the modification of GPCR-peptides with hydrophobic radicals. These data support the hypothesis that the hydrophobic radical to be localized in the locus of GPCR-peptide, where a transmembrane domain is located in the receptor. PMID- 25509129 TI - [Identification of mechanisms of the calcium signaling at influence of estradiol on porcine oocytes, stimulated by theophillin and somatotropin]. AB - Through the use of inhibitory analysis by using the fluorescent probe chlortetracycline examined the effects of estradiol on the mobilization of Ca2+ from intracellular stores of porcine oocytes stimulated by growth hormone and theophylline. It is shown that somatotropin or theophylline stimulates the mobilization of Ca2+ from intracellular stores of oocytes in control group, while their combined action does not lead to an additional exit of Ca2+ from intracellular stores. Inhibitor of protein kinase C had no effect on the release of Ca2+--from oocyte stimulated by growth hormone or theophylline. In estradiol treated oocytes, only the combined effects of growth hormone and theophylline stimulates the release of Ca2+ from intracellular stores, and that the release of Ca2+ is reduced by the use of an inhibitor of protein kinase C. In the presence of estradiol, an inhibitor of microtubule polymerization blocked the release of Ca2+ stimulated by the combined action of growth hormone and theophylline. Incubation of oocytes in the medium with the subsequent addition of ADP and GDP have an inhibitory effect on the release of Ca2+ from intracellular stores, stimulated joint action of growth hormone and theophylline. The findings suggest the involvement of estradiol in the mechanisms of calcium signaling in porcine oocytes. PMID- 25509130 TI - [Violation of the homologous chromosomes approchement as the answer to the small doses of roentgen irradiation]. AB - Any violation of the homologous chromosome DNA repair leads to the genome instability, characteristic for hereditary syndromes and for aging cells. Using low doses of ionizing radiation (3-10 cGy) we have found any transference of the homologous centromere loci of the chromosome 1 (1q12) from the periphery to the cen- tre of the nucleus in the lymphocytes of young healthy donors. The same effect was found after any influence of RNA-polymerase inhibitor a-amanitine. Some changes in the chromatin structure during aging (70-80 years old patients) result in the difficulties in chromosome displacement, accompanied with any trouble in the appro- achement of the homologous chromosome loci as an answer to low doses of radiation. PMID- 25509131 TI - [Proteasomes and their role in the extracellular space]. AB - The presented review concerns the intracellular proteasome and their possible functions. The ubiquitin-proteasome system (UPS) is responsible for the common regulated proteolysis in the cell. 26S proteasome is a central proteolytic unit of UPS and is a multisubunit protein complex consisting of a core catalytic complex, called 20S proteasome, capped at one or both ends by 19S regulatory complex. Proteasomes have been shown in the extracellular space: in alveolar and cerebrospinal fluids, blood plasma. Extracellular proteasomes are intact intracellular particles that exhibit three types of specific peptidase activity. Extracellular proteasomes have been detected in both healthy people and patients with different diseases. Its concentration has been found to be increased in patients suffering from autoimmune diseases, malignant tumors, trauma or sepsis and to correlate with the disease progression, which has both diagnostic and prognostic value. PMID- 25509132 TI - [Circadian oscillators and hormones]. AB - Circadian mechanism of clock-genes proteins (clock-proteins) directly and through an activation of clock-controlled genes initiates and tides over circadian rhythms of many processes, including secretion of hormones. However, investigations of the hormonal control of circadian oscillators of different levels and functions of clock-proteins apply to "top of iceberg" only. In the review, we analyse the investigations of clock-proteins functions and the hormonal control of clock-genes transcription and posttranslational modifications of clock-proteins. The clock-proteins had been discussed as second messengers for hormonal actions. Besides, the hormonal system is regarded as a system of synchronization of different clock-oscillators with genesis of ultradian, circadian and circannual rhythms. PMID- 25509133 TI - [Comparative morphology of the subphilum Conosa Cavalier-Smith 1998]. AB - Comparative analysis of archamoebae and slime molds morphology revealed that this organisms have a marked similarity in organization of locomotive forms, structure of glycocalix and also in organization of nuclear and flagellar apparatus. A possible scheme of formation the modern diversity of Conosa group was proposed. PMID- 25509134 TI - [Characterization of cultured Sertoli cells under high-temperature and hypoxic conditions]. AB - Sertoli cells (SCs) isolated from adult C57Bl/6 mice were characterized under four different cell culture conditions: standard conditions (34 degrees C, 21% O2 - 34_21), high-temperature conditions (37 degrees C, 21% O2 - 37_21), hypoxic conditions (34 degrees C, 5% O2 - 34_5), and combination of these conditions (37 degrees C, 5% O2 - 37_5). Proliferation and viability were promoted when SCs were grown under hypoxia: 28.5 and 24.6% of SCs were BrdU-positive at the peak of proliferation, 92.7 and 92.7% of SCs were viable after 15 days in culture at 34_5 and 37_5, respectively, versus 20.2 and 88.9% at 34_21, respectively. In SCs grown under high-temperature conditions proliferation was slightly increased, but viability was decreased: 23.1% of SCs were BrdU-positive, and only 74.9% of SCs were viable at 37_21. At the same time cultivation of SCs at 37 degrees C promoted their dedifferentiation: after 15 days in culture 98.8 and 98.6% of cells at 37_5 and 37_21, respectively, expressed a marker of immature SCs- cytokeratin-18, compared to 26.5% at 34_5 and 6.6% at 34_21. Expression of Wt1, a transcription factor controlling cell-cell junction formation and germ cell development, disappeared in most cells after 3 days in culture under all culture conditions. However, SCs forming colonies restored Wt1 expression at day 15 in culture under high-temperature conditions: 59.1 and 29.5% of SCs were Wt1 positive at 37_21 and 37_5, respectively, versus 11.1 and 3.6% at 34_21 and 34_5, respectively. Cultured SCs expressed other SC markers (vimentin, clusterin, Gata 4) under all culture conditions. Our results show that cultured SCs may be useful for reproductive biology and regenerative medicine. PMID- 25509135 TI - [Karyosphere capsule in Tribolium castaneum oocytes]. AB - Structure and composition of the karyosphere (karyosome) capsule were studied in the oocytes of a laboratory insect, Tribolium castaneum, with the use of electron microscopy and immunoelectron cytochemistry. Basing on the study of nuclear structure dynamics, we distinguished 8 stages that characterize the period of oocyte growth. At the diplotene stage, T. castaneum oocyte chromosomes conjoin early into a compact karyosphere, but a significant chromatin condensation does not occur. The process of karyosphere formation is accompanied by the development of an extensive extrachromosome capsule surrounding chromatin. The capsule consists of a material of different morphological types. Significant molecular components of the T. castaneum karyosphere capsule are represented by the proteins of nuclear matrix including F-actin and lamin B. Besides the structural proteins, the Sm proteins of small nuclear (sn) RNPs and mature 2,2,7-trimethyl guanosine (TMG) 5'-capped snRNAs are revealed immunocytochemically in the karyosphere capsule. The obtained data can form a basis for further expansion of ideas on the functions of the karyosphere capsule as a specialized extrachromosomal nuclear domain of the oocytes. We believe that the T. castaneum karyosphere capsule plays not only a structural role, but may be involved directly in the processes related to gene expression. PMID- 25509136 TI - [Investigation of the kinetics of insulin amyloid fibrils formation]. AB - Investigation of the structure of ordered protein aggregates--amyloid fibrils, the influence of the native structure of the protein and the environment on the process of fibrillation is currently the subject of intensive research. The present work is devoted to the study of the kinetics of insulin amyloid fibrils formation at low pH values (which are produced at many stages of the isolation and purification of the protein) using a fluorescent probe thioflavin T (ThT). It has been shown that the increase of fluorescence intensity of ThT during the formation of amyloid fibrils is described by a sigmoidal curve, in which 3 areas can be distinguished: the lag phase, the growth and the plateau, which characterize the various stages of fibril formation. Despite the variation in the length of the lag phase at the same experimental conditions (pH and temperature), we have found its reduction with stirring the solution and seeding. Data obtained using electron microscopy showed that the formed fibrils are long, linear filament having a diameter of -20 nm. With increasing incubation time fibril diameter did not change while their length increases to 2-3 MUm, which was accompanied by a significant increase in the number of aggregates of fibrils. All the experimental data shows that, regardless of the kinetics of the formation of amyloid fibrils, their properties after the fibrillation process are identical. The results of this work together with the previously studies of insulin amyloid fibrils might be important for clarification the mechanism of their formation, as well as for the treatment of amyloidosis associated with the aggregation of insulin. PMID- 25509137 TI - [The effect of NADP+ on electrophysiological properties of cardiomyocytes of C57BL/6 and mdx mice]. AB - We have studied the influence of NADP+ on routine ECG in 6 months old C57BL/6 and mdx mice. The animals were anestheized by ether before ECG recording. ECG registration was made with the speed of 100 mm per sec. The first ECG recording was made before intraperitoneal NADP+ injection in a dose of 13 or 80 mg/kg. The second ECG recording was made in 10 min after NADP+ injection. Then anesthesia was cut off. The mice were occasionally anestheized 45-60 min later and the third ECG was recorded in 1 h after injection of NADP+. ECG recording was made at a speed of 100 mm/s in the standard leads I, II and III and in the unipolar leads AvR, AvL and AvF. Values of standard ECG characteristics such as the P wave, intervals PQ, QT, RR, and QRS complex in milliseconds were measured in standard lead II. We did not observe any differences between ECG magnitudes of 2-3 months old C57BL/6 and mdx mice during trial experiments. Mice of both lines had sinus rhythm of heart rate. QRS complex in mdx mice had a tendency to be larger compared with that in C57BL/6 mice. Heart rates fluctuated between 722 +/- 22 and 681 +/- 23 beats per minute. NADP+ influences was studied in 6 months old mice male. The increase in the RR interval and decreased heart rate from 697 +/- 2 to 461 +/- 23 and 491 +/- 28 beats per min for C57BL/6 mice (P < 0.01) and from 722 +/- 28 beats per minute to 454 +/- 31 beats per min for mdx mice were registered in 10 min after NADP+ injection in a dose of 80 mg/kg. The increase in the RR interval can be explained by an increase in the interval QT. A statistically significant reduction in the QT interval leading to a decrease in the RR interval was observed in mdx mice in 1 h after NADP+ injection. NADP+ in a dose 13 mg/kg did not change mdx mice ECG properties significantly. ECG of mdx mice were characterized by negative repolarization of T wave in 37% between all leads. A deal of leads with the negative T wave repolarization decreased up to 3% in 1 h after NADP+ injection in a dose of 80 mg/kg. The results have shown that cytomembranes of ventricular cardiac myocyte and the degree of oxidative stress are the main touches of NADP+ influence in the cases of C57BL/6 and mdx mice hearts. PMID- 25509138 TI - [Histochemical and immunohistochemical localization of choline acetyltransferase in the nuclei oblongata rat brain]. AB - ChAT-positive neurons in the nuclei of the medulla oblongata of Wistar rats have been studied with the use of histochemical and immunohistochemical methods. We have found that the topography and the number of cholinergic neurons at the projection nuclei studied largely depend on the method of detection of these neurons. Histochemical method always revealed more neurons than immunohistochemistry. Such a feature of ChAT-positive neurons detection was clearly seen among the majority of nuclei in the medial region and in some of the nuclei in the lateral region of the medulla oblongata. The number of immunoreactive cells in the nuclei varied from 17 to 26%, whereas the histochemical reaction determined 1.5-3 times more neurons in the same nuclei. ChAT-positive cells in the nuclei of the back seam were detected mainly by a histochemical method. PMID- 25509139 TI - [Organization of mitochondria in the growing hyphae of Neurospora crassa]. AB - In vivo fluorescent labeling of mitochondria in Neurospora crassa showed the concentration of filamentous mitochondria within 30 MUm of apex in growing hyphae. These mitochondrial assemblies propagated forward with the elongation of hyphae, split and segregated as the growing tip bifurcated and formed de novo when new branches formed farther away from the apex. The efficiency of the mitochondria concentration in the apical 30 MUm zone is related to the growth rate and identical in hyphae cultivated in glucose- and sorbitol-containing media. The obtained data are discussed in connection with the behavior of microtubules in growing hyphae as well as with the electric heterogeneity of N. crassa hyphal apex described previously. PMID- 25509140 TI - [Soluble forms of adenylyl cyclases of spermatozoa]. AB - Soluble (cytosolic) forms of adenylyl cyclases (sAC), the enzymes catalyzing the conversion of ATP to the second messenger cAMP, play a key role in the regulation of spermatogenesis, control maturation of spermatozoa in the epididymis and their capacitation in the female genital tract, which determines their ability to fertilize. In the last years the significant progress was made in the study of the structural and functional organization and regulatory properties of sAC, their localization in the spermatozoa as well as in the investigation of intracellular cascades functionally coupled with sAC, including protein kinase A, cAMP-dependent phosphodiesterase, non-receptor tyrosine kinases, tyrosine phosphatases, transcription factors of CREB/CREM-family. The molecular mechanisms involved in the regulation of the intracellular concentration of bicarbonate anions, the main endogenous activators of sAC, were deciphered. Many evidences were obtained that the decrease of functional activity of sAC and signaling cascades and effector proteins coupled to it, as well as bicarbonate anion transporters lead to disturbances of spermatogenesis. As a consequence, the development of approaches for controlling the activity of sAC in spermatozoa is one of the priority ways to treat dysfunctions of the male reproductive system. Present review is devoted to advances in the study of soluble forms of AC and functionally coupled to them signaling cascades and effector proteins in the spermatozoa, as well as to the unresolved issues in this area. PMID- 25509141 TI - [Features of rat cells karyotypic abnormalities in rat cells in their transformation in vitro]. AB - Neoplastic transformation of cells is characterized by karyotypic abnormalities involving aneuploidy, quantitative changes, as well as multiple clonal rearrangements of the number and structure of chromosomes. It is probable that chromosomes are one of the mechanisms of cells immortalization and transformation. Despite many years of study of chromosomal rearrangements, data on primary chromosomal rearrangements in early stages of transformation is still insufficient. We examined karyotypic abnormalities in embryonic rat fibroblasts in both the spontaneous transformation and transformation by oncogenes at different passages in vitro. Literature data and results of our cytogenetical analysis of rat cells lines established by different methods of transformation of cells of different tissue origin in vitro have shown that cell karyotype at early passages may either be normal or acquire diverse clonal chromosomal abnormalities. At later passages, other chromosomes of karyotype are involved in new rearrangements. Despite this, some of the lines do not acquire the malignant phenotype and remain to be immortalized. The role of instable chromosomes and their loci in immortalization and transformation of cells is discussed. PMID- 25509142 TI - [Endothelial cell cytoskeleton reorganization during functional monolayer formation in vitro]. AB - The endothelium lining the inner surface of blood vessels regulates vascular permeability, permitting the exchange between the blood circulating in vessels and tissue fluid, and performs thereby the barrier function. Endothelial cells cultured in vitro retain the ability to perform a barrier function that is inherent in vascular endothelial cells in vivo. Endothelial monolayer in vitro is a unique model system that allows studying the interaction of cytoskeletal and adhesive structures of endothelial cells from the earliest stages of its formation. In this paper we describe and characterize quantitatively the changes in the cytoskeleton of endothelial cells from the time of endothelial cells spreading on the glass and formation of the first contacts between neighboring cells un- til the formation of a functional confluent monolayer. The main type of intermediate filaments of endothelial cells were vimentin filaments. The location of vimentin filaments and their number did not change at different stages of the endothelial monolayer formation, they occupied more than 80% of the cells. The system of actin filaments in endothelial cells was represented by the cortical actin at the cell periphery and bundles of actin stress fibers arranged in parallel. Upon the formation of contacts with neighboring cells the number and thickness of actin filaments increased. In addition, the formation of the endothelial monolayer led to changes in microtubule network, which was evident from the increase in the number of microtubules at the cell edge. Further, at all stages of assembling the endothelial monolayer, the number of microtubules formed at the cell margin in the area of cell-cell contacts exceeded the number of microtubules in the area of the free lamellae. PMID- 25509143 TI - [Ultrastructural organization and composition of carotenoids in the eyespot in the mutant Chlamydomonas reinhardtii]. AB - Biogenesis of the ultrastructure of the eyespot in the chloroplasts of unicellular green algae Chlamydomonas reinhardtii has been studied. We have found that the development of the structure of the eyespot correlates with the accumulation of carotenoids. Depending on their accumulation, the eyespots form from 1 to 4 lines of lipid-carotenoid globules. It has been shown that only carotenes are accumulated in the globules of the eyespots. We first have found that the composition of carotenes in the eyespots of the mutants may vary due to the changes in their composition in the membranes of chloroplasts. PMID- 25509144 TI - [Dynamics of morphofunctional changes in aging bovine ova during the prolonged culture in vitro]. AB - In the absence of activating stimuli, aging processes are initiated in matured mammalian oocytes, which negatively affect the quality of ova and their capacity for further development. On the model of the prolonged culture of bovine oocytes, the dynamics of a number of morphofunctional changes associated with the postovulatory aging was investigated in the present work. In cumulus-enclosed oocytes, migration of the first polar body relative to metaphase II chromosomes started between 18 and 22 h of maturation. The angle of the body deviation from the metaphase plate rose as the culture time increased to 30 h. By 32 h of culture, a gain in the rate of ova with the abnormal chromosome morphology was observed that continued up to 56 h. Furthermore, after 56 h, signs of spontaneous parthenogenetic activation were revealed in 16 percent of matured oocytes. During the prolonged culture of oocytes deprived of cumulus cells after 20 h of maturation, an increase in the frequency of chromosomal abnormalities was found only by 44 h. At the same time the cumulus elimination did not affect the maintenance of the meiosis II blockade in aging ova. Meanwhile, destructive chromosomal changes in oocytes were attended by a gradual rise in the level of apoptotic degeneration and reduction in the proliferative activity of surrounding cumulus cells. The results obtained point to the various temporal dynamics of distinct morphofunctional changes and to the participation of cumulus cells in modulation of the speed of metaphase chromosome destructive modifications in aging bovine ova. PMID- 25509145 TI - [Proliferative and secretory activity of human umbilical vein endothelial cells cultured under varying degrees of hypoxia]. AB - In this study we examined the impact of 3-day hypoxia of varying degrees on the viability, proliferative and secretory activity of endothelial cells in human umbilical vein (HUVEC). The gas mixture of the three components (%) was used: 1) 10 O2, 5 CO2, 85 Ar; 2) 5 O2, 5 CO2, 90 Ar and 3) 1 O2, 5 CO2, 94 Ar. The HUVEC, cultivated in CO2-incubator under conditions of atmospheric oxygen (21% O2) were the controls. Comprehensive assessment of the results after has shown that 3-day HUVEC cultivating in the presence of 1% O2 led to pathological activation of endotheliocytes: increased NO synthesis combined with the marked secretion of endothelin-1, IL-6, IL-8 and TNF-alpha, sVCAM-1, sE-cadherin and of sE-selectin, VEGF-A and bFGF, and slow proliferation. When HUVEC were cultivated at 10% O2 and 5% O2, the level of basal secretion of the substances listed above was the least against the background of increased proliferative activity. The results showing the changes in the secretory activity of endothelial cells when cultivated under the conditions of atmospheric oxygen levels have demonstrate HUVEC activation, because the secretion of NO, IL-6, IL-8 and von Willebrand factor after 3 days of cultivation in 21% 02 exceeded that in the case of 10 and 5% O2. Thus, a gaseous medium with reduced oxygen content of up to 5% provides more physiological conditions for HUVEC cultivation. The maximum proliferative activity of HUVEC with minimal basal secretion proved such a composition to be comfortable. Increasing the oxygen content to the atmospheric level leads to the activation of endotheliocytes with signs of endothelial dysfunction, and the critical reduction in oxygen to 1% causes the development of endothelial dysfunction and reduces the proliferative potential. PMID- 25509146 TI - [Apoptosis and necrosis of lymphocytes induced by UV-radiation in the presence of autological plasma]. AB - The influence of UV-light (240-390 nm) in doses 151-3020 J/m2 on the nature of the death of lymphocytes cells of donor's blood (using markers of apoptotic and necrotic death of cells) and on the level of expression of the marker of apoptotic pre-preparation--CD95-receptor has been investigated. We have shown that UV-radiation increases expression of CD95-receptors which is caused mainly by de novo synthesis of the receptors. It has been revealed that during daily incubation of photo-modified lymphocytes (151 and 755 J/m2) without autological blood cell death occurs by receptor-involved apoptosis. Exposure to high doses of radiation (1510 and 3020 J/m2) causes massive necrotic death of immunocytes. The use of autologous blood plasma during incubation of photo-modified lymphocytes allows decreasing the number of both apoptotic and necrotic cells. PMID- 25509147 TI - [Lysophosphatidic acid and human erythrocyte aggregation]. AB - The effects of lysophosphatidic acid on the morphology and aggregation of human erythrocytes has been studied. Morphology of erythrocytes and their aggregates were studied by light microscopy. It has been shown that lysophosphatidic acid changes the shape of red blood cells: diskocyte become echinocytes. Aggregation of red blood cells (rouleaux) was significantly reduced in autoplasma. At the same time there is a strong aggregation of echinocytes. This was accompanied by the formation of microvesicles. Adding normal plasma to echinocytes restores shape and aggregation of red blood cells consisting of "rouleaux". A possible mechanism of action of lysophosphatidic acid on erythrocytes is discussed. PMID- 25509148 TI - [The functioning of hormone-sensitive adenylyl cyclase system in the peripheral tissiues in diabetes mellitus]. AB - Diabetes mellitus (DM) induces changes in the functioning of hormonal signaling systems in the peripheral organs and tissues, which is one of the key reasons for the development of DM complications. The main factors that lead to such changes are insulin deficiency and hyperglycemia in type 1 DM (DM1), and insulin resistance and hyperinsulinemia in type 2 DM (DM2). Of greatest interest are the alterations in hormone-sensitive adenylate cyclase signaling system (ACSS), that controls a wide range of biochemical and physiological processes, and is subject to significant changes in pathology. There is a lot of evidence to suggest that in DM in the peripheral tissues there are significant abnormalities of the functional activity of ACSS, which leads to the development of diseases of the cardiovascular system, metabolic disorders, diabetic peripheral neuropathy, and reduced reproductive functions. These disorders affect different stages of hormonal signal transduction via ACSS and are characterized by hormone, receptor, and tissue specificity, and are strongly dependent on the type of DM, its duration and severity. This review summarizes and analyzes the literature data and the results of authors' studies on the functional state of ACSS in the peripheral tissues (the myocardium, skeletal muscle, liver, adipose tissue, and reproductive organs) in animals with experimental models of DM1 and DM2 and in patients with these diseases. It has been concluded that the study of the changes and abnormalities of ACSS in the peripheral tissues in DM necessary for understanding the etiology and pathogenesis of this disease, and for developing effective approaches to prevent and treat its complications. PMID- 25509149 TI - [Response of HeLa cells to mitomycine C. III. The analysis of nucleoli of mother and daughter cells]. AB - The comparative analysis of the number of nucleoli in cells of the established HeLa-M line was carried out before and after exposure to mitomycin C in a concentration of 10 MUg/ml for 2 h. Using time-lapse microscopy, nucleoli in mother and their respective daughter cells were computed. It has been shown that the average number of nucleoli per cell is generally higher in daughter cells than in mother cells, and a standard deviation, on the contrary, decreases. An average number of nucleoli in daughter cells, whose mother cells had been treated with mitomycin C, was higher than in corresponding cells of control group. The separate analysis has been performed for the cells having from 1 to 4 nucleoli. Nonrandom complete coincidence of the number of nucleoli in mather and daughter cells has been typicaly shown for about 1/7 of the total cell population. Mitomycin C reduces this value of about 1.5 times. PMID- 25509150 TI - [Features of cytogenetic changes in the human lymphoma U-937 cells after induction of apoptosis by tumor necrosis factor]. AB - A comparative analysis of the frequency of cytogenetic abnormalities in cell population U-937 in control conditions and after exposure to tumor necrosis factor has been performed. We have found that in such treatment there is a maximum effect after 48 h, which is expressed in the stimulation of apoptosis and the accumulation of cells with micronuclei and binuclear cells. The induction of premature chromosome condensation is an early marker of the TNF influence. Changing the composition of the population by the number of chromosomes in the cell may lead to the emergence of a subline with new properties compared to the parental cell population. PMID- 25509151 TI - [Intracellular immunoglobulins in Namalwa and U266 cells co-cultivated with mesenchymal stromal cells]. AB - There are contradictory data concerning the influence of mesenchymal stromal cells (MSC) on immunoglobulin (Ig) production. Most of them were obtained using MSC from bone marrow. Properties of MSC from other tissues are elusive. In the present work MSC cultures were derived from umbilical cord, adipose tissue, and bone marrow of healthy donors, as well as from bone marrow of patients with autoimmune diseases. MSC from all these sources had similar surface markers phenotype. The influence of co-cultivation with MSC at exponential or stationary phase on IgM and IgE content in Namalva and U266 cells was evaluated. MSC from bone marrow of healthy donors had no effect on IgM and IgE production. Proliferating MSC obtained from patients with Crohn's disease and multiple sclerosis stimulated Ig production. Exponentially growing MSC derived from umbilical cord and adipose tissue also stimulated Ig synthesis. MSC at stationary cultures amplified IgM production in Namalva cells and suppressed IgE synthesis in U266. Thus, MSC with similar phenotype but derived from different sources differ in their capacity to modulate Ig production in B-lymphoid cells. The effect of MSC depends on their growth stage and may differ for lymphoblastoid and myeloma cells. PMID- 25509152 TI - [Effect of sex inversion in embryos of domestic chicken (Gallu gallus domesticus) by influence of letrozole and tamoxifen]. AB - Realization of program of sex formation in multicellular organisms is a complex multistage process. The role of the inductor in this process is assigned to sex hormones synthesized by cells of the emerging gonads. The action of androgens on the formation of the male is now well understood. However, little is known about the involvement of estrogen the female gonad formation and the formation of a female as a whole. Here we present the results of experimental sex inversion in female chickens produced by aromatase inhibition and by the action of tamoxifen on chicken embryos. We have shown various masculinizing effect depending on the dose of active substance and the number of injections. We have noted that inhibition of aromatase does not block meiotic prophase in oogoniums. We have suggested that there are differences in the mechanisms of action of retinoic acid and estrogens on oogenesis. We have first shown proteins and nucleoproteins that interact with the estrogen receptor 1 and provided maps of their gene localization in human and chicken genomes. PMID- 25509153 TI - [Influence of cholesterol on macrophage foam cells formation at zymosan-induced inflammation of mice]. AB - It has been shown recently that significant number (to 40% from total population) of macrophage foam cells (MFC) is formed during early time (24 h) of zymosan induced peritonitis resolution and agonists of peroxisome proliferation activated receptors-alpha, -gamma (PPAR-alpha, -gamma) exert anti-inflammatory action, protecting their formation (Dushkin et al., 2007). The work is devoted to investigate of the influence of cholesterol-containing liposomes (CHL) on dinamic of zimozan-induced peritonitis in C57Bl/6 mice. The accumulation of cholesterol, the change of cytokine production, PPAR-gamma activity and cholesterol efflux in macrophages of C57Bl/6 mice has been investigated. The infiltration of neutrophils, amounts of mononuclear cells and MFC formation were significantly increased in peritonel cavity of zymosan-induced mice that led to in expansion of the period of inflammatory resolution and of the period of MFC resolution. If macrophages obtained after zymosan injection mainly accumulated triglycerides (TG) and at high speed incorporated [1-14C]oleate into TG, the injection of CHL after zymosan-indused inflammation lead to dramatic promotion MFC containing primarily free cholesterol and Ch ethers and been aggravation of [1-14C]oleate incorporation into cholesterol ethers in macrophages (mainly for 2 days). It has to shown that CHL against a background of inflammation promoted reduction of fluorescent NBD-cholesterol efflux from macrophages throughout the studied period (5 days) whereas zymosan inhibited cholesterol efflux at the early stages of inflammation (1 and 2 days), then, on 3ed day, the cholesterol efflux was recovered and increased on day 5. At the same time CHL stimulated the production of TNFalpha and TGFbeta and inhibited the production of IL-10 and DNA-binding activity of PPAR-gamma macrophages obtained at early as well as late stages of zymosan-induced peritonitis (compared with injection zymosan only). Thus, accumulation of cholesterol in inflammatory macrophages and promotion of MFC formation prolog timely resoluti- on of acute inflammation inducing alteration of pro- and anti-inflammatory cytokine balance and evoking the repression of macrophage DNA-binding activity of PPAR-gamma and cholesterol efflux. PMID- 25509154 TI - [Cellular immune system of surgical maggots Lucilia sericata (Diptera, Calliphoridae)]. AB - In the hemolymph of surgical maggots Lucilia sericata seven types of hemocytes were revealed. These are prohemocytes, stable and unstable hyaline cells, thrombocytoids, spindle cells, larval plasmatocytes and plasmatocytes I-IV, which represent sequential stages of one cell line differentiation. In contrast to Calliphora hyaline cells, this type of hemocytes in cropemptying larvae of Lucilia is elongated or vermiform in shape. Hyaline cells may be transformed to both prothrombocytoids and unstable prophenoloxydase-producing cells. Appearance and differentiation of each hemocyte type is rigidly linked with a definite stage of development. In cellular defense the main role play juvenile plasmatocytes, plasmatocytes II and III and trombocytoides. Juvenile plasmatocytes are the most active ones. After charcoal particles injection they were instantly surrounded by the thick envelope of adhered alien particles and form uniform morules aggregations or conglomerates together with thrombocytoidal agglutinates. Plasmatocytes II and III during the early stages of differentiation may be involved in adhesion and phagocytosis of alien particles and during the last stages in the engulfing of apoptose desintegrated tissues. Thus the cellular defense reaction is assisted by 4 hemocyte types--prophenoloxydase-unstable hyaline cells, thrombocytoids, juvenile plasmatocytes and plasmatocytes I-IV. PMID- 25509156 TI - [The manifestation of synergy during simultaneous thermochemical action on yeast cells]. AB - In order to obtain new fundamental knowledge, patterns of manifestation of synergy have been studied after simultaneous combined action of hyperthermia (47.5-60 degrees C) with anti-tumor agents (cyclophosphamide, cisplatin) on the survival of yeast cells. To calculate the efficiency of the synergistic interaction, the dependence of cell survival on the duration of exposure at separate and simultaneous action of chemical agents and hyperthermia was used. We have found that there is a certain temperature range within which there is a synergistic enhancement of anticancer drugs and high temperature effects. Any deviation from the optimum values of the temperature results in a decrease in synergy. The possible mechanism of the revealed patterns is discussed. PMID- 25509155 TI - [Cellular defense system of some synanthropic dipterans inhabitant of bacterially aggressive environment]. AB - The hemocytic count and defense reaction within 4 families of higher Diptera: Tabanidae, Syrphidae, Muscidae and Sarcophagidae, whose larvae inhabit bacterially aggressive environment, were investigated. The least hemocytes types (3) were revealed in Tabanidae and Syrphidae larvae--prohemocytes, plasmatocytes and prophenoloxydase-containing unstable hyaline cells (oenocytoids). In Sarcophaga crassipalpis and Musca domestica stable hyaline cells and thrombocytoids or podocytoid-like cells can be added to this set. At the time of pupariation in Sarcophaga, new generation of prohemocytes is segregated into the hemolymph, which form small round or spindle-shaped hyaline cells. So, the number of plasmatocyte types in Sarcophaga increase to six. Typical to Calliphoridae juvenile plasmatocytes in the members of investigated families are absent. Among the one hemocyte type morphology also can vary, especially in unstable prophenoloxydase hyaline cells. In Drosophila there are crystal cells containing in the cytoplasm paracrystalloidal inclusions. In Calliphoridae there are big hyaline cells with homogenous cytoplasm producing circumferential bubbles. Both in Sarcophaga and Tabanidae they contain in their cytoplasm big globules. However in Sarcophaga they rapidly disintegrate, while in Tabanidae are maintained unchanged during hours. In Muscidae and Syrphidae prophenoloxydase extrusion occurs very early and these cells obtain pycnotic nuclei and very liquid cytoplasm with strings of granules. Thrombocytoids in Musca larvae are represented by big flattened anucleated irregular cytoplasm and "naked" nuclei and cytoplasmic fragments often with fan-like projections. Plasmatocytes in all species studied are the cells with pronounced phylopodies. In larvae they contain cytoplasmic catabolic inclusions and in pupa--ragments of apoptotic tissues. Clearance of hemolymph from alien particles in Sarcophagidae and Muscidae occur by thrombocytoides, while in Tabanidae by plasmatocyte nodulation. A differing case is Syrphidae whe-e charcoal injection produce depletion of hemolymph both from particles and all types of hemocytes. So the specimen of different higher Diptera families can use different schemes of cellular defense reaction. PMID- 25509157 TI - [On the possibility of spontaneous interspecific hybridization in the nature of representatives of sibling-Species Chironomus riparius Kieffer and Chironomus piger Strenzke (Diptera, Chironomidae) from Armenia]. AB - F2 hybrid (Chironomus riparius x Chironomus piger) x C. piger was found in mixed community of C. riparius and C. piger. Mechanism of its origin and problem of hybrid viability is considered. PMID- 25509158 TI - [Characteristics of migration of adipose tissue derived mesenchymal stromal cells after co-cultivation with activated monocytes in vitro]. AB - Mesenchymal stromal cells (MSC) are considered to be promising tool of regenerative medicine. Migration of MSC toward damaged inflammatory site is essential for physiological tissue reparation. Therefore we studied modifications of migratory features of adipose tissue derived MSC (AT-MSC) after co-cultivation with activated monocytes derived from THP-1 cell line. As a result, we have observed an increased migration rate of AT-MSC in vitro in the absence of chemoattractant gradient as well as toward the gradient of PDGF BB (platelet derived growth factor BB), which is well known chemoattractant for the cells of mesenchymal origin. Furthermore, the rate of directional AT-MSC migration through fibronectin was also increased. We have established that signaling from PDGFRbeta which is activated through binding of integrin receptors with extracellular matrix may be possible way to stimulate cellular migration under simulated inflammatory conditions. PMID- 25509159 TI - [Nuclear lamins regulate osteogenic differentiation of mesenchymal stem cells]. AB - Nuclear lamins are the major proteins of nuclear envelope and provide the strength of nuclear membrane as well as the interaction of extra-nuclear structures with components of cell nucleus. Recently, it became clear that lamins not only play a structural role in the cell, but could also regulate cell fate, for example lamins could influence cell differentiation via interaction with components of the Notch signaling pathway. Human mutations in LMNA, encoding lamin A/C lead to diseases commonly referred to as laminopathies. Different mutations cause tissue specific phenotypes that affect predominantly a tissue of mesenchymal origin. The nature of this phenomenon, as well as the mechanisms by which lamins regulate cell differentiation remain poorly understood. The aim of this study was to investigate the effect of different mutations of the LMNA on human mesenchymal stem cell (MSC) osteogenic differentiation, and to explore a possible interaction of lamins and Notch signaling pathway. We modified human MSC with mutant LMNA bearing known mutations with tissue specific phenotype associated with different laminopathies. We have shown that mutations associated with different diseases have different effects on the efficiency of MSC osteogenic differentiation and on the expression of specific osteogenic markers SPP1, IBSP and BGLAP. We have also shown that one of the mechanisms involved in the regulation of MSC differentiation may be an interaction of lamins A/C with components of Notch signaling. PMID- 25509160 TI - [Effect of bone marrow cells transplantation on the decidua formation in pseudopregnant rats]. AB - One of the most common causes of the current pregnancy loss is the failure of the decidual reaction of endometrial cells. It is assumed that a partial source of decidual cells in endometrial tissue is bone marrow cells (BMCs). In the present work, we have studied possible effect of BMCs transplantation on the process of decidualization using the model of pseudopregnancy in rats. BMCs were flushed from the rat femurs and tibias. The obtained suspension of single BMCs was injected into one of rat uterine horns on the 5th day of pseudopregnancy. PBS without cells was injected into the contralateral horn served as the control. Rats were sacrificed on the 11th day of pseudopregnancy. Decidua formed in the experimental uterine horn showed an increase in the meso-antimezometral direction of their diameter of about 1.5-2 times as compared with a control horn. The weight of decidual tissue in the experimental horn exceeded 3 times the weight of the control one. The presence of transplanted BMCs in decidual tissue was documented by preliminary double staining of BMCs with membrane dye PKH 26 Red and nuclear dye Hoechst 33342. Histological analysis of decidua sections after transplantation revealed any alterations neither in cell differentiation nor in tissue structure. We conclude that BMCs transplantation stimulates decidualization in animals. PMID- 25509161 TI - [Efficacy of mesenchymal stem cells intracerebral transplantation for the correction of age-related cerebral microcirculation alterations in rats]. AB - Using a television-based vital microscopy method and immunohystochemical analysis, we have assessed the effect of intracerebral transplantation of syngeneic mesenchymal stem cells (MSC) on the brain cortex structure and the microcirculation in the pia mater of old rats. Using "open field" system, we have studied the effect of MSC transplantation on position-finding and discovery behavior of older animals. We have found that density of microvascular network of the pia mater increased ca. 1.9-fold in MSC recipients, compared to age-matched intact animals. Density of the arteriolar area of microvascular network of the pia mater increased ca. 2-fold. Reactivity of the newly formed arterioles was nearly equal to that of native microvessels. Intracerebral transplantation procedure itself was traumatic for brain cortex of rats, but it had no effect on the microcirculation in the contralateral hemisphere. Intracerebral transplantation of MSC did not improve locomotor behavi- or and emotional stage of old rats, did not increase their position-finding and discovery activity. PMID- 25509162 TI - [Filling the 3D scaffolds by the stromal bone marrow cells depends on the methods of cell seeding and the scaffold surface modifications]. AB - The distribution of bone marrow stromal cells (BMSC) is studied in a 3D poly(L,L lactide) scaffolds. It is shown that the population of cells seeding into the scaffold with a peristaltic pump (dynamic method) allows the penetration of cells inside of the scaffold compared with the application of the cell suspension on the scaffold surface (static method). In contrast to cells seeding to scaffold by dynamic method the cells seeding by static method migrate from scaffolds in the first few days almost completely. It is found that BMSCs cultured in 3D polylactide scaffold modified by fibrin form colonies, while BMSCs cultured in 3D polylactide-scaffold modified by collagen type I distribute inside scaffold such single cells. PMID- 25509163 TI - [Comparative assessment of different approaches for obtaining terminally differentiated muscle cells]. AB - Relevant cell model is essential to study pathogenesis of muscle disorders. However, in the field of muscle research there is no ultimate cell line considered as a standard for studying muscular and neuromuscular diseases. Standard cell line claimed to be well differentiated in muscle lineage, be morphological and physiological similar to mature muscle cells and be easily genetically modified. Therefore, the goal of our study was to pick up available and fruitful cell model of muscle differentiation, that could be further applied for examination of muscular disorder pathogenesis in vitro. We characterized human mesenchymal stem cells (MSC), mature murine muscle fibers and primary murine satellite cells. It has been shown that MSC have very small capacity to myogenic differentiation; moreover, they were able to differentiate only in presence of C2C12 cells. Lentiviral transduction exhibited rather high toxic effect on primary myofibers, and positively transduced cells were not able to response to electrical stimulation, i. e. were functionally inactive. Satellite cells turned out to be the most fruitful cell model since they were easily transduced via lentiviruses and rapidly formed myotubes in differentiation media. Functional analysis of obtained myotubes has confirmed their ability to react to electrical and chemical stimulations; besides, potassium and calcium channels availability has been also demonstrated via patch-clump technique. Taken together, these results imply that satellite cells are the most promising cell line for further experiments aimed at exploring the molecular pathways of muscle pathologies. PMID- 25509165 TI - [Analysis of the secondary structure of linker histone H1 based on IR absorption spectra]. AB - This work was carried out to compare the effectiveness of the methods of infrared spectroscopy in the amide I region and UV circular dichroism to the analyze the protein secondary structure by the example of linker histone H1 and bovine serum albumin (BSA). It has been shown that the application of a diamond ATR cell quantifies the proportion of alpha-helices and beta-structures in a good agreement with UV circular dichroism spectroscopy. It has been shown that histone H1 is able to aggregate, which results in considerable changes in its secondary structure. PMID- 25509164 TI - [Mass-spectrometric analysis of proteasomal subunits possessing endoribonuclease activity]. AB - Proteasomes act as the main apparatus of non-lysosomal intracellular proteolysis and participate in the regulation of most important cellular processes. Despite considerable progress in the understanding of proteasome's functioning, some issues, in particular, RNase activity of these ribonucleoprotein complexes and its regulation remain scarcely explored. In this paper we found several proteins corresponding by electrophoretic mobility to subunits of the complex 20S proteasome to possess endoribonuclease activity with respect to both sense and antisense sequences of the c-myc mRNA 3'-UTR. Mass-spectrometric analysis of tryptic hydrolysates of these proteins revealed in the samples the presence of 20S proteasome subunits--alphal (PSMA6), alpha5 (PSMA5), alpha6 (PSMA1) and alpha7 (PSMA3). A number of novel phosphorylation sites in subunits alphal (PSMA6) and alpha7 (PSMA3), and the form of subunit alpha5 (PSMA5) with a deletion of N-terminal 20 amino acid residues detected. The observed differences of individual subunits in the possession endonuclease activity could be apparently explained by postranslational modifications of these proteins, in particular--by phosphorylation. It is shown that the specificity of the proteasomal RNase activity varies after dephosphorylation and also influenced by Ca and Mg cations. The conclusions made about the impact of the PTM status of proteasome subunits on the specificity of their RNase activity. PMID- 25509166 TI - [Effects of dopamine and adenosine on regulation of water-electrolyte exchange in Amoeba proteus]. AB - Dopamine and adenosine both regulate transport of sodium chloride in the renal tubules in mammals. We have studied the effect of dopamine and adenosine on spontaneous activity of contractile vacuole of Amoeba proteous. Both substances stimulated contractile vacuole. The effect of dopamine was suppressed by D2 receptor antagonist, haloperidol, but not by D1 antagonist, SCH 39166. Adenylate cyclase inhibitor, 2.5-dideoxyadenosine, suppressed the effect of dopamine, but not of adenosine. Inhibitor of protein kinase C, staurosporine, in contrast, blocked the effect of adenosine, but not dopamine. Notably, dopamine opposed effect of adenosine and vice versa. These results suggest that similar effects of dopamine and adenosine could be mediated by different intracellulare mechanisms. PMID- 25509167 TI - [Somnology and sleep medicine in Russia]. AB - The study of human vital functions during sleep could have advantage over studies during wakefulness because sleep potentially is more predictable condition. Besides the factors accompanying sleep (minimization of external stimulation and social interactions, low mental activity, antigravity posture) also increase the quality of data acquisition comparing with wake states. Properly organized clinical investigation in the framework of sleep medicine concept could reveal these advantages and increase the interest to the sleep studies from the community and authorities. This could also promote the investigations in the field of fundamental somnology. PMID- 25509168 TI - [The role of histaminergic system of the brain in the regulation of sleep wakefulness cycle]. AB - The structure, morphological and neurochemical bindings ofhistaminergic system of the brain as one of the most important mechanisms of waking maintenance, are regarded. The biochemistry of histamine turnover and histamine receptors are briefly described. The special role of the relation between histamine and orexin/hypocretin systems is stressed. Some examples of the responses on wakefulness-sleep cycle of the effects of experimental manipulations with the histaminergic system are given. PMID- 25509169 TI - [Participation of Agouti related peptide in machanisms of wakefulness-sleep cycle regulation]. AB - Agouti-related protein (AGRP) is expresses in hypothalamic neurons in human and animals. Immunohistochemical study in rats Wistar rats demonstrates significant changes AGRP optical density in the neurons of arcuate hypothalamic nucleus as well as in processes in the hypothalamus and nucleus accumbens after the 6 hours of sleep deprivation (increase) and after 2 hours of post-deprivative sleep (decrease). Comparison of these results with earlier obtained shows the opposite trend changes in AGRP optical density and speed limiting enzyme of dopamine synthesis-tyrosine hydroxylase in the hypothalamus and in striatonigral system. The increase of AGRP was accompanied by a decrease of tyrosine hydroxylase and the decrease of AGRP, apposite, it increases. The obtained data demonstrate the role ofAGRP as a modulator of the functional activity of the dopaminergic brain neurons. The problem of the relationship of various functions of organism (food behavior, sleep, stress) is discusses by their participation in the regulation of the same neurotransmitter systems. PMID- 25509170 TI - [Sleep, emotions and the visceral control]. AB - It is known that sleep is connected with sensory isolation of the brain, inactivation of the consciousness and reorganization of the electrical activity in all cerebral cortical areas. On the other hand, sleep deprivation leads to pathology in visceral organs and finally to the death of animals, while there are no obvious changes in the brain itself. It stays the opened question how the changes in the brain activity during sleep could be con- nected with the visceral health? We proposed that the same brain areas and the same neurons, which in wakefulness process the information coming from the distant and proprioreceptors, switch during sleep to the processing of the interoceptive information. Thus, central nervous system is involved into the regulation of the life support functions of the body during sleep. Results of our experiments supported this hypothesis, explained many observations obtained in somnology and offered the mechanisms of several pathological states connected with sleep. However, at the present level of the visceral sleep theory there were no understanding of the well known link between the emotional states of the organisms and transition from wakefulness to sleep, and sleep quality. In this study the attempt is undertaken to combine the visceral theory of sleep with the need- informational theory ofemotions, proposed by P. Simonov. The visceral theory of sleep proposes that in living organisms there is a constant monitoring of the correspondence of the visceral parameters to the genetically determined values. Mismatch signals evoke the feeling of tiredness and the need of sleep. This sleep need en- ters the competition with the other actual needs of the organism. In according with the theory of P. Simonov emotions connected with a particular need play important role in their ranking for satisfaction. We propose that emotional estimation of the sleep need, based on the visceral signals, is realized in the same brain structures which undertake this estimation for other behavioral needs in wakefulness. During sleep, the same brain structures, involved in estimation of emotions, continue to rank the visceral needs and to define their order for processing in the cortical areas and in the highest level of the visceral integration. In the context of the proposed hypothesis, we discuss the results of the studies devoted to investigation of the link between sleep and emotions. PMID- 25509171 TI - [Effects of long-term isolation and anticipation of significant event on sleep: results of the project "Mars-520"]. AB - The purpose of the research was to study effect of long-term isolation on night sleep. The data were collected during international ground simulation of an interplanetary manned flight--"Mars-500". The polysomnographic recordings of six healthy men were performed before, four times during and after 520-days confinement. During the isolation sleep efficiency and delta-latency decreased, while sleep latency increased. Post-hoc analysis demonstrate significant differences between background and the last (1.5 months before the end of the experiment) measure during isolation. Frequency of nights with low sleep efficiency rose on the eve of the important for the crew events (simulation of Mars landing and the end of the confinement). Two weeks after the landing simulation, amount of the nights with a low sleep efficiency significantly decreased. Therefore, anticipation of significant event under condition of long term isolation might result in sleep worsening in previously healthy men, predominantly difficulties getting to sleep. PMID- 25509172 TI - [Structure of nocturnal sleep if there is a violation of the blood supply in the territory of internal carotid artery]. AB - The work examines the influence of degree ofstenosis or occlusion of the internal carotid artery (ICA) of noc- turnal sleep and discusses possible neurophysiological mechanisms of sleep disorders when blood flow in ca- rotid system. 24 patients (19 male and 5 female) were examined. The mean age of men was 49.75 +/- 6.55; women--46.67 +/- 5.86. Six patients with a single unilateral internal carotid stenosis (ICA) 50%; seven patients--stenosis of ICA 50-70%; eleven patients--occlusion of ICA completed the study. Polysomnography was recorded with "Neuro-Spectr-5/EP" ("NeuroSoft", Russia) and "Delta Flash" ("Deltamed", France) according to international recommendation. Stages of sleep were identified according to Re- chtschaffen A., Kales A. (1968) criteria. Patients were asked to fill in the questionnaire prior to clinical and polysomnographic evaluation. Regional cerebral blood flow (mL/100g/min) with 99mTechnetium (Gamma-camera, DST-Xli "General electric", USA) was study by single photon emission CT imaging. The result of this study showed that with stenosis of the ICA to 50% structure of nocturnal sleep is not changed: records all phases and stages of sleep, quantitative parameters that match the normative data; or decline in the representation of only the stage II sleep; at stenosis ICA of 50 70% is violation of mostly stage II sleep and slow-wave sleep, and with occlusion ICA violation slow-wave sleep and in 45% of cases--REM-sleep. PMID- 25509173 TI - [Peculiarity of cyclic sleep organization and production of melatonin in intrauterine growth retardation's newborns]. AB - The data about forming of cyclic sleep organization and production of melatonin in intrauterine growth re- tardation's newborns are presented. It was established that disturbance of cyclic sleep organization in newborns with IUGR and low melatonin production indicate the degree of brain's damage after chronic hypoxia. PMID- 25509174 TI - [Clinical and physiological aspects of the arousal reaction in young children]. AB - This review article addresses current knowledge on the arousal reaction during sleep. Diagnostic criteria of the arousal scoring in young children are provided. Possible protective role of the arousal reaction is discussed and certain abnormalities of the arousal mechanisms in some patients with different types of sleep apneas are considered. Potential links between the abnormal arousal reaction and the origins of the sudden infant death syndrome are discussed. PMID- 25509175 TI - [Unusual behaviors in sleep as "compensatory" reactions, aimed at normalizing sleep-alertness cycles]. AB - The present article is an attempt to perform a conceptual clinical and physiological analysis of a large spec- trum of sleep-related phenomena called parasomnias in children, based on data from three independent in- stitutions. Parasonmias appear in the process of falling asleep, at the time of sleep stage changes, and upon awakening. They are common for both healthy children and those with neurological and psychiatric disorders. Brief descriptions of clinical pictures of several groups of parasomnias and their polysomnographic characteristics are presented. Instances of stereotyped rhythmic movements (e.g. head rocking), paroxysmal somatic and behavioral episodes (night terrors and nightmares), "static" phenomena (sleep with open eyes, strange body positions), as well as somnambulism are specifically described. Common features of parasomnias as a group have been identified (the "Parasomnia syndrome"). It was found that sleep architecture frequently normalizes after a parasomnia episode, whereas parasomnias are self-liquidated after sleep matures (self-cure). The significance of gender differences in parasomnias have been reviewed. Possible compensatory physiological functions of parasomnias acting as "switches" or "stabilizers" of sleep stages to "off-set" deviated or immature sleep-wake mechanisms were discussed. PMID- 25509176 TI - [Low-frequency rhythmic electrocutaneous stimulation during slow-wave sleep: physiological and therapeutic effects]. AB - Neocortical EEG slow wave activity (SWA) in the delta frequency band (0.5-4.0 Hz) is a hallmark of slow wave sleep (SWS) and its power is a function of prior wake duration and an indicator of a sleep need. SWS is considered the most important stage for realization of recovery functions of sleep. Possibility of impact on characteristics of a night sleep by rhythmic (0.8-1.2 Hz) subthreshold electrocutaneous stimulation of a hand during SWS is shown: 1st night- adaptation, 2nd night--control, 3d and 4th nights--with stimulation during SWA stages ofa SWS. Stimulation caused significant increase in average duration of SWS and EEG SWA power (in 11 of 16 subjects), and also well-being and mood improvement in subjects with lowered emotional tone. It is supposed that the received result is caused by functioning of a hypothetical mechanism directed on maintenance and deepening of SWS and counteracting activating, awakening influences of the afferent stimulation. The results can be of value both for understanding the physiological mechanisms of sleep homeostasis and for development of non-pharmacological therapy of sleep disorders. PMID- 25509177 TI - [Influence of the level personal anxiety on sleep EEG of men and women]. AB - The psychophysological tests for identification level of personal anxiety and polysomnology was used in present study. The gender differences in organization of sleep phases at first three cycles and spectral density of sleep EEG on persons with high and low levels of personal anxiety were studied. PMID- 25509178 TI - [Analysis of efficiency of human sleep by Pareto principle]. AB - The results of system assessment efficiency of human night sleep which was registered on a large number of people without health problems, and data on the modeling of sleep structure by Pareto principle were showed. In contrast to the assessment of sleep efficiency, as the ratio of the duration of electrophysiological sleep to the total time of sleep, the introduced method increase adequacy assessment by taking into gender factor in the somnology and personalized medicine. PMID- 25509179 TI - [Neurosteroid dehydroepiandrosterone and brain function]. AB - For last 30 years it became clear that DHEA and DHEAS are synthesized de novo in brain. Steroids synthesized in brain structures, were received the name "neurosteroids". In the review are submitted data on a biosynthesis and metabolism of DHEA(S) including its metabolism in fatty tissue where it serves as substrate for intracellular formation of its biologically active metabolites- estradiol and testosterone. The role of a sulfatase and sulfotransferase in mutual transformations of DHEA and DHEA-sulfate are analysed. Specific differences in DHEA synthesis in adrenals are surveyed. The adrenals of primates, both human beings and monkeys, produce free DHEA and DHEA-sulphate in large quantity. Their synthesis proceeds on Delta5-pathways: cholesterol-pregnenolone 17-hydroxypregnenolone-DHEA. Adrenals of other animas species, including rats and mice, don't synthesize DHEA. From the authors point of view, process of DHEAS penetration in brain structures include two mechanisms: transformation under steroid sulfatase action DHEAS in DHEA which freely gets through a blood-brain barrier and DHEAS passing through a hypothalamus which isn't protected by a blood brain barrier. Results of researches on clinical application of DHEA as neurosteroid, with the analysis of its role in a course of Alzheimer's disease, distrurbances of cognitive function and other disorders of a CBS are presented also. The main neurobiological effects of DHEA(S) on brain structures which are studied on various models of animals include: neuroprotection, neurogenesis and neuronal survival, apoptosis, catecholamine synthesis and secretion. Neurosteroids have also antioxidant, anti-inflammatory and anti-glucocorticoid effects. PMID- 25509180 TI - [Systems biology and the project "Encode"]. AB - The goal of this review is to give an incipient knowledge on the background of system biology, the premises to its assignment as a new branch of biology, its principles, methodology and its great achievements in identification of functional elements of human genome and regulation of their concordant and differential activity. The short characteristics of functional elements including the protein-coding sequences and those coding noncoding RNAs, the DNAse 1 hypersensitivity sites and methylated CpG islets, modified histones and specific 3D structure of chromatin, are represented. The topology of transcription factors network with its main motifs, hierarchy, combination and association of transcription factors and their allelic specificity are highlighted. PMID- 25509181 TI - [Reactive oxygen species and stress signaling in plants]. AB - Data on the basic processes and the compartments, involved in formation of reactive oxygen species (ROS) in plant cells, are generalised. The features of structure and regulation of NADPH-oxidase as the one of main enzymatic producers of ROS are characterized. The two-component histidine kinases, ROS-sensitive transcript-factors, ROS-sensitive protein kinase and redox-regulated ionic channels are discussed as the possible sensors of redox-signals in plant cells. The interaction between ROS and other signal mediators, in particular nitric oxide and calcium ions, is discussed. The ROS role as the signal mediators in the development of plant resistance to hyperthermia, osmotic shock and other abiotic stressors is analyzed. PMID- 25509182 TI - [Markers and regulatory mechanisms in ovarian carcinoma]. AB - Ovarian carcinoma is one of widely spread malignant diseases of female reproductive system. Mortality rate from it is much higher than from other female malignant diseases. During last 20 years the level of ovarian carcinoma in Ukraine and vast majority of other countries remains high manifesting no signs of decrease. This arouses interest of researchers to development of new methods of early diagnosis, therapeutic approach, prognostic criteria, especially biochemical ones, and means of prophylaxis of this pathology in medical scientific society. At present there are no specific diagnostic tests which would allow revealing the tumor on the initial stages of its development. In spite of vide arsenal of tumor markers, the only reliable test for ovarian carcinoma is determination of antigen CA-125. The results of basic modern research are discussed in this survey. They are aimed at finding out regulatory mechanisms connected with metabolism of L-arginine, activities of ATP-hydrolase systems and searching new markers of ovarian carcinoma. The main possible candidates for this role are determined. PMID- 25509183 TI - Activation of glybenclamide-sensitive mitochondrial swelling under induction of cyclosporin of A-sensitive mitochondrial pore. AB - Induction of mitochondrial swelling and increased generation of reactive oxygen forms by Ca ions have been shown in suspension of mitochondria from rat uterus. These effects were suppressed by the blocker of mitochondrial Ca2+-uniporter ruthenium red and MPTP inhibitor cyclosporin A, that evidences that the induction of mitochondrial permeability transition pore by Ca ions takes place. Ca2+ induced mitochondrial swelling was blocked by ATP-sensitive channel blocker glybenclamide but only if K+ was present in the incubation medium. We also demonstrated that Ca2+-induced mitochondrial swelling can be eliminated in the presence of ROS scavengers N-acetyl cysteine and ascorbate. This effect of scavengers was also sensitive to K+ and was not revealed in the medium that contained equimolar NaCl instead of KCl. Thus, our data gave us grounds to assume that the induction of MPTP by Ca ions evokes the activation of mitochondrial ATPsensitive K+-channels, which are mediated by ROS. PMID- 25509184 TI - [Influence of vermiculite particles on antioxidant properties of cultural medium of Bacillus subtilis IMV V-7023]. AB - It is shown that in the process of cultivation of Bacillus subtilis IMV V-7023 in the medium with vermiculite (1.5-5.0 g/l) one can observe the oppressing of some indexes of antioxidant properties of cultural medium of bacteria. In particular, a decline of hydroxyl radical scavenging activity in the Fenton reaction by 2.8 11.6%, ability to inhibit formation of malondialdehyde - by 4.4-13.1% and inactivation of 2,2'-Diphenyl-l-picrylhydrazyl (DPPH.) radical - by 3.1-8.5% were observed. Thus oxidant activity increased substantially. Besides oppressing influence of particles of vermiculite on protector properties of the cultural medium of bacilli it is found out that with the increase of the content of dispersible material in the nutrient medium the reducing power of cultural medium of these bacteria increased. PMID- 25509185 TI - [Cell model for the study of receptor and regulatory functions of human proHB EGF]. AB - Developing of new models and approaches, particularly with fluorescent techniques, for investigation of intracellular transport of proHB-EGF and its ligand-receptor complexes is strongly required. In order to create a model for studying proHB-EGF functions the genetic construction pEGFP-N1-proHB-EGF, encoding proHB-EGF-EGFP which is fluorescent-labeled form of proHB-EGF with enhanced green fluorescent protein EGFP in the cytoplasmic terminus of the molecule, was obtained. Eukaryotic cells expressing fusion protein proHB-EGF-EGFP on the cell surface were obtained by transfection with pEGFP-N1-proHB-EGF. Expressed in the Vero cells proHB-EGF-EGFP could bind fluorescent derivative of nontoxic receptor-binding subunit B of diphtheria toxin mCherry-SubB. After stimulation oftransfected cells with TPA (12-O-Tet-radecanoylphorbol-13-acetate), proHB-EGF-EGFP formed a fluorescentl-labeled C-terminal fragment of the molecule CTF-EGFP. Thus, the obtained genetic construction pEGFP-N1-proHB-EGF could be helpful in visualization of molecules proHB-EGF and CTF in cells, may open new possibilities for the studying of their functions, such as receptor function of proHB-EGF for diphtheria toxin, intracellular translocation of CTF and provide possibilities for natural proHB-EGF ligands search. PMID- 25509186 TI - Effect of hypoxia on the expression of CCN2, PLAU, PLAUR, SLURP1, PLAT and ITGB1 genes in ERN1 knockdown U87 glioma cells. AB - The endoplasmic reticulum stress is an important factor of tumor growth and is induced in cancer cells. We have studied the effect of ERN1 knockdown as well as hypoxia on the expression of genes encoding factors, which control cell proliferation, in U87 glioma cells. It was shown that the complete blockade of ERN1 enzyme function leads to an increase of the PLAT (tissue plasminogen activator), CCN2 (CCN family member 2), and ITGB1 (integrin beta-1) as well as to a decrease ofPLAU (plasminogen activator, urokinase), PLAUR (plasminogen activator, urokinase receptor), and SLURP1 (secreted LY6/PLAUR domain containing 1) mRNA expressions. Moreover, we have shown that hypoxia does not affect the expression level of ITGB1 mRNA, but increases that of CCN2, PLAUR, SLURP1, and PLAT mRNA and decreases the expression level of only PLAU mRNA in control glioma cells. At the same time, in ERN1 knockdown glioma cells the expression level of PLAU PLAUR, and SLURP1 mRNA is decreased under hypoxia, but PLAT and ITGB1 mRNA expression levels are increased under these experimental conditions. Thus, results of this study have shown that the expression level of all studied genes is affected by ERN1 knockdown as well as by hypoxia and that the effect of hypoxia mostly depends on ERN1 signaling enzyme function. PMID- 25509187 TI - ERN1 knockdown modifies the hypoxic regulation of TP53, MDM2, USP7 and PERP gene expressions in U87 glioma cells. AB - Endoplasmic reticulum stress and hypoxia are necessary components of malignant tumors growth and suppression of ERN1 (from endoplasmic reticulum to nuclei-1) signalling pathway, which is linked to the apoptosis and cell death processes, significantly decreases proliferative processes. Glioma cells with ERN1 knockdown were used in order to investigate the effect of ERNI blockade on the expression of TP53, MDM2, PERP, and USP7 genes and its hypoxic regulation. We have studied the expression of TP53 (tumor protein 53), MDM2 (TP53 E3 ubiquitin protein ligase homolog), PERP (TP53 apoptosis effector), and USP7 (ubiquitin specific peptidase 7) genes, which are related to cell proliferation and apoptosis, in glioma cells with ERN1 knockdown under hypoxic condition. It was shown that blockade of ERNI gene function in U87 glioma cells intensified the expression of TP53 and USP7 genes, but decreased the expression ofMDM2 and PERP genes. Thus, an enhanced expression of TP53 gene in ERN1 knockdown glioma cells correlates with the decreased level of ubiquitin ligase MDM2 and increased expression level of USP7 which deubiquitinates TP53 and MDM2 and induces TP53-dependent cell growth repression and apoptosis. At the same time, the expression levels of TP53, MDM2, and USP7 genes do not change significantly in glioma cells with suppression of endoribonuclease activity only, but PERP gene expression is strongly increased. Moreover, the expression of TP53 and UPS7 genes is decreased in hypoxic conditions in control glioma cells only; however, MDM2 and PERP gene expressions are increased in both cell types, being more significant in ERN1 knockdown cells. Thus, the expression of genes encoding TP53 and related to TP53 factors depends upon the endoplasmic reticulum stress signaling as well as on hypoxia, and correlates with suppression of glioma growth under ERN1 knockdown. PMID- 25509188 TI - [Proapoptotic properties of total phytohemagglutinine and its individual isolectins in human cell culture 4BL]. AB - Phytohemagglutinine (PHA) is widely investigated lectin with mitogenic properties. Recently it was shown that PHA is not only cell proliferation inducer, but also has a toxic or cytostatic effect. However concentration dependence and molecular mechanisms of this effect are not enough investigated. To study proapoptotic properties of total phytohemagglutinine and its isolectins in human cell culture of not tumor origin 4BL we observed a change in the frequency of apoptotic cells in the tested cell culture under the influence of the total phytohemagglutinine and erythroagglutinin by the method of specific color luminescent dye. The activation of caspases-3 and -8 and induction of protein Bax expression under the influence of lectins were detected by Western blot analysis. It was revealed that erythroagglutinin induced apoptosis with the highest efficiency compared with leukoagglutinin and total phytohemagglutinine. The induction of apoptosis in human cell culture of not tumor origin 4BL is probably caused by activating caspase-dependent and mitochondrial signalling. PMID- 25509190 TI - Inhibition of fibrin polymerization by synthetic peptides corresponding to Aalpha195-205 and gamma69-77 sites of fibrin molecule. AB - Using the idea of "proline brackets" we have found four sites in fibrin amino acid sequence, and appropriate peptides were synthesized: gamma69NPDESSKPN77, Bbeta228QPDSSVKPY236, Bbeta455RPFFPQ460 and Aalpha195LPSRDRQHLPL205. Turbidity and electron-microscopy analyses have demonstrated that synthetic peptide Aalpha195-205 specifically inhibited the stage of fibrin protofibril formation and peptide gamma69-77 - the stage offibrin protofibril lateral association. The data obtained testify that there are the sites involved in these processes in the appropriate amino acid sequences of fibrin molecule. PMID- 25509189 TI - [Protein intercalation in DNA as one of main modes of fixation of the most stable chromatin loop domains]. AB - The main mechanism of DNA track formation during comet assay of nucleoids, obtained after removal of cell membranes and most of proteins, is the extension to anode of negatively supercoiled DNA loops attached to proteins, remaining in nucleoid after lysis treatment. The composition of these residual protein structures and the nature of their strong interaction with the loop ends remain poorly studied. In this work we investigated the influence of chloroquine intercalation and denaturation of nucleoid proteins on the efficiency of electrophoretic track formation during comet assay. The results obtained suggest that even gentle protein denaturation is sufficient to reduce considerably the effectiveness of the DNA loop migration due to an increase in the loops size. The same effect was observed under local DNA unwinding upon chloroquine intercalation around the sites of the attachment of DNA to proteins. The topological interaction (protein intercalation into the double helix) between DNA loop ends and nucleoid proteins is discussed. PMID- 25509191 TI - [State of antioxidant system of rat thymocytes in experimental ulcerogenesis]. AB - Features of free radical processes and their impact on the implementation of immunocompetent cells of their functions under conditions of peptic ulcer are insufficiently studied today. Reduced activity of catalase 1.7 and 3.4 times and that of glutathione peroxidise ~ 2.0 times, accordingly, were observed in both models of gastric ulceration (stress ulcer and ethanol one). Enzymatic activity of superoxide dismutase decreased 1.5 times and activity of glutathione transferase increased 1.8 times in the stress model in contrast to the ethanol model of stomach ulcer. Obtained results indicate the exhaustion of antioxidant system in rats' thymocytes under experi- mental ulcerogenesis. These data confirm complex negative effect of ulcer on the organism. PMID- 25509192 TI - [Influence of omega-3 polyunsaturated fatty acids on oxidative stress and cytochrome P450 2E1 expression in rat liver]. AB - Polyunsaturated fatty acids (PUFAs), omega-3 ones in particular, form phospholipid layer of biological membranes, which provides normal functioning of membrane-associated complexes of enzymes and transmembrane transport. Free omega 3 PUFAs regulate the transcription of many genes, and thereby have an effect on the level of metabolic processes, particularly control of lipid and carbohydrate metabolism in the liver. Cytochrome P450 2El (1.14.14.1) causes the transformation of lipophilic exogenous and endogenous substances, as well as involvement in homeostasis, both at the cellular and systemic levels. The aim is to study changes in expression of cytochrome P450 2E1, and to assess the antioxidant system and the level of peroxidation processes in the liver of experimental animals under the chronic action omega-3 PUFAs. During experiment more than two-fold increase in the content of cytochrome P450 2El was observed in the liver of rats which additionally received omega-3 PUFAs for 4 weeks in the standard daily diet. At the same time, such changes in the enzyme expression did not lead to an imbalance of pro- and antioxidant processes in the liver. PMID- 25509193 TI - Effect of nicotinamide on amino acids content in bone collagen depending on biological availability of vitamins in diabetic rats. AB - Connective tissue is highly susceptible to imbalances induced by diabetes. Diabetes-related osteopenia, decreased bone strength etc. may be associated with altered metabolism of various collagens: Although it is assumed that alterations in collagen amino acids (AA) may strongly affect protein properties andphysiological functions, however, very limited evidences are present at the moment regarding AA composition of bone type I collagen and its relevance to abnormal availability of vitamins which are necessary for collagen synthesis in diabetes. We have tested whether nicotinamide (NAm) can influence type Icollagen formation and AA composition as well as vitamins availability in diabetes. After 4 weeks of STZ-induced diabetes (60 mg/ kg) male Wistar rats were injected for 2 weeks with/without NAm (200 mg/kg b. w). Acid extraction of type I collagen from the bones was performed with following stepwise salting out. The content of type I collagen after its acid extraction from the bones was estimated by the amounts of hydroxyproline. Amino acids were assayed by cation exchange chromatography Diabetes-associated changes in AA composition of type I collagen mainly affect those amino acids which are known to be involved in helix formation and cross linking of the molecules. Diabetes was found to significantly reduce bone collagen contents of o-Pro, Gly, Ala, o-Lys and Pro, whereas Lys, His, Arg, Glu, Thr, Leu, Phe contents were elevated (P < 0.05). NAm treatment was able to partially normalise AA contents. In diabetes, blood serum and hepatic vitamin C and B3 contents were shown to be significantly lowered, whereas a-tocopherol was slightly increased compared with control (P < 0.05). Restoration of circulatory and liver vitamin C and B3 was observed. The data demonstrate the close relationship between the diabetes-associated decrease in type I collagen deposition, altered amino acids metabolism and impaired availability of vitamins, which are necessary for collagen synthesis. Thus, NAm might be a useful agent for treatment of bone failures related to diabetes. PMID- 25509194 TI - [Kinetics of hydrolysis of 1,4-benzodiazepine derivative by carboxylesterases in mice organism]. AB - Chemical modification of the physiologically active substances and creation of prodrugs is one of the ways for pharmacotherapy optimization. The aim of the work was determination of the kinetic parameters ofnonspecific esterases that catalyze hydrolysis of new hypnotic drug Levana (1,4-benzodiazepine derivative). The experiments were carried out using the 14C-labelled Levana and its active metabolite - 3-hydrixyphenazepam. In vitro it was shown that Levana undergoes spontaneous hydrolysis even in buffer solution (pH 7.4), though in plasma and homogenates of brain and liver this process is more intensive (conventional Vmax was 6.9 +/- 0.5, 19 +/- 4 and 12 +/- 1 mM/(h.mg of protein, correspondingly). The samples mentioned differ by activity of tissue esterases being most active in the liver (conventional K 0.45 +/- 0.04 mM for the liver and 47 +/- 11 mM for the brain). In plasma carboxylesterase activity (for Levana) is the lowest (conventional K 129 +/- 10 mM). In vivo it was shown that Levana more easily permeates brain-blood barrier (compared to 3-hydroxyphenazepam), that leads to higher concentrations (after hydrolysis) of its metabolite in brain tissue. Also it is quantitatively estimated as the increase of concentration (brain/blood) ratio ~1.4 times. PMID- 25509195 TI - [Effect of semicarbazide on the peroxidation processes and Lewis carcinoma growth in mice]. AB - Effects of various doses of semicarbazide on Lewis carcinoma metastasing and peroxidation processes in C57B1 mice have been investigated. In the animals with inoculated Lewis carcinoma, the semicarbazide in the dose of 1/120 LD50 had practical influence on the tumour growth and inhibited the metastasing into mice lungs (P < 0.05). Importantly, this dose significantly inhibited the formation of free radicals and active forms of oxygen against the background of decrease of the aldehydes level that was related to the acceptor properties of the drug. PMID- 25509197 TI - [Laureates of the Palladin Prize of the National Academy of Sciences of Ukraine (2001, 2003 years)]. PMID- 25509196 TI - [Comparative characteristic of the methods of protein antigens epitope mapping]. AB - Comparative analysis of experimental methods ofepitope mapping of protein antigens has been carried out. The vast majority of known techniques are involved in immunochemical study of the interaction of protein molecules or peptides with antibodies of corresponding specificity. The most effective and widely applicable methodological techniques are those that use synthetic and genetically engineered peptides. Over the past 30 years, these groups of methods have travelled a notable evolutionary path up to the maximum automation and the detection of antigenic determinants of various types (linear and conformational epitopes, and mimotopes). Most of epitope searching algorithms were integrated into a computer program, which greatly facilitates the analysis of experimental data and makes it possible to create spatial models. It is possible to use comparative epitope mapping for solving the applied problems; this less time-consuming method is based on the analysis of competition between different antibodies interactions with the same antigen. The physical method of antigenic structure study is X-ray analysis of antigen-antibody complexes, which may be applied only to crystallizing proteins, and nuclear magnetic resonance. PMID- 25509198 TI - [Conference-competition of young scientists "Urgent Problems of Biochemistry and Biotechnology" - 2014]. PMID- 25509199 TI - Biliary stenting as alternative therapy to stone clearance in elderly patients with bile duct stones. . AB - BACKGROUND AND STUDY AIMS: Endoscopic retrograde cholangio- pancreatography with stone retrieval following endoscopic sphinc- terotomy (ES) is the standard method for the management of cho- ledocholithiasis. However, biliary stenting is used to treat patients with endoscopically irretrievable bile duct stones, especially elderly and high-risk patients. The aim of this study was to evaluate the benefits and risks of biliary stenting versus stone clearance follow- ing ES in the management of choledocholithiasis. PATIENTS AND METHODS: Between January 2010 and December 2012, 165 patients with common bile duct stones who underwent biliary stenting or stone clearance following ES were enrolled. One 7 Fr. double pigtail plastic stent was placed without ES or stone extraction. The procedure time, hospitalization period, adverse events, additional endoscopic interventions required and one-year mortality were evaluated retrospectively. RESULTS: Ninety nine and 66 patients were included in stenting group and in stone clearance group, respectively. Except for age, number of stones, and use of antithrombotic agents in the stent group, there were no statistically significant difference between groups. The average procedure time and hospitalization period in the stenting group were significantly shorter than those in stone clearance group (mean 21 min vs. 43.9 min, P < 0.0001; 3.8 days vs. 6.5 days, P < 0.0001). No significant differences were seen in ad- verse events and additional endoscopic interventions required be- tween both groups for at least a 1.5-year follow-up. No one-year mortality occurred. CONCLUSIONS: Biliary stenting using a double pigtail stent proved to be a useful alternative therapy to stone clearance following ES in the management of choledocholithiasis in elderly patients. PMID- 25509200 TI - The role of fecal calprotectin in assessment of hepatic encephalopathy in patients with liver cirrhosis. AB - INTRODUCTION: Calprotectin is a cytoplasmatic protein of neutrophilic granulocytes and it is an established marker for the assessment of localized intestinal inflammation. AIM: To explore correlation between values of fecal calprotectin and degree of liver cirrhosis and hepatic encephalopathy. METHODS: We included 60 patients with liver cirrhosis and 37 healthy patients as controls. Patients revealing other causes of abnormal calprotectin results (gastrointestinal bleeding or inflammatory bowel disease) were excluded. The degree of liver insufficiency was assessed according to the Child-Pugh classification and Model of End Stage Liver Disease (MELD), and degree of hepatic enceph- alopathy by West-Haven criteria, serum concentration of ammonium ion and the number connection test. RESULTS: The mean value of fecal calprotectin in patients with liver cirrhosis was 189.1 +/- 168.0 MUg/g, and 35.0 +/- 26.0 MUg/g in the control group, respectively. We have confirmed significantly higher fecal calprotectin in patients with cirrhosis (p < 0.001). There were no significant differences in values of fecal calprotectin between the patients with different stages of liver cirrhosis according to Child-Pugh classification and MELD score (p > 0.05). We observed statistically significant difference comparing fecal calprotectin by West-Haven criteria of hepatic encephalopathy (p < 0.001), while there were no correlation with the number connection test and serum concentration of ammonium ion (p > 0.05). CONCLUSION: We confirmed significantly higher values of fecal calprotectin in patients with liver cirrhosis, especially in hepatic encephalopathy according to West-Haven criteria. PMID- 25509201 TI - Laparoscopic cholecystectomy in acute cholecystitis: support for an early interval surgery. AB - BACKGROUND AND STUDY AIMS: Although laparoscopic cholecystectomy is advocated for acute cholecystitis, debate still exists about its optimal timing. This retrospective study compares the outcome of laparoscopic cholecystectomy within versus later than 5 days of onset of symptoms in patients with acute cholecystitis. PATIENTS AND METHODS: One hundred thirty six patients with acute cholecystitis grade I or II were included in the study and divided in two groups. Group 1 received surgery within 5 days of symptoms and group 2 received conservative therapy and delayed surgery after 6 weeks. RESULTS: Group 1 and 2 consisted of 100 and 36 patients respec- tively. Because of failure of conservative therapy 5 patients of group 2 had surgery before 6 weeks. The remaining 31 patients underwent surgery after 6 weeks. Preoperative ERCP was indicated in 2 and 11 patients in groups 1 and 2 respectively (p < 0.001). The median total hospital stay was 3.0 days for group 1 and 11.0 days for group 2 (p < 0.001). In terms of operation time, conversion rates, intraoperative cholangiography, postoperative ERCP, morbidity or mortality both groups were comparable (p > 0.05). CONCLUSION: Laparoscopic cholecystectomy can be performed safely within 5 days after the onset of symptoms in patients with acute cholecystitis. Because of shortened total hospital stay and risk of failure of conservative therapy, early laparoscopic cholecystectomy should be favored. PMID- 25509202 TI - Efficacy of endoscopic ultrasound fine needle aspiration in diagnosing the rare (non-adenocarcinoma) tumors of pancreas. AB - BACKGROUND: Five percent of pancreatic neoplasms are non- adenocarcinoma tumors. Clinical presentation and imaging characteristics of these tumors are similar to adenocarcinoma. This study aims at evaluating the results and efficacy of Endoscopic ultrasound guided fine needle aspiration (EUS-FNA) in diagnosing the pancreatic non-adenocarcinoma tumor in patients with solid pancreatic mass. METHODOLOGY: The present study which is of a descriptive, prospective and case series nature, has been studying the diagnostic value of EUS-FNA in pancreatic non-adenocarcinoma tumor in 60 patients with pancreatic solid neoplasm. Cytopathologic diagnosis founded on EUS-FNA accepted as final diagnosis in unresectable ones. But the reference standard for the final diagnosis in patients with resectable tumor was surgical pathology. In patients with non diagnostic EUS FNA specimen, final diagnosis achieved by re-FNA, Computerized Tomography (CT) guided biopsy, or surgery. RESULTS: Ten patients (17%) found to have non adenocarcinoma tumor. Half of them were male. EUS-FNA was diagnostic in 8 cases (80%) including the 4 neuroendocrine tumors, one gastrointestinal stromal tumor, one mucinous neoplasm, one pseudopapillary tumor, and one geant cell tumor. Surgical pathology confirmed the EUS-FNA diagnosis in five patients that had resectable tumor. However EUS-FNA recognition accepted as final diagnosis in three patients that had unresectable tumor. EUS-FNA was non-diagnostic in one patient with pancreatic lymphoma and another patient with colon cancer metastasis. CONCLUSION: EUS FNA is a safe and effective for diagnosing the solid non-adenocarcinoma tumors as well as adenocarcinomas of pancreas. PMID- 25509203 TI - 99mTc-Pertechnetate imaging for detection of ectopic gastric mucosa: a systematic review and meta-analysis of the pertinent literature.. AB - BACKGROUND AND AIMS: 99mTc-pertechnetate scintigraphy has long been used for detection of ectopic gastric mucosa (EGM) in the medical practice and evaluation of children with lower gastrointestinal bleeding. In the current study, we reviewed the available medical literature in this regard. METHODS: Medline and SCOPUS were searched for relevant studies. Studies with sample size of at least 5 patients which provided enough numerical data to calculate the sensitivity and/or specificity of 99mTc-pertechnetate for detection of EGM were includ ed in the systematic review. RESULTS: Overall 40 studies were included in our systematic review. Overall diagnostic indices of the 99mTc-pertechnetate scintigraphy for EGM diagnosis were: sensitivity 92.1% [95% CI: 90.2-93.8], specificity 95.4% [943 963], positive likelihood ratio 16.5 [9.9-27.], negative likelihood ratio 0.15 [0.1-0.2], diagnostic odds ratio 120.7 [73-199]. The pooled sensitivity was higher for studies using H2 blockers as a premedication (92.4% vs. 86.4%), studies using delayed imaging (943% vs. 88.4%), children (92.3% vs. 81.8%), and patients with gastrointestinal bleeding (953% vs. 75.3%). CONCLUSIONS: 99mTc pertechnetate imaging is a highly accurate diagnostic modality for detection of EGM. This imaging is more accurate in children and patients presenting with gastrointestinal bleeding. Premedication with H2 blockers and delayed imaging can increase the diagnostic accuracy and should be routinely included in the imaging protocol. PMID- 25509204 TI - The drinking test: a current noninvasive technique to evaluate gastric accommodation and perception. AB - Impaired gastric accommodation has been proposed as an im- portant mechanism in the generation of functional dyspepsia. There is an interest in methods that allow recording and quantifica- tion of the gastric accommodation reflex. Drinking tests, with water or nutrients, have been developed as a noninvasive, inexpensive method to assess gastric perception and accommodation. These tests are easily performed, do not need any special equipment and are well tolerated by patients. Drink test results are reported as the maximum tolerated volume, individual and cumulative symptom scores. Patients with functional dyspepsia have showed lower max- imum tolerated volumes than healthy volunteers. In these patients the maximum tolerated volume reflects the severity of early satiety and predicts impaired gastric accommodation, but it remains un- clear what physiologic processes are assessed by the drinking tests. Results of drinking tests may be influenced by physiologic factors, thus these results do not guide therapy. Given these facts, drinking tests are best reserved for clinical research purposes evaluating functional dyspeptic patients or patients with gastroparesis. PMID- 25509205 TI - Belgian recommendations for the management of anemia in patients with inflammatory bowel disease. AB - Anemia is the most common extraintestinal manifestation of inflammatory bowel disease (IBD) which, in most cases, results from an absolute or functional iron deficiency. Although anemia and iron deficiency may have a dramatic impact on the quality of life of IBD patients, they are underdiagnosed and undertreated. This paper provides evidence-based consensus guidelines and practical treatment algorithms that are directly applicable to the Belgian situation. In this way, the Belgian IBD research and development Group (BIRD) aims to increase awareness and knowledge among gastroenterologists in order to improve the management of anemia and iron deficiency in their IBD patients. PMID- 25509206 TI - A mysterious anus. Amyloidosis. PMID- 25509207 TI - Primary hepatic vascular tumours. A clinicopathologic study of 10 cases. AB - BACKGROUND: Primary hepatic vascular neoplasms constitute a heterogeneous group of neoplasms with characteristic histology and variable tumour biology. AIM: To provide an updated overview on clinicopathological features, treatment and outcome of primary hepatic vascular tumours. PATIENTS AND METHODS: In our retrospective study, we reviewed 10 cases of primary hepatic vascular tumours that were diagnosed at the pathology department of Mongi Slim hospital over a thirteen-year period (2000-2012). Relevant clinical information and microscopic slides were available in all cases and were retrospec- tively reviewed. RESULTS: Our study group included 4 men and 6 women (sex ra- tio M/F = 0.66) aged between 23 and 78 years (mean = 55.5 years). Based on imaging studies, preoperative diagnosis of hemangioma was accurately made in only three cases. Three cases were misdiagnosed preoperatively as having hydatid cyst and four cases of hemangiomas were misdiagnosed preoperatively as liver metastases. All our patients underwent surgical resection of the tumour. Histopathological examination of the surgical specimen established the diagnosis of angiosarcoma in one case, cavernous hemangioma in 8 cases and sclerosing hemangioma in one case. CONCLUSION: Hepatic tumours are increasingly detected incidentally due to widespread use of modern abdominal imaging techniques. Therefore, reliable noninvasive characterization and differentiation of such liver tumours is of major importance for clinical practice. Definitive diagnosis is based on histopathologic examination. PMID- 25509208 TI - Four patients with Amanita Phalloides poisoning. AB - Mushroom poisoning by Amanita phalloides is a rare but potentially fatal disease. The initial symptoms of nausea, vomiting, abdominal pain and diarrhea, which are typical for the intoxication, can be interpreted as a common gastro-enteritis. The intoxication can progress to acute liver and renal failure and eventually death. Recognizing the clinical syndrome is extremely important. In this case report, 4 patients with amatoxin intoxication who showed the typical clinical syndrome are described. The current therapy of amatoxin intoxication is based on small case series, and no ran- domised controlled trials are available. The therapy of amatoxin intoxication consists of supportive care and medical therapy with silibinin and N-acetylcysteine. Patients who develop acute liver failure should be considered for liver transplantation. PMID- 25509209 TI - Crohn's disease presenting with acute pancreatitis. AB - Crohn's disease is often accompanied by extraintestinal inflammation. Acute pancreatitis can be a rare manifestation of Crohn's disease. The present report describes a patient who developed two episodes of pancreatitis before the diagnosis of Crohn's disease. Clinical and laboratory evaluation excluded other causes of pancreatitis, confirming a direct association of the pancreatitis with Crohn's disease. This case report supports the hypothesis that acute pancreatitis may precede the clinical manifestations and diagnosis of the underlying inflammatory bowel disease. PMID- 25509210 TI - Let's not forget herpes simplex virus in case of fulminant hepatic failure. AB - Fulminant herpes simplex virus (HSV) hepatitis is a rare condition, which is usually identified only after orthotopic liver transplantation (OLT) or at autopsy. The most commonly affected individuals are immunosuppressed patients, although HSV hepatitis can occur in immunocompetent patients as well. A high degree of suspicion combined with early diagnostic modalities may improve survival. We present a case report of fulminant herpetic hepatitis, requiring OLT. In addition, a review of the literature was performed. PMID- 25509211 TI - Succesful treatment of type-1 gastric carsinoid by endoscopic polypectomy and argon plasma coagulation. PMID- 25509212 TI - Rare complication of upper gastrointestinal endoscopy: bilateral swelling of parotid glands. PMID- 25509213 TI - An unusual polyp at the appendiceal orifice: appendix inversion. PMID- 25509214 TI - Protection of epithelial tight junction: a new therapeutic approach in the treatment of infectious diarrhea. PMID- 25509215 TI - [A word about the teacher (In memory of Oleksii Ivanovych Konons'kyi)]. PMID- 25509216 TI - [Pentiuk Oleksandr Oleksiiovych. On the 65th anniversary of his birth (1949 2009)]. PMID- 25509217 TI - Aging and health--a systems biology perspective. Introduction. PMID- 25509218 TI - Age-proof your muscles. New research pinpoints the ideal moves to protect the male body as it ages. PMID- 25509220 TI - Looking forward. Education: one of the four pillars of the American College of Surgeons. PMID- 25509221 TI - Celebrating a decade of innovation in surgical education. PMID- 25509223 TI - First-place essay--revolution: surgical training: time for a revolution. PMID- 25509224 TI - Second-place essay--revolution: five-year general surgery residency: reform or revolution? PMID- 25509225 TI - First-place essay--reform: reformation of current surgical residency and fellowship training is the best solution. PMID- 25509226 TI - Second-place essay--reform: revisiting the visions of Halsted, Churchill, and Dudley to fix surgical training a century later. PMID- 25509228 TI - Massachusetts Chapter develops new grassroots advocacy program. PMID- 25509227 TI - Optimizing the OR for bundled payments: a case study. PMID- 25509229 TI - Transplant in a patient with comorbid psychiatric illness: an ethical dilemma. AB - This article addresses a difficult ethical dilemma that transplant surgeons may potentially encounter: whether a patient with a psychiatric illness is a good candidate for a liver transplant. This case study illustrates the challenges involved when considering the ethical principles of patient self-determination, distributive justice of scarce medical resources, "social worth," and protection of vulnerable patient populations. Are patients with psychiatric illness able to provide consent for transplantation? Is it possible to avoid misallocating valuable donor organs and, at the same time, fairly allocate these resources? This article seeks to answer these questions and provide insight into this ethical dilemma. PMID- 25509230 TI - The FY 2015 Inpatient Prospective Payment System final rule. PMID- 25509231 TI - Colorectal cancer metastatic to the liver: making the unresectable resectable. PMID- 25509232 TI - The gift that keeps on giving. PMID- 25509233 TI - Hospital Engagement Networks target surgical site infections. PMID- 25509234 TI - NTDB DATA POINTS: the DTs: delirium tremens. PMID- 25509235 TI - How severe is depression in low back pain patients? AB - The aim of the present study was to determine the prevalence of depression among low back pain (LBP) patients and to investigate the sociodemographic characteristics of pa- tients with LBP and relationship between depression and pain intensity in LBP patients. The study was conducted on 99 patients treated at Clinical Department of Neurology, Split University Hospital Center. There were 36 (36%) men and 63 (64%) women. Some degree of depression was present in 73 (74%) study patients, including all patients with severe LBP. In the group of patients with severe LBP, the rate of moderate, severe and very severe depression was 1.36 fold that recorded in the gro- up of patients with moderate LBP and 2.58-fold that found in the group of patients with mild LBP (chi2 = 16.2; p = 0.003). The most common symptoms were general physical symptoms 70 (71%), psychic anxiety 69 (70%) and depressed mood 66 (67%). It is concluded that depression was more severe in LBP patients with severe disease compared to patients with mild or moderate LBP. PMID- 25509236 TI - Effect of preoperative administration of intravenous paracetamol during cesarean surgery on hemodynamic variables relative to intubation, postoperative pain and neonatal apgar. AB - Selection of anesthetic drugs for cesarean section requires many considerations. Anesthetic drugs for this purpose must prevent hemodynamic stress due to tracheal intubation, while inducing neonatal complications. This study was conducted to determine the effects of paracetamol given before induction of anesthesia on cardiovascular responses to tracheal intubation and postoperative pain in the mother, and on neonatal Apgar score. This double-blind randomized placebo controlled trial included 60 women in ASA I, without underlying diseases and fetal distress, who were candidates for elective cesarean section under general anesthesia. Patients were divided into two groups of 30 patients. Patients in the paracetamol group received 1 g intravenous (IV) paracetamol 20 min before the operation, while those in the placebo group received 1 cc normal saline at the same time. In both groups, anesthesia was induced by sodium thiopental and succinylcholine. Maternal systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and heart rate (HR) were measured before and immediately upon induction of anesthesia, and at first and fifth minute after tracheal intubation. Neonatal effects were assessed by Apgar score. Postoperative pain was assessed by use of the visual analog scale (VAS). The dose of analgesic used and the time of the first analgesic request by patients postoperatively were recorded. The SBP, DBP, MAP and HR were controlled significantly better in paracetamol group than in placebo group (P < 0.05). The mean 1-min and 5-min Apgar scores of neonates did not differ between the groups. The VAS pain score was significantly lower in paracetamol group than in placebo group at all measuring times (P < 0.05). Also, paracetamol caused later first analgesic request and lower dose of analgesic needed to control pain postoperatively (P < 0.05). In conclusion, the results of our study suggested IV paracetamol to be an efficacious agent to decrease hemodynamic responses to tracheal intubation, while providing better postoperative pain management without considerable neonatal complications in women undergoing cesarean section in general anesthesia. PMID- 25509238 TI - Incidentally elevated thyrotropin in otherwise properly treated hypothyroid patients does not require higher levothyroxine dose. AB - In 20 properly treated hypothyroid patients with normal thyrotropin (TSH) values during previous observation, TSH was incidentally mildly/moderately elevated (4.5 8.0 mIU/L; normal values 0.4-4.0) on the last follow up. However, they were continuously treated with the same levothyroxine (LT4) dose (mean: 95 MUg) and six months later all TSH values normalized. The authors suggest that the physicians, in response to incidentally increased TSH value in otherwise properly treated hypothyroid patients, refrain from prompt increasing the LT4 dose unless TSH values are persistently elevated or/and progressing. PMID- 25509237 TI - Stress and quality of life in patients with gastrointestinal cancer. AB - This study aimed to answer the question whether it is possible to predict the quality of life in individuals with gastrointestinal cancer based on the number of life events, perceived stress levels and coping strategies. The study included 60 individuals (44 male and 16 female) aged 48 to 87 years, with malignant gastrointestinal tract diseases (56 with colon or rectal cancer, 2 with stomach cancer and 2 with pancreatic cancer). The following instruments were used: Questionnaire on General Information and Lifestyle Habits (developed for the purpose of this study); Scale for Measuring Quality of Life; Coping Inventory for Stressful Situations; and Life Events Scale. Results showed that the number of life events, perceived stress levels, emotion-oriented coping and avoidance were not predictive for the quality of life. Education was the only predictor for factors contributing to the quality of life (predictive variables on the Scale for Measuring Quality of Life). Task-oriented coping and education were predictors for satisfaction with past life and task-oriented coping was predictive for criterion variables on the Scale for Measuring Quality of Life and for factor related to future expectations and comparison to other people, but the proportion of explained variance was modest. The results of this study suggest that it is important to consider other variables (e.g., personality traits and sociodemographic factors) in predicting the quality of life and psychotherapeutic work with gastrointestinal cancer patients. It is important to bear in mind that there is no universally good individual coping strategy that is acceptable in all situations, but that coping flexibility or the ability to adequately change coping strategies in response to situational demands is by far more important. PMID- 25509239 TI - The effect of post stroke depression on functional outcome and quality of life. AB - In spite of being a common and important complication of stroke, post stroke depression is often overlooked, so its impact on stroke outcome remains under recognized. The aim of the study was to determine the effect of depression on functional outcome and quality of life in stroke patients. The study included 60 patients treated for their first clinical stroke, 30 of them diagnosed with depression and 30 patients without depression. Testing was done in all patients two and six weeks after stroke. Depression was diagnosed according to the Mini International Neuropsychiatry Interview, DSM-IV diagnostic criteria, and depression severity was quantified by the Hamilton Depression Rating Scale; functional impairment was determined by the Barthel Index; and post stroke quality of life was assessed by the Short Form 36 (SF-36) questionnaires. The patients with depression had significantly more severe functional disability both at baseline and after rehabilitation treatment, although the potential for functional recovery in depressed patients was less than in non-depressed ones. The quality of life in patients with post stroke depression was impaired more severely in all SF-36 domains compared with non-depressed stroke patients, with the domains of the role of emotional functioning and social relations being most severely affected. PMID- 25509240 TI - Reverse shoulder prosthesis: implementation and experience in Croatia. AB - Reverse shoulder prosthesis has become one of the most often used prosthetic implants in shoulder replacement surgery. It has a wide spectrum of indications, starting from comminuted humeral fractures and posttraumatic arthritis to arthritis caused by the rotator cuff loss. Its application at our hospital began in 2004, at first in few specific cases and with time in ever growing number of patients. Over 8 years, more than 250 reverse shoulder prostheses were implanted at our institution. In addition, our surgeons supervised its application in other hospitals all over Croatia. In the postoperative course, the shoulder was immobilized for 4-6 weeks with a thoracobrachial cast. After removal of the cast, physical therapy was initiated. The length of physical therapy program depended upon many factors. As a rule, immobilization lasted longer in patients that were operated on due to posttraumatic arthritis and those that suffered from deltoid muscle atrophy and shoulder contracture before surgery. Complications included dislocation of the prosthesis shortly after surgery (in the first four weeks) and infection. Infection was a special problem and treatment included even explantation of the prosthesis. PMID- 25509241 TI - Metric evaluation of partially displaced temporomandibular joint disc. AB - The objective was to determine the quantitative relationship between the condyle and disc position in the glenoid fossa between two different slices of the same temporomandibular joints (TMJs) with partial anterior disc displacement (DD). The study was conducted on 40 patients with DD of TMJs (mean age, 35.5 years). The clinical diagnosis of DD was confirmed by magnetic resonance imaging. Joints from the patient groups were analyzed according to the laterality and depending on disc displacement (a total of 80 joints). Comparison was made between two different slices of 9 joints with partial DD with reduction: partial DD was analyzed in the representative centrolateral or centromedial parasagittal slice of the TMJ (TMJ partial DD--slice DD). The contralateral slice of the same joint was without DD (TMJ partial DD--slice NDD). The analysis also included 34 healthy joints without DD (TMJ NDD) of the same patients. The position of the condyle and disc was calculated using the Kurita et al. method on the parasagittal view of the TMJ. A statistically significant difference was recorded for different slices of the same TMJs with partial DD (TMJ partial DD--slice DD and TMJ partial DD- slice NDD) (p < 0.01), but no difference was found in condyle positions depending on the existence of partial DD (p > 0.05). The compared values between slice TMJ partial DD--slice NDD with the group of TMJ NDD showed no significant difference in either disc position or condyle position (p > 0.05). There were differences of disc position in various slices of the same joint with visually confirmed partial DD. The dorsocranial condyle position could not indicate partial anterior DD. PMID- 25509242 TI - Thoracic epidural analgesia for radical cystectomy improves bowel function even in traditional perioperative care: a retrospective study in eighty-five patients. AB - Radical cystectomy is associated with significant morbidity and mortality due to complex surgery and comorbidities associated with advanced age of patients. In contrast to the surgery, which is clearly the procedure of choice for patients with invasive bladder cancer, the opti- mal anesthesiologic method is still under debate. Therefore, we retrospectively analyzed 85 patients having undergone radical cystectomy at our institution, either under combined epidural-general anesthesia (CEGA) or opioid based general anesthesia (GA). The intraoperative blood loss was significantly lower in CEGA group (497.37 +/- 354.13) than in GA group (742.31 +/- 403.69; p = 0.006), due to induced hypotension. Consequently, blood transfusion requirements were lower in CEGA group (107.20 +/- 263.92) than in GA group (388.18 +/- 321.32; p = 0.001). The incidence of postoperative ileus was also lower in CEGA group (p = 0.024). There was no difference in analgesic efficacy, but a trend towards lower incidence of venous thrombosis and infection was noticed. The results of our study suggest that epidural anesthesia might have specific advantages in patients undergoing radical cystectomy. PMID- 25509243 TI - Vascular cognitive impairment in diabetes mellitus: are prevention and treatment effective? AB - Vascular dementia is caused by progressive atherosclerosis leading to multiple small strokes and subsequent brain damage. Approximately 10%-20% of all cases of dementia are attributed to vascular dementia. The 5-year survival rate is 39% for patients with vascular dementia compared with 75% for age-matched controls. It is a growing public health concern because of the lack of effective curative treatment options and rising global prevalence. Duration of diabetes mellitus of 10 years or longer, onset of diabetes before age 65, treatment with insulin and oral antidiabetic medications, and presence of diabetes complications have an impact on the incidence of vascular dementia. On the other hand, patients who suffered stroke either had or are later diagnosed with diabetes (16%-24%). Treatment of vascular dementia in diabetes patients rests on a two-pronged approach: modification of the underlying disease and prevention and treatment of dementia symptoms. PMID- 25509244 TI - Subsequent pregnancy and prognosis in breast cancer survivors. AB - An increase in the incidence of breast cancer in women aged < 40 years in conjunction with a pronounced shift towards later childbearing has been reported in recent years. Because survival from breast cancer in women of childbearing age has significantly improved, they are often concerned whether subsequent pregnancy will alter their risk of disease recurrence. In the modern era, the prognosis of pregnancy-associated breast cancer is comparable to non-pregnancy-associated breast cancer and women can bear children after breast cancer treatment without compromising their survival. Therefore, they should not be discouraged from becoming pregnant, and currently the usual waiting time of at least 2 years after the diagnosis of breast cancer is recommended. However, a small, nonsignificant adverse effect of pregnancy on breast carcinoma prognosis among women who conceive within 12 months of breast cancer diagnosis and a higher risk of relapse in women younger than 35 up to 5 years of the diagnosis may be found. Fortunately, for women with localized disease, earlier conception up to six months after completing their treatment seems unlikely to reduce their survival. Ongoing and future prospective studies evaluating the risks associated with pregnancy in young breast cancer survivors are required. PMID- 25509245 TI - Transfusion treatment at Sestre Milosrdnice University Hospital Center during a twelve-year period. AB - Transfusion treatment is administered according to clinical and laboratory results, with ongoing patient assessments. Decisions on necessary measures to prevent any adverse and unexpected events and reactions are made on the basis ofhemovigilance and ongoing gathering and analysis of relevant data. Information about transfusion treatment at the Sestre milosrdnice University Hospital Center, Vinogradska site, was retrospectively collected for a period of twelve years (2001-2012). In that period, 14137.25 +/- 1693.07 units of all blood products were used, where red blood cells (RBC) accounted for 67.34%, fresh frozen plasma (FFP) for 17.55%, and platelet concentrates (PC) for 14.32%. During the study period, the consumption of RBC was even, of FFP decreased by 45% and of PC increased by 58%. RBC transfusions were received by 10.43% of hospitalized patients, 1.46% of them during surgical procedures. Transfusions of all blood products were received by 14.63% of patients. We found 247 adverse reactions to all blood products. Febrile nonhemolytic and allergic reactions were quite equally represented, 49.5% each. As for other reactions (1%), one transfusion associated circulatory overload and one transfusion related acute lung injury were recorded. There were no fatal post-transfusion reactions. PMID- 25509246 TI - Anemia of chronic disease: illness or adaptive mechanism. AB - The anemia of chronic disease (ACD) is the most prevalent anemia after iron deficiency anemia. It is associated with infectious, inflammatory and neoplastic disease. ACD is a medical condition caused by the release of cytokines which mediate inflammatory and immune response (tumor necrosis factor, interleukins 1 and 6, and interferon). Abnormal iron metabolism with iron trapping in reticuloendothelial cells is primarily the cause of this condition, making iron unavailable for erythropoiesis although iron tissue reserves are elevated. Disorder in erythropoietin secretion and shortening of red cell life span also play a role in the pathogenesis of ACD. The main therapy is treatment of the underlying disorder and red cell transfusions in severe anemia. In more severe (protracted) anemias that lead to impaired quality of life and have an impact on the mortality and survival rate, erythropoiesis stimulating agents are used. Recently, new possibilities are being evaluated in terms of therapy for ACD in defined conditions, such as chelating agents, as well as hepcidin antagonist and other erythropoiesis stimulating agents. PMID- 25509247 TI - MTHFR C677T and prothrombin G20210A mutations in a woman from Dalmatia with silent brain infarction. . AB - A 55-year-old, previously healthy woman, presented with frequent headaches. She had no neurological disturbances, but had a positive family history; her father died from stroke. Magnetic resonance imaging showed brain infarction; therefore detailed diagnostic evaluation of thrombophilia markers and genetic testing were performed. The patient was found to be homozy- gous for the C677T mutation of the methylenetetrahydrofolate reductase gene and heterozygous for the mutation of the prothrombin G20210A gene. No other cause of cerebral infarction was found in the patient. PMID- 25509248 TI - Intravesical foreign body as a result of self catheterization: case report. AB - Foreign bodies inside urinary tract are a relatively rare condition in our practice. There are several reports published and in most cases the reason for self insertion of an object was autoerotic stimulation or psychiatric illness. Self treatment by homemade instruments is a rarely seen scenario. A 62-year-old man presented to our department complaining of lower urinary tract symptoms. On examination, a foreign body was detected inside the urinary bladder. Urethral stricture was also detected for which the patient had been previously treated on several occasions. The patient stated that he had attempted self catheterization using a homemade catheter. He had succeeded in emptying his bladder; however, the catheter entered the bladder completely and was irretrievable to him. Sachse urethrotomy was performed following retrieval of the foreign body. No psychiatric illness was detected in our patient. The patient's postoperative course was uneventful. PMID- 25509249 TI - Periocular pilomatrixoma: case report. AB - The aim is to present a case of pilomatrixoma in the periocular area in a 10-year old female through retrospective review of medical records of a single patient. A 10-year-old female developed a lesion under her right eyebrow over a period of one year. The rest of the ophthalmic history was unremarkable. On examination, oval, well-defined, subcutaneous tumor measuring 7 x 4 mm was found under the right eyebrow. It gave bluish tint under the firmly adherent overlying skin of normal color and texture. Rocky hard and non-tender, it was mobile over the underlying tissues. Total excision biopsy was performed under general anesthesia. Histopathologic analysis confirmed the diagnosis ofpilomatrixoma. Pilomatrixoma is a rare tumor with head, neck and periocular area being the commonest sites. It is often clinically misdiagnosed and/or missed on differential diagnosis. Although a benign tumor, malignant transformation into pilomatrix carcinoma has been described. Thus, total surgical excision of the mass is recommended. PMID- 25509250 TI - Recurrent lipomatous tumor of hypopharynx: case report and literature review. AB - Liposarcoma is one of the most common soft-tissue sarcomas in adults, but head and neck are rarely involved, especially regions of the larynx and hypopharynx. According to Enzinger and Weiss, liposarcoma can be divided into 5 subtypes: well differentiated, myxoid, round cell, pleomorphic and dedifferentiated. We present an unusual case of well-differentiated liposarcoma of the hypopharynx in a patient with previous three procedures of endoscopic removal of hypopharyngeal tumor classified as benign lipoma. Well-differentiated liposarcoma is a tumor of low-grade malignancy, which frequently recurs locally, but does not metastasize. Wide tumor resection with free margins is mandatory. Immunohistochemistry is a useful diagnostic tool. We also discuss recently published literature on this unusual presentation of well-differentiated liposarcoma. PMID- 25509251 TI - Vertebral artery injury in a patient with fractured C4 vertebra. AB - Vertebral artery injuries due to cervical spine trauma, although rarely described in the literature, are relatively common. While most of them will remain asymptomatic, a small percentage of patients may suffer life threatening complications. We report a case of the right vertebral artery injury in a patient with fracture of C4 vertebra, successfully treated with endovascular approach. A 78-year-old male patient was hospitalized for cervical spine injury caused by falling off the tractor. Radiological assessment revealed fracture of C4 vertebra with proximal two-thirds of C4 body dislocated five millimeters dorsally. Significant swelling of soft prevertebral tissues distally of C2 segment was also present. During emergency surgery using standard anterior approach for cervical spine, excessive bleeding started from the injured right vertebral artery. Bleeding was stopped by tamponade with oxidized regenerated cellulose sheet and C4-C5 anterior fixation; then partial reduction of displacement was done. Fifteen days later, after angiography, endovascular repair of the right vertebral artery was performed using percutaneous stent graft. Follow up computed tomography scan angiography showed valid stent patency without contrast extravasation. In cases of cervical spine trauma, surgeon should always be prepared to manage injury of vertebral artery. Bleeding can primarily be stopped by hemostatic packing, and definitive repair can be successfully achieved by endovascular approach using percutaneous stent graft. PMID- 25509252 TI - Historical review. PMID- 25509253 TI - [Exploration of prolonging health span, a new medical model in the aging society]. PMID- 25509254 TI - [Effect of qingchang huashi recipe on IL-17 in the plasma and colonic mucosa of patients with ulcerative colitis]. AB - OBJECTIVE: To detect the expression level of interleukin 17 (IL-17) in the plasma and colonic mucosa of patients with ulcerative colitis (UC), and to explore the synergistic mechanism of qingchang huashi recipe (QHR) combined with Mesalazine. METHODS: Recruited were 24 mild or moderate UC patients of damp-heat inner accumulation syndrome (DHIAS). Their samples of intestinal tissues were histologically graded. They were assigned to the combination group and the Western medicine (WM) group, 12 in each group. Besides, another 12 healthy volunteers were recruited as the healthy control group. QHR combined Mesalazine were given to patients in the combination group, while those in the WM group took Mesalazine. The therapeutic course for all was 3 months. By the end of treatment the expression level of IL-17 in the plasma and colonic mucosa was detected using ELISA. The infiltration of IL-17 in the intestinal mucosal tissue was detected by immunohistochemical SP method. RESULTS: The expression level of IL-17 in the plasma and colonic mucosa was significantly higher in UC patients than in healthy controls (P <0. 05). The higher the histological grading the higher the expression level. The expression level of IL-17 in plasma and colonic tissues decreased after treatment in the two treatment groups (P < 0.05). Besides, the expression level of IL-17 was lower in the combination group than in the WM group (P <0.05). CONCLUSION: QHR combined Mesalazine could synergically enhance the effect and effectively inhibit intestinal inflammation through down-regulating the expression of IL-17. PMID- 25509255 TI - [Shuxuening injection combined with routine therapy in treating patients with active ulcerative colitis: an analysis of efficacy ]. AB - OBJECTIVE: To observe the therapeutic effect and relevant mechanism of shuxuening Injection (SI) in treating patients with active ulcerative colitis (UC). METHODS: Totally 91 patients with active UC were randomly assigned to 2 groups, 44 in the control group and 47 in the treatment group. Patients in the control group received routine treatment, while patients in the treatment group additionally received intravenous injection of SI (15 mL), twice daily for 14 days in total. Colonoscopy was performed before and after treatment. The therapeutic effect was assessed by Mayo scoring system and the grading of activities evaluated by Baron endoscope. Serum levels of IL-6 and TNF-alpha were detected by ELISA. The activity of SOD was detected by xanthine oxidase method. The content of MDA was detected by thiobarbituricacid (TBA). Besides, 20 healthy subjects were recruited as the healthy control group. RESULTS: Totally 82 patients completed the study (40 in the control group and 42 in the treatment group). There was no statistical difference in serum levels of IL-6, TNF-alpha, SOD, MDA, the Mayo score and endoscope grading between the two groups before treatment (P >0. 05). Compared with the healthy control group, serum levels of IL-6, TNF-alpha, MDA significantly increased (P <0.01), and the serum SOD level decreased (P < 0. 05) in the treatment grup and the control group before treatment. Compared with before treatment in the same group, serum levels of IL-6, TNF-alpha, MDA, the Mayo score and endoscope grading all decreased in the treatment group and the control group after treatment (P <0. 01, P <0. 05). Compared with the control group after treatment, serum levels of IL-6, TNF-alpha, MDA, the Mayo score and endoscope grading all decreased (P <0.01, P <0.05), the serum SOD level increased (P <0.05) in the treatment group after treatment. The serum SOD level was obviously negative correlated with serum levels of IL-6, TNF-a, Mayo score, and endoscope score (r = -0. 621, -0.638, -0. 509, -0.787, P <0.01). The serum MDA level was obviously positive correlated with serum levels of IL-6, TNF-alpha, Mayo score, and endoscope score (r =0.711, 0. 882, 0. 525, 0. 639, P <0.01). CONCLUSION: SI could improve inflammatory injury and clinical symptoms of patients with active UC, and its mechanism might be associated with antioxidant and scavenging oxygen free radicals. PMID- 25509256 TI - [A correlation study between diarrhea-predominant irritable bowel syndrome complicated functional dyspepsia patients of Gan-stagnation Pi-deficiency syndrome and gastrointestinal hormones]. AB - OBJECTIVE: To investigate the correlation between the pathogeneses of diarrhea pre- dominant irritable bowel syndrome (D-IBS) complicated functional dyspepsia (FD) patients of Gan-stagnation Pi-deficiency Syndrome (GSPDS) and symptoms, psychological states, and gastrointestinal hormones. METHODS: A total of 111 patients with confirmed D-IBS complicated FD of GSPDS were recruited as the treated group by using Rome III standard and Chinese medical syndrome standard. And 30 healthy volunteers were recruited as the control group. The general condition, scoring for digestive symptoms, and the distribution of GSPDS subtype of all subjects were recorded by a questionnaire, and assessed by Symptom Checklist (SCL-90; a software for psychological test developed by Beijing Huicheng Adult Cor- poration). Meanwhile, plasma levels of 5-hydroxytryptamine (5 HT), somatostatin (SS), vasoactive intestinal peptide (VIP), endothelin (ET), interleukin 10 (IL-10), and interleukin 12 (IL-12) were measured in all subjects. RESULTS: (1) The subtype of D-IBS complicated FD of GSPDS was dominant in Pi-qi deficiency type (51/111,45.9%),Pi yang deficiency type (34/111,30.6%), and GSPDS. There was no statistical difference in the scoring of digestive symptoms among the 3 subtypes (P >0.05). (2) Compared with the control group, the anxiety factor score and the total score significantly increased in all three subtypes of D-IBS complicated FD of GSPDS, and the depression score of Pi yang deficiency type and Gan-depression type also significantly increased (P <0.05, P <0.01); the depression score of Gan-depression type was significantly higher than that of the Pi-qi deficiency type (P <0.01). Plasma 5-HT levels were obviously lower in D-IBS complicated FD patients of GSPDS accompanied with anxiety or depression than in those with no obvious psychological abnormalities, and VIP and IL-10 levels were significantly lower than those in the control group (P <0.05). Plasma VIP levels were also obviously lower in D-IBS complicated FD patients of GSPDS accompanied with anxiety or depression than in those with no obvious psychological abnormalities (P <0.01), and SS levels were significantly lower than those in the control group (P <0.05). There was no statistical difference in plasma ET or IL 12 levels in each patient group, when compared with the control group (P >0.05). (3) Compared with the.control group, plasma 5-HT levels significantly increased, plasma VIP and IL-10 levels significantly decreased in ach subtype of D-IBS complicated FD patients of GSPDS (P <0.05, P <0.01), and no significant change of SS, ET, or IL-12 occurred (P >0.05). Besides, plasma 5-HT levels were significantly higher in Gan-depression type than in Pi yang deficiency type, VIP levels were lower in Gan-depression type than in Pi-qi deficiency type (all P <0.05). CONCLUSIONS: Gan stagnation and Pi deficiency were dominant in D-IBS complicated FD patients of GSPDS. Psychological abnormalities, increased plasma 5 HT levels, and decreased plasma VIP levels were closely correlated with Gan stagnation subtype, which provided some reference for looking for objective indicators of Chinese medical syndromes in treating D-IBS complicated FD patients of GSPDS. PMID- 25509257 TI - [Distribution characteristics of basic syndromes of chronic functional constipation and its related factors analysis]. AB - OBJECTIVE: To explore the distribution characteristics of basic syndromes and its related factors in patients with chronic functional constipation (CFC). METHODS: The complete data of 538 patients with CFC were collected and initial database was established with Epidata 3. 0. TCM syndrome typing was performed. The distribution characteristics of basic syndromes were analyzed using SPSS 17. 0 Software. The univariate and multivariate Logistic regression analyses were performed with SPSS 17. 0 Software to determine basic syndrome related factors such as age, engaged professionals, sleep quality, depression, mental stress, interpersonal relations, work fatigue, stimulating beverage, exercise conditions, Western medicine type of constipation, and so on. RESULTS: The TCM syndrome frequency of CFC patients was sequenced from high to low as qi deficiency syndrome (380 cases, 70.6%), qi stagnation syndrome (337 cases, 62.6%), blood deficiency syndrome (234 cases, 43.5%), yin deficiency syndrome (220 cases, 40.9%), yang deficiency syndrome (197 cases, 36.6%), and others(58 cases, 10. 8%) . Most patients were complicated with complex syndromes, and the most common complex syndromes were qi deficiency complicated qi stagnation syndrome (275 cases, 51.1%) and qi deficiency complicated blood deficiency syndrome (222 cases, 41.3%). Aging, work fatigue, and exercise conditions were main related factors for qi deficiency syndrome (P <0. 01, P <0. 05). Poor emotional (depression and anxiety tendencies), mental stress, interpersonal relations, defecation barriers constipation were main related factors for qi stagnation syndrome (P <0.01). Sleep quality and poor emotional (depression and anxiety tendencies) were main related factors for blood deficiency syndrome (P <0. 01, P < 0.05). Stimulating beverages were main related factor for yin deficiency syndrome (P <0.05). Engaged in mental work and slow transit constipation were main related factors for yang deficiency syndrome (P < 0. 01, P <0. 05). CONCLUSIONS: CFC is featured as complex syndromes. The most common complex syndromes were qi deficiency complicated qi stagnation syndrome and qi deficiency complicated blood deficiency syndrome. Basic syndrome related factors such as age, engaged professionals, sleep quality, poor emotional (depression and anxiety tendencies), mental stress, interpersonal relations, work fatigue, stimulating beverage, exercise conditions, Western medicine type of constipation were associated with the distribution of CFC syndromes. PMID- 25509258 TI - [Effect of compound qizhu granule on cellular immunity of chronic hepatitis B patients]. AB - OBJECTIVE: To explore the effect of compound qizhu granule (CQG) on cellular immunity of chronic hepatitis B (CHB) patients. METHODS: Totally 103 CHB patients treated with lamivudin (LAM) for 6 months, who had partial virological response (HBeAg positive) were randomly assigned to two groups, 50 in the treatment group and 53 in the control group. All patients took LAM 100 mg (once a day) plus ADV 10 mg (once a day). Patients in the treatment group additionally took CQG, one dose per day. After one-year treatment hepatitis B virus (HBV) DNA negative rates, HBeAg seroconversion, levels of HBV specific cytotoxic T lymphocyte (CTL), non-specific CTL and natural killing (NK) cells were compared between the two groups. RESULTS: After 1-year treatment, HBV DNA negative rate of the treatment group was 88: 0% in 44 cases, slightly higher than that of the control group (41 cases, 77.4%), but with no statistical difference (P >0.05). HBeAg seroconversion of the treatment group was 32.0% in 16 cases, higher than that of the control group (8 cases, 15.1%), with statistical difference (P <0.05). Levels of HBV specific CTL (0.79%+/-0. 07%), non-specific CTL (19.4%+/-1.8%) and NK cells (14. 1%+/- 1.5%) of the treatment group were higher than those of the control group (0.58% +/- 0.08%, 17.5% +/- 1.7%, and 11.1%+/-1.5%, respectively; allP <0.01). CONCLUSION: Treating CHB patients with partial virological response by ADV plus CQG could improve specific and non-specific cellular immunity, thereby elevating HBeAg seroconversion rate. PMID- 25509259 TI - [Adjunctive therapy of xuezhikang capsule for coronary heart disease: a systematic review and meta-analysis of randomized controlled trials]. AB - OBJECTIVE: To systematically evaluate the effect and safety of Xuezhikang Capsule (XZKC) for adjuvant treatment for coronary heart disease (CHD) patients accompanied with or without dyslipidemia. METHODS: China National Knowledge Infrastructure (CNKI) Database, Chongqing VIP Database (VIP), Wanfang Data base, Cochrane Library, and Medline (PubMed) were retrieved with the deadline of August 30, 2013. Randomized controlled trials (RCT) of XZKC in treating CHD patients with or without dyslipidemia were all included. Assessment of bias risk for included studies was conducted according to the Cochrane Handbook for Systematic Reviews of Intervention (Version 5.0.2): Criteria for judging risk of bias in the "risk of bias" assessment tool. Review Management (5.1.0) was employed for data statistics. If there was no significant heterogeneity, results from the random effect model were presented. If the heterogeneity was not substantial, a meta analysis was not performed and a narrative and qualitative summary was performed instead. RESULTS: A total of 28 RCTs (6,949 patients) were included after screening results. The methodological quality of included trial was generally lower. Results of Metaanalysis showed that XZKC was beneficial for CHD patients in decreasing cardiovascular events: when compared with the basic treatment group, the relative risk (RR) was 0.53 and 95% confidence interval (CI) was [0.35, 0.81]; when compared with the placebo + basic treatment group, RR was 0.52 and 95% CI was [0.42, 0.65]; when compared with the basic treatment group, RR for improving symptoms of angina was 1.20 and 95% CI was [1. 12, 1.30]; when compared with the basic treatment group, RR for improving abnormal ECG was 1.38 and 95% CI was [1.21, 1.57]. Thirteen studies showed that XZKC + basic treatment was obviously superior in lowering total cholesterol (TC) to that of the basic treatment group. Three studies showed that XZKC + basic treatment was obviously superior in lowering total cholesterol (TC) to that of the placebo + basic treatment group. Thirteen studies showed that XZKC + basic treatment was obviously superior in lowering low density lipoprotein cholesterol (LDL-C) to that of the basic treatment group. Three studies showed that XZKC + basic treatment was obviously superior in lowering LDL-C to that of the placebo + basic treatment group. A total of 18 studies describing adverse reactions (ADs) involved 61 ADs in the XZKC + basic treatment group. All suffered from mild symptoms or were improved after treatment. No severe ADs occurred. CONCLUSION: Treatment of CHD by XZKC might lower the occurrence of cardiovascular events in CHD patients accompanied with or without dyslipidemia, relieve clinical symptoms, improve ECG, lower blood lipid levels, and with less adverse reactions. PMID- 25509260 TI - [Expert survey for Chinese medicine syndrome characteristics of different clinical types of coronary artery disease based on the Delphi method]. AB - OBJECTIVE: To carry out expert survey for traditional Chinese medicine (TCM) syndrome characteristics of different clinical types of coronary artery disease (CAD). METHODS: By using Delphi method, we carried out two rounds of nationwide expert surveys for modern TCM characteristics of syndrome elements and syndrome types of CAD. RESULTS: Based on expert consensus, qi deficiency, blood stasis, phlegm turbidity, qi deficiency blood stasis, and intermingled phlegm and blood stasis are common TCM syndromes for different clinical types of CAD. Of them, qi stagnation, blood stasis, phlegm turbidity, heat accumulation, cold coagulation, yang deficiency, deficiency of both qi and yang were more often seen in patients with unstable angina than in those with stable angina. Qi deficiency, yin deficiency, and deficiency of both qi and yin were less seen. We could see more excess syndrome and less deficiency syndrome (such as qi deficiency, yin deficiency, etc.) in acute ST-segment elevation myocardial infarction (STEMI) than acute non-ST-segment elevation myocardial infarction (NSTEMI). Qi deficiency, blood stasis, water retention, yang deficiency, phlegm turbidity, yin deficiency, Xin-qi deficiency, and qi deficiency blood stasis induced water retention are the most common TCM syndrome types of CAD heart failure (HF). Blood deficiency, yin deficiency, heat accumulation, deficiency of both Xin and Pi, deficiency of both qi and blood, deficiency of both qi and yin, yin deficiency and fire hyperactivity were more often seen in CAD arrhythmias. CONCLUSIONS: TCM syndrome distributions of different clinical types of CAD have common laws and individual characteristics. Results based on the expert consensus supplied evidence and support for clinical diagnosis and treatment of CAD. PMID- 25509261 TI - [Effect of acupuncture at pericardium points of amplitude of low frequency fluctuations of healthy people in resting state functional magnetic resonance imaging]. AB - OBJECTIVE: To observe the effect of acupuncture at the whole points of Hand Jueyin pericardium meridian on the amplitude of low frequency fluctuations (ALFF) of healthy people in resting state (R1) functional magnetic resonance imaging (fMRI). METHODS: Totally 16 healthy subjects received structure scan of T1 and T2. Then two fMRI scans were conducted for each participant. fMRI included the resting-state scan (R1; the scanning time was 8 min 6 s), the stimulating acupoint scan (AP; the scanning time was 8 min 6 s). fMRI data acquisition from structure scanning and function scanning were processed with format conversion and statistical analysis. RESULTS: Under R1 state, brain regions with activated ALFF signals included bilateral superior frontal gyrus, medial frontal gyrus, middle occipital gyrus, precuneus, superior temporal gyrus, and cingulate gyrus. Under the AP state, brain regions with activated ALFF signals were bilateral superior frontal gyrus, medial frontal gyrus, middle temporal gyrus, left fusiform gyrus, precuneus, posterior cingulate, and declivis. Compared with R1 state, obvious difference of ALFF signal areas of the brain caused by acupuncture at pericardium were: bilateral cuneus, precuneus, left posterior cingulate gyrus, right middle occipital gyrus, and right occipital lingual gyrus. CONCLUSION: Acupuncture at the whole points of Hand Jueyin pericardium meridian could significantly change inherent activity states of the cerebral cortex, especially in bilateral superior frontal gyrus, medial frontal gyrus, and precuneus. PMID- 25509262 TI - [Effect of xuebijing injection on perioperative coagulation function and inflammatory reaction in senile patients receiving total hip arthroplasty]. AB - OBJECTIVE: To observe the effect of xuebijing Injection (XI) on perioperative coagulation and inflammatory reaction in senile patients receiving total hip arthroplasty (THA). METHODS: Totally eighty patients receiving THA at Luoyang Orthopedics Hospital, 65 to 85 years old, were randomly assigned to the control group (40 cases) and the treatment group (40 cases). All patients received routine perioperative therapies. Those in the treatment group received XI (adding 50 mL XI in 100 mL normal saline, 30 min each time). XI was continually injected after THA, twice daily for 3 successive days. Blood samples were harvested on the morning of the 2nd admission day (TO), immediately after operation (T1), on the morning of the 3rd day after operation (T3), and on the morning of the 5th day after operation (T4) to detect prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), levels of FIB and D-dimer (D-D), changes of white blood cell (WBC), neutrophils (N), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and IL-6. Complications of surgery were compared between the two groups. RESULTS: There was no statistical difference in operation time, intraoperative blood loss, and blood transfusion between the two groups (P >0.05). Compared with TO in the same group, WBC, N, CRP, ESR, IL-6, PT, TT, and D-D all increased in the control group at T1-T4 (P < 0.05); APTT increased at T1-T2 (P <0.05); FIB increased at T1-T3 (P <0.05). WBC, N, IL-6, PT, and D-D all increased in the treatment group at T1-T3 (P <0.05); CRP and ESR increased at T1-T4 (P < 0.05); TT increased at T1-T2 (P <0.05); APTT and FIB increased at T1 (P <0.05). Compared with the control group at the same time period, WBC, N, CRP, and IL-6 all decreased in the treatment group at T1-T4 (P <0.05), ESR decreased at T3-T4 (P <0.05); PT and TT decreased at T1-T3 (P <0.05); FIB and D-D decreased at T2-T4 (P<0.05). The occurrence of each complication was significantly lower in the treatment groups than in the control group. CONCLUSION: XI could improve the perioperative high coagulation state of senile THA patients, inhibit inflammatory reactions, and reduce complications. PMID- 25509263 TI - [Effect of electro-acupuncture on metabolites in the cerebral cortex of ulcerative colitis rats based on Pi/Wei-brain related theory]. AB - OBJECTIVE: To study the effect of electro-acupuncture (EA) at points along Foot Yangming Channel on metabolite of ulcerative colitis (UC) rats' cerebral cortex and to identify key metabolites by referring to Pi/Wei-brain related theory in Chinese medicine (CM). METHODS: The UC rat model was set up by dextran sulfate sodium (DSS) method. Male SD rats were randomly divided into the model group and the EA group, 13 in each group. Another 13 rats were recruited as the blank control group. Rats in the blank control group and the model group received no EA. EA was performed at Zusanli (ST36), Shangjuxu (ST37), and Tianshu (ST25) for 5 days by using disperse-dense wave. Then all rats were sacrificed. Their recto colon and the ileocecal junction were pathomorphologically observed by light microscope and transmission electron microscope (TEM). Cerebral cortexes were extracted. Water-soluble and lipid-soluble brain tissue metabolites were respectively extracted for metabolic research using 1H nuclear magnetic resonance (1H-NMR). RESULTS: EA could obviously improve the general condition of UC model rats, decrease the value of DAI, reduce the infiltration of inflammatory cells in the intestinal tract, stabilize structures such as mitochondria, endoplasmic reticulum and so on (P <0.05). 1HNMR analysis showed that in the model group, contents of glutamic acid, cholesterol, very low density lipoproein (VLDL) in the pallium obviously decreased, while alanine and low density lipoprotein (LDL) significantly increased. After EA, levels of lactic acid, glutamic acid, total cholesterol (TC), and VLDL all increased, and levels of alanine and LDL decreased. All indices were approximate to those of the blank control group. CONCLUSION: EA at Foot Yangming channel was found to have some effect on metabolites in the brain tissue of UC model rats, which had specific metabonomic material basis and mechanism based on the Pi/Wei-brain related theory. PMID- 25509264 TI - [Regulatory effect of electroacupuncture on heart and stomach of rats]. AB - OBJECTIVE: To explore different regulatory effects of electroacupuncture (EA) at the same acupoint on the heart and the stomach. METHODS: Eighty male SD rats were randomly divided into eight groups equally, i.e., the Neiguan (PC6) group, the Quchi (LI11) group, the Tianshu (ST25) group, the Danzhong (RN17) group, the Zusanli (ST36) group, the Sanyinjiao (SP6) group, the Xinshu (BL15) group, and the Weishu (BL21) group, 10 in each group. The regulatory effects of EA (2/15 Hz, 3 mA, 2 min) at different acupoints on the gastric motility (intragastric pressure) and the cardiac function (the left ventricular pressure) were observed. The mean values of effect of two-min pre-EA and after-EA were compared. RESULTS: Compared with the pre-EA in the same group, the left ventricular pressure decreased in the Neiguan (PC6) group, the Quchi (LI11) group, the Danzhong (RN17) group, the Sanyinjiao (SP6) group, and the Xinshu (BL15) group (P <0.05). The intragastric pressure increased in the Quchi (LI11) group, the Zusanli (ST36) group, the Sanyinjiao (SP6) group, and the Xinshu (BL15) group, while it decreased in the Tianshu (ST25) group, the Danzhong (RN17) group, and the Weishu (BL21) group (P <0.05). The difference of the left ventricular pressure was sequenced from high to low as Xinshu (BL15) >Danzhong (RN17) >Neiguan (PC6) >Sanyinjiao (SP6) >Quchi (LI11). The difference of the intragastric pressure was sequenced from high to low as Tianshu (ST25) >Weishu (BL21) > Xinshu (BL15) > Danzhong (RN17) > Zusanli (ST36) > Sanyinjiao (SP6) > Quchi (LI11). CONCLUSIONS: EA at the same acupoint (2/15 Hz, 3 mA) showed different regulatory effects on the heart and stomach. There existed some difference in the direction and size due to the acupoint location, meridians, dominant nerve segment or relating organs. A fixed effect direction to the specific target was also shown. PMID- 25509265 TI - [Repair of xiangsha liujunzi decoction on damage of interstitial cells of cajal and gap junction in the gastric muscular layer of rats of Pi-Qi deficiency syndrome: an experiment study]. AB - OBJECTIVE: To explore the repair of Xiangsha Liujunzi Decoction (XSLJZD) on interstitial cells of Cajal (ICC) and gap junction (GJ) in the gastric muscular layer of rats of Pi-qi deficiency syn- drome (PQDS). METHODS: PQDS was established using purgative method with bitter and cold drugs in 30 healthy Wistar rats. After successful modeling they were randomly divided into the treatment group and the model group, 15 in each group. Another 15 healthy Wistar rats were recruited as the healthy control group. Rats in the treatment group were gastric administered with XSLJZD at 2 mL/100 g body weight, once daily for 14 successive days. Equal volume of normal saline was gastrically administered to those in the healthy control group and the model group. The gastric muscle tissues were taken out before modeling, before intervention, and after intervention, respectively. Ultrastructural changes of ICC and GJ were observed using transmission electron microscope (TEM). The number and distribution of Connexin43 (Cx43) were detected using immunohistochemistry. RESULTS: Results of TEM indicated that compared with the healthy control group, both ICC and GJ in the model group showed obvious injury. ICC and GJ were apparently repaired after intervention in the treatment group. Compared with the same group before modeling, the integrated optical density (IOD) of the Cx43 expression significantly decreased in the model group before and after intervention (P <0.05). Compared with before intervention, the IOD of the Cx43 expression significantly increased in the treatment group (P <0.05). Compared with the healthy control group, the IOD of the Cx43 expression significantly decreased in the model group before and after intervention (P <0.05). Compared with the model group, the IOD of the Cx43 expression significantly increased in the treatment group (P <0.05). CONCLUSIONS: Ultrastructures of ICC and GJ in the gastric muscular layer of rats of PQDS were obviously damaged. XSLJZD could repair the structural damage of ICC and GJ in the gastric muscle tissues of rats of PQDS. PMID- 25509266 TI - [Effect of dihydroartemisinin combined irradiation on the apoptosis of human lung cancer GLC-82 cells and its mechanism study]. AB - OBJECTIVE: To study the effect of dihydroartemisinin (DHA) combined irradiation on the apoptosis of human lung cancer GLC-82 cells and to study its mechanism. METHODS: The growth inhibition rate of GLC-82 cells acted by different concentrations DHA was detected using MTT assay at 24, 48, and 72 h, respectively. Clone forming test was used. With multi-target single-hit model, the radiosensitization effect was assessed by calculating sensitizing enhancement ratio (SER).The effect of DHA combined irradiation on the apoptosis of GLC-82 cell cycle distribution and apoptosis were measured by flow cytometry. The protein expression of p53, p21, Bcl-2, and Bax were detected by Western blot. RESULTS: Different concentrations DHA (4, 8, 16, 32, 64, and 128 MUg/mL) had cytotoxicity on GLC-82 cells. The IC50 for 24, 48, and 72 h was 38.25,20.58, and 10.36 MUg/mL, respectively, in obvious dose- and time-dependent manner. The growth inhibition rate was more significantly increased than that of the blank control group (P < 0.01, P<0.05). DHA had sensitization enhancement effect on GLC 82 cells, with SER of 1.4. DHA combined irradiation could obviously change the structure of GLC-82 cells cell cycle and induce apoptosis (with the apoptosis rate of 21.5%), which was significantly different from that of the blank control group (P < 0.05). Western blot showed the expression of p53 and p21 protein could be increased by DHA combined irradiation, and the expression of Bcl-2 protein down-regulated (P <0.01, P <0. 05). CONCLUSIONS: DHA had stronger cytotoxicity and radiosensitization on GLC-82 cells. Its mechanisms might lie in making the arrest of GLC-82 cells' growth at G0/G1 phase, decreasing the ratio of cells at S phase, restoring the function of p53, decreasing the expression of Bcl-2 protein, and inducing apoptosis in GLC-82 cells. PMID- 25509267 TI - [Regulation of naotai recipe on the expression of HIF-lalpha/VEGF signaling pathway in cerebral ischemia/reperfusion rats]. AB - OBJECTIVE: To observe the therapeutic angiogenesis effect of naotai recipe (NR) on local ischemia/reperfusion (I/R) injury of rats by observing signaling pathway of hypoxia-inducible factor-lalpha (HIF-1alpha) and vascular endothelial growth factor (VEGF). METHODS: Totally 120 Sprague-Dawley (SD) rats were randomly divided into 4 groups, namely, the normal control group (n =12), the sham operation group (n =12), the I/R model group (n =48), and the NR group (n =48). Cerebral I/R injury models were established using thread suture method. Rats in the I/R model group and the NR group were sub-divided into 4 sub-groups according to the 1st, 3rd, 5th, and 7th I/R day (n =12). The phenomenon of neovasculization was observed by immunofluorescence staining. The protein and mRNA expression levels of HIF-la, VEGF-A, and VEGFR II receptor were detected by RT-PCR. RESULTS: There were a large amount of labels for neovasculization in the ischemic area of the NR group. Double-immunofluorescence labeling [vWF (red) and BrdU (green)] was observed in the NR group. Compared with the model group, the HIF-1alpha protein expression was obviously enhanced on the 1 st day of I/R (P <0.01), and the VEGF protein expression started to enhance on the 3rd day in the NR group (P <0.01). The VEGFR protein expression level was the highest in the NR group on the 5th day of I/R (P <0.01). The protein expression of VEGF and HIF-1alpha started to decrease on the 7th day of I/R. CONCLUSION: NR could strengthen angiogenesis after I/R by elevating the expression of HIF-lalpha and activating HIF lalpha/VEGF signaling pathway. PMID- 25509268 TI - [Effect of triptolide on the expression of RANTES in the renal tissue of diabetic nephropathy rats]. AB - OBJECTIVE: To investigate the effect of triptolide (TPL) on the renal tissue of diabetic rats and its possible mechanisms. METHODS: SD rats were randomly divided into the normal control group (as the normal group), the diabetic model group (the model group), the low dose TPL treatment group (the low dose TPL group, TPL 0.2 mg/kg by gastrogavage), the high dose TPL treatment group (the high dose TPL group, TPL 0.4 mg/kg by gastrogavage). Equal volume of normal saline was given to rats in the normal group and the model group. Five rats were randomly selected from each group at week 4, 8, and 12 of the experiment to detect body weight, kidney weight, 24 h urinary albumin (24 h UAL), plasma glucose (FBG), total cholesterol (TC), total triglyeride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), white blood cell (WBC), and hemoglobin A1c (HbA1c). The mRNA and protein expression of regulated upon activation normal T cell expressed and secreted (RANTES) in the renal tissue was assessed by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). The renal tissue was pathologically stained by HE, PAS, and Masson staining. The glomerular and renal tubular interstitial lesions were observed at each time point. The glomerular sclerosis index (GSI) was observed by PAS staining, and the renal interstitial filrosis index (RIFI) was calcutated. RESULTS: Compared with the same group at week 4, the expression of 24 h UAL, RANTES, GSI, and RIFI at week 12 significantly decreased in two TPL groups (P <0.01). Compared with the same group at week 8, the expression of 24 h UAL, RANTES, GSI, and RIFI at week 12 also significantly decreased in the two TPL groups (P <0. 05, P <0.01). Compared with the normal group, body weight and the kidney weight obviously decreased at week 4, 8, and 12 in the model group (P <0. 01); 24 h UAL, FBG, TG, TC, HbA1c, RANTES, GSI, and RIFI were obviously elevated (P <0.01). Compared with the model group, 24 h UAL, RANTES, GSI, and RIFI also decreased in the two TPL treatment groups (P <0.01). Compared with the low dose TPL group, they were attenuated in the high dose TPL group (P <0. 05, P <0. 01). CONCLUSION: TPL could not only inhibit the over-expression of RANTES, but also improve the glomerular sclerosis and renal interstitial fibrosis in the renal tissue of diabetic rats. PMID- 25509270 TI - [Effective Components of three kinds of shen-supplementing Chinese medicine on self-renewal and neuron-like differentiation of NSCs in AD mouse embryos: an experimental research]. AB - OBJECTIVE: To observe the regulatory effects of psoralen, oleanolic acid, and stilbene glucoside, three active components of psoralea fruit, glossy privet fruit and tuber fleeceflower root respectively, on Abeta25-35induced self-renewal and neuron-like differentiation of neural stem cells (NSCs). METHODS: Embryonic NSCs werein vitro isolated and cultured from Kunming mice of 14-day pregnancy, and randomly divided into the control group, the Abeta25-35 group, the Abeta25-35 +psoralen group, the Abeta25-35 +oleanolic acid group, and the Abeta25-35 + stilbene glucoside group. The intervention concentration of Abeta25-35 was 25 umol/L, and the intervention concentration of three active components of Chinese medicine was 10(-7)mol/L. The effect of three active components of Chinese medicine on the proliferation of NSCs was observed by counting method. The protein expression of Tubulin was observed by Western blot and immunofluorescence. The ratio of Tubulin+/DAPI was caculated. Results Compared with the control group, the sperical morphology of NSCs was destroyed in the Abeta25-35 group, the counting of NSCs, the expression of Tubulin protein, and the ratio of Tubulin /DAPI all decreased (P <0.01, P <0.05). Compared with the Abeta25-35 group, the counting of NSCs, the expression of Tubulin protein, and the ratio of Tubulin + /DAPI all increased in the three Chinese medicine treated groups (P <0. 01, P <0. 05). CONCLUSIONS: 25 umol/L Abeta25-35 could inhibit self renewal and neuron-like differentiating of NSCs. But psoralen, oleanolic acid, and stilbene glucoside could promote self-renewal of NSCs and neuron-like differentiation. PMID- 25509269 TI - [Effect of shenluotong decoction on renal interstitial fibrosis in rats with obstructive nephropathy]. AB - OBJECTIVE: To observe the effect of Shenluotong Decoction (SD) on serum levels of aldosterone, monocyte chemoattractant protein-1 (MCP-1), alpha-smooth muscle protein (alpha-SMA), and nuclear factor-KB (NF-kappaB) in obstructive nephropathy rats, and to explore the initial mechanism of SD for inhibiting renal interstitial fibrosis. METHODS: Totally 48 healthy Wistar rats were randomly divided into the sham-operation group (n =12) and the model group (n =36). Renal interstitial fibrosis rat model was established by unilateral ureteral obstruction (UUO). After successful modeling, 36 rats were randomly divided into the model group, the Chinese medicine group, and the Western medicine group, 12 in each group. Eplerenone was added in the forage at the daily dose of 100 mg/kg for rats in the Western medicine group. Chinese medicine was added in the forage at the daily dose of 26 g/kg for rats in the Chinese medicine group. Equal volume of normal saline was administered to rats in the sham-operation group and the model group. All medication was performed once daily. The obstructive kidneys were extracted ten days after medication. The pathomorphological changes were observed. The contents of serum aldosterone and MCP-1, and the protein or mRNA expression of MCP-1, alpha-SMA, and NF-KB were detected. RESULTS: Compared with the sham-operation group, infiltration of a large amount of inflammatory cells and collagen deposition significantly increased, serum contents of aldosterone and MCP-1 obviously increased (P < 0.01), the expression of MCP-1 mRNA and protein were significantly up-regulated (P <0.01), the protein expression of alpha-SMA and NF-KB were significantly enhanced in the model group (P <0.01). Com pared with the model group, infiltration of inflammatory cells and renal collagen deposition were attenua- ted in the Chinese medicine group and the Western medicine group, the serum MCP-1 level were reduced, and the mRNA and protein expression of MCP-1 were significantly down-regulated (P <0.01), the protein expression of alpha-SMA and NF-KB were obviously inhibited (P <0. 01). At the same time, serum aldosterone level was reduced in the Chinese medicine group (P <0.01). CONCLUSIONS: inflammatory lesions of the renal tissue could promote the progress of interstitial fibrosis in rats with obstructive nephropathy. SD could attenuate interstitial fibrosis through reducing serum contents of aldosterone and MCP-1, down-regulating MCP-1/ NF-KB, and inhibiting the expression of alpha-SMA. PMID- 25509271 TI - [Buzhong yiqi decoction containing serum reversed resistance of A549/DDP to cisplatin and its effect on the expression of survivin: an experimental research ]. AB - OBJECTIVE: To analyze the reversal effect of Buzhong Yiqi Decoction (BYD) on multidrug resistance of human adenocarcinoma of lung cell line A549/DDP, and to study its effect on the expression of survivin by using serum pharmacological methods in vitro. Methods Totally 24 SD rats were divided into the high, medium and low dose groups, and the blank control group by randomized controlled method. The high dose BYD containing serum (1. 134 g/mL, 2 mL), the middle dose BYD containing serum (0.576 g/mL, 2 mL), and the low dose BYD containing serum (0.284 g/mL, 2 mL) were prepared. The inhibitory effects of different dose and concentrations BYD on the proliferation of A549 and A549/DDP cells were detected by MTT assay, and the drug resistance reversal fold was calculated. The expression of Survivin in the two cell strains were detected respectively by immunohistochemical assay, Western blot, and immunofluorescence method. RESULTS: BYD containing serum showed obvious inhibitory effect on the growth of A549 and 549/DDP. The inhibition rates of 10% dose groups were higher than those of 5% dose groups. Besides, it gradually increased along with increased concentrations. Compared with 10% blank control group, the inhibition rate increased in 10% middle and low dose groups (P <0.05). After acted with 10% middle dose BYD containing serum, IC50, of A549 and A549/DDP were both reduced (P <0.05), reversal fold (RF) both increased. Its reversal ratio on A549/DDP cells was 2. 46, decreasing the resistance of A549/DDP to DDP. Compared with A549 in the same group, the expression of Survivin was detected to decrease by immunocytochemical assay, Western blot, and immunofluorescence method (P<0.05). Compared with 10% blank control group, the inhibition rate decreased in 10% middle dose group (P <0. 05). CONCLUSIONS: 10% middle dose BYD containing serum could significantly inhibit the apoptosis of A549 and A549/DDP. Besides, it could moderately reverse the multidrug resistance of A549/DDP cells to DDP possibly through reducing the intracellular expression of Survivin and enhancing the sensitivity 549/DDP to chemotherapeutics. PMID- 25509272 TI - [Thinking about vertigo effectiveness evaluation methods in clinical research of Chinese medicine]. AB - Vertigo is a kind of patients' subjective feelings. The severity of vertigo is closely related to many factors. But we are short of a well accepted quantitative evaluation method capable of accurately and comprehensively evaluating vertigo in clinics. Reducing the onset of vertigo, enhancing the re- covery of equilibrium function, and improving the quality of life of vertigo patients should be taken as the focus of evaluating therapeutic effects. As for establishing a Chinese medical effectiveness evaluation system for vertigo, we believe we should distinguish different "diseases". We could roughly identify it as systemic vertigo and non-systemic vertigo. For systemic vertigo, the efficacy of vertigo could be comprehensively evaluated by UCLA vertigo questionnaire or dizziness handicap inventory combined with equilibrium function testing indices. But for non-systemic vertigo, the efficacy of vertigo could be comprehensively evaluated by taking UCLA vertigo questionnaire or dizziness handicap inventory as main efficacy indices. Secondly, we should analyze different reasons for vertigo, choose symptoms and signs in line with vertigo features as well as with Chinese medical theories, and formulate corresponding syndrome effectiveness standards according to different diseases. We should not simply take syndrome diagnosis standards as efficacy evaluation standards. PMID- 25509273 TI - [Discussion of Chinese medical research ideas from miRNAs features]. AB - In this paper, miRNAs features were briefly introduced and agreeable points were discussed from 4 aspects: organs relationship, syndrome research, Chinese medical pathogeneses, and actions of Chinese herbs. miRNAs, as information media for organs interrelation, was believed to explain Chinese medical pathogeneses and reveal partial molecular mechanisms of Chinese medicine. miRNAs in the body fluid could be taken as one of biological bases of syndromes. PMID- 25509275 TI - [On English translation of Yellow Emperor's Canon of Medicine]. PMID- 25509274 TI - [Study on clinical experience of using xiaochaihu decoction]. PMID- 25509276 TI - [On English Translation of Jingluo in Chinese medicine from the perspective of cognitive conception of metaphor]. PMID- 25509277 TI - [Applications of platelets in studies on traditional Chinese medicines promoting blood circulation to remove blood stasis]. AB - Thrombotic diseases in different forms become a great threat to human health. Such anti-platelet aggregation drugs as aspirin and clopidogrel are common drugs in clinic. However, along with the appearance of resistance and side effects of western anti-platelet aggregation drugs, anti-platelet aggregation traditional Chinese medicines promoting blood circulation to remove blood stasis have gradually become an important study orientation. Platelet is one of major participant in thrombosis, and plays an important role as a bioactive material in studies on traditional Chinese medicines promoting blood circulation to remove blood stasis, mainly involving two aspects--the evaluation for the anti-platelet aggregation activity of traditional Chinese medicines and the screening of their active components. This paper summarized the applications of platelets in studies on traditional Chinese medicines promoting blood circulation to remove blood stasis, so as to provide basis for further studies. PMID- 25509278 TI - [Advance in studies on antitumor and immunomodulatory effects of wogonin]. AB - Wogonin is a kind of natural flavonoid compound. According to findings in the latest studies, wogonin shows a wide range of antitumor effects, with the characteristics of multi-pathway, multi-link and multi-target, such as promoting tumor cell apoptosis through ROS or Ca(2+)-mediated signal paths, enhancing tumor cytotoxicity by TNF-alpha and TRAIL, blocking tumor cell cycle, inhibiting tumor angiogenesis and resisting cancer synergistically with chemotherapeutic drugs. Moreover, Wogonin could enhance body immune function by enhancing immune cell infiltration, regulating the immune cell phenotype and promoting relevant cytokine secretion. In this paper, the authors summarized the advance in studies on wogonin's antitumor and immunomodulatory effects. PMID- 25509279 TI - [Perspective and application of metabonomics in modern study of traditional Chinese medicine]. AB - Metabonomics is a new method to study on the metabolic network and the relationship between body and environment, which conforms to the way of traditional Chinese medicine (TCM) research. In the study process of modernization of traditional Chinese medicine, effectively conjunction with metabonomics method will facilitate the integration of TCM with modern biological science and technology, and promote the modernization of TCM. This paper introduce the application of metabonomics in the research of toxicity mechanism of TCM, compatibility mechanism of TCM formula, pharmacology effect of TCM and processing mechanism of TCM. This paper summarize the problems in the TCM metabonomics research and prospect its bright future. PMID- 25509280 TI - [Planting area estimation of Chinese Tibetan medicine Herpetospermum pedunculosum based on RS&GIS-by case study of Lengqi and Xinglong town in Luding county]. AB - The herbs used as the material for traditional Chinese medicine are mostly planted at mountain areas where there is appropriate weather condition. Due to the complex terrain condition in mountain area, the planting at such places is always associated with a scattered pattern, which inevitably bring difficulty to the work of accurate measurement for the planting area. Advanced research about monitoring the planting area for medicine-herb under complex environmental condition is so critical and meaningful for developing the medicine-herb planting to a large scale and an industry. Therefore, this research, taking the planting of Herpetospermum pedunculosum in Luding county as an example, utilizes RS&GIS: using the image data from TM and ETM datum as the remote sensing information source, integrating GPS data from quadrat survey on the spots, and analyzing on a GIS platform, to extract the planting area of H. pedunculosum in Luding county. The results indicate that: (1) the method and technology used to estimate the planting area of H. pedunculosum are feasible and can be applied to monitoring the planting area of medicine-herb at mountain area under complex environmental conditions: (2) the planting area of H. pedunculosum in Luding county is estimated to be 857. 246 acres by the methods utilized in this research, which is closed to the value from local statistical data with an error range less than 5%; (3) in consideration of those inevitable errorrs generating from the procedures such as remote sensing data acquisition, data preprocessing, data interpretation, and so on, and the fact that the classification of remote sensing data, which must be implemented by those above procedures, was used directly to extract the herb type, the accuracy of area estimation for the herb is significantly influenced by the accuracy of classification for herb type, and the estimated area is inevitably associated with some error. PMID- 25509281 TI - [Diversity and tissue distribution of fungal endophytes in Alpinia officinarum: an important south-China medicinal plant]. AB - In the present study, terminal-restriction fragment length polymorphism (T-RFLP) technique was applied to assess the diversity and tissue distribution of the fungal endophyte communities of Alpinia officinarum collected from Longtang town in Xuwen county, Guangdong province, China, at which the pharmacological effect of the medicine plant is traditional considered to be the significantly higher than that in any other growth areas in China. A total of 28 distinct Terminal Restriction Fragment (T-RFs) were detected with HhaI Mono-digestion targeted amplified fungal nuclear ribosomal internal transcribed spacer region sequences (rDNA ITS) from the root, rhizome, stem, and leaf internal tissues of A. officinarum plant, indicating that at least 28 distinct fungal species were able to colonize the internal tissue of the host plant. The rDNA ITS-T-RFLP profiles obtained from different tissues of the host plant were obvious distinct. And the numbers of total T-RFs, and the dominant T-RFs detected from various tissues were significantly different. Based on the obtained T-RFLP profiles, Shannon's diversity index and the Shannon's evenness index were calculated, which were significantly different among tissues (P < 0.05). Furthermore, two types of active chemicals, total volatile oils by water vapor distillation method and galangin by methanol extraction-HPLC method, were examined in the each tissue of the tested plant. Both of tested components were detected in all of the four tissues of the medicine plant with varying contents. And the highest was in rhizome tissue. Correlation analysis revealed there were significant negative correlations between both of the tested active components contents and calculated Shannon's diversity index, as well as the Shannon's evenness index of the fungal endophyte communities of the host plant (P = 0, Pearson correlation coefficient <= -0.962), and significant positive correlations between both of the tested active components contents and 325 bp dominant T-RF linkage to Pestalotiopsis (P = 0, Pearson correlation coefficient >= 0.975). In conclusion, A. officinarum is colonized by diverse fungal endophytes communities. The diversity of the fungal endophytes was found in the A. officinarum varied with differences of the tissue types of the host plants and was closely correlated with the accumulation of main active components, total volatile oils and galangin contents in the host plant tissue. PMID- 25509282 TI - [Impact of TDZ and NAA on adventitious bud induction and cluster bud multiplication in Tulipa edulis]. AB - To explore the method of explants directly induced bud and establish the tissue culture system of mutiple shoot by means of direct organogenesis, core bud and daughter bulbs (the top of bud stem expanded to form daughter bulb) of T. edulis were used as explants and treated with thidiazuron (TDZ) and 1-naphthlcetic acid (NAA). The results showed that the optimal medium for bud inducted form core bud and daughter bulb were MS + TDZ 2.0 mg x L(-1) + NAA 4.0 mg x L(-1) and MS +TDZ 2.0 mg x L(-1) + NAA 2.0 mg x L(-1) respectively, both of them had a bud induction rate of 72.92%, 79.22%. The optimal medium for cluster buds multiplication was MS + TDZ 0.2 mg x L(-1) + NAA 0.2 mg x L(-1), and proliferation coefficient was 2.23. After proliferation, cluster buds rooting occurred on MS medium with IBA 1.0 mg x L(-1) and the rooting rate was 52.6%, three to five seedlings in each plant. Using core bud and daughter bulb of T. edulis, the optimum medium for adventitious bud directly inducted from daughter bulb, core bud and cluster bud multiplication were screened out and the tissue culture system of multiple shoot by means of direct organogenesis was established. PMID- 25509283 TI - [Effect of substrate of edible mushroom on continuously cropping obstacle of Rehmannia glutinosa]. AB - The continuous cultivation of Rehmannia glutinosa causes the accumulation of phenolic acids in soil. It is supposed to be the reason of the so called "continuously cropping obstacle". In this study, phenolic acids (hydroxybenzoic acid, vanillic acid, eugenol, vanillin and ferulic acid) were degraded by the extracta of all the tested spent mushroom substrate (SMS) and the maximal degradation rate was 75.3%, contributed by extraction of SMS of Pleurotus eryngii. Pot experiment indicated that hydroxybenzoic acid and vanillin in soil were also degraded effectively by SMS of P. eryngii. The employment of SMS enhanced ecophysiology index to near the normal levels, such as crown width, leaves number, leaf length, leaf width and height. At the same time, the fresh and dry weight and total catalpol concentration of tuberous root weight of R. glutinosa was increased to 2.70, 3.66, 2.25 times by employment of SMS, respectively. The increase of bacteria, fungi and actinomycetes numbers in rhizosphere soil were observed after the employment of SMS by microbial counts. The employment of SMS also enhanced the enzyme activity in soils, such as sucrase, cellulase, phosphalase, urease and catelase. These results indicated that the employment of SMS alleviated the continuously cropping obstacle of R. glutinosa in some extent. PMID- 25509284 TI - [Study on seed quality test and quality standard of Pesudostellaria heterophylla]. AB - Referring to the rules for agricultural seed testing (GB /T 3543-1995) issued by China, the test of sampling, seed purity, weight per 1 000 seeds, seed moisture, seed viability and germination rate had been studied for screening seed quality test methods of Pesudostellaria heterophylla. The seed quality from different collection areas was measured. The results showed that at least 6.5 g seeds should be sampled and passed through 10-mesh sieve for purity analysis. The weight of 1 000 seeds was determined by using the 500-seed method. The phenotypic observation and size measurement were used for authenticity testing. The seed moisture was determined under the higher temperature (130 +/- 2) degrees C for 5 hours. The seeds were dipped into 0.2% TTC sustaining 1 hour at 40 degrees C, then the viability could be determined. The break dormancy seeds were cultured on sand at 10 degrees C. K cluster analysis was applied for the data analysis, the seed quality from different collection areas grading of P. Heterophylla was described as three grades. The seed quality of each grade should reach following requirements: for first grade seeds, germination rate >= 86%, 1 000-grain weight >= 2.59 g, purity >= 87%, moisture <= 13.1%; for second grade seeds, germination rate >= 70%, 1 000-grain weight >= 2.40 g, purity >= 77%, moisture <= 14.3%; for third grade seeds, germination rate >= 41%, 1 000-grain weight >= 2.29 g, purity >= 76%, moisture <= 15.8%. The seed testing methods for quality items of P. heterophylla had been initially established, as well as the primary P. heterophylla seed quality classification standard. PMID- 25509285 TI - [Optimization of induction and culture conditions for hairy roots of Salvia miltiorrhiza]. AB - To establish induction and liquid culture system for hairy roots of Danshen (Salvia miltiorrhiza), Agrobacterium rhizogenes A4, LBA9402, 15834 as test bacterium were used to infect aseptic leaves of Danshen. The hairy roots were induced and positive transgenic hairy roots were selected with PCR using rolB and rolC as the target gene. Then hairy roots of S. miltiorrhiza were harvested and salvianolic acids were extracted with 70% methanol containing 1% formic acid. The content of salvianolic acid B (SalB) and rosmarinic acid (RA) were determined by HPLC. According to the above research results, the Danshen hairy roots induced by A. rhizogenes LBA9402 were inoculated into the following group of culture media: MSOH, MS, B5, and 6,7-V liquid media. Then the same methods of extraction and determination for the content of Danshen hairy roots were adopted. Last, the hairy roots of S. miltiorrhiza induced by A. rhizogenes LBA9402 were inoculated into the MSOH liquid media with different pH values. The content of salvianolic acid were extracted with 70% methanol containing 1% formic acid and determined by HPLC. As a result, three kinds of A. rhizogenes A4, LBA9402, 15834 could induce hairy roots and Ri plasmids were integrated into the genome of S. miltiorrhiza by PCR. Danshen hairy roots induced by A. rhizogenes LBA9402 and A4 produced much more salvianolic acid, which were (3.27 +/- 0.37)% [including (1.04 +/-0.36)% of RA and (2.22 +/- 0.29)% of SalB] and (3.17 +/- 0.20)% [including (0.92 +/- 0.31)% of RA and (2.25 +/- 0.26)% of SalB], respectively. Hairy roots induced by A. rhizogenes LBA9402 when they were cultured in MSOH liquid media produced much more salvianolic acid, which was (4.56 +/- 0.36)%, including (1.12 +/- 0.26)% of RA and (3.44 +/- 0.23)% of SalB. Hairy roots induced by A. rhizogenes LBA9402 produced the most salvianolic acid when they were cultured in MSOH liquid media with the pH value 4.81, which was 4.85%, including 1.16% of RA and 3.69% of SalB. So Danshen hairy roots induced by A. rhizogenes LBA9402 and A4 produced much more salvianolic acid when they were cultured in MSOH liquid media with the pH value 4.81. The research had established the foundation on genetic engineering to improve the quality of S. miltiorrhiza. PMID- 25509286 TI - [Effects of lead stress on net photosynthetic rate, SPAD value and ginsenoside production in Ginseng (Panax ginseng)]. AB - The paper aimed to evaluate the effects of lead stress on photosynthetic performance and ginsenoside content in ginseng (Panax ginseng). To accomplish this, three years old ginseng were cultivated in pot and in phytotron with different concentrations of lead, ranging from 0 to 1000 mg x kg(-1) soil for a whole growth period (about 150 days). The photosynthetic parameters in leaves and ginsenoside content in roots of ginseng were determined in green fruit stage and before withering stage, respectively. In comparison with the control, net photosynthetic rate and SPAD value in ginseng leaves cultivated with 100 and 250 mg x kg(-1) of lead changed insignificantly, however, ginseng supplied with 500 and 1 000 mg x kg(-1) of lead showed a noticeably decline in the net rate of photosynthesis and SPAD value (P < 0.05), the lowest net photosynthetic rate and SPAD value showed in the treatment supplied with 1 000 mg x kg(-1) of lead, with decline of 57.8%,11.0%, respectively. Total content of ginsenoside in ginseng roots cultivated with 100 mg x kg(-1) of lead showed insignificantly change compared to the control, but the content increased remarkably in treatments supplied with 250, 500, 1 000 mg x kg(-1) of lead (P < 0.05), and highest content appeared in these ginsengs exposed to 1000 mg x kg(-1) of lead. The net photosynthetic rate and SPAD value in leaves of ginseng both showed significantly negative linear correlations with lead stress level (P < 0.01), and significant positive linear correlations between total content of ginsenoside and lead concentration was also observed (P < 0.05). These results strongly indicate that exposing to high level of lead negatively affects photosynthetic performance in ginseng leaves, but benefits for accumulation of secondary metabolism (total content of ginsenoside) in ginseng root. PMID- 25509287 TI - [Study on optimal harvest period of Lonicera Flos (Lonicera macranthoides)]. AB - To ascertain the optimal harvest period of Lonicera Flos (Lonicera macranthoides) the configuration yield and quality of L. macranthiodes bloom verity and bud verity flower at different develop periods were Observed. The quality of L. macranthiodes which harvested at different times of the day was Compared. The configuration was significant difference between different develop period of L. macranthiodes flower. As bud growth, yield increased. Bloom verity of L. macranthoides chlorogenic acid content was significantly lower after opening (silver flower stage, golden flower stage), before opening (young bud stage, green-white stage) have no significant difference of the quality. Bud verity of L. macranthoides macranthoidin B is significant lower at yellow-white stage, young bud stage and green-white stage have no significant difference of the quality. The chlorogenic acid and isochlorogenic acid A content is significant difference between L. macranthoides harvested at different time of the day. The optimal harvest period of bloom verity is the white stage, picking time for 10:00 before and after 18:00. The optimal harvest period is the green-white stage, picking time is 8:00 before and after 18:00. PMID- 25509288 TI - [Preparation of herpetin lyophilized liposome and evaluation on its safety and pharmacodynamics]. AB - In this study, the herpetin (HPT) lyophilized liposome was prepared, and its saftey and pharmacodynamics were evaluated. HPT lyophilized liposome was prepared by thin-film ultrasonication method. The lyoprotectant was optimized using particle size and encapsulation efficiency as indexes. Then, the influencing factors of HPT lyophilized liposome were investigated. In addition, preliminary safety and therapy efficiency of HPT lyophilized liposome to liver injury induced by CCl4 in the mice. The optimal lyoprotectant was 5% sucrose plus 5% lactose and the dispersed HPT lyophilized liposomes were spherical with the mean diameter of (107.0 +/- 1.2) nm and the mean encapsulation efficiency of (99.7 +/- 0.50)%. The lyophilized powder was sensitive to temperature, humidity and illumination. None of hemolysis, hemagglutination and vein irritation was observed after intravenous injection of HPT lyophilized liposomes into rabbits. HPT lyophilized liposome showed obviously therapy efficiency to liver injury induced by CCl4 in the mice. The improvements of ALT, AST and ALP were better than that in HPT free drug. The obtained HPT lyophilized liposome met the standard of CP with fine particle size and encapsulation efficiency after dispersion. The HPT lyophilized liposome showed good safety and enhanced the treatment efficacy of HPT. The HPT lyophilized liposome should be stored in low temperature, sealed condition far away from light. PMID- 25509289 TI - [Application of near-infrared spectroscopy technology in extraction and concentration process of Reduning injection]. AB - OBJECTIVE: To establish a rapid quantitative analysis method for the content of chlorogenic acid and solid content in the extraction liquid concentration process during the production of Reduning injection by using the near-infrared (NIR) spectroscopy, in order to reflect the concentration state in a real-time manner and really realize the quality control of concentrating process of the extraction and concentration process. METHOD: The samples during the Jinqing extraction liquid concentration process were collected. After the removal of abnormal samples, the spectra pretreatment and the wave band selection, the quantitative calibration model between NIR spectra and chlorogenic acid HPLC analytical value and solid content was established by using PLS algorithm, and unknown samples were predicted. RESULT: The correlation coefficients between the chlorogenic acid content and the solid content were respectively 0.992 1 and 0.994 0, and the correlation coefficients of the verification model were respectively 0.994 4 and 0.998 4, with the root mean square error of calibration (RMSEC) of 0.814 6 and 2.656 1 and the root mean square error of prediction (RMSEP) of 0.704 6 and 1.876 7 respectively, and the relative standard errors of predictions (RSEP) were 6.01% and 2.93% respectively. CONCLUSION: The method is simple, rapid, nondestructive, accurate and reliable, thus could be adopted for the fast monitoring of the chlorogenic acid content and the solid content during the concentration process of Reduning injection extraction liquid. PMID- 25509290 TI - [Quality assessment of sulfur-fumigated paeoniae alba radix]. AB - The samples of sulfur-fumigated Paeoniae Alba Radix acquired both by random spot check from domestic market and self-production by the research group in the laboratory were used to evaluate the effects of sulphur fumigation on the quality of Paeoniae Alba Radix by comparing sulfur-fumigated degree and character, the content of paeoniflorin and paeoniflorin sulfurous acid ester, and changes of the fingerprint. We used methods in Chinese Pharmacopeia to evaluate the character of sulfur-fumigated Paeoniae Alba Radix and determinate the content of aulfur fumigated paeoniflorin. LC-MS method was used to analyze paeoniflorin-converted products. HPLC fingerprint methods were established to evaluate the differences on quality by similarity. Results showed that fumigated Paeoniae Alba Radix became white and its unique fragrance disappeared, along with the production of pungent sour gas. It also had a significant effect on paeoniflorin content. As sulfur smoked degree aggravated, paeoniflorin content decreased subsequently, some of which turned into paeoniflorin sulfurous acid ester, and this change was not reversible. Fingerprint also showed obvious changes. Obviously, sulfur fumigation had severe influence on the quality of Paeoniae Alba Radix, but we can control the quality of the Paeoniae Alba Radix by testing the paeoniflorin sulfurous acid ester content. PMID- 25509291 TI - [Ultrasound assisted the enzymolysis of ginsenosides to prepare pare ginseng saponin Compound K]. AB - To prepare ginseng saponin Compound K with ultrasound-assisted total zymolytic ginseng saponins. The conversion rate was taken as the index to detect the pre treatment factors such as ultrasonic power and ultrasonic time, as well as the impact of enzymatic factors, such as pH value, temperature, concentration of substrate, dosage of enzyme and reaction time, on the conversion rate. The response surface method was used to optimize the preparation conditions. The enzymolytic products were identified with MS, 1H-NMR and 13C-NMR. The results showed that the optimum conditions of the ultrasound-assisted enzymolysis were 250 W for ultrasonic power, 15 min for ultrasonic time, 5.5 for enzymolytic pH, 50 degrees C for enzymolytic temperature, 36 h for enzymolytic time, 4:5 for enzymolytic dosage: substrate and 1.0 g x L(-1) for concentration of substrate. The relative molecular mass of reaction products was 622.4. Therefore, the nuclear magnetic map verified that the reaction product was rare ginseng saponin Compound K. Under the above conditions, based on the total zymolytic ginseng saponins, the conversion rate of rare ginseng saponin Compound K was 6.91% in proportion to the total of ginsenosides. The process features gentle reaction conditions, high conversion rate and simple and reliable process, which is suitable for industrial production. PMID- 25509292 TI - [Level investigation on coptidis rhizoma processing methods and product specifications]. AB - The existing processing methods, commercial specification and grades, and the marketing of Coptidis Rhizoma were systematical researched, referring to ancient, modern and contemporary medical literatures with the combination of our fieldwork on main origins of Coptidis Rhizoma and some herbs markets. Results showed that Coptidis Rhizoma processing methods mainly included sun-dried method and baked method anciently. For now, the processing methods become various, including thin paper-covering under the sun drying, direct drying, oven drying and microflame fry drying. In the literatures, the main chemical constituent berberine was determined of its content to analyze the processing methods, finding that the sun drying and baked drying affect the berberine content, so the temperature must be controlled when drying. The thin paper-covering drying method is so cumbersome for large quantities of medicinal herbs and in wind conditions that it has been eliminated. Eventually, direct drying, oven drying and microflame-fry drying are chosen to the large-scale socialized production for their convenient and simple operation, making up the current main processing methods. Coptidis Rhizoma products have 3 specifications of Weilian, Yalian, Yunlian, of each specification there are 2 levels, but in fact the market of Weilian commodities overtakes the Yunlian, which only sold in parts of Yunnan, and the no-sale Yalian. The mainstream commercial Weilian are often sold in general way, gradeless and uniformly-priced. There are regional differences of the processing methods on Coptidis Rhizoma, which needs unified research and development of relevant standard operating procedures to ensure the quality of medicine, urgently. Coptidis Rhizoma product specifications and the intrinsic quality-grade correlation need to be further improved, which could provide a more reliable standard for quality at competitive prices, and it is recommended that "medicinal commercial specification and grade standard" content be increased into the Herbs part of Chinese Pharmacopoeia. PMID- 25509293 TI - [Chemical constituents from roots of Ixeris chinensis]. AB - Silica gel column chromatography and preparative HPLC were applied to isolate the chemical constituents from the roots of Ixeris chinensis. Fifteen compounds were isolated and their structures were elucidated by the physicochemical properties and spectral analysis as chinensioide G(1), chinensioide B(2), 10alpha-hydroxy guaia-12,6-lactone-3-keton(3), chinensioide C(4), 10alpha-hydroxy-11betaH-guaia 4(5) -ene-12,6-lactone (5), 3beta, 10alpha-dihydroxy-11betaH-guaia-11 (13)-ene 12,6-lactone (6), 3beta, 10alpha-dihydroxy-4betaH, 11betaH-guaia-12,6-lactone(7), 3beta, 10alpha-dihydroxy-guaia-4 (15), 11 (13) -diene-12, 6-lactone (8), caffeic acid (9), p-hydorxyphenylacetic acid(10), methyl p-hydroxyphenylacetate (11), ethyl p-hydroxyphenylacetate (12), sitosterol (13), daucosterol (14), and ixerin D(15). Compound 1 was new, and 6 and 7 were isolated from I. chinensis for the first time. PMID- 25509294 TI - [Chemical constituents from Callicarpa nudiflora and their cytotoxic activities]. AB - The chemical consitituents from cytotoxic fraction of the Callicarpa nudiflora extract were isolated and purified by a combination of HP-20 macroporous resin, silica gel and Sephadex LH-20 column chromatographies. The structures were elucidated on the basis of the spectroscopic data and comparison of their spectroscopic data with reported data. The cytotoxicity was evaluated by the MTT assay. The 50% and 70% EtOH elutions of EtOH-extract showed significant cytotoxic activities, leading to the isolation of twelve compounds, which were identified as luteoloside(1), lutedin-4'-O-beta-D-glucoside(2), 6-hydroxyluteolin-7-O-beta glucoside(3), lutedin-7-O-neohesperidoside(4), rhoifolin (5), luteolin-7, 4'-di-O glucoside (6), forsythoside B (7), acteoside (8), alyssonoside (9), catalpol(10), nudifloside(11), and leonuride(12). Compounds 3-6, 10 and 12 were isolated from this genus for the first time, and compound 9 was isolated from this plant for the first time. The cytotoxicity assay demonstrated that flavonoids 1-6, in various concentrations, showed monolithic proliferation inhibitory activities against Hela, A549 and MCF-7 cell lines. Compounds 3, 5 and iridoid glycoside 11 possessed higher cytotoxicacivities. In short, flavonoids are the main components of cytotoxic extract from C. nudiflora, while phenylethanoid glycosides are the predominant ingredient but inactive to cancer cell lines. In addition, the minor iridoid glycoside expressed weak cytotoxic activity. PMID- 25509296 TI - [Chemical constituents from Paris mairei]. AB - Twelve compounds were isolated from the rhizome of Paris mairei Levl by silica gel, Sephadex LH-20 and ODS col-umn chromatographies. The structure elucidation was accomplished by ESI-MS and NMR methods. These compounds were identified as lupeol(1), lup-20(29) -ene-3beta-yl octacosanoate(2), palmitic acid(3), glyceryl alpha-mono-palmitate(4), alpha-spinasterol(5), diosgenin (6), (25R) diosgenin-3-O alpha-L-rhamnopyranosyl (1--> 4) -alpha-L-rhamnopyranosyl (1 --> 4) - [alpha-L rhamnopyranosyl(1 --> 2)] -beta-D-glucopyranoside(7), pennogenin(8), pennogenin-3 O-beta-D-glucopyranosyl(1 -->3) - [alpha-L-rhamnopyranosyl(1 --> 2)] -beta-D glucopyranoside(9), flazin(10), calonysterone(11), and isorhamnetin-3-O-beta gentiobioside(12). Compounds 1-5,10-11 were isolated from the genus Paris for the first time, and all compounds were isolated from this plant for the first time. PMID- 25509295 TI - [Chemical constituents from safflower injection and their bioactivity]. AB - The chemical constituents of Safflower injection were isolated and purified by polyamide, silica gel, Sephadex LH-20, ODS column chromatographies and preparative HPLC. As a result, sixteen compounds have been isolated. Based on the spectral data analysis, their structures were elucidated as scutellarin (1), kaempferol-3-O-beta-rutinoside(2), hydroxysafflor yellow A(3), rutin (4), coumalic acid(5), adenosine(6), syringoside(7), (3E)-4-(4'-hydroxyphenyl)-3-buten 2-one(8), (8Z)-decaene-4, 6-diyne-1-Obeta-D-glucopyranoside(9), 4 hydroxybenzaldehyde (10), (2E, 8E) -tetradecadiene-4, 6-diyne-1, 12, 14-triol-1-O beta-D-glucopyranoside (11), kaem-pferol-3-O-beta-sophorose (12), uridine (13), roseoside (14), cinnamic acid (15), and kaempferol (16). Compounds 1,2,7,9,11 and 12 were isolated from the Safflower injection for the first time. The anti platelet aggregation activities of the isolated compounds were assayed. The results indicated all tested compounds exhibited potent activity except for 5, while 2, 3, 9 and 12 showed strong activity against platelet aggregation. PMID- 25509297 TI - [Chemical constituents in higher polar substances from Desmodium caudatum]. AB - In this study the chemical constituents of the higher polar sustances from Desmodium caudatum were investigated.The compounds were isolated by using column chromatographies over silicagel, polyamide, ODS, Sephadex LH-20, and preparative HPLC. The structures of these compounds were identified on the basis of NMR and MS spectra. Thirteen compounds were obtained and their structures were identified as vanillin(1), loliolide(2), indole-3-carboxaldehyde(3), salicylic acid(4), swertisin(5), saccharumoside C(6), isosinensin (7), kaempferol 3-O-beta-D glucopyranoside-7-O-alpha-L-rhamnopyranoside (8), isovitexin (9), vitexin (10), nothofagin(11), resveratroloside (12), and 2"-alpha-rhamnopyranosyl-7-O methylvitexin (13). Except for compound 5, the remaining compounds were isolated from D. caudatum for the first time. Compounds 2, 3, 6-8, 11-13 were separated from the genus Desmodium for the first time. PMID- 25509298 TI - [Research on quality changes in ginseng stems and leaves before and after frost]. AB - The present study is to investigate the quality changes of ginseng stems and leaves before and after frost. The contents changes of ginsenoside, free amino acid, and total phenolic compounds, as well as DPPH radical scavenging effect before and after frost were measured. The content of 9 ginsenoside monomer in ginseng stems was decreased except for Rg, and Re after frost, but in ginseng leaves was all decreased. The total content of amino acids was decreased in ginseng stems after frost, while increased in ginseng leaves. The content of phenolic compounds in ginseng stems and leaves were both decreased after frost while the ability of DPPH radical scavenging was improved. The factor of frost has great impact on the quality of ginseng stems and leaves. PMID- 25509300 TI - [Study on quantitative methods of cleistocalycis operculati cortex]. AB - Cleistocalycis Operculati Cortex is the dry bark of Cleistocalyx operculatus. It is the raw material of Compound Hibiscuse which is external sterilization antipruritic drugs. The quality standard of Cleistocalycis Operculati Cortex in Guangdong Province "standard for the traditional Chinese medicine" (second volumes) only contains TLC identification. It is unable to effectively monitor and control the quality of Cleistocalycis Operculati Cortex. A reversed-phase HPLC method was established for the determination of 3, 3'-O-dimethylellagic acid from Cleistocalycis Operculati Cortex and the content was calculated by external standard method for the first time. Under the selected chromatographic conditions, the target components between peaks to achieve effective separation. 3,3'-O- dimethylellagic acid standard solution at the concentration of 1.00 - 25.0 mg x L(-1) showed a good linear relationship. The standard curve was Y = 77.33X + 7.904, r = 0.999 5. The average recovery was 101.0%, RSD was 1.3%. The HPLC method for the determination of 3,3'-O-dimethylellagic acid in Cleistocalycis Operculati Cortex is accurate and reliable. It can provide a strong technical support for monitoring the quality of Cleistocalycis Operculati Cortex. PMID- 25509299 TI - [Changed accumulation of active ingredient in different localities and growth period of Hemsleya zhejiangensis (Cucurbitaceae)]. AB - In this paper, the content of moisture, ethanol-soluble extractives, total saponins and polysaccharide of different tuber samples of Hemsleya zhejiangensis, from different localities, years and seasons, were detected based upon Chinese Pharmacopoeia 2010 version. The samples of roots, stems and leaves in summer were detected as well. The results are mainly as follows. (1)With tuber quality increasing, the content of total saponins increased and then decreased. The individual quality of tubers getting 594.06 g, the content of total saponins reached the peak. (2) The content of active ingredients in different localities was significantly different, and the population of Wuyanling had the maximum content of total saponins and polysaccharide. (3) The content of active ingredients revealed stability between the years 2012 and 2013, but the content of polysaccharide was significantly different. The content in 2012 was higher than that of 2013. (4) The content of active ingredients reached the peak in autumn, which was the best harvest season. (5) Among different component content detection of nutritional organs, tubers had the maximum content of ethanol soluble extractives, total saponins and polysaccharide. Leaves also contained higher content of ethanol-soluble extractives and total saponins than roots and stems. All of these provide theoretical basis for plant, harvest and production of H. zhejiangensis, which is an endemic, rare, and endangered medicinal plants. PMID- 25509301 TI - [Changes in Wnt pathway inhibiting factors in nitrosamine-induced esophageal precancerosis lesions and effect of gexia zhuyu decoction]. AB - OBJECTIVE: To discuss the changes in Wnt pathway inhibiting factors in esophageal precancerosis lesions induced by methyl benzyl nitrosamine (MBNA) and the effect of Gexia Zhuyu decoction. METHOD: Wistar rats were subcutaneously injected with MBNA (3.5 mg x kg(-1) for twice per week to establish the model. Since the 1st day after the model establishment, they were orally administered with Gexia Zhuyu decoction (16, 8 mg x kg(-1)). At the 10th week, esophageal tissues were collected to observe the pathological changes of esophageal mucosa, detect SFRP1, sFRP4, Axin1, Axin2 and GSK-3beta mRNA levels.by fluorescent quantitation PCR analysis and beta-catenin protein level by Western blotting. RESULT: Being induced by MBNA, rats in the model group showed slight atypical hyperplasia in the histopathological examination. Compared with the normal group, Gexia Zhuyu decoction dose high and low groups showed no significant pathomorphological and histological changes. The model group showed lower gene transcription levels of esophageal tissues sFRP1, sFRP4, Axin1 and Axin2 (P < 0.05 or P < 0.01) and higher beta-catenin protein expression level (P < 0.01) than the normal control group. The Gexia Zhuyu decoction low dose group showed higher gene transcription levels of esophageal tissues sFRP1, sFRP4, Axin1 and Axin2 (P < 0.05 or P < 0.01) and lower beta-catenin protein expression level (P < 0.01) than the normal control group. CONCLUSION: Up-regulated beta-catenin protein level and down regulated Wnt pathway could enhance Wnt pathway activity of MBNA-induced esophageal precancerous lesions. Gexia Zhuyu decoction could down-regulate the beta-catenin protein level and up-regulate the transcription level of Wnt pathway inhibiting factors, but could not block MBNA-induced esophageal precancerosis lesions. PMID- 25509302 TI - [Comparison of protective effects of eight ethyl acetate extracts from Eclipta prostrate on NHBE cells based on component structure theory]. AB - To analyze and compare the protective effects of active components in different ethyl acetate extracts (EAEEPs) from Eclipta prostrate, in order to study the comparison of materials bases protecting normal human bronchial epithelial (NHBE) cells. The MTT assay was taken to compare the protective effect of different EAEEPs on cigarette smoke extracts (CSE) -induced NHBE cells. The ultra performance liquid chromatography (UPLC) was applied to analyze the content of phenolic acid, coumaric grass ether and flavonoid in EAEEPs. According to the results, all of the eight EAEEPs (0-200 mg x L(-1)) showed certain protective effect on NHBE cells, with statistical difference. Specifically, the total mass of EAEEP VII (89.15 mg x L(-1)) and EAEEP VIII (57.44 mg x L(-1)), which showed the strongest activity, was not the highest, while EAEEP III (132.25 mg x L(-1)) displayed the highest total mass. In the combination with the "component structure" theory, the analysis showed a significant difference in the mass structure among phenolic acid, coumaric grass ether and flavonoid in EAEEP VIII and EAEEP VIII, which were 1.0: 1. 0: 0.5 and 1.0: 1.9: 0.8, respectively. The results suggested a specific optimal "component structure" relationship may exist in EAEEP, which could provide reference for the material base study and quality control. PMID- 25509303 TI - [Transmembrane transport behavior of in vitro HepG2 cells of ananas and its effect on lipids and glucose distribution]. AB - Pineapple (Ananas comosus) leaves contain mainly phenolic components with antioxidant and hypolipidemic effects. One of the principle components is p coumaric acid. In this study, the transport behavior of p-coumaric acid, was observed after the administration of pineapple leaf phenols in vitro. Simultaneously, the effect of the phenols on glucose, total cholesterol and triglycerides transportation and metabolism in HepG2 cells was also observed. The results showed that the phenols had good transport characteristics. 5 min after the administration, p-coumaric acid of the phenols could be detected, and the content of p-coumaric acid reached the peak concentration after 60 min of the administration. p-coumaric acid of phenols have time-and dose-dependent manner. While promoting glucose transporter (GLUT4) and low density lipoprotein receptor (LDLR) expression, the phenols decreased intracellular lipid content. This reduction of intracellular lipid content was highly correlated with the promotion of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) expression, while the reduction of intracellular glucose levels was correlated with glycogen synthesis in the cells. PMID- 25509304 TI - [Study on action mechanism of adjuvant therapeutic effect compound Ejiao slurry in treating cancers based on network pharmacology]. AB - Recently, compound Ejiao slurry (FFEJJ) had been applied to treat cancer patients in clinic, with obvious curative effect. In this study, data and literatures were collected from the TCM chemical component database to establish the chemical component database of FFEJJ. Afterwards, MetaDrug software was used to predict the targets of FFEJJ and obtain the compound-target network. Next, the compound target network was compared and analyzed to obtain the "compound-target-tumor target" heterogeneous network. Besides, further analysis was made on gene functions and metabolic pathway. The results indicated that FFEJJ could directly resist tumors by regulating cancer cell differentiation, growth, proliferation and apoptosis, and show an adjuvant therapeutic effect by enriching the blood and increasing the immunity. PMID- 25509305 TI - [Filtration of active fractions with hemostasis effect from platycladi cacumen carbonisatum]. AB - OBJECTIVE: To discuss the hemostasis of the different polarities of Platycladi Cacumen Carbonisatum (PCC) on the blood heat and hemorrhage syndrome rat model induced by dry yeast. METHOD: The SD rats were divided into seven groups. Yunnan Baiyao was taken as the positive control drug. The rats in the control group and model group were fed with CMC-Na for 7 days, and the rats in other groups were fed with corresponding drugs simultaneously. On day 7, the blood heat and hemorrhage syndrome rat model was established. Indexes including the whole blood viscosity, plasma viscosity, thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen content (FIB), red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), blood platelet count (PLT), thrombocytocrit (PCT), mean platelet volume (MPV), platelet distribution width (PDW) and the rate of platelet aggregation induced by ADP were detected. Additionally, the pathological examinations of lungs among each group were compared. RESULT: Compared with the control group, the RBC, HGB and HCT of rats in the model group increased significantly, with distinct increase in high, middle and low whole blood viscosity and plasma viscosity of rats in the model group; TT and APTT were notably prolonged, while PT was notably shortened, with significant increase in FIB content; PLT, PCT, MPV and PDW remarkably increased; Additionally, the rate of platelet aggregation induced by ADP significantly decreased. After ig administration of the ethyl acetate extract of PCC, the low whole blood viscosity and plasma viscosity remarkably decreased; TT and APTT were significantly shortened, with notable reduction in PDW and in FIB content Additionally, the rate of platelet aggregation induced by ADP significantly increased. The injury of lungs was also improved in ethyl acetate extract group. The rate of platelet aggregation induced by ADP of n-butanol extract group notablly increased. Plasma viscosity of water extract group remarkably decreased, with TT being significantly shortened. But the effects of n-butanol extract or water extract were weaker than that of ethyl acetate extract. And the effect of petroleum ether extract was the weakest. CONCLUSION: Ethyl acetate extract is the active part of PCC, showing the effect of hemostasis by reducing the low whole blood and plasma viscosity, improving coagulation function mainly by acting on the endogenous coagulation, and ameliorating the function of platelet aggregation. PMID- 25509306 TI - [Inhibitory effect of polydatin on expression of toll-like receptor 4 in ischemia reperfusion injured NRK-52E cells]. AB - Polydatin is a monocrystaline compound isolated from Polygonum cuspidatum Sieb. et Zucc. (Polygonaceae) with biological properties, such as anti-inflammation, anti-oxidative and nephroprotective effects. Increasing number of studies have demonstrated the protective effect of polydatin on renal ischemia reperfusion injury. However, the possible mechanisms of this protection are not fully elucidated. This study aimed to investigate the effect of polydatin on ischemia reperfusion induced expression of toll-like receptor4 (TLR4) in rat renal tubular epithelia cells (NRK-52E), and analyze the mechanism of polydatin on TLR4 signal pathway. The cultured NRK-52E cells were incubated in three gas incubators for a period of 6 h at hypoxia and 24h at reoxygenation to simulate the ischemia reperfusion injury in vitro. TLR4 mRNA level was analyzed by real-time-PCR, and the protein expression of TLR4 and NF-kappaB by Western blotting, while TNF-alpha and IL-1beta proteins expressions were detected by ELISA. Polydatin downregulated I/R induced mRNA and protein expressions of TLR4, and decreased the protein expression of NF-kappaB, TNF-alpha and IL-1beta. The TLR4 blocker partially antagonized the effect of I/R on NF-kappaB signaling, and such inhibitory effect was markedly enhanced by polydatin. In the present study, polydatin protects NRK 52E cells from I/R injury possibly by relieving the inflammatory response through regulation of TLR4/NF-kappaB signaling pathway. PMID- 25509308 TI - [Study on attenuate and synergistic mechanism between aconiti lateralis praeparata radix and glycyrrhizae radix for toxicity reduction based on metabonomic of MI-RI mouse cardiomyocytes]. AB - Sini decoction (SND), a classical traditional Chinese medicine emergency formula recorded in Shanghan Lun (Treatise on Febrile Diseases), which is composed of Aconiti Lateralis Preparata Radix, Glycyrrhizae Preparata Radix and Zingiberis Rhizoma. Modern clinical and pharmacological researches have shown that SND can protect the myocardium effectively during myocardial ischemia reperfusion injury (MI-RI). A myocardial ischemia reperfusion injury model of H9c2 cardiomyocytes in vitro has been established. Four groups, control group, MI-RI Model group, SND group and SND without Glycyrrhizae Radix group, were arranged. The livability, the level of LDH and CK activity in H9c2 cardiomyocytes in different groups were tested. By combining with principal components analysis (PCA), partial least squares discriminant analysis (PLS-DA), orthogonal partial least squares projection of latent structures-discriminant analysis (OPLS-DA), 17 biomarkers in extracellular fluid were identified and 15 of them were related to the pathway of biological processes. The results showed that the attenuate and synergistic mechanism between Aconiti Lateralis Praeparata Radix and Glycyrrhizae Radix for toxicity reduction was related with the glycolysis, lipid metabolism, citrate cycle and nitrogen metabolism of amino acids metabolism. The study proved the effect on H9c2 cardiomyocyte treated by MI-RI injury both SND group and SND without Glycyrrhizae Radix group, and compared with the SND without Glycyrrhizae Radix, the protective effect of myocardial ischemia reperfusion injury model of H9c2 cardiomyocyte from SND was stronger. PMID- 25509307 TI - [Relationship between regulation effect of salvia miltiorrhiza on AQP2 in kidney and promoting blood circulation and diuresis]. AB - Partial nature of "promoting blood circulation and dieresis" of Salvia Miltiorrhizain was initially demonstrated by investigating the regulation effect of AQP2 expression in kidney of trauma blood stasis model rats with the Salvia Miltiorrhizain so as to provide guidance for its clinical deployment of administration. Random allocation was taken to averagely divide 30 SD rats into two groups: 10 rats in normal group and 20 rats in blood stasis syndrome group. Trauma blood stasis rat model was established by quantitatively beating. Then the rat model group was divided into model group and salvia group. After 7 days of treatment, the rat kidney AQP2 expression was detected, the content of urine AQP2 was compared and the damaged local muscle and kidney pathological changes were observed by immunohistochemical method and western blot method. Compared with that of the normal group, rats in model group had inflammatory cells infiltration, blood stasis and edema of the injured local muscles and up regulated AQP2 expression, decreasing urinary output, and kidney tissues blood stasis and edema (P < 0.05). On the other hand, compared with that of the model group, those parameters of rats in salvia group were all decreasing except urine output (P < 0.05). Such result indicated that Salvia Miltiorrhiza can reduce trauma blood stasis rat content of urine AQP2 and down-regulated AQP2 expression in kidney tissue, so as to reduce the reabsorption of water by renal tubular and increase urine output. The promoting blood circulation effect of Salvia Miltiorrhizain can alleviate the degree of the damaged tissue edema and encourage urine drainage. This therapy is closely related to the effect of regulating AQP2 in kidney by salvia, so the purpose of this study by verifying "promoting blood circulation and diuresis" as the mechanism for the regulation effect of the salvia on AQP2 expression. PMID- 25509309 TI - [Comparative analysis on composition principles of traditional Chinese medicine prescriptions for osteoporosis and osteoarthritis]. AB - This paper collected the traditional Chinese medicine (TCM) prescriptions of osteoporosis and osteoarthritis from CNKI to set up database and used TCM inheritance system to analyze the composing principles in prescriptions. We collected 103 and 106 prescriptions for osteoporosis and osteoarthritis respectively, then analyzed inherent principles between herbs in prescriptions by using the TCM inheritance system, and obtained the frequency of each herb, and drug combinations of two diseases' prescriptions. The result showed that the principles in TCM prescriptions of osteoporosis and osteoarthritis are similarities, buch as tonifying kidney and invigorating the circulation of blood, but differences of the specific drugs. That is to say, tonifying kidney is the main method of osteoporosis treatment, however, invigorating the circulation of blood is the main method of osteoarthritis treatment. PMID- 25509310 TI - [Study on sustainable development of industy of ethnic medicine in minority area]. AB - Ethnic medicine industry is facing many problems such as narrow market, exhaustion of resource, decline of ethnic medicine and no qualified successors. Sustainable development theory was utilized to analyse the elements and problems of ethnic medicine industry, and the counter measures were put forward to get rid of the predicament and to realize the sustainable development which depends on the ethnic medicine resources, national medicine, industrial policy, personnel training and modern technology. The development issues of ethnic medicine industry can be solved by the coordination of enterprise, government and public. Finally the ethnic medicine can provide better services for society. PMID- 25509311 TI - [Resources and application of She's nationality wild medicinal plants]. AB - To make a thorough investigation of the common She's nationality wild medicinal plants resources in our country, including the species, the distribution, the folk application and the endemic medicinal plant species, Field surveyed was conducted with 25 She people mainly lived area (county, district or city) throughout the country, the folk prescription and treatment cases provided by She's medical personnel, the drug usage and dosage, the commonly used traditional She's medicine and drug samples were collected. And the distribution, growing environment of these plants were investigated, their characteristics, photographs, GPS data and track were record , and the fresh wax leaf or plants specimens were collected. In total 1 600 varieties of folk medicine of She's nationality, 450 disease names and 1 016 prescriptions were collected. 520 kinds of these medicinal plants were commonly used, growing mainly distributed in the southeastern China, about 200 meters above sea level to 1 500 meters. There are 5 First-Grade State protection wild plants (medicinal), 15 second-Grade State protection wild plants (medicinal), and 11 She characteristic medicinal plants in our study, they belong to 144 families, 312 genera 494 species, 2 subspecies, 17 varieties, 3 forms and 1 cultivated varieties of She's nationality. Folk medicine usage is different from the traditional Chinese medicine and ethnic medicine. This survey finds out the common She's nationality wild medicinal plants resources in China, including the species, the distribution, the folk application and commonly used drugs, and found the rare and endangered medicinal plants and the She's nationality endemic medicinal plants, which provides a basis for further development and use the traditional She's medicine resources. PMID- 25509312 TI - [Present situation of processing of traditional Mongolian medicine and its normalized suggestion]. AB - The processing technology of traditional Mongolian medicine materials is distinctive, and it is one of the main characteristics of Mongolian pharmacy. Most of Mongolian medicines were used in the raw, but a quarter of medicinal materials need to be produced. Since ancient times, the processing of Mongolian medicine have cooperated with the Mongolian medicine clinical, which plays an important role in improving curative effect of Mongolian medicine and ensuring the safety of the drug. At present, the Mongolian medicines are processed still according to the traditional methods of the ancient literature method which has a lot of problems such as lag in technology, method of diversification, ambiguous indicators and unclear mechanism. Standardization of Mongolian medicine processing was based on traditional Mongolian medicine basic theory, which both projecting the characteristic, inheriting the traditional colleagues and reference to modern medicine, pharmacology, toxicology and other disciplines of knowledge. In this article, the processing situation, existing problem and standardization research of Mongolian medicine were described that providing a reference for the modernization and standardization of Mongolian medicine. PMID- 25509313 TI - [Analysis of complexity in Chinese meteria medica industrial chain]. AB - Chinese meteria medica (CMM) chain is a long-span chain covering agriculture which mainly depends on the forces of nature as well as high-tech CMM industry, CMM expertise industry and fast developing CMM circulation industry. Imbalance among the development of these industries produces bottlenecks and hinders the operation of the entire production chain. After analyzing the structure of Chinese meteria medica industrial chain from the perspective of national economy industry, three industry classifications and differentiation of factor intensity, we conclude that the complex structure of CMM industry chain is attributable to these three aspects. And the complexity is mainly shown at complex industry, varied product types, different coordination of various industrial sections and different technical growth speed of varied industry. We propose that structural complexity is the natural property of the chain, which is the main reason of industry sector development imbalance and bottleneck. Results of this research could provide theoretical analysis for future research on the coordination of industrial chain and the efficiency of resource allocation. PMID- 25509314 TI - [Problems in medicinal materials research of new traditional Chinese medicine]. AB - Medicinal materials research and development of new drug of traditional Chinese medicine (TCM) research is the premise and foundation of new drug research and development, it throughout the whole process of new drug research. Medicinal materials research is one of the main content of the pharmaceutical research of new drug of TCM, and it is also the focus of the new medicine pharmaceutical evaluation content. This article through the analysis of the present problems existing in the development of TCM research of new drug of TCM, from medicine research concept, quality stability, quality standard, etc are expounded, including medicine research idea value medicine study should focus on the important role and from the purpose for the top-level design of new drug research problem. Medicinal materials quality stability should pay attention to the original, medicinal part, origin, processing, storage, planting (breeding), and other aspects. Aspect of quality standard of medicinal materials should pay attention to establish the quality standards of conform to the characteristics of new drug of TCM. As the instruction of TCM new drug research and development and the scientific nature of the review, and provide the basis for medicinal material standards. PMID- 25509315 TI - [Reliability theory based on quality risk network analysis for Chinese medicine injection]. AB - A new risk analysis method based upon reliability theory was introduced in this paper for the quality risk management of Chinese medicine injection manufacturing plants. The risk events including both cause and effect ones were derived in the framework as nodes with a Bayesian network analysis approach. It thus transforms the risk analysis results from failure mode and effect analysis (FMEA) into a Bayesian network platform. With its structure and parameters determined, the network can be used to evaluate the system reliability quantitatively with probabilistic analytical appraoches. Using network analysis tools such as GeNie and AgenaRisk, we are able to find the nodes that are most critical to influence the system reliability. The importance of each node to the system can be quantitatively evaluated by calculating the effect of the node on the overall risk, and minimization plan can be determined accordingly to reduce their influences and improve the system reliability. Using the Shengmai injection manufacturing plant of SZYY Ltd as a user case, we analyzed the quality risk with both static FMEA analysis and dynamic Bayesian Network analysis. The potential risk factors for the quality of Shengmai injection manufacturing were identified with the network analysis platform. Quality assurance actions were further defined to reduce the risk and improve the product quality. PMID- 25509316 TI - [Inheritance of academic idea and experience about using traditional Chinese medicine from JIN Shi-yuan]. AB - Professor Jin Shi-yuan has been worked in traditional Chinese medicine (TCM) over 70 years. He made prominent contributions in identification, processing, dispensing of TCM and reasonable use proprietary Chinese medicine. In over 70 years, he has mastered herbal medicine and traditional Chinese Medicine. It is also professor JIN's academic characteristic. Professor JIN's practical experiences were summarized according to the current situation about clinical medication, change of species of Juhong and Chenpi has been different from species of medical history. The quality is lower than before. Medicinal parts of Danggui, Gancao, Huangqin and Wuyao has been changed. So the actions of these herbal medicines have been changed also. Fresh herbal Qianchangpu has disappeared but it should be used clinically. Medical history, change of species, change of medicinal part, and change of preparing process in professor JIN's academic idea were be summarized periodically. The result is hoped to be referred by administration, manufacture, medical treatment of TCM. PMID- 25509317 TI - [Tri-dimensional omics analysis on effect of zhuanggu zhitong capsule against experimental postmenopausal osteoporosis]. AB - To propose the new concept of multidimensional omics, and define that the multidimensional omics is a proper method for studying the material base and mechanism of traditional Chinese medicine (TCM) compounds. Zhuanggu Zhitong capsule was taken for example to study its effect against experimental postmenopausal osteoporosis. From the perspective of chemi-omics, genomics and proteomics of TCM, it systematically interpreted the efficacious materials and mechanisms of Zhuanggu Zhitong capsule in preventing and treating experimental postmenopausal osteoporosis, while taking the lead in designing a three dimensional form to intuitively exhibit the results of the multidimensional omics study. This study provides a new idea and solution for studies on the efficacious materials and mechanisms of TCM compounds. PMID- 25509319 TI - [Foreword]. PMID- 25509320 TI - [Development of transgenic silkworms producing recombinant protein and its clinical application]. PMID- 25509318 TI - [Situation analysis for drug clinical trial institutions]. AB - Drug clinical trial is an important link in the chain of new drug research and development. The results of drug discovery and development directly depend on the extent of standardization of clinical trials. Therefore, improving the quality of drug clinical trials is of great importance, and drug clinical trial institutions play a crucial role in the quality management of drug clinical trials. After years of development, the overall level of drug clinical trials has advanced rapidly in China, and a large number of clinical trials of traditional Chinese medicine have also been carried out. However, there is still a big gap between our country and developed countries. Therefore, for the construction and management of Chinese drug clinical trial institutions, there is still a long way to go. This study aims to analyze the current development of drug clinical trial institutions in China and explore the existing problems from three aspects, including current situations of institutional organization and management, regional and professional distributions, and quality control. And some suggestions are put forward finally, including support of traditional Chinese medicine, introduction of drug-risk management system, and construction of information management. PMID- 25509321 TI - [Development of new technologies for utilizing baculoviruses and insect cell lines]. PMID- 25509322 TI - [Exploration of valuable metabolites from insect-derived microbes]. PMID- 25509323 TI - [Silkworm as a model animal for drug development]. PMID- 25509324 TI - [Search of compounds acting on the innate immunity using Drosophila]. PMID- 25509325 TI - [Analysis of the molecular and neural bases underlying the honeybee 'waggle dance']. PMID- 25509326 TI - [Discovery for antibiotics in an in vivo-mimic infection model using silkworm larvae]. PMID- 25509327 TI - [The mechanism of action of anti-juvenile hormone agents]. PMID- 25509329 TI - [Drug discovery for treatment against diabetes by using hyperglycemic silkworms]. PMID- 25509328 TI - [Sarcophaga defense molecule 5-S-GAD]. PMID- 25509330 TI - [The usefulness and development of maggots therapy using medical aseptic flies larvae for refractory wound]. PMID- 25509331 TI - [Biochemistry of glycosylphosphatidylinositol (GPI) anchored proteins]. PMID- 25509332 TI - [Shaping the membrane at submicron scale by BAR proteins and the actin cytoskeleton]. PMID- 25509333 TI - [Understanding of the regulation of plant drought-stress responses based on the structures of abscisic acid receptors]. PMID- 25509334 TI - [Ligand recognition and immune regulation system of inhibitory receptor PIR-B]. PMID- 25509335 TI - [Centrosome integrity under stress is maintained by a network of PLK4, p53 and SAPK pathways]. PMID- 25509336 TI - [Identification of RalGAPs and their downregulation in invasive bladder cancer]. PMID- 25509337 TI - [How E3 activity of Parkin is enhanced by damaged mitochondria]. PMID- 25509338 TI - [Coupling of epigenome and gene regulation on chromatin by methionine adenosyltransferase II]. PMID- 25509339 TI - [Vasopressin-mediated neuronal circuit in the suprachiasmatic nucleus and jet lag]. PMID- 25509340 TI - [Molecular mechanisms of homologous recombination promoted by budding yeast Rad52]. PMID- 25509341 TI - [Mucosal immunology and IL-13-induced intestinal injury]. PMID- 25509342 TI - [SOS-repair--60 years]. AB - This review integrates 60 years of research on SOS-repair and SOS-mutagenesis in procaryotes and eucaryotes, from Jean Weigle experiment in 1953 year (mutagenesis of lambda bacteriophage in UV-irradiated bacteria) to the latest achievements in studying SOS-mutagenesis on all living organisms--Eukarya, Archaea and Bacteria. A key role in establishing of a biochemical basis for SOS-mutagenesis belonges to the finding in 1998-1999 years that specific error-prone DNA polymerases (PolV and others) catalysed translesion synthesis on damaged DNA. This review focuses on recent studies addressing the new models for SOS-induced mutagenesis in Escherichia coli and Home sapiens cells. PMID- 25509343 TI - [Mechanisms of retroviral immunosuppressive domain-induced immune modulation]. AB - Immunosuppressive domains (ISD) of viral envelope glycoproteins provide highly pathogenic phenotypes of various retroviruses. ISD interaction with immune cells leads to an inhibition of a response. In the 1980s it was shown that the fragment of ISD comprising of 17 amino acids (named CKS-17) is carrying out such immune modulation. However the underlying mechanisms were not known. The years of thorough research allowed to identify the regulation of Ras-Raf-MEK-MAPK and PI3K AKT-mTOR cellular pathways as a result of ISD interaction with immune cells. By the way, this leads to decrease of secretion of stimulatory cytokines (e.g., IL 12) and increase of inhibitory, anti-inflammatory ones (e.g., IL-10). One of the receptor tyrosine kinases inducing signal in these pathways acts as the primary target of ISD while other key regulators--cAMP and diacylglycerol (DAG), act as secondary messengers of signal transduction. Immunosuppressive-like domains can be found not only in retroviruses; the presence of ISD within Ebola viral envelope glycoproteins caused extremely hard clinical course of virus-induced hemorrhagic fever. A number of retroviral-origin fragments encoding ISD can be found in the human genome. These regions are expressed in the placenta within genes of syncytins providing a tolerance of mother's immune system to an embryo. The present review is devoted to molecular aspects of retroviral ISD-induced modulation of host immune system. PMID- 25509344 TI - [Prenylation: from bacteria to eukaryotes]. AB - For their protection from host cell immune defense, intracellular eukaryotic parasites developed a variety of mechanisms, including secretion systems III and IV which inject bacterial effectors directly into eukaryotic cells. These effectors may be posttranslational modified by host cell machinery and may function inside the host cell. Recently, to the list of possible posttranslational modifications of bacterial proteins the prenylation was added. In this work we describe current state of the knowledge about the prenylation of eukaryotic and prokaryotic proteins and its inhibitors. The bioinformatics analyses suggest possibility of prenylation for a number of Francisella genus proteins. PMID- 25509345 TI - [Repair of bulky DNA damages--derivatives of polycyclic aromatic hydrocarbons]. AB - The genomic DNA is damaged under the influence of different environmental factors such as air pollutions, ultraviolet and ionizing radiation, and toxic substances that negatively impact on the humans. Air pollution by the products of incomplete combustion of hydrocarbon fuels and waste of various industries are main sources of polycyclic aromatic hydrocarbons. Some metabolites of these compounds can damage DNA through forming the bulky DNA adducts that potentially leads to mutagenesis and cancer. A nucleotide excision repair is the major pathway for the reparation of such DNA lesions in eukaryotic cells. The excision efficiency of bulky adducts depends on many factors including the structure of a substituent and degree of DNA double helix distortion induced by a lesion. The most danger for cell is clustered DNA lesions. To repair them the cooperation of different DNA repair systems is required in the process of damage recognition and removal. This review is focused on the features of repair mechanisms for DNA with bulky lesions appeared in the result of action of natural carcinogen benzo[a]pyrene as an example. PMID- 25509346 TI - [Role of receptor for advanced glycation end-products in pathgenesis of psoriasis]. AB - This review summarizes the existing knowledge regarding the role of receptor for advanced glycation end products which is a key participant of the inflammatory process, in pathogenesis of psoriasis. By interacting with multiple ligands and activating several signaling mechanisms, receptor for advanced glycation end products regulates gene expression via a group transcription factors, that includes NFKB and AP1. According to the published data the expression of receptor for advanced glycation end products in both immune cells and their targets, a high stability of this receptor in complexes with ligands as well as a positive feedback loop, upregulating the expression of its certain ligands, suggest receptor for advanced glycation end products as a possible principal factor that makes the inflammatory response in psoriasis sustainable. Considering receptor for advanced glycation end products as a potential master regulator of several processes that play a crucial role in development of psoriatic plaques, we believe that further experimental studies are needed to elucidate how exactly this receptor converts a transient inflammatory reaction to a sustainable inflammatory response. These studies are also needed for the development of novel medications that target receptor for advanced glycation end products and signaling mechanisms that this receptor activates. PMID- 25509347 TI - [Molecular mechanisms of transcription through a nuclesome by RNA polymerase II]. AB - The Pol II-type mechanism is conserved from yeast to human. After initiation of transcription, Pol II can be paused within the early transcribed region of a gene. Then Pol II overcomes the initial nucleosomal barrier, and efficiently proceeds through chromatin. At low- to moderate-level transcription progression of Pol II is characterized by displacement/exchange of only H2A/H2B dimer(s) and hexasome survival, likely mediated through formation of small intranucleosomal DNA loops. This mechanism helps to preserve the "histone" code during transcription. As the transcription rate is increased, the distance between transcribing Pol II complexes becomes shorter, and trailing Pol II complexes may encounter the hexasome formed after previous transcription round, before the H2A/H2B dimer re-binds to the hexasome. In this case an unstable intermediate with a smaller number of DNA-histone contacts is formed, resulting in eviction of the histone hexamer from DNA in vitro; therefore here all core histones are evicted/exchanged in vivo. Various protein factors and histone chaperones are involved in chromatin transcription by Pol II in vivo. PMID- 25509348 TI - [The role of exosomes and microvesicles in carcinogenesis]. AB - This review summarizes current knowledge on the role of tumor exosomes and microvesicles in progression, metastasis, and angiogenesis of tumors, as well as in suppression of adaptive and innate immunity. PMID- 25509349 TI - [Developmental expression patterns and association study with growth traits of bovine]. AB - As a member of the basic helix-loop-helix (bHLH) family of transcription factors, Bhlhe40 played an important role in the regulation of adipogenesis, myogenesis and the development of metabolic syndrome. In this study, we investigated the tissue expression patterns and differences of bovine Bhlhe40 gene during three developmental stages. The result showed that Bhlhe40 was ubiquitously expressed in most tissues of cattle. In addition, the expression of bovine Bhlhe40 gene showed a decreasing trend in skeletal muscle and fat during the de- velopmental stages. Then, two novel mutations (EX5 + 114 T>C, L166P and EX5 + 733 A>G, S372S) of bovine Bhlhe40 gene were identified by BamHI and ApaI ACRS PCR-RFLP in 1226 individuals from five indigenous cattle breeds in China. Frequencies of allele C at the BamHI locus varied from 0.210 to 0.340 among breeds, while frequencies of allele G at the ApaI locus varied from 0.030 to 0.114. Association analysis revealed no significant association of ApaI locus with growth traits in Nanyang breed. However, BamHI locus was significantly associated with the average daily lain at 18 months in Nanvans cattle (P < 0.05). This study aimed to lay the groundwork to further study of Bhlhe40 function at myogenesis and adipogenesis in bovine and should significantly contribute to cattle breeding and genetics through MAS program. PMID- 25509350 TI - [Intramolecular homologous recombination event occurred in the spider egg case silk gene CySp2 of wasp spider]. AB - To gain further understanding of egg case silk proteins gene family, Zhao et al. isolated two full-length cDNAs for egg case silk proteins, cylindrical silk protein 1 (CySpl) and cylindrical silk protein 2 (CySp2), from the wasp spider, Argiope bruennichi. CySp2 was reported to contain no apparent signal peptide sequences, and the CySp1-CySp2 complex, which would possess a signal peptide, would be transported across the endoplasmic reticulum and secreted to the Golgi. Genomic DNA sequencing is one approach that can be successfully utilized to retrieve 5' ends of silk genes; using this method, we retrieved the 5' end of CySp2. We found that CySp2 contained a typical signal peptide similar to that found in CySp1; thus, due to technical limitations, an artificial error had occurred in the CySp2 sequence reported by Zhao et al. PMID- 25509352 TI - [Possible role of autophagy activation in the stimulation of regeneration]. AB - Human cell senescence occurs unevenly and senescent cells in tissues frequently can disturb the function of neighbouring nonsenescent ones. Setting of tissues regeneration can have profound practical significance in medicine, especially in geriatrics. One of the approaches to solve the problem is selective elimination of senescent and damaged cells from the tissues that can be the first phase of the process. During the investigation of the mechanisms of action of the preparation for hair growth stimulation it was discovered that this preparation does not stimulate proliferation of various human cells and does not increase the resistance of cells to stress. On the contrary the preparation becomes cytotoxic at the conditions of oxidative stress although on its own account it did not induce elevation of production of reactive oxygen species. Further investigations showed that the preparation increases transcriptional activity of p53 gene, increase autophagy level and induce weak adipogenic differentiation. The hypothesis of autophagic regeneration is discussed. As a result, the selective autophagic cell death of any senescent and damaged cells that undergoes oxidative stress triggers the regeneration process which can be increased by both the rejuvenation effect of increased autophagy and at the expense of nutrients released during the autophagy. PMID- 25509351 TI - [CD271 enrichment does not help isolating mesenchymal stromal cells from]. AB - Reports on the isolation of mesencnymal stromal cells (MSCs) from granulocyte colony stimulating factor mobilized peripheral blood (G-CSF-mobilized PB) using regular culturing techniques are controversial. Enrichment techniques such as CD133 isolation have increased the success rates. CD271 is a well-known marker for enrichment of MSCs from bone marrow (BM). In the present study, we aimed to find out whether CD271 enrichment can help isolation of MSCs from G-CSF-mobilized PB. Five G-CSF-mobilized PB samples were collected from the remnant parts of the bags used for BM transplantation. Five BM samples were used as the control. Mononuclear cells (MNCs) from both resources were collected and underwent magnetic sorting for CD271-positive cells. The isolated cells were cultured, undergoing flowcytometry and differentiation assays to determine if they fulfill MSCs characteristics. CD271-positive portion of G-CSF-mobilized PB did not yield any cell outgrowth but the BM counterpart could successfully form MSC colonies. Although the percentage of CD271+ cells showed no difference between BM-MNCs and G-CSF-mobilized PB-MNCs, hematopoietic markers such as CD45, CD34 and CD133 composed a higher percentage of CD271-positive cells in the G-CSF-mobilized PB group. Results obtained indicated that CD271 enrichment does not help isolation of MSCs from G-CSF-mobilized PB. In this source, almost all of the CD271+ cells are from hematopoietic origin and the frequency of MSCs is so low that possibly during the process of cell isolation most of them are lost and the isolation fails. PMID- 25509353 TI - [Immunocytochemical visualization of P185(HER2) receptor by antibody fused with dibarnase and conjugate of barstar with colloidal gold]. AB - We studied the localization of transmembrane receptor P185(HER2) in SKOV-3 and BT 474 cancer cells by fluorescence, confocal and electron immunomicroscopy. P185(HER2) is a marker of breast and ovarian tumors, it is considered as a target for anticancer therapy. It is extremely important to choose a universal immunicytotoxic agent applicable, first, to study the distribution of P185(HER2) in cancer cells, secondly, to remove P185(HER2) from the cell surface and, thirdly, to eliminate target cells. In this work for visualization of P185HER2 We prOposed immunocytotoxic system, consisting of the monoclonal miniantibody 4D5 scFv to extracellular P185E domain fused with two molecules of barnase (ribonuclease from Bacillus amyloliquefaciens) and of its specific inhibitor barstar. Fluorescence microscopy has showed that the module 4D5 scFv dibarnase:barstar efficiently identified P185(HER2) on the surface of cancer cells. It was revealed by confocal microscopy that interaction with 4D5 scFv dibarnase lead to internalization of P185(HER2). The localization of P185(HER) in human ovarian carcinoma cells SKOV-3 and breast carcinoma cells BT-474 was compared by electron microscopy using 4D5 scFv-dibarnase:barstar-Au and 4D5 scFv dibarnase-Au complexes. P185(HER) distributed on the cell surface unequally with preferential localization on protrusions or close to their bases and in contacts between protrusions and cell membrane. At 37 degrees C, P185(HER2) internalized through coated pits and vesicles and concentrated in the endosomes and multivesicular bodies in the cells of both cell lines, as well as in lysosomes in cells BT-474. PMID- 25509354 TI - [DNA structural features on the borders of ERBB2 amplicons in breast cancer]. AB - In 25-30% of breast cancer tumor cases amplification of chromosome fragment around the ERBB2 underlies the increased expression of genes adjacent to ERBB2. Increased expression of genes within ERBB2-containing am- plicons may have an impact not only on the growth and development of the tumor, but on the sensitivity of the tumor to different types of anti-cancer therapies. The initial cause of amplification and the exact borders of ERBB2-amplified chromosome fragment are still not completely characterized. No specific DNA sequences were found on the junction regions at intrachromosomal DNA amplification. We hypothesized that amplification borders can be specified by DNA structural peculiarities rather than the particular DNA sequence. This study focused on the mapping of ERBB2 amplification borders in breast cancer and the search for unusual structural features of DNA at the borders of the identified amplicons. The copy number of 10 genes adjacent to ERBB2 were evaluated by real time PCR in 162 breast cancer samples. Several ERBB2-containing amplicons of various lengths were revealed. In the majority of the analyzed samples, the borders of these amplicons were located within ZNFNIA3 and RARA genes. A bioinformatics analysis of the nucleotide sequence peculiarities around ERBB2 gene revealed the presence of AT-rich DNA regions with high degree of flexibility. These regions were able to form stable secondary structures. Positions of these sites strongly coincide with the positions of the ERBB2-containing amplicon borders found in real time PCR experiments. On the base of results obtained one can suppose that the structural features of DNA are involved in the formation of ERBB2-containing amplicon borders in breast cancer cells and the data are of importance for understanding the mechanisms of oncogene amplification. PMID- 25509355 TI - [DR3/LARD mRNA spliced variants' frequency at colorectal cancer]. AB - There are a lot of "death receptor" DR3/LARD mRNA variants that are formed during the alternative splicing. Membrane and soluble forms of the receptor are encoded with various types of the DR3/LARD mRNA and perform different functions. Using RT PCR, the DR3/LARD mRNA spliced variants' frequency was measured in colon cancer patients' samples and cancer cell lines. In samples under investigation, four forms of the DR3/LARD mRNA were found with various frequencies. Two of them encoded the membrane receptors (LARD la mRNA and DR3beta mRNA) and other two expressed the soluble molecules (LARD 3 mRNA and soluble DR3beta mRNA). In blood of healthy volunteers 11 combinations (spectrums) of the DR3/LARD mRNA forms were revealed, and the "full" spectrum including all four variants of DR3/LARD mRNA dominated. In blood of colon cancer patients and tumour tissue samples, 6 DR3/LARD mRNA spectrums were found. The diversity of the DR3/LARD mRNA spectrums was decreased in colon cancer patients because of the frequency reduction of soluble DR3beta mRNA. Reduction of a variety of spectrums in cells of the patients was caused by decrease in occurrence of mRNA of the soluble DR3beta form. In samples of the tumor centers the spectrum with absence only mRNA of the soluble DR3beta form dominated. In blood of patients two spectrums prevailed: "full" range and presented mRNA LARD la and mRNA LARD 3. Only these two spectrums of mRNA DR3/LARD were also found in the tumor cell lines. Distinctions in occurrence of spectrums of DR3/LARD mRNA at healthy volunteers and colon cancer patients can define a different susceptibility of immunocompetent and tumor cells for apoptosis signals. PMID- 25509356 TI - [Allelic imbalance of loci 17p13.1 (TP53), 1p36.1 (RUNX3), 16p22 (CDH1) and microsatellite instability in gastric cancer]. AB - We examined allelic imbalance (AI) on loci 17p13.1 (TP53), 1p36.1 (RUNX) and 16p22 (CDHI) and microsatellite instability (MI) with BAT26 in 78 patients with gastric cancer. We have shown a significant difference in the frequency of allelic imbalance of the studied loci among different types of gastric cancer. Frequency of AI in 16p22.1 (CDH1) (p = 0.023), 17p13.1 (TP53) (p = 0.038), microsatellite instability (p = 0.047) and AD two and more loci in a single sample (p = 0.0176) was significantly higher in the intestinal type of gastric cancer than in the diffuse type. We have shown, that, frequency of AI in 16p22.1 (CDH1), and AD two and more loci in a single sample, was higher in thetumors with high or moderate type of tumor cells differentiation (p = 0.0414, p = 0.0057 respectively). We found no significant differences in the groups with metastases in regional lymph nodes, different tumor stage, localization of tumors and the generalization process. PMID- 25509357 TI - [Apoptin enhances the oncolytic activity of vaccinia virus]. AB - Chicken anemia virus gene encoding apoptin, a selective killer of cancer cells was synthesized and inserted into vaccinia virus (strain L-IVP) genome. The insertion has replaced major part of the viral C11R gene encoding viral growth factor (VGF), which is important for the virulence. The recombinant virus VVdGF ApoS24/2 was obtained through the transient dominant selection technique with the use of puromycin resistance gene as the selective marker. The expression apoptin gene from a synthetic early-late promoter of vaccinia virus effectively provides accumulation of the protein in the cells infected with the VVdGF-ApoS24/2 virus. Despite the presence of virus growth factor signal peptide at apoptin N-terminal secretion of the recombinant protein into culture medium did not occur. The recombinant virus VVdGF-ApoS24/2 was found to have a significantly greater selective lyticactivity on human cancer cell lines (A549, A431, U87MG, RD and MCF7) as compared with the parent strain L-IVP and its variant VVdGF2/6 with the deletion of the C11R gene. The results suggest that the use of apoptin represents a promising approach for improving the natural anticancer activities of vaccinia virus. PMID- 25509358 TI - [Dynamics of penetration of "solid" nanoconstructions based on double-stranded DNA complexed with gadolinium into CHO cells]. AB - Currently, neutron capture therapy is a promising cancer treatment. This method is based on the reaction of the thermal neutron capture by some non-radioactive elements (e.g., Gds57), which results in subsequent emission of electrons and gamma rays. An effective instrument for delivery of gadolinium into the tumor tissue are the particles of the "rigid" nanostructures (NS) based on double stranded DNA complexes with gadolinium (NS-Gd). The local concentration of Gd in such nanostructures may reach 40%. To optimize the process of neutron capture therapy it is very important to investigate possible penetration mechanisms of NS Gd particles into the tumor cells. In this work, the dynamics of interaction NS Gd with cultivated chinese hamster ovary cells (CHO) was studied by confocal and electron microscopy. It is shown that NS-Gd are able to enter CHO cells. This process begins in about 1 hour after the start ofincubation. After 6 h NS-Gd particles were detected in almost all cells. A further increase of the incubation time does not lead to significant changes in cell morphology, although the number NS-Gd inside the cells increases. The plasma membrane of the cells remains intact. The NS-Gd particles, which entered the cells, remain inside the cells for a long time. The data obtained show that NS-Gd are relatively low-toxic and suggest that the presence of NS-Gd in the tumor cells does not prevent their division. The data obtained are important for improving the efficiency of the neutron capture therapy method. PMID- 25509359 TI - [SOD1 gene mutations in patients with amyotrophic lateral sclerosis: potential for the method of molecular]. AB - The molecular modeling method is promising for the assessment of protein structure, being able to present an energetically beneficial protein conformation with atomic precision. This method is of great importance for studying molecular interactions and confirming pathogenic significance of the changes in the protein structure caused by particular mutations. In the present study we used molecular modeling for the assessment of mutations in the SOD1 gene in patients with amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disorder characterized by the loss of the spinal and cerebral motor neurons. The product of SOD1 is a cytosolic dimeric enzyme Cu/Zn superoxide dismutase (SOD1) responsible for detoxification of the cellular superoxide radicals. We showed that all 8 revealed coding point mutations of the gene led to moderate or significant changes of the SOD1 protein energy. Mutation His49Arg increased the protein energy, and reconstruction of the respective model pointed out to spatial destabilization of the molecule and abnormal interaction with the metal ion inside the active center. The other 7 mutations (Gly17Ala, Leu85Mal, Asn87Ser, Asp91Ala, Serl06Leu, Glu134Gly, and Leul45Phe), on the contrary, led to decrease of the protein energy and increase of the spatial stability of SOD1, which is usually accompanied by increased propensity of the 'inert' mutant molecule to misfolding and cellular aggregation. Thereby, the results of in silico analysis of the SOD1 gene mutations confirm staying of ALS within the class of the so called conformational diseases of the central nervous system, a characteristic feature of which is forming of cytotoxic insoluble protein inclusions in neurons. PMID- 25509360 TI - [[Screening of differentially expressed miRNAs related to muscle strain and their target genes]. AB - Muscle strain is one of the most common muscle injuries seen in the office of a practicing physician. To get a better understanding of this injury, we identified the differentially expressed miRNAs in muscle stem cells collected from injured muscle tissues of mouse. In this study, we downloaded the gene expression microarray (GSE26780) from Gene Expression Omnibus database. The dataset contained a total of 12 samples (murine muscle stem cells), including normal controls and samples collected from tissues at different time points after the injury. Differentially expreesed miRNAs were identified by LIMMA package and target genes of mmu-miR-143 were found by TargetScan. Then, a protein-protein in- teraction (PPI) network was constructed for the products of these target genes by using KUPS. Finally, Cytoscape and its plugins were used to identify and analyze the modules in this network. According to the results, 121, 136 and 148 differentially expressed miRNAs were identified in injured samples at each time point, and among them, 60 miRNAs were overlapping between all three groups. The expression values of mmu-miR-143 were most significantly altered over time at 36 72 h after the injury. Therefore, 510 target genes of mmu-miR-143 were found and a PPI network for the products of these target genes was constructed. Moreover, two modules were identified in the PPI network. Together with the previous studies, we suppose that proteins in module B, most of which are collagens or integrins, most likely participate in healing of strain injuries through cell adhesion processes. PMID- 25509361 TI - [Investigation of core Y-haplogroups frequency occuring in Moscow and Saint Petersburg citizens]. AB - A DNA collection of 239 Moscow and 62 SPB citizens has been investigated by means of a biochip for genotyping of Y-chromosome haplogroup markers: M130 (C), M145 (DE), P257 (G), M69 (H), U179 (I), M304 (J), M185 (L), M231 (N), M175 (0), P224 (R), L146 (R1a) and M343 (R1b). Haplogroup frequency distribution in populations native to Moscow and Saint-Petersburg has been obtained. Three subsamples varying in duration of residence (one, two or three generations) were compared. Increasing of J, G, R1b frequencies may be related to immigration from Caucasia and other regions. PMID- 25509362 TI - [[Natalizumab therapy, 2013]. AB - Multiple sclerosis (MS) is the most common chronic disease of the central nervous system in young adults. No curative therapy is known. Currently, six drugs are available that can reduce the activity of MS. The first-line drugs can completely reduce the activity of the disease in nearly two-thirds of the patients. In the remainder, who suffer from breakthrough disease, the condition of the patient worsens, and second-line therapies must be used. The second-line drug natalizumab exhibits almost double efficacy of the first-line drugs, but also have less favourable adverse effects. As a severe side-effect for instance, natalizumab carries the risk of the development of progressive multifocal leucoencephalopathy (PML), caused by a polyoma virus, the JC virus. There are three major risk factors for PML: an anti-JCV antibody status, a long duration of natalizumab treatment and prior immunosuppressant therapy. The lowest-risk group (1:14,286) comprises of patients who are anti-JCV antibody-negative, in whom the prior immunosuppressant use and duration of natalizumab therapy do not influence the risk of PML. With no prior immunosuppressant treatment, the incidence of PML increases to 1 in 192 patients after 2 years among those who are anti-JCV antibody-positive. These data may lead the physician to decide to discontinue natalizumab treatment. The half-life of natalizumab is three months; during this time other therapies can not be administered and the patients encounter the rebound effect: as the patients receiving natalizumab therapy displayed a high disease activity before treatment, the rebound effect can lead to relapses. After the termination of natalizumab second-line disease-modifying therapy with fingolimod may be introduced; no PML cases occur in response to fingolimod treatment. In the large majority of patients taking natalizumab who do not develop PML, this drug is highly effective and can prevent the progression of MS. The benefit of therapy and the risk of PML must be considered on an individual basis, with regard to the disease activity, the progression and the MRI activity, before natalizumab therapy is implemented. PMID- 25509363 TI - Depression in Parkinson's disease. AB - The prevalence of major and minor depression in Parkinson's disease is around 30 40% but, unfortunately, depression remains frequently underrecognized and often undertreated. However, recognition and appropriate treatment of depression in patients with Parkinson's disease is essential for improving the cross-sectional picture and longitudinal course. This review focuses on the epidemiology, pathophysiology and different treatment modalities of depression in Parkinson's disease. PMID- 25509364 TI - [Maybe it hurts more than we think! Neonatal pain]. AB - Neonatal pain is often undertreated. This is based on the assumption that because of the immature nervous system and the lack of the myelinisation preterm and newborn does not feel pain. It is confirmed by a number of articles that the fetus and neonate can experience and respond to painful events. This publication gives a brief overview of the ontogeny of the pain, short- and long-term postnatal consequences, as well as the perception of the possibility of a particularly frail child population: premature infants and neonates, based on animal and human studies. PMID- 25509365 TI - [The impact of levodopa-carbidopa intestinal gel on health-related quality of life in Parkinson's disease]. AB - BACKGROUND: The levodopa/carbidopa intestinal gel (LCIG) therapy can improve the severe fluctuations associated with advanced Parkinson's disease (PD). Our aim was to assess the improvement in the health related quality of life of PD patients treated with LCIG at University of Pecs. METHODS: Eight PD patients were evaluated (age: 68.1 +/- 4.4 years, disease duration: 14.5 +/- 6.2 years, duration of fluctuations: 8.9 +/- 3.1 years). Before the initiation of LCIG treatment and 6 and 12 months later, the health-relat- ed quality of life (PDQ-39 and EQ-5D-5L), severity of PD- related symptoms (MDS-UPDRS, Hoehn-Yahr Scale, Clinical Global Improvement--Severity) and major non-motor symptoms (PD Sleep Scale 2nd version: PDSS-2, Epworth Scale and Beck Depression Inventory: BDI) were assessed. RESULTS: Health-related quality life improved after LCIG treatment measured by both EQ-5D-5L (from 0.257 to 0.662, p = 0.009) and PDQ-39 (from 34 to 26 points, p = 0.038). Meanwhile PD-related symptoms (MDS-UPDRS total score: from 105 points to 68 points, p < 0.05) sleep quality (PDSS-2: from 25 to 22 points, p < 0.05), daytime sleepiness (Epworth: from 12 to 7 points, p < 0.05) and depression (BDI: from 20 to 15 points, p < 0.05) also improved. Median ON time improved form 4.5 hours to 10.0 hours; whereas, the OFF time decreased from 4.5 to 0.5 hours (p < 0.05). CONCLUSION: Both the quality of life and the clinical fea- tures of PD can be improved by LCIG treatment in advanced PD. PMID- 25509366 TI - Single dose irradiation of defined region of rat brain with stereotactic brainlab system. AB - Background and purpose of our study was to develop a precise dose delivery technique for partial brain irradiation of two rats simultaneously. METHODS: Using a self-developed frame stereotactic radiotherapy with single doses of 30-90 Gy was delivered to the frontal lobe of 22 animals. Tolerability and reproducibility of the method were evaluated and dosimetric measurements were conducted to verify the treatment plans. 2, 4 and 6 months after the irradiation magnetic resonance imaging (MRI) scans and histopathological examinations were performed to detect late radiation induced biological changes. RESULTS: Immobilization device provided excellent reproducibility and tolerability. Dosimetry revealed good correspondence with planned dose distribution, but the measured absorbed dose was 30% lower than the planned dose. During the 6 months follow-up period the procedure related death of subject animals after 30 Gy, 70 Gy and 90 Gy were 0%, 20% and 100% respectively. T2 signal and structural changes on MRI scans found to be dose and time dependent. While 30 Gy caused no detectable structural changes, 70 Gy lead to cystic necrosis in 2 cases after 4 month. Histopathology revealed signs of necrosis on macroscopic examination after 70 Gy in the high dose region involving both frontal lobes, and no obvious microscopic changes in the surrounding area were detectable. CONCLUSION: Our technique of rat cranial irradiation using human stereotactic system provided high accuracy of single dose delivery for a pair of small animals, resulting in brain injury in the defined area. This method proved to be a reproducible model for preclinical studies on radiation effects. PMID- 25509367 TI - [Examining the diagnostic accuracy of a new migraine screener]. AB - BACKGROUND: Migraine affects more than 10% of the Hungarian population, causes significant disability and severely affects patients' generic and condition specific quality of life. Despite these facts, a significant proportion of patients is not diagnosed and not treated adequately. Headache centres can provide care for only a fraction of all patients. The task of primary care providers would be greatly simplified by a reliable self-administered migraine screening questionnaire. OBJECTIVE: To develop a short and reliable questionnaire as a migraine screening tool. METHODS: Outpatients at the Headache Service, Department of Neurology, Semmelweis University completed a self-administered questionnaire which contained 9 yes/no questions about their headaches' characteristics. The number of 'yes' answers (the patients' total score) was evaluated in connection with the diagnosis based on the International Headache Society criteria. We calculated the sensitivity, specificity, positive and negative predictive value as well as the misclassification rate for each total score value and used these to establish the final cutoff value of the questionnaire. 306 patients (242 females, mean age 39.1 +/- 13.3 years) were enrolled. The diagnosis was migraine in 244. RESULTS: Completing the questionnaire did not pose any difficulty for the patients. At a cutoff value of 5 points the questionnaire's sensitivity was 0.96 and specificity was 0.61. The positive predictive value was 0.91 and the negative pre- dictive value was 0.81. The misclassification rate was 0.11. DISCUSSION: Our results show that the questionnaire may help the diagnosis of migraine. In order to use it in medical practice, its further evaluation is necessary on a large representative sample of the Hungarian population. PMID- 25509368 TI - Anti glutamate-decarboxylase antibodies: a liaison between localisation related epilepsy, stiff-person syndrome and type-1 diabetes mellitus. AB - We present two patients with partial epilepsy, type-1 diabetes and stiff person syndrome associated with high serum auto-antibody levels to glutamate decarboxylase (anti-GAD). Both patients were or have suffered from additional autoimmune conditions. The presence of stiff person syndrome and elevated anti GAD levels have to make clinicians look for additional autoimmune conditions including type-1 diabetes. On the other hand, the co-morbidity of partial epilepsy with autoimmune conditions in patients with elevated serum anti-GAD suggests an autoimmune mechanism of partial epilepsy in these cases. PMID- 25509369 TI - [Cerebral venous and sinus thrombosis]. PMID- 25509370 TI - [Natalizumab retreatment: effectiveness and long-term safety in multiple sclerosis in the STRATA study]. PMID- 25509371 TI - [Intravenous immunoglobulin therapy in neuroimmunological disorders]. PMID- 25509372 TI - [Ecology-Biogeographical properties of Saccharomyces paradoxus batchinskya yeasts and related species: earlier research]. PMID- 25509373 TI - [Influence of NAD-dependent formate dehydrogenase on anaerobic respiration of Shewanella oneidensis Mr-1]. PMID- 25509374 TI - [Identification of the process of construction bio-electrical microbial fuel cells using mutants of Shewanella oneidensis MR-1 with elevated reduction activity]. PMID- 25509375 TI - [Multiple horizontal gene transfers and duplication as the source of genetic variation of alpha-l-rhamnosidases in Clostridium methylpentosum DSM5476 ]. PMID- 25509376 TI - [Exogenous and endogenous nitric oxide influence on biofilm formation by Lactobacillus plantarum ]. PMID- 25509377 TI - [Alkylresorcin negative influence Azospirillum brasilense motility]. PMID- 25509378 TI - [Iron toxicity evaluation with luminescence bacterial test using recombinant Escherichia coli strain]. PMID- 25509379 TI - [Water soluble phenolic compounds of lichens]. PMID- 25509380 TI - [Molecular identification of industrial important strain of Ogataea parapolymorha]. PMID- 25509381 TI - [Spirosoma xylofaga sp. nov. - oligotrophic pleomorphic bacterium of mycobacterial consortia of fresh water ecosystem]. PMID- 25509382 TI - [Bacillus subtilis influence on rumen microbial consortium and and host digestion ]. PMID- 25509383 TI - [Carbohydrates oxidizing acidophilic thermotolerant bacterial consortium from sulfur soils]. PMID- 25509384 TI - [Halophilic and halotolerant aerobic methylobacteria from technogenic Solikamsk soils]. PMID- 25509385 TI - [Methane cycle in lakes under ice]. PMID- 25509386 TI - ["New" and "old" carbon cycling in soil microbial biomass]. PMID- 25509387 TI - [Extracellular polymer matrix visualisation of Chromobacterium violaceum biofilm with means of microscopy methods]. PMID- 25509388 TI - [Molecular biology detection of methanogenic archaea in oxidised water of Black sea]. PMID- 25509389 TI - [Surface layers of methanotrophic bacteria]. AB - Structural and functional characteristics of the regular glycoprotein layers in prokaryotes are analyzed with a special emphasis on aerobic methanotrophic bacteria. S-layers are present at the surfaces of Methylococcus, Methylothermus, and Methylomicrobium cells. Different Methylomicrobium species either synthesize S-layers with planar (p2, p4) symmetry or form cup-shaped or conicalstructures with hexagonal (p6) symmetry. A unique, copper-binding polypeptide 'CorA'/MopE (27/45 kDa), which is coexpressed with the diheme periplasmic cytochrome c peroxidase 'CorB'/Mca (80 kDa) was found in Methylomicrobium album BG8, Methylomicrobium alcaliphilum 20Z, and Methylococcus capsulatus Bath. This tandem of the surface proteins is functionally analogous to a new siderophore, methanobactin. Importantly, no 'CorA'/MopE homologue was found in methanotrophs not forming S-layers. The role of surface proteins in copper metabolism and initial methane oxidation is discussed. PMID- 25509390 TI - [Lipid metabolism in Aspergillus niger under conditions of heat shock]. AB - The processes of lipid synthesis and decomposition in Aspergillus niger under conditions of heat shock (HS) were studied in a pulse-chase experiment with 14C labeled sodium acetate. HS (60 min) resulted in the synthesis of phospholipids and sphingolipids intensified compared tothe.control, as was evident from incorporation of the labeled substrate. The same pattern was observed for neutral lipids, especially for triacylglycerides, while incorporation of the label into sterols remained almost the same. Further cultivation for 3 h in the medium without the labeled substrate resulted in a significant decrease of the label content in the membrane lipids of both the control and the experiment, although under HS conditions this decrease was much more pronounced, especially for phosphatidylcholines and phosphatidylethanolamines. A threefold increase of the label content in phosphatidic acids was observed only under HS conditions. These results indicate more intense metabolism of the membrane lipids under heat shock and suggest the degradation of the major cell phospholipids as the factor responsible for the increased level of phosphatidic acids in A. niger mycelium. PMID- 25509391 TI - [Comparative study of metabolism of the purple photosynthetic bacteria grown in the light and in the dark under anaerobic and aerobic conditions]. AB - For three species of anoxygenic phototrophic alphaproteobacteria differing in their reaction to oxygen and light, physiological characteristics (capacity for acetate assimilation, activity of the tricarboxylic acid (TCA) cycle enzymes, respiration, and the properties of the oxidase systems) were studied. Nonsulfur purple bacteria Rhodobacter sphaeroides, Rhodobaca bogoriensis, and aerobic anoxygenic phototrophic bacteria Roseinatronobacter thiooxidans were the subjects of investigation. All these organisms were able to grow under aerobic conditions in the dark using the respiratory system with cytochrome aa3 as the terminal oxidase. They differed, however, in their capacity for growth in the light, bacteriochlorophyll synthesis, and regulation of activity of the TCA cycle enzymes. Oxygen suppressed bacteriochlorophyll synthesis by Rha. sphaeroides and Rbc. bogoriensis both in the dark and in the light. Bacteriochlorophyll synthesis in Rna. thiooxidans occurred only in the dark and was suppressed by light. The results on acetate assimilation by the studied strains reflected the degree of their adaptation to aerobic growth in the dark. Acetate assimilation by light grown Rha. sphaeroides was significantly higher than by the dark-grown ones. Unlike Rha. sphaeroides, acetate assimilation by Rbc. bogoriensis in the light under anaerobic and aerobic conditions was much less dependent on the growth conditions. Aerobic acetate assimilation by all studied bacteria was promoted by light. In Rha. sphaeroides, activity of the TCA cycle enzymes increased significantly in the cells grown aerobically in the dark. In Rbc. bogoriensis, activity of most of the TCA cycle enzymes under aerobic conditions either decreased or remained unchanged. Our results confirm the origin of modern chemoorganotrophs from anoxygenic phototrophic bacteria. The evolution from anoxygenic photoorganotrophs to aerobic chemoorganotrophs included several stages: nonsulfur purple bacteria --> nonsulfur purple bacteria similar to Rbc. bogoriensis --> aerobic anoxygenic phototrophs --> chemoorganotrophs. PMID- 25509392 TI - [Role of bacteriochlorophyll in stabilization of the structure of the near central and peripheral light-harvesting complexes from purple photosynthetic bacteria]. AB - Pheophytinization of bacteriochlorophyll (BChl) at low pH was investigated in the core (LH1) and peripheral (LH2) light-harvesting complexes, as well as in the ensemble of the reaction center (RC) with the LH1 complex. The stages in disintegration of the native BChl forms in the LH1 complex and in its ensemble with RC were revealed. They were observed as emergence of the absorption band of monomeric BChl and an increase in its intensity, followed by its transformation into the band of monomeric bacteriopheophytin (BPh) and then into the band of aggregated BPh. Unlike the LH1 complex, in the case of the LH2 complex monomeric BChl was never detected as an intermediate product. While the spectra revealed formation of monomeric BPh, its accumulation did not occur, since its aggregation is very rapid compared to that in the LH1 complex and in the RC-LH1 ensemble. PAG electrophoresis revealed that pheophytinization of BChl in the LH2 complex was accompanied by disruption of the stable cylindrical structure of this complex with emergence of characteristic fragments consisting of alpha and beta peptides and bearing monomeric BPh, as well as of the alpha peptide aggregates bearing BPh aggregates. Unlike the LH2 complex, BChl pheophytinization in the LH1 complex did not result in its fragmentation. This is an indication of different types of structural stabilization in the LH1 and LH2 complexes. In the LH2 complex, coordination of bacteriochlorophyll Mg2+ by conservative histidine residues of the alpha and beta polypeptides is the main factor responsible for the maintenance of its cylindrical structure. Stability of the LH1 complex is probably based primarily on the highly specific hydrophobic interactions between the surfaces of individual polypeptide chains, since the presence of hydrogen bonds results in autonomy of each alphabeta3BChl2 subunit, rather than in stabilization of the LH1 complex as a whole. PMID- 25509393 TI - [Effect of a dormant state on the xenobiotic-degrading strain Pseudomonas fluorescens 26K]. AB - The changes in physiological and biochemical properties of Pseudomonas fluorescens 26K, a degrader of chlorinated aromatic compounds, were revealed after the persistence in a dormant state as cyst-like cells (CLC). The CLC maintained the ability to form colonies after long-term storage possessed enhanced resistance to damaging agents (heat and drying), and specific ultrastructural organization. In populations grown from CLC on solid media, we observed the appearance ofphenotypic variants, which differed from the dominant type in the shape, consistency, and pigmentation of the colonies. The emerging phenotypes had higher growth rates on some aromatic substrates, which required the enzymes with broadened substrate specificity for their utilization. PMID- 25509394 TI - [Factors inducing transition from growth to dormancy in rhizobacteria Azospirillum brasilense]. AB - The factors suppressing division of the cells of the rhizobacterium Azospirillum brasilense and inducing their transition to a dormant state were analyzed. These included the presence of hexylresorcinol or heavy metals (Cu and Co) in the medium, oxygen stress, and transfer of the cells into the physiological saline or phosphate buffer solution. The results were used to develop a protocol for obtaining of uncultured cells of A. brasilense Sp245, a natural symbiont of wheat. The cells lost their ability to grow on synthetic agar medium, but could revert to growth when incubated in freshly prepared liquid medium. Needle-shaped crystals differing from struvite, which has been previously reported for this strain, were found in the dormant culture of A. brasilense Sp245. PMID- 25509395 TI - [Teichoic acids of three type strains of the "Bacillus subtilis" group, Bacillus mojavensis VKM B-2650, Bacillus amyloliquefaciens subsp. amyloliquefaciens VKM B 2582, and Bacillus sonorensis VKM B-2652]. AB - Cell walls of three type strains of the "Bacillus subtilis" group, Bacillus mojavensis VKM B-2650, Bacillus amyloliquefaciens subsp. amyloliquefaciens VKM B 2582, and Bacillus sonorensis VKM B-2652, are characterized by the individual set of teichoic acids. All strains contained 1,3-poly(glycerophosphates), unsubstituted, acylated with D-alanine, and glycosylated. The latter differ in the nature of the monosaccharide residue. Teichoic acids of B. mojavensis VKM B 2650(T) and B. amyloliquefaciens subsp. amyloliquefaciens VKM B-2582(T) contained alpha-glucopyranose, while those of VKM B-2652(T) contained beta-glucopyranose and N-acetyl-alpha-D-glucosamine. Moreover cell walls of B. mojavensis VKM B 2650(T) contained a teichoic acid of poly(glycosylglycerophosphate) nature with the following structure of the repeating unit: -4)-alpha-D-alpha-D- GlcpNAc-(1--> 3]-Glcp-(1 --> 2)-sn-Gro-(3-P-. The type strains have been characterized according to the composition of cell wall sugars and polyols. Application of teichoic acids (set and structure) as chemotaxonomic characteristics is discussed for six type strains of the "Bacillus subtilis" group. Polymer structures were determined by chemical and NMR spectroscopic techniques. PMID- 25509396 TI - [Detection and analysis of sulfur metabolism genes in Sphaerotilus natans subsp. sulfidivorans representatives]. AB - The lithotrophic capacity of the betaproteobacteria Sphaerotilus natans subsp. sulfidivorans was confirmed at genetic level: functional genes of sulfur metabolism were detected (aprBA, soxB, and sqr, coding for adenylyl phosphosulfate reductase, thiosulfate-cleaving enzyme, and sulfide:quinone oxidoreductase, respectively), and the expression of aprA and soxB genes was demonstrated. An evolutionary scenario for soxB genes in Sphaerotilus representatives is suggested based on comparative analysis of codon occurrence frequency, DNA base composition (G + C content), and topology of phylogenetic trees. The ancestor bacterium of the Sphaerotilus-Leptothrix group was capable of lithotrophic growth in the presence of reduced sulfur compounds. However, in the course of further evolution, the sulfur metabolism genes, including the soxB gene, were lost by some Sphaerotilus strains. As a result, the lithotrophic Sphaerotilus-Leptothrix group split into two phylogenetic lineages, lithotrophic and organotrophic ones. PMID- 25509397 TI - [Stress-protective and cross action of the extracellular reactivating factor of the microorganisms of the domains Bacteria, Archaea, and Eukaryota]. AB - Cross protection of members of the domains Bacteria, Archaea, and lower Eukaryota from stress factors due to the action of extracellular low-molecular metabolites with adaptogenic functions was shown. The adaptogen produced by Luteococcus japonicus subsp. casei and described previously as a reactivating factor (RF) was shown to protect the yeasts Saccharomyces cerevisiae, archaea Haloarcula marismorti, and the cells of higher eukaryotes (HeLa) against weak stressor impacts. Production of an archaeal extracellular metabolite with a weak adaptogenic effect of the producer cells and capable of a threefold increase in survival of heat-inactivated yeast cells was discovered. Our results confirm the similarity of the compensatory adaptive reactions in prokaryotes (bacteria and archaea) and eukaryotes. PMID- 25509398 TI - [Effect of sodium chloride concentration in the medium on the composition of the membrane lipids and carbohydrates in the cytosol of the fungus Fusarium sp]. AB - The fungus Fusarium sp. isolated from saline soil was identified by the ITS1-5.8S ITS2 and the D1/D2 domains of LSU RNA as a member of the Fusarium incarnatum equiseti species group. Its growth patterns on media with different NaCl concentrations indicated its adaptation as halotolerance. The mechanisms of halotolerance included accumulation of arabitol a five-atom noncyclic polyol, a decreased sterols/phospholipids ratio, elevated level of phosphatidic acids in the phospholipids, and increased unsaturation of phospholipids, which was especially pronounced in the idiophase. The mechanisms of halotolerance of the mycelial fungus Fusarium sp. are discussed in comparison with yeasts and yeastlike fungi. PMID- 25509399 TI - [Accumulation and precipitation of Mn2+ by the cells of Oscillatoria terebriformis]. AB - The cyanobacterium Oscillatoria terebriformis was shown to exhibit resistance to high manganese concentrations, remaining viable at 2.5 mM MnCl2 in the medium. Cyanobacterial cells were capable of considerable manganese consumption from the medium. Dynamics of Mn sorption by the cells was the same in all experimental variants, independent on the manganese concentration. Manganese concentration in the biomass peaked after 2-3 days and depended on Mn2+ concentration in the medium and on the amount of biomass introduced. In the case of O. terebriformis, manganese removed from the medium may be subdivided into Mn absorbed by the cell, Mn bound to the cell wall, Mn absorbed by the glycocalix, and chemically precipitated Mn. Of the total 21.25 +/- 1.0 mg of consumed manganese, biological absorption and chemical precipitation were responsible for 11.78 +/- 0.98 and 9.2 +/- 0.8 mg, respectively. In the presence of cyanobacteria, Mn removal from the medium was 2.28 times higher than in the control. This process depended considerably on Mn sorption by exopolysaccharides. At 1.3 mM Mn2+, a lamellar mat was formed with interlayers of manganese carbonate. PMID- 25509400 TI - [Sulfate reduction and microbial processes of the methane cycle in the sediments of the Sevastopol bay]. AB - The rates of microbial processes of sulfate reduction and of the methane cycle were measured in the bottom sediments of the Sevastopol basin, where seeps of gaseous methane have been previously found. Typically for marine environments, sulfate reduction played the major role in the terminal phase of decomposition of organic matter (OM) in reduced sediments of this area. The rate of this process depended on the amount of available OM. The rate of methanogenesis in the sediments increased with depth, peaking in the subsurface horizons, where decreased sulfate concentration was detected in the pore water. The highest rates of sulfate-dependent anaerobic methane oxidation were found close to the methane sulfate transition zone as is typical of most investigated marine sediments. The data on the carbon isotopic composition of gaseous methane from the seeps and dissolved CH4 from the bottom sediments, as well as on the rates of microbial methanogenesis and methane oxidation indicate that the activity of the methane seeps results from accumulation of biogenic methane in the cavities of the underlying geological structures with subsequent periodic release of methane bubbles into the water column. PMID- 25509401 TI - [A novel bacterium carrying out anaerobic ammonium oxidation in a reactor for biological treatment of the filtrate of wastewater fermented residue]. AB - A new genus and species of bacteria capable of ammonium oxidation under anaerobic conditions in the presence of nitrite is described. The enrichment culture was obtained from the Moscow River silt by sequential cultivation in reactors with selective conditions for anaerobic ammonium oxidation. Bacterial cells were coccoid, -0.4 x 0.7 mm, with the intracellular membrane structures typical of bacteria capable of anaerobic ammonium oxidation (anammoxosome and paryphoplasm). The cells formed aggregates 5-25 MUm in diameter (10 MUm on average). They were readily adhered to solid surfaces. The cells were morphologically labile, they easily lost their content and changed their morphology during fixation for electron microscopy. The organism was capable of ammonium oxidation with nitrite. The semisaturation constants Ks for nitrite and ammonium were 0.38 mg N-NO2/L and 0.41 mg N-NH4/L, respectively. The maximal nitrite concentrations for growth were 90 and 75 mg N-NO2/L for single and continuous application, respectively. The doubling time was 32 days, MU(max) = 0.022 day(-1), the optimal temperature and pH were 20 degrees C and 7.8-8.3, respectively. According to the 16S rRNA gene sequencing, the bacterium was assigned to a new genus and species within the phylum Planctomycetes. The proposed name for the new bacterium is Candidatus Anammoximicrobium moscowii gen. nov., sp. nov. (a microorganisms carrying out anaerobia ammonium oxidation, isolated in the Moscow region). PMID- 25509402 TI - [Composition of the oil-slime microbial community determined by analysis of the 16S rRNA gene]. AB - Analysis of the 16S rRNA genes of the cultured microorganisms of industrial oil slime revealed predominance (-85-90%) of the Gammaproteobacteria in the community of aerobic heterotrophs and specific oil-slime degraders. Relation of the isolated strains with members of the genera Pseudomonas, Stenotrophomonas, and Enterobacter was established. Analysis of the same gene in the total DNA from the oil-slime revealed greater microbial diversity (-20 operative taxonomic units determined by T-RFLP) than in the cultured part of the community, which included 12 different colony types. Three major restriction fragments were found, with their total area -50%. These results demonstrated the low morphological and phylogenetic diversity of the oil-slime bacterial community. PMID- 25509403 TI - [Mycoplasma heat shock proteins and their genes]. AB - Mycoplasmas (class Mollicutes) are the most simply organized prokaryotic organisms capable to self-reproduction. They are considered as a model of "minimal" cell. Systems preserved by mycoplasmas in their reductive evolution may play a fundamental role in viability of any cell. Information on the genes encoding heat shock proteins (HSP) in completely sequenced mycoplasma genomes was summarized and systematized. An attempt was made to explain the presence or absence in mycoplasmas of important bacterial chaperones and proteases. These HSP are necessary not only for cell stress resistance, but for protein homeostasis under normal conditions. The mechanisms of regulation of transcription of corresponding genes are considered. Properties and functions of the most completely characterized mycoplasmal HSP are discussed: DnaK, DnaJ-like, GroEL/GroES, ClpB, and small heat shock proteins (sHSP). PMID- 25509404 TI - [Oxidation of gold-antimony ores by a thermoacidophilic microbial consortium]. AB - Antimony leaching from sulfide ore samples by an experimental consortium of thermoacidophilic microorganisms, including Sulfobacillus, Leptospirillum, and Ferroplasma strains was studied. The ores differed significantly in the content of the major metal sulfides (%): Sb(S), 0.84 to 29.95; Fe(S), 0.47 to 2.5, and As(S), 0.01 to 0.4. Independent on the Sb(S) concentration in the experimental sample, after adaptation to a specific ore and pulp compaction the microorganisms grew actively and leached/oxidized all gold-antimony ores at 39 +/- 1 degrees C. The lower was the content of iron and arsenic sulfides, the higher was antimony leaching. For the first time the investigations conducted with the use of X-ray microanalysis research made it possible to conclude that in a natural high antimony ore Sb inhibits growth of only a part of the cell population and that Ca, Fe, and Sb may compete for the binding centers of the cell. PMID- 25509405 TI - [Detection of anaerobic processes and microorganisms in immobilized activated sludge of a wastewater treatment plant with intense aeration]. AB - Attached activated sludge from the Krasnaya Polyana (Sochi) wastewater treatment plant was studied after the reconstruction by increased aeration and water recycle, as well as by the installation of a bristle carrier for activated sludge immobilization. The activated sludge biofilms developing under conditions of intense aeration were shown to contain both aerobic and anaerobic microorganisms. Activity of a strictly anaerobic methanogenic community was revealed, which degraded organic compounds to methane, further oxidized by aerobic methanotrophs. Volatile fatty acids, the intermediates of anaerobic degradation of complex organic compounds, were used by both aerobic and anaerobic microorganisms. Anaerobic oxidation of ammonium with nitrite (anammox) and the presence of obligate anammox bacteria were revealed in attached activated sludge biofilms. Simultaneous aerobic and anaerobic degradation of organic contaminants by attached activated sludge provides for high rates of water treatment, stability of the activated sludge under variable environmental conditions, and decreased excess sludge formation. PMID- 25509406 TI - [Methanocalculus natronophilus sp. nov., a new alkaliphilic hydrogenotrophic methanogenic archaeon from a soda lake, and proposal of the new family Methanocalculaceae]. AB - A mesophilic hydrogenotrophic methanogenic archaeon, strain Z-7105(T), was isolated from the bottom sediments of a collector in the vicinity of a soda lake Tanatar II (Altai, Russia). The cells were motile, irregular cocci 0.2-1.2 MUm in diameter. The organism was an obligate alkaliphile, growing within a pH range from 8.0 to 10.2 with the optimum at pH 9.0-9.5. It was obligately dependent on carbonates, growing at 0.5 to 1.6 M total carbonates with the optimum at 0.7-0.9 M. Sodium ions were also obligately required at concentrations from 0.9 to 3.3 M Na+ (optimum at 1.4-1.9 M). The organism was halotolerant, but Cl- ions were not required. Hydrogen and formate were used as electron donors. Acetate was required for anabolism. The DNA G + C content was 50.2 mol %. According to the results of its 16S rRNA gene sequence analysis, the isolate belonged to the genus Methanocalculus, being the first known alkaliphilic member of this genus. Its similarity to the neutrophilic and halotolerant Methanocalculus species (M. halotolerans, M. taiwanensis, M. pumilus, and M. chunghsingensis) was 98.2-97.1%, which is within the interspecific range for this genus. The level of DNA-DNA hybridization between strain Z-7105(T) and the Methanocalculus type species M. halotolerans DSM 14092(T) was 32%. The genus Methanocalculus, including the new isolate and the previously described species, is distant from other genera of methanogens (< 90% 16S rRNA gene similarity). Based on significant phenotypic differences and the results of phylogenetic analysis, including DNA-DNA hybridization, it is proposed to assign strain Z-7105(T) (= DSM 25006(T), = VKM B 2765(T)) to the new species Methanocalculus natronophilus sp. nov. and to incorporate the genus into the new family Methanocalculaceae fam. nov. PMID- 25509407 TI - [Sorption of humic acids by bacteria]. AB - Capacity for sorption of humic acid (HA) from water solutions was shown for 38 bacterial strains. Isotherms of HA sorption were determined for the cells of 10 strains. The bonding strength between the cells and HA (k) and the terminal adsorption (Q(max)) determined from the Langmuir equation for gram-positive and gram-negative bacteria were reliably different. Gram-positive bacteria sorbed greater amounts of HA than gram-negative ones (Q(max) = 23 +/- 10 and 5.6 +/- 1.2 mg/m2, respectively). The bonding strength between HA and the cells was higher in gram-negative bacteria than in gram-positive: k = 9 +/- 5 and 3.3 +/- 1.1 mL/mg, respectively. PMID- 25509408 TI - [Electron microscopy of the surfaces of bacillary spores]. AB - The surface structures of the spores of Bacillus. cereus, B. thuringiensis, and Brevibacillus laterosporus were studied by transmission and scanning electron microscopy. Platinum deposition and negative staining with uranyl acetate revealed appendages and exosporium in B. thuringiensis and B. cereus. The exosporium structure was visualized by negative staining and ultrathin sectioning. For staining the exosporium polysaccharide, Alcian blue was used during fixation. The results obtained show the differences in structural organization of appendages and exosporium in different strains. Canoe-shaped inclusions were revealed in all Br. laterosporus strains, while strain IGM16-92 had a fibrillar capsule as well. Electron microscopy using a dual beam scanning electron microscope Quanta 200 3D provided the information of the spore surface relief without sample treatment (fixation and dehydration). The spores of Br. laterosporus strains had folded surface, unlike the smooth surface of B. cereus and B. thuringiensis spores. Diversity of external spore structures was shown within a species, which may be used for detection of bacteria at the strain level. Optimized procedures for visualization of spore surface by different electron microscopic techniques were discussed. PMID- 25509409 TI - [Dominant phylotypes in the 16S rRNA gene clone libraries from bacterial mats of the Uzon caldera (Kamchatka, Russia) hydrothermal springs]. AB - In situ analysis of the 16S rRNA genes form bacterial mats of five hydrothermal springs (36-58 degrees C) in the Uzon caldera (Kamchatka, Russia) was carried out using clone libraries. Eight clone libraries contained 18 dominant phylotypes (over 4-5%). In most clone libraries, the phylotype of the green sulfur bacterium Chlorobaculum sp. was among the dominant ones. The phylotypes of the green nonsulfur bacteria Chloroflexus and Roseiflexus and of purple nonsulfur bacteria Rhodoblastus, Rhodopseudomonas, and Rhodoferax were also among the dominant ones. Cyanobacteria were represented by one dominant phylotype in a single spring. Among nonphototrophic bacteria, the dominant phylotypes belonged to Sulfyrihydrogenibium sp., Geothrixsp., Acidobacterium sp., Meiothermus sp., Thiomonas sp., Thiofaba sp., and Spirochaeta sp. Three phylotypes were not identified at the genus level. Most genera of phototrophic and nonphototrophic organisms corresponding to the phylotypes from Uzon hydrotherms have been previously revealed in the hydrotherms of volcanically active regions of America, Asia, and Europe. These results indicate predominance of bacterial mats carrying out anaerobic photosynthesis in the hydrotherms of the Uzon caldera. PMID- 25509410 TI - [Filterable microbial forms in the Rybinsk water reservoir]. AB - Molecular identification of the filterable forms of microorganisms in the water of the Rybinsk reservoir, one of the largest open water bodies in European Russia, was carried out. The number of ultrasmall microbial cells passing through 0.22 MUm filters was 10(4) cells/mL. These were represented by both bacteria and archaea. Most bacterial 16S rRNA gene sequences retrieved from filtered water belonged to the Betaproteobacteria and exhibited high similarity (99.0-99.5%) to thos of bacteria of the genus Polynucleobacter. The archaeal 16S rRNA gene clone library was composed of the sequences of members of the Euryarchaeota, including the orders Methanobacteriales and Methanomicrobiales, as well as of two archaeal groups (LDS and RC-V) with no characterized representatives. The species composition of filterable bacteria from reservoir water wast different from that revealed previously in bogs and small lakes at catchment areas; The pool of filterable archaea in the reservoir exhibited, however, significant similarity to that for boggy catchment areas and was characterized by perdominance of the clade LDS. Available data indicate that this archaeal group is typical of the northern freshwater ecosystems, and the organisms of this group are represented by ultrasmall cells. PMID- 25509411 TI - [Abundance and activity of microorganisms at the water-sediment interface and their effect on the carbon isotopic composition of suspended organic matter and sediments of the Kara Sea]. AB - At ten stations of the meridian profile in the eastern Kara Sea from the Yenisei estuary through the shallow shelf and further through the St. Anna trough, total microbial numbers (TMN) determined by direct counting, total activity of the microbial community determined by dark CO2 assimilation (DCA), and the carbon isotopic composition of organic matter in suspension and upper sediment horizons (delta13C, per thousand) were investigated. Three horizons were studied in detail: (1) the near-bottom water layer (20-30 cm above the sediment); (2) the uppermost, strongly hydrated sediment horizon, further termed warp (5-10 mm); and (3) the upper sediment horizon (1-5 cm). Due to decrease in the amount of isotopically light carbon of terrigenous origin with increasing distance from the Yenisei estuary, the TMN and DCA values decreased, and the delta13C changed gradually from -29.7 to -23.9 per thousand. At most stations, a noticeable decrease in TMN and DCA values with depth was observed in the water column, while the carbon isotopic composition of suspended organic matter did not change significantly. Considerable changes of all parameters were detected in the interface zone: TMN and DCA increased in the sediments compared to their values in near-bottom water, while the 13C content increased significantly, with delta13C of organic matter in the sediments being at some stations 3.5- 4.0 per thousand higher than in the near-bottom water. Due to insufficient illumination in the near-bottom zone, newly formed isotopically heavy organic matter (delta13C(-) -20 per thousand) could not be formed by photosynthesis, active growth of chemoautotrophic microorganisms in this zone is suggested, which may use reduced sulfur, nitrogen, and carbon compounds diffusing from anaerobic sediments. High DCA values for the interface zone samples confirm this hypothesis. Moreover, neutrophilic sulfur-oxidizing bacteria were retrieved from the samples of this zone. PMID- 25509412 TI - [Methanotrophic bacteria in cold seeps of the floodplains of northern rivers]. AB - Small mud volcanoes (cold seeps), which are common in the floodplains of northern rivers, are a potentially important, although poorly studied sources of atmospheric methane. Field research on the cold seeps of the Mukhrina River (Khanty-Mansiysk Autonomous okrug, Russia) revealed methane fluxes from these structures to be orders of magnitude higher than from equivalent areas of the mid taiga bogs. Microbial communities developing around the seeps were formed under conditions of high methane concentrations, low temperatures (3-5 degrees C), and near-neutral pH. Molecular identification of methane-oxidizing bacteria from this community by analysis of the pmoA gene encoding particulate methane monooxygenase revealed both type I and type II methanotrophs (classes Gammaproteobacteria and Alphaproteobacteria, respectively), with predomination of type I methanotrophs. Among the latter, microorganisms related to Methylobacterpsychrophilus and Methylobacter tundripaludum, Crenothrix polyspora (a stagnant water dweller), and a number of methanotrophs belonging to unknown taxa were detected. Growth characteristics of two isolates were determined. Methylobactersp. CMS7 exhibited active growth at 4-10 degrees C, while Methylocystis sp. SB12 grew better at 20 degrees C. Experimental results confirmed the major role ofmethanotrophic gammaproteobacteria in controlling the methane emission from cold river seeps. PMID- 25509413 TI - [Dimensional structure of bacterial communities of the winter plankton Pechora sea and its formation]. AB - For the Pechora sea, according to microbiological shootings during winter seasons 2002-2005, the analysis of conditions forming of an abundance winter bacterial communities a plankton is carried out. For the outlined varieties of waters, regularities of distribution of segregate groups bacterial communities are discussed. The natural modification of microbiologic indicators ona gradient of parametres a physical and chemical complex is shown. In subglacial conditions average number bacterioplankton 234 thousand in cell/ml, cellular volume - 0.58 MUm3, at square of 550 mm2/L. A biomass store a stratum of probed harbour area Pechora sea of 0-25 m to 187 x 10(90 G. PMID- 25509414 TI - [Reparative autophagy and autophagy death of cells. Functional and regulatory aspects]. AB - Molecular regulation of reparative/homeostatic autophagy induced by failure of vital resources and by cellular stress is considered. Extensive autophagy regulatory apparatus responds to starvation, insufficiency of growth factors and energy supply, accumulation of unfolded proteins (ER stress), reactive oxygen species, microbial invasion. Central sensor of the regulation is kinase mTOR. Part of the mTOR pool presented in lysosomes responds to the local level of amino acids and is able to induce autophagy under low rates of intralysosomal proteolysis. Autophagy is a self-regulated cell process, the peak of autophagy is followed by its regulatory weakening by amino acids formed in autophagolysosomes. Protective effect of autophagy is associated mainly with removal of permeabilized mitochondria generating ROS, and elimination of abnormally folded proteins. Autophagy has optimum of its activity: its deficiency leads to accelerated cellular aging, and the excessive autophagy brings to the deficiency of cellular survival resources and cell death. Autophagy cell death seems like a hyper stimulated self-eating of the cell, but more probably that excessive autophagy disturbs cellular energy supply and switches on some specific cell death signalization (possibly associated with kinases c-Jun, DRP-1, PI3K class I etc.). Some approaches to use reparative autophagy for prevention of cell degeneration are considered. PMID- 25509415 TI - [Colocalization of nucleoli in cell nuclei of HeLa line]. AB - The pattern of localization of nucleoli relative to each other and to cell nucleus was studied in M-HeLa cell line. For this puspose, the following morphometric parameters were introduced. For the two-nucleolar cells: 1) the ratio of the nucleus long axis to the length of a segment between the centers of the nucleoli, and 2) the angle between the segment connecting the centers of the nucleoli and a longitudinal axis of cell nucleus. For the three-nucleolar cells: the ratio perimeter of the nucleus to perimeter of a triangle with vertexes in the centre of nucleoli. We have shown that the values of these parameters are individual for each cell but their values remain constant for the cell in spite of the changes in cell shape. These results allow us to conclude that, on the one hand, the nucleoli colocalization is individual for each cell, and, on the other hand, location of nucleoli in relation to nucleus is not changed during interphase. Thereby, the distance between nucleoli increases proportionally with nucleus growth. PMID- 25509416 TI - [BDNF secretion in human mesenchymal stem cells isolated from bone marrow, endometrium and adipose tissue]. AB - The ability of mesenchymal stem cells (MSCs) to differentiate into neuronal lineage determines the potential of these cells as a substrate for a cell replacement therapy. In this paper we compare the neurogenic potential of MSCs isolated from bone marrow (BMSC), subcutaneous adipose tissue (AD MSC) and menstrual blood (eMSC). It was found that the native eMCSs, BMSCs and AD MSCs express neuronal marker beta-III-tubulin with a frequency of 90, 50 and 14%, respectively. We also showned that eMSCs have a high endogenous level of brain derived neurotrophic factor (BDNF), whereas the BMSCs and the AD MSCs are characterized by low basal BDNF levels. As induction of neuronal differentiation in the studied MSCs using differentiation medium containing B27 and N2 supplements, 5-azacytidine, retinoic acid, IBMX and dbcAMF caused changes in the cells morphology, the increased expression of beta-III-tubulin, and the appearance of neuronal markers GFAP, NF-H, NeuN and MAP2. BDNF secretion during differentiation was significantly enhanced in the BMSCs and decreased in the eMSCs cultures. However, no correlation between the basal and induced levels of the neuronal markers expression and BDNF secretion in the studied MSCs has been established. PMID- 25509417 TI - [Comparative characteristics of the stem cells isolated from subcutaneous and subepicardial adipose tissue]. AB - BACKGROUND: Stem cells (SCs) considerably vary in morphological, immunophenotypic, proliferative, and differentiation characteristics depending on their tissue source. The comparative analysis of their biological properties is essential for the optimal choice of SCs for regenerative therapies. METHODS: Using immunocytochemistry, flow cytometry, histochemistry and real-time RT-PCR, we have investigated SCs obtained from human subepicardial (SEC-AT) and subcutaneous (SC-AT) adipose tissue and cultured under similar culture conditions without any differentiation-promoting factors. RESULTS: The cultures were similar in the high proportion of proliferating cell nuclear antigen (PCNA)-positive cells. In both cultures, immunophenotyping has revealed high expression of mesenchymal stem cell surface markers CD29, CD44, CD73, and CD105, low expression of CD31, CD34 and CD45, and wide variability in CD117, CD146 and CD309 expression. The only distinction in CD marker profile was significantly lower expression of CD90 in SCs from SEC-AT. Histochemical analysis has shown the lack of Oil Red O-positive cells in both cultures and about ten-fold higher number of alkaline phosphatase-positive cells among SCs from SC-AT. In the both cultures, immunocytochemistry has detected similar low expression of slow myosin heavy chain marker MAB1628 and smooth muscle actin marker alpha-hSMA. Gap junctional protein Connexin-43 expression was markedly higher in SCs from SC-AT, and epithelial cell marker Cytokeratin-19 expression was detected only in these cells. By RT-PCR, GATA4 mRNA was found to be highly expressed only in SCs from SEC-AT. CONCLUSIONS: Our results suggest that SC-AT, as compared with SEC-AT, is richer in epithelial cell and osteogenic progenitors. In turn, SEC-AT possesses cardiomyogenic SCs, and can be considered as an alternative to SC-AT as a source of SCs for cell cardiotherapy. PMID- 25509418 TI - [Design of cell line stable expressing proteasomal subunit PSMD14 fused to the fluorescent protein EGFP and HTBH tag based on HEK293 cells]. AB - A stable cell line based on HEK293 cells that expresses proteasome subunit PSMD14 fused to the fluorescent protein EGFP and HTBH tag has been selected. This chimera was shown to be incorporated completely into proteolitic active proteasomes. The created cell line can be used for further fluorescent studies of proteasomes localization in the cell. PMID- 25509419 TI - [Effect of iodine-containing thyroid hormones on the histostructure of rat liver under the stress]. AB - Experiments with 130 outbred male rats weighing 220-250 g have show that stress "free swimming in a cage" (FSC) affects the histological structure of the liver as early as in 1 h. FSC occurred in standard plastic cages (5 animals) filled with water to a height of 15 cm and topped with a grid. One hour after FSC (the alarm-stage) caused dystrophy of hepatocytes and increased blood flow to the liver lobules, which also continued at the resistance-stage (48 h after the FSC). At the exhaustion-stage (daily 1-hour stress for 10 days) there were even greater hepatocytes dystrophy, necrosis, and their microcirculatory disturbances in the lobules. The introduction of merkazolil (intragastrically 25 mg/kg for 20 days) per se altered the histostructure of the liver tissue and under stress aggravates the microcirculatory changes, dystrophy and necrosis of the hepatocytes. Small doses of L-thyroxine (intragastrically 1.5-3.0 MUg/kg for 28 days) minimized the histological signes of the liver damage at all stages of the stress response. Consequently, the iodine-containing thyroid hormones limit the disturbance of the microstructure of the liver caused by stress. PMID- 25509420 TI - [ABCG1 transporter gene expression in peripheral blood mononuclear cells of patients with atherosclerosis]. AB - Accumulation of cholesterol in arterial wall macrophages is a main hallmark of atherosclerosis. The ABCG1 transporter mediates cholesterol efflux to high density lipoproteins (HDL) and plays an important role in macrophage foam cell formation. The goal of our study was to investigate the potential role of ABCG1 in atherosclerosis development in humans. ABCG1 gene expression has been examined in leukocytes, monocytes and monocyte-derived macrophages of patients with atherosclerosis and in the control group. Real time PCR and Western blotting were used to determine ABCG1 mRNA and ABCG1 protein levels. Monocyte ABCG1 mRNA level was inversely correlated with the rate of artery occlusion (r = -0.45, P = 0.016). Patients with 100% artery occlusions had decreased monocyte ABCG1 mRNA levels compared to patients who had smaller plaques and controls (P < 0.05). ABCG1 mRNA (P < 0.001) and ABCG1 protein (P < 0.05) levels in macrophages of patients with coronary artery stenosis were significantly reduced compared to the control group. No significant correlation between the ABCG1 gene expression in mononuclear cells and HDL cholesterol concentration has been found. Our study suggests that decrease in the ABCG1 gene expression in macrophages is associated with atherosclerosis. PMID- 25509421 TI - [The use of apoptosis inducers in the therapy of experimental influenza infection and preventing of chronic post-influenza lung damage]. AB - Influenza is a respiratory infection widely spread around the world. Influenza complications are various in nature and in most cases involve the excessive proliferation of cells in respiratory tract as a factor of pathogenesis. In the present work the efficacy of the use of apoptosis inducer 6-[3-(1-adamantyl)-4 hydroxyphenyl]-2-naphtalenecarboxylic acid (AHPN) for prophylaxis of chronic damage on the stage of post- influenza pneumonia has been studied. Mice were infected with influenza virus A/mallard/Pennsylvania/10218/84(H5N2) with further study of the level of influenza virus reproduction in the lungs, specific mortality of animals and morphology of the foci of post-influenza pneumonia on the 15th day post inoculation. AHPN was shown to decrease the infectious activity of the virus in the lungs by 1.2-1.5 log10 EID50/0.2 mL depending on the dose as compared to the control group, in a weak decrease in mortality of animals (protection index was 12.5-37.5%). The application of AHPN restricted both the proliferative and infiltrative component in chronic post-influenza lesions. It demonstrated the most pronounced effect on the lung morphology when applied on days 4 to 7 post inoculation, i. e. in the period of maximal activation of inflammatory tissue infiltration and regeneration of bronchiolar epithelium. In conclusion, the use of apoptosis inducers can partially prevent the development of chronic post-influenza lesions with proliferative component. PMID- 25509423 TI - [To memory of Georgy Petrovich Pinaev]. PMID- 25509422 TI - [Plastid stromules as specific elements of the multipurpose endoplasmic reticulum]. AB - It is supposed, that the compromise between all groups of researchers of stromules can be reached if to accept, that an external membrane of stromules together with an external membrane of initial plastid are the specific domain of endoplasmic reticulum. Such domain co-operates with other membranes of a cell by means of membrane contact sites with free permeability for small molecules (presumably to 1.5 KDa). PMID- 25509424 TI - [Classification, differentiated and topic diagnosis, and treatment of hepatic cystic lesions]. AB - Accumulated in 2004-2014 yrs in Department of laparoscopic surgery and choledocholithiasis experience of treatment in patients, suffering parasitic and nonparasitic hepatic cysts, was analyzed. Own improved classification of hepatic cystic lesions was proposed. Peculiarities of performance of open operations, of the puncture miniinvasive operations and interventions for hepatic cysts, using laparoscopic approach, were enlighten. Main indications for surgical treatment of hepatic cysts were adduced, depending on their kind, size, localization and clinical signs. PMID- 25509425 TI - [Tactics and results of treatment of acute hemorrhage in gastroduodenal erosive ulcers due to application of gastro-aggressive preparations]. AB - Results of treatment of 238 patients, suffering an acute gastrointestinal hemorrhage, occurring on background of application of medicinal preparations, were adduced. The incidence rate for an acute medicinal ulcers of foregut was analyzed, as well as possibilities for their treatment. PMID- 25509426 TI - [Immediate and late follow-up results of surgical and combined treatment of patients with colonic cancer of various localization in right half of the colon]. AB - Comparative estimation of immediate and late follow-up results of treatment was con- ducted in 520 patients, suffering cancer of the colonic right half, including coecum - in 227 (43.7% +/- 2.1%), colon ascendum - in 159(30.7% +/- 2.0%), right colonic flexure - in 66 (12.9% +/- 1.3%), right half of colon transversum - in 66 (12.9% +/- 4.2%). In 463 (89.0% +/- 1.4%) patients radical operations were performed, while in 57 (11.0% +/- 1.7%) - the symptomatic. After radical operations 8 (1.7% +/- 0.5%) patients died, and after the symptomatic - 3 (5.3% +/- 3.0%). Definite surgical treatment was performed in 258 (60,8% +/- 2,4%) patients, the combined one - in 166 (39.2% +/- 2.4%). Five-year survival have constituted (64.2% +/- 5.5%) for the patients, operated on for the colon ascendumcancer, and (19.1% +/- 5.7%) - for cancer of right colonic flexure; while after combined treatment - (40.4% +/- 5.8%) in patients, operated on for cancer of coecum, (29.4% +/- 11.9%) - right half of colon transversum; ten-year survival have constituted (16.8% +/- 2.7%) for the patients, who were radically operated for cancer of coecum, and (4.8% +/- 2.6%) - for cancer of right colonic flexure (p<0,005). Late follow-up results of radical treatment of the colonic right half depends essentially on localization and degree of the cancer spread. PMID- 25509427 TI - [Classification of an acute pancreatitis: revision by international consensus in 2012 of classification, adopted in Atlanta]. AB - In 1992 on symposium in Atlanta the general classification of an acute pancreatitis, adopted by world medical society for practical application, was proposed. Due to results of multiple investigations there were enhanced the data about an acute pancreatitis pathophysiology, the organs insufficiency, and improvement of the noninvasive and invasive methods of visualization and treatment, what caused necessity to revise the classification. Web-consultations were conducted in 2007 yr to guarantee a wide participation of pancreatologists. After first meeting the working group have directed the document project to 11 national and international associations of pancreatologists. In 2012 yr the definite conclusions, concerning consensus, were published. PMID- 25509428 TI - [A "fast track" surgical concept realization in treatment of patients with acute pancreatitis]. AB - Ten principles of a surgical concept of "fast track" surgery in the treatment of an acute pancreatitis (AP) were introduced in 57 patients, ageing from 34 to 67 yrs old, with the objective to study if it is affordable to realize this concept. In accordance to Atlanta's criteria (2007), AP of moderate severity was noted in 13 (23%) patients, and a severe one - in 44 (77%). Generally accepted principles of a "fast track" surgery were realized in the treatment program. Introduction of such a program have promoted the improvement of the patients quality of life. So, the duration of stationary treatment have had reduced by 4.7 days, and postoperative lethality - from 16.3 to 10.1%. PMID- 25509429 TI - [Modern insights into the problem of surgical treatment of chronic pancreatitis]. AB - Results of surgical treatment of 290 patients, suffering chronic pancreatitis, were ana- lyzed. Frey's operation was performed in 125 patients, and in 11 - the biliodigestive anastomoses formation was added for biliary hypertension. Pancreaticoduodenal resection was performed in 8 patients, the Bern's modification of Beger's operation and distal pancreatic resection - in 6 for each, longitudinal pancreaticojejunostomy - in 69. In 46 patients, suffering ripe pancreatic pseudocysts, a cystojejunostomy and cystopancreatojejunostomy were performed, in 6 - endoscopic cystogastrostomy and cystoduodenostomy, in 7 - external drainage of the cyst. In 17 patients, suffering duodenal or the biliary system impassability, a bypass anastomoses were formatted. PMID- 25509430 TI - [Roentgen-surgical interventions in combined treatment of patients, suffering hepatic metastases of noncolorectal cancer]. AB - Results of combined treatment, using roentgen-surgical interventions, of 58 patients, suffering noncolorectal metastatic affection of the liver, complicated in 20 (34.5%) of them by obturation jaundice, were analyzed. While resectability of the metastases, preoperatively chemotherapy (CHT) or chemoembolization of hepatic artery (CHEHA) in 1 - 2 courses were performed, and then - hepatic resection of various volume, adjuvant regional CHEHA or systemic CHT. Median survival of the patients have constituted 31.2 mo. While presence of nonresectable metastases a regional chemoinfusion via hepatic arteries or CHEHA (2 - 3 courses) were performed. Median survival of this group of patients have constituted 15.3 mo. Application of cytostatics for regional therapy have permitted in 4 (6.9%) patients, in whom partial tumor regression was achieved, to perform radical hepatic resection. Complete answer on the treatment was not achieved in any patient, partial answer was noted in 16 (33.3%), the process stabilization - in 20 (41.7%), the tumor progress - in 12 (25.0%). In total 170 endovascular and 41 transcutaneous transhepatic endobiliary interventions were performed. After operation 1 (12.5%) patient died. PMID- 25509431 TI - [The role of early enteral nutrition in multimodal program "fast track" surgery in children]. AB - Early enteral nutrition - in terms up to 6 h after operation - secures success of the program "fast track" surgery, together for small and large operations. Application of enteral nutrition after operation have promoted rapid elimination of intestinal paresis, early activation of its motor function, the mucosal regeneration improvement, early activation of absorptive function of underlying intestinal parts, reduction of the infection complications rate as well as the patients hosoital stay duration. PMID- 25509432 TI - [Performance of fragmenting operation for restoration of a correct rhythm while treating the isolated failure of a mitral valve]. AB - Possibilities of application of the proposed procedure for intraoperative restoration of the sinus rhythm while the mitral valve prosthesis (MVP) were studied up. In 161 patients, suffering the isolated mitral valve failure stage IV, a surgical treatment was conducted in Department of surgical treatment of acquired heart failures. The left atrium plasty was conducted in 119 (73.9%) of them with the objective to reduce its size and eliminate the re-entry waves passability. Fragmentation in left atrium was conducted in lowradiofrequency regime of diathermy (25-35 W) in accordance to variant (cut and sew) of operations Maze - 3 and Maze - 4. On a hospital stage 3 patients died (hospital lethality 1.9%). MVP in combination with Maze operation in a lowradiofrequency regime have permitted to restore successfully a correct rhythm in 80.2% of patients on a hospital stage and to stabilize it during 1 year postoperatively. PMID- 25509433 TI - [Immediate complications of endovascular interventions in chronic ischemia of the lower extremity tissues]. AB - The results of examination and treatment of 66 patients, suffering occlusion stenotic affection of the lower extremities arteries, to whom transcutaneous transluminal balloon angioplasty was performed, are adduced. Immediate postoperative complications after endovascular interventions have occurred in 4 (6.1%) patients. The immediate complications, causes of their occurrence, methods of treatment, ways of prophylaxis were analyzed. In 50% of patients, suffering complications of endovascular interventions in immediate postoperative period, it is possible to eliminate them, using simple prophylactic measures. PMID- 25509434 TI - [Prognostication of ischemic complications of cerebral vasospasm in surgical treatment of intracranial aneurysm in acute period of its rupture]. AB - With objective to create a model of prognostication of ischemic complications, occurred due to cerebral vasospasm (CVS), the informativeness of some clinic instrumental indices was investigated in 350 patients in an acute period of intracranial arterial aneurysm rupture, using mathematical processing of the data. The terms from the disease beginning (3 - 14th day), severe state of patient while stay in hospital, localization of rupture in internal carotid artery, conduction of operation in terms up to 11 days after the rupture occurrence, presence of intraoperative complications, pronounced spasm of 3 and more segments of arteries preoperatively in accordance to angiography data, the pronounced and critical spasm postoperatively in accordance to ultrasonography data have had evolved as a prognostically significant causes in the CVS ischemic complications occurrence. The proposed model of prognostication of a deferred ischemic complications of CVS have had sensitivity 85%, specificity 75%, what have oermitted to use it in clinical practice. PMID- 25509435 TI - [Application of multimodal anesthesia/analgesia in complex of anesthesiological support of reconstructive operations, performed on the lower extremity arteries]. AB - Anesthesiological support of 47 patients, while performing reconstructive operations on the lower extremities arteries in presence of the third level of operative risk (according to ASA), was analyzed; of them in 24 - a spinal anesthesia was applied, in 23 - a reduced spino-epidural anesthesia. Application of a spino-epidural anesthesia/analgesia with reduction of the dose of a spinal component and usage of analgesia instead of anesthesia secures lesser intraoperative oscillations of hemodynamic indices in comparison with such while performing spinal anesthesia, as well as better antinociceptive protection, is also characterized by small toxic impact on the patient, demands application of a sedative and the infusion therapy of lesser volume. While performing a potentially complex and durable reconstructive operations on the lower extremities arteries a wide application of the method depicted is recommended. PMID- 25509436 TI - [Moden approaches to orthopedic treatment of the diabetic foot osteoarthropathy]. AB - Treatment of diabetic neuropathic osteoarthropathy envisages bringing to a stop the osteolysis process and transition into chronic stage with a least losses in the bone mass and elimination of the foot decompensated deformity, orthotic support of the patients, what reduces the risk of the process exacerbation. In unstable noncompensated deformity of the foot, on level of localization IV, a surgical treatment is justified as an alternative to high amputation of lower extremity. The treatment results depend a lot on its early beginning and following the physician's recommendations by a patient. PMID- 25509437 TI - [The time factor impact on prognosis of treatment of patients with acute mesenteric ischemia]. AB - Impact of the time factor on prognosis of successful treatment in patients, suffering an acute mesenteric ischemia, was proved. The predicted probability of lethality 50% is realized in 6 h from the disease beginning, and after 12 h - lethality approaches up to 100%. Application of instrumental diagnosis and operative treatment of the patients, conducted in terms up to 6 h from the disease beginning, permit to enhance the positive outcomes rate. PMID- 25509438 TI - [Clinico-epidemiologic and clinico-nosologic characteristic of the hip trauma as a component of polysystemic damage]. AB - Clinico-epidemiological and clinico-nosological indices of the hip injury (HI) in a structure of polysystemic and polyorgan damage, depending on gender, age of the injured patients, as well as the main mechanisms and conditions of trauma, were investigated. Four hundreds of charts of stationary patients, the injured persons, suffering polytrauma, who were treated in The Ternopyl University clinic in 2008 - 2012 yrs, were analyzed. The HI, as a component of polysystemic damage, was revealed in 54 patients. In accordance to the ranking analysis data, the HI coexistence in polytrauma probably depends on gender and age of the injured persons (mainly the men of employable age). Mostly such injures have occurred while the traffic accident in 61.1% of observations and while domestic conditions - in 29.6%. Severity of coexistent HI in a polytrauma structure probably depends on their mechanisms. So, in falling down in most cases combination with other skeletal trauma and damage of head was noted; in a direct punch - with cranio cerebral trauma; in coexistence of various mechanisms the most severe injuries have occurred with damage of several anatomo-functional regions, not the hip only, but head, thorax and abdomen. PMID- 25509439 TI - [Optimization of education for laparoendoscopic technologies in Ukraine]. AB - International experience of training of surgeons, including urologists, in laparoendoscopic technologies, was analyzed. Practical course "The Fundamentals of aparoscopic Surgery" (FLS) and the European program of education for basic laparoscopic urologic skills (E-BLUS), which are used in specialized centers, constitute a standard programs of development of basic endosurgical skills. Such centers in Ukraine are absent. The project of complex system of a simulating education, testing and certification of surgeons, who are trained in endovideosurgical technologies, is proposed. While performing surveying of Ukrainian surgeons there were revealed the problems in a process of their education and introduction of highly technological methods: insufficient equipment with modern apparatuses, absence of a standardized pro- gram of education. The staged program of education was elaborated, taking into account progressive international experience and adopted to our environment and con ditions. PMID- 25509440 TI - [Analysis of tension-distraction state in the shin bones fractures in conditions of external fixation with application of apparatuses with different spatially oriented supports]. AB - In Autodesk Inventor 11 program, using method of end-capping elements, a three- dimensional computeric modelling of biomechanical systems of two models was conducted: I - "tibia - Ilizarov's apparatus with concentric location of supports"; II - "tibia - Ilizarov's apparatus with excentric location of supports". The loading, which was applied towards distal fragment in 6 standard degrees of freedom, was modelled for studying of the fixation rigidity of tibial fragments in these systems. Determination of the loading value in various directions, in which the fragment have had shifted by 1 mm, have constituted the main task of the investigation. In a model II a rigidity of the fragments fixation, in comparison with such in a model I, is bigger by 631.43% - while applying a compression loading, by 8.35 - 31.75% - the transversal one and by 19.72% - the rotation loading. While choosing the method of transosteal osteosynthesis of the shin bones the advantage, have the apparatuses with excentric location of supports, what secures the enhanced rigidity of the fragments fixation in comparison with such in apparatuses with concentric location of supports. Although, even in excentric location of supports in the apparatus the fixation rigidity is insufficient for early full loading of the traumatized extremity while walking. It is necessary to elaborate such apparatus, the form of which may be adopted toanatomic configuration of segment. PMID- 25509441 TI - [A foreign body of the intestine as the mask of acute appendicitis]. PMID- 25509442 TI - [A Fournier's gangrene, complicated by paraproctitis]. PMID- 25509443 TI - [Jubilee, which would not come...to the 75th anniversary of Professor Vladimir Sergeyevich Zemskov]. PMID- 25509444 TI - Divisions surface between healthcare workers, public over Ebola quarantines. PMID- 25509445 TI - Demand soars for Ebola supplies as cost and safety concerns rise. PMID- 25509446 TI - Arkansas' Medicaid expansion could hinge on election outcomes. PMID- 25509447 TI - Can transfusions aid Ebola fight? PMID- 25509448 TI - Liability rhetoric and reality. Medical liability premiums flat as California battles over caps on damages. PMID- 25509449 TI - Balancing healing with security. Hospital designers find creative ways to defuse tensions and boost safety. PMID- 25509450 TI - Nurses take bigger role in health IT. PMID- 25509451 TI - Why Hickox should have obeyed. PMID- 25509452 TI - Medical homes delivering on promises. PMID- 25509453 TI - No reason for hospitals to wait on UDI. PMID- 25509454 TI - Emergency department observation units offer efficiencies that cut costs, improve care. PMID- 25509455 TI - Obamacare will become like Medicare, and 'everybody will want it'. PMID- 25509456 TI - My epilepsy seems to be worsening with age. Are there any surgical treatments? I'm 69. PMID- 25509457 TI - How much water do you really need to drink on a daily basis? PMID- 25509458 TI - Promoting mental health at the workplace. PMID- 25509460 TI - Progress on pet insurance. PMID- 25509459 TI - Policy development - time for a rethink? PMID- 25509461 TI - Emergency animal diseases bulletin: crayfish plague. PMID- 25509462 TI - Rabies is a real risk in Australia. PMID- 25509463 TI - Highlights of the AVA's media program. PMID- 25509464 TI - Protection against Hendra at equestrian events. PMID- 25509465 TI - Fighting antimicrobial resistance during Antibiotic Awareness Week. PMID- 25509466 TI - South Australian study into dog bite incidents. PMID- 25509467 TI - Latest strain of avian influenza in Southeast Asia. PMID- 25509468 TI - The complicated strains of rabbit calicivirus. PMID- 25509469 TI - John Albert Majors Jr., 1920-2013, and William Harcourt Majors, 1925-2013. PMID- 25509470 TI - American Diabetes Association. Diabetes clinical practice recommendations focus attention on individualization of care. PMID- 25509471 TI - Fighting back. PMID- 25509472 TI - Direct pay: a promising care model, with challenges. Physicians say direct pay models offer a viable alternative to health insurance, but require careful planning and outreach. PMID- 25509473 TI - Solving the crisis in primary care. Direct pay models could buy physicians more time with patients to improve care and reset a fractured payment system. PMID- 25509474 TI - Best business practices to fine-tune your operation. PMID- 25509475 TI - The challenges of healthcare price transparency. The growing demand for improved access to cost information presents opportunities for practicing physicians, experts say. PMID- 25509476 TI - Physician use of social media: navigating the risks. Establish social media guidelines to protect health information, and reputation of practice and physicians. PMID- 25509477 TI - ICD-10 readiness: complications of pregnancy. PMID- 25509479 TI - Staff meetings: two small ways to create a big impact. PMID- 25509478 TI - Incident-to billing: your questions answered. PMID- 25509480 TI - Missouri 'assistant physician' law draws criticism from medical groups. PMID- 25509481 TI - Best Places to Work 2014--how we identified them. PMID- 25509482 TI - Patient outcomes. The sticking point. PMID- 25509484 TI - 'This could save L50M nationally'. PMID- 25509483 TI - A rich vein of reform. PMID- 25509485 TI - The next lease of life. PMID- 25509487 TI - Talking about an NHS revolution. PMID- 25509486 TI - Inject an NHS tax to accelerate innovation. PMID- 25509488 TI - The medicalisation epidemic must stop. PMID- 25509489 TI - Bold move brings hope for children's services. AB - Employees may not always give or achieve their best but a "one cure fits all" approach will not solve the problem. Knowing how to motivate, value and energise staff is key to successful management and retention. Sharon Crabtree looks at the different factors that can affect staff motivation and explores how to recognize why individual staff may not be achieving or trying to achieve their full potential. PMID- 25509491 TI - Lean Forward. PMID- 25509490 TI - Workforce. Happy staff mean healthy business. PMID- 25509492 TI - In your corner--strength in vulnerability. PMID- 25509493 TI - Nursing from the front lines. PMID- 25509495 TI - Growth and income: the annuity story. PMID- 25509494 TI - Superbugs? No thanks! PMID- 25509496 TI - Check it once, check it twice. PMID- 25509497 TI - Three simple tips for the perfect dental billing statement. PMID- 25509499 TI - The security risk of using Web-based email. PMID- 25509498 TI - The erosion of the solo private practice model. PMID- 25509500 TI - Another perspective on concerns regarding dental economics. PMID- 25509501 TI - Is hospital procedure volume associated with hospitalization charges and complication rates for cleft lip repairs? PMID- 25509502 TI - Endodontic treatment of teeth devitalized after enucleation of a giant cell lesion. PMID- 25509503 TI - An interview with Dr. Charles Hapcook. PMID- 25509504 TI - A clinico-pathologic correlation: fibromyxoma. PMID- 25509505 TI - Lichen sclerosus. PMID- 25509506 TI - The fix is in. PMID- 25509507 TI - How not to cut health care costs. AB - Health care providers in much of the world are trying to respond to the tremendous pressure to reduce costs--but evidence suggests that many of their attempts are counterproductive, raising costs and sometimes decreasing the quality of care. Kaplan and Haas reached this conclusion after conducting field research with more than 50 health care provider organizations. Administrators looking for cuts typically work from the line-item expense categories on their P&Ls, they found. This may appear to generate immediate results, but it usually does not reflect the optimal mix of resources needed to efficiently deliver excellent care. The authors describe five common mistakes: (1) Reducing support staff. This often lowers the productivity of clinicians, whose time is far more expensive. (2) Underinvesting in space and equipment. The costs of these are consistently an order of magnitude smaller than personnel costs, so cuts here are short-sighted if they lower people's productivity. (3) Focusing narrowly on procurement prices and neglecting to examine how individual clinicians actually consume supplies. (4) Maximizing patient throughput. Physicians achieve greater overall productivity by spending more time with fewer patients. (5) Failing to benchmark and standardize. Administrators, in collaboration with clinicians, should examine all the costs of treating patients' conditions. This will uncover multiple opportunities to improve processes in ways that lower total costs and deliver better care. PMID- 25509508 TI - [Comparative analysis of some factors in tooth color matching]. AB - Recently (nowadays) to achieve a natural looking restoration is an ever increasing demand from the patients and also from the doctor side. To select the right color of the restoration matching the remaining natural teeth is always a challenging task. A clinical study was performed at the University of Debrecen Faculty of Dentristry with the help of dental students using two different shade guides. The study tested the influence of gender and knowledge of color science on shade matching. 78 students were asked to find the right matching color of the same upper canine to two different shade guides (Vitapan Classic and Vita 3D Master) under standard condition. After informing the student about the basic principles of color the matching procedure was repeated. Results were analyzed statistically. In our study we found that gender does not influence the color choice. Matching accuracy is not increased by better knowledge of colors. We can conclude that significantly less students matched the proper color with Vitapan Classic shade guide after information of the property of colors without training the shade selection. Within the limitation of the study design it was concluded that not more students selected the proper color even after giving them information about colors, instructions about shade selections. For the same one canine several color were selected by the participants (6 types with Vitapan Classic and 19 types with Vita 3D-Master) which conformed that visual determination is not a reliably consistent way of the tooth shade selection. The Vita Company 1990s developed 3D-Master shade guide is not widely used, although we found the repeatability is more than 70%. PMID- 25509509 TI - [Recurrent European missense mutation in a Hungarian pedigree with Papillon Lefevre syndrome]. AB - Papillon-Lefevre syndrome, a rare disease with autosomal recessive inheritance, is characterized by aggressive periodontitis and palmoplantar hyperkeratosis. Mutations of the cathepsin C gene are responsible for the development of the disease. In this study, we aimed to describe in details the clinical symptoms and to determine the underlying genetic abnormality in two Hungarian siblings affected by Papillon-Lefevre syndrome. The siblings are under regular dental and dermatological care since their symptoms appeared, but, due to the fact that genetic analysis of Papillon-Lefevre syndrome has been available for one or two years in Hungary, their mutation screenings were just recently performed. We have identified a homozygous missense mutation on the cathepsin C gene, which is an already published mutation and was originally reported from Germany. Our investigations would like to draw attention to a rare disease, Papillon-Lefevre syndrome, in which first symptom can be the aggressive periodontitis, and in which genetic testing and for helping child-bearing and family planning is now available. PMID- 25509510 TI - [Chronological age estimation based on dental panoramic radiography]. AB - Determination of the dental age is a valuable tool in planning of orthodontic treatment and could be used to estimate the chronological age of unidentified human beings. Among the various age estimation methods one of the most accepted one is the Demirjian method, which has already been modified to selected Hungarian population. In this study we have evaluated the association between the dental age determined by panoramic radiography and the chronological age. 199 panoramic radiographs taken from persons between the ages of 2,8 and 20,3 years were selected to the study. The dental ages of persons were estimated either with the Demirjian or the modified Demirjian method adapted to Hungarian population and the results were compared to the chronological ages in selected age groups. Furthermore the angle of the mandible was registered on both sides with an image analysing software. Statistical analysis of data was performed using SPSS software. Our results show that mean values of mandibular angles exhibited a decreasing trend with age. The two age determination methods resulted in different values. Between 3 and 9 years and the age group between 15 and 17,3 years the adapted Hungarian method proved to be more accurate than the Demirjian method. We have established a mathematical function between the two methods. We could conclude that the panoramic radiography based dental age calculation is a reliable method to estimate the chronological age, but the utility of gonial angle has not been proved. PMID- 25509511 TI - [ParC-10 cells for modelling parotid gland tissue reorganization]. AB - Salivary gland hypofunction, which may occur in head and neck cancers following therapeutic irradiation or in Sjogren's syndrome, drastically impair the patient's quality of life. Conventional treatments do not provide a satisfactory solution to the problem, therefore it is becoming increasingly urgent to develop completely new management approaches in particular, the challenge of restoring the function of acini. Many biologically based interventions studied, thus "reprogramming" with gene therapy of survivor ducts or regeneration potential of progenitor cells in the salivary gland. Our research group has been working on several models, which have shown that by using appropriate media containing extracellular proteins (e.g. BME, basal membrane extract) can be achieved acinar differentiation. A significant proportion of in vitro models of salivary gland are submandibular of origin, which however is different from the development and function of parotid. Our research group aimed to model the potential treatment options for salivary gland hypofunction, the carrier or bioactive molecules directed differentiation, as well as the potential of gene therapy on rat parotid derived cell line (Par-C10). In our experiments, we have studied the morphological changes of Par-C10 cells cultured on permeable polyester membrane, or in three-dimensional cultures, using varying concentrations of BME. In addition, we have tested the use of recombinant adenovirus vectors that could modify Par-C10 cells and make them useful in gene therapy models. Our data suggest that Par-C10 cell line is suitable for modelling parotid gland tissue organization and may also serve as a useful gene therapy model system. PMID- 25509512 TI - [Prevention and treatment of bisphosphonate-induced jaw bone osteonecrosis. II]. PMID- 25509513 TI - Where will Obama draw the line on GOP bills to roll back reform? PMID- 25509514 TI - Government GOP victories dim chances for Medicaid expansion. PMID- 25509515 TI - Honing heart care. PMID- 25509516 TI - Hospitals going green. PMID- 25509517 TI - More pressure to control costs. PMID- 25509518 TI - In long term, much good can come from the tragedy of Ebola. PMID- 25509519 TI - 'I think we're finally past the death panels'. PMID- 25509520 TI - Chemical oxygen demand and color removal from textile wastewater by UV/H2O2 using artificial neural networks. AB - The photooxidation of pollutants, especially chemical oxygen demand (COD) and color, in textile industrial wastewater was performed in the presence of hydrogen peroxide (H2O2), using 256 nm UV light (15 W), to model the discoloration and COD elimination processes and characterize the influence of process variables. Within this study, data were obtained through a NeuroSolutions 5.06 model and successfully tested. Each sample was characterized by three independent variables (i.e., pH, H2O2 concentration, and time of operation) and two dependent variables (i.e., color and COD). The results indicated that pH was the predominant variable, and the reaction mean time and H2O2 volume were the less influential variables. The neural model obtained presented coefficients of correlation of 99% for COD and 97% for color, indicating the prediction power of the model and its character of generalization. PMID- 25509521 TI - Effect of short-term exposure of selected aromatic nitrogen compounds on wastewater treatment. AB - The biodegradation of melamine and p-nitrophenol (PNP) and their impact on wastewater treatment was evaluated after a short-term individual chemical loading in activated sludge treatment systems. Melamine was not degraded and quickly washed out of the system. PNP was degraded, but it led to a prolonged period of nitrification inhibition and deterioration of effluent quality. Both melamine and PNP loadings increased the effluent nitrogen concentrations, with their main contributors being melamine and NH4+, respectively. Nitrosomonas and Nitrospira were dominant in the activated sludge. Melamine did not affect the nitrifying assemblages, whereas PNP led to a reduced Nitrosomonas population size and complete washout of Nitrobacter. The results suggest that melamine is an inert compound if it enters the treatment facility for a short duration. Although the short-term exposure of melamine or PNP decreased effluent water quality,the impact of such aromatic nitrogen compounds on wastewater treatment performance may vary significantly. Water PMID- 25509522 TI - Simultaneous removal of pesticides from water by rice husk ash: batch and column studies. AB - The present study evaluated rice husk ash (RHA) as an adsorbent for simultaneous removal of a mixture of seven different pesticides (alachlor, metolachlor, chlorpyriphos, fipronil, alpha-endosulfan, beta-endosulfan, and p,p'-DDT) and two metabolites (p,p'-DDE and endosulfan sulfate) from water. The adsorbent RHA was prepared in the laboratory and characterized by techniques such as X-ray diffraction spectroscopy, Fourier transform infrared spectroscopy, and scanning electron microscopy/energy-dispersive X-ray spectrometry. Adsorption kinetics were well described by the pseudo-second-order kinetic model. The Freundlich isotherm model fitted the equilibrium data better than the Langmuir model, and the maximum sorption capacity varied from 0.078 to 0.166 mg/g. The column elution studies showed that 10 L of mixed pesticide-contaminated water (0.05 mg/L) can be treated with only 10 g of RHA at a removal efficiency of 90%. The results implied that RHA can be used as a low-cost, easily available, and efficient adsorbent for the simultaneous removal of pesticides from contaminated water. PMID- 25509523 TI - Evaluation of anaerobic/anoxic/oxic (A2/O) and reverse A2/O processes in biological nutrient removal. AB - ABSTRACT: A performance comparison between the conventional anaerobic/anoxic/oxic (A2/O) process and the anoxic/anaerobic/oxic (reverse A2/O) process was conducted in lab-scale at the hydraulic retention time of 0.75 d and solids retention time of 10 d for more than 200 days. Both processes demonstrated excellent removal efficiency for organic matter (> 96%) and total nitrogen (> 85%), with no significant difference in microbial activities, sludge phosphorus (P) content, sludge settling property, and nitrifying community (dominated by Nitrosomonas and Nitrospira). However, there was significant difference in P removal, with the total P removal efficiencies in the reverse A2/O and A2/O systems of 76 +/- 6% and 70 +/- 6%, respectively. Placing an anoxic stage before the anaerobic stage in the reverse A2/O process resulted in a lower oxidation-reduction potential (ORP = -268 +/- 45 mV) of the anaerobic zone, which contributed to higher P uptake by bacteria under subsequent aerobic respiration. PMID- 25509524 TI - Operation of fill-and-draw reactors fed with bisphenol A as sole carbon and energy source. AB - While there is ample evidence in the literature that many organic xenobiotics can be biodegraded as sole carbon and energy source by pure batch cultures of selected microorganisms, the same evidence is very limited for continuous or semi continuous mixed-culture processes simulating biological wastewater treatment plants. This study investigates for the first time whether Bisphenol A (BPA) can be removed and used as sole carbon and energy source by mixed microbial cultures in a semi-continuous process. Four fill and draw bioreactors were inoculated with unacclimated soil and operated at various hydraulic retention times (HRT), in the range of 1.7-4.2 d, using a feed composed solely of BPA (115 mg/l), and mineral salts. At steady-state, the BPA removal in the four reactors varied in the range 7.5-19% and did not show a significant trend with the HRT. The maximum growth rate on BPA was measured in the range 0.29-1.54 d-1. PMID- 25509525 TI - Treatment of combined sewer overflows using ferrate (VI). AB - This paper presents the results of a study conducted on the treatment of combined sewer overflows using ferrate (VI) [Fe (VI)]. At a Fe (VI) dose of 0.24 mg/L, total chemical oxygen demand (TCOD), soluble chemical oxygen demand (SCOD), total biochemical oxygen demand (TBOD5), soluble biochemical oxygen demand (SBOD5), total suspended solids (TSS), volatile suspended solids (VSS), total phosphorus (TP), total nitrogen (TN), and soluble TN removal efficiencies of 71, 75, 69, 68, 72, 83, 64, 38, and 36%, respectively, were achieved. Kinetic studies revealed that a contact time of only 15 minutes is sufficient to achieve secondary effluent criteria. An innovative technique of using primary sludge (PS) and thickened waste activated sludge as a source for the in situ synthesis of ferrate was developed. A comparative study of treatment efficiencies achieved by Fe (VI) generated from different sources was done. At 0.1 mg/L dose of Fe (VI) synthesized from PS, TCOD, SCOD, TSS, VSS, TP, and TN removal efficiencies of 60, 62, 63, 67, 30, and 25%, respectively, were achieved. PMID- 25509526 TI - A highly effective photochemical system for complex treatment of heavily contaminated wastewaters. AB - Significant efforts have been committed to the research and development of many advanced oxidation processes, including photocatalytic oxidations with titanium dioxide or the hydrogen peroxide and ferrous/ferric ion (H2O2/Fe2+(Fe3+)/UV (photo-assisted Fenton) process. This study reports the development of a novel photochemical system for complex treatment of heavily contaminated wastewaters based on the use of UV-C light and H2O2. Special attention was focused on the technology employed, including the reactor design, process controls, and performance optimization. The effects of process parameters were studied using 4 chlorophenol (4CP) as model compound, and verification of this treatment technology was assessed using actual contaminated water. Among the most influential parameters were the 4CP concentration, reaction mixture volume, H2O2 concentration, and irradiation intensity. In contrast, for H2O2 dosing (proportional continuous or cumulative one-time), the flow rate did not significantly affect process efficacy. PMID- 25509527 TI - Laboratory comparison of four iron-based filter materials for water treatment of trace element contaminants. AB - A laboratory investigation provided preliminary comparison of trace element contaminant water treatment capabilities for four iron-based filter materials. The iron-based filter materials tested were zero-valent iron (ZVI), porous iron composite (PIC), sulfur modified iron (SMI), and iron oxide/hydroxide (IOH). Two types of trace element contaminant solutions were tested, one combined As, Cr, and Se (added as AsO4(3-), CrO4(2-), and SeO4(2-), respectively), while the second combined Cd2+, Cu2+, and Pb2+. The laboratory investigation included saturated falling-head hydraulic conductivity tests, contaminant removal desorption/dissolution batch tests, and low-to-high flow rate saturated solute transport column tests. Hydraulic conductivity test results indicate that all four iron-based filter materials have sufficient water flow capacity as indicated by saturated hydraulic conductivity values greater than 1 x 10(-2) cm/s. Essentially, 100% of each trace element (As, Cd, Cr, Cu, Pb, and Se) was removed by SMI during the contaminant removal portion of the batch tests and during the column tests, while IOH exhibited good removal of each trace element except Se. Results from the contaminant removal portion of the batch tests and from the column tests showed ZVI and PIC were effective in treating Cd, Cr, Cu, and Pb. With the exception of Se adsorption/precipitation onto IOH, the desorption/dissolution portion of the batch tests showed that once As, Cd, Cr, Cu, Pb, or Se are adsorbed/precipitated onto ZVI, PIC, SMI, or IOH particle surfaces, these trace elements are then not readily desorbed or dissolved back into solution. PMID- 25509528 TI - Multivariate analyses for monitoring EDCs and PPCPs in a lake water. AB - The analysis of endocrine disrupting compounds (EDCs) and pharmaceutical and personal care products (PPCP), present at trace level in surface waters, is often expensive, time-consuming, and complex. Implementing effective monitoring strategies for these compounds is essential to determine the types of analytes, sampling locations, and sampling frequencies. Multivariate analyses were used to investigate the patterns of EDCs and PPCPs in Lake Mead, Nevada, for these purposes. The results of cluster analysis and principal component analysis to identify the patterns among compounds demonstrated that selected pharmaceuticals tended to be present together with each other, whereas hormones did not show patterns with other compounds. The results of cluster analysis and discriminant analysis to investigate the spatial variation of EDCs and PPCPs eliminated redundant sampling locations, verifying the current selection of sampling locations in Lake Mead. The results of autocorrelation provided optimal sampling frequencies for EDCs and PPCPs, suggesting either monthly or quarterly monitoring of these compounds in Lake Mead. The patterns of the compounds could be site specific; depending on weather and hydrological conditions of the water systems, but this study's approaches will facilitate effective assessment and monitoring of EDCs and PPCPs in surface water. PMID- 25509529 TI - Effects of reclaimed waters on spectral properties and leaf traits of citrus orchards. AB - Effects resulting from the use of reclaimed waters on mandarins and grapefruits are evaluated by measuring the spectral responses of their canopies and the anatomy and the chlorophyll content of their leaves against control trees irrigated with waters provided by an interbasin transfer. Spectral responses from the red (R) and near-infrared (NIR) wavelength bands, and its normalized ratio (NDVI), were acquired from a hyperspatial flight conducted after a low-moderate exposition to reclaimed waters. Chlorophyll and leaf and palisade/spongy ratio thicknesses were analyzed after a moderate-high exposition. Significant differences between controls and treatments were detected in mandarins in R and leaf chlorophyll, but not in grapefruits, likely because of their higher tolerance to saline waters. Reused waters did not affect either NIR-NDVI or anatomy traits. Hyperspatial sensing techniques are suitable for detecting chlorophyll dynamics, but NIR information and related vegetation indices may mask the detection of periods of saline stress in citrus orchards. PMID- 25509530 TI - The power of sleep. New research shows a good night's rest isn't a luxury--it's critical for your brain and for your health. PMID- 25509531 TI - How much salt is safe? PMID- 25509532 TI - 'It didn't cross my mind that I wouldn't see him come off that field.' The tragic of risks of an American obsession. PMID- 25509533 TI - Enrollment push targets young and minorities, who may be tough to reach. PMID- 25509534 TI - Exchange improvements raise hopes for open enrollment. PMID- 25509535 TI - Immigration, Ebola will dominate lame-duck session in Congress. PMID- 25509536 TI - A familiar face for the Staten Island community. PMID- 25509537 TI - Leveraging his leadership to help those in need. PMID- 25509538 TI - Rethinking Obamacare marketing. PMID- 25509539 TI - On the VA, Ebola trials and the SHOP exchanges. PMID- 25509540 TI - Creating a strong culture requires leaders who are accountable. PMID- 25509541 TI - Getting past the 'tribal mentality' to improve the patient experience. PMID- 25509542 TI - Comment on Quick, J. C. 2014. Carbon dioxide emission tallies for 210 U.S. coal fired power plants: a comparison of two accounting methods. J Air Waste Manage. Assoc. 64: 73-79. PMID- 25509543 TI - Response to comments by Gurney et al. regarding "Carbon dioxide emission tallies for 210 U.S. coal-fired power plants: a comparison of two accounting methods". PMID- 25509544 TI - Public health and components of particulate matter: the changing assessment of black carbon. PMID- 25509545 TI - Sources of atmospheric nitrous acid: state of the science, current research needs, and future prospects. AB - Nitrous acid (HONO) plays a key role in tropospheric photochemistry, primarily due to its role as a source of hydroxyl (OH) radicals via its rapid photolysis. OH radicals are involved in photooxidation processes, such as the formation of tropospheric 03 and other secondary atmospheric pollutants (peroxyacetyl nitrate/PAN] and secondary particles). Recent field and modeling studies have postulated the occurrence of a strong and unknown daytime HONO source, but there are still many significant uncertainties concerning the identification and formation mechanisms of these unknown sources. Up to now, five HONO formation pathways are known: direct emission, homogeneous gas-phase reactions, heterogeneous reactions, surface photolysis; and biological processes. In this review paper the HONO sources proposed to explain the observed HONO budget, especially during daytime, are discussed, highlighting the knowledge gaps that need further investigation. In this framework it is crucial to have available accurate and reliable measurements of atmospheric HONO concentrations; thus, a short description ofHONO measurement techniques currently available is also reported. The techniquesare divided into three basic categories: spectroscopic techniques, wet chemical techniques, and off-line methods. PMID- 25509546 TI - Characterization of indoor air quality and resident health in an Arizona senior housing apartment building. AB - A survey of key indoor air quality (IAQ) parameters and resident health was carried out in 72 apartments within a single low-income senior housing building in Phoenix, Arizona. Air sampling was carried out simultaneously with a questionnaire on personal habits and general health of residents. Mean PM10 concentrations are 66 +/- 16, 58 +/- 13, and 24 +/- 3 microg/m3 and mean PM2.5 concentrations are 62 +/- 16, 53 +/- 13, and 20 +/- 2 microg/m3 for the living room, kitchen, and outdoor balcony, respectively. Median PM10 concentrations are 17, 18 and 17 microg/m3 and median PM25 concentrations are 13, 14, and 13 microg/m3, respectively. The initial results indicate that increased indoor particle concentrations coincide with residents who report smoking cigarettes. Indoor formaldehyde concentrations revealed median levels of 36.9, 38.8, and 4.3 ppb in the living room, kitchen, and balcony, respectively. Results show that 36% of living room samples and 44% of kitchen samples exceeded the Health Canada REL for chronic exposure to formaldehyde (40 ppb). Associations between occupants' behavior self-reported health conditions, and IAQ are evaluated. PMID- 25509547 TI - Direct N2O decomposition over La2NiO4-based perovskite-type oxides. AB - Direct decomposition of N2O by perovskite-structure catalysts including La2NiO4, LaSrNiO4, and La0.7Ceo.3SrNiO4 was investigated. The catalysts were prepared by the Pechini method and characterized by x-ray diffraction (XRD), BETI scanning electron microscopy (SEM), and 02-TPD. Experimental results indicate that the properties of La2NiO4 are significantly improved by partially substituting La with Sr and Ce. N2O decomposition efficiencies achieved with LaSrNi04 and La0.7Ce0.3SrNiO4 are 44 and 36%, respectively, at 400 degrees C. As the temperature was increased to 600 degrees C, N2O decomposition efficiency achieved with LaSrNiO4 and La0.7Ce0.3SrNiO4 reached 100% at an inlet N2O concentration of 1000 ppm, while the space velocity was fixed at 8,000 hr(-1). In addition, effects of various parameters including oxygen, water vapor and space velocity were also explored. The results indicate that N2O decomposition efficiencies achieved with LaSrNiO4 and La0.7Ce0.3SrNiO4 are not significantly affected as space velocity is increased from 8,000 to 20,000 hr(-1), while La0.7Ce0.3SrNiO4 shows better tolerance for O2 and H2O(g). On the other hand, N2 yield with LaSrNiO4 as catalyst can be significantly improved by doping Ce. At a gas hour space velocity of 8000 hr(-1) and a temperature of 600 degrees C, high N2O decomposition efficiency and N2 yield were maintained throughout the durability test of 60 hr, indicating the long-term stability of La0.7Ce0.3SrNiO4 for N2O decomposition. PMID- 25509548 TI - Assessment of nitrous oxide emission from cement plants: real data measured with both Fourier transform infrared and nondispersive infrared techniques. AB - Nitrous oxide (N2O) is the third most important greenhouse gas after carbon dioxide and methane, and contributes about 6% to the greenhouse effect. Nitrous oxide is a minor component of the atmosphere, and it is a thousand times less than carbon dioxide (CO2). Nevertheless, it is much more potent than CO2 and methane, owing to its long stay in the atmosphere of approximately 120 yr and the high global warmingpotential (GWP) of298 times that of CO2. Although greenhouse gases are natural in the atmosphere, human activities have changed the atmospheric concentrations. Most of the values of emission of nitrous oxide are still obtained by means ofemission factors and not actually measured; the lack ofreal data may result in an underestimation ofcurrent emissions. The emission factors used for the calculation of N2O can be obtained from the "Guidelines for the implementation of the national inventory of emissions" of the Intergovernmental Panel on Climate Change, which refer to all nations for the realization of their inventory. This study will present real data, measured in several Italian cement plants with different characteristics. The work also shows a comparison between N2O concentration measured with in situ-Fourier transform IR (FTIR) and the reference method EN ISO 21258 based on nondispersive IR (NDIR), in order to investigate the interfering compounds in the measurement with NDIR. PMID- 25509549 TI - Major ionic compositions of fine particulate matter in an animal feeding operation facility and its vicinity. AB - Animal feeding operations (AFOs) produce particulate matter (PM) and gaseous pollutants. Investigation of the chemical composition of PM2.5 inside and in the local vicinity of AFOs can help to understand the impact of the AFO emissions on ambient secondary PM formation. This study was conducted on a commercial egg production farm in North Carolina. Samples of PM2.5 were collected from five stations, with one located in an egg production house and the otherfour located in the vicinity ofthe farm alongfour wind directions. The major ions of NH4+, Na+, K+, SO4(2-), Cl-, and NO3- were analyzed using ion chromatography (IC). In the house, the mostly abundant ions were SO4(2-), Cl-, and K+. At ambient stations, SO4(2-), and NH4+ were the two most abundant ions. In the house, NH4+, SO4(2-), and NO3- accounted for only 10% of the PM2.5 mass; at ambient locations, NH4+, SO4(2-), and NO3- accounted for 36-41% of the PM2.5 mass. In the house, NH4+ had small seasonal variations indicating that gas- phase NH3. was not the only major force driving its gas-particle partitioning. At the ambient stations, NH4+ had the highest concentrations in summer In the house, K+, Na+, and Cl- were highly correlated with each other In ambient locations, SO4(2-) and NH4+ had a strong correlation, whereas in the house, SO4(2-) and NH4+ had a very weak correlation. Ambient temperature and solar radiation were positively correlated with NH4+ and SO4(2-). This study suggests that secondary PM formation inside the animal house was not an important source of PM2.5. In the vicinity, NH3 emissions had greater impact on PM2.5 formation. PMID- 25509550 TI - Immobilization of antimony waste slag by applying geopolymerization and stabilization/solidification technologies. AB - During the processing of antimony ore by pyrometallurgical methods, a considerable amount of slag is formed. This antimony waste slag is listed by the European Union as absolutely hazardous waste with a European Waste Catalogue code of 10 08 08. Since the levels of antimony and arsenic in the leachate of the antimony waste slag are generally higher than the landfilling limits, it is necessary to treat the slag before landfilling. In this study, stabilization/solidification and geopolymerization technologies were both applied in order to limit the leaching potential of antimony and arsenic. Different combinations ofpastes by using Portland cement, fly ash, clay, gypsum, and blast furnace slag were prepared as stabilization/solidification or geopoljymer matrixes. Sodium silicate-sodium hydroxide solution and sodium hydroxide solution at 8 M were used as activators for geopolymer samples. Efficiencies of the combinations were evaluated in terms of leaching and unconfined compressive strength. None of the geopolymer samples prepared with the activators yielded arsenic and antimony leaching below the regulatory limit at the same time, although they yielded high unconfined compressive strength levels. On the other hand, the stabilization/solidification samples prepared by using water showed low leaching results meeting the landfilling criteria. Use of gypsum as an additive was found to be successful in immobilizing the arsenic and antimony. PMID- 25509551 TI - Recycling research on spent fluorescent lamps on the basis of extended producer responsibility in China. AB - Mercury is a physiological toxin released by spent fluorescent lamps (SFLs) and is considered a serious pollutant. As the world's largest producer of fluorescent lamps, China suffers from SFL pollution because of inefficient recycling and management of SFLs. Drawing upon the most successful practices worldwide, this paper suggests the recycling of SFLs on the basis of the extended producer responsibility (EPR) system in China. Manufacturers and importers are the main parties responsible for the take-back, recycling, and disposal ofSFLs in the EPR system. In view of the situation in China and to address the objectives of the EPR system, this paper recommends the implementation of a third-party take-back mode for small- and medium-scale enterprises and of a takeback mode for large enterprises to be carried out by original equipment manufacturers. This paper suggests an extended responsibility fund to finance and support the SFL recycling system and discusses in detail the different recycling network systems and fund flows of the two take-back modes. By conducting a case study, the authors determine that the subsidy rate for SFLs that a recycling company can obtain from the extended responsibility fund for recycling and disposing of lamps can be set at $1.35/kg. The authors also predict the levy level that fluorescent lamp manufacturers must submit. PMID- 25509552 TI - Indoor pollution and burning practices in wood stove management. AB - This study evaluates effects of good burning practice and correct installation and management of wood heaters on indoor air pollution in an Italian rural area. The same study attests the role of education in mitigating wood smoke pollution. In August 2007 and winters of 2007 and 2008, in a little mountain village of Liguria Apennines (Italy), indoor and outdoor benzene, toluene, ethylbenzene, and xylene (BTEX) concentrations were measured in nine wood-heated houses. During the first sampling, several mistakes in heating plant installations and management were found in all houses. Indoor BTEX concentrations increased during use of wood burning. Low toluene/benzene ratios were in agreement with wood smoke as main indoor and outdoor pollution source. Other BTEX sources were identified as the indoor use ofsolvents andpaints and incense burning. Results obtained during 2007 were presented and discussed with homeowners. Following this preventive intervention, in the second winter sampling all indoor BTEX concentrations decreased, in spite of the colder outdoor air temperatures. Information provided to families has induced the adoption of effective good practices in stoves and fire management. These results highlight the importance ofeducation, supported by reliable data on air pollution, as an effective method to reduce wood smoke exposures. PMID- 25509554 TI - Computational fluid dynamics modeling of laboratory flames and an industrial flare. AB - A computational fluid dynamics (CFD) methodology for simulating the combustion process has been validated with experimental results. Three different types of experimental setups were used to validate the CFD model. These setups include an industrial-scale flare setups and two lab-scale flames. The CFD study also involved three different fuels: C3H6/CH/Air/N2, C2H4/O2/Ar and CH4/Air. In the first setup, flare efficiency data from the Texas Commission on Environmental Quality (TCEQ) 2010 field tests were used to validate the CFD model. In the second setup, a McKenna burner with flat flames was simulated. Temperature and mass fractions of important species were compared with the experimental data. Finally, results of an experimental study done at Sandia National Laboratories to generate a lifted jet flame were used for the purpose of validation. The reduced 50 species mechanism, LU 1.1, the realizable k-epsilon turbulence model, and the EDC turbulence-chemistry interaction model were usedfor this work. Flare efficiency, axial profiles of temperature, and mass fractions of various intermediate species obtained in the simulation were compared with experimental data and a good agreement between the profiles was clearly observed. In particular the simulation match with the TCEQ 2010 flare tests has been significantly improved (within 5% of the data) compared to the results reported by Singh et al. in 2012. Validation of the speciated flat flame data supports the view that flares can be a primary source offormaldehyde emission. PMID- 25509553 TI - Characterization and seasonal variations of levoglucosan in fine particulate matter in Xi'an, China. AB - PM2.5 (particulate matter with an aerodynamic diameter <2.5 microm) samples (n = 58) collected every sixth day in Xi'an, China, from 5 July 2008 to 27 June 2009 are analyzed for levoglucosan (1,6-anhydro-beta-D-glucopyranose) to evaluate the impacts of biomass combustion on ambient concentrations. Twenty-four-hour levoglucosan concentrations displayed clear summer minima and winter maxima that ranged from 46 to 1889 ng m(-3), with an average of 428 +/- 399 ng m(-3). Besides agricultural burning, biomass/biofuel combustion for household heating with straws and branches appears to be of regional importance during the heating season in northwestern China. Good correlations (0.70 < R < 0.91) were found between levoglucosan relative to water- soluble K+, Cl-, organic carbon (OC), elemental carbon (EC), and glyoxal. The highest levoglucosan/OC ratio of2.3% wasfound in winter, followed by autumn (1.5%). Biomass burning contributed to 5.1 43.8% of OC (with an average of 17.6 +/- 8.4%). PMID- 25509555 TI - Life after war. Veterans of Iraq and Afghanistan are battling lasting wounds- both visisble and invisible. PMID- 25509556 TI - "Gender specific medicine": a focus on gender-differences in hypertension. AB - Hypertension, worldwide considered the most frequent disease, is one of the major contributors to the leading cause of death in women: cardiovascular diseases. Until recently, women have been underestimated in clinical trials. Menopause represents the moment when the so-called "female advantage" is reversed. This review is presenting some gender-specific differences that explain why women are more exposed, especially if obesity is present in post-menopausal women, to hypertension complications. The smaller percentage of optimal controlled blood pressure values in hypertensive women is explained by a lesser adherence to lifestyle modifications and to drug therapy. All these gender-associated differences must be considered in hypertension management of women. PMID- 25509557 TI - Small intestinal bacterial overgrowth is associated to symptoms in irritable bowel syndrome. Evidence from a multicentre study in Romania. AB - BACKGROUND AND AIMS: Small intestinal bacterial overgrowth (SIBO) is involved in the pathogenesis of irritable bowel syndrome (IBS). It has been suggested that by treating SIBO in IBS, symptoms may be improved. The aim of this study was to evaluate the prevalence of SIBO in patients with IBS compared with healthy volunteers (HV), to assess the effect of an intestinal antibiotic in eradicating SIBO and on the symptoms, in patients with IBS. METHODS: Design: a cross sectional multicentre study with cohort comparison performed in 6 medical centers from Romania. 331 consecutive patients diagnosed with IBS according to Rome III criteria and 105 HV were screened for SIBO using glucose hydrogen breath test (GHBT). Positive patients received 7 days therapy with the antibiotic rifaximin 1200 mg/day and were retested 1 week after completing the treatment. The IBS symptoms were assessed before and after treatment. The group was controlled with 20 age and sex matched IBS patients who did not receive any antibiotic therapy for their condition (control patients). RESULTS: SIBO was found in 105 patients with IBS (31.7%) and in 7 HV (6.6%) (OR= 6.5, p < 0.0001). Patients with IBS have been classified according to Rome III criteria into 4 groups: IBS-constipation, IBS-diarrhea, IBS-mixed (alternation of constipation/and diarrhea) and IBS unclassified. Diarrhea and mixed symptoms were found to be predictive for SIBO (OR= 2.5 for IBS-diarrhea and OR = 2.23 for mixed). Among patients with SIBO, 85.5% were found negative after treatment (p = 0.0026). SIBO patients showed an important relief of their symptoms, with complete improvement in 46.6% and partial in 31.4%. CONCLUSIONS: This study is the first to estimate the prevalence of SIBO in ibs patients from Romania (31.7%). SIBO was present in nearly half of the IBS-D patients (45.7%). Rifaximin is effective in treating SIBO in IBS patients and controlled trials are warranted. PMID- 25509558 TI - Factors affecting colonoscopy comfort and compliance: a questionnaire based multicenter study. AB - AIMS: Colonoscopy screening reduces colorectal cancer-related mortality and incidence. However, many patients are reluctant to undergo colonoscopy or return for follow-up because of the investigation's cumbersome and unpleasant nature. We aimed to identify patient-related factors significantly influencing comfort and quality of colonoscopy analyzing responses to a self-administered validated questionnaire. METHODS: Patients undergoing colonoscopy under sedation in two high-volume endoscopy units were invited to answer a short prevalidated questionnaire regarding preprocedure anxiety, satisfaction with information provided, most worrisome aspect of the procedure and knowledge of the benefits of colonoscopy. Self-reported comfort during colonoscopy as graded on a 10 point visual analog scale was the main variable considered. Univariate analysis identified factors possibly associated with a higher degree of comfort during colonoscopy that were then tested through multivariate logistical regression. RESULTS: 452 questionnaires were returned. Most patients reported an acceptable degree of discomfort during colonoscopy but 70.2% of the respondents considered the information provided prior to the procedure to be insufficient. On multivariate analysis older age, higher degree of satisfaction with information provided (p = 0.04), lower preprocedure anxiety levels (p < 0.01) and endoscopy center (p < 0.01) were shown to correlate with increased comfort during colonoscopy. Education level, previous colonoscopy, gender and bowel prep quality did not influence patient comfort. CONCLUSIONS: Patient comfort during colonoscopy is dependent on satisfaction with the information provided before the procedure. Higher availability of the physician and better interaction with the patient might decrease patient perceived burden of colonoscopy and lead to higher return rates in the screening and surveillance setting. PMID- 25509559 TI - Surprising good antioxidant status in patients with Balkan Endemic Nephropathy on hemodialysis undergoing vitamin C therapy. A pilot study. AB - AIMS: End Stage Renal Disease (ESRD) represents a microinflammatory state accompanied by oxidative stress and an imbalance between pro- and antioxidants. Vitamin C is a highly effective antioxidant, acting to lessen oxidative stress. The aim of our study was to assess the Antioxidant Capacity of Water soluble substances (ACW) and the Antioxidant Capacity of Liposoluble substances (ACL) in patients with Balkan Endemic Nephropathy (BEN) on hemodialysis undergoing Vitamin C therapy as compared to healthy controls. METHODS: Twenty-one patients with BEN on hemodialysis (HD), mean age: 63.33 +/- 5.42 years, 6 M and 15 F, were enrolled into the study. All patients received 10 vials of Vitamin C 750 mg/5 ml every 2 months. Eleven apparently healthy subjects, mean age: 63.73 +/- 5.21 years, 6 M and 5 F, served as controls. The photochemiluminescence assay was used to measure the antioxidant activity of plasma samples. The results are presented in equivalent concentration units of Vitamin C for water soluble antioxidants and in equivalent concentration units of Trolox (synthetic Vitamin E) for lipid soluble antioxidants. Both concentrations are expressed in micromols/L. Statistical analysis (non-parametric Wilcoxon test) was performed using NCSS. RESULTS: Mean duration since BEN diagnosis was: 8.24 +/- 3.5 years. Mean duration since HD initiation was: 4.92 +/- 3.4 years. Smoking status was negative in all patients. Hypertension was present in 15 patients (71.42%), cardiovascular disease in 10 (47.61%), HCV infection in 13 (61.9%), 1 patient had HBV + HCV infection, 1 had renal tuberculosis, 1 had upper urinary tract cancer, 1 genital cancer, and I autoimmune thyroid disease. The Antioxidant Capacity of Water soluble substances (ACW) in patients with BEN was 477.6 +/- 177.63 micromols/L, significantly higher as compared to controls: 198.05 +/- 196.63 micromols/L; p = 0.01, whereas the Antioxidant Capacity of Liposoluble substances (ACL) in patients with BEN was 33.9 +/- 22.99 micromols/L, non-significantly different as compared to controls: 27.38 +/- 4.21 micromols/L; p = 0.22. CONCLUSIONS: We conclude that Vitamin C therapy in patients with BEN on HD significantly increases the Antioxidant Capacity of Water soluble substances (ACW) as compared to controls and could be used to counter oxidative stress in patients with ESRD. PMID- 25509560 TI - DRESS syndrome with hepatic involvement in a patient with depressive disorder. AB - We present a 31-year-old woman with a depressive disorder admitted in the Infectious Diseases Department with high fever, cervical lymphadenopathy, generalized rash and progressive jaundice. Sepsis with hepatic involvement was initially suspected, but the bacteriological and serological profiles for viral and bacterial pathogens remained negative. The exposure to antidepressant medication including lamotrigine, an aromatic anticonvulsant molecule, raised the suspicion of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome. The antidepressants were withdrawn and methylprednisolone therapy was started with a favorable outcome and lent recovery after two months. This case highlights a rare drug allergic complication to antidepressant medication evolving as a sepsis with hepatic dysfunction. PMID- 25509561 TI - Ischemic strokes in a young patient with dermatomyositis, systemic lupus erythematosus and secondary antiphospholipid syndrome mimicking herpetic encephalitis. AB - A 44-year-old right-handed Caucasian male was initialy diagnosed in 2007 with dermatomyositis (DM) and in 2009 with systemic lupus erythematosus (SLE) (overlap syndrome). He was treated with Methylprednisolone and Hydroxychloroquine. He interrupted the treatment in the last three years. The patient presented with fever (39.8 degrees C), left zoster ophthalmicus, headache and psychomotor agitation. The cerebral CT scan showed left hemispheric hypodense lesions. Herpetic encephalitis was suspected. The patient was referred to the Institute of Infectious Diseases. The patient's neurological status worsened, he presented spastic tetraparesis and aphasia. DW-MRI, ADC, DS and AngioMRI were done, the patient proved to have an ischemic stroke due to acute thrombosis of the left internal carotid artery and multiple watershed infarctions. An infectious pathology, including HSV-1, was excluded by PLEX ID performed from CSF. Acyclovir, anti vitamin K, steroidal intravenous pulse therapy was started. The patient was referred after two weeks to the Department of Neurology. Mild inflammatory syndrome, tests for anti-double stain DNA (dsDNA), anti-Sm, anti SSA, IgM and IgG anti-cardiolipin antibodies and lupus anticoagulant were positive. He was currently treated with Methylprednisolone (48 mg/d), anti vitamin K, statin, symptomatics. The outcome was favorable, with good laboratory response. Overlap syndrome may be associated with a significant increase in the risk of stroke. Our case presented without clinically susceptible symptoms of stroke but found to have stroke after neurological assessment associated with overlap syndrome (DM and SLE). PMID- 25509562 TI - Long-standing ulcerative colitis complicated with mantle-cell lymphoma transformed in diffuse large B cell lymphoma. AB - Ulcerative colitis (UC) is a chronic, relapsing inflammatory disease of the colon and rectum. Its etiology and pathogenesis are incompletely elucidated, although there are many studies concerning these problems. Chronic inflammation and immunosuppressive treatment are risk factors for epithelial and lymphoid malignancies. We present a case of a 39-year-old man who died after a long standing untreated UC complicated with mantle cell colonic lymphoma and then with transformation towards a high grade diffuse large B cell lymphoma. Multiple colonic biopsies were collected in various moments of the disease. Microscopic and immunohistochemical features are comparatively presented. This case emphasizes the importance of constant surveillance for UC patients and reaffirms the role of multidisciplinary approach in UC management. PMID- 25509563 TI - Child abuse in the irritable bowel syndrome. AB - Stress is considered a risk factor for the irritable bowel syndrome (IBS). One of the main stress sources is represented by the negative life events and trauma suffered in childhood. Several papers have endorsed the hypothesis that youth submitted to stress are prone to develop IBS. We have undertaken a review of the literature, searching all Pubmed papers pertinent to child abuse and IBS. The data suggest that indeed, children submitted to physical, psychological and sexual abuse are at risk to develop IBS as adults. However, cultural diffferences exist. PMID- 25509564 TI - The role of heavy metals in autoimmunity. AB - Our understanding of autoimmune diseases has progressed tremendously in the past 20 years. Estimates of the prevalence of autoimmune diseases in the population may be 4% or higher. It is evident that heavy metals present serious risk to human health. Heavy metals are capable of altering the immune response; they have been implicated in influencing autoimmunity. In fact, they are usually inhibitory to immune cell proliferation and activation. This paper reviews the possible mechanisms which may play a role in metal-induced autoimmunity. A better understanding of these interactions remains a priority for the future. PMID- 25509566 TI - Delivering change. A new angle on public involvement. PMID- 25509565 TI - Functional and morphological alterations induced by Helicobacter pylori infection in gastric nerve supply. AB - Helicobacterpylori (HP) infection is the most common cause of many gastric diseases. One of its pathogenic mechanisms involves the production of a wide spectrum of alterations in different components of the gastric enteric nervous system. Changes in neural circuitry encompass structural abnormalities, sensitive and motor function impairment, altered content and release of neurotransmitters, and seem to be related rather to the inflammatory response of gastric wall than to the bacterial colonization. Although gathered data provide new insights into the complex mechanisms underlying the interactions between HP and enteric nervous system, there still are some controversial aspects. Interestingly, it has been suggested that impaired neural activity might have a potential role in gastric carcinogenesis, but this hypothesis requires further investigation. Future studies shall, therefore, elucidate the neuromodulatory influences of Helicobacter pylori infection on the enteric nervous system. A better comprehension on neural changes during HP-induced inflammation could help in identifying new therapeutic options. PMID- 25509567 TI - On the challenge to better engage with patients. PMID- 25509568 TI - Treatment of BME and foreign staff in the NHS. Race inequality exposes erosion of NHS values. PMID- 25509569 TI - NHS rationing is inevitable. . PMID- 25509570 TI - NHS land should go to affordable housing. PMID- 25509571 TI - Public and patient involvement. Sync tech and care for better health. PMID- 25509572 TI - Workforce. The role of NHS scientists under the microscope. PMID- 25509573 TI - Welcome change, don't wait for it. PMID- 25509574 TI - Stand up for yourself. PMID- 25509575 TI - Balancing "we" and "me". AB - The open office is the dominant form of workspace design for good reason: It fosters collaboration, promotes learning, and nurtures strong culture. But what most companies fail to realize is that collaboration has a natural rhythm that requires both interaction and private contemplation. Companies have been trying for decades to find the balance between public and private workspace that best supports collaboration. In 1980 52% of U.S. employees lacked workspaces where they could concentrate without distraction. In response, high-walled cubicles took over the corporate landscape. By the late 1990s, the tide had turned, and only 23% of employees wanted more privacy, and 50% wanted more access to other people. Ever since, firms have been beefing up spaces that support collaboration and shrinking areas for individual work. But the pendulum seems to have swung too far: Once again, people feel a pressing need for privacy, not only to do heads down work but to cope with the intensity of work today. To address these needs, according to the authors, we have to rethink our assumptions about privacy. Traditionally defined in physical terms, privacy is now about the individual's ability to control information and stimulation. In this article, the authors examine workspace design through the new lens of privacy and offer insights on how to foster teamwork and solitude. PMID- 25509576 TI - The transparency trap. AB - To promote accountability, productivity, and shared learning, many organizations create open work environments and gather reams of data on how individuals spend their time. A few years ago, HBS professor Ethan Bernstein set out to find empirical evidence that such approaches improve organizational performance. What he discovered is that this kind of transparency often has an unintended consequence: It can leave employees feeling vulnerable and exposed. When that happens, they conceal any conduct that deviates from the norm so that they won't have to explain it. Unrehearsed, experimental behaviors sometimes stop altogether. But Bernstein also discovered organizations that had established zones of privacy within open environments by setting four types of boundaries: around teams, between feedback and evaluation, between decision rights and improvement rights, and around periods of experimentation. Moreover, across several studies, the companies that had done all this were the ones that consistently got the most creative, efficient, and thoughtful work from their employees. Bernstein's conclusion? By balancing transparency and privacy, organizations can capture the benefits of both, and encourage just the right amount of "positive deviance" needed to increase innovation and productivity. PMID- 25509577 TI - Workspaces that move people. AB - Few companies measure whether the design of their workspaces helps or hurts performance, but they should. The authors have collected data that capture individuals' interactions, communications, and location information. They've learned that face-to-face interactions are by far the most important activity in an office; creating chance encounters between knowledge workers, both inside and outside the organization, improves performance. The Norwegian telecom company Telenor was ahead of its time in 2003, when it incorporated "hot desking" (no assigned seats) and spaces that could easily be reconfigured for different tasks and evolving teams. The CEO credits the design of the offices with helping Telenor shift from a state-run monopoly to a competitive multinational carrier with 150 million subscribers. In another example, data collected at one pharmaceuticals company showed that when a salesperson increased interactions with coworkers on other teams by 10%, his or her sales increased by 10%. To get the sales staff running into colleagues from other departments, management shifted from one coffee machine for every six employees to one for every 120 and created a new large cafeteria for everyone. Sales rose by 20%, or $200 million, afterjust one quarter, quickly justifying the capital investment in the redesign. PMID- 25509578 TI - How to stop Ebola. The latest epidemic sheds light on a little-known industry that could change the way we treat virus diseases. PMID- 25509579 TI - Can a tech strike force fix Washington? PMID- 25509580 TI - Advocate-NorthShore merger continues trend toward regional supersystems. PMID- 25509582 TI - CMS delays dialysis center ratings. PMID- 25509581 TI - Joan Rivers' death highlights risks in outpatient surgery for seniors. PMID- 25509583 TI - Providers working with Apple on smartwatch to connect with patients. PMID- 25509585 TI - Enrollment anxieties. Complex consumer choices pose challenges for outreach groups, plans and providers. PMID- 25509584 TI - Flagging protected patient data. PMID- 25509587 TI - Hospitals excel--in administrative costs. PMID- 25509586 TI - Our misplaced disease preparedness priorities. PMID- 25509588 TI - 'Peaks and valleys' in admissions prove costly. PMID- 25509589 TI - Engaging patients at Intermountain. PMID- 25509590 TI - Less care will be provided and paid for in the hospital. PMID- 25509591 TI - Liberia struggles in fight against Ebola. PMID- 25509592 TI - Who's afraid of a little vaccine? PMID- 25509593 TI - Spotlight on physician payments. PMID- 25509594 TI - When the tiny hospital can't survive. Free-standing EDs with primary care seen as new rural model. PMID- 25509595 TI - An evangelist for employee engagement. PMID- 25509596 TI - Best practices for promoting healthcare through marketing. PMID- 25509597 TI - Best practices for running an educational campaign. PMID- 25509598 TI - Beware the sophomore slump. AB - All the trends are positive as the insurance industry, the government and healthcare reform advocates gear up for the second year of open enrollment on the federal and state-run insurance exchanges. Competition is up. Price increases are modest. And politicians who thought they could ride Obamacare attack ads to election victory are finding most voters have moved on. PMID- 25509599 TI - What's at stake in effort to diminish 340B program. PMID- 25509600 TI - Custom-fit your journey to improved patient safety. PMID- 25509601 TI - Nurses need to be thought leaders and decisionmakers in the transformation of healthcare. PMID- 25509602 TI - Inova saves by cutting red-bag waste. PMID- 25509603 TI - Now arriving. The deadly Ebola virus lands in America. PMID- 25509604 TI - Racing Ebola. What the world needs to do to stop the deadly virus. PMID- 25509605 TI - Era of medical-device tracking finally arrives. PMID- 25509606 TI - High court wary about dental board's antitrust exemption. PMID- 25509607 TI - At home with the specialist. Oncologists and other specialists launching patient centered medical homes. PMID- 25509608 TI - The fire this time. PMID- 25509609 TI - Health IT: successes and missed opportunities. PMID- 25509610 TI - Thinking about growing Kindred's primary-care doc capability. . PMID- 25509611 TI - WATSON Watson, Come here. I want you. Johnson & Johnson's CEO enlists IBM's big data service to find new drugs. PMID- 25509612 TI - Republicans strategize attack on Obamacare if they win the Senate. PMID- 25509613 TI - Medicaid expansion's fate may hang on governors' races. PMID- 25509614 TI - Clumsy Ebola response tests country's faith in health leaders. PMID- 25509615 TI - Reform latecomers. Afraid of getting left behind, big insurers expand exchange participation for 2015. PMID- 25509616 TI - Providers and plans target big push to boost Medicaid enrollment. PMID- 25509617 TI - Casting light on a simpler pricing system. PMID- 25509618 TI - Learning the lessons of Ebola as events continue to unfold. PMID- 25509619 TI - Collaboration among key attributes of successful medical practices. PMID- 25509620 TI - CDC demonstrates new Ebola protocols. PMID- 25509621 TI - Seeing momentum toward repealing the ACA device tax. PMID- 25509623 TI - The Best Places to work in healthcare 2014. PMID- 25509622 TI - Best Places promote positive culture where employees can thrive. PMID- 25509624 TI - Suppliers. Best Places to work in healthcare 2014 (1 of 3). PMID- 25509625 TI - Best Providers and insurers. Places to work in healthcare 2014 (1 of 3). PMID- 25509626 TI - 'We want to be perfect'. SOMC works to keep employee-satisfaction rate above 90%. PMID- 25509627 TI - Always listening. Communication with employees key at the Women's Hospital. PMID- 25509628 TI - Commitment to satisfaction. St. Martin employees sign pledge to be supportive, respectful. PMID- 25509629 TI - Emphasizing the mission. Advisory Board Co. aims to unleash workers' capabilities. PMID- 25509630 TI - Making work life-affirming. Louisiana Organ Procurement Agency fosters 'positivity'. PMID- 25509631 TI - A culture of respect, integrity. Intelligent InSites relies on employee engagement to track progress. . PMID- 25509632 TI - Introduction. Analysis and synthesis in medieval and early modern Europe. PMID- 25509633 TI - Mercury and sulphur among the High Medieval alchemists: from Razi and Avicenna to Albertus Magnus and pseudo-Roger Bacon. AB - This essay challenges the often expressed view that the principles of metals, namely mercury and sulphur, were generally viewed by alchemists as being of a 'metaphysical' character that made them inaccessible to the tools and operations of the laboratory. By examining a number of Arabo-Latin and Latin alchemical texts in circulation before the end of the thirteenth century, the author presents evidence that most alchemists of the period considered mercury and sulphur to be materials subject to techniques of purification in the same way that naturally occurring salts and minerals could be freed of their impurities or dross. The article also points to the immense influence of Avicenna and Albertus Magnus in formulating the theory that mercury and sulphur were compounds of different materials, containing both fixed and unfixed components. Finally, the author briefly examines the relationship between this materialist approach to the principles and the chymical atomism of early modern authors who were deeply aware of medieval alchemical literature. PMID- 25509634 TI - Corporeal elements and principles in the learned German chymical tradition. AB - This paper explores diverse conceptions of the physicality and tangibility of elements and principles in early modern chymistry. By tracing the development of natural philosophical and corpuscular ideas about material elements and principles among several physicans and chymists, including Thomas Erastus, Andreas Libavius, Daniel Sennert, and Anton Gunther Billich, this article locates a learned tradition that developed predominantly in Germany, and which directly challenged a common understanding of matter held by major Paracelsians as well as authors from the French textbook tradition. Likewise, conceptions of incorporeal elements or principles are shown to have developed from the ideas of Paracelsus and Petrus Severinus, whereas authors in the learned tradition emphasised a particular interpretation of Aristotle. The article concludes by suggesting that chymical interpretations of material composition had an important influence throughout the seventeenth and eighteenth centuries, and that this provides further evidence that the so-called "compositional revolution" in chemistry was well underway prior to the eighteenth century. PMID- 25509635 TI - Hermetic atomism: Christian Adolph Balduin (1632-1682), Aurum Aurae, and the 1674 phosphor. AB - The synthesis of phosphors, or light-bearing matter, figured largely among the activities of early scientific societies and within the first scientific journals. They were prestige objects during the formative institutionalisation of experimental natural philosophy. Nevertheless, early phosphors have often appeared within the historiography of chemistry as a throwback to an earlier era. They have been represented as a fundamental epistemic and theoretical divide between a mystical alchemy (exemplified by Christian Adolph Balduin) and modern chemistry (prefigured by progressives such as Robert Boyle). The parallel phosphoric researches of Boyle and Balduin belie this divide. Recovering the theoretical context of Balduin's phosphor can both resituate it in relation to phosphoric research of the 1670s and 1680s, as well as further illuminate the intellectual sources and development of chymical atomism. PMID- 25509636 TI - Fire analysis in the eighteenth century: Herman Boerhaave and scepticism about the elements. AB - In the eighteenth century, many chemists asserted that chemical operations could not decompose a substance into its natural, constituent elements or principles. One such chemist was Herman Boerhaave (1668-1738), who claimed, following the work of Robert Boyle and Joan Baptista van Helmont, that examples of these alleged analyses were, in fact, not reductions of a body into elements, but rather the rearrangement of its particles by the fire. Since we cannot observe the shape and arrangement of particles directly, he reasoned, any claim regarding the elemental status of a substance was purely speculative and inadmissible in his chemistry. As a result, Boerhaave devised a system of chemistry which, in effect, accepted no elemental substances and which focused on understanding how the chemist's 'instruments,' including fire and chemical menstrua, effected changes in matter. I conclude by showing how Boerhaave's conclusion had ramifications for later developments in chemistry, especially those of the French Stahlians and of Antione Lavoisier. PMID- 25509637 TI - Nuclear markets, nuclear bodies. PMID- 25509638 TI - [Causes of stillbirths according to the period of pregnancy]. AB - INTRODUCTION: Stillbirths represent 50% of all perinatal mortality and remain significant and unanswered problem. OBJECTIVE: To investigate the causes of stillbirths in term and preterm fetuses and place of intrauterine growth retardation in the pathogenesis of antenatal death. MATERIALS AND METHODS: The study was retrospective for the period 2008 to 2013, covers 217 cases of stillbirths in University Hospital "Maichin dom" Sofia. Gestational age was from 23 to 41 weeks. Inclusion criteria for the study were: antenatal occurred dead and singleton pregnancy. Exclusion criteria: fetal malformations and multiple pregnancies. Thus number of enrolled cases was 153. RESULTS: The causes of stillbirths are different in different groups according gestational age. The cases of unknown cause, abruption of placenta and preeclampsia prevail in preterm group. The term stillborns headed with pathology of the umbilical cord, followed by cases of unknown cause, diabetes and infection. Overall, preterm group stillborn with mass below 10 percentile for the gestational age - 53 % predominate, compared with those born at term - 39%. CONCLUSIONS: The incidence of stillbirths is higher in preterm than term born fetuses. The causes of antenatal death in preterm is mainly abruption of placenta and preeclampsia, whereas in term - pathology of the umbilical cord. In premature stillborn intrauterine growth retardation is more common in comparison with those on term. Unexplained antenatal fetal death is more common in preterm fetuses. PMID- 25509639 TI - [Risk factors for bacterial vaginosis - a 3-year study in four medical centers]. AB - BACKGROUND: Bacterial vaginosis (BV) is the most common infection of the lower genital tract among women of reproductive age. The purpose of this study was to determine the frequency of BV and the important etiological agent Gardnerella vaginalis in Bulgarian patients of different age groups, as well as, the risk factors forBV METHODS: One thousand five hundred and twenty-three (1523) women aged 16 to 45 years without previous antimicrobial therapy were included in this study. The methods used were: scoring of Gram staining of vaginal smear and polymerase chain reaction (PCR) assay for G. vaginalis. RESULTS: Positive for BV according to the microscopic examination criteria were 47.80% from the 1523 tested women. In 88.87% from the positive samples G. vaginalis was detected using PCR, thus demonstrating high comparability of the both methods and the leading role of G. vaginalis. The most affected with BV is the age group of 21-25 years (33.21% of all subjects with BV). The most important detected risk factors were: smoking (more than 55% with BV), single marital status (only 15% with BV are married), more than I sexual partner (more than 36% had changed the sexual partner), early onset of sexual activity (75% of B V asocciated subjects started their sexual activity by the age 15-18 years). CONCLUSIONS: The established early age for aquiring BV among Bulgarian women is very important and alarming sign. This is the first study on the etiological role of G. vaginalis and on the risk factors for BV in Bulgaria. PMID- 25509640 TI - [Types of screening for congenital diseases - results in Bulgaria, conclusions and future objectives]. AB - Bulgarian statistics of recent years (2008-2012) indicate weak knowledge and use of the various screenings . Low percentage of pregnant passed screening tests and improper interpretation of the calculated risks, has led on the one hand to the high percentage of invasive diagnostics in the surveyed population (6% instead of 3%) to diagnose 90% of pregnancies with trisomy 21, and at the same time low percentage diagnosed pregnancies with Down's syndrome in the population of all pregnant women (tested and untested). We are performing invasive procedures of almost all pregnant women over 35 years old, and instead of the screening in the 1st trimester, we still use the screening in the 2nd trimester which is with limited application in Europe because of the high rate of false positive (false positive rate) and the unsatisfactory rate of recognized pregnancies with chromosomal defects (detedtion rate 70%). OBJECTIVE: To make the analysis of screening data, in the 1st and 2nd trimester for the period 2008-2012 in the Hospital "Maichin Dom" and our Center for Prenatal Diagnosis (respectively 93956 and 5046 pregnant women observed), the percentage of invasive diagnostic and percent diagnosed with Down syndr. in the total number of pregnancies, 99002 versus the number born with the disease in the country according to data of the National Statistical Institute. METHODS AND MATERIALS Used was the algorytm of FMF London to assess the effectiveness of the various screenings (Prof Nikolaides et al.) more specific for each of them - Detection rate and False positive rate, and statistical meta-analyses of H. Cuckle and D. Wright, for the estimated number of pregnancies with Down syndr.and the expected percentage of invasive diagnostics for locating over 90% of them in a population of 100,000 pregnant women. RESULTS: 99002 Surveyed pregnancies for the period 2008-2012 are around 25% of the total population (377,040 births), there are 7645 invasive procedures (i.e. 7,7 % of the expected 3%) and are diagnosed with Down's syndrome pregnancies were 181 from statistically expected about 200 (i.e., 90%) in the same period, 152 babies are born with TRI 21. CONCLUSIONS: In terms of the lack of a National Strategy for screening for congenital diseases, non-compliance with the principles and protocols for consultation of patients about the results obtained and generally poor knowledge of the various screenings have led to the negative attitude of the doctors and patients to screening programs and low percentage of pregnant women targeted or seeking such tests (about 30%) and a high percentage of invasive diagnosis (due to the high percentage of false positive rate and incorrect interpretation of the calculated risks). PMID- 25509641 TI - [Laparoscopic vs abdominal myomectomy]. AB - The aim of this study is to determine the most appropriate method for operative treatment of uterine myoma through comparison of laparoscopic myomectomy (LM) and abdominal myomectomy (AM). We will examine perioperative indicators and results for patients with uterine myomas. We operated 172 women for the period from January 2011 to April 2014. 106 patients were operated by abdominal myomectomy and 66 were operated by laparoscopic myomectomy. In this study were included only cases with intramural fibroids bigger than 5 cm. We explored the following indicators: age, BMI, preoperative Hgb, preoperative Hct, size, number and location of the myomas for both groups. We analyzed intra- and postoperative indicators operating time, hospital stay, postoperative Hgb and Hct. Data shows less postoperative decrease of Hgb and Hct, less blood loss, shorter hospital stay for the group with laparoscopic myomectomy, but significantly increased operative time compared to the group with abdominal myomectomy. PMID- 25509642 TI - [Implication of PAI-1 4G/5G polymorphism in recurrent implantation failure after IVF]. AB - During implantation, an accurate balance of coagulation, fibrin deposition and fibrinolysis is mandatory for trophoblastic invasion. Inhibition of fibrinolysis after increased activity of plasminogen activator inhibitors such as PAI-1 could impair properdeep trophoblastic invasion. This study investigated correlation between increased PAI-1 levels due to gene polymorphism (PL) 4G/5G and recurrent implantation failure after IVF procedure. Sixty one women with two or more unsuccessful IVF procedure after good quality embryo transfer and 97 health women with at least one normal delivery were investigated for carrier status for PL 4G/5G (genotype 4G/4G) and serum levels of anti-cardiolipin (ACA) and anti-beta2 glycoprotein antibody level (IgG and IgM type). The prevalence of genotype 4G/4G in women with RIF was about two times higher compared to controls although the difference did not rich significance (respectively 41% and 26.8%, OR 1.9, 95%CI 0.91-3.96, p=0.09). The prevalence of polymorphism was similar after exclusion of for women with elevated levels of ACA (respectively 42.1% and 26.8%, OR 1.99, 95%CI 0.94-4.21, p=0.075). PL 4G/5G could be possible risk factor forimpaired embryo implantation. The causative hypofibrinolysis due to increased PAI-1 levels should be interpreted in context of multifactor complexity of recurrent implantation failure development. A discussion remains for fraction heparin application and endometrial receptivity modulation in very early pregnancy wastage. PMID- 25509643 TI - [Factors family background of mothers involved in having a premature baby]. AB - Level of prematurity is an objective criterion for determining the health welfare of the population. Several family background factors of the mother increases the risk of preterm birth child - family status, unwanted pregnancy, etc. Pregnancy among unmarried women and unwanted pregnancy are associated with a higher risk of giving premature baby. Aim of this study is a survey and analysis of factors of family background of the mother (family status and unplanned pregnancy) and their influence on the birth of a premature baby. The survey found nearly three times higher risk OR = 2,83 95 % CI (1,7-4,7) for the birth of a premature baby among unmarried mothers compared to married women, and twice as high proportion of unplanned pregnancy mothers of preterm infants - 20.7% compared to terminfants 10.4%. PMID- 25509645 TI - [Neonatal hypoxic-ischemic brain injury: pathogenesis and neuropathology]. AB - The perinatal period represents a clinical setting of potential risk for injury to developing brain secondary to many causes, with the chance for long-lasting, profound neurocognitive deficits. Neonatal hypoxic-ischemic brain injury leads to serious long-term morbidities. The leading pathogenetic mechanisms are hypoxia and/or ischemia, as a result of perinatal asphyxia. Understanding of the underlying pathophysiology will help the physicians in the general supportive management and neuroprotection of the neonatal brain. PMID- 25509644 TI - [Pulmonary hypertension of the newborn - mechanisms of failed circulatory adaptation after birth, clinical presentation and diagnosis]. AB - This article reviews the recent advances in understanding the mechanisms of the persistent pulmonary hypertension of the newborn, the pathways for persistence of high pulmonary vascular resistance and disruption of the normal perinatal fetal to neonatal circulatory transition. Despite the advancements of the neonatal intensive care in the last decades pulmonary hypertension of the newborn represents a clinical, diagnostic and treatment challenge for neonatologists. In most cases pulmonary hypertension is a secondary complication of a primary disease of the fetus and newborn characterized by failure to decrease the pulmonary vascular resistance after birth associated with right to left shunts, severe hypoxemia and respiratory failure. This review discuss the factors involved in the regulation of the transition from fetal circulation with high pulmonary vascular resistance to postnatal circulation with low pulmonary vascular resistance, the balance between the vasoconstrictor and vasodilator mediators. The better understanding of these mechanisms is helpful for accurate diagnosis and appropriate treatment of pulmonary hypertension of the newborn. PMID- 25509646 TI - [Gestational surrogacy - sin, whim or necessity]. AB - The authors propose the gestational surrogacy to be permitted but only for medical indications and under exact requirements. The surrogate mother if married, her husband, too, sign with the commissioning adopting couple a legal agreement at the beginning of the procedures. PMID- 25509647 TI - [A case of gynandroblastoma in a 16-year old girl and review of literature]. AB - An ovarian tumor (gynandroblastoma) in a 16-year old girl is reported. Clinical presentation include abdominal pain, signs of virilization and irregular menstrual cycles. Ultrasound scan examination reveals a cystic mass in a left ovary. The patient underwent a left ovariosalpingectomy Grossly, a cystic mass (73x 42 x 36 mm) with smooth outersurface and with many cysts was found in the left ovary The intraoperative diagnosis was ovarian adenocarcinoma. Postoperative histological examination reveals that the tumor was presented by two patterns - nodules and nests of juvenile granulose cell pattern admixed with Sertoli-Leydig pattern as tubules and cyst and scanty Sertoli cells. On immunohistochemical staining the Granulosa cells were negative for cytokeratin AE1-AE3 and positive for Vimentin. The Sertoli cells were androgen receptor positive. A yar after operation the patient had no abdominal pain, the menstrual cycles are regular, but virilization persist. Histogenesis and differential diagnosis are discussed. PMID- 25509648 TI - [Sentinel lymph node biopsy in endometrial cancer - methods]. AB - Endometrial canceris the most common gynaecological malignancy after brest cancer. The lymph node status is with great prognostic value and it is important for postoperative treatment and survival. That is why it is looking for methods giving information for the lymph node status and not increasing postoperative complications. PMID- 25509649 TI - Sorting through new reimbursement models. An assortment of new payment models are available in attempts to fix the fee-for-service imbalance. PMID- 25509650 TI - Demystifying Medicare's: 'incident to' billing by NPs, PAs. PMID- 25509651 TI - Bundling services saves time, money. PMID- 25509652 TI - Is it the right time for you to buy another practice? PMID- 25509653 TI - Business of health series. Helping your patients kick the smoking habit. PMID- 25509654 TI - HIPAA: Training critical to protect patients, practice. . PMID- 25509655 TI - Finding the value of employee satisfaction. PMID- 25509656 TI - Making the EHR your partner in patient care. PMID- 25509657 TI - EHRs are good for patient care, doctors say. PMID- 25509658 TI - Three reasons to add behavioral health. PMID- 25509659 TI - Devicemakers challenged on resistance to value-based payment. PMID- 25509660 TI - Home dialysis grows despite cost and logistical hurdles. PMID- 25509661 TI - New strategies to curb specialty drug costs. PMID- 25509662 TI - U.S.-European partnerships improve care on both sides of the Atlantic. AB - The U.S. healthcare system is often compared to European systems in unflattering terms, yet European systems are under growing pressure to increase their care quality and efficiency. Many are looking to the U.S. for innovative, proven solutions. There is much that we can learn from each other, and newly formed collaborations are providing one vehicle for that learning. PMID- 25509663 TI - Nursing home cuts antipsychotic drug use. PMID- 25509664 TI - 'We have to stop the tide of community hospitals being closed'. PMID- 25509665 TI - Dallas error in releasing Ebola patient puts hospitals on alert. PMID- 25509666 TI - Teaching hospitals got $315 million in industry payments, CMS data show. PMID- 25509667 TI - Healthcare's hired hands. When the stakes rise in Washington, healthcare interests seek well-connected lobbying firms. PMID- 25509668 TI - Proponents see cloud technology transforming radiology. PMID- 25509669 TI - Election's senior moments. Candidates lob Medicare charges despite small odds of big changes in 2015. PMID- 25509670 TI - The value in exposing conflicts of interest. PMID- 25509671 TI - Focus on patient experience drives changes in the C-suite. PMID- 25509672 TI - No one ever complains about a CEO being paid too little. PMID- 25509673 TI - HSA growth and the associated opportunities/challenges presented by pharmacy benefits. AB - Consumer-driven health plans (CDHPs) have grown steadily and significantly over the past ten years in terms of covered employees, enrollment and assets under management. The authors explain the reasons for this growth and how CDHPs address health care costs. They discuss how pharmacy benefits present some of the greatest opportunities and challenges for CDHP growth. Challenges center on recent research that revealed decreased utilization and adherence among members of a CDHP population in four out of the five therapeutic categories examined. Although an influx of generic drugs has entered the marketplace, specialty pharmacy drugs will more than offset those savings, increasing the threat of noncompliance. Nonetheless, with appropriate design and implementation, CDHPs can be very effective for both employers and their employees. PMID- 25509674 TI - Pharmacy and consumer-directed accounts. AB - Employers must make informed design andimplementation choices in order for consumer-directed accounts to optimize the performance of pharmacy benefit strategies. Strategies must contemplate the prevalence of consumer-directed accounts, emerging technologies that support them and the potential impact on employee choices. Employers that align these factors may deliver pharmacy benefits at a lower cost and have an advantage over competitors. In pursuing this end, employers also may play a significant role in making health care affordable to as many Americans as possible. PMID- 25509675 TI - CDHPs: as enrollment goes up, a time to tune up. AB - One of the clearest findings of Mercer's annual National Survey of Employer Sponsored Health Plans is that more companies are thinking of adopting a consumer directed health plan (CDHP) approach, and more employees are enrolling in CDHPs at the companies that offer them. The authors discuss the advantages for organizations that offer CDHPs, as well as outline key considerations for companies looking to update, optimize and align their CDHPs with the realities of health care reform. They also explain how CDHPs go hand in hand with wellness and health management strategies, both of which increase collaboration between employees and employers to control costs and give employees more personal responsibility for better outcomes. PMID- 25509676 TI - Exemption from ACA contraception requirement. Burwell v. Hobby Lobby Stores, Inc., 2014 WL 2921709, (2014). PMID- 25509677 TI - Statute of limitations must be reasonable. Heimeshoff v Hartford Life & Accident Insurance Co., 134 S Ct. 604 (2013). PMID- 25509678 TI - Donning and doffing protective gear is "changing clothes". Sandifer v U. S. Steel Corp., 134 S. Ct. 870 (2014). PMID- 25509679 TI - Q.... PMID- 25509680 TI - Rotating goblet and talking profiles: does a rotating goblet increase the figural dominance of profiles in Rubin's type of figure-ground reversal patterns? AB - We present a novel three-dimensional (3-D) version of Rubin's classical bistable goblet-profiles figure. An actual goblet sculpture was produced and rotated on a turntable in front of a white background. As the goblet rotates about its central axis, small circular asymmetries around the lips and chin region give a clear impression of two white profiles talking to each other. Although the profiles actually correspond to empty space or white background, they are more likely to be perceived as 'figure' than the 3-D goblet itself. Four experiments that presented the actual goblet (experiment 1) or two-dimensional (2-D) movies of it (experiments 2-4) were designed to verify these observations. We measured perceptual dominance of profiles as 'figure' and rate of reversal as a function of three factors: motion (static vs rotating), orientation (upright vs inverted), and configuration (face-to-face vs back-to-back). Results for the rotating goblet showed a statistically reliable preference for perceiving the talking profiles as 'figure'. Deforming the profiles by manipulating the vertex angle of the mouth region produced an inverted U-shaped curve with the peak representing the stimulus condition in which the profiles perception was most remarkable. We discussed a number of 3-D and 2-D figure-ground factors that might apply to this rather complex stimulus situation. PMID- 25509681 TI - The shape of a hole is perceived as the shape of its interior. AB - In typical figure-ground displays the figure has shape and is perceived as being in front, whereas the ground is shapeless and recedes to the back. The recent literature on the visual perception of holes has questioned the nature of this coupling between shape and depth both theoretically and empirically. In this paper we provide a theoretical framework that clarifies the underlying issues and we report new evidence supporting the view that the shape of a hole is perceived as the shape of its interior region. Palmer, Davis, Nelson, and Rock (2008 Perception, 37, 1569-1586) showed that the shape of the interior region of a hole is remembered as such, even though the surface visible through it is perceived as farther in depth. The present paper extends this evidence to perceiving holes. Participants performed a speeded shape-matching task in which they compared a surrounded interior region (of either a hole or an object) or its exterior complement with one of several shapes. The results indicate that holes are perceived as shaped in the same way as their material counterparts. We conclude that the shape of a hole is encoded as the shape of its interior region, even though that region contains no surface material. These results can be reconciled with recent experiments that have provided evidence that holes are perceived differently from their material counterparts. PMID- 25509682 TI - Homing by path integration when a locomotion trajectory crosses itself. AB - Path integration is a process with which navigators derive their current position and orientation by integrating self-motion signals along a locomotion trajectory. It has been suggested that path integration becomes disproportionately erroneous when the trajectory crosses itself. However, there is a possibility that this previous finding was confounded by effects of the length of a traveled path and the amount of turns experienced along the path, two factors that are known to affect path integration performance. The present study was designed to investigate whether the crossover of a locomotion trajectory truly increases errors of path integration. In an experiment, blindfolded human navigators were guided along four paths that varied in their lengths and turns, and attempted to walk directly back to the beginning of the paths. Only one of the four paths contained a crossover. Results showed that errors yielded from the path containing the crossover were not always larger than those observed in other paths, and the errors were attributed solely to the effects of longer path lengths or greater degrees of turns. These results demonstrated that path crossover does not always cause significant disruption in path integration processes. Implications of the present findings for models of path integration are discussed. PMID- 25509683 TI - The big picture: effects of surround on immersion and size perception. AB - Despite the fear of the entertainment industry that illegal downloads of films might ruin their business, going to the movies continues to be a popular leisure activity. One reason why people prefer to watch movies in cinemas may be the surround of the movie screen or its physically huge size. To disentangle the factors that might contribute to the size impression, we tested several measures of subjective size and immersion in different viewing environments. For this purpose we built a model cinema that provided visual angle information comparable with that of a real cinema. Subjects watched identical movie clips in a real cinema, a model cinema, and on a display monitor in isolation. Whereas the isolated display monitor was inferior, the addition of a contextual model improved the viewing immersion to the extent that it was comparable with the movie theater experience, provided the viewing angle remained the same. In a further study we built an identical but even smaller model cinema to unconfound visual angle and viewing distance. Both model cinemas produced similar results. There was a trend for the larger screen to be more immersive; however, viewing angle did not play a role in how the movie was evaluated. PMID- 25509684 TI - Two sensory channels mediate perception of fingertip force. AB - In two experiments we examined the ability of humans to exert forces accurately with the fingertips, and to perceive those forces. In experiment 1 participants used visual feedback to apply a range of fingertip forces with the distal pad of the thumb. Participants made magnitude discriminations regarding these forces, and their just noticeable differences were calculated at a series of standards by means of a two-interval, forced-choice tracking paradigm. As the standard increased, participants demonstrated a relative improvement in force discrimination; and the presence of a possible inflection point, at approximately 400 g, suggested that two sensory channels may contribute to performance. If this is the case, the operative channel at low forces is almost certainly the slowly adapting type I (SA-I) channel, while another mechanoreceptor class, the SA-II nail unit, is a plausible mediator of the more accurate performance seen at high force levels. To test this two-channel hypothesis in experiment 2, we hydrated participants' thumbnails in order to reduce nail rigidity and thus prevent stimulation of underlying SA-II mechanoreceptors. This technique was found to reduce sensory accuracy in a force-matching task at high forces (1000 g) while leaving low force matching (100 g) unimpaired. Taken together, these results suggest that two sensory channels mediate the perception of fingertip forces in humans: one channel predominating at low forces (below approximately 400 g) and another responsible for perceiving high forces which is likely mediated by the SA II nail unit. PMID- 25509685 TI - Improved beat asynchrony detection in early blind individuals. AB - Although early blind (EB) individuals are thought to have a better musical sense than sighted subjects, no study has investigated the musical rhythm and beat processing abilities in EB individuals. Using an adaptive 'up and down' procedure, we measured the beat asynchrony detection threshold and the duration discrimination threshold, in the auditory and vibrotactile modalities in both EB and sighted control (SC) subjects matched for age, gender, and musical experience. We observed that EB subjects were better than SC in the beat asynchrony detection task; that is, they showed lower thresholds than SC, both in the auditory and in the vibrotactile modalities. In addition, EB subjects had a lower threshold than SC for duration discrimination in the vibrotactile modality only. These improved beat asynchrony detection abilities may contribute to the known excellent musical abilities often observed in many blind subjects. PMID- 25509686 TI - Proximal-distal, not medial-lateral, movement across an edge increases discrimination of edge sharpness. AB - Edges are fundamental properties of our environment and the objects we interact with. There is a lack of research on the haptic perception of edges, especially the sharpness of an edge. Skinner et al. [2013 PLoS ONE, 8(9): e73283] found that haptic discriminability of sharpness was clearly superior when using a relatively unrestrained, free exploration strategy compared with a static single touch strategy. In the free exploration condition two distinct movement patterns were frequently used by participants: a proximal-distal movement of the fingerpad across the test edge and a medial-lateral movement of the fingerpad along the test edge. Here, using the same stimuli and two-alternative forced-choice method of constant stimuli as Skinner et al. (2013), we demonstrate that a proximal distal movement results in substantially lower sharpness discrimination thresholds than a medial-lateral movement. The underlying neurophysiology and implications for the design of haptic displays are considered. PMID- 25509687 TI - Dissociation of prediction from conscious perception. AB - The framework of predictive coding offers a parsimonious explanation for many perceptual phenomena. According to this framework, perception of the outer world is created by the comparison of incoming sensory information with an internal predictive model based on previous experience and context. However, it is unclear whether the predicted percept needs to enter conscious awareness for the internal predictive model to be effective. Here we used an apparent motion paradigm to show that while prediction and conscious awareness of a predicted percept may coincide, a dissociation can be observed. When sensory information provides reliable input for the internal predictive model, the predicted percept does not have to be consciously perceived for successful prediction. However, when sensory input is ambiguous, conscious awareness helps the prediction to take effect. PMID- 25509688 TI - Obituary: Adam Gelbtuch (1921-2014). PMID- 25509689 TI - Early detection of subclinical edema in chronic kidney disease patients by bioelectrical impedance analysis. AB - BACKGROUND: Abnormalities in body water distribution are common in chronic kidney disease (CKD) patients. Volume expansion, even in the absence of overt edema, contributes to high blood pressure, and progressive volume expansion eventually leads to clinical edema and fluid overload. Total body water (TBW) can be accurately estimated by multifrequency bioelectrical impedance analysis (MF-BIA) which has been proposed for earlier detection of subclinical edema in CKD patients. OBJECTIVE: To study body fluid distribution and edematous states in CKD patients measured by MF-BIA, compared with clinical edema assessed by physical examination. In addition, to evaluate the correlation of MF-BIA estimated TBW and anthropometry-derived TBW calculated by Watson formula. MATERIAL AND METHOD: CKD patients at Rajavithi Hospital together with healthy adults were prospectively enrolled during a 12-month period. The body fluid compositions assessed by bioelectrical impedance analyzer (InBody(r) S20, Republic of Korea) were taken immediately after physical examination for edema detection. The patients were categorized into stages 1 to 5 according to CKD staging in the NKF-K/DOQI guidelines, and reclassified into 3 groups of stages l-2, stages 3-4, and stage 5. RESULTS: Sixty-nine CKD patients were compared with 48 healthy volunteers. The estimated glomerular filtration rate (GFR) in CKD patients and normal controls were 53.5+/-41.1 and 113.9+/-0.8 ml/min/1.73 m2 respectively. The extracellular water (ECW) to TBW ratio, which represents edematous state if higher than 0.4, was significantly higher in patients with CKD stages 3-4 (0.400+/-0.008) and stage 5 (0.404+/-0.011), than in those in CKD stages 1-2 (0.393+/-0.009) and controls (0.385+/-0.007) (p<0.001). The prevalence of edematous state detected by BIA (edema-BIA) in CKD patients was significantly greater than in normal controls (78.3% vs. 25.0%, p<0.001). The number of CKD patients with edema-BIA was also significantly higher than the number of patients with clinical edema (36.2%), which represented a significant proportion of patients (42.1%) with subclinical edema. The sensitivity and specificity of edema detected by physical examination in all CKD patients compared to the assessment by MF-BIA were 44.4% and 93.3% respectively. There was a significant correlation between the TBW calculated by the Watson formula and TBW estimated by MF-BIA (r2 = 0.848, p<0.001). CONCLUSION: The present study demonstrated that assessment of body fluid distribution by MF BIA was a reliable measure. Subclinical edema actually occurred in early stages of CKD before detection of overt edema by physical examination. TBW calculated by Watson formula can alternatively be used for evaluation of hydration status and can assist physicians in prescribing appropriate management for CKD patients. PMID- 25509690 TI - Prognostic role of thyroid transcription factor-1 (TTF-1) in advanced and inoperable adenocarcinoma subtype of lung cancer among Thai patients. AB - OBJECTIVE: To determine the role of thyroid transcription factor-1 (TTF-1) as a prognostic factor in advanced adenocarcinoma of non-small cell lung cancer. MATERIAL AND METHOD: Retrospective cohort study among lung cancer patients with inoperable or metastases, adenocarcinoma type whose tumors were already tested for TTF-1 in Rajavithi Hospital from December 2003 to November 2011. The correlation of TTF-1 to survival period and the treatment outcomes were defined. RESULTS: Of 67 patients, 48 TTF-1 positive cases and 19 TTF-1 negative cases were included in the analysis. Median overall survival for all population was 263 days (111-415 days). No significant difference was found between TTF-1 positive and negative tumors (251 and 369 days, p-value = 0.8). The systemic treatment with chemotherapy was the only effective prognostic factor for survival of this study. CONCLUSION: The prognostic factor of TTF-1 positive and negative in advanced adenocarcinoma subtype of NSCLC was not different in median overall survival. PMID- 25509691 TI - Association of colonic diverticular disease and irritable bowel syndrome in Thai patients. AB - BACKGROUND: Colonic diverticular disease exhibits mucosal outpouchings through the large intestine. Common complications of this disease are diverticular bleeding and diverticulitis. Some patients with colonic diverticular disease have abdominal symptoms resembling irritable bowel syndrome (IBS). IBS is a functional gastrointestinal disorder with abdominal discomfort, bloating or pain associated with disturbed defecation and unclear etiology. Some studies have shown a high prevalence of colonic diverticular disease in patients with IBS. OBJECTIVE: To determine the association, clinical characteristics and factors associated with colonic diverticular disease in IBS patients compared with a control group. MATERIAL AND METHOD: A cross-sectional prospective study was conducted at the Gastroenterology Unit, Department of Medicine, Rajavithi Hospital, Bangkok during December 2007 to January 2009. The study collected data regarding clinical characteristics, demographics and colonoscopic findings of colonic diverticular disease comparing among IBS patients, defined by Rome III criteria and control group patients. The study was approved by the institutional ethics committee of Rajavithi Hospital. Demographic data of patients were collected. The presence of diverticula, their location and number from colonoscopic findings were recorded. RESULTS: One hundred and fifty patients were enrolled and analyzed. The patients comprised 75 patients in the IBS group and 75 patients in the control group. The prevalence ofcolonic diverticular disease in the total population was 17.3% (26 of 150). The IBS group had a higher prevalence of colonic diverticular disease than the control group with statistical significance (18 of 75, 24.0% in the IBS group vs. 8 of 75 or 10.7% in the control group, p = 0.031). Body mass index (BMI) more than 25 kg/m2, age more than 60 years and being male were associated with colonic diverticular disease without significance (28.1% in BMI >25 kg/m2 vs. 14.3% in BMI <=25 kg/m2, p = 0.071, 23.0% in age >60 years vs. 13.5% in age <=60 years, p = 0.132 and 20.3% males vs. 15.1% females, p = 0.406). Type of IBS (IBS-C vs. IBS-D) did not affect the prevalence of colonic diverticular disease (25.8% in IBS-C and 23.1% in IBS-D, p = 0.791). There were no difference in the location of colonic diverticular disease and number ofdiverticuli between the IBS group and control group (p = 0.149 and 0.095). CONCLUSION: An increased frequency of colonic diverticular disease was observed in patients with IBS. Increasing age, high BMI and being male were factors associated with colonic diverticular disease. These results suggest that IBS and colonic diverticular disease may have a common pathogenesis. PMID- 25509692 TI - Prevalence of hypertension in suspected hypertensive patients in Rajavithi Hospital using ambulatory blood pressure monitoring. AB - BACKGROUND: Hypertension (HTN) is one of the most important health problems in Thailand and worldwide. The accuracy of diagnosis of HTN is crucial to avoid adverse reactions from medications and reduce treatment costs. In 2011, The National Institute for Health and Clinical Excellence (NICE) recommended a diagnostic guidelines for hypertension using ambulatory blood pressure monitoring (ABPM) aiming to exclude patients with white coat hypertension (WCH). We investigated the prevalence of HTN in suspected hypertensive patients at Rajavithi Hospital according to the NICE guidelines and factors associated with WCH. OBJECTIVE: To determine the prevalence of HTN in suspected hypertensive patients at Rajavithi Hospital according to the NICE guidelines (using ABPM) and risk factors associated with WCH. MATERIAL AND METHOD: This cross-sectional study enrolled 31 subjects, age 18-80 years, with systolic blood pressure (SBP) >=140 mmHg and/or diastolic blood pressure (DBP) >=90 mmHg in the Outpatient Department at Rajavithi Hospital from March 2012 to December 2012. All participants had never had a diagnosis of HTN or been treated with anti hypertensive medications in the past four weeks. 24-hour ABPM was used to confirm the diagnosis of HTN based on daytime average blood pressure >=135/85 mmHg. Subjects with an average daytime blood pressure below 135/85 mmHg were defined as having WCH. RESULTS: Among 31 subjects, 17 (54.8%) were confirmed to have HTN and 14 (45.2%) had WCH. Subjects with true HTN had a mean clinical blood pressure of 157.88+/ 7.68/94.24+/-6.56 mmHg when measured at the initial presentation using a sphygmomanometer whereas subjects with WCH had a mean clinic blood pressure of 148.18+/-7.06/89.39+/-4.10 mmHg. Mean SBP and DBP were significantly lower among WCH subjects (p = 0.001 and p = 0.018 respectively). Age, sex, smoking, alcohol consumption, BMI, lipid profile, uric acid and hemoglobin levels were not associated with the diagnosis of WCH. CONCLUSION: The prevalence of hypertension in suspected hypertensive patients using ABPM was 54.8%. WCH should be suspected in patients with relatively lower clinic BP. We proposed that ABPM should be used to confirm the diagnosis of HTN according to the NICE guidelines as a standard practice among ambulatory patients suspected of having HTN. PMID- 25509693 TI - Effects of vitamin E on chronic hepatitis C genotype 3: a randomized, double blind, placebo-controlled study. AB - BACKGROUND: Hepatitis C virus (HCV) infection is associated with chronic inflammation and oxidative damage, with hepatic steatosis being common in genotype 3 cases. Vitamin E, a potent antioxidant protective against oxidative stress-induced liver damage in vitro and in vivo, has beneficial effects on alanine aminotransferase (ALT) and histological outcomes in patients with non alcoholic steatohepatitis. OBJECTIVE: To assess the effect of vitamin E on ALT status in patients with HCV genotype 3. MATERIAL AND METHOD: This randomized, placebo-controlled, double-blind trial was conducted in a single tertiary-care hospital (Rajavithi Hospital, Bangkok) between 2010 and 2011. We included patients with HCV genotype 3 infection, unable to receive or tolerate, or did not respond to standard therapy. Responders were defined as patients exhibiting a decrease in serum ALT of at least 5% below the baseline value after 12 weeks of treatment. RESULTS: Thirty-seven eligible patients were randomly assigned either to receive vitamin E 400 IU twice daily (n = 19) or placebo (n = 18; 1 dropped outearly) for 12 weeks. In all, 11 of 19 patients in the vitamin E group (57.8%) and 5 of 17 patients in the placebo group (29.4%) were ALT responders. Among responders, serum ALT levels were greatly decreased in the vitamin E group (reducing from 122.6+/-80.1 IU/L to 68.4+/-25.3 IU/L, p = 0.016), when compared with the placebo group (reducing from 89.2+/-40.6 IU/L to 73.6+/-30.6 IU/L, p > 0.05). Vitamin E treatment was well-tolerated with no serious adverse events in the present study. CONCLUSION: Vitamin E treatment decreased serum ALT levels in patients with HCV genotype 3. Because of its good safety profile, vitamin E may be a worthwhile supportive therapy for patients with HCV particularly for those who were unable to achieve viral eradication by standard therapy. PMID- 25509694 TI - Correlation of anemia and clinical outcomes in heart failure at Rajavithi Hospital. AB - BACKGROUND: Anemia is one of the precipitating factors leading to congestive heart failure. Although much data indicate that anemia is associated with worsening clinical outcomes in heart failure patients, only few studies have been conducted on the subjects in Thailand. Hence, the researchers decided to study about this issue. OBJECTIVE: The present study aimed to evaluate whether anemia could have adverse effects on mortality and morbidity rates in patients with a diagnosis of heart failure. MATERIAL AND METHOD: A retrospective cross-sectional study was performed by collecting data from medical records of patients who were admitted in Rajavithi Hospital due to congestive heart failure from January 1, 2011 to December 31, 2012. Those data showed a total 486 patients with congestive heart failure treated during the period. Of the 486 patients, 18 were excluded on the basis of selection criteria, a total of 468. These selected patients were divided in two groups, one group of congestive heart failure patients with anemia (n = 221) and another group of congestive heart failure patients without anemia (n = 247). RESULTS: The study showed that the mortality rate in patients with the anemia group was 8.6%, whereas among nonanemic patients no deaths were reported (0%) [p-value <0.0001]. Patients with anemia had a higher incidence of no restoration of spontaneous circulation after Cardiopulmonary resuscitation (3.62%) than nonanemic patients (0%) [p-value = 0.002]. No difference was observed in the use of inotropic drugs between the two groups [p-value = 0.078]. The patients with anemia (14.75+/-20.31 days) had a longer duration of hospital admission than nonanemic patients (7.12+/-8.57 days) [p-value <0.0001]. CONCLUSION: Anemia was associated with increased morbidity and mortality rate among heart failure patients. The mortality rate tended to increases in correlation with the severity of the anemia. Moreover blood transfusion after congestive heart failure occurrence may not reduce the mortality rate. PMID- 25509695 TI - Determination of urinary neutrophil gelatinase-associated lipocalin (NGAL) cut off level for early detection of acute kidney injury in Thai adult patients undergoing open cardiac surgery. AB - BACKGROUND: Acute kidney injury (AKI) is a common complication in patients undergoing open cardiac surgery. Urinary neutrophil gelatinase-associated lipocalin (UNGAL) is an early marker of AKI, however its predictive value in adult patients undergoing open cardiac surgery has never been investigated in Thailand. OBJECTIVE: The present study aimed to determine the cut-off level of UNGAL for predicting AKI in adult patients undergoing open cardiac surgery and also to determine the risk factors for AKI development. MATERIAL AND METHOD: In all, 130 patients at Rajavithi Hospital were prospectively enrolled during a six month period UNGAL was obtained at baseline before surgery, and at 0, 3, and 6 hours after surgery and assessed by ARCHITECT NGAL assay. Serum creatinine levels were measured at baseline before surgery simultaneously for the collection of UNGAL and then daily after surgery. AKI was defined as an increment in serum creatinine of >=0.3 mg/dl within 48 hours according to the Acute Kidney Injury network (AKIN) criteria. RESULTS: Forty-six patients (35.4%) developed AKI, and 80.4% of these patients had the onset of AKI within the first 6 hours after surgery. In this group, UNGAL increased significantly at 0, 3, and 6 hours after surgery compared with patients without AK. UNGAL at 3 hours after surgery was the best time-point for predicting AKI. The cut-off value was >11.3 ng/ml with the sensitivity and specificity of 72% and 60%, respectively. By univariate analysis, older age, lower ejection fraction, impaired baseline renal function and longer cardiopulmonary bypass (CPB) time were clinical factors associated with AKI. However by multivariate analysis, only lower ejection fraction and longer CPB time were associated with AKI. CONCLUSION: UNGAL level may be a useful marker for predicting AKI in Thai adult patients undergoing open cardiac surgery. Lower ejection fraction and longer CPB time were two major risk factors for AKI development. PMID- 25509696 TI - Comparison effect of loading calcitriol and titrating calcitriol treatment to control hypocalcemia after parathyroidectomy in chronic kidney disease: randomized control trial, open labeled. AB - BACKGROUND: Postoperative parathyroidectomy hypocalcemia probably results from acute reversal of the parathyroid hormone induced contribution of bone to maintain serum calcium concentration. OBJECTIVE: Compare the effective treatment of calcitriol regimens (loaded and titrated) in control hypocalcemic hyperparathyroid (HPT) patients who were referred for parathyroidectomy. MATERIAL AND METHOD: A randomized control, open labeled study of 25 patients who underwent parathyroidectomy in Rajavithi Hospital from August 2009 to September 2010 was conducted. The authors randomized 25 patients with chronic kidney disease in two treatment arms of calcitriol (A: Titrated dose regimen, B: Loaded dose regimen), that met criteria. Biochemical factors available within 2 weeks before and after surgery were recorded and analyzed. RESULT: No significant difference was observed in amount of calcium gluconate intravenous use, hypocalcemia and hospital admission durations between titrated and loaded regimen groups, i.e., p = 0.160, 0.645 and 0.460, respectively. Loaded regimen ameliorated the mean reduction of day 7 postoperative mean change of serum calcium level by 0.33+/ 0.99 mg/dl and median change by 2.88 mg/dl (min, max = -0.80, 5.64) compared with titrate regimen mean change ofserum calcium level by 2.68+/-2.16 mg/dl; median change 0.28 mg/dl (min, max = -0.84, 1.80) with significance, p = 0.036. CONCLUSION: Loaded calcitriol regimen was superior to titrated calcitriol regimen compared with the control group the first 7 days postparathyroidectomy. Amount of calcium gluconate intravenous used, hypocalcemia and duration of hospital stay did not show any significance. PMID- 25509697 TI - Prevalence of asymptomatic gastroduodenal lesions and Helicobacter pylori infection in kidney transplant candidates. AB - BACKGROUND: Upper gastrointestinal (UGI) diseases are more common in patients with end-stage renal disease (ESRD) compared to general populations. Previous studies demonstrated that ESRD patients with UGI disease are at increased risk for developing complications following kidney transplantation (KT). Prevalence of UGI lesions and Helicobacter pylori in asymptomatic KT candidates remain unclear OBJECTIVE: To evaluate the prevalence of UGI lesions and Helicobacter pylori in nondyspeptic KT candidates. MATERIAL AND METHOD: The authors retrospectively and prospectively enrolled consecutive patients with ESRD who underwent esophagogastroduodenoscopy (EGD) as part of pre-KT evaluation at a single tertiary center (Rajavithi Hospital, Bangkok) between 2008 and 2013. Patients with significant dyspeptic symptoms, known UGI disease and received PPI/NSAIDs/antibiotics within two weeks before EGD were excluded. EGD was performed with random biopsies for rapid urease test and histology. RESULTS: In all, 107 ESRD patients were included; 53.0% were men and a median age was 38.7 (15.9-65.0) years. A total of 95% of patients had been on hemodialysis with the median duration of 2.1 (0.2-15.3) years. Significant EGD findings (defined as lesions other than normal and nonerosive gastritis) were encountered in 46% of patients; most lesions were erosive gastroduodenitis and peptic ulcers. Among several baseline demographic and laboratory parameters analyzed, only older age was significantly associated with significant EGD findings (p = 0.026). Helicobacter pylori infection was documented in 27.1% of patients. This prevalence tended to be lower than the prevalence of H. pylori of 39% in 105 sex- and age-matched, nonESRD patients without significant EGD findings who underwent EGD during the same time, but not statistically significant (p = 0.08). CONCLUSION: The authors demonstrated a considerable prevalence of acid-related UGI diseases and H. pylori infection in nondyspeptic KT candidates. Therefore, EGD is a reasonable part of routine preKT evaluations, at least in our part of the world, to promptly detect and precisely manage the problem. PMID- 25509698 TI - Quality of life in advanced non-small cell lung cancer receiving chemotherapy of platinum combination in old versus new standard chemotherapy regimen. AB - BACKGROUND AND OBJECTIVE: Non-small cell lung cancers (NSCLC) mostly are adenocarcinoma but minor squamous cell carcinoma is related to smoking. Surgery has a major role in early stage with chemotherapy or radiation in advanced stage. Platinum combination chemotherapy could increase the progression free survival which may be combined with etoposide as the old standard regimen or paclitaxel/gemcitabine as the new standard regimen with slightly more benefit. This study was conducted to evaluate quality of life (QoL) and response of chemotherapy. MATERIAL AND METHOD: The prospective study in advanced NSCLC enrolled 88 patients receiving chemotherapy with old or new standard regimen in the Oncology Unit, Medicine Department of Rajavithi Hospital from January 2004 to December 2009. The assessments were composed of the result of treatment and QoL evaluated by Functional Assessment of Cancer Therapy-Lung Cancer (FACT-L) in both groups. RESULTS: The 88 advanced NSCLC patients received old standard chemotherapy 49 cases and new standard chemotherapy 39 cases. No statistically significant difference was found in baseline characteristics and most had adenocarcinoma subtype. The overall QoL scores before and after treatment were similar except a slight decrease in social/family well-being. The overall response rate was increased in the new standard regimen group compared with the old regimen group (61.5% versus 24.5%) but without statistical difference in median progression free survival (23 and 20 weeks, respectively). CONCLUSION: New standard chemotherapy regimen demonstrated increased overall response rate and without decreased QoL. PMID- 25509699 TI - Chronic venous disease treated with endovenous microwave ablation: long-terms results and quality of life. AB - BACKGROUND: Microwave ablation is considered to be safe for treatment in chronic venous disease patients, but data is lacking about its long-terms results. The present study aimed to evaluate the effectiveness of endovenous microwave ablation. MATERIAL AND METHOD: From January 2009-June 2012, 100 patients underwent endovenous microwave ablation. Demographic data, post-operative complication, and CIVIQ-2 questionnaire scores were recorded. Microwave energy was set at 50-65 watts and the pull back speed was 3 cm/minute. RESULTS: C2 was a common finding, (59.6%). Mean follow-up time was 25.2 months and the most immediate complication was numbness (32.1%) with permanent numbness at 3.8%. Quality of life as determined by CIVIQ-2 score changedfrom 32 before operation to 24 after operation (p<0.001). Complete venous occlusion rate was 79.8% and the rate of partial venous occlusion with no venous reflux was 8.7%. CONCLUSION: Endovenous microwave ablation can be used safely. It could be an alternative treatment for patients with chronic venous disease. PMID- 25509700 TI - Bridging metallic stent placement in acute obstructed left sided malignant colorectal cancer: optimal time for surgery. AB - BACKGROUND: Colonic stenting is now the preferred treatment either for palliation or as a bridge to surgery for obstructed colorectal cancer. It reduces complications from emergency surgery and the need for colostomy formation. However, stent perforation can lead to peritoneal tumor spillage, a higher rate of infection and changing the risk of a potentially curable disease to an incurable one. Therefore, it is important to study the optimum time for operation after stent insertion. MATERIAL AND METHOD: From January 2006 to January 2012, 30 cases of acute left-sided malignant colorectal obstruction were managed by expandable metallic stent (SEMS) as a bridge to surgery. In all, 19 males and 11 females with mean age of 60.07+/-12.19 years (range 40-80 years) were included in the study. The obstructed locations were 1 case at the transverse colon, 6 cases at the descending colon, 13 cases at the sigmoid colon, 5 cases at the upper third at the rectum and 5 cases involving the middle third of the rectum. RESULTS: The perforation of SEMS was founded in 11 cases (36.67%). The mean bridging time before operation in the nonperforated group was 5.54 (+/-1.29) days shorter than in the perforated group, 10.54 (+/-4.82) days (p<0.001). All of the subjects in the perforated group reported clinical lower abdominal pain without sign of peritonitis, developed in an average 4.5 days (3-7 days). CONCLUSION: The optimum bridging time for surgery should be within 5 days. PMID- 25509701 TI - Risk factors of pelvic lymph node metastasis in cervical adenocarcinoma following radical hysterectomy and pelvic lymphadenectomy. AB - BACKGROUND: Lymph node metastasis is the most important prognostic factor in cervical cancerpatients. However, most of the available knowledge about risk factors of pelvic nodal metastasis in cervical cancer has come from studies in which the majority of patients had the squamous cell carcinoma (SCC) subtype. OBJECTIVE: To determine the risk factors of pelvic lymph node metastasis in early stage cervical adenocarcinoma (AC) patients following radical hysterectomy and bilateral pelvic lymphadenectomy. MATERIAL AND METHOD: Retrospective reviews were carried out of the medical charts and pathologic slides of 251 patients with cervical AC stage IB1-IIA who underwent radical hysterectomy and bilateral pelvic lymphadenectomy at Rajavithi Hospital from January 1, 2000 to December 31, 2011. The risk factors of pelvic lymph node metastasis were analyzed by multiple logistic regression. RESULTS: Of the 251 patients, pelvic node metastasis in stage IB1-IIA cervical AC was detected in 29 patients (11.6%). Multivariable analysis revealed that clinical stage IB2-IIA (adjusted OR 3.4, 95%CI 1.2-9.7), tumor size more than 2 cm (adjusted OR 3.5, 95%CI 1.1-11.8), and positive lymphovascular invasion (LVSI) (adjusted OR 55.5, 95%CI 7.2-427.6) were significantly associated with pelvic nodal metastasis. Early-stage cervical AC patients with no risk factor, one risk factor other than LVSI, LVSI factor alone, two risk factors, and three risk factors were identified as having pelvic nodal metastasis in 0%, 2.3%, 9.1%, 29.1% and 58.8% of cases respectively. CONCLUSION: Clinical stage IB2-IIA, tumor size of more than 2 cm, and positive LVSI were significant risk factors for pelvic nodal metastasis in early-stage cervical AC patients. Those with no risk factors were not found to have pelvic nodal metastasis and might be candidates for less radical surgery, whereas patients with the presence of LVSI and/or 2 other risk factors were found to be at high risk of pelvic node metastasis and might benefit from extensive lymphadenectomy and adjuvant therapy. PMID- 25509702 TI - Brachial plexus birth palsy: the natural history, outcome of microsurgical repair and operative reconstruction. AB - OBJECTIVE: To document the natural history of brachial plexus birth palsy in relation to the recovery of elbow flexion and shoulder flexion in the first six months of life; to assess the outcome after microsurgery of the brachial plexus in patients who had no recovery of bicep function at six months. STUDY DESIGN: The present study employed retrospective clinical data analysis. MATERIAL AND METHOD: The patients were divided in two groups, nonoperated and operated. The non-operative patients were followed either to full recovery or until the maximum expected motor recovery. The type of surgical procedure and final muscle strength was recorded in the operative group. Every child was evaluated for motor function including bicep muscle and shoulder elevation and then was followed until the surgeon considered the appropriate time for surgery. RESULTS: Between 2001 and 2010, 88 children with birth palsy were seen with 89 brachial plexus birth palsies. Seven children were excluded due to incomplete data. The remaining 82 palsies in 81 babies were classified in two groups. In the non-operated group, the spontaneous recovery occurred in 59 patients (73%) of 81 patients. All of these patients showed functional bicep within ten months of age. Bicep contraction was observed by six months of age in 63 patients (71%). In all, 22 infants in the operated group, underwent an exploration of the brachial plexus, neurolysis and neurotization, Functional recovery of the elbow occurred in 15 cases. The pre-operative AMS for elbow and shoulder flexion were 1.72 and 2.18, respectively. The postoperative mean AMS for elbow flexion was 5.30 and shoulder flexion was 5.55. CONCLUSION: Most babies with traction injuries of the brachial plexus at birth have an excellent prognosis if the recovery has started within three months. Microsurgical reconstruction was effective in improving function in the small subgroup of patients with no evidence of recovery of bicep function within the first six months of life. PMID- 25509703 TI - Comparison of visual outcomes for aspheric and spherical toric intraocular lens implantation in cataract patients with pre-existing corneal astigmatism: a randomized control trial. AB - BACKGROUND: With spherical intraocular lens (IOL) implantation, unaided vision of cataract patients with pre-existing corneal astigmatism is unsatisfactory because astigmatic spectacles will always be needed for clear vision. Toric IOL has been proven to be a major improvement in cataract surgery for spectacle independence. Aspheric property, reported to improve visual quality in a non-toric IOL, has now been added to toric IOL for even better unaided vision. OBJECTIVE: To compare visual and aberrometric outcomes of 2 toric IOL, spherical and aspheric, at 3 months after implantation. MATERIAL AND METHOD: Cataract surgery was performed in cataract patients with pre-existing corneal astigmatism using 2 types of toric IOLs, a spherical toric IOL, Acrys of SN60T (Group A) and a aspheric toric IOL, Acrts of SN6AT, (Group B) as a randomized control trial. The uncorrected distance (UDVA) and corrected (CDVA) distance visual acuities, residual astigmatism, spherical equivalent (SE) and spherical aberration were evaluated 3 months after implantation. RESULTS: The present study included 44 eyes. No statistically significant difference was found in UDVA, CDVA and residual astigmatism between both groups. The UDVA of 0.1 logMAR or better was found in 78.26% in Group A and 85.71% in Group B. In Group A, 78.26% of eyes and in Group B, 76.19% had a refractive astigmatism value within 0.50 diopter at KP90 (polar value along the 90-degree meridian). The spherical equivalent (SE) was within +/-0.5 diopter of emmetropia in 91.30% in Group A and in 80.95% in Group B. Group B had significantly lower spherical aberration Z (4, 0) than Group A. CONCLUSION: Both groups had similar clinical effectiveness for unaided visual acuity, aided visual acuity and astigmatism correction. Group B had significantly less spherical aberration induction when compared with Group A. PMID- 25509704 TI - Incidence of major adverse cardiac event in low risk chest pain patients in emergency department of Rajavithi Hospital. AB - BACKGROUND: Acute myocardial infarction is a major problem of public healthcare in Thailand. In the emergency room, patients who present chest pain are at low risk for myocardial infarction and short term risk of adverse cardiac events. In the present study, the incidence of major adverse cardiac events among low risk chest pain patients who presented at the emergency room of Rajavithi Hospital was investigated to improve treatment in the future. OBJECTIVE: To evaluate incidence of major adverse cardiac events within 30 days among patients with low risk chest pain for myocardial infarction admitted to the emergency room at Rajavithi Hospital. MATERIAL AND METHOD: This prospective observational study was undertaken at emergency the room of Rajavithi Hospital. Low risk chest pain patients, classified by normal ECG normal Troponin T level and Thrombolysis in Myocardial Infarction (TIMI) score less than 2, suspected of acute myocardial infarction, were included from October 1, 2012 to October 31, 2013. Primary endpoint was major adverse cardiac event (MACE) within 30 days after initial presentation. RESULTS: In all, 209 patients were enrolled in this study comprising females, 51.7% and mean age 54.84+/-16.44 years. A total of 84 patients had TIMI score 1 (40.2%), 67 patients had TIMI score 2 (32.1%) and 58 patients had TIMI score 0 (27.7%). At 30 days after presenting, two patients had a major adverse cardiac event (0.9%), both of them had TIMI score 2. No significant difference was observed between TIMI score 2 and other groups of TIMI scorefor major adverse cardiac adverse event (p-value = 0.075). The most common of TIMI risk factor was chest pain >=2 episodes within 24 hours (86 patients, 41.2%). The most common underlying disease or previous history was congestive heart failure (33 patients 15.8%) but no factors had statistical significance for major adverse cardiac events among low risk chest pain patients. CONCLUSION: Incidence of a major adverse cardiac event within 30 days among low risk chest pain patients was low. No significant difference was observed between each group of TIMI score 0-2 for major adverse cardiac event and no significant risk factor was found for major adverse cardiac events in low risk chest pain patients. PMID- 25509705 TI - Percutaneous balloon aortic valvuloplasty at the Queen Sirikit National Institute of Child Health: 25 years' experience. AB - BACKGROUND: Percutaneous balloon aortic valvuloplasty (BAV) is the treatment of choice in moderate and severe valvular aortic stenosis. In Thailand, the first procedure was performed at the Queen Sirikit National Institute of Child Health (QSNICH) in 1988. No previous studies have been reported regarding the outcome of these procedures at QSNICH. OBJECTIVE: To study the efficacy and complications of percutaneous balloon aortic valvuloplasty in the treatment of severe aortic stenosis. MATERIAL AND METHOD: A retrospective study from the medical records was performed. All patients with a diagnosis of moderate or severe valvular aortic stenosis treated with BAV from January 1988-December 2012 were recruited. Before 2008, the procedures were performed under local anesthesia with light systemic sedation. After that, most of the cases were performed under general anesthesia. The response to treatment was classified as good response, partial response or failure. The short-term complications were classified as vascular complications, arrhythmias and others. RESULTS: Sixty-eight recorded attempts on 60 patients (47 males = 71.67%) were enlisted in the study. The ages at the time of procedures ranged from 1 day to 15 years (mean 65.25, SD 53.54, median 51 months). Fourteen cases were under one year of age (20.58%). Immediate success comprised 85.29% with 65.51% classified as good response. Ten failures in nine cases all occurred before 1997. One of the cases was an attempted balloon aortic valvuloplasty with repeated failure. Three of the cases underwent open aortic valvuloplasty where one case (33.33%) survived. The other six cases refused to continue treatment and were lost to follow-up. Four deaths were reported. Repeated balloon aortic valvuloplasties were performed in eight cases. During the early phases (1988 1996), failures and mortality rates were extremely high. Experience and improved technology improved outcomes. Excluding the four dead cases, the only significant major complication occurred in a three-year-old boy with severe aortic stenosis who tore the chordae tendinae, producing severe, acute mitral regurgitation, together with ventricular tachycardia, requiring direct current cardioversion during the procedure and double valvuloplasty five years later. Other minor complications included transient cardiac arrhythmia in 12 cases, partial occlusion of femoral artery in 11 cases and groin hematoma in 8 cases. CONCLUSION: Percutaneous balloon aortic valvuloplasty was effective and safe for the treatment of moderate and severe aortic valve stenosis in pediatric patients without significant complications. PMID- 25509706 TI - Clinical differences between choledochal cysts in infancy and childhood: an analysis of 160 patients. AB - BACKGROUND: Choledochal cysts (CDC) can become symptomatic at any age. Clinical features of infants and older children are different and have been documented by many authors. OBJECTIVE: The aim of this report was to study the differences in clinical spectrum of CDC between the infants and children treated at our hospital during a 17-year period. MATERIAL AND METHOD: A retrospective study was conducted of 160 patients with CDC treated at Queen Sirikit National Institute of Child Health between 1996 and 2012. The patients were categorized into 2 groups based on age at clinical presentation: an infantile group (up to one year old) and a childhood group (over one year old). Clinical characteristics of patients in the infantile and childhood groups were compared with statistical analysis using the Chi-square and Fisher's exact test. RESULTS: Of the 160 patients with CDC, 48 cases (30%) were categorized in the infantile group and 112 cases (70%) in the childhood group. Over three-quarters ofthe patients in the infantile group presented with jaundice and acholic stool, and this incidence was significantly higher than in the childhood group (77% vs. 46.4%, p = 0.001 and 50% vs. 13.4%, p < 0.001). Abdominal pain was the most common symptom of patients in the childhood group, whereas it was noted in only a small number of those in the infantile group (82.1% vs. 8.3%, p < 0.001). Average amylase level in CDC content was markedly elevated in the childhood group but much lower in the infantile group (43,630.5+/-90,234.5 vs. 79+/-189.9, p < 0.001). Only type I and type IV CDC as defined by Todani's classification were found in our patients, and there were no statistical differences in incidences of type I and type IV in the two groups (79.2% vs. 67.8% and 20.8% vs. 32.2% p > 0.05). Neonates and infants with CDC had a significantly higher risk of liver cirrhosis than did the childhood group (25% vs. 8%, p < 0.001). However, surviving patients with cirrhosis in both groups were doing well at least 3 years after surgical CDC excision. CONCLUSION: Neonates and infants with CDC were more likely to present with jaundice and acholic stool, whereas older children were more likely to present with abdominal pain. Amylase level in CDC content was markedly elevated in the childhood group but at a much lower level in the infantile group. Neonates and infants with CDC tended to develop liver cirrhosis earlier and more often than older children. PMID- 25509707 TI - Clinical outcomes of children with carbapenem-resistant Acinetobacter baumannii bacteremia. AB - BACKGROUND: A relentless increase in the rate of carbapenem-resistant among Acinetobacter baumannii has substantially reduced the access to effective antimicrobial regimens. Currently limited information is available regarding the prognosis or outcomes of children with blood stream infection caused by carbapenem resistant A. baumanii. OBJECTIVE: To determine the clinical outcomes and predictors for fatality among children with carbapenem-resistant A. baumannii (CRAB) bloodstream infection (BSI). MATERIAL AND METHOD: A retrospective descriptive study was conducted among children hospitalized at the Queen Sirikit National Institute of Child Health (Children's Hospital), Bangkok, Thailand. Those who had CRAB isolated from blood cultures during theperiod between October 2005 and September 2010 were included in the study. RESULTS: A total of 89 cases of BSI caused by CRAB were identified. The incidence was 1.2 cases per 1,000 hospitalized patients. The median age at onset of bacteremia was 62 days and 88% had at least one underlying comorbidity. The 2-week and 30-day case fatality rates were 39% and 42%, respectively. A large proportion of deaths (63%) occurred before blood culture results became available. Extended spectrum resistance, defined as resistance to all other first line antibiotics at the hospital, i.e., all cephalosporins, aminoglycoside, quinolone and carbapenems, was significantly associated with a higher 2-week case fatality rate (CFR) (48% compared with 23% among their counterpart, p = 0.028) and death at an earlier stage of the bacteremia (Kaplan-Meierp = 0.016). In univariate analysis, factors associated with 2-week case fatality include malignancy-associated febrile neutropenia, fever >=2 days before the initiation of appropriate antibiotic, presence of septic shock, organ dysfunction, and being infected by extended spectrum resistant strains. Correspondingly, CFR of cases who received >=1 appropriate empiric antibiotics within 24 hours of clinical suspicion appears to be lower albeit not reaching statistical significance, than their counterpart, i.e., the CFRs between the two groups were 10% vs. 23%, respectively (p = 0.675). Colistin susceptibility based on disc diffusion test remained high (100%) in this sample. Nevertheless, those who received colistin treatment had a 2-week CFR of 20%. On the other hand, none of the cases infected with sulbactam susceptible strain, who received sulbactam containing regimen (n = 15), died. No significant renal toxicity was observed among children receiving colistin treatment in our sample. CONCLUSION: Carbapenem resistant A. baumannii bacteremia exhibited a high fatality rate, which mainly occurred before the pathogen was known to the clinicians. Extended spectrum resistance was associated with high fatality rate. Early administration of effective empirical antibiotics such as colistin and sulbactam in this sample was associated with lower fatality rate among children affected by this condition. PMID- 25509708 TI - Comparison of didactic lectures and open-group discussions in surgical teaching. AB - BACKGROUND AND OBJECTIVE: The teaching of medicine has varied and has continued to develop until today. Most courses rely on the lecture although it may bring less benefit to students. Another teaching technique, the open group discussion, may not be the most effective, but is widely accepted as a teaching development especially for its overall improvement of student skills. Basically, the teaching of surgery has more limitations than other subjects because patients with critical conditions are required. The present study was designed to compare the effectiveness of these two teaching methods, the lecture and the open group discussion, in the Department of Surgery, Rajavithi Hospital. MATERIAL AND METHOD: Fifth year medical students enrolled from 2554-2555 BE (AD 2011-2012) were recruited in the study and randomly divided in groups by the Office of Administration, College of Medicine, Rangsit University. A colorectal surgeon taught the subject, common anorectal disease, throughout the study year. The drawing method was used to randomize the members grouped by teaching methods. The assessment comprised multiple choice questions (MCQ) and multiple essay questions (MEQ). RESULTS: Seventy-three students (39 females, 34 males) were recruited. Students' basic characteristic showed no association between groups of teaching methods. Higher mean MEQ scores were found in the open discussion group (55.83%) compared with those taught by lecture (31.23%), exhibiting significant difference (p<0.001). With respect to MCQ1 and MCQ4, students in the open discussion group had higher scores than those in the lecture group), was also with statistical significance (p = 0.02). CONCLUSION: Teaching medicine differs from other disciplines. To achieve the most effective teaching performance, teaching methods may be limited in some subjects. This study was a partial project for teaching in the Department of Surgery. It was shown that students in the open discussion group had better MCQ and MEQ scores than those in the lecture group. In developing student skills, giving open discussion provided greater interaction between instructors and students. Importantly, the instructor should manage and facilitate questioning techniques to more effectively transfer course content. PMID- 25509709 TI - A case of anterior mediastinum paraganglioma presented with pericardial effusion two years before symptoms of catecholamine excess: first case report in Thailand. AB - Pheochromocytoma (PCC) and paraganglioma (PGL) are uncommon tumors. Clinical manifestations are mass effect or hormone secretion. The initial manifestation with pericardial effusion is rare. The author presented a case of anterior mediastinum paraganglioma presenting with pericardial effusion two years before symptoms of catecholamine excess. This is the first case reported in Thailand. A 34 year-old female patient presented with dyspnea. There was pericardial effusion from echocardiography was diagnosed with no definite causes of pericardial effusion. After treatment with ibuprofen, pericardial effusion was absolutely resolved from repeated echocardiography. Two years later she had headache and hypertension. Chest X-ray, there was an anterior mediastinal mass. Her 24 hours urine metanephrine was very high. By imaging, an anterior mediastinal mass was observed from CT chest without adrenal mass from CT abdomen. The result of metaiodobenzylguanidine (MIBG) scan was compatible with paraganglioma. Symptoms of headache and hypertension disappeared after surgical removal of the mass. Pericardial effusion may be the first manifestation of paraganglioma especially if the patient had hypertension or could not find the etiology. Thus, pericardial effusion should be investigated for paraganglioma. Due to long term follow-up, this indolent growing tumor may respond to NSAIDs or regress spontaneously. PMID- 25509712 TI - Editor's choice--September 2014. PMID- 25509710 TI - Observational cases report of a group of severe plaque type psoriasis patients treated with ustekinumab. AB - BACKGROUND: Psoriasis is a common chronic immunologic disease which shares common inflammatory pathways to other disease like diabetes, cardiovascular disease, and irritable bowel disease. Ustekinumab is a human monoclonal antibody that reduces the expression of interleukin-12 and interleukin-23, the key inflammatory cells of the pathology of psoriasis. MAIN OBSERVATION: Four patients with severe chronic plaque type psoriasis who were not responding well to conventional systemic therapy were included in the ustekinumab treatment. The study revealed good clinical response with at least PASI 75 response at week 12, and long-term clearing of psoriatic lesions was observed. CONCLUSION: Ustekinumab represents an effective alternative for the management of psoriasis; despite being used as a short-term treatment, it still shows efficacy on recalcitrant psoriasis. PMID- 25509713 TI - Addressing inequality and exclusion--the opinion of people affected by leprosy in Africa and Asia, as to what should be included in any post Millennium Development Goal framework. PMID- 25509714 TI - Responding to the challenge of leprosy-related disability and ultra-poverty. AB - INTRODUCTION: The Millennium Development Goals have provided much needed attention to extreme poverty reduction. However, people with disabilities are disproportionately affected by poverty and in some countries, even the goal of US$1 per day is far out of reach. For people with leprosy-related disability living in ultra-poverty (on less than 50 cents a day), many mainstream poverty reduction strategies are inaccessible and inappropriate. METHOD: A project in north-west Bangladesh developed a more contextually meaningful definition of ultra-poverty according to nutrition energy intake. A total of 2372 people with leprosy-related disability were surveyed. Of those, 1285 individuals fell below the ultra-poverty line. Individualised interventions were implemented over an extended period of time, comprised of targeted practical assistance, enhancing community links, advocacy for entitlements, and further linking with other initiatives. RESULTS: Follow-up data available for 856 individuals showed an average increase in per capita income of 83%. Personal contribution to the family income increased by 65%. There was a 51% increase in families having access to a latrine. Finally families reported eating 30% more meals per day, up from an average of two meals per day. CONCLUSIONS: The initiative sought to address poverty in a wide variety of ways, using minimal inputs. Over several years, the results indicate a significant change in the economic situation of individuals with leprosy related disabilities. Other organisations are encouraged to duplicate the intervention and share their results. PMID- 25509715 TI - How to reduce stigma in leprosy--a systematic literature review. AB - BACKGROUND: Interventions to reduce leprosy-related stigma reduce the manifestations of stigma that cause so much suffering to individuals and their families. PURPOSE: This systematic review aims to identify interventions that have been used to reduce such stigma and to summarise what is known about their efficacy. METHOD: Electronic searches were undertaken using PubMed (Medline), CINAHL and PsycInfo databases. The internet was searched using Google Scholar for papers not published in these databases. All relevant papers written in Thai or English were included. RESULTS: After reading 55 papers, three duplications and parallel literatures were removed, 18 were removed on abstract screening and nine after reading the full papers; eventually, 25 were included in this review. Interventions with some evidence of effectiveness in terms of stigma reduction comprise the integration of leprosy programmes into general health care; Information Education and Communication (IEC) programmes; and socio-economic rehabilitation. CONCLUSION: More evaluations are needed of the effect of the integration of leprosy programmes into general health services. The design and implementation of IEC interventions need to be preceded by careful study of the target area and population and should be undertaken in combination with other activities. PMID- 25509716 TI - Leprosy incidence: six years follow-up of a population cohort in Bangladesh. AB - BACKGROUND: With approximately 250,000 new leprosy cases detected annually, transmission of M. leprae appears to be ongoing in many areas of the world. By studying prospectively the number of leprosy patients found in a population sample at the beginning of the study (prevalence) and the number of new patients found during the 6-year observation period (incidence), we aim to understand better the transmission of M. leprae and the burden of disease. METHODOLOGY: To establish the prevalence and incidence rates of leprosy in the general population of a high endemic area in Bangladesh, we followed prospectively 20,218 individuals from a random cluster sample of the population and examined them at 2 yearly intervals for 6 years. RESULTS: At intake we found 27 new leprosy cases, indicating a prevalence of previously undiagnosed leprosy of 13.3/10,000. Follow up at 2, 4 and 6 years revealed 17, 16, and eight new cases, respectively, representing incidence rates of 4.0, 4.5 and 2.3/10,000 PYAR, respectively. The incidence rate over 6 years was 3.7/10,000 PYAR. The observed incidence rate is three times higher than the new case detection rate in the same area. Of all 68 new leprosy cases, five (7%) had MB leprosy. The proportion of children under 15 years was 24%. The proportion of female patients was 60%, but the incidence rate of leprosy was the same for males and females. CONCLUSIONS: The decline in incidence of leprosy in a general population sample is less pronounced than routine data from a control programme led us to expect. PMID- 25509717 TI - Leprosy--an imported disease. AB - OBJECTIVES: Leprosy remains a public health concern in Malaysia and globally. We aim to review the characteristics of leprosy patients in a tertiary institution in urban Malaysia. DESIGN: This is a case series of 27 leprosy patients who presented between 2008 and 2013. RESULTS: The majority of our patients consisted of male (74.1%), Malaysian (63.0%), blue collar workers (51.9%) and married (59.3%) patients; 48.1% had lepromatous leprosy. All except one of the patients presented with skin lesions, 25.9% had nerve involvement and 33.3% developed lepra reactions. Forty-four point four percent (44.4%) of the cases seen initially in the primary care setup were misdiagnosed. CONCLUSIONS: Doctors need to have a high index of suspicion for leprosy when patients present with suggestive skin, nerve or musculoskeletal lesions. Immigrants accounted for 37% of cases and these patients may become a reservoir of infection, thus accounting for the rise in incidence. An increasing trend in multibacillary cases may be attributed to the spread from migrants from countries with a high burden of leprosy. PMID- 25509718 TI - Drug resistance patterns in Mycobacterium leprae isolates from relapsed leprosy patients attending The Leprosy Mission (TLM) Hospitals in India. AB - Implementation of multidrug therapy (MDT) in leprosy control programmes has significantly reduced the global prevalence of the disease in the last two decades. After many years of use of MDT, it is expected that drug resistance in Mycobacterium leprae may emerge. This is a major concern, especially during the stage of elimination. In the present study, slit-skin smears were collected from 140 leprosy relapse cases from different Leprosy Mission hospitals across India. DNA extracted from 111 (79%) of these samples was analysed for the genes associated with drug resistance in M. leprae. More than 90% of the patients relapsed as multibacillary (MB) cases. In our study, four (3.6%) of the DNA samples analysed showed mutations associated with rifampicin resistance. We also observed that mutations associated with resistance to dapsone and ofloxacin were observed in 9 (8.1%) of the DNA samples each; two samples had both dapsone and ofloxacin resistance. Further surveillance and appropriate interventions are needed to ensure the continued success of chemotherapy for leprosy. PMID- 25509719 TI - Psychological distress and quality of life in leprosy patients with neuropathic pain. AB - Leprosy is widely known because of progressive damage to the peripheral nerves. In spite of multidrug therapy, some patients develop chronic neuropathic pain after bacteriological cure. Chronic pain is associated with psychological distress and is also an important predictor of poor quality of life. The aim of this study is to assess psychological distress in leprosy patients with chronic neuropathic pain, and its repercussions on their quality of life. The sample of this cross-sectional study comprised patients with chronic neuropathic pain after multidrug therapy. Neuropathic pain was confirmed by clinical examination and by the Douleur neuropathique en 4 questions questionnaire. Pain intensity was assessed using a visual analogic scale (VAS) ruler. The psychological health of the participants was measured using the 12-item General Health Questionnaire, and the WHOQOL-bref was used to assess quality of life. The mean pain intensity reported by participants on the VAS was 7.1 cm (SD = 2.9). No differences in pain intensity with respect to gender were observed. Psychological distress was present in 76.2% of participants, being higher in those with Grade 2 of disability. Patients with psychological distress had the lowest mean scores in all domains of the WHOQOL-bref. The lowest mean scores according to domain were physical (9.9; SD = 3.3), followed by environment (11.9; SD = 3.0), psychological (13.5; SD = 2.6) and social relations (14.0; SD = 3.7). In conclusion, our study identified the presence of psychological distress in most of the participants. Patients with chronic neuropathic pain who were also found to have high psychological distress levels had higher pain intensity and a poorer quality of life. PMID- 25509720 TI - Lucio Leprosy with Lucio's phenomenon, digital gangrene and anticardiolipin antibodies. AB - Lucio's phenomenon (LPh) is considered a necrotizing panvasculitis and a variant of leprosy Type 2 reaction, clinically characterised by necrotic-haemorrhagic lesions on the extremities and trunk. LPh is observed in diffuse lepromatous leprosy (DLL or Lucio-Latapi leprosy). This is a distinct form of lepromatous leprosy (LL) reported mainly in Mexico. Anti-phospholipid antibody syndrome (APS) has been rarely described in LPh. We report a case of Lucio-Latapi leprosy with LPh observed in a patient from the province of El Oro in Ecuador, who presented clinical manifestations of long standing DLL (non-nodular infiltration of the skin, collapse of the nasal pyramid, madarosis, atrophy of the earlobes), of LPh (necrotic-haemorrhagic macules with irregular shapes) and of APS (necrosis of the right big and second toe). Histopathology showed perineural and periadnexal foamy macrophages with numerous bacilli (diagnostic of LL) in the subcutis, a mild lobular panniculitis with a large subcutaneous vessel infiltrated by macrophages in the wall (typical of LPh) and vessels of the superficial and mid dermis occluded by thrombi but without signs of vasculitis (typical of occlusive vasculopathy as in APS). Our observations suggest that some cases of LPh may be associated with APS. Anti-cardiolipin antibodies (aCL) and lupus anticoagulant (LA) should be tested in patients with LPh because this may have therapeutic implications. PMID- 25509721 TI - Annular bullous lesions with atypical erythema multiforme in leprosy. AB - Erythema nodosum leprosum (ENL) is an immune complex-mediated reaction that may complicate the course of multibacillary leprosy. Bullous lesions in Type II reaction, though reported, are exceedingly rare. We report the case of a 32 year old female patient who presented initially at our OPD with erythema nodosum. Cutaneous examination revealed impaired sensation over dorsum of right foot and thickened right lateral popliteal nerve. Slit skin smear (SSS) from ear lobes revealed AFB with a bacteriological index of 2+. She was started on MDT, tablet ofloxacin 200 mg twice a day, and 30 mg oral prednisolone. Two months later, she presented with generalised pruritus, large target lesions over the back, and hemorrhagic bullae over lower extremities and annular pattern of bullae, over both arms. A SSS was repeated which was positive for AFB. Histopathology from bullous lesions was consistent with ENL. Direct Immunofluorescence (DIF) study was negative. Our patient improved rapidly after she was started on thalidomide 100 mg twice daily, with withdrawal of ofloxacin. Erythema Multiforme (EMF) and annular bullous lesions have been reported in patients on treatment with ofloxacin. This case is being presented due to the unusual and varied manifestation of Type II lepra reaction in a 34 year old female patient. PMID- 25509722 TI - Physical disability and social participation in patients affected by leprosy after discontinuation of multidrug therapy. AB - OBJECTIVES: To describe the social participation frequency and the physical disability of patients who were discharged after the multidrug therapy (MDT/WHO) and factors associated with these variables. METHOD: A cross-sectional and analytical study, examining associations, which took place Nova Iguacu/Brazil. A random sample of patients treated with multidrug therapy from 1997 to 2006 was selected. The rationale for sample size was determined by the estimated proportion of physical disability in the amount of 23%, with an acceptable sampling error rate of 5%; significance level was established as 5% among the 1080 patients finally a total sample of 225 patients. The evaluations were performed from January 2010 to December 2011 and Socio-demographic and clinical data were collected from the applications completed in the national notifiable diseases information system (SINAN). RESULTS: In the period of interest, 2179 cases were diagnosed with leprosy; 1080 met the criteria for inclusion. Of these, 225 were randomly selected patients who had mean age 56.12 (+/-17.34 years), 55.6% were women, 39.9% went to high school and 28.9% were Caucasians. A total of 55.3% (125) showed multibacillary form, with a predominant dimorphous leprosy in 40.4%. Physical disability was present in 60.9% and social restrictions in 24.9% of patients. The variable physical disability was associated with the therapeutic regimen multibacillary and social participation. CONCLUSION: We observed a high frequency of disability and social restriction after long period after the start of MDT/WHO suggesting the late diagnosis of leprosy or inadequate follow-up after discharge. This study highlights the importance of systematic monitoring of these patients with their own criteria which could be held at the Family Health Strategy. PMID- 25509723 TI - Prevalence of restless legs syndrome among leprosy patients: a hospital based study. AB - INTRODUCTION AND OBJECTIVES: Restless legs syndrome (RLS) is a type of neurological disorder which presents with an uncontrollable urge to move legs and arms. It commonly affects legs more than arms. Data regarding prevalence of restless legs syndrome in leprosy are sparse. The aims and objectives of the study were to find out the prevalence of RLS in people affected by leprosy and to determine the presence and magnitude of sleep disruption in leprosy patients with RLS. MATERIALS AND METHODS: Total 143 patients diagnosed with leprosy were enrolled in the study. A diagnosis of RLS and a severity assessment were made using the criteria described by International Restless Legs Syndrome Study Group. The Pittsburgh Sleep Quality Index (PSQI) was evaluated in all those who were diagnosed with RLS. RESULTS: Out of 143 patients recruited in the study, 56 (39.16%) patients were found to be suffering from RLS. Mean Pittsburgh Sleep Quality Index global score was higher (16.55), and the value was specifically higher among patients presenting with Type-2 lepra reaction (17.8) and pure neuritic leprosy (15.93). CONCLUSIONS: The frequency of RLS among leprosy patients is significantly higher. They suffer from bad sleep quality at night which significantly affects their quality of life. So all patients affected with leprosy should be evaluated for RLS and early treatment should be started to improve their sleep. PMID- 25509725 TI - Model Patient Card/Record (Leprosy) 2nd edition, London: ILEP, 2014. PMID- 25509724 TI - The experiences and attitudes of people affected by leprosy who voluntarily undertake leprosy services in Nepal. AB - This paper is a record of the outcome of a focus group discussion in which 22 leprosy-affected self-help group facilitators related their experiences and attitudes associated with leprosy services which they voluntarily undertake. Enthusiasm to undertake leprosy services was general. The principal rewards for participation in such activities appear to have been social ascendance and self esteem. Factors cited as being most likely to further motivate voluntary service reflected the perceived importance of personal reputation and the prestige of a clear association with Lalgadh Leprosy Services Centre. PMID- 25509726 TI - [Effects of synchronous treatment of bilateral scalp acupuncture and rehabilitation training on activities of daily life in patients with cerebral infarction at acute phase]. AB - OBJECTIVE: To observe the improvements of synchronous treatment of bilateral scalp acupuncture and rehabilitation training on activities of daily life in patients with cerebral infarction at acute phase, so as to compare the efficacy differences between scalp acupuncture at bilateral and affected side as well as differences between synchronous and non-synchronous treatment. METHODS: Ninety patients of acute-phase cerebral infarction with motor dysfunction were randomly divided into three groups. The observation group was treated with synchronous treatment of scalp acupuncture at the Dingzhongxian (middle line of vertex), bilateral Dingnieqianxiexian (anterior oblique line of vertex-temporal) and bilateral Dingniehouxiexian (posterior oblique line of vertex-temporal) and rehabilitation training; the control group A was treated with synchronous treatment of affected scalp acupuncture at the Dingzhongxian, affected Dingnieqianxiexian and affected Dingniehouxiexian and rehabilitation training; the control group B was treated with bilateral scalp acupuncture for 4 h, followed by rehabilitation training. All the patients took the treatment once a day, and 6 days for a course of treatment for total of 4 courses. The modified Barthel index (MBI), activities of daily living (ADL) and Fugl-Meyer motor assessment (FMA) were used to perform efficacy assessment before treatment, in the 14th days of treatment and in the 28th days of treatment in three groups. RESULTS: After treatment, three indices at each time point were superior to those before the treatment in three groups (all P<0.01) ; the improvements of ADL and FMA in the observation group after 28 days of treatment were superior to those in the control group A and control group B (all P<0.05), and the improvement of MBI was superior to that in the control group B (P<0.05). CONCLUSION: The synchronous treatment of bilateral scalp acupuncture and rehabilitation training could significantly improve the activities of daily life and motor function in patients with cerebral infarction at acute phase, which is superior to scalp acupuncture at affected side and non-synchronous treatment. PMID- 25509727 TI - [Clinical research of electroacupuncture at acupoints of qijie area combined with spine balance-regulating massage on posterior circulation ischemia]. AB - OBJECTIVE: To compare the clinical efficacy difference between electroacupuncture (EA) at qijie area combined with spine balance-regulating massage and medication for posterior circulation ischemia (PCI). METHODS: One hundred cases of PCI were randomly divided into a treatment group (50 cases) and a medication group (50 cases). The treatment group was treated with EA at Baihui (GV 20), Sishencong (EX HN 1), Fengchi (GB 20), Shenshu (BL 23), Danzhong (CV 17), etc. in qijie area combined with spine muscle-relieving massage and comprehensive chiropractic. The medication group was treated with oral administration of nimodipine (30 mg per time, three treatments per day) and vinpocetine injection with 500 mL of glucose injection or intravenous drip of 500 mL 0.9% sodium chloride injection, once a day. Ten treatments were taken as one course in both groups, and two courses were given. The symptom score, mean resistance index (RI) of vertebral artery (VA) and basilar artery (BA), mean velocity of blood flow (Vm) and comprehensive clinical efficacy were compared before and after treatment in two groups. RESULTS: The cured and markedly effective rate was 79.6% (39/49) in the treatment group, which was superior to 54.7% (23/42) in the medication group (P<0.05). The symptom score was both significantly improved after treatment in two groups (both P<0.05), which was more obvious in the treatment group (P<0.05). The RI of VA and BA, Vm of VA and BA were significantly improved after treatment in two groups (all P<0.05), which were more obvious in the treatment group (all P<0.05). CONCLUSION: The electroacupuncture combined with spine balance-regulating massage has superior effect on improving mean velocity of blood flow and resistance index of vertebral artery and basilar artery as well as symptom score to medication, and is believed to be a safe and effective treatment for posterior circulation ischemia. PMID- 25509728 TI - [Regulatory effects of acupuncture on exercise tolerance in patients with chronic obstructive pulmonary disease at stable phase: a randomized controlled trial]. AB - OBJECTIVE: To verify the regulatory effects of acupuncture on exercise tolerance in patients with chronic obstructive pulmonary disease (COPD) at stable phase. METHODS: Thirty cases of COPD were randomly divided into a treatment group (16 cases) and a placebo group (14 cases). Based on specified aerobic exercise, acupuncture was applied in the treatment group and placebo acupuncture was used in the placebo group. The acupoints included Danzhong (CV 17), Rugen (ST 18), Guanyuan (CV 4), Zhongwan (CV 12), Tianshu (ST 25) and so on. The needle did not penetrate into the skin for the placebo group. The treatment was required for 2 to 3 times per week for totally 5 weeks. The indices of exercise tolerance, including 6-min walking distance (6-MWD), exercise time, maximum oxygen uptake (VO2max) forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC), maximum ventilatory volume (MVV), St. George respiratory questionnaire (SGRQ) were observed in two groups before and after treatment. RESULTS: (1) Exercise tolerance: the differences of 6-MWD and exercise time were statistically significant between groups, which were more superior in the treatment group (both P<0.01); the VO2max was significantly increased after treatment in the treatment group (P<0.05), but there was no difference between two groups (P>0.05). (2) Pulmonary ventilation function: the differences of FEV1%, FEV1/FVC and MVV% were statistically significant between groups, which were more superior in the treatment group (P<0.05, P<0.01); (3) SGRQ: the SGRQ was significantly improved after treatment in the treatment group (P<0.05), but there was no difference between two groups (P>0.05). CONCLUSION: The acupuncture could improve the exercise tolerance in patients with chronic obstructive pulmonary disease at stable phase, and shorten the onset time of aerobic exercise. Besides, acupuncture combined with aerobic exercise could effectively improve the pulmonary function. PMID- 25509729 TI - [Clinical experience of direct moxibustion treatment for gouty arthritis]. PMID- 25509730 TI - [Medicinal vesiculation combined with quick cupping at Shenque (CV 8) for allergic rhinitis with syndrome of yang deficiency: a randomized controlled trial]. AB - OBJECTIVE: To compare the clinical efficacy differences between medicinal vesiculation combined with quick cupping at Shenque (CV 8) and regular medication for allergic rhinitis with syndrome of yang deficiency. METHODS: Eighty-two cases were randomly divided into an observation group (42 cases) and a control group (40 cases). The observation group was treated with medicinal vesiculation combined with quick cupping at Shenque (CV 8). The medicinal vesiculation was applied at Feishu (BL 13), Gaohuang (BL 43), Fengmen (BL 12), Mingmen (GV 4) on the dog days in the summer, one treatment on the 1st dog-day, 2nd dog-day and last dog-day respectively with an interval of 10 days between two treatments. Three treatments were taken as one course, and totally one course was given. The quick cupping was applied at Shenque (CV 8), once a day, ten treatments were taken as one course, and totally three courses was given. The control group was treated with oral administration of loratadine and nasal spray of budesonide. The loratadine was given 10 mg per time, once a day for continuous 14 days; budesonide was given once a day, ten treatments were taken as one course, and totally three courses was given. The clinical efficacy in two groups after treatment was observed, and the contents of immune globulin E (IgE), interleukin 4 (IL-4), interleukin-5 (IL-5) and tumor necrosis factor-alpha (TNF-alpha) in peripheral serum were measured before and after the treatments. RESULTS: Of all the 82 patients, 79 cases completed the treatment, and 1 patient in the observation group and 2 patients in the control group dropped out. The effective rate was 87.8% (36/41) in the observation group, which was superior to 78.9% (30/38) in the control group (P<0.05). After treatment, both groups effectively reduced the contents of IgE, IL-4, IL-5 and TNF-alpha, and the observation group had superior effect on reducing IgE and IL-4 to the control group (P<0.05). CONCLUSION: The medicinal vesiculation combined with quick cupping at Shenque (CV 8) have better effect for allergic rhinitis with syndrome of yang deficiency than oral administration of loratadine and nasal spray of budesonide. PMID- 25509731 TI - [Clinical research of medicinal vesiculation for perennial allergic rhinitis]. AB - OBJECTIVE: To compare the efficacy differences between dog-days medicinal vesiculation and regular-day medicinal vesiculation for perennial allergic rhinitis (PAR), and observe their effects on serum immune globulin E (IgE) and interleukin-4 (IL-4). METHODS: Seventy-two patients were randomly divided into a dog-days moxibustion group (34 cases) and a regular-day moxibustion group (38 cases). In the dog-days moxibustion group, medicinal vesiculation was applied on the 1st dog-day, 2nd dog-day and last dog-day in summer by lunar calendar, 3 treatments per dog-day for totally 9 times. In the regular-day moxibustion group, the moxibustion was given on the regular day for continuous 9 times. The symptom score, rhinoconjunctivitis quality of life questionnaire (RQLQ) and the level of IgE and IL-4 were compared before and after treatment in two groups; the short term and two-year efficacy evaluation were performed too. RESULTS: The short-term total effective rate was 88.2% (30/34) in the dog-days moxibustion group, which was not significantly different to 86.8% (33/38) in the regular-day moxibustion group (P>0.05). The long-term total effective rate was 97.1% (33/34) in the dog days moxibustion group, which was significantly superior to 81.6% (31/38) in the regular-day moxibustion group (P<0.05). After treatment, the serum IgE, IL-4 and RQLQ were significantly reduced (all P<0.01), but the difference between two groups was not significant (all P>0.05). CONCLUSION: Medicinal moxibustion could be taken as a regular treatment for PAR, which could be performed during the whole year, and dog-days moxibustion could be considered as an enhanced method for prevention and treatment of PAR. PMID- 25509733 TI - [Penetrating needling from Qiuxu (GB 40) to Zhaohai (KI 6) for 30 cases of palpitation]. PMID- 25509732 TI - [Warm needling at Jiaji (EX-B 2) for 62 cases of coronary heart disease]. PMID- 25509734 TI - [Efficacy observation of cervical spondylosis treated with acupuncture at three lines of cervical Jiaji (EX-B 2)]. AB - OBJECTIVE: To compare the difference in the clinical efficacy on cervical spondylosis between acupuncture at three lines of cervical Jiaji (EX-B 2) and oral administration of jingfukang granules. METHODS: Three hundred cases of cervical spondylosis were divided into an acupuncture group and a medication group, 150 cases in each one. In the acupuncture group, according to the different types of cervical spondylosis, acupuncture was applied at three lines of cervical Jiaji (EX-B 2), once a day. In the medication group, jingfukang granules were prescribed for oral administration, one bag each time, three times a day. The treatment of ten days made one session in the two groups and two sessions were required totally. Before and after two sessions of treatment, the clinical assessment scale for cervical spondylosis (CASCS) was adopted to evaluate the score of subjective symptoms, clinical physical signs and adaptability as well as the total score in the patients of the two groups and the efficacy was compared. RESULTS: The patients' symptoms and physical signs were alleviated, the adaptability was improved and the score of each item and the total score were increased in the two groups after treatment (all P<0.01). The improvements in the acupuncture group were better than those in the medication group (all P<0.01). The curative and markedly effective rate was 90.7% (136/150) in the acupuncture group, better than 66.0% (99/150) in the medication group (P<0.01). CONCLUSION: Acupuncture at three lines of cervical Jiaji (EX-B 2) achieves the significant clinical efficacy on cervical spondylosis. This therapy is superior to relieving symptoms and physical signs and recovering adaptability as compared with jingfukang granules. PMID- 25509735 TI - [Blistering moxibustion for 96 cases of cervical spondylosis]. PMID- 25509736 TI - [Efficacy of spastic pelvic floor syndrome treated with electroacupuncture at Baliao (BL 31, BL 32, BL 33 and BL 34)]. AB - OBJECTIVE: To observe the clinical efficacy on spastic pelvic floor syndrome (SPFS) treated with electroacupuncture (EA) at Shangliao (BL 31), Ciliao (BL 32), Zhongliao (BL 33) and Xialiao (BL 34). METHODS: Thirty-six cases of SPFS were treated with EA at Shangliao (BL 31), Ciliao (BL 32), Zhongliao (BL 33) and Xialiao (BL 34), intermittent wave, 60 times/min in frequency, retained for 20 min. In general, the acupoints on one side were stimulated in each treatment. The bilateral acupoints stimulation was applied in serious cases. The treatment was given once every two days, five treatments made one session and totally three sessions were required. Before and after treatment, the clinical symptoms, anal kinetic indices defecation radiographic changes were observed. The follow-up observation was done in three months after the end of treatment. RESULTS: In three-months follow-up after treatment, 14 cases were cured, 18 cases improved and 4 cases failed. The total effective rate was 88. 9%. After treatment, the cases of incomplete defecation, difficult defecation, anal pain and anal obstruction were reduced apparently as compared with those before treatment, indicating the statistically significant differences (all P<0.01). After treatment, rectal anal reflex threshold (ARA) was increased, anal maximal contraction pressure (AMCP) was reduced to (16.62+/-1.54) kPa and anal rest pressure (ARP) was significantly reduced to (7.22+/-0.36) kPa, indicating the statistical differences as compared with those before treatment (all P<0.01). After treatment, anorectal angle (ARA) in forceful defecation was increased to (116.55+/-9.42) degrees , the distance between the anorectal junction and the pubococcygeal line was decreased, and the impression of puborectal muscle was alleviated apparently as compared with that before treatment (P<0.01). CONCLUSION: EA at Shangliao (BL 31), Ciliao (BL 32), Zhongliao (BL 33) and Xialiao (BL 34) achieves definite efficacy on SPFS and this therapeutic method obviously relieves the symptoms and deserves to be promoted in clinic. PMID- 25509737 TI - [Uterine involution after cesarean section promoted with acupuncture: a randomized controlled trial]. AB - OBJECTIVE: To explore the effect and feasibility of acupuncture in uterine involution after cesarean section. METHODS: Seventy cases of cesarean section in primipara were randomized into an observation group (33 cases) and a control group (37 cases). In the control group, the conventional treatment was adopted after cesarean section. In the observation group, on the basic treatment as the control group, acupuncture was applied at Sanyinjiao (SP 6), Hegu (LI 4), Qihai (CV 6) and Guanyuan (CV 4). In 2 h after operation, acupuncture started, once a day, continuously for five times. The daily height of uterine fundus, daily uterine fundus decreasing degree, postpartum blood loss, lochia duration and ultrasonic B test in 42 days of postpartum were compared between the two groups. RESULTS: The therapeutic methods of the two groups all promoted uterine contraction. The postpartum height of uterine fundus in the observation group was lower than that in the control group (all P<0.05) and the uterine fundus decreasing degree was higher than that in the control group (all P<0.05). The blood loss in 2 h, 6 to 12 h and 24 to 48 h of postpartum was less than that in the control group (all P<0.05). The lochia duration in the observation group was shorter than that in the control group (P<0.05). CONCLUSION: Acupuncture promotes uterine contraction, reduces postpartum blood loss and lochia duration and benefits uterine involution after cesarean section. PMID- 25509738 TI - [Massage combined with acupoint application for 45 cases of fever caused by infantile indigestion with food retention]. PMID- 25509740 TI - [Case of polyorexia]. PMID- 25509739 TI - [Comparison of different moxibustion techniques in clinical treatment of diseases based on data mining]. AB - OBJECTIVE: To explore the specific efficacy of different moxibustion techniques in treatment of common diseases and clinical indications, and compare the specificity in clinical indications and efficacy among different moxibustion techniques so as to guide clinical practice better. METHODS: The modern computerization and data mining technology were adopted to set up moxibustion literature database. The relevant literature of moxibustion techniques in recent 60 years were collected, screened, examined, extracted and analyzed statistically so as to explore the advantages of different moxibustion techniques in clinical treatment. RESULTS: (1) Of 2,516 literature, moxa stick, moxe cone and moxa device were used in the highest frequency in internal medicine department, for 730 times, 278 times and 102 times respectively. The warm needling technique was used in the highest frequency, for 70 times in the surgical department. (2) In the dermatology department, the curative rate with moxa cone was the highest, 75%. In the ear-nose-throat department, the warm needing technique and moxa device achieved the highest curative rate, 49% for both of them. In the internal medicine department and surgical department, the curative rate of warm needling technique was 53% and 58% respectively. In the gynecology department, the curative rate of moxa device was the highest, 59%. In the pediatrics department, the curative rate of moxa cone was the highest, 80%. (3) The numbers of priority disorders, frequency >=20 times: 24 kinds of disease for moxa stick, five kinds of disease for moxa cone, 2 kinds of disease for warm needling technqiue and one disorder for moxa device. Facial paralysis, diarrhea, lumbar and leg pain and elbow and knee swelling pain were of the highest priority, treated with these 4 moxibustion techniques, with a certain of literature research values. (4) The warm needling technique achieved the better efficacy on elbow and knee swelling pain, lumbar and leg pain and diarrhea compared with the other three techniques and the curative rate was higher. The moxa device tecnique achieved the higher curative rate for facial paralysis compared with the other three techniques. CONCLUSION: Through the comparison of application frequency, curative rate, clinical application frequency in disorders and the efficacy of priority disorders in the treatment with different moxibustion techniques, it is found that moxa stick, moxa cone and moxa device are simple in manipulation, safe and effective. Hence, they can be extensively used in the treatment of common disorders in every department in clinic. The warm needling technique acts on the body by the co-work of needling and warming stimulation of mugwort. It achieves the particular effect on the disorders with complicated etiologies compared with the other three techniques. It can be chosen in priority for the disorders caused by blockage in meridian and collateral and stagnation of qi and blood. PMID- 25509741 TI - [Discussion on needling manipulation of Chifeng Yingyuan]. AB - Regarding the needling manipulation, Chifeng Yingyuan, there are different descriptions in ancient medical literature and the current teaching materials or clinical reports, especially for the understanding recorded in Jinzhenfu Poem of Golden Needle). In the current teaching materials and clinical reports, it is described that the needle is inserted deeply at first, and then shallowly; afterward, the needle tip is pushed to the middle layer and manipulated with lifting, thrusting and rotating technique, combined with twisting and flying method. After analyzing the original description in the book and the feasibility of function and operation, the authors introduced their recognition on its manipulation and techniques in this article. This manipulation should be: the needle is inserted to the middle layer, afterward, the needle body is pulled and tilted toward each of the four directions, on this basis, then twisting and flying method is applied. PMID- 25509742 TI - [Diagnosis of spinal nerves location combined with acupoints selection according to Hand-Sanyang meridian for 60 cases of cervical spondylosis of nerve root type]. PMID- 25509743 TI - [Effect of electroacupuncture pretreatment on expression of glucose-regulated protein 78 in hippocampus of rats with cerebral ischemia/reperfusion]. AB - OBJECTIVE: To explore the effects and action mechanism of electroacupuncture (EA) pretreatment on rats with transient cerebral ischemia/reperfusion. METHODS: A total of 144 healthy SD male rats were randomly divided into a sham operation group (group S), an ischemia/reperfusion group (group I/R) and an EA pretreatment group (group EA), 48 rats in each one. The model of cerebral ischemia/reperfusion was established by using 4-vessel occlusion method in the group I/R; after 5 min of cerebral ischemia, the reperfusion was performed. The group EA was treated with EA at "Dazhui" (GV 14) and "Baihui" (GV 20) 5 days before model establishment, 30 min per time, once a day. In group S, bilateral foramen alares were exposed without burning on the vertebral arteries, and bilateral common carotid arteries were unfolded and not occluded. The rats in the group I/R and group EA were sacrificed 6 h, 12 h, 24 h and 48 h after reperfusion and those in the group S were sacrificed at corresponding time to collect hippocampus example. The Western-blot method was used to measure the expression of glucose-regulated protein 78 (GRP 78), and HE staining method was used to count the number of surviving neurons, and TUNEL method was used to measure the number of apoptotic neurons. RESULTS: Compare with the group S, the number of surviving neurons in hippocampus was reduced at each reperfusion time point and the number of apoptotic neurons was increased (all P<0.05) in the group I/R and the group EA; the expression of GRP 78 at each reperfusion time point in group I/R and group EA was increased (P<0.05). Compared with the group I/R, the number of surviving neurons in hippocampus was increased at each reperfusion time point and the number of apoptotic neurons was reduced in the group EA (P<0.05); the expression of GRP 78 at each reperfusion time point was further increased (P<0.05). CONCLUSION: The electroacupuncture pretreatment has obvious cerebral protection on rats with ischemia/reperfusion, which is related with further increasing the expression of GRP 78 in ischemia area, leading to relieved endoplasmic reticulum stress. PMID- 25509744 TI - [Regulation effects of electroacupuncture with different acupoint combinations on blood lipid in rats with hyperlipemia]. AB - OBJECTIVE: To observe the regulatory effects of electroacupuncture with different acupoints combinations on blood lipid and atherosclerosis index (AI) in rats with hyperlipemia, so as to make a preliminary screening for the optimal acupoints combination for hyperlipemia. METHODS: One hundred and five clean-grade SD male rats were randomly divided into 9 groups, including a normal group, a model group, a Quchi group, a Zhongwan group, a Fenglong group, a Quchi+Zhongwan group, a Quchi+Fenglong group, a Zhongwan+Fenglong group and a Quchi+Zhongwan+Fenglong group (three acupoints group), 17 rats in the normal group and 11 rats in the rest groups. The normal group was fed with normal diet, while the rest groups were fed with high-fat diet for 3 weeks to prepare the hyperlipemia model. All the rats were given unlimited water. After the establishment of model, the normal group was fed freely without any treatment; the model group was bundled and immobilized everyday; the rest groups were bundled, immobilized and treated with electroacupuncture at corresponding acupoints with disperse-dense wave, 20 min per time, once a day. After 4 weeks, the blood examples were collected from abdominal aorta to measure the total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C), and analyzed the AI in each group. RESULTS: After the treatment, TC, TG, HDL-C, LDL-C and AI in each acupuncture group were all lower than those in the model group (P<0.05, P<0.01). Compared with single acupoint group and the Quchi+Zhongwan group, the content of TC in the three acupoints group was lower (P<0.01). The differences of content of TG among each acupuncture group were not significant (all P>0.05). Compared with the rest 6 acupuncture groups, the content of HDL-C and AI in the three acupoints group were significantly different (all P<0.05). The content of LDL-C in the three acupoints group was decreased as compared with the Quchi group and the Zhong-wan group. CONCLUSION: The electroacupuncture at "Quchi" (LI 11), "Zhongwan" (CV 12) and "Fenglong" (ST 40) has more advantages on regulating the content of HDL-C and LDL-C as well as improving AI in hyperlipemia rats, and it has superior effects on blood lipid metabolism. PMID- 25509745 TI - [Catgut-embedding combined with Chinese medicine for 62 cases of elderly patients with functional constipation]. PMID- 25509746 TI - [Professor Dong Gui-rong's experiences in treatment of child cerebral palsy]. AB - According to the characteristics of the etiology and pathogenesis of child cerebral palsy, on the basis of "regulating the mind in treatment of all kinds of diseases" and "regulating the functions of five zang organs with back-shu points", Professor DONG Gui-rong applied the penetrating needling technique on the scalp points and acupuncture at back-shu points of five zang organs in the treatment of child cerebral palsy. The valuable clinical experiences have been summarized as "regulating the mind with scalp needling technique, benefiting the brain and opening the orifice", "regulating five zang organs with back-shu points" and "integration of acupuncture and rehabilitation, and function reconstruction". Two effective cases were introduced. PMID- 25509747 TI - [Clinical experiences of Professor Li Zhi-dao's acupuncture technique at muscle belly for arthralgia]. AB - Professor LI Zhi-dao's acupuncture technique at muscle belly and its clinical experiences for the treatment of arthralgia are introduced. From aspects of TCM, anatomical physiology and sports biomechanics, the theory basis of this technique is explained, while its method is elaborated in details from acupoint selection and manipulation combined with classic medical cases. The acupuncture technique at muscle belly is applied at the muscles which already have pathological changes, avoiding re-stimulation on the pain area. It provides new thinking methods and references for acupuncture to treat arthralgia. PMID- 25509748 TI - [Case of thalamic pain]. PMID- 25509749 TI - [Acupuncture at lower he-sea point by using kinetic needling for 42 cases of periathritis of shoulder]. PMID- 25509750 TI - [Acupuncture combined with exercise therapy for 23 cases of knee osteoarthritis]. PMID- 25509751 TI - [Thinking of therapeutic mechanism of small knife needle in treating closed myofascitis]. AB - The authors investigated and discussed therapeutic mechanism of small knife needle in treating closed myofascitis on the basis of pathomechanism of modern medicine and acupuncture theory of TCM among numbers of clinical cases and experimental data. Therapeutic mechanism lies in 6 aspects: (1) Relieve the energy crisis of tenderness point on muscular fasciae; (2) Affect nervous system and reduce induction of harmful stimulating signal; (3) Inhibit aseptic inflammatory reaction on muscular fasciae; (4) Regulate dynamic equilibrium of soft tissue by cutting scar and releasing the conglutination; (5) Increase patients' regional threshold of feeling; (6) Reduce tension and pressure of soft tissue of tenderness point so as to relieve extrusion of nervus cutaneous. PMID- 25509752 TI - [Case of urination and defecation function disturbance after intraspinal tumor surgery]. PMID- 25509753 TI - [Anatomical basis and clinical application of "two points" acupotomology surgery program in treating cubital tunnel syndrome]. AB - OBJECTIVE: To explore an effective acupotomology surgery program in treating cubital tunnel syndrome. METHODS: According to pathogenic factors and elbow anatomy, a "two points" acupotomology surgery program was designed, which could loose the attachment point of arcuate ligament on medial border of olecroanon and medial epicondyle of humerus. Twenty-one cases of cubital tunnel syndrome were treated with acupotmology, then the efficacy was obsered. RESULTS: After one year postoperative visit, 21 patients with ulnar nerve area skin numbness were cured, claw hand deformity and medial hand muscle atrophy recovered significantly. Results of function evaluation were excellent in 17 cases, good in 2 cases, fair in 2 cases and poor in 0 cases, the good rate was 90.5%. CONCLUSION: The acupotomology surgery program which could cut the starting and ending points of osborne's ligament and solve the problem of ulnar nerve entrapment is an easy, little-traumatic and effective minimally invasive surgery which also conforms to the anatomical structure. PMID- 25509754 TI - [Thirty cases of cervical spondylosis of neck type treated with acupuncturing at Sanjian (LI 3), Yujian (Extra) and Jiaji (EX-B 2)]. PMID- 25509755 TI - [Brief introduction of acupuncture needling and teaching keypoint]. AB - We summarized our accumulated clinical and teaching experiences and explored the regularity of acupuncture needling and teaching. It is of great importance in pressing hand during inserting needle. Stroking and pressing are two crucial parts which deserve more attention, and seldom useage of pressing hand should be abolished. Operating hand needs practice before inserting needle, while it should fully relaxed during inserting. Blending "touching", "stretch" "gathering" "erupting" and "advancing" in single moment, applying appropriate dynamic mode of inserting needle such as "join 3 forces as one" "3 points in a line" expertly and naturally. In addition, enough attention should be paid on "altering direction" and "shifting point". Inserting deftly and powerfully, no/slight sensation, deqi when inserting needle are the highest reflection as an acupuncturist. PMID- 25509756 TI - [Analysis on evaluation tool for literature quality in clinical study]. AB - The tools used for the literature quality evaluation are introduced. The common evaluation tools that are publicly and extensively used for the evaluation of clinical trial literature quality in the world are analyzed, including Jadad scale, Consolidated Standards of Reporting Trials (CONSORT) statement and Grades of Recommendations Assessment, Development and Evaluation (GRADE) system and the others. Additionally, the present development, updates and applications of these tools are involved in analysis. PMID- 25509757 TI - [Ancient clinical application of herb-participated moxibustion on umbilicus]. AB - In order to further improve the curative effect of the herb-participated moxibustion on umbilicus, we collected a wide range of literature on herb participated moxibustion on umbilicus and then systematically arranged them to analyze and summarize the technology and operating methods of herb-participated moxibustion on umbilicus. We also briefly discussed issues on application of medicine, locust tree skin and ginger, the method of kneading dough for medical uses, and the appropriate size of moxa cone and its using frequency in order to form clear concepts and standardized operations to provide theories and operational basis for the clinical application of modern herb-participated moxibustion on umbilicus. PMID- 25509758 TI - [Acupuncture master Xu Yi-nian and his Practical Acupuncture in the Republic of China]. AB - By collecting and studying Practical Acupuncture written by XU Yi-nian, Guangdong acupuncture master in the Republic of China, and using literature methodology, the life story of XU Yi-nian is textually researched and his acupuncture characteristics is analyzed. The results indicate that XU Yi-nian emphasizes on the utility of acupuncture manipulations and acupoint selection, the application of folk experiences in moxibustion and Sha disorders. He pays attention to the co work of acupuncture and medicine and his work collects the therapeutic experiences of different schools and deserves to be further explored and validated. PMID- 25509759 TI - [Zhu Lian's contribution to international communication of acupuncture moxibustion]. AB - ZHU Lian is the founder of international communication of acupuncture-moxibustion after establishment of New China. This article discussed ZHU Lian's great deal of pioneering work and historic contributions from the aspects of acupuncture moxibustion treatments for foreign people, international training and communication, and the international influence of Xin Zhenjiu Xue. Our research showed that ZHU Lian's early work didn't only enlarge acupuncture's worldwide influence and spreading pace, especially in Soviet Union, India and Korea, but also accumulated precious experiences for each subject of Chinese medicine attending into international medical care and academic communication in the future. PMID- 25509760 TI - [Case of diarrhea]. PMID- 25509761 TI - [Acupuncture combined with traction therapy for lumbar disc herniation: a systematic review]. AB - To evaluate the efficacy and safety of acupuncture combined with traction therapy for lumbar disc herniation, providing the basis for future research strategies. Randomized control trials. (RCT) of acupuncture combined with traction therapy for lumber disc herniation at home and abroad from 2000 to 2013 were searched, analysis and evaluation of literature and strength of evidence were based on the principles and methods of Evidence-based Medicine. The total effective rate and curative rate were considered as primary outcome measures; pain improvement, quality of life, relapse rate and adverse effects were considered as secondary outcome measures. Seventeen RCTs were identified, Meta-analysis showed that (1) total effective rate and curative rate: acupuncture combined with traction therapy was better than single therapy (acupuncture or traction); (2) pain improvement: acupuncture combined with traction therapy was better than traction therapy; (3) relapse rate: current evidence could not support the conclusion that acupuncture combined with traction therapy was better than traction therapy. Acupuncture combined with traction therapy for lumbar disc herniation was effective. However, the included studies were with high risk of bias, important outcome measures such as quality of life, relapse rate and adverse effects were not found in most of the studies. Current evidence has not yet been able to fully reflect acupuncture combined with traction therapy for lumbar disc herniation is better than single therapy, so more RCTs of higher quality are needed to further confirm its efficacy and safety. PMID- 25509762 TI - Medical momentum. Scientists make major moves in tackling five challenging diseases. PMID- 25509763 TI - The new Ebola protocols. PMID- 25509764 TI - 12 answers to Ebola's hard questions. PMID- 25509765 TI - [Total hip arthroplasty for non-functional bony ankylosed hip in young and middle aged patients]. AB - OBJECTIVE: To explore the effectiveness of total hip arthroplasty (THA) for non functional bony ankylosed hip in young and middle-aged patients. METHODS: Between January 2010 and March 2013, 14 cases (19 hips) of non-functional bony ankylosed hip were treated by THA. There were 9 males and 5 females, aged 37.5 years on average (range, 23- 58 years). The left hip was involved in 6 cases, the right hip in 3 cases, and bilateral hips in 5 cases. The causes were tuberculosis in 2 patients, ankylosing spondylitis in 5 patients, traumatic arthritis in 5 patients, osteoarthritis in 1 patient, and suppurative infection in 1 patient. The disease duration was 7-18 years with an average of 8.9 years. Flexion stiffness was observed in 10 hips, flexion abduction stiffness in 6 hips, and flexion adduction shortening stiffness in 3 hips. Only 5 patients could walk with a crutch before operation. Harris hip score was 24.368 +/- 7.625. RESULTS: The average operation time was 63.4 minutes (range, 50-90 minutes). The average intraoperative blood loss was 196.8 mL (range, 100-400 mL). Patients obtained primary healing of incision; no complication of neurovascular injury, fracture, joint dislocation, or infection occurred. All patients were followed up 2.2 years on average (range, 1 year to 4 years and 3 months). The Harris score was 86.837 +/- 7.742 at last follow- up, showing significant difference when compared with preoperative score (t = -41.956, P = 0.000). The results were excellent in 5 hips, good in 11 hips, fair in 2 hips, and poor in 1 hip, with an excellent and good rate of 84.2%. All patients could basically take care of themselves; 2 patients could walk with crutch, and the other patients could walk without crutch. X-ray films showed that prosthesis was in good position; no shifting, loosening, or sinking was found. Heterotopic ossification occurred in 2 hips. CONCLUSION: THA is an effective surgical approach to treat non-functional bony ankylosed hip in young and middle- aged patients. PMID- 25509766 TI - [Short- and medium-term effectivenesses of stemless hip arthroplasty for treating hip joint disease in young and middle-aged patients]. AB - OBJECTIVE: To summarize the short- and medium-term effectivenesses of stemless hip arthroplasty for treating hip joint disease in young and middle-aged patients. METHODS: Between June 2005 and December 2010, 25 cases (27 hips) of hip joint disease were treated with stemless hip arthroplasty. There were 17 males (19 hips) and 8 females (8 hips) with an average age of 45.6 years (range, 30-57 years), including 13 left hips, 10 right hips, and 2 bilateral hips. The causes included avascular necrosis of the femoral head (ANFH) secondary to femoral neck fracture in 5 cases (5 hips), ANFH in 15 cases (16 hips), osteoarthritis of the hip joint caused by ankylosing spondylitis in 2 cases (3 hips), osteoarthritis of the hip joint caused by dysplasia of acetabular in 2 cases (2 hips), and rheumatoid arthritis in 1 case (1 hip). The disease duration was 1-17 years (mean, 6.1 years). Before operation, the Harris score was 47.6 +/- 14.2. RESULTS: The incision healed by first intention in all patients, and no complications occurred, such as infection, periprosthetic fracture, and deep vein thrombosis of lower extremity. Twenty-five patients (27 hips) were followed up 36-96 months (mean, 51 months). One case (1 hip) had sciatic nerve injury after operation, which was relieved by symptomatic treatment. One case (1 hip) had prosthesis loosening, which was relieved after revision. The survival rate of prosthesis was 96.3% (26/27). At last follow-up, the Harris score was 92.1 +/- 3.6, which was significantly better than preoperative score (t = 18.241, P = 0.000). The excellent and good rate was 88.9% (excellent in 19 hips, good in 5 hips, fair in 2 hips, and poor in 1 hip). The X-ray films showed good location of prosthesis, and no evidence of dislocation, bone resorption, osteolysis, and heterotopic ossification. CONCLUSION: Because of reserving femoral neck, biomechanics conduction and distribute of the proximal femur achieve natural biomechanics state of the human body. The short- and medium-term effectivenesses of stemless hip arthroplasty for treating hip joint disease in young and middle-aged patients are satisfactory, but the long-term effectiveness need further observation. PMID- 25509767 TI - [Comparison of total knee arthroplasty with computer navigation systems and conventional techniques]. AB - OBJECTIVE: To evaluate the value of total knee arthroplasty (TKA) with computer navigation by comparing with conventional TKA. METHODS: Between May 2010 and December 2011, 45 patients underwent primary unilateral TKA, and the clinical data were retrospectively analyzed. Of 45 patients, 22 cases were treated with TKA with computer navigation (group A), 23 cases with the conventional TKA (group B). There was no significant difference in gender, age, body mass index, side, cause of disease, disease duration, preoperative range of motion (ROM) of the knee, and preoperative Hospital for Special Surgery (HSS) score between 2 groups (P > 0.05). The operation time, intraoperative blood loss, incidence of patellar retinacular release, complication, and drainage volume were compared. The prosthesis loosening, postoperative HSS score, and ROM of the knee were also compared. RESULTS: No difference was found in the incidence of patellar retinacular release during TKA, and it was 13.6% (3/22) in group A and was 4.3% (1/23) in group B, showing no significant difference (chi2 = 1.198, P = 0.346). The operation time of group A was significantly longer than that of group B (t = 7.557, P = 0.000). There was no significant difference in intraoperative blood loss during TKA between 2 groups (t = -0.295, P = 0.769), while the drainage volume of group A was significantly less than that of group B (t = -2.419, P = 0.020). Incomplete fracture during TKA and acute infection occurred at 8 days after TKA in 1 case of group A respectively, while no fracture or infection was found in group B, showing significant difference (Z = -0.509, P = 0.000). The patients of 2 groups were followed up 27-46 months. No significant difference in valgus and varus of knee, and malalignment of the femoral and tibial prosthesis was found (P > 0.05). There was no significant difference in HSS score and ROM of the knee at last follow-up between 2 groups (P > 0.05). No prosthesis loosening was found in 2 groups. CONCLUSION: TKA with computer navigation has similar results to conventional TKA in the mechanical alignment, but it obviously prolongs operation time. It may also increase the incidence of infection and tractor pin related fracture. PMID- 25509768 TI - [Effectiveness of mini incision and absorbable screw fixation for treatment of anterior cruciate ligament tibial eminence avulsion fracture]. AB - OBJECTIVE: To investigate the effectiveness of open reduction by mini incision and absorbable screw internal fixation for the treatment of anterior cruciate ligament (ACL) tibial eminence avulsion fracture. METHODS: Between January 2006 and July 2012, 90 patients (90 knees) with ACL tibial eminence avulsion fracture were treated. There were 58 males and 32 females, aged from 10 to 58 years with an average of 33.7 years. The causes of injury were traffic accident injury in 60 cases, sports injury in 22 cases, and fallinginjury in 8 cases. The disease duration was 1-365 days with a median of 106 days. Combined injuries included 14 cases of meniscus injury, 5 cases of medial collateral ligament injury, and 3 cases of avulsion fracture of the anterior horn of the lateral meniscus. All patients underwent open reduction by mini incision and internal fixation with absorbable screw. Postoperative rehabilitation exercise was performed. RESULTS: Two patients had delayed healing of incision, and others obtained primary healing. All the patients were followed up 6-72 months (mean, 40.1 months). X-ray examination showed that bone union was achieved in all patients at 3-12 months after operation; nail tail came off in 7 cases at 4-13 months after operation, and the nail tail was taken out under arthroscopy. At 6-12 months after operation, the range of motion (ROM), Tegner score, Lysholm score, and International Knee Documentation Committee (IKDC) score were significantly increased when compared with preoperative ones (P < 0.05). CONCLUSION: A combination of open reduction by mini incision and absorbable screw internal fixation for the treatment of ACL tibial eminence avulsion fracture has the advantages of easy operation, firm fixation, and satisfactory functional rehabilitation, so it is a safe and effective method for the treatment of ACL tibial eminence avulsion fracture. PMID- 25509769 TI - [Application of lateral malleolus hook-plate in treatment of stage II supination adduction type medial malleolus fracture]. AB - OBJECTIVE: To investigate the application of lateral malleolus hook-plate for the treatment of stage II supination-adduction type medial malleolus fractures. METHODS: Between January 2011 and June 2013, 21 patients with stage II supination adduction type ankle fractures were treated with lateral malleolus hook-plate, including 12 males and 9 females with an average age of 55.5 years (range, 27-65 years). The injury causes were sprain in 17 cases and traffic accident in 4 cases. The mean time between injury and admission was 12.4 hours (range, 2-72 hours). The tibial distal medial articular surface collapse was found in 7 cases by CT examination and in 3 cases by X-ray film. Of 21 cases, there were 12 cases of low transverse fractures of lateral malleolus, 7 cases of short oblique fractures of lateral malleolus, and 2 cases of ankle joint lateral collateral ligament injury without fractures of lateral malleolus. After operation, the clinical outcome was evaluated according to the talus-leg angle, the recovery of Coin-sign continuity, inside-outside and top ankle gap, talus slope, American Orthopedic Foot and Ankle Society (AOFAS) score, Olerud-Molander score, Kofoed evaluation standards, and patient satisfaction. RESULTS: Seventeen cases were followed up 18.7 months on average (range, 12-25 months). Primary healing was obtained in 16 cases except 1 case of delayed healing. Fracture healed at an average of 14.6 weeks (range, 12-16 weeks). All cases achieved anatomical reduction, the continuity of Coin-sign, and consistency of inside and outside joint gap; no talus tilt occurred. There was no complication of reduction loss, loosening or breakage of internal fixation, or osteoarthritis during follow-up. The talus-leg angle of the affected side was significantly improved to (83.4 +/- 1.8) degrees at 1 week after operation from preoperative (74.8 +/- 7.1) degrees (t = 5.370, P = 0.000), but no significant difference was found when compared with normal side (83.8 +/- 2.3) degrees (t = 0.676, P = 0.509). The AOFAS score, Olerud-Molander score, and range of motion at 1 week, 3 months, and 1 year after operation were significantly improved when compared with preoperative ones (P < 0.05). According to Kofoed evaluation standard, the outcome was excellent in 15 cases and good in 2 cases; the excellent and good rate was 100%. According to patient satisfaction, the outcome was excellent in 13 cases, good in 3 cases, and poor in 1 case; the excellent and good rate was 94.1%. CONCLUSION: The use of lateral malleolus hook-plate for fixation of stage II supination-adduction type medial malleolus fracture not only can effectively maintain anatomical reduction and supporting function, but also can prevent re-collapsing of the reset joint surface. The surgical method can not increase soft tissue complication, so it is a safe and effective method. PMID- 25509770 TI - [Short-term effectiveness of minimally invasive percutaneous plate osteosynthesis in treatment of anterior pelvic ring fracture]. AB - OBJECTIVE: To investigate the short-term effectiveness of minimally invasive percutaneous plate osteosynthesis (MIPPO) in treatment of anterior pelvic ring fractures. METHODS: Between January 2012 and October 2013, 16 patients with anterior pelvic ring fractures were treated with MIPPO. There were 10 males and 6 females at the age of 20-63 years (mean, 41 years). The causes of injury were traffic accident in 9 cases and falling from height in 7 cases. The duration of injury to admission was 2 hours to 5 days (mean, 1 day). According to Tile classification, 8 cases were rated as type B2, 4 cases as type B3, 2 cases as type C1, and 2 cases as type C2. Of them, 2 cases had iliac wing fracture, and 4 cases had pelvic posterior ring fracture. The time from admission to operation was 3-12 days (mean, 6 days). RESULTS: The bleeding volume was 60-120 mL (mean, 70 mL). All wounds healed by first intention. No postoperative complication of deep venous thrombosis or long-term continuous pain occurred. All cases were followed up 5-27 months (mean, 11.5 months). No clinical manifestation of lateral femoral cutaneous nerve injury or spermatic cord injury was found, and cremasteric reflex existed in males. All cases obtained bony union, and the healing time was 12-16 weeks (mean, 13 weeks). During the follow-up period, no loss of fracture reduction and no internal fixation loosening or broken were observed. According to Matta radiological evaluation criterion, 16 cases had anatomical reduction, and 3 cases had satisfactory reduction; according to Majeed scoring system of pelvic fracture, the results were excellent in 12 cases and good in 4 cases. CONCLUSION: MIPPO for treatment of anterior pelvic ring fractures has the advantages of less intraoperative blood loss, few soft tissue complications, and low infection rate, and can get satisfactory short- term effectiveness. PMID- 25509771 TI - [Kirschner wire fixation in three joints combined with bone anchor repair for treatment of acute perilunate injury ]. AB - OBJECTIVE: To investigate the effectiveness of Kirschner wire fixation in scapholunate joint, capitolunate joint, and lunotriquetral joint combined with bone anchor repair for the treatment of acute perilunate injury. METHODS: Between January 2007 and January 2012, 35 cases of acute perilunate injury were treated. There were 30 males and 5 females with an average age of 45.5 years (range, 32-56 years). Fractures were caused by falling from height in 18 cases, by traffic accident in 11 cases, and by fall injury in 4 cases. The time from injury to operation was 2-6 days (mean, 3.4 days). There were 23 cases of trans-scaphoid perilunate dislocation, 10 cases of perilunate dislocation, and 2 cases of trans triangular perilunate dislocation. Associated injuries included median nerve injury in 6 cases, radius styloid fracture in 8 cases, ulnar styloid fracture in 2 cases, and distal tibial fracture in 1 case. All the patients were treated by open reduction, Herbert screw fixation of scaphoid fractures, and Kirschner wire fixation in scapholunate joint, capitolunate joint, and lunotriquetral joint, and the intercarpal ligaments were repaired by Mitek bone anchor. RESULTS: Superficial wound infection occurred in 2 cases, and primary healing of incision obtained in others. Thirty-five patients were followed up 12-35 months (mean, 18 months). X-ray films showed fracture union in 21 cases of scaphoid fractures, and bone nonunion in 2 cases of scaphoid fractures. During the follow-up period, there was no avascular necrosis ofscaphoid or lunate. At last follow-up, the scapholunate angle, radiolunate angle, and wrist range of motion (ROM) in extension had no significant difference between affected and unaffected sides (P > 0.05). The wrist ROM in flexion and grip strength of affected side were not up to the levels of unaffected side (P < 0.05). According to the modified Mayo wrist scoring system, the score was 79.9 +/- 10.7, which were excellent in 8 cases, good in 17 cases, fair in 7 cases, and poor in 3 cases, and the excellent and good rate was 71.4%. The disability of arm-shoulder-hand (DASH) questionnaires score was 21 +/- 10. Traumatic osteoarthritis was observed in 2 cases. CONCLUSION: Kirschner wire fixation in scapholunate joint, capitolunate joint, and lunotriquetral joint combined with bone anchor repair for the treatment of acute perilunate injury can get early stability of the carpal joint, favorable intercarpal ligament repair, and good recovery of wrist joint function. PMID- 25509772 TI - [Development of polyaxial locking plate screw system of sacroiliac joint]. AB - OBJECTIVE: To develop an instrument for sacroiliac joint fixation with less injury and less complications. METHODS: Firstly, 18 adult pelvic specimens (8 males and 10 females) were used to measure the anatomical data related to the locking plates and locking screws on the sacrum and ilium, and the polyaxial locking plate screw system of the sacroiliac joint was designed according to the anatomic data. This system was made of medical titanium alloy. Then 4 adult male plevic specimens were harvested and the experiment was divided into 3 groups: group A (normal pelvic), group B (the dislocated sacroiliac joint fixed with sacroiliac screws), and group C (the dislocated sacroiliac joint fixed with polyaxial locking plate screw system). The vertical displacement of sacroiliac joint under the condition of 0-700 N vertical load and the horizontal displacement on angle under the condition of 0-12 N.m torsional load were compared among the 3 groups by using the biological material test system. Finally, the simulated application test was performed on 1 adult male cadaveric specimen to observe soft tissue injury and the position of the locking plate and screw by X-ray films. RESULTS: According to the anatomic data of the sacrum and ilium, the polyaxial locking plate screw system of the sacroiliac joint was designed. The biomechanical results showed that the vertical displacement of the sacroiliac joint under the condition of 0-700 N vertical load in group A was significantly bigger than that in group B and group C (P < 0.05), but there was no significant difference between group B and group C (P > 0.05). The horizontal displacement on angle under the condition of 0-12 N.m torsional load in group A was significantly less than that in group B and group C (P < 0.05). The horizontal displacement on angle under the condition of 0-6 N.m torsional load in group B was bigger than that in group C, and the horizontal displacement on angle under the condition of 6-12 N.m torsional load in group B was less than that in group C, but there was no significant difference between group B and group C (P > 0.05). The test of simulating application showed that the specimen suffered less soft tissue injury, and this instrument could be implanted precisely and safely. CONCLUSION: The polyaxial locking plate screw system of the sacroiliac joint has the advantages of smaller volume and less injury; polyaxial fixation enables flexible adjustment screw direction. The simulated application test shows satisfactory fixing effect. PMID- 25509773 TI - [Biomechanical comparative study on proximal femoral locking plate and Gamma3 for treatment of stable intertrochanteric fracture]. AB - OBJECTIVE: To compare the biomechanical properties between the proximal femoral locking plate and Gamma3 for fixing stable intertrochanteric fracture so as to provide a theoretical basis for selecting internal fixation in the clinical application. METHODS: Five pairs of antiseptic femur specimens were selected. Specimens of each pair of matching were randomly divided into groups A and B (n=5). All specimens were made the intertrochanteric fracture of 31A1.1 type according to AO/Association for the Study of Internal Fixation (AO/ASIF) classification. Fracture was fixed with Gamma3 in group A and with proximal femoral locking plate in group B. The axial compression, destruction, and torsion tests were carried out on the mechanical testing machine. RESULTS: Axial compression test: The load-displacement curve of groups A and B was basically a straight line; axial stiffness of groups A and B was (621.00 +/- 36.48) N/mm and (542.55 +/- 46.94) N/mm respectively, showing significant difference (t = 3.648, P = 0.036). Destruction test: The maximum yield load of groups A and B was (4,394.82 +/- 450.37) N and (2,987.54 +/- 112.14) N respectively, showing significant difference (t = 5.433, P = -0.032). After loading maximum yield load, femoral fracture occurred again, and internal fixation and bone interface loosening were observed in group A; bending and breaking of proximal locking screw for internal fixation were found in group B, but loosening of internal fixation and bone interface was more obvious in group A than in group B. Torsion test: The torque of specimens in 2 groups increased with the increase of torsion angle (P < 0.05), the torque corresponding to the torsion angle in group B was larger than that in group A, but the difference was not significant (P > 0.05). The torsional stiffness of groups A and B was (1.78 +/- 0.16) N.mm/deg and (2.01 +/- 0.08) N.mm/deg respectively, showing no significant difference (t = -3.833, P = 0.162). CONCLUSION: Proximal femoral locking plate and Gamma3 in the treatment of stable intertrochanteric fracture have good biomechanical properties, which can meet the requirements of minimal invasion, strong internal fixation, and early activity. PMID- 25509774 TI - [Effect of cervical disc arthroplasty and anterior cervical decompression and fusion on adjacent segment degeneration]. AB - OBJECTIVE: To compare the effect on adjacent segment degeneration after cervical disc arthroplasty (CDA) and anterior cervical decompression and fusion (ACDF) for treatment of cervical spondylosis. METHODS: Between August 2009 and February 2012, 60 cases of single segmental cervical spondylosis accorded with the inclusion criteria were included. Of 60 patients, 28 patients underwent CDA (CDA group) and 32 patients underwent ACDF (ACDF group). There was no significant difference in gender, age, disease duration, pathological type, pathological segment, the time of conservation treatment, preoperative neck disability index (NDI), preoperative Japanese Orthopaedic Association (JOA) score, and degeneration of the adjacent segment and disc between 2 groups (P > 0.05). The NDI and JOA score were used to evaluate effectiveness. The range of motion (ROM) of adjacent segment was measured, and degeneration of the adjacent segment and disc was evaluated according to Kellgren grading system based on X-ray and Miyazaki grading system based on T2-weighted MRI, respectively. RESULTS: The follow-up time was 24-50 months (mean, 34 months) in 2 groups. All patients had no complication of prosthesis loosening, dislocation, or fracture of plate. The NDI and JOA scores from 12 months after operation were significantly improved compared with preoperative scores in 2 groups (P < 0.05), but no significant difference was found at each time point between 2 groups (P > 0.05). The improvement rate of JOA was 80.68% +/- 4.01% in ACDF group and was 79.44% +/- 3.76% in CDA group at last follow-up, showing no significant difference (t = 1.237, P = 0.221). And the improvement rate of JOA in 2 groups were excellent. There was no significant difference in ROM and degeneration grading of adjacent segments between at last follow-up and at pre-operation in 2 groups (P > 0.05), and between 2 groups at pre-operation and at last follow-up (P > 0.05). The degeneration grading of disc at last follow-up showed significant difference in 2 groups compared with preoperative ones (P < 0.05), but no significant difference was found between 2 groups (Z = 0.132, P = 0.895). CONCLUSION: Both CDA and ACDF can achieve good effectiveness in treating cervical spondylosis, but CDA can not significantly slow down the degeneration of adjacent segment disc. PMID- 25509775 TI - [Effectiveness of pedicle screw fixation combined with non-fusion technology for treatment of thoracolumbar fracture through Wiltse paraspinal approach]. AB - OBJECTIVE: To explore the effectiveness of pedicle screw fixation combined with non-fusion technology for the treatment of thoracolumbar fracture (AO type A) through Wiltse paraspinal approach. METHODS: Between March 2011 and December 2012, 35 cases of thoracolumbar fractures were treated with pedicle screw fixation combined with non- fusion technology by Wiltse paraspinal approach. There were 27 males and 8 females, aged from 19 to 51 years (mean, 39.7 years). The time from injury to operation varied from 3 to 15 days (mean, 5.9 days). The causes of injury were traffic accident in 17 cases, falling from height in 11 cases, and crush trauma in 7 cases. All fractures were single-segment fracture, including Ts in 1 case, T9 in 2 cases, T10 in 2 cases, T11 in 3 cases, T12 in 12 cases, L1 in 10 cases, L2 in 4 cases, and L3 in 1 case. According to AO classification, there were 17 type A1 fractures (compression fracture), 3 type A2 fractures (splitting fracture), and 15 type A3 fractures (burst fracture). Based on American Spinal Injury Association (ASIA) spinal cord injury grade, all cases were in grade E before operation. Perioperative parameters were recorded; the anterior vertebral height and kyphotic Cobb angle of vertebral bodies were measured before and after operation to evaluate the effect of correction. RESULTS: The mean operating time was 74 minutes; the mean blood loss was 125 mL; and the mean drainage volume was 51 mL. Skin necrosis of incision occurred in 2 cases and was cured after dressing change; primary healing of incision was obtained in the others. All patients were followed up 15-24 months (mean, 17.3 months). No loosening or breakage of internal fixation was found. The internal fixator was removed at 12-19 months after operation (mean, 15 months). There were significant differences in Cobb's angle and anterior vertebral body height between before operation and immediately after operation, before internal fixator removal as well as at last follow- up (P < 0.05). There was no significant difference in anterior vertebral body height among the postoperative time points (P > 0.05). There was significant difference in Cobb's angle between immediately after operation and before internal fixator removal as well as at last follow-up (P < 0.05), but the difference was not significant between before internal fixator removal and at last follow-up (P > 0.05). The motion of fixed segment was restored after internal fixator removal. CONCLUSION: It is an effective method of pedicle screw fixation combined with non-fusion technology through Wiltse paraspinal approach for the treatment of thoracolumbar fracture (AO type A). The method has the advantages of simple operation and less trauma. It can effectively rebuild the height of vertebral body and correct kyphotic deformity. PMID- 25509776 TI - [Surgical treatment of thoracic and lumbar tuberculosis complicated with severe kyphotic deformity and paraplegia]. AB - OBJECTIVE: To explore an method and the effectiveness of surgical treatment of thoracic and lumbar tuberculosis complicated with severe kyphotic deformity (Cobb angle >= 55 degrees ) and paraplegia. METHODS: Between January 2009 and January 2013, 13 cases of thoracic and lumbar tuberculosis complicated with severe kyphotic deformity and paraplegia were treated by one-stage posterior vertebral column resection (PVCR), debridement, bone grafting, and instrumentation fixation. Of 13 patients, 7 were male and 6 were female with an average age of 23.5 years (range, 14-49 years). The disease duration was 13-38 months (mean, 19 months). The Cobb angle of kyphosis was (65.23 +/- 7.95) degrees . The visual analogue scale score (VAS) was 7.38 +/- 0.31. In 13 patients with incomplete paraplegia, 1 case was classified as Frankel grade B, 7 cases as grade C, and 5 cases as grade D. The lesion involved 2 vertebrae bodies in 7 cases (T8, 9 in 1 case, T11, 12 in 2 cases, and T12, L1 in 4 cases), 3 vertebrae bodies in 4 cases (T10-12 in 2 cases, T9-11 in 1 case, and T11-L1 in 1 case), and 4 vertebrae bodies in 2 cases (T4-7 in 1 case and T6-9 in 1 case). Imaging examination showed paravertebral abscess in 10 cases. RESULTS: Healing of incision by first intention was obtained in all patients. The neurological injury and pulmonary infection occurred in 3 cases and 2 cases respectively, which were cured after symptomatic treatment. Thirteen patients were followed up 12-48 months (mean, 17 months). The erythrocyte sedimentation rate restored to normal level in all cases at 3-7 months after operation. All the patients achieved bony fusion at 10-20 months (mean, 14 months) after operation. No fixation loosening, displacement, or fracture occurred during follow-up. Common toxic symptom of tuberculosis disappeared, and there was no recurrence of local tuberculosis. The Cobb angle of kyphosis was corrected to (22.38 +/- 1.76) degrees at 1 week and (22.15 +/- 1.83) degrees at last follow-up, showing significant difference when compared with preoperative one (P < 0.05). There was no significant difference in Cobb angle of kyphosis between at 1 week after operation and at last follow-up (P > 0.05). The Frankel grading was grade B in 1 case, grade C in 10 cases, and grade D in 2 cases at 1 week after operation; and it was grade D in 1 case and grade E in 12 cases at last follow-up; significant differences were found between at pre- and post-operation (P < 0.05), and between at 1 week after operation and at last follow-up (P < 0.05). The VAS score was 4.08 +/- 0.76 at 1 week and 0.62 +/- 0.14 at last follow-up, showing significant differences between at pre- and post operation (P < 0.05) and between at 1 week after operation and at last follow-up (P < 0.05). CONCLUSION: One-stage PVCR, debridement, bone grafting, and instrumentation fixation is proved to be successful in treating thoracic and lumbar tuberculosis complicated with severe kyphotic deformity and paraplegia. PMID- 25509777 TI - [Objective assessment of combined soft tissue flap in defect repair of laryngeal carcinoma operation]. AB - OBJECTIVE: To objectively evaluate the effectiveness of the ventricular fold pull down combined with strip myofascial flap to repair laryngeal defect after early glottic carcinoma operation with glottic morphological parameters and voice parameters. METHODS: Between January 2008 and December 2012, 47 patients with early glottic carcinoma and anterior commissure involvement underwent partial laryngectomy. All patients were male, aged from 60 to 75 years (mean, 68.5 years). The disease duration was 4-11 months (mean, 7.2 months). According to American Joint Committee on Cancer (AJCC) TNM criteria, 28 cases were classified as T1aN0M0, 14 cases as T1bN0M0, and 5 cases as T2NoMo. Laryngeal defect after resection of tumor was repaired by ventricular fold pull-down combined with strip myofascial flap. At 1 day before operation and at 1 year after operation, multilayer spiral CT was used to scan larynx, to measure and compare the anteroposterior diameter of vocal area, the distance between both sides of the vocal process, and the thickness of soft tissue of vocal area, and the effect of combined soft tissue flap was objectively assessed in laryngeal morphology reconstruction. The actual voice parameters [including Fo, Jitter, Shimmer, normalized noise energy (NNE), and maximum phonatory time (MPT)] were tested and compared, and the effect of the combined soft tissue flap on postoperative laryngeal pronunciation was evaluated. RESULTS: Postoperative pathological examination revealed well-differentiated squamous cell carcinoma in 38 cases, and moderately-differentiated squamous cell carcinoma in 9 cases; no tumor was found in the resection margin. Healing of neck incision was obtained in all patients at 7-9 days after operation. Forty-four cases were decannulated at 9-11 days after operation and the remaining 3 cases were decannulated at 3 weeks after operation. Oral feeding usually started in all cases at 3-4 days after operation. All patients were followed up 1 year. At 1 year after operation, the anteroposterior diameter of vocal area was significantly reduced when compared with preoperative one (t = 15.161, P = 0.000); the distance between both sides of the vocal process and the thickness of soft tissue of vocal area had no significant changes (P > 0.05). Compared with preoperative ones, there were significant differences in Shimmer, NNE, and MPT (P < 0.05), but no significant difference was found in Fo and Jitter (P > 0.05) at 1 year after operation. CONCLUSION: Ventricular fold pull-down combined with strip myofascial flap can repair laryngeal defect effectively after partial laryngectomy and maintain the effective airway after operation. It not only has no effect on postoperative laryngeal morphology, but also can be used as new laryngeal voice vibration body. PMID- 25509778 TI - [Classification and management of sternal wound complications after cardiac surgery]. AB - OBJECTIVE: To define the classification of sternal wound complications after cardiac surgery and to explore the appropriate surgical treatment. METHODS: Between July 2008 and January 2014, 260 patients with sternal wound complications after cardiac surgery were treated. There were 124 males and 136 females, aged 11 75 years (mean, 49.5 years). The disease duration was 13-365 days (mean, 26.6 days) with a wound length of 1-25 cm (mean, 13.4 cm). The wounds were divided into type I (n = 70), type II (n = 64), type III (n = 42), type IV (n = 78), and type V (n = 6) according to self-generated classification for sternal wound complications after cardiac surgery. After debridement, wounds of type I and type II were repaired with local flap transplantation; wounds of type III were repaired with local flap transplantation combined with butterfly sternal fixation (n = 28), with bilateral pectoralis muscle flap combined with butterfly sternal fixation (n = 11), and with bilateral pectoralis muscle flap (n = 3); wounds of type IV were repaired with bilateral pectoralis muscle flap (n = 65), rectus abdominis muscle flap (n = 5), and pedicled omental flap (n = 8); and wounds of type V were repaired with pedicled omental flap. RESULTS: All the operations were successfully performed. Three patients died after pedicled omental flap repair, including 1 case of type IV and 2 cases of type V. The hospitalization time were 4-86 days (mean, 18.3 days). Primary wound healing was obtained in 248 cases (96.5%); poor healing occurred in 9 patients, which were cured after second surgery in 8 cases and after the third surgery in 1 case. CONCLUSION: The surgical treatment based on self-generated classification is appropriate to sternal wound complications after cardiac surgery. It can provide clinical evidence for the choice of subsequent operation. PMID- 25509779 TI - [Expression of connective tissue growth factor in sciatic nerve after chronic compression injury and effect of rhodiola sachalinensis on its expression]. AB - OBJECTIVE: To investigate the expression of connective tissue growth factor (CTGF) in the chronic sciatic nerve compression injury and to explore the effect of rhodiola sachalinensis on the expression of CTGF. METHODS: Forty-five adult male Sprague Dawley rats were randomly divided into groups A, B, and C: In group A (sham-operated group), only the sciatic nerve was exposed; in group B (compression group), sciatic nerve entrapment operation was performed on the right hind leg according to Mackinnon method to establish the chronic sciatic nerve compression model; and in group C (compression and rhodiola sachalinensis group), the sciatic nerve entrapment operation was performed on the right hind leg and rhodiola sachalinensis (2 g/mL) was given by gavage at a dose of 0.5 mL/100 g for 2 weeks. The nerve function index (SFI) was observed and neural electrophysiology was performed; histology, transmission electron microscope, real-time fluorescent quantitative PCR, and Western blot were performed to observe the morphological changes of the compressed nerve tissue and to determine the mRNA and protein levels of CTGF, collagen type I, and collagen type III at 2, 6, and 10 weeks after operation. RESULTS: At 6 and 10 weeks after operation, SFI of groups A and C were significantly better than that of group B (P < 0.05), but there was no significant difference between groups A and C (P > 0.05). The nerve function test showed that the nerve motor conduction velocity (MCV) and the amplitude of compound muscle action potential (CMAP) of group B were significantly lower than those of groups A and C, and distal motor latency (DML) was significantly prolonged in group B (P < 0.05), but there was no significant difference between groups A and C (P > 0.05). Histology and transmission electron microscope observations showed that myelinated nerve fibers degenerated and collagen fiber hyperplasia after sciatic nerve chronic injury in group B, and rhodiola sachalinensis could promote the repair of nerve fibers in group C. At 2 weeks postoperatively, the number of myelinated nerve fibers in groups B and C were significantly less than that of group A (P < 0.05), and the myelin sheath thickness of groups B and C were significantly larger than that of group A (P < 0.05). At 6 and 10 weeks postoperatively, the number of myelinated nerve fibers in groups B and C were significantly more than that of group A (P < 0.05); the myelin sheath thickness of group B was significantly less than that of groups A and C (P < 0.05). The effective area of nerve fiber had no significant difference among groups at each time point (P > 0.05). Real-time fluorescent quantitative PCR and Western blot results showed that the mRNA and protein expressions of CTGF, collagen type I, and collagen type III in group B were significantly higher than those in groups A and C at each time point (P < 0.05), but there was no significant difference between groups A and C (P > 0.05). CONCLUSION: Sciatic nerve fibrosis can be caused by chronic nerve compression. The increased expression of CTGF suggests that CTGF plays an important role in the process of neural injury and fibrosis. Rhodiola sachalinensis can significantly reduce the level of CTGF and plays an important role in nerve functional recovery. PMID- 25509780 TI - [Dynamic changes of matrix metalloproteinase 9 in heterotopic ossification of rat model]. AB - OBJECTIVE: To explore the value of matrix metalloproteinase 9 (MMP-9) in predicting the occurrence of heterotopic ossification by observing the expression of MMP-9 in heterotopic ossification of the early trauma rat model. METHODS: A total of 132 male Sprague Dawley rats, aged 4-5 weeks, weighing (135.0 +/- 6.5) g, were randomly divided into experimental group and control group (n = 66). In experimental group, the Achilles tendon was cut off and clamped to prepare heterotopic ossification model; in control group, only Achilles tendon was exposed by making a incision. The general condition of the rats was observed after operation; at 2, 3, 4, 5, 6, 7, and 8 days after operation, the Achilles tendon tissue was harvested for gross observation, histological observation, and immunohistochemical staining observation; the serum and Achilles tendon tissue were harvested to detect the expressions of MMP-9 protein and mRNA by ELISA and RT-PCR. The X-ray films at 5 and 10 weeks and histological examination at 10 weeks after operation were used to observe heterotopic ossification. RESULTS: All rats survived to the end of the experiment. The Achilles tendon had no significant change in control group at each time point, showing normal tendon structure. In experimental group, the hardness of Achilles tendon tissue gradually increased with the time; there were a large number of irregular connective tissue and cartilage cells; and immunohistochemical staining for MMP-9 was positive results. The MMP-9 protein and mRNA expression levels of experimental group were significantly higher than those of the control group at each time point (P < 0.05). MMP-9 protein and mRNA expression levels of experimental group showed an increasing tendency (P < 0.05). According to the results of X-ray films and histological observation, heterotopic ossification occurred at 10 weeks after operation in experimental group, but no heterotopic ossification was observed in control group. CONCLUSION: In early heterotopic ossification of rat Achilles tendon, the expression of MMP-9 increases significantly, indicating that it has reference significance in predicting heterotopic ossification. PMID- 25509781 TI - [Research of different expressions of microRNA in sinus node, atrial myocardium, and ventricular myocardium of mouse]. AB - OBJECTIVE: To study microRNA (miRNA) involved in the regulation of sinus cell differentiation by comparing sinus node, atrial myocardium, and ventricular myocardium specific miRNA expression profile differences in Kunming mice. METHODS: A total of 180 Kunming mice, aged 60-90 days and weighing 35-45 g, were selected without gender differences after the method of anatomical localization for sinus node had been confirmed by preliminary experiments in another 10 Kunming mice. All the sinus node, atrial myocardium, and ventricular myocardium tissue from 180 mice were dissected and frozen by liquid nitrogen. The structure of tissue was observed by HE staining. Total RNA were extracted and quality controlled before hybridize with miRNA chip. The chips with miRNA were used to screen specific miRNAs; and correlation analysis of gene function was done. RESULTS: The area of mice sinus node located at juncture of the superior vena cava and the right atrium junction with crista as its longitudinal axis, ranged 2.0 mm x 1.5 mm x 1.0 mm. HE staining showed the sinus cells were less, with no stripes, lightly stained cytoplasm, large and round nucleus, and there were much fibrous connective tissue around cells with a visible sinus node artery. The miRNA microarray results showed that compared with atrial myocardium and ventricular myocardium, there were 39 differentially expressed miRNAs in sinus node, including 12 up-regulated miRNAs and 27 down-regulated miRNAs. Based on the regulatory networks of differential miRNA and target gene, the regulatory miRNA was obtained. CONCLUSION: The differentially expressed miRNA in mice sinus node possibly may be involved in the regulation of sinus cell differentiation. PMID- 25509782 TI - [An in vitro study on three-dimensional cultivation with dynamic compressive stimulation for cartilage tissue engineering]. AB - OBJECTIVE: To investigate the effect of three-dimensional cultivation with dynamic compressive stimulation on promotion of cartilage growth in vitro, by constructing tissue engineered cartilage with three-dimensional porous articular cartilage extracellular matrix (ECM) scaffolds laden with rabbit chondrocytes and performing mechanical stimulation by compressive stress in bioreactor. METHODS: Chondrocytes of healthy adult New Zealand rabbits were isolated, and passage 2 chondrocytes were seeded onto three-dimensional porous articular cartilage ECM scaffolds for 5 days pre-cultivation, and then were divided into 2 groups: Group A continued static culture as control; group B (dynamic culture condition) underwent dynamic compressive strain stimulation (compressive strain of 15%, frequence of 1 Hz) in a bioreactor. Cell viability and distribution in scaffolds were observed; the glycosaminoglycan (GAG) content, collagen content, and total DNA content were measured after 3 weeks of culturing; and elastic modulus was evaluated by mechanical test. RESULTS: Laser scanning confocal microscopy indicated that cells grew well and evenly distributed in the scaffold of group B, while poor cells growth and loss of staining in the central region of the scaffolds were observed in group A. Scanning electron microscopy showed that chondrocytes possessed good adhesion, proliferation, and growth on the scaffolds of group B; while the number of chondrocytes was significantly reduced, and cells scattered in group A. Biochemical composition analysis showed that collagen, GAG, and DNA contents of cell-scaffold constructs were (675.85 +/- 27.93) MUg/mg, (621.72 +/- 26.75) MUg/mg, and (16.98 +/- 3.23) MUg/sample in group B, and were (438.72 +/- 6.35) MUg/mg, (301.63 +/- 30.51) MUg/mg, and (10.18 +/- 4.39) MUg/sample in group A respectively, which were significantly higher in group B than in group A (t = -18.512, P = 0.000; t = 17.640, P = 0.000; t = 2.790, P = 0.024). Mechanical testing indicated that the elastic modulus of group B [(0.67 +/- 0.09 ) MPa] was significantly higher than that of group A [(0.49 +/- 0.16) MPa] and cell-free scaffolds [(0.43 +/- 0.12) MPa] (P < 0.05). CONCLUSION: Mimetic compressive stress with three-dimensional dynamic conditions created in the bioreactor is superior to the ordinary static three-dimensional cultivation, it can provide the optimal environment for chondrocytes on the ECM scaffolds, which may be a good way to construct tissue engineered cartilage in vitro. PMID- 25509783 TI - [Effects of leukemia inhibitory factor combined with basic fibroblast growth factor on proliferation and differentiation of human bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To study the effects of leukemia inhibitory factor (LIF) and basic fibroblast growth factor (bFGF) on the proliferation and differentiation of human bone marrow mesenchymal stem cells (hBMSCs). METHODS: hBMSCs at passage 4 were divided into 4 groups according to different culture conditions: cells were treated with complete medium (a-MEM containing 10%FBS, group A), with complete medium containing 10 ng/mL LIF (group B), with complete medium containing 10 ng/mL bFGF (group C), and with complete medium containing 10 ng/mL LIF and 10 ng/mL bFGF (group D). The growth curves of hBMSCs at passage 4 in different groups were assayed by cell counting kit 8; cellular morphologic changes were observed under inverted phase contrast microscope; the surface markers of hBMSCs at passage 8 including CD44, CD90, CD19, and CD34 were detected by flow cytometry. RESULTS: The cell growth curves of each group were similar to the S shape; the cell proliferation rates in 4 groups were in sequence of group D > group C > group B > group A. Obvious senescence and differentiation were observed very early in group A, cells in group B maintained good cellular morphology at the early stage, with slow proliferation and late senescence; a few cells in group C differentiated into nerve-like cells, with quick proliferation; and the cells in group D grew quickly and maintained cellular morphology of hBMSCs. The expressions of CD44 and CD90 in groups A and C at passage 8 cells were lower than those of groups B and D; the expressions of CD19 and CD34 were negative in 4 groups, exhibiting no obvious difference between groups. CONCLUSION: LIF combined with bFGF can not only maintain multiple differentiation potential ofhBMSCs, but also promote proliferation of hBMSCs. PMID- 25509784 TI - [Differentiating into islet-like cell clusters from human first trimester umbilical cord perivascular cells in vitro]. AB - OBJECTIVE: To study the characteristics of the human umbilical cord perivascular cells (HUCPVC) isolated from human first trimester umbilical cord perivascular layer tissues and the differentiation into islet-like cell clusters in vitro. METHODS: The HUCPVC derived from human first trimester umbilical cord which was donated by the volunteers were isolated and subcultured. The surface markers such as stage-specific embryonic antigen 1 (SSEA-1), SSEA-3, SSEA-4, OCT-4, TRA-1-60, and TRA-1-81 were detected by immunohistochemical method. The first trimester HUCPVC were induced to embryoid bodies (EB)-like cell aggregations and islet-like cell clusters in vitro through a simple stepwise culture protocol (5 steps). The expressions of specific markers [alpha-fetoprotein (AFP), Nestin, and smooth muscle actin (SMA)] were measured by immunohistochemical method; and the ability of glucose-stimulated insulin secretion was analyzed. RESULTS: The first trimester HUCPVC were successfully isolated and could be passaged steadily more than 10 generations, which expressed SSEA-3, SSEA-4, OCT-4, TRA-1-61, and TRA-1 81. The first trimester HUCPVC were successfully induced into EB-like cell aggregations and islet-like cell clusters. The EB-like cell aggregations could express markers of three germ lineages: AFP, Nestin, and SMA. The islet-like cell clusters could release insulin significantly in response to elevated concentrations of glucose in vitro (t = 7.444, P = 0.002). The insulin contents were (23.2 +/- 5.3) mU/L and (7.0 +/- 0.5) mU/L in high and low glucose media, respectively. CONCLUSION: The first trimester HUCPVC has the ability to differentiate into islet-like cell clusters which can secret insulin in vitro. PMID- 25509785 TI - [Histological observation and vascularization evaluation of porcine acellular dermal matrix processed with matrix metalloproteinase 7 after implanted into rats]. AB - OBJECTIVE: To investigate the histological changes and vascularization of the porcine acellular dermal matrix (P-ADM) processed with matrix metalloproteinase 7 (MMP-7) (P-ADM-pm) after implanted into rats. METHODS: Sixty-two pieces of porcine reticular layer dermis which were from the pig abdominal skin and obtained by using a mechanical method, were randomly divided into group A (n = 31) and group B (n = 31). The porcine reticular layer dermis in 2 groups were treated with decellularization (P-ADM), then the P-ADM in group B were treated with processing by MMP-7 (P-ADM-pm). Thirty adult male Wistar rats were selected. P-ADM (group A) and P-ADM-pm (group B) were subcutaneously transplanted into the left and right fascia lacuna, respectively. The implants were harvested from 6 rats at 3, 7, 14, 21, and 28 days after implantation, respectively. Gross, histochemical, and immunohistochemical observations, and scanning electron microscopy (SEM) examination were performed to observe host cells, microvessels infiltration and histological changes in the implants. RESULTS: No rat died in the experiment, incision healed well and no obvious inflammatory reaction was seen in all rats. Gross observation suggested that the implants of 2 groups were encapsulated by a thin layer of connective tissue at 7 days after implantation. With the time of implantation, the microvessels increased and coarsened, and the changes of group B were more obvious than those of group A. At 21 days, the microvessels of 2 groups decreased, and the implants of group B showed complete vascularization. The histochemical and immunohistochemical observations showed that group A had more severe inflammatory response than group B. Fibroblasts and microvessels in group B appeared in the superficial zone of implant at 3 and 7 days after implantation and they could be observed in the center zone of implant at 14 and21 days. However, fibroblasts and microvessels in group A appeared in the superficial zone of implant at 3 and 14 days and they could not be observed in the center zone of implant at 28 days. Fibroblasts and microvessels of group B were significantly more than those of group A (P < 0.05). SEM examination showed that more fibroblasts and new collagen fibrils were observed in group B at 14 days. CONCLUSION: The host response to P-ADM-pm is similar to normal wound healing, and P-ADM-pm as implantable scaffold material plays a good template conduction role. PMID- 25509786 TI - [Research progress of cell sheet technology in oral tissue engineering]. AB - OBJECTIVE: Cell sheet technology (CST) demonstrates the innovation and advantage by overcoming some immanent shortcomings of traditional tissue engineering. To review the research progress of CST in oral tissue engineering. METHODS: The related home and abroad literature about CST and its application in stomatology was extensively reviewed and analyzed. RESULTS: Compared to the traditional tissue engineering technology, CST has the features of high seeding density, abundant matrix, good biological compatibility, and perfect operability, which can improve the survival rate of cell transplantation and promote functional reconstruction. It is reported that CST has been successfully used in the following fields, repair and reconstruction of periodontium, soft tissues of oral mucosa, and bones in maxillofacial region. CONCLUSION: With the development of CST and combined with the traditional tissue engineering technologies, it will promote the tissue engineering further progress in stomatology. PMID- 25509787 TI - [Research progress of in vivo bioreactor as vascularization strategies in bone tissue engineering]. AB - OBJECTIVE: To review the application and research progress of in vivo bioreactor as vascularization strategies in bone tissue engineering. METHODS: The original articles about in vivo bioreactor that can enhance vascularization of tissue engineered bone were extensively reviewed and analyzed. RESULTS: The in vivo bioreactor can be created by periosteum, muscle, muscularis membrane, and fascia flap as well as biomaterials. Using in vivo bioreactor can effectively promote the establishment of a microcirculation in the tissue engineered bones, especially for large bone defects. However, main correlative researches, currently, are focused on animal experiments, more clinical trials will be carried out in the future. CONCLUSION: With the rapid development of related technologies of bone tissue engineering, the use of in vivo bioreactor will to a large extent solve the bottleneck limitations and has the potential values for clinical application. PMID- 25509788 TI - [Progress on distal interlocking screw of cephalomedullary nail for intertrochanteric fractures]. AB - OBJECTIVE: To summarize the progress on the distal interlocking screw of cephalomedullary nail for intertrochanteric fractures. METHODS: Related literature concerning the distal interlocking screw of cephalomedullary nail was reviewed and analyzed in terms ofbiomechanics, clinical application, operating difficulties, and complications. RESULTS: Distal interlocking screw can provide extra torsional stiffness in both short and long cephalomedullary nail. It is applied in most clinical cases. In long cephalomedullary nail, placing the distal interlocking screw increases the operative time for fixation and the amount of radiation exposure notably. In short cephalomedullary nail, placing the distal interlocking screw can cause adjacent vascular injury, stress concentration, and secondary fracture around the screw. CONCLUSION: When the fracture is stable (type A1, type A2.1), it can be fixed solidly without the distal interlocking screw, but prefers to use a long nail. In unstable fracture, the distal interlocking screw should be used to prevent rotational displacement of the femur shaft and the failure of the nail. PMID- 25509789 TI - [Research progress of application of middle and lower cervical anterior transpedicular screw fixation]. AB - OBJECTIVE: To review the present situation of experimental study and clinical application of middle and lower cervical anterior transpedicular screw (CATPS) fixation. METHODS: The literature on the CATPS fixation was reviewed and summarized. RESULTS: There is a safe area to implement the CATPS fixation and anterior decompression, and fusion can be done at the same time. It can provide a new idea for surgical treatment of complex cervical disease. Although it has so many advantages, its complex operating methods and optimal design of plate should be attended. Long-term effectiveness and specific indications still should be researched. CONCLUSION: Middle and lower cervical anterior transpedicular screw is an effective and safe fixation for cervical diseases. But the time for clinical use is short, the long-term effectiveness, surgical technique, and internal fixation devices are still need further study. PMID- 25509790 TI - [Histopathologic findings of bone and joint disorders in relation to aging]. PMID- 25509791 TI - [The concept and definition of locomotive syndrome in a super-aged society]. AB - The population of elderly individuals who need nursing care is rapidly increasing in Japan. Locomotive syndrome involves a decrease in mobility due to locomotive organ dysfunction, and increases risk for dependency on nursing care service. Because gait speed and chair stand time are correlated with such risks, patients with locomotive syndrome are assessed using brief methods such as the two-step test, which involves dividing the maximum stride length by the height of the patient, and the stand-up test, which involves standing on one or both legs at different heights. One leg standing and squatting are recommended as beneficial locomotive home exercises. Locomotive syndrome has been recognized widely in Japan, and included in the National Health Promotion Movement (2013-2022). PMID- 25509792 TI - [Epidemiology of musculoskeletal diseases in Japan]. AB - We investigated the prevalence of musculoskeletal disease, such as osteoporosis and osteoarthritis, using Japanese population-based cohort data from the Research on Osteoarthritis/Osteoporosis Against Disability (ROAD) study. This study, established in 2005, comprised data from 3,040 participants. In men and women, aged >=40 years, we determine the prevalences of osteoporosis in the L2-4 vertebrae(men, 3.4%; women, 19.2%), femoral neck (men, 12.4%; women, 26.5%), and knee (Kellgren-Lawrence grade >=2; men, 42.6%; women, 62.4%). The prevalence of lumbar spondylosis, diagnosed as Kellgren-Lawrence grade >=2, was 81.5% in men and 65.5% in women. In addition, based on data from the Longitudinal Cohorts of Motor System Organ (LOCOMO) study, initiated in 2008 to integrate information from cohorts in eight communities across Japan, we examined the prevalences of knee and lumbar pain. The prevalence of knee pain was 32.7% (men, 27.9%; women, 35.1%) and that of lumbar pain was 37.7% (men, 34.2%; women, 39.4%). PMID- 25509793 TI - [Mechanism of molecular backgrounds of osteoarthritis]. AB - In efforts to know the molecular backgrounds underlying the osteoarthritis (OA) development, examinations using the experimental mouse models confirmed that type X collagen (COL10A1) that is characteristic of chondrocyte hypertrophy and initiates endochondral ossification was strongly expressed in the OA cartilage. Recent COL10A1 gene transcription assay and mouse genetic approaches found that endochondral ossification signals like hypoxia-inducible factor 2alpha (HIF 2alpha), Runx2, C/EBPbeta, carminerin, syndecan-4, hedgehog, and Notch signaling are involved in the OA development. The endochondral ossification process is likely to cause osteophyte formation at the periphery cartilage of the joint and degradation at the center during OA progression. Molecules related to endochondral ossification might become therapeutic targets altering the course of this disabling disease. PMID- 25509794 TI - [Molecular mechanisms underlying fracture repair]. AB - In the developed countries including Japan, population ageing has remarkably proceeded. Among such societies, fractures in the elder have raised as the issue, which should be resolved. To facilitate fracture healing in the clinical situations, it is essential to understand the molecular mechanisms underlying fracture repair. In this review, the molecular mechanisms of fracture repair, which have been recently reported, will be introduced. These clarifications on molecular mechanisms may open the new window for the treatment to accelerate fracture healing. PMID- 25509795 TI - [Osteoarthritis]. AB - Osteoarthritis (OA) is the most common cause of arthritis, and is associated with significant pain and disability. Epidemiological study showed a large number of the eldery in Japan suffered OA, especially OA of the knee. Rapid diagnosis and conservative treatments those includes patient education, weight loss, exercise, physical and occupational therapy are effective at early stage. Pharmacologic treatment are acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase-2 (COX-2) selective agents. Surgery of the joint arthroplasty significantly reduces knee and hip pain, and restores the functions of the patient at the end stage. PMID- 25509796 TI - [Periarthritis scapulohumeralis]. AB - Periarthritis scapulohumeralis, also known as frozen shoulder, is a common disease in which the patient has a painful and restricted range of active and passive shoulder motion involving capsular contraction with no identifiable cause. Pathogenesis is thought to be a progression of inflammation and fibrosis of the capsule. Appropriate physical examination and radiologic studies can help in differentiating this condition from rotator cuff tear and other diseases. The natural progression of a frozen shoulder includes three phases (freezing, frozen and thawing) over a duration of 1 to 3.5 years and resolves spontaneously. Conservative treatment includes physical therapy and medication for pain relief but arthroscopic capsular release is sometimes performed in refractory cases. PMID- 25509797 TI - [Lumbar spondylosis]. AB - Lumbar spondylosis is a chronic, noninflammatory disease caused by degeneration of lumbar disc and/or facet joints. The etiology of lumbar spondylosis is multifactorial. Patients with lumbar spondylosis complain of a broad variety of symptoms including discomfort in the low back lesion, whereas some of them have radiating leg pain or neurologenic intermittent claudication (lumbar spinal stenosis). The majority of patients with spondylosis and stenosis of the lumbosacral spine can be treated nonsurgically. Nonsteroidal anti-inflammatory drugs and COX-2 inhibitors are helpful in controlling symptoms. Prostaglandin, epidural injection, and transforaminal injection are also helpful for leg pain and intermittent claudication. Operative therapy for spinal stenosis or spondylolisthesis is reserved for patients who are totally incapacitated by their condition. PMID- 25509798 TI - [Cervical spondylosis]. AB - Japan has now become an aging society. In 2014, people aged more than 65 years old accounted for 25.1% of Japan's entire population. Aging is associated with an increased risk of problems related to the locomotive organs. Deterioration of locomotive ability causes falls or tumbles, which would be a threat to good health and longevity of aged people. To maintain the locomotive ability of the elderly, therefore, the Japanese Orthopaedic Association starts a campaign to promote awareness and prevention of "locomotive syndrome". Cervical spondylosis is a disorder for age-related wear affecting the disks and vertebrae of cervical spine. It would also be a cause of "locomotive syndrome". Here, we give an outline of this disease and introduce its diagnosis and treatment. PMID- 25509799 TI - [Ossification of the posterior longitudinal ligament (OPLL) and the ligamentum flavum (OLF)]. AB - The adult population is frequently sustained with ossification of the posterior longitudinal ligament (OPLL) and/or the ligamentum flavum (OLF) of the spine and the diseases may subsequently result is serious spinal cord insult with profound paralysis of the extremities. These pathologies are genetically denoted metaplasia of the elastic fibers of the ligament with consequent ectopic ossification process. The spinal cord is chronically compressed and will result in profound motor paralysis with sensory deficit. Both diseases are well imaged on CT and MRI, showing a various magnitude of spinal cord compression. PMID- 25509800 TI - [Spinal stenosis]. AB - Spinal stenosis is an abnormal narrowing of the spinal canal that mainly occurs in the cervical and lumbar regions. The number of the patients of spinal stenosis is increasing in the aging society like Japan because the major reason for the stenosis is the degeneration of the spinal components including the intervertebral disc, facet, and ligamentum flavum. The development of the disease concept is historically different between cervical spinal stenosis and lumbar spinal stenosis. Therefore, some confusion is still present in the definition and diagnosing criteria of these conditions. In this report, we mainly describe about the degenerative lumbar spinal stenosis, which is most common in the outpatient clinic, concerning the diagnosis, various options of conservative therapy, and the surgical indication. PMID- 25509801 TI - [The pathology, diagnosis and therapy on osteoporosis]. AB - The increase of elderly population in Japan suggests the importance of the prevention of osteoporotic fracture. Falls and fractures account for around 10% of the causes for requiring care services in Japan. The Japanese criteria for initiating pharmacological treatment to prevent fragility fracture were revised in 2011. There are many kinds of anti-osteoporosis drugs including bisphosphonates, SERM, teriparatide, and denosumab that have been proven to reduce fractures. Thus, it is important to select drugs appropriate for each osteoporotic patients considering the mechanisms of drug action, their efficacy and side effects. In this article, we review pathophysiology, diagnosis and treatment of osteoporosis. PMID- 25509802 TI - [Rheumatic joint diseases in the elderly]. AB - The most frequent rheumatic joint disease in the elderly is rheumatoid arthritis (RA). Recent advances in the treatment of RA improve prognosis, and gradually increase the elderly patients with RA. There are some differences in clinical features between the patients with elderly onset RA and young onset RA, such as systemic symptoms and distribution of affected joints. In addition, it is occasionally difficult to differentiate elderly onset RA from the other rheumatic diseases like polymyalgia rheumatica and RS3PE syndrome, pseudogout, and osteoarthritis. Since elderly patients tend to have more co-morbidity and co existing diseases requiring treatment with other drugs, a risk/benefit profile must always be taken into consideration when choosing the treatment in elderly patients with rheumatic joint diseases. PMID- 25509803 TI - [Metabolic bone and joint diseases]. AB - Metabolic bone and joint diseases in adults include osteomalacia, rheumatoid arthritis, gouty arthritis. Recently, the newest molecular biology procedures and the clinical observation studies can produce good results for understanding of these diseases. From this perspective, the author introduced updated information of the pathophysiology, the latest diagnostic criteria and the therapy of these diseases. PMID- 25509804 TI - [Septic arthritis and spondylitis]. AB - Septic arthritis and spondylitis in elderly adult are uncommon disease. But symptoms and signs of septic arthritis and spondylitis are an important medical emergency, with high mortality and morbidity. Delayed or inadequate treatment can result in irreversible joint destruction and neurological condition. Early diagnoses as well as prompt and effective treatment are essential for avoiding severe outcomes. In spite of advances in diagnostic imaging techniques, the incidence of septic arthritis and spondylitis appears to have been increased. The aging of the population, the widespread use of immunosuppressant therapies, including systemic corticosteroids, cytokines and anticytokines, and growing resistance to conventional antibiotics seem to be the major cause. PMID- 25509805 TI - [Four major fractures in elderly]. AB - Fractures of proximal humerus, distal radius, proximal femur and vertebral body are common in elderly patients with osteoporosis. These so called "four major fractures in elderly" can be difficult to treat because of fragile bone. They can be treated either conservatively or surgically. Except for proximal femur fracture, conservative treatment is performed as first line therapy. To avoid complications associated with conservative treatment, surgical treatment has been developed and proves to be effective. However, the risk of surgical stress and the possibility of postoperative complication have to be estimated carefully before surgery. While fracture is treated, osteoporosis should also be treated in order to prevent another fracture. PMID- 25509806 TI - [Guidance regarding exercise and daily life to prevent falls]. AB - Falls, annually occurred to about 20% of elderly women in Japan, causes severe injuries such as femoral neck fracture. I assessed 111 dwelling elderly women by 7 questionnaires and found about 47% of those have risk of falls. To prevent falls, exercise including balance training such as Taiji Quan and enough nutrition are effective. Our studies declared that blood vitamin D concentration is highly correlated to muscle power and one-leg standing time. In Japan, approximately 148,100 elderly subjects are annually suffered from femoral neck fracture, in which 13.6% patients have become bed-ridden. So medical and welfare costs of falls consume about one trillion yen yearly. To prevent falls by exercise and daily life is economical and beneficial in advanced aged society. PMID- 25509807 TI - [New fall prediction score for the prevention of fall fractures in the elderly]. AB - Elderly fracture is a critical public health issue for older adults, and falls risk assessment is an expected competency for medical worker. The prevention from fall fracture is one of the important items of medical safety, and although fall assessment is carried out, it is not much effective. One of the reasons is that there is not the simple and easy tool of the fall prediction. The aim of this study was to design an innovative method of falls risk assessment using standing ability of the elderly. We devised new fall assessment score (Mimamori score) that scored lifting assistance movement. We incorporate it in real duties after 2011, inflect for the fall prevention. PMID- 25509808 TI - [Prevention programs of risk factors for falls]. AB - Approximately 17% of Japanese older people fall for a year. The femoral neck fractures with falls caused by various functional problems make them depress remarkably activities of daily living and quality of life. In risk factors for falls in old people, muscle weakness, balance and gait disorders particularly increases to falls. The major results from recent systematic reviews have indicated that interventions of exercise, multifactorial, environmental modification and gradual withdrawal of psychotropic medication in community dwelling elderly people were effective for preventing falls. Regarding the older people in hospitals and sanatoriums, it appeared that comprehensive multifactorial interventions and vitamin D supplementation could be effective in falls rather than exercises intervention only. However, the short period of the exercise intervention may affect ineffectiveness in preventing falls. PMID- 25509809 TI - [Tailor-made programs for preventive falls]. AB - Falls are relatively common in the elderly, with approximately 30% of individuals aged 65 and older falling at least once a year and approximately half of them experiencing repeated falls. The systematic review suggested that falls can be prevented by well-designed exercise programs that target balance and involve a good amount of exercise. Recent study indicated that different factors may be related to fall incidents depending on the level of frailty of the community dwelling older adults. These findings suggest that fall prevention programs should be tailored to the elderly adult's level of physical well-being. The purpose of this review is to review approaches to fall prevention tailored to an individual's level of physical well-being. PMID- 25509810 TI - [Current evidence based interventions for preventing fall and fall-related hip fracture of the older people]. AB - For older people, the consequences of falling include injury, fear of falling, decreased activity, functional deterioration, reduced quality of life, and death. According to reliable systematic reviews and guidelines, exercise programs including balance and strength training, multifactorial interventions, and home safety assessment and modification interventions are effective at reducing the rates of falls and risks of falling among community-dwelling elderly people. Taking vitamin D supplements might be effective for reducing falls in older people who exhibit lower vitamin D levels in the blood. Hip protectors apparently reduce the risk of hip fractures in frail older residents of care facilities. Taking vitamin D with calcium supplements might reduce the risk of hip fractures. PMID- 25509811 TI - [Locomotive syndrome and metabolic syndrome]. AB - The Japanese Orthopedic Association coined the term locomotive syndrome (LS) to designate a condition of elderly people in high risk groups of requiring nursing care because of problems with their musculoskeletal diseases. LS is a socioeconomic concept, and closely associated with osteoporosis, osteoarthritis, and sarcopenia. Recent studies have revealed that metabolic syndrome (MS), a clustering of cardiovascular risk factors, has been related with LS. For example, individuals with MS have a greater risk of osteoarthritis and sarcopenia. Secreted factors from adipose tissue and skeletal muscles, namely, adipokines and myokines, are involved in the association of LS and MS. PMID- 25509812 TI - [Locomo 25--a screening tool for risk of locomotive syndrome]. AB - Locomo 25 was developed as a screening tool of locomotive syndrome by Japanese orthopedic surgeon group in 2008. It contains 25 questions in terms of musculoskeletal disorder such as walking disability, difficulty in daily living, or suffering pain on body. Its reliability and validity were already confirmed through multi-center study including 731 Japanese elderly people (over 65 y.o. average 77 y.o.). The cutoff score for identifying locomotive syndrome was set at 16, and list-upped person is considered as under high-risk condition who may soon require care services without some medical interventions. We can use Locomo 25 not only as a screening tool of locomotive syndrome but also as a measuring scale for evaluating effects of interventions in individuals. PMID- 25509813 TI - [Pain control of bone and joint diseases in the elderly]. AB - The decline of multiple physiological processes, even in the absence of disease, combined should logically influence treatment options. Decreased gastric secretions, intestinal motility, and vitamin D receptors lead to loss of appetite, malnutrition. Increased arterial thickening and rigidity elevate cardiac risk, while decreased elasticity in the lungs potentially exacerbates breathing disorders. Memory impairment and cognitive decline progress as neurons become less resilient to stress over time. Reduced hepatic and renal blood flow limit metabolism and filtration, increasing the risk for accumulation of toxic substances. Physiologic changes, drug-drug interactions resulting from polypharmacy, and drug-disease interactions combine to make elderly patients more sensitive to the AEs of medications. Effective pain management in the elderly is challenging. The purpose of this review is to highlight the use of several treatment options for elderly patients. PMID- 25509814 TI - [The approach to bone and joint disease for extending the healthy life expectancy]. AB - In Japan, the super-aged society, the difference between the healthy life expectancy and life expectancy is large, it has become a social problem. For the extension of healthy life expectancy, measures to bone and joint disease are important. Lower limb muscle strengthening is useful to decrease in pain and improvement of walking ability. Further, in order to maintain a balance function, improvement in range of motion is important. On the other hand, for patients who had joint destruction, decreased ability of exercise, muscle weakness, balance dysfunction has already occurred, it is necessary for extension of healthy life expectancy including surgical treatment. We believe that by performing the appropriate therapeutic intervention, extending healthy life expectancy would be possible. PMID- 25509815 TI - [Current status of bone/cartilage tissue engineering towards clinical applications]. AB - Osteo/chondrogenic differentiation capabilities are seen after in vivo implantation of mesenchymal stem cells (MSCs), which are currently used for the patients having bone/cartilage defects. Importantly, the differentiation capabilities are induced by culturing technology, resulting in in vitro bone/cartilage formation. Especially, the in vitro bone tissue is useful for bone tissue regeneration. For cartilage regeneration, culture expanded chondrocytes derived from patient's normal cartilage are also used for the patients having cartilage damages. Recently, the cultured chondrocytes embedded in atelocollagen gel are obtainable as tissue engineered products distributed by Japan Tissue Engineering Co. Ltd. The products are available in the well-regulated hospitals by qualified orthopedic surgeons. The criteria for these hospitals/surgeons have been established. This review paper focuses on current status of bone/cartilage tissue engineering towards clinical applications in Japan. PMID- 25509816 TI - [GATA2 deficiency]. AB - GATA2 is a transcription factor that is involved in the lympho-hematopoiesis. Mutations of GATA2 cause MonoMAC syndrome (monocytopenia and mycobacterial infections)/DCML deficiency (dendritic cell, monocyte, B and natural killer (NK) lymphoid deficiency), Emberger syndrome (lymphoedema with MDS), and MDS/AML. In this review, we explain the new function of GATA2, and describe the clinical phenotypes, laboratory findings, pathology, genetic anomalies and etiology. PMID- 25509817 TI - Effort in human factors performance and decision making. AB - OBJECTIVE: The aim of this study was to demonstrate the importance of effort in human factors. BACKGROUND: Effort has made its appearance in several diverse formats and applications. Eight of these are integrated in the current writing related to learning, looking, task switching, visual search termination, information access, choosing decision strategies, and behaving safely. METHOD: This is based upon a literature review. RESULTS: The common elements of these different effort applications are highlighted, particularly, their manifestations in either implicit or explicit expected value decisions. CONCLUSIONS: There is a need to show how the metrics of effort and workload assessment influence decisions in human factors, particularly, those related to safety. PMID- 25509818 TI - A sociotechnical model of the flight crew task. AB - OBJECTIVE: The objective of this research was to advance an improved model of Flight Crew task performance. BACKGROUND: Existing task models present a "local" description of Flight Crew task performance. METHOD: Process mapping workshops, interviews, and observations were conducted with both pilots and flight operations personnel from five airlines, as part of the Human Integration into the Lifecycle of Aviation Systems (HILAS) project. RESULTS: The functional logic of the process dictates Flight Crew task requirements and specific task workflows. The Flight Crew task involves managing different levels of operational and environmental complexity, associated with the particular flight context. In so doing, the Flight Crew act as a coordinating interface between different human agents involved in the Active Flight Operations process and other processes that interface with this process. CONCLUSION: This article presents a new sociotechnical model of the Flight Crew task. The proposed model reflects a shift from a local explanation of Flight Crew task activity to a broader process centric explanation. In so doing, it illuminates the complex role of procedures in commercial operations. APPLICATION: The task model suggests specific requirements for pilot task support tools, procedures design, performance evaluation and crew resource management (CRM) training. Also, this model might be used to assess future operational concepts and associated technology requirements. Lastly, this model provides the basis for the operational validation of both existing and future cockpit technologies. PMID- 25509819 TI - The sustained attention to response task (SART) does not promote mindlessness during vigilance performance. AB - OBJECTIVE: In this study, we evaluated the validity of the Sustained Attention to Response Task (SART) as a means for promoting mindlessness in vigilance performance. BACKGROUND: Vigilance tasks typically require observers to respond to critical signals and to withhold responding to neutral events. The SART features the opposite response requirements, which supposedly leads it to promote a mindless, non-thoughtful approach to the vigilance task To test that notion, we compared the SART to the traditional vigilance format (TVF) in terms of diagnostic accuracy assessed through decision theory measures of positive and negative predictive power (PPP and NPP), perceived mental workload indexed by the Multiple Resource Questionnaire, and oculomotor activity reflected in the Nearest Neighbor Index and fixation dwell times. METHOD: Observers in TVF and SART conditions monitored a video display for collision flight paths in a simulated air traffic control task. RESULTS: Diagnostic accuracy in terms of NPP was high in both format conditions. While PPP was poorer in the SART than in the TVF, that result could be accounted for by a loss of motor control rather than a lack of mindfulness. Identical high levels of workload were generated by the TVF and SART tasks, and observers in both conditions showed similar dynamic scanning of the visual scene. CONCLUSION: The data indicate that the SART is not an engine of mindlessness. APPLICATION: The results challenge the widespread use of the SART to support a model in which mindlessness is considered to be the principal root of detection failures in vigilance. PMID- 25509820 TI - Influencing preferences for different types of causal explanation of complex events. AB - OBJECTIVE: We examined preferences for different forms of causal explanations for indeterminate situations. Background: Klein and Hoffman distinguished several forms of causal explanations for indeterminate, complex situations: single-cause explanations, lists of causes, and explanations that interrelate several causes. What governs our preferences for single-cause (simple) versus multiple- cause (complex) explanations? METHOD: In three experiments, we examined the effect of target audience, explanatory context, participant nationality, and explanation type. All participants were college students. Participants were given two scenarios, one regarding the U.S. economic collapse in 2007 to 2008 and the other about the sudden success of the U.S. military in Iraq in 2007. The participants were asked to assess various types of causal explanations for each of the scenarios, with reference to one or more purposes or audience for the explanations. RESULTS: Participants preferred simple explanations for presentation to less sophisticated audiences. Malaysian students of Chinese ethnicity preferred complex explanations more than did American students. The form of presentation made a difference: Participants preferred complex to simple explanations when given a chance to compare the two, but the preference for simple explanations increased when there was no chance for compari- son, and the difference between Americans and Malaysians disappeared. CONCLUSIONS: Preferences for explanation forms can vary with the context and with the audience, and they depend on the nature of the alternatives that are provided. APPLICATION: Guidance for decision-aiding technology and training systems that provide explanations need to involve consideration of the form and depth of the accounts provided as well as the intended audience. PMID- 25509821 TI - A multilevel approach to relating subjective workload to performance after shifts in task demand. AB - OBJECTIVE: The aim of this laboratory experiment was to demonstrate how taking a longitudinal, multilevel approach can be used to examine the dynamic relationship between subjective workload and performance over a given period of activity involving shifts in task demand. BACKGROUND: Subjective workload and conditions of the performance environment are oftentimes examined via cross-sectional designs without distinguishing within-from between-person effects. Given the dynamic nature of performance phenomena, multilevel designs coupled with manipulations of task demand shifts are needed to better model the dynamic relationships between state and trait components of subjective workload and performance. METHOD: With a sample of 75 college students and a computer game representing a complex decision-making environment, increases and decreases in task demand were counterbalanced and subjective workload and performance were measured concurrently in regular intervals within performance episodes. Data were analyzed using hierarchical linear modeling. RESULTS: Both between- and especially within-person effects were dynamic. Nevertheless, at both levels of analysis, higher subjective workload reflected performance problems, especially more downstream from increases in task demand. CONCLUSION: As a function of cognitive-energetic processes, shifts in task demand are associated with changes in how subjective workload is related to performance over a given period of activity. Multilevel, longitudinal approaches are useful for distinguishing and examining the dynamic relationships between state and trait components of subjective workload and performance. APPLICATION: The findings of this research help to improve the understanding of how a sequence of demands can exceed a performer's capability to respond to further demands. PMID- 25509822 TI - Concurrent 3-D sonifications enable the head-up monitoring of two interrelated aircraft navigation instruments. AB - OBJECTIVE: The aim of this study was to enable the head-up monitoring of two interrelated aircraft navigation instruments by developing a 3-D auditory display that encodes this navigation information within two spatially discrete sonifications. BACKGROUND: Head-up monitoring of aircraft navigation information utilizing 3-D audio displays, particularly involving concurrently presented sonifications, requires additional research. METHOD: A flight simulator's head down waypoint bearing and course deviation instrument readouts were conveyed to participants via a 3-D auditory display. Both readouts were separately represented by a colocated pair of continuous sounds, one fixed and the other varying in pitch, which together encoded the instrument value's deviation from the norm. Each sound pair's position in the listening space indicated the left/right parameter of its instrument's readout. Participants' accuracy in navigating a predetermined flight plan was evaluated while performing a head-up task involving the detection of visual flares in the out-of-cockpit scene. RESULTS: The auditory display significantly improved aircraft heading and course deviation accuracy, head-up time, and flare detections. Head tracking did not improve performance by providing participants with the ability to orient potentially conflicting sounds, suggesting that the use of integrated localizing cues was successful. Conclusion: A supplementary 3-D auditory display enabled effective head-up monitoring of interrelated navigation information normally attended to through a head-down display. APPLICATION: Pilots operating aircraft, such as helicopters and unmanned aerial vehicles, may benefit from a supplementary auditory display because they navigate in two dimensions while performing head-up, out-of-aircraft, visual tasks. PMID- 25509823 TI - Mapping brain activity during loss of situation awareness: an EEG investigation of a basis for top-down influence on perception. AB - OBJECTIVE: The objective was to map brain activity during early intervals in loss of situation awareness (SA) to examine any co-activity in visual and high-order regions, reflecting grounds for top-down influences on Level I SA. BACKGROUND: Behavioral and neuroscience evidence indicates that high-order brain areas can engage before perception is complete. Inappropriate top-down messages may distort perception during loss of SA. Evidence of co-activity of perceptual and high order regions would not confirm such influence but may reflect a basis for it. METHOD: SA and bias were measured using Quantitative Analysis of Situation Awareness and brain activity recorded with 128-channel EEG (electroencephalography) during loss of SA. One task (15 participants) required identification of a target pattern, and another task (10 participants) identification of "threat" in urban scenes. In both, the target was changed without warning, enforcing loss of SA. Key regions of brain activity were identified using source localization with standardized low-resolution electrical tomography (sLORETA) 150 to 160 ms post-stimulus onset in both tasks and also 100 to 110 ms in the second task. RESULTS: In both tasks, there was significant loss of SA and bias shift (p < .02), associated at both 150- and 100-ms intervals with co-activity of visual regions and prefrontal, anterior cingulate and parietal regions linked to cognition under uncertainty. CONCLUSION: There was early co activity in high- order and visual perception regions that may provide a basis for top-down influence on perception. APPLICATION: Co-activity in high- and low order brain regions may explain either beneficial or disruptive top-down influence on perception affecting Level I SA in real-world operations. PMID- 25509824 TI - On the application of motivation theory to human factors/ergonomics: motivational design principles for human-technology interaction. AB - OBJECTIVE: Motivation is a driving force in human-technology interaction. This paper represents an effort to (a) describe a theoretical model of motivation in human technology interaction, (b) provide design principles and guidelines based on this theory, and (c) describe a sequence of steps for the. evaluation of motivational factors in human-technology interaction. BACKGROUND: Motivation theory has been relatively neglected in human factors/ergonomics (HF/E). In both research and practice, the (implicit) assumption has been that the operator is already motivated or that motivation is an organizational concern and beyond the purview of HF/E. However, technology can induce task-related boredom (e.g., automation) that can be stressful and also increase system vulnerability to performance failures. METHOD: A theoretical model of motivation in human technology interaction is proposed, based on extension of the self-determination theory of motivation to HF/E. This model provides the basis for both future research and for development of practical recommendations for design. RESULTS: General principles and guidelines for motivational design are described as well as a sequence of steps for the design process. CONCLUSION: Human motivation is an important concern for HF/E research and practice. Procedures in the design of both simple and complex technologies can, and should, include the evaluation of motivational characteristics of the task, interface, or system. In addition, researchers should investigate these factors in specific human-technology domains. APPLICATION: The theory, principles, and guidelines described here can be incorporated into existing techniques for task analysis and for interface and system design. PMID- 25509825 TI - Optical correction reduces simulator sickness in a driving environment. AB - OBJECTIVE: We propose and test a method to reduce simulator sickness. BACKGROUND: Prolonged work in driving simulators often leads to nausea and other symptoms summarized as simulator sickness. Visual/vestibular mismatches are a frequently addressed cause; we investigate another possibility, mismatch between actual distance to a screen and depicted distances in the simulator's graphics. METHOD: Drivers negotiated a figure-8 course in a photorealistic simulator. They reported discomfort and vection every 10 minutes up to 40 min. A correction group wore optometric test frames with + 1.75 diopter lenses and prisms to converge parallel lines of sight on a screen 56 cm from the driver's eyes, preserving the normal accommodative convergence-to-accommodation (AC/A) ratio. A control group wore neutral lenses in the same test frames. In other experiments head tilt simulated vestibular experience on curves. RESULTS: The optical correction significantly reduced simulator sickness measured on a 10-point discomfort scale, where I is no problem and 10 is about to vomit. Vection ratings were similar for correction and control groups. Some drivers failed to complete the course because of high discomfort ratings, crashes, or other causes. Head tilt in the direction opposite each curve while wearing the correction did not affect discomfort, while tilt in the same direction as each curve made simulator sickness worse. CONCLUSION: Optical corrections can significantly reduce simulator sickness, though they do not eliminate it. Head tilt while driving is not recommended. Application: Simple optical corrections in spectacle frames, easily purchased at any optical facility, should be used in screen-based driving simulators. Strength of the correction depends on distance from the driver to the screen. PMID- 25509826 TI - The effects of video game experience and active stereoscopy on performance in combat identification tasks. AB - OBJECTIVE: We investigated the effects of active stereoscopic simulation-based training and individual differences in video game experience on multiple indices of combat identification (CID) performance. BACKGROUND: Fratricide is a major problem in combat operations involving military vehicles. In this research, we aimed to evaluate the effects of training on CID performance in order to reduce fratricide errors. METHOD: Individuals were trained on 12 combat vehicles in a simulation, which were presented via either a non-stereoscopic or active stereoscopic display using NVIDIA's GeForce shutter glass technology. Self-report was used to assess video game experience, leading to four between-subjects groups: high video game experience with stereoscopy, low video game experience with stereoscopy, high video game experience without stereoscopy, and low video game experience without stereoscopy. We then tested participants on their memory of each vehicle's alliance and name across multiple measures, including photographs and videos. RESULTS: There was a main effect for both video game experience and stereoscopy across many of the dependent measures. Further, we found interactions between video game experience and stereoscopic training, such that those individuals with high video game experience in the non-stereoscopic group had the highest performance outcomes in the sample on multiple dependent measures. CONCLUSION: This study suggests that individual differences in video game experience may be predictive of enhanced performance in CID tasks. APPLICATION: Selection based on video game experience in CID tasks may be a useful strategy for future military training. Future research should investigate the generalizability of these effects, such as identification through unmanned vehicle sensors. PMID- 25509827 TI - Distracted driver performance to multiple alerts in a multiple-conflict scenario. AB - OBJECTIVE: We investigated whether collision avoidance systems (CASs) should present individual crash alerts in a multiple-conflict scenario or present only one alert in response to the first conflict. BACKGROUND: Secondary alerts may startle, confuse, or interfere with drivers' execution of an emergency maneuver. METHOD: Fifty-one participants followed a pickup truck around a test track. Once the participant was visually distracted, a trailing sedan repositioned itself into the participant's blind spot while a box was dropped from the truck Participants received a forward collision warning (FCW) alert as the box landed. Twenty-six drivers swerved left in response to the box, encountering a lateral conflict with the adjacent sedan. Half of these 26 drivers received a lane-change merge (LCM) alert. RESULTS: Drivers who received both the FCW and LCM alerts were significantly faster at steering away from the lateral crash threat than the drivers who received only the FCW alert (1.70 s vs. 2.76 s, respectively). Drivers liked receiving the LCM alert, rated it to be useful, found it easy to understand (despite being presented after the FCW alert), and did not find it to be startling. CONCLUSION: Drivers who are familiar with CASs benefit from, and feel it is appropriate to generate, multiple alerts in a multiple-conflict scenario. APPLICATION: The results may inform the design of CASs for connected and automated vehicles. PMID- 25509828 TI - The retention of manual flying skills in the automated cockpit. AB - OBJECTIVE: The aim of this study was to understand how the prolonged use of cockpit automation is affecting pilots' manual flying skills. BACKGROUND: There is an ongoing concern about a potential deterioration of manual flying skills among pilots who assume a supervisory role while cockpit automation systems carry out tasks that were once performed by human pilots. METHOD: We asked 16 airline pilots to fly routine and nonroutine flight scenarios in a Boeing 747-400 simulator while we systematically varied the level of automation that they used, graded their performance, and probed them about what they were thinking about as they flew. RESULTS: We found pilots' instrument scanning and manual control skills to be mostly intact, even when pilots reported that they were infrequently practiced. However, when pilots were asked to manually perform the cognitive tasks needed for manual flight (e.g., tracking the aircraft's position without the use of a map display, deciding which navigational steps come next, recognizing instrument system failures), we observed more frequent and significant problems. Furthermore, performance on these cognitive tasks was associated with measures of how often pilots engaged in task-unrelated thought when cockpit automation was used. CONCLUSION: We found that while pilots' instrument scanning and aircraft control skills are reasonably well retained when automation is used, the retention of cognitive skills needed for manual flying may depend on the degree to which pilots remain actively engaged in supervising the automation. PMID- 25509830 TI - [Structural changes on hands as predicative factors of structural changes in the cervical spine and atlantoaxial joint in patients with rheumatoid arthritis]. AB - Determination of changes in the cervical spine of patients with rheumatoid arthritis (RA) is important. Although they are often clinically asymptomatic, during exercise therapy complications, or even death, may occur. The aim of the study was to determine the factors which indicate changes in the cervical spine and atlantoaxial joint (AA) in patients with RA, as well as the association between those changes and changes occurring on the hands. The study included 80 patients with RA who were divided into two groups according to the duration of the disease (up to 10 years and more than 10 years). Structural changes in the hands and cervical spine were monitored by ordinary radiography. Structural changes in the cervical spine were found in both groups of patients without a statistically significant difference between them (p = 0.165). The AA joint was more often deformed in patients with a longer duration of the disease (p = 0.012). The changes on the hands were worse in patients who had the disease for longer than 10 years (p = 0.002), and they correlated with AA subluxation (p = 0.002) and luxation (p = 0.004), as well as with an erosion of the cervical s pine (p = 0.000). According to our findings, in order to recognize changes in the cervical spine, patients with RA must be regularly monitored radiographically, and monitoring should be mandatory in patients who had a longer duration of the disease as well as those with more advanced structural changes on the hands. PMID- 25509831 TI - Analysis of the course of rheumatoid arthritis depending on the climatic and geographic zones of Uzbekistan. AB - The aim of this study was to evaluate the features of rheumatoid arthritis (RA) as well as other health problems and treatment necessities in various climatic and geographic zones of Uzbekistan. The data on 2013 patients with a confirmed diagnosis of RA were collected retrospectively. The results showed that the Khorezm and Surkhandarya regions dominated by indicators of disease activity and severity, such as a more expressed progressive course; in addition, marked alterations in the reproductive system, especially in women, were observed as well. In contrast, patients from the Namangan and Tashkent zones were characterized by relatively better parameters of interest. In conclusion, the differences in climatic and geographic zones in Uzbekistan may be important for patients with RA. More in-depth studies are needed to get a more accurate insight into the possible influence of climate and environmental factors on RA. PMID- 25509832 TI - [Sex hormones, immune disorders, and inflammatory rheumatic diseases]. AB - It is a well-documented fact that sex hormones are implicated in the immune response and that androgens and estrogens modulate susceptibility and progression of autoimmune rheumatic diseases. Estrogens are considered to stimulate cell proliferation and humoral immune responses while androgens exert suppressive effects on both humoral and cellular immune responses. Autoimmune diseases are common in females, especially during the generative period, the most representative of estrogen-related autoimmune diseases being systemic lupus erythematosus. Estrogens and androgens are involved in the pathogenesis of the disease; both exogenous and endogenous estrogens are strong stimulators of cytokine production and disease activity. Some physiological conditions, as well as some drugs and chronic stress, can modulate hormone levels. Low levels of gonadal androgens have been detected in body fluids of both male and female rheumatoid arthritis patients, supporting the possibility of the pathogenic role for decreased androgen levels. Views on hormone replacement therapy or hormonal contraception in rheumatic diseases have been modified and in most rheumatic diseases, including rheumatoid arthritis, hormones are not prohibited. There are still controversies regarding systemic lupus; the new standpoint being that hormonal contraception is not contraindicated in women with inactive or stable active SLE, except for those with positive antiphospholipid antibodies. PMID- 25509833 TI - [Genetic predisposition for various forms of spondyloarthritis]. AB - In addition to the long-established association of HLA-B27 antigen and spondyloarthritis, several studies have shown a similar association with HLA-B7 antigen. But since the whole MHC region carries less than half of the risk for the development of the disease, the main goal of many recently performed researches, which implemented various high-throughput methods, was to discover the influence of genes outside the MHC region on disease development. The results showed that genes closely linked to spondyloarthritis participate in antigen processing and coding of various cytokines. This can lead to the conclusion that diseases from the spondyloarthritis group are polygenic, affected by both autoinflammatory and autoimmune mechanisms. PMID- 25509834 TI - [The significance of innate immunity in juvenile idiopathic arthritis]. AB - For years it was thought that the disorder of adaptive immunity is critical in the pathogenesis of juvenile idiopathic arthritis (JIA). However, the results of recent studies emphasize the importance of innate immunity and especially the role of alarmins, a group of multifunctional proteins that are released into the intercellular space during tissue injury or inflammation, mobilizing and activating the cells of innate immunity. These data indicate that inflammation triggered by alarmins plays a role in the pathogenesis of JIA. Furthermore, alarmins may serve as inflammatory markers and targets of therapy. PMID- 25509835 TI - [Henoch-Schonlein purpura with late-onset necrotising glomerulonephritis--a case report]. AB - Henoch-Schonlein purpura (HSP) is the most common systemic vasculitis in children, while it is rare in adults. Typical clinical manifestations include palpable purpura without thrombocytopenia and/or coagulopathy, arthritis/arthralgia, abdominal pain, and/or renal involvement. In adulthood the disease tends to be more serious than in children, with renal manifestations developing over a period of several days to one month after initial symptoms. In this article we present a 22-year-old female patient with cutaneous vasculitis and arthralgia, in whom renal disease developed 8 weeks after disease onset with microscopic hematuria and proteinuria in urinalysis. Renal biopsy subsequently performed revealed focal necrotising glomerulonephritis with IgA deposits. The patient was treated with high dose methylprednisolone followed by gradual tapering, which induced complete remission of the disease. In conclusion, patients with HSP should be carefully monitored for systemic involvement, since serious renal disease can develop even as late as two months after disease onset. PMID- 25509849 TI - [T-lymphocyte-helper type 17 mediated regulation of antibacterial (antituberculosis) immunity]. AB - The analysis of current views on functional and immunoregulatory role of T lymphocytes-helpers of type 17 (Th17) in anti-infectious immune response is presented, in particular, in the development of protective immune reactions to intracellular pathogens. Particular attention is paid to participation of these lymphocytes and cytokines produced by them in immune response to Mycobacterium tuberculosis invasion. The molecular mechanisms, underlying the predominant development of Th17-lymphocytes and/or regulatory T-cells (Treg), are studied, with evaluation of interconnection of these cell subpopulations in formation of immune imbalance in infectious pathology. PMID- 25509850 TI - [Molecular mechanisms of the alternative lipogenic function of insulin]. AB - The proposed hypothesis suggests that major function of insulin is stimulation of triglyceride accumulation in adipose tissue and glycogen synthesis in liver and muscles. The impairment of insulin functioning diminishes triglyceride storage in adipose tissue, elevates the level of its metabolite in periphery and suppresses glucose intake by cells. Leptin disturbs direct insulin action on adipocytes, and prevents fat accumulation. Leptin deficiency or impairment of its functioning facilitate lipogenic effect of insulin, and induce obesity. Lipodystrophy decreases leptin secretion and enhances triglyceride production activated by insulin. Triglycerides are not accumulated in adipose tissue because of its deficiency, and overwhelm peripheral tissues. Lipid metabolites decrease glucose consumption and induce lipoatrophic diabetes. The hypothesis on the lipogenic insulin functioning is confirmed by specific knockout of Insr gene in only tissue: muscles, adipose tissue and other, and by the restoration of its expression in transgenic mice. PMID- 25509851 TI - [Substrate specificity and properties of methyl-directed site-specific dna endonucleases]. AB - Methyl-directed site-specific DNA endonucleases (MD endonucleases) form a small group of enzymes which specifically cleave only methylated DNA. There are N6 methyladenine- and 5-methylcytosine-directed enzymes in this group. In spite of limited information on the MD endonucleases they are considered to be a very interesting subject for both fundamental investigations and practical use in biotechnology and epigenomics. In this review for the first time the data on properties of MD endonucleases are summarized in particular on substate specificity of these enzymes. The role of MD endonucleases in bacterial cells and the potential of their practical use are also discussed. PMID- 25509852 TI - [The role of multifunctional coactivator complex saga in regulation of eukaryotic gene expression]. AB - Eukaryotic gene expression is known as a multistep process of high complexity. Transcription is one of cardinal and tightly regulated phase during gene expression. To provide accurate and precise work of gene regulation apparatus including a plethora of modification of chromatin structure and nucleosome dynamic turnover must be occurred. All transcription steps are under control of large multiprotein coactivator complexes. In this review we discuss an evolutionary conservative SAGA complex, which acetylates and deubiquitinates histones during transcription activation and furthermore is involved in subsequent stages of mRNP biogenesis and export. PMID- 25509853 TI - [SAGA complex: the role in viability and development]. AB - SAGA is a histone acetyltransferase complex, that cotranscriptionally performs histone modifications and is implicated in regulation of gene expression at the level of changes in chromatin structure. SAGA is also involved in mRNP biogenesis and export. In this review, we examined a contribution of SAGA and its subunits in the development. We also discuss the diseases associated with impaired activity of SAGA subunits. PMID- 25509854 TI - [Mutation process in the protein-coding genes of human mitochondrial genome in context of evolution of the genus]. AB - The human mitochondrial genome, although it has a small size, is characterized by high level of variation, non-uniformly distributed in groups of nucleotide positions that differ in the degree of variability. Considering the mutation process in human mtDNA relative to the mitochondrial genomes of the genus Homo neandertals, denisova hominin and other primate species, it appears that more than half (56.5%) variable positions in the human mtDNA protein-coding genes are characterized by back (reverse) mutations to the pre-H. sapiens state of mitochondrial genome. It has been found that hypervariable nucleotide positions show a minimal proportion of specific to H. sapiens mutations, and, conversely, a high proportion of mutations (both nucleotide and amino acid substitutions), leading to the loss of Homo-specific variants of polymorphisms. Most often, polymorphisms specific to H. sapiens arise in result of single forward mutations and disappear mainly due to multiple back mutations, including those in the mutational "hotspots". PMID- 25509855 TI - [Polymorphism of RGS2 gene: genetic markers of risk for schizophrenia and pharmacogenetic markers of typical neuroleptics efficiency]. AB - Schizophrenia is a common psychiatric disorder affecting about 1% of the general population. Several lines of evidence indicate that Regulator of G Protein Signaling 2 (RGS2) contributes to schizophrenia vulnerability because it modulates signal transduction of neurotransmitter receptors that play a role in the pathogenesis of schizophrenia. A number of studies have shown an association of polymor- phic loci RGS2 gene with the occurrence of extrapyramidal symptoms induced by neuroleptics. DNA samples of 258 patients with paranoid schizophrenia and of 263 healthy controls of Russian and Tatar ethnic group living in the Republic of Bashkortostan were involved into the present study. In the result of the present study low risk genetic markers; high risk genetic markers of paranoid schizophrenia RGS2*G/*G (rs2746071) in Russians (p = 0.001; OR = 4.08) and in Tatars (p = 0.000; OR = 4.88); allele.RGS2*G in Russians (p = 0.00003; OR = 2.37) and Tatars (p = 0.000; OR = 2.51), high risk genetic markers of parkinsonism induced by haloperidol: RGS2*T/*T(rs2746073), RGS2*C/*C (rs4606), RGS2*A/*A (rs2746071) in Rus- sians, genetic markers of treatment efficacy in Tatars were obtained in individuals from the Republic of Bash- kortostan; considerable inter ethnic diversity of genetic risk factors for this disease was revealed The results of this study are consistent previous results and support the hypothesis that polymorphic loci RGS2 gene associated with risk of extrapyramidal symptoms induced by typicalneuroleptics-haloperidol, and are involved in schizophrenia pathway. PMID- 25509856 TI - [Enhanced expression of EPHX2 gene in the kidney of the hypertensive ISIAH rats]. AB - Epoxyeicosatrienoic acids (EETs) have antihypertensive properties and play a part in the maintenance of renal microvascular function. EETs mediate vasodilation of rat preglomerular microvessels and activate ion channels. Ephx2 is coding for the soluble epoxide hydrolase (sEH) which catalyze the degradation of EETs. Renal cortex and renal medulla were tested for Ephx2 mRNA level in hypertensive ISIAH and normotensive WAG rats at rest and emotional stress conditions. The microarray analysis and real-time PCR were used to assess the transcriptional activity of Ephx2. Enhanced transcriptional activity of Ephx2 in both renal structures of ISIAH rats was found at rest and stress conditions. The emotional stress caused elevation of Ephx2 mRNA level in renal medulla of ISIAH rats and opposite response--a decrease in Ephx2 expression in the renal medulla and cortex of WAG rats.The results suggest Ephx2 participation in the control of the vascular tone changes in kidney promoting the hypertensive state in the ISIAH rats. PMID- 25509857 TI - [Biochip for determination of genetic markers of sporadic Alzheimer's disease in the Russian Slavic population]. AB - A biological microchip (biochip) for the genetic predis- position to sporadic form of Alzheimer's disease studying has been developed. The biochip allows determina- tion of ten genetic polymorphisms within APOE, TOMM40, APOJ, EXOC3L2, GAB2, A2M, CR1, BIN1 and PICALM genes. The genotyping assay includes the amplification of loci of interest and further allele-specific hybridization of the fluorescent labeled amplicons with oligonucleotides immobilized on a biochip. Based on the results of genotyping of 166 patients and 128 controls APOE epsilon4 allele was found to be significantly associated with Alzheimer's disease susceptibility (OR = 2.275, 95% CI = 1.045-4.954,p = 0.034). Additionally, protective effects for the APOE epsilon2 allele and CLUT-allele (rs11136000) were observed (OR = 0.215, 95% CI = 0.090-0.516, p = 0.001 and OR = 0.679, 95% CI = 0.47-0.99, p = 0.042, respectively). Gene-gene interaction revealed two genotype combinations associated with Alzheimer's disease: APOE E3/E4 GAB2 G/G (OR = 2.49; CI = 1.43-4.32, p = 0.001) and APOE epsilon4 GAB2 G/G (OR = 3.55, CI = 1.23 10.24,p = 0.015). Based on the results of the combined multivariate analysis the algorithm for identifying of individuals at increased risk of Alzheimer's disease was developed. PMID- 25509858 TI - [Selection of reference genes for quantitative real-time PCR in six oil-tea camellia based on RNA]. AB - qRT-PCR is becoming a routine tool in molecular biology to study gene expression. It is nec- essary to find stable reference genes when performing qRT-PCR. The expression of genes cloned in oil-tea camellia currently can't be accurately analyzed because of a lack of suitable reference genes. We collected different tissues (including roots, stems, leaves, flowers and seeds) from six oil-tea camellia species to determine stable reference genes. Five novel and ten traditional reference gene sequences were selected from the RNA-seq database of Camellia oleifera C. Abel seeds and specific PCR primers were designed for each. Cycle threshold (Ct) data were obtained from each reaction for all samples. Three different software tools, geNorm, NormFinder and BestKeeper were applied to calculate the expression stability of the candidate reference genes according to the Ct values. The results were similar between analyzed by the three software packages, and indicated that the traditional gene TUBa-3, AC17a and the novel gene CESA were relatively stable in all species and tissues. However, no genes were sufficiently stable across all species and tissues, thus the optimal number of reference genes required for accurate normalization varied from two to six. Finally, the relative expression ofsqualene synthase (SQS) and squalene epoxidase (SQE) genes related to important ingredients squalene and tea saponin in oil-tea camellia seeds were compared by using stable to less stable reference genes. The comparison results validated the selection of reference genes in the current study. In summary, different optimal numbers of suitable reference genes were found for the different tissues of six oil-tea camellia species. PMID- 25509859 TI - [Multiplex genotyping of single nucleotide polymorphisms by MALDI-TOF mass spectrometry: ferequencies of 56 SNP in immune response genes in human populations]. AB - Single nucleotide polymorphism (SNP) are the most common type of genetic polymorphisms. Despite the progress in sequencing and postgenomic technologies, point genotyping of SNPs remains the most demanded approach in human and medical genetics. In this paper, the experience in the application of multiple SNP genotyping using MALDI-TOF mass-spectrometry for the analysis of genetic diversity of immune response genes in human populations has been described. It is demonstrated that MALDI-TOF mass-spectrometry is rapid, accurate and efficient method for medium-scale SNP genotyping. In four populations (Russian, Komi, Khant, and Buryat) the similar spectrum of allelic frequencies for 56 SNPs in 41 genes implicated in the regulation of immune response was found. Populations under study have the similar level of genetic diversity and are clustered according their geographic location. Economic effectiveness of MALDI-TOF mass spectrometry in comparison with a real time PCR technology is estimated. PMID- 25509860 TI - [The LMP1 oncogene sequence variations in patients with oral tumours associated or not associated with the Epstein Barr]. AB - The role of the Epstein-Barr virus (EBV), a ubiquitous lymphotropic human herpesvirus type 4, in the etiology of nasopharyngeal carcinoma (NPC) is not fully understood. The mechanism of NPC carcinogenesis, associated with the virus, is also not clear. The objective of present investigation was to carry out comparative analysis of the structure of an LMP1 oncogene of EBV in viral isolates obtained from patients with two types of tumors of the oral cavity: (a) associated (i.e., NPC) and (b) not associated (other tumors of the same anatomical region, OTOC) with EBV. Comparative analysis of C-terminal regions of LMP1 variants that was based on a sequence analysis of LMP1 from tumor, blood and throat washing samples of NPC and OTOC patients showed that all structural characteristics of LMP1 in both groups of patients were genetically similar, and differences found between compared parameters were statistically insignificant. Thus, for the first time it has been revealed that in NPC and OTOC patients in Russia genetically related EBV strains with structurally similar LMP1 variants are persisting that are likely to reflect a polymorphism of the virus circulating in population. The findings allow us to suggest that in non-NPC-endemic regions of the world, which include Russia, the risk of NPC development does not depend on the EBVstrain and its variant of LMP1 so much, but mostly from the genetic predisposition of infected persons to the disease and the exposure to other, as yet unknown agents. PMID- 25509861 TI - [Changes in gene expression and content of titin (connectin) in striated muscles of chronically etihanol-fed rats]. AB - Changes in gene expression and isoform composition of giant sarcomeric protein titin (connectin) in cardiac muscle, as well as changes of its isoform composition in skeletal muscle (m. soleus) of chronically ethanol-fed rats have been studied using real-time RT-PCR and low percentage SDS-gel electrophoresis. The decrease of titin content in examined muscles and the decrease in titin gene expression in myocardium of chronically ethanol-fed rats have been shown. These changes indicate the development of pathologic process. PMID- 25509862 TI - [Regulation of the genes expression of CD4+ T-lymphocytes differentiation transcription factors by galectin-3 in vitro]. AB - Now a number of CD4+ T-lymphocytes, known as Th1, Th2, Treg and Th17, is currently identified and well- studied. The methods basing on the targeted regulation of differentiation process of the Th-lymphocytes that carry out the immune response polarization attract an attention of scientists dealing with a correction of immune-mediated. In the present study, endogenous beta-galactoside binding protein of the lectin family, galectin-3, was investigated as a regulator of T-cell homeostasis. A galectin-3 is known to be actively produced by tumor cells in malignant transformation and able to influence the processes of signal transduction, cell-cell cooperation and the implementation of programmed death. As cell differentiation processes are directly connected with the regulation of gene expression, we investigated the effect of recombinant galectin-3 on expression of mRNA of transcription.factors, which guide the differentiation of CD4+ lymphocytes. The study was performed on peripheral blood mononuclear cells of healthy individuals. The gene expression levels were evaluated by a real-time PCR. In the experiments in vitro, it has been first found the recombinant galectin-3 (0.5 mg/mL) up-regulating the expression of transcription factors Gata 3 and Rorc mRNAs and down-regulating the mRNA expression of transcription factors T-bet and FoxP3. Up to a concentration of 1 mg/mL recombinant galectin-3 stimulates Th-cells by dose-dependent manner, whereas at higher concentrations stimulating effect weakens, and inhibiting action starts prevailing. Thus, one can suppose that galectin-3 through regulation of lymphocytes differentiation promote development of allergic, autoimmune and neoplastic diseases that allows us to consider the galectin-3 as a.potential target for therapy of these diseases. PMID- 25509863 TI - [Identification of transthyretin posttranslational modifications 1n human blood using mass-spectrometric methods]. AB - Transthyretin, one of the major plasma proteins, has a number of posttranslational modifications and mutations, some of which are associated with the development of severe diseases, for instance, familial amyloid neuropathy and Alzheimer's disease. In order to investigate the role of modified forms in the development of these diseases a complex analytical platform, based on two mass spectrometric approaches (bottom-up and op-down) has been developed. The high efficiency of this method was shown using 10 plasma samples obtained from patients with Alzheimer's disease and healthy individuals. PMID- 25509864 TI - [Chaotic artificial bee colony algorithm: a new approach to the problem of minimization of energy of the 3D protein structure]. AB - Frediction of the three-dimensional structure of a protein from its amino acid sequence can be considered as a global optimization problem. In this paper, the Chaotic Artificial Bee Colony (CABC) algorithm was introduced and applied to 3D protein structure prediction. Based on the 3D off-lattice AB model, the CABC algorithm combines global search and local search of the Artificial Bee Colony (ABC) algorithm with the Chaotic search algorithm to avoid the problem of premature convergence and easily trapping the local optimum solution. The experiments carried out with the popular Fibonacci sequences demonstrate that the proposed algorithm provides an effective and high-performance method for protein structure prediction. PMID- 25509865 TI - [Expression of the F3h gene in various wheat organs]. AB - In plants, the F3h gene encodes akey enzyme of flavonoid biosynthesis pathway, flavanone 3-hydroxylase. In most plant species, F3h is a single-copy gene, whereas in the genome of bread wheat (Triticum aestivum L., 2n = 6x = 42, BBAADD), four copies of this gene were found. Using RT-PCR, transcription of these copies was studied in various organs of several wheat genotypes. Three homoeologous copies (F3h-A1, F3h-B1, F3h-D1) manifested similar expression patterns and were specifically transcribed in caryopsis pericarp, culm, coleoptile and leaf colored with anthocyanins. The paralogous copy F3h-B2 in the B-genome was expressed only in wheat roots and probably is involved in biosynthesis of some uncolored flavonoid compounds unrelated to anthocyanin biosynthesis. PMID- 25509866 TI - [New cell RNA elimination method for cell-based selex of modified RNA aptamers]. PMID- 25509867 TI - [The 50th anniversary of the Institute of Biomedical Problems of the Russian Academy of Sciences]. PMID- 25509868 TI - [The effects of support-proprioceptive deprivation on visual-manual tracking and vestibular function]. AB - To determine the effects of support and proprioceptive afferentation on characteristics of the visual-manual tracking (VMT) we used a model of weightlessness - horizontal "dry" immersion. Altogether 30 subjects who stayed in immersion bath from 5 to 7 days were examined to evaluate the accuracy of VMT in tasks to pursue the jerky (saccadically) and smooth (linear, pendular and circular) movement of a point visual stimulus. Examinations were performed before, during and after immersion using electrooculography (to record eye movements) and a joystick (to record hand movements) with a biological visual feedback - one of the two visible stimuli on the screen matched the current angle of the joystick handle. Computerized visual stimulation programs were presented to subject using a virtual reality glasses. We analyzed time, amplitude and velocity characteristics of the visual and manual tracking (VT and MT), including efficiency ratio (eVT and eMT) and gain (gVT and gMT) as ratios of respectively amplitudes and velocities of eyes/hand movements to the stimulus movement. eVT was significantly decreased in comparison with baseline all the time while subject lied in the immersion bath and until R+4 day after immersion, eMT was significantly decreased only on I-1 and I-3 days in immersion. gVT significantly differed from baseline only on I-3 and I-6 days in immersion and R + 1 day after immersion. We found no significant changes in gMT. Evaluations of the vestibular function (VF) were performed before and after immersion using videooculography approach. We analyzed statical torsional otolith-cervical-ocular reflex (OCOR), dynamical vestibular-cervical-ocular reactions (VCOR), spontaneous eye movements (SpEM), the accuracy of perception of subjective visual vertical (SVV). After immersion 47% of subjects had significant decrease of OCOR with a simultaneous significant increase of VCOR on 37% of subjects as well as significant changes in accuracy of perception of SVV which correlated with changes in OCOR. We found correlation between characteristics of the VT and MT, between characteristics of the VF and VT and found no correlation between VF and MT. It was found that removal of the support and minimization of the proprioceptive afferentation has a greater impact upon accuracy of the VT then accuracy of the MT. PMID- 25509869 TI - [Prediction of human orthostatic tolerance by changes in arterial and venous hemodynamics in the microgravity environment]. AB - The authors intentionally present exclusively the results of their recent studies of arterial and venous hemodynamics as predictors of human orthostatic tolerance (OT) during space flight and on return to Earth. There is a sufficient demonstration of the in-flight OT predictability by arterial hemodynamic reactions to LBNP and venous hemodynamic changes in response to the lower extremities occlusion. Three levels of cerebral blood flow deficits in the course of the lower body negative pressure test (LBNP) performed in microgravity were first defined. The authors offer quantitative arguments for the dependence of cerebral flow deficit on the degree of LBNP tolerance degradation. Patterns of arterial hemodynamics during LBNP were used successfully to diagnose the actual orthostatic tolerance and also to follow its trend as flight extended, which attests to the predictability of OT change in an individual cosmonaut on space flight. Occlusion plethysmography of legs revealed three levels of response of the most informative venous parameters (capacity, distensibility and rate of filling) correlating with severity of OT degradation. PMID- 25509870 TI - [Mechanical stimulation of soles' support zones: non-invasive method of activation of generators of stepping movements in man]. AB - The effects of mechanical stimulation of the soles' support zones in regimens of slow and fastwalking (75 and 120 steps per minute) were studied using the model of supportlessness (legs suspension). 20 healthy subjects participated in the study. EMG activity of hip and shin muscles was recorded. Kinematic of leg movements was assessed with the use of videoanalysis system. Support stimulation was followed by leg movements in 80% of cases, in 53% it was a locomotion-like movement. EMG bursts accompanied the movements. Involvement order and alteration of bursts in muscles were similar to voluntary walking. EMG activity occurred with a delay of 5.17 +/- 1.08 seconds for hip muscles and 14.01 +/- 2.82 seconds for shin muscles, frequency of bursts differed from stimulation frequency. Support stimulation was followed by leg movements in 80% of cases, in 53% of which they had characteristics of locomotions being accompanied by the burst-like electromyographic activities. Involvement order of the leg muscles and organization of antagonistic muscles activities were analogous to that of voluntary walking. The latencies of electromyographic activity in hip muscles composed 5.17 +/- 1.083 s and 14.01 +/- 2.82 s - for shin muscles, frequency of bursts differed significantly from stimulation frequency. In 31% of cases the electromyographical activity following the stimulation of the soles' support zones was not burst-like. Its amplitude rose smoothly reaching a certain level that was subsequently maintained. Results of the study showed that soles' support zones stimulation in regimen of locomotion can activate a locomotor generator and that effect evoked by this stimulation includes not only rhythmical but also non rhythmical (probably postural) components of walking. PMID- 25509871 TI - [Researches of autonomic regulation of blood circulation in the condition of long term space flight]. AB - In the article is presented five-year experience of experimentation in autonomic regulation of blood circulation onboard the International space station. The heart rate variability (HRV) analysis was the basic methodical approach in the researches. We described probabilistic approach created on the basis of HRV analysis to an estimation of risk of pathology development in the conditions of long space flight. The individual type of autonomic regulation had essential value during the analysis of results. It is shown that the type of regulation, which is inherent in every cosmonaut in the conditions of weightlessness, remains even during following flights. We obtained the new scientific data on connection of character of adaptable reaction of an organism to the space flight factors with individual type of autonomic regulation. It is shown that staying in weightlessness is connected with changeover of regulatory systems and with transition in a zone of prenosological states. Adaptable reactions in weightlessness are characterized by tension growth of regulatory systems at preservation of sufficient functional reserves. The mobilization of additional resources after returning to the Earth is required and consequently functional reserve of mechanisms of regulation decreases. Cosmonauts with vagotonic and normo-sympatotonic types of autonomic regulation appear to be the most resistant. Knowing the type of autonomic regulation we will be able to foresee possible reaction of the cosmonaut to the factors of space flight. As a result of HRV analysis during the flight of the past few months likelihood estimations were calculated and risk categories were defined. Consequently, 3 groups of risk of pathology development were distinguished. In conclusion, theoretical and applied relevance of the conducted experiments were considered. PMID- 25509872 TI - [Features of the psychophysiological status of men with different levels of vestibuloautonomic resistance and their interrelation with motion sickness' etiology and pathogenesis]. AB - The results of more than 600 observations of 200 healthy male-volunteers of 23-45 years old including parameters of electroencephalogram, sensorimotor reactions, and questionnaires of Cattell, Strelau and Taylor were analyzed. Division into groups with high, moderate and low vestibuloautonomic resistance (VAR) was done on base of endurance of rotary test with interrupted cumulation of Coriolis accelerations. It is shown, that VAR degree along with distinctions in sensitivity of peripheral compartment of a vestibular analyzer and other sensory systems is appreciably defined by the distinctions in force, lability, activity and dynamism of a nervous system, equilibrium and mobility of processes of excitation-inhibition. VAR is also defined by the distinctions of the initial psychophysiological status characterizing psychomotor reactivity, features of personality, temperament and cognitive abilities, while expressiveness ofvestibuloautonomic disorders in susceptible to motion sickness men is essentially intensified by the influence of their psychoemotional condition during vestibular stimulation-suibjective sensation "lost in space", manifestation of mental discomfort and anxiety, accompanied by autonomic and neurohormonal reactions which extreme form can be characterized as the "syndrome of a threatened state". PMID- 25509873 TI - [Analysis of possible causes activation a stomach and pancreas excretory and incretory function after completion of space flight on the international space station]. AB - The research excretory and incretory of activity of a stomach and pancreas is carried out at astronauts in the early period after completion of space flights of various duration. It is shown, that the increase of the contents of gastric and pancreatic enzymes and hormones (insulin and C-peptide) in blood reflects increased excretory and incretory activity of organs of gastroduodenal area which arises in weightlessness. The complex of countermeasures, which prevent ingress of subjects, infected by Helicobacter pylori in space flight crew, excluded participation of this microorganism in the mechanism of increase of secretory activity of a stomach. The absence of interrelation between increase of secretory activity of gastroduodenal area organs and space flights' duration has allowed to exclude the hypokinetic mechanism which determined by duration of stay in weightlessness. It was shown that after the end of space flights the increase ofbasal excretory activity of organs of gastroduodenal area occurs simultaneously with increase of a fasting insulin secretion. The changes in gastroduodenal area organs revealed after space flights were are compared to similar changes received in ground-based experiments, simulating hemodynamic reorganization in venous system of abdominal cavity, arising in weightlessness. The conclusion is made, that the basic mechanism of changes of a functional condition of digestive system in space flights, is determined by reorganization venous hemodynamic in abdominal cavity organs reproduced in ground experiments. Increase insulin and C-peptide after space flights are considered as hormonal component of this hemodynamic mechanism. PMID- 25509874 TI - [Optimization of training: development of a new partial load mode of strength training]. AB - Hypertrophic effect of strength training is known to originate from mechanical and metabolic stimuli. During exercise with restricted blood supply ofworking muscles, that is under conditions of intensified metabolic shifts, training effect may be achieved with much lower external loads (20% of one repetition maximum (1 RM)). The aim of the study was to compare the effects of 8 wks high intensity (80-85% MVC) strength training and low-intensity (50% 1 RM) training without relaxation. The high-intensity strength training leads to somewhat higher increments in strength and size of trained muscles than training without relaxation. During high-intensity training an increase of area occupied by type II fibers at muscle cross section prevails while during training without relaxation - an increase of area occupied by type I fibers takes place. An exercise session without relaxation leads to a more pronounced increase in secretion of growth hormone, IGF-1 and cortisol. Expression of gene regulating myogenesis (Myostatin) is changed in different ways after high-intensity strength exercise session and after exercise session without relaxation. Low-intensity strength training (50% 1 RM) without relaxation is an effective way for inducing increases of strength and size of trained muscles. This low intensive type of training may be used in restorative medicine, sports and physical culture. PMID- 25509875 TI - [Specifics of activation of cortex by stimulation of support receptors in healthy subjects and in patients with lesions of CNS]. AB - Results of basic studies in space medicine revealed the mechanism of motor disorders and the importance of support input in regulation of the tone and posture system of the mammals. Progress in functional magnetic resonance tomography (fMRT) enabled in vivo estimation of activity of various parts of the brain during stimulation of support afferent pathways. The goal of our study was to detect specific activation of the cortex during stimulation of support input in healthy subjects and in patients with lesions of CNS. The study included 19 healthy volunteers (mean age of 38 +/- 15, 13 years) and 23 patients with cortical-subcortical ischemic stroke (mean age 53 +/- 9.07); all subjects underwent fMRT. During scanning of each subject, support areas of the foot soles were stimulated to imitate slow walking using the block design. In healthy volunteers, primary somatosensory cortex, premotor and dorsolateral cortex, and insula were significantly activated (corrected <0.05 at cluster level). In patients with stroke, pattern of activation of the supraspinal systems of locomotion control clearly depended on the stage of the disease. In patients with cortical-subcortical stroke undergoing motility rehabilitation, the sensomotor locomotion module was predominantly activated as the contralateral pattern. PMID- 25509876 TI - [Human lymphocyte immunophenotype after interaction with mesenchymal stromal cells]. AB - Human multipotent mesenchymalstromal cells were cocultured for 72h with allogeneic blood-borne mononuclear cells (MNCs) of different maturity (lymphocytes from adult peripheral blood and umbilical cord blood) and functional state (intact and PHA-activated human peripheral blood lymphocytes): After coculture with MMSCs the share ofB-cells among MNCs and cbMNCs decreased. The proportion ofT- and NK cells declined only among cbMNCs (p < 0.05). Only T-NK subpopulation reduced among MNC and cbMNC T-cells. The drop of CD8+ cells was detected in coculture of MMSCs and PHA-MNCs. Activated HLA-DR+ cells declined, CD25+ cells increased compared to monoculture of PHA-MNCs. MMSCs supported MNC, PHA-MNC and cbMNC viability. These results are important for understanding the physiology of the allogeneic cell-to-cell interaction in connection of potential clinical application of allogeneic cell products of blood-borne and stroinal origin. PMID- 25509877 TI - [Detection of renal and urinary tract proteins in the urine before and after space flight]. AB - The urine protein composition (proteome) of healthy human was analyzed using proteomic techniques to obtain data in physiological condition and after six months space flights. It was shown that after long duration space flights in cosmonaut's urine reveals specific minor proteins which can be identified as proteins came from kidney and urinary tract. PMID- 25509878 TI - [The effects of simulated microgravity on the pattern of gene expression in human bone marrow mesenchymal stem cells under osteogenic differentiation]. AB - It is well-known that the modified gravity affects not only the organism as a whole, but also the molecular processes in individual cells. The goal of this study was to investigate the influence of simiulated microgravity (SMG) on gene expression pattern in cultured human bone marrow mesenchymal stem cells (hMSCs) after prolonged exposure to SMG on dRPM. It was found that the expression level of 144 genes significantly changed in hMSCs after 20 days of exposure to SMG: the expression of 30 genes significantly increased and 114 - decreased. Gene analysis revealed that these genes can be attributed to the 11 major categories corresponding to its biological role in the cells. The greatest number of genes with altered expression was found to be in the groups "Matrix and Adhesion", "Inflammation and Cell-to-Cell Communications", "Metabolism" and "Signalling". Interestingly, some of the genes with down-regulated expression were related to the bone development and differentiation (COL15A1, CXCL12, DPTand WISP2) or participated in the cell-to-cell communications ofhMSCs with other cell types (CXCL12, SDF4). The obtained results indicate that the changes in gene expression in bone marrow progenitor cells can be involved into space flight-induced osteopenia. PMID- 25509879 TI - [Proteolytic signaling mechanisms in skeletal muscles in patients with alcohol induced muscle disease]. AB - Chronic alcoholic myopathy is one of most numerous and profound manifestations of chronic alcohol intoxication. This disease is characterized by the pronounced atrophy of the locomotor muscles, which involves predominantly those fibers expressing myosin isoforms of the I "fast" type. In early experiments with alcohol-fed rats and studies of patients it was shown the impairment of the anabolic intracellular signaling pathways and decrease in protein synthesis rate. We were the first to analyze the signaling pathways involved in the pathogenesis of alcoholic myopathy with different fiber atrophy levels. At the early stages of the pathogenesis we observed also the sufficient increase of mRNA of E3 ubiquitin ligases. However the ubiquitinylation level was not altered in patients as compared to the control subjects. This phenomenon could be associated with the increased expression of the heat-shock proteins, known for their protective action. PMID- 25509880 TI - [Adaptation of water-electrolytes metabolism to space flight and in its imitation]. AB - 50-years study of water-electrolytes exchange, the condition of water environments of the organism and the hormonal regulation in space flights, and also in postflight period or in its on ground modeling (hypokinesia, bed rest, immersion etc.) has shown the important role of the water-salt homeostasis in adaptation of the human and animal organisms to weightlessness. It has been revealed, that in weightlessness conditions for development of negative balance of a liquid (hypohydration) and the basic electrolytes are created. After the termination of long space flights attributes of development adaptive reactions compensating for extracellular liquid's volume come to light. In order to assess the state of the kidneys and water-electrolyte metabolism in cosmonauts and investigators, functional load tests and especial methods of diagnostic were developed. This is the basis for researches directed on improvement of the scheme of correction hydrogenous the status of an organism of the cosmonauts at the different stages of flight. PMID- 25509881 TI - [Immune system in Russian cosmonauts after orbital space flights]. AB - The article is an overview of the results of studies of the immune systems of cosmonauts. The use of a system approach to the evaluation of the various components of the immune system made it possible to identify a number of characteristics of adaptive change, including the quantitative and functional changes of the innate and adaptive immunity. Among them the most important are: changes in in the system of Toll like receptors (TLRs) manifested as a decrease in the content of circulating monocytes and granulocytes expressing TLR2, TLR4, and TLR6, and LPS-induced cytokine production; inhibition of the functional potential of natural killer (NK)- and T-cells. The article discusses possible factors and mechanisms of the identified changes. PMID- 25509882 TI - [Molecular pathological classification and its clinicopathological significance in gastrointestinal stromal tumor]. PMID- 25509883 TI - Preferential expression of OVOL1 in inner root sheath of hair, sebaceous gland, eccrine duct and their neoplasms in human skin. AB - OVOL1 is an important transcription factor for epidermal keratinization, which suppresses proliferation and switches on the differentiation of keratinocytes. A recent genome-wide association study has revealed that OVOL1 is one of the genes associated with susceptibility to atopic dermatitis. Although it is known to be expressed in murine skin and hair follicles, no investigations have focused on its localization in human skin. In the present study, we thus immunolocalized the expression of OVOL1 in normal and diseased human skin. In normal human skin, OVOL1 was preferentially expressed in the suprabasal layer of the epidermis, inner root sheath of hair, mature sebocytes and the ductal portion of the eccrine glands. Compared to this, no remarkable change in the expression of OVOL1 was observed among inflammatory skin diseases. The expression of OVOL1 was evident in eccrine poroma and hidradenoma. Moreover, it was overexpressed in Bowen's disease and sebaceous adenoma, in sharp contrast to its downregulation in their more malignant counterparts, squamous cell carcinoma and sebaceous carcinoma. OVOL1 may play an important role in human skin morphogenesis and tumorigenesis. PMID- 25509884 TI - [Personalized therapy for diabetes mellitus: the path from disease to the patient]. AB - The paper gives quick-look data on the new area in the diagnosis and treatment of diabetes mellitus (DM)- personalized medicine. It describes difficulties in the diagnosis of DM, its heterogeneity in children and adults, which may be identified by molecular genetic, immunological, hormonal, and metabolic studies. Data on the possibilities of predicting the individual, familial,; and population risks of types.1 and 2 DM are presented. Prospects for choosing the most effective and safest glucose-lowering therapy on the basis of a pharmacogenetic analysis of the susceptibility of patients to specific drugs are outlined. PMID- 25509885 TI - [Secretion of incretin hormones in people having risk factors for type 2 diabetes mellitus]. AB - AIM: To study the secretion of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP),and glucagon- like peptide 2 (GLP-2) in response to a carbohydrate load in people with risk factors for type 2 diabetes mellitus (DM2) in relation to the type of carbohydrate metabolic disturbances and age. SUBJECTS AND METHODS: One hundred and twenty-seven patients having DM2 risk factors who had not previously received glucose- lowering therapy underwent an oral glucose tolerance test (OGTT). The plasma levels of glucose, insulin, glucagon, GLP-1, GIP, and GLP-2 were determined at 0, 30, and 120 minutes of the test. RESULTS: According to the findings, the patients were divided into 3 groups: 1) normal glucose tolerance; 2) prediabetic states (impaired glucose tolerance and/or impaired fasting glycemia); 3) new-onset DM2. OGTT showed that the secretion of GLP-1 was lower and that of GIP and GLP-2 was higher in patients with DM2. GLP-1 secretion decreased with patient age. CONCLUSION: During OGTT, there is a statistically significantly difference in the secretion of incretin hormones in persons with varying degrees of carbohydrate metabolic disturbances: the peak GLP-1 secretion is the highest in healthy individuals and lowest in the patients with DM2; on the contrary, the peak GLP2 and GIP secretions are the highest in the patients with DM2. This may suggest that GLP-1 and the two other hormones (GLP-2 and GIP) show opposite effect in the regulatory mechanisms of carbohydrate metabolism. GLP-1 secretion is decreased with age, which may be one of the reasons for the higher prevalence of DM2 among the elderly. PMID- 25509886 TI - [Comparative analysis of the changing pattern of thyroid disease in patients with type 2 diabetes mellitus in the Perm region after 10 years]. AB - AIM: To comparatively analyze thyroid abnormalities in patients with type 2 diabetes mellitus (DM2) in the past 10 years. SUBJECTS AND METHODS: The thyroid state 10 years ago and presently was evaluated in 166 and 101 patient with DM2, respectively. The patients underwent in-depth physical examination and thyroid hormone functions were evaluated. RESULTS: The pattern of thyroid disease has changed in the patients with DM2 over a 10-year period. During recent mass and individual iodine deficiency prophylaxis, iodine-deficiency goiter had become substantially less frequent in DM2; the T3/T4 ratio has normalized. The prevalence of nodular goiter has remained unchanged. However, the incidence of autoimmune thyroiditis and hypothyroidism, the subclinical form of the latter in particular, has increased statistically significantly. Hypothyroidism has occurred more often during.treatment with glucose-lowering sulfanilamides than during metformin treatment or combined glucose-lowering therapy. Hypothyroidism was generally recognized untimely in the examinees, in elderly patients in particular: the clinical signs of thyroid disease were regarded as manifestations of DM2. Our preliminary data support other authors' opinion that thyroid insufficiency accelerates the rate of development and progression of vascular complications of DM2. The contrinsular effect of Levothyroxine was not recorded during replacement therapy for thyroid insufficiency. CONCLUSION: Although the incidence of thyroid abnormality is increasing in patients with DM2 in the world, its causes are yet to be explained. The diagnosis of hypothyroidism in patients with DM2 is commonly untimely. At a follow-up of patients with DM2, it is necessary to systematically monitor thyroid function and to initiate levothyroxine replacement therapy in proper time. PMID- 25509888 TI - [Adiponectin and parameters of glucose and lipid metabolism at different clinical and morphological stages of non-alcoholic fatty liver disease in patients with abdominal obesity]. AB - AIM: To compare clinical, laboratory, and morphological parameters in patients with abdominal obesity and non-alcoholic fatty liver disease (NAFLD) and to assess the relationship between the degree and stage of the disease and the cardiometabolic risk factors of type 2 diabetes mellitus and cardiovascular diseases. SUBJECTS AND METHODS: Eighty patients aged 30 to 50 years with abdominal obesity were examined. NAFLD was diagnosed after liver puncture biopsy. The parameters of carbohydrate and lipid metabolism and the activity of hepatic transaminases and the protective adipocytokine adiponectin were investigated. RESULTS: NAFLD was verified in 77 examinees. Metabolic disturbances were found in the majority of the examinees with abdominal obesity and NAFLD; they were concurrent and increased in their rate and degree with the progression of NAFLD, obesity, and insulin resistance. The patients with NAFLD had a significantly decreased adiponectin level that got worse as NAFLD progressed. CONCLUSION: The investigation has revealed that NAFLD is associated with cardiometabolic disorders (dyslipidemia, carbohydrate metabolic disturbances, and insulin resistance) increasing in their rate and degree with the progression of NAFLD and the lower adiponectin level reducing as NAFLD worsens. PMID- 25509887 TI - [Risk factors for and prognostic value of multifocal atherosclerosis in patients with diabetes mellitus]. AB - AIM: To study the prognostic value of multifocal atherosclerosis (MFA) in patients with diabetes mellitus (DM) at high risk for myocardial ischemia who need coronary angiography (CAG). SUBJECTS AND METHODS: The investigation included 148 patients: 25 with type 1 DM (DM1), 73 with type 2 DM (DM2), and 50 without DM who had undergone CAG. Duplex ultrasound scanning of lower limb vessels and brachiocephalic and renal arteries was carried out in all the patients. RESULTS: Involvement of two or more vascular beds was noted in 60% of the patients with DM1, in 68.4% of those with DM2, and in 34% of those without DM (p < 0.05). Regression analysis showed that the risk factors of MFA were defined to be myocardial infarction (MI) in the history (OR=2.4; p=0.02), DM (OR=3.9; p=0.0002), smoking (OR=2.4; p=0.05), elevated creatinine (OR=6.5; p=0.002) and fibrinogen (OR=6.8, p=0.004) levels. Among the DM patients, there were 26.5% of those who had achieved a main assessment criterion (a combined end point (CEP)), such as death, urgent hospitalization for heart failure, nonfatal MI, nonfatal stroke, lower extremity amputation, double creatinine levels, and achievement of end-stage renal failure during a 24-month follow-up. In patients without carbohydrate metabolic disturbances, this indicator was 12% (p=0.01). During the prospective study, a total of 6.1% of patients died in the DM group; all the patients in the non-DM group completed the study. Calculation of survival rates by the Kaplan-Meier method indicated that the DM patients with concurrent atherosclerotic lesion had achieved CEP significantly more frequently than the comparison group. Such differences were absent among the persons without carbohydrate metabolic disturbances. CONCLUSION: The regression analysis has shown that prior MI, DM, smoking, creatinine and fibrinogen levels are factors associated with the development of MFA in the examined groups. In the patients with DM, concurrent atherosclerosis of two or more vascular beds is an important factor for the progression of cardiovascular and renal diseases. PMID- 25509889 TI - [The levels of resistin and other adipokines in patients with hypothyroidism]. AB - AIM: To investigate the relationship of resistin, adiponectin, leptin, and hormone metabolic parameters in patients with hypothyroidism. SUBJECTS AND METHODS: Ninety-three women aged 58.0 (53.0-63.0) years with hypothyroidism were examined. A control group consisted of 10 women aged 48 (47-50) years. Anthropometric characteristics, glucose and lipid metabolic parameters, and leptin, resistin, adiponectin levels were studied. RESULTS: The patients with hypothyroidism were found to have statistically significantly enhanced insulin resistance (IR) and compensatory hyperinsulinemia in the presence of android fat distribution. The found atherogenic dyslipidemia manifested itself as an increase in the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and atherogenic index and as a reduction in high-density lipoprotein cholesterol. The concentration of leptin and resistin was increased and that of adiponectin was reduced in the patients with hypothyroidism. There was a correlation of leptin and adiponectin with fat metabolic parameters. CONCLUSION: The women with hypothyroidism had enhanced IR, as well as compensatory hyperinsulinemia in the presence of android fat distribution. Hypothyroidism is accompanied by the development of atherogenic dyslipidemia. The concentration of leptin and resistin was elevated and that of adiponectin was reduced in the examinees. PMID- 25509890 TI - [Modifying effect of physical activity on genetic predisposition to obesity]. AB - AIM: To evaluate the modifying effect of physical activity on the association of ADRB3, CLOCK, FABP2, FTO, PPARA, PPARD, PPARG, PPARGC1A, SHBG, UCP2 and UCP3 gene polymorphisms with body mass index (BMI), body fat mass, and risk of obesity. SUBJECTS AND METHODS: The investigation enrolled 582 students and 215 athletes who showed moderate and high physical activities, respectively. The students' body composition was estimated with a DIAMANT-AST bioimpedance analyzer. Gene polymorphisms were determined by polymerase chain reaction (PCR) or real-time PCR. RESULTS: No differences in the rate of obesity risk alleles were found between normal-weight, and overweight or obese students. Correlation analysis in the total group of students revealed an association of the A allele of the FTO gene with BMI (p=0.0011) and body fat mass (p=0.0031). Comprehensive analysis summarizing the total number of obesity risk alleles for 7 polymorphisms of the PPARA, PPARD, PPARG, PPARGCIA, FTO, FABP2, and UCP2) genes in each individual showed that a subgroup of male students having a large number of obesity risk alleles (4-9) had higher BMI (22.6 +/- 2.73 kg/m2) than that of students having a small number of obesity risk alleles (20.8 +/- 2.81 kg/m2; p=0.0209). This pattern was not observed in the group of athletes regardless of gender and sports specialization. CONCLUSION: This investigation has demonstrated that physical activity has modifying effects on individuals who are genetically predisposed to obesity. Moderate and high physical activity considerably reduces the risk of obesity even in the presence of genetic risk factors. PMID- 25509891 TI - [[Effect of erythropoietin and its combination with hypoxic altitude chamber training on the clinical and functional manifestations of chronic glomerulonephritis]. AB - AIM: To evaluate the efficiency of treatment for renal anemia in patients with chronic glomerulonephritis (CGN), by using erythropoietin and its combination with hypoxic altitude chamber training (HACT). SUBJECTS AND METHODS: Sixty-three patients (41 men and 22 women) (mean age 37.1 +/- 3.3 years) with CGN during the predialysis phase of chronic kidney disease (CKD) complicated by anemia. Hemoglobin (Hb), packed cell volume (PCV), and red blood cell indices (mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC)), platelet count, serum iron, fibrinogen, C-reactive protein (CRP) and creatinine levels were determined in all the patients at baseline and during a prospective follow-up. Glomerular filtration rate (GFR) was measured using with the Rehberg Tareev test. Along with standard renal protective therapy, all the patients received either epoetin beta (n=31; Group 1) or its combination with HACT (n=32; Group 2). In Group 1 patients (n=31), erythropoietin (EPO) was given in an initial dose of 20-50 IU/kg thrice daily, followed by the dose being adjusted until the target Hb level was reached. Group 2 patients (n=32) received HACT cycles by the standard procedure in combination with EPO given in lower doses (20 50 IU/kg once weekly). A prospective .follow-up of the patients was carried out during one year. RESULTS: Following one year, the number of patients who had achieved the target Hb level was 74.1% in Group 1 and 87.5% in Group 2. Over time, there were increases in the concentration of Hb (from 108.6 +/- 19.4 to 124.5 +/- 14.09 g/l; p<0.05), PCV, and red blood cell indices (MCV, MCHC) in the patients receiving EPO (Group 1). Besides an'anti-anemic effect, there was a significant decrease in the concentrations of fibrinogen from 6655 (4884-7634) to 3776 (3330-4884) mg/dL; (p<0.05), serum creatinine from 159 (89--261) to 138 (79 258) pmol/I (p<0,05), proteinuria from 2.955 (1.024-6.745) to 2.069 (0.539-4.279) (p<0.05), which was accompanied by an increase in GFR from 62.3 (37.0 - 107.4) to 76.9 (46.0-96.0) mi/min (p<0.05). In Group 2, the rise in the concentration of Hb (from 114.1 +/- 11.7 to 132.0 +/- 16.5 g/I (p<0.05), PCV, MCV, and MCHC proved to be more pronounced than that in Group 1 (p<0.05) and accompanied by an elevation in the counts of platelets (from 222.7 +/- 19.8.10(9)/1 to 249.3 +/- 21.9.10(9)/1 (p<0:05)) and red blood cells (from 4.0 +/- 0.4-10(12)/1 to 4.34 +/- 0.3 X 10(12)/I (p<0.05)). There was a more marked reduction in the degree of proteinuria from 3.092 (0.764-7.694) g at baseline to 1.600 (0.677-4.078) g one year later (p<0.05) than that in Group 1 (p<0.05). The increase in GFR from 60.1 (46.0-96.0) to 79.4 (44.0-120.0) ml/min (p<0.05) and the fall in the concentration of fibrinogen from 5555 (4884-7770) to 4107 (3776-5328) mg/dL (p<0.05) and serum creatinine from 166 (92-273) to 147 (92-152) MUmol/L (p<0.05), which were observed in Group 2, were comparable to those in Group 1. CONCLUSION: Epoetin beta used in patients with CGN has an anti-anemic effect and leads to improved renal nitrogen-excretory function. Erythropoietin in combination with HACT used in CGN provides a higher anti-anemic efficacy and a more pronounced antiproteinuric effect. PMID- 25509892 TI - [Comparative characteristics of carotid atherosclerosis in patients with hypertension concurrent with chronic coronary heart disease among the indigenous and non-indigenous population of the Yamal-Nenets Autonomic District]. AB - AIM: To evaluate the degree of carotid artery (CA) atherosclerotic lesion and lipid metabolic disturbances in patients with hypertension and in those with hypertension concurrent with coronary heart disease (CHD) in the indigenous and non-indigenous population living in the Yamal-Nenets Autonomic District. SUBJECTS AND METHODS: Two hundred men and women aged 21 to 55 years (mean age 48.2 +/- 0.7 years), who resided in the Far North, were examined. The patients were divided into 4 gender-and age-matched groups of 50 persons in each: 1) natives; 2) newcomers with hypertension only; 3) natives with CHD and hypertension; 4) non natives with the above conditions. To study CA involvement, all the patients underwent duplex scanning of the brachiocephalic arteries at the extracranial level and blood lipid analysis in an outpatient setting (Salekhard). RESULTS: In all the patients, common CA intima-media thickness was significantly greater than the upper limit of the normal range defined in the Guidelines, this indicator proved to be highest in the groups of indigenous people (p<0.001). The latter with CHD and hypertension more commonly tended to have atherosclerotic lesion in the left CA (p=0.06) than the non-indigenous people whereas the number of stenosis in other CAs was similar. In the natives versus the newcomers with CHD and hypertension, the atherogenic blood lipid composition was due to the higher levels of total cholesterol and low-density lipoproteins. In the non- indigenous patients with CHD and hypertension, the atherogenicity of the blood lipid composition was characterized by the higher levels of triglycerides (p=0.04) and very low-density lipoproteins (p=0.02) with the lower concentrations of high density lipoproteins as compared to those in the natives with CHD and hypertension. PMID- 25509893 TI - [The 2013-2014 epidemic season. Hospital monitoring and antiviral therapy for influenza ]. AB - AIM: To characterize the 2013-2014 epidemic season from the results of detection of influenza infection in patients; to provide the molecular genetic characteristics of the strains isolated from deceased patients. SUBJECTS AND METHODS: The investigators examined 1203 patients (387 children, 509 people older than 16 years of age, 307 pregnant women) admitted to Moscow Clinical Infectious Diseases Hospital One with the clinical signs of acute respiratory viral diseases. Nasal lavage and autopsy specimens were used to isolate viral strains, then to sequence genomic fragments, and to determine receptor specificity. RESULTS: Out of the 1203 examinees, 284 (23.6%) were influenza-positive: 221 (77.8%), 24 (8.5%), and 39 (13.7%) patients had influenza A(H3N2), influenza A(H1N1)pdm09, and influenza B, respectively. Influenza was notified in 42,7% of the pregnant women. There was a preponderance of its moderate form; its severe form developed in single cases having comorbidities. One fatal outcome was registered. The intake of antiviral medications in the first 48 hours of the disease could prevent complications. The investigators revealed mutations in the strain isolated from the bronchoalveolar lavage fluid of a patient with severe pneumonia complicated by acute respiratory distress syndrome. CONCLUSION: There is evidence that there are mutant A(H1N1)pdm09 viruses that have high pneumotropicity. The high risk of their circulation in the population and the risk of severe influenza forms involving the lower respiratory tract remain. Early antiviral therapy in the first 36-48 hours diminishes the clinical manifestations of influenza and reduces the risk of developing complications. PMID- 25509894 TI - [Preliminary results of an open-label observational study evaluating the efficacy and safety of Prolia used in women with postmenopausal osteoporosis]. AB - AIM: To evaluate the efficacy and safety of Denosumab (Prolia), a first-line osteoporosis (OP) medication that is a fully human monoclonal antibody to the receptor activator of nuclear factor xB ligand (RANKL), within an open-label observational study. SUBJECTS AND METHODS: Patients aged 50 years or older with postmenopausal OP, who were treated with Prolia in clinical practice, were examined. The concentrations of the bone resorption (BR) marker of C-terminal telopeptide and other laboratory indicators (total serum calcium, total alkaline phosphatase, and creatinine) were measured following 3 months. Adverse drug reactions were recorded. RESULTS: Three months after initiation of the investigation, there was a significant decrease in the BR marker C-terminal telopeptide (by 89%; p<0.0001). There were rare adverse reactions: hypocalcemia in 3 (5.9%) patients, arthralgias in 2 (3.9%), and eczema in 1 (1.9%). There were neither serious adverse events nor study withdrawal cases. CONCLUSION: The preliminary results of the open-label study of Prolia in postmenopausal OP suggest that the significantly lower BR activity determines the efficacy of this drug and its high safety. PMID- 25509895 TI - [Clinical efficacy of the antimicrobial drug furamag in nosocomial urinary tract infections]. AB - AIM: To evaluate the efficacy of the combined drug furamag (furasidine potassium and magnesium hydroxycarbonate) in combination with the third-generation cephalosporin cefotaxime versus cephalosporin monotherapy for nosocomial urinary tract infections (NUTI). SUBJECTS AND METHODS: The randomized open-label comparative parallel group clinical trial enrolled 52 male and female patients aged over 18 years with a documented diagnosis of NUTI. Group 1 (a study group) took oral furamag 300 mg/day in combination with intravenous cefotaxime 6 g/day; Group 2 (a control group) received cefotaxime monotherapy. The duration of therapy in both groups was 7 to 10 days until the efficiency levels were achieved. RESULTS: A final efficiency analysis was made in 24 and 25 patients from Groups 1 and 2 who had different forms of NUTI (catheter-associated NUTI, cystitis, pyelonephritis). On day 3 of treatment, most patients were noted to have a decreased systemic inflammatory response; lower C-reactive protein and procalcitonin levels being in the study group patients. The clinical efficiency of antibacterial therapy, which had been evaluated both immediately after treatment termination and during further control, did not substantially differ in the furamag/cefotaxime combination and control groups although there was an obvious tendency towards the more marked effect of combined therapy 7-14 days after treatment (11.8% efficiency differences; p>0.05). Analysis of bacteriological efficacy revealed its most pronounced and clinically significant differences between the groups: the cefotaxime/furamag combination led to higher pathogen eradication in all follow-up periods: after 3 days of treatment (82.6%) and following a complete therapy cycle (95.8%) versus the cefotaxime monotherapy group (43.5 and 70.8%, respectively; p<0.01). Microbiological results showed that the major NUTI pathogens (Escherichia coli, enterococci) were more susceptible to potassium furasidine (furamag) versus cefotaxime. The in vitro higher activity of furamag versus cefotaxime was attended by the significantly higher eradication of one of the two important NUTI pathogens - Enterococcus faecalis. CONCLUSION: Furamag used in combination with the third-generation cephalosporin cefotaxime showed a higher bacteriological efficacy and a rapider reduction in the symptoms of a systemic inflammatory response in patients with NUTI. On the basis of the findings, the above combination of furamag and cefotaxime may be recommended as first-line therapy for NUTI when multidrug- resistant nosocomial infection pathogens are widely distributed now. PMID- 25509896 TI - [Latent forms of adult-onset autoimmune polyglandular syndrome: diagnosis and management of patients]. AB - Autoimmune polyglandular syndromes (APS) are an autoimmune involvement of two or more endocrine glands, which are characterized by multiple organ dysfunction. Four major types of APS are presently identified. There are APS types 2, 3, and 4 in adults. There are also latent and incomplete forms of adult-onset APS, the prevalence of which in the population is well above that of clinically apparent diseases. Latent disease may strongly affect the compensation and risk of complications of the underlying condition. The examination of APS risk-group patients includes the detection of genetic (HLA Class II haplotypes, CTLA-4, PTPN22, and FOXP3 genes, etc.) and immunological (antibodies) markers in autoimmune diseases and the determination of the residual function of the target organ. the treatment of autoimmune diseases in adult-onset APS is based on general principles; however, there are a number of specific features of using drugs for the concurrence of a few endocrine diseases. In this connection, the timely identification of risk groups for developing the clinical forms of APS in patients with one autoimmune endocrine disease. PMID- 25509897 TI - [The problem of viral hepatitis C in the Russian Federation]. AB - The incidence of chronic viral hepatitides (CVH) has increased 2.2-fold in the Russian Federation over the past decade. This increase is mainly determined by an almost threefold rise in the incidence of chronic hepatitis C (CHC): from 12.9 in 1999 to 39.1 per 100,000 population in 2012. The calculated data of hepatitis C burden in the Russian Federation show that in 2010 the total medical and social losses and expenses associated with hepatitis C and its implications were 48.47 billion rubles or 0.108% of the gross domestic product, the direct medical costs were 17.1 billion (35.28%) rubles, GDP losses were 26.05 billion (53.75%) rubles, and the disability payments were 5.32 billion (10.97%) rubles. The patients (mean age 45 years) with liver cirrhosis (LC) were 15.2% in the structure of the CHC patients (mean age 37 years) admitted to Moscow infectious diseases hospitals in 2010. Analysis of the regional registers of the Russian Federation, the proportion of patients with LC among those with CHC was 18%. The existing forms for recording morbidity and mortality from poor CHC outcomes cannot significantly estimate the true disease stage distribution of patients and hepatitis C associated disability and mortality rates. In this connection, it is necessary to introduce a federal register and to change recording forms for patients with viral hepatitides. Standard interferon, pegylated interferon alpha 2a and pegylated alpha 2b, and the HCV protease inhibitors telaprevir, boceprevir, and simeprevir have been registered for the treatment of hepatitis C in the Russian Federation. PMID- 25509898 TI - [Students' free work at the Department of Internal Propedeutics is an important part of an educational process]. AB - The paper presents different forms of students' free work, which have been approved at the Department of Internal Propedeutics, such patient examination; preparation of a piece and an academic case history; night duties in a clinic; attending conferences on deontology; training in the simulation center, medical practice, assessment of practical skills and knowledge at the examination. These work forms enhance the efficiency of an educational process and extend the capabilities of mastering clinical examination methods and molding deontological culture in students. PMID- 25509899 TI - [Multiple endocrine neoplasia type 1 variants and phenocopies]. AB - Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease due to a mutation in the MENI tumor suppressor gene. The risk of the disease in first-degree relatives of MEN1 mutation carriers is 50%. MENI gene mutations are not identified in 10-30% of familiar MEN1 patients and in 60 80% of sporadic MEN1 cases, which can be explained by mutations in the noncoding regions of the MEN1 gene, large gene deletions or mutations in other yet unknown genes. Molecular genetic testing can exclude the diagnosis of MEN1 in patients who do not harbor the MEN1 mutation, thus revealing a MEN1 phenocopy. This obviates the need for annual screening for the early detection of other remaining components of the disease and its risk in progeny. PMID- 25509900 TI - [Thyroid dysfunction and the hemostatic system]. AB - Whether there is a link between thyroid dysfunction and different impairments in the hemostatic system is discussed. The level of thyroid hormones is an essential factor that influences the coagulation system. Thyroid dysfunction affects the balance between coagulation and fibrinolysis, by increasing the risk of thrombosis and hemorrhage in hyperthyroidism. However, there is no consensus of opinion regarding the mechanisms of the described hemostatic changes in the literature. PMID- 25509901 TI - [Simultaneous pancreas-kidney transplantation: patients' perspectives ]. AB - Type 1 diabetes mellitus (DM1) is a chronic disease that may affect survival and quality of life in patients due to the development of acute and chronic complications. This review highlights the publications during the past decade on survival and the degree (stabilization/regression) of complications, such as diabetic retinopathy, nephropathy, neuropathy, and macrovascular events in DM1 patients with end-stage renal disease after simultaneous pancreas-kidney transplantation. PMID- 25509902 TI - [Antithrombotic therapy after X-ray endovascular treatment: are there specific features in patients with diabetes mellitus?]. AB - According to the current guidelines for the intervention treatment of patients with coronary heart disease, the primary and secondary prevention of cardiovascular events is long-termpharmacotherapy with platelet function inhibitors. Although undeniable progress has been made in the use of this group of medicaments, there are, however, issues calling for further investigation in the population of diabetic patients in particular. Along with the general principles of thrombosis, there are mechanisms that cause additional platelet hyperactivity in the presence of insulin deficiency and insulin resistance, metabolic and cellular disorders induced by hyperglycemia. The risk of resistance to standard antithrombotic therapy suggests a search for alternative ways to inhibit platelet aggregation, which is particularly relevant in diabetic patients. PMID- 25509903 TI - [Gestational diabetes mellitus: yesterday, today, tomorrow]. AB - Gestational diabetes mellitus (GDM) is hyperglycemia that is first detected during pregnancy and does not meet the criteria for manifest diabetes. The incidence of GDM worldwide varies from 1 to 14% and that in Russia is as high as 4%. Hyperglycemia during pregnancy is associated with the development of preeclampsia, the birth of a big baby, emergency cesarean section, birth trauma, and neonatal hypoglycemia. The fact that there is no well-organized screening for GDM in our country leads to that the diagnosis of this condition is delayed for 4 -20 weeks in 50-60% of cases. The risk group distribution of pregnant women leads ,to the diagnosis of GDM only in 50% of cases. At the same time, pregnancy is accompanied by physiological insulin resistance so the latter itself is a clinically important risk factor for carbohydrate metabolic disturbances. The Hyperglycemia and Adverse Pregnancy Outcomes (HYPO) study has indicated that the previously used diagnostic criteria for GDM require reconsideration. There is a need for uniform standards for the diagnosis and treatment of carbohydrate metabolic disturbances during pregnancy. The concepts (diabetes mellitus (DM)W and (manifest (new-onset DM during pregnancy( and directly UGDM( require clear clinical and laboratory definitions. Furthermore, GDM is a risk factor for obesity, type 2 DM and cardiovascular diseases in the mother and her offspring in future. PMID- 25509904 TI - [[Current approaches to diagnosing and treating nonalcoholic fatty liver disease]. AB - Nonalcoholic fatty liver disease (NAFLD) is associated with major cardiovascular risk factors, such as type 2 diabetes mellitus, obesity, dyslipidemia, hypertension, and insulin resistance, and has been recently considered to be a new component of metabolic syndrome and it serves as a criterion for the hepatic manifestation of the latter. The review considers the present-day views and approaches to diagnosing and treating NAFLD and its dangerous manifestation - fibrosis (sclerosis), which may lead to cirrhosis and hepatocellular carcinoma. Fibrogenesis is a widespread and universal process that is a final path of chronic inflammation of and damage to different tissues (including those of the liver and cardiovascular system). Although the mechanisms for developing NAFLD remain unclear, insulin resistance, an obesity-related slowly progressive inflammatory response, and elevated levels of free fatty acids with their lipotoxicity along with possible genetic, dietary, and environmental (lifestyle) factors play a key role in the pathogenesis of this disease. So it is important for patients at high risk for NAFLD or with existing liver disease to pay attention to their life style, proper balanced diet, and slow and gradual weight loss. At present there are drugs that can improve liver function. Success in NAFLD therapy will be determined by the identification of the most significant pathogenetic factors in a specific patient and by the purposeful action on them. PMID- 25509905 TI - [Full-dose combinations of antihypertensive drugs: what has changed in experts' guidelines?]. AB - The 2013 European Society of Hypertension guidelines, including treatment policy changes presupposing that one two-component combination of antihypertensive agents may be substituted for another and their full-dose combinations may be prescribed if monotherapy is ineffective, are discussed. A rationale is provided for the most effective two-component full-dose combinations of antihypertensive drugs. PMID- 25509906 TI - [Rinsing in the combination therapy of tonsillopharyngitis]. AB - The paper gives the current aspects of the etiology and pathogenesis of acute tonsillopharyngitis and its complications. Correct evaluation of the clinical manifestations of the disease is noted to be of importance in choosing adequate treatment policy and preventing unfavorable trends in the development of the disease. Antibacterial therapy for streptococcal tonsillopharyngitis is emphasized to be of significance. The paper shows that it is expedient to perform irrigation procedures (different types of rinsing) that ensure a significant contact area and optimal conditions for the better local effect of antibacterial solutions, in particular furasol, a nitrofuran derivative (the active ingredient is furasidine potassium; the excipient is sodium chloride). There are clinical findings suggesting that furasol has a positive effect on the intensity and duration of oropharyngeal inflammatory changes, suggesting that it is advisable to use it in respective clinical situations. PMID- 25509907 TI - Wave properties of nanoparticles: the view of a problem. AB - The results of studies on nanopharmacology have made conditions to develop a hypothesis: from the standpoint of quantum mechanics an increase in pharmacological properties of nano- particle based medications is driven by the preponderance of wave properties over corpuscular ones. According to results obtained the changes of spin states in molecules is one of the es- sential properties of living matter, which is characterized by self-organization. Self organiza- tion is also common in nanostructur-es. Therefore, the quantum wave properties of nanopar- ticles with their high ability to change spin states determine pronounced pharmacological effect of nanoparticle based medications. At this stage of research the scientific facts received do not rise to the possibility to experimentally or mathematically justify the assumptions made, so pleasetake them for granted. I am convinced that this article will be the 'nanomotor' that will attract world's scientists to continue research in order to prove current hypothesis - the wave properties of nanoparticles determine their high activity - experimentally. PMID- 25509908 TI - [Morphological verification problems of Chernobyl factor influence on the testis of coal miners of Donbas-liquidators of Chernobyl accident]. AB - Problem of a diagnostic of Chernobyl factor influences on different organs and systems of Chernobyl accident liquidators are remain actually until now. Though morbidly background which development at unfavorable work conditions in underground coalminers prevents from objective identification features of Chernobyl factor influences. The qualitative and quantitative histological and immunohistochemical law of morphogenesis changes in testis of Donbas's coalminer non-liquidators Chernobyl accident in comparison with the group of Donbas's coalminers-liquidators Chernobyl accident, which we were stationed non determined problem. This reason stipulates to development and practical use of mathematical model of morphogenesis of a testis changes. PMID- 25509909 TI - [Features of fetal development in a woman with uterus duplex]. AB - Moderate doses of radiation exposure in the early period of embryogenesis may become the reason of occurrence of uterus duplex and raise a follicular unit ovarian the future girl of that predetermines a high probability of malformations of the fetus during future pregnancies after reaching adult age. PMID- 25509910 TI - [The impact of clopidogrel and aspigrel on fatty acid spectrum of platelet membrane phospholipids in patients with new-onset angina]. AB - The research of more effective unstable angina treatment is still actual despite the definite protocols exist. It was investigated the lipid acids spectrum of platelet membrane phospholipids in patients with new-onset angina and was analyzed the impact of clopidogrel and aspigrel on its changes. PMID- 25509911 TI - [Prognosis of hypertensive disorders in pregnancy]. AB - There has been dependence of probability of hypertensive disorders for pregnant women on level of antibodies to beta2 glycoprotein 1, D-dimer, coefficient of atherogenicity and results of testing thrombophilia genes. This allows detecting pregnant women having high risk of hypertensive disorders. Testing of the model on a sample which consists of 44 healthy pregnant women and 112 women with hypertensive disorders has good predictive properties. PMID- 25509912 TI - [Changes in the functional state of the vascular endothelium in patients with hypertensive disease and heart valves calcification under influence of the lipid lowering therapy]. AB - In patients with essential hypertension (EH) and calcification of heart valves (HVC) were studied the dynamics of the functional state of the vasculai endothelium uinder the various options of the lipid-loweringtherapy. In patients with essential hypertension and HVC established the beneficial effect on vasoactive endothelial function in each version of lipid-lowering therapy. In larger dose of atorvastatin (40 mg/day) were observed better performance of the vasodilating endothelial function. PMID- 25509913 TI - [Condition of lipid peroxidation and antioxidant system in patients with non alcoholic fatty liver disease]. AB - The article presents research results which made it possible to reveal processes of lipoperoxidation of neutral lipids featuring oxidative stress in patients with non-alcoholic fatty liver disease and biliary tract pathology. All the patients demonstrated contra-directed changes in the antioxidant system enzymes activity requiring therapeutic correction including pathogenetic preparations with antioxidant properties. PMID- 25509914 TI - [Peculiarities of ataxic disorders in patients with acute isolated cerebellar infarction]. AB - In this article we showed clinic-neurological and neurovisualizative investigation of 20 patients with acute isolated cerebellar infarction and taking into account frequency of symptoms of the cerebellar ataxia peculiarities of ataxic disorders were determined according to involved anatomic structures and arterial territories of the cerebellum. PMID- 25509915 TI - [Dynamics of endothelial function and markers of hypoxia in children with the facial nerve palsy during treatment]. AB - We set the authentic increase of nitric oxide and the tendency to increase the content of endothelin-1 in direct correlation with the severity of the facial nerve palsy. Noted also tends to increase the content of lactate acid and significant reduction of pyruvate depending on the degree of the facial nerve palsy. On this basis proposed the optimization of treatment by including to the comprehensive therapy the drug thiotriazolin. PMID- 25509916 TI - [Aberrometry of a new artificial implanted lenses model with changeable refractive surface]. AB - There was made an aberrometry of new IOL with changeable refractive surface. Different power of silicon oil inside the lens become changes in it refractive power. So, in this way we made three types of IOL refractive power: 17,5 D; 20 D; 22 D. The quality of experimental optical system may be comparative with optical system that made by ReSTOR IOL implantation in human eye. HOA and LOA, that generated by the new IOL, had no or small influence to the quality of optical system. PMID- 25509917 TI - [Effect of pharmacotherapy of chronic heart failure (CHF) on the parameters of hemogram]. AB - Found that different versions of the combined drug therapy of chronic heart failure accompanied by an increase of erythrocytes, hemoglobin in the blood of patients, color index, tended to increase hematocrit. The most pronounced changes are marked valid in the group of patients receiving the combination of ACE inhibitors + ARB-II + beta-blockers + diuretics. Found to have a direct positive correlation between hemoglobin levels and distance 6-minute test, the back - between hemoglobin and end-diastolic volume of the left ventricle, the functional class of heart failure. The number of red blood cells inversely correlated with functional class of heart failure, a direct positive - with a distance of 6 minute test. PMID- 25509918 TI - [Particularities and risks of symptomatic epilepsy development of premature born children]. AB - Children's localy conditioned symptomatic epilepsy. That concerns children which .were prematurely borned and had perinatal hypoxic-ischemic damage of brain were researchedlat 8,2 % of patients. Epileptic paroxysms of that contingent of children'significantly impair motional, language and cognitive development. PMID- 25509920 TI - [The status of acid-base homeostasis in oral fluid during gestation]. AB - The article presents information on the nature and dynamics of metabolic changes in oral fluid in women during gestation. It is shown that dystrophic-inflammatory processes of periodontal tissues grow backed by the progression of metabolic acidosis. High content of sulfhydryl groups and disulfide ties in soluble proteins and low molecular weight compounds of oral fluid during pregnancy and activation of enzymatic antioxidant defense system periodontal tissues are found. PMID- 25509919 TI - [Features of biochemical changes in blood serum according to the form of progression of idiopathic and dysplastic coxarthrosis]. AB - Carried out biochemical studies of blood serum (collagenase activity, glycosamineglicans and hydroxyproline fractions) of 72 patients with hip idiopathic osteoarthrosis and 30 patients with dysplastic osteoarthrosis of the iv-th stage in.accordance with J. H. Kellgren and J. S. Lavrence depending on the form of pathologic process progression. It has been proved that both with idiopathic and dysplastic coxartrosis metabolism of basic protein of osteochonrous tissue was broken both in catabolic and in synthetic phase of this process. The most deep changes 1 of biochemical values (collagenase, free and proteinbinded hydroxyprolines, the content of glycosamines) have been observed with rapid form of course progression of idiopathic and dysplastic coxarthrosis. Definite appropriateness promotesin.patients better understanding of coxarthrosis pathogenese, development of diagnostic and medical measures for patients with this severe orthopedic pathology. PMID- 25509921 TI - [Use of memantine for elderly patients in the mild stage of Alzheimer's and vascular dementia]. AB - To evaluate the efficiency menantine (antagonist of NMDA-type glutamate receptor) for treatment of the mild stage of Alzheimer and vascular dementia, we conducted a comprehensive neurological, experimental psychological, neurophysiological examination of 33 patients. It was found that the treatment course with memantine, 5-10 mg daily during 3 months resulted in reducing the severity of cognitive impairment, improved bioelectric activity of the brain in patients with dementia, and also helped to improve the patients' behavior, which resulted in stress loads on the surrounding people. It is shown that the treatment was well tolerated, and memantine may be recommended as one of the drugs for treatment of cognitive impairment accompanying aging in the mild stage of dementia of different genesis. PMID- 25509922 TI - [Using hepatomaks forte in the treatment of chronic alcoholic hepatitis]. AB - Installed significantly more pronounced positive effect on clinical manifestations and laboratory indicators of liver in patients with chronic alcoholic hepatitis who received within 4 weeks of basal therapy in conjunction with Gepatomax Forte in comparison with a group of patients with chronic alcoholic hepatitis who received during the same time only basic therapy. Side adverse effects in the group of patients receiving Gepatomax Forte were not registered. PMID- 25509923 TI - [Study of specific activity of tincture "Venoton"]. AB - The specific activity of the complex was investigated by infusion. Established that the plant complex has a pronounced anti-inflammatory effect on the model of the rat formalin edema, affecting exudative phase of inflammation. It is shown that the drug has a pronounced effect on the permeability of blood vessels and for this indicator exceeds the drug comparison aescusan. "Venoton" with eskuzan has an inhibitory effect on the development of edema in rats. The obtained results allow predicting the use of integrated infusion, as an independent product, and as a constituent of medicines. PMID- 25509924 TI - [Polish health care system]. AB - The purpose of the discussion is to evaluate certain aspects of the Polish health care system - its ability to respond to contemporary dynamic social, economic and epidemiological changes (including the spread of chronic diseases, aging population or family crisis - its possibilities for providing care of the sick). The analysis of such a problem was based on a critically-oriented perspective that is developed in the field of the sociology of health and illness. The text pays particular attention to the problem of deepening social inequalities, which can be considered as one of the major factors that hinder access to health care and influence poorer health condition: In this context the mechanism of "saving health" and borrowing in order to satisfy the health needs in the face of financial difficulties was mentioned. Moreover, the text includes the attempt to evaluate the effectiveness of health promo- tion programs in our country as potentially the most effective way of raising the level of public health. There is also the issue of public confidence in health care institutions and the approval of attempts towards reforming the medical system in our country. A separate part of the discussion was devoted to criticism of the idea of reducing the role of the state in the health care sector. PMID- 25509925 TI - [Hygiene requirements for the level of intellectual intensivity loads in foreign language learning]. AB - The material of this article provides information about the basics of hygiene conditions and nature of intellectual loads of students of secondary schools in the perception of information in a foreign language. Are the most favorable conditions for the successful training of perception and assimilation of information supplied in the course of the learning process in one foreign language or some more different ones? It was found that the process of perception and assimilation of educational information in foreign languages is associated with some degree of mental and emotional stress of students. At the same time, the effectiveness of the learning process depends on the degree of stress. Certain parameters of the psychological and emotional stress students usually have a stimulating effect on their central nervous system. Another level, the psychological and emotional stress of students on the contrary, causes a braking effect of functional activity of the relevant structures of the central nervous system of students and reduces the effectiveness of training. PMID- 25509927 TI - Brain trust. PMID- 25509928 TI - Inaugural speech of the Honorable President of India Shri Pranab Mukherjee on the occasion of Platinum Jubilee celebrations of Tuberculosis Association of India, held at Rashtrapati Bhawan auditorium on 23.2.2014. PMID- 25509929 TI - Female genital tuberculosis--a diagnostic and therapeutic challenge. PMID- 25509930 TI - Adrenal insufficiency with special reference to tuberculosis. PMID- 25509931 TI - Indian Red Cross initiative for tuberculosis control. PMID- 25509932 TI - Global scale-up of the programmatic management of multidrug-resistant tuberculosis. AB - Worldwide, an estimated 8.6 million people develop tuberculosis (TB) each year resulting in 1.3 million deaths. Although rates of TB are declining in many areas of the world, the emergence of drug-resistant strains of M. tuberculosis threatens to undermine TB control programmes. Multidrug-resistant TB (MDR-TB), strains that are resistant to at least isoniazid and rifampicin, are more difficult to diagnose and treat than other forms of TB and are associated with a higher mortality rate. Unfortunately, most countries with a high burden of MDR-TB detect less than 25% of the estimated MDR-TB cases and among those detected only 82% are treated. Of the estimated 300,000 MDR-TB patients among notified TB cases, only 6% are eventually detected and treated successfully. There are many gaps in the programmatic management of drug-resistant TB (PMDT) that must be closed in order for us to successfully control TB and additional financing will be required. Through these new efforts, we hope to see more rapid scale up of PMDT activities and ultimately control and prevention of drug-resistant TB. PMID- 25509933 TI - Reaching all tuberculosis patients in India with quality care: challenges, opportunities and the way forward to address the missing millions. PMID- 25509934 TI - Reasons for interruption of anti-tubercular treatment among the retreatment patients in category II of RNTCP in Chandigarh, north India. AB - INTRODUCTION: More re-treatment TB patients are notified in India than any other country in the world, and default among this group is a serious public health problem. Adherence to the long course of TB treatment is a complex, dynamic phenomenon with a wide range of factors impacting on treatment taking behaviour. The main aim of the study was to study the basic clinical and demographic profile of the defaulters and the reasons for discontinuation of treatment among these retreatment patients in category II of RNTCP. METHODS: A longitudinal study was designed and the patients registered under RNTCP category II from June 2010 to December 2011 at various centres in Chandigarh formed the study cohort. Out of total 607 patients registered during this period under category II of RNTCP in Chandigarh, 545 consented to participate in the study. These were followed up to September 2012 till the completion of treatment. 32 patients among the registered 545 defaulted from the treatment during the period. These patients were traced in the community and information regarding reasons for interruption and barriers to treatment was obtained from them using a pre-structured pre-tested questionnaire. Data were analysed using SPSS 18 statistical software package. RESULTS: 32(5.9%) patients defaulted from the treatment under RNTCP category II. 29(90.6%) were pulmonary patients while 3(9.4%) were extra-pulmonary patients. 46.9% of the defaulters were in the age group of 20-35 years, followed by 31.3% in the age group of 36-50 years. 21.9% went to traditional healers for cure while 12.5% tried herbal medicine during the treatment. 25% (eight) patients did not have faith on the DOTS treatment. Most common side effects of treatment complained by the patients were GI upset (62.5%), fatigue (59.4%), drowsiness (34.4%) and itching (31.3%). 46.8% believed that ATT induced side-effects were the main reason for treatment interruption. Maximum treatment interruption was seen at the end of the third month (31.3%). CONCLUSIONS: Maximum interruptions were found to occur by end of third month of ATI. AT" induced side-effects were the main reason for treatment interruption. Efforts need to be made to improve the pre-treatment counselling, increase proportion of patients treated by community-based DOTS providers, repeated health education to the patients emphasizing the need to continue treatment. PMID- 25509935 TI - RNTCP in Gujarat: a comparative study between tribal and non-tribal areas. AB - BACKGROUND: Tribal population resides in difficult to reach terrain. It is vital to know, in context of "Universal care approach", whether they are equitably benefited by RNTCP. OBJECTIVE: To compare RNTCP performance in tribal areas with non-tribal areas and to detect whether the difference in performance indicators is statistically significant. METHODS: A comparative analysis of RNTCP performance indicators like total case detection rate, new smear positive case detection rate, etc., was carried out using annual data of last three years in tribal and non-tribal areas. T-test was applied to confirm statistically significant difference. RESULTS: The performance of tribal area is better in terms of suspects examined per lakh population per year, total case detection rate, NSP case detection rate and success rate. The difference was close to statistically significant difference at 95% confidence limit and the difference was significant at 90% confidence limit. The extra-pulmonary case notification rate was significantly higher in non-tribal areas with understandable reasons. CONCLUSION: Significantly high previously treated smear positive case notification rate in tribal area is a matter of concern. The incentives to tribal areas appear to reap better results and these need to be supported PMID- 25509936 TI - Use of complementaryand alternative therapies among rural TB patients in Nalgonda, Andhra Pradesh: a qualitative study. AB - BACKGROUND: A considerable number of studies have been conducted on health seeking behaviour of TB patients in different parts of the world. However, these studies largely ignored the prevalence and use of complementary and alternative medical practices (CAM) among TB patients. This present study was prompted by the recognition that, an understanding of different factors influencing CAM use in a medically pluralistic setting has important implications for providing patient centred comprehensive care, and improving the quality of life for TB patients. AIM: The objective of the study was to explore the reasons and motivations for the use of Complementary and Alternative Medicine (CAM) therapies among rural TB patients. METHODS: A sample of 110 respondents were recruited purposively from two selected rural TB units at Yadagirigutta and Chintapally in Nalgonda district in Andhra Pradesh (A.P.). Semi-structured interview schedule and case study methods were used for the collection of primary data. A qualitative content analysis method was employed to analyse and interpret the data. RESULTS: TB patients employed a variety of alternative therapies such as massage, prayer, amulets, diet, faith or spiritual healing, restriction in alcohol consumption and smoking, abstinence from sex, and herbal teas as an adjunct to biomedical TB treatment. Engaging in alternative medical practices resulted in a sense control and relief from physical and psychological suffering and trauma associated TB illness. CONCLUSION: There is a need on the part of the health care professionals and health policy managers to gain insight into the motivations and reasons for CAM use among the TB patients. Such a shift in thinking will impact on reducing non-compliance, and identifying and dealing with unmet needs of patients which are seen as major deterrents to successful TB control programmes. PMID- 25509937 TI - Interleukin-3 and interleukin-17 do not play a dynamic role in the immunopathogenesis of osteoarticular tuberculosis. AB - BACKGROUND: Osteoarticular tuberculosis accounts for one to three per cent of all cases of active TB. IL-3 stimulates the proliferation, differentiation and survival of pluripotent stem cells. IL-17 has shown to promote inflammatory cell recruitment and granuloma organization throughout infection with Mycobacterium tuberculosis. During the chronic phase of the infection, a balance between Th1 and Th17 responses needs to be achieved to limit immunopathology. AIM: To correlate the serum levels of IL-3 and IL-17 at presentation and after completion of treatment in clinicoradiologically proven cases of osteoarticular tuberculosis. METHODS: 32 clinicoradiologically confirmed cases of osteoarticular tuberculosis were included. Archived serum samples of eight patients of osteoarticular tuberculosis of an earlier study, confirmed by PCR, AFB smear or by histopathology with previously determined IL-12 and TGF-beta levels were available. A detailed history was noted and their general physical, local and relevant systemic examination was performed. Various laboratory parameters including TL-3 and IL-17 levels in serum were estimated at presentation and at six months of DOTS CAT-1 treatment. RESULTS: There was a significant improvement in the clinical and radiological parameters after treatment. No correlation was found between IL-3 and IL-17 levels before and after treatment. A significant correlation (p value= 0.022) was shown between levels of IL-3 and IL-12 after six months of treatment. CONCLUSIONS: Qualitative and quantitative fluctuations in IL 3 and IL-17 levels were not able to serve as useful indices of disease activity. PMID- 25509938 TI - Multi-drug resistant tuberculosis among category I treatment failures--a retrospective study. AB - BACKGROUND: Tuberculosis (TB) remains a major global health problem and ranks as the second leading cause of death worldwide. An important cause of TB epidemic is the emergence of multi drug resistant (MDR) strains of Mycobacterium tuberculosis. Despite the availability of treatment that is expected to cure most cases of TB, levels of MDR-TB remain worryingly high in India. OBJECTIVE: This study was carried out to ascertain the prevalence of MDR-TB among category I pulmonary TB treatment failure patients. METHODS: This was a retrospective study involving 750 pulmonary tuberculosis patients enrolled at six district centres of Delhi State under RNTCP who failed to respond to CAT I treatment and whose sputum samples were submitted for culture and drug sensitivity testing (DST) over a period of three years (2009-2012). MDR-TB was defined as TB caused by bacilli showing resistance to at least isoniazid and rifampicin. RESULTS: Out of the total 750 patients included in the study, 470 (62.6 %) were culture positive. Of these, 377 (80.2%) were subjected to DST and rest 93 (19.7%) were excluded. Ultimately, DST result was available for 353 (93.6 %) cases. 239 (68%) cases were detected as multi drug resistant TB. CONCLUSION: High proportion of MDR-TB (68%) among culture positive CAT I treatment failure cases highlights the need for rapid diagnostic tests which will enable the detection of MDR-TB at an early stage and will thus minimize the risk of transmission as well as the possible errors associated with the treatment. PMID- 25509939 TI - Evaluation of hormonal changes in menstrual cycle of women infected with pulmonary tuberculosis in Nnewi, south eastern Nigeria. AB - BACKGROUND & OBJECTIVE: The present study was designed to evaluate the hormonal changes in menstrual cycle of premenopausal women infected with pulmonary tuberculosis in Nnamdi Azikiwe University Teaching Hospital Nnewi. MATERIAL AND METHODS: A prospective study involving sixty-seven (67) female participants within the child-bearing age were randomly recruited and grouped based on their tuberculosis status as: Symptomatic TB infected females (n=20), Symptomatic TB infected females on ATT (n=20) and Control females (n=27). After due consent, a detailed medical history was obtained and routine investigations of pulmonary tuberculosis and confirmation using Ziehl Neelsen and sputum culture techniques for AFB and chest x-ray were done. Blood samples collected from the participants were used for hormonal assay using immunoenzymometric method. RESULTS: The results showed that the serum levels of FSH and LH (IU/ml) were significantly higher while progesterone and estradiol were significantly lower in Symptomatic TB females compared to Symptomatic TB females on ATT at follicular and luteal phases of menstrual cycle (P<0.05). The serum levels of FSH and LH were significantly reduced in Symptomatic TB females on ATT while progesterone and estradiol were significantly increased at follicular and luteal phases of menstrual cycle (P<0.05). FSH was significantly higher at follicular phase while estradiol was significantly higher at luteal phase of menstrual cycle in Symptomatic TB females on ATT. CONCLUSION: Tuberculosis induced hypogonadism in affected women which seemed to be reversed on treatment. Routine investigation for Tuberculosis should be done for women presenting with infertility, since early treatment can reverse the abnormality. PMID- 25509940 TI - Primary cutaneous tuberculosis of the pinna: an unusual presentation. AB - Cutaneous tuberculosis is an uncommon form of extra-pulmonary tuberculosis. A young female presented with chronic, non-healing ulceration involving the left pinna. Serology and skin biopsy suggested tuberculosis. Anti-tubercular therapy resulted in complete resolution of lesions. The recent increase in tuberculosis has led to myriad forms of the disease which often mimic non-specific dermatitis in morphology. The diagnostic dilemma encountered in such clinical settings has prompted us to present this unusual case. On review of literature, we could find only three case reports of ulcerative form of primary tuberculosis of pinna. PMID- 25509941 TI - Total replacement of a lung by tuberculosis pneumatocele--an unusual post tuberculosis sequel. AB - Total replacement of a lung by pneumatocele in pulmonary tuberculosis is rare. The formation of pneumatoceles in adult pulmonary tuberculosis can occur before, during or after anti-tuberculosis treatment. A case of pneumatocele formation in a 19-year young female following pulmonary tuberculosis is reported. The left lung was completely replaced by pneumatocele. Total replacement of a lung by pneumatocele inspite of successful chemotherapy of tuberculosis is rare and should be considered as one of the differential diagnosis for acquired cysts of the lung. PMID- 25509942 TI - A rare case of an isolated intraventricular tuberculoma with a dismal outcome: an unusual location of a common pathology and lessons learnt. AB - Isolated involvement of the ventricle by tuberculosis is extremely rare and only nine cases have been reported till now. We report a 13-year-old immuno-competent boy who presented with features of raised intracranial pressure with altered sensorium. Computed Tomography showed a ring enhancing intraventricular lesion with obstructive hydrocephalus. Gross total resection of the lesion was achieved and diagnosis was confirmed histologically. The patient had medical complications in the postoperative period and succumbs five days after the surgery. This report presents the unusual location of a common disease with a review of its clinical, radiological and histopathological features as well as the treatment modalities available. PMID- 25509943 TI - GeneXpert brings new hope for challenges to tuberculosis 2050. PMID- 25509944 TI - Removal of chlorophenols from wastewater using commercial acid washed activated carbon. AB - The presence of chlorophenols in wastewater represents a serious challenge for its treatment and its further reuse. In this study, the use of commercial acid washed activated carbon as sorbent material for the removal of 2 chlorophenol, 2,4 dichlorophenol and 2,4,6 trichlorophenol from synthetic. aqueous solutions is evaluated. Variables affecting the uptake of these compounds (weight of sorbent material, pH, temperature and shaking time) are investigated to achieve the optimum conditions of removal process. The kinetics of the uptake process indicated that the process was best explained using a pseudo-second order model. As well, the adsorption of the studied chlorophenols on commercially available AC followed the Freundlich isotherm. The thermodynamic parameters further indicated the favorability of the process and that the adsorption was primarily physical in nature enhanced by chemisorptions. PMID- 25509945 TI - Studies on adsorption of phenol from wastewater by agricultural waste. AB - In this paper, preliminary investigation of various agricultural wastes-Rice mill residue (RM), Wheat mill reside (WM), Dall mill residue (DM) and the Banana peels (BM) was carried out to study their ability to be used as adsorbents for phenol removal from wastewater. This study reports the feasibility of employing dal mill residue waste (DM) as an adsorbent for removing phenol from wastewater. The performance of DM was compared with the commercially available activated carbon (CAC). Batch mode experiments were conducted with activated DM to study the effects of initial concentration of phenol, pH and the temperature of aqueous solution on adsorption. Equilibrium adsorption isotherms and kinetics were investigated. The experimental data were analyzed by the Langmuir, Freundlich and Temkin models and the isotherm data fitted well to the Freundlich isotherm with monolayer adsorption capacity of 6.189 mg/g. The kinetic data obtained at different concentrations were analyzed using a pseudo-first order and pseudo second- order equation. The experimental data fitted very well with the pseudo first-order kinetic model. The FTIR analysis revealed that carboxyl and hydroxyl functional groups were mainly responsible for the sorption of phenol. Finally, the DM was found to be a promising adsorbent for phenol adsorption as compared to activated carbon. PMID- 25509946 TI - Fixed bed column study for Cu (II) removal from aqueous solution using water hyacinth (Eichornia crassipes) biomass. AB - This paper reports the results of the study on the performance of low-cost biosorbent water hyacinth (WH) in removing Cu (II) from aqueous solution. The adsorbent material adopted was found to be an efficient media for the removal of Cu (II) in continuous mode using fixed bed column. The column studies were conducted with 10 mg/L metal solution with a flow rate of 10 mL/min with different bed depths such as 10, 20 and 30 cm. The column design parameters like adsorption rate constant, adsorption capacity and minimum bed depth were calculated. It was found that, the adsorption capacity of copper ions by water hyacinth increased by increasing the bed depth and the contact time. PMID- 25509947 TI - Assessment of heavy metals in the industrial effluents, tube-wells and municipal supplied water of Dehradun, India. AB - The bio-geochemical cycles of metals involve the lands, rivers, oceans and the atmosphere. Although a large number of metals are introduced to the water bodies during their mining and extraction processes and geochemical weathering of rocks, but the role of domestic and industrial wastes is predominant and of much concern. Increased industrial activities has increased the incidence of percolation of toxic metal ions to the soil and water bodies and presently their presence in ecosystem, have reached to an alarming level that environmentalists are finding it difficult to enforce control measures. Human activities and large number of small and big industrial units are increasingly discharging deleterious metals present in the effluents and wastes, to the environment and aquatic systems and have contaminated heavily even the ground water. The toxic metals have a great tendency of bioaccumulation through which they enter the food chain system and ultimately affect adversely the life on this planet Earth in various ways. Further, due to contamination of irrigation system by the harmful Chemicals and toxic metals, the farm products, vegetables, fruits, potable water and even milk is not spared. This paper describes the assessment of the heavy metal concentration in various industrial effluents of the surrounding area. Various physico-chemical characteristics of the effluents collected from various sites are also reported. To assess the status of ground water quality, water samples from four tube wells of different localities of the area and four drinking water samples supplied by Municipal Distribution System were also analyzed. PMID- 25509948 TI - Assessment of alpha radioactivity and dose estimation in widely used medicinal plants environmental monitoring of afforestation. AB - This paper reports the presence of alpha radioactivity in a few medicinal plants, which form the main components of some hebal drugs. Assessment of effective dose has also. been done. The total alpha radio activity in medicinal plants has been found within 47 - 245 Bq/Kg and the effective dose found in the range 2.8 - 4.7 MUSv. This data is required for environmental monitoring. PMID- 25509949 TI - Hydrogeochemistry of boron in borewell water of Durgapur coal mine area, District Chandrapur, Maharashtra, India. AB - Two formations, Barakar and Talchir belonging to Lower Gondwana sequence form aquifer in Durgapur area. Groundwater of these formations sampled for boron investigation in two seasons, Post-monsoon and Pre-monsoon. The water quality differed from aquifer to aquifer, mainly with respect to conductivity and B contents. Talchir groundwater shows greater conductivity and greater B content than Barakar groundwater. The maximum concentration of B was found in Talchir pre monsoon groundwater. Greater B in Talchir groundwater is attributed to glacio marine environment of sediment deposition. The correlation of B with major ions also varies. It shows positive correlation with conductivity, Na, HCO3 and SO4 in Barakar groundwater and with SO4 in Talchir groundwater. Seasonal variation in concentration of B exists but not appreciable. PMID- 25509950 TI - Microbial quality of lakes around Dharwad City, Karnataka, India. AB - Water being an essential component of food chain of living beings is contaminated day-by-day in the increasing order due to public apathy and improper management of water sources like lakes, reservoirs and ponds. The microbiological studies of Kelageri, Nuggikeri, Navalur, Neerasagar and Salakinakoppa lakes located around Dharwad were carried out with respect to total plate count (TPC),Total Fungal count (TFC) and total Coliform. They are highly contaminated with bacterial species like fecal Coliforms, E. coli, Bacillus species, Actinomycetes, Monococcus sps, Streptococcus sps. and Fungal sps like Pencilium, Fusarium, Mucor , Rhizopus, Yeast cells. The results indicate that the lakes except Neerasagar lake were considered to be unfit for drinking purpose due to the excess of anthropogenic activities, inflow of water through widespread agricultural land and stream, where the dairy industry, poultry, brick manufacturing unit, animal husbandry are maintained. The extent of pollution of water depends upon the dense population of these microorganisms which vary in rainy, winter and summer seasons. The presence of Fecal Streptococcal species viz., S. fecalis, S. equinus, S. faecium, S. bovis, S. avium, indicate the fecal pollution with seasonal variations throughout the year. PMID- 25509951 TI - Comparative evaluation of leachate pollution index of MSW landfill site of Kolkata with other metropolitan cities of India. AB - The uncontrolled tipping of mixed urban solid waste in landfill site causes serious negative impacts on the environment. The major issue in this context is the generation of leachate which possesses potential of polluting freshwater ecosystem including groundwater besides associated health hazards and depletion of soil fertility. In this context, a pseudo computation quantitative tool, known as leachate pollution index (LPI), has been developed by some researchers for scaling pollution potential of landfill site owing to emergence of leachate. This paper. deals with the assessment of leachate quality of existing landfill site of Kolkata situated at Dhapa waste dumping ground through evaluation of the LPI from experimental analysis of leachate. The leachate was collected from this site in different seasons. 18 parameters were tested with real leachate samples in the Environmental Engineering Laboratory of Civil Engineering Department of Jadavpur University Kolkata. The results exhibited a very high value of organic pollutants in the leachate with COD as 21,129 mg/L and also values of TDS, Fe2+, Cr, Zn, chloride and ammonical nitrogen. The LPI value of Kolkata landfill site at Dhapa was estimated and also compared with leachate quality data of other metropolitan cities viz. Mumbai, Delhi, Chennai as available in literatures. It is found that LPI of the Kolkata landfill site is highest compared to all other landfill sites of other metropolitan cities in India. PMID- 25509952 TI - Experimental analysis to utilize the solid wastes in brick production. AB - Utilization of industrial, municipal, agricultural and other waste products in the industry has been the focus of research for economical, environmental, and technical reasons. Two solid wastes, i.e. Sugar-cane bagasse--is a fibrous waste product of the sugar refining industry and granite processing industry generates a large amount of wastes mainly in the form of powder during sawing and polishing processes, which pollute and damage the environment, have been taken to experimental study. The objective of this study is to utilize the bagasse ash and granite waste for the manufacturing of bricks. Mixtures were prepared with 0, 10, 20, 30, 40 and 50% wastes of total weight of clay. The produced bricks are tested for mechanical properties, such as water absorption and compressive strength, according to Indian Standard Code. The result showed that 20% of bagasse ash and granite waste is optimum percentage to be used in the manufacturing of conventional bricks. PMID- 25509953 TI - Characterization and open windrow composting of MSW in Jodhpur City, Rajasthan, India. AB - Solid waste is sometimes not suitable for direct land application. Processing solid waste through composting converts it to a humus-containing organic material advantageous for agriculture/horticulture use. Major advantages of composting are stabilization of the wastes; substantially reduced C/N ratio and gas formation, and virtually elimination of odors and pathogens. Composting is accomplished under aerobic conditions developing temperatures of 55 degrees C or above. The windrow technique is simple and accomplished easily with standard equipments. The open windrow composting of municipal solid waste (MSW) in windrows was analyzed in this study for six weeks. The raw MSW was introduced to active composting without any source segregations. The moisture content of the MSW dropped from 58.88% to 48.06% and windrow attained a thermophillic temperature for about two weeks. It was observed that the pH, C/N ratio and temperature variations were comparable to that of traditional windrow composting. The peak temperature recorded was 68 degrees C and temperature remained above 60 degrees C for more than three weeks. The volume reduction was obtained by using one-cu.m. cage. The results indicate that the bulk composting could reduce by about 29% the total mass of the waste. PMID- 25509954 TI - Submerged aerated bio-filter (SAB)--a post treatment option for UASB effluent treating sewage. AB - This paper presents exploratory results of the performance of submerged aerated bio-filter (SAB-1.5 L) for the post treatment of UASB effluent treating sewage in order to bring the effluent quality in compliance with discharge standards. The study was carried out in three stages with varied dissolved oxygen (DO) levels of 0 to 2.0, 2.0 to 4.0, 4.0 to 6.0 and > 6.0 mg/L. The hydraulic retention time (HRT) and hydraulic loading rate (HLR) were maintained 0.67 h & 0.1 m3/ m2 x h respectively in all stage of study. The performance in terms of BOD removal efficiency was increased with increase in DO levels. Results revealed that the average BOD and SS removal efficiencies in phases 3 and 4 were 51.3 and 59.5% and 58.8 and 67.5% respectively. Significant ammonical nitrogen (NH4-N) removal of 60% was observed in phase 4. The BOD and SS in phases 3 and 4 were reduced to well below the effluent disposal standards. The SAB at DO >= 4 mg/L can be considered a viable alternative for the post treatment of effluent from UASB treating domestic wastewater. PMID- 25509955 TI - Accumulation of heavy metals (Cu, Cr, Pb and Cd) in freshwater micro algae (Chlorella sp.). AB - Some selected micro algae were used for the removal of heavy metals from wastewater. In this present investigation, Chlorella sp was studied for accumulation of heavy metals, namely copper, chromium, lead and cadmium. The salts containing heavy metals were dissolved in Blue Green 11 medium at different concentrations in a glass jar of 10 litre capacity each and subsequently they were bubbled with air for 12 days at a temperature of 33 degrees C and light intensity of 2200 lux. The removal rates of heavy metals were recorded for every 4 days during the experimental period. Chlorella sp. removed 37%, 43% and 67% of copper after 4, 8, 12 days respectively. The percentage removal of chromium was 34%, 43% and 50% respectively at 4, 8, and 12 days. Lead removal rates of Chlorella sp were 56% after 4 days, 69% after 8 days and 77% after 12 days. The reduction of cadmium in the culture medium after 12 days was 93%. From the present investigation, it is concluded that heavy metal removal ability of Chlorella sp. can be exploited for metal detoxification and environmental clean up. PMID- 25509956 TI - Evaluation and modification of existing CETP. AB - For the development of small and medium scale industries in various Gujarat industrial development corporation (GIDC) areas and in clusters of industrial areas, the common effluent treatment plant (CETP) has always been found advantageous in view of cost of treatment, operation and maintenance and disposal of residues being produced. In small scale industrial units due to market requirement, product changes and quantity enhancement are taking place. Due to such changes, the effluent characteristics are continuously changing which affects performance of CETP. Hence it has been found necessary to study continuously the performance, evaluation and modification in the working of the CETP. This paper contains a case study of one of the existing CETP near Baroda which is facing the problem of disposal of treated effluent in which the important parameters like COD, BOD, Suspended Solid, NH3-N and oil and grease were analyzed. Based on the characterization of wastewater, the various treatability studies were carried out on CETP wastewater. To comply with disposal standard prescribed by Effluent Channel Project Ltd.(ECPL)* and Gujarat Pollution Control Board (GPCB) for discharge of industrial effluent into channel, various treatments in form of ammonia stripping, coagulation and flocculation, biological treatment, filtration and chlorination are suggested. PMID- 25509957 TI - Strain improvement of Trametes hirsuta by physical and chemical mutagenesis for better laccases production. AB - The Laccases production efficiency was investigated by the wild fungal strains Trametes hirsuta by treating it with physical mutagen [ultraviolet radiation (UV) and X-rays] and chemical mutagens [Ethidium bromide, Colchicine and Hydrogen peroxide]. The present work aimed to apply mutagenesis for enhancement of the enzyme production. Effective changes were observed in the efficiency of enzyme production when treated with physical and chemical mutagens. The effect of X-rays showed a decrease in production with increasing exposure in T. hirsuta (Max. at 2 sec.). UV irradiation influenced the enzyme production with higher exposure time (8 minutes) but the maximum dosage led to inhibition in fungal growth and low enzyme production. Among the three chemical mutagens used, hydrogen peroxide was found to be having lethal effects to the fungi but a minimum concentration (2 MUg/mL) was positively effecting enzyme production. Colchicine showed increase in enzyme production with increasing concentrations (Max. at 9 MUg) and with Ethidium bromide, maximum enzyme production was observed at concentration of 7 MUg/ mL. The study on morphological differences in wild and mutant shows that there was an improvement in strains of the white rot fungi. PMID- 25509958 TI - Energy drinks: physiologists' social concern. PMID- 25509959 TI - Mid-latency auditory evoked potential response revealed as an evidence of neural plasticity in blinnd individuals. AB - There is a general impression that visually blind individuals show an exceptionally better perception of other sensory modalities such as hearing, touch and smell sensations. In this study, we intended to compare the mid-latency auditory evoked potential response (MLAEP) or Middle latency Response (MLR) to get an idea of the activity pattern of auditory thalamus and cortex between 30 visually handicapped subjects and 30 normal sighted subjects. The results showed a decrease in many of the MLR wave latencies, but highly significant for the wave Pa (P value <0.002). This fact can be reflected as an evidence of existence of cross-modal neuroplasticity. We also inferred that there are significant gender differences with latencies shorter in males than females (P value <0.02) in the blind subjects group which could be attributed to their rehabilitation training. PMID- 25509960 TI - Pulmonary function parameters in workers of woolen industry. AB - There is an increase in proportion of workers suffering from occupational diseases. In occupational respiratory diseases, pulmonary function tests are the most important and widely used diagnostic tool. Limited studies have been conducted to evaluate the effect of wool dust on pulmonary function parameters. Hence, the present study was undertaken to evaluate the pulmonary function parameters in workers of woolen industry. This study was done on 150 subjects of either gender who were divided into two groups of 75 each. Group I comprised of healthy subjects who served as controls and group II included workers of woolen industry. The values of lung function parameters i.e. volumes and flow rates in these workers were found to be lower than the healthy controls. The significant reduction in percentage predicted values of FEV1 (82 vs 59), FVC (79 vs 63) and MVV (77 vs 64) in workers as compared to healthy controls indicates obstructive pattern of respiratory abnormality. In male workers, percentage predicted FEV1% was significantly lower. The values of all other parameters were lower in female workers. There was a significant decrease in FEV and FVC with increase in age in group I and this negative correlation was statistically significant. The decrease in respiratory volumes and flow rates was more with increase in duration of exposure to wool dust. It can be concluded that wool dust present in environment of woolen industry affected the pulmonary function parameters of the workers leading to obstructive pattern of respiratory changes. PMID- 25509962 TI - Effects of short-term two weeks low intensity plyometrics combined with dynamic stretching training in improving vertical jump height and agility on trained basketball players. AB - Sport specific training in basketball players should focus on vertical jump height and agility in consistent with demands of the sport. Since plyometrics training improves vertical jump height and agility, it can be useful training strategy to improve the performance of basketball players. A convenience sample of thirty professional basketball players were recruited. Following pre intervention assessment, interventions using plyometrics training and dynamic stretching protocol was administered on the basketball players. The outcome measures were assessed before the intervention and at the end of first and second week. Statistically significant improvements in vertical jump height (31.68 +/- 11.64 to 37.57 +/- 16.74; P < 0.012) and agility (16.75 +/- 2.49 to 16.51 +/- 2.80; P <0.00) were observed between pretest--posttest measures and no changes in muscle girth and isometric muscle strength. The study concludes that short term two weeks plyometrics training combined with dynamic stretching as a useful sport specific training strategy to improve vertical jump height and agility on trained basketball players. PMID- 25509961 TI - Ameliorating effect of black tea extract on cadmium chloride-induced alteration of serum lipid profile and liver histopathology in rats. AB - Cadmium is one among the most environmental pollutants that affects many organs like kidney, liver and testis. The present study was aimed to assess the simultaneous effects of black tea extracts (BTE) on cadmium chloride induced alterations in lipid profile and liver histology. Adult rats were divided into four groups (n=6/group), group I (normal saline), group II (CdCl2, 1.0 mg/kg, b.wt; i.p), group III (black tea extract, 2.5 gm tea leaf/dl of water that is 2.5% of aqueous BTE) and group IV (cadmium chloride + BTE). Cadmium chloride intoxicated rats showed significant increase in serum total cholesterol, triglycerides, and low density lipoprotein-cholesterol and there is a significant decrease in the serum high density lipoprotein-cholesterol. In the liver, cadmium chloride showed changes in normal architecture, swollen hepatocytes, kupffer cells hyperplasia, dilation and congestion of central vein. Oral administration of black tea extracts with cadmium chloride significantly improves lipid profile and liver architecture as compared to the cadmium chloride group. The results indicate that BTE is beneficial in preventing cadmium-induced lipid alterations and hepatocellular damage. PMID- 25509963 TI - Assessment of tear secretions in healthy Indian volunteers. AB - Dry eye syndrome is currently seen with increasing frequency throughout the world including India. An evaluation of tear physiology in the form of tear secretion and tear film stability is the most important aspect of dry eye diagnosis. The aim of this study is to investigate the age and gender related changes in the result of these tear function tests (Schirmers Test and Tear Break up time) in normal Indian population. This cross- sectional observational study included 120 normal subjects (60 Male and 60 females) with no ocular symptoms or ocular surface disorders. Schirmer and tear film break-up time tests were assessed in both eyes of each subject. The study subjects were divided into 4 groups according to their ages (<20 y, 20-40 y, 41-60 y and >60 y) each group was composed of 60 eyes of 30 subjects (15 male and 15 female subjects). The One way ANOVA test and the Statagraphic software was used for statistical analysis. We detected a statistically significant decline in both the tear function tests with increasing age. Tear function tests did not show statistically significant difference according to sex. This study suggests that the age of subjects should be taken into consideration in the evaluation of tear function test results. It is also revealed that Indian population values are different from Caucasian and Chinese values. We propose age specific cut off values of tear function tests in Indian population to aid in the diagnosis of dry eye in Indian conditions. PMID- 25509964 TI - Physiological variables, psychosocial factors and age at menarche among Punjabi girls. AB - The term menarche signifying the onset of menstruation is merely one manifestation of puberty. The age at menarche has been getting earlier all over the world with varying rates. An average decline of about 4 months per decade has been reported from the United States and in Western Europe over the period 1830 1960, while that in Eastern Europe since the late nineteenth century. There have been reports that there is a fairly good correlation between the age of menarche of mothers' and their daughters'. The objective of this study was to find out the present age at menarche among Punjabi girls and correlate it with relevant variables. The age at menarche in the present study has been found to be significantly less as compared to data from the same region (Punjab, India). The decline in the mean age at menarche between the mothers and the daughters was statistically highly significant. There was a positive correlation between menarche and weight, height, triceps skinfold thickness, body mass index and maternal age at menarche. No significant correlation was obtained between menarche and income class and a negative correlation was obtained between menarche and birth order. PMID- 25509965 TI - Gender correlation of stress levels and sources of stress among first year students in a medical college. AB - Medical courses in India are very demanding for the students thus making career in medical education very stressful. The study was designed to determine the prevalence of stress levels in 100 first year medical students and to explore the sources of stress & it's relationship across the male and female students. Demographic information and Qualitative data from investigator tailored Medical Student Stress Questionnaire (MSSQ) by self rating under supervision of investigators were subjected to a thematic analysis. Stress perceived was more in males students (82.2%) as compared to females (61.8%) and their MSSQ index score was significantly different (U=985; P=0.02). Moderate to high academic stress was present among 79% of students more so in males with the academic domain score significantly different from that of females (U=883; P=0.007). Females perceived more stress in inter personal domain (12.7%) with the score significantly different from males (U=953.5; P=0.02). Group and Teaching stress was equally present in males and females. PMID- 25509966 TI - A study of serum cholesterol level in young adults and its relation to body mass index and waist-circumference. AB - The present study was carried out to determine the serum total cholesterol (TC) level in young adults of Dibrugarh town of Assam and to find the association of serum cholesterol level with body mass index (BMI) and waist-circumference (WC). A cross-sectional study was done among 150 healthy young adults aged 20-30 years. TC was estimated by the enzymatic method. Hypercholesterolemia was defined as TC > 200 mg/dl. Cases were classified into different categories of BMI and WC according to the recommendations of WHO/IASO/IOTF (2000). The range of TC level in the study group was found to be (146-212) mg/dl. Mean cholesterol level in males and females were 169.5+/-3.6 and 172.3+/-15.09 mg/dl respectively. 7% of the cases had hypercholesterolemia. TC was significantly correlated with BMI (r=0.90, p<0.001) and WC (r=0.73, p<0.001 in males and r=0.86, p<0.001 in females). We conclude that young adults >=20 years of age and especially who are overweight should be advised routine cholesterol testing so that preventive measures can be adopted to avoid hypercholesterolemia and it's complications in future life. PMID- 25509967 TI - Effect of rajyoga meditation on chronic tension headache. AB - Chronic tension-type headache (CTTH) is the most common type of headache with no truly effective treatment. This study was designed to correlate the additive effect of meditation on CTTH patients receiving medical treatment. 50 patients (aged 18-58 years) presenting with a clinical diagnosis of CCTH, were divided in 2 groups. Group 1 (n=30) received 8 lessons and practical demonstration of Brahmakumaris spiritual based meditation known as Rajyoga meditation for relaxation therapy, in addition to routine medical treatment (analgesics and muscle relaxants). Group 2 (n=20) patients received analgesics and muscle relaxants twice a day but no relaxation therapy in the form of meditation. Both groups were followed up for 8 weeks period. The parameters studied were severity, frequency and duration of CCTH, and their headache index calculated. Patients in both groups showed a highly significant reduction in headache variables (P<0.001) after 8 weeks. But the percentage of patients showing highly significant relief in severity of headache, duration & frequency in Group 1 was 94%, 91% and 97% respectively whereas in Group 2 it was 36%, 36% and 49% respectively. Headache relief as calculated by headache index was 99% in Group 1 as compared to 51% in Group 2. Even Short term spiritual based relaxation therapy (Rajyoga meditation) was highly effective in causing earlier relief in chronic tension headache as measured by headache parameter. PMID- 25509968 TI - Impact of physical activity on ovarian reserve markers in normal, overweight and obese reproductive age women. AB - Physical inactivity is a leading risk factor for overweight and obesity in the society. Prevalence of overweight and obesity in the reproductive age group women not only affects maternal health but also the health of the off spring. Infertility is a common problem in India affecting 13-19 million people at any given time. Even though it is not life threatening, infertility causes intense mental agony and trauma that can only be best described by infertile couples themselves. Infertility is more common in overweight and obese individuals compared to normal weight individuals. Decreasing ovarian reserve is an important factor for infertility in women. This study examined the impact of physical activity on ovarian reserve markers in normal, overweight and obese reproductive age women. The observations made in this study reveal that physical activity improves ovarian reserve markers in all reproductive age women but this improvement is more distinct and statistically significant in overweight and obese women compared to normal weight women. PMID- 25509969 TI - Effects of age and body mass index on peak-expiratory flow rate in Indian population. AB - Peak expiratory flow rate (PEFR) is a measure of ventilatory capacity measured by peak flow meter. It is regarded as a basic physiological parameter for the diagnosis, follow up and treatment of patients with respiratory illnesses such as asthma, chronic bronchitis, and emphysema. This study establishes the relationship of PEFR with age and BMI in healthy adult males (N=300) of Kumaon region of Uttarakhand. Overall, the mean PEFR is 478.37+/-68.14. The age is significantly affecting the PEFR unlike BMI. Age as an independent predictor predicts the 72.3% variability (R2 is 72.3%) in PEFR while BMI > 23 as an independent predictor predicts only 1.4% variability (R2 is 0.014). PEFR declines with advancing age due to degenerative changes in musculoskeletal system leading to decrease in respiratory muscle strength. PEFR shows some decline with high BMI in elderly age group. PMID- 25509970 TI - Effect of gender and body mass index on pulmonary function tests in adolescents of tribal population of a north eastern state of India. AB - The present study was planned to assess the pulmonary function in tribal adolescents (age 12-16 yrs) of Tripura, a north eastern state of India, and to evaluate the effect of body mass index (BMI) on pulmonary functions of male and female subjects from tribal population. One hundred and seventeen male and seventy female subjects were selected for the study through a randomized method of sampling. Pulmonary function parameter recorded were forced vital capacity (FVC), forced expired volume in 1 second (FEV1), peak expiratory flow rate (PEFR) and maximal expiratory pressure (MEP). Values of all the pulmonary function parameters recorded in female subjects were found to be lower than the male subjects. FVC, FEV1, PEFR, MEP recorded in subjects from both the sexes correlated significantly with BMI. The results of the study provide basic data on pulmonary function parameters of tribal adolescents from Tripura. PMID- 25509971 TI - Effect of skin to skin care to neonates on pulse rate, respiratory rate SPO2 and blood pressure in mothers. AB - Physiological benefits of skin to skin care (STS) to newborns are known but there is scarcity of data on changes in physiological parameters like pulse rate, respiratory rate, SPO2 and blood pressure in mothers during STS. We hypothesize that STS is beneficial to mothers with respect to these parameters. Objective of this study was to assess the changes of these parameters in mothers while providing STS for one hour. STS was provided by 52 mothers for a total of 127 times and parameters were recorded at starting of STS, at 15 min, at 30 min, at 60 min of STS and at 5 min rest after stopping STS. There were no significant changes in pulse rate and SPO2 but blood pressure and respiratory rate reduced significantly during STS as compared to rest after stopping STS. Thus STS is physiologically beneficial to mothers. PMID- 25509972 TI - Effect of short-term physical exercise on serum total testosterone levels in young adults. AB - The effect of short term (12 weeks) physical exercise on serum total testosterone level was evaluated in 30 young male adults, aged 18-27 years (mean age 21.67+/ 2.26 years). These medical students, having sedentary life style underwent heavy exercise by attaining heart rate 125-150 beats/min on bicycle ergometer for 15 min on alternate day basis amounted to 670 kilopond metre per minute work done and percentage of VO2max was 71+/-3. Pre-exercise serum total testosterone levels (5.49+/-1.31) of students were compared with those obtained after 1 week and 12 weeks of initiation of exercise. The serum total testosterone was measured by DRG Testosterone ELISA kit. After 1 week of exercise, a statistically insignificant decrease (5.488+/-1.32; P>0.05) was found while after 12 weeks of exercise, a statistically significant increase (6.41+/-2.28 P<0.05) was noticed between the pre-and post-exercise serum total testosterone levels. We conclude that short term exercise produces an elevation in serum testosterone levels in young adults. PMID- 25509973 TI - A study of reticulocyte count in the cord blood of pre-eclamptics and healthy pregnant women. PMID- 25509974 TI - Validity of Cooper's 12-min run test for estimation of maximum oxygen uptake in female university students. PMID- 25509975 TI - Natural rubber latex allergy: occupational exposure to latex glove among clinical laboratory workers. PMID- 25509976 TI - Pain experienced during and after office hysteroscopy with and without intracervical anesthesia. AB - We designed this study to evaluate if intracervical anesthesia reduces pain experienced during and after office hysteroscopy (OH). Two hundred women undergoing OH were randomized into two groups. Group I received intracervical anesthesia (10 ml %2 prilocaine), group II did not receive any anesthesia before procedure. The intensity of pain during procedure, 30 and 60 minutes later on visual analog scale (VAS) was assessed. Groups were similar in age, parity, previous number of vaginal delivery, or presence of menopausal status. The mean of pain scores during OH was less in group I (0.82 +/- 0.11) than in group II (0.86 +/- 0.09) and the difference was statistically significant (p = 0.04). But, the difference of mean pain scores 30 and 60 minutes after procedure between the groups were not statistially significant. In conclusion, intracervical anesthesia reduces pain experienced during OH, but this effect does not last longer. PMID- 25509977 TI - Human papillomavirus (HPV) is not the main cause of preinvasive and invasive cervical cancer among patients in Delta Region, Egypt. AB - BACKGROUND: Cervical cancer remains a significant problem worldwide particularly in underdeveloped countries. It is necessary to have a persistent infection of the cervix with a high-risk or oncogenic human Papillomavirus (HPV) virus to develop cervical cancer. OBJECTIVES: To study the association between HPV and pre invasive and invasive cancer cervix among patients referred to Early Cancer Detection Clinic of Obstetrics and Gynecology Department, Mansoura University Hospital, Delta region, Egypt. METHODS: Cervical specimens of 100 histologically confirmed premalignant and malignant cervical lesions were subjected to HPV detection and genotyping by extraction of DNA from cervical biopsy using a commercial PCR kit. RESULTS: HPV DNA testing was done, 36 cases were positive (36%). Correlations of age, duration of marriage, and parity were non significant (P = 0.56, 0.72, and 0.35 respectively) while correlations of residence, oral contraceptive use, smoking, and immunosuppresion were sig- nificant (P = 0.006, 0.001, 0.001, and 0.01 respectively). The prevalence of HPV in premalignant and malignant cervical lesions in our study was 39.5% & 33.3% respec tively. The commonest HPV genotypes associated with premalignant cervical lesions were HPV16; 11/17(64.7%) and HPV18; 11/17 (64.7%) mostly in the form of mul- tiple infections with HPV16+18; 7/17 (41.17%). The commonest HPV genotypes associated with malignant cervical lesions in our cases were HPV16; 15/19 (78.9%) and HPV18; 13/19 (68.42%) also in the form of multiple infections with HPV16+18; 10/19 (52.63%). CONCLUSION: The prevalence of HPV in premalignant and malignant cervical lesions was 39.5% & 33.3% respectively, this means that HPV is not the main cause of premalignant and malignant cervical lesions in Delta region in Egypt. HPV infection mostly in the form of multiple infections with HPV16+18 genotypes. Further studies are needed to clarify actual association of HPV and premalignant and malignant cervical lesions to determine the usefulness of HPV vaccination in our locality. PMID- 25509978 TI - A rare case of acute abdomen: torsionated ovarian myoma. AB - Ovarian leiomyoma is a rare ovarian tumor and also rare cause of acute abdomen. A 64 year old, postmenopausal woman applied to our clinic with severe acute abdominal pain. On abdominal examination, there were abdominal tenderness, defense and rebound. On ultrasonographic examination, we detected a 6 cm of pelvic mass. Because she had acute abdomen we performed laparotomy by midline incision and excised a 6cm ovarian mass on right ovary. The mass had been reported as ovarian leiomyoma on frozen section by pathology department. PMID- 25509979 TI - Two consecutive twin and a singleton pregnancy in a patient with chronic myeloid leukemia. AB - Consecutive multiple pregnancies with Chronic myeloid leukemia is a rare event and little is known about its prevalence and management with or without chemotherapy. We present a case of three consecutive pregnancies in a woman with CML, two of which were multiple pregnancies. PMID- 25509980 TI - Hemangiopericytoma of the uterus: a rare case of pelvic mass. AB - Hemangiopericytoma (HPC) is an uncommon perivascular tumor which may arise from anywhere in the body accounts for 1% of primary vascular tumors. Uterine hemangiopericytomas are usually low grade malignancies with better prognosis. The primary treatment is usually total hysterectomy and bilateral salpingo oophorectomy. In this report, we aimed to evaluate the clinical characteristics of an 83 years of woman admitted to our clinic with pelvic mass who underwent laparotomy and underwent total hysterectomy and bilateral salpingo-ooforectomy. Postoperative pathology was hemangiopericytoma. PMID- 25509981 TI - Retention of fetal bones 8 years following termination of pregnancy. AB - Foreign bodies; in particular, fetal bones may present with a variety of clinical symptoms and signs including infertility, vaginal discharge, disparonia, pelvic pain, abnormal uterine bleeding. Many case reports were described post- abortal removal of retained fetal bone at varying time intervals from the previous (D&E), ranging from weeks to years. In our case, a 34-year-old woman presented with abnormal uterine bleeding and secondary infertility, her only pregnancy being a termination 8 years previously at 15 weeks' gestation. A transvaginal ultrasound revealed a normal-sized, normal-shaped uterus with an echogenic scarred endometrium. After then office hysterescopy revealed fragments of the immature bone. All the immature bones were removed by operative hysterescopy. Significant numbers of patients may have endometrial pathology; the differential diagnosis of such unusual findings on ultrasound examination includes intrauterine contraceptive devices, foreign bodies, calcified submucous fibroids and Asherman's syndrome, as well as rarities such as heterotopic bone. The presence of this pathology may be a causal or contributory factor to subfertilty, and will remain undetected if the endometrium is not routinely evaluated. Indeed, these cases highlight the advantage of performing a hysteroscopy at the same time as the more invasive laparoscopy and dye insufflation, in selected cases. PMID- 25509982 TI - Incidentally detected ectopic right kidney following total abdominal hysterectomy and bilateral salpingoophorectomy. AB - Congenital organ anomalies in surgical patients can be incidentally detected during operation. A pelvis located right kidney was found incidentally in 54 year old women after total abdominal histerectomy and bilateral salpingoophorectomy. The clinical importance of pelvic kidney detected during the surgery was discussed in this case report. PMID- 25509984 TI - Gold-Gold Sulfide nanoparticles intensify thermal effects of radio frequency electromagnetic field. AB - PURPOSE: This study aimed to determine the efficacy of thermotherapy resulting from the presence of gold-gold sulfide nanoshells (GGS) in radio frequency electromagnetic field (13.56 MHz) onthe survival of CT26 colon carcinoma cells. MATERIALS AND METHODS: GGS was synthesized and after characterizing and determining the features, the RF-radiation effects on aquatic environments were determined by recording temperature changes. To investigate the biological effects, cell survival rate due to GGS usage at five different concentrations, each one with applying three different exposure times of RF field, at CT26 cells were evaluated by MTT assay. RESULT: In the presence of 100 mg/L GGS and 5 min RF exposure, increasing in temperature was recorded more than 60 degrees C. A significant difference in cell survival rate was observed, when both GGS and RF field were applied with each other or separately (p<0.001). The GGS concentration of 25mg/L with a 4 min exposure causes cell death with the efficiency of 80 percent more than using them separately. CONCLUSION: The GGS as an available nanostructure (i.e. it's not expensive and can be synthesized simply) is an environmental friendly material which has the ability to cause damage to malignant cell effectively, by absorbing the non-invasive and deeply penetrating energy of RF field. PMID- 25509983 TI - Anticancer activity of pristimerin in ovarian carcinoma cells is mediated through the inhibition of prosurvival Akt/NF-kappaB/mTOR signaling. AB - Pristimerin isaquinonemethidetriterpenoidthathasshown anticancer activity against some cancer types. However, the antitumor effects of pristimerin (PM) in ovarian cancer cells have not been adequately studied. The objective of the present study was to determine the anticancer activity and its mechanism of action in human ovarian carcinoma cell lines. PM strongly inhibited the proliferation of ovarian cancer cells by inducing apoptosis characterized by increased annexin V-binding, cleavage of poly (ADP-ribose) polymerase (PARP-1) and procaspases-3, -8 and -9. Furthermore, PM caused mitochondrial depolarization. Western blot analysis showed inhibition of prosurvival phospho-AKT (p-AKT), nuclear factor kappa B (NF-kappaB) (p65) and phospho-mammalian target of rapamycin (p-mTOR) signaling proteins in cells treated with PM. Treatment with PM also inhibited the expression of NF kappaB-regulated antiapoptotic Bcl-2, Bcl-xL, c-IAP1 and survivin. Thus, our data showing potent antiproliferative and apoptosis-inducing activity of PM in ovarian carcinoma cells through the inhibition of AKT/ NF-kappaB/ mTOR signaling pathway warrant further investigation of PM for the management of ovarian cancer. PMID- 25509986 TI - Prognostic and therapeutic applications of the molecular events in clinical management of urothelial carcinoma of bladder. AB - Urothelial carcinoma of bladder being the commonest malignancy of the urinary tract progresses through successive accumulation of genetic alterations and bears high metastatic potential. Despite significant advances in its prognosis and treatment, including surgical techniques, various adjuvant therapies, radical cystectomy and robot-assisted radical cystectomy, tumor recurs with a poor 5 year survival rate thereby necessitating the need to institute an additional form of novel target based therapies to improve the overall outcome. Improved understanding of the molecular pathways critical for both early and late stage disease not only leads to better prognostication but may also enhance therapeutic index. This review article highlights the recent progress in the development of novel anti-cancer targeted therapies that may modulate clinical response of cytotoxic drugs with minimal adverse side effects and provide insight for the potential reversion of the resistance in patients failing therapy. PMID- 25509985 TI - An AF9/ENL-targted peptide with therapeutic potential in mixed lineage leukemias. AB - Misregulation of transcription elongation is proposed to underlie the pathobiology of MLL leukemia. AF4, AF9, and ENL, common MLL fusion partners, are found in complex with positive transcription elongation factor b (P-TEFb). AF9 and its homolog ENL directly interact with AF4 within these complexes. Previously, we designed a peptide that mimics the AF9 binding domain of AF4 and reported that MLL leukemia cell lines are inhibited by it. Extending these studies, we have modified the peptide design in order to avoid recognition by proteases. The peptide is as effective as its predecessor in vitro and enhances survival in mice bearing MLL leukemia cell lines. PMID- 25509987 TI - Identification of the pattern of copper as an etiological factor in oral submucous fibrosis: a cytological study. AB - Oral Submucous Fibrosis (OSF) is a well-recognized, potentially malignant disorder causing generalized fibrosis of the submucosal oral soft tissues. Though this disease is believed to be multi-factorial, areca nut chewing has emerged as the most important causative factor for OSF. Areca nut is known to have high levels of copper, which is believed to cause lysyl oxidase associated fibrosis. AIM: To evaluate the pattern of copper in buccal mucosal cells of OSF patients, areca nut chewers and normal healthy individuals and to elicit the etiology of copper in OSF. MATERIALS AND METHODS: Patients were divided into three groups each comprising of 20 individuals- Healthy individuals (Group I); areca nut chewers without OSF (Group II); histopathologically confirmed OSF (Group Ill). The cytological smears made from each patient were stained with rhodanine stain for copper and evaluated for the qualitative and quantitative parameters of copper by using specific grading criteria. RESULTS: Quantitative estimation of copper content showed a marked variation in the mean values. Mean value of group I was 0.11 +/- 0.39; group II was 1.09 +/- 0.81 and group III was 2.34 +/- 0.74 (p<0.001). Mean values for qualitative estimation of copper were - 0.01 +/- 0.36 for group I, 1.08 +/- 0.82 for group II and 2.39 +/- 0.72 for group III (p<0.001). Chi square analysis was used to assess the percentage distribution of copper granules. This revealed that the colour intensity and the number of granules were seen to maximum in OSF patients, areca nut chewers without OSF having intermediated values and normal healthy individuals having the least values. CONCLUSION: An evident increase in the copper staining in group III individuals as compared to group I and group II was well appreciated. Increased copper levels in the local environment of the oral cavity indicates its role in lysyl oxidase associated submucosal fibrosis. PMID- 25509988 TI - CD147 expression in uterine smooth muscle tumors, and its potential role as a diagnostic and prognostic marker in patients with leiomyosarcoma. AB - OBJECTIVE: To investigate the role of CD147 expression in uterine smooth muscle neoplasms, as a potential diagnostic and prognostic marker in patients with leiomyosarcoma (LMS). STUDY DESIGN: We investigated CD147 protein expression in uterine smooth muscle tumor samples from patients diagnosed with leiomyoma (n = 22), atypical leiomyoma (BLM) (n = 5), smooth muscle tumor of uncertain malignant potential (STUMP) (n = 14), and LMS (n = 22). The intensity and extensity of immunohistochemical staining were compared to determine its potential role in differential diagnosis. Spearman's rank correlation tests were performed to determine the relationship between CD147 expression and prognostic clinical and pathological criteria in the patients with LMS. RESULTS: CD147 was strongly expressed in 81.8% (n = 18) of the LMS tissue samples. In fact expression of CD147 in LMS tissues was significantly higher than that of the three other uterine smooth muscle tumor types (p = 0.000). However, high CD147 expression was found in only one BLM sample and one STUMP sample. Furthermore, CD147 percent expression positively correlated with Ki67 percent expression (r = 0.466, p<0.05) and mitotic index (r = 0.554, p<0.05), respectively. CONCLUSION: Our results suggest that immunohistochemistry may be a helpful tool in determining whether CD147 is a useful marker in the differential diagnosis of certain uterine smooth muscle tumors. CD147 may also have prognostic value for patients with LMS. Yet, in order to determine the extent of this potential marker's utility as a diagnostic and prognostic indicator, a larger randomized multicenter study must be performed. PMID- 25509989 TI - [Ad nauseam]. PMID- 25509990 TI - [Alberto Chalmeta Tomas (Catarroja, Valencia 1897-Paris 1987?) Professor of practical pharmacy at the Central University: a broken life]. PMID- 25509991 TI - [History of the rural physician in Ourense: a rain of conflicts and the collegial umbrella]. PMID- 25509992 TI - [Splenic artery aneurysm: a rare differential diagnosis of upper gastrointestinal bleeding]. PMID- 25509993 TI - [Therapeutic use of immune sera. Ebola survivors as lifesavers?]. PMID- 25509994 TI - [These modern syringes are rubbish]. PMID- 25509995 TI - [Perhaps we should be role models for our patients - naturally very tactfully]. PMID- 25509996 TI - [Healthy Kinzig Valley. The patient determines the therapy goal]. PMID- 25509997 TI - [BSG: physicians with "previous convictions" are not advised about regress action]. PMID- 25509998 TI - [The legal texts must be clarified - it is your obligation as an employer]. PMID- 25509999 TI - [Complex care. No special codes for cancer patients]. PMID- 25510000 TI - [Possible BG accounting. It is worthwhile to ask about the accident cause]. PMID- 25510001 TI - [Preferably hospice care than assisted suicide]. PMID- 25510002 TI - [Future WHO goal. Tuberculosis elimination]. PMID- 25510003 TI - [Screening and diagnostic procedures in trial. Breath test for lung cancer]. PMID- 25510004 TI - [Evaluating bronchial hyperreactivity. Provocation test unmasks overtreatment in bronchial asthma]. PMID- 25510005 TI - [Asthma risk in offspring. New argument for counseling young smokers]. PMID- 25510006 TI - [Lung White Paper is expanded. Lung disease challenge]. PMID- 25510007 TI - [Cutting edge prevention and therapy. Fit for the influenza season?]. PMID- 25510008 TI - [Naturopathy consultation. Natural management of female and male ailments]. PMID- 25510010 TI - [PET study. Winter blues: serotonin transporter is responsible]. PMID- 25510011 TI - [Hepatic encephalopathy. Early therapy is most important!]. PMID- 25510012 TI - [Beef allergy. Caution with the prick test]. PMID- 25510013 TI - [Psoriasis therapy. Dose regulation or aspirin to control flush]. PMID- 25510014 TI - [Galenus von Pergamon Prize and Charity Award 2014. Prizes for innovation and ideas]. PMID- 25510015 TI - [Fall season - common cold season. The fifth cough in a row: is an immune deficiency the cause?]. PMID- 25510016 TI - [Inadequate care and the sequelae. Dangerous errors in routine general practice]. PMID- 25510017 TI - [Brain doping in high stress periods]. PMID- 25510018 TI - [CO2 reduction improves long-term survival in COPD with chronic hypercapnia]. PMID- 25510019 TI - [Without doubt tablet change worsens medication compliance]. PMID- 25510020 TI - [High risk despite polypectomy]. PMID- 25510021 TI - [How and where do centenarians actually die?]. PMID- 25510022 TI - [More security for elderly people]. PMID- 25510023 TI - [Ambient assisted living - a sleeping giant]. PMID- 25510024 TI - [In the elderly avoidance of hypoglycemia is in the foreground]. PMID- 25510025 TI - [Intervention to prevent falls among older people in a primary care setting]. PMID- 25510026 TI - [Male hypogonadism - recommendations for diagnosis and therapy]. PMID- 25510027 TI - [New approaches in diagnosis and therapy of irritable bowel syndrome]. PMID- 25510028 TI - [Penile cherry angiomas]. PMID- 25510029 TI - [Abdominal pain in children and adolescents]. PMID- 25510030 TI - [Complex regional pain syndrome]. PMID- 25510031 TI - [Gastrointestinal motility disorders. Effective phytotherapy alternatives to MCP (metoclopramide)]. PMID- 25510032 TI - [Interview with Prof. Dr. Ralf Baron. Pain: toward causality oriented therapy]. PMID- 25510033 TI - [Ultrasonography of the uterus cicatrix during the third pregnancy trimester after a Cesarean section]. PMID- 25510034 TI - [Tocolysis with nifedipin; its use in current practice]. AB - AIM: The aim of the study is to establish the safety and efficacy of calcium channel blocker- Nifedipin as tocolytic agents. A wide range of tocolytics have been utilized for the management of preterm labor Calcium channel blockers, namely nifedipine, gained popularity as tocolytics due to the oral route of administration, availability of immediate- and slow-release preparations, the low incidence of maternal adverse effects associated with their use, and the fact that they are inexpensive. METHODS: 88 pregnant women in preterm labor participated in a prospective longitudinal study Inclusion criteria were: gestational age between 24 and 34 weeks gestation; uterine contractions in 10-15 min interval; single pregnancy, lack of contraindications for tocolysis. In all cases the calcium antagonist Nifedipine was used in dosage 4 x 10 mg per os. The clinical response to tocolysis, gestational age at delivery and potential side effects were analyzed. RESULTS: 91 pregnant women participated in the study. Three were excluded because they refused to participate. 88 pregnancies were finally analyzed. In nine of them maternal contractions persisted despite of treatment. The other 79 pregnancies were delayed 48 hours to receive antenatal corticosteroids. From all these 79 pregancies 66 delayed 7 days. The most common adverse effects were tachycardia, hypotonia, headache, dizziness, but they escape soon after the first dose. CONCLUSION: Nifedipine is an effective oral tocolytic with few maternal side effects. PMID- 25510035 TI - [Perinatal mortality of IUGR neonates]. AB - This study was conducted to evaluate the role of intrauterine fetal growth restriction (IUGR) in the perinatale mortality. A prospective study was designed, including 329 consecutive singleton pregnancies between 24 to 40 weeks' gestation, whose body weight is under 10th percentile for the gestational week. The control group consist of 530 appropriate for the gestational week (AGA) in the same period of gestation. The fetuses are without inborn malformations. The results show grater stillbirth rate in the group of hypotrophic than in the eutrophic neonates. In the group under 27th week of gestation is 2.6% forAGA and 8.3% for IUGR, for the group between 28-31 w.g. is 9.6% and 21.1% respectively and for 32-35 wg. is 2.3% against 13.1%. Perinatal mortality rate (stillbirth and demised before discharged) for the group before 27th w.g. is 65.8% for AGA and 72.2% for IUGR (P > 0.05). Between 28-31 w.g. is 28.4% and 50.0%, for 32-35 is 6.9% and 27.8% respectively (P > 0.01). After 37th w.g. perinatal mortality rate is less in AGA than in SGA fetuses. In conclusion the stillbirth rate is more frequent in IUGR fetuses than in AGA and frequencies is more pronounce in late preterm pregnancy. The fetal hypotrophy has deleterious effect on neonatal survival rate. PMID- 25510036 TI - [Identification of preterm labor: the role of fetal fibronectin in parents with symptoms]. AB - AIM: To determine whether the presence of fetal fibronectin in vaginal secretions of patients with symptoms suggestive of preterm labor predicts preterm delivery. Fetal fibronectin, a large molecular weight glycoprotein produced in the chorion, is expressed in cervical and vaginal secretions in women with disruption of the choriodecidual junction by labor or by inflammation. METHODS: A prospective observational longitudinal study from January 2013 till December 2013 was performed on patients between 24 and 32 weeks of gestation with symptoms of preterm labor, intact membranes, and cervical dilation < 4 cm (total patients = 86). The endpoint was the delivery at 34 weeks or more. The screening methods used were: the fFN test and the cervical length measurement by transvaginal according to an established protocol. CONCLUSION: The presence of FFN in vaginal or cervical secretions before 35 weeks is a is a strong predictor that preterm delivery is unlikely within the next 7 to 14 days. The predictive power of FFN is stronger at earlier gestation ages (24-29 wks) than it is later in pregnancy and is stronger for short-term prediction (7-14 d). PMID- 25510037 TI - [The pregnancy outcome in patients WITH beta-thalassemia minor]. AB - Thalassemia syndromes are heterogenic group hereditary hemoglobinopathies, provoking chronic hemolytic anemia. They affect approximately 100 million people, mostly in the Mediterranean (including Bulgaria), South-eastern Asia and Africa. Thalassemia syndromes are the second reason for hypochromic anemia and anemia in pregnancy after iron deficiency. OBJECTIVE: To determine pregnancy outcome of women with beta-thalassemia minor. MATERIALS AND METHODS: It is an ambispective study in University Hospital of Obstetrics and Gynecology" Maichin dom", Sofia, for a year. Patients are divided in two groups regarding the presence of beta thalassemia minor. Preeclampsia, gestational diabetes mellitus, olygo- and polyhydramnion, preterm labor intrauterine growth retardation (IUGR), Cesarean section delivery are recorded in study groups. RESULTS: Cases with beta thalassemia minor have significantly higher prevalence of oligohydramnion and Cesarean section delivery. There is no significant difference regarding Apgar score in 1st and 5th minute, IUGR, gestational diabetes mellitus and preeclampsia between two study groups. CONCLUSION: beta-Thalassemia minor does not significantly influence the pregnancy in negative way. PMID- 25510038 TI - [Puerperal infections after Cesarean section and after a natural childbirth]. PMID- 25510039 TI - [Induced abortion--clinical problems, regulatory gaps, chaos. How much longer?]. AB - Induced abortion is becoming more and more frequent in the contemporary clinical practice. Usually these are pregnant women with diagnosed foetal malformations. Most of them reach a final diagnose in the late second trimester and hence need a pregnancy termination at this gestational age. They are treated in accordance with The Artificial Pregnancy Termination Regulations and put on N 142 clinical care pathway. The presentation describes the patients' journey form the diagnose through the induced abortion and to the discharge. Analyses the regulations, the multiple inaccuracies and striking omissions with regards to the procedure. Stimulates a discussion on the clinical problems and offers reasonable and realistic solutions. PMID- 25510040 TI - [Preterm birth in Bulgaria--changes in aetiology and incidence in the last decade]. AB - There is no decrease in the incidence of preterm birth in Bulgaria and in the world, despite of all the therapeutic and prophylactic efforts. The rate of prematurity in University Maternity Hospital 'Maichin dom' in the last decade has increased significantly- from 11.6% in 2003 to 17.5% in 2013. The numbers are higher than the national average due to the essence of the Hospital being a leading clinical and scientific center. Thorough analysis demonstrates significant increase in the first grade prematurity being 5.8% of all live births in 2003 and 10.2% of all live births in 2013. In fact 58% of all premature births result in first grade preterm newborn. There is no significant increase in the forth grade- severe prematurity in the last decade. We believe that this increase in preterm birth rate is due to several reasons: the success of assisted reproductive technologies, which in Bulgaria leads to a significant increase in the number of multiple pregnancies; destructive/ablative methods of treatment of cervical intraepithelial neoplasia, especially LLETZ (LEEP), postponing of first pregnancy, increase in the number of adult primiparous women and as a whole pregnancy at later age, pregnancy in puberty. All these impose changes in the protocol for pregnancy follow up. Furthermore, we believe it is high time to increase the effectiveness of this service, as lack of adequate follow up is a reason for preterm birth on its own. PMID- 25510041 TI - [Twin reversed arterial perfusion sequence in monochorionic pregnancy - two clinical cases]. PMID- 25510042 TI - [Ovarian vein thrombophlebitis during pregnancy--with a contribution of one clinical case]. AB - Ovarian vein thrombosis (OVT) is a rare, but serious condition that affects mostly postpartum women but may also be associated with pelvic inflammatory disease, malignancies and pelvic surgical procedures. Concerning ovarian vein thrombosis in earlier stages of pregnancy there are only very few case reports. The authors consider this rare but potentially deadly disease and describe the clinical case study. PMID- 25510043 TI - [Recombinant human chorionic gonadotropin - always contemporary]. PMID- 25510044 TI - [Therapeutical algorithm for life threatening haemorrhage during caesarean delivery or massive vaginal or cervical rupture following vaginal delivery]. PMID- 25510045 TI - [Medical abortion 15-22g.w. first experience with mifepriston administration in Bulgaria]. AB - Medical abortion by definition is termination of pregnancy by means of administration of abortifacient pharmaceutical drugs. The most widely spread abortifacients are Mifepriston and Misoprostol. This is the gold standard for induced abortion worldwide, for first trimester, as well as for second. In Bulgaria Mifepriston is available as of June 2014. We represent here our first experience in administering Mifepriston for induced abortion in second trimester. We share our first impressions and discuss the results. PMID- 25510046 TI - [Medical abortion--evidence-based practice]. PMID- 25510047 TI - [Plasma D-dimer levels in preeclampsia]. AB - Preeclampsia is a multifactorial disease characterized by hypertension and proteinuria after 20 weeks of gestation of the pregnancy. Preeclampsia is characterized by the deposition of fibrin in the walls of small blood vessels. D dimer was used as a marker for degradation/synthesis of fibrin in vivo. D-dimer has emerged as a useful indicator in the diagnosis of thrombotic conditions because its plasma concentration has a high predictive value for the assessment of venous thromboembolism. The purpose of this study was to evaluate plasma levels of D-dimer and preeclampsia compared to normal pregnancy occurs. We found that elevated levels of D-dimer is associated with the development of preeclampsia in the third trimester of pregnancy compared with normal pregnancy occurs. Preliminary findings highlight the need for further in-depth studies during pregnancy in order to fully clarify the diagnostic/prognostic role of D dimer preeclampsia. PMID- 25510048 TI - [Antenatal diagnosis of placenta accreta]. AB - Placenta accreta is a potentially life-threatening obstetric condition. Diagnosis of placenta accreta before delivery allows multidisciplinary planning in an attempt to minimize potential maternal or neonatal morbidity and mortality The diagnosis is usually established by 2D, 3D Ultrasonography and Color Doppler ultrasonography and occasionally supplemented by Magnetic Resonance Imaging. PMID- 25510049 TI - [Location of the placenta in pregnancy with previous caesarean section]. AB - Previous Caesarean section (SC) is considered to be established predisposing factor for abnormal placentation. In this study we examined whether prior SC is a risk factor for low laying placenta. Retrospective documentation was studied of 171 pregnant women after a SC (test group) and of 150 pregnant women after a normal birth (control), and cases of hysterectomy after giving birth to five years. Pathological lying placenta have established at 1.34% in the test group versus 0.67% in controls (p - 0.058), i.e. no proven link between prior Cesarean section and location of the placenta in the lower uterine segment during the next pregnancy. The analysis of cases of postpartum hysterectomy is found that the combination of condition after Cesarean section, placenta praevia and placenta accreta is a risk factor for hysterectomy after childbirth. PMID- 25510050 TI - [The influence of pregnancy on the systemic lupus erythematosus]. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease caused by the interaction between genetic and environment factors which leads to abnormal immune responses. SLE affects more commonly women of childbearing age which raises the following questions--the influence of the disease activity on pregnancy and the influence of pregnancy on disease activity. On the one hand physiological changes occurring during pregnancy could lead to increased SLE activity, on the other hand the latter could mimic SLE activity. Differentiating these manifestations is important for the clinical practice--pregnancy and delivering guidance and SLE therapy. PMID- 25510051 TI - [Diabetes and pregnancy]. AB - We tried to summarize our and foreign experience in the field of diabetes and pregnancy AIM: Our aim was to detect pregnant women with diabetes mellitus, as well as to introduce screening method for early detection and apply a suitable diet and treatment for these patients. MATERIAL AND METHODS: Patients with diabetes and pregnancy were researched for the period of 2007-2014 (70 patients). RESULTS: Introducing a screening method in the second trimester between 24-28 gestational week, applying a suitable diet and treatment lead to better outcome of this disease and to more safe delivery outcome. CONCLUSION: Future research work will give additional light in this field. PMID- 25510052 TI - [Effective tocolysis without beta-agonists]. AB - Many years the beta-mimetics (Partussisten, Gynipral) were first line tocolytic agents in terms of delaying premature delivery in our country. As these medicaments have been withdrawn from the pharmacy network, some concerns began to appear among our colleges considering the administration of other tocolytics and their effectiveness. Our goal is to compare the efficacy of other tocolytics with beta-mimetics. That is why we reviewed the structure of premature deliveries in the University Hospital "Stoyan Kirkovich", Stara Zagora for two periods: 01.01.2013 - 31.12. 2013 and 01.01.2014 - 01.06.2014. RESULTS: 45 of 326 pregnancies (13.8%) > 20 weeks of gestation for 2013, treated with Gynipral have ended with a premature delivery vs. 13 of 110 pregnancies (11.8%), treated with magnesium (Mg SO4, Magnerich, Magnerot), calcium channel blockers and spasmolyticsfor the period - 01:01.2014 - 01.06.2014. CONCLUSION: The results show, that at this stage, several months after the cessation of use of beta mimetics, there is no rise of number and percentage of premature deliveries, but there is even a tendence of decline. Larger periods and greater number of cases are needed to formulate conclusions with greater significance. PMID- 25510054 TI - [The asphyxia of the fetus--cardiotocography and ultrasound methods of diagnosis]. AB - The asphyxia of the fetus remains a main cause for neonatal morbility and mortality. And the possibility of it developing antenatal or intrapartal. The main objective of the antenatal fetus examination tests is the timely diagnosis of the signs of the asphyxia of the fetus. PMID- 25510053 TI - [Successful full-term pregnancy in the Herlyn-Werner-Wunderlich syndrome: a case report and review of literature]. AB - Herlyn-Werner-Wunderlich Syndrome results in a doubling of the internal genitalia accompanied by unilateral gynatresia (with hemi-hematokolpos, hemi-hematometra and/or hemi-hematosalpings) and ipsilateral renal agenesis. The authors considered the case of a successful full-term pregnancy in one uterus after pregnancy failure in the other imposed surgical removal of the same. PMID- 25510055 TI - [In this issue of Ginecologia y Obstetricia de Mexico]. PMID- 25510056 TI - [Causes of delays in obstetric complications care. What is necessary to address? ]. AB - This article reviews the published evidences associated with the causes of delays in cases of maternal death and in those for which the patients survived the obstetric complication, in order to build an analytical framework to identify factors not investigated yet, as part of the search for a preventive model of maternal risk. We reviewed articles in the PubMed, EBSCO and Web of Science database using the following keywords: delays, maternal, mortality. Latin American items were extracted from the Google Scholar database. Three types of delays were analyzed: in seeking care (first delay) in reaching care (second delay), and in diagnosis and treatment (third delay). The main causes of the first delay were lack of decision to seek care at the time of complication (79%) and not recognizing the warm signs of the complication (82.1%). The second delay was mainly due to the lack of transport (92.3%) at the time of transfer to another hospital. The third delay was related to poor quality of care in health services (63%). Educational interventions appropriate to the context are required to integrate knowledge of warning signs and conditions of gender. Studies are needed to analyze the causes of delay in health services in order to be able to propose preventive models aimed at their reduction. PMID- 25510057 TI - [Influence of the level of training of the specialist in intra and post operative pain in patients who undergo officinal hysteroscopy ]. AB - BACKGROUNDS: There are variable results regarding the risk factors associated with levels of pain during office hysteroscopy. OBJECTIVE: Describe levels of pain in Colombian patients who undergo office hysteroscopy performed by doctors in training. MATERIAL AND METHODS: Case series study. Conducted in patients who undergo office hysteroscopy without anesthesia in outpatient clinic in May 2012. The procedure was performed by Gynecologists in training and under supervision of the specialist. The Obstetric and Gynecological history was obtained through questionnaire. The pain perception, according to visual analog scale (VAS), was taken at three moments during the study: (1) 5 minutes before the procedure, (2) At the end of the procedure, (3) 10 minutes after the procedure.The major outcomes were: VAS 0-4, considered as absent or mild pain and VAS 5-10 considered as moderate or severe pain. RESULTS: We studied 44 patients, aged between 29 and 65 years. The group of patients with a VAS score >5 was mainly compose by: (1) Patients older than 50 years (58.8%), (2) with positive history of C-section (66.7%), (3) with positive history of abortion (75%) and menopausal (56.3%). CONCLUSION: 47.7% of our patients presentVAS score > 5. The majority of this group was composed by patients with risk factors to have pain during office hysteroscopy. Then we can't conclude that the level of pain experimented by our patients was due to the level of training of the doctors. PMID- 25510058 TI - [Complex location of a single rod contraceptive implant]. AB - BACKGROUND: The subdermic single-rod contraceptive implant is used for more than 2.5 million of womens around the world (in Mexico there are around 600 000 collocated implants). in a small number of cases an incorrect insertion procedure is caused by a complex localizaron.. METHODS: A clinical, retrospective, descriptive study was conducted in the period January 2011 to December 2013. the Family Planning Service of the General Hospital of Mexico Dr. Eduardo Liceaga. RESULTS: A total of 21 patients were included. In all cases the implant was not palpable in 20 patients and was located by ultrasound and removed. 10 implants were in Fatty tissue, 6 in muscle, 2 in fatty tissue and muscle and 2 were located in armpit. CONCLUSIONS: Due to simplitcity and accessibility, the ultrasound is the selected method for identifying deeply non-palpable implants. PMID- 25510059 TI - [Gynecological care to children and adolescents. Twelve-year experience at National Pediatrics Institute, Mexico]. AB - BACKGROUND: In major regions of the world, the importance of gynecological care to children and adolescents has been recognized. There are multiple publications, journals and associations dedicated to this purpose. In Mexico, it has not been the case. OBJECTIVE: The aim of this publication is to raise awareness to the medical community about the importance of sub specialized gynecological care to children and adolescents. MATERIAL AND METHODS: Retrospective study. The number of office evalu- ations issued by the Department of Gynecology of the National Institute of Pediatrics (INP) from January 1, 2002 to December 31, 2013 were counted. Results were grouped by age groups. Group 1: 1 year or less. Group 2: 2 to 9 years. Group 3: 10 to 18 years. The major causes of morbidity were analyzed by groups and in general. RESULTS: In the 12 year period reported, 21,190 girls granted gynecological consultation: 15.2% were first consultations (n = 3,221), 74.76% subsequent consultations (n = 15,842) and 10.04% evaluations and interconsultations (n = 2,127). The yearly average was 1,766 consultations. From 2002 to 2005, two certififyed obstetrician-gynecologists (OB-GYN) worked in the Departament, with the subsecuent increase in the number of attentions; 2005 was the year with the highest productivity (2,265). From 2006, only one OB-GYN continued laboring, and the number of visits decreased gradually. 2013 was the year with fewer productivity (1,351). The main causes of morbidity were: abnormal uterine bleeding (26.48%), inflammatory conditions of vagina and vulva (13.58%), dysmenorrhea (12.31%); which occupied 52.37% of the total (10,404 / 19,867). 81% of the patients corresponded to group 3 (17,079/21,190). To a younger patient, corresponded a smaller number of visits. CONCLUSION: It is required to institute the subspecialty of Child and Adolescent Gynecology in Mexico and to establish Services formed by subspecialists in this matter in the top pediatric hospitals of the country. PMID- 25510060 TI - [Diagnosis and treatment of hemophilia A acquired during postpartum ]. AB - Acquired hemophilia A is a truly exceptional hemorrhagic diathesis, that consists of the emergence of polyclonal autoantibodies (inhibitor) IgG-type (subclasses 1 and 4, in most cases) against the coagulant function of the circulating factor VIII, which acts in the domains C2, A2 and A3 of the molecule, thus interfering their interaction with the factor IXa, the phospholipids and the Von Willebrand factor. Its morbidity and mortality are high, but nevertheless its low incidence (1-1.5 cases per million population per year) is the most frequent autoimmune disorder. This paper reports the clinical case of two patients; the first one, 36 years old, who the tenth day of postpartum required re-entry due to a diagnosis of hematoma of the abdominal wall that was surgically drained twice. The patient of case 2 was 39 years old and at six days of postpartum went to the emergency room due to bleeding, she was underwent to curettage and therapeutic transfusion of 3 UCH. Because of the persistence of bleeding, which was not possible to control with medical treatment and conservative measures, therapeutic hysterectomy was performed, with blood transfusion later. Due to the hemorrhagic complications of this condition and the serious clinical consequences derived from them, it is important to establish an early diagnosis; it is therefore critical to know the existence of this very rare disease to be able to avoid its consequences. PMID- 25510061 TI - [Herpes gestationis. A case report]. AB - Case report. 21 years old woman with 30 week pregnancy, complicated by a 3 month multitreated skin condition, who was referred to General Hospital Morelia, with probable diagnosis of Kapossi sarcoma and sus- pected HIV. She presented with exulcerations involving the palate, lips, chest, abdomen, back and extremities. The lesions were, itchy and painful, with thick yellowish secretion, accompanied by dysphagia to solid foods. Laboratory results showed normochromic normocytic anemia, elevation of ESR, hypocalcaemia, increased PCR, results in alterations in various TORCH listing, HIV negative. The biopsy of a lesion of the forearm reported histological changes consistent with herpes, subsequently confirmed by direct immunofluorescence. Liquid aspiration secretion of one of the lesions reported coagulase negative staphylococcus sp and Enterobacter cloacae. The final diagnosis was 30 weeks pregnant women with gestational herpes complicated by pyogenic infection of the lesions, discarding infection with HIV and found positive for IgG to toxoplasma, rubella, cytomegalovirus and herpes virus. PMID- 25510062 TI - [Laparoscopic hysterectomy assisted with robot. Report of first case in Mexico ]. AB - Some 15 years ago since the DaVinci system is launched in the market and since then has been gaining ground in the field of surgery. There have been published case series and large casuisticals comparing the benefits from robotic surgery versus laparoscopic. In 2005 the Food & Drug Administration (FDA) approves its use for gynecological surgery. In Mexico, we have no experience in the use of this technology in this field of medicine. To describe the first laparoscopic hysterectomy case assisted with a robot (LHAR) intervened in Mexico, the results and review of the literature reported at the global level. CLINICAL CASE: this is a 47 year-old patient with clinical and ultrasonographic diagnosis of uterine fibroids of large items, who is scheduled for laparoscopic hysterectomy assisted with robot at Hospital Angeles del Pedregal in May of 2014. It examines the parameters of surgical time, transoperative bleeding, surgical complications, postoperative pain and hospital stay. It is also a review of the literature and compared the results obtained with what is reported in the literature world. The surgery had a duration of 2 hours 35 minutes. Blood loss was less than 50 mL. There were no complications and the patient had an EVA test of 2 at 24 hours after surgery. Hospital stay was 2 days. Laparoscopic hysterectomy assisted with a robot is a reliable procedure according to what is reported at the global level, offering benefits to both the surgeon and the patient. PMID- 25510063 TI - [Obstructed hemivagina and ipsilateral renal anomaly: unusual cause of piocolpos. Report a case and review of literature ]. AB - OHVIRA (Obstructed hemivagina and ipsilateral renal anomaly) by acronym and abbreviations in English or Herlyn Werner Wunderlich syndrome is a rare congenital malformation caused by an alteration in the Mullerian ducts and Wolffian Ducts. Which is characterized by a triad: uterus didelphys, obstructed and ipsilateral renal agenesis hemivagina still uncertain etiology. Patients are usually asymptomatic until menarche where the most common clinical presentation is pelvic pain, followed by a vaginal or abdominal mass, normal menstrual periods, infertility, and vaginal discharge rarely appears. The case of a female patient of 15 years, nubile with chronic fetid vaginal discharge, initially diagnosed and treated as pelvic inflammatory disease occurs, however because it is an exceptional condition with the background of the patient, by complementary studies were conducted where pelvic ultrasound revealed pyocolpos and absence of left kidney, uterus didelphys, blind hemivagina by other imaging studies, where we could integrate Herlyn-Werner-Wunderlich syndrome. In conclusion, abnormalities in the development of the Miillerian ducts are difficult to diagnose early, so you must have the embryological knowledge, conduct thorough clinical assessment and detailed picture in whom the coridition is suspected to identify malformations coexisting urinary tract and vaginal defects with the importance of preserving reproductive success through appropriate planning of surgical approach, given that the fertility rate in these patients is comparable to the average. PMID- 25510064 TI - [Pregnant women's attitudes towards the acceptable age limits for conceiving and giving birth to a child]. AB - AIM: To assess whether there are socially determined permissible and desirable age limits for conceiving and childbirth among pregnant women in Bulgaria and their relation to age, general and obstetrical medical history, method of conception, level of education and whether pregnancy has been postponed or not. MATERIALS AND METHODS: 388 patients from the Fetal Medicine Clinic of the State University Hospital "Maichin Dom" in Sofia were provided with anonymous questionnaires, containing 38 questions. Two of the questions were essensial: 1) "What is the maximal permissible age for a woman to become pregnant and give birth to a child?". 2) "What is the maximal desirable age for a woman to become pregnant and deliver the planned numberof children?". The questionnaire contained also 23 questions related to the demographic characteristics of the participants and to their general and obstetric medical history. Data were processed with SPSS 13.0 statistical package. Descriptive and comparative analysis was performed after grouping according to one or mare chracteristics. P values < 0.05 were considered statistically significant. RESULTS: 54.2% (208/388) of the respondents determined a limit of the maximal permissible age for woman to conceive and give birth to a child. 53.4% (111/208) of them set the age limit of 40 years (28.9% of all patients). 63.6% (245/388) of the interrogated set a desirable age limit for conception and giving birth. Among then 82.9% (203/245) have set the limit at 40 years. The factors that influenced significantly the attitude towards the permissible age forconception/giving birth were the mode of conception, age and the level of education. Patients who had conceived spontaneously and had higher educational level were more confident when assessing the permissible age for conception/giving birth. Patients who had conceived by IVF/ICSI were significantly less confident answering the questions about age limits. The understanding for the permissible age for conception was not influenced by past obstetric history, deliberate postponemend of reproductive plans and the presence of chronic medical disorders. The understanding that pregnancy is always permissible (irrespective of age) was not influenced significantly by any of the factors. The understanding about the desirable age for conceiving/giving birth was influenced significantly only by the educational level--patients with higher degree of education were more confident in setting a desirable age limit. PMID- 25510065 TI - [Preplacentation pregnancy loss in cases of angiotensin-converting enzyme insertion/deletion polymorphism]. AB - The balance between coagulation and fibrinolysis processes is critical for establishment and development of early pregnancy. Angiotensin-converting enzyme (ACE) is related with plasminogen activator inhibitor-1 activity which is a key regulator in embryo implantation. Therefor polymorphisms in ACE gene and variation in ACE activity could be associated with an early pregnancy wastage risk. This study investigated carrier status for insertion/deletion (I/D) polymorphism in introne 16 of ACE gene in 71 women with two or more pregnancy loss in preplacentation period (between 10 and 14 weeks of gestation) and 75 women without pregnancy complications. DD genotype for I/D polymorphism was found respectively in 31% and 24% in patients and controls. Heterozygosity of D allele was found correspondingly in 47.9% and 54.7%. The dominant genetic model was used for allele prevalence comparison. D allele in DD genotype was not significantly prevalent in women with early pregnancy wastage compared with the control subjects, OR = 1.42, 95% CI (0.64-3.15). The study found a weak association between I/D polymorphism and preplacentation pregnancy loss. The additive effect over the pregnancy loss risk of I/D polymorphism could be supposed in a presence of other inherited or acquired factors connected with endometrial receptivity and implantation process. PMID- 25510066 TI - [Reliable microbiological diagnosis of vulvovaginal candidiasis]. AB - INTRODUCTION: Vulvovaginal candidiasis is common infection among those affecting the vulva and vagina. Is caused by the perpesentatives from the genus Candida, in most cases C. albicans (85-90%). An increase in the percentage of the so-called non-albicans agents is seen and these pathgogens are often resistant to the most commonly used in the practice antifungals. Faulty diagnosis, incorrect use of azoles, and self-treatment lead to selection of resistant strains and recurrent infections. AIM: Identification of Candida species associated with vulvovaginal candidiasis by conventional and PCR techniques. MATERIALS AND METHODS: For six months a total number of 213 vaginal secretions were tested applying Gram stain and cultivation on ChromAgar. API Candida fermentation tests and API 20CAUX assimilation tests were performed for the identification of the bacteria. Extraction of DNA of all the smears with subsequent PCR detection of different Candida species were done. RESULTS: 80.7% materials showed presence of blastospores and/or hyphae. Positive culture results were detected in 60 (28.2%) samples. The species specific identification revealed presence of C. albicans in 51 (85%) smears, C. glabrata--in 8 (13.3%), C. krusei--in 2 (3.3%), and S. cervisie--in 1 (2.1%). The PCR technique confirmed the results of the conventional methods. It is worth to mention that 51 of the tested smears were positive for G. vaginalis using additional PCR. CONCLUSIONS: The correct diagnosis of the cause of vulvovaginal candidiasis helps in the correct choice of appropriate antifungal therapy and prevents development of recurrent infections and consequences. The PCR based method is rapid, specific and sensitive. It perfectly correlates with the results from the conventional diagnostic tests so it could be selected as a method of choice for the diagnosis of vulvovaginal candidiasis. PMID- 25510067 TI - [Morphologically qnd immunohistochemically based screening criteria for selection of patients with possible mutation of BRCA1 gene in primary ovarian cancer]. AB - SUMMARY AND AIM: Breast cancer (BC) and Ovarian cancer (OC) are some of the most common cancers affecting women. Environmental factors and genetic alterations are involved in the etiology of both cancers. The main susceptibility genes that predisposed to BC and OC are BRCA1 (BReast CAncer 1) and BRCA 2 (BReast CAncer 2). Those of BC and OC which are due to germline mutation in BRCA 1/2 are defined as hereditary. Because of the expensiveness of genetic testing for mutations in BRCA1 we aimed to select patients with ovarian cancer suitable for genetic testing, on the base of certain morphological and immunohistochemical criteria. MATERIAL AND METHODS: We have conducted a retrospective analysis of 29 cases with serous papillary OC, taken from the archives of the Department of Clinical Pathology, University Hospital "Dr. G. Stranski" Pleven. We performed morphological assessment and subsequent immunohistochemical study with antibodies against p53, anti BRCA1 and anti proliferative marker Ki-67. RESULTS: Nineteen (65.52%) of all 29 cases were found with loss of immunohistochemical expression of BRCA1 and we defined them as suitable for genetic testing of BRCA1 mutations. CONCLUSION: A set of morphological and immunohistochemical criteria allows screening of women that should be referred for genetic testing, as it is expensive, and the incidence of BRCA1 mutations in the general population is very low. PMID- 25510068 TI - [Uterine scar after caeserean section- predicting the risk of uterine rupture and decision on the way of delivery]. AB - The Cesarean section rate in University Maternity Hospital 'Maichin dom' is 46 to 48%. The rate of repeated Cesarean section is also increasing. However there is an increasing number of women wishing to deliver vaginally after having had a Cesarean section for their first baby. On the other hand, with postponing pregnancy, increasing number of woman nowadays experience surgeries on their uterus prior to giving birth. With regards to the above-mentioned, pregnancy in scarred uterus is a common thing. Examining the uterine scar gives valuable information for the risk of uterine rupture during pregnancy and the decision making on the safest way of delivery. The current article shows ultrasound pics of uterine scar in pregnant and non-pregnant uterus. Gives recommendations for the timing of the US examination and the reference range for thickness of the uterine scar (residual myometrial thickness) in the view of the risk of rupture and the safest way of delivery. All this information is based on the most recent clinical trials. PMID- 25510069 TI - [Diagnosis and treatment of lichen sclerosus--review]. AB - Lichen sclerosus (LS) is a chronic skin disease of the vulva which affects mostly women in the postmenopausal period. The disease affects also men and children. Its frequency is from 1/70 up to 1/1000, whereas for women it is 10 times more frequently. The disease has unknown etiology. Due to the high frequency of accompanying, autoimmune diseases, it is presumed that this disease is a result of immunological processes. Some of patients diagnosed with LS have vulvar intraepithelial neoplasia, while 0.3% - 4.9% of them have squamous cell carcinoma. The aim of this review is to summarize our knowledge regarding the frequency, clinical features, diagnosis and therapy of LS in view of the prevention of the complications that may occur. MATERIAL AND METHODS: We researched the available literature and Medline on the topic for the period of 1971 until 2014 year. We summarized the most interesting, contemporary and scientifically substantiated facts regarding this disease. DISCUSSION: Early diagnosis, the proper and timely treatment, as well as the continuous follow up the patients with LS is mandatory due to the fact that the spontaneous remission is extremely rare and the complications may lead to significant deterioration of the quality of life. PMID- 25510070 TI - [Uterine smooth muscle tumors--determination of clinical behavior and classification]. AB - The establishment of the clinical behavior of uterine smooth muscle tumors /USMT/ is an essential stage of modern diagnostics. There are significant differences in the criteria determining the malignant potential of smooth muscle gynecological tumors. Generally USMT generating diagnostic problems are classified into: clinically benign tumors; clinically malignant tumors with benign morphological features; smooth muscle tumors of uncertain malignant potential (SMTUMP) and lesions whose smooth muscle differentiation is not obvious. The knowledge in this area is essential for an adequate therapeutic approach. PMID- 25510071 TI - [Application of inhaled nitric oxide in extreme preterm neonates with with BPD]. AB - Prolonged inhaled nitric oxide (iNO) from birth in preterm neonates with BPD improves endogenous surfactant function as well as lung growth, angiogenesis, and alveologenesis. As a result there is a reduction in the frequency of the "new" form of BPD in neonates under 28 weeks of gestation and birth weight under 1000 gr. Delivery of inhaled nitric oxide is a new method of prevention of chronic lung disease. According to a large number of randomized trials iNO in premature neonates reduces pulmonary morbidity and leads to a reduction of the mortality in this population of patients. This new therapy does not have serious side effects. PMID- 25510072 TI - [Pulmonary hypertension of the newborn--recent advances in the management and treatment]. AB - Pulmonary hypertension of the newborn is a clinical syndrome with diverse etiology in which the transition from fetal circulation with high pulmonary vascular resistance to postnatal circulation with low pulmonary vascular resistance failed. The persistence of high pulmonary vascular pressure leads to right-left shunts and marked cyanosis. Despite of the advances in neonatology, the treatment of some forms of PPHN is often difficult and mortality rate remains high. In infants with PPHN appropriate interventions are critical to reverse hypoxemia, improve pulmonary and systemic perfusion and preserve end-organ function. Our understanding for management of PPHN has evaluated over decades. This review summarizes the current strategies for treatment of pulmonary hypertension of the newborn: general care, cardiovascular support, the advantages and limitations of different ventilatory strategies, oxygen therapy, extracorporal membrane oxygenation, and the evidence-based inhaled nitric oxide therapy. The balance between pulmonary vasoconstrictor and vasodilator mediators plays an important role for pulmonary vascular resistance. Recent studies are designed to develop evidence-based therapies for regulation of pulmonary vascular tone, safe medications for selective pulmonary vasodilatation effective for treatment of PPHN and other forms of pulmonary hypertension in the neonatal intensive care unit. PMID- 25510073 TI - [A rare case of giant leiomyoma in postmenopausal woman]. AB - 67 years old patient with huge abdominal tumor cardiovascular and respiratory failure is admitted urgently in hospital. Diagnostic difficulties posed by that case as well as surgical intervention for removal of 23kg leiomyoma are presented. After uneventful postoperative period the patient is discharged from hospital in good general condition. PMID- 25510074 TI - [Giant cutaneous benign fibrous histiocytoma of the breast: successful surgical approach in a young female patient]. AB - Morphologically, the benign fibrous histiocytoma is a proliferation of the dermal areas and fibroblasts where the last may have a heterogenic localization in the human body. A number of malignant and benign skin lesions may be interpreted as a possible differential diagnosis. We are presenting a female patient with a tumor formation located under the right breast which, after the performance of an elliptical excision, was verified to be a benign fibrous histiocytoma with a tendency toward xantomatization. PMID- 25510075 TI - Colouring the human landscapes. Lennart Nilsson and the spectacular world of scanning electron micrographs. AB - This article explores the relationship between Swedish photographer Lennart Nilsson's scanning electron micrographs and commercial culture from the late 1960s to the mid-1980s. By retracing how Nilsson's micrographs of the internal structures of the human body were made, circulated, and received, its aim is to investigate three aspects of this relationship. First, it highlights how the complex and sometimes conflicting interplay between the photographer and various actors in science, industry and the media shaped the pictures and their trajectories. Second, it analyses the processes used to colour Nilsson's original black-and-white micrographs in relation to tendencies in the media and the advertising industry during this period. Third, it examines what motivated Nilsson and his collaborators in their use of colour and also the critical debates concerning the spectacular and commercial qualities of his pictures. In the concluding section, the implications of this analysis for the history of the objectivity of scientific images is discussed. PMID- 25510076 TI - Domenico Cirillo's collections. A recently rediscovered 18th-century Neapolitan herbarium. AB - The herbarium of the 19th-century Neapolitan botanists Vincenzo and Francesco Briganti was acquired by Orazio Comes in 1892 for the Royal Higher School of Agriculture in Naples. Based on a study of the handwriting on their labels, Comes concluded that some of the dried specimens were the sole remains of the herbarium of Domenico Cirillo, the distinguished 18th-century Neapolitan botanist, entomologist and physician. The current arrangement of the specimens not uniform and it is clear that they underwent extensive handling and rearrangement Some of the exsiccata are preserved in two packets, fixed on sheets bearing a printed label that reads "Herbarium D. Cyrilli". In an additional label Gaetano Nicodemi's handwriting and not Cirillo's as stated by Comes was identified. Other specimens, many of them mounted in a different manner from those in the first group, are arranged in another three packets. Certain characteristics of the herbarium may be explained by the vicissitudes of its history, including a hasty salvage operation. A study of the collection was conducted, including an analysis of the handwritten labels and notes, leading to conclusions that shed light on the significance of the Cirillo collection within the historical and scientific context of 18th-century Naples. PMID- 25510077 TI - The life history of whole-organism performance. AB - For almost 40 years, studies of whole-organism performance have formed a cornerstone of evolutionary physiology. Although its utility as a heuristic guide is beyond question, and we have learned much about morphological evolution from its application, the ecomorphological paradigm has frequently been applied to performance evolution in ways that range from unsatisfactory to inappropriate. More importantly, the standard ecomorphological paradigm does not account for tradeoffs among performance and other traits, nor between performance traits that are mediated by resource allocation. A revised paradigm that includes such tradeoffs, and the possible ways that performance and fitness-enhancing traits might affect each other, could potentially revivify the study of phenotypic evolution and make important inroads into understanding the relationships between morphology and performance and between performance and Darwinian fitness. We describe such a paradigm, and discuss the various ways that performance and key life-history traits might interact with and affect each other. We emphasize both the proximate mechanisms potentially linking such traits, and the likely ultimate factors driving those linkages, as well as the evolutionary implications for the overall, multivariate phenotype. Finally, we highlight several research directions that will shed light on the evolution and ecology of whole-organism performance and related life-history traits. PMID- 25510079 TI - Where does cognition occur: in one's head or in one's embodied/extended environment? AB - Turning points in science occur when an issue has reached maturity, when a critical mass of new facts cries out for a new synthesis, and when there is a general sense of urgency to reconsider basic assumptions" (von der Malsburg et al. 2010:xiii). PMID- 25510080 TI - [Neurohumoral effect of the dopaminergic system on development of alimentary constitutional obesity]. AB - Decrease in quantity and activity of dopamine receptors at patients with obesity is established. This leads to overeating, and abnormal weight gain. The article presents data on the impact of the dopaminergic system in the levels of leptin, prolactin, insulin, and the development of alimentary-constitutional obesity in these patients. PMID- 25510078 TI - Blood, bulbs, and bunodonts: on evolutionary ecology and the diets of Ardipithecus, Australopithecus, and early Homo. AB - Beginning with Darwin, some have argued that predation on other vertebrates dates to the earliest stages of hominid evolution, and can explain many uniquely human anatomical and behavioral characters. Other recent workers have focused instead on scavenging, or particular plant foods. Foraging theory suggests that inclusion of any food is influenced by its profitability and distribution within the consumer's habitat. The morphology and likely cognitive abilities of Ardipithecus, Australopithecus, and early Homo suggest that while hunting and scavenging occurred, their profitability generally would have been considerably lower than in extant primates and/or modern human hunter-gatherers. On the other hand, early hominid diet modelers should not focus solely on plant foods, as this overlooks standard functional interpretations of the early hominid dentition, their remarkable demographic success, and the wide range of available food types within their likely day ranges. Any dietary model focusing too narrowly on any one food type or foraging strategy must be viewed with caution. We argue that early hominid diet can best be elucidated by consideration of their entire habitat-specific resource base, and by quantifying the potential profitability and abundance of likely available foods. PMID- 25510082 TI - [The lipid acids spectrum of platelet in patients with new-onset and progressive angina]. AB - The coronary thrombosis is the main factor which leads to acute coronary syndrome. The mechanisms of the coronary thrombogenesis are not found out in detail. It was investigated the changes of the lipid acids spectrum of platelet membrane phospholipids in patients with unstable angina. PMID- 25510081 TI - [Endothelial dysfunction as a marker of vascular aging syndrome on the background of hypertension, coronary heart disease, gout and obesity]. AB - Under observation were 40 hypertensive patients with coronary heart disease, gout and obesity I and II degree. Patients with hypertension in combination with coronary heart disease, gout and obesity, syndrome of early vascular aging is shown by increased stiffness of arteries, increased peak systolic flow velocity, pulse blood presure, the thickness of the intima-media complex, higher level endotelinemia and reduced endothelial vasodilation. Obtained evidence that losartan in complex combination with basic therapy and metamaks in complex combination with basic therapy positively affect the elastic properties of blood vessels and slow the progression of early vascular aging syndrome. PMID- 25510083 TI - [Biomarkers of iron metabolism and inflammation in patients with chronic heart failure and various types of left ventricular dysfunction]. AB - Study the level of some of the indicators of iron metabolism and inflammatory markers in patients with chronic heart failure due to hypertension and coronary heart disease. The results of the study in systolic and diastolic dysfunction of the left ventricle, the varying degrees of severity of heart failure. The level of the studied parameters determined by the severity of heart failure and does not depend on the nature of left ventricular dysfunction. PMID- 25510084 TI - [Atypical risk factors of atherosclerosis in patients with hypothyroidism]. AB - The non-traditional risk factors for atherosclerotic lesions of the cardiovascular system (C-reactive protein, uric acid, fibrinogen, homocysteine) in blood plasma of patients with manifestative hypothyroidism at the age of 23 to 73 years were assessed in the study. An increase in the average values of C reactive protein was revealed in patients with hypothyroidism without arterial hypertension (AH), as well as under its presence, and increased BMI. Uric acid level also was increased with the combination of hypothyroidism and hypertension. Average level of fibrinogen was within the values of the control group and increased only in 23.4% of patients with hypothyroidism. Homocysteine content was elevated in 32% of patients and was not associated with the presence of AH. Increased levels of these markers of cardiovascular lesions risk coincided with the increased diameter of the common carotid artery. PMID- 25510085 TI - [Diagnostic algorithm for complicated calculous cholecystitis]. AB - This paper contains results of 312 patients who were examined and treated over complicated calculouscholecystitis Institute of Surgery and Transplantology named A. A. Shalimov NAMS of Ukraine from 2010 to 2012. Depending on the complexity of the diagnosis of the patients were divided into two groups. The first group--188 patients in which was enough to do a standard algorithm testing. The second group consisted of 124 patients in whom standard survey methods were insufficient to establish the correct diagnosis. PMID- 25510086 TI - [Proinflammatory cytokines in patients with pyelonephritis]. AB - The antiinflammatory cytokines participate in antiinfective immunity, that is why it is advisable to study their peculiarities in determination of the role in immunologic pathogenesis of pyelonephritis. Of the work is to study the levels of pro-inflammatory blood cytokines in the patients with pyelonephritis (PN), to determine the peculiarities in acute and chronic its course in children and adults. The immuno-enzymic method ELISA and the corresponding test-systems were used to study the levels of cytokines in blood. There were studied the levels of pro-inflammatory cytokines (TNF, MCP and IL-23) in blood serum of patients with acute (APN) and chronic (CPN) pyelonephritis. The analysis showed the reliable increase in levels of all studied findings in both forms of PN--both in all 173 patients and in every group--children (87) and adults (86). The MCP-1 levels in APN are reliably higher than in CPN, while in TNF-b and IL-23--do not differ. The levels of all three cytokines in blood of adults were higher than in children in APN, but TNF--in CPN as well. The high level of TNF, MCP-1 and IL-23 in blood of adults and children confirm their important role both in APN and CPN, but MCP-1 can be considered as a predictor of acute/exacerbation of chronic pyelonephritis. By the findings of the studied cytokines, more expressed immune response was noted in the adults. PMID- 25510087 TI - [Frequency of vitamin D deficiency in type 2 diabetes mellitus patients with obesity]. AB - The research has been carried out concerning the level of Vitamin D for patients suffering from Diabetes mellitus type 2 having obesity. The connection is revealed between Vitamin D deficit with the level of glycozilated hemoglobin and more effective decrease HbA1c for the patients who were given compensative treatment. PMID- 25510088 TI - [Psychological status of patients with different clinical variants of irritable bowel syndrome]. AB - In the study of psychological status of patients with different clinical variants of irritable bowel syndrome we found each variant to be characterized by worry, but the anxiety is typical only of IBS with diarrhea, while depression is typical of IBS with constipation in contrast to other IBS variants (nonspecific IBS and mixed IBS ones). PMID- 25510089 TI - [Comparison of the effectiveness of omeprazole and pantoprazole treatment of gastroesophageal reflux disease in patients with asthma]. AB - The combination of bronchial asthma with pathology of the digestive tract--one of the most frequent, clinically diverse and difficult, which complicates its course. The prevalence of gastroesophageal reflux disease in patients with asthma ranged from 33 to 90%. Aggravation of GERD is considered as one of the triggers of asthma attacks. The basis for treatment of GERD is acid suppression. Select proton pump inhibitors as the primary means of therapy related to their antisecretory action. Among the PPI pantoprazole can be identified that has high bioavailability, has minimal drug interactions with other drugs and a favorable safety profile. In patients taking pantoprazole pH-metry approached the norm, the proportion of time with pH < 4 decreased from 2 h 31 min to 52 min. On the background of pantoprazole indicators of lung function were better and significantly higher than in the groupwith omeprazole. Patients with combined pathology requiring compulsory treatment concomitant GERD, which will improve the course of asthma and help to achieve control. PMID- 25510090 TI - [Biochemical indices of connective tissue metabolism in patients with chronic hepatitis B and C]. AB - 37 patients with chronic hepatitis B and C were examined. Patients were divided into 3 groups depending on the degree of connective tissue dysplasia. We investigated: free and protein-bounded hydroxyproline, collagenase activity, total alkaline phosphatase and its bone fraction, creatinine, calcium and phosphorus content in the blood serum and urine. It has been found the dependence of collagen synthesis from the state of connective tissue. The higher is the degree of dysplasia, the more intensive is the process of collagen synthesis (P < 0.05). The index of corellation between protein-bounded and free fraction can be used as a biochemical marker for determination the stage of pathological process in the liver and for monitoring the effectiveness of therapy. PMID- 25510091 TI - [Surgical tactics at "difficult" perforative duodenal ulcers]. AB - Bacteriological research of abdominal cavities exsudate is conducted to 264 patients on perforative duodenal ulcers and the dynamics of peritonitis motion is studied in a postoperative period. It is set that already hour-long after the perforation of duodenal ulcer, according to information of peritoneal maintenance pH-metry and it's bacteriologic research, the optimum conditions for progress of inflammatory and infectious factors are created in an abdominal cavity. Therefore a formal term from the moment of perforation can not be the index of degree of inflammation (bacterial contamination) of peritoneum. The methods of duodenoplasty are improved at the giant perforative ulcers of duodenum and ulcers, combined with tubular stenosis of duodenum, allowed to avoid development of purulent-septic postoperative complications through insolvency of stitches and severe motor function disturbances. PMID- 25510092 TI - [About the impact of the dendritic cell autovaccine on the results of treatment of non-small-cell lung cancer patients]. AB - In thoracic department of the National Cancer Institute studied the effectiveness of dendritic cell autovaccine in the postoperative period in non-small-cell lung cancer patients. The results, showing good tolerance dendritic cell autovaccine. Shows the formation of the expressed antigen immune response after repeated injections dendritic cell autovaccine, as manifested after 4 revaccination. Results of survival patients non-small-cell lung cancer who received postoperative dendritic cell autovaccines demonstrate the high efficiency of the method and its applicability with a minimum of side effects. Further study of survival of patients non-small-cell lung cancer who received immunotherapy treatment, monitoring of compliance with the best mode of repeated injections. PMID- 25510093 TI - [Photoselective vaporization of the prostate using laser "greenlight" 120 w compared with monopolar transurethral resection]. AB - A total of 120 patients (60 vs 60 men in each group) were randomized. Median IPSS scores at 1 year follow-up were 11.8 +/- 1.9 for PVP versus 7.8 +/- 4.4 for TURP. Median length of stay was significantly shorter in the PVP group than in the TURP group, with a median of 2.4 +/- 1.3 versus 4.2 +/- 0.5, respectively (P < 0.01). Uroflowmetry parameters and complications were comparable in both groups. Sexual outcomes were better in the PVP group with statistical significance. PMID- 25510094 TI - [Studying the dynamics of the levels CD4+CD25+, CD4+ HLA-DR4 + and CD4+CD95+ cells in the semen of men with oligosymptomatic forms of chronic urogenital infection complicated infertility under the influence of fortege]. AB - The markers of activating of lymphocytes in sperm of men with the oligosymptomatic forms of chronic urogenital infection depending on fertility. It is set that the increasing of correlation of CD25/CD95 brings to growth of pathological forms of spermatozoa and, consequently, to the decline of impregnating ability of men. Fortege application leads to the normalization of this correlation and a reduction of pathological forms of sperm and thus to the increasing of the fertilizing potential. PMID- 25510095 TI - [The research of biodegradation of a composite material used in reconstructive and reparative surgery of maxillofacial area]. AB - Dates about the research of biodegradation of epoxy-polyurethane composite material used in reconstructive and reparative surgery of maxillofacial area are reflected in the article. Was founded: 1) notable biodegradation of species from epoxy-polyurethane composition in the term of observation up to 6 months was not founded. That testifies their preservation of physical and mechanical properties. 2) founded, that in species from epoxy-polyurethane composition, which contain levamisole, processes of biodegradation are faster then in species from pure epoxy-polyurethane composition and in species from epoxy-polyurethane composition with hydroxyapatite; 3) material from epoxy-polyurethane composition, which contains levamisole and hydroxyapatite, stays in biological environment in small quantity of petty fragments during the incubation in term of 2 years. So, it biodegrades practically totally. Authors suggest on the basis of achieved information, that the use of epoxy-polyurethane constructions that biodegrade, is pertinently in reconstructive maxillofacial surgery. PMID- 25510096 TI - [Antenatal factors of caries susceptibility formation in children]. AB - The role of the intrauterine growth retardation (IUGR) in the remodeling of a fetal parotid gland at late pregnancy has been presented in the paper. Thirty fetal parotid glands at 20-22 weeks gestation, including, 20--with IUGR and 10- at physiological pregnancy (control) were studied morphologically and morphometrically. Results have shown violations of gland's growth and differentiation, increased volume fraction of pathologic changes. Above mentioned processes may cause salivary glands' dysfunction, which eventually could result in child's dental caries. PMID- 25510097 TI - [Experemental modeling of ovary hyperstimulation syndrome in test animals]. AB - The experimental simulation of ovary hyperstimulation syndrome (OHSS) in test murine by administration with several dozes of exogenous gonadotropic hormones has been performed. It has been shown that mouse ovary hormone stimulation leads to manifestation of all OHSS symptoms: ovary swelling and hyperemia, injury of their structure, cystic corpus luteum formation, hemorrhagic follicles, folliculogenesis disturbance, oocyte and embryo morphology injury. The degree of OHSS symptom manifestation depends on hormone doze. On the third day after human chorionic gonadotropin administration all OHSS symptoms take place as an evidence of this syndrome prolonged character. PMID- 25510098 TI - [Conceptual foundations of creation of branch database of technology and intellectual property rights owned by scientific institutions, organizations, higher medical educational institutions and enterprises of healthcare sphere of Ukraine]. AB - The question of implementation of the state policy in the field of technology transfer in the medical branch to implement the law of Ukraine of 02.10.2012 No 5407-VI "On Amendments to the law of Ukraine" "On state regulation of activity in the field of technology transfers", namely to ensure the formation of branch database on technology and intellectual property rights owned by scientific institutions, organizations, higher medical education institutions and enterprises of healthcare sphere of Ukraine and established by budget are considered. Analysis of international and domestic experience in the processing of information about intellectual property rights and systems implementation support transfer of new technologies are made. The main conceptual principles of creation of this branch database of technology transfer and branch technology transfer network are defined. PMID- 25510099 TI - [Chlamydial infection morbidity in Lviv region during 1992-2012]. AB - An epidemiological analysis (in retrospective form) of registered chlamydial infection morbidity in Lviv region during 1992-2012 on the basis of Lviv Regional Dermatovenerology Dispensary was performed. Two trends were detected during the epidemiological study of STI dynamic in Lviv region during 1992-2012: the decline in the number of registered patients with gonorrhea, syphilis, trichomoniasis, and increase the number of people suffering from urogenital mycoplasmosis. Chlamydial infection during last years has tended to reduce the number of registered patients, although the rates of decline are negligible. The number of patients with Chlamydial infection is growing among rural population. PMID- 25510100 TI - [Monitoring of cardiovascular risk in patients with biliary dysfunction as an element of screening in the family physician's practice]. AB - Proposed and justified a screening algorithm to monitor the cardiovascular risk inpatients with biliary dysfunction. Defines the basic steps of monitoring these patients in the primary care level in terms of its development on the principles of general practice--family medicine. PMID- 25510101 TI - [Features of morbidity, hospitalization, incapacity of servicemen which accepted participating in international operations to support peace and security]. AB - The article analyzes the reasons for seeking medical care, the reasons for hospitalization, incapacity participants in international operations in support of peace and security, the structure of morbidity, hospitalization, and incapacity. PMID- 25510102 TI - [Professional medical education in Russia]. AB - There is a tendency to increase the role of education process in the life of the individual, caused by necessity of new knowledge, experience and skills, which is the effective measure to adapt human being to the current social and economic conditions. The idea of education as a relatively short period of life is gone. It becomes obvious, that use of forms and types of adult education becomes limited and inefficient. The development of the modern education system involves training with a high level of independence and leadership of the individual student; provision by vocational education institutions a wide range of educational services; adequate to the needs of the labor market; variability of methods and forms of education; active use of the modern educational technology as one of the most convenient ways of training. PMID- 25510103 TI - [Development of transgenic chicken with a gene of human granulocyte colony stimulating factor using sperm-mediated gene transfer]. AB - Transgenic poultry with a gene of human granulocyte colony-stimulating factor (gcsf) was developed by arti- ficial insemination with the transfected sperm using the "Lipofectamin 2000" reagent. The ratio of trans- genic chickens carrying the human gcsf genome was 33.3% of the total number of birds obtained. It was shown that the concentration-of the human G-csfprotein in blood serum oftransgenic specimens varied from 50 to 220 pg/ml. The first generation of poultry was obtained as a result of insemination oftransgenic hens by sperm of anti-transgenic cocks, thereby inheritance of the foreign gene was found in 37.5% of the obtained chickens. PMID- 25510104 TI - [Influx of Ca2+ via Car1.3 calcium channels in satellite cells of muscle fibers in rats ]. AB - Voltage-dependent L-type Cav1.3 channels have been detected in satellite cells localized to muscle fibers. It was established that the action of carbachol, which activates nicotinic acetylcholine receptors and causes cell membrane to depolarize, resulted in the activation of these channels. In addition, verapamil and amlodipine, selective L-type calcium channel blockers, suppressed extracellular calcium influx into the cytoplasm. It was noted that in a calcium free medium, carbachol had no influence on the concentration of calcium in the cytoplasm of satellite cells, whereas adrenaline induced calcium efflux from intracellular stores. In addition, calcium influx into the cytoplasm was not suppressed by verapamil and amlodipine under the action of adrenaline and noradrenalin in a medium with calcium, and an ICI- 118551 blocker of beta2 adrenoreceptros significantly decreased the increase in the concentration of calcium in the cytoplasm. PMID- 25510105 TI - [Characteristics of functioning of succinate dehydrogenase from flight muscles of the bumblebee Bombus terrestris (L.)]. AB - It was found that the succinate oxidation rate in mitochondria of flight muscles of Bombus terrestris L. in- creased by a factor of 2.15 after flying for 1 h. An electrophoretically homogenous preparation of succinate dehydrogenase with a specific activity of 7.14 U/mg protein and 81.55-fold purity was isolated from B. terrestris flight muscles. It is shown that this enzyme is represented in the muscle tissue by only one isoform with R,f = 0.24. The molecular weight of the native molecule and its subunits A and B was determined. The kinetic characteristics ofsuccinate dehydrogenase (Km = 0.33 mM) and the optimal concentration of hydrogen ions (pH 7.8) were established, and the effect of salts on the enzyme activity was studied. The role of succinate as a respiratory substrate in stress and the structural and functional characteristics of the succinate dehydrogenase system in the flight muscles of insects are discussed. PMID- 25510106 TI - [Informativity of some of the molecular markers most frequently used in population genetics of salmonids]. AB - The genetic parameters of donor and artificial populations of Siberian salmon (Oncorhynchus keta) have been analyzed. The parameters were obtained Wvith the use of different molecular markers as well as mathematic modeling based on experimental data. The difference between results is explained by the different resolving power of individual markers and/or stochastic effects. It is assumed that these factors together with temporal differentiation of spawning salmonid populations and the stable interpopulation gene flow constrain resolution of methods based on the use of molecular markers and designated for the analysis of differentiation of salmonid populations. PMID- 25510107 TI - [Metabolic isotopic effects of carbon and production process in cultivated plants in light of oscillatory concept for photosynthesis]. AB - Some perspectives on the use of stable carbon isotopes (13C/12C) in studying production processes are considered. It has been shown that the efficiency of the isotope technique depends on the adequacy of the chosen model. The model of isotope fractionation proposed based on the oscillatory concept of photosynthesis provides for more accurate and comprehensive description of the observed empirical correlations between the yield (bioproductivity) and carbon isotope composition in cereal cultures as compared with the widely used stationary model. PMID- 25510108 TI - [The content of phenolic compounds in medicinal plants of a botanical garden (Kaliningrad Oblast)]. AB - The total content of phenolic compounds and antioxidants has been determined in medicinal plants (66 species from 31 families). Promising plant species with high antioxidant activity and maximum content of phenols have been found. Based on these data, the plants can be used as a basis for making innovative functional food products with an increased antioxidant effect. PMID- 25510109 TI - [Relationship between the aggressiveness and catalase activity of Septoria nodorum berk. in wheat]. AB - A comparative study of hydrogen peroxide (H202) generation, the character of a fungal catalase gene expression, and the catalase activity in wheat plants, infected with Septoria nodorum Berk. strains differing in their aggressiveness, has been carried out. The decreased intensity of H202 accumulation in infected tissues, influenced by an aggressive S. nodorum strain and caused by the enhanced transcriptional activity of the fungal catalase gene and the heightened synthesis of its product, has been revealed to be more expressed compared to a similar decrease influenced by a less aggressive strain. An assumption was made that the expression activity of the catalase gene and, therefore, the activity ofcatalase involved in the regulation of the H202 content in the infected zone represent important factors providing high.aggressiveness and pathogenicity of S. nodorum. PMID- 25510110 TI - [Properties of the initial stages of embryoidogenesis in vitro in wheat calli of various origin ]. AB - The formation of embryoids obtained in vitro both in the culture of anthers and in the culture of the germs of spring soft wheat was analyzed using light microscopy and electron microscopy. The features ofembryoid for- mation in the calli of both types are detected. PMID- 25510111 TI - [Histological structure of tripartite mushroom bodies in ground beetles (Insecta, Coleoptera: Carabidae)]. AB - Contrary to members of the suborder Polyphaga; ground beetles have been found to possess tripartite mushroom bodies, which are poorly developed in members of basal taxa and maximally elaborated in evolutionarily advanced groups. Nevertheless, they do not reach the developmental stage, which has been previously found in particular families of beetles. It has been pointed out that anew formation of the Kenyon cells occurs during at least the first months of adult life, and inactive neuroblasts are found even in one-year-old beetles. It has been suggested that there is a relation between the Kenyon cell number and development of the centers of Kenyon cell new-formation. PMID- 25510112 TI - [Care of young, aggressiveness, and secretion of testosterone in male rodents: a correlation analysis ]. AB - To test the current hypotheses on the relationship between the mating system, reproductive strategy, aggression, and secretion of testosterone, a comparative study of interactions in pair encounters, the level of parental care, and the gonadal testosterone level in males was performed in six rodent species (Clethrionomys rutilus, Meriones meridianus, Microtus arvalis, Lagurus lagurus, Lasiopodomys Mandarinus, and Meriones unguiculatus) with different types of spatial-and-ethological population structures (SEPSs). It is shown that this. dependence is absent in species with promiscuous mating and dominance hierarchy among males (C. rutilus and M. meridianus, SEPS type II). A trade-off, or negative correlation, was found in M. arvalis-aspecies with weak pair bonds and male competition for receptive females (SEPS type III). In species with persistent pair bonds and structured family groups (L. Mandarinus and M. unguiculatus, SEPS type IV), no inverse relationship between the secretion of testosterone and paternal behavior was found either. Moreover, in male L. Mandarinus androgens appear to stimulate paternal care. PMID- 25510113 TI - [Dynamics of parasite communities in an age series of Arctic Cisco Coregonus migratorius (Georgi, 1775)]. AB - Parasite communities of Arctic cisco from Chivyrkui Bay of Lake Baikal have been analyzed at levels of a host individual (infracommunity), a individual age group of a host-(assemblages of infracommunities), and a host population (component community). Significant positive correlations of parameters of species richness (number of parasite species, Margalef and Menhinick indices) with the age of Arctic cisco were recorded only at the level of parasite inffacommunities. The absence of linear positive correlations between the parameters of species richness and the age of Arctic cisco at the level of assemblages of parasite infracommunities were revealed for the first time for fish of Lake Baikal. The peculiarity of the dynamics of parasite communities of. Arctic cisco is determined by specific features of the host physiology and ecology, primarily by the age dynamics of the feeding spectrum. PMID- 25510114 TI - [Conjugated variability of spontaneous activity and behavioral response to olfactory stimuli in the taiga tick (Ixodes persulcatus)]. AB - According to -the automatic tracing of the movement of ticks in a Petri dish, motivational variability of the spontaneous activity and behavioral response of the taiga tick to olfactory stimuli was analyzed. In the studied sample, two groups of ticks that differ in the movement trajectory in the absence of stimulus were isolated, including ticks that mainly moved on the edge of the dish at maximum accessible height (group 1) and ticks that mainly moved at the bottom and wall of the dish (group 2). It was registered that ticks of group 1 (as opposed to ticks of group 2) demonstrated a pronounced behavioral response to olfactory stimuli (human synthetic pheromones and ammonia) and negative geotaxis. It was established that belonging to these groups depended On the time of day when the testing was performed and did not depend on the physiological age and infectious status. PMID- 25510115 TI - [Distribution of fruit flies (Chloropidae: Meromyza Mg.) in Vologda oblast and east Poland]. AB - Species diversity and abundance of fruit flies from the genus Meromyza have been assessed in coastal biotopes, grasslands, and agro-ecosystems of Vologda oblast (Russia) and Warsaw province (Poland). The Jaccard quotient of similarity (IG) of fruit fly abundance has shown a uniformity between coastal banks and grasslands along these banks, as well as between cultivated cereals (except for oats) and field boundaries, cultivated fields, and some reach-in-herbs grasslands, including hayfields. Considerable heterogeneity of species composition of the flies has been revealed in similar biotopes. The biotopes studied have been found to be dominated by one species of fruit flies. It has been discovered that cereal rotation in agro-ecosystem results in change in the dominant species of fruit fly. The cereal height has been foundto influence the abundance and diversity of fruit flies. No regularities have been observed in the correlation between the abundances of fruit flies in different biotopes. It has been pointed out that M. nigriseta Fed. and M. veriegata Mg. can feed on cultivated cereals. PMID- 25510116 TI - [Spatial structure of acid properties of litter in the succession row of swamp birch woods ]. AB - The general potential, exchange, and actual (pH) acidities were investigated in the litter of the succession row of swamp birch woods. Their variabilities constitute, respectively, 75.9-174.4, 3.7-25.8 mmol (+)/100 g of the sampling, 3.7-5.5. For the first time, using the methods ofgeostatistics, their spatial variability was analyzed and the contributions of the trend, autocorrelation component, and the radius of the spatial correlation were estimated. It was established that in combination with the tree waste, which is uniformly distributed along the ecological profile, the specific composition of the grass moss tier, which corresponds to the humidity of edaphon, forms the picture of the spatial structure of acid properties of the litter. It was noted that the prime cause of variability consists in the particularities of the water regime of the habitats of swamp birch woods. PMID- 25510118 TI - [Sickle cell disease: patients, racism and indifference]. PMID- 25510117 TI - [A lengthy discussion concerning the composition of the Genus Margaritifera Schum., 1915 (Mollusca, Bivalvia)]. AB - The arguments given by Bolotov et al. (Ivz. Ross. Akad. Nauk, Ser. Biol., 2013, no. 2, pp. 245-256) were shown to be invalid because the allometric growth of mollusks was not taken into account. PMID- 25510119 TI - [Cannabis and road safety]. PMID- 25510120 TI - [Abces migrateur de Chompret-L'Hirondel abscess]. PMID- 25510121 TI - [Amyloidoses]. AB - Amyloidoses are rare diseases, defined by the accumulation of extracellular deposits with ultrastructural fibrillary organization, and molecular beta-pleated conformation. Amyloidoses are defined by the type of protein aggregates, the most common being immunoglobulin light-chains amyloidosis (AL). The treatment of AL amyloidosis has recently been improved by serum immunoglobulin light chains assay for close treatment monitoring; prognostic markers of cardiac damage such as BNP, NT-proBNP and troponin; and the emergence of new anti plasma cell drugs. AA amyloidosis should be screened by a search of proteinuria in every patient with chronic inflammatory disease. To diagnose rare hereditary amyloidoses requires to gather clinical, pathological and genetic data. Recent therapeutic advances showed efficacy of a molecule stabilizing transthyretin in early forms of amyloid neuropathy due to transthyretin mutations. PMID- 25510122 TI - [The bibliography of the thesis in 10 lessons: # 8]. PMID- 25510123 TI - [Hospital pay for performance: a major failure]. PMID- 25510124 TI - [The effect of a intermittent blockade of the vagus nerve on morbid obesity is disappointing]. PMID- 25510125 TI - [HIV infection. Screening, broadcast treatment and prevention of infection are now linked ]. PMID- 25510127 TI - [Prevention and screening of HIV infection ]. AB - The prevention of the HIV infection remains relevant considering the dynamics of the epidemic and the slackening of the preventive behavior of certain populations. The strategies associate initiatives of universal prevention: information, education, communication, screening; and specific actions in the direction of the most exposed populations. The paradigms of prevention evolved a lot these last years to take into account the preventive efficiency of antiretrovirals. If the condom remains the reference method, it is advisable for the populations the most exposed today to associate all the tools of prevention: behavioral methods, screening and antiretroviral. The possibility given to non governmental organizations to realize test of fast screening allowed to go to closer of the most exposed populations.The arrival on the market of the autotests must be supervised to touch the people who do not turn to the screening. PMID- 25510126 TI - [Overview of the HIV epidemics in France and worldwide ]. AB - In 2012, an estimated 35.3 million people were living with HIV worldwide and new HIV infections (2.3 million) were down 20% compared to 2001. Over the past year, tremendous progress has been achieved in the fight against HIV, including expanded access to antiretroviral therapy (ART) and services to prevent mother-to child transmission of HIV. However, progress is uneven. The regions most affected by HIV, Sub-Saharan Africa and the Caribbean, have seen a significant increase in ART coverage and drop in new HIV infections, while for other regions, such as the Middle East, North Africa, Eastern Europe and Central Asia, HIV trends have become worrisome. In many high-income countries, such as France, HIV epidemics are far from over, especially among men who have sex with men, where the HIV epidemic remains uncontrolled. Global, rapid scale-up of ART programs significantly decreased HIV/AIDS-related morbidity and mortality but has not been successful in preventing late HIV diagnosis. Reducing the time interval between HIV infection and diagnosis remains one of the biggest challenges that all HIV affected countries have to face to further reduce HIV/AIDS-related mortality and control the HIV epidemic. PMID- 25510128 TI - [Pre-exposure prophylaxis of HIV infection ]. PMID- 25510129 TI - [Primary HIV infection: still insufficiently detected! ]. PMID- 25510130 TI - [Initial antiretroviral therapy in HIV-infected patients]. AB - In 2014 an antiretroviral treatment should be initiated in any HIV-infected patient, whatever his/her CD4 lymphocyte count. The objectives of antiretroviral treatment are both individual (restoration or preservation of immune functions, decreased morbidity and mortality, decreased chronic systemic inflammation) and collective (decreased risk of HIV sexual transmission). Preferred initial regimens include two nucleoside reverse transcriptase inhibitors (tenofovir/emtricitabine or abacavir/lamivudine) plus a third agent, either a non nucleoside reverse transcriptase inhibitor (rilpivirine or efavirenz), or a ritonavir-boosted protease inhibitor (atazanavir or darunavir). Alternatively, the third agent may be chosen among integrase inhibitors (raltegravir, dolutegravir, elvitegravir/cobicistat). Immunologic and virologic response to first-line antiretroviral therapy should be monitored closely according to specific criteria and objectives. PMID- 25510132 TI - [Which future for HIV-infected children at adolescence and adulthood? ]. PMID- 25510131 TI - [Comorbidities in HIV infection and aging with HIV ]. AB - HIV infection has become a chronic condition with a life-long treatment. As AIDS related mortality is decreasing, persons living with HIV are aging, their life expectancy tending to reach that of the general population. Aging with the virus and on antiretroviral drugs is raising new challenges: "non AIDS-defining" cancers, cardiovascular diseases, osteoporosis, and maybe neurocognitive disorders represent a new set of comorbidities in this setting, and some of them are now becoming significant causes of death. It is now clear that risk factors for these conditions include the classical risk factors known in the general population, but also risk factors specifically related to the history of HIV infection and its treatment. As a consequence, treating persons with HIV infection now follows two main objectives: controlling the virus and taking long term comorbidities into account (prevention, testing and treatment). Specificitiesare linked to the existence of HIV-specific risk factors and to the problem of drug-drug interactions with antiretrovirals. PMID- 25510133 TI - [Giving care to immigrants living with HIV in France: stakes and specificities]. AB - Representing 40% of the new infections, immigrants living in France appear as a target population for prevention. Care givers have to adapt their practice in taking into account their specificities which are not restricted to cultural differences but include socio-economic determinants playing a major role. In addition to trainings on the foreigners rights and socio- cultural basic knowledge, care-givers (especially clinicians) have to give more time (especially at the beginning of the relationship) and to accept sharing the "medical power" with other people, including mediators, having the possibility of taking into account the other aspects of the patients' life in addition to the medical one. Assuming the fact there is no evidence for any difference regarding adherence between migrants and the other patients, this is probably the price to pay to insure long term therapeutic success. PMID- 25510134 TI - [HIV infection and social condition: a disease which remains singular]. AB - Increased efficacy of HIV therapy has resulted in a dramatic improvement in patient's health condition regarding life expectancy and life quality. However, such favorable evolution had no significant impact on the social condition of the population living with HIV, which remains more exposed to socio-economical difficulties and to different forms of stigmatization and discrimination. Public policies do address these issues. The national HIV/AIDS and STI strategic plan 2010-2014 provides a range of actions aimed at fighting against discriminations and improving social care for the most vulnerable people living with HIV. It notably tries to achieve equal access to programs and services developed for patients with chronic diseases and to improve their condition regarding access to care, employment, housing and income. Implementation of these measures, however, proves difficult. Addressing social and societal concerns that HIV infection still raises is part of the care and support that should be offered to patients. Providing this comprehensive approach remains critical for ensuring optimized individual therapeutic outcomes as well as an efficient collective response to the epidemic. PMID- 25510135 TI - [Lines of research in the treatment of HIV infection]. AB - Antiretroviral treatment have completely modified the face of HIV infection. Research of new therapeutic approaches during infection focus on the use of antiretroviral drugs and on new targets, treatment of immune activation and viral eradication. Recommendations for c-ART initiation are now broader. Future development in the area of antiretroviral therapy concern their use for prevention and the design of long-acting drugs. Extensive research efforts have led to the proposal of strategies that aim to treat immune activation which favor the occurrence of non AIDS defining disease and to eradicate HIV through the use of several different strategies (therapeutic vaccines, anti latency compounds). Results of these new approaches remain preliminary and antiretroviral treatment remain the only weapon to fight HIV infection. PMID- 25510136 TI - [Epidemiology of hemoglobin disorders]. PMID- 25510137 TI - [Hemoglobin disorders: an advantage against malaria, but the risk of severe disease]. PMID- 25510138 TI - [How to interpret an hemoglobin electrophoresis]. PMID- 25510139 TI - [Management of acute complications in sickle cell disease ]. AB - Acute complications in sickle cell disease are a major and life-long cause for hospital referral. The most frequent events are painful acute vaso-occlusive crisis involving the limbs and back, and acute chest syndrome. Acute vaso occlusive crisis is a therapeutic emergency because of the very high level of pain. Acute chest syndrome may be potentially fatal and must be adequately searched for and treated. Sickle cell patients are susceptible to pneumococcal infections notably, but any infection may favour vaso-occlusive crisis. Triggers of sickle cell vase occlusion must be tracked and corrected, if possible. Moderate crisis can be managed at home, but referral is necessary as soon as opiates are needed and/or if acute chest syndrome is suspected. Additional treatments besides opiates include co analgesics, oxygen, hydration, physiotherapy. Blood transfusion may be required but is not systematic. Acute spleen sequestration occurs in young children and requires immediate hospital referral for transfusion. PMID- 25510140 TI - [Chronic complications of sickle cell disease]. AB - Chronic complications of sickle cell disease take an increasing role in the management of patients due to their morbidity and mortality impact. The prevalence of chronic organ damages increases as the age of patients followed in France. Few organs seem unaffected by the disease. The natural history of chronic complication is highly variable from one patient to another, and the distribution of those manifestations throughout life, is different depending on their nature and pathophysiology. Thus we can, for example, distinguish SS patients presenting a "hyperhemolytic" phenotype associated with dense red blood cells that have a high risk of vascular complications including kidney disease, pulmonary hypertension, leg ulcers and priapism, from SC patients with high hemoglobin levels, who have a higher risk of retinopathy, osteonecrosis and sensory syndrome, probably related to hyperviscosity. Dependent on the age, we could also oppose cerebral vasculopathy responsible of ischemic stroke since childhood, and kidney damage which effects are visible more gradually with aging. Sickle cell disease is one of the most systemic pathologies contrasting with its monogenic characteristic and its inter- and intra-individual variability. A better understanding of pathophysiological mechanisms responsible for those complications is necessary to develop new preventive and therapeutic approaches. PMID- 25510141 TI - [Treatment with hydroxyurea has revolutionized the evolution of sickle cell disease ]. PMID- 25510142 TI - [Risks associated with transfusions in sickle cell disease: delayed hemolytic transfusion reaction]. PMID- 25510143 TI - [Indications for allogeneic hematopoietic stem cell transplantion in sickle cell disease]. PMID- 25510144 TI - [Clinical management of beta-thalassaemia]. AB - Beta-thalassemia syndromes are autosomal recessive disorders related to the inability to produce beta-globin chains. Thalassemia major is by definition a transfusion dependent anemia and iron overload is the leading cause of death and morbidity. Beta-thalassemia is rarely encountered in France where patients mainly originated from Mediterranean countries and South East Asia. Recently, two major advances have substantially improved the disease management: oral iron chelation therapy and the introduction of cardiac MRI for monitoring cardiac iron. Hematopoietic stem cell transplantation remains, in clinical practice, the only curative approach and is proposed to children having an HLA-identical sibling. Diagnosis of thalassemia trait is important in order to propose genetic counseling to couples at risk. Thalassemia intermedia is a clinical entity where anemia is mild or moderate, requiring no or occasional transfusion. Clinical severity increases with age with a more severe anemia, thrombotic complications and extra-medullary hematopoiesis. Iron overload, optimally monitored with liver MRI, occurs in adult patients and is related to increased iron hyper-absorption. PMID- 25510145 TI - [Thalassemia alpha]. PMID- 25510146 TI - [Teaching medicine in 2014 (and forward)]. PMID- 25510147 TI - [Predictors of pre-eclampsia]. PMID- 25510149 TI - [Infective endocarditis]. PMID- 25510148 TI - [Management of pre-eclampsia]. PMID- 25510150 TI - [Pruritus]. PMID- 25510151 TI - [How to explore pruritus?]. PMID- 25510152 TI - [Sleep disorders in children and adults]. PMID- 25510153 TI - Quantitative 3-dimensional computed tomography measurements of coronoid fractures. AB - PURPOSE: Using quantitative 3-dimensional computed tomography (Q3DCT) modeling, we tested the null hypothesis that there was no difference in fracture fragment volume, articular surface involvement, and number of fracture fragments between coronoid fracture types and patterns of traumatic elbow instability. METHODS: We studied 82 patients with a computed tomography scan of a coronoid fracture using Q3DCT modeling. Fracture fragments were identified and fragment volume and articular surface involvement were measured within fracture types and injury patterns. Kruskal-Wallis test was used to evaluate the Q3DCT data of the coronoid fractures. RESULTS: Fractures of the coronoid tip (n = 45) were less fragmented and had the smallest fragment volume and articular surface area involvement compared with anteromedial facet fractures (n = 20) and base fractures (n = 17). Anteromedial facet and base fractures were more fragmented than tip fractures, and base fractures had the largest fragment volume and articular surface area involvement compared with tip and anteromedial facet fractures. We found similar differences between fracture types described by Regan and Morrey. Furthermore, fractures associated with terrible triad fracture dislocation (n = 42) had the smallest fragment volume, and fractures associated with olecranon fracture dislocations (n = 17) had the largest fragment volume and articular surface area involvement compared with the other injury patterns. CONCLUSIONS: Analyzing fractures of the coronoid using Q3DCT modeling demonstrated that fracture fragment characteristics differ significantly between fracture types and injury patterns. Detailed knowledge of fracture characteristics and their association with specific patterns of traumatic elbow instability may assist decision making and preoperative planning. CLINICAL RELEVANCE: Quantitative 3DCT modeling can provide a more detailed understanding of fracture morphology, which might guide decision making and implant development. PMID- 25510154 TI - Long-term functional outcomes after bilateral total wrist arthrodesis. AB - PURPOSE: To report on the long-term outcomes of bilateral total wrist arthrodeses. METHODS: We conducted a review of all living patients who underwent bilateral wrist arthrodeses from 1980 to 2010 within a single institution. Outcome measures included pain, Disabilities of the Arm, Shoulder, and Hand questionnaire, Patient-Rated Wrist Evaluation, Michigan Hand Questionnaire, satisfaction scores, complications, and revision surgeries. RESULTS: Thirteen patients (26 wrists) were treated with an average follow-up of 14 years (range, 3 28 y). Average time for contralateral wrist arthrodesis was 16 months after initial wrist arthrodesis. Eleven wrists had undergone prior surgery. Eleven patients had a primary diagnosis of inflammatory arthritis. Wrists were fused from 5 degrees flexion to 30 degrees extension, with all but one patient's wrist fused within 10 degrees of the contralateral wrist. There was a significant improvement in postoperative grip strength and pain levels. Postoperative Disabilities of the Arm, Shoulder, and Hand, Patient-Rated Wrist Evaluation, and Michigan Hand Questionnaire scores were 21, 29, and 73, respectively. Increasing age, preoperative steroid usage, and concomitant shoulder or elbow disorders were associated with worse outcomes. Twelve patients (93%) were satisfied and would repeat the surgery and 9 returned to full-time work. The major functional limitation was turning a doorknob or tight jar lid. Seven patients underwent additional surgery including 5 revision arthrodeses and 2 plate removals. Revision surgeries were more common in patients with prior surgeries or preoperative steroid usage, women, smokers, those with ipsilateral elbow dysfunction, and those with fixation with a dorsal locking plate. CONCLUSIONS: Bilateral total wrist arthrodesis improved pain while enabling patients with severe carpal arthrosis to maintain a satisfactory level of extremity function and quality of life. In general, patients adapted and were satisfied with functional capabilities. This is a viable salvage option for patients with severe bilateral disease. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 25510155 TI - Proximity of the posterior interosseous nerve during cortical button guidewire placement for distal biceps tendon reattachment. AB - PURPOSE: To assess the distance between the posterior interosseous nerve (PIN) and a distally and ulnarly directed guide pin for placement of a cortical button to reattach a distal biceps tendon. METHODS: We used 10 fresh frozen cadaveric upper limbs without deformities and identified the PIN through a dorsal approach. We performed a single incision anterior surgical approach, detached the biceps tendon, and drilled a 1.6-mm K-wire from the base of the biceps tendon insertion in 3 different trajectories, sequentially, measuring the following drilling angles: 30 degrees distal and 30 degrees ulnar, 30 degrees ulnar, and 30 degrees distal. In each testing scenario, we measured the minimum distance in millimeters between the tip of the K-wire and the PIN using a digital caliper through the dorsal incision. RESULTS: The mean and median distances from the guide wire to the PIN in each testing trajectory were each significantly different from each other, with the 30 degrees ulnar direction leading to the greatest distance from the nerve. CONCLUSIONS: We found that the 30 degrees ulnar drilling direction resulted in a significantly greater distance from the guide wire to the PIN, in comparison with the distal-ulnar and the distal-only trajectories. CLINICAL RELEVANCE: This study helps define the safe trajectory for guide wire placement in bicortical fixation of distal biceps tendon injuries. PMID- 25510156 TI - The effect of capitellar impaction fractures on radiocapitellar stability. AB - PURPOSE: To determine the effect of capitellar impaction fractures on radiocapitellar stability in a model that simulated a terrible triad injury. METHODS: Six cadaveric elbows were dissected free of skin and muscles. Tendons were preserved. The lateral collateral ligament was released and repaired (surgical control). Two sizes of capitellar impaction defects were created. After lateral collateral ligament release and repair, we then sequentially created osseous components of a terrible triad injury (partial radial head resection and coronoid fracture) through an olecranon osteotomy that was fixed with a plate. Radiocapitellar stability was recorded after the creation of each new condition. RESULTS: Significantly less force was required for radiocapitellar subluxation after the creation of 20 degrees and 40 degrees capitellar defects compared with the surgical control (intact capitellum). After the addition of a Mason type II radial head defect and then a coronoid defect, stability decreased significantly further. CONCLUSIONS: Impaction fractures of the distal portion of the capitellum may contribute to a loss of radiocapitellar stability, particularly in an elbow fracture-dislocation. CLINICAL RELEVANCE: Because these injuries may be unrecognized, consideration should be given to diagnosing and addressing them. PMID- 25510157 TI - A modular surface gliding implant (CapFlex-PIP) for proximal interphalangeal joint osteoarthritis: a prospective case series. AB - PURPOSE: To evaluate the one-year postoperative clinical and patient-rated outcomes in patients receiving proximal interphalangeal (PIP) joint arthroplasty with a modular surface gliding implant, CapFlex-PIP. METHODS: 10 patients each with primary osteoarthritis of a single PIP joint were assessed preoperatively (baseline), at 6 weeks, and 3, 6, and 12 months after CapFlex-PIP arthroplasty for lateral stability and range of motion of the affected digit. In addition, patients rated their pain using a numeric rating scale and function and overall assessment of their treatment and condition using the quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) and Patient Evaluation Measure (PEM) questionnaires, respectively. RESULTS: The mean baseline active mobility of the affected PIP joint increased from 42 degrees to 51 degrees by one year, although this change was not significant. Patients reported reduced pain at one year, which was statistically significant. There was also a significant improvement between baseline and one-year QuickDASH (43 points vs 15 points, respectively) and PEM scores (51 vs 25 points, respectively). Absent or low lateral instability was observed in 9 joints at follow-up. All implants remained intact over the one-year postoperative period and there was no migration, osteolysis, or implant fracture. After study completion, 2 patients underwent tenolysis. CONCLUSIONS: Patients experienced a significant reduction in pain and a trend towards increased mobility. All implants showed complete osteointegration without evidence of radiological migration. Lateral stability improved. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 25510158 TI - A systematic review of outcomes reporting for brachial plexus reconstruction. AB - PURPOSE: To better understand the manner in which outcomes are reported after brachial plexus reconstruction, we conducted a systematic review of the scientific literature. METHODS: We included English-language articles describing treatment of brachial plexus injuries to restore motor function of the shoulder, elbow, forearm, and/or wrist with nerve repair, nerve graft, and/or nerve transfer. We recorded the anatomical location of injury, the treatment used, and the manner in which motor function, active and passive range of motion, pain, quality of life, function or disability, patient satisfaction, and psychosocial health was reported. RESULTS: In reviewing 88 papers with outcomes for 5,189 patients, 83 (94%) of the papers reported postoperative motor function. Of these, 49 (59%) did not include any other measures of patient outcome. Active range of motion was reported in 24 (27%) studies, pain was reported in 15 (17%) studies, quality of life was reported in 4 (5%) studies, function or disability was reported in 5 (6%) studies, patient satisfaction in 3 (3%) studies, and psychosocial health in 1 study. CONCLUSIONS: To date, outcome reporting for brachial plexus surgery has largely centered on motor recovery and typically has not included measures of function or nonmusculoskeletal recovery. Incorporating currently used measures of physical recovery with patient-derived outcomes measures such as quality of life, function, pain, and satisfaction will likely help provide a more comprehensive understanding of the effect of brachial plexus reconstruction surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 25510160 TI - Contact quotient versus closed quotient: a comparative study on professional male singers. AB - OBJECTIVES: The term "closed quotient" is frequently used for data derived both from inverse filtering and from electroglottography. In the former case, it is defined as the ratio between the closed phase and the period, as measured in flow glottograms (FLOGG), whereas in the latter case, it is defined as the time interval between the falling and rising parts of the electroglottogram (EGG), measured at some percentage of the peak-to-peak amplitude. The study aims at analyzing differences between EGG- and FLOGG-based closed quotients and their relationships with voice source parameters. STUDY DESIGN: Comparative study. METHODS: FLOGG- and EGG-based measures collected from five professional male singers were compared, under different pitch and loudness conditions. RESULTS: Compared with the FLOGG-based quotient, the EGG-based quotient (i) varied more between subjects, (ii) presented greater values, (iii) varied less with subglottal pressure, (iv) varied less with the normalized amplitude quotient (ie, the ratio between the flow pulse amplitude and the product of period and maximum flow declination rate), and (v) varied less with the relative amplitude of the voice source fundamental. CONCLUSIONS: Although positively related, FLOGG- and EGG-based closed quotients differ and must not be confused. PMID- 25510159 TI - Proteins in aggregates functionally impact multiple neurodegenerative disease models by forming proteasome-blocking complexes. AB - Age-dependent neurodegenerative diseases progressively form aggregates containing both shared components (e.g., TDP-43, phosphorylated tau) and proteins specific to each disease. We investigated whether diverse neuropathies might have additional aggregation-prone proteins in common, discoverable by proteomics. Caenorhabditis elegans expressing unc-54p/Q40::YFP, a model of polyglutamine array diseases such as Huntington's, accrues aggregates in muscle 2-6 days posthatch. These foci, isolated on antibody-coupled magnetic beads, were characterized by high-resolution mass spectrometry. Three Q40::YFP-associated proteins were inferred to promote aggregation and cytotoxicity, traits reduced or delayed by their RNA interference knockdown. These RNAi treatments also retarded aggregation/cytotoxicity in Alzheimer's disease models, nematodes with muscle or pan-neuronal Abeta1-42 expression and behavioral phenotypes. The most abundant aggregated proteins are glutamine/asparagine-rich, favoring hydrophobic interactions with other random-coil domains. A particularly potent modulator of aggregation, CRAM-1/HYPK, contributed < 1% of protein aggregate peptides, yet its knockdown reduced Q40::YFP aggregates 72-86% (P < 10(-6) ). In worms expressing Abeta1-42, knockdown of cram-1 reduced beta-amyloid 60% (P < 0.002) and slowed age-dependent paralysis > 30% (P < 10(-6)). In wild-type worms, cram-1 knockdown reduced aggregation and extended lifespan, but impaired early reproduction. Protection against seeded aggregates requires proteasome function, implying that normal CRAM-1 levels promote aggregation by interfering with proteasomal degradation of misfolded proteins. Molecular dynamic modeling predicts spontaneous and stable interactions of CRAM-1 (or human orthologs) with ubiquitin, and we verified that CRAM-1 reduces degradation of a tagged-ubiquitin reporter. We propose that CRAM-1 exemplifies a class of primitive chaperones that are initially protective and highly beneficial for early reproduction, but ultimately impair aggregate clearance and limit longevity. PMID- 25510161 TI - Frequency measurement of vowel formants produced by Brazilian children aged between 4 and 8 years. AB - OBJECTIVE: To investigate frequency measurement of the first three formants of the seven oral Brazilian Portuguese vowels of healthy children aged 4-8 years. METHODS: Two hundred seven children of both genders were selected by oral expression screening and perceptive-auditory analysis. They were separated into four age groups (G1, G2, G3, and G4) and by gender. The voice signals were obtained from key sentence utterance and segments of the seven Brazilian Portuguese oral vowels in tonic position used to estimate formant frequency measurement. Software Praat was used to for processing the recordings. RESULTS: Findings were presented by mean values of each of the investigated parameters. A rate of 61.90% of statistically significant differences between genders was found, and when analyzing the age groups and genders, we observed that 65 of the 84 items studied (seven vowels * three formant frequencies * four groups) had higher frequencies of formants for girls. There was a decrease in the frequencies values of the first three formants with age. The results recommended grouping of G1 and G2, and they showed a clear difference between this new formed group and G4. In the age groups of 5-year old to 6 years 11 months (G2 and G3) and 6-year old to 7 years 11 months (G3 and G4), there were statistically significant changes that were random for parameter and vowel. There was a decrease in the frequencies values of the first three formants with age. CONCLUSION: Formant frequencies showed a tendency to differentiate genders and their absolute values were in general higher in girls. Age increases showed decreases in formant frequencies. Tests for statistical differences led to grouping of G1 and G2 and a clear difference between this new formed group and G4. The comparison between G2 and G3 and G3 and G4 showed random changes. The changes during this age period (5 year old to 7 years 11 months) were attributed to a transition stage of acoustic measurements in children. As formant frequencies vary according to structural and postural aspects of the vocal tract and speech organs, their study in healthy children contributes for the understanding of the development of the pediatric phonation system, in addition to offering a reference data set for future studies of children with vocal disorders that can potentially impact the resonance system. PMID- 25510162 TI - Relationships among smoking, organic, and functional voice disorders in Korean general population. AB - OBJECTIVE: The relationship between smoking and voice disorders is still controversial. This study has investigated the relationship between voice disorders and smoking by using a nationwide representative survey of the Korean population. STUDY DESIGN: Cross-sectional analysis of a national health survey. METHODS: The study sample 7941 Korean adults, aged 19 years or older (3422 men and 4519 women), who participated in the fifth Korea National Health and Nutrition Examination Survey, a nationwide representative survey of the noninstitutionalized population of the Republic of Korea. Laryngeal disorders were classified into functional voice disorders (vocal cord nodule, vocal polyp, Reinke edema, and laryngitis) and organic voice disorders (sulcus vocalis, vocal cyst, laryngeal granuloma, laryngeal keratosis, laryngeal leukoplakia, laryngeal papilloma, and suspected malignant neoplasm of the larynx). Multinomial logistic regression analyses were conducted to examine the association between smoking and voice disorders. RESULTS: Adjusting for covariates (age, gender, education level, occupation, income, alcohol drinking, self-reported voice problems, and self reported health status), past smokers (odds ratio (OR) = 2.97, 95% confidence interval (CI): 1.14-9.03) and current smokers (OR = 3.22, 95% CI: 1.18-10.25) compared with nonsmokers, were more likely to have organic voice disorders. However, smoking was not associated with functional voice disorders. CONCLUSIONS: Smoking is independently associated with organic voice disorders in the Korean general population. PMID- 25510163 TI - Postviral Vagal Neuropathy: What Is the Role of Laryngeal Electromyography in Improving Diagnostic Accuracy? AB - OBJECTIVES: To investigate the convenience of laryngeal electromyography (EMG) findings in patients with chronic cough thought to be postviral vagal neuropathy (PVVN) with the clinical symptoms. STUDY DESIGN: Prospective cohort study. METHODS: We applied PVVN questionnaire and chronic cough quality of life (QoL) questionnaire, which is for determining the effect of chronic cough on the QoL, to 20 chronic cough applicants who has no explanatory cause in differential diagnosis. We also carried out videolaryngostroboscopy (VLS) and laryngeal needle EMG in these patients. RESULTS: The mean duration of persisting cough was 1.875 months (SD +/-0.825). The overall mean symptom score of chronic cough questionnaire was 58.80 (SD +/-9.89). There was a significant positive correlation between total EMG score and chronic cough score (Spearman r, 0.489, P < 0.05). The correlation between VLS findings and either chronic cough scores or EMG scores did not reach statistical significance. CONCLUSIONS: Cranial nerves might be affected by inflammatory processes as occur in the PVVN, which must be considered in the etiology of chronic cough. We showed that the laryngeal EMG can be used as an appropriate diagnostic tool for these patients. PMID- 25510164 TI - Effects of vocal demands on voice performance of student singers. AB - PURPOSE: The objective of this study was to investigate the effect of cumulative vocal demands on the voices of music students majoring in voice throughout an academic semester. METHOD: Acoustic and aerodynamic voice parameters captured across an academic semester were analyzed. This study was designed as a time course investigation, in which all participants were tested individually at three separate times distributed equally over an academic semester. General effects were verified with the application of one-way within-participants analysis of variances with repeated measures. The equipment used for monitoring vocal behavior consisted of the Computerized Speech Lab, the Phonatory Aerodynamic System, and the Ambulatory Phonation Monitor, computer-based systems for the assessment of voice. Self-reported data regarding voice usage were also collected. RESULTS: In this study, comparisons of voice parameters of student singers repeatedly measured throughout an extended period of time did not lead to statistically significant differences. Self-reported information suggested a reasonable level of knowledge and awareness regarding voice concerns in this population. CONCLUSIONS: The results of this study indicated consistent stability of voice acoustic and aerodynamic parameters in this group throughout an academic semester. PMID- 25510165 TI - Short- and long-term outcomes after silastic medicalization laryngoplasty: are arytenoid procedures needed? AB - OBJECTIVE: To evaluate short- and long-term vocal outcomes after medialization laryngoplasty (ML) using a silastic implant in patients with unilateral vocal fold paralysis (UVFP). DESIGN AND METHODS: Prospective study of consecutive patients undergoing ML with silastic (MLS) diagnosed with UVFP from 2009 till 2012 and with at least 9 months follow-up. Pre- and post-treatment maximum phonation time (MPT) and voice handicap index (VHI) scores were compared to assess the impact of ML on these outcomes. Patients with high vagal lesions or lateralized vocal folds (very low MPT) were compared with the entire group and the literature. RESULTS: A total of 124 patients with UVFP underwent MLS. Forty six patients were excluded as they either had a Gore-Tex implant (eight), short follow-up (20), or the primary case was a revision (18). Seventy-eight patients were included. Pretreatment mean VHI (total score) was 67 for the entire cohort. Postoperative VHI score was significantly lower both in short-term (3-8 weeks) follow-up, mean score 27 (paired t-test, P < 0.05) and in long-term follow-up (9 12 months), mean score 22 (P < 0.05). MPT was significantly improved from 8.3 pretreatment to 22.6 at short-term follow-up (P < 0.05) and to 24.2 long-term follow-up (P < 0.05). There were no significant differences between entire cohort and patients with a lateralized vocal fold or high vagal lesion. Comparable results were present when compared with the literature using similar metrics in patients undergoing an arytenoid procedure with/without medialization. CONCLUSION: MLS alone is effective in managing UVFP in most patients. PMID- 25510166 TI - Reduced set averaging of face identity in children and adolescents with autism. AB - Individuals with autism have difficulty abstracting and updating average representations from their diet of faces. These averages function as perceptual norms for coding faces, and poorly calibrated norms may contribute to face recognition difficulties in autism. Another kind of average, known as an ensemble representation, can be abstracted from briefly glimpsed sets of faces. Here we show for the first time that children and adolescents with autism also have difficulty abstracting ensemble representations from sets of faces. On each trial, participants saw a study set of four identities and then indicated whether a test face was present. The test face could be a set average or a set identity, from either the study set or another set. Recognition of set averages was reduced in participants with autism, relative to age- and ability-matched typically developing participants. This difference, which actually represents more accurate responding, indicates weaker set averaging and thus weaker ensemble representations of face identity in autism. Our finding adds to the growing evidence for atypical abstraction of average face representations from experience in autism. Weak ensemble representations may have negative consequences for face processing in autism, given the importance of ensemble representations in dealing with processing capacity limitations. PMID- 25510167 TI - Case report of pigmented villonodular synovitis arising from the calcaneocuboid joint in a 12 year old male. AB - INTRODUCTION: Pigmented villonodular synovitis (PVNS) is a benign proliferative disorder of the synovium of unknown aetiology. It usually presents in adults between the ages of 30 and 40 years of age and is rare in the paediatric population. In the literature, there are a total of 43 cases of PVNS affecting the paediatric population and only one case affecting the calcaneocuboid joint. METHODS: We report a case of diffuse PVNS affecting the calcaneocuboid joint of a 12 year old male. The patient presented with a 3 month history of a painless swelling affecting the lateral aspect of the hindfoot region with no preceding history of trauma. Examination revealed a lesion which was firm in texture, originating in the region of the calcaneocuboid joint, and clinically appeared to originate from deeper structures with no overlying skin changes or warmth. Routine blood tests were within normal limits. Radiographs demonstrated an erosive lesion into the calcaneocuboid joint and magnetic resonance imaging demonstrated a lesion consistent with PVNS. RESULTS: Following surgical excision of the lesion, the patient recovered to full activities after a brief period of immobilisation in plaster to allow wound healing. At six months follow-up, there was no evidence of recurrence. CONCLUSIONS: Our case report of PVNS involving the calcaneocuboid joint is only the second report in the literature and highlights the importance of considering PVNS as a differential diagnosis in children presenting with swelling of the foot and ankle with normal blood and clinical parameters. The combination of the case report along with radiographic and magnetic resonance imaging and intra-operative photographs also aids the reader in understanding of the condition. PMID- 25510168 TI - Bilateral tarsometatarsal joint injuries: An unusual mechanism producing unusual variants. AB - Tarsometatarsal (Lisfranc) joint injuries are rare but potentially devastating conditions requiring anatomical reduction and internal fixation or arthrodesis. We describe an unusual mechanism involving forced eversion and dorsiflexion on both fully supinated feet resulting in bilateral tarsometatarsal joint injury. The injury pattern involved incongruity between the medial and middle columns extending between the cuneiform bones with associated fracture of the cuboid on the right and the cuboid, os calcis and talus on the left. Operative fixation is discussed and the clinical outcome was good at 4 years post-operatively. We believe this introduces an additional and potentially serious mechanism of injury and pattern of ligamentous and osseous disruption into the pantheon of injuries classed as Lisfranc, which surgeons should be aware of. Furthermore, we recommend attention to the mechanism of injury in consideration with classification to aid in operative reduction and fixation. PMID- 25510169 TI - Mental wellbeing amongst younger and older migrant workers in comparison to their urban counterparts in Guangzhou city, China: a cross-sectional study. AB - BACKGROUND: There has been a dramatic increase in internal migrant workers in China over recent decades, and there is a recent concern of poor mental health particularly amongst younger or "new generation" migrants who were born in 1980 or later. METHODS: A cross-sectional study was conducted in Guangzhou city between May and July in 2012. Mental wellbeing was measured using the World Health Organization Five-item Well-Being Index Scale and the 36 Item Short Form Health Survey mental health scale. Linear and logistic regression models were used to investigate the differences between migrant workers and their urban counterparts and between younger and older migrants. RESULTS: Migrant workers (n = 914) showed a small but significant advantage in mental wellbeing compared to their urban counterparts (n = 814). There was some evidence for age modification effect (p for interaction = 0.055-0.095); better mental wellbeing in migrants than urbanites were mainly seen in the older compared to the younger group, and the difference attenuated somewhat after controlling for income satisfaction. Older migrants showed better mental health than younger migrants. Factors that were independently associated with poor mental health in migrants included being male, longer working hours, and income dissatisfaction, whilst older age, factory job, high income, and increased use of social support resources were associated with reduced risk. CONCLUSIONS: Efforts to promote mental health amongst migrant workers may be usefully targeted on younger migrants and include measures aimed to improve working conditions, strengthen the social support network, and address age-specific needs. PMID- 25510170 TI - Demographic, socioeconomic and clinical correlates of self-management in multiple sclerosis. AB - PURPOSE: Our aim was to identify demographic, clinical and socioeconomic predictors of self-management in multiple sclerosis (MS). METHODS: The study was performed on a group of 283 patients with multiple sclerosis who completed Multiple Sclerosis Self-Management Scale - Revised (MSSM-R), Multiple Sclerosis Impact Scale (MSIS-29), Actually Received Support Scale (part of Berlin Social Support Scale), Expanded Disability Status Scale (EDSS) and Socioeconomic resources scale. Patients were recruited through cooperation with Multiple Sclerosis Rehabilitation Centre in Borne Sulinowo and Polish Society of Multiple Sclerosis. Demographic and illness-related problems were determined with self report survey. RESULTS: The group consisted of 185 women and 98 men, with a mean age of 48 years. The level of disability and disease severity varied, mean time elapsed since MS diagnosis was 13 years. The final predictive model of self management in MS was based on two main predictors: received support and available socioeconomic resources. Patients with MS who received adequate support from the closest relatives (R(2 )= 0.07, F(1, 279) = 21.84, p <= 0.01) and had larger available socioeconomic resources (R(2) = 0.11, F(2, 278) = 17.06, p <= 0.01), turned out to be the most effective in self-management. Moreover, a relationship between self-management in MS and gender as well as monthly income attributable to one family member was documented. CONCLUSION: We identified a group of MS patients who are at an increased risk of poor self-management and therefore require more attention from medical staff. This group includes patients with low level of received support, low socioeconomic resources and to a lesser degree men, and also persons receiving low monthly income. Implications for Rehabilitation Self-management of chronic illness is a key component of active participation in rehabilitation process. Low self-management in multiple sclerosis (MS) is considered to be one of the most important factors contributing to low rehabilitation efficacy, more severe long-term complications and increase in healthcare costs. Knowledge on predictors of self-management should be used in clinical practice when providing treatment, support, education and rehabilitation for patients with MS. Increasing support and improving social conditions are potentially important targets for interventions aimed at optimization of self management, and thereby reduction of health care costs and improvement of health. PMID- 25510171 TI - Real-time cell analysis for monitoring cholera toxin-induced human intestinal epithelial cell response. AB - The pathogenic mechanism of Vibrio cholerae manifests as diarrhea and causes life threatening dehydration. Here, we observe the human intestinal epithelial cells (HIEC) response to Cholera toxin (CT) by a real-time cell analysis (RTCA) platform, and disclose the difference from CT-induced cytotoxicity and others in HIEC. An HIEC cell of 1.0 * 10(5) cells/mL was characterized as the suitable concentration for each well. For experimentation, the assay requires an inoculation of CT dissolved in Dulbecco's phosphate-buffered saline with 0.1 % gelatin for a period of 18-25 h. The dimensionless impedance cell index curve presented characteristic dose- and time-dependent drop responses at the first stage, and the CT-induced cytotoxicity was the most remarkable following exposure for 18-25 h (P = 0.0002). Following the obvious cytotoxic reaction, the CI curve gradually increased over time until the original CI value, indicating that self recovery occurred. The CT-induced CI curve for HIEC was different from that induced by other toxins, including diphtheria and Clostridium difficile toxin. Collectively, these results suggest that the CT-induced cytotoxicity in HIEC was absolutely different from that induced by C. difficile and other toxins because of the different pathogeneses that were correlated with the specific CI curve generated by the RTCA system. In summary, our data show that the assay described here is a convenient and rapid high-throughput tool for real-time monitoring of host cellular responses to CT on the basis of the characteristic CI curve. PMID- 25510172 TI - Marinobacter piscensis sp. nov., a moderately halophilic bacterium isolated from salty food in Tunisia. AB - An aerobic, Gram-negative, moderately halophilic bacterium, oxidase, and catalase positive-designated Abdou3(T), was isolated from salted traditional foods (Anchovies) in Tunisia. Cells were rod-shaped, non-spore-forming and motile. Growth occurred at 15-45 degrees C (optimum, 37 degrees C), pH 5.5-8.75 (optimum, 7.3), and in the presence of 1-15 % NaCl (optimum, 10 %). Strain Abdou3(T) used glucose, D-arabinose, and sucrose. Strain Abdou3(T) had Q9 as the major respiratory quinone and C18:1 omega9c and C16:0 as predominant fatty acids. The DNA G+C content was 55.2 mol%. Phylogenetic analysis of the small-subunit ribosomal RNA (rRNA) gene sequence indicated that strain Abdou3(T) had as its closest relative Marinobacter maritimus (identity of 96 %). Based on phenotypic, phylogenetic, and taxonomic characteristics, strain Abdou3(T) is proposed as a novel species of the genus Marinobacter within the order Alteromonadales, for which the name M. piscensis sp. nov. is proposed. The type strain is Abdou3(T) (=DSM 26804(T)). PMID- 25510173 TI - Segmental vs extended colectomy in the management of hereditary nonpolyposis colorectal cancer: a systematic review and meta-analysis. AB - AIM: The optimal surgical approach to the management of colorectal cancer in the setting of hereditary nonpolyposis colorectal cancer (HNPCC) is contentious. While some advocate total colectomy, others perform segmental resection followed by regular endoscopic surveillance. This systematic review evaluates the evidence for segmental colectomy (SC) and total (extended) colectomy (TC) in the management of HNPCC. METHOD: Two major databases (PubMed and Cochrane) were searched using predefined terms. All original articles, published in English, comparing the oncological outcomes of SC and TC in HNPCC patients from January 1950 to July 2013 were included. RESULTS: Eighty-four studies were identified. After applying exclusion criteria, six studies involving 948 patients were included (mean age 47.4 years, 51.8% male). SC was more commonly performed than TC (n = 780; 82.3%). Mean follow-up was 106.5 months. Metachronous high-risk adenomas were detected more often after SC, although the difference was not statistically significant (23.4% vs 9.6%; OR 2.258, P = 0.057). Metachronous cancers occurred more frequently after SC than after TC (23.5% vs 6.8%; OR 3.679, P < 0.005). However, there was no difference in overall survival (90.7% vs 89.8% for SC and TC, respectively; P = 0.085). Only one study reported operative mortality (0% in each group), there was no report of operative morbidity or functional outcome. CONCLUSION: The optimal surgical approach in the management of HNPCC remains unclear. More adenomas and cancers occur after SC than after TC but there certainly is no evidence to suggest that more radical surgery leads to improved survival. PMID- 25510174 TI - Environmental chemistry of organosiloxanes. PMID- 25510176 TI - Monitoring of Short-Term Erythropoietin Therapy in Rats with Acute Spinal Cord Injury Using Manganese-Enhanced Magnetic Resonance Imaging. AB - BACKGROUND AND PURPOSE: To evaluate the short-term outcome of erythropoietin (EPO) therapy in rats with spinal cord injury (SCI) using manganese-enhanced magnetic resonance imaging (MEMRI). METHODS: Rats were divided in an EPO and a control group. Laminectomy at Th11 was performed, followed by SCI. MnCl2 was applied into the cisterna magna and functional recovery was examined after injury using BBB-scoring. Then, rats were euthanized and the spinal cord was extracted for MEMRI. Finally, histological analysis was performed and correlated with MEMRI. RESULTS: EPO-treated animals showed significantly better functional recovery (P = .008, r = .62) and higher mean signal-to-noise ratio (SNR) in MEMRI compared to controls for slices 10-13 (P = .017, R(2) = .31) at the level of the lesion epicenter. Functional recovery correlated significantly with higher SNR values, determined using the mean SNR between slices 10 and 13 (P = .047, R(2) = .36). In this region, histology revealed a significantly decreased number of microglia cells and apoptosis in EPO-treated animals. CONCLUSION: MEMRI successfully depicts the therapeutic effect of EPO in early SCI that leads to a significant recovery in rats, a significantly reduced immune response and significantly reduced number of apoptotic cells at the height of the lesion epicenter. PMID- 25510177 TI - A robust generic method for grid detection in white light microscopy Malassez blade images in the context of cell counting. AB - In biology, cell counting is a primary measurement and it is usually performed manually using hemocytometers such as Malassez blades. This work is tedious and can be automated using image processing. An algorithm based on Fourier transform filtering and the Hough transform was developed for Malassez blade grid extraction. This facilitates cell segmentation and counting within the grid. For the present work, a set of 137 images with high variability was processed. Grids were accurately detected in 98% of these images. PMID- 25510175 TI - Early life environment and natural history of inflammatory bowel diseases. AB - BACKGROUND: Early life exposures may modify risk of inflammatory bowel diseases (IBD; Crohn's disease (CD), ulcerative colitis (UC)). However, the relationship between early life exposures and natural history of IBD has not been previously examined. METHODS: This single center study included patients with CD or UC recruited in a prospective IBD registry. Enrolled patients completed a detailed environmental questionnaire that assessed various early life environmental exposures. Our primary outcome was requirement for disease-related surgery in CD and UC. Logistic regression models defined independent effect of early life exposures, adjusting for potential confounders. RESULTS: Our study included 333 CD and 270 UC patients. Just over half were female with a median age at diagnosis of 25 years. One-third of the cohort had history of bowel surgery (31%) and nearly half had used at least one biologic agent (47%). Among those with CD, being breastfed was associated with reduced risk of CD-related surgery (34% vs. 55%), while childhood cigarette smoke exposure was associated with increased risk. On multivariate analysis, history of being breastfed (odds ratio (OR) 0.21, 95% confidence interval [CI] 0.09-0.46) and cigarette smoke exposure as a child (OR 2.17, 95% CI 1.10-4.29) remained independently associated with surgery. None of the early life variables influenced disease phenotype or outcome in UC. CONCLUSION: A history of being breastfed was associated with a decreased risk while childhood cigarette smoke exposure was associated with an increased risk of surgery in patients with CD. Further investigation to examine biological mechanisms is warranted. PMID- 25510178 TI - MicroRNAs as a potential tool in the differential diagnosis of thyroid cancer: a systematic review and meta-analysis. AB - OBJECTIVE: Thyroid cancer is the most common endocrine malignancy, and its incidence has been increasing over the last 30 years. Several studies have suggested that miRNAs may play a significant role in the differential diagnosis of indeterminate thyroid nodules. To systematically evaluate the utility of miRNAs in discriminating malignant thyroid nodules from benign ones on fine needle aspiration biopsy (FNAB) samples, a systematic review and meta-analysis of the published literatures were carried out. PATIENTS AND DESIGN: Three hundred and sixty-one samples, obtained from 341 patients, were included in the research, and summary sensitivities (SEN), specificities (SPE), positive likelihood ratios, negative likelihood ratios and diagnostic odds ratio were calculated. Then, summary receiver operating characteristic curves (SROCs) and areas under the SROC curves (AUCs) were calculated to further estimate the overall diagnostic value of miRNAs in thyroid cancer. RESULTS: The overall pooled SEN, SPE and AUC are 0.75, 0.81 and 0.89, respectively. For multiple miRNAs assays, the pooled SEN, SPE and AUC are 0.87, 0.75 and 0.68, respectively. For single miRNA assays, the corresponding results are 0.71, 0.84 and 0.87, respectively. The corresponding statistical results for differentiating indeterminate FNAB samples are 0.92, 0.68 and 0.86, respectively. CONCLUSION: Our current meta-analysis suggests that miRNAs may serve as a novel diagnostic tool in distinguishing malignant thyroid nodules from benign ones on FNAB specimens. In addition, subgroup analysis suggests that a panel of miRNAs may have a higher sensitivity but a relatively lower specificity than that of single miRNA in distinguishing thyroid nodules. PMID- 25510179 TI - Overexpression of miR-126 sensitizes osteosarcoma cells to apoptosis induced by epigallocatechin-3-gallate. AB - BACKGROUND: miR-126 plays an important role in the proliferation, invasion, migration, and chemotherapeutics resistance in cancer. Epigallocatechin-3-gallate (EGCG), as the major polyphenolic constituent present in green tea, is a promising anticancer agent. However, the role of miR-126 in EGCG anticancer remains unclear. Here, we investigated the effects of miR-126 and EGCG on cell viability, apoptosis, cell cycle distribution of osteosarcoma cells and the sensitization of miR-126 on osteosarcoma cells to EGCG. METHODS: The cell viability, apoptosis and cycle distribution were analyzed using MTT assay and flow cytometry. RESULTS: Our results showed that EGCG (0.025, 0.05, 0.1, 0.2 g/L) suppresses proliferation of osteosarcoma MG63 and U2OS cells in a concentration dependent and time-dependent manner and the inhibitory effects of 0.05 g/L EGCG on U2OS cells were roughly equivalent to 20 MUM cisplatin (DDP); miR-126 could promote apoptosis and inhibit proliferation in U2OS cells but without significant effects on cell cycle G1 phase arrest; EGCG suppressed proliferation of U2OS cells through induction of cell cycle G1 arrest and apoptotic death; overexpression of miR-126 enhanced the inhibitory effects of EGCG on proliferation in U2OS cells via promotion of apoptosis. CONCLUSIONS: Our results demonstrate that enhanced expression of miR-126 increased the sensitivity of osteosarcoma cells to EGCG through induction of apoptosis. PMID- 25510180 TI - Interval colorectal cancer after colonoscopy. AB - BACKGROUND: As more patients are screened for colorectal cancer a small but significant number of interval cancers develop after colonoscopy for colorectal cancer screening. MATERIALS AND METHODS: We reviewed records of 75,314 adult patients who underwent colonoscopy for screening or diagnostic purposes between 1998 and 2006 inclusively, and identified 77 who developed interval cancers within the next 5 years. We reviewed their original endoscopic findings to determine the clinical and endoscopic factors that might predict a greater risk for future cancers. RESULTS: Patients aged >= 60 years had a higher risk of an interval neoplasm (P < .0001). Interval cancers were more common on the right side of the colon and in the hepatic flexure (both P < .0001). We did not observe an increased rate of interval cancers in patients with poor preparation (P = .799); however, examination completion rates did affect the rate of interval cancers (P = .016). CONCLUSION: Better identification of higher risk patients and assurance of follow-up examinations might increase the percentage of colon cancers discovered at an early stage. Special attention to careful examination of the right colon is key. PMID- 25510181 TI - Incidence of spontaneous twin anemia-polycythemia sequence in monochorionic diamniotic twin pregnancies: Single-center prospective study. AB - AIM: The purpose of this study was to prospectively estimate the incidence of spontaneous twin anemia-polycythemia sequence (TAPS) in monochorionic-diamniotic twin pregnancies. METHODS: We prospectively examined umbilical cord hemoglobin (Hb) and reticulocyte count of consecutive monochorionic-diamniotic twin pregnancies delivered at Seirei Hamamatsu General Hospital from December 2006 to September 2013. We excluded cases of twin-twin transfusion syndrome, intrauterine fetal demise, and missing data (Hb and reticulocyte count missing from the medical record). TAPS was diagnosed using the postnatal criteria of intertwin Hb difference >8.0 g/dL and reticulocyte count ratio >1.7. Acute feto-fetal hemorrhage was defined as Hb difference >7 g/dL and reticulocyte count ratio <1.7. RESULTS: A total of 185 monochorionic-diamniotic twin pregnancies were included in this study. Three fulfilled the diagnostic criteria for postnatal TAPS, and one fulfilled the diagnostic criteria for acute feto-fetal hemorrhage. CONCLUSION: The incidence of spontaneous TAPS in monochorionic-diamniotic twin pregnancies was 1.6% (3/185) at Seirei Hamamatsu General Hospital. PMID- 25510183 TI - Compartmentalization of Inflammatory Response Following Gut Ischemia Reperfusion. AB - OBJECTIVE/BACKGROUND: Gut ischemia reperfusion (IR) is thought to trigger systemic inflammation, multiple organ failure, and death. The aim of this study was to investigate inflammatory responses in blood and in two target organs after gut IR. METHODS: This was a controlled animal study. Adult male Wistar rats were randomized into two groups of eight rats: control group and gut IR group (60 minutes of superior mesenteric artery occlusion followed by 60 minutes of reperfusion). Lactate and four cytokines (tumor necrosis factor-a, interleukin [IL]-1b, IL-6, and IL-10) were measured in mesenteric and systemic blood. The relative gene expression of these cytokines was determined by real time polymerase chain reaction in the gut, liver, and lung. RESULTS: Gut IR significantly increased lactate levels in mesenteric (0.9 +/- 0.4 vs. 3.7 +/- 1.8 mmol/L; p < .001) and in systemic blood (1.3 +/- 0.2 vs. 4.0 +/- 0.3 mmol/L; p < .001). Gut IR also increased the levels of four cytokines in mesenteric and systemic blood. IL-6 and IL-10 were the main circulating cytokines; there were no significant differences between mesenteric and systemic cytokine levels. IL-10 was upregulated mainly in the lung,suggesting that this organ could play a major role during gut reperfusion. CONCLUSION: The predominance of IL-10 over other cytokines in plasma and the dissimilar organ responses,especially of the lung, might be a basis for the design of therapies, for example lung protective ventilation strategies, to limit the deleterious effects of the inflammatory cascade. A multi-organ protective approach might involve gut directed therapies, protective ventilation, hemodynamic optimization, and hydric balance. PMID- 25510182 TI - Equitable access to developmental surveillance and early intervention- understanding the barriers for children from culturally and linguistically diverse (CALD) backgrounds. AB - BACKGROUND AND OBJECTIVE: Children from culturally and linguistically diverse (CALD) backgrounds are at risk of having developmental problems go undetected prior to starting school, and missing out on early intervention. Our aim was to explore the family and service characteristics, beliefs and experiences that influence the journey of families from CALD backgrounds in accessing developmental surveillance (DS) and early intervention services in south-eastern Sydney, Australia. DESIGN, SETTING AND PARTICIPANTS: This qualitative study used in-depth interviews conducted with 13 parents from CALD backgrounds and 27 health and early childhood professionals in Sydney. The Andersen Behavioural Model of Health Service Use (BM) was the underlying theoretical framework for thematic analysis. RESULTS AND DISCUSSION: Family and service knowledge about early childhood development (ECD), community attitudes, social isolation and English language proficiency were dominant themes that impacted on the probability of families accessing services in the first place. Those that impeded or facilitated access were resources, extended family and social support, information availability, competing needs, complex service pathways and community engagement. There were variable practices of early detection through DS. Children from CALD backgrounds with developmental problems were perceived to miss out on DS and early intervention despite language delay being a key issue identified by participants. CONCLUSION: This study highlights the importance of increased community and family awareness and professional training in ECD; better coordination of health and early childhood services, with simpler referral pathways to early intervention to prevent children from CALD backgrounds 'slipping through the net'. PMID- 25510184 TI - Methylisothiazolinone and benzisothiazolinone are widely used in paint: a multicentre study of paints from five European countries. AB - BACKGROUND: In view of the current epidemic of contact allergy to methylisothiazolinone (MI), it is important to clarify the extent of use of MI and related isothiazolinones in paints currently available for the consumer and worker in Europe. OBJECTIVES: To elucidate the use and concentrations of MI, methylchloroisothiazolinone (MCI) and benzisothiazolinone (BIT) in paints on the European retail market. METHODS: Wall paints (n = 71) were randomly purchased in retail outlets in five European countries. The paints were quantitatively analysed for their contents of MI, MCI and BIT by high-performance liquid chromatography coupled to tandem mass spectrometry. RESULTS: MI was found in 93.0% (n = 66) of the paints, with concentrations ranging from 0.7 to 180.9 ppm, MCI in 23.9% (n = 17), ranging from 0.26 to 11.4 ppm, and BIT in 95.8% (n = 68), ranging from 0.1 to 462.5 ppm. High concentrations of MI were found in paints from all five countries. Paints purchased in Denmark and Sweden contained especially high concentrations of BIT. CONCLUSION: The use of MI across European countries is extensive. In view of the ongoing epidemic of MI contact allergy, an evaluation of the safety of MI in paints is needed. PMID- 25510185 TI - Associations between diabetes, major depressive disorder and generalized anxiety disorder comorbidity, and disability: findings from the 2012 Canadian Community Health Survey--Mental Health (CCHS-MH). AB - OBJECTIVE: To examine the associations between diabetes, disability, and the likelihood of comorbid major depressive disorder (MDD) and generalized anxiety disorder (GAD). METHODS: Data were obtained from the 2012 Canadian Community Health Survey - Mental Health (N=17 623). Diabetes assessment consisted of a self reported diagnosis of diabetes made by a health care professional. Disability was assessed via self-report. 12-Month and lifetime MDD and GAD were assessed with the Composite International Diagnostic Interview 3.0. RESULTS: In multinomial logistic regression models adjusted for sociodemographic and health-related factors, having diabetes was associated with a greater likelihood of 12-month comorbid MDD and GAD (OR=1.99, 95% CI [1.22, 3.25], p=.006), compared with those with neither MDD nor GAD. No significant associations were found for MDD without GAD or GAD without MDD. This pattern of effects held when lifetime diagnoses of MDD and GAD were considered. For individuals with diabetes (n=1730), adjusted binary logistic regression models demonstrated that with 12-month diagnoses, MDD without GAD (OR=2.79, 95% CI [1.39-5.62], p=.004), GAD without MDD (OR=3.69, 95% CI [1.34-10.11], p=.01), and comorbid MDD and GAD (OR=4.17, 95% CI [1.66-10.51], p=.002) were associated with greater disability than the control group. Only comorbid MDD and GAD were associated with disability when lifetime diagnoses of MDD and GAD were considered. CONCLUSIONS: Individuals with diabetes may be particularly vulnerable to comorbid MDD and GAD, and MDD-GAD comorbidity may exacerbate disability in persons with diabetes. PMID- 25510187 TI - Psychological distress in patients with restless legs syndrome (Willis-Ekbom disease): a population-based door-to-door survey in rural Ecuador. AB - BACKGROUND: Reported prevalence of restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), varies from country to country, and methodologic inconsistencies limit comparison of data. Impact of RLS on quality of life and health has been studied primarily in industrialized countries, particularly Europe and the United States. Many studies have relied exclusively on self-report of symptoms or have assessed only medical populations. Recently, interest has emerged on the impact of WED in rural, underserved populations globally. METHODS: In a population-based survey conducted in rural Ecuador, we assessed the relationship of psychological distress to WED, evaluated with the Depression Anxiety Stress Scales-21. WED was diagnosed through a 2-phase method in which all residents were screened with the International Restless Legs Syndrome Study Group (IRLSSG) questionnaire and all suspected cases were subsequently confirmed through expert medical examination. WED severity was assessed with the IRLSSG rating scale. RESULTS: Of 665 persons (mean [SD] age, 59.5 [12.6] years; women, 386 [58%]), 76 had depression, 93 had anxiety, and 60 reported stress. Forty persons (6%) had WED, with 15 (38%) having severe disease. In a regression model adjusted for age and sex, the prevalence of depression, anxiety, and stress was about 3 times greater among persons with WED than the general population. CONCLUSIONS: Although cross-sectional data cannot establish causation, this study shows the large behavioral health burden associated with WED in an untreated, rural population. PMID- 25510186 TI - Anxiety and depressive symptoms and medical illness among adults with anxiety disorders. AB - OBJECTIVE: Anxiety is linked to a number of medical conditions, yet few studies have examined how symptom severity relates to medical comorbidity. PURPOSE: The current study assessed associations between severity of anxiety and depression and the presence of medical conditions in adults diagnosed with anxiety disorders. METHOD: Nine-hundred eighty-nine patients diagnosed with panic, generalized anxiety, social anxiety, and posttraumatic stress disorders reported on the severity of anxiety and depressive symptoms and on diagnoses of 11 medical conditions. RESULTS: Severity of anxiety and depressive symptoms was strongly associated with having more medical conditions over and above control variables, and the association was as strong as that between BMI and disease. Odds of having asthma, heart disease, back problems, ulcer, migraine headache and eyesight difficulties also increased as anxiety and depressive symptom severity increased. Anxiety symptoms were independently associated with ulcer, whereas depressive symptoms were independently associated with heart disease, migraine, and eyesight difficulties. CONCLUSIONS: These findings add to a growing body of research linking anxiety disorders with physical health problems and indicate that anxiety and depressive symptoms deserve greater attention in their association with disease. PMID- 25510189 TI - Balance during walking on an inclined instrumented pathway following incomplete spinal cord injury. AB - OBJECTIVES: To study the postural adaptations of subjects with incomplete spinal cord injury (iSCI) and non-injured subjects during overground walking on level and inclined surfaces. METHODS: Six subjects with iSCI and seven non-injured subjects walked on an inclined surface (slope: 15%) and a level surface at their natural gait speed and at a slow gait speed (non-injured subjects only). Maximal stabilizing and minimal destabilizing forces were calculated to quantify dynamic balance during walking. Correlational analysis identified the variables that influence these stabilizing and destabilizing forces. RESULTS: Subjects with iSCI and good sensorimotor recovery were similar to non-injured subjects with respect to maximal stabilizing and minimal destabilizing forces when they walked at the same speed. The MaxSF was mainly explained by the center of pressure speed and step length, whereas the minimal destabilizing force was moderately correlated with body mass and height. CONCLUSION: The influence of gait speed on balance should be considered with a group comparison. With regard to dynamic balance, highly functioning subjects with iSCI do not seem to be sufficiently challenged while walking at their preferred gait speed. Asking individuals with subtle impairments to walk faster following an iSCI may reveal postural adaptations and have an effect on balance abilities. PMID- 25510188 TI - First co-expression of a lipase and its specific foldase obtained by metagenomics. AB - BACKGROUND: Metagenomics is a useful tool in the search for new lipases that might have characteristics that make them suitable for application in biocatalysis. This paper reports the cloning, co-expression, purification and characterization of a new lipase, denominated LipG9, and its specific foldase, LifG9, from a metagenomic library derived from a fat-contaminated soil. RESULTS: Within the metagenomic library, the gene lipg9 was cloned jointly with the gene of the foldase, lifg9. LipG9 and LifG9 have 96% and 84% identity, respectively, with the corresponding proteins of Aeromonas veronii B565. LipG9 and LifG9 were co-expressed, both in N-truncated form, in Escherichia coli BL21(DE3), using the vectors pET28a(+) and pT7-7, respectively, and then purified by affinity chromatography using a Ni(2+) column (HiTrap Chelating HP). The purified enzyme eluted from the column complexed with its foldase. The molecular masses of the N truncated proteins were 32 kDa for LipG9, including the N-terminal His-tag with 6 residues, and 23 kDa for LifG9, which did not have a His-tag. The biochemical and kinetic characteristics of the purified lipase-foldase preparation were investigated. This preparation was active and stable over a wide range of pH values (6.5-9.5) and temperatures (10-40 degrees C), with the highest specific activity, of 1500 U mg(-1), being obtained at pH 7.5 at 30 degrees C. It also had high specific activities against tributyrin, tricaprylin and triolein, with values of 1852, 1566 and 817 U mg(-1), respectively. A phylogenetic analysis placed LipG9 in the lipase subfamily I.1. A comparison of the sequence of LipG9 with those of other bacterial lipases in the Protein Data Bank showed that LipG9 contains not only the classic catalytic triad (Ser(103), Asp(250), His(272)), with the catalytic Ser occurring within a conserved pentapeptide, Gly-His-Ser-His Gly, but also a conserved disulfide bridge and a conserved calcium binding site. The homology-modeled structure presents a canonical alpha/beta hydrolase folding type I. CONCLUSIONS: This paper is the first to report the successful co expression of a lipase and its associated foldase from a metagenomic library. The high activity and stability of Lip-LifG9 suggest that it has a good potential for use in biocatalysis. PMID- 25510190 TI - Adaptation and validation of the Spanish self-report version of the Spinal Cord Independence Measure (SCIM III). AB - STUDY DESIGN: This is a cross-sectional validation study. OBJECTIVE: The objective of this study was to adapt and validate a self-report version of the Spinal Cord Independence Measure (SCIM III) for the Spanish population. METHODS: A cross-cultural adaptation of the self-report version of the SCIM III for the Spanish population was performed on the basis of international guidelines. A total of 100 patients with spinal cord injury (SCI) were recruited. A team of healthcare professionals administered the SCIM III by observation. In addition, the patients completed the Spanish self-report version (eSCIM-SR). Data from both questionnaires were analysed jointly. RESULTS: A high correlation was observed between SCIM III and eSCIM-SR. Lin's concordance correlation coefficient for the global score was 0.998 (95% confidence interval: 0.997, 0.998), and the subscale scores were 0.988 (0.982, 0.992) for self-care, 0.992 (0.988, 0.995) for respiration and sphincter management and 0.997 (0.995, 0.998) for Mobility. Bland Altman plots showed a small bias of -0.32 (95% limits of agreement: -3.01, 2.37). The estimated bias was low in all three domains, with values of -0.22 (-2.12, 1.68), -0.1 (-2.02, 1.82) and -0.03 (-1.69, 1.63) for the self-care, respiration and sphincter management and mobility subscales, respectively. CONCLUSION: Our study validates the eSCIM-SR as a tool for the functional assessment of patients with SCI, principally in the outpatient setting. PMID- 25510191 TI - Identification and treatment of sleep-disordered breathing in chronic spinal cord injury. AB - STUDY DESIGN: A follow up on an ongoing prospective cohort study. OBJECTIVE: Spinal cord injury or disorder (SCI/D) patients have higher rates of sleep disordered breathing (SDB) than the general population. The objectives of this study were to examine predictors of SDB diagnosis and to estimate rates of SDB treatment in SCI/D patients. SETTING: A SCI clinical sleep research laboratory. METHODS: Twenty-eight SCI/D patients (7 women, age 42.8 +/- 15.8 years; 16 cervical and 12 thoracic level injuries) completed a battery of questionnaires (Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), Berlin questionnaire (BQ) and fatigue severity scale (FSS)) and had one night of attended laboratory polysomnography (PSG). Participants were then notified of the results of their PSG and were interviewed approximately 1 year later to assess clinical outcomes. RESULTS: The majority of patients reported poor sleep quality on all questionnaires. On the basis of PSG, 22 (79%) patients had SDB (apnea hypopnea index (AHI)? 5 events per hour), and 17 (61%) had moderate/severe SDB (AHI?15 events per hour). Higher ESS scores were associated with a higher risk of AHI ? 5; however, other questionnaires did not distinguish between those with and without SDB using either AHI cutoff. In follow-up interviews, only 50% of patients had spoken to a health-care provider about SDB and only six patients with SDB were prescribed treatment, four of whom were using the treatment at follow-up. CONCLUSION: SDB is common and severe among SCI/D patients. Screening questionnaires do not appear to differentiate between those with and without SDB. Even when SDB was recognized, many patients remained untreated. The increased prevalence of cardiovascular disease in SCI/D patients could represent a consequence of untreated SDB, and improving diagnosis and management of SDB has the potential to improve outcomes for these patients. PMID- 25510193 TI - Relationship quality and perceived social support in persons with spinal cord injury. AB - STUDY DESIGN: This is a cross-sectional study. OBJECTIVES: The objective of this study was to examine the associations among the quality of couple relationship, perceived social support and health-related quality of life (HRQoL) in persons with spinal cord injury (SCI). SETTING: The study was conducted in Italy. METHODS: Forty-three persons with SCI were administered questionnaires for the evaluation of relationship quality (Dyadic Adjustment Scale), perceived social support (Multidimensional Scale of Perceived Social Support) and HRQoL (Short Form 36). RESULTS: Many significant correlations between the scores of relationship quality and social support were detected. Relationship quality also correlated with relevant measures of HRQoL, such as Mental Health and Vitality. No correlation between spousal support and HRQoL was found, whereas friends' support correlated with Physical Role Functioning. CONCLUSIONS: Data suggest that the perception of social support is strictly related to relationship quality and that marital satisfaction might be related to relevant aspects of HRQoL more likely than social support itself. PMID- 25510192 TI - Challenges for defining minimal clinically important difference (MCID) after spinal cord injury. AB - STUDY DESIGN: This is a review article. OBJECTIVES: This study discusses the following: (1) concepts and constraints for the determination of minimal clinically important difference (MCID), (2) the contrasts between MCID and minimal detectable difference (MDD), (3) MCID within the different domains of International Classification of Functioning, disability and health, (4) the roles of clinical investigators and clinical participants in defining MCID and (5) the implementation of MCID in acute versus chronic spinal cord injury (SCI) studies. METHODS: The methods include narrative reviews of SCI outcomes, a 2-day meeting of the authors and statistical methods of analysis representing MDD. RESULTS: The data from SCI study outcomes are dependent on many elements, including the following: the level and severity of SCI, the heterogeneity within each study cohort, the therapeutic target, the nature of the therapy, any confounding influences or comorbidities, the assessment times relative to the date of injury, the outcome measurement instrument and the clinical end-point threshold used to determine a treatment effect. Even if statistically significant differences can be established, this finding does not guarantee that the experimental therapeutic provides a person living with SCI an improved capacity for functional independence and/or an increased quality of life. The MDD statistical concept describes the smallest real change in the specified outcome, beyond measurement error, and it should not be confused with the minimum threshold for demonstrating a clinical benefit or MCID. Unfortunately, MCID and MDD are not uncomplicated estimations; nevertheless, any MCID should exceed the expected MDD plus any probable spontaneous recovery. CONCLUSION: Estimation of an MCID for SCI remains elusive. In the interim, if the target of a therapeutic is the injured spinal cord, it is most desirable that any improvement in neurological status be correlated with a functional (meaningful) benefit. PMID- 25510194 TI - Astrovirus as a possible cause of congenital tremor type AII in piglets? AB - BACKGROUND: Congenital tremor is associated with demyelination of the brain and spinal cord and is clinically noted as outbreaks of trembling and shaking in newborn piglets during a limited time-period. Six forms of the disease have been described, where form AII may be caused by an, as yet, unidentified viral infection. This study aimed to investigate the presence of astrovirus and circovirus by sequencing and polymerase chain reaction (PCR) analysis and by relating the findings to the occurrence of disease and lesions in the brain, in 4 6 days-old piglets obtained from a clinical outbreak of congenital tremor. RESULTS: In piglets with congenital tremor, there were mild to moderate vacuolar changes of the white matter in the cerebrum, brain stem and cerebellum. In healthy piglets, less conspicuous vacuolar changes were detected. One healthy and one diseased piglet were positive for porcine circovirus type 2. The nested pan PCR showed the presence of astrovirus in at least one brain region in all piglets and by sequencing, two different porcine astrovirus lineages were identified. CONCLUSIONS: The results do not support previous studies identifying porcine circovirus type 2 as the cause of congenital tremor. The demonstration of astrovirus in the brain of piglets suffering from congenital tremor is interesting. However, astrovirus was demonstrated in both healthy and diseased individuals and therefore, further studies are warranted to determine the possible involvement of astrovirus in the pathogenesis of congenital tremor in pigs. PMID- 25510195 TI - Is the whole the sum of its parts? Configural processing of headless bodies in the right fusiform gyrus. AB - The current study aimed to explore the functional magnetic resonance (fMR) adaption effect by presenting intact and scrambled headless bodies and faces. This fMR-adaption paradigm allows investigating processing specificity in distinct brain areas by comparing the blood-oxygen-level-dependent (BOLD) signal related to the presentation of same or different pairs of bodies. There is clear evidence that we prefer whole bodies compared to the sum of their parts. This effect refers to a subtype of configural processing termed first-order relational information. The preference for whole bodies seems to be associated with activation pattern in body-sensitive brain regions. However, it remains unclear until now, which cortical area exactly mediates this preference. In the present study, we investigated whether there are neuronal populations that show a selective adaption to whole bodies compared to the sum of their parts. The right fusiform body area (FBA) showed a preference for whole bodies compared to the sum of their parts as the right and left fusiform face area showed a preference for whole faces compared to the sum of their parts. Thus, the present data support the idea that configural body and face processing is mediated by the fusiform gyrus. The current data further support the view that bodies are a special stimulus class with specific characteristics which are processed in body sensitive brain areas. PMID- 25510196 TI - Hesperidin ameliorates behavioral impairments and neuropathology of transgenic APP/PS1 mice. AB - In addition to cognitive impairments, deficits in non-cognitive behaviors are also common neurological sequelae in Alzheimer's disease and its animal models. Hesperidin, a flavanone glycoside found abundantly in citrus fruits, was orally given (100 mg/kg body weight) to 5-month-old transgenic APP/PS1 mice, a mouse model of cerebral amyloidosis for Alzheimer's disease. After a relatively short term treatment of 10 days, hesperidin significantly restored deficits in non cognitive nesting ability and social interaction. Further immunohistochemical analysis showed significantly attenuated beta-amyloid deposition, plaque associated APP expression, microglial activation and TGF-beta immunoreactivity in brains of APP/PS1 mice, which suggests that ameliorated behavioral impairments might be attributable to reduced Abeta deposition and attenuated neuro inflammatory reaction. Additionally, efficient anti-inflammatory effects of hesperidin were confirmed in vitro. Our findings suggest that hesperidin might be a potential candidate for the treatment of AD or even other neurodegenerative diseases. PMID- 25510197 TI - Dopamine and cognitive control: sex-by-genotype interactions influence the capacity to switch attention. AB - Cognitive performance in healthy persons varies widely between individuals. Sex differences in cognition are well reported, and there is an emerging body of evidence suggesting that the relationship between dopaminergic neurotransmission, implicated in many cognitive functions, is modulated by sex. Here, we examine the influence of sex and genetic variations along the dopaminergic pathway on aspects of cognitive control. A total of 415 healthy individuals, selected from an international consortium linked to Brain Research and Integrative Neuroscience Network (BRAINnet), were genotyped for two common and functional genetic variations of dopamine regulating genes: the catechol-O-methyltransferase [COMT] gene (rs4680) and the dopamine receptor D2 [DRD2] gene (rs6277). Cognitive measures were selected to explore sustained attention (using a continuous performance task), switching of attention (using a Trails B adaptation) and working memory (a visual computerised adaptation of digit span). While there were no main effects for genotype across any tasks, analyses revealed significant sex by genotype interactions for the capacity to switch attention. In relation to COMT, superior performance was noted in females with the Val/Val genotype and for DRD2, superior performance was seen for TT females and CC males. These findings highlight the importance of considering genetic variation in baseline dopamine levels in addition to sex, when considering the impact of dopamine on cognition in healthy populations. These findings also have important implications for the many neuropsychiatric disorders that implicate dopamine, cognitive changes and sex differences. PMID- 25510198 TI - The effects of different basal levels of anxiety on the behavioral shift analyzed in the central platform of the elevated plus maze. AB - The aim of the present research was to study the effects of different basal levels of anxiety on the behavioral shift studied in the central platform of the elevated plus maze. To this purpose, quantitative and multivariate analyses, the latter based on transition matrix elaboration, were carried out on Wistar and on DA/Han rats the latter belonging to a strain characterized by different reactivity to anxiogenic stimuli. Wistar rats spent 74.11+/-5.11 s in the central platform, whereas DA/Han significantly more: 127.08+/-9.87. Per cent distributions evidenced a clear-cut difference in walking activities (46.25% in Wistar, 28.4% in DA/Han rats) and in the sniffing activities (45.82% in Wistar, 62.54% in DA/Han). Mean frequencies of each behavioral element showed in DA/Han strain a value significantly lower than in Wistar for central-platform entry, open arm-entry and closed-arm entry and a significant higher value for central- platform sniffing, open-arm sniffing and corner-rearing. Moreover, the ratio open arm entry/open-arm sniffing and closed-arm entry/closed-arm-sniffing showed significant higher values in the Wistar strain. Finally, by means of hierarchical clustering analysis, strong differences between the two strains were observed in the behavioral architecture: a cascade-shaped dendrogram, branching from Walking activities, indicates that Wistar rat behavior is oriented to cross the central platform so to rapidly reach an arm; on the contrary, the dendrogram of DA/Han rats displays a behavior heavily oriented toward the permanence in the central platform. The results show that different basal levels of anxiety provoke significant differences in the behavioral shift studied in the central platform of the elevated plus maze. Such differences, evidenced by means of transition matrices elaboration, might represent the behavioral expression of anxiety induced modifications of decision making process underlying behavioral shift activities. PMID- 25510199 TI - Remarkable improvement in microwave absorption by cloaking a micro-scaled tetrapod hollow with helical carbon nanofibers. AB - Helical nanofibers are prepared through in situ growth on the surface of a tetrapod-shaped ZnO whisker (T-ZnO), by employing a precursor decomposition method then adding substrate. After heat treatment at 900 degrees C under argon, this new composite material, named helical nanofiber-T-ZnO, undergoes a significant change in morphology and structure. The T-ZnO transforms from a solid tetrapod ZnO to a micro-scaled tetrapod hollow carbon film by reduction of the organic fiber at 900 degrees C. Besides, helical carbon nanofibers, generated from the carbonization of helical nanofibers, maintain the helical morphology. Interestingly, HCNFs with the T-hollow exhibit remarkable improvement in electromagnetic wave loss compared with the pure helical nanofibers. The enhanced loss ability may arise from the efficient dielectric friction, interface effect in the complex nanostructures and the micro-scaled tetrapod-hollow structure. PMID- 25510200 TI - Primary cutaneous mucormycosis caused by Mucor irregularis in an elderly person. AB - Primary cutaneous mucormycosis is a rare but often lethal severe fungal infection, which usually occurs in immunocompromised patients. We report a case of primary cutaneous mucormycosis caused by Mucor irregularis in an elderly patient. Seven months after the surgical dissection of the involved skin, cutaneous mucormycosis recurred at the peripheral edge of the skin graft. Shortly subsequent to the administration of liposomal amphotericin B, the remaining skin lesion was excised again. M. irregularis is rarely but increasingly reported as a cause of mucormycosis in immunocompetent individuals, especially in Asian farmers. M. irregularis may be largely disseminated in the soils of Asia and thus the trivial trauma at the time of farm work may be a trigger for the onset. These cases tend to leave severe cosmetic damage even in healthy individuals, although the vital prognosis is not affected. PMID- 25510201 TI - Acral peeling skin syndrome resulting from mutations in TGM5. PMID- 25510203 TI - Black and yellow anatase titania formed by (H,N)-doping: strong visible-light absorption and enhanced visible-light photocatalysis. AB - Black and yellow anatase TiO2 doped with hydrogen and nitrogen elements annealed under a N2/Ar/air atmosphere are produced. More interestingly, one kind of black TiO2 has excellent performance for degradation of methylene blue under visible light irradiation but photodegradation of the other is quite limited. PMID- 25510202 TI - Prenatal nicotine alters the developmental neurotoxicity of postnatal chlorpyrifos directed toward cholinergic systems: better, worse, or just "different?". AB - This study examines whether prenatal nicotine exposure sensitizes the developing brain to subsequent developmental neurotoxicity evoked by chlorpyrifos, a commonly-used insecticide. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. We evaluated indices for acetylcholine (ACh) synaptic function throughout adolescence, young adulthood and later adulthood, in brain regions possessing the majority of ACh projections and cell bodies; we measured nicotinic ACh receptor binding, hemicholinium-3 binding to the presynaptic choline transporter and choline acetyltransferase activity, all known targets for the adverse developmental effects of nicotine and chlorpyrifos given individually. By itself nicotine elicited overall upregulation of the ACh markers, albeit with selective differences by sex, region and age. Likewise, chlorpyrifos alone had highly sex selective effects. Importantly, all the effects showed temporal progression between adolescence and adulthood, pointing to ongoing synaptic changes rather than just persistence after an initial injury. Prenatal nicotine administration altered the responses to chlorpyrifos in a consistent pattern for all three markers, lowering values relative to those of the individual treatments or to those expected from simple additive effects of nicotine and chlorpyrifos. The combination produced global interference with emergence of the ACh phenotype, an effect not seen with nicotine or chlorpyrifos alone. Given that human exposures to nicotine and chlorpyrifos are widespread, our results point to the creation of a subpopulation with heightened vulnerability. PMID- 25510205 TI - Important elements of measuring participation for children who need or use power mobility: a modified Delphi survey. AB - AIM: To identify and reach consensus on important elements of measuring participation in everyday life for children who need or use power mobility. METHOD: A panel (n=74) of parents, therapists, and researchers with pediatric power mobility and participation expertise completed an online modified Delphi survey. Three rounds determined important elements of participation for two groups: early childhood (18mo-5y) and school-aged (6-12y). 'Elements of participation' defined the 'who, what, where, and how' of measuring participation, generated from a literature review and participants' suggestions. Consensus was set a priori as >=80% agreement. RESULTS: Consensus was reached on 21 out of 48 elements of participation important to measure for our population: eight elements for the younger group and 18 elements for the older group. When ranked by importance, four of the top five elements were common across both age groups. INTERPRETATION: For children using power mobility, measuring participation in a variety of settings is critical, along with considering both the child's and family's participation. Evaluating child engagement and enjoyment of participation are priorities, as is measuring barriers and facilitators. For school-aged children, evaluating child and parent reports of participation are essential. These elements can guide tool selection and/or development. PMID- 25510204 TI - Effects of Kuan-Sin-Yin decoction on immunomodulation and tumorigenesis in mouse tumor models. AB - BACKGROUND: Complementary therapies are widely used among cancer patients. Kuan Sin-Yin (KSY) decoction, a popular qi-promoting herbal medicine, was constituted with several herbs known to exhibit immunomodulating or anticancer activity. After combining these herbs as a compound formula, it is necessary to reassess the immunomodulation effects, the effects on tumor growth, and possible toxicity of KSY. METHODS: The anti-cancer effects of KSY in vivo were determined by measuring the tumor volumes, anticancer-associated cytokines (IFN-gamma, TNF alpha, IL-2, and IL-12), accumulation of tumor infiltrating leukocytes (TILs), proliferation and apoptosis-related molecular markers (Ki-67, p53, p21, activated caspase 3, and cleaved PARP), and an in situ TUNEL assay. The body weight and serum chemistry of treated mice were also assessed. In vitro, the effects of KSY were evaluated using MTT assay, BrdU incorporation assay and cell growth curve. RESULTS: In vivo, KSY suppressed bladder or lung cancer growth but did not promote the production of cytokines nor increase the accumulation of TILs. The expression of p53 and p21 in KSY-treated mice were increased. The numbers of apoptotic tumor cells and the expression of apoptosis marker proteins (Caspase 3 and cleaved PARP) were not significantly elevated after KSY treatment. In vitro, the viability and proliferation of tumor cells, but not normal cells, were suppressed by KSY treatment. No significant toxicity was found in KSY-treated mice. CONCLUSIONS: KSY suppressed the tumor growth in vivo and in vitro, which resulted from its cytostatic effects on cancer cells, rather than the induction of anti-cancer immunity. Under these experimental conditions, no apparent toxicity was observed. PMID- 25510207 TI - When bugs and drugs converge: promoting safe practices in the emergency department. PMID- 25510206 TI - Evidence-based practice: best neuroimaging practice in non traumatic headaches. PMID- 25510208 TI - Nursing Ethics and Disaster Triage: Applying Utilitarian Ethical Theory. PMID- 25510209 TI - Malignant melanoma of the nasal cavity treated with stereotactic radiotherapy using CyberKnife: report of 2 cases. AB - Radiotherapy with high doses per fraction may have the potential to control radioresistant tumors, such as malignant melanoma. Here we report 2 cases with malignant melanoma of the nasal cavity treated with hypofractionated stereotactic radiotherapy using CyberKnife(r). PMID- 25510210 TI - Intratympanic dexamethasone versus high dosage of betahistine in the treatment of intractable unilateral Meniere disease. AB - PURPOSE: The objective of our randomized, double-blind study was to compare the effectiveness of intratympanic (IT) dexamethasone versus high-dosage of betahistine in the treatment of patients with intractable unilateral Meniere disease (MD). MATERIALS AND METHODS: Sixty six patients with definite unilateral MD were randomly divided in two groups: Group A received a combination of IT dexamethasone (DX) and identical-appearing placebo pills while Group B received a combination of high-dosage betahistine and IT saline. Intratympanic injections were repeated for three times with an interlude of 3days. High-dosage of betahistine entailed 144mg/day. Mean outcome measures consisted of vertigo control, pure tone average (PTA), speech discrimination score, Functional Level Score, Dizziness Handicap Inventory and Tinnitus Handicap Inventory. RESULTS: Fifty nine patients completed the study and were available at 12months for analysis. In Group A complete vertigo control (class A) was attained in 14 patients (46.6%) and substantial control (class B) in 7 patients (20%). In Group B, 12 patients (41%) achieved complete vertigo control (class A), 5 patients (17%) substantial control (class B). There is no statistical difference in vertigo control between the two treatment groups. In Group A hearing was unchanged in 14 patients and improved in 4 patients, while in Group B hearing was unchanged in 16 patients and improved in 2 patients. CONCLUSIONS: Our preliminary results demonstrate that high-dosage of betahistine achieved similar outcomes as IT dexamethasone in the control of vertigo and hearing preservation. PMID- 25510212 TI - IL-22 Up-Regulates beta-Defensin-2 Expression in Human Alveolar Epithelium via STAT3 but Not NF-kappaB Signaling Pathway. AB - Human beta-defensin-2(HBD-2) is one of the two major vertebrate antimicrobial peptide families (alpha and beta), which is highly expressed by proinflammatory induction in the lung and exhibit broad-spectrum antimicrobial activity. We observed that IL-22 receptors high expressed on the membrane of A549 cells; HBD-2 mRNA was expressed in a time- and concentration-dependent manners in A549 cells when treated with IL-22; further studies demonstrated that HBD-2 expression was attenuated by AG490, but to JSH-23, inhibitors of p-STAT3 DNA binding and NF kappaB/p65 subunit nuclear translocation, respectively. These results support that IL-22-mediated signalling pathway of HBD-2 gene expression involved STAT3 but not NF-kappaB in human alveolar epithelium. These findings provide a new insight into how IL-22 may play an important link between innate and adaptive immunity, thereby anti-infection locally in the alveolar epithelium. PMID- 25510211 TI - Direct conversion of mouse and human fibroblasts to functional melanocytes by defined factors. AB - Direct reprogramming provides a fundamentally new approach for the generation of patient-specific cells. Here, by screening a pool of candidate transcription factors, we identify that a combination of the three factors, MITF, SOX10 and PAX3, directly converts mouse and human fibroblasts to functional melanocytes. Induced melanocytes (iMels) activate melanocyte-specific networks, express components of pigment production and delivery system and produce melanosomes. Human iMels properly integrate into the dermal-epidermal junction and produce and deliver melanin pigment to surrounding keratinocytes in a 3D organotypic skin reconstruct. Human iMels generate pigmented epidermis and hair follicles in skin reconstitution assays in vivo. The generation of iMels has important implications for studies of melanocyte lineage commitment, pigmentation disorders and cell replacement therapies. PMID- 25510213 TI - The effects of psychological interventions on depression and anxiety among Chinese adults with cancer: a meta-analysis of randomized controlled studies. AB - BACKGROUND: Our previous studies found the high prevalence of depression and anxiety among Chinese cancer patients, and many empirical studies have been conducted to evaluate the effects of psychological interventions on depression and anxiety among Chinese cancer patients. This study aimed to conduct a meta analysis in order to assess the effects of psychological interventions on depression and anxiety in Chinese adults with cancer. METHODS: The four most comprehensive Chinese academic database- CNKI, Wanfang, Vip and CBM databases were searched from their inception until January 2014. PubMed and Web of Science (SCIE) were also searched from their inception until January 2014 without language restrictions, and an internet search was used. Randomized controlled studies assessing the effects of psychological interventions on depression and anxiety among Chinese adults with cancer were analyzed. Study selection and appraisal were conducted independently by three authors. The pooled random effects estimates of standardized mean difference (SMD) and 95% confidence intervals (CI) were calculated. Moderator analysis (meta-regression and subgroup analysis) was used to explore reasons for heterogeneity. RESULTS: We retrieved 147 studies (covering 14,039 patients) that reported 253 experimental-control comparisons. The random effects model showed a significant large effect size for depression (SMD = 1.199, p < 0.001; 95% CI = 1.095-1.303) and anxiety (SMD = 1.298, p < 0.001; 95% CI = 1.187-1.408). Cumulative meta-analysis indicated that sufficient evidence had accumulated since 2000-2001 to confirm the statistically significant effectiveness of psychological interventions on depression and anxiety in Chinese cancer patients. Moderating effects were found for caner type, patients' selection, intervention format and questionnaires used. In studies that included lung cancer, preselected patients with clear signs of depression/anxiety, adopted individual intervention and used State-Trait Anxiety Inventory (STAI), the effect sizes were larger. CONCLUSIONS: We concluded that psychological interventions in Chinese cancer patients have large effects on depression and anxiety. The findings support that an adequate system should be set up to provide routine psychological interventions for cancer patients in Chinese medical settings. However, because of some clear limitations (heterogeneity and publication bias), these results should be interpreted with caution. PMID- 25510214 TI - The emotional distress of children with cancer in China: an item response analysis of C-Ped-PROMIS Anxiety and Depression short forms. AB - PURPOSE: The pediatric patient-reported outcomes measurement information system (PROMIS) was developed to provide self-reported item banks and short forms for children and adolescents (aged 8-17 years) experiencing a chronic illness to assess their quality of life and symptoms. The pediatric PROMIS short forms have been translated into Chinese and applied in children with cancer in China. This study aimed to describe psychometric properties of the Anxiety and Depression measures. METHODS: A total of 232 children and adolescents with cancer were recruited in hospital-based inpatient and outpatient clinics. Eight Chinese versions of pediatric PROMIS (C-Ped-PROMIS) measures were administered. Categorical confirmatory factor analysis (CCFA) were conducted to evaluate scale dimensionality and item local dependence of the C-Ped-PROMIS Anxiety and Depression items. Multiple indicator multiple cause models were used to analyze differential item functioning (DIF), item response theory parameters were calculated, and test information against T scores was reported for each measure. RESULTS: The results of the CCFA confirmed that both C-Ped-PROMIS Anxiety and Depression scales appropriately measure the theoretical constructs as designed. No significant DIF was found for the items of the two scales according to age and gender. Both scales have high test reliability as long as their T scores are not on the low or high extremes. CONCLUSIONS: The pediatric PROMIS Anxiety and Depression measures were developed to provide efficient and flexible assessment of emotional distress domains. Our results provide evidence that the two C-Ped PROMIS measures can be readily applied to measure anxious and depressive symptoms in Chinese children with cancer. PMID- 25510215 TI - Mapping the disease-specific LupusQoL to the SF-6D. AB - PURPOSE: To derive a mapping algorithm to predict SF-6D utility scores from the non-preference-based LupusQoL and test the performance of the developed algorithm on a separate independent validation data set. METHOD: LupusQoL and SF-6D data were collected from 320 patients with systemic lupus erythematosus (SLE) attending routine rheumatology outpatient appointments at seven centres in the UK. Ordinary least squares (OLS) regression was used to estimate models of increasing complexity in order to predict individuals' SF-6D utility scores from their responses to the LupusQoL questionnaire. Model performance was judged on predictive ability through the size and pattern of prediction errors generated. The performance of the selected model was externally validated on an independent data set containing 113 female SLE patients who had again completed both the LupusQoL and SF-36 questionnaires. RESULTS: Four of the eight LupusQoL domains (physical health, pain, emotional health, and fatigue) were selected as dependent variables in the final model. Overall model fit was good, with R(2) 0.7219, MAE 0.0557, and RMSE 0.0706 when applied to the estimation data set, and R(2) 0.7431, MAE 0.0528, and RMSE 0.0663 when applied to the validation sample. CONCLUSION: This study provides a method by which health state utility values can be estimated from patient responses to the non-preference-based LupusQoL, generalisable beyond the data set upon which it was estimated. Despite concerns over the use of OLS to develop mapping algorithms, we find this method to be suitable in this case due to the normality of the SF-6D data. PMID- 25510217 TI - Replacement of a dominant viral pathogen by a fungal pathogen does not alter the collapse of a regional forest insect outbreak. AB - Natural enemies and environmental factors likely both influence the population cycles of many forest-defoliating insect species. Previous work suggests precipitation influences the spatiotemporal patterns of gypsy moth outbreaks in North America, and it has been hypothesized that precipitation could act indirectly through effects on pathogens. We investigated the potential role of climatic and environmental factors in driving pathogen epizootics and parasitism at 57 sites over an area of ~72,300 km(2) in four US mid-Atlantic states during the final year (2009) of a gypsy moth outbreak. Prior work has largely reported that the Lymantria dispar nucleopolyhedrovirus (LdNPV) was the principal mortality agent responsible for regional collapses of gypsy moth outbreaks. However, in the gypsy moth outbreak-prone US mid-Atlantic region, the fungal pathogen Entomophaga maimaiga has replaced the virus as the dominant source of mortality in dense host populations. The severity of the gypsy moth population crash, measured as the decline in egg mass densities from 2009 to 2010, tended to increase with the prevalence of E. maimaiga and larval parasitoids, but not LdNPV. A significantly negative spatial association was detected between rates of fungal mortality and parasitism, potentially indicating displacement of parasitoids by E. maimaiga. Fungal, viral, and parasitoid mortality agents differed in their associations with local abiotic and biotic conditions, but precipitation significantly influenced both fungal and viral prevalence. This study provides the first spatially robust evidence of the dominance of E. maimaiga during the collapse of a gypsy moth outbreak and highlights the important role played by microclimatic conditions. PMID- 25510218 TI - Narrative abilities in early implanted children. AB - OBJECTIVES/HYPOTHESIS: To investigate the effect of age at cochlear implant activation on oral narrative ability in children implanted before 2.5 years of age and to examine the role of other variables (gender, parental education level, stimulation modality) in narrative skills. STUDY DESIGN: retrospective nonrandomized group study METHODS: Thirty children (21 females; 9 males) with congenital, bilateral severe-to-profound sensorineural hearing loss were included in this study. The mean age at cochlear implant activation was 14.7 months (standard deviation [SD] +/- 5.3). The Renfrew Bus Story was used to analyze oral narrative skills at mean chronological age of 63 months (SD +/- 0.2). RESULTS: The total information on the Renfrew Bus Story raw score ranged from 8 to 40, with a mean of 22.7 (SD +/- 8.6). Children produced on average 7.5 words in a sentence (SD +/- 1.5). The mean score for complexity was 2.2 (SD +/- 1.5). Regression analysis revealed a highly significant and negative linear effect of age at cochlear implant activation on all outcomes. The mother's education level had a positive strong effect on sentence length but a weak effect on total information and complexity. The paternal education score had a weak influence on the sentence length. Gender, age at diagnosis, and stimulation modality were not correlated with the narrative outcomes. CONCLUSIONS: Early implanted children can develop narrative skills close to normal hearing children. The sociocultural context, expressed by maternal and paternal educational level, are positively related to the development of oral narrative. PMID- 25510216 TI - Health status and quality of life: results from a national survey in a community dwelling sample of elderly people. AB - PURPOSE: To investigate the relation between age and HRQoL indicators in a community-dwelling population aged 65 years and older. METHODS: Data were collected within a sample stratified by age (65-69; 70-74; 75-79; 80-84; 85-89; 90 years and above) and sex and randomly selected in the population records in Switzerland. The EQ-5D was used to assess HRQoL. Analyses were conducted on the entire available sample (N = 3,073) and on the subsample with no missing data in the EQ-5D (N = 2,888), considering age, gender, education and region. RESULTS: Results of multiple regression analyses showed different age-related patterns across the EQ-5D. The proportion of respondents reporting no problems ranged from 51 % in the 65- to 69-year age group to 20 % in the 90 years and above age group. Odds ratio (OR) for Mobility problems increased from 2.04 in the 75- to 79-year age group to 13.34 in the 90 years and above age group; OR for Usual Activities increased from 1.76 to 11.68 and from 1.55 to 2.32 for Pain/Discomfort; OR for Self-Care increased from 5.26 in the 80- to 84-year age group to 30.36 in the 90 years and above age group. Problems with Self-Care remained low, increasing from 6.22 % in the 80- to 84-year age group to 26.21 % in the oldest age group. The magnitude of the gender, region and education effects was much lower than that of age. CONCLUSION: HRQoL is globally preserved in older adults in Switzerland, even if substantial impairment is reported in very old age affecting mainly functional health dimensions. Anxiety/Depression and Pain/Discomfort did not appear to be affected by age; high rates of difficulties were reported for Pain/Discomfort but not for Anxiety/Depression. PMID- 25510219 TI - Successful treatment of occult hepatitis B virus infection related membranous nephropathy after entecavir therapy. AB - We have reported a case of occult hepatitis B virus infection (OBI) associated membranous nephropathy (MN) with complete remission under an ongoing 3.5-year entecavir monotherapy. A 59-year-old man with a 3-year history of liver cirrhosis was introduced to our department because of oliguria, proteinuria and microscopic haematuria. He, with negative serum HBV surface antigen, was not detected HBV DNA in his serum. Renal biopsy was performed and was compatible with a diagnosis of hepatitis B virus-related membranous nephropathy (HBV-MN). The patient was prescribed diuretics and intravenous albumin, and his ascites and oedema remitted gradually. At the same time, entecavir 0.5 mg per day was started. Entecavir treatment was continuing for 3.5 years and finally resulted in complete remission of proteinuria. This suggests that entecavir monotherapy may induce and maintain complete remission of MN associated with OBI. PMID- 25510221 TI - Rational design, synthesis, and biological evaluation of lactam-bridged gramicidin A analogues: discovery of a low-hemolytic antibacterial peptide. AB - A linear peptide, gramicidin A (GA), folds into a beta(6.3) -helix, functions as an ion channel in the cell membrane, and exerts antibacterial activity. Herein we describe the rational design, synthesis, and biological evaluation of lactam bridged GA analogues. The GA analogue with a 27-membered macrolactam was found to adopt a stable beta(6.3) -helical conformation and exhibits higher ion-exchange activity than GA. Furthermore, this GA analogue retains the potent antibiotic activity of GA, but its hemolytic activity and toxicity toward mammalian cells are significantly lower than those of GA. This study thus dissociates the antibacterial and hemolytic/cytotoxic activities of GA, and charts a rational path forward for the development of new ion-channel-based antibiotics. PMID- 25510223 TI - [Diagnostic for Charcot foot]. AB - BACKGROUND: Early recognition of Charcot foot can save a long period of suffering for the patient, high doctor and hospital costs and ultimately amputation. OBJECTIVES: This article aims to raise awareness of the diagnostics of Charcot foot also known as diabetic neuropathic osteoarthropathy (DNOAP) and the possible differential diagnostic options (e.g. diabetic foot, erysipelas and peripheral arterial occlusive disease). MATERIAL AND METHODS: Clinical diagnostic pathways and classifications are presented and the resulting treatment options are discussed. RESULTS: In recent years new technologies for wound treatment and interventional radiological optimization of vessels have been developed. Many promising surgical options are available for stabilizing and reconstructimg a plantigrade foot. CONCLUSION: Treatment of Charcot foot should be based on a structured diagnosis and classification. In addition to conservative treatment new surgical options are also available. PMID- 25510222 TI - A Process-Oriented Approach to Teaching Religion and Spirituality in Psychiatry Residency Training. AB - OBJECTIVES: Although the importance of addressing issues of spirituality and religion is increasingly acknowledged within psychiatry training, many questions remain about how to best teach relevant knowledge, skills, and attitudes. Current literature on curricula highlights the importance of maintaining a clinical focus and the balance between didactic content and process issues. The authors present findings from a program evaluation study of a course on religion, spirituality, and psychiatry that deliberately takes a primarily process-oriented, clinically focused approach. METHODS: Two six-session courses were offered. The first course targeted fourth-year psychiatry residents and the second targeted third-year psychiatry residents. Teaching sessions consisted of brief didactics combined with extensive process-oriented discussion. A two-person faculty team facilitated the courses. Clinical case discussions were integrated throughout the curriculum. A panel of chaplains was invited to participate in one session of each course to discuss the interface between spiritual counsel and psychiatry. A modified version of the Course Impact Questionnaire, a 20-item Likert scale utilized in previous studies of spirituality curricula in psychiatry, assessed residents' personal spiritual attitudes, competency, change in professional practice, and change in professional attitudes before and after the course (N = 20). Qualitative feedback was also elicited through written comments. RESULTS: The results from this study showed a statistically significant difference between the pre- and post-test scale for residents' self-perceived competency and change in professional practice. CONCLUSION: The findings suggest improvement in competency and professional practice scores in residents who participated in this course. This points toward the overall usefulness of the course and suggests that a process-oriented approach may be effective for discussing religion and spirituality in psychiatric training. PMID- 25510224 TI - [Full contact plaster cast for conservative treatment of Charcot foot]. AB - BACKGROUND: The gold standard for treatment of early stages of Charcot foot are immobilization with a full contact plaster cast, whereby different periods and loading concepts are described in the literature. OBJECTIVES: The etiology, disease course and preparation for an early conservative therapy are described and a key point is a full contact plaster cast. METHODS: An overview of the etiology, pathogenesis and indications for correct evaluation of the wound situation is given. The correct technique for the total cast is described and illustrated step by step with pictures. RESULTS: If treatment of Charcot foot is initiated in the early stages prevention or healing of ulcers can be achieved; therefore, the correct indications and technique are necessary and the cast should be changed periodically which is a key point of the healing process. Healing results in a reduction of redness, temperature and swelling which should be measured and documented. CONCLUSIONS: Treatment of Charcot foot by full contact cast and immobilization should be initiated as soon as possible. PMID- 25510225 TI - Polymorphism of interleukin-17 and its relation to mineral density of bones in perimenopausal women. AB - BACKGROUND: Recognition of different genetic variants underlying osteoporosis would make it possible to introduce individual, symptomatic treatment as well as early prophylaxis of osteoporosis. The aim of the study was to evaluate the frequency of the rs2275913 (-197G > A) polymorphism of the IL-17 gene and assess the relation of this polymorphism with the clinical parameters of the osseous turnover and degree of the postmenopausal osteoporosis. METHODS: The study included 800 women of postmenopausal (505) and reproductive (295) ages throughout the Wielkopolska region in Poland. The postmenopausal group included women with osteoporosis and osteopenia, and those who were healthy. Women at reproductive age were healthy. The frequency of the tested gene polymorphism was evaluated in the group where bone mineral density (BMD) was marked and in the control group. RESULTS: The results obtained showed that the T-score in the female population with osteopenia was remarkably lower in women showing the GG genotype of -197G > A polymorphism of IL-17 gene compared to patients with heterozygous GA genotype. It has been shown that the BMD value for L2-L4 YA in the evaluated female population with osteoporosis is significantly higher in women with the GA genotype of -197G > A polymorphism of IL-17 gene compared to women with the GG genotype (76.32% versus 59.93%, P <0.05). It has also been noted that the BMD value for L2 to L4 AM in patients with the GG genotype was lower than in women with the AA genotype (69.73% versus 80.88%, P <0.05). CONCLUSIONS: It is suggested that the -197G > A polymorphism of the IL-17 gene may be considered as a genetic factor of postmenopausal osteoporosis. This polymorphism can influence the bone mineral density and T-score value in young women and postmenopausal women. PMID- 25510226 TI - Letter to the Editor on 'Pyrogenic organic matter production from wildfires: a missing sink in the global carbon cycle'. PMID- 25510228 TI - The dynamics of inextensible capsules in shear flow under the effect of the natural state. AB - The effect of the natural state on the motion of an inextensible capsule in two dimensional shear flow has been studied numerically. The energy barrier based on such natural state plays a role for having the transition between two well-known motions, tumbling and tank-treading (TT) with the long axis oscillating about a fixed inclination angle (a swinging mode), when varying the shear rate. Between tumbling and TT with a swinging mode, the intermittent region has been obtained for the capsule with a biconcave rest shape. The estimated critical value of the swelling ratio for having the intermittent region is <0.7, i.e., the capsule with the rest shape closer to a full disk has no intermittent behavior. The capsule intermittent behavior is a mixture of tumbling and TT. Just like the TT with a swinging mode, which can be viewed as TT with an incomplete tumbling, the membrane tank-treads backward and forward within a small range while tumbling. As the capillary number is very close to and below the threshold for pure TT with a swinging mode, the capsule tumbles once after several TT periods in each cycle. The number of TT periods in one cycle decreases when decreasing the capillary number, until the capsule has one tumble and one TT period alternatively and such alternating motion exists over a range of the capillary number; and then the capsule performs more tumbling between two consecutive TT periods when reducing the capillary number further, and finally has tumbling only. PMID- 25510229 TI - Blood brain barrier precludes the cerebral arteries to intravenously-injected antisense oligonucleotide. AB - Alternative splicing of the ryanodine receptor subtype 3 (RyR3) produces a short isoform (RyR3S) able to negatively regulate the ryanodine receptor subtype 2 (RyR2), as shown in cultured smooth muscle cells from mice. The RyR2 subtype has a crucial role in the control of vascular reactivity via the fine tuning of Ca(2+) signaling to regulate cerebral vascular tone. In this study, we have shown that the inhibition of RyR3S expression by a specific antisense oligonucleotide (asRyR3S) was able to increase the Ca(2+) signals implicating RyR2 in cerebral arteries ex vivo. Moreover, we tried to inhibit the expression of RyR3S in vivo. The asRyR3S was complexed with JetPEI and injected intravenously coupled with several methods known to induce a blood brain barrier disruption. We tested solutions to induce osmotic choc (mannitol), inflammation (bacteria lipopolysaccharide and pertussis toxin), vasoconstriction or dilatation (sumatriptan, phenylephrine, histamine), CD73 activation (NECA) and lipid instability (Tween80). All tested technics failed to target asRyR3 in the cerebral arteries wall, whereas the molecule was included in hepatocytes or cardiomyocytes. Our results showed that the RyR3 alternative splicing could have a function in cerebral arteries ex vivo; however, the disruption of the blood brain barrier could not induce the internalization of antisense oligonucleotides in the cerebral arteries, in order to prove the function of RYR3 short isoform in vivo. PMID- 25510227 TI - Analysis of passive cardiac constitutive laws for parameter estimation using 3D tagged MRI. AB - An unresolved issue in patient-specific models of cardiac mechanics is the choice of an appropriate constitutive law, able to accurately capture the passive behavior of the myocardium, while still having uniquely identifiable parameters tunable from available clinical data. In this paper, we aim to facilitate this choice by examining the practical identifiability and model fidelity of constitutive laws often used in cardiac mechanics. Our analysis focuses on the use of novel 3D tagged MRI, providing detailed displacement information in three dimensions. The practical identifiability of each law is examined by generating synthetic 3D tags from in silico simulations, allowing mapping of the objective function landscape over parameter space and comparison of minimizing parameter values with original ground truth values. Model fidelity was tested by comparing these laws with the more complex transversely isotropic Guccione law, by characterizing their passive end-diastolic pressure-volume relation behavior, as well as by considering the in vivo case of a healthy volunteer. These results show that a reduced form of the Holzapfel-Ogden law provides the best balance between identifiability and model fidelity across the tests considered. PMID- 25510230 TI - Etomidate, propofol and diazepam potentiate GABA-evoked GABAA currents in a cell line derived from human glioblastoma. AB - GABAA receptors are pentameric chloride ion channels that are opened by GABA. We have screened a cell line derived from human glioblastoma, U3047MG, for expression of GABAA receptor subunit isoforms and formation of functional ion channels. We identified GABAA receptors subunit alpha2, alpha3, alpha5, beta1, beta2, beta3, delta, gamma3, pi, and theta mRNAs in the U3047MG cell line. Whole cell GABA-activated currents were recorded and the half-maximal concentration (EC50) for the GABA-activated current was 36 MUM. The currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and enhanced by the benzodiazepine diazepam (1 MUM) and the general anesthetics etomidate and propofol (50 MUM). In line with the expressed GABAA receptors containing at least the alpha3beta3theta subunits, the receptors were highly sensitive to etomidate (EC50=55 nM). Immunocytochemistry identified expression of the alpha3 and beta3 subunit proteins. Our results show that the GABAA receptors in the glial cell line are functional and are modulated by classical GABAA receptor drugs. We propose that the U3047MG cell line may be used as a model system to study GABAA receptors function and pharmacology in glial cells. PMID- 25510231 TI - Telmisartan ameliorates cisplatin-induced nephrotoxicity by inhibiting MAPK mediated inflammation and apoptosis. AB - Nephrotoxicity is a major adverse effect of the widely used anticancer drug cisplatin. Oxidative stress, inflammation and apoptosis are implicated in the pathophysiology of cisplatin-induced acute renal injury. Moreover, cisplatin activates many signal transduction pathways involved in cell injury and death, particularly mitogen activated protein kinase (MAPK) pathway. With this background, we aimed to investigate the protective effect of telmisartan, a widely used antihypertensive drug, in cisplatin-induced nephrotoxicity model in rats. To accomplish this, male albino wistar rats (150-200 g) were divided into 6 groups: Normal, cisplatin-control, telmisartan (2.5, 5 and 10 mg/kg) and telmisartan per se treatment groups. Normal saline or telmisartan was administered orally to rats for 10 days and cisplatin was given on 7th day (8 mg/kg; i.p.) to induce nephrotoxicity. On 10th day, rats were killed and both the kidneys were harvested for biochemical, histopathological and molecular studies. Cisplatin injected rats showed depressed renal function, altered proxidant antioxidant balance and acute tubular necrosis which was significantly normalized by telmisartan co-treatment. Furthermore, cisplatin administration activated MAPK pathway that caused tubular inflammation and apoptosis in rats. Telmisartan treatment significantly prevented MAPK mediated inflammation and apoptosis. Among the three doses studied telmisartan at 10 mg/kg dose showed maximum nephroprotective effect which could be due to maintenance of cellular redox status and inhibition of MAPK activation. PMID- 25510232 TI - Melatonin ameliorates metabolic risk factors, modulates apoptotic proteins, and protects the rat heart against diabetes-induced apoptosis. AB - The present study investigated the ability of melatonin in reducing metabolic risk factors and cardiac apoptosis induced by diabetes. Streptozotocin (60 mg/kg, i.p.) was injected into male rats, and after diabetic induction melatonin (10mg/kg i.g.) was administered orally for 21 days. Diabetic hearts showed increased number of apoptotic cells with downregulation of Bcl-2 and activation of p53 and CD95 as well as the caspases 9, 8 and 3. In addition, there was a significant decrease in insulin level, hyperglycemia, elevated HOMA-IR, glycosylated hemoglobin (HbA1c), total lipids, triglycerides, total cholesterol, low and very low-density lipoprotein and decreased high-density lipoprotein. These changes were coupled with a significant increase in the activities of creatin kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in the serum of the diabetic rats indicating myocardium injury. Oral administration of melatonin for 3 weeks after diabetes induction ameliorated the levels of hyperglycemia, insulin, HbA1c, lipids profile and HOMA-IR. The oral melatonin treatment of diabetic rats significantly decreased the number of apoptotic cells in the heart compared to diabetic rats. It enhanced Bcl-2 expression and blocked the activation of CD95 as well as caspases 9, 8 and 3. These changes were accompanied with significant improvement of CK-MB and LDH in the serum indicating the ameliorative effect of melatonin on myocardium injury. Melatonin effectively ameliorated diabetic myocardium injury, apoptosis, reduced the metabolic risk factors and modulated important steps in both extrinsic and intrinsic pathways of apoptosis. Thus, melatonin may be a promising pharmacological agent for ameliorating potential cardiomyopathy associated with diabetes. PMID- 25510234 TI - Mast cell promotion of T cell-driven antigen-induced arthritis despite being dispensable for antibody-induced arthritis in which T cells are bypassed. AB - OBJECTIVE: The function of mast cells (MCs) in autoimmune disorders has been a subject of controversy recently. MC-deficient Kit(W/W-v) mice were found to be resistant to K/BxN serum-transfer arthritis, whereas Kit(W-sh/W-sh) mice and a genetic model of MC deficiency independent of the Kit mutation were found to be fully susceptible. This debate might lead to the assumption that MCs are dispensable in autoimmunity in general. Thus, the purpose of this study was to examine the relevance of MCs to arthritis using a genetic model of inducible MC deficiency without compromised Kit signaling. METHODS: We compared MC functions in K/BxN serum-induced arthritis and in collagen-induced arthritis (CIA) in a mouse model of inducible MC deficiency by analyzing joint inflammation, parameters of cartilage degradation and bone erosion, and the autoreactive adaptive immune response. RESULTS: We observed a redundant role of MCs in K/BxN serum-induced arthritis, where joint inflammation is triggered by cartilage-bound immune complexes independently of T cells. In contrast, we found MCs to be critically relevant in CIA, which is provoked by two arms of autoimmune attack: autoreactive antibodies and effector T cells. In addition to diminished joint inflammation in the absence of MCs, we found a dramatic loss of T cell expansion upon immunization, accompanied by reduced T cell cytokine responses. CONCLUSION: In this analysis of an arthritis model in which the cellular arm of adaptive immunity was not bypassed, we identified MCs as important promoters of T cell conditioned autoimmune disorders and, consequently, as potential therapeutic targets in rheumatoid arthritis. PMID- 25510233 TI - The Ethics of Ironic Science in Its Search for Spoof. AB - The goal of most scientific research published in peer-review journals is to discover and report the truth. However, the research record includes tongue-in cheek papers written in the conventional form and style of a research paper. Although these papers were intended to be taken ironically, bibliographic database searches show that many have been subsequently cited as valid research, some in prestigious journals. We attempt to understand why so many readers cited such ironic science seriously. We draw from the literature on error propagation in research publication for ways categorize citations. We adopt the concept of irony from the fields of literary and rhetorical criticism to detect, characterize, and analyze the interpretations in the more than 60 published research papers that cite an instance of ironic science. We find a variety of interpretations: some citing authors interpret the research as valid and accept it, some contradict or reject it, and some acknowledge its ironic nature. We conclude that publishing ironic science in a research journal can lead to the same troubles posed by retracted research, and we recommend relevant changes to publication guidelines. PMID- 25510235 TI - Sequence-dependent dsDNA-templated formation of fluorescent copper nanoparticles. AB - There are only a few systematic rules about how to selectively control the formation of DNA-templated metal nanoparticles (NPs) by varying sequence combinations of double-stranded DNA (dsDNA), although many attempts have been made. Herein, we develop a facile method for sequence-dependent formation of fluorescent CuNPs by using dsDNA as templates. Compared with random sequences, AT sequences are better templates for highly fluorescent CuNPs. Other specific sequences, for example, GC sequences, do not induce the formation of CuNPs. These results shed light on directed DNA metallization in a sequence-specific manner. Significantly, both the fluorescence intensity and the fluorescence lifetime of CuNPs can be tuned by the length or the sequence of dsDNA. In order to demonstrate the promising practicality of our findings, a sensitive and label free fluorescence nuclease assay is proposed. PMID- 25510236 TI - The implications of a tracheal bronchus on one-lung ventilation and fibreoptic bronchoscopy in a patient undergoing thoracic surgery: a case report. AB - PURPOSE: Due to its anatomical complexity, a tracheal bronchus has important clinical implications for one-lung ventilation (OLV). We present a case of successful OLV in a patient with a high a type I (i.e., high take-off) tracheal bronchus. This anomaly presented unusual fibreoptic bronchoscopic (FOB) views that were difficult to discern from the normal carinal bifurcation. CLINICAL FEATURES: A 35-yr-old male presented for posterior basal segmentectomy of the left lower lobe under video-assisted thoracoscopy. The preoperative chest radiography was reported as normal, but a computed tomography scan of the chest revealed a right upper lobe tracheal bronchus. The inlet of the tracheal bronchus was located high above the carina, and the distal trachea had significant narrowing. Because the main trachea was divided into a tracheal bronchus and a distal trachea with similar diameters and with an acute angle of divergence, FOB views of the tracheal bronchus take-off appeared similar to the normal carinal bifurcation. Moreover, the actual carina had an atypical appearance with the main bronchi shifted laterally and a blunted carinal ridge. As a result of this atypical tracheobronchial anatomy, we used an Arndt endobronchial blocker system instead of a double-lumen tube (DLT) for right-sided OLV. One-lung ventilation was satisfactory throughout the uncomplicated operation. CONCLUSION: Careful preoperative assessment of tracheobronchial anatomy is imperative in order to choose an appropriate method of OLV and prevent potential complications. In a type I tracheal bronchus with a narrowed distal trachea, a bronchial blocker may have advantages over the conventional DLT in achieving OLV. PMID- 25510237 TI - Survey of pre-clerkship medical students' knowledge and perceptions of anesthesiology at one Canadian university. PMID- 25510238 TI - Two-in-one aortic valve sizing and valvuloplasty conductance balloon catheter. AB - BACKGROUND: Inaccurate aortic valve sizing and selection is linked to paravalvular leakage in transcatheter aortic valve replacement (TAVR). Here, a novel sizing valvuloplasty conductance balloon (SVCB) catheter is shown to be accurate, reproducible, unbiased, and provides real-time tool for aortic valve sizing that fits within the standard valvuloplasty procedure. METHODS AND RESULTS: The SVCB catheter is a valvuloplasty device that uses real-time electrical conductance measurements based on Ohm's Law to size the balloon opposed against the aortic valve at any given inflation pressure. Accuracy and repeatability of the SVCB catheter was performed on the bench in phantoms of known dimension and ex vivo in three domestic swine aortic annuli with comparison to computed tomography (CT) and dilator measurements. Procedural workflow and safety was demonstrated in vivo in three additional domestic swine. SVCB catheter measurements had negligible bias or error for bench accuracy considered as the gold standard (Bias: -0.11 +/- 0.26 mm; Error: 1.2%), but greater disagreement in ex vivo versus dilators (Bias: -0.3 +/- 1.1 mm; Error: 4.5%), and ex vivo versus CT (Bias: -1.0 +/- 1.6 mm; Error: 8.7%). The dilator versus CT accuracy showed similar agreement (Bias: -0.9 +/- 1.5 mm; Error: 7.3%). Repeatability was excellent on the bench (Bias: 0.02 +/- 0.12 mm; Error: 0.5%) and ex vivo (Bias: 0.4 +/- 0.9 mm; Error: 4.6%). In animal studies, the device fit well within the procedural workflow with no adverse events or complications. CONCLUSIONS: Due to the clinical relevance of this accurate, repeatable, unbiased, and real-time sizing measurement, the SVCB catheter may provide a useful tool prior to TAVR. These findings merit a future human study. PMID- 25510239 TI - Knowledge and attitude of healthcare workers about Middle East Respiratory Syndrome in multispecialty hospitals of Qassim, Saudi Arabia. AB - BACKGROUND: With the increase in prevalence of Middle East Respiratory Syndrome (MERS), healthcare workers (HCWs) are at risk of acquiring and subsequently transmitting this lethal virus. In view of this, HCWs were evaluated for their knowledge of and attitude towards MERS in Saudi Arabia. METHODS: A cross sectional study was performed in two hospitals of Qassim region in Saudi Arabia. A total of 280 healthcare workers were selected to participate in this study. Knowledge and attitude were assessed by using self-administered and pretested questionnaire. Descriptive statistics were carried out to express participants' demographic information, mean knowledge score and mean attitude score of HCWs. Inferential statistics (Mann-Whitney U test and Kruskal Wallis tests, p < 0.05) were used to examine differences between study variables. Chi squares tests were used to assess the association between study variables and attitude questions. Spearman's rho correlation was used to identify the association between the knowledge, attitude scores. RESULT: Participants demonstrated good knowledge and positive attitude towards MERS. The mean scores of knowledge and attitude were 9.45 +/- 1.69 (based on 13 knowledge questions) and 1.82 +/- 0.72 (based on 7 attitude questions). The correlation between knowledge and attitude was significant (correlation coefficient: 0.12; P <0.001). HCWs were less educated about the management (42.4%), source (66%) and consequences of MERS (67.3%), while a majority of them were well aware of the hallmark symptoms (96%), precautionary measures (96%) and hygiene issues (94%). Although the majority of respondents showed positive attitude towards the use of protective measures (1.52 +/- 0.84), their attitude was negative towards their active participation in infection control program (2.03 +/- 0.97). Gender and experience were significantly associated with knowledge and attitude (P < 0.05). CONCLUSIONS: The findings of this study showed that healthcare workers in Qassim region of Saudi Arabia have good knowledge and positive attitude towards MERS. Yet there are areas where low knowledge and negative attitude of HCWs was observed. However, studies are required to assess the knowledge and attitude of HCWs at national level so that effective interventions could be designed as surveillance and infection control measures are critical to global public health. PMID- 25510240 TI - Association of Organic Cation Transporter 1 With Intolerance to Metformin in Type 2 Diabetes: A GoDARTS Study. AB - Metformin is the most widely prescribed medication for the treatment of type 2 diabetes (T2D). However, gastrointestinal (GI) side effects develop in ~25% of patients treated with metformin, leading to the discontinuation of therapy in ~5% of cases. We hypothesized that reduced transport of metformin via organic cation transporter 1 (OCT1) could increase metformin concentration in the intestine, leading to increased risk of severe GI side effects and drug discontinuation. We compared the phenotype, carriage of reduced-function OCT1 variants, and concomitant prescribing of drugs known to inhibit OCT1 transport in 251 intolerant and 1,915 fully metformin-tolerant T2D patients. We showed that women and older people were more likely to be intolerant to metformin. Concomitant use of medications, known to inhibit OCT1 activity, was associated with intolerance (odds ratio [OR] 1.63 [95% CI 1.22-2.17], P = 0.001) as was carriage of two reduced-function OCT1 alleles compared with carriage of one or no deficient allele (OR 2.41 [95% CI 1.48-3.93], P < 0.001). Intolerance was over four times more likely to develop (OR 4.13 [95% CI 2.09-8.16], P < 0.001) in individuals with two reduced-function OCT1 alleles who were treated with OCT1 inhibitors. Our results suggest that reduced OCT1 transport is an important determinant of metformin intolerance. PMID- 25510241 TI - Operating theatre time, where does it all go? A prospective observational study. AB - OBJECTIVE: To assess the accuracy of surgeons and anaesthetists in predicting the time it will take them to complete an operation or procedure and therefore explain some of the difficulties encountered in operating theatre scheduling. DESIGN: Single centre, prospective observational study. SETTING: Plastic, orthopaedic, and general surgical operating theatres at a level 1 trauma centre serving a population of about 370,000. PARTICIPANTS: 92 operating theatre staff including surgical consultants, surgical registrars, anaesthetic consultants, and anaesthetic registrars. INTERVENTION: Participants were asked how long they thought their procedure would take. These data were compared with actual time data recorded at the end of the case. PRIMARY OUTCOME MEASURE: Absolute difference between predicted and actual time. RESULTS: General surgeons underestimated the time required for the procedure by 31 minutes (95% confidence interval 7.6 to 54.4), meaning that procedures took, on average, 28.7% longer than predicted. Plastic surgeons underestimated by 5 minutes (-12.4 to 22.4), with procedures taking an average of 4.5% longer than predicted. Orthopaedic surgeons overestimated by 1 minute (-16.4 to 14.0), with procedures taking an average of 1.1% less time than predicted. Anaesthetists underestimated by 35 minutes (21.7 to 48.7), meaning that, on average, procedures took 167.5% longer than they predicted. The four specialty mean time overestimations or underestimations are significantly different from each other (P=0.01). The observed time differences between anaesthetists and both orthopaedic and plastic surgeons are significantly different (P<0.05), but the time difference between anaesthetists and general surgeons is not significantly different. CONCLUSION: The inability of clinicians to predict the necessary time for a procedure is a significant cause of delay in the operating theatre. This study suggests that anaesthetists are the most inaccurate and highlights the potential differences between specialties in what is considered part of the "anaesthesia time." PMID- 25510242 TI - Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide. AB - Despite recent treatment improvements, multiple myeloma remains an incurable disease. Since antibody-dependent cell-mediated cytotoxicity is an important effector mechanism of daratumumab, we explored the possibility of improving daratumumab-mediated cell-mediated cytotoxicity by blocking natural killer cell inhibitory receptors with the human monoclonal anti-KIR antibody IPH2102, next to activation of natural killer cells with the immune modulatory drug lenalidomide. In 4-hour antibody-dependent cell-mediated cytotoxicity assays, IPH2102 did not induce lysis of multiple myeloma cell lines, but it did significantly augment daratumumab-induced myeloma cell lysis. Also in an ex vivo setting, IPH2102 synergistically improved daratumumab-dependent lysis of primary myeloma cells in bone marrow mononuclear cells (n=21), especially in patients carrying the FcgammaRIIIa-158F allele or the FcgammaRIIa-131R allele, who bind IgG1 with lower affinity than patients carrying the FcgammaRIIIa-158V allele or the FcgammaRIIa 131H allele. Finally, a further synergistically improved myeloma cell lysis with the daratumumab-IPH2102 combination was observed by adding lenalidomide, which suggests that more effective treatment strategies can be designed for multiple myeloma by combining daratumumab with agents that independently modulate natural killer cell function. PMID- 25510245 TI - Total-scattering pair-distribution function of organic material from powder electron diffraction data. AB - This paper shows that pair-distribution function (PDF) analyses can be carried out on organic and organometallic compounds from powder electron diffraction data. Different experimental setups are demonstrated, including selected area electron diffraction and nanodiffraction in transmission electron microscopy or nanodiffraction in scanning transmission electron microscopy modes. The methods were demonstrated on organometallic complexes (chlorinated and unchlorinated copper phthalocyanine) and on purely organic compounds (quinacridone). The PDF curves from powder electron diffraction data, called ePDF, are in good agreement with PDF curves determined from X-ray powder data demonstrating that the problems of obtaining kinematical scattering data and avoiding beam damage of the sample are possible to resolve. PMID- 25510243 TI - Multiple human papillomavirus infections are highly prevalent in the anal canal of human immunodeficiency virus-positive men who have sex with men. AB - BACKGROUND: Anal cancer has become one of the most common non-AIDS-defined tumors among Human Immunodeficiency Virus-positive (HIV+) individuals, and a rise in its incidence among HIV+ Men who have Sex with Men (MSM) has been shown, despite the introduction of Highly Active Anti-Retroviral Therapy (HAART). Human Papillomavirus (HPV) infections are highly prevalent among HIV+ MSM and recent studies have shown high rates of HPV-associated anal intraepithelial neoplasia (AIN) and anal cancer among this population. METHODS: In the present study we determined the prevalence and nature of HPV co-infections in the anal canal of 324 HIV+ MSM attending a high specialty medical center in Mexico City, DNA extraction and amplification with generic primers for HPV was performed, followed by detection of specific types and co-infections with INNO-Lipa, and identification of variants by amplification and sequencing of the E6 and LCR region of HPV 16. RESULTS: We found a very high prevalence of HPV infections among this cohort (86%), with more than one fourth of them (28%) positive for type 16. Among HPV16-positive patients, European variants were the most prevalent, followed by Asian-American ones. Among these individuals (HPV-16+), we identified co-infections with other 21 HPV types namely; 11, 51, 52, 6, 66, 68, 74, 18, 45, 35, 26, 44, 70, 53, 54, 82, 31, 33, 56, 58, 59. CONCLUSIONS: HIV+ MSM show a very high rate of HPV infections in the anal canal and those with type 16 exhibited a multiplicity of associated types. This study emphasizes the need for an early detection of HPV infections among HIV+ MSM in order to establish its utility to prevent anal neoplasia and cancer. PMID- 25510244 TI - Embryo selection: the role of time-lapse monitoring. AB - In vitro fertilization has been available for over 3 decades. Its use is becoming more widespread worldwide, and in the developed world, up to 5% of children have been born following IVF. It is estimated that over 5 million children have been conceived in vitro. In addition to giving hope to infertile couples to have their own family, in vitro fertilization has also introduced risks as well. The risk of multiple gestation and the associated maternal and neonatal morbidity/mortality has increased significantly over the past few decades. While stricter transfer policies have eliminated the majority of the high-order multiples, these changes have not yet had much of an impact on the incidence of twins. A twin pregnancy can be avoided by the transfer of a single embryo only. However, the traditionally used method of morphologic embryo selection is not predictive enough to allow routine single embryo transfer; therefore, new screening tools are needed. Time-lapse embryo monitoring allows continuous, non-invasive embryo observation without the need to remove the embryo from optimal culturing conditions. The extra information on the cleavage pattern, morphologic changes and embryo development dynamics could help us identify embryos with a higher implantation potential. These technologic improvements enable us to objectively select the embryo(s) for transfer based on certain algorithms. In the past 5-6 years, numerous studies have been published that confirmed the safety of time lapse technology. In addition, various markers have already been identified that are associated with the minimal likelihood of implantation and others that are predictive of blastocyst development, implantation potential, genetic health and pregnancy. Various groups have proposed different algorithms for embryo selection based on mostly retrospective data analysis. However, large prospective trials are needed to study the full benefit of these (and potentially new) algorithms before their introduction into daily practice can be recommended. PMID- 25510246 TI - Experimental validation of predicted subcellular localizations of human proteins. AB - BACKGROUND: Computational methods have been widely used for the prediction of protein subcellular localization. However, these predictions are rarely validated experimentally and as a result remain questionable. Therefore, experimental validation of the predicted localizations is needed to assess the accuracy of predictions so that such methods can be confidently used to annotate the proteins of unknown localization. Previously, we published a method called ngLOC that predicts the localization of proteins targeted to ten different subcellular organelles. In this short report, we describe the accuracy of these predictions using experimental validations. FINDINGS: We have experimentally validated the predicted subcellular localizations of 114 human proteins corresponding to nine different organelles in normal breast and breast cancer cell lines using live cell imaging/confocal microscopy. Target genes were cloned into expression vectors as GFP fusions and cotransfected with RFP-tagged organelle-specific gene marker into normal breast epithelial and breast cancer cell lines. Subcellular localization of each target protein is confirmed by colocalization with a co expressed organelle-specific protein marker. Our results showed that about 82.5% of the predicted subcellular localizations coincided with the experimentally validated localizations. The highest agreement was found in the endoplasmic reticulum proteins, while the cytoplasmic location showed the least concordance. With the exclusion of cytoplasmic location, the average prediction accuracy increased to 90.4%. In addition, there was no difference observed in the protein subcellular localization between normal and cancer breast cell lines. CONCLUSIONS: The experimentally validated accuracy of ngLOC method with (82.5%) or without cytoplasmic location (90.4%) nears the prediction accuracy of 89%. These results demonstrate that the ngLOC method can be very useful for large scale annotation of the unknown subcellular localization of proteins. PMID- 25510247 TI - Engineering of Serine-Deamination pathway, Entner-Doudoroff pathway and pyruvate dehydrogenase complex to improve poly(3-hydroxybutyrate) production in Escherichia coli. AB - BACKGROUND: Poly(3-hydroxybutyrate) (PHB), a biodegradable bio-plastic, is one of the most common homopolymer of polyhydroxyalkanoates (PHAs). PHB is synthesized by a variety of microorganisms as intracellular carbon and energy storage compounds in response to environmental stresses. Bio-based production of PHB from renewable feedstock is a promising and sustainable alternative to the petroleum based chemical synthesis of plastics. In this study, a novel strategy was applied to improve the PHB biosynthesis from different carbon sources. RESULTS: In this research, we have constructed E. coli strains to produce PHB by engineering the Serine-Deamination (SD) pathway, the Entner-Doudoroff (ED) pathway, and the pyruvate dehydrogenase (PDH) complex. Firstly, co-overexpression of sdaA (encodes L-serine deaminase), L-serine biosynthesis genes and pgk (encodes phosphoglycerate kinase) activated the SD Pathway, and the resulting strain SD02 (pBHR68), harboring the PHB biosynthesis genes from Ralstonia eutropha, produced 4.86 g/L PHB using glucose as the sole carbon source, representing a 2.34-fold increase compared to the reference strain. In addition, activating the ED pathway together with overexpressing the PDH complex further increased the PHB production to 5.54 g/L with content of 81.1% CDW. The intracellular acetyl-CoA concentration and the [NADPH]/[NADP(+)] ratio were enhanced after the modification of SD pathway, ED pathway and the PDH complex. Meanwhile, these engineering strains also had a significant increase in PHB concentration and content when xylose or glycerol was used as carbon source. CONCLUSIONS: Significant levels of PHB biosynthesis from different kinds of carbon sources can be achieved by engineering the Serine-Deamination pathway, Entner-Doudoroff pathway and pyruvate dehydrogenase complex in E. coli JM109 harboring the PHB biosynthesis genes from Ralstonia eutropha. This work demonstrates a novel strategy for improving PHB production in E. coli. The strategy reported here should be useful for the bio based production of PHB from renewable resources. PMID- 25510248 TI - Metabolomics reveal 1-palmitoyl lysophosphatidylcholine production by peroxisome proliferator-activated receptor alpha. AB - PPARalpha is well known as a master regulator of lipid metabolism. PPARalpha activation enhances fatty acid oxidation and decreases the levels of circulating and cellular lipids in obese diabetic patients. Although PPARalpha target genes are widely known, little is known about the alteration of plasma and liver metabolites during PPARalpha activation. Here, we report that metabolome analysis implicated upregulation of many plasma lysoGP species during bezafibrate (PPARalpha agonist) treatment. In particular, 1-palmitoyl lysophosphatidylcholine [LPC(16:0)] is increased by bezafibrate treatment in both plasma and liver. In mouse primary hepatocytes, the secretion of LPC(16:0) increased on PPARalpha activation, and this effect was attenuated by PPARalpha antagonist treatment. We demonstrated that Pla2g7 gene expression levels in the murine hepatocytes were increased by PPARalpha activation, and the secretion of LPC(16:0) was suppressed by Pla2g7 siRNA treatment. Interestingly, LPC(16:0) activates PPARalpha and induces the expression of PPARalpha target genes in hepatocytes. Furthermore, we showed that LPC(16:0) has the ability to recover glucose uptake in adipocytes induced insulin resistance. These results reveal that LPC(16:0) is induced by PPARalpha activation in hepatocytes; LPC(16:0) contributes to the upregulation of PPARalpha target genes in hepatocytes and the recovery of glucose uptake in insulin-resistant adipocytes. PMID- 25510249 TI - Activation of prostaglandin E2-EP4 signaling reduces chemokine production in adipose tissue. AB - Inflammation of adipose tissue induces metabolic derangements associated with obesity. Thus, determining ways to control or inhibit inflammation in adipose tissue is of clinical interest. The present study tested the hypothesis that in mouse adipose tissue, endogenous prostaglandin E2 (PGE2) negatively regulates inflammation via activation of prostaglandin E receptor 4 (EP4). PGE2 (5-500 nM) attenuated lipopolysaccharide-induced mRNA and protein expression of chemokines, including interferon-gamma-inducible protein 10 and macrophage-inflammatory protein-1alpha in mouse adipose tissue. A selective EP4 antagonist (L161,982) reversed, and two structurally different selective EP4 agonists [CAY10580 and CAY10598] mimicked these actions of PGE2. Adipose tissue derived from EP4 deficient mice did not display this response. These findings establish the involvement of EP4 receptors in this anti-inflammatory response. Experiments performed on adipose tissue from high-fat-fed mice demonstrated EP4-dependent attenuation of chemokine production during diet-induced obesity. The anti inflammatory actions of EP4 became more important on a high-fat diet, in that EP4 activation suppressed a greater variety of chemokines. Furthermore, adipose tissue and systemic inflammation was enhanced in high-fat-fed EP4-deficient mice compared with wild-type littermates, and in high-fat-fed untreated C57BL/6 mice compared with mice treated with EP4 agonist. These findings provide in vivo evidence that PGE2-EP4 signaling limits inflammation. In conclusion, PGE2, via activation of EP4 receptors, functions as an endogenous anti-inflammatory mediator in mouse adipose tissue, and targeting EP4 may mitigate adipose tissue inflammation. PMID- 25510250 TI - Factors Associated With Hyperphagic Behavior in Patients With Dementia Living at Home. AB - OBJECTIVE: To investigate the prevalence and patterns of and factors associated with hyperphagic behavior in Taiwanese patients with dementia living at home. METHODS: A cross-sectional and correlational design was used. A total of 104 patients with dementia and their primary caregivers were recruited from the geriatric, neurology, and memory clinics of a regional hospital, a medical center and two day-care centers in central Taiwan. The data related to hyperphagic behavior, functional abilities, medical conditions, body weight, and demographic characteristics of patients as well as the demographic characteristics of their primary caregivers were collected between January and May 2013. RESULTS: Based on a strict criterion (a median score of 3 for the hyperphagic subscale), the prevalence of hyperphagia in patients with dementia was 53.8%. Specific hyperphagic patterns exhibited included increased food intake (49% of patients with dementia), hoarding (8.7%), oral exploration (6.8%), and pica (3.9%). Years of education of the patient, the use of antipsychotics in patients, and the age of primary caregivers explained 16.3% of the variance in hyperphagic behavior subscale scores (F = 6.47, p < .001). CONCLUSIONS: For the early identification and treatment of hyperphagic behavior in patients with dementia in home care or in clinic services provided by health professionals, specific attention should be paid to the usual eating behaviors of patients with lower levels of education or who are taking antipsychotic medication or those who have a female primary caregiver. PMID- 25510252 TI - Magic for mastalgia with HT7. PMID- 25510251 TI - GNB3 and FTO Polymorphisms and Pregnancy Weight Gain in Black Women. AB - BACKGROUND: Gestational weight gain (GWG) is a modifiable risk factor for obesity in women. Black women have the greatest prevalence of high body mass, which predisposes them to excessive GWG. Increased understanding of genetic influences on GWG has implications for the health of women. The purpose of this study was to explore the associations of GNB3 and FTO risk alleles in pregnant women with prepregnancy body mass index (BMI), GWG, and postpartum and infant birth weights. RESEARCH DESIGN AND METHODS: This was an observational, prospective candidate gene association study. Pregnant, low-income Black women (N = 97) were enrolled in early pregnancy and followed until 6 months postpartum. RESULTS: GWG differed depending on number of FTO risk alleles. The mean 6-month postpartum BMI differed, although not significantly, by 4 kg/m(2) between homozygous women. There was an interaction between the FTO risk allele and prepregnancy BMI (p = .022), with obese homozygote AA women having significantly higher mean GWG than obese TT women. When controlling for age and smoking, the FTO gene and physical activity predicted GWG (p = .032). Although not statistically significant, women who carried the GNB3 T risk allele gained 6 pounds more than noncarriers, and mean 6-month postpartum BMI differed by 2.2 kg/m(2) between homozygous women. Neither the GNB3 nor FTO gene predicted prepregnancy BMI, infant birth weight, or postpartum weight. CONCLUSION: Obese women homozygous for the FTO risk allele were at greater risk of excessive GWG compared to nonrisk allele homozygous obese women or nonobese women. This study provides evidence of the FTO gene's effect on GWG in Black women. PMID- 25510253 TI - Standardisation of moxibustion: challenges and future development. AB - International organisations such as WHO and the International Organization for Standardization are increasingly committed to the development of traditional Chinese medicine (TCM). Moxibustion is an integral modality of acupuncture that has been in use for thousands of years. It stands out as a health choice due to its potential effects in disease prevention, health promotion and maintenance, as well as affordability and accessibility. As the use of moxibustion increases, concerns are being raised regarding its safety and quality. The need to establish standards to protect patient safety is paramount in all medical fields. As a form of medical practice, it is essential to develop moxibustion standards in the areas of terminology, moxibustion products, treatment rooms and practice to ensure its harmonisation and safe usage. The evidence base guiding policy and decision making has to be based on evidence from basic and clinical research. Promoting strategic basic and clinical research on the safety and effectiveness of moxibustion will answer some of the fundamental questions surrounding moxibustion, create a climate of awareness and acceptance and, in turn, drive its standardisation. PMID- 25510254 TI - Visualizing cancer and response to therapy in vivo using Cy5.5-labeled factor VIIa and anti-tissue factor antibody. AB - We have developed a specific technique for imaging cancer in vivo using Cy5.5 labeled factor VIIa (fVIIa), clotting-deficient FFRck-fVIIa, paclitaxel-FFRck fVIIa, and anti-tissue factor (TF) antibody. FVIIa is the natural ligand for TF. We took advantage of the fact that vascular endothelial cells (VECs) in cancer, but not normal tissue, aberrantly express TF due to its induction by vascular endothelial growth factor (VEGF). Under physiological conditions, TF is expressed by stromal cells and outer blood vessel layers (smooth muscle and adventitia), but not by VECs. We hypothesized that labeled fVIIa or anti-TF antibodies could be used to image the tumor vasculature in vivo. To test this, Cy5.5-labeled fVIIa, FFRck-fVIIa, paclitaxel-FFRck-fVIIa, and anti-TF antibody were developed and administered to athymic nude mice carrying xenografts including glioma U87EGFRviii, pancreatic cancer ASPC-1 and Mia PaCa-2, and squamous cell carcinoma KB-V1. Cy5.5 labeled with these targeting proteins specifically localized to the tumor xenografts for at least 14 days but unconjugated Cy5.5 did not localize to any xenografts or organs. This method of imaging TF in the tumor VECs may be useful in detecting primary tumors and metastases as well as monitoring in vivo therapeutic responses. PMID- 25510256 TI - The role of the NF-kappaB, SAPK/JNK, and TLR4 signalling pathways in the responses of RAW 264.7 cells to extremely low-intensity microwaves. AB - PURPOSE: To investigate the role of the toll-like receptor 4 (TLR4), nuclear factor kappaB (NF-kappaB), and stress activated protein kinases/Jun N-terminal kinase (SAPK/JNK) signalling pathways in the responses of RAW 264.7 macrophages to low-intensity microwaves (MW). MATERIALS AND METHODS: Three inhibitors of TLR4, SAPK/JNK, and NF-kappaB signalling, namely CLI-095, SP600125, and IKK Inhibitor XII, respectively, were added to cultured RAW 264.7 macrophages before MW treatment. RESULTS: MW exposure resulted in stimulation of RAW 264.7 cell activity manifested by increases in cytokine production and the stimulation of cell signalling. The blocking of a key kinase of the NF-kappaB pathway by IKK Inhibitor XII resulted in decreased MW-induced TLR4 expression and increased SAPK/JNK and NF-kappaB phosphorylation in irradiated cells. In addition, IKK Inhibitor XII significantly decreased tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin 1alpha (IL-1alpha), interleukin 6 (IL 6), and interleukin 10 (IL-10) production in both exposed and unexposed RAW 264.7 macrophages. Inhibitor SP6000125 did not prevent an MW effect on signal proteins with the exception of decreased SAPK/JNK phosphorylation in RAW 264.7 cells. Cytokine production was markedly decreased in MW-exposed cells cultured with SP6000125. The inhibitor of TLR4, CLI-095, did not affect signal proteins and cytokine production changes in MW-exposed cells. CONCLUSIONS: The results suggest that low-intensity MW promotes macrophage activity via mechanisms involving cellular signalling, particularly the NF-kappaB pathway. PMID- 25510255 TI - Effect of whole-body exposure to the 848.5 MHz code division multiple access (CDMA) electromagnetic field on adult neurogenesis in the young, healthy rat brain. AB - INTRODUCTION: Whether exposure to the 848.5 MHz code division multiple access (CDMA) signal affects adult neurogenesis is unclear. MATERIALS AND METHODS: An animal experiment was performed with a reverberation chamber designed as a whole body CDMA exposure system. Male Sprague-Dawley rats were assigned to three groups (n = 6 per group): Cage-control, sham-exposed, and CDMA-exposed groups. Rats in the CDMA-exposed group were exposed to the CDMA signal at a 2 W/kg whole-body specific absorption rate (SAR) for 1 or 8 h daily, 5 days per week, for 2 weeks. Rats received a single intraperitoneal injection of Bromodeoxyuridine (BrdU) to label proliferative cells daily for the last five consecutive days of CDMA signal exposure. An unbiased stereological method was used to estimate the number of BrdU(+) cells in the subventricular zone (SVZ) and dentate gyrus (DG). RESULTS: We found no significant changes in the number of BrdU(+) cells in the SVZ or DG in the CDMA-exposed rats, compared with rats in the cage-control and sham-exposed groups (p > 0.05). CONCLUSION: Our results suggest that exposure to the CDMA signal does not affect neurogenesis in the adult rat brain, at least under our experimental conditions. PMID- 25510257 TI - The contribution of thermally labile sugar lesions to DNA double-strand break formation in cells grown in the presence of BrdU. AB - PURPOSE: Radiosensitization by bromodeoxyuridine (BrdU) is commonly attributed to an increase in the yield of double-strand breaks (DSB) in the DNA and an associated decrease in the reparability of these lesions. Radiation chemistry provides a mechanism for the increased yield of DSB through the generation, after bromine loss, of a highly reactive uracilyl radical that attacks the sugar moiety of the nucleotide to produce a single-strand break (SSB). The effects underpinning DSB repair inhibition remain, in contrast, incompletely characterized. A possible source of reduced reparability is a change in the nature or complexity of the DSB in BrdU-substituted DNA. Recent studies show that DSB-complexity or DSB-nature may also be affected by the presence within the cluster of thermally labile sugar lesions (TLSL) that break the DNA backbone only if they chemically evolve to SSB, a process thought to occur within the first hour post-irradiation. Since BrdU radiosensitization might be associated with increased yields and reduced reparability of DSB, we investigated whether BrdU underpins these effects by shifting the balance in the generation of TLSL. METHODS AND MATERIALS: We employed asymmetric-field-inversion gel electrophoresis (AFIGE), a pulsed-field gel electrophoresis (PFGE) method to quantitate DSB in a battery of five cells lines grown in the presence of different concentrations of BrdU. We measured specifically the yields of promptly forming DSB (prDSB) using low temperature lysis protocols, and the yields of total DSB (tDSB = prDSB + tlDSB; tlDSB form after evolution to SSB of TLSL) using high temperature lysis protocols. RESULTS: We report that incorporation of BrdU generates similar increases in the formation of tlDSB and prDSB, but variations are noted among the different cell lines tested. CONCLUSIONS: The similar increase in the yields of tlDSB and prDSB in BrdU substituted DNA showed that shifts in the yields of these forms of lesions could not be invoked to explain BrdU radiosensitization. PMID- 25510258 TI - Cell inactivation by combined low dose-rate irradiation and intermittent hypoxia. AB - PURPOSE: To investigate in detail the earlier observed combined effect of low dose-rate beta-irradiation delivered at a dose-rate of 15 mGy/h and continued intermittent hypoxia that leads to extensive cell death after approximately 3-6 weeks. MATERIAL AND METHODS: Continuous low dose-rate beta-irradiation at a dose rate of 15, 1.5 or 0.6 mGy/h was given by incorporation of [(3)H]-labelled valine into cellular protein. The cells were cultivated in an atmosphere with 4% O2 using an INVIVO2 hypoxia glove box. Clonogenic capacity, cell-cycle distribution and cellular respiration were monitored throughout the experiments. RESULTS: After 3-6 weeks most cells died in response to the combined treatment, giving a surviving fraction of only 1-2%. However, on continued cultivation a few cells survived and restarted proliferation as the cellular oxygen supply increased with the reduced cell number. Irradiating the T-47D cells grown in an atmosphere with 4% O2 at dose-rates 10 and 25 times lower than 15 mGy/h did not have a pronounced effect on the clonogenic capacity with surviving fractions of 60-80%. CONCLUSIONS: Treatment of T-47D cells with low dose-rate beta-irradiation leads to a specific effect on intermittent hypoxic cells, inactivating more than 98% of the cells in the population. Given improved oxygen conditions, the few surviving cells can restart their proliferation. PMID- 25510259 TI - Neutron autoradiography to study boron compound microdistribution in an oral cancer model. AB - PURPOSE: We previously reported the therapeutic efficacy of Sequential Boron Neutron Capture Therapy (Seq-BNCT), i.e., BPA (boronophenylalanine) - BNCT followed by GB-10 (decahydrodecaborate) - BNCT 1 or 2 days later, in the hamster cheek pouch oral cancer model. We have utilized the neutron autoradiography methodology to study boron microdistribution in tissue. The aim was to use this method to evaluate if the distribution of GB-10 is altered by prior application of BPA-BNCT in Sequential BNCT protocols. MATERIALS AND METHODS: Extensive qualitative and quantitative autoradiography analyses were performed in the following groups: G1 (animals without boron); G2 (animals injected with BPA); G3 (animals injected with GB-10); G4 (same as G3, 24 h after BPA-BNCT); and G5 (same protocol as G4, 48 h interval). RESULTS: A detailed study of boron localization in the different tissue structures of tumor, premalignant and normal tissue in the hamster cheek pouch was performed. GB-10 accumulated preferentially in non neoplastic connective tissue, whereas for BPA neoplastic cells showed the highest boron concentration. Boron distribution was less heterogeneous for GB-10 than for BPA. In premalignant and normal tissue, GB-10 and BPA accumulated mostly in connective tissue and epithelium, respectively. CONCLUSIONS: BPA-BNCT could alter boron microlocalization of GB-10 administered subsequently. Boron targeting homogeneity is essential for therapeutic success. PMID- 25510260 TI - Suboptimal surgery and omission of neoadjuvant therapy for upper rectal cancer is associated with a high risk of local recurrence. AB - AIM: The aim of the present study was to estimate the risk of local recurrence in an audited cohort of patients, with a particular focus on patients with upper rectal cancer treated by partial mesorectal excision without neoadjuvant therapy. METHOD: Perioperative clinical data on all patients who underwent mesorectal excision for primary adenocarcinoma of the rectum in the period from 2007 to 2010 were prospectively collected and follow-up data on oncological outcome were retrieved from patient records. Three-year actuarial local recurrence rates were estimated using Kaplan-Meier methods. RESULTS: Local recurrence was diagnosed in 17 of 247 patients treated with curative intent. The 3-year actuarial local recurrence rate was 7.0% (95% CI 4.0-11.8). The risk of local recurrence was negatively associated with tumour stage (P = 0.015), an involved circumferential resection margin (P = 0.007) and tumour height (P = 0.044). The local recurrence rate at 3 years was 13.5% after partial mesorectal excision, 2.9% following total mesorectal excision and 5.7% after extralevator abdominoperineal excision (P = 0.032). CONCLUSION: Tumour stage and an involved circumferential resection margin were the most important predictors of local recurrence. For cancer of the upper rectum, partial mesorectal excision was associated with a high risk of local recurrence. PMID- 25510261 TI - Comorbidity profiles in association with vitiligo: a nationwide population-based study in Taiwan. AB - BACKGROUND: The previous literature has demonstrated the association of autoimmune and atopic diseases with vitiligo, but there has been no large-scale nationwide study conducted to confirm this. OBJECTIVES: The present study was conducted to clarify the comorbid profiles in vitiligo patients and thereby better understand their clinical scenarios and underlying pathogenesis. METHODS: This was a retrospective population-based study conducted from 1996 to 2011 via the National Health Insurance Research Database in Taiwan. The differences in the prevalence of multiple autoimmune and atopic diseases between case subjects and controls were analysed by multiple logistic regression method. RESULTS: A total of 14883 vitiligo patients and 59532 controls were enroled. The prevalence of vitiligo was 0.064% and the peak of onset age was 40-59 years old. The non stratified analysis evidenced a significant association between vitiligo and several comorbid diseases, including alopecia areata, Hashimoto thyroiditis, myasthenia gravis, psoriasis, Graves' disease, Sjogren's syndrome, systemic lupus erythematosus and atopic dermatitis. Vitiligo patients also had higher prevalence of multiple comorbidities than controls. In the age- and gender-stratified analysis, increased risks of systemic lupus erythematosus and Sjogren's syndrome were observed only in subjects aged 60-79. The association of vitiligo with myasthenia gravis and rheumatoid arthritis was identified only in the subgroup aged 20-39 and in females aged 60-79 respectively. CONCLUSION: Our study not only confirmed the significant association of vitiligo with multiple autoimmune and atopic diseases in Taiwan but also disclosed several unique findings, including the much lower prevalence of vitiligo, delayed onset of vitiligo by three decades, different associated comorbidity profiles comparing to westerners and the age- and gender-specific approach for the vitiligo-associated comorbidities. PMID- 25510262 TI - Sulforaphane enhances progerin clearance in Hutchinson-Gilford progeria fibroblasts. AB - Hutchinson-Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS. PMID- 25510263 TI - Incidental Diagnosis of Cerebral Cortical Venous Thrombosis in Postdural Puncture Headache on Brain Computed Tomography. AB - Diagnosis of cerebral cortical venous thrombosis in patients with postdural puncture headache (PDPH) is usually secondary to changes in headache pattern or cerebral infarctions. Nevertheless, incidental discovery of asymptomatic forms on brain imaging has never been reported before and its management thus remains ill defined. We describe 2 cases of patients with asymptomatic cortical vein thrombosis in the context of PDPH. In both cases, brain computed tomography (CT) scans showed an isolated cortical vein thrombosis without cerebral damage. Neurological examination revealed the typical orthostatic feature of PDPH, independently of cortical vein thrombosis which was considered as a radiological incidental finding. Clinical and radiological signs resolved after bed rest, oral caffeine, and anticoagulation therapy. Asymptomatic cortical vein thrombosis may be found on radiological exploration, even basic like brain CT scan without contrast, of PDPH. Utility of anticoagulation therapy, which could increase the risk of cerebral hemorrhagic complications in this specific context, has to be assessed. PMID- 25510265 TI - Molar tubal ectopic pregnancy: Report of two cases. AB - Ectopic molar pregnancy is a rare occurrence and consequently not often considered as a diagnostic possibility. We report two cases of molar hydatidiform tubal pregnancy. Diagnosis of ectopic pregnancy was confirmed on clinical biological and sonographic investigations. Diagnosis of molar pregnancy was done on histopathology. The clinical course was favorable for both patients. Although rare, molar changes can occur at any site of an ectopic pregnancy. Clinical diagnosis of a molar pregnancy is difficult but histopathology is the gold standard for diagnosis. PMID- 25510264 TI - A longitudinal study of the association of adolescent polydrug use, alcohol use and high school non-completion. AB - AIMS: Failure to complete high school predicts substantial economic and social disadvantage in adult life. The aim of this study was to determine the longitudinal association of mid-adolescent polydrug use and high school non completion, relative to other drug use profiles. DESIGN: A longitudinal analysis of the relationship between polydrug use in three cohorts at grade 9 (age 14-15 years) and school non-completion (reported post-high school). SETTING: A State representative sample of students across Victoria, Australia. PARTICIPANTS: A total of 2287 secondary school students from 152 high schools. The retention rate was 85%. MEASUREMENTS: The primary outcome was non-completion of grade 12 (assessed at age 19-23 years). At grade 9, predictors included 30-day use of eight drugs, school commitment, academic failure and peer drug use. Other controls included socio-economic status, family relationship quality, depressive symptoms, gender, age and cohort. FINDINGS: Three distinct classes of drug use were identified-no drug use (31.7%), mainly alcohol use (61.8%) and polydrug use (6.5%). Polydrug users were characterized by high rates of alcohol, tobacco and cannabis use. In the full model, mainly alcohol users and polydrug users were less likely to complete school than non-drug users [odds ratio (OR) = 1.54, 95% confidence interval (CI) = 1.17-2.03) and OR = 2.51, 95% CI = 1.45-4.33), respectively, P < 0.001]. These effects were independent of school commitment, academic failure, peer drug use and other controls. CONCLUSIONS: Mid-adolescent polydrug use in Australia predicts subsequent school non-completion after accounting for a range of potential confounding factors. Adolescents who mainly consume alcohol are also at elevated risk of school non-completion. PMID- 25510267 TI - When cancer and immunology meet. PMID- 25510269 TI - The role of mutations in epigenetic regulators in myeloid malignancies. AB - Over the past decade, genomic studies have identified a number of novel and recurrent somatic mutations that affect epigenetic patterning in patients with myeloid malignancies, including myeloproliferative neoplasms, myelodysplastic syndrome, and acute myeloid leukemia. Many of these mutations occur in genes with established roles in the regulation and maintenance of DNA methylation and/or chromatin modifications in hematopoietic stem/progenitor cells. Subsequent genetic and functional studies have revealed that these mutations affect epigenetic patterning in myeloid diseases. In this review, we discuss historical and recent studies implicating epigenetic modifiers in the development and evolution of the various myeloid malignancies and discuss how this knowledge has and will lead to future clinical and biologic insights. PMID- 25510270 TI - New themes in the biological functions of 5-methylcytosine and 5 hydroxymethylcytosine. AB - 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) play a critical role in development and normal physiology. Alterations in 5-mC and 5-hmC patterns are common events in hematopoietic neoplasms. In this review, we begin by emphasizing the importance of 5-mC, 5-hmC, and their enzymatic modifiers in hematological malignancies. Then, we discuss the functions of 5-mC and 5-hmC at distinct genic contexts, including promoter regions, gene bodies, intron-exon boundaries, alternative promoters, and intragenic microRNAs. Recent advances in technology have allowed for the study of 5-mC and 5-hmC independently and specifically permitting distinction between the bases that show them to have transcriptional effects that vary by their location relative to gene structure. We extend these observations to their functions at enhancers and transcription factor binding sites. We discuss dietary influences on 5-mC and 5-hmC levels and summarize the literature on the effects of folate and vitamin C on 5-mC and 5-hmC, respectively. Finally, we discuss how these new themes in the functions of 5-mC and 5-hmC will likely influence the broader research field of epigenetics. PMID- 25510271 TI - Epigenetics in T-cell acute lymphoblastic leukemia. AB - Normal T-cell development is a strictly regulated process in which hematopoietic progenitor cells migrate from the bone marrow to the thymus and differentiate from early T-cell progenitors toward mature and functional T cells. During this maturation process, cooperation between a variety of oncogenes and tumor suppressors can drive immature thymocytes into uncontrolled clonal expansion and cause T-cell acute lymphoblastic leukemia (T-ALL). Despite improved insights in T ALL disease biology and comprehensive characterization of its genetic landscape, clinical care remained largely similar over the past decades and still consists of high-dose multi-agent chemotherapy potentially followed by hematopoietic stem cell transplantation. Even with such aggressive treatment regimens, which are often associated with considerable side effects, clinical outcome is still extremely poor in a significant subset of T-ALL patients as a result of therapy resistance or hematological relapses. Recent genetic studies have identified recurrent somatic alterations in genes involved in DNA methylation and post translational histone modifications in T-ALL, suggesting that epigenetic homeostasis is critically required in restraining tumor development in the T-cell lineage. In this review, we provide an overview of the epigenetic regulators that could be implicated in T-ALL disease biology and speculate how the epigenetic landscape of T-ALL could trigger the development of epigenetic-based therapies to further improve the treatment of human T-ALL. PMID- 25510272 TI - Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. AB - On July 1, 2014, the United States Food and Drug Administration granted 'breakthrough therapy' designation to CTL019, the anti-CD19 chimeric antigen receptor T-cell therapy developed at the University of Pennsylvania. This is the first personalized cellular therapy for cancer to be so designated and occurred 25 years after the first publication describing genetic redirection of T cells to a surface antigen of choice. The peer-reviewed literature currently contains the outcomes of more than 100 patients treated on clinical trials of anti-CD19 redirected T cells, and preliminary results on many more patients have been presented. At last count almost 30 clinical trials targeting CD19 were actively recruiting patients in North America, Europe, and Asia. Patients with high-risk B cell malignancies therefore represent the first beneficiaries of an exciting and potent new treatment modality that harnesses the power of the immune system as never before. A handful of trials are targeting non-CD19 hematological and solid malignancies and represent the vanguard of enormous preclinical efforts to develop CAR T-cell therapy beyond B-cell malignancies. In this review, we explain the concept of chimeric antigen receptor gene-modified T cells, describe the extant results in hematologic malignancies, and share our outlook on where this modality is likely to head in the near future. PMID- 25510268 TI - TET proteins and 5-methylcytosine oxidation in hematological cancers. AB - DNA methylation has pivotal regulatory roles in mammalian development, retrotransposon silencing, genomic imprinting, and X-chromosome inactivation. Cancer cells display highly dysregulated DNA methylation profiles characterized by global hypomethylation in conjunction with hypermethylation of promoter CpG islands that presumably lead to genome instability and aberrant expression of tumor suppressor genes or oncogenes. The recent discovery of ten-eleven translocation (TET) family dioxygenases that oxidize 5mC to 5 hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) in DNA has led to profound progress in understanding the mechanism underlying DNA demethylation. Among the three TET genes, TET2 recurrently undergoes inactivating mutations in a wide range of myeloid and lymphoid malignancies. TET2 functions as a bona fide tumor suppressor particularly in the pathogenesis of myeloid malignancies resembling chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS) in human. Here we review diverse functions of TET proteins and the novel epigenetic marks that they generate in DNA methylation/demethylation dynamics and normal and malignant hematopoietic differentiation. The impact of TET2 inactivation in hematopoiesis and various mechanisms modulating the expression or activity of TET proteins are also discussed. Furthermore, we also present evidence that TET2 and TET3 collaborate to suppress aberrant hematopoiesis and hematopoietic transformation. A detailed understanding of the normal and pathological functions of TET proteins may provide new avenues to develop novel epigenetic therapies for treating hematological malignancies. PMID- 25510274 TI - Do we need more drugs for chronic myeloid leukemia? AB - The introduction of protein tyrosine kinase inhibitors (TKIs) in 1998 transformed the management of chronic myeloid leukemia (CML), leading to significantly reduced mortality and improved 5 year survival rates. However, the CML community is faced with several clinical issues that need to be addressed. Ten to 15% of CML patients are diagnosed in advanced phase, and small numbers of chronic phase (CP) cases experience disease progression each year during treatment. For these patients, TKIs induce only transient responses and alternative treatment strategies are urgently required. Depending on choice of first line TKI, approximately 30% of CML CP cases show suboptimal responses, due to a combination of poor compliance, drug intolerance, and drug resistance, with approximately 50% of TKI-resistance caused by kinase domain mutations and the remainder due to unknown mechanisms. Finally, the chance of successful treatment discontinuation is on the order of only 10-20% related to disease persistence. Disease persistence is a poorly understood phenomenon; all CML patients have functional Philadelphia positive (Ph+) stem and progenitor cells in their bone marrows and continue to express BCR-ABL1 by DNA PCR, even when in very deep remission and following treatment discontinuation. What controls the maintenance of these persisting cells, whether it is necessary to fully eradicate the malignant clone to achieve cure, and how that might be approached therapeutically are open questions. PMID- 25510275 TI - Peripheral T-cell and NK cell lymphoproliferative disorders: cell of origin, clinical and pathological implications. AB - T-cell lymphoproliferative disorders are a heterogeneous group of neoplasms with distinct clinical-biological properties. The normal cellular counterpart of these processes has been postulated based on functional and immunophenotypic analyses. However, T lymphocytes have been proven to be remarkably capable of modulating their properties, adapting their function in relationship with multiple stimuli and to the microenvironment. This impressive plasticity is determined by the equilibrium among a pool of transcription factors and by DNA chromatin regulators. It is now proven that the acquisition of specific genomic defects leads to the enforcement/activation of distinct pathways, which ultimately alter the preferential activation of defined regulators, forcing the neoplastic cells to acquire features and phenotypes distant from their original fate. Thus, dissecting the landscape of the genetic defects and their functional consequences in T-cell neoplasms is critical not only to pinpoint the origin of these tumors but also to define innovative mechanisms to re-adjust an unbalanced state to which the tumor cells have become addicted and make them vulnerable to therapies and targetable by the immune system. In our review, we briefly describe the pathological and clinical aspects of the T-cell lymphoma subtypes as well as NK cell lymphomas and then focus on the current understanding of their pathogenesis and the implications on diagnosis and treatment. PMID- 25510276 TI - Targeting the bone marrow microenvironment in multiple myeloma. AB - Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow (BM). Despite the significant advances in treatment, MM is still a fatal malignancy. This is mainly due to the supportive role of the BM microenvironment in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM microenvironment is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a non-cellular compartment. In this review, we discuss the interaction between the malignant plasma cell and the BM microenvironment and the strategy to target them. PMID- 25510273 TI - Novel immunotherapies for hematologic malignancies. AB - The immune system is designed to discriminate between self and tumor tissue. Through genetic recombination, there is fundamentally no limit to the number of tumor antigens that immune cells can recognize. Yet, tumors use a variety of immunosuppressive mechanisms to evade immunity. Insight into how the immune system interacts with tumors is expanding rapidly and has accelerated the translation of immunotherapies into medical breakthroughs. Herein, we appraise novel strategies that exploit the patient's immune system to kill cancer. We review various forms of immune-based therapies, which have shown significant promise in patients with hematologic malignancies, including (i) conventional monoclonal therapies like rituximab; (ii) engineered monoclonal antibodies called bispecific T-cell engagers; (iii) monoclonal antibodies and pharmaceutical drugs that block inhibitory T-cell pathways (i.e. PD-1, CTLA-4, and IDO); and (iv) adoptive cell transfer therapy with T cells engineered to express chimeric antigen receptors or T-cell receptors. We also assess the idea of using these therapies in combination and conclude by suggesting multi-prong approaches to improve treatment outcomes and curative responses in patients. PMID- 25510278 TI - Mechanisms of pre-B-cell receptor checkpoint control and its oncogenic subversion in acute lymphoblastic leukemia. AB - Pre-B cells within the bone marrow represent the normal counterpart for most acute lymphoblastic leukemia (ALL). During normal early B-cell development, survival and proliferation signals are dominated by cytokines, particularly interleukin-7 (IL-7) for murine developing B cells. With expression of a functional pre-B-cell receptor (BCR), cytokine signaling is attenuated and the tonic/autonomous pre-BCR signaling pathway provides proliferation as well as differentiation signals. In this review, we first describe checkpoint mechanisms during normal B-cell development and then discuss how genetic lesions in these pathways function as oncogenic mimicries and allow transformed pre-B cells to bypass checkpoint control. We focus on cytokine receptor signaling that is mimicked by activating lesions in receptor subunits or downstream mediators as well as aberrant activation of non-B lymphoid cytokine receptors. Furthermore, we describe the molecular switch from cytokine receptor to pre-BCR signaling, how this pathway is of particular importance for certain ALL subtypes, and how pre BCR signaling is engaged by genetic lesions, such as BCR-ABL1. We discuss the transcriptional control mechanisms downstream of both cytokine- and pre-BCR signaling and how normal checkpoint control mechanisms are circumvented in pre-B ALL. Finally, we highlight new therapeutic concepts for targeted inhibition of oncogenic cytokine or pre-BCR signaling pathways. PMID- 25510280 TI - Role of the ubiquitin proteasome system in hematologic malignancies. AB - Ubiquitination is a post-translational modification process that regulates several critical cellular processes. Ubiquitination is orchestrated by the ubiquitin proteasome system (UPS), which constitutes a cascade of enzymes that transfer ubiquitin onto protein substrates. The UPS catalyzes the destruction of many critical protein substrates involved in cancer pathogenesis. This review article focuses on components of the UPS that have been demonstrated to be deregulated by a variety of mechanisms in hematologic malignancies. These include E3 ubiquitin ligases and deubiquitinating enzymes. The prospects of specific targeting of key enzymes in this pathway that are critical to the pathogenesis of particular hematologic neoplasia are also discussed. PMID- 25510279 TI - The eukaryotic translation initiation factor eIF4E in the nucleus: taking the road less traveled. AB - The eukaryotic translation initiation factor eIF4E is a potent oncogene. Although eIF4E has traditional roles in translation initiation in the cytoplasm, it is also found in the nucleus, suggesting that it has activities beyond its role in protein synthesis. The road less traveled has been taken to study these nuclear activities and to understand their contribution to the oncogenic potential of eIF4E. The molecular features and biological pathways underpinning eIF4E's nuclear mRNA export are described. New classes of eIF4E regulators have been identified and their relevance to cancer shown. The studies presented here reveal the molecular, biophysical, and structural bases for eIF4E regulation. Finally, recent clinical work targeting eIF4E in acute myeloid leukemia patients with ribavirin is discussed. In summary, these findings provide a novel paradigm for eIF4E function and the molecular basis for targeting it in leukemia patients. PMID- 25510282 TI - Splice factor mutations and alternative splicing as drivers of hematopoietic malignancy. AB - Differential splicing contributes to the vast complexity of mRNA transcripts and protein isoforms that are necessary for cellular homeostasis and response to developmental cues and external signals. The hematopoietic system provides an exquisite example of this. Recently, discovery of mutations in components of the spliceosome in various hematopoietic malignancies (HMs) has led to an explosion in knowledge of the role of splicing and splice factors in HMs and other cancers. A better understanding of the mechanisms by which alternative splicing and aberrant splicing contributes to the leukemogenic process will enable more efficacious targeted approaches to tackle these often difficult to treat diseases. The clinical implications are only just starting to be realized with novel drug targets and therapeutic strategies open to exploitation for patient benefit. PMID- 25510277 TI - Man's best friend: what can pet dogs teach us about non-Hodgkin's lymphoma? AB - Animal models are essential for understanding lymphoma biology and testing new treatments prior to human studies. Spontaneously arising lymphomas in pet dogs represent an underutilized resource that could be used to complement current mouse lymphoma models, which do not adequately represent all aspects of the human disease. Canine lymphoma resembles human lymphoma in many important ways, including characteristic translocations and molecular abnormalities and similar therapeutic responses to chemotherapy, radiation, and newer targeted therapies (e.g. ibrutinib). Given the large number of pet dogs and high incidence of lymphoma, particularly in susceptible breeds, dogs represent a largely untapped resource for advancing the understanding and treatment of human lymphoma. This review highlights similarities in molecular biology, diagnosis, treatment, and outcomes between human and canine lymphoma. It also describes resources that are currently available to study canine lymphoma, advantages to be gained by exploiting the genetic breed structure in dogs, and current and future challenges and opportunities to take full advantage of this resource for lymphoma studies. PMID- 25510281 TI - Protein ubiquitination in lymphoid malignancies. AB - Human lymphoid malignancies inherit gene expression networks from their normal B cell counterpart and co-opt them for their own oncogenic purpose, which is usually governed by transcription factors and signaling pathways. These transcription factors and signaling pathways are precisely regulated at multiple steps, including ubiquitin modification. Protein ubiqutination plays a role in almost all cellular events and in many human diseases. In the past few years, multiple studies have expanded the role of ubiquitination in the genesis of diverse lymphoid malignancies. Here, we discuss our current understanding of both proteolytic and non-proteolytic functions of the protein ubiquitination system and describe how it is involved in the pathogenesis of human lymphoid cancers. Lymphoid-restricted ubiquitination mechanisms, including ubiquitin E3 ligases and deubiquitinating enzymes, provide great opportunities for the development of targeted therapies for lymphoid cancers. PMID- 25510284 TI - Case of Merkel cell carcinoma with squamous cell carcinoma possibly arising in chronic radiodermatitis of the hand. AB - We report a case of Merkel cell carcinoma (MCC) on the dorsal aspect of the right middle finger associated with multiple squamous cell carcinomas (SCC) possibly arising in chronic radiation dermatitis of the hand of an 80-year-old surgeon. In spite of resection of the primary lesion and right axillary lymph nodes, he died of the tumor 5 months after the first visit. Cutaneous and lymph node lesions of MCC were negative for Merkel cell polyoma virus (MCPyV) by immunostaining using monoclonal antibody (CM2B4) and anti-large T antigen of MCPyV polyclonal antibody, and real-time polymerase chain reaction. Several differences in clinicopathological findings have been found between MCPyV-positive cases and negative ones. Several authors have reported that MCPyV-negative cases have a worse prognosis than MCPyV-positive ones. Furthermore, in cases of MCC associated with SCC, most tumors have been reported to be MCPyV-negative. We should pay more attention to the relationship between the carcinogenesis of MCC and ionizing irradiation. PMID- 25510287 TI - Too early to dismiss the block & replace regime for Graves' disease. PMID- 25510285 TI - Essential oil of Melaleuca alternifolia for the treatment of oral candidiasis induced in an immunosuppressed mouse model. AB - BACKGROUND: The search for alternative therapies for oral candidiasis is a necessity and the use of medicinal plants seems to be one of the promising solutions. The objective of this study was to evaluate the in vitro and in vivo effects of the essential oil of Melaleuca alternifolia on Candida albicans. METHODS: The minimum inhibitory concentration (MIC) and minimum biofilm eradication concentration (MBEC) of M. alternifolia were determined by the broth microdilution assay. For the in vivo study, twelve immunosuppressed mice with buccal candidiasis received topical applications of M. alternifolia with MBEC. After treatment, yeasts were recovered from the mice and quantified (CFU/mL). Mice were killed for morphologic analysis of the tongue dorsum by optical and scanning electron microscopy. Data were analyzed using Student's t test or Mann Whitney test. RESULTS: The MIC of M. alternifolia was 0.195% and the MBEC was 12.5%. Treatment with M. alternifolia achieved a 5.33 log reduction in C. albicans and reduced the microscopic lesions of candidiasis. CONCLUSIONS: M. alternifolia oil at a 12.5% was effective to eradicate a C. albicans biofilm formed in vitro and to reduce yeasts of C. albicans in an immunosuppressed mouse model. PMID- 25510286 TI - Circulating cardiac biomarkers and postoperative atrial fibrillation in the OPERA trial. AB - BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication after cardiac surgery and predicts increased morbidity and mortality. Identification of patients at high risk of POAF with the help of circulating biomarkers may enable early preventive treatment but data are limited, especially in contemporary surgical patients. METHODS: Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) were measured at enrollment, on the morning of cardiac surgery, at end surgery, and 2 days postsurgery in 562 patients undergoing cardiac surgery, randomized to perioperative supplementation with oral fish oil or placebo in the Omega-3 Fatty Acids for Prevention of Post-Operative Atrial Fibrillation trial (OPERA). The primary endpoint was incident POAF lasting >= 30 s, centrally adjudicated and confirmed electrocardiographically. RESULTS: Higher levels of NT proBNP and hs-cTnT before surgery were associated with older age, renal or cardiac dysfunction and EuroSCORE. NT-proBNP peaked on postoperative day 2 (2172 [1238-3758] ng/L, median [Q1-Q3]), while hs-cTnT peaked at the end of surgery (373 [188-660] ng/L). Fish oil supplementation did not alter the time course of the cardiac biomarkers (P > 0.05). Concentrations of NT-proBNP or hs-cTnT, on the morning of surgery, or changes in their level between morning of surgery and postsurgery, were not significantly associated with POAF after adjustment for clinical and surgical characteristics. CONCLUSION: Among patients undergoing cardiac surgery, NT-proBNP and hs-cTnT are related to clinical and surgical characteristics, have different perioperative time courses but are not independently associated with risk of POAF. PMID- 25510283 TI - Targeting protein-protein interactions in hematologic malignancies: still a challenge or a great opportunity for future therapies? AB - Over the past several years, there has been an increasing research effort focused on inhibition of protein-protein interactions (PPIs) to develop novel therapeutic approaches for cancer, including hematologic malignancies. These efforts have led to development of small molecule inhibitors of PPIs, some of which already advanced to the stage of clinical trials while others are at different stages of preclinical optimization, emphasizing PPIs as an emerging and attractive class of drug targets. Here, we review several examples of recently developed inhibitors of PPIs highly relevant to hematologic cancers. We address the existing skepticism about feasibility of targeting PPIs and emphasize potential therapeutic benefit from blocking PPIs in hematologic malignancies. We then use these examples to discuss the approaches for successful identification of PPI inhibitors and provide analysis of the protein-protein interfaces, with the goal to address 'druggability' of new PPIs relevant to hematology. We discuss lessons learned to improve the success of targeting new PPIs and evaluate prospects and limits of the research in this field. We conclude that not all PPIs are equally tractable for blocking by small molecules, and detailed analysis of PPI interfaces is critical for selection of those with the highest chance of success. Together, our analysis uncovers patterns that should help to advance drug discovery in hematologic malignancies by successful targeting of new PPIs. PMID- 25510288 TI - MICA/B and ULBP1 NKG2D ligands are independent predictors of good prognosis in cervical cancer. AB - BACKGROUND: NKG2D (natural killer group 2, member D) is thought to play an important role in mediating the activation of anticancer immune response. Expression of NKG2D ligands (NKG2DLs) is pronounced in malignancies and the heterogeneity of NKG2DL expression remains unclear. Here, we investigate the expression and clinical significance of NKG2DLs in cervical cancer. METHODS: Immunohistochemical analyses of MICA/B, ULBP1, ULBP2, ULBP3, RAET1E, and RAET1G were performed using tissue microarray analysis of 200 cervical cancers, 327 high grade cervical intraepithelial neoplasias (CINs), 99 low-grade CINs, and 541 matched nonadjacent normal cervical epithelial tissues and compared the data with clinicopathologic variables, including the survival of cervical cancer patients. RESULTS: MICA/B, ULBP1, and RAET1E expression was higher in cervical cancer than in low-grade CIN (p<0.001, p=0.012, p=0.013, respectively) and normal cervix (all p<0.001). Among these markers, expression of ULBP1 was significantly different depending on patient tumor stage (p=0.010) and tumor size (p=0.045). ULBP1 expression was correlated with MICA/B (p<0.001) and ULBP2 (p=0.002) expression in cervical cancer. While MICA/B+ or ULBP1+ patients had improved disease-free survival time (p=0.027 and p=0.009, respectively) relative to that of the low expression group, RAET1E+ or RAET1G+ was correlated with shorter survival time (p=0.018 and p=0.029, respectively). However, in terms of overall survival, the ULBP1+ group had significantly longer survival time than the low expression group (p=0.009). Multivariate analysis indicated that MICA/B+/ULBP1+ (HR=0.16, p=0.015) and ULBP1+ (HR=0.31, p=0.024) are independent prognostic factors of disease-free survival in cervical cancer. CONCLUSIONS: High expression of either ULBP1 or MICA/B and ULBP1 combined is an indicator of good prognosis in cervical cancer, suggesting their potential utility as prognostic tests in clinical assessment. PMID- 25510290 TI - Development of a bedside pain assessment kit for the classification of patients with osteoarthritis. AB - There are no standardized bedside assessments for subtyping patients with osteoarthritis (OA) based on pain mechanisms. Thus, we developed a bedside sensory testing kit (BSTK) to classify OA patients based on sensory profiles potentially indicative of pain mechanism. After usability and informal reliability testing (n = 22), the kit was tested in a formal reliability study (n = 20). Patients completed questionnaires and sensory testing: pressure algometry to detect hyperalgesia; repeat algometry after heterotopic noxious conditioning stimulation to measure diffuse noxious inhibitory control (DNIC); light touch using Von Frey filaments; and cold allodynia using a brass rod. The procedure was brief and well tolerated. Algometry and filament testing were highly reliable [intra-class correlation coefficients (ICCs) 0.71-0.91]; DNIC was acceptably reliable (ICCs 0.53-0.91); brass rod reliability was inconclusive. Patients were classified empirically into four groups: "All abnormal findings" (primary and secondary hyperalgesia and dysfunctional DNIC); "all normal findings"; and two intermediate groups. The "all abnormal findings" group had more neuropathic pain symptoms, and lower WOMAC total, stiffness, and activity scores than the "all normal findings" group. Simple BSTK procedures, consolidated in a kit, reliably classified OA patients into subgroups based on sensory profile, suggesting that OA patients differ in underlying pain mechanisms. Further research is needed to confirm these subgroups and determine their validity in predicting response to treatment. PMID- 25510291 TI - Development, linguistic and clinimetric validation of the WOMAC VA3.01 Bangla for Bangladesh Index. AB - The aim of this study was to develop and to validate a Bengali version of the Western Ontario and McMaster Osteoarthritis (WOMAC) index in Bangladesh. The WOMAC was translated into the local language of Bangladesh (Bengali) and adapted in the local sociocultural context, following the standard guidelines by Beaton et al. Content validity of the preliminary Bengali version was assessed by using the index of content validity (ICV) and floor and ceiling effects. Patients were assessed at the Department of Rheumatology of Bangabandhu Sheikh Mujib Medical University and were diagnosed to have knee OA by American College of Rheumatology criteria and recruited according to the requirements of the validation study. Convergent and divergent validity were measured by comparing with Health Assessment Questionnaire (HAQ) and the Short Form-36 (SF-36), and internal consistency was assessed using Cronbach's alpha coefficient. The questionnaire was readministered to 40 patients within a week for assessing reliability by using intra-class correlation coefficient (ICC) and Spearman's rank correlation coefficient. In addition, factor analysis of Bengali WOMAC questionnaire was performed to examine the number of factors influencing a common set of items. A Bengali version was developed with changes in three items to suit local practices. The ICV of the content validity was 1 for all items. The Bengali WOMAC had similar construct validity when compared to the HAQ (rho 0.74, n = 70) and SF 36 bodily pain and physical functioning. It had dissimilar construct validity to SF-36 mental health domain except WOMAC pain. Factor analysis revealed five factors with eigenvalues of more than 1.0. Cronbach's alpha and ICC exceeded 0.7 in all domains. In the test-retest reliability testing, Spearman's rho for all items exceeded 0.4 (n = 40). This study has demonstrated that the Bengali version of WOMAC is a valid tool for assessing quality of life of patients with knee osteoarthritis in Bangladesh and is reliable. PMID- 25510292 TI - Green light may improve diagnostic accuracy of nailfold capillaroscopy with a simple digital videomicroscope. AB - Nailfold capillaroscopy is a non-invasive and safe technique for the analysis of microangiopathologies. Imaging quality of widely used simple videomicroscopes is poor. The use of green illumination instead of the commonly used white light may improve contrast. The aim of the study was to compare the effect of green illumination with white illumination, regarding capillary density, the number of microangiopathologies, and sensitivity and specificity for systemic sclerosis. Five rheumatologists have evaluated 80 images; 40 images acquired with green light, and 40 images acquired with white light. A larger number of microangiopathologies were found in images acquired with green light than in images acquired with white light. This results in slightly higher sensitivity with green light in comparison with white light, without reducing the specificity. These findings suggest that green instead of white illumination may facilitate evaluation of capillaroscopic images obtained with a low-cost digital videomicroscope. PMID- 25510289 TI - Effects of cigarette smoking on early arthritis: a cross-sectional study-data from the Argentine Consortium for Early Arthritis (CONAART). AB - Our objective was to analyze the effects of cigarette smoking on disease activity, functional capacity, radiographic damage, serology and presence of extraarticular manifestations in patients with rheumatoid arthritis and undifferentiated arthritis. This is a cross-sectional study of 1,305 patients (729 with rheumatoid arthritis and 576 with undifferentiated arthritis) from CONAART, the Argentine Consortium for Early Arthritis that includes patients older than 16 years with <2 years of disease. Sociodemographic data, clinical characteristics of the disease and smoking history were collected. In patients with rheumatoid arthritis the disease activity score of 28 joints was 5.4 +/- 1.3 in current smokers, 5.2 +/- 1.4 in former smokers and 5.1 +/- 1.4 in never smokers (p = 0.011). The simple erosion narrowing score was higher in current smokers and former smokers than in never smokers (M 14.0, R Q 6.0-21.0; M 15.0, R Q 7.0-24.0; M 10.0, R Q 5.0-17.0; p = 0.006). Current smokers had higher rheumatoid factor titer (M 160.0, R Q 80.0-341.0) than former smokers (M 146.8, R Q 6.03-255.5) and never smokers (M 15.0, R Q 9.0-80.0) (p = 0.004). The variable independently associated with tobacco exposure was simple erosion narrowing score (OR = 1.03, 95 % CI 1.00-1.05; p = 0.012). In patients with undifferentiated arthritis, an association between smoking status and parameters of activity or radiographic damage was not observed. Neither was tobacco exposure related to the presence of extraarticular manifestations or to the degree of disability in any of the two groups of patients. No relation was found between disease activity and severity, and number of packs smoked per year. Tobacco. PMID- 25510293 TI - Environmental applications of three-dimensional graphene-based macrostructures: adsorption, transformation, and detection. AB - Just as graphene triggered a new gold rush, three-dimensional graphene-based macrostructures (3D GBM) have been recognized as one of the most promising strategies for bottom-up nanotechnology and become one of the most active research fields during the last four years. In general, the basic structural features of 3D GBM, including its large surface area, which enhances the opportunity to contact pollutants, and its well-defined porous structure, which facilitates the diffusion of pollutant molecules into the 3D structure, enable 3D GBM to be an ideal material for pollutant management due to its excellent capabilities and easy recyclability. This review aims to describe the environmental applications and mechanisms of 3D GBM and provide perspective. Thus, the excellent performance of 3D GBM in environmental pollutant adsorption, transformation and detection are reviewed. Based on the structures and properties of 3D GBM, the removal mechanisms for dyes, oils, organic solvents, heavy metals, and gas pollutants are highlighted. We attempt to establish "structure-property application" relationships for environmental pollution management using 3D GBM. Approaches involving tunable synthesis and decoration to regulate the micro-, meso-, and macro-structure and the active sites are also reviewed. The high selectivity, fast rate, convenient management, device applications and recycling utilization of 3D GBM are also emphasized. PMID- 25510294 TI - Inflammation and weight gain in reproductive-aged women. AB - AIM: To investigate whether mid-pregnancy inflammation predicts the rate of subsequent gestational weight gain (GWG) and whether inflammation at 3 years post partum is associated with weight and waist circumference (WC) gain during a median of 4.4 years follow-up. SUBJECTS AND METHODS: This study quantified CRP, IL-6 and TNF-alpha in plasma of 886 women at ~28 weeks gestation and calculated GWG rate (kg/week) from blood draw to delivery. At ~3 years post-partum, CRP and IL-6 were assessed from 351 women and weight and WC were measured at 3 and 7 years post-partum. This study used linear regression to investigate the relationship between mid-pregnancy inflammation and subsequent GWG rate and the association of inflammation at 3 years post-partum with weight and WC change during follow-up. RESULTS: After accounting for confounders, a small dose response association of mid-gestation CRP with subsequent GWG was observed; women in the 4th CRP quartile gained weight at 0.05 (95% CI = 0.01, 0.10) kg/week faster than those in the 1st quartile. Neither IL-6 nor TNF-alpha was related to GWG. Post-partum inflammation was not associated with subsequent weight or WC gain. CONCLUSIONS: Higher mid-gestation CRP was related to modestly higher subsequent GWG rate. Future studies are warranted to confirm these findings. PMID- 25510295 TI - IOP agreement between I-Care TA01 rebound tonometer and the Goldmann applanation tonometer in eyes with and without glaucoma. AB - To analyze correlation of intraocular pressure (IOP) measurement between new rebound tonometer (RBT) I-Care TA01 and Goldmann applanation tonometer (GAT). One hundred eighty-five eyes of 185 subjects presenting with glaucoma or cataract were enrolled in the study. In all patients, IOP was obtained by an ophthalmologist using I-Care TA01 and GAT. IOP between the two were compared at range of 8-15, 16-21, and >22 mmHg and difference was considered as significant at p < 0.05 (t test). Bland-Altman analysis tested agreement between instruments overall and for each subgroup of patients with glaucoma or no glaucoma (cataract only). Of 185 patients, 86 had glaucoma; 99 did not. Mean age of patients was 55.77 +/- 14.46 years; with no difference between the two subgroups (p = 0.12). There was no significant difference in mean IOP between the two tonometers at IOP between 8-15 mmHg (p = 0.097) and 16-21 mmHg (p = 0.51). However, a significant difference was observed between the two at IOP > 22 mmHg (p = 0.023) with mean GAT (24.8 mmHg) being higher than mean RBT (23.16 mmHg). Overall, there was no difference between the two (p = 0.59) and they had a high correlation (Pearson correlation r = 0.815; p = 0.01). The mean difference between the two was 0.1 (95 % agreement limits: UL +6 (1.96SD), LL -5.8 (-1.96SD)), in patients with no glaucoma was 0.091 (95 % AL: UL +4.8 (1.96SD), LL -4.6 (-1.96SD)), and in patients with glaucoma was 0.151 (95 % AL: UL +7.25 (1.96SD), LL -6.9 (-1.96SD)). RBT I-Care TA01 and Goldmann tonometer cannot be used interchangeably due to large limits of agreement. PMID- 25510296 TI - CD147 renal expression as a biomarker for progressive IgAN. AB - BACKGROUND/AIMS: Recent studies have demonstrated that tubulointerstitial injury can predict renal outcomes better than the other histological parameters in patients with IgA nephropathy (IgAN). CD147 is a key regulator of renal tubulointerstitial fibrosis in cellular and animal models. However, it is not clear whether the expression of CD147 correlates with tubulointerstitial injury in IgAN patients. METHODS: We analyzed the degree of CD147 expression and localization in renal biopsy tissues from IgAN patients and correlated their immunostaining scores with clinical and histological parameters. RESULTS: Elevated CD147 expression was found in the basolateral membrane of renal tubules in IgAN patients; however, in normal kidney samples, positive staining for CD147 was not found in the tubular epithelial cells (P = 0.000). CD147 protein expression in the renal tubules showed a negative correlation with estimated glomerular filtration rate (eGFR; r = -0.600, P = 0.000) and a positive correlation with serum creatinine (Scr; r = 0.322, P = 0.002) and tubulointerstitial lesions (r = 0.525, P = 0.000). Moreover, a high level of CD147 correlated with the activation of Slug expression and E-cadherin repression in patients with IgAN. Kaplan-Meier survival curves showed that elevated CD147 expression was associated with decreased renal survival. Multivariate analyses further demonstrated that a high CD147 immunostaining score was an independent predictor of renal outcome in patients with IgAN (HR = 8.731, P = 0.041). CONCLUSION: CD147 expression is associated with tubulointerstitial injury and predicts renal prognosis in IgA nephropathy. CD147 may be an early marker for tubulointerstitial injury IgA nephropathy. PMID- 25510297 TI - Prevalence and pathogens of subclinical mastitis in dairy goats in China. AB - Subclinical mastitis, a costly disease for the dairy industry, is usually caused by intramammary bacterial infection. The aim of this study was to investigate the prevalence of and pathogens involved in subclinical mastitis in dairy goats in China. A total of 683 dairy goats in the main breeding areas of China were selected, and milk samples were collected. Out of these, 313 (45.82 %) goats were detected distinct or strong positive for subclinical mastitis by using California mastitis test. Among these positive goats, 209 milk samples were used to identify the causing agents by a multiplex PCR assay, and results were listed as follows: coagulase-negative staphylococci (59.52 %), Staphylococcus aureus (15.24 %), Escherichia coli (11.43 %), and Streptococcus spp. (10.95 %). In conclusion, subclinical mastitis is a highly prevalent disease in dairy goats in China, and coagulase-negative staphylococci are the predominant pathogens. PMID- 25510298 TI - Phenotypic characteristics and trypanosome prevalence of Mursi cattle breed in the Bodi and Mursi districts of South Omo Zone, southwest Ethiopia. AB - The study was conducted to characterize the morphological features of Mursi cattle breed and to identify the species of trypanosome infecting the cattle and its prevalence in these traditionally managed cattle in the Bodi and Mursi pastoral communities. Cattle body description and measurements were made on 201 matured animals. Blood samples were collected from 409 animals into heparin treated capillary tubes and were centrifuged to 12,000 rpm for 5 min to identify trypanosome species from the wet smeared buffy coat and to estimate the degree of anemia (PCV). Tsetse flies were collected using phenol-treated biconical trap and the caught flies identified to species level. The breed possesses variable coat color pattern, coat color type, and have small to medium hump size on the thoracic vertebrae. Body measurement of Mursi cattle in the two locations did not show significant differences except chest girth, rump width, and horn length. Trypanosome prevalence in the Mursi cattle breed was 6.1%. The highest trypanosome infection was caused by Trypanosoma congolense (56%) followed by Trypanosoma vivax (40%) and Trypanosoma brucei (4%). Trypanosome prevalence significantly varies between dry (2.0%) and late rainy (10.1%) seasons (P < 0.001) and between lean (11.9%) and medium (2.4%) body condition score (P < 0.01). The PCV value was 22.1 +/- 0.5%, which is significantly varied with season (P < 0.01) and parasitism (P < 0.001). Parasitaemic cattle show the lowest PCV value (20.4 +/- 1%) than aparasitaemic (23.7 +/- 0.3%) cattle and cattle with lean BCS showed the lowest (P < 0.0001) PCV value (20.4 +/- 0.6%). Tsetse fly species identified in the study area were Glossina pallidipes, Glossina morsitans submorsitans, and Glossina fuscipes. The number of flies captured in late rainy season was higher than in dry season (P < 0.01). Despite the existence of trypanosome and high tsetse fly infestation in the areas, large proportion of the Mursi cattle shows medium BCS, low trypanosome prevalence, and higher PCV value. PMID- 25510299 TI - Evaluation of endothelial damage in sepsis-related ARDS using circulating endothelial cells. AB - PURPOSE: Endothelial cell activation and dysfunction are involved in the pathophysiology of ARDS. Circulating endothelial cells (CECs) may be a useful marker of endothelial dysfunction and damage but have been poorly studied in ARDS. We hypothesized that the CEC count may be elevated in patients with sepsis related ARDS compared to those with sepsis without ARDS. METHODS: ARDS was defined according to the Berlin consensus definition. The study population included 17 patients with moderate or severe ARDS, 9 with mild ARDS, 13 with sepsis and no ARDS, 13 non-septic patients, and 12 healthy volunteers. Demographic, hemodynamic, and prognostic variables, including PaO(2)/FiO(2) ratio, 28-day survival, blood lactate, APACHE II, and SOFA score, were recorded. CECs were counted in arterial blood samples using the reference CD146 antibody based immunomagnetic isolation and UEA1-FITC staining method. Measurements were performed 12-24 h after diagnosis of ARDS and repeated daily for 3 days. RESULTS: The median day-1 CEC count was significantly higher in patients with moderate or severe ARDS than in mild ARDS or septic-control patients [27.2 (18.3-49.4) vs. 17.4 (11-24.5) cells/ml (p < 0.034), and 18.4 (9.1-31) cells/ml (p < 0.035), respectively]. All septic patients (with or without ARDS) had higher day-1 CEC counts than the non-septic patients [19.6 (14.2-30.6) vs. 10.8 (5.7-13.2) cells/ml, p = 0.002]. CONCLUSION: The day-1 CEC count was significantly higher in ARDS patients than in other critically ill patients, and in moderate or severe ARDS patients compared to those with milder disease, making it a potentially useful marker of ARDS severity. PMID- 25510300 TI - Response to Katz et al.: lung ultrasound in the intensive care unit: an idea that may be too good to be true. PMID- 25510302 TI - Lung ultrasound in the intensive care unit: an idea that may be too good to be true. PMID- 25510303 TI - [Professor Gerhart Hitzenberger on his 85th birthday]. PMID- 25510301 TI - Incidence, characteristics and outcome of ICU-acquired candidemia in India. AB - PURPOSE: A systematic epidemiological study on intensive care unit (ICU)-acquired candidemia across India. METHOD: A prospective, nationwide, multicentric, observational study was conducted at 27 Indian ICUs. Consecutive patients who acquired candidemia after ICU admission were enrolled during April 2011 through September 2012. Clinical and laboratory variables of these patients were recorded. The present study is an analysis of data specific for adult patients. RESULTS: Among 1,400 ICU-acquired candidemia cases (overall incidence of 6.51 cases/1,000 ICU admission), 65.2 % were adult. Though the study confirmed the already known risk factors for candidemia, the acquisition occurred early after admission to ICU (median 8 days; interquartile range 4-15 days), even infecting patients with lower APACHE II score at admission (median 17.0; mean +/- SD 17.2 +/- 5.9; interquartile range 14-20). The important finding of the study was the vast spectrum of agents (31 Candida species) causing candidemia and a high rate of isolation of Candida tropicalis (41.6 %). Azole and multidrug resistance were seen in 11.8 and 1.9 % of isolates. Public sector hospitals reported a significantly higher presence of the relatively resistant C. auris (8.2 vs. 3.9 %; p = 0.008) and C. rugosa (5.6 vs. 1.5 %; p = 0.001). The 30-day crude and attributable mortality rates of candidemia patients were 44.7 and 19.6 %, respectively. Logistic regression analysis revealed significant independent predictors of mortality including admission to public sector hospital, APACHE II score at admission, underlying renal failure, central venous catheterization and steroid therapy. CONCLUSION: The study highlighted a high burden of candidemia in Indian ICUs, early onset after ICU admission, higher risk despite less severe physiology score at admission and a vast spectrum of agents causing the disease with predominance of C. tropicalis. PMID- 25510304 TI - What is the impingement-free range of motion of the asymptomatic hip in young adult males? AB - BACKGROUND: Femoroacetabular impingement is a recognized cause of chondrolabral injury. Although surgical treatment for impingement seeks to improve range of motion, there are very little normative data on dynamic impingement-free hip range of motion (ROM) in asymptomatic people. Hip ultrasound demonstrates labral anatomy and femoral morphology and, when used dynamically, can assist in measuring range of motion. QUESTIONS/PURPOSES: The purposes of this study were (1) to measure impingement-free hip ROM until labral deflection is observed; and (2) to measure the maximum degree of sagittal plane hip flexion when further flexion is limited by structural femoroacetabular abutment. METHODS: Forty asymptomatic adult male volunteers (80 hips) between the ages of 21 and 35 years underwent bilateral static and dynamic hip ultrasound examination. Femoral morphology was characterized and midsagittal flexion passive ROM was measured at two points: (1) at the initiation of labral deformation; and (2) at maximum flexion when the femur impinged on the acetabular rim. The mean age of the subjects was 28 +/- 3 years and the mean body mass index was 25 +/- 4 kg/m(2). RESULTS: Mean impingement-free hip passive flexion measured from full extension to initial labral deflection was 68 degrees +/- 17 degrees (95% confidence interval [CI], 65-72). Mean maximum midsagittal passive flexion, measured at the time of bony impingement, was 96 degrees +/- 6 degrees (95% CI, 95-98). CONCLUSIONS: Using dynamic ultrasound, we found that passive ROM in the asymptomatic hip was much less than the motion reported in previous studies. Measuring ROM using ultrasound is more accurate because it allows anatomic confirmation of terminal hip motion. CLINICAL SIGNIFICANCE: Surgical procedures used to treat femoroacetabular impingement are designed to restore or increase hip ROM and their results should be evaluated in light of precise normative data. This study suggests that normal passive impingement-free femoroacetabular flexion in the young adult male is approximately 95 degrees . PMID- 25510305 TI - CORR Insights((r)): incidence and risk factors of allograft bone failure after calcaneal lengthening. PMID- 25510306 TI - The Use of Physostigmine by Toxicologists in Anticholinergic Toxicity. AB - The anticholinergic toxidrome is well described and relatively common. Despite controversy, studies have shown that physostigmine is relatively safe and effective in reversing this toxidrome. We would expect toxicologists would be liberal in its use. We retrospectively analyzed data in the Toxicology Investigators Consortium (ToxIC) registry, representing data from medical toxicologists in multiple institutions nationwide, searching for patients who exhibited an anticholinergic toxidrome, determining what treatment(s) they received, and classifying the treatments as physostigmine, benzodiazepines, physostigmine and benzodiazepines, antipsychotics, or no definitive treatment. The causal agents of the toxidrome were as reported by the treating toxicologist. Eight hundred fifteen consecutive patients with anticholinergic toxidromes were analyzed. Benzodiazepines alone were given in 28.7 %, 12.4 % were given physostigmine alone, 8.8 % received both physostigmine and benzodiazepines, 2.7 % were given antipsychotics, and 47.4 % were given no definitive treatment. In patients who received only physostigmine, there was a significant difference in the rate of intubation (1.9 vs. 8.4 %, OR 0.21, 95 % CI 0.05-0.87) versus other treatment groups. Physostigmine was given at varying rates based on causative agent with use in agents with mixed or unknown effects (15.1 %) being significantly lower than those with primarily anticholinergic effects (26.6 %) (p < 0.001). Patients with anticholinergic toxicity were more likely to receive benzodiazepines than physostigmine. Those patients who received only physostigmine had a significantly lower rate of intubation. Physostigmine was more likely to be used with agents exerting primarily anticholinergic toxicity than in those agents with multiple actions. PMID- 25510308 TI - Exercise E/e' for the assessment of left ventricular filling pressures: with caution in clinical practice? PMID- 25510307 TI - A preliminary randomized controlled trial of a distress tolerance treatment for opioid dependent persons initiating buprenorphine. AB - BACKGROUND: Buprenorphine opioid agonist treatment (OAT) has established efficacy for treating opioid dependency but early relapse rates are high and are often associated with withdrawal-related or emotional distress. METHODS: To determine whether a novel distress tolerance (DT) intervention during buprenorphine initiation decreases opioid relapse, we conducted a preliminary randomized controlled trial with opioid-dependent outpatients. Participants received buprenorphine-naloxone induction and 3-months of maintenance buprenorphine plus seven, 50-min manualized, individual sessions (DT vs. health education (HE) control) over a 28-day period, linked to clinician medication dosing visits, and beginning 2 days prior to buprenorphine induction. Primary outcomes included use of illicit opioids (positive defined as any self-reported use in the prior 28 days or detected by urine toxicology) and treatment drop out. RESULTS: Among 49 participants, the mean age was 41 years, 65.3% were male. Persons randomized to DT had lower rates of opioid use at all three monthly assessments, and at 3 months, 72% of HE participants were opioid positive compared with 62.5% of DT participants. Rates of dropout were 24% and 25% in the HE and DT arms, respectively. CONCLUSIONS: This distress tolerance treatment produced a small, but not statistically significant reduction in opioid use during the first three months of treatment although no differences were found in drop-out rates between conditions. If replicated in a larger study, DT could offer clinicians a useful behavioral treatment to complement the effects of buprenorphine. PMID- 25510309 TI - Role of inflammation in the aging bones. AB - Chronic inflammation in aging is characterized by increased inflammatory cytokines, bone loss, decreased adaptation, and defective tissue repair in response to injury. Aging leads to inherent changes in mesenchymal stem cell (MSC) differentiation, resulting in impaired osteoblastogenesis. Also, the pro inflammatory cytokines increase with aging, leading to enhanced myelopoiesis and osteoclastogenesis. Bone marrow macrophages (BMMs) play pivotal roles in osteoblast differentiation, the maintenance of hematopoietic stem cells (HSCs), and subsequent bone repair. However, during aging, little is known about the role of macrophages in the differentiation and function of MSC and HSC. Aged mammals have higher circulating pro-inflammatory cytokines than young adults, supporting the hypothesis of increased inflammation with aging. This review will aid in the understanding of the potential role(s) of pro-inflammatory (M1) and anti inflammatory (M2) macrophages in differentiation and function of osteoblasts and osteoclasts in relation to aging. PMID- 25510310 TI - Fibrinogen in trauma, an evaluation of thrombelastography and rotational thromboelastometry fibrinogen assays. AB - BACKGROUND: Identifying hypofibrinogenemia in trauma is important. The optimal method of fibrinogen determination is unknown. We therefore evaluated fibrinogen levels determined by two whole blood viscoelastic hemostatic assays, thrombelastography functional fibrinogen (FF) and rotational thromboelastometry FIBTEM in trauma patients and compared these with the plasma-based Clauss method. MATERIALS AND METHODS: Prospective study of consecutive adult trauma patients admitted to a level I trauma center. Levels of fibrinogen were analyzed by Clauss, FF, and FIBTEM on arrival. These methods were compared, and we then investigated whether specific cutoffs of fibrinogen levels were indicative for an increased risk of receiving a transfusion within the initial 6 h. RESULTS: A total of 182 patients with an Injury Severity Score of 17 (9-26) were enrolled. Functional fibrinogen maximum amplitude (FF MA) and FIBTEM maximum clot firmness (MCF) had identical correlation coefficients when compared with those of Clauss fibrinogen (both rho = 0.64, P < 0.001), and FF MA and FIBTEM MCF correlated with each other (rho = 0.71, P < 0.001). By logistic regression, the following cutoffs of fibrinogen levels were associated with increased odds of receiving a transfusion, red blood cell concentrates: Clauss <2.5 g/L, FF MA <14.9 mm, FIBTEM MCF <10 mm; fresh frozen plasma and platelets: Clauss <2.5 g/L, FF MA <16.9 mm, FIBTEM MCF <14 mm. CONCLUSIONS: The viscoelastic hemostatic assays for determining fibrinogen levels, FIBTEM and FF, are both correlated with the Clauss fibrinogen level, and there are no differences in the strength of these correlations. In this study, specific fibrinogen levels at arrival to the emergency department were indicative, although not necessarily causal, of increased odds of receiving a transfusion. PMID- 25510311 TI - Assembly of Fe/S proteins in bacterial systems: Biochemistry of the bacterial ISC system. AB - Iron/sulfur clusters are key cofactors in proteins involved in a large number of conserved cellular processes, including gene expression, DNA replication and repair, ribosome biogenesis, tRNA modification, central metabolism and respiration. Fe/S proteins can perform a wide range of functions, from electron transfer to redox and non-redox catalysis. In all living organisms, Fe/S proteins are first synthesized in an apo-form. However, as the Fe/S prosthetic group is required for correct folding and/or protein stability, Fe/S clusters are inserted co-translationally or immediately after translation by specific assembly machineries. These systems have been extensively studied over the last decade, both in prokaryotes and eukaryotes. The present review covers the basic principles of the bacterial housekeeping Fe/S biogenesis ISC system, and related recent molecular advances. Some of the most exciting recent highlights relating to this system include structural and functional characterization of binary and ternary complexes involved in Fe/S cluster formation on the scaffold protein IscU. These advances enhance our understanding of the Fe/S cluster assembly mechanism by revealing essential interactions that could never be determined with isolated proteins and likely are closer to an in vivo situation. Much less is currently known about the molecular mechanism of the Fe/S transfer step, but a brief account of the protein-protein interactions involved is given. This article is part of a Special Issue entitled: Fe/S proteins: Analysis, structure, function, biogenesis and diseases. PMID- 25510312 TI - Revision of the family Gymnophallidae Odhner, 1905 (Digenea) based on morphological and molecular data. AB - This paper reviews the family Gymnophallidae, recognizing as valid seven genera; four within the subfamily Gymnophallinae: Gymnophallus Odhner, 1900 (syn. Meiogymnophallus Ching, 1965), Paragymnophallus Ching, 1973, Pseudogymnophallus Hoberg, 1981, and Bartolius Cremonte, 2001, and three in the Parvatrematinae: Parvatrema Cable, 1953, Lacunovermis Ching, 1965, and Gymnophalloides Fujita, 1925. Specimens representing one species of each available genus were chosen from those well-described and non controversial species, for which strong morphological information was available, and used for molecular studies (ITS1 5.8S-ITS2-28S rDNA strands were sequenced). The presence or absence of a pars prostatica differentiates between the 2 subfamilies, Gymnophallinae and Parvatrematinae. The characters used to differentiate genera are: location of the ovary (pre-, post- or inter-testicular), size and location of the genital pore (inconspicuous and located at the anterior margin of the ventral sucker, or conspicuous and located at some distance from the anterior margin of ventral sucker), presence of caecal pockets, and presence or absence of ventral pit (a muscular structure which can be either well-developed, similar in size and musculature to the ventral sucker, or be poorly developed). The characters previously used to distinguish among genera that actually should be considered to separate species include: shape of tegument spines (broad, sharp or serrated), presence of lateral projections on the oral sucker (also called papillae or lips), shape of the seminal vesicle (unipartite or bipartite), shape of the prostatic duct (elongate or oval), presence of papillae on the genital pore, shape of the genital atrium (tubular, wide, oval), shape of the vitellaria (follicular in a variable degree, paired or single), shape of the excretory vesicle (V or Y), and extension of uterus (restricted to forebody, at hindbody or extending in both). Additionally, some of these characters may vary with the age of worm. The morphological and molecular information obtained in this study provided strong support for recognizing seven valid genera in the family Gymnophallidae. PMID- 25510314 TI - A longitudinal study of back dimension changes over 1 year in sports horses. AB - Major back dimension changes over time have been observed in some horses, the speed of which may be influenced by work type, skeletal maturity, nutrition and saddle fit. Currently, there are no longitudinal data quantifying changes in back dimensions. The objectives of this study were to quantify back dimension changes over time, to identify the effects of horse, saddle and rider on these dimensions, and to determine their association with season, weight, work and saddle management. A prospective, longitudinal study was performed, using stratified random sampling within a convenience sample of 104 sports horses in normal work. Thoracolumbar dimensions/symmetry were measured at predetermined sites every second month over 1 year; weight, work and saddle management changes were recorded. Descriptive statistics, and univariable and multiple mixed effects linear regression were performed to assess the association between management changes, horse-saddle-rider factors and back dimension changes. Complete data was available for 63/104 horses, including horses used for dressage (n= 26), showjumping (n= 26), eventing (n= 26) and general purpose (n= 26), with age groups 3-5 years (n = 24), 6-8 years (n = 28), 9-12 years (n = 24) and >= 13 years (n = 28). There were considerable variations in back dimensions over 1 year. In the multivariable analysis, the presence of gait abnormalities at initial examination and back asymmetry were significant and had a negative effect on changes in back dimensions. Subsequent improved saddle fit, similar or increased work intensity, season (summer versus winter) and increased bodyweight retained significance, having positive effects on changes in back dimensions. In conclusion, quantifiable changes in back dimensions occur throughout the year. Saddle fit should be reassessed professionally several times a year, especially if there has been a change in work intensity. PMID- 25510313 TI - Effectiveness of a school-based physical activity intervention on obesity in school children: a nonrandomized controlled trial. AB - BACKGROUND: Childhood obesity has been a serious public health problem. An effective school-based physical activity (PA) intervention is still lacking in China. This study aimed to assess the effectiveness of a school-based physical activity intervention during 12 weeks on obesity and related health outcomes in school children. METHODS: It was a non-randomized controlled trial. Altogether 921 children aged 7 to 15 years were recruited at baseline survey. Children in the intervention group (n = 388) participated in a multi-component physical activity intervention during 12 weeks that included improvement of physical education, extracurricular physical activities for overweight/obese students, physical activities at home, and health education lectures for students and parents. Children (n = 533) in the control group participated in usual practice. RESULTS: Participants had mean age of 10.4 years, mean body mass index (BMI) of 19.59 kg/m2, and 36.8 % of them were overweight or obese at baseline survey. The change in BMI in intervention group (-0.02 +/- 0.06 kg/m2) was significantly different from that in control group (0.41 +/- 0.08 kg/m2). The adjusted mean difference was -0.43 kg/m2 (95% CI: -0.63 to -0.23 kg/m2, P < 0.001). The effects on triceps, subscapular, abdominal skinfold thickness and fasting glucose were also significant in intervention group compared with control group (all P < 0.05). The change in duration of moderate to vigorous physical activity (MVPA) in intervention group (8.9 +/- 4.3 min/day) was significantly different from that in control group (-13.8 +/- 3.3 min/day). The adjusted mean difference was 22.7 min/day (95% CI: 12.2 to 33.2 min/day, P < 0.001). CONCLUSIONS: The school-based, multi-component physical activity intervention was effective to decreasing levels of BMI, skinfold thickness, fasting glucose and increasing duration of MVPA. These findings provided evidence for the development of effective and feasible school-based obesity interventions. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02074332 (2014-02-26). PMID- 25510316 TI - Comparison of the cyclic fatigue resistance of 5 different rotary pathfinding instruments made of conventional nickel-titanium wire, M-wire, and controlled memory wire. AB - INTRODUCTION: This study compared the cyclic fatigue resistance of current nickel titanium rotary path-finding instruments. METHODS: Five types of nickel-titanium rotary pathfinding instruments were used in steel canals with a 90 degrees curvature and a curvature radius of 3 mm (n = 10) and 5 mm (n = 10). The cyclic fatigue of the following instruments was tested at 4 mm from the tip: PathFile (#16 and a .02 taper; Dentsply Maillefer, Ballaigues, Switzerland), G-File (#12 and a .03 taper; Micro-Mega, Besancon Cedex, France), Scout Race (#15 and a .02 taper; FKG Dentaire, La Chaux-de-Fonds, Switzerland), HyFlex GPF (#15 and a .02 taper; Coltene-Whaledent, Allstetten, Switzerland), and ProGlider (#16 with a mean taper of .04125 and a .02 at the first 4 mm from the tip, Dentsply Maillefer). The length of the fractured parts was measured, and the number of cycles to fracture (NCF) was calculated. The data were statistically analyzed using Kruskal-Wallis and Mann-Whitney tests (alpha = .05). After Bonferroni correction, the new P value was set as .005. RESULTS: The difference in the cyclic fatigue of all the files at both curvatures was statistically significant (P values from .0035 to less than .0001). The ranking of the instruments from the highest to the lowest NCF was as follows: HyFlex GPF, G files, ProGlider, PathFile, and Scout Race. The length of the fractured part of the instruments was similar in all the groups (P > .05). All the tested instruments had a lower NCF at a curvature radius of 3 mm when compared with a curvature radius of 5 mm (P < .0001). CONCLUSIONS: Within the limitations of this study, the cyclic fatigue resistance of the HyFlex GPF instrument was the highest, and the curvature radius had a significant effect on the fatigue resistance. PMID- 25510315 TI - Effect of superficial harrowing on surface properties of sand with rubber and waxed-sand with fibre riding arena surfaces: a preliminary study. AB - A recent epidemiological study identified various aspects of arena surfaces and arena surface maintenance that were related to risk of injury in horses and that arena maintenance is important in reducing injury risk. However, there has been little research into how properties of arena surfaces change with harrowing. This study aimed to compare the properties of different arena surface types pre- and post-harrowing. The Orono Biomechanical Surface Tester fitted with accelerometers and a single- and a three-axis load cell was used to test 11 arenas with two different surfaces types, sand with rubber (SR) and waxed-sand with fibre (WSF). Three drop tests were carried out at 10 standardised locations on each arena. Mixed models were created to assess the effect of surface type, pre- or post harrowing, and drop number on the properties of the surface, including maximum horizontal deceleration, maximum vertical deceleration, maximum vertical load and maximum horizontal load. Post-harrowing, none of the parameters were altered significantly on SR. On WSF, maximum vertical deceleration and maximum vertical load significantly decreased post-harrowing. The differences in the effects of superficial harrowing on SR and WSF could be attributed to the different compositions and sizes of the surface material. The results suggest that different maintenance techniques may be more suitable for different surface types and that the effects of superficial harrowing are short-lived due to the rapid re compaction of the surface with repeated drops on WSF. Further work is required to determine the effects of other maintenance techniques, and on other surface types. PMID- 25510317 TI - Involvement of platelet-derived growth factor receptor beta in fibrosis through extracellular matrix protein production after ischemic stroke. AB - Fibrosis is concomitant with repair processes following injuries in the central nervous system (CNS). Pericytes are considered as an origin of fibrosis-forming cells in the CNS. Here, we examined whether platelet-derived growth factor receptor beta (PDGFRbeta), a well-known indispensable molecule for migration, proliferation, and survival of pericytes, was involved in the production of extracellular matrix proteins, fibronectin and collagen type I, which is crucial for fibrosis after ischemic stroke. Immunohistochemistry demonstrated induction of PDGFRbeta expression in vascular cells of peri-infarct areas at 3-7days in a mouse stroke model. The PDGFRbeta-expressing cells extended from peri-infarct areas toward the ischemic core after day 7 while expressing fibronectin and collagen type I in the infarct areas. In contrast, desmin and alpha-smooth muscle actin, markers of pericytes, were only expressed in vascular cells. In PDGFRbeta heterozygous knockout mice, the expression of fibronectin and collagen type I was attenuated at both mRNA and protein levels with an enlargement of the infarct volume after ischemic stroke compared with that in wild-type littermates. In cultured brain pericytes, the expression of PDGF-B, PDGFRbeta, fibronectin, and collagen type I, but not desmin, was significantly increased by serum depletion (SD). The SD-induced upregulation of fibronectin and collagen type I was suppressed by SU11652, an inhibitor of PDGFRbeta, while PDGF-B further increased the SD-induced upregulation. In conclusion, the expression level of PDGFRbeta may be a crucial determinant of fibrosis after ischemic stroke. Moreover, PDGFRbeta signaling participates in the production of fibronectin and collagen type I after ischemic stroke. PMID- 25510319 TI - Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression. AB - Diabetes and Alzheimer's disease share pathologic links toward cognitive deficits. Pharmacologic agonist of the nuclear receptor, peroxisomal proliferator activating receptor gamma (PPARgamma), that is, rosiglitazone (rosi), are insulin sensitizing agents that improve memory in Alzheimer's disease. However, direct molecular signaling targets that improve memory by PPARgamma in the hippocampus have not been investigated. We compared outcomes from oral versus intracerebroventricular (ICV) administration of rosi on memory and changes in synaptic plasticity in type 2 diabetic (db/db) mice. Db/db mice treated with rosi (ICV) showed significant improvement in memory, long-term potentiation, and post tetanic potentiation but did not improve peripheral insulin sensitivity. Gene and protein analysis revealed increased brain-derived neurotrophic factor (BDNF) in db/db mice treated with rosi (ICV). Transcriptional activation of exon IX as determined by luciferase assays confirmed PPARgamma regulation of BDNF promoter activity. Transient transfection of constitutively active PPARgamma plasmid in hippocampal neuronal cells induced increased BDNF, AMPA, and NMDA receptors expression and spine formation. Findings from the present study implicate a novel PPARgamma-BDNF molecular signaling mechanism as a potential therapeutic target for cognitive impairment. PMID- 25510320 TI - Chronic pancreatitis, a comprehensive review and update. Part I: epidemiology, etiology, risk factors, genetics, pathophysiology, and clinical features. PMID- 25510318 TI - Biphasic bisperoxovanadium administration and Schwann cell transplantation for repair after cervical contusive spinal cord injury. AB - Schwann cells (SCs) hold promise for spinal cord injury (SCI) repair; however, there are limitations for its use as a lone treatment. We showed that acute inhibition of the phosphatase and tensin homolog deleted on chromosome ten (PTEN) by bisperoxovanadium (bpV) was neuroprotective and enhanced function following cervical hemicontusion SCI. We hypothesized that combining acute bpV therapy and delayed SC engraftment would further improve neuroprotection and recovery after cervical SCI. Adult female Sprague-Dawley (SD) rats were randomly sorted into 5 groups: sham, vehicle, bpV, SC transplantation, and bpV+SC transplantation. SCs were isolated from adult green fluorescent protein (GFP)-expressing SD rats (GFP SCs). 200 MUg/kg bpV(pic) was administered intraperitoneally (IP) twice daily for 7 days post-SCI in bpV-treated groups. GFP-SCs (1*10(6) in 5 MUl medium) were transplanted into the lesion epicenter at the 8th day post-SCI. Forelimb function was tested for 10 weeks and histology was assessed. bpV alone significantly reduced lesion (by 40%, p<0.05) and cavitation (by 65%, p<0.05) and improved functional recovery (p<0.05) compared to injury alone. The combination promoted similar neuroprotection (p<0.01 vs. injury); however, GFP-SCs alone did not. Both SC-transplanted groups exhibited remarkable long-term SC survival, SMI-31(+) axon ingrowth and RECA-1(+) vasculature presence in the SC graft; however, bpV+SCs promoted an 89% greater axon-to-lesion ratio than SCs only. We concluded that bpV likely contributed largely to the neuroprotective and functional benefits while SCs facilitated considerable host-tissue interaction and modification. The combination of the two shows promise as an attractive strategy to enhance recovery after SCI. PMID- 25510321 TI - A quantitative 1H nuclear magnetic resonance (qHNMR) method for assessing the purity of iridoids and secoiridoids. AB - This paper utilized a quantitative (1)H nuclear magnetic resonance (qHNMR) method for assessing the purity of iridoids and secoiridoids. The method was fully validated, including specificity, linearity, accuracy, precision, reproducibility, and robustness. For optimization of experimental conditions, several experimental parameters were investigated, including relaxation delay (D1), scan numbers (NS) and power length (PL1). The quantification was based on the area ratios of H-3 from analytes relative to aromatic protons from 1,4 dinitrobenzene (internal standard) with methanol-d4 as solvent. Five iridoids and secoiridoids (sweroside, swertiamarin, gentiopicroside, geniposide, genipin) were analyzed. Furthermore, the results were validated by the high performance liquid chromatography coupled with ultraviolet detection (HPLC-UV) method. It can be concluded that the qHNMR method was simple, rapid, and accurate, providing a reliable and superior method for assessing the purity of iridoids and secoiridoids. PMID- 25510322 TI - Aspalathin and nothofagin from rooibos (Aspalathus linearis) inhibit endothelial protein C receptor shedding in vitro and in vivo. AB - Aspalathin (Asp) and nothofagin (Not) are two major active dihydrochalcones found in green rooibos, which have been reported for their anti-oxidant activity. Increasing evidence has demonstrated that beyond its role in the activation of protein C, endothelial cell protein C receptor (EPCR) is also involved in vascular inflammation. EPCR activity is markedly changed by ectodomain cleavage and its release as the soluble EPCR. EPCR can be shed from the cell surface, which is mediated by tumor necrosis factor-alpha converting enzyme (TACE). However, little is known about the effects of Asp and Not on EPCR shedding. Our results demonstrated that Asp and Not induced potent inhibition of phorbol-12 myristate 13-acetate (PMA)-, tumor necrosis factor (TNF)-alpha-, interleukin (IL) 1beta, and cecal ligation and puncture (CLP)-induced EPCR shedding. Asp and Not also inhibited the expression and activity of PMA-induced TACE in endothelial cells. Asp and Not also suppressed CLP-induced protein C decrease in mice and thrombin generation in HUVECs. In addition, treatment with Asp and Not resulted in reduced PMA-stimulated phosphorylation of p38, extracellular regulated kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK). These results demonstrate the potential of Asp and Not as an anti-sEPCR shedding reagent against PMA and CLP mediated EPCR shedding. PMID- 25510323 TI - Galbanic acid inhibits HIF-1alpha expression via EGFR/HIF-1alpha pathway in cancer cells. AB - Hypoxia Inducible Factor-1 plays a key transcriptional role in the adaptation of hypoxic solid tumors to low oxygen environment. Here, we aimed to investigate galbanic acid (GBA) inhibitory effects on HIF-1 activation during hypoxia and normoxia. MTT survival and Annexin V assays were used to evaluate GBA cytotoxicity and apoptosis in treated cells. Quantitative real time PCR and western blotting were used to estimate mRNA expression and translated protein, respectively. Results showed that GBA dose- and time-dependently decreased the in vitro growth of OVCAR-3 human epithelial carcinoma cells with an IC50 of approximately 37, 12.1 and 10MUM GBA at 24, 48 and 72h, respectively. Following phosphatidylserine of outer leaflet of the plasma membrane revealed occurrence of early/late apoptosis in GBA treated cells. In addition, we found that GBA down regulates HIF-1alpha and HIF-1beta mRNA expression in both hypoxia and normoxia. To determine the mechanism of action, we showed that GBA did not inhibit Akt and EGFR mRNA expression, yet protein degradation investigation showed that GBA shortened the half-life of EGFR through decreasing its stability with a decrease of nearly 2 and 3h in A549 and OVCAR-3 cell lines, respectively. We also found that downstream genes contributed in glycolysis, including Eno 1 and GluT-1, are underexpressed in GBA treated cells in hypoxia. Conclusively, GBA may inhibit HIF 1 activation through down-regulation of its subunit expression in hypoxia, and increasing of EGFR degradation in normoxia. PMID- 25510325 TI - The role of oxygen vacancies and their location in the magnetic properties of Ce(1-x)Cu(x)O(2-delta) nanorods. AB - Ceria (CeO2) is a promising dilute magnetic semiconductor. Several studies report that the intrinsic and extrinsic structural defects are responsible for room temperature ferromagnetism in undoped and transition metal doped CeO2 nanostructures; however, the nature of the kind of defect necessary to promote and stabilize the ferromagnetism in such a system is still a matter of debate. In the work presented here, nanorods from the system Ce1-xCuxO2-delta with x = 0, 0.01, 0.03, 0.05 and 0.10, with the more stable {111} surface exposed were synthesized by a microwave-assisted hydrothermal method. A very careful structure characterization confirms that the Cu in the samples assumes a majority 2+ oxidation state, occupying the Ce (Ce(4+) and Ce(3+)) sites with no secondary phases up to x = 0.05. The inclusion of the Cu(2+) in the CeO2 structure leads to the introduction of oxygen vacancies in a density proportional to the Cu(2+) content. It is supposed that the spatial distribution of the oxygen vacancies follows the Cu(2+) distribution by means of the formation of a defect complex consisting of Cu(2+) ion and an oxygen vacancy. Superconducting quantum interference device magnetometry demonstrated a diamagnetic behavior for the undoped sample and a typical paramagnetic Curie-Weiss behavior with antiferromagnetic interactions between the Cu(2+) ions for the single phase doped samples. We suggest that the presence of oxygen vacancies is not a sufficient condition to mediate ferromagnetism in the CeO2 system, and only oxygen vacancies in the surface of nanostructures would lead to such a long range magnetic order. PMID- 25510324 TI - Assessment of ovarian reserve using anti-Mullerian hormone levels in benign gynecologic conditions and surgical interventions: a systematic narrative review. AB - The usefulness of anti-Mullerian hormone (AMH) for the quantitative evaluation of ovarian reserve has been established. Therefore, serum AMH has been recently applied to the assessment of ovarian reserve outside infertility treatment. We conducted a computer-based search, using keywords, through the PubMed database from inception until May 2014 and summarized available studies evaluating ovarian damage caused by gynecologic diseases, such as endometriosis and ovarian tumor, as well as surgical interventions, such as cystectomy and uterine artery embolization (UAE), to discuss the usefulness of serum AMH. Most of the studies demonstrated a decline of serum AMH levels after cystectomy for endometriomas. It is not conclusive whether electrocoagulation or suturing is preferable. The effects of other gynecologic diseases and interventions, such as hysterectomy and UAE, on ovarian reserve are controversial. Serum AMH levels should be considered in determining the indication and selection of operative methods for benign gynecologic conditions. PMID- 25510326 TI - Intramuscular fat in lamb muscle and the impact of selection for improved carcass lean meat yield. AB - Intramuscular fat percentage (IMF%) has been shown to have a positive influence on the eating quality of red meat. Selection of Australian lambs for increased lean tissue and reduced carcass fatness using Australian Sheep Breeding Values has been shown to decrease IMF% of the Muscularis longissimus lumborum. The impact this selection has on the IMF% of other muscle depots is unknown. This study examined IMF% in five different muscles from 400 lambs (M. longissimus lumborum, Muscularis semimembranosus, Muscularis semitendinosus, Muscularis supraspinatus, Muscularis infraspinatus). The sires of these lambs had a broad range in carcass breeding values for post-weaning weight, eye muscle depth and fat depth over the 12th rib (c-site fat depth). Results showed IMF% to be highest in the M. supraspinatus (4.87 +/- 0.1, P<0.01) and lowest in the M. semimembranosus (3.58 +/- 0.1, P<0.01). Hot carcass weight was positively associated with IMF% of all muscles. Selection for decreasing c-site fat depth reduced IMF% in the M. longissimus lumborum, M. semimembranosus and M. semitendinosus. Higher breeding values for post-weaning weight and eye muscle depth increased and decreased IMF%, respectively, but only in the lambs born as multiples and raised as singles. For each per cent increase in lean meat yield percentage (LMY%), there was a reduction in IMF% of 0.16 in all five muscles examined. Given the drive within the lamb industry to improve LMY%, our results indicate the importance of continued monitoring of IMF% throughout the different carcass regions, given its importance for eating quality. PMID- 25510329 TI - Radical anionic versus neutral 2,2'-bipyridyl coordination in uranium complexes supported by amide and ketimide ligands. AB - The synthesis and characterization of (bipy)(2)U(N[t-Bu]Ar)(2) (1-(bipy)(2), bipy = 2,2'-bipyridyl, Ar = 3,5-C(6)H(3)Me(2)), (bipy)U(N[(1)Ad]Ar)(3) (2-bipy), (bipy)(2)U(NC[t-Bu]Mes)(3) (3-(bipy)(2), Mes = 2,4,6-C(6)H(2)Me(3)), and IU(bipy)(NC[t-Bu]Mes)(3) (3-I-bipy) are reported. X-ray crystallography studies indicate that bipy coordinates as a radical anion in 1-(bipy)(2) and 2-bipy, and as a neutral ligand in 3-I-bipy. In 3-(bipy)(2), one of the bipy ligands is best viewed as a radical anion, the other as a neutral ligand. The electronic structure assignments are supported by NMR spectroscopy studies of exchange experiments with 4,4'-dimethyl-2,2'-bipyridyl and also by optical spectroscopy. In all complexes, uranium was assigned a +4 formal oxidation state. PMID- 25510328 TI - Smear plus Detect-TB for a sensitive diagnosis of pulmonary tuberculosis: a cost effectiveness analysis in an incarcerated population. AB - BACKGROUND: Prison conditions can favor the spread of tuberculosis (TB). This study aimed to evaluate in a Brazilian prison: the performance and accuracy of smear, culture and Detect-TB; performance of smear plus culture and smear plus Detect-TB, according to different TB prevalence rates; and the cost-effectiveness of these procedures for pulmonary tuberculosis (PTB) diagnosis. METHODS: This paper describes a cost-effectiveness study. A decision analytic model was developed to estimate the costs and cost-effectiveness of five routine diagnostic procedures for diagnosis of PTB using sputum specimens: a) Smear alone, b) Culture alone, c) Detect-TB alone, d) Smear plus culture and e) Smear plus Detect TB. The cost-effectiveness ratio of costs were evaluated per correctly diagnosed TB case and all procedures costs were attributed based on the procedure costs adopted by the Brazilian Public Health System. RESULTS: A total of 294 spontaneous sputum specimens from patients suspected of having TB were analyzed. The sensibility and specificity were calculated to be 47% and 100% for smear; 93% and 100%, for culture; 74% and 95%, for Detect-TB; 96% and 100%, for smear plus culture; and 86% and 95%, for smear plus Detect-TB. The negative and positive predictive values for smear plus Detect-TB, according to different TB prevalence rates, ranged from 83 to 99% and 48 to 96%, respectively. In a cost-effectiveness analysis, smear was both less costly and less effective than the other strategies. Culture and smear plus culture were more effective but more costly than the other strategies. Smear plus Detect-TB was the most cost-effective method. CONCLUSIONS: The Detect-TB evinced to be sensitive and effective for the PTB diagnosis when applied with smear microscopy. Diagnostic methods should be improved to increase TB case detection. To support rational decisions about the implementation of such techniques, cost-effectiveness studies are essential, including in prisons, which are known for health care assessment problems. PMID- 25510330 TI - Disulfide stress and its targets in acute pancreatitis. AB - Under physiological conditions, the balance between ROS production and removal properly maintains the intracellular redox-sensitive signaling as well as the appropriate status of protein thiols and disulfides. However, inflammation among other factors can modify this balance causing a rapid increase in intracellular ROS levels and hence thiol oxidation, eventually leading to oxidative stress. In the case of acute pancreatitis, both redox signaling and oxidative stress seem to contribute to the progression of the severe form of the disease. In this review we will focus on the reversible oxidation of protein cysteines during the course of acute pancreatitis. We describe disulfide stress in an acute inflammatory process, which is characterized by thiol oxidation in proteins, particularly protein cysteinylation, without significant changes in the glutathione redox status. PMID- 25510331 TI - Molecular-like hierarchical self-assembly of monolayers of mixtures of particles. AB - We present a technique that uses an externally applied electric field to self assemble monolayers of mixtures of particles into molecular-like hierarchical arrangements on fluid-liquid interfaces. The arrangements consist of composite particles (analogous to molecules) which are arranged in a pattern. The structure of a composite particle depends on factors such as the relative sizes of the particles and their polarizabilities, and the electric field intensity. If the particles sizes differ by a factor of two or more, the composite particle has a larger particle at its core and several smaller particles form a ring around it. The number of particles in the ring and the spacing between the composite particles depend on their polarizabilities and the electric field intensity. Approximately same sized particles form chains (analogous to polymeric molecules) in which positively and negatively polarized particles alternate. PMID- 25510332 TI - Nanodiamond-mediated drug delivery and imaging: challenges and opportunities. AB - INTRODUCTION: The field of nanoparticle-based therapeutic systems is rapidly expanding encompassing a wide variety of practices ranging from detection to diagnosis to treatment. Recently a great potential of nanodiamond (ND) particles as a multimodal imaging/therapy platform has been demonstrated. AREAS COVERED: This review describes a unique set of properties of ND particles attractive for drug delivery and imaging applications and highlights the most recent ND-based multimodal imaging/therapy approaches and related biocompatibility studies. The spectrum of major advancements includes marked improvements in tumor treatment efficacy and safety based on integration of ND with doxorubicin (DOX). Recent progress of ND-mediated drug delivery in orthopedic, dental and ophthalmic applications is also discussed. EXPERT OPINION: ND particles possess a unique set of properties attractive for drug delivery applications, including exceptional biocompatibility, large carrier capacity and versatile surface chemistry properties, which enhance drug binding and provide sustainable drug release. Other unique attributes of NDs embrace bright stable fluorescence based on crystallographic defects. A roadmap toward a clinical translation comprises identification of ND-therapeutic compounds that display marked improvements over clinical standards with respects to efficacy, safety and cost. PMID- 25510333 TI - Ultra-responsive soft matter from strain-stiffening hydrogels. AB - The stiffness of hydrogels is crucial for their application. Nature's hydrogels become stiffer as they are strained. This stiffness is not constant but increases when the gel is strained. This stiffening is used, for instance, by cells that actively strain their environment to modulate their function. When optimized, such strain-stiffening materials become extremely sensitive and very responsive to stress. Strain stiffening, however, is unexplored in synthetic gels since the structural design parameters are unknown. Here we uncover how readily tuneable parameters such as concentration, temperature and polymer length impact the stiffening behaviour. Our work also reveals the marginal point, a well-described but never observed, critical point in the gelation process. Around this point, we observe a transition from a low-viscous liquid to an elastic gel upon applying minute stresses. Our experimental work in combination with network theory yields universal design principles for future strain-stiffening materials. PMID- 25510334 TI - Lymph node melanosis. Should it be managed as a high-risk melanoma? A case report and review of the literature. PMID- 25510335 TI - Assessment of the quality of patient-orientated internet information on surgery for ulcerative colitis. AB - AIM: This study examines the quality of websites providing information on ulcerative colitis, including treatment options and surgery. METHOD: Two search engines (Google and Yahoo) and the search term 'surgery for ulcerative colitis' were used. The first 50 sites obtained with each search engine were assessed. Sites were evaluated for content and scored using the DISCERN instrument, which evaluates the quality of health information on treatment choices. RESULTS: One hundred sites were examined, of which 14 were duplicates. Of the remainder, 58 provided patient-orientated information for adults and one site provided information for surgery in children. The other 27 sites included six scientific articles, three blogs, three links, six resources for clinicians, five fora, two video links and two dead links. Of the 58 websites that provided patient information for adults, only 26 (44.8%) had been updated within the last 2 years. Only 13/58 (22.4%) were affiliated to hospitals and clinics. Most sites (38/58, 65.5%) were associated with private companies with commercial interests. Although most websites contained information on symptoms and treatment options for ulcerative colitis, 37 (63.8%) did not describe any of the risks of surgery. Overall, only seven (12.1%) websites were identified as being 'good' or 'excellent' using the DISCERN criteria. CONCLUSION: The quality of patient information on surgery for ulcerative colitis is highly variable. There is potential for internet provision of valuable information and clinicians should guide patients with to access high-quality websites. PMID- 25510336 TI - Postinfectious Opsoclonus-Myoclonus Syndrome in a 41-Year-Old Patient-Visualizing Hyperactivation in Deep Cerebellar Nuclei by Cerebral [(18) F]-FDG- PET. AB - A 41-year-old woman presented with acute onset headache, vertigo, nausea, and gait disorder, initially interpreted as a common cold. Within 2 weeks, she developed a severe opsoclonus-myoclonus syndrome with truncal ataxia. Cerebrospinal fluid examination and serological findings suggested a recent infection with Coxsackie B3 virus. [(18) F]-FDG-PET proved to be the only imaging tool to identify the underlying pathology depicting hyperactivation in the vestibulo- and spinocerebellum as well as hyperactivation of the ocular muscles. At the clinical follow-up 4 months later, the patient's symptoms were considerably improved with only intermittent low-frequency opsoclonus. Corresponding PET findings were able to depict the response to therapy in the ocular muscles and the inferior vermis, whereas the deep cerebellar nuclei were still hyperactivated, however, to a lesser extent. This finding highlights the usefulness of functional/metabolic brain imaging to study the pathophysiology of this type of disorder. PMID- 25510337 TI - Physiologically based GPS speed zones for evaluating running demands in Women's Rugby Sevens. AB - High-speed running (>5 m . s-1) is commonly reported in men's rugby union and sevens; however, the appropriateness of using the same speed threshold for Women's Rugby Sevens players is unclear, and likely underestimates the degree of high-intensity exercise completed by female players. The aim of this study was to establish, for international Women's Rugby Sevens players, a physiologically defined threshold - speed at the second ventilatory threshold (VT(2peed)) - for the analysis of high-intensity running, using mean and individualised thresholds. Game movement patterns (using 5 Hz GPS) of 12 international Women's Rugby Sevens players (23.5 +/- 4.9 ears, 1.68 +/- 0.04 m, 68.2 +/- 7.7 kg; mean +/- s) were collected at an international tournament. Seven of these players also completed a treadmill VO(2max) test to estimate VT(2speed). Compared to the mean VT(2speed) threshold (3.5 m . s-1), the industry-used threshold of 5 m . s-1 underestimated the absolute amount of high-intensity running completed by individual players by up to 30%. Using an individualised threshold, high-intensity running could over- or underestimating high-intensity running by up to 14% compared to the mean VT(2peed) threshold. The use of individualised thresholds provides an accurate individualised assessment of game demands to inform the prescription of training. PMID- 25510339 TI - The influence of industry actions on the availability of alcoholic beverages in the African region. AB - AIMS: The alcohol beverage industry has been expanding its corporate social responsibility and other business activities in sub-Saharan Africa. The aim of this paper is to evaluate the effects of these activities on the physical, economic, psychological and social availability of alcohol in the region. METHODS: Narrative review. Source materials came from the business press, industry sources (websites, annual reports, press releases, conference proceedings) and the scientific literature published since 2000. RESULTS: The alcohol industry has intensified its activities in the African region, through their funding of social aspect organizations, technical publications, policy workshops and other corporate social responsibility activities. Marketing campaigns, new product designs and the development of industry-civil society partnerships have increased. There is evidence that the alcohol industry also engages in lobbying, information dissemination and legal action to thwart effective public health measures. CONCLUSIONS: The corporate social responsibility activities of the global alcohol industry have provided a vehicle to promote industry-favorable policies and increase the physical, economic, social and psychological availability of alcohol. PMID- 25510338 TI - Hypoxia disrupts proteostasis in Caenorhabditis elegans. AB - Oxygen is fundamentally important for cell metabolism, and as a consequence, O2 deprivation (hypoxia) can impair many essential physiological processes. Here, we show that an active response to hypoxia disrupts cellular proteostasis - the coordination of protein synthesis, quality control, and degradation that maintains the functionality of the proteome. We have discovered that specific hypoxic conditions enhance the aggregation and toxicity of aggregation-prone proteins that are associated with neurodegenerative diseases. Our data indicate this is an active response to hypoxia, rather than a passive consequence of energy limitation. This response to hypoxia is partially antagonized by the conserved hypoxia-inducible transcription factor, hif-1. We further demonstrate that exposure to hydrogen sulfide (H2S) protects animals from hypoxia-induced disruption of proteostasis. H2S has been shown to protect against hypoxic damage in mammals and extends lifespan in nematodes. Remarkably, our data also show that H2S can reverse detrimental effects of hypoxia on proteostasis. Our data indicate that the protective effects of H2S in hypoxia are mechanistically distinct from the effect of H2S to increase lifespan and thermotolerance, suggesting that control of proteostasis and aging can be dissociated. Together, our studies reveal a novel effect of the hypoxia response in animals and provide a foundation to understand how the integrated proteostasis network is integrated with this stress response pathway. PMID- 25510340 TI - Do Asian women do as well as their Caucasian counterparts in IVF treatment: Cohort study. AB - AIM: To evaluate if there is a difference in pregnancy rate between Asian and Caucasian women when they undergo in vitro fertilization (IVF). METHODS: This was a retrospective cohort study set in a private reproductive medicine clinic. The study consisted of a total of 2594 patients (Asian, n = 522; Caucasian, n = 2072) undergoing IVF managed by a single doctor over a 10 year period. The main outcome measures were clinical pregnancy rate and live birth rate. Logistic regression was used to control for confounding factors. RESULTS: Asian women achieved a significantly lower clinical pregnancy and live birth rate than their Caucasian counterparts, despite replacement of more embryos. This difference was not significant after controlling for age and duration of infertility. Despite higher doses of gonadotrophin, they achieved fewer oocytes and had resultant fewer embryos for transfer or cryopreservation. CONCLUSIONS: In a study designed to reduce the effect of confounding factors by looking at a large number of patients from a single IVF unit under the care of a single doctor, there does not appear to be a difference in IVF pregnancy rate as a result of race. Asian women tend to present for IVF treatment at a later age after having tried for a longer period of time and this contributes significantly to their lower pregnancy rate. PMID- 25510342 TI - A revolution in electrodes: recent progress in rechargeable lithium-sulfur batteries. AB - As a promising candidate for future batteries, the lithium-sulfur battery is gaining increasing interest due to its high capacity and energy density. However, over the years, lithium-sulfur batteries have been plagued by fading capacities and the low Coulombic efficiency derived from its unique electrochemical behavior, which involves solid-liquid transition reactions. Moreover, lithium sulfur batteries employ metallic lithium as the anode, which engenders safety vulnerability of the battery. The electrodes play a pivotal role in the performance of lithium-sulfur batteries. A leap forward in progress of lithium sulfur batteries is always accompanied by a revolution in the electrode technology. In this review, recent progress in rechargeable lithium-sulfur batteries is summarized in accordance with the evolution of the electrodes, including the diversified cathode design and burgeoning metallic-lithium-free anodes. Although the way toward application has still many challenges associated, recent progress in lithium-sulfur battery technology still paints an encouraging picture of a revolution in rechargeable batteries. PMID- 25510341 TI - The number of intestinal bacteria is not critical for the enhancement of antitumor activity and reduction of intestinal toxicity of irinotecan by the Chinese herbal medicine PHY906 (KD018). AB - BACKGROUND: The four-herb Chinese medicine PHY906(KD018) has been shown to both enhance the in vivo antitumor activity of irinotecan (CPT-11) against colon cancer tumor allografts and alleviate intestinal toxicity caused by CPT-11. METHODS: Since intestinal bacteria can metabolize CPT-11 and PHY906, we investigated whether intestinal bacteria play a critical role in the in vivo activity of PHY906 in murine Colon-38 tumor-bearing mice. Intestinal bacteria were depleted using streptomycin/neomycin for 10 days before and during treatment with PHY906 and/or CPT-11. qPCR using 16S DNA group-specific primers was used to quantify the levels of the major intestinal bacteria. RESULTS: Both PHY906 and antibiotic treatment changed the profile of intestinal bacteria species: Lactobacillus/Enterococcus, Bacteroides, Clostridium leptum, and E. rectale/C. coccoides. Antibiotic treatment did not alter the ability of PHY906 to enhance the antitumor activity of CPT-11. Antibiotic treatment alone partially reduced animal body weight loss in CPT-11-treated mice. However, PHY906 treatment was able to protect against the body weight loss in the CPT-11/antibiotic treatment group. H&E and PCNA staining of intestine showed that antibiotic treatment partially reduced the intestinal damage caused by CPT-11 but not as effectively as PHY906 treatment. Antibiotic treatment plus PHY906 conferred the most effective protection of intestine histological structure against damage by CPT 11. Both PHY906 and antibiotic treatment inhibited CPT-11-associated inflammatory processes, including infiltration of the intestine by neutrophils, MCP1 and TNF alpha mRNA expression in the intestine, and expression of pro-inflammatory cytokines G-CSF and MCP1 proteins in the plasma. However, whereas antibiotic treatment suppressed the mRNA expression of two important intestinal progenitor/stem cell markers, Olfm4 and Lgr5, PHY906 treatment resulted in enhanced expression of these two stem cell markers. CONCLUSIONS: Alterations in the population of intestinal bacteria did not affect the abilities of PHY906 to enhance CPT-11 antitumor activity or reduce the intestinal toxicity associated with CPT-11 treatment. The major species of intestinal bacteria do not appear to play a role in PHY906's enhancement of the therapeutic index of CPT-11 in tumor bearing mice. Thus, patients with different intestinal bacterial profiles may still benefit from PHY906 treatment alongside CPT-11. PMID- 25510343 TI - Sleep magnetic resonance imaging with electroencephalogram in obstructive sleep apnea syndrome. AB - OBJECTIVE: To evaluate the mechanism and level of upper airway obstruction in obstructive sleep apnea (OSA) patients during natural sleep, together with synchronous electroencephalogram and respiratory events registration at 3-Tesla magnetic resonance imaging (MRI) platform with high spatial and temporal resolution. STUDY DESIGN: A prospective cohort study of 20 randomly selected OSA patients. METHODS: Fifteen of 20 patients were able to complete spontaneous sleep during MRI. While asleep, dynamic MR images of pharynx were obtained in the midline sagittal view. During the scan, nasal and oral airflow, thoracoabdominal wall effort, and electroencephalogram were synchronously recorded. The physiologic data were retrospectively scored to identify periods of apneas and synchronized with dynamic MR images. RESULTS: In all 15 patients, the site of complete airway obstruction occurred at the retropalatal space. We noticed different positions of the soft palate during apneic events. In seven of 15 patients (47%), the soft palate was attached to the tongue base and moved backward, compressing the airway. In five of 15 patients (33%), the soft palate was detached from the tongue base and solely moved backward, compressing the airway. In three patients (20%), we recorded both mechanisms of complete airway obstruction. In cases with attached soft palate to the tongue base, we noticed significant narrowing of the retrolingual space during apneic events. CONCLUSION: We describe a novel mechanism of obstruction dependent on the position of soft palate. This mechanism might play an important role in selecting candidates for surgery or treatment with hypoglossal nerve stimulation. LEVEL OF EVIDENCE: 2b. PMID- 25510344 TI - Molecular characterization of the skin fungal microbiome in patients with psoriasis. AB - The skin surface is colonized by a wide variety of fungi and bacteria. While many of these organisms, including Malassezia, Candida, Streptococcus and Staphylococcus species, are associated with provocation and/or exacerbation of psoriasis, a detailed analysis of the cutaneous fungal microbiome in psoriatic patients has yet to be performed. To identify the disease-specific fungal microbiota on psoriatic scale samples, fungal rRNA gene sequences from 12 psoriatic patients and 12 healthy controls were analyzed by pyrosequencing. A total of 317 806 high-quality sequences were obtained, representing 142 genera. Malassezia species were the most abundant sequences in both populations (46.9 +/- 14.0% in psoriasis vs. 76.0 +/- 14.6% for healthy controls). Principal coordinate analysis revealed that the fungal microbiomes were independent. Although an association between the cutaneous fungal microbiome and psoriasis has yet to be established, our data indicate that the microbiome in patients with psoriasis is independent of that in healthy controls. PMID- 25510345 TI - Stimulator of interferon genes-associated vasculitis of infancy. PMID- 25510346 TI - A versatile cyclic 2,2'-azobenzenophane with a functional handle and its polymers: efficient synthesis and effect of topological structure on chiroptical properties. AB - Two novel cyclic azobenzenophanes (SC, RC) with functional handles have been synthesized efficiently by a Glaser coupling reaction. Through a Suzuki coupling reaction, alternating ring/linear polymers with rigid (conjugated)/flexible (unconjugated) bridges were obtained from the resultant cyclic azobenzenophanes. The optical activities of linear, cyclic, and macromolecular binaphethyl azobenzene derivatives were investigated by UV/Vis and circular dichroism (CD) spectra and the time-dependent (TD)-DFT method. Experimental results and theoretical analyses indicated that the cyclic configurations exhibited better chiroptical features than the others, and the reverse conformation and difference of dextro-/levo-rotation of azobenzenophanes were detected by comparing linear and cyclic structures, which provides an opportunity for the optical-rotation controlled "smart" materials systems in future. PMID- 25510347 TI - tris-Heteroleptic cyclometalated iridium(III) complexes with ambipolar or electron injection/transport features for highly efficient electrophosphorescent devices. AB - A series of tris-heteroleptic phosphorescent cyclometalated Ir(III) complexes with two different cyclometalating ligands and one ancillary ligand was synthesized. Through manipulation of the electronic features of individual cyclometalating ligands, not only the emission color and electrochemical properties of these Ir(III) complexes can be tuned, but also unique charge carrier injection and transport traits can be conferred to them. Owing to the enhanced electron injection/transport and ambipolar characters associated with these tris-heteroleptic structures, these Ir(III) emitters showed very impressive electroluminescent performance with a maximum external quantum efficiency of 20.20 %, luminance efficiency of 69.41 cd A(-1) and power efficiency of 35.15 Lm W(-1) . These results provide a new outlet to design and synthesize highly efficient electrophosphors for phosphorescent organic light-emitting diodes. PMID- 25510348 TI - Bayesian Chance-Constrained Hydraulic Barrier Design under Geological Structure Uncertainty. AB - The groundwater community has widely recognized geological structure uncertainty as a major source of model structure uncertainty. Previous studies in aquifer remediation design, however, rarely discuss the impact of geological structure uncertainty. This study combines chance-constrained (CC) programming with Bayesian model averaging (BMA) as a BMA-CC framework to assess the impact of geological structure uncertainty in remediation design. To pursue this goal, the BMA-CC method is compared with traditional CC programming that only considers model parameter uncertainty. The BMA-CC method is employed to design a hydraulic barrier to protect public supply wells of the Government St. pump station from salt water intrusion in the "1500-foot" sand and the "1700-foot" sand of the Baton Rouge area, southeastern Louisiana. To address geological structure uncertainty, three groundwater models based on three different hydrostratigraphic architectures are developed. The results show that using traditional CC programming overestimates design reliability. The results also show that at least five additional connector wells are needed to achieve more than 90% design reliability level. The total amount of injected water from the connector wells is higher than the total pumpage of the protected public supply wells. While reducing the injection rate can be achieved by reducing the reliability level, the study finds that the hydraulic barrier design to protect the Government St. pump station may not be economically attractive. PMID- 25510349 TI - Provisional hybrid 2-stent Strategy utilizing bioresorbable vascular scaffold and drug-eluting metal stent: "T-stenting and small protrusion" technique. AB - We present a case of side-branch restenosis after T-stenting and small protrusion (TAP) technique using a bioresorbable vascular scaffold and a drug-eluting metallic stent. According to intravascular ultrasound imaging findings, the simultaneous balloon deflation after kissing balloon post-dilatation was the likely cause of restenosis. In cases where bifurcation treatment requires the TAP technique, operators should pay particular attention to perform kissing balloon inflation with sequential deflation (main branch first, side branch last). PMID- 25510350 TI - Nonalcoholic fatty liver disease and age are strong indicators for atherosclerosis in morbid obesity. AB - OBJECTIVE: Whether nonalcoholic fatty liver disease (NAFLD) can predict atherosclerosis in obese patients remains unclear. The aim of our study was to investigate the usefulness of NAFLD and other cardiometabolic parameters in predicting subclinical atherosclerosis in obese patients. DESIGN, PATIENTS AND MEASUREMENTS: We studied 314 consecutive obese subjects (223 women; mean age, 45.04 +/- 9.34 years; body mass index 44.3 +/- 5 kg/m(2) ) and 47 healthy lean individuals. Hepatic steatosis and atherosclerosis [carotid intima-media thickness (cIMT) >0.8 mm and/or presence of plaques] were evaluated ultrasonographically. Liver biopsies were obtained in 51 patients. RESULTS: In obese patients, mean c-IMT was greater in those with NAFLD (P < 0.001). Hepatic steatosis and age were independent predictors of atherosclerosis: the NAFLD associated OR for atherosclerosis was 5.96 (95%CI, 1.60-22.25; P = 0.008) in men and 8.26 (95%CI, 4.02-16.99; P < 0.001) in women, and the age-associated OR for atherosclerosis was 1.14 (95%CI, 1.07-1.22; P < 0.001) in men and 1.12 (95%CI, 1.08-1.17; P < 0.001) in women. The sensitivity, specificity and positive and negative predictive values of steatosis for atherosclerosis were 78.70%, 70.50%, 74.00% and 75.60% (AUC = 0.840) in men >=43.5 years and 86.90%, 52.50%, 68.80% and 76.80% (AUC = 0.761) in women >=47.5 years, respectively. Agreement between ultrasound-diagnosed steatosis and histology was good (ICC = 0.79). Combined NAFLD and age was the strongest predictor of atherosclerosis in obesity. CONCLUSIONS: Nonalcoholic fatty liver disease and age may be independent risk factors for carotid atherosclerosis in obese individuals. Obese men and women with steatosis aged over 43.5 and 47.5 years, respectively, should be screened for carotid atherosclerosis. However, further evidence is necessary before suggesting an intervention based on current findings. PMID- 25510352 TI - Most recent common ancestor of TTR Val30Met mutation in Italian population and its potential role in genotype-phenotype correlation. AB - INTRODUCTION: Transthyretin (TTR)-related amyloidosis is characterized by autosomal transmission of amyloidogenic mutated TTR. Val30Met is one of the most common amyloidogenic TTR mutations, showing a worldwide distribution with phenotypic heterogeneity among human populations. Multiple founder mutations for Val30Met foci have been hypothesized and the different origins may explain the phenotypic variability. The aim of our study is to determine the origin of Italian Val30Met and to analyze the genetic relationship of other Val30Met foci. METHODS: We analyzed the origin of Italian Val30Met through 11 microsatellite markers around the TTR gene in 29 patients and 34 healthy controls. RESULTS: Our genetic analysis showed an estimated age of origin of 34-36 generations ago for the Italian Val30Met. Comparing Italian Val30Met haplotypes with those from Sweden and Portugal highlights relevant differences that seem to be consistent with an independent origin of Italian Val30Met mutation. This genetic evidence agrees with the disease phenotypic variation in these populations. DISCUSSION AND CONCLUSIONS: Italian Val30Met mutation should have originated before the Portuguese and Swedish Val30Met ones (which arose through independent mutational events). This indicates a genetic diversity in the surrounding regions of three different Val30Met mutations, supporting the hypothesis that TTR non-coding regions may contribute to phenotypic heterogeneity. PMID- 25510351 TI - L1CAM is expressed in triple-negative breast cancers and is inversely correlated with androgen receptor. AB - BACKGROUND: Breast cancer is a heterogeneous disease displaying distinct molecular features and clinical outcome. The molecular profile of triple-negative breast cancers (TNBCs) overlaps with that of basal-like breast cancers that in turn show similarities with high-grade serous ovarian and endometrial carcinoma. L1CAM is an established biomarker for the latter cancers and we showed before that approximately 18% of primary breast cancers are positive for L1CAM and have a bad prognosis. Here we analysed the expression of L1CAM breast cancer subtypes. METHODS: We analyzed mRNA and protein expression data from different breast cancer cohorts for L1CAM, estrogen receptor, progesterone receptor, Her-2 and Androgen receptor (AR) and correlated the data. We performed Western blot analysis on tumor cell lysates and carried out chromatin-immuno-precipitation (CHIP) after AR overexpression. RESULTS: We find that L1CAM is expressed preferentially though not exclusively in TNBCs. Using the human cancer genome atlas database and two independent breast cancer cohorts we find that L1CAM is inversely correlated with androgen receptor (AR) expression. We found that L1CAM(high)AR(low) primary breast tumors have the worst clinical outcome. Overexpression of AR in MDA-MB436 breast cancer cells decreased L1CAM expression at the protein and mRNA level and CHIP-analysis revealed binding of AR to the L1CAM promoter region. CONCLUSIONS: These results suggest that L1CAM in breast cancer is under AR control. The data also strongly advocate the use of L1CAM assessment in breast cancer diagnosis. We suggest that L1CAM expression could be causally related to the bad prognosis of TNBCs. PMID- 25510353 TI - The myocardial contraction fraction is superior to ejection fraction in predicting survival in patients with AL cardiac amyloidosis. AB - Cardiac amyloidosis is a cause of diastolic heart failure in which ejection fraction (EF) remains "normal" despite progression of disease. The myocardial contraction fraction (MCF) is an index of myocardial function, defined as stroke volume (SV) over myocardial volume (MV). We hypothesized that MCF would be superior to EF, the conventional measure of left ventricular function, in predicting survival among patients with cardiac amyloidosis. Sixty-six subjects (mean age = 67 +/- 12 years; 20% women) with cardiac amyloidosis (34 with light chain amyloid and 32 with transthyretin amyloid) underwent two-dimensional echocardiography to determine left ventricular structure and function. Cox proportional hazard modeling was used to determine the association of MCF and EF with survival. Over a mean follow-up of 1.86 +/- 1.78 years (range 0.03-7.36 years), 37 subjects (56.1%) died. Mean EF of the study population was 51 +/- 13%. There was no significant difference in EF between patients who survived the study period and those who died (54 +/- 11% versus 49 +/- 14%; p = 0.1196) while there was a significant difference in MCF (35 +/- 19% versus 23 +/- 10%, p = 0.0065). Using Cox proportional hazards modeling, MCF was associated with death (HR = 0.953, 95% CI of 0.932-0.984, p = 0.0031) while EF was not (HR = 0.991, 95% CI of 0.968-1.014, p = 0.4320). In a multivariate model, amyloid light-chain (AL) amyloid type was an independent risk predictor of death with a HR of 2.841 (95% CI of 1.214-6.648, p = 0.0161) along with a MCF < 30 with a HR of 2.567 (95% CI of 1.197-5.508, p = 0.0155), which was driven by a higher risk in AL subjects with a MCF < 30, HR of 3.39 (95% CI of 1.20-9.55, p = 0.021) than TTR subjects with a MCF < 30, HR of 1.26 (95% CI of 0.36-3.28, p = 0.87). In conclusion, MCF, a novel measure of myocardial chamber function, is superior to EF in predicting overall survival among patients with AL cardiac amyloidosis. PMID- 25510354 TI - Attention Biases Towards and Away from Threat Mark the Relation between Early Dysregulated Fear and the Later Emergence of Social Withdrawal. AB - Fearful temperament, mostly studied as behavioral inhibition (BI), has been extensively associated with social withdrawal in childhood and the later emergence of anxiety disorders, especially social anxiety disorder (SAD). Recent studies have characterized a distinct type of fearful temperament marked by high levels of fear in low threat situations - labeled dysregulated fear. Dysregulated fear has been related to SAD over and above risks associated with BI. However, the mechanism by which dysregulated fear is related to SAD has not been studied. Cognitive mechanisms, such as attentional bias towards threat, may be a possible conduit. We examined differences in attentional bias towards threat in six-year olds who displayed a pattern of dysregulated fear at age two (N = 23) compared with children who did not display dysregulated fear (N = 33). Moreover, we examined the concurrent relation between attentional bias and social withdrawal. Results indicated that children characterized by dysregulated fear showed a significant bias away from threat, and that this bias was significantly different from the children without dysregulated fear, who showed no significant bias. Moreover, attentional bias towards threat was positively related to social withdrawal only for the dysregulated fear group. These results are discussed in consideration of the existing knowledge of attentional bias to threat in the developmental and pediatric anxiety literatures, as well as recent studies that find important heterogeneity in attentional bias. PMID- 25510355 TI - Understanding Early Contextual and Parental Risk Factors for the Development of Limited Prosocial Emotions. AB - A growing body of evidence suggests that parenting influences the development of youth callous unemotional (CU) behavior. However, less is known about the effects of parenting or contextual risk factors on 'limited prosocial emotions' (LPE), a recent conceptualization of CU behavior added to the DSM-5. We focused on LPE at ages 10-12 and age 20 among low income, urban males (N = 310), and examined potential developmental precursors, including contextual risk factors assessed during infancy and observed maternal warmth during the toddler period. We found unique direct associations between maternal warmth, maternal aggression, and low empathetic awareness on LPE at ages 10-12, controlling for concurrent self reported antisocial behavior. Further, there were indirect effects of maternal aggression, low empathetic awareness, and difficult infant temperament assessed in infancy on LPE at ages 10-12 via their influence on maternal warmth at age 2. Finally, there were lasting indirect effects of parental warmth on LPE at age 20, via LPE at ages 10-12. We discuss the implications of these findings for ecological models of antisocial behavior and LPE development, and preventative interventions that target the broader early parenting environment. PMID- 25510356 TI - Role of HXXXD-motif/BAHD acyltransferases in the biosynthesis of extracellular lipids. AB - Terrestrial plants have evolved specific adaptations to preserve water and protect themselves from their environment. Such adaptations range from secondary metabolites and specialized structures that conduct water and nutrients, to cell wall modifications (i.e., cuticle and suberin) that prevent dehydration and provide a physical barrier to pathogens. Both the plant cuticle and suberized cell walls contain a lipid polymer framework embedded with waxes, and constitute a promising target for controlled genetic modification to improve desirable agronomic traits. Recent advances in genomic and molecular techniques coupled with the development of robust analytical methods have accelerated progress in comprehending these intractable lipid polymers. Gene products characterized in the wax, cutin and suberin pathways include a subset of HXXXD/BAHD family enzymes that catalyze acyl transfer reactions between CoA-activated hydroxycinnamic acid derivatives and hydroxylated aliphatics. This review highlights our current understanding of HXXXD/BAHD acyltransferases in extracellular lipid biosynthesis and discusses the chemical, ultrastructural and physiological ramifications of impairing the expression of BAHD acyltransferase-encoding genes related to cutin and suberin synthesis. PMID- 25510357 TI - Alternative splicing of mini-exons in the Arabidopsis leaf rust receptor-like kinase LRK10 genes affects subcellular localisation. AB - KEY MESSAGE: AtLRK10L1.2 produces a variety of alternatively spliced variants in the region a mini-exon and skipping of the mini-exon alters the subcellular localization of the protein. We have examined expression and alternative splicing in the gene encoding Arabidopsis LRK10-like 1 (AtLRK10L1) which is most closely related to wheat leaf rust 10 disease-resistance locus receptor-like protein kinase (LRK10). AtLRK10L1 produces two different transcripts, LRK10L1.1 and 1.2 through the use of two different promoters. We found no evidence of alternative splicing for the AtLRK10L1.1 transcript but identified numerous alternative splicing variants of AtLRK10L1.2 by sequencing of cloned cDNAs prepared from RNA isolated from whole cell, nucleolar and nucleoplasmic fractions. Many of these transcripts contained unspliced introns and accumulated differentially in the nucleolus and the nucleoplasm consistent with intron retention transcripts being retained in the nucleus (Gohring et al., Plant Cell 26:754-764, 2014). We examined the fate of different alternatively spliced transcripts by fusing variants to YFP and expressing them by agroinfiltration in Nicotiana benthamiana. AtLRK10L1 contains a 45 nt mini-exon which encodes part of a putative transmembrane domain. Full-length cDNA of LRK10L1.2 fused to YFP targeted the fusion protein to the plasma membrane while expression of transcripts where the mini-exon had been deleted, altered the localization of the fusion protein to the endoplasmic reticulum. Similarly, expression of full-length and mini-exon deleted versions of three other members of the LRK10 receptor-like kinase (RLK) gene family also showed the switch in localization. Thus, the mini-exons in Arabidopsis LRK10 genes are required for localization to the plasma membrane. PMID- 25510358 TI - Salvage cryosurgery for locally recurrent prostate cancer after primary cryotherapy. AB - OBJECTIVE: To report our preliminary experience of salvage cryosurgery (SCS) for locally recurrent prostate cancer (PCa) after primary cryotherapy and determine the efficacy of cryoablation of the prostate in the salvage setting. PATIENTS AND METHODS: We conducted a retrospective review of the records of all patients who underwent SCS for locally recurrent PCa after primary cryotherapy between February 2008 and March 2012. Patients were assessed after treatment by prostate specific antigen (PSA) testing, transrectal ultrasonography, radiologic imaging, and biopsy. Biochemical failure was defined using the Phoenix criteria. RESULTS: Data from 12 patients who had undergone SCS were entered. Median age at SCS was 77.5 year. Before SCS, patients had a median PSA level of 2.5 ng/ml and median Gleason sum of 7. Patients underwent SCS at a median of 7.8 months after primary CS. Median PSA nadir after SCS was 1.32 ng/ml. The mean (range) follow-up was 33.5 months. Three patients were started on hormonal therapy for disease progression at a median post-SCS period of 12 months. Two patients underwent repeat cryoablation. Only one patient developed mild incontinence after SCS. Urethral sloughing occurred in one patient. Only two patients suffered from transient impotence. CONCLUSIONS: It is feasible for patients with PCa to adopt SCS when primary cryotherapy has failed. The application of SCS also allows hormonal therapy to be deferred for a sufficient period of time. PMID- 25510359 TI - Inhalation and dietary exposure to PCBs in urban and rural cohorts via congener specific measurements. AB - Polychlorinated biphenyls (PCBs) are a group of 209 persistent organic pollutants, whose documented carcinogenic, neurological, and respiratory toxicities are expansive and growing. However, PCB inhalation exposure assessments have been lacking for North American ambient conditions and lower chlorinated congeners. We assessed congener-specific inhalation and dietary exposure for 78 adolescent children and their mothers (n = 68) in the Airborne Exposure to Semi-volatile Organic Pollutants (AESOP) Study. Congener-specific PCB inhalation exposure was modeled using 293 measurements of indoor and outdoor airborne PCB concentrations at homes and schools, analyzed via tandem quadrupole GS-MS/MS, combined with questionnaire data from the AESOP Study. Dietary exposure was modeled using Canadian Total Diet Survey PCB concentrations and National Health and Nutrition Examination Survey (NHANES) food ingestion rates. For ?PCB, dietary exposure dominates. For individual lower-chlorinated congeners (e.g., PCBs 40+41+71, 52), inhalation exposure was as high as one-third of the total (dietary+inhalation) exposure. ?PCB inhalation (geometric mean (SE)) was greater for urban mothers (7.1 (1.2) MUg yr(-1)) and children (12.0 (1.2) MUg yr(-1)) than for rural mothers (2.4 (0.4) MUg yr(-1)) and children (8.9 (0.3) MUg yr( 1)). Schools attended by AESOP Study children had higher indoor PCB concentrations than did homes, and account for the majority of children's inhalation exposure. PMID- 25510360 TI - The role of oxidation in FSL-1 induced signaling pathways of an atopic dermatitis model in HaCaT keratinocytes. AB - Oxidative stress (OS) is common in inflammatory conditions and may be important in atopic dermatitis (AD) etiology. The aim of this project was to study the involvement of oxidation in FSL-1 (deacylated lipoprotein)-triggered signaling pathways leading to AD-typical cytokine expression in HaCaT keratinocytes. HaCaT keratinocytes, pretreated with the inhibitor to OS N-acetylcysteine (NAC), were exposed to FSL-1, a stimulator of AD-related cytokines. Cytokines expression was studied by real time polymerase chain reaction (PCR); nuclear factor-kappa B (NF kappaB) and p38 mitogen activated protein kinase (MAPK) activities were studied by western blotting; and the oxidative state of cells was determined by the dichlorofluorescein (DCF) assay. We found that endogenous OS in keratinocytes appeared 4 h after FSL-1 administration. OS activated NF-kappaB, but not p38 MAPK, and the inhibition of OS reduced FSL-1 induced interleukin (IL) 33, thymic stromal lymphopoietin (TSLP) and TNFalpha mRNA expression. We conclude that FSL-1 triggers an OS reaction in HaCaT keratinocytes, which is probably a secondary event affecting the expression of specific AD typical cytokines, possibly through the NF-kappaB pathways. This role of OS in the inflammatory response in AD is worth further investigating. PMID- 25510362 TI - The role of nitric oxide synthase in an early phase Cd-induced acute cytotoxicity in MCF-7 cells. AB - Literature to date has confirmed that cadmium (Cd) can accomplish its toxic effects via the free radical-induced damage, but Cd itself cannot generate free radicals directly. Nitric oxide (NO) is a fundamental molecule that interplays with reactive oxygen species (ROS), which may be associated with the Cd-induced cytotoxicity. However, the role of nitric oxide synthase (NOS) in an early phase Cd-induced acute cytotoxicity and its interaction has not been studied. In this report, we provide data showing that CdCl2 (10 MUM, 100 MUM, 1 mM) could modulate NOS activity in terms of NO production which was first suppressed with the release of Ca(2+) and Zn(2+), then induced with the transcriptional and translational activation of the three NOS isoforms in a possible feedback manner. The ROS level in cells was increased after CdCl2 exposure. By using the free radical scavenger N-acetyl-L-cysteine (LNAC) or the NOS activity inhibitor N(G) methyl-L-arginine (LNMMA), it was demonstrated that NOS played a critical role on the Cd-induced ROS generation. The Cd-induced cytotoxicity was associated with the NOS-mediated oxidative stress in MCF-7 cells. PMID- 25510361 TI - Incorporating measures of sleep quality into cancer studies. AB - INTRODUCTION/BACKGROUND: Sleep disturbance may influence the development of cancer and responses to treatment. It is also closely tied to recovery and quality of life in cancer patients, survivors, and caregivers, and recent studies have begun to show beneficial effects of sleep-promoting interventions. Despite the importance of sleep to cancer and its treatment and the availability of numerous tools for measuring sleep quality and quantity, sleep measurements are underutilized in cancer studies. METHODS: This review, written for cancer researchers interested in incorporating sleep measures into their studies, is designed to raise awareness about the importance of sleep and suggests strategies for including sleep evaluation in cancer studies. CONCLUSIONS: Inclusion of readily available sleep measures may ultimately improve cancer care by facilitating studies that lead to a greater understanding of how sleep and sleep disturbance influence all aspects of cancer care and the patient experience. PMID- 25510364 TI - An effective fractal-tree closure model for simulating blood flow in large arterial networks. AB - The aim of the present work is to address the closure problem for hemodynamic simulations by developing a flexible and effective model that accurately distributes flow in the downstream vasculature and can stably provide a physiological pressure outflow boundary condition. To achieve this goal, we model blood flow in the sub-pixel vasculature by using a non-linear 1D model in self similar networks of compliant arteries that mimic the structure and hierarchy of vessels in the meso-vascular regime (radii [Formula: see text]). We introduce a variable vessel length-to-radius ratio for small arteries and arterioles, while also addressing non-Newtonian blood rheology and arterial wall viscoelasticity effects in small arteries and arterioles. This methodology aims to overcome substantial cut-off radius sensitivities, typically arising in structured tree and linearized impedance models. The proposed model is not sensitive to outflow boundary conditions applied at the end points of the fractal network, and thus does not require calibration of resistance/capacitance parameters typically required for outflow conditions. The proposed model convergences to a periodic state in two cardiac cycles even when started from zero-flow initial conditions. The resulting fractal-trees typically consist of thousands to millions of arteries, posing the need for efficient parallel algorithms. To this end, we have scaled up a Discontinuous Galerkin solver that utilizes the MPI/OpenMP hybrid programming paradigm to thousands of computer cores, and can simulate blood flow in networks of millions of arterial segments at the rate of one cycle per 5 min. The proposed model has been extensively tested on a large and complex cranial network with 50 parent, patient-specific arteries and 21 outlets to which fractal trees where attached, resulting to a network of up to 4,392,484 vessels in total, and a detailed network of the arm with 276 parent arteries and 103 outlets (a total of 702,188 vessels after attaching the fractal trees), returning physiological flow and pressure wave predictions without requiring any parameter estimation or calibration procedures. We present a novel methodology to overcome substantial cut-off radius sensitivities. PMID- 25510363 TI - Characteristics of inpatient anterior cruciate ligament reconstructions and concomitant injuries. AB - PURPOSE: The purpose of this epidemiologic study was to quantify the incidence, expense, and concomitant injuries for anterior cruciate ligament reconstruction (ACLR) procedures in the USA from 2003 to 2011 that required an inpatient stay. It was hypothesized that the relative reported rates of concomitant knee injuries would be greater with the MCL and menisci compared to all other concomitant knee injuries. METHODS: The National Inpatient Sample from 2003 to 2011 was retrospectively sampled using ICD-9-CM codes to identify ACLR patients and to extrapolate national averages. RESULTS: Between the years of 2003-2011, an average of 9,037 +/- 1,728 inpatient hospitalization included ACLRs, of which 4,252 +/- 1,824 were primarily due to the ACLR. Inpatient visits primarily due to ACLR involved an average hospitalization of 1.7 +/- 0.2 days and cost $30,118 +/- 9,066 per patient. Knee injuries that were commonly reported along with inpatient ACLRs included medial meniscus damage (18.1 %), lateral meniscus damage (16.8 %), collateral ligament repairs (12.3 %), and medial collateral ligament strains (6.9 %). Prevalence of meniscus injuries was consistent across years, but MCL-related injuries increased over time. CONCLUSIONS: ACLR-related inpatient hospitalizations account for approximately 7.1 % of the total ACLRs performed annually in the USA. Inpatient ACLR procedures continue to decrease in frequency; however, the mean cost per patient increased. Meniscus and collateral ligament injuries were the most commonly reported concomitant knee injuries. The clinical relevance of this investigation is that it informs, on a large clinical cohort of patients, the current state of incidence and expense for ACLR surgeries in an inpatient setting. LEVEL OF EVIDENCE: Prognostic, retrospective study, Level II. PMID- 25510365 TI - Erratum to: Strategies African-American Cancer Survivors Use to Overcome Fears and Fatalistic Attitudes. PMID- 25510367 TI - Awareness of Risk Factors for Breast, Lung and Cervical Cancer in a UK Student Population. AB - The objective of this study is to identify levels of risk awareness for breast, lung and cervical cancer, in a UK student population. A sample of male (N=62) and female (N=58) university students, mean age 21.62 years completed a questionnaire identifying which risk factors they knew for each cancer. Analysis of variance was used to compare differences in risk awareness across gender and cancer types. Risk factor awareness was highest for lung cancer (0.78), mid-range for breast cancer (0.61) and lowest for cervical cancer (0.47). Women had greater risk factor awareness (0.67) than males (0.57) across all three cancers. There is also significant belief in mythic risk factors such as stress (from 14 to 40% across the three cancers). Previous research has demonstrated that risk factor awareness increases with educational status, yet even in a university student population, in which the majority of females would have been offered the HPV vaccination, risk factor awareness for cancers is variable. More health education is needed particularly around the risk factors for cervical cancer. PMID- 25510366 TI - Awareness, Attitude, and Adherence to Preventive Measures in Patients at High Risk of Melanoma. A Cross-Sectional Study on 185 Patients. AB - Melanoma is potentially curable if diagnosed at its earliest stages and treated properly. The best approaches for reducing deaths due to melanoma are primary and secondary prevention. The objective of this study is to evaluate patient awareness of the risk factors for developing melanoma and attitudes toward its prevention. Also, this study aims to assess observance of recommended preventive measures and to identify possible factors associated with a low adoption of these measures. This cross-sectional study based on an online questionnaire included 185 consecutively enrolled subjects at risk of developing melanoma monitored in a pigmented lesion unit in Valencia (Spain). Level of knowledge, attitude, and observance of preventive measures were evaluated. Statistical analysis was carried out using contingency tables, chi-squared test, and Spearman correlation. Out of those who reported practicing skin self-examination, only 24.1 % performed it in the optimal way. A better attitude was observed in low-risk patients (r = 0.28, p < 0.01). Being female (p < 0.01), aged 18-35 (p = 0.02), fair-haired (p = 0.02), having skin phototype I-II (p < 0.01), and a suitable attitude (p = 0.05) and knowledge (p < 0.01) were related to a better use of sunscreens and avoidance of sun exposure. Knowledge was inversely associated with age (p = 0.01). Despite the high level of knowledge and positive attitude, inadequate practice of compliance with recommended primary and secondary preventive measures was observed in our risk population. PMID- 25510368 TI - A Framework for Training Transdisciplinary Scholars in Cancer Prevention and Control. AB - Traditionally, postdoctoral training programs largely have focused efforts within a single discipline or closely related fields. Yet, addressing the complex questions around cancer prevention and control increasingly requires the ability to work and communicate across disciplines in order to gain a perspective that encompasses the multilevel and multifaceted issues involved with this public health issue. To address this complexity, a transdisciplinary training program was implemented to cultivate the professional and scientific development of the postdoctoral fellows in Washington University in St Louis School of Medicine's Division of Public Health Sciences and NCI-funded centers (Community Networks Program Center and Transdisciplinary Research in Energetics in Cancer Center). Fellows are matched with primary mentors and assemble a multidisciplinary mentoring team. Structured programs support the transition of fellows from disciplinary trainees to independent transdisciplinary scholars and provide exposure to multiple disciplines. This article describes the training program, challenges encountered in implementation, solutions to those problems, and the metrics employed to evaluate the program's success. The goal of the program is to train emerging investigators in the conceptual bases, language, and practices that underlie a transdisciplinary perspective on cancer prevention and control research, to create an infrastructure for continued cross-discipline dialogue and collaboration, and to develop disseminable strategies for such training. PMID- 25510369 TI - Effects of Patient Navigation on Patient Satisfaction Outcomes. AB - Patient navigation (PN) may reduce cancer health disparities. Few studies have investigated the effects of PN on patient-reported satisfaction with care or assessed patients' satisfaction with navigators. The objectives of this study are to test the effects of PN on patient satisfaction with cancer care, assess patients' satisfaction with navigators, and examine the impact of barriers to care on satisfaction for persons with abnormal cancer-related screening tests or symptoms. Study participants included women and men with abnormal breast, cervical, or colorectal cancer screening tests and/or symptoms receiving care at 18 clinics. Navigated (n=416) and non-navigated (n=292) patients completed baseline and end-of-study measures. There was no significant difference between navigated and non-navigated patients in change in patient satisfaction with cancer care from baseline to exit. African-American (p<0.001), single (p=0.03), low income (p<0.01), and uninsured patients (p<0.001) were significantly less likely to report high patient satisfaction at baseline. A significant effect was found for change in satisfaction over time by employment status (p=0.04), with full-time employment showing the most improvement. The interaction between satisfaction with navigators and satisfaction with care over time was marginally significant (p=0.08). Baseline satisfaction was lower for patients who reported a barrier to care (p=0.02). Patients reporting other-focused barriers (p=0.03), including transportation (p=0.02), had significantly lower increases in satisfaction over time. Overall, results suggested that assessing barriers to cancer care and tailoring navigation to barrier type could enhance patients' experiences with health care. PN may have positive effects for healthcare organizations struggling to enhance quality of care. PMID- 25510370 TI - Innovative and Community-Guided Evaluation and Dissemination of a Prostate Cancer Education Program for African-American Men and Women. AB - African Americans (AA) are more likely to develop and die from cancer than any other racial or ethnic group. The aims of this research were to (1) evaluate current education materials being implemented in a community-based prostate cancer education program for AA communities, (2) refine materials based on findings from aim 1, (3) share updated materials with participants from aim 1 for additional improvements, and (4) disseminate and evaluate the improved education program through a statewide videoconference with AA men and women. AA individuals evaluated the current education program through a mail survey (n=32) and community forum (n=38). Participants reported that the existing prostate cancer education program content could be understood by lay persons, but recommendations for improvement were identified. They included the following: defining unknown and/or scientific terminology, increasing readability by increasing font size and enlarging images, and including more recent and relevant statistics. Following refinement of the education materials based on survey and forum feedback, a statewide videoconference was implemented. Following the videoconference, participants (25 men; 3 women) reported that they would encourage others to learn more about prostate cancer, talk to their doctor about whether or not to get screened for prostate cancer, and recommend the conference to others. There is great potential for using this type of iterative approach to education program development with community and clinical partners for others conducting similar work. PMID- 25510371 TI - What shall we do this year? PMID- 25510372 TI - The special case of the 2 * 2 table: asymptotic unconditional McNemar test can be used to estimate sample size even for analysis based on GEE. AB - OBJECTIVES: Aligning the method used to estimate sample size with the planned analytic method ensures the sample size needed to achieve the planned power. When using generalized estimating equations (GEE) to analyze a paired binary primary outcome with no covariates, many use an exact McNemar test to calculate sample size. We reviewed the approaches to sample size estimation for paired binary data and compared the sample size estimates on the same numerical examples. STUDY DESIGN AND SETTING: We used the hypothesized sample proportions for the 2 * 2 table to calculate the correlation between the marginal proportions to estimate sample size based on GEE. We solved the inside proportions based on the correlation and the marginal proportions to estimate sample size based on exact McNemar, asymptotic unconditional McNemar, and asymptotic conditional McNemar. RESULTS: The asymptotic unconditional McNemar test is a good approximation of GEE method by Pan. The exact McNemar is too conservative and yields unnecessarily large sample size estimates than all other methods. CONCLUSION: In the special case of a 2 * 2 table, even when a GEE approach to binary logistic regression is the planned analytic method, the asymptotic unconditional McNemar test can be used to estimate sample size. We do not recommend using an exact McNemar test. PMID- 25510373 TI - A systematic review highlights a knowledge gap regarding the effectiveness of health-related training programs in journalology. AB - OBJECTIVES: To investigate whether training in writing for scholarly publication, journal editing, or manuscript peer review effectively improves educational outcomes related to the quality of health research reporting. STUDY DESIGN AND SETTING: We searched MEDLINE, Embase, ERIC, PsycINFO, and the Cochrane Library for comparative studies of formalized, a priori-developed training programs in writing for scholarly publication, journal editing, or manuscript peer review. Comparators included the following: (1) before and after administration of a training program, (2) between two or more training programs, or (3) between a training program and any other (or no) intervention(s). Outcomes included any measure of effectiveness of training. RESULTS: Eighteen reports of 17 studies were included. Twelve studies focused on writing for publication, five on peer review, and none fit our criteria for journal editing. CONCLUSION: Included studies were generally small and inconclusive regarding the effects of training of authors, peer reviewers, and editors on educational outcomes related to improving the quality of health research. Studies were also of questionable validity and susceptible to misinterpretation because of their risk of bias. This review highlights the gaps in our knowledge of how to enhance and ensure the scientific quality of research output for authors, peer reviewers, and journal editors. PMID- 25510374 TI - Metal-assisted synthesis of unsymmetrical magnolol and honokiol analogs and their biological assessment as GABAA receptor ligands. AB - We present the synthesis of new derivatives of natural products magnolol (1) and honokiol (2) and their evaluation as allosteric ligands for modulation of GABAA receptor activity. New derivatives were prepared via metal assisted cross coupling reactions in two consecutive steps. Compounds were tested by means of two-electrode voltage clamp electrophysiology at the alpha1beta2gamma2 receptor subtype at low GABA concentrations. We have identified several compounds enhancing GABA induced current (IGABA) in the range similar or even higher than the lead structures. At 3MUM, compound 8g enhanced IGABA by factor of 443, compared to 162 and 338 of honokiol and magnolol, respectively. Furthermore, 8g at EC10-20 features a much bigger window of separation between the alpha1beta2gamma2 and the alpha1beta1gamma2 subtypes compared to honokiol, and thus improved subtype selectivity. PMID- 25510375 TI - Phosphatidylcholine bearing 6,6-dideuterated oleic acid: a useful solid-state (2)H NMR probe for investigating membrane properties. AB - Lipid organization has been at the center of research on lipid rafts. Dioleoylphosphatidylcholine (DOPC) is a typical unsaturated lipid. Very few studies have reported its thermodynamics in raft-like membranes. Herein, we have developed a highly efficient synthetic method for [C6-(2)H2] oleic acid, and newly synthesized [C6-(2)H2] DOPC. In raft-like oriented bilayers, [C6-(2)H2] DOPC shows clear phase separation and characteristic phase behavior at various temperature. It has been successfully utilized for the comparison of membrane properties between sphingomyelin (SM) and dihydrosphingomyelin (DHSM) membranes. PMID- 25510376 TI - Management of Node-Positive Bladder Cancer After Neoadjuvant Chemotherapy and Radical Cystectomy: A Survey of Current UK Practice. AB - INTRODUCTION: Because of the lack of published evidence, this study was done to explore the decisions and rationale of uro-oncology consultants regarding the treatment of patients with muscle-invasive bladder cancer who have positive lymph nodes after radical cystectomy (RC) and neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: An electronic survey was sent to UK pelvic cancer centers regarding: (1) choice of NAC regimen; (2) indications for reimaging; (3) choice and indication of adjuvant chemotherapy (AC) for patients with nodal disease after NAC and RC; (4) choice and indication of chemotherapy regimen if disease continues to progress in patients with advanced bladder cancer; and (5) guidelines used by those surveyed. RESULTS: Consultant uro-oncologists from 77% of UK pelvic cancer centers responded, who treated a median of 13 patients per year with NAC before RC. Three cycles of gemcitabine and cisplatin was the most common NAC regimen, with 93% and 67% respondents giving it for downstaging of cN1 and cN2- and 3-positive patients, respectively. Forty-five percent would not give AC after NAC and RC in patients with positive lymph nodes. The patient's performance status, followed by response to NAC were key factors in dictating the use of AC. In the presence of disease progression, 46% of participants would use a taxane. Fifty-two percent of responders do not follow any guidelines. CONCLUSION: In the United Kingdom, the treatment of patients with nodal disease after NAC and RC is variable. There is little evidence on which to base the management of such patients. The creation of national and international guidelines might help clinicians to optimize care for these patients. PMID- 25510377 TI - Association between beta-1 adrenergic receptor gene polymorphism and ischemic stroke in North Indian population: a case control study. AB - Stroke is a multi-factorial disease caused by a combination of genetic and environmental factors. The purpose of this case control study was to determine the relationship of beta-1 adrenergic receptor polymorphism with ischemic stroke in North Indian population. In this study, 224 patients and 224 age- and sex matched controls were recruited from the outpatient department and neurology ward of All India Institute of Medical Sciences, New Delhi. Genotyping was performed by using polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) method. PCR results were confirmed by DNA sequencing. Frequency distributions of genotypes and alleles were compared between cases and controls using logistic regression. Mean age of cases and controls was 53.9 +/- 13.4 and 53.6 +/- 12.9 years respectively. Multivariate logistic regression analysis showed an independent association between Ser49Gly polymorphism and ischemic stroke under a dominant model of inheritance (OR, 2.5; 95% CI, 1.2 to 5) and large vessel disease (LVD) under a recessive model of inheritance (OR, 6.5; 95% CI, 1.7 to 23; P=0.005). Independent association of Arg389Gly polymorphism with small vessel disease (SVD) (OR, 7.09; 95% CI, 1.9 to 25; P=0.003) under recessive model of inheritance. The findings of the present study Ser49Gly polymorphism of the ADRB1 gene confer higher risk of ischemic stroke in a North Indian population and especially in patients with LVD. Our findings also show that Arg389Gly polymorphism of ADRB1 confers higher risk of SVD in North Indian population. PMID- 25510378 TI - New Pooled Cohort Risk equations: application to a recent stroke patient population. AB - BACKGROUND: Recently, Pooled Cohort Risk (PCR) equations, which incorporate new sex- and race-specific estimates of the 10-year risk for atherosclerotic cardiovascular disease (ASCVD) including stroke, for ASCVD-free adults were introduced. Given the importance of secondary stroke prevention and benefit of a potential tool to readily identify stroke patients at high intermediate-term vascular risk for appropriate treatment, we evaluated the prediction and discrimination of the PCR and Framingham Cardiovascular Risk (FCR) equations after a recent stroke. METHOD: We conducted an analysis of Vitamin Intervention for Stroke Prevention dataset of 3555 recent non-cardioembolic stroke patients aged >= 35 years and followed for 2 years. Subjects were categorized as having low-PCR/low-FCR (<20%), high-PCR/high-FCR (>= 20%), and known-ASCVD. Independent associations of high-PCR/high-FCR with recurrent stroke (primary outcome) and stroke/coronary heart disease (CHD)/vascular death (secondary outcomes) were assessed. RESULTS: Both PCR and FCR were independently related to both outcomes: compared with low-PCR, high-PCR was associated with stroke (adjusted hazard ratio, 1.79; 95% CI, 1.25-2.57) and stroke/CHD/vascular death (2.05; 1.55-2.70). Compared with low-FCR, high-FCR was associated with stroke (2.06; 1.34-3.16) and stroke/CHD/vascular death (1.57; 1.12-2.20). The c-statistic of PCR/FCR as a continuous variable for stroke was 0.56 (95% CI, 0.54-0.58) and 0.56 (0.54-0.57), respectively and for stroke/CHD/vascular death was 0.62 (0.60-0.63) and 0.61 (0.59-0.63), respectively. CONCLUSIONS: Both PCR and FCR are significant predictors of recurrent vascular events among patients after a recent non cardioembolic stroke, but neither one of them is an optimal model for discriminating intermediate-term ASCVD prediction among stroke patients already receiving secondary stroke prevention. PMID- 25510379 TI - Identification of microRNAs as novel biomarkers for glioma detection: a meta analysis based on 11 articles. AB - BACKGROUND: Glioma is the most common and lethal primary brain tumors, and is regarded as one of the deadliest of human cancers. To date, a growing number of studies have tested the diagnostic accuracy of microRNAs (miRNAs) in glioma detection and altered levels of characteristic miRNAs have also been identified in glioma. However, there are some conflicting conclusions. Thus, we conducted this meta-analysis to evaluate the overall accuracy of miRNAs in the diagnosis of glioma. METHODS: A comprehensive literature search was conducted using a combination of keywords. The random effect model was used to calculate the pooled diagnostic parameters. The summary receiver operator characteristic (SROC) curves were plotted to assess the overall diagnostic performance of miRNAs. Subgroup and sensitivity analyses were conducted to analyze the potential sources of heterogeneity. RESULTS: In total, 28 studies from 11 articles covering 1729 patients and 1491 controls were available in this meta-analysis. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.87 (95% CI: 0.83-0.91), 0.87 (95% CI: 0.81-0.91), 6.6 (95% CI: 4.5-9.6), 0.15 (95% CI: 0.10-0.21), 45 (95% CI: 23-90), and 0.93 (95% CI: 0.91-0.95), respectively. Subgroup analysis demonstrated that panels of multiple miRNAs could largely improve the diagnostic accuracy. An independent meta-analysis of five included studies was conducted to evaluate the diagnostic efficacy of miR-21 in patients with glioma, with a pooled sensitivity of 0.82, specificity of 0.94, PLR of 13.2, NLR of 0.19, DOR of 69 and AUC of 0.95. CONCLUSION: This meta-analysis indicated the great potential of miRNAs, especially panels of multiple miRNAs, as promising biomarkers in glioma detection and monitoring. As one of the most representative miRNAs, we also found that a single miR-21 could be a powerful clinical biomarker in glioma diagnosis. PMID- 25510380 TI - Carnosic acid attenuates apoptosis induced by amyloid-beta 1-42 or 1-43 in SH SY5Y human neuroblastoma cells. AB - Amyloid-beta (Abeta) peptides, Abeta 1-42 (Abeta42) and Abeta43 in particular, cause neurotoxicity and cell death in the brain of Alzheimer's disease (AD) at higher concentrations. Carnosic acid (CA), a phenolic diterpene compound in the labiate herbs rosemary and sage, serves as an activator for neuroprotective and neurotrophic functions in brain cells. We investigated the effect of CA on apoptosis induced by Abeta42 or Abeta43 in cultured SH-SY5Y human neuroblastoma cells. Treatment of the cells with Abeta42 or Abeta43 (monomer, 10 MUM each) induced apoptosis, which was confirmed by the cleavage of poly-(ADP-ribose) polymerase (PARP) and apoptosis-inducing factor (AIF). Concurrently, the Abeta treatment induced the activation of caspase (Casp) cascades including an effector Casp (Casp3) and initiator Casps (Casp4, Casp8 and Casp9). Pretreatment of the cells with CA (10 MUM) partially attenuated the apoptosis induced by Abeta42 or Abeta43. CA pretreatment also reduced the cellular oligomers of Abeta42 and Abeta43. These results suggest that CA suppressed the activation of Casp cascades by reducing the intracellular oligomerization of exogenous Abeta42/43 monomer. The ingestion of an adequate amount of CA may have a potential in the prevention of Abeta-mediated diseases, particularly AD. PMID- 25510381 TI - Mendelian disorders of PI metabolizing enzymes. AB - More than twenty different genetic diseases have been described that are caused by mutations in phosphoinositide metabolizing enzymes, mostly in phosphoinositide phosphatases. Although generally ubiquitously expressed, mutations in these enzymes, which are mainly loss-of-function, result in tissue-restricted clinical manifestations through mechanisms that are not completely understood. Here we analyze selected disorders of phosphoinositide metabolism grouped according to the principle tissue affected: the nervous system, muscle, kidney, the osteoskeletal system, the eye, and the immune system. We will highlight what has been learnt so far from the study of these disorders about not only the cellular and molecular pathways that are involved or are governed by phosphoinositides, but also the many gaps that remain to be filled to gain a full understanding of the pathophysiological mechanisms underlying the clinical manifestations of this steadily growing class of diseases, most of which still remain orphan in terms of treatment. This article is part of a Special Issue entitled Phosphoinositides. PMID- 25510382 TI - Vascular contributions to cognitive impairment and dementia including Alzheimer's disease. AB - Scientific evidence continues to demonstrate the linkage of vascular contributions to cognitive impairment and dementia such as Alzheimer's disease. In December, 2013, the Alzheimer's Association, with scientific input from the National Institute of Neurological Disorders and Stroke and the National Heart, Lung and Blood Institute from the National Institutes of Health, convened scientific experts to discuss the research gaps in our understanding of how vascular factors contribute to Alzheimer's disease and related dementia. This manuscript summarizes the meeting and the resultant discussion, including an outline of next steps needed to move this area of research forward. PMID- 25510384 TI - Carotid plaque as a predictor of dementia in older adults: the Three-City Study. AB - BACKGROUND: The contribution of carotid atherosclerosis to incident dementia remains unclear. We examined the association between carotid plaques (CP) and common carotid intima media thickness (CCA-IMT) with incident dementia and its subtypes, and their added value for dementia risk prediction. METHODS: At baseline, 6025 dementia-free subjects aged 65-86 years underwent bilateral carotid ultrasonography measures of CP and plaque-free CCA-IMT. Subjects were followed-up over 7 years for the detection of dementia. RESULTS: After a mean 5.4 years of follow-up, 421 subjects developed dementia including 272 Alzheimer's disease and 83 vascular/mixed dementia (VaD). Only CP were independently related to VaD (HR(>=2 sites with plaques) = 1.92; 95% confidence interval or CI = 1.13 3.22) and improved VaD risk prediction (continuous Net Reclassification Index = 30.1%; 95% CI = 8.4-51.7) beyond known dementia risk factors. Accounting for stroke or competing risk by death marginally modified the results. CONCLUSION: In older adults, CP are independent predictors of incident VaD and may improve VaD risk prediction. PMID- 25510383 TI - Down syndrome and Alzheimer's disease: Common pathways, common goals. AB - In the United States, estimates indicate there are between 250,000 and 400,000 individuals with Down syndrome (DS), and nearly all will develop Alzheimer's disease (AD) pathology starting in their 30s. With the current lifespan being 55 to 60 years, approximately 70% will develop dementia, and if their life expectancy continues to increase, the number of individuals developing AD will concomitantly increase. Pathogenic and mechanistic links between DS and Alzheimer's prompted the Alzheimer's Association to partner with the Linda Crnic Institute for Down Syndrome and the Global Down Syndrome Foundation at a workshop of AD and DS experts to discuss similarities and differences, challenges, and future directions for this field. The workshop articulated a set of research priorities: (1) target identification and drug development, (2) clinical and pathological staging, (3) cognitive assessment and clinical trials, and (4) partnerships and collaborations with the ultimate goal to deliver effective disease-modifying treatments. PMID- 25510385 TI - Prognosis of patients with suspected pulmonary embolism in Buenos Aires: a prospective cohort study. AB - BACKGROUND: The prognosis of patients with suspected pulmonary embolism (PE) in whom PE has been ruled out (RPE) is unclear. We aimed to evaluate survival and diagnosis of new cancer in suspected PE patients at follow up. METHODS: A prospective cohort study nested in a prospective Institutional Registry of Venous Thromboembolic Disease was performed between 2006 and 2011. This study was designed to evaluate all consecutive, incident cases of suspected PE in adults. The study was performed at the Hospital Italiano de Buenos Aires, a tertiary level hospital, in hospitalized patients and outpatients. Suspected PE cases were collected using a computerized system that alerts whenever a physician requests pulmonary angiography, angiotomography, or ventilation-perfusion scintigraphy. PE was defined by pre-specified criteria and RPE was defined when diagnostic tests were negative for PE. RESULTS: We included 1736 cases of suspected PE. The prevalence of PE was 29% (n = 504). There was no difference in the overall survival at 30 days and follow-up between PE and RPE patients. The presence of provoked or unprovoked venous thromboembolic disease in these patients did not affect survival. The main causes of death were PE in the confirmed PE group (60%), and neoplasm (42%) and sepsis (37%) in the RPE group. Survival at 90 days was 63% for PE (95% CI 58-67%) and 67% for RPE patients (95% CT 64-69%). At follow-up, there was no difference in diagnosis of new cancer between PE and RPE patients (2% vs 2%, p = 0.82), even when taking into account the unprovoked group. CONCLUSIONS: Even when the main cause of death in PE patients is PE itself, the overall mortality is similar between PE and RPE patients. The reason for this finding could be because of the more frequent and severe comorbidities in RPE than in PE patients. TRIAL REGISTRATION: HomeClinicalTrial.gov: NCT01372514. PMID- 25510386 TI - Extending the use of stiripentol to other epileptic syndromes: a case of PCDH19 related epilepsy. AB - Stiripentol is an antiepileptic drug (AED) approved by the European Medicines Agency for the treatment of Dravet Syndrome (DS) as adjunct treatment with valproate and clobazam. PCDH19-related epilepsy is an emerging epileptic syndrome characterized by the occurrence of epilepsy in female patients associated with mental retardation and autistic features in most cases. It shares many features with DS: age of onset, normal development before the onset, fever sensitivity, cognitive impairment during the time, drug-resistance. Basing on the numerous similarities between DS and PCDH19-related epilepsy, we tried stiripentol in a nine and half year old female patient with PCDH19-related resistant epilepsy, as add-on treatment to valproate and clobazam. It had a surprising efficacy as the patient had a two years and ten months seizure free period, as never in her epilepsy history. Up to date, clinical trials of stiripentol have been always focused on DS. The delineation of new epileptic syndromes, as PCDH19-related epilepsy, opens new scenarios to the utilization of this AED. This case report is suggestive of a good response of PCDH19-related Epilepsy to stiripentol. However further cases and above all clinical trials are necessary to confirm this result. PMID- 25510387 TI - A critical analysis of the cynomolgus macaque, Macaca fascicularis, as a model to test HIV-1/SIV vaccine efficacy. AB - The use of a number of non-rhesus macaque species, but especially cynomolgus macaques as a model for HIV-1 vaccine development has increased in recent years. Cynomolgus macaques have been used in the United Kingdom, Europe, Canada and Australia as a model for HIV vaccine development for many years. Unlike rhesus macaques, cynomolgus macaques infected with SIV show a pattern of disease pathogenesis that more closely resembles that of human HIV-1 infection, exhibiting lower peak and set-point viral loads and slower progression to disease with more typical AIDS defining illnesses. Several advances have been made recently in the use of the cynomolgus macaque SIV challenge model that allow the demonstration of vaccine efficacy using attenuated viruses and vectors that are both viral and non-viral in origin. This review aims to probe the details of various vaccination trials carried out in cynomolgus macaques in the context of our modern understanding of the highly diverse immunogenetics of this species with a view to understanding the species-specific immune correlates of protection and the efficacy of vectors that have been used to design vaccines. PMID- 25510388 TI - Interchangeability of meningococcal group C conjugate vaccines with different carrier proteins in the United Kingdom infant immunisation schedule. AB - An open, non-randomised study was undertaken in England during 2011-12 to evaluate vaccine antibody responses in infants after completion of the routine primary infant immunisation schedule, which included two doses of meningococcal group C (MenC) conjugate (MCC) vaccine at 3 and 4 months. Any of the three licensed MCC vaccines could be used for either dose, depending on local availability. Healthy term infants registered at participating general practices (GPs) in Hertfordshire and Gloucestershire, UK, were recruited prospectively to provide a single blood sample four weeks after primary immunisation, which was administered by the GP surgery. Vaccination history was obtained at blood sampling. MenC serum bactericidal antibody (SBA) and IgG antibodies against Haemophilus influenzae b (Hib), pertussis toxin (PT), diphtheria toxoid (DT), tetanus toxoid (TT) and thirteen pneumococcal serotypes were analysed according to MCC vaccines received. MenC SBA responses differed significantly (P<0.001) according to MCC vaccine schedule as follows: MenC SBA geometric mean titres (GMTs) were significantly lower in infants receiving a diphtheria cross-reacting material-conjugated MCC (MCC-CRM) vaccine followed by TT-conjugated MCC (MCC-TT) vaccine (82.0; 95% CI, 39-173; n=14) compared to those receiving two MCC-CRM (418; 95% CI, 325-537; n=82), two MCC-TT (277; 95% CI, 223-344; n=79) or MCC-TT followed by MCC-CRM (553; 95% CI, 322-949; n=18). The same group also had the lowest Hib geometric mean concentrations (0.60 MUg/mL, 0.27-1.34) compared to 1.85 MUg/mL (1.23-2.78), 2.86 MUg/mL (2.02-4.05) and 4.26 MUg/mL (1.94-9.36), respectively. Our results indicate that MCC vaccines with different carrier proteins are not interchangeable. When several MCC vaccines are available, children requiring more than one dose should receive MCC vaccines with the same carrier protein or, alternatively, receive MCC-TT first wherever possible. PMID- 25510389 TI - Application of bluetongue Disabled Infectious Single Animal (DISA) vaccine for different serotypes by VP2 exchange or incorporation of chimeric VP2. AB - Bluetongue is a disease of ruminants caused by the bluetongue virus (BTV). Bluetongue outbreaks can be controlled by vaccination, however, currently available vaccines have several drawbacks. Further, there are at least 26 BTV serotypes, with low cross protection. A next-generation vaccine based on live attenuated BTV without expression of non-structural proteins NS3/NS3a, named Disabled Infectious Single Animal (DISA) vaccine, was recently developed for serotype 8 by exchange of the serotype determining outer capsid protein VP2. DISA vaccines are replicating vaccines but do not cause detectable viremia, and induce serotype specific protection. Here, we exchanged VP2 of laboratory strain BTV1 for VP2 of European serotypes 2, 4, 8 and 9 using reverse genetics, without observing large effects on virus growth. Exchange of VP2 from serotype 16 and 25 was however not possible. Therefore, chimeric VP2 proteins of BTV1 containing possible immunogenic regions of these serotypes were studied. BTV1, expressing 1/16 chimeric VP2 proteins was functional in virus replication in vitro and contained neutralizing epitopes of both serotype 1 and 16. For serotype 25 this approach failed. We combined VP2 exchange with the NS3/NS3a negative phenotype in BTV1 as previously described for serotype 8 DISA vaccine. DISA vaccine with 1/16 chimeric VP2 containing amino acid region 249-398 of serotype 16 raised antibodies in sheep neutralizing both BTV1 and BTV16. This suggests that DISA vaccine could be protective for both parental serotypes present in chimeric VP2. We here demonstrate the application of the BT DISA vaccine platform for several serotypes and further extend the application for serotypes that are unsuccessful in single VP2 exchange. PMID- 25510390 TI - Human papillomavirus vaccines: WHO position paper, October 2014-Recommendations. AB - This article presents the World Health Organization's (WHO) recommendations for the use of vaccines against diseases caused by human papillomaviruses (HPV) from the WHO position paper on Human papillomavirus vaccines: WHO position paper - October 2014, recently published in the Weekly Epidemiological Record [1]. This position paper summarizes the most recent developments in the field of HPV vaccines and the WHO position on HPV vaccine schedules in females. This document replaces the first WHO position paper on vaccines against diseases caused by HPV published in 2009 [2]. Footnotes to this paper provide a number of core references. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its April 2014 meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html. PMID- 25510391 TI - Updated data on effective and safe immunizations with live-attenuated vaccines for children after living donor liver transplantation. AB - BACKGROUND: Although immunizations using live-attenuated vaccines are not recommended for children post-liver transplant due to their theoretical risks, they will inevitably encounter vaccine-preventable viral diseases upon returning to real-life situations. The window of opportunity for vaccination is usually limited prior to transplantation because these children often have unstable disease courses. Also, vaccine immunity does not always persist after transplantation. METHODS: Beginning in 2002, subcutaneous immunizations with four individual live-attenuated vaccines (measles, rubella, varicella, and mumps) to pediatric patients following living donor liver transplantation (LDLT) were performed for those who fulfilled the clinical criteria, including humoral and cell-mediated immunity. Written informed consent was collected. We included the study on 70 immunizations for 18 cases that we reported in 2008 (Shinjoh et al., 2008). RESULTS: A total of 196 immunizations were administered to 48 pediatric post-LDLT recipients. Of these, 144 were first immunizations and 52 were repeated immunizations following LDLT. The seroconversion rates at the first dose for measles (AIK-C), rubella (TO-336), varicella (Oka), and mumps (Hoshino) were 100% (36/36), 100% (35/35), 70% (23/33), and 75% (24/32), respectively. Antibody levels did not fall over time in patients immunized with rubella vaccine. Three mild cases of breakthrough varicella were observed. Two cases with transient parotid gland swelling were observed after mumps immunization. Two admissions because of fever at 2-3 weeks after the measles vaccine were reported but the patients had no symptoms of measles. CONCLUSIONS: Immunizations using selected live-attenuated vaccines were safe and effective for post-LDLT children who were not severely immunosuppressed. However, with the exception of rubella, repeated immunization may be necessary. PMID- 25510392 TI - Prenatal physical activity and diet composition affect the expression of nutrient transporters and mTOR signaling molecules in the human placenta. AB - INTRODUCTION: Adequate nutrient delivery to the fetus is essential for optimal growth. Differences in prenatal physical activity level and diet quality influence maternal energy balance and these factors may alter placental nutrient transport. We investigated the associations between meeting physical activity guidelines and the quality of maternal diet on the expression of genes involved in fatty acid, amino acid and glucose transport, and mammalian target of rapamycin (mTOR) and insulin signaling in the placenta from 16 term pregnancies. METHODS: Physical activity was directly measured with accelerometry, diet composition was assessed with 24 h dietary recalls, and gene expression was measured with custom polymerase chain reaction (PCR) arrays. RESULTS: Women who met physical activity guidelines had lower gene expression of fatty acid transport protein 4 (FATP4), insulin-like growth factor 1 (IGF1), and the beta non-catalytic subunit of AMP-activated protein kinase (AMPK), and a higher expression of SNAT2. There was a strong positive correlation observed between total sugar intake and glucose transporter 1 (GLUT1) (r = 0.897, p = 0.000, n = 12), and inverse correlations between total sugar and mTOR and IGF1 expression. Percentage of total calories from protein was inversely related to insulin-like growth factor 1 receptor (IGF1R) (r = -0.605, p = 0.028, n = 13). DISCUSSION: Variations in maternal physical activity and diet composition altered the expression of genes involved in fatty acid, amino acid and glucose transport and mTOR signaling. Future research on placental nutrient transport should include direct measures of maternal PA and dietary habits to help eliminate confounding factors. PMID- 25510393 TI - Adolescent and adult male rats habituate to repeated isolation, but only adolescents sensitize to partner unfamiliarity. AB - We investigated whether adolescent male rats show less habituation of corticosterone release than adult male rats to acute vs repeated (16) daily one hour episodes of isolation stress, as well as the role of partner familiarity during recovery on social behavior, plasma corticosterone, and Zif268 expression in brain regions. Adolescents spent more time in social contact than did adults during the initial days of the repeated stress procedures, but both adolescents and adults that returned to an unfamiliar peer after isolation had higher social activity than rats returned to a familiar peer (p=0.002) or undisturbed control rats (p<0.001). Both ages showed evidence of habituation, with reduced corticosterone response to repeated than acute isolation (p=0.01). Adolescents, however, showed sensitized corticosterone release to repeated compared with an acute pairing with an unfamiliar peer during recovery (p=0.03), a difference not found in adults. Consistent with habituation of corticosterone release, the repeated isolation groups had lower Zif268 immunoreactive cell counts in the paraventricular nucleus (p<0.001) and in the arcuate nucleus (p=0.002) than did the acute groups, and adolescents had higher Zif268 immunoreactive cell counts in the paraventricular nucleus than did adults during the recovery period (p<0.001), irrespective of stress history and partner familiarity. Partner familiarity had only modest effects on Zif268 immunoreactivity, and experimental effects on plasma testosterone concentrations were only in adults. The results highlight social and endocrine factors that may underlie the greater vulnerability of the adolescent period of development. PMID- 25510394 TI - New oral anticoagulants in severe trauma patients: enemy at the gates? AB - The high incidence of trauma, especially in elderly people anticoagulated with new oral anticoagulants (NOAs), has become a major challenge, particularly in critical situations with life-threatening bleeding. Under these circumstances, urgent NOA reversion becomes mandatory. Prothrombin complex has become a frequent indication in critical situations in which rapid reversal of anticoagulation is needed and where the use of fresh frozen plasma is limited. This study offers our point of view regarding the usefulness of NOAs, not only in the prevention of cardioembolic events but also as regards their emergent reversion in cases of severe bleeding associated to trauma. PMID- 25510396 TI - Psychologists' firm was paid $81m to implement CIA's "enhanced interrogation" program. PMID- 25510395 TI - Age-specific gender differences in early mortality following ST-segment elevation myocardial infarction in China. AB - OBJECTIVE: To assess whether younger, but not older, women in China have higher in-hospital mortality following ST-Segment Elevation Myocardial Infarction (STEMI) compared with men, and whether this relationship varied over the last decade or across rural/urban areas. METHODS: We analysed a nationally representative sample of 11 986 patients with STEMI from 162 Chinese hospitals in 2001, 2006 and 2011, in the China PEACE-Retrospective AMI Study and compared in hospital mortality between women and men with gender-age interactions in multivariable models. RESULTS: The overall in-hospital mortality rate was higher in women compared with men (17.2% vs 9.1%, p<0.0001; unadjusted OR 2.07, 95% CI 1.85 to 2.33). The unadjusted OR for mortality in women, compared with men, was 2.20 (95% CI 1.59 to 3.04), 2.21 (95% CI 1.74 to 2.79), 1.37 (95% CI 1.15 to 1.65) and 1.25 (95% CI 0.97 to 1.63) for ages <60, 60-69, 70-79 and >=80 years, respectively. After adjustment for patient characteristics, hospital characteristics and year of study, the OR for mortality comparing women with men was 1.69 (95% CI 1.01 to 2.83), 1.64 (95% CI 1.24 to 2.19), 1.15 (95% CI 0.90 to 1.46) and 0.82 (95% CI 0.60 to 1.11) for ages <60, 60-69, 70-79 and >=80 years, respectively. The gender-age interaction for mortality was statistically significant (p=0.009), even after adjustment for a wide range of confounders, and did not vary over time or across rural/urban areas. CONCLUSIONS: Among a Chinese population with STEMI, gender differences in early mortality were age-dependent and greatest in the younger groups <70 years of age. TRIAL REGISTRATION NUMBER: http://www.clinicaltrials.gov (NCT01624883). PMID- 25510397 TI - Trend of different molecular markers in the last decades for studying human migrations. AB - Anatomically modern humans are known to have widely migrated throughout history. Different scientific evidences suggest that the entire human population descended from just several thousand African migrants. About 85,000 years ago, the first wave of human migration was out of Africa, that followed the coasts through the Middle East, into Southern Asia via Sri Lanka, and in due course around Indonesia and into Australia. Another wave of migration between 40,000 and 12,000 years ago brought humans northward into Europe. However, the frozen north limited human expansion in Europe, and created a land bridge, "Bering land bridge", connecting Asia with North America about 25,000 years ago. Although fossil data give the most direct information about our past, it has certain anomalies. So, molecular archeologists are now using different molecular markers to trace the "most recent common ancestor" and also the migration pattern of modern humans. In this study, we have studied the trend of molecular markers and also the methodologies implemented in the last decades (2003-2014). From our observation, we can say that D-loop region of mtDNA and Y chromosome based markers are predominant. Nevertheless, mtDNA, especially the D-loop region, has some unique features, which makes it a more effective marker for tracing prehistoric footprints of modern human populations. Although, natural selection should also be taken into account in studying mtDNA based human migration. As per technology is concerned, Sanger sequencing is the major technique that is being used in almost all studies. But, the emergence of different cost-effective-and-easy-to-handle NGS platforms has increased its popularity over Sanger sequencing in studying human migration. PMID- 25510398 TI - The LEP G-2548A gene polymorphism is associated with age at menarche and breast cancer susceptibility. AB - Leptin is an adipocytokine made by fat cells and plays a key role in proliferation, cell survival, migration and immune response. It has a powerful effect on the initiation of puberty and in determining age at menarche. The current study is the first investigation to examine the effect of G-2548A leptin gene polymorphism on the age at menarche and breast cancer susceptibility. This case-control study was performed on 203 patients with breast cancer and 171 healthy women. The leptin genotypes were determined using the PCR-RFLP method and age at menarche was obtained by questionnaires. There was a significant difference between the leptin G-2548A genotypes between case and control groups (P<0.05). AA genotype is significantly higher in patients compared to the controls. Furthermore, women carrying the AA genotype had a significantly younger age at menarche (12.47 years) than women with the AG (12.94 years) and GG (13.47 years) genotypes. Also, we found that the AA genotype frequency in women with age at menarche <13 years was higher than in women with age at menarche >=13 years (OR: 3.4, 95% CI: 1.7-6.7, P: 0.001). In conclusion, the G-2548A leptin gene polymorphism has an important role in the onset of menarche and breast cancer susceptibility. PMID- 25510399 TI - CD226 rs727088A>G polymorphism increases the susceptibility to gastric cancer in Chinese populations. AB - Gastric cancer (GC) is one of the most common cancers worldwide, especially in Asia. The development of GC is a multifactorial process and numerous studies have linked genetic variation to GC risk. In this study, we evaluated the effects of single nucleotide polymorphisms (SNPs) of CD226 on GC susceptibility in Chinese populations including 687 cancer patients and 936 control subjects. We found that the G allele of the rs727088A>G polymorphism in the 3'-untranslated region of CD226 was significantly associated with risk of GC using logistic regression (P<10(-3)). GC patients who harbored the rs727088G allele had significantly increased cancer risk (odds ratio=1.43, 95% confidence interval=1.23-1.67) compared with those patients harboring the rs727088A allele. Moreover, functional relevance was further performed that individuals carrying the rs727088G allele were correlated with lower expression level of CD226 than individuals carrying the rs727088AA homozygous genotype. These findings indicated that functional polymorphism rs727088A>G in CD226 might modify the susceptibility for the development of GC. PMID- 25510400 TI - Impact of HbA1c, followed from onset of type 1 diabetes, on the development of severe retinopathy and nephropathy: the VISS Study (Vascular Diabetic Complications in Southeast Sweden). AB - OBJECTIVE: HbA1c is strongly related to the development of diabetes complications, but it is still controversial which HbA1c level to strive for in the treatment of type 1 diabetes. The aim of the current study was to evaluate HbA1c, followed from diagnosis, as a predictor of severe microvascular complications and to formulate HbA1c target levels for treatment. RESEARCH DESIGN AND METHODS: A longitudinal observation study followed an unselected population of 451 patients diagnosed with type 1 diabetes during 1983-1987 before the age of 35 years in a region of Southeast Sweden. Retinopathy was evaluated by fundus photography and nephropathy data collected from medical records. HbA1c was measured starting from diagnosis and during the whole follow-up period of 20-24 years. Long-term weighted mean HbA1c was then calculated. Complications were analyzed in relation to HbA1c levels. RESULTS: The incidence of proliferative retinopathy and persistent macroalbuminuria increased sharply and occurred earlier with increasing long-term mean HbA1c. None of the 451 patients developed proliferative retinopathy or persistent macroalbuminuria below long-term weighted mean HbA1c 7.6% (60 mmol/mol); 51% of the patients with long-term mean HbA1c above 9.5% (80 mmol/mol) developed proliferative retinopathy and 23% persistent macroalbuminuria. CONCLUSIONS: Long-term weighted mean HbA1c, measured from diagnosis, is closely associated with the development of severe complications in type 1 diabetes. Keeping HbA1c below 7.6% (60 mmol/mol) as a treatment target seems to prevent proliferative retinopathy and persistent macroalbuminuria for up to 20 years. PMID- 25510402 TI - Mutations in the 'DRY' motif of the CB1 cannabinoid receptor result in biased receptor variants. AB - The role of the highly conserved 'DRY' motif in the signaling of the CB1 cannabinoid receptor (CB1R) was investigated by inducing single-, double-, and triple-alanine mutations into this site of the receptor. We found that the CB1R R3.50A mutant displays a partial decrease in its ability to activate heterotrimeric Go proteins (~80% of WT CB1R (CB1R-WT)). Moreover, this mutant showed an enhanced basal beta-arrestin2 (beta-arr2) recruitment. More strikingly, the double-mutant CB1R-D3.49A/R3.50A was biased toward beta-arrs, as it gained a robustly increased beta-arr1 and beta-arr2 recruitment ability compared with the WT receptor, while its G-protein activation was decreased. In contrast, the double-mutant CB1R-R3.50A/Y3.51A proved to be G-protein-biased, as it was practically unable to recruit beta-arrs in response to agonist stimulus, while still activating G-proteins, although at a reduced level (~70% of CB1R-WT). Agonist-induced ERK1/2 activation of the CB1R mutants showed a good correlation with their beta-arr recruitment ability but not with their G-protein activation or inhibition of cAMP accumulation. Our results suggest that G-protein activation and beta-arr binding of the CB1R are mediated by distinct receptor conformations, and the conserved 'DRY' motif plays different roles in the stabilization of these conformations, thus mediating both G-protein- and beta-arr-mediated functions of CB1R. PMID- 25510404 TI - Adsorbate-driven morphological changes on Cu(111) nano-pits. AB - Adsorbate-driven morphological changes of pitted-Cu(111) surfaces have been investigated following the adsorption and desorption of CO and H. The morphology of the pitted-Cu(111) surfaces, prepared by Ar(+) sputtering, exposed a few atomic layers deep nested hexagonal pits of diameters from 8 to 38 nm with steep step bundles. The roughness of pitted-Cu(111) surfaces can be healed by heating to 450-500 K in vacuum. Adsorption of CO on the pitted-Cu(111) surface leads to two infrared peaks at 2089-2090 and 2101-2105 cm(-1) for CO adsorbed on under coordinated sites in addition to the peak at 2071 cm(-1) for CO adsorbed on atop sites of the close-packed Cu(111) surface. CO adsorbed on under-coordinated sites is thermally more stable than that of atop Cu(111) sites. Annealing of the CO covered surface from 100 to 300 K leads to minor changes of the surface morphology. In contrast, annealing of a H covered surface to 300 K creates a smooth Cu(111) surface as deduced from infrared data of adsorbed CO and scanning tunnelling microscopy (STM) imaging. The observation of significant adsorbate driven morphological changes with H is attributed to its stronger modification of the Cu(111) surface by the formation of a sub-surface hydride with a hexagonal structure, which relaxes into the healed Cu(111) surface upon hydrogen desorption. These morphological changes occur ~150 K below the temperature required for healing of the pitted-Cu(111) surface by annealing in vacuum. In contrast, the adsorption of CO, which only interacts with the top-most Cu layer and desorbs by 200 K, does not significantly change the morphology of the pitted Cu(111) surface. PMID- 25510401 TI - Relations of digital vascular function, cardiovascular risk factors, and arterial stiffness: the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) cohort study. AB - BACKGROUND: Vascular dysfunction is an early expression of atherosclerosis and predicts cardiovascular (CV) events. Peripheral arterial tonometry (PAT) evaluates basal pulse amplitude (BPA), endothelial function (PAT ratio), and wave reflection (PAT-AIx) in the digital microvessels. In Brazilian adults, we investigated the correlations of PAT responses to CV risk factors and to carotid femoral pulse wave velocity (PWV), a measure of arterial stiffness. METHODS AND RESULTS: In a cross-sectional study, 1535 participants of the ELSA-Brasil cohort underwent PAT testing (52+/-9 years; 44% women). In multivariable analyses, more impaired BPA and PAT ratios were associated with male sex, higher body mass index (BMI), and total cholesterol/high-density lipoprotein. Higher age and triglycerides were related to higher BPA, whereas lower systolic blood pressure, hypertension (HTN) treatment, and prevalent CV disease (CVD) were associated with lower PAT ratio. PAT-AIx correlated positively with female sex, advancing age, systolic and diastolic blood pressures, and smoking and inversely to heart rate, height, BMI, and prevalent CVD. Black race was associated with lower BPA, higher PAT ratio, and PAT-AIx. Microvessel vasodilator function was not associated with PWV. Higher PAT-AIx was modestly correlated to higher PWV and PAT ratio and inversely correlated to BPA. CONCLUSION: Metabolic risk factors are related to impaired microvessel vasodilator function in Brazil. However, in contrast to studies from the United States, black race was not associated with an impaired microvessel vasodilator response, implying that vascular function may vary by race across populations. PAT-AIx relates to HTN, may be a valid measure of wave reflection, and provides distinct information from arterial stiffness. PMID- 25510403 TI - Needs assessment to strengthen capacity in water and sanitation research in Africa: experiences of the African SNOWS consortium. AB - BACKGROUND: Despite its contribution to global disease burden, diarrhoeal disease is still a relatively neglected area for research funding, especially in low income country settings. The SNOWS consortium (Scientists Networked for Outcomes from Water and Sanitation) is funded by the Wellcome Trust under an initiative to build the necessary research skills in Africa. This paper focuses on the research training needs of the consortium as identified during the first three years of the project. METHODS: We reviewed the reports of two needs assessments. The first was a detailed needs assessment led by one northern partner, with follow-up visits which included reciprocal representation from the African universities. The second assessment, led by another northern partner, focused primarily on training needs. The reports from both needs assessments were read and stated needs were extracted and summarised. RESULTS: Key common issues identified in both assessments were supervisory skills, applications for external research funding, research management, and writing for publication in the peer-reviewed scientific literature. The bureaucratisation of university processes and inconsistencies through administration processes also caused problems. The lack of specialist laboratory equipment presented difficulties, particularly of inaccessibility through a lack of skilled staff for operation and maintenance, and of a budget provision for repairs and running costs. The lack of taught PhD modules and of research training methods also caused problems. Institutionally, there were often no mechanisms for identifying funding opportunities. On the other hand, grantees were often unable to understand or comply with the funders' financial and reporting requirements and were not supported by their institution. Skills in staff recruitment, retention, and performance were poor, as were performance in proposal and paper writing. The requirements for ethical clearance were often not known and governance issues not understood, particularly those required by funders. CONCLUSIONS: SNOWS believes that working with African universities to develop networks that support African-led research driven by the local context is an effective approach to develop and retain research skills needed to change policy and practice in water, sanitation, and hygiene in Africa. PMID- 25510405 TI - Genomic selection in a pig population including information from slaughtered full sibs of boars within a sib-testing program. AB - Genomic selection is becoming a common practise in dairy cattle, but only few works have studied its introduction in pig selection programs. Results described for this species are highly dependent on the considered traits and the specific population structure. This paper aims to simulate the impact of genomic selection in a pig population with a training cohort of performance-tested and slaughtered full sibs. This population is selected for performance, carcass and meat quality traits by full-sib testing of boars. Data were simulated using a forward-in-time simulation process that modeled around 60K single nucleotide polymorphisms and several quantitative trait loci distributed across the 18 porcine autosomes. Data were edited to obtain, for each cycle, 200 sires mated with 800 dams to produce 800 litters of 4 piglets each, two males and two females (needed for the sib test), for a total of 3200 newborns. At each cycle, a subset of 200 litters were sib tested, and 60 boars and 160 sows were selected to replace the same number of culled male and female parents. Simulated selection of boars based on performance test data of their full sibs (one castrated brother and two sisters per boar in 200 litters) lasted for 15 cycles. Genotyping and phenotyping of the three tested sibs (training population) and genotyping of the candidate boars (prediction population) were assumed. Breeding values were calculated for traits with two heritability levels (h 2=0.40, carcass traits, and h 2=0.10, meat quality parameters) on simulated pedigrees, phenotypes and genotypes. Genomic breeding values, estimated by various models (GBLUP from raw phenotype or using breeding values and single-step models), were compared with the classical BLUP Animal Model predictions in terms of predictive ability. Results obtained for traits with moderate heritability (h 2=0.40), similar to the heritability of traits commonly measured within a sib-testing program, did not show any benefit from the introduction of genomic selection. None of the considered genomic models provided improvements in prediction ability of pigs with no recorded phenotype. However, a few advantages were found for traits with low heritability (h 2=0.10). These heritability levels are characteristic for meat quality traits recorded after slaughtering or for reproduction or health traits, typically recorded on field and not in performance stations. Other scenarios of data recording and genotyping should be evaluated before considering the implementation of genomic selection in a pig-selection scheme based on sib testing of boars. PMID- 25510406 TI - What Are Complex eHealth Innovations and How Do You Measure Them? Position Paper. AB - OBJECTIVES: eHealth and innovation are often regarded as synonyms - not least because eHealth technologies and applications are new to their users. This position paper challenges this view and aims at exploring the nature of eHealth innovation against the background of common definitions of innovation and facts from the biomedical and health informatics literature. A good understanding of what constitutes innovative eHealth developments allows the degree of innovation to be measured and interpreted. METHODS: To this end, relevant biomedical and health informatics literature was searched mainly in Medline and ACM digital library. This paper presents seven facts about implementing and applying new eHealth developments hereby drawing on the experience published in the literature. RESULTS: The facts are: 1. eHealth innovation is relative. 2. Advanced clinical practice is the yardstick. 3. Only used and usable eHealth technology can give birth to eHealth innovatio. 4. One new single eHealth function does not make a complex eHealth innovation. 5. eHealth innovation is more evolution than revolution. 6. eHealth innovation is often triggered behind the scenes; and 7. There is no eHealth innovation without sociocultural change. CONCLUSIONS: The main conclusion of the seven facts is that eHealth innovations have many ingredients: newness, availability, advanced clinical practice with proven outcomes, use and usability, the supporting environment, other context factors and the stakeholder perspectives. Measuring eHealth innovation is thus a complex matter. To this end we propose the development of a composite score that expresses comprehensively the nature of eHealth innovation and that breaks down its complexity into the three dimensions: i) eHealth adoption, ii) partnership with advanced clinical practice, and iii) use and usability of eHealth. In order to better understand the momentum and mechanisms behind eHealth innovation the fourth dimension, iv) eHealth supporting services and means, needs to be studied. Conceptualising appropriate measurement instruments also requires eHealth innovation to be distinguished from eHealth sophistication, performance and quality, although innovation is intertwined with these concepts. The demanding effort for defining eHealth innovation and measuring it properly seem worthwhile and promise advances in creating better systems. This paper thus intends to stimulate the necessary discussion. PMID- 25510407 TI - Layer speciation and electronic structure investigation of freestanding hexagonal boron nitride nanosheets. AB - Chemical imaging, thickness mapping, layer speciation and polarization dependence have been performed on single and multilayered (up to three layers and trilayered nanosheets overlapping to form 6 and 9 layers) hexagonal boron nitride (hBN) nanosheets by scanning transmission X-ray microscopy. Spatially-resolved XANES directly from freestanding regions of different layers has been extracted and compared with sample normal and 30 degrees tilted configurations. Notably a double feature sigma* excitonic state and a stable high energy sigma* state were observed at the boron site in addition to the intense pi* excitonic state. The boron projected sigma* DOS, especially the first sigma* exciton, is sensitive to surface modification, particularly in the single layered hBN nanosheet which shows more significant detectable contaminants and defects such as tri coordinated boron/nitrogen oxide. The nitrogen site has shown very weak or no excitonic character. The distinct excitonic effect on boron and nitrogen was interpreted to the partly ionic state of hBN. Bulk XANES of hBN nanosheets was also measured to confirm the spectro-microscopic STXM result. Finally, the unoccupied electronic structures of hBN and graphene were compared. PMID- 25510408 TI - Gender aspects of survival after surgical treatment for rectal cancer. AB - AIM: Longer survival in women than men after rectal cancer surgery has been reported. Our hypothesis was that after correction for their longer life expectancy a survival benefit for women would still remain. METHOD: We studied 2792 patients diagnosed with rectal cancer in the southern part of Sweden between 1996 and 2006. The following parameters were included in a prespecified multivariable Cox regression analysis: age at diagnosis, gender, preoperative radiotherapy, stage, year and type of surgery. In addition to overall survival, relative survival was calculated using the Hakulinen approach utilizing an age-, gender- and calendar year-matched Swedish control cohort. RESULTS: Female patients were significantly older, received neoadjuvant treatment less often and were more often operated on by local excision. Overall survival was significantly longer in women. In the multivariable analysis of relative survival, controlling for neoadjuvant treatment, Dukes stage and year and type of surgery, no significant effect of gender [hazard ratio (HR) 1.10 for men, P = 0.114] was found, whereas an improved relative survival with increased age (HR 0.96 per year, P < 0.001) was seen. In contrast, using the same multivariable model with no correction for underlying mortality in the population, male gender (HR 1.38, P < 0.001) and greater age (HR 1.05 per year, P < 0.001) increased the risk of death. CONCLUSION: The results show that after correction for the underlying longer survival in women and some known confounders, survival after surgical treatment for rectal cancer appears to be gender neutral. PMID- 25510410 TI - Sustainable synthetic route for gamma-Fe2O3/C hybrid as anode material for lithium-ion batteries. AB - A facile, high-yield and sustainable method is developed to synthesize iron oxide/C hybrids. Starch is chosen as the carbon source due to its superior gelatinization property and natural abundance, and ferric nitrate is used as the iron salt for the sustainable synthesis. The iron oxide in the final products exists in the gamma-Fe2O3 phase. The gamma-Fe2O3/C hybrids are used as anode materials for lithium-ion batteries. The batteries exhibit better cyclability as the content of gamma-Fe2O3 decreases, but in turn the reversible capacity declines. The gamma-Fe2O3/C hybrid with 63.96 wt% of gamma-Fe2O3 has an initial discharge capacity of 1149 mA h g(-1) and after the 80(th) cycle the reversible capacity is maintained at over 720 mA h g(-1) at a current density of 0.5 A g( 1). Even when tested at a current density of 5 A g(-1), a substantial discharge capacity of ~300 mA h g(-1) can be obtained. PMID- 25510409 TI - Correction of hypothermic and dilutional coagulopathy with concentrates of fibrinogen and factor XIII: an in vitro study with ROTEM. AB - BACKGROUND: Fibrinogen concentrate treatment can improve coagulation during massive traumatic bleeding. The aim of this in vitro study was to determine whether fibrinogen concentrate, or a combination of factor XIII and fibrinogen concentrates, could reverse a haemodilution-induced coagulopathy during hypothermia. METHODS: Citrated venous blood from 10 healthy volunteers was diluted in vitro by 33% with 130/0.42 hydroxyethyl starch (HES) or Ringer's acetate (RAc). The effects of fibrinogen concentrate corresponding to 4 gram per 70 kg, or a combination of the same dose of fibrinogen with factor XIII (20 IU per kg), were measured using rotational thromboelastometry (ROTEM). The blood was analysed at 33 degrees C or 37 degrees C with ROTEM EXTEM and FIBTEM reagents. Clotting time (CT), clot formation time (CFT), alpha angle (AA) and maximal clot formation (MCF) were recorded. RESULTS: Fibrinogen with or without factor XIII improved all ROTEM parameters in either solution irrespective of temperature, with the exception of EXTEM-AA and EXTEM-CFT in HES haemodilution. Fibrinogen increased FIBTEM-MCF more in the samples diluted with RAc than HES, particularly in presence of factor XIII. CONCLUSIONS: Fibrinogen improved in vitro haemodilution-induced coagulopathy at both 33 degrees C and 37 degrees C, though more efficiently after crystalloid than HES haemodilution. Factor XIII had an additional effect on FIBTEM-MCF, but only after crystalloid dilution. PMID- 25510411 TI - Analysis of enoxaparin dose titration at a large, tertiary teaching facility. AB - Therapeutic drug monitoring of enoxaparin with antifactor Xa levels (AXALs) is recommended in some populations; however, the approach to dose titration is poorly described. Our study at a large, tertiary teaching facility examined the dose response to titration of enoxaparin based on AXAL. Patients from 2008 to 2012 receiving enoxaparin were included, provided 2 or more steady state AXAL were obtained within 30 days and that the enoxaparin was prescribed for treatment rather than prophylaxis. The primary outcome was the percentage of dose change required to obtain goal range AXAL following dose titration. Eighty-seven patients were available for analysis with the following key characteristics: renal dysfunction during treatment 72%, obesity 8%, and solid organ transplant 26%. Initial goal AXAL was attained in 27 (31%) patients, and ultimately 54 (62%) patients achieved goal AXAL. Of the 31 patients who had initial AXAL above goal, 13 (42%) patients reached goal with a median dose decrease of 24%. In the 29 patients who had an initial AXAL below goal, 11 (38%) achieved therapeutic AXAL with a median dose increase of 16%. The AXAL monitoring can guide enoxaparin titration with subtherapeutic or supratherapeutic AXAL and an increase or decrease of roughly 20% is suggested as an initial change. PMID- 25510412 TI - Soluble Programmed Death 1 (PD-1) Is Decreased in Patients With Immune Thrombocytopenia (ITP): Potential Involvement of PD-1 Pathway in ITP Immunopathogenesis. AB - Immune thrombocytopenia (ITP) is an autoimmune disease characterized by dysregulation of T cells. Programmed death (PD) 1 and programmed death 1 ligand 1 (PD-L1) are cosignaling molecules, and the major role of the PD-1 pathway is the inhibition of self-reactive T cells and to protect against autoimmune diseases. We measured levels of serum soluble PD 1 (sPD-1) and serum soluble PD-L1 (sPD-L1) in 67 patients with ITP (24 newly diagnosed ITP [ndITP], 43 chronic ITP [cITP]) and 21 healthy controls (HCs). We determined decreased serum sPD-1 levels both in patients with ndITP and in patients with cITP when compared to HC. Moreover, there was a positive correlation between sPD-1 levels and platelet counts. The sPD-L1 levels were decreased in patients with ndITP when compared to patients with cITP. This is the first study investigating PD-1 signaling pathway in ITP. Decreased sPD-1 levels may have a role in ITP pathogenesis as without the inhibitory regulation of PD-1, sustained activation of T cells may cause inflammatory responses which is the case in ITP. PMID- 25510413 TI - Survival-apoptosis associated signaling in GNE myopathy-cultured myoblasts. AB - GNE Myopathy (GNEM) is a neuromuscular disorder caused by mutations in the GNE gene. It is a slowly progressive distal and proximal muscle weakness sparing the quadriceps. In this study, we applied our model of mutated M743T GNE enzyme skeletal muscle-cultured myoblasts and paired healthy controls to depict the pattern of signaling proteins controlling survival and/or apoptosis of the PI3K/AKT, BCL2, ARTS/XIAP pathways, examined the effects of metabolic changes/stimuli on their expression and activation, and their potential role in GNEM. Immunoblot analysis of the GNEM myoblasts indicated a notable increased level of activated PTEN and PDK1 and a trend of relative differences in the expression and activation of the examined signaling molecules with variability among the cultures. ANOVA analysis showed a highly significant interaction between the level of PTEN and the patients groups. In parallel, the interaction between the level of BCL2, BAX and PTEN with the specific PI3K/AKT inhibitor LY294002 was highly significant for BCL2 and nearly significant for PTEN and BAX. The pattern of the ARTS/XIAP signaling proteins of GNEM and the paired controls was variable, with no significant differences between the two cell types. The response of the GNEM cells to the metabolic changes/stimuli: serum depletion and insulin challenge, as indicated by expression of selected signaling proteins, was variable and similar to the control cells. Taken together, our observations provide a clearer insight into specific signaling molecules influencing growth and survival of GNEM muscle cells. PMID- 25510414 TI - TRIM22 can activate the noncanonical NF-kappaB pathway by affecting IKKalpha. AB - Tripartite motif 22 (TRIM22) is involved in various cellular processes. It has been reported that TRIM22 can activate nuclear factor-kappaB (NF-kappaB) pathway, but the precise mechanism remains unclear. In this study, we explored the exact role of TRIM22 in activating the NF-kappaB pathway. Different to tumor necrosis factor-alpha (TNF-alpha) induction, we found that the overexpression of TRIM22 could induce the processing of p100 to p52 in HEK293T cells. Furthermore, based on the results of co-immunoprecipitation and co-localization experiments, we demonstrated that TRIM22 could interact with IkappaB kinase (IKK)alpha but not IKKbeta and could increase the level and phosphorylation of IKKalpha through its really interesting new gene (RING) and spla-ryanodine receptor (SPRY) domains. These results suggest that TRIM22 is able to activate the noncanonical but not the canonical NF-kappaB pathway by activating IKKalpha. This finding will aid our understanding of the biological function of TRIM22. PMID- 25510415 TI - 1D magnetic materials of Fe3O4 and Fe with high performance of microwave absorption fabricated by electrospinning method. AB - Fe3O4 and Fe nanowires are successfully fabricated by electrospinning method and reduction process. Wiry microstructures were achieved with the phase transformation from alpha-Fe2O3 to Fe3O4 and Fe by partial and full reduction, while still preserving the wire morphology. The diameters of the Fe3O4 and Fe nanowires are approximately 50-60 nm and 30-40 nm, respectively. The investigation of microwave absorption reveals that the Fe3O4 nanowires exhibit excellent microwave absorbing properties. For paraffin-based composite containing 50% weight concentration of Fe3O4 nanowires, the minimum reflection loss reaches 17.2 dB at 6.2 GHz with the matching thickness of 5.5 mm. Furthermore, the calculation shows that the modulus of the ratio between the complex permittivity and permeability |epsilon/MU| is far away from unity at the minimum reflection loss point, which is quite different from the traditional opinions. PMID- 25510416 TI - Evidence for zoonotic potential of ovine scrapie prions. AB - Although Bovine Spongiform Encephalopathy (BSE) is the cause of variant Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic potential of scrapie prions remains unknown. Mice genetically engineered to overexpress the human prion protein (tgHu) have emerged as highly relevant models for gauging the capacity of prions to transmit to humans. These models can propagate human prions without any apparent transmission barrier and have been used used to confirm the zoonotic ability of BSE. Here we show that a panel of sheep scrapie prions transmit to several tgHu mice models with an efficiency comparable to that of cattle BSE. The serial transmission of different scrapie isolates in these mice led to the propagation of prions that are phenotypically identical to those causing sporadic CJD (sCJD) in humans. These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions. PMID- 25510417 TI - Inducible Mixotrophy in the Dinoflagellate Prorocentrum minimum. AB - Prorocentrum minimum is a neritic dinoflagellate that forms seasonal blooms and red tides in estuarine ecosystems. While known to be mixotrophic, previous attempts to document feeding on algal prey have yielded low grazing rates. In this study, growth and ingestion rates of P. minimum were measured as a function of nitrogen (-N) and phosphorous (-P) starvation. A P. minimum isolate from Chesapeake Bay was found to ingest cryptophyte prey when in stationary phase and when starved of N or P. Prorocentrum minimum ingested two strains of Teleaulax amphioxeia at higher rates than six other cryptophyte species. In all cases -P treatments resulted in the highest grazing. Ingestion rates of -P cells on T. amphioxeia saturated at ~5 prey per predator per day, while ingestion by -N cells saturated at 1 prey per predator per day. In the presence of prey, -P treated cells reached a maximum mixotrophic growth rate (MUmax ) of 0.5 d(-1), while -N cells had a MUmax of 0.18 d(-1). Calculations of ingested C, N, and P due to feeding on T. amphioxeia revealed that phagotrophy can be an important source of all three elements. While P. minimum is a proficient phototroph, inducible phagotrophy is an important nutritional source for this dinoflagellate. PMID- 25510420 TI - Mediating positive moods: the impact of experiencing compassion at work. AB - AIM: The aim of this study was to examine the mediating effects of positive moods underlying the relationship between experiencing compassion at work and both job performance and organisational citizenship behaviour (OCB). BACKGROUND: Employees who have experienced compassion might have more positive moods while at work; such moods have been connected to a host of important organisational outcomes such as better job performance and OCB. METHODS: This study adopted a two-stage survey whose participants consisted of 269 registered nurses employed by hospitals in Taiwan. All hypotheses were tested using hierarchical regression analyses. RESULTS: The results showed that positive moods mediate completely the relationship between experiencing compassion at work and both job performance and OCB. CONCLUSION: When nurses frequently feel that their hospital, supervisors or co-workers are willing to listen to them, the strength that arises from this compassion can effectively increase job performance and OCB though the positive moods process. IMPLICATIONS FOR NURSING MANAGEMENT: It is importance to cultivate a compassionate and caring culture throughout hospitals' hierarchies, especially from the top down. Nurses will have more opportunities to experience it, witness it, or participate in it when they work within a compassionate and caring organisational culture. PMID- 25510419 TI - First report of Rickettsia felis in China. AB - BACKGROUND: Rickettsia felis is a recently described flea-borne spotted fever group Rickettsia that is an emerging human pathogen. Although there is information on the organism from around the world, there is no information on the organism in China. METHODS: We used a commercial ELISA to detect antibodies reactive against R. felis in blood samples and developed a PCR to detect the gltA of the organism in blood samples and external parasites. RESULTS: We found reactive antibodies in people (16%; 28/180), dogs (47%; 128/271) and cats (21%; 19/90) and positive PCRs with DNA from people (0.1%; 1/822), dogs (0.8%; 8/1,059), mice (10%; 1/10), ticks (Rhipicephalus sanguineus; 10%; 15/146), lice (Linognathus setosus; 16%; 6/37), fleas (Ctenocephalides felis felis; 95%; 57/60) and mosquitoes (Anopheles sinensis, Culex pipiens pallens; 6%; 25/428), but not from cats (0/135) or canine fecal swabs (0/43). CONCLUSIONS: This is the first report of R. felis in China where there is serological and/ or PCR evidence of the organism in previously reported [people, dogs, cats, ticks (Rhipicephalus sanguineus), fleas (Ctenocephalides felis felis) and mosquitoes (Anopheles sinensis, Culex pipiens pallens)] and novel species [mice and lice (Linognathus setosus)]. PMID- 25510421 TI - Mechanistic Insight into the Yolk@Shell Transformation of MnO@Silica Nanospheres Incorporating Ni(2+) Ions toward a Colloidal Hollow Nanoreactor. AB - As an effort to develop a simple and versatile synthetic strategy that contributes to the evolution of hollow nanostructures with increasing complexity and functionality, this research is devoted to study the hollow transformation within a nanosized solid matrix. Through an in-depth investigation of a hollowing process of MnO nanocrystals confined within a Ni(2+) incorporating silica nanosphere, a very distinct transformation pathway can be explained that produces the yolk@shell nanostructure with a single Ni nanocrystal inside a silicate nanoshell. The yolk@shell structure is developed by a mechanism combining different processes, including the formation of a (Ni0.1 Mn0.9 )O mixed-metal oxide and subsequent segregation of the reduced Ni. Furthermore, this study also devises a protocol to exploit the solid-state-synthesized powder for fabricating a colloidal hollow nanoreactor that can selectively catalyze the reduction of nitroarenes and be recycled via the magnetic process. PMID- 25510418 TI - Gene therapy for neurologic manifestations of mucopolysaccharidoses. AB - INTRODUCTION: Mucopolysaccharidoses (MPS) are a family of lysosomal disorders caused by mutations in genes that encode enzymes involved in the catabolism of glycoaminoglycans. These mutations affect multiple organ systems and can be particularly deleterious to the nervous system. At the present time, enzyme replacement therapy and hematopoietic stem-cell therapy are used to treat patients with different forms of these disorders. However, to a great extent, the nervous system is not adequately responsive to current therapeutic approaches. AREAS COVERED: Recent advances in gene therapy show great promise for treating MPS. This article reviews the current state of the art for routes of delivery in developing genetic therapies for treating the neurologic manifestations of MPS. EXPERT OPINION: Gene therapy for treating neurological manifestations of MPS can be achieved by intraventricular, intrathecal, intranasal and systemic administrations. The intraventricular route of administration appears to provide the most widespread distribution of gene therapy vectors to the brain. The intrathecal route of delivery results in predominant distribution to the caudal areas of the brain. The systemic route of delivery via intravenous infusion can also achieve widespread delivery to the CNS; however, the distribution to the brain is greatly dependent on the vector system. Intravenous delivery using lentiviral vectors appear to be less effective than adeno-associated viral (AAV) vectors. Moreover, some subtypes of AAV vectors are more effective than others in crossing the blood-brain barrier. In summary, the recent advances in gene vector technology and routes of delivery to the CNS will facilitate the clinical translation of gene therapy for the treatment of the neurological manifestations of MPS. PMID- 25510422 TI - Decreased beta-catenin expression in first-trimester villi and decidua of patients with recurrent spontaneous abortion. AB - AIM: We aimed to study the relation between Wnt/beta-catenin signaling pathway and recurrent spontaneous abortion through investigating the expression of beta catenin and Dickkof-1 in first-trimester villi and decidua of recurrent spontaneous abortion patients. MATERIAL AND METHODS: Villous and decidual tissues were collected from 40 women (20 patients with recurrent spontaneous abortion and 20 patients with normal, early pregnancy). Western blots were used to measure the protein levels of beta-catenin in villi and decidua, and the localization of beta catenin was investigated by immunohistochemistry. Quantitative real-time reverse transcription polymerase chain reaction was used to quantify the mRNA levels of beta-catenin and Dickkof-1 in villi and decidua, respectively. RESULTS: Our results indicated that beta-catenin was expressed predominantly in plasma membranes of the villous cytotrophoblasts and glandular epithelium. What's more, its expression significantly decreased at both mRNA and protein levels, whereas the mRNA levels of Dickkof-1 significantly increased in villi and decidua of the recurrent spontaneous abortion group compared with the normal control group. CONCLUSION: We therefore speculated that the downregulated Wnt/beta-catenin signaling pathway might be associated with the process of the pathogenesis of recurrent spontaneous abortion. PMID- 25510433 TI - A predictive model for alternative admission to dental education. AB - AIM: To compare academic progress and performance of students admitted through two admission systems and to analyse the predictive power of different components in an alternative admission. SAMPLE AND METHODS: The subjects were students admitted to the dental programme at Malmo University, Sweden. The grade admission group was admitted on grades from secondary school (n = 126) and the alternative admission group via an alternative admission procedure (n = 157). The alternative admission procedure consisted of the following components: problem-solving matrices, spatial capacity tested with folding and tin models, manual dexterity, capacity for empathy and interview. Comparisons were made for academic progress (dropouts from the programme and study rate) and academic performance (examinations failed and outcomes of a comprehensive clinical examination). Spearman correlation was calculated for each component of the alternative admission procedure and academic progress as well as academic performance. Multivariate analyses were also carried out. RESULTS: Compared to the grade admission group, the alternative admission group presented lower rate of dropouts (3% vs. 20%, P < 0.001) and a larger proportion graduated within the expected time (88% vs. 60%, P < 0.01). There was no difference between the groups concerning academic performance. Capacity of empathy was correlated with study rate and outcomes of the clinical examination. The matrices predicted low proportion failed examinations and high students' self-assessments in the clinical examination. Predictive power of folding was limited and so was that of the interview. Manual dexterity was not correlated with academic progress or performance. CONCLUSIONS: Results support further development of admission selection criteria, particularly emphatic capacity that predicts important student academic achievements. PMID- 25510432 TI - Critical role of retinoid/rexinoid signaling in mediating transformation and therapeutic response of NUP98-RARG leukemia. AB - While the nucleoporin 98-retinoic acid receptor gamma (NUP98-RARG) is the first RARG fusion protein found in acute leukemia, its roles and the molecular basis in oncogenic transformation are currently unknown. Here, we showed that homodimeric NUP98-RARG not only acquired unique nuclear localization pattern and ability of recruiting both RXRA and wild-type NUP98, but also exhibited similar transcriptional properties as RARA fusions found in acute promyelocytic leukemia (APL). Using murine bone marrow retroviral transduction/transformation assay, we further demonstrated that NUP98-RARG fusion protein had gained transformation ability of primary hematopoietic stem/progenitor cells, which was critically dependent on the C-terminal GLFG domain of NUP98 and the DNA binding domain (DBD) of RARG. In contrast to other NUP98 fusions, cells transformed by the NUP98-RARG fusion were extremely sensitive to all-trans retinoic acid (ATRA) treatment. Interestingly, while pan-RXR agonists, SR11237 and LGD1069 could specifically inhibit NUP98-RARG transformed cells, mutation of the RXR interaction domain in NUP98-RARG had little effect on its transformation, revealing that therapeutic functions of rexinoid can be independent of the direct biochemical interaction between RXR and the fusion. Together, these results indicate that deregulation of the retinoid/rexinoid signaling pathway has a major role and may represent a potential therapeutic target for NUP98-RARG-mediated transformation. PMID- 25510434 TI - Functional anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies in patients with systemic lupus erythematosus. AB - OBJECTIVE: Recently we serendipitously identified a patient with systemic lupus erythematosus (SLE) who was positive for autoantibodies to CD94/natural killer receptor group 2A (NKG2A). The present study was undertaken to investigate the occurrence and function of autoantibodies targeting lectin-like NK cell receptors in SLE. METHODS: Sera from 203 SLE patients and 90 healthy individuals were analyzed, by flow cytometry, for Ig binding to Ba/F3 cells transfected with CD94/NKG2A, CD94/NKG2C, or NKG2D. Autoantibodies identified were characterized with regard to interference with HLA-E binding, effect on NK cell activation in response to HLA-E-transfected K562 cells, and capacity to facilitate antibody dependent cell-mediated cytotoxicity (ADCC). Levels of autoantibodies were determined in longitudinally sampled sera, and correlations with disease activity (SLE Disease Activity Index 2000) and severity (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) were investigated. RESULTS: Anti-CD94/NKG2A autoantibodies were identified in 7 SLE patients. The autoantibodies from 6 patients inhibited binding of HLA-E to CD94/NKG2A, whereas those from the seventh patient augmented this binding. Autoantibodies from 2 patients also reacted with the activating receptor CD94/NKG2C, with inhibition of the binding of HLA-E to CD94/NKG2C observed in 1 case and enhancement of this binding in the other. None of the sera contained anti-NKG2D autoantibodies. The levels of anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies correlated with disease activity and with a more severe SLE phenotype. Mechanistically, anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies both interfered with HLA-E-mediated regulation of NK cell activation and facilitated the elimination of target cells expressing CD94/NKG2A or CD94/NKG2C through ADCC. CONCLUSION: Anti-CD94/NKG2A and anti-CD94/NKG2C autoantibodies occur in a subset of patients with clinically active SLE. Given their capacity to deplete certain NK cell subsets and interfere with particular NK cell function, such autoantibodies may promote the pathogenesis of SLE. PMID- 25510436 TI - Application of a single-colony coculture technique to the isolation of hitherto unculturable gut bacteria. AB - Molecular studies have led to postulation of a relationship between gut microbiota and certain diseases. However, because studies of hitherto uncultured species in vivo are essential for characterizing the biology and pathogenic properties of gut bacteria, techniques for culturing and isolating such bacteria must be developed. Here, a technique is described that partially overcomes the obstacles that prevent detection of interbacterial communication in vitro and are thus responsible for the failure to culture certain bacterial species. For this purpose, a ring with a membrane filter at the bottom was designed and a relatively simple nutrient medium was used instead of conventional media. Gut bacteria were cocultivated in soft agar separated by the membrane filter to simulate interbacterial communication in vitro. Use of this soft agar coculture technique led to the successful isolation of hitherto uncultured bacteria and the demonstration of multistage interbacterial communication among gut bacteria in vitro. Cultivation and isolation of single colonies of bacteria that require other bacteria for growth will enhance efforts to better understand the physiological and pathogenic roles of gut microbiota. PMID- 25510437 TI - Long-term groundwater depletion in the United States. AB - The volume of groundwater stored in the subsurface in the United States decreased by almost 1000 km3 during 1900-2008. The aquifer systems with the three largest volumes of storage depletion include the High Plains aquifer, the Mississippi Embayment section of the Gulf Coastal Plain aquifer system, and the Central Valley of California. Depletion rates accelerated during 1945-1960, averaging 13.6 km3/year during the last half of the century, and after 2000 increased again to about 24 km3/year. Depletion intensity is a new parameter, introduced here, to provide a more consistent basis for comparing storage depletion problems among various aquifers by factoring in time and areal extent of the aquifer. During 2001-2008, the Central Valley of California had the largest depletion intensity. Groundwater depletion in the United States can explain 1.4% of observed sea-level rise during the 108-year study period and 2.1% during 2001-2008. Groundwater depletion must be confronted on local and regional scales to help reduce demand (primarily in irrigated agriculture) and/or increase supply. PMID- 25510435 TI - Ethyl acetate extract of Wedelia chinensis inhibits tert-butyl hydroperoxide induced damage in PC12 cells and D-galactose-induced neuronal cell loss in mice. AB - BACKGROUND: Wedelia chinensis is traditionally used as a hepatoprotective herb in Taiwan. The aim of this study was to evaluate the neuroprotective potential of W. chinensis. METHODS: An ethyl acetate extract of W. chinensis (EAW) was prepared and analyzed by HPLC. The neuroprotective potential of EAW was assessed by tert butylhydroperoxide (t-BHP)-induced damage in PC12 cells and D-galactose-induced damage in mouse cortex. RESULTS: EAW exhibited potent radical scavenging property and highly contained luteolin and wedelolactone. EAW decreased t-BHP-induced reactive oxygen species (ROS) accumulation, cytotoxicity and apoptosis in PC12 cells. EAW and its major constituents blocked t-BHP-induced cytochrome C release and Bcl-2 family protein ratio change. EAW and its major constituents increased the endogenous antioxidant capacity evaluated by the binding activity assay of nuclear factor E2-related factor 2 (Nrf2) to antioxidant response element (ARE) and nuclear translocation of Nrf2 respectively in PC12 cells. Finally, EAW inhibited D-galactose-induced lipid peroxidation, apoptosis and neuron loss in the cerebral cortex of mice. CONCLUSION: These results demonstrate that W. chinensis has neuroprotective potential through blocking oxidative stress-induced damage and that luteolin and wedelolactone contribute to the protective action. PMID- 25510438 TI - Cyclic stability testing of aminated-silica solid sorbent for post-combustion CO2 capture. AB - The National Energy Technology Laboratory (NETL) is examining the use of solid sorbents for CO2 removal from coal-fired power plant flue gas streams. An aminated sorbent (previously reported by the NETL) is tested for stability by cyclic exposure to simulated flue gas and subsequent regeneration for 100 cycles. Each cycle was quantified using a traced gas in the simulated flue gas monitored by a mass spectrometer, which allowed for rapid determination of the capacity. PMID- 25510439 TI - Total synthesis of the tiacumicin B (lipiarmycin A3/fidaxomicin) aglycone. AB - Tiacumicin B (lipiarmycin A3, fidaxomicin) is an atypical macrolide antibiotic which is used for the treatment of Clostridium difficile infections. Tiacumicin B is also a potent inhibitor of Mycobacterium tuberculosis, but due to its limited oral bioavailability is unsuitable for systemic therapy. To provide a basis for structure-activity studies that might eventually lead to improved variants of tiacumicin B, we have developed an efficient approach to the synthesis of the tiacumicin B aglycone. The synthesis features a high-yielding intramolecular Suzuki cross-coupling reaction to effect macrocyclic ring closure. Key steps in the synthesis of the macrocyclization precursor were a highly selective, one-pot Corey-Peterson olefination and an ene-diene cross-metathesis reaction. Depending on the reaction conditions, the final deprotection delivered either the fully deprotected tiacumicin B aglycone or partially protected versions thereof. PMID- 25510440 TI - Anti-fibrotic and anti-tumorigenic effects of rhein, a natural anthraquinone derivative, in mammalian stellate and carcinoma cells. AB - Anthraquinone compounds have been recognized to possess antiinflammatory, anti fibrotic and anti-tumour properties and thus applied in human and veterinary therapeutics as active substances of medicinal products. Amongst the anthraquinones isolated from Rheum palmatum, also known as da-huang, rhein was detected as one of the highest metabolite contents in the bloodstream of mammals. The biological activities of rhein therefore deserve detailed investigation. In this study, we aimed to delineate the mechanism of inhibitory actions of rhein on fibrotic and tumorigenic processes by means of various biochemical assays, such as immunofluorescent staining, real-time polymerase chain reaction (PCR) and western blotting analyses in rat pancreatic stellate cells (LTC-14), human pancreatic ductal adenocarcinoma cells (PANC-1) and human colon carcinoma cells (SW480 and SW620). Our results demonstrated that the application of rhein notably suppressed the mRNA and protein levels of various fibrotic and tumorigenic mediators including alpha-smooth muscle actin, type I collagen, fibronectin, N cadherin and matrix metalloproteinases in the testing mammalian cells. The mechanism of the suppressive actions of rhein was associated with the modulation of the sonic hedgehog and serine-threonine kinase signalling pathways. In conclusion, we suggest that rhein may serve as a therapeutic or an adjuvant agent in anti-fibrotic and anti-tumorigenic approaches. PMID- 25510441 TI - A randomized study comparing the use of a pelvic lead shield during trans-radial interventions: Threefold decrease in radiation to the operator but double exposure to the patient. AB - OBJECTIVES: To determine the efficacy of a 0.5-mm lead apron across the patient's abdomen in addition to standard operator protection for the reduction of scatter radiation on operator and patient radiation exposure BACKGROUND: Cardiac angiography using the radial access compared to the femoral approach is associated with reduced complication rate and improved patient comfort but has significantly increased radiation dose. Improvements in radiation protection are needed METHODS: We randomly assigned 332 patients undergoing coronary angiography to a group with pelvic lead shielding and a group with standard protection. In each procedure, eight digital dosimeters were used to measure operator radiation dose [under the lead apron, outside the thyroid shield, and at the left side of the head], patient dose at the level of the umbilicus [above and beneath the lead apron], and two on the acrylic shielding and one on the image receptor to measure scattered radiation RESULTS: Both groups were similar in BMI, procedures performed, and number of sequences. Usage of lead shielding statistically significantly reduced the radiation dose of the operator at all three sites measured: under lead apron [all in uSv]: 0.53 +/- 1.4 vs. 0.17 +/- 0.6, on thyroid collar 5.9 +/- 7.7 vs. 2.9 +/- 3.4, and left side of head 3.3 +/- 3.4 vs. 2.1 +/- 2.2, P<0.001. However the radiation to the patient was doubled from 15.4 +/- 24.1 to 28.9 +/- 81.1, P=0.04 CONCLUSIONS: The use of a pelvic lead shield during radial angiography reduced the operator radiation exposure at multiple measurement sites. However there was an increased exposure to the patient. This balance should be further investigated before the widespread adoption of this method. . PMID- 25510443 TI - Endoscopic ventral skull base surgery: Is early postoperative imaging warranted for detecting complications? AB - OBJECTIVES/HYPOTHESIS: Following endoscopic ventral skull base surgery (EVSBS), it is common practice to obtain early postoperative imaging. The role of postoperative computed tomography (CT) and magnetic resonance imaging (MRI) scans in these patients remains unclear. This study aims to determine the clinical utility of early postoperative imaging after EVSBS for detecting postoperative complications. METHODS: A retrospective chart analysis of 224 cases of purely EVSBS between 2009 and 2014 was performed. Data were collected regarding postoperative CT and MRI as well as hospital course. Interpretations of postoperative imaging were separated into two groups: 1) using radiologist's interpretation alone and 2) using surgeon knowledge of the case in tandem with imaging. RESULTS: Postoperative imaging was obtained in 213 cases (204 CT, 170 MRI) within 48 hours of surgery. Interpretation by a radiologist yielded a significantly higher rate of false positives (FP) on CT (15/204) and MRI (8/170) when compared to surgeon interpretation (CT FP =1/204 and MRI FP = 1/170) (P = 0.0004 and P = 0.0366, respectively), as well as a significantly lower rate of true negatives (TN) on CT (172/204 vs. 186/204) (P = 0.0497), whereas MRI data had a similar rate of TN (150/170 vs. 157/170; P = 0.2717). The rate of postoperative complications was 7.14% (16/224). In all cases of postoperative complications that required intervention, patients exhibited clinical symptoms. CONCLUSION: Based on our findings, the benefit of early postoperative imaging to detect complications may be limited. When positive imaging findings were encountered, their value were somewhat negated by preceding clinical symptoms. LEVEL OF EVIDENCE: 4. PMID- 25510444 TI - Mycobacterium marinum infection initially diagnosed as metastatic Crohn's disease. PMID- 25510442 TI - Metabolic response to selenium supplementation in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: We are aware of no study examining the effects of selenium supplementation on metabolic profiles of patients with polycystic ovary syndrome (PCOS). This study was conducted to evaluate the effects of selenium supplementation on glucose homeostasis parameters and lipid concentrations in women with PCOS. DESIGN, PATIENTS AND MEASUREMENTS: This randomized, double blind, placebo-controlled trial was conducted among 70 women diagnosed with PCOS and aged 18-40 years old. Participants were randomly divided into two groups to receive 200 MUg per day selenium supplements (N = 35) or placebo (N = 35) for 8 weeks. Fasting blood samples were taken at baseline and after 8 weeks intervention to quantify glucose, insulin and lipid concentrations. RESULTS: After 8 weeks of intervention, subjects who received selenium supplements had significantly decreased serum insulin levels (-29.83 +/- 47.29 vs +9.07 +/- 77.12 pmol/l, P = 0.013), homeostasis model of assessment-insulin resistance (HOMA-IR) (-1.15 +/- 1.81 vs +0.42 +/- 3.09, P = 0.011), homeostatic model assessment-beta cell function (HOMA-B) (-19.06 +/- 30.95 vs +4.55 +/- 47.99, P = 0.017) and increased quantitative insulin sensitivity check index (QUICKI) (+0.03 +/- 0.04 vs +0.0009 +/- 0.05, P = 0.032) compared with placebo. In addition, supplementation with selenium resulted in a significant reduction in serum triglycerides (-0.14 +/- 0.55 vs +0.11 +/- 0.30 mmol/l, P = 0.025) and VLDL-C concentrations (-0.03 +/- 0.11 vs +0.02 +/- 0.06 mmol/l, P = 0.025) compared with placebo. CONCLUSIONS: In conclusion, 200 microgram per day selenium supplementation for 8 weeks among PCOS women had beneficial effects on insulin metabolism parameters, triglycerides and VLDL-C levels; however, it did not affect FPG and other lipid profiles. PMID- 25510445 TI - MRI predictors of clinical success in MR-guided focused ultrasound (MRgFUS) treatments of uterine fibroids: results from a single centre. AB - OBJECTIVES: To assess the technical and clinical results of MRgFUS treatment and factors affecting clinical treatment success. MATERIALS AND METHODS: A total of 252 women (mean age, 42.1 +/- 6.9 years) with uterine fibroids underwent MRgFUS. All patients underwent MRI before treatment. Results were evaluated with respect to post-treatment nonperfused volume (NPV), symptom severity score (SSS), reintervention rate, pregnancy and safety data. RESULTS: NPV ratio was significantly higher in fibroids characterized by low signal intensity in contrast-enhanced T1-weighted fat saturated MR images and in fibroids distant from the spine (>3 cm). NPV ratio was lower in fibroids with septations, with subserosal component and in skin-distant fibroids (p < 0.001). NPV ratio was highly correlated with clinical success: NPV of more than 80 % resulted in clinical success in more than 80 % of patients. Reintervention rate was 12.7 % (mean follow-up time, 19.4 +/- 8 months; range, 3-38). Expulsion of fibroids (21 %) was significantly correlated with a high clinical success rate. No severe adverse events were reported. CONCLUSIONS: Adequate patient selection and correct treatment techniques, based on the learning curve of this technology, combined with technical advances of the system, lead to higher clinical success rates with low complications rate, comparable to other uterine-sparing treatment options. KEY POINTS: * MRgFUS appears to be a valid alternative to other uterus-preserving therapies * Patient selection is a significant factor in achieving high NPV ratios * MRI screening parameters correlate with the amount of fibroid ablation in MRgFUS * NPV results of more than 80 % correlate with higher clinical success rates. PMID- 25510446 TI - Cerebral computed tomography angiography using a 70 kVp protocol: improved vascular enhancement with a reduced volume of contrast medium and radiation dose. AB - OBJECTIVES: To determine the feasibility of using a 70-kVp protocol compared with a 120-kVp protocol for cerebral CT angiography. An additional target was to investigate a possible reduction in the volume of contrast medium (CM) using the 70-kVp protocol. METHODS: Attenuation value and CNR for iodine were determined at various tube voltage settings using a phantom. Sixty-nine volunteers were randomly assigned to one of three protocols: group A (120-kVp and CM 64 mL), group B (70-kVp and CM 64 mL), or group C (70-kVp and CM 40 mL). The attenuation value, SNR, and CNR of cerebral arteries, subjective image quality, and radiation dose were compared among the groups. RESULTS: The vascular attenuation, SNR, and CNR of group B were significantly higher than those of group A. Group C had a significantly higher vascular attenuation than group A. Groups B and C were significantly better than group A with respect to subjective image quality. An effective dose of 70-kVp was 10 % lower than that of 120-kVp. CONCLUSIONS: Using 70-kVp improved arterial enhancement, SNR, and CNR, and provided better subjective image quality, using a 10 % lower effective dose. Furthermore, the 70 kVp protocol may both reduce volume of CM by 37.5 % and improve arterial enhancement. KEY POINTS: * Cerebral CT angiography at 70-kVp substantially improved vascular enhancement * Subjective image quality was better at 70-kVp, with lower radiation dose * The volume of contrast media can be substantially reduced at 70-kVp. PMID- 25510447 TI - Adipose tissue compartments, muscle mass, muscle fat infiltration, and coronary calcium in institutionalized frail nonagenarians. AB - OBJECTIVE: to compare the different adipose tissue (AT) compartments, muscle mass, muscle fat infiltration, coronary calcium, as well as associations among changes in different AT compartments between frail and robust nonagenarians. MATERIALS AND METHODS: Forty-two elderly subjects took part in this study: 29 institutionalized frail elderly (92.0 +/- 8 years) and 13 robust elderly (88.2 +/ 4.1 years). All patients underwent helical thoracic, abdominal and thigh computed tomography (CT). In addition, a non-enhanced prospectively ECG-triggered cardiac CT was performed to quantify the amount of coronary artery calcification and measure pericardial AT. RESULTS: The robust group presented significantly greater pericardial and abdominal AT volume, as well as greater axial and appendicular muscle size and high-density muscle tissue (greater muscle quality) than the frail group (P < 0.001), whereas no differences between groups were observed in coronary calcium. There were positive correlations between pericardial AT with visceral and subcutaneous AT values, as well as between pericardial AT and quadriceps, hamstrings, psoas and paravertebral low-density muscle tissues in the frail and robust groups (r = 0.57 to 0.91,P < 0.05). CONCLUSIONS: Robust group presented greater muscle size and quality in the axial and appendicular muscles, as well as pericardial and abdominal AT area than the frail group. KEY POINTS: * Robust nonagenarians presented more pericardial and abdominal AT volume than frail. * Frailty is associated with lower muscle size and high-density muscle tissue. * Muscle-fat infiltration shares analogous pattern of visceral and pericardial AT distribution. PMID- 25510448 TI - Preparation and characterization of gatifloxacin-loaded alginate/poly (vinyl alcohol) electrospun nanofibers. AB - The aim of this study was to develop novel biomedicated electrospun nanofibers for controlled release. Pre-formulation studies were carried out for nanofibers of sodium alginate (SA) (2 wt %)/polyvinyl alcohol (PVA) (10 wt %) composites (2/8, 3/7 and 4/6), by an electrospinning technique. The morphology and average diameter of the nanofibers were investigated by scanning electron microscopy (SEM). The optimum ratio (3/7) was used to load gatifloxacin hydrochloride (GH) (1wt %), found to form smooth fibers with uniform structures. The drug entrapment in the composite nanofibers was confirmed by SEM, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermo gravimetric analysis (TGA), differential scanning calorimetry (DSC), and swelling behavior. The drug release behavior was investigated using phosphate-buffered saline (PBS) (pH 7.4) at 37 degrees C for 24 h. The XRD and FTIR data demonstrate that there are good interactions between PVA and SA, possibly caused by hydrogen bonds. As much as 90% of the GH was released from the electrospun fibers within 6 h of incubation. Beyond this, the release was sustained for 24 h. The thickness of nanofibers greatly influenced the initial release and rate of drug release. Moreover, GH loaded sodium alginate/PVA composite nanofibers exhibited a useful and convenient method for electrospinning in order to control the rate and period of drug release in wound-healing applications. PMID- 25510451 TI - [Dedicated bridge year: a blessing?]. PMID- 25510449 TI - Expression of matrix metalloproteinases and their inhibitors in different immunohistochemical-based molecular subtypes of breast cancer. AB - BACKGROUND: Metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) are involved in several key pathways of tumor growth, invasion and metastasis, but little is known about their expression according to different molecular subtypes of breast cancer. The aims of this study were to assess the prevalence and clinical significance of MMP and TIMP expression in invasive breast cancer and to determine its association with immunohistochemical based molecular classification. METHODS: Tissue microarray sections were immunostained for estrogen receptor-alpha (ER-alpha), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR) and with specific antibodies against MMP-1, 2, 7, 9, 11, 13, and 14 and TIMP-1, 2, and 3. Based on the immunostaining data from five of the markers used (ER-alpha, PR, HER2, EGFR and CK5/6), three major subtypes (123 luminal A, 31 basal-like, and 17 HER2-overexpressing) were selected. RESULTS: Statistically significant differences in the expression of MMPs and TIMPs among the three subtypes were found in tumoral MMP7 (P = 0.005), tumoral MMP-9 (P = 0.000), tumoral MMP-13 (P = 0.016) and stromal MMP-13 (P = 0.016). The incidence of tumoral MMP-9 expression in the HER2-overexpressing subtype was significantly higher than in the luminal A subtype (P = 0.021). Tumoral MMP-9 and stromal MMP-13 expression were significantly higher in the HER2 overexpressing subtype than in the basal-like subtype (P = 0.000 and P = 0.016, respectively). Tumoral MMP-7 expression was significantly higher in the basal like subtype compared to luminal A (P = 0.007) and HER2-overexpressing subtype (P = 0.004). Tumoral MMP-13 showed a higher expression in the basal-like subtype than in the HER2-overexpressing subtype (P = 0.010). In multivariate analysis, stage and stromal MMP-1 expression were significantly related to overall survival. Stage was of independent prognostic significance for disease-free survival. CONCLUSION: We found some variations in MMP and TIMP expression among the immunohistochemical-based molecular subtypes of breast carcinomas, suggesting differences in their tumor pathophysiology. Additional studies are needed to determine the mechanisms underlying the differences of MMP and TIMP expression in the molecular subtypes for the development of specific therapeutic targets for breast cancer subtypes. PMID- 25510450 TI - A comprehensive peer network intervention to improve social communication of children with autism spectrum disorders: a randomized trial in kindergarten and first grade. AB - The purpose of this randomized control group study was to examine the effects of a peer network intervention that included peer mediation and direct instruction for Kindergarten and First-grade children with autism spectrum disorders. Trained school staff members provided direct instruction for 56 children in the intervention group, and 39 children participated in a comparison group. Results showed children in the intervention group displayed significantly more initiations to peers than did the comparison group during non-treatment social probes and generalization probes. Treatment session data showed significant growth for total communications over baseline levels. Children in treatment also showed more growth in language and adaptive communication. Finally, teachers' ratings of prosocial skills revealed significantly greater improvements for the intervention group. PMID- 25510453 TI - [New insights into ways of determining cortisol exposure in patients with bipolar disorder]. AB - BACKGROUND: Previous research has shown a relationship between the stress hormone cortisol and bipolar disorder. The level of cortisol exposure is usually examined by means of measurements that provide a snapshot of cortisol exposure or by means of dynamic testing. Recently, a new technique has been introduced which can measure, retrospectively, the cortisol level in scalp hair over longer periods of time. AIM: To provide insight into various methods used in psychiatry for measuring the hypothalamus-pituitary-adrenal (HPA)-axis activity and also to highlight recent research into measurements of cortisol in scalp hair of patients with bipolar disorder. METHOD: We give a brief overview of the literature relating to HPA-axis testing in psychiatric patients. As a result of our recent studies with 100 patients suffering from bipolar disorder, we are now able to determine the levels of cortisol in scalp hair. RESULTS: Tests that measure hpa activity can be divided into three categories: point measurements, stimulation tests and inhibition tests. In our recent study of bipolar patients we found that a raised level of cortisol in scalp hair was related to a later onset of bipolar disorder (in patients over 30) or to multiple psychiatric diagnoses. Lower levels of cortisol level in scalp hair of bipolar patients were observed in bipolar patients with comorbid panic disorder. CONCLUSION: The use of hair analysis to measure mean cortisol levels over long periods seems to give added value to the hpa-axis tests currently used for measuring cortisol exposure. The technique may make it easier to differentiate between various subtypes of bipolar disorder. PMID- 25510452 TI - [Psychometric properties of the Hospital Ethical Climate Survey: a cross sectional study among Belgian psychiatric nurses]. AB - BACKGROUND: The task of caring for psychiatric patients is so complex that it often leads to ethical dilemmas. The ethical climate on a ward is a crucial factor. This is the first study about the ethical climate in mental healthcare. AIM: To investigate whether the only instrument currently available for measuring the ethical climate in general hospitals, namely the 'Hospital Ethical Climate Survey' (HECS), is a reliable and valid instrument for use on psychiatric wards. METHOD: A cross-sectional study was performed in a psychiatric hospital in Belgium. All 320 nurses were invited to participate (response rate = 265). The factor structure of the HECS was examined by means of explorative principal component analysis (PCA) and confirmatory factor analysis (CFA). The reliability of the constructed scale and subscales was investigated. RESULTS: Five factors were identified. The structure of these factors in the translated list was almost identical to the structure obtained with the original instrument and its underlying theoretical basis. Items relating to several other allied healthcare professions were added. This addition widened the subscale 'relationship with physician' so that it included 'relationship with other disciplines' (medical and allied healthcare workers). CONCLUSION: The reliability of the instrument appeared to be good and yielded scores comparable to those obtained as a result of earlier research performed in general hospitals. The setting for our investigation produced a significantly higher main score for the ethical climate than did previous studies. PMID- 25510454 TI - [Alexithymia in fibromyalgia: prevalence]. AB - BACKGROUND: In fibromyalgia, problems of affect regulation are considered important. Alexithymia, too, is related to disturbed affect regulation. Recognising alexithymia is important with regard to the doctor-patient relationship, the pitfalls in this relationship and the therapeutic strategy. AIM: To look into the prevalence of alexithymia in fibromyalgia and find out which measures were used. METHOD: We reviewed the literature systematically using Medline, PubMed and Cochrane and key words. RESULTS: We found 11 relevant studies which revealed a significantly high prevalence of alexithymia in fibromyalgia patients, namely between 15 and 52%, whereas the prevalence in the general population was only 6 to 8%. All of these studies used the Toronto Alexithymia Scale (20-item or 26-item version) as the only test for alexithymia. Male fibromyalgia patients were not examined adequately, nor were patients in a residential setting. Three studies used patients with a painful chronic condition as a control group, but we did not find any studies that involved psychiatric control groups. CONCLUSION: In view of the high prevalence of alexithymia and the implications of this for therapy, we recommend that patients with fibromyalgia should be screened systematically for alexithymia. Further research involving male patients and residential fibromyalgia patients is required and future studies will have to include psychiatric control groups. PMID- 25510455 TI - [The new draft law on care and coercion. Concerning the use and the reduction of antipsychotics without a valid indication in people with intellectual disabilities]. AB - BACKGROUND: In the Netherlands, many people with an intellectual disability and challenging behavior are still prescribed antipsychotic medication, often for many years and in high doses. According to the new draft law on care and coercion, prescribing antipsychotics, without a valid indication, for people with an intellectual disability, will be regarded as coercion. The effect for clinical practice will be that such antipsychotic medication will have to be re-assessed and, in many cases, reduced and stopped. AIM: To comment on the effectiveness, the side effects and futility of prescribing antipsychotics to people with an intellectual disability and challenging behavior in order to arrive at recommendations about the evaluation of antipsychotics and, if possible, about the reduction of antipsychotics for intellectually challenged people who do not really require such medication. METHOD: Practical recommendations are made based on recent literature and clinical experience. RESULTS: Thorough evaluation and - when possible - the reduction of antipsychotics for people with an intellectual disability requires psychiatrists to invest time and energy in diagnosis and stability of patients, to invest in the patient's environment and to opt for a controlled reduction of antipsychotics. CONCLUSION: The new draft law on care and coercion highlights the urgent need for guidelines concerning the reduction of antipsychotics for people with an intellectual disability when there is no clear indication that such a step will benefit the patient. PMID- 25510456 TI - [DSM-5 classification of personality disorders in older persons]. AB - BACKGROUND: Although it is generally agreed that personality disorders are an important topic in old-age psychiatry, DSM-5 has paid relatively little attention to older persons affected with this severe mental disorder. AIM: To look closely and carefully at several aspects of the way in which DSM-5 defines personality disorders relating to older persons. METHOD: We make a critical evaluation of the description of personality disorders given in DSM-5. RESULTS: First of all, we question whether the phrase 'personality change due to another medical condition' should really be included in the dsm-5 chapter of personality disorders because a personality change actually has the features of a persistent conduct disorder. Secondly, we argue that in a future revised version of dsm-5 personality disorders affecting older persons should be referred to specifically as 'late onset' personality disorders. Thirdly, we stress that the research programme relating to the dimensional dsm-5 model of personality disorders should involve a larger number of older persons. In addition, more research is needed with regard to the use, wording and validity of the phrase 'personality change due to a medical condition'. Those responsible for the revision of the DSM-5 should ensure that the concept 'late-onset personality disorders' is incorporated in the text. CONCLUSION: The description of personality disorders in DSM-5 is confusing. This is probably due to the transitional period between the old categorical (dsm-iv) system and the newly proposed dimensional approach to personality disorders in DSM-5, an approach that needs further investigation. However, this intervening period could be a good opportunity for doing further research into personality disorders in older adults. PMID- 25510457 TI - [Paroxysmal events after anxiety treatment with fluoxetine in a child with autism spectrum disorder]. AB - Anxiety is common in children and adolescents with autism spectrum disorders and can cause severe dysfunction and suffering. An 11-year-old boy with an autism spectrum disorder and suffering from anxiety and mood problems responded positively to treatment with fluoxetine. After four weeks he developed clinically observable paroxysmal events accompanied by absence and confusion. PMID- 25510458 TI - [Reaction on 'Neurolaw: its relevance for forensic psychiatry' and 'Forensic psychiatrists and forensic psychologists: mind the gap']. PMID- 25510461 TI - Ultrafast hydrolysis of a Lewis photoacid. AB - This study explores the concept that electronic excitation can dramatically enhance Lewis acidity. Specifically, it is shown that photoexcitation transforms an electron-deficient organic compound of negligible Lewis acidity in its electronic ground state into a potent excited-state Lewis acid that releases a proton from a nearby water molecule in 3.1 ps. It was shown previously (Peon et al. J. Phys. Chem. A 2001, 105, 5768) that the excited state of methyl viologen (MV(2+)) is quenched rapidly in aqueous solution with the formation of an unidentified photoproduct. In this study, the quenching mechanism and the identity of the photoproduct were investigated by the femtosecond transient absorption and fluorescence upconversion techniques. Transient absorption signals at UV probe wavelengths reveal a long-lived species with a pH-dependent lifetime due to reaction with hydronium ions at a bimolecular rate of 3.1 * 10(9) M(-1) s( 1). This species is revealed to be a charge-transfer complex consisting of a ground-state MV(2+) ion and a hydroxide ion formed when a water molecule transfers a proton to the bulk solvent. Formation of a contact ion pair between MV(2+) and hydroxide shifts the absorption spectrum of the former ion by a few nm to longer wavelengths, yielding a transient absorption spectrum with a distinctive triangle wave appearance. The slight shift of this spectrum, which is in excellent agreement with steady-state difference spectra recorded for MV(2+) at high pH, is consistent with an ion pair but not with a covalent adduct (pseudobase). The long lifetime of the ion pair at neutral pH indicates that dissociation occurs many orders of magnitude more slowly than predicted by the Smoluchowski-Debye equation. Remarkably, there is no evidence of geminate recombination, suggesting that the proton that is transferred to the solvent is conducted at least several water shells away. Although the hydrolysis mechanism has yet to be fully established, evidence suggests that the strongly oxidizing excited state of MV(2+) triggers the proton-coupled oxidation of a water molecule. The observed kinetic isotope effect of 1.7 seen in D2O vs H2O is of the magnitude expected for an ultrafast concerted proton-electron transfer reaction. The ultrafast hydrolysis seen here may be a general excited-state quenching mechanism for electronically excited Lewis acids and other powerful photooxidants in aqueous solution. PMID- 25510462 TI - Noscapine Increases the Sensitivity of Drug-Resistant Ovarian Cancer Cell Line SKOV3/DDP to Cisplatin by Regulating Cell Cycle and Activating Apoptotic Pathways. AB - Cisplatin is a first-line chemotherapy drug against ovarian cancer. However, its strong toxic side effects and the development of cisplatin resistance in human cancer cells seriously influence the effects of chemotherapy and quality of life in patients. Noscapine (Nos), a non-toxic benzylisoquinoline alkaloid extracted from opium, has been recently reported to have anti-cancer activity, but the mechanism of that effect has not been clearly established. In the present study, we investigated cytotoxicity of Nos in combination with cisplatin (DDP) in drug resistant human ovarian cancer cell line SKOV3/DDP in vitro and in vivo null mice xenograft model. Cell proliferation was measured by MTT assay, flow cytometry was used to analyze cell cycle and apoptosis, protein expression of several apoptotic factors was investigated by flow cytometry and immunohistochemical method, and their mRNA expression levels were determined by real-time PCR. In vitro experiments showed that Nos significantly inhibited proliferation of SKOV3/DDP cells. DDP/Nos-combined treatment notably enhanced DDP-induced inhibition of cell proliferation and increased the pro-apoptotic effect of DDP in SKOV3/DDP cells. DDP/Nos administration increased the proportion of G2/M cells, reduced both protein and mRNA expression of anti-apoptotic factors XIAP, surviving and NF-kB, and augmented protein and mRNA levels of pro-apoptotic caspase-3. In vivo experiments revealed that Nos/DDP treatment increased the apoptotic rate of xenograft tumors in null mice. Tumor volume decreased from 1.733 +/- 0.155 g in mice treated with DDP alone to 1.191 +/- 0.106 g in animals treated with Nos/DDP. These observations suggest that Nos increases the anti-cancer activity of DDP against the drug-resistant ovarian cancer cell line SKOV3/DDP by modulating the cell cycle and activating apoptotic pathways. The study provides a new chemotherapy strategy for the treatment of DDP-resistant human ovarian cancer. PMID- 25510459 TI - Pharmacological and molecular characterization of functional P2 receptors in rat embryonic cardiomyocytes. AB - Purinergic receptors activated by extracellular nucleotides (adenosine 5' triphosphate (ATP) and uridine 5'-triphosphate (UTP)) are well known to exert physiological effects on the cardiovascular system, whether nucleotides participate functionally in embryonic heart development is not clear. The responsiveness of embryonic cardiomyocytes (E) 12 to P2 receptor agonists by measuring Ca(2+) influx did not present response to ATP, but responses to P2 agonists were detected in cardiomyocytes taken from E14 and E18 rats. Photometry revealed that the responses to ATP were concentration-dependent with an EC50 of 1.32 MUM and 0.18 MUM for E14 and E18 cardiomyocytes, respectively. In addition, other P2 agonists were also able to induce Ca(2+) mobilization. RT-PCR showed the presence of P2X2 and P2X4 receptor transcripts on E14 cardiomyocytes with a lower expression of P2X3 and P2X7 receptors. P2X1 and a low level of P2X5 receptor messenger RNA (mRNA) were also expressed at E18. Immunofluorescence data indicated that only P2X2 and P2X4 receptor proteins were expressed in E14 cardiomyocytes while protein for all the P2X receptor subtypes was expressed in E18, except for P2X3 and P2X6. Responses mediated by agonists specific for P2Y receptors subtypes showed that P2Y receptors (P2Y1, P2Y2, P2Y4 and P2Y6) were also present in both E14 and E18 cardiomyocytes. Dye transfer experiments showed that ATP induces coupling of cells at E12, but this response is decreased at E14 and lost at E18. Conversely, UTP induced coupling with five or more cells in most cells from E12 to E18. Our results show that specific P2 receptor subtypes are present in embryonic rat cardiomyocytes, including P2X7 and P2Y4 receptors that have not been identified in adult rat cardiomyocytes. The responsiveness to ATP stimulation even before birth, suggests that ATP may be an important messenger in embryonic as well as in adult hearts. PMID- 25510463 TI - Abdominovaginal fistula after incomplete removal of an intravaginal slingplasty. PMID- 25510464 TI - The management of massive haematomas after insertion of retropubic mid-urethral slings. AB - INTRODUCTION AND HYPOTHESIS: The retropubic mid-urethral sling (MUS) is the most commonly performed procedure for the treatment of stress urinary incontinence and is associated with a low risk of complications. Large retropubic haematomas occur sporadically and may have life-threatening consequences. Because of their infrequent nature, there is a dearth of information regarding this serious complication. The aim of this study was to identify the incidence of large haematomas and any lessons learnt from their treatment. METHODS: A retrospective cohort study was conducted between December 1999 and June 2014. Massive haematoma was defined as a haematoma greater than 8 cm and/or a drop in haemoglobin of more than 4 g/dl. The hospital notes of all patients diagnosed with a massive haematoma were reviewed and a detailed history, operation details and the information on the management of haematoma were obtained. RESULTS: Seven (0.33 %) patients were identified with a massive retropubic haematoma out of a total of 2,091 retropubic MUS procedures performed. Six patients presented acutely with symptoms within 24 h. Haemoglobin levels dropped on average by 5.7 g/dl (range 2.9 to 8.6). The size of the haematoma ranged from 8 to 12 cm in diameter. Six patients required surgical drainage of the haematoma. Three patients received evacuation within 2 post-operative days. Haematomas were removed via laparotomy, vaginal drainage or suprapubic drainage. CONCLUSIONS: Massive retropubic haematomas are uncommon but serious complications of MUS procedures. Our experience suggests that to reduce short- and long-term complications, early evacuation of massive haematomas via the suprapubic approach is recommended. PMID- 25510465 TI - The effect of age on stress and urgency urinary incontinence outcomes in women undergoing primary midurethral sling. AB - INTRODUCTION AND HYPOTHESIS: The primary aim was to characterize stress urinary incontinence (SUI) symptom distress and impact after a midurethral sling (MUS) in women >=70 compared to women <70 years of age. METHODS: A retrospective cohort study of women undergoing a primary MUS was conducted. The primary outcome was SUI symptoms defined as either "moderately" or "quite a bit" responses to >=1 of the two SUI questions of the Pelvic Floor Distress Inventory-20 (PFDI-20). Urgency urinary incontinence (UUI) was defined as either moderately or quite a bit responses to the UUI question of the PFDI-20. The Pelvic Floor Impact Questionnaire (PFIQ-7), Patient Satisfaction Questionnaire (PSQ), and Patient Global Impression of Improvement (PGI-I) questionnaires were also administered. RESULTS: The mean age of patients >=70 years (n = 160) was 75.4 +/- 4.5 and <70 years (n = 536) was 56.2 +/- 9.4. Multivariable analysis revealed no difference in SUI failure rates in older compared to younger cohorts, adjusted odds ratio (OR) 1.7, 95 % confidence interval (CI) 0.9-3.1. Women <70 demonstrated greater improvement in urinary incontinence (UI) symptom impact [-20.4 (33.0) vs -12.2 (30.7), p = 0.01] and women >=70 had greater persistent UUI symptoms (31.5 vs 23.3 %, p = 0.04); there was no difference between cohorts in resolution of UUI (29.6 vs 34.2 %, p = 0.34). Younger women reported a greater impression of improvement compared to older women (67.7 vs 56.6 %, p = 0.01, respectively). CONCLUSIONS: Older and younger women have similar SUI outcomes after MUS; however, older women have more persistent UUI and a worse impression of improvement of their urinary tract condition. PMID- 25510466 TI - Bladder pseudodiverticulum and debilitating dyspareunia: diagnostic and management dilemmas of a rare case. AB - Dyspareunia in a woman often lacks a well-defined cause with complex etiology. Similarly wide-mouthed nonobstructive bladder diverticula are mostly managed conservatively with no single etiology. Herein a rare case of dyspareunia and urinary symptoms is described, which started following a lower segment cesarean section (LSCS). Ultrasonography, micturating cystogram, and cystoscopy revealed a large wide-mouthed bladder diverticulum. After 3 years of failed and varied conservative therapy and management dilemmas, exploration was done for diverticulectomy which revealed a diagnostic surprise. A post-LSCS thick adhesive band was found between the uterus and anterior abdominal wall as a direct cause for both the bladder diverticulum and dyspareunia. Adhesions after LSCS may cause varied symptoms which may be difficult to diagnose and leave the patient refractory to conservative therapy. Laparoscopy or exploration may be useful in such cases. PMID- 25510467 TI - Comparison of catheter tip migration using flexible and stimulating catheters inserted into the adductor canal in a cadaver model. AB - Use of adductor canal blocks and catheters for perioperative pain management following total knee arthroplasty is becoming increasingly common. However, the optimal equipment, timing of catheter insertion, and catheter dislodgement rate remain unknown. A previous study has suggested, but not proven, that non-tunneled stimulating catheters may be at increased risk for catheter migration and dislodgement after knee manipulation. We designed this follow-up study to directly compare tip migration of two catheter types after knee range of motion exercises. In a male unembalmed human cadaver, 30 catheter insertion trials were randomly assigned to one of two catheter types: flexible or stimulating. All catheters were inserted using an ultrasound-guided short-axis in-plane technique. Intraoperative knee manipulation similar to that performed during surgery was simulated by five sequential range of motion exercises. A blinded regional anesthesiologist performed caliper measurements on the ultrasound images before and after exercise. Changes in catheter tip to nerve distance (p = 0.547) and catheter length within the adductor canal (p = 0.498) were not different between groups. Therefore, catheter type may not affect the risk of catheter tip migration when placed prior to knee arthroplasty. PMID- 25510469 TI - Room temperature fabrication of dielectric Bragg reflectors composed of a CaF2/ZnS multilayered coating. AB - We describe the design, fabrication, and characterization of mechanically stable, reproducible, and highly reflecting distributed Bragg reflectors (DBR) composed of thermally evaporated thin films of calcium fluoride (CaF2) and zinc sulfide (ZnS). CaF2 and ZnS were chosen as the low and high refractive index components of the multilayer DBR structures, with n = 1.43 and n = 2.38 respectively, because neither material requires substrate heating during the deposition process in order to produce optical quality thin films. DBRs consisting of seven pairs of CaF2 and ZnS layers, were fabricated with thicknesses of 96 and 58 nm, respectively, as characterized by high-resolution scanning electron microscopy (HR-SEM), and exhibited a center wavelength of lambdac = 550 nm and peak reflectance exceeding 99%. The layers showed good adhesion to each other and to the glass substrate, resulting in mechanically stable DBR coatings. Complete optical microcavities consisting of two such DBR coatings and a CaF2 spacer layer between them could be fabricated in a single deposition run. Optically, these structures exhibited a resonator quality factor of Q > 160. When a CaF2/ZnS DBR was grown, without heating the substrate during deposition, on top of a thin film containing the fluorescent dye Rhodamine 6G, the fluorescence intensity showed no degradation compared to an uncoated film, in contrast to a MgF2/ZnS DBR coating grown with substrate heating which showed a 92% reduction in signal. The ability to fabricate optical quality CaF2/ZnS DBRs without substrate heating, as introduced here, can therefore enable formation of low-loss high-reflectivity coatings on top of more delicate heat-sensitive materials such as organics and other nanostructured emitters, and hence facilitate the development of nanoemitter-based microcavity device applications. PMID- 25510468 TI - Tipping off endothelial tubes: nitric oxide drives tip cells. AB - Angiogenesis, the formation of new blood vessels from pre-existing vessels, is a complex process that warrants cell migration, proliferation, tip cell formation, ring formation, and finally tube formation. Angiogenesis is initiated by a single leader endothelial cell called "tip cell," followed by vessel elongation by "stalk cells." Tip cells are characterized by their long filopodial extensions and expression of vascular endothelial growth factor receptor-2 and endocan. Although nitric oxide (NO) is an important modulator of angiogenesis, its role in angiogenic sprouting and specifically in tip cell formation is poorly understood. The present study tested the role of endothelial nitric oxide synthase (eNOS)/NO/cyclic GMP (cGMP) signaling in tip cell formation. In primary endothelial cell culture, about 40% of the tip cells showed characteristic sub cellular localization of eNOS toward the anterior progressive end of the tip cells, and eNOS became phosphorylated at serine 1177. Loss of eNOS suppressed tip cell formation. Live cell NO imaging demonstrated approximately 35% more NO in tip cells compared with stalk cells. Tip cells showed increased level of cGMP relative to stalk cells. Further, the dissection of NO downstream signaling using pharmacological inhibitors and inducers indicates that NO uses the sGC/cGMP pathway in tip cells to lead angiogenesis. Taken together, the present study confirms that eNOS/NO/cGMP signaling defines the direction of tip cell migration and thereby initiates new blood vessel formation. PMID- 25510470 TI - Visual grading characteristics and ordinal regression analysis during optimisation of CT head examinations. AB - OBJECTIVES: To evaluate visual grading characteristics (VGC) and ordinal regression analysis during head CT optimisation as a potential alternative to visual grading assessment (VGA), traditionally employed to score anatomical visualisation. METHODS: Patient images (n = 66) were obtained using current and optimised imaging protocols from two CT suites: a 16-slice scanner at the national Maltese centre for trauma and a 64-slice scanner in a private centre. Local resident radiologists (n = 6) performed VGA followed by VGC and ordinal regression analysis. RESULTS: VGC alone indicated that optimised protocols had similar image quality as current protocols. Ordinal logistic regression analysis provided an in-depth evaluation, criterion by criterion allowing the selective implementation of the protocols. The local radiology review panel supported the implementation of optimised protocols for brain CT examinations (including trauma) in one centre, achieving radiation dose reductions ranging from 24 % to 36 %. In the second centre a 29 % reduction in radiation dose was achieved for follow-up cases. CONCLUSIONS: The combined use of VGC and ordinal logistic regression analysis led to clinical decisions being taken on the implementation of the optimised protocols. This improved method of image quality analysis provided the evidence to support imaging protocol optimisation, resulting in significant radiation dose savings. MAIN MESSAGES: * There is need for scientifically based image quality evaluation during CT optimisation. * VGC and ordinal regression analysis in combination led to better informed clinical decisions. * VGC and ordinal regression analysis led to dose reductions without compromising diagnostic efficacy. PMID- 25510472 TI - Microplatforms for gradient field generation of various properties and biological applications. AB - Well-designed microfluidic platforms can be excellent tools to eliminate bottleneck problems or issues that have arisen in biological fields by providing unprecedented high-resolution control of mechanical and chemical microenvironments for cell culture. Among such microtechnologies, the precise generation of biochemical concentration gradients has been highly regarded in the biorelated scientific fields; even today, the principles and mechanisms for gradient generation continue to be refined, and the number of applications for this technique is growing. Here, we review the current status of the concentration gradient generation technologies achieved in various microplatforms and how they have been and will be applied to biological issues, particularly those that have arisen from cancer research, stem cell research, and tissue engineering. We also provide information about the advances and future challenges in the technological aspects of microscale concentration gradient generation. PMID- 25510471 TI - Digital microfluidics for automated hanging drop cell spheroid culture. AB - Cell spheroids are multicellular aggregates, grown in vitro, that mimic the three dimensional morphology of physiological tissues. Although there are numerous benefits to using spheroids in cell-based assays, the adoption of spheroids in routine biomedical research has been limited, in part, by the tedious workflow associated with spheroid formation and analysis. Here we describe a digital microfluidic platform that has been developed to automate liquid-handling protocols for the formation, maintenance, and analysis of multicellular spheroids in hanging drop culture. We show that droplets of liquid can be added to and extracted from through-holes, or "wells," and fabricated in the bottom plate of a digital microfluidic device, enabling the formation and assaying of hanging drops. Using this digital microfluidic platform, spheroids of mouse mesenchymal stem cells were formed and maintained in situ for 72 h, exhibiting good viability (>90%) and size uniformity (% coefficient of variation <10% intraexperiment, <20% interexperiment). A proof-of-principle drug screen was performed on human colorectal adenocarcinoma spheroids to demonstrate the ability to recapitulate physiologically relevant phenomena such as insulin-induced drug resistance. With automatable and flexible liquid handling, and a wide range of in situ sample preparation and analysis capabilities, the digital microfluidic platform provides a viable tool for automating cell spheroid culture and analysis. PMID- 25510474 TI - The voxel visibility model: an efficient framework for transfer function design. AB - Volume visualization is a very important work in medical imaging and surgery plan. However, determining an ideal transfer function is still a challenging task because of the lack of measurable metrics for quality of volume visualization. In the paper, we presented the voxel vibility model as a quality metric to design the desired visibility for voxels instead of designing transfer functions directly. Transfer functions are obtained by minimizing the distance between the desired visibility distribution and the actual visibility distribution. The voxel model is a mapping function from the feature attributes of voxels to the visibility of voxels. To consider between-class information and with-class information simultaneously, the voxel visibility model is described as a Gaussian mixture model. To highlight the important features, the matched result can be obtained by changing the parameters in the voxel visibility model through a simple and effective interface. Simultaneously, we also proposed an algorithm for transfer functions optimization. The effectiveness of this method is demonstrated through experimental results on several volumetric data sets. PMID- 25510473 TI - Microscale 3D collagen cell culture assays in conventional flat-bottom 384-well plates. AB - Three-dimensional (3D) culture systems such as cell-laden hydrogels are superior to standard two-dimensional (2D) monolayer cultures for many drug-screening applications. However, their adoption into high-throughput screening (HTS) has been lagging, in part because of the difficulty of incorporating these culture formats into existing robotic liquid handling and imaging infrastructures. Dispensing cell-laden prepolymer solutions into 2D well plates is a potential solution but typically requires large volumes of reagents to avoid evaporation during polymerization, which (1) increases costs, (2) makes drug penetration variable and (3) complicates imaging. Here we describe a technique to efficiently produce 3D microgels using automated liquid-handling systems and standard, nonpatterned, flat-bottomed, 384-well plates. Sub-millimeter-diameter, cell-laden collagen gels are deposited on the bottom of a ~2.5 mm diameter microwell with no concerns about evaporation or meniscus effects at the edges of wells, using aqueous two-phase system patterning. The microscale cell-laden collagen-gel constructs are readily imaged and readily penetrated by drugs. The cytotoxicity of chemotherapeutics was monitored by bioluminescence and demonstrated that 3D cultures confer chemoresistance as compared with similar 2D cultures. Hence, these data demonstrate the importance of culturing cells in 3D to obtain realistic cellular responses. Overall, this system provides a simple and inexpensive method for integrating 3D culture capability into existing HTS infrastructure. PMID- 25510475 TI - Whole-genome sequence of a novel Chinese cyprinid herpesvirus 3 isolate reveals the existence of a distinct European genotype in East Asia. AB - Cyprinid herpesvirus 3 (CyHV3), also known as koi herpesvirus (KHV), can be subdivided primarily into European and Asian genotypes, which are represented by CyHV3-U or CyHV3-I and CyHV3-J, respectively. In this study, the whole genome sequence of a novel Chinese CyHV3 isolate (GZ11) was determined and annotated. CyHV3-GZ11 genome was found to contain 295,119 nucleotides with 52.9% G/C content, which is highly similar to those of published CyHV3-U, CyHV3-I, and CyHV3-J strains. With reference to CyHV3-U, CyHV3-I, and CyHV3-J, CyHV3-GZ11 was also classified into 164 open reading frames (ORF), which include eight repeated ORFs. On the basis of the 12 alloherpeviruses core genes, results from phylogenetic analysis showed that CyHV3-GZ11 had closer evolutionary relationships with CyHV3-U and CyHV3-I than with CyHV3/KHV-J, which were also supported by genome wide-based single nucleotide substitution analysis and the use of a series of developed molecular markers. This study was the first to reveal the presence of a distinct European CyHV3 genotype in East and Southeast Asia at a whole genome level, which will evoke new insights on exploring the origin, evolution, and epidemiology of the virus. PMID- 25510476 TI - The safety of low molecular-weight heparin after blunt liver and spleen injuries. AB - BACKGROUND: Anticoagulation is routinely administered to all trauma patients owing to the high incidence of venous thromboembolism (VTE). However, the timing of administration of anticoagulation is not clearly defined when patients have blunt spleen or liver injuries because of the perceived risk of hemorrhage with early administration. METHODS: A retrospective chart review was performed of all blunt trauma patients who sustained blunt liver and/or spleen injuries during the 5-year period from 2007 to 2011. Data were collected for all patients managed with nonoperative therapy for these injuries while also receiving routine prophylactic anticoagulation with low molecular-weight heparin. Patients were categorized based on the initiation of enoxaparin therapy after injury: early (<48 hours), intermediate (48 to 72 hours), and late (>72 hours). Primary and secondary outcomes were designated as need for operative or radiologic intervention secondary to spleen or liver hemorrhage, number of transfusions, and incidence of VTE. RESULTS: Three hundred and twenty-eight patients were included. There were no enoxaparin-related hemorrhagic complications or hemorrhage necessitating operative intervention. Patients in the early, intermediate, and late groups received an average of .9, .93, and 1.55 units of blood, respectively. There was 1 pulmonary embolism in the early group, and there were 6 VTE complications in the late group (3 deep venous thromboses and 3 pulmonary embolisms). CONCLUSIONS: There are currently no standards for the initiation of prophylactic anticoagulation in trauma patients with blunt liver and spleen injuries. Early administration may be safe and reduce the incidence of thrombotic complications in patients with blunt spleen and liver injuries. Prospective studies in this area are warranted. PMID- 25510477 TI - Patients at elevated risk of major adverse events following endarterectomy for asymptomatic carotid stenosis. AB - BACKGROUND: Carotid endarterectomy (CEA) as treatment in patients with asymptomatic carotid stenosis is the subject of much debate. METHODS: The National Surgical Quality Improvement Program database from 2005 to 2012 was queried. Patients undergoing CEA for asymptomatic carotid stenosis were identified. Preoperative risk factors and patient demographics were compared using chi-square analysis and logistic regression to determine their relation with stroke and death. RESULTS: During an 8-year period, 24,211 CEAs performed for asymptomatic carotid stenosis were identified. Patients with dependent functional status (12.5%), recent myocardial infarction (6.3%), chronic heart failure (5.0%), hypoalbuminemia (4.8%), angina (4.1%), dialysis dependence (3.4%), steroid dependence (3.4%), chronic obstructive pulmonary disease (3.3%), and American Society of Anesthesiologists > 3 (3.2%) had a clinically significant increase in risk of stroke and death. Patients with none of the above risk factors had a stroke and death rate of 1.08%, which was significantly less than the overall stroke and death rate (P < .001). CONCLUSIONS: A high-risk subset of patients undergoing CEA for asymptomatic carotid stenosis can be identified. If patient selection is optimized and perioperative morbidity and mortality are minimized, CEA will continue to play an important role in stroke prevention for those with significant asymptomatic carotid stenosis. PMID- 25510478 TI - The changing characteristics of hepatocellular cancer in Hawaii over time. AB - BACKGROUND: The incidence of hepatocellular cancer (HCC) is increasing, and we sought to characterize the differences and trends in HCC over 2 decades in Hawaii. METHODS: This retrospective study of 821 HCC cases analyzed risk factors, diabetes, alpha-fetoprotein (AFP), tumor characteristics, and treatment, comparing 5-year eras (1993 to 2012). RESULTS: With succeeding eras, there were fewer Asians, immigrants, and hepatitis B-related HCC. Hepatitis C, diabetes, hyperlipidemia, and body mass index have increased. Over time, more patients had normal AFP, and normal AFP was seen more often in nonviral HCC (49.6% vs 33.2%, P = .007). Over time, the proportion of patients who underwent resection or transplant was stable, but fewer patients underwent no therapy. CONCLUSIONS: Characteristics of HCC are changing, and diagnosis may be more difficult as metabolic factors are becoming more important than viral factors. AFP seems to be a less important biomarker, and clearly, better diagnostic tools will be necessary to identify HCC in the future. PMID- 25510479 TI - The Randall B. Griepp Honorary Paper. PMID- 25510480 TI - Defining frailty: "I know it when I see it". PMID- 25510481 TI - Studying classical swine fever virus: making the best of a bad virus. AB - Classical swine fever (CSF) is a highly contagious and often fatal disease that affects domestic pigs and wild boars. Outbreak of CSF can cause heavy economic losses to the pig industry. The strategies to prevent, control and eradicate CSF disease are based on containing the disease through a systematic prophylactic vaccination policy and a non-vaccination stamping-out policy. The quest for prevention, control and eradication of CSF has moved research forward in academia and industry, and has produced noticeable advances in understanding fundamental aspects of the virus replication mechanisms, virulence, and led to the development of new vaccines. In this review we summarize recent progress in CSFV epidemiology, molecular features of the genome and proteome, the molecular basis of virulence, and the development of anti-virus technologies. PMID- 25510482 TI - Pulmonary tuberculosis patients with a vitamin D deficiency demonstrate low local expression of the antimicrobial peptide LL-37 but enhanced FoxP3+ regulatory T cells and IgG-secreting cells. AB - Control of human tuberculosis (TB) requires induction and maintenance of both macrophage and T cell effector functions. We demonstrate that pulmonary TB patients with a vitamin D deficiency had significantly reduced local levels of the vitamin D-inducible antimicrobial peptide LL-37 in granulomatous lesions compared to distal parenchyma from the infected lung. Instead, TB lesions were abundant in CD3(+) T cells and FoxP3(+) regulatory T cells as well as IgG secreting CD20(+) B cells, particularly in sputum-smear positive patients with cavitary TB. Mycobacteria-specific serum IgG titers were also elevated in patients with active TB. An up-regulation of the B cell stimulatory cytokine IL 21 correlated with mRNA expression of CD20, total IgG and also IL-10 in the TB lesions. Altogether, vitamin D-deficient TB patients expressed a weak antimicrobial response but an IL-21 associated expansion of IgG-secreting B cells combined with a rise in FoxP3(+) regulatory T cells at the local site of infection. PMID- 25510483 TI - A systematic review on tracheostomy decannulation: a proposal of a quantitative semiquantitative clinical score. AB - BACKGROUND: Tracheostomy is one of the most common surgical procedures performed in critical care patient management; more specifically, ventilation through tracheal cannula allows removal of the endotracheal tube (ETT). Available literature about tracheostomy care and decannulation is mainly represented by expert opinions and no certain knowledge arises from it. METHODS: In lack of statistical requirements, a systematic and critical review of literature regarding tracheostomy tube removal was performed in order to assess predictor factors of successful decannulation and to propose a predictive score. We combined 3 terms and a literature search has been performed using the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE via Ovid SP; EMBASE via Ovid SP; EBSCO. Abstracts were independently reviewed: for those studies fitting the inclusion criteria on the basis of the title and abstract, full-text was achieved. We included studies published from January 1, 1995 until March 31, 2014; any sort of review and expert opinion has been excluded by our survey. English language restriction was applied. Ten studies have been considered eligible for inclusion in the review and were analysed further. RESULTS: Cough effectiveness and ability to tolerate tracheostomy tube capping are the most considered parameters in clinical practice; other parameters are taken into different consideration by many authors in order to proceed to decannulation. Among them, we distinguished between objective quantitative parameters and semi quantitative parameters more dependent from clinician's opinion. We then built a score (the Quantitative semi Quantitative score: QsQ score) based on selected parameters coming from literature. CONCLUSIONS: On our knowledge, this review provides the first proposal of decannulation score system based on current literature that is hypothetical and requires to be validated in daily practice. The key point of our proposal is to give a higher value to the objective parameters coming from literature compared to less quantifiable clinical ones. PMID- 25510484 TI - [Finding information to choose a training unit to become a Family and Community Nursing Resident?]. PMID- 25510485 TI - Evidence-based RT-PCR methods for the detection of the 8 most common MLL aberrations in acute leukemias. AB - MLL aberrations are detected in around 5-10% of acute myeloid and lymphatic leukemias and an additional 5% of acute myeloid leukemias show a partial internal MLL duplication (PTD). MLL rearrangements are important for therapy stratification, assessment of minimal residual disease and for targeted therapies. However, no truly evidence-based RT-PCR methods for the detection of most of these aberrations have been published yet. Based on the large data collection of MLL genomic breakpoints in acute leukemias comprising more than 1.600 cases at the Diagnostic Center for Acute Leukemias (DCAL) in Frankfurt, Germany that provide an overview over the experimentally observed fusion transcript variants, we developed RT-PCR methods for the reliable detection of the 8 most common MLL aberrations (MLL-AF4, MLL-AF6, MLL-AF9, MLL-AF10, MLL-ENL, MLL-ELL, MLL-EPS15, MLL PTD), together accounting for around 90% of MLL-r cases. The easily implementable RT-PCRs should enable a reliable detection of these MLL fusion transcripts by RT-PCR. PMID- 25510488 TI - [Theory of action on patient relationships. A different way of representing and understanding the behaviour of the family doctor in the clinic]. AB - OBJECTIVE: To identify the "theory in the action", according to the concept of Argyris and Schon, in a group of Family Doctors and to examine whether this "theory" seems to be a valid representation of their behaviour, as well as a comparison with results of other studies. DESIGN: Descriptive, cross-sectional study. SETTING: Primary Care. PARTICIPANTS: Ten Family Doctors with a minimum of 10 years experience in Health Centres of a city and its surrounding area. METHOD: Intentional sampling was used to select the participants, according to age, sex, characteristics of the Health Centre, and style of practice style. Data was collected from recordings and transcription of self-recordings, as well as from observations in the consulting room. Inductive formulation and grouping of the propositions was performed from the identification of the behaviours in the consulting room and as well as their context following the proposals of Argyris and Schon. A comparison was also made of the propositions of the participants of this study and with those in the literature. RESULTS AND DISCUSSION: The 84 propositions from the interviews were grouped into 9 topical categories, which in order of weight were: confidence / interest, prescribing medications, subjective dimension, direction, negotiation, distance, and information. The propositions of the first two topics are basically similar, while differences appear in the "theory in action" of various doctors. The propositions were comparable with the results of other studies. CONCLUSION: It is possible to formulate the theory in action of Family Doctors that appears to be an overall and coherent representation of their behaviour in the consulting room. PMID- 25510486 TI - Thymineless death in F10-treated AML cells occurs via lipid raft depletion and Fas/FasL co-localization in the plasma membrane with activation of the extrinsic apoptotic pathway. AB - The polymeric fluoropyrimidine F10 displays excellent anti-leukemia activity in pre-clinical models of acute myelogenous leukemia (AML) through dual targeting of thymidylate synthase and DNA topoisomerase 1. Here we report that F10 activates the extrinsic apoptotic pathway in AML cells by enhancing localization of Fas and Fas ligand (FasL) at the plasma membrane and while reducing overall lipid raft levels promotes Fas/FasL co-localization in remaining lipid rafts. The HMG-CoA synthase inhibitor simvastatin was synergistic with F10 and induced cell death via similar apoptotic processes. Our results are consistent with diverse processes activating a common apoptotic pathway characterized by reduced overall levels of lipid rafts and Fas/FasL co-localization in the plasma membrane, including in remaining lipid rafts which may play a role in both cell-survival and cell death signaling. PMID- 25510487 TI - Investigating the impact of Echinococcus multilocularis vesicular fluid on human cells from healthy blood donors. AB - CONTEXT AND OBJECTIVES: Alveolar echinococcosis (AE) is a severe chronic helminthic disease that mimics slow-growing liver cancer. Previous studies using murine models suggest that Echinococcus multilocularis (Em) metacestodes have developed mechanisms which impair the natural inflammatory host response. The aim of this study was to investigate in vitro the impact of Em vesicular fluid (VF) on monocytes, monocytes derived dendritic cells and lymphocytes from healthy blood donors. METHODS: First, assays were performed to investigate whether or not Em-VF influences monocyte-derived dendritic cell (MoDC) differentiation and maturation. Monocytes during differentiation and immature MoDCs were exposed to Em-VF. The effect of Em-VF was assessed using flow cytometry (CD86, CD83, CD80) and immune assays (IL-10 and TGFbeta). Second, assays were performed to investigate the interaction between Em-VF, peripheral blood monocyte cells (PBMC) and Toll-like Receptor (TLR) agonists (LPS, PolyIC, R848 and CpG). PBMC were stimulated by each of the TLR agonists with and without Em-VF. The subsequent TGFbeta production was assessed. RESULTS: Exposure to Em-VF had bearing on both differentiation and maturation of MoDC, but only partially. A decrease in the expression of co-stimulatory molecules was observed; however, levels of immune regulatory cytokines were stable. PBMC exposed simultaneously to Em-VF and LPS induced a significant increase of TGFbeta (p<0.05, Wilcoxon signed-rank test). Further experiments showed that TGFbeta production was lymphocyte-dependent. CONCLUSION: The assays performed confirmed that Em-VF influences the host immune response. However, only minor changes were observed when investigating the Em-VF impact on cells from healthy blood donors. Assays with TLR agonists suggested that co-stimulation with LPS reinforces the response of healthy blood donors exposed to Em-VF. PMID- 25510490 TI - [Not Available]. PMID- 25510489 TI - [Prevalence and associated factors of falls in community-dwelling elderly]. AB - OBJECTIVE: To estimate the prevalence of falls and to identify their associated factors in community-dwelling elderly. DESIGN: A descriptive, cross-sectional study. SETTING: Primary Health Care, Lleida. PARTICIPANTS: Six hundred and forty people aged 75 and older were included, in possession of a health card and living in single-family houses, through random sampling. Main measurements Data source comes from the survey of frailty in Lleida (FRALLE Survey). The variables used were the occurrence of falls, sociodemographic factors, health status, quality of life related to health and fear of falling. RESULTS: The prevalence of falls was 25.0% (95% CI 24.8-25.1). After multivariate analysis, basic disability (OR=2.17; 95% CI 1.32-3.58), depressive symptoms (OR=1.67; 95% CI 1.07-2.59) and fear of falling (OR=2.53; 95% CI 1.63-3.94) were the only factors independently associated with falls in the last year. CONCLUSIONS: One out of 4 older people reported at least a fall in the last year. This study demonstrates that fear of falling, depressive symptoms and basic disability are independent variables associated with previous falls. These 3 factors can lead to a flattering spiral of falling and may be potential targets for effective functioning in the context of falls. PMID- 25510491 TI - PROTEOFORMER: deep proteome coverage through ribosome profiling and MS integration. AB - An increasing amount of studies integrate mRNA sequencing data into MS-based proteomics to complement the translation product search space. However, several factors, including extensive regulation of mRNA translation and the need for three- or six-frame-translation, impede the use of mRNA-seq data for the construction of a protein sequence search database. With that in mind, we developed the PROTEOFORMER tool that automatically processes data of the recently developed ribosome profiling method (sequencing of ribosome-protected mRNA fragments), resulting in genome-wide visualization of ribosome occupancy. Our tool also includes a translation initiation site calling algorithm allowing the delineation of the open reading frames (ORFs) of all translation products. A complete protein synthesis-based sequence database can thus be compiled for mass spectrometry-based identification. This approach increases the overall protein identification rates with 3% and 11% (improved and new identifications) for human and mouse, respectively, and enables proteome-wide detection of 5'-extended proteoforms, upstream ORF translation and near-cognate translation start sites. The PROTEOFORMER tool is available as a stand-alone pipeline and has been implemented in the galaxy framework for ease of use. PMID- 25510492 TI - Mycobacterial RNA polymerase forms unstable open promoter complexes that are stabilized by CarD. AB - Escherichia coli has served as the archetypal organism on which the overwhelming majority of biochemical characterizations of bacterial RNA polymerase (RNAP) have been focused; the properties of E. coli RNAP have been accepted as generally representative for all bacterial RNAPs. Here, we directly compare the initiation properties of a mycobacterial transcription system with E. coli RNAP on two different promoters. The detailed characterizations include abortive transcription assays, RNAP/promoter complex stability assays and DNAse I and KMnO4 footprinting. Based on footprinting, we find that promoter complexes formed by E. coli and mycobacterial RNAPs use very similar protein/DNA interactions and generate the same transcription bubbles. However, we find that the open promoter complexes formed by E. coli RNAP on the two promoters tested are highly stable and essentially irreversible (with lifetimes much greater than 1 h), while the open promoter complexes on the same two promoters formed by mycobacterial RNAP are very unstable (lifetimes of about 2 min or less) and readily reversible. We show here that CarD, an essential mycobacterial transcription activator that is not found in E. coli, stabilizes the mycobacterial RNAP/open promoter complexes considerably by preventing transcription bubble collapse. PMID- 25510493 TI - Small antisense oligonucleotides against G-quadruplexes: specific mRNA translational switches. AB - G-quadruplexes (G4) are intricate RNA structures found throughout the transcriptome. Because they are associated with a variety of biological cellular mechanisms, these fascinating structural motifs are seen as potential therapeutic targets against many diseases. While screening of chemical compounds specific to G4 motifs has yielded interesting results, no single compound successfully discriminates between G4 motifs based on nucleotide sequences alone. This level of specificity is best attained using antisense oligonucleotides (ASO). Indeed, oligonucleotide-based strategies are already used to modulate DNA G4 folding in vitro. Here, we report that, in human cells, the use of short ASO to promote and inhibit RNA G4 folding affects the translation of specific mRNAs, including one from the 5'UTR of the H2AFY gene, a histone variant associated with cellular differentiation and cancer. These results suggest that the relatively high specificity of ASO-based strategies holds significant potential for applications aimed at modulating G4-motif folding. PMID- 25510495 TI - Update on RefSeq microbial genomes resources. AB - NCBI RefSeq genome collection http://www.ncbi.nlm.nih.gov/genome represents all three major domains of life: Eukarya, Bacteria and Archaea as well as Viruses. Prokaryotic genome sequences are the most rapidly growing part of the collection. During the year of 2014 more than 10,000 microbial genome assemblies have been publicly released bringing the total number of prokaryotic genomes close to 30,000. We continue to improve the quality and usability of the microbial genome resources by providing easy access to the data and the results of the pre computed analysis, and improving analysis and visualization tools. A number of improvements have been incorporated into the Prokaryotic Genome Annotation Pipeline. Several new features have been added to RefSeq prokaryotic genomes data processing pipeline including the calculation of genome groups (clades) and the optimization of protein clusters generation using pan-genome approach. PMID- 25510494 TI - Structural basis for the interaction of protein S1 with the Escherichia coli ribosome. AB - In Gram-negative bacteria, the multi-domain protein S1 is essential for translation initiation, as it recruits the mRNA and facilitates its localization in the decoding centre. In sharp contrast to its functional importance, S1 is still lacking from the high-resolution structures available for Escherichia coli and Thermus thermophilus ribosomes and thus the molecular mechanism governing the S1-ribosome interaction has still remained elusive. Here, we present the structure of the N-terminal S1 domain D1 when bound to the ribosome at atomic resolution by using a combination of NMR, X-ray crystallography and cryo-electron microscopy. Together with biochemical assays, the structure reveals that S1 is anchored to the ribosome primarily via a stabilizing pi-stacking interaction within the short but conserved N-terminal segment that is flexibly connected to domain D1. This interaction is further stabilized by salt bridges involving the zinc binding pocket of protein S2. Overall, this work provides one hitherto enigmatic piece in the 'ribosome puzzle', namely the detailed molecular insight into the topology of the S1-ribosome interface. Moreover, our data suggest novel mechanisms that have the potential to modulate protein synthesis in response to environmental cues by changing the affinity of S1 for the ribosome. PMID- 25510496 TI - A magnesium-induced RNA conformational switch at the internal ribosome entry site of hepatitis C virus genome visualized by atomic force microscopy. AB - The 5' untranslated region of hepatitis C virus (HCV) genomic RNA contains an internal ribosome entry site (IRES) element, composed of domains II-IV, which is required for cap-independent translation initiation. Little information on the 3D structure of the whole functional HCV IRES is still available. Here, we use atomic force microscopy to visualize the HCV IRES conformation in its natural sequence context, which includes the upstream domain I and the essential, downstream domains V and VI. The 574 nt-long molecule analyzed underwent an unexpected, Mg(2+)-induced switch between two alternative conformations: from 'open', elongated morphologies at 0-2 mM Mg(2+) concentration to a 'closed', comma-shaped conformation at 4-6 mM Mg(2+). This sharp transition, confirmed by gel-shift analysis and partial RNase T1 cleavage, was hindered by the microRNA miR-122. The comma-shaped IRES-574 molecules visualized at 4-6 mM Mg(2+) in the absence of miR-122 showed two arms. Our data support that the first arm would contain domain III, while the second one would be composed of domains (I-II)+(V VI) thanks to a long-range RNA interaction between the I-II spacer and the basal region of domain VI. This reinforces the previously described structural continuity between the HCV IRES and its flanking domains I, V and VI. PMID- 25510497 TI - Comparative functional characterization of the CSR-1 22G-RNA pathway in Caenorhabditis nematodes. AB - As a champion of small RNA research for two decades, Caenorhabditis elegans has revealed the essential Argonaute CSR-1 to play key nuclear roles in modulating chromatin, chromosome segregation and germline gene expression via 22G-small RNAs. Despite CSR-1 being preserved among diverse nematodes, the conservation and divergence in function of the targets of small RNA pathways remains poorly resolved. Here we apply comparative functional genomic analysis between C. elegans and Caenorhabditis briggsae to characterize the CSR-1 pathway, its targets and their evolution. C. briggsae CSR-1-associated small RNAs that we identified by immunoprecipitation-small RNA sequencing overlap with 22G-RNAs depleted in cbr-csr-1 RNAi-treated worms. By comparing 22G-RNAs and target genes between species, we defined a set of CSR-1 target genes with conserved germline expression, enrichment in operons and more slowly evolving coding sequences than other genes, along with a small group of evolutionarily labile targets. We demonstrate that the association of CSR-1 with chromatin is preserved, and show that depletion of cbr-csr-1 leads to chromosome segregation defects and embryonic lethality. This first comparative characterization of a small RNA pathway in Caenorhabditis establishes a conserved nuclear role for CSR-1 and highlights its key role in germline gene regulation across multiple animal species. PMID- 25510498 TI - T-lex2: genotyping, frequency estimation and re-annotation of transposable elements using single or pooled next-generation sequencing data. AB - Transposable elements (TEs) constitute the most active, diverse and ancient component in a broad range of genomes. Complete understanding of genome function and evolution cannot be achieved without a thorough understanding of TE impact and biology. However, in-depth analysis of TEs still represents a challenge due to the repetitive nature of these genomic entities. In this work, we present a broadly applicable and flexible tool: T-lex2. T-lex2 is the only available software that allows routine, automatic and accurate genotyping of individual TE insertions and estimation of their population frequencies both using individual strain and pooled next-generation sequencing data. Furthermore, T-lex2 also assesses the quality of the calls allowing the identification of miss-annotated TEs and providing the necessary information to re-annotate them. The flexible and customizable design of T-lex2 allows running it in any genome and for any type of TE insertion. Here, we tested the fidelity of T-lex2 using the fly and human genomes. Overall, T-lex2 represents a significant improvement in our ability to analyze the contribution of TEs to genome function and evolution as well as learning about the biology of TEs. T-lex2 is freely available online at http://sourceforge.net/projects/tlex. PMID- 25510499 TI - VectorBase: an updated bioinformatics resource for invertebrate vectors and other organisms related with human diseases. AB - VectorBase is a National Institute of Allergy and Infectious Diseases supported Bioinformatics Resource Center (BRC) for invertebrate vectors of human pathogens. Now in its 11th year, VectorBase currently hosts the genomes of 35 organisms including a number of non-vectors for comparative analysis. Hosted data range from genome assemblies with annotated gene features, transcript and protein expression data to population genetics including variation and insecticide resistance phenotypes. Here we describe improvements to our resource and the set of tools available for interrogating and accessing BRC data including the integration of Web Apollo to facilitate community annotation and providing Galaxy to support user-based workflows. VectorBase also actively supports our community through hands-on workshops and online tutorials. All information and data are freely available from our website at https://www.vectorbase.org/. PMID- 25510501 TI - Are some diets "mass murder"? PMID- 25510500 TI - Adhesin competence repressor (AdcR) from Streptococcus pyogenes controls adaptive responses to zinc limitation and contributes to virulence. AB - Altering zinc bioavailability to bacterial pathogens is a key component of host innate immunity. Thus, the ability to sense and adapt to the alterations in zinc concentrations is critical for bacterial survival and pathogenesis. To understand the adaptive responses of group A Streptococcus (GAS) to zinc limitation and its regulation by AdcR, we characterized gene regulation by AdcR. AdcR regulates the expression of 70 genes involved in zinc acquisition and virulence. Zinc-bound AdcR interacts with operator sequences in the negatively regulated promoters and mediates differential regulation of target genes in response to zinc deficiency. Genes involved in zinc mobilization and conservation are derepressed during mild zinc deficiency, whereas the energy-dependent zinc importers are upregulated during severe zinc deficiency. Further, we demonstrated that transcription activation by AdcR occurs by direct binding to the promoter. However, the repression and activation by AdcR is mediated by its interactions with two distinct operator sequences. Finally, mutational analysis of the metal ligands of AdcR caused impaired DNA binding and attenuated virulence, indicating that zinc sensing by AdcR is critical for GAS pathogenesis. Together, we demonstrate that AdcR regulates GAS adaptive responses to zinc limitation and identify molecular components required for GAS survival during zinc deficiency. PMID- 25510502 TI - Multiple victimizations before and after leaving home associated with PTSD, depression, and substance use disorder among homeless youth. AB - Exposure to multiple forms of maltreatment during childhood is associated with serious mental health consequences among youth in the general population, but limited empirical attention has focused on homeless youth-a population with markedly high rates of childhood maltreatment followed by elevated rates of street victimization. This study investigated the rates of multiple childhood abuses (physical, sexual, and emotional abuse) and multiple street victimizations (robbery, physical assault, and sexual assault) and examined their relative relationships to mental health outcomes (meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for post traumatic stress disorder [PTSD], depression, and substance use disorder) among a large (N = 601) multisite sample of homeless youth. Approximately 79% of youth retrospectively reported multiple childhood abuses (two or more types) and 28% reported multiple street victimizations (two or more types). Each additional type of street victimization nearly doubled youths' odds for meeting criteria for substance use disorder. Furthermore, each additional type of childhood abuse experienced more than doubled youths' odds for meeting criteria for PTSD. Both multiple abuses and multiple street victimizations were associated with an approximate twofold increase in meeting depression criteria. Findings suggest the need for screening, assessment, and trauma-informed services for homeless youth who consider multiple types of abuse and victimization experiences. PMID- 25510504 TI - In response to: Relation of mean platelet volume and red blood distribution width with epistaxis. PMID- 25510503 TI - HIF-1alpha restricts NF-kappaB-dependent gene expression to control innate immunity signals. AB - Hypoxia and inflammation are intimately linked. It is known that nuclear factor kappaB (NF-kappaB) regulates the hypoxia-inducible factor (HIF) system, but little is known about how HIF regulates NF-kappaB. Here, we show that HIF-1alpha represses NF-kappaB-dependent gene expression. HIF-1alpha depletion results in increased NF-kappaB transcriptional activity both in mammalian cells and in the model organism Drosophila melanogaster. HIF-1alpha depletion enhances the NF kappaB response, and this required not only the TAK-IKK complex, but also CDK6. Loss of HIF-1alpha results in an increased angiogenic response in mammalian cancer cells and increased mortality in Drosophila following infection. These results indicate that HIF-1alpha is required to restrain the NF-kappaB response, and thus prevents excessive and damaging pro-inflammatory responses. PMID- 25510505 TI - HSP47 and FKBP65 cooperate in the synthesis of type I procollagen. AB - Osteogenesis imperfecta (OI) is a genetic disorder that results in low bone mineral density and brittle bones. Most cases result from dominant mutations in the type I procollagen genes, but mutations in a growing number of genes have been identified that produce autosomal recessive forms of the disease. Among these include mutations in the genes SERPINH1 and FKBP10, which encode the type I procollagen chaperones HSP47 and FKBP65, respectively, and predominantly produce a moderately severe form of OI. Little is known about the biochemical consequences of the mutations and how they produce OI. We have identified a new OI mutation in SERPINH1 that results in destabilization and mislocalization of HSP47 and secondarily has similar effects on FKBP65. We found evidence that HSP47 and FKBP65 act cooperatively during posttranslational maturation of type I procollagen and that FKBP65 and HSP47 but fail to properly interact in mutant HSP47 cells. These results thus reveal a common cellular pathway in cases of OI caused by HSP47 and FKBP65 deficiency. PMID- 25510506 TI - A mouse model of urofacial syndrome with dysfunctional urination. AB - Urofacial syndrome (UFS) is an autosomal recessive disease with severe dysfunctional urination including urinary incontinence (UI). Biallelic mutations of HPSE2 are discovered from UFS patients, suggesting that HPSE2 is a candidate disease gene. Here, we show that deletion of Hpse2 is sufficient to cause the UFS like phenotype in mice. Hpse2 knockout mutants display a distended bladder (megacystis) phenotype and abnormal voiding behavior similar to that found in patients. While Hpse2 is largely dispensable for detrusor smooth muscle and urothelial cell fate determination, the mutants have significantly lower rates of cell proliferation than wild-type littermate controls. All Hpse2 mutants have a growth retardation phenotype and die within a month after birth. Comprehensive blood chemistry and urinalysis indicate that Hpse2 mutants have renal dysfunction and malnutrition. We provide evidence that transforming growth factor beta (Tgfbeta) signaling is attenuated at birth. However, Tgfbeta activity is significantly enhanced at later stages when the urological phenotype is severe, and the mutant bladders have accumulated excessive amount of fibrotic tissue. Together, these findings strongly suggest that Hpse2 is a causative gene of human UFS and further uncover unexpected roles of Hpse2 in bladder physiology, tissue remodeling and Tgfbeta signaling. PMID- 25510507 TI - Care provided and care setting transitions in the last three months of life of cancer patients: a nationwide monitoring study in four European countries. AB - BACKGROUND: This is an international study across four European countries (Belgium[BE], the Netherlands[NL], Italy[IT] and Spain[ES]) between 2009 and 2011, describing and comparing care and care setting transitions provided in the last three months of life of cancer patients, using representative GP networks. METHODS: General practitioners (GPs) of representative networks in each country reported weekly all non-sudden cancer deaths (+18y) within their practice. GPs reported medical end-of-life care, communication and circumstances of dying on a standardised questionnaire. Multivariate logistic regressions (BE as a reference category) were conducted to compare countries. RESULTS: Of 2,037 identified patients from four countries, four out of five lived at home or with family in their last year of life. Over 50% of patients had at least one transition in care settings in the last three months of life; one third of patients in BE, IT and ES had a last week hospital admission and died there. In the last week of life, a treatment goal was adopted for 80-95% of those having palliation/comfort as their treatment goal. Cross-country differences in end-of-life care provision included GPs in NL being more involved in palliative care (67%) than in other countries (35%-49%) (OR 1.9) and end-of-life topics less often discussed in IT or ES. Preference for place of death was less often expressed in IT and ES (32-34%) than in BE and NL (49-74%). Of all patients, 88-98% were estimated to have distress from at least one physical symptom in the final week of life. CONCLUSION: Although palliative care was the main treatment goal for most cancer patients at the end of life in all four countries, frequent late hospital admissions and the symptom burden experienced in the last week of life indicates that further integration of palliative care into oncology care is required in many countries. PMID- 25510508 TI - Lipid profile after long-term APAP in OSA patients. AB - PURPOSE: This study aimed to explore the impact of an 8-year therapy with autoadjusting positive airway pressure (APAP) on fasting lipid level in a sample of Portuguese moderate/severe obstructive sleep apnea (OSA) patients. Besides contributing to the comprehension of the complex relationship between dyslipidemia and OSA, it provided new data regarding the effectiveness of a long term APAP treatment. METHODS: Thirty-nine male patients with moderate to severe OSA were included in the study. APAP was prescribed to all patients. Fifteen patients were under lipid-lowering medication throughout the study, and another 15 patients never used lipid-lowering medication at any time during the study. Fasting morning venous blood samples were collected at three time points (baseline 6 months and 8 years) and lipids were estimated. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) 21.0 software. RESULTS: After 8 years of APAP treatment, patients presented a similar body mass index but a significantly less severe daytime sleepiness. Patients on lipid-lowering medication exhibited a higher reduction in total cholesterol than those naif from that medication, but the reduction was not statistically significant after adjusting for medication and APAP adherence. CONCLUSIONS: Long term APAP treatment improves OSA but does not seem to contribute to changes in fasting lipids. PMID- 25510509 TI - Cortical fast-spiking parvalbumin interneurons enwrapped in the perineuronal net express the metallopeptidases Adamts8, Adamts15 and Neprilysin. AB - The in situ hybridization Allen Mouse Brain Atlas was mined for proteases expressed in the somatosensory cerebral cortex. Among the 480 genes coding for protease/peptidases, only four were found enriched in cortical interneurons: Reln coding for reelin; Adamts8 and Adamts15 belonging to the class of metzincin proteases involved in reshaping the perineuronal net (PNN) and Mme encoding for Neprilysin, the enzyme degrading amyloid beta-peptides. The pattern of expression of metalloproteases (MPs) was analyzed by single-cell reverse transcriptase multiplex PCR after patch clamp and was compared with the expression of 10 canonical interneurons markers and 12 additional genes from the Allen Atlas. Clustering of these genes by K-means algorithm displays five distinct clusters. Among these five clusters, two fast-spiking interneuron clusters expressing the calcium-binding protein Pvalb were identified, one co-expressing Pvalb with Sst (PV-Sst) and another co-expressing Pvalb with three metallopeptidases Adamts8, Adamts15 and Mme (PV-MP). By using Wisteria floribunda agglutinin, a specific marker for PNN, PV-MP interneurons were found surrounded by PNN, whereas the ones expressing Sst, PV-Sst, were not. PMID- 25510510 TI - Molecular mechanisms of placebo responses in humans. AB - Endogenous opioid and non-opioid mechanisms (for example, dopamine (DA), endocannabinoids (eCB)) have been implicated in the formation of placebo analgesic effects, with initial reports dating back three decades. Besides the perspective that placebo effects confound randomized clinical trials, the information so far acquired points to neurobiological systems that when activated by positive expectations and maintained through conditioning and reward learning are capable of inducing physiological changes that lead to the experience of analgesia and improvements in emotional state. Molecular neuroimaging techniques with positron emission tomography and the selective MU-opioid and D2/3 radiotracers [(11)C]carfentanil and [(11)C]raclopride have significantly contributed to our understanding of the neurobiological systems involved in the formation of placebo effects. This line of research has described neural and neurotransmitter networks implicated in placebo responses and provided the technical tools to examine inter-individual differences in the function of placebo-responsive mechanisms, and potential surrogates (biomarkers). As a consequence, the formation of biological placebo effects is now being linked to the concept of resiliency mechanisms, partially determined by genetic factors, and uncovered by the cognitive emotional integration of the expectations created by the therapeutic environment and its maintenance through learning mechanisms. Further work needs to extend this research into clinical conditions where the rates of placebo responses are high and its neurobiological mechanisms have been largely unexplored (for example, mood and anxiety disorders, persistent pain syndromes or even Parkinson disease and multiple sclerosis). The delineation of these processes within and across diseases would point to biological targets that have not been contemplated in traditional drug development. PMID- 25510512 TI - Common polygenic variation and risk for childhood-onset schizophrenia. AB - Childhood-onset schizophrenia (COS) is a rare and severe form of the disorder, with more striking abnormalities with respect to prepsychotic developmental disorders and abnormities in the brain development compared with later-onset schizophrenia. We previously documented that COS patients, compared with their healthy siblings and with adult-onset patients (AOS), carry significantly more rare chromosomal copy number variations, spanning large genomic regions (>100 kb) (Ahn et al. 2014). Here, we interrogated the contribution of common polygenic variation to the genetic susceptibility for schizophrenia. We examined the association between a direct measure of genetic risk of schizophrenia in 130 COS probands and 103 healthy siblings. Using data from the schizophrenia and autism GWAS of the Psychiatric Genomic Consortia, we selected three risk-related sets of single nucleotide polymorphisms from which we conducted polygenic risk score comparisons for COS probands and their healthy siblings. COS probands had higher genetic risk scores of both schizophrenia and autism than their siblings (P<0.05). Given the small sample size, these findings suggest that COS patients have more salient genetic risk than do AOS. PMID- 25510513 TI - Reversal of opioid overdose syndrome in morphine-dependent rats using buprenorphine. AB - The method of choice for reversal of opioid-toxicity is administration of naloxone. This treatment can be accompanied by complications including acute lung injury, myocardial infarction, or withdrawal-syndrome (in dependent-patients). We aimed to evaluate the efficacy of buprenorphine in reversal of opioid-overdose syndrome in dependent-rats. A prospective case-control study was designed, in which a total of 30 rats were put on opioid-dependency protocol with 10 mg/kg of intra-peritoneal morphine twice daily for 10 days. After confirmation of dependency by naloxone administration, the rats were overdosed by giving 16 mg/kg of intra-peritoneal methadone. They were divided into four groups receiving naloxone (n=7; 2 mg/kg) and buprenorphine(n=8, 8, and 7 with doses of 3 mg/kg, 6 mg/kg, and 10 mg/kg), respectively. These four groups were compared regarding reversal of opioid signs/symptoms and development of withdrawal-syndrome. Rats in the first group showed signs/symptoms of opioid-withdrawal severely and with a higher frequency (P<0.001). In the groups 2-4, all doses recovered the intoxicated-rats without inducing signs/symptoms of withdrawal; however, the 3mg/kg dose reversed toxicity slower (P<0.001) and one rat in this group died later due to the re-development of signs of toxicity. Buprenorphine recovers opioid-overdose in morphine-dependent rats and bypasses the withdrawal-syndrome due to administration of naloxone. PMID- 25510514 TI - Affinities of organophosphate flame retardants to tumor suppressor gene p53: an integrated in vitro and in silico study. AB - Health concerns have been raised in regards to the environmental impact of the more frequently used organophosphate flame retardants (OPFRs). In this study, the effects of two typical OPFRs (TCPP and TPhP) on p53 gene expression in human embryo liver L02 cells were determined by quantitative real-time PCR. To better understand the relationship between molecular structural features of OPFRs and binding affinities for the tumor suppressor genes p53, an integrated experimental and in silico approach was used. The interaction of 9 OPFRs with p53 DNA fragment under simulated physiological conditions (phosphate buffer solution of pH 7.40), was explored by UV absorption spectroscopy, fluorescence spectroscopy and molecular modeling method. The binding constants of 9 OPFRs with p53 DNA fragment were determined respectively, using ethidium bromide (EB) as fluorescence probe of DNA. From docking analysis, hydrogen bonding and hydrophobic interactions were found to be the dominant interactions. Based on the observed interactions, appropriate molecular structural parameters were adopted to develop a quantitative structure-activity relationship (QSAR) model. The binding affinities of OPFRs to p53 DNA fragment were related with molecular electrostatic potential. The developed QSAR model had good robustness, predictive ability and mechanism interpretability. PMID- 25510511 TI - Durable fear memories require PSD-95. AB - Traumatic fear memories are highly durable but also dynamic, undergoing repeated reactivation and rehearsal over time. Although overly persistent fear memories underlie anxiety disorders, such as posttraumatic stress disorder, the key neural and molecular mechanisms underlying fear memory durability remain unclear. Postsynaptic density 95 (PSD-95) is a synaptic protein regulating glutamate receptor anchoring, synaptic stability and certain types of memory. Using a loss of-function mutant mouse lacking the guanylate kinase domain of PSD-95 (PSD 95(GK)), we analyzed the contribution of PSD-95 to fear memory formation and retrieval, and sought to identify the neural basis of PSD-95-mediated memory maintenance using ex vivo immediate-early gene mapping, in vivo neuronal recordings and viral-mediated knockdown (KD) approaches. We show that PSD-95 is dispensable for the formation and expression of recent fear memories, but essential for the formation of precise and flexible fear memories and for the maintenance of memories at remote time points. The failure of PSD-95(GK) mice to retrieve remote cued fear memory was associated with hypoactivation of the infralimbic (IL) cortex (but not the anterior cingulate cortex (ACC) or prelimbic cortex), reduced IL single-unit firing and bursting, and attenuated IL gamma and theta oscillations. Adeno-associated virus-mediated PSD-95 KD in the IL, but not the ACC, was sufficient to impair recent fear extinction and remote fear memory, and remodel IL dendritic spines. Collectively, these data identify PSD-95 in the IL as a critical mechanism supporting the durability of fear memories over time. These preclinical findings have implications for developing novel approaches to treating trauma-based anxiety disorders that target the weakening of overly persistent fear memories. PMID- 25510515 TI - Anterior vertebral body tethering for immature adolescent idiopathic scoliosis: one-year results on the first 32 patients. AB - PURPOSE: This retrospective chart review evaluates the clinical and radiographic outcomes of anterior vertebral body tethering (VBT) at 1-year follow-up. Anterior VBT offers a fusionless treatment option for skeletally immature patients with adolescent idiopathic scoliosis. It is a growth-modulation technique, which utilizes patients' growth to attain progressive scoliosis correction. Numerous animal models support its promise; however, clinical data remain sparse. METHODS: Clinical and radiographic data were retrospectively analyzed. We reviewed 32 patients who underwent thoracic VBT with a minimum one-year follow-up. Pertinent clinical and radiographic data were collected. ANOVA, Student's t test and Fisher's exact test were utilized to compare different time points. RESULTS: 32 patients with thoracic idiopathic scoliosis (72 % female) with a minimum one-year follow-up were identified; mean age at surgery was 12 years. All patients were considered skeletally immature pre-operatively; mean Risser score 0.42, mean Sanders score 3.2. Patients underwent tethering of an average of 7.7 levels (range 7-11). Median blood loss was 100 cc. The mean pre-operative thoracic curve magnitude was 42.8 degrees +/- 8.0 degrees which corrected to 21.0 degrees +/- 8.5 degrees on first erect and 17.9 degrees +/- 11.4 degrees at most recent. The pre-operative lumbar curve of 25.2 degrees +/- 7.3 degrees demonstrated progressive correction (first erect = 18.0 degrees +/- 7.1 degrees , 1 year = 12.6 degrees +/- 9.4 degrees , p < 0.00001). Thoracic axial rotation measured 13.4 degrees pre-operatively and 7.4 degrees at the most recent measurement (p < 0.00001). One patient experienced prolonged atelectasis which required a bronchoscopy; otherwise, no major complications were observed. CONCLUSIONS: Our early results indicate that anterior VBT is a safe and potentially effective treatment option for skeletally immature patients with idiopathic scoliosis. These patients experienced an improvement of their scoliosis with minimal major complications. However, longer term follow-up of this cohort will reveal the true benefits of this promising technique. LEVEL OF EVIDENCE: IV. PMID- 25510517 TI - How to be a good reviewer. PMID- 25510516 TI - Comparison of unilateral versus bilateral pedicle screw fixation with cage fusion in degenerative lumbar diseases: a meta-analysis. AB - PURPOSE: To compare the results between unilateral and bilateral pedicle screw (PS) fixation for the patients with degenerative lumbar diseases. METHODS: A systematic review and meta-analysis of cohort studies were conducted between unilateral PS fixation with cage fusion (unilateral group) and bilateral PS fixation with cage fusion (bilateral group) for the treatment of degenerative lumbar diseases from 1990 to June 2014. An extensive search of studies was performed in PubMed, Mediline, Embase and the Cochrane library. The following outcome measures were extracted: visual analogue scale (VAS), Oswestry disability index (ODI), Short-Form health survey (SF-36), fusion rate, complications, blood loss and operation time. Data analysis was conducted with RevMan 5.0. RESULTS: Eight RCTs involving 545 patients were included in this meta-analysis. The pooled analysis showed that there was no statistically significant difference in terms of the VAS, ODI and SF-36 scores, fusion rate [OR = 0.49 (0.23, 1.04), P = 0.06], complication rate(implant-related complication: P = 0.35, general complication rate: P = 0.71) and blood loss between two groups. However, there was less operation time in the unilateral group compared with bilateral group. Four patients (1.48 %) in unilateral group and one patient (0.36 %) in bilateral group were found cage migration, the difference did not achieve statistical significance (P = 0.213). CONCLUSIONS: As compared to bilateral PS fixation with cage fusion, unilateral PS fixation with cage fusion achieves a similar VAS, ODI and SF-36 scores, fusion rate, complications and smaller surgical trauma. However, it is still uncertain whether unilateral pedicle screw fixation with cage fusion is as effective and safe as bilateral pedicle screw fixation with cage fusion. PMID- 25510518 TI - Childhood actinic lichen planus: four cases report in Caucasian Spanish children and review of the literature. PMID- 25510522 TI - Central venous catheter-related thrombosis and thromboprophylaxis in children: a systematic review and meta-analysis: discussion. PMID- 25510520 TI - Evaluation of magnetic resonance imaging-detected tenosynovitis in the hand and wrist in early arthritis. AB - OBJECTIVE: Magnetic resonance imaging (MRI) is a sensitive method to detect inflammation in rheumatoid arthritis (RA), visualizing synovitis, bone marrow edema, and tenosynovitis. The prevalence of MRI-detected tenosynovitis and its diagnostic value in early arthritis are unclear. This study was undertaken to identify the frequency of MRI-detectable tenosynovitis at the metacarpophalangeal (MCP) and wrist joints in early arthritis and the association of these with RA and the severity of RA. METHODS: A total of 178 patients with early arthritis underwent unilateral 1.5T extremity MRI at baseline. The MCP and wrist joints were scored using the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system and Haavardsholm's tenosynovitis score. Sixty-nine patients fulfilled the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for RA during the first year and were compared with the non-RA patients. Among the RA patients, comparisons were made with regard to anti citrullinated protein antibody (ACPA) positivity and radiographic progression during year 1. RESULTS: Of all patients, 65% had MRI-detected tenosynovitis. RA patients had tenosynovitis more often than non-RA patients (75% versus 59%; P = 0.023). The flexor tendons at MCP5 and the extensor tendons at MCP2 and MCP4 and in extensor compartment I of the wrist were more frequently affected in RA patients than in other patients (odds ratios 2.8 [95% confidence interval (95% CI) 1.2-7.0], 9.1 [95% CI 1.9-42.8], 14.2 [95% CI 1.7-115.9], and 4.0 [95% CI 1.4 11.1], respectively). These associations were independent of local MRI synovitis. Specificities were all >=82%. Within the group of RA patients, tenosynovitis scores were not associated with ACPA positivity or radiographic progression. CONCLUSION: MRI-detected tenosynovitis is commonly seen in early arthritis. The flexor tendons at MCP5, the extensor tendons at MCP2 and MCP4, and the first extensor compartment of the wrist are more often affected in RA, independent of local synovitis. PMID- 25510524 TI - Keeping the pressure on mineralocorticoid replacement in congenital adrenal hyperplasia. PMID- 25510523 TI - HIV-1 transmitted drug resistance-associated mutations and mutation co-variation in HIV-1 treatment-naive MSM from 2011 to 2013 in Beijing, China. AB - BACKGROUND: Transmitted drug resistance (TDR) is an important public health issue, because TDR-associated mutation may affect the outcome of antiretroviral treatment potentially or directly. Men who have sex with men (MSM) constitute a major risk group for HIV transmission. However, current reports are scarce on HIV TDR-associated mutations and their co-variation among MSM. METHODS: Blood samples from 262 newly diagnosed HIV-positive, antiretroviral therapy (ART)-naive MSM, were collected from January 2011 and December 2013 in Beijing. The polymerase viral genes were sequenced to explore TDR-associated mutations and mutation co variation. RESULTS: A total of 223 samples were sequenced and analyzed. Among them, HIV-1 CRF01_AE are accounted for 60.5%, followed by CRF07_BC (27.8%), subtype B (9.9%), and others. Fifty-seven samples had at least one TDR-associated mutation, mainly including L10I/V (6.3%), A71L/T/V (6.3%), V179D/E (5.4%), and V106I (2.7%), with different distributions of TDR-associated mutations by different HIV-1 subtypes and by each year. Moreover, eight significant co variation pairs were found between TDR-associated mutations (V179D/E) and seven overlapping polymorphisms in subtype CRF01_AE. CONCLUSIONS: To date, this work consists the most comprehensive genetic characterization of HIV-1 TDR-associated mutations prevalent among MSM. It provides important information for understanding TDR and viral evolution among Chinese MSM, a population currently at particularly high risk of HIV transmission. PMID- 25510526 TI - Simulation study comparing exposure matching with regression adjustment in an observational safety setting with group sequential monitoring. AB - Sequential methods are well established for randomized clinical trials (RCTs), and their use in observational settings has increased with the development of national vaccine and drug safety surveillance systems that monitor large healthcare databases. Observational safety monitoring requires that sequential testing methods be better equipped to incorporate confounder adjustment and accommodate rare adverse events. New methods designed specifically for observational surveillance include a group sequential likelihood ratio test that uses exposure matching and generalized estimating equations approach that involves regression adjustment. However, little is known about the statistical performance of these methods or how they compare to RCT methods in both observational and rare outcome settings. We conducted a simulation study to determine the type I error, power and time-to-surveillance-end of group sequential likelihood ratio test, generalized estimating equations and RCT methods that construct group sequential Lan-DeMets boundaries using data from a matched (group sequential Lan-DeMets-matching) or unmatched regression (group sequential Lan-DeMets-regression) setting. We also compared the methods using data from a multisite vaccine safety study. All methods had acceptable type I error, but regression methods were more powerful, faster at detecting true safety signals and less prone to implementation difficulties with rare events than exposure matching methods. Method performance also depended on the distribution of information and extent of confounding by site. Our results suggest that choice of sequential method, especially the confounder control strategy, is critical in rare event observational settings. These findings provide guidance for choosing methods in this context and, in particular, suggest caution when conducting exposure matching. PMID- 25510525 TI - Vitamin D receptor protein is associated with interleukin-6 in human skeletal muscle. AB - Vitamin D is associated with skeletal muscle physiology and function and may play a role in intramuscular inflammation, possibly via the vitamin D receptor (VDR). We conducted two studies to examine (1) whether serum 25-hydroxyvitamin D (25OHD) and/or intramuscular VDR protein concentrations are associated with intramuscular interleukin-6 (IL-6) and/or tumor necrosis factor-alpha (TNFalpha); and (2) whether 16-week supplementation with vitamin D3 alters intramuscular IL-6 and/or TNFalpha. Potential-related signaling pathways were also examined. Muscle biopsies of 30 older, mobility-limited adults were obtained at baseline. A subset of 12 women were supplemented with either 4,000 IU/day of vitamin D3 (N = 5) or placebo (N = 7), and biopsies were repeated at 16 weeks. Serum 25OHD was measured, and intramuscular VDR, IL-6, and TNFalpha gene expressions and protein concentrations were analyzed. Baseline serum 25OHD was not associated with intramuscular IL-6 or TNFalpha gene expression or protein concentration. Baseline intramuscular VDR protein concentration, adjusted for baseline serum 25OHD, was positively associated with intramuscular IL-6 gene expression (n = 28; p = 0.04), but negatively associated with intramuscular IL-6 protein (n = 18; p = 0.03). Neither intramuscular IL-6 nor TNFalpha gene expression was different between placebo (n = 7) or vitamin D3 supplementation groups (n = 5) after 16 weeks (p = 0.57, p = 0.11, respectively). These data suggest that VDR is a better predictor than serum 25OHD concentration of intramuscular IL-6 gene and protein expressions. A similar relationship was not observed for TNFalpha expression. Further, supplementation with 4,000 IU vitamin D3 per day does not appear to affect intramuscular IL-6 or TNFalpha gene expression after 16 weeks. PMID- 25510528 TI - Cytologic and Genetic Characteristics of Endobiotic Bacteria and Kleptoplasts of Virgulinella fragilis (Foraminifera). AB - The benthic foraminifer Virgulinella fragilis Grindell and Collen 1976 has multiple putative symbioses with both bacterial and kleptoplast endobionts, possibly aiding its survival in environments from dysoxia (5-45 MUmol-O2 /L) to microxia (0-5 MUmol-O2 /L) and in the dark. To clarify the origin and function of V. fragilis endobionts, we used genetic analyses and transmission electron microscope observations. Virgulinella fragilis retained delta-proteobacteria concentrated at its cell periphery just beneath the cell membranes. Unlike another foraminifer Stainforthia spp., which retains many bacterial species, V. fragilis has a less variable bacterial community. This suggests that V. fragilis maintains a specific intracellular bacterial flora. Unlike the endobiotic bacteria, V. fragilis klepto-plasts originated from various diatom species and are found in the interior cytoplasm. We found evidence of both retention and digestion of kleptoplasts, and of fragmentation of the kleptoplastid outer membrane that likely facilitates transport of kleptoplastid products to the host. Accumulations of mitochondria were observed encircling endobiotic bacteria. It is likely that the bacteria use host organic material for carbon oxidation. The mitochondria may use oxygen available around the delta-proteobacteria and synthesize adenosine triphosphate, perhaps for sulfide oxidation. PMID- 25510529 TI - Ignorance is bliss. How parents of preschool children make sense of front-of package visuals and claims on food. AB - With growing scrutiny over how the food industry advertises products aimed toward children and fewer consumers using nutrition facts panels and ingredient lists, the fronts of food packages have become an increasingly important marketing tool to understand. Front-of-package (FOP) visual and verbal claims play a critical role in capturing consumers' attention and helping them choose foods that fit their goals. Due to only possessing emergent literacy skills, preschool children are attuned to FOP visuals while parents are able to use the visuals in combination with verbal claims to make food choices for their children. The purpose of this focus group study was to explore how parents of preschool children make sense of FOP visual and verbal claims on packaged food products that are intended for their children. Thematic analysis revealed that parents associated aspects that most appeal to their preschool children - the characters and other playful visuals - with higher sugar content and artificial ingredients. However, parents were also easily led to believe the product was healthier based on visuals of fruit, more realistic pictures, health claims, cross-branding with healthier foods, and visuals suggesting the product is more natural. While parents recognized that the health claims and some visuals may not truly mean the food is healthier, they agreed that they rarely think beyond their initial impression. The food industry needs better regulatory guidance on how to communicate flavors and ingredients on package fronts in a way that helps consumers - particularly parents wanting to encourage healthy eating habits for their young children - better match their nutrition goals. PMID- 25510530 TI - Getting my child to eat the right amount. Mothers' considerations when deciding how much food to offer their child at a meal. AB - Feeding young children successfully requires parenting skills, trust that children will eat, and nutrition and child development knowledge to ensure that foods and the amounts offered are developmentally appropriate. Mothers are often responsible for determining how much food is offered to their children; however, the influences on mothers' decisions regarding how much to offer their children- their motivations, goals for feeding and child consumption--have not been investigated. Study aims included gathering qualitative data regarding mothers' decisional processes related to preparing a dinner meal plate for her preschooler. Low income mothers (n = 15 African American and n = 15 Latina mothers) were recruited from preschools in the Denver, CO metropolitan area to participate in semi-structured interviews. Mothers prepared a plate for their preschooler and were asked about influences on their decisions about portion sizes and their expectations for children's eating. Data were coded by 2 independent coders using a consensus coding process and analyzed by investigators. Three themes emerged: (1) portion sizes differ for children who are "good" eaters and "picky" eaters; (2) mothers know the "right amounts" to serve their child; and (3) mothers have emotional investments in their children's eating. Some influencing factors were child-centered (e.g. child's likes and dislikes, "picky" and "good" eaters, and foods previously eaten in the day) and some related to adult expectations and concerns (nutrient content and waste). Interventions focusing on portion size may be more effective if tailored to the mothers' perceptions regarding her child's eating characteristics. PMID- 25510531 TI - Effects of polydextrose on different levels of energy intake. A systematic review and meta-analysis. AB - INTRODUCTION: Dietary fibers help to control energy intake and reduce the risk of developing obesity. Recent studies show that the consumption of polydextrose reduces energy intake at a subsequent meal. In this systematic review and meta analysis we examine the subsequent effects of polydextrose on different levels of energy intake (EI). METHOD: The review followed the PRISMA methodology. Meta analyses were expressed as Standardized Mean Difference (SMD). A linear regression approach was used to model the relationship between the polydextrose dose and the different levels of EI expressed as a relative change (%). RESULTS: All the studies included in this review administered polydextrose as part of a mid-morning snack. Six studies were included in the analysis of EI at an ad libitum lunch; and three were included in the analysis of EI during the rest of the day, as well as total daily EI. The meta-analysis showed that the consumption of polydextrose is associated with a reduction in EI at lunch time (SMD = 0.35; P <0.01; I(2) = 0). The dose of polydextrose consumed correlated significantly with this reduction in EI, EILunch (%) = -0.67 Polydextrose (g/day) (R(2) = 0.80; P <0.01). The meta-analysis of EI during the rest of the day and daily EI did not show any difference. Nevertheless, the regression equation indicates that there is a dose-dependent effect on the reduction of daily EI, EIDaily (%) = -0.35 * Polydextrose (g/day) (R(2) = 0.68; P <0.05). Sex-specific results are consistent with results for the whole group. CONCLUSION: The studies included in this meta analysis support the notion that the consumption of polydextrose reduces voluntary energy intake at a subsequent meal. Furthermore, this reduction in energy intake occurs in a dose-dependent manner. PMID- 25510532 TI - Outcomes and predictors of mortality after transcatheter aortic valve implantation: results of the Brazilian registry. AB - OBJECTIVE: The study sought to evaluate outcomes and predictors of mortality after transcatheter aortic valve implantation (TAVI). BACKGROUND: TAVI registries can reliably address outcomes and issues that adversely affect results in real life. METHODS: All endpoints and complications were analyzed according to Valve Academic Research Consortium-2 criteria. RESULTS: Between January 2008 and January 2013, 418 patients underwent TAVI in 18 centers and were included in the Brazilian registry. The transfemoral approach was used in 96.2% of the procedures. The CoreValve and Sapien XT prosthesis were used in 360 (86.1%) and 58 (13.9%) cases, respectively. All-cause mortality at 30 days and 1 year were 9.1 and 21.5%. Chronic obstructive pulmonary disease (COPD) (HR: 3.50), acute kidney injury (AKI) (HR: 3.07), stroke (HR: 2.71) and moderate/severe paravalvular regurgitation (PVR) (HR: 2.76) emerged as independent predictors of overall mortality. COPD (OR: 3.00), major vascular complications (OR: 7.99) and device malpositioning (OR: 6.97) were predictors of early (<=30 days) mortality, while COPD (HR: 2.68), NYHA class III/IV (HR: 3.04), stroke (HR: 4.15), AKI (HR: 2.44) and moderate/severe PVR (HR: 3.20) impacted late (>30 days) mortality. The use of transesophageal echocardiogram (TEE) to monitor the procedure was found to be a protective factor against overall (HR: 0.57) and late (HR: 0.47) mortality. CONCLUSION: This multicenter registry reflected a real-life national TAVI experience. Comorbidities, periprocedural complications and moderate/severe PVR were associated with increased mortality and the use of TEE to monitor the procedure acted as a protective factor. PMID- 25510533 TI - Outcomes of chronic hypotony following trabeculectomy. PMID- 25510534 TI - Band engineering for novel two-dimensional atomic layers. AB - The discovery of graphene has sparked much interest in science and lead to the development of an ample variety of novel two-dimensional (2D) materials. With increasing research interest in the field of 2D materials in recent years, the researchers have shifted their focus from the synthesis to the modification of 2D materials, emphasizing their electronic structures. In this review, the possibilities of altering the band structures are discussed via three different approches: (1) alloying 2D materials, so called ternary 2D materials, such as hexagonal carbonized boron nitrides (h-BCN) and transition metal dichalcogenides (TMDs) ternary materials; (2) stacking 2D materials vertically, which results in 2D heterostructures named van der Waals (vdW) solids (using hexagonal boron nitrides (h-BN)/graphene and TMDs stacking as examples), and growing lateral TMDs heterostructrues; (3) controlling the thickness of 2D materials, that is, the number of layers. The electronic properties of some 2D materials are very sensitive to the thickness, such as in TMDs and black phosphorus (BP). The variations of band structures and the resulting physical properties are systematically discussed. PMID- 25510535 TI - Cost analysis of spinal and general anesthesia for the surgical treatment of lumbar spondylosis. AB - Lumbar spine surgery is typically performed under general anesthesia, although spinal anesthesia can also be used. Given the prevalence of lumbar spine surgery, small differences in cost between the two anesthetic techniques have the potential to make a large impact on overall healthcare costs. We sought to perform a cost comparison analysis of spinal versus general anesthesia for lumbar spine operations. Following Institutional Review Board approval, a retrospective cohort study was performed from 2009-2012 on consecutive patients undergoing non instrumented, elective lumbar spine surgery for spondylosis by a single surgeon. Each patient was evaluated for both types of anesthesia, with the decision for anesthetic method being made based on a combination of physical status, anatomical considerations, and ultimately a consensus agreement between patient, surgeon, and anesthesiologist. Patient demographics and clinical characteristics were compared between the two groups. Operating room costs were calculated whilst blinded to clinical outcomes and reported in percentage difference. General anesthesia (n=319) and spinal anesthesia (n=81) patients had significantly different median operative times of 175 +/- 39.08 and 158 +/- 32.75 minutes, respectively (p<0.001, Mann-Whitney U test). Operating room costs were 10.33% higher for general anesthesia compared to spinal anesthesia (p=0.003, Mann Whitney U test). Complications of spinal anesthesia included excessive movement (n=1), failed spinal attempt (n=3), intraoperative conversion to general anesthesia (n=2), and a high spinal level (n=1). In conclusion, spinal anesthesia can be performed safely in patients undergoing lumbar spine surgery. It has the potential to reduce operative times, costs, and possibly, complications. Further prospective evaluation will help to validate these findings. PMID- 25510536 TI - Microvascular decompression for hemifacial spasm secondary to vertebrobasilar dolichoectasia: surgical strategies, technical nuances and clinical outcomes. AB - Hemifacial spasm (HFS) due to direct compression of the facial nerve by a dolichoectatic vertebrobasilar artery is rare. Vessels are often non-compliant and tethered by critical brainstem perforators. We set out to determine surgical strategies and outcomes for this challenging disease. All patients undergoing surgery for HFS secondary to vertebrobasilar dolichoectasia were reviewed. Hospital records, clinic notes and radiographic imaging were collected for outcome measures. Seventeen patients (eight males, nine females) were identified. Sixteen patients (94%) were treated with Teflon pledgets (DuPont, Wilmington, DE, USA) and one (6%) patient had a vascular sling placed around a severely diseased vertebral artery. All patients had significant reduction in symptoms and 82% of patients had complete resolution of symptoms (average follow-up: 41.4 months). One patient suffered persistent facial nerve paresis and swallowing difficulty. Two other patients suffered a 1 point decrease in the House-Brackmann facial nerve grading scale. Four patients (23%) required re-operation (infection, cerebrospinal fluid leak, and two patients with delayed recurrence of HFS). Of the latter, one patient required repositioning of a Teflon pledget and another patient underwent a sling decompression. There were no perioperative strokes or death. Excellent relief of symptoms with acceptable preoperative morbidity can be achieved using Teflon pledgets alone in most cases. In recalcitrant cases, sling transposition can be used to further augment the decompression. Careful attention must be paid to prevent vascular kinking and preserve brainstem perforators. PMID- 25510538 TI - Inclusion body myositis: a review of clinical and genetic aspects, diagnostic criteria and therapeutic approaches. AB - Inclusion body myositis is the most common myopathy in patients over the age of 40 years encountered in neurological practice. Although it is usually sporadic, there is increasing awareness of the influence of genetic factors on disease susceptibility and clinical phenotype. The diagnosis is based on recognition of the distinctive pattern of muscle involvement and temporal profile of the disease, and the combination of inflammatory and myodegenerative changes and protein deposits in the muscle biopsy. The diagnostic importance of immunohistochemical staining for major histocompatibility complex I and II antigens, for the p62 protein, and of the recently identified anti-cN1A autoantibody in the serum, are discussed. The condition is generally poorly responsive to conventional immune therapies but there have been relatively few randomised controlled trials and most of these have been under-powered and of short duration. There is an urgent need for further well-designed multicentre trials of existing and novel therapies that may alter the natural history of the disease. PMID- 25510537 TI - Predictors of malignant brain edema in middle cerebral artery infarction observed on CT angiography. AB - Patients with middle cerebral artery (MCA) infarction accompanied by MCA occlusion with or without internal carotid artery (ICA) occlusion have a poor prognosis, as a result of brain cell damage caused by both the infarction and by space-occupying and life-threatening edema formation. Multiple treatments can reduce the likelihood of edema formation, but tend to show limited efficacy. Decompressive hemicraniectomy with duroplasty has been promising for improving functional outcomes and reducing mortality, particularly improved functional outcomes can be achieved with early decompressive surgery. Therefore, identifying patients at risk for developing fatal edema is important and should be performed as early as possible. Sixty-four patients diagnosed with major MCA infarction with MCA occlusion within 8 hours of symptom onset were retrospectively reviewed. Early clinical, laboratory, and computed tomography angiography (CTA) parameters were analyzed for malignant brain edema (MBE). Twenty of the 64 patients (31%) had MBE, and the clinical outcome was poor (3month modified Rankin Scale >2) in 95% of them. The National Institutes of Health Stroke Scale (NIHSS) score, Alberta Stroke Program Early Computed Tomography Score, Clot Burden Score, and Collateral Score (CS) showed statically significant differences in both groups. Multivariable analyses adjusted for age and sex identified the independent predictors of MBE: NIHSS score >18 (odds ratio [OR]: 4.4, 95% confidence interval [CI]: 1.2-16.0, p=0.023) and CS on CTA <2 (OR: 7.28, 95% CI: 1.7-30.3,p=0.006). Our results provide useful information for selecting patients in need of aggressive treatment such as decompressive surgery. PMID- 25510539 TI - Underlying effect of age on outcome differences in arteriovenous malformation associated intracerebral hemorrhage. AB - Brain arteriovenous malformations (AVM) are the most common cause of intracerebral hemorrhage (ICH) in young adults. Although previous studies have found that the mortality and morbidity of ICH due to AVM (AVM-ICH) is lower than in spontaneous ICH, it is unclear whether the more favorable prognosis is directly related to the presence of the vascular malformation. We included 34 patients with AVM-ICH and 187 with spontaneous intracerebral hemorrhage (sICH) due to either hypertension or cerebral amyloid angiopathy. Patient data were obtained from the prospective Intracerebral Hemorrhage Outcomes Project, which enrolls ICH patients admitted to Columbia University Medical Center. Using ICH etiology (AVM-ICH or sICH) and previously verified predictors of ICH outcome, two multivariate analyses were performed with and without age to compare the odds of death at 3 months and the functional outcome. Although mortality in AVM-ICH group was lower than the sICH group (20.6% versus 43.3%, respectively), this value was only significant when age was excluded (p=0.017) and lost its significance when we controlled for age (p=0.157). There was an analogous loss of significance with functional outcome using the modified Rankin Scale. In conclusion, our data suggests that the previously observed lower case fatality rate and more favorable functional outcomes in the AVM-ICH group compared to the sICH group may largely be the result of age. PMID- 25510540 TI - alpha-thalassemia-associated hydrops fetalis: A rare cause of thyrotoxic cardiomyopathy. AB - alpha degrees -thalassemia is a well-known cause of hydrops fetalis in South-East Asia and can be detected in utero. We report a very rare case of thyrotoxic cardiomyopathy associated with hyperplacentosis secondary to alpha degrees thalassemia-associated hydrops fetalis. A 22-year-old primigravida with microcytic anemia presented at 27 weeks' gestation with pre-eclampsia, hyperthyroidism and cardiac failure. Serum beta-human chorionic gonadotrophin was markedly elevated and abdominal ultrasound revealed severe hydropic features and enlarged placenta. Serum beta-human chorionic gonadotrophin, cardiac function and thyroid function tests normalized after she delivered a macerated stillbirth. Histopathology of the placenta showed hyperplacentosis. Blood DNA analysis revealed that both patient and husband have the alpha degrees -thalassemia trait. This case illustrates a very atypical presentation of alpha degrees -thalassemia associated hydrops fetalis and the importance of early prenatal diagnosis of alpha-thalassemia in women of relevant ethnic origin with microcytic anemia so that appropriate genetic counseling can be provided to reduce maternal morbidity and the incidence of hydrops fetalis. PMID- 25510541 TI - Adaptation of an outbreaking insect defoliator to chronic nutritional stress. AB - During insect outbreaks, the high number of individuals feeding on its host plant causes a depletion of the food source. Reduced availability and decreased quality of nutrients negatively influence life-history traits of insects driving them to develop adaptive strategies to persist in the environment. In a laboratory experiment with three repetitions, we tested the effect of chronic nutritional stress on spruce budworm performance during three generations to determine the adaptive strategies employed by the insect to deal with a selection pressure produced by low-quality diet. Our results show that all tested life-history traits (mortality, developmental time, pupal mass, growth rate and female fecundity) but female fertility were negatively influenced by the low-quality diet simulating food depletion during outbreak conditions. However, especially females in the third generation under chronic nutritional stress show an adaptive response in life-history traits when compared to those reared only one generation on low-quality diet. Larval developmental time significantly decreased and pupal mass, growth rate and fecundity significantly increased. The study demonstrates the capacity of spruce budworm to react to chronic nutritional stress with adaptations that may be caused by epigenetic parental effects. This information can help to understand the course of an outbreak especially at peak densities and during the collapse. PMID- 25510542 TI - Threatening social context facilitates pain-related fear learning. AB - This study investigated the effects of a threatening and a safe social context on learning pain-related fear, a key factor in the development and maintenance of chronic pain. We measured self-reported pain intensity, pain expectancy, pain related fear (verbal ratings and eyeblink startle responses), and behavioral measures of avoidance (movement-onset latency and duration) using an established differential voluntary movement fear conditioning paradigm. Participants (N = 42) performed different movements with a joystick: during fear acquisition, movement in one direction (CS+) was followed by a painful stimulus (pain-US) whereas movement in another direction (CS-) was not. For participants in the threat group, an angry face was continuously presented in the background during the task, whereas in the safe group, a happy face was presented. During the extinction phase the pain-US was omitted. As compared to the safe social context, a threatening social context led to increased contextual fear and facilitated differentiation between CS+ and CS- movements regarding self-reported pain expectancy, fear of pain, eyeblink startle responses, and movement-onset latency. In contrast, self-reported pain intensity was not affected by social context. These data support the modulation of pain-related fear by social context. PERSPECTIVE: A threatening social context leads to stronger acquisition of (pain related) fear and simultaneous contextual fear but does not affect pain intensity ratings. This knowledge may aid in the prevention of chronic pain and anxiety disorders and shows that social context might modulate pain-related fear without immediately affecting pain intensity itself. PMID- 25510543 TI - Pressure selected reactivity and kinetics deduced from photoinduced dissociation of ethylene glycol. AB - The photon-induced reactivity of liquid ethylene glycol (EG) was investigated in a diamond anvil cell at pressures up to ~4 GPa and ambient temperature. The near UV radiation at lambda = 350 nm was employed to photodissociate EG via the two photon absorption processes. The reaction evolution was monitored as a function of time and the reaction products were characterized by using in situ FTIR spectroscopy. At low initial loading pressures, the IR spectra show two distinctive sets of profile evaluations indicating sequential photoinduced chemical reactions, which are designated as primary and secondary photochemical processes, respectively. By careful examination of the characteristic IR bands and possible reaction pathways, over ten species as the primary and secondary reaction products were unambiguously identified. Significantly, we found that one of the photodissociation product CO2 forms specific clathrate hydrate structures or clusters that are both time- and pressure-dependent, indicating interesting and unique sequestration behavior of CO2 at high pressures. Quantitative analysis on selective reaction products allows detailed reaction kinetics involving competitive reaction channels to be probed. In particular, the type and quantity of reaction products as well as the kinetics were found highly pressure dependent. Moreover, the pressure variation of the system along the reaction progression allows the interpretation of possible reaction mechanisms of photodissociation of EG under high pressures. PMID- 25510545 TI - Environmental parameters influence on the dynamics of total and pathogenic Vibrio parahaemolyticus densities in Crassostrea virginica harvested from Mexico's Gulf coast. AB - The influence of environmental parameters on the total and pathogenic Vibrio parahaemolyticus seasonal densities in American oysters (Crassostrea virginica) was evaluated for 1 year. Harvesting site A yielded the highest mean densities of V. parahaemolyticus tlh+, tdh+/trh-, tdh-/trh+ and tdh+/trh+ during spring season at 2.57, 1.74, 0.36, and -0.40 log10 MPN/g, respectively, and tdh+/orf8+ during winter season (0.90 log10 MPN/g). V. parahaemolyticus tlh+ densities were associated to salinity (R(2)=0.372, P<0.022), tdh+/trh+ to turbidity (R(2)=0.597, P<0.035), and orf8+ to temperature, salinity, and pH (R(2)=0.964, P<0.001). The exposure to salinity and temperature conditions during winter and spring seasons regulated the dynamics of V. parahaemolyticus harboring potentially pathogenic genotypes within the oyster. The adaptive response of V. parahaemolyticus to seasonal environmental changes may lead to an increase in survival and virulence, threatening the seafood safety and increasing the risk of illness. PMID- 25510544 TI - Assessment of the tautomeric population of benzimidazole derivatives in solution: a simple and versatile theoretical-experimental approach. AB - Herein, we present a simple and versatile theoretical-experimental approach to assess the tautomeric distribution on 5(6)-aminobenzimidazole (5(6)-ABZ) derivatives in solution via one-photon absorption. The method is based on the optimized weighted sum of the theoretical spectra of the corresponding tautomers. In this article we show how the choice of exchange-correlation functional (XCF) employed in the calculations becomes crucial for the success of the approach. After the systematic analysis of XCFs with different amounts of exact-exchange we found a better performance for B3LYP and PBE0. The direct test of the proposed method on omeprazole, a well-known 5(6)-benzimidazole based pharmacotherapeutic, demonstrate its broader applicability. The proposed approach is expected to find direct applications on the tautomeric analysis of other molecular systems exhibiting similar tautomeric equilibria. PMID- 25510546 TI - Depositional record of trace metals and degree of contamination in core sediments from the Mandovi estuarine mangrove ecosystem, west coast of India. AB - The concentrations of seven trace metals (Fe, Mn, Cu, Cr, Co, Pb and Zn) in three sediment cores were analysed to assess the depositional trends of metals and their contamination level in the Mandovi estuary, west coast of India. All sediment cores showed enrichment of trace metals in the upper part of core sediments and decrease in concentration with depth, suggesting excess of anthropogenic loading (including mining activities) occurred during the recent past. Scanning electron microscope (SEM) images distinguished the shape, size and structure of particles derived from lithogenic and anthropogenic sources in core sediments. The geo-accumulation index (I(geo)) values indicate that Mandovi estuary is 'moderately polluted' with Pb, whereas 'unpolluted to moderately polluted' with Fe, Mn, Cu, Cr, Co and Zn. The comparative analysis of trace metals revealed that Fe and Mn were highly enriched in the Mandovi estuary compared to all other Indian estuaries. PMID- 25510547 TI - Studies on crude oil removal from pebbles by the application of biodiesel. AB - Oil residues along shorelines are hard to remove after an oil spill. The effect of biodiesel to eliminate crude oil from pebbles alone and in combination with petroleum degrading bacteria was investigated in simulated systems. Adding biodiesel made oil detach from pebbles and formed oil-biodiesel mixtures, most of which remained on top of seawater. The total petroleum hydrocarbon (TPH) removal efficiency increased with biodiesel quantities but the magnitude of augment decreased gradually. When used with petroleum degrading bacteria, the addition of biodiesel (BD), nutrients (NUT) and BD+NUT increased the dehydrogenase activity and decreased the biodegradation half lives. When BD and NUT were replenished at the same time, the TPH removal efficiency was 7.4% higher compared to the total improvement of efficiency when BD and NUT was added separately, indicating an additive effect of biodiesel and nutrients on oil biodegradation. PMID- 25510549 TI - Spatial and vertical distributions of heavy metals and their potential toxicity levels in various beach sediments from high-background-radiation area, Kerala, India. AB - The spatial and vertical distribution of heavy metals and the sediment characteristics of beaches in Kerala, India (the upper surface sediments and the first, second and third one-foot-thick strata) were assessed in this study. The concentrations of most of the studied metals were highest at sampling site S1 (Cochin). The measured concentrations were compared with background and toxicological reference values. The results show that definite adverse biological effects are possible at most of the sampling sites due to the high Pb levels. Three different indexes were calculated to investigate the potential toxicity level. Most of the studied metals and all calculated indexes were highest in the third foot of sediment. Multivariate statistical analyses were performed and suggested that particular heavy metals, e.g., Pb, Cd, Cr and Ni, may represent contamination from a common source. The Cd and Pb concentrations and all the calculated index values show a relationship with the content of organic matter. The results of the present study suggest the recommendation that a systematic analysis is needed to monitor heavy metal levels in the studied area. PMID- 25510548 TI - Natural radioactivity level in beach sand along the coast of Xiamen Island, China. AB - The activity concentration of (40)K, (232)Th and (226)Ra was determined in beach sand samples collected from Xiamen Island, China using gamma ray spectrometry. The activity concentrations of (40)K, (232)Th and (226)Ra in the beach sand range from 197.4 to 487.6, 6.5 to 41.4 and 7.9 to 25.7 Bq kg(-1) with the mean of 401.0, 11.3 and 14.1 Bq kg(-1), respectively, which are lower than the averages of Chinese soil and world soil. The radium equivalent activity values in all beach sand samples are lower than the recommended limit of 370 Bq kg(-1). The external hazard index values are less than unity. The outdoor air absorbed dose rate and the corresponding annual effective dose rate of beach sand investigated are lower than the worldwide average. PMID- 25510550 TI - Implications of heterogeneous distributions of organisms on ballast water sampling. AB - Ballast water sampling is one of the problems still needing investigation in order to enforce the D-2 Regulation of the International Convention for the Control and Management of Ship Ballast Water and Sediments. Although statistical "representativeness" of the sample is an issue usually discussed in the literature, neither a definition nor a clear description of its implications are presented. In this context, we relate it to the heterogeneity of the distribution of organisms in ballast water and show how to specify compliance tests under different models based on the Poisson and negative binomial distributions. We provide algorithms to obtain minimum sample volumes required to satisfy fixed limits on the probabilities of Type I and II errors. We show that when the sample consists of a large number of aliquots, the Poisson model may be employed even under moderate heterogeneity of the distribution of the organisms in the ballast water tank. PMID- 25510551 TI - Constructions of masculinity and femininity and sexual risk negotiation practices among women in urban Ghana. AB - Using qualitative data gathered through in-depth interviews with women in Accra, Ghana, this paper explores narratives of masculinity and femininity and sexual risk negotiation practices among women. While women framed 'proper' masculinity in terms of stereotypical reproductive norms, they also acknowledged the fluidity and multiplicity of masculinities. Femininity was more uniformly characterised in terms of physical attractiveness and beauty, responsibility and reproduction. These features, especially those related to adherence to morally and socially appropriate sexual norms (e.g., menstrual and bodily hygiene, unplanned pregnancy etc.), influenced women's approach to sexual negotiation. Work aiming to support women to negotiate sex safely needs to pay attention to their notions of gender and practices of sexual negotiation. PMID- 25510552 TI - Social inequalities in young children's sports participation and outdoor play. AB - BACKGROUND: Research on social inequalities in sports participation and unstructured physical activity among young children is scarce. This study aimed to assess the associations of family socioeconomic position (SEP) and ethnic background with children's sports participation and outdoor play. METHODS: We analyzed data from 4726 ethnically diverse 6-year-old children participating in the Generation R Study. Variables were assessed by parent-reported questionnaires when the child was 6 years old. Low level of outdoor play was defined as outdoor play <1 hour per day. Series of multiple logistic regression analyses were performed to assess associations of family SEP and ethnic background with children's sports participation and outdoor play. RESULTS: Socioeconomic inequalities in children's sports participation were found when using maternal educational level (p < 0.05), paternal educational level (p < 0.05), maternal employment status (p < 0.05), and household income (p < 0.05) as family SEP indicator (less sports participation among low SEP children). Socioeconomic inequalities in children's outdoor play were found when using household income only (p < 0.05) (more often outdoor play <1 hour per day among children from low income household). All ethnic minority children were significantly more likely to not to participate in sports and play outdoor <1 hour per day compared with native Dutch children. Adjustment for family SEP attenuated associations considerably, especially with respect to sports participation. CONCLUSION: Low SEP children and ethnic minority children are more likely not to participate in sports and more likely to display low levels of outdoor play compared with high SEP children and native Dutch children, respectively. In order to design effective interventions, further research, including qualitative studies, is needed to explore more in detail the pathways relating family SEP and ethnic background to children's sports participation and outdoor play. PMID- 25510553 TI - FoxO1 negatively regulates leptin-induced POMC transcription through its direct interaction with STAT3. AB - FoxO1, which is up-regulated during early stages of diet-induced leptin resistance, directly interacts with STAT3 and prevents STAT3 from binding to specificity protein 1 (SP1)-pro-opiomelanocortin (POMC) promoter complex, and thereby inhibits STAT3-mediated regulation of POMC transcription. FoxO1 also binds directly to the POMC promoter and negatively regulates its transcription. The present study aims to understand the relative contribution of the two interactions in regulating POMC expression. We studied the structural requirement of FoxO1 for its interaction with STAT3 and POMC promoter, and tested the inhibitory action of FoxO1 mutants by using biochemical assays, molecular biology and computer modelling. FoxO1 mutant with deletion of residues Ala137-Leu160 failed to bind to STAT3 or inhibit STAT3-mediated POMC activation, although its binding to the POMC promoter was unaffected. Further analysis mapped Gly140 Leu160 to be critical for STAT3 binding. The identified region Gly140-Leu160 was conserved among mammalian FoxO1 proteins, and showed a high degree of sequence identity with FoxO3, but not FoxO4. Consistently, FoxO3 could interact with STAT3 and inhibit POMC promoter activity, whereas FoxO4 could not bind to STAT3 or affect POMC promoter activity. We further identified that five residues (Gln145, Arg147, Lys148, Arg153 and Arg154) in FoxO1 were necessary in FoxO1-STAT3 interaction, and mutation of these residues abolished its interaction with STAT3 and inhibition of POMC promoter activity. Finally, a FoxO1-STAT3 interaction interface model generated by computational docking simulations confirmed that the identified residues of FoxO1 were in close proximity to STAT3. These results show that FoxO1 inhibits STAT3-mediated leptin signalling through direct interaction with STAT3. PMID- 25510554 TI - Expiratory flow rate, breath hold and anatomic dead space influence electronic nose ability to detect lung cancer. AB - BACKGROUND: Electronic noses are composites of nanosensor arrays. Numerous studies showed their potential to detect lung cancer from breath samples by analysing exhaled volatile compound pattern ("breathprint"). Expiratory flow rate, breath hold and inclusion of anatomic dead space may influence the exhaled levels of some volatile compounds; however it has not been fully addressed how these factors affect electronic nose data. Therefore, the aim of the study was to investigate these effects. METHODS: 37 healthy subjects (44 +/- 14 years) and 27 patients with lung cancer (60 +/- 10 years) participated in the study. After deep inhalation through a volatile organic compound filter, subjects exhaled at two different flow rates (50 ml/sec and 75 ml/sec) into Teflon-coated bags. The effect of breath hold was analysed after 10 seconds of deep inhalation. We also studied the effect of anatomic dead space by excluding this fraction and comparing alveolar air to mixed (alveolar + anatomic dead space) air samples. Exhaled air samples were processed with Cyranose 320 electronic nose. RESULTS: Expiratory flow rate, breath hold and the inclusion of anatomic dead space significantly altered "breathprints" in healthy individuals (p < 0.05), but not in lung cancer (p > 0.05). These factors also influenced the discrimination ability of the electronic nose to detect lung cancer significantly. CONCLUSIONS: We have shown that expiratory flow, breath hold and dead space influence exhaled volatile compound pattern assessed with electronic nose. These findings suggest critical methodological recommendations to standardise sample collections for electronic nose measurements. PMID- 25510555 TI - The role of mathematical modelling in modern criminology: comment on "Statistical physics of crime: a review" by M.R. D'Orsogna and M. Perc. PMID- 25510556 TI - Total synthesis of ramonanins A-D. AB - The first total synthesis of the ramonanin family of lignan natural products is described. The short synthesis involves a 2,5-diaryl-3,4-dimethylene tetrahydrofuran intermediate, which participates in an unexpectedly facile Diels Alder dimerization, generating all four natural products. Insights into the reactivity and stereoselectivity of the key dimerization are provided through computational studies employing B3LYP/6-31G(d) and M06-2X/6-31G(d) model chemistries. PMID- 25510558 TI - Oxidative addition of SiH4 and GeH4 to Ir(PPh3)2(CO)Cl: structural and spectroscopic evidence for the formation of products derived from cis oxidative addition. AB - X-ray diffraction studies demonstrate that oxidative addition of SiH(4) to Ir(PPh(3))(2)(CO)Cl yields Ir(PPh(3))(2)(CO)(Cl)(SiH(3))H, which features a cis arrangement of the SiH(3) and H ligands in which H is located trans to CO, rather than trans to Cl as originally reported. (1)H NMR spectroscopic studies indicate that oxidative addition of GeH(4) to Ir(PPh(3))(2)(CO)Cl also occurs in a cis manner but results in the formation of two isomers of Ir(PPh(3))(2)(CO)(Cl)(GeH(3))H, which are related by H being trans to either CO or Cl. PMID- 25510557 TI - Poly-traumatization and harmful behaviors in a sample of emergency department Psychiatric Intake Response Center youth. AB - The purpose of this study is to examine risk factors for poly-traumatization, and the impact of poly-traumatization on harmful behaviors (suicidal, self-harm, and violent), among a group of pediatric patients presenting at an emergency department's psychiatric intake response center. We employed a retrospective medical chart review in a children's hospital for a 2-year span (N=260). The study employed 2 statistical analyses. The first analysis used multinomial logistic regression to model the odds of harmful behaviors comparing increasing numbers of co-occurring traumatization types. The second analysis employed latent class modeling techniques in three ways to (a) define different poly traumatization populations, (b) examine the relationship between predictors and class assignment, and (c) examine the relationship between class assignment and harmful behavioral outcomes. About 62% of the sample presented with at least 1 traumatization type and about 50% one harmful behavior type. Compared to those with 1, 2, or 3 traumatization types, patients with 4 or more traumatization types have higher odds of harmful behaviors. The latent class analysis revealed 2 populations: High serious victimization and minimal traumatization. History of family mental health issues was the only significant predictor of class membership. Class membership was associated with all of the harmful behavioral outcome categories. These findings support consideration of poly-traumatization as a risk factor for the high occurrence of harmful behaviors in this sample of pediatric psychiatric patients and that history of family mental health issues may contribute to the high co-occurrence of poly-traumatization. PMID- 25510560 TI - Xanthine oxidase inhibitory activity of extracts prepared from Polygonaceae species. AB - The xanthine oxidase (XO) inhibitory activity of aqueous and organic extracts of 27 selected species belonging in five genera (Fallopia, Oxyria, Persicaria, Polygonum and Rumex) of the family Polygonaceae occurring in the Carpathian Basin were tested in vitro. From different plant parts (aerial parts, leaves, flowers, fruits and roots), a total of 196 extracts were prepared by subsequent extraction with methanol and hot H2O and solvent-solvent partition of the MeOH extract yielding n-hexane, chloroform and 50% MeOH subextracts. It was found that the chloroform subextracts and/or the remaining 50% MeOH extracts of Fallopia species (F. bohemica, F. japonica and F. sachalinensis), Rumex species (R. acetosa, R. acetosella, R. alpinus, R. conglomeratus, R. crispus, R. hydrolapathus, R. pulcher, R. stenophyllus, R. thyrsiflorus, R. obtusifolius subsp. subalpinus, R. patientia) and Polygonum bistorta, Polygonum hydropiper, Polygonum lapathifolium and Polygonum viviparum demonstrated the highest XO inhibitory activity (>85% inhibition) at 400 ug/mL. The IC50 values of the active extracts were also determined. On the basis of the results, these plants, and especially P. hydropiper and R. acetosella, are considered worthy of activity-guided phytochemical investigations. PMID- 25510559 TI - What is your patient's cognitive profile? Three distinct subgroups of cognitive function in persons with heart failure. AB - PURPOSE: The aim of this study was to determine whether patients with heart failure (HF) have distinct profiles of cognitive impairment. BACKGROUND: Cognitive impairment is common in HF. Recent work found three cognitive profiles in HF patients-(1) intact, (2) impaired, and (3) memory-impaired. We examined the reproducibility of these profiles and clarified mechanisms. METHODS: HF patients (68.6 +/- 9.7 years; N=329) completed neuropsychological testing. Composite scores were created for cognitive domains and used to identify clusters via agglomerative-hierarchical cluster analysis. RESULTS: A 3-cluster solution emerged. Cluster 1 (n=109) had intact cognition. Cluster 2 (n=123) was impaired across all domains. Cluster 3 (n=97) had impaired memory only. Clusters differed in age, race, education, SES, IQ, BMI, and diabetes (ps <= .026) but not in mood, anxiety, cardiovascular, or pulmonary disease (ps >= .118). CONCLUSIONS: We replicated three distinct patterns of cognitive function in persons with HF. These profiles may help providers offer tailored care to patients with different cognitive and clinical needs. PMID- 25510561 TI - Periovulatory time in the bitch: what's new to know?: Comparison between ovarian histology and clinical features. AB - The ability to recognize specific events happening in the ovaries during periovulatory time allows optimal management of canine reproduction. The objective of this study was to assess the efficacy of vaginal cytology and blood progesterone (P4) assay to identify accurately the changes occurring at the ovarian structures, mainly during the fertile period. Tertiary follicles, corpora hemorrhagica (CHs) and corpora lutea (CLs) from forty healthy bitches undergoing ovariohysterectomy were evaluated by histo-morphometry based on their aspect, number and size. The tertiary follicles distribution (small, medium and large) was statistically different (P<0.002) among all the stages of the reproductive cycle, except for small follicles (<2mm), which were always observed from proestrus to anestrus. Very large follicles (>4mm) were predominant (P=0.008) around ovulation when P4 mean level was 6.1+/-1.7ng/mL. The early postovulatory estrous period was characterized by CHs (P<0.002) and P4 level of 16.7+/ 5.9ng/mL. The end of the fertile period - start of diestrus - coincided with the development of CLs (P=0.001) associated with a P4 mean level of 73.9+/-9.9ng/mL. The small (P<0.001) and medium (P<0.05) follicle diameters were positively correlated with the bitch size. The number of follicles larger than 4mm was significantly lower in bitches younger than 4 years (P<0.02). This study provides insight into some critical steps in the canine reproductive processes in the periovulatory phase and the end of the fertile period, essential to plan breeding programs. PMID- 25510562 TI - Breed-specific fetal biometry and factors affecting the prediction of whelping date in the German shepherd dog. AB - To date many studies have been published about predicting parturition by ultrasonographic fetal measurements in the bitch. Given that accuracy in such prediction is a key point for clinicians and breeders, formulas to calculate the whelping date were mainly obtained from small and medium sized dogs, which means poor accuracy when applied to large or giant breeds. Based on the evidence that ethnicity significantly affects fetal biometry in humans, this study aimed at developing a breed-specific linear regression model for estimating parturition date in the German shepherd dog. For this purpose, serial ultrasonographic measurements of the inner chorionic cavity diameter (ICC) and the fetal biparietal diameter (BP) were collected in 40 pregnant German shepherd bitches. The quality of the regression models for estimating parturition date was further verified in 22 other pregnant German shepherd bitches. Accuracy related to the prediction of parturition date was higher than previously reported: 94.5% and 91.7% within +/-2 days interval based on ICC and BP measurements, respectively. Additional investigation was performed on the effects of maternal weight, age and litter size in relation to fetal biometry and to accuracy of parturition estimation. Moreover, the study included a comparison between hormonal and fetal ultrasound (ICC and BP) measurements connected to the estimation of whelping date. We suggest that specific equations from a single breed are likely to offer excellent accuracy, comparable to that of periovulatory progesteronemia, in parturition prediction and to avoid morphological variables present in dogs of different breeds even with the same size/weight. PMID- 25510563 TI - Bifunctional silver(I) complex-catalyzed CO2 conversion at ambient conditions: synthesis of alpha-methylene cyclic carbonates and derivatives. AB - The chemical conversion of CO2 at atmospheric pressure and room temperature remains a great challenge. The triphenylphosphine complex of silver(I) carbonate was proved to be a robust bifunctional catalyst for the carboxylative cyclization of propargylic alcohols and CO2 at ambient conditions leading to the formation of alpha-methylene cyclic carbonates in excellent yields. The unprecedented performance of [(PPh3)2Ag]2CO3 is presumably attributed to the simultaneous activation of CO2 and propargylic alcohol. Moreover, the highly compatible basicity of the catalytic species allows propargylic alcohol to react with CO2 leading to key silver alkylcarbonate intermediates: the bulkier [(Ph3P)2Ag(I)](+) effectively activates the carbon-carbon triple bond and enhances O nucleophilicity of the alkylcarbonic anion, thereby greatly promoting the intramolecular nucleophilic cyclization. Notably, this catalytic protocol also worked well for the reaction of propargylic alcohols, secondary amines, and CO2 (at atmospheric pressure) to afford beta-oxopropylcarbamates. PMID- 25510564 TI - From cells to muropeptide structures in 24 h: peptidoglycan mapping by UPLC-MS. AB - Peptidoglycan (PGN) is ubiquitous in nearly all bacterial species. The PGN sacculus protects the cells against their own internal turgor making PGN one of the most important targets for antibacterial treatment. Within the last sixty years PGN composition has been intensively studied by various methods. The breakthrough was the application of HPLC technology on the analysis of muropeptides. However, preparation of pure PGN relied on a very time consuming method of about one week. We established a purification protocol for both Gram positive and Gram-negative bacteria which can be completely performed in plastic reaction tubes yielding pure muropeptides within 24 hours. The muropeptides can be analyzed by UPLC-MS, allowing their immediate determination. This new rapid method provides the feasibility to screen PGN composition even in high throughput, making it a highly useful tool for basic research as well as for the pharmaceutical industry. PMID- 25510566 TI - MicroRNA-421 is a new potential diagnosis biomarker with higher sensitivity and specificity than carcinoembryonic antigen and cancer antigen 125 in gastric cancer. AB - CONTEXT: The sensitivity and specificity of blood microRNA-421 (miR-421) as a gastric cancer (GC) biomarker has not been determined. OBJECTIVE: To investigate the diagnostic value of blood miR-421 as GC biomarker. MATERIALS AND METHODS: miR 421 in serum and peripheral blood mononuclear cells (PBMCs) of 90 GC patients and 90 controls was detected by quantitative real-time PCR. The correlation of miR 421 to GC clinicopathological features as well as the diagnostic value of miR-421 comparing to carcinoembryonic antigen (CEA) and cancer antigen 125 (CA-125) were analyzed. RESULTS: miR-421 increased significantly in GC patients than in controls. miR-421 in either serum or PBMCs had higher sensitivity and specificity than CEA and CA-125 in GC diagnosis. The GC positive prediction rates of miR-421 were also significantly higher than those of CEA and CA-125. DISCUSSION AND CONCLUSIONS: miR-421 in serum or PBMCs may be a new potential diagnostic biomarker for GC. PMID- 25510567 TI - Advances in reduced port laparoscopic liver resection. AB - Reduced port surgery has been attracting attention in the field of minimally invasive surgery. Although the use of SILS is becoming widespread, technical difficulty has delayed its adoption for laparoscopic liver resection. Recently, advances in laparoscopic liver resection have been made in tandem with advances in surgical skill and devices. The main driver in conventional laparoscopic liver resection's evolution to become less surgically invasive seems to be single incision laparoscopic liver resection (SILLR). To date, most reports on SILLR have been single case reports or case series. Only a few cohort studies on conventional laparoscopic surgery and SILLR have been conducted. Recent reports have described the use of SILLR for well-localized lesions and solitary tumors located in the anterolateral segments of the liver or left liver lobe, but its application remains limited to partial resection and left lateral sectionectomy. The feasibility and safety of SILLR have been demonstrated, but additional work is needed for standardization of the procedure. PMID- 25510568 TI - At the BJUI the best things in life are free. PMID- 25510569 TI - Geography: an increasingly important variable in prostate cancer clinical trials. PMID- 25510570 TI - Retroperitoneal lymph node dissection (RPLND) - open surgery's next challenger is ready to enter the ring. PMID- 25510571 TI - The prostate: a gateway to men's health. PMID- 25510572 TI - Cognitive training and assessment in robotic surgery - is it effective? PMID- 25510575 TI - An insect pupal cell with antimicrobial properties that suppress an entomopathogenic fungus. AB - Soil-dwelling insects have developed various mechanisms to defend against pathogen infection. The pecan weevil, Curculio caryae, spends two to three years in the soil inside an earthen cell. We hypothesized that the cell may possess antimicrobial properties. In a laboratory study, we tested the hypothesis using the fungus Beauveria bassiana as a model. B. bassiana is a common endemic pathogen of C. caryae. We compared the number of colony-forming-units on selective media when B. bassiana was exposed to autoclaved soil, non-autoclaved soil, or soil from a C. caryae pupal cell. Soil from C. caryae cells was suppressive to B. bassiana. To our knowledge this is the first report of antimicrobial properties associated with an insect soil cell. The findings expand our knowledge of host-pathogen relationships. Additional research is needed to determine the basis for the suppressive effects observed. PMID- 25510576 TI - The clinical relevance of alloantibody in liver transplantation. AB - The transplanted liver appears resistant to antibody-mediated injury compared to other transplanted organs such as kidney or heart. However, a growing number of reports suggest that alloantibody to the liver is associated with poorer outcomes. The data surrounding this field are unclear, and their interpretation remains controversial. Mechanistically, there is not a clear explanation for the liver's resistance to antibody-mediated injury, and the pathological criteria for antibody-mediated rejection (AMR) remain ill-defined. Furthermore, treatment of AMR is non-uniform. The field would benefit from better outcome data based on measurement of antibody at the time of transplantation and at the time of rejection. Consensus opinion regarding antibody and the liver might emerge with better standardization of antibody measurement and pathological definition of AMR. PMID- 25510573 TI - Effect of selected local medicinal plants on the asexual blood stage of chloroquine resistant Plasmodium falciparum. AB - BACKGROUND: The development of resistant to current antimalarial drugs is a major challenge in achieving malaria elimination status in many countries. Therefore there is a need for new antimalarial drugs. Medicinal plants have always been the major source for the search of new antimalarial drugs. The aim of this study was to screen selected Malaysian medicinal plants for their antiplasmodial properties. METHODS: Each part of the plants were processed, defatted by hexane and sequentially extracted with dichloromethane, methanol and water. The antiplasmodial activities of 54 plant extracts from 14 species were determined by Plasmodium falciparum Histidine Rich Protein II ELISA technique. In order to determine the selectivity index (SI), all plant extracts demonstrating a good antiplasmodial activity were tested for their cytotoxicity activity against normal Madin-Darby Bovine Kidney (MDBK) cell lines by 3-(4, 5-Dimethylthiazol-2 yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. RESULTS: Twenty three extracts derived from Curcuma zedoaria (rhizome), Curcuma aeruginosa (rhizome), Alpinia galanga (rhizome), Morinda elliptica (leaf), Curcuma mangga (rhizome), Elephantopus scaber (leaf), Vitex negundo (leaf), Brucea javanica (leaf, root and seed), Annona muricata (leaf), Cinnamomun iners (leaf) and Vernonia amygdalina (leaf) showed promising antiplasmodial activities against the blood stage chloroquine resistant P. falciparum (EC50 < 10 MUg/ml) with negligible toxicity effect to MDBK cells in vitro (SI >=10). CONCLUSION: The extracts belonging to eleven plant species were able to perturb the growth of chloroquine resistant P. falciparum effectively. The findings justified the bioassay guided fractionation on these plants for the search of potent antimalarial compounds or formulation of standardized extracts which may enhance the antimalarial effect in vitro and in vivo. PMID- 25510577 TI - Liver disease related to the heart. AB - In this article, we review both acute and chronic liver diseases that occur as a result of heart or circulatory system failure. Ischemic hepatitis, congestive hepatopathy, cardiac cirrhosis, and Fontan liver disease are reviewed. We review clinical presentation, diagnostic data, prognosis, and available therapeutic strategies for these entities. We aim to increase awareness about cardio-hepatic disease as the prevalence of this disorder in adults is increasing. Due to advances in medical and surgical care, patients with heart disease are living longer and thus exposing long-term effects on the liver that are clinically relevant. There may be a role for dual organ transplantation in some cases, but this is a very challenging endeavor, and newer ideas about treatment or prevention are needed. PMID- 25510578 TI - Management of de novo malignancies after liver transplantation. AB - Due to advances in medical and surgical expertise leading to significant improvements in graft and patient survival, there is an increased recognition of long term complications in survivors such as de novo malignancies, cardiovascular events and infections. Data show solid organ transplant recipients have 2-3 times the increased risk of developing a de novo malignancy compared to an age-matched and sex-matched general population and malignancy is expected to be the number one cause of mortality in long term transplant recipients in the next two decades. Risk factors include an aging transplant population, oncogenic viruses and the long term effects of immunosuppression in the development of carcinogenesis. This review summarizes common de novo malignancies occurring in the post liver transplant population and current strategies for their prevention and management. Unfortunately, due to limited evidence based data, robust screening guidelines for post transplant cancer prevention have yet to be implemented in this population. PMID- 25510579 TI - Too Fit To Fracture: outcomes of a Delphi consensus process on physical activity and exercise recommendations for adults with osteoporosis with or without vertebral fractures. AB - An international consensus process resulted in exercise and physical activity recommendations for individuals with osteoporosis. Emphasis was placed on strength, balance, and postural alignment. Rather than providing generic restrictions, activity should be encouraged while considering impairments, fracture risk, activity history, and preference, and guidance on spine sparing techniques should be provided. INTRODUCTION: The objectives of this study were to establish expert consensus on key questions posed by patients or health care providers regarding recommended assessment domains to inform exercise prescription, therapeutic goals of exercise, and physical activity and exercise recommendations for individuals with osteoporosis or osteoporotic vertebral fracture. METHODS: The Too Fit To Fracture expert panel identified researchers and clinicians with expertise in exercise and osteoporosis and stakeholder groups. We delivered a modified online Delphi survey (two rounds) to establish consensus on assessment, exercise, and physical activities for three cases with varying risk (osteoporosis based on bone mineral density; 1 spine fracture and osteoporosis; multiple spine fractures, osteoporosis, hyperkyphosis, and pain). Duplicate content analyses of free text responses were performed. RESULTS: Response rates were 52% (39/75) and 69% (48/70) for each round. Key consensus points are the following: (a) Current physical activity guidelines are appropriate for individuals with osteoporosis without spine fracture, but not for those with spine fracture; (b) after spine fracture, physical activity of moderate intensity is preferred to vigorous; (c) daily balance training and endurance training for spinal extensor muscles are recommended for all; (d) providing guidance on spine-sparing techniques (e.g., hip hinge) during activities of daily living or leisure, considering impairments, fracture risk, activity history, and preference, is recommended rather than providing generic restrictions (e.g., lifting <10 lbs, no twisting), but for those with vertebral fracture, especially in the presence of pain, multiple fractures, or hyperkyphosis, the risks of many activities may outweigh the benefits-physical therapist consultation is recommended. Examples of spine-sparing techniques and exercise prescription elements are provided. CONCLUSIONS: Our recommendations guide health care providers on assessment, exercise prescription, and safe movement for individuals with osteoporosis. PMID- 25510580 TI - Is thoracolumbar fascia injury the cause of residual back pain after percutaneous vertebroplasty? A prospective cohort study. AB - Some patients with osteoporotic vertebral compression fractures still suffer from back pain after percutaneous vertebroplasty. We have found that osteoporotic vertebral compression fractures with thoracolumbar fascia injury are common and that thoracolumbar fascia injury may account for the residual pain after percutaneous vertebroplasty. PURPOSE: Osteoporotic vertebral compression fractures are successfully treated with percutaneous vertebroplasty (PVP). However, some patients still suffer from back pain after the procedure. We hypothesized that there is a relationship between thoracolumbar (TL) fascia injury and residual postoperative pain. METHODS: This prospective study included 133 elderly patients (age range 55 - 92 years) with osteoporotic vertebral compression fractures treated with PVP from February 2010 to March 2012 in our hospital. The patients were divided into two groups based on the presence of TL fascia injury. A visual analog scale (VAS) and the Chinese modified Oswestry Disability Index were used to evaluate the pain before and after PVP. RESULTS: The mean VAS score and the Chinese modified Oswestry Disability Index in the patients with TL fascia injury were reduced from 9.11 +/- 0.76 to 6.4 +/- 1.1 and 73.93 +/- 1.46% to 44.6 +/- 3.1%, respectively, and in the patients without TL fascia injury from 9.26 +/- 0.82 to 8.0 +/- 1.3 and 73.96 +/- 1.38% to 51.7 +/- 1.8%, respectively. Pain and disability were reduced more in patients without TL fascia injury than in those with TL fascia injury (both p < 0.05). CONCLUSIONS: There may be a relationship between TL fascia injury and residual back pain after PVP. PMID- 25510583 TI - Direct experimental observation of stacking fault scattering in highly oriented pyrolytic graphite meso-structures. AB - Stacking fault defects are thought to be the root cause for many of the anomalous transport phenomena seen in high-quality graphite samples. In stark contrast to their importance, direct observation of stacking faults by diffractive techniques has remained elusive due to fundamental experimental difficulties. Here we show that the stacking fault density and resistance can be measured by analyzing the non-Gaussian scatter observed in the c-axis resistivity of mesoscopic graphite structures. We also show that the deviation from Ohmic conduction seen at high electrical field strength can be fit to a thermally activated transport model, which accurately reproduces the stacking fault density inferred from the statistical analysis. From our measurements, we conclude that the c-axis resistivity is entirely determined by the stacking fault resistance, which is orders of magnitude larger than the inter-layer resistance expected from a Drude model. PMID- 25510581 TI - Quantitative ultrasonometry during pregnancy and lactation: a longitudinal study. AB - This study describes bone mass changes during pregnancy and lactation measured by a special ultrasound method. Pregnant women showed a decrease of bone mass followed by a stable bone mass while breast-feeding afterwards. Later in life, there is a recovery of bone mass loss. INTRODUCTION: The aim of this study was to evaluate bone changes during pregnancy using the radiation-free method of quantitative ultrasonometry (QUS). METHODS: One hundred twenty-five pregnant women who underwent prenatal care were included in this study. Ultrasound measurement of the calcaneus was performed in each trimester and then 6 weeks, 3 months, and 1 year postpartum. The calcaneal QUS measurements were carried out using the Achilles plus device (GE/Lunar Corporation, Madison, WI). Three ultrasound variables were measured: speed of sound (SOS, m/s), broadband ultrasound attenuation (BUA, dB/MHz), and the "stiffness index" (expressed as the percentage of the mean value in young adults). SOS and BUA raw data result in the t-score and z-score. RESULTS: A complete panel of six measurements was acquired over the time period in 101 patients (80.8%). Forty-two percent of the included patients were primipara, while 58% had given birth to at least one child (47%) previously. There was a statistically significant change of the t-score (tv = 2.14, p = 0.035) and the stiffness index (tv = 2.46, p = 0.016) from the second to the third trimester, followed by a plateau during lactation. Interestingly, the t-score remained stable during lactation, regardless of the duration of lactation (<3 months, 3-6 months, and >6 months). CONCLUSIONS: Young primiparas who had a sedentary adolescence were at the highest risk of bone loss during pregnancy. Bone loss that occurred during pregnancy was typically recovered later on, based on unknown molecular and biochemical mechanisms that must be elucidated with further studies. PMID- 25510584 TI - Malloapelta B suppresses LPS-induced NF-kappaB activation and NF-kappaB-regulated target gene products. AB - Nuclear factor-kappaB (NF-kappaB) and the signaling pathways that regulate its activity have become a focal point for intense drug research and development efforts. NF-kappaB regulates the transcription of a large number of genes, particularly those involved in immune, inflammatory, and anti-apoptotic responses. In our search for NF-kappaB inhibitors from natural resources, we identified malloapelta B as an inhibitor of NF-kappaB activation from Mallotus apelta Muell-Arg. In the present study, we demonstrated the effect of malloapelta B on NF-kappaB activation in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. This compound suppressed NF-kappaB activation through the inhibition of IkappaB kinase (IKK) activation, thereby blocking the phosphorylation and degradation of the inhibitor of NF-kappaB alpha (IkappaBalpha), and the nuclear translocation and DNA-binding activity of p65. The suppression of NF-kappaB by malloapelta B led to the down-regulation of target genes involved in inflammation and proliferation. Taken together, this study extends our understanding on the mechanisms underlying the possible anti-inflammatory and anti-cancer activities of malloapelta B. Our findings provide new insight into its mechanisms of action and propose a potential application of malloapelta B for inflammatory diseases as well as certain cancers associated with abnormal NF-kappaB activation. PMID- 25510582 TI - Adult bone strength of children from single-parent families: the Midlife in the United States Study. AB - Bone health may be negatively impacted by childhood socio-environmental circumstances. We examined the independent associations of single-parent childhood and parental death or divorce in childhood with adult bone strength indices. Longer exposure to a single-parent household in childhood was associated with lower bone strength in adulthood. INTRODUCTION: Because peak bone mass is acquired during childhood, bone health may be negatively impacted by childhood socio-environmental disadvantage. The goal of this study was to determine whether being raised in a single-parent household is associated with lower bone strength in adulthood. METHODS: Using dual-energy X-ray absorptiometry data from 708 participants (mean age 57 years) in the Midlife in the United States Biomarker Project, we examined the independent associations of composite indices of femoral neck bone strength relative to load (in three failure modes: compression, bending, and impact) in adulthood with the experience of single-parent childhood and parental death or divorce in childhood. RESULTS: After adjustment for gender, race, menopause transition stage, age, and body mass index, each additional year of single-parent childhood was associated with 0.02 to 0.03 SD lower indices of adult femoral neck strength. In those with 9-16 years of single-parent childhood, the compression strength index was 0.41 SD lower, bending strength index was 0.31 SD lower, and impact strength index was 0.25 SD lower (all p values < 0.05). In contrast, parental death or divorce during childhood was not by itself independently associated with adult bone strength indices. The magnitudes of these associations were unaltered by additional adjustment for lifestyle factors and socioeconomic status in childhood and adulthood. CONCLUSIONS: Independent of parental death or divorce, growing up in a single-parent household is associated with lower femoral neck bone strength in adulthood, and this association is not entirely explained by childhood or adult socioeconomic conditions or lifestyle choices. PMID- 25510585 TI - Curcumin attenuated acute Propionibacterium acnes-induced liver injury through inhibition of HMGB1 expression in mice. AB - Curcumin is a phenolic product isolated from the rhizome of Curcuma longa and has protective effects on inflammatory diseases. Here we investigated the protective effect of curcumin in acute Propionibacterium acnes (P. acnes)-induced inflammatory liver injury. C57BL/6 mice were primed with P. acnes followed by LPS challenge to induce fulminant hepatitis. Curcumin or vehicle control was administered perorally by gavage once daily starting 2days before P. acnes priming. We found that curcumin significantly improved mouse mortality. Then, to investigate the underlying mechanisms of curcumin in this acute inflammatory liver injury model, we primed C57BL/6 mice with P. acnes only. We found that curcumin treatment attenuated P. acnes-induced liver injury as evidenced by decreased production of ALT. In addition, curcumin treatment reduced the production of proinflammatory cytokines such as TNF-alpha and IFN-gamma, accompanied by reduced hepatocyte apoptosis. Furthermore, curcumin treatment significantly reduced HMGB1 cytoplasmic translocation and expression by down regulating acetylation of lysine. Taken together, our results suggest that curcumin protects mice from P. acnes-induced liver injury through reduction of HMGB1 cytoplasmic translocation and expression. PMID- 25510586 TI - Evaluation of the Feasibility and Utility of a Pharmacist-Centered Collaborative Drug Therapy Management Program for Oncology-Based Symptom Management. AB - Collaborative drug therapy management (CDTM) is a practice agreement between a pharmacist and a physician, which allows the pharmacist to assume responsibility of drug therapy management. There has been limited documentation of CDTM practices in the oncology setting. Therefore, a CDTM program in the gynecology oncology clinic at Roswell Park Cancer Institute (RPCI) was initiated to establish the feasibility and utility of CDTM and its effects on patient care and physician satisfaction. Primarily, 3 symptoms were managed by the CDTM pharmacists, namely chemotherapy-induced nausea and vomiting (CINV), chemotherapy induced peripheral neuropathy (CIPN), and women's health. The CDTM program showed favorable results after a short 4-month period. The CDTM pharmacists were referred a total of 12 consultations for CDTM purposes; 8 patients enrolled in the CIPN CDTM protocol, 3 in the CINV protocol, and 1 in the women's health protocol. The CDTM pharmacists were able to perform a total of 54 consultations, with a mean time of 16.9 minutes spent with each patient per consultation. Additionally, the CDTM pharmacists made 70 interventions and identified 6 medication-related adverse effects. The patient and physician satisfaction survey demonstrated the value of the CDTM pharmacists, and respondents were supportive of the program. PMID- 25510587 TI - Introduction: pharmacy practice has changed. PMID- 25510588 TI - Wear-resistant and antismudge superoleophobic coating on polyethylene terephthalate substrate using SiO2 nanoparticles. AB - It is of interest to create superoleophobic surfaces that exhibit high oil contact angle, low contact angle hysteresis, high wear resistance, antismudge properties, and optical transparency for industrial applications. In the superoleophobic surfaces developed to date, the mechanical durability data is lacking. By dip-coating polyethylene terephthalate substrate with hydrophobic SiO2 nanoparticles and methylphenyl silicone resin, followed by O2 plasma treatment and vapor deposition of 1H,1H,2H,2H-perfluorooctyltrichlorosilane, a durable superoleophobic surface was fabricated. The degree of superoleophobicity was found to be dependent on the particle-to-binder ratio. The coatings were found to exhibit wear resistance on microscale and macroscale, antismudge properties, and transparency. PMID- 25510590 TI - [Othello syndrome]. PMID- 25510589 TI - [Perception of knowledge in palliative care housing for the elderly workers in a basic health zone]. AB - OBJECTIVE: To analyze the level of knowledge in palliative care that health and non health housing for the elderly workers refer, to study the differences between professional categories and to detect their interest in receiving palliative care training. PATIENTS AND METHODS: Cross-sectional study conducted among physicians, nurses, physiotherapists, nursing assistant and occupational therapists applying a questionnaire assisting terminal patients with 22 items grouped into four sections: generalities palliative care, physical care, psycho emotional and spiritual. Each question is answered using a four point scale in much-regulate-little-nothing. RESULTS: 86.8% of respondents know quite what they mean or regular palliative care. 3.8% consider themselves sufficiently trained in palliative care. We found significant differences in non-pharmacological management of dyspnea and insomnia where concerns have less knowledge worker. Medicine and nursing reported having more knowledge in the recognition of a tumor ulcer. CONCLUSIONS: There is a very high interest in receiving palliative care training and these are considered very useful. Required impact on the acquisition of knowledge in the medical staff not optional as to non-pharmacological management of major symptoms It also emphasizes the need to approach not to question the patient's pain by physicians. The test to detect cognitive impairment are not well known for nursing assistants. The spiritual realm is the acceptable level of knowledge on the part of all professional categories surveyed. PMID- 25510591 TI - [Comparison of the cardiovascular predictive value of MDRD and CKD-EPI in estimating chronic kidney disease]. AB - OBJECTIVE: To assess predictive value of the cardiovascular prognosis by comparing the two most used formulas for the estimation of glomerular filtration rate in hypertensive patients. MATERIAL AND METHODS: A retrospective cohort study was designed that included 405 patients diagnosed with essential hypertension. The patients were referred from Primary Care to the Hypertension and Vascular Risk Unit between January 1, 1998 and August 31, 1999. Blood pressure measurements, blood and urine analysis, and echocardiography were simultaneously performed. They were followed up for 12.5 years (mean [+/- IQR]: 10.61 [+/- 3.11] years) and 174 events were recorded. RESULTS: The study included 405 patients (53.8% women), with a mean age of 55.5 years. The estimated glomerular filtration rate according to the MDRD and CKD-EPI equations was 73.9+/-2.6 mL/min/1.73m(2) and 76.9+/-2.2 mL/min/1.73m(2), respectively. The prevalence of chronic kidney disease was 31.6% and 23.9%, respectively. Using the CKD-EPI equation led to the re-classification of 22.9% of patients. The incidence rate ratio (IRR [95%CI] for chronic kidney disease identified by the MDRD equation was 2.4 [1.8-3.3], and for the CKD-EPI calculation it was 2.5 [1.8 to 3.3]). CONCLUSIONS: Both equations estimate similar magnitudes of renal function, although the CKD-EPI equation has less false positives, and both have similar prognostic values in patients at high cardiovascular risk as well those at low risk. PMID- 25510592 TI - Organization-level predictors of sustained social movement participation. AB - Long-term sustained participation represents one of the most important resources available to community organizations and social movement organizations (SMOs). The participatory literature on community and SMOs has identified a host of individual-level factors that influence participation beyond initial engagement, and has more recently identified contextual factors that influence participation. This study builds upon current understandings of participation in SMOs by examining how sustained participation in movement activities is affected by two qualities of SMO settings: repertoire of organizational activity, and equality of staff contact with organization members to cultivate and facilitate individual participation. To this end, we employ multi-level regression techniques to examine longitudinal data on participation within 50 local chapters of a national congregation-based community organizing federation. We find that the conduct of organizational activities previously shown to increase levels of participation among individual persons does not necessarily lead to increases in aggregate or organization-level participation. Further, we find that conditions of unequal staff contact among organization members represent a notable drag on organization level participation over time. Our findings suggest that organizers and organizational leaders may well see greater levels of participation in their organizations by simply re-distributing resources and opportunities more equitably within their organizations. PMID- 25510593 TI - Individual and community resilience factors among lesbian, gay, bisexual, queer and questioning youth and adults in Israel. AB - Drawing on resilience theories, this study examined the individual and community factors of Israeli lesbians, gays, bisexuals, queers, and questioning (LGBQs) that contribute to positive mental health and the degree to which individual and community protective factors mitigate the adverse effect of risk factors for poor mental health. Differences in resilience factors between LGBQ youth and adults were explored. Data were collected on 890 LGBQ youth and adults. Findings emphasize the role of community-level resilience factors in the lives of LGBQs, and that these support systems differ slightly between the two age groups. Among youth, family support was both a strong predictor for well-being and a protective factor for mental distress. Although family support was found as a resilience factor among adults as well, other community-level factors (friends' support, LGBT connectedness and having steady partner) were found as protective factors for poorer mental health. These findings suggest for efforts on fostering familial support for LGBQ youth and a multi-level system that offers support at the familial, peer, relationship and community levels for both LGBQ youth and adults. PMID- 25510594 TI - Poetic justice: engaging in participatory narrative analysis to find solace in the "killer corridor". AB - The author engaged with adolescents at a community-based youth organization as "co-researchers" to delve deeper into the lived experiences of youth of color residing in an urban neighborhood undergoing change. Participatory narrative analysis was used to empower participants to produce texts to make sense of their lives and their home, school, and neighborhood contexts. The process of engaging youth as co-researchers and experts in issues pertaining to their own neighborhood is discussed. Nuanced analyses of poems-as-data is shown to be critical in informing the recent surge of interdisciplinary, community-engaged, place-based initiatives focused on neighborhood revitalization, violence prevention, and positive youth development. PMID- 25510595 TI - [Prevalence and genotype distribution changes in hepatitis C virus co-infection among human immunodeficiency virus-infected patients]. AB - BACKGROUND: The prevalence of hepatitisC is decreasing among new diagnoses of HIV/HCV coinfection in Spain. The increasing use of the HCV treatment could have changed the HCV genotype distribution. The aim of this study is to analyze changes in the prevalence of HCV coinfection and in HCV genotype distribution among HIV-infected patients. METHODS: A serial cross-sectional study was conducted that included all HIV-infected patients who attended the Outpatient Clinic of a hospital in Andalusia, between September 2008 and February 2009 (first period), and between January 2013 and June 2013 (second period). RESULTS: A total of 520 and 651 patients were included in the first and second period, respectively. The risk factors of HCV infection in the first vs. second period were: IDU, 319 (61%) vs. 348 (53%); heterosexual contact, 111 (21%) vs. 135 (21%); homosexual men, 76 (15%) vs. 114 (22%) (P=.006). The prevalence of HCV antibody per period was: 358 (69%) vs. 380 (58%) (P=<.001), and for the HCV-RNA was 255 (49%) vs. 240 (37%) (P=<.001). In both periods, the HCV genotype distribution was: 1, 137 (60%) vs. 138 (59%); 3, 45 (20%) vs. 42 (18%); 4, 42 (18%) vs. 47 (20%) (P=.881). CONCLUSIONS: The prevalence of HCV infection in HIV infected patients has decreased in our area, including overall exposure to HCV virus and active infection during the last 5 years. However, the HCV genotype distribution has not changed. PMID- 25510596 TI - Mammary cancer initiation and progression studied with magnetic resonance imaging. AB - INTRODUCTION: Previous work from this laboratory demonstrated that magnetic resonance imaging (MRI) detects early murine mammary cancers and reliably differentiates between in situ and invasive cancer. Based on this previous work, we used MRI to study initiation and progression of murine mammary cancer, and monitor the transition from the in situ to the invasive phase. METHODS: In total, seven female C3(1) SV40 Tag mice were imaged every two weeks between the ages of 8 to 23 weeks. Lesions were identified on T2-weighted images acquired at 9.4 Tesla based on their morphology and growth rates. Lesions were traced manually on MR images of each slice. Volume of each lesion was calculated by adding measurements from individual slices. Plots of lesion volume versus time were analyzed to obtain the specific growth rate (SGR). The time at which in situ cancers (referred to as 'mammary intraepithelial neoplasia (MIN)') and invasive cancers were first detected; and the time at which in situ cancers became invasive were recorded. RESULTS: A total of 121 cancers (14 to 25 per mouse) were identified in seven mice. On average the MIN lesions and invasive cancers were first detected when mice were 13 and 18 weeks old, respectively. The average SGR was 0.47 +/- 0.18 week(-1) and there were no differences (P >0.05) between mice. 74 lesions had significantly different tumor growth rates before and after ~17 weeks of age; with average doubling times (DT) of 1.88 and 1.27 weeks, respectively. The average DT was significantly shorter (P <0.0001) after 17 weeks of age. However, the DT for some cancers was longer after 17 weeks of age, and about 10% of the cancers detected did not progress to the invasive stage. CONCLUSIONS: A wide range of growth rates were observed in SV40 mammary cancers. Most cancers transitioned to a more aggressive phenotype at approximately 17 weeks of age, but some cancers became less aggressive. The results suggest that the biology of mammary cancers is extremely heterogeneous. This work is a first step towards use of MRI to improve understanding of factors that control and/or signal the development of aggressive breast cancer. PMID- 25510597 TI - Metformin use in patients with type 2 diabetes mellitus is associated with reduced risk of deep vein thrombosis: a non-randomized, pair-matched cohort study. AB - BACKGROUND: Metformin, an insulin-sensitizer, may correct several physiologic abnormalities owing to insulin resistance in patients with type 2 diabetes mellitus (DM). The effects of metformin on venous thrombosis in patient with type 2 DM have not been reported. Our study strived to explore the relationship of metformin therapy and the subsequent development of deep vein thrombosis (DVT) using a nationwide, population-based database. METHODS: From 1997 to 2003, we identified a study cohort consisting of patients with type 2 DM using metformin 7154 cases in the National Health Insurance Research Database. A control cohort without metformin, matched for age, sex, comorbidities, and medications was selected for comparison. RESULTS: Of the 14945 patients (7167 patients with metformin vs. 7778 control), 60 (0.40%) patients developed DVT during a mean follow-up period of 3.74 years, including 16 (0.21%) from the cohort with metformin and 44 (0.56%) from the control group. Subjects with metformin experienced a 0.427 fold (95% confidence interval 0.240-0.758; P = 0.004) changes of risk reduction in development of DVT, which was independent of age, sex and co morbidities. Kaplan-Meier analysis also revealed metformin therapy is associated with lower occurrence of DVT (log-rank test, P = 0.001). CONCLUSIONS: Metformin may have protective effect in patients with type 2 DM for DVT. PMID- 25510598 TI - Improved delivery of the natural anticancer drug tetrandrine. AB - The study aims at designing a nanoparticle-based delivery system to improve the efficacy of the natural compound tetrandrine against lung cancer. Nanoparticles from poly(lactic-co-glycolic acid) (PLGA) were prepared by the emulsion solvent diffusion method and characterized for their physicochemical properties and drug loading efficiency. Furthermore, the cellular uptake and the anti-cancerous activity was studied on A549 cell line. To investigate the surface properties and uptake, three different stabilizers were used to analyze the effect on size and zeta potential of nanoparticles as well as the effect on the cellular uptake. Nanoparticles in the size range of 180-200 nm with spherical shape were obtained with polyvinyl alcohol (PVA), Pluronic-F127 (PF127) and didodecyldimethylammonium bromide (DMAB), 2%, 1% and 0.1%, respectively. An entrapment efficiency of 50-60% with a loading of 1.5-2% was observed. In vitro release profile at pH 7.4 PBS solution showed a consistent release over 168 h. All particle systems showed an improved performance over the pure drug at the same drug concentration. DMAB stabilized particles demonstrated the most pronounced effect against A549 cells compared to pure drug while PVA stabilized particles were least effective in terms of antitumor activity. PMID- 25510599 TI - Lactosylated PLGA nanoparticles containing epsilon-polylysine for the sustained release and liver-targeted delivery of the negatively charged proteins. AB - The acidic internal pH environment, initial burst release and lack of targeting property are main limitations of poly(lactide-co-glycolide) (PLGA) nanoparticles for carrying proteins. In this study, epsilon-polylysine (epsilon-PL) was used as an anti-acidic agent and a protein protectant to prepare PLGA nanoparticles for the protein delivery. To obtain the liver-targeting capability, lactosylated PLGA (Lac-PLGA) was synthesized by conjugation of lactose acid to PLGA at both ends, and then used to prepare nanoparticles containing epsilon-PL by the nanoprecipitation method. Bovine serumal bumin (BSA), a negatively charged protein, was efficiently loaded into Lac-PLGA/epsilon-PL nanoparticles and exhibited significant decreased burst release in vitro, sustained release in the blood and increased liver distribution in mice after intravenous injections. The enhanced stability of BSA was due to its electrical interaction with epsilon-PL and the neutralized internal environment of nanoparticles. In conclusion, Lac PLGA/epsilon-PL nanoparticle system can be used as a promising carrier for the negatively charged proteins. PMID- 25510600 TI - Targeted killing of cancer cells in vivo and in vitro with IGF-IR antibody directed carbon nanohorns based drug delivery. AB - Oxidized single-wall carbon nanohorns (oxSWNHs) have shown great potential in drug delivery. The purpose of this study was to design an effective targeted drug delivery system (DDS) based on oxSWNHs, which could carry high dose of drug to tumor sites and improve the therapeutic efficacy with less adverse effects. OxSWNHs incorporated the anticancer drug vincristine (VCR) via physical adsorption, then wrapped DSPE-PEG-IGF-IR monoclonal antibody (mAb) through an amide liker to obtain the drug delivery system, VCR@oxSWNHs-PEG-mAb. The in vitro release behavior study indicated that the DDS had good sustained release and the cumulative release of VCR was 80% at 144h. Compared with free VCR, the tumor targeting drug delivery efficiently enhanced the cytotoxicity in cultured MCF-7 cells in vitro, and afforded higher antitumor efficacy without obvious toxic effects to normal organs in tumor mice in vivo. In addition, the targeted DDS could reduce the toxicity of VCR to the living mice. This study demonstrated that VCR@oxSWNHs-PEG-mAb might be promising for high treatment efficacy with minimal side effects in future cancer therapy. PMID- 25510601 TI - Solidification of liposomes by freeze-drying: the importance of incorporating gelatin as interior support on enhanced physical stability. AB - The main purpose of this study was to investigate the effect of gelatin as interior support on the physical stability of freeze-dried liposomes. Anticancer agent paclitaxel (PTX) was selected as a model drug. Freeze-dried liposomes containing interior gelatin support (GLs) were prepared by thin-film dispersion/freeze-drying method. Several properties of the GLs, including entrapment efficiency, particle size and gelation temperature, were extensively characterized. Encapsulation efficiency of conventional liposomes (CLs) and liposomes containing lyoprotectants as interior support dropped to lower than 20% after reconstitution, while GLs still maintained an entrapment efficiency of over 84%. Scanning electron microscopy revealed well preserved liposomal structure of GLs after reconstitution. Meanwhile, the particle size and entrapment efficiency of GLs were also well preserved after reconstitution. In contrary, deformation of CLs and recrystallization of PTX were observed, as well as significant changes in particle size and entrapment efficiency. Taken together, interior gelatin support obviously enhanced the physical stability of liposomes against the lyophilization stress. PMID- 25510602 TI - Evaluation of fasted and fed state simulated and human intestinal fluids as solvent system in the Ussing chambers model to explore food effects on intestinal permeability. AB - The Ussing chambers model is almost exclusively used in the presence of plain aqueous phosphate buffers as solvent system. In an attempt to further elucidate the effect of luminal ingredients and postprandial conditions on intestinal permeability, pooled fasted and fed state human intestinal fluids (FaHIFpool, FeHIFpool) were used. In addition, simulated intestinal fluids of both nutritional states (FaSSIF, FeSSIF) were evaluated as possible surrogate media for HIF. The use of FaHIFpool generated a broad range of Papp values for a series of 16 model drugs, ranging from 0.03*10(-6)cm/s (carvedilol) to 33.8*10(-6)cm/s (naproxen). A linear correlation was observed between Papp values using FaSSIF and FaHIFpool as solvent system (R=0.990), justifying the use of FaSSIF as surrogate medium for FaHIF in the Ussing chambers. In exclusion of the outlier carvedilol, a strong sigmoidal relationship was found between Papp and fahuman of 15 model drugs, illustrated by correlation coefficients of 0.961 and 0.936 for FaHIFpool and FaSSIF, respectively. When addressing food effects on intestinal permeability, the use of FeHIFpool resulted in a significantly lower Papp value for nine out of sixteen compounds compared to fasting conditions. FeSSIF as solvent system significantly overestimated Papp values in FeHIFpool. To conclude, the optimized Ussing chambers model using biorelevant media as apical solvent system holds great potential to investigate food effects in a more integrative approach, taking into account drug solubilisation, supersaturation and formulation effects. PMID- 25510603 TI - Mechanisms of cell death induced by infusion sets leachables in in vitro experimental settings. AB - Leachable materials that are released from infusion sets during their use can induce local and systemic toxic effects. We studied the mechanisms and kinetics of cell death induced by infusion sets leachates in vitro using L-929 and bEnd. 3 cells. Changes in cell morphology and metabolic activity were determined using light microscopy and the MTT test, respectively. Detailed analysis of the mechanisms of cell death was performed using membrane integrity and caspases 3 and 7 activity tests, annexin V-FITC/7-AAD analysis by FACS, and DAPI nuclear staining followed by confocal microscopy. Infusion sets released toxic leachables and induced toxic effects. Latex flashball was the most toxic part of the studied infusion sets, and it potently induced cell oncosis via increased permeability of the cell membrane. Latex-induced decrease in cells metabolic activity and cell death were not accompanied by activation of caspases 3 and 7, changes in nuclear morphology, or substantial annexin V-FITC cell staining. Leachables from the tube part of the infusion sets were less toxic, and induced some biochemical changes without altering the cells morphology. Further studies are needed to reveal the in vivo toxicity of infusion sets and its correlation with the results of in vitro toxicity studies. PMID- 25510604 TI - Controlled release and reversal of multidrug resistance by co-encapsulation of paclitaxel and verapamil in solid lipid nanoparticles. AB - Paclitaxel (PTX) has been used in the treatment of wide range of cancers but its entry into cancer cell is restricted by p-glycoprotein (p-gp). Also, it was reported that verapamil (VP) could inhibit p-gp efflux. Hence, three kinds of solid lipid nanoparticles (SLN) such as PVS (PTX and VP co-loaded SLN), PSV (PTX loaded SLN, later added VP) and PVSV (PTX and VP co-loaded SLN, later added VP) were prepared to overcome MDR by combination of PTX and VP. PVS was the SLN loaded with both PTX and VP at the same time. PSV was the SLN loaded with PTX and then modified with VP - complexed hydroxypropyl-beta-cylcodextrin (HPCD). Finally, PVSV was the SLN loaded with PTX and half of VP at the same time subsequently, modified with half of VP - complexed HPCD. The physicochemical characterizations of PVS, PSV or PVSV such as particle size, zeta potential, encapsulation efficiency or in vitro PTX release were examined. PVSV showed that release of VP was higher than PTX solution in first 15h and sustained release of both VP and PTX. PVSV showed significantly higher cytotoxicity and cellular uptake than that of the PTX solution in MCF-7/ADR resistant cells. Furthermore, PVSV significantly down regulated the expression of p-gp than the PTX solution in MCF-7/ADR resistant cells. Based on these findings, this study indicated that the PVSV exhibited great potential for breast cancer therapy. PMID- 25510605 TI - Diagnostic utility of candidate definitions for demonstrating axial spondyloarthritis on magnetic resonance imaging of the spine. AB - OBJECTIVE: A recent consensus statement has suggested >=3 corner inflammatory lesions (CILs) or several corner fatty lesions (CFLs) as candidate criteria indicative of axial spondyloarthritis (SpA) on magnetic resonance imaging (MRI) of the spine. The aim of this study was to evaluate the diagnostic utility of these cutoffs in nonradiographic axial SpA and ankylosing spondylitis (AS). METHODS: One hundred thirty consecutive patients with back pain who were <=50 years of age and newly referred to 2 university clinics (cohorts A and B) were classified according to rheumatologist expert opinion based on results of clinical examination and pelvic radiography as having nonradiographic axial SpA (n = 50), AS (n = 33), or nonspecific back pain (n = 47). Cohort A also included 20 age-matched healthy controls. Four blinded readers assessed MRIs of the spine using the standardized Canada-Denmark module. Readers recorded CILs and CFLs in 23 discovertebral units. We tested the diagnostic utility (mean sensitivity and specificity over 4 readers) of the cutoff for the number of lesions on spinal MRI as proposed in the literature (>=2 or >=3 CILs and >=6 CFLs), and we tested for possible thresholds (from >=1 CIL or CFL to >=10 CILs or CFLs) for nonradiographic axial SpA and AS patients in both cohorts. RESULTS: None of the spinal thresholds (>=2 or >=3 CILs and >=6 CFLs) showed clinically relevant diagnostic utility (positive likelihood ratio [LR] range 1.38-2.36) when comparing patients with nonradiographic axial SpA to patients with nonspecific back pain. A threshold of >=6 CILs had moderate to substantial diagnostic utility (positive LR 13.26 and 6.74 in cohorts A and B, respectively) in nonradiographic axial SpA, while >=4 CILs showed small diagnostic utility (positive LR 3.83 and 2.72 in cohorts A and B, respectively) but specificities of >0.90. CONCLUSION: None of the previously proposed candidate criteria for a positive spinal MRI finding of axial SpA showed clinically relevant diagnostic utility in nonradiographic axial SpA. These results question the value of proposed definitions for a positive finding of SpA based on MRI of the spine alone. PMID- 25510606 TI - Knowledge based word-concept model estimation and refinement for biomedical text mining. AB - Text mining of scientific literature has been essential for setting up large public biomedical databases, which are being widely used by the research community. In the biomedical domain, the existence of a large number of terminological resources and knowledge bases (KB) has enabled a myriad of machine learning methods for different text mining related tasks. Unfortunately, KBs have not been devised for text mining tasks but for human interpretation, thus performance of KB-based methods is usually lower when compared to supervised machine learning methods. The disadvantage of supervised methods though is they require labeled training data and therefore not useful for large scale biomedical text mining systems. KB-based methods do not have this limitation. In this paper, we describe a novel method to generate word-concept probabilities from a KB, which can serve as a basis for several text mining tasks. This method not only takes into account the underlying patterns within the descriptions contained in the KB but also those in texts available from large unlabeled corpora such as MEDLINE. The parameters of the model have been estimated without training data. Patterns from MEDLINE have been built using MetaMap for entity recognition and related using co-occurrences. The word-concept probabilities were evaluated on the task of word sense disambiguation (WSD). The results showed that our method obtained a higher degree of accuracy than other state-of-the-art approaches when evaluated on the MSH WSD data set. We also evaluated our method on the task of document ranking using MEDLINE citations. These results also showed an increase in performance over existing baseline retrieval approaches. PMID- 25510607 TI - Predicting treatment process steps from events. AB - MOTIVATION: The primary economy-driven documentation of patient-specific information in clinical information systems leads to drawbacks in the use of these systems in daily clinical routine. Missing meta-data regarding underlying clinical workflows within the stored information is crucial for intelligent support systems. Unfortunately, there is still a lack of primary clinical needs driven electronic patient documentation. Hence, physicians and surgeons must search hundreds of documents to find necessary patient data rather than accessing relevant information directly from the current process step. In this work, a completely new approach has been developed to enrich the existing information in clinical information systems with additional meta-data, such as the actual treatment phase from which the information entity originates. METHODS: Stochastic models based on Hidden Markov Models (HMMs) are used to create a mathematical representation of the underlying clinical workflow. These models are created from real-world anonymized patient data and are tailored to therapy processes for patients with head and neck cancer. Additionally, two methodologies to extend the models to improve the workflow recognition rates are presented in this work. RESULTS: A leave-one-out cross validation study was performed and achieved promising recognition rates of up to 90% with a standard deviation of 6.4%. CONCLUSIONS: The method presented in this paper demonstrates the feasibility of predicting clinical workflow steps from patient-specific information as the basis for clinical workflow support, as well as for the analysis and improvement of clinical pathways. PMID- 25510608 TI - Direct growth of ultrafast transparent single-layer graphene defoggers. AB - The idea flat surface, superb thermal conductivity and excellent optical transmittance of single-layer graphene promise tremendous potential for graphene as a material for transparent defoggers. However, the resistance of defoggers made from conventional transferred graphene increases sharply once both sides of the film are covered by water molecules which, in turn, leads to a temperature drop that is inefficient for fog removal. Here, the direct growth of large-area and continuous graphene films on quartz is reported, and the first practical single-layer graphene defogger is fabricated. The advantages of this single-layer graphene defogger lie in its ultrafast defogging time for relatively low input voltages and excellent defogging robustness. It can completely remove fog within 6 s when supplied a safe voltage of 32 V. No visible changes in the full defogging time after 50 defogging cycles are observed. This outstanding performance is attributed to the strong interaction forces between the graphene films and the substrates, which prevents the permeation of water molecules. These directly grown transparent graphene defoggers are expected to have excellent prospects in various applications such as anti-fog glasses, auto window and mirror defogging. PMID- 25510609 TI - Inventory development for perfluorooctane sulfonic acid (PFOS) in Turkey: challenges to control chemicals in articles and products. AB - Perfluorooctane sulfonic acid (PFOS) and related substances have been listed as persistent organic pollutants (POPs) in the Stockholm Convention. Countries which have ratified the Convention need to take appropriate actions to control PFOS use and release. This study compiles and enhances the findings of the first inventory of PFOS and related substances use in Turkey conducted within the frame of the Stockholm Convention National Implementation Plan (NIP) update. The specific Harmonized Commodity Description and Coding System (Harmonized System (HS)) codes of imported and exported goods that possibly contain PFOS and 165 of Chemical Abstracts Service (CAS) numbers of PFOS-related substances were assessed for acquiring information from customs and other authorities. However, with the current approaches available, no useful information could be compiled since HS codes are not specific enough and CAS numbers are not used by customs. Furthermore, the cut-off volume in chemical databases in Turkey and the reporting limit in the HS system (0.1 %) are too high for controlling PFOS. The attempt of modeling imported volumes by a Monte Carlo simulation did not also result in a satisfactory estimate, giving an upper-bound estimate above the global production volumes. The replies to questionnaires were not satisfactory, highlighting that an elaborated approach is needed in the communication with potentially PFOS-using stakeholders. The experience of the challenges of gathering information on PFOS in articles and products revealed the gaps of controlling highly hazardous substances in products and articles and the need of improvements. PMID- 25510610 TI - Effect of heavy-metal-resistant bacteria on enhanced metal uptake and translocation of the Cu-tolerant plant, Elsholtzia splendens. AB - A hydroponics trial was employed to study the effects of Pseudomonas putida CZ1 (CZ1), a heavy-metal-resistant bacterial strain isolated from the rhizosphere of Elsholtzia splendens (E. splendens), on the uptake and translocation of copper (Cu) in E. splendens. Significant promotion of plant growth coupled with the obvious plant-growth-promoting (PGP) characters of the bacteria suggested that CZ1 would be a plant-growth-promoting rhizobacterium (PGPR) to E. splendens under Cu stress condition. The results of inductively coupled plasma optical emission spectrometry (ICP-OES) showed that CZ1 increased the concentration of Cu in the shoots (up to 211.6% compared to non-inoculation treatment) and translocation factor (TF) (from 0.56 to 1.83%) of those exposed to Cu. The distribution of Cu in root cross section measured by synchrotron-based X-ray fluorescence microscopy (SRXRF) indicated that CZ1 promoted the transport of Cu from cortex to xylem in roots, which contributed to the accumulation of Cu in shoots. Furthermore, CZ1 improved the uptake of nutrient elements by plants to oppose to the toxicity of Cu. In summary, P. putida CZ1 acted as a PGPR in resistance to Cu and promoted the accumulation and translocation of Cu from root to shoot by element redistribution in plant root; hence, CZ1 is a promising assistance to phytoremediation. PMID- 25510611 TI - Assessment of the quality of polluted areas based on the content of heavy metals in different organs of the grapevine (Vitis vinifera) cv Tamjanika. AB - In this study, the samples of the spatial soil and organs of the grapevine (Vitis vinifera) cultivar Tamjanika were collected from the selected zones near the Mining and Smelting Complex Bor (East Serbia). They were analyzed by ICP-OES to determine the content of Cu, Zn, Pb, As, Cd, and Ni with the aim of ascertaining if these data may help in the assessment and improvement of the quality of environment in polluted areas such as Bor and its surrounding area. The results obtained from the calculated biological and enrichment factors, as well as from the Pearson correlation study and hierarchical cluster analysis confirmed that very useful information is recorded in plant organs: root, stem, leaves, and fruit. Yet, when the atmospheric pollution is the sphere of interest, the most informative data are found in unwashed leaves. The results of this study indicated also that the investigated plant species has some highly effective strategies involved in tolerance to the stress induced by heavy metals, which makes it an excellent candidate for phytostabilization purposes. Planting of this grapevine cultivar can be recommended in all areas that are severely polluted with heavy metals. PMID- 25510612 TI - Transport and bioaccumulation of polychlorinated dibenzo-p-dioxins and dibenzofurans at the Bien Hoa Agent Orange hotspot in Vietnam. AB - The Bien Hoa airbase (south of Vietnam) is known as one of the Agent Orange hotspots which have been seriously contaminated by Agent Orange/dioxin during the Vietnam War. Hundreds of samples including soil, sediment and fish were collected at the Bien Hoa Agent Orange hotspot for assessment of the environmental contamination caused by dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs). The toxicity equivalency quotient (TEQ) concentration of PCDD/Fs in soil and sediment varied from 7.6 to 962,000 and 17 to 4860 pg/g dry wt, respectively, implying very high contamination of PCDD/Fs in several areas. PCDD/F levels in fish ranged between 1.8 and 288 pg/g TEQ wet wt and was generally higher than advisory guidelines for food consumption. 2,3,7,8 Tetrachlorinated dibenzo-p-dioxins (2,3,7,8-TCDD) contributed 66-99 % of TEQ for most of the samples, suggesting 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) from Agent Orange as the major source of the contamination. The vertical transport of PCDD/Fs was observed in soil column with high TEQ levels above 1000 pg/g dry wt (Vietnamese limit for necessary remediation activities- TCVN 8183:2009 (2009)) even at a depth of 1.8 m. The vertical transport of PCDD/Fs has probably mainly taken place during the "Ranch Hand" defoliant spray activities due to the leaks and spills of phenoxy herbicides and solvents. The congener patterns suggest that transports of PCDD/Fs by weathering processes have led to their redistribution in the low-land areas. Also, an estimate for the total volume of contaminated soil requiring remediation to meet Vietnamese regulatory limits is provided. PMID- 25510613 TI - A pilot study of indoor air quality in screen golf courses. AB - The aims of this study were to provide basic data for determining policies on air quality for multi-user facilities, including the legal enrollment of the indoor air quality regulation as designated by the Ministry of Environment, and to establish control plans. To this end, concentrations of ten pollutants (PM10, carbon monoxide (CO), carbon dioxide (CO2), nitrogen dioxide (NO2), formaldehyde (HCHO), total volatile organic compounds (TVOCs), radon (Rn), oxone (O3), total bacteria counts (TBC), and asbestos) in addition to nicotine, a smoking index material used to determine the impact of smoking on the air quality, were investigated in indoor game rooms and lobbies of 64 screen golf courses. The average concentration of none of the ten pollutants in the game rooms and lobbies of screen golf courses was found to exceed the limit set by the law. There were, however, pollutant concentrations exceeding limits in some screen golf courses, in order to establish a control plan for the indoor air quality of screen golf courses, a study on the emission sources of each pollutant was conducted. The major emission sources were found to be facility users' activities such as smoking and the use of combustion appliances, building materials, and finishing materials. PMID- 25510614 TI - Protective effect of Mn(III)-desferrioxamine B upon oxidative stress caused by ozone and acid rain in the Brazilian soybean cultivar Glycine max "Sambaiba". AB - This study aimed to investigate the effects of the Mn complex (Mn(III) desferrioxamine B (MnDFB)) on oxidative stress in the Brazilian soybean cultivar Glycine max "Sambaiba" following exposure to ozone and acid rain. We determined the suitable dose of MnDFB to apply to G. max seedlings using a dose-response curve. The highest superoxide dismutase (SOD) activity and Mn content in leaves were found upon the application of 8 MUM MnDFB. Thus, G. max seedlings pretreated with 8 MUM MnDFB were individually exposed to ozone and acid rain simulated. Pretreatment with MnDFB reduced lipid peroxidation upon ozone exposure and increased SOD activity in leaves; it did not alter the metal content in any part of the plant. Conversely, following acid rain exposure, neither the metal content in leaves nor SOD enzyme activity were directly affected by MnDFB, unlike pH. Our findings demonstrated that exogenous MnDFB application before ozone exposure may modulate the MnSOD, Cu/ZnSOD, and FeSOD activities to combat the ROS excess in the cell. Here, we demonstrated that the applied dose of MnDFB enhances antioxidative defenses in soybean following exposure to acid rain and especially to ozone. PMID- 25510615 TI - Effects of pH and natural organic matter (NOM) on the adsorptive removal of CuO nanoparticles by periphyton. AB - The presence of nanoparticles (NPs) in natural aquatic environment is a potential risk to aquatic and human life. Periphyton, ubiquitous in aquatic environment, has been used to remove pollutants from aquatic systems. Understanding the interaction between NPs and periphyton will help to better predict the behavior and fate of NPs in aquatic media. This study was aimed to investigate the CuO NP biosorption mechanism by periphyton at acidic, neutral, and alkaline pH and with varying natural organic matter (NOM) concentrations. The rate of adsorption and removal of CuO NPs was decreased with increase in initial pH and NOM concentration. The zeta potential study suggests that the biosorption of CuO NPs by periphyton was related to electrostatic force of attraction. The particle size distribution of CuO NPs in solution with different NOM concentrations played an important role in CuO NP removal. The well fit between pseudo-first-order kinetics and adsorption process indicated that physical sorption appears to be the dominating process. These results show that periphyton can be employed for an environmentally benign and effective solution for NP removal. PMID- 25510616 TI - Changes in mesophyll element distribution and phytometabolite contents involved in fluoride tolerance of the arid gypsum-tolerant plant species Atractylis serratuloides Sieber ex Cass. (Asteraceae). AB - Atractylis serratuloides is an abundant native spiny species that grows in the surroundings of superphosphate factories in Tunisia. This plant species is adapted to arid environments and tolerates a high level of fluoride pollution in soils. The aim of this study was to better understand the physiological mechanisms of fluoride tolerance of this species, comparing the fluoride contaminated sites of Gabes and Skhira with the reference site of Smara. Results demonstrated the involvement of leaf element and phytometabolite balances in the in situ response of A. serrulatoides to fluoride. Calcium, sulphur and magnesium were differently distributed between the sites of Gabes and Smara in all plant organs. No specific tissue fluorine accumulation in root, stem and leaf, even in the most contaminated site at Gabes, was detected by EDAX mapping. Lower anthocyan and flavonol levels but enhanced nitrogen balance index were found in A. serrulatoides leaves from Gabes compared to the two other sites. A. serratuloides appeared as a fluoride excluder and its tolerance involved calcium interactions with fluoride. Moreover, an occurrence of dark septate endophytes and arbuscular mycorhizal fungi in root systems of A. serratuloides was reported for the first time, and these symbioses were present but low at all sites. We suggest the use of this plant species for fluoride-polluted soil stabilization. PMID- 25510617 TI - Naturally evolved enhanced Cd tolerance of Dianthus carthusianorum L. is not related to accumulation of thiol peptides and organic acids. AB - Two contrasting ecotypes of Dianthus carthusianorum L., metallicolous (M) and nonmetallicolous (NM), were cultivated in hydroponics at 0-50 MUM Cd for 14 days to compare their Cd accumulation, sensitivity and tolerance mechanisms. While both ecotypes contained similar concentrations of Cd in the shoots and roots, the M ecotype was more Cd-tolerant (as measured by fresh weight production and root and leaf viability). Both ecotypes accumulated phytochelatins (PCs) in response to Cd with a higher amount thereof found in the NM ecotype. Concentrations of PCs remained unchanged with increasing Cd concentrations in the root tissues, but their content in the shoots increased. The addition of L-buthionine-sulfoximine (BSO) diminished glutathione (GSH) accumulation and arrested PC production, which increased the sensitivity to Cd of the NM, but not M ecotype. Organic acids (malate and citrate) as well as proline accumulation did not change significantly after Cd exposition and was at the same level in both ecotypes. The enhanced Cd tolerance of the M ecotype of D. carthusianorum cannot be explained in terms of restricted Cd uptake and differential production of PCs, organic acids or proline; some other mechanisms must be involved in its adaptation to the high Cd content in the environment. PMID- 25510618 TI - Interval training-induced alleviation of rigidity and hypertonia in patients with Parkinson's disease is accompanied by increased basal serum brain-derived neurotrophic factor. AB - OBJECTIVE: To examine the effects of cycloergometric interval training on parkinsonian rigidity, relaxed biceps brachii muscle tone in affected upper extremities, and serum level of brain-derived neurotrophic factor. DESIGN: Case series, repeated-measures design, pilot study. SUBJECTS/PATIENTS: Eleven patients with mild-to-moderate Parkinson's disease (Hoehn & Yahr scale 2.3 +/- 0.72), recruited from a neurological clinic, underwent cycle training and were tested along with non-trained, healthy control subjects (n = 11) in a motor control laboratory. METHODS: Patients underwent 8 weeks of interval training (3 * 1-h sessions weekly, consisting of a 10-min warm-up, 40 min of interval exercise, and 10-min cool-down) on a stationary cycloergometer. Parkinsonian rigidity (Unified Parkinson's Disease-Rating-Scale) in the upper extremity, resting biceps brachii muscle tone (myometric stiffness and frequency), and brain-derived neurotrophic factor level were measured 1-3 days before interval training cycle started and 6 10 days after the last training session. RESULTS: Training resulted in a decrease in rigidity (p = 0.048) and biceps brachii myometric muscle stiffness (p = 0.030) and frequency (p = 0.006), and an increase in the level of brain-derived neurotrophic factor (p = 0.035) relative to pre-training values. The increase in brain-derived neurotrophic factor level correlated with improvements in parkinsonian rigidity (p = 0.025), biceps brachii myometric stiffness (p = 0.001) and frequency (p = 0.002). CONCLUSION: Training-induced alleviation of parkinsonian rigidity and muscle tone decrease may be associated with neuroplastic changes caused by a training-induced increase in the level of brain derived neurotrophic factor. PMID- 25510619 TI - Broadband infrared photoluminescence in silicon nanowires with high density stacking faults. AB - Making silicon an efficient light-emitting material is an important goal of silicon photonics. Here we report the observation of broadband sub-bandgap photoluminescence in silicon nanowires with a high density of stacking faults. The photoluminescence becomes stronger and exhibits a blue shift under higher laser powers. The super-linear dependence on excitation intensity indicates a strong competition between radiative and defect-related non-radiative channels, and the spectral blue shift is ascribed to the band filling effect in the heterostructures of wurtzite silicon and cubic silicon created by stacking faults. PMID- 25510620 TI - New explanations for old observations: marginal band coiling during platelet activation. AB - Blood platelets are tiny cell fragments derived from megakaryocytes. Their primary function is to control blood vessel integrity and ensure hemostasis if a vessel wall is damaged. Circulating quiescent platelets have a flat, discoid shape maintained by a circumferential microtubule bundle, called the marginal band (MB). In the case of injury platelets are activated and rapidly adopt a spherical shape due to microtubule motor-induced elongation and subsequent coiling of the MB. Platelet activation and shape change can be transient or become irreversible. This depends on the strength of the activation stimulus, which is translated into a cytoskeletal crosstalk between microtubules, their motors and the actomyosin cortex, ensuring stimulus-response coupling. Following microtubule motor-driven disc-to-sphere transition, a strong stimulus will lead to compression of the sphere through actomyosin cortex contraction. This will concentrate the granules in the center of the platelet and accelerate their exocytosis. Once granules are released, platelets have crossed the point of no return to irreversible activation. This review summarizes the current knowledge of the molecular mechanism leading to platelet shape change, with a special emphasis on microtubules, and refers to previously published observations, which have been essential for generating an integrated view of cytoskeletal rearrangements during platelet activation. PMID- 25510621 TI - Cloud-based privacy-preserving remote ECG monitoring and surveillance. AB - BACKGROUND: The number of technical solutions for monitoring patients in their daily activities is expected to increase significantly in the near future. Blood pressure, heart rate, temperature, BMI, oxygen saturation, and electrolytes are few of the physiologic factors that will soon be available to patients and their physicians almost continuously. The availability and transfer of this information from the patient to the health provider raises privacy concerns. Moreover, current data encryption approaches expose patient data during processing, therefore restricting their utility in applications requiring data analysis. METHODS: We propose a system that couples health monitoring techniques with analytic methods to permit the extraction of relevant information from patient data without compromising privacy. This proposal is based on the concept of fully homomorphic encryption (FHE). Since this technique is known to be resource-heavy, we develop a proof-of-concept to assess its practicality. Results are presented from our prototype system, which mimics live QT monitoring and detection of drug induced QT prolongation. RESULTS: Transferring FHE-encrypted QT and RR samples requires about 2 Mbps of network bandwidth per patient. Comparing FHE-encrypted values--for example, comparing QTc to a given threshold-runs quickly enough on modest hardware to alert the doctor of important results in real-time. CONCLUSIONS: We demonstrate that FHE could be used to securely transfer and analyze ambulatory health monitoring data. We present a unique concept that could represent a disruptive type of technology with broad applications to multiple monitoring devices. Future work will focus on performance optimizations to accelerate expansion to these other applications. PMID- 25510624 TI - Sexual orientation in the 2013 national health interview survey: a quality assessment. AB - Objective-This report presents a set of quality analyses of sexual orientation data collected in the 2013 National Health Interview Survey (NHIS). NHIS sexual orientation estimates are compared with those from the National Survey of Family Growth (NSFG) and the National Health and Nutrition Examination Survey (NHANES). Selected health outcomes by sexual orientation are compared between NHIS and NSFG. Assessments of item nonresponse, item response times, and responses to follow-up questions to the sexual orientation question are also presented. Methods-NHIS is a multipurpose health survey conducted continuously throughout the year by the Centers for Disease Control and Prevention's National Center for Health Statistics. Analyses in this report were based on NHIS data collected in 2013 from 34,557 adults aged 18 and over. Sampling weights were used to produce national estimates that are representative of the civilian noninstitutionalized U.S. adult population. Data from the 2006-2010 NSFG and 2009-2012 NHANES were used for the comparisons. Results-Based on the 2013 NHIS data, 96.6% of adults identified as straight, 1.6% identified as gay/lesbian, and 0.7% identified as bisexual. The remaining 1.1% of adults identified as ''something else,'' stated ''I don't know the answer,'' or refused to answer. Responses to follow-up questions suggest that the sexual orientation question is producing little classification error. In addition, largely similar patterns of association between sexual orientation and health were observed for NHIS and NSFG. Analyses of item nonresponse rates revealed few data quality issues, although item response times suggest possible shortcutting of the question and comprehension problems for select respondents. PMID- 25510625 TI - Recurring highly contagious virus infections in pigs. PMID- 25510623 TI - Role of intracellular and extracellular annexin A1 in migration and invasion of human pancreatic carcinoma cells. AB - BACKGROUND: Annexin A1 (ANXA1), a 37 kDa multifunctional protein, is over expressed in tissues from patients of pancreatic carcinoma (PC) where the protein seems to be associated with malignant transformation and poor prognosis. METHODS: The expression and localization of ANXA1 in MIA PaCa-2, PANC-1, BxPC-3 and CAPAN 2 cells were detected by Western Blotting and Immunofluorescence assay. Expression and activation of Formyl Peptide Receptors (FPRs) were shown through flow cytometry/PCR and FURA assay, respectively. To investigate the role of ANXA1 in PC cell migration and invasion, we performed in vitro wound-healing and matrigel invasion assays. RESULTS: In all the analyzed PC cell lines, a huge expression and a variable localization of ANXA1 in sub-cellular compartments were observed. We confirmed the less aggressive phenotype of BxPC-3 and CAPAN-2 compared with PANC-1 and MIA PaCa-2 cells, through the evaluation of Epithelial Mesenchymal Transition (EMT) markers. Then, we tested MIA PaCa-2 and PANC-1 cell migration and invasiveness rate which was inhibited by specific ANXA1 siRNAs. Both the cell lines expressed FPR-1 and -2. Ac2-26, an ANXA1 mimetic peptide, induced intracellular calcium release, consistent with FPR activation, and significantly increased cell migration/invasion rate. Interestingly, in MIA PaCa 2 cells we found a cleaved form of ANXA1 (33 kDa) that localizes at cellular membranes and is secreted outside the cells, as confirmed by MS analysis. The importance of the secreted form of ANXA1 in cellular motility was confirmed by the administration of ANXA1 blocking antibody that inhibited migration and invasion rate in MIA PaCa-2 but not in PANC-1 cells that lack the 33 kDa ANXA1 form and show a lower degree of invasiveness. Finally, the treatment of PANC-1 cells with MIA PaCa-2 supernatants significantly increased the migration rate of these cells. CONCLUSION: This study provides new insights on the role of ANXA1 protein in PC progression. Our findings suggest that ANXA1 protein could regulate metastasis by favouring cell migration/invasion intracellularly, as cytoskeleton remodelling factor, and extracellularly like FPR ligand. PMID- 25510622 TI - Hospitalizations associated with influenza and respiratory syncytial virus among patients attending a network of private hospitals in South Africa, 2007-2012. AB - BACKGROUND: Influenza and respiratory syncytial virus (RSV) infection are common causes of lower respiratory tract illness. Data on their burden in low and middle income settings and from Africa are scarce. We aimed to estimate age-specific rates of hospitalization attributable to influenza and RSV among patients attending private hospitals in South Africa during 2007-2012. METHODS: We estimated annual age-specific rates of influenza- and RSV-associated hospitalization (that is respiratory hospitalizations likely due to influenza or RSV infection) by applying regression models to monthly administrative hospitalization data from a national private hospital group, using influenza and RSV surveillance data as covariates. RESULTS: Estimated mean hospitalization rates associated with seasonal influenza were 75 (95% confidence interval (CI), 41-108) and 3 (95% CI, 2-5) per 100,000 person-years for all-respiratory and all circulatory causes, respectively. Children <1 year and adults >=75 years were the most affected, with influenza-associated all-respiratory hospitalization rates estimated at 255 (95% CI, 143-358) and 380 (95% CI, 227-506) per 100,000 person years, respectively. Excess all-circulatory hospitalizations associated with seasonal influenza were only observed in adults >=65 years. Annual hospitalization rates associated with RSV averaged an estimate of 223 (95% CI, 128-317) per 100,000 person-years for all-respiratory causes. Among children <1 year, RSV-associated all-respiratory hospitalization rate of 7,601 (95% CI, 4,312 10,817) per 100,000 person-years was estimated. CONCLUSIONS: Influenza and RSV substantially contributed to hospitalizations over the study period. PMID- 25510627 TI - [Reduction of intraocular pressure and ocular pulse amplitude during general anesthesia]. AB - AIM: Measurement of the intraocular pressure (IOP) is an important tool for glaucoma diagnostics in children or patients with impaired cooperation. General anesthesia (GA) may significantly influence the IOP. This study aimed to evaluate the reduction of IOP during GA. PATIENTS AND METHODS: The IOP was measured in 229 patients in a recumbent position in the non-operated eye prior to and 5 min after the beginning of GA with a dynamic contour tonometer (DCT). RESULTS: The average IOP decreased from 19.9 +/- 3.7 mmHg prior to GA to 14.1 +/- 3.5 mmHg 5 min after beginning GA (p < 0.0001, IOP decrease 30 %). The GA caused a decrease of up to 2 mmHg in 6.1 %, 2-4 mmHg in 18.8 %, 4-6 mmHg in 21.0 %, 6-8 mmHg in 36.6 %, 8-10 mmHg in 13.6 %, 10-12 mmHg in 2.2 % and more than 12 mmHg in 1.7 % of the eyes. The ocular pulse amplitude (OPA) decreased from a mean of 3.4 +/- 1.5 mmHg to 1.9 +/- 1.0 mmHg (p < 0.0001, OPA decrease 41 %) under GA. CONCLUSION: A significant decrease of IOP (mean 6 mmHg) occurs during GA and under extreme conditions up to 13.8 mmHg. A decrease of OPA of 1.5 mmHg should be taken into consideration for patients under general anesthesia and under extreme conditions up to 7 mmHg. PMID- 25510628 TI - Background matching ability and the maintenance of a colour polymorphism in the red devil cichlid. AB - The evolution and maintenance of colour polymorphisms remains a topic of considerable research interest. One key mechanism thought to contribute to the coexistence of different colour morphs is a bias in how conspicuous they are to visual predators. Although individuals of many species camouflage themselves against their background to avoid predation, differently coloured individuals within a species may vary in their capacity to do so. However, to date, very few studies have explicitly investigated the ability of different colour morphs to plastically adjust their colouration to match their background. The red devil (Amphilophus labiatus) is a Neotropical cichlid fish with a stable colour polymorphism, with the gold morph being genetically dominant and having a myriad of documented advantages over the dark morph. However, gold individuals are much rarer, which may be related to their heightened conspicuousness to would-be predators. Here, we tested the ability of differently coloured individuals to phenotypically adjust the shade of their body colour and patterns to match their background. In particular, we filmed dark, gold and mottled (a transitioning phase from dark to gold) individuals under an identical set-up on light vs. dark coloured substrates. We found that, in contrast to individuals of the dark morph, gold and mottled individuals were less capable of matching their body colouration to their background. As a result, gold individuals appeared to be more conspicuous. These results suggest that a difference in background matching ability could play an important role in the maintenance of colour polymorphisms. PMID- 25510629 TI - Synthesis and anticancer activities of a novel class of mono- and di-metallic Pt(II)(salicylaldiminato)(DMSO or Picolino)Cl complexes. AB - A series of novel Pt(ii) complexes [cis- and trans Pt(ii)(salicylaldimine)(DMSO)Cl (), trans-Pt(ii)(salicylaldimine)(4-picoline)Cl (), Pt(ii)(salicylaldimine)Cl (), trans- and cis/trans Pt2(ii)(salicylaldimine)(DMSO)2Cl2 (), trans-Pt2(ii)(salicylaldimine)(4 picoline)2Cl2 () was synthesized and characterized. The structures of -cis, trans and were determined using a single crystal X-ray analysis. This class of Pt(ii) complexes has been studied for their in vitro cytotoxicity in multiple human cancer cell lines, including breast (MCF-7), liver (HepG2), lung (A549), colon (HCT116) and cervical (Hela) cancers. -trans, and -trans showed significant cytotoxicity to these cancer cells comparable to cisplatin. A time- and dose dependent MTT assay revealed that these complexes can suppress cell viability and cell proliferation. Mechanistically these complexes induced pro-apoptotic gene expression such as BAX, PUMA and NOXA and thereby enhanced apoptosis. Moreover, PARP cleavage in a dose-dependent manner indicated their cytotoxic effect against cancer cells. Apoptosis of cancer cells occurred through apoptotic pathways as explained by the cytometry analysis. The DNA unwinding properties of these active Pt(ii) complexes were studied by gel electrophoresis using pBR322 plasmid DNA as a target. Changes in the morphology of cancer cells were also observed upon the addition of -trans, and -trans. PMID- 25510630 TI - Phospho-iTRAQ: assessing isobaric labels for the large-scale study of phosphopeptide stoichiometry. AB - The ability to distinguish between phosphopeptides of high and low stoichiometry is essential to discover the true extent of protein phosphorylation. We here extend the strategy whereby a peptide sample is briefly split in two identical parts and differentially labeled preceding the phosphatase treatment of one part. Our use of isobaric tags for relative and absolute quantitation (iTRAQ) marks the first time that isobaric tags have been applied for the large-scale analysis of phosphopeptides. Our Phospho-iTRAQ method focuses on the unmodified counterparts of phosphorylated peptides, which thus circumvents the ionization, fragmentation, and phospho-enrichment difficulties that hamper quantitation of stoichiometry in most common phosphoproteomics methods. Since iTRAQ enables multiplexing, simultaneous (phospho)proteome comparison between internal replicates and multiple samples is possible. The technique was validated on multiple instrument platforms by adding internal standards of high stoichiometry to a complex lysate of control and EGF-stimulated HeLa cells. To demonstrate the flexibility of Phospho-iTRAQ with regards to the experimental setup, the proteome coverage was extended through gel fractionation, while an internal replicate measurement created more stringent data analysis opportunities. The latest developments in MS instrumentation promise to further increase the resolution of the stoichiometric measurement of Phospho-iTRAQ in the future. The data have been deposited to the ProteomeXchange with identifier PXD001574. PMID- 25510631 TI - [Non-cirrhotic portal hypertension associated with didanosine: An unusual cause of gastrointestinal bleeding]. PMID- 25510632 TI - [Storage of human samples for research: Autonomy and genomic data]. PMID- 25510633 TI - Conservative adenomyomectomy with transient occlusion of uterine arteries for diffuse uterine adenomyosis. AB - AIM: This study aimed to determine the feasibility and safety of adenomyomectomy with transient occlusion of uterine arteries (TOUA) in patients with symptomatic diffuse uterine adenomyosis. MATERIAL AND METHODS: Twenty-six patients with symptomatic diffuse uterine adenomyosis underwent adenomyomectomy with TOUA by a single surgeon at Ulsan University Hospital between May 2011 and September 2012. Surgical outcomes included operative time, intraoperative injury to blood vessels, nerves, and pelvic organs and operative blood loss. We assessed the degree of improvement in dysmenorrhea and menorrhagia at the 4-month follow-up after completion of adjuvant gonadotrophin-releasing hormone agonist. RESULTS: The mean age of patients was 37.73 years (range, 27-49 years). The mean total surgical time was 95.0 min (range, 60-145 min; SD, 34.49). The mean estimated blood loss was 191.54 mL (range, 80-400 mL; SD, 110.91) and there were no cases of injury to the uterine arteries or pelvic nerves. The mean time of TOUA was 9.79 min (range, 6-16 min; SD, 2.74). The mean duration of hospital stay was 5.65 days (range, 4-7 days; SD, 0.85). There were no major complications requiring reoperation or readministration during the mean follow-up period of 13.5 months. At the 7-month follow-up after adenomyomectomy with TOUA, complete remission of dysmenorrhea and menorrhagia was observed in 94.4% and 100% of patients, respectively. CONCLUSIONS: Adenomyomectomy with TOUA could be a safe and effective surgical method in women with symptomatic diffuse uterine adenomyosis to preserve fertility. PMID- 25510634 TI - Gastrointestinal stromal tumor of the adrenal gland:a case report and review of the literature. AB - Gastrointestinal stromal tumors (GISTs) are rare neoplasms of the gastrointestinal (GI) tract. The occurrence of these neoplasms ectopically outside the GI tract is extremely uncommon. Only one case of primary adrenal GIST has been reported in the literature. In this account, we report a second case of primary adrenal GIST in a 34-year-old male who presented with a 5-week history of gradually progressive left flank pain and early satiety. Whole-body positron emission tomography (PET)/computed tomography (CT) scan showed a 14 * 11 cm hypermetabolic (18)fluorodeoxyglucose (FDG)-avid mass lesion involving the left adrenal gland and dorsal part of the left hemi-diaphragm. Biopsy of the lesion revealed tumor cells that are immunoreactive to CD-117 and CD-34 and negative to CD-31, S-100, cytokeratin, desmin, and vimentin, features characteristic of GIST. The patient was given imatinib, which drastically decreased his complaints with almost complete resolution of the tumor on his last follow-up radiographic images. Primary left adrenal GIST is an extremely rare neoplasm and can be confused with GISTs arising from the greater curvature of the stomach. Imatinib therapy is optimal in the management of these tumors. PMID- 25510636 TI - Micro-invasive suture trabeculotomy after canaloplasty: preliminary results. AB - BACKGROUND: In this study, a conjunctival-sparing ab interno approach for circumferential trabeculotomy, termed micro-invasive suture trabeculotomy (MIST) and its preliminary results are presented. DESIGN: Retrospective case-series in a university setting. PARTICIPANTS: A total of 31 patients with open-angle glaucoma with history of canaloplasty. METHODS: A conjunctival-sparing ab interno approach for circumferential trabeculotomy, termed MIST. MAIN OUTCOME MEASURES: Mean decrease of intraocular pressure (IOP) and number of pressure-lowering medications. RESULTS: Mean decrease of IOP was 11.1 mmHg (standard deviation [SD], 9.9 mmHg) at 6 months, 12.1 mmHg (SD, 10.5 mmHg) at 12 months and 13.5 mmHg (SD, 11.4 mmHg) at 24 months. The average percent lowering of IOP was 36.7% (SD, 32.8%) at 6 months, 41.4% (SD, 35.9%) at 12 months and 44.6% (SD, 37.7%) at 24 months. The number of pressure-lowering medications decreased by 1.1 (SD, 1.3) at month 6, by 1.2 (SD, 1.5) at month 12, and by 1.3 (SD, 1.6) at month 24. CONCLUSIONS: MIST is a promising approach for the treatment of open-angle glaucoma, which is insufficiently controlled with canaloplasty. The procedure achieved significant and sustained lowering of the intraocular pressure and demonstrated an excellent safety profile. The main advantages of the procedure are: easy to learn, fast to perform, and sparing of the conjunctiva for further filtration surgery, if necessary. PMID- 25510635 TI - An extraordinary case of mesenchymal chondrosarcoma metastasis in the thyroid. AB - Secondary tumours of the thyroid gland account for 1.25 to 3 % in clinical series and reach 24 % in autopsy series. Chondrosarcoma is a rare malignant mesenchymal tumour of chondrogenic nature; the mesenchymal variant represents less than 3 % of all chondrosarcomas, being therefore extremely rare. A mesenchymal chondrosarcoma metastasis in the thyroid is exceptional; to our knowledge, only three previous cases of chondrosarcoma metastasis in the thyroid have been reported to date but none of such cases corresponded to a mesenchymal chondrosarcoma. We present the first of such a case in a 27-year-old woman with a 4-year history of mesenchymal chondrosarcoma of the sacrum that was treated by surgery and chemotherapy. At the present admission, head and neck computed tomography revealed a well-defined nodule in the thyroid gland. The diagnosis of metastasis from the mesenchymal chondrosarcoma was made in the right lobectomy specimen. PMID- 25510637 TI - Lateral neck recurrence from papillary thyroid carcinoma: Predictive factors and prognostic significance. AB - OBJECTIVES/HYPOTHESIS: The aim of this study was to identify any possible predictive factors of lateral neck recurrence in patients with papillary thyroid carcinoma with no ultrasonographic and/or cytological evidence of lymph node metastasis at time of diagnosis. The influence of lateral neck recurrence on survival was also investigated. STUDY DESIGN: Observational retrospective study. METHODS: Retrospective review of clinical records of 610 patients surgically treated for papillary thyroid carcinoma with clinically negative lymph nodes at the Otolaryngology Unit of the Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy, from January 1984 to December 2008. RESULTS: Lateral neck recurrences were ipsilateral to the primary tumor in all cases and were associated with the occurrence of more aggressive histological variants and central neck metastasis. Lateral neck recurrences were more frequently observed in patients with distant metastases and were associated with a reduced disease specific survival. CONCLUSION: Lateral neck compartment ipsilateral to the tumor was the most common site of recurrence, with about half of cases appearing in the first 28 months of follow-up. In patients with papillary thyroid carcinoma, detection of lateral neck metastases prior to first surgery is crucial to surgical planning. Aggressive histological variants and postsurgical evidence of lymph node metastasis from papillary thyroid carcinoma in central neck compartment are associated with a higher risk of lateral neck recurrence. In these patients, a closer postsurgical ultrasound surveillance of the lateral neck compartments seems worthwhile. LEVEL OF EVIDENCE: 4. PMID- 25510638 TI - Transcatheter aortic valve implantation using the left transcarotid approach in patients with previous ipsilateral carotid endarterectomy. AB - OBJECTIVES: To assess the feasibility and safety of transcatheter aortic valve implantation (TAVI) through a left transcarotid approach in patients previously operated on for ipsilateral carotid endarterectomy (CEA). BACKGROUND: The healthcare impact of extracranial carotid artery disease is essential as stroke is the third-leading cause of death in industrialized nations and CEA is often present in the history of patients awaiting TAVI. METHODS: The primary endpoint was to evaluate 30-day mortality and freedom from major TAVI-related complications in an observational analysis. RESULTS: From December 2011 to February 2014, we performed 9 TAVI. The mean age was 84.6 years. The procedure was performed without any technical complication or vascular injury in every patient. There was neither intraoperative mortality nor intraoperative major complications. One (11.1%) patient experienced spatial-temporal disorientation but cerebral computed tomography did not show any sign of stroke. Two (22.2%) patients needed the implantation of a pacemaker due to third-degree atrioventricular block appearance. Three (33.3%) patients were transfused with packed red blood cells and 1 (11.1%) patient developed a groin hematoma. Only 1 (11.1%) patient showed a residual paravalvular regurgitation >= 2. At 30-day follow-up there was neither mortality nor other TAVI-related complications and echocardiography parameters remained stable. CONCLUSIONS: TAVI through a left transcarotid approach in patients previously operated on for ipsilateral CEA is feasible and safe. The presence of a previous ipsilateral CEA represents no more a limitation to the utilization of this promising access route. At short-term follow-up, mortality and major complications rates are low. PMID- 25510639 TI - Antiproliferative activity of synthetic fatty acid amides from renewable resources. AB - In the work, the in vitro antiproliferative activity of a series of synthetic fatty acid amides were investigated in seven cancer cell lines. The study revealed that most of the compounds showed antiproliferative activity against tested tumor cell lines, mainly on human glioma cells (U251) and human ovarian cancer cells with a multiple drug-resistant phenotype (NCI-ADR/RES). In addition, the fatty methyl benzylamide derived from ricinoleic acid (with the fatty acid obtained from castor oil, a renewable resource) showed a high selectivity with potent growth inhibition and cell death for the glioma cell line-the most aggressive CNS cancer. PMID- 25510641 TI - Accumulation of iron oxide nanoparticles by cultured primary neurons. AB - Magnetic iron oxide nanoparticles (IONPs) are frequently used for biomedical applications. Although nanoparticles can enter the brain, little is known so far on the uptake of IONPs in neurons and on their neurotoxic potential. Hence, we applied dimercaptosuccinate (DMSA)-coated IONPs to cultured primary rat cerebellar granule neurons. These IONPs had average hydrodynamic diameters of around 80 nm and 120 nm when dispersed in incubation medium in the absence and the presence of 10% fetal calf serum, respectively. Acute exposure of neurons with IONPs for up to 6 h did neither alter the cell morphology nor compromise cell viability, although neurons accumulated large amounts of IONPs in a time- and concentration-dependent manner which caused delayed toxicity. For the first 30 min of incubation of neurons at 37 degrees C with IONPs the cellular iron content increased proportionally to the concentration of IONPs applied irrespective of the absence and the presence of serum. IONP-exposure in the absence of serum generated maximal cellular iron contents of around 3000 nmol iron/mg protein after 4 h of incubation, while the accumulation in the presence of 10% serum was slower and reached already within 1 h maximal values of around 450 nmol iron/mg protein. For both incubation conditions was the increase in cellular iron contents significantly lowered by reducing the incubation temperature to 4 degrees C. Application of inhibitors of endocytotic pathways did not affect neuronal IONP accumulation in the absence of serum, while inhibitors of clathrin-mediated endocytosis lowered significantly the IONP accumulation in the presence of serum. These data demonstrate that DMSA-coated IONPs are not acutely toxic to cultured neurons and that a protein corona around the particles strongly affects their interaction with neurons. PMID- 25510640 TI - Effect of lysine to alanine mutations on the phosphate activation and BPTES inhibition of glutaminase. AB - The GLS1 gene encodes a mitochondrial glutaminase that is highly expressed in brain, kidney, small intestine and many transformed cells. Recent studies have identified multiple lysine residues in glutaminase that are sites of N acetylation. Interestingly, these sites are located within either a loop segment that regulates access of glutamine to the active site or the dimer:dimer interface that participates in the phosphate-dependent oligomerization and activation of the enzyme. These two segments also contain the binding sites for bis-2[5-phenylacetamido-1,2,4-thiadiazol-2-yl]ethylsulfide (BPTES), a highly specific and potent uncompetitive inhibitor of this glutaminase. BPTES is also the lead compound for development of novel cancer chemotherapeutic agents. To provide a preliminary assessment of the potential effects of N-acetylation, the corresponding lysine to alanine mutations were constructed in the hGACDelta1 plasmid. The wild type and mutated proteins were purified by Ni(+)-affinity chromatography and their phosphate activation and BPTES inhibition profiles were analyzed. Two of the alanine substitutions in the loop segment (K311A and K328A) and the one in the dimer:dimer interface (K396A) form enzymes that require greater concentrations of phosphate to produce half-maximal activation and exhibit greater sensitivity to BPTES inhibition. By contrast, the K320A mutation results in a glutaminase that exhibits near maximal activity in the absence of phosphate and is not inhibited by BPTES. Thus, lysine N-acetylation may contribute to the acute regulation of glutaminase activity in various tissues and alter the efficacy of BPTES-type inhibitors. PMID- 25510643 TI - Inadequate response to ustekinumab in atopic dermatitis - a report of two patients. PMID- 25510644 TI - Chronic exercise confers neuroprotection in experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is an autoimmune disease that affects the CNS, resulting in accumulated loss of cognitive, sensory, and motor function. This study evaluates the neuropathological effects of voluntary exercise in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Two groups of C57BL/6J mice were injected with an emulsion containing myelin oligodendrocyte glycoprotein and then randomized to housing with a running wheel or a locked wheel. Exercising EAE mice exhibited a less severe neurological disease score and later onset of disease compared with sedentary EAE animals. Immune cell infiltration and demyelination in the ventral white matter tracts of the lumbar spinal cord were significantly reduced in the EAE exercise group compared with sedentary EAE animals. Neurofilament immunolabeling in the ventral pyramidal and extrapyramidal motor tracts displayed a more random distribution of axons and an apparent loss of smaller diameter axons, with a greater loss of fluorescence immunolabeling in the sedentary EAE animals. In lamina IX gray matter regions of the lumbar spinal cord, sedentary animals with EAE displayed a greater loss of alpha-motor neurons compared with EAE animals exposed to exercise. These findings provide evidence that voluntary exercise results in reduced and attenuated disability, reductions in autoimmune cell infiltration, and preservation of axons and motor neurons in the lumbar spinal cord of mice with EAE. PMID- 25510645 TI - Prospective comparison of simple suturing and elevation debridement in compound depressed fractures with no significant mass effect. AB - BACKGROUND: Compound depressed fractures have conventionally been managed surgically with elevation and debridement to avoid infection, especially when there is dural penetration, nonetheless with little evidence. This study was to prospectively compare outcomes after simple suturing and elevation debridement in patients with compound depressed fractures. METHODS: Patients of compound depressed fracture with GCS of five or more, no serious systemic injury, and no significant mass effect were prospectively studied for various factors in relation to infection, hospital stay, survival, and late post-traumatic seizures. Univariate and multivariate analyses were performed using SPSS21. RESULTS: Of the total 232 patients with complete clinico-radiological and follow-up data, 183 underwent simple cleansing and suturing, and 49 underwent surgical elevation debridement. The surgical group at baseline had significantly lower GCS, greater dural violation, and brain matter herniation compared to the conservative arm. Univariate analysis showed simple suturing group to have significantly shorter hospital stay (2.4 vs. 10.3 days) (p < 0.001), lesser infection among survivors (4 vs. 21 %) (p = 0.001), and greater 'survival with no infection' (85 vs. 69 %) (p = 0.01). Multivariate analysis adjusting for age, sex, GCS, dural penetration, and surgical intervention confirmed significantly shorter hospital stay (p < 0.001) and lesser infection among survivors (p = 0.02) in the simple suturing group. Overall, there was no benefit offered by surgical debridement. Simple suturing had a better outcome in most subgroups, except in those with brain matter herniation and GCS 5-8, which showed non-significant benefit with surgical intervention. CONCLUSIONS: Simple suturing seems to be an equally good option in patients with compound depressed fracture with no significant mass effect or brain matter herniation. PMID- 25510646 TI - Prospective study of the correlation between admission plasma homocysteine levels and neurological outcome following subarachnoid hemorrhage: a case for the reverse epidemiology paradox? AB - BACKGROUND: Homocysteine (tHcy) has been known over the last few decades for its putative impact on vascular diseases, but has not been evaluated much in patients with subarachnoid hemorrhage (SAH). This study was carried out to assess its prognostic impact on the neurological outcome following SAH. METHODS: Admission plasma tHcy was evaluated in 90 SAH patients and prospectively studied in relation to various factors and the Glasgow Outcome Scale (GOS) at 3 months. Univariate and multivariate analyses were performed using SPSS 21. RESULTS: tHcy was significantly higher following SAH compared to matched controls [median (IQR): 25.7 (17.3-35.9) vs. 14.0 (9.8-17.6) MUmol/l, p < 0.001]. It was significantly higher in younger patients. However, systemic disease, WFNS and Fisher grades did not have a significant impact on its levels. tHcy was significantly lower among patients who died [median (IQR): 16.0 (14.4-20.6) vs. 29.7 (21.8-40.2) MUmol/l, p < 0.001] and those with unfavorable outcome (GOS 1-3) [median (IQR): 21.6 (14.5-28.2) vs. 30.3 (20.4-40.7) MUmol/l, p = 0.004] compared to others, with a significant continuous positive correlation between tHcy and GOS (p = 0.002). The beneficial association of tHcy with outcome was homogeneous with no significant subgroup difference. Multivariate analysis using binary logistic regression adjusting for the effects of age, systemic disease, WFNS grade, Fisher grade, site of aneurysm, clipping or coiling revealed higher tHcy to have a significant independent association with both survival (p = 0.01) and favorable outcome (p = 0.04). CONCLUSIONS: Higher homocysteine levels following SAH appear to have a significant association with both survival and favorable neurological outcome, independent of other known prognostic factors, apparently exemplifying "reverse epidemiology paradox" in which a conventional risk factor seems to impart a survival advantage. PMID- 25510647 TI - Gamma Knife radiosurgery for low-grade tectal gliomas. AB - BACKGROUND: Tectal gliomas are present in a critical location that makes their surgical treatment difficult. Stereotactic radiosurgery presents an attractive noninvasive treatment option. However, tectal gliomas are also commonly associated with aqueductal obstruction and consequently hydrocephalus. This necessitates some form of CSF diversion procedure before radiosurgery. The aim of the study was to assess the efficacy and safety of Gamma Knife radiosurgery for tectal gliomas. PATIENTS AND METHODS: Between October 2002 and May 2011, 11 patients with tectal gliomas were treated with Gamma Knife radiosurgery. Five patients had pilocytic astrocytomas and six nonpilocytic astrocytomas. Ten patients presented with hydrocephalus and underwent a CSF diversion procedure [7 V-P shunt and 3 endoscopic third ventriculostomy (ETV)]. The tumor volume ranged between 1.2-14.7 cc (median 4.5 cc). The prescription dose was 11-14 Gy (median 12 Gy). RESULTS: Patients were followed for a median of 40 months (13-114 months). Tumor control after radiosurgery was seen in all cases. In 6/11 cases, the tumors eventually disappeared after treatment. Peritumoral edema developed in 5/11 cases at an onset of 3-6 months after treatment. Transient tumor swelling was observed in four cases. Four patients developed cysts after treatment. One of these cases required aspiration and eventually disappeared, one became smaller spontaneously, and two remained stable. CONCLUSION: Gamma Knife radiosurgery is an effective and safe technique for treatment of tectal gliomas. Tumor shrinkage or disappearance after Gamma Knife radiosurgery may preclude the need for a shunt later on. PMID- 25510648 TI - Red blood cell distribution width predicts outcome of cryoballoon-based atrial fibrillation ablation. AB - PURPOSE: Elevated red blood cell distribution width (RDW) has been associated with atrial fibrillation (AF) in cross-sectional and prospective studies. In this study, we aim to evaluate the relation of preablation RDW levels to late AF recurrence following cryoablation. METHODS: A total of 299 patients with symptomatic paroxysmal or persistent AF despite >= 1 antiarrhythmic drug(s) who were scheduled for cryoballoon-based AF ablation were enrolled in this prospective study. RESULTS: A total of 299 patients (55.40 +/- 10.60 years, 49.20 % male) were involved and followed up at a median time of 24 (6-44) months. Patients with late AF recurrence had higher RDW levels (14.30 +/- 0.93 vs. 13.52 +/- 0.93 %, p < 0.001). Multivariate Cox proportional hazard regression analysis showed that RDW level was an independent predictor for late AF recurrence (HR 1.88, 95 % CI 1.41-2.50, p < 0.001) along with left atrial (LA) diameter (HR 3.09, 95 % CI 1.81-5.27, p < 0.001), duration of AF (HR 1.04, 95 % CI 1.01-1.07, p = 0.02), and early AF recurrence (HR 6.39, 95 % CI 3.41-11.97, p < 0.001). A cut-off level of 13.75 % for RDW predicted late AF recurrence following cryoballoon-based pulmonary vein isolation (PVI) with a sensitivity and specificity of 78.00 and 70.00 %, respectively. CONCLUSION: These findings suggest that elevated RDW may be a predictor of late recurrence following cryoballoon-based AF ablation. Further studies are needed to establish its exact pathophysiologic and prognostic roles. PMID- 25510649 TI - Effects of hypoxia on anabolic and catabolic gene expression and DNA methylation in OA chondrocytes. AB - BACKGROUND: Cartilage is an avascular and aneural tissue. Chondrocytes thrive in this restricted environment of low oxygen tension and poor nutrient availability which has led to suggestions that hypoxia may be a protective mechanism against the development of osteoarthritis (OA). There is also a growing body of evidence to support the role of epigenetic factors in the pathogenesis of OA. However, few studies have investigated the epigenetic-OA process within a hypoxic environment. The current study has investigated the effects of hypoxia on gene expression and DNA methylation of anabolic and catabolic genes involved in the pathogenesis of OA. METHODS: Chondrocytes extracted from OA femoral heads were incubated in normoxia and hypoxia (20% and 2% oxygen concentrations respectively). Interleukin 1-beta (IL-1beta) plus oncostatin M (OSM), 5-azadeoxycytidine (5-aza-dC) or media alone (control) were added twice weekly to the incubated samples. After 5 weeks, levels of Collagen type IX (COL9A1), IL1B, and matrix metalloproteinase-13 (MMP13) gene expression were measured using SYBR Green-based qRT-PCR and were correlated with methylation status analysed by pyrosequencing methodology. RESULTS: Hypoxia resulted in a >50-fold and >10-fold increase in relative expression of COL9A1 and IL1B respectively. This was inversely correlated to the DNA methylation status of these genes. Expression of MMP13 was reduced at 2% oxygen tension in control cells. Relative expression of MMP13 increased in cells stimulated with IL-1beta and 5-aza-dC in normoxic conditions, and this effect was eliminated at low oxygen tension although no correlation with methylation status was observed. CONCLUSIONS: These findings demonstrate a role for hypoxia in the regulation of anabolic and catabolic gene expression and the influence of changes in DNA methylation. These results further support the role of epigenetics in OA and, critically, highlight the complex relationship between the physiological environment of cartilaginous cells and the osteoarthritic process with implications for therapeutic intervention and our understanding of OA pathophysiology. PMID- 25510650 TI - The antigens contributing to the serological cross-reactions of Proteus antisera with Klebsiella representatives. AB - Proteus sp. and Klebsiella sp. mainly cause infections of the urinary and respiratory tracts or wounds in humans. The representatives of both genera produce virulence factors like lipopolysaccharide (LPS) or outer membrane proteins (OMPs) having much in common in the structures and/or functions. To check how far this similarity is revealed in the serological cross-reactivity, the bacterial masses of 24 tested Klebsiella sp. strains were tested in ELISA with polyclonal rabbit antisera specific to the representatives of 79 Proteus O serogroups. The strongest reacting systems were selected to Western blot, where the majority of Klebsiella masses reacted in a way characteristic for electrophoretic patterns of proteins. The strongest reactions were obtained for proteins of near 67 and 40 kDa and 12.5 kDa. Mass spectrometry analysis of the proteins samples of one Proteus sp. and one Klebsiella sp. strain showed the GroEL like protein of a sequence GI number 2980926 to be similar for both strains. In Western blot some Klebsiella sp. masses reacted similarly to the homologous Proteus LPSs. The LPS contribution in the observed reactions of the high molecular-mass LPS species was confirmed for Klebsiella oxytoca 0.062. PMID- 25510651 TI - CO extrusion in homogeneous gold catalysis: reactivity of gold acyl species generated through water addition to gold vinylidenes. AB - Herein, we describe a new gold-catalyzed decarbonylative indene synthesis. Synergistic sigma,pi-activation of diyne substrates leads to gold vinylidene intermediates, which upon addition of water are transformed into gold acyl species, a type of organogold compound hitherto only scarcely reported. The latter are shown to undergo extrusion of CO, an elementary step completely unknown for homogeneous gold catalysis. By tuning the electronic and steric properties of the starting diyne systems, this new reactivity could be exploited for the synthesis of indene derivatives in high yields. PMID- 25510652 TI - Unravelling the pivotal role of Alix in MVB sorting and silencing of the activated EGFR. AB - Endosomal sorting complex required for transport (ESCRT)-III-mediated membrane invagination and scission are a critical step in multivesicular body (MVB) sorting of ubiquitinated membrane receptors, and generally thought to be required for degradation of these receptors in lysosomes. The adaptor protein Alix is critically involved in multiple ESCRT-III-mediated, membrane-remodelling processes in mammalian cells. However, Alix knockdown does not inhibit degradation of the activated epidermal growth factor receptor (EGFR) in mammalian cell lines, leading to a widely held notion that Alix is not critically involved in MVB sorting of ubiquitinated membrane receptors in mammalian cells. In the present study, we demonstrate that, despite its non-essential role in degradation of the activated EGFR, Alix plays a critical role in its MVB sorting and silencing Epidermal growth factor (EGF) stimulation of mammalian cell lines induces Alix's interaction with the ubiquitinated EGFR via the Alix V domain, and increases Alix's association with membrane-bound charged multivesicular body protein 4 (CHMP4) via the Alix Bro1 domain. Under both continuous and pulse-chase EGF stimulation conditions, inhibition of Alix's interaction with membrane-bound CHMP4, inhibition of Alix dimerization through the V domain or Alix knockdown dramatically inhibits MVB sorting of the activated EGFR and promotes sustained activation of extracellular-signal regulated kinase (ERK)1/2. Under the continuous EGF stimulation conditions, these cell treatments also retard degradation of the activated EGFR. These findings indicate that Alix is critically involved in MVB sorting of ubiquitinated membrane receptors in mammalian cells. PMID- 25510654 TI - Risk of warfarin-associated intracerebral haemorrhage after ischaemic stroke is low and unchanged during the 2000s. PMID- 25510655 TI - The effect of a paramagnetic metal ion within a molecule: comparison of the structurally identical paramagnetic [3,3-Fe(1,2-C2B9H11)2]- with the diamagnetic [3,3-Co(1,2-C2B9H11)2]- sandwich complexes. AB - Derivatives of the ferrabisdicarbollide [3,3'-Fe(1,2-C(2)B(9)H(11))(2)](-) have been produced starting from the zwitterion [3,3'-Fe(8-(OCH(2)CH(2))(2)-1,2 C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))], 1, upon reaction with nucleophiles: alkoxides, halides and hydrosulfide ions HS(-). The result has been the preparation of [3,3'-Fe(8-(OCH(2)CH(2))(2)R/X-1,2-C(2)B(9)H(10))(1',2' C(2)B(9)H(11))] (R = OMe, [2](-); OEt, [3](-); OCH(2)CH(2)OCH(3), [4](-); and X = Cl, [5](-); Br, [6](-); I, [7](-); and SH, [8](-)). The reaction behavior of is comparable to the well-studied cobalt equivalent, [3,3'-Co(8-(OCH(2)CH(2))2-1,2 C(2)B(9)H(10))(1',2'-C(2)B(9)H(11))], and the yields and stability of the resulting complexes are similar. These results are relevant taking into account that [3,3'-Fe(1,2-C(2)B(9)H(11))(2))(-) is a paramagnetic anion. Implications of this are observed in the (11)B-, (1)H and (13)C NMR spectra of [3,3'-Co(1,2 C(2)B(9)H(11))(2)](-) and [3,3'-Fe(1,2-C(2)B(9)H(11))(2)](-) that having identical sandwich molecular structures and the same negative charge have absolutely different widths of the NMR field, between 15 and -25 ppm for [3,3' Co(1,2-C(2)B(9)H(11))(2)](-) and in the range 150 to -550 ppm for [3,3'-Fe(1,2 C(2)B(9)H(11))(2)](-). The sharpness of both spectra is on the other hand comparable, although no B-H couplings are observed in the Fe metallacarborane or its derivatives. Remarkable is the comparative influence vs. [3,3'-Co(1,2 C(2)B(9)H(11))(2)](-) of replacing Co by Fe on the elements of the cluster layer nearest to the metal. The two equivalent C cluster (Cc) atoms are influenced at 36 840 Hz, the two equivalent B atoms that are adjacent to the two Cc are influenced at 38 157 Hz and the single B that is adjacent to the two B atoms is influenced at 44 062 Hz. Remarkable is the similar influence on B and on C, taking into account that the values have been obtained from two distinct NMR spectra of (11)B and (13)C. The {(11)B-(11)B} COSY NMR and {(1)H-(11)B} HETEROCOSY NMR spectra of [3,3'-Fe(1,2-C(2)B(9)H(11)(2)](-) have been obtained and are reported for the first time. PMID- 25510653 TI - Quantifying initial cellular events of mouse radiation lymphomagenesis and its tumor prevention in vivo by positron emission tomography and magnetic resonance imaging. AB - Radiation-induced thymic lymphoma (RITL) in mice is induced by fractionated whole body X-irradiation (FX) and has served as a useful model for studying radiation carcinogenesis. In this model, the initial postirradiation cellular events in the thymus and bone marrow (BM) are critically important for tumorigenesis, and BM transplantation (BMT) prevents RITL. However, direct assessment of these events is so far restricted by the lack of noninvasive monitoring techniques. Here, we have developed positron emission tomography (PET) and magnetic resonance imaging (MRI) methods to quantify the events critical for RITL development and the effects of BMT in living animals. Apparent diffusion coefficients (ADCs) were calculated from diffusion-weighted MRI to evaluate the changes in the BM of mice receiving FX. ADC values dramatically changed in the irradiated BM, corresponding to pathological findings of the irradiated BM, returning to normal levels following BMT sooner than with spontaneous recovery. PET with 4'-[methyl (11)C]thiothymidine, a novel tracer for cell proliferation, revealed that the irradiated thymus showed significantly higher tracer uptake than the unirradiated thymus 1 week after FX. Interestingly, its increased uptake was completely abolished by BMT, even with very few donor-derived cells in the thymus. Thereafter, the thymus receiving BMT had significantly increased tracer uptake. These findings suggest that BMT first suppresses FX-induced aberrant thymocyte proliferation and then accelerates thymic regeneration. This study demonstrates the feasibility of using PET and MRI for noninvasive monitoring of tumorigenic cellular processes in an animal model of radiation-induced cancer. PMID- 25510656 TI - Rapid generation of clinical-grade antiviral T cells: selection of suitable T cell donors and GMP-compliant manufacturing of antiviral T cells. AB - BACKGROUND: The adoptive transfer of allogeneic antiviral T lymphocytes derived from seropositive donors can safely and effectively reduce or prevent the clinical manifestation of viral infections or reactivations in immunocompromised recipients after hematopoietic stem cell (HSCT) or solid organ transplantation (SOT). Allogeneic third party T-cell donors offer an alternative option for patients receiving an allogeneic cord blood transplant or a transplant from a virus-seronegative donor and since donor blood is generally not available for solid organ recipients. Therefore we established a registry of potential third party T-cell donors (allogeneic cell registry, alloCELL) providing detailed data on the assessment of a specific individual memory T-cell repertoire in response to antigens of cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus (ADV), and human herpesvirus (HHV) 6. METHODS: To obtain a manufacturing license according to the German Medicinal Products Act, the enrichment of clinical-grade CMV-specific T cells from three healthy CMV-seropositive donors was performed aseptically under GMP conditions using the CliniMACS cytokine capture system (CCS) after restimulation with an overlapping peptide pool of the immunodominant CMVpp65 antigen. Potential T-cell donors were selected from alloCELL and defined as eligible for clinical-grade antiviral T-cell generation if the peripheral fraction of IFN-gamma(+) T cells exceeded 0.03% of CD3(+) lymphocytes as determined by IFN-gamma cytokine secretion assay. RESULTS: Starting with low concentration of IFN-gamma(+) T cells (0.07-1.11%) we achieved 81.2%, 19.2%, and 63.1% IFN-gamma(+)CD3(+) T cells (1.42 * 10(6), 0.05 * 10(6), and 1.15 * 10(6)) after enrichment. Using the CMVpp65 peptide pool for restimulation resulted in the activation of more CMV-specific CD8(+) than CD4(+) memory T cells, both of which were effectively enriched to a total of 81.0% CD8(+)IFN-gamma(+) and 38.4% CD4(+)IFN-gamma(+) T cells. In addition to T cells and NKT cells, all preparations contained acceptably low percentages of contaminating B cells, granulocytes, monocytes, and NK cells. The enriched T-cell products were stable over 72 h with respect to viability and ratio of T lymphocytes. CONCLUSIONS: The generation of antiviral CD4(+) and CD8(+) T cells by CliniMACS CCS can be extended to a broad spectrum of common pathogen-derived peptide pools in single or multiple applications to facilitate and enhance the efficacy of adoptive T cell immunotherapy. PMID- 25510658 TI - MAOA, COMT and 5-HTTLPR frequencies in convicted and never convicted Afro Caribbeans in the Netherlands. PMID- 25510657 TI - Variations in vascular mortality trends, 2001-2010, among 1.3 million women with different lifestyle risk factors for the disease. AB - AIMS: Vascular disease mortality has declined rapidly in most Western countries, against a background of improved treatments and falling prevalence of smoking, but rising obesity. We examined whether this decline differed by lifestyle risk factors for vascular disease. METHODS AND RESULTS: During 2001-2010, there were 9241 vascular disease deaths in a prospective study of 1.3 million women in middle age, about one-quarter of all UK women in the eligible age range (50-64 years in 1996-2001). We estimated percentage declines in mortality from coronary heart disease, cerebrovascular disease and other vascular diseases, overall and by age, smoking, alcohol consumption, adiposity, physical activity, socioeconomic status and age at leaving school. Over 10 years, coronary heart disease mortality fell by half (52%), cerebrovascular disease mortality by two-fifths (42%) and other vascular disease mortality by one-fifth (22%). Lean women experienced greater declines in coronary heart disease mortality than overweight or obese women (70%, 48% and 26%, respectively; P < 0.001 for heterogeneity) and women in the highest and middle thirds of socioeconomic status experienced greater declines in other (non-coronary, non-cerebrovascular) vascular disease mortality than women in the lowest third (41% and 42% and -9%, respectively; P = 0.001). After accounting for multiple testing, there were no other significant differences in vascular mortality trends by any lifestyle risk factor, including by smoking status. CONCLUSION: Vascular disease mortality trends varied in this cohort by adiposity and socioeconomic status, but not by smoking status or other lifestyle risk factors. Prevention and treatment of vascular disease appear not to have been equally effective in all subgroups of UK women. PMID- 25510659 TI - Monoamine oxidase A alleles in violent offenders with antisocial personality disorder: high activity associated with proactive aggression. PMID- 25510660 TI - National Osteoporosis Society practical clinical guideline on vitamin D and bone health. PMID- 25510662 TI - Massively sub-wavelength guiding of electromagnetic waves. AB - Recently a new form of ultra-thin flexible waveguide consisting of a conducting comb-like structure with a thickness of the order of 1/600(th) of the operating wavelength was presented. However, whilst the thickness of the guide was massively sub-wavelength, the remaining dimensions (the height and period of the comb) were much longer. In this paper we propose, and experimentally verify, that a modified guiding geometry consisting of a chain of ultra-thin conducting spirals allows guiding of electromagnetic waves with wavelengths that are many times (40+) longer than any characteristic dimension of the guide, enabling super sub-wavelength guiding and localisation of electromagnetic energy. PMID- 25510661 TI - Mitochondrial abnormalities and low grade inflammation are present in the skeletal muscle of a minority of patients with amyotrophic lateral sclerosis; an observational myopathology study. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a primary progressive neurodegenerative disease characterised by neuronal loss of lower motor neurons (in the spinal cord and brainstem) and/or upper motor neurons (in the motor cortex) and subsequent denervation atrophy of skeletal muscle. AIM: A comprehensive examination of muscle pathology from a cohort of clinically confirmed ALS patients, including an investigation of inflammation, complement activation, and deposition of abnormal proteins in order to compare them with findings from an age-matched, control group. MATERIAL AND METHODS: 31 muscle biopsies from clinically confirmed ALS patients and 20 normal controls underwent a comprehensive protocol of histochemical and immunohistochemical stains, including HLA-ABC, C5b-9, p62, and TDP-43. RESULTS: Neurogenic changes were confirmed in 30/31 ALS cases. In one case, no neurogenic changes could be detected. Muscle fibre necrosis was seen in 5/31 cases and chronic mononuclear inflammatory cell infiltration in 5/31 (2 of them overlapped with those showing muscle necrosis). In four biopsies there was an increase in the proportion of cytochrome oxidase (COX) negative fibres (2-3%). p62 faintly stained cytoplasmic bodies in eight cases and none were immunoreactive to TDP-43. CONCLUSION: This large series of muscle biopsies from patients with ALS demonstrates neurogenic atrophy is a nearly uniform finding and that mild mitochondrial abnormalities and low-grade inflammation can be seen and do not rule out the diagnosis of ALS. These findings could lend support to the notion that ALS is a complex and heterogeneous disorder. PMID- 25510663 TI - MicroRNA-17 promotes normal ovarian cancer cells to cancer stem cells development via suppression of the LKB1-p53-p21/WAF1 pathway. AB - The mechanism underlying the development of human ovarian cancer is poorly understood. The liver kinase protein, LKB1, is hypothesized to play a pivotal role in tumor cell proliferation and invasion capacity through regulation of p53 and p21/WAF1 expression. Previous studies suggest LKB1 may, in turn, be regulated by microRNA-17. Here, we examined the role of miR-17 in the expression of LKB1 and the downstream effects on proliferation and invasion capacity of normal ovarian cancer cells (OCCs) and ovarian stem cells. In this study, both the mRNA and protein expression levels of LKB1, p53, and p21 decreased in OCCs following transfection with a miR-17 expression plasmid. MiR-17 expression affected cell cycle regulation and stimulated the proliferation and invasion capacity of OCCs in vitro. ChIP assays indicated that the binding efficiency of p53 to the p21/WAF1 gene promoter was much lower in miR-17 transfected OCCs than in OCCs transfected with a mutated miR-17. Co-immunoprecipitation and western blotting showed significantly lower levels of p53 and p53 Ser15-pho in the miR-17 transfected OCCs as compared to the mutant miR-17 transfected OCCs. Xenograft experiments confirmed that suppression of tumor growth in vivo occurred in the absence of functional miR-17. These findings suggest that mature miR-17 expression may have an important role in the pathogenesis of human ovarian tumors through its interference with the LKB1-p53-p21/WAF1 pathway expression by epigenetic modification. These findings are of potential importance in the identification of novel therapeutic targets in human ovarian cancer. PMID- 25510664 TI - Acquired resistance to EGFR tyrosine kinase inhibitor in A431 squamous cell carcinoma xenografts is mediated by c-Kit pathway transduction. AB - Epidermal growth factor inhibitors (EGFRIs), the first targeted cancer therapy, are currently an essential treatment for many advance-stage epithelial cancers. These agents have the superior ability to target cancers cells and better safety profile compared to conventional chemotherapies. However, all responding patients eventually developed acquired resistance to EGFRIs and the mechanisms of acquired resistance invariably develops. In the current study, we reported the tumor xenografts of the human A431 squamous cell carcinoma, after 25-week consecutive therapy with EGFR inhibitor (gefitinib) that developed resistance as a result of c-Kit overexpression. Moreover, combined therapeutic inhibition of EGFR and c-Kit may abrogate this acquired mechanism of drug resistance due to an enhanced apoptotic effect in gefitinib-resistant xenograft model. Taken together, the results suggest that at least in the A431 xenograft model displaying acquired resistance to gefitinib can emerge in vivo, at least in part, by mechanisms involving the c-Kit overexpression. PMID- 25510665 TI - EMSY promoted the growth and migration of ovarian cancer cells. AB - Epithelial ovarian cancer is one of the most common and aggressive diseases among the female reproductive organ malignancies, and the molecular mechanism underlying this disease remains largely unknown. EMSY, a binding partner of BRCA2, has been reported to be amplified in ovarian cancer. However, the expression pattern and biological functions of EMSY in the progression of ovarian cancer are not fully understood. In this study, it was found that the expression of EMSY was significantly elevated in ovarian cancer samples compared to their adjacent normal tissues. Moreover, overexpression of EMSY promoted the growth and migration of ovarian cancer cells, while knocking down the expression of EMSY inhibited the growth, migration, and tumorigenesis of ovarian cancer cells in vitro and in vivo. Mechanistically, EMSY was found to interact with beta-catenin and activate beta-catenin/TCF signaling. Our study demonstrated that EMSY played an oncogenic role in the progression of ovarian cancer cells and EMSY might be a promising target for the treatment. PMID- 25510666 TI - Upregulated expression of miR-106a by DNA hypomethylation plays an oncogenic role in hepatocellular carcinoma. AB - Aberrant microRNA (miRNA) expression has been widely recognized to play an extremely important role in several cancers, including hepatocellular carcinoma (HCC). According to the previous studies, abnormal miR-106a expression was closely related to various cancer occurrences. However, the miR-106a expression in HCC remains unclear. In our study, we firstly detected the miR-106a expression levels in 36 pairs of HCC tissues. The results showed that miR-106a expression in HCC tissues was apparently higher than the level in the adjacent tissues. Then, we used quantitative real-time PCR (qPCR) and BSP to analyze miR-106a expression and promoter methylation in HCC cell lines. There came to a conclusion that the methylation status of the miR-106a promoter region was inversely correlated with the expression of miR-106a. After prediction with online software, we further used dual-luciferase reporter gene assay to ensure that TP53INP1 and CDKN1A might be the direct targets of miR-106a. At last, we explored the functions of miR-106a in HCC cells in vitro. Our results manifested that high-miR-106a cell line had stronger invasiveness, faster cell cycle progression, and more resistance to apoptosis compared with the low-miR-106a cell line. Therefore, our study suggested that upregulated expression of miR-106a by its promoter hypomethylation might contribute to the progression of HCC, which might be considered as a potentially effective biomarker and therapeutic approach in the future. PMID- 25510667 TI - The methylenetetrahydrofolate reductase (MTHFR) 677 C>T polymorphism increases the risk of developing chronic myeloid leukemia-a case-control study. AB - The methylenetetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C polymorphisms are associated with variations in folate levels, a phenomenon linked to the development of various malignancies. The aim of this study was to investigate the influence of the 677 C>T and 1298 A>C polymorphisms in the MTHFR gene on the risk of developing chronic myeloid leukemia (CML). Our study included 151 patients with CML and 305 controls. The MTHFR 677 C>T and 1298 A>C polymorphisms were investigated by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and allele-specific PCR techniques. The CT and TT genotypes of the MTHFR 677 C>T polymorphism were associated with an increased risk of developing CML (odds ratio (OR) = 1.556, 95% confidence interval (CI) = 1.017-2.381, p value = 0.041, and OR = 1.897, 95% CI = 1.046-3.44, p value = 0.035, respectively). No association was observed between the prognostic factors (blasts, basophils, additional chromosomal abnormalities, EUTOS score, Sokal and Hasford risk groups) and the MTHFR 677 C>T and 1298 A>C variant genotypes in CML patients. Our study shows that the MTHFR 677 C>T polymorphism is significantly associated with the risk of CML in Romanian patients. PMID- 25510668 TI - HIF-1alpha (1772C>T) polymorphism as marker for breast cancer development. AB - Hypoxia-inducible factor 1alpha (HIF-1alpha) is an important transcription factor that regulates different cellular responses to hypoxia. HIF-1alpha is rapidly degraded by von Hippel-Lindau (VHL) protein under normoxic conditions and stabilized under hypoxia. A common variant of HIF-1alpha (1772C>T) (rs 11549465) polymorphism, corresponding to an amino acid change from proline to serine at 582 position within the oxygen-dependent degradation domain, results in increased stability of the protein and altered transactivation of its target genes. The present study was aimed to find the association between HIF-1alpha (1772C>T) (rs 11549465) polymorphism and breast cancer development. For this purpose, 348 primary breast cancer patients and 320 healthy and age-matched controls were genotyped through PCR-RFLP method. The genotype frequencies were compared between patients and controls, and their influence on clinical characteristics of breast cancer patients was analyzed. Our study revealed a significant increase of TT genotype in breast cancer patients compared to controls (p = 0.038). Further, TT genotype and T allele were found to be associated with progesterone receptor (PR) negative status (p < 0.09). None of the clinical variables revealed significant association with HIF-1alpha (1772C>T) (rs 11549465) polymorphism. PMID- 25510669 TI - Let-7b inhibits cell proliferation, migration, and invasion through targeting Cthrc1 in gastric cancer. AB - Dysregulation of specific microRNAs (miRNAs) is found to play a vital role in carcinogenesis and progression of gastric cancer (GC). In the present study, we investigated the expression profiles of miRNAs in gastric cancer. Let-7b was found downregulated remarkably in gastric cancer tissues and was correlated with Helicobacter pylori infection, tumor stage, and lymphatic metastasis. Ectopic expression of let-7b suppressed the growth, migration, invasion, and tumorigenicity of GC cells, whereas let-7b knockdown promoted these phenotypes. Bioinformatic analysis predicted collagen triple helix repeat containing 1 (Cthrc1) as a direct target of let-7b. Luciferase assay showed that let-7b repressed the activity of Cthrc1 through binding its 3'UTR. Western blotting also confirmed that the protein levels of Cthrc1 were decreased by let-7b. Cthrc1 was significantly upregulated and reversely correlated with let-7b levels in GC. Co expression of let-7b and Cthrc1 without its 3'UTR could rescue cell growth, migration, and invasion inhibited by let-7b. These results suggest that let-7b may directly target Cthrc1 and function as a tumor suppressor gene in GC. PMID- 25510670 TI - The tumor suppressor role of PAQR3 in osteosarcoma. AB - Osteosarcoma is the most common primary bone malignancy; however, the molecular mechanisms of development are not well understood. Progestin and AdipoQ receptors (PAQR3), a protein specifically localized in the Golgi apparatus, was recently characterized as a new tumor suppressor. Little is known about the expression and function of PAQR3 in osteosarcoma. Here, we showed that PAQR3 was downregulated in osteosarcoma tissues compared with the adjacent normal regions in 80 paired samples. Moreover, lower levels of PAQR3 were associated with metastasis in clinical osteosarcoma patients. In addition, overexpression of PAQR3 in the osteosarcoma cell line MG-63 inhibited cell proliferation, migration, and invasion by promoting ERK phosphorylation. Taken together, our results indicated that PAQR3 might act as a tumor suppressor in osteosarcoma, providing a novel diagnostic and therapeutic option for human osteosarcoma in the future. PMID- 25510671 TI - Selective hydrogenation of lactic acid to 1,2-propanediol over highly active ruthenium-molybdenum oxide catalysts. AB - Modification of Ru/C with a small amount of MoOx (Ru?MoOx /C) enhanced the catalytic activity in the hydrogenation of L-lactic acid to form 1,2-propanediol and maintained high selectivity. The turnover frequency based on the amount of Ru over the optimized Ru?MoOx /C catalyst (Mo/Ru molar ratio=1:16) was 114 h(-1) at 393 K, which was about 4 times higher than that over Ru/C. The same effect of MoOx was obtained over Ru?MoOx /SiO2 , although Ru?MoOx /SiO2 showed slightly lower activity than that of Ru?MoOx /C. Ru?MoOx /C achieved a high yield of 95 % in 18 h at 393 K and was applicable to various carboxylic acids to provide the corresponding alcohols in high yields. Modification with MoOx also brought about suppression of racemization and (S)-1,2-propanediol was obtained in high enantiomeric excess at 353 K. Based on kinetic analysis and characterization data, such as XRD, TEM, CO adsorption by a volumetric method, FTIR spectroscopy, and X-ray absorption spectroscopy, for Ru?MoOx /C and Ru?MoOx /SiO2 , the catalyst structure and reaction mechanism are proposed. PMID- 25510672 TI - Impact of platelet phenotype on myocardial infarction. AB - In acute myocardial infarction patients the injured vascular wall triggers thrombus formation in the damage site. Fibrin fibers and blood cellular elements are the major components of thrombus formed in acute occlusion of coronary arteries. It has been established that the initial thrombus is primarily composed of activated platelets rapidly stabilized by fibrin fibers. This review highlights the role of platelet membrane phenotype in pathophysiology of myocardial infarction. Here, we regard platelet phenotype as quantitative and qualitative parameters of the plasma membrane outer surface, which are crucial for platelet participation in blood coagulation, development of local inflammation and tissue repair. PMID- 25510673 TI - Long term headache duration is a factor predicting nonresponse to detoxification and advice in medication overuse headache. AB - BACKGROUND: Medication overuse headache (MOH) is a very heterogeneous disorder for which a recommended treatment is not yet available. The purpose of this study was to investigate any possible roles of demographic and clinical characteristics of MOH patients that might predict a response to detoxification and advice with or without preventive treatment. FINDINGS: This ancillary study is part of the Sodium vAlproate in the treatment of Medication Overuse HeadAche (SAMOHA) study that randomized 88 MOH patients for 3-month treatment period with sodium valproate (VPA) (800 mg/day) or placebo after a 6-day outpatient detoxification regimen. Demographic and clinical characteristics obtained on patients from both study arms were analyzed to point out an association with the response to the treatment. While for patients from VPA arm no significant results were obtained, comparing responders to non-responders to detoxification and advice to withdraw from MOH, a significant difference in headache duration was observed. Specifically, the efficacy of such treatment resulted ineffective in headache lasting longer than 30 years. CONCLUSIONS: Our findings suggest that the benefit from detoxification and advice can be excluded in MOH of long duration. Therefore, a preventive treatment is suggested particularly for these patients. PMID- 25510674 TI - Comparison of Recharge Estimation Methods During a Wet Period in a Karst Aquifer. AB - Management of water resources, implying their appropriate protection, calls for a sound evaluation of recharge. Such assessment is very complex in karst aquifers. Most methods are developed for application to detrital aquifers, without taking into account the extraordinary heterogeneity of porosity and permeability of karst systems. It is commonly recommended to estimate recharge using multiple methods; however, differences inherent to the diverse methods make it difficult to clarify the accuracy of each result. In this study, recharge was estimated in a karst aquifer working in a natural regime, in a Mediterranean-type climate, in the western part of the Sierra de las Nieves (southern Spain). Mediterranean climate regions are characterized by high inter-annual rainfall variability featuring long dry periods and short intense wet periods, the latter constituting the most important contribution to aquifer water input. This paper aims to identify the methods that provide the most plausible range of recharge rate during wet periods. Six methods were tested: the classical method of Thornthwaite Mather, the Visual Balan code, the chloride balance method, and spatially distributed methods such as APLIS, a novel spatiotemporal estimation of recharge, and ZOODRM. The results help determine valid methods for application in the rest of the unit of study and in similar karst aquifers. PMID- 25510675 TI - Salvianolic acid B promotes bone formation by increasing activity of alkaline phosphatase in a rat tibia fracture model: a pilot study. AB - BACKGROUND: Radix Salviae miltiorrhizae is a herb frequently used within traditional Chinese medicine for the treatment of cardiovascular- and trauma related diseases. Danshen is the dried root of Salviae miltiorrhizae, from which the polyphenolic compound Salvianolic acid B (Sal B) can be obtained. Sal B is a key component of Danshen. The aim of this study was to determine the effect of Sal B on the healing of long bones following trauma in a rat tibia fracture model. METHODS: Tibia fractures were created in 20 male Sprague Dawley rats. The animals were divided into two groups: (1) experimental group (n = 10); and (2) control group (n = 10). Rats in the experimental group were intraperitoneally administered with Sal B (40 mg/kg/d) for 3 weeks, while rats in the control group received an identical volume of physiological saline solution, administered in the same way. X-ray photographs were taken of all animals at the time points. Rats were euthanized at weeks 1, 3, 8 and 12 post-fracture. Fracture calluses were measured and callus sections were obtained and stained using hematoxylin and eosin (HE) and the calcium cobalt method. HE stained sections were observed and evaluated according to different grades of bone remodeling. Sections stained using the calcium cobalt method were analyzed with an imagine analysis system. RESULTS: Data showed that callus growth was significantly greater in the experimental group compared with the control group (P < 0.05). Furthermore, histological scores in the Sal B-treated group were statistically higher than in the saline treated group at weeks 1, 3 and 8 post-fracture (P < 0.05). Alkaline phosphatase (ALP) activity was enhanced in the experimental group at weeks 1 and 3 post-fracture (P < 0.05). CONCLUSIONS: Our results suggest that Sal B may accelerate early-stage fracture healing. Increased activity of ALP may be one factor which promotes the healing process. This pilot study provides brief insight into the effect of Sal B in fracture healing. These findings will contribute to the development of more and enhanced treatment options for trauma fracture patients. PMID- 25510676 TI - Sex differences in DNA damage produced by the carcinogen 2-acetylaminofluorene in cultured human hepatocytes compared to rat liver and cultured rat hepatocytes. AB - Male rats are more susceptible to the induction of liver cancer by the aromatic amine 2-acetylaminofluorene (AAF) than are females. To assess the basis for this difference and to determine whether sex differences in susceptibility to AAF are present in human liver cells, the DNA reactivity of AAF was measured in livers of male and female Sprague-Dawley (SD) rats and in cultured SD rat and human hepatocytes of both sexes. In livers of rats administered oral doses of AAF, the total levels of adducts measured by nucleotide postlabelling at up to 8 weeks were about twofold greater in males than in females. Similarly, the level of AAF DNA adducts formed in cultured male rat hepatocytes dosed with AAF was about twofold greater than in female rat hepatocytes. Also, the level of DNA repair synthesis was about threefold greater in AAF-dosed cultured male rat hepatocytes compared with female, indicating that the greater adduct levels in males was not due to lesser repair. In contrast, in cultured human hepatocytes of both sexes, AAF produced similar levels of adducts and DNA repair synthesis, which were intermediate between those produced in male and female rat hepatocytes. Thus, the greater susceptibility of male rats to AAF hepatocarcinogenicity is due at least in part to greater bioactivation and formation of AAF-DNA adducts in hepatocytes. Moreover, the data from human hepatocytes suggest that human liver could be less susceptible than male rat liver to the carcinogenic effects of aromatic amine carcinogens of the AAF type. PMID- 25510677 TI - Pathologic and molecular profiling of rapid-onset fibrosis and inflammation induced by multi-walled carbon nanotubes. AB - Multi-walled carbon nanotubes (MWCNT) are new materials with a wide range of industrial and commercial applications. However, their nano-scaled size and fiber like shape render them respirable and potentially fibrogenic if inhaled into the lungs. To understand MWCNT fibrogenesis, we analyzed the pathologic and molecular aspects of the early phase response to MWCNT in mouse lungs. MWCNT induced rapid and pronounced lesions in the lungs characterized by increased cellularity and formation of fibrotic foci, most notably near where MWCNT deposited, within 14 days post-exposure. Deposition of collagen fibers was markedly increased in the alveolar septa and fibrotic foci, accompanied by elevated expression of fibrotic genes Col1a1, Col1a2, and Fn1 at both mRNA and protein levels. Fibrosis was induced rapidly at 40 MUg, wherein fibrotic changes were detected on day 1 and reached a maximal intensity on day 7 through day 14. Induction of fibrosis was dose-dependent at the dose range of 5-40 MUg, 7 days post-exposure. MWCNT elicited rapid and prominent infiltrations of neutrophils and macrophages alongside fibrosis implicating acute inflammation in the fibrotic response. At the molecular level, MWCNT induced elevated expression of proinflammatory cytokines TNFalpha, IL1alpha, IL1beta, IL6, and CCL2 in lung tissues as well as the bronchoalveolar lavage fluid, in a dose- and time-dependent manner. MWCNT also increased the expression of fibrogenic growth factors TGF-beta1 and PDGF-A in the lungs significantly. These findings underscore the interplay between acute inflammation and the early fibrotic response in the initiation and propagation of pulmonary fibrosis induced by MWCNT. PMID- 25510678 TI - Programming of cardiovascular disease across the life-course. AB - Cardiovascular disease (CVD) is the leading cause of morbidity and mortality, affecting both developed and developing countries. Whilst it is well recognized that our risk of CVD can be determined by the interaction between our genetics and lifestyle, this only partly explains the variability at the population level. Based on these well-known risk factors, for many years, intervention and primary prevention strategies have focused on modifying lifestyle factors in adulthood. However, research shows that our risk of CVD can be pre-determined by our early life environment and this area of research is known as the Developmental Origins of Health and Disease. The aim of this review is to evaluate our current understanding of mechanisms underlying the programming of CVD. This article is part of a special issue entitled CV Aging. PMID- 25510679 TI - The Wilms' tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression. AB - Angiogenesis, activation of metastasis and avoidance of immune destruction are important for cancer progression. These biological capabilities are, apart from cancer cells, mediated by different cell types, including endothelial, haematopoietic progenitor and myeloid-derived suppressor cells. We show here that all these cell types frequently express the Wilms' tumour suppressor Wt1, which transcriptionally controls expression of Pecam-1 (CD31) and c-kit (CD117). Inducible conditional knockout of Wt1 in endothelial, haematopoietic and myeloid derived suppressor cells is sufficient to cause regression of tumour vascularization and an enhanced immune response, leading to decreased metastasis, regression of established tumours and enhanced survival. Thus, Wt1 is an important regulator of cancer growth via modulation of tumour vascularization, immune response and metastasis formation. PMID- 25510681 TI - The primary microbial pathogens associated with premature rupture of the membranes in China: a systematic review. AB - To describe the spectrum of pathogens isolated from Chinese women experiencing premature rupture of the membranes (PROM) and those of their neonates, in order to provide effective management of PROM. We searched Ovid Medline, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, and VIP Database for Chinese Technical Periodicals up to April 2012. The quality of studies was assessed utilizing the Strengthening the Reporting of Observational Studies in Epidemiology Statement. Among the included 36 studies, 11 (30.55%) were deemed to be at Level A, 12 (33.33%) at Level B, three (8.33%) at Level C, and 10 (27.78%) at Level D. Staphylococcus and Escherichia coli were the two primary microorganisms isolated from women with PROM and their infants. Subgroup analysis showed the distribution of microorganisms from the six regions of China varied. Staphylococcus bacteria were resistant to penicillins, except oxacillin, but more sensitive to first- and second-generation cephalosporins. Escherichia were sensitive to first- and second-generation cephalosporins and were more sensitive to aztreonam than cephalosporins. The main pathogens derived from women with PROM and their newborns were Staphylococcus and E. coli, which differs from the pathogens in Western countries. Hence, one might infer that the pathogens involved in PROM should be defined in each region to maximize antibiotic effectiveness. In addition, randomized controlled studies are needed to compare prophylactic use of antibiotics versus use of antibiotics after a positive culture for newborn infants with a history of PROM. PMID- 25510682 TI - Pelvic floor dysfunction, and effects of pregnancy and mode of delivery on pelvic floor. AB - Pelvic floor dysfunction (PFD), although seems to be simple, is a complex process that develops secondary to multifactorial factors. The incidence of PFD is increasing with increasing life expectancy. PFD is a term that refers to a broad range of clinical scenarios, including lower urinary tract excretory and defecation disorders, such as urinary and anal incontinence, overactive bladder, and pelvic organ prolapse, as well as sexual disorders. It is a financial burden on the health care system and disrupts women's quality of life. Strategies applied to decrease PFD are focused on the course of pregnancy, mode and management of delivery, and pelvic exercise methods. Many studies in the literature define traumatic birth, usage of forceps, length of the second stage of delivery, and sphincter damage as modifiable risk factors for PFD. Maternal age, fetal position, and fetal head circumference are nonmodifiable risk factors. Although numerous studies show that vaginal delivery affects pelvic floor structures and their functions in a negative way, there is not enough scientific evidence to recommend elective cesarean delivery in order to prevent development of PFD. PFD is a heterogeneous pathological condition, and the effects of pregnancy, vaginal delivery, cesarean delivery, and possible risk factors of PFD may be different from each other. Observational studies have identified certain obstetrical exposures as risk factors for pelvic floor disorders. These factors often coexist; therefore, the isolated effects of these variables on the pelvic floor are difficult to study. The routine use of episiotomy for many years in order to prevent PFD is not recommended anymore; episiotomy should be used in selected cases, and the mediolateral procedures should be used if needed. PMID- 25510683 TI - Medical treatment for adenomyosis and/or adenomyoma. AB - Uterine adenomyosis and/or adenomyoma is characterized by the presence of heterotopic endometrial glands and stroma within the myometrium, >2.5 mm in depth in the myometrium or more than one microscopic field at 10 times magnification from the endometrium-myometrium junction, and a variable degree of adjacent myometrial hyperplasia, causing globular and cystic enlargement of the myometrium, with some cysts filled with extravasated, hemolyzed red blood cells, and siderophages. Hysterectomy is a "gold standard" and definitive therapy for uterine adenomyosis, and many cases of adenomyosis have been diagnosed by pathological review retrospectively. As such, the diagnosis of adenomyosis is difficult, and this subsequently results in difficulty in the management of these patients, especially those who are symptomatic but have a strong desire to preserve their uterus. In our previous review, we found that the use of uterine sparing surgery in the management of uterine adenomyosis and/or adenomyoma is still controversial, although some data support its feasibility. Conservative treatment is still needed in the group of patients that requires preservation of fertility and improvement of quality of life. However, studies focusing on the topic of medical treatment for adenomyosis are rare. In this article, current knowledge regarding the use of medical therapy for uterine adenomyosis, partly based on the understanding of endometriosis, is reviewed. PMID- 25510684 TI - Laparoscopic management of ectopic pregnancies in unusual locations. AB - OBJECTIVE: The aim of this study was to evaluate the feasibility and efficacy of laparoscopic surgery for patients with ectopic pregnancies in unusual locations. MATERIALS AND METHODS: This is a retrospective case series of 31 patients from 6 weeks to 10 weeks postmenstrual who were referred for diagnosis and treatment and suspected of having an unruptured cesarean scar pregnancy (CSP) or cornual pregnancy (CP). The diagnosis was confirmed with transvaginal ultrasound, and all of the patients underwent laparoscopic management. RESULTS: A diagnosis of CSP or CP was confirmed in all of the patients during the laparoscopic procedure. None of the patients required conversion to laparotomy. The total operative time ranged from 40 minutes to 120 minutes. The total blood loss was limited, ranging from 30 mL to 200 mL. All of the women tolerated the operation well and had uneventful recoveries. CONCLUSION: When performed by a well-trained gynecologist, laparoscopy appears to be a reasonable alternative for the treatment of unruptured CSP or CP. PMID- 25510685 TI - Accessibility and surgical outcomes of transumbilical single-port laparoscopy using straight instruments for hysterectomy in difficult conditions. AB - OBJECTIVES: To evaluate the accessibility of transumbilical single-port laparoscopy for hysterectomy in difficult conditions. MATERIALS AND METHODS: This prospective observational study recruited patients with benign diseases who were scheduled for laparoscopic hysterectomy between March 2010 and October 2011 to undergo the transumbilical single-port approach with straight instruments and a laparoscope. RESULTS: In total, 109 patients were included with a mean [+/- standard error of the mean (SEM)] age of 45.9 +/- 0.4 years and mean body mass index of 23.9 +/- 0.3 kg/m(2). The yielded mean uterine weight was 403.4 +/- 25.3 g, with 28 (25.7%) weighing >=500 g, including four specimens >1000 g, and 44 (40.4%) needed concurrent adhesiolysis. The operative time was 117.2 +/- 4.2 minutes, estimated blood loss was 270.3 +/- 22.9 mL, and the postoperative hospital stay was 2.8 +/- 0.1 days. Patients with a uterus weighing >=500 g had a higher intraoperative blood loss in comparison with those with a uterus weighing <500 g (375.4 +/- 55.3 mL vs. 234.0 +/- 23.0 mL; p < 0.05) and a higher incidence of blood transfusion (17.9% and 6.2%, respectively). The single-port approach was abandoned in four (3.7%) patients with severe pelvic adhesion--an additional port was opened for extensive adhesiolysis. None of the patients with a voluminous uterus needed an additional port. There were no major intraoperative or postoperative complications. CONCLUSION: The single-port approach using straight, conventional laparoscopic instruments was feasible and safe in the majority of the patients undergoing hysterectomy, and was found to be accessible even in cases with a large uterus. The patients benefitted from this approach and had less abdominal wounds. However, patients with a voluminous uterus tended to have more intraoperative blood loss, and in some cases with severe adhesions, additional port(s) were required for surgical effectiveness. PMID- 25510687 TI - Prevalence and contributing factors of severe perineal damage following episiotomy-assisted vaginal delivery. AB - OBJECTIVE: This study was conducted to investigate the risk factors of third- and fourth-degree lacerations following vaginal deliveries in Taiwanese women, and to offer clinical guidance for the reduction of severe perineal lacerations. MATERIALS AND METHODS: A total of 1879 women who underwent vaginal deliveries assisted by midline episiotomy at a tertiary hospital were included. Obstetric risk factors were analyzed for women with and without third- and fourth-degree lacerations. RESULTS: Two hundred and five deliveries (10.9%) resulted in third- or fourth-degree lacerations. Parity, duration of first and second stages of labor, rate of instrument-assisted vaginal deliveries, the newborn's birth weight and head circumference, and the ratio of the newborn's birth weight to maternal body mass index were significantly different between women with and without severe perineal lacerations. Logistic regression demonstrated that nulliparity (odds ratio = 3.626, p < 0.001), duration of second stage of labor (odds ratio = 1.102, p = 0.044), instrument-assisted vaginal delivery (odds ratio = 4.102, p < 0.001), and newborn's head circumference (odds ratio = 1.323, p < 0.001) were independent risk factors of severe perineal lacerations. Instrument-assisted vaginal delivery was a common independent risk factor for severe lacerations shared between primiparous and multiparous women. CONCLUSIONS: With regard to severe perineal lacerations during vaginal delivery, there are multiple obstetric contributory factors despite routine episiotomy, among them, nulliparity, longer labor duration, greater newborn head circumference, and instrument-assisted vaginal delivery. The latter should only be performed after careful evaluation. PMID- 25510686 TI - Bicuspid aortic valve in pregnancy. AB - OBJECTIVE: The outcomes in pregnant patients with bicuspid aortic valves (BAVs) are rarely reported, despite the potentially critical nature of the condition. The aim of this study is to present the clinical complications of BAV in pregnancy. MATERIALS AND METHODS: A MEDLINE database search and a Google internet search were conducted to find literature on BAV in pregnancy published between 1980 and 2012. RESULTS: BAV in pregnancy can lead to critical cardiovascular events including aortic dissection, aortic valve disorders, and infective endocarditis; some of these complications may lead to poor maternal outcomes or fetal demise. No differences were noted in either maternal or fetal mortality between syndromic and nonsyndromic pregnant patients with BAV (maternal: 50% vs. 28.6%; p = 0.4959; fetal: 25% vs. 0%; p = 0.1987). The peak and mean pressure gradients across the aortic valve increased significantly with advancing gestational trimester; a remarkable decrease in peak pressure gradients was seen postpartum. The calculated aortic valve area showed a significant decrease in the third trimester compared with the prepregnancy value, as well as a considerable postpartum decrease. CONCLUSION: Syndromic and nonsyndromic BAVs may have similar importance for maternal and fetal mortality. Aortic valve stenosis may become more severe with advancing pregnancy, with attenuation after delivery. Patients may require surgical intervention for the complications of BAV during pregnancy. PMID- 25510688 TI - Operative outcomes of single-port-access laparoscopy-assisted vaginal hysterectomy compared with single-port-access total laparoscopic hysterectomy. AB - OBJECTIVE: This study aims to compare between operative outcomes of single-port access laparoscopy-assisted vaginal hysterectomy (SPA-LAVH) and single-port access total laparoscopic hysterectomy (SPA-TLH), further subdivided by vaginal cuff closure via laparoscopic suture (VCC-L) or via the vaginal route (VCC-V). MATERIALS AND METHODS: A custom-made port was used for single-port laparoscopy in 111 patients who underwent SPA-LAVH (n = 33), SPA-TLH with VCC-L (n = 35), and SPA-TLH with VCC-V (n = 43) during October 2009-October 2010. Records were reviewed retrospectively. RESULTS: A significant difference in the operating time was observed among the groups (p = 0.009). SPA-TLH with VCC-L took a significantly longer time to be performed (118.6 +/- 41.8 minutes) than SPA-TLH with VCC-V (98.6 +/- 21.3 minutes) or SPA-LAVH (102.0 +/- 20.3 minutes). The decrease in hemoglobin level on the 1(st) day postsurgery was significantly smaller in case of SPA-LAVH (1.56 +/- 0.97 g/dL, p = 0.005) compared with that in case of SPA-TLH with VCC-L (2.19 +/- 0.95 g/dL) and SPA-TLH with VCC-V (2.24 +/- 0.95 g/dL). No significant differences in other surgical outcomes were found. CONCLUSION: SPA-TLH with laparoscopic vaginal suture required the longest operating time, and hemoglobin changes were smaller in the SPA-LAVH group than in the other groups. In patients undergoing SPA laparoscopy, we recommend the SPA LAVH procedure. PMID- 25510689 TI - Serum arylesterase and paraoxonase activities in patients with ovarian tumors. AB - OBJECTIVE: High levels of toxic reactive oxygen species have been found in many types of cancer cells. Serum arylesterase (ARE) and paraoxonase (PON) are esterase enzymes that have strong antioxidant characteristics. The main purpose of our study was to evaluate the activity of ARE and PON in the sera of patients with ovarian cancer and benign ovarian tumors. MATERIALS AND METHODS: This study included 30 patients with ovarian cancer, 42 patients with benign ovarian tumors, and 19 healthy age- and sex-matched individuals. ARE and PON activities were measured using spectrophotometry. RESULTS: Serum ARE activity was significantly different among the three studied groups (p<0.0001). However, posthoc tests revealed that ARE activity was lower in the benign ovarian tumor group (median, 1.53 U/mL; range, 0.43-2.47 U/mL) than in the other groups. There were no differences in ARE activity between patients with ovarian cancer (1.89 U/mL; range, 1.01-2.56 U/mL) and healthy individuals (2.05 U/mL; range, 0.79-2.44 U/mL). We found no differences in PON activity or the PON:ARE activity ratio between the studied groups. Tumor size in the benign ovarian tumor group was positively correlated with ARE activity (R Spearman=0.46, p=0.003) and negatively correlated with PON activity (R Spearman=-0.50, p=0.001). The ARE and PON activities were not influenced by histological type, ovarian cancer grade, or disease advancement. CONCLUSION: ARE activity is higher in patients with ovarian cancer than in patients with benign ovarian tumors; however, the serum activity of ARE is similar between patients with cancer and healthy individuals. PMID- 25510690 TI - Persistent papillomavirus type-31 and type-45 infections predict the progression to squamous intraepithelial lesion. AB - OBJECTIVE: Human papillomavirus (HPV) has been recognized as the major etiologic agent of cervical squamous cell carcinoma. However, it has been demonstrated that HPV infection is usually a self-limited process and does not lead to significant epithelial lesions or cancer. Recent data indicate that persistent high-risk HPV (HR-HPV) infections have a significantly increased risk of developing incident high-grade cervical intraepithelial neoplasia and cervical cancer. Our aim, therefore, was to assess whether there exist HPV genotypes whose persistence can be considered powerful surrogates of a progressive disease. We retrospectively selected all patients with a negative cytological diagnosis or with atypical squamous cells of undetermined significance, with a positive test for HR-HPV, different from HPV types 16 and 18, and assessed the significance of the risk of progression based on the persistence of the specific HR-HPV. MATERIALS AND METHODS: We retrospectively queried the database of our Colposcopy Clinic for all patients with a negative cytological diagnosis or with atypical squamous cells of undetermined significance and a positive test for HR-HPV, and we calculated the incidence of progression to lesions greater than or equal to low-grade squamous intraepithelial lesions after 6 months, according to the HPV type. RESULTS: A progression rate of 48.27% was found in patients tested positive for HPV-31 (Group 1), 38.46% in patients tested positive for HPV-45 (Group 2), and 5.73% in patients tested positive for HPV types other than HPV-16, HPV-18, HPV-31, and HPV 45 (Group 3). CONCLUSION: Our data demonstrate that the persistence of HPV-31 and HPV-45 is strongly associated with the occurrence of squamous intraepithelial lesion. PMID- 25510691 TI - Ovarian failure in diabetic rat model: nuclear factor-kappaB, oxidative stress, and pentraxin-3. AB - OBJECTIVE: The aim of the present study was to investigate the effects of diabetes mellitus (DM) on ovarian reserve and injury by considering laboratory and histopathological parameters in rat models. MATERIALS AND METHODS: An experimental DM model was created in 16 rats. Eight rats with normal blood glucose levels were included in the control group. Diabetic rats were divided randomly into two groups: nontreated and resveratrol-treated groups. Histopathological examination and nuclear factor (NF)-kappaB immunoexpression level determination were performed. Plasma malondialdehyde, glutathione, pentraxin-3, and anti-Mullerian hormone levels were measured. Relations between the variables were compared by Student t test, analysis of variance, and Mann Whitney U and chi(2) tests. RESULTS: We found statistically significantly lower glutathione and anti-Mullerian hormone levels, and higher malondialdehyde and pentraxin-3 levels in nontreated diabetic group when compared with the control and resveratrol-treated diabetic groups. Stromal degeneration, follicle degeneration, stromal fibrosis scores, and NF-kappaB immunoexpression levels were significantly higher in nontreated diabetic rats. Primordial and primary follicle counts were significantly lower in the nontreated diabetic group when compared with the control and resveratrol-treated groups. There was no statistically significant difference in secondary and tertiary follicles between these groups. CONCLUSION: These findings provide strong evidence that the ovarian follicle pool in nontreated diabetic rats is affected in the early stages of the follicle development process. We precluded negative effects of DM on ovaries by inhibiting the NF-kappaB pathway with resveratrol. We thought that the NF-kappaB pathway plays a role in the pathophysiology of ovarian failure in diabetic rats. Further studies should evaluate this precise mechanism that leads to a decline in the anti-Mullerian hormone levels. In addition, the relationship between this abnormality and reproductive function in diabetic patients should be analyzed further. PMID- 25510693 TI - Frequent and increased expression of human METCAM/MUC18 in cancer tissues and metastatic lesions is associated with the clinical progression of human ovarian carcinoma. AB - OBJECTIVES: Human METCAM/MUC18 (huMETCAM/MUC18), a cell adhesion molecule, plays an important role in the progression of several epithelial cancers; however, its role in the progression of epithelial ovarian cancers is unknown. To initiate the study we determined expression of this protein in normal and cancerous ovarian tissues, cystadenomas, metastatic lesions, and ovarian cancer cell lines. MATERIALS AND METHODS: Immunoblotting and immunohistochemical (IHC) methods were used to determine huMETCAM/MUC18 expression in lysates of frozen and formalin fixed, paraffin-embedded tissue sections of normal human ovaries, and ovarian (benign) cystadenomas, carcinomas and metastatic lesions. We also determined expression levels of several downstream effectors of METCAM/MUC18 in these tissues. RESULTS: HuMETCAM/MUC18 levels in ovarian carcinomas and metastatic lesions were significantly higher than in normal tissues and cystadenomas. IHC results showed that expression of huMETCAM/MUC18 in normal tissues and cystadenomas was mostly absent from epithelial cells, but in carcinomas and metastatic lesions it was localized to epithelial cells. In higher pathological grades of ovarian cancer and metastatic lesions, the percentage of cells stained in IHC was increased. Thirty percent of normal tissues weakly expressed the huMETCAM/MUC18 antigen, but 70% of cancer tissues and 100% of metastatic lesions expressed the antigen. Expression levels of several downstream effectors of huMETCAM/MUC18, Bcl2, PCNA and VEGF, were elevated in cancerous tissues, however, not that of Bax. The phospho-AKT/AKT ratio was elevated in metastatic lesions. CONCLUSION: Upexpression of huMETCAM/MUC18 may be a marker for the malignant potential of ovarian carcinomas. Progression of ovarian cancer may involve increased signaling in anti-apoptosis, proliferation, survival/proliferation pathway, and angiogenesis. PMID- 25510692 TI - Effects of reactive oxygen species levels in prepared culture media on embryo development: a comparison of two media. AB - OBJECTIVE: This study determined the correlation between the levels of reactive oxygen species (ROS) in prepared culture media and the early development of human embryos. MATERIALS AND METHODS: This was an autocontrolled comparison study. A total of 159 patients undergoing in vitro fertilization/intracytoplasmic sperm injection treatment were recruited in this study. The pH values, osmolarity pressures, and ROS levels of 15 batches of two culture media were measured. Sibling oocytes or embryos from individual patients were randomly assigned to two culture groups with Quinn's Advantage Cleavage and Blastocyst media (QAC/QAB) or GIII series cleavage and blastocyst media (G1.3/G2.3). The difference between the two culture groups was analyzed using one-sample t test. RESULTS: The QAC/QAB and G1.3/G2.3 media exhibited similar pH values and osmolarity pressures. However, the prepared QAC/QAB media were characterized to contain lower amounts of ROS than the G1.3/G2.3 media. Furthermore, the blastocysts that developed under the QAC/QAB media were morphologically superior to those that developed under the G1.3/G2.3 media. CONCLUSION: The elevated ROS levels in culture media were associated with poor development of blastocyst-stage embryos. Measurement of ROS levels may be a valuable process for medium selection or modification. PMID- 25510694 TI - Addition of parity to the risk of malignancy index score in evaluating adnexal masses. AB - OBJECTIVE: The aim of our study was to evaluate the individual contribution of parity when incorporated as another parameter into the four risk of malignancy indices (RMI 1-4) to differentiate noninvasive benign lesions from invasive malignant ovarian lesions. MATERIALS AND METHODS: After calculating RMI 1-4 for each patient included in this study, the resulting RMI scores were further multiplied by the parity score (P) of each patient to calculate the RMI parity (RMIP) score. RESULTS: A cutoff value of 300 for RMIP 1 yielded 95.0% specificity, 97.4% negative predictive value (NPV), 88.5% sensitivity, and 79.3% positive predictive value (PPV) and performed better than RMI 1 in the preoperative diagnosis of invasive malignant lesions. RMIP 2 with a cutoff value of 400 yielded 95.0% specificity, 97.4% NPV, 88.5% sensitivity, and 79.3% PPV, and it also performed better than RMI 2. A cutoff value of 400 for RMIP 3 provided 97.5% specificity, 97.5% NPV, 88.5% sensitivity, and 88.5% PPV and performed better than RMI 3. However, a cutoff value of 400 for RMIP 4 provided 90.0% specificity, 97.3% NPV, 88.5% sensitivity, and 65.7% PPV but did not perform better than RMI 4 in the preoperative diagnosis of invasive malignant lesions. CONCLUSION: RMIP 1-3 scales were more reliable tools for the preoperative diagnosis of invasive adnexal masses compared with the traditional RMI 1-3 scales. PMID- 25510695 TI - Single-port compared with conventional laparoscopic cystectomy for ovarian dermoid cysts. AB - OBJECTIVE: We compared the immediate surgical outcomes of single-port laparoscopic cystectomy (SLC) and conventional laparoscopic cystectomy (CLC) for managing ovarian dermoid cysts. MATERIALS AND METHODS: A retrospective case control study was conducted to enroll 71 patients with dermoid cysts, including 34 patients in the SLC group and 37 patients in the CLC group. The outcome measures included operative time, blood loss, postoperative pain, analgesic use, and serum levels of hormones, including estrogen (E2), follicle-stimulating hormone, luteinizing hormone, and anti-Mullerian hormone. RESULTS: SLC was associated with less time required for specimen retrieval (1.3 +/- 0.8 vs. 12.0 +/- 3.4 minutes, p < 0.001), fewer ruptured bags (0% vs. 10.8%, p = 0.049), and less need of additional wound elongation (0% vs. 27.0%, p = 0.001) when respectively compared with CLC. Additionally, patients who underwent SLC reported lower postoperative lower abdominal pain and less accumulated postoperative analgesics when respectively compared with patients who underwent CLC. There was no significant difference of hormones between two groups. CONCLUSION: Our study demonstrated the feasibility of using the single-port method in place of CLC in the management of ovarian dermoid without increased difficulty of techniques or risk of ovarian damage. PMID- 25510696 TI - Endometriosis and the subsequent risk of epithelial ovarian cancer. AB - OBJECTIVE: There is a possible correlation between endometriosis and an increased risk of epithelial ovarian cancer (EOC), but many uncertainties remain, including race, exposure or surveillance time, and surgical confirmation. Therefore, we carried out a large-scale, nationwide, controlled cohort study in the Taiwanese women to respond to these uncertainties. MATERIALS AND METHODS: A historical cohort study was performed by linking the National Health Insurance Research Database of Taiwan. Each patient diagnosed with endometriosis (n = 7537) between 2000 and 2009 was background matched with up to two women without endometriosis (n = 15,074). The total was 136,643 person-years of follow-up and 24 women having new EOC. Cox regression analysis was used to determine the relationship between the EOC incidence rate and an endometriosis status. RESULTS: The EOC incidence rate of the endometriosis and non-endometriosis women was 3.31 per 10,000 person years and 0.99 per 10,000 person-years, respectively, contributing to an adjusted hazard ratio (HR) of 3.28 (95% confidence interval, 1.37-7.85). The women with surgical confirmation had a much higher adjusted HR (3.87; 95% confidence interval, 1.58-9.47). No significantly statistical difference of surveillance time between women with and without endometriosis (3.87 years vs. 3.73 years). The occurrence of EOC was not also affected by exposure time of women with endometriosis. CONCLUSION: Taiwanese women with endometriosis really had a risk of newly developed EOC, especially those who had a surgical diagnosis, and this three-fold increase of risk was neither influenced by exposure time nor biased by surveillance. PMID- 25510697 TI - Serum microRNAs in clear cell carcinoma of the ovary. AB - OBJECTIVE: To identify candidate microRNAs (miRNAs) in the serum of patients with clear cell carcinomas in monitoring disease progression. MATERIALS AND METHODS: The sera of patients with diagnosed ovarian clear cell carcinoma were collected from 2009 to 2012. Real-time quantitative polymerase chain reaction (PCR) analysis for 270 miRNAs was performed. To offset the potential extraction bias, an equal amount of Caenorhabditis elegans cel-miR-238 was added to each serum specimen before miRNA isolation. miRNA expression was analyzed using the DeltaCt method, with cel-miR-238 as controls. RESULTS: Twenty-one patients with clear cell carcinoma were included. In the discovery phase on four pairs of pre- and postoperative sera, 18 differentially expressed miRNAs were selected from 270 miRNAs. In the validation phase on an independent set of 11 pairs of pre- and postoperative sera, 4 miRNAs (hsa-miR-130a, hsa-miR-138, hsa-miR-187, and hsa-miR 202) were confirmed to be higher in the preoperative sera. In the application phase, hsa-miR-130a remained consistent with the different time points in seven of the 10 patients during clinical follow-up periods. More importantly, in three patients, hsa-miR-130a levels were elevated in early disease recurrences before CA125 was found to be elevated. CONCLUSION: Hsa-miR-130a may be a useful serum biomarker for detecting recurrence of ovarian clear cell cancer, and warrants further studies. PMID- 25510698 TI - Sexual orientations of women with polycystic ovary syndrome: clinical observation in Taiwan. AB - OBJECTIVE: This study was conducted to explore the association between sexual orientations and polycystic ovary syndrome (PCOS)-related parameters. MATERIALS AND METHODS: A cross-sectional study with participants recruited from the regular outpatient clinic at the Department of Obstetrics and Gynecology at Taipei Medical University Hospital, Taipei, Taiwan between July 2012 and December 2013 was carried out. A total of 97 women met the criterion of having been diagnosed with PCOS. Among these 97 women, 89 were heterosexuals and eight were self identified as lesbians. At the same time, 78 women without PCOS were enrolled to serve as the control group. Participants were given a standard questionnaire and had blood withdrawn for biochemical analysis of androgen parameters--including total testosterone, androstenedione, sex hormone binding globulin, free androgen index, 17beta-estradiol (E2), luteinizing hormone, and follicular-stimulating hormone. The biochemical data were measured to compare the PCOS clinical parameters present in people of different sexual orientations (lesbians and heterosexuals). RESULTS: The women with PCOS, regardless of sexual orientation, had higher percentages and serum levels of hyperandrogenism-related clinical parameters than the women without PCOS [acne (87.5% and 60.7% vs. 23.1%), p < 0.001]; hirsutism (62.5% and 57.3% vs. 15.4%, p <= 0.001)]; and biochemical parameters (total T, p < 0.05 or p < 0.001, and luteinizing hormone/follicular stimulating hormone ratio, p <= 0.001]. The sexual orientation of women with PCOS affected their body mass index (BMI), because lesbians with PCOS possessed higher BMI than heterosexual women with PCOS (26.5 +/- 1.9 vs. 22.5 +/- 0.55; p < 0.05). However, hyperandrogenism-related clinical and biochemical parameters were not significantly different statistically between women with PCOS but of different sexual orientations. CONCLUSION: Our preliminary data showed that sexual orientation influenced the BMI of women with PCOS, but did not affect hyperandrogenism-related clinical or biochemical characteristics. This observation requires further confirmation. PMID- 25510699 TI - Comparison of early-stage primary serous fallopian tube carcinomas and equivalent stage serous epithelial ovarian carcinomas. AB - OBJECTIVE: To investigate the outcome of patients with early-stage primary fallopian tube carcinomas (PFTC) and those of patients with equivalent-stage serous epithelial ovarian carcinomas (SEOC). MATERIALS AND METHODS: A balanced and matched, case-control comparison was conducted in a university-based tertiary hospital database between 1978 and 2007. All PFTC and SEOC patients were treated with complete staging surgery followed by multiagent chemotherapy. One SEOC control was matched for each PFTC patient in a very uniform manner (characteristics and treatment). Disease-free survival (DFS) and overall survival (OS) were then compared using Kaplan-Meier analysis. RESULTS: Twenty-six paired patients were analyzed. Patients with PFTC were significantly older than the SEOC patients (58 years vs. 51 years, p = 0.001). In terms of recurrence, PFTC patients frequently had an extra-abdominal metastasis (3/4, 75%), in contrast to the SEOC patients, who did not (1/5, 20%). The 5-year DFS rate was similar in both groups (85% vs. 81%, p = 0.05), contributing to a similar OS rate (89% vs. 85%, p = 0.50). The median DFS and OS of patients with PFTC and SEOC were also similar without a statistically significant difference (125 months vs. 109 months, and 125 months vs. 122 months, respectively). CONCLUSION: Our study demonstrated that the survival outcome of International Federation of Gynecology and Obstetrics (FIGO) I/II PFTC patients was similar to that of FIGO I/II SEOC patients, and both groups had a >80% 5-year DFS rate after complete staging surgery, followed by multiagent chemotherapy. This finding is worthy of being investigated. PMID- 25510700 TI - A comparative study of laparoscopic sacrocolpopexy and total vaginal mesh procedure using lightweight polypropylene meshes for prolapse repair. AB - OBJECTIVE: Use of vaginal meshes for treatment of pelvic organ prolapse (POP) remains controversial. A trend toward abdominal approaches and the development of new meshes has been noted. We compared the 1-year results of two different approaches using new lightweight meshes. MATERIALS AND METHODS: Sixty-nine (95.8%) of 72 women with POP Stage >= 2, who underwent laparoscopic sacrocolpopexy (LSC) (n = 39) or a total vaginal mesh (TVM) procedure (n = 30) using lightweight polypropylene meshes, were studied. Baseline and follow-up assessments included a pelvic examination and a composite condition-specific questionnaire. A detailed comparison of 1-year outcomes was made. Data were analyzed using appropriate statistical methods. RESULTS: Compared to the TVM group, the LSC group was characterized by a younger age (53.7 years vs. 64.1 years, p < 0.001) and a longer operating time (264 minutes vs. 177.6 minutes, p < 0.001). Objective anatomic success (POP Stage <= 1) rates were similar between groups after statistical adjustment, i.e., 84.6% (33/39) and 86.7% (26/30) after LSC and TVM (p = 0.94), respectively. However, the dominant recurrence sites were different with anterior (n = 6) most frequent after LSC and apical (n = 4) most frequent after TVM. Reoperations were needed for the four (13.3%) apical recurrences in the TVM group. No serious complications were noted. We found "cystocele as the dominant prolapse" (p = 0.016; odds ratio = 6.94) and "suspension of prolapsed (POP Stage >= 2) uterus" (p = 0.025; odds ratio = 7.00) significantly affected recurrence after LSC and TVM, respectively. CONCLUSION: POP repair by LSC or TVM using the new lightweight polypropylene meshes seems to be safe and has comparable outcomes, but limitations may vary. PMID- 25510701 TI - Gene expression of cumulus cells in women with poor ovarian response after dehydroepiandrosterone supplementation. AB - OBJECTIVE: Our previous study showed the potential benefits of dehydroepiandrosterone (DHEA) supplementation in women with a poor ovarian response (POR). Because the connection between cumulus cells (CCs) and oocytes is a key step for oocyte maturation, we supposed that altered gene expression of CCs in women with POR after DHEA supplementation might favor oocyte maturation. MATERIALS AND METHODS: Women with POR treated with flexible daily gonadotropin releasing hormone antagonist in vitro fertilization (IVF) cycles at The Reproductive Center in Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan between January 2013 and October 2013 were enrolled for this prospective study. CCs were isolated during IVF before and after DHEA (CPH-Formulation, Oakdale, CA, USA) supplementation. Nine genes of isolated CCs, including hyaluronan synthase (HAS2), versican (VCAN), thrombospondin 1 (THBS1), runt-related transcription factor 2 (RUNX2), chromobox homolog 3 (CBX3), tripartite motif-containing 28 (TRIM28), B-cell lymphoma 2 (BCL2), BCL2-associated X protein (BAX), and ankyrin repeat domain 57 (ANKRD57), were compared. RESULTS: There was a significant difference in the expression of genes in women with POR before and after DHEA supplementation (all p < 0.05). All genes related to extracellular matrix (ECM) formation, including HAS2, VCAN, and THBS1, were upregulated. By contrast, all genes involving cell development, differentiation, and apoptosis regulation were downregulated. Unknown function gene ANKRD57 was also downregulated after DHEA supplementation. Although expressions of both BCL2 and BAX were decreased in women with POR after DHEA supplementation compared to those before treatment, the ratio of BCL2 and BAX was significantly increased in women with POR after DHEA supplementation, suggesting that DHEA supplementation might activate the antiapoptosis process of CCs, which might be beneficial to the improvement of ovarian function in women with POR. CONCLUSION: The study showed that DHEA therapy positively affected the gene expression of CCs in women with POR, and provided evidence to support the positive effect of DHEA supplementation on women with POR. PMID- 25510702 TI - Interphase fluorescence in situ hybridization characterization of mosaicism using uncultured amniocytes and cultured stimulated cord blood lymphocytes in prenatally detected Pallister-Killian syndrome. AB - OBJECTIVE: This study aims to present molecular cytogenetic characterization of Pallister-Killian syndrome (PKS). MATERIALS AND METHODS: A 37-year-old woman underwent amniocentesis at 18 weeks of gestation. Amniocentesis revealed a karyotype of 47,XY,+i(12)(p10)[6]/48,XY,+i(12)(p10)*2[1]/46,XY[6]. Repeated amniocentesis was performed at 20 weeks of gestation. Array comparative genomic hybridization (aCGH) was performed using uncultured amniocytes, cord blood, and skin. Quantitative fluorescent polymerase chain reaction (QF-PCR) was performed using uncultured amniocytes and parental bloods. Interphase fluorescence in situ hybridization (FISH) analysis was performed using uncultured amniocytes and cultured stimulated cord blood lymphocytes. Conventional cytogenetic analysis was performed using cultured cells from amniotic fluid, skin, placenta, umbilical cord, and cord blood. RESULTS: Repeated amniocentesis revealed a mosaic tetrasomy 12p level of 25% (10/40), cultured cord blood lymphocytes had no mosaicism, cultured skin fibroblasts had a mosaic tetrasomy 12p level of 52.5% (21/40), umbilical cord fibroblasts had a mosaic tetrasomy 12p level of 72.5% (29/40), and the placental cells had a mosaic tetrasomy 12p level of 2.5% (1/40) on conventional cytogenetics. An aCGH analysis revealed that the increases in gene dosage in 12p for uncultured amniocytes, skin, and cord blood were the log2 ratios of 0.9, 0.7, and 0.7, respectively. Interphase FISH on uncultured amniocytes revealed a mosaic level of 73.1% (49/67) (tetrasomy 12p: 33; hexasomy 12p: 16). Interphase FISH analysis of stimulated cultured cord blood lymphocytes revealed a mosaic level of 58.3% (60/103) (tetrasomy 12p: 51; hexasomy 12p: 9). CONCLUSION: In the diagnosis of PKS by conventional culture cytogenetics, cord blood samplings and placental samplings are prone to a negative result when compared with amniocentesis. Whenever cord blood sampling is applied for prenatal diagnosis of PKS, aCGH on uncultured cord blood or interphase FISH on cultured cord blood can be used for the diagnosis, in addition to conventional cytogenetics. PMID- 25510703 TI - First-trimester molecular diagnosis of complete hydatidiform mole associated with dizygotic twin pregnancy conceived by intrauterine insemination. AB - OBJECTIVE: To present first-trimester molecular diagnosis of complete hydatidiform mole (CHM) associated with dizygotic twin pregnancy conceived by intrauterine insemination. MATERIALS AND METHODS: A 32-year-old woman presented to the hospital with a huge complex cystic mass measuring about 8.5 cm * 4.1 cm in the uterine cavity and a living co-existing fetus with fetal biometry equivalent to 9 weeks. She underwent chorionic villus sampling at 13 weeks of gestation, and microsatellite genotyping for molar pregnancy test was applied. A molar pregnancy test was performed by a short tandem repeat (STR) identifier polymerase chain reaction (PCR) polymorphic marker analysis. The pregnancy was terminated at 14 weeks of gestation. Postnatal polymorphic DNA marker analysis of the placenta by quantitative fluorescent PCR (QF-PCR) was performed. Analysis of maternal blood total beta-human chorionic gonadotropin revealed a high level of 551,600 mIU/mL at 10 weeks of gestation and a level of 1.0 mIU/mL at 15 weeks postpartum. The woman was doing well at 4 months after delivery. RESULTS: The results of STR identifier PCR polymorphic marker analysis showed androgenic conception in the complex cystic mass and biparental conception in the living fetus. Pathological analysis of the cystic mass confirmed the diagnosis of CHM. The results of QF-PCR showed biparental inheritance in the normal fetus and complete paternal homozygosity in the CHM of the abnormal fetus in all STRs, indicating dizygotic twinning and CHM of monospermy. CONCLUSION: Prenatal sonographic diagnosis of placentomegaly with many grape-like vesicles should include a differential diagnosis of CHM, partial hydatidiform mole (PHM), placental mesenchymal dysplasia (PMD), and recurrent hydatidiform mole. Microsatellite genotyping for molar pregnancy testing and zygosity testing is useful in cases of prenatal diagnosis of placentomegaly associated with many grape-like vesicles and a twin pregnancy with a living fetus in the first trimester. PMID- 25510704 TI - Prenatal diagnosis of 17q12 duplication and deletion syndrome in two fetuses with congenital anomalies. AB - OBJECTIVE: The objective of this study was to characterize the genetic abnormalities in two fetuses with congenital anomalies in prenatal screening. MATERIALS AND METHODS: The mother of Fetus 1 was 26 years old and had a second trimester serum screening that indicated the fetus was at low risk. The prenatal ultrasound and magnetic resonance imaging (MRI) at 28 weeks of gestation showed mild ventriculomegaly, microcephaly, and agenesis of the corpus callosum. The mother of Fetus 2 was 25 years old and also had a second trimester serum screening that indicated the fetus was at low risk. The prenatal ultrasound at 32 weeks of gestation showed the presence of hyperechogenic and enlarged kidneys with multicystic renal dysplasia bilaterally and a persistent left superior vena cava (PLSVC). Both pregnant women underwent cord blood samplings because of the abnormal imaging results. Karyotype analysis revealed normal results in the two fetuses. Chromosome microarray analysis (CMA) was then performed to provide genetic analysis of the cord blood and parental blood samples. Ultimately, the pregnancies were both terminated. RESULTS: CMA detected a 1.56-Mb duplication at 17q12 in Fetus 1 and a 1.93-Mb deletion of 17q12 in Fetus 2. Both the duplicated and deleted regions included the HNF1B and LHX1 genes. Neither the duplication nor deletion was inherited from the parents. CONCLUSION: This study is the first to report the prenatal diagnosis of a 17q12 duplication syndrome. Our results further confirmed that genes in this region, including HNF1B and LHX1, are essential for normal brain and kidney development, and also indicated some genes that may be associated with the cardiovascular abnormality. Combined with imaging examination, the use of CMA will improve the diagnosis of submicroscopic chromosomal aberrations in fetuses with congenital anomalies. PMID- 25510705 TI - Prenatal diagnosis and molecular cytogenetic characterization of a 1.07-Mb microdeletion at 5q35.2-q35.3 associated with NSD1 haploinsufficiency and Sotos syndrome. AB - OBJECTIVE: To present prenatal diagnosis and molecular cytogenetic characterization of a de novo 5q35 microdeletion associated with Sotos syndrome. METHODS: This was the first pregnancy of a 29-year-old woman. The pregnancy was uneventful until 27 weeks of gestation when left ventriculomegaly was first noted. At 31 weeks of gestation, polyhydramnios, macrocephaly, and ventriculomegaly were prominent on ultrasound, and left pyelectasis and bilateral ventriculomegaly were diagnosed on magnetic resonance imaging. The woman underwent amniocentesis and cordocentesis at 32 weeks of gestation. Conventional cytogenetic analysis was performed using cultured amniocytes and cord blood lymphocytes. Array comparative genomic hybridization (aCGH) was performed on uncultured amniocytes and parental blood. Metaphase fluorescence in situ hybridization (FISH) was performed on cultured lymphocytes. RESULTS: Conventional cytogenetics revealed a karyotype of 46,XX. aCGH on uncultured amniocytes revealed a de novo 1.07-Mb microdeletion at 5q35.2-q35.3 encompassing NSD1. Metaphase FISH analysis on the cord blood lymphocytes confirmed the deletion at 5q35.2. The postnatal phenotype was consistent with Sotos syndrome. CONCLUSION: Fetuses with Sotos syndrome may present macrocephaly, polyhydramnios, ventriculomegaly, and pyelectasis in the third trimester. aCGH and metaphase FISH are useful for rapid diagnosis of 5q35 microdeletion associated with Sotos syndrome. PMID- 25510706 TI - Pelvic actinomycosis with abundant ascites, pleural effusion, and lymphadenopathy diagnosed with endometrial biopsy and treated with medication only. AB - OBJECTIVE: Pelvic actinomycosis almost always presents as a "dry" type, and pelvic actinomycosis with ascites is extremely rare. We present an unusual case of pelvic actinomycosis with ascites, pleural effusion, and lymphadenopathy. Because of these atypical clinical features, a malignant process such as ovarian cancer or peritoneal carcinomatosis was suspected, but an endometrial biopsy revealed pelvic actinomycosis, which was treated without surgical intervention. CASE REPORT: A 50-year-old Korean woman presented to our clinic with a 3-month history of abdominal pain and weight loss. An abdominopelvic computed tomography scan demonstrated ascites, pleural effusion, bilateral adnexal tubular structures, several enlarged lymph nodes in the paraaortic area, and diffuse peritoneal infiltration. Ultrasonography showed fluid collections measuring 2.7 cm in the cul-de-sac, 2.42 cm in the right paracolic gutter, and 3.13 cm in the left paracolic gutter. Endometrial/endocervical specimens showed marked chronic inflammation with sulfur granules, with a colony of filamentous organisms consistent with Actinomyces infection. The patient underwent antibiotic treatment for 6 months and recovered without complications or adverse events in the 13 months of follow up. CONCLUSION: Pelvic actinomycosis should always be considered in patients with a pelvic mass and peritoneal infiltration, especially in the presence of intrauterine device use, despite the fact that abundant ascites, pleural effusion, and lymphadenopathy almost never accompany pelvic actinomycosis. Endometrial/endocervical biopsy may yield a diagnosis without an invasive procedure and should be performed. Because of the excellent response to penicillin, medical treatment alone is an effective method to eradicate pelvic actinomycosis without the need for surgical intervention. PMID- 25510707 TI - Complete trisomy 9 with unusual phenotypic associations: Dandy-Walker malformation, cleft lip and cleft palate, cardiovascular abnormalities. AB - OBJECTIVE: Trisomy 9 is a rare chromosomal abnormality usually associated with first-trimester miscarriage; few fetuses survive until the second trimester. We report two new cases of complete trisomy 9 that both present unusual phenotypic associations, and we analyze the genetic pathway involved in this chromosomal abnormality. CASE REPORT: The first fetus investigated showed Dandy-Walker malformation, cleft lip, and cleft palate) at the second trimester scan. Cardiovascular abnormalities were characterized by a right-sided, U-shaped aortic arch associated with a ventricular septal defect (VSD). Symmetrical intrauterine growth restriction and multicystic dysplastic kidney disease were associated findings. The second fetus showed a dysmorphic face, bilateral cleft lip, hypoplastic corpus callosum, and a Dandy-Walker malformation. Postmortem examination revealed cardiovascular abnormalities such as persistent left superior vena cava draining into the coronary sinus, membranous ventricular septal defect, overriding aorta, pulmonary valve with two cusps and three sinuses, and the origin of the left subclavian artery distal to the junction of ductus arteriosus and aortic arch. CONCLUSION: Complete trisomy 9 may result in a wide spectrum of congenital abnormalities, and the presented case series contributes further details on the phenotype of this rare aneuploidy. PMID- 25510708 TI - Partial trisomy 8 mosaicism not detected by cultured amniotic-fluid cells. AB - OBJECTIVE: Prenatal detection of trisomy 8 mosaicism can be misleading and remains challenging in genetic counseling. Identifying cases of partial or complete trisomy 8 mosaicism will highlight the pitfalls of conventional karyotyping in prenatal amniocentesis for partial or complete trisomy 8 mosaicism. CASE REPORT: The patient was born uneventfully at term to a healthy 34 year-old mother. Analysis of the amniotic fluid (AF) cells showed a normal male karyotype. At birth, the newborn presented dysmorphic features, including asymmetric mandibles and ears, anteverted nostrils with a relatively long philtrum, retrognathia, and a clenched hand on the left side. Imaging studies revealed agenesis of the corpus callosum with bilateral colpocephaly, a common arterial trunk bifurcating into the left subclavian and carotid arteries, and bilateral pelviectasis. Cytogenetic analysis of the blood revealed mosaicism of partial trisomy 8: 47,XY,+del(8) (q21.3) [8]/46,XY [12]. Array comparative genomic hybridization (array-CGH) revealed 82.9 Mb duplications at chromosome 8p23.3-8q21.3 with dosage variations. Interphase fluorescence in situ hybridization analysis of urine sediments and buccal smears were compatible with mosaic compositions. A small colony of AF cells was found to have partial trisomy 8 in repeated analysis. CONCLUSION: Conventional karyotyping through amniocentesis has limitations particularly in detecting rare trisomy mosaicism if trisomic cells show growth disadvantage. Array-CGH using uncultured cells may be of help in providing more information on genetic dosage variations in such cases. PMID- 25510709 TI - Prenatal diagnosis of a de novo 9p terminal chromosomal deletion in a fetus with major congenital anomalies. AB - OBJECTIVE: We describe a prenatal ultrasonography diagnosis of omphalocele and symbrachydactyly in a fetus and review the literature on prenatal diagnosis of 9p terminal chromosomal deletions. CASE REPORT: A 31-year-old woman (gravida 3, para 1) was referred for genetic counseling because a fetal omphalocele had been detected. Prenatal ultrasonography at 17+ weeks of gestational age revealed a singleton female fetus with biometry equivalent to 18 weeks with an omphalocele. In addition, symbrachydactyly was also noted in the right arm; the wrist bones as well as the metacarpals were missing. A chromosomal study was arranged for a congenital anomaly involving omphalocele. We obtained Giemsa-banded chromosomes from fetal tissue cells, and an abnormal male karyotype with a terminal deletion of the short arm of chromosome 9 at band 9p13 was noted. After delivery, the fetus showed omphalocele, symbrachydactyly, trigonocephaly, sex reversal, a long philtrum, low-set ears, telecanthus, and a frontal prominence. CONCLUSION: Prenatal diagnosis of abnormal ultrasound findings with omphalocele and symbrachydactyly should include the differential diagnosis of a chromosome 9p deletion. PMID- 25510710 TI - Eu(III)-functionalized MIL-124 as fluorescent probe for highly selectively sensing ions and organic small molecules especially for Fe(III) and Fe(II). AB - A layerlike MOF (MIL-124, orGa2(OH)4(C9O6H4)) has been prepared and chosen as a parent compound to encapsulate Eu(3+) cations by one uncoordinated carbonyl group in its pores. The Eu(3+)-incorporated sample (Eu(3+)@MIL-124) is fully characterized, which shows excellent luminescence and good fluorescence stability in water or other organic solvents. Subsequently, we choose Eu(3+)@MIL-124 as sensitive probe for sensing metal ions, anions, and organic small molecules because of its robust framework. Studying of the luminescence properties reveals that the complex Eu(3+)@MIL-124 was developed as a highly selective and sensitive probe for detection of Fe(3+) (detection limit, 0.28 MUM) and Fe(2+) ions through fluorescence quenching of Eu(3+) and MOF over other metal ions. In connection to this, a probable sensing mechanism was also discussed in this paper. In addition, when Eu(3+)@MIL-124 was immersed in the different anions solutions and organic solvents, it also shows highly selective for Cr2O7(2-)(detection limit, 0.15 MUM)and acetone. Remarkably, it is the first Eu-doped MOF to exhibit an excellent ability for the detection of Fe(3+) and Fe(2+) in an aqueous environment without any structural disintegration of the framework. PMID- 25510712 TI - [Contribution of proteomics in medical mycology in 2014: For who? For what?]. PMID- 25510711 TI - Crystallographic and spectroscopic characterization and reactivities of a mononuclear non-haem iron(III)-superoxo complex. AB - Mononuclear non-haem iron(III)-superoxo species (Fe(III)-O2(-.)) have been implicated as key intermediates in the catalytic cycles of dioxygen activation by non-haem iron enzymes. Although non-haem iron(III)-superoxo species have been trapped and characterized spectroscopically in enzymatic and biomimetic reactions, no structural information has yet been obtained. Here we report the isolation, spectroscopic characterization and crystal structure of a mononuclear side-on (eta(2)) iron(III)-superoxo complex with a tetraamido macrocyclic ligand. The non-haem iron(III)-superoxo species undergoes both electrophilic and nucleophilic oxidation reactions, as well as O2-transfer between metal complexes. In the O2-transfer reaction, the iron(III)-superoxo complex transfers the bound O2 unit to a manganese(III) analogue, resulting in the formation of a manganese(IV)-peroxo complex, which is characterized structurally and spectroscopically as a mononuclear side-on (eta(2)) manganese(IV)-peroxo complex. The difference in the redox distribution between the metal ions and O2 in iron(III)-superoxo and manganese(IV)-peroxo complexes is rationalized using density functional theory calculations. PMID- 25510713 TI - Recombinase polymerase amplification-based assay to diagnose Giardia in stool samples. AB - Giardia duodenalis is one of the most commonly identified parasites in stool samples. Although relatively easy to treat, giardiasis can be difficult to detect as it presents similar to other diarrheal diseases. Here, we present a recombinase polymerase amplification-based Giardia (RPAG) assay to detect the presence of Giardia in stool samples. The RPAG assay was characterized on the bench top using stool samples spiked with Giardia cysts where it showed a limit of-detection nearly as low as the gold standard polymerase chain reaction assay. The RPAG assay was then tested in the highlands of Peru on 104 stool samples collected from the surrounding communities where it showed 73% sensitivity and 95% specificity against a polymerase chain reaction and microscopy composite gold standard. Further improvements in clinical sensitivity will be needed for the RPAG assay to have clinical relevance. PMID- 25510714 TI - Insect-specific viruses detected in laboratory mosquito colonies and their potential implications for experiments evaluating arbovirus vector competence. AB - Recently, there has been a dramatic increase in the detection and characterization of insect-specific viruses in field-collected mosquitoes. Evidence suggests that these viruses are ubiquitous in nature and that many are maintained by vertical transmission in mosquito populations. Some studies suggest that the presence of insect-specific viruses may inhibit replication of a super infecting arbovirus, thus altering vector competence of the mosquito host. Accordingly, we screened our laboratory mosquito colonies for insect-specific viruses. Pools of colony mosquitoes were homogenized and inoculated into cultures of Aedes albopictus (C6/36) cells. The infected cells were examined by electron microscopy and deep sequencing was performed on RNA extracts. Electron micrograph images indicated the presence of three different viruses in three of our laboratory mosquito colonies. Potential implications of these findings for vector competence studies are discussed. PMID- 25510715 TI - Single-dose indigenous liposomal amphotericin B in the treatment of Indian visceral leishmaniasis: a phase 2 study. AB - Liposomal amphotericin B is an effective and safe alternative for the treatment of visceral leishmaniasis in the Indian subcontinent. In this study, we used a higher-dose regimen of an indigenously manufactured liposomal amphotericin B (FUNGISOME; L-AmBL), which was intended to improve the efficacy in terms of long lasting cure rate. Thirty men and thirty women between 12 and 60 years old with parasitologically confirmed visceral leishmaniasis were enrolled in two cohorts of 15 patients each. Subjects in cohort I were administered one dose (10 mg/kg body weight) of L-AmBL intravenously. After the safety at this dose was confirmed in cohort I, patients were recruited in cohort II. They received one infusion of an escalated dose (15 mg/kg body weight). The safety of these two doses was evaluated over a period of 30 days, and efficacy was assessed for initial cure at day 30 and definitive cure at 6 months. FUNGISOME was found to be safe, with an initial cure rate of 100% at day 30 and a definitive cure rate of 93.3% at the 6 month follow-up in both the cohorts. PMID- 25510716 TI - International aid and natural disasters: a pre- and post-earthquake longitudinal study of the healthcare infrastructure in Leogane, Haiti. AB - The reconstruction of healthcare systems in developing countries after natural disasters is poorly understood. Using data collected before and after the 2010 Haiti earthquake, we detail the response of aid agencies and their interaction with local healthcare providers in Leogane, the city closest to the epicenter. We find that the period after the earthquake was associated with an increase in the total number of healthcare facilities, inpatient beds, and surgical facilities and that international aid has been a driving force behind this recovery. Aid has funded 12 of 13 new healthcare facilities that have opened since the earthquake as well as the reconstruction of 7 of 8 healthcare facilities that have been rebuilt. Despite increases in free, aid-financed healthcare, private Haitian healthcare facilities have remained at a constant number. The planned phase-out of several aid-financed facilities, however, will leave Leogane with fewer inpatient beds and healthcare services compared with the pre-earthquake period. PMID- 25510717 TI - From clinician to suspect case: my experience after a needle stick in an Ebola treatment unit in Sierra Leone. PMID- 25510718 TI - Bacteroides-associated pylephlebitis in a patient with strongyloidiasis. AB - Strongyloidiasis is associated with Gram-negative bacteremia. Septic portal vein thrombosis or pylephlebitis is a rare but serious complication of intra-abdominal infection, and it is often associated with Bacteroides bacteremia. We present the first report of pylephlebitis with Bacteroides bacteremia associated with underlying Strongyloides stercoralis infection and briefly review the management of septic portal vein thrombosis. PMID- 25510720 TI - Out of (west) Africa-who lost in the end? PMID- 25510719 TI - Malaria-related anemia in patients from unstable transmission areas in Colombia. AB - Information about the prevalence of malarial anemia in areas of low-malaria transmission intensity, like Latin America, is scarce. To characterize the malaria-related anemia, we evaluated 929 malaria patients from three sites in Colombia during 2011-2013. Plasmodium vivax was found to be the most prevalent species in Tierralta (92%), whereas P. falciparum was predominant in Tumaco (84%) and Quibdo (70%). Although severe anemia (hemoglobin < 7 g/dL) was almost absent (0.3%), variable degrees of non-severe anemia were observed in 36.9% of patients. In Tierralta, hemoglobin levels were negatively associated with days of illness. Moreover, in Tierralta and Quibdo, the number of previous malaria episodes and hemoglobin levels were positively associated. Both Plasmodium species seem to have similar potential to induce malarial anemia with distinct cofactors at each endemic setting. The target age in these low-transmission settings seems shifting toward adolescents and young adults. In addition, previous malaria experience seems to induce protection against anemia development. Altogether, these data suggest that early diagnosis and prompt treatment are likely preventing more frequent and serious malaria-related anemia in Colombia. PMID- 25510721 TI - Isolation and characterization of Mayaro virus from a human in Acre, Brazil. AB - Mayaro virus (MAYV) is widely distributed throughout South America and is the etiologic agent of Mayaro fever, an acute febrile illness often presenting with arthralgic manifestations. The true incidence of MAYV infection is likely grossly underestimated because the symptomatic presentation is very similar to that of dengue fever and other acute febrile tropical diseases. We report the complete genome sequence of a MAYV isolate detected from an Acrelandia patient presenting with fever, chills, and sweating, but with no arthralgia. Results show that this isolate belongs to genotype D and is closely related to Bolivian strains. Our results suggest that the Acre/Mayaro strain is closely related to the progenitor of these Bolivian strains that were isolated between 2002 and 2006. PMID- 25510723 TI - Economic cost and burden of dengue in the Philippines. AB - Dengue, the world's most important mosquito-borne viral disease, is endemic in the Philippines. During 2008-2012, the country's Department of Health reported an annual average of 117,065 dengue cases, placing the country fourth in dengue burden in southeast Asia. This study estimates the country's annual number of dengue episodes and their economic cost. Our comparison of cases between active and passive surveillance in Punta Princesa, Cebu City yielded an expansion factor of 7.2, close to the predicted value (7.0) based on the country's health system. We estimated an annual average of 842,867 clinically diagnosed dengue cases, with direct medical costs (in 2012 US dollars) of $345 million ($3.26 per capita). This is 54% higher than an earlier estimate without Philippines-specific costs. Ambulatory settings treated 35% of cases (representing 10% of direct costs), whereas inpatient hospitals served 65% of cases (representing 90% of direct costs). The economic burden of dengue in the Philippines is substantial. PMID- 25510722 TI - Trained community volunteers improve tuberculosis knowledge and attitudes among adults in a periurban community in southwest Nigeria. AB - Nigeria has the world's 10th largest tuberculosis (TB) burden. Targeted community based interventions can potentially help reduce TB incidence. We designed an intervention in a periurban community where 10 community volunteers were trained to provide community TB education and also detect and refer TB suspects to a nearby clinic. To determine the effect of the intervention on knowledge, attitude, and preventive practices of TB, we compared results from a pre intervention survey with those of a post-intervention survey. Pre-intervention, respondents had a mean knowledge score of 10.6 +/- 7.0 of a possible 34, a mean attitude score of 5.8 +/- 3.3 of a possible 10, and a mean practice score of 5.3 +/- 1.4 of a possible 7. The intervention significantly increased the mean knowledge score to 16 +/- 5.4 (P < 0.001) and mean attitude score to 7.0 +/- 1.8 (P < 0.001); however, there was no statistically significant difference in the mean practice score. Eight TB suspects were referred to the clinic, and one suspect was subsequently diagnosed with TB. The use of trained community volunteers to share information on TB improved the overall knowledge and attitudes of respondents. Continued empowerment of the community should be encouraged to promote TB prevention and care. PMID- 25510724 TI - Being ready to treat Ebola virus disease patients. AB - As the outbreak of Ebola virus disease (EVD) in West Africa continues, clinical preparedness is needed in countries at risk for EVD (e.g., United States) and more fully equipped and supported clinical teams in those countries with epidemic spread of EVD in Africa. Clinical staff must approach the patient with a very deliberate focus on providing effective care while assuring personal safety. To do this, both individual health care providers and health systems must improve EVD care. Although formal guidance toward these goals exists from the World Health Organization, Medecin Sans Frontieres, the Centers for Disease Control and Prevention, and other groups, some of the most critical lessons come from personal experience. In this narrative, clinicians deployed by the World Health Organization into a wide range of clinical settings in West Africa distill key, practical considerations for working safely and effectively with patients with EVD. PMID- 25510726 TI - Amphotericin B formulations and other drugs for visceral leishmaniasis. PMID- 25510725 TI - Foodborne outbreak of human brucellosis caused by ingested raw materials of fetal calf on Jeju Island. AB - Since the first reported case of human brucellosis in 2002 in South Korea, its incidence has been increasing nationally. However, bovine brucellosis has not been present from 2005 to date on Jeju Island. Despite Jeju Island being considered a clean area for bovine brucellosis, we experienced an outbreak of human brucellosis between 2012 and 2013. Herein, we report cases with human brucellosis after ingestion of raw materials of fetal calf at a restaurant. Patients were identified by isolation of the Brucella abortus in their blood and joint tissue. Because all patients developed zoonosis by a faulty folk remedy, we emphasize the importance of educational programs to increase the awareness of zoonosis, and the need for active surveillance and detection of illegal distribution channels of the infected animal. After the outbreak, we took control of the involved restaurant and its illegal distribution channel, and there have been no further outbreaks. PMID- 25510727 TI - Pain and bloody ear discharge in a returning traveler. AB - Cochliomyia hominivorax, the New World screwworm, was a serious livestock pest in the southern United States until the 1960s, when it was successfully eradicated by the release of sterile male flies. It remains endemic in parts of the Caribbean and South America, and there is concern that climate change may extend its geographic distribution. Cochliomyia hominivorax is voracious and can cause extensive damage to soft tissue and bone. We describe the case of a 26-year-old traveler who presented with otalgia and bloody otorrhea after returning from a vacation in the Dominican Republic, where exposure to screwworm flies most likely occurred during a nap on the beach. The causative agent was recognized by its characteristic larval anatomy, which includes pigmented dorsal tracheal trunks and posterior spiracles with an open peritreme. PMID- 25510728 TI - Taxonomy and phylogeny of the Leptographium procerum complex, including Leptographium sinense sp. nov. and Leptographium longiconidiophorum sp. nov. AB - Leptographium procerum (Ophiostomatales, Ascomycota) is a well-known fungal associate of pine root-infesting bark beetles and weevils, occurring in several countries of the world. The fungus is not a primary pathogen but has been associated with white pine root decline in the USA and with serious damage caused by the introduced red turpentine beetle (RTB) Dendroctonus valens in China. Several species closely related to L. procerum have been described during the past decade. The aim of this study was to reevaluate species boundaries in the L. procerum complex using multigene phylogenetic analyses and morphological comparisons. Phylogenetic analyses of seven gene regions (ITS2-LSU, actin, beta tubulin, calmodulin, translation elongation factor 1-alpha, and the mating type genes MAT1-1-3 and MAT1-2-1) distinguished between nine species in the complex. These included L. procerum, L. bhutanense, L. gracile, L. profanum, L. pini densiflorae, L. sibiricum, L. sinoprocerum, as well as two new species described here as Leptographium sinense sp. nov. from Hylobitelus xiaoi on Pinus elliottii in China, and Leptographium longiconidiophorum sp. nov. from Pinus densiflora in Japan. Leptographium latens is reduced to synonymy with L. gracile, and an epitype is designated for L. procerum, because a living culture associated with the holotype of L. procerum did not exist. Amplification patterns of the mating type genes suggest that all known species in the L. procerum complex are heterothallic, although sexual states have not been observed for any of the species. The results also suggest that Eastern Asia is most probably the centre of species diversity for the L. procerum complex. PMID- 25510729 TI - Erratum to: Siansivirga jejunensis sp. nov., isolated from seawater of Jeju Island in Korea and emendation of the genus Siansivirga. PMID- 25510730 TI - Low-voltage Driven Graphene Foam Thermoacoustic Speaker. AB - A low-voltage driven thermoacoustic speaker is fabricated based on three dimensional graphene foams synthesized by a nickel-template assisted chemical vapor deposition method. The corresponding thermoacoustic performances are found to be related to its microstructure. Graphene foams exhibit low heat-leakage to substrates and feasible tunability in structures and thermoacoustic performances, having great promise for applications in flexible or ultrasonic acoustic devices. PMID- 25510731 TI - Evaluation of antinociceptive effect of ethanol extract of Hedyotis corymbosa Linn. whole plant in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hedyotis corymbosa (Linn.) Lam. is a small herb commonly called as khetpapra, traditionally used to treat a wide range of diseases including abdominal pain, arthritis and inflammation. This study was conducted to evaluate the antinociceptive effect of ethanol extract of Hedyotis corymbosa (EEHC) whole plant. MATERIALS AND METHODS: The antinociceptive activity of EEHC was evaluated in mice using both chemical- and heat-induced pain models such as acetic acid-induced writhing, hot plate, tail immersion, formalin, and glutamate tests at 50, 100, and 200mg/kg doses. In order to verify the possible involvement of opioid receptors in the central antinociceptive effect of EEHC, the effects found in hot plate and tail immersion tests were antagonized with naloxone. RESULTS: EEHC produced a dose-dependent antinociceptive effect against the chemical- and heat-induced pain in mice, significantly at 100 and 200mg/kg doses. These findings suggest that the action of EEHC involves both peripheral and central antinociceptive mechanisms. The antinociceptive activity of EEHC was significantly attenuated by pretreatment with naloxone, indicating the influence of opioid receptors on the exertion of EEHC action centrally. CONCLUSIONS: This study reports the antinociceptive activity of Hedyotis corymbosa and possible underlying mechanism(s) that supports the traditional use of this plant in the treatment of different painful conditions. PMID- 25510732 TI - Jinlida granule inhibits palmitic acid induced-intracellular lipid accumulation and enhances autophagy in NIT-1 pancreatic beta cells through AMPK activation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Jinlida granule (JLDG), composed of seventeen Chinese medical herbs, is a widely used Chinese herbal prescription for treating diabetes mellitus. However, the mechanism underlying this effect remains unclear. To determine the main components in JLDG and to explore the effect of JLDG on autophagy and lipid accumulation in NIT-1 pancreatic beta cells exposed to politic acid (PA) through AMP activated protein kinase (AMPK) signaling pathway. MATERIALS AND METHODS: JLDG was prepared and the main components contained in the granules were identified by ultra performance liquid chromatography (UPLC) fingerprint. Intracellular lipid accumulation in NIT-1 cells was induced by culturing with medium containing PA. Intracellular lipid droplets were observed by Oil Red O staining and triglyceride (TG) content was measured by colorimetric assay. The formation of autophagosomes was observed under transmission electron microscope. The expression of AMPK and phospho-AMPK (pAMPK) proteins as well as its downstream fatty acid metabolism-related proteins (fatty acid synthase, FAS; acetyl-coA carboxylase, ACC; carnitine acyltransferase 1, CPT-1) and autophagy related genes (mammal target of rapamycin, mTOR; tuberous sclerosis complex 1, TSC1; microtubule-associated protein 1 light chain 3, LC3-II) were determined by Western blot. The expression of sterol regulating element binding protein 1c (SREBP-1c) mRNA was examined by real time PCR (RT-PCR). RESULTS: Our data showed that JLDG could significantly reduce PA-induced intracellular lipid accumulation in NIT-1 pancreatic beta cells. This effect was associated with increased protein expression of pAMPK and AMPK in NIT-1 cells. Treatment with JLDG also decreased the expression of AMPK downstream lipogenic genes (SREBP-1c mRNA, FAS and ACC proteins) whereas increased the expression of fatty acid oxidation gene (CPT-1 protein). Additionally, JLDG-treated cells displayed a markedly increase in the number of autophagosomes which was accompanied by the down-regulation of mTOR and the up-regulation of TSC1 and LC3-II proteins expression. However, when AMPK phosphorylation was inhibited by Compound C, JLDG supplementation did not exhibit any effect on the expression of these AMPK downstream molecules in NIT-1 cells. CONCLUSIONS: The results suggest that JLDG could reduce intracellular lipid accumulation and enhance the autophagy in NIT-1 pancreatic beta cells cultured with PA. The mechanism is possibly mediated by AMPK activation. PMID- 25510734 TI - Buruli ulcer - a rapidly changing scene. PMID- 25510733 TI - Protective effects of Penthorum chinense Pursh against chronic ethanol-induced liver injury in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Penthorum chinense Pursh (Penthoraceae) has been used as a Miao ethnomedicine for the treatment of jaundice, cholecystitis, edema, infectious hepatitis and anti-drunk hangover in China. The aim of present study is to investigate the possible protective effects of Penthorum chinense against chronic ethanol-induced liver injury. MATERIAL AND METHODS: Mice were fed a Lieber-DeCarli liquid diet containing alcohol or isocaloric maltose dextrin as control diet with or without aqueous extract of Penthorum chinense (PCP, 5.15 and 10.30 g/kg/BW) for 4 weeks. Silymarin (86 mg/kg) was used as positive control to compare the efficacy of PCP against chronic ethanol-induced hepatotoxicity. RESULTS: Treatment with PCP (10.30 g/kg) significantly reduced the increases in serum ALT and AST levels, hepatic lipid accumulation and inflammatory cytokines (i.e. TNF-alpha, IL-6), which were induced by chronic ethanol exposure. PCP was also found to attenuate reactive oxygen species (ROS) generation and malondialdehyde (MDA) level, restore the glutathione (GSH) depletion, and increase the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. In addition, PCP supplementation (10.30 g/kg) inhibited the induction of hepatic cytochrome P450 2E1 (CYP2E1), a major contributor to ethanol-mediated oxidative stress, and up-regulated the expression of nuclear factor erythroid 2 related factor 2 (Nrf2) and its downstream anti-oxidant protein heme oxygenase-1 (HO-1) in ethanol-treated mice. CONCLUSIONS: These results indicate that the co treatment with aqueous extract of Penthorum chinense (10.30 g/kg) protects against chronic ethanol-induced liver injury, possibly through suppressing CYP2E1 mediated oxidative stress and enhancing the oxidant defense systems via the activation of Nrf2/HO-1 pathway. PMID- 25510735 TI - Atomic force microscopy identifies regions of distinct desmoglein 3 adhesive properties on living keratinocytes. AB - Desmosomes provide strong cell-cell adhesion which is crucial for the integrity of tissues such as the epidermis. However, nothing is known about the distribution and binding properties of desmosomal adhesion molecules on keratinocytes. Here we used atomic force microscopy (AFM) to simultaneously visualize the topography of living human keratinocytes and the distribution and binding properties of the desmosomal adhesion molecule desmoglein 3 (Dsg3). Using recombinant Dsg3 as sensor, binding events were detectable diffusely and in clusters on the cell surface and at areas of cell-cell contact. This was blocked by removing Ca(2+) and by addition of Dsg3-specific antibodies indicating homophilic Dsg3 binding. Binding forces of Dsg3 molecules were lower on the cell surface compared to areas of cell-cell contact. Our data for the first time directly demonstrate the occurrence of Dsg3 molecules outside of desmosomes and show that Dsg3 adhesive properties differ depending on their localization. From the clinical editor: Using atomic force microscopy in the study of keratinocytes, this study directly demonstrates the occurrence of desmoglein 3 molecules outside of desmosomes and reveales that the adhesive properties of these molecules do differ depending on their localization. PMID- 25510736 TI - Visit-to-visit blood pressure variability is a marker of cardiac diastolic function and carotid atherosclerosis. AB - BACKGROUND: The associations between visit-to-visit blood pressure (BP) variability and cardiac function and carotid atherosclerosis is not clear. METHODS: Study subjects were 144 subjects (80 were female, aged 73 +/- 9 years) who underwent echocardiography and cervical ultrasonography. The ratio of early ventricular filling velocity to early diastolic mitral annular velocity (E/e'), ejection fraction, left ventricular mass index (LVMI), and maximum intima-media thickness (max-IMT) of the carotid artery were compared between the highest (high variability) and lowest (low variability) tertiles of the standard deviation of systolic BP (9.9 +/- 3.5 mmHg). RESULTS: E/e' and max-IMT were significantly greater in the high variability group than in the low variability group after adjusting for age, sex, baseline systolic BP, and other covariates (high variability vs. low variability; E/e': 13.03 +/- 5.33 vs. 10.66 +/- 3.30, multivariate-adjusted difference (beta) = 1.82, 95% confidence interval 0.06 3.58; max-IMT: 1.65 +/- 0.43 mm vs. 1.42 +/- 0.46 mm, beta = 0.20 mm, 95% confidence interval 0.03-0.36 mm). There were no significant differences in LVMI or ejection fraction. CONCLUSION: These results indicate that high visit-to-visit BP variability is associated with diastolic function and carotid atherosclerosis, and is a possible risk factor for diastolic dysfunction and atherosclerosis. PMID- 25510737 TI - Targeted labeling of an early-stage tumor spheroid in a chorioallantoic membrane model with upconversion nanoparticles. AB - In vivo detection of cancer at an early-stage, i.e. smaller than 2 mm, is a challenge in biomedicine. In this work target labeling of an early-stage tumor spheroid (~500 MUm) is realized for the first time in a chick embryo chorioallantoic membrane (CAM) model with monoclonal antibody functionalized upconversion nanoparticles (UCNPs-mAb). PMID- 25510738 TI - Down in a hole: a new laser ablation model of hemostasis. PMID- 25510739 TI - Prevalence of Coinfection with Gastric Non-Helicobacter pylori Helicobacter (NHPH) Species in Helicobacter pylori-infected Patients Suffering from Gastric Disease in Beijing, China. AB - BACKGROUND: The Helicobacter heilmannii sensu lato (H. heilmannii s.l.) group consists of long, spiral-shaped bacteria naturally colonizing the stomach of animals. Moreover, bacteria belonging to this group have been observed in 0.2-6% of human gastric biopsy specimens, and associations have been made with the development of chronic gastritis, peptic ulceration, and gastric MALT lymphoma in humans. MATERIALS AND METHODS: To gain insight into the prevalence of H. heilmannii s.l. infections in patients suffering from gastric disease in China, H. heilmannii s.l. species-specific PCRs were performed on DNA extracts from rapid urease test (RUT)-positive gastric biopsies from 1517 patients followed by nucleotide sequencing. At the same time, Helicobacter pylori cultivation and specific PCR was performed to assess H. pylori infection in these patients. RESULTS: In total, H. heilmannii s.l. infection was detected in 11.87% (178/1499) of H. pylori-positive patients. The prevalence of H. suis, H. felis, H. bizzozeronii, H. heilmannii sensu stricto (s.s.), and H. salomonis in the patients was 6.94%, 2.20%, 0.13%, 0.07%, and 2.54%, respectively. Results revealed that all patients with H. heilmannii s.l. infection were co-infected with H. pylori, and some patients were co-infected with more than two different Helicobacter species. CONCLUSIONS: Helicobacter heilmannii s.l. infections are fairly common in Chinese patients. This should be kept in mind when diagnosing the cause of gastric pathologies in patients. Helicobacter suis was shown to be by far the most prevalent H. heilmannii s.l.species. PMID- 25510740 TI - Sleep and breathing in premature infants at 6 months post-natal age. AB - BACKGROUND: Poor sleep contributes to the developmental problems seen in preterm infants. We evaluated sleep problems in preterm infants 6 months of post gestational age using the subjective Brief Infant Sleep Questionnaire (BISQ) and objective sleep tests. We also compared the sleep of premature infants with that of full-term infants. METHODS: The study included 68 6-month-old full-term healthy infants and 191 premature infants born at <37 weeks gestation. All parents completed the BISQ-Chinese version and sleep diaries. At the same time, all premature infants were submitted to one night of polysomnography (PSG) in the sleep laboratory and also were set up with an actigraph kept for 7 days. Statistical analyses were performed using correlation coefficients and the t-test with SPSS version 18 to compare questionnaire responses with other subjective and objective measures of sleep. RESULTS: The sleep problems indicated in the subjective questionnaire for the premature infants, particularly: "the nocturnal sleep duration, number of night awakenings, daytime sleep duration, duration of time with mouth breathing, and loud-noisy breathing" had significant correlations with sleep diaries, actigraphy and PSG results. The BISQ showed that duration of infant's sleeping on one side, nocturnal sleep duration, being held to fall asleep, number of nighttime awakenings, daytime sleep duration, subjective consideration of sleep problems, loud-noisy breathing, and duration spent crying during the night were significantly different between the premature infants and the term infants. PSG confirmed the presence of a very high percentage (80.6%) of premature infants with AHI > 1 event/hour as indicated by the questionnaire. CONCLUSION: Premature infants have more sleep problems than full-term infants, including the known risk of abnormal breathing during sleep, which has been well demonstrated already with the BISQ-Chinese (CBISQ). PMID- 25510741 TI - Voltage regulation of connexin channel conductance. AB - Voltage is an important parameter that regulates the conductance of both intercellular and plasma membrane channels (undocked hemichannels) formed by the 21 members of the mammalian connexin gene family. Connexin channels display two forms of voltage-dependence, rectification of ionic currents and voltage dependent gating. Ionic rectification results either from asymmetries in the distribution of fixed charges due to heterotypic pairing of different hemichannels, or by channel block, arising from differences in the concentrations of divalent cations on opposite sides of the junctional plaque. This rectification likely underpins the electrical rectification observed in some electrical synapses. Both intercellular and undocked hemichannels also display two distinct forms of voltage-dependent gating, termed Vj (fast)-gating and loop (slow)-gating. This review summarizes our current understanding of the molecular determinants and mechanisms underlying these conformational changes derived from experimental, molecular-genetic, structural, and computational approaches. PMID- 25510743 TI - Adjuvant radiotherapy outcome of stage I testicular seminoma: a single institution study. AB - PURPOSE: To analyze treatment outcome and side effects of adjuvant radiotherapy using radiotherapy fields and doses which have evolved over the last two decades in a single institution. MATERIALS AND METHODS: Forty-one patients received radiotherapy after orchiectomy from 1996 to 2007. At our institution, the treatment field for stage I seminoma has changed from dog-leg (DL) field prior to 2003 to paraaortic (PA) field after 2003. Fifteen patients were treated with the classic fractionation scheme of 25.5 Gy at 1.5 Gy per fraction. Other patients had been treated with modified schedules of 25.05 Gy at 1.67 Gy per fraction (n=15) and 25.2 Gy at 1.8 Gy per fraction (n=11). RESULTS: With a median follow up of 112 months, the 5-year and 10-year survival rates were 100% and 96%, respectively, and 5-year and 10-year relapse-free survival rates were both 97.1%. No in-field recurrence occurred. Contralateral seminoma occurred in one patient 5 years after treatment. No grade III-IV acute toxicity occurred. An increased rate of grade 1-2 acute hematologic toxicity was found in patients with longer overall treatment times due to 1.5 Gy per fraction. The rate of grade 2 acute gastrointestinal toxicity was significantly higher with DL field than with PA field and also higher in the 1.8-Gy group than in the 1.5-Gy and 1.67-Gy groups. CONCLUSION: Patients with stage I seminoma were safely treated with PA-only radiotherapy with no pelvic failure. Optimal fractionation schedule needs to be explored further in order to minimize treatment-related toxicity. PMID- 25510742 TI - Anthocyanin induces apoptosis of DU-145 cells in vitro and inhibits xenograft growth of prostate cancer. AB - PURPOSE: To investigate the effects of anthocyanins extracted from black soybean, which have antioxidant activity, on apoptosis in vitro (in hormone refractory prostate cancer cells) and on tumor growth in vivo (in athymic nude mouse xenograft model). MATERIALS AND METHODS: The growth and viability of DU-145 cells treated with anthocyanins were assessed using the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay and apoptosis was assessed by DNA laddering. Immunoblotting was conducted to evaluate differences in the expressions of p53, Bax, Bcl, androgen receptor (AR), and prostate specific antigen (PSA). To study the inhibitory effects of anthocyanins on tumor growth in vivo, DU-145 tumor xenografts were established in athymic nude mice. The anthocyanin group was treated with daily oral anthocyanin (8 mg/kg) for 14 weeks. After 2 weeks of treatment, DU-145 cells (2*106) were inoculated subcutaneously into the right flank to establish tumor xenografts. Tumor dimensions were measured twice a week using calipers and volumes were calculated. RESULTS: Anthocyanin treatment of DU-145 cells resulted in 1) significant increase in apoptosis in a dose-dependent manner, 2) significant decrease in p53 and Bcl-2 expressions (with increased Bax expression), and 3) significant decrease in PSA and AR expressions. In the xenograft model, anthocyanin treatment significantly inhibit tumor growth. CONCLUSION: This study suggests that anthocyanins from black soybean inhibit the progression of prostate cancer in vitro and in a xenograft model. PMID- 25510744 TI - Predictors of sick sinus syndrome in patients after successful radiofrequency catheter ablation of atrial flutter. AB - PURPOSE: The identification of sick sinus syndrome (SSS) in patients with atrial flutter (AFL) is difficult before the termination of AFL. This study investigated the patient characteristics used in predicting a high risk of SSS after AFL ablation. MATERIALS AND METHODS: Out of 339 consecutive patients who had undergone radiofrequency ablation for AFL from 1991 to 2012, 27 (8%) had SSS (SSS group). We compared the clinical characteristics of patients with and without SSS (n=312, no-SSS group). RESULTS: The SSS group was more likely to have a lower body mass index (SSS: 22.5+/-3.2; no-SSS: 24.0+/-3.0 kg/m2; p=0.02), a history of atrial septal defects (ASD; SSS: 19%; no-SSS: 6%; p=0.01), a history of coronary artery bypass graft surgery (CABG; SSS: 11%; no-SSS: 2%; p=0.002), and a longer flutter cycle length (CL; SSS: 262.3+/-39.2; no-SSS: 243.0+/-40; p=0.02) than the no-SSS group. In multivariate analysis, a history of ASD [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.2-11.4, p=0.02] and CABG (7.1, 95% CI 1.5-32.8, p=0.01) as well as longer flutter CL (1.1, 95% CI 1.0-1.2, p=0.04) were independent risk factors for SSS. CONCLUSION: A history of ASD and CABG as well as longer flutter CL increased the risk of SSS after AFL ablation. While half of the patients with SSS after AFL ablation experienced transient SSS, heart failure was associated with irreversible SSS. PMID- 25510745 TI - Screening for abdominal aortic aneurysm during transthoracic echocardiography in patients with significant coronary artery disease. AB - PURPOSE: Coronary artery disease (CAD) shares several risk factors with abdominal aortic aneurysm (AAA). We evaluated the prevalence during transthoracic echocardiography (TTE) and risk factors of AAA in patients with CAD. MATERIALS AND METHODS: A total of 1300 CAD patients were screened from August 2009 to May 2010, and measurement of abdominal aorta size was feasible in 920 patients (71%) at the end of routine TTE. An AAA was defined as having a maximal diameter of >=30 mm. RESULTS: Of the 920 patients, 22 (2.4% of the study population) were diagnosed with AAA; of these AAA patients, 86% were male, and 82% were over 65 years-old. Abdominal aortic size was weakly correlated with aortic root diameter (r=0.22, p<0.01). Although the proportions of male gender, hypertension, and dyslipidemia were higher in AAA patients, such differences were not statistically significant. Advanced age [odds ratio (OR)=1.07; 95% confidence interval (CI): 1.01-1.12; p<0.01], smoking (OR=3.44; 95% CI: 1.18-10.04; p=0.02), and peripheral arterial disease (OR=5.88; 95% CI: 1.38-25.05; p=0.01) were found to be associated with AAA. CONCLUSION: Although prevalence of AAA is very low in the Asian population, the prevalence of AAA in Asian CAD patients is higher than the general population. Therefore, opportunistic examination of the abdominal aorta during routine TTE could be effective, especially for male CAD patients over 65 years with a history of smoking or peripheral arterial disease. PMID- 25510746 TI - Impact of statin treatment on strut coverage after drug-eluting stent implantation. AB - PURPOSE: To evaluate the effect of statin treatment on strut coverage after drug eluting stent (DES) implantation. MATERIALS AND METHODS: In this study, 60 patients were randomly assigned to undergo sirolimus-eluting stent (SES) or biolimus-eluting stent (BES) implantation, after which patients were randomly treated with pitavastatin 2 mg or pravastatin 20 mg for 6 months. The degree of strut coverage was assessed by 6-month follow-up optical coherence tomography, which was performed in 52 DES-implanted patients. RESULTS: The percentages of uncovered struts were 19.4+/-14.7% in pitavastatin-treated patients (n=25) and 19.1+/-15.2% in pravastatin-treated patients (n=27; p=0.927). A lower percentage of uncovered struts was significantly correlated with a lower follow-up low density lipoprotein (LDL) cholesterol level (r=0.486; p=0.009) and a greater decline of the LDL cholesterol level (r=-0.456; p=0.015) in SES-implanted patients, but not in BES-implanted patients. In SES-implanted patients, the percentage of uncovered struts was significantly lower among those with LDL cholesterol levels of less than 70 mg/dL after 6 months of follow-up (p=0.025), but no significant difference in this variable according to the follow-up LDL cholesterol level was noted among BES-implanted patients (p=0.971). CONCLUSION: Lower follow-up LDL cholesterol levels, especially those less than 70 mg/dL, might have a protective effect against delayed strut coverage after DES implantation. This vascular healing effect of lower LDL cholesterol levels could differ according to the DES type. PMID- 25510747 TI - Mitochondrial DNA 4977bp deletion mutation in peripheral blood reflects atrial remodeling in patients with non-valvular atrial fibrillation. AB - PURPOSE: Recently, mitochondrial DNA 4977bp deletion (mtDNA4977-mut), a somatic mutation related to oxidative stress, has been shown to be associated with atrial fibrillation (AF). We hypothesized that patient age, as well as electroanatomical characteristics of fibrillating left atrial (LA), vary depending on the presence of mtDNA4977-mut in peripheral blood among patients with non-valvular AF. MATERIALS AND METHODS: Analyzing clinical and electroanatomical characteristics, we investigated the presence of the mtDNA4977-mut in peripheral blood of 212 patients (51.1+/-13.2 years old, 83.5% male) undergoing catheter ablation for non valvular AF, as well as 212 age-matched control subjects. RESULTS: The overall frequency of peripheral blood mtDNA4977-mut in patients with AF and controls was not significantly different (24.5% vs. 19.3%, p=0.197). When the AF patient group was stratified according to age, mtDNA4977-mut was more common (47.4% vs. 20.0%, p=0.019) in AF patients older than 65 years than their age-matched controls. Among AF patients, those with mtDNA4977-mut were older (58.1+/-11.9 years old vs. 48.8+/-11.9 years old, p<0.001). AF patients positive for the mtDNA mutation had greater LA dimension (p=0.014), higher mitral inflow peak velocity (E)/diastolic mitral annular velocity (Em) ratio (p<0.001), as well as lower endocardial voltage (p=0.035), and slower conduction velocity (p=0.048) in the posterior LA than those without the mutation. In multivariate analysis, E/Em ratio was found to be significantly associated with the presence of mtDNA4977-mut in peripheral blood. CONCLUSION: mtDNA4977-mut, an age-related somatic mutation detected in the peripheral blood, is associated with advanced age and electro-anatomical remodeling of the atrium in non-valvular AF. PMID- 25510748 TI - Clinical characteristics and impact of diabetes mellitus on outcomes in patients with nonvalvular atrial fibrillation. AB - PURPOSE: Studies have shown that diabetes mellitus (DM) is a risk factor for cardiovascular disease, including atrial fibrillation (AF); however, the clinical characteristics and prognostic impact of DM in patients with nonvalvular AF have not been well understood in China. MATERIALS AND METHODS: Included were 1644 consecutive patients with nonvalvular AF. Endpoints included all-cause mortality, cardiovascular mortality, stroke, major bleeding, and combined endpoint events (CEE) during a 1-year follow-up. RESULTS: The prevalence of DM was 16.8% in nonvalvular AF patients. Compared with non-diabetic AF patients, diabetic AF patients were older and tended to coexist with other cardiovascular diseases. Most patients with DM (93.5%) were eligible for anticoagulation, as determined by CHADS2 scores. However, only 11.2% of patients received anticoagulation. During a 1-year follow-up, the all-cause mortality and CEE rate in the DM group were significantly higher than those of the non-DM group, while the incidence of stroke was comparable. After multivariate adjustments, DM was still an independent risk factor for 1-year all-cause mortality [hazard ratio (HR)=1.558; 95% confidence interval (CI) 1.126-2.156; p=0.007], cardiovascular mortality (HR=1.615; 95% CI 1.052-2.479; p=0.028), and CEE (HR=1.523; 95% CI 1.098-2.112; p=0.012), yet not for stroke (HR=1.119; 95% CI 0.724-1.728; p=0.614). CONCLUSION: DM is a common morbidity coexisting with nonvalvular AF and is associated with an increased risk of 1-year all-cause mortality, cardiovascular mortality, and CEE. However, no increased risk of stroke was found during a 1-year follow-up in patients with AF and DM. PMID- 25510749 TI - Efficacy and safety of endoscopic resection therapies for rectal carcinoid tumors: a meta-analysis. AB - PURPOSE: Several endoscopic resection therapies have been applied for the treatment of rectal carcinoid tumors. However, there is currently no consensus regarding the optimal strategy. We performed a meta-analysis to compare the efficacy and safety of endoscopic mucosal resection (EMR) or modified EMR (m-EMR) versus endoscopic submucosal dissection (ESD) for the treatment of rectal carcinoid tumors. MATERIALS AND METHODS: PubMed, Web of Science, Medline, Embase and CNKI were searched up to the end of January 2014 in order to identify all studies on the effects of EMR (or m-EMR) and ESD on rectal carcinoid tumors. RESULTS: A total of fourteen studies involving 782 patients were included. The pooled data suggested a significantly higher rate of pathological complete resection among patients treated with ESD or m-EMR than those treated with EMR [odds ratio (OR)=0.42, 95% confidence interval (CI): 0.25-0.71; OR=0.10, 95% CI: 0.03-0.33, respectively], while there was no significant difference between the m EMR group and ESD group (OR=1.19, 95% CI: 0.49-2.86); The procedure time of ESD was longer than EMR or m-EMR groups [mean differences (MD)=-11.29, 95% CI: -14.19 - -8.38, MD= -10.90, 95% CI: -18.69 - -3.11, respectively], but it was insignificance between the EMR and m-EMR groups. No significant differences were detected among the treatment groups with regard to complications or recurrence. CONCLUSION: The results of this meta-analysis suggest that treatment of rectal carcinoid tumors with ESD or m-EMR is superior to EMR, and the efficacy of m-EMR is equivalence to ESD treatment. However, more well-designed studies are needed to confirm these findings. PMID- 25510750 TI - Immunohistochemical detection of p53 expression in patients with preoperative chemoradiation for rectal cancer: association with prognosis. AB - PURPOSE: The expression of p53 in patients with rectal cancer who underwent preoperative chemoradiation and and its potential prognostic significance were evaluated. MATERIALS AND METHODS: p53 expression was examined using immunohistochemistry in pathologic specimens from 210 rectal cancer patients with preoperative chemoradiotherapy and radical surgery. All patients were classified into two groups according to the p53 expression: low p53 (<50% nuclear staining) and high p53 (>=50%) groups. RESULTS: p53 expression was significantly associated with tumor location from the anal verge (p=0.036). In univariate analysis, p53 expression was not associated with disease-free survival (p=0.118) or local recurrence-free survival (p=0.089). Multivariate analysis showed that tumor distance from the anal verge (p=0.006), ypN category (p=0.011), and perineural invasion (p=0.048) were independent predictors of disease-free survival; tumor distance from the anal verge was the only independent predictor of local recurrence-free survival. When the p53 groups were subdivided according to ypTNM category, disease-free survival differed significantly in patients with ypN+ disease (p=0.027) only. CONCLUSION: Expression of p53 in pathologic specimens as measured by immunohistochemical methods may have a significant prognostic impact on survival in patients with ypN+ rectal cancer with preoperative chemoradiotherapy. However, it was not an independent predictor of recurrence or survival. PMID- 25510751 TI - Insulin resistance is an important risk factor for cognitive impairment in elderly patients with primary hypertension. AB - PURPOSE: Insulin resistance plays a role in the development of dementia and hypertension. We investigated a possible relationship between cognitive impairment and insulin resistance in elderly Chinese patients with primary hypertension. MATERIALS AND METHODS: One hundred and thirty-two hypertensive elderly patients (>60 years) were enrolled in this study, and assigned into either the cognitive impairment group (n=61) or the normal cognitive group (n=71). Gender, age, education, body mass index (BMI), waist hip ratio (WHR), total cholesterol (TC), triglyceride (TG), C-reactive protein (CRP), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), creatinine (Cr), fasting plasma glucose (FPG), fasting insulin (FINS), homeostasis model of assessment for insulin resistance index (HOMA-IR), systolic blood pressure, diastolic blood pressure, smoking history, atherosclerosis and the proportion of uncontrolled hypertension were compared between the two groups. Multi-factorial logistic regression analysis was performed. RESULTS: No significant differences were found in gender, age, TC, CRP, HDL-C, LDL-C, Cr, BP, smoking history, atherosclerosis and the proportion of uncontrolled hypertension between the two groups. The cognitive impairment group had lower education levels, and higher BMI, WHR, TG, FPG, FINS, and HOMA-IR levels than the control group. Logistic regression analysis revealed the levels of education, BMI, WHR, and HOMA-IR as independent factors that predict cognitive impairment in patients. CONCLUSION: Our study demonstrates that poor education and increased BMI, WHR, and HOMA-IR are independent risk factors for cognitive impairment in elderly patients with hypertension. Insulin resistance plays an important role in the development of cognitive impairment in primary elderly hypertensive patients. PMID- 25510752 TI - Reference values of body composition indices: the Korean National Health and Nutrition Examination Surveys. AB - PURPOSE: An increase in the prevalence of obesity has been observed in children and adolescents. As remarkable changes in body composition occur with growth during the adolescent period, it is important that changes in body composition be monitored. The purpose of this study was to propose reference percentile values for body composition indices including body mass index (BMI) in children and adolescents in Korea. MATERIALS AND METHODS: This study was performed using data from the Fourth and Fifth Korea National Health and Nutrition Examination Surveys. Body composition data were obtained using dual-energy X-ray absorptiometry. The percentile curves of body composition indices were constructed by the LMS method. RESULTS: A total of 2123 children and adolescents between the ages of 10 and 19 years were included in this study. We obtained the percentile curves for BMI and body composition indices. CONCLUSION: The reference values for body composition from this study could help with assessing body composition in Korean adolescents. PMID- 25510753 TI - Efficacy of surgical treatment for brain metastasis in patients with non-small cell lung cancer. AB - PURPOSE: Patients with non-small cell lung cancer (NSCLC) and simultaneously having brain metastases at the initial diagnosis, presenting symptoms related brain metastasis, survived shorter duration and showed poor quality of life. We analyzed our experiences on surgical treatment of brain metastasis in patients with NSCLC. MATERIALS AND METHODS: We performed a single-center, retrospective review of 36 patients with NSCLC and synchronous brain metastases between April 2006 and December 2011. Patients were categorized according to the presence of neurological symptoms and having a brain surgery. As a result, 14 patients did not show neurological symptoms and 22 patients presented neurological symptoms. Symptomatic 22 patients were divided into two groups according to undergoing brain surgery (neurosurgery group; n=11, non-neurosurgery group; n=11). We analyzed overall surgery (OS), intracranial progression-free survival (PFS), and quality of life. RESULTS: Survival analysis showed there was no difference between patients with neurosurgery (OS, 12.1 months) and non-neurosurgery (OS, 10.2 months; p=0.550). Likewise for intracranial PFS, there was no significant difference between patients with neurosurgery (PFS, 6.3 months) and non neurosurgery (PFS, 5.3 months; p=0.666). Reliable neurological one month follow up by the Medical Research Council neurological function evaluation scale were performed in symptomatic 22 patients. The scale improved in eight (73%) patients in the neurosurgery group, but only in three (27%) patients in the non neurosurgery group (p=0.0495). CONCLUSION: Patients with NSCLC and synchronous brain metastases, presenting neurological symptoms showed no survival benefit from neurosurgical resection, although quality of life was improved due to early control of neurological symptoms. PMID- 25510754 TI - The effect of bortezomib on expression of inflammatory cytokines and survival in a murine sepsis model induced by cecal ligation and puncture. AB - PURPOSE: Although the proteasome inhibitor known as bortezomib can modulate the inflammatory process through the nuclear factor-kappa B signaling pathway, the immunomodulatory effect of pre-incubated bortezomib has not been fully evaluated for inflammation by infectious agents. Therefore, we evaluated the effect of bortezomib on the expression of inflammatory cytokines and mediators in macrophage cell lines and on survival in a murine peritonitis sepsis model. MATERIALS AND METHODS: Bortezomib was applied 1 hr before lipopolysaccharide (LPS) stimulation in RAW 264.7 cells. The cecal ligation and puncture (CLP) experiments were performed in C57BL/6J mice. RESULTS: Pre-incubation with bortezomib (25 nM or 50 nM) prior to LPS (50 ng/mL or 100 ng/mL) stimulation significantly recovered the number of viable RAW 264.7 cells compared to those samples without pre-incubation. Bortezomib decreased various inflammatory cytokines as well as nitric oxide production in LPS-stimulated cells. The 7-day survival rate in mice that had received bortezomib at 0.01 mg/kg concentration 1 hr prior to CLP was significantly higher than in the mice that had only received a normal saline solution of 1 mL 1 hr prior to CLP. In addition, the administration of bortezomib at 0.01 mg/kg concentration 1 hr before CLP resulted in a significant decrease in inflammation of the lung parenchyma. Collectively, pretreatment with bortezomib showed an increase in the survival rate and changes in the levels of inflammatory mediators. CONCLUSION: These results support the possibility of pretreatment with bortezomib as a new therapeutic target for the treatment of overwhelming inflammation, which is a characteristic of severe sepsis. PMID- 25510756 TI - Characteristics and trends of published adult hip research over the last decade. AB - PURPOSE: We designed this study to demonstrate recent trends in the proportion of adult hip research in orthopedics, to identify countries leading the adult hip research, and to evaluate the relationship between the economic power of the countries and their contributions. MATERIALS AND METHODS: Studies published in seven select orthopedic journals were retrieved from PubMed. Among them, we determined the number of adult hip studies. The countries-of-origin of adult hip studies, and the economic power of the countries were investigated. RESULTS: A total of 7218 orthopedic publications and 1993 (27.6%) addressed adult hip research were identified. Adult hip studies increased from 313 (23.7%) in 2000 to 555 (27.9%) in 2011. Twenty-five countries accounted for 97.6% of the total number of adult hip studies, and gross domestic product correlated with publication volume (Spearman's rho, 0.723; p=0.000). CONCLUSION: Researchers from a limited number of developed countries have published their studies in the adult hip discipline. PMID- 25510755 TI - Risk factors for osteoarthritis and contributing factors to current arthritic pain in South Korean older adults. AB - PURPOSE: Although previous studies have focused on risk factors for osteoarthritis, there is some debate on this issue. Furthermore, associated factors with arthritic symptom (arthralgia) have not been sufficiently investigated, despite its clinical importance in the management of osteoarthritis. This study was performed to examine the risk factors for osteoarthritis and the contributing factors to current arthritic pain in older adults. MATERIALS AND METHODS: The Fourth Korean National Health and Nutrition Examination Surveys was conducted in 2009. Therein, 720 males and 1008 females aged 65 years and older were included. Comprehensive data on habitual, socioeconomic, medical, nutritional, and psychological factors were collected along with the presence of osteoarthritis and arthritic pain. After univariate analysis, binary logistic regression analysis was performed to identify risk factors for osteoarthritis and contributing factors to current arthritic pain. RESULTS: Age (p=0.005), female gender (p<0.001), higher body mass index (BMI) (p<0.001), and osteoporosis (p<0.001) were significant risk factors for osteoarthritis, while higher education level (p=0.025) was a protective factor for osteoarthritis. Higher BMI (p=0.047), lack of weekly moderate intensity activity (p<0.001), and unfavorable subjective health status (p<0.001) were significant factors contributing to current arthritic pain among subjects with osteoarthritis. Both osteoarthritis and current arthritic pain adversely affected health related quality of life. CONCLUSION: Higher BMI, lack of weekly moderate intensity activity, and unfavorable subjective health status were significant factors contributing to current arthritic pain. More attention needs to be paid to psychiatric effects on osteoarthritis and joint related pain. PMID- 25510757 TI - Incidence of deep vein thrombosis after major lower limb orthopedic surgery: analysis of a nationwide claim registry. AB - PURPOSE: We aimed to evaluate the nationwide incidence and risk factors for symptomatic deep vein thrombosis (DVT) after major lower limb orthopedic surgeries. MATERIALS AND METHODS: The Korean Health Insurance Review and Assessment Service database was used to retrospectively identify International Classification of Disease-10 codes for DVT and operation codes representing hip arthroplasty, knee arthroplasty, and hip fracture surgeries. The age- and gender adjusted annual incidence of DVT, rates of major lower limb orthopedic surgeries, and the postoperative incidence of DVT according to the surgical procedure were assessed. RESULTS: The age- and gender-adjusted annual incidence of DVT was 70.67 per 100000 persons/year. Compared to patients aged <49 years, the relative risk of DVT was five times higher in patients aged 50-69 and 10 times higher in patients aged >70 years (p<0.001). Females showed a greater relative risk for DVT than males (1.08; p<0.001). The incidence of postoperative DVT, according to the type of surgery, was significantly greater for knee replacement arthroplasty than for other forms of surgery (p<0.002). The relative risk of postoperative DVT was higher in females in knee replacement arthroplasty (1.47) and hip fracture surgery (2.25) groups, although relatively lower in those who underwent hip replacement arthroplasty (0.97). CONCLUSION: Among major lower limb surgeries, advanced age, female gender, and undergoing a knee replacement arthroplasty were found to be risk factors for developing postoperative DVT. These findings further emphasize the need for orthopedic surgeons to consider the development of DVT after surgery in high-risk patients. PMID- 25510758 TI - Finite element analysis for comparison of spinous process osteotomies technique with conventional laminectomy as lumbar decompression procedure. AB - PURPOSE: The purpose of this study was to evaluate and compare the biomechanical behavior of the lumbar spine after posterior decompression with the spinous process osteotomy (SPiO) technique or the conventional laminectomy (CL) technique using a finite element (FE) model. MATERIALS AND METHODS: Three validated lumbar FE models (L2-5) which represented intact spine and two decompression models using SPiO and CL techniques at the L3-4 segment were developed. In each model, the ranges of motion, the maximal von Mises stress of the annulus fibrosus, and the intradiscal pressures at the index segment (L3-4) and adjacent segments (L2-3 and L4-5) under 7.5 Nm moments were analyzed. Facet contact forces were also compared among three models under the extension and torsion moments. RESULTS: Compared to the intact model, the CL and SPiO models had increased range of motion and annulus stress at both the index segment (L3-4) and the adjacent segments under flexion and torsion. However, the SPiO model demonstrated a reduced range of motion and annulus stress than the CL model. Both CL and SPiO models had an increase of facet contact force at the L3-4 segment under the torsion moment compared to that of the intact model. Under the extension moment, however, three models demonstrated a similar facet contact force even at the L3-4 model. CONCLUSION: Both decompression methods lead to postoperative segmental instability compared to the intact model. However, SPiO technique leads to better segmental stability compared to the CL technique. PMID- 25510759 TI - Effect of the starting point of half-pin insertion on the insertional torque of the pin at the tibia. AB - PURPOSE: The authors have observed a failure to achieve secure fixation in elderly patients when inserting a half-pin at the anteromedial surface of the tibia. The purpose of this study was to compare two methods for inserting a half pin at tibia diaphysis in elderly patients. MATERIALS AND METHODS: Twenty cadaveric tibias were divided into Group C or V. A half-pin was inserted into the tibias of Group C via the conventional method, from the anteromedial surface to the interosseous border of the tibia diaphysis, and into the tibias of Group V via the vertical method, from the anterior border to the posterior surface at the same level. The maximum insertion torque was measured during the bicortical insertion with a torque driver. The thickness of the cortex was measured by micro computed tomography. The relationship between the thickness of the cortex engaged and the insertion torque was investigated. RESULTS: The maximum insertion torque and the thickness of the cortex were significantly higher in Group V than Group C. Both groups exhibited a statistically significant linear correlation between torque and thickness by Spearman's rank correlation analysis. CONCLUSION: Half pins inserted by the vertical method achieved purchase of more cortex than those inserted by the conventional method. Considering that cortical thickness and insertion torque in Group V were significantly greater than those in Group C, we suggest that the vertical method of half-pin insertion may be an alternative to the conventional method in elderly patients. PMID- 25510760 TI - Feasibility of translaminar screw placement in Korean population: morphometric analysis of cervical spine. AB - PURPOSE: To analyze the feasibility of unilateral and bilateral translaminar screw placement in Koran population, and compare the acceptance rate using previously reported data in American population. MATERIALS AND METHODS: The translaminar lengths, thickness, heights, and sagittal-diagonal measurements were performed. The feasibility analysis was performed using unilateral and bilateral 3.5 mm cervical screw placement on the CT scans within 0.5 mm of safety margin. We also performed radiographic analysis of the morphometric dimensions and the feasibility of unilateral and bilateral translaminar screw placement at C3-C7. RESULTS: Korean population had similar or significantly shorter translaminar lengths and thickness (lengths and thickness in C7 among males; lengths in C6-C7 and thickness in C4 among females) than American population, but had similar or significantly longer translaminar heights and sagittal-diagonal measurements (heights in C3-C7 and sagittal-diagonal measurements in C3-C6 among males; heights in C7 and sagittal-diagonal measurements in C3-C7 among females). Unilaterally, translaminar screw acceptance rates in C3-C7 were similar between Korean and American male population, but the rates in C4-C6 were significantly smaller between Korean and American female population. Bilaterally, translaminar screw acceptance rates in C3 and C5-C6 were significantly larger between Korean and American male population, but the rates in C3-C7 were similar between Korean and American female population. CONCLUSION: The feasibility of unilateral and bilateral translaminar screw placement is different depending on different ethnics. Subaxial cervical unilateral translaminar screw placement among Korean male population and bilateral placement at C4-C7 among Korean female population are more acceptable than American population. PMID- 25510761 TI - Various applications of deep temporal fascia in rhinoplasty. AB - PURPOSE: In Asians, nasal dorsal and tip augmentation procedures are usually performed at the same time, and most dorsal augmentations use implants. In this study, dorsal augmentation was given by various types of grafts using deep temporal fascia (DTF) for primary rhinoplasty cases using only autologous tissues to improve the curve of hump noses and depressions. For secondary rhinoplasty cases, DTF was used to improve implant demarcation and transparency. Such effectiveness and utility of DTF is discussed. MATERIALS AND METHODS: Between May 2009 and May 2012, we performed rhinoplasty using DTF in 175 patients, which included 78 secondary surgery patients and 128 female patients. The mean age of the patients was 31.4. DTF was utilized with various types of grafts without implants to improve the curve in dorsal augmentation of hump noses and cases that required curve betterment. DTF was used to improve implant demarcation and transparency for secondary cases. RESULTS: The mean follow-up duration was 1.5 years. Of the 175 patients, 81% were satisfied with the natural correction achieved, whereas 19% complained of undercorrection, which was resolved with additional surgery. No specific complications such as nasal inflammation or contractures were observed. CONCLUSION: DTF can be used with various graft methods for correction of radix, dorsal, and tip irregularities. It can also be used to correct implant contour transparency in secondary rhinoplasty and thus may be considered as a useful supplementary graft material in rhinoplasty for Asians. PMID- 25510762 TI - Clinical implications of microsatellite instability in T1 colorectal cancer. AB - PURPOSE: The estimation of regional lymph node metastasis (LNM) risk in T1 colorectal cancer is based on histologic examination and imaging of the primary tumor. High-frequency microsatellite instability (MSI-H) is likely to decrease the possibility of metastasis to either regional lymph nodes or distant organs in colorectal cancers. This study evaluated the clinical implications of MSI in T1 colorectal cancer with emphasis on the usefulness of MSI as a predictive factor for regional LNM. MATERIALS AND METHODS: A total of 133 patients who underwent radical resection for T1 colorectal cancer were included. Genomic DNA was extracted from normal and tumor tissues and amplified by polymerase chain reaction (PCR). Five microsatellite markers, BAT-25, BAT-26, D2S123, D5S346, and D17S250, were used. MSI and clinicopathological parameters were evaluated as potential predictors of LNM using univariate and multivariate analyses. RESULTS: Among 133 T1 colorectal cancer patients, MSI-H, low-frequency microsatellite instability (MSI-L), and microsatellite stable (MSS) colorectal cancers accounted for 7.5%, 6%, and 86.5%, respectively. MSI-H tumors showed a female predominance, a proximal location and more retrieved lymph nodes. Twenty-two patients (16.5%) had regional LNM. Lymphovascular invasion and depth of invasion were significantly associated with LNM. There was no LNM in 10 MSI-H patients; however, MSI status was not significantly correlated with LNM. Disease-free survival did not differ between patients with MSI-H and those with MSI-L/MSS. CONCLUSION: MSI status could serve as a negative predictive factor in estimating LNM in T1 colorectal cancer, given that LNM was not detected in MSI-H patients. However, validation of our result in a different cohort is necessary. PMID- 25510763 TI - Overcoming the limitations of fine needle aspiration biopsy: detection of lateral neck node metastasis in papillary thyroid carcinoma. AB - PURPOSE: Ultrasound (US) and US-guided fine needle aspiration biopsies (FNAB) are considered the modalities of choice for assessing lymph nodes suspected of containing metastases, but the sensitivity of FNAB varies and is specific to the operator. We analyzed the risk of FNAB providing false negative results of lateral neck node metastasis, and evaluated diagnostic accuracy of FNAB, in patients with papillary thyroid cancer. MATERIALS AND METHODS: FNAB was performed in 242 patients suspected of having lateral neck node metastasis on preoperative imaging. Thyroglobulin in the fine-needle aspirate washout (FNA wash-out Tg) and computed tomography enhancement (Hounsfield units) were measured. Patients with negative results on FNAB were examined by intraoperative frozen section. The false negative and true negative groups were compared. RESULTS: Of the 242 patients, 130 were confirmed as having lateral neck node metastases. In 74 patients, the metastasis was identified by FNAB. False positive results were observed in 2 patients (0.8%) and false negatives in 58 (44.6%). Risk analysis showed that patient age <45 years (p=0.006), tumor size >1 cm (p=0.008) and elevated FNA wash-out Tg (p=0.004) were significantly associated with false negative results on FNAB. The accuracy of FNAB increased significantly when combined with FNA wash-out Tg (p=0.003). CONCLUSION: To reduce the false negative rate of FNAB, patient age (<45 years), tumor size (>1 cm) and FNA wash-out Tg (>34.8 ng/mL) should be considered in preoperative planning. Accuracy may be improved by combining the results of FNAB and FNA wash-out Tg. PMID- 25510764 TI - The first experiences of robotic single-site cholecystectomy in Asia: a potential way to expand minimally-invasive single-site surgery? AB - PURPOSE: Herein, we firstly present the robotic single-site cholecystectomy (RSSC) as performed in Asia and evaluate whether it could overcome the limitations of conventional laparoscopic single-site cholecystectomy. MATERIALS AND METHODS: From October 2013 to November 2013, RSSC for benign gallbladder (GB) disease was firstly performed consecutively in five patients. We evaluated these early experiences of RSSC and compared factors including clinicopathologic factors and operative outcomes with our initial cases of single-fulcrum laparoscopic cholecystectomy (SFLC). RESULTS: Four female patients and one male patient underwent RSSC. Neither open conversion nor bile duct injury or bile spillage was noted during surgery. In comparisons with SFLC, patient-related factors in terms of age, sex, Body Mass Index, diagnosis, and American Society of Anesthesiologist score showed no significant differences between two groups. There were no significant differences in the operative outcomes regarding intraoperative blood loss, bile spillage during operation, postoperative pain scale values, postoperative complications, and hospital stay between the two groups (p<0.05). Actual dissection time (p=0.003) and total operation time (p=0.001) were significantly longer in RSSC than in SFLC. There were no drain insertion or open conversion cases in either group. CONCLUSION: RSSC provides a comfortable environment and improved ergonomics to laparoscopic single-site cholecystectomy; however, this technique needs to be modified to allow for more effective intracorporeal movement. As experience and technical innovations continue, RSSC will soon be alternative procedure for well-selected benign GB disease. PMID- 25510765 TI - Attenuation of peripheral regulatory T-cell suppression of skin-homing CD8+T cells in atopic dermatitis. AB - PURPOSE: Cutaneous lymphocyte-associated antigen (CLA)-expressing CD8+T cells have been known to play an important role in the pathogenesis of atopic dermatitis (AD). However, the mechanisms underlying the loss of self-tolerance remain unclear. Regulatory T cells (Tregs) play a key role in the development of homeostasis in the immune system. We, therefore, hypothesized that a reduced ability of Tregs to inhibit autologous CD8+CLA+T cells might be underlying mechanism in AD. MATERIALS AND METHODS: CD8+CLA+T cells and Tregs were obtained from the peripheral blood of AD patients and control volunteers. The frequencies of CD8+CLA+T cells were evaluated. The proliferative responses of CD8+CLA+T cells were assessed by flow cytometry, and the levels of transforming growth factor beta1 (TGF-beta1) and interleukin-10 (IL-10) in culture supernatants were detected by enzyme-linked immunosorbent assay. RESULTS: Our results revealed higher frequency and increased expression of perforin and granzyme-B in peripheral CD8+CLA+T cells in AD, and lower inhibitory ability of Tregs on proliferation of CD8+CLA+T cells in AD. Meanwhile, the levels of TGF-beta1 produced by Tregs were significantly lower in AD, and anti-TGF-beta1 abolished such suppression. CONCLUSION: The attenuated inhibitory ability of Tregs on hyper activated autologous CD8+CLA+T cells, mediated by TGF-beta1, plays an important role in the pathogenesis of AD. PMID- 25510766 TI - NGF and HB-EGF: potential biomarkers that reflect the effects of fesoterodine in patients with overactive bladder syndrome. AB - PURPOSE: To determine whether levels of nerve growth factor (NGF) and heparin binding epidermal growth factor-like growth factor (HB-EGF) can be used to objectively assess overactive bladder syndrome (OAB) treatment outcome and to evaluate the effects of fixed-dose fesoterodine on OAB symptoms. MATERIALS AND METHODS: This study included 124 participants (62 patients with OAB and 62 controls) in Severance Hospital between 2010 and 2012. In patients with OAB, 4 mg fesoterodine was administered once daily. Repeated evaluations of putative biomarker levels, urine creatinine (Cr) levels, and questionnaire responses, including the Overactive Bladder Symptom Score (OABSS) and the Overactive Bladder Questionnaire (OAB q), were performed from baseline to 16 weeks. RESULTS: Urinary levels of NGF/Cr (OAB: 1.13+/-0.9 pg/mg; control: 0.5+/-0.29 pg/mg) and HB-EGF/Cr (OAB: 8.73+/-6.55 pg/mg; control: 4.45+/-2.93 pg/mg) were significantly higher in subjects with OAB than in controls (p<0.001). After 16 weeks of fixed-dose fesoterodine treatment, urinary NGF/Cr levels (baseline: 1.13+/-0.08 pg/mg; 16 weeks: 0.60+/-0.4 pg/mg; p=0.02) and HB-EGF/Cr levels significantly decreased (baseline: 8.73+/-6.55 pg/mg; 16 weeks: 4.72+/-2.69 pg/mg; p=0.03, respectively). Both the OABSS and OAB q scores improved (p<0.001). However, there were no a statistically significant correlations between these urinary markers and symptomatic scores. CONCLUSION: Urinary levels of NGF and HB-EGF may be potential biomarkers for evaluating outcome of OAB treatment. Fixed-dose fesoterodine improved OAB symptoms. Future studies are needed to further examine the significance of urinary NGF and HB-EGF levels as therapeutic markers for OAB. PMID- 25510767 TI - Efficacy of veno-venous extracorporeal membrane oxygenation in severe acute respiratory failure. AB - PURPOSE: The objective of this study was to evaluate our institutional experience with veno-venous (VV) extracorporeal membrane oxygenation (ECMO) in patients with severe acute respiratory failure (ARF). MATERIALS AND METHODS: From January 2007 to August 2013, 31 patients with severe ARF that was due to various causes and refractory to mechanical ventilation with conventional therapy were supported with VV ECMO. A partial pressure of arterial oxygen (PaO2)/inspired fraction of oxygen (FiO2) <100 mm Hg at an FiO2 of 1.0 or a pH <7.25 due to CO2 retention were set as criteria for VV ECMO. RESULTS: Overall, 68% of patients survived among those who had received VV ECMO with a mean PaO2/FiO2 of 56.8 mm Hg. Furthermore, in trauma patients, early use of ECMO had the best outcome with a 94% survival rate. CONCLUSION: VV ECMO is an excellent, life-saving treatment option in patients suffering from acute and life-threatening respiratory failure due to various causes, especially trauma, and early use of VV ECMO therapy improved outcomes in these patients. PMID- 25510768 TI - Epidemiology of trauma patients and analysis of 268 mortality cases: trends of a single center in Korea. AB - PURPOSE: There is an increasing incidence of mortality among trauma patients; therefore, it is important to analyze the trauma epidemiology in order to prevent trauma death. The authors reviewed the trauma epidemiology retrospectively at a regional emergency center of Korea and evaluated the main factors that led to trauma-related deaths. MATERIALS AND METHODS: A total of 17007 trauma patients were registered to the trauma registry of the regional emergency center at Wonju Severance Christian Hospital in Korea from January 2010 to December 2012. RESULTS: The mean age of patients was 35.2 years old. The most frequent trauma mechanism was blunt injury (90.8%), as well as slip-and-fall down injury, motor vehicle accidents, and others. Aside from 142 early trauma deaths, a total of 4673 patients were admitted for further treatment. The most common major trauma sites of admitted patients were on the extremities (38.4%), followed by craniocerebral, abdominopelvis, and thorax. With deaths of 126 patients during in hospital treatment, the overall mortality (142 early and 126 late deaths) was 5.6% for admitted patients. Ages >=55, injury severity score >=16, major craniocerebral injury, cardiopulmonary resuscitation at arrival, probability of survival <25% calculated from the trauma and injury severity score were independent predictors of trauma mortality in multivariate analysis. CONCLUSION: The epidemiology of the trauma patients studied was found to be mainly blunt trauma. This finding is similar to previous papers in terms of demographics and mechanism. Trauma patients who have risk factors of mortality require careful management in order to prevent trauma-related deaths. PMID- 25510769 TI - A polymorphism of the renin gene rs6682082 is associated with essential hypertension risk and blood pressure levels in Korean women. AB - PURPOSE: The aim of the present study was to investigate associations between the renin gene (REN) and the risk of essential hypertension and blood pressure (BP) levels in Koreans. MATERIALS AND METHODS: To outline the functional role of a single nucleotide polymorphism in the transcription of the REN gene, we conducted a case-control study of 1975 individuals: 646 hypertension (HT) patients and 1329 ethnically and age-matched normotensive subjects. RESULTS: Logistic regression analysis indicated that the genotypes AA/AG were strongly associated with risk of HT (odds ratio, 1.493; 95% confidence interval, 1.069-2.086, p=0.018) in female subjects. The genotypes AA/AG also showed significant association with higher blood pressure levels, both systolic and diastolic, in postmenopausal HT women (p=0.003 and p=0.017, respectively). Analysis of the promoter containing rs6682082 revealed a 2.4+/-0.01-fold higher activity in the A variant promoter than the G variant promoter, suggesting that rs6682082 is itself a functional variant. CONCLUSION: We suggest that the A allele of rs6682082 is a positive genetic marker for predisposition to essential hypertension and high BP in Korean women and may be mediated through the transcriptional activation of REN. PMID- 25510770 TI - The effects of different noise types on heart rate variability in men. AB - PURPOSE: To determine the impact of noise on heart rate variability (HRV) in men, with a focus on the noise type rather than on noise intensity. MATERIALS AND METHODS: Forty college-going male volunteers were enrolled in this study and were randomly divided into four groups according to the type of noise they were exposed to: background, traffic, speech, or mixed (traffic and speech) noise. All groups except the background group (35 dB) were exposed to 45 dB sound pressure levels. We collected data on age, smoking status, alcohol consumption, and disease status from responses to self-reported questionnaires and medical examinations. We also measured HRV parameters and blood pressure levels before and after exposure to noise. The HRV parameters were evaluated while patients remained seated for 5 minutes, and frequency and time domain analyses were then performed. RESULTS: After noise exposure, only the speech noise group showed a reduced low frequency (LF) value, reflecting the activity of both the sympathetic and parasympathetic nervous systems. The low-to-high frequency (LF/HF) ratio, which reflected the activity of the autonomic nervous system (ANS), became more stable, decreasing from 5.21 to 1.37; however, this change was not statistically significant. CONCLUSION: These results indicate that 45 dB(A) of noise, 10 dB(A) higher than background noise, affects the ANS. Additionally, the impact on HRV activity might differ according to the noise quality. Further studies will be required to ascertain the role of noise type. PMID- 25510771 TI - Effects of diabetic case management on knowledge, self-management abilities, health behaviors, and health service utilization for diabetes in Korea. AB - PURPOSE: This study aimed to evaluate the effects of a case management program for diabetics, using a pre-post comparison design. MATERIALS AND METHODS: The study population comprised 6007 diabetics who received case management intervention in 2006 and were sampled nationwide in Korea. Before and after the intervention, the study population answered questions regarding their knowledge of diabetes, self-management ability, and health behaviors. Body mass index (BMI) was also calculated. Healthcare service utilization for diabetes was extracted from health insurance claim data from 2005 to 2007. RESULTS: The case management program significantly improved the study population's knowledge of diabetes and ability to self-manage nutrition, blood glucose monitoring, foot and oral care, and medications. This program also significantly changed the study population's health behaviors regarding smoking, alcohol drinking, and exercise, and BMI was positively affected. In the over-serviced subgroup, there was a significant decrease in the number of consultations (mean=7.0; SD=19.5) after intervention. Conversely, in the under-serviced subgroup, there was a significant increase in the number of consultations (mean=3.2; SD=7.9) and the days of prescribed medication (mean=66.4; SD=120.3) after intervention. CONCLUSION: This study showed that the case management program led the study population to improve their knowledge, self-management ability, health behaviors, and utilization of health care. It is necessary in future studies to evaluate the appropriateness of healthcare usage and clinical outcome by using a control group to determine the direct effectiveness of this case management program. PMID- 25510772 TI - Quantitative analysis of the effect of iterative reconstruction using a phantom: determining the appropriate blending percentage. AB - PURPOSE: To investigate the optimal blending percentage of adaptive statistical iterative reconstruction (ASIR) in a reduced radiation dose while preserving a degree of image quality and texture that is similar to that of standard-dose computed tomography (CT). MATERIALS AND METHODS: The CT performance phantom was scanned with standard and dose reduction protocols including reduced mAs or kVp. Image quality parameters including noise, spatial, and low-contrast resolution, as well as image texture, were quantitatively evaluated after applying various blending percentages of ASIR. The optimal blending percentage of ASIR that preserved image quality and texture compared to standard dose CT was investigated in each radiation dose reduction protocol. RESULTS: As the percentage of ASIR increased, noise and spatial-resolution decreased, whereas low-contrast resolution increased. In the texture analysis, an increasing percentage of ASIR resulted in an increase of angular second moment, inverse difference moment, and correlation and in a decrease of contrast and entropy. The 20% and 40% dose reduction protocols with 20% and 40% ASIR blending, respectively, resulted in an optimal quality of images with preservation of the image texture. CONCLUSION: Blending the 40% ASIR to the 40% reduced tube-current product can maximize radiation dose reduction and preserve adequate image quality and texture. PMID- 25510773 TI - Characteristics of inpatient care and rehabilitation for acute first-ever stroke patients. AB - PURPOSE: The purpose of this study was to analyze the status of inpatient care for acute first-ever stroke at three general hospitals in Korea to provide basic data and useful information on the development of comprehensive and systematic rehabilitation care for stroke patients. MATERIALS AND METHODS: This study conducted a retrospective complete enumeration survey of all acute first-ever stroke patients admitted to three distinct general hospitals for 2 years by reviewing medical records. Both ischemic and hemorrhagic strokes were included. Survey items included demographic data, risk factors, stroke type, state of rehabilitation treatment, discharge destination, and functional status at discharge. RESULTS: A total of 2159 patients were reviewed. The mean age was 61.5+/-14.4 years and the ratio of males to females was 1.23:1. Proportion of ischemic stroke comprised 54.9% and hemorrhagic stroke 45.1%. Early hospital mortality rate was 8.1%. Among these patients, 27.9% received rehabilitation consultation and 22.9% underwent inpatient rehabilitation treatment. The mean period from admission to rehabilitation consultation was 14.5 days. Only 12.9% of patients were transferred to a rehabilitation department and the mean period from onset to transfer was 23.4 days. Improvements in functional status were observed in the patients who had received inpatient rehabilitation treatment after acute stroke management. CONCLUSION: Our analysis revealed that a relatively small portion of patients who suffered from an acute first-ever stroke received rehabilitation consultation and inpatient rehabilitation treatment. Thus, applying standardized clinical practice guidelines for post-acute rehabilitation care is needed to provide more effective and efficient rehabilitation services to patients with stroke. PMID- 25510774 TI - Reliability and validity of the Upper Limb Physician's Rating Scale in children with cerebral palsy. AB - PURPOSE: The Upper Limb Physician's Rating Scale (ULPRS) is a tool that assesses movement quality of the upper limbs. It is used as an outcome measure after botulinum toxin type A injection in children with cerebral palsy (CP). This study aimed to investigate the reliability and validity of the ULPRS in children with spastic CP. MATERIALS AND METHODS: Thirty children with spastic CP (M:F=17:13) aged 5 to 13 years old were recruited. The ULPRS was scored based on recorded videotapes by four physicians on two separate occasions. The Melbourne Assessment of Unilateral Upper Limb Function (MUUL) was scored by an occupational therapist. Intraclass correlation coefficients (ICCs), 95% confidence intervals and weighted kappa statistics were calculated for the scores of ULPRS to obtain interrater and intrarater reliability. The relationship between ULPRS and MUUL was assessed using Pearson correlation coefficients. RESULTS: The ICCs for the total ULPRS scores were 0.94 between raters and 0.99 to 1.00 within raters. The weighted kappa statistics for subitem scores for the ULPRS ranged from 0.67 to 1.00 within raters and from 0.46 to 0.86 between raters. The relationship between ULPRS and MUUL was strong (Pearson correlation coefficient=0.751; p<0.05). CONCLUSION: The results demonstrated the high reliability of the total ULPRS score within and between raters. A significant concurrent validity between ULPRS and MUUL also supports the clinical utility of the ULPRS as an outcome measure of spastic upper limb in children with CP. PMID- 25510776 TI - Predictors of response to corticosteroid treatment in patients with early acute respiratory distress syndrome: results of a pilot study. AB - Prospective observational cohort study was performed to evaluate predictors for responsiveness to corticosteroid treatment in patients with acute respiratory distress syndrome (ARDS). Over the study period, a total of 20 patients (male 70%, median age 69) with ARDS were treated with corticosteroid within 72 h after intubation. The median lung injury score (LIS) and partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratios (PF ratios) were 3.0 (interquartile range, 2.7-3.0) and 146.6 (119.9-179.4), respectively. The median levels of triggering receptor expressed on myeloid cells (TREM-1) and procollagen peptide type III in bronchoalveolar lavage (BAL) fluid were 349.3 (225.6-634.9) pg/mL and 19.6 (11.7-39.7) pg/mL, respectively. After 7 days of corticosteroid treatment, 10 (50%) patients showed response to the treatment (successful extubation in 7 and 1-point or more reduction in LIS in 3). Compared to non responders, responders had higher initial PF ratios (170.5 vs. 127.2, p=0.023), lower level of TREM-1 in BAL fluid (313.6 pg/mL vs. 520.5 pg/mL, p=0.029), and greater reduction in LIS at 3 days (-1 vs. 0, p<0.001). In conclusion, PF ratios and TREM-1 level in BAL fluid at baseline, and reduction in LIS at day 3 after the treatment were associated with the response to prolonged corticosteroid treatment (ClinicalTrials.gov Identifier: NCT01093287). PMID- 25510775 TI - Biologic response of degenerative living human nucleus pulposus cells to treatment with cytokines. AB - PURPOSE: To investigate the molecular responses of various genes and proteins related to disc degeneration upon treatment with cytokines that affect disc-cell proliferation and phenotype in living human intervertebral discs (IVDs). Responsiveness to these cytokines according to the degree of disc degeneration was also evaluated. MATERIALS AND METHODS: The disc specimens were classified into two groups: group 1 (6 patients) showed mild degeneration of IVDs and group 2 (6 patients) exhibited severe degeneration of IVDs. Gene expression was analyzed after treatment with four cytokines: recombinant human bone morphogenic protein (rhBMP-2), transforming growth factor-beta (TGF-beta), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha). Molecular responses were assessed after exposure of cells from the IVD specimens to these cytokines via real-time polymerase chain reaction and immunofluorescence staining. RESULTS: mRNA gene expression was significantly greater for aggrecan, type I collagen, type II collagen, alkaline phosphatase, osteocalcin, and Sox9 in group 1 than mRNA gene expression in group 2, when the samples were not treated with cytokines. Analysis of mRNA levels for these molecules after morphogen treatment revealed significant increases in both groups, which were much higher in group 1 than in group 2. The average number of IVD cells that were immunofluorescence stained positive for alkaline phosphatase increased after treatment with rhBMP-2 and TGF-beta in group 1. CONCLUSION: The biologic responsiveness to treatment of rhBMP-2, TGF-beta, TNF-alpha, and IL-1beta in the degenerative living human IVD can be different according to the degree of degeneration of the IVD. PMID- 25510777 TI - Bacteroides faecis and Bacteroides intestinalis recovered from clinical specimens of human intestinal origin. AB - We report three cases of recently named Bacteroides spp. isolates, two B. faecis isolates and one B. intestinalis isolate from clinical specimens of inpatients at a Korean tertiary-care hospital in 2011. All isolates were susceptible to piperacillin-tazobactam, imipenem, meropenem, chloramphenicol, and metronidazole. PMID- 25510778 TI - Efficacy of team-based financial incentives for smoking cessation in the workplace. AB - Worksite smoking cessation programs offer accessibility of the target population, availability of occupational health support, and the potential for peer pressure and peer support. The purpose of this study was to identify the efficacy of the financial incentives given to various teams in the workplace. St. Paul's Hospital's employees were enrolled. Each team of employees consisted of smoking participants and non-smoking fellow workers from the same department. The financial incentive of 50000 won (about $45) was rewarded to the team for each successful participant-not to individual members-after the first week and then after one month. If the smokers in the team remained abstinent for a longer time period, the team was given an incentive of 100000 won for each successful participant after 3 and 6 months. A total 28 smoking participants and 6 teams were enrolled. Self-reported abstinence rates validated by urinary cotinine test at 3, 6, and 12 months after the initial cessation were 61%, 54%, and 50%, respectively. Smokers with high nicotine dependence scores or those who began participation 1 month after enrollment initiation had a lower abstinence rate at 3 months, but not at 6 and 12 months. Participants who succeeded at smoking cessation at 12 months were more likely to be older and have a longer smoking duration history. The financial incentives given to teams could be promising and effective to improve long-term rates of smoking cessation. This approach could use peer pressure and peer support in the workplace over a longer period. PMID- 25510779 TI - The first Korean case of HDR syndrome confirmed by clinical and molecular investigation. AB - Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is a rare condition inherited as autosomal dominant trait and characterized by hypoparathyroidism, sensorineural deafness, and renal dysplasia. HDR syndrome is caused by haploinsufficiency of the GATA3 gene located on chromosome 10p15. Here, we report the case of a 32-day-old Korean male with HDR syndrome. He was presented due to repeated seizures over previous 3 days. The patient was born after 40 weeks of gestation with birth weight of 2930 g, and was the first-born baby of healthy Korean parents. Hypoparathyroidism was first noticed due to seizure. A multicystic left dysplastic kidney and vesicoureteral reflux were detected by ultrasound after birth. Auditory brainstem response (ABR) testing revealed that the patient had moderate sensorineural deafness, with hearing losses of 80 dB at the mid and higher frequencies for both ears. Echocardiography finding revealed secundum atrial septal deftect. Based on biochemical results and clinical findings, a presumptive diagnosis of HDR syndrome was made. GATA3 mutation analysis identified a heterozygous deletion, c.153del (p.Phe51Leufs*144) in exon 1 causing a frameshift mutation, which is a novel de novo mutation. Therefore, we suggest that HDR syndrome should be considered in the differential diagnosis in symptomatic or asymptomatic patients with hypoparathyroidism, and that renal ultrasound or ABR testing be performed to prevent a missed diagnosis. This is the first report on Korean patient with confirmed HDR syndrome with novel mutation. PMID- 25510780 TI - A case of life-threatening acute kidney injury with toxic encephalopathy caused by Dioscorea quinqueloba. AB - Some herbal medications induce acute kidney injury. The acute kidney injuries caused by herbal medications are mild and commonly treated by palliative care. A 51-years-old man who drank the juice squeezed from the raw tubers of Dioscorea quinqueloba (D. quinqueloba) was admitted with nausea, vomiting and chilling. He developed a seizure with decreased level of consciousness. He was diagnosed with acute kidney injury, which was cured by continuous venovenous hemodialfiltration. Non-detoxified D. quinqueloba can cause severe acute kidney injury with toxic encephalopathy. It is critical to inform possible adverse effects of the medicinal herbs and to implement more strict regulation of these products. PMID- 25510781 TI - Intralesional 3% sodium tetradecyl sulfate for treatment of cutaneous Kaposi's sarcoma. PMID- 25510782 TI - Does liver resection provide long-term survival benefits for breast cancer patients with liver metastasis? A question yet to be answered. PMID- 25510784 TI - Women's Experiences With Mammography Screening Through 6 Years of Participation- A Longitudinal Qualitative Study. AB - In this article we explore women's experiences with 6 years of mammography screening. Regular and repeated mammography screening is promoted as an important tool for disease prevention among women worldwide. The purpose of the present study was to explore how continued participation in screening influences how women perceive screening and breast cancer. We carried out focus groups with 24 screening participants in 2003 and 2009. Our analysis highlights that while women were excited about the examination in 2003, it was perceived as routine in 2009. Waiting for the results became easier over the years, while stress related to receiving the results letter did not diminish. Knowledge of risk factors for breast cancer did not change. Personal risk assessment remained low, though high incidence of cancer among acquaintances suggested high risk for breast cancer among women in general. Analysis of participant experiences suggests that continuous participation in screening has led surveillance medicine to become a part of ordinary life. PMID- 25510783 TI - MicroRNA in exosomes isolated directly from the liver circulation in patients with metastatic uveal melanoma. AB - BACKGROUND: Uveal melanoma is a tumour arising from melanocytes of the eye, and 30 per cent of these patients develop liver metastases. Exosomes are small RNA containing nano-vesicles released by most cells, including malignant melanoma cells. This clinical translational study included patients undergoing isolated hepatic perfusion (IHP) for metastatic uveal melanoma, from whom exosomes were isolated directly from liver perfusates. The objective was to determine whether exosomes are present in the liver circulation, and to ascertain whether these may originate from melanoma cells. METHODS: Exosomes were isolated from the liver perfusate of twelve patients with liver metastases from uveal melanoma undergoing IHP. Exosomes were visualised by electron microscopy, and characterised by flow cytometry, Western blot and real-time PCR. Furthermore, the concentration of peripheral blood exosomes were measured and compared to healthy controls. RESULTS: The liver perfusate contained Melan-A positive and RNA containing exosomes, with similar miRNA profiles among patients, but dissimilar miRNA compared to exosomes isolated from tumor cell cultures. Patients with metastatic uveal melanoma had a higher concentration of exosomes in their peripheral venous blood compared to healthy controls. CONCLUSIONS: Melanoma exosomes are released into the liver circulation in metastatic uveal melanoma, and is associated with higher concentrations of exosomes in the systemic circulation. The exosomes isolated directly from liver circulation contain miRNA clusters that are different from exosomes from other cellular sources. PMID- 25510785 TI - [Research out of Hospital Juarez de Mexico]. PMID- 25510786 TI - [Effect of cryotherapy over the expression of vascular endothelial growth factor and pigment epithelium-derived factor]. AB - BACKGROUND: Cryotherapy is a no invasive technique that uses intense cold to freeze and destroy cancer tissues. There are no descriptions of its effects over the expression of vascular endothelial growth factor and pigment epithelium derived factor. METHODS: Experimental study in cryogenic spot were applied in the right sclera of twelve pigs for ten minutes. Other 3 pigs were used as normal controls. Animals were sacrificed at 7, 14 and 21 and the tissues of choriodes and retina were dissected in areas of approximately 1 cm2 surrounding cryogenic spots. Expression levels of vascular endothelial growth factor and pigment epithelium-derived factor were determined analyzed using polymerase chain reaction coupled to reverse-transcription. RESULTS: Vascular endothelial growth factor was significantly downregulated (24%, p< 0.05) seven days post-treatment meanwhile pigment epithelium-derived factor levels increased 44.8% (p< 0.05) as compared to normal controls (untreated). Both vascular endothelial growth factor and pigment epithelium-derived factor levels remain the same until day 14 but returned to basal expression at day 21. DISCUSSION: This work expose the relation of cryotherapy with the expression of two factors related to angiogenesis. RESULTS showed significant changes on the expression of vascular endothelial growth factor and pigment epithelium-derived factor illustrating that both proteins are regulated in response to cryogenic treatment in relatively short periods (21 days). PMID- 25510787 TI - [Anatomopathological findings during development of diabetic cardiomyopathy in rats]. AB - BACKGROUND: The diabetic cardiomyopathy occurs in both type 1 and type 2 diabetes mellitus. Hyperglycemia and associated metabolic changes participate in the pathogenesis of this disease. OBJECTIVE: To characterizes various pathological changes occurring during the development of diabetic cardiomyopathy in rats. METHODS: Diabetic rats were used for streptozotocin administration. At 7, 14, 21 and 30 days after toxic administration, the heart was obtained and placed in a Hartman solution and 4% p-formaldehyde. Five-micrometer thick sections were stained with hematoxylin-eosin, Masson trichrome and immunocytochemistry using anti-beta-tubulin antibody. RESULTS: At 14 days after application of streptozotocin, dilated sinusoids with endothelial lining in the myocardium and collagen deposits in the cardiac interstitium and between the Purkinje fibers were observed. At 21 days there was a slight decrease of the arteriolar lumen due to hyperplasia of the medial layer. It is important to note that cardiac sinusoids as well as collagen deposits became more evident at 30 day of the study, as well as a major derangement of the microtubular system of the cardiomyocytes. CONCLUSIONS: Cardiac sinusoids representing fetal vascular pattern and interstitial fibrosis in the myocardium and the microtubular derangement of cardiomyocytes support the fact that the pathophysiological mechanism of diabetic cardiomyopathy begins in the coronary microcirculation due to changes in cardiac metabolism, contributing to the development of myocardial dysfunction in diabetes. PMID- 25510788 TI - [Medullary carcinoma experience in breast oncology unit of Hospital Juarez Mexico]. AB - BACKGROUND: Medullary breast cancer is a rare type, considered of good prognosis. OBJECTIVE: To know the epidemiological and clinical characteristics of the population attended in the Hospital Juarez de Mexico, to know if they are alike to described worldwide and if the treatments proposed internationally are applicable for this hospitable center. METHODS: We performed a retrospective analysis. Reviewing the records with histopathologic diagnosis of medullary breast cancer from February 1993 to February 2011. Finding 41 patients in the oncology unit of the institution. RESULTS: We report an incidence of 3.04%, originating in 11 Mexican States, with a low to middle socioeconomic level in 39.02%. The average age at the time of diagnosis was 50 years. No family history was reported but some patients had medical history for type 2 diabetes, hypertension and previous breast cancer. 63.41% were menopausal. The average clinical size of the tumor was 58 mm. The 63% of the cases were located in the left breast. The 53.1% were clinical stages I and II, 46.3% were clinical stages III and in 9.6% of the cases primary tumor could not be assessed. Only 47% of the patients had positive axillary lynph nodes at diagnosis. The inmunohistochemestry was only reported in 14 of the 41 patients, according to the molecular classification of breast cancer: 8 were triple negative, 2 luminal A, 1 luminal B and 3 Her2neu. CONCLUSIONS: The Mexican population presents epidemiological and clinical characteristics similar to those patients described in other studies worldwide. PMID- 25510789 TI - [Frequency of cancer in a specialty hospital in Mexico City. Implications for the development of early detection methods]. AB - BACKGROUND: Cancer is the second cause of death in Mexico. The Juarez Hospital of Mexico is a highly specialized general hospital in which the frequency of cancer treated at the Oncology Unit is a representative sample of the frequency of cancer in the country. OBJECTIVE: To learn about the frequency of presentation of tumors diagnosed in a third level hospital. METHODS: We reviewed all the biopsies and surgical specimens diagnosed as cancer or malignant tumors registered in the pathology unit during the years 2006 to 2010. We grouped the cases by age, sex, and anatomic site. RESULTS: We identified the 10 most common cancers for both sexes, age groups and sex affected, raising the chances of early detection campaigns reinforce for the most common cancers and try to increase control and cure rates and improve coverage of the economically weak, for their integration into health systems. CONCLUSIONS: Information obtained reflects the reality of the country to the general population without entitlements. That in our country women suffer more than men of cancer that breast neoplasms and genital tract are the most frequent, and timely detection systems exist and should be strengthened to achieve greater eligible for early identification of cases in our population. PMID- 25510790 TI - [Serum hormones that regulate the reproductive axis in men with testicular germ cell cancer and its impact on fertility]. AB - BACKGROUND: Epidemiological studies treat testicular germ cancer as a single disease, the behavior of the two histological types of cancer; seminoma and nonseminoma have differences in reproductive hormone secretion and impair fertility differently. OBJECTIVE: To demonstrate that the serum concentration of pituitary hormones involved in fertility and spermatogenesis in the affected male is different in the two histological types. METHODS: Were determined by radioimmunoassay or inmunoradiometric assay, luteinizing hormone, follicle stimulating hormone, total testosterone, prolactin, estradiol, human chorionic gonadotropin and alpha fetoprotein in 37 patients with germ cell cancer (15 seminoma and 22 nonseminoma) and 35 controls. We analyzed the semen of patients, and were questioned about paternity before the cancer diagnosis. RESULTS: Age was higher in patients with seminoma cancer, showed decreased luteinizing hormone, follicle stimulating hormone, and testosterone and increased estradiol and prolactin in nonseminoma compared with seminoma. In patients with nonseminoma they had 9 children, 5 were oligozoospermic, 3 azoospermic and 6 normal concentration, 8 did not provide sample, seminoma group they had eight children, only one azoospermic, nine normal concentration, and 5 did not provide sample . CONCLUSIONS: The hormonal behavior is different in men with nonseminoma compared with seminoma, so that the negative impact on the reproductive axis and fertility is higher in cases of non-seminoma. PMID- 25510791 TI - [Risk factors related to surgical site infection in elective surgery]. AB - BACKGROUND: The risk factors for surgical site infections in surgery should be measured and monitored from admission to 30 days after the surgical procedure, because 30% of Surgical Site Infection is detected when the patient was discharged. AIM: Calculate the Relative Risk of associated factors to surgical site infections in adult with elective surgery. METHODS: Patients were classified according to the surgery contamination degree; patient with surgery clean was defined as no exposed and patient with clean-contaminated or contaminated surgery was defined exposed. Risk factors for infection were classified as: inherent to the patient, pre-operative, intra-operative and post-operative. Statistical analysis; we realized Student t or Mann-Whitney U, chi square for Relative Risk (RR) and multivariate analysis by Cox proportional hazards. RESULTS: Were monitored up to 30 days after surgery 403 patients (59.8% women), 35 (8.7%) developed surgical site infections. The factors associated in multivariate analysis were: smoking, RR of 3.21, underweight 3.4 hand washing unsuitable techniques 4.61, transfusion during the procedure 3.22, contaminated surgery 60, and intensive care stay 8 to 14 days 11.64, permanence of 1 to 3 days 2.4 and use of catheter 1 to 3 days 2.27. CONCLUSION: To avoid all risk factors is almost impossible; therefore close monitoring of elective surgery patients can prevent infectious complications. PMID- 25510792 TI - [Bilateral spontaneously reattached rhegmatogenous retinal detachment. Case report and differential diagnosis with pigmentary retinopathies]. AB - BACKGROUND: A dark pigmentation of the ocular fundus presents in degenerative diseases such as retinitis pigmentosa; this disease must be distinguished from others whose evolution is not progressive, in order to estimate the functional prognosis of the patient. OBJECTIVE: To analyze the features which distinguish spontaneously reattached retinal detachment from other causes of ocular fundus pigmentation, in order to be able to identify it even in bilateral cases. CLINICAL CASE: A case of a female with chronic visual loss is presented, who was referred for evaluation with the diagnosis of a pigmented retinopathy. Clinical exploration discarded causes as retinitis pigmentosa, retinal inflammatory diseases or trauma. Based on the clinical features, on the topography of pigmentation and in the information provided by electroretinography, a bilateral spontaneous reattachment of rhegmatogenous retinal detachment was diagnosed made. Clinical features of this entity are discussed, as well as the diagnostic approach to distinguish it from other pigment retinopathies. CONCLUSION: Clinical features of spontaneously reattached retinal detachment allow the explorer to distinguish it from other causes of bilateral pigmentation, despite presenting bilaterally. Since the prognosis of the attached retina is better than that of a degenerative disease, the correct diagnosis makes rehabilitation easier. PMID- 25510794 TI - [Infraorbital schwannoma. Case report]. AB - BACKGROUND: Infraorbital schwannoma is a benign tumor of the peripheral nerve seath composed of Schwann cells. Usually occurs between 20 and 70 years of age, are usually asymptomatic and can cause progressive, painless proptosis during growth. CLINICAL CASE: A 32-year-old male admitted to ophthalmologic hospital with a painless, slowly progressive mass above the left lacrimal sac. At the ophthalmologic examination the tumor had a rubbery consistency and was firmly attached to the surrounding structures. The transillumination was negative. The B mode ultrasound disclosed a phakic eye as well as an infraorbital well circumscribed homogeneous mass with a largest diameter of 19.7 mm, without involvement of the lacrimal pathway. The A mode ultrasound showed medium-high reflectivity with small internal vascularity. The computed tomography showed a homogeneous wellcircumscribed solid mass anterior and inferior to the left globe without bony erosion. Through subdermic incision the mass was excised. The histopathological diagnosis was "Infraorbital schwannoma". CONCLUSIONS: The schwannoma is a rare benign tumor in the orbit, few cases have been reported. The definitive diagnosis is made by histopathologic findings as the presence of a true capsule, hyper-and hypocellular areas, thickening and hyalinization of the vessel walls. When these findings are not be confused with benign fusocellular tumors. We report a new case of infraorbital schwannoma and compared it with those cases previously reported. PMID- 25510793 TI - [Mesectodermal leiomyoma. Unusual tumor of the ciliary body]. AB - BACKGROUND: Mesectodermal leiomyoma is a benign tumor of smooth muscle of the ciliary body, which is derived from the neural crest. CLINICAL CASE: We report the case of a 35-year-old Mexican woman with visually impaired and blurred vision of the right eye of 2 months duration. The clinical and imaging presuntional diagnosis was adenoma of the non pigmented epithelium of the ciliary body and it was surgically resected. Microscopically, the tumor was composed of cells with round nuclei and scant cytoplasm without atypia or mitosis, arranged in a fibrillary background. The immunohistochemical markers for vimentin, muscle specific actin, smooth muscle actin and calponin were strongly positive in the cytoplasm of the neoplastic cells, while for glial fibrillary acidic protein and S-100 protein were negative in the same cellular population. CONCLUSIONS: Mesectodermal leiomyoma of the ciliary body is benign tumor of smooth muscle extremely rare in this location. Until now, there are just 25 previous reported cases in the literature and, the main differential diagnosis is uveal malignant melanoma, therefore some eyes were enucleated. The ultrabiomicroscopy, A and B scan imaging studies are useful in the evaluation, however, is mandatory the microsocpic examination with routine and histochemical stains as well as the use of immunohistochemical markers such as vimentin, specific muscle actin, smooth muscle actin andcalponin to stablish the smooth muscle origin of this neoplasm, and rule out other malignant neoplams such as malignant melanoma. PMID- 25510795 TI - [Giant cystic lymphangioma breast. Report of a case with 20-year follow-up and review of the literature]. AB - BACKGROUND: Lymphangiomas are congenital malformations or acquired (secondary to trauma, infection or neoplasia) in the mammary gland, are extremely rare. These lesions tend to infiltrate surrounding tissues and malignant degeneration is extremely rare. Clinically manifests as benign masses, slow growing; diagnosed clinically and by imaging studies. Suegery with removal of the mass is performed for aesthetic reasons and to make differential diagnosis with other common injuries. CLINICAL CASE: Women 45 years of age with progressive increase in size of the left breast, breast trauma concerns and has no other symptoms.The histologic diagnosis was cystic lymphangioma giant left mammary gland. DISCUSSION: Lymphangiomas are uncommon lesions and extremely rare in the mammary gland, locally aggresive behavior and are benign, where abnormal lymphatic tissue has some ability to proliferate and accumulate large amounts of liquid, representing cystic appearance, as presented in our case. Local surgical excision is the treatment. CONCLUSION: In this first case of giant breast cystic lymphangioma reported in Mexico, which corroborates the benignity of the lesion. PMID- 25510796 TI - [Moderately differentiated squamous cell carcinoma associated pilonidal cyst]. AB - BACKGROUND: Malignant degeneration of pilonidal sinus is a rare complication observed mainly in recurrent chronic cases of the disease, associated to a very bad prognosis. In the world's literature we find it like an infrequent entity. In Spain had reviewed 367 patients with simple and complicated pilonidal cysts. We found three cases (0.81%) of epidermoid carcinoma. CLINICAL CASE: Men's 60 years of age, with clinical picture of 50 years of evolution with the presence of sacral tumor, is resection and histopathological reporting of pilonidal cyst; taking evolution at healing, with necrotic edges; resection of these will decide and report is squamous cell carcinoma. CONCLUSIONS: Pilonidal sinus epidermoid carcinoma is an infrequent disease predicting for very poor outcome. PMID- 25510797 TI - [Primary posterior perineal hernia. Case report and review of the literature]. AB - BACKGROUND: Perineal hernias may occur after the completion of surgery in this region, or may occur as a primary lesion. Among the less frequent are the perineal hernias. CLINICAL CASE: Female patient, 42 years old, with perineal tumor mass on the right of the anus, spontaneously occurring, five years of evolution, with dimensions of 6 * 10 cm, soft and reducible behind transverse perineal muscle. With dignosis of primary posterior perineal hernia, surgery was performed by the perineum with Mersilene mesh placement. There was no recurrence after 18 months follow-up. CONCLUSION: The perineal plasty can be a good alternative for the surgical treatment of primary perineal hernias, as it allows for a better seal, dissect the hernia sac and reduce it properly. PMID- 25510798 TI - [Molecular markers: an important tool in the diagnosis, treatment and epidemiology of invasive aspergillosis]. AB - Increase in the incidence of invasive aspergillosis has represented a difficult problem for management of patients with this infection due to its high rate of mortality, limited knowledge concerning its diagnosis, and therapeutic practice. The difficulty in management of patients with aspergillosis initiates with detection of the fungus in the specimens of immunosuppressed patients infected with Aspergillus fumigatus; in addition, difficulty exists in terms of the development of resistance to antifungals as a consequence of their indiscriminate use in prophylactic and therapeutic practice and to ignorance concerning the epidemiological data of aspergillosis. With the aim of resolving these problems, molecular markers is employed at present with specific and accurate results. However, in Mexico, the use of molecular markers has not yet been implemented in the routine of intrahospital laboratories; despite the fact that these molecular markers has been widely referred in the literature, it is necessary for it to validated and standardized to ensure that the results obtained in any laboratory would be reliable and comparable. In the present review, we present an update on the usefulness of molecular markers in accurate identification of A. fumigatus, detection of resistance to antifugal triazoles, and epidemiological studies for establishing the necessary measures for prevention and control of aspergillosis. PMID- 25510799 TI - [Micronutrients and diabetes, the case of minerals]. AB - Minerals are essential nutrients for the body, are of inorganic nature which gives them the characteristic of being resistant to heat, are involved in a lot of chemical reactions in metabolism, regulating electrolyte balance, in maintaining bone, in the process of blood clotting and the transmission of nerve impulses, particularly its role as enzyme cofactors confers a key role in various physiological processes. Glucose homeostasis involves a fine coordination of events where hormonal control by insulin plays a key role. However, the role of minerals like magnesium, zinc, chromium, iron and selenium in the diabetes is less obvious and in some cases may be controversial. This review shows the knowledge of these five elements and their correlation with diabetes. PMID- 25510800 TI - Strategic Development for Middle School Students Struggling With Fractions: Assessment and Intervention. AB - Research has suggested that different strategies used when solving fraction problems are highly correlated with students' problem-solving accuracy. This study (a) utilized latent profile modeling to classify students into three different strategic developmental levels in solving fraction comparison problems and (b) accordingly provided differentiated strategic training for students starting from two different strategic developmental levels. In Study 1 we assessed 49 middle school students' performance on fraction comparison problems and categorized students into three clusters of strategic developmental clusters: a cross-multiplication cluster with the highest accuracy, a representation strategy cluster with medium accuracy, and a whole-number strategy cluster with the lowest accuracy. Based on the strategic developmental levels identified in Study 1, in Study 2 we selected three students from the whole-number strategy cluster and another three students from the representation strategy cluster and implemented a differentiated strategic training intervention within a multiple baseline design. Results showed that both groups of students transitioned from less advanced to more advanced strategies and improved their problem-solving accuracy during the posttest, the maintenance test, and the generalization test. PMID- 25510801 TI - Grade II gliomas-not so low grade. PMID- 25510802 TI - What we can learn from our patients. PMID- 25510803 TI - Chemotherapy for treatment of grade II gliomas. AB - Gliomas classified as grade II by the World Health Organization (WHO) include astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. This heterogeneous group of conditions is associated with a more favorable prognosis and longer-term survival than high-grade gliomas (HGGs). Neurosurgical resection and radiation therapy improve survival in symptomatic, progressive, or high-risk grade II gliomas. Until recently, the role of chemotherapy has been less clear. This review draws on insights from the management of HGGs and emerging data on the addition of PCV (procarbazine, lomustine [CCNU], and vincristine) to radiation for these neoplasms. Specifically, this review focuses on the current status of chemotherapeutic management of grade II gliomas, including optimal timing of treatment, and management of 1p19q codeleted and non-codeleted tumors. PMID- 25510804 TI - Chemotherapy for low-grade gliomas: lessons and questions. PMID- 25510805 TI - Tailoring chemotherapy for low-grade gliomas. PMID- 25510806 TI - Improving outcomes in advanced DLBCL: systemic approaches and radiotherapy. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Approximately half of patients will present with advanced (stage III/IV) disease. The cornerstone of treatment is a combination of chemotherapy and immunotherapy, most commonly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Efforts to improve upon R-CHOP-including more chemotherapy cycles, dose-dense chemotherapy, alternative drug combinations, high-dose chemotherapy with autologous stem cell transplant, and maintenance rituximab-have generally proved unsuccessful. There is a growing body of retrospective and prospective data, however, suggesting a benefit for consolidation radiation therapy (RT) in select patients with advanced DLBCL. Consolidation RT has been shown to improve outcomes for patients with advanced DLBCL generally, and in specific instances including initially bulky disease, bone involvement, or in the setting of a partial response to systemic therapy. In these settings consolidation RT is highly efficacious at achieving local disease control and improving overall outcomes. PMID- 25510807 TI - Advanced DLBCL: as systemic therapy improves, the need for RT diminishes. PMID- 25510808 TI - Who should-or should not-receive RT for DLBCL? PMID- 25510809 TI - Cancer stem cells: implications for cancer therapy. AB - The survival of patients with cancer has improved significantly, primarily because of multidisciplinary care, improved chemotherapeutic agents in both the adjuvant and metastatic settings, the introduction of targeted biologic agents, and the incorporation of palliative care services into the management scheme. However, despite these advances, a significant proportion of patients continue to experience recurrence after adjuvant treatment, and survival associated with stage IV solid tumors still remains low. A primary or acquired resistance to chemotherapeutic and biologic agents is responsible for the failure of many of the agents used to treat patients with a malignancy. This can be explained by the presence of intratumoral heterogeneity and the molecular complexity of many cancers. Factors contributing to intratumoral heterogeneity include genetic mutations, interactions with the microenvironment-and the presence of cancer stem cells. Cancer stem cells have been identified in a number of solid tumors, including breast cancer, brain tumors, lung cancer, colon cancer, and melanoma. Cancer stem cells have the capacity to self-renew, to give rise to progeny that are different from them, and to utilize common signaling pathways. Cancer stem cells may be the source of all the tumor cells present in a malignant tumor, the reason for the resistance to the chemotherapeutic agent used to treat the malignant tumor, and the source of cells that give rise to distant metastases. This review will focus on properties of cancer stem cells; will compare and contrast the cancer stem cell model with the clonal evolution model of tumorigenesis; will discuss the role of cancer stem cells in the development of resistance to chemotherapy; and will review the therapeutic implications and challenges of targeting cancer stem cells, with an assessment of the potential such an approach holds for improving outcomes for patients with cancer. PMID- 25510810 TI - Cancer stem cells. PMID- 25510811 TI - Base of the skull metastases in metastatic castration-resistant prostate cancer. PMID- 25510812 TI - ACR appropriateness Criteria(r) Postradical prostatectomy irradiation in prostate cancer. AB - The purpose of this article is to present an updated set of American College of Radiology consensus guidelines formed from an expert panel on the appropriate use of radiation therapy in postprostatectomy prostate cancer. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Recent and relevant literature reviewed by the panel led to establishment of criteria for appropriate use of radiation therapy in postprostatectomy prostate cancer. The discussion includes treatment technique, appropriate dose, field design, and the role of prostate-specific antigen (PSA). Ratings and commentary of the panel on multiple treatment parameters were used to reach consensus. Patients with high-risk pathologic features benefit from postprostatectomy radiation therapy. PMID- 25510813 TI - Complicated Henoch-Schonlein purpura. AB - We present a case of Henoch Schonlein pupura in a 6-year-old boy demonstrating some of the diagnostic pitfalls, complications and management challenges of this common paediatric condition. PMID- 25510814 TI - Endoscopic ultrasound, GIST, and ovarian cancer. PMID- 25510815 TI - Colonic tuberculosis masquerading as colorectal malignancy. PMID- 25510817 TI - Carbohydrates in the treatment and prevention of Type 2 diabetes. PMID- 25510816 TI - Laparoscopic versus open appendectomy for complicated appendicitis in high risk patients. AB - INTRODUCTION: Laparoscopic appendectomy is widely used for the treatment of complicated appendicitis. Its use in patients with high operative risk is still on debate. The aim of the presented study was to investigate the benefits of laparoscopic appendectomy in patients with high peri- and postoperative risk factors. METHODS: We performed a retrospective analysis of all patients who underwent appendectomy in our center between 2006 and 2013. Patients were classified according to their preoperative risk (classification of the American Society of Anesthesia--ASA score). Only patients with ASA 3 and 4 were included and were divided into two groups--open appendectomy (OA group) and laparoscopic appendectomy (LA group). RESULTS: The operation time was slightly longer in the LA group (p = 0.05), but hospital stay was shorter (p = 0.05). Complications graded according to the Clavien Dindo classification were slightly more frequent in patients after LA, whereas severe complications occurred more frequently in patients after OA (p = 0.01). The postoperative WBC decreased steadily and significantly in patients after OA, whereas the decrease in patients after LA was delayed (p = 0.03). CRP slightly increased after OA and decreased thereafter, whereas it steadily decreased after LA (p = 0.05). CONCLUSION: Laparoscopic appendectomy can be recommended for patients with complicated appendicitis even with higher risk categories. PMID- 25510819 TI - Amniotic components in the uterine vasculature and their role in amniotic fluid embolism. AB - AIM: To evaluate whether the presence of amniotic components in the maternal uterine vasculature could be a specific pathological indicator for amniotic fluid embolism (AFE). METHODS: Medical records of patients treated between January 2006 and March 2013 were retrospectively examined to identify patients who underwent post-partum hysterectomy or autopsy due to maternal death. Three subjects with AFE with disseminated intravascular coagulation (DIC)-type post-partum hemorrhage (PPH), and 13 non-AFE subjects were included in analysis. Histochemical staining using hematoxylin-eosin (HE) and alcian blue, and immunohistochemical staining for sialyl-Tn were conducted to detect amniotic components in the maternal uterine vasculature. RESULTS: Alcian blue was positive for amniotic components in the uterine vasculature of all subjects with AFE and of several subjects without AFE. Similarly, HE and sialyl-Tn were negative in some AFE subjects and positive in some non-AFE subjects. CONCLUSIONS: The presence of maternal intravascular fetal material is not a specific indicator for AFE with DIC-type PPH. Therefore, the presence of fetal components in the uterine vasculature is unlikely to be a definitive indicator for AFE. PMID- 25510818 TI - Biomarkers of Parkinson's disease: present and future. AB - Sporadic or idiopathic Parkinson's disease (PD) is an age-related neurodegenerative disorder of unknown origin that ranks only second behind Alzheimer's disease (AD) in prevalence and its consequent social and economic burden. PD neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta; however, more widespread involvement of other CNS structures and peripheral tissues now is widely documented. The onset of molecular and cellular neuropathology of PD likely occurs decades before the onset of the motor symptoms characteristic of PD. The hallmark symptoms of PD, resting tremors, rigidity and postural disabilities, are related to dopamine (DA) deficiency. Current therapies treat these symptoms by replacing or boosting existing DA. All current interventions have limited therapeutic benefit for disease progression because damage likely has progressed over an estimated period of ~5 to 15years to a loss of 60%-80% of the nigral DA neurons, before symptoms emerge. There is no accepted definitive biomarker of PD. An urgent need exists to develop early diagnostic biomarkers for two reasons: (1) to intervene at the onset of disease and (2) to monitor the progress of therapeutic interventions that may slow or stop the course of the disease. In the context of disease development, one of the promises of personalized medicine is the ability to predict, on an individual basis, factors contributing to the susceptibility for the development of a given disease. Recent advances in our understanding of genetic factors underlying or contributing to PD offer the potential for monitoring susceptibility biomarkers that can be used to identify at-risk individuals and possibly prevent the onset of disease through treatment. Finally, the exposome concept is new in the biomarker discovery arena and it is suggested as a way to move forward in identifying biomarkers of neurological diseases. It is a two-stage scheme involving a first stage of exposome-wide association studies (EWAS) to profile omic features in serum to discover molecular biomarkers. The second stage involves application of this knowledge base in follow-up studies. This strategy is unique in that it promotes the use of data-driven (omic) strategies in interrogating diseased and healthy populations and encourages a movement away from using only reductionist strategies to discover biomarkers of exposure and disease. In this short review we will examine 1) advances in our understanding of the molecular mechanisms underlying PD that have led to candidate biomarkers for diagnosis and treatment efficacy and 2) new technologies on the horizon that will lead to novel approaches in biomarker development. PMID- 25510820 TI - Educational interventions for general practitioners to identify and manage depression as a suicide risk factor in young people: a systematic review and meta analysis protocol. AB - BACKGROUND: Suicide is a major public health problem and globally is the second leading cause of death in young adults. Globally, there are 164,000 suicides per year in young people under 25 years. Depression is a strong risk factor for suicide. Evidence shows that 45% of those completing suicide, including young adults, contact their general practitioner rather than a mental health professional in the month before their death. Further evidence indicates that risk factors or early warning signs of suicide in young people go undetected and untreated by general practitioners. Healthcare-based suicide prevention interventions targeted at general practitioners are designed to increase identification of at-risk young people. The rationale of this type of intervention is that early identification and improved clinical management of at risk individuals will reduce morbidity and mortality. This systematic review will synthesise evidence on the effectiveness of education interventions for general practitioners in identifying and managing depression as a suicide risk factor in young people. METHODS/DESIGN: We shall conduct a systematic review and meta analysis following the Cochrane Handbook for Systematic Reviews of Interventions guidelines and conform to the reporting guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. Electronic databases will be systematically searched for randomised controlled trials and quasi-experimental studies investigating the effectiveness of interventions for general practitioners in identifying and managing depression as a suicide risk factor in young people in comparison to any other intervention, no intervention, usual care or waiting list. Grey literature will be searched by screening trial registers. Only studies published in English will be included. No date restrictions will be applied. Two authors will independently screen titles and abstracts of potential studies. The primary outcome is identification and management of depression. Secondary outcomes are suicidal ideation, suicide attempts, deliberate self-harm, knowledge of suicide risk factors and suicide-related behaviours, attitudes towards suicide risk and suicide-related behaviours, confidence in dealing with suicide risk factors and suicide-related behaviour. DISCUSSION: Our study will inform the development of future education interventions and provide feasibility and acceptability evidence, to help general practitioners identify and manage suicidal behaviour in young people. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42014009110. PMID- 25510821 TI - Dexamethasone intravitreous implant versus bevacizumab for central retinal vein occlusion-related macular oedema: a prospective randomized comparison--response. PMID- 25510822 TI - Clinical associations of incidentally detected parotid gland calcification on CT. AB - OBJECTIVES/HYPOTHESIS: Parotid gland calcifications can be incidental findings on computed tomography (CT) and have been reported to be associated with chronic inflammatory conditions. Associations between parotid gland calcification and other common medical conditions have not been reported. METHODS: Following institutional review board approval, 1,571 patients who underwent noncontrast head CT with 1.25-mm slice thickness on a 64-detector row CT between January 2011 and July 2011 were retrospectively reviewed for parotid gland calcifications. Medical records were reviewed for chronic kidney disease, alcoholism, autoimmune conditions, endocrine disorders, elevated alkaline phosphatase, and HIV (human immunodeficiency virus) status. Statistical analyses were performed using Fisher's exact test and multiple logistic regression. RESULTS: Sixty-three of 1,571 (4%) patients had parotid gland calcifications. Significant associations were observed between parotid gland calcifications and HIV infection (P = 0.002), chronic kidney disease (P < 0.0001), alcoholism (P < 0.0001), elevated alkaline phosphatase (P = 0.003), and autoimmune disease (P = 0.02). CONCLUSION: Parotid gland calcifications were associated with HIV, alcoholism, chronic kidney disease, autoimmune disease, and elevated alkaline phosphatase. LEVEL OF EVIDENCE: 4. PMID- 25510823 TI - Early, but not late chronotypes, are up during their biological night when working the night shift. PMID- 25510824 TI - Author response: early, but not late chronotypes, are up during their biological night when working the night shift. PMID- 25510825 TI - Microvascular anastomosis using modified micro-stents: a pilot in vivo study. AB - INTRODUCTION: Microvascular sutured anastomosis remains the gold standard in microvascular flap surgery but is technically challenging, time-consuming, and sometimes unreliable. The goal of our study has been to develop a microvascular stenting system that can be used for microvascular anastomosis, even without the use of a microscope. MATERIALS AND METHODS: Custom-made stainless-steel stents were used to re-establish vessel continuity after the severance of the abdominal aortic vessel in nine rats. At 30 min after re-opening the blood flow, Doppler flowmetry and indocyanine green (ICG) angiography were used to assess vessel patency, and vessels were inspected microscopically for signs of thrombosis. RESULTS: Eight of the nine animals survived the procedure. In one case, the abdominal aorta was torn during balloon dilation of the stent. Four out of the nine stent anastomoses showed an excellent fit. In the remaining four cases, a collagen membrane and fibrin glue were successfully used to stop vascular leakage. However, these additional steps might have had a negative impact on vessel patency, and thrombus formation impaired blood flow completely in one case. CONCLUSION: Microvascular stent anastomosis is feasible and might in some cases be superior to standard sutured anastomosis. However, a number of technical difficulties remain to be addressed, and long-term results are not yet available. PMID- 25510826 TI - Interoperator and intraoperator (in)accuracy of stent selection based on visual estimation. AB - OBJECTIVES: The objectives of this study were to evaluate the ability of interventional cardiologists to accurately measure lesion length and select appropriate stents. BACKGROUND: Inaccurate measurement of lesion length during percutaneous coronary intervention (PCI) increases the risk of restenosis. METHODS: Interventional cardiologists (n = 40) evaluated 25 matched orthogonal angiographic images that were prescored using quantitative coronary angiography (QCA) by a core laboratory. Visual estimates of lesion length and stent length selection were compared to the maximum QCA value. A 2-4 mm stent overlap of both the proximal and distal lesion edges was considered to be optimal. Based on optimal stent overlap, accurate lesion lengths were those measured from -1 to +4 mm from the QCA. Likewise, appropriate stent lengths were those that measured between +4 mm to +8 mm from the QCA value. Five images were repeated to assess intrarater variability. RESULTS: Lesion length measurements were short and long for 51.1% (95% CI 47.6-54.6%) and 19.0% (95% CI 16.3-21.9%) of the images, respectively. Stent length selections that were short and long were recorded for 55.0% (95% CI 51.5-58.5%) and 22.8% (95% CI 19.9-25.8%) of the images, respectively. Intrarater variability evaluation indicated that 38.5% (95% CI 31.7 45.6%) of lesion length measurements and 37.5% (95% CI 30.8-44.6%) of stent length selections were >3 mm different between the first and second evaluation of repeated images. CONCLUSIONS: Visual estimation of coronary lesion length has a high degree of variability, which may lead to inappropriate stent selection. Improving the accuracy of lesion length measurement may improve patient outcomes. PMID- 25510827 TI - Serum leptin measured in early pregnancy is higher in women with preeclampsia compared with normotensive pregnant women. AB - Leptin, an adipocyte-derived hormone, plays an important role in reproduction and angiogenesis. Studies examining leptin in preeclampsia are inconsistent, possibly because of small sample sizes and variability in sampling and outcome. We conducted a nested case-control study to examine associations between serum leptin (measured: 9-26 weeks gestation) and preeclampsia among 430 primiparous preeclamptic women and 316 primiparous normotensive controls from the Danish National Birth Cohort. Median (interquartile range) leptin concentrations were calculated. Associations between leptin and preeclampsia (blood pressure >=140/90 mm Hg), term preeclampsia (preeclampsia and delivery >=37 weeks gestation), or preterm preeclampsia (preeclampsia and delivery <37 weeks gestation) were examined using generalized linear models adjusting for body mass index, gestational age at blood draw, maternal age, smoking, and socio-occupational status. As leptin is increased in obese women and the risk of preeclampsia increases with body mass index, we used the Sobel test to examine whether leptin is a mediator of this relationship. After adjustments, leptin concentrations were significantly higher in women with preeclampsia (30.5 [24.6]; P=0.0117) and term preeclampsia (30.4 [24.9]; P=0.0228) compared with controls (20.9 [28.3]). There was no significant difference between preterm preeclampsia (30.6 [23.4]; P=0.2210) and controls. Leptin is a possible mediator of the association between body mass index and preeclampsia (P=0.0276). Leptin concentrations are higher in women with preeclampsia compared with normotensive controls and may mediate some of the relationship between body mass index and preeclampsia. PMID- 25510828 TI - Novel role for endogenous hepatocyte growth factor in the pathogenesis of intracranial aneurysms. AB - Inflammation plays a key role in formation and rupture of intracranial aneurysms. Because hepatocyte growth factor (HGF) protects against vascular inflammation, we sought to assess the role of endogenous HGF in the pathogenesis of intracranial aneurysms. Circulating HGF concentrations in blood samples drawn from the lumen of human intracranial aneurysms or femoral arteries were compared in 16 patients. Tissue from superficial temporal arteries and ruptured or unruptured intracranial aneurysms collected from patients undergoing clipping (n=10) were immunostained with antibodies to HGF and its receptor c-Met. Intracranial aneurysms were induced in mice treated with PF-04217903 (a c-Met antagonist) or vehicle. Expression of inflammatory molecules was also measured in cultured human endothelial, smooth muscle cells and monocytes treated with lipopolysaccharides in presence or absence of HGF and PF-04217903. We found that HGF concentrations were significantly higher in blood collected from human intracranial aneurysms (1076+/-656 pg/mL) than in femoral arteries (196+/-436 pg/mL; P<0.001). HGF and c Met were detected by immunostaining in superficial temporal arteries and in both ruptured and unruptured human intracranial aneurysms. A c-Met antagonist did not alter the formation of intracranial aneurysms (P>0.05), but significantly increased the prevalence of subarachnoid hemorrhage and decreased survival in mice (P<0.05). HGF attenuated expression of vascular cell adhesion molecule-1 (P<0.05) and E-Selectin (P<0.05) in human aortic endothelial cells. In conclusion, plasma HGF concentrations are elevated in intracranial aneurysms. HGF and c-Met are expressed in superficial temporal arteries and in intracranial aneurysms. HGF signaling through c-Met may decrease inflammation in endothelial cells and protect against intracranial aneurysm rupture. PMID- 25510830 TI - Indexes of aortic pressure augmentation markedly underestimate the contribution of reflected waves toward variations in aortic pressure and left ventricular mass. AB - Although indexes of wave reflection enhance risk prediction, the extent to which measures of aortic systolic pressure augmentation (augmented pressures [Pa] or augmentation index) underestimate the effects of reflected waves on cardiovascular risk is uncertain. In participants from a community sample (age >16), we compared the relative contribution of reflected (backward wave pressures and the reflected wave index [RI]) versus augmented (Pa and augmentation index) pressure wave indexes to variations in central aortic pulse pressure (PPc; n=1185), and left ventricular mass index (LVMI; n=793). Aortic hemodynamics and LVMI were determined using radial applanation tonometry (SphygmoCor) and echocardiography. Independent of confounders, RI and backward wave pressures contributed more than forward wave pressures, whereas Pa and augmentation index contributed less than incident wave pressure to variations in PPc (P<0.0001 for comparison of partial r values). In those <50 years of age, while backward wave pressures (partial r=0.28, P<0.0001) contributed more than forward wave pressures (partial r=0.15, P<0.001; P<0.05 for comparison of r values), Pa (partial r=0.13, P<0.005) contributed to a similar extent as incident wave pressure (partial r=0.22, P<0.0001) to variations in LVMI. Furthermore, in those >=50 years of age, backward wave pressures (partial r=0.21, P<0.0001), but not forward wave pressures (P=0.98), while incident wave pressure (partial r=0.23, P<0.0001), but not Pa (P=0.80) were associated with LVMI. Pa and augmentation index underestimated the effect of wave reflection on PPc and LVMI in both men and women. Thus, as compared with relations between indexes of aortic pressure augmentation and PPc or LVMI, strikingly better relations are noted between aortic wave reflection and PPc or LVMI. PMID- 25510829 TI - Oscillatory cerebral blood flow is associated with impaired neurocognition and functional hyperemia in postural tachycardia syndrome during graded tilt. AB - We hypothesize that upright cognitive impairment in patients with postural tachycardia syndrome (POTS) is caused by reduced cerebral blood flow (CBF). The CBF velocity (CBF(v)) measured by transcranial Doppler ultrasound decreased excessively during 70 degrees tilt in a minority of patients with intermittent hyperpnea/hypocapnia. Incremental tilt showed no difference in mean CBF(v). But N back memory tasking indicated progressive compromised memory, reduced functional hyperemia, and reduced neurovascular coupling. Orthostasis caused slow oscillations in CBF(v) linked to oscillations in arterial pressure in patients with POTS. We also hypothesize that oscillatory CBF(v) degrades neurovascular coupling. We performed 2-back testing when subjects were in supine position and during incremental tilts to 15 degrees , 30 degrees , 45 degrees , and 60 degrees in 11 patients with POTS and 9 controls. Oscillatory arterial pressure, oscillatory CBF(v), and neurovascular coupling were similar in supine position. The oscillatory arterial pressure increased by 31%, 45%, 67%, and 93% in patients with POTS during tilt and remained unchanged in the controls. Oscillatory CBF(v) increased by 61%, 82%, 161%, and 264% in patients with POTS during tilt and remained unchanged in the controls. Functional hyperemia decreased from 4.1% to 3.0%, 1.1%, 0.2%, and to 0.04% in patients with POTS, but it was unchanged at 4% in the controls. Percent correct N-back responses decreased from 78% to 33% in patients with POTS, whereas they remained at 89% in the controls. In patients with POTS, oscillatory CBF(v) was linearly correlated with functional hyperemia (r(2)=0.76). Increased oscillatory CBF is associated with reduced neurovascular coupling and diminished cognitive performance in patients with POTS. PMID- 25510831 TI - Estimation of the chemical-induced eye injury using a Weight-of-Evidence (WoE) battery of 21 artificial neural network (ANN) c-QSAR models (QSAR-21): part II: corrosion potential. AB - This is part II of an in silico investigation of chemical-induced eye injury that was conducted at FDA's CFSAN. Serious eye damage caused by chemical (eye corrosion) is assessed using the rabbit Draize test, and this endpoint is an essential part of hazard identification and labeling of industrial and consumer products to ensure occupational and consumer safety. There is an urgent need to develop an alternative to the Draize test because EU's 7th amendment to the Cosmetic Directive (EC, 2003; 76/768/EEC) and recast Regulation now bans animal testing on all cosmetic product ingredients and EU's REACH Program limits animal testing for chemicals in commerce. Although in silico methods have been reported for eye irritation (reversible damage), QSARs specific for eye corrosion (irreversible damage) have not been published. This report describes the development of 21 ANN c-QSAR models (QSAR-21) for assessing eye corrosion potential of chemicals using a large and diverse CFSAN data set of 504 chemicals, ADMET Predictor's three sensitivity analyses and ANNE classification functionalities with 20% test set selection from seven different methods. QSAR-21 models were internally and externally validated and exhibited high predictive performance: average statistics for the training, verification, and external test sets of these models were 96/96/94% sensitivity and 91/91/90% specificity. PMID- 25510832 TI - Derivation of exposure factors for infant lactational exposure to persistent organic pollutants (POPs). AB - Quantifying the influence of breastfeeding on infant's dose and biological levels is critical for the risk assessment of persistent organic pollutant (POP) early exposures. We aimed to quantify infants' exposure relative to the mother for POPs. Using a validated pharmacokinetic model, Monte-Carlo simulations of infants' exposure during the first 2 years of life for POPs of different half lives (i.e., 1-20 years) were performed. Infant:mother (I:M) ratios for dose and biological levels throughout infancy were derived. To evaluate model accuracy, simulated I:M biological level ratios were compared to ratios calculated from Inuit mothers' and infants' measured plasma levels of 2,2',4,4',5,5' hexachlorobiphenyl (PCB-153), p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB). Practically all measured I:M biological level ratios from the Inuit cohort fell below the 95th percentile of the distributions of simulated PCB-153, p,p'-DDE and HCB levels. Peak I:M dose ratios were observed at the beginning of lactation with 95th percentile values of 13, 53, 84, 102 and 113 for half-lives of 1, 5, 10, 15 and 20 years, respectively. In contrast, peak I:M biological level ratios occurred after approximately 1 year of breastfeeding and plateaued at approximately 10.5 (95th percentile) for chemicals of half-lives >5 years. Simulated I:M dose and biological level ratios could be employed in risk assessment of early POP exposures through breastfeeding. PMID- 25510833 TI - Pharmacology and clinical efficacy of dalfampridine for treating multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is the most frequent cause of neurological impairment and sustained disability in young adults. Currently approved disease modifying drugs do not directly ameliorate the most common symptoms, such as walking impairment. Dalfampridine (DAL), currently approved in all forms of MS, might represent an answer to unmet needs in the symptomatic treatment of MS. AREAS COVERED: The main pharmacological and clinical properties and safety issues of DAL, an extended-release formulation of 4-aminopyridine (4-AP), a broad spectrum voltage-dependent potassium channel blocker, are described. Relevant publications were identified from a search of PubMed from 1966 to June 2014 (search terms 'dalfampridine OR fampridine OR 4-aminopyridine). DAL, 10 mg twice daily, improves walking ability in approximately one-third and walking speed in about 25% of patients, independently from disease course, compared with placebo; it also improves leg strength. Treatment is generally well tolerated, although there is a dose-dependent increased risk of seizures, especially with dosages > 10 mg twice daily. EXPERT OPINION: DAL represents an option in the symptomatic treatment of MS. Improved ambulation can impact quality of life, motivation and adherence, enhancing the successful management of MS. It has still to be established whether this favorably impacts costs associated with MS. PMID- 25510834 TI - Relaxation-compensated difference spin diffusion NMR for detecting 13C-13C long range correlations in proteins and polysaccharides. AB - The measurement of long-range distances remains a challenge in solid-state NMR structure determination of biological macromolecules. In 2D and 3D correlation spectra of uniformly (13)C-labeled biomolecules, inter-residue, inter-segmental, and intermolecular (13)C-(13)C cross peaks that provide important long-range distance constraints for three-dimensional structures often overlap with short range cross peaks that only reflect the covalent structure of the molecule. It is therefore desirable to develop new approaches to obtain spectra containing only long-range cross peaks. Here we show that a relaxation-compensated modification of the commonly used 2D (1)H-driven spin diffusion (PDSD) experiment allows the clean detection of such long-range cross peaks. By adding a z-filter to keep the total z-period of the experiment constant, we compensate for (13)C T1 relaxation. As a result, the difference spectrum between a long- and a scaled short-mixing time spectrum show only long-range correlation signals. We show that one- and two bond cross peaks equalize within a few tens of milliseconds. Within ~200 ms, the intensity equilibrates within an amino acid residue and a monosaccharide to a value that reflects the number of spins in the local network. With T1 relaxation compensation, at longer mixing times, inter-residue and inter-segmental cross peaks increase in intensity whereas intra-segmental cross-peak intensities remain unchanged relative to each other and can all be subtracted out. Without relaxation compensation, the difference 2D spectra exhibit both negative and positive intensities due to heterogeneous T1 relaxation in most biomolecules, which can cause peak cancellation. We demonstrate this relaxation-compensated difference PDSD approach on amino acids, monosaccharides, a crystalline model peptide, a membrane-bound peptide and a plant cell wall sample. The resulting difference spectra yield clean multi-bond, inter-residue and intermolecular correlation peaks, which are often difficult to resolve in the parent 2D spectra. PMID- 25510835 TI - The solution structure of the MANEC-type domain from hepatocyte growth factor activator inhibitor-1 reveals an unexpected PAN/apple domain-type fold. AB - A decade ago, motif at N-terminus with eight-cysteines (MANEC) was defined as a new protein domain family. This domain is found exclusively at the N-terminus of >400 multi-domain type-1 transmembrane proteins from animals. Despite the large number of MANEC-containing proteins, only one has been characterized at the protein level: hepatocyte growth factor activator inhibitor-1 (HAI-1). HAI-1 is an essential protein, as knockout mice die in utero due to placental defects. HAI 1 is an inhibitor of matriptase, hepsin and hepatocyte growth factor (HGF) activator, all serine proteases with important roles in epithelial development, cell growth and homoeostasis. Dysregulation of these proteases has been causatively implicated in pathological conditions such as skin diseases and cancer. Detailed functional understanding of HAI-1 and other MANEC-containing proteins is hampered by the lack of structural information on MANEC. Although many MANEC sequences exist, sequence-based database searches fail to predict structural homology. In the present paper, we present the NMR solution structure of the MANEC domain from HAI-1, the first three-dimensional (3D) structure from the MANEC domain family. Unexpectedly, MANEC is a new subclass of the PAN/apple domain family, with its own unifying features, such as two additional disulfide bonds, two extended loop regions and additional alpha-helical elements. As shown for other PAN/apple domain-containing proteins, we propose a similar active role of the MANEC domain in intramolecular and intermolecular interactions. The structure provides a tool for the further elucidation of HAI-1 function as well as a reference for the study of other MANEC-containing proteins. PMID- 25510836 TI - Chemopreventive activity of systemically administered curcumin on oral cancer in the 4-nitroquinoline 1-oxide model. AB - Curcumin has therapeutic potential in preventing several types of cancer, including colon, liver, prostate, and breast. The goal of this study was to evaluate the chemopreventive activity of systemically administered curcumin on oral carcinogenesis induced by 4-nitroquinolone-1-oxide (4-NQO). A total of 50 male albino rats, Rattus norvegicus, (Holtzman), were divided into five groups (n = 10 per group). Four of these groups were exposed to 50 ppm 4-NQO in their drinking water ad libitum for 8 or 12 weeks, two groups were treated with curcumin by oral gavage at 30 or 100 mg/kg per day, and one group was treated with corn oil (vehicle) only. The negative control group was euthanized at baseline. Tongues of all animals were removed after euthanasia and used in the subsequent analysis because the tongue is the primary site of carcinogenesis in this model. Descriptive histological analysis and immunohistochemistry for PCNA, Bcl-2, SOCS1 e-3, and STAT3 were performed to assess the oncogenic process. The gene expression of Vimentin, E-cadherin, N-cadherin, or TWIST1 was assessed using RT-qPCR as a representative of epithelial-mesenchymal transition (EMT) events. The administration of curcumin at 100 mg/kg during the 12 weeks markedly decreased the expression of PCNA, Bcl-2, SOCS1 e -3, and STAT3. Curcumin also minimized the cellular atypia under microscopic analysis and diminished the expression of the genes associated with EMT. These findings demonstrate that the systemic administration of curcumin has chemopreventive activity during oral carcinogenesis induced by 4-NQO. PMID- 25510837 TI - Tuning the colloidal crystal structure of magnetic particles by external field. AB - Manipulation of the self-assembly of magnetic colloidal particles by an externally applied magnetic field paves a way toward developing novel stimuli responsive photonic structures. Using microradian X-ray scattering technique we have investigated the different crystal structures exhibited by self-assembly of core-shell magnetite/silica nanoparticles. An external magnetic field was employed to tune the colloidal crystallization. We find that the equilibrium structure in absence of the field is random hexagonal close-packed (RHCP) one. External field drives the self-assembly toward a body-centered tetragonal (BCT) structure. Our findings are in good agreement with simulation results on the assembly of these particles. PMID- 25510838 TI - Validation of the rheumatoid arthritis diagnosis in the Swedish National Patient Register: a cohort study from Stockholm County. AB - BACKGROUND: The Swedish National Patient Register offers unique possibilities for identification of large cohorts, such as patients with rheumatoid arthritis (RA). Although the overall diagnostic validity in the register has been reported as good, the aims of this study were to a) specifically validate the RA diagnosis from contemporary outpatient specialist care in this register, and b) assess the proportion of patients identified via algorithms to define incident RA in the register who in clinical practice also have new-onset disease. METHODS: 211 individuals with prevalent or incident RA in the National Patient Register were included. By extracting diagnosis-related parameters from their medical records, we determined if the patient fulfilled the 2010 ACR/EULAR- and the 1987 ACR classification criteria for RA. We also determined whether clinical diagnosis was synchronous with disease onset as defined through register-based algorithms. RESULTS: For 91% of the prevalent patients, the RA diagnosis in the National Patient Register fulfilled classification criteria or clinical diagnosis for RA. Among individuals identified with incident RA using a strict algorithm for new onset disease, the RA diagnosis was substantiated in 91%, of whom 92% also represented new-onset disease. CONCLUSIONS: The validity of the RA diagnosis in the National Patient Register was high and, by using specific algorithms, new onset RA can be defined. These findings strengthen the notion that the National Patient Register may be used to define RA populations with high validity to allow for high-quality epidemiological studies. PMID- 25510840 TI - [Left ventricular pseudoaneurysm during neonatal aortic valvuloplasty]. PMID- 25510841 TI - [Risk factors for cerebrovascular accident in a university hospital]. PMID- 25510839 TI - beta-Alanine ingestion increases muscle carnosine content and combat specific performance in soldiers. AB - The purpose of this study was to examine the effect of beta-alanine (BA) ingestion on tissue carnosine levels and the impact such changes would have on combat specific activity. Eighteen soldiers (19.9 +/- 0.8 year) from an elite combat unit were randomly assigned to either a BA or placebo (PL) group. Before and following a 30-day supplementation period carnosine content of the gastrocnemius muscle and brain was determined by proton magnetic resonance spectroscopy. During each testing session, participants performed military relevant tasks that included a 2.5 km run, a 1-min sprint, 50-m casualty carry, repeated 30-m sprints with target shooting, and a 2-min serial subtraction test (SST) to assess cognitive function under stressful conditions. A significant elevation (p = 0.048) in muscle carnosine content was noted in BA compared to PL. Changes in muscle carnosine content was correlated to changes in fatigue rate (r = 0.633, p = 0.06). No changes (p = 0.607) were observed in brain carnosine content. Following supplementation, no differences were noted in 2.5 km run, 1 min sprint, repeated sprint, or marksmanship performance, but participants in BA significantly (p = 0.044) improved their time for the 50-m casualty carry and increased their performance (p = 0.022) in the SST compared to PL. In summary, 30 days of BA ingestion can increase muscle carnosine content and improve aspects of military specific performance. Although cognitive performance was significantly greater in participants consuming BA compared to placebo, current study methods were unable to detect any change in brain carnosine levels, thus, the precise mechanism underlying these effects remains elusive. PMID- 25510842 TI - [The importance of being careful with the concepts on autism spectrum disorders]. PMID- 25510843 TI - Acoustofluidic control of bubble size in microfluidic flow-focusing configuration. AB - This paper reports a method to control the bubble size generated in a microfluidic flow-focusing configuration. With an ultrasonic transducer, we induce acoustic streaming using a forward moving, oscillating gas-liquid interface. The induced streaming substantially affects the formation process of gas bubbles. The oscillating interface acts as a pump that increases the gas flow rate significantly and forms a larger bubble. This method is applicable to a wide range of gas pressure from 30 to 90 kPa and flow rate from 380 to 2700 MUL h(-1). The bubble size can be tuned repeatedly with the response time on the order of seconds. We believe that this method will enhance the capability of a microfluidic bubble generator to produce a tunable bubble size. PMID- 25510844 TI - Pre-immature dendritic cells (PIDC) pulsed with HPV16 E6 or E7 peptide are capable of eliciting specific immune response in patients with advanced cervical cancer. AB - BACKGROUND: The protein products of the early genes E6 and E7 in high-risk HPV types 16 and 18 have been implicated in the oncogenic capability of these viruses. Therefore, these peptides represent attractive vaccine therapy targets. METHODS: Thirty-two patients with advanced cervical cancer (HPV16 or 18 positive) were treated with HPV16 E6 (18-26) (Arm A) or HPV16 E7 (12-20) peptide (Arm B) pulsed on PBMCs in order to illicit immune response against the relevant peptide on both arms. These PBMCs were cultured for a short time (48 hours only) and in the presence of GM- CSF, accordingly, they were identified as "Pre-Immature Dentritic Cells". RESULTS: 51Cr release assay and ELISPOT demonstrated evidence of specific immune response against the relevant peptide in 10/16 (63%) evaluable patients in arm A and 7/12 (58%) in arm B. HPV16 E6 was found to be homologous to HPV18 E6 in both vivo and vitro. The median overall survival (OS) and progression free survival (PFS) for the full cohort was 10.0 and 3.5 months, respectively. There were no RECIST responses in any patient. The majority of toxicities were grade I and II. CONCLUSIONS: We demonstrated the feasibility and ability of Pre Immature Dentritic Cells pulsed with HPV16 E6 (18-26) or HPV16 E7 (12-20) to induce a specific immune response against the relevant peptide despite the advanced disease of the cervical cancer patients treated on this trial. We believe that this observation deserves further investigations. PMID- 25510845 TI - Do people with mental illness receive adequate smoking cessation advice? A systematic review and meta-analysis. AB - BACKGROUND: Prevalence rates of smoking in people with mental illness are high, and premature mortality attributed to tobacco related physical comorbidity is a major concern. We conducted a meta-analysis comparing rates of receipt of smoking cessation advice among people with and without mental illness. METHOD: Major electronic databases were searched from inception till August 2014 for studies comparing rates of receipt of smoking cessation advice of people with and without a mental illness. Two independent authors completed methodological appraisal and extracted data. A random-effects meta-analysis was utilized. RESULTS: Seven studies of satisfactory methodological quality (n mental illness=68,811, n control=652,847) were included. Overall there was no significant difference in smoking cessation advice rates between those with and without a mental illness [relative risk (RR)=1.02, 95% confidence interval (CI)=0.94-1.11, n=721,658, Q=1421, P<.001]. Subgroup analyses demonstrated people with severe mental illness (SMI) received comparable rates of smoking cessation advice to those without SMI (RR=1.09, 95% CI=0.98-1.2, n=559,122). This remained true for people with schizophrenia (RR=1.09, 95% CI=0.68-1.70) and bipolar disorder (RR=1.14, 95% CI=0.85-1.5). People with non-SMIs were slightly more likely to receive smoking cessation advice (RR=1.16, 95% CI=1.04-1.30, Q=1364, P<.001, n=580,206). CONCLUSIONS: People with SMI receive similar smoking cessation advice rates to people without mental illness, while those with non-SMI are slightly more likely to receive smoking cessation advice. While progress has been made, offering smoking cessation advice should receive a higher priority in everyday clinical practice for patients with a mental health diagnosis. PMID- 25510846 TI - Carrier-dependent magnetic anisotropy of cobalt doped titanium dioxide. AB - Using first-principles calculations, we predict that the magnetic anisotropy energy of Co-doped TiO2 sensitively depends on carrier accumulation. This magnetoelectric phenomenon provides a potential route to a direct manipulation of the magnetization direction in diluted magnetic semiconductor by external electric-fields. We calculate the band structures and reveal the origin of the carrier-dependent magnetic anisotropy energy in k-space. It is shown that the carrier accumulation shifts the Fermi energy, and consequently, regulates the competing contributions to the magnetic anisotropy energy. The calculations provide an insight to understanding this magnetoelectric phenomenon, and a straightforward way to search prospective materials for electrically controllable spin direction of carriers. PMID- 25510847 TI - Polyhydramnios in sac of parasitic twin: atypical manifestation of twin reversed arterial perfusion sequence. PMID- 25510848 TI - Evaluation of clinical bradycardiac effect and respiratory adverse effect of beta blocking agents in coronary computed tomography angiography based on theoretical analysis. AB - beta-blocking agents are used for patients with tachycardia to improve the image quality of coronary computed tomography angiography (CCTA). In this study, we analyzed the clinical bradycardiac effects and the adverse respiratory effects of five beta-blocking agents (landiolol, esmolol, propranolol, metoprolol and atenolol) used for CCTA. The changes of the occupancy binding to beta1 or beta2 receptor of these drugs were calculated based on the receptor occupancy theory. Thereafter, we predicted both the rate of heart rate decline (?HR) as a clinical effect and the rate of decrease in forced expiratory volume in 1 s (?FEV1) as an adverse effect, by using the ternary complex model. The results showed that the drugs with ?HR greater than 10 %, necessary for CCTA, were as follows: landiolol at 13.5 %, propranolol at 11.0 %, and atenolol at 22.6 %. The ?HR values at the end of CCTA for those three drugs were 0.3, 6.7, and 22.9 %, respectively. It is desirable for the bradycardiac effect to disappear at the end of CCTA. Therefore, landiolol is thought to be a preferable drug. On the other hand, ?FEV1 at start and end of CCTA for those three drugs was 0.04-2.5, 34.9-40.3, and 6.0-6.1 %, respectively. Our results suggested that landiolol has the most appropriate effect and safety for patients with tachycardia who are undergoing a CCTA procedure. PMID- 25510850 TI - An aqueous zinc-ion battery based on copper hexacyanoferrate. AB - A new zinc-ion battery based on copper hexacyanoferrate and zinc foil in a 20 mM solution of zinc sulfate, which is a nontoxic and noncorrosive electrolyte, at pH 6 is reported. The voltage of this novel battery system is as high as 1.73 V. The system shows cyclability, rate capability, and specific energy values near to those of lithium-ion organic batteries based on Li4 Ti5 O12 and LiFePO4 at 10 C. The effects of Zn(2+) intercalation and H2 evolution on the performance of the battery are discussed in detail. In particular, it has been observed that hydrogen evolution can cause a shift in pH near the surface of the zinc electrode, and favor the stabilization of zinc oxide, which decreases the performance of the battery. This mechanism is hindered when the surface of zinc becomes rougher. PMID- 25510849 TI - Wnt5a regulates dental follicle stem/progenitor cells of the periodontium. AB - INTRODUCTION: Dental follicle gives rise to one or several tissues of the periodontium including the periodontal ligament, cementum and/or alveolar bone. Whether Wnt5a is expressed in the postnatal periodontium or regulates dental follicle stem/progenitor cells is unknown. METHODS: Dental follicle stem/progenitor cells were isolated from postnatal day 1 (p1) to p11 from rat mandibular first molars. Immunolocalization mapped Wnt5a expression in the alveolar bone, periodontal ligament, and the developing ameloblast and odontoblast layers. Mononucleated and adherent cells were isolated from p7 dental follicle. Wnt5a was overexpressed in dental follicle stem/progenitor cells to study their proliferation, osteogenic differentiation and migration behavior, with subpopulations of native dental follicle stem/progenitor cells as controls, using real-time PCR (Taqman), Lenti-viral transfection, Western blotting and immunofluorescence. RESULTS: Wnt5a was expressed consistently in p1 to p11 rat peridontium. Native, p7 dental follicle stem/progenitor cells had modest ability to mineralize in the tested 14 days. Even in chemically defined osteogenesis medium, dental follicle stem/progenitor cells only showed modest mineralization. Upon addition of 300 ng/mL Wnt5a protein in osteogenesis medium, dental follicle stem/progenitor cells displayed mineralization that was still unremarkable. Chemically induced or Wnt5a-induced mineralization of dental follicle cells only occurred sparsely. Combination of Wnt5a with 100 ng/mL BMP2 finally prompted dental follicle stem/progenitor cells to produce robust mineralization with elevated expression of Runx2, alkaline phosphatase, collagen 1alpha1 and osteocalcin. Thus, native dental follicle stem/progenitor cells or some of their fractions may be somewhat modest in mineralization. Strikingly, Wnt5a protein significantly augmented RANKL ligand, suggesting putative regulatory roles of dental follicle stem/progenitor cells for the monocyte/osteoclast lineage and potential involvement in alveolar bone remodeling and/or resorption. P-Jnk1/2 was activated in Wnt5a overexpressed dental follicle cells; conversely, exposure to SP600125, a c-Jun N-terminal kinase (JNK) inhibitor attenuated Runx2, collagen 1alpha1 and osteocalcin expression either in the presence or absence of Wnt5a. Wnt5a overexpression in dental follicle stem/progenitor cells significantly reduced their proliferation rates, but robustly augmented their migration capacity. CONCLUSIONS: These findings provide a glimpse of Wnt5a's putative roles in dental follicle stem/progenitor cells and the periodontium with implications in periodontal disease, tooth eruption, dental implant bone healing and orthodontic tooth movement. PMID- 25510851 TI - Tuning reactivity and site selectivity of simple arenes in C-H activation: ortho arylation of anisoles via arene-metal pi-complexation. AB - Current approaches to achieve site selectivity in the C-H activation of arenes involve the use of directing groups or highly electron-poor arenes. In contrast, simple arenes, such as anisole, are characterized by poor reactivity and selectivity. We report that pi-complexation to a Cr(CO)3 unit enhances the reactivity of anisoles providing an unprecedented ortho-selective arylation. This mild methodology can be used for the late stage functionalization of bioactive compounds containing the anisole motif, allowing the construction of novel organic scaffolds with few synthetic steps. PMID- 25510852 TI - Genetic characterization of three novel chicken parvovirus strains based on analysis of their coding sequences. AB - Chicken parvovirus (ChPV) is one of the causative agents of viral enteritis. Recently, the genome of the ABU-P1 strain of ChPV was fully sequenced and determined to have a distinct genomic composition compared with that of vertebrate parvoviruses. However, no comparative sequence analysis of coding regions of ChPVs was possible because of the lack of other sequence information. In this study, we obtained the nucleotide sequences of all genomic coding regions of three ChPVs by polymerase chain reaction using 13 primer sets, and deduced the amino acid sequences from the nucleotide sequences. The non-structural protein 1 (NS1) gene of the three ChPVs showed 95.0 to 95.5% nucleotide sequence identity and 96.5 to 98.1% amino acid sequence identity to those of NS1 from the ABU-P1 strain, respectively, and even higher nucleotide and amino acid similarities to one another. The viral proteins (VP) gene was more divergent between the three ChPV Korean strains and ABU-P1, with 88.1 to 88.3% nucleotide identity and 93.0% amino acid identity. Analysis of the putative tertiary structure of the ChPV VP2 protein showed that variable regions with less than 80% nucleotide similarity between the three Korean strains and ABU-P1 occurred in large loops of the VP2 protein believed to be involved in antigenicity, pathogenicity, and tissue tropism in other parvoviruses. Based on our analysis of full-length coding sequences, we discovered greater variation in ChPV strains than reported previously, especially in partial regions of the VP2 protein. PMID- 25510853 TI - The Angelina Jolie effect: how high celebrity profile can have a major impact on provision of cancer related services. AB - INTRODUCTION: It is frequent for news items to lead to a short lived temporary increase in interest in a particular health related service, however it is rare for this to have a long lasting effect. In 2013, in the UK in particular, there has been unprecedented publicity in hereditary breast cancer, with Angelina Jolie's decision to have genetic testing for the BRCA1 gene and subsequently undergo risk reducing mastectomy (RRM), and a pre-release of the NICE guidelines on familial breast cancer in January and their final release on 26th June. The release of NICE guidelines created a lot of publicity over the potential for use of chemoprevention using tamoxifen or raloxifene. However, the longest lasting news story was the release of details of film actress Angelina Jolie's genetic test and surgery. METHODS: To assess the potential effects of the 'Angelina Jolie' effect, referral data specific to breast cancer family history was obtained from around the UK for the years 2012 and 2013. A consortium of over 30 breast cancer family history clinics that have contributed to two research studies on early breast surveillance were asked to participate as well as 10 genetics centres. Monthly referrals to each service were collated and increases from 2012 to 2013 assessed. RESULTS: Data from 12 family history clinics and 9 regional genetics services showed a rise in referrals from May 2013 onwards. Referrals were nearly 2.5 fold in June and July 2013 from 1,981 (2012) to 4,847 (2013) and remained at around two-fold to October 2013. Demand for BRCA1/2 testing almost doubled and there were also many more enquiries for risk reducing mastectomy. Internal review shows that there was no increase in inappropriate referrals. CONCLUSIONS: The Angelina Jolie effect has been long lasting and global, and appears to have increased referrals to centres appropriately. PMID- 25510854 TI - Key residues at the membrane-distal surface of KACL, but not glycosylation, determine the functional interaction of the keratinocyte-specific C-type lectin like receptor KACL with its high-affinity receptor NKp65. AB - Keratinocyte-associated C-type lectin (KACL) is a peculiar C-type lectin-like receptor (CTLR) due to its selective expression by human keratinocytes and cognate interaction with the genetically coupled CTLR NKp65. KACL and NKp65 are members of the CLEC2 and NKRP1 subfamilies of natural killer gene complex (NKC) encoded CTLR, respectively. Most NKRP1 molecules are expressed on NK cells and T cells and act as receptors of CLEC2 glycoproteins with their genes being intermingled in a certain sub-region of the mammalian NKC. The reasons for the tight genetic linkage of these dedicated receptor/ligand pairs are unknown, as is the physiological expression of NKp65. Recently, we reported that the CTLR NKp65 and KACL interact with high affinity, resulting in activation of NKp65-expressing NK-92MI cells. Here, we address the molecular basis of this high-affinity interaction by analysing KACL mutants with KACL-specific monoclonal antibodies (mAb), soluble NKp65 (sNKp65) and NK-92MI-NKp65 cells. We find that none of the three N-linked carbohydrates of KACL glycoproteins significantly contributes to KACL surface expression and NKp65 interaction. However, KACL mutants with non conservative amino acid substitutions of arginine 158 or isoleucine 161 abrogated binding of both KACL-specific mAb OMA1 and sNKp65, well in line with the blockade of NKp65-KACL interaction by OMA1. Accordingly, functional recognition of these KACL mutants by NK-92M-NKp65 cells was completely abolished. Arginine 158 and isoleucine 161 located at the membrane-distal surface of KACL were defined as residues, decisively determining functional KACL-NKp65 interaction that is independent of KACL glycosylation. PMID- 25510856 TI - The influences of CYP2D6 genotypes and drug interactions on the pharmacokinetics of venlafaxine: exploring predictive biomarkers for treatment outcomes. AB - RATIONALE: Two biomarkers: concentration ratio of O desmethylvenlafaxine/venlafaxine and concentration sum of venlafaxine + O desmethylvenlafaxine were adopted to indicate venlafaxine responses, but neither is validated. OBJECTIVES: To evaluate the ability of two biomarkers in reflecting venlafaxine pharmacokinetic variations, and to further examine their relationship with venlafaxine treatment outcomes. METHODS: Two well-defined influencing factors: CYP2D6 genotypes and drug interactions were enriched into a three-period crossover study to produce venlafaxine pharmacokinetic variations: In each period, healthy CYP2D6 extensive metabolizers (EM group; n = 12) and CYP2D6*10/*10 intermediate metabolizers (IM group; n = 12) were pretreated with clarithromycin (CYP3A4 inhibitor), or nothing (control), or clarithromycin + paroxetine (CYP3A4 + CYP2D6 inhibitors), before administration of a single-dose of 75 mg venlafaxine. Both biomarkers were evaluated (1) for their relationship with the influencing factors in healthy volunteers and (2) for their relationships with the venlafaxine responses/adverse events reported in two patient studies. RESULTS: Significant venlafaxine pharmacokinetic variations were observed between the EM and IM groups (geometric mean ratio [95 % CI] of area under the curve, 3.0 [1.8-5.1] in the control period), and between the control and clarithromycin + paroxetine periods (4.1 [3.5-4.7] and 2.0 [1.7-2.4] in the EM and IM group, respectively). O-Desmethylvenlafaxine/venlafaxine was superior to venlafaxine + O-desmethylvenlafaxine to reflect the influencing factors. In the patient studies, O-desmethylvenlafaxine/venlafaxine > 4 showed high precision in predicting venlafaxine responders/partial-responders (92 %) and patients without venlafaxine-related adverse events (88 %); the O desmethylvenlafaxine/venlafaxine < 4 and venlafaxine + O-desmethylvenlafaxine > 400 ng/ml combination showed higher precision (100 %) than O desmethylvenlafaxine/venlafaxine < 4 alone (65 %) in predicting venlafaxine non responders. CONCLUSION: We propose using O-desmethylvenlafaxine/venlafaxine for CYP2D6 phenotyping, and O-desmethylvenlafaxine/venlafaxine with venlafaxine + O desmethylvenlafaxine for predicting venlafaxine treatment outcomes in future prospective studies. PMID- 25510855 TI - Dopa therapy and action impulsivity: subthreshold error activation and suppression in Parkinson's disease. AB - RATIONALE: Impulsive actions entail (1) capture of the motor system by an action impulse, which is an urge to act and (2) failed suppression of that impulse in order to prevent a response error. Several studies indicate that dopaminergic treatment can induce action impulsivity in patients diagnosed with Parkinson's disease (PD). Whether this effect is due to increased impulse expression or to decreased impulse suppression remains to be deciphered. METHOD: We used a novel approach based on electromyographic (EMG) analyses to decipher the effects of the patient's usual dopaminergic therapy on the expression and suppression of subliminal erroneous impulses. To this end, we used a within-subject design and took advantage of the Simon task, that elicits prepotent response tendencies. The patients (N = 15) performed the task on their usual dopaminergic medication and after complete medication withdrawal (for at least 12 h). RESULTS: The correction rate that measures the ability to suppress subthreshold impulsive muscle activity was lower when the patients were on medication as compared to their off medication state (p < 0.05). The incorrect activation rate that measures the capture of the motor system by action impulses was unaffected by medication. CONCLUSIONS: Dopa therapy affected action impulsivity. Although medication did not influence the incidence of fast action impulses, it significantly reduced patients' ability to abort and suppress muscle activation related to the incorrect response alternative. PMID- 25510857 TI - Multilevel impact of the dopamine system on the emotion-potentiated startle reflex. AB - RATIONALE/OBJECTIVES: The pathogenetic mechanism of emotion-related disorders such as anxiety disorders is considered to be complex with an interaction of genetic, biochemical, and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic system-partly conferred by catechol-O-methyltransferase (COMT) gene variation-and for distorted emotional processing to constitute risk factors for anxiety and anxiety-related disorders. METHODS: Applying a multilevel approach, we analyzed the main and interactive effects of the functional COMT val158met polymorphism and L-dopa (single-dose 50 mg levodopa and 12.5 mg carbidopa; double-blind, placebo-controlled design) on the emotion-potentiated (unpleasant, neutral, and pleasant IAPS pictures) startle response as an intermediate phenotype of anxiety in a sample of 100 healthy probands (f = 52, m = 48). RESULTS: The COMT 158val allele was associated with an increased startle potentiation by unpleasant stimuli as compared with neutral stimuli irrespective of L-dopa or placebo intervention. COMT 158met/met genotype carriers, while displaying no difference in startle magnitude in response to unpleasant or neutral pictures in the placebo condition, showed startle potentiation by unpleasant pictures under L-dopa administration only. CONCLUSIONS: The present proof-of-concept study provides preliminary support for a complex, multilevel impact of the dopaminergic system on the emotion potentiated startle reflex suggesting increased phasic dopamine transmission driven by the more active COMT 158val allele and/or a single dose of L-dopa to predispose to maladaptive emotional processing and thereby potentially also to anxiety-related psychopathological states. PMID- 25510858 TI - Neuroplasticity of A-type potassium channel complexes induced by chronic alcohol exposure enhances dendritic calcium transients in hippocampus. AB - RATIONALE: Chronic alcohol-induced cognitive impairments and maladaptive plasticity of glutamatergic synapses are well-documented. However, it is unknown if prolonged alcohol exposure affects dendritic signaling that may underlie hippocampal dysfunction in alcoholics. Back-propagation of action potentials (bAPs) into apical dendrites of hippocampal neurons provides distance-dependent signals that modulate dendritic and synaptic plasticity. The amplitude of bAPs decreases with distance from the soma that is thought to reflect an increase in the density of Kv4.2 channels toward distal dendrites. OBJECTIVE: The aim of this study was to quantify changes in hippocampal Kv4.2 channel function and expression using electrophysiology, Ca(2+) imaging, and western blot analyses in a well-characterized in vitro model of chronic alcohol exposure. RESULTS: Chronic alcohol exposure significantly decreased expression of Kv4.2 channels and KChIP3 in hippocampus. This reduction was associated with an attenuation of macroscopic A-type K(+) currents in CA1 neurons. Chronic alcohol exposure increased bAP evoked Ca(2+) transients in the distal apical dendrites of CA1 pyramidal neurons. The enhanced bAP-evoked Ca(2+) transients induced by chronic alcohol exposure were not related to synaptic targeting of N-methyl-D-aspartate (NMDA) receptors or morphological adaptations in apical dendritic arborization. CONCLUSIONS: These data suggest that chronic alcohol-induced decreases in Kv4.2 channel function possibly mediated by a downregulation of KChIP3 drive the elevated bAP-associated Ca(2+) transients in distal apical dendrites. Alcohol-induced enhancement of bAPs may affect metaplasticity and signal integration in apical dendrites of hippocampal neurons leading to alterations in hippocampal function. PMID- 25510861 TI - MiR-200b modulates the properties of human monocyte-derived dendritic cells by targeting WASF3. AB - AIMS: The aim of the study was to explore the effect of miR-200b on the development of human peripheral blood monocyte-deriveddendritic-cell (DC) and its mechanisms. MAIN METHODS: Expression levels of miR-200b and its predicted targets were measured by real time-PCR. Protein expression of WASF3 was determined by Western blot and immunohistochemistry. Human peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll-Hypaque density gradient centrifugation from the buffy coat fraction of anticoagulated blood. Monocytes were purified from PBMCs using anti-CD14 microbeads. The immunophenotypes of DCs were tested by flow cytometry. KEY FINDINGS: A strong reduction in miR-200b expression was associated with human peripheral blood monocyte-derivedDC differentiation. The overexpression of miR-200b significantly reduced the numbers of protruding veils in mature DCs (mDCs) that are critical for promoting antigen-specificT-cell activation. Further experiments showed that miR-200b could regulate the function of DCs by targeting WASF3, a protein involved in cell movement and invasion. SIGNIFICANCE: Our results define an important function of miR-200b in the negative regulation of DC development and provide a potential form of miRNA mediated cell therapy for diseases that range from auto-immunity to graft-versus host disease. PMID- 25510862 TI - Three-dimensional eukaryotic genomic organization is strongly correlated with codon usage expression and function. AB - It has been shown that the distribution of genes in eukaryotic genomes is not random; however, formerly reported relations between gene function and genomic organization were relatively weak. Previous studies have demonstrated that codon usage bias is related to all stages of gene expression and to protein function. Here we apply a novel tool for assessing functional relatedness, codon usage frequency similarity (CUFS), which measures similarity between genes in terms of codon and amino acid usage. By analyzing chromosome conformation capture data, describing the three-dimensional (3D) conformation of the DNA, we show that the functional similarity between genes captured by CUFS is directly and very strongly correlated with their 3D distance in Saccharomyces cerevisiae, Schizosaccharomyces pombe, Arabidopsis thaliana, mouse and human. This emphasizes the importance of three-dimensional genomic localization in eukaryotes and indicates that codon usage is tightly linked to genome architecture. PMID- 25510860 TI - Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress in acetaminophen-induced hepato-renal injury. AB - BACKGROUND: Acetaminophen (APAP)-induced toxicity is a predominant cause of acute hepatic and renal failure. In both humans and rodents toxicity begins with a reactive metabolite that binds to proteins. This leads to mitochondrial dysfunction and nuclear DNA fragmentation resulting in necrotic cell death. Pleurotus ostreatus (an edible oyster mushroom) is well recognized as a flavourful food, as well as a medicinal supplement. In the present study, we evaluated the role of Pleurotus ostreatus in the protection against APAP-induced hepato-renal toxicity. We also explored the mechanism by which Pleurotus ostreatus exerts its effects. METHODS: Ninety adult male Swiss albino mice were divided into three groups (30 mice/group). Mice were offered normal diet (control and APAP groups), or diet supplemented with 10% Pleurotus ostreatus (APAP + Pleurotus ostreatus) for 10 days. Mice were either treated with vehicle (control group, single intra-peritoneal injection.), or APAP (APAP and APAP + Pleurotus ostreatus groups, single intra-peritoneal injection, 500 mg/kg), 24 hours after the last meal. RESULTS: APAP increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) glutamate dehydrogenase (GDH), creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (KIM-1), and hepatic and renal malondialdehyde (MDA) content. APAP decreased hepatic and renal glutathione (GSH) content, as well as glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Supplementation with Pleurotus ostreatus significantly reduced APAP-induced elevated levels of ALT, AST, GDH, creatinine, BUN, KIM-1and MDA, while GSH level, and GSH-Px and SOD activities were significantly increased. Our findings were further validated by histopathology; treatment with Pleurotus ostreatus significantly decreased APAP-induced cell necrosis in liver and kidney tissues. CONCLUSIONS: We report here that the antioxidant effect of Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress accompanying APAP over-dose, with subsequent clinically beneficial effects on liver and kidney tissues. PMID- 25510859 TI - Enhanced motivation for food reward induced by stress and attenuation by corticotrophin-releasing factor receptor antagonism in rats: implications for overeating and obesity. AB - RATIONALE: Overeating beyond individuals' homeostatic needs critically contributes to obesity. The neurobehavioral mechanisms underlying the motivation to consume excessive foods with high calories are not fully understood. OBJECTIVE: The present study examined whether a pharmacological stressor, yohimbine, enhances the motivation to procure food reward with an emphasis on comparisons between standard lab chow and high-fat foods. The effects of corticotropin-releasing factor (CRF) receptor blockade by a CRF1-selective antagonist NBI on the stress-enhanced motivation for food reward were also assessed. METHODS: Male Sprague-Dawley rats with chow available ad libitum in their home cages were trained to press a lever under a progressive ratio schedule for deliveries of either standard or high-fat food pellets. For testing yohimbine stress effects, rats received an intraperitoneal administration of yohimbine 10 min before start of the test sessions. For testing effects of CRF1 receptor blockade on stress responses, NBI was administered 20 min prior to yohimbine challenge. RESULTS: The rats emitted higher levels of lever responses to procure the high-fat food pellets compared with their counterparts on standard food pellets. Yohimbine challenge facilitated lever responses for the reward in all of the rats, whereas the effect was more robust in the rats on high-fat food pellets compared with their counterparts on standard food pellets. An inhibitory effect of pretreatment with NBI was observed on the enhancing effect of yohimbine challenge but not on the responses under baseline condition without yohimbine administration. CONCLUSIONS: Stress challenge significantly enhanced the motivation of satiated rats to procure extra food reward, especially the high-fat food pellets. Activation of CRF1 receptors is required for the stress-enhanced motivation for food reward. These results may have implications for our better understanding of the biobehavioral mechanisms of overeating and obesity. PMID- 25510863 TI - The effectiveness of yoga in modifying risk factors for cardiovascular disease and metabolic syndrome: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Yoga, a popular mind-body practice, may produce changes in cardiovascular disease (CVD) and metabolic syndrome risk factors. DESIGN: This was a systematic review and random-effects meta-analysis of randomized controlled trials (RCTs). METHODS: Electronic searches of MEDLINE, EMBASE, CINAHL, PsycINFO, and The Cochrane Central Register of Controlled Trials were performed for systematic reviews and RCTs through December 2013. Studies were included if they were English, peer-reviewed, focused on asana-based yoga in adults, and reported relevant outcomes. Two reviewers independently selected articles and assessed quality using Cochrane's Risk of Bias tool. RESULTS: Out of 1404 records, 37 RCTs were included in the systematic review and 32 in the meta-analysis. Compared to non-exercise controls, yoga showed significant improvement for body mass index ( 0.77 kg/m(2) (95% confidence interval -1.09 to -0.44)), systolic blood pressure ( 5.21 mmHg (-8.01 to -2.42)), low-density lipoprotein cholesterol (-12.14 mg/dl ( 21.80 to -2.48)), and high-density lipoprotein cholesterol (3.20 mg/dl (1.86 to 4.54)). Significant changes were seen in body weight (-2.32 kg (-4.33 to -0.37)), diastolic blood pressure (-4.98 mmHg (-7.17 to -2.80)), total cholesterol (-18.48 mg/dl (-29.16 to -7.80)), triglycerides (-25.89 mg/dl (-36.19 to -15.60), and heart rate (-5.27 beats/min (-9.55 to -1.00)), but not fasting blood glucose ( 5.91 mg/dl (-16.32 to 4.50)) nor glycosylated hemoglobin (-0.06% Hb (-0.24 to 0.11)). No significant difference was found between yoga and exercise. One study found an impact on smoking abstinence. CONCLUSIONS: There is promising evidence of yoga on improving cardio-metabolic health. Findings are limited by small trial sample sizes, heterogeneity, and moderate quality of RCTs. PMID- 25510866 TI - Putting numbers on chromatin and its interacting partners. PMID- 25510864 TI - microRNA-379 couples glucocorticoid hormones to dysfunctional lipid homeostasis. AB - In mammals, glucocorticoids (GCs) and their intracellular receptor, the glucocorticoid receptor (GR), represent critical checkpoints in the endocrine control of energy homeostasis. Indeed, aberrant GC action is linked to severe metabolic stress conditions as seen in Cushing's syndrome, GC therapy and certain components of the Metabolic Syndrome, including obesity and insulin resistance. Here, we identify the hepatic induction of the mammalian conserved microRNA (miR) 379/410 genomic cluster as a key component of GC/GR-driven metabolic dysfunction. Particularly, miR-379 was up-regulated in mouse models of hyperglucocorticoidemia and obesity as well as human liver in a GC/GR-dependent manner. Hepatocyte specific silencing of miR-379 substantially reduced circulating very-low-density lipoprotein (VLDL)-associated triglyceride (TG) levels in healthy mice and normalized aberrant lipid profiles in metabolically challenged animals, mediated through miR-379 effects on key receptors in hepatic TG re-uptake. As hepatic miR 379 levels were also correlated with GC and TG levels in human obese patients, the identification of a GC/GR-controlled miRNA cluster not only defines a novel layer of hormone-dependent metabolic control but also paves the way to alternative miRNA-based therapeutic approaches in metabolic dysfunction. PMID- 25510867 TI - Evaluation of the natural perinatal transmission of bovine leukaemia virus. AB - The perinatal transmission of bovine leukaemia virus (BLV) plays a critical role in the spread and persistence of BLV infection in cattle herds. The purpose of this study was to examine the frequency of perinatal infections in an area in Japan and investigate some risk factors associated with infection. Altogether, 129 calves born to BLV-infected cows in a herd in Japan were tested for infection immediately after birth and again at one month of age using nested PCR. Twenty four calves (18.6 per cent) were infected with BLV, of which 14 (10.8 per cent) and 10 (7.7 per cent) calves were infected via the transplacental and the birth canal routes, respectively. Maternal viral loads, breed, the presence or absence of assistance during parturition and the number of births per dam were evaluated to investigate risk factors associated with infection. Maternal viral load was significantly correlated with the frequency of perinatal infection, and more than 40 per cent of newborn calves born to dams with high viral loads were infected with BLV. The results of this study could contribute towards developing effective eradication programmes by providing necessary data for replacement of breeding cow in the field. PMID- 25510865 TI - Transposable element islands facilitate adaptation to novel environments in an invasive species. AB - Adaptation requires genetic variation, but founder populations are generally genetically depleted. Here we sequence two populations of an inbred ant that diverge in phenotype to determine how variability is generated. Cardiocondyla obscurior has the smallest of the sequenced ant genomes and its structure suggests a fundamental role of transposable elements (TEs) in adaptive evolution. Accumulations of TEs (TE islands) comprising 7.18% of the genome evolve faster than other regions with regard to single-nucleotide variants, gene/exon duplications and deletions and gene homology. A non-random distribution of gene families, larvae/adult specific gene expression and signs of differential methylation in TE islands indicate intragenomic differences in regulation, evolutionary rates and coalescent effective population size. Our study reveals a tripartite interplay between TEs, life history and adaptation in an invasive species. PMID- 25510868 TI - Functional Interaction Between the ESCRT-I Component TSG101 and the HSV-1 Tegument Ubiquitin Specific Protease. AB - Similar to phosphorylation, transient conjugation of ubiquitin to target proteins (ubiquitination) mediated by the concerted action of ubiquitin ligases and de ubiquitinating enzymes (DUBs) can affect substrate function. As obligate intracellular parasites, viruses rely on different cellular pathways for their own replication and the well conserved ubiquitin conjugating/de-conjugating system is not an exception. Viruses not only usurp the host proteins involved in the ubiquitination/de-ubiquitination process, but they also encode their own ubiquitin ligases and DUBs. Here we report that an N-terminal variant of the herpes simplex virus (HSV) type-1 large tegument protein VP1/2 (VP1/2(1-767)), encompassing an active DUB domain (herpesvirus tegument ubiquitin specific protease, htUSP), and TSG101, a component of the endosomal sorting complex required for transport (ESCRT)-I, functionally interact. In particular, VP1/2(1 767) modulates TSG101 ubiquitination and influences its intracellular distribution. Given the role played by the ESCRT machinery in crucial steps of both cellular pathways and viral life cycle, the identification of TSG101 as a cellular target for the HSV-1 specific de-ubiquitinating enzyme contributes to the clarification of the still under debate function of viral encoded DUBs highly conserved throughout the Herpesviridae family. PMID- 25510869 TI - Effect of perfluorooctane sulfonate on pluripotency and differentiation factors in mouse embryoid bodies. AB - Perfluorooctane sulfonate (PFOS) poses potential risks to early development, but the molecular mechanisms how PFOS affects embryonic development are still unclear. Mouse embryoid bodies (mEBs) provide ideal models for testing safety or toxicity of chemicals in vitro. In this study, mEBs were exposed to PFOS up to 6 days and then their pluripotency and differentiation markers were evaluated. Our data showed that the mRNA and protein levels of pluripotency markers (Oct4, Sox2, Nanog) in mEBs were significantly increased following exposure to PFOS. Meanwhile, the expressions of miR-134, miR-145, miR-490-3p were decreased accordingly. PFOS reduced the mRNA levels of endodermal markers (Sox17, FOXA2), mesodermal markers (SMA, Brachyury) and ectodermal markers (Nestin, Fgf5) in mEBs. Meanwhile, PFOS increased the mRNA and protein levels of polycomb group (PcG) family members (Cbx4, Cbx7, Ezh2). Overall, our results showed that PFOS could increase the expression levels of pluripotency factors and decrease the differentiation markers. PMID- 25510870 TI - Lactational exposure to low levels of the six indicator non-dioxin-like polychlorinated biphenyls induces DNA damage and repression of neuronal activity, in juvenile male mice. AB - Previously, we evaluated the effects of lactational exposure to a representative mixture of the six indicator non-dioxin-like polychlorinated biphenyls (?6 NDL PCBs) at low levels on the neurobiological changes and developmental/behavioral performances in mice. In this study, we analyzed the global gene expression profile in cerebellar neurons isolated from male mice presenting the most significant induction of anxiety-like behavior in our previous study (10 ng/kg ?6 NDL-PCBs). Our results revealed changes in the expression of 16658 genes in the neurons of the exposed mice. Among these, 693 upregulated [fold change (FC)>2; p<0.05] and 665 downregulated (FC<2; p<0.05) genes were statistically linked to gene ontology terms (GO). Overexpressed genes belonged to GO terms involved with the cell cycle, DNA replication, cell cycle checkpoint, response to DNA damage stimulus, regulation of RNA biosynthetic processes, and microtubule cytoskeleton organization. Downregulated genes belonged to terms involved with the transmission of nerve impulses, projection neurons, synapse hands, cell junctions, and regulation of RNA biosynthetic processes. Using qPCR, we quantified gene expression related to DNA damage and validated the transcriptomic study, as a significant overexpression of Atm-Atr Bard1, Brca2, Fancd2, Figf, Mycn, p53 and Rad51 was observed between groups (p<0.001). Finally, using immunoblots we determined the expression level of six selected proteins. We found that changes in the protein expression of Atm Brca1, p53, Kcnma1, Npy4r and Scn1a was significant between exposed and control groups (p<0.05), indicating that the expression pattern of these proteins agreed with the expression pattern of their genes by qPCR, further validating our transcriptomic findings. In conclusion, our study showed that early life exposure of male mice to a low level of ?6 NDL-PCBs induced p53-dependent responses to cellular stress and a decrease in the expression of proteins involved in the generation, conduction, and transmission of electrical signals in neurons. PMID- 25510871 TI - Successful treatment of Morbihan disease with long-term minocycline and its association with mast cell infiltration. PMID- 25510872 TI - Reply to letter to the editor--Anti-inflammatory effects of enteral nutrition on mesentery fat in patients with Crohn's disease. PMID- 25510873 TI - Anti-inflammatory effects of enteral nutrition on mesentery fat in patients with Crohn's disease. PMID- 25510875 TI - Trust and recognition: coming to terms with models. PMID- 25510874 TI - Predictors of dietitian consult on medical and surgical wards. AB - BACKGROUND & AIM: Guidelines promote dietitian consult (DC) for nutrition support. In Canada, dietitians are involved in the assessment of malnutrition and provide specialized dietary counseling. It is unknown however, what leads to a DC for patients fed orally. This study identifies independent predictors for a DC and determines what is the proportion of malnourished patients seeing a dietitian. METHODS: The Canadian Malnutrition Task Force conducted a prospective cohort study in medical and surgical wards of 18 Canadian hospitals. 947 patients who did not receive enteral or parenteral nutrition were analyzed. At admission, subjective global assessment (SGA), body mass index, patient demography were collected. During hospitalization clinical data, including dietary intake and presence of a DC were obtained. Multivariate logistic regression was completed with dietitian consult <= 3 days and 4 + days as the outcome variables. RESULTS: The prevalence of malnutrition (SGA B + C) was 45%. Dietitians were consulted for 23% of patients, and of these consults 44% were well nourished (SGA-A), 37% were mildly/moderately malnourished (SGA-B), and 19% were severely malnourished (SGA C). DC missed 75% of the SGA-B and 60% of SGA-C patients. Predictors of consultation within 3 days of hospitalization were: renal diet (OR 5.75) modified texture diet (OR 5.38), metabolic diagnosis (3.91), ONS use pre-admission (OR 2.33), severe malnutrition (SGA-C, OR 1.88) and age (OR 0.98). Predictors for 4 + days were: dysphagia (OR 11.4), a new medical diagnosis (OR 2.3), severe malnutrition (OR 2.17), constipation (OR 2.16), more than one diagnosis (OR 1.8), antibiotic use (OR 1.6), and male gender (OR 1.6). Consuming < 50% of food in the first week was not a predictor as only 19% of those with low intake had a DC at 4 + days. CONCLUSIONS: Overall predictors of DC were appropriate but SGA B and C patients and those eating <50% were missed. Screening at admission with algorithms of care that include referral to the dietitian are needed to improve the process of nutrition care. PMID- 25510876 TI - Recent advances in carbon nanodots: synthesis, properties and biomedical applications. AB - Herein, a mini review is presented concerning the most recent research progress of carbon nanodots, which have emerged as one of the most attractive photoluminescent materials. Different synthetic methodologies to achieve advanced functions and better photoluminescence performances are summarized, which are mainly divided into two classes: top-down and bottom-up. The inspiring properties, including photoluminescence emission, chemiluminescence, electrochemical luminescence, peroxidase-like activity and toxicity, are discussed. Moreover, the biomedical applications in biosensing, bioimaging and drug delivery are reviewed. PMID- 25510877 TI - Visualizing inconsistency in network meta-analysis by independent path decomposition. AB - BACKGROUND: In network meta-analysis, several alternative treatments can be compared by pooling the evidence of all randomised comparisons made in different studies. Incorporated indirect conclusions require a consistent network of treatment effects. An assessment of this assumption and of the influence of deviations is fundamental for the validity evaluation. METHODS: We show that network estimates for single pairwise treatment comparisons can be approximated by the evidence of a subnet that is decomposable into independent paths. Path based estimates and the estimate of the residual evidence can be used with their contribution to the network estimate to set up a forest plot for the consistency assessment. Using a network meta-analysis of twelve antidepressants and controlled perturbations in the real and constructed consistent data, we discuss the consistency assessment by the independent path decomposition in contrast to an approach using a recently presented graphical tool, the net heat plot. In addition, we define influence functions that describe how changes in study effects are translated into network estimates. RESULTS: While the consistency assessment by the net heat plot comprises all network estimates, an independent path decomposition and visualisation in a forest plot is tailored to one specific treatment comparison. It allows for the recognition as to whether inconsistencies between different paths of evidence and outlier effects do affect the considered treatment comparison. CONCLUSIONS: The approximation of the network estimate for a single comparison by the evidence of a subnet and the visualisation of the decomposition into independent paths provide the applicability of a graphical validation instrument that is known from classical meta-analysis. PMID- 25510878 TI - Fetal programming via maternal diabetes: the controversy continues. PMID- 25510879 TI - Early life determinants of low IQ at age 6 in children from the 2004 Pelotas Birth Cohort: a predictive approach. AB - BACKGROUND: Childhood intelligence is an important determinant of health outcomes in adulthood. The first years of life are critical to child development. This study aimed to identify early life (perinatal and during the first year of life) predictors of low cognitive performance at age 6. METHODS: A birth cohort study started in the city of Pelotas, southern Brazil, in 2004 and children were followed from birth to age six. Information on a broad set of biological and social predictors was collected. Cognitive ability-the study outcome-was assessed using the Wechsler Intelligence Scale for Children (WISC). IQ scores were standardized into z-scores and low IQ defined as z < -1. We applied bootstrapping methods for internal validation with a multivariate logistic regression model and carried out external validation using a second study from the 1993 Pelotas Birth Cohort. RESULTS: The proportion of children with IQ z-score < -1 was 16.9% (95% CI 15.6-18.1). The final model included the following early life variables: child's gender; parents' skin color; number of siblings; father's and mother's employment status; household income; maternal education; number of persons per room; duration of breastfeeding; height-for-age deficit; head circumference-for age deficit; parental smoking during pregnancy; and maternal perception of the child's health status. The area under the ROC curve for our final model was 0.8, with sensitivity of 72% and specificity of 74%. Similar results were found when testing external validation by using data from the 1993 Pelotas Birth Cohort. CONCLUSIONS: The study results suggest that a child's and her/his family's social conditions are strong predictors of cognitive ability in childhood. Interventions for promoting a healthy early childhood development are needed targeting children at risk of low IQ so that they can reach their full cognitive potential. PMID- 25510880 TI - Interactions between specific parameters of MDMA use and cognitive and psychopathological measures. AB - The aim of the present study was to investigate the relevance of different parameters of 3,4-methylenedioxymethamphetamine (MDMA) use, including age of first use, cumulative lifetime dose and highest daily dose for predicting cognitive performance and self-reported psychopathology. Moreover, interactions between those parameters were examined. Ninety-six new MDMA users were interviewed to assess their drug use, and they completed a battery of cognitive tests concerning attention and information processing speed, episodic memory and executive functioning and self-reported psychopathology. Subjects participated again after 1year to provide follow-up data. Significant associations between age of first use and cumulative lifetime dose have been found for attention and information processing speed. Furthermore, the results showed a significant effect of age of first use on the recognition performance of the episodic memory. The findings of the current study provide a first estimation of the interactions between different MDMA use parameters. Future research should focus upon additional parameters of drug use and concentrate on consequent follow-up effects. PMID- 25510882 TI - Will a quadruple multiplexed point-of-care screening strategy for HIV-related co infections be feasible and impact detection of new co-infections in at-risk populations? Results from cross-sectional studies. AB - OBJECTIVES: Multiplexed point-of-care (POC) devices can rapidly screen for HIV related co-infections (eg, hepatitis C (HCV), hepatitis B (HBV), syphilis) in one patient visit, but global evidence for this approach remains limited. This study aimed to evaluate a multiplex POC testing strategy to expedite screening for HIV related co-infections in at-risk populations. METHODS: A multiplex strategy was developed with two subsequent versions of an investigational device Miriad. It was evaluated in two non-comparable settings and populations in two countries for feasibility of conduct, detection of new infections, preference and accuracy. Version 1 was evaluated in 375 sexually transmitted disease clinic attendees in Mumbai, India; version 2 was evaluated in 119 injection drug users in Montreal, Canada. RESULTS: Feasibility (completion rate) of the multiplex strategy was high (86.1% Mumbai; 92.4% Montreal). A total of 170 new infections were detected in Mumbai (56 HIV, 75 HBV, 37 syphilis, 2 HCV) versus 2 in Montreal. Preference was 60% in Mumbai and 97% in Montreal. Miriad version 1 specificities were high: HIV 99.7% (98.3% to 100%), HBV 99.3% (97.6% to 99.9%), HCV 99.7% (98.5% to 99.9%), syphilis 85.2% (80.9% to 88.8%); sensitivities were as follows: HIV 100% (94.8% to 100%), HBV 13.3% (6.6% to 23.2%), HCV 50% (1.3% to 98.7%), syphilis 86.1% (70.5% to 95.3%). With version 2, specificities improved: HIV 100% (97.2% to 100%), HBV 100% (97.3% to 100%), HCV 85.3% (73.8% to 93.0%), syphilis 98.1% (93.3% to 99.8%); sensitivities were: HIV 100% (47.3% to 100%), HCV 80.4% (66.1% to 90.6%), syphilis 100% (22.4% to 100%). CONCLUSIONS: A quad multiplex POC strategy for HIV and co-infections was feasible to operationalise and preferred by patients in both settings. Many new infections were identified in Mumbai and accuracy improved with version 2 of the assay. Such a strategy will help expedite screening for co-infections, particularly where baseline screening is low. These findings are valuable to practitioners, researchers, policymakers and funders involved in initiatives for all four diseases with implications for scale-up. PMID- 25510881 TI - The prrF-encoded small regulatory RNAs are required for iron homeostasis and virulence of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an opportunistic pathogen that requires iron to cause infection, but it also must regulate the uptake of iron to avoid iron toxicity. The iron-responsive PrrF1 and PrrF2 small regulatory RNAs (sRNAs) are part of P. aeruginosa's iron regulatory network and affect the expression of at least 50 genes encoding iron-containing proteins. The genes encoding the PrrF1 and PrrF2 sRNAs are encoded in tandem in P. aeruginosa, allowing for the expression of a distinct, heme-responsive sRNA named PrrH that appears to regulate genes involved in heme metabolism. Using a combination of growth, mass spectrometry, and gene expression analysis, we showed that the DeltaprrF1,2 mutant, which lacks expression of the PrrF and PrrH sRNAs, is defective for both iron and heme homeostasis. We also identified phuS, encoding a heme binding protein involved in heme acquisition, and vreR, encoding a previously identified regulator of P. aeruginosa virulence genes, as novel targets of prrF-mediated heme regulation. Finally, we showed that the prrF locus encoding the PrrF and PrrH sRNAs is required for P. aeruginosa virulence in a murine model of acute lung infection. Moreover, we showed that inoculation with a DeltaprrF1,2 deletion mutant protects against future challenge with wild-type P. aeruginosa. Combined, these data demonstrate that the prrF-encoded sRNAs are critical regulators of P. aeruginosa virulence. PMID- 25510884 TI - Pregnancy-associated outcomes in women who spent some of their childhood looked after by local authorities: findings from the UK Millennium Cohort Study. AB - OBJECTIVES: There has been very little description of the health and social outcomes at pregnancy and early motherhood of girls who were previously looked after by local authorities. The objectives of this study were to compare the sociodemographic and health profiles of mothers who had spent time in a children's home or with foster parents as a child to mothers who had not. In particular, to examine associations between being looked after and the likelihood of smoking during pregnancy, birth weight, the presence of symptoms of maternal depression and the initiation of breastfeeding. DESIGN: A retrospective cross sectional study using the baseline questionnaire of the Millennium Cohort Study. SETTING: The UK. PARTICIPANTS: A nationally representative study of 18,492 mothers of babies born in the UK during 2000-2002. EXPOSURE: A history of spending time in a children's home or with foster parents. OUTCOME MEASURES: (1) Smoking during pregnancy; (2) low birth weight; (3) symptoms of maternal depression and (4) initiation of breastfeeding. RESULTS: In univariable analyses, women who had been looked after by local authorities were significantly less likely to be of a higher social class, live in a high-income household or have achieved a high level of education. They were more likely to have a low birthweight baby and be a single parent. In multivariable analyses, women who had been looked after by local authorities were more likely to smoke during pregnancy (adjusted OR 3.0 95% CI 2.14 to 4.3) and were more likely to have symptoms of depression (adjusted OR 1.98 95% CI 1.4 to 2.7) compared with women who had not been looked after. CONCLUSIONS: Our results suggest that these women carry social disadvantage into motherhood, with the potential of continuing the cycle of deprivation. There is a case for increasing our attention on this group, which can be readily accessed by maternity and early years' services. PMID- 25510885 TI - Attitudes, access and anguish: a qualitative interview study of staff and patients' experiences of diabetic retinopathy screening. AB - OBJECTIVE: To examine the experiences of patients, health professionals and screeners; their interactions with and understandings of diabetic retinopathy screening (DRS); and how these influence uptake. DESIGN: Purposive, qualitative design using multiperspectival, semistructured interviews and thematic analysis. SETTING: Three UK Screening Programme regions with different service-delivery modes, minority ethnic and deprivation levels across rural, urban and inner-city areas, in general practitioner practices and patients' homes. PARTICIPANTS: 62 including 38 patients (22 regular-screening attenders, 16 non-regular attenders) and 24 professionals (15 primary care professionals and 9 screeners). RESULTS: Antecedents to attendance included knowledge about diabetic retinopathy and screening; antecedents to non-attendance included psychological, pragmatic and social factors. Confusion between photographs taken at routine eye tests and DRS photographs was identified. The differing regional invitation methods and screening locations were discussed, with convenience and transport safety being over-riding considerations for patients. Some patients mentioned significant pain and visual disturbance from mydriasis drops as a deterrent to attendance. CONCLUSIONS: In this, the first study to consider multiperspectival experiential accounts, we identified that proactive coordination of care involving patients, primary care and screening programmes, prior to, during and after screening is required. Multiple factors, prior to, during and after screening, are involved in the attendance and non-attendance for DRS. Further research is needed to establish whether patient self-management educational interventions and the pharmacological reformulation of shorter acting mydriasis drops, may improve uptake of DRS. This might, in turn, reduce preventable vision loss and its associated costs to individuals and their families, and to health and social care providers, reducing current inequalities. PMID- 25510886 TI - Evaluation of postextraction bleeding incidence to compare patients receiving and not receiving warfarin therapy: a cross-sectional, multicentre, observational study. AB - OBJECTIVES: We investigated incidence and risk factors for postextraction bleeding in patients receiving warfarin and those not receiving anticoagulation therapy. DESIGN: Cross-sectional, multicentre, observational study. SETTING: 26 hospitals where an oral surgeon is available. PARTICIPANTS: Data on 2817 teeth (from 496 patients receiving warfarin, 2321 patients not receiving warfarin; mean age (SD): 62.2 (17.6)) extracted between 1 November 2008 and 31 March 2010, were collected. Warfarin-receiving patients were eligible when prothrombin time international normalised ratio (PT-INR) measured within 7 days prior to the extraction was less than 3.0. INTERVENTIONS: Simple dental extraction was performed, and incidence of postextraction bleeding and comorbidities were recorded. PRIMARY AND SECONDARY OUTCOME MEASURES: Postextraction bleeding not controlled by basic haemostasis procedure was clinically significant. RESULTS: Bleeding events were reported for 35 (7.1%) and 49 (2.1%) teeth, of which 18 (3.6%) and 9 (0.4%) teeth were considered clinically significant, in warfarin and non-warfarin groups, respectively, the difference between which was 3.24% (CI 1.58% to 4.90%). The incidence rates by patients were 2.77% and 0.39%, in warfarin and non-warfarin groups, respectively (incidence difference 2.38%, CI 0.65% to 4/10%). Univariate analyses showed that age (OR 0.197, p=0.001), PT-INR (OR 3.635, p=0.003), mandibular foramen conduction anaesthesia (OR 4.854, p=0.050) and formation of abnormal granulation tissue in extraction socket (OR 2.900, p=0.031) significantly correlate with bleeding incidence. Multivariate analysis revealed that age (OR 0.126, p=0.001), antiplatelet drugs (OR 0.100, p=0.049), PT-INR (OR 7.797, p=0.001) and history of acute inflammation at extraction site (OR 3.722, p=0.037) were significant risk factors for postextraction bleeding. CONCLUSIONS: Our results suggest that there is slight but significant increase in the incidences of postextraction bleeding in patients receiving warfarin. Although absolute incidence was low in both groups, the bleeding risk is not negligible. PMID- 25510887 TI - Random sample community-based health surveys: does the effort to reach participants matter? AB - OBJECTIVES: Conducting health surveys with community-based random samples are essential to capture an otherwise unreachable population, but these surveys can be biased if the effort to reach participants is insufficient. This study determines the desirable amount of effort to minimise such bias. DESIGN: A household-based health survey with random sampling and face-to-face interviews. Up to 11 visits, organised by canvassing rounds, were made to obtain an interview. SETTING: Single-family homes in an underserved and understudied population in North Miami-Dade County, Florida, USA. PARTICIPANTS: Of a probabilistic sample of 2200 household addresses, 30 corresponded to empty lots, 74 were abandoned houses, 625 households declined to participate and 265 could not be reached and interviewed within 11 attempts. Analyses were performed on the 1206 remaining households. PRIMARY OUTCOME: Each household was asked if any of their members had been told by a doctor that they had high blood pressure, heart disease including heart attack, cancer, diabetes, anxiety/ depression, obesity or asthma. Responses to these questions were analysed by the number of visit attempts needed to obtain the interview. RESULTS: Return per visit fell below 10% after four attempts, below 5% after six attempts and below 2% after eight attempts. As the effort increased, household size decreased, while household income and the percentage of interviewees active and employed increased; proportion of the seven health conditions decreased, four of which did so significantly: heart disease 20.4-9.2%, high blood pressure 63.5-58.1%, anxiety/depression 24.4-9.2% and obesity 21.8-12.6%. Beyond the fifth attempt, however, cumulative percentages varied by less than 1% and precision varied by less than 0.1%. CONCLUSIONS: In spite of the early and steep drop, sustaining at least five attempts to reach participants is necessary to reduce selection bias. PMID- 25510890 TI - Ironic Effects of Sexual Minority Group Membership: Are Lesbians Less Susceptible to Invoking Negative Female Stereotypes than Heterosexual Women? AB - The traditional stereotype of the typical woman has been described as "nice, but incompetent." However, such general gender stereotypes are applied to individual targets only under certain conditions: They are used to "fill in the blanks" (Heilman, 2012) if little personal information is provided about a target. "Typical lesbians" are regarded to have more typically masculine (agentic) characteristics such as task competence than the typical woman does. We thus hypothesized that if a woman displays behavior coinciding with the stereotype of the typical woman, it is more readily interpreted as stereotypically female if performed by a heterosexual woman than by a lesbian. Participants (N = 296) read a hypothetical job interview in which we manipulated the target's sexual orientation (between subjects). Findings demonstrated that a lesbian was judged as more competent than a heterosexual woman in the presence of behavior that may be interpreted as gender-stereotypical (Experiments 1 and 2). This difference in competence judgments was not found in the absence of gender-stereotypical behavior (Experiment 1). Judging the heterosexual woman as low in masculinity was related to a judgment of lower competence (Experiment 2). Our findings demonstrate that there are conditions under which lesbians, a group often stereotyped negatively, are less susceptible to invoking negative female stereotypes than heterosexual women are. PMID- 25510888 TI - Increasing proportion of female patients with ankylosing spondylitis: a population-based study of trends in the incidence and prevalence of AS. AB - OBJECTIVE: With the introduction of MRI in diagnosis and tumour necrosis factor inhibitors for treatment, the field of ankylosing spondylitis (AS) has undergone significant changes. We carried out a population-based study of the trends in incidence and prevalence of AS over the past 15 years. METHODS: This is a retrospective analysis of provincial health administrative databases. Residents of Ontario, Canada aged 15 years or older diagnosed with AS between 1995 and 2010 were included in the study. Crude as well as age-standardised and sex standardised incidence and prevalence of AS between 1995 and 2010 were calculated. Trends in prevalence and incidence of male and female patients with AS were separately analysed. RESULTS: We identified 24,976 Ontarians with AS. Age/sex-standardised AS prevalence increased from 79/100,000 in 1995 to 213/100,000 in 2010. Men had higher prevalence than women, but the male/female prevalence ratio decreased from 1.70 in 1995 to 1.21 by 2010. A higher proportion of male compared with female patients with AS were diagnosed in the 15-45 age group. Annual incidence rates revealed increasing diagnosis of AS among women after 2003. CONCLUSIONS: The prevalence of AS in Ontario has nearly tripled over the past two decades. The proportion of women with new diagnosis of AS is increasing, a trend that began around the year 2003. A higher proportion of male compared with female patients with AS are diagnosed at an earlier age. PMID- 25510891 TI - Stress-Related Growth among Suicide Survivors: The Role of Interpersonal and Cognitive Factors. AB - Although stress-related growth had been documented in bereaved individuals, it is still not clear to what extent it can be experienced by suicide survivors or which psychological processes facilitate it. The current study examined the role of interpersonal factors-self disclosure and social supports as well as cognitive coping strategies in stress-related growth among suicide survivors. The sample consisted of 135 suicide survivors (104 women and 31 men) aged 18-70. All participants completed the stress-related growth questionnaire as well as instruments measuring interpersonal activities, cognitive strategies, and demographic characteristics concerning the bereavement. The findings showed significant positive correlations between time elapsed since death, self disclosure, social support, adaptive cognitive strategies, and stress-related growth. Furthermore, hierarchical regression analysis revealed that together these variables accounted for over 38% of the variance in stress-related growth. Interpersonal activities such as talking and interacting with others, as well as a cognitive focus on planning for the future emerged as important factors in personal transformation after suicide loss. PMID- 25510889 TI - Effect of rapid HIV testing on HIV incidence and services in populations at high risk for HIV exposure: an equity-focused systematic review. AB - OBJECTIVE: To assess the effects of rapid voluntary counselling and testing (VCT) for HIV on HIV incidence and uptake of HIV/AIDS services in people at high risk for HIV exposure. DESIGN: Cochrane systematic review and meta-analysis. DATA SOURCES: We searched PubMed, EMBASE, AIDSearch, LILACS, Global Health, Medline Africa, PsychInfo, CINAHL, Cochrane CENTRAL, Cochrane HIV/AIDS Group Specialized Register and grey literature from 1 January 2001 to 5 June 2014 without language restriction. DATA SELECTION: We included controlled studies that compared rapid VCT with conventional testing among people at risk for HIV exposure. DATA EXTRACTION: Two reviewers extracted data. We used Cochrane risk of bias tool and GRADE criteria: risk of bias, inconsistency, indirectness, imprecision and publication bias. For observational studies we used the Newcastle-Ottawa Scale. We used the PRISMA-Equity reporting guideline. RESULTS: From 2441 articles, we included 8 randomised controlled trials and 5 observational studies. Rapid VCT was associated with a threefold increase in HIV-testing uptake (relative risk (RR)=2.95 95% CI 1.69 to 5.16) and a twofold increase in the receipt of test results (RR=2.14, 95% CI 1.08 to 4.24). Women accepted testing more often than men in rapid VCT arm, but no differences in effect for age or socioeconomic status. Observational studies also showed rapid VCT led to higher rates of uptake of testing. Heterogeneity was high. A cluster-randomised trial reported an 11% reduction in HIV incidence in intervention communities (RR=0.89, 95% CI=0.63 to 1.24) over 3 years trial. CONCLUSIONS: Rapid VCT in health facilities and communities was associated with a large increase in HIV-testing uptake and receipt of results. This has implications for WHO guidelines. The routine use of rapid VCT may also help avoid human rights violations among marginalised populations where testing may occur without informed consent and where existing stigma may create barriers to testing. PMID- 25510893 TI - Presentation of primary ciliary dyskinesia in children: 30 years' experience. AB - AIM: Primary ciliary dyskinesia (PCD) is a rare (1:15,000) condition resulting in recurrent suppurative respiratory tract infections, progressive lung damage and hearing impairment. As the diagnosis is often delayed for years, the purpose of this study was to review the presenting features of children with PCD attending Australia's initial diagnostic PCD service over a 30-year period. METHOD: A retrospective review of the symptoms of children diagnosed with PCD at Concord Hospital between 1982 and 2012 was undertaken. RESULTS: One thousand thirty-seven paediatric patients were referred for assessment and underwent nasal ciliary brushing. Eighty-four (8.1%) had PCD based on microscopic analysis of nasal cilia. This included 81 with ciliary ultrastructural abnormalities demonstrated on electron microscopy and 3 with a suggestive phenotype, reduced ciliary beat frequency and a family history of PCD. The median age at diagnosis was 6.4 years (range 0.1 to 18.2 years). Forty-six per cent had situs abnormalities and 31% had a family member with PCD. Recurrent cough (81%), rhinosinusitis (71%), recurrent otitis media (49%) and neonatal respiratory distress (57%) were reported. Bronchiectasis at presentation was documented in 32%. Situs abnormalities and neonatal respiratory distress were present together in 26%. CONCLUSION: PCD remains under-recognised by health-care workers. The combination of neonatal respiratory distress, chronic suppurative cough and rhinosinusitis was the most common documented symptom cluster at presentation in cases of PCD. A heightened awareness of the clinical features of the disease may help to lower the age at diagnosis, facilitate appropriate treatment and improve long-term outcomes. PMID- 25510892 TI - Assessing physical and cognitive function of older adults in continuing care retirement communities: who are we recruiting? AB - PURPOSE: In partnership with six Continuing Care Retirement Communities (CCRCs), the current study focused on the feasibility of recruiting a representative sample of residents and then assessing their functional health. MATERIAL AND METHODS: With our guidance, each of the six CCRCs recruited a volunteer (V-Group) and random (R-Group) sample of independent living residents. We provided face-to face training and ongoing remote electronic support to the CCRC staff on the testing battery and the Web-based data entry system. The testing battery was consisted of demographic, physical function, and psychosocial assessments. RESULTS: After training, CCRC staff were receptive to the study goals and successfully used the data entry Website. In the V-Group (N=189), 76% were already participating in CCRC wellness programs. We attempted to recruit a random, unbiased (R-Group) sample of 20% (n=105) of eligible residents; however, only 30 consented to be tested and 70% of this group (21/30) were also already participating in a wellness program. Mean age of all participants was 82.9 years. The V-Group had a higher Short Physical Performance Battery (SPPB) total score (least squares mean [SE], 9.4 [0.2] vs 8.2 [0.4], p=0.014) and SPPB gait speed component score (3.5 [0.1] vs 3.0 [0.2], p=0.007) and spent more time doing moderate-to-vigorous physical activity (300 [21] vs 163 [49] min/week, p=0.013) compared to the R-Group. IMPLICATIONS: While it is feasible to recruit, assess and transmit data on residents' functional health in partnership with CCRCs, population validity was severely compromised. Attention needs to be given to the development of more effective methods to recruit less interested residents. PMID- 25510894 TI - Persimmon tannin represses 3T3-L1 preadipocyte differentiation via up-regulating expression of miR-27 and down-regulating expression of peroxisome proliferator activated receptor-gamma in the early phase of adipogenesis. AB - PURPOSE: Currently, obesity has become a worldwide health problem. Adipocyte differentiation is closely associated with the onset of obesity. Our previous studies suggested that persimmon tannin might be a potent anti-adipogenic dietary bioactive compound. However, the mechanism of persimmon tannin on adipocyte differentiation is still unknown. The purpose of this study was to investigate the effect of persimmon tannin on adipogenic differentiation in 3T3-L1 preadipocytes and the underlying mechanisms. METHODS: Adipogenic differentiation was induced by cocktail in the presence or absence of persimmon tannin. Intracellular lipid accumulation was determined by Oil red O staining and enzymatic colorimetric methods. Gene expression and protein levels were measured by real time RT-PCR and Western blot. RESULTS: Persimmon tannin inhibited intracellular lipid accumulation markedly, and the inhibitory effect was largely limited to the early stage of adipocyte differentiation. Persimmon tannin suppressed the expression of C/EBPalpha and peroxisome proliferator-activated receptor-gamma (PPARgamma), significantly. Furthermore, genes related to lipogenesis, such as sterol regulatory element-binding protein 1, were down regulated by persimmon tannin. In addition, adipocyte fatty acid binding protein (aP2), which is a target gene of PPARgamma, was suppressed by persimmon tannin notably. Correspondingly, the expression of miR-27a and miR-27b were up-regulated by persimmon tannin from Day 2 to Day 8 significantly. CONCLUSION: Persimmon tannin inhibited adipocyte differentiation through regulation of PPARgamma, C/EBPalpha and miR-27 in early stage of adipogenesis. PMID- 25510895 TI - Crystal networks in silk fibrous materials: from hierarchical structure to ultra performance. AB - This review provides a comprehensive survey of the structural characteristics of crystal networks of silk soft fibrous materials in correlation with the macroscopic properties/performance and the network formation mechanisms. The correlation between the hierarchical mesoscopic structures and the mechanical properties of silk soft fibrous materials including silk fibroin hydrogels and naturally spun silk fibers are addressed based on the hierarchical crystal network models. Namely, two types of hierarchical networks are identified: the weak nanofibril-nanofibril interaction case (i.e., silk fibroin hydrogels), and the strong nanofibril-nanofibril interaction case (i.e., silk fibers). The macroscopic properties, i.e., the rheological/mechanical properties, can be controlled in terms of tuning different levels of hierarchical network structures by ultrasonication-induced gelation, introducing the initial nucleation centers, etc. Such controls take effect by different mesoscale assembly pathways, which are found to occur via different routes of the nucleation and growth processes. Furthermore, the hierarchical network model of soft fibrous materials can be applied to explain the superior mechanical properties and the unique strain hardening behaviors of spider silk fibers within the framework of hierarchical breaking mechanism. Obviously, a knowledge of crystal networks will allow the prediction of the performance and engineering strategy of silk fibrous materials in generals. PMID- 25510896 TI - Hemoglobin Area and Time Index Above 90 g/L are Associated with Improved 6-Month Functional Outcomes in Patients with Severe Traumatic Brain Injury. AB - PURPOSE: There is conflicting data on the relationship between anemia and outcomes in patients with traumatic brain injuries (TBI). The objective of this study was to determine if the proportion of time and area under the hemoglobin time curve of >=90 g/L are independently associated with 6-month functional outcomes. METHODS: Retrospective cohort study of 116 patients with a severe TBI who underwent invasive neuromonitoring between June 2006 and December 2013. Hemoglobin area (HAI) and time (HTI) indices were calculated by dividing the total area, or time, under the hemoglobin-time curve at 90 g/L or above by the total duration of monitoring. Multivariable log-binomial regression was used to model the association between HAI or HTI and 6 month favorable neurologic outcome (Glasgow Outcome Score 4 or 5). RESULTS: Patients had a mean age of 38 years (SD 16) with a median admission Glasgow Coma Scale of 6 (IQR 4-7). There were 1523 hemoglobin measurements and 523 monitoring days. Patients had a hemoglobin >=90 g/L for a median of 70 % (IQR 37-100) of the time. Each 10 g/L increase in HAI (RR 1.23, 95 %CI 1.04-1.44, P = 0.011), and 10 % increase in HTI (1.10, 95 %CI 1.04-1.16, P < 0.001) were associated with improved neurologic outcome. Thirty one patients (27 %) received a transfusion with the median pre-transfusion hemoglobin being 81 g/L (IQR 76-87). CONCLUSIONS: In patients with severe TBI, increased area under the curve and percentage of time that the hemoglobin concentration was >=90 g/L, were associated with improved neurologic outcomes. PMID- 25510897 TI - Web-Based Assessment of Outcomes After Subarachnoid and Intracerebral Hemorrhage: A New Patient Centered Option for Outcomes Assessment. AB - BACKGROUND: Clinical outcomes are typically assessed by trained staff. We tested the hypothesis that outcomes reported by the patient or a caregiver on the web would be correlated with a validated interview. METHODS: We assessed surviving patients with intracerebral and subarachnoid hemorrhage at 1- , 3- , and 12-month follow-up with a validated interview for the modified Rankin Scale (mRS, a validated ordinal scale from 0, no symptoms to 5, severe disability). Health related quality of life (HRQoL) was assessed on the web with NIH Patient-Reported Outcomes Measurement Information System (PROMIS) and Neuro-QOL using computer adaptive testing by the patient, proxy reporting by a caregiver, or proxy entry by study staff. RESULTS: A coincident mRS and HRQoL assessment was available for 149 (71 %) of 209 patients at one, three, or 12 months. There were 89 assessments with proxy entry by study staff, 89 by the patient on the web, and 58 with proxy report by a caregiver on the web. PROMIS physical function assessments were completed in median of 4 questions, and T scores were associated with the mRS (P < 0.001), regardless of respondent. Mean T scores in every category of the mRS were different from every other category (P <= 0.003 for all). Results were similar for Neuro-QOL mobility. CONCLUSIONS: Web-based HRQoL assessment with NIH PROMIS and Neuro-QOL is feasible and correlated with a validated interview for the mRS. T scores distinguished between individual categories of the mRS, detecting modest differences in physical function and mobility HRQoL that are difficult to detect with the mRS. PROMIS and Neuro-QOL provide powerful and sensitive outcomes for potentially large cohorts. PMID- 25510898 TI - Ebola virus disease: implications for solid organ transplantation. PMID- 25510899 TI - The TLR2 agonist in polysaccharide-K is a structurally distinct lipid which acts synergistically with the protein-bound beta-glucan. AB - Protein-bound polysaccharide-K (Krestin; PSK) is a hot-water extract of Trametes versicolor with immune stimulatory activity. It has been used for the past 30 years and has demonstrated anti-tumor efficacy in multiple types of cancer. The ability of PSK to activate dendritic cells and T cells is dependent on its ability to stimulate Toll-like receptor 2 (TLR2), yet it remains unknown which structural component within PSK activates TLR2. The purpose of this study was to identify the TLR2 agonist within PSK and understand its role in the overall mechanism of PSK's immunogenic activity. TLR2 activity was eliminated by treatment with lipoprotein lipase but not by trypsin or lyticase. Rapid centrifugation of PSK can separate the fraction with TLR2 agonist activity from the soluble beta-glucan fraction. To study the potential interaction between the beta-glucan component and the lipid component, we labeled the soluble beta-glucan with fluorescein. Uptake of the labeled beta-glucan by J774A macrophages and JAWSII dendritic cells was inhibited by anti-Dectin-1 antibody but not by anti TLR2 antibody, confirming that Dectin-1 is the receptor for beta-glucan. Interestingly, pre-treatment of JAWSII cells with the TLR2-active lipid fraction significantly enhanced the uptake of the soluble beta-glucan, indicating the synergy between the TLR2 agonist component and the beta-glucan component. Altogether, these results present evidence that PSK has two active components-the well-characterized protein-bound beta-glucan and a previously unreported lipid which work synergistically via the Dectin-1 and TLR2 receptors. PMID- 25510900 TI - Calcitriol and its analogues enhance the antiproliferative activity of gefitinib in breast cancer cells. AB - Coexpression of EGFR and HER2 has been associated with poor disease outcome, high rates of metastasis and resistance to conventional treatments in breast cancer. Gefitinib, a tyrosine kinase inhibitor, reduces both cell proliferation and tumor growth of breast cancer cells expressing EGFR and/or HER2. On the other hand, calcitriol and some of its synthetic analogs are important antineoplastic agents in different breast cancer subtypes. Herein, we evaluated the effects of the combined treatment of gefitinib with calcitriol or its analogs on cell proliferation in breast cancer cells. The presence of EGFR, HER2 and vitamin D receptor were evaluated by Western blot in two established breast cancer cell lines: SUM-229PE, SKBR3 and a primary breast cancer-derived cell line. The antiproliferative effects of gefitinib alone or in combination with calcitriol and its analogs, calcipotriol and EB1089, were assessed by growth assay using a DNA content-based method. Inhibitory concentrations on cell proliferation were calculated by non-linear regression analysis using sigmoidal fitting of dose response curves. Pharmacological effects of the drug combinations were calculated by the Chou-Talalay method. Phosphorylation of ERK1/2 MAPK was evaluated by Western blot. Gene expression of EGFR, HER2 and BIM was assessed by real time PCR. BIM protein levels were analyzed in cells by flow cytometry. The effects of the drugs alone or combinated on cell cycle phases were determined using propidium iodide. Apoptosis was evaluated by detection of subG1 peak and determination of active caspase 3 by flow cytometry. Gefitinib, calcitriol, calcipotriol and EB1089 inhibited cell proliferation in a dose dependent manner. The combinations of gefitinib with calcitriol or its analogs were more effective to inhibit cell growth than each compound alone in all breast cancer cells studied. The gene expression of EGFR and HER2 was downregulated and not affected, respectively, by the combined treatment. Furthermore, phosphorylation of ERK 1/2 was inhibited a greater extent in co-treated cells than in the cells treated with alone compounds. The combination of gefitinib with calcitriol or their synthetic analogs induced apoptosis in SUM-229PE cells, this was shown by the significant upregulation of BIM protein levels, higher percentages of cells in subG1 peak and increase of caspase 3-positive cells. The combination of gefitinib with calcitriol or their synthetic analogs resulted in a greater antiproliferative effect than with either of the agents alone in EGFR and HER2 positive breast cancer cells. The mechanistic explanation for these results includes downregulation of MAPK signaling pathway, decrease of cells in G2/M phase and induction of apoptosis mediated by upregulation of BIM and activation of caspase 3. This article is part of a Special Issue entitled '17th Vitamin D Workshop'. PMID- 25510901 TI - Molecular underpinnings of Th17 immune-regulation and their implications in autoimmune diabetes. AB - The emergence of Th17 cells as a unique sub-population of CD4(+) T cells has revolutionized the current understanding of adaptive immune system and autoimmune diseases. Th17 cells are characterized by the expression of effector cytokines IL 17A, IL-17F, IL-21 and IL-22, and lineage specific transcription factor ROR-C in human and ROR-gammat in mice. Generation and differentiation of Th17 cells from naive CD4(+) T cells is driven by transforming growth factor (TGF)-beta, IL-6, IL 23, IL-1beta and IL-21. Recent studies suggest that the pathogenicity of Th17 cells is determined by the presence of IL-23 and TGF-beta3 in local micro environment. Emerging reports highlight the importance of T-helper cell plasticity in pathogenesis of various autoimmune diseases. Th17 cells exhibit significant plasticity and converted to Th1-like cells under pathogenic conditions. Albeit growing body of evidences stating a pathogenic role for Th17 cells in autoimmune diabetes, conflicting reports also state an indifferent or protective role for Th17 cells. The operating mechanisms modulating Th17 immune response in autoimmune diabetes remain elusive. This review discusses recent advances in the understanding of transcriptional and post-transcriptional mechanisms of Th17 polarization, factors influencing pathogenicity of Th17 cells, molecular mechanisms of Th17/Th1 and Treg/Th17 plasticity and implications of these phenomena in autoimmune diabetes. PMID- 25510902 TI - The choroid plexus and the paradox of interferons in the aging brain. AB - The choroid plexus (CP) function is largely viewed as the source of cerebrospinal fluid (CSF) and as a barrier between the blood and the CSF. Other functions of the CP are becoming increasingly recognized as in the recent publication by Baruch et. al. who demonstrate increased expression of interferon type I mRNA signature (irf7, ifnbeta and ifit1) in CP of aged brains compared to younger brains, whereas interferon type II dependent genes (icam1, cxcl10, and ccl17) are reduced in the aging CP. The authors speculate an IFN-dependent mechanism that plays a role in the aging process and cognitive decline. This short communication summarizes the findings by the authors and highlights the seemingly paradoxical roles of IFN type I and type II in neuroinflammation. PMID- 25510903 TI - Activin signalling and pre-eclampsia: from genetic risk to pre-symptomatic biomarker. AB - Pre-eclampsia is a multi-system condition in pregnancy that is characterised by the onset of hypertension and proteinuria in women after the 20th week and it remains a leading cause of maternal and fetal mortality. Despite this the causative molecular basis of pre-eclampsia remains poorly understood. As a result, an intensive research effort has focused on understanding the molecular mechanisms involved in pre-eclampsia and using this information to identify new pre-symptomatic bio-markers of the condition. Activin A and its receptor, ACVR2A, have been extensively studied in this regard. Activin A is a member of the transforming growth factor (TGF)-beta superfamily that has a wide range of biological functions depending on the cellular context. Recent work has shown that polymorphisms in ACVR2A may be a genetic risk factor for pre-eclampsia. Furthermore, both placenta and serum levels of Activin A are significantly increased in pre-eclampsia suggesting that Activin A may be a possible biomarker for the condition. Here we review the latest advances in this field and link these with new molecular data that suggest that the oxidative stress and pro inflammatory cytokine production seen in pre-eclampsia may result in increased placental Activin A secretion in an attempt to maintain placental function. PMID- 25510904 TI - Neurocognitive similarities between severe chronic schizophrenia and behavioural variant frontotemporal dementia. AB - This study focuses on a group of patients with chronic schizophrenia who have a more severe form of the disorder, as indicated by socio-functional decline, treatment resistance, and recurrent hospitalisation. Previous research has suggested that the pattern and severity of cognitive deficits in people with severe chronic schizophrenia is similar to that observed in behavioural variant frontotemporal dementia (bvFTD). In the current study, we compared neurocognitive performance in 16 cognitive domains in 7 inpatients with severe chronic schizophrenia, 13 community-dwelling outpatients with chronic schizophrenia, 12 patients with bvFTD, and 18 healthy controls. Our findings revealed more similar cognitive profiles between the schizophrenia inpatient and bvFTD groups compared to the schizophrenia outpatient group, who outperformed the former groups. The current results provide preliminary evidence for a distinct schizophrenia subgroup, distinguishable from other chronic schizophrenia patients by poorer clinical and functional status, who have levels of cognitive impairment comparable to those seen in bvFTD patients. PMID- 25510905 TI - Bullying behaviors among Chinese school-aged youth: a prevalence and correlates study in Guangdong Province. AB - Bullying among school-aged youth is a common issue worldwide and is increasingly being recognized as an important problem affecting both victims and perpetrators. Most of the bullying studies have been conducted in western countries, and their implications in other regions are limited due to different cultural contexts. The goal of our study is to identify the prevalence of bullying and its correlates school-aged youth in Guangdong province. In total, 1098 (7.1%) students reported having bullied other students, 744 (4.8%) students reported having been bullied by other students and 396 (2.6%) students reported having both bullied other students and been bullied by other students. There was a strong association between bullying others as well as being bullied and suicidal ideations, suicidal attempts, and self-harm behaviors. The prevalence of bullying and its associations with delinquent behaviors warrant the importance of school facility based preventive intervention taking into account both victims and perpetrators. PMID- 25510906 TI - Acute suicidal ideation in middle-aged adults from Brazil. Results from the baseline data of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - Suicidal ideation represents an important burden worldwide. However, little is known about it in low-/middle-income countries. We investigated this issue in a large cross-sectional of Brazilian civil servants (ELSA-Brasil, the Brazilian Health Longitudinal Study, n=15,105). Logistic univariate and multivariate analyses were performed to evaluate the strength of association (odds ratio, OR) between clinical and sociodemographic variables with acute life-weariness (tiredness of life) and suicidal thoughts. The presence of major depressive disorder (MDD), common mental disorders (CMDs), stressful life-events (SLEs) and poor self-perceived physical health was also collected. MDD and CMDs were strongly associated with suicidal ideation in univariate and multivariate analyses. For life-weariness thoughts, a modest, consistent association was found for female gender, being single, non-White ethnicity and poor education. SLEs and poor self-perceived physical health were also associated with suicidal ideation. Espiritism-Kardecism, but not other religions or Atheism/Agnosticism, was associated with lower rates of life-weariness and suicidal thoughts. To conclude, suicidal ideation does not differ in Brazil compared to developed countries, being primarily associated with psychiatric disorders and, to a lesser but significant extent, to social disadvantage, SLEs, poor self-perceived health and being single. PMID- 25510907 TI - Inhibitory control in people who self-injure: evidence for impairment and enhancement. AB - Self-injury is often motivated by the desire to reduce the intensity of negative affect. This suggests that people who self-injure may have difficulty suppressing negative emotions. We sought to determine whether self-injuring individuals exhibit impaired inhibitory control over behavioral expressions of negative emotions, when responding to images containing aversive emotional content. Self injuring participants and healthy controls completed a Stop Signal Task in which they were asked to judge the valence (positive or negative) of images. Three types of images depicted emotional content (neutral/positive/negative). A fourth type depicted self-cutting. An unpredictable "stop signal" occurred on some trials, indicating that participants should inhibit their responses to images presented on those trials. Compared to controls, self-injuring participants showed poorer inhibition to images depicting negative emotional content. Additionally, they showed enhanced inhibition to self-injury images. In fact, self-injuring participants showed comparable response inhibition to cutting images and positive images, whereas controls showed worse inhibition to cutting images compared to all other types of images. Consistent with the emotion regulation hypothesis of self-injury, people who self-injure showed impaired negative emotional response inhibition. Self-injuring individuals also demonstrated superior control over responses to stimuli related to self-injury, which may have important clinical implications. PMID- 25510909 TI - Anthropometric, metabolic and molecular determinants of human epidermal growth factor receptor 2 expression in luminal B breast cancer. AB - Genomic and trascriptomic profiling has recently contributed details to the characterization of luminal B breast cancer. We explored the contribution of anthropometric, metabolic, and molecular determinants to the multifaceted heterogeneity of this breast cancer subtype, with a specific focus on the association between body mass index (BMI), pre-treatment fasting glucose, hormone receptors, and expression of human epidermal growth factor receptor 2 (HER2). Extensively annotated specimens were obtained from 154 women with luminal B breast cancer diagnosed at two Italian comprehensive cancer centres. Participants' characteristics were descriptively analyzed overall and by HER2 status (positive vs. negative). BMI (<25 vs >=25), pre-treatment fasting glucose (=94) and percentage of hormone receptors were tested for association with HER2 expression in regression models. In univariate models, BMI, fasting glucose and, at a lesser extent, percentage of estrogen receptors (ER) were significantly and inversely associated with HER2 expression (OR: 0.32, 95% CI: 0.16-0.66; 0.43, 0.23-0.82; 0.96, 0.94-0.97, respectively). The multivariate models confirmed the protective role of BMI and ER on HER2 expression, with luminal B HER2 positive patients being significantly less frequent among women within the highest category of BMI and percentage expression of ER compared with their counterparts (OR: 0.22, 95% CI: 0.09-0.53; 0.95, 0.93 0.97). In conclusions, BMI and percentage of ER representation are inversely associated with HER2 expression in luminal B breast cancers. Upon confirmatory findings, this might help identify patient subgroups who may best benefit from the use of interventions targeting insulin resistance in well depicted breast cancer scenarios. PMID- 25510910 TI - Reciprocal modulation of histone deacetylase inhibitors sodium butyrate and trichostatin A on the energy metabolism of breast cancer cells. AB - Tumor cells display different bioenergetic profiles when compared to normal cells. In the present work we showed metabolic reprogramming by means of inhibitors of histone deacetylase (HDACis), sodium butyrate and trichostatin A in breast cancer cells representing different stages of aggressiveness and metabolic profile. When testing the effect of NaB and TSA on viability of cells, it was shown that non-tumorigenic MCF-10A cells were less affected by increasing doses of the drugs than the tumorigenic, hormone dependent, tightly cohesive MCF-7, T 47D and the highly metastatic triple-negative MDA-MB 231 cells. T-47D cells were the most sensitive to treatment with both, NaB and TSA. Experiments measuring anchorage- independent growth of tumor cells showed that MCF-7, T-47D, and MDA-MB 231 cells were equally sensitive to the treatment with NaB. The NaB induced an attenuation of glycolysis, reflected by a decrease in lactate release in MCF-7 and T47D lines. Pyruvate kinase activity was significantly enhanced by NaB in MDA MB-231 cells only. In contrast, the inhibitor enhanced lactate dehydrogenase activity specifically in T-47 D cells. Glucose-6-phosphate dehydrogenase activity was shown to be differentially modulated by NaB in the cell lines investigated: the enzyme was inhibited in MCF-7 cells, whereas in T-47D and MDA-MB-231 cells, G6PDH was activated. NaB and TSA were able to significantly increase the oxygen consumption by MDA-MB-231 and T-47D cells. Collectively the results show that epigenetic changes associated to acetylation of proteins in general affect the energy metabolism in all cancer cell lines and that mitochondria may occupy a central role in metastasis. PMID- 25510908 TI - Estrogen receptor alpha deficiency protects against development of cognitive impairment in murine lupus. AB - BACKGROUND: One of the more profound features of systemic lupus erythematosus (SLE) is that females have a 9:1 prevalence of this disease over males. Up to 80% of SLE patients have cognitive defects or affective disorders. The mechanism of CNS injury responsible for cognitive impairment is unknown. We previously showed that ERalpha deficiency significantly reduced renal disease and increased survival in lupus-prone mice. We hypothesized that ERalpha deficiency would be similarly protective in the brain, and that ERalpha may play a role in modulating blood-brain barrier (BBB) integrity and/or neuroinflammation in lupus-prone mice. METHODS: MRL/lpr ERalpha+/+ and ERalphaKO mice (n = 46) were ovariectomized, received 17beta-estradiol pellets, and underwent radial arm water maze (WRAM) and novel object recognition (NOR) testing starting at eight weeks of age. Mice were sacrificed and brains were hemisected and processed for either immunohistochemistry, or hippocampus and parietal cortex dissection for Western blotting. RESULTS: MRL/lpr ERalphaKO mice (n = 21) performed significantly better in WRAM testing than wild-type MRL/lpr mice (n = 25). There was a significant reduction in reference memory errors (P <0.007), working memory errors (P <0.05), and start arm errors (P <0.02) in ERalphaKO mice. There were significant differences in NOR testing, particularly total exploration time, with ERalpha deficiency normalizing behavior. No significant differences were seen in markers of tight junction, astrogliosis, or microgliosis in the hippocampus or cortex by Western blot, however, there was a significant reduction in numbers of Iba1+ activated microglia in the hippocampus of ERalphaKO mice, as evidenced by immunohistochemietry (IHC). CONCLUSION: ERalpha deficiency provides significant protection against cognitive deficits in MRL/lpr mice as early as eight weeks of age. Additionally, the significant reduction in Iba1+ activated microglia in the MRL/lpr ERalphaKO mice was consistent with reduced inflammation, and may represent a biological mechanism for the cognitive improvement observed. PMID- 25510911 TI - Prevalence and risk factors of superior segmental optic hypoplasia in a Korean population: the Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: This study investigated the prevalence and risk factors for superior segmental optic hypoplasia (SSOH) in a Korean population based on the data from the nationwide Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: We performed a retrospective review of the KNHANES dataset covering January 2012 to December 2012. The study population comprised 5,612 subjects (>=19 years of age) who had participated in a medical interview covering demographic and systemic information, been issued a questionnaire regarding associated SSOH risk factors including gender, age, systemic disease, and family history, and had undergone an ophthalmologic examination. Two masked readers evaluated fundus photography, paying special attention to the presence of SSOH. Associations of risk factors (identified in the medical interview portion) with SSOH prevalence were investigated using multivariate logistic regression analysis. RESULTS: SSOH was detected in 16 eyes of 14 subjects, or 0.24% of the 5,612 subjects. All 16 eyes showed a corresponding visual-field defect. In multivariate logistic regression analyses, maternal history of diabetes (Odds ratio (OR), 7.666; 95% Confidence interval (CI), 2.601 ~ 22.593, p < 0.001) and paternal history of ischemic heart disease (IHD) (OR, 11.105; CI, 3.361 ~ 36.686, p < 0.001) were associated with increased risk of SSOH. CONCLUSIONS: This study provides the first representative population-based data on SSOH prevalence in Korea. Additionally, multivariate analyses revealed that a history of maternal diabetes and paternal IHD was the most important factor influencing the prevalence of SSOH. PMID- 25510915 TI - Management of malignant pleural effusion. PMID- 25510912 TI - HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice. AB - Mutant ataxin-1 (Atxn1), which causes spinocerebellar ataxia type 1 (SCA1), binds to and impairs the function of high-mobility group box 1 (HMGB1), a crucial nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. In this study, we established that transgenic or virus vector-mediated complementation with HMGB1 ameliorates motor dysfunction and prolongs lifespan in mutant Atxn1 knock-in (Atxn1-KI) mice. We identified mitochondrial DNA damage repair by HMGB1 as a novel molecular basis for this effect, in addition to the mechanisms already associated with HMGB1 function, such as nuclear DNA damage repair and nuclear transcription. The dysfunction and the improvement of mitochondrial DNA damage repair functions are tightly associated with the exacerbation and rescue, respectively, of symptoms, supporting the involvement of mitochondrial DNA quality control by HMGB1 in SCA1 pathology. Moreover, we show that the rescue of Purkinje cell dendrites and dendritic spines by HMGB1 could be downstream effects. Although extracellular HMGB1 triggers inflammation mediated by Toll-like receptor and receptor for advanced glycation end products, upregulation of intracellular HMGB1 does not induce such side effects. Thus, viral delivery of HMGB1 is a candidate approach by which to modify the disease progression of SCA1 even after the onset. PMID- 25510917 TI - Transcaval access for TAVR across a polyester aortic graft. AB - Transcaval access to the aorta allows transcatheter aortic valve replacement in patients without other good access options. The resulting aorto-caval fistula is closed with a nitinol cardiac occluder device. There is no experience traversing a synthetic aortic graft to perform transcaval access and closure. We describe a patient who underwent successful traversal of a polyester aortic graft using radiofrequency energy applied from the tip of a guidewire, to allow retrograde transcatheter aortic valve replacement from a femoral vein, along with details of our technique. The patient did well and was discharged home after 3 days. There was residual aorto-caval fistulous flow immediately after implantation of a polyester-seeded nitinol muscular ventricular septal defect occluder device, but this fistula spontaneously occluded within one month. PMID- 25510918 TI - The diverse oncogenic and tumour suppressor roles of p63 and p73 in cancer: a review by cancer site. AB - p63 and p73, the two other members of the p53 family, were identified almost 15 years ago. Here, we review their potential use for diagnosis, prognosis and prediction of response to therapy in various cancers. The two genes show distinct expression patterns in both normal and cancer tissues and each gene gives rise to multiple protein isoforms with different activities, including those with tumour suppressor or oncogenic effects. Despite such complexity, some common themes emerge; p63 is commonly overexpressed as the DeltaNp63 isoform and sometimes associated with TP63 amplification, whereas p73 is often reduced (by methylation or gene loss), or there is an increase in the ratio of DeltaNp73 to TAp73. These generalisations do not apply universally; TAp63 is overexpressed in haematological malignancies, TP63 mis-sense mutations have been reported in squamous cancers and TP63 translocations occur in lymphomas and some lung adenocarcinomas. There are associations with disease prognosis and response to specific therapies in individual cancer types for both p63 and p73, making their analysis of clinical relevance. We also discuss their utility for aiding in differential diagnosis, which has been demonstrated for p63, but not yet for p73. Throughout, we highlight the discrepant nature of many studies due to the variable methodologies employed, the lack of systematic evaluation of isoforms and the problems of poor antibody characterization and cross-reactions within the p63/p73 family. Finally, we emphasize the value of recently developed isoform specific reagents that have clear advantages for the study of p63 and p73 experimentally and clinically. PMID- 25510919 TI - Diagnosis of fetal submicroscopic chromosomal abnormalities in failed array CGH samples: copy number by sequencing as an alternative to microarrays for invasive fetal testing. AB - OBJECTIVES: Array comparative genomic hybridization (CGH) has become the technology of choice for high-resolution prenatal whole genome analysis. Limitations of microarrays are mainly related to the analog nature of the analysis, and poor-quality DNA can result in failed quality metrics with these platforms. We examined a cohort of abnormal fetuses with failed array CGH results using a next-generation sequencing algorithm, CNV-Seq. We assessed the ability of the platform to handle suboptimal prenatal samples and generate interpretable molecular karyotypes. METHODS: Nine samples obtained from abnormal fetuses and one from a normal control fetus were sequenced using an Illumina GAIIx. A segmentation algorithm for sequencing data was used to determine regional copy number data on the sequencing datasets. RESULTS: Phred quality scores were satisfactory for analysis of all samples. CNV-Seq identified both large- and small-scale abnormalities in the cohort, and normal results were obtained for fetuses for which microarray data were previously uninterpretable. No variants of uncertain significance were detected. Analysis of the digital sequencing datasets offered some advantages over array CGH output. CONCLUSIONS: Using next-generation sequencing for the detection of genomic copy number variants may be advantageous for poor-quality, invasively-acquired prenatal samples. CNV-Seq could become a potential alternative to array CGH in this setting. PMID- 25510920 TI - Retinal nerve fibre layer thickness measurements after successful retinal detachment repair with silicone oil endotamponade. AB - AIMS: To measure peripapillary retinal nerve fibre layer thickness (RNFL) by using spectral domain optical coherence tomography (OCT) in patients who underwent successful retinal detachment repair with silicone oil tamponade. METHODS: Sixty patients treated with pars plana vitrectomy and silicone oil tamponade for retinal detachment were prospectively enrolled in a study. Peripapillary RNFL thickness was measured with a Cirrus HD-OCT at 7, 30, 90 and 180 days postoperatively, using an Optic Disc Cube 200*200 protocol. The fellow eye of each study patient served as a control. Median peripapillary RNFL thickness in silicone oil filled eyes was compared with control eyes. RESULTS: The median RNFL thickness in the group of vitrectomised eyes was significantly higher compared with control eyes at every visit. The analysis of variance showed that the median thickness in vitrectomised eyes differed between visits (F=4,3023; p=0.006). There was no time-related trend for RNFL thickness in this group. The analysis of variance of RNFL thickness in the fellow, unoperated eyes showed no difference between visits (F=2,3426; p=0.075). CONCLUSIONS: In patients with silicone oil tamponade, peripapillary RNFL was significantly thicker in comparison with fellow unoperated eyes over a 6-month period. TRIAL REGISTRATION NUMBER: NCT 01255306. PMID- 25510921 TI - Mesenchymal stem cell-mediated suppression of hypertrophic scarring is p53 dependent in a rabbit ear model. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) are considered to play important roles in wound repair and tissue remodeling. Hypertrophic scar (HTS) is a cutaneous condition characterized by deposits of excessive amount of collagen after an acute skin injury. However, currently there is little knowledge about the direct relationship between MSCs and HTS. METHODS: The hypertrophic scar model was established on rabbit ears. MSCs were isolated from rabbit femur bone marrow and transplanted through ear artery injection. Hypertrophic scar formation was examined using frozen-section analysis, hematoxylin and eosin (HE) staining, Masson's trichrome staining, and scar elevation index. The role of p53 in the MSCs-mediated anti-scarring effect was examined by gene knockdown using p53 shRNA. RESULTS: In this study, MSCs engraftment through ear artery injection significantly inhibited the hypertrophic scarring in a rabbit ear hypertrophic scar model, while this anti-scarring function could be abrogated by p53 gene knockdown in MSCs. Additionally, we found that MSCs down-regulated the expression of TGF-beta receptor I (TbetaRI) and alpha-smooth muscle actin (alpha-SMA) at both mRNA and protein levels in a paracrine manner, and this down-regulation was rescued by p53 gene knockdown. Moreover, our results showed that MSCs with p53 gene knockdown promoted the proliferation of fibroblasts through increasing nitric oxide (NO) production. CONCLUSIONS: These results suggest that MSCs inhibit the formation of HTS in a p53 dependent manner through at least two mechanisms: inhibition of the transformation of HTS fibroblast to myofibroblast; and inhibition of the proliferation of fibroblasts through inhibition of NO production. PMID- 25510922 TI - Enhancing brain-machine interface (BMI) control of a hand exoskeleton using electrooculography (EOG). AB - BACKGROUND: Brain-machine interfaces (BMIs) allow direct translation of electric, magnetic or metabolic brain signals into control commands of external devices such as robots, prostheses or exoskeletons. However, non-stationarity of brain signals and susceptibility to biological or environmental artifacts impede reliable control and safety of BMIs, particularly in daily life environments. Here we introduce and tested a novel hybrid brain-neural computer interaction (BNCI) system fusing electroencephalography (EEG) and electrooculography (EOG) to enhance reliability and safety of continuous hand exoskeleton-driven grasping motions. FINDINGS: 12 healthy volunteers (8 male, mean age 28.1 +/- 3.63y) used EEG (condition #1) and hybrid EEG/EOG (condition #2) signals to control a hand exoskeleton. Motor imagery-related brain activity was translated into exoskeleton driven hand closing motions. Unintended motions could be interrupted by eye movement-related EOG signals. In order to evaluate BNCI control and safety, participants were instructed to follow a visual cue indicating either to move or not to move the hand exoskeleton in a random order. Movements exceeding 25% of a full grasping motion when the device was not supposed to be moved were defined as safety violation. While participants reached comparable control under both conditions, safety was frequently violated under condition #1 (EEG), but not under condition #2 (EEG/EOG). CONCLUSION: EEG/EOG biosignal fusion can substantially enhance safety of assistive BNCI systems improving their applicability in daily life environments. PMID- 25510923 TI - Buried treasure: Unlocking the secrets of medicinal mushrooms. AB - In this issue of the Biomedical Journal, we investigate the potential of plants and fungi as a source of beneficial molecules for human health. We explore the weird and wonderful world of the mushroom and examine how Western medicine still has a lot to learn from Eastern practices dating back thousands of years. We also discuss a study further supporting claims that flaxseed, the plant kingdom's richest source of omega-3 fatty acids, can have lipid-lowering and fat-busting properties in the right physiological context. Finally, this issue also includes several validation studies of medical procedures or devices that define optimal conditions for their use in Asian populations. PMID- 25510924 TI - Mushrooms - From cuisine to clinic. PMID- 25510925 TI - Surface topography and ultrastructural architecture of the tegument of adult Carmyerius spatiosus Brandes, 1898. AB - Adult Carmyerius spatiosus or stomach fluke has an elongate, cylindrical-shaped, straight to slightly curved body, with conical anterior end and truncated posterior end. The worm measures about 8.7-11.2mm in body length and 2.3-3.0mm in body width across the mid-section. When observed by SEM, the tegumental surface in all part of the body appears highly corrugated with ridges and furrows, and having no spines. The ventral surface has more complex corrugation than those of the dorsal surface. Both anterior and posterior suckers have thick edges covered with transverse folds and appear spineless. The genital pore is located at the anterior part of the body. There are two types of sensory papillae on the surface: type 1 is bulbous in shape with nipple-like tips; type 2 has a similar shape with short cilia on the tip. The dorsal surface exhibits similar surface features, but papillae appear less numerous and are smaller. When observed by TEM, the tegument is divided into four layers. The first layer includes the ridges and furrows which are covered by a trilaminate membrane underlined by a dense lamina and coated externally with the glycocalyx. The second layer of the tegument is a narrow region of cytoplasm that contains high concentrations of ovoid electron lucent tegumental granules (TG1), and disc-shaped electron dense tegumental granules (TG2) as well as lysosomes. TG1 close to the surface invariably exocytose their content into bottoms of the ridges, while some TG2 are fused and have their membrane joined up with the surface membrane. The third layer is the widest middle area of the tegument which contains numerous and evenly distributed mitochondria. Both TG1 and TG2 granules are present but in much fewer number than in the first and second layers. The fourth layer is the innermost zone that rests on and couples with a thick basal lamina. The cytoplasm in this layer is loosely packed and contains numerous infoldings of the basal plasma membrane with closely associated mitochondria. It also contains fairly large numbers of TG1 and TG2 granules which are produced and transported to the tegument by one type of tegumental cells lying in rows underneath the muscular layers. PMID- 25510927 TI - Analysis of metabolic changes in plant pathosystems by imprint imaging DESI-MS. AB - The response of plants to microbial pathogens is based on the production of secondary metabolites. The complexity of plant-pathogen interactions makes their understanding a challenging task for metabolomic studies requiring powerful analytical approaches. In this paper, the ability of ambient mass spectrometry to provide a snapshot of plant metabolic response to pathogen invasion was tested. The fluctuations of glycoalkaloids present in sprouted potatoes infected by the phytopathogen Pythium ultimum were monitored by imprint imaging desorption electrospray ionization mass spectrometry (DESI-MS). After 8 d from the inoculation, a decrease of the relative abundance of potato glycoalkaloids alpha solanine (m/z 706) and alpha-chaconine (m/z 722) was observed, whereas the relative intensity of solanidine (m/z 398), solasodenone (m/z 412), solanaviol (m/z 430), solasodiene (m/z 396), solaspiralidine (m/z 428), gamma-solanine/gamma chaconine (m/z 560) , beta-solanine (m/z 706), and beta-chaconine (m/z 722) increased. The progression of the disease, expressed by the development of brown necrotic lesions on the potato, led to the further decrease of all the glycoalkaloid metabolites. Therefore, the applicability of imprint imaging DESI MS in studying the plant metabolic changes in a simple pathosystem was demonstrated with minimal sample preparation. PMID- 25510926 TI - Cognitive Enhancement Therapy in substance misusing schizophrenia: results of an 18-month feasibility trial. AB - Substance use is a frequent problem in schizophrenia, and although many substance misusing patients with the disorder also experience considerable cognitive impairments, such individuals have been routinely excluded from clinical trials of cognitive remediation that could support their functional and addiction recoveries. This study conducted a small-scale feasibility trial of Cognitive Enhancement Therapy (CET) in substance misusing schizophrenia patients to assess the feasibility and efficacy of implementing comprehensive neurocognitive and social-cognitive remediation in this population. A total of 31 schizophrenia outpatients meeting addiction severity criteria for alcohol and/or cannabis use were randomized to 18months of CET or usual care. Feasibility findings indicated high degrees of satisfaction with CET, but also presented significant challenges in the recruitment and retention of substance misusing patients, with high levels of attrition (50%) over the study period, primarily due to positive symptom exacerbation. Intent-to-treat efficacy analyses showed large and significant improvements in neurocognition (d=.86), social cognition (d=1.13), and social adjustment (d=.92) favoring CET. Further, individuals treated with CET were more likely to reduce alcohol use (67% in CET vs. 25% in usual care) during treatment (p=.021). These results suggest that once engaged and stabilized, CET is a feasible and potentially effective treatment for cognitive impairments in patients with schizophrenia who misuse alcohol and/or cannabis. Substance misusing patients who are able to engage in treatment may be able to benefit from cognitive remediation, and the treatment of cognitive impairments may help improve substance use outcomes among this underserved population. PMID- 25510928 TI - An ESI-MS method to determine yield and enantioselectivity in a single assay. AB - A mass spectrometry assay is presented here that allows for the simultaneous determination of yield and enantioselectivity in a single analysis. The assay makes use of molecules that are structurally similar to the analytes of interest as standards. The assay predicts the yields of the reactions reasonably well and with little error. For example, in the pig liver esterase catalyzed hydrolysis of one prochiral malonate, the yield predicted by the assay was 72%, while larger scale isolated reaction yields were within 5% of this value. This assay provides a fast method to determine yield and enantioselectivity in one analysis. The strengths and limitations of this method are discussed. PMID- 25510929 TI - Analysis of silicones released from household items and baby articles by direct analysis in real time-mass spectrometry. AB - Direct analysis in real time-mass spectrometry (DART-MS) enables screening of articles of daily use made of polydimethylsiloxanes (PDMS), commonly known as silicone rubber, to assess their tendency to release low molecular weight silicone oligomers. DART-MS analyses were performed on a Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer. Flexible silicone baking molds, a watch band, and a dough scraper, as baby articles different brands of pacifiers, nipples, and a teething ring have been examined. While somewhat arbitrarily chosen, the set can be regarded as representative of household items, baby articles, and other objects made of silicone rubber. For comparison, two brands of silicone septa and as blanks a glass slide and a latex pacifier were included. Differences between the objects were mainly observed in terms of molecular weight distribution and occasional release of other compounds in addition to PDMS. Other than that, all objects made of silicone rubber released significant amounts of PDMS during DART analysis. To provide a coarse quantification, a calibration based on silicone oil was established, which delivered PDMS losses from 20 MUg to >100 MUg during the 16-s period per measurement. Also, the extraction of baking molds in rapeseed oil demonstrated a PDMS release at the level of 1 MUg mg(-1). These findings indicate a potential health hazard from frequent or long-term use of such items. This work does not intend to blame certain brands of such articles. Nonetheless, a higher level of awareness of this source of daily silicone intake is suggested. PMID- 25510930 TI - Development of multi-membrane near-infrared diode mass spectrometer for field analysis of aromatic hydrocarbons. AB - Membrane Inlet Mass Spectrometry (MIMS) is a technique that incorporates a semi permeable membrane selective for differing organic molecules and chemistries. This eliminates the need for time-consuming sample preparation and facilitates near instantaneous analysis. This study will examine how the front end of MIMS incorporates three dual inlet ports, allowing for differing MIMS materials and selectivity for specific environments. Polydimethylsiloxane (PDMS) membranes have proven to be selective of benzene, toluene, and xylene (BTX) as well as aromatic hydrocarbons that are common in petroleum products while remaining selective against the aliphatic chains. PDMS has proven to be a successful choice of membrane with high permeability in atmospheric environments. In addition, polycyclic aromatic hydrocarbons (PAHs) such as acenaphthene, acenapthylene, naphthalene, and fluorene have recently been detected to the 5 ppb level in a nitrogen atmosphere with our current configuration. This preliminary work provides proof of concept using near-infrared laser diodes that act upon the membrane to increase its permeability and provide higher sensitivity of aromatic samples. PMID- 25510933 TI - Two-dimensional aperture coding for magnetic sector mass spectrometry. AB - In mass spectrometer design, there has been a historic belief that there exists a fundamental trade-off between instrument size, throughput, and resolution. When miniaturizing a traditional system, performance loss in either resolution or throughput would be expected. However, in optical spectroscopy, both one dimensional (1D) and two-dimensional (2D) aperture coding have been used for many years to break a similar trade-off. To provide a viable path to miniaturization for harsh environment field applications, we are investigating similar concepts in sector mass spectrometry. Recently, we demonstrated the viability of 1D aperture coding and here we provide a first investigation of 2D coding. In coded optical spectroscopy, 2D coding is preferred because of increased measurement diversity for improved conditioning and robustness of the result. To investigate its viability in mass spectrometry, analytes of argon, acetone, and ethanol were detected using a custom 90-degree magnetic sector mass spectrometer incorporating 2D coded apertures. We developed a mathematical forward model and reconstruction algorithm to successfully reconstruct the mass spectra from the 2D spatially coded ion positions. This 2D coding enabled a 3.5* throughput increase with minimal decrease in resolution. Several challenges were overcome in the mass spectrometer design to enable this coding, including the need for large uniform ion flux, a wide gap magnetic sector that maintains field uniformity, and a high resolution 2D detection system for ion imaging. Furthermore, micro-fabricated 2D coded apertures incorporating support structures were developed to provide a viable design that allowed ion transmission through the open elements of the code. PMID- 25510931 TI - Ion mobility spectrometry-hydrogen deuterium exchange mass spectrometry of anions: part 1. Peptides to proteins. AB - Ion mobility spectrometry (IMS) coupled with hydrogen deuterium exchange (HDX) mass spectrometry (MS) has been used to study the conformations of negatively charged peptide and protein ions. Results are presented for ion conformers of angiotensin 1, a synthetic peptide (SP), bovine insulin, ubiquitin, and equine cytochrome c. In general, the SP ion conformers demonstrate a greater level of HDX efficiency as a greater proportion of the sites undergo HDX. Additionally, these ions exhibit the fastest rates of exchange. Comparatively, the angiotensin 1 ions exhibit a lower rate of exchange and HDX level presumably because of decreased accessibility of exchange sites by charge sites. The latter are likely confined to the peptide termini. Insulin ions show dramatically reduced HDX levels and exchange rates, which can be attributed to decreased conformational flexibility resulting from the disulfide bonds. For the larger ubiquitin and protein ions, increased HDX is observed for larger ions of higher charge state. For ubiquitin, a conformational transition from compact to more elongated species (from lower to higher charge states) is reflected by an increase in HDX levels. These results can be explained by a combination of interior site protection by compact conformers as well as decreased access by charge sites. The elongated cytochrome c ions provide the largest HDX levels where higher values correlate with charge state. These results are consistent with increased exchange site accessibility by additional charge sites. The data from these enhanced IMS-HDX experiments are described in terms of charge site location, conformer rigidity, and interior site protection. PMID- 25510935 TI - Does the Edinburgh Postnatal Depression Scale measure the same constructs across time? AB - The Edinburgh Postnatal Depression Scale is the most widely used measure for screening for depression in perinatal populations. A weakness is that the factor structure of the scale is inconsistent across studies. It is unclear the degree to which this inconsistency results from variability arising from the Edinburgh Postnatal Depression Scale (EPDS). The present study aimed to determine whether the EPDS factor structure remained stable in the same individuals reporting on their levels of distress across two testing occasions. Data were analysed for 636 postpartum inpatient females who were administered the EPDS at admission and discharge from a psychiatric mother and baby unit. Exploratory factor analyses (EFAs) and confirmatory factor analyses (CFAs) were conducted separately on the admission and discharge data to determine the optimal factor structure at each time point. The EFAs and CFAs supported a two-factor model at admission and a three-factor model at discharge. Given that the EPDS did not demonstrate an invariant number of factors, no further tests of measurement invariance were conducted. The EPDS does not appear to be invariant from admission to discharge. These findings suggest that individuals may respond differently to items depending on their level of distress. Potential implications for the EPDS in terms of comparability of scores across groups/time and its screening abilities are discussed. PMID- 25510934 TI - Mass spectrometry in the home and garden. AB - Identification of active components in a variety of chemical products used directly by consumers is described at both trace and bulk levels using mass spectrometry. The combination of external ambient ionization with a portable mass spectrometer capable of tandem mass spectrometry provides high chemical specificity and sensitivity as well as allowing on-site monitoring. These experiments were done using a custom-built portable ion trap mass spectrometer in combination with the ambient ionization methods of paper spray, leaf spray, and low temperature plasma ionization. Bactericides, garden chemicals, air fresheners, and other products were examined. Herbicide applied to suburban lawns was detected in situ on single leaves 5 d after application. PMID- 25510932 TI - Molecular basis for structural heterogeneity of an intrinsically disordered protein bound to a partner by combined ESI-IM-MS and modeling. AB - Intrinsically disordered proteins (IDPs) form biologically active complexes that can retain a high degree of conformational disorder, escaping structural characterization by conventional approaches. An example is offered by the complex between the intrinsically disordered N(TAIL) domain and the phosphoprotein X domain (P(XD)) from measles virus (MeV). Here, distinct conformers of the complex are detected by electrospray ionization-mass spectrometry (ESI-MS) and ion mobility (IM) techniques yielding estimates for the solvent-accessible surface area (SASA) in solution and the average collision cross-section (CCS) in the gas phase. Computational modeling of the complex in solution, based on experimental constraints, provides atomic-resolution structural models featuring different levels of compactness. The resulting models indicate high structural heterogeneity. The intermolecular interactions are predominantly hydrophobic, not only in the ordered core of the complex, but also in the dynamic, disordered regions. Electrostatic interactions become involved in the more compact states. This system represents an illustrative example of a hydrophobic complex that could be directly detected in the gas phase by native mass spectrometry. This work represents the first attempt to modeling the entire N(TAIL) domain bound to P(XD) at atomic resolution. PMID- 25510936 TI - Predictors of dizziness in older persons: a 10-year prospective cohort study in the community. AB - BACKGROUND: The current diagnosis-oriented approach of dizziness does not suit older patients. Often, it is difficult to identify a single underlying cause, and when a diagnosis is made, therapeutic options may be limited. Identification of predictors of dizziness may provide new leads for the management of dizziness in older patients. The aim of the present study was to investigate long-term predictors of regular dizziness in older persons. METHODS: Population-based cohort study of 1,379 community-dwelling participants, aged >=60 years, from the Longitudinal Aging Study Amsterdam (LASA). Regular dizziness was ascertained during face-to-face medical interviews during 7- and 10-year follow-up. We investigated 26 predictors at baseline from six domains: socio-demographic, medical history, medication, psychological, sensory, and balance/gait. We performed multivariate logistic regression analyses with presence of regular dizziness at 7- and 10-year follow-up as dependent variables. We assessed the performance of the models by calculating calibration and discrimination. RESULTS: Predictors of regular dizziness at 7-year follow-up were living alone, history of dizziness, history of osteo/rheumatoid arthritis, use of nitrates, presence of anxiety or depression, impaired vision, and impaired function of lower extremities. Predictors of regular dizziness at 10-year follow-up were history of dizziness and impaired function of lower extremities. Both models showed good calibration (Hosmer-Lemeshow P value of 0.36 and 0.31, respectively) and acceptable discrimination (adjusted AUC after bootstrapping of 0.77 and 0.71). CONCLUSIONS: Dizziness in older age was predicted by multiple factors. A multifactorial approach, targeting potentially modifiable predictors (e.g., physical exercise for impaired function of lower extremities), may add to the current diagnosis-oriented approach. PMID- 25510938 TI - Ensuring quality in genomic medicine: amid the rise in complex laboratory developed tests, regulatory officials are seeking the right balance on quality assurance. PMID- 25510940 TI - Immunologic and inflammatory aspects of epilepsy. Introduction. PMID- 25510937 TI - Hippocampal cannabinoid transmission modulates dopamine neuron activity: impact on rewarding memory formation and social interaction. AB - Disturbances in cannabinoid type 1 receptor (CB1R) signaling have been linked to emotional and cognitive deficits characterizing neuropsychiatric disorders, including schizophrenia. Thus, there is growing interest in characterizing the relationship between cannabinoid transmission, emotional processing, and dopamine (DA)-dependent behavioral deficits. The CB1R is highly expressed in the mammalian nervous system, particularly in the hippocampus. Activation of the ventral hippocampal subregion (vHipp) is known to increase both the activity of DAergic neurons located in the ventral tegmental area (VTA) and DA levels in reward related brain regions, particularly the nucleus accumbens (NAc). However, the possible functional relationship between hippocampal CB1R transmission and VTA DA neuronal activity is not currently understood. In this study, using in vivo neuronal recordings in rats, we demonstrate that activation of CB1R in the vHipp strongly increases VTA DA neuronal firing and bursting activity, while simultaneously decreasing the activity of VTA non-DA neurons. Furthermore, using a conditioned place preference procedure and a social interaction test, we report that intra-vHipp CB1R activation potentiates the reward salience of normally sub threshold conditioning doses of opiates and induces deficits in natural sociability and social recognition behaviors. Finally, these behavioral effects were prevented by directly blocking NAc DAergic transmission. Collectively, these findings identify hippocampal CB1R transmission as a critical modulator of the mesolimbic DA pathway and in the processing of reward and social-related behavioral phenomena. PMID- 25510941 TI - Experimental studies in epilepsy: immunologic and inflammatory mechanisms. AB - In this article, we review the literature based on experimental studies lending credence to a relationship between epilepsy and immune-mediated mechanisms linked to central nervous system innate immunity. The brain innate immunity responses to neuronal injury or excessive neuronal activity are mediated by resident microglia and astroglia, but also neurons play an immunomodulatory role. Antigens or antibodies applied to the brain trigger an epileptogenic and inflammatory response. Furthermore, seizure activity and status epilepticus elicit the production and release of proinflammatory cytokines and chemokines. The immune pathogenesis of epilepsy involves complex cell-to-cell interactions including a cross talk between astrocytes and neurons, between astrocytes and brain microvascular endothelial cells, as well as reciprocal leukocyte-endothelial interactions in the context of disruption of the blood-brain barrier. There is a large body of literature from experimental studies showing that seizures can initiate a cascade of innate and adaptive immune responses from various cellular sources and perpetuate neuroinflammation through mechanisms involving transcription of inflammatory genes or posttranslational changes in cytokine release machinery. These inflammatory processes could also possibly contribute to the pathogenesis of comorbidities often associated with epilepsy. This opens exciting possibilities for the development of disease-modifying drugs aimed at mitigating neuroinflammation as a means of ameliorating epileptogenesis and lessening or preventing postictal brain injury. PMID- 25510943 TI - Generalized epilepsies: immunologic and inflammatory mechanisms. AB - This article focuses on the inflammatory processes in patients with generalized epilepsies. We specifically review the data regarding West, Lennox-Gastaut, and Landau-Kleffner syndromes as they have generalized clinical or electroencephalogram features. There is substantial evidence for a pathogenic implication of immune mechanisms in these epilepsies. Animal models and abnormalities in both cellular and humoral immunity support this hypothesis. They also appear to be particularly responsive to immunomodulatory therapies, which has raised the speculation that an unbalanced immune system may play an important role in the pathophysiology of these epileptic syndromes. In this article, we discuss clinical and experimental data that support the potential implication of immune mediated inflammation and immune response in the mechanism of these entities. PMID- 25510942 TI - Focal epilepsies: immunologic and inflammatory mechanisms. AB - There is increasing evidence documenting activation of inflammatory processes in focal epilepsies. This review article summarizes current data regarding immune mediated inflammatory processes in patients with symptomatic partial epilepsies such as mesial temporal sclerosis, focal cortical dysplasia, and Rasmussen's encephalitis. We have also reviewed several neuronal surface antibody-associated syndromes, which have been recently described with focal seizures as an important part of clinical presentation, such as antibody-associated limbic encephalitis and N-methyl-D-aspartic acid receptor antibody syndrome. An autoimmune mechanism may be one pathogenic factor in some symptomatic epilepsies acting as a triggering event in the process leading to the development of epilepsy. PMID- 25510944 TI - Status epilepticus: immunologic and inflammatory mechanisms. AB - Status epilepticus (SE) can be difficult to treat, particularly if refractory, and lead to significant morbidity and mortality. Prolonged seizures are also a risk factor for the subsequent diagnosis of epilepsy. Activation of the immune system and inflammation are areas of recent interest in the field of epilepsy, and there is growing evidence that these may be involved in the pathogenesis of ongoing SE and subsequent epileptogenesis. We review the current data on this topic in both animal models and human disease. We conclude that there is evidence suggesting a role for immunologic and inflammatory mechanisms in SE. Further research, especially human studies, is necessary to determine whether targeting the immune system would improve control of SE and prevent sequelae such as epileptogenesis. PMID- 25510945 TI - Epilepsy in systemic autoimmune disorders. AB - Autoimmunity and inflammation have been implicated as causative factors of seizures and epilepsy. Autoimmune disorders can affect the central nervous system as an isolated syndrome or be part of a systemic disease. Examples of systemic autoimmune disorders include systemic lupus erythematosus, antiphospholipid syndrome, rheumatic arthritis, and Sjogren syndrome. Overall, there is a 5-fold increased risk of seizures and epilepsy in children with systemic autoimmune disorders. Various etiologic factors have been implicated in causing the seizures in these patients, including direct inflammation, effect on blood vessels (vasculitis), and production of autoantibodies. Potential treatments for this autoimmune injury include steroids, immunoglobulins, and other immune-modulatory therapies. A better understanding of the mechanisms of epileptogenesis in patients with systemic autoimmune diseases could lead to targeted treatments and better outcomes. PMID- 25510946 TI - Immunomodulatory treatments in epilepsy. AB - The role of immunity and inflammation appears to be an integral part of the pathogenic processes associated with some seizures, particularly with refractory epilepsy. Prompt treatment with immunotherapy may lead to better outcomes. Immune treatment options for treatment of epilepsy include therapies such as corticosteroids, immunoglobulins, plasmapheresis, or steroid-sparing drugs such as azathioprine. Recent alternatives have included even more aggressive treatment with cyclophosphamide, anti-pre-B-lymphocyte monoclonal antibody rituximab, and monoclonal antibodies such as efalizumab or natalizumab, which are presently used for other inflammatory disorders. Randomized controlled trials of immunotherapy in presumed autoimmune epilepsy are needed to provide further support for the rapid use of immunotherapy in patients with immune mediated epilepsy. PMID- 25510948 TI - Brain volume in male patients with recent onset schizophrenia with and without cannabis use disorders. AB - BACKGROUND: Schizophrenia is highly comorbid with cannabis use disorders (CUDs), and this comorbidity is associated with an unfavourable course. Early onset or frequent cannabis use may influence brain structure. A key question is whether comorbid CUDs modulate brain morphology alterations associated with schizophrenia. METHODS: We used surface-based analysis to measure the brain volume, cortical thickness and cortical surface area of a priori-defined brain regions (hippocampus, amygdala, thalamus, caudate, putamen, orbitofrontal cortex, anterior cingulate cortex, insula, parahippocampus and fusiform gyrus) in male patients with schizophrenia or related disorders with and without comorbid CUDs and matched healthy controls. Associations between age at onset and frequency of cannabis use with regional grey matter volume were explored. RESULTS: We included 113 patients with (CUD, n = 80) and without (NCUD, n = 33) CUDs and 84 controls in our study. As expected, patients with schizophrenia (with or without a CUD) had smaller volumes of most brain regions (amygdala, putamen, insula, parahippocampus and fusiform gyrus) than healthy controls, and differences in cortical volume were mainly driven by cortical thinning. Compared with the NCUD group, the CUD group had a larger volume of the putamen, possibly driven by polysubstance use. No associations between age at onset and frequency of use with regional grey matter volumes were found. LIMITATIONS: We were unable to correct for possible confounding effects of smoking or antipsychotic medication. CONCLUSION: Patients with psychotic disorders and comorbid CUDs have larger putamen volumes than those without CUDs. Future studies should elaborate whether a large putamen represents a risk factor for the development of CUDs or whether (poly)substance use causes changes in putamen volume. PMID- 25510950 TI - Design modifications of high-flexion TKA do not improve short term clinical and radiographic outcomes. AB - BACKGROUND: The prosthesis of contemporary total knee arthroplasty (TKA) has been modified to provide a more familiar environment for higher flexion angle of the replaced knee. The design modifications continue based on evidence reported in the literature. However, whether these modifications of the prosthesis design lead to improvements in clinical results needs further investigation. We determined whether the prosthesis modifications based on recent evidence improve clinical and radiographic results following high flexion TKA. METHODS: 524 patients who underwent primary TKA using two different high flexion prostheses were divided to Group 1 (HF-1) using a high flexion prosthesis, group 2 (HF-2) using the more recently devised high flexion prosthesis, which claims to be adopted from evidence proposed in the literature. Clinical outcomes included ranges of motion (ROM), the Knee Society knee and function score (KSKS and KSFS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, radiologic evaluation, and complication related to surgery. RESULTS: No differences in terms of clinical and radiographic results were observed between the groups at the 2 year follow-up. The mean ROM was 123 degrees and 124 degrees in the HF-1 and HF-2 groups, respectively. KSKS were 90 and 89.1, KSFS were 76.6 and 81.8, and total WOMAC scores were 23.1 and 24.9 in the HF-1 and HF- 2 groups. No differences of the incidences of radiolucency on radiographs (1.4% in HF-1, 2.1% in HF-2) and dislocation (1 case in HF-1 only) was observed. CONCLUSIONS: Even if recent modifications in the design of high flexion TKA prosthesis were based on evidence in the literature, they did not provide meaningful improvements in short-term clinical and radiographic outcomes after TKA. Surgeons should consider our findings when choosing a prosthesis for their patients. PMID- 25510949 TI - The risk for major depression conferred by childhood maltreatment is multiplied by BDNF and SERT genetic vulnerability: a replication study. AB - BACKGROUND: There is limited evidence for a moderating role of both serotonin transporter (SERT) and brain-derived neurotrophic factor (BDNF) genes on the risk for major depression (MD) developing after childhood maltreatment. However, research on this topic remains inconclusive, and there is a lack of data from longitudinal studies with large and representative population samples. Our study aimed to clarify whether, in the presence of previous childhood maltreatment, individuals carrying low functional alleles for both SERT 5-HTTLPR and BDNF Val66Met polymorphisms had a higher risk for MD. METHODS: We explored 2- and 3 way gene (SERT and BDNF) * environment (childhood maltreatment) interactions in a large sample of Spanish adults who were followed up over a 3-year period and assessed in person for both DSM-IV MD and exposure to childhood maltreatment. RESULTS: Our study included 2679 participants. Those with both the 5-HTTLPR s allele and the BDNF Met allele showed the highest risk of MD if they had previously experienced emotional (z = 2.08, p = 0.037), sexual (z = 2.19, p = 0.029) or any kind of childhood abuse (z = 2.37, p = 0.018). These 3-way interactions remained significant regardless of whether the 5-HTTLPR triallelic or the 5-HTTLPR biallelic polymorphisms were included in the analyses. LIMITATIONS: Retrospective assessment of childhood maltreatment may have resulted in a moderate degree of recall bias. CONCLUSION: Our results confirm that the risk of depression conferred by childhood maltreatment is modified by variation at both SERT and BDNF genes. PMID- 25510951 TI - Negative pressure wound therapy for cervical esophageal perforation with abscess. AB - Perforation of the cervical esophagus is a rare but life-threatening condition. Cervical esophageal perforation with abscess formation can be usually treated with conservative treatments of simple drainage and antibiotics. Aggressive surgical treatments are considered if conservative treatments fail. But the aggressive treatments have low success rate and high morbidity in cervical esophageal perforation. Negative pressure wound therapy (NPWT) was widely used in various complicated wounds, such as diabetic foot ulcers, open abdomen, pressure ulcers, open fractures, sterna wounds, grafts, and flaps since it had been introduced in 1997. NPWT is known to be a valuable tool in the management of various complicated wounds. In this report, we described a case of intractable cervical esophageal perforation with abscess, which was successfully treated with NPWT after the failure of conservative management. PMID- 25510953 TI - The effect of storage conditions on salivary cortisol concentrations using an enzyme immunoassay. AB - Saliva samples are easy to collect and are applicable for home-sampling, e.g. when studying HPA-axis dynamics to characterize diurnal cortisol profiles and the cortisol awakening response. However, the storing and transport conditions might be critical in the home-sampling approach. Here, we tested the stability of saliva cortisol in samples stored at different temperatures and after repeated thawing-freezing cycles when measured with an Enzyme Immuno Assay (EIA). Thirteen healthy volunteers, six women and seven men, mean age 31 (range 26-49) years collected saliva either in the morning hours (08:00-10:00 h) or before lunch (11:00-12:00 h). Storage at six different conditions were tested: Storage at - 18 degrees C, - 4 degrees C, 4 degrees C and room temperature for 72 h. One condition tested was at - 18 degrees C for 72 h and then kept in an envelope for 72 h with a freezing element in room temperature surroundings where after it was stored at - 80 degrees C. The last tube was stored directly at - 80 degrees C and served as the 'gold standard'. The saliva samples were assayed using Salivary Cortisol Diagnostic EIA. Differences in cortisol measurements between each of the five conditions and the 'gold standard' (- 80 degrees C) were evaluated by one sample t-test. No significant differences were observed. This indicates that an EIA method can be used reliably when measuring salivary cortisol samples obtained by home-sampling including a postal delivery. PMID- 25510952 TI - Contribution of rivaroxaban to the international normalized ratio when switching to warfarin for anticoagulation as determined by simulation studies. AB - AIM: This study evaluated the influence of rivaroxaban 20 mg once daily on international normalized ratio (INR) during the co-administration period when switching from rivaroxaban to warfarin. METHODS: We developed a calibrated coagulation model that was qualified with phase I clinical data. Prothrombin time and INR values were simulated by use of phospholipid concentrations that matched Neoplastin Plus(r) and Innovin(r) reagents. To simulate the combined effects of rivaroxaban and warfarin on INR during switching, warfarin initiation was simulated by adjusting the magnitude of the warfarin effect to reach the desired target INRs over the course of 21 days. The warfarin effect values (obtained every 6 h) and the desired rivaroxaban plasma concentrations were used. Nomograms were generated from rivaroxaban induced increases in INR. RESULTS: The simulation had good prediction quality. Rivaroxaban induced increases in the total INR from the warfarin attributed INR were seen, which increased with rivaroxaban plasma concentration. When the warfarin only INR was 2.0-3.0, the INR contribution of rivaroxaban with Neoplastin Plus(r) was 0.5-1.2, decreasing to 0.3-0.6 with Innovin(r) at median trough rivaroxaban plasma concentrations (38 MUg l(-1) ). CONCLUSIONS: The data indicate that measuring warfarin induced changes in INR are best performed at trough rivaroxaban concentrations (24 h after rivaroxaban dosing) during the co-administration period when switching from rivaroxaban to warfarin. Furthermore, Innovin(r) is preferable to Neoplastin Plus(r) because of its substantially lower sensitivity to rivaroxaban, thereby reducing the influence of rivaroxaban on the measured INR. PMID- 25510954 TI - TNFalpha polymorphism as marker of immunosenescence for rheumatoid arthritis patients. AB - BACKGROUND: Expansion of CD4(+)CD28(null), a common feature of immunosenescence, which has been reported in rheumatoid arthritis (RA) patients, may also be associated with a CD4(+) imbalance. Although the increase of CD4(+)CD28(null) cells has been related to TNFalpha exposure, nothing is known about the possible role of genetic variants of this cytokine. METHODS: Participants were genotyped for TNFA rs1800629 (-308 G>A) and frequency of the CD4(+)CD28(null), regulatory T cells and Th1 cells subsets were quantified in peripheral blood samples by flow cytometry in 129 RA patients and 33 healthy controls. RESULTS: The expansion of CD4(+)CD28(null) cells in RA patients was associated with TNFA genotype, even at diagnosis, and linked to markers of aggressive disease in patient carriers of the minor allele. Analysis of regulatory T cells and IFNgamma-CD4(+) expression suggested that defective suppression and/or Th1-shift could underlie the expansion of this population in these patients. Finally, although treatment with TNFalpha-blockers reduced CD4(+)CD28(null) cells in most patients, only those carriers of the common GG genotype reached values within the range of HC and showed a disease activity improvement correlated to this decrease. CONCLUSIONS: Our results provide evidence for a genetic basis of the premature immunosenescence of RA patients and highlight its potential role in clinical outcome after TNFalpha blockade. PMID- 25510955 TI - Burden of inherited ichthyosis: a French national survey. AB - Moderate to severe ichthyosis is known to have a significant impact on quality of life. A French national survey was performed to describe in more detail how ichthyosis impacts the patients' lives. A questionnaire specifically dedicated to ichthyosis was distributed to patients followed in hospital expert centres or members of the French association of patients. A total of 241 questionnaires were completed and returned (response ratio: 29% for children and 71% for adults). A negative impact of ichthyosis was obvious in terms of domestic life (skin care, housework, clothing, etc.), educational/professional lives (rejections by other children, workplace discrimination, absenteeism, etc) and for leisures/sports activities. The patient's economical resources were also heavily impacted by ichthyosis with important out-of-pocket expenses. PMID- 25510956 TI - Melatonin has differential effects on age-induced stoichiometric changes in daily chronomics of serotonin metabolism in SCN of male Wistar rats. AB - Suprachiasmatic nucleus (SCN) controls various physiological, endocrine and behavioral functions by regulating conversion of serotonin (5-HT) to melatonin (MEL). Aging leads to alterations in the neural and temporal organization of the SCN leading to circadian dysfunction. Age-induced stoichiometric alterations in daily chronomics of various components of 5-HT metabolism were studied by constructing interactomes between parameters. The levels of tryptophan (TRP), 5 hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT), N-acetylserotonin (NAS), N acetyl 5-methoxytryptamine (MEL), 5-hydroxyindoleacetic acid (5-HIAA), 5 methoxyindole acetic acid (5-MIAA), 5-hydroxytryptophol (5-HTOH), 5 methoxytryptophol (5-MTOH) and N-acetyltryptamine (NAT) were measured at (Zeitgeber time 0, 6, 12 and 18) in male rat SCN of 3, 12 and 24 months age groups. Age-induced decrease was observed in mean levels of NAS, MEL, 5-HIAA, 5 MIAA, 5-MTOH, and NAT and increase was observed in TRP, 5-HTP, 5-HT and 5-HTOH in rat SCN. Daily pulses decreased with aging significantly for TRP, 5-HT, NAS, MEL, 5-HIAA, 5-MIAA and NAT. We report here, the age-induced change in interactions between various 5-HT metabolism components by middle age (12 m) changing further by 24 m. The daily rhythms persisted with aging for NAS, MEL and 5-HTOH. Though, rhythms were abolished for TRP, 5-HTP, 5-HIAA, 5-MIAA, 5-MTOH and NAT differentially at 12 and 24 m. The MEL administration showed restoration in 5-HT ratio with 5-HTP, MEL and 5-HTOH in 24 m and NAS and 5-HIAA in 12 m SCN. Thus, MEL administration effects alterations of age-induced stoichiometry in levels and chronomics of serotonin metabolic network interactomes. PMID- 25510958 TI - Transoral arytenoid adduction with minimal cervical incision. PMID- 25510957 TI - Candida glabrata sepsis associated with chorioamnionitis in an IVF twin pregnancy: Should we deliver? AB - We report a case of in vitro fertilization (IVF)-acquired Candida glabrata chorioamnionitis successfully treated through systemic maternal antifungal treatment prior to delivery. To the best of our knowledge, this is the first case of its kind in the literature. C. glabrata chorioamnionitis in pregnancy is rare, but the current literature suggests a very high fetal fatality in such cases. It is known to have an association with cervical stitch, amniocentesis, chorionic villous sampling, and assisted reproductive techniques such as IVF. Given the increasing global use of artificial reproductive techniques, it is important to raise awareness of this condition and highlight its potential complications. Early recognition of possible fetal infection could enable early initiation of systemic antifungal treatment. It would be prudent to consider early delivery once fetal maturity is achieved despite normal fetal monitoring. PMID- 25510959 TI - Continuous measurement of cardiac output with the electrical velocimetry method in patients under spinal anesthesia for cesarean delivery. AB - In this study, we aimed to continuously measure cardiac output (CO) with the electrical velocimetry (EV) method and characterize the hemodynamic profile of patients undergoing spinal anesthesia for elective cesarean delivery (CD), and to discuss the potential benefit of using real time CO monitoring to guide patient management. Forty-two patients scheduled for elective CD under spinal anesthesia were enrolled in this observational study. A non-invasive CO monitor incorporating the electrical velocimetry algorithm, ICON((r)) (Cardiotronic((r)), La Jolla, California, USA), was used to measure CO and stroke volume (SV) continuously. Peripheral venous pressure was measured intermittently at pre defined time points. Systemic vascular resistance was calculated retrospectively after completion of the study. Hemodynamic changes at pre-defined time points and caused by phenylephrine administration were analyzed. Hypotension (MAP reduction more than 20% from baseline values) occurred in 71.1% of patients after spinal anesthesia, while the coinstantaneous CO was increased >=20% from baseline in the majority of patients (76.3%) at the same time. Significant increase in CO took place at 3-2 min before the administration of phenylephrine bolus. Treatment of hypotension with phenylephrine was associated with significant decrease in CO. Continuous CO monitoring with EV enables clinicians to determine CO and SV changes prior to onset of hypotension and to better understand patients' hemodynamics. It is an important addition to the current monitoring. The benefit of routinely using this technique remains to be determined in term of the patient outcomes. PMID- 25510960 TI - Conducting polymer transistors making use of activated carbon gate electrodes. AB - The characteristics of the gate electrode have significant effects on the behavior of organic electrochemical transistors (OECTs), which are intensively investigated for applications in the booming field of organic bioelectronics. In this work, high specific surface area activated carbon (AC) was used as gate electrode material in OECTs based on the conducting polymer poly(3,4 ethylenedioxythiophene) (PEDOT) doped with poly(styrenesulfonate) (PSS). We found that the high specific capacitance of the AC gate electrodes leads to high drain source current modulation in OECTs, while their intrinsic quasi-reference characteristics make unnecessary the presence of an additional reference electrode to monitor the OECT channel potential. PMID- 25510961 TI - Submicron polyacrolein particles in situ embedded with upconversion nanoparticles for bioassay. AB - We report a new surface modification approach of upconversion nanoparticles (UCNPs) structured as inorganic hosts NaYF4 codoped with Yb(3+) and Er(3+) based on their encapsulation in a two-stage process of precipitation polymerization of acrolein under alkaline conditions in the presence of UCNPs. The use of tetramethylammonium hydroxide both as an initiator of acrolein polymerization and as an agent for UCNP hydrophilization made it possible to increase the polyacrolein yield up to 90%. This approach enabled the facile, lossless embedment of UCNPs into the polymer particles suitable for bioassay. These particles are readily dispersible in aqueous and physiological buffers, exhibiting excellent photoluminescence properties, chemical stability, and also allow the control of particle diameters. The feasibility of the as-produced photoluminescent polymer particles mean-sized 260 nm for in vivo optical whole animal imaging was also demonstrated using a home-built epi-luminescence imaging system. PMID- 25510963 TI - Increased interventricular septum wall thickness predicts all-cause death in patients with coronary artery disease. AB - BACKGROUND: There is debate regarding the predictive value of interventricular septum (IVS) wall thickness for adverse events. AIMS: The study investigated the association between the severity of thickened IVS and all-cause death in Chinese patients with coronary artery disease (CAD). METHODS: A total of 2297 CAD patients verified by angiography was consecutively included. Patients were grouped according to the severity of thickened IVS. Cox regression analysis was conducted to determine the independent prognostic value of thickened IVS for all cause death. RESULTS: During a median follow up of 25 months, 149 patients died. A gradient increase in the risk of death was observed across thickened IVS groups. Compared to patients with normal IVS thickness, the adjusted hazard ratio (HR) was 1.49 (95% confidence interval (CI) 1.00-2.23, P = 0.05) and 2.13 (95% CI 1.29-3.54, P = 0.003) for all-cause death in those with mildly and moderately/severely thickened IVS respectively. For one unit increase in IVS thickness, the risk of all-cause death was elevated by 14% (adjusted HR 1.14, 95% CI 1.05-1.24, P = 0.003). In patients with normal indexed left ventricular mass, thickened IVS was also demonstrated as an independent risk factor for all-cause death. CONCLUSION: Thickened IVS can be served as a reliable marker for predicting all-cause death in Chinese patients with CAD, even in those with normal left ventricular mass. PMID- 25510964 TI - Analysis of the volatile organic compounds from leaves, flower spikes, and nectar of Australian grown Agastache rugosa. AB - BACKGROUND: The foraging choices of honey bees are influenced by many factors, such as floral aroma. The composition of volatile compounds influences the bioactivity of the aromatic plants and honey produced from them. In this study, Agastache rugosa was evaluated as part of a project to select the most promising medicinal plant species for production of bioactive honey. METHODS: Headspace solid-phase microextraction HS-SPME /GC-MS was optimized to identify the volatile bioactive compounds in the leaves, flower spikes, and for the first time, the flower nectar of Australian grown A. rugosa. RESULTS: Methyl chavicol (= estragole) was the predominant headspace volatile compound in the flowers with nectar, flower spikes, and leaves, with a total of 97.16%, 96.74% and 94.35%, respectively. Current results indicate that HS-SPME/GC-MS could be a useful tool for screening estragole concentration in herbal products. CONCLUSION: Recently, estragole was suspected to be carcinogenic and genotoxic, according to the European Union Committee on Herbal Medicinal Products. Further studies are needed on safe daily intake of Agastache as herbal tea or honey, as well as for topical uses. PMID- 25510962 TI - The sigma-1 receptors are present in monomeric and oligomeric forms in living cells in the presence and absence of ligands. AB - The sigma-1 receptor (S1R) is a 223-amino-acid membrane protein that resides in the endoplasmic reticulum and the plasma membrane of some mammalian cells. The S1R is regulated by various synthetic molecules including (+)-pentazocine, cocaine and haloperidol and endogenous molecules such as sphingosine, dimethyltryptamine and dehydroepiandrosterone. Ligand-regulated protein chaperone functions linked to oxidative stress and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and neuropathic pain have been attributed to the S1R. Several client proteins that interact with S1R have been identified including various types of ion channels and G-protein coupled receptors (GPCRs). When S1R constructs containing C-terminal monomeric GFP2 and YFP fusions were co expressed in COS-7 cells and subjected to FRET spectrometry analysis, monomers, dimers and higher oligomeric forms of S1R were identified under non-liganded conditions. In the presence of the prototypic S1R agonist, (+)-pentazocine, however, monomers and dimers were the prevailing forms of S1R. The prototypic antagonist, haloperidol, on the other hand, favoured higher order S1R oligomers. These data, in sum, indicate that heterologously expressed S1Rs occur in vivo in COS-7 cells in multiple oligomeric forms and that S1R ligands alter these oligomeric structures. We suggest that the S1R oligomerization states may regulate its function(s). PMID- 25510965 TI - Cystobactamids: myxobacterial topoisomerase inhibitors exhibiting potent antibacterial activity. AB - The development of new antibiotics faces a severe crisis inter alia owing to a lack of innovative chemical scaffolds with activities against Gram-negative and multiresistant pathogens. Herein, we report highly potent novel antibacterial compounds, the myxobacteria-derived cystobactamids 1-3, which were isolated from Cystobacter sp. and show minimum inhibitory concentrations in the low MUg mL(-1) range. We describe the isolation and structure elucidation of three congeners as well as the identification and annotation of their biosynthetic gene cluster. By studying the self-resistance mechanism in the natural producer organism, the molecular targets were identified as bacterial type IIa topoisomerases. As quinolones are largely exhausted as a template for new type II topoisomerase inhibitors, the cystobactamids offer exciting alternatives to generate novel antibiotics using medicinal chemistry and biosynthetic engineering. PMID- 25510966 TI - The association between abnormal microRNA-10b expression and cancer risk: a meta analysis. AB - Several studies have investigated the association between abnormal microRNA-10b expression and the risk of various developing cancers, but the results are inconsistent. We searched all publications addressing the level of microRNA-10b expression in cancer cases and noncancerous controls (Accessed: August 2014). Thirty-six studies on 14 types of cancer were included. Among them, 25 studies were subjected to the meta-analysis with a vote-counting strategy, 13 studies were estimated using odds ratio (OR) and diagnostic accuracy, and 2 studies were assessed by both methods. It was found that vestibular schwannomas ranked first among the reported cancer types with up-regulated microRNA-10b expression; melanoma ranked first among the reported cancer types with down-regulated microRNA-10b expression; while breast cancer and hepatocellular cancer presented inconsistent microRNA-10b regulation. Of 13 included studies calculated for OR and diagnostic accuracy, it was shown that high-expression of microRNA-10b could be significantly associated with cancer risk (OR = 32.80, 95% CI: 11.90-90.37, P<0.0001), and the area under the summary receiver operating characteristic (SROC) curve for microRNA-10b high-expression in the diagnosis of cancer is 0.81, which suggested that high-expression of microRNA-10b can predict worse outcomes in some types of cancer and the regular monitoring of miR-10b expression might be useful in the clinical practice. PMID- 25510967 TI - Antibiotics in dental practice: how justified are we. AB - Antibiotics are prescribed by dentists in dental practice, during dental treatment as well as for prevention of infection. Indications for the use of systemic antibiotics in dentistry are limited because most dental and periodontal diseases are best managed by operative intervention and oral hygiene measures. The use of antibiotics in dental practice is characterised by empirical prescription based on clinical and bacteriological epidemiological factors, resulting in the use of a very narrow range of broad-spectrum antibiotics for short periods of time. This has led to the development of antimicrobial resistance (AMR) in a wide range of microbes and to the consequent inefficacy of commonly used antibiotics. Dentists can make a difference by the judicious use of antimicrobials--prescribing the correct drug, at the standard dosage and appropriate regimen--only when systemic spread of infection is evident. The increasing resistance problems of recent years are probably related to the over- or misuse of broad-spectrum agents. There is a clear need for the development of prescribing guidelines and educational initiatives to encourage the rational and appropriate use of drugs in dentistry. This paper highlights the need for dentists to improve antibiotic prescribing practices in an attempt to curb the increasing incidence of antibiotic resistance and other side effects of antibiotic abuse. The literature provides evidence of inadequate prescribing practices by dentists for a number of factors, ranging from inadequate knowledge to social factors. PMID- 25510968 TI - Structure, morphology, and assembly behavior of kafirin. AB - Prolamins from grains have attracted intensive attention in recent years due to their potential in satisfying the demand for environmentally friendly (biodegradable), abundantly available (sustainable), and cost-effective biomaterials. However, for kafirin, the prolamin from sorghum, its composition, structure, morphology, and self-assembly behaviors have not been fully characterized. In this paper, kafirin was extracted from the whole sorghum grain and found to contain 68, 14, 6, and 12% of alpha-, beta-, and gamma-fractions and cross-linked kafirin, respectively. Freeze-dried kafirin contained ~49% alpha helix in the solid state. When dissolved in 65% (v/v) isopropanol, 60% (v/v) tert butanol, and 85% (v/v) ethanol aqueous solvents, the relative alpha-helix content in kafirin increased with the decrease of solvent polarity. Structural analysis using small-angle X-ray scattering (SAXS) indicated that kafirin (2 mg/mL) took stretched and extended conformations with dimensions of 118 * 15 * 15 and 100 * 11 * 11 A in 60% tert-butanol and 65% isopropanol, respectively. More elongated conformation of individual kafirin with high-order assembly was observed in 85% ethanol. Protein aggregation occurred as protein concentration increased in its good solvent. The morphology of kafirin assemblies captured by atomic force microscopy (AFM) revealed that kafirin protein took uniform particle morphology at low concentration, and disk-like or rod-like structures resulting from solvent evaporation induced particle interactions emerged at high concentrations. These results suggest that both protein concentration and solvent polarity can effectively regulate kafirin assemblies from thick rod-like to slim rod-like structures, a convenient way to tune the fibrillation of prolamin-based biomaterials. PMID- 25510969 TI - Targeted resequencing of GWAS loci reveals novel genetic variants for milk production traits. AB - BACKGROUND: Genome wide association study (GWAS) has been proven to be a powerful tool for detecting genomic variants associated with complex traits. However, the specific genes and causal variants underlying these traits remain unclear. RESULTS: Here, we used target-enrichment strategy coupled with next generation sequencing technique to study target regions which were found to be associated with milk production traits in dairy cattle in our previous GWAS. Among the large amount of novel variants detected by targeted resequencing, we selected 200 SNPs for further association study in a population consisting of 2634 cows. Sixty six SNPs distributed in 53 genes were identified to be associated significantly with on milk production traits. Of the 53 genes, 26 were consistent with our previous GWAS results. We further chose 20 significant genes to analyze their mRNA expression in different tissues of lactating cows, of which 15 were specificly highly expressed in mammary gland. CONCLUSIONS: Our study illustrates the potential for identifying causal mutations for milk production traits using target-enrichment resequencing and extends the results of GWAS by discovering new and potentially functional mutations. PMID- 25510970 TI - Momordica charantia polysaccharides could protect against cerebral ischemia/reperfusion injury through inhibiting oxidative stress mediated c-Jun N terminal kinase 3 signaling pathway. AB - Momordica charantia (MC) is a medicinal plant for stroke treatment in Traditional Chinese Medicine, but its active compounds and molecular targets are unknown yet. M. charantia polysaccharide (MCP) is one of the important bioactive components in MC. In the present study, we tested the hypothesis that MCP has neuroprotective effects against cerebral ischemia/reperfusion injury through scavenging superoxide (O2(-)), nitric oxide (NO) and peroxynitrite (ONOO(-)) and inhibiting c-Jun N-terminal protein kinase (JNK3) signaling cascades. We conducted experiments with in vivo global and focal cerebral ischemia/reperfusion rat models and in vitro oxygen glucose deprivation (OGD) neural cells. The effects of MCP on apoptotic cell death and infarction volume, the bioactivities of scavenging O2(-), NO and ONOO(-), inhibiting lipid peroxidation and modulating JNK3 signaling pathway were investigated. Major results are summarized as below: (1) MCP dose-dependently attenuated apoptotic cell death in neural cells under OGD condition in vitro and reduced infarction volume in ischemic brains in vivo; (2) MCP had directing scavenging effects on NO, O2(-) and ONOO(-) and inhibited lipid peroxidation; (3) MCP inhibited the activations of JNK3/c-Jun/Fas-L and JNK3/cytochrome C/caspases-3 signaling cascades in ischemic brains in vivo. Taken together, we conclude that MCP could be a promising neuroprotective ingredient of M. charantia and its mechanisms could be at least in part attributed to its antioxidant activities and inhibiting JNK3 signaling cascades during cerebral ischemia/reperfusion injury. PMID- 25510971 TI - Characterizing inner-shell with spectral phase interferometry for direct electric field reconstruction. AB - In many atomic, molecular and solid systems, Lorentzian and Fano profiles are commonly observed in a broad research fields throughout a variety of spectroscopies. As the profile structure is related to the phase of the time dependent dipole moment, it plays an important role in the study of quantum properties. Here we determine the dipole phase in the inner-shell transition using spectral phase interferometry for direct electric-field reconstruction (SPIDER) with isolated attosecond pulses (IAPs). In addition, we propose a scheme for pulse generation and compression by manipulating the inner-shell transition. The electromagnetic radiation generated by the transition is temporally compressed to a few femtoseconds in the extreme ultraviolet (XUV) region. The proposed pulse-compression scheme may provide an alternative route to producing attosecond pulses of light. PMID- 25510972 TI - HAuCl4: a dual agent for studying the chloride-assisted vertical growth of citrate-free Ag nanoplates with Au serving as a marker. AB - We have investigated the vertical growth of citrate-free Ag nanoplates into truncated right bipyramids and twinned cubes with truncated corners in the presence of Cl(-) ions at low and high concentrations, respectively, with Au serving as a marker for electron microscopy analysis. Both the Cl(-) ions and Au atoms could be introduced through the use of HAuCl4 as a dual agent. When HAuCl4 was added into an aqueous mixture of citrate-free Ag nanoplates, ascorbic acid (AA), and poly(vinylpyrrolidone), Au would be immediately formed and deposited on the surfaces of the nanoplates due to the reduction by both Ag and AA. The deposited Au could be easily resolved under STEM to reveal the growth patterns of the nanoplates. We found that the presence of Au did not change the growth pattern of the original Ag nanoplates. In contrast, the Cl(-) ions could deterministically direct the formation of Ag nanoplates with a triangular or hexagonal shape, followed by their further growth into truncated right bipyramids or twinned cubes with truncated corners upon the introduction of AgNO3. This work demonstrates, for the first time, that citrate-free Ag nanoplates could be transformed into right bipyramids or twinned cubes by controlling a single experimental parameter: the concentration of Cl(-) ions in the growth solution. The mechanistic understanding represents a step forward toward the rational design and shape-controlled synthesis of nanocrystals with desired properties. PMID- 25510973 TI - Development of dielectric-barrier-discharge ionization. AB - Dielectric-barrier-discharge ionization is an ambient-ionization technique. Since its first description in 2007, it has attracted much attention in such fields as biological analysis, food safety, mass-spectrometry imaging, forensic identification, and reaction monitoring for its advantages, e.g., low energy consumption, solvent-free method, and easy miniaturization. In this review a brief introduction to dielectric barrier discharge is provided, and then a detailed introduction to the dielectric-barrier-discharge-ionization technique is given, including instrumentation, applications, and mechanistic studies. Based on the summary of reported work, possible future uses of this type of ionization source are discussed at the end. PMID- 25510974 TI - Lysobacter caeni sp. nov., isolated from the sludge of a pesticide manufacturing factory. AB - Strain BUT-8(T), a Gram-stain-negative, non-motile and rod-shaped aerobic bacterium, was isolated from the activated sludge of a herbicide-manufacturing wastewater treatment facility. Comparative 16S rRNA gene sequence analysis revealed that strain BUT-8(T) clustered with species of the genus Lysobacter and was closely related to Lysobacter ruishenii DSM 22393(T) (98.3 %) and Lysobacter daejeonensis KACC 11406(T) (98.7 %). The DNA G+C content of the genomic DNA was 70.6 mol%. The major respiratory quinone was ubiquinone-8, and the major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and an aminolipid. The major cellular fatty acids were iso C15 : 0, iso-C16 : 0, iso-C17 : 0, iso-C11 : 0, iso-C11 : 0 3OH and summed feature 9 (comprising iso-C17 : 1omega9c and/or C16 : 010-methyl). The DNA-DNA relatedness between strain BUT-8(T) and its closest phylogenetic neighbours was below 70 %. Phylogenetic, chemotaxonomic and phenotypic results clearly demonstrated that strain BUT-8(T) belongs to the genus Lysobacter and represents a novel species for which the name Lysobacter caeni sp. nov. is proposed. The type strain is BUT-8(T) ( = CCTCC AB 2013087(T) = KACC 17141(T)). PMID- 25510975 TI - Pyrobaculum ferrireducens sp. nov., a hyperthermophilic Fe(III)-, selenate- and arsenate-reducing crenarchaeon isolated from a hot spring. AB - A novel hyperthermophilic, anaerobic, archaeon was isolated from a terrestrial hot spring at Uzon Caldera, Kronotsky Nature Reserve, Kamchatka, Russia. The isolate, strain 1860(T), grew optimally at 90-95 degrees C and pH 6.0-7.0. The cells were non-motile straight rods, 1.5-5.0 um in length, covered with surface layer lattice. Strain 1860(T) utilized complex proteinaceous compounds as electron donors and ferrihydrite, Fe(III) citrate, nitrate, thiosulfate, selenite, selenate and arsenate as electron acceptors for growth. The sequence of the 16S rRNA gene of strain 1860(T) had 97.9-98.7 % similarity with those of members of the genus Pyrobaculum. On the basis of its physiological properties and phylogenetic analyses including in silico genome to genome hybridization, the isolate is considered to represent a novel species, for which the name Pyrobaculum ferrireducens sp. nov. is proposed. The type strain is 1860(T) ( = DSM 28942(T) = VKM B-2856(T)). PMID- 25510977 TI - A complicated case of orbital cellulitis: When the fog doesn't clear. AB - Orbital cellulitis is a potential sight-threatening infection of the ocular adnexal structures posterior to the orbital septum. Acute bacterial sinusitis remains the most common cause of orbital cellulitis in the paediatric age group. Simultaneous intracranial and orbital complications from orbital cellulitis are rare. We describe a case of orbital cellulitis, which proceeded to sub-periosteal abscess formation and intracranial abscess within days of the initial presentation. The specific features of this case including the rapid progression of the orbital inflammation, failure of improvement over 48 h despite maximal medical treatment and incorrect initial reporting of computed tomography imaging all contributed to the complications seen in this case. PMID- 25510976 TI - Acinetobacter variabilis sp. nov. (formerly DNA group 15 sensu Tjernberg & Ursing), isolated from humans and animals. AB - We aimed to define the taxonomic status of 16 strains which were phenetically congruent with Acinetobacter DNA group 15 described by Tjernberg & Ursing in 1989. The strains were isolated from a variety of human and animal specimens in geographically distant places over the last three decades. Taxonomic analysis was based on an Acinetobacter-targeted, genus-wide approach that included the comparative sequence analysis of housekeeping, protein-coding genes, whole-cell profiling based on matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS), an array of in-house physiological and metabolic tests, and whole-genome comparative analysis. Based on analyses of the rpoB and gyrB genes, the 16 strains formed respective, strongly supported clusters clearly separated from the other species of the genus Acinetobacter. The distinctness of the group at the species level was indicated by average nucleotide identity values of <=82 % between the whole genome sequences of two of the 16 strains (NIPH 2171(T) and NIPH 899) and those of the known species. In addition, the coherence of the group was also supported by MALDI-TOF MS. All 16 strains were non-haemolytic and non-gelatinase-producing, grown at 41 degrees C and utilized a rather limited number of carbon sources. Virtually every strain displayed a unique combination of metabolic and physiological features. We conclude that the 16 strains represent a distinct species of the genus Acinetobacter, for which the name Acinetobacter variabilis sp. nov. is proposed to reflect its marked phenotypic heterogeneity. The type strain is NIPH 2171(T) ( = CIP 110486(T) = CCUG 26390(T) = CCM 8555(T)). PMID- 25510979 TI - Criteria for the Research Institute for Fragrance Materials, Inc. (RIFM) safety evaluation process for fragrance ingredients. AB - The Research Institute for Fragrance Materials, Inc. (RIFM) has been engaged in the generation and evaluation of safety data for fragrance materials since its inception over 45 years ago. Over time, RIFM's approach to gathering data, estimating exposure and assessing safety has evolved as the tools for risk assessment evolved. This publication is designed to update the RIFM safety assessment process, which follows a series of decision trees, reflecting advances in approaches in risk assessment and new and classical toxicological methodologies employed by RIFM over the past ten years. These changes include incorporating 1) new scientific information including a framework for choosing structural analogs, 2) consideration of the Threshold of Toxicological Concern (TTC), 3) the Quantitative Risk Assessment (QRA) for dermal sensitization, 4) the respiratory route of exposure, 5) aggregate exposure assessment methodology, 6) the latest methodology and approaches to risk assessments, 7) the latest alternatives to animal testing methodology and 8) environmental risk assessment. The assessment begins with a thorough analysis of existing data followed by in silico analysis, identification of 'read across' analogs, generation of additional data through in vitro testing as well as consideration of the TTC approach. If necessary, risk management may be considered. PMID- 25510978 TI - Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century: an international comparison. AB - AIMS: Improving glycaemic control in people with Type 1 diabetes is known to reduce complications. Our aim was to compare glycaemic control among people with Type 1 diabetes using data gathered in regional or national registries. METHODS: Data were obtained for children and/or adults with Type 1 diabetes from the following countries (or regions): Western Australia, Austria, Denmark, England, Champagne-Ardenne (France), Germany, Epirus, Thessaly and Thessaloniki (Greece), Galway (Ireland), several Italian regions, Latvia, Rotterdam (The Netherlands), Otago (New Zealand), Norway, Northern Ireland, Scotland, Sweden, Volyn (Ukraine), USA and Wales) from population or clinic-based registries. The sample size with available data varied from 355 to 173 880. Proportions with HbA1c < 58 mmol/mol (< 7.5%) and >= 75 mmol/mol (>= 9.0%) were compared by age and sex. RESULTS: Data were available for 324 501 people. The proportions with HbA1c 58 mmol/mol (< 7.5%) varied from 15.7% to 46.4% among 44 058 people aged < 15 years, from 8.9% to 49.5% among 50 766 people aged 15-24 years and from 20.5% to 53.6% among 229 677 people aged >= 25 years. Sex differences in glycaemic control were small. Proportions of people using insulin pumps varied between the 12 sources with data available. CONCLUSION: These results suggest that there are substantial variations in glycaemic control among people with Type 1 diabetes between the data sources and that there is room for improvement in all populations, especially in young adults. PMID- 25510980 TI - Postoperative adhesions as a consequence of pelvic surgery. AB - Adhesions represent a frequent thought-provoking surgical ramification that greatly affects clinical practice, thereby making adhesion deterrence an important area of public health intervention, research, and the fiscal budget. Postoperative adhesions have been observed in up to 94% of patients after laparotomy. Adhesion-related readmissions, 1 year after surgery, were found to be in 1.3% to 1.5% of the therapeutic and diagnostic laparoscopic procedures. This systematic review looks at gynecologic experience with the management of postoperative adhesions and related complications and recommends intervention when data permits. PMID- 25510981 TI - Feasibility and surgical outcome in obese versus nonobese patients undergoing laparoendoscopic single-site hysterectomy: a multicenter case-control study. AB - OBJECTIVE: To assess the feasibility and perioperative outcomes of laparoendoscopic single-site (LESS) hysterectomy in obese and nonobese women. DESIGN: A multicentric retrospective case-control study (Canadian Task Force II 2). SETTING: Catholic University of the Sacred Heart and National Cancer Institute "Regina Elena" (Rome, Italy), Massachusetts General Hospital (Boston, MD), and Johns Hopkins Hospital (Baltimore, MD). PATIENTS: From July 2009 to April 2013, 120 women underwent LESS hysterectomy. Five women (8%) were excluded from the analysis. The remaining 115 women were divided into 2 groups: obese (n = 43, body mass index [BMI] >=30 kg/m(2)) and nonobese (n = 72, BMI <30 kg/m(2)). INTERVENTIONS: Total LESS hysterectomies for malignant and premalignant uterine disease or at least for prophylactic intent were performed. MEASUREMENTS AND MAIN RESULTS: No statistical differences regarding perioperative outcomes were observed between the 2 groups. Conversion to standard laparoscopy occurred in 2 obese (5%) and 2 (5%) nonobese women (p = .62). Conversion to laparotomy occurred in 1 obese (2.3%) and 3 (4.2%) nonobese women (p = .212). The median operative time was 115 minutes (range, 48-300 minutes) in obese and 114 minutes (range, 55 342 minutes) in nonobese women (p = .787). The intraoperative complication rate was 11.6% and 9.6% in obese and nonobese women, respectively (p = .712). The early postoperative complication rate was 6.9% in obese and 4.1% in nonobese women (p = .516). CONCLUSION: Despite the fact that the present analysis was performed in a relatively small group of patients, this study suggests that obesity (BMI >=30) does not preclude successful completion of total LESS hysterectomy. Further prospective studies are required to confirm these preliminary data and to clarify potential advantages and disadvantages of LESS in obese women. PMID- 25510983 TI - TransOral endoscopic UltraSonic Surgery (TOUSS): a preliminary report of a novel robotless alternative to TORS. AB - The objective of this study is to describe and evaluate the feasibility of TransOral UltraSonic Surgery (TOUSS), a new endoscopic alternative to transoral robotic surgery for approaching pharyngeal and laryngeal tumours based on ultrasonic scalpel as a resection tool. This is a prospective study on 11 consecutive patients with pharyngeal and supraglottic carcinomas between December 2013 and August 2014. All tumours were resected transorally with 35 cm ThunderbeatTM. Exposure was achieved using GyrusTM FK-retractor and Olympus ENDOEYE Flex 5 mm 2D/10 mm 3D deflecting tip video laparoscopes. We evaluated tumour staging, surgical margins, surgical time, blood transfusions, tracheostomy, enteral feeding, postoperative pain and hospital stay. The operating room setup and procedure are described. This series comprised seven early and four locally advanced carcinomas. The mean setup for TOUSS and resection time were 16 and 70.9 minutes. No major intraoperative complications were identified. The average time of nasogastric feeding tube dependence (n = 9) was 13 days. Gastrostomy was performed in one patient. The average hospital stay was 14.3 days. Postoperative pain was satisfactory treated with nonsteroidal anti inflammatory drugs. We have described TOUSS as a new feasible and intuitive procedure to approach endoscopically pharyngeal and supraglottic tumours, with good intraoperative conditions and functional outcomes. PMID- 25510984 TI - Effect of antibiotic use on bacterial flora of tonsil core in patients with recurrent tonsillitis. AB - The aim of this study was to investigate the effects of commonly used antibiotics on bacterial flora of the tonsil core. Patients who underwent tonsillectomy for recurrent chronic tonsillitis were included in the study. Three groups were formed: group 1 was treated for 10 days preoperatively with amoxicillin/clavulanic acid; group 2 was treated for 10 days preoperatively with clarithromycin; and group 3 included patients who underwent tonsillectomy without preoperative antibiotic use. The removed palatine tonsils were sent to our microbiology department in sterile tubes for bacteriological analysis. Seventy three patients (group 1 = 19, group 2 = 20, group 3 = 34 patients) aged 3-18 years (mean 7 years) were included in the study. At least one bacterium was isolated from all tonsils, except for two cases in group 1; the difference in single bacterial growth among groups was not significant (p = 0.06). On the other hand, the numbers of patients with pathogenic bacterial growth was significantly lower in group 2 (n = 2) compared with group 1 (n = 10) and group 3 (n = 27) (p < 0.001). The bacterium isolated most frequently from the tonsils was Streptococcus viridans. Pseudomonas aeruginosa was the only pathogenic bacterium that grew in all three groups. Clarithromycin was more effective than amoxicillin/clavulanic acid in eradicating pathogenic bacteria in the tonsil core. Pseudomonas aeruginosa might be responsible for resistant or recurrent tonsil infections. To prevent endocarditis, antibiotic prophylaxis toward S. viridians, which is the most prevalent bacterium in the tonsil core, should be kept in mind for patients with heart valve damage. PMID- 25510982 TI - The BDNF p.Val66Met polymorphism, childhood trauma, and brain volumes in adolescents with alcohol abuse. AB - BACKGROUND: Previous studies have indicated that early life adversity, genetic factors and alcohol dependence are associated with reduced brain volume in adolescents. However, data on the interactive effects of early life adversity, genetic factors (e.g. p.Met66 allele of BDNF), and alcohol dependence, on brain structure in adolescents is limited. We examined whether the BDNF p.Val66Met polymorphism interacts with childhood trauma to predict alterations in brain volume in adolescents with alcohol use disorders (AUDs). METHODS: We examined 160 participants (80 adolescents with DSM-IV AUD and 80 age- and gender-matched controls) who were assessed for trauma using the Childhood Trauma Questionnaire (CTQ). Magnetic resonance images were acquired for a subset of the cohort (58 AUD and 58 controls) and volumes of global and regional structures were estimated using voxel-based morphometry (VBM). Samples were genotyped for the p.Val66Met polymorphism using the TaqMan(r) Assay. Analysis of covariance (ANCOVA) and post hoc t-tests were conducted using SPM8 VBM. RESULTS: No significant associations, corrected for multiple comparisons, were found between the BDNF p.Val66Met polymorphism, brain volumes and AUD in adolescents with childhood trauma. CONCLUSIONS: These preliminary findings suggest that the BDNF p.Met66 allele and childhood trauma may not be associated with reduced structural volumes in AUD. Other genetic contributors should be investigated in future studies. PMID- 25510985 TI - Association between XRCC3 Thr241Met polymorphism and laryngeal cancer susceptibility in Turkish population. AB - DNA repair systems are essential for normal cell function. Genetic alterations in the DNA repair genes such as X-ray repair cross-complementing group 3 (XRCC3), can cause a change in protein activity which results in cancer susceptibility. The aim of this study was to investigate the association of XRCC3 Thr241Met single nucleotide polymorphism (SNP), smoking and alcohol consumption with the risk of laryngeal cancer in Turkish population. The frequencies of Thr241Met SNP were studied in 58 laryngeal cancer cases (SSC) and 67 healthy individuals. Genomic DNA was isolated from peripheral blood samples of both controls and laryngeal cancer cases. Thr241Met SNP was genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. The genotype and allele frequencies of Thr241Met polymorphism were not statistically significant between the laryngeal cancer and control groups. Carrying mutant allele was not associated with the risk of laryngeal cancer. On the other hand, smoking and chronic alcohol consumption were associated with the risk of laryngeal cancer but there is no association between Thr241Met, smoking and alcohol consumption in laryngeal cancer cases. These results indicate that Thr241Met polymorphism was not associated with the development of laryngeal cancer in Turkish population. However, it should be kept in mind that the association of a polymorphism with cancer susceptibility can differ due to several factors such as cancer type, selection criteria, ethnic differences and size of the studied population. PMID- 25510986 TI - Cross-cultural adaptation and validation of the sino-nasal outcome test (SNOT-22) for Spanish-speaking patients. AB - Our objective was to perform translation, cross-cultural adaptation and validation of the sino-nasal outcome test 22 (SNOT-22) to Spanish language. SNOT 22 was translated, back translated, and a pretest trial was performed. The study included 119 individuals divided into 60 cases, who met diagnostic criteria for chronic rhinosinusitis according to the European Position Paper on Rhinosinusitis 2012; and 59 controls, who reported no sino-nasal disease. Internal consistency was evaluated with Cronbach's alpha test, reproducibility with Kappa coefficient, reliability with intraclass correlation coefficient (ICC), validity with Mann Whitney U test and responsiveness with Wilcoxon test. In cases, Cronbach's alpha was 0.91 both before and after treatment, as for controls, it was 0.90 at their first test assessment and 0.88 at 3 weeks. Kappa coefficient was calculated for each item, with an average score of 0.69. ICC was also performed for each item, with a score of 0.87 in the overall score and an average among all items of 0.71. Median score for cases was 47, and 2 for controls, finding the difference to be highly significant (Mann-Whitney U test, p < 0.001). Clinical changes were observed among treated patients, with a median score of 47 and 13.5 before and after treatment, respectively (Wilcoxon test, p < 0.001). The effect size resulted in 0.14 in treated patients whose status at 3 weeks was unvarying; 1.03 in those who were better and 1.89 for much better group. All controls were unvarying with an effect size of 0.05. The Spanish version of the SNOT-22 has the internal consistency, reliability, reproducibility, validity and responsiveness necessary to be a valid instrument to be used in clinical practice. PMID- 25510987 TI - To exenterate or not? An unusual case of pediatric rhinocerebral mucormycosis. AB - Rhinocerebral mucormycosis (RM) is a rare, potentially lethal fungal infection. Traditional teaching encourages aggressive surgical resection until viable bleeding tissue is encountered, often leading to orbital exenteration, skull base resection, and cerebral debridement, in addition to systemic antifungal therapy. We present a 2-year-old male with acute lymphocytic leukemia undergoing chemotherapy presenting with RM and unilateral orbital and intracranial involvement. After aggressive sinonasal debridement, systemic antifungal and hyperbaric oxygen therapies, he recovered without need for further aggressive tissue resection. We report the successful management of invasive orbital and intracranial RM without orbital exenteration or cerebral debridement. PMID- 25510988 TI - The temporary placement of endobronchial stents in the management of bronchial compression by transiently enlarged mediastinal structures. AB - Enlargement of mediastinal structures can cause compression of the trachea and/or bronchi. We describe two case reports in which stenosis of left main bronchus, secondary to compression from an enlarged mediastinal structure, were successfully managed with temporary placement of a metallic self-expanding stent while waiting for the compression to relieve. PMID- 25510989 TI - [Diagnosing streptococcal pharyngotonsillitis in children and adolescents: the limitations of the clinical features]. PMID- 25510991 TI - [Clinical, laboratorial and radiographic predictors of Bordetella pertussis infection]. AB - OBJECTIVE: To identify clinical, laboratorial and radiographic predictors for Bordetella pertussis infection. METHODS: This was a retrospective study, which analyzed medical records of all patients submitted to a molecular diagnosis (qPCR) for B. pertussis from September 2011 to January 2013. Clinical and laboratorial data were reviewed, including information about age, sex, signs/symptoms, length of hospitalization, blood cell counts, imaging findings, coinfection with other respiratory pathogens and clinical outcome. RESULTS: 222 cases were revised. Of these, 72.5% had proven pertussis, and 60.9% were under 1 year old. In patients aging up to six months, independent predictors for B. pertussis infection were cyanosis (OR 8.0, CI 95% 1.8-36.3; p=0.007) and lymphocyte count >10(4)/MUL (OR 10.0, CI 95% 1.8-54.5; p=0.008). No independent predictors of B. pertussis infection could be determined for patients older than six months. Co-infection was found in 21.4% of patients, of which 72.7% were up to six months of age. Adenovirus was the most common agent (40.9%). In these patients, we were not able to identify any clinical features to detect patients presenting with a respiratory co-infection, even though longer hospital stay was observed in patients with co-infections (12 vs. 6 days; p=0.009). CONCLUSIONS: Cyanosis and lymphocytosis are independent predictors for pertussis in children up to 6 months old. PMID- 25510992 TI - [Epidemiological profile of exogenous poisoning in children and adolescents from a municipality in the state of Mato Grosso]. AB - OBJECTIVE: To study the epidemiology of exogenous intoxications in children and adolescents of Barra Garcas, Mato Grosso, from January 2008 to September 2013. METHOD: This was a cross-sectional, retrospective, and descriptive epidemiological study. Data were collected from the Disease Notification System (Sistema de Informacao de Agravos de Notificacao [SINAN]) of the municipality, processed using Microsoft Excel, and evaluated through BIOESTAT statistical software. The variables included were: sex; age; toxic agent; time and place of service; route of administration; circumstance; and classification of intoxication. The age range was established according to the Brazilian Institute of Geography and Statistics, comprising children aged from 0 to 9 years old and adolescents aged from 10 to 19 years old. RESULTS: A total of 125 cases of accidental exogenous poisoning was registered, including 77 children and 48 adolescents. Food and beverages (38.4%) and drugs (24.0%) were the most common groups of toxic agents responsible for the poisoning. The largest age group affected by intoxication was composed of children aged from 0 to 4 years old (43.2%) and adolescents aged from 10 to 14 years old (19.7%). Regarding the circumstances, intoxication occurred due to suicide attempts (16.8%) and accidental events (23.2%) in adolescents and children, respectively. The study revealed a higher frequency of poisoning in girls. CONCLUSION: Exogenous intoxications occurred predominantly in children up to 4 years old, through the accidental consumption of food or drinks. Thus, the adoption of educational prevention programs for children's family members and caregivers is necessary. PMID- 25510990 TI - [Diagnosis of streptococcal pharyngotonsillitis in children and adolescents: clinical picture limitations]. AB - OBJECTIVE: To assess the utility of clinical features for diagnosis of streptococcal pharyngotonsillitis in pediatrics. METHODS: A total of 335 children aged 1-18 years old and presenting clinical manifestations of acute pharyngotonsillitis (APT) were subjected to clinical interviews, physical examinations, and throat swab specimen collection to perform cultures and latex particle agglutination tests (LPATs) for group A streptococcus (GAS) detection. Signs and symptoms of patients were compared to their throat cultures and LPATs results. A clinical score was designed based on the multivariate logistic regression analysis and also was compared to throat cultures and LPATs results. Positive throat cultures and/ or LPATs results were used as a reference standard to establish definitive streptococcal APT diagnosis. RESULTS: 78 children (23.4%) showed positivity for GAS in at least one of the two diagnostic tests. Coryza absence (odds ratio [OR]=1.80; p=0.040), conjunctivitis absence (OR=2.47; p=0.029), pharyngeal erythema (OR=3.99; p=0.006), pharyngeal exudate (OR=2.02; p=0.011), and tonsillar swelling (OR=2.60; p=0.007) were significantly associated with streptococcal pharyngotonsilitis. The highest clinical score, characterized by coryza absense, pharyngeal exudate, and pharyngeal erythema had a 45.6% sensitivity, a 74.5% especificity, and a likelihood ratio of 1.79 for streptococcal pharyngotonsilitis. CONCLUSIONS: Clinical presentation should not be used to confirm streptococcal pharyngotonsilitis, because its performance as a diagnostic test is low. Thus, it is necessary to enhance laboratory test availability, especially of LPATs that allow an acurate and fast diagnosis of streptococcal pharyngotonsilitis. PMID- 25510993 TI - [The effect of air pollutants on birth weight in medium-sized towns in the state of Sao Paulo]. AB - OBJECTIVE: To investigate the effect of air pollution on birth weight in a medium sized town in the State of Sao Paulo, Southeast Brazil. METHODS: Cross-sectional study using data of live births to mothers residing in Sao Jose dos Campos from 2005 to 2009. Data was obtained from the Department of Information and Computing of the Brazilian Unified Health System. Air pollutant data (PM, SO and O) and daily averages of their concentrations were obtained from the Environmental Sanitation & Technology Company. Statistical analysis was performed by linear and logistic regressions using the Excel and STATA v.7 software programs. RESULTS: Maternal exposure to air pollutants was not associated with low birth weight, with the exception of exposure to SO within the last month of pregnancy (OR=1,25; IC95% 1,00-1,56). Maternal exposure to PM and SO during the last month of pregnancy led to lower weight at birth (0.28 g and 3.15 g, respectively) for each 1mg/m(3) increase in the concentration of these pollutants, but without statistical significance. CONCLUSIONS: This study failed to identify a statistically significant association between the levels of air pollutants and birth weight, with the exception of exposure to SO within the last month of pregnancy. PMID- 25510994 TI - [Prevalence and clinical characteristics of wheezing in children in the first year of life, living in Cuiaba, Mato Grosso, Brazil]. AB - OBJECTIVE: To evaluate the prevalence and the clinical characteristics of wheezing in 12-15 months old infants in the city of Cuiaba, Mato Grosso State, Midwest Brazil. METHODS: Parents and/or guardians of infants were interviewed and completed a written standardized questionnaire of the "Estudio Internacional de Sibilancia en Lactantes" (EISL) - phase 3 at primary health care clinics at the same day of children vaccination or at home, from August 2009 to November 2010. RESULTS: 1,060 parents and/or guardians completed the questionnaire, and 514 (48.5%) infants were male. Among the studied infants, 294 (27.7%) had at least one episode of wheezing during the first year of life, beginning at 5.8+/-3.0 months of age, with a predominance of male patients. The prevalence of occasional wheezing (<3 episodes of wheezing) was 15.0% and recurrent wheezing (>= 3 episodes) was 12.7%. Among the infants with recurrent wheezing, the use of inhaled beta2-agonist, oral corticosteroid, leukotriene receptor antagonist, as well as night symptoms, respiratory distress and hospitalization due to severe episodes were significantly more frequent. Physician-diagnosed asthma was observed in 28 (9.5%) of the wheezing infants. Among the wheezing infants, 80 (27.7%) were diagnosed with pneumonia, of whom 33 (11.2%) required hospitalization, neverthless no differences between occasional and recurrent wheezing infants were found. CONCLUSIONS: The prevalence of recurrent wheezing and physician-diagnosed asthma in infants were lower compared with those found in other Brazilian studies Recurrent wheezing had early onset and high morbity. PMID- 25510995 TI - [Pulmonary function of children with acute leukemia in maintenance phase of chemotherapy]. AB - OBJECTIVE: The aim of this study was to assess the pulmonary function of children with acute leukemia. METHODS: Cross-sectional observational analytical study that enrolled 34 children divided into groups A (17 with acute leukemia in the maintenance phase of chemotherapy) and B (17 healthy children). The groups were matched for sex, age and height. Spirometry was measured using a spirometer Microloop Viasys((r)) in accordance with American Thoracic Society and European Respiratory Society guidelines. Maximal respiratory pressures were measured with an MVD300 digital manometer (Globalmed((r))). Maximal inspiratory pressures and maximal expiratory pressures were measured from residual volume and total lung capacity, respectively. RESULTS: Group A showed a significant decrease in maximal inspiratory pressures when compared to group B. No significant difference was found between the spirometric values of the two groups, nor was there any difference between maximal inspiratory pressure and maximal expiratory pressure values in group A compared to the lower limit values proposed as reference. CONCLUSION: Children with acute leukemia, myeloid or lymphoid, during the maintenance phase of chemotherapy exhibited unchanged spirometric variables and maximal expiratory pressure; However, there was a decrease in inspiratory muscle strength. PMID- 25510996 TI - [Should pediatric parenteral nutrition be individualized?]. AB - INTRODUCTION: Parenteral nutrition (PN) formulations are commonly individualized, since their standardization seem inadequate for the pediatric population. This study aimed to evaluate the nutritional state and the reasons for PN individualization in pediatric patients using PN hospitalized in a tertiary hospital in Campinas, Sao Paulo. METHODS: This longitudinal study comprised patients using PN followed by up to 67 days. Nutritional status was classified according to the criteria established by the World Health Organization (WHO) (2006) and WHO (2007). The levels of the following elements on blood were analyzed: sodium, potassium, ionized calcium, chloride, magnesium, inorganic phosphorus and triglycerides (TGL). Among the criteria for individualization, were considered undeniable: significant reduction in blood levels of potassium (<3 mEq/L), sodium (<125 mEq/)L, magnesium (<1 mEq/L), phosphorus (<1.5 mEq/L), ionic calcium (<1 mmol) and chloride (<90 mEq/L) or any value above the references. RESULTS: Twelve pediatric patients aged 1 month to 15 years were studied (49 individualizations). Most patients were classified as malnourished. It was observed that 74/254 (29.2%) of examinations demanded individualized PN by indubitable reasons. CONCLUSION: The nutritional state of patients was considered critical in most cases. Thus, the individualization performed in the beginning of PN for energy protein adequacy was indispensable. In addition, the individualized PN was indispensable in at least 29.2% of PN for correction of alterations found in biochemical parameters. PMID- 25510997 TI - [Anthropometric indices among schoolchildren from a municipality in Southern Brazil: a descriptive analysis using the LMS method]. AB - OBJECTIVE: To describe the percentile values for body mass index (BMI), waist circumference (WC) and waist-to-height (WHtR) of children from Colombo, Brazil, and compare them with data of children from other countries. METHODS: This was a cross-sectional study with a random sample of 2,035 children aged 6-11 years. Age and sex-specific smoothed percentiles curves for BMI, WC and WHtR were created using the LMS method. Values of 10(th), 50(th) and 90(th) percentiles from Brazilian children were compared with data from other countries. RESULTS: There was a trend of increasing BMI and WC with age in both sexes. WHtR remained constant with advancing age in boys and girls. Comparison of the growth pattern among countries showed clear differences. Southern Brazil boys and girls had elevated 90(th) percentile values for BMI, which was similar to German children and higher than the North American and World Health Organization percentile values. However, children from this study had intermediate values for WC and WHtR in comparison to children from other countries. CONCLUSIONS: Elevated BMI values were observed among southern Brazilian children, but WC and WHtR percentile values were lower in southern Brazilian children than in children from other countries. Interventions at different levels should be made to avoid a probable increase of nutritional disorders (especially general obesity) in the next years. PMID- 25510998 TI - [Physical, clinical, and psychosocial parameters of adolescents with different degrees of excess weight]. AB - OBJECTIVE: To compare body composition, hemodynamic parameters, health-related physical fitness, and health-related quality of life of adolescents with anthropometric diagnosis of overweight, obesity, and severe obesity. METHODS: 220 adolescents with excess body weight were enrolled. They were beginners in a intervention program that included patients based on age, availability, presence of excess body weight, place of residence, and agreement to participate in the study. This study collected anthropometric and hemodynamic variables, health related physical fitness, and health-related quality of life of the adolescents. To compare the three groups according to nutritional status, parametric and non parametric tests were applied. Significance level was set at p<0.05. RESULTS: There was no significant difference in resting heart rate, health-related physical fitness, relative body fat, absolute and relative lean mass, and health related quality of life between overweight, obese, and severely obese adolescents (p>0.05). Body weight, body mass index, waist and hip circumference, and systolic blood pressure increased as degree of excess weight increased (p<0.05). Dyastolic blood pressure of the severe obesity group was higher than the other groups (p<0.05). There was an association between the degree of excess weight and the prevalence of altered blood pressure (overweight: 12.1%; obesity: 28.1%; severe obesity: 45.5%; p<0.001). The results were similar when genders were analyzed separately. CONCLUSION: Results suggest that overweight adolescents presented similar results compared to obese and severely obese adolescents in most of the parameters analyzed. PMID- 25511000 TI - [Factors associated with low levels of lumbar strength in adolescents in Southern Brazil]. AB - OBJECTIVE: To determine the prevalence and factors associated with low levels of lumbar strength in adolescents. METHOD: This was a cross-sectional study involving 601 adolescents, aged 14 to 17 years, enrolled in public schools in the western region of Santa Catarina State - Southern Brazil. Lumbar strength was analyzed by the lumbar extension test developed by the Canadian Society of Exercise Physiology, which proposes different cutoffs for boys and girls. Independent variables were sex, age, socioeconomic status, dietary habits, alcohol consumption, physical activity, and aerobic fitness. For data analysis, univariate and multivariate logistic regression were used, with significance level of 5%. RESULTS: The prevalence of low levels of lumbar strength was 27.3%. The population subgroups most likely to present low levels of lumbar strength were females (OR: 1.54, 95% CI: 1.06 to 2.23), adolescents with low levels of aerobic fitness (OR: 2.10, 95% CI: 1.41 to 3.11) and the overweight (OR: 2.28, 95% CI: 1.35 to 3.81). CONCLUSION: Almost one-third of the studied students have low levels of lumbar strength. Interventions in the school population should be taken with special attention to female adolescents, those with low levels of aerobic fitness, and those with overweight, as these population subgroups were most likely to demonstrate low levels of lumbar strength. PMID- 25510999 TI - [Nutritional status, metabolic changes and white blood cells in adolescents]. AB - OBJECTIVE: To analyze the relationship between the peripheral blood white cells, metabolic changes, and nutritional status of adolescents with and without excess weight and body fat. METHODS: This cross-sectional study evaluated the body mass index (BMI) and percentage body fat (%BF) in 362 adolescents from 15 to 19 years of age, of both sexes. White blood cell count, platelet count, uric acid, fasting glucose, insulin, and lipid profile were measured. The inclusion criteria were agreement to participate in the study and signature of the informed consent. Exclusion criteria were: presence of chronic or infectious disease; use of medications that could cause changes in biochemical tests; pregnancy; participation in weight reduction and weight control programs; use of diuretics and laxatives; or the presence of a pacemaker. The following statistical tests were applied: Kolmogorov-Smirnov test, Student's t or Mann-Whitney test, Pearson or Spearman correlation tests, and chi-squared test, considering p<0.05. RESULTS: Overweight was observed in 20.7% of adolescents. The total cholesterol (TC) had a higher percentage of inadequacy (52.2%), followed by high-density lipoprotein (HDL) (38.4%). There was a positive correlation between white cells and serum lipids, insulin, body fat, and BMI. Monocytes were negatively correlated with BMI, and rods with BMI, body fat, and insulin. CONCLUSIONS: Nutritional status is related to an inflammatory process, and adolescents with excess weight or body fat presented higher amounts of white blood cells. PMID- 25511001 TI - [Vulnerabilities of children admitted to a pediatric inpatient care unit]. AB - OBJECTIVE: To identify the vulnerabilities of children admitted to a pediatric inpatient unit of a university hospital. METHODS: Cross-sectional, descriptive study from April to September 2013 with 36 children aged 30 days to 12 years old, admitted to medical-surgical pediatric inpatient units of a university hospital and their caregivers. Data concerning sociocultural, socioeconomic and clinical context of children and their families were collected by interview with the child caregiver and from patients' records, and analyzed by descriptive statistics. RESULTS: Of the total sample, 97.1% (n=132) of children had at least one type of vulnerability, the majority related to the caregiver's level of education, followed by caregiver's financial situation, health history of the child, caregiver's family situation, use of alcohol, tobacco, and illicit drugs by the caregiver, family's living conditions, caregiver's schooling, and bonding between the caregiver and the child. Only 2.9% (n=4) of the children did not show any criteria to be classified in a category of vulnerability. CONCLUSIONS: Most children were classified has having a social vulnerability. It is imperative to create networks of support between the hospital and the primary healthcare service to promote healthcare practices directed to the needs of the child and family. PMID- 25511002 TI - [Spatial analysis of neonatal mortality in the state of Sao Paulo, 2006-2010]. AB - OBJECTIVE: The aim of this study was to identify spatial patterns of distribution of overall, early, and late neonatal mortality rates in Sao Paulo state. METHODS: An ecological and exploratory study was carried in micro-regions of Sao Paulo sate. Mortality rates per 1,000 live births (LB) were calculated using data on overall, early, and late neonatal mortality in Sao Paulo between 2006 and 2010; these data were obtained from Information System and Information Technology Department of the Brazilian National Healthcare System (DATASUS). The global Moran's indices (I) were calculated for rates and thematic maps were built with these rates. Micro-regions with a high priority for intervention were identified by the box map. The software TerraView 4.2.1 was used for spatial analysis. RESULTS: The rates of early and late neonatal mortality were 6.2 per thousand LB and 2.5 per thousand LB, respectively. The global Moran's indexes (I) were I=0.13, I=0.15, and I=0.26 for overall, early, and late neonatal mortality rates, respectively; all global Moran's indices showed p-values <0.05. Thematic maps showed clusters of micro-regions with high rates located in the southwest and east of the state. CONCLUSION: The results presented in this study allow the implementation of policies by health managers, aiming to reduce neonatal mortality. PMID- 25511003 TI - [Extremes of maternal age and child mortality: analysis between 2000 and 2009]. AB - OBJECTIVE: To analyze the characteristics of infant mortality at the extremes of maternal age. METHOD: Retrospective, cross-sectional quantitative study using data from Live Birth Certificates, Death Certificates and from Child Death Investigation records in Londrina, Parana, in the years of 2000-2009. RESULTS: During the 10-year study period, there were 176 infant deaths among mothers up to 19 years of age, and 113 deaths among mothers aged 35 years or more. The infant mortality rate among young mothers was 14.4 deaths per thousand births, compared to 12.9 deaths in the other age group. For adolescent mothers, the following conditions prevailed: lack of a stable partner (p<0.001), lack of a paid job (p<0.001), late start of prenatal care in the second trimester of pregnancy (p<0.001), fewer prenatal visits (p<0.001) and urinary tract infections (p<0.001). On the other hand, women aged 35 or more had a higher occurrence of hypertension during pregnancy (p<0.001), and of surgical delivery (p<0.001). Regarding the underlying cause of infant death, congenital anomalies prevailed in the group of older mothers (p=0.002), and external causes were predominant in the group of young mothers (p=0.019). CONCLUSION: Both age groups deserve the attention of social services for maternal and child health, especially adolescent mothers, who presented a higher combination of factors deemed hazardous to the child's health. PMID- 25511004 TI - [Impact of a virtual reality-based intervention on motor performance and balance of a child with cerebral palsy: a case study]. AB - OBJECTIVE: To verify the effect of an intervention protocol using virtual reality (VR) on the motor performance and balance of a child with cerebral palsy (CP). CASE DESCRIPTION: To comply with the proposed objectives, a 7-year old child with spastic hemiplegic cerebral palsy (cP), GMFcS level I, was submitted to a physiotherapy intervention protocol of 12 45-minute sessions, twice a week, using virtual reality-based therapy. The protocol used a commercially-available console (XBOX((r))360 Kinect((r))) able to track and reproduce body movements on a screen. Prior to the intervention protocol, the child was evaluated using the Motor Development Scale (MDS) and the Pediatric Balance Scale (PBS) in order to assess motor development and balance, respectively. Two baseline assessments with a 2-week interval between each other were carried out for each tool. Then, the child was re-evaluated after the twelfth session. The results showed no changes in the two baseline scores. After the intervention protocol, the child improved his scores in both tools used: the PBS score increased by 3 points, reaching the maximal score, and the MDS increased from a much inferior motor performance to just an inferior motor performance. COMMENTS: The evidence presented in this case supports the use of virtual reality as a promising tool to be incorporated into the rehabilitation process of patients with neuromotor dysfunction. PMID- 25511005 TI - [Pain assessment scales in newborns: integrative review]. AB - OBJECTIVE: To analyze studies on methods used to assess pain in newborns. DATA SOURCES: Integrative review study of articles published from 2001 to 2012, carried out in the following databases: Scopus, PubMed, CINAHL, LILACS and Cochrane. The sample consisted of 13 articles with level of evidence 5. DATA SYNTHESIS: 29 pain assessment scales in newborns, including 13 one-dimensional and 16 multidimensional, that assess acute and prolonged pain in preterm and full term infants were available in scientific publications. CONCLUSION: Based on the characteristics of scales, one cannot choose a single one as the most appropriate scale, as this choice will depend on gestational age, type of painful stimulus and the environment in which the infant is inserted. It is suggested the use of multidimensional or one-dimensional scales; however, they must be reliable and validated. PMID- 25511006 TI - [Nutritional impact of inflammatory bowel diseases on children and adolescents]. AB - OBJECTIVE: To perform a systematic review of the literature about the nutritional impact of inflammatory bowel diseases in children and adolescents. DATA SOURCES: A systematic review was performed using PubMed/MEDLINE, LILACS and SciELo databases, with inclusion of articles in Portuguese and in English with original data, that analyzed nutritional aspects of inflammatory bowel diseases in children and adolescents. The initial search used the terms "inflammatory bowel diseases" and "children" or "adolescents" and "nutritional evaluation" or "nutrition deficiency". The selection of studies was initially performed by reading the titles and abstracts. Review studies and those without data for pediatric patients were excluded. Subsequently, the full reading of the articles considered relevant was performed. RESULTS: 237 studies were identified, and 12 of them were selected according to the inclusion criteria. None of them was performed in South America. During the analysis of the studies, it was observed that nutritional characteristics of patients with inflammatory bowel disease may be altered; the main reports were related to malnutrition, growth stunting, delayed puberty and vitamin D deficiency. CONCLUSION: There are nutritional consequences of inflammatory bowel diseases in children and adolescents, mainly growth stunting, slower pubertal development, underweight and vitamin deficiencies. Nutritional impairments were more significant in patients with Crohn's disease; overweight and obesity were more common in patients with ulcerative rectocolitis. A detailed nutritional assessment should be performed periodically in children and adolescents with inflammatory bowel disease. PMID- 25511007 TI - Development of an improved vaccine evaluation protocol to compare the efficacy of Newcastle disease vaccines. AB - While there is typically 100% survivability in birds challenged with vNDV under experimental conditions, either with vaccines formulated with a strain homologous or heterologous (different genotype) to the challenge virus, vaccine deficiencies are often noted in the field. We have developed an improved and more stringent protocol to experimentally evaluate live NDV vaccines, and showed for the first time under experimental conditions that a statistically significant reduction in mortality can be detected with genotype matched vaccines. Using both vaccine evaluation protocols (traditional and improved), birds were challenged with a vNDV of genotype XIII and the efficacy of live heterologous (genotype II) and homologous (genotype XIII) NDV vaccines was compared. Under traditional vaccination conditions there were no differences in survival upon challenge, but the homologous vaccine induced significantly higher levels of antibodies specific to the challenge virus. With the more stringent challenge system (multiple vaccine doses and early challenge with high titers of vNDV), the birds administered the homologous vaccine had superior humoral responses, reduced clinical signs, and reduced mortality levels than those vaccinated with the heterologous vaccine. These results provide basis for the implementation of more sensitive methods to evaluate vaccine efficacy. PMID- 25511008 TI - Teriflunomide for the treatment of relapsing-remitting multiple sclerosis. AB - Teriflunomide, a once-daily, oral disease-modifying therapy, is a valuable new treatment option for the management of patients with relapsing-remitting multiple sclerosis. This article reviews key efficacy and safety data arising from pivotal teriflunomide studies that demonstrate the utility in treating both treatment naive patients and those previously treated with another disease-modifying therapy who, for a variety of reasons, may require an alternative treatment. PMID- 25511009 TI - A Brown Mesoporous TiO2-x /MCF Composite with an Extremely High Quantum Yield of Solar Energy Photocatalysis for H2 Evolution. AB - A brown mesoporous TiO2-x /MCF composite with a high fluorine dopant concentration (8.01 at%) is synthesized by a vacuum activation method. It exhibits an excellent solar absorption and a record-breaking quantum yield (Phi = 46%) and a high photon-hydrogen energy conversion efficiency (eta = 34%,) for solar photocatalytic H2 production, which are all higher than that of the black hydrogen-doped TiO2 (Phi = 35%, eta = 24%). The MCFs serve to improve the adsorption of F atoms onto the TiO2 /MCF composite surface, which after the formation of oxygen vacancies by vacuum activation, facilitate the abundant substitution of these vacancies with F atoms. The decrease of recombination sites induced by high-concentration F doping and the synergistic effect between lattice Ti(3+)-F and surface Ti(3+)-F are responsible for the enhanced lifetime of electrons, the observed excellent absorption of solar light, and the photocatalytic production of H2 for these catalysts. The as-prepared F-doped composite is an ideal solar light-driven photocatalyst with great potential for applications ranging from the remediation of environmental pollution to the harnessing of solar energy for H2 production. PMID- 25511010 TI - Nanostructured microfluidic digestion system for rapid high-performance proteolysis. AB - A novel microfluidic protein digestion system with a nanostructured and bioactive inner surface was constructed by an easy biomimetic self-assembly strategy for rapid and effective proteolysis in 2 minutes, which is faster than the conventional overnight digestion methods. It is expected that this work would contribute to rapid online digestion in future high-throughput proteomics. PMID- 25511011 TI - Behavior and body mass changes of a mother and calf Pacific walrus (Odobenus rosmarus divergens) during the suckling period. AB - The behavior of a 13-year-old female Pacific walrus and her first calf is described during the first 7 months of the 19-month suckling period. The calf vocalized before 62% of suckling sessions. The mother immediately responded after 84% of vocalizations; after 44% she allowed a suckling session. The number of suckling sessions per 24-h period decreased from on average nine in the second week after birth to two by the thirteenth week. Thereafter, the number of suckling sessions fluctuated between 3 and 5/day. The average suckling session duration increased from 4 min/day to around 17 min/day. The average effective suckling time per session increased from on average 2 to 10 min. The number of breaks decreased during the study period from around 40 to 20 per session. The mother spent on average 47% of her time resting, the calf 44%. The remaining time was spent in locomotion, and suckling, playing, investigating, and looking. Mother and calf spent on average 51% of time indoors. The mother spent 43% of her time in the water, the calf 39%. The calf's body mass at birth was 55 kg; it increased to 178 kg at 27 weeks. The mother did not eat for the first 5 days after delivery, and she ate less than usual during the next 6 days. The mother's mass eventually stabilized at 1024 kg (>before gestation). The calf was not given formula and was weaned onto fish. This is the first detailed description of a captive Pacific walrus's suckling period. It could benefit the husbandry of future captive-born walruses, and may elucidate the behavior of wild walruses during suckling. PMID- 25511012 TI - A Social-Cognitive Moderated Mediated Model of Psychological Safety and Empowerment. AB - This study examines the indirect role of psychological safety in shaping the four cognitions of psychological empowerment (i.e., meaning, competence, self determination, impact) through three social mechanisms: authentic interactions, spiritual development, and perceived organizational voice. Data were collected from 229 congregation members of a nondenominational church. Preliminary analyses reveal psychological safety is: (a) linked to all four empowerment cognitions, (b) associated with the three proximal social mechanisms, and (c) indirectly predicts three of the four empowerment cognitions through heightened level of authentic interactions, spiritual development, and perceived organizational voice. Moreover, extraversion moderated the relationship of psychological safety with authentic interactions which, in turn, strengthened the size of the indirect effect for the meaning subcomponent of empowerment. Overall, this study suggests empowerment research can draw upon the potential, but frequently untapped, benefits of cultivating a secure space to facilitate member motivation through sincerity, personal development, and perceived voice. PMID- 25511013 TI - Outcomes of adjuvant chemoradiation and predictors of survival after extended cholecystectomy in gall bladder carcinoma: a single institution experience from an endemic region. AB - PURPOSE: The purpose of the study was to analyse outcomes with adjuvant concurrent chemoradiotherapy (cCRT) followed by adjuvant chemotherapy (AC) in radically resected gall bladder carcinoma (GBC) in Indian patients. METHODS AND MATERIALS: We retrospectively reviewed the records of GBC patients who received adjuvant cCRT after extended cholecystectomy (EC) between January 2007 and December 2011. Patterns of recurrence, disease-free survival (DFS), overall survival (OS) and adverse prognostic factors were evaluated. RESULTS: Thirty-two patients were analysed. At a median follow-up of 53 months, 40 % of patients had recurrence either locoregionally (12 %) or had distant metastases (28 %). The 5 year OS and DFS was 25 % and 53 %, respectively. When prognostic factors were evaluated, the median OS was 51 versus 23 months for node-negative (n = 8) versus node-positive disease (n = 24), not reached versus 34 months for stage 2 (n = 4) versus for stage 3 (n = 28), 46 versus 23 months for R0 (n = 11) versus R1 resection (n = 21), 51 versus 12 months (p = 0.15) for well-differentiated (n = 16) versus poorly differentiated tumours (n = 8), and 10 versus 51 months for lymphovascular invasion presence (n = 4) versus absence (n = 28) (p = 0.01). CONCLUSION: Outcome in Indian patients with cCRT followed by AC is similar to that reported in the literature. Adjuvant cCRT followed by AC improves outcomes in patients with R1 and node-positive disease. Advanced stage, nodal positivity, poor differentiation, presence of perineural invasion and lymphovascular invasion are adverse prognostic features. Further research is required with treatment intensification in patients with adverse prognostic factors to improve outcome. PMID- 25511014 TI - Comparison of clinical and cone beam computed tomography measurements to diagnose furcation involvement. AB - AIM: This study aimed to determine the degree of discrepancy between clinical measurement of furcation involvement (FI) and cone beam computed tomography image analysis of multirooted teeth. METHODS: FI measurements obtained from clinical records were compared to CBCT images of the same teeth to determine the degree of discrepancy between CBCT FI grading and clinical FI grading. RESULTS: Of the hundred and fifty-four sites analysed, 22% of FI measurements from probing and CBCT were in agreement. Fifty-eight percent of clinical FI recordings were overestimated, and 20% were underestimated when compared to CBCT analysis. CONCLUSION: Clinical recording of FI is both over and underestimated compared to CBCT analysis. This was highest for probing recording grade I furcation involvement where it was highly overestimated. The occurrence of over and under estimation of FI will affect the assignment of prognosis to multirooted teeth, which can influence treatment planning for periodontal therapy and may result in inappropriate treatment. PMID- 25511015 TI - Prolonged complete remission of metastatic HER2-positive breast cancer after continuous trastuzumab treatment: a case report and review of the literature. AB - Metastatic breast cancer is considered an incurable disease. Targeted treatments against the human epidermal growth factor receptor 2 (HER2), however, significantly improve survival in patients with metastatic HER2-positive breast cancer. Some patients may respond with prolonged complete remission. Evidence on safety of long-term trastuzumab and risk of relapse after trastuzumab cessation is limited. We present a case of an 81-year-old patient with HER2-amplified metastatic breast cancer (MBC) in the liver. Following taxane-based chemotherapy in combination with trastuzumab after local treatment resulted in a complete radiological remission after 21 months of trastuzumab maintenance therapy. The patient remains in complete remission 6 years later and continues to receive trastuzumab as maintenance therapy. Prolonged remission in cases with complete response under trastuzumab-based regimens for metastatic HER2-positive breast cancer can be observed in some patients. Reviewing the few available cases published in the literature, these patients share some common characteristics: hormone receptor negative disease and metastases to the liver. There is no evidence that trastuzumab maintenance treatment can be safely interrupted after a certain time period. PMID- 25511016 TI - [Fetal death beyond 14 weeks of gestation: induction of labor and obtaining of uterine vacuity]. AB - The objective of this review was to assess benefits and harms of different management options for induction of labor and obtaining of uterine vacuity in case of fetal death beyond of 14 weeks of gestation. In second-trimester, the data are numerous but low methodological quality. In terms of efficiency (induction-expulsion time and uterine evacuation within 24 hours rate) and tolerance in the absence of antecedent of caesarean section, the best protocol for induction of labor in the second-trimester of pregnancy appears to be mifepristone 200mg orally followed 24-48 hours later by vaginal administration of misoprostol 200 to 400 MUg every 4 to 6 hours. In third-trimester, there is very little data. The circumstances are similar to induction of labor with living fetus. A term or near term, oxytocin and dinoprostone have a marketing authorization in this indication but misoprostol may be an alternative as the Bishop score and dose of induction of labor with living fetus. In case of previous caesarean section, the risk of uterine rupture is increased in case of a medical induction of labor with prostaglandins. The lowest effective doses should be used (100 to 200 MUg every 4 to 6 hours). Prior cervical preparation by the administration of mifepristone and possibly the use of laminar seems essential in this situation. PMID- 25511017 TI - [E.G. Simon, S. Calle, F. Perrotin in reply to the article by L. Sonnier et al. Elastography of cervix to predict delay from induction ot delivery. Gynecol Obstet Fertil 2014;42:827-31]. PMID- 25511019 TI - Kimura's disease of the lacrimal gland mimicking IgG4-related orbital disease. AB - BACKGROUND: Kimura's disease (KD) is a rare and benign chronic inflammatory soft tissue disorder of unknown origin, which predominantly inflicts young male adults in Asia. IgG4-related disease is a new disease concept, established this century and characterized by fibrosis and sclerosis of the involved organs, with infiltration of IgG4-positive plasma cells. These two kinds of diseases share similar characteristics, which may complicate their diagnosis. CASE PRESENTATION: A 47-year-old Chinese man presented to our Department of Ophthalmology with a 26 month history of painless swelling and redness left upper eyelid. Surgical excisions of the left lacrimal gland were performed. A histopathology examination showed follicular hyperplasia with reactive germinal centres and eosinophilic infiltration involving the interfollicular areas as well as proliferation of post capillary venules, all signs of Kimura disease. Immunohistochemical analysis of the cells demonstrated positive staining for CK, Vimentin, CD3, CD4, CD20, CD21, CD117, CD5, CD8, CD23, IgG and IgG4 (30 per high-power field) and negative staining for CD10 and CD34. Some ophthalmologists in our department questioned whether the histological and immunohistochemical findings were also compatible with features of IgG4-related diseases. There was no sign of recurrence during the twelve months of regular follow-up. CONCLUSION: Kimura's disease may present with high serum IgG4 levels, which may be an epiphenomenon related to chronic antigen exposure. As clinical doctors, especially ophthalmologists, we should recognize the possibility of the occurrence of increased serum levels of IgG4 in Kimura's disease to ensure correct diagnosis. PMID- 25511020 TI - Single center experience: Implantation failures, early, and late complications after implantation of a partially biodegradable ASD/PFO-device (BioStar(r)). AB - INTRODUCTION: In the search for a biodegradable device that leaves nothing but the tissue of the patient after complete endotheliazation and absorption, the BioSTAR(r) device was introduced in 2007 (CE Mark in European community and HPB in Canada) for ASD and PFO closure. It consists of a metal framework covered by a biodegradable membrane generated from a layer of porcine collagen that is broken down and absorbed over time. In a sheep model, the results were promising, showing complete closure of the defect with degradation of approximately 90% of the implanted membrane material after two years. METHODS: We report a retrospective analysis of implantation failures, early and late complications in a series of 34 patients with 30 implanted BioStar(r) devices in a single center with a total follow-up of more than 75 patient years. RESULTS: We report 12% of implantation failures, 9% of early and 12% of late complications. Implantation failures include one embolized device, which was interventionally retrieved. Early complications were exclusively rhythm disturbances, one patient needed electrical and pharmacological therapy. Four relevant late complications occurred. One device required explantation after 61 days because of recurrent severe fever episodes, severe headache, and malaise that subsequently subsided after device removal. One patient presented with Dressler's syndrome with pericardial effusion 5 month after implantation requiring pericardiocentesis and steroid treatment. One device showed a central residual shunt that was not clearly seen initially. Finally, one device was explanted after hemorrhagic pericardial effusion due to perforation of an arm of the frame through the right atrial roof into the pericardial fold after 19 months. CONCLUSION: We conclude that implantation of the Biostar(r) device is difficult in patients with deficient aortic rims and early complications are similar to those seen in other devices. Of importance, the late complications seen with the Biostar(r) device might be attributable to specific material and immunological properties of the partially biodegradable device. Although a biodegradable device might theoretically be more favorable more efforts for optimization of these devices have to be taken. PMID- 25511018 TI - Transient transfection of human CDNF gene reduces the 6-hydroxydopamine-induced neuroinflammation in the rat substantia nigra. AB - BACKGROUND: The anti-inflammatory effect of the cerebral dopamine neurotrophic factor (CDNF) was shown recently in primary glial cell cultures, yet such effect remains unknown both in vivo and in 6-hydroxydopamine (6-OHDA) models of Parkinson's disease (PD). We addressed this issue by performing an intranigral transfection of the human CDNF (hCDNF) gene in the critical period of inflammation after a single intrastriatal 6-OHDA injection in the rat. METHODS: At day 15 after lesion, the plasmids p3xNBRE-hCDNF or p3xNBRE-EGFP, coding for enhanced green florescent protein (EGFP), were transfected into the rat substantia nigra (SN) using neurotensin (NTS)-polyplex. At day 15 post transfection, we measured nitrite and lipoperoxide levels in the SN. We used ELISA to quantify the levels of TNF-alpha, IL-1beta, IL-6, endogenous rat CDNF (rCDNF) and hCDNF. We also used qRT-PCR to measure rCDNF and hCDNF transcripts, and immunofluorescence assays to evaluate iNOS, CDNF and glial cells (microglia, astrocytes and Neuron/Glial type 2 (NG2) cells). Intact SNs were additional controls. RESULTS: In the SN, 6-OHDA triggered nitrosative stress, increased inflammatory cytokines levels, and activated the multipotent progenitor NG2 cells, which convert into astrocytes to produce rCDNF. In comparison with the hemiparkinsonian rats that were transfected with the EGFP gene or without transfection, 6-OHDA treatment and p3xNBRE-hCDNF transfection increased the conversion of NG2 cells into astrocytes resulting in 4-fold increase in the rCDNF protein levels. The overexpressed CDNF reduced nitrosative stress, glial markers and IL-6 levels in the SN, but not TNF-alpha and IL-1beta levels. CONCLUSION: Our results show the anti-inflammatory effect of CDNF in a 6-OHDA rat of Parkinson's disease. Our results also suggest the possible participation of TNF-alpha, IL 1beta and IL-6 in rCDNF production by astrocytes, supporting their anti inflammatory role. PMID- 25511021 TI - Cardiac axis shift within the cardiac cycle of normal fetuses and fetuses with congenital heart defect. AB - OBJECTIVES: To investigate changes in the cardiac axis (CAx) within the cardiac cycle of normal fetuses and fetuses with congenital heart defects (CHD). METHODS: This was a retrospective case-control study in which stored videoclips of four chamber views from 527 prenatal ultrasound examinations performed at 18 + 0 to 36 + 6 weeks of gestation were reviewed. Among the ultrasound scans included, 287 were of normal fetuses (controls) and 240 were of fetuses with CHD. In each case, the CAx was measured at end systole (just before the atrioventricular (AV) valve opened) and at end diastole (just before the AV valve closed). CAx measurements of fetuses with CHD were compared to those of controls. RESULTS: The mean CAx in the control group was 45.9 +/- 8.5 degrees at end systole and 38.3 +/- 8.4 degrees at end diastole (P < 0.001), resulting in an average difference of 7.6 +/- 3.2 degrees . The mean CAx in fetuses with CHD was 53.4 +/- 17.8 degrees at end systole and 47.5 +/- 17.3 degrees at end diastole (P < 0.001), resulting in an average difference of 5.9 +/- 6.3 degrees . However, in some forms of CHD, such as hypoplastic left heart syndrome and L-transposition of the great arteries, the CAx was greater at end diastole than at end systole, with a difference of more than 5 degrees . In 21.3% of control fetuses, there was a CAx shift within the cardiac cycle of >= 10 degrees . Abnormal CAx measured at end systole was strongly associated with CHD. CONCLUSIONS: Measurement of the CAx at end systole provides values that differ from those when measured at end diastole, in both normal fetuses and those with CHD. We recommend that the CAx be measured at end systole as a greater proportion of fetuses with CHD and fewer normal fetuses have an abnormal CAx at this stage compared to at end diastole. The occurrence of an abnormal CAx and the CAx shift within the fetal cardiac cycle depend on the type of CHD. PMID- 25511022 TI - Tiotropium as part of inhaled polytherapy: adherence and associated health-care utilization. AB - BACKGROUND AND OBJECTIVE: Previous studies had demonstrated association between Tiotropium therapy (once-daily inhaled anticholinergic) and reductions of exacerbations, improvements in dyspnoea and quality of life in chronic obstructive pulmonary disease (COPD) patients. Little is known about the influence of adherence to Tiotropium on health-care utilization. Our objective was to examine whether adherence to Tiotropium is associated with decreased health-care utilization. METHODS: A computerized medical database was used to identify patients with COPD registered in an academic pulmonology institute who began therapy of Tiotropium 18 mg between 2008 and 2011 (n = 193). Adherence was assessed by calculating the proportion of days covered and defined as coverage of at least 80% of the follow-up period. Adherence to long-acting beta-agonists and/or inhaled corticosteroids (LABA and/or ICS) and health-care utilization were analysed 1 year before and 2 years after initiation of Tiotropium. A multivariate regression model was applied to examine determinants of change in health-care utilization. RESULTS: The median age of study population was 67 (80% male). Forty one percent of study population (n = 79) adhered to Tiotropium. Hospitalization costs decreased 1 year following treatment initiation only among adherent patient when their adherence to LABA and/or ICS improved (beta = -463.6, P = 0.033). This cost did not change significantly in the consecutive second year (beta = 206.3, P = 0.583). CONCLUSIONS: Adherence to Tiotropium was associated with decreased hospitalizations only among patients who improved their adherence to LABA and/or ICS as well. Exploring reasons for high non-adherence and ways to improve adherence may optimize utilization of the scarce hospital resources. PMID- 25511023 TI - S100A4 expression and prognosis of gastric cancer: a meta-analysis. AB - The prognostic role of S100A4 in gastric cancer is still under debate. The present meta-analysis aimed to evaluate the relationship between S10A4 levels and the prognosis of gastric cancer. We performed a meta-analysis of published studies assessing the relationship between S100A4 and gastric cancer prognosis. We used the Revman 5.0 software to perform literature retrieval, article selection, data collection, and statistical analysis. A fixed-effect model was used to pool the hazard ratio (HR) and 95% confidence intervals (95%CI). A total of 7 eligible studies that included 1257 gastric cancer patients were analyzed. We did not find a prognostic value for S100A4 in gastric cancer (HR = 1.48, 95%CI = 0.77 to 2.82, P = 0.24). In conclusion, the present study indicated that S100A4 expression level is not a prognostic factor for gastric cancer. PMID- 25511024 TI - Genetic identification of Theobroma cacao L. trees with high Criollo ancestry in Soconusco, Chiapas, Mexico. AB - Criollo-type cacao trees are an important pool of genes with potential to be used in cacao breeding and selection programs. For that reason, we assessed the diversity and population structure of Criollo-type trees (108 cultivars with Criollo phenotypic characteristics and 10 Criollo references) using 12 simple sequence repeat (SSR) markers. Cultivars were selected from 7 demes in the Soconusco region of southern Mexico. SSRs amplified 74 alleles with an average of 3.6 alleles per population. The overall populations showed an average observed heterozygosity of 0.28, indicating heterozygote deficiency (average fixation index F = 0.50). However, moderate allelic diversity was found within populations (Shannon index for all populations I = 0.97). Bayesian method analysis determined 2 genetic clusters (K = 2) within individuals. In concordance, an assignment test grouped 37 multilocus genotypes (including 10 references) into a first cluster (Criollo), 54 into a second (presumably Amelonado), and 27 admixed individuals unassigned at the 90% threshold likely corresponding to the Trinitario genotype. This classification was supported by the principal coordinate analysis and analysis of molecular variance, which showed 12% of variation among populations (FST = 0.123, P < 0.0001). Sampled demes sites (1- 7) in the Soconusco region did not show any evidence of clustering by geographic location, and this was supported by the Mantel test (Rxy = 0.54, P = 0.120). Individuals with high Criollo lineage planted in Soconusco farms could be an important reservoir of genes for future breeding programs searching for fine, taste, flavor, and aroma cocoa. PMID- 25511025 TI - Genetic divergence among sweet corn lines estimated by microsatellite markers. AB - The purpose of this study was to analyze the genetic diversity of 15 sugary-1 sweet corn lines by microsatellite markers. One hundred pairs of simple sequence repeat primers that were mapped for field corn were tested. Of these primers, 15% were polymorphic, and all were selected for the evaluation. These primers identified a total of 39 alleles among the 15 loci that were evaluated. The number of alleles per locus in the genotypes ranged from 2 to 4, with an average of 2.60 alleles per locus; the highest number of alleles was observed at the loci Bnlg1083, Umc1241, and Umc1590. The occurrence of null alleles at locus Umc1363 was evident only in line DN44. The proportion of polymorphic loci was the highest in lines DN17.1 and DN6 (73.33%), whereas lines DN47, DN23, and DN28 were more monomorphic than other lines. The loci Bnlg1083 and Umc1506 were polymorphic in 8 and 7 lines, respectively, indicating that these loci might be effective and promising for the identification of polymorphism in other sweet corn lines. The genetic diversity calculated by Rogers' genetic distances indicated the lowest genetic similarity between lines DN9 and DN28 (0.7603) and the highest similarity between lines DN19 and DN6 (0.3724). The dendrogram obtained by the unweighted pair-group method based on arithmetic averages indicated the formation of 4 major groups, showing the crossing of the genotypes DN19 and DN6 with DN8 as a possible alternative for the expression of heterozygosis. PMID- 25511026 TI - Evaluation of whether the ACE gene I/D polymorphism constitutes a risk factor for chronic obstructive pulmonary disease in the Turkish population. AB - Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction that occurs as a result of the normal inflammatory process to protect against harmful irritants and chemicals. Another physiological regulatory process, the renin angiotensin system (RAS), plays an important role in the pathology of many diseases. Angiotensin converting enzyme (ACE) is a key enzyme of RAS. We investigated the frequency of the ACE gene I/D polymorphism in patients with COPD in Turkey. This study was performed on 47 unrelated patients with COPD and 64 healthy subjects. DNA samples were isolated from peripheral blood, and ACE DNA was amplified by polymerase chain reaction. The frequencies of ACE genotypes were 27.7, 55.3, and 17% for DD, ID, and II in the COPD group, respectively, and 43.8, 43.8, and 12.4% in the control group. There was no statistically significant difference between groups (X(2) = 3.078; df = 2; P = 0.220). The distributions of ACE gene D alleles were 38.2% (N = 52) in the COPD group and 61.8% (N = 84) in the control group; and those of I alleles were 48.8% (N = 42) in the COPD group and 51.2% (N = 44) in the control group. There was no statistically significant difference between groups for allele frequency (X(2) = 2.419; df = 2; P = 0.120). We believe these results can be useful for large-scale population genetic research considering the frequency of the ACE gene variation in COPD patients in the Turkish population. PMID- 25511027 TI - Therapeutic potential of mesenchymal stem cells to treat Achilles tendon injuries. AB - Rupture of the Achilles tendon diminishes quality of life. The gold-standard therapy is a surgical suture, but this presents complications, including wound formation and inflammation. These complications spurred evaluation of the therapeutic potential of mesenchymal stem cells (MSCs) from adipose tissue. New Zealand rabbits were divided into 6 groups (three treatments with two time points each) evaluated at either 14 or 28 days after surgery: cross section of the Achilles tendon (CSAT); CSAT + Suture; and CSAT + MSC. A comparison between all groups at both time points showed a statistically significant increase in capillaries and in the structural organization of collagen in the healed tendon in the CSAT + Suture and CSAT + MSC groups at the 14-day assessment. Comparison between the two time points within the same group showed a statistically significant decrease in the inflammatory process and an increase in the structural organization of collagen in the CSAT and CSAT + MSC groups. A study of the genomic integrity of the cells suggested a linear correlation between an increase of injuries and culture time. Thus, MSC transplantation is a good alternative for treatment of Achilles tendon ruptures because it may be conducted without surgery and tendon suture and, therefore, has no risk of adverse effects resulting from the surgical wound or inflammation caused by nonabsorbable sutures. Furthermore, this alternative treatment exhibits a better capacity for wound healing and maintaining the original tendon architecture, depending on the arrangement of the collagen fibers, and has important therapeutic potential. PMID- 25511028 TI - Tuberculoma masked by glioma: a case report. AB - Tuberculous meningitis (TM), a common infectious disease of the central nervous system that is also seen in other types of tuberculosis infections, has higher mortality rates in young and middle-aged patients. TM is difficult to diagnose and treat owing to its non-specific clinical features and often atypical cerebrospinal fluid changes. Patients who present with focal neurologic signs, cough, low-grade fever and illness duration of more than 5 days, have intracalvarial abnormalities, and do not meet Thwaites' criterion findings should be diagnosed using computed tomography or magnetic resonance imaging. Mycobacterium infections can also be diagnosed by acid-fast staining of smears, cerebrospinal fluid culture, diagnostic polymerase chain reaction for Mycobacterium tuberculosis, and purified protein derivative test. To prevent TM misdiagnosis, clinicians must have sufficient knowledge of the clinical manifestations of tuberculosis. Appropriate application of tuberculosis chemotherapy drug principles, including early diagnosis and treatment, combination therapies, and consistent administration of treatment at appropriate dosages, can greatly reduce TM mortality rates and improve satisfactory treatment outcomes. PMID- 25511029 TI - Genetic diversity of different populations and improved growth in the F1 hybrids in the swimming crab (Portunus trituberculatus). AB - The swimming crab, Portunus trituberculatus, is widely distributed throughout the coastal waters of Asian-Pacific nations and is an important economic species in this region. The aquaculture of swimming crabs has been plagued by problems associated with low growth rates, poor flesh quality, and weak disease resistance. To overcome these problems, selective breeding programs have been suggested as a means of genetically improving these traits in stock populations. In this study, we evaluated the genetic differentiation of 3 different geographical populations (Zhoushan: S; Laizhou Bay: L; and Haizhou Bay: H) using 8 polymorphic microsatellite loci. Nine strains of first filial generation were obtained, with 3 geographically populations as parental stock. We assessed the growth and survival rates of the F1 generation to identify new strains or breeds showing improvements in these economically important traits. Our results indicated that pairwise FST among populations was significantly higher than 0 (P = 0.0000) for every population pair, ranging from 0.0810 to 0.1083 for 3 different geographical populations. We observed significant heterosis for the growth and viability (survival) traits, although some strains (crossbred combinations) showed evidence of hybrid weakness in some growth measurements. One particular strain ("SL") outperformed other combinations, displaying the greatest extent of heterosis over the growth and viability (survival) traits. These results indicate that hybridization may be used to increase the performance of P. trituberculatus in aquaculture. PMID- 25511030 TI - Correlation of genetic variation among wild Trigonella foenum-graecum L. accessions with their antioxidant potential status. AB - In this study, we analyzed the correlation between genetic variation based on random amplified polymorphic DNA (RAPD), acid phosphatase, and glutamate oxaloacetate transaminase isozymes, and amino acid composition with the antioxidant potential status of 7 wild Trigonella foenum-graecum L. accessions collected from diverse ecogeographical regions. RAPD revealed that 90 DNA products had highly polymorphism value (94.12%) based on band numbers, with sizes ranging from 50-2100 base pairs, and band intensity. Of 49 DNA polymorphic bands, 31 unique and 3 monomorphic bands were scored. Acid phosphatase and glutamate oxaloacetate transaminase showed total polymorphism values of 90.00 and 93.75%, respectively, based on zymogram number, relative front (Rf), and optical intensity. Because isozymes are composed of amino acids, they were analyzed using high-performance liquid chromatography, which revealed the presences of 16 amino acids of variable content ranging from 13.21-15.35%, 9 of which are essential amino acids in humans. RAPD and isozymes showed similarly high estimates of genetic variability. Genetic relationships revealed by unweighted pair group method with arithmetic mean clustering analysis based on data obtained from all primers of RAPD and each isozyme were very similar. The antioxidant potential based on free radical scavenging, 2, 2-diphenyl-1-picrylhydrazyl, b-carotene linoleate, total phenolic, and flavonoid contents values were variable among accessions. We found that fenugreek is a valuable genetic resource with high antioxidant activity. Their genotypes, based on data and clustering of RAPD, isozymes, and variable amino acid contents, combined with their antioxidant potential statues are important in fenugreek breeding and improvement programs. PMID- 25511031 TI - Identification of differently expressed genes in leukemia using multiple microarray datasets. AB - The purpose of this study was to identify differentially expressed genes and analyze biological processes related to leukemia. A meta-analysis was performed using the Rank Product package of Gene Expression Omnibus datasets for leukemia. Next, Gene Ontology-enrichment analysis and pathway analysis were performed using the Gene Ontology website and Kyoto Encyclopedia of Genes and Genomes. A protein protein interaction network was constructed using the Cytoscape software. Using the Rank Product package for leukemia, we identified a total of 1294 differentially expressed genes, 357 of which were not involved in individual differentially expressed genes. Gene Ontology-enrichment analyses showed that these 357 genes were enriched in biological processes such as mRNA metabolism, RNA splicing, and mRNA processing. Pathway-enrichment analysis showed that the genes were involved in the intestinal immune network for IgA production, endocytosis, and the mitogen-activated protein kinase signaling pathway. The protein-protein interaction network indicated that HRAS, CD44, STAT1, SMAD2, and COPS5 were important in many interactions. Our study revealed genes that were consistently differentially expressed in leukemia, as well as the biological pathways and protein-protein interaction network associated with these genes. PMID- 25511032 TI - Analysis of the genetic diversity of Chinese native Cannabis sativa cultivars by using ISSR and chromosome markers. AB - Hemp (Cannabis sativa) is an important fiber crop, and native cultivars exist widely throughout China. In the present study, we analyzed the genetic diversity of 27 important Chinese native hemp cultivars, by using inter-simple sequence repeats (ISSR) and chromosome markers. We determined the following chromosome formulas: 2n = 20 = 14m + 6sm; 2n = 20 = 20m; 2n = 20 = 18m + 2sm; 2n = 20 = 16m + 4sm; and 2n = 20 = 12m + 8sm. The results of our ISSR analysis revealed the genetic relationships among the 27 cultivars; these relationships were analyzed by using the unweighted pair-group method based on DNA polymorphism. Our results revealed that all of the native cultivars showed considerable genetic diversity. At a genetic distance of 0.324, the 27 varieties could be classified into five categories; this grouping corresponded well with the chromosome formulas. All of the investigated hemp cultivars represent relatively primitive types; moreover, the genetic distances show a geographical distribution, with a small amount of regional hybridity. PMID- 25511033 TI - Clinical image and pathology of hypertrophic cranial pachymeningitis. AB - The objective of this study was to examine the clinical findings, magnetic resonance imaging (MRI), pathological features, and treatment experiments of patients with hypertrophic cranial pachymeningitis (HCP). The clinical findings, MRI, and pathological appearances of 9 patients with HCP were analyzed retrospectively. The thickened dura mater was markedly enhanced after contrast media injection. The lesion near the brain hemisphere presented long regions of T1- and T2-weighted abnormal signal intensities. The abnormal signal intensities of the brain tissue were decreased significantly. Pathological examination demonstrated chronic inflammation changes, with cerebral dura mater fibrous tissue showing obvious hyperplasia, and the periphery of the blood vessel showing a great quantity of infiltrating phlegmonosis cells. HCP mainly presents headache and paralysis of multiple cranial nerves. The distinctive signs on brain MRIs involve strengthening the signal in the cerebral dura. PMID- 25511034 TI - Assessing the genotoxicities of sparteine and compounds isolated from Lupinus mexicanus and L. montanus seeds by using comet assay. AB - The genus Lupinus is widely distributed. Its seeds are used for animal and human food, and Lupinus possesses pharmacological potential because of its high content of quinolizidine alkaloids and flavonoids; however, there is little available information about its genotoxicity. We used the comet assay and staminal nuclei of Tradescantia (clone 4430) to evaluate the in vitro genotoxicity of 4 concentrations (0.01, 0.1, 0.5, and 1.0 mM) of alkaloid extracts of Lupinus mexicanus and Lupinus montanus, flavonoids of L. mexicanus, and commercial sparteine; nitrosodiethylamine was used as a positive control and untreated nuclei were used as a negative control. All concentrations of L. mexicanus and L. montanus showed significant genotoxic activity (P <= 0.05). A similar behavior was observed for flavonoid extracts of L. montanus except the 1.0 mM concentration. Sparteine showed genotoxic activity only at 0.5 mM. The order of genotoxicity of the compounds studied was as follows: L. mexicanus > L. montanus > flavonoids of L. montanus > sparteine. There is evident genotoxic activity in the compounds that were studied, particularly at lower concentrations (0.01 and 0.1 mM). Given the limited information about the genotoxicity of the compounds of L. mexicanus and L. montanus, further studies are necessary. PMID- 25511035 TI - Nineteen polymorphic microsatellite markers developed for Trachinotus ovatus. AB - To evaluate the population genetic diversity of the ovate pompano, we isolated and characterized 19 microsatellite markers using a (CA)13-enriched genomic library. Polymorphism was assessed in 30 individuals from a single population collected from the Daya Bay Aquaculture Center, Guangdong, China. The number of alleles per locus ranged from 2 to 18 with an average of 7.8. The observed and expected heterozygosities varied from 0.2667 to 1.000 and from 0.3960 to 0.9435, respectively. Sixteen of 19 loci conformed to Hardy-Weinberg equilibrium, and no significant linkage disequilibrium was detected between any locus pairs. Our study supplies candidate microsatellite markers that can be useful for studying the population genetic structure of ovate pompano. PMID- 25511036 TI - Successful treatment of pituitary abscess with intravenous antibiotics: a case report and literature review. AB - Pituitary abscess is a rare intrasellar infectious disease. It is usually treated with a combination of surgical drainage and intravenous antibiotics. We describe the case of a 38-year-old man with headache, fever, left earache, subsequent diabetes insipidus, and anterior pituitary insufficiency due to pituitary abscess, which was confirmed on the basis of clinical symptoms, laboratory examination results, and magnetic resonance imaging features. He was treated nonsurgically with intravenous antibiotics, with complete resolution of the pituitary abscess and recovery of pituitary function. Nonsurgical treatment may be an option for pituitary abscess. PMID- 25511037 TI - Association between hypoxia-inducible factor-1a levels in serum and synovial fluid with the radiographic severity of knee osteoarthritis. AB - Osteoarthritis (OA) is primarily characterized by articular cartilage degradation. Hypoxia-inducible factor-1a (HIF-1a), a subunit of the basic helix loop-helix-containing PER-ARNT-SIM (PAS) domain transcription factors, plays a vital role in the survival of articular chondrocytes to the hostile hypoxic microenvironment and complicates the progression of OA. In this study, we examined whether HIF-1a levels in the serum and synovial fluid (SF) of patients with knee OA were increased and whether the increase was correlated with the radiographic severity of the disease. A total of 278 knee OA patients and 203 healthy controls were enrolled in this study. Knee OA radiographic grading was performed according to Kellgren-Lawrence (KL) grading system by evaluating X-ray changes observed on anteroposterior knee radiography. HIF-1a levels in the serum and SF were determined using an enzyme-linked immunosorbent assay. Serum HIF-1a levels in patients with knee OA were higher than those in healthy controls. Knee OA patients with KL grade 4 showed significantly elevated HIF-1a levels in the serum and SF compared with those with KL grades 2 and 3. Knee OA patients with KL grade 3 showed significantly higher SF levels of HIF-1a than those with KL grade 2. HIF-1a levels in the serum and SF of knee OA patients were significantly correlated with disease severity according to KL grading criteria. HIF-1a levels in the serum and SF were closely related to the radiographic severity of OA and may serve as an alternative biomarker for the progression and prognosis of knee OA. PMID- 25511038 TI - Acanthopanax senticosus attenuates inflammation in lipopolysaccharide-induced acute lung injury by inhibiting the NF-kappaB pathway. AB - The dried roots of the plant Acanthopanax senticosus (AS) are used in traditional Oriental medicine and reportedly possess anti-inflammatory properties in vitro. However, whether AS has the same anti-inflammatory effect in vivo and the underlying mechanisms of this action remain unknown. In this study, we pretreated a mouse model of lipopolysaccharide-induced acute lung injury with AS and found that the levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and neutrophils in bronchoalveolar lavage fluid were reduced and that inflammation in lung tissues was attenuated. To determine the mechanisms of these actions, we next assessed the effects of AS on the activation of the nuclear factor (NF)-kB pathway. We found that AS decreased the level of NF-kB and the DNA-binding activity of NF-kB. In summary, we found that AS attenuated the levels of TNF alpha and IL-6 in the lung tissue of a mouse model of acute lung injury by inhibiting the NF-kB pathway. PMID- 25511039 TI - Molecular characterization of tumor necrosis factor receptor-associated factor 6 (TRAF6) in pearl oyster Pinctada martensii. AB - Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a key signaling adaptor molecule for tumor necrosis factor receptor superfamily and Toll-like receptor/interleukin-1 receptor family members. It signals the upstream receptors and is involved in a wide range of biological functions, such as immunity and bone metabolism. In this report, the TRAF6 gene from the pearl oyster Pinctada martensii (designated as PmTRAF6) was identified and characterized. The obtained full-length PmTRAF6 cDNA was 2273 bp, containing a 5'-untranslated region (UTR) of 297 bp, a 3'-UTR of 128 bp with a 42-bp poly (A) tail, and an open reading frame of 1848 bp that encoded 616-amino acid residues. The deduced protein sequence of PmTRAF6 contained a conserved TRAF family motif including a RING-type zinc finger, two TRAF-type zinc fingers, and a coiled-coil region followed by one meprin and TRAF homology domain. Multiple-sequence alignment indicated that TRAF6 was highly conserved among species, and PmTRAF6 showed 53% sequence identity to Azumapecten farreri and Mizuhopecten yessoensis. Furthermore, an amino acid sequence containing a low-complexity region was inserted in the TRAF6s from mollusk. Quantitative real-time polymerase chain reaction analysis demonstrated that PmTRAF6 was constitutively expressed in all tissues studied, with the most abundant mRNA expression in hepatopancreas and gill in P. martensii. After lipopolysaccharide stimulation, the expression of PmTRAF6 mRNA was dramatically upregulated. These results suggested that the obtained PmTRAF6 was a member of the TRAF6 family and perhaps involved in the innate immune response of pearl oyster. PMID- 25511040 TI - Cloning of flanking sequence in transgenic plants by restriction site-anchored single-primer polymerase chain reaction. AB - Determining the insertion position of an exogenous gene in the target plant genome is one of the main issues in the transgenic plant field. This study introduced a simple, rapid, and accurate method to clone the flanking sequences of the transgenic bar gene as the anchoring gene in the transgenic maize genome using single-primer polymerase chain reaction (PCR). This method was based on the distribution of restriction sites in the maize genome and adopted the single primer PCR method. Cloning the flanking sequences with the restriction site anchored single-primer PCR simplified the experimental procedures by about 70% and reduced the experimental time by more than 80%. In conclusion, the restriction site-anchored single-primer PCR was a simple, rapid method to obtain the unknown flanking sequences in the transgenic plants. PMID- 25511041 TI - Hypoxia induces dysregulation of local renin-angiotensin system in mouse Lewis lung carcinoma cells. AB - The renin-angiotensin system (RAS) influences cancer biology and is frequently dysregulated in malignancy. However, regulation of tumor local RAS remains poorly understood. Hypoxia is a hallmark of solid tumors and affects nearly every major aspect of cancer biology. Previous studies have shown that hypoxia can regulate RAS expression in somatic tissues and cells. The aim of this study was to investigate the influence of hypoxia on local RAS expression in mouse Lewis lung carcinoma (LLC) cells. For hypoxia treatment, LLC cells were cultured in a hypoxia incubator or treated with hypoxia-mimetic cobalt chloride. Hypoxia up regulated angiotensin II, angiotensin-converting enzyme (ACE), and angiotensin II type 1 receptor (AT1R), and down-regulated ACE2 and angiotensin II type 2 receptor in LLC cells. Captopril, an ACE inhibitor, and losartan, an AT1R blocker, decreased expression of ACE and AT1R, but increased expression of ACE2 and angiotensin II type 2 receptor in LLC cells under hypoxia. Captopril and losartan also suppressed vascular endothelial growth factor-A expression in LLC cells under hypoxia. These findings suggest that hypoxia induces dysregulation of local RAS in LLC cells. The pathophysiological importance of hypoxia-induced RAS dysregulation and potentially therapeutic effects of RAS inhibitors on hypoxic tumor cells should be further examined. PMID- 25511042 TI - Detection of a novel single nucleotide polymorphism and imprinted status analysis of the Ras protein-specific guanine nucleotide-releasing factor 1 gene in domestic pigs. AB - The aim of this study was to determine the imprinting status of the Ras protein specific guanine nucleotide-releasing factor 1 (Rasgrf1) gene in domestic pigs. In this study, a 228-bp partial sequence located in exon 14 and a 193-bp partial sequence located in exon 1 of the Rasgrf1 gene in domestic pigs were obtained. A novel single nucleotide polymorphism, a G/A transition, was identified in Rasgrf1 exon 14, and then the reciprocal Berkshire x Wannan black F1 hybrid model and the reverse transcription-polymerase chain reaction-restriction fragment length polymorphism method were used to detect the imprinting status of the porcine Rasgrf1 gene at the 1-day-old developmental stage. Imprinting analysis showed that, compared to the imprinted expression of the Rasgrf1 gene in mouse and rat, a variable imprinting status was observed in domestic pigs. In principle, the porcine Rasgrf1 gene was maternally expressed in the liver and small intestine, paternally expressed in the lung, and biallelically expressed in brain, heart, spleen, kidney, stomach, pancreas, fat, testis, ovary, longissimus dorsi, and pituitary tissues. In conclusion, our results indicated that the Rasgrf1 gene shows both species- and tissue-specific variation in imprinted expression. PMID- 25511043 TI - Proposed method for dimensionality reduction based on framework in gene expression domain. AB - The excessive use of attributes may affect the search for patterns and extraction of useful knowledge, because they harm the learning performance of algorithms in both speed and success rate. The use of dimensionality reduction methods is therefore an important alternative; however, these methods do not deal with the reduction of attributes in a specific area. This article presents a method based on framework concepts of domain for reducing attributes in a domain. The input method is a set of databases related to a domain, and the main process is the identification of common and variable attributes, plus the reduction of attributes in the original database. The proposed method was applied in the gene expression domain, using databases. The method can be used to analyze the most relevant attributes in a specific domain, granting greater confidence for models created for the application of a data mining task, thus, a previously known method in data mining. Attribute selection was also applied in the three databases for the comparison of the results. Analyses of the results using the criterion of cross-validation revealed that the employment of the methods resulted in the improvement of success rates compared to the databases containing the full range of attributes. PMID- 25511044 TI - Allelopathy of the invasive plant Bidens frondosa on the seed germination of Geum japonicum var. chinense. AB - Five gradient concentrations (0.02, 0.04, 0.06, 0.08, and 0.10 g/mL) of leaching liquors from the roots, stems, and leaves of the invasive plant Bidens frondosa were used as conditioning fluid to examine its influence on seed germination conditions of the native plant Geum japonicum var. chinense in Huangshan. All leaching liquors of organs suppressed the seed germination of Geum japonicum var. chinense and reduced the final germination percentage and rate, and increased the germination inhibition rate, with a bimodal dependence on concentration. The leaching liquor inhibited the seed germination significantly at the concentration of 0.02 g/mL respectively. The seed germination was also inhibited as the concentration reached to 0.04 g/mL and beyond. Hence the allelopathic effects of the organs were significantly enhanced respectively. This phenomenon represented the presence of allelopathy substances in the root, stem and leaf of Bidens frondosa. PMID- 25511045 TI - Retraction of "effects of destrin pathway mutations on the gene expression profile" by J.N. Xiu, X. Liu, H. Wang, C.M. Hu, Q.H. Luo and Q.Q. Zhou. Genet. Mol. Res. 13 (2): 2628-2637 (2014). PMID- 25511046 TI - Genetic, epigenetic, and mechanistic studies of temporomandibular disorders and overlapping pain conditions. AB - Leaders in the fields of Temporomandibular Disorders (TMD) and its accompanying overlapping pain conditions presented their latest findings at the Seventh Scientific Meeting of The TMJ Association, September 7-9, 2014, in Bethesda, MD. The meeting was co-sponsored by The TMJ Association and the National Institutes of Health. Topics of the scientific sessions included epidemiology and diagnostic criteria, basic mechanisms of chronic pain including the genetic and epigenetic basis of chronic pain, and the development of novel drugs for treatment of these conditions. Discussions were directed toward formulating a set of recommendations to advance research in this field. PMID- 25511047 TI - Call for change. PMID- 25511048 TI - Setting stronger "Firewalls". PMID- 25511049 TI - Evaluation of the analgesic and anti-inflammatory activity of fixed dose combination: non-steroidal anti-inflammatory drugs in experimental animals. AB - BACKGROUND: In India, a number of fixed dose drug combinations of non-steroidal anti-inflammatory drugs (NSAID's) are available, often as over-the-counter products. These combinations are being prescribed too. Evidence for efficacy of NSIAD fixed dose combination is lacking. OBJECTIVES: The current study was undertaken to assess the analgesic and anti-inflammatory efficacy of these combinations over their individual components. MATERIALS AND METHODS: The study used three NSAIDs viz; paracetamol, ibuprofen and diclofenac sodium, alone or in combination with paracetamol. Animals were divided into six groups with six animals in each group. Analgesic activity was tested by writhing test and paw edema model was used to assess the anti-inflammatory activity. The test drugs were administered orally 30 min prior to injecting 0.6% solution of glacial acetic acid intraperitoneally for writhing test. For paw edema test, after 30 min of drugs administration, animals were injected with 0.1 ml of 1% carrageenan in subplanter region for inducing inflammation. Paw volume was again measured at baseline and after 3 h of subplanter injection of 1% carrageenan. RESULTS: The analgesic and the anti-inflammatory activity of paracetamol and ibuprofen combination were significantly greater than the individual agents when used alone. However, no significant difference in the analgesic or anti-inflammatory activity was found between diclofenac sodium and its combination with paracetamol. It was observed that diclofenac sodium was the most efficacious of the analgesics tested. Combining paracetamol with diclofenac did not show superior analgesic activity compared to diclofenac alone (P = 0.18). CONCLUSION: Combining paracetamol with ibuprofen enhances analgesic/anti-inflammatory activity over their individual component but potentiation of analgesic activity of diclofenac was not seen when paracetamol was added to it. PMID- 25511050 TI - Assessing extent of single stranded DNA damage in oral mucosal cells of patients with oral squamous cell carcinoma and its correlation with TNM staging. AB - CONTEXT: This study was carried out on the assumption that oral mucosal cells might show DNA damage in oral squamous cell carcinoma (OSCC). AIMS: To evaluate the extent of DNA damage in oral smears of patients with OSCC and determine correlation if any of the extent of DNA damage to TNM staging of oral cancer. SETTINGS AND DESIGN: A randomized controlled study at a regional cancer centre was designed for this project. Smears were taken from lesion proper of 30 patients with OSCC and from the buccal mucosa of 30 normal healthy volunteers. MATERIALS AND METHODS: Collected cells were centrifuged and single-cell gel electrophoresis (SCGE) assay was performed. DNA damage was visualized under a fluorescent microscope. Statistical analysis used : Mean DNA damage levels of both the groups were measured and statistically analyzed with students' test. The extent of DNA damage was correlated with the TNM stages by employing the one way ANOVA 'F' technique. RESULTS: High statistical significance (P < 0.0001) was found in DNA damage levels between control and study groups. A stepwise increase in DNA damage levels with high statistical significance (P < 0.005) was also found between all the TNM stages. CONCLUSIONS: Statistically significant increased DNA damage levels in OSCC patients and their correlation to clinical staging suggest that comet assay may be used effectively to assess the prognosis of OSCC. PMID- 25511051 TI - Development and validation of oral health-related early childhood quality of life tool for North Indian preschool children. AB - OBJECTIVE: The purpose of this study was to develop a reliable instrument [Oral Health related Early Childhood Quality of Life (OH- ECQOL) scale] for measuring oral health related quality of life (OHrQoL) in preschool children in North Indian population. METHODOLOGY: Four pediatric dentists evaluated a pool of 65 items from various QoL questionnaires to assess their relevance to Indian population. These items were discussed with eight independent pediatric dentists and two community dentists who were not a part of this study to assess relevance of these items to preschool age children based on their comprehensiveness and clarity. Based on their responses and feedback a modified pool of items was developed and administered to a convenience sample of 20 parents who rated these items according to their relevance. The test retest reliability was evaluated on another sample of 20 parents of 2-5 year old children. The final questionnaire comprised of 16 items (12 child and 4 family). This was administered to 300 parents of 24-71 months old children divided on the basis of early childhood caries to assess its reliability and validity. RESULTS: OH-ECQOL scores were significantly associated with parental ratings of their child's general and oral health, and the presence of dental disease in the child. Cronbach's alpha was 0.862, and the ICC for test-retest reliability was 0.94. CONCLUSIONS: The OH ECQOL proved reliable and valid tool for assessing the impact of oral disorders on the quality of life of preschool children in Northern India. PMID- 25511052 TI - Immunolocalization of heme oxygenase-1 in periodontal diseases. AB - CONTEXT: Chronic periodontitis is an inflammatory condition of supporting tissues initiated by organisms in dental plaque. The reactive oxygen species and free radicals mediate connective tissue destruction in periodontitis. In order to counteract the free radical mediated tissue damage, numerous antioxidant mechanisms exist within the host. One such system is heme oxygenase enzymes. Heme oxygenase is the key enzyme involved in catabolism of heme. It cleaves the heme molecule to yield equimolar amounts of biliverdin, carbon monoxide, and iron. These end products act as important scavengers of reactive oxygen metabolites. Increased heme oxygenase expression has been identified in inflammatory condition, such as pancreatitis, diabetes, nephritis, and atherosclerosis. Since chronic periodontitis is one such inflammatory condition, we assessed the expression of heme oxygenase-1, in smokers and periodontitis group using immunohistochemistry technique. AIMS: The aim of this study is to compare the expression of heme oxygenase-1 in patients with healthy periodontium, periodontitis and smokers. MATERIALS AND METHODS: Gingival tissue samples were taken from 30 patients, who were divided into three groups healthy controls (n = 10), chronic periodontitis (n = 10), and smokers with chronic periodontitis (n = 10). All the samples were subjected to immunohistochemical staining using the antiheme oxygenase-1 antibody and were tested for efficiency by staining a positive control (prostate cancer tissue sections) and a negative control. The results were tabulated and analyzed. RESULTS: Our results showed increased expression of heme oxygenase-1 in the gingival tissue samples taken from smokers compared with periodontitis and healthy tissue. CONCLUSION: The results of our study is an increasing evidence of involvement of antioxidant enzymes like heme oxygenase-1 in periodontal inflammation and their implication for treatment of chronic periodontitis. PMID- 25511053 TI - Correlation between clinical and radiographic findings on the occurrence of furcation involvement in patients with periodontitis. AB - Aim : The aim of the present study was to determine the occurrence of furcation involvement in the molars of patients with chronic periodontitis and correlate clinical and radiographic findings. MATERIALS AND METHODS: Seventy subjects aged 35-69 years enrolled for treatment at a periodontics specialization program in Pernambuco, Brazil (EAP-SCDP-ABO/PE) participated in the study, comprising a total of 350 molars examined. The clinical diagnosis of furcation involvement was performed with a horizontal Nabers probe, whereas the radiographic examination was performed with periapical and bite-wing radiographs. The images were analyzed with an X-ray viewer at 3* magnification. The Chi-square test was used, with the level of significance set at 5%. RESULTS: A total of 64.5% individuals presented with furcation involvement, 43.1% of whom had degree II furcation. A significant association (P = 0.0060) was found between tooth type and frequency of furcation involvement. The first lower and upper molars were affected in 64.5 and 58.5% of cases, respectively. Adequate agreement (0.65) was observed between the clinical and radiographic findings. CONCLUSION: Taking into consideration the method employed and the results obtained, it may be concluded that the clinical and radiographic examinations performed are effective tools for diagnosing furcation involvement in teeth affected with periodontal disease. PMID- 25511054 TI - Efficiency and effectiveness evaluation of three glass fiber post removal techniques using dental structure wear assessment method. AB - AIM: This study evaluated the efficiency and effectiveness of three glass fiber post removal techniques. MATERIALS AND METHODS: Forty-five extracted maxillary teeth were endodontically treated and cross-sectioned in thirds. Presence of cementing agent and dental structure wear were assessed by analyzing images taken before luting of glass fiber post and after removal procedure. Teeth were divided into 3 groups: Group 1 - diamond bur + Largo reamer; Group 2 - ultrasonic insert; Group 3 - carbide bur + ultrasonic insert. Time spent on removal procedures, dental structure wear and amount of remaining cement agent were recorded and results submitted to ANOVA, Kruskal Wallis and Tukey-Kramer tests. RESULTS: Group 1 - 16'46", 33.33% and 6.99%; Group 2 - 12'31", 40% and 7.86%; and Group 3 - 10'24", 80% and 8.14%. Group 3 presented the most effective removal of glass fiber posts. CONCLUSION: There was no significant difference in efficiency among the evaluated techniques. PMID- 25511055 TI - In-silico analysis of heat shock protein 47 for identifying the novel therapeutic agents in the management of oral submucous fibrosis. AB - BACKGROUND: Heat shock proteins-47 (HSP47) is a collagen specific molecular chaperone, involved in the processing and/or secretion of procollagen. It seems to be regularly upregulated in various fibrotic or collagen disorders. Hence, this protein can be a potential target for the treatment of various fibrotic diseases including oral submucous fibrosis (OSF), which is a collagen metabolic disorder of oral cavity and whose etiopathogeneic mechanism and therapeutic protocols are still not well documented. AIM: The aim of this study is to identify the novel therapeutic agents using in-silico methods for the management of OSF. OBJECTIVES: The objectives of this study are to identify the binding sites of HSP47 on the collagen molecule and to identify the lead compound with anti-HSP47 activity from the library of natural compounds, using in-silico methodology. MATERIALS AND METHODS: The web-based and tool based in-silico analysis of the HSP47 and collagen molecules are used in this study. The crystal structure of collagen and HSP47 were retrieved from Protein Data Bank website. The binding site identification and the docking studies are done using Molegro Virtual Docker offline tool. RESULTS: Out of the 104 Natural compounds, six ligands are found to possess best binding affinity to the binding amino acid residues. Silymarin binds with the 4AU2A receptor and the energy value are found to be -178.193 with four Hbonds. The other best five natural compounds are hesperidin, ginkgolides, withanolides, resveratrol, and gingerol. Our findings provide the basis for the in-vitro validation of the above specified compounds, which can possibly act as "lead" molecules in designing the drugs for OSF. CONCLUSION: HSP47 can be a potential candidate to target, in order to control the production of abundance collagen in OSF. Hence, the binding sites of HSP47 with collagen are identified and some natural compounds with a potential to bind with these binding receptors are also recognized. These natural compounds might act as anti-HSP47 lead molecules in designing novel therapeutic agents for OSF, which are so far unavailable. PMID- 25511056 TI - Evaluation of changes in clinical crown length of lower anterior teeth after treatment with Frankel-2's appliance. AB - PURPOSE: The aim of this study was to test the null hypothesis that there is no change in the lower anterior teeth's crown size when measured just after the treatment with Frankel-2's orthopedic appliance and in a long-term posttreatment follow-up. MATERIALS AND METHODS: The sample was composed of 34 plaster models belonging to 9 male and 8 female individuals, treated at the College of Health, Methodist University of Sao Paulo, Sao Bernardo do Campo, Sao Paulo, Brazil, with mean age of 12 years and 6 months (standard deviation [SD] =7 months) at T1 (end of the treatment with Frankel-2's function regulator), and 19 years and 8 months (SD = 7 months) at T2 (7.11 years after the end of the treatment). RESULTS: The distance from the incisal edge to the most concave portion of the gingival margin of the lower incisors and canines was measured using a digital caliper. Data analysis was carried out by means of Student's t-test and paired-t test. Among the lower anterior teeth, the teeth 31, 33, 42 and 43 showed a statistically significant increase in their crown length, whereas the teeth 32 and 41 showed no changes. CONCLUSION: It can be concluded that there is a tendency to increase the clinical crown of lower anterior teeth throughout the years after the mandibular advancement treatment by using functional devices, rejecting the null hypotheisis. PMID- 25511058 TI - Comparative evaluation of bovine derived hydroxyapatite and synthetic hydroxyapatite graft in bone regeneration of human maxillary cystic defects: a clinico-radiological study. AB - INTRODUCTION: Bone grafts are frequently used in the treatment of bone defects. Bone harvesting can cause postoperative complications and sometimes does not provide a sufficient quantity of bone. Therefore, synthetic biomaterials have been investigated as an alternative to autogenous bone grafts. AIM AND OBJECTIVES: The aim of this study was to evaluate and compare bovine derived hydroxyapatite (BHA) and synthetic hydroxyapatite (SHA) graft material as bone graft substitute in maxillary cystic bony defects. Patients were analyzed by computerized densitometric study and digital radiography. MATERIALS AND METHODS: In this study, 12 patients in each group were included randomly after clinical and radiological evaluation. The integration of hydroxyapatite was assessed with mean bone density, surgical site margin, and radiological bone formation characteristics, of the successful graft cases using computer densitometry and radio-visiograph. Statistical analysis was carried out using Mann-Whitney U-test, Wilcoxon matched pairs test and paired t-test. RESULTS: By the end of 24 th week, the grafted defects radiologically and statistically showed similar volumes of bone formation. However, the significant changes observed in the formation of bone and merging of material and surgical site margin at 1 st week to 1 st month. The results were significant and correlating with all the parameters showing the necessity of the grafting for early bone formation. However, the bone formation pattern is different in both BHA and SHA group at 3 rd month interval with significant P value. CONCLUSION: Both BHA and SHA graft materials are biocompatible for filling bone defects, showing less resorption and enhanced bone formation with similar efficacy. Our study showed maximum bone healing within 12 weeks of grafting of defects. The BHA is economical; however, price difference between the two is very nominal. PMID- 25511057 TI - The effect of Emdogain gel on periodontal regeneration in autogenous transplanted dog's teeth. AB - AIM: The aim of this study was to assess the enamel matrix derivative (EMD) as biomaterial used in autogenous tooth transplantation. MATERIAL AND METHODS: The study consisted of 3 beagle dogs, 5 months old, in which six incisors and six premolars were transplanted to mechanically prepared recipient alveolar sockets. One group of teeth was transplanted to a recipient bed, with EMD in the root surface. The second groups of teeth were transplanted using saline solution in the root surface. Every week, clinical examinations were done. Nine weeks later, the animals were killed and the specimens decalcified and prepared for histological and imunohistochemical analysis. Periodontal healing was evaluated by undertaking histomorphometric investigation and analyzed using the Mann- Whitney test (P = 0.05). RESULTS: In both groups, all the transplanted teeth survived. Between the experimental groups, there was statistically significant difference in the complete healing (P = 0.004). There was statistically significant difference between the treatment group in the occurrence of inflammatory root resorption (P = 0.015) and the occurrence of replacement root resorption (P = 0.041). CONCLUSIONS: Emdogain gel used on the surface of transplanted teeth improves the occurrence of complete healing and reduces root resorption. PMID- 25511059 TI - Problematic eating and its association with early childhood caries among 46-71 month-old children using Children's Eating Behavior Questionnaire (CEBQ): a cross sectional study. AB - CONTEXT: Problematic eating behavior in children presents a wide spectrum from anorexia, selective eating, and fussy eating to neophobia. Pouching of food and slow eating represents eating behavioral problems that may be relevant to pediatric dentist as far as early childhood caries (ECC) is concerned. AIM: The aim of this study was to determine the prevalence of problematic eating and its association with ECC among 46-71-month-old children in Bengaluru city, India. SETTINGS AND DESIGN: A cross-sectional study was carried out in 250 children aged 46-71 months old in various schools of Bengaluru city. SUBJECTS AND METHODS: All the selected children were clinically examined for dental caries using decayed, missing, filled surfaces index. Children's eating behavior was assessed using Children's Eating Behavior Questionnaire (CEBQ) which was filled by the parents. STATISTICAL ANALYSIS USED: Both descriptive statistics as well as Chi-square test was used with SPSS 16.00. RESULTS: The prevalence of dental caries was found to be 34%. It was observed that 81.6% of the children did not have a tendency to keep food in their mouth all the time and ECC was found to be significantly less. Furthermore, approximately 90% of the children did not have a tendency to eat too much and in those, 68% of them were caries free which was statistically significant. Prevalence of ECC was highest (52.6%) in children who ate more when they had nothing else to do. CONCLUSION: Problematic eating behavior is prevalent in the preschooler group and needs to be considered by the pediatric dentist. PMID- 25511060 TI - Effect of four different intracanal medicaments on the apical seal of the root canal system: a dye extraction study. AB - AIM: The aim was to determine the effect of four different intracanal medicaments on the apical seal of the root canal system in vitro. METHODOLOGY: Fifty freshly extracted intact human permanent maxillary central incisors were collected, stored and disinfected. The root canals were prepared to a master apical size of number 50 using step back technique. Depending upon the intracanal medicament used, the teeth were divided randomly into five groups of 10 teeth each including one control group and four experimental groups. Group A: No intracanal medicament. Group B: Calcium hydroxide powder mixed with distilled water. Group C: Calcium hydroxide gutta percha points (calcium hydroxide points). Group D: 1% chlorhexidine gel (hexigel). Group E: Chlorhexidine gutta percha points (Roeko Activ Points). The medication was left in canals for 14 days. Following removal of the intracanal medicament, all the groups were obturated with lateral compaction technique. The apical leakage was then evaluated using dye extraction method with the help of a spectrophotometer. RESULTS: RESULTS were statistically analyzed using Kruskal-Wallis and Mann-Whitney U-test, which showed statistically significant difference among the five groups tested. CONCLUSION: It can be concluded from this study that the control group showed least amount of leakage, whereas the 1% chlorhexidine gel group showed maximum amount of leakage. Apical leakage was observed with all the experimental groups with little variations in between them. Under the parameters of this study, it can be concluded that use of intracanal medicaments during endodontic treatment has a definite impact on the apical seal of the root canal system. PMID- 25511062 TI - Smear layer removal efficacy of different irrigating solutions: a comparative scanning electron microscope evaluation. AB - AIMS: Comparative evaluation of cleaning efficacy of smear layer removal by different irrigating solutions such as 2.5% sodium hypochlorite (NaOCl), 17% ethylenediaminetetraacetic acid (EDTA) with 2.5% NaOCl, 10% citric acid with 2.5% NaOCl and 1% tetracycline Hydrochloride (HCl) with 2.5% NaOCl for smear layer removal in the apical third of root canal. SETTINGS AND DESIGN: In vitro material science study. MATERIALS AND METHODS: Seventy-five single rooted permanent maxillary central incisor teeth were subjected to standardized root canal instrumentation (crown down technique). The teeth were randomly divided into five groups with 15 teeth in each groups: (1) Normal saline (n = 15) (2) 2.5% NaOCl (n = 15) (3) 17% EDTA + 2.5% NaOCl (n = 15) (4) 10% citric acid + 2.5% NaOCl (n = 15) (5) 1.0% tetracycline HCL + 2.5% NaOCl (n = 15). After final irrigation, the teeth were prepared for scanning electron microscope analysis to evaluate the cleaning of apical third of radicular dentine to determine the presence or absence of smear layer. STATISTICAL ANALYSIS USED: The results were analyzed by nonparametric statistical analysis techniques. Kruskal-Wallis test, Mann-Whitney test and Chi-square tests were carried out. RESULTS: There was no significant statistical difference in the efficacy of smear layer removal when 2.5% NaOCl was compared with 17% EDTA with 2.5% NaOCl, 10% citric acid with 2.5% NaOCl and 1% tetracycline HCl with 2.5% NaOCl in apical third of root canals. CONCLUSIONS: The present study suggests that irrigating agents, citric acid and tetracycline HCl can be used as an alternative to EDTA for the removal of smear layer in endodontics. PMID- 25511061 TI - Comparative evaluation of serum superoxide dismutase and glutathione levels in periodontally diseased patients: an interventional study. AB - BACKGROUND: Periodontal disease is an immune-inflammatory disease characterized by connective tissue breakdown, loss of attachment, and alveolar bone resorption. Under normal physiological conditions, a dynamic equilibrium is maintained between the reactive oxygen species (ROS) and antioxidant defense capacity. Oxidative stress occurs when this equilibrium shifts in favor of ROS. Oxidative stress is thought to play a causative role in the pathogenesis of periodontal diseases. AIM: The present study was designed to estimate and compare the superoxide dismutase (SOD) and glutathione (GSH) levels in the serum of periodontitis, gingivitis, and healthy individuals before and after nonsurgical periodontal therapy. MATERIALS AND METHODS: The present study was conducted in the Department of Periodontics, A. B. Shetty Memorial Institute of Dental Sciences, Deralakatte, Mangalore. The study was designed as a single blinded interventional study comprising 75 subjects, inclusive of both sexes and divided into three groups of 25 patients each. Patients were categorized into chronic periodontitis, gingivitis, and healthy. The severity of inflammation was assessed using gingival index and pocket probing depth. Biochemical analysis was done to estimate the SOD and GSH levels before and after nonsurgical periodontal therapy. RESULTS obtained were then statistically analyzed using ANOVA test and paired t test. RESULTS: The results showed a higher level of serum SOD and GSH in the healthy group compared to the other groups. The difference was found to be statistically significant (P < 0.0001). The post-treatment levels of SOD were statistically higher than the pre-treatment levels in periodontitis and gingivitis group. PMID- 25511064 TI - Corrosion of orthodontic brackets in different spices: in vitro study. AB - CONTEXT: Moist environment in the mouth varies and causes variable amounts of corrosion of dental materials. This is of concern particularly when metallic implants, metallic fillings, orthodontic appliances are placed in the hostile electrolytic environment in the human mouth. Components of diet rich in salt and spices are important factors influencing the corrosion of metallic appliances placed in the oral cavity. AIMS: To study in vitro corrosion of orthodontic metallic brackets immersed in solutions of salt and spices in artificial saliva. MATERIALS AND METHODS: Orthodontic brackets were used for corrosion studies in artificial saliva, salt, and spices using electrochemical technique and surface analysis. Electrochemical studies using different parameters were done in solutions of artificial saliva containing salt and spices. Photomicrographs from the optical microscope were also obtained. RESULTS: RESULTS of corrosion studies have clearly demonstrated that certain spices such as turmeric and coriander are effective in reducing corrosion, whereas salt and red chili have been found to enhance it. Surface analysis of small pits present on the surface of the as received bracket will initiate corrosion which leads to more pitting. PMID- 25511065 TI - Strain gauges's analysis on implant-retained prosthesis' cast accuracy. AB - INTRODUCTION: A proper cast is essential for a successful rehabilitation with implant prostheses, in order to produce better structures and induce less strain on the implants. AIMS: The aim of this study was to evaluate the precision of four different mold filling techniques and verify an accurate methodology to evaluate these techniques. MATERIALS AND METHODS: A total of 40 casts were obtained from a metallic matrix simulating three unit implant-retained prostheses. The molds were filled using four different techniques in four groups (n = 10): Group 1 - Single-portion filling technique; Group 2 - Two-step filling technique; Group 3 - Latex cylinder technique; Group 4 - Joining the implant analogs previously to the mold filling. A titanium framework was obtained and used as a reference to evaluate the marginal misfit and tension forces in each cast. Vertical misfit was measured with an optical microscope with an increase of 120 times following the single-screw test protocol. Strain was quantified using strain gauges. Data were analyzed using one-way ANOVA (Tukey's test) (alpha =0.05). The correlation between strain and vertical misfit was evaluated by Pearson test. RESULTS: The misfit values did not present statistical difference (P = 0.979), while the strain results showed statistical difference between Groups 3 and 4 (P = 0.027). CONCLUSIONS: The splinting technique was considered to be as efficient as the conventional technique. The strain gauge methodology was accurate for strain measurements and cast distortion evaluation. There was no correlation between strain and marginal misfit. PMID- 25511063 TI - Comparison of the dental arch changes in patients with different malocclusions. AB - AIMS AND OBJECTIVES: To evaluate the pre-treatment and post-treatment dental arch changes in both upper and lower arches in orthodontic patients treated with extraction of first premolar teeth. SUBJECTS AND METHODS: Measurements were made on casts of 50 post treated cases in the age group of 12-30 years for individual tooth measurements, width of the arches (inter-incisal, inter-canine, inter premolar and inter-molar) arch length (both right and left sides, anterior segment, posterior segment and total arch length for both for the maxillary and mandibular dental casts. STATISTICAL ANALYSIS USED: Kolmogorov-Smirnov test for Normality, Regression Analysis was done as variables were tested and proved to follow normality. Statistical software Statistical Package for the Social Sciences version 18 (SPSS Inc.; Chicago, Illinois, USA) was used for data analysis. Descriptive statistics and paired t-tests were used to compare the changes in the Class I and Class II div 1 groups. RESULTS: There was a significant increase in the inter-incisor and inter-canine width post-treatment in the Class I and Class II div 1 subjects in the upper arch but no significant change in inter-incisor width in the lower arch in class I subjects. A significant decline in the inter-molar arch width in both the groups were seen. The inter-premolar arch width declined significantly in Class I cases while it increased significantly in Class II div 1 subjects. There was a significant increase in anterior arch length and a significant decrease in posterior arch length in all subjects. CONCLUSIONS: The findings of this original clinical research should significantly help the orthodontists in orthodontic treatment planning in patients requiring extractions of premolars. PMID- 25511066 TI - Evaluation of the marginal fit of metal copings fabricated on three different marginal designs using conventional and accelerated casting techniques: an in vitro study. AB - INTRODUCTION: Abundant resources and techniques have been used for complete coverage crown fabrication. Conventional investing and casting procedures for phosphate-bonded investments require a 2- to 4-h procedure before completion. Accelerated casting techniques have been used, but may not result in castings with matching marginal accuracy. AIMS AND OBJECTIVES: The study measured the marginal gap and determined the clinical acceptability of single cast copings invested in a phosphate-bonded investment with the use of conventional and accelerated methods. MATERIALS AND METHODS: One hundred and twenty cast coping samples were fabricated using conventional and accelerated methods, with three finish lines: Chamfer, shoulder and shoulder with bevel. Sixty copings were prepared with each technique. Each coping was examined with a stereomicroscope at four predetermined sites and measurements of marginal gaps were documented for each. STATISTICAL ANALYSIS: A master chart was prepared for all the data and was analyzed using Statistical Package for the Social Sciences version. Evidence of marginal gap was then evaluated by t-test. Analysis of variance and Post-hoc analysis were used to compare two groups as well as to make comparisons between three subgroups . RESULTS: Measurements recorded showed no statistically significant difference between conventional and accelerated groups. CONCLUSION: Among the three marginal designs studied, shoulder with bevel showed the best marginal fit with conventional as well as accelerated casting techniques. Accelerated casting technique could be a vital alternative to the time-consuming conventional casting technique. The marginal fit between the two casting techniques showed no statistical difference. PMID- 25511067 TI - Prevalence of dental anomalies on panoramic radiographs in a population of the state of Para, Brazil. AB - INTRODUCTION: Dental anomalies (DAs) are the result of disorders that are able to modify the shape, number, size, and structure of teeth. This study aimed to evaluate the prevalence of DAs using panoramic radiographs in a population of the City of Belem, northern Brazil. MATERIALS AND METHODS: In this study, 487 panoramic radiographs were evaluated searching for DAs. Dental records were reviewed for diagnostic confirmation. DAs related to the shape, number, size, and structure of teeth were investigated. RESULTS: Our results showed a DA prevalence of 56.9%. The most prevalent DA was taurodontism, which was present in 27.19% of cases. Root dilaceration was the second most prevalent DA in adults, whereas hypodontia was the second most prevalent DA in children. A total of 13 DAs were found. CONCLUSIONS: Dental anomalies were present in over half of the sample, and most of them were related to the shape of the teeth. Although there was a high prevalence of shape-related DAs, these alterations are generally of lower severity, and most do not require specific treatment. However, in 19.25% of cases, DAs were found involving the number, size and structure of the teeth. These DAs should be diagnosed and treated early, avoiding thus more serious complications. PMID- 25511068 TI - Socioeconomic mobility and tobacco consumption patterns in fish industry workers in Udupi District of coastal Karnataka. AB - AIM: The aim of this study was to understand the tobacco consumption patterns and their relationship with life course socioeconomic mobility among fish industry workers as this could provide important information in dealing with the tobacco problem in this very vulnerable population. MATERIALS AND METHODS: Socioeconomic life course data and information about tobacco habits was collected from 102 fish industry workers. A subject was considered to be upwardly mobile if the family head's educational attainment and the number of earning members increased and the number of children and dependents decreased since childhood in his or her household. Oral examination was also done for malignant/premalignant lesions. RESULTS: Of the 102 subjects, 64 regularly consumed tobacco either in smoking or smokeless forms and the common reasons for the habit were the co-workers' influence and to keep awake at work. Fourteen subjects had premalignant lesions in the oral cavity and all them were in the buccal mucosa. The prevalence of the tobacco habit was much lesser (25%) among the upwardly mobile group when compared to the minimal or no improvement group (75%). A majority of those free from the habit (73.7%) were belonging to the group, which showed improved educational attainment. Among those with good social mobility, the percentage of workers with high frequency of tobacco consumption and those with a longer duration of the tobacco habit was low when compared to the minimal social mobility group. CONCLUSION: A holistic approach consisting of efforts to improve the overall socioeconomic conditions can be more effective than piecemeal solutions in dealing with the tobacco menace. PMID- 25511069 TI - Relationship between periodontitis and systemic diseases: leptin, a new biomarker? AB - BACKGROUND: Leptin is a polypeptide hormone associated with the occurrence of legion of diseases including obesity, cardiovascular diseases, and diabetes. Periodontitis, that is, inflammation of the periodontium has also been linked to a number of systemic manifestations. AIM: The aim of the present study was to analyze the role of leptin as a biomarker linking periodontitis with obesity, cardiovascular diseases, and diabetes. SETTING AND DESIGN: The inclusion criteria included, clinical trials available in English language; studies involving human participants; studies relating leptin and periodontal diseases to either obesity, cardiovascular diseases or diabetes. Exclusion criteria enlisted manuscripts in language other than English; if they were case reports, narrative reviews, personal communication, conference presentations, editorial and expert opinion; experiments not involving humans. METHODS: We performed a literature search encompassing the time period from January 2000 to May 2013. A systematic search of the Cochrane Library and the Medline through PubMed was performed using the selected keywords/phrases "leptin and periodontitis," "leptin and periodontal diseases," "leptin, periodontitis and obesity," "leptin, periodontitis and cardiovascular diseases," and "leptin, periodontitis, and diabetes." RESULT: A total of 23 studies was obtained using the selected keywords/phrases. On screening, the chosen studies seven fulfilled the inclusion criteria. Four demonstrated association of leptin with periodontitis and obesity. One study associated cardiovascular diseases and periodontitis through leptin whereas two were found linking leptin, periodontitis, and diabetes mellitus. CONCLUSION: We could find some positive consociation between the serum concentration of leptin, periodontitis, and systemic diseases including obesity and cardiovascular diseases. The results were conflicting when its relation with diabetes mellitus type 2 was examined, as one study favored the association whereas the other one claimed that there was no effect on the levels of leptin. PMID- 25511070 TI - Functional approach to a Class II patient with upper first molar impaction. AB - The lack of the left first molar maxillary and the left second molar maxillary, caused respectively by impaction and agenesis is a very rare case, which determines an important occlusal imbalance and asymmetrical mandible movement. A gnatologic and functional orthodontic approach were planned to improve the retrognathic mandible and the muscular activity using kinesiograph and electromyography. PMID- 25511071 TI - Orthodontic-surgical management of a case of severe mandibular deficiency due to condylar ankylosis. AB - Dentofacial deformities involve deviations from the normal facial proportions and dental relationships and can range from mild to being severe enough to be severely handicapping.The term handicapping malocclusions though not a term commonly used, involves a fortunately small section (2-4%) of patients who can suffer from esthetic,psychological and functional problems. Craniofacial Orthodontics is the area of orthodontics that treats patients with congenital and acquired deformities of the integument and it's underlying musculoskeletal system within the craniofacial area and associated structures.This case report of a young woman with severe mandibular deficiency and facial asymmetry due to condylar ankylosis highlights the importance of team work in rehabilitation of such severe craniofacial deformities. PMID- 25511072 TI - Oral fibrolipoma: a rare histological variant. AB - Lipomas are benign soft tissue mesenchymal neoplasms. Fibrolipoma is a histological variant of lipoma that mostly affects the buccal mucosa and causes functional and cosmetic disabilities. The diagnosis and differentiation of fibrolipoma with clinically similar lesions such as fibroma and pleomorphic adenoma is very essential for a correct treatment plan and complete follow-up. This article presents a case of a 35-year-old female with a fibrolipoma on the lingual marginal gingiva of the mandibular left third molar. PMID- 25511073 TI - Isolated bilateral zygomatic complex and zygomatic arch fractures with oral submucous fibrosis: an unusual and rare case report. AB - Zygomatic bone forms major buttress of the facial skeleton and plays an important role in facial contour. Fractures of zygomatic complex are second most common only next to nasal bone fractures. Motor vehicle accidents and interpersonal violence are common causes. Bilateral fractures of zygomatic complex and zygomatic arch are very rare. We present a case report of isolated fractures involving bilateral zygomatic complex and zygomatic arch with oral submucous fibrosis, which is unique and first of its kind to be reported. PMID- 25511074 TI - Orthodontic extrusion of subgingivally fractured tooth using a removable appliance: an alternative treatment to reestablish biological width. AB - Restoration of a traumatically injured tooth presents a clinical challenge for a predictable aesthetic outcome. This case report describes a multidisciplinary approach of a subgingivally fractured permanent maxillary central incisor. A removable orthodontic appliance was used for orthodontic extrusion of root, and surgical gingival recontouring was done with electrocautery to reestablish the biological width. Form and function were restored establishing biological width and esthetics was repaired with porcelain fused to metal crown. PMID- 25511075 TI - Indian dental research--need for self appraisal. PMID- 25511076 TI - Improved reclassification of mortality risk by assessment of physical activity in patients referred for exercise testing. AB - BACKGROUND: Inability to meet minimal guidelines on physical activity is associated with poor health outcomes, but quantifying activity can be complex. We studied whether a simple question regarding participation in regular activity improves risk classification for all-cause mortality. METHODS: Maximal exercise testing was performed in 6962 patients (mean age, 58.9 +/- 11 years) for clinical reasons. Subjects also were assessed for participation in regular activity using a simple yes/no response to meeting minimal recommendations on activity. The incremental value of adding a simple physical activity assessment to clinical, demographic, and exercise test information to predict mortality was determined using Cox proportional hazards models, net reclassification improvement, and integrated discrimination index during a mean follow-up of 9.7 +/- 4 years. RESULTS: Subjects who did not meet the minimal guidelines on activity had a lower exercise capacity (7.4 +/- 4.3 vs 9.1 +/- 3.6 metabolic equivalents, P < .0001) and a higher annual mortality rate (2.42% vs 1.71%, P < .001). Not meeting activity guidelines was associated with an age-adjusted 36% higher risk of mortality (hazard ratio, 1.36; 95% confidence interval, 1.22-1.51, P < .0001). Among clinical and exercise test variables, fitness had the highest C-index for predicting mortality (0.72, P < .001). The addition of physical activity classification to a model including traditional risk factors resulted in a net reclassification improvement of 22.8% (P < .001); adding fitness to the traditional risk factor model resulted in a net reclassification improvement of 43.5% (P < .001). CONCLUSIONS: The addition of a simple assessment of physical activity status significantly improves reclassification of risk for all-cause mortality among patients who are referred for exercise testing. PMID- 25511078 TI - Joint effects of gray matter atrophy and altered functional connectivity on cognitive deficits in amnestic mild cognitive impairment patients. AB - BACKGROUND: Gray matter (GM) atrophy and disrupted intrinsic functional connectivity (IFC) are often present in patients with amnestic mild cognitive impairment (aMCI), which shows high risk of developing into Alzheimer's disease. Little is known, however, about the relationship between GM atrophy and altered IFC, and whether they are related to cognitive decline. METHOD: A total of 30 aMCI and 26 cognitively normal (CN) subjects were recruited for this study. Optimized voxel-based morphometric and resting-state functional connectivity magnetic resonance imaging approaches were performed to measure the GM volumes (GMVs) and atrophy-related IFC, respectively. Multivariate linear regression analysis was used to examine the effects of GM atrophy and IFC on cognitive performance across subjects, after controlling for the effects of age, education, gender and group. RESULTS: Compared with CN subjects, aMCI subjects showed significantly reduced GMVs and decreased IFC in the frontal-parietal and medial temporal lobe systems. Multivariate regression analysis further demonstrated that the GMVs and decreased IFC simultaneously affected the cognitive function. Specifically, GMVs were positively correlated with cognitive performances, including global cognition and episodic memory, and showed a strong trend in correlation between GMVs and non-episodic memory, whilst IFC was positively correlated with the above three cognitive measures, across all subjects. In addition, significant correlation was found between GMVs and altered IFC strength across all subjects. CONCLUSIONS: Our findings demonstrated that GMVs and IFC jointly contribute to cognitive performance, and combining quantitative information about GMVs and the strength of functional connectivity may serve as an indicator of cognitive deficits in non-demented elderly. PMID- 25511077 TI - Epidermal tight junction barrier function is altered by skin inflammation, but not by filaggrin-deficient stratum corneum. AB - BACKGROUND: The tight junction (TJ) barrier is located in the granular layer of the epidermis. Filaggrin deficiency predisposes patients to atopic dermatitis (AD) by impairing stratum corneum (SC) barrier function. Altered TJ barrier function has been observed in the skin of patients with AD; however, it remains unclear whether TJ function is influenced by filaggrin deficiency directly or secondarily via skin inflammation. OBJECTIVE: To investigate the in vivo effects of filaggrin deficiency and skin inflammation on epidermal TJ function. METHODS: Morphological changes in the TJ were investigated in filaggrin knockout mice and mice with hapten-induced dermatitis using en face visualization of epidermal sheets, and functional changes in the TJ were assessed with an in vivo permeation assay using tracers of various sizes. RESULTS: In filaggrin knockout mice, there was no apparent change in the honeycomb morphology of the TJ, TJ component mRNA expression, or TJ barrier function in neonates and adults, indicating that filaggrin-deficiency had no direct effects on the TJ. By contrast, in mice with hapten-induced dermatitis, the mRNA expression of TJ components was decreased markedly and the TJ barrier function was size-dependently impaired: the TJ leaked small tracers (<5 kDa), but not large tracers (>30 kDa). CONCLUSION: Filaggrin deficiency did not affect the epidermal TJ barrier directly, but once dermatitis occurred, the skin inflammation induced TJ dysfunction. Since TJ dysfunction induces the SC barrier impairment, skin inflammation will enhance skin permeability to external antigens and result in a vicious cycle of barrier dysfunction and skin inflammation. PMID- 25511080 TI - The functional mechanism of simvastatin in experimental osteoporosis. AB - Osteoporosis is a systemic and metabolic bone disease. New drugs with good curative effect, fewer side effects, and high safety need to be developed urgently. Recently, simvastatin has been used to treat osteoporosis more frequently; however, its clinical effect and treatment mechanism are still unknown. With the use of animal models, the treatment effectiveness of simvastatin on experimental osteoporosis was investigated and the functional mechanism was preliminarily explored. The results show that simvastatin significantly increased the mechanical parameters such as maximum load, stiffness, and energy-absorbing capacity, and improved the microarchitecture. They indicated that the antiosteoporosis activity of simvastatin may be due to the promotion of proliferation and differentiation of osteoblasts. Simvastatin was effective in treating experimental osteoporosis. This study provides necessary experimental evidence for the clinical application of simvastatin in osteoporosis treatment. PMID- 25511082 TI - Dental fluorosis in the Blue Mountains and Hawkesbury, New South Wales, Australia: policy implications. AB - AIM: The aim of the present study was to determine whether the adjustment of the fluoride concentration to 1 ppm in the drinking water supplied to the Blue Mountains, New South Wales, Australia in 1993 was associated with fluorosis incidence. METHODS: In 2003, children attending schools in the Blue Mountains and a control region (fluoridated in 1967) that had been randomly selected at baseline in 1992 were examined for dental fluorosis (maxillary central incisors only) using Dean's index. A fluoride history for each child was obtained by questionnaire. Associations between fluorosis and 58 potential explanatory variables were explored. RESULTS: The response rate was 63%. A total of 1138 children aged from 7 to 11 years with erupted permanent central incisors were examined for dental fluorosis. Fluorosis prevalence was the same in both regions. The Community Index of Dental Fluorosis values were slightly different, but were both above 0.6, indicative of public health concern. CONCLUSIONS: For the group as a whole, we concluded that: (a) fluorosis prevalence (0.39) in both regions was similar; and (b) the higher-than-expected prevalence and severity of fluorosis was due mainly to two factors: (a) the higher-than-optimal fluoride level in drinking water; and (b) swallowing of fluoride toothpaste in early childhood. PMID- 25511083 TI - Interventional cardiology: BMI inversely associated with bleeding and mortality after PCI. PMID- 25511081 TI - Strength-balance supplemented with computerized cognitive training to improve dual task gait and divided attention in older adults: a multicenter randomized controlled trial. AB - BACKGROUND: Exercise interventions often do not combine physical and cognitive training. However, this combination is assumed to be more beneficial in improving walking and cognitive functioning compared to isolated cognitive or physical training. METHODS: A multicenter parallel randomized controlled trial was conducted to compare a motor to a cognitive-motor exercise program. A total of 182 eligible residents of homes-for-the-aged (n = 159) or elderly living in the vicinity of the homes (n = 23) were randomly assigned to either strength-balance (SB) or strength-balance-cognitive (SBC) training. Both groups conducted similar strength-balance training during 12 weeks. SBC additionally absolved computerized cognitive training. Outcomes were dual task costs of walking, physical performance, simple reaction time, executive functions, divided attention, fear of falling and fall rate. Participants were analysed with an intention to treat approach. RESULTS: The 182 participants (mean age +/- SD: 81.5 +/- 7.3 years) were allocated to either SB (n = 98) or SBC (n = 84). The attrition rate was 14.3%. Interaction effects were observed for dual task costs of step length (preferred walking speed: F(1,174) = 4.94, p = 0.028, eta2 = 0.027, fast walking speed: F(1,166) = 6.14, p = 0.009, eta2 = 0.040) and dual task costs of the standard deviation of step length (F(1,166) = 6.14, p = 0.014, eta2 = 0.036), in favor of SBC. Significant interactions in favor of SBC revealed for in gait initiation (F(1,166) = 9.16, p = 0.003, eta2 = 0.052), 'reaction time' (F(1,180) = 5.243, p = 0.023, eta2 = 0.028) & 'missed answers' (F(1,180) = 11.839, p = 0.001, eta2 = 0.062) as part of the test for divided attention. Within-group comparison revealed significant improvements in dual task costs of walking (preferred speed; velocity (p = 0.002), step time (p = 0.018), step length (p = 0.028), fast speed; velocity (p < 0.001), step time (p = 0.035), step length (p = 0.001)), simple reaction time (p < 0.001), executive functioning (Trail making test B; p < 0.001), divided attention (p < 0.001), fear of falling (p < 0.001), and fall rate (p < 0.001). CONCLUSIONS: Combining strength-balance training with specific cognitive training has a positive additional effect on dual task costs of walking, gait initiation, and divided attention. The findings further confirm previous research showing that strength-balance training improves executive functions and reduces falls. TRIAL REGISTRATION: This trial has been registered under ISRCTN75134517. PMID- 25511086 TI - Less than full circumferential fusion of a tibial nonunion is sufficient to achieve mechanically valid fusion--proof of concept using a finite element modeling approach. AB - BACKGROUND: Although minimally invasive approaches are widely used in many areas of orthopedic surgery nonunion therapy remains a domain of open surgery. Some attempts have been made to introduce minimally invasive procedures into nonunion therapy. However, these proof of concept studies showed fusion rates comparable to open approaches never gaining wider acceptance in the clinical community. We hypothesize that knowledge of mechanically relevant regions of a nonunion might reduce the complexity of percutaneous procedures, especially in complex fracture patterns, and further reduce the amount of cancellous bone that needs to be transplanted. The aim of this investigation is to provide a proof of concept concerning the hypothesis that mechanically stable fusion of a nonunion can be achieved with less than full circumferential fusion. METHODS: CT data of an artificial tibia with a complex fracture pattern and anatomical LCP are converted into a finite element mesh. The nonunion area is segmented. The finite element mesh is assigned mechanical properties according to data from the literature. An optimization algorithm is developed that reduces the number of voxels in the non union area until the scaled von Mises stress in the implant reaches 20% of the maximum stress in the implant/bone system that occurs with no fusion in the nonunion area at all. RESULTS: After six iterations of the optimization algorithm the number of voxels in the nonunion area is reduced by 96.4%, i.e. only 3.6% of voxels in the non union area are relevant for load transfer such that the von Mises stress in the implant/bone system does not exceed 20% of the maximal scaled von Mises stress occurring in the system with no fusion in the non union area at all. CONCLUSIONS: The hypothesis that less than full circumferential fusion is necessary for mechanical stability of a nonunion is confirmed. As the model provides only qualitative information the observed reduction of fusion area may not be taken literally but needs to be calibrated in future experiments. However this proof of concept provides the mechanical foundation for further development of minimally invasive approaches to delayed union and nonunion therapy. PMID- 25511087 TI - Phylogenetic identification of methanogens assimilating acetate-derived carbon in dairy and swine manures. AB - In order to develop approaches for reducing the carbon footprint of the swine and dairy industries, it is important first to identify the methanogenic communities that drive methane emissions from stored manure. In this study, the metabolically active methanogens in substrate-starved manure samples taken from two dairy and one swine manure storage tanks were identified using [(13)C]-acetate and DNA stable-isotope probing (DNA-SIP). Molecular analysis of recovered genomic [(13)C] DNA revealed that two distinct clusters of unclassified methanogen populations affiliated with the Methanoculleus genus, and the populations affiliated with Methanoculleus chikugoensis assimilated acetate-derived carbon (acetate-C) in swine and dairy starved manure samples, respectively. Furthermore, carbon flow calculations indicated that these populations were the primary contributors to methane emissions during these anoxic SIP incubations. Comparative analysis of mcrA gene abundance (coding for a key enzyme of methanogenesis) for Methanoculleus spp. in fresh feces and a wider range of stored dairy or swine manure samples, by real-time quantitative PCR using newly designed specific primers, demonstrated that the abundance of this genus significantly increased during storage. The findings supported the involvement of these particular methanogen populations as methane emitters from swine and dairy manure storage tanks. The study revealed that the ability to assimilate acetate-C for growth in manure differed within the Methanoculleus genus. PMID- 25511084 TI - Management of acute aortic syndrome. AB - Acute aortic syndrome (AAS) encompasses a group of severe, life-threatening disorders of the aorta, including acute aortic dissection, intramural haematoma (IMH), and penetrating aortic ulcer (PAU). The concept of AAS was developed to enable the early identification and definitive treatment of patients with chest pain from an aortic origin. Aortic dissection is the most common form of AAS, followed by IMH and PAU. Congenital cardiovascular defects, genetic syndromes, and nonsyndromic genetic variants have all been linked with the development of AAS. The diagnosis of AAS in the clinic can be made using imaging modalities such as CT, echocardiography, and MRI. The initial management of patients with AAS is focussed on the control of blood pressure to reduce aortic wall stress. A multidisciplinary team is required to assess each patient and decide whether endovascular or open surgical treatment, or further medical management is indicated. The optimal treatment of patients with AAS remains a challenging clinical dilemma, and further studies are required to fully characterize conditions within the AAS spectrum and to design individualized, patient-centred treatment plans. PMID- 25511085 TI - MicroRNAs in myocardial infarction. AB - MicroRNAs (miRNAs) are small noncoding RNAs that block translation or induce degradation of mRNA and thereby control patterns of gene expression. Acute myocardial infarction is a common cardiovascular event that results in cardiac remodelling and can consequently lead to the development of chronic heart failure. Several miRNAs have been shown to control important processes that contribute to the pathophysiological consequences of acute myocardial infarction. miRNAs can either promote or inhibit cardiomyocyte cell death, and also regulate postischaemic neovascularization. Cardiac regeneration can also be regulated by miRNAs that control cardiomyocyte proliferation or interfere with cardioprotective effects mediated by stem or progenitor cells. miRNAs can also be used for direct reprogramming of cardiac fibroblasts into cardiomyocytes. In this Review, we focus on the current understanding of the role of miRNAs in these processes, and particularly discuss the therapeutic potential of miRNAs in treating acute myocardial infarction. PMID- 25511088 TI - [Chinese expert consensus on cardiac rehabilitation for patients with chronic stable heart failure]. PMID- 25511089 TI - [Chinese expert consensus on early morning blood pressure]. PMID- 25511090 TI - [Predict value of soluble ST2 on one-year mortality for hospitalized patients with chronic heart failure]. AB - OBJECTIVE: To explore the predict value of plasma soluble ST2 (sST2) on one-year mortality for hospitalized patients with chronic heart failure (HF). METHODS: A total of 1 244 consecutive hospitalized patients admitted to Heart Failure Center Fuwai Hospital between March 2009 and July 2012 and with HF as their primary diagnosis were included. Plasma sST2 was measured in all patients and patients were followed up for 1 year, and the primary endpoint was defined as all-cause death. RESULTS: There were 193 deaths during follow up. sST2 concentrations at admission were positively correlated with NT-proBNP, NYHA functional class and heart rate, and negatively correlated with left ventricular ejection fraction, blood sodium, total cholesterol and glomerular filtration rate at admission. sST2 concentrations were significantly higher in non-survivors compared with survivors (P < 0.001). Multivariable Cox regression analyses showed that sST2 independently predicted 1-year mortality (per 1 log unit, hazard ratio 1.87, 95% confidence interval: 1.56 to 2.25, P < 0.001). In receiver operating characteristic analyses, the area under the curve for ST2 was 0.776 which was similar to that of N-terminal pro-B-type natriuretic peptide (NT-proBNP) (AUC = 0.775). The prognostic value was improved when combining these two biomarkers together (AUC = 0.813). CONCLUSIONS: sST2 concentration at admission is correlated with clinical and biochemical indexes and associated with 1-year mortality for hospitalized patients with HF. PMID- 25511091 TI - [Factors associated with the efficacy of cardiac resynchronization therapy in patients with chronic heart failure]. AB - OBJECTIVE: To observe the clinical effects of cardiac resynchronization therapy (CRT) in patients with chronic heart failure, and compare the clinical characteristics and outcome between responders and non-responders to define factors related to the efficacy of CRT. METHODS: We retrospectively analyzed the data of patients underwent CRT-P/D implantation from January 2006 to December 2012 in our Hospital. All patients received long-term follow-up including NYHA classification, left ventricular ejection fraction (LVEF) and left ventricular internal dimension at end diastole (LVIDd). RESULTS: A total of 204 patients were included (130 males, mean age (64.8 +/- 11.9) years). The total response rate of CRT was 61.3%. Women, QRS duration >= 150 ms, and left bundle branch block (LBBB) were related with better response after CRT (all P < 0.05). Multivariate regression analysis showed that QRS duration was an independent determinant for CRT response. All-cause mortality rate was significantly lower in responder group than in non-responder group (P < 0.001). CONCLUSIONS: In patients with chronic heart failure, women, QRS duration >= 150 ms, and LBBB are related with better CRT response rate post CRT. QRS duration >= 150 ms is an independent predictor of CRT response, and positive response is associated with lower all-cause mortality in this patient cohort. PMID- 25511092 TI - [Cognitive function and factors related to cognitive function in hospitalized patients with chronic heart failure]. AB - OBJECTIVE: To explore the cognitive function status and potential influence factors on cognitive function in hospitalized patients with chronic heart failure. METHODS: Using a cross-sectional research design, CHF patients (n = 267, mean age (63.8 +/- 9.4) years) were recruited from two care units-Heart Failure Care Unit and Intensive Care Unit of our hospital. Cognitive function status was evaluated by the Montreal Cognitive Assessment (MoCA) screen test. RESULTS: Based on the MoCA score, 37.8% (101/267) patients suffered from cognitive impairment (score<26), especially on the three specific cognitive functions-memory, langue and executive capability. Multifactorial analysis showed that after controlling for other factors, there was a downward trend on cognitive function with aging (OR = 1.09, 95%CI:1.05-1.14) while higher left ventricular ejection fraction (LVEF) was related to better cognitive function (OR = 0.97, 95%CI:0.95-0.99); patients who took medicine regularly also had better cognitive function (OR = 3.71, 95%CI:1.40-10.91); cognitive function was better in patients with high level of social support compared those with low social support (OR = 0.92, 95%CI:0.88-0.96). CONCLUSIONS: Incidence of cognitive impairment is high in hospitalized patients with chronic heart failure. Age, LVEF, whether taking medication regularly and social support are factors related to cognitive function in CHF patients. PMID- 25511093 TI - [Relationship between atherosclerotic plaque characteristics and extracellular matrix metalloproteinase inducer and urokinase-type plasminogen activator in patients with coronary artery disease]. AB - OBJECTIVE: To explore the association between extracellular matrix metalloproteinase inducer (EMMPRIN) and urokinase-type plasminogen activator (uPA) and the severity of coronary artery lesions in coronary heart disease (CHD) patients. METHODS: This study enrolled 88 patients with acute coronary syndrome (ACS) and 46 patients with stable angina pectoris (SAP). The mean fluorescence intensity (MFI) of EMMPRIN on monocytes of peripheral blood (PBMCs) were examined by flow cytometry. uPA in serum was measured with ELISA . 64-slice spiral computed tomography coronary artery imaging was performed in 108 CHD patients. Coronary artery plaques were divided into type I (33 patients), type II (59 patients) and type III (44 patients) through plaque morphology characteristics according to coronary angiography. Coronary artery plaques were divided into soft (42 patients), fibrous (34 patients) and calcified plaque (32 patients) according to CT characteristics. RESULTS: (1) Type II plaque (48 patients) and soft plaque (35 patients) were the major plaque types in the ACS patients, while type Iplaque (20 patients) and type III plaque (17 patients) and fibrous plaque (16 patients) and calcified plaque (22 patients) were the major plaque types in the SAP patients. (2) The EMMPRIN expression and uPA levels were significantly higher in typeII plaque group (EMMPRIN MFI: 11.61 +/- 0.81, uPA: (0.89 +/- 0.17) mg/L) than those in the typeIplaque group (EMMPRIN MFI: 6.65 +/- 1.32, uPA: (0.53 +/- 0.06) mg/L) and in the type III plaque group (EMMPRIN MFI: 9.47 +/- 1.16, uPA:(0.56 +/- 0.04) mg/L, all P < 0.05). The EMMPRIN expression was higher in the typeIII plaque group (MFI: 9.47 +/- 1.16) than in the typeIplaque group (MFI:6.65 +/- 1.32, P < 0.05), but uPA levels were similar between the 2 groups ((0.56 +/- 0.04) mg/L vs. (0.53 +/- 0.06) mg/L). (3) The EMMPRIN expression and uPA levels in the soft plaque group (EMMPRIN MFI:11.37 +/- 0.76, uPA: (0.97 +/- 0.12)mg/L) were significantly higher than those in the fibrous plaque group (EMMPRIN MFI: 8.93 +/- 1.21), uPA:(0.52 +/- 0.09) mg/L) and calcified plaque group (EMMPRIN MFI: 6.94 +/- 1.19, uPA:(0.49 +/- 0.12) mg/L, P < 0.05). The EMMPRIN expression in the fibrous plaque group (MFI:8.93 +/- 1.21) was higher than in the calcified plaque group (MFI:6.94 +/- 1.19, P < 0.05), but uPA levels were similar between the two groups. CONCLUSION: Higher EMMPRIN expression and uPA levels were associated with plaque instability, which might be used to evaluate plaque stability in CHD patients. PMID- 25511094 TI - [Feasibility of transcatheter closure of atrial septal defect under the guidance of transthoracic echocardiography]. AB - OBJECTIVE: To explore the feasibility of transcatheter closure of atrial septal defect (ASD) under transthoracic echocardiography (TTE) guidance. METHODS: Retrospective analysis was performed in 65 patients with simple ASD who underwent transcatheter closure under echocardiography guidance in Fuwai hospital from February to August 2013. They were divided into TTE group (n = 30) and transesophageal echocardiography (TEE) group (n = 35). The TTE group patients who underwent localized anesthesia or basal anesthesia received transcatheter closure of ASD under the guidance of TTE. The TEE group patients who underwent tracheal intubation and general anesthesia received transcatheter closure of ASD under the guidance of TEE. The patients were followed up with TTE and electrocardiogram at one month after procedure at outpatient department. RESULTS: In the TTE group, 28 occluders were implanted successfully and 2 patients were subsequently switched to TEE guidance because of unclear TTE images, and the occluder implantation in these 2 patients was successful. There were no obvious differences in age, sex, body weight, ASD size, and time of hospital stay between the two groups (all P > 0.05) . Compared with TEE group, the TTE group had a significantly shorter operation time ((52.77 +/- 9.00 ) min vs. (60.11 +/- 9.15) min, P < 0.05), respirator ventilation duration ((0.25 +/- 0.95) h vs. (3.17 +/- 0.69) h, P < 0.05), and stay time in ICU ((1.50 +/- 1.96) h vs. (16.43 +/- 6.99) h, P < 0.05). The dose of propofol required was significantly lower in the TTE group compared to TEE group ((2.41 +/- 2.97) mg/kg vs. (9.43 +/- 3.70) mg/kg, P < 0.05). The patients in both groups had no complications such as residual shunt, peripheral vascular injury or cardiac perforation at the time of hospitalization.No complications, such as occluder dislocation, residual shunt, or pericardial effusion were seen during follow-up at one month post procedure in both groups. CONCLUSION: Transcatheter closure of ASD under TTE guidance is feasible and has a broad application prospects. PMID- 25511095 TI - [Association between echocardiography derived right ventricular function parameters with cardiac magnetic resonance derived right ventricular ejection fraction and 6-minute walk distance in pulmonary hypertension patients]. AB - OBJECTIVE: To explore the association between transthoracic echocardiography (TTE) derived right ventricular (RV) function parameters with cardiovascular magnetic resonance imaging (CMR) derived RV ejection fraction (RVEF) and 6 minute walk distance (6MWD) in pulmonary hypertension (PH) patients. METHODS: A total of 40 PH patients (37 pulmonary artery hypertension (PAH) and 3 chronic thromboembolic pulmonary hypertension (CTEPH)) hospitalized in our department between March 2011 and March 2013 were enrolled in this study. PH diagnosis was established by right heart catheterization and TTE, CMR and 6MWT were performed within one week post TTE examination. TTE parameters included: tricuspid annular peak systolic excursion (TAPSE), isovolumic contraction acceleration (IVA), peak systolic velocity (S') at the lateral tricuspid annulus derived from tissue Doppler imaging, RV myocardial performance index (MPI) and RV fractional area change (FAC). RVEF was obtained from CMR. RESULTS: S' (r = 0.69, P < 0.001), TAPSE (r = 0.65, P < 0.001), FAC (r = 0.62, P < 0.001), IVA (r = 0.43, P = 0.006), MPI (r = -0.38, P < 0.05) correlated significantly with RVEF obtained from CMR. The best parameter to detect RVEF <= 20% was S' < 8.79 cm/s (area under the ROC curve was 0.92 (95% CI: 0.72-0.84), sensitivity 0.91, and specificity 0.80) . No correlation was found between TTE parameters and 6MWD and between RVEF obtained from CMR and 6MWD. CONCLUSION: S', derived from tissue Doppler imaging correlates best with RVEF obtained from CMR and may facilitate simple and quantitative assessment of RV function. The best parameter to detect RVEF <= 20% is S' < 8.79 cm/s. PMID- 25511096 TI - [Analysis of traditional cardiovascular risk factors in patients with systemic lupus erythematosus]. AB - OBJECTIVE: To evaluation the prevalence of hypertension, diabetes, dyslipidemia in systemic lupus erythematosus (SLE) patients, and investigate the factors that affecting lipid levels in SLE patients. METHODS: A total of 540 adult SLE patients hospitalized in Peking Union Medical College Hospital from March 2010 to March 2013 were retrospectively included (SLE group), and 1 080 gender and age matched (1: 2) healthy controls were selected from our medical examination center (control group). The prevalence rate of hypertension, diabetes, dyslipidemia and the levels of serum lipid were compared between the two groups, the factors affecting lipid levels in SLE patients were also analyzed. RESULTS: The percentage of hypertension, diabetes, dyslipidemia, elevated total cholesterol (TC), elevated triglyceride (TG), decreased high density lipoprotein cholesterol (HDL-C) and elevated low density lipoprotein cholesterol (LDL-C) in SLE patients were significantly higher than those in healthy controls (all P < 0.01) . Compared with the control group, SLE patients had significantly higher TC, TG, LDL-C levels and significantly lower HDL-C levels (all P < 0.01) . Multifactor regression analysis showed that TC and LDL-C levels were positively correlated with lupus nephritis (beta = 0.695,0.437), corticosteroids therapy (beta = 1.195, 0.715), complement C4 levels (beta = 4.817, 3.382) and 24 hours urine protein content (beta = 0.112, 0.078) (all P < 0.01) , but negatively correlated with serum albumin (Alb) (beta = -0.107, -0.077) and high sensitive C reactive protein (hsCRP) levels (beta = -0.021, -0.014) (all P < 0.01). TG levels were positively correlated with lupus nephritis (beta = 0.359) and 24 hours urine protein content (beta = 0.045) (both P < 0.05), negatively correlated with male gender (beta = 0.605), age (beta = -0.014) and Alb levels (beta = -0.053) (P < 0.01 or 0.05). HDL-C levels were positively correlated with age (beta = 0.007), lupus nephritis (beta = 0.188), corticosteroids therapy (beta = 0.342), consecutive 30 days cumulative corticosteroids dose before serum lipid were measured (beta<0.001), and complement C3 levels(beta = 0.351) (all P < 0.01) , negatively correlated with hsCRP levels (beta = -0.005, P < 0.01). Serum lipid levels did not correlate with disease duration, disease activity, corticosteroids therapy time, corticosteroids daily dose before serum lipid measurement, serum creatinine levels and erythrocyte sedimentation rate (ESR) (all P > 0.05). CONCLUSION: The prevalence rate of hypertension, diabetes and dyslipidemia in SLE hospitalized patients are significantly higher compared to normal controls and lipid levels of SLE patients are related to various SLE disease factors. PMID- 25511097 TI - [Effects of astragalus and its active ingredients on ischemia reperfusion injury in isolated guinea-pig heart]. AB - OBJECTIVE: To explore the effects of astragalus (AST) , total flavone of astragalus (TFA), total saponins of astragalus (TSA) and astragalus polysaccharides (APS) on ischemia/reperfusion (40 min/60 min) injury in isolated guinea-pig heart. METHODS: Isolated guinea-pig hearts underwent ischemia, then followed by K-H perfusion (I/R group), AST (60 mg/L),AST (60 mg/L), TFA (60 mg/L), TSA (60 mg/L) and APS (60 mg/L) perfusion (n = 6 each).Isolated hearts without ischemia serve as control group (n = 6). Activity of lactate dehydrogenas (LDH) and creatine kinase (CK) in effluent were measured.Infarct size, myocardial superoxide dismutase (SOD) activity and malondiadehyde (MDA) contents were also determined. RESULTS: Compared to control hearts, heart rate, coronary flow and myocardial superoxide dismutase (SOD) activity were significantly reduced, while LDH and CK in effluent as well as myocardial MDA were significantly increased in the I/R hearts during reperfusion (all P < 0.05), these changes could be partly reversed by AST and TFA perfusion.Infarct size was also significantly reduced in AST (11.9 +/- 2.03) % and TFA (13.31 +/- 1.17) % treated hearts compared to that in I/R group (18.9 +/- 2.27) % (all P < 0.01). CONCLUSIONS: The findings indicate that AST and TFA could attenuate I/R injury in isolated guinea-pig heart possibly through enhancing the activity of SOD and reducing lipid peroxidation. PMID- 25511098 TI - [Effects and related mechanisms of ghrelin on myocardial neovascularization in diabetic rats with experimental myocardial infarction]. AB - OBJECTIVE: To investigate the effects and related mechanisms of ghrelin on myocardial neovascularization in diabetic rats with experimental myocardial infarction (MI). METHODS: Adult male SD rats were divided into six groups (n = 20 each group): control, diabetes mellitus (DM), MI, DM+MI, DM+MI+ghrelin, DM+MI+ghrelin+D-Lys3-GHRP-6 (GHSR1a inhibitor). DM was induced by streptozotocin (STZ, 60 mg/kg), 3 months later, MI was induced by left anterior descending artery ligation in DM rats. DM+MI+ghrelin group received ghrelin 200 ug*kg(-1)*d( 1) and DM+MI+ghrelin+D-Lys3-GHRP-6 group received ghrelin 200 ug*kg(-1)*d(-1) and D-Lys3-GHRP-6 50 mg*kg(-1)*d(-1) for 4 weeks. Then, cardiac function was measured by echocardiography, microvascular density (MVD) was measured by CD34 immunohistochemistry, myocardial infarct size was determined by Masson staining, the mRNA and protein expressions of vascular endothelial growth factor (VEGF) and receptors Flk-1, Flt-1 were detected by real-time PCR and Western-blot, respectively. RESULTS: Compared with MI group, MVD (15.3 +/- 1.0 vs.20.7 +/- 1.6, P < 0.05), left ventricular ejection fraction (LVEF) ((64.2 +/- 3.4)% vs. (81.3 +/- 3.8)%, P < 0.01), left ventricular fractional shortening (LVFS) ((31.7 +/- 1.1)% vs. (48.8 +/- 3.3)%, P < 0.01) and the mRNA and protein expression of VEGF, Flk-1 and Flt-1 (P < 0.01) were reduced, while myocardial infarct size ((55.8 +/- 3.1)% vs. (35.7 +/- 2.5)%, P < 0.01) was increased in DM+MI group. These effects were partly reversed in DM+MI+ghrelin group and the beneficial effects of ghrelin were partly abolished by D-Lys3-GHRP-6 (all P < 0.05). CONCLUSIONS: Our results demonstrate that ghrelin could improve microvascular density, cardiac function, and reduce myocardial infarct size of diabetic rats with myocardial infarction via modulating GHSR1a-mediated expressions of VEGF, Flk-1 and Flt-1. PMID- 25511099 TI - [Association between cigarette smoking and hypertension in men: a dose response relationship analysis]. AB - OBJECTIVE: To estimate the dose response relationship between cigarette smoking and hypertension in men based on restricted cubic spline method. METHODS: Under the proportion to the population size, 38 520 subjects were randomly selected from May to August 2012 with cluster sampling method in urban and rural areas of Kunshan, China.Each participant received face-to-face interview with the standardized questionnaire, and physical examination.Restricted cubic spline was employed to estimate the dose response relation of cigarette smoking on the risk of hypertension. RESULTS: The overall prevalence of cigarette smoking was 22.6% (8 691/38 520), prevalence of cigarette smoking in men was 46.1% (8 499/18 454). Multiple logistic regression analysis showed that current smoking (OR = 1.16, 95%CI:1.05-1.28) and previous cigarette smoking (OR = 1.32, 95%CI:1.07-1.63) were associated with hypertension after adjusted confounding factors (age, sex, body mass index, education, family income per month, urban or rural areas, physical activity and physical exercise) in men. After further adjusting drinking status, only previous cigarette smoking was associated with hypertension (OR = 1.28, 95%CI:1.04-1.58). The restricted cubic spline model indicated a linear dose response relation between hypertension and cigarette smoking per day in men (non linearity test P = 0.604 1).However, a non-linear dose response relation was found between duration of smoking (non-linearity test P < 0.000 1), smoking index (non-linearity test P = 0.009 9) and hypertension. CONCLUSION: Long-term and heavy cigarette smoking is associated with hypertension in men. PMID- 25511100 TI - [Impact of ideal cardiovascular health behaviors and factors on resting heart rate in individuals without cardiovascular diseases]. AB - OBJECTIVE: To investigate the impact of ideal cardiovascular health behaviors and factors on resting heart rate (RHR). METHODS: A cross-sectional study method was used in our study.83 824 workers who had participated in the 2006-2007 Kailuan health examination were included, individuals with arrhythmia, hemoglobin <= 90g/L, taking drugs which might affect RHR, history of cerebral infarction or myocardial infarction or cancer were excluded.Related information was obtained from the unified questionnaire, blood biochemistry was performed. Multivariate logistic regression was used to analyze the impact of ideal cardiovascular health behaviors and factors on the RHR. RESULTS: (1) The RHR was (76.4 +/- 10.3), (75.2 +/- 10.3), (74.3 +/- 9.9), (73.6 +/- 10.0), (72.6 +/- 9.9), (72.1 +/- 9.7) and (71.8 +/- 9.2) beats/min in workers whose number of ideal cardiovascular health behaviors and factors was 1, 2, 3, 4, 5 and >= 6 respectively (P < 0.01). (2) Multivariate logistic regression showed that, after adjusted by gender, age, triglyceride, high density lipoprotein cholesterol, high-sensitive C-reactive protein, tea drinking, alcohol drinking, the risk of RHR >= 80 beats/min gradually reduces along with the increasing of number of ideal cardiovascular health behaviors and factors (1, 2, 3, 4, 5 and >= 6) compared with those who did not have ideal cardiovascular health behaviors and factors, the value of OR (95%CI) was 0.79 (0.71-0.87), 0.68 (0.62-0.75), 0.61 (0.55-0.67), 0.52 (0.47 0.58), 0.50 (0.44-0.56), 0.49 (0.40-0.60) respectively. CONCLUSION: Ideal cardiovascular health behavior and factors is related to lower RHR in individuals without cardiovascular diseases. PMID- 25511101 TI - [Familial transthyretin amyloidosis with Gly47Arg mutation and cardiac involvement: a case report]. PMID- 25511102 TI - [Research advances on relationship between large conductance Ca(2)+-activated K(+) channels and hypertension]. PMID- 25511103 TI - [Update on vascular smooth muscle cells phenotype modulation by microRNA]. PMID- 25511104 TI - [Update on the association between endothelial-to-mesenchymal transition and cardiac fibrosis]. PMID- 25511105 TI - Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose, open-label, parallel group study. AB - AIMS: Serelaxin is a recombinant form of human relaxin-2 in development for treatment of acute heart failure. This study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with hepatic impairment. Secondary objectives included evaluation of immunogenicity, safety and tolerability of serelaxin. METHODS: This was an open-label, parallel group study (NCT01433458) comparing the PK of serelaxin following a single 24 h intravenous (i.v.) infusion (30 MUg kg(-1) day(-1) ) between patients with mild, moderate or severe hepatic impairment (Child-Pugh class A, B, C) and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non compartmental PK parameters [including area under the serum concentration-time curve AUC(0-48 h) and AUC(0-infinity) and serum concentration at 24 h post-dose (C24h )] were compared between each hepatic impairment group and healthy controls. RESULTS: A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, the serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12-24 h and then declined following completion of infusion, with a mean terminal half-life of 7-8 h. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to adverse events or deaths were reported. No serelaxin treatment-related antibodies developed during this study. CONCLUSIONS: The PK and safety profile of serelaxin were not affected by hepatic impairment. No dose adjustment is needed for serelaxin treatment of 48 h i.v. infusion in patients with hepatic impairment. PMID- 25511107 TI - 4-Vinylcyclohexene diepoxide reduces fertility in female Siberian hamsters when treated during their reproductively active and quiescent states. AB - The industrial compound 4-vinylcyclohexene diepoxide (VCD) destroys ovarian follicles and reduces fertility in rodents, but to date VCD has not been tested in species that experience seasonal anestrus. To determine if VCD destroys follicles when administered during reproductive quiescence, Siberian hamsters were treated with VCD (240mg/kg i.p. daily for 10 days) during short days, and outcomes were compared with reproductively active females that were maintained and treated in long days. Primordial follicle numbers were significantly reduced by VCD under both day lengths, and reproductive quiescence in short days did not appear to render the ovaries less susceptible to VCD-induced follicle depletion. Independent of day length and reproductive state, VCD-treated hamsters weaned substantially fewer offspring than controls. These results suggest that time of year may not be an important consideration for optimizing use of VCD in the field when the target pest species is a seasonally breeding rodent. PMID- 25511106 TI - In utero preeclampsia exposure, milk intake and pubertal development. AB - Cord blood insulin-like growth factor-1 (IGF-1) concentrations are lower in preeclamptic (PE) than normotensive (NT) pregnancies. PE offspring have increased risk of cardiovascular disease and decreased risk of some cancers including breast. We examined the effects of PE exposure in utero, infant feeding and childhood diet at 3-5 years on IGF-1 and breast development in 194 female offspring who were followed from birth until follow-ups at 10.8 and 12.9 years. Diet was not associated with serum IGF-1 levels at 10.8 years. PE exposure was associated with reduced odds of thelarche at 10.8 years only among exclusively breastfed girls. Milk, butter and ice cream consumption at 3-5 years was inversely related to the OR of breast development at 10.8 years. Child's weight and maternal overweight were positively associated with breast development at 10.8 years; child's height and weight were positively associated with breast development at 12.9 years. PMID- 25511109 TI - Comparative efficacy of up to 50% partial fish meal replacement with fermented soybean meal or enzymatically prepared soybean meal on growth performance, nutrient digestibility and fecal microflora in weaned pigs. AB - This study was conducted to determine the comparative efficacy of partial fish meal (FM) replacement (up to 50%) with fermented soybean meal (FSBM; SoELAB, PepSoyGen and Soytide) or enzymatically prepared SBM (HP 300) on growth performance, nutrient digestibility and fecal microflora in weaned pigs. A total of 100 weaned pigs (body weight 6.59 +/- 0.29 kg) were used in experimental feeding trials, lasting for up to 6 weeks, and were randomly allotted to five groups with four block replicates of five pigs per pen serving as one block. Dietary treatments were as follows: (i) 100% FM, (ii) 50% FM + 50% SoELAB-54, (iii) 50% FM + 50% PepSoyGen, (iv) 50% FM + 50% Soytide and (v) 50% FM + 50% HP 300. Concerning growth performance, none of the treated SBM preparations demonstrated any significantly different effect compared with FM treatment. With respect to nutrient digestibility, SoELAB and HP 300 treatments demonstrated no significant difference compared with FM treatment. Lastly, none of the SBM preparations demonstrated any significant differences in animal fecal score and all of the differentially treated SBM increased fecal Lactobacillus counts, while maintaining similar Escherichia coli counts compared with FM treatment. PMID- 25511108 TI - Esophageal cancer-related gene-4 (ECRG4) interactions with the innate immunity receptor complex. AB - OBJECTIVE AND DESIGN: The human c2orf40 gene encodes a tumor suppressor gene called esophageal cancer-related gene-4 (ECRG4) with pro- and anti-inflammatory activities that depend on cell surface processing. Here, we investigated its physical and functional association with the innate immunity receptor complex. METHODS: Interactions between ECRG4 and the innate immunity receptor complex were assessed by flow cytometry, immunohistochemistry, confocal microscopy, and co immunoprecipitation. Phage display was used for ligand targeting to cells that overexpress the TLR4-MD2-CD14. RESULTS: Immunoprecipitation and immunohistochemical studies demonstrate a physical interaction between ECRG4 and TLR4-MD2-CD14 on human granulocytes. Flow cytometry shows ECRG4 on the cell surface of a subset of CD14(+) and CD16(+) leukocytes. In a cohort of trauma patients, the C-terminal 16 amino acid domain of ECRG4 (ECRG4(133-148)) appears to be processed and shed, presumably at a thrombin-like consensus sequence. Phage targeting this putative ligand shows that this peptide sequence internalizes into cells through the TLR4/CD14/MD2 complex, but modulates inflammation through non canonical, NFkappaB signal transduction. CONCLUSIONS: ECRG4 is present on the surface of human monocytes and granulocytes. Its interaction with the human innate immunity receptor complex supports a role for cell surface activation of ECRG4 during inflammation and implicates this receptor in its mechanism of action. PMID- 25511110 TI - A comparative immunological analysis of CoCl2 treated cells with in vitro hypoxic exposure. AB - The hypoxic preconditioning of mammalian cells has been shown to have beneficial effects against hypoxic injuries. However, very little information is available on the comparative analysis of immunological responses to hypoxic and hypoxia mimetic exposure. Therefore, in the present study, mouse peritoneal macrophages and splenocytes were subjected to hypoxia exposure (0.5 % O2) and hypoxia mimetic Cobalt chloride (CoCl2) treatment to evaluate their effect on immune response and delineate the underlying signaling mechanisms. The results obtained indicated that super oxide generation increased while TLR4 expression and cell surface markers like CD25, CD40 and CD69 were suppressed in both the treatments as compared to normoxia. Cobalt chloride treatment increased NF-kappaB expression, nitric oxide (NO) and iNOS expression, cytokines TNF-alpha and IL-6 as compared to hypoxia exposure. Our study showed that CoCl2 stabilizes HIF-1alpha to create hypoxia like conditions but it mainly influences the inflammatory response via NF kappaB signaling pathway by skewing the production of proinflammatory molecules like TNF-alpha, IL-6 and NO. PMID- 25511111 TI - Efficacy of platelet-rich fibrin matrix on viability of diced cartilage grafts in a rabbit model. AB - OBJECTIVES/HYPOTHESIS: The objective of this study was to compare the viability of cartilage grafts embedded in platelet-rich fibrin matrix (PRFM) wrapped with no material (bare diced cartilage grafts), oxidized methylcellulose (Surgicel), or acellular dermal tissue (AlloDerm). STUDY DESIGN: Experimental study. METHODS: In this study, six New Zealand rabbits were used. Cartilage grafts including perichondrium were excised from each ear and diced into 2-mm-by 2-mm pieces. There were four comparison groups: 1) group A, diced cartilage (not wrapped with any material); 2) group B, diced cartilage wrapped with AlloDerm; 3) group C, diced cartilage grafts wrapped with Surgicel; and 4) group D, diced cartilage wrapped with PRFM. Four cartilage grafts were implanted under the skin at the back of each rabbit. All rabbits were sacrificed at the end of 10 weeks. The cartilages were stained with hematoxylin-eosin, Masson's Trichrome, and Orcein. After that, they were evaluated for the viability of chondrocytes, collagen content, fibrillar structure of matrix, and changes in peripheral tissues. RESULTS: When the viability of chondrocytes, the content of fiber in matrix, and changes in peripheral tissues were compared, the cartilage embedded in the PRFM group was statistically significantly higher than in the other groups (P < 0.05). CONCLUSION: We concluded that PRFM has significant advantages in ensuring the chondrocyte viability of diced cartilage grafts. It is also biocompatible, with relatively lesser inflammation and fibrosis. PMID- 25511112 TI - Development of a fluorescent enzyme-linked DNA aptamer-magnetic bead sandwich assay and portable fluorometer for sensitive and rapid listeria detection. AB - A fluorescent DNA aptamer-magnetic bead sandwich assay was developed to detect listeriolysin O (LLO) protein from pathogenic Listeria bacteria using a peroxidase-linked system, Amplex Ultra Red (AUR; derivatized resazurin) substrate, and a custom-designed handheld fluorometer. The assay is highly sensitive with demonstrated limits of detection (LODs) in the range of 4 to 61 L. monocytogenes cells or the equivalent LLO produced by 4 to 61 cells on average in separate titration trials. Total assay processing and analysis time was approximately 30 mins. The assay has demonstrated the ability to detect 6 species of Listeria as desired by the USDA's Food Safety Inspection Service (FSIS). The portable system was designed to be used primarily with surface swab samples from fomites, but it can also be used to assess enrichment cultures. The minimal time to detect a positive enrichment culture in our hands from an initial 10 cell inoculum in 200 ml of broth has been 8 h post-incubation at 37 degrees C in shaker flask cultures. An optional automated magnetic bead assay processing and wash device capable of simultaneously processing 6 samples with low and consistent fluorescence background for higher volume central laboratories is also described. PMID- 25511113 TI - The photophysical properties of multi-functional quantum dots-magnetic nanoparticles--indium octacarboxyphthalocyanine nanocomposite. AB - This work presents the development of a multifunctional hybrid nanoparticle made of L-glutathione capped quantum dots (GSH-CdSe@ZnS), amino functionalized Fe(3)O(4) magnetic nanoparticles and indium octacarboxy phthalocyanine (ClInPc(COOH)(8)). In this work we investigate the photophysical properties of the individual components and the hybrid nanoparticle, in addition we study the energy transfer (Forster Resonance Energy Transfer (FRET)) in the complex. FRET efficiencies of ~48 % were obtained for energy transfer between the QDs (when alone or linked to MNPs). Both triplet yields and lifetimes of ClInPc(COOH)(8) increase in the nanocomposite, with a decrease in fluorescence lifetime. The hybrid nanoparticle showed improved photophysical properties and as a result can be used in photodynamic therapy. PMID- 25511114 TI - Potential drug-drug interactions in infant, child, and adolescent patients in children's hospitals. AB - BACKGROUND AND OBJECTIVES: Hospitalized infants, children, and adolescents are typically exposed to numerous distinct medications during inpatient admissions, increasing their risk of potential drug-drug interactions (PDDIs). We assessed the prevalence and characteristics of PDDI exposure of pediatric patients treated in children's hospitals. METHODS: This retrospective cohort study included patients <21 years old hospitalized in children's hospitals throughout the United States. PDDIs were identified by using the MicroMedex DRUG-REAX system. We calculated the patients exposed to PDDIs, stratified according to the seriousness of the interaction; daily and cumulative counts of PDDI exposures; and characterization of the cited potential adverse effects. RESULTS: Of 498 956 hospitalizations in 2011, 49% were associated with >=1 PDDI, with a "contraindicated" PDDI occurring in 5% of all hospitalizations, a "major" PDDI present in 41%, a "moderate" PDDI in 28%, and a "minor" PDDI in 11%. Opioids were involved in 25% of all PDDIs, followed by antiinfective agents (17%), neurologic agents (15%), gastrointestinal agents (13%), and cardiovascular agents (13%). One half of all PDDI exposures were due to specific drug pairs occurring in <=3% of patients per hospital day. The most common potential adverse drug events included additive respiratory depression (in 21% of PDDIs), bleeding risk (5%), QT interval prolongation (4%), reduced iron absorption/availability (4%), central nervous system depression (4%), hyperkalemia (3%), and altered diuretic effectiveness (3%). CONCLUSIONS: Exposure to PDDIs is common among hospitalized children. Empirical data are needed to determine the probability and magnitude of the actual harm for each specific PDDI, particularly for less common drug pairs. PMID- 25511115 TI - Rapid normalization of vitamin D levels: a meta-analysis. AB - BACKGROUND: Vitamin D deficiency may represent a modifiable risk factor to improve outcome in severe illness. The efficacy of high-dose regimens in rapid normalization of vitamin D levels is uncertain. METHODS: We conducted a systematic review of pediatric clinical trials administering high-dose vitamin D to evaluate 25-hydroxyvitamin D (25[OH]D) response and characteristics associated with final 25(OH)D levels by using Medline, Embase, and the Cochrane Central Register of Controlled Trials, including reference lists of systematic reviews and eligible publications. Uncontrolled and controlled trials reporting 25(OH)D levels after high-dose (>=1000 IU) ergocalciferol or cholecalciferol were selected. Two reviewers independently extracted and verified predefined data fields. RESULTS: We identified 88 eligible full-text articles. Two of 6 studies that administered daily doses approximating the Institute of Medicine's Tolerable Upper Intake Level (1000-4000 IU) to vitamin D-deficient populations achieved group 25(OH)D levels >75 nmol/L within 1 month. Nine of 10 studies evaluating loading therapy (>50 000 IU) achieved group 25(OH)D levels >75 nmol/L. In meta regression, baseline 25(OH)D, regimen type, dose, age, and time factors were associated with final 25(OH)D levels. Adverse event analysis identified increased hypercalcemia risk with doses >400 000 IU, but no increased hypercalcemia or hypercalciuria with loading doses <400 000 IU (or 10 000 IU/kg). Few studies in adolescents evaluated loading dose regimens >300 000 IU. CONCLUSIONS: Rapid normalization of vitamin D levels is best achieved by using loading therapy that considers disease status, baseline 25(OH)D, and age (or weight). Loading doses >300 000 IU should be avoided until trials are conducted to better evaluate risk and benefit. PMID- 25511116 TI - Family-initiated dialogue about medications during family-centered rounds. AB - BACKGROUND AND OBJECTIVE: Experts suggest family engagement in care can improve safety for hospitalized children. Family-centered rounds (FCRs) can offer families the opportunity to participate in error recovery related to children's medications. The objective of this study was to describe family-initiated dialogue about medications and health care team responses to this dialogue during FCR to understand the potential for FCR to foster safe medication use. METHODS: FCR were video-recorded daily for 150 hospitalized children. Coders sorted family initiated medication dialogue into mutually exclusive categories, reflecting place of administration, therapeutic class, topic, and health care team responses. Health care team responses were coded to reflect intent, actions taken by the team, and appropriateness of any changes. RESULTS: Eighty-three (55%) of the 150 families raised 318 medication topics during 347 FCR. Most family initiated dialogue focused on inpatient medications (65%), with home medications comprising 35%. Anti-infectives (31%), analgesics (14%), and corticosteroids (11%) were the most commonly discussed medications. The most common medication topics raised by families were scheduling (24%) and adverse drug reactions (11%). Although most health care team responses were provision of information (74%), appropriate changes to the child's medications occurred in response to 8% of family-initiated dialogue, with most changes preventing or addressing adverse drug reactions or scheduling issues. CONCLUSIONS: Most families initiated dialogue regarding medications during FCRs, including both inpatient and home medications. They raised topics that altered treatment and were important for medication safety, adherence, and satisfaction. Study findings suggest specific medication topics that health care teams can anticipate addressing during FCR. PMID- 25511119 TI - Off-label prescribing in pediatric outpatients. AB - OBJECTIVE: To study the characteristics of off-label prescribing and adverse drug reaction (ADR) occurrence in a sample of pediatric outpatients treated by general practitioners. METHODS: A survey on pediatric drug prescribing was implemented in 46 general practices in southwestern France. All consecutive patients aged 0 to 16 years were included. Patient characteristics, reasons for consultation, and drug prescribed (including indications) were collected. ADRs occurring <=10 days after the date of consultation were recorded by the general practitioners (spontaneous notification). Off-label prescription was defined as prescribing outside the specifications of the Summary of Product Characteristics. RESULTS: Among the 2313 children seen between March 8, 2011 and July 31, 2011, 1960 were exposed to >=1 prescribed drug. Mean age was 5.6 years, with a gender ratio of 1.1. Among children with prescriptions, 37.6% (n = 736) were exposed to >=1 off label prescription and 6.7% (n = 132) to >=1 unlicensed drug. Off-label prescribing involved an unapproved indication in 56.4% of cases (n = 416), a lower dosage (26.5%, n = 195) or higher dosage (19.5%, n = 144) than specified, age not labeled (7.2%, n = 53), incorrect route of administration (3.5%, n = 26), and contraindication (0.3%, n = 2). A total of 23 ADRs were reported (1.5% of patients with off-label prescriptions). ADR occurrence was not significantly related to off-label drug prescribing. CONCLUSIONS: Despite the numerous initiatives implemented for promoting rational medicine use in children, the prevalence of off-label prescription in outpatient pediatric practice remains high. PMID- 25511117 TI - Anaerobic antimicrobial therapy after necrotizing enterocolitis in VLBW infants. AB - OBJECTIVE: To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (<=1500 g) infants. METHODS: We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobic antimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infants exposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity score stratified by NEC severity (medical and surgical). The primary composite outcome was in-hospital death or intestinal stricture. We assessed the relationship between anaerobic antimicrobial therapy and outcome by using a conditional logistic regression on the matched cohort. RESULTS: A total of 1390 infants exposed to anaerobic antimicrobial therapy were matched with 1390 infants not exposed. Mean gestational age and birth weight were 27 weeks and 946 g, respectively, and were similar in both groups. We found no significant difference in the combined outcome of death or strictures, but strictures as a single outcome were more common in the anaerobic antimicrobial therapy group (odds ratio 1.73; 95% confidence interval, 1.11-2.72). Among infants with surgical NEC, mortality was less common with anaerobic antimicrobial therapy (odds ratio 0.71; 95% confidence interval, 0.52-0.95). CONCLUSIONS: Anaerobic antimicrobial therapy was not associated with the composite outcome of death or strictures but was associated with an increase in intestinal strictures. This higher incidence of intestinal strictures may be explained by the fact that death is a competing outcome for intestinal strictures, and mortality was slightly lower in the anaerobic cohort. Infants with surgical NEC who received anaerobic antimicrobial therapy had lower mortality. PMID- 25511118 TI - Risk factors for exclusive e-cigarette use and dual e-cigarette use and tobacco use in adolescents. AB - OBJECTIVE: To describe electronic cigarette (e-cigarette) use and cigarette use among adolescents and determine whether established risk factors for smoking discriminate user categories. METHODS: School-based survey of 1941 high school students (mean age 14.6 years) in Hawaii; data collected in 2013. The survey assessed e-cigarette use and cigarette use, alcohol and marijuana use, and psychosocial risk and protective variables (eg, parental support, academic involvement, smoking expectancies, peer smoking, sensation seeking). Analysis of variance and multinomial regression examined variation in risk and protective variables across the following categories of ever-use: e-cigarette only, cigarette only, dual use (use of both products), and nonuser (never used either product). RESULTS: Prevalence for the categories was 17% (e-cigarettes only), 12% (dual use), 3% (cigarettes only), and 68% (nonusers). Dual users and cigarette only users were highest on risk status (elevated on risk factors and lower on protective factors) compared with other groups. E-cigarette only users were higher on risk status than nonusers but lower than dual users. E-cigarette only users and dual users more often perceived e-cigarettes as healthier than cigarettes compared with nonusers. CONCLUSIONS: This study reports a US adolescent sample with one of the largest prevalence rates of e-cigarette only use in the existing literature. Dual use also had a substantial prevalence. The fact that e-cigarette only users were intermediate in risk status between nonusers and dual users raises the possibility that e-cigarettes are recruiting medium-risk adolescents, who otherwise would be less susceptible to tobacco product use. PMID- 25511120 TI - A treatable metabolic cause of encephalopathy: cobalamin C deficiency in an 8 year-old male. AB - Neurologic regression in a previously healthy child may be caused by metabolic or neurodegenerative disorders, many of which have no definitive treatment. We report a case of a previously healthy 8-year-old boy who presented with a month long history of waxing and waning encephalopathy and acute regression, followed by seizures. Evaluation for a metabolic disorder revealed methylmalonic acidemia and hyperhomocysteinemia of the cobalamin C type due to a single, presumed homozygous pathogenic c.394 C>T mutation in the MMACHC gene. With the appropriate diet restrictions and vitamin replacement, he improved significantly and returned to his premorbid level of behavior. This case illustrates an unusual presentation of a treatable metabolic disorder and highlights the need to consider cobalamin defects in the differential diagnosis of healthy children with neurologic regression. PMID- 25511121 TI - Vitamin D in fetal development: findings from a birth cohort study. AB - Birth cohort studies provide an invaluable resource for studies of the influence of the fetal environment on health in later life. It is uncertain to what extent maternal vitamin D status influences fetal development. Using an unselected community-based cohort of 901 mother-offspring pairs (the Western Australian Pregnancy Cohort [Raine] Study), we examined the relationship between maternal vitamin D deficiency at 18 weeks' pregnancy and long-term health outcomes of offspring who were born in Perth, Western Australia (32 degrees South), in 1989 1991. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] <50 nmol/L) was present in 36% (323 of 901) of the pregnant women. After adjusting for relevant covariates, maternal vitamin D deficiency during pregnancy was associated with impaired lung development in 6-year-old offspring, neurocognitive difficulties at age 10, increased risk of eating disorders in adolescence, and lower peak bone mass at 20 years. In summary, vitamin D may have an important, multifaceted role in the development of fetal lungs, brain, and bone. Experimental animal studies support an active contribution of vitamin D to organ development. Randomized controlled trials of vitamin D supplementation in pregnant women with long-term follow-up of offspring are urgently required to examine whether the correction of vitamin D deficiency in pregnant women is beneficial for their offspring and to determine the optimal level of maternal serum 25(OH)D for fetal development. PMID- 25511122 TI - Methylphenidate and the risk of trauma. AB - BACKGROUND AND OBJECTIVE: Children and adolescents with attention deficit/hyperactivity disorder (ADHD) are prone to sustaining trauma that requires emergency department (ED) admission. Methylphenidate (MPH) can reduce ADHD symptoms and may thus theoretically reduce the risk of trauma-related ED admission, but previous studies do not make this association clear. This study examines this association. METHODS: A total of 17 381 patients aged 6 to 19 years who received MPH prescriptions were identified by using the Clinical Data Analysis & Reporting System (2001-2013). Using a self-controlled case series study design, the relative incidence of trauma-related ED admissions was compared with periods of patient exposure and nonexposure to MPH. RESULTS: Among 17 381 patients prescribed MPH, 4934 had at least 1 trauma-related ED admission. The rate of trauma-related ED admission was lower during exposed periods compared with nonexposed periods (incidence rate ratio [IRR]: 0.91 [95% confidence interval (CI): 0.86-0.97]). The findings were similar only when the incident trauma episode was assessed (IRR: 0.89 [95% CI: 0.82-0.96]). A similar protective association was found in both genders. In validation analysis using nontrauma related ED admissions as a negative control outcome, no statistically significant association was found (IRR: 0.99 [95% CI: 0.95-1.02]). All sensitivity analyses demonstrated consistent results. CONCLUSIONS: This study supports the hypothesis that MPH is associated with a reduced risk of trauma-related ED admission in children and adolescents. A similar protective association was found in both male and female patients. This protective association should be considered in clinical practice. PMID- 25511123 TI - Core symptoms of autism improved after vitamin D supplementation. AB - Autism spectrum disorder (ASD) is a common neurodevelopmental disorder caused by a complex interaction between genetic and environmental risk factors. Among the environmental factors, vitamin D3 (cholecaliferol) seems to play a significant role in the etiology of ASD because this vitamin is important for brain development. Lower concentrations of vitamin D3 may lead to increased brain size, altered brain shape, and enlarged ventricles, which have been observed in patients with ASD. Vitamin D3 is converted into 25-hydroxyvitamin D3 in the liver. Higher serum concentrations of this steroid may reduce the risk of autism. Importantly, children with ASD are at an increased risk of vitamin D deficiency, possibly due to environmental factors. It has also been suggested that vitamin D3 deficiency may cause ASD symptoms. Here, we report on a 32-month-old boy with ASD and vitamin D3 deficiency. His core symptoms of autism improved significantly after vitamin D3 supplementation. This case suggests that vitamin D3 may play an important role in the etiology of ASD, stressing the importance of clinical assessment of vitamin D3 deficiency and the need for vitamin D3 supplementation in case of deficiency. PMID- 25511124 TI - Presepsin for the detection of late-onset sepsis in preterm newborns. AB - BACKGROUND: Late-onset sepsis (LOS) is among the leading causes of morbidity and mortality in preterm newborns, and currently available diagnostic tools are inadequate. The objective of this study was to evaluate the accuracy of presepsin (P-SEP) as novel biomarker of bacterial infection for the diagnosis of LOS in preterm newborns. METHODS: We prospectively studied newborns <=32 weeks' gestational age with LOS (n = 19) and noninfected controls (n = 21) at 4 to 60 days' postnatal age. At enrollment, and 1, 3, and 5 days later, we ascertained the C-reactive protein, procalcitonin, and P-SEP in the LOS group, whereas P-SEP alone was ascertained in the control group. RESULTS: P-SEP at enrollment was higher in the LOS than the control group (median 1295 vs 562 ng/L, P = .00001) and remained higher throughout the study period. In the LOS group, P-SEP had a borderline reduction at day 1 versus values at enrollment (median 1011 vs 1295 ng/L, P = .05), whereas C-reactive protein and procalcitonin at day 1 did not differ from baseline values. The receiver operating characteristic curve of P-SEP at enrollment shows an area under the curve of 0.972. The best calculated cutoff value was 885 ng/L, with 94% sensitivity and 100% specificity. Negative likelihood ratio was 0.05, and positive likelihood ratio was infinity. CONCLUSIONS: We demonstrated for the first time in a cohort of preterm newborns that P-SEP is an accurate biomarker for the diagnosis of possible LOS and may also provide useful information for monitoring the response to therapeutic interventions. PMID- 25511126 TI - Nanoflaky MnO2/functionalized carbon nanotubes for supercapacitors: an in situ X ray absorption spectroscopic investigation. AB - The surfaces of acid- and amine-functionalized carbon nanotubes (C-CNT and N-CNT) were decorated with MnO2 nanoflakes as supercapacitors by a spontaneous redox reaction. C-CNT was found to have a lower edge plane structure and fewer defect sites than N-CNT. MnO2/C-CNT with a highly developed surface area exhibited favorable electrochemical performance. To determine the atomic/electronic structures of the MnO2/functionalized CNTs (MnO2/C-CNT and MnO/N-CNT) during the charge/discharge process, in situ X-ray absorption spectroscopy (XAS) measurements were made at the Mn K-edge. Both C-CNT and N-CNT are highly conductive. The effect of the scan rate on the capacitance behavior was also examined, revealing that the pi* state of CNT and the size of the tunnels in pseudo-capacitor materials (which facilitate conduction and the transport of electrolyte ions) are critical for the capacitive performance, and their role depends on the scan rate. In the slow charge/discharge process, MnO2/N-CNT has a more symmetrical rectangular cyclic voltammetry (CV) curve. In the fast charge/discharge process, MnO2/C-CNT with a highly developed surface provides fast electronic and ionic channels that support a reversible faradaic redox reaction between MnO2 nanoflakes and the electrolyte, significantly enhancing its capacitive performance over that of MnO2/N-CNT. The MnO2/C-CNT architecture has great potential for supercapacitor applications. The information that was obtained herein helps to elucidate CNT surface modification and the design of the MnO2/functionalized CNT interface with a view for the further development of supercapacitors. This work, and especially the combination of CV with in situ XAS measurements, will be of value to readers with an interest in nanomaterial, nanotechnology and their applications in energy storage. PMID- 25511128 TI - Reversible cerebral vasoconstriction syndrome. AB - Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical-radiological syndrome characterised by severe thunderclap headaches with or without other neurological symptoms and multifocal constriction of cerebral arteries that usually resolves spontaneously within 3 months. Most patients recover completely, but up to 10% have a permanent neurological disability and some even die. Previously RCVS has been described in many clinical contexts and under different names with the term RCVS first being suggested in 2007 to unify the group. The condition may be spontaneous, but in up to 60% of cases it is secondary to another cause, including vasoactive substances (medications and illicit drugs), blood products and the post-partum state. It is believed to have a similar pathophysiological mechanism to the posterior reversible encephalopathy syndrome (PRES), and both can occur in similar clinical contexts and are frequently associated. Treatment options include calcium channel antagonists. RCVS occurs in a broad range of clinical situations making it an increasingly recognised condition about which doctors in various specialties need to be aware. PMID- 25511127 TI - Differential calcium handling by the cis and trans regions of the Golgi apparatus. AB - High Ca2+ content in the Golgi apparatus (Go) is essential for protein processing and sorting. In addition, the Go can shape the cytosolic Ca2+ signals by releasing or sequestering Ca2+. We generated two new aequorin-based Ca2+ probes to specifically measure Ca2+ in the cis/cis-to-medial-Go (cGo) or the trans-Go (tGo). Ca2+ homoeostasis in these compartments and in the endoplasmic reticulum (ER) has been studied and compared. Moreover, the relative size of each subcompartment was estimated from aequorin consumption. We found that the cGo accumulates Ca2+ to high concentrations (150-300 MUM) through the sarco plasmic/endoplasmic reticulum Ca2+-ATPase (SERCA). The tGo, in turn, is divided into two subcompartments: tGo1 and tGo2. The subcompartment tGo1 contains 20% of the aequorin and has a high internal [Ca2+]; Ca2+ is accumulated in this subcompartment via the secretory pathway Ca2+-ATPase 1 (SPCA-1) at a very high affinity (K50=30 nM). The subcompartment tGo2 contains 80% of aequorin, has a lower [Ca2+] and no SPCA-1 activity; Ca2+ uptake happens through SERCA and is slower than in tGo1. The two tGo subcompartments, tGo1 and tGo2, are diffusionally isolated. Inositol trisphosphate mobilizes Ca2+ from the cGo and tGo2, but not from tGo1, whereas caffeine releases Ca2+ from all the Golgi regions, and nicotinic acid dinucleotide phosphate and cADP ribose from none. PMID- 25511125 TI - Nanopore sensing of botulinum toxin type B by discriminating an enzymatically cleaved Peptide from a synaptic protein synaptobrevin 2 derivative. AB - Botulinum neurotoxins (BoNTs) are the most lethal toxin known to human. Biodefense requires early and rapid detection of BoNTs. Traditionally, BoNTs can be detected by looking for signs of botulism in mice that receive an injection of human material, serum or stool. While the living animal assay remains the most sensitive approach, it is costly, slow and associated with legal and ethical constrains. Various biochemical, optical and mechanical methods have been developed for BoNTs detection with improved speed, but with lesser sensitivity. Here, we report a novel nanopore-based BoNT type B (BoNT-B) sensor that monitors the toxin's enzymatic activity on its substrate, a recombinant synaptic protein synaptobrevin 2 derivative. By analyzing the modulation of the pore current caused by the specific BoNT-B-digested peptide as a marker, the presence of BoNT B at a subnanomolar concentration was identified within minutes. The nanopore detector would fill the niche for a much needed rapid and highly sensitive detection of neurotoxins, and provide an excellent system to explore biophysical mechanisms for biopolymer transportation. PMID- 25511129 TI - Hypnotic relaxation results in elevated thresholds of sensory detection but not of pain detection. AB - BACKGROUND: Many studies show an effectiveness of hypnotic analgesia. It has been discussed whether the analgesic effect is mainly caused by the relaxation that is concomitant to hypnosis. This study was designed to evaluate the effects of hypnotic relaxation suggestion on different somatosensory detection and pain thresholds. METHODS: Quantitative sensory testing (QST) measurements were performed before and during hypnosis in twenty-three healthy subjects on the dorsum of the right hand. Paired t-test was used to compare threshold changes. The influence of hypnotic susceptibility was evaluated by calculating correlation coefficients for threshold changes and hypnotic susceptibility (Harvard group scale). RESULTS: During hypnosis significantly changed somatosensory thresholds (reduced function) were observed for the following sensory detection thresholds: Cold Detection Threshold (CDT), Warm Detection Threshold (WDT), Thermal Sensory Limen (TSL) and Mechanical Detection Threshold (MDT). The only unchanged sensory detection threshold was Vibration Detection Threshold (VDT). No significant changes were observed for the determined pain detection thresholds (Cold Pain Thresholds, Heat Pain Thresholds, Mechanical Pain Sensitivity, Dynamic Mechanical Allodynia, Wind-up Ratio and Pressure Pain Threshold). No correlation of hypnotic susceptibility and threshold changes were detected. CONCLUSION: Hypnotic relaxation without a specific analgesic suggestion results in thermal and mechanical detection, but not pain threshold changes. We thus conclude that a relaxation suggestion has no genuine effect on sensory pain thresholds. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT02261155 (9th October 2014). PMID- 25511130 TI - Highly regio- and enantioselective synthesis of gamma,delta-unsaturated amido esters by catalytic hydrogenation of conjugated enamides. AB - An efficient and highly regio- and enantioselective catalytic asymmetric hydrogenation of alpha,gamma-dienamido esters to gamma,delta-unsaturated amido esters has been achieved using Rh/TangPhos as the catalyst. A series of gamma,delta-unsaturated amido acids were furnished in excellent yields with up to 99% ee. This effective methodology was applied in the asymmetric synthesis of key intermediate of Ramipril, an ACE inhibitor. PMID- 25511133 TI - Activation of Endogenous Phytase and Degradation of Phytate in Wheat Bran. AB - Wheat bran contains a significant amount of the anti-nutritional factor phytate. This study is the first to explore the effectiveness of activating endogenous phytase and further reducing phytate content through resulting programmed cell death (PCD). Effects of solid-liquid ratio (1:1, 1:2, 1:3, and 1:6), incubation temperature (4, 20, 38, 55, and 70 degrees C), metal ions (Na+, K+, Ca2+, and Mg2+), gibberellin concentration (0, 5, 50, 500, 2000, and 5000 mg/L), hydrogen peroxide concentration (0, 0.2, 0.4, 0.6, 0.8, and 1.0%), and incubation time (30, 80, 180, and 360 min) on activation of endogenous phytase activity and phytate degradation in wheat bran samples are discussed in this study. It was found that when the wheat bran was incubated with distilled water at 55 degrees C for 80 min, its endogenous phytase activity was dramatically increased 4-fold from 12.96 to 53.54 FTU/g, whereas the phytate content was reduced by about 70% from 45.20 to 13.52 mg/g. By comparison of photomicrographs of raw wheat bran sample and sample incubated with distilled water for 360 min at 55 degrees C, a conclusion could be drawn that PCD in aleurone cells had occurred. PMID- 25511132 TI - Minor injuries in older adults have different characteristics, injury patterns, and outcomes when compared with younger adults: an emergency department correlation study. AB - AIM: To examine the injury patterns, characteristics, and outcomes of older adults presenting with minor injuries compared with younger adults. BACKGROUND: Sustaining a minor injury is one of the most common reasons people present to an Emergency Department. Many presentations involve older Australians and greater than 50% of older adults are discharged from the Emergency Department. However, little is known about the characteristics, injury patterns, and outcomes of minor injuries in older adults compared to younger adults. METHODS: A 12-month exploratory correlational study was conducted using Emergency Department electronic medical record data from a single metropolitan hospital located in Sydney, Australia. Older adults were defined as >=65 years with younger adults defined as 18-64 years. Minor injuries were classified by diagnoses as fractures/dislocations, sprains/strains, wounds/burns/infections, minor head injuries, eye/ear/nose/oral injuries. Exclusion criteria included: triage category 1 or 2, major trauma, critical care admission, or injuries and fractures to the hip or neck of femur. RESULTS: There were 36,671 Emergency Department presentations of which 7582 (21%) were for older adults and 19,234 (52%) were younger adults (aged 18-64). Injuries represented 21% (n = 7754) of all Emergency Department presentations with 1294 (17%) occurring in those aged 65 years and older and 3937 (20%) in younger adults. Of the minor injuries (n = 3594; 10%), the most common presentation in younger adults was sprains/strains (n = 1045; 36%) but in older adults it was fractures (n = 229; 32%). There was a statistical (Pearson's chi(2) test 63.4, df = 4, P < 0.001) difference with injury pattern when comparing age groups. Older adults were allocated proportionately higher triage categories when compared with younger adults (Pearson's chi(2) test 26.3, df = 2, P < 0.001). Older adults with minor injuries had a longer mean stay (315 min; SD 238.9 min; younger adults 198 min, SD 132.3 min) and this difference was statistically (P <= 0.001) and clinically significant. Fewer older adults were discharged home (n = 531, 73%; n = 2648, 92%; P < 0.001) and more were admitted for minor injuries (n = 179, 25%; n = 156, 5%; P < 0.001) when compared with younger adults. CONCLUSION: Older adults with minor injuries have different injury patterns, higher acuity, longer length of stay, and lower discharge rates compared with younger adults. Clinicians may need to modify their approach and differential diagnoses when treating older adults with minor injuries. Further research is needed to explore the reasons for these differences and whether older adults have different service needs compared with younger adults with minor injuries. PMID- 25511131 TI - An integrated microfluidic chip system for single-cell secretion profiling of rare circulating tumor cells. AB - Genetic and transcriptional profiling, as well as surface marker identification of single circulating tumor cells (CTCs) have been demonstrated. However, quantitatively profiling of functional proteins at single CTC resolution has not yet been achieved, owing to the limited purity of the isolated CTC populations and a lack of single-cell proteomic approaches to handle and analyze rare CTCs. Here, we develop an integrated microfluidic system specifically designed for streamlining isolation, purification and single-cell secretomic profiling of CTCs from whole blood. Key to this platform is the use of photocleavable ssDNA-encoded antibody conjugates to enable a highly purified CTC population with <75 'contaminated' blood cells. An enhanced poly-L-lysine barcode pattern is created on the single-cell barcode chip for efficient capture rare CTC cells in microchambers for subsequent secreted protein profiling. This system was extensively evaluated and optimized with EpCAM-positive HCT116 cells seeded into whole blood. Patient blood samples were employed to assess the utility of the system for isolation, purification and single-cell secretion profiling of CTCs. The CTCs present in patient blood samples exhibit highly heterogeneous secretion profile of IL-8 and VEGF. The numbers of secreting CTCs are found not in accordance with CTC enumeration based on immunostaining in the parallel experiments. PMID- 25511134 TI - Safety considerations in the laboratory testing of specimens suspected or known to contain Ebola virus. PMID- 25511135 TI - Physician productivity: issues and controversies. PMID- 25511136 TI - Starting at the beginning, ending at the end. PMID- 25511137 TI - Confidence, knowledge, and skills at the beginning of residency. A survey of pathology residents. AB - OBJECTIVES: To document the pathology learning experiences of pathology residents prior to residency and to determine how confident they were in their knowledge and technical skills. METHODS: An online survey was distributed to all pathology residency program directors in the United States, who were requested to forward the survey link to their residents. Data were obtained on pathology electives, grossing experience, and frozen section experience. Likert scale questions assessed confidence level in knowledge and skills. RESULTS: In total, 201 pathology residents responded (8% of residents in the United States). Prior to starting residency, most respondents had exposure to anatomic pathology through elective rotations. Few respondents had work-related experience. Most did not feel confident in their pathology-related knowledge or skills, and many did not understand what pathology resident duties entail. CONCLUSIONS: Respondents gained exposure to pathology primarily through elective rotations, and most felt the elective experience prepared them for pathology residency. However, elective time may be enhanced by providing opportunities for students to increase hands-on experience and understanding of resident duties. PMID- 25511138 TI - Measurement of circulating cell-free DNA levels by a simple fluorescent test in patients with breast cancer. AB - OBJECTIVES: To evaluate circulating cell-free DNA (CFD) measured by a simple fluorescent assay as a biomarker of breast cancer. METHODS: We enrolled 38 patients with breast cancer before surgery, two patients with noncancerous breast lesions, nine patients after surgery, 16 healthy participants, and 29 control women admitted to the hospital emergency ward and released without hospitalization. CFD levels were measured by a direct fluorescence assay. RESULTS: Presurgery patients with cancer had elevated CFD levels (1,010 +/- 642 ng/mL), which were higher than those measured in the healthy control group (395 +/- 248 ng/mL, P < .001), the noncancer breast lesion group (386 +/- 40 ng/mL), the nonhospitalized control group (492 +/- 193 ng/mL, P < .001), and the postsurgery cancer group (398 +/- 162 ng/mL, P < .01). The area under the receiver operating characteristic curve of the presurgery vs healthy patient group was 0.83. CFD levels correlated with tumor size (P = .03, rho = 0.36), nodal involvement (P = .0003, rho = 0.56), and TNM stage (P = .0002, rho = 0.56). All patients with axillary node involvement had a CFD value greater than 600 ng/mL. CONCLUSIONS: CFD measured using a simple fluorometric assay has shown good correlation to stage and enhanced sensitivity to locally advanced disease. A large prospective study is warranted to evaluate if inclusion of this method as a decisive marker before mammography is advantageous. PMID- 25511139 TI - Cytogenetic and flow cytometry evaluation of Richter syndrome reveals MYC, CDKN2A, IGH alterations with loss of CD52, CD62L and increase of CD71 antigen expression as the most frequent recurrent abnormalities. AB - OBJECTIVES: Richter syndrome (RS) is a transformation of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) into high-grade lymphoma. There are only limited data on flow cytometry (FCM) and cytogenetics in RS. METHODS: In this study, FCM, classic cytogenetics (CC), and fluorescence in situ hybridization (FISH) were performed in eight RS cases. RESULTS: Most cases of RS were characterized by a loss/decrease of CD52 and CD62L and increased CD71 expression. CC identified complex karyotypes, with losses of 9/9p and 17/17p as the most frequent in four of seven cases. Seven RS cases demonstrated MYC abnormalities. Disruptions of CDKN2A and IGH were identified in five of seven and four of seven RS cases, respectively. CONCLUSIONS: Newly diagnosed RS is an oncologic emergency, and a quick diagnostic decision is crucial in clinical practice. Therefore, in patients with CLL/SLL and rapidly enlarging asymmetric lymphadenopathy and/or extranodal tumors, we strongly advise FCM of fine-needle aspiration biopsy (FNAB) material, including CD62L, CD52, and CD71 analysis as well as assessment of karyotype and at least MYC abnormalities by FISH of the same FNAB material. Loss of CD52 expression in RS most likely predicts resistance to alemtuzumab therapy, which is frequently used in CLL. PMID- 25511140 TI - Lymphocytic cholecystitis/cholangitis. AB - OBJECTIVES: To describe four cases of an uncommon type of acalculous cholecystitis/cholangitis characterized by increased intraepithelial lymphocytes within the biliary epithelium. METHODS: Cases were prospectively compiled during regular surgical pathology sign-out. Clinical information was obtained from the electronic medical record and the gross appearance from the surgical pathology reports. Microscopic examination was performed with emphasis on the type, location, and distribution of the inflammatory pattern; presence of intraepithelial lymphocytes (>30 per 100 biliary cells); and presence of metaplasia and epithelial hyperplasia. Immunohistochemical stains for CD3, CD8, and IgG4 were performed in some cases. RESULTS: All patients were adults who had either biliary pain or obstructive symptoms. All gallbladders had a relatively normal gross appearance and did not contain gallstones or biliary sludge. Microscopic examination showed numerous intraepithelial lymphocytes in the biliary epithelium. The mucosa was frequently expanded by dense inflammatory cell infiltrates. The inflammatory process was more severe in the infundibulum and bile ducts than in the body of the gallbladder. The intraepithelial lymphocytes were CD3+, CD8+. IgG4+ plasma cells were absent. CONCLUSIONS: The term lymphocytic cholecystitis/cholangitis is proposed. The potential clinical implications and pathogenesis of this inflammatory pattern and the differential diagnosis with other forms of acalculous cholecystitis are discussed. PMID- 25511141 TI - Enhanced creatinine and estimated glomerular filtration rate reporting to facilitate detection of acute kidney injury. AB - OBJECTIVES: While acute kidney injury (AKI) can be diagnosed based on specified increases in a patient's plasma creatinine level, standard creatinine reporting methods typically only flag creatinine results as abnormal when outside the reference range and often fail to identify rising creatinine values indicative of AKI. Here, we evaluate the impact of this limitation in standard creatinine reporting and develop and implement an enhanced creatinine reporting algorithm. METHODS: We evaluated 59,712 plasma creatinine results collected over approximately 3 months, using computational simulations and statistical analyses. RESULTS: Our analyses demonstrated that 29% of creatinine results substantially increased over the patient's baseline and concerning for AKI remained within the normal reference range. These concerning results would not be flagged as abnormal using standard reporting. Likewise, we found that simple delta checks are also insensitive at AKI detection. To improve creatinine reporting, we developed and implemented an algorithm within our laboratory information system to alert clinicians to rising creatinine results, which we describe in this report. CONCLUSION: While both creatinine reference limits and simple delta checks are insensitive for AKI identification, a simple algorithm can be implemented within a common laboratory information system to enhance AKI identification. PMID- 25511142 TI - Most clinical laboratory testing in Kampala occurs in high-volume, high-quality laboratories or low-volume, low-quality laboratories. A tale of two cities. AB - OBJECTIVES: To describe key characteristics (laboratory quality, test volumes, and complexity) of clinical laboratories in Kampala, Uganda (population ~1.7 million). METHODS: Cross-sectional survey using a standard questionnaire to document laboratory type and quality, as well as test menus and volumes. Quality was based on the World Health Organization-Africa Region checklist. RESULTS: Of the 954 laboratories identified (a density of one laboratory per 1,781 persons), 779 (82%) performed only simple kit tests or light microscope examinations. The 95% (907/954) of laboratories for whom volumes were obtained performed an average aggregate of 13,189 tests daily, for a test utilization rate of around 2 tests per individual per year. Laboratories could be segregated into eight groups based on quality, test volume, and complexity. However, 90% of the testing was performed by just two groups: (1) low-volume (<=100 tests daily), low-quality laboratories performing simple tests or (2) high-volume (>100 tests daily), high quality laboratories. Each of these two groups did 45% of the daily testing volume (90% combined). CONCLUSIONS: Clinical laboratory density in Kampala (1/1,781 persons) is high, approaching that in the United States (1/1,347 persons). Low-volume/low-quality and high-volume/high-quality laboratories do 90% of the daily aggregate testing. Quality improvement (QI) schemes for Africa must be appropriate to low-volume laboratories as well as to the large laboratories that have been the focus of previous QI efforts. PMID- 25511143 TI - Blood flow cytometry in Sezary syndrome: new insights on prognostic relevance and immunophenotypic changes during follow-up. AB - OBJECTIVES: Sezary syndrome (SS) is characterized by erythroderma, generalized lymphadenopathy, and the presence of circulating atypical lymphocytes, which are difficult to identify by morphologic data. METHODS: We revised our series of 107 patients in an attempt to better define the phenotypic aberrancies in blood at diagnosis and the immunophenotypic stability over time detected by flow cytometry. Polymerase chain reaction assay was also used to study CD26/dipeptidyl peptidase IV (DPPIV) gene methylation. RESULTS: The most common aberrancies were represented by the lack of CD26 (96/107) or CD38 (101/107) expression and the presence of a "dim" CD3, CD4, or CD2 population. There was a high variability in CD7 expression. In total, 31% of the patients had phenotypical heterogeneity in CD26 and CD7 expression at diagnosis. The phenotype was stable over time in 73 of 95 patients with available follow-up data, while 22 of 95 patients developed changes in CD26, CD7, or CD2 expression. CD4+CD26- SS showed hypermethylation of the CpG islands for the promoter region of CD26/DPPIV. Multivariate analysis showed that CD26 expression is a favorable prognostic factor (hazard ratio, 2.94; P = .045). CONCLUSIONS: We confirm the relevance of CD26 negativity in SS diagnosis and monitoring. Nevertheless, the presence of rare CD26+ cases suggests that a multiparameter flow cytometry approach should be used. Changes in methylation profile could account for phenotypical heterogeneity. PMID- 25511145 TI - A limited plasma cell flow cytometry panel with reflex CD138 immunohistochemistry is an optimal workflow process for evaluating plasma cell neoplasms in bone marrow specimens. AB - OBJECTIVES: To determine the optimal workflow combination of flow cytometry (FC) and immunohistochemistry tests for efficient and cost-effective evaluation of plasma cell (PC) neoplasms (PCNs) in bone marrow (BM) specimens. METHODS: Various workflow combinations of immunohistochemistry and FC for 4,031 BM specimens worked up for PCNs were compared. Turnaround time (TAT), immunohistochemistry usage, technical charges, and addendum/amendment rates were compared between periods to determine the optimal workflow combination. RESULTS: Five distinct workflow periods were identified, with varying combinations of full or limited FC panels for assessing PC clonality and CD138/kappa/lambda immunohistochemistry for PC quantification. Replacement of full FC with limited FC was associated with significant reductions in TAT and number of immunostains performed per case. Elimination of immunohistochemistry on cases determined to be polyclonal by FC also resulted in significant reductions in immunohistochemistry usage and significant cost savings. CONCLUSIONS: Assessment of PC clonality using a limited FC panel followed by reflex CD138 immunohistochemistry on cases that are monoclonal by FC provides an optimal and cost-effective workflow for evaluating PCNs in BM samples. PMID- 25511144 TI - Clinical presentation, progression, and outcome of patients with clonal B-cell counts of less than 5 * 10(9)/l, 5 to 10 * 10(9)/l, and more than 10 * 10(9)/l and chronic lymphocytic leukemia immunophenotype. AB - OBJECTIVES: The flow cytometric evaluation of peripheral lymphocytosis has led to a dramatic increase in the diagnosis of early stage chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL). Few studies exist to better delineate the natural history and differences between MBL and CLL. METHODS: Applying the recently updated B-lymphocyte threshold of 5 * 10(9) B lymphocytes/L for the diagnosis of CLL, we evaluated the differences in initial presentation, disease progression, time to treatment (TTT), and 10-year overall survival rates between patients with less than 5 * 10 * 10(9)/L, 5 to 10 * 10(9)/L, and more than 10 * 10(9)/L B cells. These clinical/treatment parameters were also compared among the MBL, 5 to 10 CLL Rai stage 0, and more than 10 CLL Rai stage 0 groups. RESULTS: In total, 310 patients were included, with 67 in the less than 5, 75 in the 5 to 10, and 168 in the more than 10 B-cell groups. Statistically significant differences were seen when comparing the 5 to 10 and more than 10 B-cell groups regarding anemia (P = .021 for median hemoglobin; P = .028 for anemia <11 g/dL), platelet count (P = .041 for median platelet count), splenomegaly (P = .013), initial management plan (P = .012 for observation; P = .0021 for treatment with chemotherapy), and TTT (P = .0033). No statistically significant difference was seen among the MBL, 5 to 10, and more than 10 CLL Rai stage 0 groups regarding TTT and 10-year overall survival. CONCLUSIONS: Findings suggest that patients with B-cell counts of 5 to 10 * 10(9)/L behave clinically more similar to patients with B-cell counts of less than 5 * 10(9)/L. PMID- 25511146 TI - Upfront special staining for Helicobacter pylori in gastric biopsy specimens is not indicated. AB - OBJECTIVES: The practice of routine upfront use of special stains in biopsy specimens with minimal or no inflammation has not been evaluated. This study was conducted to determine the value of special stains for Helicobacter pylori in gastric biopsy specimens showing variable degrees of inflammation and to evaluate the practice of upfront ancillary staining of all mucosal biopsy specimens. METHODS: Immunohistochemical or Diff-Quik stains were done on sections of 570 gastric biopsy specimens. The rates of positivity for H pylori were calculated in each category based on the degree of inflammation and classified as normal, minimal, mild, moderate, or severe. RESULTS: H pylori was not detected in 386 (67.7%) biopsy specimens that were classified as normal (6.0%) or with minimal inflammation (28.2%) or mild inactive gastritis (33.5%). The organism was identified by Diff-Quik or immunohistochemical stain in 76 (89.4%) of 85 with moderate active gastritis and 30 (93.8%) of 32 biopsy specimens showing severe active gastritis. CONCLUSIONS: Upfront staining of gastric biopsy specimens is not cost-effective since a significant proportion of the gastric biopsy specimens were normal or showed minimal inflammation; in none of these biopsy specimens was the organism found. Special stains should be performed only in selected biopsy specimens that reveal any degree of chronic active gastritis or moderate inactive gastritis. PMID- 25511147 TI - Evaluation of allele-specific PCR and immunohistochemistry for the detection of BRAF V600E mutations in hairy cell leukemia. AB - OBJECTIVES: Detection of BRAF V600E mutations in hairy cell leukemia (HCL) has important diagnostic utility. In this study, we sought to compare immunohistochemistry with an antibody specific for this mutation to a sensitive molecular assay. METHODS: The performance of the BRAF V600E-specific VE1 antibody was compared with that of allele-specific polymerase chain reaction (PCR) in 22 formalin-fixed, paraffin-embedded (FFPE) specimens with HCL involvement, along with nine splenic marginal zone lymphomas (SMZLs), 10 follicular lymphomas (FLs), 10 mantle cell lymphomas (MCLs), and 10 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLLs). An additional 11 SMZLs, 100 FLs, 20 MCLs, 83 CLL/SLL specimens, and 49 reactive tonsils within tissue microarrays were stained with VE1. RESULTS: A BRAF V600E mutation was detected in 17 (77.3%) of 22 HCL cases by PCR. Immunohistochemistry demonstrated VE1 staining in 20 (90.9%) cases, identifying low-level (~1%) involvement in three HCL cases that were mutation negative by PCR. Evaluation of additional material from these patients confirmed the presence of BRAF V600E. Thirty-nine non-HCL cases were negative by both methods. Within tissue microarrays, weak false-positive staining was observed in two (0.8%) of 263 non-HCL cases. CONCLUSIONS: VE1 immunohistochemistry is more sensitive than allele-specific PCR in FFPE bone marrow specimens and can be applied to decalcified core biopsy specimens that are not appropriate for molecular techniques. PMID- 25511148 TI - Downtime procedures for the 21st century: using a fully integrated health record for uninterrupted electronic reporting of laboratory results during laboratory information system downtimes. AB - OBJECTIVES: Downtimes of the laboratory information system (LIS) or its interface to the electronic medical record (EMR) disrupt the reporting of laboratory results. Traditionally, laboratories have relied on paper-based or phone-based reporting methods during these events. METHODS: We developed a novel downtime procedure that combines advance placement of orders by clinicians for planned downtimes, the printing of laboratory results from instruments, and scanning of the instrument printouts into our EMR. RESULTS: The new procedure allows the analysis of samples from planned phlebotomies with no delays, even during LIS downtimes. It also enables the electronic reporting of all clinically urgent results during downtimes, including intensive care and emergency department samples, thereby largely avoiding paper- and phone-based communication of laboratory results. CONCLUSIONS: With the capabilities of EMRs and LISs rapidly evolving, information technology (IT) teams, laboratories, and clinicians need to collaborate closely, review their systems' capabilities, and design innovative ways to apply all available IT functions to optimize patient care during downtimes. PMID- 25511149 TI - Blast phase in chronic myelogenous leukemia is skewed toward unusual blast types in patients treated with tyrosine kinase inhibitors: a comparative study of 67 cases. AB - OBJECTIVES: To compare the features of the blast phase of chronic myelogenous leukemia (CML) in patients treated with tyrosine kinase inhibitors (TKIs) with those in the pre-TKI era. METHODS: Sixty-seven patients with blast phase CML were identified in the Duke Pathology database from 1991 to 2011. The morphology and immunophenotype of blasts were evaluated, along with cytogenetic studies and associated findings in the peripheral blood and bone marrow. RESULTS: In the TKI era, the blasts were more frequently of a type other than the usual myeloid or lymphoid types when compared with the pre-TKI era. Blast phase in TKI-treated patients was associated with a higher peripheral WBC count and a lower blast percentage in the bone marrow. Of the 23 patients with cytogenetic studies during blast phase, additional cytogenetic changes more frequently occurred in patients with an unusual blast type, and some patients showed these changes months before the onset of blast phase. CONCLUSIONS: Blast phase CML in TKI- and non-TKI treated patients differs in the morphology and immunophenotype of blasts, cytogenetic findings, and associated findings in the peripheral blood and bone marrow. PMID- 25511150 TI - The utility of BRAF V600E mutation-specific antibody VE1 for the diagnosis of hairy cell leukemia. AB - OBJECTIVES: BRAF V600E mutation is characteristic of hairy cell leukemia (HCL). A V600E mutation-specific antibody, VE1, has been recently developed. We studied the diagnostic utility of this antibody in HCL and compared it with other B-cell neoplasms. METHODS: VE1 activity was assessed using immunohistochemistry in 90 mature B-cell neoplasms, including HCL (n = 17), HCL variant (n = 6), chronic lymphocytic leukemia (CLL) (n = 20), and 47 other B-cell lymphomas. Most (87/90) specimens were formalin-fixed, paraffin-embedded bone marrow (BM) biopsy specimens decalcified in either hydrochloric acid or formic acid. RESULTS: VE1 was positive in 15 (88%) cases of HCL and two (10%) cases of CLL and was negative in all other tumors assessed. The VE1-positive HCL cases showed uniform staining in all tumor cells, but intensity was variable. The two VE1-negative HCL cases had BRAF V600 mutations proven by molecular analysis. The two CLL cases positive with VE1 showed an atypical staining pattern with expression in a minority of lymphoma cells. Immunohistochemistry using the VE1 antibody had a sensitivity of 88% and a specificity of 97% for HCL. CONCLUSIONS: VE1 immunohistochemistry is a useful and convenient surrogate for detecting BRAF V600E mutation in BM biopsy specimens decalcified with hydrochloric or formic acid-based solutions. PMID- 25511152 TI - Reference intervals data mining: no longer a probability paper method. AB - OBJECTIVES: To describe the application of a data-mining statistical algorithm for calculation of clinical laboratory tests reference intervals. METHODS: Reference intervals for eight different analytes and different age and sex groups (a total of 11 separate reference intervals) for tests that are unlikely to be ordered during routine screening of disease-free populations were calculated using the modified algorithm for data mining of test results stored in the laboratory database and compared with published peer-reviewed studies that used direct sampling. The selection of analytes was based on the predefined criteria that include comparability of analytical methods with a statistically significant number of observations. RESULTS: Of the 11 calculated reference intervals, having upper and lower limits for each, 21 of 22 reference interval limits were not statistically different from the reference studies. CONCLUSIONS: The presented statistical algorithm is shown to be an accurate and practical tool for reference interval calculations. PMID- 25511151 TI - Reliability of the Xpert HPV assay to detect high-risk human papillomavirus DNA in a colposcopy referral population. AB - OBJECTIVES: The Xpert HPV Assay (Xpert; Cepheid, Sunnyvale, CA) was developed for the multianalytic GeneXpert platform. METHODS: In a colposcopy referral population of 708 women living in the United States, two cervical specimens, A and B, were collected, and both were tested by the Xpert assay for high-risk human papillomavirus (hrHPV) DNA, permitting an evaluation of its test reliability. Specimen B was also tested by Hybrid Capture 2 (hc2; Qiagen, Germantown, MD) and the cobas HPV Test (cobas; Roche Molecular Systems, Pleasanton, CA). RESULTS: The kappa and percent agreement for any hrHPV for the two Xpert results were 0.88 and 94.5%, respectively. There was no statistical difference in testing positive on both specimens by Xpert (P = .62). The sensitivity for detection of cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) was 89.0% using specimen A and 90.4% using specimen B for Xpert, 90.4% for cobas, and 81.6% for hc2. CONCLUSIONS: The Xpert assay was sensitive and reliable for the detection of hrHPV and the identification of women with CIN2+. PMID- 25511153 TI - Uncovering bias in the cytologic evaluation of cervical squamous lesions. AB - OBJECTIVES: It is well recognized that biases exist in medical decision making. We sought evidence for such bias in diagnostic testing. METHODS: We investigated whether a cytotechnologist's Papanicolaou (Pap) test interpretation of a squamous cell abnormality influenced the likelihood of making the same interpretation again that day using analysis based on the beta distribution. RESULTS: For squamous intraepithelial lesion (SIL) interpretations, significant deviation away from the mean daily diagnostic rate was seen within all three cytotechnologists and, for atypical squamous cells of undetermined significance interpretations, within two of three. CONCLUSIONS: Cytotechnologists are not influenced by an expected number of abnormal Pap cases per day since this would result in deviation toward the mean daily rate of diagnosis. Possible explanations for the unanticipated clustering of SIL interpretations include clinical clustering effects or, alternatively, the influence a SIL interpretation might have on lowering the threshold for this interpretation again in subsequent specimens on the same day. The analysis presented here could serve as a model to detect bias in other aspects of medical decision making. PMID- 25511155 TI - Silvano Arieti's novel The Parnas: a scene from the Holocaust. AB - Silvano Arieti was an Italian psychoanalyst who undertook psychoanalysis of schizophrenic patients in the 1960s and 1970s. He left Italy in 1939 at the age of twenty-four following the Race Laws of 1938, and moved to New York until his death in 1981. A training analyst and author of several psychoanalytic and academic books, Arieti kept his research open in a wide variety of directions, giving equal weight to the internal world--as it seen from the psychoanalytic viewpoint--and to the organic functioning of the brain, as viewed from the perspective of the neurosciences. Arieti's interpretation of schizophrenia helped to overcome the dichotomies between the classical psychoanalytic approach, neurobiological research, and research into cognition, and opened up new paths for an interdisciplinary understanding of mental functioning and creative processes. This paper examines Arieti's book The Parnas (1979); this is a partly fictionalised account of a pre-eminent figure (Parnas in Hebrew means "head") in the Jewish community in Pisa, Giuseppe Pardo Roques, in the 1930s and early 1940s, who experienced mental illness and was killed in the Nazi extermination of Jews. The paper examines Arieti?s reflections on what he sees as the 'insights' provided by mental illness, which are considered through the figure of Giuseppe Pardo Roques, and in the context of the trauma of the Shoah in Italy. PMID- 25511157 TI - Should ovaries be removed or not in (early-stage) adenocarcinoma of the uterine cervix: a review. AB - OBJECTIVES: There is considerable controversy regarding the safety of ovarian preservation in adenocarcinoma of the cervix. The aim of this review is to determine the incidence of ovarian metastasis in patients with adenocarcinoma of the cervix (particularly in early-stage disease), identify risk factors for ovarian metastasis and evaluate the outcome of patients with ovarian preservation. METHODS: Relevant articles were identified from MEDLINE and EMBASE. Included studies were prospective or retrospective cohort and cross-sectional studies analyzing the incidence of ovarian metastasis in adenocarcinoma of the cervix and studies evaluating the outcome of patients with ovarian preservation. RESULTS: Ten articles including 1204 patients evaluated the frequency of ovarian metastasis. The incidence considering all FIGO stages was 3.7% (range: 0%-12.9%) and the incidence in FIGO stage IB was 2% (range: 0.8%-3.2%). Six articles evaluated the outcome of patients with ovarian preservation. With more than 100 patients with adenocarcinoma of the cervix FIGO stage (CIS-IIA), none developed an ovarian relapse with a mean follow-up time of 56months. Six articles including 31 patients with ovarian spread were analyzed. At least one of the following risk factor was present in 30/31 (96.7%) of the patients: age >45, FIGO stage >IB, positive lymph nodes, deep stromal invasion, lympho-vascular space invasion, corpus invasion, parametrial invasion or tumor size >4cm. CONCLUSION: Ovarian preservation in young women with early-stage adenocarcinoma of the uterine cervix is safe. Herein, we propose a set of selection criteria to properly identify candidates for ovarian preservation. PMID- 25511156 TI - Transcriptomic signatures of peroxisome proliferator-activated receptor alpha (PPARalpha) in different mouse liver models identify novel aspects of its biology. AB - BACKGROUND: The peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-activated transcription factor that regulates lipid catabolism and inflammation and is hepatocarcinogenic in rodents. It is presumed that the functions of PPARalpha in liver depend on cross-talk between parenchymal (hepatocytes) and non-parenchymal (Kupffer and endothelial cells) fractions as well as inter-organ interactions. In order to determine how cellular composition and inter-organ interactions influence gene expression upon pharmacological activation of PPARalpha, we performed a meta-analysis of transcriptomics data obtained from mouse hepatocytes (containing only the parenchymal fraction), mouse liver slices (containing both fractions), and mouse livers exposed to a PPARalpha agonist. The aim was to obtain a comprehensive view of common and model-specific PPARalpha-dependent genes and biological processes to understand the impact of cross-talk between parenchymal and non-parenchymal fractions as well as the effect of inter-organ interactions on the hepatic PPARalpha transcriptome.To this end we analyzed microarray data of experiments performed in mouse primary hepatocytes treated with the PPARalpha agonist Wy14643 for 6 or 24 h (in vitro), mouse precision cut liver slices treated with Wy14643 for 24 h (ex vivo), and livers of wild type and Ppara knockout mice treated with Wy14643 for 6 h or 5 days (in vivo). RESULTS: In all models, activation of PPARalpha significantly altered processes related to various aspects of lipid metabolism. In ex vivo and in vivo models, PPARalpha activation significantly regulated processes involved in inflammation; these processes were unaffected in hepatocytes. Only in vivo models showed significant regulation of genes involved in coagulation, carcinogenesis, as well as vesicular trafficking and extracellular matrix. CONCLUSIONS: PPARalpha-dependent regulation of genes/processes involved in lipid metabolism is mostly independent of the presence of non-parenchymal cells or systemic factors, as it was observed in all liver models. PPARalpha-dependent regulation of inflammatory genes requires the presence of non-parenchymal cells, as it was observed only ex vivo and in vivo. However, the full spectrum of PPARalpha biology at the level of lipid metabolism, immunity, carcinogenesis, as well as novel aspects of PPARalpha signaling such as coagulation, vesicular trafficking and the extracellular matrix, seems to require systemic factors, as it was observed exclusively in vivo. PMID- 25511158 TI - Recurrence patterns and survival endpoints in women with stage II uterine endometrioid carcinoma: a multi-institution study. AB - OBJECTIVE: There is paucity of data in regard to prognostic factors and outcome of women with 2009 FIGO stage II disease. The objective of this study was to investigate prognostic factors, recurrence patterns and survival endpoints in this group of patients. METHODS: Data from four academic institutions were analyzed. 130 women were identified with 2009 FIGO stage II. All patients underwent hysterectomy, oophorectomy and lymph node evaluation with or without pelvic and paraaortic lymph node dissections and peritoneal cytology. The Kaplan Meier approach and Cox regression analysis were used to estimate recurrence-free (RFS), disease-specific (DSS) and overall survival (OS). RESULTS: Median follow up was 44months. 120 patients (92%) underwent simple hysterectomy, 78% had lymph node dissection and 95% had peritoneal cytology examination. 99 patients (76%) received adjuvant radiation treatment (RT). 5-year RFS, DSS and OS were 77%, 90%, and 72%, respectively. On multivariate analysis of RFS, adjuvant RT, the presence of lymphovascular space invasion (LVSI) and high tumor grades were significant predictors. For DSS, LVSI and high tumor grades were significant predictors while older age and high tumor grade were the only predictors of OS. CONCLUSIONS: In this multi-institutional study, disease-specific survival for women with FIGO stage II uterine endometrioid carcinoma is excellent. High tumor grade, lymphovascular space invasion, adjuvant radiation treatment and old age are important prognostic factors. There was no significant difference in the outcome between patients who received vaginal cuff brachytherapy compared to those who received pelvic external beam radiation treatment. PMID- 25511159 TI - Fertility and gonadal function after adjuvant therapy in women diagnosed with a malignant ovarian germ cell tumor (MOGCT) during the "cisplatin era". AB - PURPOSE: By self-report and serum levels of anti-Mullerian hormone (AMH) this study aims to assess post-treatment fertility after modern treatment of women with malignant ovarian germ cell tumors (MOGCT). PATIENTS AND METHODS: In 2013 a questionnaire-based survey was performed in 61 MOGCT patients diagnosed at age <40years from 1980-2009. Forty-nine of them also attended the out-patient clinic. The event of first post-treatment pregnancy ("fertility") was documented as cumulative estimates for all 61 patients and within each of 4 treatment groups: Group 1: Surgery only (n=10); Group 2: <=3cycles of cisplatin-based chemotherapy (CBCT) (n=20); Group 3: >3cycles of CBCT (n=15) and Group 4: other adjuvant treatment (n=16). AMH was determined in 22 women <40years at survey. Statistics were based on Kaplan Meier procedure, log-rank test and a significance level p<0.05. RESULTS: At least one post-treatment pregnancy was reported by 34 of 39 MOGCT survivors who attempted motherhood after treatment. The 15-year cumulative post-treatment fertility estimate was 28% (95% CI: 26-30) for all 61 survivors and was significantly higher in patients treated with 3 or fewer cycles of CBCT (53% [95% CI: 50-55]) than those treated with more than 3cycles (20% [95% CI: 17 22]) (P=0.03). Of 22 AMH levels, two were <3pmol/l, with one women being pregnant at survey. CONCLUSION: After fertility-sparing surgery and modern cisplatin-based chemotherapy, fertility is preserved in most MOGCT survivors though dependent on the number of cycles. AMH's role as a biomarker of gonadal function seems promising but requires further research. PMID- 25511162 TI - Using an auditory sensory substitution device to augment vision: evidence from eye movements. AB - Sensory substitution devices convert information normally associated with one sense into another sense (e.g. converting vision into sound). This is often done to compensate for an impaired sense. The present research uses a multimodal approach in which both natural vision and sound-from-vision ('soundscapes') are simultaneously presented. Although there is a systematic correspondence between what is seen and what is heard, we introduce a local discrepancy between the signals (the presence of a target object that is heard but not seen) that the participant is required to locate. In addition to behavioural responses, the participants' gaze is monitored with eye-tracking. Although the target object is only presented in the auditory channel, behavioural performance is enhanced when visual information relating to the non-target background is presented. In this instance, vision may be used to generate predictions about the soundscape that enhances the ability to detect the hidden auditory object. The eye-tracking data reveal that participants look for longer in the quadrant containing the auditory target even when they subsequently judge it to be located elsewhere. As such, eye movements generated by soundscapes reveal the knowledge of the target location that does not necessarily correspond to the actual judgment made. The results provide a proof of principle that multimodal sensory substitution may be of benefit to visually impaired people with some residual vision and, in normally sighted participants, for guiding search within complex scenes. PMID- 25511160 TI - Altitudinal population structure and microevolution of the malaria vector Anopheles cruzii (Diptera: Culicidae). AB - BACKGROUND: In Brazil, the autochthonous transmission of extra-Amazonian malaria occurs mainly in areas of the southeastern coastal Atlantic Forest, where Anopheles cruzii is the primary vector. In these locations, the population density of the mosquito varies with altitude (5-263 m above sea level), prompting us to hypothesise that gene flow is also unevenly distributed. Describing the micro-geographical and temporal biological variability of this species may be a key to understanding the dispersion of malaria in the region. We explored the homogeneity of the An. cruzii population across its altitudinal range of distribution using wing shape and mtDNA gene analysis. We also assessed the stability of wing geometry over time. METHODS: Larvae were sampled from lowland (5-20 m) and hilltop (81-263 m) areas in a primary Atlantic Forest region, in the municipality of Cananeia (State of Sao Paulo, Brazil). The right wings of males and females were analysed by standard geometric morphometrics. Eighteen landmarks were digitised for each individual and a discriminant analysis was used to compare samples from the hilltop and lowland. A 400-bp DNA fragment of the mitochondrial cytochrome oxidase gene subunit I (CO-I) was PCR-amplified and sequenced. RESULTS: Wing shapes were distinct between lowland and hilltop population samples. Results of cross-validated tests based on Mahalanobis distances showed that the individuals from both micro-environments were correctly reclassified in a range of 54-96%. The wings of hilltop individuals were larger. The CO-I gene was highly polymorphic (haplotypic diversity = 0.98) and altitudinally structured (Fst = 0.085 and Jaccard = 0.033). We found 60 different haplotypes but only two were shared by the lowland and hilltop populations. Wing shape changed over the brief study period (2009-2013). CONCLUSIONS: Wing geometry and CO-I gene analysis indicated that An. cruzii is vertically structured. Wing shape varied rapidly, but altitude structure was maintained. Future investigations should identify the biotic/abiotic causes of these patterns and their implications in the local epidemiology of malaria. PMID- 25511161 TI - Canadian Society of Nephrology commentary on the KDIGO clinical practice guideline for CKD evaluation and management. AB - We congratulate the KDIGO (Kidney Disease: Improving Global Outcomes) work group on their comprehensive work in a broad subject area and agreed with many of the recommendations in their clinical practice guideline on the evaluation and management of chronic kidney disease. We concur with the KDIGO definitions and classification of kidney disease and welcome the addition of albuminuria categories at all levels of glomerular filtration rate (GFR), the terminology of G categories rather than stages to describe level of GFR, the division of former stage 3 into new G categories 3a and 3b, and the addition of the underlying diagnosis. We agree with the use of the heat map to illustrate the relative contributions of low GFR and albuminuria to cardiovascular and renal risk, though we thought that the highest risk category was too broad, including as it does people at disparate levels of risk. We add an albuminuria category A4 for nephrotic-range proteinuria and D and T categories for patients on dialysis or with a functioning renal transplant. We recommend target blood pressure of 140/90mm Hg regardless of diabetes or proteinuria, and against the combination of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors. We recommend against routine protein restriction. We concur on individualization of hemoglobin A1c targets. We do not agree with routine restriction of sodium intake to <2g/d, instead suggesting reduction of sodium intake in those with high intake (>3.3g/d). We suggest screening for anemia only when GFR is <30mL/min/1.73m(2). We recognize the absence of evidence on appropriate phosphate targets and methods of achieving them and do not agree with suggestions in this area. In drug dosing, we agree with the recommendation of using absolute clearance (ie, milliliters per minute), calculated from the patient's estimated GFR (which is normalized to 1.73m(2)) and the patient's actual anthropomorphic body surface area. We agree with referral to a nephrologist when GFR is <30mL/min/1.73m(2) (and for many other scenarios), but suggest urine albumin-creatinine ratio > 60mg/mmol or proteinuria with protein excretion > 1g/d as the referral threshold for proteinuria. PMID- 25511163 TI - Self-motion sensitivity to visual yaw rotations in humans. AB - While moving through the environment, humans use vision to discriminate different self-motion intensities and to control their actions (e.g. maintaining balance or controlling a vehicle). How the intensity of visual stimuli affects self-motion perception is an open, yet important, question. In this study, we investigate the human ability to discriminate perceived velocities of visually induced illusory self-motion (vection) around the vertical (yaw) axis. Stimuli, generated using a projection screen (70 * 90 deg field of view), consist of a natural virtual environment (360 deg panoramic colour picture of a forest) rotating at constant velocity. Participants control stimulus duration to allow for a complete vection illusion to occur in every single trial. In a two-interval forced-choice task, participants discriminate a reference motion from a comparison motion, adjusted after every presentation, by indicating which rotation feels stronger. Motion sensitivity is measured as the smallest perceivable change in stimulus intensity (differential threshold) for eight participants at five rotation velocities (5, 15, 30, 45 and 60 deg/s). Differential thresholds for circular vection increase with stimulus velocity, following a trend well described by a power law with an exponent of 0.64. The time necessary for complete vection to arise is slightly but significantly longer for the first stimulus presentation (average 11.56 s) than for the second (9.13 s) and does not depend on stimulus velocity. Results suggest that lower differential thresholds (higher sensitivity) are associated with smaller rotations, because they occur more frequently during everyday experience. Moreover, results also suggest that vection is facilitated by a recent exposure, possibly related to visual motion after-effect. PMID- 25511164 TI - Modulation of hand aperture during reaching in persons with incomplete cervical spinal cord injury. AB - The intact neuromotor system prepares for object grasp by first opening the hand to an aperture that is scaled according to object size and then closing the hand around the object. After cervical spinal cord injury (SCI), hand function is significantly impaired, but the degree to which object-specific hand aperture scaling is affected remains unknown. Here, we hypothesized that persons with incomplete cervical SCI have a reduced maximum hand opening capacity but exhibit novel neuromuscular coordination strategies that permit object-specific hand aperture scaling during reaching. To test this hypothesis, we measured hand kinematics and surface electromyography from seven muscles of the hand and wrist during attempts at maximum hand opening as well as reaching for four balls of different diameters. Our results showed that persons with SCI exhibited significantly reduced maximum hand aperture compared to able-bodied (AB) controls. However, persons with SCI preserved the ability to scale peak hand aperture with ball size during reaching. Persons with SCI also used distinct muscle coordination patterns that included increased co-activity of flexors and extensors at the wrist and hand compared to AB controls. These results suggest that motor planning for aperture modulation is preserved even though execution is limited by constraints on hand opening capacity and altered muscle co-activity. Thus, persons with incomplete cervical SCI may benefit from rehabilitation aimed at increasing hand opening capacity and reducing flexor-extensor co-activity at the wrist and hand. PMID- 25511165 TI - Kinematic and kinetic evidence for functional lateralization in a symmetrical motor task: the water polo eggbeater kick. AB - Bilaterality and motor lateralization have been associated with neural lateralization, suggesting that the dominant and non-dominant systems might have different specializations. The study of symmetrical motor tasks can provide evidence relating to this hypothesis. The water polo eggbeater kick is a skill comprising anti-phase and directionally opposite rotations of the right and left lower limbs to provide upward thrust to elevate the body. Effectiveness of the skill depends on moving the feet in predominantly horizontal directions with an orientation that produces lift throughout as much of the cycle as possible. The purpose of this study was to investigate the motor lateralization of the dominant (D) and non-dominant (ND) lower limbs during the execution of the water polo eggbeater kick technique. Twelve right-handed and right-footed water polo players performed eggbeater kicks in the vertical position to maintain maximum height. Three-dimensional kinematics and the pattern of vertical forces were quantified for nine cycles for each player. The pattern of vertical force produced showed asymmetries between the equivalent phases of the cycles of the dominant and non dominant limbs (D, 222.8 N; ND, 201.0 N; p < 0.001). Based on the vertical force patterns, the non-dominant ankle had a less efficient motion during the phase of knee flexion (recovery phase). This was a consequence of larger negative pitch angles created by the non-dominant foot for the equivalent phase. Negative pitch angles counteract the lift forces responsible for the upward propulsion of the player. The effectiveness of the dominant side during the recovery phase was a consequence of bilateral differences in rotation and inversion motions by the ankle and hip. Differences in the technique of the dominant and non-dominant side, particularly during the phase of knee flexion, supported the 'dynamic dominance theory' where each hemisphere/limb might be tuned to control different parameters of task performance. PMID- 25511167 TI - Task-relevancy effects on movement-related gating are modulated by continuous theta-burst stimulation of the dorsolateral prefrontal cortex and primary somatosensory cortex. AB - Movement-related gating ensures that decreased somatosensory information from external stimulation reaches the cortex during movement when compared to resting levels; however, gating may be influenced by task-relevant manipulations, such that increased sensory information ascends to the cortex when information is relevant to goal-based actions. These task-relevancy effects are hypothesized to be controlled by a network involving the dorsolateral prefrontal cortex (DLPFC) based on this region's known role in selective attention, modulating the primary somatosensory cortex (S1). The purpose of the current study was first to verify task-relevancy influences on movement-related gating in the upper limb, and second to test the contribution of the DLPFC and the primary somatosensory cortex (S1) to these relevancy effects. Ten healthy participants received median nerve stimulation at the left wrist during three conditions: rest, task-irrelevant movement, and task-relevant movement. Cortical responses to median nerve stimulations were measured in the form of somatosensory evoked potentials (SEPs). The three conditions were collected on a baseline day and on two separate days following continuous theta-burst (cTBS), which transiently reduces cortical excitability, over either the contralateral S1 or DLPFC. Results demonstrated a significant interaction between stimulation and condition, with a priori contrasts revealing that cTBS over either S1 or DLPFC diminished the relevancy based modulation of SEP amplitudes; however, the degree of this effect was different. These results indicate that DLPFC influences over S1 are involved in the facilitation of relevant sensory information during movement. PMID- 25511166 TI - Sonification and haptic feedback in addition to visual feedback enhances complex motor task learning. AB - Concurrent augmented feedback has been shown to be less effective for learning simple motor tasks than for complex tasks. However, as mostly artificial tasks have been investigated, transfer of results to tasks in sports and rehabilitation remains unknown. Therefore, in this study, the effect of different concurrent feedback was evaluated in trunk-arm rowing. It was then investigated whether multimodal audiovisual and visuohaptic feedback are more effective for learning than visual feedback only. Naive subjects (N = 24) trained in three groups on a highly realistic virtual reality-based rowing simulator. In the visual feedback group, the subject's oar was superimposed to the target oar, which continuously became more transparent when the deviation between the oars decreased. Moreover, a trace of the subject's trajectory emerged if deviations exceeded a threshold. The audiovisual feedback group trained with oar movement sonification in addition to visual feedback to facilitate learning of the velocity profile. In the visuohaptic group, the oar movement was inhibited by path deviation-dependent braking forces to enhance learning of spatial aspects. All groups significantly decreased the spatial error (tendency in visual group) and velocity error from baseline to the retention tests. Audiovisual feedback fostered learning of the velocity profile significantly more than visuohaptic feedback. The study revealed that well-designed concurrent feedback fosters complex task learning, especially if the advantages of different modalities are exploited. Further studies should analyze the impact of within-feedback design parameters and the transferability of the results to other tasks in sports and rehabilitation. PMID- 25511168 TI - Effects of age and cognitive load on response reprogramming. AB - A dual-task paradigm was used to examine the effect of cognitive load on motor reprogramming. We propose that in the face of conflict, both executive control and motor control mechanisms become more interconnected in the process of reprogramming motor behaviors. If so, one would expect a concurrent cognitive load to compromise younger adults' (YAs) motor reprogramming ability and further exacerbate the response reprogramming ability of older adults (OAs). Nineteen YAs and 14 OAs overlearned a sequence of key presses. Deviations of the practiced sequence were introduced to assess motor reprogramming ability. A Serial Sevens Test was used as the cognitive load. A 3D motion capture system was used to parse finger movements into planning and motor execution times. Global response time analysis revealed that under single-task conditions, during prepotent transitions, OAs responded as quickly as YAs, but they were disproportionately worse than YAs during conflict transitions. Under dual-task conditions, YAs performance became more similar to that of OAs. Movement data were decomposed into planning and movement time, revealing that under single-task conditions, when responding to conflicting stimuli YAs reduced their movement time in order to compensate for delayed planning time; however, additional cognitive load prevented them from exhibiting this compensatory hastening on conflict transitions. We propose that age-related declines in response reprogramming may be linked to reduced cognitive capacity. Current findings suggest that cognitive capacity, reduced in the case of OAs or YAs under divided attention conditions, influences the ability to flexibly adapt to conflicting conditions. PMID- 25511169 TI - Lateralized discrimination of emotional scenes in peripheral vision. AB - This study investigates whether there is lateralized processing of emotional scenes in the visual periphery, in the absence of eye fixations; and whether this varies with emotional valence (pleasant vs. unpleasant), specific emotional scene content (babies, erotica, human attack, mutilation, etc.), and sex of the viewer. Pairs of emotional (positive or negative) and neutral photographs were presented for 150 ms peripherally (>=6.5 degrees away from fixation). Observers judged on which side the emotional picture was located. Low-level image properties, scene visual saliency, and eye movements were controlled. Results showed that (a) correct identification of the emotional scene exceeded the chance level; (b) performance was more accurate and faster when the emotional scene appeared in the left than in the right visual field; (c) lateralization was equivalent for females and males for pleasant scenes, but was greater for females and unpleasant scenes; and (d) lateralization occurred similarly for different emotional scene categories. These findings reveal discrimination between emotional and neutral scenes, and right brain hemisphere dominance for emotional processing, which is modulated by sex of the viewer and scene valence, and suggest that coarse affective significance can be extracted in peripheral vision. PMID- 25511171 TI - How solid-liquid adhesive property regulates liquid slippage on solid surfaces? AB - The influence of solid-liquid adhesive property on liquid slippage at solid surfaces has been investigated using experiment approach on well-defined model surfaces as well as theoretical analysis. Based on a classical molecular-kinetic description for molecular and hydrodynamic slip, we propose a simple theoretical model that directly relates the liquid slip length to the liquid adhesive force on solid surfaces, which yields an exponential decay function. Well-defined smooth surfaces with varied surface wettability/adhesion are fabricated by forming self-assembled monolayers on gold with different mole ratios of hydrophobic and hydrophilic thiols. The adhesive force of a water droplet and the molecular slippage on these surfaces are probed by surface force apparatus and quartz crystal microbalance measurements, respectively. The experiment results are well consistent with our theoretical prediction. Our finding benefits the understanding of the underlying mechanism of liquid slippage on solid surfaces at molecular level and the rational design of microfluidics with an aim to be frictionless or highly controllable. PMID- 25511170 TI - A recoverable state of axon injury persists for hours after spinal cord contusion in vivo. AB - Therapeutic strategies for spinal cord injury (SCI) commonly focus on regenerating disconnected axons. An alternative approach would be to maintain continuity of damaged axons, especially after contusion. The viability of such neuropreservative strategies depends on the degree to which initially injured axons can recover. Here we use morphological and molecular in vivo imaging after contusion SCI in mice to show that injured axons persist in a metastable state for hours. Intra-axonal calcium dynamics influence fate, but the outcome is not invariably destructive in that many axons with calcium elevations recover homeostasis without intervention. Calcium enters axons primarily through mechanopores. Spontaneous pore resealing allows calcium levels to normalize and axons to survive long term. Axon loss can be halted by blocking calcium influx or calpain, even with delayed initiation. Our data identify an inherent self preservation process in contused axons and a window of opportunity for rescuing connectivity after nontransecting SCI. PMID- 25511172 TI - A new double-trouble phenotype: fascioscapulohumeral muscular dystrophy ameliorates hereditary spastic paraparesis due to spastin mutation. PMID- 25511173 TI - BCL11B expression in intramembranous osteogenesis during murine craniofacial suture development. AB - Sutures, where neighboring craniofacial bones are separated by undifferentiated mesenchyme, are major growth sites during craniofacial development. Pathologic fusion of bones within sutures occurs in a wide variety of craniosynostosis conditions and can result in dysmorphic craniofacial growth and secondary neurologic deficits. Our knowledge of the genes involved in suture formation is poor. Here we describe the novel expression pattern of the BCL11B transcription factor protein during murine embryonic craniofacial bone formation. We examined BCL11B protein expression at E14.5, E16.5, and E18.5 in 14 major craniofacial sutures of C57BL/6J mice. We found BCL11B expression to be associated with all intramembranous craniofacial bones examined. The most striking aspects of BCL11B expression were its high levels in suture mesenchyme and increasingly complementary expression with RUNX2 in differentiating osteoblasts during development. BCL11B was also expressed in mesenchyme at the non-sutural edges of intramembranous bones. No expression was seen in osteoblasts involved in endochondral ossification of the cartilaginous cranial base. BCL11B is expressed to potentially regulate the transition of mesenchymal differentiation and suture formation within craniofacial intramembranous bone. PMID- 25511175 TI - A validation study of the Hospital Anxiety and Depression Scale (HADS) in a large sample of French employees. AB - BACKGROUND: The Hospital Anxiety and Depression Scale (HADS) is a questionnaire widely used for detecting anxiety and depressive disorders. It is used extensively in France, but has never been the subject of a full study in a population at work. The objectives of this study were to present some psychometric properties of the HADS on a large sample of French employees. METHOD: The HADS questionnaire was given to salaried employees at 19 major French companies as part of their biennial occupational medical examination. In 2011, 20992 employees filled in the questionnaire. HADS's structure was studied first by exploratory, then confirmatory factorial analyses. RESULTS: The model selected was the original two-factor structure. The two subscales showed good internal consistency. Women scored higher than the men for anxiety and depression; the scores increased with age; engineers and managers had lower average scores than other occupational status (blue- or white-collar workers and technicians). CONCLUSION: The results of the analyses are consistent with those in literature relating to other populations studied in other countries. The HADS questionnaire is pertinent for detecting symptoms of anxiety and depression in a population of people at work. PMID- 25511176 TI - Acetylcholine beyond bronchoconstriction: roles in inflammation and remodeling. AB - Acetylcholine is the primary parasympathetic neurotransmitter in the airways, where it not only induces bronchoconstriction and mucus secretion, but also regulates airway inflammation and remodeling. In this review, we propose that these effects are all primarily mediated via the muscarinic M3 receptor. Acetylcholine promotes inflammation and remodeling via direct effects on airway cells, and via mechanical stress applied to the airways sequential to bronchoconstriction. The effects on inflammation and remodeling are regulated by both neuronal and non-neuronal acetylcholine. Taken together, we believe that the combined effects of anticholinergic therapy on M3-mediated bronchoconstriction, mucus secretion, inflammation, and remodeling may account for the positive outcome of treatment with these drugs for patients with chronic pulmonary obstructive disease (COPD) or asthma. PMID- 25511174 TI - Multi-walled carbon nanotube-induced gene expression in vitro: concordance with in vivo studies. AB - There is a current interest in reducing the in vivo toxicity testing of nanomaterials in animals by increasing toxicity testing using in vitro cellular assays; however, toxicological results are seldom concordant between in vivo and in vitro models. This study compared global multi-walled carbon nanotube (MWCNT) induced gene expression from human lung epithelial and microvascular endothelial cells in monoculture and coculture with gene expression from mouse lungs exposed to MWCNT. Using a cutoff of 10% false discovery rate and 1.5 fold change, we determined that there were more concordant genes (gene expression both up- or downregulated in vivo and in vitro) expressed in both cell types in coculture than in monoculture. When reduced to only those genes involved in inflammation and fibrosis, known outcomes of in vivo MWCNT exposure, there were more disease related concordant genes expressed in coculture than monoculture. Additionally, different cellular signaling pathways are activated in response to MWCNT dependent upon culturing conditions. As coculture gene expression better correlated with in vivo gene expression, we suggest that cellular cocultures may offer enhanced in vitro models for nanoparticle risk assessment and the reduction of in vivo toxicological testing. PMID- 25511177 TI - Tobacco industry direct mail receipt and coupon use among young adult smokers. AB - OBJECTIVE: To examine young adult smokers' receipt of tobacco industry direct mail and use of coupons to purchase cigarettes. METHOD: A total of 699 young adults from a 2011 national survey who reported smoking every day/some days provided self-report data on past-six month receipt of direct mail and past-six month use of coupons to purchase cigarettes. Multivariable logistic regression models were used to calculate adjusted odds of direct mail receipt and coupon use. RESULTS: Overall, 25.1% of young adult smokers reported receiving direct mail from a tobacco company and 24.2% had used a coupon to buy cigarettes in the past 6 months. Direct mail receipt and coupon use to purchase cigarettes were significantly higher among females, daily smokers, and whites. Nearly 70% of smokers who received direct mail had also used a coupon to purchase cigarettes in the preceding 6 months. Brand websites were the most commonly reported means of joining a direct mailing list. CONCLUSION: This study adds to limited research showing receipt of direct mail and use of price reducing coupons by young adults. Also, higher rates of direct mail receipt and coupon use among females suggest that these strategies may be especially effective in encouraging smoking in females. PMID- 25511178 TI - The relationship between gasoline price and patterns of motorcycle fatalities and injuries. AB - OBJECTIVE: Economic factors such as rising gasoline prices may contribute to the crash trends by shaping individuals' choices of transportation modalities. This study examines the relationship of gasoline prices with fatal and non-fatal motorcycle injuries. METHODS: Data on fatal and non-fatal motorcycle injuries come from California's Statewide Integrated Traffic Records System for 2002-2011. Autoregressive integrated moving average (ARIMA) regressions were used to estimate the impact of inflation-adjusted gasoline price per gallon on trends of motorcycle injuries. RESULTS: Motorcycle fatalities and severe and minor injuries in California were highly correlated with increasing gasoline prices from 2002 to 2011 (r=0.76, 0.88 and 0.85, respectively). In 2008, the number of fatalities and injuries reached 13,457--a 34% increase since 2002, a time period in which inflation-adjusted gasoline prices increased about $0.30 per gallon every year. The majority of motorcycle riders involved in crashes were male (92.5%), middle aged (46.2%) and non-Hispanic white (67.9%). Using ARIMA modelling, we estimated that rising gasoline prices resulted in an additional 800 fatalities and 10,290 injuries from 2002 to 2011 in California. CONCLUSIONS: Our findings suggest that increasing gasoline prices led to more motorcycle riders on the roads and, consequently, more injuries. Aside from mandatory helmet laws and their enforcement, other strategies may include raising risk awareness of motorcyclists and investment in public transportation as an alternative transportation modality to motorcycling. In addition, universally mandated training courses and strict licensing tests of riding skills should be emphasised to help reduce the motorcycle fatal and non-fatal injuries. PMID- 25511179 TI - Biologicals for the treatment of systemic lupus erythematosus: current status and emerging therapies. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disease resulting from the dysregulation of various immunological pathways. There has been major progress in recent years in the understanding of the pathogenesis of SLE, which has led to an emergence of a new class of drugs designed to target specific components of the disease process.Evidence from a number of open-label, uncontrolled studies has supported the use of rituximab (an anti-CD20 monoclonal antibody) in SLE for more than one decade. However, these promising results are in clear contrast with the poor results of the completed Efficacy and Safety of Rituximab in Patients with Severe SLE (EXPLORER) and Efficacy and Safety of Rituximab in Subjects with class III or IV Lupus Nephritis (LUNAR) randomized controlled trials. In contrast to EXPLORER and LUNAR results, controlled trials for belimumab (a fully humanized monoclonal antibody against B lymphocyte stimulator) showed positive results and subsequently, belimumab was the first drug approved for the treatment of SLE patients. This has paved the way for the development of further biological agents, potentially revolutionizing the treatment of SLE. In this study, the potential benefits of novel biological agents are explored, obstacles to the development of a treatment target in SLE are identified, and possible strategies to achieve this goal are discussed. PMID- 25511180 TI - Disruption of dopaminergic transmission remodels tripartite synapse morphology and astrocytic calcium activity within substantia nigra pars reticulata. AB - The substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia circuitry particularly sensitive to pathological dopamine depletion. Indeed, hyperactivity of SNr neurons is known to be responsible for some motor disorders characteristic of Parkinson's disease. The neuronal processing of basal ganglia dysfunction is well understood but, paradoxically, the role of astrocytes in the regulation of SNr activity has rarely been considered. We thus investigated the influence of the disruption of dopaminergic transmission on plastic changes at tripartite glutamatergic synapses in the rat SNr and on astrocyte calcium activity. In 6-hydroxydopamine-lesioned rats, we observed structural plastic changes of tripartite glutamatergic synapses and perisynaptic astrocytic processes. These findings suggest that subthalamonigral synapses undergo morphological changes that accompany the pathophysiological processes of Parkinson's disease. The pharmacological blockade of dopaminergic transmission (with sulpiride and SCH-23390) increased astrocyte calcium excitability, synchrony and gap junction coupling within the SNr, suggesting a functional adaptation of astrocytes to dopamine transmission disruption in this output nucleus. This hyperactivity is partly reversed by subthalamic nucleus high frequency stimulation which has emerged as an efficient symptomatic treatment for Parkinson's disease. Therefore, our results demonstrate structural and functional reshaping of neuronal and glial elements highlighting a functional plasticity of neuroglial interactions when dopamine transmission is disrupted. PMID- 25511181 TI - Under-expression of alpha8 integrin aggravates experimental atherosclerosis. AB - Integrins play an important role in vascular biology. The alpha8 integrin chain attenuates smooth muscle cell migration but its functional role in the development of atherosclerosis is unclear. Therefore, we studied the contribution of alpha8 integrin to atherosclerosis and vascular remodelling. We hypothesized that alpha8 integrin expression is reduced in atherosclerotic lesions, and that its under-expression leads to a more severe course of atherosclerosis. alpha8 Integrin was detected by immunohistochemistry and qPCR and alpha8 integrin deficient mice were used to induce two models of atherosclerotic lesions. First, ligation of the carotid artery led to medial thickening and neointima formation, which was quantified in carotid cross-sections. Second, after crossing into ApoE deficient mice, the formation of advanced vascular lesions with atherosclerotic plaques was quantified in aortic en face preparations stained with Sudan IV. Parameters of renal physiology and histopathology were assessed: alpha8 integrin was detected in the media of human and murine vascular tissue and was down regulated in arteries with advanced atherosclerotic lesions. In alpha8 integrin deficient mice (alpha8(-/-) ) as well as alpha8(+/-) and alpha8(+/+) littermates, carotid artery ligation increased media:lumen ratios in all genotypes, with higher values in ligated alpha8(-/-) and alpha8(+/-) compared to ligated alpha8(+/+) animals. Carotid artery ligation increased smooth muscle cell number in the media of alpha8(+/+) mice and, more prominently, of alpha8(-/-) or alpha8(+/-) mice. On an ApoE(-/-) background, alpha8(+/-) and alpha8(-/-) mice developed more atherosclerotic plaques than alpha8(+/+) mice. alpha8 Integrin expression was reduced in alpha8(+/-) animals. Renal damage with increased serum creatinine and glomerulosclerosis was detected in alpha8(-/-) mice only. Thus, under-expression of alpha8 integrin aggravates vascular lesions, while a complete loss of alpha8 integrin results in reduced renal mass and additional renal disease in the presence of generalized atherosclerosis. Our data support the hypothesis that integrin alpha8beta1 has a protective role in arterial remodelling and atherosclerosis. PMID- 25511182 TI - Pluripotent stem cell-based models of spinal muscular atrophy. AB - Motor neuron diseases, as the vast majority of neurodegenerative disorders in humans, are incurable conditions that are challenging to study in vitro, owing to the obstacles in obtaining the cell types majorly involved in the pathogenesis. Recent advances in stem cell research, especially in the development of induced pluripotent stem cell (iPSC) technology, have opened up the possibility of generating a substantial amount of disease-specific neuronal cells, including motor neurons and glial cells. The present review analyzes the practical implications of iPSCs, generated from fibroblasts of patients affected by spinal muscular atrophy (SMA), and discusses the challenges in the development and optimization of in vitro disease models. Research on patient-derived disease specific cells may shed light on the pathological processes behind neuronal dysfunction and death in SMA, thus providing new insights for the development of novel effective therapies. PMID- 25511183 TI - Differential expression and localization of glycosidic residues in in vitro- and in vivo-matured cumulus-oocyte complexes in equine and porcine species. AB - Glycoprotein oligosaccharides play major roles during reproduction, yet their function in gamete interactions is not fully elucidated. Identification and comparison of the glycan pattern in cumulus-oocyte complexes (COCs) from species with different efficiencies of in vitro spermatozoa penetration through the zona pellucida (ZP) could help clarify how oligosaccharides affect gamete interactions. We compared the expression and localization of 12 glycosidic residues in equine and porcine in vitro-matured (IVM) and preovulatory COCs by means of lectin histochemistry. The COCs glycan pattern differed between animals and COC source (IVM versus preovulatory). Among the 12 carbohydrate residues investigated, the IVM COCs from these two species shared: (a) sialo- and betaN acetylgalactosamine (GalNAc)-terminating glycans in the ZP; (b) sialylated and fucosylated glycans in cumulus cells; and (c) GalNAc and N-acetylglucosamine (GlcNAc) glycans in the ooplasm. Differences in the preovulatory COCs of the two species included: (a) sialoglycans and GlcNAc terminating glycans in the equine ZP versus terminal GalNAc and internal GlcNAc in the porcine ZP; (b) terminal galactosides in equine cumulus cells versus terminal GlcNAc and fucose in porcine cohorts; and (c) fucose in the mare ooplasm versus lactosamine and internal GlcNAc in porcine oocyte cytoplasm. Furthermore, equine and porcine cumulus cells and oocytes contributed differently to the synthesis of ZP glycoproteins. These results could be attributed to the different in vitro fertilization efficiencies between these two divergent, large-animal models. PMID- 25511184 TI - RIS-PACS, patient safety, and clinical risk management. AB - PURPOSE: Clinical risk management is the basis of safety procedures also in radiological workflows. In the literature, it has been documented that the incidence of reconciled radiological studies ranges between 0.2 and 0.5 % of stored studies, a non-negligible value if we consider the high number of diagnostic tests performed. MATERIALS AND METHODS: In radiology, "non-compliance" or, more generally, data to be reconciled means any circumstance in which wrong information is recorded in RIS and/or PACS, which requires processing to amend or correct images, reports or other information in order to attribute them to the right patient/episode. Non-compliance corrections account for almost 50 % of the medical system administrator's (SA) workload. This paper describes how the Reggio Emilia Province Diagnostic Imaging and Laboratory Medicine Department manages risk in clinical radiology, in compliance with Regional indications on RIS-PACS safety. A dedicated RIS webpage has been developed in order to manage reconciliation requests. Native integration with PACS makes information about ongoing reconciliations available to anyone who consults the images. RESULTS: In 2013, non-compliances reported by radiology staff ranged between 0.25 and 0.35 % of studies sent to the PACS. More than 50 % of non-compliances can be related to high clinical risk, which requires implementation of efficient and effective rapid mechanisms of action-reaction inside and outside the radiology department. CONCLUSIONS: The RIS-integrated module has been the starting point for managing and monitoring errors, allowing improvement initiatives to guarantee and optimise workflow. Request and event traceability have allowed us to define personalised training programmes, designed to minimise procedural and/or systematic errors. To protect the availability and consistency of information produced by radiology units, it is necessary to provide integrated and effective mechanisms for reconciliation management. The integrated tool described in this paper is now widely used (not only by our centre): radiographers and radiologists can indicate non-compliances in an efficient and effective manner, informing all the operators involved with just a click of the mouse. Similar functionality should be implemented in the next generation of RIS-PACS in order to maintain the highest possible safety level for patients and workers. PMID- 25511186 TI - Management of renal extraskeletal mesenchymal chondrosarcoma. AB - BACKGROUND: Primary mesenchymal chondrosarcoma of the kidney is an extremely rare malignant tumor. To our best knowledge, only 9 such cases have been reported so far. CASE PRESENTATION: In the current paper, we present the case of a 67 year old patient with recurrent left lumbar pain, increased fatigability and intermittent macroscopic hematuria. He underwent a surgical resection of the left kidney and left hemicolon.The pathological diagnosis was primary extraskeletal renal mesenchymal chondrosarcoma. Overall survival was 9 months, with pulmonary metastasis and local recurrence at 6 months. The management of the patient is described, from the initial differential diagnosis, after the first clinical examination to the surgical resection, with a special emphasis on the surgical procedures that were carried out. CONCLUSION: Extraskeletal chondrosarcoma of primary origin in the kidney are extremely rare tumors with a highly malignant potential and very poor prognosis. Because the role of chemotherapy or radiation therapy has not been evaluated properly yet, we underline the importance of surgery in the management of such cases as the main and best approach to achieve clinical remission and long-term survival, provided the patient is referred to a surgical consult in time. PMID- 25511185 TI - Effectiveness of app-based relaxation for patients with chronic low back pain (Relaxback) and chronic neck pain (Relaxneck): study protocol for two randomized pragmatic trials. AB - BACKGROUND: Chronic low back pain (LBP) and neck pain (NP) are highly prevalent conditions resulting in high economic costs. Treatment guidelines recommend relaxation techniques, such as progressive muscle relaxation, as adjuvant therapies. Self-care interventions could have the potential to reduce costs in the health care system, but their effectiveness, especially in a usual care setting, is unclear. The aim of these two pragmatic randomized studies is to evaluate whether an additional app-delivered relaxation is more effective in the reduction of chronic LBP or NP than usual care alone. METHODS/DESIGN: Each pragmatic randomized two-armed study aims to include a total of 220 patients aged 18 to 65 years with chronic (>12 weeks) LBP or NP and an average pain intensity of >= 4 on a numeric rating scale (NRS) in the 7 days before recruitment. The participants will be randomized into an intervention and a usual care group. The intervention group will be instructed to practice one of these 3 relaxation techniques on at least 5 days/week for 15 minutes/day over a period of 6 months starting on the day of randomization: autogenic training, mindfulness meditation, or guided imagery. Instructions and exercises will be provided using a smartphone app, baseline information will be collected using paper and pencil. Follow-up information (daily, weekly, and after 3 and 6 months) will be collected using electronic diaries and questionnaires included in the app. The primary outcome measure will be the mean LBP or NP intensity during the first 3 months of intervention based on daily pain intensity measurements on a NRS (0 = no pain, 10 = worst possible pain). The secondary outcome parameters will include the mean pain intensity during the first 6 months after randomization based on daily measurements, the mean pain intensity measured weekly as the average pain intensity of the previous 7 days over 3 and 6 months, pain acceptance, 'LBP- and NP-related' stress, sick leave days, pain medication intake, adherence, suspected adverse reaction, and serious adverse events. DISCUSSION: The designed studies reflect a usual self-care setting and will provide evidence on a pragmatic self care intervention that is easy to combine with care provided by medical professionals. TRIAL REGISTRATION: ClinicalTrials.gov identifier Relaxback NCT02019498, Relaxneck NCT02019134 registered on 18 December 2013. PMID- 25511188 TI - Skin cancer. Golden age of melanoma therapy. PMID- 25511189 TI - Immunotherapy: personalizing tumour vaccines. PMID- 25511187 TI - Advances in umbilical cord blood manipulation-from niche to bedside. AB - The use of umbilical cord blood (UCB) as an alternative haematopoietic cell source in lieu of bone marrow for haematopoietic reconstitution is increasingly becoming a mainstay treatment for both malignant and nonmalignant diseases, as most individuals will have at least one available, suitably HLA-matched unit of blood. The principal limitation of UCB is the low and finite number of haematopoietic stem and progenitor cells (HSPC) relative to the number found in a typical bone marrow or mobilized peripheral blood allograft, which leads to prolonged engraftment times. In an attempt to overcome this obstacle, strategies that are often based on native processes occurring in the bone marrow microenvironment or 'niche' have been developed with the goal of accelerating UCB engraftment. In broad terms, the two main approaches have been either to expand UCB HSPC ex vivo before transplantation, or to modulate HSPC functionality to increase the efficiency of HSPC homing to the bone marrow niche after transplant both of which enhance the biological activities of the engrafted HSPC. Several early phase clinical trials of these approaches have reported promising results. PMID- 25511190 TI - Multiple myeloma and chronic leukaemias in 2014: improved understanding of disease biology and treatment. AB - In 2014, strides were made in the care of haematological malignancies. In particular, the heterogeneity of multiple myeloma was unravelled, and new diagnostic criteria and frontline standards of care were proposed; new therapeutic approaches have been validated and approved in chronic lymphocytic leukaemia; and in chronic myeloid leukaemia, complete cytogenetic response was confirmed as the primary therapeutic end point. PMID- 25511191 TI - Characterisation of an IMP-7-producing ST357 Pseudomonas aeruginosa isolate detected in Denmark using whole genome sequencing. PMID- 25511192 TI - Prospective audit and feedback in antimicrobial stewardship: is there value in early reviewing within 48 h of antibiotic prescription? AB - Antimicrobial stewardship programme (ASP) methodologies are not well defined, with most preferring to wait >=72-96 h following antibiotic prescription before reviewing patients. However, we hypothesise that early ASP reviews and interventions are beneficial and do not adversely impact patient safety. This study aimed to evaluate the impact of early ASP interventions within 48 h of antibiotic prescription on patient outcomes and safety. A prospective review of ASP interventions made within 48 h of antibiotic prescription in Singapore General Hospital (SGH) from January to December 2012 was conducted. Patient demographics and outcomes were extracted from the database maintained by the ASP team. For culture-directed treatment, there was a shorter mean duration of therapy (DOT) in the accepted group compared with the rejected group (2.26 days vs. 5.56 days; P<0.001). ASP interventions did not alter the length of hospital stay (LOS), 30-day mortality, 14-day Clostridium difficile infection (CDI), 30 day re-admissions and 14-day re-infection (all P>0.05). For empirical treatment, a shorter DOT (3.61 days vs. 6.25 days; P<0.001) and decreased 30-day all-cause mortality (P=0.003) and infection-related mortality (P=0.002) were observed among patients in the accepted group compared with the rejected group. There was no significant difference in LOS, 14-day CDI and 30-day re-admission (all P>0.05). In conclusion, acceptance of early interventions recommended by ASP in SGH was associated with a reduction in DOT without compromising patient safety. This is evident even during empirical therapy when not all clinical information was available. PMID- 25511193 TI - Translational Stroke Research: Where Have We Been and Where are We Going? Interviewing Dr. Marc Fisher (editor of Stroke). PMID- 25511194 TI - Impact of periodontal status on oral health-related quality of life among police personnel in Virajpet, India. AB - AIM: The aim of the present study was to determine the association between oral health-related quality of life (OHRQoL) and periodontal status among police personnel in Virajpet, India. METHODS: Police personnel were randomly selected from the 296 police staff working in Virajpet, India. A self-administered questionnaire was used to collect information on their demographics and dental visit behavior, and to determine their OHRQoL. The community periodontal index (CPI) and loss of attachment were used to assess periodontal status. RESULTS: All 72 invited participants joined this study. The majority (n = 133) had good OHRQoL. For those with a good OHRQoL, 74 had CPI = 0, 25 had CPI = 1, 20 had CPI = 2, and 14 had CPI >= 3. For those who had an average or poor OHRQoL (n = 37), 19 had CPI = 0, one had CPI = 1, eight had CPI = 2, and nine had CPI >= 3. There was a statistically-significant association between OHRQoL and CPI (P < 0.003). Most participants with good OHRQoL (127/133), but only less than half with an average or poor OHRQoL (22/37), had no loss of periodontal attachment (P < 0.0001). CONCLUSION: In the present study, there was an association between OHRQoL and periodontal status among police personnel in Virajpet, Coorg. PMID- 25511195 TI - Evaluation of a rapid immunochromatographic ODK0501 assay for detecting Streptococcus pneumoniae antigens in the sputum of pneumonia patients with positive S. pneumoniae urinary antigens. AB - BACKGROUND: A novel, rapid and noninvasive test (ODK0501, RAPIRUN((r))Streptococcus pneumoniae) uses polyclonal antibodies to detect C polysaccharide of S. pneumoniae derived from sputum samples using an immunochromatographic assay. We evaluated its usefulness in Japanese patients with pneumonia who exhibited positive urinary antigen tests for S. pneumoniae (BinaxNOW((r))S. pneumoniae). PATIENTS AND METHODS: Forty adult patients with pneumonia treated between May 2011 and August 2013 were enrolled. Bacterial cultures, Gram staining and ODK0501 assays of sputum as well as urinary antigen tests for S. pneumoniae using urine samples obtained from the same patients were performed upon admission, the fourth day after starting antimicrobial treatment and at the end of the antimicrobial treatment. RESULTS: Twenty-seven of the 40 patients were positive for ODK0501, while a negative result for ODK0501 was associated with low-quality sputum samples according to the Geckler classification of sputum. The sensitivity and specificity of the ODK0501 assay in the 40 patients were 90.9% and 61.1%, respectively, based on the culture results. The results obtained with this kit were more favorable than those observed on Gram staining. The ODK0501 assay also showed a rapid reaction to the disappearance of S. pneumoniae in the sputum samples, while approximately 80% of the patients exhibited persistent positive results on the urinary antigen detection tests at the end of treatment. CONCLUSIONS: The ODK0501 test is a noninvasive, rapid and accurate tool for diagnosing respiratory infections caused by S. pneumoniae, although good quality sputum must be obtained prior to adequate treatment with antibiotics. PMID- 25511196 TI - MANF silencing, immunity induction or autophagy trigger an unusual cell type in metamorphosing Drosophila brain. AB - Glia are abundant cells in the brain of animals ranging from flies to humans. They perform conserved functions not only in neural development and wiring, but also in brain homeostasis. Here we show that by manipulating gene expression in glia, a previously unidentified cell type appears in the Drosophila brain during metamorphosis. More specifically, this cell type appears in three contexts: (1) after the induction of either immunity, or (2) autophagy, or (3) by silencing of neurotrophic factor DmMANF in glial cells. We call these cells MANF immunoreactive Cells (MiCs). MiCs are migratory based on their shape, appearance in brain areas where no cell bodies exist and the nuclear localization of dSTAT. They are labeled with a unique set of molecular markers including the conserved neurotrophic factor DmMANF and the transcription factor Zfh1. They possess the nuclearly localized protein Relish, which is the hallmark of immune response activation. They also express the conserved engulfment receptor Draper, therefore indicating that they are potentially phagocytic. Surprisingly, they do not express any of the common glial and neuronal markers. In addition, ultrastructural studies show that MiCs are extremely rich in lysosomes. Our findings reveal critical molecular and functional components of an unusual cell type in the Drosophila brain. We suggest that MiCs resemble macrophages/hemocytes and vertebrate microglia based on their appearance in the brain upon genetically challenged conditions and the expression of molecular markers. Interestingly, macrophages/hemocytes or microglia-like cells have not been reported in the fly nervous system before. PMID- 25511199 TI - Laws of cognition and the cognition of law. AB - This paper presents a compact synthesis of the study of cognition in legal decisionmaking. Featured dynamics include the story-telling model (Pennington & Hastie, 1986), lay prototypes (Smith, 1991), motivated cognition (Sood, 2012), and coherence-based reasoning (Simon, Pham, Le, & Holyoak, 2001). Unlike biases and heuristics understood to bound or constrain rationality, these dynamics identify how information shapes a variety of cognitive inputs-from prior beliefs to perceptions of events to the probative weight assigned new information-that rational decisionmaking presupposes. The operation of these mechanisms can be shown to radically alter the significance that jurors give to evidence, and hence the conclusions they reach, within a Bayesian framework of information processing. How these dynamics interact with the professional judgment of lawyers and judges, the paper notes, remains in need of investigation. PMID- 25511200 TI - Association study between CYP17 gene polymorphism and endometriosis risk: a meta analysis. AB - The cytochrome P450 subfamily 17 (CYP17) gene T > C polymorphism is associated with endometriosis risk. However, studies on the association between the genotyping of MspA1 polymorphism in the 5'-untranslated region of the CYP17 gene and endometriosis risk have reported controversial results. The aim of the present study was to obtain a more precise estimate of the relationship of CYP17 gene polymorphism with endometriosis risk. Relevant articles published up to April 2014 were obtained from Pubmed, Embase, and Cochrane Central electronic databases. Case-control studies about the association between CYP17 gene polymorphisms and endometriosis were selected. Eligible data were extracted by two independent reviewers. The strength of the association between CYP17 and endometriosis was assessed by pooled odds ratios (OR) with 95% confidence intervals (CI). Eligible case-control studies involving 1000 cases and 1167 controls were analyzed from 280 studies. The pooled results showed no association between the CYP17 gene T > C polymorphism and endometriosis risk in the overall population (CC vs TT: OR = 0.92, 95% CI = 0.52-1.61, P = 0.762; TC vs TT: OR = 1.01, 95% CI = 0.72-1.42, P = 0.949; dominant model: OR = 0.94, 95% CI = 0.64 1.39, P = 0.763; recessive model: OR = 0.93, 95% CI = 0.64-1.35, P = 0.712). In the subgroup analysis based on ethnicity, no significant association was found in Asians, Caucasians and mixed population under a recessive model (Asians: OR = 0.76, 95% CI = 0.53-1.07, P = 0.118; Caucasians: OR = 2.47, 95% CI = 0.45-13.66, P = 0.300; mixed population: OR = 1.40, 95% CI = 0.65-3.02, P = 0.712). In conclusion, the meta-analysis suggested that the CYP17 gene polymorphism was not associated with endometriosis risk. Considering the limited sample size and ethnicity included in our meta-analysis, an updated meta-analysis needs to be conducted when larger and more well-designed studies are published. PMID- 25511197 TI - Are stem cells a potential therapeutic tool in coeliac disease? AB - Despite the growing understanding of its pathogenesis, the treatment of coeliac disease is still based on a lifelong gluten-free diet that, although efficacious, is troublesome for affected patients, and a definitive cure is still an unmet need. In this regard, the development of new chemical- and biological-derived agents has often resulted in unsatisfactory effects when tested in vivo, probably because of their ability to target only a single pathway, whilst the immunological cascade responsible for tissue injury is complex and redundant. The advent of cellular therapies, mainly based on the use of stem cells, is an emerging area of interest since it has the advantage of a multi-target strategy. Both haematopoietic and mesenchymal stem cells have been employed in the treatment of refractory patients suffering from autoimmune diseases, with promising results. However, the lack of immunogenicity makes mesenchymal stem cells more suitable than their haematopoietic counterpart, since their transplantation may be performed in the absence of a myeloablative conditioning regimen. In addition, mesenchymal stem cells have been shown to harbour strong modulatory effects on almost all cells involved in immune response, together with a potent regenerative action. It is therefore conceivable that over the next few years their therapeutic use will increase as their biological interactions with injured tissues become clearer. PMID- 25511201 TI - Relationships between physical symptoms, emotional distress, and pain appraisal in fibromyalgia: the moderator effect of alexithymia. AB - Alexithymia is a personality construct that is frequently identified in fibromyalgia (FM). Previous studies have explored the relationship between alexithymia and emotional distress in this disease. Yet, the additional link with factors of pain appraisal is unknown. This study examined the moderating effect of alexithymia in the relationship between emotional distress and pain appraisal in 97 FM women. A control group of 100 healthy women also participated in the study. All participants completed several self-reports about pain experience, sleep quality, impairment, emotional distress, pain appraisal, and alexithymia. FM women showed significantly more difficulty in identifying and describing feelings, but less externally oriented thinking than healthy women. In the clinical group, difficulty in identifying feelings and difficulty in describing feelings significantly correlated with lower sleep quality, higher anxiety and depression, and increased pain catastrophizing and fear of pain. Difficulty in describing feelings significantly correlated with higher pain experience and vigilance to pain. Externally oriented thinking was not correlated with any of the clinical variables. Difficulty in identifying feelings moderated the relationship between anxiety and pain catastrophizing, and difficulty in describing feelings moderated the relationship between anxiety and fear of pain. Implications of the findings for the optimization of care of FM patients are discussed. PMID- 25511202 TI - The sporting body: body image and eating disorder symptomatology among female athletes from leanness focused and nonleanness focused sports. AB - Female athletes experience pressure to conform to social and sporting norms concerning body weight. This study compared general and sporting body dissatisfaction and disordered eating symptomatology among 320 elite, recreational, and noncompetitive female athletes aged 17 to 30 years competing in leanness focused sports and nonleanness focused sports. Participants completed an online questionnaire including demographic questions, the Eating Attitudes Test, and the Figure Rating Scale. Athletes from leanness focused sports reported higher levels of body dissatisfaction and greater disordered eating symptomatology regardless of participation level. Elite athletes reported higher levels of body dissatisfaction and greater disordered eating symptomatology regardless of sport type, and differences between recreational and noncompetitive athletes were not found. More than 60% of elite athletes from leanness focused and nonleanness focused sports reported pressure from coaches concerning body shape. The findings have important implications for identifying risk factors for eating disorders among female athletes, where athletes who compete at elite level and those who compete in leanness focused sports at any level may be at higher risk for developing eating disorders. PMID- 25511203 TI - Incidence of behavior problems in toddlers and preschool children from families living in poverty. AB - Few studies have examined the incidence of behavior problems in toddlers and preschool children from families living in poverty. The available research suggests behavior problems occur at higher rates in children living in poverty and may have long-term negative outcomes if not identified and properly treated. This study included an ethnically representative sample of 357 children, five years of age and younger, from a diverse, low-income, urban area. All families' incomes met the federal threshold for living in poverty. Behavior problems were assessed by parent report through a questionnaire specifically designed for low income families. Boys and younger children were reported as demonstrating a higher rate of externalizing behaviors than girls and older children. The overall rate of children scoring at least one standard deviation above the sample's mean for challenging behaviors was 17.4% and was not related to the child's gender, age or ethnicity. This study also sampled children's positive behaviors, which is unique in studies of behavior problems. Gender and age were not related to the frequency of reported positive behaviors. Ethnicity did influence scores on the positive scale. African American children appeared to present their parents more difficulty on items reflecting cooperative behaviors than Caucasian or Latino children. The implications of the study are discussed based on the recognized need for universal screening of behavior problems in young children and the small number professional training programs targeting the identification and treatment of early childhood behavior problems, despite the availability of evidence-based treatment programs tailored to young children in low-income families. PMID- 25511204 TI - The Perceived Leadership Communication Questionnaire (PLCQ): Development and Validation. AB - The Perceived Leadership Communication Questionnaire (PLCQ) is a short, reliable, and valid instrument for measuring leadership communication from both perspectives of the leader and the follower. Drawing on a communication-based approach to leadership and following a theoretical framework of interpersonal communication processes in organizations, this article describes the development and validation of a one-dimensional 6-item scale in four studies (total N = 604). Results from Study 1 and 2 provide evidence for the internal consistency and factorial validity of the PLCQ's self-rating version (PLCQ-SR)-a version for measuring how leaders perceive their own communication with their followers. Results from Study 3 and 4 show internal consistency, construct validity, and criterion validity of the PLCQ's other-rating version (PLCQ-OR)-a version for measuring how followers perceive the communication of their leaders. Cronbach's alpha had an average of.80 over the four studies. All confirmatory factor analyses yielded good to excellent model fit indices. Convergent validity was established by average positive correlations of.69 with subdimensions of transformational leadership and leader-member exchange scales. Furthermore, nonsignificant correlations with socially desirable responding indicated discriminant validity. Last, criterion validity was supported by a moderately positive correlation with job satisfaction (r =.31). PMID- 25511198 TI - Nuclear bile acid signaling through the farnesoid X receptor. AB - Bile acids (BAs) are amphipathic molecules produced from cholesterol by the liver. Expelled from the gallbladder upon meal ingestion, BAs serve as fat solubilizers in the intestine. BAs are reabsorbed in the ileum and return via the portal vein to the liver where, together with nutrients, they provide signals to coordinate metabolic responses. BAs act on energy and metabolic homeostasis through the activation of membrane and nuclear receptors, among which the nuclear receptor farnesoid X receptor (FXR) is an important regulator of several metabolic pathways. Highly expressed in the liver and the small intestine, FXR contributes to BA effects on metabolism, inflammation and cell cycle control. The pharmacological modulation of its activity has emerged as a potential therapeutic strategy for liver and metabolic diseases. This review highlights recent advances regarding the mechanisms by which the BA sensor FXR contributes to global signaling effects of BAs, and how FXR activity may be regulated by nutrient sensitive signaling pathways. PMID- 25511205 TI - Why does interactional justice promote organizational loyalty, job performance, and prevent mental impairment? The role of social support and social stressors. AB - Using social exchange theory as a conceptual framework, we investigated the relationship between interactional justice and the outcomes organizational loyalty (affective commitment, turnover intentions), perceived job performance (self-rated performance, personal accomplishment), and mental impairment (cognitive irritation, emotional exhaustion) in an online survey of 218 employees working in the field of computer technology. Specifically, we predicted that interactional justice would heighten the quality of social exchange relationships and therefore expected perceived social support (POS) and bullying to mediate the proposed relationships. We tested our hypotheses applying a latent structural equation model. Our findings revealed that POS mediated the relationship between interactional justice and organizational loyalty, whereas bullying mediated the relationship between interactional justice and mental impairment. Practical implications are discussed concerning how to foster interactional justice and POS and how to weaken bullying behavior. PMID- 25511206 TI - Design of a multi-site multi-state clinical trial of home monitoring of chronic disease in the community in Australia. AB - BACKGROUND: Telehealth services based on at-home monitoring of vital signs and the administration of clinical questionnaires are being increasingly used to manage chronic disease in the community, but few statistically robust studies are available in Australia to evaluate a wide range of health and socio-economic outcomes. The objectives of this study are to use robust statistical methods to research the impact of at home telemonitoring on health care outcomes, acceptability of telemonitoring to patients, carers and clinicians and to identify workplace cultural factors and capacity for organisational change management that will impact on large scale national deployment of telehealth services. Additionally, to develop advanced modelling and data analytics tools to risk stratify patients on a daily basis to automatically identify exacerbations of their chronic conditions. METHODS/DESIGN: A clinical trial is proposed at five locations in five states and territories along the Eastern Seaboard of Australia. Each site will have 25 Test patients and 50 case matched control patients. All participants will be selected based on clinical criteria of at least two hospitalisations in the previous year or four or more admissions over the last five years for a range of one or more chronic conditions. Control patients are matched according to age, sex, major diagnosis and their Socio-Economic Indexes for Areas (SEIFA). The Trial Design is an Intervention control study based on the Before-After-Control-Impact (BACI) design. DISCUSSION: Our preliminary data indicates that most outcome variables before and after the intervention are not stationary, and accordingly we model this behaviour using linear mixed-effects (lme) models which can flexibly model within-group correlation often present in longitudinal data with repeated measures. We expect reduced incidence of unscheduled hospitalisation as well as improvement in the management of chronically ill patients, leading to better and more cost effective care. Advanced data analytics together with clinical decision support will allow telehealth to be deployed in very large numbers nationally without placing an excessive workload on the monitoring facility or the patient's own clinicians. TRIAL REGISTRATION: Registered with Australian New Zealand Clinical Trial Registry on 1st April 2013. Trial ID: ACTRN12613000635763. PMID- 25511208 TI - The Geneva Faces and Voices (GEFAV) database. AB - Although many facial and vocal databases are available for research, very few of them have controlled the range of attractiveness of the stimuli that they offer. To fill this gap, we created the GEneva Faces and Voices (GEFAV) database, providing standardized faces (static and dynamic neutral, smiling) and voices (speaking sentences, vowels) of young European adults. A total of 61 women and 50 men 18-35 years old agreed to be part of the GEFAV stimuli, and two rating studies involving 285 participants provided evaluations of the facial and vocal samples. The final set of stimuli was satisfactory in terms of attractiveness range (wide and rather symmetrical distribution over the attractiveness continuum) and the reliability of the ratings (high consistency between the two rating studies, high interrater agreement in the final rating study). Moreover, the database showed an adequate validity, since a series of findings described by earlier research on human attractiveness were confirmed-namely, that facial and vocal attractiveness are predicted by femininity and health in women, and by masculinity, dominance, and trustworthiness in men. In future studies, the GEFAV stimuli may be used intact or transformed, individually or in multimodal combinations, to investigate a wide range of mechanisms, such as the behavioral, neuropsychological, and neurophysiological processes involved in social cognition. PMID- 25511207 TI - Mycobacterium tuberculosis cell division protein, FtsE, is an ATPase in dimeric form. AB - FtsE is one of the earliest cell division proteins that assembles along with FtsX at the mid-cell site during cell division in Escherichia coli. Both these proteins are highly conserved across diverse bacterial genera and are predicted to constitute an ABC transporter type complex, in which FtsE is predicted to bind ATP and hydrolyse it, and FtsX is predicted to be an integral membrane protein. We had earlier reported that the MtFtsE of the human pathogen, Mycobacterium tuberculosis, binds ATP and interacts with MtFtsX on the cell membrane of M. tuberculosis and E. coli. In this study, we demonstrate that MtFtsE is an ATPase, the active form of which is a dimer, wherein the participating monomers are held together by non-covalent interactions, with the Cys84 of each monomer present at the dimer interface. Under oxidising environment, the dimer gets stabilised by the formation of Cys84-Cys84 disulphide bond. While the recombinant MtFtsE forms a dimer on the membrane of E. coli, the native MtFtsE seems to be in a different conformation in the M. tuberculosis membrane. Although disulphide bridges were not observed on the cytoplasmic side (reducing environment) of the membrane, the two participating monomers could be isolated as dimers held together by non covalent interactions. Taken together, these findings show that MtFtsE is an ATPase in the non-covalent dimer form, with the Cys84 of each monomer present in the reduced form at the dimer interface, without participating in the dimerisation or the catalytic activity of the protein. PMID- 25511209 TI - Can we improve operating room efficiency? PMID- 25511210 TI - An analysis of time utilization and cancellations of scheduled cases in the main operation theater complex of a tertiary care teaching institute of North India. AB - CONTEXT: Operation theater (OT) utilization. AIMS: To analyze the time utilization and to assess the stated causes of cancellations of scheduled cases in the OT complex of a tertiary care teaching institute. SETTINGS AND DESIGN: This prospective study was carried out from December 2010 to April 2011. MATERIALS AND METHODS: each of the 16 OT tables was observed for 6 days (total 96 days). The available resource hours were taken as 0800-1600 hrs. (480 min/day; 46,080 min in 96 days). The following parameters were recorded--time spent on supportive services, time spent on actual surgery, room turn over time, time spent for total procedure and time between entry and exit of patient. STATISTICAL ANALYSIS: Data were analyzed using the SPSS software version 15. RESULTS: Of the total 325 scheduled cases, 252 were operated and 73 (22.5%) were cancelled. There were delays on 15 days (15.63%) in starting the OT table at the scheduled time. Of the total resource hours (46,080 min), the mean "Raw utilization" was 37,573 min (81.54%) and the "Adjusted utilization" was 39,668 min (86.09%). The mean time spent on "supportive services" was 5539 min (12.02%) and on "actual surgery"' was 28,277 min (61.37%), and the "room turn over time" was 2095 min (5.39%). Among the stated reasons for cancellations, lack of operating time--57 cases (78.1%)--was the most common. CONCLUSION: Study of time utilization and cancellation are important tools in assessing the optimal utilization of available resource hours in an OT. PMID- 25511211 TI - Genetic polymorphisms associated with sulphadoxine-pyrimethamine drug resistance among Plasmodium falciparum field isolates in malaria endemic areas of Assam. AB - BACKGROUND: The emergence of antimalarial drug resistance malaria parasite is widespread in North eastern region of India. During January 2012-December 2013, we conducted active surveillance for detection of antifolate resistance associated genetic polymorphisms in Plasmodium falciparum malaria parasite from different malaria endemic areas of Assam. MATERIALS AND METHODS: A total of 281 field samples were collected from suspected malaria patients of which 106 malaria P. falciparum positive cases were detected in microscopic slide examination. A nested PCR was done for amplification of a 648 bp portion of the dhfr gene and 710 bp portion of the dhps gene. RESULTS: Mutation analysis revealed existence of three different haplotypes of the P. falciparum dhfr gene of which ANRNI was highly prevalent (90%). Triple mutant haplotypes AIRNI (N51I+C59R+S108N) of the dhfr gene associated with pyrimethamine resistance were prevalent in Chirang district of Assam. Whereas, dhps mutation study revealed that triple mutant haplotype AGEAA (S436A+A437G+K540E) associated with Sulphadoxine resistance was found among 26% of P. falciparum field isolates. However, P. falciparum dhfr-dhps two locus mutation analysis showed that there were a total of nine dhfr-dhps genotypes. CONCLUSION: It was noticed that 93.62% (88/94) isolates had mutations in the sequences of both enzymes, which is an indication of prevalence of high grade of Sulphadoxine - pyrimethamine resistance in P. falciparum malaria parasites in Assam. PMID- 25511212 TI - Cyclin D1 and Ki-67 expression in normal, hyperplastic and neoplastic endometrium. AB - BACKGROUND: Proliferation and differentiation of cancer cells are regulated by various cell cycle promoting and inhibiting factors. Our knowledge about these proteins and mechanisms regulating cell cycle progression has increased dramatically in recent years. AIM: The present study was undertaken to examine the expression profile of cell cycle regulatory proteins in normal proliferative endometrium, hyperplasias (simple, complex and atypical) and endometrial carcinoma in a quantitative approach as also to assess correlations of Cyclin D1 expression with Ki-67 a proliferation marker. SETTINGS AND DESIGN: A retrospective case control study in a tertiary referral centre. MATERIALS AND METHODS: We evaluated and compared the expression profile of Cyclin D1 and Ki-67 expressions in 61 endometrial samples submitted as either endometrial curetting or hysterectomy specimens, which were diagnosed as simple hyperplasia (n=11), complex hyperplasia (n=13), atypical hyperplasia (n=7), and endometrial carcinoma (n=20). RESULTS: There was increased expression of Cyclin D1 and Ki-67 in patients with endometrial carcinoma relative to proliferative endometrium and simple hyperplasia, but there was no such difference between cases of atypical hyperplasia and endometrial carcinoma. Cyclin D1 expression had a positive correlation with Ki-67 expression. Cyclin D1 together with Ki-67 may be a marker for endometrial carcinogenesis and tumor cell proliferation. PMID- 25511213 TI - Correlation of renin angiotensin system (RAS) candidate gene polymorphisms with response to Ramipril in patients with essential hypertension. AB - BACKGROUND: The renin-angiotensin system (RAS) is an important facet of blood pressure regulation physiology. Treatment of essential hypertension targets the RAS using Angiotensin Converting Enzyme Inhibitors (ACEIs). However, ACEIs are not uniformly effective and show inter-individual pharmacodynamic variations. AIM: To assess the correlation between genetic polymorphisms in the genes coding for RAS components (angiotensin converting enzyme (ACE I/D), alpha-adducin (ADD1) and beta1 -adrenoreceptor (beta1-ADR)) and response to Ramipril. MATERIALS AND METHODS: We recruited 120 patients with essential hypertension who were administered Ramipril monotherapy initially, followed by combination therapy, if needed, based on their responses. Relationship between genotypes of the three candidate genes and decrease in the blood pressure (BP) was analyzed. RESULTS: One hundred and six patients were evaluable at the end of the study period and 21 different genotypes were observed among them. Seven of them were classified as responders after 8 weeks and at the end of 12 weeks, an additional 77 (72.64%) were deemed responders. 19/22 non-responders were treated with combination therapy and 7/19 (36.84%) showed a response to the same. There was a significant difference between the proportions of responders and non-responders among the genotypes of the ADD1 and beta1-ADR genes (P=0.005 and 0.003, respectively). The best predictors of response to Ramipril 5 mg daily were the II/GG/SS, II/TG/SS, II/GG/SG, ID/GG/SS, ID/GG/SG and ID/TT/SS and DD/GG/SS; II/GG/GG, II/TT/SG, ID/TG/SG, ID/TT/SG, DD/GG/SG and DD/GG/GG were moderately predictive and II/TT/SS, II/TG/GG, ID/TG/GG, DD/TG/SG and DD/TG/GG were poorly predictive of response. DISCUSSION: Variable responses to Ramipril may be the result of genetic factors. CONCLUSION: Pre-prescription genotyping may help individualize treatment. PMID- 25511214 TI - The effect of addition of low dose fentanyl to epidural bupivacaine (0.5%) in patients undergoing elective caesarean section: A randomized, parallel group, double blind, placebo controlled study. AB - BACKGROUND: Opioids have synergistic action with local anesthetics which may alter characteristics of epidural block. Giving opioids to mother before delivery of baby is still fully not accepted with some fearing risk of neonatal depression. AIMS: Our primary aim was to evaluate the analgesic effect of addition of 50 MUg fentanyl to epidural 0.5% bupivacaine in patients undergoing elective caesarean section using visual analog scale. The secondary aim was to assess onset of analgesia, volume of drug required to achieve T6 level, grade and duration of motor block and Apgar score. MATERIALS AND METHODS: In this prospective, randomized, double blind, placebo controlled study 64 patients scheduled for elective caesarean section under epidural anesthesia were randomly divided into two groups of 32 each. The fentanyl group received 1 ml of 50 MUg fentanyl and the saline group received 1 ml of normal saline mixed with 10 ml of 0.5% bupivacaine for epidural anesthesia. VAS score, time to achieve T6 level, dose of bupivacaine, intraoperative analgesic consumption and duration of analgesia, grade and duration of motor block and any adverse maternal and neonatal effects were noted. STATISTICAL ANALYSIS: Data was analyzed using Students t test, chi-square test and Mann-Whitney U-test. The values of P<0.05 were considered statistically significant. RESULTS: Fentanyl improved the VAS score significantly (1.6+/-1.32) compared to the saline group (3.77+/-1.0, P<0.0001). It also reduced the intraoperaitve analgesic supplementation compared to the saline group. (P=0.031). The postoperative duration of analgesia was prolonged in the fentanyl group (275.80+/-13.61 min) compared to the saline group (191.47+/-12.16 min, P<0.0001). The other characteristics of epidural block were unaltered. CONCLUSION: Addition of 50 MUg fentanyl to epidural 0.5% bupivacaine significantly reduces the VAS score. It also reduces intra-operative analgesia supplementation and prolongs the duration of postoperative analgesia without altering the other characteristics of block. The neonatal outcome is not affected with addition of fentanyl before delivery of baby. PMID- 25511215 TI - Pediatric meningiomas an aggressive subset: a clinicopathological and immunohistochemical study. AB - BACKGROUND: Meningiomas are uncommon neoplasms in the pediatric age group and differ in various aspects from their adult counterparts. They account for 0.4 4.6% of all primary brain tumors. AIMS: To retrospectively analyze the clinicopathological and immunohistochemical features of pediatric meningiomas. MATERIALS AND METHODS: Meningiomas in patients under 18 years of age diagnosed between January 2001 to December 2011 were analyzed retrospectively. The hematoxylin and eosin stained sections and Ki 67 labelling index (LI) were reviewed for all the cases Results: The pediatric meningiomas accounted for 1.52% of total meningiomas (15/983). The mean age at presentation was 12 years with male to female ratio of 1.5:1. The presenting symptoms were headache, seizures, and motor deficits. The histology included 9 cases (60%) of atypical meningioma (WHO grade II) followed by 4 cases (26.67%) of WHO grade-I and 2 cases (13.33%) of anaplastic meningioma (WHO grade III). Five cases had a recurrence. Ki67 LI ranged from 0.5% to 1.5% in grade I, 0.5% to 15% in grade II and 13% to 24% in grade III meningiomas. CONCLUSION: Meningiomas are rare in children and show a male preponderance. There was a higher incidence of atypical and anaplastic meningiomas in pediatric population. PMID- 25511216 TI - Cervical spinal cord infarction associated with the use of oral contraceptives for the treatment of acne in a healthy young woman. PMID- 25511217 TI - Syndrome of remitting seronegative symmetrical synovitis with pitting edema: a case series. AB - Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE) is a rare clinical entity that is easily missed due to lack of knowledge. It was formerly considered as a subset of rheumatoid arthritis (RA), but is now regarded as a distinct disease/syndrome. The diagnosis of RS3PE is not easy, as it is always hindered by the lack of definite diagnostic criteria and presence of other much common rheumatological disorders that mimic it. We report a series of seven cases that attended our clinic in the last year, which highlight the salient features of the disease. The disease was found to have a heterogeneous presentation. Immunogenetic, clinical, laboratory, radiological, and possible etiological factors and associations with the neoplasm are described, as also other peculiar presentations. Finally, a comparison with other common rheumatological disorders is made to alert the clinician about this rare, but easily treatable disease. PMID- 25511218 TI - Postoperative pyoderma gangrenosum: a rare complication after appendectomy. AB - Pyoderma gangrenosum (PG) is an uncommon inflammatory ulcerative skin disease. It is characterized by painful progressive necrosis of the wound margins. Rarely, postoperative pyoderma gangrenosum (PPG) manifests as a severe disturbance of wound healing following surgical interventions. Only rare cases of this complication have been reported after appendectomy. We report a case of PPG in a 29-year-old female after appendectomy. She was successfully treated with oral prednisolone. Postoperative pyoderma gangrenosum should be kept in mind in the differential diagnosis of any postoperative delayed wound healing, because this disease is simply distinguished from a postoperative wound. PMID- 25511219 TI - Hemophagocytic lymphohistiocytosis secondary to Epstein Barr virus and Leishmania co-infection in a toddler. AB - This is the report of an EBV+Leishmanial co-infection. The patient developed hemophagocytic syndrome (HLH) and was treated with the standard HLH-2004 protocol. However, PCR in bone marrow discovered this secondary cause for HLH. In endemic countries, visceral leishmaniasis should be considered in the differential diagnosis even in EBV-related HLH, as chemotherapy toxicity may be avoided. PMID- 25511220 TI - Hyperimmunoglobulin syndrome due to CD40 deficiency: possibly the first case from India. AB - Hyperimmunoglobulin M (HIGM) type 3 due to CD40 deficiency is a very rare syndrome. Only 16 cases have been reported thus far. The clinical presentation is very variable. We present the first case of this rare disorder from India. The case is of a two-and-a-half-year-old female, with a history of repeated episodes of skin infections and diarrhea since birth. Laboratory evaluation revealed elevated absolute lymphocyte count and an absolute neutrophil count (ANC) of 1026/mm3. The lymphocyte subset analysis showed normal absolute counts of Natural Killer (NK) cells and elevated absolute counts of T-cells (CD4 and CD8) and B cells. The serum immunoglobulin estimation showed low levels of IgG, IgA, IgE and an elevated level of IgM. The CD154 analysis was normal and expression of CD40 was absent on the B-cells. Molecular analysis showed a novel mutation, with deletion of 3bp (AAG) [p.Glu107GlyfsX84] in the homozygous state, in the CD40 gene. Thus the patient was diagnosed as HIGM type 3. The parents were screened and counseled regarding prenatal diagnosis at the time of next pregnancy. PMID- 25511221 TI - A probable case of histoplasmosis presenting as portal hypertension and bone lesion in a case of common variable immunodeficiency syndrome. PMID- 25511222 TI - Diabetes plus third nerve palsy not always diabetic third nerve palsy. PMID- 25511223 TI - Diagnostic dilemma in a case of a leech in the upper aerodigestive tract. PMID- 25511224 TI - Transient memory steal: a rare phenomenon of subclavian steal syndrome. PMID- 25511225 TI - Extranodal follicular dendritic cell sarcoma: a frequently misdiagnosed entity. PMID- 25511226 TI - Use of visual aids in presenting study results. PMID- 25511227 TI - Combining pharmacological treatments in geriatric population: weighing the balance. PMID- 25511228 TI - Dr. Manu Liladhar Kothari (M.S., M.Sc.): 19 November 1935-16 October 2014. PMID- 25511230 TI - The pinnacle of world cricket--research that supports the game. PMID- 25511229 TI - Phosphate binders prevent phosphate-induced cellular senescence of vascular smooth muscle cells and vascular calcification in a modified, adenine-based uremic rat model. AB - Clinical and experimental studies have reported that phosphate overload plays a central role in the pathogenesis of vascular calcification in chronic kidney disease. However, it remains undetermined whether phosphate induces cellular senescence during vascular calcification. We established a modified uremic rat model induced by a diet containing 0.3% adenine that showed more slowly progressive kidney failure, more robust vascular calcification, and longer survival than the conventional model (0.75% adenine). To determine the effect of phosphate on senescence of vascular smooth muscle cells (VSMCs) and the protective effect of phosphate binders, rats were divided into four groups: (1) normal control rats; (2) rats fed with the modified adenine-based diet (CKD); (3) CKD rats treated with 6% lanthanum carbonate (CKD-LaC); and (4) CKD rats treated with 6% calcium carbonate (CKD-CaC). After 8 weeks, CKD rats showed circumferential arterial medial calcification, which was inhibited in CKD-LaC and CKD-CaC rats. CKD rats showed increased protein expression of senescence associated beta-galactosidase, bone-related proteins, p16 and p21, and increased oxidative stress levels in the calcified area, which were inhibited by both phosphate binders. However, serum levels of oxidative stress and inflammatory markers, serum fibroblast growth factor 23, and aortic calcium content in CKD-CaC rats were higher than those in CKD-LaC rats. In conclusion, phosphate induces cellular senescence of VSMCs in the modified uremic rat model, and phosphate binders can prevent both cellular senescence and calcification of VSMCs via phosphate unloading. Our modified adenine-based uremic rat model is useful for evaluating uremia-related complications, including vascular calcification. PMID- 25511231 TI - Distribution of radioactive cesium and stable cesium in cattle kept on a highly contaminated area of Fukushima nuclear accident. AB - Radioactivity inspection of slaughtered cattle is generally conducted using a portion of the neck muscle; however, there is limited information about the distribution of radioactive cesium in cattle. In this study, therefore, we measured not only radioactive cesium but also stable cesium in various tissues of 19 cattle that had been kept in the area highly contaminated by the Fukushima nuclear accident. Skeletal muscles showed approximately 1.5-3.0 times higher concentration of radioactive cesium than internal organs. Radioactive cesium concentration in the tenderloin and top round was about 1.2 times as high as that in the neck muscle. The kidney showed the highest concentration of radioactive cesium among internal organs, whereas the liver was lowest. Radioactive cesium concentration in the blood was about 8% of that in the neck muscle. Characteristics of stable cesium distribution were almost the same as those of radioactive cesium. Correlation coefficient between radioactive cesium and stable cesium in tissues of individual cattle was 0.981 +/- 0.012. When a suspicious level near 100 Bq/kg is detected in the neck of slaughtered cattle, re-inspection should be conducted using a different region of muscle, for example top round, to prevent marketing of beef that violates the Food Sanitation Act. PMID- 25511232 TI - Rhodium(III)-catalyzed cyclative capture approach to diverse 1-aminoindoline derivatives at room temperature. AB - A Rh(III) -catalyzed C-H activation/cyclative capture approach, involving a nucleophilic addition of C(sp(3) )-Rh species to polarized double bonds is reported. This constitutes the first intermolecular catalytic method to directly access 1-aminoindolines with a broad substituent scope under mild conditions. PMID- 25511233 TI - Evaluation of 2 multiplex real-time PCR assays for the detection of HSV-1/2 and Varicella zoster virus directly from clinical samples. AB - We compared the performance of 2 multiplex assays (Focus Simplexa and Quidel Lyra) to individual real-time PCR for the detection of herpes simplex virus-1 (HSV-1), HSV-2, and Varicella zoster virus (VZV) from clinical specimens. Results were compared to a consensus standard, defined as the result obtained by at least 2 of the 3 molecular methods. The sensitivity of the Quidel assay ranged from 92.0% for HSV-1 to 97.7% for HSV-2, while the specificity for all targets was 100%. The Focus assay demonstrated 100% sensitivity for all targets, and the percent specificity ranged from 96.8% for HSV-1 to 100% for HSV-2 and VZV. PMID- 25511234 TI - Raynaud's phenomenon associated with Fabry disease. PMID- 25511235 TI - Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: urinary organic acid profiles and expanded spectrum of mutations. AB - Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase (HMCS2) deficiency results in episodes of hypoglycemia and increases in fatty acid metabolites. Metabolite abnormalities described to date in HMCS2 deficiency are nonspecific and overlap with other inborn errors of metabolism, making the biochemical diagnosis of HMCS2 deficiency difficult. Urinary organic acid profiles from periods of metabolic decompensation were studied in detail in HMCS2-deficient patients from four families. An additional six unrelated patients were identified from clinical presentation and/or qualitative identification of abnormal organic acids. The diagnosis was confirmed by sequencing and deletion/duplication analysis of the HMGCS2 gene. Seven related novel organic acids were identified in urine profiles. Five of them (3,5-dihydroxyhexanoic 1,5 lactone; trans-5-hydroxyhex-2-enoate; 4 hydroxy-6-methyl-2-pyrone; 5-hydroxy-3-ketohexanoate; 3,5-dihydroxyhexanoate) were identified by comparison with synthesized or commercial authentic compounds. We provisionally identified trans-3-hydroxyhex-4-enoate and 3-hydroxy-5 ketohexanoate by their mass spectral characteristics. These metabolites were found in samples taken during periods of decompensation and normalized when patients recovered. When cutoffs of adipic >200 and 4-hydroxy-6-methyl-2-pyrone >20 MUmol/mmol creatinine were applied, all eight samples taken from five HMCS2 deficient patients during episodes of decompensation were flagged with a positive predictive value of 80% (95% confidence interval 35-100%). Some ketotic patients had increased 4-hydroxy-6-methyl-2-pyrone. Molecular studies identified a total of 12 novel mutations, including a large deletion of HMGCS2 exon 1 in two families, highlighting the need to perform quantitative gene analyses. There are now 26 known HMGCS2 mutations, which are reviewed in the text. 4-Hydroxy-6-methyl 2-pyrone and related metabolites are markers for HMCS2 deficiency. Detection of these metabolites will streamline the biochemical diagnosis of this disorder. PMID- 25511236 TI - Long-term outcomes associated with the transaortic approach to transcatheter Aortic valve replacement. AB - OBJECTIVE: We investigated the long-term safety, efficacy and clinical outcomes associated with transaortic (TAO) transcatheter aortic valve replacement (TAVR) in the United States. BACKGROUND: We previously reported the technical feasibility and short-term safety of TAO TAVR. Compared to transapical (TAP) access, the TAO approach was associated with shorter median intensive care unit (ICU) length of stay (LOS) and more favorable technical learning curve. However, outcomes data beyond 30 days were lacking and the longer-term clinical consequences of this strategy were unknown. METHODS: Mortality outcomes at 1 year (and longer) of 44 consecutive patients who underwent TAO TAVR in our institution were compared with that of 76 consecutive patients who underwent TAP TAVR at our site. Risk-adjusted analysis was performed in propensity-matched patients (25 from each group) to account for baseline differences. RESULTS: TAO TAVR was associated with a trend towards lower all-cause mortality at 1 year compared to TAP TAVR (18% vs. 34%, P=0.09 in the overall sample; 12% vs. 40%, P=0.05 in the matched cohort). The higher probability of survival with TAO TAVR persisted after a median follow-up period of 23 months (hazard ratio [HR]=1.96, P=0.06 in the overall sample; HR=3.4, P=0.01 in the matched cohort). Cardiovascular mortality at 1 year was lower with TAO TAVR (2% vs. 22%, P=0.01 in the overall sample; 4% vs. 28%, P=0.05 in the matched cohort). ICU LOS (shorter in the TAO group) and implantation of second prosthetic valve (higher incidence in the TAP group) were independent predictors of long-term mortality. CONCLUSION: The outcomes associated with TAO TAVR compare favorably with TAP TAVR. Our results appear to corroborate the long-term safety and efficacy of the TAO approach in TAVR patients with inadequate iliofemoral access. PMID- 25511237 TI - Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunction in rodents. AB - The Ankrd1 (ankyrin repeat domain 1) gene is known to be up-regulated in heart failure and acts as a co-activator of p53, modulating its transcriptional activity, but it remains inconclusive whether this gene promotes or inhibits cell apoptosis. In the present study, we attempted to investigate the role of Ankrd1 on AngII (angiotensin II)- or pressure-overload-induced cardiomyocyte apoptosis. In the failing hearts of mice with pressure overload, the protein expression of Ankrd1-encoded CARP (cardiac ankyrin repeat protein) was significantly increased. In NRCs (neonatal rat cardiomyocytes), AngII increased the expression of Ankrd1 and CARP. In the presence of AngII in NRCs, infection with a recombinant adenovirus containing rat Ankrd1 cDNA (Ad-Ankrd1) enhanced the mitochondrial translocation of Bax and phosphorylated p53, increased mitochondrial permeability and cardiomyocyte apoptosis, and reduced cell viability, whereas these effects were antagonized by silencing of Ankrd1. Intra-myocardial injection of Ad-Ankrd1 in mice with TAC (transverse aortic constriction) markedly exacerbated cardiac dysfunction with an increase in the lung weight/body weight ratio and a decrease in left ventricular fractional shortening. Cardiomyocyte apoptosis and the expression of phosphorylated p53 were also significantly increased in Ad-Ankrd1 infected TAC mice, whereas knockdown of Ankrd1 significantly inhibited the apoptotic signal pathway as well as cardiomyocyte apoptosis in pressure-overload mice. These findings indicate that overexpression of Ankrd1 exacerbates pathological cardiac dysfunction through enhancement of cardiomyocyte apoptosis mediated by the up-regulation of p53. PMID- 25511238 TI - Estimating systemic exposure to ethinyl estradiol from an oral contraceptive. AB - OBJECTIVE: This study was conducted to compare single-dose pharmacokinetics of ethinyl estradiol in an oral contraceptive with steady-state values and to assess whether any simpler measures could provide an adequate proxy of the "gold standard" 24-hour steady-state area under the curve (AUC) value. Identification of a simple, less expensive measure of systemic ethinyl estradiol exposure would be useful for larger studies that are designed to assess the relationship between an individual's ethinyl estradiol exposure and side-effects. STUDY DESIGN: We collected 13 samples over 24 hours for pharmacokinetic analysis on days 1 and 21 of the first cycle of a monophasic oral contraceptive that contained 30 MUg ethinyl estradiol and 150 MUg levonorgestrel in 17 nonobese healthy white women. We also conducted an abbreviated single-dose 9-sample pharmacokinetic analysis after a month washout. Ethinyl estradiol was measured by liquid chromatography tandem mass spectrometry. We compared results of a full 13-sample steady-state pharmacokinetic analysis with results that had been calculated with the use of fewer samples (9 or 5) and after the single doses. We calculated Pearson correlation coefficients to evaluate the relationships between these estimates of systemic ethinyl estradiol exposure. RESULTS: The AUC, maximum, and 24-hour values were similar after the 2 single oral contraceptive doses (AUC; r=0.92). The steady-state 13-sample 24-hour AUC value was correlated highly with the average 9-sample AUC value after the 2 single doses (r=0.81; P=.0002). This correlation remained the same if the number of single-dose samples was reduced to 4, taken at time 1, 2.5, 4, and 24 hours. The 24-hour value at steady-state was correlated highly with the 24-hour steady-state AUC value (r=0.92; P<.0001). The average of the 24-hour values after the 2 single doses was also correlated quite highly with the steady-state AUC value (r=0.72; P=.0026). CONCLUSION: Limited blood sampling, including results from 2 single doses, gave highly correlated estimates of an oral contraceptive user's steady-state ethinyl estradiol exposure. PMID- 25511239 TI - Risk of venous thromboembolism in abdominal versus minimally invasive hysterectomy for benign conditions. AB - OBJECTIVE: We sought to describe the incidence of venous thromboembolism (VTE) following hysterectomy for benign conditions and to estimate if VTE incidence differs for abdominal and minimally invasive hysterectomy. STUDY DESIGN: Data for patients who underwent hysterectomy for benign conditions from 2010 through 2012 were abstracted from the American College of Surgeons National Surgical Quality Improvement Program database. Cases of VTE were compared to those without VTE. Minimally invasive hysterectomy was defined as both vaginal and laparoscopic hysterectomy. Pearson chi2 test, Student t test, and binary logistic regression were used for analysis. RESULTS: A total of 44,167 patients underwent hysterectomy; 12,733 (28.8%) underwent open hysterectomy, 22,559 (51.1%) underwent laparoscopic hysterectomy, and 8875 (20.1%) underwent vaginal hysterectomy. The incidence of VTE for open hysterectomy was higher (0.6%, 81/12,733) than minimally invasive hysterectomy (0.2% 73/31,434, P<.001). Open surgery (P<.001), body mass index (P=.006), race (P<.001), diabetes (P=.037), preoperative functional status (P<.001), American Society of Anesthesiologists class (P<.001), total operative time (P<.001), and time from surgery to discharge (P<.001) were each associated with VTE. Age, hypertension, current smoking, pack year history, and year operation was performed were not associated with VTE. Using binary logistic regression, open surgery (P<.001), operative time (P<.001), and length of stay (P<.001) remained associated with VTE. The odds ratio for VTE after open hysterectomy compared with minimally invasive hysterectomy was 2.45 (95% confidence interval, 1.77-3.40). CONCLUSION: In this large quality database, a minimally invasive approach to hysterectomy was independently associated with a decreased incidence of VTE when compared with open hysterectomy. PMID- 25511240 TI - Can the practice of nonclosure of visceral and parietal peritoneum during cesarean delivery be justified? PMID- 25511242 TI - Can the practice of nonclosure of visceral and parietal peritoneum during cesarean delivery be justified? Reply. PMID- 25511241 TI - Contraception and mental health: a commentary on the evidence and principles for practice. AB - Among the most prevalent and disabling chronic diseases affecting reproductive aged women worldwide, depression and anxiety can contribute to adverse reproductive health outcomes, including an increased risk of unintended pregnancy and its health and social consequences. For women with these common mental health conditions who want to avoid an unintended pregnancy, effective contraception can be an important strategy to maintain and even improve health and well-being. Reproductive health clinicians play a critical role in providing and managing contraception to help women with mental health considerations achieve their desired fertility. In this commentary, we review the literature on relationships between mental health and contraception and describe considerations for the clinical management of contraception among women with depression and anxiety. We discuss issues related to contraceptive method effectiveness and adherence concerns, mental health-specific contraceptive method safety and drug interaction considerations, and clinical counseling and management strategies. Given important gaps in current scientific knowledge of mental health and contraception, we highlight areas for future research. PMID- 25511243 TI - Why the United States preterm birth rate is declining. AB - The preterm birth rate in the United States declined to 11.4% in 2013, the lowest level since 1997. Although the United States has one of the highest preterm birth rates in the developed world, we are improving this outcome and therefore improving the lives of thousands of infants. Demographic changes that may be responsible include a reduced teenage birth rate and fewer higher-order multiple births. Additionally, a public policy shift to prevent nonmedically indicated births at <39 weeks' gestation and smoking bans in several states have been associated with the reduced rate of preterm births. Last, interventions such as 17 hydroxyprogesterone caproate, vaginal progesterone, and the use of cerclage in selected populations probably are contributing to the reduction in preterm deliveries. However, a large portion of these births could still be prevented with greater access and implementation of our current interventions, the reduction of modifiable risk factors for preterm birth, and expanded reporting of outcomes and risk factors to facilitate research for both prevention and treatment. PMID- 25511245 TI - Genital ulcer as a new clinical clue to PFAPA syndrome. AB - Vaginal ulcers can be associated with a number of different diseases. We describe two girls who presented genital ulcers as a persistent symptom of PFAPA (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis) syndrome. The possibility of considering this clinical manifestation as a clue for the diagnosis of PFAPA is discussed. PMID- 25511244 TI - Fall predictors in older cancer patients: a multicenter prospective study. AB - BACKGROUND: In the older population falls are a common problem and a major cause of morbidity, mortality and functional decline. The etiology is often multifactorial making the identification of fall predictors essential for preventive measures. Despite this knowledge, data on falls within the older cancer population are limited. The objective of this study was to evaluate the occurrence of falls within 2 to 3 months after cancer treatment decision and to identify predictors of falls (>=1 fall) during follow-up. METHODS: Older patients (70 years or more) with a cancer treatment decision were included. At baseline, all patients underwent geriatric screening (G8 and Flemish Triage Risk Screening Tool), followed by a geriatric assessment including living situation, activities of daily living (ADL), instrumental activities of daily living (IADL), fall history in the past 12 months, fatigue, cognition, depression, nutrition, comorbidities and polypharmacy. Questionnaires were used to collect follow-up (2 3 months) data. Univariate and multivariate analyses were performed to identify predictors for falls (>=1 fall) during follow-up. RESULTS: At baseline, 295 (31.5%) of 937 included patients reported at least one fall in the past 12 months with 88 patients (29.5%) sustaining a major injury. During follow-up (2-3 months), 142 (17.6%) patients fell, of whom 51.4% fell recurrently and 17.6% reported a major injury. Baseline fall history in the past 12 months (OR = 3.926), fatigue (OR = 0.380), ADL dependency (OR = 0.492), geriatric risk profile by G8 (OR = 0.471) and living alone (OR = 1.631) were independent predictors of falls (>=1 fall) within 2-3 months after cancer treatment decision. CONCLUSION: Falls are a serious problem among older cancer patients. Geriatric screening and assessment data can identify patients at risk for a fall. A patient with risk factors associated with falls should undergo further evaluation and intervention to prevent potentially injurious fall incidents. PMID- 25511246 TI - Demonstration of a folding after binding mechanism in the recognition between the measles virus NTAIL and X domains. AB - In the past decade, a wealth of experimental data has demonstrated that a large fraction of proteins, while functional, are intrinsically disordered at physiological conditions. Many intrinsically disordered proteins (IDPs) undergo a disorder-to-order transition upon binding to their biological targets, a phenomenon known as induced folding. Induced folding may occur through two extreme mechanisms, namely conformational selection and folding after binding. Although the pre-existence of ordered structures in IDPs is a prerequisite for conformational selection, it does not necessarily commit to this latter mechanism, and kinetic studies are needed to discriminate between the two possible scenarios. So far, relatively few studies have addressed this issue from an experimental perspective. Here, we analyze the interaction kinetics between the intrinsically disordered C-terminal domain of the measles virus nucleoprotein (NTAIL) and the X domain (XD) of the viral phosphoprotein. Data reveal that NTAIL recognizes XD by first forming a weak encounter complex in a disordered conformation, which is subsequently locked-in by a folding step; i.e., binding precedes folding. The implications of our kinetic results, in the context of previously reported equilibrium data, are discussed. These results contribute to enhancing our understanding of the molecular mechanisms by which IDPs recognize their partners and represent a paradigmatic example of the need of kinetic methods to discriminate between reaction mechanisms. PMID- 25511250 TI - Supervised exercise reduces cancer-related fatigue: a systematic review. AB - QUESTION: Does supervised physical activity reduce cancer-related fatigue? DESIGN: Systematic review with meta-analysis of randomised trials. PARTICIPANTS: People diagnosed with any type of cancer, without restriction to a particular stage of diagnosis or treatment. INTERVENTION: Supervised physical activity interventions (eg, aerobic, resistance and stretching exercise), defined as any planned or structured body movement causing an increase in energy expenditure, designed to maintain or enhance health-related outcomes, and performed with systematic frequency, intensity and duration. OUTCOME MEASURES: The primary outcome measure was fatigue. Secondary outcomes were physical and functional wellbeing assessed using the Functional Assessment of Cancer Therapy Fatigue Scale, European Organisation for Research and Treatment of Cancer Quality of Life QUESTIONnaire, Piper Fatigue Scale, Schwartz Cancer Fatigue Scale and the Multidimensional Fatigue Inventory. Methodological quality, including risk of bias of the studies, was evaluated using the PEDro Scale. RESULTS: Eleven studies involving 1530 participants were included in the review. The assessment of quality showed a mean score of 6.5 (SD 1.1), indicating a low overall risk of bias. The pooled effect on fatigue, calculated as a standardised mean difference (SMD) using a random-effects model, was -1.69 (95% CI -2.99 to -0.39). Beneficial reductions in fatigue were also found with combined aerobic and resistance training with supervision (SMD=-0.41, 95% CI -0.70 to -0.13) and with combined aerobic, resistance and stretching training with supervision (SMD=-0.67, 95% CI 1.17 to -0.17). CONCLUSION: Supervised physical activity interventions reduce cancer-related fatigue. These findings suggest that combined aerobic and resistance exercise regimens with or without stretching should be included as part of rehabilitation programs for people who have been diagnosed with cancer. REGISTRATION: PROSPERO CRD42013005803. PMID- 25511252 TI - Genetic and antigenic analysis of foot-and-mouth disease virus serotype O responsible for outbreaks in India during 2013. AB - In recent times, majority of the foot-and-mouth disease (FMD) outbreaks in India are caused by serotype O Ind2001 lineage. The lineage has diverged into four sub lineages (Ind2001a, b, c and d). We report here the genetic and antigenic analyses of nine Ind2001d isolates that caused outbreaks during April 2013-March 2014 in India. The length of the genomes of outbreak viruses varied between 8153 and 8181 nucleotides without any insertion or deletion in the coding region. Of the nine isolates analyzed antigenically against the currently used Indian vaccine strain INDR2/1975, eight showed good cross serological match (>0.3) indicating optimal antigenic coverage by the vaccine strain. An unprecedented deletion of 22 nucleotides between position 57 and 78 was observed in the 3' untranslated region of one of the isolates without compromising the virus viability, which imply that partial distortion in SL2 of 3'UTR may not have influence on virus viability at least under in-vitro conditions. Recently the Ind2001 lineage has been reported from several countries including Libya and spread of this lineage across a wide geographical area needs to be monitored carefully to avoid any future pandemic. PMID- 25511251 TI - Phylogenetic analysis of environmental Legionella pneumophila isolates from an endemic area (Alcoy, Spain). AB - Environmental surveillance of Legionella pneumophila is a key component of the control measures established in urban settlements to ensure water safety and quality, with the aim of minimizing and limiting opportunistic infections in humans. In this work, we present results on the detection and genetic characterization of these bacteria in the outbreak-recurrent region of Alcoy (Comunidad Valenciana, Spain) using water and biofilm samples. We were particularly interested in studying the presence and distribution of L. pneumophila in the absence of outbreak or sporadic cases of legionellosis and in comparing the efficacy of culturing from water samples with a biofilm-based detection procedure using molecular amplification. To this end, water samples were taken from 120 sites distributed all around the city and its surroundings, as well as 60 biofilm swabs from half of the sampling sites. L. pneumophila could be isolated from water in just 4 of the locations. Touchdown PCR was applied to DNA extracted from water and also biofilm swabs, as a rapid method for both routine and outbreak investigations. L. pneumophila was detected by this method in 14 of the sites in which both water and biofilms were taken, although 13 of them tested positive using only the biofilm samples. These results show a ten fold increase in the success rate of Legionella detection over water samples. The application of this method to study the presence of L. pneumophila in the water supply system and risk facilities of Alcoy revealed different strains distributed in different areas of the city. Sequence Type ST578, endemic in the area and responsible for most clinical cases, was detected in one of the sampling sites. The number of positive samples correlated with water temperature but not with chlorine levels. The direct analysis of biofilm swabs improves the detection rate and genetic characterization of L. pneumophila and can complement analyses based on bacterial culture. PMID- 25511253 TI - Rhenium and technetium tricarbonyl, {M(CO)3} (+) (M = Tc, Re), binding to mammalian metallothioneins: new insights into chemical and radiopharmaceutical implications. AB - This paper deals with the binding of the four mammalian metallothioneins (MTs) to the organometallic metal fragment {fac-M(CO)3}(+) (M = (99)Tc, Re), which is highly promising for the preparation of second-generation radiopharmaceuticals. The study of the transmetallation reaction between zinc and rhenium in Zn7-MT1 by means of UV-vis and CD spectroscopy demonstrated the incorporation of the {fac Re(CO)3}(+) fragment to the MTs. This reaction should be performed at 70 degrees C to accelerate the reaction rate, a result that is consistent with the reported reactivity of the rhenium fragment. ESI-TOF MS demonstrated the formation of mixed-metal species as Zn6,{Re(CO)3}-MT, Zn6,{Re(CO)3}2-MT, and Zn5,{Re(CO)3}3 MT, as well as the different reactivity of the four MT isoforms. Hence, Zn-MT3 showed the highest reactivity, in agreement with its high Cu-thionein character, whereas Zn-MT2 exhibited the lowest reactivity, in line with its high Zn-thionein character. The reactivity of the Zn-loaded forms of MT1 and MT4 is intermediate between those of MT3 and MT2. The study of the binding of the {fac (99)Tc(CO)3}(+) fragment to MTs showed a significant and very interesting different reactivity in relation to rhenium. The transmetallation reaction is much more effective with technetium than with rhenium and significant amounts of mixed Zn x ,{(99)Tc(CO)3} y -MT species were formed with the four MT isoforms whereas only MT3 rendered similar amounts of rhenium derivatives. The results obtained in this study support the possible use of technetium for labelling mammalian metallothioneins and also for possible radiopharmaceutical applications. PMID- 25511254 TI - Protonophore properties of hyperforin are essential for its pharmacological activity. AB - Hyperforin is a pharmacologically active component of the medicinal plant Hypericum perforatum (St. John's wort), recommended as a treatment for a range of ailments including mild to moderate depression. Part of its action has been attributed to TRPC6 channel activation. We found that hyperforin induces TRPC6 independent H(+) currents in HEK-293 cells, cortical microglia, chromaffin cells and lipid bilayers. The latter demonstrates that hyperforin itself acts as a protonophore. The protonophore activity of hyperforin causes cytosolic acidification, which strongly depends on the holding potential, and which fuels the plasma membrane sodium-proton exchanger. Thereby the free intracellular sodium concentration increases and the neurotransmitter uptake by Na(+) cotransport is inhibited. Additionally, hyperforin depletes and reduces loading of large dense core vesicles in chromaffin cells, which requires a pH gradient in order to accumulate monoamines. In summary the pharmacological actions of the "herbal Prozac" hyperforin are essentially determined by its protonophore properties shown here. PMID- 25511255 TI - Iron, copper, and manganese complexes with in vitro superoxide dismutase and/or catalase activities that keep Saccharomyces cerevisiae cells alive under severe oxidative stress. AB - Due to their aerobic lifestyle, eukaryotic organisms have evolved different strategies to overcome oxidative stress. The recruitment of some specific metalloenzymes such as superoxide dismutases (SODs) and catalases (CATs) is of great importance for eliminating harmful reactive oxygen species (hydrogen peroxide and superoxide anion). Using the ligand HPClNOL {1-[bis(pyridin-2 ylmethyl)amino]-3-chloropropan-2-ol}, we have synthesized three coordination compounds containing iron(III), copper(II), and manganese(II) ions, which are also present in the active site of the above-noted metalloenzymes. These compounds were evaluated as SOD and CAT mimetics. The manganese and iron compounds showed both SOD and CAT activities, while copper showed only SOD activity. The copper and manganese in vitro SOD activities are very similar (IC50~0.4 MUmol dm(-3)) and about 70-fold higher than those of iron. The manganese compound showed CAT activity higher than that of the iron species. Analyzing their capacity to protect Saccharomyces cerevisiae cells against oxidative stress (H2O2 and the O2(*-) radical), we observed that all compounds act as antioxidants, increasing the resistance of yeast cells mainly due to a reduction of lipid oxidation. Especially for the iron compound, the data indicate complete protection when wild-type cells were exposed to H2O2 or O2(*-) species. Interestingly, these compounds also compensate for both superoxide dismutase and catalase deficiencies; their antioxidant activity is metal ion dependent, in the order iron(III)>copper(II)>manganese(II). The protection mechanism employed by the complexes proved to be independent of the activation of transcription factors (such as Yap1, Hsf1, Msn2/Msn4) and protein synthesis. There is no direct relation between the in vitro and the in vivo antioxidant activities. PMID- 25511256 TI - Observational cohort study on correlates of mortality in older community-dwelling outpatients: The value of functional assessment. AB - AIM: To analyze correlates of mortality with admission features/factors in older community-dwelling outpatients. METHOD: This is an observational cohort study including 608 patients aged >60 years admitted to the geriatrics outpatient clinics of a university hospital. On admission, demographic characteristics, history of smoking-alcohol consumption, individual comorbidities, individual drugs, number of comorbidities, number of drugs and the components of comprehensive geriatric assessment (functional status, nutritional status, depression and cognition screening) of the patients were recorded. Survival status was assessed through the related official website. The relationship between mortality and recorded parameters were analyzed individually by univariate analyses. Consequently, stepwise forward Cox regression analysis was carried out to detect independent correlates for mortality (for those variables statistically significantly related to mortality.) RESULTS: The mean age was 73.8 +/- 6.9 years. 66.6% of participants were female. The mean follow-up time was 40.4 +/- 25.3 months. The mortality rate was 17.8%. Correlates of mortality were calculated using univariate analysis. They were age, sex, nutritional status, activities of daily living (ADL), instrumental ADL, diabetes mellitus (P < 0.001 for all), suspected dementia (P = 0.002), hyperlipidemia (P = 0.048) and total number of diseases (P = 0.025). Independent correlates of mortality were advanced age (HR 1.10, 95% CI 1.06-1.13; P < 0.001, low ADL score (HR 1.22, 95% CI 1.12 1.32; P < 0.001), the presence of diabetes (HR 2.64, 95% CI 1.78-3.91, P < 0.001), male sex (HR 1.68, 95% CI 1.13-2.49; P = 0.01) and suspected dementia (HR 1.51, 95% CI 1.02-2.22; P < 0.05). CONCLUSION: In the present study--taking many factors into consideration--the variables associated with mortality were advanced age, low ADL score, presence of diabetes, male sex and suspected dementia. Functional status emerged as the second most significant factor associated with higher mortality--after advanced age. The present study highlights the importance of functional assessment in geriatric outpatient clinics. PMID- 25511258 TI - Coping with change: a framework for environmental signals and how neuroendocrine pathways might respond. AB - The Earth has always been a changeable place but now warming trends shift seasons and storms occur with greater frequency, intensity and duration. This has prompted reference to the modern era as the Anthropocene caused by human activity. This era poses great challenges for all life on earth and important questions include why and how some organisms can cope and others cannot? It is of heuristic value to consider a framework for types of environmental signals and how they might act. This is especially important as predictable changes of the environment (seasonality) are shifting rapidly as well as unpredictable changes (perturbations) in novel ways. What we need to know is how organisms perceive their environment, transduce that information into neuroendocrine signals that orchestrate morphological, physiological and behavioral responses. Given these goals we can begin to address the questions: do neuroendocrine systems have sufficient flexibility to acclimate to significant change in phenology, are genetic changes leading to adaptation necessary, or both? PMID- 25511259 TI - Educational attainment and life expectancy: a perspective from the NIH Office of Behavioral and Social Sciences Research. AB - The NIH Office of Behavioral and Social Sciences Research (OBSSR) furthers the mission of the NIH by stimulating behavioral and social sciences research throughout NIH and integrating these areas of research more fully into the NIH health research enterprise, thereby improving our understanding, treatment, and prevention of disease. OBSSR accomplishes this mission through several strategic priorities: (1) supporting the next generation of basic behavioral and social sciences research, (2) facilitating interdisciplinary research, (3) promoting a multi-level systems perspective of health and behavior, and (4) encouraging a problem-focused perspective on population health. PMID- 25511257 TI - Seasonal control of gonadotropin-inhibitory hormone (GnIH) in birds and mammals. AB - Animals inhabiting temperate and boreal latitudes experience marked seasonal changes in the quality of their environments and maximize reproductive success by phasing breeding activities with the most favorable time of year. Whereas the specific mechanisms driving seasonal changes in reproductive function vary across species, converging lines of evidence suggest gonadotropin-inhibitory hormone (GnIH) serves as a key component of the neuroendocrine circuitry driving seasonal changes in reproduction and sexual motivation in some species. In addition to anticipating environmental change through transduction of photoperiodic information and modifying reproductive state accordingly, GnIH is also positioned to regulate acute changes in reproductive status should unpredictable conditions manifest throughout the year. The present overview summarizes the role of GnIH in avian and mammalian seasonal breeding while considering the similarities and disparities that have emerged from broad investigations across reproductively photoperiodic species. PMID- 25511262 TI - [Effect of lead-exposed astrocytes on neuronal synaptic formation]. AB - OBJECTIVE: To investigate the effect of lead-exposed astrocyte conditioned medium (ACM) on the synaptic formation of neurons and to provide reference for the mechanism of lead neurotoxicity. METHODS: Astrocytes were cultured in the medium containing 50, 100, 200, 400, and 800 umol/L lead acetate for 72 h. Alamar Blue was used to assess the cell viability of astrocytes, and then ACM was collected. Primarily cultured neurons were divided into six groups: pure culture group, non glutamic acid (Glu)-induced ACM treatment group, Glu-induced lead-free ACM treatment group, and Glu-induced 50, 100, and 200 umol/L lead acetate-exposed ACM treatment groups. Neurons were collected after being cultured in ACM for 24, 48, or 72 h. The content of synaptophysin (SYP) in neurons was determined by Western blot. The SYP expression in neurons was measured by immunofluorescence after being cultured in ACMfor 72 h. RESULTS: In all lead-exposed groups, the cell viability of astrocytes declined with increasing concentration of lead (P < 0.05). The Western blot showed that compared with the pure culture group, the non Glu-induced ACM treatment group and Glu-induced lead- free ACM treatment group had significantly increased content of SYP in neurons (P < 0.01); compared with the non-Glu-induced ACM treatment group, the Glu-induced ACM treatment groups had significantly reduced SYP expression in neurons (P < 0.05); compared with the Glu induced lead-free ACM treatment group, all lead-exposed ACM treatment groups had the content of SYP in neurons significantly reduced with increasing concentration of lead after 72-h culture (P < 0.01), the 200 umol/L lead-exposed ACM treatment group had significantly reduced content of SYP in neurons after 48-h culture (P < 0.01), and all lead-exposed ACM treatment groups showed no significant changes in the content of SYP in neurons after 24-h culture. Double-labeling immunofluorescence of SYP showed that all lead-exposed ACM treatment groups had a significant decrease in the number of SYP-fluorescent particles after 72-h culture (P < 0.05). CONCLUSION: Astrocytes promote synaptic formation of neurons, which may be inhibited during lead exposure. PMID- 25511261 TI - Primary immunodeficiencies: a decade of shifting paradigms, the current status and the emergence of cutting-edge therapies and diagnostics. AB - A shift has occurred in the diagnostic and therapeutic modalities considered for patients with primary immunodeficiency diseases (PIDs). Early diagnosis remains the mainstay in appropriate management and remarkably influences the prognosis. More specific diagnostic tests as well as therapeutic modalities have been introduced in the last few decades. Nonetheless, the importance of a thorough history taking and physical examination should not be neglected. Novel diagnostic modalities including genetic sequencing have led to the recognition of previously unknown defects underlying PIDs. In addition, newborn screening is being advocated as an imperative diagnostic test. In terms of treatment, hematopoietic stem cell transplantation is considered the optimal treatment modality for many cases and has dramatically improved the outcome. Gene transfer into hematopoietic stem cells prior to transplantation has improved the efficacy of hematopoietic stem cell transplantation. In this article, the latest advances made in terms of diagnosis and treatment of PIDs are reviewed. PMID- 25511260 TI - Bu-zhong-yi-qi pill alleviate the chemotherapy-related fatigue in 4 T1 murine breast cancer model. AB - BACKGROUND: Paclitaxel induced fatigue still remains underrecognized and undertreated, partly because of limited understanding of its pathophysiology and lack of effective treatments. This study is aim to evaluate the anti-fatigue effects and mechanism of Bu-Zhong-Yi-Qi pill in murine 4 T1 breast cancer mice were treated with paclitaxel. METHODS: Breast cancer mice established with murine 4 T1 cells were randomly and repectively divided into five groups: negative control group (NC), tumor control group (TC), paclitaxel group (PTX), Bu-Zhong-Yi Qi pill group (BZYQ) and Bu-Zhong-Yi-Qi pill plus paclitaxel group (BZYQ + PTX). The mice were administered for 21 days. During this period, the tumor volume, body weight and the weight-loaded swimming time were measured. After the last administration, all mice were sacrificed, weighted the tumor, measured immune cell cytokines and oxidative stress indicator. The remaining 10 mice in each group were observed for survival analysis. RESULTS: Treatments with BZYQ + PTX and PTX significantly reduced the rates of tumor volume in comparison with TC starting on the 9th day and the 18th day respectively (P < 0.05-0.01), and presented decreased tumor weight compared to TC (P < 0.05-0.01). Compared with mice in TC group, the median survival time and the average survival time in BZYQ + PTX group, BZYQ group and PTX group were significantly prolonged (P < 0.05 0.01). The swimming time of the BZYQ + PTX group gradually increased, which is longer than the PTX group on Day 14 and Day 21 (P < 0.01). The level of TNF-alpha was lower in BZYQ + PTX group than PTX group (P < 0.01). The level of SOD activity in BZYQ + PTX group was lower than the NC group (P <0.01), but much higher than the PTX group (P < 0.01). The level of MDA of BZYQ + PTX group was higher than the NC group (P < 0.01), but significant lower than the PTX group (P < 0.01). CONCLUSIONS: BZYQ has the potential of alleviating paclitaxel chemotherapy-related fatigue in 4 T1 breast cancer mice by reducing the serum levels of TNF-alpha and modulating the level of MDA and the SOD activity. PMID- 25511263 TI - [Effect of melatonin on p38MAPKsignaling pathway in rats with phosgene-induced lung injury]. AB - OBJECTIVE: To investigate the effect of melatonin (MT) on p38 mitogen-activated protein kinase (MAPK) signaling pathway in rats with phosgene-induced lung injury. METHODS: Fifty specific pathogen-free male Sprague-Dawley rats were randomly divided into phosgene inhalation group, air control group, saline control group, MT treatment group, and SB203580 (specific inhibitor of p38 MAPK) group, with 10 mice in each group. All groups except the air control group were exposed to phosgene, and the animals were sacrificed 6 h later. Lung wet/dry weight (W/D) ratio and the content of malondialdehyde (MDA) and nitric oxide (NO) and activity of myeloperoxidase (MPO) in bronchoalveolar lavage fluid (BALF) were measured. The qualitative and quantitative expression of p38 MAPK and phospho-p38 MAPK (p-p38) was measured by immunohistochemistry (IHC) and Western blot, respectively. Inducible nitric oxide synthase (iNOS) level in lung tissue was determined by Western blot. RESULTS: Compared with the air control group, the phosgene inhalation group had significantly increased lung W/D ratio and neutrophil count in BALF (P < 0.01); the MT treatment group had significantly lower neutrophil count and lung W/D ratio than the phosgene inhalation group (P < 0.05). IHC demonstrated that the air control group had relatively weak expression of p-p38 in lung tissue; the expression of p-p38 was significantly up-regulated after phosgene inhalation, and it was mainly distributed in infiltrating inflammatory cells and vascular endothelial cells, positive in the cytoplasm and nucleus of many cells. The distribution of p-p38-positive cells in the MT treatment and SB203580 groups was similar to that in the phosgene inhalation group, but the MT treatment and SB203580 groups had a significantly reduced number of cells with p-p38-positive nuclei and a significantly reduced intensity of p-p38 expression signals. The phosgene inhalation group had significantly increased content of MDA and NO and activity of MPO compared with the air control group (P < 0.01); the MT treatment and SB203580 groups had significantly reduced content of MDA and NO and activity of MPO compared with the phosgene inhalation group (P < 0.05), but had higher content of MDA and NO and activity of MPO than the air control group. The Western blot showed that the phosgene inhalation group had significantly increased expression of iNOS and p-p38 compared with the air control group (P < 0.01); the MT treatment and SB203580 groups had lower expression of iNOS and p-p38 than the phosgene inhalation group (P < 0.05). CONCLUSION: MT and SB203580 have a significant protective effect in rats with phosgene-induced lung injury, and the mechanism may be associated with scavenging free radicals and inhibiting activation of p38 MAPK and expression of iNOS. PMID- 25511264 TI - [Effects of adenovirus-delivered angiopoietin-1 siRNA on expression of matrix metalloproteinases in rats with acute lung injury induced by phosgene]. AB - OBJECTIVE: To investigate the effects of adenovirus-delivered angiopoietin-1 siRNA (Ad. Ang-1siRNA) on the expression of matrix metalloproteinase-2, 9 (MMP-2, 9) and tissue inhibitor of metallopro-teinase-1 (TIMP-1) in rats with acute lung injury (ALI) induced by phosgene (Psg). METHODS: We first established a rat model of Psg-induced acute lung injury (ALI). The rats were randomly divided into 6 groups: air control group with exposure to air, air+adenovirus (air+Ad) group with caudal vein injection of 1*10(8) pfu/ml adenovirus 1 h after air exposure, air+Ad/Ang1 group with caudal vein injection of 1*10(8) pfu/ml Ad.Ang-1siRNA 1 h after air exposure, Psg group with exposure to 8.33 mg/L Psg (purity 100%, of the same volume as the inhaled air in the air control group) for 5 min, Psg+Ad group with caudal vein injection of 1*10(8) pfu/ml adenovirus 1 h after exposure to the same dose of Psg, and Psg+Ad/Ang1 group with caudal vein injection of 1*10(8) pfu/ml Ad.Ang-1siRNA 1 h after exposure to the same dose of Psg. Serum, bronchoalveolar lavage fluid (BALF), and lung tissue were collected 36 h after exposure. The protein expression of Ang-1, MMP-2, 9, and TIMP-1 in serum and BALF was determined by double-antibody sandwich ELISA. RT-PCR was used to determine the mRNA levels of Ang-1, MMP-2, 9, and TIMP-1 in lung tissue. The protein expression of MMP-2, 9 and TIMP-1 in lung tissue was determined by Western blot. RESULTS: A rat model of Psg-induced ALI was successfully established. The levels of MMP-2, 9 in serum, BALF, and lung tissue were significantly increased in the Psg group and Psg+Ad/Ang1 group as compared with the control group (P<0.01); no significant change was observed in serum TIMP-1 protein expression (P>0.05); interestingly, TIMP-1 protein expression in BALF and lung tissue was significantly increased (P<0.01). Compared with the Psg group, the Psg+Ad/Ang1 group showed a significant decrease in MMP-2, 9 expression in BALF, serum, and lung tissue (P<0.05), but no significant change in protein expression of TIMP-1 was discovered (P>0.05). CONCLUSION: Ad.Ang-1siRNA has a potential beneficial effect in rats with Psg-induced ALI through inhibition of MMP-2, 9 expression, but has no significant effect on the expression of TIMP-1. PMID- 25511266 TI - [Roles of cytochrome c, caspase-9, and caspase-3 in pentavalent vanadium-induced neuronal apoptosis]. AB - OBJECTIVE: To investigate the roles of cytochrome c (Cyt-c), caspase-9, and caspase-3 in pentavalent vanadium-induced neuronal apoptosis and to provide a basis for mechanism research. METHODS: Neurons from rats aged 1-3 days were cultured and treated with vanadium pentoxide (V2O5) at 5, 10, or 20 mmol/L. Neuronal apoptosis was detected by TdT-mediated dUTP-biotin nick end labeling (TUNEL). The protein levels of Cyt-c, caspase-9, and caspase-3 were determined by Western blot. RESULTS: Apoptosis bodies were detected in the nuclei of neurons by TUNEL. The number of neurons with apoptosis bodies increased with increasing dose of V2O5 The apoptosis index (AI) was significantly higher in the 10 and 20 mm/L exposure groups than in the control group (P < 0.05 or P < 0.01). Western blot showed that the protein expression levels of Cyt-c and caspase-3 significantly increased in the 5 mmol/L exposure group as compared with the control group (P < 0.05). In the 10 and 20 mmol/L exposure groups, the protein expression of Cyt-c, caspase-9, and caspase-3 all increased as compared with the control group (P < 0.01). Neuronal AI was positively correlated with Cyt-c, caspase-9, and caspase-3 (r = 0.954, P < 0.01; r = 0.938, P < 0.01; r = 0.943, P < 0.01). CONCLUSION: Pentavalent vanadium may induce neuronal apoptosis. The protein expression of Cyt c, caspase-9, and caspase-3 may play an important role in neuronal apoptosis induced by pentavalent vanadium. PMID- 25511265 TI - [Changes in expression of motor protein for axonal transport in nerve tissues of carbon disulfide-intoxicated rats]. AB - OBJECTIVE: To study the changes in microtubule motor protein expression in the spinal cord and sciatic nerve of rats exposed to carbon disulfide, and to investigate the possible molecular mechanism of changes in axonal transport in carbon disulfide-induced peripheral neuropathy. METHODS: Healthy adult male Wistar rats were randomly divided into one control group and three experimental groups (10 rats per group). The rats in experimental groups were intoxicated by gavage of carbon disulfide at a dose of 200, 400, or 600 mg/kg 6 times a week for 6 consecutive weeks, while the rats in control group were given the same volume of corn oil by gavage. Animals were sacrificed after exposure, with nerve tissue separated. The levels of dynein, dynactin, and kinesin in the spinal cord and sciatic nerve were determined by Western blot. RESULTS: The content of dynein, dynactin, and kinesin in the sciatic nerve decreased significantly under exposure to carbon disulfide. The levels of dynein in the sciatic nerve were reduced by 23.47% and 33.34% at exposure doses of 400 and 600 mg/kg, respectively. The levels of dynactin in the sciatic nerve of the three experimental groups were reduced by 19.91%, 24.23%, and 41.30%, respectively. The level of kinesin was reduced by 25.98%under exposure to 600 mg/kg carbon disulfide. All the differences were statistically significant (P < 0.01). As compared with the control group, the 600 mg/kg group experienced a 28.24% decrease in level of dynactin in the spinal cord (P < 0.01), but no significant change was observed in the level of dynein or kinesin. CONCLUSION: Carbon disulfide has an impact on microtubule motor protein expression in nerve tissues, which might be involved in the development of carbon disulfide-induced peripheral neuropathy. PMID- 25511268 TI - [Protective effects of n-acetylcysteine against decabromodiphenyl ether-induced brain oxidative injury in mice]. AB - OBJECTIVE: To study the protective effects of N-acetylcysteine (NAC) against oxidative injury in the brain tissue of mice induced by decabromodiphenyl ether (PBDE-209) and the expression of mitogen activated protein kinase (MAPK)-related proteins in the hippocampus. METHODS: Twenty-one male BALB/c mice were randomly divided into three groups with seven mice in each group: solvent control group, PBDE-209 group with gavage of 500 mg/kg PBDE-209, and PBDE-209 +NAC group which received intraperitoneal injection of 100 mg/kg NAC 0.5 h before exposure to PBDE 209. Mice were sacrificed 6 weeks after exposure. Malondialdehyde (MDA) level, superoxide dismutase (SOD) activity, and glutathione (GSH) level in the cerebral cortex, hippocampus, cerebellum, and striatum, as well as the protein expression of extracellular signal-regulated kinase (ERK), phosphorylated ERK (p-ERK), p38 MAPK (p38), and phosphorylated p38 (p-p38) in the hippocampus, were determined by Western blot. RESULTS: Compared with the hippocampal and cerebellar levels of MDA in control group [(4.91+/-1.60) and (2.42+/-1.41) nmol/mg pro] and PBDE-209+NAC group [(6.16+/-1.03) and (2.83+/-0.85) nmol/mg pro], the MDA levels in PBDE-209 group [(12.12+/-6.39) and (4.24+/-1.15) nmol/mg pro] were significantly increased (P < 0.05). The striatum MDA level in PBDE-209 group [(12.92+/-4.30) nmol/mg pro] was significantly increased as compared with that of the control group [(4.05+/ 2.23) nmol/mg pro] (P < 0.05). The hippocampal SOD activity of PBDE-209 group [(59.29+/-37.09) U/mg pro] was reduced significantly as compared with those of the control group [(93.28+/-21.75) U/mg pro] and PBDE-209+NAC group [(98.92+/ 21.54) U/mgpro] (P < 0.05). The GSH levels in the cerebral cortex, striatum, and cerebellum in PBDE-209 group [(40.98+/-13.19), (24.46+/-11.30), and (3.55+/-1.55) mg GSH/g pro] were significantly reduced as compared with those of the control group [(75.79+/-26.51), (44.52+/-13.15) and (8.01+/-3.23) mg GSH/g pro] and the PBDE-209+NAC group [(89.86+/-28.39), (39.01+/-9.05) and (10.34+/-2.58) mg GSH/g pro] (P < 0.05). Western blot results showed that the ratios of p-p38/p38 and p ERK/ERK in the hippocampus were significantly higher in the PBDE-209 group than in the control group and PBDE-209+NAC group (P < 0.05). CONCLUSION: Antioxidant NAC has a protective effect against PBDE-209-induced brain injury in mice to some extent, and reduces the expression of MAPK-related proteins. PMID- 25511267 TI - [Relationship between pathological features and 64-MSCT findings of pulmonary nodules in patients with coal workers' pneumoconiosis]. AB - OBJECTIVE: To analyze the relationship between the pathological features and 64 multislice spiral computed tomography (64-MSCT) findings of pulmonary nodules in autopsies from patients with coal workers' pneumoconiosis (CWP), to investigate the optimal imaging method for the distribution of pulmonary nodules, and to provide data for the establishment of CT diagnostic criteria for CWP. METHODS: Cadaveric lung specimens were collected from 7 CWP patients. All of them were men, aged 42~77 years (mean, 60.00+/-13.00 years), and their dust exposure time was 5~30 years (mean, 15.4+/-8.01 years). The cadaveric lung specimens were treated by aeration, sectioning, and immobilization and were then examined by coronary 64-MSCT. The primitive images were reconstructed into the maximumintensity projection (MIP) images (slice thickness: 3 mm, 5 mm, and 8 mm). The sensitivities of imaging methods with different slice thickness were evaluated based on the pathology and anatomy of local pulmonary nodules, and the correlation between pathological results and radiological findings was analyzed. RESULTS: There were significant differences between the stages determined by pathological examination and high-kV chest radiography (before death) (chi(2) = 4.667, P < 0.05; kappa value = 0.167, P < 0.05). A total of 271 nodules were found in all pathological sections, including peribronchovascular nodules (27, 9.9%), centrilobular nodules (67, 24.6%), interlobular nodules (65, 24.3%), nodules within 5 mm from the pleura (45, 16.5%), pleural plaque-like nodules on the lateral chest wall (45, 16.5%), and nodules on the interlobar pleura (22, 8.1%). The likelihood ratio was the highest (0.981) between 5-mm MIP images and pathological results according to the chi-square test. CONCLUSION: The stage of pulmonary nodules determined by pathological examination is significantly different from that determined by high-kV chest radiography. The 5-mm MIP images of 64-MSCT provide a good reflection of the local pathology and anatomy of pulmonary nodules in CWP patients. PMID- 25511269 TI - [Investigation of coping strategy for occupational stress among workers in thirteen enterprises]. AB - OBJECTIVE: To investigate the influential factors for the coping strategy for occupational stress among workers in thirteen enterprises. METHODS: An anonymous survey was conducted in 6711 workers in 13 enterprises selected by cluster sampling from November 2008 to June 2009. Coping strategy, occupational stressors, stress response, and social support were measured using occupational stress instruments, job content questionnaire, and effort-reward imbalance questionnaire. The data from 5338 workers were statistically analyzed; the overall response rate was 79.6%. RESULTS: The median coping strategy score was 26 (23-30) (P25~P75). The coping strategy score of male workers (26.56+/-5.30) was significantly higher than that of female workers (26.07+/-5.37) (Z = 10.02, P < 0.01). Coping strategy score was the highest in managers (27.41+/-4.86) and the lowest in front-line workers (26.28+/-5.36), with a significant difference between the two groups (chi(2) = 5.38, P < 0.01). The coping strategy scores of workers with weekly job times of <=40 h, 41-50 h, 51-59 h, and >= 60 h were 26.93+/-5.36, 26.72+/-5.11, 25.74+/-5.30, and 25.09+/-5.83, respectively (chi(2) = 22.12, P < 0.01). Correlation analysis revealed that coping strategy score was positively correlated with decision level (r = 0.183, P < 0.01), reward (r = 0.207, P < 0.01), positive emotion (r = 0.244, P < 0.01), superior support (r = 0.176, P < 0.01), coworker support (r = 0.176, P < 0.01), and job satisfaction (r = 0.171, P < 0.01), but negatively correlated with psychological demands (r = 0.157, P < 0.01), physical demands (r = -0.099, P < 0.01), negative emotion (r = 0.093, P < 0.01), and depressive symptoms scores (r = -0.208, P < 0.01). Compared with those with middle or low coping strategy scores, workers with high coping strategy scores reported higher decision level, reward, social support, job satisfaction, and positive emotion scores (P < 0.01) but lower depressive symptom and negative emotion scores (P < 0.01). CONCLUSION: Enterprise type, individual factors, health status, and work time, have effects on the coping strategy for occupational stress of occupational stress. PMID- 25511270 TI - [Analysis on new cases of pneumoconiosis in Xinjiang Production and Construction Corps from2001 to 2012]. PMID- 25511271 TI - [Effect of smoking on the microRNAs expression in pneumoconiosis patients]. AB - OBJECTIVE: To investigate the effect of smoking on the microRNAs (miRNAs) expression in pneumoconiosis patients. METHODS: Real-time qPCR was used to measure the expression levels of miR-21, miR-200c, miR-16, miR-204, miR-206, miR 155, let-7g, miR-30b, and miR-192 in 36 non-smoking patients with pneumoconiosis and 38 smoking patients with pneumoconiosis, and the differences in expression levels between the two groups were evaluated by two-independent samples t-test. RESULTS: The expression of miR-192 in serum showed a significant difference between non-smoking and smoking pneumoconiosis patients (P < 0.05), and it decreased gradually in smoking patients with stage I and II pneumoconiosis. In the serum of all pneumoconiosis patients, the expression level of miR-16 was the highest, while the expression level of miR-204 was the lowest. CONCLUSION: Pneumoconiosis patients have differential expression of miRNAs in serum, and smoking has an effect on the miRNAs expression in pneumoconiosis patients. PMID- 25511272 TI - [Investigation of health-promoting lifestyle in emergency nurses]. PMID- 25511273 TI - [Investigation and analysis of factors that affect the health of children in the plastic recycling and regeneration processing region]. AB - OBJECTIVE: To investigate the main influential factors for the health of children in the plastic waste recovery and recycling area. METHODS: A cross-sectional survey was performed among children aged 9~17 years from three natural villages engaged in plastic waste recovery and recycling and four control villages engaged in planting. The health status of children was investigated by random household survey using a face-to-face questionnaire, and the main influential factors were analyzed accordingly. RESULTS: The incidence rates of respiratory symptoms (cough and expectoration, nasal congestion, and sore throat) (78.4%, 69/88) and digestive diseases (gastrointestinal disease and liver disease) (14.8%, 13/88) in the waste processing area were significantly higher than those in the control area (64.0%, 71/111; 6.3%, 7/111) (P < 0.05). CONCLUSION: Multivariate logistic regression analysis indicated that skin diseases are related to whether plastic can be smelt around the residential area. PMID- 25511274 TI - [Observation of serumlevel of 25-hydroxyvitamins D in pneumoconiosis patients]. PMID- 25511275 TI - [Combination treatment of tetrandrine and huanggen tablet in the 60 cases of pneumoconiosis]. PMID- 25511276 TI - [A case report of malignant peritoneal mesothelioma caused by asbestos]. PMID- 25511278 TI - [Application of intravenous anesthesia in pneumoconiosis diagnosis and treatment with Bronchoscope]. PMID- 25511277 TI - [Effects of Qili Qiangxin capsules on NT-proBNP level and cardiac function in silicosis patients]. AB - OBJECTIVE: To investigate the effects of Qili Qiangxin capsules on the amino terminal pro-brain natriuretic peptide (NT-proBNP) level and cardiac function in patients with silicosis. METHODS: Hospitalized silicosis patients with heart failure were divided into treatment group (41 cases) and control group (30 cases) according to their own will. Both groups received comprehensive symptomatic treatment; in addition, the treatment group received Qili Qiangxin capsules. The treatment lasted 6 months. The observed items included NT-proBNP level, 6-minute walk test, ultrasonic cardiogram, and NYHA classification before and after treatment. RESULTS: According to NYHA classification, the response rate was 29.27%in the treatment group and 10.00%in the control group; there was a significant difference between the two groups (P < 0.05). The average walk distance in the treatment group was increased from 150.96+/-73.12 m before treatment to 169.32+/-77.04 m after treatment, and the improvement was statistically significant (P < 0.05). The average NT-proBNP level in the treatment group was reduced from 1154.44 +/- 480.79 ng/L before treatment to 494.49 +/- 342.61 ng/L after treatment, and the reduction was statistically significant (P < 0.01). Left ventricular ejection fraction was significantly improved in the treatment group (P < 0.05). CONCLUSION: Qili Qiangxin capsules in addition to comprehensive symptomatic treatment can significantly reduce NT proBNP level and improve cardiac function in silicosis patients, and thereby improve patients' quality of life. PMID- 25511279 TI - [Pathological observation of progressive massive fibrosis in autophy frompatients with coal worker's pneumoconiosis]. AB - OBJECTIVE: To study the pathological features of progressive massive fibrosis (PMF) in the lung tissues of patients with coal workers' pneumoconiosis (CWP). METHODS: A retrospective analysis was made on the autopsies from 8 patients with CWP, which were observed under a microscope by HE staining, given their occupational history. RESULTS: The age of 8 cases ranged 47-71 years (mean, 59.9 years), and their dust exposure time was 18-32 years (mean, 25.1 years). All the 8 cases were complicated by chronic bronchitis as well as emphysema, 7 cases by pulmonary heart disease, and 4 cases by pulmonary tuberculosis. In this group of patients, PMF was mainly distributed in the hilum and the upper lobe of the lung, including 7 cases of nodular fusion type and 1 case of PMF type. The collagen fibers around PMF extended radially and destroyed its surrounding tissue. CONCLUSION: Nodular fusion type is the main form of PMF in the lung tissues of CWP patients. It has a progressive and destructive process, which is the manifestation of advanced CWP. PMID- 25511280 TI - [3 cases of delayed encephalopathy after acute carbon monoxide poisoning complicated with pulmonary embolism]. PMID- 25511281 TI - [9 cases with toxic encephalopathy induced by xylene]. PMID- 25511282 TI - [Research on biological effects of multi-walled carbon nanotubes]. PMID- 25511283 TI - [Laminin and pulmonary fibrosis]. PMID- 25511284 TI - [Advances in research on the role of Gas 6/TAMin inflammation response and silicosis induced by silica dusts]. PMID- 25511285 TI - [Toxicity and treatment strategies of phosphorus oxychloride]. PMID- 25511287 TI - Trauma and sympathy in Buck. PMID- 25511288 TI - Highly water repellent but highly adhesive surface with segregation of poly(ethylene oxide) side chains. AB - Polymer surfaces were modified using methacrylate terpolymers containing both perfluoroalkyl (Rf) groups and poly(ethylene oxide) (PEO) as side chains in the same molecule. The structure and properties of the modified surfaces were evaluated using X-ray photoelectron spectroscopy and by measuring the dynamic contact angles and 90 degrees peel strength. It was found that not only Rf groups but also PEO side chains were segregated on the surface being against the order of the surface free energy. The terpolymer modified surface is hydrophobic in air because Rf groups are predominant, but it becomes hydrophilic in water because the surface is covered with PEO side chains. This response to the environment is rapid and reversible. The modified surface showed high water repellency because of the surface Rf groups and high adhesive strength because of the side chains. PMID- 25511289 TI - In reference to Relation of mean platelet volume and red blood cell distribution width with epistaxis. PMID- 25511286 TI - Comparison of environmental and isolate Sulfobacillus genomes reveals diverse carbon, sulfur, nitrogen, and hydrogen metabolisms. AB - BACKGROUND: Bacteria of the genus Sulfobacillus are found worldwide as members of microbial communities that accelerate sulfide mineral dissolution in acid mine drainage environments (AMD), acid-rock drainage environments (ARD), as well as in industrial bioleaching operations. Despite their frequent identification in these environments, their role in biogeochemical cycling is poorly understood. RESULTS: Here we report draft genomes of five species of the Sulfobacillus genus (AMDSBA1 5) reconstructed by cultivation-independent sequencing of biofilms sampled from the Richmond Mine (Iron Mountain, CA). Three of these species (AMDSBA2, AMDSBA3, and AMDSBA4) have no cultured representatives while AMDSBA1 is a strain of S. benefaciens, and AMDSBA5 a strain of S. thermosulfidooxidans. We analyzed the diversity of energy conservation and central carbon metabolisms for these genomes and previously published Sulfobacillus genomes. Pathways of sulfur oxidation vary considerably across the genus, including the number and type of subunits of putative heterodisulfide reductase complexes likely involved in sulfur oxidation. The number and type of nickel-iron hydrogenase proteins varied across the genus, as does the presence of different central carbon pathways. Only the AMDSBA3 genome encodes a dissimilatory nitrate reducatase and only the AMDSBA5 and S. thermosulfidooxidans genomes encode assimilatory nitrate reductases. Within the genus, AMDSBA4 is unusual in that its electron transport chain includes a cytochrome bc type complex, a unique cytochrome c oxidase, and two distinct succinate dehydrogenase complexes. CONCLUSIONS: Overall, the results significantly expand our understanding of carbon, sulfur, nitrogen, and hydrogen metabolism within the Sulfobacillus genus. PMID- 25511290 TI - Developing a xylanase XYNZG from Plectosphaerella cucumerina for baking by heterologously expressed in Kluyveromyces lactis. AB - BACKGROUND: Xylanase can replace chemical additives to improve the volume and sensory properties of bread in the baking. Suitable baking xylanase with improved yield will promote the application of xylanase in baking industry. The xylanase XYNZG from the Plectosphaerella cucumerina has been previously characterized by heterologous expression in Pichia pastoris. However, P. pastoris is not a suitable host for xylanase to be used in the baking process since P. pastoris does not have GRAS (Generally Regarded As Safe) status and requires large methanol supplement during the fermentation in most conditions, which is not allowed to be used in the food industry. Kluyveromyces lactis, as another yeast expression host, has a GRAS status, which has been successfully used in food and feed applications. No previous work has been reported concerning the heterologous expression of xylanase gene xynZG in K. lactis with an aim for application in baking. RESULTS: The xylanase gene xynZG from the P. cucumerina was heterologously expressed in K. lactis. The recombinant protein XYNZG in K. lactis presented an approximately 19 kDa band on SDS-PAGE and zymograms analysis. Transformant with the highest halo on the plate containing the RBB-xylan (Remazol Brilliant Blue-xylan) was selected for the flask fermentation in different media. The results indicated that the highest activity of 115 U/ml at 72 h was obtained with the YLPU medium. The mass spectrometry analysis suggested that the hydrolytic products of xylan by XYNZG were mainly xylobiose and xylotriose. The results of baking trials indicated that the addition of XYNZG could reduce the kneading time of dough, increase the volume of bread, improve the texture, and have more positive effects on the sensory properties of bread. CONCLUSIONS: Xylanase XYNZG is successfully expressed in K. lactis, which exhibits the highest activity among the published reports of the xylanase expression in K. lactis. The recombinant XYNZG can be used to improve the volume and sensory properties of bread. Therefore, the expression yield of recombinant XYNZG can be further improved through engineered strain containing high copy numbers of the XYNZG, and optimized fermentation condition, making bread-baking application possible. PMID- 25511291 TI - Inhibin-alpha, E-cadherin, calretinin and Ki-67 antigen in the immunohistochemical evaluation of canine and human testicular neoplasms. AB - INTRODUCTION: The steady increase of dogs with diagnosed testicular neoplasms observed in recent years prompted us to carry out immunohistochemical (IHC) studies for their better characterization. The aim of the study was to analyze most common canine testicular neoplasms (seminomas, Leydig cell and Sertoli cell tumors) with selected IHC markers and to compare the expressions of these proteins in corresponding canine and human testicular tumors. MATERIAL AND METHODS: Studies were carried out on testicular canine tumors: 40 cases of seminoma, 40 cases of Leydig cell tumor and 40 cases of Sertoli cell tumor. Moreover, 15 cases of human seminomas and 5 cases of human Leydig cell tumors were also analyzed. Immunohistochemistry was performed on paraffin sections by standard technique using monoclonal anti-human antibodies against E-cadherin, inhibin-alpha, calretinin and Ki-67. The slides were subjected to computer-aided image analysis and the intensity of the immunoreactivity was assessed by a semi quantitative scoring system. RESULTS: Due to the very low prevalence of the Sertoli cell-derived tumors in the human population, we were able to examine the markers' expression only in the canine gonadal tumors. We revealed that, apart from E-cadherin in Leydig cell tumors and calretinin in seminomas, the expression of all the analyzed markers in canine and human testicular tumors was similar. E.g. there was no immunoexpression of inhibin-alpha in 75% of canine and 100% of human cases of seminoma. The immunoreactivity of Ki-67 was intense in 40% of canine and 60% of human seminomas. Immunoexpression of inhibin-alpha in Leydig cell tumor was intense in 70% of canine and 100% of human cases, respectively. Also the immunoreactivity of calretinin was intense in 75% of cases of canine and 100% of human Leydig cell tumors. In 50% of canine and 40% of human Leydig cell tumors, the immunoexpression of Ki-67 was weak. CONCLUSIONS: The applied anti human monoclonal antibodies against common antigens and markers of human testicular neoplasms could be routinely used for the immunohistochemical evaluation of canine testicular tumors. PMID- 25511292 TI - Protein and siRNA delivery by transportan and transportan 10 into colorectal cancer cell lines. AB - INTRODUCTION: Cell penetrating peptides (CPPs) have the ability to translocate through cell membranes with high efficiency and therefore can introduce biological agents with pharmaceutical properties into the cell. Transportan (TP) and its shorter analog transportan 10 (TP10) are among the best studied CPPs, however, their effects on viability of and cargo introduction into colorectal cancer (CRC) cells have yet not been investigated. The aim of our study was to evaluate the cytotoxic effects of TP and TP10 on representative CRC lines and the efficiency of protein (streptavidin) and siRNA cargo delivery by TP-biotinylated derivatives (TP-biot). MATERIAL AND METHODS: HT29 (early stage CRC model) and HCT116 (metastatic CRC model) cell lines were incubated with TP, TP10, TP-biot1, TP-biot13 and TP10-biot1. The effects of studied CPPs on cell viability and cell cycle were assessed by MTT and annexin V assays. The uptake of streptavidin-FITC complex into cells was determined by flow cytometry and fluorescence microscopy, with the inhibition of cellular vesicle trafficking by brefeldin A. The efficiency of siRNA for SASH1 gene delivery was measured by quantitative PCR (qPCR). RESULTS: Since up to 10 uM concentrations of each CPP showed no significant cytotoxic effect, the concentrations of 0.5-5 uM were used for further analyses. Within this concentration range none of the studied CPPs affected cell viability and cell cycle. The efficient and endocytosis-independent introduction of streptavidin-FITC complex into cells was observed for TP10-biot1 and TP-biot1 with the cytoplasmic location of the fluorescent cargo; decreased SASH1 mRNA level was noticed with the use of siRNA and analyzed CPPs. CONCLUSIONS: We conclude that TP, TP10 and their biotinylated derivatives can be used as efficient delivery vehicles of small and large cargoes into CRC cells. PMID- 25511295 TI - Placental hypoxia: the lesions of maternal malperfusion. AB - The placental lesions classically ascribed to placental hypoxia, here denoted maternal malperfusion (MMP), are among the more significant that a placental pathologist may encounter. Yet the appearance of these lesions may be subtle, and the clinical implication of their diagnosis is frequently unclear. The aim of this review is to provide a more nuanced perspective on the clinical utility of placental pathology for the detection of MMP. The review will first detail MMP lesions in the placenta and discuss their associations with pregnancy complications. The review will then delve into the diagnostic and interpretive difficulties of these lesions. Finally, recent research findings that may aid in the development of better diagnostic tools will be briefly discussed. PMID- 25511293 TI - Flicker-defined form perimetry in glaucoma patients. AB - PURPOSE: To assess the potential of flicker-defined form (FDF) perimetry to detect functional loss in patient groups with beginning glaucoma, and to evaluate the dynamic range of the FDF stimulus in individual patients and at individual test positions. METHODS: FDF perimetry and standard automated perimetry (SAP) were performed at identical test locations (adapted G1 protocol) in 60 healthy subjects and 111 glaucoma patients. All patients showed glaucomatous optic disc appearance. Grouping within the glaucoma cohort was based on SAP-performance: 33 "preperimetric" open-angle glaucoma (OAG) patients, 28 "borderline" OAG (focal defects and SAP-mean defect (MD) <2 dB), 33 "early" OAG (SAP-MD < 5 dB), 17 "advanced" OAG. All participants were experienced in psychophysical and perimetric tests. Defect values and the areas under receiver operating characteristic curves (ROC) in patient groups were statistically compared. RESULTS: The values of FDF-MD in the preperimetric, borderline, and early OAG group were 2.7 +/- 3.4 dB, 5.5 +/- 2.6 dB, and 8.5 +/- 3.4 dB respectively (all significantly above normal). The percentage of patients exceeding normal FDF-MD was 27.3 %, 60.7 %, and 87.9 % respectively. The age-adjusted FDF-mean defect (MD) of the G1X-protocol was not significantly correlated with refractive error, lens opacity, pupil size, or gender. Occurrence of ceiling effects (inability to detect targets at highest contrast) showed a high correlation with visual field losses (R = 0.72, p < 0.001). Local analysis indicates that SAP losses exceeding 5 dB could not be distinguished with the FDF technique. CONCLUSION: The FDF stimulus was able to detect beginning glaucoma damage. Patients with SAP-MD values exceeding 5 dB should be monitored with conventional perimetry because of its larger dynamic range. PMID- 25511294 TI - Author's responses to the comment by Daniele Lantagne on "Household effectiveness vs. laboratory efficacy of point-of-use chlorination". PMID- 25511296 TI - A pathologist's perspective on the perinatal autopsy. AB - The perinatal autopsy is an important tool in the investigation of fetal and neonatal death, and a complete understanding of its risks and benefits is necessary for providers of perinatal care. This review, from the perspective of a perinatal pathologist, reports the details of the autopsy procedure, its goals, its value to individual patients and the health care system in general, and its alternatives. Even with new emerging technologies, the conventional perinatal autopsy remains the gold standard for determining the cause of death and the final summary of all pathologic findings. Therefore, the information provided in this review can help providers properly convey information about perinatal autopsy to bereaved families. PMID- 25511297 TI - Perineural tumor spread to the muscle: An alternative for muscle metastasis? PMID- 25511298 TI - Co-infection with Schistosoma mansoni and Human Immunodeficiency Virus-1 (HIV-1) among residents of fishing villages of north-western Tanzania. AB - BACKGROUND: Co-infection with S. mansoni and Human Immunodeficiency Virus-1 (HIV 1) has been described in sub-Saharan Africa. However, few community-based studies have been conducted to assess the association between the two diseases. The present study examined whether the infection with HIV-1 is associated with an altered susceptibility to S. mansoni infection by comparing the prevalence and intensity of S. mansoni infection among those infected and not infected with HIV 1. Any influence of HIV-1 associated immunodeficiency on the intensity of S. mansoni infection was also investigated. METHODS: A cross-sectional study was conducted among 1,785 randomly selected adults (aged 21-55 years) in fishing villages of north-western Tanzania. Single stool samples were obtained and examined for S. mansoni eggs using the Kato Katz technique. Finger prick and venous blood samples were collected for HIV-1 screening and CD4(+) cell quantification. Demographic information was collected by questionnaire. RESULTS: Of the 1,785 individuals from whom complete data were obtained, 854 (47.85%, 95% CI; 40.46 - 56.57) were infected with S. mansoni and had a mean intensity of 183.21(95% CI; 165.61-202.70) eggs per gram of faeces (epg). A total of 125 individuals (6.29%, 95% CI 3.59-11.04) were infected with HIV-1 and only 40% (n=50) of them were co-infected with S. mansoni. No differences in prevalence of S. mansoni infection or intensities of infection, as estimated by egg count (epg), were observed between HIV-1 sero-positive individuals and HIV-1 negative individuals. In generalized regression models (adjusted for sex, age, occupation, residence and level of education), being infected with HIV-1 did not increase the risk (APR=1.01, 95%; 0.83-1.21, P=0.93) or intensity (AOR = 0.84, 95% CI; 0.56 1.25, P = 0.33) of S. mansoni infection. Among individuals co-infected with HIV-1 and S. mansoni infection, the intensity of infection (epg) was not associated (P = 0.21) or correlated (P = 0.13) with CD4(+) cell counts. CONCLUSION: Our findings suggest that HIV-1 infection may not have a major effect on S. mansoni infection or on the excretion of eggs from the co-infected individuals. However, further studies are needed to understand the biological interaction between HIV-1 and S. mansoni in a large cohort of co-infected individuals. PMID- 25511300 TI - Dentifrice pH but not consistency may affect fluoride uptake in plaque. AB - OBJECTIVE: Test the ability of acidic fluoridated solutions to enhance fluoride (F) bound on bacteria (1) and the effect of dentifrice consistency on plaque fluid F uptake (2). METHODS: (1) Streptococcus mutans isolates were grown in BHI medium (37 degrees C/18h). Bacteria were washed either with EDTA or CaCl2 both at 1mM to remove or add calcium, respectively. Pellets were incubated with 12 mM NaF at pH 4.5 or 7 for 1 min and F was quantified in the lysates and supernatants with the electrode, after HMDS-facilitated diffusion. (2) A randomized, double blind, crossover clinical trial was performed in three phases with nineteen adults (20-35 years) that used one of the dentifrices: commercial toothpaste (1100 ppm F, pH7.0 and conventional viscosity (Sorriso Fresh((r)))); experimental liquid dentifrice (ELD) (1100 ppm F, pH7.0 and low viscosity [1.1% carboxymethylcellulose (CMC)]) and ELD (1100 ppm F and high viscosity pH7.0 (2.2% CMC)). F concentration in plaque fluid was analyzed using an inverted F electrode. RESULTS: (1) Significantly higher F amounts were detected in the lysates of bacteria incubated with NaF solution at pH4.5 compared to the supernatant, which was not seen at pH7.0, being this effect calcium-dependent. (2) Significantly higher F concentrations in plaque fluid were found 1h after toothbrushing compared to 12h, but no significant differences were seen among the toothpastes. CONCLUSIONS: F at low pH binds more efficiently to S. mutans than at neutral pH and dentifrice viscosity does not interfere in plaque fluid fluoride incorporation. CLINICAL SIGNIFICANCE: pH of the dentifrice but not consistency may be important to F uptake in plaque. PMID- 25511299 TI - An ecdysone-responsive nuclear receptor regulates circadian rhythms in Drosophila. AB - Little is known about molecular links between circadian clocks and steroid hormone signalling, although both are important for normal physiology. Here we report a circadian function for a nuclear receptor, ecdysone-induced protein 75 (Eip75/E75), which we identified through a gain-of-function screen for circadian genes in Drosophila melanogaster. Overexpression or knockdown of E75 in clock neurons disrupts rest:activity rhythms and dampens molecular oscillations. E75 represses expression of the gene encoding the transcriptional activator, CLOCK (CLK), and may also affect circadian output. PER inhibits the activity of E75 on the Clk promoter, thereby providing a mechanism for a previously proposed de repressor effect of PER on Clk transcription. The ecdysone receptor is also expressed in central clock cells and manipulations of its expression produce effects similar to those of E75 on circadian rhythms. We find that E75 protects rhythms under stressful conditions, suggesting a function for steroid signalling in the maintenance of circadian rhythms in Drosophila. PMID- 25511301 TI - Post-irradiation hardness development, chemical softening, and thermal stability of bulk-fill and conventional resin-composites. AB - OBJECTIVES: To measure bottom/top hardness ratio of bulk-fill and conventional resin-composite materials, and to assess hardness changes after dry and ethanol storage. Filler content and kinetics of thermal decomposition were also tested using thermogravimetric analysis (TGA). METHODS: Six bulk-fill (SureFil SDR, Venus bulk fill, X-tra base, Filtek bulk fill flowable, Sonic fill, and Tetric EvoCeram bulk-fill) and eight conventional resin-composite materials (Grandioso flow, Venus Diamond flow, X-flow, Filtek Supreme Ultra Flowable, Grandioso, Venus Diamond, TPH Spectrum, and Filtek Z250) were tested (n=5). Initial and 24h (post cure dry storage) top and bottom microhardness values were measured. Microhardness was re-measured after the samples were stored in 75% ethanol/water solution. Thermal decomposition and filler content were assessed by TGA. Results were analysed using one-way ANOVA and paired sample t-test (alpha=0.05). RESULTS: All materials showed significant increase of microhardness after 24h of dry storage which ranged from 100.1% to 9.1%. Bottom/top microhardness ratio >0.9 was exhibited by all materials. All materials showed significant decrease of microhardness after 24h of storage in 75% ethanol/water which ranged from 14.5% to 74.2%. The extent of post-irradiation hardness development was positively correlated to the extent of ethanol softening (R(2)=0.89, p<0.001). Initial thermal decomposition temperature assessed by TGA was variable and was correlated to ethanol softening. CONCLUSIONS: Bulk-fill resin-composites exhibit comparable bottom/top hardness ratio to conventional materials at recommended manufacturer thickness. Hardness was affected to a variable extent by storage with variable inorganic filler content and initial thermal decomposition shown by TGA. CLINICAL SIGNIFICANCE: The manufacturer recommended depth of cure of bulk-fill resin composites can be reached based on the microhardness method. Characterization of the primary polymer network of a resin-composite material should be considered when evaluating its stability in the aqueous oral environment. PMID- 25511302 TI - An antifungal coating for dental silicones composed of chlorhexidine nanoparticles. AB - OBJECTIVES: The aims of this study were to synthesise a range of chlorhexidine containing nanoparticles (CHX-NPs), and investigate the feasibility of using these as an antifungal coating for dental silicones. METHODS: CHX-NPs were precipitated in aqueous reaction by mixing solutions of CHX digluconate with solutions of sodium triphosphate (TP), trimetaphosphate (TMP) or hexametaphosphate (HMP). CHX-NPs were deposited on commercial dental silicones by immersion coating, and these were characterised for hydrophilicity (contact angle) and water uptake (mass change). Soluble CHX elution into artificial saliva was measured using ultraviolet spectrophotometry. Antifungal efficacy against Candida albicans was investigated using a cell proliferation assay. RESULTS: Coating silicones with CHX-NPs did not significantly affect hydrophilicity, as assessed using water contact angle, or water uptake as assessed by mass change following 16 weeks' immersion in artificial saliva. CHX-NP-coated silicone specimens released soluble CHX into artificial saliva. The salt of CHX and the immersion time affected the rate, concentration and duration of CHX release, with CHX-HMP exhibiting a slow, sustained release and CHX-TP and CHX-TMP exhibiting a faster, more concentrated release. C. albicans metabolic activity was inhibited by presence of CHX-HMP-NPs in suspension. CONCLUSIONS: CHX-NPs provided a localised, controlled dose of soluble CHX at the surface of dental silicones without adversely affecting hydrophilicity or water uptake. CHX-HMP NPs provided effective antifungal control of C. albicans in a cell proliferation assay. Coating materials with these nanoparticles could be an effective way of delivering low, but clinically relevant, concentrations of chlorhexidine in the oral environment. CLINICAL SIGNIFICANCE: Denture stomatitis is a common oral infection and is associated with fungal infestation of denture soft lining and obturator materials, which are often silicones such as those used here. Our study suggests that CHX-NPs may be a useful strategy in design of antifungal coatings for these materials. PMID- 25511304 TI - Kpna7 interacts with egg-specific nuclear factors in the rainbow trout (Oncorhynchus mykiss). AB - Nuclear proteins are required for the initiation of transcription in early embryos before embryonic genome activation. The regulated transport of nuclear proteins is mediated by factors known as importins (karyopherins). Kpna7, a newly discovered member of the importin alpha family, is critical for early development in mammals. In this study, we characterize rainbow trout Kpna7. The cDNA for rainbow trout Kpna7 encodes a 519 amino acid protein that contains a conserved importin beta binding (IBB) domain and seven armadillo/beta-catenin-like repeat (ARM) motifs. Reverse-transcriptase PCR and Western blot analyses revealed that Kpna7 is specifically expressed in eggs/ovary. Real-time PCR analysis demonstrated that expression of Kpna7 mRNA is high in unfertilized eggs, gradually decreases in early-stage embryos until 3 days post-fertilization, and declines sharply thereafter, reaching a level that is barely detectable in 4-day old embryos. Using a yeast two-hybrid screening system, we identified two Kpna7 interacting proteins from a rainbow trout egg cDNA library: Stl3 (rhamnose binding lectin 3) and an uncharacterized protein. Both genes appear to be expressed specifically in eggs/testis. Co-immunoprecipitation assays confirmed the interaction between Kpna7 and Stl3, and co-transfection experiments using EGFP-tagged Stl3 showed that Kpna7 facilitates the nuclear transport of Stl3 through an interaction with the predicted nuclear-localization signal cluster at the carboxy-terminus of Stl3. Our data suggest that Kpna7 may function in early embryonic development as a unique nuclear transporter for egg-specific proteins. PMID- 25511303 TI - Comparisons of computational methods for differential alternative splicing detection using RNA-seq in plant systems. AB - BACKGROUND: Alternative Splicing (AS) as a post-transcription regulation mechanism is an important application of RNA-seq studies in eukaryotes. A number of software and computational methods have been developed for detecting AS. Most of the methods, however, are designed and tested on animal data, such as human and mouse. Plants genes differ from those of animals in many ways, e.g., the average intron size and preferred AS types. These differences may require different computational approaches and raise questions about their effectiveness on plant data. The goal of this paper is to benchmark existing computational differential splicing (or transcription) detection methods so that biologists can choose the most suitable tools to accomplish their goals. RESULTS: This study compares the eight popular public available software packages for differential splicing analysis using both simulated and real Arabidopsis thaliana RNA-seq data. All software are freely available. The study examines the effect of varying AS ratio, read depth, dispersion pattern, AS types, sample sizes and the influence of annotation. Using a real data, the study looks at the consistences between the packages and verifies a subset of the detected AS events using PCR studies. CONCLUSIONS: No single method performs the best in all situations. The accuracy of annotation has a major impact on which method should be chosen for AS analysis. DEXSeq performs well in the simulated data when the AS signal is relative strong and annotation is accurate. Cufflinks achieve a better tradeoff between precision and recall and turns out to be the best one when incomplete annotation is provided. Some methods perform inconsistently for different AS types. Complex AS events that combine several simple AS events impose problems for most methods, especially for MATS. MATS stands out in the analysis of real RNA-seq data when all the AS events being evaluated are simple AS events. PMID- 25511305 TI - HRCT findings of small cell lung cancer measuring 30 mm or less located in the peripheral lung. AB - PURPOSE: To evaluate the high-resolution CT (HRCT) features of peripherally located small cell lung cancer (SCLC). MATERIALS AND METHODS: We retrospectively reviewed the HRCT findings of 33 patients with peripherally located SCLC measuring 30 mm or less. The shape and marginal and internal characteristics of the nodules were evaluated. We also assessed the differences in these HRCT findings associated with the differences in the stages of disease. In 10 surgically treated cases, the HRCT-pathological correlations were evaluated. RESULTS: The findings of a well-defined margin (97.0 %), lobulation (78.8 %), thickening of the bronchovascular bundle (BVB) (57.6 %) and inhomogeneous enhancement (64.0 %) were common. A vermiform/branching and polygonal shape were observed in 33.3 and 21.2 % of cases, respectively. Air bronchograms (15.2 %) and marginal ground-glass opacity (GGO) (3.0 %) were less common findings. The vermiform/branching shape and thickening of the BVB were more frequently observed in non-stage I than in stage I tumors. The pathologic findings showed expansive tumor growth along the lymphatics and minimal necrosis between the tumor nests. CONCLUSION: A non-round shape and thickening of the BVB were common, while marginal GGO and air bronchogram were less common in small-sized, peripherally located SCLC. Furthermore, the vermiform/branching shape and thickening of the BVB suggested relatively advanced disease. PMID- 25511306 TI - Implementation of physical activity programs after COPD hospitalizations: Lessons from a randomized study. AB - Pulmonary rehabilitation (PR), following an acute exacerbation of chronic obstructive pulmonary disease (COPD), has been found effective in some studies in reducing readmission rates as and has recently been recommended by the PR guidelines. However, very recent reports suggested that PR is not feasible after a hospital admission for a COPD exacerbation. The objective of this study is to investigate the knowledge gap on the underlying reasons for nonparticipation in PR in the posthospitalization period. We qualitatively analyzed the responses of 531 patients hospitalized for a COPD exacerbation who were not interested in participating in either PR (home or center based) or physical activity monitoring program after being discharged from the hospital. The responses were coded thematically, and independent reviewers compiled the raw data into themes. The characteristics of the 531 subjects (45% male) who declined the intervention are as follows: age was 70 +/- 10 years, mean forced expiratory volume in one second (FEV1%) predicted 40 +/- 16, and age, dyspnea, and airflow obstruction index 6.0 +/- 1.6 (scale 0-10). The themes for not attending include lack of interest (39%), the perception of "being too ill or frail or disabled" (24%), the perception of being "too busy or having too much to do" (11%), distance or the need of travel (11%), commitment issues (7%), comorbidities (6%), and lack of social support (2%). We identified barriers for PR or just physical activity programs after a hospitalization that may affect implementation of such programs. Implementing posthospitalizations program in COPD may require patient engagement and mindful and compassionate professionals who may individualize program components to focus specific deficits and particularly patients' preferences. PMID- 25511308 TI - Attributable fraction estimation from complex sample survey data. AB - PURPOSE: A review of methods for the estimation of attributable fraction (AF) statistics from case-control, cross-sectional, or cohort data collected under a complex sample design. Provide guidance on practical methods of complex sample AF estimation and inference using contemporary software tools. METHODS: Statistical literature on AF estimation from complex samples for the period 1980 to 2014 is reviewed. A general approach based on weighted sum estimators of the AF and application of Jackknife repeated replication and Bootstrap resampling methods for estimating the variance of AF estimates is outlined and applied to an example analysis of risk factors for alcohol dependency. RESULTS: The literature lays the theoretical foundation to address the problem of AF estimation and inference from complex samples. To date, major statistical software packages do not provide a complete program but the approach is easily implemented using the modeling software and macro/function language capabilities available in major statistical analysis packages. In an example application, weighted sum estimation and inference for the population AF showed stable and consistent results under both Jackknife repeated replication and Bootstrap methods of variance estimation. CONCLUSIONS: Future work on AF estimation for complex samples should focus on simulation studies and empirical testing to investigate the properties of the resampling variance estimation methods across a range of complex study design features and populations. PMID- 25511307 TI - Estimating population attributable fractions to quantify the health burden of obesity. AB - PURPOSE: Obesity is a highly prevalent condition in the United States and elsewhere and is associated with increased mortality and morbidity. Here, we discuss some issues involved in quantifying the health burden of obesity using population attributable fraction (PAF) estimates and provide examples. METHODS: We searched PubMed for articles reporting attributable fraction estimates for obesity. We reviewed eligible articles to identify methodological concerns and tabulated illustrative examples of PAF estimates for obesity relative to cancer, diabetes, cardiovascular disease, and all-cause mortality. RESULTS: There is considerable variability among studies regarding the methods used for PAF calculation and the selection of appropriate counterfactuals. The reported estimates ranged from 5% to 15% for all-cause mortality, -0.2% to 8% for all cancer incidence, 7% to 44% for cardiovascular disease incidence, and 3% to 83% for diabetes incidence. CONCLUSIONS: To evaluate a given estimate, it is important to consider whether the exposure and outcome were defined similarly for the PAF and for the relative risks, whether the relative risks were suitable for the population at hand, and whether PAF was calculated using correct methods. Strong causal assumptions are not necessarily warranted. In general, PAFs for obesity may be best considered as indicators of association. PMID- 25511309 TI - A retrospective analysis of the relationship between rhinosinusitis and sinus lift dental implantation. AB - INTRODUCTION: Dental implants have been associated with the occurrence of postoperative rhinosinusitis. In some patients, preoperative sinus lifting must be performed to increase the chances of successful implant placement. This retrospective study examines the relationship of dental implants after sinus lifting with the occurrence of postoperative rhinosinusitis. METHODS: A total of 268 dental implants were inserted in 94 patients (62 Males, 32 Females) between 2011-2013. The ages ranged from 29-71 (in males) and 33-64 (in females). Additionally, bilateral sinus lifing was performed in 51 patients, and unilateral sinus lifting was performed in 43 of the patients. Patients were evaluated for sinus pathology for a period of 5-47 months postoperatively using a satisfaction questionnaire, conventional radiographic examination, and nasal endoscopic examination. RESULTS: Four of the patients (4.2%) had a complication of postoperative sinusitis and were treated medically. In one patient, the implant was unsuccessful (even after treatment) and was removed. None of the patients needed surgery due to the sinusitis or any associated complications. CONCLUSION: The risk for postoperative rhinosinusitis was found to be higher in patients who suffer from chronic sinusitis and in cases in which a large amount of graft was utilized for sinus lifting. These predisposing factors need to be considered when evaluating patients for dental implants and sinus lift procedures. PMID- 25511310 TI - Pancytopenia in a surgical patient, a rare presentation of hyperthyroidism. AB - BACKGROUND: Pancytopenia is a rare complication of hyperthyroidism. Various mechanisms have been described such as immunological, bone marrow suppression. The possibility of hyperthyroidism should be considered in patients with unexplained pancytopenia. There are many case reports showing the association between hyperthyroidism and pancytopenia. All of these reports show association between Graves disease and pancytopenia but our case shows association between Multinodular goitre and pancytopenia. Besides it is uncommon to find such association in a surgical patient. CASE PRESENTATION: This case report describes a 62 yr old hindu female with splenic injury and pancytopenia. On further investigations the patient was found to have hyperthyroidism. CONCLUSION: Though the definite mechanism regarding the association of pancytopenia with hyperthyroidism isn't clear, various cases have been described in the literature. This case shows the diagnostic dilemma that can occur in patients with pancytopenia. Any patient with unexplained pancytopenia should undergo thyroid function tests to rule out hyperthyroidism. PMID- 25511311 TI - Genetics of adrenal diseases in 2014: Genetics improves understanding of adrenocortical tumours. PMID- 25511312 TI - Adipose tissue biology in 2014: Advances in our understanding of adipose tissue homeostasis. PMID- 25511313 TI - Bone: Will breast cancer chemoprevention stand on 'solid bone'? PMID- 25511314 TI - Diabetes: Artificial pancreas--first head-to-head comparison of dual-hormone and single-hormone systems. PMID- 25511315 TI - Incomes and hardship in early transitions to retirement. AB - Canada and other countries are changing the age for public pension eligibility. A policy concern is the welfare of those individuals exiting the labour force before the age of pension eligibility. This study, through the use of the Survey of Labour and Income Dynamics data, addressed early retirements by (a) examining the incomes of those who are not working at near-retirement ages, and (b) examining how these Canadians avoid economic hardship. It found that around three quarters of those not working have been able to avoid low-income status. Most important for avoiding low income are other family income sources, good health, and employment-related pension income. PMID- 25511317 TI - Misattributing speech and jumping to conclusions: a longitudinal study in people at high risk of psychosis. AB - Biases in cognition such as Jumping to Conclusions (JTC) and Verbal Self Monitoring (VSM) are thought to underlie the formation of psychotic symptoms. This prospective study in people with an At Risk Mental State (ARMS) for psychosis examined how these cognitive biases changed over time, and predicted clinical and functional outcomes. Twenty-three participants were assessed at clinical presentation and a mean of 31 months later. Performance on a JTC and VSM tasks were measured at both time points. Relationships to symptom severity, level of function and the incidence of psychotic disorder were then examined. The levels of symptoms, function and VSM all improved over time, while JTC was stable. Five participants (22%) developed a psychotic disorder during the follow up period, but the risk of transition was not related to performance on either task at baseline, or to longitudinal changes in task performance. JTC performance correlated with symptom severity at baseline and follow-up. Similarly, performance on the two tasks was not related to the level of functioning at follow-up. Thus, while the ARMS is associated with both VSM and JTC biases, neither predict the onset of psychosis or the overall functional outcome. PMID- 25511318 TI - Histidine-tryptophan-ketoglutarate solution with added ebselen augments myocardial protection in neonatal porcine hearts undergoing ischemia/reperfusion. AB - Whether modified histidine-tryptophan-ketoglutarate (HTK) solution offers myocardial protection to newborn heart has not been documented. The purpose of this study was to compare myocardial protection using HTK added by ebselen with HTK in a piglet model of cardiopulmonary bypass (CPB). Fifteen piglets were randomly assigned to three groups: the control group (C group, n = 5), HTK solution group (HTK group, n = 5), and HTK added by 10 nM ebselen group (HTK+E group, n = 5). Animals in the two experimental groups were placed on hypothermic CPB, after which the ascending aorta had been clamped for 2 h. The control animals underwent normothermic CPB without cardiac arrest. Myocardial antioxidant activities, myocytes apoptosis and mitochondrial structures, as well as the release of cytochrome c and the expression of Bax, Bcl-2, and HSP72 protein in myocardium were measured. Increased myocardial superoxide dismutase (SOD) and Mn SOD activities, decreased TUNEL-positive cells, and reduced release of cytochrome c were noted in the HTK+E group compared with those in the HTK group (P = 0.021, P = 0.020, P = 0.045, and P = 0.010, respectively). The Bax/Bcl-2 ratio in the HTK group was significantly higher than that in the C group (P = 0.024). The expression of HSP72 protein and mRNA in the HTK+E group was higher than that in the HTK group (P = 0.039 and P = 0.035, respectively). Mitochondrial score under electron microscope in the HTK+E group was lower than that in the HTK group (P = 0.047). Improved antioxidant defense, reduced myocytes apoptosis, and better preserved mitochondrial structure were observed in the HTK+E group. Ebselen added to HTK provides better myocardioprotection to HTK solution for the neonatal heart. PMID- 25511319 TI - Rituximab and bortezomib (RB): a new effective regimen for refractory or relapsed indolent lymphomas. AB - This study was conducted to evaluate the efficacy and safety of rituximab and Bortezomib in relapsed or refractory indolent B cell non-Hodgkin's lymphoma (NHL). Treatments consisted of rituximab 375 mg/m(2), i.v. on days 1, 8, 15, and 22 of cycle 1 and on day one of cycles 2-5, bortezomib 1.6 mg/m(2), given by intravenous injection (3-s to 5-s bolus) on days 1, 8, 15, and 22 of a maximum of five cycles. The primary end points were the overall survival (OS) and progression-free survival (PFS). Secondary endpoints included response rate (ORR; CR) and toxicities. From January 2008 to December 2010, 60 successive patients at Tianjin cancer hospital lymphoma department were enrolled in this study. All patients were recurrent or refractory indolent B cell NHL, including follicular lymphoma grades 1-2 (n = 35), small lymphocytic lymphoma/chronic lymphocytic leukemia (LL/CLL; n = 16) and marginal zone lymphoma (n = 9). The median follow up time was 30 months (range 12-48). The overall response rate was 70.0 %, with a CR/CRu rate of 31.7 %. The 2-year OS and PFS of all patients were 75.0 and 41.0 %, respectively. Grade 3-4 neutropenia and thrombocytopenia occurred in 10 and 3.3 % of patients, respectively. Higher IPI and refractory disease were independently associated with worse survival and PFS. RB chemotherapy in patients with refractory or relapsed indolent B cell NHL was effective with low toxicity. PMID- 25511316 TI - Are stressful life events causally related to the severity of obsessive compulsive symptoms? A monozygotic twin difference study. AB - Traumatic or stressful life events have long been hypothesized to play a role in causing or precipitating obsessive-compulsive symptoms but the impact of these environmental factors has rarely been investigated using genetically informative designs. We tested whether a wide range of retrospectively-reported stressful life events (SLEs) influence the lifetime presence and severity of obsessive compulsive symptoms (OCS) in a large Swedish population-based cohort of 22,084 twins. Multiple regression models examined whether differences in SLEs within twin pairs were significantly associated with differences in OCS. In the entire sample (i.e., both monozygotic [MZ] and dizygotic twin pairs), two SLEs factors, "abuse and family disruption" and "sexual abuse", were significantly associated with the severity of OCS even after controlling for depressive symptoms. Other SLEs factors were either not associated with OCS ("loss", "non-sexual assault") or were no longer associated with OCS after controlling for depression ("illness/injury"). Within MZ pair analyses, which effectively control for genetic and shared environmental effects, showed that only the "abuse and family disruption" factor remained independently related to within-pair differences in OCS severity, even after controlling for depressive symptoms. Despite being statistically significant, the magnitude of the associations was small; "abuse and family disruption" explained approximately 3% of the variance in OCS severity. We conclude that OCS are selectively associated with certain types of stressful life events. In particular, a history of interpersonal abuse, neglect and family disruption may make a modest but significant contribution to the severity of OCS. Further replication in longitudinal cohorts is essential before causality can be firmly established. PMID- 25511320 TI - Evaluation of urinary miRNA-96 as a potential biomarker for bladder cancer diagnosis. AB - For bladder cancer, a new diagnostic marker is needed to avoid painful cystoscopy. The aim of this study was to explore the efficacy of urinary miRNA-96 as molecular marker in bladder cancer diagnosis and its relation to bilharziasis. Urine cytology, serologic assessment of schistosomiasis and estimation of miRNA 96 by real-time PCR were carried out for 94 bladder cancer patients, 30 benign bladder lesions and 60 healthy individuals. Expression of miRNA-96 showed a significant difference among the three tested groups and also between benign and malignant bilharzial cases. Urinary miRNA-96 is a good noninvasive diagnostic biomarker for bladder cancer. PMID- 25511321 TI - Predictive value of F-18 FDG PET/CT quantization parameters in diffuse large B cell lymphoma: a meta-analysis with 702 participants. AB - F-18 fluorodeoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) is considered to be the most beneficial imaging method for staging patients with lymphoma. Whether maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) acquired from F-18 FDG PET/CT are predictors of prognosis of diffuse large B cell lymphoma (DLBCL) is controversial, with some studies concluding that it is and others concluding the opposite. Therefore, a systematic review was performed to explore the relationship of F-18 FDG PET/CT quantization parameters with the prognosis of DLBCL. Seven trials with a total of 703 DLBCL patients were included for analysis. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS), and odds ratios (ORs) for 3-year PFS and OS were pooled using the STATA package. Combined results suggested a strong link between the high SUVmax, MTV and TLG values and the poor 3-year PFS with ORs of 2.59, 3.69 and 2.29, respectively. Similarly, high MTV and TLG values unfavorably influenced the 3 year OS with ORs of 5.40 and 2.19, respectively. The pooled results also showed that high SUVmax and MTV were negative predictors of PFS with HRs of 1.61 (p = 0.038) and 2.18 (p = 0.000), respectively. The TLG value was not predictive of PFS. And for OS, only high MTV was a strong predictor of poor prognosis in DLBCL with HR 2.99 (p = 0.000). Our results suggested that SUVmax and MTV may be significant prognostic markers for PFS and MTV may be the only predictor for OS in DLBCL. PMID- 25511322 TI - Adjunctive traditional Chinese medicine therapy for patients with chronic rhinosinusitis: a population-based study. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a chronic illness with a high prevalence worldwide. The purpose of this study was to investigate the characteristics of adjunctive traditional Chinese medicine (TCM) use in patients with CRS. METHODS: Data were retrieved from a dataset made available by the Taiwan National Health Insurance Research Database (NHIRD) containing the medical records of 1,000,000 randomly sampled beneficiaries insured in the year 2000. Patients newly diagnosed with CRS in the year 2000 were enrolled, and their medical records during the period 2000 to 2011 were collected and analyzed. RESULTS: A total of 14,806 CRS subjects were enrolled in this study: 10,512 were non-TCM users and 4294 were TCM users. TCM group had a significantly higher proportion of females, were younger, and a greater proportion lived in urban areas compared with the non-TCM group (all p < 0.0001). Ninety-seven percent (97%) of the TCM users received herbal remedies. The most common Chinese herbal formula used was Xin-Yi-Qing-Fei-Tang and the most commonly used single herb was Baizhi. The hazard ratio (HR) for functional endoscopic sinus surgery (FESS) was 0.17 for TCM users (95% confidence interval [CI], 0.15 to 0.20) compared with non TCM users after adjusting for age, sex, urbanization, and comorbidities. CONCLUSION: Our investigation found that 29% of CRS patients used TCM in addition to Western medical treatment. A lower proportion of patients in the TCM group underwent ESS compared with that in the non-TCM group. These findings may be of value in further studies evaluating the efficacy and safety of TCM use in CRS patients. PMID- 25511323 TI - Self-perceived health among Eastern European immigrants over 50 living in Western Europe. AB - OBJECTIVES: This paper examines whether Eastern European immigrants aged 50 and over living in Northern and Western Europe face a health disadvantage in terms of self-perceived health, with respect to the native-born. We also examined health changes over time (2004-2006-2010) through the probabilities of transition among self-perceived health states, and how they vary according to nativity status and age group. METHODS: Data were obtained from the Survey of Health, Ageing and Retirement in Europe (SHARE). Logistic regressions and probabilities of transition were used. RESULTS: Results emphasise the health disadvantage of Eastern European immigrants living in Germany, France and Sweden with respect to the native-born, even after controlling for socio-economic status. Probabilities of transition also evidenced that people born in Eastern Europe were more likely to experience worsening health and less likely to recover from sickness. CONCLUSIONS: This paper suggests that health inequalities do not affect immigrant groups in equal measure and confirm the poorer and more steeply deteriorating health status of Eastern European immigrants. PMID- 25511325 TI - The role of emotional intelligence in symptom reduction after psychotherapy in a heterogeneous psychiatric sample. AB - BACKGROUND: Emotional intelligence of the patient has been claimed to potentially be an important factor in psychotherapy. Empirical studies are largely lacking. The purpose of this study was to examine if (i) pre-intervention emotional intelligence predicts outcome of psychotherapy and (ii) change in emotional intelligence during psychotherapy is associated with change in symptoms in a patient sample with heterogeneous psychiatric symptoms. METHODS: Participants were 166 patients with different diagnoses who were hospitalized at the Center for Psychological Recovery. Before, after hospitalization and 6months after hospitalization they were asked to complete the BarOn-EQi for emotional intelligence and the Symptom Checklist-90. RESULTS: Level of emotional intelligence at the start of hospitalization largely did not predict psychological symptoms at post-intervention or at 6month follow-up. However, an increase in the level of emotional intelligence over the course of the intervention was associated with lower levels of psychological symptoms, both immediately post-intervention and at 6-month follow-up. CONCLUSIONS: The results suggest that while the pre-intervention level of emotional intelligence has no substantial effect on treatment outcome, an increase in emotional intelligence may have a positive effect on symptom decrease and on the preservation of treatment results. PMID- 25511324 TI - Designs of two randomized, community-based trials to assess the impact of alternative cookstove installation on respiratory illness among young children and reproductive outcomes in rural Nepal. AB - BACKGROUND: Acute lower respiratory infections (ALRI) are a leading cause of death among children. Low birthweight is prevalent in South Asia and associated with increased risks of mortality, and morbidity, high levels of indoor household air pollution caused by open burning of biomass fuels are common and associated with high rates of ALRI and low birthweight. Alternative stove designs that burn biomass fuel more efficiently have been proposed as one method for reducing these high exposures and lowering rates of these disorders. We designed two randomized trials to test this hypothesis. METHODS/DESIGN: We conducted a pair of community based, randomized trials of alternative cookstove installation in a rural district in southern Nepal. Phase one was a cluster randomized, modified step wedge design using an alternative biomass stove with a chimney. A pre installation period of morbidity assessment and household environmental assessment was conducted for six months in all households. This was followed by a one year step-wedge phase with 12 monthly steps for clusters of households to receive the alternative stove. The timing of alternative stove introduction was randomized. This step-wedge phase was followed in all households by another six month follow-up phase. Eligibility criteria for phase one included household informed consent, the presence of a married woman of reproductive age (15-30 yrs) or a child < 36 months. Children were followed until 36 months of age or the end of the trial. Pregnancies were identified and followed until completion or end of the trial. Phase two was an individually randomized trial of the same alternative biomass stove versus liquid propane gas stove in a subset of households that participated in phase one. Follow-up for phase two was 12 months following stove installation. Eligibility criteria included the same components as phase one except children were only enrolled for morbidity follow-up if they were less than 24 months.The primary outcomes included: incidence of ALRI in children and birthweight. DISCUSSION: We presented the design and methods of two randomized trials of alternative cookstoves on rates of ALRI and birthweight. TRIAL REGISTRATION: Clinicaltrials.gov (NCT00786877, Nov. 5, 2008). PMID- 25511326 TI - Effects of propofol and sevoflurane on isolated human umbilical arteries pre contracted with dopamine, adrenaline and noradrenaline. AB - AIM: To assess the effects of propofol and sevoflurane on the contraction elicited by dopamine, adrenaline and noradrenaline on isolated human umbilical arteries. METHODS: Umbilical arteries were cut into endothelium-denuded spiral strips and suspended in organ baths containing Krebs-Henseleit solution bubbled with O2 +CO2 mixture. Control contraction to phenylephrine (10(-5) M) was recorded. Response curves were obtained to 10(-5) M dopamine, 10(-5) M adrenaline or 10(-5) M noradrenaline. Afterwards, either cumulative propofol (10(-6) M, 10(-5) M and 10(-4) M) or cumulative sevoflurane (1.2%, 2.4% and 3.6%) was added to the organ bath, and the responses were recorded. Responses are expressed percentage of phenylephrine-induced contraction (mean +/- standard deviation) (P < 0.05 = significance). RESULTS: Propofol and sevoflurane elicited concentration-dependent relaxations in strips pre-contracted with dopamine, adrenaline and noradrenaline (P < 0.05). Highest (10(-4) M) concentration of propofol caused significantly higher relaxation compared with the highest (3.6%) concentration of sevoflurane in the contraction elicited by dopamine. High (10( 5) M) and highest concentrations of propofol caused significantly higher relaxation compared with the high (2.4%) and highest concentrations of sevoflurane on the contraction elicited by adrenaline. High and highest concentrations of sevoflurane caused significantly higher relaxation compared with the high and highest concentrations of propofol on the contraction elicited by noradrenaline. CONCLUSION: Dopamine, adrenaline and noradrenaline elicit contractions in human umbilical arteries, and noradrenaline causes the highest contraction. Both propofol and sevoflurane inhibit these contractions in a dose dependent manner. Propofol caused greater relaxation in the contractions elicited by dopamine and adrenaline while sevoflurane caused greater relaxation in the contraction elicited by noradrenaline. PMID- 25511328 TI - An association analysis of the R1628P and G2385R polymorphisms of the LRRK2 gene in multiple system atrophy in a Chinese population. AB - BACKGROUND: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been reported to be responsible for autosomal dominant late-onset sporadic Parkinson's disease (PD). The R1628P and G2385R polymorphisms of the LRRK2 gene have been identified as exclusively associated with PD in Asian populations, particularly in Han Chinese population. Considering that there is overlap of the clinical manifestations and pathological characteristics between PD and MSA, we studied the possible associations between R1628P and G2385R polymorphisms of the LRRK2 and MSA in a population of Han Chinese patients. METHODS AND PATIENTS: A total of 318 MSA patients and 350 unrelated age- and sex-matched healthy controls (HCs) were included in the study. All subjects were genotyped for R1628P and G2385R using polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) analysis and direct sequencing. RESULTS: No significant differences were observed in the genotype distribution and minor allele frequency (MAF) of R1628P between MSA patients and HCs (P = 0.418 and P = 0.424), between MSA-C and HCs (P = 0.347 and P = 0.353), between MSA-P and HCs (P = 0.787 and P = 0.790), and between MSA-C and MSA-P (P = 0.606 and P = 0.610). In addition, no significant differences were also observed in the genotype distribution and MAF of G2385R between MSA patients and HCs (P = 0.141 and P = 0.051), between MSA-C and HCs (P = 0.061 and P = 0.065), between MSA-P and HCs (P = 0.184 and P = 0.158), and between MSA-C and MSA-P (P = 0.354 and P = 0.853). CONCLUSION: The present study suggests that R1628P and G2385R polymorphisms of the LRRK2 are not risk factors for MSA in the Han Chinese population. PMID- 25511329 TI - Reasons for mild parkinsonian signs - which constellation may indicate neurodegeneration? AB - INTRODUCTION: Mild parkinsonian signs (MPS) are common in the elderly population. Several factors including physical decline and comorbidities in addition to neurodegeneration may be possible sources for MPS. The objective was to examine whether MPS are associated with a history of orthopedic disturbances, vascular diseases or prodromal markers for neurodegeneration. METHODS: The TREND study is a prospective longitudinal cohort study in individuals >50 years with biennial assessments designed to identify prodromal markers for neurodegeneration. In this substudy, 1091 elderly individuals were evaluated for a possible association of MPS with prodromal markers for neurodegeneration, orthopedic disturbances, vascular diseases, as well as cerebral abnormalities. These factors were assessed by self-administered questionnaires, with a structured health interview, a neurological examination and by transcranial sonography. RESULTS: 82 participants showed MPS. They were found to have more often hyposmia and RBD, had a higher autonomic dysfunction score and they more frequently showed hyperechogenicity of the substantia nigra compared to controls. Neither orthopedic disturbances nor vascular diseases were significantly associated with the prevalence of MPS. CONCLUSION: MPS might be a sign of early neurodegeneration rather than caused by other motor influencing diseases. PMID- 25511330 TI - Resting activity in visual and corticostriatal pathways in Parkinson's disease with hallucinations. AB - BACKGROUND: Visual hallucinations are an important non-motor complication of Parkinson's disease (PD) and carry a negative prognosis. Their biological basis is uncertain, but may relate to the activity of resting state networks in brain. We therefore aimed to investigate functional activity of brain in patients with visual hallucinations (PDVH) in resting state compared to patients without hallucinations (PDnonVH) and a healthy control group (HC). METHODS: Resting state functional MRI was acquired and the primary analysis compared the amplitude of low-frequency fluctuations (ALFF) across groups. This informed a secondary analysis, in the PD groups only, comparing functional connectivity between a 'seed' region in the occipital lobe and the rest of the brain. RESULTS: Individuals with PDVH showed lower ALFF in bilateral lingual gyrus and cuneus and greater ALFF in temporo-parietal regions, medial temporal gyrus and cerebellum than PDnonVH and HC. PDnonVH also had lower ALFF in occipitoparietal region and greater ALFF in medial temporal gyrus, temporo-parietal and cerebellum regions than HC. Functional connectivity analysis revealed that, although both PD groups had lower occipital functional connectivity relative to the HC group, occipital - corticostriatal connectivity was significantly higher in those with PDVH compared with PDnonVH. CONCLUSION: Our study reveals widespread hemodynamic alterations in PD. However, within a functionally abnormal occipital lobe, those with PDVH have even lower ALFF than non-hallucinators, but have higher occipital functional connectivity with cortical-striatal regions. These findings suggest disruption of pathways underpinning both primary visual perceptual and intrinsic visual integration may contribute to visual hallucinations in PD. PMID- 25511331 TI - Distinguishing idiopathic Parkinson's disease from other parkinsonian syndromes by breath test. AB - INTRODUCTION: Diagnosis of different parkinsonian syndromes is linked with high misdiagnosis rates and various confounding factors. This is particularly problematic in its early stages. With this in mind, the current pilot study aimed to distinguish between Idiopathic Parkinson's Disease (iPD), other Parkinsonian syndromes (non-iPD) and healthy subjects, by a breath test that analyzes the exhaled volatile organic compounds using a highly sensitive nanoarray. METHODS: Breath samples of 44 iPD, 16 non-iPD patients and 37 healthy controls were collected. The samples were passed over a nanoarray and the resulting electrical signals were analyzed with discriminant factor analysis as well as by a K-fold cross-validation method, to test the accuracy of the model. RESULTS: Comparison of non-iPD with iPD states yielded 88% sensitivity, 88% accuracy, and 88% Receiver Operating Characteristic area under the curve in the training set samples with known identity. The validation set of this comparison scored 81% sensitivity and accuracy and 92% negative predictive value. Comparison between atypical parkinsonism states and healthy subjects scored 94% sensitivity and 85% accuracy in the training set samples with known identity. The validation set of this comparison scored 81% sensitivity and 78% accuracy. The obtained results were not affected by l-Dopa or MAO-B inhibitor treatment. CONCLUSIONS: Exhaled breath analysis with nanoarray is a promising approach for a non-invasive, inexpensive, and portable technique for differentiation between different Parkinsonian states. A larger cohort is required in order to establish the clinical usefulness of the method. PMID- 25511332 TI - Can we spin straw into gold? An evaluation of immigrant legal status imputation approaches. AB - Researchers have developed logical, demographic, and statistical strategies for imputing immigrants' legal status, but these methods have never been empirically assessed. We used Monte Carlo simulations to test whether, and under what conditions, legal status imputation approaches yield unbiased estimates of the association of unauthorized status with health insurance coverage. We tested five methods under a range of missing data scenarios. Logical and demographic imputation methods yielded biased estimates across all missing data scenarios. Statistical imputation approaches yielded unbiased estimates only when unauthorized status was jointly observed with insurance coverage; when this condition was not met, these methods overestimated insurance coverage for unauthorized relative to legal immigrants. We next showed how bias can be reduced by incorporating prior information about unauthorized immigrants. Finally, we demonstrated the utility of the best-performing statistical method for increasing power. We used it to produce state/regional estimates of insurance coverage among unauthorized immigrants in the Current Population Survey, a data source that contains no direct measures of immigrants' legal status. We conclude that commonly employed legal status imputation approaches are likely to produce biased estimates, but data and statistical methods exist that could substantially reduce these biases. PMID- 25511333 TI - Non-crossing weighted kernel quantile regression with right censored data. AB - Regarding survival data analysis in regression modeling, multiple conditional quantiles are useful summary statistics to assess covariate effects on survival times. In this study, we consider an estimation problem of multiple nonlinear quantile functions with right censored survival data. To account for censoring in estimating a nonlinear quantile function, weighted kernel quantile regression (WKQR) has been developed by using the kernel trick and inverse-censoring probability weights. However, the individually estimated quantile functions based on the WKQR often cross each other and consequently violate the basic properties of quantiles. To avoid this problem of quantile crossing, we propose the non crossing weighted kernel quantile regression (NWKQR), which estimates multiple nonlinear conditional quantile functions simultaneously by enforcing the non crossing constraints on kernel coefficients. The numerical results are presented to demonstrate the competitive performance of the proposed NWKQR over the WKQR. PMID- 25511334 TI - What matters time? The importance of time for those with advanced progressive disease and their families. PMID- 25511335 TI - Obstructive sleep apnea: awakening the hidden truth. AB - Obstructive sleep apnea (OSA) is a common type of sleep apnea and is caused by obstruction of upper airway. Sleep apnea is clinically defined as frequent episodes of apnea, hypopnea and symptoms of functional impairment, which could be life-threatening and associated with extreme daytime hyper somnolence, dysfunction, discrements in health-related quality of life, automobile accidents, and cardiovascular morbidity and mortality. Etiopathogenic factors that contribute to OSA include reduced upper-airway dilator muscle activity during sleep, upper-airway anatomical features, ventilatory control insufficiency, lung volume, and rostral fluid shifts. The presence of risk factors such as age, gender and obesity increases the incidence of OSA. The repetitive nocturnal hypoxemia experienced by patients with OSA is associated with activation of a number of neural, humoral, thrombotic, metabolic, and inflammatory disease mechanisms, all of which have also been implicated in the pathophysiology of various systemic diseases. This article summarizes the etiopathogenesis, epidemiology, associated systemic diseases such as cardiovascular diseases, diabetes, and dental diseases with OSA and the influence of tongue on oropharyngeal airway in OSA patients. PMID- 25511336 TI - Evaluation of panoramic radiographs taken from 1,056 Turkish children. AB - OBJECTIVE: Panoramic radiographs (PRs) play an important role in the diagnosis and treatment planning of a wide range of dental and maxillofacial diseases and conditions. To examine and to determine the status of oral lesions, dental anomalies and pathologies in panoramic radiographs, which were taken at the department of pediatric dentistry, Dental School, Marmara University, Istanbul, Turkey. MATERIALS AND METHODS: This retrospective study consists of 1,056 randomly selected PRs of children aged from 4 to 12 years old, conducted at the department of pediatric dentistry at Dental School, Marmara University, between 5 th December 2011 and 17 th January 2012. The following information was obtained from the patients' records and PRs: Gender, age, presence or absence of oral lesions, dental anomalies and pathologies such as mesiodentes, supernumerary teeth, odontoma, radicular cyst, impacted tooth, and fusion. RESULTS: One thousand and fifty-six PRs from 520 girls and 536 boys were observed. The mean and standard deviation age of the patients was 8.43 +/- 2.17. Among 1,056 patients, 457 (43.28%) of them had oral lesions, discovered by the PRs. The age of these 457 patients was ranged from 4 to 12 years. There were 37 (3.50%) mesiodentes, 9 (0.85%) supernumerary teeth, 4 (0.38%) odontoma, 12 (1.14%) radicular cyst, 16 (1.52%) impacted tooth, and 20 (1.89%) fusion. CONCLUSIONS: Oral lesions with a rate of 43.28% could be detected relatively at early age, as presented in the present study. Early treatment of these lesions, dental anomalies, and pathologies could avoid maxillofacial deformity and other complications. PMID- 25511337 TI - Alcohol consumption among pregnant women attending the ante-natal clinic of a tertiary hospital in South-South Nigeria. AB - BACKGROUND: As efforts to reduce maternal and childhood mortality rates continue to yield results in Nigeria, it is time to put more emphases on the health of children. Alcohol consumption is one of the few modifiable risk factors for poor pregnancy outcome. This study assessed the consumption of alcohol among pregnant women attending the antenatal clinic of the University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria. MATERIALS AND METHODS: This study was carried out using a descriptive cross-sectional study design, with data collected using an interviewer-administered questionnaire. The questionnaire was used to collect information on the knowledge of the harmful effects of alcohol on the fetus, attitudes toward alcohol use by pregnant women, and alcohol use by the respondents. RESULTS: A total of 221 subjects were studied. The respondents had an average age of 29.5 +/- 4.6 years, were mostly married (96.83%), Christians (94.57%), and had tertiary education (73.76%). Only, 51.58% of the respondents knew of the harmful effects of alcohol on the fetus; of whom, 62.29% were told by a health professional. More than half (59.28%) of the respondents had taken alcohol during the index pregnancy, about a third (39.40%) of whom drank alcohol on a regular basis, whereas 25.79% were binge drinkers. There were no statistically significant differences in the marital (P = 0.16) and educational status (P = 0.15) of the respondents who abstained from alcohol in the index pregnancy, compared with those who drank alcohol; although, statistically significant differences were observed in the age (P < 0.001), parity (P = 0.02) and religion (P < 0.001) of the respondents. CONCLUSION: The level of alcohol consumption among the pregnant women is high. Health education is, therefore, required to change the attitude of the public and the knowledge and behavior of the pregnant women. PMID- 25511338 TI - Drugs with anticholinergic side-effects in primary care. AB - BACKGROUND: Anticholinergic drugs in elderly people have been associated with some serious side-effects. Patients in Turkey tend to attend primary care centers to have prescriptions of the drugs they chronically use. However, very little are known about how frequent that these drugs are prescribed and their side-effects in Turkish population. We aimed to investigate the usage and side-effects of drugs with anticholinergic properties in patients over 65 years of age attending to primary care centers. MATERIALS AND METHODS: Five hundred and sixty-three subjects were interviewed with a questionnaire of 16 questions inquiring their medication and possible side-effects. Timed up and go test (TUGT) and standardized mini-mental test (SMMT) were also performed. RESULTS: Medical records of 563 individuals were screened to detect anticholinergic medication. Twenty-eight patients were using anticholinergic medication. Mean duration of anticholinergic medication usage was 3.17 years. Mean number of falls occurred in the previous year was 1.14 +/- 1.17. Mean SMMT score was 27.20 +/- 1.13. Mean TUGT scores mean was 12.4 +/- 1.25. Drowsiness in 18 patients (65%), dry mouth in 15 patients (53%), dry eyes in 15 patients (53%), constipation in 11 patients (39%), blurred vision in 11 patients (%39), urinary hesitancy in eight patients (28%), confusion in six patients (21%) were reported. We found that none of the subjects were evaluated in terms of fall risk or mental status by their doctors before the prescription of drugs with anticholinergic effects. CONCLUSIONS: A suggested approach to improve drug safety was reported as to reduce the use of anticholinergic drugs when it is possible. Psychiatrists and family physicians should select less anticholinergic drugs for medication and have to evaluate their patients' fall risk and their cognitive status before prescribing drugs with anticholinergic side effects. PMID- 25511339 TI - What co-morbidities do people with malaria have and what are their patterns of health seeking in Nigeria? AB - BACKGROUND: This study assessed the comorbidities associated with malaria and patterns of health seeking in southeast Nigeria. MATERIALS AND METHODS: The survey was undertaken in Enugu state, Southeast Nigeria. Data were collected from 500 householders, 200 in-patient and outpatient exit surveys and data abstraction from 125 inpatient and outpatient records. RESULTS: A total of 307 (64.2%) households had an episode of malaria within 1 month of the interview. The most common malaria comorbidities were upper respiratory tract infection and diarrhea. Most patients first sought treatment from patent medicine vendors. The average monthly cost of treating the comorbidities was 270 Naira (1.75 USD) and 601 Naira (3.89 USD) for outpatient department and inpatient department respectively. CONCLUSION: The economic burden of malaria is compounded by comorbidities and inappropriate health seeking behavior. Interventions to control malaria are required to also control common comorbidities. PMID- 25511340 TI - Prevalence of placenta Plasmodium parasitemia and pregnancy outcome in asymptomatic patients at delivery in a university teaching hospital in Nigeria. AB - BACKGROUND: Malaria is an important public health issue in pregnancy association with poor fetal and maternal outcome, especially in malaria endemic area like Nigeria. OBJECTIVE: The objective was to determine the prevalence of placental malaria in asymptomatic women in labor and to compare the fetal and maternal outcome between affected and unaffected women. SUBJECTS AND METHODS: A prospective cross-sectional study of 210 women who delivered at a tertiary health facility in Nigeria. Participants' peripheral venous blood, cord blood, and placental blood samples were examined microscopically for the presence of malaria parasite. Data collected were analyzed using SPSS version 16. RESULTS: Prevalence of placental malaria was 65.2%. Nulliparity was significantly associated with placental malaria (chi2 = 21.32, P = 0.0000039, odds ratio [OR] =5.6). Poor compliance to intermittent preventive therapy was significantly associated with placental malaria (chi2 = 16.67, P = 0.00004). The mean gestational age at delivery was 38.57 +/- 1.7 weeks and 12.85% of women had preterm delivery. Sixty seven (31.9%) women had anemia and malaria parasitemia was significantly associated with anemia (chi2 = 8.34, P = 0.0039, OR = 2.6). Fourteen (6.67%) babies had low birth weight, but placental malaria was not significantly associated with low birth weight (chi2 = 0.03, P = 0.87). CONCLUSION: There is a high prevalence of placental malaria in the study population. Nulliparity, poor drug compliance, and maternal anemia were associated with placental malaria. PMID- 25511341 TI - Maternal knowledge and care-seeking behaviors for newborn jaundice in Sagamu, Southwest Nigeria. AB - BACKGROUND: Delay in the presentation of infants with jaundice at the hospital is a reason for the persistence of the severe forms of jaundice. OBJECTIVE: The aim was to determine the influence of maternal knowledge on newborn jaundice on their care-seeking practices. METHODS: In a cross-sectional survey, mothers whose infants presented with significant hyperbilirubinemia were assessed for knowledge about jaundice in relation to their care seeking behaviors. RESULTS: Out of 98 mothers, 57.1% had good knowledge on newborn jaundice. Most of the mothers with good knowledge had tertiary education (P = 0.004), had good care-seeking behavior for newborn jaundice (P = 0.027) and their infants did not develop kernicterus (P = 0.0001). Mothers with tertiary education also had significantly better performances on the knowledge and care-seeking evaluation scales. CONCLUSION: Maternal knowledge on newborn jaundice, as well as tertiary maternal education, influenced appropriate care-seeking behavior for infants with jaundice and reduced the risk of complications. PMID- 25511342 TI - Outbreak of serotype W135 Neisseria meningitidis in central river region of the Gambia between February and June 2012: a hospital-based review of paediatric cases. AB - BACKGROUND: Meningitis still accounts for many deaths in children especially during epidemics in countries within the African meningitis belt. Between February and May 2012, the Gambia witnessed an outbreak of meningitis in two of its six regions. This study presents a clinical perspective of this outbreak in central river region of the Gambia. It evaluated the outbreak pattern, clinical features, and mortality among suspected cases that presented to the hospital during the outbreak. METHODOLOGY: This is a prospective observational study of suspected cases of meningitis that presented to the pediatric ward of the Bansang Hospital during the outbreak period. Confirmed cases of meningitis were consecutively enrolled, and those with negative blood cultures presenting during the same period were employed as controls. RESULT: Two hundred and four suspected cases of meningitis presented to the pediatric ward during the outbreak. Ninety were confirmed as meningitis cases. The W135 strain of Neisseria meningitidis was responsible for 89 (98.9%) of meningitis cases seen with an incidence rate of 74.9/100,000 in children (0-14 years) and in-hospital case fatality rate of 7.9%. Highest attack rate was among the 12-49 months age group. Clinical features such as meningeal signs (neck stiffness), conjunctivitis, and joint swelling were seen more in cases than controls. Contact history with relatives, who had fever in previous 2 weeks prior to illness was significantly seen more in cases. Adjusted regression analysis showed 7.5 more likelihood of infection with positive contact history (odds ratio [OR]: 7.2 confidence interval [CI]: [3.39-15.73]). There was no significant difference in death outcome between cases and controls (OR: 0.78 CI: [0.29-2.13]). The double peak wave-like pattern of the epidemic curve noted during this outbreak suggests a disseminated outbreak originating from an index case with propagated spread. CONCLUSION: There is need for more effective surveillance and incorporation of vaccine against meningitis into the expanded program on immunization schedule of the Gambia and other countries within the meningitic epidemic belt. PMID- 25511343 TI - Human rotavirus genotypes causing acute watery diarrhea among under-five children in Benin City, Nigeria. AB - BACKGROUND: Diarrhea is a major cause of childhood morbidity and mortality in the developing countries. Rotavirus is a major cause of acute watery diarrhea. AIM: This study aims at characterizing the prevalent rotavirus G-genotypes among under five children presenting with acute watery diarrhea in Benin City, Nigeria. METHODOLOGY: A total of 470 children <5 years presenting with diarrhea of <2 weeks duration, were over a period of 1 year consecutively recruited for the study. Stool samples were collected for rotavirus antigen detection using Enzyme Linked Immunosorbent Assay (ELISA) and further analyzed with reverse transcriptase polymerase chain reaction (RT-PCR) for VP7 genotyping. RESULTS: Comparing the ability of the two methods to detect rotavirus in stool samples, 65 (13.8%) and 90 (19.2%) of the stools tested positive for rotavirus using ELISA and RT-PCR, respectively. Using VP7 primers, genotypes G1 were detected in 49 out of 90 stool samples (54.4%), G2 in 26 out of 90 stool samples (28.9%), G3 in 19 out of 90 stool samples (21.1%), G4 in 34 out of 90 stool samples (37.8%) and G9 in 8 of the 90 stool samples (8.9%). Some strains were observed to be reactive with 2 or more of the primers yielding dual or triple VP7 genotype reactivity. CONCLUSION: Rotavirus of varying genotypes as shown cause acute watery diarrhea among under-five children and vaccine with strains peculiar to this environment should be introduced. Techniques such as RT-PCR rather than ELISA, where affordable, should be used in stool rotavirus screening. PMID- 25511344 TI - Investigation of possible virulence factors in Candida strains isolated from blood cultures. AB - BACKGROUND: The Candida species, which are one of the most common causes of nosocomial bloodstream infections, present with high mortality and morbidity rates. This study aims to investigate the production of esterase, phospholipase, proteinase, and biofilm formation ability of the Candida strains isolated from the blood cultures. MATERIALS AND METHODS: Between June 2011 and July 2012, the Candida strains, which were isolated from blood cultures of a total of 50 patients, were studied. The esterase activity was analyzed in the Tween-80 agar, while phospholipase activity was studied in the egg yolk agar. The proteinase activity and biofilm formation were identified by using the petri dish method and microplate method, respectively. RESULTS: Of 50 specimens obtained from individual patients, 17 (34%) were identified as C. albicans, 14 (28%) as C. glabrata, 9 (18%) as C. parapsilosis, 5 (10%) as C. krusei, 4 (8%) as C. kefyr, and 1 (2%) as C. tropicalis. The rate of proteinase, phospholipase, and esterase positivity was higher in the C. albicans isolates. Biofilm formation was the highest in the C. parapsilosis strains. CONCLUSIONS: Higher rate of virulence factors in the most commonly isolated Candida species than other species indicates that these virulence factors play a crucial role in the pathogenesis. PMID- 25511345 TI - Oral health and related factors in a group of children with cystic fibrosis in Istanbul, Turkey. AB - BACKGROUND: Cystic fibrosis (CF) patients can be considered as high caries risk patients because they frequently consume sugar-rich food between meals and they have a high intake of sugar containing syrups, aerosols, and salivary flow reducing medication. Variable caries prevalences were reported in CF patients in previous studies. There are no studies related to CF and salivary thromboplastic activity, which can be presented as a marker of wound healing and bleeding tendency of oral cavity. OBJECTIVE: The aim of this study was to compare oral health status and salivary pH, flow rate, and thromboplastic activity in children with CF and healthy controls. MATERIALS AND METHODS: A sample of 35 children with CF (23 girls and 12 boys), and 12 healthy control subjects (6 girls and 6 boys) were selected. Caries experience, oral hygiene, and dental erosion were assessed. Salivary flow rate, pH, thromboplastic activity, and total protein content were determined. Differences between the groups were evaluated using Chi-square test with a significance level set at 0.05. RESULTS: The differences between children with CF and healthy controls in tooth brushing frequency, use of fluoride tablets, caries experience, dental erosion index, oral hygiene index, salivary flow rate and total protein levels were not statistically significant (P > 0.05). Salivary thromboplastic activity of the CF group was significantly lower than the healthy controls (P < 0.01). CONCLUSION: Large population studies may be necessary to establish the role of salivary thromboplastic activity in children with CF considering our findings related to the decreased salivary thromboplastic activity, which may indicate delayed oral wound healing process. PMID- 25511346 TI - Assessment of knowledge and factors that may predict willingness to volunteerism: a pilot study of community-directed distributors in Anambra state. AB - BACKGROUND: Malaria as a leading cause of death in many developing countries requires urgent interventions. In order to improve access to healthcare, trained volunteers are used to distribute health commodities. The present study aims at determining knowledge and factors that may predict willingness to volunteerism in a developing country. METHODOLOGY: This was a cross-sectional descriptive study carried out in 2014 among 284 community-directed distributors in three rural communities in Anambra, Southeast Nigeria using pretested semi-structured questionnaires. RESULTS: The age range of volunteers was 21-79 years. Most (71.8%) are females and are married (83.1). Only 5.6% of the volunteers did not have any formal education. The predominant occupation is trading (52.5). Most volunteers (78.5%) could define the term volunteerism. Less than half (40.1%) knew the resources that could be volunteered. Most (67.3%) felt that volunteerism is most needed in church activities. Many respondents (58.8%) had volunteered for one or more programs previously. The most common challenge faced was interference with other income generating activities (66.5%). Retired males were more likely to volunteer than retired females (P <= 0.01). However, females are more likely to volunteer if the main reason of volunteering is to help people (P <= 0.01). The more educated ones believe that volunteerism will help them to be selected for other community programs. CONCLUSION: Most respondents had volunteered for other programs and the motivating factors included the satisfaction derived from helping others and the hope of being used for other community programs. PMID- 25511347 TI - The effect of intravenous preemptive paracetamol on postoperative fentanyl consumption in patients undergoing open nephrectomy: a prospective randomized study. AB - AIM: We investigated the efficacy of intravenous (IV) preemptive paracetamol on postoperative total fentanyl consumption and fentanyl-related side effects in patients undergoing open nephrectomy. MATERIALS AND METHODS: A total of 60 patients scheduled for elective open nephrectomy under general anesthesia were included. All patients received Patient-controlled IV analgesia with fentanyl postoperatively. Patients were randomly allocated into three equal groups: The fentanyl group received 100 mL of IV normal saline as a placebo, with the first dose ending 30 min before intubation. In paracetamol group, IV 1 g paracetamol was given to the patients 30 min after extubation with repeated doses every 6 h totally 4 times a day. In preemptive paracetamol group, patients received IV 1 g paracetamol every 6 h, with the first dose ending 30 min before intubation. RESULTS: Postoperative cumulative fentanyl consumption for 24 h was significantly higher in the fentanyl group (1009 +/- 139.361 MUg) than those of paracetamol (752.25 +/- 112.665 MUg) and preemptive paracetamol groups (761.10 +/- 226.625 MUg) (P = 0.001 for both). In early postoperative period (0-4 h); whereas total fentanyl consumption showed no statistically significant difference among groups (P = 0.186), the nausea-vomiting scores were significantly higher in the fentanyl group compared with other groups (P = 0.012). CONCLUSION: In patients undergoing open nephrectomy, use of preemptive or postoperative paracetamol reduces fentanyl related nausea-vomiting without a decrease in total fentanyl consumption in the early postoperative period. Furthermore, use of preemptive or postoperative paracetamol reduces total fentanyl requirements in the first 24 h postoperatively providing a safe and effective postoperative analgesia. PMID- 25511348 TI - Impact of an educational intervention on smoking counseling practice among Nigerian dentists and dental students. AB - INTRODUCTION: Oral health professionals are important in smoking cessation and prevention as their role is very crucial given the impact of smoking on oral health. Therefore, dental professionals need adequate education in tobacco use prevention and cessation skills to increase their confidence and be able to help patients to quit smoking. This study was aimed at determining the impact of an educational intervention on the attitudes, willingness, and perceived barriers of a group of Nigerian dental students and dentists to smoking cessation counseling in the dental clinic. METHODS: A self-administered questionnaire-based study was conducted in September 2007 at the Lagos University Teaching Hospital Idi Araba, Lagos. This was followed by a series of lectures and seminars using the brief intervention strategies for patients willing to quit using the Ask, Advise, Assess, Assist, and Arrange of cessation. A repeat study was conducted in January 2009 using the same questionnaire. Post intervention attitudes were significantly improved over pre intervention values for each parameter used in the assessment. RESULTS: A significantly higher proportion of the respondents were interested in providing cessation services after the intervention (P = 0.00002). Most (83.1%) of the respondents were willing to undergo training with a slight increase in the post intervention group from 80.9% to 86%. All the reported barriers were significantly reduced after the intervention (P = 0.000). CONCLUSION: This study has shown that educational interventions such as didactic instructions and practical training in tobacco use cessation can help to increase the willingness, confidence, and ability to provide information, during encounters with patients. PMID- 25511349 TI - Cigarette smoking and perception of its advertisement among antenatal clinic attendees in referral health facilities in Enugu, Nigeria. AB - BACKGROUND: The most predominant form of tobacco use is cigarette smoking, and it poses serious threats to maternal and child health. The magnitude of cigarette smoking in pregnancy in our environment is not well-known. The study aimed to determine the prevalence of cigarette smoking among pregnant women in Enugu, Nigeria as well as their exposures and perceptions of cigarette smoking advertisement. MATERIALS AND METHODS: Questionnaires were administered to a cross section of pregnant women randomly selected from three hospitals in Enugu, South East Nigeria, from May 2, 2012 to June 12, 2012. Analysis was both descriptive and inferential at 95% confidence levels. RESULTS: The prevalence of tobacco smoking in pregnancy was 4.5% (9/200). Over 90% of respondents admitted that cigarette smoking could harm both mother and unborn baby. In all, 79.5% (159/200) of respondents had seen or heard of advertisement for cigarette smoking as against 82.5% (165/200) that had seen or heard of antismoking advertisement (P = 0.444, odds ratio = 1.2 [95% confidence intervals: 0.74, 2.00]). CONCLUSIONS: The prevalence of cigarette smoking in pregnancy in Enugu, Nigeria was low, and there was high exposure to both pro-and anti-smoking advertisement. The awareness of harmful health effect of smoking was high but, that of the specific diseases associated with smoking in pregnancy was limited. Hence, antenatal classes and antismoking advertisement should be scaled-up to include maternal and peri-natal diseases/conditions associated with cigarette smoking. PMID- 25511350 TI - Evaluation of traumatic dental injuries in a group of Turkish population. AB - BACKGROUND: Traumatic dental injuries (TDIs) are significant clinical problems that may have complex etiologies and may cause physical and physiological impairment. AIM: The aim of this study was to determine the demographic and clinical characteristics of TDIs in a group of Turkish subjects. MATERIALS AND METHODS: The prevalence of TDIs and the pattern of traumatized teeth were studied in relation to age, gender, cause, location, and type of injury. This study was carried out to include all age groups and teeth. TDIs were recorded using the World Health Organization classification modified by Andreasen et al. RESULTS: The prevalence of TDIs was found to be 4.4% (255 injured patients/5800 presented patients), and the injuries were most commonly observed in the age group of 11-20 years. Males were more affected than females (males, 153; females, 102). The most common cause of traumatic injury was falling (68.2%), and the most common place of trauma was outdoors (56.1%). 4, 7% of patients injured because of their systemic diseases. The most frequently injured teeth were the upper central incisors (primary teeth, 64.5%; permanent teeth, 72.5%), and the most common type of dental injury was uncomplicated crown fracture in both primary (63%) and permanent dentition (47%). CONCLUSION: In the surveyed population, the prevalence of TDIs was found to be low. However, the teacher and family of adolescents and the caregivers of patients with some systemic diseases like epilepsy should be warned about TDIs. PMID- 25511351 TI - Stimulant: a correlate of brain fag syndrome among undergraduate students in a Nigerian university? AB - CONTEXT: Brain fag syndrome (BFS) is a culture-bound syndrome that occurs commonly among African people involve in intellectual activities like students. The features include intellectual (cognitive) impairment, somatic symptoms, disturbances of affect, and sleepiness. The Psychophysiological Theory identifies the use of stimulants as an etiological basis for the development of BFS; however, few researchers have linked BFS with stimulants use. AIMS: This study was to determine the prevalence of BFS, investigate whether there was an association between the use of stimulants and BFS and to find out sociodemographic factors that may be associated with BFS. SETTINGS AND DESIGN: University campus, a cross-sectional study with undergraduate students as respondents. SUBJECTS AND METHODS: Multi-stage sampling technique was used to select 500 students, who completed questionnaires consisting socio-demographic characteristics, BFS scale (BFSS), and the stimulant use section of the World Health Organization Questionnaire for Student Drug Use Survey; while observing standard ethical conditions. STATISTICAL ANALYSIS USED: Statistical Package for Social Sciences (SPSS) was used, employing Chi-square and frequency distribution. RESULTS: The prevalence of BFS was 42.9%. There was a significant association between stimulant use and BFS; thus giving credence to the Psychophysiological Theory of causation of BFS by Morakinyo. No sociodemographic variable was found to be associated with BFS. CONCLUSIONS: The control of use of stimulants is at the crux of the prevention of BFS. PMID- 25511353 TI - National neonatal resuscitation training program in Nigeria (2008-2012): a preliminary report. AB - BACKGROUND: Routine institutional training of doctors and nurses on newborn resuscitation have commenced, to improve the quality of resuscitation available to high-risk babies, in Nigeria, as a means of reducing newborn deaths in the country. Perinatal asphyxia contributes to 26% of newborn deaths in Nigeria. Perinatal asphyxia results when babies have difficulty establishing spontaneous respiration after birth. MATERIALS AND METHODS: Between 2008 and 2012, doctors and nurses drawn from all the geo-political zones were trained using the Neonatal Resuscitation Training (NRT) manual of the American Heart Association and the American Academy of Pediatrics. Questionnaire-based, cross-sectional surveys of doctor and nurse trainees from the six geo-political zones in Nigeria were conducted eight months after the primary training, to evaluate the post-training neonatal resuscitation activities. RESULTS: Over the period of study, 357 doctors and 370 nurse/midwives were primarily trained in NRT. The overall ratio of step down training was 1:22 with 1:18 for doctors and 1:26 for nurses. In 2008, the delivery attendance rates were 11 per doctor and 9 per nurse/midwife. These rates increased to 30 per doctor and 47 per nurse in 2012. Between 88 and 94% of the doctors and between 72 and 93% of the nurses successfully used bag and mask to help babies breathe in the post-training period. The nurses used bag and mask for infant resuscitation more frequently, compared to doctors, with the rate fluctuating between two-to-one and four-to-one. Over the years, 87 to 94% of the doctors and 92 to 97% of the nurses/midwives trained other birth attendants. CONCLUSION: The NRT in Nigeria is well-subscribed and the frequency of secondary training is good. PMID- 25511352 TI - Sickle cell disease clinical phenotypes in children from South-Western, Nigeria. AB - BACKGROUND: The clinical phenotypes of children with sickle cell disease (SCD) are poorly described in many sub-Saharan countries including Nigeria. OBJECTIVES: The objective was to highlight various clinical phenotypes of SCD in children and investigate the influence of sociodemographic indices on the development of SCD complications. METHODS: We carried out a cross-sectional study of 240 pediatric patients attending the sickle cell clinic and the emergency room in a teaching hospital in South-Western Nigeria over a 12-month period. The clinical phenotypes and severity of the disease were documented, and the influence of sociodemographic variables was investigated. RESULTS: The five leading clinical phenotypes in our patients were significant pain episodes, that is, vaso occlusive crisis in 159 (66.3%); anemic crisis in 62 (25.8%); severe bacterial infections, 57 (23.8%); acute chest syndrome (ACS), 27 (11.3%) and stroke, 7 (2.9%). Forty-two (33.1%) had a previous history of dactylitis (hand-foot syndrome). Other clinical phenotypes such as avascular necrosis of the femur, 4 (1.7%); nephropathy, 2 (0.8%); priapism, gallstone and chronic leg ulcer, one (0.4%) each, were not commonly seen. More children with a history of asthma had ACS. Furthermore, high steady-state white blood cell count was associated with severe disease. CONCLUSION: The clinical phenotypes of SCD in children from South Western Nigeria are highly variable with the disease manifesting very early and about 10% having significant complications. Sociodemographic characteristics appear to have little influence on the development of SCD complications among our patients, but age and low-socioeconomic class are associated with anemic crisis. PMID- 25511354 TI - Transperineal versus transrectal prostate biopsy: our findings in a tertiary health institution. AB - CONTEXT AND OBJECTIVE: Prostate cancer is a major public health issue. Its incidence is rising, especially in Nigeria. Prompt diagnosis is necessary by histology. Transperineal and transrectal approaches to prostate biopsy are well documented. Both methods are fraught with complications though, most times minor. Studies carried out to compare both methods were carried out mainly on Caucasians, generating conflicting results. This study aims to compare the complication rates and tissue yield of these two methods in Nigerian men. MATERIALS AND METHODS: Seventy-five patients completed the study. Forty-five patients had transperineal prostate biopsy (TPbx), while 30 patients had transrectal prostate biopsy. Pain perception for all patients was determined by visual analog scale; whereas the complications were ascertained by a validated purpose designed questionnaire administered on the 7 th and 30 th day post operatively. RESULTS: The risk of rectal bleeding was higher for transrectal prostate biopsy compared to transperineal (Odds ratio: 0.03; 95% confidence interval (CI): 0.001-0.450; P = 0.012). TPbx was more painful than transrectal (P < 0.0001; df: 75; t: 4.98; 95%CI of difference in mean: -2.98-[-1.28]). There was no statistical difference between transperineal and transrectal prostate biopsy in hemospermia, fever, prostatic abscess, urethral bleeding, acute retention and tissue yield. CONCLUSION: TPbx is more painful than transrectal prostate biopsy though with a significantly reduced risk of rectal bleeding. There appears to be no significant difference with respect to risk of fever, urethral bleeding, hematospermia, prostatic abscess and acute retention. Both routes provided sufficient prostate tissue for histology. PMID- 25511355 TI - Changing the bonding force of impression tray to edentulous maxillary jaw simulator with impression valve system: in vitro study. AB - OBJECTIVE: The aim of this study was to evaluate the effect of an impression valve system (IVS) on the bonding force between an impression tray and an edentulous maxillary jaw. MATERIALS AND METHODS: In this in vitro study, a polyether-coated maxillary jaw simulator (PM) was used to model an edentulous maxillary jaw. The IVS was placed into individual impression trays. An irreversible hydrocolloid impression was taken of the PM when the IVS was open and closed. The impression tray bonding force was measured using a digital dynamometer. Student's t-test was used to determine the significance of the difference between these two groups. RESULTS: The impression tray was more easily separated from the PM when the IVS was open (108 +/- 3.9 N). The separation was more difficult when the IVS was closed (153.7 +/- 14.2 N). The difference between these two findings (P = 0.000) was significant. CONCLUSION: The use of an IVS facilitates the removal of the impression tray from the mouth when taking impressions from an edentulous maxillary jaw. PMID- 25511356 TI - Complications of arteriovenous fistula with polytetraflouroethylen grafts in hemodialysis patients. AB - PURPOSE: Vessels with high venous flow rate are needed for the application of hemodialysis in patients needing chronic hemodialysis. The increase in the number of chronic hemodialysis patients has led to an increase in the number of vascular surgical operations. The aim of this study was to evaluate the results of polytetraflouroethylen (PTFE) graft arteriovenous fistula (AVF) applications. MATERIALS AND METHODS: Files of 596 patients who received hemodialysis treatment at the Nephrology Unit of the Sanliurfa Mehmet Akif Inan State Hospital between September 2009 and 2013 were retrospectively analyzed. PTFE grafts and autogenous AVFs applied in 22 patients were analyzed, and demographic data and PTFE graft associated complications of these patients were evaluated. RESULTS: We found that the graft patency duration (months +/- standard deviation) and the patency after graft revision were 16 +/- 13 and 83.3%. Complications were detected in 14 patients (63%). One patient developed hematoma in early stages. CONCLUSIONS: We conclude that even if PFTE graft AVF applications cause significant complications, the procedure has a high patency rate after graft revision. PMID- 25511357 TI - Surface roughness and morphologic changes of zirconia: effect of different surface treatment. AB - PURPOSE: The purpose of this study was to investigate the surface roughness and morphologic changes of pre-sintered ZrO 2 after sandblasting and erbium, chromium: Yttrium, scandium, gallium, garnet (Er, Cr: YSGG) laser application of different intensities. MATERIAL AND METHODS: Eighty pre-sintered ZrO 2 cylinders (7 mm diameter, 3 mm height) were prepared and divided into eight groups. Specimens in the control group were not treated. The following treatments were applied: Er, Cr: YSGG laser irradiation with different energy intensities (1-6 W at 20 Hz, with air-water cooling proportion of 65%/55%) and air abrasion with Al 2 O 3 particles (120 MUm). Then, all the specimens were sintered. The average surface roughness of each specimen was determined with a profilometer, and the morphology changes of a specimen from each group were evaluated with scanning electron microscope (SEM) analyses. The surface roughness data were analyzed through one-way analysis of variance and Tukey's honestly significant difference test (P < 0.05). RESULTS: There were significant differences between 2 and 6 W irradiations and control group. The highest surface roughness value was obtained with 6 W irradiation (8.14 +/- 1.26 Ra), followed by the 5 W (7.60 +/- 1.12 Ra), 4 W (7.50 +/- 0.90 Ra), 3 W (5.86 +/- 1.03 Ra), 2 W (4.54 +/- 0.53 Ra) and sandblasting group (2.18 +/- 0.92 Ra). 1 W laser irradiation (0.80 +/- 0.06 Ra) presented Ra values similar to the control group (0.77 +/- 0.03). CONCLUSION: The result of the statistical analyses and SEM images showed that Er, Cr: YSGG laser irradiation with 4-6 W/20 Hz presented significantly effect in surface roughness changes of zirconia than other surface treatments. PMID- 25511358 TI - Scanning electron microscopic evaluation of root canal surfaces prepared with three rotary endodontic systems: Lightspeed, ProTaper and EndoWave. AB - BACKGROUND AND OBJECTIVES: The purpose of this in vitro study was to evaluate and compare the cleaning efficiency, preparation time, instrument deformation and fracture with LightSpeed (LS), ProTaper (PT) and EndoWave (Ew) rotary instruments. MATERIALS AND METHODS: A total of 45 freshly extracted human mandibular premolars were subjected for the study. They were divided into three groups, each group consisting of 15 teeth. Group 1: The canals were prepared with LS system; Group 2: PT rotary system, Group 3: Ew rotary system. All the groups were prepared according to manufacturer's recommendation, using 5.25% sodium hypochlorite and 17% ethylenediaminetetraacetic acid (dent wash, prime dent) alternately as an irrigants. Crowns of each tooth were removed with diamond disks at the level of cemento enamel junction. Canal length was determined by placing a size 10 K-file. The working length was 0.5 mm short of canal length. Two longitudinal grooves were prepared on the lingual and buccal surfaces of each root to facilitate vertical splitting with a chisel after canal instrumentation. The sections were then observed under scanning electron microscope for presence or absence of debris and smear layer and the photographs were taken at coronal, middle and apical 1/3 with a magnification of * 200 and * 1000 respectively. The time taken to enlarge each canal was recorded in minutes and seconds. The instruments were examined after every use for deformation. The scores recorded were statistically analyzed using one-way analysis of variance and Mann-Whitney test. RESULTS: There was statistically significant difference with regard to removal of debris and smear layer at coronal, middle and apical third for LS versus PT and LS versus Ew (P < 0.01). There was no significant difference between PT and Ew. The mean preparation time for LS, PT and Ew was 1.76, 2.50 and 2.75 respectively. INTERPRETATION AND CONCLUSION: The study demonstrated that, LS instrumentation removed debris and smear layer effectively with shorter preparation time and Ew instrument showed deformation. PMID- 25511359 TI - A report of heat stroke in two Nigerian siblings. AB - Infants and children are at higher risk of heat stroke for several reasons. We report these cases to highlight the danger of leaving children unsupervised in vehicles, aid prompt diagnosis, and management of heat stroke. Two Nigerian siblings aged ranges 5 and 3 years old, were trapped inside an unlocked vehicle and subsequently developed heat stroke. Both children presented with hyperthermia, severe dehydration, convulsions, and loss of consciousness. One of them also had hematuria. They were treated by spraying water onto their bodies to bring down the temperature, intravenous fluid resuscitation, oxygen therapy, and anticonvulsants. Both eventually recovered and were discharged with no obvious neurologic sequalae, but are being followed-up. PMID- 25511360 TI - Reattachment of dehydrated tooth fragments: two case reports. AB - Anterior crown fractures are the most common type of injury in dental trauma. The ideal treatment is to reattach the fragments as quickly as possible following intraoral and radiographic examination, but sometimes delayed treatment appointments are necessary because of uninformed patients/parents or multidisciplinary cases included endodontically and periodontically. Delayed reattachment may lead to unesthetic results because of the dehydration of fragments. The purpose of this study was to present 1-year follow-ups of reattachment of dehydrated fragments using dentin bondings and flowable composites in two different cases. The color of the dehydrated fragments was natural in the control appointments and 1-year follow-ups show harmonious integration of color, form and texture after the reattachment of the original piece of tooth. Restoration of the tooth by reattaching the original fragment is the best way of treatment in esthetic, conservative and economic point of view. PMID- 25511361 TI - Interdisciplinary orthognathic treatment of high angle class III malocclusion. AB - For Class III adult patients, combined treatment strategy must be followed which includes either further dentoalveolar compensation or orthognathic surgery following decompensation of the teeth. This case report presents the interdisciplinary approach of a skeletal Class III malocclusion with increased vertical facial dimension, occlusal cant, extracted posterior teeth on the right upper and left lower segments, extensive restorations, and total circular crossbite. The orthodontic alignment took 10 months. LeFort 1 osteotomy with 7 mm advancement, 5 mm impaction on the left side, 3 mm impaction on the right side and 2 mm rotation for midline correction toward the left side, 3 mm set-back of mandible with bilateral sagittal split osteotomy were done. The surgery simulation, postoperative and 2-year follow-up records were compatible. The treatment was finalized in a straight profile with stable occlusion and good smile characteristics without airway disturbance. PMID- 25511362 TI - The effect of different levels of realism of context learning on the prescribing competencies of medical students during the clinical clerkship in internal medicine: an exploratory study. AB - PURPOSE: The aim of this study is to evaluate the effect of different levels of realism of context learning on the prescribing competencies of medical students during the clinical clerkship in internal medicine. METHODS: Between 2001 and 2007, 164 medical students took part in the prospective explorative study during their clinical clerkship in internal medicine at the VU University Medical Center, Amsterdam, The Netherlands. In a fixed order, each student had to formulate a treatment plan for a real patient in three situations of increasing realism: a minimal level (studying a patient record), medium level (preparing for a therapeutic consultation), and optimal level (preparing for and performing a therapeutic consultation with the patient). RESULTS: In comparison to studying a patient record (minimal context level), preparing a therapeutic consultation (medium context) improved four of the six steps of the WHO six-step plan. Preparing and performing a therapeutic consultation with a real patient (optimal context) further improved three essential prescribing competencies, namely checking for contraindications and interactions, prescription writing, and instructions to the patient. CONCLUSION AND RECOMMENDATIONS: The results of this first explorative study suggest that enrichment of the learning context (responsibility for patient care) might be an important factor to improve the training of rational prescribing skills of medical students during their clinical clerkship in internal medicine. Clinical (pharmacology) teachers should be aware that seemingly small adaptations in the learning context of prescribing training during clinical clerkships (i.e., with or without involvement with and responsibility for patient care) may have relatively large impact on the development of prescribing competencies of our future doctors. PMID- 25511363 TI - Nutrient sufficiency in beef cows grazing on a dwarf bamboo-dominated forestland pasture in Japan. AB - The nutritional status of cows grazing on a 120-ha public alpine forestland pasture dominated by the dwarf bamboo Sasa senanensis located in central Japan was evaluated over the course of 2 years. Data were collected during grazing seasons in three periods: early (June), mid- (August) and late (late September early October) periods. During these periods, the number of experimental Japanese Black cows varied between three and six. With the exception of the dry matter (DM) intake in 2005 and the crude protein (CP) digestibility in 2006, the DM and CP intake and digestibility were lower in the mid- and late periods than in the early period for both years (P < 0.05). Metabolizable energy intake was slightly insufficient for the requirement of the cows in the late period of 2005; in the mid- and late periods of 2006, the metabolizable energy intake was 0.4 to 0.5 times the requirement. These results suggest that the energy intake of cows grazing on forestland pasture dominated by S. senanensis would not satisfy their requirements starting in the mid-period (August) grazing, even though the pasture had abundant herbage resources during these periods. PMID- 25511364 TI - Cationic RAFT polymerization using ppm concentrations of organic acid. AB - A metal-free, cationic, reversible addition-fragmentation chain-transfer (RAFT) polymerization was proposed and realized. A series of thiocarbonylthio compounds were used in the presence of a small amount of triflic acid for isobutyl vinyl ether to give polymers with controlled molecular weight of up to 1*10(5) and narrow molecular-weight distributions (Mw /Mn <1.1). This "living" or controlled cationic polymerization is applicable to various electron-rich monomers including vinyl ethers, p-methoxystyrene, and even p-hydroxystyrene that possesses an unprotected phenol group. A transformation from cationic to radical RAFT polymerization enables the synthesis of block copolymers between cationically and radically polymerizable monomers, such as vinyl ether and vinyl acetate or methyl acrylate. PMID- 25511365 TI - External validation of the Ottawa subarachnoid hemorrhage clinical decision rule in patients with acute headache. AB - We aim to externally validate the Ottawa subarachnoid hemorrhage (OSAH) clinical decision rule. This rule identifies patients with acute nontraumatic headache who require further investigation. We conducted a medical record review of all patients presenting to the emergency department (ED) with headache from January 2011 to November 2013. Per the OSAH rule, patients with any of the following predictors require further investigation: age 40 years or older, neck pain, stiffness or limited flexion, loss of consciousness, onset during exertion, or thunderclap. The rule was applied following the OSAH rule criteria. Patients were followed up for repeat visits within 7 days of initial presentation. Data were electronically harvested from the electronic medical record and manually abstracted from individual patient charts using a standardized data abstraction form. Calibration between trained reviewers was performed periodically. A total of 5034 ED visits with acute headache were reviewed for eligibility. There were 1521 visits that met exclusion criteria, and 3059 had headache of gradual onset or time to maximal intensity greater than or equal to 1 hour. The rule was applied to 454 patients (9.0%). There were 9 cases of subarachnoid hemorrhage (SAH), yielding an incidence of 2.0% (95% confidence interval [CI], 1.0%-3.9%) in the eligible cohort. The sensitivity for SAH was 100% (95% CI, 62.9%-100%); specificity, 7.6% (95% CI, 5.4%-10.6%); positive predictive value, 2.1% (95% CI 1.0%-4.2%); and negative predictive value, 100% (95% CI, 87.4%-100%). The OSAH rule was 100% sensitive for SAH in the eligible cohort. However, its low specificity and applicability to only a minority of ED patients with headache (9%) reduce its potential impact on practice. PMID- 25511366 TI - What diseases are disguised as dengue? PMID- 25511367 TI - Anton syndrome during oxygen-ozone therapy. AB - Ozone (O3) gas is a molecule that consists of 3 oxygen atoms, found out in the mid-19th century [1]. Ozone gas preserves humans from detrimental influences of ultraviolet radiation [1]. In spite of harmful effects of O3 gas, investigators think that it has excessive curative effects [1]. Nowadays, O3 therapy is used for many fields of medicine in precise therapeutic doses [1] and [2]. It is known that O3 therapy is helpful in dental procedures, cerebrovascular diseases, tinnitus, acquired immunodeficiency syndrome, hypercholesterolemia, sensorial hypoacusis, senile dementia, multiple sclerosis, irradiation sensitive tumors, herpes simplex and herpes zoster virus infections, muscular hypertonia, and chronic otitis media, etc.[2]. The complications and disadvantages of O3 therapy could be observed in the future. Herein, we presented a case of ischemic stroke after an oxygen-O3 therapy, which is called also Anton syndrome. PMID- 25511368 TI - No effect of scalp cooling on survival among women with breast cancer. AB - Scalp cooling can prevent chemotherapy-induced alopecia in some cancer patients. It is not used in all countries. No data are available regarding its impact, if any, on survival. The aim of this study was to compare overall survival according to whether or not scalp cooling was used during neoadjuvant or adjuvant chemotherapy for non-metastatic breast cancer. We conducted a retrospective cohort study of 1,370 women with non-metastatic invasive breast carcinoma who received chemotherapy in the neoadjuvant or adjuvant setting. A total of 553 women who used scalp cooling came from a tertiary breast cancer clinic in Quebec City (diagnosed between 1998 and 2002) and 817 were treated in other hospitals in the province of Quebec (between 1998 and 2003) where scalp cooling was not routinely available. Overall survival of women who used scalp cooling and those who did not was compared using Cox proportional hazards models. Median follow-up for the scalp-cooled and the non-scalp-cooled groups was 6.3 years and 8.0 years, respectively. Overall mortality was no different (adjusted hazard ratio 0.89, 95 % confidence interval: 0.68-1.17, p = 0.40) among scalp-cooled women, compared to those not getting scalp cooling. Among women getting neoadjuvant or adjuvant chemotherapy for non-metastatic breast cancer, scalp cooling used to prevent chemotherapy-induced alopecia had no negative effect on survival. To our knowledge, this is the first study to compare survival of women who used scalp cooling to that of women who did not. PMID- 25511369 TI - Multimodality imaging of attenuated plaque using grayscale and virtual histology intravascular ultrasound and optical coherent tomography. AB - BACKGROUND: Although attenuated plaque is a marker for plaque vulnerability, the quantification and its implication have not been known. METHODS: Multimodality pre-procedural imaging using grayscale intravascular ultrasound (IVUS), virtual histology-IVUS (VH-IVUS), and optical coherence tomography (OCT) were performed in 115 coronary lesions with diameter stenosis (DS) >30% and plaque burden >=50% and compared the diagnostic accuracies for detecting thin-cap fibroatheromas (TCFA). RESULTS: A maximal arc of attenuation (40 MHz IVUS) >=29.0 degrees was the cutoff for predicting VH-TCFA (sensitivity 74%, specificity 66%); and OCT TCFA (sensitivity 89%, specificity 64%), while a maximal arc attenuation >=29.0 degrees (20MHz IVUS) showed a poor sensitivity for predicting TCFA. Compared to the lesions with an arc of attenuation <30 degrees as a rough cutoff value, the lesions with a maximum arc of attenuation >=30 degrees (40 MHz) were associated with more severe (smaller angiographic minimum lumen diameter and greater DS, smaller IVUS-MLA and a larger plaque burden) and had more unstable lesion characteristics: (1) larger remodeling index and more plaque ruptures (grayscale IVUS); (2) greater %necrotic core and more VH-TCFAs (VH-IVUS); and (3) more lipid, macrophages, cholesterol crystals, and microchannels; thinner fibrous caps; and more OCT-TCFAs, OCT-detected plaque ruptures, and red and white thrombi (OCT). Among 58 patients treated with stent implantation, postintervention peak CK-MB was higher in patients with the maximal attenuation >=30 degrees compared to those without (median 2.7 ng/ml [IQR 0.9-18.7 ng/ml] vs. median 0.9 ng/ml [IQR 0.7-2.1 ng/ml], P = 0.012). CONCLUSION: Attenuated plaque with a maximal attenuation >=30 degrees vs. <30 degrees (40 MHz, but not 20 MHz IVUS) were more likely to be associated with unstable lesion morphology that may contribute to the immediate poststenting CK-MB elevation. (c) 2016 Wiley Periodicals, Inc. PMID- 25511370 TI - Diagnostic accuracy of anaesthesiologists' prediction of difficult airway management in daily clinical practice: a cohort study of 188 064 patients registered in the Danish Anaesthesia Database. AB - Both the American Society of Anesthesiologists and the UK NAP4 project recommend that an unspecified pre-operative airway assessment be made. However, the choice of assessment is ultimately at the discretion of the individual anaesthesiologist. We retrieved a cohort of 188 064 cases from the Danish Anaesthesia Database, and investigated the diagnostic accuracy of the anaesthesiologists' predictions of difficult tracheal intubation and difficult mask ventilation. Of 3391 difficult intubations, 3154 (93%) were unanticipated. When difficult intubation was anticipated, 229 of 929 (25%) had an actual difficult intubation. Likewise, difficult mask ventilation was unanticipated in 808 of 857 (94%) cases, and when anticipated (218 cases), difficult mask ventilation actually occurred in 49 (22%) cases. We present a previously unpublished estimate of the accuracy of anaesthesiologists' prediction of airway management difficulties in daily routine practice. Prediction of airway difficulties remains a challenging task, and our results underline the importance of being constantly prepared for unexpected difficulties. PMID- 25511371 TI - Effect of pilates exercise for improving balance in older adults: a systematic review with meta-analysis. AB - OBJECTIVES: To investigate the effect of Pilates on balance and falls in older adults, and whether programs tested in prior studies met best-practice recommendations for exercise to prevent falls. DATA SOURCES: MEDLINE, SPORTDiscus, CINAHL, PubMed, Physiotherapy Evidence Database, and The Cochrane Library were searched from earliest record to July 2014. STUDY SELECTION: Randomized and controlled clinical trials evaluating the effect of Pilates on balance and/or falls in older adults. DATA EXTRACTION: Two reviewers independently extracted demographic, intervention, and outcome data. Six studies were included in this review. DATA SYNTHESIS: High-quality studies in this area are lacking. When compared with nonactive control groups, Pilates was shown to improve balance (standardized mean difference [SMD]=.84; 95% confidence interval [CI], .44-1.23; 6 studies) and reduce the number of falls (SMD=-2.03; 95% CI, 2.66 to -1.40; 1 study). Three studies provided sufficient detail to enable assessment of compliance with the recommendation of exercises providing a moderate or high challenge to balance. In these studies, 2% to 36% of exercises were assessed as providing a moderate or high challenge to balance. All studies provided >=2 hours of exercise per week, and 1 study provided >50 hours of exercise during the study period. CONCLUSIONS: The evidence suggests Pilates can improve balance, an important risk factor for falls in older adults. However, there is limited data on the impact of Pilates on falls. Effects may have been overestimated because of the low methodological quality of studies. Best-practice recommendations were rarely applied in prior studies, indicating greater effects may have been achieved if recommendations were incorporated. PMID- 25511372 TI - Chronic kidney disease and underdiagnosis of renal insufficiency among diabetic patients attending a hospital in Southern Ethiopia. AB - BACKGROUND: Diabetic patients with chronic kidney disease (CKD), as defined by a reduced glomerular filtration rate (GFR), are at greater risk for cardiovascular and renal events and mortality. The aim of this study was to determine the prevalence of CKD among diabetic patients attending a hospital in southern Ethiopia, and to assess underdiagnosis of renal insufficiency among those with normal serum creatinine. METHODS: A total of 214 randomly selected diabetics attending the follow-up clinic at Butajira hospital of southern Ethiopia participated in this study during the period from September 1 to October 31, 2013. All patients completed an interviewer-administered questionnaire and underwent clinical assessment. The simplified Modification of Diet in Renal Disease (MDRD) and Cockroft-Gault (C-G) equations were used to estimate GFR (eGFR) from serum creatinine. RESULTS: CKD, defined as eGFR<60 ml/min/1.73 m2, was present in 18.2% and 23.8% of the study participants according to the MDRD and Cockcroft-Gault (C-G) equations, respectively. Only 9.8% of the total participants, and 48.7% (for the MDRD) and 37.3% (for C-G) of those with eGFR<60 ml/min/1.73 m2 had abnormal serum creatinine values, i.e. >1.5 mg/dl. Normal serum creatinine was observed in 90.2% of participants attending the hospital. A large proportion of participants ranging from 38.9-56.5% have shown to have mild to moderate renal insufficiency (stage 2-3 CKD) despite normal creatinine levels. CKD, eGFR<60 ml/min/1.73 m2, was found in 10.4 and 16.9% of participants with normal serum creatinine using the MDRD and C-G equations, respectively. CONCLUSION: CKD is present in no less than 18% of diabetics attending the hospital, but it is usually undiagnosed. A significant number of diabetics have renal insufficiency corresponding to stages 2-3 CKD despite normal creatinine levels. Therefore, GFR should be considered as an estimate of renal insufficiency, regardless of serum creatinine levels being in normal range. PMID- 25511373 TI - Prevalence of rheumatic heart disease in young adults from New Caledonia. AB - BACKGROUND: Rheumatic heart disease (RHD) is an important public health issue, particularly in the Pacific region, but its true burden is unknown. OBJECTIVES: To evaluate the prevalence of rheumatic heart disease (RHD) in young adults from New Caledonia, based on echocardiography, and to evaluate the accuracy of dynamic criteria, focusing on mitral valve (MV) leaflet motion. METHODS: Blind analysis of echocardiography by three cardiologists; diagnosis of RHD required at least one dynamic criterion (exaggerated or restricted MV leaflet motion); subjects with morphological criteria (MV leaflet thickening), but without dynamic criteria, were considered as borderline. RESULTS: There were 834 subjects from three socioeconomic groups, aged 18-22 years: 699 had normal echocardiography; 93 (11.5%) had physiological regurgitation; nine (0.9%) had borderline RHD; and five (0.59%) had RHD. The prevalence of RHD in New Caledonia was thus estimated at 5.9 per 1000 (95% confidence interval 2.6-12.2). The RHD cases were of Pacific ethnicity. Physiological regurgitation was more frequent in Pacific subjects (13.7%) than in non-Pacific subjects (6.9%; P<0.0001). RHD was more prevalent in the lowest socioeconomic group. No disagreement occurred between the three reviewers concerning analysis of dynamic criteria; all disagreements were related to morphological criteria. CONCLUSIONS: The prevalence of echocardiographically diagnosed RHD in adults in New Caledonia is estimated at 5.9 per 1000; it occurs most frequently in Pacific subjects and those with low incomes. Dynamic criteria were more accurate and reproducible than standard morphological criteria. PMID- 25511374 TI - Asymmetric autocatalysis of pyrimidyl alkanol and its application to the study on the origin of homochirality. AB - CONSPECTUS: Amplification of enantiomeric excess (ee) is a key feature for the chemical evolution of biological homochirality from the origin of chirality. We describe the amplification of ee in the asymmetric autocatalysis of 5-pyrimidyl alkanols in the reaction between diisopropylzinc (i-Pr2Zn) and pyrimidine-5 carbaldehydes. During the reaction, an extremely low ee (ca. 0.00005% ee) can be amplified to >99.5% ee, and therefore, the initial slightly major enantiomer is automultiplied by a factor of ca. 630000, while the initial slightly minor enantiomer is automultiplied by a factor of less than 1000. In addition, pyrimidyl alkanols with various substituents at the 2-position of the pyrimidine ring, 3-quinolyl alkanol, 5-carbamoyl-3-pyridyl alkanol, and large multifunctionalized pyrimidyl alkanols also act as highly efficient asymmetric autocatalysts in the addition of i-Pr2Zn to the corresponding aldehydes. The asymmetric autocatalysis of pyrimidyl alkanol can discriminate the chirality of various compounds. Chiral substances such as alcohols, amino acids, hydrocarbons, metal complexes, and heterogeneous chiral materials can act as chiral triggers for asymmetric autocatalysis to afford pyrimidyl alkanols with the corresponding absolute configuration of the initiator. This recognition ability of chiral compounds is extremely high, and chiral discrimination of a cryptochiral quaternary saturated hydrocarbon was established by applying asymmetric autocatalysis. By using the large amplification effect of the asymmetric autocatalysis, we can link various proposed origins of chirality with highly enantioenriched organic compounds in conjunction with asymmetric autocatalysis. Thus, a statistical fluctuation in ee of racemic compounds can be amplified to high ee by using asymmetric autocatalysis. Enantiomeric imbalance induced by irradiation of circularly polarized light can affect the enantioselectivity of asymmetric autocatalysis. The asymmetric autocatalysis was also triggered by the morphology of inorganic chiral crystals such as quartz, sodium chlorate, and cinnabar. Chiral organic crystals of achiral compounds also act as chiral initiators, and during the study of a crystal of cytosine, enantioselective chiral crystal phase transformation of the cytosine crystal was achieved by removal of the water of crystallization in an achiral monohydrate crystal. Enantioselective C-C bond formation was realized on the surfaces of achiral single crystals based on the oriented prochirality of achiral aldehydes. Furthermore, asymmetric autocatalysis of pyrimidyl alkanols is a highly sensitive reaction that can recognize and amplify the significantly small effect of a chiral compound arising solely from isotope substitution of hydrogen, carbon, and oxygen (D/H, (13)C/(12)C, and (18)O/(16)O). These examples show that asymmetric autocatalysis with an amplification of chirality is a powerful tool for correlating the origin of chirality with highly enantioenriched organic compounds. Asymmetric autocatalysis using two beta-amino alcohols reveals a reversal of enantioselectivity in the addition of i-Pr2Zn to aldehyde and is one approach toward understanding the mechanism of asymmetric dialkylzinc addition, where heteroaggregates act as the catalytic species. PMID- 25511375 TI - Gain of glucose-independent growth upon metastasis of breast cancer cells to the brain. AB - Breast cancer brain metastasis is resistant to therapy and a particularly poor prognostic feature in patient survival. Altered metabolism is a common feature of cancer cells, but little is known as to what metabolic changes benefit breast cancer brain metastases. We found that brain metastatic breast cancer cells evolved the ability to survive and proliferate independent of glucose due to enhanced gluconeogenesis and oxidations of glutamine and branched chain amino acids, which together sustain the nonoxidative pentose pathway for purine synthesis. Silencing expression of fructose-1,6-bisphosphatases (FBP) in brain metastatic cells reduced their viability and improved the survival of metastasis bearing immunocompetent hosts. Clinically, we showed that brain metastases from human breast cancer patients expressed higher levels of FBP and glycogen than the corresponding primary tumors. Together, our findings identify a critical metabolic condition required to sustain brain metastasis and suggest that targeting gluconeogenesis may help eradicate this deadly feature in advanced breast cancer patients. PMID- 25511376 TI - Perinatal and familial risk factors for brain tumors in childhood through young adulthood. AB - Perinatal factors, including high birth weight, have been associated with childhood brain tumors in case-control studies. However, the specific contributions of gestational age and fetal growth remain unknown, and these issues have never been examined in large cohort studies with follow-up into adulthood. We conducted a national cohort study of 3,571,574 persons born in Sweden in 1973-2008, followed up for brain tumor incidence through 2010 (maximum age 38 years) to examine perinatal and familial risk factors. There were 2,809 brain tumors in 69.7 million person-years of follow-up. After adjusting for potential confounders, significant risk factors for brain tumors included high fetal growth [incidence rate ratio (IRR) per additional 1 SD, 1.04; 95% confidence interval (CI), 1.01-1.08, P = 0.02], first-degree family history of a brain tumor (IRR, 2.43; 95% CI, 1.86-3.18, P < 0.001), parental country of birth (IRR for both parents born in Sweden vs. other countries, 1.21; 95% CI, 1.09 1.35, P < 0.001), and high maternal education level (Ptrend = 0.01). These risk factors did not vary by age at diagnosis. The association with high fetal growth appeared to involve pilocytic astrocytomas, but not other astrocytomas, medulloblastomas, or ependymomas. Gestational age at birth, birth order, multiple birth, and parental age were not associated with brain tumors. In this large cohort study, high fetal growth was associated with an increased risk of brain tumors (particularly pilocytic astrocytomas) independently of gestational age, not only in childhood but also into young adulthood, suggesting that growth factor pathways may play an important long-term role in the etiology of certain brain tumor subtypes. PMID- 25511378 TI - BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance. AB - Pan- or multidrug resistance is a central problem in clinical oncology. Here, we use a genetically engineered mouse model of BRCA2-associated hereditary breast cancer to study drug resistance to several types of chemotherapy and PARP inhibition. We found that multidrug resistance was strongly associated with an EMT-like sarcomatoid phenotype and high expression of the Abcb1b gene, which encodes the drug efflux transporter P-glycoprotein. Inhibition of P-glycoprotein could partly resensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel, and doxorubicin. We propose that multidrug resistance is a multifactorial process and that mouse models are useful to unravel this. PMID- 25511377 TI - Role of chitinase 3-like-1 and semaphorin 7a in pulmonary melanoma metastasis. AB - The prototypic chitinase-like protein Chi3l1 is induced in cancers and portends a poor prognosis, but whether it contributes to cancer progression is unknown. To address this gap in knowledge, we investigated the production of Chi3l1 in melanoma lung metastases. We found that Chi3l1 was induced during pulmonary melanoma metastasis and that this induction was regulated by the semaphorin Sema7a, interacting in stimulatory or inhibitory ways with its beta1 integrin or Plexin C1 receptors, respectively. In mouse strains with genetic deletions of Chi3l1 or Sema7a, there was a significant reduction in pulmonary metastasis. Notably, antiserum raised against Chi3l1 or Sema7a phenocopied the reduction produced by genetic deletions. Melanoma lung metastasis was also decreased in the absence of IL13Ralpha2, a recently identified receptor for Chi3l1, consistent with a key role for Chi3l1 in melanoma spread. We confirmed roles for Sema7a and Chi3l1 in pulmonary metastasis of EMT6 breast cancer cells. Taken together, our studies establish a novel pathway through which Sem7a and its receptors regulate Chi3l1, revealing a host axis involving IL13Ralpha2 that plays a critical role in generating a pulmonary microenvironment that is critical to license metastasis. PMID- 25511379 TI - Clear cell acanthoma on the axilla successfully treated with carbon dioxide laser. PMID- 25511380 TI - Neutrophils in asthma--a review. AB - Asthma is a chronic inflammatory disease, with an array of cells involved in the pathogenesis of the disease. The role of neutrophils in the development of bronchial asthma is found to be complex, as they may trigger activation of immunocompetent cells and are a potent source of free oxygen radicals and enzymes participating in airway remodeling. The review highlights the role of neutrophils in bronchial asthma. PMID- 25511381 TI - Automatic classification of canine PRG neuronal discharge patterns using K-means clustering. AB - Respiratory-related neurons in the parabrachial-Kolliker-Fuse (PB-KF) region of the pons play a key role in the control of breathing. The neuronal activities of these pontine respiratory group (PRG) neurons exhibit a variety of inspiratory (I), expiratory (E), phase spanning and non-respiratory related (NRM) discharge patterns. Due to the variety of patterns, it can be difficult to classify them into distinct subgroups according to their discharge contours. This report presents a method that automatically classifies neurons according to their discharge patterns and derives an average subgroup contour of each class. It is based on the K-means clustering technique and it is implemented via SigmaPlot User-Defined transform scripts. The discharge patterns of 135 canine PRG neurons were classified into seven distinct subgroups. Additional methods for choosing the optimal number of clusters are described. Analysis of the results suggests that the K-means clustering method offers a robust objective means of both automatically categorizing neuron patterns and establishing the underlying archetypical contours of subtypes based on the discharge patterns of group of neurons. PMID- 25511382 TI - Reliability of peak O2 uptake and O2 uptake kinetics in step exercise tests in healthy subjects. AB - To date little is known about the reliability of peak oxygen consumption (VO2PEAK) in incremental metronome paced step tests (IST) and the reliability of on-kinetics VO2 has never been studied. We aimed to study the reliability of both tests. Eleven healthy subjects performed two ISTs until exhaustion. On two different days two duplicate 4min constant metronome paced step tests (CST) were performed. VO2PEAK, mean response time (MRT) and phase II time constant (tau) were tested for reproducibility using the paired t-tests, in addition to the limits of agreement (LOA) and within subject coefficient of variation (COV). With a 95% LOA of 0.38 to 0.26Lmin(-1), -8.7 to 9.1s and -9.9 to 10.5s they exhibit a COV of 3%, 4.5% and 6.9% for VO2PEAK, MRT and tau respectively. ST are sufficiently reliable for maximal and submaximal aerobic power assessments in healthy subjects and new studies of oxygen uptake kinetics in selected patient groups are warranted. PMID- 25511383 TI - Cyclooxygenase pathway in modulation of the ventilatory response to hypercapnia by interleukin-1beta in rats. AB - At the present time very little is known about interactions between the systemic inflammatory and ventilatory control. Our previous study has demonstrated that the elevation of the major inflammatory cytokines interleukin-1beta (IL-1beta) in the cerebrospinal fluid (CSF) may affect the control of ventilation. The aim of the current study was to compare the respiratory effects of IL-1beta before and after pretreatment with diclofenac, a nonspecific cyclooxygenase (COX) inhibitor. Using the method of rebreathing with hyperoxic gas mixture we demonstrate that the slope of the ventilatory response to carbon dioxide decreased almost twofold from 5.6+/-0.52 to 2.5+/-0.28 ml min(-1)mmHg(-1) (p<0.01) 40 min after cerebroventricular administration of IL-1beta. In contrast, the basal level of lung ventilation increased after the elevation of IL-1beta in CSF. Diclofenac pretreatment eliminated these respiratory effects of IL-1beta. The data indicate that the ability of IL-1beta to enhance basal ventilation and to reduce the ventilatory hypercapnic response is mediated by the COX pathway. PMID- 25511384 TI - A randomized controlled clinical study of the effect of daily intake of Ascophyllum nodosum alga on calculus, plaque, and gingivitis. AB - OBJECTIVE: The aim of this study is to evaluate, in a randomized controlled cross over study, the effect of daily intake of the alga Ascophyllum nodosum on supragingival calculus, plaque formation, and gingival health over a 6-month period. MATERIAL AND METHODS: Sixty-one adults with moderate to heavy calculus formation since their last yearly recall visit participated. In a randomized order over two 6-month periods, they swallowed two capsules daily, comprising a total of 500 mg dried marine alga powder (Ascophyllum nodosum, ProDen PlaqueOff(r)) or two negative control tablets. During the study, the participants maintained their regular oral habits. Their teeth were professionally cleaned at the start of each period and after the 6-month registrations. A wash out period of 1 month separated the two 6-month periods. Supragingival calculus (Volpe Manhold), gingivitis (Loe and Silness), gingival bleeding (Ainamo and Bay), and plaque (Quigley-Hein) were registered at screening and at the end of the two periods. Differences in oral health between the test and control periods were analyzed using a paired t test and Wilcoxon signed rank test. RESULTS: Fifty-five participants completed the study. After the alga intake, the mean calculus reduction was 52% compared to the control (p < 0.0001). Fifty-two participants showed less calculus formation in the alga group than in the control group. Plaque (p = 0.008) and gingival bleeding (p = 0.02) were also significantly less in the alga group. However, no significant difference was found between the groups for gingivitis (p = 0.13). CONCLUSIONS: The alga intake significantly reduced the formation of supragingival calculus and plaque and occurrence of gingival bleeding. The alga has a systemic effect on oral health. CLINICAL RELEVANCE: Daily intake of the alga Ascophyllum nodosum as an adjunct to customary oral hygiene showed a major reduction of supragingival calculus formation and reduced plaque formation. In addition, the calculus in the alga group was characterized by a more porous and less solid structure and was easier to remove than the calculus in the control group. PMID- 25511386 TI - Tissue reactions after simultaneous alveolar ridge augmentation with biphasic calcium phosphate and implant insertion--histological and immunohistochemical evaluation in humans. AB - OBJECTIVES: Simultaneous lateral augmentation and implant placement is considered as standard procedure in deficient edentulous ridges in oral implantology. Histological studies monitoring osteogenesis after application of alloplastic bone substitutes in humans are scarce. Bone formation upon simultaneous augmentation with biphasic calcium phosphate (BCP) and implantation was histologically investigated after 6 months in situ. The results of this secondary analysis are reported tempting to ascribe specific observations to uneventful submerged healing or compromised healing of soft tissues including occurrence of dehiscences and premature graft exposure. MATERIALS AND METHODS: Histology of biopsies from lateral, crestal bone augmentations using alloplastic BCP comprising seven sites with compromised, prematurely exposed healing and six sites with uneventful submerged healing was investigated for expression of osteogenic, osteoclastogenic, and angiogenic differentiation markers. RESULTS: Histology revealed alkaline phosphatase (ALP)-positive osteoblasts and immunoreactivity for osteogenic markers osteocalcin and collagen type I in biopsies with submerged healing, while inflammatory infiltrates and accumulations of multinucleated giant cells around BCP granules were observed in compromised sites. All specimens presented adequate vessel density. Multinucleated giant cells showed inconsistent staining for the osteoclast marker tartrate-resistant acid phosphatase (TRAP). CONCLUSIONS: The histological findings of this study indicate an osteoconductive nature of the BCP applied. Premature exposure of the bone substitute reduced new bone formation and may bear a risk for inflammatory and foreign body reactions. CLINICAL RELEVANCE: A predictable appositional bone formation in simultaneously augmented sites using BCP is linked to an uneventful healing process. PMID- 25511387 TI - Step-by-step magic state encoding for efficient fault-tolerant quantum computation. AB - Quantum error correction allows one to make quantum computers fault-tolerant against unavoidable errors due to decoherence and imperfect physical gate operations. However, the fault-tolerant quantum computation requires impractically large computational resources for useful applications. This is a current major obstacle to the realization of a quantum computer. In particular, magic state distillation, which is a standard approach to universality, consumes the most resources in fault-tolerant quantum computation. For the resource problem, here we propose step-by-step magic state encoding for concatenated quantum codes, where magic states are encoded step by step from the physical level to the logical one. To manage errors during the encoding, we carefully use error detection. Since the sizes of intermediate codes are small, it is expected that the resource overheads will become lower than previous approaches based on the distillation at the logical level. Our simulation results suggest that the resource requirements for a logical magic state will become comparable to those for a single logical controlled-NOT gate. Thus, the present method opens a new possibility for efficient fault-tolerant quantum computation. PMID- 25511385 TI - Stage-related treatment concept of medication-related osteonecrosis of the jaw-a case series. AB - OBJECTIVES: There is no general consensus for treatment of medication-related osteonecrosis of the jaw (MRONJ). A stage-related approach that primarily aims to minimize morbidity and preserve function was prospectively evaluated. PATIENTS AND METHODS: Treatment goals are stable mucosal closure and absence of clinical symptoms. Patients were enrolled between March 2010 and October 2011. MRONJ lesions were treated either by conservative means or surgically by debridement or resective surgery. RESULTS: In total, 38 patients were treated. Six patients were healed by undergoing conservative measures; nine were treated palliatively. Four patients dropped out after surgery in the recall phase. In 17 of 19 patients (89.5%) surgical treatment was successful. After a 1-year observation period, the success rate was 92% (23 of 25), including all patients treated as per protocol. CONCLUSION: In stage-related treatment, conservative means or surgical debridement can be successful at early stages. Extensive resection is solely indicated in cases of extended necrosis. CLINICAL RELEVANCE: The number of patients with MRONJ is steadily increasing. Guidelines to deal with this condition are helpful for both clinicians and dental practitioners. PMID- 25511388 TI - Roles of the orexin system in central motor control. AB - The neuropeptides orexin-A and orexin-B are produced by one group of neurons located in the lateral hypothalamic/perifornical area. However, the orexins are widely released in entire brain including various central motor control structures. Especially, the loss of orexins has been demonstrated to associate with several motor deficits. Here, we first summarize the present knowledge that describes the anatomical and morphological connections between the orexin system and various central motor control structures. In the next section, the direct influence of orexins on related central motor control structures is reviewed at molecular, cellular, circuitry, and motor activity levels. After the summarization, the characteristic and functional relevance of the orexin system's direct influence on central motor control function are demonstrated and discussed. We also propose a hypothesis as to how the orexin system orchestrates central motor control in a homeostatic regulation manner. Besides, the importance of the orexin system's phasic modulation on related central motor control structures is highlighted in this regulation manner. Finally, a scheme combining the homeostatic regulation of orexin system on central motor control and its effects on other brain functions is presented to discuss the role of orexin system beyond the pure motor activity level, but at the complex behavioral level. PMID- 25511390 TI - Alzheimer's disease and chronic periodontitis: is there an association? AB - Alzheimer's disease, an affliction of old age, is one of the leading causes for dementia worldwide. Various risk factors including family history, genetics and infections have been implicated in its pathogenesis. The cognitive decline in this condition is mainly a result of the formation of amyloid deposits that provoke neuroinflammation, ultimately resulting in cell death. Recently, an association between peripheral inflammation and Alzheimer's disease was hypothesized. It was suggested that chronic systemic inflammation worsened the inflammatory processes in the brain. This was mainly attributed to increased levels of pro-inflammatory mediators, such as interleukin-1, interleukin -6 and tumor necrosis factor-alpha in the plasma. As chronic periodontitis is a widespread peripheral immunoinflammatory condition, it has been proposed to play a significant role in the aggravation of Alzheimer's disease. With this background, the current review focuses on the relationship between Alzheimer's disease and chronic periodontitis, and its therapeutic implications. PMID- 25511389 TI - Epoxyeicosatrienoic acids act through TRPV4-TRPC1-KCa1.1 complex to induce smooth muscle membrane hyperpolarization and relaxation in human internal mammary arteries. AB - Human left internal mammary arteries (LIMAs) are commonly used as donor grafts for coronary bypass surgery. Previous reports suggested that 11,12 epoxyeicosatrienoic acid (11,12-EET) is an important endothelial-derived hyperpolarizing factor (EDHF) in human LIMAs and that EETs act through large conductance Ca2+-activated K+ channels (KCa1.1) to induce smooth muscle cell hyperpolarization and relaxation in these tissues. In this study, we aimed to explore the role of vanilloid transient receptor potential channel 4 (TRPV4) and canonical transient receptor potential channel 1 (TRPC1) channels in the EET induced smooth muscle hyperpolarization and vascular relaxation in human LIMAs. Co-immunoprecipitation studies demonstrated that TRPV4, TRPC1, and KCa1.1 physically interacted with each other to form a complex. Sharp microelectrode and vascular tension studies demonstrated that 11,12-EET (300 nmol/L) and 4alpha phorbol 12,13-didecanoate (5 MUmol/L) were able to induce smooth muscle membrane hyperpolarization and vascular relaxation in isolated human LIMA segments. The hyperpolarizing and relaxant effects were markedly reduced by treatments that could suppress the expression/activity of TRPV4, TRPC1, or KCa1.1. With the use of human embryonic kidney 293 cells that over-expressed with TRPV4, TRPC1 and KCa1.1, we found that TRPC1 is the linker through which TRPV4 and KCa1.1(alpha) can interact. The present study revealed that 11,12-EET targets the TRPV4-TRPC1 KCa1.1 complex to induce smooth muscle cell hyperpolarization and vascular relaxation in human LIMAs. This finding provides novel mechanistic insights for the EET action in human LIMAs. PMID- 25511391 TI - Introducing Kirill A. Martemyanov, the 2014 recipient of the Cogan Award. PMID- 25511393 TI - Structural improvement of compounds with analgesic activity: AC-MPF4, a compound with mixed anti-inflammatory and antinociceptive activity via opioid receptor. AB - Successful pain control is a world health problem, which indicates an ever growing need in the discovery of new molecules with improved analgesic activity and reduced side effects. The aim of this study was to describe the synthesis and biological activity of AC-MPF4, a new acetyl- and pyrazole-containing molecule derivate from MPF4. Firstly, we evaluated the analgesic and anti-edematogenic effect of AC-MPF4 in the carrageenan test. AC-MPF4 presented similar analgesic properties to MPF4 (opioid drug) and acetylsalicylic acid (ASA-a non-steroidal anti-inflammatory drug) (maximal effect of 85.4+/-10.9%, 62.0+/-11.0% and 95.0+/ 10.4% of allodynia reduction, respectively). Regarding anti-edematogenic properties, AC-MPF4 presented similar results to ASA, while MPF4 presented no effect (maximal effect of 42.2+/-8.3% and 46.1+/-5.1% in paw thickness reduction, respectively). Remarkably, Naloxone fully prevented the analgesic effect of MPF4 and partially prevented the analgesic effect of AC-MPF4. However, neither ASA nor the anti-edematogenic activity was affected by Naloxone. The gastrointestinal motility and gastric mucosa integrity, which are parameters affected by opioid and NSAID drugs, respectively, were also evaluated. Neither of these parameters showed alterations induced by AC-MPF4, whereas ASA induced gastric ulceration (10 fold higher), and MPF4 decreased gastrointestinal motility (62.0+/-7.7%). Together, these data indicate that AC-MPF4 presents good analgesic and anti edematogenic effects with no detectable side effects. AC-MPF4 may be considered a good prototype for the development of new analgesic/anti-inflammatory drugs. PMID- 25511394 TI - Helping mothers to get the message about influenza: are texts the future for increased immunization? AB - Pregnant women and children are at increased risk of severe influenza infections. Despite existing recommendations, uptake of influenza vaccine in these vulnerable groups remains low. Text message reminder-recalls are a feasible and scalable method for promoting influenza vaccination. In randomized controlled trials, text message interventions have demonstrated small but significant increases in influenza vaccine coverage. They should be considered one of many tools available for increasing vaccination and thus improving maternal and child health. PMID- 25511392 TI - G protein signaling in the retina and beyond: the Cogan lecture. PMID- 25511396 TI - [Current and future perspectives of chronic hepatitis C virus infection in China]. PMID- 25511398 TI - [Experience in diagnosis and treatment of fever of unknown origin]. PMID- 25511397 TI - [Decreasing mortality in severe infectious patients: how shall we learn from epidemiologic studies ?]. PMID- 25511399 TI - [Albumin, the most familiar stranger]. PMID- 25511400 TI - [Optimal thyroid stimulating hormone suppression in treatment of thyroid cancer: from experience to evidence-base]. PMID- 25511395 TI - Protective effect of Xuebijing injection on paraquat-induced pulmonary injury via down-regulating the expression of p38 MAPK in rats. AB - BACKGROUND: Exposure to paraquat results in acute lung injury. A systemic inflammatory response has been widely established as a contributor to paraquat induced acute lung injury. Recent studies have reported that consumption of Xuebijing prevents inflammatory response-induced diseases. This study investigated whether consumption of Xuebijing protected rats against paraquat induced acute lung injury. METHODS: Adult male Sprague Dawley rats were randomly divided into four groups: control group; paraquat group; paraquat + Xuebijing group; and paraquat + dexamethasone group. Rats in the paraquat, paraquat + Xuebijing and paraquat + dexamethasone groups were intraperitoneally injected with paraquat (30 mg/kg) or administered paraquat and Xuebijing at 8 mL/kg or dexamethasone at 5 mg/kg, respectively, via an injection into the tail vein. Lung p38 MAPK, NF-kappaB65, IkB, p-IkappaB-alpha, HIF-1alpha, Nrf2 and TGF-beta1 expression were essayed using western blotting. IL-6, TNF-alpha, IL-1beta, IL-10, TGF-beta1 and PIIIP were measured using ELISA. ROS, oxidised glutathione and glutathione activity were measured. RESULTS: After inducing acute lung injury with paraquat for 24 h, Xuebijing was observed to block lung p-p38 MAPK, NF kappaB65, HIF-1alpha, p-IkappaB-alpha and TGF-beta1 expression, and increased Nrf2 and IkB expression. The numbers of neutrophils and lymphocytes and total number of cells were significantly lower in the Xuebijing group compared with the control group. IL-6, TNF-alpha, IL-1beta, TGF-beta1 and PIIIP levels were significantly decreased in the Xuebijing group. ROS and oxidised glutathione activity were markedly inhibited by Xuebijing. Histological evaluation showed attenuation of the effects of Xuebijing on paraquat-induced lung injury. Compared with the paraquat + dexamethasone group, the Xuebijing + paraquat group showed no significant differences. CONCLUSIONS: Inhibiting the expression of p38 MAPK and NF-kappaB65 was crucial for the protective effects of Xuebijing on paraquat induced acute lung injury. The findings suggest that Xuebijing could effectively ameliorate paraquat-induced acute lung injury in rats. Xuebijing was as effective as dexamethasone at improving paraquat-induced lung injury by regulating lung inflammation, lung function and oxidative stress responses. PMID- 25511401 TI - [Tenofovir rescue therapy for chronic hepatitis B patients after suboptimal response to treatment with lamivudine plus adefovir dipivoxil]. AB - OBJECTIVE: To evaluate the efficacy of tenofovir (TDF) 300 mg/d, comparing with entecavir (ETV), in adults with chronic HBV infection who had previously virologic failure with lamivudine(LAM) and failed with rescue treatment of LAM combined adefovir(ADV). METHODS: Fifty-seven patients of chronic hepatitis B on rescue treatment with TDF were analyzed retrospectively. The serum HBV DNA levels, HBeAg, ALT and serum creatinine (Cr) were detected after treatment for 12, 24 and 48 weeks respectively. In addition, data of 40 cases treated with ETV 1 mg per day as a control group were also collected. RESULTS: The baseline characteristics including HBV viral loads, median age, serum levels of ALT and Cr were compatible between TDF group and ETV group. At the time point of 24 weeks, there was only one patient (2.5%) in ETV group with HBV DNA<100 IU/ml, which means negative viral replication, while 49 patients in TDF group reached HBV negativity (86.0% vs 2.5%, chi(2) = 22.26, P < 0.001). At the time point of 48 weeks, the proportion of patients with HBV DNA<100 IU/ml in TDF group was significantly higher than that in ETV group (87.7% vs 12.5%,chi(2) = 24.17, P < 0.001). The ratios of ALT normalization (84.2% vs 77.5%, P = 0.431) and HBeAg seroconversion were similar in both groups. Elevated Cr was not found in both cohorts at the end of treatment. CONCLUSIONS: Tenofovir (300 mg/d) is an effective and safe rescue therapy in chronic hepatitis B patients who failed initial treatment with LAM and secondary treatment of LAM plus ADV. PMID- 25511402 TI - [The value of (18)F-FDG PET/CT in diagnosing giant cell arteritis presenting as fever of unknown origin]. AB - OBJECTIVE: To evaluate the clinical diagnostic contribution of (18)F-FDG PET/CT in giant cell arteritis with initial presentation as fever of unknown origin (FUO) . METHODS: Eight cases with initial presentation as FUO diagnosed with the contribution of PET/CT were retrospectively studied in Peking Union Medical College Hospital. The radiologic manifestations of PET/CT were analyzed. RESULTS: Eight patients (4 men and 4 women) with average (63 +/- 7) years (range from 55 75 years) were included in our study based on the criteria.Non-specific clinical symptoms were common in these patients, including fatigue, night sweat and weight loss. They all suffered from anemia of chronic disease.Not surprisingly, the inflammatory parameters were elevated significantly in all patients. The medical history, physical examination and routine lab and radiologic examinations couldn't reveal the causes of fever. PET/CT was performed in all of them, which demonstrated intense (18)F-FDG uptake in the area of aorta and its major branches with maximal standard uptake value (SUVmax) 2.1- 4.6 (3.6 +/- 0.9).Immunosuppressive agents were effective to control the inflammation activity. The SUV decreased significantly after treatment in the follow-up PET/CT. CONCLUSIONS: PET/CT has demonstrated high yield of diagnostic contribution in giant cell arteritis with initial presentation as fever of unknown origin. As to elderly FUO patients presenting with prominent inflammatory reaction, PET/CT may provide potential value to differentiate diagnosis from maligancies. PMID- 25511403 TI - [An analysis of risk factors and their prognostic effects on Chinese women's outcomes after ischemic stroke]. AB - OBJECTIVE: To explore the risk factors and their prognostic value in Chinese female patients with ischemic stroke. METHODS: A total of 4 442 female patients with ischemic stroke were enrolled in the study from the Chinese National Stroke Registry System. According to the modified Rankin Scale (mRS) score, patients were divided into the group A (with good outcomes, mRS = 0-2) and the group B(with bad outcomes, mRS = 3-6), with the follow-up for 12 months. The risk factors were collected at month 3 and month 12, including age, family history, body mass index (BMI), hypertension, diabetes mellitus (DM), hyperlipidemia, atrial fibrillation (AF), coronary heart disease (CHD), smoking and moderate or heavy alcohol intake. The multivariate logistic regression was performed to determine the prognostic value of those risk factors. RESULTS: Patients in the group B were older than those in the group A [month 3: (71.3 +/- 11.4) years old vs (65.5 +/- 11.8) years old and month 12: (71.9 +/- 11.3) years old vs (65.1 +/- 11.6) years old, with both P < 0.001]. Patients in the group B were found to have higher ratio of BMI < 25 kg/m(2) (66.3% vs 62.0%, P = 0.006; 66.6% vs 61.8%, P = 0.002) and more likely to have the history of DM (27.0% vs 23.3%, 26.6% vs 23.6%, respectively; both P < 0.05), AF (18.0% vs 6.2%, 17.9% vs 6.3%, respectively; both P < 0.001) and CHD (21.4% vs 14.4%, 21.8% vs 14.2%, respectively; both P < 0.001) than those in the group A. The multivariate logistic regression analysis showed that women's age (OR = 1.04, 1.05, 95%CI 1.03-1.05, 1.04-1.06, respectively), the histories of DM (both OR = 1.35, 95%CI 1.15-1.58, respectively) and AF(OR = 2.91, 2.84, 95%CI 2.33-3.64, 2.27-3.56, respectively) were significantly associated with the bad outcomes at month 3 and month 12. The history of CHD was associated with the bad outcomes at month 12 (OR = 1.20, 95%CI 1.00-1.43), while the history of hyperlipidemia might improve the outcome at month 12 (OR = 0.75, 95%CI 0.60- 0.94). CONCLUSIONS: The risk factors may have different prognostic value in female patients with ischemic stroke. The diagnosis and treatment for DM, AF and CHD may be helpful to improve the prognosis in Chinese female patients with ischemic stroke. PMID- 25511404 TI - [Increased risk of severe acute graft-versus-host disease in low body mass index patients undergoing haploidentical allogeneic stem cell transplantation]. AB - OBJECTIVE: To investigate the impact of body mass index (BMI) before transplantation on clinical outcomes of haploidentical allogeneic stem cell transplantation (allo-HSCT). METHODS: We performed a retrospective cohort study of 253 adult patients with acute or chronic leukemia who received haploidentical allo-HSCT from August 2008 to September 2011. All conditioning regimens were myeloablative and bulsufan based. Patients were stratified according to BMI values (low BMI group: <18 kg/m(2); normal BMI group: >= 18 and < 25 kg/m(2); overweight BMI group: >= 25 kg/m(2)). Other possible risk factors correlated with GVHD, relapse, transplant related mortality (TRM) and overall survival (OS) included age and gender of donor and recipient, HLA disparity, relationship between donor and recipient, diagnosis, status of disease, ATG dose in conditioning regime(10 mg/kg , 6 mg/kg), mononuclear cells (MNC), CD(+)34 and CD(+)3 cell amount from granulocyte colony-stimulating factor (G-CSF) primed bone marrow grafts (G-BM) and G-CSF mobilized peripheral blood grafts(G-PB). Cox regression analysis was used to determine the related risk factors. RESULTS: The median age of all 253 patients was 31 (18-56) years, including 128 cases with acute myeloid leukemia (AML), 95 cases with acute lymphocytic leukemia (ALL), and 30 cases with chronic myeloid leukemia (CML). According to primary diseases, 185 patients were classified in the standard -risk group and 68 cases in the high risk group. Median follow-up time was 929 days (range: 48-1762 days) post transplantation. Engraftment has been attained 252 (99.6%) recipients with the median time of granulocyte and platelet recovery 12 days (ranging from 9 to 45 days) and 16 days (ranging from 7 to 180 days), respectively. Cumulative incidences of acute GVHD was 33.2% with median time of 25 days (range: 13-88 days) after transplant. Multivariate analysis identified that low BMI was associated with an increased risk of grade III-IV acute GVHD (HR = 5.736, 95%CI 1.779-18.491, P = 0.003). There was no significant impact of BMI to other manifestations of GVHD, TRM, relapse or OS in different groups. CONCLUSIONS: Our findings demonstrate a correlation between pre transplant BMI and clinical outcome post-transplant. Low BMI was associated with increased risk of severe acute GVHD in leukemia patients receiving haploidentical allo-HSCT. Meticulous supportive care pre-transplantation is required for low BMI patients. PMID- 25511406 TI - [The value of prone position lung ultrasound examination in predicting the prognosis of Acute Respiratory Distress Syndrome receiving prone ventilation]. AB - OBJECTIVE: To investigate the value of prone position lung ultrasound examination (PLUE) in monitoring the prone position during and predicting the outcome of Acute Respiratory Distress Syndrome (ARDS) patients. METHODS: All the ARDS patients needed to receive prone position were enrolled, a three hours PLUE was performed during the prone position for the first time. For each of the 16 regions examined, ultrasound patterns were recorded and the aeration scores were calculated at the beginning of the prone position and 3 hours later. The correlation of the aeration score variation (ASV) and the oxygen fraction were evaluated. The relationship between the ASV and the outcome indexes such as oxygen fraction, free of mechanical ventilation and mortality were also evaluated. RESULTS: A total of 29 patients were enrolled in this study. The aeration score of the lung was significantly reduced three hours after the beginning than the beginning (19.15 +/- 7.98 vs 26.96 +/- 6.43, P < 0.01) , with the significant increasing of the oxygen fraction. The ASV was significantly higher in the patients with oxygen fractions >300 mmHg (1 mmHg = 0.133 kPa) in Day 7 than those with oxygen fractions <300 mmHg (9.53 +/- 4.34 vs 4.86 +/- 2.96, P < 0.05). The ASV was also higher in the patients free of mechanical ventilation in Day 7 than those who needed mechanical ventilation (10.17 +/- 4.45 vs 5.23 +/- 3.03, P < 0.05). The area under the receiver operating characteristic curve was 0.840 and 0.824 respectively for detecting the validity of the prone position and the possibility of free of mechanical ventilation with ASV. For predicting the oxygen fraction >300 mmHg in Day 7, the cutoff value of ASV was >= 5.5, resulting a sensitivity of 86.7% and a specificity of 71.4%. For predicting the patients free of mechanical ventilation in Day 7, the cutoff value of ASV was 7, resulting a sensitivity of 75.0% and a specificity of 76.5%. CONCLUSION: Bedside lung ultrasound is valuable in evaluating the ASV during the prone position in ARDS patients. The three hours PLUE can predict the outcome of ARDS patients such as validity of prone position and free of ventilation in Day 7. The value of predicting the mortality needs further investigation. PMID- 25511405 TI - [An analysis of results of the elderly colorectal cancer screening study]. AB - OBJECTIVE: To evaluate the detection rates of colorectal polyps and cancer in the elderly and characterize the pathological features of the colorectal neoplasm in DongLi District in Tianjin. METHOD: Totally, 46 743 subjects aged 60-74 were recruited from the national colorectal cancer screening program, including subjects registered from November 2012 to April 2013 in DongLi District in Tianjin. Each subject completed a questionnaire and a fecal occult blood test. Colonoscopies were conducted in 434 subjects with high risk for colorectal cancer. RESULTS: Among all the subjects, 2 880 were at high risk for colorectal cancer which accounts for 6.16% (2 880/46 743) of the total subjects. Among the subjects who underwent the colonoscopy, 165 (men: 105, women: 60) were colorectal polyps accounting for 5.73% (165/2 880) in the total risk, with 51 subjects (1.77%) advanced neoplasms and 4 subjects (0.14%) cancer. The detection rates of colorectal polyps is 0.35% (165/46 743), and colorectal cancer is 8.6/10(5) (4/46 743). More polyps were found on the left colon compared with the right. More tubular adenoma was found compared with the other pathological types. Most of the polyps were smaller than 0.5 cm. Colorectal polyps and advanced neoplasms were more frequent in men than women [45.45% (105/231) vs 29.56% (60/203), 16.02% (37/231) vs 6.90% (14/203), all P < 0.01]. Multiple polyps (P < 0.05) and polyps with diameter larger than 1.0 cm (P < 0.01) were more often in men than in women. Men tended to have more colorectal polyps in right colon and higher detection rate for moderate or sever atypical hyperplasia than women (all P < 0.05). CONCLUSION: There is a higher incidence of colorectal polyps in the elderly. It is important to establish the national sequential colorectal cancer screening program for the early diagnoses of colorectal polyps and cancer in the elderly. PMID- 25511407 TI - [An analysis of abnormal magnetic resonance imaging of sacroiliac joints in patients misdiagnosed as spondyloarthritis]. AB - OBJECTIVE: To study the imaging features of sacroiliac joints (SIJ) in patients who were misdiagnosed as spondyloarthritis (SpA). METHODS: A total of 34 patients with chief complaint of back pain and misdiagnosed as SpA from January 2007 to April 2013 in Department of Rheumatology Chinese PLA General Hospital were enrolled. The imaging, clinical manifestations, laboratory examinations data were analyzed. RESULT: The main reason for misdiagnosis as SpA was because of sacroiliitis presenting on imaging. The final diagnoses included 24 patients as SIJ infection, 4 patients as neoplastic diseases, 2 patients as metabolic bone diseases, 2 patients as sacroiliac joint degeneration, 1 patient as gout of sacroiliac joint, 1 patient as diffuse idiopathic bone hypertrophy. For patients with infection, there were 10 patients receiving X-ray and 22 patients receiving CT of SIJ. However, 5 and 7 patients had negative results respectively. These patients with infection had abnormalities in MRI including all with bone marrow edema, 21 patients with erosion of bone and joint, 22 patients with muscle involved. As to the patients with malignancies, SIJ CT scan appeared normal. Bone marrow edema and erosion in MRI were found in all neoplasm patients expect one as ependymoma. Adjacent muscles were involved in the patient with Ewing's sarcoma. Either X-ray or CT in other patients demonstrated obvious abnormalities, but only mild erosion of bone was found in MRI. CONCLUSION: Bone marrow edema of SIJ in MRI represented not only in patients with SpA. Rheumatologists should analyze the clinical manifestations and laboratory examinations comprehensively in order to avoid the misdiagnoses. PMID- 25511408 TI - [The protective role of peroxisome proliferator activated receptors-alpha and pathomechanism in D-galactosamine/lipopolysaccharide- induced acute liver failure in rats]. AB - OBJECTIVE: To determine the role and mechanism of peroxisome proliferator activated receptors (PPAR) alpha in a mouse model of D galactosamine/lipopolysaccharide (D-GalN/LPS)-induced acute liver failure (ALF). METHODS: Firstly, C57BL/6 mice were randomly divided into control group (n = 8), ALF 2h group (n = 8), ALF 4h group (n = 8), ALF 6h group (n = 8). Secondly C57BL/6 mice were randomly divided into control group (n = 8), ALF group (n = 8), WY14643 group (n = 8). To induce ALF, the mice were injected intraperitoneally with D-GalN (700 mg/kg) and LPS (10 ug/kg). WY14643 (6 mg/kg), the selective agonist of PPAR alpha, was administered via tail vein two hours prior to D GalN/LPS exposure. Two, four, and six hours after D-GalN/LPS treatment in the first study, mice were anesthetized and blood was collected, 6h after D-GalN/LPS treatment in the second study, blood was collected. The liver tissue was harvested for histology and mRNA extraction. Serum levels of ALT and AST were measured to evaluate the hepatic damage. Inflammatory cytokines (TNFalpha, IL 1beta, IL-6) and chemokines (CXCL-1, CXCL-10) were detected by real-time quantitative PCR. Differential protein expression of p-NF-kappaBp65, p-JNK, p ERK, p-p38 in inflammatory pathways was detected by Western blotting. Significance of inter-group differences was assessed by one-way ANOVA, and pairwise comparison was performed by the least significant difference test. RESULTS: The gene and protein expression of PPAR alpha were gradually reduced during the development of ALF. Compared with the model group, the liver architecture was better preserved almost with normal morphology in WY14643 treated mice. Serum ALT and AST levels in WY14643-treated group were significantly lower [ALT: (555 +/- 62)U/L vs (2 898 +/- 822) U/L, P < 0.05; AST: (791 +/- 58) U/L vs (3 013 +/- 997) U/L, P < 0.05]. The expression of proinflammatory cytokines and chemokines was significantly suppressed during the activation of PPAR alpha. In the second study, the levels of gene expression of proinflammatory cytokines and chemokines were detected in control group, ALF group and WY14643 group respectively as followings: TNFalpha (0.161 +/- 0.085, 7.996 +/- 1.068, 3.346 +/- 0.94, P < 0.05), IL-1beta (0.041 +/- 0.002, 3.657 +/- 0.904, 0.176 +/- 0.089, P < 0.01), IL-6 (0.018 +/- 0.008, 1.762 +/- 0.589, 0.163 +/- 0.0487, P < 0.05), CXCL-1 (0.063 +/- 0.008, 7.881 +/- 0.966, 2.737 +/- 0.864, P < 0.01), CXCL-10 (0.054 +/- 0.005, 5.671 +/- 0.948, 2.578 +/- 0.804, P < 0.05). CONCLUSION: Our findings first demonstrate that PPARalpha protects liver from injury in an ALF mouse model by suppressing inflammatory response, indicating PPARalpha as a potential new therapeutic target for ALF. PMID- 25511409 TI - RNA-Seq gene expression profiling of HepG2 cells: the influence of experimental factors and comparison with liver tissue. AB - BACKGROUND: Human hepatoma HepG2 cells are used as an in vitro model of the human liver. High-throughput transcriptomic sequencing is an advanced approach for assessing the functional state of a tissue or cell type. However, the influence of experimental factors, such as the sample preparation method and inter laboratory variation, on the transcriptomic profile has not been evaluated. RESULTS: The whole-transcriptome sequencing of HepG2 cells was performed using the SOLiD platform and validated using droplet digital PCR. The gene expression profile was compared to the results obtained with the same sequencing method in another laboratory and using another sample preparation method. We also compared the transcriptomic profile HepG2 cells with that of liver tissue. Comparison of the gene expression profiles between the HepG2 cell line and liver tissue revealed the highest variation, followed by HepG2 cells submitted to two different sample preparation protocols. The lowest variation was observed between HepG2 cells prepared by two different laboratories using the same protocol. The enrichment analysis of the genes that were differentially expressed between HepG2 cells and liver tissue mainly revealed the cancer-associated gene signature of HepG2 cells and the activation of the response to chemical stimuli in the liver tissue. The HepG2 transcriptome obtained with the SOLiD platform was highly correlated with the published transcriptome obtained with the Illumina and Helicos platforms, with moderate correspondence to microarrays. CONCLUSIONS: In the present study, we assessed the influence of experimental factors on the HepG2 transcriptome and identified differences in gene expression between the HepG2 cell line and liver cells. These findings will facilitate robust experimental design in the fields of pharmacology and toxicology. Our results were supported by a comparative analysis with previous HepG2 gene expression studies. PMID- 25511410 TI - Tb(III)-doped silica nanoparticles for sensing: effect of interfacial interactions on substrate-induced luminescent response. AB - The present work introduces the easy modification of the water-in-oil microemulsion procedure aimed at the doping of the Tb(III) complexes within core or shell zones of the silica nanoparticles (SNs), which are designated as "core shell", "shell", and "core". The dye molecules, chelating ligands, and copper ions were applied as the quenchers of Tb(III)-centered luminescence through dynamic or/and static mechanisms. The binding of the quenchers at the silica/water interface results in the quenching of the Tb(III) complexes within SNs, which, in turn, is greatly dependent on the synthetic procedure. The luminescence of "core" SNs remains unchanged under the binding of the quenchers at the silica/water interface. The quenching through dynamic mechanism is more significant for "core-shell" and "shell" than for "core" SNs. Thus, both "core shell" and "shell" SNs have enough percentage of the Tb(III) complexes located close to the interface for efficient quenching through the energy transfer. The quenching through the ion or ligand exchange is most efficient for "core-shell" SNs due to the greatest percentage of the Tb(III) complexes at the silica/water interface, which correlates with the used synthetic procedure. The highlighted regularities introduce the applicability of "core-shell" SNs used as silica beads for phosphatidylcholine bilayers in sensing their permeability toward the quenching ions. PMID- 25511411 TI - In response to "histopathologic validation of 3'-deoxy-3'-(18)F-fluorothymidine PET for detecting tumour repopulation during fractionated radiotherapy in human FaDu squamous cell carcinoma in nude mice". PMID- 25511412 TI - Utility of cell viability assays for use with ex vivo vocal fold epithelial tissue. AB - OBJECTIVES/HYPOTHESIS: Ex vivo models are routinely used to investigate the barrier function of the vocal fold epithelium. However, there are limited reports on assays that can be used to investigate the effect of clinically relevant challenges on vocal fold epithelial tissue viability. Our objective was to determine the utility of two assays routinely used in cell culture-a cellular metabolic activity assay and a cell membrane integrity assay-to investigate the viability of ex vivo porcine vocal fold epithelium. STUDY DESIGN: Prospective, ex vivo animal study. METHODS: Porcine vocal folds were exposed to acrolein, hydrochloric acid, or hydrogen peroxide challenge. An untreated, sham challenge was included as a control. Assays including metabolic activity, cell membrane integrity, and histology were used to determine whether challenges reduced epithelial viability as compared to sham. RESULTS: Cell membrane integrity and metabolic activity assays detected reductions in viability following hydrochloric acid and hydrogen peroxide challenges but not acrolein challenge as compared to sham. No challenge produced significant changes in epithelial appearance as evidenced by light microscopy. CONCLUSIONS: Metabolic activity and cell membrane integrity assays are valuable tools that can be used to evaluate the viability of ex vivo vocal fold epithelial tissue following clinically relevant challenges. As viability is reduced, the ability of epithelial tissue to maintain its barrier function is compromised. Accurate assessment of viability may provide us clues into understanding mechanisms underlying vocal fold epithelial injury and disease. LEVEL OF EVIDENCE: NA Laryngoscope, 125:E180-E185, 2015. PMID- 25511413 TI - Anal incontinence, urinary incontinence and sexual problems in primiparous women a comparison between women with episiotomy only and women with episiotomy and obstetric anal sphincter injury. AB - BACKGROUND: Obstetric anal sphincter injuries (OASIS) might cause anal incontinence (AI) and sexual dysfunction, and might be associated with urinary incontinence (UI). Episiotomy has been identified both as a risk and a protective factor of OASIS. Lately, episiotomies with specific characteristics have shown to be protective against the risk of OASIS. However, little is known about episiotomy characteristics and pelvic floor dysfunction. This study investigates AI, UI, and sexual problems in primiparous women with episiotomy, comparing women with and without OASIS. Associations between episiotomy characteristics and AI, UI, and sexual problems were assessed. METHODS: This is a matched case-control study investigating 74 women with one vaginal birth, all with an episiotomy. Among these, 37 women sustained OASIS and were compared to 37 women without OASIS. The two groups were matched for vacuum/forceps. AI, UI and sexual problem symptoms were obtained from St. Mark's scoring-tool and self-administered questionnaires. The episiotomy characteristics were investigated and results assessed for the whole group. RESULTS: The mean time from birth was 34.5 months (range1.3-78.2) for those with OASIS and 25.9 months (range 7.0-57.4) for those without OASIS, respectively. More women with OASIS reported AI: 14 (38%) vs. 3 (8%) p = 0.05 (OR 4.66, 95% CI 1.34-16.33) as well as more problem with sexual desire p = 0.02 (OR 7.62, 95% CI 1.30-44.64) compared to women without OASIS. We found no association between episiotomy with protective characteristics and dysfunctions. CONCLUSION: Women with OASIS had more AI and sexual problems than those without OASIS. Episiotomy characteristics varied greatly between the women. Episiotomy with protective characteristics was not associated with increased dysfunctions. OASIS should be avoided, and correct episiotomy used if indicated. PMID- 25511414 TI - Overexpression of SCLIP promotes growth and motility in glioblastoma cells. AB - SCLIP, a microtubule-destabilizing phosphoprotein, is known to be involved in the development of the central nervous system (CNS). It has been well established that there are notable parallels between normal development and tumorigenesis, especially in glioma. However, no studies have examined the significance of SCLIP in gliomagenesis. To address this, we investigated the expression of SCLIP and its roles in the development of gliomas. Notably, we found that SCLIP was highly expressed in various grades of glioma samples, as compared with normal brain tissues. Overexpression of SCLIP dramatically stimulated tumor cell migration and invasion as well as proliferation and downregulation of SCLIP showed opposite effects, establishing an important oncogenic role for this gene. Furthermore, we revealed that STAT3 was required to maintain SCLIP stability, suggesting that overexpression of STAT3 may be a critical step to facilitate microtubule dynamics and subsequently promotes migration and invasion of glioma cells. Taken together, our findings demonstrate that SCLIP plays an important role in glioma pathology, and may represent a novel therapeutic strategy against human glioma. PMID- 25511415 TI - Stereotactic radiotherapy for vestibular schwannoma. AB - BACKGROUND: Vestibular schwannomas (acoustic neuromas) are common benign tumours that arise from the Schwann cells of the vestibular nerve. Management options include observation with neuroradiological follow-up, microsurgical resection and stereotactic radiotherapy. OBJECTIVES: To assess the effect of stereotactic radiotherapy compared to observation, microsurgical resection, any other treatment modality, or a combination of two or more of the above approaches for vestibular schwannoma. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials; PubMed; EMBASE; CINAHL; Web of Science; CAB Abstracts; ISRCTN and additional sources for published and unpublished trials. The date of the search was 24 July 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) exploring the efficacy of stereotactic radiotherapy compared with observation alone, microsurgical resection or any other possible treatment or combination of treatments in patients with a cerebellopontine angle tumour up to 3 cm in diameter, presumed to be a vestibular schwannoma. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: There is no high quality evidence in the literature from RCTs to determine whether stereotactic radiotherapy is better than microsurgical resection or observation alone for patients with a vestibular schwannoma. In the absence of such evidence, the treatment method should be chosen on an individual basis, taking into consideration the patient's preferences, clinician experience and the availability of radiotherapeutic equipment. With the growing availability of radiotherapeutic equipment, randomised controlled trials should be undertaken to evaluate the role of stereotactic radiotherapy in comparison with other treatment options. PMID- 25511417 TI - c-Jun N-terminal kinase inhibitor SP600125 enhances barrier function and elongation of human pancreatic cancer cell line HPAC in a Ca-switch model. AB - c-Jun N-terminal kinase (JNK), known as a stress-activated protein kinase, regulates normal epithelial biological processes, including assembly of adherens and tight junctions, and it is involved in the development of several cancers. The JNK inhibitor SP600125 enhances epithelial barrier function through modulation of tight junction molecules in normal human pancreatic epithelial cells. Furthermore, this JNK inhibitor suppresses the growth of human pancreatic cancer cells. However, the effects of SP600125 on the epithelial barrier in human pancreatic cancer cells remain unknown. In the present study, the JNK inhibitor SP600125 markedly enhanced the barrier function and cell elongation of well differentiated human pancreatic cancer cell line HPAC in a Ca-switch model. The epithelial barrier function induced by SP600125 was regulated by phosphorylated beta-catenin without changes in the tight junction molecules. The cell elongation induced by SP600125 was closely related to the expression of the F-actin-binding protein DrebrinE. These findings suggest that JNK is involved in the regulation of the epithelial barrier function and cell shape during remodeling of pancreatic cancer cells. The JNK inhibitor SP600125 may have potential as a therapeutic drug for pancreatic cancer via induction of differentiation. PMID- 25511416 TI - Inhibition of small HA fragment activity and stimulation of A2A adenosine receptor pathway limit apoptosis and reduce cartilage damage in experimental arthritis. AB - Recent studies have found that the inactivation of small hyaluronan (HA) fragments originating from native HA during inflammation reduced the inflammatory response in models of experimental arthritis. The stimulation of adenosine receptors A2A reduced inflammation by inhibiting NF-kB activation. The combination of both treatments was significantly more effective than either of the individual treatments. The aim of this study was to further investigate the effects of a combined treatment using the HA inhibitor Pep-1 and a selective A2AR agonist (CV-1808) on the structure and ultrastructure of the articular cartilage and on apoptosis in a model of collagen-induced arthritis (CIA) in mice. Arthritic mice were treated with Pep-1 and/or CV-1808 intraperitoneally daily for 20 days. At day 35, the hind limbs were processed for light microscopy (hematoxylin/eosin and Safranin-O-Fast Green) and for transmission and scanning electron microscopy. CIA increased IL-6, caspase-3 and caspase-7 mRNA expression and the related protein levels in arthritic articular cartilage, and significantly increased concentrations of Bcl-2-associated X protein (Bax), while B cell-lymphoma-2 protein (Bcl-2) was markedly reduced. The combined Pep-1/CV 1808 treatment significantly reduced CIA injury, particularly at the highest doses, demonstrated by the presence of Safranin-O-positive cartilage, with a smooth surface and normal chondrocytes in the superficial, intermediate and deep zones. Morphological data and histological scoring were strongly supported by the reduction in inflammation and apoptotic markers. The results further support the role of HA degradation and A2A receptors in arthritis. PMID- 25511418 TI - Chromosome 13q14 deletion in a mammary-type myofibroblastoma of the big toe. PMID- 25511419 TI - Re: Puppo V, Puppo G. 2014. anatomy of sex: Revision of the new anatomical terms used for the clitoris and the female orgasm by sexologists. PMID- 25511421 TI - High quality-factor optical nanocavities in bulk single-crystal diamond. AB - Single-crystal diamond, with its unique optical, mechanical and thermal properties, has emerged as a promising material with applications in classical and quantum optics. However, the lack of heteroepitaxial growth and scalable fabrication techniques remains the major limiting factors preventing more wide spread development and application of diamond photonics. In this work, we overcome this difficulty by adapting angled-etching techniques, previously developed for realization of diamond nanomechanical resonators, to fabricate racetrack resonators and photonic crystal cavities in bulk single-crystal diamond. Our devices feature large optical quality factors, in excess of 105, and operate over a wide wavelength range, spanning visible and telecom. These newly developed high-Q diamond optical nanocavities open the door for a wealth of applications, ranging from nonlinear optics and chemical sensing, to quantum information processing and cavity optomechanics. PMID- 25511420 TI - Molecular characterization of cryptic species of Anopheles barbirostris van der Wulp in China. AB - BACKGROUND: Anopheles barbirostris sensu lato belongs to the Barbirostris subgroup of the subgenus Anopheles that is distributed in Southeast Asia. Different molecular forms have been identified based on the rDNA-ITS2 and mtDNA COI sequences. Anopheles barbirostris occurs in China. The species status was uncertain due to the lack of molecular characterization. The present study characterized Chinese An. barbirostris using rDNA-ITS2 and mtDNA-COI gene sequences. Two cryptic species were identified. FINDINGS: DNA was extracted from morphologically identified An. barbirostris specimens collected in Yunnan and Hainan from China, the sequences of rDNA-ITS2 and mtDNA-COI regions of 40 individuals were amplified and analyzed. The sequence comparison revealed two cryptic species, corresponding to An. barbirostris A1/clade III and A2/clade IV, respectively. The molecular characterization updated the species composition of the An. barbirostris complex in China. CONCLUSIONS: This study distinguished two molecular forms in the An. barbirostris s. l. in China. PMID- 25511422 TI - Identification of metabolites from 2D (1)H-(13)C HSQC NMR using peak correlation plots. AB - BACKGROUND: Identification of individual components in complex mixtures is an important and sometimes daunting task in several research areas like metabolomics and natural product studies. NMR spectroscopy is an excellent technique for analysis of mixtures of organic compounds and gives a detailed chemical fingerprint of most individual components above the detection limit. For the identification of individual metabolites in metabolomics, correlation or covariance between peaks in (1)H NMR spectra has previously been successfully employed. Similar correlation of 2D (1)H-(13)C Heteronuclear Single Quantum Correlation spectra was recently applied to investigate the structure of heparine. In this paper, we demonstrate how a similar approach can be used to identify metabolites in human biofluids (post-prostatic palpation urine). RESULTS: From 50 (1)H-(13)C Heteronuclear Single Quantum Correlation spectra, 23 correlation plots resembling pure metabolites were constructed. The identities of these metabolites were confirmed by comparing the correlation plots with reported NMR data, mostly from the Human Metabolome Database. CONCLUSIONS: Correlation plots prepared by statistically correlating (1)H-(13)C Heteronuclear Single Quantum Correlation spectra from human biofluids provide unambiguous identification of metabolites. The correlation plots highlight cross-peaks belonging to each individual compound, not limited by long-range magnetization transfer as conventional NMR experiments. PMID- 25511423 TI - What do we know about ribosomal RNA methylation in Escherichia coli? AB - A ribosome is a ribonucleoprotein that performs the synthesis of proteins. Ribosomal RNA of all organisms includes a number of modified nucleotides, such as base or ribose methylated and pseudouridines. Methylated nucleotides are highly conserved in bacteria and some even universally. In this review we discuss available data on a set of modification sites in the most studied bacteria, Escherichia coli. While most rRNA modification enzymes are known for this organism, the function of the modified nucleotides is rarely identified. PMID- 25511424 TI - Factors associated with the referral of anxious children to mental health care: the influence of family functioning, parenting, parental anxiety and child impairment. AB - This study aims to identify factors that predict the mental health care referral of anxious children. In total, 249 children and families, aged 8-13 years, participated: 73 children were referred with anxiety disorders to mental health care [mean (M) age = 10.28, standard deviation (SD) = 1.35], 176 non-referred anxious children recruited in primary schools (M age = 9.94, SD = 1.22). Child anxiety and other disorders were assessed with semi-structured interviews. Child anxiety symptoms, behavioural problems, parental anxiety, the parenting styles overprotection, autonomy encouragement, rejection, and the family functioning dimensions control and relational functioning, were assessed with child, father and mother report on questionnaires. The summed interference rating of children's anxiety disorders was a predictor of referral, consistent over child and parent reports, but not comorbidity. Most family and parenting variables did not predict referral, nor differed between the referred and non-referred sample. Contrary to our hypothesis, maternal self-reported anxiety decreased the odds of referral and child reported parental autonomy granting increased, while child reported overprotection decreased the odds of referral. The impairment for the child due to the number and severity of their anxiety disorder(s) is, based on child, mother and father report associated with referral. This indicates that those who need it most, receive clinical treatment. PMID- 25511425 TI - Pulmonary Vein Stenosis After Cryoablation Using 28-mm Second-Generation Balloon. PMID- 25511426 TI - Microwave assisted extraction, antioxidant potential and chromatographic studies of some Rasayana drugs. AB - OBJECTIVE: To study and compare the conventional extraction procedure with microwave assisted extraction (MAE) for some Ayurvedic Rasayana drugs and to evaluate their antioxidant potential and carry out the characterization of extracts by thin layer chromatography. METHODS: Three Ayurvedic rasayana plants Allium sativum Linn., Bombax ceiba Linn. and Inula racemosa Hook. were evaluated for an improved MAE methodology by determining the effects of grinding degree, extraction solvent, effect of dielectric constant and duration of time on the extractive value. Antioxidant potential of all three drugs was evaluated with 2,2 diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and reducing power was determined by using Gallic acid as standard. Further thin layer chromatographic (TLC) analysis was performed on pre-activated Silica Gel G plates and Rf value were compared with those reported for the important biomarkers. RESULTS: The total extractive value for Allium sativum Linn. was 36.95% (w/w) and 49.95% (w/w) for ethanol extraction respectively. In case of Bombax ceiba Linn. the yield of aqueous extract by MAE was 50% (w/w) compared to 42% (w/w) in ethanol (50% v/v). Percent yield of Inula racemosa Hook. in aqueous extract was found to be 27.55% (w/w) which was better than ethanol extract (50%) where the yield was 25.95% (w/w). Upon antioxidant activity evaluation. sativum extract showed an absorbance of 0.980+/-0.92 at concentration of 500 MUg with maximum reducing capacity. This was followed by. ceiba Linn. 0.825+/-0.98 and. racemosa Hook. with 0.799+/-2.01 at a concentration of 500 MUg. TLC based standardization of. sativum Linn. extract shows single spot with Rf value of 0.38, B. ceiba Linn. extract shows Rf values were 0.23, 0.58, 0.77, 0.92 and I. racemosa Hook. extract spot had a Rf value of 0.72. CONCLUSIONS: A significant improvement in extractive values was observed as a factor of time and other advantages by using MAE technology. All three drugs have high antioxidant potential and a TLC profiling similar to reported ones. The presence of fructan type polysaccharide can be further utilized for bioactivity directed fractionation and evaluation of immunomodulatory activity. PMID- 25511427 TI - Effects of Biejia Ruangan Tablet-containing serum on matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in cultured renal interstitial fibroblasts. AB - OBJECTIVE: To investigate the effects of Biejia Ruangan Tablet ([symbol in text], BRT)-containing serum on the expression of matrix metalloproteinase (MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1) in cultured renal interstitial fibroblasts. METHODS: Different BRT-containing sera were prepared by gastric gavages to rats with the high-dose (7 g/kg), mid-dose (3.5 g/kg), and low-dose (1.75 g/kg) BRT respectively. The expression of extracellular matrix in NRK-49F cells was induced by treatment with human transforming growth factor-beta1 (recombined human TGF-beta1), and BRT-containing serum. Western blotting and Northern blotting were used to measure type I and III procollagen, MMP-9, and TIMP-1. RESULTS: The high dose BRT-containing serum could decrease the type I and III procollagen gene expression which boosted by TGF-beta1, at the same time cut down TIMP-1 protein and gene expression which increased by TGF-beta1 (P <0.05). Treatment of cells with recombined human TGF-beta1 had no significant effect on MMP-9 expression and BRT-containing serum also had no effect on MMP-9 expression. CONCLUSIONS: High dose BRT has anti-fibrosis effects in NRK-49F cells, as indicated by its inhibition of type I and III procollagen and TIMP-1 expression. PMID- 25511429 TI - New method of dialysate drainage flow analysis: an implication for automated peritoneal dialysis prescription. PMID- 25511428 TI - Smilax china L. rhizome extract inhibits nuclear factor-kappaB and induces apoptosis in ovarian cancer cells. AB - OBJECTIVE: To study the antitumor effects and associated mechanisms of extract of the Smilax china L. rhizome (SCR) on ovarian cancer cells. METHODS: Ovarian cancer cells A2780 were treated with different concentrations of SCR extract (SCRE), and compared with controls. Effects on cell growth were evaluated by cell counting kit-8 (CCK-8) assay; proliferation effects by EdU incorporation assay; cell cycle by propidium iodide staining; apoptosis by annexin V-fluorescein isothiocyanate/propidium iodide; cellular distribution of nuclear factor-kappaB (NF-kappaB) by immunofluorescence; protein levels of NF-kappaB, caspase-3, poly adenosine diphosphate (ADP)-ribose polymerase (PARP), Bcl-2-associated X protein (Bax), cellular inhibitor of apoptosis (cIAP)-1, anti-X-linked inhibitor of apoptosis protein (XIAP), B-cell lymphoma-extra large (Bcl-XL), B-cell lymphoma-2 (Bcl-2) and AKT by Western blotting; and effects of SCRE combined with cisplatin or adriamycin on A2780 cells by CCK-8 assay. RESULTS: SCRE suppressed A2780 cell proliferation in a dose-dependent manner (P<0.05,P<0.01), arrested cells in G2/M phase and induced apoptosis by activating caspase-3, PARP and Bax. SCRE treatment also correlated with inhibition of NF-kappaB and downregulation of Bcl-2, Bcl-XL, cIAP-1, XIAP and AKT. SCRE can promote chemosensitivity to cisplatin and adriamycin in A2780 cells (P<0.01). CONCLUSION: SCR effectively inhibits NF kappaB, induces apoptosis and reduces chemoresistance to cisplatin and adriamycin in ovarian cancer cells, which might be its molecular basis for treating ovarian cancer. PMID- 25511430 TI - Population genetics: the African Genome Variation Project. PMID- 25511431 TI - Clinical value of exogenous factor XIII for prolonged air leak following pulmonary lobectomy: a case control study. AB - BACKGROUND: We examined the effect of exogenous factor XIII (FXIII) concentrate in patients with prolonged air leak (PAL) after pulmonary lobectomy for non-small cell lung cancer. METHODS: We performed a retrospective analysis of 297 patients who underwent pulmonary lobectomy between July 2007 and March 2014: 90 had an air leak on the first postoperative day, which resolved spontaneously within 5 days in 53 cases (SR group). FXIII concentrate was administered to the remaining 37 patients (PAL group) for 5 days. This group was subdivided into those in whom the air leak resolved during FXIII treatment (EF group) and those who needed additional intervention (inEF group). The clinical and perioperative characteristics of the groups were compared. RESULTS: Although plasma FXIII activity did not differ significantly between the SR and PAL groups before surgery or on the fifth postoperative day, the proportional perioperative fall in FXIII activity was significantly greater in the SR group (33%) than the PAL group (22%, p = 0.044) and inEF group (14%, p = 0.048). On the fifth postoperative day, FXIII activity was significantly lower in the EF group than in the inEF group (74% versus 91%, p = 0.030). The optimal cut-off point for postoperative plasma FXIII activity to distinguish between the EF and inEF groups was 86%. CONCLUSIONS: Insufficient plasma FXIII consumption and lower postoperative FXIII activity may play a role in the resolution of PAL, and exogenous FXIII concentrate may be an effective, safe and non-invasive treatment. PMID- 25511432 TI - Comprehensive gene expression analysis of rice aleurone cells: probing the existence of an alternative gibberellin receptor. AB - Current gibberellin (GA) research indicates that GA must be perceived in plant nuclei by its cognate receptor, GIBBERELLIN INSENSITIVE DWARF1 (GID1). Recognition of GA by GID1 relieves the repression mediated by the DELLA protein, a model known as the GID1-DELLA GA perception system. There have been reports of potential GA-binding proteins in the plasma membrane that perceive GA and induce alpha-amylase expression in cereal aleurone cells, which is mechanistically different from the GID1-DELLA system. Therefore, we examined the expression of the rice (Oryza sativa) alpha-amylase genes in rice mutants impaired in the GA receptor (gid1) and the DELLA repressor (slender rice1; slr1) and confirmed their lack of response to GA in gid1 mutants and constitutive expression in slr1 mutants. We also examined the expression of GA-regulated genes by genome-wide microarray and quantitative reverse transcription-polymerase chain reaction analyses and confirmed that all GA-regulated genes are modulated by the GID1 DELLA system. Furthermore, we studied the regulatory network involved in GA signaling by using a set of mutants defective in genes involved in GA perception and gene expression, namely gid1, slr1, gid2 (a GA-related F-box protein mutant), and gamyb (a GA-related trans-acting factor mutant). Almost all GA up-regulated genes were regulated by the four named GA-signaling components. On the other hand, GA down-regulated genes showed different expression patterns with respect to GID2 and GAMYB (e.g. a considerable number of genes are not controlled by GAMYB or GID2 and GAMYB). Based on these observations, we present a comprehensive discussion of the intricate network of GA-regulated genes in rice aleurone cells. PMID- 25511435 TI - Characterization of the KstR2 regulator responsible of the lower cholesterol degradative pathway in Mycobacterium smegmatis. AB - The interaction of KstR2-dependent promoters of the divergon constituted by the MSMEG_6000-5999 and MSMEG_6001-6004 operons of Mycobacterium smegmatis which encode the genes involved in the lower cholesterol degradative pathway has been characterized. Footprint analyses have demonstrated experimentally for the first time that KstR2 specifically binds to an operator region of 29 nucleotides containing the palindromic sequence AAGCAAGNNCTTGCTT. This region overlaps with the -10 and -35 boxes of the putative P(6000) and P(6001) divergent promoters, suggesting that KstR2 represses their transcription by preventing the binding of the ribonucleic acid polymerase. A three-dimensional model of the KstR2 protein revealed a typical TetR-type regulator folding with two domains, a deoxyribonucleic acid (DNA)-binding N-terminal domain and a regulator-binding C terminal domain composed by three and six helices respectively. KstR2 is an all alpha protein as confirmed by circular dichroism. We have determined that M. smegmatis is able to grow using sitolactone (HIL) as the only carbon source and that this compound induces the kstR2 regulon in vivo. HIL or its open form 5OH HIP were unable to release in vitro the KstR2-DNA operator interaction, suggesting that 5OH-HIP-CoA or a further derivative would induce the lower cholesterol catabolic pathway. PMID- 25511434 TI - Genome-based metabolic mapping and 13C flux analysis reveal systematic properties of an oleaginous microalga Chlorella protothecoides. AB - Integrated and genome-based flux balance analysis, metabolomics, and (13)C-label profiling of phototrophic and heterotrophic metabolism in Chlorella protothecoides, an oleaginous green alga for biofuel. The green alga Chlorella protothecoides, capable of autotrophic and heterotrophic growth with rapid lipid synthesis, is a promising candidate for biofuel production. Based on the newly available genome knowledge of the alga, we reconstructed the compartmentalized metabolic network consisting of 272 metabolic reactions, 270 enzymes, and 461 encoding genes and simulated the growth in different cultivation conditions with flux balance analysis. Phenotype-phase plane analysis shows conditions achieving theoretical maximum of the biomass and corresponding fatty acid-producing rate for phototrophic cells (the ratio of photon uptake rate to CO2 uptake rate equals 8.4) and heterotrophic ones (the glucose uptake rate to O2 consumption rate reaches 2.4), respectively. Isotope-assisted liquid chromatography-mass spectrometry/mass spectrometry reveals higher metabolite concentrations in the glycolytic pathway and the tricarboxylic acid cycle in heterotrophic cells compared with autotrophic cells. We also observed enhanced levels of ATP, nicotinamide adenine dinucleotide (phosphate), reduced, acetyl-Coenzyme A, and malonyl-Coenzyme A in heterotrophic cells consistently, consistent with a strong activity of lipid synthesis. To profile the flux map in experimental conditions, we applied nonstationary (13)C metabolic flux analysis as a complementing strategy to flux balance analysis. The result reveals negligible photorespiratory fluxes and a metabolically low active tricarboxylic acid cycle in phototrophic C. protothecoides. In comparison, high throughput of amphibolic reactions and the tricarboxylic acid cycle with no glyoxylate shunt activities were measured for heterotrophic cells. Taken together, the metabolic network modeling assisted by experimental metabolomics and (13)C labeling better our understanding on global metabolism of oleaginous alga, paving the way to the systematic engineering of the microalga for biofuel production. PMID- 25511433 TI - PHOTOSYSTEM II PROTEIN33, a protein conserved in the plastid lineage, is associated with the chloroplast thylakoid membrane and provides stability to photosystem II supercomplexes in Arabidopsis. AB - Photosystem II (PSII) is a multiprotein complex that catalyzes the light-driven water-splitting reactions of oxygenic photosynthesis. Light absorption by PSII leads to the production of excited states and reactive oxygen species that can cause damage to this complex. Here, we describe Arabidopsis (Arabidopsis thaliana) At1g71500, which encodes a previously uncharacterized protein that is a PSII auxiliary core protein and hence is named PHOTOSYSTEM II PROTEIN33 (PSB33). We present evidence that PSB33 functions in the maintenance of PSII-light harvesting complex II (LHCII) supercomplex organization. PSB33 encodes a protein with a chloroplast transit peptide and one transmembrane segment. In silico analysis of PSB33 revealed a light-harvesting complex-binding motif within the transmembrane segment and a large surface-exposed head domain. Biochemical analysis of PSII complexes further indicates that PSB33 is an integral membrane protein located in the vicinity of LHCII and the PSII CP43 reaction center protein. Phenotypic characterization of mutants lacking PSB33 revealed reduced amounts of PSII-LHCII supercomplexes, very low state transition, and a lower capacity for nonphotochemical quenching, leading to increased photosensitivity in the mutant plants under light stress. Taken together, these results suggest a role for PSB33 in regulating and optimizing photosynthesis in response to changing light levels. PMID- 25511437 TI - Intractability in Epilepsy: Role of EEG Desynchronization in Early Identification. PMID- 25511436 TI - Genotypes and antibiotic resistance of bovine Campylobacter and their contribution to human campylobacteriosis. AB - Campylobacter jejuni and Campylobacter coli are the most important bacterial causes of human gastroenteritis. Chicken has been recognized as a major source for human infection, whereas cattle might also contribute to a lesser extent. However, there is a paucity of information available regarding Campylobacter in Swiss cattle and their role for human campylobacteriosis. To gain more information on genotypes and antibiotic resistance of bovine C. jejuni and C. coli and on their contribution to human disease, 97 cattle isolates were analysed. Multilocus sequence typing (MLST) and flaB typing were applied and the gyrA and 23S rRNA genes were screened for point mutations responsible for quinolone and macrolide resistance, respectively. A total of 37 sequence types (STs) and 44 flaB types were identified, including two sequence types and five flaB types not previously described. Most common sequence types were ST21 (21%), ST61 (12%) and ST48 (11%). Only one isolate was macrolide resistant while 31% (n = 30) were quinolone resistant. Source attribution indicated chicken as the main source of human infection with cattle being second. In conclusion, cattle should not be underestimated as a potential source of human campylobacteriosis. PMID- 25511438 TI - Influence of integration of TiO2 nanorods into its nanodot films on pre osteoblast cell responses. AB - Design of an implant surface with appropriate nanostructures has been considered to be an effective way to promote osteoblast cell growth and osseointegration. In this work, TiO2 nanorods were integrated into TiO2 nanodot films by hydrothermal growth to engineer a nanostructured surface composed of two nano-structural elements. The surface microstructure of the films depended on the integration degree. Low integration led to a surface nanostructure with exposure of the two nano-structural elements, and high integration resulted in a similar surface to a nanorod film. The nanorod integration had an obvious influence on pre-osteoblast cell responses and accelerated the cellular osteogenesis. Two factors of the integrated nano-structural element and the changed surface topology are believed to be responsible for enhancing cellular responses. The former is considered to play a more significant role because the nanorods tended to adsorb human fibronectin preferentially so as to begin differentiation to osteogenesis earlier. We anticipate this work may assist to gain insight into understanding of the interactions between nanostructured surfaces with cells. PMID- 25511439 TI - Insights into the relation between adhesion force and chalcopyrite-bioleaching by Acidithiobacillus ferrooxidans. AB - This paper presents a study on the relation between bacterial adhesion force and bioleaching rate of chalcopyrite, which sheds light on the influence of interfacial interaction on bioleaching behavior. In our research, Acidithiobacillus ferrooxidans (A. ferrooxidans) were adapted to grow with FeSO4 . 7H2O, element sulfur or chalcopyrite. Then, surface properties of Acidithiobacillus ferrooxidans and chalcopyrite were analyzed by contact angle, zeta potential and Fourier transform infrared spectroscopy (FTIR). Adhesion force between bacteria and chalcopyrite was measured by atomic force microscopy (AFM). Attachment and bioleaching behaviors were also monitored. The results showed that A. ferrooxidans adapted with chalcopyrite exhibited the strongest adhesion force to chalcopyrite and the highest bioleaching rate. Culture adapted with sulfur bacteria took second place and FeSO4 . 7H2O-adapted bacteria were the lowest. Bioleaching rate and bacterial attachment capacity were positively related to bacterial adhesion force, which is affected by the nature of energy source. According to this work, the attachment of bacteria to chalcopyrite surface is one of the most important aspects that influence the bioleaching process of chalcopyrite. PMID- 25511440 TI - Partially photodegradable hybrid hydrogels with elasticity tunable by light irradiation. AB - This paper reports a simple technique to synthesize elasticity tunable hybrid hydrogels using photocleavable (N-hydroxysuccinimide terminated photocleavable tetra-arm poly(ethylene glycol); NHS-PC-4armPEG) and non-photocleavable (N hydroxysuccinimide terminated tetra-arm poly(ethylene glycol); NHS-4armPEG) activated-ester type crosslinkers. Partially photodegradable hybrid hydrogels were synthesized by reacting the crosslinker mixture with amino-terminated tetra arm poly(ethylene glycol) (amino-4armPEG). The photocleavable crosslinks are cleaved by irradiating light while the non-photocleavable crosslinks remain intact, resulting in decreased elasticity. We demonstrate that hydrogel elasticity can be controlled by adjusting the ratio of photocleavable NHS-PC 4armPEG and non-photocleavable NHS-4armPEG, and by varying the light exposure energy. We also show how micropatterned elasticity can be obtained in the hydrogels by irradiating with micropatterned light. These techniques could provide a novel platform to tailor the elasticity of hydrogels with microscale precision for biological studies in the near future. PMID- 25511441 TI - Pulsatile venoarterial perfusion using a novel synchronized cardiac assist device augments coronary artery blood flow during ventricular fibrillation. AB - Patients with cardiogenic shock have a very high mortality. Here we report the first use of a percutaneous pulsatile cardiac assist device, based on a diagonal pump synchronized with the heart cycle by means of an electrocardiographic signal in adult pigs. Eight domestic pigs underwent mandatory ventilation. During sinus rhythm, there were no differences between pulsatile and nonpulsatile perfusion with regard to pulmonary artery pressure, pulmonary wedge pressure, central venous pressure, mean arterial pressure (MAP), mean pulse pressure, and mean coronary artery flow (CAF). After 2 min of complete cardiac arrest (ventricular fibrillation), circulatory support with the i-cor in venoarterial nonpulsatile extracorporeal membrane oxygenation (ECMO) mode (3 L/min) restored systemic circulation, with an increase of MAP to 78.3 mm Hg and CAF to 5.27 mL/min. After changing from ECMO settings to pulsatile mode (3 L/min, 75 bpm, pulse amplitude range 3500 rpm), MAP did not change significantly (75.6 mm Hg); however, CAF increased to 8.45 mL/min. After changing back to nonpulsatile mode, MAP remained stable (83.6 mm Hg), but CAF decreased to 4.85 mL/min. Thereafter, pulsatile cardiac assist was established with a reduced blood flow of 2.5 L/min, and the pulse amplitude range was extended to 4500 rpm. Under these conditions, MAP remained stable (71.0 mm Hg), but CAF significantly increased to 15.2 mL/min (P < 0.05). Percutaneous cardiac support using a venoarterial cardiac assist device equipped with a novel diagonal pump is able to restore and increase systemic and coronary circulation during ventricular fibrillation. Electrocardiographically triggered synchronized cardiac assist provides an additional increase of coronary artery flow. These promising results are to be confirmed in humans. PMID- 25511443 TI - [Complications in endocrine surgery]. PMID- 25511442 TI - Longitudinal improvement and stability of the SNOT-22 survey in the evaluation of surgical management for chronic rhinosinusitis. AB - BACKGROUND: Patients with chronic rhinosinusitis (CRS) have significant quality of-life (QOL) improvements following endoscopic sinus surgery (ESS). These improvements remain stable and persist between 6 months and 20 months as measured by the Rhinosinusitis Disability Index and the Chronic Sinusitis Survey. There has yet to be an evaluation of the longitudinal stability of the 22-item Sino Nasal Outcome Test (SNOT-22) after ESS in patients with CRS. METHODS: Adults with medically recalcitrant CRS who were considered surgical candidates were enrolled in a prospective, multicenter, observational cohort study from February 2011 to February 2013. Baseline evaluation of subjects included assessment of clinical characteristics, measures of CRS-specific disease severity, and QOL evaluation using the SNOT-22. Subjects were then re-evaluated at approximately 6-month, 12 month, and 18-month intervals postoperatively. Data was analyzed using repeated measures analysis of variance (ANOVA) with Bonferroni corrections for matched pairwise comparisons. RESULTS: A total of 110 patients completed baseline evaluations and follow-up for all 3 postoperative time points. Significant improvement in SNOT-22 scores was seen between baseline and 6 months across both SNOT-22 total and subdomain scores (p < 0.001). There was no statistically significant difference between the 6-month, 12-month, and 18-month time points in the total SNOT-22 score or its domains (p >= 0.125) for both the entire cohort or subgroups (p >= 0.077). CONCLUSION: Postoperative improvement in CRS-specific QOL and symptom severity, as measured by the SNOT-22, suggest stability and durability between 6 months and 18 months. Further study on the longitudinal stability of the SNOT-22 past the 18-month time frame will help further refine clinical study of CRS and provide further understanding of temporal improvements following ESS. PMID- 25511444 TI - Age-dependent association of MDM2 promoter polymorphisms and uterine leiomyoma in South-East Iran: A preliminary report. AB - AIM: Murine double minute clone 2 (MDM2) is an important regulator of p53 tumor suppressor protein. Because increased MDM2 expression has been observed in different tumors, its polymorphisms are proposed to be associated with accelerated tumor formation. The aim of this study was to examine the association between T309G (rs2279744) and 40-bp Insertion/deletion (rs3730485) polymorphisms of the MDM2 gene and risk of uterine leiomyoma (UL). METHODS: We analyzed the MDM2 gene polymorphisms of 154 UL patients and 197 healthy controls by polymerase chain reaction (PCR) or PCR restriction fragment length polymorphism (RFLP) methods. RESULTS: The frequency of MDM2 T309G polymorphism genotypes was not different between UL women and controls. Although there was an association between MDM2 40-bp del/del genotype and UL before and after adjustment for age, the association between Insertion/deletion (Indel) genotype and UL was significant after adjustment for age. CONCLUSION: MDM2 T309G polymorphism was not associated with UL and MDM2 40-bp Indel polymorphism could be an age-related risk factor for UL. PMID- 25511445 TI - Dentate Gyrus Local Circuit is Implicated in Learning Under Stress--a Role for Neurofascin. AB - The inhibitory synapses at the axon initial segment (AIS) of dentate gyrus granular cells are almost exclusively innervated by the axo-axonic chandelier interneurons. However, the role of chandelier neurons in local circuitry is poorly understood and controversially discussed. The cell adhesion molecule neurofascin is specifically expressed at the AIS. It is crucially required for the stabilization of axo-axonic synapses. Knockdown of neurofascin is therefore a convenient tool to interfere with chandelier input at the AIS of granular neurons of the dentate gyrus. In the current study, feedback and feedforward inhibition of granule cells was measured in the dentate gyrus after knockdown of neurofascin and concomitant reduction of axo-axonic input. Results show increased feedback inhibition as a result of neurofascin knockdown, while feedforward inhibition remained unaffected. This suggests that chandelier neurons are predominantly involved in feedback inhibition. Neurofascin knockdown rats also exhibited impaired learning under stress in the two-way shuttle avoidance task. Remarkably, this learning impairment was not accompanied by differences in electrophysiological measurements of dentate gyrus LTP. This indicates that the local circuit may be involved in (certain types) of learning. PMID- 25511447 TI - How do children view other children who have visible enamel defects? AB - BACKGROUND: Facial and dental appearance influences how individuals are perceived by others. AIM: This study aimed to determine whether young people make judgements about other young people with visible enamel opacities. DESIGN: Focus group findings were used to develop a social attribute questionnaire to capture young people's dental appearance-related judgements. 547 pupils (aged 11-15 years), from two different schools, participated in the study. Half the participants were given full-face photographs of a boy and girl without an enamel defect, and the other half were given the same two photographs with the subjects' incisors digitally modified to show enamel opacities. Participants completed the attribute questionnaire to rate the photographic subjects according to six positive and five negative descriptors using a four-point Likert scale. The total attribute score (TAS) could range from 11 (most negative) to 44 (most positive). RESULTS: TAS was significantly lower for photographic subjects with enamel defects compared to the same subject with normal enamel appearance (P < 0.001, one sample t-test). Gender had a significant impact on TAS, with boys making more negative judgements than girls. Age and socio-economic status did not have an effect. CONCLUSION: Young people may make negative psychosocial judgements on the basis of enamel appearance. PMID- 25511449 TI - "Effectiveness of continuous vertebral resonant oscillation using the POLD method in the treatment of lumbar disc hernia". A randomized controlled pilot study. AB - This study analyses the efficacy of manual oscillatory therapy, following the POLD technique, for acute Lumbar Disc Hernia (LDH) and compares it to usual treatment. A randomised, controlled, triple-blind pilot clinical trial. The sample of 30 patients was divided into two homogeneous groups to receive usual treatment (A) or treatment with the POLD technique (B). We analysed range of motion and subjective variables such as the severity (visual analogue pain scale (VAS)) and extension of the pain. With the application of POLD therapy, patients presented significant changes on range of motion (forward flexion with p < 0.05) at completion of the trial in comparison with the control group. They showed a significant reduction in the severity of pain with a mean VAS scale for lumbar, glutaeus and thigh pain, which improved from 5.09 to 0.79, 5.07 to 0.97 and 4.43 to 0.49 respectively (p < 0.05), and also when compared to usual treatment (p < 0.05) for all body regions. Moreover, we observed a reduction in pain extension (centralization phenomena) (p < 0.001) in comparison with usual treatment. In our study the POLD Method was shown to be an effective manual therapy approach for reducing the severity and irradiation of the pain in LDH patients with sciatica, and more efficient than usual treatment. PMID- 25511448 TI - Clinical challenges of classification based targeted therapies for non-specific low back pain: What do physiotherapy practitioners and managers think? AB - BACKGROUND: Classification of non-specific low back pain (NSLBP) was recommended to better target care and so maximise treatment potential. This study investigated physiotherapy practitioners' (PPs) and managers' (PMs) views, experiences and perceptions of barriers and enablers for using classification systems (CSs) to better target treatment for NSLBP in the NHS primary care setting. DESIGN: Qualitative focus group and interviews. METHODS: Data from semi structured interviews of three PMs and a focus group with five PPs, considered local opinion leaders in physiotherapy, was thematically analysed. RESULTS: Five themes emerged (i) CS knowledge: PPs and PMs were aware of CSs and agreed with its usefulness. PPs were mostly aware of CSs informing specific treatments whilst PMs were aware of prognosis based CSs. (ii) Using CSs: PPs classify by experience and clinical reasoning skills, shifting between multiple CSs. PMs were confident that evidence-based practice takes place but believed CSs may not be always used. (iii) Advantages/disadvantages of CSs: Effective targeting of treatments to patients was perceived as advantageous; but the amount of training required was perceived as disadvantageous. (iv) Barriers: Patients' expectations, clinicians' perceptions, insufficiently complex CSs, lack of training resources. (v) Enablers: Development of sufficiently complex CSs, placed within the clinical reasoning process, mentoring, positive engagement with stakeholders and patients. CONCLUSIONS: PPs and PMs were aware of CSs and agreed with its usefulness. The current classification process was perceived to be largely influenced by individual practitioner knowledge and clinical reasoning skills rather than being based on one CS alone. Barriers and enablers were identified for future research. PMID- 25511450 TI - Cascade N-Alkylation/Hemiacetalization for Facile Construction of the Spiroketal Skeleton of Acortatarin Alkaloids with Therapeutic Potentiality in Diabetic Nephropathy. AB - The concise building of the spiroketal core of acortatarin-type alkaloids as potential therapeutic agents in diabetic nephropathy was established in four steps, through a tandem N-alkylation/hemiacetalization between pyrrole units and the corresponding halo alcohols generated by convenient halomethylation of chiral lactones from natural aldoses. PMID- 25511446 TI - Mechanism of Oxidative Stress and Synapse Dysfunction in the Pathogenesis of Alzheimer's Disease: Understanding the Therapeutics Strategies. AB - Synapses are formed by interneuronal connections that permit a neuronal cell to pass an electrical or chemical signal to another cell. This passage usually gets damaged or lost in most of the neurodegenerative diseases. It is widely believed that the synaptic dysfunction and synapse loss contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although pathological hallmarks of AD are senile plaques, neurofibrillary tangles, and neuronal degeneration which are associated with increased oxidative stress, synaptic loss is an early event in the pathogenesis of AD. The involvement of major kinases such as mitogen-activated protein kinase (MAPK), extracellular receptor kinase (ERK), calmodulin-dependent protein kinase (CaMKII), glycogen synthase-3beta (GSK 3beta), cAMP response element-binding protein (CREB), and calcineurin is dynamically associated with oxidative stress-mediated abnormal hyperphosphorylation of tau and suggests that alteration of these kinases could exclusively be involved in the pathogenesis of AD. N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation and beta amyloid (Abeta) toxicity alter the synapse function, which is also associated with protein phosphatase (PP) inhibition and tau hyperphosphorylation (two main events of AD). However, the involvement of oxidative stress in synapse dysfunction is poorly understood. Oxidative stress and free radical generation in the brain along with excitotoxicity leads to neuronal cell death. It is inferred from several studies that excitotoxicity, free radical generation, and altered synaptic function encouraged by oxidative stress are associated with AD pathology. NMDARs maintain neuronal excitability, Ca(2+) influx, and memory formation through mechanisms of synaptic plasticity. Recently, we have reported the mechanism of the synapse redox stress associated with NMDARs altered expression. We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis. PMID- 25511452 TI - Numbers are not the whole story: a qualitative exploration of barriers and facilitators to increased physical activity in a primary care based walking intervention. AB - BACKGROUND: The majority of mid-life and older adults in the UK are not achieving recommended physical activity levels and inactivity is associated with many health problems. Walking is a safe, appropriate exercise. The PACE-UP trial sought to increase walking through the structured use of a pedometer and handbook, with and without support from a practice nurse trained in behaviour change techniques (BCTs). Understanding barriers and facilitators to engagement with a primary care based physical activity intervention is essential for future trials and programmes. METHODS: We conducted semi-structured telephone interviews using a topic guide with purposive samples of participants who did and did not increase their walking from both intervention groups. Interviews were audio recorded, transcribed and coded independently by researchers prior to performing a thematic analysis. Responsiveness to the specific BCTs used was also analysed. RESULTS: Forty-three trial participants were interviewed in early 2014. Almost all felt they had benefitted, irrespective of their change in step-count, and that primary care was an appropriate setting.Important facilitators included a desire for a healthy lifestyle, improved physical health, enjoyment of walking in the local environment, having a flexible routine allowing for an increase in walking, appropriate self and external monitoring and support from others.Important barriers included physical health problems, an inflexible routine, work and other commitments, the weather and a mistrust of the monitoring equipment.BCTs that were reported to have the most impact included: providing information about behaviour-health link; prompting self-monitoring and review of goals and outcomes; providing feedback; providing specific information about how to increase walking; planning social support/change; and relapse prevention. Rewards were unhelpful. CONCLUSIONS: Despite our expectation that there would be a difference between the experiences of those who did and did not objectively increase their walking, we found that most participants considered themselves to have succeeded in the trial and benefitted from taking part. Barriers and facilitators were similar across demographic groups and trial outcomes. Findings indicated several BCTs on which PA trial and programme planners could focus efforts with the expectation of greatest impact as well as strong support for primary care as an appropriate venue. TRIAL REGISTRATION: ISRCTN98538934. PMID- 25511453 TI - Cardiovascular safety of conjugated estrogens plus bazedoxifene: meta-analysis of the SMART trials. AB - OBJECTIVES: Five randomized, phase-3 trials demonstrated the efficacy and safety of conjugated estrogens/bazedoxifene (CE/BZA) in treating menopausal symptoms and preserving bone. This pooled analysis of these studies describes the cardiovascular safety of CE/BZA. METHODS: We pooled cardiovascular adjudicated safety data from healthy, non-hysterectomized, postmenopausal women who received >= 1 dose of CE 0.45 mg/BZA 20 mg (n = 1585), CE 0.625 mg/BZA 20 mg (n = 1583), any CE/BZA dose (n = 4868), or placebo (n = 1241) for up to 2 years in five trials. Venous thromboembolic events (VTEs), coronary heart disease (CHD), and cerebrovascular events were reviewed by three different independent adjudication committees and summarized using a meta-analytic approach. RESULTS: The rate of VTEs per 1000 woman-years (95% confidence interval, CI) was 0.3 (0.0-2.0) in women taking CE 0.45 mg/BZA 20 mg, 0 (0.0-1.5) in those taking CE 0.625 mg/BZA 20 mg, 0.7 (0.0-1.5) among women taking any CE/BZA dose, and 0.6 (0.0-2.9) with placebo. The incidence of stroke per 1000 woman-years (95% CI) was 0.4 (0.0-2.4), 0.2 (0.0-1.9), 0.44 (0.0-1.1), and 0.0 (0.0-1.7), respectively. The CHD rate per 1000 woman-years was 2.6 (0.0-5.6), 1.4 (0.0-3.9), 2.4 (1.00-3.7) and 2.0 (0.0 5.2). Compared with placebo, relative risk (95% CI) with any CE/BZA dose was 0.5 (0.1-1.8) for VTE, 0.5 (0.1-2.6) for stroke, and 0.63 (0.23-1.74) for CHD. CONCLUSIONS: Up to 2 years of CE 0.45 or CE 0.625 mg with BZA 20 mg had an acceptable cardiovascular safety profile, with rates of stroke and CHD comparable to placebo in healthy postmenopausal women. VTE risk was low. PMID- 25511451 TI - Notch4 promotes gastric cancer growth through activation of Wnt1/beta-catenin signaling. AB - Gastric cancer (GC) is one of the most common cancers and lethal malignancies in the world. Discovering novel biomarkers that correlate with GC may provide opportunities to reduce the severity of GC. As one of Notch receptor family members in mammals, Notch4 plays an important role in carcinogenesis of several tumors. However, the precise function and mechanism of Notch4 in GC remain undefined. To address this question, we investigated whether Notch4 could be involved in GC progression. We found that Notch4 was activated by overexpressing exogenous intracellular domain of Notch4 (ICN4), and Notch4 activation promoted GC growth in vitro and in vivo, while Notch4 inhibition using ICN4 siRNA had opposite effects. In addition, Notch4 activation induced expression and activation of Wnt1, beta-catenin and downstream target genes, c-Myc and cyclin D1, in GC cells, while Notch4 inhibition had opposite effects. Moreover, beta catenin depletion by siRNA attenuated cell proliferation induced by Notch4 activation. Therefore, our results revealed that Notch4 activates Wnt1/beta catenin signaling to regulate GC growth. PMID- 25511454 TI - Genome mining-directed activation of a silent angucycline biosynthetic gene cluster in Streptomyces chattanoogensis. AB - Genomic sequencing of actinomycetes has revealed the presence of numerous gene clusters seemingly capable of natural product biosynthesis, yet most clusters are cryptic under laboratory conditions. Bioinformatics analysis of the completely sequenced genome of Streptomyces chattanoogensis L10 (CGMCC 2644) revealed a silent angucycline biosynthetic gene cluster. The overexpression of a pathway specific activator gene under the constitutive ermE* promoter successfully triggered the expression of the angucycline biosynthetic genes. Two novel members of the angucycline antibiotic family, chattamycins A and B, were further isolated and elucidated. Biological activity assays demonstrated that chattamycin B possesses good antitumor activities against human cancer cell lines and moderate antibacterial activities. The results presented here provide a feasible method to activate silent angucycline biosynthetic gene clusters to discover potential new drug leads. PMID- 25511457 TI - Diversity of ankA and msp4 genes of Anaplasma phagocytophilum in Slovenia. AB - Granulocytic anaplasmosis is a tick transmitted emerging disease in Europe and worldwide. The agent, Anaplasma phagocytophilum is transmitted by ticks of the genus Ixodes and causes infections in humans and domestic animals. The analysis of different target genes showed that in nature several genetic variants of A. phagocytophilum were present. The purpose of our study was to genetically characterize A. phagocytophilum strains from eight humans, 16 dogs, 12 wild boars, one bear and 18 tick pools from Slovenia. Therefore, the ankA and msp4 genes of A. phagocytophilum were chosen. The same genetic ankA and msp4 variant of A. phagocytophilum was detected in humans, wild boar and a part of the pooled ticks indicating that it circulates in a zoonotic cycle between wild boar and ticks. In dogs, three ankA variants of A. phagocytophilum were detected. One of them was identical to the one that was found in humans. In contrast, all dogs harboured the same msp4 variant as humans and wild boar. In ticks, numerous ankA and msp4 variants were present. PMID- 25511458 TI - Bimodal signatures of germline methylation are linked with gene expression plasticity in the coral Acropora millepora. AB - BACKGROUND: In invertebrates, genes belonging to dynamically regulated functional categories appear to be less methylated than "housekeeping" genes, suggesting that DNA methylation may modulate gene expression plasticity. To date, however, experimental evidence to support this hypothesis across different natural habitats has been lacking. RESULTS: Gene expression profiles were generated from 30 pairs of genetically identical fragments of coral Acropora millepora reciprocally transplanted between distinct natural habitats for 3 months. Gene expression was analyzed in the context of normalized CpG content, a well established signature of historical germline DNA methylation. Genes with weak methylation signatures were more likely to demonstrate differential expression based on both transplant environment and population of origin than genes with strong methylation signatures. Moreover, the magnitude of expression differences due to environment and population were greater for genes with weak methylation signatures. CONCLUSIONS: Our results support a connection between differential germline methylation and gene expression flexibility across environments and populations. Studies of phylogenetically basal invertebrates such as corals will further elucidate the fundamental functional aspects of gene body methylation in Metazoa. PMID- 25511459 TI - Chronic up-regulation of the SHH pathway normalizes some developmental effects of trisomy in Ts65Dn mice. AB - Down Syndrome (DS) is a highly complex developmental genetic disorder caused by trisomy for human chromosome 21 (Hsa21). All individuals with DS exhibit some degree of brain structural changes and cognitive impairment; mouse models such as Ts65Dn have been instrumental in understanding the underlying mechanisms. Several phenotypes of DS might arise from a reduced response of trisomic cells to the Sonic Hedgehog (SHH) growth factor. If all trisomic cells show a similar reduced response to SHH, then up-regulation of the pathway in trisomic cells might ameliorate multiple DS phenotypes. We crossed Ptch1tm1Mps/+ mice, in which the canonical SHH pathway is expected to be up-regulated in every SHH-responsive cell due to the loss of function of one allele of the pathway suppressor, Ptch1, to the Ts65Dn DS model and assessed the progeny for possible rescue of multiple DS related phenotypes. Down-regulation of Ptch produced several previously unreported effects on development by itself, complicating interpretation of some phenotypes, and a number of structural or behavioral effects of trisomy were not compensated by SHH signaling. However, a deficit in a nest-building task was partially restored in Ts;Ptch+/- mice, as were the structural anomalies of the cerebellum seen in Ts65Dn mice. These results extend the body of evidence indicating that reduced response to SHH in trisomic cells and tissues contributes to various aspects of the trisomic phenotype. PMID- 25511460 TI - Roles of ADAM8 in elimination of injured muscle fibers prior to skeletal muscle regeneration. AB - Skeletal muscle regeneration requires processes different from developmental myogenesis. One important difference is a requirement of inflammatory reactions prior to regenerative myogenesis, by which injured muscle fibers must be eliminated to make new myotubes. In this study, we show that efficient elimination of injured muscle fibers during regeneration requires ADAM8, a member of a disintegrin and metalloprotease (ADAM) family. Skeletal muscle of dystrophin null mice, an animal model for Duchenne Muscular Dystrophy, deteriorates by the lack of ADAM8, which is characterized by increased area of muscle degeneration and increased number of necrotic and calcified muscle fibers. Adam8 is highly expressed in neutrophils. Upon cardiotoxin-induced skeletal muscle injury, neutrophils invade into muscle fibers through the basement membrane and form large clusters in wild type, but not in ADAM8-deficient mice, although neutrophils of the latter infiltrate into interstitial tissues similarly to those of wild type mice. Neutrophils lose their adhesiveness to blood vessels after infiltration, which includes an ectodomain shedding of P-Selectin Glycoprotein Ligand-1 (PSGL-1) on their surface. Expression of PSGL-1 on the surface of neutrophils remains higher in ADAM8-deficient than in wild type mice. These results suggest that ADAM8 mediates an enhanced invasiveness of neutrophils into injured muscle fibers by the removal of their adhesiveness to blood vessels after infiltration into interstitial tissues. PMID- 25511462 TI - Is the kidney disease quality of life-36 (KDQOL-36) a valid instrument for Chinese dialysis patients? AB - BACKGROUND: The aim of this study is to determine the validity and reliability of the Cantonese Chinese version of the Kidney Disease Quality of Life-36 (KDQOL 36TM) questionnaire. The scale has been translated into Cantonese Chinese, but has not been tested among the Cantonese-speaking populations. METHODS: A total of 110 dialysis patients and 122 renal transplant patients were recruited. The data for the KDQOL-36TM were extracted from the KDQOL-Short Form. The criterion validity and scale equivalence were examined using the KDQOL-Short Form scores as the gold standard. The Hospital Anxiety and Depression scale was used to identify the correlations between depression, anxiety, and quality of life to establish the convergent validity. Discriminant validity was examined using the transplant patients to compare the quality of life of dialysis patients. The Cronbach's alpha coefficient and test-retest were used for estimating reliability. RESULTS: There were very strong positive correlations for the physical and mental component summary between the KDQOL-36TM and KDQOL-Short Form. Despite the strong correlations, the effect size was 0.6 and 0.13 for the physical composite summary and mental composite summary score, respectively. Most of the subscales demonstrated significant moderate correlations with the Hospital Anxiety and Depression Scale, from -0.265 to -0.516. The discriminant validity was confirmed with a significant difference between the dialysis and transplant group patients. A high intraclass correlation of >0.98 was demonstrated in the test-retest. CONCLUSION: The Cantonese Chinese KDQOL-36TM was reliable. Further testing will be required to determine its validity for the physical health summary scale. PMID- 25511461 TI - Disrupting Foxh1-Groucho interaction reveals robustness of nodal-based embryonic patterning. AB - The winged-helix transcription factor Foxh1 is an essential regulator of Nodal signaling during the key developmental processes of gastrulation, anterior posterior (A-P) patterning, and the derivation of left-right (L-R) asymmetry. Current models have Foxh1 bound to phospho-Smad2/3 (pSmad2/3) as a central transcriptional activator for genes targeted by Nodal signaling including Nodal itself, the feedback inhibitor Lefty2, and the positive transcriptional effector Pitx2. However, the conserved Engrailed homology-1 (EH1) motif present in Foxh1 suggests that modulated interaction with Groucho (Grg) co-repressors would allow Foxh1 to function as a transcriptional switch, toggling between transcriptional on and off states via pSmad2-Grg protein-switching, to ensure the properly timed initiation and suppression, and/or amplitude, of expression of Nodal and its target genes. We minimally mutated the Foxh1 EH1 motif, creating a novel Foxh1(mEH1) allele to test directly the contribution of Foxh1-Grg-mediated repression on the transient, dynamic pattern of Nodal signaling in mice. All aspects of Nodal and its target gene expression in Foxh1(mEH1/mEH1) embryos were equivalent to wild type. A-P patterning and organ situs in homozygous embryos and adult mice were also unaffected. The finding that Foxh1-Grg-mediated repression is not essential for Nodal expression during mouse embryogenesis suggests that other regulators compensate for the loss of repressive regulatory input that is mediated by Grg interactions. We suggest that the pervasive inductive properties of Nodal signaling exist within the context of a strongly buffered regulatory system that contributes to resilience and accuracy of its dynamic expression pattern. PMID- 25511464 TI - Persistent effects after camphor ingestion: a case report and literature review. AB - BACKGROUND: Camphor is a well-known toxin responsible for thousands of poisonings per year. It can be found in many over-the-counter remedies and illegally imported substances. The toxidrome manifests within minutes and includes gastrointestinal, neurologic, pulmonary, and cardiac effects. Severe ingestions may progress to seizures, apnea, and coma. Most individuals are no longer symptomatic outside the 24-48 h window, but physiologic derangement may persist for far longer in some instances. CASE REPORT: This is a case report of a 25-year old Guatemalan woman with no past medical history who ingested a cube of camphor for a facial rash. She presented to the Emergency Department with persistent delirium and headache 6 days after ingestion. She had a protracted recovery but returned to her baseline state of health 19 days after ingestion. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Persistent toxic effects of camphor are not well described, and most sources state that the toxidrome resolves in 24-48 h. Given the frequency of camphor poisoning, it is crucial to increase public awareness of camphor toxicity, to understand the biological mechanism of the effects, and to develop more targeted treatments. From the emergency physician's perspective, it is important to realize that toxic effects of camphor poisoning may persist far beyond the 24-48 h window and require attention. PMID- 25511463 TI - Cranberry proanthocyanidins have anti-biofilm properties against Pseudomonas aeruginosa. AB - BACKGROUND: Bacteria within a biofilm are phenotypically more resistant to antibiotics, desiccation, and the host immune system, making it an important virulence factor for many microbes. Cranberry juice has long been used to prevent infections of the urinary tract, which are often related to biofilm formation. Recent studies have found that the A-type proanthocyanidins from cranberries have anti-biofilm properties against Escherichia coli. METHODS: Using crystal violet biofilm staining, resazurin metabolism assays, and confocal imaging, we examined the ability of A-type proanthocyanidins (PACs) to disrupt the biofilm formation of Pseudomonas aeruginosa. We used mass spectrometry to analyze the proteomic effects of PAC treatment. We also performed synergy assays and in vitro and in vivo infections to determine whether PACs, alone and in combination with gentamicin, could contribute to the killing of P. aeruginosa and the survival of cell lines and G. mellonella. RESULTS: Cranberry PACs reduced P. aeruginosa swarming motility. Cranberry PACs significantly disrupted the biofilm formation of P. aeruginosa. Proteomics analysis revealed significantly different proteins expressed following PAC treatment. In addition, we found that PACs potentiated the antibiotic activity of gentamicin in an in vivo model of infection using G. mellonella. CONCLUSIONS: Results suggest that A-type proanthocyanidins may be a useful therapeutic against the biofilm-mediated infections caused by P. aeruginosa and should be further tested. PMID- 25511465 TI - Acute Fitz-Hugh-Curtis syndrome in a man due to gonococcal infection. AB - BACKGROUND: Fitz-Hugh-Curtis syndrome is a rare extra-pelvic complication of genital infection involving the perihepatic capsule. Most cases have been described in women in association with pelvic inflammatory disease; in rare cases it has been reported in men. Because the main symptom is acute abdominal pain, and laboratory and imaging findings are frequently nonspecific, the differential diagnosis, considering other gastrointestinal or renal diseases, can be difficult in the early stage of the syndrome, leading to frequent misdiagnosis and mismanagement. CASE REPORT: We report a case of Fitz-Hugh-Curtis syndrome in a 26 year-old man who first presented to the emergency department with acute abdominal pain, vomiting, and fever. Diagnosis was possible on the basis of clinical signs of orchiepididymitis, abnormal ultrasound findings, and specialist consultation with the Sexually Transmitted Infection Clinic. An acute gonoccocal infection was revealed, which was complicated by a collection of free perihepatic fluid and a subcapsular hypoechoic focal lesion. Prompt antibiotic therapy was established, with complete resolution of the symptoms within a few days. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Awareness of the clinical presentation, imaging, and laboratory findings during the acute phase of Fitz-Hugh-Curtis syndrome could help emergency physicians to make an early diagnosis and to correctly manage such patients. Improved diagnostic skills could prevent chronic complications that are especially a risk in the case of delayed or minor genitourinary symptoms. PMID- 25511467 TI - Acute rejection of a cryopreserved arterial homograft. AB - The use of arterial homograft is indicated especially in case of prosthetic graft infections after bypass surgery. We report the case of a patient who experienced the loss of a cryopreserved femoral artery caused by an acute rejection. This homograft had to be explanted 1 month after implantation because of an acute aneurysmal deterioration. Histology of the explanted artery showed inflammatory cells infiltration, pseudoaneurysms and necrosis. It was then replaced by a second cryopreserved femoral artery which is currently well tolerated. This first case of acute rejection of a cryopreserved artery, to our knowledge, raises again the question of the immunogenicity of cryopreserved homografts. The case report is followed by a brief discussion. PMID- 25511468 TI - Palmoplantar pustulosis secondary to rituximab: a case report and literature review. PMID- 25511466 TI - Effectiveness of multifactorial interventions in primary health care settings for primary prevention of cardiovascular disease: A systematic review of systematic reviews. AB - OBJECTIVE: To evaluate the effectiveness of multifactorial interventions carried out in the community setting to decrease cardiovascular risk in healthy patients. METHODS: Systematic review of the MEDLINE (via PubMed), Web of Science and Cochrane Library databases from January 1980 to January 2014. Identified for inclusion were systematic reviews of clinical trials that included multifactorial interventions carried out in primary care or community settings, targeting more than one cardiovascular risk factor, and implementing more than one type of intervention. The methodological quality of the included articles was evaluated using the AMSTAR tool. RESULTS: Eight systematic reviews were selected, including 219 studies. All of these reviews provided information about the effectiveness of multifactorial interventions in reducing mortality and morbidity due to cardiovascular diseases. Four reviews reported moderate effectiveness and four showed limited effectiveness. CONCLUSION: Multifactorial community interventions improve cardiovascular risk factors and have a small but potentially important effect on mortality. These interventions seem to be more effective in the at-risk population and when they are carried out at a high level of intensity. PMID- 25511469 TI - Celebrating Soft Matter's 10th Anniversary: monitoring colloidal growth with holographic microscopy. AB - Holographic video microscopy offers valuable and previously unavailable insights into the progress of colloidal synthesis by providing measurements of the size and refractive index of individual colloidal particles in the dispersion. These measurements are precise enough to track subtle changes in particles' properties and rapid enough for real-time process control. We demonstrate this technique by applying it to the synthesis of monodisperse samples of crosslinked polydimethysiloxane (PDMS) spheres. The measured time dependence of these spheres' most probable radius is consistent with the LaMer model for colloidal growth. The joint distribution of size and refractive index, however, also reveals a small proportion of undersize, lower-density spheres. Trends in the distribution's time evolution offer insights into their origin. Applied over longer time periods, holographic characterization also tracks how the newly synthesized spheres age, and illuminates the aging mechanism. PMID- 25511470 TI - Transcatheter closure of atrial septal communication during pregnancy in women with Ebstein's anomaly of the tricuspid valve and cyanosis. AB - Transcatheter atrial septal defect occlusion is described in three pregnant patients with Ebstein's anomaly and exercise-induced cyanosis. Procedures took place in the second and third trimester. Careful hemodynamic testing was performed prior to permanent atrial septal occlusion to confirm the capacity of the right ventricle to accept the entirety of systemic venous return in the volume-expanded state of pregnancy. Outcomes for mother and fetus were favorable in all patients with significant reduction in maternal symptoms and resolution of cyanosis. PMID- 25511471 TI - Advantages and limitations of common testing methods for antioxidants. AB - Owing to the importance of antioxidants in the protection of both natural and man made materials, a large variety of testing methods have been proposed and applied. These include methods based on inhibited autoxidation studies, which are better followed by monitoring the kinetics of oxygen consumption or of the formation of hydroperoxides, the primary oxidation products. Analytical determination of secondary oxidation products (e.g. carbonyl compounds) has also been used. The majority of testing methods, however, do not involve substrate autoxidation. They are based on the competitive bleaching of a probe (e.g. ORAC assay, beta-carotene, crocin bleaching assays, and luminol assay), on reaction with a different probe (e.g. spin-trapping and TOSC assay), or they are indirect methods based on the reduction of persistent radicals (e.g. galvinoxyl, DPPH and TEAC assays), or of inorganic oxidizing species (e.g. FRAP, CUPRAC and Folin Ciocalteu assays). Yet other methods are specific for preventive antioxidants. The relevance, advantages, and limitations of these methods are critically discussed, with respect to their chemistry and the mechanisms of antioxidant activity. A variety of cell-based assays have also been proposed, to investigate the biological activity of antioxidants. Their importance and critical aspects are discussed, along with arguments for the selection of the appropriate testing methods according to the different needs. PMID- 25511472 TI - Loss of p53 in stromal fibroblasts enhances tumor cell proliferation through nitric-oxide-mediated cyclooxygenase 2 activation. AB - Overexpression of cyclooxygenase 2 (COX-2) by stromal fibroblasts plays a critical role in the early stage of carcinogenesis. COX-2 expression is thought to be positively or negatively regulated by inflammatory chemical mediators or tumor suppressors. In this study, the contributions of inducible nitric oxide synthase (iNOS) and p53 to COX-2 expression were examined using mouse embryonic fibroblasts (MEFs) from wild-type, p53-deficient, iNOS-deficient, and p53/iNOS deficient mice. These MEFs were treated with 1 MUg/mL of lipopolysaccharide and 100 IU/mL of interferon gamma for up to 72 h. iNOS and COX-2 expression were analyzed by Western blotting. iNOS was induced earlier (16 h) in p53-deficient MEFs than in wild-type MEFs (48 h). Elevated expression of COX-2 was sustained for a longer duration in the p53-deficient MEFs. In contrast, COX-2 expression was reduced earlier in the iNOS-deficient MEFs. Addition of an exogenous NO donor (0.8 mM of S-nitroso-l-glutathione) to the iNOS-deficient MEFs augmented COX-2 expression. Co-culture with stimulated p53-deficient MEFs promoted cell proliferation of mouse rectal polyploid carcinoma CMT93 cells, but treatment with a COX-2-specific inhibitor counteracted this effect. These results suggest that loss of function of the p53 gene in stromal fibroblasts enhances COX-2 expression by enhancing iNOS expression and the resultant production of NO, contributing to the promotion of tumor growth. PMID- 25511473 TI - Endoplasmic reticulum stress and Nrf2 repression in circulating cells of type 2 diabetic patients without the recommended glycemic goals. AB - Endoplasmic reticulum (ER) stress plays a role in the pathogenesis of type 2 diabetes mellitus (T2DM), with activation of the unfolded protein response (UPR) and ER apoptosis in beta-cells. The aim of the study is investigating the role of the prolonged glycemic, inflammatory, and oxidative impairment as possible UPR and ER apoptosis inductors in triggering the ER stress response and the protective nuclear erythroid-related factor 2 (Nrf2)/antioxidant-related element (ARE) activation in peripheral blood mononuclear cells (PBMC) of T2DM patients without glycemic target. Oxidative stress markers (oxidation product of phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine [oxPAPC], and malondialdehyde [MDA]), the UPR and ER apoptosis, the activation of the pro inflammatory nuclear factor-kappa B (NF-kB) with its inhibitory protein inhibitor kBalpha, and the expression of the protective Nrf2 and heme oxygenase-1 (HO-1) were evaluated in PBMC of 15 T2DM patients and 15 healthy controls (C). OxPAPC concentrations (in PBMC and plasma), MDA levels (in plasma), the expressions of the glucose-regulated protein 78 kDa (or BiP) as representative of UPR, and of the CCAAT/enhancer-binding protein homologous protein as representative of ER apoptosis were significantly higher (p < 0.01) in T2DM with respect to C. IkBalpha expression was significantly lower (p < 0.01) in T2DM as well as Nrf2 and HO-1. In vitro experiments demonstrated that hyperglycemic conditions, if prolonged, were NF-kB inductors, without a corresponding Nrf2/ARE response. In PBMC of T2DM without glycemic target achievement, there is an activation of the UPR and of the ER apoptosis, which may be related to the chronic exposure to hyperglycemia, to the augmented inflammation, and to the augmented oxidative stress, without a corresponding Nrf2/ARE defense activation. PMID- 25511474 TI - Reliability and validity of the Japanese version of the simplified nutritional appetite questionnaire in community-dwelling older adults. AB - AIM: To translate the Simplified Nutritional Appetite Questionnaire (SNAQ) into Japanese, and assess its reliability and validity in Japanese community-dwelling older adults. METHODS: A total of 84 community-dwelling older adults people aged 65 years or older were included in the present study, and those with a Mini Mental State Examination score of <24, had dementia, had digestive disease or who did not complete the examination were excluded. The SNAQ was translated into Japanese according to an internationally accepted methodology. The internal reliability of the SNAQ was evaluated by Cronbach's alpha coefficient. Test retest reliability was evaluated using the intraclass correlation coefficient. The dimensionality of the SNAQ was evaluated by factor analysis. Concurrent validity was evaluated by measuring the Pearson's correlation coefficient between the SNAQ and Mini-Nutritional Assessment Short-Form scores, Geriatric Depression Scale scores, walking speed test, chair-stand test, hand grip strength test, or the Timed Up and Go test. RESULTS: The mean score of the Japanese version of the SNAQ was 15.5, with a Cronbach's alpha coefficient of 0.545 and intraclass correlation coefficient of 0.754. Factor analysis showed a single factor with 50.0% explained variance. The SNAQ was significantly associated with the Mini Nutritional Assessment Short-Form, Geriatric Depression Scale, walking speed test, chair-stand test and the Timed Up and Go test. Handgrip strength test did not show a significant association with the SNAQ. CONCLUSION: The Japanese version of the SNAQ had sufficient reliability and validity. Furthermore, SNAQ (Japanese version) is useful for evaluating the appetite of community-dwelling older adults in Japan. Geriatr Gerontol Int 2015; 15: 1264-1269. PMID- 25511475 TI - Examining the educational value of a CanMEDS roles framework in pediatric morbidity and mortality rounds. AB - BACKGROUND: In order to determine whether the CanMEDS roles could be helpful in solidifying knowledge during clinical training, we examined quality of care issues identified during morbidity and mortality (M&M) rounds. METHODS: During the M&M rounds, following the case presentation, there was a pause and attendees were asked to identify quality of care issues that were present in the case. The attendees were assigned to a CanMEDS prompted group or non-prompted group. Following the rounds, the issues were identified, coded according to CanMEDS role, and compared between groups. RESULTS: A total of 111 individuals identified a total of 350 issues; 57 individuals were in the CanMEDS-prompted group and 54 were in the unprompted group. The mean number of issues identified was significantly higher in the CanMEDS-prompted group compared to the unprompted group (3.7 versus 2.6, p = 0.039). There were significantly more issues raised in the prompted group for the roles of communicator, collaborator, scholar and professional. CONCLUSIONS: Using CanMEDS roles as prompts, attendees at M&M rounds identify more quality of care issues than if not given a prompt. Use of the CanMEDS framework may assist learners to consolidate the linkage between expected training objectives and the complexities of clinical practice. PMID- 25511476 TI - Socio-economic costs of osteoarthritis: a systematic review of cost-of-illness studies. AB - OBJECTIVE: The burden of illness that can be attributed to osteoarthritis is considerable and ever increasing. The aim of this systematic review is to analyze currently available data derived from cost-of-illness studies on the healthcare and non-healthcare costs of osteoarthritis. METHODS: PubMed, Index Medicus Espanol (IME), and the Spanish Database of Health Sciences [Indice Bibliografico Espanol en Ciencias de la Salud (IBECS)] were searched up to the end of April 2013. This study adhered to the PRISMA guidelines. Articles were reviewed and the study quality assessed by two independent investigators with consensus resolution of discrepancies. RESULTS: We identified 39 studies that investigated the socio economic cost of osteoarthritis. Only nine studies took a social perspective. Rather than estimating the incremental cost of osteoarthritis, nine studies estimated the total cost of treating patients with osteoarthritis without a control for comorbidity. The other 30 studies determined the incremental cost with or without a control group. Only nine studies assessed a comprehensive list of healthcare resources. The annual incremental healthcare costs of generalized osteoarthritis ranged from ?705 to ?19,715. The annual incremental non-healthcare related costs of generalized osteoarthritis ranged from ?432 to ?11,956. CONCLUSIONS: The study concludes that the social cost of osteoarthritis could be between 0.25% and 0.50% of a country's GDP. This should be considered in order to foster studies that take into account both healthcare and non-healthcare costs. PMID- 25511477 TI - The myth of the difficult airway: airway management revisited. PMID- 25511478 TI - Advanced laparoscopic fellowship training decreases conversion rates during laparoscopic cholecystectomy for acute biliary diseases: a retrospective cohort study. AB - INTRODUCTION: Acute biliary pathology is a risk factor for conversion to open surgery and increased surgical morbidity during laparoscopic cholecystectomy (LC). The purpose of our study was to examine the impact of an advanced laparoscopic fellowship-trained surgeon on risks of conversion, surgical morbidity, and postoperative complications in this patient population. METHODS: Of 1382 patients who underwent an LC from January 2008 to August 2011, 592 patients were diagnosed with an acute biliary process and were included in the study. Patients were divided into two groups; those operated on by an advanced laparoscopic fellowship-trained surgeon (N=237), and those operated on by a non laparoscopic fellowship-trained surgeon (N=355). The primary end-points were conversion rates and surgical morbidity. The secondary end-point was operative time. RESULTS: Fellowship-trained surgeons were more likely to perform IOC (57%) versus non-fellowship trained surgeons (20%) (p<0.0001). The conversion rate for the fellowship-trained group was significantly lower than for the non-fellowship trained group (1.7% vs 8.5%, p=0.0004). The intraoperative and postoperative complication rates for the fellowship-trained group were not significantly different. The operative time was slightly longer in the non-fellowship trained group compared to the fellowship-trained group (104 min vs 111 min, p=0.04). DISCUSSION: Our data demonstrate that advanced laparoscopic fellowship training decreases conversion rates of laparoscopic cholecystectomy for acute biliary pathology. Moreover, given the lower conversion rates, patients may have experienced shorter hospitalizations. CONCLUSIONS: Formal advanced laparoscopic fellowship training may decrease length of stay among patients presenting with acute biliary pathology who undergo laparoscopic cholecystectomy. PMID- 25511479 TI - Toughening mystery of natural rubber deciphered by double network incorporating hierarchical structures. AB - As an indispensible material for modern society, natural rubber possesses peerless mechanical properties such as strength and toughness over its artificial analogues, which remains a mystery. Intensive experimental and theoretical investigations have revealed the self-enhancement of natural rubber due to strain induced crystallization. However a rigorous model on the self-enhancement, elucidating natural rubber's extraordinary mechanical properties, is obscured by deficient understanding of the local hierarchical structure under strain. With spatially resolved synchrotron radiation micro-beam scanning X-ray diffraction we discover weak oscillation in distributions of strain-induced crystallinity around crack tip for stretched natural rubber film, demonstrating a soft-hard double network structure. The fracture energy enhancement factor obtained by utilizing the double network model indicates an enhancement of toughness by 3 orders. It's proposed that upon stretching spontaneously developed double network structures integrating hierarchy at multi length-scale in natural rubber play an essential role in its remarkable mechanical performance. PMID- 25511481 TI - Meeting report VLPNPV: Session 10: Rapid total particle quantification. PMID- 25511480 TI - The evaluation of thioridazine as a hematopoietic progenitor cell mobilizing agent in healthy human subjects. PMID- 25511482 TI - [Changes of ideas and models in tumor interventional treatment]. PMID- 25511483 TI - [An analysis of clinical factors in patients with hepatocellular carcinoma after transcatheter arterial chemoembolization complicated with diabetes]. AB - OBJECTIVE: To investigate related clinical factors of hepatocellular carcinoma (HCC) patients received transcatheter arterial chemoembolization (TACE) complicated with hepatogenous diabetes (HD). METHODS: Forty eight cases of HCC line after TACE combined HD patients as the case group, and another forty eight cases of HCC line after TACE without HD patients as control group. A case-control study was retrospectively analyzed among two groups. A logistic regression modelwas established. RESULTS: Multivariates analysis showed that family history of diabetes (OR = 3.464, 95% CI 1.100-10.909, P = 0.034), HBV DNA >1 * 105 IU/ml (OR = 5.420, 95% CI 1.235-23.792, P = 0.025), liver function Child-Pugh C (OR = 7.653, 95% CI 1.385-42.301, P = 0.020), major larger tumors >10 cm (OR = 5.347, 95% CI 1.499-19.067, P = 0.010), the initial embolism area > 70% (OR = 9.031, 95% CI 1.782-48.537, P = 0.008), TACE > 3 times (OR = 3.726, 95% CI 1.151-12.065, P = 0.028) were independent risk factors of HD in patients with HCC after TACE. CONCLUSION: Family history of diabetes, HBV DNA > 1 * 105 IU/ml, Child-Pugh C, major tumors size > 10 cm, the initial embolism area > 70%, TACE > 3 times were independent risk factors of HD in HCC patients after TACE. As for factors to these patients, the blood glucose was monitored promptly in order to early diagnosis and treatment. PMID- 25511484 TI - [Clinical observation of transcatheter arterial chemoembolization plus sorafenib in the treatment of hepatocellular carcinoma with portal vein tumor thrombosis]. AB - OBJECTIVE: To investigate the efficacy of transcatheter arterial chemoembolization (TACE) plus sorafenib in the treatment of hepatocellular carcinoma with portal vein tumor thrombosis. METHODS: A total of forty four patients of hepatocellular carcinoma with portal vein tumor thrombosis were retrospectively analyzed. There were twenty one patients in the treatment group, and the patients took oral 0.4 g sorafenib twice a day 7 days before or 14 days after TACE. Twenty three patients of control group were treated by TACE without sorafenib. Disease control rate (DCR), overall survival (OS), time to tumor progression (TTP) and side effects were followed up. RESULTS: The times of TACE in the treatment group was more than that in the control group (2.5 +/- 1.1 vs 1.8 +/- 1.1, P = 0.019). DCR of the treatment group and the control group were 81.0% vs 26.1%, 47.6% vs 0, 19.0 vs 0, and 4.8% vs 0, 3, 6, 9, and 12 months after TACE respectively, and the DCR of the treatment group were significantly higher than that of control group (P < 0.05). The median OS of the treatment group and the control group were (252 +/- 32) d and (123 +/- 18) d (P = 0.001) respectively. The median TTP of the treatment group and the control group were (187 +/- 16) d and (71 +/- 8) d (P = 0.000) respectively. Hand foot skin reaction and diarrhea of the treatment group and the control group were 90.5% vs 0 (P = 0.000) and 66.7% vs 8.7% (P = 0.000) respectively. CONCLUSION: Sorafenib is efficacious, and may prolong OS and TTP in hepatocellular carcinoma with PVTT treated by TACE. PMID- 25511485 TI - [Long-term outcomes of percutaneous microwave ablation versus repeat hepatectomy for treatment of late recurrent small hepatocellular carcinoma: a retrospective study]. AB - OBJECTIVE: To compare the effectiveness of percutaneous microwave ablation with those of repeat hepatectomy in the treatment of late recurrent small hepatocellular carcinoma measuring <= 5 cm (interval of recurrence from initial hepatectomy was > 12 months). METHODS: 66 patients who underwent initial hepatectomy for primary liver cancer in April 1998 to December 2010, and subsequent initial recurrent hepatocellular carcinoma treated with percutaneous microwave ablation or repeat hepatectomy, were enrolled in the study. Among these patients 39 were treated with percutaneous microwave ablation and 27 were treated with repeat hepatectomy. Technique effectiveness was evaluated by means of contrast enhanced techniques one month after ablation. The overall survival and disease-free survival were evaluated by using the Kaplan-Meier method. RESULTS: The technique effectiveness rate determined one month after ablation was 94.9%. The 1, 3, and 5 year overall survival rates were 86.2%, 73.3%, and 62.2%, respectively, for the microwave ablation group and 96.2%, 76.9%, and 61.2%, respectively, for the repeat hepatectomy group (P = 0.471). The corresponding recurrence-free survival rates were 65.8%, 28.0%, and 14.0%, respectively, for the microwave ablation group and 66.7%, 50.7%, and 43.4%, respectively, for the repeat hepatectomy group (P = 0.323). CONCLUSIONS: In patients with late recurrent small hepatocellular carcinoma, Percutaneous microwave ablation was efficient, and showed similar long-term survival and recurrence-free survival compared with repeat hepatectomy. PMID- 25511486 TI - [Application study of vertebral column metastasis tumor with embedment of 125I by CT guide]. AB - OBJECTIVE: To discuss the method, safety and effect of embedding 125I to Brachytherapy vertebral column metastasis tumor by CT guided. METHODS: 31 cases of vertebral column metastasis tumor were treated with percutaneous embedding 125I by CT guided. They were observed the preoperative size and contour of lesions and were planed the activity and dosage of 125I , the PD (prescribed dose) was 110-140 Gy, and the particle activity was 26.0-29.6 Mbq. CT scanning and therapeutic effect analysis were immediately carried out after operations. We also made CT scanning regularly to analyze the effect. RESULTS: 31 cases of vertebral column metastasis tumor were respectively re-examed of CT in 2, 4, 6 and 12 months after operation. We surveyed the local rate, evaluate the easement of pain and observed the tumor. The local response rate of 19 cases with paravertebral mass was 19/19, 19/19, 18/19, 17/19 cases in turn. The probability of odynolysis 31 cases after 2, 4, 6 months therapy was 96.8% (30/31) , 96.8% (30/31) , 90.3% (28/31) , 71.0% (22/31) in turn. 9.68% of 31 cases that was happened significant ossification in the devastated vertebral body. 12 cases appeared skin pigmentation without myelodiastasis or cutaneous ulcer. CONCLUSION: The method to treat the vertebral column metastasis tumor of embedding 125I by CT guided was simple, reliable and safety. PMID- 25511488 TI - [Impact of sequential targeted therapy on progression-free survival in metastatic renal cell carcinoma]. AB - OBJECTIVE: To evaluate the impact of sequential targeted therapy including vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI) and everolimus on progression-free survival (PFS) in metastatic renal carcinoma. METHODS: A total of 17 patients of metastatic renal cell carcinoma from Department of Kidney Cancer and Melanoma, Peking University Cancer Hospital since January 2008 until April 2014 were enrolled into this retrospective study. They took at least 2 lines of VEGFR-TKIs and everolimus. The data of total PFS and PFS of each therapy were extracted and analyzed. RESULTS: The sequential targeted therapies affected total PFS (18.0 vs 46.0 months, Kaplan-Meier survival analysis, P = 0.015) with a statistical dislike of VEGFR-TKI/VEGFR-TKI/mTOR inhibitor (TTM) over VEGFR-TKI/mTOR inhibitor/VEGFR-TKI (TMT) , HR = 5.44 (Cox regression analysis, 95% CI 1.18-25.06). CONCLUSION: TMT may prolong the total PFS of metastatic renal cell carcinoma. PMID- 25511487 TI - [Metabolic activity measured by 18F-FDG PET/CT in newly diagnosed patients with non-Hodgkin lymphoma: correlation with immunophenotype]. AB - OBJECTIVE: To compare the metabolic activity by 18F-fluorodeoxyglucose (18F-FDG) uptake across the various histologic subtypes of non-Hodgkin lymphoma (NHL) and to investigate the relationship between metabolic activity and immunophenotype. METHODS: Positron emission tomography/computed tomography (PET/CT) studies of patients with newly diagnosed NHL from Jul 2010 to Mar 2012 were retrospectively reviewed, 82 patients were enrolled in our study according to the inclusion and exclusion criteria. The maximum standardized uptake value (SUVmax) of each patient reflecting the metabolic activity was recorded. Mean SUVmax of aggressive B-cell NHL, indolent B-cell NHL and T-cell NHL were compared. Pearson and Spearman test were used to analyze the relationship between SUVmax and immunophenotype. RESULTS: The SUVmax of various subtypes of lymphoma revealed a wide range from 0.9 to 40.3, but lesions of 79 patients in this study showed obviously FDG uptake. SUVmax of indolent B-cell NHL (4.5 +/- 2.4) was significantly lower than that of aggressive B-cell NHL (13.1 +/- 7.6) (P = 0.000), T-cell NHL (8.0 +/- 3.8) (P = 0.03). SUVmax of aggressive B-cell NHL was significantly higher than that of indolent B-cell NHL, T-cell NHL (P = 0.000, P = 0.005). SUVmax of B-cell NHL had positive correlation with Ki-67 expression (r = 0.493, P = 0.001) and negative correlation with CD138 (r = -0.654, P = 0.008). While SUVmax of T-cell NHL had no correlation with Ki-67 expression (P = 0.213), but had negative correlation with CD56 (r = -0.545, P = 0.044). CONCLUSIONS: Different subtype of NHL manifests markedly different intensity of FDG uptake, but most lesions of lymphoma are FDG avid. Metabolic activity is lower in indolent B-cell NHL than in aggressive B-cell NHL and T-cell lymphoma, which is concordant with its aggressiveness. SUVmax of B-cell NHL correlates with expression of Ki-67 and CD138. SUVmax of T-cell NHL is associated with the expression of CD56, no correlation is detected between SUVmax of T-cell NHL and Ki-67 proliferation. PMID- 25511489 TI - [Evaluation and analysis of cognitive function in chronic renal failure patients]. AB - OBJECTIVE: To explore the characteristics of cognitive impairment and correlation analysis in patients with chronic renal failure (CRF). METHODS: The Addenbrooke's cognitive examination revised (ACE-R) scale was used to evaluate the cognitive function for 101 cases of chronic renal failure patients (group CRF) receiving outpatient and inpatient treatments and selected 30 individuals with normal renal function as normal controls (group NC) for cross-sectional analysis. T test, receiver operating characteristic (ROC) curve and other statistical methods were adopted for comparing differences. RESULTS: (1) Compared with group NC (83.4 +/- 6.5), group CRF (71.9 +/- 17.6) showed significantly statistical difference on Addenbrooke's cognitive examination revised (ACE-R) scale scores (P < 0.01); (2)compared with normal controls, the patients with CRF had significantly statistical difference on the scores of visual spatial ability (11.5 +/- 3.2, 14.0 +/- 3.0 respectively), language fluency (7.0 +/- 2.6, 8.7 +/- 1.9) (P < 0.01) and memory (18.1 +/- 7.0, 21.5 +/- 3.6 respectively) (P < 0.05); (3) the cognitive function of patients with CRF were significantly positive correlated with glomerular filtration rate (GFR) (r = 0.614, P < 0.01) and negatively correlated with the duration of illness (r = -0.492, P < 0.01); (4) From ROC curve and the area under curve (AUC), ACE-R scale (AUC = 0.680) showed a higher sensitivity than mini-mental state examination scale (AUC = 0.576) in assessing cognitive function in patients with CRF (P < 0.01). CONCLUSION: (1) Under similar basic conditions of age, level of education and background, CRF patients showed significant damage overall cognitive function, cognitive impairment in visual spatial ability, executive function, long-term memory and logical judgment ability was particularly impaired. Immediate and delayed memory, attention, orientation and language ability also manifested different degrees of decline; (2) the severity of cognitive impairment in patients with CFR was closely related with the level of GFR; (3) the ACE-R scale showed a higher sensitivity than mini mental state examination scale in assessing cognitive function in patients with CRF. PMID- 25511490 TI - [Healing status of surgical incisions in human immunodeficiency virus-positive patients with fractures]. AB - OBJECTIVE: To observe the healing status of surgical incisions in human immunodeficiency virus (HIV)-positive patients with fractures and explore the factors related with poor wound healing, treatment and preventive measures. METHODS: Retrospective analyses were performed for the clinical data of 61 HIV positive patients with fractures. And the influencing factors, treatment and outcomes of poor wound healing were analyzed. RESULTS: Among them, the healing status was good (n = 50) and poor (n = 11). And the outcomes included redness (n = 10), oozing (n = 8), split (n = 3), infection (n = 2), hematoma (n = 1), fat liquefaction (n = 2) and delayed healing (n = 2). All healed well after treatment. There was no infection or death during the follow-up period. Compared with HIV-negative patients, it was not statistically significant in wound infection. However, poor healing rates were significantly different (P < 0.05). The risk factors included advanced age, low body mass index, low albumin, low hemoglobin, low total lymphocyte count, low CD4+ T lymphocyte count, high HIV infection clinical stage, long operative duration, emergency surgery and incision contamination. CONCLUSION: In HIV-positive patients with fractures, the healing of surgical incision is generally good. However few have poor wound healing due to multiple factors. If poor healing is identified early and handled timely and correctly, good healing ensues. PMID- 25511491 TI - [Association of body mass index and male primary osteoporosis]. AB - OBJECTIVE: To explore the association between body mass index (BMI) and male primary osteoporosis (OP) in a Chinese Han population. METHODS: The association of BMI with OP was assessed in 276 Chinese healthy aged males for physical examination. They were classified into OP, osteopenia and normal groups according to the World Health Organization (WHO) criteria, i.e. OP was defined arbitrarily when any T-score was -2.5 standard deviations or less at femoral neck, total hip or lumbar spine (L1-4) site. We also classified the subjects as different BMI groups of low weight, normal weight, overweight and obesity. The prevalence of OP was compared among different BMI groups. We determined the sensitivity, specificity and area under the curve of receiver operating characteristic (ROC) for validating the valuation of BMI to predict male primary OP. RESULTS: Among them, 6/12 had OP in the low weight group, 17.36% (21/121) in the normal group and 12.59% (18/143) in the overweight and obesity group. And the difference was significant. The analysis of ROC curve showed that BMI was of limited value in predicting OP (P > 0.05). CONCLUSION: BMI has a positive correlation with male OP. The value of BMI is limited for predicting OP in males. And the relevant factors associated with male OP should to be further studied. PMID- 25511492 TI - [Mortality risks of type 2 diabetes mellitus among elderly patients: a 17-year cohort study]. AB - OBJECTIVE: To explore the mortality risks of elders with and without type 2 diabetes mellitus (T2DM) during a fellow-up period of 17 years. METHODS: The subjects were elderly patients (>60 years old) undergoing annual health examinations at our hospital. And the incidence and risk factors were analyzed by Kaplan-Meier method and COX's proportional hazard. RESULTS: A total of 2 142 subjects were divided into T2DM group (DM, n = 746) and non-T2DM group (N-DM, n = 1 396). During a 17-year follow-up, the mortality rate of all causes was 50.9% in DM group versus 32.45% in N-DM group (P < 0.01). The major mortality causes were malignant tumor, respiratory disease and cardiovascular disease. Kaplan-Meier analysis revealed that the accumulative mortality of all causes and cardiovascular with DM was significantly above that of N-DM. The independent mortality risk factors of elders was T2DM (P < 0.01, HR = 1.36, 95% CI: 1.192 1.558) and cardiovascular disease (P < 0.01, HR = 3.26, 95% CI: 2.887-3.690) based upon the COX's proportional hazard analysis. CONCLUSION: Type 2 diabetes mellitus is an independent risk factor for elders with increased mortality risk. PMID- 25511493 TI - [Early diagnosis of painful diabetic neuropathy by corneal confocal microscopy]. AB - OBJECTIVE: To explore the early diagnosis of painful diabetic neuropathy by observing the alterations in corneal innervation with corneal confocal microscopy. METHODS: Fifty aged-matched control subjects, 45 diabetic neuropathy including 20 subjects with type 2 diabetes and painful neuropathy (PDN) and 25 subjects with type 2 diabetes and painless neuropathy (PLN) underwent detailed evaluations of their neuropathic symptoms. The examinations of visual analogue scale (VAS), contact heat evoked potential (CHEP) and corneal confocal microscopy (CCM) were employed to quantify small nerve fiber pathology and their degree of pain. We evaluated the use of a novel in vivo technique CCM in assessing painful neuropathy compared to CHEP. RESULTS: The results of CHEP and CCM were significantly different in the diabetic groups compared to controls. T test indicated patients with PDN had significant reductions in corneal nerve fiber length (NFL), nerve branch density (NBD), nerve fiber density (NFD) and increased corneal nerve fiber tortuosity (NFT) (13 +/- 4 vs 11 +/- 3, 62 +/- 24 vs 47 +/- 19, 32 +/- 13 vs 22 +/- 8, 2.8 +/- 0.9 vs 3.2 +/- 0. 8; t = 40.43, 27.27, 42.21, 194.39, P = 0.039, 0.011, 0.017, 0.006), (t = 40.43, 27.27, 42.21, 194.39, P = 0.039, 0.011, 0.017, 0.006). Pearson's correlation analysis showed pain severity correlated significantly with cornea nerves damage. VAS correlated significantly with NFL, NBD, NFD and NFT (r = 0.782, -0.376, -0.504, all P < 0.001). CONCLUSION: CCM provides a sensitive and noninvasive modality of detecting small nerve fiber damage in patients with PFN. And these abnormalities may be a sensitive predictor for the presence of pain in diabetic neuropathy patients. PMID- 25511494 TI - [Application of two and three-dimensional ultrasound measurement of fetal thymus in fetal intrauterine growth restriction]. AB - OBJECTIVE: To measure the ultrasonic parameters of transverse diameter, anteroposterior diameter and volume of fetal thymus through two and three dimensional (2D and 3D) probes, establish normal reference range of fetal thymus development and assess the correlation between fetal intrauterine growth restriction and fetal thymus development. METHODS: A total of 53 patients with suspected fetal intrauterine growth restriction (IUGR) at our hospital from December 2012 to May 2014 were selected into the observation group while another 53 cases as the control group corresponding to the former group's gestational week (GA). The transverse and anteroposterior diameters were measured in the three vessel view by 2D-ultrasound and the volume of fetal thymus was measured through 3D ultrasound. The control parameters were analyzed by linear regression analysis. And two groups of parameters were tested by rank sum test. P < 0.05 was deemed significant. RESULTS: The regression equation of fetal thymus transverse diameter and GA was: Y = 0.14X-1.174, R2 = 0.766, P < 0.05; the regression equation of fetal thymus anteroposterior diameter and GA was: Y = 0.49X-0.166, R2 = 0.792, P < 0.05; the regression equation of fetal thymus volume and GA was: Y = 0.652X-10.611, R2 = 0.791, P < 0.05. Two groups underwent rank sum test of fetal thymus transverse diameter, anteroposterior diameter and volume (P < 0.05). CONCLUSION: Fetal thymus transverse diameter, anteroposterior diameter and volume increase with gestational weeks. In IUGR, fetal thymus transverse diameter, anteroposterior diameter and volume are less than those of the same GA fetal thymus. PMID- 25511495 TI - [Clinical misdiagnosis analysis of valproate encephalopathy]. AB - OBJECTIVE: To analyze the clinical and laboratory characteristics of postoperative patients of valproate encephalopathy (VHE), summarize the diagnostic and treatment experiences, discuss the reason of misdiagnosis and improve the level of early diagnosis. METHODS: A total of 12 VHE patients diagnosed after an application of valproate were recruited from January 2010 to April 2013. The characteristics of clinical manifestations and laboratory examinations were retrospectively analyzed. RESULTS: Among them, the misdiagnoses included intracranial hemorrhage (n = 1), secondary brain edema (n = 1), postoperative cerebral infarction (n = 1), postoperative epileptic deterioration (n = 4), electrolyte disorder (n = 2), intracranial infection (n = 1), vasospasm (n = 1) and non-specific (n = 1). All patients had disturbance of consciousness associated with elevated blood ammonia. The symptoms of VHE were not correlated with the dosage and concentration of valproate. VHE was more likely to occur in patients treated with valproic acid sodium injection or other antiepileptic drugs. The symptoms dramatically improved after a withdrawal of valproate. CONCLUSION: VHE should be considered in postoperative neurosurgical valproate treated patients with unknown disturbance of consciousness. Timely diagnosis is needed and valproate should be withdrawn to avoid serious consequences. PMID- 25511496 TI - [Antagonistic effects of estrogen on iron-induced bone resorption and its mechanism]. AB - OBJECTIVE: To explore the antagonistic effect of estrogen on iron-induced bone resorption and the role of oxidative stress. METHODS: In vivo, 8-week-old female imprinting control region mice were randomly divided into 3 groups of ferritin (F), ovariectomy (OVX) and F+OVX. Intervention was made by ferric ammonium citrate (FAC) and OVX. Serum levels of ferritin, malondialdehyde (MDA) and superoxide dismutase (SOD) were measured. The expression changes of TRAP, CTR, matrix metallopeptidase 9 (MMP9) and CTK derived from murine bilateral tibia were detected by reverse transcription-polymerase chain reaction (RT-PCR). A high resolution micro-computed tomography was utilized for scanning distal femur. In vitro, RAW264.7 cells were used and intervened by FAC and estradiol. Tartrate resistant acid phosphatase (TRAP) staining was performed and wine-red TRAP positive cells were counted. ROS level was detected by 2', 7'-dichloro dihydrofluorescein diacetate (DCFH-DA) with a multi-detection reader. RESULTS: The serum ferritin were heightened in F and F+OVX groups [(335.30 +/- 44.10) vs (41.38 +/- 5.56) ug/L, (324.80 +/- 38.60) vs (41.38 +/- 5.56) ug/L respectively, P < 0.01]. The trend of MDA level was F+OVX>OVX>F while SOD level was quite opposite. Body mass density of F+OVX group was lower than that of OVX group (0.114 +/- 0.013 vs 0.187 +/- 0.029 mg/mm3, P < 0.05) or F group (0.114 +/- 0.013 vs 0.902 +/- 0.064 mg/mm3, P < 0.05). RT-PCR: TRAP and CTK gene expression of OVX group was lower than that of F+OVX group. However, TRAP, CTR and CTK gene expression of F+OVX group was higher than that of F group. TRAP staining: FAC increased the number of TRAP positive cells (41.7 +/- 5.5 vs 20.0 +/- 4.0, P < 0.05) while estradiol decreased it (14.8 +/- 5.1 vs 41.7 +/- 5.5, P < 0.05). DCFH DA test show that reactive oxygen species was elevated by FAC (160% +/- 8% vs 100% +/- 9%, P < 0.05) and reduced by estradiol (53% +/- 13% vs 160% +/- 8%, P < 0.05). CONCLUSION: The antagonistic effect of estrogen on iron-induced bone resorption is probably regulated by oxidative stress. PMID- 25511497 TI - [The influence of miR-16 on proliferation and angiogenesis of U87MG in vivo]. AB - OBJECTIVE: To explore the proliferation inhibition of miR-16 to U87MG in vivo. METHODS: The miR-16 over-expression U87MG cells were obtained by infecting U87MG with lentivirus-hsa-GFP-miR-16. The models of subcutaneous transplantation and orthotopic brain glioma were obtained by injecting cells into flank and brains of nude mouse separately. Untransfected U87MG, negative control U87MG and miR-16 over-expression U87MG were separatively cultured and injected into brains of balb/c-nu mice for establishing an orthotopic model of brain glioma. Tumor growth curve was calculated for subcutaneous tumor. The brains were sectioned and stained with hematoxylin & eosin (H&E) and immunohistochemistry for CD31 and cyclinD1. RESULTS: The miR-16 over-expression U87MG cells formed no apparent tumors while the negative control U87MG grew into large tumors. HE stain of brains showed that gliomas of miR-16 over-expression U87MG (0.11 +/- 0.04 mm3) were smaller than those of negative control U87MG (6.50 +/- 1.41 mm3) and untransfected (6.41 +/- 0.91 mm3) in murine brains. Immunohistochemistry showed that cyclinD1 staining was less in gliomas of miR-16 over-expression U87MG than the other two groups. CD31 immunohistochemistry also yielded the similar results. The mean microvascular density (MVD) of gliomas of miR-16 over-expression U87MG (4.50 +/- 1.58/* 200) was smaller than negative control (30.40 +/- 6.57/* 200) and untransfected (29.40 +/- 4.93/* 200) (P < 0.05). CONCLUSION: miR-16 can significantly inhibit the in vivo growth of U87MG glioma. This is probably the results of cell proliferation inhibition and angiogenesis suppression. PMID- 25511498 TI - [Treatment of ovarian cancer cell line SKOV3 with IL-24 gene under the control of ovarian-specific promoter-1]. AB - OBJECTIVE: To explore the in vitro antitumor effect of interleukin-24 (IL-24) gene regulated by ovarian-specific promoter-1 (OSP-1) on human ovarian cancer cell line SKOV3. METHODS: An expression vector (pcDNA3.0-OSP-1-IL-24) containing IL-24 gene under ovarian-specific promoter-1 was constructed by molecular biological methods and then transfected into human ovarian cancer cell SKOV3, human hepatoma cell HepG2 and human fibroblast BJ by cationic liposome. Reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect the IL-24 gene in cells and supernatants. The antitumor effects of IL-24 gene were investigated by direct cell count, flow cytometry and methyl thiazolyl tetrazolium (MTT) assay. RESULTS: After transfections with pcDNA3.0-OSP-1-IL-24, the expression of IL-24 gene was detected only in SKOV3 cells. And only the growth of SKOV3 cells was inhibited significantly while those of HepG2 and BJ cells were not affected. The culture supernatant of SKOV3 cells transfected with pcDNA3.0-OSP-1-IL-24 could significantly inhibit the growth of SKOV3 cells. But the antitumor efficiency in SKOV3 cells of OSP-1 system was significantly lower than that of CMV promoter system. CONCLUSION: With a high specificity, IL-24 gene therapy under the control of ovarian-specific promoter-1 is a novel target for the treatment of ovarian cancer. PMID- 25511499 TI - [Effects of telmisartan on inflammation and fibrosis after acute myocardial infarction in rats]. AB - OBJECTIVE: To explore the protection mechanisms of telmisartan on inflammation and fibrosis after myocardial infarction in rats. METHODS: The model of acute myocardial infarction (AMI) was established by ligating left anterior descending coronary artery. The surviving rats were divided into AMI (AMI) and telmisartan treatment (telmisartan) groups. And another sham operation group (sham) was designated (n = 8). At the end of study, total heart weight (THW), left ventricular weight (LVW) and weight index were measured; myocardial infarction and inflammatory reactions detected by hematoxylin and eosin and Masson staining; the serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNFalpha), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6) and interleukin-1 beta (IL-1beta) by enzyme-linked immunosorbent assay (ELISA); the levels of transforming growth factor 1 (TGFbeta1), collagen I, collagen III and MMP9 mRNA in myocardial tissue by reverse transcription-polymerase chain reaction (RT-PCR); the expressions of TGFbeta1, collagen I, collagen III, matrix metallopeptidase 9 (MMP9) and nuclear factor-kappa B (NF-kappaB) by Western blot. RESULTS: Compared with sham group, significant pathological changes of myocardium occurred in AMI group. The serum levels of CRP [(472 +/- 132) vs (104 +/- 28) ng/ml], TNFalpha [(229 +/- 41) vs (18 +/- 5) pg/ml], MCP-1[(558 +/- 116) vs (158 +/- 20) pg/ml], IL-6 [(404 +/- 63) vs (21 +/- 4) pg/ml] and IL-1beta [(625 +/- 145) vs (189 +/- 34) pg/ml] increased (P < 0.05). RT-PCR analysis showed that the expression levels of TGFbeta1, collagen I, collagen III and MMP9 increased significantly. The results of Western blot were consistent and NF-kappaB was activated significantly (P < 0.05). Compared with AMI group, the above-mentioned indicators decreased obviously in telmisartan group (P < 0.05). CONCLUSION: Telmisartan may regulate inflammation and myocardial fibrosis after acute myocardial infarction by signaling pathways of NF-kappaB and TGFbeta in rats. PMID- 25511500 TI - Self-assembly and chemical reactivity of alkenes on platinum nanoparticles. AB - Stable platinum nanoparticles were synthesized by the self-assembly of alkene derivatives onto the platinum surface, possibly forming platinum-vinylidene (Pt?C?CH-) or -acetylide (Pt-C=) interfacial bonds as a result of dehydrogenation and transformation of the olefin moieties catalyzed by platinum. Transmission electron microscopic measurements showed that the nanoparticles were well dispersed without apparent agglomeration, indicating effective passivation of the nanoparticles by the ligands, and the average core was estimated to be 1.34 +/- 0.39 nm. FTIR measurements showed the emergence of a new vibrational band at 2023 cm(-1), which was ascribed to the formation of Pt-H and C=C from the dehydrogenation of alkene ligands on platinum surfaces. Consistent behaviors were observed in photoluminescence measurements, where the emission profiles were similar to those of alkyne-functionalized Pt nanoparticles that arose from intraparticle charge delocalization between the particle-bound acetylene moieties. Selective reactivity with imine derivatives further confirmed the formation of Pt?C?CH- or Pt-C= interfacial linkages, as manifested in NMR and electrochemical measurements. Further structural insights were obtained by X-ray absorption near-edge spectroscopy and extended X-ray absorption fine structure analysis, where the coordinate numbers and bond lengths of the Pt-Pt and Pt-C linkages suggested that the metal-ligand interfacial bonds were in the intermediate between those of Pt-C= and Pt-Csp(2). PMID- 25511501 TI - "Wave" signal-smoothing and mercury-removing device for laser ablation quadrupole and multiple collector ICPMS analysis: application to lead isotope analysis. AB - A novel "wave" signal-smoothing and mercury-removing device has been developed for laser ablation quadrupole and multiple collector ICPMS analysis. With the wave stabilizer that has been developed, the signal stability was improved by a factor of 6.6-10 and no oscillation of the signal intensity was observed at a repetition rate of 1 Hz. Another advantage of the wave stabilizer is that the signal decay time is similar to that without the signal-smoothing device (increased by only 1-2 s for a signal decay of approximately 4 orders of magnitude). Most of the normalized elemental signals (relative to those without the stabilizer) lie within the range of 0.95-1.0 with the wave stabilizer. Thus, the wave stabilizer device does not significantly affect the aerosol transport efficiency. These findings indicate that this device is well-suited for routine optimization of ICPMS, as well as low repetition rate laser ablation analysis, which provides smaller elemental fractionation and better spatial resolution. With the wave signal-smoothing and mercury-removing device, the mercury gas background is reduced by 1 order of magnitude. More importantly, the (202)Hg signal intensity produced in the sulfide standard MASS-1 by laser ablation is reduced from 256 to 0.7 mV by the use of the wave signal-smoothing and mercury removing device. This result suggests that the mercury is almost completely removed from the sample aerosol particles produced by laser ablation with the operation of the wave mercury-removing device. The wave mercury-removing device that we have designed is very important for Pb isotope ratio and accessory mineral U-Pb dating analysis, where removal of the mercury from the background gas and sample aerosol particles is highly desired. The wave signal-smoothing and mercury-removing device was applied successfully to the determination of the (206)Pb/(204)Pb isotope ratio in samples with low Pb content and/or high Hg content. PMID- 25511503 TI - Recreation and procreation: A critical view of sex in the human female. AB - This review deals critically with many aspects of the functional genital anatomy of the human female in relation to inducing sexual arousal and its relevance to procreation and recreation. Various controversial problems are discussed including: the roles of clitorally versus coitally induced arousal and orgasm in relation to the health of women, the various sites of induction of orgasm and the difficulty women find in specifically identifying them because of "'ambiguity problems" and "genital site pareidolia," the cervix and sexual arousal, why there are so many sites for arousal, why multiple orgasms occur, genital reflexes and coitus, the sites of arousal and their representation in the brain, and identifying aspects and functions of the genitalia with appropriate new nomenclature. PMID- 25511502 TI - Kv1.5 blockers preferentially inhibit TASK-1 channels: TASK-1 as a target against atrial fibrillation and obstructive sleep apnea? AB - Atrial fibrillation and obstructive sleep apnea are responsible for significant morbidity and mortality in the industrialized world. There is a high medical need for novel drugs against both diseases, and here, Kv1.5 channels have emerged as promising drug targets. In humans, TASK-1 has an atrium-specific expression and TASK-1 is also abundantly expressed in the hypoglossal motor nucleus. We asked whether known Kv1.5 channel blockers, effective against atrial fibrillation and/or obstructive sleep apnea, modulate TASK-1 channels. Therefore, we tested Kv1.5 blockers with different chemical structures for their TASK-1 affinity, utilizing two-electrode voltage clamp (TEVC) recordings in Xenopus oocytes. Despite the low structural conservation of Kv1.5 and TASK-1 channels, we found all Kv1.5 blockers analyzed to be even more effective on TASK-1 than on Kv1.5. For instance, the half-maximal inhibitory concentration (IC50) values of AVE0118 and AVE1231 (A293) were 10- and 43-fold lower on TASK-1. Also for MSD-D, ICAGEN 4, S20951 (A1899), and S9947, the IC50 values were 1.4- to 70-fold lower than for Kv1.5. To describe this phenomenon on a molecular level, we used in silico models and identified unexpected structural similarities between the two drug binding sites. Kv1.5 blockers, like AVE0118 and AVE1231, which are promising drugs against atrial fibrillation or obstructive sleep apnea, are in fact potent TASK-1 blockers. Accordingly, block of TASK-1 channels by these compounds might contribute to the clinical effectiveness of these drugs. The higher affinity of these blockers for TASK-1 channels suggests that TASK-1 might be an unrecognized molecular target of Kv1.5 blockers effective in atrial fibrillation or obstructive sleep apnea. PMID- 25511504 TI - Atorvastatin regulates apoptosis in chronically ischemic myocardium. AB - BACKGROUND: We previously demonstrated that atorvastatin upregulates proangiogenic proteins and increases arteriolar density in ischemic myocardium. Despite this, there was a lack of collateral-dependent perfusion, possibly related to apoptosis. We utilized a swine model of metabolic syndrome and chronic myocardial ischemia to investigate the effects of atorvastatin on apoptosis. MATERIALS AND METHODS: Sixteen Ossabaw miniswine were fed a high-cholesterol diet for 14 weeks then underwent surgical placement of an ameroid constrictor to their circumflex artery inducing chronic ischemia. Eight pigs additionally received supplemental atorvastatin (1.5 mg/kg daily). Myocardium was harvested six months later for western blotting and TUNEL staining. RESULTS: Animals supplemented with atorvastatin had significant increases in markers associated with apoptosis including p-38, BAX, and caspase 3 (p < 0.05). Atorvastatin supplementation also resulted in significant increases in expression of cell survival proteins Bcl-2 and P-ERK and an overall decrease in apoptosis demonstrated by TUNEL staining (p < 0.05). CONCLUSIONS: Atorvastatin acts on multiple pathways and its effects on angiogenesis remain unclear. Although there is increased expression in several markers of apoptosis, key anti-apoptotic proteins were also upregulated with an overall decrease in apoptosis. Further investigation of these pathways may provide insight into the role of statins on myocardial protection after ischemia. PMID- 25511505 TI - Assembly of water-soluble chlorophyll-binding proteins with native hydrophobic chlorophylls in water-in-oil emulsions. AB - The challenges involved in studying cofactor binding and assembly, as well as energy- and electron transfer mechanisms in the large and elaborate transmembrane protein complexes of photosynthesis and respiration have prompted considerable interest in constructing simplified model systems based on their water-soluble protein analogs. Such analogs are also promising templates and building blocks for artificial bioinspired energy conversion systems. Yet, development is limited by the challenge of introducing the essential cofactors of natural proteins that are highly water-insoluble into the water-soluble protein analogs. Here we introduce a new efficient method based on water-in-oil emulsions for overcoming this challenge. We demonstrate the effectiveness of the method in the assembly of native chlorophylls with four recombinant variants of the water-soluble chlorophyll-binding protein of Brassicaceae plants. We use the method to gain new insights into the protein-chlorophyll assembly process, and demonstrate its potential as a fast screening system for developing novel chlorophyll-protein complexes. PMID- 25511506 TI - Speed of response to electroconvulsive therapy compared with ketamine. PMID- 25511507 TI - Comparison of ketamine vs. ECT in major depressive disorder: need for ECT standard dosing and duration parameters. PMID- 25511508 TI - All-dielectric metasurface analogue of electromagnetically induced transparency. AB - Metasurface analogues of electromagnetically induced transparency (EIT) have been a focus of the nanophotonics field in recent years, due to their ability to produce high-quality factor (Q-factor) resonances. Such resonances are expected to be useful for applications such as low-loss slow-light devices and highly sensitive optical sensors. However, ohmic losses limit the achievable Q-factors in conventional plasmonic EIT metasurfaces to values <~10, significantly hampering device performance. Here we experimentally demonstrate a classical analogue of EIT using all-dielectric silicon-based metasurfaces. Due to extremely low absorption loss and coherent interaction of neighbouring meta-atoms, a Q factor of 483 is observed, leading to a refractive index sensor with a figure-of merit of 103. Furthermore, we show that the dielectric metasurfaces can be engineered to confine the optical field in either the silicon resonator or the environment, allowing one to tailor light-matter interaction at the nanoscale. PMID- 25511510 TI - Effectiveness of two novel anionic and cationic platinum complexes in the treatment of osteosarcoma. AB - AIM: This study aimed to characterize the cellular basis of the platinum cytotoxicity of two novel platinum complexes, 3Pt and 1Pt, in comparison with that of cisplatin. 3Pt comprises anionic phosphate moieties, while 1Pt comprises neutral aromatic ligands. METHODS: We compared the cytotoxic potency of 3Pt and 1Pt with that of cisplatin in osteosarcoma cell lines and an orthotopic mouse model. RESULTS: The cytotoxic potency of 3Pt was markedly higher than that of cisplatin in all cell lines. Both novel platinum complexes showed a complete lack of cross resistance in cisplatin-resistant cells. Caffeine enhanced the cytotoxic potency of these novel platinum complexes, as observed for cisplatin. Apoptosis after drug administration was observed by DNA ladder formation and an annexin V/PI assay. DNA double-strand breaks were confirmed by phosphorylation of histone H2AX. In vivo, the antitumor activity of 3Pt and 1Pt was superior and similar, respectively, to that of cisplatin. Both novel platinum complexes exerted strong antitumor effects on osteosarcoma in vitro and in vivo. CONCLUSIONS: 3Pt may be an effective drug for the treatment of bone cancer because the PO3 moiety has a high affinity to bone, as exhibited by bisphosphonates, and is expected to decrease the incidence of side effects at extraskeletal sites and overcome drug resistance. Cationic 1Pt may also be an effective antitumor drug because of its unique chemical structure and properties. Further investigations to detail the antitumor effects of these ionic Pt complexes on osteosarcoma are warranted. PMID- 25511509 TI - Identification of skin-expressed genes possibly associated with wool growth regulation of Aohan fine wool sheep. AB - BACKGROUND: Sheep are valuable resources for the animal fibre industry. Therefore, identifying genes which regulate wool growth would offer strategies for improving the quality of fine wool. In this study, we employed Agilent sheep gene expression microarray and proteomic technology to compare the gene expression patterns of the body side (hair-rich) and groin (hairless) skins of Aohan fine wool sheep (a Chinese indigenous breed). RESULTS: Comparing the body side to the groin skins (S/G) of Aohan fine wool sheep, the microarray study revealed that 1494 probes were differentially expressed, including 602 more highly expressed and 892 less highly expressed probes. The microarray results were verified by means of quantitative PCR. Cluster analysis could distinguish the body side skin and the groin skin. Based on the Database for Annotation, Visualization and Integrated Discovery (DAVID), 38 of the differentially expressed genes were classified into four categories, namely regulation of receptor binding, multicellular organismal process, protein binding and macromolecular complex. Proteomic study revealed that 187 protein spots showed significant (p < 0.05) differences in their respective expression levels. Among them, 46 protein entries were further identified by MALDI-TOF/MS analyses. CONCLUSIONS: Microarray analysis revealed thousands of differentially expressed genes, many of which were possibly associated with wool growth. Several potential gene families might participate in hair growth regulation. Proteomic analysis also indentified hundreds of differentially expressed proteins. PMID- 25511511 TI - Synthesis and anticancer activity evaluation of some benzothiazole-piperazine derivatives. AB - Synthesis, characterization and cytotoxic activities of ten benzothiazole piperazine derivatives were reported. In vitro cytotoxic activities of compounds were screened against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT 116) cancer cell lines by sulphorhodamine B assay. Based on the GI50 values of the compounds, most of the benzothiazole-piperazine derivatives are active against HUH-7, MCF-7 and HCT-116 cancer cell lines. Aroyl substituted compounds 1h and 1j were found to be the most active derivatives. In addition, further investigation of compounds 1h and 1j by Hoechst staining and FACS revealed that these compounds cause apoptosis by cell cycle arrest at subG1 phase. PMID- 25511512 TI - Targeting mitochondrial citrate transport in breast cancer cell lines. AB - Lipogenesis is considered to be a very important aspect of cancer metabolism and targeting de novo lipid synthesis or related pathways are among novel approaches to treat cancer. Many targets of the pathway including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase and fatty acid synthase have been evaluated for their potential in cancer treatment. However the role of citrate transport protein (CTP), another important component of lipogenesis pathway, is not well known for cancer metabolism and cell survival. Here we report that while chemical inhibition of CTP reduces cytoplasmic citrate levels and limits breast cancer cell viability effectively, siRNA based inhibition had little effect on both. We also compared the effects of CTP inhibition with ACLY and found that the inhibition of ACLY reduced cytoplasmic citrate levels and limited cell viability more effectively than CTP inhibition. Finally we have demonstrated that neither cell cycle arrest nor autophagy was induced in cells treated with CTP or ACLY siRNA. Inhibitions triggered apoptosis but only slightly. Growth inhibitory effects do not occur in normal mammary epithelial MCF-10A cell line. PMID- 25511513 TI - Encouraging microRNA-based Therapeutic Strategies for Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common and rapidly fatal malignancies worldwide with poor prognosis. Most of the HCC patients died quickly because of the rapid tumor progression with no effective therapy except for liver resection or transplantation. Recently, microRNAs (miRNAs) have emerged as key factors involved in a series of biological processes ranging from embryogenesis to programmed cell death with aberrant expression profiles, potentially attractive diagnosis, prognosis or therapeutic applications for related-diseases. Accumulating evidences have indicated the roles of miRNAs as tumor suppressor in hepatocyte malignant transformation including development, differentiation, proliferation and tumorigenesis. This article reviews that the recent progress underlies the development of novel miRNA-based HCC therapeutic strategies in the coming future. PMID- 25511515 TI - A Short Review on the Synthetic Strategies of Duocarmycin Analogs that are Powerful DNA Alkylating Agents. AB - The duocarmycins and CC-1065 are members of a class of DNA minor groove, AT sequence selective, and adenine-N3 alkylating agents, isolated from Streptomyces sp. that exhibit extremely potent cytotoxicity against the growth of cancer cells grown in culture. Initial synthesis and structural modification of the cyclopropa[c] pyrrolo[3,2-e]indole (CPI) DNA-alkylating motif as well as the indole non-covalent binding region in the 1980s have led to several compounds that entered clinical trials as potential anticancer drugs. However, due to significant systemic toxicity none of the analogs have passed clinical evaluation. As a result, the intensity in the design, synthesis, and development of novel analogs of the duocarmycins has continued. Accordingly, in this review, which covers a period from the 1990s through the present time, the design and synthesis of duocarmycin SA are described along with the synthesis of novel and highly cytotoxic analogs that lack the chiral center. Examples of achiral analogs of duocarmycin SA described in this review include seco-DUMSA (39 and 40), seco amino-CBI-TMI (13, Centanamycin), and seco-hydroxy-CBI-TMI (14). In addition, another novel class of biologically active duocarmycin SA analogs that contained the seco-iso-cyclopropylfurano[2,3-e]indoline (seco-iso-CFI) and seco cyclopropyltetrahydrofurano[2,3-f]quinoline (seco-CFQ) DNA alkylating submit was also designed and synthesized. The synthesis of seco-iso-CFI-TMI (10, Tafuramycin A) and seco-CFQ-TMI (11, Tafuramycin B) is included in this review. PMID- 25511516 TI - A Review on the Synthesis and Anti-cancer Activity of 2-substituted Quinolines. AB - Quinolines substituted at C-2 on the quinoline scaffold have shown interesting anticancer activity in a number of anticancer assays such as breast (MCF-7, MDA MB 231), human cervical epithelioid (HeLa), oral squamous cell carcinoma (SAS), human stomach adenocarcinoma (AGS, MKN45), hepatocellular (SKHep, HepG-2, Hep 3B), prostate (PC-3, DU145), lung (A549, H-460), gastric (HGC, MNK-74), leukemia (K562, U937, REH, NALM6, CEM/ADR 5000), colon (Colo-205, HCT 116, SW620, Caco-2, HT29), neuroblastoma (IMR32), CNS (SF-268), oesophageal (EAC) and melanoma (A 375). They have been synthesised by a number of strategies starting with isatin, anilines, nitrobenzenes and benzamides and some even with cyclohexanone and cyclohexa-1,3-diones with ammonium acetate. Many of the synthetic strategies employ the derivatisation of quinoline precursors itself. We review here the synthesis of 145 bioactive anticancer quinolines substituted at the 2-position and their anticancer activity. PMID- 25511517 TI - Funny and late: targeting currents governing heart rate in atrial fibrillation. PMID- 25511514 TI - Lessons from Nature: Sources and Strategies for Developing AMPK Activators for Cancer Chemotherapeutics. AB - Adenosine Monophosphate-Activated Protein Kinase or AMPK is a highly-conserved master-regulator of numerous cellular processes, including: Maintaining cellular energy homeostasis, modulation of cytoskeletaldynamics, directing cell growth rates and influencing cell-death pathways. AMPK has recently emerged as a promising molecular target in cancer therapy. In fact, AMPK deficiencies have been shown to enhance cell growth and proliferation, which is consistent with enhancement of tumorigenesis by AMPK-loss. Conversely, activation of AMPK is associated with tumor growth suppression via inhibition of the Mammalian Target of Rapamycin Complex-1 (mTORC1) or the mTOR signal pathway. The scientific communities' recognition that AMPK-activating compounds possess an anti neoplastic effect has contributed to a rush of discoveries and developments in AMPK-activating compounds as potential anticancer-drugs. One such example is the class of compounds known as Biguanides, which include Metformin and Phenformin. The current review will showcase natural compounds and their derivatives that activate the AMPK-complex and signaling pathway. In addition, the biology and history of AMPK-signaling and AMPK-activating compounds will be overviewed, their anticancer-roles and mechanisms-of-actions will be discussed, and potential strategies for the development of novel, selective AMPK-activators with enhanced efficacy and reduced toxicity will be proposed. PMID- 25511518 TI - The validity of military screening for mental health problems: diagnostic accuracy of the PCL, K10 and AUDIT scales in an entire military population. AB - Depression, alcohol use disorders and post-traumatic stress disorder (PTSD) are serious issues among military personnel due to their impact on operational capability and individual well-being. Several military forces screen for these disorders using scales including the Kessler Psychological Distress Scale (K10), Alcohol Use Disorders Identification Test (AUDIT), and Post-traumatic Stress Disorder Checklist (PCL). However, it is unknown whether established cutoffs apply to military populations. This study is the first to test the diagnostic accuracy of these three scales in a population-based military cohort. A large sample of currently-serving Australian Defence Force (ADF) Navy, Army and Air Force personnel (n = 24,481) completed the K10, AUDIT and PCL-C (civilian version). Then, a stratified sub-sample (n = 1798) completed a structured diagnostic interview detecting 30-day disorder. Data were weighted to represent the ADF population (n = 50,049). Receiver operating characteristic (ROC) analyses suggested all three scales had acceptable sensitivity and specificity, with areas under the curve from 0.75 to 0.93. AUDIT and K10 screening cutoffs closely paralleled established cutoffs, whereas the PCL-C screening cutoff resembled that recommended for US military personnel. These self-report scales represent a cost effective and clinically-useful means of screening personnel for disorder. Military populations may need lower cutoffs than civilians to screen for PTSD. PMID- 25511519 TI - Pediatric resuscitation training-instruction all at once or spaced over time? AB - AIM: Healthcare providers demonstrate limited retention of knowledge and skills in the months following completion of a resuscitation course. Resuscitation courses are typically taught in a massed format (over 1-2 days) however studies in education psychology have suggested that spacing training may result in improved learning and retention. Our study explored the impact of spaced instruction compared to traditional massed instruction on learner knowledge and pediatric resuscitation skills. METHODS: Medical students completed a pediatric resuscitation course in either a spaced or massed format. Four weeks following course completion students completed a knowledge exam and blinded observers used expert-developed checklists to assess student performance of three skills (bag valve mask ventilation (BVMV), intra-osseous insertion (IOI) and chest compressions (CC)). RESULTS: Forty-five out of 48 students completed the study protocol. Students in both groups had similar scores on the knowledge exam spaced: (37.8+/-6.1) vs. massed (34.3+/-7.6)(p<0.09) and overall global rating scale scores for IOI, BVMV and CC; however students in the spaced group also performed critical procedural elements more frequently than those in the massed training group CONCLUSION: Learner knowledge and performance of procedural skills in pediatric resuscitation taught in a spaced format is at least as good as learning in a massed format. Procedures learned in a spaced format may result in better retention of skills when compared to massed training. PMID- 25511520 TI - Clinical considerations in transitioning patients with epilepsy from clonazepam to clobazam: a case series. AB - INTRODUCTION: In treating refractory epilepsy, many clinicians are interested in methods used to transition patients receiving clonazepam to clobazam to maintain or increase seizure control, improve tolerability of patients' overall drug therapy regimens, and to enhance quality of life for patients and their families. However, no published guidelines assist clinicians in successfully accomplishing this change safely. CASE PRESENTATIONS: The following three case reports provide insight into the transition from clonazepam to clobazam. First, an 8-year-old Caucasian boy with cryptogenic Lennox-Gastaut syndrome beginning at 3.5 years of age, who was experiencing multiple daily generalized tonic-clonic, absence, myoclonic, and tonic seizures at presentation. Second, a 25-year-old, left handed, White Hispanic man with moderate mental retardation and medically refractory seizures that he began experiencing at 1 year of age, secondary to tuberous sclerosis. When first presented to an epilepsy center, he had been receiving levetiracetam, valproate, and clonazepam, but reported having ongoing and frequent seizures. Third, a 69-year-old Korean woman who had been healthy until she had a stroke in 2009 with subsequent right hemiparesis; as a result, she became less physically and socially active, and had her first convulsive seizure approximately 4 months after the stroke. CONCLUSIONS: From these cases, we observe that a rough estimate of final clobazam dosage for each mg of clonazepam under substitution is likely to be at least 10-fold, probably closer to 15-fold for many patients, and as high as 20-fold for a few. Consideration and discussion of the pharmacokinetic, pharmacologic, and clinical properties of 1,4- and 1,5-benzodiazepine action provide a rationale on why and how these transitions were successful. PMID- 25511522 TI - The effect of motor familiarity during simple finger opposition tasks. AB - Humans are more familiar with performing (and observing) index-thumb than with any other finger to thumb grasping and the effect of familiarity has not been tested specifically with simple and intransitive actions. The study of simple and intransitive motor actions (i.e. simple actions without need of object interaction) provides the opportunity to investigate specifically the brain motor regions reducing the effect of non-motor aspects that are related with more complex and/or transitive motor actions. The aim of this study is to evaluate brain activity patterns during the execution of simple and intransitive finger movements with different degrees of familiarity. With this in mind, a functional Magnetic Resonance Imaging (fMRI) study was performed in which participants were asked to execute finger to thumb opposition tasks with all the different fingers (index, middle, ring and little) with a fixed frequency (1 Hz) determined by a visual cue. This movement is considered as the pantomime of a precision grasping action. Significant activity was identified in the Sensory Motor Cortex (SMC), posterior parietal and premotor regions for all simple conditions (index finger>control, middle-finger>control, ring-finger>control and little finger>control). However, a linear trend contrast (index=50 py: 2.45, 95% CI: 1.41-4.23). Current smoking (HR = 2.45, 95% CI: 1.81-3.32) and each additional 10 py smoked (HR = 1.16, 95% CI: 1.11-1.22) were associated with statistically significant increases in the risk of other-cause mortality. The effect of current smoking on other cause mortality decreased with advancing stage and increasing body mass index (BMI). Breast cancer-specific mortality was associated with current smoking of >=50 py (HR = 2.36, 95% CI: 1.26-4.44), and each additional 10 py smoked (HR = 1.07, 95% CI: 1.01-1. 14). Current smoking, but not former smoking, was associated with increased risk of breast cancer-specific mortality in women with local disease (HR = 2.32, 95% CI: 1.32-4.09), but not in those with regional and distant disease (HR = 1.10, 95% CI: 0.73-1.68). Our findings suggest that current smoking at the time of breast cancer diagnosis may be associated with increased risk of breast-cancer specific and other-cause mortality, whereas former smoking is associated with increased risk of other-cause mortality. Smoking cessation at the time of diagnosis may lead to better prognosis among women with breast cancer. PMID- 25511537 TI - Disseminated nocardiosis caused by Nocardia transvalensis in a patient with mixed immunodeficiency. PMID- 25511538 TI - Rate-dependent bundle branch block and myocardial bridge: Other chest pain's causes. PMID- 25511543 TI - [New aspects in surgery of the nasal tip]. AB - The creation of both a functionally and aesthetically pleasing nasal tip contour is demanding and depends on a variety of parameters. Typically, procedures are performed with emphasis on narrowing the nasal tip structure. Excisional techniques alone inevitably lead to reduction in skeletal support and are often prone to unpredictable deformities. But long-term results of classical suture techniques have also shown unfavorable outcomes. Particularly pinching of the alae and displacement of the caudal margin of the lateral crus below the cephalic margin belong in this category. A characteristic loss of structural continuity between the domes and the alar lobule and an undesirable shadowing occur. These effects lead to an unnatural appearance of the nasal tip and frequently to impaired nasal breathing. Stability and configuration of the alar cartilages alone do not allow for an adequate evaluation of the nasal tip contour. Rather a three-dimensional approach is required in order to describe all nasal tip structures. Especially the rotational angle of the alar surface as well as the position of the lateral crus in relation to the cranial septum should be considered in the three-dimensional analysis. Taking the various parameters into account the authors present new aspects in nasal tip surgery which contribute to the creation of a functionally and aesthetically pleasing as well as durable nasal tip contour. PMID- 25511544 TI - Case of pure ovarian squamous cell carcinoma resistant to combination chemotherapy with paclitaxel and carboplatin but responsive to monotherapy with weekly irinotecan. AB - Primary ovarian squamous cell carcinoma is uncommon, and the optimal treatment strategy for this disease has not yet been established. A 71-year-old woman diagnosed with FIGO stage IIb pure ovarian squamous cell carcinoma underwent cytoreductive surgery followed by combination chemotherapy with paclitaxel and carboplatin. After the second treatment course, a recurrent mass grew rapidly, and serum tumor maker levels increased. Monotherapy with weekly irinotecan was then instituted. This second-line chemotherapy was remarkably effective, and the patient subsequently underwent complete interval debulking surgery with a pathological complete response after the third treatment course. Weekly irinotecan is an effective choice for primary ovarian squamous cell carcinoma resistant to combination chemotherapy with paclitaxel and carboplatin. PMID- 25511545 TI - Association between being overweight and oral health in Serbian schoolchildren. AB - BACKGROUND: Childhood obesity, dental caries, and periodontal disease are major public health problems due to their adverse impact on the growth and development of children. AIM: To examine the association between nutritional status, oral health, and lifestyle habits among schoolchildren in Serbia. DESIGN: This cross sectional study assessed 422 children and adolescents aged 6-18 years with the following dental indexes analyzed: DMF/dmf (decayed, missed, and filled teeth), plaque index (PI), and gingival index (GI). Depending on their nutritional status, the subjects were categorized, as being 'normal weight,' 'at risk of overweight,' and 'overweight.' Logistic regression was applied to study the association between the dental indexes and independent variables: gender, age, toothbrushing, nutritional status, and lifestyle factors. RESULTS: Being overweight positively correlated with GI, but negatively correlated with the DMF/dmf index among the participants. Multivariate analysis showed a strong association between the weight category and toothbrushing with GI and PI. Overweight children (6-11 years) were less likely to have caries, whereas in older children/adolescents (12-18 years), caries was associated with the intake of sugar-sweetened juices. CONCLUSIONS: Being overweight was found to be significantly associated with a higher probability of developing gingivitis and negatively associated with caries prevalence in Serbian children and adolescents. PMID- 25511546 TI - A new tumor biomarker, serum protein peak at 3,144 m/z, in patients with node positive breast cancer. AB - PURPOSE: To explore the association between the 3,144 m/z protein peak and the clinicopathological features and prognosis in breast cancer. METHODS: Using SELDI TOF MS, we analyzed serum protein peak at 3,144 m/z in 283 patients with node positive breast cancer, its relationship with clinicopathological features and their prognosis evaluating value of survival. RESULTS: 3,144 m/z positive rate was higher in elderly patients (42.8 % in >=50-year-old vs. 31.2 % in <50, P = 0.04). However, no correlation was observed between 3,144 m/z and other clinicopathological features (body mass index, menstrual status, family history, TNM, molecular subtypes, vascular invasion, neural invasion, p53 and CA15-3). However, the positive rate of 3,144 m/z was higher than that of CA15-3 (35.5 vs. 11.4 %, McNemar chi (2) test, p < 0.001). 3,144 m/z-negative patients (n = 177) had a better 3-year overall survival (OS) than 3,144 m/z-positive patients (n = 106) (89.8 vs. 81.2 %, P = 0.045). Younger patients (P = 0.016), postmenopausal status (P = 0.019), small tumor (P < 0.001), less positive nodes (P < 0.001), early stage (P < 0.001), favorable molecular subtype (P = 0.007), normal CA15-3 (P = 0.003) and neoadjuvant chemotherapy (P = 0.001) predicted better survival. Cox analysis showed that T3-4 (95 % CI 1.419-8.057, P = 0.006), lymph node metastasis (95 % CI 1.242-3.632, P = 0.006) and p53 mutation (95 % CI 1.088 6.378, P = 0.032) were independent adverse prognostic factors. But childbirth >=2 (95 % CI 0.163-0.986, P = 0.046), adjuvant chemotherapy (95 % CI 0.062-0.921, P = 0.038) and adjuvant radiotherapy (95 % CI 0.148-0.928, P = 0.034) were the independent factors in reducing risk of death in breast cancer patients. Combination testing of 3,144 m/z and CA15-3 will improve the prognosis value of 3 year survival (P = 0.011); patients with CA153-/3144- were characterized by the longest survival (89.8 %) and the CA153+/3144+ patients by the shortest. CONCLUSIONS: Serum protein peak at 3,144 m/z is a new biomarker for breast cancer diagnosis and prognosis and showed a higher positive rate than serum CA15-3. Combining 3,144 m/z and CA15-3 testing may improve prognosis of longer survival in breast cancer patients. PMID- 25511547 TI - The use of interferon in melanoma patients: a systematic review. AB - Interferon (IFN) and PEG-IFN are the only drugs approved as adjuvant therapy in patients with melanoma at high-risk of recurrence after surgical resection. Several clinical trials of adjuvant IFN, using different doses and durations of therapy, have been conducted in these patients. Results generally suggest relapse free survival and overall survival benefits; however, questions over the optimal dose and duration of treatment and concerns over toxicity have limited its use. IFN exerts its biological activity in melanoma via multiple mechanisms of action, most of which can be considered as indirect immunomodulatory effects. As such, IFN may also be of benefit in the neoadjuvant setting, where it may have a role in melanoma patients with locally advanced disease for whom immediate surgical excision is not possible. However, this has not been well studied. The use of IFN in patients with metastatic melanoma is controversial, with limited data and no convincing evidence of a survival benefit. However, IFN therapy combined with novel biological and immunotherapies offers the potential for a synergistic effect and improved clinical outcomes. Predictive and prognostic factors to better select melanoma patients for IFN treatment have been identified (e.g. disease stage, ulceration, various cytokines) and may also enhance its therapeutic efficacy, but their incorporation into the clinical decision-making process requires validation in prospective trials. In conclusion, the modest efficacy of IFN shown in clinical trials is largely a reflection of differences in response between patients. Despite advancements in the understanding of its biological mechanisms of action, the huge potential of IFN remains to be fully explored and utilized in patients with melanoma. PMID- 25511549 TI - Acupuncture for sleep quality, BDNF levels and immunosenescence: a randomized controlled study. AB - Poor sleep in elderly populations is associated with detrimental neuropsychological, and physiological changes including premature immunosenescence and reduced brain derived neurotrophic factor (BDNF). Here, we evaluated the effects of acupuncture on sleep quality, psychological distress and immunosenescence in elderly, as well as effects on BDNF levels. Forty-eight community-dwelling elderly were randomized into true or placebo acupuncture, and intervention consisted of ten sessions. Sleep quality, depression and stress scores were evaluated by the Pittsburgh sleep quality index (PSQI), beck depression inventory (BDI II) and perceived stress scale (PSS), respectively, before and after the intervention. Lymphocyte subsets commonly associated with stress, sleep impairment and immunosenescence were phenotyped by flow cytometry. BDNF plasma levels were assessed by ELISAs. Acupuncture was highly effective for improving sleep quality (-53.23%; p<0.01), depression (-48.41%; p<0.01), and stress (-25.46%; p<0.01). However, neither lymphocyte subpopulations nor BDNF levels changed following the intervention. PMID- 25511548 TI - Association of the mt-ND2 5178A/C polymorphism with Parkinson's disease. AB - Mitochondria play an important role in the etiology of Parkinson's disease (PD). While mutations in the mitochondrial DNA (mtDNA) have been shown to accumulate in PD, no specific mtDNA polymorphisms have been associated with susceptibility or resistance to PD. A cytosine to adenine transversion at base pair 5178 in the mtDNA has been associated with increased longevity and resistance against a number of age related disorders and has been shown to decrease mitochondrial reactive oxygen species (ROS) production. We sought to determine whether 5178A is associated with resistance against PD in a Han Chinese population. To assess its association with PD, we genotyped 484 idiopathic PD patients and 710 control individuals for 5178C/A. Genotyping was performed using restriction fragment length polymorphism (RFLP) analysis. There was no significant association between 5178A and PD (P=0.308) when analyzing the entire population. However, sub-group analysis revealed that in males the frequency of 5178A was significantly lower in PD patients (27.7% in controls vs 20.0% in PD patients, P=0.027). Stratification of the population by age showed that this trend held across age groups but only reached statistical significance in males aged 60-70 (29.1% in controls vs 14.05 in PD patients, P=0.011). In conclusion, we demonstrated that the frequency of 5178A was significantly decreased in male PD patients in a Han Chinese population. This polymorphism may be associated with resistance against the development of PD when in combination with loci on the Y chromosome. PMID- 25511550 TI - Blueberry treatment decreased D-galactose-induced oxidative stress and brain damage in rats. AB - D-galactose (GAL) causes aging-related changes and oxidative stress in the organism. We investigated the effect of whole fresh blueberry (BB) (Vaccinium corymbosum L.) treatment on oxidative stress in age-related brain damage model. Rats received GAL (300 mg/kg; s.c.; 5 days per week) alone or together with 5 % (BB1) and 10 % (BB2) BB containing chow for two months. Malondialdehyde (MDA),protein carbonyl (PC) and glutathione (GSH) levels, and Cu Zn-superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione transferase (GST) activities as well as acetylcholinesterase (AChE) activities were determined. Expressions of B cell lymphoma-2 (Bcl-2), Bax and caspase-3 were also evaluated in the brain by immunohistochemistry. MDA and PC levels and AChE activity increased, but GSH levels, SOD and GSH-Px activities decreased together with histopathological structural damage in the brain of GAL-treated rats. BB treatments, especially BB2 reduced MDA and PC levels and AChE activity and elevated GSH levels and GSH-Px activity. BB1 and BB2 treatments diminished apoptosis and ameliorated histopathological findings in the brain of GAL-treated rats. These results indicate that BB partially prevented the shift towards an imbalanced prooxidative status and apoptosis together with histopathological amelioration by acting as an antioxidant (radical scavenger) itself in GAL treated rats. PMID- 25511551 TI - Decreased efficacy of twice-weekly intravaginal dehydroepiandrosterone on vulvovaginal atrophy. AB - OBJECTIVE: While daily intravaginal administration of 0.50% (6.5 mg) dehydroepiandrosterone (DHEA, prasterone) for 12 weeks has shown clinically and statistically significant effects on moderate to severe (MS) dyspareunia as the most bothersome symptom (MBS), the present study analyzes the effect of a reduced dosing regimen on MBS vaginal dryness. METHOD: Daily intravaginal 0.50% prasterone for 2 weeks followed by twice weekly for 10 weeks versus placebo. RESULTS: Maximal beneficial changes in vaginal parabasal and superficial cells and pH were observed at 2 weeks as observed for intravaginal 10 MUg estradiol (E2). This was followed by a decrease or lack of efficacy improvement after switching to twice-weekly dosing. The decrease in percentage of parabasal cells, increase in percentage of superficial cells and decrease in vaginal pH were all highly significant (p < 0.0001 to 0.0002 over placebo) at 12 weeks. In parallel, the statistical significance over placebo (p value) on MBS vaginal dryness at 6 weeks was 0.09 followed by an increase to 0.198 at 12 weeks. For MBS dyspareunia, the p value of 0.008 at 6 weeks was followed by a p value of 0.077 at 12 weeks, thus illustrating a decrease of efficacy at the lower dosing regimen. The improvements of vaginal secretions, color, epithelial integrity and epithelial surface thickness were observed at a p value < 0.01 or 0.05 over placebo at 2 weeks, with a similar or loss of statistical difference compared to placebo at later time intervals. No significant adverse event was observed. Vaginal discharge related to the melting of Witepsol was reported in 1.8% of subjects. CONCLUSION: The present data show that daily dosing with 0.50% DHEA for 2 weeks followed by twice-weekly dosing is a suboptimal treatment of the symptoms/signs of vulvovaginal atrophy resulting from a substantial loss of the efficacy achieved at daily dosing. PMID- 25511552 TI - High accuracy of Karplus equations for relating three-bond J couplings to protein backbone torsion angles. AB - (3) JC'C' and (3) JHNHalpha couplings are related to the intervening backbone torsion angle ${?varphi }$ by standard Karplus equations. Although these couplings are known to be affected by parameters other than ${?varphi }$, including H-bonding, valence angles and residue type, experimental results and quantum calculations indicate that the impact of these latter parameters is typically very small. The solution NMR structure of protein GB3, newly refined by using extensive sets of residual dipolar couplings, yields 50-60 % better Karplus equation agreement between ${?varphi }$ angles and experimental (3) JC'C' and (3) JHNHalpha values than does the high-resolution X-ray structure. In intrinsically disordered proteins, (3) JC'C' and (3) JHNHalpha couplings can be measured at even higher accuracy, and the impact of factors other than the intervening torsion angle on (3) J will be smaller than in folded proteins, making these couplings exceptionally valuable reporters on the ensemble of ${?varphi }$ angles sampled by each residue. PMID- 25511556 TI - Higher self-reported prevalence of hypertension among Moluccan-Dutch than among the general population of The Netherlands: results from a cross-sectional survey. AB - BACKGROUND: Several studies in The Netherlands revealed ethnic disparities in hypertension prevalence, but none have focused on the Moluccan-Dutch, a migrant group from Indonesia that settled in The Netherlands in 1951. The Moluccan-Dutch are considered to be fairly well integrated in Dutch society. The aim of this study was to compare hypertension prevalence among the Moluccan-Dutch to the native Dutch and to explore the contribution of known risk factors. METHODS: A health interview survey was conducted from August 2012 till March 2013 among nineteen Moluccan neighborhoods, resulting in the inclusion of 708 participants. The primary outcome variable was self-reported prevalence of hypertension. Explanatory variables were BMI, exercise, smoking, alcohol intake and mental health status. Data on the control group was extracted from the Dutch National Health Survey 2011, using a similar questionnaire. Differences in risk factor exposure were explored using Chi-square tests and the contribution of risk factors, separately and combined, was explored using multivariate logistic regression analysis. RESULTS: Moluccan-Dutch showed higher odds for reporting hypertension when compared to native Dutch, after adjusting for age and level of education (OR = 1.38; 95% CI = 1.13-1.69) and additional risk factors (OR = 1.49; 95% CI = 1.19-1.88). A higher prevalence of hypertension was found in both Moluccan-Dutch men (26.4% vs. 16.7%; p < 0.001) and women (26.7% vs. 17.9%; p < 0.001), when compared to the control group. Not only middle-aged, but also young Moluccan-Dutch men showed higher prevalence of hypertension. CONCLUSION: The Moluccan-Dutch may be at increased risk for reporting hypertension. These results suggest that long-term stay over several generations does not necessarily result in similar levels of hypertension prevalence as the host population. PMID- 25511557 TI - Notes from the Field: Residents' Perceptions of Simulation-Based Skills Assessment in Obstetrics and Gynecology. AB - Simulation in obstetrics and gynecology (OBGYN) training captures a range of interpersonal, cognitive, and technical skills. However, trainee perspectives on simulation-based assessment remain unexplored. After an observed structured clinical examination (OSCE) simulation hybrid exam, two focus groups of residents were conducted. Analysis grounded in a thematic coding guided the qualitative research process. Responses suggest a valuation of cognitive and technical skills over interpersonal skills. Realism was seen as critical and residents perceived the assessment as more valuable for the educator than the learner. Feedback was highly valued. Resident perspectives on this exam give insight into their perceptions of simulation-based assessment as well as their conceptions of their own learning through simulations. PMID- 25511558 TI - Prognostic Benefit of Beta-blockers After Acute Coronary Syndrome With Preserved Systolic Function. Still Relevant Today? AB - INTRODUCTION AND OBJECTIVES: The scientific evidence for using beta-blockers after acute coronary syndrome stems from studies conducted in the days before coronary revascularization and in patients with ventricular dysfunction. The aim of this study was to analyze the current long-term prognostic benefit of beta blockers in patients with acute coronary syndrome and preserved left ventricular ejection fraction. METHODS: We conducted a retrospective cohort study of 3236 patients with acute coronary syndrome and left ventricular ejection fraction >= 50%. We performed a propensity-matched analysis to draw up two groups of 555 patients paired according to whether or not they had been treated with beta blockers. The prognostic value of beta-blockers to predict mortality during follow-up was analyzed using Cox regression. RESULTS: During the follow-up (median, 5.2 years), 506 patients (15.6%) died. Patients treated with beta blockers (n=2277 [70.4%]) had a lower mortality rate (11.6% vs 25.2%; P<.001). After propensity score matching, we found that mortality during follow-up was still lower in the beta-blocker group (14.4% vs 18.9%; P=.020). Therefore, this treatment was an independent protective factor after adjusting for confounding variables in the multivariate Cox regression analysis (hazard ratio=0.64; 95% confidence interval, 0.48-0.87; P=.004). CONCLUSIONS: Beta-blocker treatment in patients with acute coronary syndrome and preserved left ventricular ejection fraction is associated with lower long-term mortality. PMID- 25511559 TI - Systolic aortic regurgitation. A new prognostic marker in heart failure patients? PMID- 25511560 TI - Histological Findings in Tako-tsubo Syndrome. PMID- 25511561 TI - Phylogeography of Avian influenza A H9N2 in China. AB - BACKGROUND: During the past two decades, avian influenza A H9N2 viruses have spread geographically and ecologically in China. Other than its current role in causing outbreaks in poultry and sporadic human infections by direct transmission, H9N2 virus could also serve as an progenitor for novel human avian influenza viruses including H5N1, H7N9 and H10N8. Hence, H9N2 virus is becoming a notable threat to public health. However, despite multiple lineages and genotypes that were detected by previous studies, the migration dynamics of the H9N2 virus in China is unclear. Increasing such knowledge would help us better prevent and control H9N2 as well as other future potentially threatening viruses from spreading across China. The objectives of this study were to determine the source, migration patterns, and the demography history of avian influenza A H9N2 virus that circulated in China. RESULTS: Using Bayesian phylogeography framework, we showed that the H9N2 virus in mainland China may have originated from the Hong Kong Special Administrative Region (SAR). Southern China, most likely the Guangdong province acts as the primary epicentre for multiple H9N2 strains spreading across the whole country, and eastern China, most likely the Jiangsu province, acts as an important secondary source to seed outbreaks. Our demography inference suggests that during the long-term migration process, H9N2 evolved into multiple diverse lineages and then experienced a selective sweep, which reduced its genetic diversity. Importantly, such a selective sweep may pose a greater threat to public health because novel strains confer higher fitness advantages than strains being replaced and could generate new viruses through reassortment. CONCLUSION: Our analyses indicate that migratory birds, poultry trade and transportation have all contributed to the spreading of the H9N2 virus in China. The ongoing migration and evolution of H9N2, which poses a constant threat to the human population, highlights the need for a more comprehensive surveillance of wild birds and for the enhancement of biosafety for China's poultry industry. PMID- 25511562 TI - Screening for childhood lead poisoning in the industrial region of Fez, Morocco. AB - The study objectives were to estimate lead poisoning prevalence among children living next to an industrial area, to compare it to that in a control population, and to establish clinical and biological follow-up of the poisoned children. This is a descriptive cross-sectional study including 150 children (exposed and unexposed) performed between January 2012 and April 2013. It was meant to determine blood lead levels (BLLs) in children considered to be an exposed population (EP N 90), living in the industrial area Ain Nokb Fez compared with BLLs of children of other areas belonging to the same city supposed to be unexposed [UP (N = 60)]. A sociodemographic questionnaire was obtained, and a blood lead analysis was performed. Clinical and biological follow-up has been performed of poisoned children. The sample consisted of 90 EP children with an average age of 6.82 +/- 3.32 years and male-to-female sex ratio (SR) of 1.5 and 60 UP children with an average age of 6.45 +/- 3.29 years and an SR of 1.2. Among the 150 children recruited, the average of BLLs was 58.21 +/- 36 ug/L (18-202.3 MUg/L). The average of BLLs in EP children (71 +/- 40 ug/L) was statistically greater (p < 0.0001) than that registered in UP children (38 +/- 13 ug/L). All poisoned children belonged to the EP group at a prevalence of 21.1 %. The clinical and biological examinations of poisoned children showed a few perturbations such as anemia, hypocalcaemia, and deficiencies in magnesium and iron. No renal disease or objective neurological disorders were observed. In the follow-up of the children with BLL >=100 ug/L (19 cases). BLL monitoring showed a significant decrease in average of blood concentration ranging from 136.75 +/- 32.59 to 104.58 +/- 32.73 ug/L (p < 0.0001) and in lead poisoning prevalence (p < 0.001), which decreased to 7.8 % from 21.1. Our study showed a high prevalence of lead poisoning (21.1 %) in EP children. The relocation of the industrial site associated with corrective and preventive measures has contributed to a decrease of exposure and lead poisoning prevalence in the aforementioned population. PMID- 25511563 TI - Surface functionalized mesoporous silica nanoparticles as an effective carrier for epirubicin delivery to cancer cells. AB - Recent studies with inorganic nanoparticles modified with functional groups have demonstrated improvement in drug delivery into cancer cells. In the present study, we prepared, characterized, and evaluated mesoporous silica nanoparticles (MSNs) as carriers for epirubicin hydrochloride (EPI) in order to improve the antitumor efficacy of this drug. MSNs were prepared and functionalized with phosphonate, polyethylene glycol (PEG) and polyethylenimine-polyethylene glycol (PEI-PEG) groups. Different nanoparticulate formulations were loaded with EPI. The in vitro cytotoxicity and the in vivo antitumor efficacy of MSNs containing EPI were evaluated versus free EPI. The EPI release from nanoparticles was shown to be pH-dependent. The size of MSNs functionalized with polyethyleneimine polyethylene glycol (MSN-PEI-PEG) was 123.8 +/- 4.8 nm. This formulation showed the best antitumor effects at an EPI dose of 9 mg/kg in C-26 colon carcinoma model. The biodistribution results proved that MSN-PEI-PEG-EPI had a higher tumor accumulation compared to free EPI, 3h after drug administration. The results indicated that this formulation could be effective nanocarriers for anti-tumor therapies. PMID- 25511564 TI - Understanding physicians' behavior toward alerts about nephrotoxic medications in outpatients: a cross-sectional analysis. AB - BACKGROUND: Although most outpatients are relatively healthy, many have chronic renal insufficiency, and high override rates for suggestions on renal dosing have been observed. To better understand the override of renal dosing alerts in an outpatient setting, we conducted a study to evaluate which patients were more frequently prescribed contraindicated medications, to assess providers' responses to suggestions, and to examine the drugs involved and the reasons for overrides. METHODS: We obtained data on renal alert overrides and the coded reasons for overrides cited by providers at the time of prescription from outpatient clinics and ambulatory hospital-based practices at a large academic health care center over a period of 3 years, from January 2009 to December 2011. For detailed chart review, a group of 6 trained clinicians developed the appropriateness criteria with excellent inter-rater reliability (kappa=0.93). We stratified providers by override frequency and then drew samples from the high- and low-frequency groups. We measured the rate of total overrides, rate of appropriate overrides, medications overridden, and the reason(s) for override. RESULTS: A total of 4120 renal alerts were triggered by 584 prescribers in the study period, among which 78.2% (3,221) were overridden. Almost half of the alerts were triggered by 40 providers and one-third was triggered by high-frequency overriders. The appropriateness rates were fairly similar, at 28.4% and 31.6% for high- and low frequency overriders, respectively. Metformin, glyburide, hydrochlorothiazide, and nitrofurantoin were the most common drugs overridden. Physicians' appropriateness rates were higher than the rates for nurse practitioners (32.9% vs. 22.1%). Physicians with low frequency override rates had higher levels of appropriateness for metformin than the high frequency overriders (P=0.005). CONCLUSION: A small number of providers accounted for a large fraction of overrides, as was the case with a small number of drugs. These data suggest that a focused intervention targeting primarily these providers and medications has the potential to improve medication safety. PMID- 25511565 TI - Medical students and controversial ethical issues: results from the multicenter study SBRAME. AB - BACKGROUND: Medical students(MS) will face ethical issues throughout their lives as doctors. The present study aims to investigate medical students' opinions on controversial ethical issues and factors associated with these opinions. METHODS: SBRAME (Spirituality and Brazilian Medical Education) is a multicenter study involving 12 Brazilian medical schools with 5950 MS. Participants completed a questionnaire that collected information on socio-demographic data, medical schools characteristics, religious beliefs and opinions on controversial ethical issues. Of all MS, 3630 participated in the survey (61.0%). RESULTS: The sample was 53.8% women and the mean age was 22.5 years. In general, most MS have no objections to prescription of birth control (90.8%), adult stem cell use (87.5%), embryonic stem cell use (82.0%) and abortion for genetic reasons (51.2%). Approximately half of students have no objections to human cloning (47.3%), 45.7% to withdrawal of artificial life support, 41.4% to euthanasia and 23.3% to abortion for failed contraception. Socio-demographic data such as age, gender and income had little influence on MS opinions. On the other hand, medical schools characteristics (number of medical students in the university, year of medical school foundation, location of the university and type of university) and religious aspects (religious affiliation, religious attendance, non organizational religiousness and intrinsic religiousness) were highly correlated with their opinions. In general, MS with more supportive opinions on controversial ethical issues were less religious and from non-traditional (newer), urban, public and bigger universities. CONCLUSION: The current study reveals MS have different opinions regarding controversial ethical issues. Noteworthy, these opinions seem to be shaped more by university characteristics and religious beliefs than socio-demographic data. PMID- 25511567 TI - Non-radical resection versus bypass procedure for pancreatic cancer - a consecutive series and systematic review. AB - BACKGROUND: Most survival studies comparing non-radical resections to bypass surgery in patients with pancreatic cancer often do not differentiate between an R1 and R2 resection. The aim of this study was to evaluate whether non-radical R1 and R2 resections have better postoperative outcomes and survival compared to a palliative bypass. METHODS: A single center cohort study was performed analyzing mortality, morbidity and 1-year survival after R1 (tumor cells within 1 mm from the circumferential margin), R2 and bypass surgery in patients with pancreatic cancer. For the systematic review, studies were identified comparing R1 or R2 resections with bypass, in patients with pancreatic cancer. Postoperative outcomes were compared including the cohort study. RESULTS: The cohort study (n=405) showed higher morbidity rates after R1 (n=191) and R2 (n=11) resections compared to bypass (52% and 73% vs. 34%, p < 0.01). In-hospital mortality did not differ (overall 1.7%). 1-year survival rates were 71%, 46% and 32% after R1, R2 resection and bypass (p=0.6 between R2 and bypass). The systematic review identified 8 studies, after including the cohort study 1535 patients were analyzed. Increased morbidity after R1-R2 resection (48%) compared to bypass (30 34%) was found. Median survival was 14-18 months after R1 resection vs. 9-13 months after bypass and 8.5-11.5 months after R2 resection vs. 7.5-10.7 months after bypass. CONCLUSION: An R2 resection should be avoided in patients with pancreatic cancer due to its poor prognosis. Survival benefit after an R1 resection, as compared to bypass surgery, justifies a resection despite the increased morbidity rate. PMID- 25511568 TI - Cytotoxicity of curcumin silica nanoparticle complexes conjugated with hyaluronic acid on colon cancer cells. AB - We report results of our investigations on the cytotoxic efficacy of Organically modified silica nanoparticle (SiNp)-curcumin complex conjugated with hyaluronic acid (HA) (HA-SiNp-cur) and HA free SiNp-cur complex in human colon carcinoma (colo-205) cells. Curcumin was loaded in SiNp and resulting complexes were conjugated with HA, which has a strong affinity for cancer cells expressing CD44. After conjugation with HA, the average size of the SiNp-cur nanoparticles increased from 45 nm to 70 nm, and zeta potential changed to -33 mV from -26 mV. Compared to free curcumin and SiNp-cur, curcumin in HA-SiNp was more stable. The uptake and cytotoxicity of curcumin delivered through HA-SiNp-cur was significantly higher in monolayer and spheroids as compared to free curcumin and HA free SiNp-cur. Concomitantly, HA-SiNp-cur complex treatment resulted in higher inhibition of growth and migration of cells in spheroids. Further, incubation of colo-205 cancer cells with an excess of HA impaired the uptake of HA-SiNp-cur confirming the involvement of receptor mediated endocytosis in the uptake of HA conjugated nanocomplex. Time dependent increase in the fluorescence of curcumin observed in the release media when HA-SiNp-cur was incubated with hyaluronidase suggests involvement of enzyme in release of curcumin from nanoparticle. PMID- 25511566 TI - Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization. AB - Melanocytic lesions originating from the oral mucosa or cutaneous epithelium are common in the general dog population, with up to 100,000 diagnoses each year in the USA. Oral melanoma is the most frequent canine neoplasm of the oral cavity, exhibiting a highly aggressive course. Cutaneous melanocytomas occur frequently, but rarely develop into a malignant form. Despite the differential prognosis, it has been assumed that subtypes of melanocytic lesions represent the same disease. To address the relative paucity of information about their genomic status, molecular cytogenetic analysis was performed on the three recognized subtypes of canine melanocytic lesions. Using array comparative genomic hybridization (aCGH) analysis, highly aberrant distinct copy number status across the tumor genome for both of the malignant melanoma subtypes was revealed. The most frequent aberrations included gain of dog chromosome (CFA) 13 and 17 and loss of CFA 22. Melanocytomas possessed fewer genome wide aberrations, yet showed a recurrent gain of CFA 20q15.3-17. A distinctive copy number profile, evident only in oral melanomas, displayed a sigmoidal pattern of copy number loss followed immediately by a gain, around CFA 30q14. Moreover, when assessed by fluorescence in situ hybridization (FISH), copy number aberrations of targeted genes, such as gain of c-MYC (80 % of cases) and loss of CDKN2A (68 % of cases), were observed. This study suggests that in concordance with what is known for human melanomas, canine melanomas of the oral mucosa and cutaneous epithelium are discrete and initiated by different molecular pathways. PMID- 25511569 TI - The making of might-have-beens: effects of free will belief on counterfactual thinking. AB - Counterfactual thoughts are based on the assumption that one situation could result in multiple possible outcomes. This assumption underlies most theories of free will and contradicts deterministic views that there is only one possible outcome of any situation. Three studies tested the hypothesis that stronger belief in free will would lead to more counterfactual thinking. Experimental manipulations (Studies 1-2) and a measure (Studies 3-4) of belief in free will were linked to increased counterfactual thinking in response to autobiographical (Studies 1, 3, and 4) and hypothetical (Study 2) events. Belief in free will also predicted the kind of counterfactuals generated. Belief in free will was associated with an increase in the generation of self and upward counterfactuals, which have been shown to be particularly useful for learning. These findings fit the view that belief in free will is promoted by societies because it facilitates learning and culturally valued change. PMID- 25511570 TI - Dermoscopic features in fungal melanonychia. AB - BACKGROUND: Data on the dermoscopic features of fungal melanonychia are limited. AIM: To identify the dermoscopic features of fungal melanonychia. METHODS: We reviewed patient files, clinical history and dermoscopic images of all cases with a diagnosis of fungal melanonychia seen at our dermoscopy unit within the past year. RESULTS: In total, 14 cases with 20 involved nails were reviewed. The most common type of melanonychia was melanonychia striata (7/20). Multicoloured pigmentation was observed in 19 of the nails. The main dermoscopic pattern was homogeneous pigmentation; however, black pigmented aggregates, presenting as either coarse granules or pigmented clumps, accompanied this homogeneous pigmentation in 16 lesions. Matt black pigmentation, matt white pigmentation, yellow to brown pigmentation, black reverse triangle (wider at the distal than the proximal end), superficial transverse striation and blurred appearance were the other features. CONCLUSIONS: We have identified a number of dermoscopic features appearing in fungal melanonychia, which should help in diagnosis of this disease. PMID- 25511571 TI - N-terminal pro-B-type natriuretic peptide-ratio predicts mortality after transcatheter aortic valve replacement. AB - OBJECTIVES: We studied the prognostic value of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP)-ratio, which is independent of individual cutoff levels, in predicting mortality in patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Elevated levels of natriuretic peptides are associated with adverse outcomes across a wide spectrum of cardiovascular diseases. However, cutoff values differ according to age, gender, and body weight. METHODS: 244 TAVR patients with preprocedural NT-proBNP levels were analyzed, and the predictive value of NT-proBNP-ratio (measured NT-proBNP/maximal normal NT-proBNP values specific for age and gender) on all-cause-mortality was assessed in a multivariate model. RESULTS: Median NT-proBNP-ratio was 4.2 [IQR 1.8-9.7]. All-cause mortality at 30 days was 3.4% in patients with less than median NT-proBNP-ratio, and 14.0% in patients with more than median NT-proBNP ratio (P=0.02). All-cause mortality at 1 year was 8.5% in patients with less than median NT-proBNP-ratio, and 32.1% in those with more than median NT-proBNP-ratio (P=0.001). Cumulative survival declined with increasing quartiles of NT-proBNP ratio (log rank P=0.001). All patients with a NT-proBNP-ratio below 1.5 survived at 1-year follow-up. In ROC analysis, NT-proBNP-ratio significantly predicted 30 day (AUC=0.72; P=0.002) and 1-year all-cause mortality (AUC=0.72; P<0.001). By multivariate Cox regression analysis, NT-proBNP-ratio, chronic obstructive pulmonary disease, and serum creatinine were the only independent predictors of all-cause mortality. CONCLUSIONS: Elevated NT-proBNP-ratio was associated with increased short- and long-term mortality after TAVR, and independently predicted all-cause mortality. NT-proBNP-ratio should be considered in the risk stratification of patients undergoing TAVR. PMID- 25511573 TI - Vesicoureteral reflux index (VURx): a novel tool to predict primary reflux improvement and resolution in children less than 2 years of age. AB - PURPOSE: Surgical correction of vesicoureteral reflux (VUR) is influenced by recurrent urinary tract infection (UTI) risk and the likelihood of spontaneous resolution. We aimed to identify factors associated with VUR resolution in children less than 2 years of age and to design a simple scoring tool to predict improvement and resolution. MATERIALS AND METHODS: Children less than 2 years old with primary VUR were identified. Patient demographics, voiding cystourethrogram (VCUG) findings and clinical outcomes over time were assessed. Multivariate analysis with time to resolution was performed to identify factors predictive of VUR improvement and resolution. A random forest model was used to confirm the VUR index (VURx) with normalized importance. RESULTS: Two-hundred and twenty-nine children met all inclusion criteria. Mean age at initial VCUG was 0.46+/-0.43 years. Median clinical follow-up was 1.6 years (range 0.5-4.4 years). Children with grade 4-5 reflux, complete ureteral duplication or periureteral diverticula, and filling phase VUR, as well as female gender, had significantly (p<0.01) longer time to improvement or resolution on multivariate survival analysis. VURx 1 to 5-6 had improvement/resolution rates of 89%, 69%, 53%, 16% and 11%, respectively. CONCLUSIONS: Female gender, high-grade VUR, ureteral anomalies, and filling reflux are associated with longer time to improvement and non-resolution. VURx reliably predicts resolution of primary reflux in children less than 2 years of age. PMID- 25511574 TI - Oral submucous fibrosis--a treatment protocol based on clinical study of 100 patients in central India. AB - PURPOSE: Oral submucous fibrosis till date is a very poorly understood and unsatisfactorily treated disease with variable signs and symptoms. In this paper, we have classified the disease in different groups according to the clinical signs, radiological assessment, histopathological confirmation, progress, and severity of disease and proposed a treatment algorithm for effective treatment of the disease in 100 patients. MATERIAL AND METHOD: In our study, we randomly selected 100 patients of oral submucous fibrosis and classified them in to five groups based on clinical symptoms and radiological and histopathological parameters. We have given specific treatment for each group and followed them up for 2 years regularly. RESULTS: We found that almost all patients got symptomatic relief from the disease. Patient's interincisal mouth opening increased significantly. All patients can take regular diet. Progressive malignant transformation can be detected earlier to avoid future morbidity and mortality. CONCLUSION: Oral submucous fibrosis (OSMF) scoring index is very effective to decide the severity of disease and progress. Based on this scoring and grouping we can give definite prompt treatment to the patients with satisfactory results. Such a way this proposed scoring and staging can play major role in controlling and treating this widespread global disease. PMID- 25511575 TI - Clinical trial simulation to evaluate population pharmacokinetics and food effect: capturing abiraterone and nilotinib exposures. AB - The objectives of this study were to determine (1) the accuracy with which individual patient level exposure can be determined and (2) whether a known food effect can be identified in a trial simulation of a typical population pharmacokinetic trial. Clinical trial simulations were undertaken using NONMEM VII to assess a typical oncology pharmacokinetic trial design. Nine virtual trials for each compound were performed for combinations of different levels of between-occasion variability, number of patients in the trial, and magnitude of a food covariate on oral clearance. Less than 5% and 20% bias and precision were obtained in individual clearance estimated for both abiraterone and nilotinib using this design. This design resulted in biased and imprecise population clearance estimates for abiraterone. The between-occasion variability in most trials was captured with less than 30% of percent bias and precision. The food effect was detectable as a statistically significant covariate on oral clearance for abiraterone and nilotinib with percent bias and precision of the food covariate less than 20%. These results demonstrate that clinical trial simulation can be used to explore the ability of specific trial designs to evaluate the power to identify individual and population level exposures, covariate, and variability effects. PMID- 25511576 TI - Effect of high-dose clopidogrel according to CYP2C19*2 genotype in patients undergoing percutaneous coronary intervention- a systematic review and meta analysis. AB - INTRODUCTION: High-dose clopidogrel has been recommended to overcome clopidogrel non-responsiveness in patients undergoing percutaneous coronary intervention (PCI), especially those with CYP2C19 loss-of-function genotypes. However, there is controversy over the pharmacodynamics and clinical effects of the strategy. This meta-analysis was conducted to evaluate the antiplatelet effects of high dose clopidogrel according to CYP2C19*2 alleles in patients undergoing PCI. METHODS: Based on PubMed, Cochrane, and EMBASE prior to June 1st, 2014, a systematic review and meta-analysis was conducted to evaluate the antiplatelet effects of high-dose clopidogrel on platelet reactivity and clinical outcomes in PCI treated patients according to CYP2C19*2 genotypes. The reported outcomes including on-treatment platelet reactivity (OTPR), high on-treatment platelet reactivity (HTPR), major adverse cardiovascular events (MACE), stent thrombosis and composite cardiovascular events. RESULTS: Nineteen studies involving 10,960 patients were included. After high-dose clopidogrel administration (600/900 mg loading dose and/or 150 mg/day maintenance dose), compared with non-carriers, carriers of CYP2C19*2 genotype had significantly increased OTPR (SMD for VASP assay: 0.69, 95% CI: 0.48-0.90, p = 4 * 10(-4); for VerifyNow P2Y12 assay: 0.70, 95% CI: 0.54-0.85, p < 10(-5); for LTA assay:0.58, 95% CI: 0.48-0.69, p = 4 * 10( 4)). The incidence rate of HTPR was higher in CYP2C19*2 carriers after high-dose clopidogrel treatment (RR: 1.21, 95% CI:1.05-1.39, p = 0.008 for cutoff PRI > 50% by VASP assay; RR: 1.69, 95% CI: 1.44-1.98, p < 1 * 10(-4) for cutoff PRU > 230 by VerifyNow P2Y12 assay). As for clinical outcomes, CYP2C19*2 was associated with higher risk for MACE (RR: 1.68, 95% CI: 1.19- 2.37, p = 0.003), stent thrombosis (RR: 1.75, 95% CI: 1.31-2.34, p = 0.0001), as well as composite cardiovascular events (RR: 1.82, 95% CI: 1.42- 2.34, p < 10(-5)) after treated by high-dose clopidogrel. CONCLUSION: High-dose clopidogrel could not overcome the variability of clopidogrel antiplatelet effects between the CYP2C19 *2 carriers and non-carriers in patients treated with PCI. PMID- 25511577 TI - Time trends in pulmonary embolism mortality in France, 2000-2010. AB - BACKGROUND: Pulmonary Embolism (PE) is a potentially fatal complication of venous thrombosis. Recent and comprehensive estimates of PE incidence and mortality are scarce. Moreover, while contemporary mortality trends of PE would enable the evaluation of prevention and quality of care, such data are lacking. The aim of this study was to provide nationwide estimations of PE mortality and time trends in France between 2000 and 2010. METHODS: Mortality data were obtained from the French Epidemiology Center on medical causes of death. Mortality rates were calculated with PE as an underlying or one of multiple causes of death. The annual percentage changes were assessed using a Poisson regression model. Age standardized PE mortality rates were also assessed. RESULTS: In 2010, the overall age-adjusted PE mortality rate was 21.0 per 100000. This rate was 30% higher in men than in women and decreased by 3% per year between 2000 and 2010. Over this period, PE mortality declined in men and women over 55 years but only slightly decreased in patients younger than 55. Cancer, obesity, osteopathies and complications of surgery were often coded as the underlying causes of death when PE was an associated cause of death recorded on certificate. DISCUSSION: This study is the first to provide a contemporary and exhaustive nationwide estimation of PE mortality and time trends in France. The observed decrease in PE mortality between 2000 and 2010 is encouraging, but further efforts in prevention are needed to ensure that this reduction is widespread in all age groups. PMID- 25511578 TI - Annexin A5 haplotypes in the antiphospholipid syndrome. PMID- 25511579 TI - Fibrinogen levels in the late stage of twin pregnancy. AB - INTRODUCTION: Twin pregnancy is a risk factor of complications, such as pregnancy induced hypertension, venous thromboembolism, and postpartum hemorrhage, the pathogenesis of which may involve aberrations of the coagulation-fibrinolysis system. MATERIALS AND METHODS: Fibrinogen data for 129 and 1202 blood specimens from 84 and 902 women with twin and singleton pregnancies, respectively, at gestational week (GW)>=32 were analyzed retrospectively. None of the 986 women developed complications in which blood fibrinogen levels may be altered. Thirty six and 288 women with twin and singleton pregnancies were examined longitudinally, respectively. RESULTS: The fibrinogen levels of 403+/-63 and 403+/-77 mg/dL at GW 32-33 and 34-35, respectively, decreased significantly to 366+/-57 mg/dL at GW 36-37 in women with twins, while corresponding levels (422+/ 79, 420+/-65, and 415+/-64, respectively) and that at GW>=38 (408+/-60 mg/dL) did not change significantly in women with singleton pregnancies. The fibrinogen levels determined within 3 weeks before delivery were consistently and significantly lower in women with twin than singleton pregnancies. The fibrinogen levels were significantly inversely correlated with GW in women with twins (R= 0.36, P=0.002), but not in those with singleton pregnancies. CONCLUSIONS: The fibrinogen level of twin pregnancy decreases significantly and is significantly lower than that in singleton pregnancy in the last few weeks of pregnancy. PMID- 25511580 TI - Effectiveness and safety of different duration of thromboprophylaxis in 16,865 hip replacement patients--a real-word, prospective observational study. AB - INTRODUCTION: Clinical trials have provided evidence about efficacy and safety of extended thromboprophylaxis among total hip replacement (THR) patients. There is a lack of evidence on effectiveness and safety of extended treatment in unselected patients from routine clinical practice. We examined the effectiveness and safety of short (1-6 days) and standard (7-27 days) compared with extended (>=28 days) thromboprophylaxis using population-based design. MATERIAL AND METHODS: Among all primary THR procedures performed in Denmark from 2010 through 2012 (n=16,865), we calculated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) for risk of symptomatic venous thromboembolism (VTE) and major bleeding, in addition to net clinical benefit, defined as the number of VTE avoided minus the number of excess bleeding events occurring among patients prescribed short-term and standard versus extended treatment. RESULTS: The 90-day risks of VTE were 1.1% (short), 1.4% (standard), and 1.0% (extended), yielding aHRs of 0.83 (95% CI: 0.52-1.31) and 0.82 (95% CI: 0.50-1.33) for short and standard versus extended treatment. The risk of major bleeding was 1.1% (short), 1.0% (standard), and 0.7% (extended), resulting in aHRs of 1.64 (95% CI: 0.83 3.21) and 1.24 (95%CI: 0.61-2.51) for short and standard versus extended thromboprophylaxis. Direct comparison between benefits and harms using net clinical benefit analyses did not favor any of the three treatment durations. The same results were found for VTE or death. CONCLUSIONS: In a real-word observational cohort of unselected THR patients, we observed no difference in the risks of symptomatic VTE, VTE/ death or bleeding with respect to thromboprophylaxis duration. PMID- 25511581 TI - A study of the characteristics of karst groundwater circulation based on multi isotope approach in the Liulin spring area, North China. AB - Due to the significance of karst groundwater for water supply in arid and semi arid regions, the characteristics of the karst groundwater flow system in the Liulin spring area, North China, are analysed through isotopic tracing (delta(2)H, delta(18)O, delta(13)C and (3)H) and dating approaches ((14)C). The results show that the primary recharge source of karst groundwater is precipitation. Evaporation during dropping and infiltration of rainfall results in a certain offset in the values of delta(2)H and delta(18)O in groundwater samples from the global meteoric water line (GMWL) and the local meteoric water line (LMWL). The altitudes of the recharge region calculated by delta(18)O range from 1280 to 2020 m above sea level, which is consistent with the altitudes of the recharge area. The Liulin spring groups could be regarded as the mixing of groundwater with long and short flow paths at a ratio of 4:1. In the upgradient of the Liulin spring, the groundwater represents modern groundwater features and its [Formula: see text] is mainly derived from dissolution of soil CO(2), while in the downgradient of the Liulin spring, the (14)C age of dissolved inorganic carbon (DIC) in groundwater shows an apparent increase and [Formula: see text] is mainly derived from the dissolution of carbonate rocks. The mean flow rate calculated by (14)C ages of DIC between IS10 and IS12 is 1.23 m/year. PMID- 25511582 TI - Identification of promising strategies to sustain improvements in hospital practice: a qualitative case study. AB - BACKGROUND: A quality improvement collaborative is an intensive project involving a combination of implementation strategies applied in a limited "breakthrough" time window. After an implementation project, it is generally difficult to sustain its success. In the current study, sustainability was described as maintaining an implemented innovation and its benefits over a longer period of time after the implementation project has ended. The aim of the study was to explore potentially promising strategies for sustaining the Enhanced Recovery After Surgery (ERAS) programme in colonic surgery as perceived by professionals, three to six years after the hospital had successfully finished a quality improvement collaborative. METHODS: A qualitative case study was performed to identify promising strategies to sustain key outcome variables related to the ERAS programme in terms of adherence, time needed for functional recovery and hospital length of stay (LOS), as achieved immediately after implementation. Ten hospitals were selected which had successfully implemented the ERAS programme in colonic surgery (2006-2009), with success defined as a median LOS of 6 days or less and protocol adherence rates above 70%. Fourteen semi-structured interviews were held with eighteen key participants of the care process three to six years after implementation, starting with the project leader in every hospital. The interviews started by confronting them with the level of sustained implementation results. A direct content analysis with an inductive coding approach was used to identify promising strategies. The mean duration of the interviews was 37 minutes (min 26 minutes - max 51 minutes). RESULTS: The current study revealed strategies targeting professionals and the organisation. They comprised internal audit and feedback on outcomes, small-scale educational booster meetings, reminders, changing the physical structure of the organisation, changing the care process, making work agreements and delegating responsibility, and involving a coordinator. A multifaceted self-driven promising strategy was applied in most hospitals, and in most hospitals promising strategies were suggested to sustain the ERAS programme. CONCLUSIONS: Joining a quality improvement collaborative may not be enough to achieve long-term normalisation of transformed care, and additional investments may be needed. The findings suggest that certain post implementation strategies are valuable in sustaining implementation successes achieved after joining a quality improvement collaborative. PMID- 25511583 TI - Novel stable hard transparent conductors in TiO2-TiC system: design materials from scratch. AB - Two new ternary compounds in the TiO2-TiC system, Ti5C2O6 and Ti3C2O2, are reported for the first time based on ab initio evolutionary algorithm. Ti5C2O6 has a tube-structure in which sp(1) hybridized carbon chains run through the lattice along the b-axis; while in the Ti3C2O2 lattice, double TiO6 polyhedral are separated by the non-coplanar sp(2) hybridized hexagon graphite layers along the c-axis, forming a sandwich-like structure. At ambient conditions, the two compounds are found to be mechanically and dynamically stable and intrinsic transparent conductors with high hardness (about twice harder than the conventional transparent conducting oxides). These mechanical, electronic, and optical properties make Ti5C2O6 and Ti3C2O2 ternary compounds be promising robust, hard, transparent, and conductive materials. PMID- 25511585 TI - Ring-opening homo- and co-polymerization of lactides and epsilon-caprolactone by salalen aluminum complexes. AB - Aluminum complexes of non-chiral-salalen ligands were investigated in the catalysis of ring-opening polymerization (ROP) of lactide and epsilon caprolactone and in their copolymerization. The aluminum-salalen complexes were found to polymerize all varieties of lactide, namely: l-, d-, rac- and meso lactide, and showed moderate productivities. rac-LA gave rise to isotactic polylactides (with Pm up to 72%), while meso-LA gave rise to heterotactic polylactides (with a Pm of 79%). An experiment was designed for distinguishing between chain-end control and enantiomorphic-site control combined with polymeryl exchange for the isotactic stereoblock microstructure observed for the PLA produced from rac-LA; it gave strong evidence for polymeryl exchange between propagating species. Finally, this class of catalysts promoted the copolymerization of epsilon-caprolactone and lactides. In particular, compound allowed controlled random copolymerization of epsilon-caprolactone and l-lactide. PMID- 25511584 TI - Regulation of chondroitin-4-sulfotransferase (CHST11) expression by opposing effects of arylsulfatase B on BMP4 and Wnt9A. AB - In this report, the gene regulatory mechanism by which decline in arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase) reduces CHST11 (chondroitin-4 sulfotransferase; C4ST) mRNA expression in human colonic epithelial cells and in colonic epithelium of ARSB-deficient mice is presented. ARSB controls the degradation of chondroitin 4-sulfate (C4S) by removing the 4-sulfate group at the non-reducing end of the C4S chain, but has not previously been shown to affect C4S biosynthesis. The decline in CHST11 expression following ARSB reduction is attributable to effects of ARSB on bone morphogenetic protein (BMP)4, since BMP4 expression and secretion declined when ARSB was silenced. Inhibition of BMP4 by neutralizing antibody also reduced CHST11 expression. When C4S was more sulfated due to decline in ARSB, more BMP4 was sequestered by C4S in the cell membrane, and CHST11 expression declined. Exogenous recombinant BMP4, acting through a phospho-Smad3 binding site in the CHST11 promoter, increased the mRNA expression of CHST11. In contrast to the decline in BMP4 that followed decline in ARSB, Wnt9A mRNA expression was previously shown to increase when ARSB was silenced and C4S was more highly sulfated. Galectin-3 bound less to the more highly sulfated C4S, leading to increased nuclear translocation and enhanced galectin-3 interaction with Sp1 in the Wnt9A promoter. Silencing Wnt9A increased the expression of CHST11 in the colonic epithelial cells, and chromatin immunoprecipitation assay demonstrated enhancing effects of Wnt9A siRNA and exogenous BMP4 on the CHST11 promoter through the pSmad3 binding site. These findings suggest that cellular processes mediated by differential effects of Wnt9A and BMP4 can result from opposing effects on CHST11 expression. PMID- 25511586 TI - Control and role of pH in peptide-lipid interactions in oriented membrane samples. AB - To understand the molecular mechanisms of amphiphilic membrane-active peptides, one needs to study their interactions with lipid bilayers under ambient conditions. However, it is difficult to control the pH of the sample in biophysical experiments that make use of mechanically aligned multilamellar membrane stacks on solid supports. HPLC-purified peptides tend to be acidic and can change the pH in the sample significantly. Here, we have systematically studied the influence of pH on the lipid interactions of the antimicrobial peptide PGLa embedded in oriented DMPC/DMPG bilayers. Using solid-state NMR (31P, 2H, 19F), both the lipid and peptide components were characterized independently, though in the same oriented samples under typical conditions of maximum hydration. The observed changes in lipid polymorphism were supported by DSC on multilamellar liposome suspensions. On this basis, we can present an optimized sample preparation protocol and discuss the challenges of performing solid-state NMR experiments under controlled pH. DMPC/DMPG bilayers show a significant up field shift and broadening of the main lipid phase transition temperature when lowering the pH from 10.0 to 2.6. Both, strongly acidic and basic pH, cause a significant degree of lipid hydrolysis, which is exacerbated by the presence of PGLa. The characteristic re-alignment of PGLa from a surface-bound to a tilted state is not affected between pH of 7 to 4 in fluid bilayers. On the other hand, in gel-phase bilayers the peptide remains isotropically mobile under acidic conditions, displays various co-existing orientational states at pH7, and adopts an unknown structural state at basic pH. PMID- 25511587 TI - Detection of liposomal cholesterol and monophosphoryl lipid A by QS-21 saponin and Limulus polyphemus amebocyte lysate. AB - Liposomes containing cholesterol (Chol) have long been used as an important membrane system for modeling the complex interactions of Chol with adjacent phospholipids or other lipids in a membrane environment. In this study we utilize a probe composed of QS-21, a saponin molecule that recognizes liposomal Chol and causes hemolysis of erythrocytes. The interaction of QS-21 with liposomal Chol results in a stable formulation which, after injection into the tissues of an animal, lacks toxic effects of QS-21 on neighboring cells that contain Chol, such as erythrocytes. Here we have used liposomes containing different saturated phospholipid fatty acyl groups and Chol, with or without monophosphoryl lipid A (MPLA), as model membranes. QS-21 is then employed as a probe to study the interactions of liposomal lipids on the visibility of membrane Chol. We demonstrate that changes either in the mole fraction of Chol in liposomes, or with different chain lengths of phospholipid fatty acyl groups, can have a substantial impact on the detection of Chol by the QS-21. We further show that liposomal MPLA can partially inhibit detection of the liposomal Chol by QS-21. The Limulus amebocyte lysate assay is used for binding to and detection of MPLA. Previous work has demonstrated that sequestration of MPLA into the liposomal lipid bilayer can block detection by the Limulus assay, but the binding site on the MPLA to which the Limulus protein binds is unknown. Changes in liposomal Chol concentration and phospholipid fatty acyl chain length influenced the detection of the liposome-embedded MPLA. PMID- 25511588 TI - [Diagnostic value of interleukin-27 in tuberculous pleural effusion]. AB - OBJECTIVE: To explore the diagnostic value of interleukin-27 (IL-27) in tuberculous pleural effusion. METHODS: A total of 76 patients of pleural effusion treated at Shandong Provincial Hospital from March 2013 to February 2014 in accordance with the natures of effusion fluid were divided into: (1) Tuberculosis group of tuberculous pleural effusion (n = 40), including 22 males and 18 females; aged 19 to 73 years; (2) Malignant group of malignant pleural effusion (n = 36), including 20 males and 16 females; aged 33 to 78 years old; including lung cancer (n = 28), lymphoma (n = 3), esophageal (n = 1) and uncertain primary tumor site (n = 4). The effusion and serum levels of IL-27 were detected by enzyme-linked immunosorbent assay (ELISA) and the results analyzed. And the curve of receiver operating characteristic (ROC) was employed to determine the diagnostic value of IL-27 in tuberculous pleural effusion. RESULTS: The level of IL-27 was (1 402 +/- 321) ng/L in tuberculous pleural effusion and it was significantly higher than those in malignant pleural effusion (556 +/- 133) ng/L and sera (499 +/- 88) ng/L (both P < 0.05). According to the ROC curve, the cut off value of IL-27 was 838 ng/L in diagnosing tuberculous pleural effusion. And the rates of diagnostic sensitivity, specificity and accuracy of IL-27 were 95.0%, 97.2% and 96.1% respectively. CONCLUSIONS: Detection of pleural effusion IL-27 concentration is of great importance in the diagnosis of tuberculous pleural effusion. And it is worthy of wider clinical promotion. PMID- 25511589 TI - [Correlation of alpha fetoprotein with the prognosis of hepatocellular carcinoma after hepatectomy in an ethnic Chinese population]. AB - OBJECTIVE: To explore the correlation between alpha fetoprotein (AFP) and the prognosis of hepatocellular carcinoma after hepatectomy in an ethnic Chinese population. METHODS: This study retrospectively analyzed the surgical outcomes of hepatocellular carcinoma (HCC) in 779 patients undergoing hepatic resection between June 1999 and March 2010 at our hospital. The postoperative prognostic factors were assessed by univariate Kaplan-Meier analysis and a multivariate Cox proportional hazard model. RESULTS: The cut-off value of AFP was 18.98 ug/L by receiver operating characteristic (ROC) curve statistics and the sensitivity and specificity rates were 54.6% and 82.0% respectively. The overall survival (OS) rate of AFP negative group (AFP < 20 ug/L) for 1, 3 and 5-year was 94.4%, 77.3% and 58.9% while the OS rate of AFP positive group (AFP >= 20 ug/L) for 1, 3 and 5 year 90.6%, 64.5% and 49.6%. According to univariate analysis, better prognosis for OS was associated with asymptomatic presentation, no ascites, small tumor, single lesion, serological AFP negativity, serological alkaline phosphatase (ALP) negativity, high-grade histological differentiation, no carcinoma cell embolus, no/mild cirrhosis, Child-Pugh class A, no transfusion, no regional lymph node metastasis, no major vascular invasion, no direct invasion of adjacent organs or with perforation of visceral peritoneum. In multivariate analysis, asymptomatic presentation, young age, single lesion, Alpha-Fetoprotein (AFP) negative expression, serological alkaline phosphatase (ALP) negative expression, Child Pugh class A, no carcinoma cell embolus, serological no regional lymph node metastasis, no major vascular invasion, no direct invasion of adjacent organs, no perforation of visceral peritoneum and non-transfusion were independent factors for longer OS. Then all patients were classified into different groups by various OS time of 1, 2, 3, 5-year respectively. The statistical results showed that patients with a low expression of serum AFP had better prognosis. CONCLUSION: Lower serum level of AFP indicates better prognosis while higher AFP level is directly correlated with more aggressive biological tumor activities, poor background of liver and poor prognosis. PMID- 25511590 TI - [Esophageal motility characteristics of refractory heartburn: a study based on high resolution manometry and 24 hour pH-impedance monitoring]. AB - OBJECTIVE: To analyze the esophageal motility characteristics of refractory heartburn with different reflux patterns and preliminarily clarify the roles of esophageal disorder in refractory heartburn. METHODS: A total of 176 refractory heartburn patients were enrolled from 2009 to 2013. After gastroscopy and 24 hour pH-impedance monitoring, they were divided into 4 groups of reflux esophagitis (RE, n = 29), non-erosive reflux disease with acid reflux (NERD-acid, n = 51), NERD with weakly acidic reflux (NERD-weakly acid, n = 51) and non-reflux associated heartburn (n = 45). All subjects undertake high resolution manometry test and their esophageal motility functions were analyzed by the Chicago classification criteria 2012. RESULTS: Among them, 60.23% (106/176) patients presented esophageal motility disorders. And 42.61% (75/176) fulfilled the criteria of weak peristalsis, 7.39% (13/176) distal esophageal spasm, 4.55% (8/176) rapid contraction, 3.98% (7/176) EGJ outflow obstruction, 1.14% (2/176) hiatus hernia and 1 Jackhammer esophagus. The detection rates of esophageal motility disorder were similar among 4 groups and weak peristalsis was the most common disorder in all groups (41.38% in RE, 37.25% in NERD-acid patients, 54.90% in NERD-weakly acid and 35.56% in non-reflux associated heartburn patients). However, hypertensive motility disorders in non-reflux associated heartburn group (31.11%, 14/45) were more than GERD subgroups (11.45%, 15/131) (P < 0.05) . The relax ratio of low esophagus sphincter (LES) in GERD subgroups were higher than that in non-reflux associated heartburn patients. And the relax ratio of NERD weakly acid was significantly higher than that in non-reflux associated heartburn patients (65% (50%-80%) vs 58% (42%-67%) , P < 0.05). The integrated relaxation pressure in GERD subgroups were lower than that of non-reflux associated heartburn patients without significant differences (P > 0.05). CONCLUSIONS: Esophageal weak peristalsis is one of the most common motility disorders in refractory heartburn patients, and esophageal hypertensive motility disorders are common in non-reflux associated heartburn patients. Esophageal manometry is necessary for the diagnosis and treatment of refractory heartburn. PMID- 25511591 TI - [Levels and clinical significances of interleukin 11 in breast tissue and serum of bone metastasis of breast cancer]. AB - OBJECTIVE: To explore the expression level and clinical significance of interleukin-11 (IL-11) in the tissue and serum samples of in breast cancer bone metastasis patients. METHODS: Peripheral blood samples were collected from 180 breast cancer patients at Tianjin Medical University Cancer Hospital from May 2007 to January 2009 and confirmed by histological pathology. According to the occurrence of bone metastases, they were divided into 2 groups of bone metastasis (MBC-B) and without bone metastasis (PBC) (n = 90 each). Another 20 healthy controls were selected from the same hospital during the same period after excluding a history of endocrine and metabolic diseases and other chronic diseases. Peripheral blood samples were collected to detect the expression level of IL-11 by enzyme-linked immunosorbent assay. At the same time, tumor tissue samples were collected from 40 breast cancer patients with bone metastasis and 40 breast cancer patients without bone metastasis. And their complete archive data were available. The expression levels of IL-11 in tumor tissue samples were detected by tissue chip and immunohistochemistry. The IL-11 mRNA expression levels of different breast tissue samples were analyzed by fluorescent quantitative reverse transcription-polymerase chain reaction (RT-PCR). Independent prognostic indicators of postoperative patient survival were screened and layered by the median level of serum concentration. Log-rank test was employed for survival analysis. RESULTS: The serum concentrations of IL-11 in MBC B, PBC and healthy control groups were (242.9 +/- 56.3), (85.9 +/- 35.7) and (66.4 +/- 20.3) ug/L. And it had statistically significant difference (F = 43.532, P < 0.05); MBC-B group was significantly higher than PBC group (t = 40.44, P < 0.001). High expression rates of IL-11 were 57.5% and 14.3% in MBC-B and PBC groups. MBC-B group was significantly higher than PBC group (chi2 = 36.626, P < 0.01). The survival time of breast cancer patients with bone metastases and high levels of IL-11 was 25.2 months and it was shorter than those with bone metastases and low levels of IL-11 (44.6 months). The difference was statistically significant (chi2 = 9.550, P < 0.01). CONCLUSION: The expression level of IL-11 is associated with the occurrence of bone metastasis in breast cancer. And breast cancer with a high expression level of IL-11 may be more susceptible to bone metastases. PMID- 25511592 TI - [Risk factors for non-sentinel lymph node metastasis in patients after neoadjuvant chemotherapy]. AB - OBJECTIVE: To evaluate the risk factors for non-sentinel lymph node (NSLN) metastasis in patients after neoadjuvant chemotherapy (NCT) so as to develop a new predictive model. METHODS: A total of 512 consecutive patients with metastasis in sentinel lymph node (SLN) on neoadjuvant chemotherapy between August 2005 and March 2013 were recruited to evaluate the factors affecting the involvement of NSLN. Logistic regression analysis was performed to construct a predictive model. RESULTS: There were 115 (22.4%) patients with metastasis in NSLN after axillary lymph node dissection. Univariate analysis showed that tumor size, number of positive SLN, hormone receptor (HR), micrometastasis and clinical response of primary tumor after NCT were associated with the involvement of NSLN (P < 0.05). Multivariate analysis indicated that tumor size, number of positive SLN, HR, micrometastasis and clinical response of primary tumor after NCT were significant independent predictors for NSLN metastasis. Area under the curve was 0.779. CONCLUSION: Tumor size, number of positive SLN, HR, micrometastasis and clinical response of primary tumor after NCT were significant independent predictors for NSLN metastasis in patients after NCT. The new model is to be further validated. PMID- 25511593 TI - [Application of continuous renal replacement therapy in the treatment of myonephropathic metabolic syndrome caused by acute lower extremity ischemia]. AB - OBJECTIVE: To summarize the experiences of using continuous renal replacement therapy in the treatment of myonephropathic metabolic syndrome caused by acute lower limb ischemia. METHODS: Retrospective study of patients diagnosed acute lower limb ischemia with surgical treatment between January 2008 and December 2013, among which 22 patients with myonephropathic metabolic syndrome received continuous renal replacement therapy. Summarize the change tendency of myoglobin, urine volume and serum creatinine levels during treatment and analysis the condition changes and prognosis of the patients. RESULTS: Among them, 2 patients were amputated and two died after surgery. The major causes of death were acute renal failure, metabolic acidosis, circulation failure and liver failure, etc. Myoglobin was significantly higher at Day 1 after surgery than that was before surgery (P < 0.05). Urine volume was significantly lower at Day 1 after surgery than that on the day of surgery (P < 0.05). CK was significantly lower at Day 2 after surgery than the day before (P < 0.05). Hemoglobin was significantly lower at Day 1 after surgery than that before surgery (P < 0.05). Serum creatinine levels remained steady. CONCLUSION: In patients of acute lower limb ischemia with myonephropathic metabolic syndrome, early targeted continuous renal replacement therapy may decrease the serum concentrations of myoglobin and CK, improve urine volume, maintain homeostasis, prevent renal function deterioration and improve the prognosis of patients. And it is highly recommended. PMID- 25511594 TI - [Efficacy of tigecycline in treating severe infections of patients with hematological diseases]. AB - OBJECTIVE: To evaluate the efficacy and safety of tigecycline in treating secondary infections of patients with hematological diseases. METHODS: A total of 85 cases of hematological patients with secondary infections were classified into empirical and targeted therapy groups. Empirical therapy group was composed of patients receiving tigecycline as an alternative due to ineffective anti infection treatment for 3-5 days in the absence of microbiological evidence while those taking tigecycline based on microbiological evidence belonged to targeted therapy group. Dosage regimen of tigecycline: loading dose 100 mg, 50 mg every 12 hours as maintenance therapy for 2-4 weeks. RESULTS: Among them, except for 11 cases of bloodstream infections and 2 cases of fever for unknown reasons, the most common site for infection was lower respiratory tract. Among 45 isolated bacterial strains, Stenotrophomonas maltophilia (40%) was the most commonly seen while extended spectrum beta-lactamases (ESBLS)+ multidrug resistant gram negative bacilli 15.6%. Among 5 bacterial strains, there were 3 methicillin resistant Staphylococcus aureus+golden staphylococci strains and 2 excrement enterococci. The total effective rate of tigecycline was 72.9%. And the bacterial clearance rates of acinetobacter baumannii, ESBLS+ gram-negative bacillus and stenotrophomonas maltophilia were 85%, 70% and 55% respectively. The effect of tigecycline was equivalent for two groups. Pneumonia patients obtained an effective rate of 71%, compared to those with bloodstream infections (54.5%). For patients whose absolute neutrophil counts were less than 0.2 * 109/L, the effective rate decreased obviously (45% vs 81.5%, P = 0.003). Adverse reaction was mild due to mostly gastrointestinal symptoms. CONCLUSION: Tigecycline is a new treatment choice in treating secondary multidrug resistant infections of patients with hematological diseases. Empirical therapy of tigecycline may improve the therapeutic efficacy of patients non-responding favorably to conventional anti-infectives. PMID- 25511596 TI - [Sensitivity and specificity of noninvasive prenatal fetal RhD genotesting: a meta-analysis]. AB - OBJECTIVE: To explore the sensitivity, specificity and clinical validity of fetal Rh genotyping from maternal blood. METHODS: A comprehensive literature search of PubMed, Embase and Web of Science was performed for describing fetal RhD determination from maternal blood. The inclusion criteria were established based on the validity criteria for diagnostic research. And the eligible entries were collected and analyzed with MetaDisc4.0. RESULTS: This meta-analysis included 55 studies with a total of 17 138 samples. The random-effect model was used for analysis because of heterogeneity. The pooled sensitivity and specificity were 98.5% and 97.3% respectively. The SROC curve was plotted and the area under the curve (AUC) calculated (AUC = 0.994). The subgroup and sensitivity analyses were performed. The sensitivity of 25 studies with samples<100 (94.6%) was significantly lower than those of 19 studies with samples 100-300 (98.5%) and 11 studies with samples>300 (99.0%) (chi2 = 36.800, 106.062, P < 0.05). The sensitivity of 19 studies with samples 100-300 (98.5%) was not different from that of 11 studies with samples >300 (99.0%)( chi2 = 3.068, P > 0.05). CONCLUSIONS: Noninvasive prenatal diagnosis of fetal RhD status from maternal blood represents a significant achievement in the application of research with high sensitivity and specificity. It may be applied for screening testing of all RhD- negative pregnant women. PMID- 25511595 TI - [A systemic review of low intensity anticoagulation therapy for Chinese population with heart valve replacement]. AB - OBJECTIVE: To investigate the safety and efficacy of low intensity anticogulation therapy for chinese population underwent heart valve replacemnt. METHODS: From January 1999 to October 2010, the literatures concering anticoagulation therapy for chinese population with heart valve replacement were researched in following databases: CBM, CNKI, VIP, Pubmed as well as cochrane library. Screening and quality evaluation was conducted according to the inclusion and exclusion criteria. Meta-analysis of control studies and descriptive analysis of descriptive studies were conducted. RESULTS: Total 61 articles were reviewed, including 4 control studies and 57 descriptive studies. Both Meta analysis and descriptive analysis results showed also that the rates of total anticoagulation related complications as well as bleeding events were significantly decreased in patients receiving low intensity anticoagulation therapy in compared with classical intensity strategy (RR = -0.06, 95%CI: -0.08--0.03, P < 0.001;RR = 0.06 , 95%CI:-0.08-0.04, P < 0.001), while no significant differeces were noted as for risk of thrmoboembolic events among two different intensity groups (RR = 0.01, 95%CI:-0.01-0.03, P > 0.05). CONCLUSIONS: Low intensity anticoagulation therapy (INR <= 2.5) could effectively miminze the anticoagulation-related hemorrhage and mortality rates and while without increasing the rates of thrmoboembolic event. This therapy was safe, effective and suitable for the coagulation characteristics of Chinese population. PMID- 25511597 TI - [Clinical significance of CIP2A expression in bladder cancer]. AB - OBJECTIVE: To explore the expression of cancerous inhibitor of PP2A (CIP2A) and evaluate its role in bladder cancer. METHODS: RT-PCR was used to detect the expression of CIP2A mRNA from 38 cases of patients with bladder cancer and 12 cases of normal bladder tissue. The CIP2A protein expression levels in 99 cases of patients with bladder cancer and 12 cases of normal tissue was detected by immunohistochemical staining . And the serum contents of CIP2A protein of 38 patients with bladder cancer and 40 normal controls were detected by ELISA. RESULTS: The expression of CIP2A mRNA was detected in 29/38 cases (76.32%) of bladder cancer. And there was no expression in normal tissue (P < 0.05). The positive rate of CIP2A protein was 63.64% in 99 cases of bladder cancer tissues and no expression detected in normal tissues(P < 0.05). ELISA results showed that the serum content of CIP2A in patients with bladder cancer was significantly higher than that in normal controls (median:0.015 2 vs 0.001 8 ng/L, P < 0.05). CONCLUSIONS: The tissue and serum expressions of CIP2A in patients with bladder cancer are higher than those in normal controls. And CIP2A may be used as an indicator of the biological behavior of bladder cancer. PMID- 25511598 TI - [Clinical characteristics and analysis of mass spectrometric data in patients with ornithine transcarbamylase deficiency]. AB - OBJECTIVE: To explore the clinical manifestations and biochemical characteristics of patients with ornithine transcarbamylase deficiency (OTCD) so as to increase the clinician awareness for this disease. METHODS: The clinical manifestations, blood ammonia levels, citrulline levels, urinary orotic acid and uracil levels were analyzed for 40 patients with OTCD from 2005 to 2013. And comparisons were made with 25 healthy children. RESULTS: Among them, the median age of onset was 1.4 years (3 days-29 years). The major clinical manifestations were feeding difficulties, persistent vomiting, convulsions, unconsciousness and hyperammonemia, etc. The blood levels of citrulline in these patients were significantly lower than those of the control group (6.35 (1.84-21.11) vs 13.65 (10.23-24.52) umol/L, P < 0.05) . The urinary levels of orotic acid and uracil in these patients were significantly higher than those in the control group (167.77 (1.21-1 650.45) vs 0.25 (0-2.32) mmol/molCr, 52.67 (3.50-338.64) vs 0.69 (0-2.87) mmol/molCr, P < 0.05) . CONCLUSION: For patients with hyperammonemia, the decreased levels of citrulline in blood tested by tandem mass spectrometry and increased orotic acid and uracil in urine on gas chromatography-mass spectrometry may aid the diagnosis OTCD. PMID- 25511599 TI - [Renal artery computed tomography angiography for the application of severe bleeding after PCNL]. AB - OBJECTIVE: To evaluate the clinical values of computed tomography angiography (CTA) for severe hemorrhage after percutaneous nephrolithotomy (PCNL). METHODS: A total of 50 patients with bleeding after PCNL were enrolled. All patients underwent renal artery CTA. There were 34 males and 16 females with an average age of 45.7 years. Left (n = 31) and right (n = 19) sides were affected. The criteria of severe bleeding included a one-off amount of bleeding over 400 ml after PCNL or/and hemoglobin decreased 20 g/L after PCNL. RESULTS: Among them, CTA showed pseudoaneurysm (n = 24), arteriovenous fistula (n = 6), suspicious bleeding spot (n = 4) and no obvious bleeding spot (n = 16). And 24 pseudoaneurysm and 6 arterovenous fistula patients underwent digital subtraction angiography (DSA) immediately. The bleeding spots were successfully intervened and coil embolization treatment was performed. Three of 4 suspicious bleeding cases had rebleeding mini-pseudoaneurysms. The remaining one case of rebleeding was successfully controlled by conservative measures. CONCLUSION: Renal artery CTA is the first-line screening technique for severe bleeding after PCNL. But for arterial hemorrhage patients, DSA examination may be directly conducted. PMID- 25511600 TI - [Function of CD4+ T cells in CD8+ T cell mediated rejection]. AB - OBJECTIVE: To explore the absence of CD4+ T cells, naive CD8+ T cells and memory CD8+ T (CD8+ Tm) cells in the role of mediated acute graft rejection and discuss its possible mechanism. METHODS: Mice were randomly divided into three groups (n = 6). And at Day 2 pre-transplantation, two types of cells (CD8+ T cells (CD8+ T group) or CD8+ Tm cells (CD8+ Tm group)) were transferred into nude mice (1 * 106 cells/one mice) via tail vein injections. At Day 0, C57BL/6 mice were used as donors for cervical heterotopic heart transplantation with nude mice as recipients (control group without transplantation). The survival of transplants was recorded and the mean survival time (MST) calculated. Then at Day 10 post transplantation, the recipient's heart graft, spleen and lymph node were collected for immunological detections. And the ratio of CD8+ cells in spleen and lymph nodes and serum levels of IL-2 in recipients were tested. RESULTS: In the group of adoption naive CD8+ T cells and heart grafting, there was no occurrence of acute graft rejection (MST>60 d) , while in the group of adoption memory CD8+ Tm cells and heart grafting, there was serious rejection(MST: (8.9 +/- 0.5) d) (P < 0.01). In the group of adoption naive CD8+ T cells and heart grafting, cell proliferation of transferred CD8+ T cells in spleen and lymph node showed no statistical difference compared with non-transplanted mice (2.70% +/- 0.08% vs 2.27% +/- 0.22%, 3.41% +/- 0.25% vs 2.80% +/- 0.62%, both P > 0.05). However, in the group of adoption CD8+ Tm cells and heart grafting, cell proliferation of transferred CD8+ Tm cells in spleen and lymph node showed significant statistical difference with non-transplanted mice (9.65% +/- 0.60% vs 2.12% +/- 0.18%, 11.15% +/- 1.35% vs 3.03% +/- 0.10%, both P < 0.01). The levels of IL-2 secretion before and after transplantation, naive CD8+ T cells showed no statistical difference (P > 0.05), CD8+ Tm cells showed significant statistical difference (P < 0.01). CONCLUSIONS: In the absence of CD4+ T lymphocyte helping, naive CD8+ T cells can not activate and show immunological functions. But memory CD8+ T can activate, proliferate and generate effector cells to mediate immune response. PMID- 25511601 TI - [Application of detecting mannose-binding lectins in pulmonary aspergillosis in rats]. AB - OBJECTIVE: To explore the effects of mannose-binding lectins (MBL) in pulmonary aspergillosis. METHODS: A total of 96 adult Wistar rats were randomly divided into 3 groups of aspergillus fumigatus (A.fumigatus) pulmonary, colonization and normal (n = 32 each). An intramuscular injection (0.6 mg/kg * 3 d) of dexamethasone sodium phosphate and a nostril drop (1 * 107 cfu/ml) were administered for modeling. The animals were sacrificed at Days 3, 7, 14 and 28 post-inoculation and blood samples were obtained by cardiac puncture for MBL detection. Lung tissues were prepared for routine pathology examinations. The lung tissues infected with A.fumigatus showed remarkable inflammatory reactions. The serum value of MBL was detected by enzyme-linked immunosorbent assay (ELISA). And the results were compared and analyzed. RESULTS: All infected lung tissues showed remarkable inflammatory reactions. The serum MBL levels of A.fumigatus pulmonary and colonization groups were (8.57 +/- 0.88) and (7.87 +/- 0.45) ng/ml and both significantly increased compared with non-pulmonary aspergillosis group (P < 0.05). The area under the curve was 0.744 (P = 0.002). The diagnosis of MBL had a sensitivity of 75.0%, a specificity of 86.7%, a positive predictive value of 87.1% and a negative predictive value of 74.3% for pulmonary aspergillosis. The inflammatory cells infiltration were detected in pathology in infection and colonization groups at Day 3 and Day 7. CONCLUSION: The detection of serum MBL may be used for the diagnosis of pulmonary aspergillosis. PMID- 25511602 TI - [Effects of smoking on expressions of HIF-1alpha and HDAC2 in asthmatic mice]. AB - OBJECTIVE: To explore the effects of smoking on airway inflammation through the expressions of hypoxia-inducible factor-1alpha (HIF-1alpha) and histone deacetylase-2 (HDAC2) in asthmatic mice. METHODS: A total of 30 female SPF BALB/c mice were divided randomly into 3 groups of control (C), asthma (A) and smoking asthma (S). The latter two groups were sensitized and challenged with ovalbumin (OVA) for asthmatic modeling. The mice of group S were placed into a self-made fumigating box for passive smoking. While group S was sensitized and challenged with normal saline instead of OVA. The pathological changes of different groups were observed. The different cell counts of bronchoalveolar fluid (BALF) were analyzed. The expressions of HIF-1alpha and HDAC2 were detected by immunohistochemistry. The level of interleukin (IL)-8 in BALF was detected by enzyme-linked immunosorbent assay (ELISA). And the levels of HIF-1alpha and HDAC2 in lung homogenate were measured by Western blot. RESULTS: The ratios of eosinophil (EOS) to total cell numbers of BALF in groups A and S were significantly higher than that in group C ((8.90 +/- 1.60)%, (7.52 +/- 0.63)% vs (0.60 +/- 0.10)%, both P < 0.01), while the ratio of neutrophile (NEU) in group S was higher than that in group A ((18.24 +/- 5.19)% vs (8.46 +/- 1.58)%, P < 0.01). Western blot showed that HIF-1alpha expressions in lung homogenate of groups A and S were significantly elevated than that in groups C (0.144 +/- 0.008, 0.238 +/- 0.015 vs 0.081 +/- 0.005, both P < 0.01). While the HIF-1alpha level of group S was higher than that of group A (P < 0.01). And the expressions of HDAC2 in groups A and S significantly decreased than that in group C (0.287 +/ 0.008, 0.164 +/- 0.015 vs 0.452 +/- 0.041, both P < 0.01). While the HDAC2 level of group S was lower than that of group A (P < 0.01). The BALF level of IL-8 in group S was higher than those in groups A and C ((42.07 +/- 4.54) vs (21.66 +/- 2.78), (14.33 +/- 3.73) pg/ml, both P < 0.01). There were significantly negative correlations between the expressions of HIF-1alpha and HDAC2 (r = -0.950, P < 0.01) in lung as well as HDAC2 in lung and IL-8 (r = -0.855, P < 0.01) in BALF. CONCLUSION: Cigarette smoking aggravates the airway inflammation through a down regulated expression of HDAC2 by activating HIF-1alpha. PMID- 25511603 TI - [Effects of fibroblasts on the proliferation and migratory capacity of renal cell carcinoma cell lines and sensitivity to everolimus]. AB - OBJECTIVE: To observe the effects of normal human renal fibroblast (NHRF) on renal cell carcinoma cell lines. METHODS: Renal cell carcinoma (RCC) cell lines 786-O and Caki-1 were co-cultured with NHRF for assessing the proliferation and migratory capacities of renal cell carcinoma cell lines and the sensitivity to everolimus. RESULTS: Co-culturing with NHRF substantially increased the proliferation capacity of both RCC cell lines (786-O: 2.35 +/- 0.05 vs1.93 +/- 0.15, P = 0.01;Caki-1: 2.35 +/- 0.21 vs 1.24 +/- 0.11, P = 0.001). Similarly the migratory capacities of both cell lines became significantly enhanced after co culturing (786-O: 1.53 +/- 0.11 vs 0.98 +/- 0.11, P = 0.04; Caki-1: 1.53 +/- 0.11vs 0.98 +/- 0.11, P = 0.04) compared with untreated control. Furthermore, the sensitivities of both cell lines to everolimus (1, 5, 10 umol/L) dramatically decreased in those pre-co-cultured with NHRF (786-O:P value 0.04, 0.35, 0.18); Caki-1: P value 0.02, 0.03, 0.024). CONCLUSION: NHRF promotes the proliferation and migration capacities of 786-O and Caki-1. And it may be involved in the resistance of RCC to everolimus. PMID- 25511604 TI - Mold contamination in schools with either high or low prevelance of asthma. AB - BACKGROUND: Mold exposures have been linked to the development and exacerbation of asthma. The purpose of this study was to determine whether the Environmental Relative Moldiness Index (ERMI) metric, developed to quantify mold exposures in homes, might be applied to evaluating the mold contamination in schools. METHODS: Settled dust samples (n = 10) were collected on each level of a water-damaged school in Springfield, Massachusetts and two samples per level in five Idaho schools. Each dust sample was analyzed for the 36 molds that make up the ERMI. The concentration of 2.5-MUm particulate matter (PM2.5 ) was measured in each school at two locations during the spring of 2013. RESULTS: The average ERMI value in the Springfield school, 15.51, was significantly greater (p < 0.001) than the average ERMI value, -2.87, in the Idaho schools. Ten of the twenty-six Group 1 molds, which are associated with water-damaged environments, were in significantly greater concentrations in the Springfield school. The populations of Group 2 molds, which are common indoors even without water damage, were essentially the same in Springfield and Idaho schools. The average PM2.5 concentration in the Springfield and Idaho schools was 11.6 and 3.4 MUg/m(3) , respectively. CONCLUSIONS: The ERMI scale might be useful in comparing the relative mold contamination in schools. PMID- 25511608 TI - Interfacial assembly of dendritic microcapsules with host-guest chemistry. AB - The self-assembly of nanoscale materials to form hierarchically ordered structures promises new opportunities in drug delivery, as well as magnetic materials and devices. Herein, we report a simple means to promote the self assembly of two polymers with functional groups at a water-chloroform interface using microfluidic technology. Two polymeric layers can be assembled and disassembled at the droplet interface using the efficiency of cucurbit[8]uril (CB[8]) host-guest supramolecular chemistry. The microcapsules produced are extremely monodisperse in size and can encapsulate target molecules in a robust, well-defined manner. In addition, we exploit a dendritic copolymer architecture to trap a small hydrophilic molecule in the microcapsule skin as cargo. This demonstrates not only the ability to encapsulate small molecules but also the ability to orthogonally store both hydrophilic and hydrophobic cargos within a single microcapsule. The interfacially assembled supramolecular microcapsules can benefit from the diversity of polymeric materials, allowing for fine control over the microcapsule properties. PMID- 25511607 TI - Metal carbonyl vapor generation coupled with dielectric barrier discharge to avoid plasma quench for optical emission spectrometry. AB - The scope of dielectric barrier discharge (DBD) microplasma as a radiation source for optical emission spectrometry (OES) is extended by nickel carbonyl vapor generation. We proved that metal carbonyl completely avoids the extinguishing of plasma, and it is much more suitable for matching the DBD excitation and OES detection with respect to significant DBD quenching by concomitant hydrogen when hydride generation is used. A concentric quartz UV reactor allows sample solution to flow through the central channel wherein to efficiently receive the uniformly distributed UV irradiation in the confined cylindrical space between the concentric tubes, which facilitates effective carbonyl generation in a nickel solution. The carbonyl is transferred into the DBD excitation chamber by an argon stream for nickel excitation, and the characteristic emission of nickel at 232.0 nm is detected by a charge-coupled device (CCD) spectrometer. A 1.0 mL sample solution results in a linear range of 5-100 MUg L(-1) along with a detection limit of 1.3 MUg L(-1) and a precision of 2.4% RSD at 50 MUg L(-1). The present DBD-OES system is validated by nickel in certified reference materials. PMID- 25511605 TI - Comparative analysis of carotenoid accumulation in two goji (Lycium barbarum L. and L. ruthenicum Murr.) fruits. AB - BACKGROUND: The traditional Chinese medicinal plants Lycium barbarum L. and L. ruthenicum Murr. are valued for the abundance of bioactive carotenoids and anthocyanins in their fruits, respectively. However, the cellular and molecular mechanisms contributing to their species-specific bioactive profiles remain poorly understood. RESULTS: In this study, the red fruit (RF) of L. barbarum was found to accumulate high levels of carotenoids (primarily zeaxanthin), while they were undetectable in the black fruit (BF) of L. ruthenicum. Cytological and gene transcriptional analyses revealed that the chromoplast differentiation that occurs in the chloroplast during fruit ripening only occurs in RF, indicating that the lack of chromoplast biogenesis in BF leads to no sink for carotenoid storage and the failure to synthesize carotenoids. Similar enzyme activities of phytoene synthase 1 (PSY1), chromoplast-specific lycopene beta-cyclase (CYC-B) and beta-carotene hydroxylase 2 (CRTR-B2) were observed in both L. ruthenicum and L. barbarum, suggesting that the undetectable carotenoid levels in BF were not due to the inactivation of carotenoid biosynthetic enzymes. The transcript levels of the carotenoid biosynthetic genes, particularly PSY1, phytoene desaturase (PDS), zeta-carotene desaturase (ZDS), CYC-B and CRTR-B2, were greatly increased during RF ripening, indicating increased zeaxanthin biosynthesis. Additionally, carotenoid cleavage dioxygenase 4 (CCD4) was expressed at much higher levels in BF than in RF, suggesting continuous carotenoid degradation in BF. CONCLUSIONS: The failure of the chromoplast development in BF causes low carotenoid biosynthesis levels and continuous carotenoid degradation, which ultimately leads to undetectable carotenoid levels in ripe BF. In contrast, the successful chromoplast biogenesis in RF furnishes the sink necessary for carotenoid storage. Based on this observation, the abundant zeaxanthin accumulation in RF is primarily determined via both the large carotenoid biosynthesis levels and the lack of carotenoid degradation, which are regulated at the transcriptional level. PMID- 25511609 TI - Carotid Ultrasonography Can Identify Stroke Patients Ineligible for Intravenous Thrombolysis Therapy due to Acute Aortic Dissection. AB - Acute aortic dissection is the most common acute aortic condition requiring urgent surgical therapy. Due to lack of typical symptoms, it is sometimes difficult to identify acute aortic dissection causing ischemic stroke. We report a case of a patient with acute ischemic stroke who was deemed ineligible for intravenous recombinant tissue plasminogen activator treatment based on a finding of acute aortic dissection detected by carotid ultrasonography. After urgent aortic replacement surgery, the patient recovered with no neurological deficit. This case underscores the crucial role of carotid ultrasonography for the investigation of possible underlying acute aortic dissection when considering the use of intravenous recombinant tissue plasminogen activator therapy for hyperacute stroke. PMID- 25511610 TI - High process yield rates of thermoplastic nanofluidic devices using a hybrid thermal assembly technique. AB - Over the past decade, thermoplastics have been used as alternative substrates to glass and Si for microfluidic devices because of the diverse and robust fabrication protocols available for thermoplastics that can generate high production rates of the desired structures at low cost and with high replication fidelity, the extensive array of physiochemical properties they possess, and the simple surface activation strategies that can be employed to tune their surface chemistry appropriate for the intended application. While the advantages of polymer microfluidics are currently being realized, the evolution of thermoplastic-based nanofluidic devices is fraught with challenges. One challenge is assembly of the device, which consists of sealing a cover plate to the patterned fluidic substrate. Typically, channel collapse or substrate dissolution occurs during assembly making the device inoperable resulting in low process yield rates. In this work, we report a low temperature hybrid assembly approach for the generation of functional thermoplastic nanofluidic devices with high process yield rates (>90%) and with a short total assembly time (16 min). The approach involves thermally sealing a high T(g) (glass transition temperature) substrate containing the nanofluidic structures to a cover plate possessing a lower T(g). Nanofluidic devices with critical feature sizes ranging between 25 250 nm were fabricated in a thermoplastic substrate (T(g) = 104 degrees C) and sealed with a cover plate (T(g) = 75 degrees C) at a temperature significantly below the T(g) of the substrate. Results obtained from sealing tests revealed that the integrity of the nanochannels remained intact after assembly and devices were useful for fluorescence imaging at high signal-to-noise ratios. The functionality of the assembled devices was demonstrated by studying the stretching and translocation dynamics of dsDNA in the enclosed thermoplastic nanofluidic channels. PMID- 25511611 TI - Dissociated stimulus and response conflict effect in the Stroop task: evidence from evoked brain potentials and brain oscillations. AB - The Stroop task is a classic paradigm that can be used to examine cognitive control as it contains conditions with and without interference. Cumulative evidence suggests that both stimulus and response conflict contribute to the Stroop interference effect. However, it remains unclear whether there are dissociable event-related potential (ERP) or frequency band-specific electroencephalographic (EEG) power changes associated with stimulus conflict and response conflict. To investigate potential markers for each form of conflict, we applied a Stroop 2-1 mapping task in 20 healthy young adults. Results showed that a negative deflection in the 350-500ms time window (N450) and a positive deflection in the 600-900ms time window (late positive component, LPC) were associated with response conflict and stimulus conflict, respectively. Time frequency analyses found that both stimulus and response conflict induced theta band power changes and that response conflict additionally induced a beta band power change. These results indicate that stimulus and response conflict in the Stroop task are associated with different ERP effects and brain oscillatory features. PMID- 25511612 TI - Metastatic breast cancer presenting as sequential cranial nerve palsy: a case report. AB - INTRODUCTION: Cranial nerve palsy is a common presentation in the neuro ophthalmology clinic and investigations are directed towards the cause. Metastatic breast cancer presenting as carcinomatous meningitis leading to sequential fourth, third and sixth nerve palsy is very rare. This is the first case to be reported to the best of our knowledge. CASE PRESENTATION: A 66-year old Caucasian woman presented with vertical double vision for the previous 3 weeks. At 6-weeks follow up this had resolved. However, she presented with a new third and sixth cranial nerve palsy. Neuroimaging with contrast revealed carcinomatous meningitis. CONCLUSIONS: Metastatic cancer may manifest as cerebral metastases or carcinomatous meningitis. This is evident on neuroimaging with contrast and may be missed on unenhanced scans. PMID- 25511613 TI - Epidermal Growth Factor Receptor targeting in non-small cell lung cancer: revisiting different strategies against the same target. AB - Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the paradigm of treatment in non-small cell lung cancer (NSCLC). The molecular biology study of EGFR has led to clinical trials that select patients more accurately, regarding the presence of EGFR activating mutations. Nonetheless, a lack of response or a temporary condition of the response has been detected in patients on EGFR TKIs. This has urged to study potential resistance mechanisms underneath. The most important ones are the presence of secondary mutations in EGFR, such as T790M, or the overexpression of mesenchymal-epithelial transition factor (MET) that may explain why patients who initially respond to EGFR TKIs, may ultimately become refractory. Several approaches have been taken and new drugs both targeting EGFR resistance-mutation or MET are currently being developed. Here we review and update the EGFR biological pathway as well as the clinical data leading to approval of the EGFR TKIs currently in the market. New compounds under investigation targeting resistance mutations or dually targeting EGFR and other relevant receptors are also reviewed and discussed. PMID- 25511614 TI - The role of cMet in non-small cell lung cancer resistant to EGFR-inhibitors: did we really find the target? AB - The advent of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represented the most important innovation in NSCLC treatment over the last years. However, despite a great initial activity, secondary mutations in the same target, or different alterations in other molecular pathways, inevitably occur, leading to the emergence of acquired resistance, in median within the first year of treatment. In this scenario, the mesenchymal epidermal transition (cMET) tyrosine kinase receptor and its natural ligand, the hepatocyte growth factor (HGF), seem to play an important role. Indeed either the overexpression or the amplification of cMET, as well as the overexpression of the HGF, have been reported in a substantial subgroup of NSCLC patients resistant to EGFR-TKIs. Several cMET-inhibitors have been developed as potential therapeutic candidates, and are currently under investigation in clinical trials. These compounds include both monoclonal antibodies and TKIs, and most of them have been investigated as dual combinations including an anti-EGFR TKI, to improve the efficacy of the available treatments, and ultimately overcome acquired resistance to EGFR-inhibitors. PMID- 25511615 TI - Factors decreasing caregiver burden to allow patients with cerebrovascular disease to continue in long-term home care. AB - BACKGROUND: This study attempted to assess continued long-term home care by examining patients' independent activities of daily living (ADLs) and caregivers' free time. METHODS: We surveyed the main caregivers of 52 patients with cerebrovascular disease with continuous home care from 1999 to 2010. Survey items were patients' ADLs, the frequency of use of care services, care requirements, and caregiver sense of burden. We compared the survey results between years. RESULTS: ADLs of excretory control, verbal expression, verbal comprehension, and range of activities showed significant deterioration from 1999 to 2010. Patient need for care increased significantly but use of care services did not. Main caregivers were typically spouses who aged together with the patients. Main caregivers rarely changed; occasionally, a son or daughter-in-law became the main caregiver. Patients typically required less than 3 hours of care daily, which did not change over time. Caregivers had significantly more difficulty maintaining their own health in 2010 than 1999. However, they did not identify increases in difficulties with housework or coping with work. They felt that caregiving was a burden but did not indicate that the family relationship had deteriorated. CONCLUSIONS: Regardless of degree of independence of patients' ADLs, caregiver burden was severe. To decrease caregiver burden, it is necessary to use care services, reduce care time, and allow caregivers free time. In addition, it is possible to continue long-term home care by maintaining their relationships. PMID- 25511616 TI - Gaps and hurdles deter against following stroke guidelines for thrombolytic therapy in Iran: exploring the problem. AB - BACKGROUND: Insufficient information is available on the barriers that explain low rates of thrombolytic therapy for acute ischemic stroke (AIS) in developing countries compared with rates in developed societies. By the present study, we aimed to assess the implementation of thrombolytic therapy in the northeast of Iran to explore the gaps and hurdles against thrombolysis as the generally accepted treatment for AIS. METHODS: In a 1-year cohort study among AIS patients admitted to the second largest tertiary neurologic referral center in Iran, those who met the prespecified selection criteria were treated with intravenous recombinant tissue plasminogen activator (rtPA). RESULTS: Among 1,144 patients admitted with AIS, only 14 (1.2%) were treated with rtPA. The mean onset-to needle and door-to-needle times were 172 and 58 minutes, respectively; 980 (85.6%) patients were initially excluded from the study because of late arrival. Additionally, 60 patients in total were omitted because of either their high age (3.7%) or passing the gold standard time limit for rtPA therapy after preliminary evaluations (1.6%), and 90 more patients (7.9%) were considered not suitable for thrombolysis because of the severity of the symptoms or the higher risk of bleeding on rtPA. CONCLUSIONS: Access to thrombolytic therapy for AIS in Iran is less than in most developed countries but comparable with other developing countries. Awareness campaigns are needed to minimize barriers and improve access to thrombolysis and specialized stroke care in Iran. PMID- 25511617 TI - Association between seizures and outcomes among intracerebral hemorrhage patients: the China National Stroke Registry. AB - BACKGROUND: To determine whether the presence of seizures in patients with spontaneous intracerebral hemorrhage (ICH) was associated with in-hospital complications and measured outcomes. METHODS: This prospective cohort study from the China National Stroke Registry included consecutive patients with ICH between August 2007 and September 2008. In-hospital complications, functional outcomes, and mortality at 3, 6, and 12 months were compared between patients with seizures and those without seizures occurring at ICH onset and during hospitalization. Poor functional outcome was defined as a modified Rankin Scale score between 3 and 6. Poor functional outcome and mortality were stratified by stroke severity using Glasgow Coma Scale scores on admission. RESULTS: The study included 3216 patients with ICH and 139 of them (4.3%) experienced seizures. The presence of seizures was associated with high in-hospital complications including atrial fibrillation (P = .004), pneumonia (P = .001), as well as lower rehabilitation assessment rates (P = .033) compared with patients without seizures. ICH patients with seizures had poorer functional outcome at 3-month (P = .012), 6-month (P = .007), and 12-month (P = .001) follow-up. They also had higher mortality at 3 months (P = .045), 6 months (P = .005), and 12 months (P = .002). Patients with mild strokes had poorer functional outcome and higher mortality (P < .005) if seizures occurred. CONCLUSIONS: The presence of seizures in patients with ICH was associated with high in-hospital complications and indicates poor outcomes at 3-, 6-, and 12-month follow-up. Quality improvement strategies targeting ICH patients with seizures especially mild stroke may help improve prognoses. PMID- 25511618 TI - Prognostic value of morning blood pressure surge in clinical events: a meta analysis of longitudinal studies. AB - BACKGROUND: Cardiovascular (CV) events tend to occur more often in the morning. Thus, morning blood pressure surge (MS) may be related to the risk of CV events. The results of several studies evaluating the prognostic value of MS are inconsistent. In this study, we conducted a systematic review and meta-analysis to summarize the significance of MS in predicting future CV events. METHODS: Among the related literature, we discovered 7 eligible longitudinal studies that had evaluated MS and had followed 14,133 patients with a mean follow-up period of 7.1 years. We evaluated the predictive value of MS for future CV events, stroke, and all-cause mortality in this meta-analysis. RESULTS: For subjects with higher pre-waking MS than those with lower pre-waking MS, the pooled relative risk (RR) of all-cause mortality, stroke, and total CV events were 1.20 (95% confidence interval [CI]: .85-1.70, P = .290; 4 studies), 1.20 (95% CI: .94-1.53, P = .146; 3 studies), and 1.24 (95% CI: .60-2.53, P = .562; 3 studies), respectively. For subjects with higher sleep-trough MS, the pooled RR of all-cause mortality was 1.29 (95% CI: 1.11-1.52, P = .001; 4 studies). No significant publication bias was observed. CONCLUSIONS: Excess sleep-trough MS is a strong predictor for future all-cause mortality. Individuals with higher pre-waking MS showed a tendency for increased risk of CV outcomes, but the differences were insignificant. PMID- 25511621 TI - Beneficial metabolic activities of inflammatory cytokine interleukin 15 in obesity and type 2 diabetes. AB - In obesity, chronic inflammation is believed to induce insulin resistance and impairs adipose tissue function. Although this view is supported by a large body of literature, it has been challenged by growing evidence that pro-inflammatory cytokines may favor insulin sensitivity through induction of energy expenditure. In this review article, interleukin 15 (IL-15) is used as a new example to explain the beneficial effects of the proinflammatory cytokines. IL-15 is secreted by multiple types of cells including macrophages, neutrophils and skeletal muscle cells. IL-15 expression is induced in immune cells by endotoxin and in muscle cells by physical exercise. Its transcription is induced by transcription factor NF-kappaB. IL-15 binds to its receptor that contains three different subunits (alpha, beta and gamma) to activate JAK/STAT, PI3K/Akt, IKK/NF kappaB and JNK/AP1 pathways in cells. In the regulation of metabolism, IL-15 reduces weight gain without inhibiting food intake in rodents. IL-15 suppresses lipogenesis, stimulates brown fat function, improves insulin sensitivity through weight loss and energy expenditure. In human, circulating IL-15 is negatively associated with body weight. In the immune system, IL-15 stimulates proliferation and differentiation of T cells, NK cells, monocytes and neutrophils. In the anti obesity effects of IL-15, T cells and NK cells are not required, but leptin receptor is required. In summary, evidence from human and rodents supports that the pro-inflammatory cytokine IL-15 may enhance energy expenditure to protect the body from obesity and type 2 diabetes. The mechanism of IL-15 action remains to be fully uncovered in the regulation of energy expenditure. PMID- 25511620 TI - Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review. AB - Sickle cell disease (SCD) is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vasoocclusion but also precipitates inflammation, oxidative stress and chronic organ dysfunction. Oxidative stress is increasingly recognized as an important intermediate in these pathophysiological processes and is therefore an important target for therapeutic intervention. The transcription factor nuclear erythroid derived-2 related factor 2 (Nrf2) controls the expression of anti-oxidant enzymes and is emerging as a protein whose function can be exploited with therapeutic intent. This review article is focused on triterpenoids that activate Nrf2, and their potential for reducing oxidative stress in SCD as an approach to prevent organ dysfunction associated with this disease. A brief overview of oxidative stress in the clinical context of SCD is accompanied by a discussion of several pathophysiological mechanisms contributing to oxidative stress. Finally, these mechanisms are then related to current management strategies in SCD that are either utilized currently or under evaluation. The article concludes with a perspective on the potential of the various therapeutic interventions to reduce oxidative stress and morbidity associated with SCD. PMID- 25511623 TI - A clinical study of lung cancer dose calculation accuracy with Monte Carlo simulation. AB - BACKGROUND: The accuracy of dose calculation is crucial to the quality of treatment planning and, consequently, to the dose delivered to patients undergoing radiation therapy. Current general calculation algorithms such as Pencil Beam Convolution (PBC) and Collapsed Cone Convolution (CCC) have shortcomings in regard to severe inhomogeneities, particularly in those regions where charged particle equilibrium does not hold. The aim of this study was to evaluate the accuracy of the PBC and CCC algorithms in lung cancer radiotherapy using Monte Carlo (MC) technology. METHODS AND MATERIALS: Four treatment plans were designed using Oncentra Masterplan TPS for each patient. Two intensity modulated radiation therapy (IMRT) plans were developed using the PBC and CCC algorithms, and two three-dimensional conformal therapy (3DCRT) plans were developed using the PBC and CCC algorithms. The DICOM-RT files of the treatment plans were exported to the Monte Carlo system to recalculate. The dose distributions of GTV, PTV and ipsilateral lung calculated by the TPS and MC were compared. RESULT: For 3DCRT and IMRT plans, the mean dose differences for GTV between the CCC and MC increased with decreasing of the GTV volume. For IMRT, the mean dose differences were found to be higher than that of 3DCRT. The CCC algorithm overestimated the GTV mean dose by approximately 3% for IMRT. For 3DCRT plans, when the volume of the GTV was greater than 100 cm(3), the mean doses calculated by CCC and MC almost have no difference. PBC shows large deviations from the MC algorithm. For the dose to the ipsilateral lung, the CCC algorithm overestimated the dose to the entire lung, and the PBC algorithm overestimated V20 but underestimated V5; the difference in V10 was not statistically significant. CONCLUSIONS: PBC substantially overestimates the dose to the tumour, but the CCC is similar to the MC simulation. It is recommended that the treatment plans for lung cancer be developed using an advanced dose calculation algorithm other than PBC. MC can accurately calculate the dose distribution in lung cancer and can provide a notably effective tool for benchmarking the performance of other dose calculation algorithms within patients. PMID- 25511622 TI - Genomic and pharmacogenetic studies of childhood acute lymphoblastic leukemia. AB - With the cure rate of childhood acute lymphoblastic leukemia (ALL) approaching 90%, further improvement in the treatment outcome and quality of life of patients will require better understanding of the mechanisms of drug resistance, identifying new leukemic cell genetic lesions that are amendable to available target therapy, and optimizing treatment based on host pharmacodynamics and pharmacogenomics. Deeper characterization of leukemic cell genetic abnormalities has discovered new subtypes of leukemia such as early T-cell precursor ALL and Philadelphia chromosome-like ALL, and identified many genomic alterations that have diagnostic, prognostic, or therapeutic implications. In this regard, several novel fusion transcripts are responsive to ABL tyrosine kinase inhibitors and potentially to JAK inhibitors. Genome-wide analyses have also unraveled the role of inherited cancer predisposing genes and small nucleotide polymorphisms of several genes in the development of childhood ALL. These advances promise to lead to more sophisticated personalized treatment strategies in the near future. PMID- 25511624 TI - Circuit life versus bleeding risk: the impact of achieved activated partial thromboplastin time versus achieved filtration fraction. AB - Whilst prolonging hemofilter (circuit) life, heparin increases bleeding risk. The impact of achieved activated partial thromboplastin time (APTT) on circuit life and bleeding risk has not been assessed in a modern critically ill cohort. Lowering filtration fraction may be an alternative means of prolonging circuit life, but is often overlooked in critical care. An observational study of 309 consecutive circuits in a general intensive care unit was conducted using a wide target APTT range. Multilevel modeling was used to predict circuit life and bleeding according to achieved APTT and filtration fraction. Independent predictors of circuit failure (i.e. unplanned ending of treatment) included filtration fraction (P<0.001, HR 1.07 per 1% increase), peak APTT (P<0.001, HR 0.8 per 10 s increase or 0.3 APTR increase) and baseline PT (P=0.014, HR 0.91 for every 50% increase). The only significant predictor of bleeding was peak APTT (P=0.017, OR 1.05 per 10 s increase). Every 10 s APTT increase was associated with a 20% reduction in circuit failure, but a 5% increase in hemorrhage. A 3% reduction in filtration fraction was associated with the same improvement in circuit life as a 10 s increase in APTT. Increasing APTT prolongs circuit life but carries a substantial risk of bleeding even in modern practice. Filtration fraction has a large impact on circuit life in the critically ill: a 3% reduction in filtration fraction, e.g. by increasing blood flow or delivering some of the clearance via dialysis, would be expected to reduce circuit failure as much as a 10 s increase in APTT. PMID- 25511625 TI - Are cyclic lipopeptides produced by Bacillus amyloliquefaciens S13-3 responsible for the plant defence response in strawberry against Colletotrichum gloeosporioides? AB - The antagonistic strain Bacillus amyloliquefaciens strain S13-3 decreased the severity of strawberry anthracnose caused by Colletotrichum gloeosporioides. The foliar application of S13-3 triggered the expression of pathogenesis-related proteins, chitinase and beta-1,3-glucanase, in strawberry leaves. We identified lipopeptide antibiotics, including iturin A, fengycin, mixirin, pumilacidin and surfactin, produced and secreted by S13-3. Iturin A and surfactin elicited the gene expression of the pathogenesis-related proteins in strawberry leaves, suggesting that antagonistic strain S13-3 confers resistance to strawberry leaves through the production of lipopeptide antibiotics. In fact, iturin A and surfactin triggered induced systemic resistance on strawberry plants, resulting in the reduction of the severity of anthracnose disease caused by Colletotrichum gloeosporioides. The bifunctional activity of S13-3, which consists of the antagonistic effect and the induction of plant defence response by the antibiotics produced by it, may make S13-3 an innovative biological control agent against phytopathogens in strawberry. SIGNIFICANCE AND IMPACT OF THE STUDY: This study tries to determine whether biocontrol of phytopathogens by Bacillus amyloliquefaciens in strawberry can be connected to induced plant resistance. The results suggested that the antagonistic strain B. amyloliquefaciens S13-3 confers resistance to strawberry through the production of lipopeptide antibiotics. PMID- 25511626 TI - [The function of a general concept of disease from an historical perspective]. AB - This article questions why medicine fails to provide a general concept of disease for use by doctors, patients and society because the lack of such a unified concept inhibits any definitive distinction between "deviant" and "disease". By providing an historical overview of the particularities related to this question the authors demonstrate that the ever-changing concepts of disease were not driven by the process through which medicine became a science. In contrast to naturalistic concepts of disease, anthropological, sociocultural and psychosomatic concepts are grounded in an understanding of disease that cannot be determined, described and categorized by pathology alone. As a consequence, disease can only be determined or defined in relation to social and scientific frames of reference, as illustrated by an example from the Berlin Nervenklinik (psychiatric clinic) in the early twentieth century. The ways in which the definition of a disease concept represents a normative interpretation can be observed. The authors of this paper argue for the acceptance of this normative definition as a matter of societal agreement. Consequently, transparency is required in the shaping of general disease concepts. PMID- 25511627 TI - [Takotsubo cardiomyopathy after electroconvulsive therapy: A case report]. PMID- 25511628 TI - Visualization of placental hypocirculation with typical patterns using conventional magnetic resonance imaging: Two case reports. AB - We report two cases of clinically suspected placental hypocirculation, as per evidenced by specific half-Fourier acquisition single-shot turbo spin-echo (HASTE) magnetic resonance findings of the whole placenta. Patient 1 was a case of fetal growth restriction caused by pregnancy-induced hypertension, while patient 2 experienced a discordant dichorionic diamniotic twin pregnancy with fetal growth restriction complication with a velamentous insertion of the umbilical cord in the smaller twin. In both cases, HASTE images showed noticeably decreased signal intensity with high-intensity signal spots present in the central region of the placenta. In the twin pregnancy case, the low-intensity signal area in the placenta of the smaller twin was much lower compared to that of the larger twin. Pathological findings failed to support or explain these observations. HASTE images might reflect compensatory alternation of the distribution of maternal blood and villus caused by hypocirculation. In conclusion, our results suggest that HASTE imaging might be a useful approach for the visualization of placental hypocirculation. PMID- 25511630 TI - BET 1: use of glucagon for oesophageal food bolus impaction. AB - A shortcut review was carried out to establish whether intravenous glucagon is a safe and effective treatment for patients with suspected lower oesophageal food bolus impaction. Seven studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that there is no evidence for the effectiveness of glucagon in this situation. Its use may be associated with adverse effects such as vomiting, with the potential risk of oesophageal perforation. Intravenous glucagon should therefore be avoided. PMID- 25511632 TI - BET 2: should ST elevation be measured at the J point or 60 ms later? AB - A shortcut systematic review was carried out to establish whether in patients with suspected acute coronary syndromes presenting to the emergency department, measurement of electrocardiographic ST elevation at the J point or 60 ms after the J point will lead to more accurate identification of patients with acute coronary occlusion who may benefit from immediate coronary revascularisation. Three studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that the current evidence does not justify a shift away from measurement of ST elevation at the J point, as advocated in international guidance. Due to the limited available evidence, however, further research in this area is necessary. PMID- 25511633 TI - Clinical experiences and success rates of acromegaly treatment: the single center results of 62 patients. AB - BACKGROUND: This study aimed to report the clinical and outcome data from a large cohort of patients diagnosed with acromegaly and treated at our institution over a 20-year period. METHODS: Sixty-two acromegaly patients (32 women and 30 men) treated and monitored at the endocrinology polyclinic between 1984 and 2013 were enrolled in this retrospective study. Clinical features and patients' treatment outcomes were evaluated. A level of growth hormone (GH) of <2.5 ng/ml was considered as the criterion for remission, and the normal insulin-like growth factor (IGF) range was based on gender and age. RESULTS: The mean age at the time of diagnosis was 38.8 +/- 1.4 years, the time to diagnosis was 4.5 +/- 0.3 years, and the follow-up duration was 7.3 +/- 0.8 years. Among patients' symptoms, growth in hands and feet and typical facial dysmorphism were the most prominent (92%). The number of patients with diabetes mellitus, hypertension and hyperprolactinemia were 22 (35%), 13 (21%) and 13 (21%), respectively. Microadenomas and macroadenomas were found in eight and 54 patients, respectively. A significant correlation was found between the initial tumor diameters and GH levels (p = 0.002). The mean GH and IGF-1 levels were 39.18 +/- 6.1 ng/ml and 993.5 +/- 79 ng/ml, respectively. Visual field defect was found in 16 patients (32%). Thirty-one patients were treated by transsphenoidal surgery. Four of these were cured, 10 patients developed postoperative anterior pituitary hormone deficiency, and one patient developed diabetes insipidus. Twenty patients were treated by transcranial surgery, of which two were cured, while 17 patients developed postoperative anterior pituitary hormone deficiency. In total, five of the patients who were not cured after surgery were given conventional radiotherapy, of which two were cured. Four of 15 patients, on whom Gamma Knife radiosurgery was performed, were cured. Biochemical remission was achieved in 32 of 52 patients who received octreotide treatment, and in two of five patients who received lanreotide treatment. CONCLUSIONS: The rate of surgical success in our patients was found to be low. This could be explained by an absence of experienced pituitary surgical centers or surgeons in our region, and the fact that most patients presented late at the macroadenoma stage. PMID- 25511635 TI - Ocular and cervical vestibular-evoked myogenic potentials in children with cochlear implant. AB - OBJECTIVE: To define the profile of ocular and cervical vestibular-evoked myogenic potentials (oVEMPs and cVEMPs) in children with cochlear implant (CI), we studied air-conducted sound (ACS)-evoked responses pre- and postoperatively. METHODS: The ACS-evoked oVEMPs and cVEMPs of 31 children with cochlear implantation were investigated. Thresholds, amplitudes, P1 and N1 latencies, and interpeak latencies of VEMPs were measured and analyzed. RESULTS: Before CI, the response rates of oVEMPs and cVEMPs were 71.0% and 67.7%, respectively. The oVEMPs and cVEMPs on the operated side disappeared after CI, which resulted in a decrease in response rates, whether the device was switched on (12.9% and 32. 0%) or off (19.2% and 34.8%). In the case when VEMPs could be elicited on the operated side after CI, the parameters of waveforms showed abnormal changes, including threshold elevation (maximum of 8.34-dB SPL in oVEMP and 8.75-dB SPL in cVEMP) and amplitude decrease (maximum of 4.10MUV in oVEMP and 191.82MUV in cVEMP). CONCLUSIONS: Disappearance and impairment of VEMPs could be observed after CI, and the waveforms of oVEMP and cVEMP could reflect the degree of damage to the utricle and saccule caused by CI and other related factors. SIGNIFICANCE: The oVEMPs and cVEMPs prove to be accurate methods to evaluate vestibular function in children with CI. PMID- 25511636 TI - Opportunities and methodological challenges in EEG and MEG resting state functional brain network research. AB - Electroencephalogram (EEG) and magnetoencephalogram (MEG) recordings during resting state are increasingly used to study functional connectivity and network topology. Moreover, the number of different analysis approaches is expanding along with the rising interest in this research area. The comparison between studies can therefore be challenging and discussion is needed to underscore methodological opportunities and pitfalls in functional connectivity and network studies. In this overview we discuss methodological considerations throughout the analysis pipeline of recording and analyzing resting state EEG and MEG data, with a focus on functional connectivity and network analysis. We summarize current common practices with their advantages and disadvantages; provide practical tips, and suggestions for future research. Finally, we discuss how methodological choices in resting state research can affect the construction of functional networks. When taking advantage of current best practices and avoid the most obvious pitfalls, functional connectivity and network studies can be improved and enable a more accurate interpretation and comparison between studies. PMID- 25511634 TI - Early-life adversity and adolescent depression: mechanisms involving the ventral striatum. AB - Early-life adversity is a well-established risk factor for the development of depression later in life. Here we discuss the relationship between early-life adversity and depression, focusing specifically on effects of early-life caregiver deprivation on alterations in the neural and behavioral substrates of reward-processing. We also examine vulnerability to depression within the context of sensitive periods of neural development and the timing of adverse exposure. We further review the development of the ventral striatum, a limbic structure implicated in reward processing, and its role in depressive outcomes following early-life adversity. Finally, we suggest a potential neurobiological mechanism linking early-life adversity and altered ventral striatal development. Together these findings may help provide further insight into the role of reward circuitry dysfunction in psychopathological outcomes in both clinical and developmental populations. PMID- 25511638 TI - A mutation study of sperm head shape and motility in the mouse: lessons for the clinic. AB - Mouse mutants that show effects on sperm head shape, the sperm tail (flagellum), and motility were analysed in a systematic way. This was achieved by grouping mutations in the following classes: manchette, acrosome, Sertoli cell contact, chromatin remodelling, and mutations involved in complex regulations such as protein (de)phosphorylation and RNA stability, and flagellum/motility mutations. For all mutant phenotypes, flagellum function (motility) was affected. Head shape, including the nucleus, was also affected in spermatozoa of most mouse models, though with considerable variation. For the mutants that were categorized in the flagellum/motility group, generally normal head shapes were found, even when the flagellum did not develop or only poorly so. Most mutants are sterile, an occasional one semi-sterile. For completeness, the influence of the sex chromosomes on sperm phenotype is included. Functionally, the genes involved can be categorized as regulators of spermiogenesis. When extrapolating these data to human sperm samples, in vivo selection for motility would be the tool for weeding out the products of suboptimal spermiogenesis and epididymal sperm maturation. The striking dependency of motility on proper sperm head development is not easy to understand, but likely is of evolutionary benefit. Also, sperm competition after mating can never act against the long-term multi-generation interest of genetic integrity. Hence, it is plausible to suggest that short-term haplophase fitness i.e., motility, is developmentally integrated with proper nucleus maturation, including genetic integrity to protect multi-generation fitness. We hypothesize that, when the prime defect is in flagellum formation, apparently a feedback loop was not necessary as head morphogenesis in these mutants is mostly normal. Extrapolating to human-assisted reproductive techniques practice, this analysis would supply the arguments for the development of tools to select for motility as a continuous (non-discrete) parameter. PMID- 25511637 TI - Position paper update: whole bowel irrigation for gastrointestinal decontamination of overdose patients. AB - CONTEXT: A position paper on the use of whole bowel irrigation (WBI) was first published in 1997 by the American Academy of Clinical Toxicology (AACT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) and updated in 2004. The aims of this paper are to briefly summarize the content of the 2004 Position Paper and to present any new data and recommendations. METHODS: A systematic review of the literature from January 2003 to February 28, 2013 was conducted using multiple online databases for articles concerning WBI for gastrointestinal decontamination. An evidence table was created for applicable articles. The authors produced the initial draft that was reviewed by AACT and EAPCCT. RESULTS: The literature search produced 60 articles with the possibility of applicable human data. Based mainly on volunteer studies, WBI can be considered for potentially toxic ingestions of sustained-release or enteric coated drugs particularly for those patients presenting later than 2 h after drug ingestion when activated charcoal is less effective. WBI can be considered for patients who have ingested substantial amounts of iron, lithium, or potassium as the morbidity is high and there is a lack of other potentially effective options for gastrointestinal decontamination. WBI can be considered for removal of ingested packets of illicit drugs in "body packers." However, controlled data documenting improvement in clinical outcome after WBI are lacking. WBI is contraindicated in patients with bowel obstruction, perforation, or ileus, and in patients with hemodynamic instability or compromised unprotected airways. WBI should be used cautiously in debilitated patients and in patients with medical conditions that might be further compromised by its use. The concurrent administration of activated charcoal and WBI might decrease the effectiveness of the charcoal. The clinical relevance of this interaction is uncertain. CONCLUSION: WBI can facilitate removal of select toxicants from the gastrointestinal tract in some patients, but there is no convincing evidence from clinical studies that it improves the outcome of poisoned patients. There is no new evidence that would require a major revision of the conclusions of the 2004 position statement. PMID- 25511639 TI - Stroke and systemic embolism prevention in patients with atrial fibrillation in Belgium: comparative cost effectiveness of new oral anticoagulants and warfarin. AB - BACKGROUND AND OBJECTIVE: Management of non-valvular atrial fibrillation (NVAF) focuses on the use of anticoagulation to mitigate the risk of stroke. Until recently, vitamin K antagonist (VKA) treatment was considered the standard of care, with the emergence of non-VKA oral anticoagulants (NOACs) shifting treatment practice. The objective of this study was therefore to assess the use of warfarin and the NOACs for stroke prevention in patients with NVAF from the perspective of a Belgian healthcare payer using a cost-effectiveness analysis and the efficiency frontier approach. METHODS: A previously published Markov model was adapted to the Belgian healthcare setting. Clinical events modelled include ischaemic and haemorrhagic stroke, systemic embolism, intracranial haemorrhage, other major bleeding, clinically relevant non-major bleeding, myocardial infarction, cardiovascular hospitalisation and treatment discontinuations. Efficacy and bleeding data for warfarin and apixaban 5 mg twice daily were obtained from the ARISTOTLE trial, whilst those for other NOACs (rivaroxaban 20 mg once daily, dabigatran 110 mg twice daily, dabigatran 150 mg twice daily) were from published indirect comparisons. Acute medical costs were obtained from reimbursement payments made to Belgian hospitals, whilst long-term medical costs and utility data were derived from the literature. The efficiency frontier was calculated using total costs and quality-adjusted life-years (QALYs) as outcomes. Univariate and probabilistic sensitivity analyses were performed. RESULTS: Warfarin and apixaban were the two optimal treatment choices, as the other three treatment alternatives including dabigatran 110 mg, dabigatran 150 mg switching to dabigatran 110 mg at the age of 80 years and rivaroxaban were extendedly or strictly dominated on the efficiency frontier. Apixaban was a cost-effective alternative vs warfarin at an incremental cost-effectiveness ratio of 7,212/QALY gained. CONCLUSIONS: Amongst NOACs, apixaban may be the most economically efficient alternative to warfarin in NVAF patients who are suitable for VKA treatment and eligible for stroke prevention in Belgium. PMID- 25511640 TI - Additive effects of miglitol and anagliptin on insulin-treated type 2 diabetes mellitus: a case study. AB - The aim of this case study was to examine the efficacy of a dipeptidyl peptidase 4 inhibitor (anagliptin) and an alpha-glucosidase inhibitor (miglitol) when added to ongoing insulin treatment in patients with type 2 diabetes mellitus. Continuous glucose monitoring was performed in four Japanese insulin-treated inpatients with type 2 diabetes. Baseline data were collected on day 1. Miglitol was administered on days 2 and 3. On day 4, miglitol and anagliptin were coadministered before breakfast. On days 1, 3, and 5, blood was drawn for plasma glucose, serum C-peptide, plasma glucagon, total and active glucagon-like peptide 1 (GLP-1), and total and active glucose-dependent insulinotropic peptide (GIP) measurements. Coadministration of anagliptin with miglitol resulted in additional improvements in glycemic control over the entire day in three of the four patients. The C-peptide, glucagon, and total and active GLP-1 and GIP responded differently to the medications for each patient, suggesting interindividual differences in hormonal responses, which may be complicated by multifactorial effects. PMID- 25511642 TI - Influence of professional experience on detection and treatment decision of occlusal caries lesions in primary teeth. AB - AIM: To evaluate the influence of examiner's clinical experience on detection and treatment decision of caries lesions in primary molars. DESIGN: Three experienced dentists (Group A) and three undergraduate students (Group B) used the International Caries Detection and Assessment System (ICDAS) criteria and bitewing radiographs (BW) to perform examinations twice in 77 primary molars that presented a sound or carious occlusal surface. For the treatment decision (TD), the examiners attributed scores, analyzing the teeth in conjunction with the radiographs. The presence and the depth of lesion were validated histologically, and reproducibility was evaluated. The sensitivity, specificity, accuracy, and area under the ROC curve values were calculated for ICDAS and BW. The associations between ICDAS, BW, and TD were analyzed by means of contingency tables. RESULTS: Interexaminer agreement for ICDAS, BW, and TD were excellent for Group B and moderate for Group A. The two groups presented similar and satisfactory performance for caries lesion detection using ICDAS and BW. In the treatment decision, Group A was shown to have a less invasive approach than Group B. CONCLUSION: The examiner's experience was not determinant for the clinical and radiographic detection of occlusal lesions in primary teeth but influenced the treatment decision of initial lesions. PMID- 25511641 TI - Consensus models for CDK5 inhibitors in silico and their application to inhibitor discovery. AB - Cyclin-dependent kinase 5 (CDK5) has emerged as a principal therapeutic target for Alzheimer's disease. It is highly desirable to develop computational models that can predict the inhibitory effects of a compound towards CDK5 activity. In this study, two machine learning tools (naive Bayesian and recursive partitioning) were used to generate four single classifiers from a large dataset containing 462 CDK5 inhibitors and 1,500 non-inhibitors. Then, two types of consensus models [combined classifier-artificial neural networks (CC-ANNs) and consensus prediction] were applied to combine four single classifiers to obtain superior performance. The results showed that both consensus models outperformed four single classifiers, and (MCC = 0.806) was superior to consensus prediction (MCC = 0.711) for an external test set. To illustrate the practical applications of the CC-ANN model in virtual screening, an in-house dataset containing 29,170 compounds was screened, and 40 compounds were selected for further bioactivity assays. The assay results showed that 13 out of 40 compounds exerted CDK5/p35 inhibitory activities with IC50 values ranging from 9.23 to 229.76 MUM. Interestingly, three new scaffolds that had not been previously reported as CDK5 inhibitors were found in this study. These studies prove that our protocol is an effective approach to predict small-molecule CDK5 affinity and identify novel lead compounds. PMID- 25511643 TI - High nuclear/cytoplasmic ratio of Cdk1 expression predicts poor prognosis in colorectal cancer patients. AB - BACKGROUND: Cdk1 (cyclin-dependent kinase 1) is critical regulator of the G2-M checkpoint. Cyclin-dependent kinase pathways are considered possible targets for cancer treatment; however, the prognostic role of Cdk1 in colorectal cancer is still controversial. Therefore, we attempted to determine the impact of Cdk1 on the clinical outcome of colorectal cancer patients to further identify its role in colorectal cancer. METHODS: Cdk1 immunoreactivity was analyzed by immunohistochemistry (IHC) in 164 cancer specimens from primary colorectal cancer patients. The medium follow-up time after surgery was 3.7 years (range: 0.01 to 13.10 years). The prognostic value of Cdk1 on overall survival was determined by Kaplan-Meier analysis and Cox proportional hazard models. RESULTS: All samples displayed detectable Cdk1 expression with predominant location in the cytoplasm and nucleus. A high Cdk1 nuclear/cytoplasmic (N/C) expression ratio was correlated with poor overall survival (5-year survival rate: 26.3% vs 46.9%, N/C ratio >=1.5 vs N/C ratio <1.5, log-rank p = 0.027). Accordingly, a Cdk1 N/C expression ratio >=1.5 was identified as an independent risk factor by multivariate analysis (hazard ratio = 1.712, P = 0.039). CONCLUSIONS: We suggest that Cdk1 N/C expression ratio determined by IHC staining could be an independent prognostic marker for colorectal cancer. PMID- 25511644 TI - Host Cxcr2-dependent regulation of mammary tumor growth and metastasis. AB - Host-derived angiogenic and inflammatory tumor supportive microenvironment regulates progression and metastasis, but the molecular mechanism(s) underlying host-tumor interactions remains unclear. Tumor expression of CXCR2 and its ligands have been shown to regulate angiogenesis, invasion, tumor growth, and metastasis. In this report, we hypothesized that host-derived Cxcr2-dependent signaling plays an important role in breast cancer growth and metastasis. Two mammary tumor cell lines Cl66 and 4T1 cells were orthotopically implanted into the mammary fat pad of wild-type and Cxcr2(-/-) female BALB/c mice. Tumor growth and spontaneous lung metastasis were monitored. Immunohistochemical analyses of the tumor tissues were performed to analyze proliferation, angiogenesis, apoptosis and immune cell infiltration. Our results demonstrated that knock-down of host Cxcr2 decreases tumor growth and metastasis by reducing angiogenesis, proliferation and enhancing apoptosis. Host Cxcr2 plays an important role in governing the pro-inflammatory response in mammary tumors as evaluated by decreased Gr1(+) tumor-associated granulocytes, F4/80(+) tumor associated macrophages, and CD11b(+)Gr1(+) myeloid derived suppressor cells in Cxcr2(-/-) mice as compared to control wild-type mice. Together, these results demonstrate that host Cxcr2-dependent signaling regulates mammary tumor growth and metastasis by promoting angiogenesis and pro-inflammatory responses. PMID- 25511646 TI - [e-cigarette: who cannot see the wood for the tree? Letter on the article "Electronic cigarette: reliable and efficient?"]. PMID- 25511645 TI - Association of serum hs-CRP and lipids with obesity in school children in a 12 month follow-up study in Japan. AB - OBJECTIVES: To investigate the association of serum lipids and high-sensitivity C reactive protein (hs-CRP) with obesity in school children and to explore whether hs-CRP levels could be used to predict the presence or absence of obesity 12 months later. METHODS: The subjects were school children (6-11 years old) in Japan. Blood sampling and physical measurements were performed in school (2001); low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and hs-CRP levels were measured. Data from children who could be followed 12 months later were analyzed. Subjects weighing 20% or more over his/her standard weight were regarded as obese, and the association of obesity with serum parameters was analyzed. RESULTS: Data from 612 subjects were analyzed (follow-up rate, 75.4%). The mean of each serum parameter was significantly higher (inverse for HDL-C; lower) in obese than that in non-obese children. Logistic regression analysis for obesity at baseline showed that the odds ratio (OR) of hs-CRP was the highest [OR, 2.15; 95% confidence interval (CI), 1.65-2.78 for an interquartile rage (IQR) increase]; the association with triglycerides and LDL-C/HDL-C was significant. At the 12-month follow-up, the OR of high hs-CRP remained the highest of all serum parameters (2.09; 95% CI, 1.63 2.69 for an IQR increase). CONCLUSIONS: High levels of triglycerides, LDL-C/HDL C, and hs-CRP increased the risk of obesity in school children. Hs-CRP is considered to be a better predictor of obesity 12 months later than is LDL-C/HDL C. PMID- 25511647 TI - [Drug induced angioedema (ACE-inhibitors and other)]. AB - Angiotensin Converting Enzyme inhibitors (ACE-I) use is a frequent cause of AE and must be suspected systematically in all patients with AE. The risk of AE is increased in: black people, transplanted patients, those who take gliptins or immunosuppressants (mTOR i). Angiotensin converting enzyme inhibitors induced angioedema (ACE-I AE) can occur a few days to several years after the beginning of this treatment and persist a few months after stopping it. ACE-I AE affect mainly the face and particularly the tongue but also the abdomen. ACE-I AE can be life threatening, due to the involvement of the tongue and the larynx. ACE-I AE must be treated as in the hereditary form when life threatening signs are present, with icatibant or C1 inhibitor concentrate. AE can occur in 10% of angiotensin receptor blockers (ARBs) treated patients who had developed ACE-I AE. PMID- 25511648 TI - [Patient's point of view]. AB - Several efficient treatments are today available for improving the quality of life of patients affected per hereditary angioedema (HAE). Choosing the right and well-adjusted treatment is not an easy task, as several complex parameters should be taken into account, due to the complexity of the disease and the large variability from patient to patient. The quality of the relationship between the patient and his medical doctor is a key point to reach the optimized and individualized treatment. PMID- 25511649 TI - [Intervention to improve the knowledge of the trustworthy person in inpatients (before and after survey)]. PMID- 25511650 TI - [Wine is good for those... who sell it! Letter on the article "Wine: good for all cardiovascular diseases?"]. PMID- 25511651 TI - [Hereditary angioedema in childhood. Diagnosis and therapeutic challenges]. AB - Hereditary angioedema is a rare disease. In case of laryngeal edema or chronic abdominal pains, diagnosis is difficult in childhood because numerous differential diagnoses possibilities are to be considered. The diagnosis of hereditary angioedema with normal C1Inh (type III) is also a challenge because it is based only on clinical features. Important school absenteeism can be due to recurrent abdominal attacks. Early diagnosis, specific management, and therapeutic education are necessary for improvement of quality of life. Actually, subcutaneous treatment is not yet available for children. Studies are going on. In the meantime, C1Inh concentrate intravenous administration must be available for children quickly and safely. PMID- 25511652 TI - [Hereditary angioedema and hormones]. AB - Hereditary angioedema (HAE) is a rare disease, which shows a preponderance of female sufferers. There are various types of HAE, with or without C1 inhibitor deficiency but estrogens may worsen the course of the disease in all the types. It is thus mandatory to know this sensitivity to estrogens in order to improve the management of women with HAE during their child-bearing ages. Contraceptive progestin can help to reduce the frequency and severity of the attacks. Pregnancies can be associated with worsening or improvement. Some other situations where endogenous or exogenous estrogens concentration can increase are possibly associated with an aggravation of the attacks (ART, tamoxifene). PMID- 25511653 TI - [Hyperemesis gravidarum: a ten-year French retrospective study of 109 patients]. AB - BACKGROUND: Hyperemesis gravidarum is the most severe form of nausea and vomiting of pregnancy. This condition has been rarely studied in France. OBJECTIVES: To study the clinical and biological features of a French cohort of women with hyperemesis gravidarum. METHODS: Retrospective data was searched in medical records for all the women admitted for hyperemesis gravidarum in the gynecologic units of the university center of Tours between January 2001 and December 2010. Data were available for 109 women. RESULTS: The prevalence of hyperemesis gravidarum was 3.9 per 1000 deliveries in our center. Half the women were not of French origin. The mean duration of the first hospitalization was 4.6+/-2.6 days (range: 1-17). Hyperemesis gravidarum was recurrent in 1/3 of the women. Routine liver function tests were found abnormal at admission or during hospitalization in 39.6% of cases with an increased ALT (>35IU/L) in 28.7% of patients. Women with elevated ALAT had more often a body mass index>25kg/m(2) (odds ratio [OR], 3.98; 95% confidence interval [CI], 1.29-12.59; P=0.01), a weight loss >=6kg (OR, 4.52; CI, 1.53-13.77; P=0.002), and a hospital stay>=6 days (OR, 3.43; CI, 1.19 9.97; P=0.009). There was no difference in pregnancy outcomes between women with normal or increased ALT. Prothrombin time was decreased (<70%) in 25.6% of cases secondary to a vitamin K deficiency. CONCLUSION: This study shows that hyperemesis gravidarum in our center is frequently associated with a non-French origin, and that abnormal liver function tests and decreases of prothrombin time are common in this condition. Our results suggest that increased ALT is a factor of severity in hyperemesis gravidarum. PMID- 25511654 TI - [Hereditary angioedema biological diagnosis]. AB - C1 inhibitor (C1 Inh) activity is an essential parameter for kinins angioedema (AE) diagnosis either hereditary or acquired or sporadic, it is analysed on plasma exclusively. Hereditary AE with C1 Inh functional deficiency is associated with alterations of the SERPING1 gene. Hereditary AE with normal C1 Inh (HAE nC1 Inh) is combined with F12 gene mutations, it is coding for Factor XII whose activity is controlled by C1 Inh, they are found in about 5% of HAE nC1 Inh cases. Every loss of C1 Inh activity must be taken as anormal by clinicians even for women with oral oestroprogestatives, it would be confirmed by the presence of cleaved C1 Inh. The kinins (primarily bradykinin) are the mediators responsible for local increase of vascular permeability. Bradykinin is released from high MW kininogen (HK) during the contact system activation. Plasma proteases mainly support this proteolytic activity controlled by C1 Inh. Family of a patient diagnosed with HAE must be studied, symptomatic as asymptomatic members indeed clinical symptoms regularly emerge very late in the life. PMID- 25511655 TI - [Emergency management of bradykinin-mediated angioedema]. AB - In the emergency setting, the diagnosis of bradykinin-mediated angioedema is based exclusively on history and physical examination. Severe attacks must be identified because the evolution is unpredictable with a risk of life-threatening airway obstruction. Underestimate the severity of the attack is a management pitfall to avoid. All attack under the shoulders should be considered as severe and must benefit from early specific treatment. PMID- 25511656 TI - [Diagnosis of hereditary angioedema]. AB - Hereditary angioedema is a rare disease, potentially life-threatening. It requires a specific treatment. Angioedema without wheals associated with abdominal attacks are very specific of this disease. Antigenemy and functional C1Inhibitor assays are necessary for the diagnosis. The hereditary angioedema with normal C1Inh (type III) is a diagnostic challenge. Bradykinin, secondary to kallikrein-kinin system activation is the key mediator of hereditary angioedema. Female are more symptomatic. Attacks can be induced by menstruations, pregnancies or contraceptive pills. PMID- 25511657 TI - [Recurrent painful ophthalmoplegia revealing orbital myositis]. PMID- 25511658 TI - Geographic origin is not supported by the genetic variability found in a large living collection of Jatropha curcas with accessions from three continents. AB - Increasing economic interest in Jatropha curcas requires a major research focus on the genetic background and geographic origin of this non-edible biofuel crop. To determine the worldwide genetic structure of this species, amplified fragment length polymorphisms, inter simple sequence repeats, and novel single nucleotide polymorphisms (SNPs) were employed for a large collection of 907 J. curcas accessions and related species (RS) from three continents, 15 countries and 53 regions. PCoA, phenogram, and cophenetic analyses separated RS from two J. curcas groups. Accessions from Mexico, Bolivia, Paraguay, Kenya, and Ethiopia with unknown origins were found in both groups. In general, there was a considerable overlap between individuals from different regions and countries. The Bayesian approach using STRUCTURE demonstrated two groups with a low genetic variation. Analysis of molecular varience revealed significant variation among individuals within populations. SNPs found by in silico analyses of Delta12 fatty acid desaturase indicated possible changes in gene expression and thus in fatty acid profiles. SNP variation was higher in the curcin gene compared to genes involved in oil production. Novel SNPs allowed separating toxic, non-toxic, and Mexican accessions. The present study confirms that human activities had a major influence on the genetic diversity of J. curcas, not only because of domestication, but also because of biased selection. PMID- 25511660 TI - A promising candidate with D-A-A-A architecture as an efficient sensitizer for dye-sensitized solar cells. AB - A series of metal-free organic dyes with electron-rich (D) and electron-deficient units (A) as pi linkers have been studied theoretically by means of density functional theory (DFT) and time-dependent DFT calculations to explore the effects of pi spacers on the optical and electronic properties of triphenylamine dyes. The results show that Dye 1 with a structure of D-A-A-A is superior to the typical C218 dye in various key aspects, including the maximum absorption (lambdamax =511 nm), the charge-transfer characteristics (D/Deltaq/t is 5.49 A/0.818 e(-) /4.41 A), the driving force for charge-carrier injection (DeltaGinject =1.35 eV)/dye regeneration (DeltaGregen =0.27 eV), and the lifetime of the first excited state (tau=3.1 ns). It is thus proposed to be a promising candidate in dye-sensitized solar cell applications. PMID- 25511659 TI - Effects of dietary creatine supplementation on systemic microvascular density and reactivity in healthy young adults. AB - BACKGROUND: Dietary creatine supplementation (CrS) is a practice commonly adopted by physically active individuals. However, the effects of CrS on systemic microvascular reactivity and density have never been reported. Additionally, CrS is able to influence blood levels of homocysteine, resulting in presumed effects on vascular endothelial function. Thus, we investigated the effects of CrS on the systemic microcirculation and on homocysteine levels in healthy young individuals. METHODS: This open-label study was performed on a group of 40 healthy male, moderately physically active subjects aged 27.7 +/- 13.4 years who received one week of CrS at a dose of 20 g/day of commercially available micronized creatine monohydrate. Laser speckle contrast imaging was used in the evaluation of cutaneous microvascular reactivity, and intra-vital video microscopy was used to evaluate skin capillary density and reactivity, before and after CrS. RESULTS: CrS did not alter plasma levels of homocysteine, although CrS increased creatinine (p = 0.0001) and decreased uric acid (p = 0.0004) plasma levels. Significant changes in total cholesterol (p = 0.0486) and LDL-cholesterol (p = 0.0027) were also observed along with a reduction in plasma levels of T3 (p = 0.0074) and an increase in T4 levels (p = 0.0003). Skin functional capillary density (p = 0.0496) and capillary recruitment during post-occlusive reactive hyperemia (p = 0.0043) increased after CrS. Increases in cutaneous microvascular vasodilation induced by post-occlusive reactive hyperemia (p = 0.0078) were also observed. CONCLUSIONS: Oral supplementation with creatine in healthy, moderately physically active young adults improves systemic endothelial-dependent microvascular reactivity and increases skin capillary density and recruitment. These effects are not concurrent with changes in plasma homocysteine levels. PMID- 25511661 TI - Meta-analysis of superficial versus deep injection of radioactive tracer and blue dye for lymphatic mapping and detection of sentinel lymph nodes in breast cancer. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in early breast cancer. Currently, no consensus exists on the optimal site of injection of the radioactive tracer or blue dye. METHODS: A systematic review and meta-analysis of studies comparing superficial and deep injections of radioactive tracer or blue dye for lymphatic mapping and SLNB was performed. The axillary and extra-axillary sentinel lymph node (SLN) identification rates obtained by lymphoscintigraphy and intraoperative SLNB were evaluated. Pooled odds ratios (ORs) and 95 per cent c.i. were estimated using fixed-effect analyses, or random-effects analyses if there was statistically significant heterogeneity (P < 0.050). RESULTS: Thirteen studies were included in the meta-analysis. There was no significant difference between superficial and deep injections of radioactive tracer for axillary SLN identification on lymphoscintigraphy (OR 1.59, 95 per cent c.i. 0.79 to 3.17), during surgery (OR 1.27, 0.60 to 2.68) and for SLN identification using blue dye (OR 1.40, 0.83 to 2.35). The rate of extra-axillary SLN identification was significantly greater when deep rather than superficial injection was used (OR 3.00, 1.92 to 4.67). The discordance rate between superficial and deep injections ranged from 4 to 73 per cent for axillary and from 0 to 61 per cent for internal mammary node mapping. CONCLUSION: Both superficial and deep injections of radioactive tracer and blue dye are effective for axillary SLN identification. Clinical consequences of discordance rates between the two injection techniques are unclear. Deep injections are associated with significantly greater extra-axillary SLN identification; however, this may not have a significant impact on clinical management. PMID- 25511662 TI - Natural and inducible Tregs in swine: Helios expression and functional properties. AB - Within the population of regulatory T cells (Tregs) natural Tregs (nTregs) and inducible Tregs (iTregs) can be distinguished. Although information about Tregs in swine exists, porcine iTregs were not under investigation yet. In this study, Foxp3(+) iTregs were generated from CD4(+)Foxp3(-) T cells by in vitro stimulation in the presence of IL-2 and TGF-beta. In comparison to ex vivo Tregs these iTregs had a similar suppressive capacity on the proliferation of CD3 stimulated PBMC, caused higher levels of IL-10 in PBMC/Treg co-cultures, but did not suppress IFN-gamma levels. The Ikaros family member Helios is currently discussed to distinguish iTregs and nTregs or to serve as an activation marker of Tregs. In this study, we demonstrate the cross-reactivity of an anti-mouse/human Helios mAb with porcine Helios. Flow cytometric analyses with this antibody showed that porcine iTregs do not express Helios after in vitro iTreg induction. Nevertheless, thymic Foxp3(+) T cells, which arise at the CD4/CD8alpha single positive stage of T-cell development and are defined as nTregs, entirely expressed Helios. Although this might suggest the suitability of Helios as an nTreg-iTreg differentiation marker we also found that Helios(-) Tregs displayed a phenotype of naive CD4(+) T cells in vivo. Since iTregs are by definition activated/differentiated Tregs, this finding precludes that all Helios(-) Tregs are iTregs and thus also the use of Helios as a selection marker for porcine nTregs. Furthermore, Helios(+) Tregs displayed a more differentiated phenotype indicating that Helios might rather serve as a Treg activation/differentiation marker. PMID- 25511663 TI - A qualitative study of children's snack food packaging perceptions and preferences. AB - BACKGROUND: Food marketing is pervasive in high- and low/middle-income countries and is recognized as a significant risk factor for childhood obesity. Although food packaging is one of the most important marketing tools to persuade consumers at the point-of-sale, scant research has examined how it influences children's perceptions. This study was conducted in Guatemala and aimed to understand which snack foods are the most frequently purchased by children and how aspects of food packaging influence their product perceptions. METHODS: Six activity-based focus groups were conducted in two elementary public schools with thirty-seven children (Grades 1 through 6, age range 7-12 years old). During each focus group, children participated in three activities: 1) list their most frequently purchased food products; 2) select the picture of their favorite product, the packaging they liked best, and the product they thought was the healthiest from eight choices; and 3) draw the package of a new snack. RESULTS: Children reported purchasing salty snacks most frequently. Most children chose their favorite product based on taste perceptions, which can be influenced by food packaging. Visual elements influenced children's selection of favorite packaging (i.e., characters, colors) and healthiest product (i.e., images), and persuaded some children to incorrectly think certain foods contained healthy ingredients. When children generated their own drawings of a new product, the most frequently included packaging elements in the drawings were product name, price, product image and characters, suggesting those aspects of the food packaging were most significant to them. CONCLUSIONS: Policies regulating package content and design are required to discourage consumption of unhealthy snacks. This might be another public health strategy that can aid to halt the obesity epidemic. PMID- 25511664 TI - Coronary artery bypass grafting in single-ventricle patients palliated with Fontan procedure: future consideration. PMID- 25511665 TI - Comments to: Aristotle Score for ''Hybrid Procedure''. PMID- 25511666 TI - Bone density in children with single ventricle physiology. AB - Children with chronic diseases are at risk for low bone mineral density (BMD). There are no studies of BMD in children with congenital heart disease and particularly single ventricle (SV). Children with this defect are often treated with warfarin, suspected to negatively impact BMD in adults. We assessed BMD in patients with SV physiology and compared the BMD of subjects taking warfarin to those who were not. Subjects 5-12 years with SV were included. BMD z scores by dual-energy X-ray absorptiometry of the spine and total body less head (TBLH) were obtained. Calcium intake, activity level, height, and Tanner stage were assessed. Linear regression models and t tests were used to investigate differences between participants and normative data as well as between subjects' subgroups. Twenty-six subjects were included and 16 took warfarin. Mean BMD z score at the spine was significantly lower than expected at -1.0 +/- 0.2 (p < 0.0001), as was the BMD z score for TBLH at -0.8 +/- 0.2 (p < 0.0001). Those results remained significant after adjusting for height. Subjects who were on warfarin tended to have lower BMD at both the spine and TBLH than those who were not, with a z score difference of 0.6 +/- 0.46 at the spine (p = 0.106) and a difference of 0.4 +/- 0.34 at TBLH (p = 0.132). BMD is significantly reduced in children with SV. Warfarin appears to lower BMD but the effect is less conclusive. Continued evaluation is recommended for these patients at risk for reduced bone density. Evaluation of other cardiac patients on warfarin therapy should also be considered. PMID- 25511667 TI - De novo assembly of the desert tree Haloxylon ammodendron (C. A. Mey.) based on RNA-Seq data provides insight into drought response, gene discovery and marker identification. AB - BACKGROUND: Haloxylon ammodendron (C. A. Mey.) is widely distributed across a range of habitats, including gravel desert, clay desert, fixed and semi-fixed sand, and saline land in Asian and African deserts. To date, no genomic information or expressed sequence tag-simple sequence repeat (EST-SSR) marker has been reported for H. ammodendron plants. RESULTS: Using Illumina sequencing technology, we generated over two billion bases of high-quality sequence data on H. ammodendron and conducted de novo assembly and annotation of genes without prior genome information. These reads were assembled into 79,918 unigenes (mean length = 728 bp). Based on similarity searches comparing these unigenes with known proteins in the non-redundant (nr) protein database, 25,619 unigenes were functionally annotated with a cut-off E-value of 10-5. In addition, DGE reads were mapped to the assembled transcriptome for gene expression analysis under drought stress. In total, 1,060 differentially expressed genes were identified. Among these genes, 356 genes were upregulated after drought treatment, and 704 genes were downregulated. We used the KEGG database to annotate these drought induced genes; 207 unigenes were identified in the KEGG pathway annotation, and approximately 12.1% of the unigenes with known function fell into categories related to fatty acid metabolism, starch and sucrose metabolism, and nitrogen metabolism, suggesting that these pathways or processes may be involved in the drought response. Together, a total of 35 drought-inducible transcription factors were identified, including WRKY, MYB and bZIP family members. CONCLUSIONS: Our study is the first to provide a transcriptome sequence resource for H. ammodendron plants and to determine its digital gene expression profile under drought conditions using the assembled transcriptome data for reference. These data provide a valuable resource for genetic and genomic studies of desert plants under abiotic conditions. PMID- 25511668 TI - Nonray-tracing determination of the 3D refractive index profile of polymeric fibres using single-frame computed tomography and digital holographic interferometric technique. AB - In this paper, we present a nonray-tracing technique for evaluating the three dimensional distribution of the refractive index values inside polymeric fibres. This technique, named 'single-frame computed-tomography (SFCT)', is applied to digital holography. A comparative study between the calculated optical phase values using ordinary tomography and SFCT is carried out, and a negligible deviation is detected. The proposed technique is used to determine the three dimensional refractive index profile of isotactic Polypropylene fibres, IPP. The variation of the optical properties is measured before, during and after the formation of the necking phenomenon. In addition, SFCT technique is applied to the online determination of the change of the optical properties of IPP fibres. Holograms are given for illustration. PMID- 25511669 TI - Support for the hypoxia theory in the pathogenesis of infantile haemangioma. AB - BACKGROUND: The pathogenesis of infantile haemangioma (IH) is unknown. Several mechanisms have been proposed, including hypoxia, which triggers upregulation and stabilization of hypoxia-inducible factor (HIF)1alpha. HIF1alpha stimulates downstream transcription of target genes that enhance angiogenesis. AIM: To identify possible involvement of hypoxia in the pathogenesis of IH, as hypoxia signalling constitutes a potential therapeutic target. METHODS: IH tissue samples collected during the period 1991-2011 (preserved in paraffin wax) were immunohistochemically analysed for HIF1alpha and the known HIF1alpha targets: BCL2/adenovirus E1B kD-interacting protein family member 3 (BNIP3), carbon anhydrase (CA)-IX, glucose transporter (GLUT)-1, phosphorylated protein kinase B (pAKT), phosphorylated S6 protein (pS6) and vascular endothelial growth factor (VEGF). Four observers independently assessed the findings. RESULTS: Of the 10 IH samples, 2 appeared to be in the growth phase. In all samples, GLUT-1, BNIP3, pAKT and VEGF were positive, CA-IX was weakly positive, and HIF1alpha was negative. pS6 was positive in 9/10 cases and negative in 1/10. CONCLUSIONS: Several factors implicated in hypoxia-induced angiogenesis may be involved in IH development. However, the small sample size and retrospective approach of the study preclude definitive conclusions. Prospective studies are needed to conclusively determine which of the factors involved in the (hypoxia) cascade are required for an IH to grow, and could thus be a possible target of drugs for IH treatment. PMID- 25511671 TI - Predictive modeling for epidural abscess: what we can, can't, and should do about it. PMID- 25511672 TI - Letter concerning "Adolescent idiopathic scoliosis: the possible harm of bracing and the likely benefit of exercise" by Falk et al. PMID- 25511673 TI - Adolescent idiopathic scoliosis: the possible harm of bracing and the likely benefit of exercise. PMID- 25511674 TI - In memoriam: A life scientific--John Woodland 'Woody' Hastings (1927-2014). PMID- 25511679 TI - Readmission following ventral hernia repair: a model derived from the ACS-NSQIP datasets. AB - BACKGROUND: Institutions are now incentivized to decrease rates of preventable readmissions. The purpose of this study was to examine readmissions following open ventral hernia repair (VHR), to ultimately create a model to preoperatively identify high-risk patients. STUDY DESIGN: Utilizing the 2011 and 2012 ACS-NSQIP datasets, patients undergoing open VHR were identified by CPT codes. Patients who were readmitted in 2011 within 30 days of the procedure were compared to those who were not with regard to preoperative and operative characteristics. A bootstrap analysis was performed to identify internally validated risk factors to be included in the final logistic regression, which was utilized to create a weighted model to predict the risk of readmission. This model was then validated with VHR patients in 2012. RESULTS: Overall, 10,745 patients were included for model generation. Of these, 850 (7.9%) patients were readmitted within 30 days. The final bootstrap analysis demonstrated that active smoking, ASA >= 3, a history of bleeding disorder or anemia, long operative time, inpatient status, and concurrent panniculectomy were all independently associated with readmission following ventral hernia repair. Significant variables were assigned a weighted score, ranging from 1 to 3. Each patient was then placed into one of four cohorts according to their summed score. The internally validated model [Hernia Readmission Risk (HERR) Score] demonstrated that risk increased in a linear fashion, with the highest risk cohort having a 21% risk of 30-day readmission. CONCLUSIONS: Perioperative predictors of readmission following VHR include smoking, ASA score, operative magnitude, concurrent panniculectomy, and preoperative anemia and bleeding disorders. The presented model based on these factors can aid in perioperative risk stratification for readmission. PMID- 25511681 TI - Novel therapeutic combination demonstrates more than additive effects in cutaneous T-cell lymphoma. PMID- 25511682 TI - Monoclonal B-lymphocytosis in patients aged over 90 years is common but not inevitable, and has a prevalence comparable to that in individuals aged 65-90 years. PMID- 25511680 TI - Induction of TAp73 by platinum-based compounds to overcome drug resistance in p53 dysfunctional chronic lymphocytic leukemia. AB - In chronic lymphocytic leukemia (CLL), strategies to overcome drug resistance due to p53 dysfunction are highly needed. Platinum-based compounds such as cisplatinum (CDDP) are active in fludarabine-refractory CLL through a largely unknown mechanism. We analyzed the mechanism of action of CDDP in the context of p53 dysfunctionality. In vitro treatment with CDDP did not induce death in quiescent CLL cells, but did induce apoptosis in CD40-ligand (and CpG) stimulated and proliferating cells, irrespective of p53 function. In the p53 dysfunctional prolymphocytic cell-line MEC1, CDDP treatment resulted in apoptosis, cell cycle arrest and ABL1-dependent expression of TAp73, CDKN1A, PUMA and BID. TAp73 RNA interference decreased sensitivity to CDDP. Finally, both in vitro stimulated CLL cells and lymph node (LN) derived CLL cells showed increased TAp73 expression in comparison with quiescent peripheral blood derived cells. Activity of CDDP may therefore be mediated by TAp73, especially in the context of activation such as occurs in the LN microenvironment. PMID- 25511683 TI - Apoptosis in ovarian granulosa cells of cattle: morphological features and clearance by homologous phagocytosis. AB - Apoptosis is involved in many physiological processes of the ovary, such as recruitment of prenatal germ cells, follicular atresia, ovulation, and luteolysis. Based on the need for the involvement of phagocytic cells to achieve apoptosis clearance and that follicular atresia is triggered by weak apoptotic stimuli, we postulate that granulosa cells engullng apoptotic corpses (ACs) must carry out this macrophagic process. Since apoptosis was early defined in terms of morphological aspects, here we describe apoptosis induced by a GnRH analog (leuprolide acetate, LA) at histological level on bovine granulosa cells (primary culture, CPGB, and an established cell line, BGC-1). We observed two main types of apoptosis. In type A, the whole cell or most of it is compacted into a single large AC that is then engulfed by neighboring cells or simply detached. In type B, small portions of cells, either with or without nuclear material, become ACs that are also phagocytosed. Apoptosis and homologous phagocytosis were confirmed by TUNEL and immunocytochemistry for Bax and active caspase 3. Induction of apoptosis was significant in BGC-1 cells treated for 24 h with 100 nM LA. CPGB cells showed two types of response with different doses of LA. Fetal calf serum was necessary to find apoptosis induced by LA. PMID- 25511684 TI - 2,1,3-Benzothiadiazole-5,6-dicarboxylic imide--a versatile building block for additive- and annealing-free processing of organic solar cells with efficiencies exceeding 8%. AB - A new photoactive polymer comprising benzo[1,2-b:3,4-b':5,6-d']trithiophene and 2,1,3-benzothiadiazole-5,6-dicarboxylic imide is reported. The synthetic design allows for alkyl chains to be introduced on both electron-rich and electron deficient components, which in turn allows for rapid optimization of the alkyl chain substitution pattern. Consequently, the optimized polymer shows a maximum efficiency of 8.3% in organic photovoltaic devices processed in a commercially viable fashion without solvent additives, annealing, or device engineering. PMID- 25511685 TI - Dapagliflozin twice daily or once daily: effect on pharmacokinetics and urinary glucose excretion in healthy subjects. AB - The primary objective of this single-centre, open-label crossover study (NCT01072578) was to assess the effect of dapagliflozin on the amount of glucose in the blood and urine in healthy volunteers when dapagliflozin was administered once a day (10 mg) versus twice a day (5 mg every 12 h) after 5 days of dosing. At steady state, the AUC(ss)0-24 (area under the dapagliflozin curve (0-24 hours) at steady state), C(ss,av) (average concentration at steady state) between dapagliflozin 5 mg twice daily and 10 mg once daily were similar AUC(ss)0-24 [5 mg bid, (458.0 (28.7)) and 10 mg qd, (470.0 (28.5))] and C(ss,av) [5 mg bid 18.8 (28.9)) and 10 mg qd, (19.6(28.5))], but minimum and maximum plasma levels of dapagliflozin differed significantly. Percent inhibition of renal glucose reabsorption (%IRGRA) and total urinary glucose excretion over 24 h were similar for both doses. The relationship between the mean dapagliflozin concentration and %IRGRA and the total urinary glucose excreted was well described by a maximum effect model. The results indicate that dapagliflozin may be used for either once daily or twice daily administration. PMID- 25511687 TI - Demonstration of a refractometric sensor based on an optical micro-fiber three beam interferometer. AB - With diameter close to the wavelength of the guided light and high index contrast between the fiber and the surrounding, an optical micro-fiber shows a variety of interesting waveguiding properties, including widely tailorable optical confinement, strong evanescent fields and waveguide dispersion. Among various micro-fiber applications, optical sensing has been attracting increasing research interest due to its possibilities of realizing miniaturized fiber optic sensors with small footprint, high sensitivity, and low optical power consumption. Typical micro-fiber based sensing structures, including Michelson interferometer, Mach-Zenhder interferometer, Fabry-Perot interferometer, micro-fiber ring resonator, have been proposed. The sensitivity of these structures heavily related to the fraction of evanescent field outside micro-fiber. In this paper, we report the first theoretical and experimental study of a new type of refractometric sensor based on micro-fiber three-beam interferometer. Theoretical and experimental analysis reveals that the sensitivity is not only determined by the fraction of evanescent field outside the micro-fiber but also related to the values of interferometric arms. The sensitivity can be enhanced significantly when the effective lengths of the interferometric arms tends to be equal. We argue that this has great potential for increasing the sensitivity of refractive index detection. PMID- 25511688 TI - The immediate effect of kinesiology taping on muscular imbalance in the lateral flexors of the neck in infants: a randomized masked study. AB - OBJECTIVE: To investigate the immediate effect of kinesiology taping (KT) on muscular imbalance in the lateral flexors of the neck. DESIGN: Randomized controlled trial. PARTICIPANTS: Twenty-nine infants with congenital muscular torticollis and muscular imbalance in the lateral flexors of the neck were chosen consecutively. In addition, 5 healthy infants with no signs of muscular imbalance in the neck were tested. METHOD: The infants were randomly allocated to either an intervention group or a control group. The intervention group had kinesiology taping applied on the affected side using the muscle-relaxing technique. The healthy infants were tested both with and without kinesiology taping. The evaluator was blinded to whether the infants were or were not taped. RESULTS: There was a significant difference in the change of Muscle Function Scale (MFS) scores between the groups (P < .0001). In the intervention group, there were significantly lower scores on the affected side that had been taped (P < .0001) and also significantly higher scores on the unaffected side (P = .01). There were no significant differences in the control group. For the healthy infants, with no imbalance in the lateral flexors of the neck, there were no changes to the MFS scores regardless of whether the kinesiology tape was applied. CONCLUSIONS: For infants with congenital muscular torticollis, kinesiology taping applied on the affected side had an immediate effect on the MFS scores for the muscular imbalance in the lateral flexors of the neck. PMID- 25511686 TI - Altered thyroid hormone profile in offspring after exposure to high estradiol environment during the first trimester of pregnancy: a cross-sectional study. AB - BACKGROUND: The increasing number of babies conceived by in vitro fertilization and embryo transfer (IVF-ET) shifts concern from pregnancy outcomes to long-time health of offspring. Maternal high estradiol (E2) is a major characteristic of IVF-ET and lasts throughout the first trimester of pregnancy. The fetal thyroid develops during this period and may thus be affected by exposure to the supra physiological E2. The aim of this study is to investigate whether the high E2 maternal environment in the first trimester increases the risk of thyroid dysfunction in children born following IVF-ET. METHODS: A cross-sectional survey design was used to carry out face-to-face interviews with consecutive children attending the hospital. A total of 949 singletons born after fresh embryo transfer (ET) (n=357), frozen ET (n=212), and natural conception (NC) (n=380), aged 3 to 10 years old, were included. All children were thoroughly examined. Meanwhile, another 183 newborns, including 55 fresh ET, 48 frozen ET, and 80 NC were studied. Levels of serum T3, FT3, T4, FT4, and TSH and levels of maternal E2 at different stages of the first trimester were examined. RESULTS: The mean serum E2 levels of women undergoing fresh ET during the first trimester of pregnancy were significantly higher than those of the women undergoing frozen ET or following NC. The thyroid hormone profile, especially the levels of T4, FT4, and TSH, were significantly increased in 3- to 10-year-old children conceived by fresh ET compared to NC. The same tendency was confirmed in newborns. However, levels of T4 and TSH in the frozen ET group were nearer to that of the NC group. Furthermore, levels of T4 and FT4 in fresh ET were positively correlated with maternal serum levels of E2 during early pregnancy. CONCLUSIONS: The maternal high E2 environment in the first trimester is correlated with increased risk of thyroid dysfunction. Frozen ET could reduce risks of thyroid damage in children conceived by IVF. Further studies are needed to confirm these findings and to better determine the underlying molecular mechanisms and clinical significance. TRIAL REGISTRATION: ChicCTR-OCC-14004682 (22-05-2014). PMID- 25511689 TI - Radiologic presentation of a type 1 dens fracture. PMID- 25511690 TI - Inpatient and emergency room visits for adolescents and young adults with spina bifida living in South Carolina. AB - OBJECTIVE: To compare emergency room (ER) and inpatient hospital (IP) use rates for persons with spina bifida (SB) to peers without SB, when transition from pediatric to adult health care is likely to occur; and to analyze those ER and IP rates by age, race, socioeconomic status, gender, and type of residential area. DESIGN: A retrospective cohort study. SETTING: Secondary data analysis in South Carolina. PARTICIPANTS: We studied individuals who were between 15 and 24 years old and enrolled in the State Health Plan (SHP) or state Medicaid during the 2000 2010 study period. METHODS: Individuals with SB were identified using ICD-9 billing codes (741.0, 741.9) in SHP, Medicaid, and hospital uniform billing (UB) data. ER and IP encounters were identified using UB data. Multivariable Generalized Estimating Equation (GEE) Poisson models were estimated to compare rates of ER and IP use among the SB group to the comparison group. MAIN OUTCOME MEASURES: Total ER rate and IP rate, in addition to cause-specific rates for ambulatory care sensitive conditions (ACSC) and other condition categories. RESULTS: We found higher rates of ER and IP use in persons with SB compared to the control group. Among individuals with SB, young adults (those 20-24 years old) had higher rates of ER use due to all ACSC (P = .023), other ACSC (P = .04), and urinary tract infections (UTI; P = .002) compared to adolescents (those 15-19 years old). CONCLUSIONS: Young adulthood is associated with increased ER use overall, as well as in specific condition categories (most notably UTI) in individuals 15-24 years old with SB. This association may be indicative of changing healthcare access as people with SB move from adolescent to adult health care, and/or physiologic changes during the age range studied. PMID- 25511691 TI - Knee flexion contractures in patients with osteoarthritis: clinical features and histologic characterization of the posterior capsule. AB - OBJECTIVE: To (1) identify demographic and clinical factors associated with knee flexion contracture (KFlC) in the setting of osteoarthritis (OA) and (2) histologically compare the posterior knee capsule of patients with OA with and without KFlC. DESIGN: Cross-sectional study. SETTING: Primary care, including private and institutional practice. PATIENTS: Thirteen patients with primary OA and KFlC and 8 patients with primary OA without KFlC. METHODS: We compared the KFlC and non-KFlC groups to identify demographic and clinical factors associated with KFlC. We examined the histology of the posterior knee capsules of 9 patients with KFlC and 6 without. MAIN OUTCOME MEASUREMENTS: Patient demographic and clinical factors. For histology we measured the proportional composition of collagenous, adipose, and synovial tissues; fibroblast and adipocyte cellularity; and synovial thickness. RESULTS: Patients with contracture had longer duration of OA, reduced flexion of the surgical knee, and reduced extension of the contralateral knee (P = .04, <.01, and <.01 respectively). Histologically, there was a greater proportion of collagenous tissue and a lower proportion of adipose and synovial tissues in the contracture group than in the noncontracture group; however, the differences were not statistically significant. Cellularity was similar between the 2 groups. CONCLUSIONS: Longer duration of knee OA, reduced surgical knee flexion, and reduced contralateral, nonsurgical knee extension were associated with KFlC in the OA knee undergoing total arthroplasty. Monitoring bilateral knee range of motion in patients with longer-duration OA could allow earlier intervention, reducing functional loss. Capsular tissue composition analysis may indicate a fibrotic disease process. Further research in which a larger sample size is used will help clarify these novel findings. PMID- 25511692 TI - Increased risk of glomerulonephritis and chronic kidney disease in relation to the severity of psoriasis, concomitant medication, and comorbidity: a nationwide population-based cohort study. AB - BACKGROUND: Few studies have examined the association between psoriasis and glomerulonephritis (GN) as well as chronic kidney disease (CKD). OBJECTIVES: To determine the risk of CKD in patients with psoriasis and evaluate the impact of the severity of psoriasis, comorbidities and concomitant drugs on the risk of GN and CKD in patients with psoriasis. METHODS: We identified 4344 patients with psoriasis for the study cohort and randomly selected 13,032 subjects as a control cohort. Each subject was individually followed for up for 5 years to identify those who subsequently developed GN and CKD. RESULTS: After adjustment for traditional CKD risk factors, psoriasis was found to be independently associated with an increased risk of CKD during the follow-up period [hazard ratio (HR) 1.28; 95% confidence interval (CI) 1.14-1.44]. The increased incidence of GN in patients with psoriasis (HR 1.50, 95% CI 1.24-1.81) may contribute to the positive association between psoriasis and CKD. Patients with mild and severe psoriasis had an increased risk of CKD and GN compared with the control cohort; the risk increased with severity. Patients with psoriasis and arthritis exhibited a higher risk of CKD than patients without arthritis (HR 1.62 vs. 1.26). Among drugs, nonsteroidal anti-inflammatory drugs (NSAIDs) have the strongest association with CKD in patients with psoriasis (adjusted odds ratio 1.69, 95% CI 1.14-2.49). CONCLUSIONS: Psoriasis was associated with a higher risk of developing CKD and GN. High severity, psoriatic arthritis involvement and concomitant NSAIDs use further increased the risk of CKD in patients with psoriasis. PMID- 25511693 TI - Glucagon directly interacts with vagal afferent nodose ganglion neurons to induce Ca(2+) signaling via glucagon receptors. AB - Glucagon is released from the pancreatic islets postprandially and under hypoglycemic and cold conditions, and regulates glucose metabolism, feeding, energy expenditure and heat production, the functions partly controlled by the brain. Peripheral glucagon could signal to the brain via passing through the blood-brain barrier and/or acting on the vagal afferent. However, the latter remains to be determined. The present study aimed to clarify whether glucagon directly interacts with the nodose ganglion (NG) neurons of vagal afferent nerves in mice. In vivo study showed that intraperitoneal injection of glucagon induced phosphorylation of extracellular signal regulated kinase 1 and 2 (ERK1/2), cellular activation makers, in NG neurons. In fura-2 microfluorometric studies, glucagon increased cytosolic Ca(2+) concentration ([Ca(2+)]i) in single NG neurons. The glucagon-induced [Ca(2+)]i increases were suppressed by a glucagon receptor antagonist, des-His(1)-[Glu(9)]-Glucagon (1-29) amide, and the glucagon receptor mRNA was expressed in NG neurons. The majority of glucagon-responsive NG neurons exhibited [Ca(2+)]i responses to insulin and cholecystokinin-8, the hormones that are secreted postprandially and implicated in satiety. These results demonstrate that glucagon, by interacting with the glucagon receptor, directly activates vagal afferent nerves, possibly being relayed to the signaling to the brain and formation of satiety. PMID- 25511694 TI - Rho-kinase signaling controls nucleocytoplasmic shuttling of class IIa histone deacetylase (HDAC7) and transcriptional activation of orphan nuclear receptor NR4A1. AB - Rho-kinase (ROCK) has been well documented to play a key role in RhoA-induced actin remodeling. ROCK activation results in myosin light chain (MLC) phosphorylation either by direct action on MLC kinase (MLCK) or by inhibition of MLC phosphatase (MLCP), modulating actin-myosin contraction. We found that inhibition of the ROCK pathway in induced pluripotent stem cells, leads to nuclear export of HDAC7 and transcriptional activation of the orphan nuclear receptor NR4A1 while in cells with constitutive ROCK hyperactivity due to loss of function of the RhoGTPase activating protein Oligophrenin-1 (OPHN1), the orphan nuclear receptor NR4A1 is downregulated. Our study identify a new target of ROCK signaling via myosin phosphatase subunit (MYPT1) and Histone Deacetylase (HDAC7) at the nuclear level and provide new insights in the cellular functions of ROCK. PMID- 25511695 TI - Activation of apoptosis by caspase-3-dependent specific RelB cleavage in anticancer agent-treated cancer cells: involvement of positive feedback mechanism. AB - DTCM-glutarimide (DTCM-G) is a newly found anti-inflammatory agent. In the course of experiments with lymphoma cells, we found that DTCM-G induced specific RelB cleavage. Anticancer agent vinblastine also induced the specific RelB cleavage in human fibrosarcoma HT1080 cells. The site-directed mutagenesis analysis revealed that the Asp205 site in RelB was specifically cleaved possibly by caspase-3 in vinblastine-treated HT1080 cells. Moreover, the cells stably overexpressing RelB Asp205Ala were resistant to vinblastine-induced apoptosis. Thus, the specific Asp205 cleavage of RelB by caspase-3 would be involved in the apoptosis induction by anticancer agents, which would provide the positive feedback mechanism. PMID- 25511696 TI - Overexpression of malic enzyme in the larval stage extends Drosophila lifespan. AB - Metabolic modifications during the developmental period can extend longevity. We found that malic enzyme (Men) overexpression during the larval period lengthened the lifespan of Drosophila. Men overexpression by S106-GeneSwitch-Gal4 driver increased pyruvate content and NADPH/NADP(+) ratio but reduced triglyceride, glycogen, and ATP levels in the larvae. ROS levels increased unexpectedly in Men overexpressing larvae. Interestingly, adults exposed to larval Men-overexpression maintained ROS tolerance with enhanced expression levels of glutathione-S transferase D2 and thioredoxin-2. Our results suggest that metabolic changes mediated by Men during development might be related to the control of ROS tolerance and the longevity of Drosophila. PMID- 25511697 TI - Glycine receptor-mediated inhibition of medial prefrontal cortical pyramidal cells. AB - Using whole-cell patch clamp recording on medial prefrontal cortical slices of rats aged 17-33 postnatal days, we demonstrated the glycine-induced strychnine sensitive outward currents. The amplitude of the peak current increased with the concentrations of glycine with an EC50 of 74.7 MUM. Application of 1MUM strychnine alone to cells caused a slight inward current without blocking the sIPSCs, indicating that GlyRs in the mPFC are activated by an endogenous ligand that can be released tonically. Glycine reversibly depressed firing rate in cells from both layer 6 and layer 3, with significantly greater inhibition on the former than the latter (EC50 12.9 vs 85.6 MUM). Glycine hyperpolarized membrane potential in cells of both layer 6 and layer 3 depending on its concentrations, with an IC50 of 99.1 and 207.2 MUM, respectively. We propose that GlyRs participate in a novel inhibitory mechanism in mPFC, modulating neuronal activity. This finding further supports an important role of GlyR in cortical function and dysfunction. PMID- 25511698 TI - The MUC1 oncomucin regulates pancreatic cancer cell biological properties and chemoresistance. Implication of p42-44 MAPK, Akt, Bcl-2 and MMP13 pathways. AB - MUC1 is an oncogenic mucin overexpressed in several epithelial cancers, including pancreatic ductal adenocarcinoma, and is considered as a potent target for cancer therapy. To this aim, we undertook to study MUC1 biological effects on pancreatic cancer cells and identify pathways mediating these effects. Our in vitro experiments indicate that inhibiting MUC1 expression decreases cell proliferation, cell migration and invasion, cell survival and increases cell apoptosis. Moreover, lack of MUC1 in these cells profoundly altered their sensitivity to gemcitabine and 5-Fluorouracil chemotherapeutic drugs. In vivo MUC1-KD cell xenografts in SCID mice grew slower. Altogether, we show that MUC1 oncogenic mucin alters proliferation, migration, and invasion properties of pancreatic cancer cells and that these effects are mediated by p42-44 MAPK, Akt, Bcl-2 and MMP13 pathways. PMID- 25511700 TI - Novel protein-protein interaction between spermidine synthase and S adenosylmethionine decarboxylase from Leishmania donovani. AB - Polyamine biosynthesis pathway has long been considered an essential drug target for trypanosomatids including Leishmania. S-adenosylmethionine decarboxylase (AdoMetDc) and spermidine synthase (SpdSyn) are enzymes of this pathway that catalyze successive steps, with the product of the former, decarboxylated S adenosylmethionine (dcSAM), acting as an aminopropyl donor for the latter enzyme. Here we have explored the possibility of and identified the protein-protein interaction between SpdSyn and AdoMetDc. The protein-protein interaction has been identified using GST pull down assay. Isothermal titration calorimetry reveals that the interaction is thermodynamically favorable. Fluorescence spectroscopy studies also confirms the interaction, with SpdSyn exhibiting a change in tertiary structure with increasing concentrations of AdoMetDc. Size exclusion chromatography suggests the presence of the complex as a hetero-oligomer. Taken together, these results suggest that the enzymes indeed form a heteromer. Computational analyses suggest that this complex differs significantly from the corresponding human complex, implying that this complex could be a better therapeutic target than the individual enzymes. PMID- 25511699 TI - Human DNA methyltransferase gene-transformed yeasts display an inducible flocculation inhibited by 5-aza-2'-deoxycytidine. AB - Mammalian DNA methyltransferases (DNMTs) play an important role in establishing and maintaining the proper regulation of epigenetic information. However, it remains unclear whether mammalian DNMTs can be functionally expressed in yeasts, which probably lack endogenous DNMTs. We cotransformed the budding yeast Saccharomyces cerevisiae with the human DNMT1 gene, which encodes a methylation maintenance enzyme, and the DNMT3A/3B genes, which encode de novo methylation enzymes, in an expression vector also containing the GAL1 promoter, which is induced by galactose, and examined the effects of the DNMT inhibitor 5-aza-2' deoxycytidine (5AZ) on cell growth. Transformed yeast strains grown in galactose- and glucose-containing media showed growth inhibition, and their growth rate was unaffected by 5AZ. Conversely, 5AZ, but not 2'-deoxycytidine, dose-dependently interfered with the flocculation exhibited by DNMT-gene transformants grown in glucose-containing medium. Further investigation of the properties of this flocculation indicated that it may be dependent on the expression of a Flocculin encoding gene, FLO1. Taken together, these findings suggest that DNMT-gene transformed yeast strains functionally express these enzymes and represent a useful tool for in vivo screening for DNMT inhibitors. PMID- 25511701 TI - microRNA-218 inhibits prostate cancer cell growth and promotes apoptosis by repressing TPD52 expression. AB - The tumor protein D52 (TPD52) is an oncogene overexpressed in prostate cancer (PC) due to gene amplification. Although the oncogenic effect of TPD52 is well recognized, how its expression is regulated is still not clear. This study tried to explore the regulative role of miR-218, a tumor suppressing miRNA on TPD52 expression and prostate cancer cell proliferation. We found the expression of miR 218 was significantly lower in PC specimens. Based on gain and loss of function analysis, we found miR-218 significantly inhibit cancer cell proliferation by inducing apoptosis. These results strongly suggest that miR-218 plays a tumor suppressor role in PC cells. In addition, our data firstly demonstrated that miR 218 directly regulates oncogenic TPD52 in PC3 cells and the miR-218-TPD52 axis can regulate growth of this prostate cancer cell line. Knockdown of TPD52 resulted in significantly increased cancer cell apoptosis. Clearly understanding of oncogenic TPD52 pathways regulated by miR-218 might be helpful to reveal new therapeutic targets for PC. PMID- 25511702 TI - Transmitochondrial mito-miceDelta and mtDNA mutator mice, but not aged mice, share the same spectrum of musculoskeletal disorders. AB - The spectra of phenotypes associated with aging and mitochondrial diseases sometimes appear to overlap with each other. We used aged mice and a mouse model of mitochondrial diseases (transmitochondrial mito-miceDelta with deleted mtDNA) to study whether premature aging phenotypes observed in mtDNA mutator mice are associated with aging or mitochondrial diseases. Here, we provide convincing evidence that all the mice examined had musculoskeletal disorders of osteoporosis and muscle atrophy, which correspond to phenotypes prevalently observed in the elderly. However, precise investigation of musculoskeletal disorders revealed that the spectra of osteoporosis and muscle atrophy phenotypes in mtDNA mutator mice were very close to those in mito-miceDelta, but different from those of aged mice. Therefore, mtDNA mutator mice and mito-miceDelta, but not aged mice, share the spectra of musculoskeletal disorders. PMID- 25511703 TI - Polymethoxylated flavones potentiate the cytolytic activity of NK leukemia cell line KHYG-1 via enhanced expression of granzyme B. AB - Polymethoxylated flavones (PMFs) are found in the peel tissues of some citrus species. Here, we report that PMFs, such as nobiletin, potentiate the cytolytic activity of KHYG-1 natural killer (NK) leukemia cells. Nobiletin markedly enhanced the expression of granzyme B, a serine protease that plays critical roles in the cytolytic activity of NK cells. The potentiated cytolytic activity induced by nobiletin was canceled by the granzyme B inhibitor Z-AAD-CMK. Nobiletin also increased the levels of phosphorylated CREB, ERK1/2, and p38 MAPK in KHYG-1 cells, which are known to participate in NK cell function. Inhibition of an upstream kinase of ERK1/2 failed to reduce the granzyme B expression and KHYG-1 cytolytic activity. Meanwhile, inhibition of p38 MAPK attenuated both granzyme B expression and KHYG-1 cytolytic activity. These results suggest that the primary role of nobiletin in KHYG-1 cytolytic activity lies in upregulation of granzyme B expression, at least in part, mediated through p38 MAPK function. PMID- 25511705 TI - Crystal structure of the polo-box domain of polo-like kinase 2. AB - Polo-like kinase 2 (PLK2) is a crucial regulator in cell cycle progression, DNA damage response, and neuronal activity. PLK2 is characterized by the conserved N terminal kinase domain and the unique C-terminal polo-box domain (PBD). The PBD mediates diverse functions of PLK2 by binding phosphorylated Ser-pSer/pThr motifs of its substrates. Here, we report the first crystal structure of the PBD of PLK2. The overall structure of the PLK2 PBD is similar to that of the PLK1 PBD, which is composed by two polo boxes each contain beta6alpha structures that form a 12-stranded beta sandwich domain. The edge of the interface between the two polo boxes forms the phosphorylated Ser-pSer/pThr motifs binding cleft. On the hand, the peripheral regions around the core binding cleft of the PLK2 PBD is distinct from that of the PLK1 PBD, which might confer the substrate specificity of the PBDs of the polo-like kinase family. PMID- 25511704 TI - Phosphorylation of glucocorticoid receptor tau1c transactivation domain enhances binding to CREB binding protein (CBP) TAZ2. AB - The glucocorticoid receptor (GR) N-terminal domain (NTD) contains a transactivation domain (activation function 1; AF-1). GR AF-1 is phosphorylated, but effects of this modification upon AF-1 activity and cofactor recruitment are not completely clear. GR AF-1 activity is mostly confined to a short unstructured domain called tau1c (amino acids 187-244) that contains three phosphorylation sites and binds a short cysteine rich fragment (CH3) of the coactivator CREB binding protein (CBP). Since the CH3 domain overlaps the CBP transcriptional adaptor zinc binding (TAZ) 2 domain, implicated in phosphorylation dependent binding to other unstructured transcription factor domains, we set out to investigate whether GR interacts with TAZ2 and whether this binding event is modulated by phosphorylation. We find that GR tau1c is absolutely required for enhancement of GR function and GR/CBP association in cultured cells. Tau1c interacts with TAZ2 in vitro and peptide mapping reveals CBP binding determinants throughout tau1c. Phosphorylation at GR Ser203, not involved in transactivation, does not affect tau1c/TAZ2 interactions. However, phosphorylation at Ser211 and Ser226, markers of GR transcriptional activity, greatly enhances TAZ2 binding in a synergistic fashion. We propose that GR tau1c phosphorylation could promote CBP recruitment and enhance AF-1 activity. PMID- 25511706 TI - Sinapic acid protects heart against ischemia/reperfusion injury and H9c2 cardiomyoblast cells against oxidative stress. AB - The present study was designed to evaluate antioxidant and cardioprotective potential of sinapic acid (SA) against ischemia/reperfusion (I/R) injury. Cardiac functional recovery after I/R was evaluated by percentage rate pressure product (%RPP) and percentage coronary flow (%CF). Myocardial injury was evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining and LDH enzyme leakage. Oxidative stress was estimated by lipid peroxidation level. eNOS protein expression in reperfused heart was assessed using Western blot method. Finally, in order to support the antioxidant effect of SA, in vitro protective potential of SA was assessed on H2O2-induced oxidative stress in H9c2 cardiomyoblast cells. The overall results demonstrated that I/R induced cardiac dysfunction, injury and oxidative stress was attenuated by SA treatment. Moreover, in vitro results also shown that, SA protects H9c2 cells from oxidative stress and modulates mitochondrial membrane permeability transition (MPT). In conclusion, coupled results from both in vivo and in vitro experiments have confirmed that SA with antioxidant role protects cardiac cells and its functions from I/R induced oxidative stress. PMID- 25511708 TI - Sigma 1 Receptor antagonist potentiates the anti-cancer effect of p53 by regulating ER stress, ROS production, Bax levels, and caspase-3 activation. AB - Over the last years, many improvements have been made in the treatment of breast cancer; however, novel and less toxic therapies are still needed, especially for relapsing and chemo-resistant patients. Here, we analyzed the therapeutic potential of p53 and Rimcazole, a Sigma 1 Receptor antagonist. Rimcazole and p53 are being evaluated in preclinical and clinical trials, respectively. While p53 is a promising antitumor therapeutic agent, antagonists of Sigma 1 Receptor also inhibit tumor cell survival and induce apoptosis. Our current study demonstrates for the first time the synergistic effect of p53 in combination with the Sigma 1 Receptor antagonist Rimcazole. Furthermore, we show that shRNA knockdown of Sigma 1 Receptor in combination with p53, lead to a similar synergistic effect, and that this synergistic effect, in breast cancer growth suppression occurs independent of p53 status. Furthermore, this combination treatment induced ER stress, p38 MAPK activation, ROS production, and proteins involved in apoptosis (caspases-3, Bax) in breast cancer cells. Combining these therapeutic anti-cancer molecules provides an innovative approach for potentially treating human breast cancer. PMID- 25511707 TI - Triptolide inhibits proliferation of Epstein-Barr virus-positive B lymphocytes by down-regulating expression of a viral protein LMP1. AB - Epstein-Barr virus (EBV) infects various types of cells and mainly establishes latent infection in B lymphocytes. The viral latent membrane protein 1 (LMP1) plays important roles in transformation and proliferation of B lymphocytes infected with EBV. Triptolide is a compound of Tripterygium extracts, showing anti-inflammatory, immunosuppressive, and anti-cancer activities. In this study, it is determined whether triptolide inhibits proliferation of Epstein-Barr virus positive B lymphocytes. The CCK-8 assays were performed to examine cell viabilities of EBV-positive B95-8 and P3HR-1 cells treated by triptolide. The mRNA and protein levels of LMP1 were examined by real time-PCR and Western blotting, respectively. The activities of two LMP1 promoters (ED-L1 and TR-L1) were determined by Dual luciferase reportor assay. The results showed that triptolide inhibited the cell viability of EBV-positive B lymphocytes, and the over-expression of LMP1 attenuated this inhibitory effect. Triptolide decreased the LMP1 expression and transcriptional levels in EBV-positive B cells. The activity of LMP1 promoter ED-L1 in type III latent infection was strongly suppressed by triptolide treatment. In addition, triptolide strongly reduced growth of B95-8 induced B lymphoma in BALB/c nude mice. These results suggest that triptolide decreases proliferation of EBV-induced B lymphocytes possibly by a mechanism related to down-regulation of the LMP1 expression. PMID- 25511709 TI - From genes to folds: a review of cortical gyrification theory. AB - Cortical gyrification is not a random process. Instead, the folds that develop are synonymous with the functional organization of the cortex, and form patterns that are remarkably consistent across individuals and even some species. How this happens is not well understood. Although many developmental features and evolutionary adaptations have been proposed as the primary cause of gyrencephaly, it is not evident that gyrification is reducible in this way. In recent years, we have greatly increased our understanding of the multiple factors that influence cortical folding, from the action of genes in health and disease to evolutionary adaptations that characterize distinctions between gyrencephalic and lissencephalic cortices. Nonetheless it is unclear how these factors which influence events at a small-scale synthesize to form the consistent and biologically meaningful large-scale features of sulci and gyri. In this article, we review the empirical evidence which suggests that gyrification is the product of a generalized mechanism, namely the differential expansion of the cortex. By considering the implications of this model, we demonstrate that it is possible to link the fundamental biological components of the cortex to its large-scale pattern-specific morphology and functional organization. PMID- 25511711 TI - Psychological care of food-allergic children and their families: an exploratory analysis. PMID- 25511712 TI - Coupling of a headspace autosampler with a programmed temperature vaporizer for stable carbon and hydrogen isotope analysis of volatile organic compounds at microgram per liter concentrations. AB - One major challenge for the environmental application of compound-specific stable isotope analysis (CSIA) is the necessity of efficient sample treatment methods, allowing isolation of a sufficient mass of organic contaminants needed for accurate measurement of the isotope ratios. Here, we present a novel preconcentration technique--the coupling of a headspace (HS) autosampler with a programmed temperature vaporizer (PTV)--for carbon (delta(13)C) and hydrogen (delta(2)H) isotope analysis of volatile organic compounds in water at concentrations of tens of micrograms per liter. The technique permits large volume injection of headspace samples, maintaining the principle of simple static HS extraction. We developed the method for multielement isotope analysis (delta(13)C and delta(2)H) of methyl tert-butyl ether (MTBE), benzene, toluene, ethylbenzene, and o-xylene (BTEX), and analysis of delta(13)C for chlorinated benzenes and ethenes. Extraction and injection conditions were optimized for maximum sensitivity and minimum isotope effects. Injection of up to 5 mL of headspace sample from a 20 mL vial containing 13 mL of aqueous solution and 5 g of NaCl (10 min of incubation at 90 degrees C) resulted in accurate delta(13)C and delta(2)H values. The method detection limits (MDLs) for delta(13)C were from 2 to 60 MUg/L (MTBE, BTEX, chlorinated ethenes, and benzenes) and 60-97 MUg/L for delta(2)H (MTBE and BTEX). Overall, the HS-PTV technique is faster, simpler, isotope effect-free, and requires fewer treatment steps and less sample volume than other extraction techniques used for CSIA. The environmental applicability was proved by the analysis of groundwater samples containing BTEX and chlorinated contaminants at microgram per liter concentrations. PMID- 25511710 TI - The AtRAD21.1 and AtRAD21.3 Arabidopsis cohesins play a synergistic role in somatic DNA double strand break damage repair. AB - BACKGROUND: The RAD21 cohesin plays, besides its well-recognised role in chromatid cohesion, a role in DNA double strand break (dsb) repair. In Arabidopsis there are three RAD21 paralog genes (AtRAD21.1, AtRAD21.2 and AtRAD21.3), yet only AtRAD21.1 has been shown to be required for DNA dsb damage repair. Further investigation of the role of cohesins in DNA dsb repair was carried out and is here reported. RESULTS: We show for the first time that not only AtRAD21.1 but also AtRAD21.3 play a role in somatic DNA dsb repair. Comet data shows that the lack of either cohesins induces a similar high basal level of DNA dsb in the nuclei and a slower DNA dsb repair kinetics in both cohesin mutants. The observed AtRAD21.3 transcriptional response to DNA dsb induction reinforces further the role of this cohesin in DNA dsb repair. The importance of AtRAD21.3 in DNA dsb damage repair, after exposure to DNA dsb damage inducing agents, is notorious and recognisably evident at the phenotypical level, particularly when the AtRAD21.1 gene is also disrupted. CONCLUSIONS: Our data demonstrates that both Arabidopsis cohesin (AtRAD21.1 and AtRAD21.3) play a role in somatic DNA dsb repair. Furthermore, the phenotypical data from the atrad21.1 atrad21.3 double mutant indicates that these two cohesins function synergistically in DNA dsb repair. The implications of this data are discussed. PMID- 25511713 TI - Theoretical predictions for hot-carrier generation from surface plasmon decay. AB - Decay of surface plasmons to hot carriers finds a wide variety of applications in energy conversion, photocatalysis and photodetection. However, a detailed theoretical description of plasmonic hot-carrier generation in real materials has remained incomplete. Here we report predictions for the prompt distributions of excited 'hot' electrons and holes generated by plasmon decay, before inelastic relaxation, using a quantized plasmon model with detailed electronic structure. We find that carrier energy distributions are sensitive to the electronic band structure of the metal: gold and copper produce holes hotter than electrons by 1 2 eV, while silver and aluminium distribute energies more equitably between electrons and holes. Momentum-direction distributions for hot carriers are anisotropic, dominated by the plasmon polarization for aluminium and by the crystal orientation for noble metals. We show that in thin metallic films intraband transitions can alter the carrier distributions, producing hotter electrons in gold, but interband transitions remain dominant. PMID- 25511714 TI - Association of HLA class II markers with autoantibody-negative ketosis-prone atypical diabetes compared to type 2 diabetes in a population of sub-Saharan African patients. AB - AIM: We investigated the association of HLA DRB1 and DQB1 alleles, haplotypes and genotypes with unprovoked antibody-negative ketosis-prone atypical diabetes (A(-) KPD) in comparison to type 2 diabetes (T2D). METHODS: A(-) KPD and T2D sub Saharan African patients aged 19-63 years were consecutively recruited. Patients positive for cytoplasmic islet cell, insulin, glutamic acid decarboxylase or islet antigen-2 autoantibodies were excluded. Odds ratios were obtained via logistic regression after considering alleles with a minimum frequency of 5% in the study population. Bonferroni correction was used in the case of multiple comparisons. RESULTS: Among the 130 participants, 35 (27%) were women and 57 (44%) were A(-) KPD. DRB1 and DQB1 allele frequencies were similar for both A(-) KPD and T2D patients; they did not confer any substantial risk even after considering type 1 diabetes susceptibility and resistance alleles. We found no association between A(-) KPD and the derived DRB1*07-DQB1*02:02 (OR: 0.55 [95%CI: 0.17-1.85], P=0.336); DRB1*11-DQB1*03:01 (OR: 2.42 [95%CI: 0.79-7.42], P=0.123); DRB1*15-DQB1*06:02 (OR: 0.87 [95%CI: 0.39-1.95], P=0.731) and DRB1*03:01 DQB1*02:01 (OR: 1.48 [95%CI: 0.55-3.96], P=0.437) haplotypes. Overall, we did not find any evidence of susceptibility to ketosis associated with DRB1 and DQB1 genotypes (all P>0.05) in A(-) KPD compared to T2D. Similar results were obtained after adjusting the analysis for age and sex. CONCLUSION: Factors other than DRB1 and DQB1 genotype could explain the propensity to ketosis in A(-) KPD. These results need to be confirmed in a larger population with the perspective of improving the classification and understanding of the pathophysiology of A(-) KPD. PMID- 25511715 TI - Alpha-lipoic acid modifies circulating angiogenic factors in patients with type 2 diabetes mellitus. AB - AIMS: In recent years interest has been focused on angiogenesis as a process involved in coronary artery disease (CAD) and diabetic distal sensorimotor polyneuropathy (DSPN). Recent studies have demonstrated the possible angiogenesis modulating potential of alpha-lipoic acid (ALA) for DSPN and CAD. The aim of our study was to investigate the influence of ALA on serum angiogenic factors in patients with DM-2 (type 2 diabetes) with CAD and DSPN. METHODS: Sixty patients with type 2 DM (T2DM) and CAD and 25 non-diabetic subjects were studied. Thirty patients with T2DM, CAD and DSPN were given 600 mg of ALA a day for 90 days. VEGF, bFGF, MCP-1, angiogenin, IL-12 and IL-10 concentrations in the sera were measured by flow cytometry. RESULTS: ALA significantly increased VEGF, bFGF and IL-10 and decreased MCP-1 serum concentrations in patients with T2DM and CAD and DSPN. VEGF and IL-10 serum levels, both before and after ALA-treatment, were higher in this group than in T2DM and CAD patients, while circulating bFGF was higher and MCP-1 serum level lower in patients with T2DM and CAD and DSPN only in the post-ALA-treatment, compared to the T2DM and CAD group. CONCLUSIONS: ALA may influence angiogenesis in type 2 diabetic patients through an effect on some circulating factors including VEGF, bFGF, MCP-1 and IL-10. PMID- 25511716 TI - Symptomatic Spinal Migration of Subarachnoid Hemorrhage due to Ruptured Intradural Vertebral Artery Aneurysm. AB - A 55-year-old patient was admitted to the hospital with severe acute back pain. Thoracolumbar magnetic resonance (MR) imaging showed hemorrhage in subarachnoidal subdural space. On cranial MR imaging and MR angiography, an aneurysm was suspected in the V4 segment of the right vertebral artery. Angiography showed a fusiform dissecting aneurysm in the V4 segment of right vertebral artery. The final diagnosis was ruptured V4 segment aneurysm with subsequent symptomatic migration of hemorrhage into the spinal subarachnoidal-subdural space. The patient was treated endovascularly by coil occlusion of both the aneurysm and vertebral artery. This rare cause and possible mechanisms for spinal migration of intracranial hemorrhage after aneurysmal rupture is discussed. PMID- 25511717 TI - Posttraumatic stress: state-of-the-art research and clinical implications for China. PMID- 25511718 TI - Social support, oxytocin, and PTSD. AB - BACKGROUND: A lack of social support and recognition by the environment is one of the most consistent risk factors for posttraumatic stress disorder (PTSD), and PTSD patients will recover faster with proper social support. The oxytocin system has been proposed to underlie beneficial effects of social support as it is implicated in both social bonding behavior and reducing stress responsivity, notably amygdala reactivity (Koch et al., 2014; Olff et al., 2010; Olff, 2012). The amygdala is found to be hypersensitive in people with PTSD. METHOD: In order to investigate neurobiological mechanisms underlying potential preventive and therapeutic effects of intranasal oxytocin, we performed a series of fMRI studies (funded with a prestigious NWO TOP grant): BONDS standing for "Boosting Oxytocin after trauma: Neurobiology and the Development of Stress-related psychopathology" in acutely traumatized persons admitted to the emergency department (Frijling et al., 2014); BOOSTER "Boosting oxytocin after trauma: the effects of intranasal oxytocin administration on emotional and motivational processing and neural activity in PTSD" in police officers with and without PTSD. RESULTS: In this presentation, we present the BOOSTER results on the effects of a single oxytocin administration on amygdala reactivity in response to emotional faces in PTSD patients versus traumatized controls. We found significantly decreased bilateral amygdala reactivity towards emotional faces in PTSD patients compared to traumatized controls. CONCLUSIONS: These promising results call for intervention studies such as studying the effects of medication (oxytocin) enhanced psychotherapy in PTSD patients. PMID- 25511719 TI - The concept and treatment of psychological trauma. AB - Despite a large and rapidly expanding literature on psychological trauma, many fundamental questions remain about its basic nature: Is it a psychological problem or a biological one?; Is it a past event somehow stuck in the present or is it something new which has been triggered and shaped by that event?; Does it reside only within the patient or does it live between the patient and other people (including within the therapeutic relationship)? This presentation will review the history of the concept of psychological trauma and explore the theoretical bases for current evidence-based psychotherapies for PTSD, each of which will be shown to describe psychological trauma as a problem in bringing the past and the present together in memory and cognition. These theories primarily differ on the question of whether a traumatic memory becomes pathogenic, because it cannot be biologically processed or because it must be psychologically avoided. Psychoanalytic concepts of transference and countertransference will be shown to be of practical importance regardless of the type of treatment chosen. If researchers and clinicians can build on what they hold in common rather than become divided by their differences, we can improve our ability to understand and alleviate the effects of psychological trauma. PMID- 25511720 TI - 311 disaster and mental health countermeasures. AB - On 11 March 2011, a devastating earthquake struck off the coast of Japan, causing blustering tsunami that swept over the northeast coast of the country. Many struggled to evacuate from their homes, schools, and workplaces as 8- to 9-m-tall tsunami rapidly reached the coast within half an hour after the earthquake (Emergency Disaster Response Headquarters). The officials reported a record breaking magnitude of 9.0 Mw, which made this earthquake the most devastating earthquake in the Japan's history. It had not been long since the previous massive earthquake had hit Kobe in 1995, killing 6,434 people (Japan Meteorological Agency). The author presents the outline of the initial mental health-care responses at various levels. It has focused on the comprehensive strategies and policies that were intended to cover all the affected areas but has not described the individual countermeasures and reactions in each prefecture and city. The psychological effects of the atomic plant accident in Fukushima has not been mentioned in detail, because the scope of the physiological effect of the accident has not been settled yet and the society is not necessarily ready to deal with the accident as a psychological matter rather than a sociopolitical one. A number of psychiatric professionals are deeply concerned with the psychological and prolonged impact of the accident, including those who are in the Fukushima prefecture and conducting heroic efforts to care for the residents. PMID- 25511721 TI - Psychosocial recovery after serious injury. AB - BACKGROUND: The 2010 iteration of the Global Burden of Disease statistics (Murray et al., 2012) points to the growing impact of injury and highlights the mounting burden of psychiatric disorder. It is essential to examine the intersection between these two contributors to disease burden. METHODS: The Australian Injury Vulnerability Study collected data of over 1,000 injury patients from their initial hospitalization to 6 years post-injury. Structured clinical interviews were used to diagnose psychiatric disorder and self-report measures for disability and symptom severity. RESULTS: A wide range of psychiatric disorders developed following injury, which included posttraumatic stress disorder, agoraphobia, depression, and substance use disorders (Bryant, O'Donnell, Creamer, Silove, & McFarlane, 2010). Although prevalence rates for these disorders were generally consistent over time, examination of trajectory data showed that different people had the disorders at different times. Importantly, the data showed that early anxiety, depression, and PTSD symptoms played a significant role in the development of long term disability after injury (Carty, O'Donnell, Evans, Kazantzis, & Creamer, 2011; O'Donnell et al., 2013). CONCLUSIONS: These data support the view that transdiagnostic models for early intervention may be required to address the complex psychiatric disorder trajectories that develop after injury. PMID- 25511722 TI - PTSD and loss: preliminary findings from a territory-wide epidemiology study in Hong Kong. AB - BACKGROUND: The study examined the prevalence of trauma and posttraumatic stress disorder (PTSD) symptoms among community dwelling Chinese adults in Hong Kong. The relationship of traumatic life events (including loss) and mental health has been investigated. METHODS: The sampling of the collaborative study (HKMMS: Hong Kong Mental Morbidity Survey) adopts a multi-stage stratification approach with the distribution of residential premises in different geographical districts and the relative proportion of private versus public housing units taken into consideration. In Phase I of this study, 4,644 adults were screened for PTSD with the Trauma Screening Questionnaire (TSQ) and Life Event Checklist (LEC), Beck's scales and CIS-R (Revised Clinical Interview Schedule). In Phase II of the study, clinical psychologists conducted the Structured Clinical Interview for DSM Disorders (SCID) for 92 participants (results not reported here). RESULTS: Among Phase I participants, 65% reported traumatic experience (including 18% who reported personal experience of sudden death of significant others). Age and gender make a difference in traumatic experience. When compared to participants who reported no traumatic experience in the past, participants who reported to have personal experience of sudden death of significant others or other traumatic experiences were found to have higher TSQ scores, higher psychological distress, lower social support (PSS: Multidimensional Scale of Perceived Social Support), and lower life functioning (SOFAS: Social and Occupational Functioning Assessment Scale), p<0.001. Findings of hierarchical regression showed that type of trauma (i.e., loss, other trauma, or no trauma) contributed significantly to the prediction of all the mental health indices after demographic and social variables were controlled. CONCLUSIONS: Public education on the association of traumatic experience and psychological health, as well as the monitoring of mental health for at-risk individuals are suggested for early identification of people in need of mental health services. PMID- 25511723 TI - Proximal relationships between PTSD and drinking behavior. AB - Co-morbid PTSD and alcohol use disorders are both common and debilitating. However, many of these studies rely on cross-sectional studies that obscure more complex relationships between PTSD and drinking. Event-level studies allow for examination of proximal relationships between PTSD and drinking. Among women (n=136 with past sexual victimization, n=40 no past trauma history), a two-part mixed hurdle model was used to examine daily PTSD and drinking. On days women experienced more intrusive and behavioral avoidance symptoms, they were more likely to drink. For a 2 SD increase in symptoms, there was a 5% increased likelihood of drinking, and for a 2 SD increase in dysphoric symptoms or negative affect, women drank approximately half drink less. Daily-level coping self efficacy moderated the association between distress and drinking (IRR=0.91, p<0.01). Women who reported less coping drank more as their distress increased on a certain day whereas women who reported more coping drank about the same regardless of distress. Overall, findings suggest that specific PTSD symptoms are associated with higher alcohol use and that these relationships are moderated by daily coping self-efficacy. Implications of these findings for informing models of PTSD/AUD comorbidity, as well as clinical implications will be discussed. PMID- 25511724 TI - Web-based interventions for traumatized people in mainland China. AB - BACKGROUND: The Internet is now becoming a new channel for delivering psychological interventions. METHOD: This paper reported a first application of web-based intervention in mainland China. It first summarized primary barriers to mental health help-seeking behavior in Chinese society. Then, it introduced the current utilization of the Internet within mental health services in mainland China and discussed how the Internet would help to improve people's help-seeking behaviors. More importantly, it presented main empirical findings from a randomized controlled trial (RCT) which investigated the efficacy of a web-based self-help intervention program (Chinese My Trauma Recovery website, CMTR) for 103 urban and 93 rural traumatized Chinese persons. RESULTS: The data revealed that 59% urban and 97% rural participants completed the posttest. In the urban sample, data showed a significant group*time interaction in Posttraumatic Diagnostic Scale (PDS) scores (F1,88=7.65, p=0.007). CMTR reduced posttraumatic symptoms significantly with high effect size after intervention (F1,45=15.13, Cohen's d=0.81, p<0.001) and the reduction was sustained over a 3-month follow-up (F1,45=17.29, Cohen's d=0.87, p<0.001). In the rural sample, the group*time interaction was also significant in PDS scores (F1,91=5.35, p=0.02). Posttraumatic symptoms decreased significantly after intervention (F1,48=43.97, Cohen's d=1.34, p<0.001) and during the follow-up period (F1,48=24.22, Cohen's d=0.99, p<0.001). CONCLUSIONS: These findings give preliminary support for the short-term efficacy of CMTR in the two Chinese populations. Finally, some implications are given for the future application of web-based interventions for PTSD in mainland China. PMID- 25511725 TI - Treating intrusions, promoting resilience: an overview of therapies for trauma related psychological disorders. AB - The efficacy of psychotherapeutic approaches in the treatment of posttraumatic stress disorder (PTSD) can be regarded as empirically demonstrated. Overall, effect sizes appear to be higher for psychotherapy than for medication. Many well controlled trials with a mixed variety of trauma survivors have demonstrated that trauma-focused cognitive-behavioral therapy (TF-CBT) is effective in treating PTSD. Prolonged exposure therapy (PE) is currently seen as the treatment with the strongest evidence for its efficacy. Cognitive therapy (CT) and cognitive processing therapy (CPT), with their stronger emphasis on cognitive techniques, and Eye Movement Desensitization and Reprocessing (EMDR) seem equally effective. More recent developments include brief eclectic psychotherapy for PTSD (BEPP) and narrative exposure therapy (NET). Emerging evidence shows that TF-CBT can successfully be applied in PTSD patients suffering from severe comorbidities such as borderline personality disorder or substance abuse disorder (Schnyder & Cloitre, 2015). There is also a trend towards developing "mini-interventions," that is, short modules tailored to approach specific problems. Moreover, evidence based approaches should be complemented by interventions that aim at promoting human resilience to stress. Finally, given the globalization of our societies (Schnyder, 2013), culture-sensitive psychotherapists should try to understand the cultural components of a patient's illness and help-seeking behaviors, as well as their expectations with regard to treatment. PMID- 25511726 TI - The stress systems in depression: a postmortem study. AB - After trauma, depressive disorders are among the most frequent emerging diagnoses. However, although the symptoms of depression are well characterized, the molecular mechanisms underlying this disorder are largely unknown. Factors involved in the heterogeneous pathogenesis of depression include polymorphisms in stress-related genes, gender, age, developmental history, and environmental (traumatic) stressors such as epigenetic factors. These factors may make different parts of the stress-related brain systems more vulnerable to different stressful or traumatic life events or psychological stresses, causing alterations in a network of neurotransmitters and neuromodulators including amines, amino acids, nitric oxide (NO), and neuropeptides, and finally make individuals at risk for depression. The hypothalamo-pituitary-adrenal (HPA) axis has a prominent position in this network. With the postmortem brain material obtained from the Netherlands Brain Bank, we have carried on a series of studies with the aim to elucidate the specific changes in these systems in relation to special subtypes of depression. Our final destination is to set up tailor-made treatment for depressive patients on the basis of his/her developmental history, genetic and epigenetic background, and the vulnerability in particular neurobiological systems. This presentation is a review of our findings of changes in systems of sex steroids, receptors in the hypothalamic paraventricular nucleus, corticotrophin-releasing hormone, orexin, gamma-aminobutyric acid, and NO in the etiology of depression, in relation to HPA activity, sex differences, and suicide. PMID- 25511727 TI - Narrative exposure therapy: an evidence-based treatment for multiple and complex trauma. AB - Narrative exposure therapy (NET) is a recently developed, short-term treatment for patients with a posttraumatic stress disorder (PTSD) as a result of multiple trauma. NET can be applied very successfully in patients with complex trauma complaints (Jongedijk, 2014; Schauer, Neuner, & Elbert, 2011). An important feature of NET is that trauma processing is never an isolated event but is always embedded in the context of a traumatic event and in the life history as a whole. At the start, the lifeline is laid. The lifeline is made up of a rope, with flowers (happy events), stones (traumatic events), sometimes candles (grief), or recently also sticks for aggressive acts (NET for offenders; see Stenmark, Cuneyt Guzey, Elbert, & Holen, 2014). These symbols are laid down along the rope, in chronological order. Subsequently, in the subsequent therapy sessions the lifeline is processed in chronological order, giving attention to all the important events a person has experienced in his or her life, both the adverse as well as the pleasurable ones. The narration ends with a written testimony. To date, there is good evidence NET is effective in the treatment of PTSD patients, with support from 18 RCTs (N=950). For culturally diverse populations, NET is recommended as the most evidence-based trauma treatment, besides culturally adapted CBT. NET has been investigated in different populations in Africa, Europe, and Asia. In Asia, research has been carried out in Sri Lanka as well as in China. In China, NET was conducted and investigated with survivors of the Sichuan earthquake (Zang, Hunt, & Cox, 2013, 2014). NET is understandable, even appealing and also supportive for patients with multiple trauma. In this presentation, the treatment principles and the practice of NET will be explained. PMID- 25511728 TI - The treatment and research for posttraumatic stress disorder with Chinese medicine. AB - There is no disease called posttraumatic stress disorder (PTSD) in traditional Chinese medicine (TCM). However, Huangdi's Canon of Medicine written in about 200 BC, one of the most famous TCM classics, recorded diseases with similar etiology, pathogenesis, and clinical symptoms. Moreover, contemporary TCM also attaches great importance to diseases caused by trauma. Especially after 2008, there is a mini-rush of study on PTSD as a result of Sichuan earthquake. Referring to ancient and modern literature, we summarize the TCM treatment of PTSD and wish to contribute to the further study on TCM remedy for PTSD. PMID- 25511729 TI - Localization of post-disaster psychosocial care in China. AB - Disaster is not independent of society and culture and always happens in specific cultural and social contexts. Cultural and social characteristics influence the responses of people affected by disaster, as well as the process of disaster relief. As one of the countries in the world that suffer most from natural disasters, various ethnic groups in China vary greatly in psychology and behavior characteristics after major disasters due to different geographical environments and economic and political conditions. To launch an effective post-disaster psychosocial care, 1) it is necessary to consider how to satisfy material, health, and other fundamental biological needs of affected people; 2) it is necessary to relieve disaster victims of their mental pain (spiritual in Chinese) and help them restore their psychological health; 3) it is necessary to revitalize the seriously unbalanced communities affected by disasters so that these communities would burst with vitality again. In addition, it is necessary to take specific ethnic and regional culture into account when helping people in these areas gradually achieve social adaptation and cultural identification. All these require us to intensify our efforts in the following four aspects: 1) to strengthen legislation and institutional construction in this field; 2) to help citizens master the most fundamental psychological principles and methods of coping with disasters to enable timely self-aid and mutual-aid; 3) to build a national database of the post-disaster psychosocial care teams; 4) to continue the research on disaster psychology, so as to provide a scientific basis as well as techniques and methods for implementing disaster relief efforts in a scientific way. PMID- 25511730 TI - Adherence to a web-based intervention program for traumatized persons in mainland China. AB - BACKGROUND: This paper investigated adherence to a self-help web-based intervention for PTSD (Chinese My Trauma Recovery, CMTR) in mainland China and evaluated the association between adherence measures and potential predictors, for example, traumatic symptoms and self-efficacy. METHODS: Data from 56 urban and 90 rural trauma survivors were reported who used at least one of the seven recovery modules of CMTR. RESULTS: The results showed that 80% urban users visited CMTR four or less days and 87% rural users visited CMTR for 5 or 6 days. On average, urban users visited 2.54 (SD=1.99) modules on the first visiting day and less from the second day; rural users visited 1.10 (SD=0.54) modules on the first visiting day, and it became stable in the following days. In both samples, depression scores at pre-test were significantly or trend significantly associated with the number of visited web pages in the relaxation and professional help modules (r=0.20-0.26, all p<0.14); traumatic symptom scores at pre-test significantly or trend significantly correlated to the number of visited web pages in the relaxation, professional help, and mastery tools modules (r=0.20 0.26, all p<0.10). Moreover, urban users' coping self-efficacy scores at pre-test significantly or trend significantly related to the number of visited web pages in the relaxation, professional help, social support, and mastery tool modules (r=0.20-0.33, all p<0.16). CONCLUSIONS: These findings suggest that individuals tend to focus on one or two recovery modules when they visit CMTR, and the number of web pages visited during the intervention period relates to users' traumatic and depressive symptoms and self-efficacy before intervention. PMID- 25511731 TI - Patterns and predictors of primary mental health service use following bushfire and flood disasters. AB - BACKGROUND: Mental health care services play an important role following disasters (Reifels et al., 2013). The aim of this study is to examine patterns and predictors of primary mental health care service use, following two major Australian natural disaster events. METHOD: Utilizing referral and session data from a national minimum dataset, descriptive and regression analyses were conducted to identify levels and predictors of the use of the Access to Allied Psychological Services (ATAPS) program over a 2-year period following two major Australian bushfire and flood/cyclone disasters. Predictor variables examined in negative binomial regression analysis included consumer (age, gender, household structure, previous mental health care history, and diagnosis) and event characteristics (disaster type). RESULTS: The bushfire disaster resulted in significantly greater service volume, with more than twice the number of referrals and nearly three times the number of sessions. Service delivery for both disasters peaked in the third quarter. Consumers affected by bushfires, diagnosed with depression, anxiety, or both of these disorders utilized sessions at significantly higher rates. CONCLUSIONS: The substantial demand for primary mental health services following disaster can vary with disaster type. Disaster type and need-based variables as key drivers of service use intensity indicate an equitable level of service use. Established usage patterns assist with estimating future service capacity requirements. Flexible referral pathways can enhance access to disaster mental health care. Future research should examine the impact of program- and agency-level factors on mental health service use and factors underpinning treatment non-adherence following disaster. PMID- 25511732 TI - The association between social resources and depression among female migrants affected by domestic violence. AB - BACKGROUND: Interpersonal violence (IPV) is associated with higher risk of depression. Female Chinese rural-to-urban migrants may experience greater depression following exposure to IPV due to lack of social support and integration within their receiving communities. The current study estimated the prevalence of IPV among rural-to-urban migrants in Guangzhou, China, and evaluated the moderating effects of social resources on migrant's depression symptoms. METHOD: We recruited 1,368 women (1,003 migrants and 365 local-born) of childbearing age from population and family planning centers in two districts using a quota sampling method matched to the 2012 population census. Chinese versions of the Conflict Tactics Scale 2 Short Form, Center for Epidemiological Studies Depression Scale and the Social Support Rating Scale measured IPV, depression, and social support. Social integration was measured with a locally derived scale. RESULTS: Migrants reported a similar prevalence for IPV (41.20%) to local women (39.20%). Bivariate comparisons demonstrated that migrants reported greater depression (11.8+/-8.9 vs. 10.0+/-8.8, t=-3.27, p<0.001) and less social support (22.2+/-5.1 vs. 27.1+/-5.5, t=14.84, p<0.001). Regression analysis indicated that the effect of violence on depression symptoms for migrant women was moderated by social integration. Women who experienced violence and had greater integration in their community reported less depression than women who experienced violence but reported less social integration. CONCLUSION: A high prevalence of IPV was reported in our sample. Social integration is a key risk factor for migrant mental health. Social services aimed to reduce IPV and integrate migrants in their new communities are needed. PMID- 25511733 TI - Prevalence of potentially traumatic events, depression, alcohol use, and social network supports among Chinese migrants: an epidemiological study in Guangzhou, China. AB - BACKGROUND: Addressing the health needs of Chinese migrants is a critical public health concern. Epidemiological studies are needed to establish the prevalence of potentially traumatic events (PTEs) and common mental disorders among Chinese migrants and identify protective community and social resources. METHOD: Utilizing random household sampling, we are in the process of recruiting a representative sample of Chinese adults (N=1,000) in two districts home to a large number of internal migrants. Data are collected using face-to-face interviews and participant self-report methods. Chinese versions of the Life Events Checklist, Alcohol Use Disorders Identification Test, Patient Health Questionnaire and the Social Support Rating Scale measured exposure to PTEs, alcohol use disorder, depression, and social support networks. RESULTS: Preliminary results indicate a high proportion (68%) of the sample was exposed directly or indirectly to at least one PTE. The most commonly reported events were transportation accidents (43%), natural disasters (39%), and physical assault (26%). A total of 17% of the sample reported drinking consistent with having an alcohol use disorder. Moderate or severe depression was reported by 9% of the sample. The majority (75%) reported having three or more people to rely on for support, and 41% reported active participation in civic groups. Despite these strengths, only half the sample reported having trust in their community. CONCLUSION: Preliminary evidence from this population-level survey indicates high exposure to PTEs and a high potential burden of alcohol use disorders. The role of social networks will be explored as potentially useful for community-based intervention development. PMID- 25511735 TI - Posttraumatic stress disorder among earthquake survivors of the Wenchuan area (Sichuan, China). AB - BACKGROUND: On May 12, 2008, an earthquake with a power of 8.0 M on the Richter scale occurred in the Wenchuan County of Sichuan Province in southwest China, which was unprecedented in magnitude and aftermath. Approximately 70,000 people were killed and nearly 20,000 went missing. The earthquake caused a wide number of mental and physical health outcomes among survivors, and posttraumatic stress disorder (PTSD) was one of the most commonly studied. METHODS: We conducted a systematic overview to assess research achievements about PTSD in the past 6 years after the Wenchuan earthquake, including symptoms and risk factors about PTSD among Wenchuan earthquake survivors, as well as research developments in genetics, molecular biology, and treatment of PTSD. RESULTS: The large body of research conducted after the Wenchuan earthquake suggests that the burden of PTSD among persons with high exposure was substantial. Adolescents and adults were among the most studied populations with high prevalence rates. Phytotherapy with Chinese herbs as well as acupuncture were rarely studied as of yet, although published data indicated promising therapy effects. Genome-wide microarray technologies are widely used in experimental mice and rat models to study PTSD mechanisms as well as in patients suffering from PTSD and other psychosomatic disorders to search for novel biomarkers and to monitor the effectiveness of treatment interventions. CONCLUSIONS: Using genomic and transcriptomic technologies, our future research will focus on the efficacy and safety of Chinese medicine to find potential interventions and effective treatments of PTSD. PMID- 25511734 TI - Oxytocin is associated with PTSD's anxious arousal symptoms in Chinese male earthquake survivors. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is a complex and severe mental disorder triggered by exposure to an extraordinarily traumatic event. Human and animal studies have implied the functional role of the oxytocin system in the development of PTSD (Cochran, Fallon, Hill, & Frazier, 2013; Koch et al., 2014; Olff, 2012). Specification of the role of the oxytocin system in the emergence and progression of PTSD symptomatology would provide evidence to inform both theory and clinical practice. METHODS: This study examined the association between oxytocin serum levels and PTSD symptoms. A total of 106 Chinese male adults who suffered from the deadly 2008 Wenchuan earthquake participated in this study. PTSD symptoms were measured with PTSD Checklist for DSM-5 (PCL-5), and serum oxytocin level was determined with ELISA oxytocin kits. RESULTS: The mean score on the PCL-5 was 19.30 (SD=14.50, range: 1-65) in this sample. The mean oxytocin level was 101.59 pg/ml (SD=55.89, range: 31.50-286.71). The results indicated that although the oxytocin was not associated with total PTSD symptoms, it was associated with PTSD's anxious arousal symptoms. CONCLUSION: These findings support that the oxytocin may play an important functional role in the development of PTSD and contribute to the extant knowledge on the genetic basis of the PTSD symptoms. PMID- 25511736 TI - Stressful parental bonding exaggerate the functional and emotional disturbances of primary dysmenorrhea. AB - BACKGROUND: Some evidence suggests that women with primary dysmenorrhea (or painful period) often have traumatic experience with parental attachments, but the exact relationship between styles of the parental bonding and the detailed aspects of the disorder is unclear. METHODS: From university-student women, we invited 50 primary dysmenorrhea patients and 111 healthy volunteers to undergo tests of the functional and emotional measure of dysmenorrhea (FEMD), the Family Relationship Questionnaire (FRQ), and the visual analog scale for the pain intensity experienced. RESULTS: Besides the high scores of the FEMD functional and emotional scales, the dysmenorrhea patients also scored significantly higher than the healthy controls on the FRQ scales of paternal dominance and maternal abuse. In patients, the FEMD Emotional scale was negatively predicted by the Paternal Freedom Release scale and the FEMD functional scale was positively predicted by the Maternal Dominance scale. CONCLUSION: Inappropriate parental bonding or chronic traumatic attachment styles have respective relationships with the functional and emotional disturbances experienced by the primary dysmenorrhea patients. PMID- 25511737 TI - Toll like receptor 4 facilitates invasion and migration as a cancer stem cell marker in hepatocellular carcinoma. AB - Cancer stem cells (CSCs) or tumor-initiating cells (TICs), a small subset of tumor cells, are involved in tumor initiation, progression, recurrence and metastasis. In human hepatocellular carcinoma (HCC), TICs are enriched with cell surface markers and play a key role in chemotherapy resistance, tumor invasion and migration. Toll like receptor 4 (TLR4), acting as a receptor for lipopolysaccharide (LPS), has been reported to be responsible for carcinogenesis, invasion, metastasis and cancer progression. In our study, two HCC cell lines and a splenic vein metastasis of the nude mouse model were used to study the invasive ability of TLR4 positive HCC cells in vitro and in vivo. Stem-like features were also detected in TLR4 positive HCC cells. A total of 88 clinical samples from HCC patients were used to evaluate the association of TLR4 and stem-cell marker expression, and the relationship between TLR4 expression and clinicopathological characteristics was analyzed. The in vitro and in vivo experiments indicated that TLR4 positive HCC cells displayed significantly enhanced invasion and migration, and stem-like properties were also detected in TLR4 positive HCC cells. Clinically, TLR4 expression levels were found to be significantly higher in HCC tissues with microvascular invasion. Additionally, high expression of TLR4 in HCC tissues was strongly associated with both early recurrence and poor survivals in patients. Our results indicated that there was a relationship between TLR4 expression and CSC's features, TLR4 may act as a CSC marker, prompting tumor invasion and migration, which contributes to the poor prognosis of HCC. PMID- 25511738 TI - Genome-wide transcriptional analyses of Chinese patients reveal cell migration is attenuated in IDH1-mutant glioblastomas. AB - Patients with isocitrate dehydrogenase 1 (IDH1)-mutant glioblastoma exhibit increased survival compared with those with wild-type IDH1 tumors. The magnitude of this finding has led to the use of IDH1 mutations as diagnostic and prognostic biomarkers. However, the mechanisms underlying the reported correlation between the IDH1 mutation and increased survival have not been fully revealed. In this work, based on genome-wide transcriptional analyses of 69 Chinese patients with glioblastoma, we have found that the focal adhesion pathway is significantly downregulated in IDH1-mutant glioblastomas. The impaired focal adhesion leads to compromised cell migration and tumor invasion, contributing to the optimistic prognosis of these patients. Moreover, the signature genes of HIF-1alpha, the downstream factor of mutated IDH1, are found to be suppressed in IDH1-mutant gliomas. Given the role of HIF-1alpha in cell migration, we conclude that the attenuation of HIF-1alpha-dependent glioblastoma cell infiltration contributes to the better outcomes of patients with IDH1-mutant gliomas. PMID- 25511739 TI - High-mobility group box 1: a novel inducer of the epithelial-mesenchymal transition in colorectal carcinoma. AB - Proinflammatory cytokine high-mobility group box 1 (HMGB1) mediates critical processes of tumour metastasis. Because the epithelial-to-mesenchymal transition (EMT) is a key player in metastasis, the aim of this study was to determine whether and through which mechanism HMGB1 induces EMT in colorectal carcinoma. The direct treatment of cells with recombinant human HMGB1 induced alterations in the epithelial morphology consistent with the EMT and enhanced cell migration through a process mediated by the receptor for advanced glycation end-products (RAGE). The levels of Snail and phospho-NF-kappaB were upregulated during the HMGB1-induced EMT, and these effects were reversed by inhibiting Snail and NF kappaB. In addition, HMGB1 increased the expression of MMP-7 but not that of MMP 9, and this effect was also regulated by Snail/NF-kappaB signalling. Collectively, these findings indicate that HMGB1 acts as a potent driver of cancer EMT through the RAGE/Snail/NF-kappaB signalling pathways accompanied by the activation of MMP-7, thereby suggest the feasibility of targeting HMGB1 for the treatment of tumour metastasis. PMID- 25511742 TI - miR-7-5p suppresses cell proliferation and induces apoptosis of breast cancer cells mainly by targeting REGgamma. AB - Proteasome activator subunit 3 (REGgamma) has a key role in breast cancer by promoting protein proteolysis, but methods to block REGgamma expression remain elusive. In this study, we found that the expression of REGgamma is significantly upregulated in breast cancer, and that the knockdown of REGgamma expression suppresses cell proliferation and induces apoptosis in vitro. Furthermore, REGgamma was identified as a direct downstream target of miR-7-5p, and there was an inverse correlation between the expression of REGgamma and miR-7-5p. The overexpression of miR-7-5p inhibited cell proliferation and induced apoptosis by mainly targeting REGgamma in vitro and in vivo. Our data indicate that miR-7-5p has a critical function through blocking REGgamma in breast cancer cells. PMID- 25511741 TI - Tumor matrix protein collagen XIalpha1 in cancer. AB - The extracellular matrix is increasingly recognized as an essential player in cancer development and progression. Collagens are one of the most important components of the extracellular matrix, and have themselves been implicated in many aspects of neoplastic transformation. Collagen XI is a minor collagen whose main physiologic function is to regulate the diameter of major collagen fibrils. The alpha1 chain of collagen XI (colXIalpha1) has known pathogenic roles in several musculoskeletal disorders. Recent research has highlighted the importance of colXIalpha1 in many types of cancer, including its roles in metastasis, angiogenesis, and drug resistance, as well as its potential utility in screening tests and as a therapeutic target. High levels of colXIalpha1 overexpression have been reported in multiple expression profile studies examining differences between cancerous and normal tissue, and between beginning and advanced stage cancer. Its expression has been linked to poor progression-free and overall survival. The consistency of these data across cancer types is particularly striking, including colorectal, ovarian, breast, head and neck, lung, and brain cancers. This review discusses the role of collagen XIalpha1 in cancer and its potential as a target for cancer therapy. PMID- 25511743 TI - Natural killer cells: the journey from puzzles in biology to treatment of cancer. AB - Natural Killer (NK) cells are innate immune effectors that are primarily involved in immunosurveillance to spontaneously eliminate malignantly transformed and virally infected cells without prior sensitization. NK cells trigger targeted attack through release of cytotoxic granules, and secrete various cytokines and chemokines to promote subsequent adaptive immune responses. NK cells selectively attack target cells with diminished major histocompatibility complex (MHC) class I expression. This "Missing-self" recognition by NK cells at first puzzled researchers in the early 1990s, and the mystery was solved with the discovery of germ line encoded killer immunoglobulin receptors that recognize MHC-I molecules. This review summarizes the biology of NK cells detailing the phenotypes, receptors and functions; interactions of NK cells with dendritic cells (DCs), macrophages and T cells. Further we discuss the various strategies to modulate NK cell activity and the practice of NK cells in cancer immunotherapy employing NK cell lines, autologous, allogeneic and genetically engineered cell populations. PMID- 25511740 TI - Identification of epidermal growth factor receptor (EGFR) genetic variants that modify risk for head and neck squamous cell carcinoma. AB - EGFR polymorphisms have not been thoroughly evaluated for association with head and neck squamous cell carcinoma (HNSCC) risk. We genotyped 578 HNSCC patients and 588 cancer-free controls for 60 EGFR single nucleotide polymorphisms (SNPs) and tested associations with HNSCC risk. EGFR intronic SNPs rs12535536, rs2075110, rs1253871, rs845561 and rs6970262 and synonymous SNP rs2072454 were associated with HNSCC risk among all subjects (p < 0.05). SNPs rs12538371, rs845561, and rs6970262 were significantly associated with HNSCC risk (p < 0.05) among never tobacco users. We identified EGFR variants that likely modify risk for HNSCC including three variants that contribute to tobacco-independent risk. PMID- 25511744 TI - Mechanism of injury and management in traumatic anterior shoulder dislocation with concomitant humeral shaft and ipsilateral scapula fracture: a case report and review of the literature. AB - INTRODUCTION: Traumatic anterior dislocation of the shoulder is an emergency and warrants urgent attention. However, it becomes difficult to manage in cases of associated fractures of humerus and other bones surrounding the shoulder joint. There have been reports of traumatic anterior dislocation of the shoulder associated with humeral fractures in the literature but the trilogy of anterior dislocation of the shoulder; humeral shaft fracture; and scapular fracture have never been described. CASE PRESENTATION: We present the case of a 27-year-old south Asian man presenting with the above-mentioned injury. He was managed with open reduction and internal fixation of the fracture and subsequent reduction at the shoulder joint. The fracture of the scapula was managed conservatively. Radiological union was achieved at 14 weeks with a good range of movements at the shoulder. CONCLUSIONS: Shoulder dislocation associated with fractures of humerus and scapula occurs in rare circumstances due the peculiar mechanism of injury. There is risk of neurovascular damage while attempting joint reduction without fracture fixation so, in these cases, the fracture should be addressed first and dislocation later. PMID- 25511745 TI - Non-invasive screening for cardiac allograft vasculopathy: go small or go home? PMID- 25511746 TI - Comprehensive review and suggested strategies for the detection and management of aortic insufficiency in patients with a continuous-flow left ventricular assist device. PMID- 25511747 TI - Concomitant aortic valve procedures in patients undergoing implantation of continuous-flow left ventricular assist devices: An INTERMACS database analysis. AB - BACKGROUND: Management of existing aortic insufficiency (AI) and mechanical aortic valves in patients undergoing left ventricular assist device (LVAD) implantation remains controversial. Surgical options to address these issues include closure, repair or replacement of the valve. METHODS: Continuous-flow LVAD/biventricular VAD patients entered into the INTERMACS database between June 2006 and December 2012 were included (n = 5,344) in this analysis. Outcomes were compared between patients who underwent aortic valve (AV) closure (n = 125), repair (n = 95) and replacement (n = 85). RESULTS: Among patients who underwent an AV procedure, actuarial survival was significantly reduced for AV closures (63.2%) compared with AV repairs (76.8%) and replacements (71.8%) (p = 0.0003). Differences were greater between groups when only INTERMACS Level 1 or 2 patients were analyzed (p = 0.003). After multivariate adjustment, AV closure remained a significant risk factor for mortality (hazard ratio = 1.87, 95% confidence interval 1.39 to 2.53, p < 0.0001). At 6 to 12 months post-operatively, moderate to severe AI developed in 19%, 5%, 9% and 10% of patients with available echocardiography who underwent repair, closure, replacement and no intervention, respectively (p < 0.0001). Competing outcomes demonstrate that, at 1-year, fewer patients with AV closures were transplanted compared with patients with repairs/replacements (14% vs 19%). No differences were observed between groups with respect to cause of death, re-hospitalization, right heart failure or stroke. CONCLUSIONS: AV closure was associated with increased mortality when compared with repair or replacement in patients with AI who underwent LVAD insertion. The reasons for this association require further investigation. This is the largest study to date to examine concomitant AV procedures in patients undergoing LVAD insertion. PMID- 25511748 TI - S-nitroso human serum albumin attenuates pulmonary hypertension, improves right ventricular-arterial coupling, and reduces oxidative stress in a chronic right ventricle volume overload model. AB - BACKGROUND: This study examined the acute effect of intravenous S-nitroso human serum albumin (S-NO-HSA) infusion on overall hemodynamics and oxidative stress in a chronic left-to-right shunt-induced pulmonary arterial hypertension model with right ventricle (RV) failure. METHODS: An aortocaval fistula (pulmonary-to systemic blood flow ratio [Qp/Qs] > 2.0) was surgically created in 50 male Wistar rats. After 10 weeks, they were randomly treated with S-NO-HSA (n = 20) or human serum albumin (HSA; n = 25) infusion (0.5 umol/kg/h) for 60 minutes. A sham group (n = 10) received S-NO-HSA. RV contractility, RV-vascular coupling, and ventricular interdependence were assessed in vivo at different pre-loads by biventricular conductance catheters. Heart and lung biopsy specimens were obtained for determination of high-energy phosphates, oxidative stress (oxidized glutathione/reduced glutathione), and endothelial nitric oxide synthase protein expression. RESULTS: S-NO-HSA, compared with HSA infusion, reduced RV afterload expressed by effective pulmonary arterial elastance (Ea; 0.49 +/- 0.3 vs 1.2 +/- 0.2 mm Hg/ml; p = 0.0005) and improved RV diastolic function (slope of end diastolic pressure-volume relationship) as well as contractility indicated by slope of end-systolic pressure-volume relationship (Ees). Therefore an increase in efficiency of ventricular-vascular coupling (Ees/Ea) occurred after S-NO-HSA (0.35 +/- 0.17 to 0.94 +/- 0.21; p = 0.005), but not HSA infusion, leading to positive effect on ventricular interdependence with increased left ventricular stroke volume (56% +/- 4% vs 19% +/- 5%; p = 0.0013). S-NO-HSA, compared with HSA, treatment improved adenosine 5'-triphosphate (13.9 +/- 1.1 vs 7.0 +/- 1.8 umol/g protein) and phosphocreatine (5.9 +/- 3.3 vs 1.9 +/- 0.6 umol/g protein; p = 0.01) RV content and decreased the tissue oxidized glutathione/reduced glutathione ratio (p = 0.001). CONCLUSIONS: S-NO-HSA reduces pulmonary hypertension and improves RV systolic and diastolic function and RV-arterial coupling, with a positive effect on ventricular interdependence by increasing energetic reserve and reducing oxidative stress. PMID- 25511749 TI - Phosphorylated S6 kinase and S6 ribosomal protein are diagnostic markers of antibody-mediated rejection in heart allografts. AB - BACKGROUND: Anti-MHC Class I alloantibodies have been implicated in the processes of acute and chronic rejection. These antibodies (Ab) bind to endothelial cells (EC) and transduce signals leading to the activation of cell survival and proliferation pathways, including Src, FAK and mTOR, as well as downstream targets ERK, S6 kinase (S6K) and S6 ribosomal protein (S6RP). We tested the hypothesis that phosphorylation of S6K, S6RP and ERK in capillary endothelium may serve as an adjunct diagnostic tool for antibody-mediated rejection (AMR) in heart allografts. METHODS: Diagnosis of AMR was based on histology or immunoperoxidase staining of paraffin-embedded tissue, consistent with 2013 ISHLT criteria. Diagnosis of acute cellular rejection (ACR) was based on ISHLT criteria. Endomyocardial biopsies from 67 heart transplant recipients diagnosed with acute rejection [33 with pAMR, 18 with ACR (15 with Grade 1R, 3 with Grade >=2R), 16 with pAMR and ACR (13 with 1R and 3 with >=2R)] and 40 age- and gender matched recipients without rejection were tested for the presence of phosphorylated forms of ERK, S6RP and S6K by immunohistochemistry. RESULTS: Immunostaining of endomyocardial biopsies with evidence of pAMR showed a significant increase in expression of p-S6K and p-S6RP in capillary EC compared with controls. A weaker association was observed between pAMR and p-ERK. CONCLUSIONS: Biopsies diagnosed with pAMR often showed phosphorylation of S6K and S6RP, indicating that staining for p-S6K and p-S6RP is useful for the diagnosis of AMR. Our findings support a role for antibody-mediated HLA signaling in the process of graft injury. PMID- 25511750 TI - Influence of intestinal microbiota on body weight gain: a narrative review of the literature. AB - In recent decades, experimental and clinical studies have associated the development of obesity with the composition of the gut microbiota. Mechanisms potentially involved in the contribution of gut microbiota to body weight gain include changes in energy extraction from the diet and the modulation of lipid metabolism, endocrine functions, and the immune system. The host's specific genetic heritage, the type and amount of food intake, chronic inflammation, reduced body energy expenditure, and exposure to obesogenic pollutants are also potential contributing factors. The pathophysiological processes involved in the relationship between gut microbiota and obesity are not fully understood, and further studies are needed to establish whether differences in gut bacterial diversity between obese and normal body weight individuals are the cause or a consequence of obesity. PMID- 25511751 TI - Embolization of arterial gastric supply in obesity (EMBARGO): an endovascular approach in the management of morbid obesity. proof of the concept in the porcine model. AB - BACKGROUND: Embolization of the left gastric artery (LGA) reduces circulating levels of ghrelin, but might prevent from further obesity surgery, particularly sleeve gastrectomy (SG), since the gastroesophageal junction (GEJ), depending on LGA, would be devascularized. Our aim was to evaluate, in an experimental animal study, an endovascular approach targeting arteries of the gastroepiploic arcade aiming to modulate ghrelin levels and to generate an increased vascular supply of the GEJ to reduce the risks of staple-line leaks after SG. METHODS: Seven pigs underwent embolization of both left and right gastroepiploic arteries (LGEA and RGEA) using 500-700-MU microspheres (embolization of arterial gastric supply in obesity (EMBARGO)-alpha). A SG was performed in six pigs 3 weeks after EMBARGO alpha and on eight controls. Capillary lactates were measured at the cardia and pylorus. Five pigs underwent coiling of RGEA and embolization of LGEA using both coils and 100-300-MU microspheres (EMBARGO-beta). Ghrelin levels were assessed before and once per week after both EMBARGOs. Control celiac trunk angiography was performed at 3 weeks (alpha) and 4 weeks (beta). RESULTS: No significant ghrelin reduction was obtained with EMBARGO-alpha at 3 weeks when compared to baseline. Significant ghrelin reduction was found 3 weeks (p = 0.0363) and 4 weeks (p = 0.025) after EMBARGO-beta. Post-EMBARGO-alpha animals presented a significantly lower increase in cardia lactates when compared to controls after SG. Control angiography showed a significantly increased fundic vascular network in 5/6 animals after EMBARGO-alpha and in 5/5 after EMBARGO-beta. CONCLUSIONS: EMBARGO is effective to decrease ghrelin production and can enhance the vascular supply of the GEJ, preparing the vascular background for a SG. PMID- 25511752 TI - The Preceding Surgeon Factor in Bariatric Surgery: a Positive Influence on the Learning Curve of Subsequent Surgeons. AB - BACKGROUND: The learning curve of laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery has been well investigated. The learning curve is defined by complications and/or by duration of surgery (DOS). Previous studies report an inverse relationship between patient outcome and patient volume. In this study, we investigate whether the learning curve of preceding bariatric surgeons is of additional influence for surgeons who start to perform LRYGB in the same centre. MATERIALS AND METHODS: We retrospectively analysed the records of all 713 consecutive primary LRYGB patients operated in our centre from December 2007 until July 2012. Surgeon 1 and 3 had previous laparoscopic bariatric experience whilst Surgeon 2 and 4 had not. We stratified the data between the four surgeons with different levels of experience and in a chronology of 50 cases. RESULTS: Sixty-seven (9.4 %) complications occurred in the study period. Surgeon 1 had more complications occurring within the first 50 cases than Surgeon 4 (10 versus 1, p < 0.05). There was no difference in complication rate between groups of 50 consecutive cases. None of the patients died. DOS decreased for every consecutive surgeon, irrespective of their experience. The learning curve defined by DOS was steepest for Surgeon 1, followed by Surgeon 2, 3 and 4. CONCLUSION: In this study, we show that the learning curve of the preceding surgeon positively influences the learning curve of latter surgeons, irrespective of their experience. Therefore, the 'preceding surgeon factor' should be taken in account in addition to volume requirements when starting new bariatric facilities. PMID- 25511753 TI - Over-the-Scope Clip (OTSC) System for Sleeve Gastrectomy Leaks. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is currently being widely accepted for its role in the treatment of morbid obesity. Staple-line leakage is one of the most reported complications found in 0.5-7 % of the population, in which the Over-the-Scope Clip (OTSC) (Ovesco Endoscopy, Tubingen, Germany), a novel device, is employed. We present our experience with this system in LSG leaks. METHODS: A retrospective analysis of prospectively collected data from patients with LSG leakage was performed, and these patients were treated with the OTSC system. Efficiency was defined as complete oral nutrition without any evidence of additional leakage. RESULTS: Overall, 26 patients underwent endoscopic OTSC treatment. The median age was 39 years (range 26-60), and 12 were male patients (46.15 %). The mean body mass index (BMI) was 42.89 kg/m(2), and 10 patients (38.46 %) came from a revisional bariatric procedure (SRVG or LAGB). Twenty-two patients (84.61 %) had upper staple-line leaks (near the GEJ), and the remaining 4 (15.38 %) had lower antral leaks. Number of endoscopy sessions ranged from 2 to 7 (median 3). There were five failures: 2 of them had an antral leak, and the remaining 3 had an upper staple-line leak. Twenty-one (80.76 %) leaks were successfully treated within 32 days' median time till complete oral nutrition was attained (range 14-70). CONCLUSIONS: The success rate was high with the OTSC system, and it is concluded to be a safe and effective treatment for LSG leaks. PMID- 25511754 TI - Repetitive immunoadsorption cycles for treatment of severe atopic dermatitis. AB - The purpose of the study was to investigate the clinical efficacy of repetitive IgE immunoadsorption (IA) cycles in severe atopic dermatitis (AD) with high serum IgE levels. A total of seven patients with severe AD with a history of no significant or longterm Scoring Atopic Dermatitis (SCORAD) reduction and total serum IgE levels >700 IU/mL were enrolled. The patients received one to five series of IA (Ig-Therasorb adsorber columns; Miltenyi Biotec, Teterow, Germany) each consisting of five consecutive treatments which were performed on a monthly regimen. Overall, one patient received one, two patients two, one patient three, two patients four and one patient five cycles of IA. IA was well tolerated in all the studied AD patients and led to a significant decrease of SCORAD and IgE levels during each IA cycle in all the patients. The relative decrease of SCORAD and serum IgE levels after treatment was 11.1% and 80%, respectively, after five immunoadsorption series, 24.1% and 83.6%, respectively, after four series, 37.6% and 75.9%, respectively, after three series, 27.9% and 74.2%, respectively, after two series, and 25.1% and 74.8% after the 1st IA cycle. One of the patients exhibited a long lasting clinical benefit over more than 12 months after the 5th IA cycle. Repetitive IA with more than two cycles at intervals of 4 weeks induces a profound and persisting IgE reduction which is remarkable clinical efficacy improving SCORAD in severe AD with high serum IgE levels. PMID- 25511755 TI - Antioxidant and anti-ageing activities of mycelia zinc polysaccharide from Pholiota nameko SW-03. AB - BACKGROUND: Edible fungi polysaccharides usually exhibit antioxidant activity, and zinc has been shown to have antioxidant properties. In the present work, Pholiota nameko SW-03 was used as a vector of zinc biotransformation in order to obtain mycelia zinc polysaccharide (MZPS), and the structural characterization and anti-ageing activity of MZPS were investigated. RESULTS: Pholiota nameko SW 03 could accumulate zinc in the form of zinc-enriched polysaccharide, and the zinc content in MZPS was 16.39 +/- 0.72 mg g(-1) . Three fractions (MZPS-1, MZPS 2 and MZPS-3) were successfully isolated. The main fraction (MZPS-2) with the highest antioxidant activity in vitro was composed of glucose, mannose, glucuronic acid, galactose, galacturonic acid and arabinose in a molar ratio of 172.59:5.29:4.61:4.20:1.01:1.00, with a weight-average molecular weight of 13.63 kDa. The anti-ageing capability was measured in d-galactose-induced ageing mice, and the results showed that MZPS could improve antioxidant status (superoxide dismutase, total antioxidant capability, malondialdehyde and lipid peroxide), indicating that MZPS had strong anti-ageing capability in vivo. CONCLUSION: This study suggested that organification of zinc through edible fungi liquid fermentation provided a novel method to produce MZPS, which might be used as a natural antioxidant to slow the progression of ageing. PMID- 25511756 TI - Ankle ligament laxity and stiffness in chronic ankle instability. AB - BACKGROUND: The contribution of mechanical laxity and ligament stiffness to chronic ankle instability is unclear, particularly when using the inversion laxity test, and may have implications for diagnosis, prognosis, and treatment. Our purpose was to determine if individuals with chronic ankle instability demonstrate greater mechanical ligament laxity and altered stiffness compared to controls and copers (those with a healed sprain) during an instrumented arthrometer inversion stress test. METHODS: Recreationally active individuals were classified as those with chronic ankle instability (n = 16), copers (n = 16), or controls (n = 16) based on injury history and self-reported score on the Cumberland Ankle Instability Tool (CAIT). Three trials of an inversion stress test were applied with an instrumented arthrometer utilizing a reliable tester. Talocrural inversion (degrees) and stiffness values were extracted. One-way ANOVAs were calculated, and Tukey post hoc testing was applied (alpha <= .05). RESULTS: Groups were not different in age, height, or weight. The chronic ankle instability group (19 +/- 6) had significantly lower CAIT scores than the control (30 +/- 1) and coper (29 +/- 1) groups (P < .001). The chronic ankle instability group (23 +/- 12 degrees) demonstrated significantly greater inversion than the controls (13 +/- 9 degrees) (P = .04) but was not significantly different than the copers (17 +/- 10 degrees). No significant differences were detected in stiffness between the groups. CONCLUSION: The chronic ankle instability group demonstrated decreased self-reported ankle function and increased mechanical laxity utilizing an instrumented arthrometer for inversion compared to the control group but not the coper group. Laxity, but not stiffness, may be a factor affecting chronic ankle instability and self-reported function. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 25511757 TI - An analysis of 2 fusion methods for the treatment of osteomyelitis following fractures about the ankle. AB - BACKGROUND: In the setting of chronic osteomyelitis following fractures about the ankle, reconstruction through bony arthrodesis may be used as a reconstructive alternative to amputation. During these cases, surgeons often avoid using internal fixation in an attempt to avoid reinfection or premature hardware failure. In this retrospective review, we analyzed the outcomes of chronic osteomyelitic patients who had an arthrodesis of the ankle using either internal or external fixation, focusing on salvage rates, infection clearance, union rates, and functional outcomes. No device was implanted into a known active infection. METHODS: We performed a retrospective chart review of adult patients undergoing arthrodesis in the setting of a previously septic ankle following a traumatic injury. In each case, multiple irrigation and debridement procedures and local and systemic antibiotics were used. Infection status was determined by clinical exam, MRI, nuclear medicine studies, and ultimately bone biopsies. No fixation device was implanted in ankles with known active infections. Patients were divided into 2 cohorts: those fused with internal devices and those fused with external fixators. Thirty patients underwent a total of 32 arthrodesis procedures. Mean follow up time was 27 months (range, 6 to 144). RESULTS: Nineteen fusions were performed using internal fixation; only 2 required amputations, therefore limb salvage was 90%. Fifteen were able to ambulate with or without the assistance of an orthosis (79%). Four patients experienced recurrent infection (21%) and 5 developed nonunion (26%). Of the 13 fusions performed with external fixators, only 1 required an amputation, putting limb salvage at 92%. Ten patients were able to walk with or without the assistance of an orthosis as their final functional status (77%). Two patients experienced recurrent infection (15%), and 4 went on to nonunion (31%). CONCLUSION: When analyzing these 2 fusion methods in posttraumatic patients with previously septic ankles, with the numbers available both methods achieved similar rates of limb salvage and final functional status in these patients, as well as similar rates of infection clearance and bony union. As internal fixation is often less labor intensive for the surgeon and more palatable for the patient postoperatively, we encourage surgeons to consider arthrodesis with internal fixation once the infection is successfully eradicated, especially in a noncompliant patient population. LEVEL OF EVIDENCE: Level III, retrospective comparative series. PMID- 25511758 TI - Cardiovascular disease in CKD in 2014: new insights into cardiovascular risk factors and outcomes. AB - Chronic kidney disease (CKD) is an established independent risk factor for increased cardiovascular events and cardiovascular mortality. During 2014, several research efforts focused on clarifying the complex pathophysiology, assessing the prognostic associations and improving the treatment of cardiovascular disease in patients with CKD. PMID- 25511759 TI - Renal transplantation in 2014: renal transplantation-reducing risk and improving outcome. AB - Several studies published in 2014 might facilitate improvements in the treatment and long-term care of renal transplant recipients. The potential risks of living kidney donation, the efficacy and safety of alemtuzumab-based induction therapy, and the treatment of chronic hepatitis E virus infection have been addressed. PMID- 25511760 TI - Polycystic kidney disease. HALTing PKD progression--revival of blood pressure control. AB - New research suggests that rigorous blood pressure control is beneficial in early autosomal dominant polycystic kidney disease (ADPKD). Although a positive effect on the rate of decline of estimated glomerular filtration rate remains to be demonstrated, this study is likely to change current treatment strategies for young patients with ADPKD. PMID- 25511761 TI - Kidney care in Haiti--the role of partnerships. AB - Establishing a programme for the prevention and treatment of acute kidney injury, chronic kidney disease and end-stage renal disease in a developing country involves unique challenges. We became involved in a collaborative effort to improve nephrology care in Haiti after participating in the emergency response to the 2010 earthquake. The focus of this ongoing project is overcoming barriers to implementation with the goal of improving training and resources for Haitian health-care workers and developing programmes for renal disease prevention and treatment in a setting of limited resources. Here, we offer practical advice for nephrologists who would like to help to advance medical care in developing countries. Rather than technical issues related to the prevention and treatment of renal disease, we focus on collaboration, education and the building of partnerships. PMID- 25511762 TI - [Osteolytic diaphyseal tibial lesion with increasing constant dull tibial pain]. PMID- 25511763 TI - Anticipated and unanticipated consequences of abuse deterrent formulations of opioid analgesics. PMID- 25511764 TI - Selenium supplementation in radiotherapy patients: do we need to measure selenium levels in serum or blood regularly prior radiotherapy? AB - Considering the review by Puspitasari and colleagues, an additional discussion of the endpoints of the Se supplementation studies described would be helpful. In our view, selenium can safely be given to selenium-deficient cancer patients prior to and during radiotherapy. Therefore, in order to help the radiation oncologist in decision making, we strongly advocate to determine the selenium status prior to and during a potential adjuvant selenium supplementation, e.g. when trying to ease the side-effects of radiation treatment or in the aftercare situation when the selenium status may become insufficient. PMID- 25511765 TI - Editorial: thiopurine withdrawal during sustained clinical remission in inflammatory bowel disease. PMID- 25511766 TI - Editorial: prolonged remission from hepatic encephalopathy with rifaximin. PMID- 25511767 TI - Editorial: allergy and recurrent abdominal pain of childhood/irritable bowel syndrome. PMID- 25511768 TI - Editorial: TIPSS in patients with cirrhosis and hepatocellular carcinoma. PMID- 25511769 TI - Editorial: TIPSS in patients with cirrhosis and hepatocellular carcinoma - authors' reply. PMID- 25511770 TI - Letter: clinical predictors of Clostridium difficile infection - advanced age and residential status are important factors for prediction and prevention. PMID- 25511771 TI - Letter: clinical predictors of Clostridium difficile infection - advanced age and residential status are important factors for prediction and prevention - authors' reply. PMID- 25511772 TI - Letter: prunes for the treatment of constipation. PMID- 25511773 TI - Letter: leucocytapheresis as a nonpharmacologic treatment for patients with ulcerative colitis during pregnancy. PMID- 25511774 TI - Letter: leucocytapheresis as a nonpharmacologic treatment for patients with ulcerative colitis during pregnancy - authors' reply. PMID- 25511775 TI - Letter: safe and effective cessation of long-term nucleos(t)ide analogue therapy in noncirrhotic patients with HBeAg-negative chronic hepatitis B. PMID- 25511776 TI - Side of ovarian endometrioma does not affect the outcome of in vitro fertilization/intracytoplasmic sperm injection in infertile women after laparoscopic cystectomy. AB - AIM: The aim of this study was to assess the impact of the laterality of ovarian endometrioma on pregnancy outcome of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) in infertile patients undergoing laparoscopic cystectomy. MATERIAL AND METHODS: A total of 103 IVF/ICSI cycles in patients who had undergone laparoscopic cystectomy for unilateral endometriomas were reviewed retrospectively from January 2005 through December 2009. There were 41 cycles where laparoscopic cystectomy had been carried out for right endometriomas and 62 cycles after left-side surgery. Primary outcome measures were ovarian reserve and ovarian response. Secondary outcome measures were the implantation rate, clinical pregnancy rate, and live birth rate. RESULTS: There was no difference among the two groups with regard to antral follicle count, number of oocytes retrieved, the dosage of gonadotrophin, estradiol level on human chorionic gonadotrophin day, good-quality embryos for transfer, and fertilization rate. The clinical pregnancy rate and live birth rate were similar between the two groups; however, the implantation rate was significantly lower in the cycles with left-side ovarian endometrioma compared to the right counterpart (10.1% vs 20.2%; P = 0.015). CONCLUSION: There were no associations among the laterality of ovarian endometrioma, ovarian reserve and ovarian response in IVF/ICSI cycles. However, left ovarian endometrioma after laparoscopic cystectomy may impair implantation rate as compared to right ovarian endometrioma. PMID- 25511778 TI - Tissue-Specific Glucocorticoid Signaling May Determine The Resistance Against Glucocorticoids In Autoimmune Diseases. AB - Endogenous glucocorticoids exert a diverse array of physiological processes including immune-modulatory or anti-inflammatory responses and play an important role in the pathogenesis of inflammatory and autoimmune diseases. Regulation of inflammatory processes by glucocorticoids is controlled in a cytokine-hypothalamo pituitary-adrenal axis feedback circuit and on the local, cell-type and context specific local regulatory system. At the tissue level the sensitivity and response to glucocorticoids are determined by multiple factors: including the local availability to glucocorticoids transported by blood, the locally-formed bioactive glucocorticoids (synthesized and metabolized 11beta-hydroxysteroid dehydrogenase enzymes), the number and function of the glucocorticoid receptor (GR) and the GR affinity to its ligands. Numerous molecular factors are known to influence the sensitivity of glucocorticoid response through the GR. Cytokines are one of the major components that can inhibit GR function and can potentiate the resistance against glucocorticoids. GR isoforms, generated by alternative splicing, alternative translation and post-translation modification are further mechanisms which modulate glucocorticoid signaling. Genetic variants within the GR encoding gene are other potential factors that may influence the susceptibility and severity of autoimmune disorders and may play a key role in individual response to medication. In this review our aim was to summarize our knowledge about the connections between the cell type-specific glucocorticoid signaling and the local immune system. Prediction of individual sensitivity to steroids and identification of key players in development of glucocorticoid resistance are essential in individualized therapies. The local, tissue-specific glucocorticoid signaling and its influence by cytokines may be important in determining the magnitude of inflammatory reactions, and may also be related to the success of glucocorticoid-containing therapeutic strategies. PMID- 25511777 TI - Antimicrobial photodynamic therapy suppresses dental plaque formation in healthy adults: a randomized controlled clinical trial. AB - BACKGROUND: Oral care is important for oral and systemic health, especially for elderly institutionalized individuals and compromised patients. However, conventional mechanical plaque control is often difficult for these patients because of the pain or the risk of aspiration. Although antimicrobial photodynamic therapy (aPDT), which is considered an alternative or adjunct to mechanical approaches, has potential application as a less stressful method of daily plaque control, no clinical application of this technique has been reported. METHODS: We investigated the inhibitory effect of a combination of toluidine blue O (TBO), and a red light-emitting diode (LED) on dental plaque formation in healthy volunteers. The optimal concentration of TBO was determined in preliminary in vitro experiments to evaluate the bactericidal effect of aPDT on Streptococcus oralis and to clarify its safety in fibroblast cells. To survey the mechanism of TBO-mediated aPDT, the quality and quantity of reactive oxygen species (ROS) generated during aPDT were also examined using electron spin resonance (ESR) spectroscopy. Subsequently, the inhibitory effect of aPDT on dental plaque formation was investigated in eleven subjects as a clinical pilot study. The right or left mandibular premolars were randomly assigned to the treatment (with aPDT) or control (without aPDT) groups. In total, aPDT was applied six times (twice per day) to the teeth in the test group over a period of four days. On the fourth day, the study concluded and the analyses were performed. RESULTS: A combination of 500 or 1000 MUg/ml TBO and LED irradiation for 20 s significantly decreased the number of colony forming units of Streptococcus oralis. The cytotoxicity of aPDT was comparable to that of standard antiseptics used in the oral cavity. Hydroxyl radicals were detected by ESR analysis, but singlet oxygen was not. A randomized controlled trial demonstrated that aPDT with 1000 MUg/ml TBO and red LED irradiation significantly suppressed dental plaque formation without harming teeth or the surrounding tissues. CONCLUSIONS: aPDT has the potential to be a promising novel technical modality for dental plaque control. TRIAL REGISTRATION: This trial was registered with University Hospital Medical Information Network Clinical Trials Registry (number UMIN000012504). PMID- 25511779 TI - Multi-kinase inhibitors. AB - The limitations of many mono-kinase inhibitors can be overcome by agents with multi-target action. An important advantage of targeting more than one kinase, is an increase in potency, due to the synergistic effect. Moreover, this approach can reduce the possibility of developing drug resistance. Several multitarget agents have been designed as single kinase inhibitors and found to be multi target inhibitors because of the structural homology among the ATP-binding site of kinases. In other cases, these inhibitors have been obtained by optimization of potent individual inhibitors or by combination of selective ligands. Also some irreversible inhibitors act on different kinases and covalently modify the cysteine residues located near the ATP-binding pocket. In this review the most recent examples of multi-kinase inhibitors are reported, focusing on chemical structures, structure-activity relationship (SAR) and biological activity. These inhibitors, suitably substituted, could be used in designing other multitarget agents. Virtual molecular docking would suggest potential targets of molecules, moreover combining pharmacophore combination and screening methods could probably help in the discovery of more potent multikinase inhibitors. PMID- 25511780 TI - Progress and issues of the genome-wide association study for hypertension. AB - Over the past few years, use of the genome-wide association study (GWAS) has made it possible to identify the primary genetic mechanisms of essential hypertension. GWAS results have helped identify many loci in or near genes that generally were not expected to be associated with blood pressure or essential hypertension. However, considering the great expectations of improving clinical outcomes and the billions of dollars that have been spent on various GWASs, the progress made so far has been slow. There are several factors that could be responsible for the relative lack of success of GWASs. First, it is possible that the number of people enrolled in the various GWASs was not enough, thereby limiting the power to detect additional markers. Second, although the alleles that are associated with a modest increase in risk are constantly being found, their discriminatory ability and use as predictive markers has been quite low. Difficulties with control group selection along with unrepeatability have also been problematic when using GWASs. The current paper summarizes the recent progress attained when using a GWAS of hypertension to identify the many loci associated with essential hypertension. In this review, we discuss the progress and issues of a GWAS for hypertension. PMID- 25511781 TI - Changing Beliefs about Trauma: A Qualitative Study of Cognitive Processing Therapy. AB - BACKGROUND: Controlled qualitative methods complement quantitative treatment outcome research and enable a more thorough understanding of the effects of therapy and the suspected mechanisms of action. AIMS: Thematic analyses were used to examine outcomes of cognitive processing therapy (CPT) for posttraumatic stress disorder (PTSD) in a randomized controlled trial of individuals diagnosed with military-related PTSD (n = 15). METHOD: After sessions 1 and 11, participants wrote "impact statements" describing their appraisals of their trauma and beliefs potentially impacted by traumatic events. Trained raters coded each of these statements using a thematic coding scheme. RESULTS: An analysis of thematic coding revealed positive changes over the course of therapy in participants' perspective on their trauma and their future, supporting the purported mechanisms of CPT. CONCLUSION: Implications of this research for theory and clinical practice are discussed. PMID- 25511782 TI - Early urbanization and mobility at Tell Brak, NE Syria: the evidence from femoral and tibial external shaft shape. AB - Urbanization at Tell Brak began in the late 5th millennium BCE and the site reached its maximum size in the Late Chalcolithic (LC) 3, ca. 3900-3600 BCE. During that time, a large midden was formed at the edge of the early city, now known as Tell Majnuna. Rescue excavations at Tell Majnuna revealed several clusters of commingled human remains and a cemetery on the top. Several human skeletons dated to the LC 3 and Early Bronze Age (EBA) were found also at Tell Brak itself and it was possible to investigate differences in cross-sectional femoral and tibial shaft shapes between LC 3 and EBA to test the hypothesis that rapid and extensive urbanization in the LC 3 induced increase in mobility. External midshaft and subtrochanteric measurements of at least 152 femora and measurements of 55 tibiae at the nutrient foramen were taken to investigate the differences in the level of terrestrial mobility between four LC 3 and one EBA chronological subsets. Also the correlation was examined between shaft cross sectional shapes and frequency of linear enamel hypoplasia (LEH) in canines, as a proxy indicator of population stress. Due to post-mortem damage, sex assessment was based only on the size of measured bones. In spite of the limited quality of the gathered data, significant differences in femoral midshaft shape in males were observed between the LC 3 and EBA subsets and the average shape index scores appeared to be correlated with the LEH frequencies. No such result was obtained for females, suggesting that only males were more mobile in the LC 3 and their mobility level was associated with general population stress. In contrast, in females the average shape of subtrochanteric femoral cross-section was more variable between temporal subsets. The patterns of temporal differences in tibial cross-section at the nutrient foramen were not conclusive due to the small sample size. Obtained results suggest that males in the LC 3, the period of rapid urbanization, were more mobile than in the EBA, when the population size was considerably smaller. This mobility may have been related to need of searching for alternative resources for the overpopulated early city. PMID- 25511783 TI - Type of myocardial infarction presentation in patients with chronic kidney disease. AB - BACKGROUND AND AIM: Association of coronary and renal disease has been frequently found in epidemiological studies. Whether ECG-graphic presentation of myocardial infarction [S-T Elevated MI (STEMI) or Non S-T Elevated MI (NSTEMI)] is related to the degree of renal dysfunction is still unclear. METHODS AND RESULTS: We examined 146 patients with acute myocardial infarction, consecutively entering the Coronary Care Unit of our ward. At entry, patients underwent clinical, ECG graphic and echocardiographic examination, and blood samples were withdrawn for cardiac markers and general biochemistry. GFR was calculated using the CKD-EPI equation. STEMI was found in 71 cases and NSTEMI in 75 cases. Renal function was normal in 61 patients (stage 1), mildly impaired (<90 mL/min/1.73 m(2) and >= 60 mL/min/1.73 m(2)) in 60 (stage 2) and moderately to severely impaired (GFR <60 mL/min/1.73 m(2)) in 25 cases (stages 3-4). Patients were, thereafter, clustered into two groups (stages 1-2 and stages 3-4). Compared to stage 1-2 subjects, stages 3-4 patients were older, were more likely to be diabetic and had more frequently previous cardiovascular diseases. The probability of presentation of NSTEMI for stage 3-4 patients was 4-fold greater than for stage 1-2 patients (p = 0.02). CONCLUSIONS: These data support the evidence that 1) NSTEMI is associated with more severe kidney dysfunction, likely due to more severe and/or longer lasting exposition to risk factors; 2) cardiac and renal impairment are strongly associated. ClinicalTrials.gov Identifier: NCT01636427. PMID- 25511784 TI - In vitro effects of fermented papaya (Carica papaya, L.) on platelets obtained from patients with type 2 diabetes. AB - BACKGROUND AND AIM: Oxidative stress is associated with insulin resistance pathogenesis, insulin secretion deficiency, and complication onset. Fermented papaya preparation (FPP), a dietary supplement obtained by fermentation of the papaya fruit, may be used as an antioxidant in the prevention of diabetic complications. METHODS AND RESULTS: Platelets from 30 patients with type 2 diabetes mellitus (DM 2) and 15 healthy subjects were analyzed to evaluate the in vitro effects of FPP incubation. Na(+)/K(+)-adenosine triphosphatase (ATPase) activity, membrane fluidity, total antioxidant capacity (TAC), superoxide dismutase (SOD) activity, and conjugated diene levels were determined. In vitro FPP incubation improved platelet function, by enhancing Na(+)/K(+)-ATPase activity and membrane fluidity, and ameliorated the antioxidant system functionality, through an increase in TAC and SOD activity and a parallel decrease in conjugated diene levels in patients with DM 2. CONCLUSION: Our data suggest that the incubation with FPP may have a protective effect on platelets from patients with DM 2, by preventing the progression of oxidative damage associated with diabetes and its complications. PMID- 25511786 TI - Drastic calorie restriction in preparation for bariatric surgery. PMID- 25511785 TI - Associations between serum uric acid concentrations and metabolic syndrome and its components in the PREDIMED study. AB - BACKGROUND AND AIMS: Several studies have demonstrated a relationship between increased serum uric acid (SUA) concentrations and the prevalence of metabolic syndrome (MetS) in the oriental population. However, to the best of our knowledge, the association between SUA and MetS has never been investigated in elderly European individuals at high cardiovascular risk. The aim of this study was to conduct a cross-sectional and prospective evaluation of the associations between SUA concentrations and the MetS in elderly individuals at high cardiovascular risk. METHODS AND RESULTS: Men and women (55-80 years of age) from different PREDIMED (Prevencion con DIeta MEDiterranea) recruiting centers were studied. Baseline cross-sectional (n = 4417) and prospective assessments (n = 1511) were performed. MetS was defined in accordance with the updated harmonized criteria. Anthropometric measurements and biochemical determinations were assessed at baseline and yearly during follow-up. Unadjusted and adjusted regression models were fitted to assess the risk of MetS and its components according to the levels of baseline SUA. Participants in the highest baseline sex adjusted SUA quartile showed an increased prevalence of MetS than those in the lowest quartile, even after adjusting for potential confounders (odd ratio (OR): 2.3 (95% confidence interval (CI), 1.8-2.8); P < 0.001). Participants in the highest baseline sex-adjusted SUA quartile presented a higher incidence of new onset MetS than those in the lowest quartile (hazard ratios (HR): 1.4 (95% CI, 1.1-1.9); P < 0.001). Participants initially free at baseline of hypertriglyceridemia (HR: 1.9 (1.6-2.4); P < 0.001), low high-density lipoprotein (HDL)-cholesterol (HR: 1.4 (1.1-1.7); P = 0.002), and hypertension components of MetS (HR: 2.0 (1.2-3.3); P = 0.008) and who were in the upper quartile of SUA had a significantly higher risk of developing these MetS components during follow-up. CONCLUSIONS: Elevated SUA concentrations are significantly associated with the development of MetS. PMID- 25511787 TI - Requirement of carbon dioxide for initial growth of facultative methylotroph, Acidomonas methanolica MB58. AB - The facultative methylotrophic bacterium Acidomonas methanolica MB58 can utilize C1 compounds via the ribulose monophosphate pathway. A large gene cluster comprising three components related to C1 metabolism was found in the genome. From upstream, the first was an mxa cluster encoding proteins for oxidation of methanol to formaldehyde; the second was the rmp cluster encoding enzymes for formaldehyde fixation; and the third was the cbb gene cluster encoding proteins for carbon dioxide (CO2) fixation. Examination of CO2 requirements for growth of A. methanolica MB58 cells demonstrated that it did not grow on any carbon source under CO2-free conditions. Measurement of ribulose-1,5-bisphosphate carboxylase activity and RT-PCR analysis demonstrated enzymatic activity was detected in A. methanolica MB58 at growth phase, regardless of carbon sources. However, methanol dehydrogenase and 3-hexlose-6-phosphate synthase expression was regulated by methanol or formaldehyde; it were detected during growth and apparently differed from ribulose-1,5-bisphosphate carboxylase expression. These results suggested that A. methanolica MB58 may be initially dependent on autotrophic growth and that carbon assimilation was subsequently coupled with the ribulose monophosphate pathway at early- to mid-log phases during methylotrophic growth. PMID- 25511788 TI - Production of biomass and bioactive compounds from adventitious roots by optimization of culturing conditions of Eurycoma longifolia in balloon-type bubble bioreactor system. AB - The present study aimed to optimize the conditions for the production of adventitious roots from Eurycoma longifolia Jack, an important medicinal woody plant, in bioreactor culture. The effects of the type and concentration of auxin on root growth were studied, as well as the effects of the NH4(+):NO3(-) ratio on adventitious root growth and the production of phenolics and flavonoids. Approximately 5 g L(-1) fresh weight of adventitious roots was inoculated into a 3 L balloon-type bubble bioreactor, which contained 2 L 3/4 MS medium supplemented with 30 g L(-1) sucrose and cultures were maintained in the dark for 7 weeks at 24 +/- 1 degrees C. Higher concentrations of IBA (7.0 and 9.0 mg L( 1)) and NAA (5.0 mg L(-1)) enhanced the biomass and accumulation of total phenolics and flavonoids. The adventitious roots were thin, numerous, and elongated in 3/4 MS medium supplemented with 5.0 and 7.0 mg L(-1) IBA, whereas the lateral roots were shorter and thicker with 5.0 mg L(-1) NAA compared with IBA treatment. The optimum biomasses of 50.22 g L(-1) fresh weight and 4.60 g L( 1) dry weight were obtained with an NH4(+):NO3(-) ratio of 15:30. High phenolic and flavonoid productions (38.59 and 11.27 mg L(-1) medium, respectively) were also obtained with a ratio of 15:30. Analysis of the 2,2-diphenyl-1 picrylhydrazyl (DPPH)-scavenging activity indicated higher antioxidant activity with an NH4(+):NO3(-) ratio of 30:15. These results suggest that balloon-type bubble bioreactor cultures are suitable for the large-scale commercial production of E. longifolia adventitious roots which contain high yield of bioactive compounds. PMID- 25511789 TI - Levetiracetam versus phenytoin for seizure prophylaxis during and early after craniotomy for brain tumours: a phase II prospective, randomised study. AB - OBJECTIVE: Phenytoin (PHT) is routinely used for seizure prophylaxis in patients with brain tumours during and after craniotomy, despite incomplete evidence. We performed a prospective, randomised study to investigate the significance of prophylactic use of levetiracetam (LEV), in comparison with PHT, for patients with supratentorial tumours in the perioperative period. METHODS: Patients were randomised to receive LEV, 500 mg/body every 12 h until postoperative day 7, or PHT, 15-18 mg/kg fosphenytoin followed by 125 mg PHT every 12 h until postoperative day 7. The primary end point was the occurrence of seizures, and secondary end points included the occurrence of haematological and non haematological adverse events. RESULTS: One hundred and forty-six patients were randomised to receive LEV (n=73) or PHT (n=73). The incidence of seizures was significantly less in the LEV group (1.4%) compared with the PHT group (15.1%, p=0.005), suggesting benefit of LEV over PHT. The observed OR for being seizure free in the LEV prophylaxis group relative to the PHT group was 12.77 (95% CI 2.39 to 236.71, p=0.001). In a subgroup analysis of patients who did not have seizures before craniotomy, similar results were demonstrated: the incidence of seizures was 1.9% (LEV) and 13.8% (PHT, p=0.034), and OR was 8.16 (95% CI 1.42 to 154.19, p=0.015). LEV was completed in all cases, although PHT was withdrawn in five patients owing to liver dysfunction (1), skin eruption (2) and atrial fibrillation (2). CONCLUSIONS: Prophylactic use of LEV in the perioperative period is recommended because it is safe and significantly reduces the incidence of seizures in this period. TRIAL REGISTRATION NUMBER: UMIN13971. PMID- 25511790 TI - Stiff-person syndrome: insights into a complex autoimmune disorder. AB - Stiff-person syndrome (SPS) is characterised by progressive rigidity and muscle spasms affecting the axial and limb muscles. Since its initial description in 1956, marked progress has been made in the clinical characterisation, understanding of pathogenesis and therapy of this disorder. SPS can be classified according to the clinical presentation into classic SPS and SPS variants: focal or segmental-SPS, jerking-SPS and progressive encephalomyelitis with rigidity and myoclonus. Most patients with SPS have antibodies directed against the glutamic acid decarboxylase, the rate-limiting enzyme for the production of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Antibodies directed against GABA(A) receptor-associated protein, and the glycine-alpha1 receptor can also be observed. Paraneoplastic SPS is commonly associated with antiamphiphysin antibodies and breast cancer. Treatment of SPS with drugs that increase the GABAergic tone combined with immunotherapy can improve the neurological manifestations of these patients. The prognosis, however, is unpredictable and spontaneous remissions are unlikely. PMID- 25511791 TI - Differentiating between right-lateralised semantic dementia and behavioural variant frontotemporal dementia: an examination of clinical characteristics and emotion processing. AB - BACKGROUND AND PURPOSE: Right-lateralised semantic dementia (right SD) and behavioural-variant frontotemporal dementia (bvFTD) appear clinically similar, despite different patterns of underlying brain changes. This study aimed to elucidate distinguishing clinical and cognitive features in right SD versus bvFTD, emphasising emotion processing and its associated neural correlates. METHODS: 12 patients with right SD and 19 patients with bvFTD were recruited. Clinical features were documented. All patients were assessed on standardised neuropsychological tests and a facial emotion processing battery. Performance was compared to 20 age-matched and education-matched controls. Grey matter intensity was related to emotion processing performance using whole-brain voxel-based morphometry analysis. RESULTS: Patients with right SD exhibited disproportionate language dysfunction, prosopagnosia and a suggestion of increased obsessive personality/behavioural changes versus patients with bvFTD. In contrast, patients with bvFTD demonstrated pronounced deficits in attention/working memory, increased apathy and greater executive dysfunction, compared to patients with right SD. Decreased empathy, disinhibition and diet changes were common to both dementia subtypes. Emotion processing deficits were present in both FTD syndromes but were associated with divergent patterns of brain atrophy. In right SD, emotion processing dysfunction was associated with predominantly right medial and lateral temporal integrity, compared to mainly left temporal, inferior frontal and orbitofrontal and right frontal gyrus integrity in bvFTD. CONCLUSIONS: This study demonstrates comparable deficits in facial emotion processing in right SD and bvFTD, in keeping with their similar clinical profiles. These deficits are attributable to divergent neural substrates in each patient group, namely, right lateralised regions in right SD, versus predominantly left lateralised regions in bvFTD. PMID- 25511792 TI - Natalizumab improves ambulation in relapsing-remitting multiple sclerosis: results from the prospective TIMER study and a retrospective analysis of AFFIRM. AB - BACKGROUND AND PURPOSE: Impaired ambulation is a prominent disabling symptom of multiple sclerosis and can lead to reduced quality of life. Whether natalizumab, a monoclonal antibody shown to reduce disease activity in relapsing-remitting multiple sclerosis, could impact ambulation performance was examined. METHODS: A prospective open-label study, TIMER, was conducted in natalizumab-naive patients (n = 215). The timed 25-foot walk (T25FW) and timed 100-m walk (T100MW) were assessed at baseline and at weeks 24 and 48 of natalizumab therapy, together with Expanded Disability Status Scale scores. The effects of natalizumab on T25FW performance were also examined in a retrospective analysis of natalizumab-treated patients (n = 627) and placebo control patients (n = 315) from the AFFIRM study. RESULTS: In TIMER, a significant increase from baseline in T25FW speed was seen at week 24 (P = 0.0074) and in T100MW speed at weeks 24 and 48 (both P < 0.001). A greater proportion of patients showed clinically meaningful increases (>=20%) in walking speed on the T100MW (25%) than on the T25FW (13%) at week 48 (P = 0.032). In AFFIRM, natalizumab increased the proportion of patients with >=20% confirmed improvement in T25FW speed at year 2 by 78% versus placebo (P = 0.0133). CONCLUSIONS: Natalizumab increased walking speed in patients with relapsing-remitting multiple sclerosis. The T100MW may be more sensitive to changes in ambulation capacity than the T25FW, and both tests appear to detect clinically meaningful improvements in ambulatory function. PMID- 25511793 TI - Influence of sex and race on mycophenolic acid pharmacokinetics in stable African American and Caucasian renal transplant recipients. AB - BACKGROUND AND OBJECTIVES: No evaluation of sex and race influences on mycophenolic acid (MPA) pharmacokinetics and adverse effects (AEs) during enteric coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. The primary objective of this study was to investigate the influence of sex and race on MPA and MPA glucuronide (MPAG) pharmacokinetics in stable renal transplant recipients receiving ECMPS and tacrolimus METHODS: The pharmacokinetics of MPA and MPAG and their associated gastrointestinal AEs were investigated in 67 stable renal transplant recipients: 22 African American males (AAMs), 13 African American females (AAFs), 16 Caucasian males (CMs), and 16 Caucasian females (CFs) receiving ECMPS and tacrolimus. A validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting, and acid suppressive therapy was completed. Apparent clearance, clearance normalized to body mass index (BMI), area under the concentration-time curve from time zero to 12 h (AUC12) and dose-normalized AUC12 (AUC*) were determined using a statistical model that incorporated gastrointestinal AE and clinical covariates. RESULTS: Males had more rapid apparent MPA clearance (CMs 13.8 +/- 6.27 L/h vs. AAMs 10.2 +/- 3.73 L/h) than females (CFs 8.70 +/- 3.33 L/h and AAFs 9.71 +/- 3.94 L/h; p = 0.014) with a race-sex interaction (p = 0.043). Sex differences were observed in MPA clearance/BMI (p = 0.033) and AUC* (p = 0.033). MPA AUC12 was greater than 60 mg.h/L in 57 % of renal transplant recipients (RTR) with 71 % of patients demonstrating gastrointestinal AEs and a higher score noted in females. In all patients, females exhibited 1.40-fold increased gastrointestinal AE scores compared with males (p = 0.024). Race (p = 0.044) and sex (p = 0.005) differences were evident with greater MPAG AUC12 in AAFs and CFs. CONCLUSION: Sex and race differences were evident, with females having slower MPA clearance, higher MPAG AUC12, and more severe gastrointestinal AEs. These findings suggest sex and race should be considered during MPA immunosuppression. PMID- 25511795 TI - Gila monster (Heloderma suspectum) envenomation: Descriptive analysis of calls to United States Poison Centers with focus on Arizona cases. AB - BACKGROUND: The Gila monster (Heloderma suspectum) is a venomous lizard native to the deserts of southwestern United States (US) and northern Mexico. The purpose of this study was to describe human exposures to Gila monsters reported to US poison control centers (PCCs) with a focus on Arizona cases. METHODS: The American Association of Poison Control Centers' National Poison Data System (NPDS) was used to access and retrospectively review all calls to US PCCs, concerning Gila monsters between January 1, 2000 and October 31, 2011. In addition, detailed records from the two Arizona PCCs were reviewed for the same time period. RESULTS: A total of 319 calls regarding Gila monsters were identified in the NPDS. Of these, 105 (33%) were human exposures; most (79%) occurred in males. A total of 71 (68%) of these 105 cases were referred to a health care facility (HCF); 30 (29%) were managed on-site. Of the 71 HCF referrals, 36 (51%) were discharged home and 17 (24%) were admitted. Most (65%) admissions were to an intensive care unit (ICU). Arizona's PCCs received 70 unique reports of Gila monster bite. Most (77%) of the bites in Arizona involved an upper extremity. Eight (11%) involved patients under the age of 18 years. Eleven (16%) Arizona cases were work-related. Twenty-eight (40%) of the 70 bites in Arizona were evaluated in a HCF, but not admitted. Eleven (16%) were admitted, of which five were to an ICU. Six patients had edema of airway structures; three required emergent airway management, one by cricothyrotomy. There were no deaths. CONCLUSION: Gila monster bites are uncommon. Many cases did not require hospitalization. Edema of airway structures is an infrequent, but life threatening complication. PMID- 25511794 TI - Effects of alcohol on human carboxylesterase drug metabolism. AB - BACKGROUND AND OBJECTIVE: Human carboxylesterase-1 (CES1) and human carboxylesterase-2 (CES2) play an important role in metabolizing many medications. Alcohol is a known inhibitor of these enzymes but the relative effect on CES1 and CES2 is unknown. The aim of this study was to determine the impact of alcohol on the metabolism of specific probes for CES1 (oseltamivir) and CES2 (aspirin). METHODS: The effect of alcohol on CES1- and CES2-mediated probe drug hydrolysis was determined in vitro using recombinant human carboxylesterase. To characterize the in vivo effects of alcohol, healthy volunteers received each probe drug alone and in combination with alcohol followed by blood sample collection and determination of oseltamivir, aspirin, and respective metabolite pharmacokinetics. RESULTS: Alcohol significantly inhibited oseltamivir hydrolysis by CES1 in vitro but did not affect aspirin metabolism by CES2. Alcohol increased the oseltamivir area under the plasma concentration-time curve (AUC) from 0 to 6 h (AUC0 -> 6 h) by 27% (range 11-46%, p = 0.011) and decreased the metabolite/oseltamivir AUC0 -> 6 h ratio by 34% (range 25-41%, p < 0.001). Aspirin pharmacokinetics were not affected by alcohol. CONCLUSIONS: Alcohol significantly inhibited the hydrolysis of oseltamivir by CES1 both in vitro and in humans, but did not affect the hydrolysis of aspirin to salicylic acid by CES2. These results suggest that alcohol's inhibition of CES1 could potentially result in clinically significant drug interactions with other CES1-substrate drugs, but it is unlikely to significantly affect CES2-substrate drug hydrolysis. PMID- 25511796 TI - Effect of subthalamic nucleus stimulation on penicillin induced focal motor seizures in primate. AB - BACKGROUND: Drug-resistant motor epilepsies are particularly incapacitating for the patients. In a primate model of focal motor seizures induced by intracortical injection of penicillin, we recently showed that seizures propagated from the motor cortex towards the basal ganglia. OBJECTIVE: Using the same animal model here, we hypothesized that disruption of subthalamic nucleus (STN) activity by chronic high frequency stimulation (HFS) could modify pathological excessive cortical synchronisation occurring during focal motor seizures, and therefore could reduce seizure activity. METHODS: Two monkeys were chronically implanted with one electrode positioned into the STN. In each experiment, seizures were induced during 6 hours by injecting penicillin into the motor cortex. During stimulation sessions, HFS-STN was applied at the beginning of penicillin injection. RESULTS: Our results indicate that HFS-STN improved focal motor seizures by delaying the occurrence of the first seizure, by decreasing the number of seizures by 47% and therefore the total time spent seizing by 53% compared to control. These results argue for a therapeutic use of HFS-STN in motor seizures because they were obtained in a very severe primate model of motor status similar to that seen in human. Furthermore, HFS-STN was much more efficient than direct cortical HFS of the epileptic focus, which we already tested in the same primate model. CONCLUSIONS: The present study suggests that HFS-STN could be used as an experimental therapy when other therapeutic strategies are not possible or have failed in humans suffering from motor epilepsy but the present study still warrants controlled studies in humans. PMID- 25511797 TI - Transcranial direct current stimulation for pure alexia: effects on brain and behavior. PMID- 25511799 TI - The dental health of children subject to a child protection plan. AB - BACKGROUND: In the United Kingdom, child maltreatment is an area of increased awareness and concern. AIM: To compare the dental health of children subject to child protection plans with controls. DESIGN: Children had to be aged between two and 11 years, medically healthy, and subject either to a child protection plan or attending the paediatric outpatient orthopaedic or general surgery clinics (control group). All children had a standardized oral examination. RESULTS: Seventy-nine children were examined in each group. Children with child protection plans had statistically higher levels of primary tooth decay than controls (mean dmft 3.82 and 2.03, Mann-Whitney U test P = 0.002). After adjusting for socioeconomic status, the incidence rate ratios for the occurrence of dental caries in the primary dentition in children with a child protection plan was 1.76 (95% CI: 1.44-2.15) relative to the controls. There was no statistical difference in the levels of permanent tooth decay between the study and control groups (mean DMFT 0.71 and 0.30, respectively). The care index was significantly lower (P = 0.008, Mann-Whitney U test) in the study group (1.69%) compared to the control group (6.02%). CONCLUSIONS: Children subject to child protection plans had significantly higher levels of dental caries in the primary dentition. PMID- 25511798 TI - Deficiency of very large G-protein-coupled receptor-1 is a risk factor of tumor related epilepsy: a whole transcriptome sequencing analysis. AB - The majority of patients with low-grade glioma (LGG) experience epileptic seizures as their initial symptom, while the underlying mechanisms of tumor related seizures are still far from being fully understood. In addition to tumor type and location, genetic changes of LGGs are considered to be influential factors in causing epileptic seizures. Nevertheless, the molecular biomarkers associated with tumor-related epilepsy have rarely been identified. RNA sequence data from 80 patients with histologically confirmed LGG were collected from the Chinese glioma genome atlas database and significant differences in expression levels of 33 genes were found. One of the genes, Very large G-protein-coupled receptor-1 (VLGR1), had been previously associated with seizures. Therefore, we investigated the association between LGG-related epilepsy and VLGR1, which played a role in idiopathic epilepsy. The level of VLGR1 expression was compared between patients with epileptic seizures and those without using the reads per kilobase transcriptome per million method. To evaluate the prognostic role of VLGR1 gene expression, the progression-free survival was determined by the Kaplan-Meier method and a multivariate Cox model. We demonstrated that VLGR1 had a significantly lower expression level in patients with epileptic seizures compared to seizure-free patients (p = 0.003). Furthermore, VLGR1 was highly associated with the presence of seizures in a multivariate statistical model. However, VLGR1 could not serve as an independent prognostic factor to determine progression-free survival of LGG patients. Based on RNA sequence data analysis, our results suggest that low expression of VLGR1 is a significant risk factor of epileptic seizures in patients with LGG. PMID- 25511800 TI - Prognostic influence of cyclooxygenase-2 protein and mRNA expression in node negative breast cancer patients. AB - BACKGROUND: Cyclooxygenases (COX) play a key role in prostaglandin metabolism and are important for tumor development and progression. The aim of this study was to analyze the prognostic impact of COX-2 expression in a cohort of lymph node negative breast cancer patients not treated in the adjuvant setting. METHODS: COX 2 expression was determined by immunohistochemistry (IHC) in tumor tissue of 193 node-negative breast cancer patients. Additionally, mRNA expression was determined in corresponding tumor samples using microarray based gene-expression data. Univariate and multivariate Cox regression analyses adjusted for age at diagnosis, tumor size, histological grade, human epithelial growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR) were performed to evaluate the association of both COX-2 protein and mRNA expression with survival. Survival rates were determined by the Kaplan-Meier method. Correlations between COX-2 expression and established prognostic factors were analyzed using the Chi-square test. A potential correlation between COX-2 protein expression and COX-2 mRNA expression was assessed utilizing the Kruscal-Wallis-H test. RESULTS: COX-2 protein expression was positive in 24.9% of the breast cancer samples. Univariate analysis showed that COX-2 protein expression was associated with shorter disease-free survival (DFS) (P = 0.0001), metastasis-free survival (MFS) (P = 0.002) as well as breast cancer specific overall survival (OS) (P = 0.043). In multivariate analysis COX-2 expression retained its significance independent of established prognostic factors for shorter DFS (P < 0.001, HR = 2.767, 95% CI = 1.563-4.901) and for inferior MFS (P = 0.002, HR = 2.7, 95% CI = 1.469-5.263) but not for OS (P = 0.096, HR = 1.929, 95% CI = 0.889 4.187). In contrast, COX-2 mRNA expression was not related to survival and failed to show a correlation with protein expression (P = 0.410). CONCLUSIONS: The present findings support the hypothesis that COX-2 protein but not mRNA expression is associated with an unfavorable outcome in node-negative breast cancer. PMID- 25511801 TI - Autologous transplantation of CD34(+) bone marrow derived mononuclear cells in management of non-reconstructable critical lower limb ischemia. AB - Patients with a decrease in limb perfusion with a potential threat to limb viability manifested by ischemic rest pain, ischemic ulcers, and/or gangrene are considered to have critical limb ischemia (CLI). Because of this generally poor outcome, there is a strong need for attempting any procedure to save the affected limb. The aim of this work is to evaluate the possibility to use stem cell therapy as a treatment option for patients with chronic critical lower limb ischemia with no distal run off. This study includes 20 patients with chronic critical lower limb ischemia with no distal run off who are unsuitable for vascular or endovascular option. These patients underwent stem cell therapy (SCT) by autologous transplantation of bone marrow derived mononuclear cells. 55 % of patients treated with SCT showed improvement of the rest pain after the first month, 60 % continued improvement of the rest pain after 6 months, 75 % after 1 year and 80 % after 2 years and continued without any deterioration till the third year. Limb salvage rate after STC was 80 % after the first year till the end of the second and third years. SCT can result in angiogenesis in patients with no-option CLI, providing a foundation for the application of this therapy to leg ischemia. PMID- 25511802 TI - Improving the methods for isolation of monocyte and establishing macrophage cell culture in caprine model. AB - Monocytes are widely used for immunological research, especially in the study of innate immune system. Although methods for isolation of human monocytes have been established, the procedure for non-human monocyte has not been well developed. This paper describes an improved method for isolation of monocyte and the subsequent macrophage cultivation from caprine blood. Monocytes were isolated from 16 ml of heparinized caprine blood using double density methods; the Ficoll and Percoll. The number of monocytes obtained was 5.12 +/- 0.89 * 10(7) cells/ml at 70 % purity. The isolated monocytes were maintained in 10 % fetal bovine serum enriched Dulbecco's Modified Eagle Medium for maturation to form macrophage cell culture. At the end of the experiment, the harvested macrophage was 2.48 +/- 0.33 * 10(6) cells/ml. PMID- 25511803 TI - Dopaminergic dysfunction is associated with IL-1beta-dependent mood alterations in experimental autoimmune encephalomyelitis. AB - Mood disturbances are frequent in patients with multiple sclerosis (MS), even in non-disabled patients and in the remitting stages of the disease. It is still largely unknown how the pathophysiological process on MS causes anxiety and depression, but the dopaminergic system is likely involved. Aim of the present study was to investigate depressive-like behavior in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS, and its possible link to dopaminergic neurotransmission. Behavioral, amperometric and biochemical experiments were performed to determine the role of inflammation in mood control in EAE. First, we assessed the independence of mood alterations from motor disability during the acute phase of the disease, by showing a depressive-like behavior in EAE mice with mild clinical score and preserved motor skills (mild EAE). Second, we linked such behavioral changes to the selective increased striatal expression of interleukin-1beta (IL-1beta) in a context of mild inflammation and to dopaminergic system alterations. Indeed, in the striatum of EAE mice, we observed an impairment of dopamine (DA) neurotransmission, since DA release was reduced and signaling through DA D1- and D2-like receptors was unbalanced. In conclusion, the present study provides first evidence of the link between the depressive-like behavior and the alteration of dopaminergic system in EAE mice, raising the possibility that IL-1beta driven dysfunction of dopaminergic signaling might play a role in mood disturbances also in MS patients. PMID- 25511805 TI - Denial of abortion in legal settings. AB - BACKGROUND: Factors such as poverty, stigma, lack of knowledge about the legal status of abortion, and geographical distance from a provider may prevent women from accessing safe abortion services, even where abortion is legal. Data on the consequences of abortion denial outside of the US, however, are scarce. METHODS: In this article we present data from studies among women seeking legal abortion services in four countries (Colombia, Nepal, South Africa and Tunisia) to assess sociodemographic characteristics of legal abortion seekers, as well as the frequency and reasons that women are denied abortion care. RESULTS: The proportion of women denied abortion services and the reasons for which they were denied varied widely by country. In Colombia, 2% of women surveyed did not receive the abortions they were seeking; in South Africa, 45% of women did not receive abortions on the day they were seeking abortion services. In both Tunisia and Nepal, 26% of women were denied their wanted abortions. CONCLUSIONS: The denial of legal abortion services may have serious consequences for women's health and wellbeing. Additional evidence on the risk factors for presenting later in pregnancy, predictors of seeking unsafe illegal abortion, and the health consequences of illegal abortion and childbirth after an unwanted pregnancy is needed. Such data would assist the development of programmes and policies aimed at increasing access to and utilisation of safe abortion services where abortion is legal, and harm reduction models for women who are unable to access legal abortion services. PMID- 25511804 TI - Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake. AB - The dopamine (DA) transporter (DAT), a membrane glycoprotein expressed in dopaminergic neurons, clears DA from extracellular space and is regulated by diverse presynaptic proteins like protein kinases, alpha-synuclein, D2 and D3 autoreceptors. DAT dysfunction is implicated in Parkinson's disease and depression, which are therapeutically treated by dopaminergic D2/D3 receptor (D2/D3R) agonists. It is, then, important to improve our understanding of interactions between D3R and DAT. We show that prolonged administration of pramipexole (0.1mg/kg/day, 6 to 21 days), a preferential D3R agonist, leads to a decrease in DA uptake in mouse striatum that reflects a reduction in DAT affinity for DA in the absence of any change in DAT density or subcellular distribution. The effect of pramipexole was absent in mice with genetically-deleted D3R (D3R(-/ )), yet unaffected in mice genetically deprived of D2R (D2R(-/-)). Pramipexole treatment induced a physical interaction between D3R and DAT, as assessed by co immunoprecipitation and in situ proximity ligation assay. Furthermore, it promoted the formation of DAT dimers and DAT association with both D2R and alpha synuclein, effects that were abolished in D3R(-/-) mice, yet unaffected in D2R(-/ ) mice, indicating dependence upon D3R. Collectively, these data suggest that prolonged treatment with dopaminergic D3 agonists provokes a reduction in DA reuptake by dopaminergic neurons related to a hitherto-unsuspected modification of the DAT interactome. These observations provide novel insights into the long term antiparkinson, antidepressant and additional clinical actions of pramipexole and other D3R agonists. PMID- 25511806 TI - Topical Lyogel Containing Corticosteroid Decreases IgE Expression and Enhances the Therapeutic Efficacy Against Atopic Eczema. AB - Hydrocortisone cream intended for atopic eczema often produces unwanted side effects after long-term use. These side effects are essentially due to repeated percutaneous administration of the medication for skin dermatitis, as atopic eczema is a relapsing disorder. Hence, there is a need to develop a new hydrocortisone formulation that will deliver the drug more effectively and require a reduced dosing frequency; therefore, the side effects could be minimized. In this study, a hydroxypropyl methylcellulose (HPMC) lyogel system based on 80% organic and 20% aqueous solvents containing 1% hydrocortisone was formulated. The hydrocortisone lyogel physicochemical characteristics, rheological properties, stability profile, and in vitro Franz cell drug release properties, as well as the in vivo therapeutic efficacies and dermal irritancy in Balb/c mice were investigated. The HPMC lyogel appeared clear and soft and was easy to rub on the skin. The lyogel also showed a higher drug release profile compared with commercial hydrocortisone cream. Similar to the cream, HPMC lyogels exhibited pseudoplastic behavior. From the mouse model, the hydrocortisone lyogel showed higher inflammatory suppressive effects than the cream. However, it did not reduce the transepidermal water loss as effectively as the control did. The dermal irritancy testing revealed that the hydrocortisone lyogel caused minimal irritation. In conclusion, HPMC lyogel is a promising vehicle to deliver hydrocortisone topically, as it showed a higher drug release in vitro as well as enhanced therapeutic efficacy in resolving eczematous inflammatory reaction compared with commercial cream. PMID- 25511807 TI - Controlled Extraction Studies Applied to Polyvinyl Chloride and Polyethylene Materials: Conclusions from the ELSIE Controlled Extraction Pilot Study. AB - The effective management of leachables in pharmaceutical products is a critical aspect of their development. This can be facilitated if extractables information on the materials used in a packaging or delivery system is available to assist companies in selecting materials that will be compatible with the drug product formulation and suitable for the intended use. The Extractables and Leachables Safety Information Exchange (ELSIE) materials working group developed and executed a comprehensive extraction study protocol that included a number of extraction solvents, extraction techniques, and a variety of analytical techniques. This was performed on two test materials, polyethylene (PE) and polyvinyl chloride (PVC), that were selected due to their common use in pharmaceutical packaging. The purpose of the study was to investigate if the protocol could be simplified such that (i) a reduced number or even a single extraction technique could be used and (ii) a reduced number of solvents could be used to obtain information that is useful for material selection regardless of product type. Results indicate that, at least for the PVC, such reductions are feasible. Additionally, the studies indicate that levels of extractable elemental impurities in the two test materials were low and further confirm the importance of using orthogonal analytical detection techniques to gain adequate understanding of extraction profiles. PMID- 25511808 TI - A novel oral preparation of hydroxysafflor yellow A base on a chitosan complex: a strategy to enhance the oral bioavailability. AB - Hydroxysafflor yellow A (HSYA), the main active pharmaceutical ingredient of the safflower plant (Carthamus tinctorius L.), is a hydrophilic drug with low oral bioavailability (BA). The objective of the present study was to improve the oral BA of HSYA by formulation design. The effect of several pharmaceutical excipients on enhancing BA, including Poloxamer 188 (P188), sodium caprate (SC), sodium deoxycholate, and beta-cyclodextrin (beta-CD), was investigated through animal models. Sodium caprate, with a relative BA of 284.2%, was able to improve the oral BA of HSYA. Furthermore, HSYA can bind with chitosan (CS) by Coulomb attraction and form a HSYA-CS complex. The preparation process was optimized, and the binding rate reached 99.4%. HSYA granules were prepared using a HSYA-CS complex and SC. The results of the pharmacokinetics showed that the relative BA of HSYA granules was 476%, much higher than HSYA/SC. PMID- 25511809 TI - Effects of the Preparation Method on the Formation of True Nimodipine SBE-beta CD/HP-beta-CD Inclusion Complexes and Their Dissolution Rates Enhancement. AB - The aims of this study were to enhance the solubility and dissolution rate of nimodipine (ND) by preparing the inclusion complexes of ND with sulfobutylether-b cyclodextrin (SBE-beta-CD) and 2-hydroxypropyl-b-cyclodextrin (HP-beta-CD) and to study the effect of the preparation method on the in vitro dissolution profile in different media (0.1 N HCl pH 1.2, phosphate buffer pH 7.4, and distilled water). Thus, the inclusion complexes were prepared by kneading, coprecipitation, and freeze-drying methods. Phase solubility studies were conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were investigated with differential scanning calorimetry (DSC), X-ray diffractometry (X-RD), and Fourier transform infrared spectroscopy (FT-IR). Stable complexes of ND/SBE-beta-CD and ND/HP-beta-CD were formed in distilled water in a 1:1 stoichiometric inclusion complex as indicated by an AL-type diagram. The apparent stability constants (Ks) were 1334.4 and 464.1 M(-1) for ND/SBE-beta-CD and ND/HP-beta-CD, respectively. The water-solubility of ND was significantly increased in an average of 22- and 8-fold for SBE-beta-CD and HP beta-CD, respectively. DSC results showed the formation of true inclusion complexes between the drug and both SBE-beta-CD and HP-beta-CD prepared by the kneading method. In contrast, crystalline drug was detectable in all other products. The dissolution studies showed that all the products exhibited higher dissolution rate than those of the physical mixtures and ND alone, in all mediums. However, the kneading complexes displayed the maximum dissolution rate in comparison with drug and other complexes, confirming the influence of the preparation method on the physicochemical properties of the products. PMID- 25511810 TI - Intraoral film containing insulin-phospholipid microemulsion: formulation and in vivo hypoglycemic activity study. AB - Non-invasive administration of insulin is expected for better diabetes mellitus therapy. In this report, we developed intraoral preparation for insulin. Insulin was encapsulated into nanocarrier using self-assembly emulsification process. To increase lipophilicity of insulin, it was dispersed in phospholipid resulted in insulin-phospholipid solid dispersion. The microemulsion formula was established from our previous work which contained glyceryl monooleate (GMO), Tween 20, and polyethylene glycol (PEG 400) in a ratio of 1:8:1. To confirm the formation of insulin-phospholipid solid dispersion, PXRD, FTIR spectroscopy, and Raman spectroscopy were performed. Then, the microemulsion was evaluated for droplet size and distribution, zeta potential, entrapment efficiency, physical stability, and Raman spectroscopy. In addition, microemulsion with expected characteristic was evaluated for in vitro release, in vitro permeation, and in vivo activity. The droplets size of ~100 nm with narrow distribution and positive charge of +0.56 mV were formed. The insulin encapsulated in the oil droplet was accounted of >90%. Water-soluble chitosan seems to be a promising film matrix polymer which also functioned as insulin release controller. Oral administration of insulin microemulsion to healthy Swiss-Webster mice showed hypoglycemic effect indicating the success of this protein against a harsh environment of the gastrointestinal tract. This effectiveness significantly increased by fourfold as compared to free insulin. Taken together, microemulsion seems to be a promising carrier for oral delivery of insulin. PMID- 25511811 TI - Influence of beta-cyclodextrin on the Properties of Norfloxacin Form A. AB - Cyclodextrins are able to form host-guest complexes with hydrophobic molecules to result in the formation of inclusion complexes. The complex formation between norfloxacin form A and beta-cyclodextrin was studied by exploring its structure affinity relationship in an aqueous solution and in the solid state. Kneading, freeze-drying, and physical mixture methods were employed to prepare solid complexes of norfloxacin and beta-cyclodextrin. The solubility of norfloxacin significantly increased upon complexation with beta-cyclodextrin as demonstrated by a solubility isotherm of the AL type along with the results of an intrinsic dissolution study. The complexes were also characterized in the solid stated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffractometry, scanning electron microscopy (SEM), and solid-state nuclear magnetic resonance (ssNMR) spectrometry. The thermal analysis showed that the thermal stability of the drug is enhanced in the presence of beta-cyclodextrin. Finally, the microbiological studies showed that the complexes have better potency when compared with pure drug. PMID- 25511812 TI - Isothermal microcalorimetry accurately detects bacteria, tumorous microtissues, and parasitic worms in a label-free well-plate assay. AB - Isothermal microcalorimetry is a label-free assay that allows monitoring of enzymatic and metabolic activities. The technique has strengths, but most instruments have a low throughput, which has limited their use for bioassays. Here, an isothermal microcalorimeter, equipped with a vessel holder similar to a 48-well plate, was used. The increased throughput of this microcalorimeter makes it valuable for biomedical and pharmaceutical applications. Our results show that the sensitivity of the instrument allows the detection of 3 * 10(4) bacteria per vial. Growth of P. mirabilis in Luria Broth medium was detected between 2 and 9 h with decreasing inoculum. The culture released 2.1J with a maximum thermal power of 76 MUW. The growth rate calculated using calorimetric and spectrophotometric data were 0.60 and 0.57 h(-1) , respectively. Additional insight on protease activities of P. mirabilis matching the last peak in heat production could be gathered as well. Growth of tumor microtissues releasing a maximum thermal power of 2.1 MUW was also monitored and corresponds to a diameter increase of the microtissues from ca. 100 to 428 MUm. This opens new research avenues in cancer research, diagnostics, and development of new antitumor drugs. For parasitic worms, the technique allows assessment of parasite survival using motor and metabolic activities even with a single worm. PMID- 25511813 TI - [A comparison of pulmonary rehabilitation delivered in the home or at a centre for patients with COPD]. AB - AIM: There are few data showing how pulmonary rehabilitation (PR) for COPD patients carried out at home impacts on health-related quality of life (HRQL). The aim of this study was to determine if PR conducted at home improves quality of life. METHODS: We compared the results of home-based PR versus PR performed in an outpatient center. The outcomes were the HRQL measured by the Saint-George's Hospital questionnaire and the 6-minute walk test distance (6MWT). Fifty-six COPD patients were included for PR either at home (n=27) or in the outpatient center (n=29) depending on distance from the center and patients preference. The two groups were similar for sex, age, BMI, lung function, and initial peak oxygen uptake. RESULTS: 6MWT showed a similar non-significant improvement in both groups after PR (+12+/-46m in home-based PR,+13+/-34m in outpatient center). HRQL was significantly improved in the home-based group in 2 domains : "Activity" (-8.6+/ 6.4 vs -0.7+/-17.7, P<0.05), "Impact" (-8.4+/-6.5 vs 1.6+/-11.7, P<0.001) and total score (-8.2+/-4.0 vs 0.0+/-8.8, P<0.001). CONCLUSION: Pulmonary rehabilitation at home is associated with improvements in health-related quality of life, and thus can be considered where availability of treatment in specialized centers is limited. PMID- 25511815 TI - Influence of synthesis pH and oxidative strength of the catalyzing acid on the morphology and chemical structure of hydrothermal carbon. AB - A specific control of the morphology and chemical structure of hydrothermal carbon (HTC) is of crucial importance for its application, both in catalyst supports or electrochemical devices. Here we show how the morphology, that is, particles size and homogeneity, and the distribution of functional groups can be controlled by the control of the synthesis pH of the hydrothermal carbonization. A complementary analysis of liquid byproducts by HPLC provides useful information on the nature of the polymeric species produced during the poly-condensation in the hydrothermal process and reveals the potential implementation of the process into the biorefinery concept. The acidic byproducts levulinic acid and formic acid determine the hydrothermal carbonization autocatalytically by additional supply of protons to the reaction medium. Thus, for a starting pH>3, only minor structural differences can be detected for HTC. The use of oxidizing acids favors higher yields of HTC and improves carbonization towards higher condensed carbon domains. Scaling up the process in a stirred 2 L batch reactor favors carbonization leading to higher condensed carbonaceous products. The relative trends of pH variation are maintained. PMID- 25511816 TI - Randomized clinical trial comparing neurological outcomes after carotid endarterectomy or stenting. AB - BACKGROUND: Silent infarction in the brain can be detected in around 34 per cent of patients after carotid endarterectomy (CEA) and 54 per cent after carotid angioplasty and stenting (CAS). This study compared the risk of new infarctions in the brain in patients undergoing CEA or CAS. METHODS: Consecutive patients with internal carotid artery (ICA) stenosis exceeding 70 per cent were screened for inclusion in this prospective study. Patients with indications for intervention, and eligible for both methods, were allocated randomly to CEA or CAS. Neurological examination, cognitive function tests and MRI of the brain were undertaken before and 24 h after intervention. RESULTS: Of 150 randomized patients, 73 (47 men; mean age 64.9(7.1) years) underwent CEA and 77 (58 men; 66.4(7.5) years) had CAS. New infarctions on MRI were found more frequently after CAS (49 versus 25 per cent; P = 0.002). Lesion volume was also significantly greater after CAS (P = 0.010). Multiple logistic regression analyses identified intervention in the right ICA as the only independent predictor of brain infarction (odds ratio 2.10, 95 per cent c.i. 1.03 to 4.25; P = 0.040). Stroke or transient ischaemic attack occurred in one patient after CEA and in two after CAS. No significant differences were found in cognitive test results between the groups. CONCLUSION: These data confirm a higher risk of silent infarction in the brain on MRI after CAS in comparison with CEA, but without measurable change in cognitive function. REGISTRATION NUMBER: NCT01591005 ( http://www.clinicaltrials.gov). PMID- 25511817 TI - Diverse functional roles of lipocalin-2 in the central nervous system. AB - Lipocalin-2 (LCN2) is an acute phase protein with multiple functions that has garnered a great deal of interest over the last decade. However, its precise role in the pathophysiology of the central nervous system (CNS) remains to be outlined. Emerging evidence indicates that LCN2 is synthesized and secreted as an inducible factor from activated microglia, reactive astrocytes, neurons, and endothelial cells in response to inflammatory, infectious, or injurious insults. More recently, it has been recognized as a modulatory factor for diverse cellular phenotypes in the CNS, such as cell death, survival, morphology, migration, invasion, differentiation, and functional polarization. LCN2 induces chemokine production in the CNS in response to inflammatory challenges, and actively participates in the innate immune response, cellular influx of iron, and regulation of neuroinflammation and neurodegeneration. LCN2 also modulates several biobehavioral responses including pain hypersensitivity, cognitive functions, emotional behaviors, depression, neuronal excitability, and anxiety. This review covers recent advances in our knowledge regarding functional roles of LCN2 in the CNS, and discusses how LCN2 acts as an autocrine mediator of astrocytosis, a chemokine inducer, and a modulator of various cellular phenotypes in the CNS. We finally explore the possibilities and challenges of employing LCN2 as a signature of several CNS anomalies. PMID- 25511814 TI - Effect of calcium supplementation on bone resorption in pregnancy and the early postpartum: a randomized controlled trial in Mexican women. AB - BACKGROUND: Calcium needs are physiologically upregulated during pregnancy and lactation to meet demands of the developing fetus and breastfeeding infant. Maternal calcium homeostasis is maintained by hormonal adaptive mechanisms, thus, the role of dietary calcium supplementation in altering maternal responses to fetal-infant demand for calcium is thought to be limited. However, increased calcium absorption is directly related to maternal calcium intake and dietary supplementation has been suggested to prevent transient bone loss associated with childbearing. METHODS: In a double-blind, randomized placebo-controlled trial, we randomly assigned 670 women in their first trimester of pregnancy to 1,200 mg/day calcium (N = 334) or placebo (N = 336). Subjects were followed through 1-month postpartum and the effect on urinary cross-linked N-telopeptides (NTx) of type I collagen, a specific marker of bone resorption, was evaluated using an intent-to treat analysis. Women with a baseline and at least one follow-up measurement (N = 563; 84%) were included. Subsequent analyses were conducted stratifying subjects by compliance assessed using pill counts. In random subsets of participants, bone specific alkaline phosphatase (BAP) (N = 100) and quantitative ultrasound (QUS) (N = 290) were also measured. RESULTS: Calcium was associated with an overall reduction of 15.8% in urinary NTx relative to placebo (p < 0.001). Among those who consumed >=50%, >=67%, and >=75% of pills, respectively, the effect was associated with 17.3%, 21.3%, and 22.1% reductions in bone resorption (all p < 0.001). There was no significant effect of calcium on bone formation measured by BAP. However, by 1-month postpartum, those in the calcium group had significantly lower NTx/BAP ratios than those in the placebo group (p = 0.04) indicating a net reduction in bone loss in the supplement group by the end of follow-up. Among subjects who consumed >=50% and >=75% of pills, respectively, calcium was also associated with an increase of 26.3 m/s (p = 0.03) and 59.0 m/s (p = 0.009) in radial SOS relative to placebo by 1-month postpartum. CONCLUSIONS: Calcium administered during pregnancy and the early postpartum period, to women with intakes around adequacy, was associated with reduced bone resorption and, thus, may constitute a practical intervention to prevent transient skeletal loss associated with childbearing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00558623. PMID- 25511818 TI - The cognitive roles of behavioral variability: idiosyncratic acts as the foundation of identity and as transitional, preparatory, and confirmatory phases. AB - Behavior in obsessive compulsive disorder (OCD), in habitual daily tasks, and in sport and cultural rituals is deconstructed into elemental acts and categorized into common acts, performed by all individuals completing a similar task, and idiosyncratic acts, not performed by all individuals. Never skipped, common acts establish the pragmatic part of motor tasks. Repetitive performance of a few common acts renders rituals a rigid form, whereby common acts may serve as memes for cultural transmission. While idiosyncratic acts are not pragmatically necessary for task completion, they fulfill important cognitive roles. They form a long preparatory phase in tasks that involve high stakes, and a long confirmatory phase in OCD rituals. Idiosyncratic acts also form transitional phases between motor tasks, and are involved in establishing identity and preserving the flexibility necessary for adapting to varying circumstances. Behavioral variability, as manifested in idiosyncrasy, thus does not seem to be a noise or by-product of motor activity, but an essential cognitive component that has been preserved in the evolution of behavioral patterns, similar to the genetic variability in biology. PMID- 25511819 TI - Mass fatality preparedness among medical examiners/coroners in the United States: a cross-sectional study. AB - BACKGROUND: In the United States (US), Medical Examiners and Coroners (ME/Cs) have the legal authority for the management of mass fatality incidents (MFI). Yet, preparedness and operational capabilities in this sector remain largely unknown. The purpose of this study was twofold; first, to identify appropriate measures of preparedness, and second, to assess preparedness levels and factors significantly associated with preparedness. METHODS: Three separate checklists were developed to measure different aspects of preparedness: MFI Plan Elements, Operational Capabilities, and Pre-existing Resource Networks. Using a cross sectional study design, data on these and other variables of interest were collected in 2014 from a national convenience sample of ME/C using an internet based, anonymous survey. Preparedness levels were determined and compared across Federal Regions and in relation to the number of Presidential Disaster Declarations, also by Federal Region. Bivariate logistic and multivariable models estimated the associations between organizational characteristics and relative preparedness. RESULTS: A large proportion (42%) of respondents reported that less than 25 additional fatalities over a 48-hour period would exceed their response capacities. The preparedness constructs measured three related, yet distinct, aspects of preparedness, with scores highly variable and generally suboptimal. Median scores for the three preparedness measures also varied across Federal Regions and as compared to the number of Presidential Declared Disasters, also by Federal Region. Capacity was especially limited for activating missing persons call centers, launching public communications, especially via social media, and identifying temporary interment sites. The provision of staff training was the only factor studied that was significantly (positively) associated (p < .05) with all three preparedness measures. Although ME/Cs ranked local partners, such as Offices of Emergency Management, first responders, and funeral homes, as the most important sources of assistance, a sizeable proportion (72%) expected federal assistance. CONCLUSIONS: The three measures of MFI preparedness allowed for a broad and comprehensive assessment of preparedness. In the future, these measures can serve as useful benchmarks or criteria for assessing ME/Cs preparedness. The study findings suggest multiple opportunities for improvement, including the development and implementation of national strategies to ensure uniform standards for MFI management across all jurisdictions. PMID- 25511821 TI - A novel chemoreceptor MCP2983 from Comamonas testosteroni specifically binds to cis-aconitate and triggers chemotaxis towards diverse organic compounds. AB - Comamonas testosteroni CNB-1 behaves chemotactically toward a wide range of organic compounds, and 19 methyl-accepting chemotaxis proteins (MCPs) were annotated from the genome of strain CNB-2, a plasmid-curing derivative from strain CNB-1. The MCP-free mutant CNB-1Delta20 completely lost its chemotactic responses. In this study, we found that a chemoreceptor, namely MCP2983, restored chemotactic responses toward nine carboxylic acids and ten aromatic compounds to CNB-1Delta20. Isothermal titration calorimetry analysis indicated that the ligand binding domain (LBD) of MCP2983 specifically binds to cis-aconitate but not other tested compounds. Deletion of the LBD of MCP2983 impaired chemotactic responses toward cis-aconitate as well as other tested compounds, indicating that the LBD of MCP2983 was essential for triggering chemotactic responses. Five amino acid residues (M(81), S(156), E(157), I(158), and L(159)) that are located at a putative ligand-binding pocket were identified to be involved in binding to cis aconitate. So far, the MCP2983 represents the sole biochemically identified chemoreceptor that specifically binds to cis-aconitate and is able to trigger chemotaxis towards diverse organic compounds. PMID- 25511822 TI - Immobilization on macroporous resin makes E. coli RutB a robust catalyst for production of (-) Vince lactam. AB - A novel (+) gamma-lactamase gene (rutB) was cloned from Escherichia coli JM109 and expressed in E. coli BL21 (DE3), and the recombinant protein was characterized. The optimal conditions for the enzyme were pH 7.0 and temperature 30 degrees C, which indicated that it was a mesophilic protein. The free purified enzyme was deactivated when incubated at 50 degrees C for 30 min. However, the k cat value of RutB at its optimal temperature was about 2.5 times that of the archaeal enzyme from Sulfolobus sofataricus at its optimal temperature (85 degrees C). After immobilization on macroporous resin using glutaraldehyde cross-linkage, the thermostability of the crude enzyme was greatly enhanced and the deactivating temperature was raised to 70 degrees C. After immobilization, the minimal substrate inhibition concentration for RutB also improved from 0.75 to 1.5 M. The optimal concentrations of immobilized enzyme and substrate were determined to be 250 mg/ml and 1.5 M, when the initial reaction velocity was the response variable in batch transformations. This immobilization of RutB on macroporous resins provides another feasible approach for the preparation of optically active Vince lactam. As a member of the isochorismatase superfamily, RutB was demonstrated to be another typical gamma-lactamase that showed catalytic promiscuity. PMID- 25511820 TI - Genome-wide association and biological pathway analysis for milk-fat composition in Danish Holstein and Danish Jersey cattle. AB - BACKGROUND: The milk fat profile of the Danish Holstein (DH) and Danish Jersey (DJ) show clear differences. Identification of the genomic regions, genes and biological pathways underlying the milk fat biosynthesis will improve the understanding of the biology underlying bovine milk fat production and may provide new possibilities to change the milk fat composition by selective breeding. In this study a genome wide association scan (GWAS) in the DH and DJ was performed for a detailed milk fatty acid (FA) profile using the HD bovine SNP array and subsequently a biological pathway analysis based on the SNP data was performed. RESULTS: The GWAS identified in total 1,233 SNPs (FDR < 0.10) spread over 18 chromosomes for nine different FA traits for the DH breed and 1,122 SNPs (FDR < 0.10) spread over 26 chromosomes for 13 different FA traits were detected for the DJ breed. Of these significant SNPs, 108 SNP markers were significant in both DH and DJ (C14-index, BTA26; C16, BTA14; fat percentage (FP), BTA14). This was supported by an enrichment test. The QTL on BTA14 and BTA26 represented the known candidate genes DGAT and SCD. In addition we suggest ACSS3 to be a good candidate gene for the QTL on BTA5 for C10:0 and C15:0. In addition, genetic correlations between the FA traits within breed showed large similarity across breeds. Furthermore, the biological pathway analysis revealed that fat digestion and absorption (KEGG04975) plays a role for the traits FP, C14:1, C16 index and C16:1. CONCLUSION: There was a clear similarity between the underlying genetics of FA in the milk between DH and DJ. This was supported by the fact that there was substantial overlap between SNPs for FP, C14 index, C14:1, C16 index and C16:1. In addition genetic correlations between FA showed a similar pattern across DH and DJ. Furthermore the biological pathway analysis suggested that fat digestion and absorption KEGG04975 is important for the traits FP, C14:1, C16 index and C16:1. PMID- 25511823 TI - Phytoremediation potentiality of garlic roots for 2,4-dichlorophenol removal from aqueous solutions. AB - 2,4-Dichlorophenol (2,4-DCP) is considered as an important pollutant because of its high toxicity and wide distribution in wastewaters. Innocuous remediation technologies have been studied for the removal of this pollutant. This study investigated the feasibility of using garlic roots as a plant system for the removal of 2,4-DCP. The optimal conditions for its removal were established based on orthogonal experiments (OA25 matrix). Significant factors that affect removal efficiency, arranged from high to low importance, include pH, reaction time, 2,4 DCP concentration, and H2O2 concentration. In addition, garlic roots could be re used for as much as three consecutive cycles. The decrease in pH and the increase of Cl(-) ion content in the post-removal solutions indicated that 2,4-DCP dehalogenation occurred during transformation. Changes in the deposition pattern of lignin in roots exposed to 2,4-DCP suggested that several of the products deposited were lignin-type polymers. The acute toxicity test revealed that the post-removal solutions were less toxic than the parent solutions. Therefore, garlic roots have considerable potential to effectively and safely remove 2,4-DCP from wastewater. PMID- 25511824 TI - Biosynthesis of a steroid metabolite by an engineered Rhodococcus erythropolis strain expressing a mutant cytochrome P450 BM3 enzyme. AB - In the present study, the use of Rhodococcus erythropolis mutant strain RG9 expressing the cytochrome P450 BM3 mutant M02 enzyme has been evaluated for whole cell biotransformation of a 17-ketosteroid, norandrostenedione, as a model substrate. Purified P450 BM3 mutant M02 enzyme hydroxylated the steroid with >95 % regioselectivity to form 16-beta-OH norandrostenedione, as confirmed by NMR analysis. Whole cells of R. erythropolis RG9 expressing P450 BM3 M02 enzyme also converted norandrostenedione into the 16-beta-hydroxylated product, resulting in the formation of about 0.35 g/L. Whole cells of strain RG9 itself did not convert norandrostenedione, indicating that metabolite formation is P450 BM3 M02 enzyme mediated. This study shows that R. erythropolis is a novel and interesting host for the heterologous expression of highly selective and active P450 BM3 M02 enzyme variants able to perform steroid bioconversions. PMID- 25511825 TI - Editorial. Biotechniques for air pollution control and bioenergy. PMID- 25511826 TI - Pharmacists pan Genentech distribution model. PMID- 25511828 TI - Medicare retains ASP-plus-6% rate for separately payable drugs in 2015. PMID- 25511830 TI - Stability of ampicillin and amoxicillin in peritoneal dialysis solutions. PMID- 25511831 TI - Retreatment of a treatment-experienced patient with genotype 6 hepatitis C virus infection: follow-up on a reported case. PMID- 25511833 TI - Use of automated dispensing cabinets to enhance processes for safe handling of high-alert drugs in pharmacy cleanrooms. PMID- 25511832 TI - Effect of target-specific oral anticoagulants on a pharmacist-managed anticoagulation clinic. PMID- 25511834 TI - Choosing your fourth-year rotations wisely. PMID- 25511835 TI - Oral disease-modifying therapies for relapsing-remitting multiple sclerosis. AB - PURPOSE: The efficacy and safety of the three oral agents approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS) are reviewed. SUMMARY: Limitations to parenteral disease modifying therapies (DMTs) (interferon beta-1a, interferon beta-1b, and glatiramer acetate) for the treatment of RRMS have been addressed by the approval of three oral DMTs: fingolimod, teriflunomide, and dimethyl fumarate. In clinical trials, each of the oral DMTs was superior to placebo in annualized relapse rate, a key indicator of clinical efficacy, and in neuroradiological efficacy. A reduction in disability progression was evident with higher doses of teriflunomide but was not consistently demonstrated with fingolimod or dimethyl fumarate. Each of the oral DMTs demonstrated acceptable safety in clinical trials, with adverse-effect profiles that differ from injectable agents. The safety of both teriflunomide and dimethyl fumarate is supported by long-term use of related agents for other diseases; however, postmarketing surveillance studies are needed to determine the safety of each of the oral DMTs in patients with RRMS. Dimethyl fumarate seems to have the most innocuous safety profile of the three agents. Fingolimod requires first-dose inpatient monitoring due to cardiac safety concerns and multiple laboratory tests prior to initiation of therapy, while teriflunomide has been associated with hepatotoxicity and teratogenicity. CONCLUSION: With the approval of three oral drugs for RRMS-fingolimod, teriflunomide, and dimethyl fumarate-the therapeutic strategy for RRMS has evolved to include options that are efficacious and appear to have administration advantages over established parenteral treatments. PMID- 25511836 TI - Hypoxemia associated with nimodipine in a patient with an aneurysmal subarachnoid hemorrhage. AB - PURPOSE: A case of probable nimodipine-induced hypoxemia in a patient undergoing treatment for aneurysmal subarachnoid hemorrhage (SAH) is reported. SUMMARY: A 62 year-old man hospitalized for SAH developed symptoms of respiratory distress on several occasions within days of initiation of nimodipine therapy (60 mg every four hours, with three doses withheld during intubation for intracranial surgery). Several hours after extubation (on hospital day 5), the patient had rapidly worsening tachypnea and declining arterial oxygen saturation (SPO2) despite increased oxygen delivery by mask, necessitating reintubation. When a nurse noted that the declines in SPO2 occurred soon after nimodipine administration, the patient's respiratory and hemodynamic functions were closely monitored after a single dose of nimodipine via nasogastic tube; the monitoring results supported the suspicion that nimodipine's vascular effects were a causal or contributory factor in the hypoxemia episodes. With subsequent fractionated dosing (30 mg every two hours), the patient completed the prescribed 21-day course of nimodipine therapy. Using the rating scale of Naranjo et al., this case was assigned a score of 7, indicating a probable pulmonary adverse reaction to nimodipine. As nimodipine is commonly used in cases of SAH to reduce delayed neurologic deficits due to persistent cerebral vasospasm, clinicians should be mindful of its potential hypoxemic effects in vulnerable patients. CONCLUSION: A patient with aneurysmal SAH developed hypoxemia associated with the administration of nimodipine. Hypoxemia is a known complication of treatment with other vasodilatory agents, particularly in patients who have concomitant pulmonary disease. PMID- 25511838 TI - Outcomes of expanded use of clinical pharmacist practitioners in addition to team based care in a community health system intensive care unit. AB - PURPOSE: Clinical and cost benefits achieved through expanded use of state licensed clinical pharmacist practitioners (CPPs) with prescribing authority on a critical care team are reported. METHODS: A retrospective pre-post analysis was conducted to evaluate patient care outcomes and cost savings during one-year periods before and after the number of CPPs on a North Carolina community health system's neurotrauma intensive care unit (NTICU) team was increased from one to three. Outcomes assessed included the number and types of medication management encounters, estimated cost savings, and the rate of preventable adverse drug events (ADEs) with expanded use of CPPs. RESULTS: During the two-year study period, CPPs conducted 13,386 documented medication encounters involving 2,198 patients; associated cost savings totaled an estimated $2,118,426. During the 12 months after CPP involvement on the NTICU team was increased, there was a 182% increase in encounters for therapeutic optimization (p = 0.01), with an associated 29% increase in cost savings and an improved return on investment. The CPP service expansion was also associated with a reduction in preventable ADEs, including a 75% reduction in prescribing-related ADEs (risk ratio [RR], 0.25; 95% confidence interval [CI], 0.05-1.2; p = 0.09) and a 37% reduction in higher severity ADEs (RR, 0.63; 95% CI, 0.25-1.57; p = 0.36). CONCLUSION: With expanded CPP involvement on the NTICU team, there was a substantial increase in therapeutic optimization interventions and a clinically notable reduction in preventable ADEs, as well as an estimated 30% increase in associated cost savings. PMID- 25511837 TI - Nadolol for the treatment of infantile hemangioma. AB - PURPOSE: The successful use of nadolol as an alternative to propranolol therapy in three cases of infantile hemangioma is reported. SUMMARY: Infantile hemangioma is a benign vascular neoplastic disorder that affects up to 10% of newborns and can lead to deformity or local complications in severe cases. Propranolol, administered alone or in combination with corticosteroids, is increasingly used to treat infantile hemangioma, but its ability to cross the blood-brain barrier and potentially cause central nervous system adverse effects has prompted research on alternative beta-blocker therapies for the disorder that have more favorable safety profiles, including nadolol. This article describes the use of nadolol to treat three pediatric patients with a buccal or genital hemangioma who developed adverse reactions (mainly, irritability and sleep disturbances) or resistance to initial treatment with propranolol. The patients were 10 months, 12 months, and 4 years of age, respectively, when hemangioma treatment was initiated. The results of nadolol therapy were favorable, with involution of lesions and gradual disappearance of propranolol-associated adverse effects occurring in all three cases. As with any use of beta-blocker therapy in a pediatric patient, a cardiac workup is advised before the start of nadolol therapy; blood pressure and heart rate monitoring should be performed at one and two hours after the first dose and continued during dose escalation. CONCLUSION: Nadolol was an effective alternative to propranolol in three pediatric patients with hemangiomas. PMID- 25511839 TI - Gluten content of medications. AB - PURPOSE: The establishment of a database for the identification of the presence of gluten in excipients of prescription medications is described. SUMMARY: While resources are available to ascertain the gluten content of a given medication, these resources are incomplete and often do not contain a source and date of contact. The drug information service (DIS) at Robert Wood Johnson University Hospital (RWJUH) determined that directly contacting the manufacturer of a product is the best method to determine the gluten content of medications. The DIS sought to establish a resource for use within the institution and create directions for obtaining this information from manufacturers to ensure uniformity of the data collected. To determine the gluten content of a medication, the DIS analyzed the manufacturer's package insert to identify any statement indicating that the product contained gluten or inactive ingredients from known sources of gluten. If there was any question about the source of an inactive ingredient or if no information about gluten content appeared in the package insert, the manufacturer of the particular formulation of the queried medication was contacted to provide clarification. Manufacturers' responses were collected, and medications were categorized as "gluten free," "contains gluten," or "possibly contains gluten." To date, the DIS at RWJUH has received queries about 84 medications and has cataloged their gluten content. CONCLUSION: The DIS at RWJUH developed a database that categorizes the gluten status of medications, allowing clinicians to easily identify drugs that are safe for patients with celiac disease. PMID- 25511840 TI - Pharmacist input into statewide treatment protocols for emergency medical services. AB - PURPOSE: A pharmacist's role in helping Vermont health officials standardize pharmacotherapy-related protocols used by emergency medical services (EMS) personnel across the state is described. SUMMARY: Pharmacists with expertise in emergency medicine (EM) or critical care are ideally positioned to provide guidance on optimizing and standardizing medication-use aspects of state and local EMS protocols. In 2012, the medical director of the EMS division of the Vermont Department of Health requested that an EM pharmacist at a Burlington academic medical center review draft EMS protocols designed to replace the existing patchwork of local protocols with statewide standards of care; among the 92 draft protocols reviewed, 62 pertained to medication use. The pharmacist provided a wide range of suggestions on 33 protocols, including (1) evidence based recommendations on use of vasopressor agents for septic shock, (2) recommendations to optimize medication ordering and preparation in the prehospital setting, (3) recommendations on prehospital management of pediatric shock and appropriate use of chemical restraints, and (4) recommendations to promote use of smart infusion pumps by EMS personnel. All of the pharmacist's suggestions were incorporated into the final protocols, which took effect in March 2014. The protocols have helped standardize care for patients receiving EMS services throughout Vermont while reducing the potential for medication errors. CONCLUSION: An EM pharmacist participated in the review and development of statewide EMS treatment protocols that focused on choice of medication therapy, dosage, administration, and identification and minimization of potential risks of medication errors. PMID- 25511841 TI - Use of Twitter at a major national pharmacy conference. AB - PURPOSE: The results of a study of Twitter use by attendees of the 2013 ASHP Midyear Clinical Meeting (MCM) and other interested parties are presented. METHODS: All messages posted on the social media platform Twitter under the official MCM "hashtag" (#ashpmidyear) during the five-day conference were archived and evaluated. Demographic data on authors of MCM-related tweets were collected by evaluating information provided by Twitter users in their public profiles. The archived messages were classified by content type. RESULTS: A total of 1539 messages originating from 400 unique U.S.- and foreign-based Twitter accounts were posted under the MCM hashtag, an average of 3.84 tweets per account. The estimated rate of conference-related Twitter use by MCM attendees was 1.7%. One third of Twitter users posting conference-related tweets were identified as pharmacists; 86 (21.5%) and 65 (16.25%) tweets originated from accounts held by pharmacy students and pharmaceutical industry representatives, respectively. The authors of MCM-related tweets represented a broad cross-section of pharmacy practice settings and specialties. About 39% of the evaluated Twitter postings were classified as social, with about 31% of postings pertaining to specific MCM educational sessions and nearly 25% classified as advertising. CONCLUSION: The majority of MCM-related tweets by onsite and remote Twitter users were social in nature or pertained to educational sessions held over the course of the conference. PMID- 25511842 TI - Implementation and outcomes of a pharmacist-managed clinical video telehealth anticoagulation clinic. AB - PURPOSE: The use of clinical video telehealth (CVT) technology to optimize the deployment of clinical pharmacy specialist resources in a community-based outpatient clinic (CBOC) is described. SUMMARY: In 2012, clinical pharmacy specialists at a Veterans Affairs (VA) medical center began using CVT technology to provide anticoagulation therapy management services to patients at a CBOC about 12 miles away. Using videoconferencing technology (video cameras and high definition widescreen monitors), the remotely located pharmacists conduct patient interviews, evaluate International Normalized Ratio (INR) values, and gather other clinical data for use in therapeutic planning. Under the supervision of pharmacists, CBOC telehealth technicians perform targeted physical assessments (e.g., point-of-care INR values, measurements of vital signs), and the results are transmitted to the medical center for pharmacist evaluation. CVT policies and procedures jointly developed by pharmacy, telehealth, and CBOC nursing staff require focused training for clinic personnel and informed patient consent to receive CVT services. During the first few months of CVT clinic operations, the mean percentage of time patients' INR values were within the therapeutic range remained stable (about 81%, compared with about 77% under the previous face-to face clinic model), and a high level of patient satisfaction was maintained. Implementation of CVT anticoagulation monitoring services enabled pharmacist resource reallocation to other duties. CONCLUSION: Through the use of CVT technology, high-quality anticoagulation services and patient satisfaction were maintained and the allocation of clinical pharmacy specialist resources was optimized. PMID- 25511843 TI - Strategic considerations for centralization of services across the pharmacy enterprise. PMID- 25511845 TI - An uncommon dermatophyte infection: two cases of cutaneous infection with Trichophyton verrucosum. AB - Zoophilic dermatophytes can cause highly inflammatory cutaneous infections. Cattle represent the largest reservoir for the zoophilic dermatophyte Trichophyton verrucosum. Effective vaccination programmes have contributed to a low rate of livestock infection in central and northern Europe, and T. verrucosum infection is relatively more common in southern Europe and in Arabic countries. Transmission to humans typically results from direct contact with infected livestock. It may also be transmitted from person to person. We report two cases of T. verrucosum skin infections in Irish farmers. In both cases, effective treatment was delayed due to misdiagnosis of the condition as a bacterial infection in the primary care setting. Both cases responded rapidly to treatment with oral terbinafine. Culture of T. verrucosum can take 3 weeks or longer to grow, therefore a high index of clinical suspicion is necessary, and skin scrapings for potassium hydroxide microscopy and culture are essential for accurate diagnosis. PMID- 25511846 TI - Implementation of optical diagnosis for colorectal polyps: standardization of studies is needed. PMID- 25511847 TI - Long-term chemiluminescence signal is produced in the course of luminol oxidation catalyzed by enhancer-independent peroxidase purified from Jatropha curcas leaves. AB - Isoenzyme c of horseradish peroxidase (HRP-C) is widely used in enzyme immunoassay combined with chemiluminescence (CL) detection. For this application, HRP-C activity measurement is usually based on luminol oxidation in the presence of hydrogen peroxide (H2O2). However, this catalysis reaction was enhancer dependent. In this study, we demonstrated that Jatropha curcas peroxidase (JcGP1) showed high efficiency in catalyzing luminol oxidation in the presence of H2O2. Compared with HRP-C, the JcGP1-induced reaction was enhancer independent, which made the enzyme-linked immunosorbent assay (ELISA) simpler. In addition, the JcGP1 catalyzed reaction showed a long-term stable CL signal. We optimized the conditions for JcGP1 catalysis and determined the favorable conditions as follows: 50 mM Tris buffer (pH 8.2) containing 10 mM H2 O2, 14 mM luminol and 0.75 M NaCl. The optimum catalysis temperature was 30 degrees C. The detection limit of JcGP1 under optimum condition was 0.2 pM. Long-term stable CL signal combined with enhancer-independent property indicated that JcGP1 might be a valuable candidate peroxidase for clinical diagnosis and enzyme immunoassay with CL detection. PMID- 25511848 TI - 'It is safe to use if you are healthy': A discursive analysis of men's online accounts of ephedrine use. AB - Ephedrine use in sport is a common practice among men. Less well understood is men's use of ephedrine as a slimming aid. Arguably fuelled by the 'war on obesity' and the drive for muscularity, the Internet has become awash with claims presenting ephedrine as safe. The use of this psychoactive substance can have acute health implications such as tachycardia, arrhythmias and cardiovascular disease. Given the tension between health risk and ephedrine-induced weight loss, how men justify their use of ephedrine becomes an important question. In particular, we wished to analyse how male users talked to others about ephedrine in discussions linked to an online version of a popular men's magazine. Because we were particularly interested in how men accounted for their ephedrine use, we used discourse analysis to examine their posts. In analysing the data, we noted that a 'community of practice' was constructed online categorising legitimate (and barred) users, emphasising the benefits of ephedrine and downplaying health defeating side effects. Our analysis has clear implications for engaging men who use ephedrine in health promotion interventions. PMID- 25511850 TI - Seasonal allergies and serial changes of serum levels of IgG4 in cases treated with maintenance therapy for IgG4-related disease. PMID- 25511851 TI - Synthesis and catalytic activity of crown jewel-structured (IrPd)/Au trimetallic nanoclusters. AB - Crown-jewel-structured (IrPd)/Au trimetallic nanoclusters are prepared by a galvanic replacement reaction using Ir/Pd nanoclusters with a structure of Ir rich in the core and Pd rich in the shell as mother clusters. The catalytic activity of the top Au atoms for aerobic glucose oxidation of the trimetallic nanoclusters is the highest ever reported among all supported and colloidal catalysts. PMID- 25511849 TI - Systemic sclerosis induces pronounced peripheral vascular dysfunction characterized by blunted peripheral vasoreactivity and endothelial dysfunction. AB - Systemic sclerosis (SSc) vasculopathy can result in a digital ulcer (DU) and/or pulmonary arterial hypertension (PAH). We hypothesized that bedside brachial artery flow-mediated dilation (FMD) testing with duplex ultrasound could be used in SSc patients to identify features of patients at risk for DU or PAH. Thirty eight SSc patients were compared to 52 age-matched healthy controls from the VAMC Utah Vascular Research Laboratory. Peripheral hemodynamics, arterial structure, and endothelial function were assessed by duplex ultrasound. A blood pressure cuff was applied to the forearm and 5-min ischemia was induced. Post-occlusion, brachial artery vascular reactivity (peak hyperemia/area under the curve [AUC]), shear rate, and endothelial function (FMD) were measured. SSc patients had smaller brachial artery diameters (p < 0.001) and less reactive hyperemia (p < 0.001), peak shear rate (p = 0.03), and brachial artery FMD (p < 0.001) compared with healthy controls. Brachial artery FMD was lower (p < 0.05) in SSc patients with DU. Tertile analysis suggested the 2 lower FMD tertiles (<5.40 %) had a 40 50 % chance of presenting with DU while the SSc patients with highest FMD tertile (>5.40 %) had less than 15 % chance of DU. All brachial artery FMD measurements were similar between SSc patients with and without PAH (all p > 0.05). Compared to healthy controls, SSc patients had significantly smaller brachial artery diameter and blunted peripheral vascular reactivity and endothelial function. SSc patients with DU have even greater impairments in endothelial function compared to those without DU. FMD testing has clinical utility to identify SSc patients at risk for DU. PMID- 25511852 TI - Special issue: Colorectal polyps: recent advances from genetics to management: 2nd Genoa meeting 14 April 2014. Foreword. PMID- 25511853 TI - Special issue: Colorectal polyps: recent advances from genetics to management: 2nd Genoa meeting 14 April 2014. Preface. PMID- 25511854 TI - The genetics of inherited predispositions to colorectal polyps: a quick guide for clinicians. PMID- 25511855 TI - Epidemiology and screening: what's new? PMID- 25511856 TI - Serrated polyps. PMID- 25511857 TI - Prevention of colorectal adenomas. PMID- 25511858 TI - Recent advances to improve the endoscopic detection and differentiation of early colorectal neoplasia. PMID- 25511859 TI - Colorectal polyp diagnosis: results with the second-generation colon capsule (CCE 2). PMID- 25511860 TI - Imaging of colorectal polyps and early rectal cancer. PMID- 25511861 TI - Piecemeal mucosectomy, submucosal dissection or transanal microsurgery for large colorectal neoplasm. PMID- 25511862 TI - Surgery for colorectal polyps: histological features, current indications, critical points, future perspective and ongoing studies. PMID- 25511863 TI - Colorectal polyposis: clinical presentation and surgical treatment. PMID- 25511865 TI - Superenhancers: novel opportunities for nanowire optoelectronics. AB - Nanowires play a crucial role in the development of new generation optoelectronic devices ranging from photovoltaics to photodetectors, as these designs capitalize on the low material usage, utilize leaky-mode optical resonances and possess high conversion efficiencies associated with nanowire geometry. However, their current schemes lack sufficient absorption capacity demanded for their practical applicability, and more efficient materials cannot find widespread usage in these designs due to their rarity and cost. Here we suggest a novel and versatile nanoconcentrator scheme utilizing unique optical features of non-resonant Mie (NRM) scattering regime associated with low-index structures. The scattering regime is highly compatible with resonant Mie absorption effect taking place in nanowire absorbers. This technique in its optimized forms can provide up to 1500% total absorption enhancement, 400-fold material save and is suitable for large area applications with significant area preservation compared to thin-film of same materials. Proposed superenhancer concept with its exceptional features such as broadband absorption enhancement, polarization immunity and material independent manner paves the way for development of efficient nanowire photosensors or solar thermophotovoltaic devices and presents novel design opportunities for self-powered nanosystems. PMID- 25511866 TI - Momelotinib treatment-emergent neuropathy: prevalence, risk factors and outcome in 100 patients with myelofibrosis. AB - Momelotinib (a JAK1 and JAK2 inhibitor) induces both anaemia and spleen responses in myelofibrosis (MF). Momelotinib treatment-emergent peripheral neuropathy (TE PN) was documented in 44 (44%) of 100 MF patients treated at our institution; median time of TE-PN onset was 32 weeks and duration 11 months. Improvement after drug dose reduction or discontinuation was documented in only two patients. TE-PN was significantly associated with treatment response (P = 0.02) and longer survival (P = 0.048) but significance was lost during multivariate analysis that included treatment duration. TE-PN did not correlate with initial or maximum momelotinib dose or previous treatment with JAK inhibitor or thalidomide. PMID- 25511867 TI - Areal bone mineral density in children and adolescents with Marfan syndrome: evidence of an evolving problem. AB - Marfan syndrome (MFS), an autosomal dominant disorder of connective tissue, is due to defective fibrillin-1. Defects involve the cardiovascular system, the eye, the lungs, and the skeleton. The aim of the current study was to characterize the bone mineral status in children and adolescents with MFS. We performed an observational cross-sectional study and a longitudinal follow-up of two years. We enrolled 73 young patients with MFS (3-17years). A subset of 44 patients participated in the longitudinal study. Healthy children were studied as controls for biochemical analyses. Bone mineral density (BMD) was measured at lumbar spine, femoral neck and total femur by dual-energy X-ray absorptiometry. BMD values were expressed as Z-scores adjusted for height using height-for-age Z scores. BMD measurements corrected for height were significantly lower than reference at all skeletal sites (P<0.0001). Patient on cardiac treatment with losartan had lower BMD measurements corrected for height compared to non-treated patients. Total femur BMD decreased significantly over time (P=0.027). BMD at the other two skeletal sites did not change significantly during follow-up, but remained significantly low compared to reference (P<0.0001). In conclusion, young patients with MFS have markedly low BMD at the lumbar spine and femur, and values show a tendency to decrease over time in the peripheral skeleton. Because increased life expectancy of MFS patients, the reduced BMD during childhood may lead to a low peak bone mass, increasing the fracture risk during adult life. PMID- 25511864 TI - Parasite distribution and associated immune response during the acute phase of Toxoplasma gondii infection in sheep. AB - BACKGROUND: In many countries, Toxoplasma gondii (T. gondii) is a major cause of reproductive disorders and abortions in the sheep industry, and therefore responsible for important financial and economic losses. In addition, undercooked infected lamb is an important risk factor for human toxoplasmosis. In the present study, the initial phase of the infection was investigated: the parasite's entry site, the subsequent distribution of the parasite and the host-immune response. RESULTS: Parasite DNA was already detected in the cranial small intestinal mucosa the first days after oral infection with T. gondii tissue cysts. Simultaneously, high IFN-gamma and IL-12 responses were induced mainly in the mesenteric lymph nodes. The emergence of IgG1 (at 8dpi), and IgG2 (at 11 dpi) was accompanied by a decrease or even disappearance of the IFN-gamma and IL-12 response in the Peyers' patches (PP), PBMC's and popliteal LN's. Meanwhile the parasite DNA could be recovered from most mucosal and systemic tissues to become undetectable in the small intestine, popliteal LN, PBMC and spleen 3 weeks pi. CONCLUSIONS: Our results indicate that parasites enter the cranial small intestine the first days after infection and that after an increase the first two weeks after infection, the parasite DNA levels in the intestine drop below the detection limit three weeks after infection. This coincides with an increase in parastic-specific serum IgG1 and IgG2 and a decrease of the antigen-specific IFN-gamma response in PP, PBMC and popliteal LN. We suggest a role for IFN-gamma and IL-12 in controlling the infection. PMID- 25511868 TI - Apoptolidins A and C activate AMPK in metabolically sensitive cell types and are mechanistically distinct from oligomycin A. AB - Apoptolidin A was first isolated as a secondary metabolite of a Nocardiopsis sp. and is the founding member of a family of potential selective cancer cell toxins. We now report the isolation, production and pharmacological characterization of apoptolidins A and C from an alternate actinomycete producer, an Amycolatopsis sp. from soil samples collected in Indonesia. We investigated the action of apoptolidins A and C in representative human glioblastoma cells, lung cancer cells and mouse embryonic fibroblasts (MEFs) to better understand the mechanism of action of the known apoptolidins. Shifts in cellular metabolism in intact cells and the status of the AMP-activated protein kinase (AMPK) stress pathway in response to apoptolidin A were entirely consistent with the actions of an ATP synthase inhibitor. We find the metabolic phenotype of the cell to be a critical determinant of apoptolidin sensitivity and the likely basis for cancer cell selectivity. The apoptolidins induce indirect activation of AMPK and trigger autophagy in sensitive cell types without significant inhibition of mTORC1. Human U87-MG glioblastoma cells and wild type MEFs showed increased phosphorylation of AMPK (Thr172), ACC (Ser79) and ULK1 (Ser555), whereas AMPKalpha-null MEFs and more glycolytic SF-295 glioblastoma cells lacked this response. Although both are reported to be selective inhibitors of mitochondrial ATP synthase, differences between apoptolidin- and oligomycin A-induced responses in cells indicate that the action of these macrolides is not identical. PMID- 25511869 TI - Monochromatic light increases anthocyanin content during fruit development in bilberry. AB - BACKGROUND: Light is one of the most significant environmental factors affecting to the accumulation of flavonoids in fruits. The composition of the light spectrum has been shown to affect the production of phenolic compounds during fruit ripening. However, specific information on the biosynthesis of flavonoids in fruits in response to different wavelengths of light is still scarce. In the present study bilberry (Vaccinium myrtillus L.) fruits, which are known to be rich with anthocyanin compounds, were illuminated with blue, red, far-red or white light during the berry ripening process. Following the illumination, the composition of anthocyanins and other phenolic compounds was analysed at the mature ripening stage of fruits. RESULTS: All the three monochromatic light treatments had significant positive effect on the accumulation of total anthocyanins in ripe fruits compared to treatment with white light or plants kept in darkness. The elevated levels of anthocyanins were mainly due to a significant increase in the accumulation of delphinidin glycosides. A total of 33 anthocyanin compounds were detected in ripe bilberry fruits, of which six are novel in bilberry (cyanidin acetyl-3-O-galactose, malvidin acetyl-3-O-galactose, malvidin coumaroyl-3-O-galactose, malvidin coumaroyl-3-O-glucose, delphinidin coumaroyl-3 O-galactose, delphinidin coumaroyl-3-O-glucose). CONCLUSIONS: Our results indicate that the spectral composition of light during berry development has significant effect on the flavonoid composition of ripe bilberry fruits. PMID- 25511870 TI - Circumventing failed antiviral immunity in chronic hepatitis B virus infection: triggering virus-specific or innate-like T cell response? AB - Therapeutic vaccination for the treatment of chronic hepatitis B has thus far been unsatisfactory. In this review, we discuss potential new therapeutic vaccination strategies and other immunotherapeutic approaches that aim to achieve efficient restoration of HBV immunity in chronically infected patients. PMID- 25511872 TI - Phosphate ion targeted colorimetric and fluorescent probe and its use to monitor endogeneous phosphate ion in a hemichannel-closed cell. AB - Fluorescent probe 1, the first inorganic phosphate (Pi) targeted colorimetric and fluorescent probe to detect endogenous Pi in hemichannel-closed cells, has been developed. Probe 1 undergoes a unique Pi induced hydrolytic reaction in DMSO HEPES (V/V = 9:1) buffered (0.02 M, pH 7.4) solutions that produces a colorimetric change associated with a 62 nm red-shift in the UV-vis absorption maximum and up to a 780-fold enhancement in the fluorescence intensity. The mechanistic proposal that these spectroscopic changes are associated with reaction Pi with 1 to form coumarin gains support from the results of theoretical calculations and mass spectrometry studies. Observations made in fluorescence imaging studies with HeLa cells and C. elegans show that 1 can be employed to monitor Pi production in vivo caused by apyrase-catalyzed ATP hydrolysis. Moreover, probe 1 was utilized to show that apoptosis of hemichannel-closed Sf9 cells is caused by Inx3 promoted dephosphorylation of Akt (RAC serine/threonine protein kinase), leading to an elevation of the concentration of Pi. Overall, the study has produced the first fluorescent sensor 1 for endogenous inorganic phosphate. Moreover, the utility of 1 for measuring Pi release in vitro has been demonstrated and utilized to elucidate the mechanism of Inx3 action in hemichannel-closed Sf9 cells. PMID- 25511873 TI - Exhaled nitric oxide in children with allergic rhinitis: a potential biomarker of asthma development. PMID- 25511871 TI - Therapeutic vaccines in treating chronic hepatitis B: the end of the beginning or the beginning of the end? AB - The antiviral treatment of chronic hepatitis B virus (HBV) infection has greatly improved over the last 20 years since it has allowed a disappearance of cirrhosis decompensation and a significant reduction of the incidence of hepatocellular carcinoma. However, a complete HBV cure has not been achieved, and alternative treatments are still needed to optimize the current treatments. Therapeutic vaccination is a promising new strategy for controlling persistent infections and tumors. However, this approach has not been as successful as initially anticipated for chronic hepatitis B. General impairment of the immune responses generated during persistent HBV infection, with exhausted T cells not responding correctly to therapeutic vaccination, is most likely responsible for the poor clinical responses observed to date. We describe here the past approaches of therapeutic vaccination, in the hope that useful lessons will emerge from these previous clinical trials. Intensive research efforts are now focusing on a better understanding of immune responses in liver, on mechanisms by which HBV escapes innate immunity and on an accurate selection of the patients susceptible to benefit of immune therapy, which could increase the efficacy of therapeutic vaccination. PMID- 25511875 TI - Calciphylaxis presenting as digital ischemia. PMID- 25511874 TI - High mobility explains demand sharing and enforced cooperation in egalitarian hunter-gatherers. AB - 'Simple' hunter-gatherer populations adopt the social norm of 'demand sharing', an example of human hyper-cooperation whereby food brought into camps is claimed and divided by group members. Explaining how demand sharing evolved without punishment to free riders, who rarely hunt but receive resources from active hunters, has been a long-standing problem. Here we show through a simulation model that demand-sharing families that continuously move between camps in response to their energy income are able to survive in unpredictable environments typical of hunter-gatherers, while non-sharing families and sedentary families perish. Our model also predicts that non-producers (free riders, pre-adults and post-productive adults) can be sustained in relatively high numbers. As most of hominin pre-history evolved in hunter-gatherer settings, demand sharing may be an ancestral manifestation of hyper-cooperation and inequality aversion, allowing exploration of high-quality, hard-to-acquire resources, the evolution of fluid co residence patterns and egalitarian resource distribution in the absence of punishment or warfare. PMID- 25511876 TI - Transcatheter closure of a congenital coronary artery to right ventricle fistula: a case report. AB - INTRODUCTION: Congenital coronary artery fistula is a rare anomaly that may cause angina, atrial fibrillation, endocarditis, aneurysmal dilation and myocardial infarction. Both spontaneous regression and life-threatening complications have been described. Treatment can be conservative, surgical or more recently through transcatheter closure. CASE PRESENTATION: We report the case of a 27-year-old Tunisian man with a large coronary artery fistula from the left anterior descending artery to the right ventricle associated with pulmonary stenosis. This patient underwent a successful transcatheter closure of his coronary artery fistula followed by pulmonary dilatation and had an uneventful recovery after treatment. CONCLUSIONS: Transcatheter closure of a congenital coronary artery fistula is feasible and should be considered in carefully selected patients. Recanalization of the treated coronary fistula can occur, so follow-up angiography or other imaging modality should be performed in these patients. PMID- 25511877 TI - Glycated peptides are associated with the variability of endothelial dysfunction in the cerebral vessels and the kidney in type 2 diabetes mellitus patients: a cross-sectional study. AB - BACKGROUND: Diabetic atherosclerosis and microangiopathy parallel diabetic nephropathy. The aim of our study was to evaluate the pattern of endothelial dysfunction in two vascular territories, the kidney and the brain, both affected by diabetic vasculopathic complications. The endothelial variability was evaluated in relation to advanced glycation end-products modified peptides. METHODS: Seventy patients with type 2 diabetes mellitus and 11 healthy subjects were assessed concerning urine albumin: creatinine ratio, plasma and urinary advanced glycation end-products, plasma asymmetric dimethyl-arginine, serum cystatin C, intima-media thickness in the common carotid arteries, the pulsatility index, the resistance index in the internal carotid arteries and the middle cerebral arteries, the cerebrovascular reactivity through the breath holding test. RESULTS: The breath-holding index correlated with asymmetric dimethyl-arginine (R2=0.151; p<0.001), plasma advanced glycation end-products (R2=0.173; p<0.001), C-reactive protein (R2=0.587; p<0.001), duration of diabetes mellitus (R2=0.146; p=0.001), cystatin C (R2=0.220; p<0.001), estimated glomerular filtration rate (R2=0.237; p=0.001). Urine albumin: creatinine ratio correlated with urinary advanced glycation end-products (R2=0.257; p<0.001), but not with asymmetric dimethyl-arginine (R2=0.029; p=0.147). CONCLUSIONS: In type 2 diabetic patients endothelial dysfunction in the cerebral vessels appears to be dissociated from glomerular endothelial dysfunction in early diabetic nephropathy. Advanced glycation end-products could impact both the cerebral vessels and the glomerular endothelium. PMID- 25511878 TI - Failure of hyperglycemia and hyperinsulinemia to compensate for impaired metabolic response to an oral glucose load. AB - OBJECTIVE: To evaluate whether the augmented insulin and glucose response to a glucose challenge is sufficient to compensate for defects in glucose utilization in obesity and type 2 diabetes, using a breath test measurement of integrated glucose metabolism. METHODS: Non-obese, obese normoglycemic and obese type 2 diabetic subjects were studied on 2 consecutive days. A 75g oral glucose load spiked with 13C-glucose was administered, measuring exhaled breath 13CO2 as an integrated measure of glucose metabolism and oxidation. A hyperinsulinemic euglycemic clamp was performed, measuring whole body glucose disposal rate. Body composition was measured by DEXA. Multivariable analyses were performed to evaluate the determinants of the breath 13CO2. RESULTS: Breath 13CO2 was reduced in obese and type 2 diabetic subjects despite hyperglycemia and hyperinsulinemia. The primary determinants of breath response were lean mass, fat mass, fasting FFA concentrations, and OGTT glucose excursion. Multiple approaches to analysis showed that hyperglycemia and hyperinsulinemia were not sufficient to compensate for the defect in glucose metabolism in obesity and diabetes. CONCLUSIONS: Augmented insulin and glucose responses during an OGTT are not sufficient to overcome the underlying defects in glucose metabolism in obesity and diabetes. PMID- 25511879 TI - Primary healthcare system capacities for responding to storm and flood-related health problems: a case study from a rural district in central Vietnam. AB - BACKGROUND: As a tropical depression in the East Sea, Vietnam is greatly affected by climate change and natural disasters. Knowledge of the current capacity of the primary healthcare system in Vietnam to respond to health issues associated with storms and floods is very important for policy making in the country. However, there has been little scientific research in this area. OBJECTIVE: This research was to assess primary healthcare system capacities in a rural district in central Vietnam to respond to such health issues. DESIGN: This was a cross-sectional descriptive study using quantitative and qualitative approaches. Quantitative methods used self-administered questionnaires. Qualitative methods (in-depth interviews and focus groups discussions) were used to broaden understanding of the quantitative material and to get additional information on actions taken. RESULTS: 1) Service delivery: Medical emergency services, especially surgical operations and referral systems, were not always available during the storm and flood seasons. 2) Governance: District emergency plans focus largely on disaster response rather than prevention. The plans did not clearly define the role of primary healthcare and had no clear information on the coordination mechanism among different sectors and organizations. 3) Financing: The budget for prevention and control of flood and storm activities was limited and had no specific items for healthcare activities. Only a little additional funding was available, but the procedures to get this funding were usually time-consuming. 4) Human resources: Medical rescue teams were established, but there were no epidemiologists or environmental health specialists to take care of epidemiological issues. Training on prevention and control of climate change and disaster-related health issues did not meet actual needs. 5) Information and research: Data that can be used for planning and management (including population and epidemiological data) were largely lacking. The district lacked a disease early-warning system. 6) Medical products and technology: Emergency treatment protocols were not available in every studied health facility. CONCLUSIONS: The primary care system capacity in rural Vietnam is inadequate for responding to storm and flood-related health problems in terms of preventive and treatment healthcare. Developing clear facility preparedness plans, which detail standard operating procedures during floods and identify specific job descriptions, would strengthen responses to future floods. Health facilities should have contingency funds available for emergency response in the event of storms and floods. Health facilities should ensure that standard protocols exist in order to improve responses in the event of floods. Introduction of a computerized health information system would accelerate information and data processing. National and local policies need to be strengthened and developed in a way that transfers into action in local rural communities. PMID- 25511880 TI - Perceptions of climate change and its impact on human health: an integrated quantitative and qualitative approach. AB - BACKGROUND: The World Health Organization emphasized that climate change is a significant and emerging threat to public health, especially in lower income populations and tropical/subtropical countries. However, people in Asia and Africa were the least likely to perceive global warming as a threat. In Vietnam, little research has been conducted concerning the perceptions of effects of climate change on human health. OBJECTIVE: The aim of this study was to explore the perceptions on climate change and its impact on human health among people in Hanoi. DESIGN: We applied a combined quantitative and qualitative approach to study perceptions on climate change among people in Hanoi. A total of 1,444 people were recruited, including 754 people living in non-slum areas and 690 people living in slum areas of Hanoi. A structured questionnaire was used to collect quantitative data on their perceptions. In a parallel qualitative study, two focus group discussions and 12 in-depth interviews (IDs) were carried out involving 24 people from both slum and non-slum areas. RESULTS: The majority of the respondents in the study had heard about climate change and its impact on human health (79.3 and 70.1% in non-slum and slum areas, respectively). About one third of the respondents reported that members of their family had experienced illness in the recent summer and winter compared to the same seasons 5 years ago. The most common symptoms reported during hot weather were headaches, fatigue, and dizziness; hypertension and other cardiovascular diseases were also reported. During cold weather, people reported experiencing cough, fever, and influenza, as well as pneumonia and emerging infectious diseases such as dengue and Japanese encephalitis. CONCLUSIONS: The observed high level of awareness on the links between climate change and human health may help to increase the success of the National Prevention Program on Climate Change. Moreover, understanding the concerns of the people may help policy makers to develop and implement effective and sustainable adaptation measures for Hanoi City as well as for Vietnam as a whole. PMID- 25511881 TI - Influenza-like illness in a Vietnamese province: epidemiology in correlation with weather factors and determinants from the surveillance system. AB - BACKGROUND: Seasonal influenza affects from 5 to 15% of the world's population annually and causes an estimated 250,000-500,000 deaths worldwide. The World Health Organization (WHO) recommends 'sentinel surveillance' for influenza-like illness (ILI) because it is simple and calls for standardized methods at a relatively low cost that can be implemented throughout the world. In Vietnam, ILI is a key priority for public health also because of its annually recurring temporal pattern. Two major factors, on which the spread of influenza depends, are the strain of the virus and its rate of mutation, since flu strains constantly mutate as they compete with host immune systems. In the context of global climate change, the role of climatic factors has been discussed, as they may significantly contribute to the cause of large outbreaks of ILI. OBJECTIVES: 1) To describe the epidemiology of ILI in Ha Nam province, Vietnam; 2) to seek scientific evidence on the association of ILI occurrence with weather factors in Ha Nam province; and 3) to analyze factors from the Ha Nam ILI surveillance system that contribute to explaining the correlation between the ILI and the weather factors. DESIGN: A data set of 89,270 monthly reported ILI cases from 2008 to 2012 in Ha Nam was used to describe ILI epidemiological characteristics. Spearman correlation analyses between ILI cases and weather factors were conducted to identify which preceding period of months and weather patterns influenced the occurrence of ILI cases. Ten in-depth interviews with health workers in charge of recording and reporting ILI cases at different levels of the ILI surveillance system were conducted to gain a deeper understanding of factors contributing to explaining the relation between the ILI and the weather factors. RESULTS: The results indicated that the ILI occurred annually in all districts of the Ha Nam province in the five studied years. An epidemic occurred in 2009 with the number of cases three times higher than the average threshold. There was a relation between the ILI cases in the previous 1 month with ILI cases of the following month. A seasonal cycle of ILI and correlation between weather elements were not clearly detected. A qualitative study showed that the number of ILI cases reported by the Provincial Preventive Medicine Centre (PPMC) in Ha Nam might not have reflected the accurate number of seasonal ILI occurring in this area. This was due to three gaps in the ILI surveillance system that initially were detected through key in-depth interviews in the Duy Tien and Binh Luc districts. They reported inconsistent ways of recording and reporting ILI cases among communes, lack of ILI survey forms, and irregular and delayed feedback from the PPMC. CONCLUSIONS: There were no clear patterns of association between weather factors and ILI cases detected from the five studied years. The number of ILI cases reported by the PPMC in Ha Nam may not reflect adequately the actual number of seasonal ILI occurring in this area due to three weak points in the ILI surveillance system initially detected through the case of the Duy Tien and Binh Luc districts. These three weak points of the system should be examined by a study conducted in the remaining districts in Ha Nam. PMID- 25511882 TI - Epidemiology of dengue fever in Hanoi from 2002 to 2010 and its meteorological determinants. AB - BACKGROUND: Dengue fever (DF) is a growing public health problem in Vietnam. The disease burden in Vietnam has been increasing for decades. In Hanoi, in contrast to many other regions, extrinsic drivers such as weather have not been proved to be predictive of disease frequency, which limits the usefulness of such factors in an early warning system. AIMS: The purpose of this research was to review the epidemiology of DF transmission and investigate the role of weather factors contributing to occurrence of DF cases. METHODS: Monthly data from Hanoi (2002 2010) were used to test the proposed model. Descriptive time-series analysis was conducted. Stepwise multivariate linear regression analysis assuming a negative binomial distribution was established through several models. The predictors used were lags of 1-3 months previous observations of mean rainfall, mean temperature, DF cases, and their interactions. RESULTS: Descriptive analysis showed that DF occurred annually and seasonally with an increasing time trend in Hanoi. The annual low occurred from December to March followed by a gradual increase from April to July with a peak in September, October. The amplitude of the annual peak varied between years. Statistically significant relationships were estimated at lag 1-3 with rainfall, autocorrelation, and their interaction while temperature was estimated as influential at lag 3 only. For these relationships, the final model determined a correlation of 92% between predicted number of dengue cases and the observed dengue disease frequencies. CONCLUSIONS: Although the model performance was good, the findings suggest that other forces related to urbanization, density of population, globalization with increasing transport of people and goods, herd immunity, government vector control capacity, and changes in serotypes are also likely influencing the transmission of DF. Additional research taking into account all of these factors besides climatic factors is needed to help developing and developed countries find the right intervention for controlling DF epidemics, and to set up early warning systems with high sensitivity and specificity. Immediate action to control DF outbreak in Hanoi should include an information, communication, and education program that focuses on training Hanoi residents to more efficiently eliminate stagnant puddles and water containers after each rainfall to limit the vector population growth. PMID- 25511883 TI - Seasonality in mortality and its relationship to temperature among the older population in Hanoi, Vietnam. AB - BACKGROUND: Several studies have established a relationship between temperature and mortality. In particular, older populations have been shown to be vulnerable to temperature effects. However, little information exists on the temperature mortality relationship in Vietnam. OBJECTIVES: This article aims to examine the monthly temperature-mortality relationship among older people in Hanoi, Vietnam, over the period between 2005 and 2010, and estimate seasonal patterns in mortality. METHODS: We employed Generalized Additive Models, including smooth functions, to model the temperature-mortality relationships. A quasi-Poisson distribution was used to model overdispersion of death counts. Temporal trends, seasonality, and population size were adjusted for while estimating changes in monthly mortality over the study period. A cold month was defined as a month with a mean temperature below 19 degrees C. RESULTS: This study found that the high peak of mortality coincided with low temperatures in the month of February 2008, during which the mean temperature was the lowest in the whole study period. There was a significant relationship between mean monthly temperature and mortality among the older people (p<0.01). Overall, there was a significant decrease in the number of deaths in the year 2009 during the study period. There was a 21% increase in the number of deaths during the cold season compared to the warm season. The increase in mortality during the cold period was higher among females compared to males (female: IRR [incidence relative risk] =1.23; male: IRR=1.18). CONCLUSIONS: Cold temperatures substantially increased mortality among the older population in Hanoi, Vietnam, and there were gender differences. Necessary preventive measures are required to mitigate temperature effects with greater attention to vulnerable groups. PMID- 25511884 TI - Estimates of meteorological variability in association with dengue cases in a coastal city in northern Vietnam: an ecological study. AB - BACKGROUND: Dengue fever (DF) is a vector-borne disease that is sensitive to weather and climate variability. To date, however, this relationship in coastal northern Vietnam has not been well documented. OBJECTIVES: This paper aims to examine the associations between meteorological variables and dengue incidence in Haiphong, Vietnam, over the period 2008-2012. METHODS: Monthly data on dengue incidence from all commune health stations and hospitals of Haiphong (with a total population of ~1.8 million) were obtained in accordance with the WHO's recommendations over a 5-year period (2008-2012). Temperature, rainfall, and humidity were recorded as monthly averages by local meteorological stations. The association between ecologic weather variables and dengue cases was assessed using a Poisson regression model. The estimation of regression parameters was based on the method of maximum likelihood using the R program package. RESULTS: From 2008 through 2012, 507 cases of dengue were reported. The risk of dengue was increased by sevenfold during the September-December period compared with other months over the period 2008-2012. DF cases in Haiphong were correlated with rainfall and humidity. In the multivariable Poisson regression model, an increased risk of dengue was independently associated with months with a higher amount of rainfall (RR=1.06; 95% CI 1.00-1.13 per 50 mm increase) and higher humidity (RR=1.05; 95% CI 1.02-1.08 per 1% increase). CONCLUSION: These data suggest that rainfall and relative humidity could be used as ecological indicators of dengue risk in Haiphong. Intensified surveillance and disease control during periods with high rainfall and humidity are recommended. This study may provide baseline information for identifying potential long-term effects and adaptation needs of global climate change on dengue in the coming decades. PMID- 25511885 TI - Diet and nutritional status among children 24-59 months by seasons in a mountainous area of Northern Vietnam in 2012. AB - BACKGROUND: Seasonal variation affects food availability. However, it is not clear if it affects dietary intake and nutritional status of children in Vietnam. OBJECTIVES: This paper aims at examining the seasonal variation in nutrition status and dietary intake of children aged 24-59 months. DESIGN: A repeated cross sectional study design was used to collect data of changes in nutritional status and diets of children from 24 to 59 months through four seasons in Chiem Hoa district, Tuyen Quang province, a predominately rural mountainous province of northern Vietnam. The quantitative component includes anthropometric measurements, 24 hours dietary recall and socio-economic characteristics. The qualitative component was conducted through focus group discussions (FGDs) with mothers of the children surveyed in the quantitative component. The purpose of FGDs was to explore the food habits of children during the different seasons and the behaviours of their mothers in relation to the food that they provide during these seasons. RESULTS: The prevalence of underweight among children aged 24-59 months is estimated at around 20-25%; it peaked in summer (24.9%) and reached a low in winter (21.3%). The prevalence of stunting was highest in summer (29.8%) and lowest in winter (22.2%). The prevalence of wasting in children was higher in spring and autumn (14.3%) and lower in summer (9.3%). Energy intake of children was highest in the autumn (1259.3 kcal) and lowest in the summer (996.9 kcal). Most of the energy and the nutrient intakes during the four seasons did not meet the Vietnamese National Institute of Nutrition recommendation. CONCLUSIONS: Our study describes some seasonal variation in nutrition status and energy intake among children in a mountainous area northern Vietnam. Our study indicated that the prevalence of stunting and underweight was higher in summer and autumn, while the prevalence of wasting was higher in spring and autumn. Energy intake did not always meet national recommendations, especially in summer. PMID- 25511886 TI - The effect of temperature on cardiovascular disease hospital admissions among elderly people in Thai Nguyen Province, Vietnam. AB - BACKGROUND: Projected increases in weather variability due to climate change will have severe consequences on human health, increasing mortality, and disease rates. Among these, cardiovascular diseases (CVD), highly prevalent among the elderly, have been shown to be sensitive to extreme temperatures and heat waves. OBJECTIVES: This study aimed to find out the relationship between daily temperature (and other weather parameters) and daily CVD hospital admissions among the elderly population in Thai Nguyen province, a northern province of Vietnam. METHODS: Retrospective data of CVD cases were obtained from a data base of four hospitals in Thai Nguyen province for a period of 5 years from 2008 to 2012. CVD hospital admissions were aggregated by day and merged with daily weather data from this period. Distributed lag non-linear model (DLNM) was used to derive specific estimates of the effect of weather parameters on CVD hospital admissions of up to 30 days, adjusted for time trends using b-splines, day of the week, and public holidays. RESULTS: This study shows that the average point of minimum CVD admissions was at 26 degrees C. Above and below this threshold, the cumulative CVD admission risk over 30 lag days tended to increase with both lower and higher temperatures. The cold effect was found to occur 4-15 days following exposure, peaking at a week's delay. The cumulative effect of cold exposure on CVD admissions was statistically significant with a relative risk of 1.12 (95% confidence interval: 1.01-1.25) for 1 degrees C decrease below the threshold. The cumulative effect of hot temperature on CVD admissions was found to be non significant and was estimated to be at a relative risk of 1.17 (95% confidence interval: 0.90-1.52) for 1 degrees C increase in the temperature. No significant association was found between CVD admissions and the other weather variables. CONCLUSION: Exposure to cold temperature is associated with increasing CVD admission risk among the elderly population. PMID- 25511887 TI - Local research evidence for public health interventions against climate change in Vietnam. PMID- 25511888 TI - Characterization and effect of year of harvest on the nutritional properties of three varieties of white lupine (Lupinus albus L.). AB - BACKGROUND: Three cultivars of Lupinus albus L. (Lutteur, Lublanca and Multitalia) were assessed for proximate composition, fatty acids, alkaloids and in vitro fermentation characteristics over three harvest years. RESULTS: The chemical composition varied greatly during the three harvest years. Crude protein content ranged from 353 to 456 g kg(-1) dry matter (DM), neutral detergent fiber content from 209 to 321 g kg(-1) DM and lignin content from 3.0 to 63.9 g kg(-1) DM. Lublanc showed the highest crude protein (417 g kg(-1) DM) and lignin (35 g kg(-1) DM) contents. High levels of lipids (89.9 g kg(-1) DM) and starch (93.3 g kg(-1) DM) were found in all samples. Alkaloid content ranged from 3.63 to 165 mg per 100 g. Lutteur and Lublanc showed more favorable n-3/n-6 polyunsaturated fatty acid ratios (from 0.44 to 0.73) and lower values of the anti-quality factor 'erucic acid' (from 5.8 to 20.9 g kg(-1) ) than Multitalia. Lutteur showed higher degradability (897 g kg(-1) ), gas production (330 mL g(-1) organic matter (OM)) and volatile fatty acid production (117 mmol g(-1) OM) than the other varieties. CONCLUSION: The present data suggest L. albus L. cv. Lutteur to be a promising crop as food thanks to its high nutritive traits and most constant yield over time. PMID- 25511890 TI - Demyelinating disease: Is TOPIC the last trial for clinically isolated syndrome? PMID- 25511893 TI - Parkinson disease: Facilitating detection of prodromal Parkinson disease in primary care clinics. PMID- 25511898 TI - Parkinson disease: How reliable are prodromal indicators of Parkinson disease? PMID- 25511900 TI - Neurodevelopmental disorders. Unmuting Ube3a in mice alleviates Angelman syndrome. PMID- 25511902 TI - Yield performance and stability of CMS-based triticale hybrids. AB - KEY MESSAGE: CMS-based triticale hybrids showed only marginal midparent heterosis for grain yield and lower dynamic yield stability compared to inbred lines. Hybrids of triticale (*Triticosecale Wittmack) are expected to possess outstanding yield performance and increased dynamic yield stability. The objectives of the present study were to (1) examine the optimum choice of the biometrical model to compare yield stability of hybrids versus lines, (2) investigate whether hybrids exhibit a more pronounced grain yield performance and yield stability, and (3) study optimal strategies to predict yield stability of hybrids. Thirteen female and seven male parental lines and their 91 factorial hybrids as well as 30 commercial lines were evaluated for grain yield in up to 20 environments. Hybrids were produced using a cytoplasmic male sterility (CMS) inducing cytoplasm that originated from Triticumtimopheevii Zhuk. We found that the choice of the biometrical model can cause contrasting results and concluded that a group-by-environment interaction term should be added to the model when estimating stability variance of hybrids and lines. midparent heterosis for grain yield was on average 3 % with a range from -15.0 to 11.5 %. No hybrid outperformed the best inbred line. Hybrids had, on average, lower dynamic yield stability compared to the inbred lines. Grain yield performance of hybrids could be predicted based on midparent values and general combining ability (GCA) predicted values. In contrast, stability variance of hybrids could be predicted only based on GCA-predicted values. We speculated that negative effects of the used CMS cytoplasm might be the reason for the low performance and yield stability of the hybrids. For this purpose a detailed study on the reasons for the drawback of the currently existing CMS system in triticale is urgently required comprising also the search of potentially alternative hybridization systems. PMID- 25511903 TI - Heterotic groups of tropical indica rice germplasm. AB - KEY MESSAGE: Four heterotic groups were identified for tropical indica rice germplasm to develop hybrid rice in the tropics based on two studies. Heterotic groups are of fundamental importance in hybrid crop breeding. This study investigated hybrid yield, yield heterosis and combining ability within and among groups based on genetic distance derived from single-nucleotide polymorphism markers. The main objectives of the study were to (1) evaluate the magnitude of yield heterosis among marker-based groups, (2) identify possible heterotic groups for tropical indica hybrid rice, and (3) validate heterotic patterns concluded from a previous study. Seventeen rice parents selected from improved indica germplasm from the tropics with high genetic divergence and 136 derived hybrids were evaluated in five environments. The hybrids had more yield than their parents with an average of 24.1 % mid-parent heterosis. Genotype * environment interaction was the major factor affecting variations in yield and yield heterosis, which raised a necessity and a challenge to develop heterotic rice hybrid adapted to different regions and seasons in the tropics. Yield, yield heterosis and combining ability were significantly increased in inter-group than in intra-group hybrids. Four heterotic groups and three promising hybridization patterns, which could be used in tropical hybrid rice breeding, were identified based on marker-based grouping, yield and yield heterosis analyses in the two studies. The study reveals that molecular markers analysis can serve as a basis for assigning germplasm into heterotic groups and to provide guidelines for parental selection in hybrid rice breeding. PMID- 25511894 TI - Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases. AB - Alzheimer disease (AD) and Parkinson disease (PD) are the most common neurodegenerative disorders. For both diseases, early intervention is thought to be essential to the success of disease-modifying treatments. Cerebrospinal fluid (CSF) can reflect some of the pathophysiological changes that occur in the brain, and the number of CSF biomarkers under investigation in neurodegenerative conditions has grown rapidly in the past 20 years. In AD, CSF biomarkers are increasingly being used in clinical practice, and have been incorporated into the majority of clinical trials to demonstrate target engagement, to enrich or stratify patient groups, and to find evidence of disease modification. In PD, CSF biomarkers have not yet reached the clinic, but are being studied in patients with parkinsonism, and are being used in clinical trials either to monitor progression or to demonstrate target engagement and downstream effects of drugs. CSF biomarkers might also serve as surrogate markers of clinical benefit after a specific therapeutic intervention, although additional data are required. It is anticipated that CSF biomarkers will have an important role in trials aimed at disease modification in the near future. In this Review, we provide an overview of CSF biomarkers in AD and PD, and discuss their role in clinical trials. PMID- 25511904 TI - Geographic miss of lung tumours due to respiratory motion: a comparison of 3D vs 4D PET/CT defined target volumes. AB - BACKGROUND: PET/CT scans acquired in the radiotherapy treatment position are typically performed without compensating for respiratory motion. The purpose of this study was to investigate geographic miss of lung tumours due to respiratory motion for target volumes defined on a standard 3D-PET/CT. METHODS: 29 patients staged for pulmonary malignancy who completed both a 3D-PET/CT and 4D-PET/CT were included. A 3D-Gross Tumour Volume (GTV) was defined on the standard whole body PET/CT scan. Subsequently a 4D-GTV was defined on a 4D-PET/CT MIP. A 5 mm, 10 mm, 15 mm symmetrical and 15*10 mm asymmetrical Planning Target Volume (PTV) was created by expanding the 3D-GTV and 4D-GTV's. A 3D conformal plan was generated and calculated to cover the 3D-PTV. The 3D plan was transferred to the 4D-PTV and analysed for geographic miss. Three types of miss were measured. Type 1: any part of the 4D-GTV outside the 3D-PTV. Type 2: any part of the 4D-PTV outside the 3D PTV. Type 3: any part of the 4D-PTV receiving less than 95% of the prescribed dose. The lesion motion was measured to look at the association between lesion motion and geographic miss. RESULTS: When a standard 15 mm or asymmetrical PTV margin was used there were 1/29 (3%) Type 1 misses. This increased 7/29 (24%) for the 10 mm margin and 23/29 (79%) for a 5 mm margin. All patients for all margins had a Type 2 geographic miss. There was a Type 3 miss in 25 out of 29 cases in the 5, 10, and 15 mm PTV margin groups. The asymmetrical margin had one additional Type 3 miss. Pearson analysis showed a correlation (p < 0.01) between lesion motion and the severity of the different types of geographic miss. CONCLUSION: Without any form of motion suppression, the current standard of a 3D- PET/CT and 15 mm PTV margin employed for lung lesions has an increasing risk of significant geographic miss when tumour motion increases. Use of smaller asymmetric margins in the cranio-caudal direction does not comprise tumour coverage. Reducing PTV margins for volumes defined on 3D-PET/CT will greatly increase the chance and severity of a geometric miss due to respiratory motion. 4D-imaging reduces the risk of geographic miss across the population of tumour sizes and magnitude of motion investigated in the study. PMID- 25511905 TI - Long-term outcomes of thalidomide in refractory Crohn's disease. AB - BACKGROUND: Several open-label and retrospective studies have indicated that thalidomide may be beneficial in patients with refractory Crohn's disease (CD). AIM: To report our long-term experience with the use of thalidomide for adults with refractory Crohn's disease. METHODS: We conducted a retrospective study of long-term clinical and safety outcomes among adults treated with thalidomide for refractory Crohn's disease. Response was defined as a clinician's assessment of improvement after at least 7 days treatment of one or more of the following: bowel movement frequency, fistula output, rectal bleeding, abdominal pain, extraintestinal manifestations, or well-being. Remission required all of the following: <3 stools/day, no bleeding, abdominal pain or extraintestinal manifestations and increased well-being. RESULTS: Thirty-seven adults with refractory Crohn's disease were treated with thalidomide for a median of 4.4 months and followed up for a median of 58 months. Clinical response and remission rates were 54% and 19%, respectively. About 40% of patients were able to stop steroids. Response rates were higher for those treated with more than 50 mg/day (85%) than for those treated with a maximum of 50 mg/day (40%; P = 0.01). An adverse event occurred in 68% of patients. Approximately one-third of patients (38%) experienced neuropathy. CONCLUSIONS: Thalidomide appears to be safe and effective in some patients with refractory Crohn's disease. Although side effects may limit long-term use, thalidomide has potential to induce significant clinical responses. PMID- 25511907 TI - Nonlinear dynamic behaviors and control based on simulation of high-purity heat integrated air separation column. AB - In this paper, the dynamic behaviors on the basis of simulation for high-purity heat integrated air separation column (HIASC) are studied. A nonlinear generic model control (GMC) scheme is proposed based on the nonlinear behavior analyses of a HIASC process, and an adaptive generic model control (AGMC) scheme is further presented to correct the model parameters online. Related internal model control (IMC) scheme and multi-loop PID (M-PID) scheme are also developed as the comparative base. The comparative researches are carried out among these linear and nonlinear control schemes in detail. The simulation research results show that the proposed AGMC schemes present advantages in both servo control and regulatory control for the high-purity HIASC. PMID- 25511906 TI - Cost-effectiveness of caries excavations in different risk groups - a micro simulation study. AB - BACKGROUND: Whilst being the most prevalent disease worldwide, dental caries is increasingly concentrated in high-risk populations. New caries treatments should therefore be evaluated not only in terms of their cost-effectiveness in individuals, but also their effects on the distribution of costs and benefits across different populations. To treat deep caries, there are currently three strategies: selective (one-step incomplete), stepwise (two-step incomplete) and complete excavation. Building on prior research that found selective excavation generally cost-effective, we compared the costs-effectiveness of different excavations in low- and high-risk patients, hypothesizing that selective excavation had greater cost-effectiveness-advantages in patients with high compared with low risk. METHODS: An average tooth-level Markov-model was constructed following the posterior teeth in an initially 18-year old male individual, either with low or high risk, over his lifetime. Risk was assumed to be predicted by several parameters (oral hygiene, social position, dental service utilization), with evidence-based transition probabilities or hazard functions being adjusted for different risk status where applicable. Total lifetime treatment costs were estimated for German healthcare, with both mixed public private and only private out-of-pocket costs being calculated. For cost effectiveness-analysis, micro-simulations were performed and joint parameter uncertainty introduced by random sampling of probabilities. Cohort analyses were used for assessing the underlying reasons for potential differences between strategies and populations. RESULTS: Selective excavation was more effective and less costly than both alternatives regardless of an individual's risk. All three strategies were less effective and more costly in patients with high compared with low risk, whilst the differences between risk groups were smallest for selective excavation. Thus, the cost-effectiveness-advantages of selective excavation were more pronounced in high-risk groups, who also benefitted the most from reduced private out-of-pocket treatment costs. CONCLUSIONS: Whilst caries excavation does not tackle the underlying sources for both the development of caries lesions and the potential differences of individuals' risk status, selective excavation seems most suitable to treat deep lesions, especially in patients with high risk, who over-proportionally benefit from the resulting health-gains and cost-savings. PMID- 25511909 TI - Performance IQ in children is associated with blood cadmium concentration in early pregnancy. AB - OBJECTIVE: To investigate whether performance IQ in children is associated with maternal blood cadmium concentration in early pregnancy. METHOD: The present study is a component of the Mothers' and Children's Environmental Health (MOCEH) study, a multi-center birth cohort project in Korea that began in 2006. The study cohort consisted of 119 children whose mothers underwent testing of blood cadmium during early pregnancy. All children were evaluated using the Korean version of the Wechsler Preschool and Primary Scale of Intelligence, revised edition (WPPSI R), at 60 months of age. Multivariate linear regression analysis was performed to analyze the correlation between IQ in children and maternal blood cadmium concentration in early pregnancy, after adjustment for covariates. RESULTS: Maternal blood cadmium concentration during early pregnancy was inversely associated with performance IQ, after adjustment for covariates such as sex, educational levels of both parents, family income, and maternal BMI. Maternal blood cadmium concentration, however, was not associated with cognitive IQ. CONCLUSION: Performance IQ in children is associated with maternal blood cadmium concentration in early pregnancy. PMID- 25511908 TI - Dutch Chronic Pancreatitis Registry (CARE): design and rationale of a nationwide prospective evaluation and follow-up. AB - BACKGROUND: Chronic pancreatitis is a complex disease with many unanswered questions regarding the natural history and therapy. Prospective longitudinal studies with long-term follow-up are warranted. METHODS: The Dutch Chronic Pancreatitis Registry (CARE) is a nationwide registry aimed at prospective evaluation and follow-up of patients with chronic pancreatitis. All patients with (suspected) chronic or recurrent pancreatitis are eligible for CARE. Patients are followed-up by yearly questionnaires and review of medical records. Study outcomes are pain, disease complications, quality of life, and pancreatic function. The target sample size was set at 500 for the first year and 1000 patients within 3 years. RESULTS: A total of 1218 patients were included from February 2010 until June 2013 by 76 participating surgeons and gastroenterologist from 33 hospitals. Participation rate was 90% of eligible patients. Eight academic centers included 761 (62%) patients, while 25 community hospitals included 457 (38%). Patient centered outcomes were assessed by yearly questionnaires, which had a response rate of 85 and 82% for year 1 and 2, respectively. The median age of patients was 58 years, 814 (67%) were male, and 38% had symptoms for less than 5 years. DISCUSSION: The CARE registry has successfully recruited over 1200 patients with chronic and recurrent pancreatitis in about 3 years. The defined inclusion criteria ensure patients are included at an early disease stage. Participation and compliance rates are high. CARE offers a unique opportunity with sufficient power to investigate many clinical questions regarding natural course, complications, and efficacy and timing of treatment strategies. PMID- 25511910 TI - Selenium and coenzyme Q10 interrelationship in cardiovascular diseases--A clinician's point of view. AB - A short review is given of the potential role of selenium deficiency and selenium intervention trials in atherosclerotic heart disease. Selenium is an essential constituent of several proteins, including the glutathione peroxidases and selenoprotein P. The selenium intake in Europe is generally in the lower margin of recommendations from authorities. Segments of populations in Europe may thus have a deficient intake that may be presented by a deficient anti-oxidative capacity in various illnesses, in particular atherosclerotic disease, and this may influence the prognosis of the disease. Ischemic heart disease and heart failure are two conditions where increased oxidative stress has been convincingly demonstrated. Some of the intervention studies of anti-oxidative substances that have focused on selenium are discussed in this review. The interrelationship between selenium and coenzyme Q10, another anti-oxidant, is presented, pointing to a theoretical advantage in using both substances in an intervention if there are deficiencies within the population. Clinical results from an intervention study using both selenium and coenzyme Q10 in an elderly population are discussed, where reduction in cardiovascular mortality, a better cardiac function according to echocardiography, and finally a lower concentration of the biomarker NT-proBNP as a sign of lower myocardial wall tension could be seen in those on active treatment, compared to placebo. PMID- 25511911 TI - Comment on: "Desideratum for evidence-based epidemiology". PMID- 25511912 TI - Authors' reply to Hennessy and Leonard's comment on "Desideratum for evidence based epidemiology". PMID- 25511913 TI - Long-term neurodevelopmental outcome of children from euploid pregnancies with increased nuchal translucency in the first trimester screening. AB - OBJECTIVE: To assess the long-term neurodevelopmental outcome of children born from singleton euploid pregnancies with increased fetal nuchal translucency (NT) in the first trimester ultrasound screening and without structural anomalies in the second trimester ultrasound screening. STUDY DESIGN: This is a register-based retrospective cohort study carried out at a tertiary referral centre from 2002 to 2007. Children were followed up until 2012. All fetuses had increased NT (>95th percentile) at the first trimester ultrasound screening and normal findings in the second trimester ultrasound screening. Data about the neurodevelopmental outcome was retrieved from the hospital databases, The National Institute for Health and Welfare, and the Finnish Causes of Death Statistics Database. Information about received disability allowances was gathered from the Social Insurance Institute of Finland. RESULTS: The study population consists of 691 children. The mean follow-up time was 6.5 years. Neurodevelopmental disorders occurred in 29 children (4.2%). Twelve of these 29 children (1.7%) had severe neurodevelopmental impairment. CONCLUSIONS: The long-term neurodevelopmental outcome of children after increased fetal NT is reassuring. This information should be added to the parental counselling of such cases. (c) 2014 John Wiley & Sons, Ltd. PMID- 25511914 TI - Pregnancy management for a patient with graft occlusion after right iliac artery bypass surgery. AB - We describe an extremely rare case of a pregnant woman who had a successful delivery despite developing bypass graft occlusion after right external iliac bypass surgery. External and common iliac artery bypass surgery is often performed when arteriosclerosis obliterans or thromboangiitis obliterans result in iliac artery occlusion or when revascularization is required because of iliac artery injury. Because arteriosclerosis obliterans and thromboangiitis obliterans rarely develop in young women or girls, most physicians have little experience with graft occlusion after iliac artery bypass surgery. Here we describe and discuss the published work pertaining to this extremely rare case. PMID- 25511915 TI - Therapeutic inferences for individual patients. AB - RATIONALE, AIMS AND OBJECTIVES: Increased awareness of the gap between controlled research and medical practice has raised concerns over whether the special attention of doctors to probability estimates from clinical trials really improves the care of individuals. Evidence-based medicine has acknowledged that research results are not applicable to all kinds of patients, and consequently, has attempted to overcome this limitation by introducing improvements in the design and analysis of clinical trials. METHODS: A clinical case is used to highlight the premises required to support reasonable extrapolations from controlled research to individuals. Then, the prospects of two key methodological improvements - pragmatic randomized controlled trials and subgroup analysis - are critically appraised. RESULTS: A principle to guide therapeutic inferences is suggested. According to this principle, the probabilities of interest for purposes of therapeutic decision making are those of the set defined by everything that is relevant to the patient and the outcome of interest at the time of the decision. It is argued that the conditions necessary to authorize automatic extrapolations of research results to specific patients are highly demanding. Furthermore, these requirements are rarely accomplished in real practice, even in the event that probability estimates come from samples generally taken as representative and are derived from specific subsets of patients. CONCLUSIONS: Clinicians should generally avoid unreflective extrapolations from research and address, as explicitly as possible, the challenge of estimating probabilities for individual patients. A key element of this task is the integration of data from research and non-research sources. PMID- 25511916 TI - Reply: To PMID 24839206. PMID- 25511917 TI - Methods to Make Homogenous Antibody Drug Conjugates. AB - Antibody drug conjugates (ADCs) have progressed from hypothesis to approved therapeutics in less than 30 years, and the technologies available to modify both the antibodies and the cytotoxic drugs are expanding rapidly. For reasons well reviewed previously, the field is trending strongly toward homogeneous, defined antibody conjugation. In this review we present the antibody and small molecule chemistries that are currently used and being explored to develop specific, homogenous ADCs. PMID- 25511918 TI - Dependence of PEI and PAMAM Gene Delivery on Clathrin- and Caveolin-Dependent Trafficking Pathways. AB - PURPOSE: Non-viral gene delivery vehicles such as polyethylenimine and polyamidoamine dendrimer effectively condense plasmid DNA, facilitate endocytosis, and deliver nucleic acid cargo to the nucleus in vitro. Better understanding of intracellular trafficking mechanisms involved in polymeric gene delivery is a prerequisite to clinical application. This study investigates the role of clathrin and caveolin endocytic pathways in cellular uptake and subsequent vector processing. METHODS: We formed 25-kD polyethylenimine (PEI) and generation 4 (G4) polyamidoamine (PAMAM) polyplexes at N/P 10 and evaluated internalization pathways and gene delivery in HeLa cells. Clathrin- and caveolin dependent endocytosis inhibitors were used at varying concentrations to elucidate the roles of these important pathways. RESULTS: PEI and PAMAM polyplexes were internalized by both pathways. However, the amount of polyplex internalized poorly correlated with transgene expression. While the caveolin-dependent pathway generally led to effective gene delivery with both polymers, complete inhibition of the clathrin-dependent pathway was also deleterious to transfection with PEI polyplexes. Inhibition of one endocytic pathway may lead to an overall increase in uptake via unaffected pathways, suggesting the existence of compensatory endocytic mechanisms. CONCLUSIONS: The well-studied clathrin- and caveolin dependent endocytosis pathways are not necessarily independent, and perturbing one mechanism of trafficking influences the larger trafficking network. PMID- 25511919 TI - Multi-scale modelling of powder dispersion in a carrier-based inhalation system. AB - PURPOSE: Carrier-based dry powder inhalers (DPIs) are widely used for rapid and convenient delivery of drug to the site of action. This work aimed to predict powder aerosolisation in DPIs through numerical modelling. METHODS: A multi-scale modelling technique based on the combined computational fluid dynamics (CFD) and discrete element method (DEM) approach was developed. RESULTS: The simulation results of the detachments of the drug particles from single carrier under different impact velocities and angles were comparable with those measured in the experiments in terms of fine particle fraction FPF loaded . Empirical equations were developed to link the detachment performance with impact velocity and impact angle. Then the dynamics of the carrier particles in Aerolizer(r) was simulated. The results indicated that the carrier-wall impaction was the dominant mechanism for drug aerosolisation performance. By linking the empirical equations with the carrier-wall impact energy, the predictions showed that for a given formulation mass with a fixed carrier/drug ratio, the inhaler performance decreased with carrier size and increased with air flow rate. Device empty efficiency, however, was independent with carrier size and flow rate. CONCLUSIONS: The multi-scale model was able to provide quantitative information to better understand the aerosolisation mechanisms of carrier-based formulation. PMID- 25511921 TI - Transplantation of bone marrow-derived mesenchymal stem cells facilitates epithelial repair and relieves the impairment of gastrointestinal function in a rat model of enteritis. AB - BACKGROUND: To examine whether the bone marrow-derived MSCs (BM-MSCs) could facilitate epithelial repair and thereby reduce impairment of gastrointestinal structure and function in chronic murine enteritis induced by indomethacin (IDM). METHODS: MSCs were isolated from young Sprague-Dawley rats. After in vitro expansion and characterization, BM-MSCs were labelled with the fluorescent dye PKH26 and transfused, via the tail veins, into rats with enteritis induced by IDM. The controls were infused with sterile saline. The homing and differentiation of the transplanted BM-MSCs were tracked by means of fluorescent staining. The clinical symptoms of the IDM-treated rats were assessed, and the macroscopic and microscopic histological evaluations of the intestines were performed. RESULTS: Compared to controls that received saline infusion, BM-MSCs treated rats showed lower scores of weight loss, stool consistency, and stool blood. The PKH26-labelled cells resided at the injured intestine, where they co localize with the proliferating cell nuclear antigen (PCNA), Lgr-5, and Msi-1. The BM-MSCs treated rats showed significantly higher intestinal villi with larger areas relative to the saline-treated rats. CONCLUSION: The transplanted BM-MSCs are able to recognize the injured intestine, where they proliferate and transdifferentiate into intestinal stem cells which repair the injured intestinal tissues. Therefore, BM-MSCs are able to relieve the impairment of gastrointestinal function in IMD-treated rats. PMID- 25511920 TI - Colonoscopy: the current king of the hill in the USA. AB - Colonoscopy is the dominant colorectal cancer screening strategy in the USA. There are no randomized controlled trials completed of screening colonoscopy, but multiple lines of evidence establish that colonoscopy reduces colorectal cancer incidence in both the proximal and distal colon. Colonoscopy is highly operator dependent, but systematic efforts to measure and improve quality are impacting performance. Colonoscopy holds a substantial advantage over other strategies for detection of serrated lesions, and a recent case-control study suggests that once only colonoscopy or colonoscopy at 20-year intervals, by a high-level detector, could ensure lifetime protection from colorectal cancer for many patients. PMID- 25511922 TI - Patient health utility, work productivity, and lifestyle impairment in chronic hepatitis C patients in France. AB - BACKGROUND: France has a high prevalence of patients with chronic hepatitis C virus (HCV). Clinical consequences of HCV are well-recognized, while health related quality of life (HRQoL) and productivity impacts remain less understood. This study evaluates how HCV disease severity and HCV treatment outcomes impact HRQoL and productivity among patients in France. METHODS: From October 2012 to January 2013, physicians treating HCV patients in France completed Patient Record Forms, which included information on patient demographics, disease stage, and treatment status. Subsequently, these HCV patients completed the EQ-5D-3L health state instrument and the HCV-specific Work Productivity and Activity Impairment (WPAI:HepC) Questionnaire. Results are reported in descriptive and stratified analyses by disease stage and treatment status. Linear regression analyses were performed to determine independent associations between disease severity and treatment status with EQ-5D and WPAI:HepC. RESULTS: There were 297 matched physician and patient response forms completed. Mean EQ-5D Index score was 0.764, and mean EQ-VAS score was 65.85. Regression analyses showed that older age and worse disease severity were significantly associated with lower EQ-5D Index and EQ-VAS scores. Stratification of EQ-5D Index and EQ-VAS scores showed significantly better scores for HCV treatment responders compared to non responders. Stratification of WPAI:HepC questions by disease stage revealed greater productivity impact on HCV patients with more severe disease. CONCLUSIONS: In a cross-sectional sample of HCV patients in France, worsening HRQoL and productivity/activity impairment was significantly associated with disease progression and increasing age. This information provides insight into the benefits of treating HCV patients and preventing disease progression. PMID- 25511924 TI - Tethered ribozyme ligation enables detection of molecular proximity in homogeneous solutions. AB - In contemporary drug discovery, bulk selection represents an important alternative to time consuming and expensive high-throughput screening. The selection methods, however, generally rely on affinity separation, a step that limits overall selection process efficiency. To overcome common drawbacks of conventional methods, we exploited the unique catalytic properties of an artificial enzyme, ribozyme ligase, to develop a selection methodology in which the entire detection process takes place in a homogeneous solution, thus eliminating the need for affinity separation. A molecular target is associated with the ribozyme, and library compounds are attached to a barcoded oligonucleotide that is a substrate for the ribozyme ligase. Spatial proximity resulting from specific target-compound interactions increases the probability of ribozyme ligation to the oligo-substrate, thus differentiating the interacting species from the bulk mixture. The covalent link formed between the ribozyme and target-interacting compounds diminishes the mass-action effect on the efficiency with which low-affinity and rare active species are detected. In addition, the magnitude of the detection signal associated with the interaction event renders the methodology an efficient platform for identifying inhibitors of intermolecular interactions. The proposed solution-based tethered ribozyme ligation proximity detection method may facilitate the discovery of target interacting compounds using both library selection and high-throughput screening approaches. PMID- 25511923 TI - Cost-utility analysis of maintenance therapy with gemcitabine or erlotinib vs observation with predefined second-line treatment after cisplatin-gemcitabine induction chemotherapy for advanced NSCLC: IFCT-GFPC 0502-Eco phase III study. AB - BACKGROUND: The IFCT-GFPC 0502 phase III study reported prolongation of progression-free survival with gemcitabine or erlotinib maintenance vs. observation after cisplatin-gemcitabine induction chemotherapy for advanced non small-cell lung cancer (NSCLC). This analysis was undertaken to assess the incremental cost-effectiveness ratio (ICER) of these strategies for the global population and pre-specified subgroups. METHODS: A cost-utility analysis evaluated the ICER of gemcitabine or erlotinib maintenance therapy vs. observation, from randomization until the end of follow-up. Direct medical costs (including drugs, hospitalization, follow-up examinations, second-line treatments and palliative care) were prospectively collected per patient during the trial, until death, from the primary health-insurance provider's perspective. Utility data were extracted from literature. Sensitivity analyses were conducted. RESULTS: The ICERs for gemcitabine or erlotinib maintenance therapy were respectively 76,625 and 184,733 euros per quality-adjusted life year (QALY). Gemcitabine continuation maintenance therapy had a favourable ICER in patients with PS = 0 (52,213 ?/QALY), in responders to induction chemotherapy (64,296 ?/QALY), regardless of histology (adenocarcinoma, 62,292 ?/QALY, non adenocarcinoma, 83,291 ?/QALY). Erlotinib maintenance showed a favourable ICER in patients with PS = 0 (94,908 ?/QALY), in patients with adenocarcinoma (97,160 ?/QALY) and in patient with objective response to induction (101,186 ?/QALY), but it is not cost-effective in patients with PS =1, in patients with non adenocarcinoma or with stable disease after induction chemotherapy. CONCLUSION: Gemcitabine- or erlotinib-maintenance therapy had ICERs that varied as a function of histology, PS and response to first-line chemotherapy. PMID- 25511926 TI - Thin-film electroencephalographic electrodes using multi-walled carbon nanotubes are effective for neurosurgery. AB - BACKGROUND: Intraoperative morphological and functional monitoring is essential for safe neurosurgery. Functional monitoring is based on electroencephalography (EEG), which uses silver electrodes. However, these electrodes generate metal artifacts as silver blocks X-rays, creating white radial lines on computed tomography (CT) images during surgery. Thick electrodes interfere with surgical procedures. Thus, thinner and lighter electrodes are ideal for intraoperative use. METHODS: The authors developed thin brain electrodes using carbon nanotubes that were formed into thin sheets and connected to electrical wires. RESULTS: The nanotube sheets were soft and fitted the curve of the head very well. When attached to the head using paste, the impedance of the newly developed electrodes was 5 kOmega or lower, which was similar to that of conventional metal electrodes. These electrodes can be used in combination with intraoperative CT, magnetic resonance imaging (MRI), or cerebral angiography. Somatosensory-evoked potentials, auditory brainstem responses, and visually evoked potentials were clearly identified in ten volunteers. The electrodes, without any artifacts that distort images, did not interfere with X-rays, CT, or MR images. They also did not cause skin damage. CONCLUSIONS: Carbon nanotube electrodes may be ideal for neurosurgery. PMID- 25511927 TI - New insights of Sacbrood virus. PMID- 25511930 TI - Optimising electron holography in the presence of partial coherence and instrument instabilities. AB - Off-axis electron holography provides a direct means of retrieving the phase of the wavefield in a transmission electron microscope, enabling measurement of electric and magnetic fields at length scales from microns to nanometers. To maximise the accuracy of the technique, it is important to acquire holograms using experimental conditions that optimise the phase resolution for a given spatial resolution. These conditions are determined by a number of competing parameters, especially the spatial coherence and the instrument instabilities. Here, we describe a simple, yet accurate, model for predicting the dose rate and exposure time that give the best phase resolution in a single hologram. Experimental studies were undertaken to verify the model of spatial coherence and instrument instabilities that are required for the optimisation. The model is applicable to electron holography in both standard mode and Lorentz mode, and it is relatively simple to apply. PMID- 25511931 TI - Dose limited reliability of quantitative annular dark field scanning transmission electron microscopy for nano-particle atom-counting. AB - Quantitative annular dark field scanning transmission electron microscopy (ADF STEM) has become a powerful technique to characterise nano-particles on an atomic scale. Because of their limited size and beam sensitivity, the atomic structure of such particles may become extremely challenging to determine. Therefore keeping the incoming electron dose to a minimum is important. However, this may reduce the reliability of quantitative ADF STEM which will here be demonstrated for nano-particle atom-counting. Based on experimental ADF STEM images of a real industrial catalyst, we discuss the limits for counting the number of atoms in a projected atomic column with single atom sensitivity. We diagnose these limits by combining a thorough statistical method and detailed image simulations. PMID- 25511929 TI - Importance of genetics in fetal alcohol effects: null mutation of the nNOS gene worsens alcohol-induced cerebellar neuronal losses and behavioral deficits. AB - The cerebellum is a major target of alcohol-induced damage in the developing brain. However, the cerebella of some children are much more seriously affected than others by prenatal alcohol exposure. As a consequence of in utero alcohol exposure, some children have substantial reductions in cerebellar volume and corresponding neurodevelopmental problems, including microencephaly, ataxia, and balance deficits, while other children who were exposed to similar alcohol quantities are spared. One factor that likely plays a key role in determining the impact of alcohol on the fetal cerebellum is genetics. However, no specific gene variant has yet been identified that worsens cerebellar function as a consequence of developmental alcohol exposure. Previous studies have revealed that mice carrying a homozygous mutation of the gene for neuronal nitric oxide synthase (nNOS-/- mice) have more severe acute alcohol-induced neuronal losses from the cerebellum than wild type mice. Therefore, the goals of this study were to determine whether alcohol induces more severe cerebellum-based behavioral deficits in nNOS-/- mice than in wild type mice and to determine whether these worsened behavior deficits are associated with worsened cerebellar neuronal losses. nNOS-/- mice and their wild type controls received alcohol (0.0, 2.2, or 4.4mg/g) daily over postnatal days 4-9. In adulthood, the mice underwent behavioral testing, followed by neuronal quantification. Alcohol caused dose related deficits in rotarod and balance beam performance in both nNOS-/- and wild type mice. However, the alcohol-induced behavioral deficits were substantially worse in the nNOS-/- mice than in wild type. Likewise, alcohol exposure led to losses of Purkinje cells and cerebellar granule cells in mice of both genotypes, but the cell losses were more severe in the nNOS-/- mice than in wild type. Behavioral performances were correlated with neuronal number in the nNOS-/- mice, but not in wild type. Thus, homozygous mutation of the nNOS gene increases vulnerability to alcohol-induced cerebellar dysfunction and neuronal loss. nNOS is the first gene identified whose mutation worsens alcohol-induced cerebellar behavioral deficits. PMID- 25511934 TI - Anterior knee pain. PMID- 25511932 TI - Educational interventions to improve prescription and dispensing of antibiotics: a systematic review. AB - BACKGROUND: Excessive and inappropriate antibiotic use contributes to growing antibiotic resistance, an important public-health problem. Strategies must be developed to improve antibiotic-prescribing. Our purpose is to review of educational programs aimed at improving antibiotic-prescribing by physicians and/or antibiotic-dispensing by pharmacists, in both primary-care and hospital settings. METHODS: We conducted a critical systematic search and review of the relevant literature on educational programs aimed at improving antibiotic prescribing and dispensing practice in primary-care and hospital settings, published in January 2001 through December 2011. RESULTS: We identified 78 studies for analysis, 47 in primary-care and 31 in hospital settings. The studies differed widely in design but mostly reported positive results. Outcomes measured in the reviewed studies were adherence to guidelines, total of antibiotics prescribed, or both, attitudes and behavior related to antibiotic prescribing and quality of pharmacy practice related to antibiotics. Twenty-nine studies (62%) in primary care and twenty-four (78%) in hospital setting reported positive results for all measured outcomes; fourteen studies (30%) in primary care and six (20%) in hospital setting reported positive results for some outcomes and results that were not statistically influenced by the intervention for others; only four studies in primary care and one study in hospital setting failed to report significant post-intervention improvements for all outcomes. Improvement in adherence to guidelines and decrease of total of antibiotics prescribed, after educational interventions, were observed, respectively, in 46% and 41% of all the reviewed studies. Changes in behaviour related to antibiotic-prescribing and improvement in quality of pharmacy practice was observed, respectively, in four studies and one study respectively. CONCLUSION: The results show that antibiotic use could be improved by educational interventions, being mostly used multifaceted interventions. PMID- 25511933 TI - Irregular transcriptome reprogramming probably causes thec developmental failure of embryos produced by interspecies somatic cell nuclear transfer between the Przewalski's gazelle and the bovine. AB - BACKGROUND: Interspecies somatic cell nuclear transfer (iSCNT) has been regarded as a potential alternative for rescuing highly endangered species and can be used as a model for studying nuclear-cytoplasmic interactions. However, iSCNT embryos often fail to produce viable offspring. The alterations in normal molecular mechanisms contributing to extremely poor development are for the most part unknown. RESULTS: Przewalski's gazelle-bovine iSCNT embryos (PBNT) were produced by transferring Przewalski's gazelle fibroblast nuclei into enucleated bovine oocytes. The percentages of PBNT embryos that developed to morula/blastocyst stages were extremely low even with the use of various treatments that included different SCNT protocols and treatment of embryos with small molecules. Transcriptional microarray analyses of the cloned embryos showed that the upregulation of reprogramming-associated genes in bovine-bovine SCNT (BBNT) embryos was significantly higher than those observed in PBNT embryos (1527:643). In all, 139 transcripts related to various transcription regulation factors (TFs) were unsuccessfully activated in the iSCNT embryos. Maternal degradation profiles showed that 1515 genes were uniquely downregulated in the BBNT embryos, while 343 genes were downregulated in the PBNT embryos. Incompatibilities between mitochondrial DNA (mtDNA) and nuclear DNA revealed that the TOMM (translocase of outer mitochondrial membrane)/TIMM (translocase of inner mitochondrial membrane) complex-associated genes in BBNT embryos had the highest expression levels, while the PBNT embryos exhibited much lower expression rates. CONCLUSIONS: Improper degradation of maternal transcripts, incomplete activation of TFs and abnormal expression of genes associated with mitochondrial function in PBNT embryos likely contributed to incomplete reprogramming of the donor cell nuclei and therefore led to the developmental failure of these cloned embryos. PMID- 25511936 TI - Drop transfer between superhydrophobic wells using air logic control. AB - Superhydrophobic surfaces aid biochemical analysis by limiting sample loss. A system based on wells here tolerated tilting up to 20 degrees and allowed air logic transfer with evidence of mixing. Conditions for intact transfer on 15 to 60 MUL drops using compressed air pressure operation were also mapped. PMID- 25511935 TI - Percutaneous CT-guided cryoablation for the treatment of refractory pudendal neuralgia. AB - PURPOSE: To evaluate the safety and efficacy of percutaneous CT-guided cryoablation of the pudendal nerve for the treatment of refractory pudendal neuralgia. MATERIALS AND METHODS: Eleven patients were selected to undergo percutaneous CT-guided cryoablation of the pudendal nerve based on established diagnostic criteria. Brief Pain Inventory questionnaires were administered prior to the procedure, during the immediate 24 h post procedure, and 45 days and 6 months following the procedure. RESULTS: Prior to treatment, the average level of pain on a scale from 0 (no pain) to 10 (worst pain imaginable) was 7.6, with pain described as "burning" (80%), "pulling" (37.5%), "crushing" (50%), "pressure" (84.5%), "throbbing" (50%), "knife-life" (52%), and "other" (60%). At 24 h, 45 days, and 6 months post-treatment, pain intensity dropped to 2.6, 3.5, and 3.1, respectively (p < 0.005). There were no procedure-related complications. CONCLUSIONS: CT-guided percutaneous cryoablation may represent a safe and efficacious option for selected patients with refractory pudendal neuralgia. PMID- 25511937 TI - Susceptibility-Weighted Phase Imaging and Oxygen Extraction Fraction Measurement during Sedation and Sedation Recovery using 7T MRI. AB - BACKGROUND & PURPOSE: In this work, we demonstrate oxygen extraction fraction (OEF) measurement using 7T MRI with susceptibility-weighted imaging (SWI), in sedated and nonsedated adults. METHODS: Ten healthy subjects (30.3 +/- 4.5 years, 9 men, 1 woman) formed control (n = 5) and sedation groups (n = 5). Midazolam and propofol injection was administered to the same sedation group subjects during 2 different scanning sessions. Two-dimensional SPGR imaging was performed before, during, and twice after (propofol, +10, +30 minutes; midazolam, +10, +40 minutes) conscious sedation. The equivalent procedure was performed with the control group without sedation. After SWI analysis, change in OEF between scans was quantified, and parcelated DeltaOEF maps were generated with 77 gray matter (GM)-containing volumes-of-interest (VOIs). RESULTS: Significant decreases in OEF were shown in 14 GM VOIs during sedation relative to the control group, most notably during midazolam sedation (P < .05). In contrast, no significant decrease was observed after 10 minutes and in only 4 VOIs after 40 minutes recovery. CONCLUSION: Significant change in DeltaOEF during conscious sedation using midazolam and propofol could be measured using SWI at 7T in vivo. This may be a potentially useful approach for the noninvasive assessment of OEF in the brain on a clinical basis. PMID- 25511938 TI - [Perioperative complications of transurethral resection of bladder tumor in patients receiving antithrombotic therapy]. AB - We examined perioperative complications of transurethral resection of bladder tumor (TURBT) in patients receiving antithrombotic therapy. We retrospectively studied 276 patients who underwent TURBT in our institute from January 2007 to March 2013. The study group consisted of 105 patients (38%) who were receiving antithrombotic agents, and the other 171 patients (62%) without antithrombotic agents were assigned to the control group. The period of discontinuation of antithrombotic agents complied with our institutional rule. The most frequently used agent was aspirin (69 patients : 66%), followed by warfarin (25 patients : 24%). Fourteen patients receiving warfarin (56%) needed heparin bridging therapy. There was no significant difference in average operative time (51 minutes versus 54 minutes), or average days to removal of urethral catheter (3.7 days versus 3.3 days) between the study and control groups. Hemorrhagic and ischemic complications were noted in 11 (10.5%) and 2 (1.9%) patients in the study group and 11 (6.4%) and none (0%) of the patients in the control group, respectively, with no significant difference between the 2 groups. However, prevalence of hemorrhagic complications in patients receiving heparin bridging therapy (21.4%) was significantly higher than that in the control group. Ischemic complications in the study group included chest pain suggestive of angina in one patient and acute myocardial infarction leading to death in another patient. We should pay attention to hemorrhagic complications in patients receiving heparin bridging therapy and keep in mind the possibility of lethal ischemic complications after discontinuation of antithrombotic agents. PMID- 25511939 TI - [Assessing the effect of subcuticular buried sutures with subcutaneous closed suction drain to prevent surgical site infection in patients undergoing total cystectomy with urinary diversion using intestine]. AB - We assessed the effect of subcuticular buried sutures with subcutaneous closed suction drain to prevent surgical site infection (SSI) in patients undergoing total cystectomy with urinary diversion using the intestine. We reviewed the clinical charts of 43 consecutive patients who underwent total cystectomy with urinary diversion using the intestine from February 2006 to March 2011 at Nishi Kobe Medical Center. All patients received intravenous prophylactic antibiotics before and throughout surgery as well as for three days after surgery. Skin closure was performed with interrupted vertical mattress sutures with 2-0 nylon on the first 22 patients (mattress group), and with interrupted subcuticular buried sutures with 4-0 absorbable monofilament with subcutaneous closed suction drain on the remaining 21 patients (subcuticular buried suture with subcutaneous drain; SBD group). SSI occurred in 7 (31.8%) patients in the mattress group, but did not affect any patient in the SBD group. We compared risk factors for SSI between the groups, and found that the method of skin closure was significant risk factor for SSI (P = 0.005). We concluded that interrupted subcuticular buried sutures with 4-0 absorbable monofilament with subcutaneous suction drain is effective for prevention of SSI in total cystectomy with urinary diversion using the intestine. PMID- 25511940 TI - [Development of a preoperative criterion to select candidates for nerve-sparing radical prostatectomy at Kyoto University Hospital]. AB - Neurovascular bundle (NVB) preservation is a mandatory procedure to maintain erectile function of localized prostate cancer patients after radical prostatectomy (RP). However, in terms of cancer control, indications to select appropriate patients for nerve-sparing RP are still controversial. In this study, we examined the pathological findings of RP specimens to develop a preoperative criterion for NVB preservation during RP. The study included 76 patients who underwent RP at our institution from 2006 to 2008, and we retrospectively analyzed RP specimens pathologically. The distance between NVB and foci of prostate cancer was measured in 135 prostate sides, and preoperative factors which predict the distance of <=2 mm was evaluated. Univariate analysis showed that side-specific positive biopsy core rate >=33.3%, side-specific maximum tumor length in biopsy core >=5 mm and side-specific tumor involvement rate in biopsy core >=50% was associated with the risk of the distance of <=2 mm. Multivariate analysis revealed that side-specific positive biopsy core rate >=33.3% was the only significant predictor of the ipsilateral NVB-tumor distance <=2 mm (p = 0.0055, odds ratio 3.49). Based on this study, a nerve-sparing criterion of <33.3% side-specific percent positive biopsy core was developed at our institution. Prospective data on patients who were applied this criterion are needed to evaluate its clinical safety and feasibility. PMID- 25511941 TI - [Unilateral synchronous occurrence of renal pelvic urothelial carcinoma and renal cell carcinoma : report of two cases]. AB - Two cases of unilateral synchronous occurrence of renal pelvic urothelial carcinoma and renal cell carcinoma are presented. Case 1 : A 70-year-old woman presented with macroscopic hematuria. Retroperitoneoscopic nephroureterectomy was performed under the diagnosis of renal pelvic carcinoma. Pathological diagnosis was not only renal pelvic urothelial carcinoma but also renal cell carcinoma 1.5*0.5 mm in diameter. Case 2 : A 79-year-old man with hormonal therapy for prostate cancer complained of macroscopic hematuria. Right nephroureterectomy was performed under the diagnosis of right renal pelvic carcinoma and right renal cell carcinoma. Pathological findings were the same as preoperative diagnosis. To our knowledge, 21 cases of unilateral synchronous occurrence of renal pelvic urothelial carcinoma and renal cell carcinoma have been reported in the Japanese literature including our cases and the clinical features are reviewed. PMID- 25511942 TI - [Case of inflammatory pseudotumor occurring in the renal pelvis]. AB - Inflammatory pseudotumor most commonly involves the lung. However, inflammatory pseudotumor has been reported in various sites in the abdomen, including the kidneys, retroperitoneum and urinary tract. We present a rare case of pathologically proven inflammatory pseudotumor in the renal pelvis. A 45-year-old woman was referred to our hospital with gross hematuria. Computed tomography demonstrated a mass around the right renal pelvocalyceal system suggestive of cystic renal cell carcinoma. Retrogradepyelography was done. Pelvic urine cytology was class III. The possibility of urothelial carcinoma could not be denied. Retroperitoneoscopic nephroureterectomy with open bladder cuff excision was performed. The histological examination revealed an inflammatory pseudotumor. She showed no evidence of disease 44 months after the operation. PMID- 25511943 TI - [Paraganglioma of the bladder : two case reports]. AB - Case 1. A 48-year-old man with no history of hypertension was referred to our hospital with a 1 cm bladder tumor. According to cystoscopy, magnetic resonance imaging and 131I-MIBG scintigraphy, we diagnosed it as a paraganglioma of the bladder. Partial cystectomy was performed. The histological findings supported the diagnosis of paraganglioma of the bladder. Six years later, he was free of any evidence of recurrence. Case 2. A 64-year-old woman with hypertension was pointed out to have a 1cm bladder mass by ultrasound in a health examination. She was referred to our hospital for further examination. Cystoscopoy revealed a 1 cm intramural nodule covered by intact urothelium at the right posterior wall. Submucosal bladder tumor was not diagnosed as paraganglioma by cold punch biopsy. So, transurethral resection of the bladder tumor was performed for differential diagnosis. The tumor was hypervascular and involved the muscular layer of the bladder. Although a transient elevation of blood pressure occurred during the procedure, the tumor was resected as completely as possible. The histological diagnosis was paraganglioma of the bladder. She has been followed up for 27 months after operation without any evidence of recurrence. PMID- 25511944 TI - [Suicide attempt by an interstitial cystitis patient : a case report]. AB - We report a suicide attempt by an interstitial cystitis patient. A 68-year-old woman consulted several clinics with complaints of urinary frequency and bladder pain, but her symptoms did not improve. She was admitted to our hospital and diagnosed with interstitial cystitis. Hydrodistention was performed, and the urethral catheter removed one day after surgery. The next day, the patient was afraid that her symptoms had not improved and, due to this physical and mental distress, cut her wrist with a razor. Vascular anastomosis and neuroanastomosis were performed accordingly. Eighteen months after hydrodistention, the patient's symptoms of interstitial cystitis have much improved. PMID- 25511945 TI - [Case of primary malignant melanoma of the female urethra at age 94 : a case report]. AB - A 94-year-old woman visited a local urological clinic in January 2011 complaining of dysuria and vulvar discomfort that lasted for a month. Clinical examination showed a hematoma-like tumor at the external urethral meatus. She refused an operation. After 2 months, the tumor became hemorrhagic and she was referred to our hospital for operation. A black tumor of fingertip-size was seen at the external urethral meatus. Urinary sediment examination and urine cytology revealed malignant melanoma cells. The tumor showed T1WI high intensity, and T2WI low intensity by magnetic resonance imaging. Collectively, the patient was diagnosed with malignant melanoma. The tumor was extirpated. Pathological diagnosis showed malignant nodular melanoma. However, additional therapy was not performed due to her age and thereafter, the patient was followed up carefully. After 3 months, right inguinal LN swelled, and tumor recurred at the external urethral meatus. She died from multiple metastases 11 months from the initial consultation. We herein report this case of primary malignant melanoma of the female urethra in an elderly patient. PMID- 25511946 TI - [Case of portal venous gas and pneumatosis cystoides intestinalis occurring during chemotherapy for a castration-resistant prostate cancer]. AB - Portal venous gas is a rare complication. We present a case of hepatic portal venous gas (HPVG) and pneumatosis cystoides intestinalis (PCI) in a patient treated with docetaxel for prostate cancer. An 80-year-old man with castration resistant prostate cancer received 5 cycles of docetaxel. Diarrhea and vomiting appeared on the 4th day of the 5th cycle. An abdominal computed tomography (CT) scan revealed HPVG and PCI. Since there were neither peritoneal irritation signs nor intestinal necrosis, we performed conservative management. The HPVG and PCI were no longer detected in the abdominal CT scan on the 18th day. Mucosal injury of the bowel wall by docetaxel might have caused HPVG and PCI. This case report is the first description of HPVG and PCI in a patient with castration-resistant prostate cancer in Japan. PMID- 25511947 TI - [Leiomyosarcoma of the prostate treated with neoadjuvant intra-arterial chemotherapy and pelvic excenteration ; a case report]. AB - A 34-year-old man presented with left inguinal discomfort. Digital rectal examination revealed an enlarged nodular prostate. Computed tomography showed an enlarged prostate invading the bladder and rectum. A histological examination of transrectal prostatic needle biopsy specimens revealed sarcoma of the prostate. He received three courses of neoadjuvant arterial injection chemotherapy consisting of adriamycin (30 mg/m2) and cisplatin (70 mg/m2). Total pelvic excenteration was perfomed. Histopathological examination of the tumor revealed leiomyosarcoma of the prostate. He remains alive 11 months after the operation without recurrence. PMID- 25511948 TI - [Case of azoospermia patient with a chromosomal abnormality considered a ring Y chromosome]. AB - A 43-year-old man came to our clinic complaining of infertility and semen analysis showed azoospermia. Analysis of chromosomes showed a mosaic 45, XO/46, X, +mar1/46, X, +mar2 karyotype, and the marker chromosomes were considered to be two kinds of ring Y chromosomes. Y chromosome microdeletion analysis showed partial deletion of Azoospermic Factor (AZF) a, and complete deletion of AZFb and AZFc. The patient gave up having a child because these results indicated that no sperm would be collected even if Testicular Sperm Extraction (TESE) were performed. PMID- 25511949 TI - [Case of primary scrotal sclerosing lipogranuloma : review of 227 cases reported in Japan]. AB - We report a case of primary scrotal sclerosing lipogranuloma. A 39-year-old man who had complained of a painless intrascrotal mass was introduced to our hospital for detailed examinations. He denied having received any injection of exogenous substances or having suffered from any trauma. Physical examination revealed a U shaped elastic hard mass surrounding the penile shaft in the scrotum. T2-weighted magnetic resonance imaging (MRI) demonstrated an ill-defined U-shaped lesion which exhibited relatively low signal intensity. Primary scrotal sclerosing lipogranuloma was the most suspected. The mass gradually disappeared after 47 days from tumor open biopsy for definitive diagnosis. We found 227 cases reported in Japan, and we discuss the diagnosis, treatment and clinical features with reference to previous reports. PMID- 25511951 TI - Influencing your government. PMID- 25511950 TI - [Case of Behcet's disease diagnosed by bilateral epididymitis]. AB - A 24-year-old man visited our emergency room with testicular pain and left shoulder pain, and was admitted to our hospital for diagnosis of bilateral epididymitis. Antibiotics and anti-inflammatory medication were started, but the symptoms did not improve. During hospitalization, ulcerous lesions, erythema nodosum, folliculitis-like exanthema and multiple oral aphtha appeared. Then, we consulted the department of dermatology. As he had a combination of arthritis and epididymitis, he was diagnosed with the abortive form of Behcet's disease. After diagnosis, we began administering colchicine. Then, all symptoms improved in a few days, and he has remained free of the disease after the discontinuation of colchicine. PMID- 25511952 TI - Re: C-terminal cross-linking telopeptide test-based protocol for patients on oral bisphosphonates requiring extractions: a prospective single-center controlled study. PMID- 25511953 TI - Is oral cancer unique in terms of chemotherapeutic and targeted drug metabolism? PMID- 25511954 TI - Use of computer-assisted templates for placement of osteotomies in lateral gap arthroplasty. AB - PURPOSE: To evaluate the effectiveness of computer-generated surgical templates for precise bone removal in the treatment of temporomandibular joint (TMJ) ankylosis with a medially displaced condyle. MATERIALS AND METHODS: Patients found to have a medially displaced condylar head and lateral bony fusion from January 2012 through January 2014 were included in the study. ProPlan CMF 1.4 software (Materialise Medical, Leuven, Belgium) was used to design the osteotomies for the lateral bony fusion and protect the medial condylar head. Surgical templates were fabricated to transfer the design to the operation and effectiveness was evaluated postoperatively using computed tomographic (CT) scan comparisons. RESULTS: In 5 surgeries with a total of 7 joints, the surgical templates fit well and accurately guided the osteotomies. The skull base, external auditory canal, major vessels, and residual condyle were well protected. Postoperative CT difference analysis calculated an average difference of 1.044 mm. CONCLUSIONS: Computer-assisted surgical templates accurately guided bone removal and protected the residual condylar head, skull base, and external auditory canal in the treatment of TMJ ankylosis. PMID- 25511955 TI - Midline submental intubation might be the preferred alternative to oral and nasal intubation in elective oral and craniomaxillofacial surgery when indicated. AB - PURPOSE: No consensus exists to date regarding the best method of controlling the airway for oral or craniomaxillofacial surgery when orotracheal and nasotracheal intubations are unsuccessful or contraindicated. The most commonly used method of tracheostomy has been associated with a high degree of morbidity. Therefore, the present study was conducted to determine the indications, safety, efficacy, time required, drawbacks, complications, and costs of the midline submental intubation (SMI) approach in elective oral and craniomaxillofacial surgical procedures. MATERIALS AND METHODS: A retrospective case series study was used to evaluate the surgical, financial, and photographic records of all patients who had undergone oral or craniomaxillofacial operations at Sharda University School of Dental Sciences, Greater Noida, from April 2006 to March 2014. The indications, drawbacks, time required for the procedure, ability to provide a secure airway, intra- and postoperative complications, and additional costs associated with SMI were analyzed. RESULTS: Of the 2,823 patients treated, the present study included 120 patients (97 men and 23 women, aged 19 to 60 years). The average time required for SMI was 10 +/- 2 minutes. No episode of intraoperative oxygen desaturation was noted. One intraoperative complication, an injury to the ventral surface of the tongue, was encountered. Two patients developed infection at the skin incision site. No significant additional cost was incurred with the use of SMI. CONCLUSIONS: SMI has been successfully used in elective oral and craniomaxillofacial surgical procedures for which oral and nasal intubations were either not indicated or not possible. The advantages include a quick procedure, insignificant complications, the ability to provide a stable airway, and no added costs, making SMI a quick, safe, efficient, and cost-effective alternative in such cases. PMID- 25511956 TI - Temporal correlation between bisphosphonate termination and symptom resolution in osteonecrosis of the jaw: a pooled case report analysis. AB - PURPOSE: To investigate whether termination of bisphosphonates (BPs) affects resolution of bone exposure and symptomatic disease in patients with established medication-related osteonecrosis of the jaw (MRONJ). PATIENTS AND METHODS: The studied population included 84 patients with established MRONJ who discontinued BP therapy before treatment (n = 21), at treatment initiation (n = 38), or later (or never) in the treatment course (n = 25). These 3 groups were compared using Kaplan-Meier curves and log-rank tests for differences in the respective times to resolution of 1) bone exposure for any treatment modality, 2) bone exposure not requiring radical surgery, and 3) disease symptoms. RESULTS: Patients who continued BPs after the start of treatment exhibited significantly delayed resolution of symptoms (median 12 months; 95% confidence interval 8 to 15) compared with those who discontinued BPs before (3 months; 2 to 5) and at (6 months; 3 to 7) presentation (P < .005). CONCLUSIONS: Independent of treatment modality and MRONJ stage at presentation, discontinuing BP before or at treatment initiation is associated with faster resolution of MRONJ symptoms compared with continuing the drug throughout jaw treatment. Patients should be counseled that continuing their BP medication after an established MRONJ diagnosis (compared to stopping the BP at diagnosis) may delay resolution of maxillofacial symptoms by approximately 6 months. PMID- 25511957 TI - Concomitant treatment of mandibular ameloblastoma and bilateral temporomandibular joint osteoarthritis with bone graft and total joint prostheses. AB - Temporomandibular joint (TMJ) osteoarthritis is a degenerative disease that can create clinical problems in the masticatory musculature, jaws, occlusion, and other associated structures and is commonly accompanied by inflammatory changes and pain. Many cases of TMJ dysfunction can be managed with nonsurgical therapies, but patients with irreversible TMJ damage may require surgical intervention for repair or reconstruction. Despite various methods of TMJ reconstruction, the patient-fitted total joint prostheses may be the best option to achieve good outcomes. Multicystic ameloblastoma is a benign odontogenic neoplasm of the jaws that is found most often in the mandible, in the region of the molars, and the ramus. Ameloblastomas usually progress slowly, but are locally invasive and may cause significant morbidity and sometimes death. This report describes a case of concomitant treatment of recurrent mandibular ameloblastoma and severe bilateral TMJ osteoarthritis treated by resection of the tumor, reconstruction with bone grafting, and bilateral TMJ reconstruction in a 63-year-old woman. PMID- 25511958 TI - Frequency and distribution pattern of minor salivary gland tumors in a northeastern Chinese population: a retrospective study of 485 patients. AB - PURPOSE: The relative frequency of individual minor salivary gland tumors (MSGTs) is not well documented in the literature. The aim of this study was to determine the range and demographics of all histologically diagnosed MSGTs in a northeastern Chinese population. MATERIALS AND METHODS: A total of 485 cases of MSGT were retrospectively studied. The files of the Department of Oral and Maxillofacial Pathology, School of Stomatology, China Medical University served as a source of material for this study. All epithelial tumors from minor salivary glands accessioned from August 2004 to April 2014 were analyzed for demographic features, anatomic location of tumors, and pathologic classification. Tumors were classified according to the 2005 World Health Organization classification of salivary gland tumors. Statistical analysis was performed using analysis of variance. RESULTS: MSGTs were identified in 485 (2.60%) of 18,670 accessed cases. There were 268 (55.26%) benign and 217 (44.74%) malignant tumors. Female outnumbered male patients (male-to-female ratio, 1:1.43). The mean ages of patients with benign and malignant MSGTs were 47.58 and 51.51 years, respectively. Pleomorphic adenoma and adenoid cystic carcinoma were the most frequent types of benign and malignant tumors, respectively. The palate was the most commonly affected site (64.74%), followed by the buccal mucosa (7.63%) and the tongue (5.98%). CONCLUSIONS: From the results of this study and a review of the literature, it is suggested that MSGTs in the northeastern Chinese population may be characterized by a higher incidence of MSGTs than in the populations of other reviewed regions, a higher incidence of myoepithelioma, a rarer occurrence of polymorphous low-grade adenocarcinoma, and an absence of canalicular adenoma occurrence. PMID- 25511960 TI - Lipomas of the submandibular space: case report of a sialolipoma and review of diagnostic investigations available. AB - This report describes and discusses the radiologic investigations available for the investigation of fatty tumors of the submandibular triangle, with a focus on sialolipomas. A 33-year-old woman presented with a 3-year history of a slowly growing, painless mass in her right submandibular region. She underwent multiple imaging modalities before having a histologic diagnosis of a sialolipoma. To the best of the authors' knowledge, this is the first reported case using ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) for investigation of a sialolipoma of the submandibular gland region. Ultrasound and fine-needle aspiration offer a tentative diagnosis of a lipoma without the associated radiation and cost associated with CT and MRI, respectively. CT and MRI offer the definite diagnosis of a lipoma, with MRI depicting better delineation and the ability to identify glandular elements of the tumor. Importantly, the development of sarcomatous change within the lipoma cannot be out ruled at imaging and requires a histologic specimen. PMID- 25511959 TI - Comprehensive therapy for hemangioma presenting with Kasabach-Merritt syndrome in the maxillofacial region. AB - PURPOSE: To summarize the characteristics of Kasabach-Merritt syndrome (KMS) and to evaluate the therapeutic effect of drug therapy combined with transarterial embolization. PATIENTS AND METHODS: From 2007 to 2011, 6 cases of KMS that underwent drug therapy and transarterial embolization were retrospectively analyzed, comprising of 3 male and 3 female patients; the ages of the patients ranged from 3 to 40 days. The lesions were located in the temporal region (1 of 6, 16.7%), parotid region (2 of 6, 33.3%), or submandibular region and neck (3 of 6, 50%). All the patients were followed for 12 to 18 months. Therapeutic outcomes were assessed by evaluating the platelet count, coagulation parameters, and size of the lesion. RESULTS: Positive responses were visible shrinkage of the hemangioma or lightening of the skin color of the cutaneous tumor (or both) within 8 to 72 hours in 4 patients (66.67%). These occurred within 1 week in 5 patients (83.33%) and within 2 weeks in all patients (100%). The mean platelet count before treatment was 18,000/L (range, 8,000 to 33,000/L). After the first week of medical treatment, the mean platelet count increased to above 80,000/L in 5 patients (83.33%); it began to increase on the second day after embolization and reached 102,000/L in 1 patient (16.67%). All 6 cases (100%) showed good results with treatment. A 12- to 18-month follow-up evaluation was obtained for all treated patients, and no rebound growth or platelet count decreases were observed. No severe or obvious adverse complications were noted during all treatment courses. CONCLUSIONS: For most hemangiomas presenting with KMS, good results can be obtained with systemic medical treatment. Transcatheter arterial embolization with polyvinyl alcohol particles combined with systemic medical treatment should be considered an efficacious and important therapeutic option for challenging cases. PMID- 25511961 TI - Combat-related facial burns: analysis of strategic pitfalls. AB - PURPOSE: Burns constitute approximately 10% of all combat-related injuries to the head and neck region. We postulated that the combat environment presents unique challenges not commonly encountered among civilian injuries. The purpose of the present study was to determine the features commonly seen among combat facial burns that will result in therapeutic challenges and might contribute to undesired outcomes. MATERIALS AND METHODS: The present study was a retrospective study performed using a query of the Burn Registry at the US Army Institute of Surgical Research Burn Center for all active duty facial burn admissions from October 2001 to February 2011. The demographic data, total body surface area of the burn, facial region body surface area involvement, and dates of injury, first operation, and first facial operation were tabulated and compared. A subset analysis of severe facial burns, defined by a greater than 7% facial region body surface area, was performed with a thorough medical record review to determine the presence of associated injuries. RESULTS: Of all the military burn injuries, 67.1% (n = 558) involved the face. Of these, 81.3% (n = 454) were combat related. The combat facial burns had a mean total body surface area of 21.4% and a mean facial region body surface area of 3.2%. The interval from the date of the injury to the first operative encounter was 6.6 +/- 0.8 days and was 19.8 +/- 2.0 days to the first facial operation. A subset analysis of the severe facial burns revealed that the first facial operation and the definitive coverage operation was performed at 13.45 +/- 2.6 days and 31.9 +/- 4.1 days after the injury, respectively. The mortality rate for this subset of patients was 32% (n = 10), with a high rate of associated inhalational injuries (61%, n = 19), limb amputations (29%, n = 9), and facial allograft usage (48%, n = 15) and a mean facial autograft thickness of 10.5/1,000th in. CONCLUSIONS: Combat-related facial burns present multiple challenges, which can contribute to suboptimal long-term outcomes. These challenges include prolonged transport to the burn center, delayed initial intervention and definitive coverage, and a lack of available high-quality color-matched donor skin. These gaps all highlight the need for novel anti-inflammatory and skin replacement strategies to more adequately address these unique combat-related obstacles. PMID- 25511962 TI - Simple computed tomography-based calculations of orbital floor fracture defect size are not sufficiently accurate for clinical use. AB - PURPOSE: The precise computed tomography-based calculation of the size of an orbital floor (OF) fracture defect is tedious and time-consuming. The aims of this study were to evaluate the accuracy of simple, rapid methods of calculating OF fracture defect size and to determine their suitability for clinical use. MATERIALS AND METHODS: A retrospective review of the electronic medical records of patients with OF fractures presenting to Baylor Scott and White Hospital between October 2009 and April 2013 was performed. True OF defect sizes (the outcome variable) were calculated using a previously validated formula, on the basis of measurements obtained from coronally reformatted thin (<3-mm) axial computed tomographic images. Estimated OF defect sizes (the predictor variable) were calculated using geometric area formulas, assuming that the defect approximated the shape of an ellipse, circle, square, or rectangle on the basis of measurements obtained from coronal and sagittal computed tomographic images. Accuracy, sensitivity, specificity, and negative and positive predictive values in declaring a defect critical were determined for each method. RESULTS: Ninety nine patients with OF fractures were identified (69 men, 30 women; mean age = 46.9 years); 55 patients had a true OF defects of critical (>=2 cm(2)) or greater size. Geometric formulas showed ranges of accuracy (0.76 to 0.93), sensitivity (0.62 to 1.0), and specificity (0.63 to 0.91). The accuracy of defect size approximation using the area of an ellipse was highest. CONCLUSIONS: The geometric formulas estimated OF defect area with good but, in the authors' opinion, clinically unacceptable accuracy. Although highly sensitive, the formulas lacked specificity and tended to overestimate true defect sizes in most cases. Using rapid, simple geometric methods to assess the sizes of OF defects may lead to inappropriate surgical decisions. Thus, the most accurate estimation of OF defect size still requires the calculation of average defect length from coronal computed tomographic images, knowledge of slice thickness, and knowledge of the number of slices involved. PMID- 25511963 TI - Are embrasure wires better than arch bars for intermaxillary fixation? AB - PURPOSE: To compare the outcomes of mandible fractures treated with open reduction and internal fixation versus adjunctive intermaxillary fixation (IMF) using 2 different techniques. MATERIALS AND METHODS: We performed a retrospective medical record review. The medical records of consecutive patients with mandible fractures treated surgically with adjunctive use of IMF (embrasure wires vs arch bars) were reviewed for demographic data, etiology, fracture location, antibiotic use, and interval to repair. Specifically, the complications, including infection, malunion or nonunion, hardware failure, and wound dehiscence, were recorded. The data were analyzed using Student's t test and the chi-square test or Fisher's exact test, as appropriate. Statistical significance was set at P < .05. A descriptive cost analysis was also performed and compared with those from previously published studies. RESULTS: The data from 86 subjects were included in the present study. Of the 86 subjects, 33 were in the embrasure wire group and 53 in the arch bar group. Of the patients in the arch bar group, 26% had complications compared with 15% in the embrasure wire IMF group. No statistically significant difference between the groups in terms of infection (P = .63), hardware failure (P = .75), malocclusion (P = .85), and nonunion (P = 1.0). However, the cost of arch bar placement and removal was approximately $2,672 more than the placement of embrasure wires. CONCLUSIONS: Patients treated with embrasure wire IMF had slightly better clinical outcomes compared with those treated with arch bar IMF. Also, the cost reduction for patients treated with embrasure wire IMF was significant. PMID- 25511964 TI - Modified technique for rehabilitation of facial paralysis using autogenous fascia lata grafts. AB - PURPOSE: In this retrospective study we used a modified surgical technique for midface reanimation in patients with facial nerve paralysis. Facial atonicity can cause functional impairment regarding speech articulation, oral competence, breathing, and eyelid closure. Furthermore, esthetic and psychological aspects play an important role in patients' emotional interaction and social integration. The chosen rehabilitative technique should offer support against prolapse of facial structures and remedy of functional disabilities and, thereby, prevention of social stigmatization due to disease-related changes in appearance. MATERIALS AND METHODS: Between 2005 and 2013, fascia lata grafts were used as static support in 15 cases of unilateral facial paralysis. Two fascia lata grafts were subcutaneously inserted in the upper and lower lips crossing the midline and sutured at 4 points, including the unaffected part of the orbicularis oris muscle and modiolus. The slings were suspended against the zygomatic arch with an osteosynthesis plate. RESULTS: The patients perceived surgery results as considerably improving their appearance, speech, and alimentation. In 93.3% of cases, no postoperative complications occurred. The follow-up results (8 months to 8 years) remained stable. CONCLUSIONS: This retrospective study showed the advantages of static facial reanimation in appropriate cases. The bony fixated support of the fascial slings allows an immediate improvement of facial symmetry. Additional attachment points including the unaffected part of the orbicularis oris muscle and the use of 2 independent fascia lata slings allow a more accurate adjustment of suspension forces and an incomplete dynamic reanimation of the mouth corner. With respect to its simplicity and minimal invasiveness, this surgical procedure is associated with low morbidity and rapid improvement of the patient's esthetic appearance. PMID- 25511965 TI - Stair ascent and descent in assessing donor-site morbidity following osteocutaneous free fibula transfer: a preliminary study. AB - PURPOSE: The aim of this study was to investigate gait kinematic parameters during stair ascent and descent after fibula free flap removal for facial reconstruction. MATERIALS AND METHODS: Eight patients who underwent facial reconstruction with fibula free flap removal ascended and descended 3 standard steps. Their movements were recorded by a motion analyzer; gait kinematic parameters were obtained and compared with those calculated in 8 control subjects. RESULTS: Stride time, percentage of swing, and support phases did not differ among healthy and operated limbs and control subjects (Kruskal-Wallis, P > .05). No significant differences were found for hip and knee movements, pelvis rotation and tilt, and body center of mass displacements. During stair descent, the patients had significantly larger pelvis inclinations than the control subjects (P < .05). CONCLUSIONS: No functional limitations during stair performance were found. The only significant difference could indicate a minor control of the pelvis and should be used to define specific rehabilitative interventions. PMID- 25511966 TI - Use of allogenic (iliac) corticocancellous graft for Le Fort I interpositional defects: technique and results. AB - PURPOSE: We performed a retrospective review of a consecutive series of 50 patients who had undergone Le Fort I with interpositional grafting during a 3 year period. MATERIALS AND METHODS: Maxillary repositioning included horizontal advancement and vertical and transverse change to the extent that an interpositional graft was considered necessary. Allogenic (iliac) corticocancellous bone was used in all cases. Each patient underwent analytic model planning to document the maxillary vector change data points. The recorded data served as an indicator of the osteotomy site gaps requiring grafting. Standardized photographs in centric relation at a minimum of 12 months after treatment were analyzed to measure overjet, overbite, midline position, and first molar lateral occlusion. Specific maxillary region wound healing parameters were reviewed. RESULTS: The patients' mean age at surgery was 32 years (range 15 to 60). Analytic model planning clarified that the study patients had an average of 8 mm horizontal advancement, 2 mm vertical lengthening, and 2 mm of transverse expansion. The data confirmed a favorable occlusion at a minimum of 1 year after surgery with maintenance of a normal overjet (49 of 50 patients, 98%), normal overbite (48 of 50 patients, 96%), planned dental midline positioning (45 of 50 patients, 90%), and ideal first molar lateral occlusion (48 of 50 patients, 96%) for most patients. None of the study patients sustained wound healing complications. Also, no cases of postoperative sepsis or viral illness developed. CONCLUSIONS: The results of the present study have confirmed that iliac corticocancellous allograft has minimal systemic or recipient site complications and can be safely used to fill complex 3-dimensional interpositional defects associated with Le Fort I osteotomy and/or repositioning. PMID- 25511967 TI - Esthetic evaluation of the facial profile in rehabilitated adults with complete bilateral cleft lip and palate. AB - PURPOSE: To assess the facial esthetics of patients with complete bilateral cleft lip and palate, and to compare the judgment of raters related and unrelated to cleft care. MATERIALS AND METHODS: The sample comprised 23 adult patients (7 women and 16 men) with a mean age of 26.1 years, rehabilitated at a single center. Standardized photographs of the right and left facial profile were taken of each patient and subjectively evaluated by 25 examiners: 5 orthodontists and 5 plastic surgeons with expertise in oral cleft rehabilitation, 5 orthodontists and 5 plastic surgeons without expertise in oral cleft rehabilitation, and 5 laypersons. The facial profiles were classified into 3 categories: esthetically unpleasant, esthetically acceptable, and esthetically pleasant. Intraexaminer and interexaminer agreements were evaluated with the Spearman correlation coefficient and Kendall coefficient of concordance. The differences between rater categories were analyzed using the Student-Newman-Keuls test (with P < .05 indicating a statistically significant difference). RESULTS: Most of the sample was classified as esthetically acceptable. Orthodontists and plastic surgeons related to oral cleft rehabilitation gave the best scores to the facial profiles, followed by layperson examiners and by orthodontists and plastic surgeons unrelated to oral cleft rehabilitation. The middle third of the face, the nose, and the upper lip were frequently pointed out as contributors to the esthetic impairment. CONCLUSIONS: The facial profile of rehabilitated adult patients with complete bilateral cleft lip and palate was considered esthetically acceptable because of morphologic limitations in the structures affected by the cleft. Laypersons and professionals unrelated to oral cleft rehabilitation seem to be more critical regarding facial esthetics than professionals involved with cleft rehabilitation. PMID- 25511968 TI - Tumor suppressor gene mutation in a patient with a history of hyperparathyroidism jaw tumor syndrome and healed generalized osteitis fibrosa cystica: a case report and genetic pathophysiology review. AB - Hyperparathyroidism-jaw tumor (HPT-JT) was first observed by Jackson in 1958 in a family who exhibited hyperparathyroidism and recurrent pancreatitis. The author noticed the presence of jaw tumors in the affected family and reported them as fibrous dysplasia. However, it was not until 1990 that a familial variety of hyperparathyroidism with fibro-osseous jaw tumors was recognized as HPT-JT syndrome and reported as a clinically and genetically distinct syndrome. Hyperparathyroidism generally arises from glandular hyperplasia or parathyroid adenomas, with only about 1% of cases resulting from parathyroid carcinoma. However, parathyroid carcinoma develops in about 15% of HPT-JT patients. The true incidence of HPT-JT is unknown, although the prevalence of about 100 published cases suggests its rarity. Twenty percent of HPT-JT cases have renal hamartomas or tumors, and female patients with HPT-JT have been reported to have carcinoma of the uterus. This syndrome appears to arise from a variety of mutations that deactivate the tumor suppressor gene CDC73 (also known as HRPT2) and its production of the tumor suppressor protein parafibromin. Functional parafibromin has 531 amino acids, and mutations result in a short nonfunctional protein. CDC73 disorders exhibit dominant germline gene behavior, with varying degrees of penetration. In most cases an affected person has 1 parent with the condition, which raises the need for family investigation and genetic counseling. We report a case of HPT-JT syndrome in a male patient who presented to the local community hospital 6 years previously with a history of back pain. Investigations showed elevated serum parathyroid hormone and calcium levels, and a technetium 99m sestamibi parathyroid scan showed increased activity at the site of the lower left gland that proved to be a substernal parathyroid carcinoma. The patient's parathyroid hormone level dropped from 126 to 97 pg/mL at 5 minutes and was 65 pg/mL at 10 minutes after excision of the gland, and the calcium chemistry findings returned to normal. Parathyroid histologic analysis showed substantial cytologic atypia with nuclear pleomorphism and prominent nucleoli, but infrequent mitoses. Although the capsule was described as showing foci of vascular invasion by the carcinoma, there has been no evidence of recurrence. Six years later, the patient presented with bilateral mandibular cemento-ossifying fibromas, but no evidence of hyperparathyroidism. The larger left tumor was excised and immediately reconstructed with an autogenous iliac crest bone graft, and the right lesion was enucleated. There has been no recurrence in 12 months. This case illustrates that the hyperparathyroidism and the fibro-osseous tumors are independent features of the persistent germline tumor suppressor gene (CDC73) mutation. The syndromic fibro-osseous tumors are odontogenic cemento-ossifying fibromas, which only occur in the jaws. PMID- 25511969 TI - Tissue-engineered oral mucosa grafts for intraoral lining reconstruction of the maxilla and mandible with a fibula flap. AB - PURPOSE: Many types of soft tissue grafts have been used for grafting or prelaminating bone flaps for intraoral lining reconstruction. The best results are achieved when prelaminating free flaps with mucosal grafts. We suggest a new approach to obtain keratinized mucosa over a fibula flap using full-thickness, engineered, autologous oral mucosa. PATIENTS AND METHODS: We report on a pilot study for grafting fibula flaps for mandibular and maxilla reconstruction with full-thickness tissue-engineered autologous oral mucosa. We describe 2 different techniques: prelaminating the fibula flap and second-stage grafting of the fibula after mandibular reconstruction. Preparation of the full-thickness tissue engineered oral mucosa is also described. RESULTS: The clinical outcome of the tissue-engineered intraoral lining reconstruction and response after implant placement are reported. A peri-implant granulation tissue response was not observed when prelaminating the fibula, and little response was observed when intraoral grafting was performed. CONCLUSION: Tissue engineering represents an alternative method by which to obtain sufficient autologous tissue for reconstructing mucosal oral defects. The full-thickness engineered autologous oral mucosa offers definite advantages in terms of reconstruction planning, donor site morbidity, and quality of the intraoral soft tissue reconstruction, thereby restoring native tissue and avoiding peri-implant tissue complications. PMID- 25511971 TI - Synthetic studies toward polytwistane hydrocarbon nanorods. AB - A synthetic strategy toward the intriguing hydrocarbon nanorod polytwistane is outlined. Our approach aims toward the polymerization of acetylene starting from precursors that would provide a helical bias for the formation of polytwistane. Both transition-metal-catalyzed and radical polymerizations were investigated. Two potential initiator molecules were synthesized that could be used for either approach. Although the intended regioselectivities were not observed, unusual organopalladium complexes and numerous compounds with novel carbon skeletons were obtained. PMID- 25511970 TI - Instability in patient and nurse characteristics, unit complexity and patient and system outcomes. AB - AIMS: To explore key factors related to nursing unit instability, complexity and patient and system outcomes. BACKGROUND: The relationship between nurse staffing and quality of patient outcomes is well known. The nursing unit is an important but different aspect that links to complexity and to system and patient outcomes. The relationship between the instability, complexity and outcomes needs further exploration. DESIGN: Descriptive. METHODS: Data were collected via a nurse survey, unit profile and review of patient records on 62 nursing units (wards) across three states of Australia between 2008-2010. Two units with contrasting levels of patient and nurse instability and negative system and patient outcomes, were profiled in detail from the larger sample. RESULTS: Ward A presented with greater patient stability (low occupancy, high planned admissions, few ICU transfers, fewer changes to patient acuity/work re-sequencing) and greater nurse instability (nurses changing units, fewer full-time staff, more temporary/casual staff) impacting system outcomes negatively (high staff turnover). In contrast, Ward B had greater patient instability, however, more nurse stability (greater experienced and permanent staff, fewer casuals), resulting in high rates for falls, medication errors and other adverse patient outcomes with lower rates for system outcomes (lower intention to leave). CONCLUSION: Instability in patient and nurse factors can contribute to ward complexity with potentially negative patient outcomes. The findings highlight the variation of many aspects of the system where nurses work and the importance of nursing unit managers and senior nurse executives in managing ward complexity. PMID- 25511973 TI - A perspective on the status of globalism in neurosurgery: 2015. PMID- 25511972 TI - ToxRead: a tool to assist in read across and its use to assess mutagenicity of chemicals. AB - Life sciences, and toxicology in particular, are heavily impacted by the development of methods for data collection and data analysis; they are moving from an analytical approach to a modelling approach. The scarce availability of experimental data is a known bottleneck in assessing the properties of new chemicals. Even when a model is available, the resulting predictions have to be assessed by close scrutiny of the chemicals and the biological properties of the compounds concerned. To avoid unnecessary testing, a read across strategy is often suggested and used. In this paper we discuss how to improve and standardize read across activity using ad hoc visualization and data search methods which use similarity measures and fragment search to organize in a chart a picture of all the relevant information that the expert needs to make an assessment. We show in particular how to apply our system to the case of mutagenicity. PMID- 25511974 TI - The birth of World Neurosurgery. PMID- 25511975 TI - World Neurosurgery at 5: lightning has been captured. PMID- 25511976 TI - World Federation of Neurosurgical Societies: 2009-2013. PMID- 25511977 TI - Testimony: lessons learned while navigating the minefield of society journal editorship. PMID- 25511979 TI - When do we judge IVIg for myasthenia gravis ineffective? PMID- 25511981 TI - Using feature films as a teaching aid with medical students. PMID- 25511980 TI - Effects of dietary creatine supplementation for 8 weeks on neuromuscular coordination and learning in male albino mouse following neonatal hypoxic ischemic insult. AB - Creatine monohydrate (Cr) is a dietary supplement known to improve cognitive functions and has positive therapeutic results under various clinical conditions. The aim of this study was to determine the effect of 2 % Cr supplementation on learning, memory formation, neuromuscular coordination, exploratory and locomotory in male albino mice following hypoxic ischemic insult. At postnatal day, 10 male albino mice pups were subjected to right common carotid artery ligation followed by 8 % hypoxia for 25 min. On postnatal day 20, male mice were separated from the litter and divided into two groups on the basis of special diet supplementation. One group was supplemented with 2 % Cr in diet while the other group was raised on ordinary rodent chow for 8 weeks. Behavioral observations were made during rota rod, open field and Morris water maze test for both treatments. It was observed that supplementation with 2 % Cr for 8 weeks following neonatal brain damage resulted in enhanced muscular strength, neuromuscular coordination and improved body weight. In Morris water maze test, it was observed that Cr supplementation significantly improved mean swimming speed and mice on 2 % Cr diet covered more distance but the spatial memory was not improved significantly following hypoxia ischemia encephalopathy (HIE). Open field parameters and percentage of infarct volume remained unaffected following Cr supplementation. We concluded that 2 % dietary Cr supplementation has a potential to improve the muscle strength and body weight in male albino mice following (HIE) and should be considered for the treatment of neurological ailments. PMID- 25511982 TI - Deliberate practice as a framework for evaluating feedback in residency training. AB - OBJECTIVE: Using the theory of deliberate practice, a key component of Ericsson's theory of expertise development, this study aims to evaluate the quality of written feedback given to learners. METHODS: The authors created a feedback scoring system based on the key elements of deliberate practice and used it to assess the quality of written feedback provided to residents in 205 mini-CEX encounter forms. Scores were assigned to each feedback entry for identification of the following: Task, performance gap and action plan. RESULTS: The scoring system allowed for reliable identification of the components that facilitate deliberate practice in written feedback provided to trainees. However, only one of these components was identified in 70% of the feedback entries. A specific task was identified in 56%, whereas specific performance gaps and action plans were identified in only 3.9% and 13.7% of encounters, respectively. CONCLUSIONS: Scoring written feedback identified that tasks were often specifically described, but performance gaps and action plans were less frequently and specifically mentioned. Educators might improve feedback effectiveness by better articulating to trainees the gap between their performance and an expert standard, as well as by providing them with specific learning plans. PMID- 25511983 TI - Inherent electrochemistry of layered post-transition metal halides: the unexpected effect of potential cycling of PbI2. AB - The development of two-dimensional nanomaterials has expedited the growth of advanced technological applications. PbI2 is a layered inorganic solid with important and unique properties suitable for applications in the detection of electromagnetic radiation. While the optical and electrical properties of layered PbI2 have been generally established, its electrochemistry has remained largely unexplored. In this work, we examine the inherent electrochemistry of PbI2 in relation to its morphological and structural properties. A direct comparison between commercially available and solution-grown PbI2 showed high similarity in properties based on characterizations by X-ray photoelectron spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. The respective layered PbI2 materials also exhibited similar inherent electrochemistry. Electrochemical potential cycling of PbI2 in phosphate buffer resulted in the dissolution of iodide ions from PbI2 to form complex lead phosphate-chloride with the oxygen groups of the phosphate ions while retaining the hexagonal structure. In the case of KCl solution, the formation of PbO2 was observed. PMID- 25511984 TI - Variation at presentation among colon cancer patients with metastases: a population-based study. AB - AIM: The study aimed to describe and follow a 2 year cohort of colon cancer patients with Stage IV disease from presentation to long-term outcome. METHOD: The records of 177 colon cancer patients diagnosed in southeast Sweden during 2009-2010 with disseminated disease at presentation were reviewed retrospectively. RESULTS: The patients were heterogeneous with respect to age, performance status and survival. Despite metastatic disease, local symptoms from the primary tumour dominated the initial clinical picture. Forty-one per cent had anaemia. The time from suspicion of colon cancer to established diagnosis of disseminated disease varied from 0 to 231 days (emergency cases included, median 12 days). The majority (77%) were diagnosed in hospital. In 53% the primary tumour and the metastases were not diagnosed on the same occasion which may increase the risk for misinformation or delays in the care process. The possibility of simultaneous diagnosis was doubled when the patient was investigated as an inpatient. Patients were seen by one to 12 physicians (median three) in the investigation phase, and one to 47 (median 11) from diagnosis until the last record in the hospital notes. The 1-year survival was 46%. CONCLUSION: Patients with metastatic colon cancer at presentation are heterogeneous and warrant an adapted multidisciplinary approach to achieve the goal of individualized treatment for each patient in accordance with the Swedish national cancer strategy. PMID- 25511985 TI - In vivo evaluation of mutant selection window of cefquinome against Escherichia coli in piglet tissue-cage model. AB - BACKGROUND: The resistance of cephalosporins is significantly serious in veterinary clinic. In order to inhibit the bacterial resistance production, the mutant selection window (MSW) hypothesis with Escherichia coli (E. coli) ATCC 25922 exposed to cefquinome in an animal tissue-cage model was investigated. RESULTS: Localized infection with E. coli was established in piglets, and the infected animals were administrated intramuscularly with various doses and intervals of cefquinome to provide antibiotic concentrations below the MIC99, between the MIC99 and the mutant prevention concentration (MPC), and above the MPC. E. coli lost susceptibility when drug concentrations fluctuated between the lower and upper boundaries of the window, which defined in vitro as the MIC99 (0.06 MUg/mL) and the MPC (0.16 MUg/mL) respectively. For PK/PD parameters, there were no mutant selection enrichment when T>MIC99 was <= 25% or T>MPC was >= 50% of administration interval. When T>MIC99 was > 25% and T>MPC was <50% of administration interval, resistance selection was observed. When AUC24 h/MIC99 and AUC24 h/MPC were considered, the mutant selection window extended from 32.84 h to 125.64 h and from 12.83 h to 49.09 h, respectively. CONCLUSIONS: These findings demonstrate that the MSW exists in vivo for time-dependent antimicrobial agents, and its boundaries fit well with those determined in vitro. Maintenance of antimicrobial concentrations above the MPC for > 50% of administration interval is a straightforward way to restrict the acquisition of resistance in this tissue cage model. This situation was achieved with daily intramuscular doses of 1 mg cefquinome/kg body weight. PMID- 25511986 TI - Levodopa/benserazide microsphere (LBM) prevents L-dopa induced dyskinesia by inactivation of the DR1/PKA/P-tau pathway in 6-OHDA-lesioned Parkinson's rats. AB - L-3, 4-dihydroxyphenylalanine (L-dopa) is the gold standard for symptomatic treatment of Parkinson's disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). In the present study, L-dopa and benserazide were loaded by poly (lactic-co-glycolic acid) microspheres (LBM), which can release levodopa and benserazide in a sustained manner in order to continuous stimulate dopaminergic receptors. We investigated the role of striatal DR1/PKA/P-tau signal transduction in the molecular event underlying LID in the 6 OHDA-lesioned rat model of PD. We found that animals rendered dyskinetic by L dopa treatment, administration of LBM prevented the severity of AIM score, as well as improvement in motor function. Moreover, we also showed L-dopa elicits profound alterations in the activity of three LID molecular markers, namely DR1/PKA/P-tau (ser396). These modifications are totally prevented by LBM treatment, a similar way to achieve continuous dopaminergic delivery (CDD). In conclusion, our experiments provided evidence that intermittent administration of L-dopa, but not continuous delivery, and DR1/PKA/p-tau (ser396) activation played a critical role in the molecular and behavioural induction of LID in 6-OHDA lesioned rats. In addition, LBM treatment prevented the development of LID by inhibiting the expression of DR1/PKA/p-tau, as well as PPEB mRNA in dyskintic rats. PMID- 25511987 TI - Trend of eGFR in an Italian cohort of mother-to-child HIV-infected patients exposed to tenofovir for at least 2 years. AB - The aim of this study is to describe longitudinal changes in estimated glomerular filtration rate (eGFR) in a cohort of mother-to-child HIV-infected adolescents exposed to tenofovir dixoproxil fumarate (TDF) for at least 2 years. We retrospectively examined eGFR at starting TDF (T0), at 24 months (T2) and at the final assessment (T3). Twenty-nine patients were studied. The mean duration of TDF exposure was 67 months (24-123). At baseline, the mean eGFR was 152 ml/min/1.73 m(2) (105-227, SD, 33). There was a significant decrease of eGFR from a mean of 152 ml/min/1.73 m(2) (SD, 33) at T0 to 140 ml/min/1.73 m(2) (SD, 33) at T2 and 123 ml/min/1.73 m(2) (SD, 14) at T3. The decrease of eGFR was significant, with DeltaGFR (T3-T0) of -29 ml/min/1.73 m(2) (SD, 30; p < 0.0001) and a mean DeltaGFR per year of -6 and ml/min/1.73 m(2) (SD, 8). CONCLUSION: We noted a long term decline in eGFR in this small cohort of mother-to-child HIV-infected adolescents receiving TDF-containing cART, even if the lack of a control group and the small sample size are major limitations. PMID- 25511988 TI - Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review. AB - CONTEXT: There is great interest in using magnetic resonance imaging (MRI) for men on active surveillance for prostate cancer. OBJECTIVE: To systematically review evidence regarding the use of MRI in men with low- or intermediate-risk prostate cancer suitable for active surveillance. EVIDENCE ACQUISITION: Ovid Medline and Embase databases were searched for active surveillance, prostate cancer, and MRI from inception until April 25, 2014 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses process. Identified reports were critically appraised according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) criteria. EVIDENCE SYNTHESIS: A lesion on MRI suspicious for prostate cancer (positive MRI) is seen in two-thirds of men otherwise suitable for active surveillance. A positive MRI makes the identification of clinically significant disease at repeat biopsy more likely, especially when biopsies are targeted to suspicious MRI lesions. Radical prostatectomy data show that positive MRI is more likely to be associated with upgrading (Gleason score>3+3) than a negative MRI (43% vs 27%). A positive MRI is not significantly more likely to be associated with upstaging at radical prostatectomy (>T2) than a negative MRI (10% vs 8%). Although MRI is of interest in the monitoring of men on active surveillance, robust data on the use of repeat MRI in active surveillance are lacking. Prospective studies with clear definitions of radiological significance and progression are needed before this approach can be adopted. CONCLUSIONS: MRI is useful for detection of clinically significant disease at initial assessment of men considering active surveillance. To use MRI as a monitoring tool in surveillance, it will be necessary to define both radiological significance and radiological progression. PATIENT SUMMARY: This review assesses evidence for the use of magnetic resonance imaging (MRI) in men on active surveillance for prostate cancer. MRI at the start of surveillance can detect clinically significant disease in one-third to half of men. There are few data to assess the use of MRI as a monitoring tool during surveillance, so there is a need to define significant disease on MRI and significant changes over time. PMID- 25511989 TI - Swedish general practitioners' attitudes towards treatment guidelines - a qualitative study. AB - BACKGROUND: Drug therapy in primary care is a challenge for general practitioners (GPs) and the prescribing decision is influenced by several factors. GPs obtain drug information in different ways, from evidence-based sources, their own or others' experiences, or interactions with opinion makers, patients or colleagues. The need for objective drug information sources instead of drug industry-provided information has led to the establishment of local drug and therapeutic committees. They annually produce and implement local treatment guidelines in order to promote rational drug use. This study describes Swedish GPs' attitudes towards locally developed evidence-based treatment guidelines. METHODS: Three focus group interviews were performed with a total of 17 GPs working at both public and private primary health care centres in Skane in southern Sweden. Transcripts were analysed by conventional content analysis. Codes, categories and themes were derived from data during the analysis. RESULTS: We found two main themes: GP-related influencing factors and External influencing factors. The first theme emerged when we put together four main categories: Expectations and perceptions about existing local guidelines, Knowledge about evidence-based prescribing, Trust in development of guidelines, and Beliefs about adherence to guidelines. The second theme included the categories Patient-related aspects, Drug industry-related aspects, and Health economic aspects. The time-saving aspect, trust in evidence-based market-neutral guidelines and patient safety were described as key motivating factors for adherence. Patient safety was reported to be more important than adherence to guidelines or maintaining a good patient doctor relationship. Cost containment was perceived both as a motivating factor and a barrier for adherence to guidelines. GPs expressed concerns about difficulties with adherence to guidelines when managing patients with drugs from other prescribers. GPs experienced a lack of time to self-inform and difficulties managing direct-to-consumer drug industry information. CONCLUSIONS: Patient safety, trust in development of evidence-based recommendations, the patient doctor encounter and cost containment were found to be key factors in GPs' prescribing. Future studies should explore the need for transparency in forming and implementing guidelines, which might potentially increase adherence to evidence-based treatment guidelines in primary care. PMID- 25511990 TI - Variation in the persistence of memory: An interplay between actin dynamics and AMPA receptors. AB - William James noted that memories could persist from minutes to weeks. This essay attempts to explain this variation by situating the explanation in the biochemistry of dendritic spines. Two outcomes are critical to generate the synaptic basis of memory: (1) the actin cytoskeleton in the spine must be degraded to permit (2) additional AMPA receptors (GluA1s) to enter new "hot spots" in the postsynaptic density. These initial outcomes can support short lasting memories. The threshold for these events is low but the underlying synaptic changes cannot resist the endocytic processes that remove the added AMPA receptors. For the memory to persist the degraded actin cytoskeleton must be rebuilt and the vacated "hot spots" refilled with GluA2 receptors. A primary claim is that it is the stabilization of an enlarged actin cytoskeleton that is the target outcome that consolidates the synaptic basis of memory (see Lynch et al., 2007). The stabilized actin cytoskeleton has properties that enable it to garner the synaptic proteins it needs to self sustain the potentiated state and to benefit from activation of memory modulation systems. This article is part of a Special Issue entitled Brain and Memory. PMID- 25511991 TI - Signature changes in ubiquilin expression in the R6/2 mouse model of Huntington's disease. AB - Ubiquilin proteins have been implicated in the cause and the pathology of neurodegenerative diseases. In the R6/2 mouse model of Huntington's disease (HD), ubiquilin levels decline during disease progression. Restoration of their levels by transgenic expression of ubiquilin-1 extends survival. Here we provide a comprehensive assessment of the expression and localization of all four ubiquilin proteins in both normal and R6/2-affected mice brains, using antibodies specific for each protein. Ubiquilin-1, 2 and 4 proteins were detected throughout the brain, with increased expression seen in the hippocampus and cerebellum. Ubiquilin-3 expression was not detected. All three ubiquilins expressed in the brain were found in Htt inclusions. Their expression changed during development and disease. Ubiquilin-1 and ubiquilin-2 protein levels decreased from 6 to 18 weeks of mouse development, independent of disease. Ubiquilin-1 and ubiquilin-4 protein levels also changed during HD disease progression. Ubiquilin-4 proteins that are normally expressed in the brain were lost and instead replaced by a novel 115 kDa higher molecular weight immunoreactive band. Taken together, our results demonstrate that all ubiquilin proteins are involved in HD pathology and that distinct changes in the signature of ubiquilin-4 expression could be useful for monitoring end-stage of HD disease. PMID- 25511993 TI - Rapid increase of spines by dihydrotestosterone and testosterone in hippocampal neurons: Dependence on synaptic androgen receptor and kinase networks. AB - Rapid modulation of hippocampal synaptic plasticity by locally synthesized androgen is important in addition to circulating androgen. Here, we investigated the rapid changes of dendritic spines in response to the elevation of dihydrotestosterone (DHT) and testosterone (T), by using hippocampal slices from adult male rats, in order to clarify whether these signaling processes include synaptic/extranuclear androgen receptor (AR) and activation of kinases. We found that the application of 10nM DHT and 10nM T increased the total density of spines by approximately 1.3-fold within 2h, by imaging Lucifer Yellow-injected CA1 pyramidal neurons. Interestingly, DHT and T increased different head-sized spines. While DHT increased middle- and large-head spines, T increased small-head spines. Androgen-induced spinogenesis was suppressed by individually blocking Erk MAPK, PKA, PKC, p38 MAPK, LIMK or calcineurin. On the other hand, blocking CaMKII did not inhibit spinogenesis. Blocking PI3K altered the spine head diameter distribution, but did not change the total spine density. Blocking mRNA and protein synthesis did not suppress the enhancing effects induced by DHT or T. The enhanced spinogenesis by androgens was blocked by AR antagonist, which AR was localized postsynaptically. Taken together, these results imply that enhanced spinogenesis by DHT and T is mediated by synaptic/extranuclear AR which rapidly drives the kinase networks. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25511994 TI - The interplay between referential processing and local syntactic/semantic processing: ERPs to written Chinese discourse. AB - Two event-related brain potential experiments were conducted to investigate the functional interplay between discourse-level referential processing and local syntactic/semantic processing of phrases. We manipulated both the syntactic/semantic coherence of a noun phrase (NP) and the referential ambiguity of the same NP. Incoherence of the NP elicited a P600 effect in both experiments. Referential ambiguities elicited a sustained negativity (Nref) in a subset of the participants in both experiments. Crucially, among participants showing robust Nref effects to referential ambiguity in the coherent condition, Nref effects were absent when the NP was incoherent. These results provide evidence against theories in which referential processing is functionally independent of local syntactic/semantic processing of phrases. Instead, a local phrase anomaly can block aspects of referential processing concerning ambiguity. PMID- 25511992 TI - Biochemical principles underlying the stable maintenance of LTP by the CaMKII/NMDAR complex. AB - Memory involves the storage of information at synapses by an LTP-like process. This information storage is synapse specific and can endure for years despite the turnover of all synaptic proteins. There must, therefore, be special principles that underlie the stability of LTP. Recent experimental results suggest that LTP is maintained by the complex of CaMKII with the NMDAR. Here we consider the specifics of the CaMKII/NMDAR molecular switch, with the goal of understanding the biochemical principles that underlie stable information storage by synapses. Consideration of a variety of experimental results suggests that multiple principles are involved. One switch requirement is to prevent spontaneous transitions from the off to the on state. The highly cooperative nature of CaMKII autophosphorylation by Ca(2+) (Hill coefficient of 8) and the fact that formation of the CaMKII/NMDAR complex requires release of CaMKII from actin are mechanisms that stabilize the off state. The stability of the on state depends critically on intersubunit autophosphorylation, a process that restores any loss of pT286 due to phosphatase activity. Intersubunit autophosphorylation is also important in explaining why on state stability is not compromised by protein turnover. Recent evidence suggests that turnover occurs by subunit exchange. Thus, stability could be achieved if a newly inserted unphosphorylated subunit was autophosphorylated by a neighboring subunit. Based on other recent work, we posit a novel mechanism that enhances the stability of the on state by protection of pT286 from phosphatases. We posit that the binding of the NMNDAR to CaMKII forces pT286 into the catalytic site of a neighboring subunit, thereby protecting pT286 from phosphatases. A final principle concerns the role of structural changes. The binding of CaMKII to the NMDAR may act as a tag to organize the binding of further proteins that produce the synapse enlargement that underlies late LTP. We argue that these structural changes not only enhance transmission, but also enhance the stability of the CaMKII/NMDAR complex. Together, these principles provide a mechanistic framework for understanding how individual synapses produce stable information storage. This article is part of a Special Issue entitled SI: Brain and Memory. PMID- 25511995 TI - Real-time effects of insulin-induced hypoglycaemia on hippocampal glucose and oxygen. AB - The hippocampus plays a vital role in learning and memory and is susceptible to damage following hypoglycaemic shock. The effect of an acute administration of insulin on hippocampal function has been described in terms of behavioural deficits but its effect on hippocampal oxygen and glucose is unclear. Glucose oxidase biosensors (detecting glucose) and carbon paste electrodes (detecting oxygen) were implanted into the hippocampus of Sprague Dawley rats. Animals were allowed to recover and real-time recordings were made in order to determine the effects of fasting, insulin administration (15 U/kg; i.p.) and reintroduction of food on hippocampal oxygen and glucose. Fasting caused a significant decrease in hippocampal glucose over the course of 24h. Insulin administration produced a significant decrease in hippocampal glucose along with a significant increase in hippocampal oxygen. Finally, the reintroduction of food resulted in glucose levels significantly increasing along with a transient but significant increase in oxygen levels. The findings presented here suggest that even a single acute period of hypoglycaemia may substantially disrupt hippocampal oxygen and glucose and therefore affect hippocampal function. PMID- 25511996 TI - VEGF overexpression enhances the accumulation of phospho-S292 MeCP2 in reactive astrocytes in the adult rat striatum following cerebral ischemia. AB - PURPOSE: Astrocytes can be reactivated after cerebral ischemia by expressing nestin and other characteristic markers of neural stem cells (NSCs). However, the epigenetic features of reactive astrocytes are not well known. Methyl-CpG-binding protein 2 (MeCP2) is a vital transcriptional modulator in brain development. Although the expression and function of some phosphorylated MeCP2 isoforms have been clarified, phospho-serine 292 (pS292) MeCP2 has not yet drawn much attention. In this study, we used western blot analysis and immunohistochemical and immunofluorescent staining to reveal the expressive features of pS292 MeCP2 and MeCP2 in the adult rat striatum following transient middle cerebral artery occlusion (MCAO). RESULTS: We first discovered that the ischemia-induced expression of cytoplasmic pS292 MeCP2 is primarily accumulated in nestin-positive reactive astrocytes in the stroke-injured striatum. Moreover, the enhancement of astrocytic pS292 MeCP2 was correlated with the augmentation of VEGF in astrocytes, as determined by the substantial co-localization of pS292 MeCP2 and VEGF after stroke. Finally, the exogenous overproduction of VEGF further promoted the expression of pS292 MeCP2 in reactive astrocytes, and this effect was accompanied by a marked increase in reactive astrocytes. On the contrary, MeCP2 was predominantly expressed in the neuronal nucleus, and the level of this protein was not significantly altered after ischemic injury and VEGF overproduction. CONCLUSION: Our data provide the first demonstration that overexpression of VEGF enhances the accumulation of pS292 MeCP2 in reactive astrocytes in the ischemic-injured rat striatum, implicating a pS292 MeCP2 related epigenetic role of exogenous VEGF in reactive astrocytes following cerebral ischemia. PMID- 25511997 TI - Porcine endogenous retrovirus infection of human peripheral blood mononuclear cells. PMID- 25511998 TI - A dynamic supramolecular polymer with stimuli-responsive handedness for in situ probing of enzymatic ATP hydrolysis. AB - Design of artificial systems, which can respond to fluctuations in concentration of adenosine phosphates (APs), can be useful in understanding various biological processes. Helical assemblies of chromophores, which dynamically respond to such changes, can provide real-time chiroptical readout of various chemical transformations. Towards this concept, here we present a supramolecular helix of achiral chromophores, which shows chiral APs responsive tunable handedness along with dynamically switchable helicity. This system, composing of naphthalenediimides with phosphate recognition unit, shows opposite handedness on binding with ATP compared with ADP or AMP, which is comprehensively analysed with molecular dynamic simulations. Such differential signalling along with stimuli dependent fast stereomutations have been capitalized to probe the reaction kinetics of enzymatic ATP hydrolysis. Detailed chiroptical analyses provide mechanistic insights into the enzymatic hydrolysis and various intermediate steps. Thus, a unique dynamic helical assembly to monitor the real-time reaction processes via its stimuli-responsive chiroptical signalling is conceptualized. PMID- 25511999 TI - Design, Synthesis, and Biological Evaluation of Novel Benzoyl Diarylamine/ether Derivatives as Potential Anti-HIV-1 Agents. AB - A series of benzoyl diarylamine/ether derivatives were designed, synthesized, and evaluated for their activity against human immunodeficiency virus (HIV) in MT-4 cells. Three compounds (3b, 5a, and 6a1) exhibited moderate activities against wild-type (wt) HIV-1 with EC50 values ranging from 11 to 56 MUm. Among them, compound 5a was the most potent inhibitor with a novel chemical skeleton, affording a new lead compound for further molecular optimization. An enzyme assay was also implemented to confirm the binding target of the active compounds represented by 6a1. Molecular simulation studies on compound 5a, 6a1, and 7a4 were carried out to understand their binding mode with wt HIV-1 reverse transcriptase (RT) and provided useful information for further rational design of NNRTIs. PMID- 25512000 TI - Novel long-chain diol phospholipids from some bacteria belonging to the class Thermomicrobia. AB - Polar lipids of bacteria from the class Thermomicrobia are known to contain long chain 1,2-diols instead of glycerol, although the nature of polar head groups has not been investigated. We have studied phospholipid classes of two species from the class Thermomicrobia-Sphaerobacter thermophilus and Thermomicrobia sp. WKT50.2. TLC and (31)P-NMR analysis of polar lipids revealed that both S. thermophilus and Thermomicrobia sp. WKT50.2 contain the same set of four major phospholipid classes. Structures of the novel phospholipids in S. thermophilus were established as 2-acylalkyldiol-1-O-phosphoinositol, 2-acylalkyldiol-1-O phosphoinositol mannoside, 2-acylalkyldiol-1-O-phospho-acylmannoside, and 2 acylalkyldiol-1-O-phosphoinositol acylmannoside. To our knowledge, this is the first report of a phospholipid with a mannose directly bound to the phosphate. We also analyzed fatty acids and long-chain 1,2-diols of S. thermophilus and Thermomicrobia sp. WKT50.2 and compared our data with available information for T. roseum. All species share a similar set of fatty acids, with 12-Me 18:0 being the major fatty acid. The major diol in S. thermophilus was identified as 13-Me 19:0 (66.2 %). The 21:0 diol was the major component both in Thermomicrobia sp. WKT50.2 (50.6 %) and in T. roseum (56.6 %). PMID- 25512001 TI - Instrumental and sensory analyses of quality attributes of grafted specialty melons. AB - BACKGROUND: Soilborne disease management remains a great challenge in melon production with the phaseout of soil fumigant methyl bromide. Grafting has been shown to be an effective approach to control soilborne diseases. However, previous research has yielded mixed results regarding the impacts of rootstock on fruit quality. Very few studies have assessed melon quality attributes using both sensory evaluation and instrumental methods. RESULTS: Galia melon 'Arava' (Cucumis melo L. var. reticulatus Ser.) and honeydew melon 'Honey Yellow' (C. melo L. var. inodorus Naud.) were grafted onto commercial hybrid squash (Cucurbita maxima Duchesne * Cucurbita moschata Duchesne) rootstocks and root knot nematode-resistant Cucumis metulifer E. Mey. ex Naud. rootstock. The grafting combinations were evaluated under different production conditions. Grafting with hybrid squash rootstocks resulted in reduced soluble solids content (SSC) and decreased sensory ratings of 'Arava' fruit. By contrast with grafted 'Arava', grafted 'Honey Yellow' did not exhibit significant differences in sensory properties and instrumental measurements regardless of production conditions and rootstock selection. CONCLUSION: The effects of grafting on fruit quality attributes differed between the two distinctive types of melon scion used. Potential negative impacts of rootstocks on melon fruit quality need to be considered in the selection and use of disease-resistant rootstocks. PMID- 25512002 TI - Loss of function variants in human PNPLA8 encoding calcium-independent phospholipase A2 gamma recapitulate the mitochondriopathy of the homologous null mouse. AB - Mitochondriopathies are a group of clinically heterogeneous genetic diseases caused by defects in mitochondrial metabolism, bioenergetic efficiency, and/or signaling functions. The large majority of proteins involved in mitochondrial function are encoded by nuclear genes, with many yet to be associated with human disease. We performed exome sequencing on a young girl with a suspected mitochondrial myopathy that manifested as progressive muscle weakness, hypotonia, seizures, poor weight gain, and lactic acidosis. She was compound heterozygous for two frameshift mutations, p.Asn112HisfsX29 and p.Leu659AlafsX4, in the PNPLA8 gene, which encodes mitochondrial calcium-independent phospholipase A2 gamma (iPLA2 gamma). Western blot analysis of affected muscle displayed the absence of PNPLA8 protein. iPLA2 s are critical mediators of a variety of cellular processes including growth, metabolism, and lipid second messenger generation, exerting their functions through catalyzing the cleavage of the acyl groups in glycerophospholipids. The clinical presentation, muscle histology and the mitochondrial ultrastructural abnormalities of this proband are highly reminiscent of Pnpla8 null mice. Although other iPLA2 -related diseases have been identified, namely, infantile neuroaxonal dystrophy and neutral lipid storage disease with myopathy, this is the first report of PNPLA8-related disease in a human. We suggest PNPLA8 join the increasing list of human genes involved in lipid metabolism associated with neuromuscular diseases due to mitochondrial dysfunction. PMID- 25512004 TI - Role of islet microRNAs in diabetes: which model for which question? AB - MicroRNAs are important regulators of gene expression. The vast majority of the cells in our body rely on hundreds of these tiny non-coding RNA molecules to precisely adjust their protein repertoire and faithfully accomplish their tasks. Indeed, alterations in the microRNA profile can lead to cellular dysfunction that favours the appearance of several diseases. A specific set of microRNAs plays a crucial role in pancreatic beta cell differentiation and is essential for the fine-tuning of insulin secretion and for compensatory beta cell mass expansion in response to insulin resistance. Recently, several independent studies reported alterations in microRNA levels in the islets of animal models of diabetes and in islets isolated from diabetic patients. Surprisingly, many of the changes in microRNA expression observed in animal models of diabetes were not detected in the islets of diabetic patients and vice versa. These findings are unlikely to merely reflect species differences because microRNAs are highly conserved in mammals. These puzzling results are most probably explained by fundamental differences in the experimental approaches which selectively highlight the microRNAs directly contributing to diabetes development, the microRNAs predisposing individuals to the disease or the microRNAs displaying expression changes subsequent to the development of diabetes. In this review we will highlight the suitability of the different models for addressing each of these questions and propose future strategies that should allow us to obtain a better understanding of the contribution of microRNAs to the development of diabetes mellitus in humans. PMID- 25512005 TI - Glucose, blood pressure and cholesterol levels and their relationships to clinical outcomes in type 2 diabetes: a retrospective cohort study. AB - AIMS/HYPOTHESIS: We aimed to describe the shape of observed relationships between risk factor levels and clinically important outcomes in type 2 diabetes after adjusting for multiple confounders. METHODS: We used retrospective longitudinal data on 246,544 adults with type 2 diabetes from 600 practices in the Clinical Practice Research Datalink, 2006-2012. Proportional hazards regression models quantified the risks of mortality and microvascular or macrovascular events associated with four modifiable biological variables (HbA1c, systolic BP, diastolic BP and total cholesterol), while controlling for important patient and practice covariates. RESULTS: U-shaped relationships were observed between all cause mortality and levels of the four biometric risk factors. Lowest risks were associated with HbA1c 7.25-7.75% (56-61 mmol/mol), total cholesterol 3.5-4.5 mmol/l, systolic BP 135-145 mmHg and diastolic BP 82.5-87.5 mmHg. Coronary and stroke mortality related to the four risk factors in a positive, curvilinear way, with the exception of systolic BP, which related to deaths in a U-shape. Macrovascular events showed a positive and curvilinear relationship with HbA1c but a U-shaped relationship with total cholesterol and systolic BP. Microvascular events related to the four risk factors in a curvilinear way: positive for HbA1c and systolic BP but negative for cholesterol and diastolic BP. CONCLUSIONS/INTERPRETATION: We identified several relationships that support a call for major changes to clinical practice. Most importantly, our results support trial data indicating that normalisation of glucose and BP can lead to poorer outcomes. This makes a strong case for target ranges for these risk factors rather than target levels. PMID- 25512003 TI - The effects of capillary dysfunction on oxygen and glucose extraction in diabetic neuropathy. AB - Diabetic neuropathy is associated with disturbances in endoneurial metabolism and microvascular morphology, but the roles of these factors in the aetiopathogenesis of diabetic neuropathy remain unclear. Changes in endoneurial capillary morphology and vascular reactivity apparently predate the development of diabetic neuropathy in humans, and in manifest neuropathy, reductions in nerve conduction velocity correlate with the level of endoneurial hypoxia. The idea that microvascular changes cause diabetic neuropathy is contradicted, however, by reports of elevated endoneurial blood flow in early experimental diabetes, and of unaffected blood flow when early histological signs of neuropathy first develop in humans. We recently showed that disturbances in capillary flow patterns, so called capillary dysfunction, can reduce the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow. In fact, tissue blood flow must be adjusted to ensure sufficient oxygen extraction as capillary dysfunction becomes more severe, thereby changing the normal relationship between tissue oxygenation and blood flow. This review examines the evidence of capillary dysfunction in diabetic neuropathy, and whether the observed relation between endoneurial blood flow and nerve function is consistent with increasingly disturbed capillary flow patterns. The analysis suggests testable relations between capillary dysfunction, tissue hypoxia, aldose reductase activity, oxidative stress, tissue inflammation and glucose clearance from blood. We discuss the implications of these predictions in relation to the prevention and management of diabetic complications in type 1 and type 2 diabetes, and suggest ways of testing these hypotheses in experimental and clinical settings. PMID- 25512007 TI - Obesity in children- a chronic disease? PMID- 25512006 TI - Platelet transfusion in hematology, oncology and surgery. AB - BACKGROUND: The standard recommendation to date has been that acute hypoproliferative thrombocytopenia should be treated with a prophylactic platelet transfusion if the morning platelet count is less than 10 000/MUL, or less than 20 000/MUL if there are additional risk factors. For chronic thrombocytopenia, transfusion has been recommended if the platelet count is less than 5000/MUL. In Germany, half a million platelet transfusions are now being given every year, and the number is rising. New studies indicate, however, that a more restrictive transfusion strategy is justified. METHODS: A selective literature search was carried out in PubMed, with additional attention to recommendations from Germany and abroad, and to the guidelines of medical specialty societies. RESULTS: Prophylactic platelet transfusions should be given when clinically indicated in consideration of the individual hemorrhagic risk. To prevent severe hemorrhage, it is more important to respond to the first signs of bleeding than to pay exclusive attention to morning platelet counts below 10 000/MUL. This threshold value remains standard for patients with acute leukemia. According to recent studies, however, clinically stable patients who are at low risk for bleeding e.g., patients who have undergone autologous hematopoietic stem-cell transplantation-may be well served by a therapeutic, rather than prophylactic, platelet transfusion strategy, in which platelets are transfused only when evidence of bleeding has been observed. For cancer patients, intensive-care patients, and patients with other risk factors, a clinically oriented transfusion strategy is recommended, in addition to close attention to threshold platelet values. CONCLUSION: The number of platelet transfusions could be safely lowered by a more restrictive transfusion strategy that takes account of the risk of bleeding, as recommended in the hemotherapy guidelines. PMID- 25512009 TI - Osteoarthritis: MicroRNA-mediated meniscal injury repair in rats. PMID- 25512008 TI - Weight loss in children and adolescents. AB - BACKGROUND: 15% of children and adolescents in Germany are overweight, including 6.3% who are affected by obesity. The efficacy of conservative weight-loss treatments has been demonstrated, but there has not yet been a detailed analysis of their efficacy in terms of the amount of weight loss that can be expected. We re-evaluated the available evidence on this question, with particular attention to the methodological quality of clinical trials, in order to derive information that might be a useful guide for treatment. METHODS: We conducted a systematic literature search of Medline for the period May 2008 (final inclusion date for a 2009 Cochrane Review) to December 2013. The identified studies were analyzed qualitatively. RESULTS: 48 randomized controlled clinical trials with a total of 5025 participants met the predefined inclusion criteria for this analysis. In the ones that met predefined criteria for methodological quality, conservative weight loss treatments led to weight loss in amounts ranging from 0.05 to 0.42 BMI z score (standard deviation score of the body mass index) over a period of 12-24 months. Information on trial dropout rates was available for 41 of the 48 trials; the dropout rate was 10% or higher in 27 of these (66% ), and 25% or higher in 9 (22% ). CONCLUSION: The available evidence consistently shows that only a modest degree of weight loss can be expected from conservative treatment. Families seeking treatment should be informed of this fact. Future research should focus on determining predictive factors for therapeutic benefit, and on the evaluation of additional types of psychological intervention to promote coping with obesity. PMID- 25512011 TI - Genetics: Mapping autoimmune disease epigenetics: what's on the horizon? PMID- 25512013 TI - Rheumatoid arthritis: Inflammation feeds inflammation-HDAC5 downregulation leads to activation of fibroblast-like synoviocytes in RA. PMID- 25512010 TI - TLR4 signalling in osteoarthritis--finding targets for candidate DMOADs. AB - Osteoarthritis (OA), the most common rheumatic disease, is characterized by joint space narrowing due to progressive cartilage degradation and alterations in subchondral bone and the synovial membrane. These articular disturbances can have severe consequences, including pain, disability and loss of joint architectural integrity. Although the aetiology of OA is not understood, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by damage-associated molecules are thought to be involved. In this Review, we examine the relationship between Toll-like receptor 4 (TLR4) and OA in cartilage as well as in other OA-affected tissues, such as subchondral bone and synovium. We also discuss the different TLR4 agonists associated with OA and their effects in joint tissues. Finally, we describe existing and novel strategies that might be used to develop TLR4-specific disease-modifying OA drugs (DMOADs). PMID- 25512012 TI - Advances in biomarkers for paediatric rheumatic diseases. AB - The search for biomarkers in paediatric rheumatic diseases, particularly juvenile idiopathic arthritis (JIA), childhood lupus nephritis (LN), and juvenile idiopathic inflammatory myopathies (JIIMs) is attracting increased interest. In JIA, a number of biomarkers have shown potential for predicting clinical phenotype, disease activity and severity, clinical remission and relapse, response to treatment, and disease course over time. In systemic JIA, measurement of biomarkers that reflect the degree of activation and expansion of T cells and macrophages might be helpful for detecting subclinical macrophage activation syndrome. Urine biomarkers for childhood LN hold promise for facilitating early diagnosis and improving disease monitoring and assessment of response to therapy. Myositis-specific autoantibodies define distinct serological subgroups of JIIMs, albeit with similar clinical features, responses to therapy, and prognoses. Use of biomarkers may potentially help to avoid invasive procedures, such as renal biopsy in systemic lupus erythematosus and muscle biopsy in juvenile dermatomyositis. Incorporation of effective and reliable biomarkers into routine practice might facilitate adoption of a stratified approach to investigation and management, foster the implementation of research into the design of personalized and targeted therapies, and ultimately lead to more rational and effective clinical care. PMID- 25512014 TI - Osteoarthritis in 2014: Changing how we define and treat patients with OA. AB - Important advances in 2014 foster new perspectives on definitions of early and end-stage disease, and promote a shift in the clinical management of osteoarthritis (OA) through implementing treatment algorithms intended to minimize strain on current health-care models. Collectively, these changes shed new light on developing and optimizing approaches to OA treatment. PMID- 25512015 TI - Five-year follow-up of children receiving comprehensive dental care under general anesthesia. AB - BACKGROUND: Dental general anesthesia (DGA) is part of public dental care in Finland, but the intention is to return the patient to routine dental care. The aims of this study were to describe the details of treatments under DGA given to generally healthy children and to explore the outcome of their dental care during a 5-year follow-up, with special focus on preventive care. In particular, we examined the return of the patients to routine dental care, of which, to our knowledge, little is known. METHODS: Our prospective 5-year follow-up of generally healthy children (aged 0-13 years) treated under DGA by the Helsinki Public Dental Service in 2004 was based on official dental and general anesthesia documents. The statistical analyses employed chi-square tests, t-tests, Pearson's correlation coefficient (r), Fisher's transformation to test r ? 0, and logistic regression modeling. RESULTS: The most common reason for DGA was uncooperation (82%), followed by dental fear (56%). Filling therapy predominated in the treatments given under anesthesia, and the mean number of treatments per patients was 9.5 (SD = 4.2). Throughout the follow-up, 54% of the patients continued to have co-operation problems and 53% expressed dental fear; 11% of the patients received repeat DGA. The mean follow-up time was 48 (median 52) months. The postoperative review visit was actualized within 1.5 (SD = 0.8) months and the first visit to the home dental clinic of the patients in 12.0 (SD = 11.8) months for the 0-5-year-olds and in 7.2 (SD = 5.9) months for the 6-13-year-olds (p < 0.001). The mean time elapsed to the first need for treatment was 18.5 (SD = 14.1) months. During the follow-up, the mean number of treatments per patient was 5.3 (SD = 4.9); almost all patients (97%) received preventive treatment at one of two visits, but the control of dental fear remained rare. CONCLUSIONS: To return to routine dental care after DGA, most of the generally healthy children in our study still needed special attention due to their uncooperation and dental fear, thus calling for a renewal of practices to treat these patients. PMID- 25512016 TI - Increased dosage of cyclosporine induces myopathy with increased seru creatine kinase in an elderly patient on chronic statin therapy. AB - WHAT IS KNOWN AND OBJECTIVE: The concomitant administration of atorvastatin and cyclosporine has been shown to increase the serum concentration of 3-hydroxy-3 methylglutaryl coenzyme A, which may be associated with the elevation of creatine kinase and an increased risk of myopathy. Our objective is to report on a case of statin-induced myopathy associated with concomitant use of cyclosporine and other contributing factors. CASE SUMMARY: An 88-year-old Chinese male patient with comorbidities received polypharmacy treatment, including atorvastatin and cyclosporine. After the dosage of cyclosporine was increased to 300 mg every day for 8 months, the patient developed body pain and leg weakness, with a serum creatine kinase increase and evidence on magnetic resonance imaging of muscle oedema. WHAT IS NEW AND CONCLUSION: Cyclosporine is a moderate inhibitor of the cytochrome P450 CYP3A4 isoenzyme, which is known to increase the serum level of atorvastatin. We hypothesized that the pharmacological and pharmacokinetic properties of atorvastatin-induced myopathy are the result of its interaction with high dosage of cyclosporine. PMID- 25512017 TI - A procedure to estimate the origins and the insertions of the knee ligaments from computed tomography images. AB - The estimation of the origin and insertion of the four knee ligaments is crucial for individualised dynamic modelling of the knee. Commonly this information is obtained ex vivo or from high resolution MRI, which is not always available. Aim of this work is to devise a method to estimate the origins and insertions from computed tomography (CT) images. A reference registration atlas was created using a set of 16 bone landmarks visible in CT and eight origins and insertions estimated from MRI and in vitro data available in the literature for three knees. This atlas can be registered to the set of bone landmarks palpated on any given CT using an affine transformation. The resulting orientation and translation matrices and scaling factors can be used to find also the ligament origin and insertions. This procedure was validated on seven pathological knees for which both CT and MRI of the knee region were available, using a proprietary software tool (NMSBuilder, SCS srl, Italy). To assess the procedure reproducibility and repeatability, four different operators performed the landmarks palpation on all seven patients. The average difference between the values predicted by registration on the CT scan and those estimated on the MRI was 2.1+/-1.2 mm for the femur and 2.7+/-1.0 mm for the tibia, respectively. The procedure is highly repeatable, with no significant differences observed within or between the operators (p>0.1) and allows to estimate origins and insertions of the knee ligaments from a CT scan with the same level of accuracy obtainable with MRI. PMID- 25512018 TI - Heparin in the treatment of prosthetic valve thrombosis. PMID- 25512019 TI - Dietary supplementation with omega-3 polyunsaturated fatty acids modulate matrix metalloproteinase immunoreactivity in a mouse model of pre-abdominal aortic aneurysm. AB - BACKGROUND: Two-day infusion of angiotensin II to apolipoprotein E-deficient (ApoE(-/-)) mice provides a model of pre-abdominal aortic aneurysm. Long chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory effects. This study examined the effect of an eight-week low or high n-3 PUFA diet in ApoE(-/-) mice on matrix metalloproteinase (MMP) expression and elastin degradation. METHODS: ApoE(-/-) mice were fed a low or high n-3 PUFA diet for eight weeks prior to two-day infusion with angiotensin II. The omega-3 index, MMP 2, MMP-9, TIMP-1, and TGF-beta1 immunoreactivity, and elastin fragmentation were measured. RESULTS: The omega-3 index with the low and high n-3 PUFA diet was 3.78% and 13.03%, respectively. MMP-9 immunoreactive stain intensity was lower in mice fed the high, compared to the low n-3 PUFA diet in endothelial cells (suprarenal aorta), and inflammatory cells (suprarenal and infrarenal aorta). Inflammatory cells had higher TIMP-1 and TGF-beta1 stain intensity in mice fed the high, compared to the low n-3 PUFA diet (suprarenal aorta). MMP-2 immunoreactivity was unaffected by diet. A non-significant trend for reduced elastin fragmentation was observed in mice fed the high n-3 PUFA diet. CONCLUSION: Dietary supplementation with n-3 PUFAs may have protective anti inflammatory effects mediated through modulation of MMPs and TIMPs. PMID- 25512021 TI - Prostaglandin E2 impairs osteogenic and facilitates adipogenic differentiation of human bone marrow stromal cells. AB - The synthetic glucocorticoid dexamethasone (dex) is a mandatory additive to induce osteogenic differentiation of bone marrow stromal cell (BMSC) in vitro; however it is also known to promote the pathogenesis of osteoporotic bone disease in vivo. In this study human (h)BMSC were cultured in osteogenic medium containing beta-glycerophosphate and ascorbate (OM) and in OM containing dex (OM/D). It was seen that dex induced in human (h)BMSC both, osteogenic and adipogenic differentiation markers. Dex reveals its anti-inflammatory effect by reducing endogenous prostaglandin E2 (PGE2) formation and by suppressing the inducible enzymes cyclooxygenase 2 and microsomal PGE2 synthase 1. It was further seen that dex enhanced the expression of prostaglandin receptors, mainly EP2 and EP4 receptor subtypes. We thus hypothesized that dex enforces the susceptibility of hBMSC to respond to exogenous PGE2. Permanent exposure of hBMSC which were cultured in OM/D to PGE2, decreased osteogenic and increased adipogenic differentiation markers. The effects of PGE2 were preferentially mediated by receptor subtypes EP2 and EP4; EP1 was partially involved in pro-adipogenic effects, and EP3 was partially involved in anti-osteogenic effects. These results suggest that dex suppresses the formation of endogenous PGE2 but also enables hBMSC to respond to PGE2 due to the induction of PGE2 receptors EP2 and EP4. PGE2 then shifts in hBMSC the balance from osteogenic to adipogenic differentiation. PMID- 25512020 TI - Consumers and Carers Versus Pharmacy Staff: Do Their Priorities for Australian Pharmacy Services Align? AB - BACKGROUND: Health professionals, including pharmacists, are encouraged to meet the needs of their consumers in an efficient and patient-centred manner. Yet, there is limited information as to what consumers with chronic conditions need from pharmacy as a healthcare destination or how well pharmacy staff understand these needs. OBJECTIVE: The aim of this study was to identify service user priorities for ideal community pharmacy services for consumers with chronic conditions and their carers, and compare these priorities with what pharmacy staff think these groups want. METHODS: The nominal group technique was undertaken with pharmacist, pharmacy support staff, consumer and carer groups in four Australian regions between December 2012 and April 2013. Participant ideas and priorities for ideal services or care were identified, and contextual insight was obtained by thematic analysis. RESULTS: Twenty-one nominal group sessions are accepted, including 15 consumer and carer, four pharmacist and two pharmacy support staff groups. Pharmacy staff views generally aligned with consumer priorities, such as access, affordability, patient-centred care and continuity and coordinated care, yet diverged with respect to consumer information or education on medication and services. Fundamentally, consumers and carers sought streamlined access to information and medication, in a coordinated, patient centred approach. Alleviating financial burden was a key consumer priority, with a call for the continuation and extension of medication subsidies. CONCLUSION: Overall, pharmacy staff had a reasonable understanding of what consumers would prioritise, but further emphasis on the importance, delivery, or both, of consumer information is needed. Greater consideration is needed from policy makers regarding the financial barriers to accessing medication for consumers with chronic conditions. PMID- 25512023 TI - Fetal cardiac biometry and function in HIV-infected pregnant women exposed to HAART therapy. AB - OBJECTIVE: Previous studies have suggested that antiretroviral therapy in human immunodeficiency virus (HIV)-infected pregnant women can cause alterations in cardiac structure and function in fetuses or children, although the results are not very clear. The aim of this study is to assess whether or not these alterations are present in the heart of fetuses of HIV-infected pregnant women, undergoing treatment with highly active antiretroviral therapy (HAART). STUDY DESIGN: We performed a prospective study on 29 consecutive HIV-positive pregnant women treated with HAART and 70 consecutive HIV-negative pregnant women as controls. Fetal cardiac biometry and function was evaluated by echocardiography at 30-32 weeks of gestation. Fetal biometry, estimated fetal weight and umbilical artery Doppler were also measured. RESULTS: We found E/A tricuspid ratio values slightly increased (0.84 vs 0.80, p = 0.03) and diastolic length shortened (49.7 vs 51.7%, p = 0.03) in the HIV-infected group. The rest of the biometric and functional cardiac parameters were not different between both groups. There were no cases of vertical transmission of HIV infection. CONCLUSION: In HIV-infected pregnant women treated with HAART, no significant changes are showed in fetal cardiac parameters. PMID- 25512022 TI - Dietary flax oil rich in alpha-linolenic acid reduces renal disease and oxylipin abnormalities, including formation of docosahexaenoic acid derived oxylipins in the CD1-pcy/pcy mouse model of nephronophthisis. AB - The CD1-pcy/pcy mouse model of nephronophthisis displays reduced renal docosahexaenoic acid (DHA) levels and alterations in renal cyclooxygenase and lipoxygenase oxylipins derived from n-6 fatty acids. Since dietary flax oil ameliorates disease progression, its effect on renal fatty acids and oxylipins was examined. Sixteen weeks of feeding resulted in reduced disease progression and enrichment of renal phospholipid alpha-linolenic acid (ALA) and eicosapentaenoic acid, reduction in arachidonic acid (AA), but no change in linoleic acid (LA) or DHA. In diseased kidneys, flax oil feeding mitigated the elevated levels of renal cyclooxygenase derived oxylipins formed from AA and the lowered lipoxygenase and cytochrome P450 derived oxylipins formed from ALA and DHA. Increased DHA oxylipins occurred with flax feeding despite not altering DHA levels. Dietary flax oil may therefore reduce disease progression via mitigation of oxylipin abnormalities. This study also provides evidence of in vivo ALA conversion to DHA in amounts necessary to restore DHA oxylipin levels. PMID- 25512024 TI - Prediction of perinatal outcomes based on primary symptoms in women with placental abruption. AB - AIMS: Placental abruption is an important cause of perinatal mortality and morbidity. Although there are many reports on the risk factors for placental abruption, there are few on its classification. Our aim is to evaluate the associations between primary symptoms and the outcomes of placental abruption. MATERIAL AND METHODS: We carried out a retrospective cohort study of 12,474 births at the Perinatal Center for Maternity and Neonates of the Yokohama City University Medical Center between January 2000 and December 2012. There were 151 women with placental abruption, 136 of whom were included in this study. The subjects were classified into two groups according to their primary symptoms: those with bleeding (external bleeding group) and those with abdominal pain (abdominal pain group). Maternal and neonatal outcomes were compared between the two groups. RESULTS: Both fetal and maternal outcomes were significantly poorer in the abdominal pain group than in the external bleeding group in terms of intrauterine fetal death (6.5% vs 33.3%, P < 0.001), perinatal mortality (8.1% vs 33.3%, P = 0.001), umbilical arterial pH < 7.1 (15.7% vs 57.1%, P < 0.001), bleeding volume, rate of blood transfusion, and disseminated intravascular coagulation incidence. CONCLUSIONS: This classification based on primary symptoms was found to be useful for predicting both maternal and neonatal outcomes of placental abruption. PMID- 25512025 TI - Detection and characterization of broad-spectrum antipathogen activity of novel rhizobacterial isolates and suppression of Fusarium crown and root rot disease of tomato. AB - AIMS: To detect and characterize broad-spectrum antipathogen activity of indigenous bacterial isolates obtained from potato soil and soya bean leaves for their potential to be developed as biofungicides to control soilborne diseases such as Fusarium crown and root rot of tomato (FCRR) caused by Fusarium oxysporum f. sp. radicis-lycopersici (Forl). METHODS AND RESULTS: Thirteen bacterial isolates (Bacillus amyloliquefaciens (four isolates), Paenibacillus polymyxa (three isolates), Pseudomonas chlororaphis (two isolates), Pseudomonas fluorescens (two isolates), Bacillus subtilis (one isolate) and Pseudomonas sp. (one isolate)) or their volatiles showed antagonistic activity against most of the 10 plant pathogens in plate assays. Cell-free culture filtrates (CF) of five isolates or 1-butanol extracts of CFs also inhibited the growth of most pathogen mycelia in plate assays. PCR analysis confirmed the presence of most antibiotic biosynthetic genes such as phlD, phzFA, prnD and pltC in most Pseudomonas isolates and bmyB, bacA, ituD, srfAA and fenD in most Bacillus isolates. These bacterial isolates varied in the production of hydrogen cyanide (HCN), siderophores, beta-1,3-glucanases, chitinases, proteases, indole-3-acetic acid, salicylic acid, and for nitrogen fixation and phosphate solubilization. Gas chromatography-mass spectrometry analysis identified 10 volatile compounds from 10 isolates and 18 compounds from 1-butanol extracts of CFs of five isolates. Application of irradiated peat formulation of six isolates to tomato roots prior to transplanting in a Forl-infested potting mix and field soil provided protection of tomato plants from FCRR disease and enhanced plant growth under greenhouse conditions. CONCLUSIONS: Five of the 13 indigenous bacterial isolates were antagonistic to eight plant pathogens, both in vitro and in vivo. Antagonistic and plant-growth promotion activities of these isolates might be related to the production of several types of antibiotics, lytic enzymes, phytohormones, secondary metabolites, siderophores and volatile compounds; however, any specific role of each needs to be determined. SIGNIFICANCE AND IMPACT OF THE STUDY: Indigenous antagonistic bacterial isolates have the potential to be developed as biofungicides for minimizing early crop losses due to soilborne diseases caused by Fusarium and other soilborne pathogens. PMID- 25512026 TI - Half-life and safety of canakinumab in pediatric patients: comment on the article by Ilowite et Al. PMID- 25512027 TI - Croatian dentists' knowledge, experience, and attitudes in regard to child abuse and neglect. AB - BACKGROUND: Child abuse and neglect (CAN) is a widespread social phenomenon encompassing all forms of maltreatment with serious lifelong consequences. Dentists and dental team members are in the unique position to identify the symptoms of CAN often visible in craniofacial region. AIM: To evaluate Croatian dentists' level of knowledge, experience, and attitude towards CAN issue. DESIGN: Investigation was conducted in five major Croatian cities (Zagreb, Varazdin, Osijek, Rijeka, and Split). A previously used questionnaire regarding knowledge and experience in child protection was adopted to Croatian terminology and distributed to 544 dentists. RESULTS: A total of 510 dentists who returned a questionnaire with valid data 26.27% reported to have had suspicion of CAN during professional career and 5.1% reported their suspicion within the last 6 months, mostly to social services and police. Fear of violence towards the child and uncertainty about observations were the most frequently reported barriers towards referring and only 11.4% knew the procedure. About 80% of respondents want further training in identifying and reporting of physical abuse. CONCLUSIONS: Study showed a lack of knowledge and uncertainty in recognizing and reporting CAN cases in Croatian dentists. They expressed the need for undergraduate and post graduate continuing education on this issue. PMID- 25512028 TI - Biofortification of rice with lysine using endogenous histones. AB - Rice is the most consumed cereal grain in the world, but deficient in the essential amino acid lysine. Therefore, people in developing countries with limited food diversity who rely on rice as their major food source may suffer from malnutrition. Biofortification of stable crops by genetic engineering provides a fast and sustainable method to solve this problem. In this study, two endogenous rice lysine-rich histone proteins, RLRH1 and RLRH2, were over expressed in rice seeds to achieve lysine biofortification. Their protein sequences passed an allergic sequence-based homology test. Their accumulations in rice seeds were raised to a moderate level by the use of a modified rice glutelin 1 promoter with lowered expression strength to avoid the occurrence of physiological abnormalities like unfolded protein response. The expressed proteins were further targeted to protein storage vacuoles for stable storage using a glutelin 1 signal peptide. The lysine content in the transgenic rice seeds was enhanced by up to 35 %, while other essential amino acids remained balanced, meeting the nutritional standards of the World Health Organization. No obvious unfolded protein response was detected. Different degrees of chalkiness, however, were detected in the transgenic seeds, and were positively correlated with both the levels of accumulated protein and lysine enhancement. This study offered a solution to the lysine deficiency in rice, while at the same time addressing concerns about food safety and physiological abnormalities in biofortified crops. PMID- 25512029 TI - Short and long-term exposure to diclofenac alter oxidative stress status in common carp Cyprinus carpio. AB - Diclofenac (DCF) has been detected in significant amounts in municipal treated wastewater effluent. Diverse studies report that trace concentrations of DCF may induce toxic effects on different aquatic organisms as well as developmental, reproductive and renal damage. This study aimed to determine whether short and long-term exposure to DCF alter the oxidative stress (OS) status in blood, muscle, gills, brain and liver of common carp Cyprinus carpio. The median lethal concentration of DCF at 96 h (96-h LC50) and subsequently the lowest observed adverse effect level were determined. Carp were exposed (short and long-term) to the latter value for different exposure times (4 and 24 days) and the following biomarkers were evaluated in gill, brain, liver and blood: hydroperoxides content (HPC), lipid peroxidation (LPX), protein carbonyl content (PCC) and the activity of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Also, the DCF was determined by LC-MS/MS. Significant increases in HPC, LPX and PCC were observed respect to control (P < 0.05) particularly in blood, muscle, gill, brain and liver. SOD, CAT and GPx activity also increased in these organs, with respect to controls (P < 0.05). DCF concentrations decreased and increased in water system and carp, respectively. Cyprinus carpio exposed to DCF was affected in OS status during the initial days of the study (at 4 days), exhibiting an increased response at 24 days in blood and liver. In contrast, a decrease was observed in muscle, gills and brain at 24 days with respect to 4 days. In conclusion, DCF induces OS on blood, muscle, gills, brain and liver in the carp C. carpio in short and long-term exposure. The biomarkers employed in this study are useful in the assessment of the environmental impact of this agent on aquatic species. PMID- 25512031 TI - Buprenorphine added to bupivacaine prolongs femoral nerve block duration and improves analgesia in patients undergoing primary total knee arthroplasty-a randomised prospective double-blind study. AB - The aim of the study was to determine whether the addition the long-acting opioid buprenorphine as an adjuvant to the local anaesthetic agent would improve quality and prolong duration of femoral nerve blockade in post-operative analgesia following primary total knee arthroplasty. The study involved 48 patients. The femoral nerve was anaesthetised with a 0.25% solution of bupivacaine with adrenaline or with the addition of 0.3mg of buprenorphine. The duration of the sensory block and analgesic effect was assessed according to NRS scale at 12, 24, 36, 48, 60 and 72 hours post-surgery. Patients who received buprenorphine as an adjuvant to the local anaesthetic had significantly longer sensory blockade and lower NRS-rated pain intensity with the difference reaching statistical significance at 12 hours post-surgery. PMID- 25512030 TI - Anthracycline-free neoadjuvant therapy induces pathological complete responses by exploiting immune proficiency in HER2+ breast cancer patients. AB - BACKGROUND: Neoadjuvant Chemotherapy (NC) including trastuzumab induces a high rate of pathological Complete Responses (pCR) in patients with locally advanced HER2-overexpressing Breast Cancer (BC), but is penalized by a severe cardiotoxicity when combined with anthracyclines. A phase II study was designed to assess whether an anthracycline-free NC regimen based on the early addition of trastuzumab to paclitaxel may increase the pCR rate without inducing severe cardiotoxicity in patients with locally advanced HER2-overexpressing BC. Immunomonitoring was performed to assess the contribution of patients' immunological background to the induction of clinical responses. METHODS: Stage II-III HER2-positive BC patients received 24 weeks paclitaxel and trastuzumab NC, followed by 1 year adjuvant trastuzumab +/- hormonal and/or radio-therapy. Assessment of pCR rate was the primary endpoint. A group of HER2-negative BC patients treated with neoadjuvant taxanes and anthracyclines was included. Serum levels of 10 cytokines and the efficiency of trastuzumab-mediated antibody dependent cell cytotoxicity (ADCC) were monitored in vitro every 3 months. RESULTS: From July 2006 to February 2013, we enrolled 109 patients including 46 evaluable HER2-positive cases. A pCR rate of 50% was reached and no severe cardiotoxicity occurred. Serum cytokine profiling revealed only an IL-10 decrease (P = 0.02) in patients achieving a partial response, while HER2-negative patients disclosed marked cytokines changes. Compared to the unfavourable F/F genotype, patients carrying the V allele in the FcgammaRIIIa-158 polymorphism showed a higher efficacy of trastuzumab-ADCC throughout treatment (P <=0.05). CONCLUSIONS: In the absence of anthracyclines, trastuzumab and paclitaxel induced a high rate of pCR, exploiting the synergy between the immunomodulating properties of these drugs and the retained immunological proficiency of patients with HER2 overexpressing BC. TRIAL REGISTRATION: Trial registration number: NCT02307227, registered on ClinicalTrials.gov (http://www.clinicaltrials.gov, November 26, 2014). PMID- 25512032 TI - The Patient's Age and American Society of Anesthesiologists Status Are Reasonable Criteria for Deciding Whether to Perform Same-Day Bilateral TKA. AB - We investigated whether basing a decision to perform same-day bilateral TKA (SD BTKA) on the patient's age and American Society of Anesthesiologists (ASA) status was reasonable. We retrospectively reviewed the records of 1386 patients who underwent 2086 TKAs (686 unilateral TKAs [UTKAs], 1038 SD BTKAs, and 362 one-week staged BTKAs). For the entire cohort, patients undergoing SD BTKA had a higher risk of major complications compared to those undergoing UTKA. However, there was no difference in the incidence of complications for patients aged<75 years with an ASA status of 1 or 2 who underwent UTKA or SD BTKA. If patients are selected based on age and ASA status, SD BTKA may have a risk of postoperative complication similar to UTKA. PMID- 25512033 TI - An unusual and serious cause of gastritis: emphysematous gastritis. PMID- 25512034 TI - Spontaneous healing of an osteochondroma fracture. AB - Osteochondroma is the most common benign tumor of bone, usually asymptomatic. Fracture of an osteochondroma is a rare complication and has been recognized as a cause of pain. Treatment of this fracture is controversial and some authors suggest fracture as an indication for surgical excision. We present a case of fractured osteochondroma that healed without complication. PMID- 25512035 TI - Granular cell breast cancer: a rare misleading lesion. PMID- 25512036 TI - Multicystic kidney disease: a complication of crizotinib. PMID- 25512037 TI - Engineering connectivity by multiscale micropatterning of individual populations of neurons. AB - Functional networks are the basis of information processing in the central nervous system. Essential for their formation are guided neuronal growth as well as controlled connectivity and information flow. The basis of neuronal development is generated by guiding cues and geometric constraints. To investigate the neuronal growth and connectivity of adjacent neuronal networks, two-dimensional protein patterns were created. A mixture of poly-L-lysine and laminin was transferred onto a silanized glass surface by microcontact printing. The structures were populated with dissociated primary cortical embryonic rat neurons. Triangular structures with diverse opening angles, height, and design were chosen as two-dimensional structures to allow network formation with constricted gateways. Neuronal development was observed by immunohistochemistry to pursue the influence of the chosen structures on the neuronal outgrowth. Neurons were stained for MAP2, while poly-L-lysine was FITC labeled. With this study we present an easy-to-use technique to engineer two-dimensional networks in vitro with defined gateways. The presented micropatterning method is used to generate daisy-chained neuronal networks with predefined connectivity. Signal propagation among geometrically constrained networks can easily be monitored by calcium-sensitive dyes, providing insights into network communication in vitro. PMID- 25512038 TI - Precision and neuronal dynamics in the human posterior parietal cortex during evidence accumulation. AB - Primate studies show slow ramping activity in posterior parietal cortex (PPC) neurons during perceptual decision-making. These findings have inspired a rich theoretical literature to account for this activity. These accounts are largely unrelated to Bayesian theories of perception and predictive coding, a related formulation of perceptual inference in the cortical hierarchy. Here, we tested a key prediction of such hierarchical inference, namely that the estimated precision (reliability) of information ascending the cortical hierarchy plays a key role in determining both the speed of decision-making and the rate of increase of PPC activity. Using dynamic causal modelling of magnetoencephalographic (MEG) evoked responses, recorded during a simple perceptual decision-making task, we recover ramping-activity from an anatomically and functionally plausible network of regions, including early visual cortex, the middle temporal area (MT) and PPC. Precision, as reflected by the gain on pyramidal cell activity, was strongly correlated with both the speed of decision making and the slope of PPC ramping activity. Our findings indicate that the dynamics of neuronal activity in the human PPC during perceptual decision-making recapitulate those observed in the macaque, and in so doing we link observations from primate electrophysiology and human choice behaviour. Moreover, the synaptic gain control modulating these dynamics is consistent with predictive coding formulations of evidence accumulation. PMID- 25512039 TI - Non-holistic coding of objects in lateral occipital complex with and without attention. AB - A fundamental issue in visual cognition is whether high-level visual areas code objects in a part-based or a view-based (holistic) format. Previous behavioral and neuroimaging studies that examined the viewpoint invariance of object recognition have yielded ambiguous results, providing evidence for either type of representational format. A critical factor distinguishing the two formats could be the availability of attentional resources, as a number of priming studies have found greater viewpoint invariance for attended compared to unattended objects. It has therefore been suggested that the activation of part-based representations requires attention, whereas the activation of holistic representations occurs automatically irrespective of attention. Using functional magnetic resonance imaging in combination with a novel multivariate pattern analysis approach, the present study probed the format of object representations in human lateral occipital complex and its dependence on attention. We presented human participants with intact and half-split versions of objects that were either attended or unattended. Cross-classifying between intact and split objects, we found that the object-related information coded in activation patterns of intact objects is fully preserved in the patterns of split objects and vice versa. Importantly, the generalization between intact and split objects did not depend on attention. We conclude that lateral occipital complex codes objects in a non holistic format, both in the presence and absence of attention. PMID- 25512040 TI - Brain activity dynamics in human parietal regions during spontaneous switches in bistable perception. AB - The neural mechanisms underlying conscious visual perception have been extensively investigated using bistable perception paradigms. Previous functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) studies suggest that the right anterior superior parietal (r-aSPL) and the right posterior superior parietal lobule (r-pSPL) have opposite roles in triggering perceptual reversals. It has been proposed that these two areas are part of a hierarchical network whose dynamics determine perceptual switches. However, how these two parietal regions interact with each other and with the rest of the brain during bistable perception is not known. Here, we investigated such a model by recording brain activity using fMRI while participants viewed a bistable structure-from-motion stimulus. Using dynamic causal modeling (DCM), we found that resolving such perceptual ambiguity was specifically associated with reciprocal interactions between these parietal regions and V5/MT. Strikingly, the strength of bottom-up coupling between V5/MT to r-pSPL and from r-pSPL to r-aSPL predicted individual mean dominance duration. Our findings are consistent with a hierarchical predictive coding model of parietal involvement in bistable perception and suggest that visual information processing underlying spontaneous perceptual switches can be described as changes in connectivity strength between parietal and visual cortical regions. PMID- 25512041 TI - Neural mechanisms underlying song and speech perception can be differentiated using an illusory percept. AB - The issue of whether human perception of speech and song recruits integrated or dissociated neural systems is contentious. This issue is difficult to address directly since these stimulus classes differ in their physical attributes. We therefore used a compelling illusion (Deutsch et al. 2011) in which acoustically identical auditory stimuli are perceived as either speech or song. Deutsch's illusion was used in a functional MRI experiment to provide a direct, within subject investigation of the brain regions involved in the perceptual transformation from speech into song, independent of the physical characteristics of the presented stimuli. An overall differential effect resulting from the perception of song compared with that of speech was revealed in right midposterior superior temporal sulcus/right middle temporal gyrus. A left frontotemporal network, previously implicated in higher-level cognitive analyses of music and speech, was found to co-vary with a behavioural measure of the subjective vividness of the illusion, and this effect was driven by the illusory transformation. These findings provide evidence that illusory song perception is instantiated by a network of brain regions that are predominantly shared with the speech perception network. PMID- 25512043 TI - Some long-standing and emerging research lines in Africa. AB - Early research on child development in Africa was dominated by expatriates and was primarily addressed to the topics of testing the cross-cultural validity of theories developed "in the West," and the search for universals. After a brief review of the outcome of that research, we propose two additional types of motivation that seem important to us as African researchers begin to take the lead in articulating research agendas for the study of child development in Africa: articulating the contextual relevance and practical usefulness of developmental psychology in Africa; and making developmental psychology intelligible to local audiences. We highlight two major challenges for African societies in this era that call for attention by the emerging field of African child development research: linguistic hegemony and its effects on research and schooling; and the process of indigenization. We end with a preview of chapters in the rest of the volume. PMID- 25512042 TI - Vascular and lung function related to ultrafine and fine particles exposure assessed by personal and indoor monitoring: a cross-sectional study. AB - BACKGROUND: Exposure to ambient air particulate matter (PM) has been linked to decline in pulmonary function and cardiovascular events possibly through inflammation. Little is known about individual exposure to ultrafine particles (UFP) inside and outside modern homes and associated health-related effects. METHODS: Associations between vascular and lung function, inflammation markers and exposure in terms of particle number concentration (PNC; d = 10-300 nm) were studied in a cross-sectional design with personal and home indoor monitoring in the Western Copenhagen Area, Denmark. During 48-h, PNC and PM2.5 were monitored in living rooms of 60 homes with 81 non-smoking subjects (30-75 years old), 59 of whom carried personal monitors both when at home and away from home. We measured lung function in terms of the FEV1/FVC ratio, microvascular function (MVF) and pulse amplitude by digital artery tonometry, blood pressure and biomarkers of inflammation including C-reactive protein, and leukocyte counts with subdivision in neutrophils, eosinophils, monocytes, and lymphocytes in blood. RESULTS: PNC from personal and stationary home monitoring showed weak correlation (r = 0.15, p = 0.24). Personal UFP exposure away from home was significantly inversely associated with MVF (1.3% decline per interquartile range, 95% confidence interval: 0.1-2.5%) and pulse amplitude and positively associated with leukocyte and neutrophil counts. The leukocyte and neutrophil counts were also positively and pulse amplitude negatively associated with total personal PNC. Indoor PNC and PM2.5 showed positive association with blood pressure and inverse association with eosinophil counts. CONCLUSIONS: The inverse association between personal exposure away from home and MVF is consistent with adverse health effects of UFP from sources outside the home and might be related to increased inflammation indicated by leukocyte counts, whereas UFP from sources in the home could have less effect. PMID- 25512044 TI - Biomedical risk, psychosocial influences, and developmental outcomes: lessons from the pediatric HIV population in Africa. AB - Sub-Saharan Africa is home to millions of HIV-affected children. These children are likely to experience multiple developmental delays. In this chapter, I present data highlighting compromised neurobehavioral, mental health, and scholastic outcomes for children affected by HIV. Furthermore, I discuss biomedical factors (e.g., disease severity and nutritional status) that may exacerbate the adverse effects of HIV on childhood outcomes. I also present evidence on how psychosocial risk factors such as poor maternal mental health, orphanhood, and poverty may aggravate the effects of HIV. The concluding section of the chapter highlights conceptual and methodological refinements in research on the impact of HIV on child development in Sub-Saharan Africa. PMID- 25512045 TI - African early childhood development curriculum and pedagogy for Turkana nomadic pastoralist communities of Kenya. AB - Western conceptions of child development and the models of early education they engender predominantly shape services for young children in the first eight years of life all over Africa. This chapter brings a reconceptualist perspective to the critique of Kenya's continuing failure to ground early childhood programs and services in local cultural conceptions, developmental values, childrearing practices, and the practical day-to-day realities of children's learning through participation and apprenticeship in the contexts of family routines, community experiences, and economic survival activities. The chapter draws on work I have conducted in nomadic pastoralist communities in Kenya. That research reveals the disconcerting reality that (a) early childhood education programs privilege Western pedagogical practices over equally effective and locally more relevant ones, and (b) local communities are increasingly resentful of an educational system that alienates their children from their cultural roots in the name of modernization. Asserting the educational value of indigenous knowledge, I present a framework for integrating that knowledge and the naturalistic learning processes in local contexts into instructional programs in formal ECE settings. PMID- 25512046 TI - Promoting children's sustainable access to early schooling in Africa: reflections on the roles of parents in their children's early childhood care and education. AB - Sub-Saharan Africa has predominantly rural populations unable to offer children sustainable access to early literacy and childhood care and education. Children's literacy development starts very early in life through participation and experiences in the home and preschool. My research in rural Zimbabwe, Kenya, Uganda, and Tanzania shows that the transition from home to school is compromised by acute barriers such as lack of parental participation, lack of encouragement and support from teachers, and unavailability of learning materials. However, rural homes and communities are well endowed with a stock of practices, knowledge, and skills relevant to the promotion of literacy development. In this chapter, I reflect on how to empower parents to draw on knowledge and resources within the local context to become better involved in their children's education while also empowering teachers to better recognize and take advantage of local knowledge and resources to enrich instruction and enhance meaningful learning. PMID- 25512047 TI - Design and validation of assessment tests for young children in Zambia. AB - Early childhood education has received unprecedented attention among African policymakers in recent years, recognizing that the early years form an important foundation upon which later development is anchored and noting evidence that various Early Childhood Development (ECD) indicators are predictive of future academic success. Central to the provision of quality early childhood education is assessment of developmental outcomes. But currently there is little systematic documentation of culturally appropriate child assessment instruments in Africa. We briefly review the literature on cross-cultural issues in child assessment and identify a variety of approaches to test design and adaptation. We then describe the process through which two child assessment instruments were developed in the Zambian context and empirical evidence was collected of their ecocultural and psychometric validity: the Panga Munthu Test and the Zambia Child Assessment Tool (ZamCAT). Implications are derived from these examples for future development of culturally responsive child assessment instruments in Africa. PMID- 25512048 TI - Some growth points in African child development research. AB - We reflect on ways in which research presented in earlier chapters responds to challenges of generating an African child development field and identify additional issues calling for the field's attention. The chapters collectively display a variety of African contexts and reflexive evidence of the authors' African cultural roots. Connecting research with African audiences demands cooperative communication between educational practitioners and parents with low literacy, and cross-sector communication among professionals. Intracultural exploration of factors influencing the pattern of human development has begun to document the potential of indigenous African cultures as a fund of resources for enhancing child development. Priority topics for future African developmental research include multilingualism, musical performance, socially distributed caregiving, and the relation between adolescence and economic activity. Integration of multiple disciplines in the application of research-based principles to service delivery in the fields of community-based (re)habilitation and early childhood care and education calls for researcher collaboration with practitioners. PMID- 25512049 TI - About seed and soil. PMID- 25512050 TI - The unthinking or confident extremist? Political extremists are more likely than moderates to reject experimenter-generated anchors. AB - People with extreme political opinions are alternatively characterized as being relatively unthinking or as confident consumers and practitioners of politics. In three studies, we tested these competing hypotheses using cognitive anchoring tasks (total N = 6,767). Using two different measures of political extremity, we found that extremists were less influenced than political moderates by two types of experimenter-generated anchors (Studies 1-3) and that this result was mediated by extremists' belief superiority (Study 2). Extremists and moderates, however, were not differentially influenced by self-generated anchors (Study 2), which suggests that extremists differentiated between externally and internally generated anchors. These results are consistent with the confident-extremist perspective and contradict the unthinking-extremist perspective. The present studies demonstrate the utility of adopting a basic cognitive task to investigate the relationship between ideology and cognitive style and suggest that extremity does not necessarily beget irrationality. PMID- 25512051 TI - All claims in the original article hold as stated: a response to Arkes (2015). PMID- 25512052 TI - What is typical is good: the influence of face typicality on perceived trustworthiness. AB - The role of face typicality in face recognition is well established, but it is unclear whether face typicality is important for face evaluation. Prior studies have focused mainly on typicality's influence on attractiveness, although recent studies have cast doubt on its importance for attractiveness judgments. Here, we argue that face typicality is an important factor for social perception because it affects trustworthiness judgments, which approximate the basic evaluation of faces. This effect has been overlooked because trustworthiness and attractiveness judgments have a high level of shared variance for most face samples. We show that for a continuum of faces that vary on a typicality-attractiveness dimension, trustworthiness judgments peak around the typical face. In contrast, perceived attractiveness increases monotonically past the typical face, as faces become more like the most attractive face. These findings suggest that face typicality is an important determinant of face evaluation. PMID- 25512053 TI - ATM and ATR as therapeutic targets in cancer. AB - In order to maintain genomic stability, cells have developed sophisticated signalling pathways to enable DNA damage or DNA replication stress to be resolved. Key mediators of this DNA damage response (DDR) are the ATM and ATR kinases, which induce cell cycle arrest and facilitate DNA repair via their downstream targets. Inhibiting the DDR has become an attractive therapeutic concept in cancer therapy, since (i) resistance to genotoxic therapies has been associated with increased DDR signalling, and (ii) many cancers have defects in certain components of the DDR rendering them highly dependent on the remaining DDR pathways for survival. ATM and ATR act as the apical regulators of the response to DNA double strand breaks and replication stress, respectively, with overlapping but non-redundant activities. Highly selective small molecule inhibitors of ATM and ATR are currently in preclinical and clinical development, respectively. Preclinical data have provided a strong rationale for clinical testing of these compounds both in combination with radio- or chemotherapy, and in synthetic lethal approaches to treat tumours with deficiencies in certain DDR components. Whole genome sequencing studies have reported that mutations in DDR genes occur with a high frequency in many common tumour types, suggesting that a synthetic lethal approach with ATM or ATR inhibitors could have widespread utility, providing that appropriate biomarkers are developed. PMID- 25512055 TI - How needs and preferences of employees influence participation in health promotion programs: a six-month follow-up study. AB - BACKGROUND: Low participation in health promotion programs (HPPs) might hamper their effectiveness. A potential reason for low participation is disagreement between needs and preferences of potential participants and the actual HPPs offered. This study aimed to investigate employees' need and preferences for HPPs, whether these are matched by what their employers provide, and whether a higher agreement enhanced participation. METHODS: Employees of two organizations participated in a six-month follow-up study (n = 738). At baseline, information was collected on employees' needs and preferences for the topic of the HPP (i.e. physical activity, healthy nutrition, smoking cessation, stress management, general health), whether they favored a HPP via their employer or at their own discretion, and their preferred HPP regarding three components with each two alternatives: mode of delivery (individual vs. group), intensity (single vs. multiple meetings), and content (assignments vs. information). Participation in HPPs was assessed at six-month follow-up. In consultation with occupational health managers (n = 2), information was gathered on the HPPs the employers provided. The level of agreement between preferred and provided HPPs was calculated (range: 0-1) and its influence on participation was studied using logistic regression analyses. RESULTS: Most employees reported needing a HPP addressing physical activity (55%) and most employees preferred HPPs organized via their employer. The mean level of agreement between the preferred and offered HPPs ranged from 0.71 for mode of delivery to 0.84 for intensity, and was 0.47 for all three HPP components within a topic combined. Employees with a higher agreement on mode of delivery (OR: 1.72, 95% CI: 0.87-3.39) and all HPP components combined (OR: 2.36, 95% CI: 0.68-8.17) seemed to be more likely to participate in HPPs, but due to low participation these associations were not statistically significant. CONCLUSION: HPPs aimed at physical activity were most needed by employees. The majority of employees favor HPPs organized via the employer above those at their own discretion, supporting the provision of HPPs at the workplace. This study provides some indications that a higher agreement between employees' needs and preferences and HPPs made available by their employers will enhance participation. PMID- 25512056 TI - Long-term efficacy of current thyroid prophylaxis and future perspectives on thyroid protection during 131I-metaiodobenzylguanidine treatment in children with neuroblastoma. AB - PURPOSE: Treatment with (131)I-MIBG is associated with significant thyroid damage. This study was undertaken to investigate the long-term efficacy of current thyroid prophylaxis, to explore the relationship between thyroid dysfunction and thyroid volume after exposure to (131)I-MIBG and to evaluate the possible negative effects of (131)I(-) on the parathyroid glands. METHODS: Of 81 long-term surviving patients with neuroblastoma treated with (131)I-MIBG during the period 1999-2012, 24 were finally evaluated. Patients received thyroxine (T4), methimazole and potassium iodide as thyroid protection. In all patients (para)thyroid function was evaluated and ultrasound investigation of the (para)thyroid gland(s) was performed. Thyroid dysfunction was defined as a plasma thyrotropin concentration >5.0 mU/L (thyrotropin elevation, TE) or as the use of T4 at the time of follow-up. Hyperparathyroidism was defined as a serum calcium concentration above the age-related reference range in combination with an inappropriately high parathyroid hormone level. RESULTS: At a median follow-up of 9.0 years after (131)I-MIBG treatment, thyroid disorders were seen in 12 patients (50 %; 9 with TE, 5 with a thyroid nodule and 1 patient was subsequently diagnosed with differentiated thyroid carcinoma). No significant risk factors for the occurrence of thyroid damage could be identified. In 14 of 21 patients (67 %) in whom thyroid volume could be determined, the volume was considered small (< 2SD) for age and gender. Patients treated with T4 at the time of follow-up had significantly smaller thyroid volumes for age than patients without T4 treatment (p = 0.014). None of the patients was diagnosed with hyperparathyroidism. CONCLUSION: Thyroid protection during treatment with (131)I-MIBG needs attention and must be further improved, as thyroid disorders are still frequently seen despite current thyroid prophylaxis. Reduced thyroid volume in neuroblastoma survivors may be related to previous (131)I-MIBG therapy or current T4 treatment. No deleterious effects of (131)I-MIBG on the parathyroid glands could be found. PMID- 25512054 TI - Genes associated with thermosensitive genic male sterility in rice identified by comparative expression profiling. AB - BACKGROUND: Thermosensitive genic male sterile (TGMS) lines and photoperiod sensitive genic male sterile (PGMS) lines have been successfully used in hybridization to improve rice yields. However, the molecular mechanisms underlying male sterility transitions in most PGMS/TGMS rice lines are unclear. In the recently developed TGMS-Co27 line, the male sterility is based on co suppression of a UDP-glucose pyrophosphorylase gene (Ugp1), but further study is needed to fully elucidate the molecular mechanisms involved. RESULTS: Microarray based transcriptome profiling of TGMS-Co27 and wild-type Hejiang 19 (H1493) plants grown at high and low temperatures revealed that 15462 probe sets representing 8303 genes were differentially expressed in the two lines, under the two conditions, or both. Environmental factors strongly affected global gene expression. Some genes important for pollen development were strongly repressed in TGMS-Co27 at high temperature. More significantly, series-cluster analysis of differentially expressed genes (DEGs) between TGMS-Co27 plants grown under the two conditions showed that low temperature induced the expression of a gene cluster. This cluster was found to be essential for sterility transition. It includes many meiosis stage-related genes that are probably important for thermosensitive male sterility in TGMS-Co27, inter alia: Arg/Ser-rich domain (RS) containing zinc finger proteins, polypyrimidine tract-binding proteins (PTBs), DEAD/DEAH box RNA helicases, ZOS (C2H2 zinc finger proteins of Oryza sativa), at least one polyadenylate-binding protein and some other RNA recognition motif (RRM) domain-containing proteins involved in post-transcriptional processes, eukaryotic initiation factor 5B (eIF5B), ribosomal proteins (L37, L1p/L10e, L27 and L24), aminoacyl-tRNA synthetases (ARSs), eukaryotic elongation factor Tu (eEF Tu) and a peptide chain release factor protein involved in translation. The differential expression of 12 DEGs that are important for pollen development, low temperature responses or TGMS was validated by quantitative RT-PCR (qRT-PCR). CONCLUSIONS: Temperature strongly affects global gene expression and may be the common regulator of fertility in PGMS/TGMS rice lines. The identified expression changes reflect perturbations in the transcriptomic regulation of pollen development networks in TGMS-Co27. Findings from this and previous studies indicate that sets of genes involved in post-transcriptional and translation processes are involved in thermosensitive male sterility transitions in TGMS Co27. PMID- 25512057 TI - Embolic and Hemodynamic Transcranial Doppler Characteristics in Patients with Acute Ischemic Stroke due to Carotid Occlusive Disease: Contribution to the Different Infarct Patterns on MRI. AB - BACKGROUND AND PURPOSE: Whether hemodynamic and/or embolic transcranial Doppler (TCD) features of internal carotid artery (ICA) stenosis contribute to the classification of stroke patterns on MRI. PATIENTS AND METHODS: Consecutive patients presenting symptomatic >=50% ICA stenosis were included. Microembolic signals (MES) detection and measurement of cerebral vasoreactivity (VR) were performed by TCD. Only acute MRI lesions, territorial (TT) and/or borderzone (BZ) were considered. RESULTS: A total of 72 ICA stenoses, 27 (38%) moderate (50-69%), and 45 (62%) high grade (70-99%) were included. MRI lesions showed 32 (44%) pure TT, 20 (28%) pure BZ, and 20 (28%) mixed TT and BZ. Impaired VR was found more frequently among patients with higher degrees of stenoses (P < .001) whereas MES were similarly encountered in both groups (P = NS). Impaired VR was more common in the BZ (10/20, 50%) than in the TT group (9/32, 28%, P < .1) while MES were present in 47% (15/32) of patients with TT and in 30% (6/20, P < .1) of those with BZ lesions, in particular in cortical BZ infarcts (P < .02). CONCLUSION: Our findings suggest that TCD characteristics of the ICA stenosis contribute to better define stroke patterns on MRI in about one-third of the patients presenting with pure TT or BZ lesions. PMID- 25512058 TI - Relatively high levels of anti-HLA antibodies (measured by Luminex Single-Antigen bead assay) are required to mediate inhibition of lymphocyte proliferation induced by sera from alloimmunized renal patients. AB - BACKGROUND: Rejection of transplanted organs is caused by alloimmune responses, primarily against HLA molecules. Anti-donor HLA antibodies are associated with antibody-mediated rejection (AMR) and poor graft outcome. Because of clinical interest in detecting these antibodies, new technologies have recently been introduced to increase the sensitivity of detection. The Luminex Single-Antigen (LSA) bead assay may yield new information, but it must be validated against biological and clinical data. MATERIAL AND METHODS: Based on previously published data regarding the in vitro effects of anti-HLA antibodies on lymphocytes, we measured the effect on lymphocytes of sera from patients on the transplant waiting list who had high titers of anti-HLA antibodies. Anti-CD3-mediated lymphocyte activation was studied in the presence of whole serum from these patients. Changes in lymphocyte proliferation, measured by carboxyfluorescein succinimidyl ester (CFSE) labeling, were detected, and these changes correlated with the level of anti-HLA antibodies. RESULTS: Whole serum containing anti-HLA antibodies inhibited lymphocyte proliferation; this effect correlated with the level of antibodies, as measured by LSA. This inhibitory effect was HLA-specific, as shown by adsorption experiments. We also found that relatively high levels of anti-HLA antibodies were necessary to induce changes in an in vitro model of lymphocyte proliferation. CONCLUSIONS: Our results demonstrate the clinical utility of detecting anti-HLA antibodies by LSA. PMID- 25512059 TI - MRI findings in soccer players with long-standing adductor-related groin pain and asymptomatic controls. AB - BACKGROUND: Soccer players are commonly affected by long-standing adductor related groin pain (ARGP), but the clinical significance of MRI findings in these athletes is largely unknown. Our aims were (1) to evaluate whether MRI findings are associated with long-standing ARGP in soccer players, (2) to assess MRI findings in asymptomatic soccer players and non-soccer playing controls. METHODS: This cross-sectional study included 28 male soccer players with long-standing ARGP, 17 male asymptomatic soccer players and 20 male asymptomatic non-soccer playing athletes of matching age and athletic exposure. Participants underwent identical standardised and reliable clinical examination, and MRI scans (3 T) of the pelvis performed by a blinded observer. Images were consensus rated by three blinded radiologists according to a standardised MRI evaluation protocol. The associations between clinical adductor-related findings and pathological MRI findings were investigated with chi(2) statistics and OR. RESULTS: Central disc protrusion (p=0.027) and higher grades of pubic bone marrow oedema (BMO; p=0.027) were significantly more present in symptomatic players than asymptomatic players. However, up to 71% of asymptomatic soccer players displayed different positive MRI findings, and asymptomatic soccer players had significantly higher odds (OR ranging from 6.3 to 13.3) for BMO, adductor tendinopathy and degenerative changes than non-soccer players. CONCLUSIONS: ARGP in soccer players was associated with central disc protrusion and higher grades of pubic BMO. Moreover, positive MRI findings were significantly more frequent in soccer players compared with non soccer players irrespective of symptoms, suggesting that these MRI changes may be associated with soccer play itself rather than clinical symptoms. PMID- 25512061 TI - A home-based individualized information communication technology training program for older adults: a demonstration of effectiveness and value. AB - PURPOSE: To demonstrate the effectiveness and value of a home-based information communication technology (ICT) training program for older adults. METHODS: Thirteen older adults were provided in-home ICT training by graduate occupational therapy students using an iPad. The breadth and frequency of ICT use, perspectives on technology, and perceived independence were recorded at baseline, during the 3-month training and at follow-up, along with an end-of-study questionnaire. Non-parametric Friedman analysis was conducted to verify trends in the outcome measures. The qualitative data were examined by content analysis. RESULTS: Participants' breadth of ICT activities showed a significant trend across 6 months. Leisure accounted for the significant increase, while health management and social connections activities increased modestly. A positive trend in participants' perspectives on technology was evident along with a marginal increase in perceived independence. Participants' perspectives were thematically categorized as technology experiences, interactions with coach, training approach, and specific activities. As reflection of the training program's value, 12 of the 13 participants took ownership of the iPad at the end of the study. CONCLUSION: Building capacity of older adults to utilize the multifaceted potential of ICT is critical in addressing declines in health, impending disabilities, and social isolation. Implications for Rehabilitation A one-on-one home-based individualized information communication technology (ICT) training program for older adults could result in a progressive increase in the breadth of online activities carried out by them. Specifically, the increase in their usage of ICT could be expected in leisure-based online activities. Individualized training programs designed based on needs, priorities, and learning style of older adults could have a positive impact on their technological perspectives and intrinsic motivation to adopt ICT. PMID- 25512060 TI - Lasers for nevi: a review. AB - A nevus is described as a benign, often pigmented, skin growth that can be congenital or acquired. Different types of nevi are located at different depths within the skin. Traditional treatments for nevi include topical treatments, dermabrasion, and excision, which are generally ineffective, invasive, and often result in scars and dyspigmentation. Lately, laser therapy has been used as an alternative. Based on the theory of selective photothermolysis, melanin can be specifically targeted, minimizing adverse effects and increasing effectiveness of laser treatments. Several types of lasers and lights have been studied for this purpose without a concise agreement as to which is the best. In general, quality switched lasers are preferred for the treatment of pigmented lesions. However, there is controversy about this therapy because certain nevi may have malignant potential. This article serves as a comprehensive review of available laser treatments for nevi and discusses the appropriate measures that should be taken before and after laser therapy. Based on the reviewed literature, laser treatment has generally been proven to be a safe and effective therapy for nevi with minimal side effects. PMID- 25512063 TI - Application of a multidisciplinary model to a case example of presurgical epilepsy planning. AB - This article presents a case example which illustrates the multidisciplinary model for presurgical assessment for epilepsy patients. Nearly three million people in the United States are diagnosed with epilepsy and more than one third of this population is refractory to pharmacological treatment. Poor seizure control is associated with additional impairment in quality of life and cognitive and social functioning, and even with premature death. In accordance with these concerns, surgical intervention is increasingly recognized as a viable treatment option, which should be considered soon after drug resistance becomes apparent. Despite the widespread evidence of effectiveness surgery is often delayed, in part because of the necessity, and difficulties, of correctly applying a multidisciplinary approach to presurgical assessment. And yet, a multidisciplinary team is crucial in the evaluation of risks and benefits of possible surgical intervention and in guiding the surgical procedure to maximize seizure control and minimize risk to eloquent cortex. In the model and complex case presented, the neuropsychologist has a critical role in the presurgical evaluation, as well as in the postsurgical evaluation of outcome. PMID- 25512064 TI - Polymorphisms in the feline TNFA and CD209 genes are associated with the outcome of feline coronavirus infection. AB - Feline infectious peritonitis (FIP), caused by feline coronavirus (FCoV) infection, is a highly lethal disease without effective therapy and prevention. With an immune-mediated disease entity, host genetic variant was suggested to influence the occurrence of FIP. This study aimed at evaluating cytokine associated single nucleotide polymorphisms (SNPs), i.e., tumor necrosis factor alpha (TNF-alpha), receptor-associated SNPs, i.e., C-type lectin DC-SIGN (CD209), and the five FIP-associated SNPs identified from Birman cats of USA and Denmark origins and their associations with the outcome of FCoV infection in 71 FIP cats and 93 FCoV infected non-FIP cats in a genetically more diverse cat populations. A promoter variant, fTNFA - 421 T, was found to be a disease-resistance allele. One SNP was identified in the extracellular domain (ECD) of fCD209 at position +1900, a G to A substitution, and the A allele was associated with FIP susceptibility. Three SNPs located in the introns of fCD209, at positions +2276, +2392, and +2713, were identified to be associated with the outcome of FCoV infection, with statistical relevance. In contrast, among the five Birman FIP cat associated SNPs, no genotype or allele showed significant differences between our FIP and non-FIP groups. As disease resistance is multifactorial and several other host genes could involve in the development of FIP, the five genetic traits identified in this study should facilitate in the future breeding of the disease resistant animal to reduce the occurrence of cats succumbing to FIP. PMID- 25512066 TI - Characterisation of chlorate reduction in the haloarchaeon Haloferax mediterranei. AB - BACKGROUND: Haloferax mediterranei is a denitrifying haloarchaeon using nitrate as a respiratory electron acceptor under anaerobic conditions in a reaction catalysed by pNarGH. Other ions such as bromate, perchlorate and chlorate can also be reduced. METHODS: Hfx. mediterranei cells were grown anaerobically with nitrate as electron acceptor and chlorate reductase activity measured in whole cells and purified nitrate reductase. RESULTS: No genes encoding (per)chlorate reductases have been detected either in the Hfx. mediterranei genome or in other haloarchaea. However, a gene encoding a chlorite dismutase that is predicted to be exported across the cytoplasmic membrane has been identified in Hfx. mediterranei genome. Cells did not grow anaerobically in presence of chlorate as the unique electron acceptor. However, cells anaerobically grown with nitrate and then transferred to chlorate-containing growth medium can grow a few generations. Chlorate reduction by the whole cells, as well as by pure pNarGH, has been characterised. No clear chlorite dismutase activity could be detected. CONCLUSIONS: Hfx. mediterranei pNarGH has its active site on the outer-face of the cytoplasmic membrane and reacts with chlorate and perchlorate. Biochemical characterisation of this enzymatic activity suggests that Hfx. mediterranei or its pure pNarGH could be of great interest for waste water treatments or to better understand biological chlorate reduction in early Earth or Martian environments. GENERAL SIGNIFICANCE: Some archaea species reduce (per)chlorate. However, results here presented as well as those recently reported by Liebensteiner and co-workers [1] suggest that complete perchlorate reduction in archaea follows different rules in terms of biological reactions. PMID- 25512065 TI - Photocytotoxicity of a cyanine dye with two chromophores toward melanoma and normal cells. AB - BACKGROUND: Due to high optical absorption, triplet quantum yield and affinity to biological structures bichromophoric cyanine dyes (BCDs) can be considered promising sensitizers for application in photodynamic therapy (PDT). In this work, we report on the study of the BCD photocytotoxicity toward melanoma and normal cells in comparison with that of commercial photosensitizer Photogem(r). METHODS: The cytotoxic and phototoxic effects were measured by standard tests of cell viability. The drug uptake was obtained by the flow cytometry and optical absorption techniques. The BCD intracellular distribution was obtained by the fluorescence image microscopy using specific organelle markers. RESULTS: Both drugs demonstrated increased cytotoxicity under irradiation, while in darkness their cytotoxic effect at concentrations lower than 20 MUM after 24 h of incubation did not exceed 20%. For 5 h of incubation, BCD photocytotoxicity in relation to melanoma cells reached 100% already at concentrations below 5 MUM, while for normal cells the effect did not exceed 70% even for the 20 MUM concentration. It is shown that BCD penetrates into the cells and is located predominantly in perinuclear cytoplasmic structures. CONCLUSIONS: The BCD photosensitizing characteristics appear more adequate for application in PDT than that of the actually applied commercial photosensitizer Photogem(r). Higher light absorption by BCD in the near IR region and its preferential localization in mitochondria can explain its high photocytotoxicity. GENERAL SIGNIFICANCE: BCD can be considered as a new promising photosensitizer class for cancer PDT. PMID- 25512067 TI - Post-translational modifications on yeast carbon metabolism: Regulatory mechanisms beyond transcriptional control. AB - BACKGROUND: Yeast cells have developed a variety of mechanisms to regulate the activity of metabolic enzymes in order to adjust their metabolism in response to genetic and environmental perturbations. This can be achieved by a massive reprogramming of gene expression. However, the transcriptional response cannot explain the complexity of metabolic regulation, and mRNA stability regulation, non-covalent binding of allosteric effectors and post-translational modifications of enzymes (such as phosphorylation, acetylation and ubiquitination) are also involved, especially as short term responses, all converging in modulating enzyme activity. SCOPE OF REVIEW: The functional significance of post-translational modifications (PTMs) to the regulation of the central carbon metabolism is the subject of this review. MAJOR CONCLUSIONS: A genome wide analysis of PTMs indicates that several metabolic enzymes are subjected to multiple PTMs, suggesting that yeast cells can use different modifications and/or combinations of them to specifically respond to environmental changes. Glycolysis and fermentation are the pathways where phosphorylation, acetylation and ubiquitination are most frequent, while enzymes of storage carbohydrate metabolism are especially phosphorylated. Interestingly, some enzymes, such as the 6-phosphofructo-2-kinase Pfk26, the phosphofructokinases Pfk1 and Pfk2 and the pyruvate kinase Cdc19, are hubs of PTMs, thus representing central key regulation nodes. For the functionally better characterized enzymes, the role of phosphorylations and lysine modifications is discussed. GENERAL SIGNIFICANCE: This review focuses on the regulatory mechanisms of yeast carbon metabolism, highlighting the requirement of quantitative, systematical studies to better understand PTM contribution to metabolic regulation. PMID- 25512068 TI - Comments on "Quantifying hypoxia-induced chemoreceptor sensitivity in the awake rodent" by Morgan et al. PMID- 25512069 TI - Reply to Joseph. PMID- 25512070 TI - Full 180 degrees magnetization reversal with electric fields. AB - Achieving 180 degrees magnetization reversal with an electric field rather than a current or magnetic field is a fundamental challenge and represents a technological breakthrough towards new memory cell designs. Here we propose a mesoscale morphological engineering approach to accomplishing full 180 degrees magnetization reversals with electric fields by utilizing both the in-plane piezostrains and magnetic shape anisotropy of a multiferroic heterostructure. Using phase-field simulations, we examined a patterned single-domain nanomagnet with four-fold magnetic axis on a ferroelectric layer with electric-field-induced uniaxial strains. We demonstrated that the uniaxial piezostrains, if non collinear to the magnetic easy axis of the nanomagnet at certain angles, induce two successive, deterministic 90 degrees magnetization rotations, thereby leading to full 180 degrees magnetization reversals. PMID- 25512072 TI - The Effectiveness of a Facebook-Assisted Teaching Method on Knowledge and Attitudes About Cervical Cancer Prevention and HPV Vaccination Intention Among Female Adolescent Students in Taiwan. AB - BACKGROUND: Lack of education is a known barrier to vaccination, but data on the design and effectiveness of interventions remain limited. OBJECTIVE: This study aims to identify the effectiveness of a Facebook-assisted teaching method on female adolescents' knowledge and attitudes about cervical cancer prevention and on their human papillomavirus vaccination intention. METHOD: A quasi-experimental time series research design was used. Two hundred female adolescents at a senior high school in Taipei were recruited into two groups. Following a classroom lecture, one group was provided a Facebook-assisted online discussion, and the other group was provided an in-person discussion forum. A demographic questionnaire and cervical cancer prevention questionnaire were distributed. Data were analyzed for descriptive statistics and generalized estimation equations. RESULTS: Improvement from T0 to T2 in knowledge and attitude scores was 4.204 and 4.496 points, respectively. The Facebook group's improvement in vaccination intention from T0 to T2 was 2.310 times greater than the control group's improvement under conditions of out-of-pocket expenses and 2.368 times greater under conditions of free vaccination. CONCLUSIONS: School-based cervical cancer prevention education can be effective. The Facebook-assisted discussion method was more effective than the in-person discussion. Providing the human papillomavirus vaccine free of charge would increase female adolescents' intention to be vaccinated. PMID- 25512071 TI - Abdominal sarcoidosis: cross-sectional imaging findings. AB - Sarcoidosis is a multisystem inflammatory disease of unknown etiology. The lungs and the lymphoid system are the most commonly involved organs. Extrapulmonary involvement is reported in 30% of patients, and the abdomen is the most common extrapulmonary site with a frequency of 50%-70%. Although intra-abdominal sarcoidosis is usually asymptomatic, its presence may affect the prognosis and treatment options. The lesions are less characteristic and may mimick neoplastic or infectious diseases such as lymphoma, diffuse metastasis, and granulomatous inflammation. The liver and spleen are the most common abdominal sites of involvement. Sarcoidosis of the gastrointestinal system, pancreas, and kidneys are extremely rare. Adenopathy which is most commonly found in the porta hepatis, exudative ascites, and multiple granulomatous nodules studding the peritoneum are the reported manifestations of abdominal sarcoidosis. Since abdominal sarcoidosis is less common and long-standing, unrecognized disease can result in significant morbidity and mortality. Imaging contributes to diagnosis and management of intra abdominal sarcoidosis. In this report we reviewed the cross-sectional imaging findings of hepatobiliary, gastrointestinal, and genitourinary sarcoidosis. PMID- 25512073 TI - From broken windows to busy streets: a community empowerment perspective. AB - In the present article, we introduce a community empowerment perspective to understanding neighborhoods. A preponderance of literature exists on neighborhood risk factors for crime. Yet less is known about positive factors that make neighborhoods safe and desirable. We propose community empowerment as a conceptual foundation for understanding neighborhood factors that promote social processes, and ultimately, lead to an improvement in structural factors. We suggest that neighborhoods are empowered because they include processes and structures for positive social interactions to emerge and develop. We present busy streets as a mechanism that creates a positive social context, in which social cohesion and social capital thrive. Thus, empowered communities are characterized by climates that promote busy streets. Our article underscores the need to examine both the broader, structural context and social processes operating within this context. Such an integrative perspective is necessary to fully understand how to empower neighborhoods, particularly in the face of structural challenges. PMID- 25512074 TI - Evaluating the Impact of Six Supplemental Nutrition Assistance Program Education Interventions on Children's At-Home Diets. AB - BACKGROUND: Nutrition education in the Supplemental Nutrition Assistance Program Education (SNAP-Ed) is designed to promote healthy eating behaviors in a low income target population. PURPOSE: To evaluate the effectiveness of six SNAP-Ed interventions delivered in child care centers or elementary school settings in increasing participating children's at-home fruit and vegetable (F/V) consumption by 0.3 cups per day and use of fat-free or low-fat milk instead of whole or reduced-fat milk during the prior week. METHOD: Clustered randomized or quasi experimental clustered trials took place in child care centers or elementary schools between 2010 and 2012. Parents of children at intervention and control sites completed baseline and follow-up surveys about their child's at home F/V consumption and other dietary behaviors. RESULTS: One of the six interventions was successful in meeting the objective of increasing children's F/V consumption by 0.3 cups per day. For three of the six interventions, there was a small but statistically significant increase in F/V consumption and/or use of low-fat or fat-free milk. CONCLUSION: Although not all interventions were effective, these findings suggest that it is possible for some SNAP-Ed interventions to improve dietary habits among low-income children among some families. The effective interventions appear to have benefited from implementation experience and sustained efforts at intervention refinement and improvement. PMID- 25512075 TI - Metering Self-Reported Adherence to Clinical Outcomes in Malaysian Patients With Hypertension: Applying the Stages of Change Model to Healthful Behaviors in the CORFIS Study. AB - The CORFIS (Community-Based Cardiovascular Risk Factors Intervention Strategies) program was piloted in community clinics in Malaysia to address the lack of health education in chronic disease management. The stages of change model was applied in a multicenter quasi-experimental design to evaluate adherence to advocated behaviors in CORFIS patients with hypertension. Based on submitted diet and exercise records (n = 209), adherence to sodium reduction, regular exercise, and increasing fruit and vegetable intake behaviors were quantified against weight, waist circumference (WC), systolic blood pressure (SBP), and diastolic blood pressure (DBP) changes. Patients were categorized at 6 months into nonadherent/N-A (Precontemplation, Contemplation, and Preparation), newly adherent/NA (Action) and totally adherent/TA (Maintenance) groups. Self-reported adherence records did not meet recommended targets for healthful behaviors, but clinical benefits were achieved by adherent groups as indicated by effect size (Cohen's d) comparisons. SBP reduction was associated with adherence to sodium reduction in NA (d = 0.60, p < .001) and TA (d = 0.45, p < .001) compared to N-A (d = 0.13, p > .05). Marginally increasing fruit and vegetable consumption (Delta = 0.41 servings) resulted in sizeable reductions in weight for NA (d = 0.81, p < .001) > TA (d = 0.54, p < .001) > N-A (d = 0.21, p > .05) and in WC for NA (d = 0.68, p < .00) > TA (d = 0.53, p < .001) > N-A (d = 0.52, p > .05). Exercise behavior was least successful as pedometer counting was below 10,000 steps but sizeable weight and WC reductions were largest for NA (d = 0.71 and 0.79, respectively) > TA (d = 0.60 and 0.53, respectively) > N-A (d = 0.33 and 0.35, respectively). Patients reporting a shift to positive stages of change behaviors enjoyed clinically beneficial reductions in SBP, DBP, weight, and WC. PMID- 25512076 TI - A photoreactive G-quadruplex ligand triggered by green light. AB - A photoreactive molecular dye targeting the G-quadruplex nucleic acid (G4) of the human telomeric sequence Tel22, and several mutated analogues, was activated by green light (lambda=532 nm). Highly selective covalent modification of G4 versus single-stranded and double-stranded DNA was achieved with efficiency up to 64%. The phenoxyl radical was generated and detected by laser-flash photolysis as a reactive intermediate that targeted loop thymine residues. These insights may suggest a non-invasive tool for selective nucleic acid tagging and "pull-down" cellular applications. PMID- 25512077 TI - An elevated preoperative serum carbohydrate antigen 19-9 level is a significant predictor for peritoneal dissemination and poor survival in colorectal cancer. AB - AIM: Many studies support the role of carcinoembryonic antigen (CEA) as a strong indicator of the status of colorectal cancer patients, but evidence for carbohydrate antigen 19-9 (CA19-9) is poor. For this reason the study aimed to evaluate the prognostic value of preoperative serum CA19-9 levels in colorectal cancer patients. METHOD: In all, 1190 colorectal cancer patients were included in this study, of whom 955 underwent a potentially curative resection. These were analysed for recurrence and survival. The 255 patients with Stage IV disease were analysed for metastatic status. RESULTS: Patients with an elevated preoperative CEA with Stage II and III disease showed a significantly poorer survival than those with normal levels. In contrast patients with elevated preoperative CA19-9 levels were associated with a significantly poorer survival irrespective of disease stage. Of the 255 patients with Stage IV disease, 92 (39.1%) had peritoneal dissemination at laparotomy observed more frequently in patients with an elevated CA19-9 (47.9%). Of the 955 patients having a curative resection, 18 (1.9%) developed peritoneal dissemination. In multivariate analysis, an elevated preoperative CA19-9 level was a significant risk factor for postoperative peritoneal recurrence. CONCLUSION: After curative surgery for colorectal cancer the preoperative CA19-9 level is a strong prognostic indicator of higher risk of peritoneal dissemination. PMID- 25512078 TI - Epigenetically silenced long noncoding-SRHC promotes proliferation of hepatocellular carcinoma. AB - PURPOSE: To investigate the expression of SRHC and the role of SRHC in the pathogenesis of hepatocellular carcinoma (HCC). METHODS: We analyzed HCC samples and matched non-tumor liver tissues (controls) collected from 81 patients who underwent hepatectomy in Shanghai, China. The expression levels of SRHC were determined by quantitative reverse-transcription polymerase chain reaction. Statistical analyses were used to associate the levels of SRHC with tumor features and patient outcomes. RESULTS: We found that a lower SRHC expression level was significantly more frequent in tissues with a high serum a-fetoprotein level (positive, >20 ug/L, P = 0.004) and a low degree of differentiated tumors (poorly differentiated, P = 0.017). Furthermore, we found that the promoter region of SRHC contains a CpG-rich island and that SRHC is down-regulated in tumors by DNA methylation. CONCLUSION: Here, we identified a new long noncoding RNA designated as SRHC that is capable of inhibiting cancer proliferation and is down-regulated in tumors at least partly by DNA methylation. PMID- 25512080 TI - Eczema is associated with osteoporosis and fractures in adults: a US population based study. PMID- 25512079 TI - Convergence with SEER database achieved by a breast cancer network: a longitudinal benchmark of 5-year relative survival. AB - PURPOSE: To benchmark outcomes of a German breast cancer network with the Surveillance Epidemiology and End Results programme (SEER) of the USA from a longitudinal point of view. METHODS: All women receiving primary breast cancer therapy of three hospitals in a rural district of Marburg-Biedenkopf (Germany) of time intervals 1996-1997 and 2003-2004 were used to define local benchmark objects. Data from SEER-programme contributed longitudinal benchmark objects from national level (1988-2004). All benchmark objects were compared with the time fixed benchmark reference of SEER (2004). Stage distributions and 5-year relative survival ratios were combined to estimate standardized screening-, case-mix-, work-up-, treatment- and relative overall performance index. RESULTS: From the entry cohort of 877 German women, 97.7 % of the patients accounted for the institutional sample (N = 857) and 65.8 % accounted for the regional sample (N = 577). Stage distributions, relative survival ratios and indices of the German breast cancer network improved over time. Developed indices converged with SEER (2004). CONCLUSIONS: Effectiveness gap between one exemplary German breast cancer network and international benchmark defined by SEER has been closed. Reasons are manifold, and further research is recommended. PMID- 25512081 TI - RAC2 loss-of-function mutation in 2 siblings with characteristics of common variable immunodeficiency. PMID- 25512082 TI - Claudin-1 polymorphism modifies the effect of mold exposure on the development of atopic dermatitis and production of IgE. PMID- 25512084 TI - Verneuil's disease, innate immunity and vitamin D: a pilot study. AB - BACKGROUND: Verneuil's disease is a chronic inflammatory skin disease of the follicles in apocrine glands rich area of the skin (axillary, inguinal, anogenital) and is associated with a deficient skin innate immunity. It is characterized by the occurrence of nodules, abscesses, fistulas, scars. Recently, vitamin D has been shown to stimulate skin innate immunity. OBJECTIVE: The primary objective of the study was to assess whether Verneuil's disease was associated with vitamin D deficiency. The secondary objective was to determine whether vitamin D supplementation could improve inflammatory lesions. METHODS: First, 25(OH) vitamin D3 serum levels in patients with Verneuil's disease followed at Nantes University Hospital were compared to those of healthy donors from the French Blood Bank. Then, a pilot study was conducted in 14 patients supplemented with vitamin D according to their vitamin D level at baseline at months 3 and 6. The endpoints at 6 months were decreased by at least 20% in the number of nodules and in the frequency of flare-ups. RESULTS: Twenty-two patients (100%) had vitamin D deficiency (level <30 ng/mL) of whom 36% were severely deficient (level <10 ng/mL), having correlation with the disease severity (P = 0.03268) vs. 20 controls with vitamin D deficiency (91%) of whom 14% were severely deficient. In 14 patients, the supplementation significantly decreased the number of nodules at 6 months (P = 0.01133), and the endpoints were achieved in 79% of these patients. A correlation between the therapeutic success and the importance of the increase in vitamin D level after supplementation was observed (P = 0.01099). CONCLUSION: Our study shows that Verneuil's disease is associated with a major vitamin D deficiency, correlated with the disease severity. It suggests that vitamin D could significantly improve the inflammatory nodules, probably by stimulating the skin innate immunity. A larger randomized study is needed to confirm these findings. PMID- 25512083 TI - The sphingosine-1-phosphate/sphingosine-1-phosphate receptor 2 axis regulates early airway T-cell infiltration in murine mast cell-dependent acute allergic responses. AB - BACKGROUND: Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid produced by mast cells (MCs) on cross-linking of their high-affinity receptors for IgE by antigen that can amplify MC responses by binding to its S1P receptors. An acute MC-dependent allergic reaction can lead to systemic shock, but the early events of its development in lung tissues have not been investigated, and S1P functions in the onset of allergic processes remain to be examined. OBJECTIVE: We used a highly specific neutralizing anti-S1P antibody (mAb) and the sphingosine-1 phosphate receptor 2 (S1PR2) antagonist JTE-013 to study the signaling contributions of S1P and S1PR2 to MC- and IgE-dependent airway allergic responses in mice within minutes after antigen challenge. METHODS: Allergic reaction was triggered by a single intraperitoneal dose of antigen in sensitized mice pretreated intraperitoneally with anti-S1P, isotype control mAb, JTE-013, or vehicle before antigen challenge. RESULTS: Kinetics experiments revealed early pulmonary infiltration of mostly T cells around blood vessels of sensitized mice 20 minutes after antigen exposure. Pretreatment with anti-S1P mAb inhibited in vitro MC activation, as well as in vivo development of airway infiltration and MC activation, reducing serum levels of histamine, cytokines, and the chemokines monocyte chemoattractant protein 1/CCL2, macrophage inflammatory protein 1alpha/CCL3, and RANTES/CCL5. S1PR2 antagonism or deficiency or MC deficiency recapitulated these results. Both in vitro and in vivo experiments demonstrated MC S1PR2 dependency for chemokine release and the necessity for signal transducer and activator of transcription 3 activation. CONCLUSION: Activation of S1PR2 by S1P and downstream signal transducer and activator of transcription 3 signaling in MCs regulate early T-cell recruitment to antigen-challenged lungs through chemokine production. PMID- 25512085 TI - A self-assembling lanthanide molecular nanoparticle for optical imaging. AB - Chromophores that incorporate f-block elements have considerable potential for use in bioimaging applications because of their advantageous photophysical properties compared to organic dye, which are currently widely used. We are developing new classes of lanthanide-based self-assembling molecular nanoparticles as reporters for imaging and as multi-functional nanoprobes or nanosensors for use with biological samples. One class of these materials, which we call lanthanide "nano-drums", are homogeneous 4d-4f clusters approximately 25 to 30 A in diameter. These are capable of emitting from the visible to near infrared wavelengths. Here, we present the synthesis, crystal structure, photophysical properties and comparative cytotoxicity data for a 32 metal Eu-Cd nano-drum [Eu(8)Cd(24)L(12)(OAc)(48)] (1). We also explored the imaging capabilities of this nano-drum using epifluorescence, TIRF, and two-photon microscopy platforms. PMID- 25512086 TI - Long-term impact of a real-world coordinated lifestyle promotion initiative in primary care: a quasi-experimental cross-sectional study. AB - BACKGROUND: Integration of lifestyle promotion in routine primary care has been suboptimal. Coordinated care models (e.g. screening, brief advice and referral to in-house specialized staff) could facilitate lifestyle promotion practice; they have been shown to increase the quality of services and reduce costs in other areas of care. This study evaluates the long-term impact of a coordinated lifestyle promotion intervention with a multidisciplinary team approach in a primary care setting. METHODS: A quasi-experimental, cross-sectional design was used to compare three intervention centres using a coordinated care model and three control centres using a traditional model of lifestyle promotion care. Outcomes were inspired by using the RE-AIM framework: reach, the proportion of patients receiving lifestyle promotion; effectiveness, self-reported attitudes and competency among staff; adoption, proportion of staff reporting daily practice of lifestyle promotion and referral; and implementation, of the coordinated care model. The impact was investigated after 3 and 5 years. Data collection involved a patient questionnaire (intervention, n = 433-497; control, n = 455-497), a staff questionnaire (intervention, n = 77-76; control, n = 43-56) and structured interviews with managers (n = 8). The chi(2) test or Fisher exact test with adjustment for clustering by centre was used for the analysis. Problem driven content analysis was used to analyse the interview data. RESULTS: The findings were consistent over time. Intervention centres did not show higher rates for reach of patients or adoption among staff at the 3- or 5-year follow up. Some conceptual differences between intervention and control staff remained over time in that the intervention staff were more positive on two of eight effectiveness outcomes (one attitude and one competency item) compared with control staff. The Lifestyle team protocol, which included structural opportunities for coordinated care, was implemented at all intervention centres. Lifestyle teams were perceived to have an important role at the centres in driving the lifestyle promotion work forward and being a forum for knowledge exchange. However, resources to refer patients to specialized staff were used inconsistently. CONCLUSIONS: The Lifestyle teams may have offered opportunities for lifestyle promotion practice and contributed to enabling conditions at centre level but had limited impact on lifestyle promotion practices. PMID- 25512088 TI - Methyleneation of peptides by N,N,N,N-tetramethylethylenediamine (TEMED) under conditions used for free radical polymerization: a mechanistic study. AB - Free radical polymerization is often used to prepare protein and peptide-loaded hydrogels for the design of controlled release systems and molecular imprinting materials. Peroxodisulfates (ammonium peroxodisulfates (APS) or potassium peroxodisulfates (KPS)) with N,N,N,N-tetramethylethylenediamine (TEMED) are frequently used as initiator and catalyst. However, exposure to these free radical polymerization reagents may lead to modification of the protein and peptide. In this work, we show the modification of lysine residues by ammonium peroxodisulfate (APS)/TEMED of the immunostimulant thymopentin (TP5). Parallel studies on a decapeptide and a library of 15 dipeptides were performed to reveal the mechanism of modification. LC-MS of APS/TEMED-exposed TP5 revealed a major reaction product with an increased mass (+12 Da) with respect to TP5. LC-MS(2) and LC-MS(3) were performed to obtain structural information on the modified peptide and localize the actual modification site. Interpretation of the obtained data demonstrates the formation of a methylene bridge between the lysine and arginine residue in the presence of TEMED, while replacing TEMED with a sodium bisulfite catalyst did not show this modification. Studies with the other peptides showed that the TEMED radical can induce methyleneation on peptides when lysine is next to arginine, proline, cysteine, aspargine, glutamine, histidine, tyrosine, tryptophan, and aspartic acid residues. Stability of peptides and protein needs to be considered when using APS/TEMED in in situ polymerization systems. The use of an alternative catalyst such as sodium bisulfite may preserve the chemical integrity of peptides during in situ polymerization. PMID- 25512087 TI - N,N-diethylaminobenzaldehyde (DEAB) as a substrate and mechanism-based inhibitor for human ALDH isoenzymes. AB - N,N-diethylaminobenzaldehyde (DEAB) is a commonly used "selective" inhibitor of aldehyde dehydrogenase isoenzymes in cancer stem cell biology due to its inclusion as a negative control compound in the widely utilized Aldefluor assay. Recent evidence has accumulated that DEAB is not a selective inhibitory agent when assayed in vitro versus ALDH1, ALDH2 and ALDH3 family members. We sought to determine the selectivity of DEAB toward ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1, ALDH2, ALDH3A1, ALDH4A1 and ALDH5A1 isoenzymes and determine the mechanism by which DEAB exerts its inhibitory action. We found that DEAB is an excellent substrate for ALDH3A1, exhibiting a Vmax/KM that exceeds that of its commonly used substrate, benzaldehyde. DEAB is also a substrate for ALDH1A1, albeit an exceptionally slow one (turnover rate ~0.03 min(-1)). In contrast, little if any turnover of DEAB was observed when incubated with ALDH1A2, ALDH1A3, ALDH1B1, ALDH2 or ALDH5A1. DEAB was neither a substrate nor an inhibitor for ALDH1L1 or ALDH4A1. Analysis by enzyme kinetics and QTOF mass spectrometry demonstrates that DEAB is an irreversible inhibitor of ALDH1A2 and ALDH2 with apparent bimolecular rate constants of 2900 and 86,000 M(-1) s(-1), respectively. The mechanism of inactivation is consistent with the formation of quinoid-like resonance state following hydride transfer that is stabilized by local structural features that exist in several of the ALDH isoenzymes. PMID- 25512089 TI - N-heterocyclic carbene catalyzed highly chemoselective intermolecular crossed acyloin condensation of aromatic aldehydes with trifluoroacetaldehyde ethyl hemiacetal. AB - A highly chemoselective intermolecular crossed acyloin condensation between aromatic aldehydes and trifluoroacetaldehyde ethyl hemiacetal has been developed under mild reaction conditions using N-heterocyclic carbene as a catalyst. A wide range of aromatic aldehydes bearing electron-withdrawing and -donating substituents underwent a smooth transformation to their corresponding trifluoromethyl containing acyloin derivatives in moderate to good yields. PMID- 25512090 TI - Total pleural covering technique for intractable pneumothorax in patient with Ehlers-Danlos syndrome. AB - We report a patient with vascular-type Ehlers-Danlos syndrome (vEDS) who developed pneumothorax and was treated with a total pleural covering technique (TPC). A 24-year-old man developed repeat pneumothorax with intermittent hemo sputum. Based on unusual radiological manifestations of lung lesions and physical findings, EDS was suspected as an underlying cause of the pneumothorax. Surgical treatment was performed using a mediastinal fat pad and TPC, and no relapse was seen up to 2 years after surgery. TPC is a less invasive surgical approach for selected patients with vEDS. Accurate underlying diagnosis of vEDS and systemic evaluation of vascular complications are necessary before planning surgery. PMID- 25512091 TI - Long-term outcome of surgical resection for residual or regrown advanced non small cell lung carcinomas following EGFR-TKI treatment: report of four cases. AB - We report the long-term outcome of 4 patients who underwent pulmonary resection for residual or regrown primary lesion of non-small cell lung cancer (NSCLC) treated with a epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) gefitinib. Two patients underwent surgical resection for localized regrown primary lesion after gefitinib for stage IV disease. The remaining two patients underwent surgery for localized residual primary lesion that was downstaged to N0 after gefitinib for initially inoperable cN2 (stage IIIA) disease. Three patients developed recurrence with a median progression-free period of 1.2 years (0.2 2.2), but they survived more than 5 years postoperatively with good local control. One patient who initially had cN2 disease is alive without recurrence after 4 years with continued postoperative gefitinib. Although our series is small, the relatively favorable long-term survival indicates the need for further investigation of the role of surgery during molecular-targeted therapy for advanced NSCLC. PMID- 25512092 TI - Liver cancer in Malaysia: epidemiology and clinical presentation in a multiracial Asian population. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is an important cancer in Malaysia. This study aimed to determine the epidemiological characteristics and clinical presentations of patients in a multiracial population consisting of three major Asian races: Malays, Chinese and Indians. METHODS: Consecutive patients with HCC were prospectively studied from 2006 to 2009. HCC was diagnosed principally on multiphasic computed tomography and magnetic resonance imaging scans of the liver. The tumor was staged according to the Barcelona Clinic Liver Cancer (BCLC) classification. RESULTS: Altogether, 348 patients were diagnosed with HCC. There were 239 (68.7%) Chinese patients, 71 (20.4%) Malays and 38 (10.9%) Indians, with the median age of 62.5 years and the male to female ratio of 3.4:1. The predominant etiology in Malay and Chinese patients was hepatitis B virus infection (>60%) and in Indian patients was alcohol intake (26.3%) and cryptogenic cause (29.0%). Hepatitis C was seen in 18.3% of Malays, but less than 10% in Chinese and Indians. BCLC staging was: Stage A, 120 (34.5%); Stage B, 75 (21.6%); Stage C, 84 (24.1%); and Stage D, 69 (19.8%). A larger proportion of Indian than Chinese and Malays patients (44.7%) presented with stage D disease. Portal vein invasion was noted in 124 patients (35.6%) and extrahepatic metastases in 68 (19.5%). Surgical resection and radiofrequency ablation with curative intent was carried out in >90% of stage A patients and transarterial chemoembolization in 49.3% and 21.4% of stages B and C patients, respectively. CONCLUSIONS: HCC is most common among Chinese, followed by Malays and Indians in Malaysia. The etiology of HCC shows a peculiar racial pattern. PMID- 25512093 TI - Novel mutations in the DYNC1H1 tail domain refine the genetic and clinical spectrum of dyneinopathies. AB - The heavy chain 1 of cytoplasmic dynein (DYNC1H1) is responsible for movement of the motor complex along microtubules and recruitment of dynein components. Mutations in DYNC1H1 are associated with spinal muscular atrophy (SMA), hereditary motor and sensory neuropathy (HMSN), cortical malformations, or a combination of these. Combining linkage analysis and whole-exome sequencing, we identified a novel dominant defect in the DYNC1H1 tail domain (c.1792C>T, p.Arg598Cys) causing axonal HMSN. Mutation analysis of the tail region in 355 patients identified a de novo mutation (c.791G>T, p.Arg264Leu) in an isolated SMA patient. Her phenotype was more severe than previously described, characterized by multiple congenital contractures and delayed motor milestones, without brain malformations. The mutations in DYNC1H1 increase the interaction with its adaptor BICD2. This relates to previous studies on BICD2 mutations causing a highly similar phenotype. Our findings broaden the genetic heterogeneity and refine the clinical spectrum of DYNC1H1, and have implications for molecular diagnostics of motor neuron diseases. PMID- 25512095 TI - Ultralight nanofibre-assembled cellular aerogels with superelasticity and multifunctionality. AB - Three-dimensional nanofibrous aerogels (NFAs) that are both highly compressible and resilient would have broad technological implications for areas ranging from electrical devices and bioengineering to damping materials; however, creating such NFAs has proven extremely challenging. Here we report a novel strategy to create fibrous, isotropically bonded elastic reconstructed (FIBER) NFAs with a hierarchical cellular structure and superelasticity by combining electrospun nanofibres and the fibrous freeze-shaping technique. Our approach causes the intrinsically lamellar deposited electrospun nanofibres to assemble into elastic bulk aerogels with tunable densities and desirable shapes on a large scale. The resulting FIBER NFAs exhibit densities of >0.12 mg cm(-3), rapid recovery from deformation, efficient energy absorption and multifunctionality in terms of the combination of thermal insulation, sound absorption, emulsion separation and elasticity-responsive electric conduction. The successful synthesis of such fascinating materials may provide new insights into the design and development of multifunctional NFAs for various applications. PMID- 25512094 TI - Hypoxia-induced cell stemness leads to drug resistance and poor prognosis in lung adenocarcinoma. AB - BACKGROUND: Since cancer stem cells exhibit embryonic-like self-renewal characteristics and malignant behavior, including drug resistance and metastasis, they may be the origin of tumorigenesis and cancer recurrence. Cancer cell stemness is also highly relevant to cancer in hypoxic environments. METHODS: In our study, we used cobalt dichloride (CoCl2) to create a hypoxic environment for lung adenocarcinoma A549 cells and the cisplatine-resistant cell line A549/DDP. The cancer stem-like CD166 positive population and the cells' stemness were detected by flowcytometry and quantitative real-time PCR after separation using magnetic antibodies. Drug resistance to cisplatine, docetaxel and pemetrexed was also measured. Finally, a tissue array was used to analyze the relationship between hypoxia-induced stemness and overall survival after radical surgery. RESULTS: Data showed that chemical-induced hypoxia changed cell stemness by enhancing stem cell transcription factors and markers of chemotherapeutic drug resistance. The CD166-positive cancer stem cell-like population showed greater drug resistance than the CD166-negative cells. Tissue array studies also suggested a poorer prognosis for patients whose tissue expressed higher CD166 levels. CONCLUSION: Our findings indicate that chemical hypoxia may augment cancer cell stemness and drug resistance in CD166-positive stem cells. Therefore, targeting the stem-like cell population, especially CD166-positive cells, may represent a novel therapeutic strategy to treat lung cancer. PMID- 25512097 TI - The subjective impact of a diagnosis of gestational diabetes among ethnically diverse pregnant women: a qualitative study. AB - OBJECTIVE: Women diagnosed with gestational diabetes mellitus (GDM) require enhanced medical care, social support and health behaviour changes to reduce the complications of pregnancy and future adverse health outcomes. Little is known about how a GDM diagnosis positively and negatively impacts women, especially those of diverse ethnic backgrounds. This qualitative study sought to gain insight into the reactions and experiences of multiethnic women diagnosed with GDM. METHODS: A qualitative descriptive approach was used to analyze semistructured telephone interviews conducted with 19 pregnant women of diverse backgrounds who were diagnosed with GDM. Interviews were recorded and transcribed and then coded and analyzed using content analysis. RESULTS: This study identified 2 main themes and several subthemes. First, women reported many negative effects of a GDM diagnosis, including heightened pressure to fulfill multiple roles, financial impact, and a disconnect between diabetes-prevention recommendations and their cultural practices. Second, a GDM diagnosis also had positive effects on many women. Women indicated being motivated to make health behaviour changes after a GDM diagnosis and viewed it as a wake-up call to modify their lifestyles. CONCLUSIONS: To help pregnant women with self-management of gestational diabetes, healthcare providers should pay greater attention to the adverse effects of GDM on women, including role expectations, cultural issues and financial barriers. Healthcare providers also need to focus on the positive effects and capitalize on women's motivation to make lifestyle changes to reduce their future risk for diabetes. PMID- 25512096 TI - Cost effectiveness of novel oral anticoagulants for stroke prevention in atrial fibrillation depending on the quality of warfarin anticoagulation control. AB - BACKGROUND: Vitamin K antagonists, such as warfarin, are standard treatments for stroke prophylaxis in patients with atrial fibrillation. Patient outcomes depend on quality of warfarin management, which includes regular monitoring and dose adjustments. Recently, novel oral anticoagulants (NOACs) that do not require regular monitoring offer an alternative to warfarin. The aim of this study was to evaluate whether cost effectiveness of NOACs for stroke prevention in atrial fibrillation depends on the quality of warfarin control. METHODS: We developed a Markov decision model to simulate warfarin treatment outcomes in relation to the quality of anticoagulation control, expressed as percentage of time in the therapeutic range (TTR). Standard treatment with adjusted-dose warfarin and improved anticoagulation control by genotype-guided dosing were compared with dabigatran, rivaroxaban, apixaban and edoxaban. The analysis was performed from the Slovenian healthcare payer perspective using 2014 costs. RESULTS: In the base case, the incremental cost-effectiveness ratio for apixaban, dabigatran and edoxaban was below the threshold of ?25,000 per quality-adjusted life-years compared with adjusted-dose warfarin with a TTR of 60%. The probability that warfarin was a cost-effective option was around 1%. This percentage rises as the quality of anticoagulation control improves. At a TTR of 70%, warfarin was the preferred treatment in half the iterations. CONCLUSION: The cost effectiveness of NOACs for stroke prevention in patients with nonvalvular atrial fibrillation who are at increased risk for stroke is highly sensitive to warfarin anticoagulation control. NOACs are more likely to be cost-effective options in settings with poor warfarin management than in settings with better anticoagulation control, where they may not represent good value for money. PMID- 25512098 TI - Denmark's comparative position regarding health status, healthcare provision, self-management and social support: Diabetes Attitudes, Wishes and Needs second study (DAWN2). AB - AIMS: The aim of this study was to benchmark the Danish sample of the second Diabetes, Attitudes, Wishes and Needs (DAWN2) study with the global average in order to determine Denmark's comparative position for health status, healthcare provision, self-management and social support from the perspective of people with diabetes, family members of people with diabetes and healthcare professionals. METHODS: A total of 502 Danish people with diabetes (PWD), 122 adult family members of people with diabetes (FM) and 283 healthcare professionals (HCPs) participated in the study. Data on healthcare provision and physical and psychosocial wellbeing were collected from the 17 participating countries. RESULTS: Psychological wellbeing was higher among Danish PWD; conversely, self management behaviour of PWD ranked below the global average. A substantial gap was found in the perceptions of PWD and HCPs regarding the extent to which healthcare provision was deemed person-centred. The gap was found to be larger, however, when looking at the global data. Danish FM reported higher education participation and satisfaction rates as well as lower distress than the global average, but there appears to be an untapped potential when it comes to converting education participation of FM into social support for PWD. CONCLUSIONS: Our findings suggest that PWD in Denmark rank above the global average on measures of psychological wellbeing, despite psychological wellbeing being under-prioritised by HCP. However, there is room for improvement when it comes to self-management behaviours. Special attention is needed to address this issue without compromising the psychological wellbeing of the PWD. PMID- 25512099 TI - Renal, efficacy and safety outcomes following late conversion of kidney transplant patients from calcineurin inhibitor therapy to everolimus: the randomized APOLLO study. AB - AIMS: The primary objective of this trial was to demonstrate, based on the estimated glomerular filtration rate (eGFR), superior renal function at month 12 after conversion of maintenance kidney transplant patients from calcineurin inhibitor (CNI) therapy to everolimus, compared to continuing a standard CNI regimen. MATERIALS AND METHODS: APOLLO was an open-label, 12-month, prospective, multicenter study in which 93 maintenance kidney transplant patients were randomized to convert from CNI to everolimus (n = 46) or remain on standard CNI based immunosuppression (n = 47). The primary efficacy variable was eGFR (Nankivell formula) 12 months after randomization. The study was terminated prematurely due to slow recruitment and was thus underpowered. RESULTS: Mean time post-transplant was 83.5 months with everolimus and 70.1 months with CNI. Adjusted values for eGFR (Nankivell) at month 12 were 61.6 (95% CI 58.1, 65.1) mL/ min/1.73 m2 with everolimus and 58.8 (95% CI 55.2, 62.3) mL/min/1.73 m2 with CNI, a difference of 2.8 (95% CI -1.0, 6.7) mL/ min/1.73 m2 (p = 0.145) i.e., the primary objective was not met. Using the modification of diet in renal disease (MDRD) formula, adjusted eGFR at month 12 was significantly higher with everolimus (p = 0.030). In the subpopulation who remained on the study drug (n = 52), the difference in the adjusted change from randomization was 6.6 (95% CI 1.5, 11.6) mL/min/1.73 m2 (p = 0.013) in favor of everolimus. There was no biopsyproven acute rejection and no graft losses. Adverse events led to discontinuation of everolimus and CNI in 32.6% and 10.6% of patients, respectively. CONCLUSIONS: Conversion from CNI to everolimus to preserve renal function can be considered several years after kidney transplantation and does not compromise immunosuppressive efficacy. PMID- 25512100 TI - Proenkephalin predicts acute kidney injury in cardiac surgery patients. AB - AIMS: Acute kidney injury (AKI) occurs in up to 40% of patients undergoing cardiac surgery. Proenkephalin A 119-159 (pro-ENK) is a novel, stable surrogate biomarker for enkephalins, endogenous opioids involved in various physiological processes, including neurohormonal stress. MATERIAL AND METHODS: 92 patients undergoing cardiac surgery at the Veterans Affairs San Diego Healthcare System had a post-hoc analysis performed to determine the ability of pro-ENK to predict AKI as well as to compare it against other risk factors for development of AKI. RESULTS: Of 92 patients, 20 patients developed AKI post-operatively. Pro-ENK levels were significantly elevated in patients who develop AKI. Log pro-ENK value pre-operatively has an odds ratio of 23.8 (p = 0.011, 95% CI = 2 - 270) in its association with AKI. Pro-ENK performs similarly to baseline creatinine in its ability to predict post-operative AKI. Importantly, pro-ENK has a strong positive correlation with creatinine (r = 0.806). Additionally, changes in pro-ENK level, from pre-operatively to 12 hours post-operatively have greatest area under curve by ROC analysis for AKI after post-operative day 1. CONCLUSION: Pro-ENK is associated with prediction of AKI in patients undergoing cardiac surgery. Pro-ENK likely has decreased clearance in the setting of AKI. However, future studies analyzing this novel biomarker should be considered to further elucidate its clinical utility and to better understand mechanisms of renal injury. PMID- 25512101 TI - Sodium polystyrene sulfonate – is it truly effective treatment for hyperkalemia? PMID- 25512102 TI - Composition of lymphocyte subpopulations in normal canine lymph nodes. AB - BACKGROUND: Flow cytometric immunophenotyping of lymph node aspirates has become a standard practice of canine lymphoma diagnostic workup. Ultimately, the combination of flow cytometry data, histopathology, and clinical signs allows consensus classification, and improves prognostic accuracy and therapeutic approaches. OBJECTIVES: Although there is a growing body of information regarding lymphocyte population subsets in various types of lymphoma, only few studies provide information regarding the composition of the normal canine lymph node. The aim of this prospective study was to establish exploratory reference data for lymphocyte subpopulations in normal canine lymph nodes using an extended panel of antibodies. METHODS: Popliteal lymph nodes excised from normal dogs were analyzed by cytology, multi-color flow cytometry using 11 different canine-specific and anti-human cross-reactive monoclonal antibodies, and polymerase chain reaction for antigen receptor rearrangement (PARR). RESULTS: Subpopulations from lymph nodes of 26 dogs were classified according to the following positive antibody reactions: CD11a(+) 92.2 +/- 12.3%, CD3(+) 55.0 +/- 14.1%, CD3-12(+) 57.3 +/- 14%, CD5(+) 52.3 +/- 12.7%, CD21(+) 33.9 +/- 11.8%, CD79alphacgamma(+) 46.9 +/- 14.8%, CD56(+) 4.9 +/- 5.9%, and CD14(+) 5.5 +/- 6.8%. There were 58.7 +/- 9% CD4(+) and 21.3 +/- 7.8% CD8(+) cells inside the gate of CD3(+) cells. Cytology revealed a mixed population of mostly lymphoid cells in all samples. The absence of a monoclonal or oligoclonal neoplastic population was confirmed by PARR. CONCLUSION: This study establishes for the first time flow cytometry data of lymphocyte populations in a larger group of normal canine lymph nodes, including populations positive for some new antibodies against CD3-12, CD5, CD11a, CD56, and CD79alphacy. PMID- 25512104 TI - Connectivity of the intracytoplasmic membrane of Rhodobacter sphaeroides: a functional approach. AB - The photosynthetic apparatus in the bacterium Rhodobacter sphaeroides is mostly present in intracytoplasmic membrane invaginations. It has long been debated whether these invaginations remain in topological continuity with the cytoplasmic membrane, or form isolated chromatophore vesicles. This issue is revisited here by functional approaches. The ionophore gramicidin was used as a probe of the relative size of the electro-osmotic units in isolated chromatophores, spheroplasts, or intact cells. The decay of the membrane potential was monitored from the electrochromic shift of carotenoids. The half-time of the decay induced by a single channel in intact cells was about 6 ms, thus three orders of magnitude slower than in isolated chromatophores. In spheroplasts obtained by lysis of the cell wall, the single channel decay was still slower (~23 ms) and the sensitivity toward the gramicidin concentration was enhanced 1,000-fold with respect to isolated chromatophores. These results indicate that the area of the functional membrane in cells or spheroplasts is about three orders of magnitude larger than that of isolated chromatophores. Intracytoplasmic vesicles, if present, could contribute to at most 10% of the photosynthetic apparatus in intact cells of Rba. sphaeroides. Similar conclusions were obtained from the effect of a ?pH-induced diffusion potential in intact cells. This caused a large electrochromic response of carotenoids, of similar amplitude as the light-induced change, indicating that most of the system is sensitive to a pH change of the external medium. A single internal membrane and periplasmic space may offer significant advantages concerning renewal of the photosynthetic apparatus and reallocation of the components shared with other bioenergetic pathways. PMID- 25512105 TI - Optomagnetic read-out enables easy, rapid, and cost-efficient qualitative biplex detection of bacterial DNA sequences. AB - There is an increasing need to develop novel bioassay methods for low-cost, rapid, and easy-to-use multiplex detection of pathogens in various fields ranging from human infectious disease diagnosis, drinking water quality control, to food safety applications. Due to their unique advantages, magnetic and optomagnetic bioassay principles are particularly promising for biodetection platforms that will be used in developing countries. In this paper, an optomagnetic method for rapid and cost-efficient qualitative biplex detection of bacterial DNA sequences is demonstrated. Within less than two hours, the assay gives an answer to whether none, both, or only one of the bacterial DNA sequences is present in the sample. The assay relies on hybridization of oligonucleotide-functionalized magnetic nanobeads of two different sizes to rolling circle amplification (RCA) products originating from two different bacterial targets. The different bead sizes are equipped with different oligonucleotide probes, complementary to only one of the RCA products, and the read-out is carried out in the same sample volume. In an optomagnetic setup, the frequency modulation of transmitted laser light in response to an applied AC magnetic field is measured. The presented methodology is potentially interesting for low-cost screening of pathogens relating to both human and veterinary medicine in resource-poor regions of the world. PMID- 25512106 TI - Medically unexplained otorhinolaryngological symptoms: Towards integrated psychiatric care. AB - OBJECTIVE: To evaluate the presence of medically unexplained otorhinolaryngological symptoms in a patient cohort and propose an interdisciplinary approach for their care. STUDY DESIGN: Prospective cohort study. METHODS: The study describes the population of patients presenting consecutively at the Department of Otorhinolaryngology at the Maastricht University Medical Center. Patients with symptoms who did not meet clear "medical" criteria and were associated with psychological distress and high health care utilization were enrolled in the study by two experienced otorhinolaryngologists following informed consent. The aim of the study is 1) to specify the presence of medically unexplained otorhinolaryngological symptoms and 2) to evaluate the integration of otorhinolaryngological and psychiatric treatment in an interdisciplinary approach in order to help otorhinolaryngologists improve patient care. RESULTS: Of the 102 patients included, 41% (N = 42) did not have a proven somatic otorhinolaryngological diagnosis. For only 10.8% (N = 4) of the latter, no psychiatric diagnosis had been established. Overall, 78% of the study population (N = 80) was diagnosed with psychiatric morbidity/comorbidity, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. CONCLUSION: The preliminary data suggest that the majority of patients with these unexplained complaints may suffer from under- or undiagnosed psychiatric morbidity. Therefore, easy access to integrated interdisciplinary care (otorhinolaryngology and psychiatry) should be offered to patients with medically unexplained otorhinolaryngological symptoms after detailed information is made available to them about the pathogenesis of the complaints and the foreseen psychosomatic approach. PMID- 25512103 TI - A fresh look at the evolution and diversification of photochemical reaction centers. AB - In this review, I reexamine the origin and diversification of photochemical reaction centers based on the known phylogenetic relations of the core subunits, and with the aid of sequence and structural alignments. I show, for example, that the protein folds at the C-terminus of the D1 and D2 subunits of Photosystem II, which are essential for the coordination of the water-oxidizing complex, were already in place in the most ancestral Type II reaction center subunit. I then evaluate the evolution of reaction centers in the context of the rise and expansion of the different groups of bacteria based on recent large-scale phylogenetic analyses. I find that the Heliobacteriaceae family of Firmicutes appears to be the earliest branching of the known groups of phototrophic bacteria; however, the origin of photochemical reaction centers and chlorophyll synthesis cannot be placed in this group. Moreover, it becomes evident that the Acidobacteria and the Proteobacteria shared a more recent common phototrophic ancestor, and this is also likely for the Chloroflexi and the Cyanobacteria. Finally, I argue that the discrepancies among the phylogenies of the reaction center proteins, chlorophyll synthesis enzymes, and the species tree of bacteria are best explained if both types of photochemical reaction centers evolved before the diversification of the known phyla of phototrophic bacteria. The primordial phototrophic ancestor must have had both Type I and Type II reaction centers. PMID- 25512107 TI - One-to-one peer support in cancer care: a review of scholarship published between 2007 and 2014. AB - The primary goal of this review was to determine whether one-to-one peer support programmes benefit cancer patients. The secondary goal was to assess the quality of the research methodology and of the peer programme description as reported in original research studies. MEDLINE and PsycINFO databases were systematically searched in order to identify relevant studies published between May 2007 and July 2014. Eligible articles were evaluated using pre-existing criteria based on the Consolidated Standards of Reporting Trials Statement Checklist. This review included 13 studies: four randomised controlled trials, one non-randomised comparative study and eight one-group descriptive studies. All studies reported high participant satisfaction with the peer support intervention, and the majority noted positive outcomes regarding psychological adjustment. The quality of the description of the peer support programmes as well as the research methodology of the studies was rated as fair. Methodological weaknesses included biased recruitment strategies and limited information regarding peer volunteers, non-users of peer support and those who withdrew from support programmes. One-to one peer support programmes have the unique advantage of being a low-cost intervention approach, but also showing potential for relieving the health-care system by reallocating some aspects of the cancer care to community settings. Future research should address the methodological weaknesses in study design and reporting. PMID- 25512108 TI - From workstations to workbenches: Towards predicting physicochemically viable protein-protein interactions across a host and a pathogen. AB - The understanding of protein-protein interactions is indispensable in comprehending most of the biological processes in a cell. Small-scale experiments as well as large-scale high-throughput techniques over the past few decades have facilitated identification and analysis of protein-protein interactions which form the basis of much of our knowledge on functional and regulatory aspects of proteins. However, such rich catalog of interaction data should be used with caution when establishing protein-protein interactions in silico, as the high throughput datasets are prone to false positives. Numerous computational means developed to pursue genome-wide studies on protein-protein interactions at times overlook the mechanistic and molecular details, thus questioning the reliability of predicted protein-protein interactions. We review the development, advantages, and shortcomings of varied approaches and demonstrate that by providing a structural viewpoint in terms of shape complementarity and interaction energies at protein-protein interfaces coupled with information on expression and localization of proteins homologous to an interacting pair, it is possible to assess the credibility of predicted interactions in biological context. With a focus on human pathogen Mycobacterium tuberculosis H37Rv, we show that such scrupulous use of details at the molecular level can predict physicochemically viable protein-protein interactions across host and pathogen. Such predicted interactions have the potential to provide molecular basis of probable mechanisms of pathogenesis and hence open up ways to explore their usefulness as targets in the light of drug discovery. PMID- 25512110 TI - A feed additive containing Bacillus toyonensis (Toyocerin((r)) ) protects against enteric pathogens in postweaning piglets. AB - AIMS: This study evaluated the efficacy of a probiotic containing Bacillus toyonensis spores (Toyocerin((r)) ) in postweaning piglets against enteric pathogens. METHODS AND RESULTS: Seven hundred and ninety-two healthy weaning pigs of a commercial farrow-to-finish pig farm were used. The negative control group fed without Toyocerin((r)) and two experimental groups fed similar to the negative control group, but supplemented with Toyocerin((r)) at t 500 mg kg(-1) diet (Toyocerin 500 group) and 1000 mg kg(-1) diet (Toyocerin 1000 group), respectively. No significant difference (P > 0.05) in morbidity and mortality rate between groups was noticed. The Toyocerin groups showed higher body weight (P < 0.05) and lower feed conversion ratio compared to the negative control group. Diarrhoea score was less in both Toyocerin groups than negative control group (P < 0.05). Moreover, the use of Toyocerin((r)) at 1000 mg kg(-1) diet resulted in higher average daily feed intake compared to other groups (P < 0.05), reduction of some enteric pathogens and increase of the number of lactic acid bacteria. CONCLUSIONS: The use of Toyocerin((r)) in weaning pigs, especially at 1000 mg kg(-1) diet, improved their health and growth performance. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that a feed additive containing B. toyonensis (Toyocerin((r)) ) protects against enteric pathogens in postweaning piglets when fed this additive at a proper dose. The use of Toyocerin((r)) at 1000 mg kg(-1) diet resulted in higher average daily feed intake, decrease of some enteric pathogens and higher number of lactic acid bacteria. The effect of the probiotic in other age groups remains to be established. PMID- 25512109 TI - Cancer-associated fibroblasts induce high mobility group box 1 and contribute to resistance to doxorubicin in breast cancer cells. AB - BACKGROUND: Cancer-associated fibroblasts and high mobility group box 1 (HMGB1) protein have been suggested to mediate cancer progression and chemotherapy resistance. The role of such fibroblasts in HMGB1 production in breast cancer is unclear. This study aimed to investigate the effects of cancer-associated fibroblasts on HMGB1 expression in breast cancer cells and its role in chemotherapeutic response. METHODS: Breast cancer-associated fibroblasts (BCFs) and non-tumor-associated fibroblasts (NTFs) were isolated from human breast cancers or adjacent normal tissues and established as primary cultures in vitro. After confirmation of the activated status of these fibroblasts, conditioned media (CM) were collected and applied to MDA-MB-231 human triple negative breast cancer cells. The levels of intracellular and extracellular HMGB1 were measured by real-time PCR and/or Western blot. The response of BCF-CM-pre-treated cancer cells to doxorubicin (Dox) was compared with those pre-treated with NTF-CM or control cultures. The effect of an HMGB1 neutralizing antibody on Dox resistance induced by extracellular HMGB1 from non-viable Dox-treated cancer cells or recombinant HMGB1 was also investigated. RESULTS: Immunocytochemical analysis revealed that BCFs and NTFs were alpha-smooth muscle actin (ASMA) positive and cytokeratin 19 (CK19) negative cells: a phenotype consistent with that of activated fibroblasts. We confirmed that the CM from BCFs (but not NTFs), could significantly induce breast cancer cell migration. Intracellular HMGB1 expression was induced in BCF-CM-treated breast cancer cells and also in Dox-treated cells. Extracellular HMGB1 was strongly expressed in the CM after Dox-induced MDA-MB-231 cell death and was higher in cells pre-treated with BCF-CM than NTF-CM. Pre treatment of breast cancer cells with BCF-CM induced a degree of resistance to Dox in accordance with the increased level of secreted HMGB1. Recombinant HMGB1 was shown to increase Dox resistance and this was associated with evidence of autophagy. Anti-HMGB1 neutralizing antibody significantly reduced the effect of extracellular HMGB1 released from dying cancer cells or of recombinant HMGB1 on Dox resistance. CONCLUSIONS: These findings highlight the potential of stromal fibroblasts to contribute to chemoresistance in breast cancer cells in part through fibroblast-induced HMGB1 production. PMID- 25512111 TI - Vaginal carcinoma in a young woman who underwent fertility-sparing treatment involving chemotherapy and conservative surgery. AB - Vaginal carcinoma is a rare gynecological malignancy that is usually treated by radiation therapy and/or surgery combined with chemotherapy. Here, we report a case of invasive vaginal carcinoma in a young woman who underwent fertility sparing treatment involving neoadjuvant chemotherapy and conservative surgery. A 36-year-old non-parous woman had a solid tumor in the vagina. Positron emission tomography/computed tomography showed a tumor in the vagina with high FDG uptake (SUV = 17.33) but no metastatic lesions. The patient was diagnosed with vaginal squamous cell carcinoma, FIGO stage I, T1N0M0. Because she wished to retain her fertility, neoadjuvant chemotherapy consisting of irinotecan hydrochloride and nedaplatin was initiated. After four courses of chemotherapy, partial vaginectomy was carried out and the pathological diagnosis of the residual lesion was VAIN 3. Following two further courses of the same chemotherapy, she obtained complete response, and has shown no evidence of disease for 14 months. PMID- 25512112 TI - A decades-long investigation of acute metabolism-based hepatotoxicity by herbal constituents: a case study of pennyroyal oil. AB - Herbal supplements are often regarded as "natural", and are, therefore, considered by many to be safer than pharmaceuticals; however, the adverse effects of these supplements are under-reported in many cases. Many herbal supplements, such as pyrrolizidine alkaloids, kava, chaparral and germander, are known to induce liver injury, which, in general, is one of the main toxicity liabilities observed in the clinic and accounts for about half of total liver failures. One example is the hepatotoxicity of pennyroyal oil, which is ingested as an abortifacient, among other uses. For three decades, the late Professor Sidney Nelson contributed to our understanding of the mechanism of toxicity of pennyroyal and broadened our understanding of chemical toxicology. Here we present the studies and review the findings on acute hepatotoxicity of pennyroyal oil. These studies involved the isolation and characterization of pennyroyal components, determination of the appropriate animal models, identification of the structural requirement for toxicity and determination of the target enzymes and the enzymes involved in the process of bioactivation. Studies with stable isotope labeled pennyroyal metabolites, pulegone and menthofuran, furthered our understanding of the role of cytochrome P450 in the oxidation of these compounds. This review presents the investigational tools used in the study of pennyroyal oil, allowing the reader to not only appreciate these methods but also utilize them to tackle and better understand metabolism-based toxicity in their own projects. PMID- 25512113 TI - Flavonoids furom Coreopsis tinctoria adjust lipid metabolism in hyperlipidemia animals by down-regulating adipose differentiation-related protein. AB - BACKGROUND: To identify the chemical structure of Coreopsis tinctoria extracts and their effect and mechanism on reducing blood lipid in hyperlipemia mice. METHODS: The flavonoids were extracted from Coreopsis tinctoria. The chemical structure was identified by HPLC. 59 mice were divided randomly into 5 groups. (group 1: normal diet control; group 2: hyperlipemia model; group 3: hyperlipemia mice treated with Coreopsis tinctoria, low dose 100 mg/kg; group 4: hyperlipemia mice treated with Coreopsis tinctoria high dose group 200 mg/kg; group 5 hyperlipemia mice treated with Fenofibrate. After 2 week of hyperlipid diet, the treatment of Coreopsis tinctoria and Fenofibrate were given for another 6 weeks with continuous hyperlipid diet. The TC, TG, HDL, histology, adipose differentiation-related protein (ADRP) expression in different groups were compared. RESULTS: Compared with normal diet group, TC, TG in hyperlipemia model group increased ( P<0.01). After treatment with Coreopsis tinctoria low dose group, high dose group, TC of the hyperlipemia mice decreased (P<0.05) without increasing AST, ALT and ALP. Fenofibrate can also decrease TC and TG but increase AST, ALT and ALP. Expression of hepatic ADRP increased in hyperlipemia mice. Coreopsis tinctoria high dose group 200 mg/kg can inhibit ADRP as Fenofibrate does. CONCLUSION: The flavonoids from Coreopsis tinctoria extracts can reduce blood lipid without liver function damage, showing better anti- hyperlipemia effect than Fenofibrate by down-regulating ADRP. PMID- 25512114 TI - Lupus nephritis: glycogen synthase kinase 3beta promotion of renal damage through activation of the NLRP3 inflammasome in lupus-prone mice. AB - OBJECTIVE: Glycogen synthase kinase 3beta (GSK-3beta) has been demonstrated to be involved in immune and inflammatory responses via multiple signaling pathways, leading to the production of proinflammatory cytokines. The purpose of this study was to investigate the role of GSK-3beta in the pathogenesis of lupus nephritis in 2 mouse models. METHODS: Thiadiazolidinone 8 (TDZD-8), a selective inhibitor of GSK-3beta, was administered intraperitoneally to 12-week-old MRL/lpr mice for 8 weeks or to 22-week-old (NZB * NZW)F1 mice for 12 weeks. The expression of GSK 3beta and NLRP3 inflammasome components was analyzed. Proteinuria, biochemical parameters, proinflammatory cytokines, anti-double-stranded DNA (anti-dsDNA) antibody levels, and renal pathology were examined. In vitro, the effect of GSK 3beta-directed small interfering RNA (siRNA) on NLRP3 inflammasome activation was evaluated in bone marrow-derived macrophages (BMMs) from the mice and in the J774A.1 macrophage cell line. RESULTS: The incidence of severe proteinuria and renal inflammation was significantly attenuated in both models, with a significant reduction in anti-dsDNA antibody production, immune complex deposition in the kidney, and circulating proinflammatory cytokine levels. TDZD-8 inhibited the activation of GSK-3beta and caspase 1, with a concomitant decrease in interleukin-1beta (IL-1beta) synthesis. In vitro, GSK-3beta siRNA transfection of mouse BMMs and the J774A.1 cell line with GSK-3beta siRNA inhibited the expression of GSK-3beta, the activation of caspase 1, and the production of IL 1beta. CONCLUSION: These results show that GSK-3beta promotes lupus nephritis at least partly by activating the NLRP3/IL-1beta pathway. The linking of GSK-3beta to the NLRP3/IL-1beta pathway is a novel observation in our study. Our results suggest that the GSK-3beta/NLRP3/IL-1beta pathway may be a potential therapeutic target for lupus in humans. PMID- 25512115 TI - Effect of codon adaptation on codon-level and gene-level translation efficiency in vivo. AB - BACKGROUND: There is a significant difference between synonymous codon usage in many organisms, and it is known that codons used more frequently generally showed efficient decoding rate. At the gene level, however, there are conflicting reports on the existence of a correlation between codon adaptation and translation efficiency, even in the same organism. RESULTS: To resolve this issue, we cultured Escherichia coli under conditions designed to maintain constant levels of mRNA and protein and subjected the cells to ribosome profiling (RP) and mRNA-seq analyses. We showed that the RP results correlated more closely with protein levels generated under similar culture conditions than with the mRNA abundance from the mRNA-seq. Our result indicated that RP/mRNA ratio could be used as a measure of translation efficiency at gene level. On the other hand, the RP data showed that codon-specific ribosome density at the decoding site negatively correlated with codon usage, consistent with the hypothesis that preferred codons display lower ribosome densities due to their faster decoding rate. However, highly codon-adapted genes showed higher ribosome densities at the gene level, indicating that the efficiency of translation initiation, rather than higher elongation efficiency of preferred codons, exerted a greater effect on ribosome density and thus translation efficiency. CONCLUSIONS: These findings indicate that evolutionary pressure on highly expressed genes influenced both codon bias and translation initiation efficiency and therefore explains contradictory findings that codon usage bias correlates with translation efficiency of native genes, but not with the artificially created gene pool, which was not subjected to evolution pressure. PMID- 25512116 TI - The probability of involvement of human papillomavirus in the carcinogenesis of bladder small cell carcinoma, prostatic ductal adenocarcinoma, and penile squamous cell carcinoma: a case report. AB - BACKGROUND: Human papillomavirus is associated with urogenital carcinogenesis such as penile and uterine cervix cancer. On the other hand, association between human papillomavirus infection and risk of bladder and prostatic cancer remains controversial. CASE PRESENTATION: We report a rare case of a 67-year-old Japanese man with synchronous triple urogenital cancer including bladder small cell carcinoma, prostatic ductal adenocarcinoma, and penile squamous cell carcinoma, who presented with a history of asymptomatic gross hematuria. Bladder small cell carcinoma and prostatic ductal adenocarcinoma were diagnosed by histopathological examination after transurethral resection of the tumor. Moreover, he was diagnosed with penile carcinoma based on the exfoliative cytodiagnosis of nodular and papillary tumors inside the preputial collar. He was treated with laparoscopic radical cystectomy, urethrectomy, partial penectomy with pelvic lymph node dissection, and ileal conduit urinary diversion. To identify a common pathogenesis, we considered human papillomavirus as an etiologic factor because it is a known risk factor for penile carcinoma. Human papillomavirus deoxyribonucleic acid bands were detected by polymerase chain reaction in the three tumors. There was a possibility that human papillomavirus was involved in the carcinogenesis of the triple cancer. CONCLUSIONS: To the best of our knowledge, this is the first report of the synchronous triple urogenital cancer of small cell carcinoma of the bladder, ductal adenocarcinoma of the prostate and penile squamous cell carcinoma. We believe that human papillomavirus may have been involved in the carcinogenesis of the triple urogenital cancer described in this case. PMID- 25512117 TI - A view from the frontlines in Slavyansk, Ukraine: HIV prevention, drug treatment, and help for people who use drugs in a conflict zone. PMID- 25512118 TI - A network meta-analysis of progression free survival and overall survival in first-line treatment of chronic lymphocytic leukemia. AB - BACKGROUND: A limited evidence exists regarding comparisons of clinical effectiveness of available therapies for first-line treatment of chronic lymphocytic leukemia (CLL). METHODS: We compared available therapies for treatment-naive, symptomatic CLL regarding progression free survival (PFS) and overall survival (OS) in all the identified random control trials and in subgroups composed of younger/fit and older/unfit patients, using a Bayesian network meta-analysis. RESULTS: In younger/fit patients we obtained median of projected mean PFS of: 19, 26, 31, 43, 51 and 75months for chlorambucil, fludarabine, alemtuzumab, fludarabine with cyclophosphamide (FC), bendamustine and fludarabine with cyclophosphamide and rituximab (FCR), respectively. We noted median OS of: 59, 66, 66, 70months for FC, chlorambucil, FCR and fludarabine, respectively. In older/unfit patients we noted PFS of: 16, 17, 24, 30, 60months for chlorambucil, fludarabine and chlorambucil with ofatumumab (OClb) or rituximab (RClb) or obinutuzumab (GClb), respectively. We obtained median OS of: 44, 58, 59 and 90months for fludarabine, RClb, chlorambucil and GClb, respectively. CONCLUSIONS: Our results suggest that: (1) FCR has higher potential of preventing CLL progression in younger/fit patients over four therapy options, which were subject of previous meta-analysis but also over bendamustine; (2) in these patients FCR does not entail prolonging of OS in comparison with chlorambucil and it is outperformed by fludarabine; (3) in older/unfit patients GClb demonstrates longer projected PFS than all assessed comparators; (4) in this group GClb has also the highest potential of increasing OS. PMID- 25512119 TI - Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity. AB - Regimen-related toxicities remain a priority concern within the field of supportive care in cancer. Despite this, many forms of toxicity are under reported and consequently poorly characterised. Although there have been significant improvements in our understanding of regimen-related toxicities, symptom management continues to occur independently raising concerns such as drug interactions and the tendency to emphasise management of a single symptom at the expense of others. This review focuses on two important toxicities induced by chemotherapy; neuropathy/pain and gastrointestinal toxicity, introducing the Toll like receptor (TLR) 4 pathway as a common component of their pathobiology. Given the global observation of toxicity clusters, identification of a common initiating factor provides an excellent opportunity to simultaneously target multiple side effects of anticancer treatment. Furthermore, identification of common biological underpinnings could perhaps reduce polypharmacy and have pharmacoeconomic benefits. PMID- 25512120 TI - Factors affecting the utilization of genetic counseling services among Israeli Arab women. AB - OBJECTIVES: To assess the factors associated with utilization of genetic counseling services among pregnant Israeli Arab women. METHODS: A case-control study was conducted among 414 pregnant Arab women who were referred by a family physician or a perinatologist to genetic counseling services between 2008 and 2011. Data was collected using interviews, with both groups 'users' and 'non users' of genetic counseling, based on a structured questionnaire including demographic, socio-economic, medical and cultural variables. RESULTS: In multivariate analysis, factors affecting women's utilization of genetic counseling service were high income level (OR 3.44, 95%CI 1.8-6.5, p < 0.001), high service accessibility (OR 0.75, 95%CI 0.67-0.84, p = 0.001), more positive attitude toward genetic counseling (OR 0.43, 95%CI 0.27-0.67, p = 0.012) and lower religiosity level (OR 1.40, 95%CI 0.94-2.09, p = 0.04). However, when we examined the following variable: pregnant woman's age, woman's education, consanguinity and pregnancy' age, knowledge level and the perspective toward abortion, no significant differences were found between the users and non-users groups. CONCLUSIONS: The underutilization of genetic counseling services among pregnant Israeli Arab women was associated with the following: lower income level, attitude toward genetic counseling, accessibility to service and religiosity. Thus, it is advisable to expand genetic counseling service within this community. (c) 2014 John Wiley & Sons, Ltd. PMID- 25512121 TI - Enantioseparation of aromatic alpha-hydroxycarboxylic acids: the application of a dinuclear Cu2(II)-beta-cyclodextrin complex as a chiral selector in high speed counter-current chromatography compared with native beta-cyclodextrin. AB - The use of a dinuclear Cu2(II)-beta-cyclodextrin complex (Cu2-beta-CyD) as a chiral selector (CS) was successfully applied to chiral high speed counter current chromatography (HSCCC) for the enantioseparation of aromatic alpha hydroxycarboxylic acids. alpha-cyclohexylmandelic acid (CHMA) as a case was studied to optimize the separation temperature, the pH value of the aqueous phase, and the concentration of the chiral selector, which were comparatively studied between Cu2-beta-CyD and native beta-cyclodextrin (beta-CyD) as CSs. The thermodynamic parameters of the formation of the complex between the enantiomers and the CSs were obtained, and the complex formation constants between the enantiomers and Cu2-beta-CyD or beta-CyD were determined using induced circular dichroism technology. The results indicate that Cu2-beta-CyD can remarkably improve the enantioseparation compared with beta-CyD, mainly due to the ion pairing interactions between the deprotonation of carboxyl group of CHMA and the Cu(II) ion of Cu2-beta-CyD. Five of other aromatic alpha-hydroxycarboxylic acids were also enantioseparated successfully by HSCCC using Cu2-beta-CyD as a CS. PMID- 25512122 TI - Particle size effects on protein and virus-like particle adsorption on perfusion chromatography media. AB - The resin structure, chromatographic behavior, and adsorption kinetics of proteins and virus-like-particles (VLPs) are studied for POROS HS 20 and POROS HS 50 (23 and 52 MUm mean diameter, respectively) to determine the effects of particle size on perfusion chromatography and to determine the predictive ability of available models. Transmission electron microscopy (TEM) and inverse size exclusion chromatography (iSEC) show similar structures for the two resins, both containing 200-1000 nm pores that transect a network of much smaller pores. For non-binding conditions, trends of the height equivalent to a theoretical plate (HETP) as a function of reduced velocity are consistent with perfusion. The estimated intraparticle flow fractions for these conditions are 0.0018 and 0.00063 for POROS HS 20 and HS 50, respectively. For strong binding conditions, confocal laser scanning microscopy (CLSM) shows asymmetrical intraparticle concentrations profiles and enhanced rates of IgG adsorption on POROS HS 20 at 1000 cm/h. The corresponding effective diffusivity under flow is 2-3 times larger than for non-flow conditions and much larger than observed for POROS HS 50, consistent with available models. For VLPs, however, adsorption is confined to a thin layer near the particle surface for both resins, suggesting that the bound VLPs block the pores. PMID- 25512123 TI - Graphene oxide bound silica for solid-phase extraction of 14 polycyclic aromatic hydrocarbons in mainstream cigarette smoke. AB - Polycyclic aromatic hydrocarbons (PAHs) were considered as a source of carcinogenicity in mainstream cigarette smoke (MSS). Accurate quantification of these components was necessary for assessing public health risk. In our study, a solid-phase extraction (SPE) method using graphene oxide (GO) bound silica as adsorbent for purification of 14 PAHs in MSS was developed. During SPE process, large matrices interferences of MSS were adsorbed on SPE column. The result of FTIR spectra demonstrated that these matrices interferences were adsorbed on GO mainly through OH and CO groups. The concentrations of PAHs in MSS extract were determined by gas chromatography-mass spectrometry (GC-MS). The limit of detection (LOD) and limit of quantification (LOQ) of the developed method for 14 PAHs ranged from 0.05 to 0.36 ng/cig and 0.17 to 1.19 ng/cig, respectively. The accuracy of the measurement of 14 PAHs was from 73 to 116%. The relative standard deviations of intra- and inter-day analysis were less than 7.8% and 13.9%, respectively. Moreover, the developed method was successfully applied for analysis of real cigarette containing 1R5F reference cigarette and 12 top-selling commercial cigarettes in China. PMID- 25512124 TI - Transverse dispersion in ordered pillar arrays as a Markov chain: extension of the Galton-board model. AB - An extension of the Galton-board model of the transverse solute dispersion in laminar flow through ordered arrays of non-porous cylindrical pillars was proposed. In contrast to the original model, which describes the dispersion process as a one-dimensional random walk with independent, equally probable steps, the extended model treats the process as a Markov chain, namely as a random walk with such correlated steps that the velocity-dependent probability to make a step in the same direction as the preceding step is smaller than the probability to reverse the direction of motion. The relationship between the average squared transverse displacement of the solute and the number of steps in the chain was used to find the expression for the velocity dependence of the transverse dispersion coefficient. The obtained equation differs from the one in the Galton-board model by the multiplier that accounts for the leveling-off of the experimental dependences at high reduced velocities. Although this modified Galton-board model cannot be directly applied to low velocities, a few additional assumptions lead to the expression that fits the whole range of the recent simulated dispersion data well. PMID- 25512125 TI - Preparation and evaluation of a novel hybrid monolithic column based on pentafluorobenzyl imidazolium bromide ionic liquid. AB - To develop a novel hybrid monolithic column based on pentafluorobenzyl imidazolium bromide ionic liquid, a new ionic liquid monomer was synthesized from 1-vinylimidazole and pentafluorobenzyl bromide. By employing a facile one-step copolymerization of polyhedral-oligomeric-silsesquioxane-type (POSS) cross linking agent and the home-made ionic liquid monomer, the hybrid monolithic columns were in situ fabricated in fused-silica capillary. The morphology of monolithic column was characterized by scanning electron microscope (SEM) and the chemical composition was confirmed by Fourier-transform infrared spectroscopy (FT IR) and elemental analysis. Excellent mechanical stability and slight swelling propensity were exhibited which was ascribed to the rigid hybrid monolithic skeleton. Reproducibility results of run-to-run, column-to-column, batch-to-batch and day-to-day were investigated and the RSDs were less than 0.46%, 1.84%, 3.96% and 3.17%, respectively. The mixed-mode retention mechanism with hydrophobic interaction, pi-pi stacking, ion-exchange, electrostatic interaction and dipole dipole interaction was explored systematically using analytes with different structure types. Satisfied separation capability and column efficiency were achieved for the analysis of small molecular compounds such as alkylbenzenes, polycyclic aromatic hydrocarbons, nucleosides and halogenated compounds. PMID- 25512126 TI - Evaluation of sorbent materials for the sampling and analysis of phosphine, sulfuryl fluoride and methyl bromide in air. AB - Phosphine (PH3), sulfuryl fluoride (SO2F2) and methyl bromide (CH3Br) are highly toxic chemical substances commonly used for fumigation, i.e., pest control with gaseous pesticides. Residues of fumigation agents constitute a health risk for workers affected, and therefore accurate methods for air sampling and analysis are needed. In this study, three commercial adsorbent tubes; Carbosieve SIIITM, Air ToxicsTM and Tenax TATM, were evaluated for sampling these highly volatile chemicals in air and their subsequent analysis by thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). The breakthrough volume (BTV) of each fumigant was experimentally determined on the different adsorbents at concentrations at or above their permissible exposure limits, using a method based on frontal chromatography of generated fumigant atmospheres. Carbosieve SIIITM, a molecular sieve possessing a very high specific area, proved to be a better adsorbent than both Air ToxicsTM and Tenax TATM, resulting in at least a 4 fold increase of the BTV50%. BTV50% for Carbosieve SIIITM at 20 degrees C was measured as 4.7L/g, 5.5L/g and 126L/g for phosphine, sulfuryl fluoride and methyl bromide, respectively, implying safe sampling volumes of 1.9L, 2.2L and 50L, respectively, for a commercial tube packed with 800mg Carbosieve SIIITM. The temperature dependence of BTV was strong for Carbosieve SIIITM, showing a reduction of 3-5%/ degrees C in breakthrough volume within the range -20 to 40 degrees C. Furthermore, although Carbosieve SIIITM reportedly has a higher affinity for water than most other adsorbents, relative humidity had only a moderate influence on the retention capacity of phosphine. Overall, the applicability of Carbosieve SIIITM adsorbent sampling in combination with TD-GC MS analysis was demonstrated for highly volatile fumigants. PMID- 25512128 TI - Successful treatment of oral itraconazole for infantile hemangiomas: a case series. AB - Infantile hemangiomas can present a therapeutic challenge to clinicians, especially when associated with severe pain and feeding difficulties. The standard therapeutic management includes corticosteroids and propranolol. However, the clinical response is not always satisfactory. We present six cases of infantile hemangiomas successfully treated with oral itraconazole approximately 5 mg/kg per day. In the first month, the red color of the lesions became a little lighter and the growth of the lesions was controlled in all cases. An obvious clinical improvement was noted in all cases during the 3-month period, with 80-100% improvement in each patient at the end of the treatment, which was judged by both their parents and the dermatologists. Compliance with treatment instructions of oral itraconazole in infants was judged to be very good. Side-effects were mild and limited. Although itraconazole can inhibit angiogenesis and tumor growth in vitro and in vivo associated with some cancers, further research is required to understand the pathogenesis of infantile hemangiomas and the mechanism of itraconazole. PMID- 25512127 TI - A cross-sectional study of geographic differences in health risk factors among young Australian adults: the role of socioeconomic position. AB - BACKGROUND: It remains unclear why living outside of an urban environment affects aspects of health, particularly whether these differences can be explained by other factors such as socioeconomic position (SEP). The aim of this study was to compare health risk factors between metropolitan and non-metropolitan young Australian adults and examine whether socioeconomic position (SEP) mediates any differences. METHODS: Cross-sectional data came from an Australia-wide sample of 26-36 year-olds (n = 2567). Information on demographic characteristics, smoking, alcohol consumption, diet, physical activity (PA, mins/week) and mental health were collected by questionnaire, BMI from measured height and weight and daily steps using pedometers. Metropolitan versus non-metropolitan residence was classified from addresses. SEP included individual-level (education, occupation) and area-level measures. Prevalence ratios and ratio of means were calculated using log binomial, log multinomial and linear regression techniques. RESULTS: Non-metropolitan residents were less likely to meet 2 or more dietary guidelines, reported less leisure-time PA and active commuting but more occupational and domestic PA than metropolitan residents. Non-metropolitan women were more likely to smoke and be obese. No differences in mental health were found. After adjusting for SEP, differences remained significant except for leisure-time PA (men and women) and smoking (women). CONCLUSIONS: Living outside metropolitan areas was associated with more risk factors in these young adults. Individual SEP and area-level disadvantage generally did not explain these differences, suggesting that a focus on geographic location as its own social determinant of health, beyond SEP, is warranted. PMID- 25512130 TI - Large scale patterning of hydrogel microarrays using capillary pinning. AB - Capillary barriers provide a simple and elegant means for autonomous fluid-flow control in microfluidic systems. In this work, we report on the fabrication of periodic hydrogel microarrays in closed microfluidic systems using non fluorescent capillary barriers. This design strategy enables the fabrication of picoliter-volume patterns of photopolymerized and thermo-gelling hydrogels without any defects and distortions. PMID- 25512131 TI - Virological and serological findings in dogs with naturally occurring distemper. AB - Canine distemper virus (CDV) is the cause of a severe and highly contagious disease in dogs. The unpredictable and variable course of CDV-related disease may hamper correct diagnosis of infection and makes it crucial the collection of samples suitable for laboratory confirmation. In the present study we were able to follow the disease in two dogs infected naturally, collecting different biological matrices during the entire period of infection. By real time RT-PCR, viral RNA was detected and quantified, suggesting that urine and rectal swabs would be useful for ante-mortem diagnosis of distemper in dogs, regardless of the clinical stage and form of the illness. PMID- 25512132 TI - A phage-displayed single domain antibody fused to alkaline phosphatase for detection of porcine circovirus type 2. AB - The fusion of single domain antibodies (sdAbs) and alkaline phosphatase (AP) has been demonstrated to be useful as an immunodiagnostic reagent. In this work, a porcine circovirus type-2 (PCV2) specific sdAb (psdAb) was expressed as fusion with an AP. The binding activity of psdAb-AP fusion was examined by Western blot, enzyme linked immunosorbent assay (ELISA), and surface plasmon resonance (SPR). To assess the practicality of psdAb-AP fusion as a diagnostic reagent, the fusion was used in a Western blot, a direct ELISA, and an immunocytochemistry assay (ICC) for PCV2 detection. The results indicated that the binding activity and specificity of psdAb-AP fusion was similar with psdAb, but the functional affinity of psdAb-AP fusion was about 5 times greater than psdAb as determined by SPR. As a tracer, psdAb-AP fusion could detect PCV2 cap protein down to 0.01 MUg/lane and 0.05 MUg/ml in Western blot and direct ELISA respectively. When compared with a control indirect fluorescence assay (IFA), the ICC psdAb-AP fusion was more efficient, needed less operation steps and ended in a shorter time. The results demonstrate that the fusion of psdAb to AP provides a valuable route to the development of psdAb-based immuno-reagents, which offers a simple, convenient, and sensitive method for PCV2 detection. PMID- 25512133 TI - Rapid and simple detection of Japanese encephalitis virus by reverse transcription loop-mediated isothermal amplification combined with a lateral flow dipstick. AB - Japanese encephalitis virus (JEV) is a major cause of viral encephalitis in geographical areas, such as Asia and Western Pacific, where it is a threat to human and animal health. To control this disease, it is necessary to develop a rapid, simple, accurate method for diagnosis. In this study, a method based on reverse transcription loop-mediated isothermal amplification (RT-LAMP) coupled with a lateral flow dipstick (LFD) has been developed to detect JEV (JEV RT-LAMP LFD). The entire assay can be completed within 70 min, and in this study, no false positive results were observed when other pathogens were tested, indicating that the assay is a highly specific method for the detection of JEV. Additionally, the sensitivity of the RT-LAMP-LFD assay for SA14-14-2 strain was 50 pg of RNA, which was similar to that of RT-PCR and RT-LAMP combined with gel electrophoresis, and was 10-fold more sensitive than RT-LAMP combined with calcein. The limit of detection for this assay was 5 pg of RNA. In addition, no false positive results were obtained with 14 serum samples. Our results indicate that this RT-LAMP-LFD assay will be of great value for JEV infection testing due to its rapid and highly specific and sensitive properties. PMID- 25512134 TI - Finger and toenail onycholysis. AB - Onycholysis - the separation of the nail plate from the nail bed occurs in fingers and toenails. It is diagnosed by the whitish appearance of the separated nail plate from the nail bed. In fingers, the majority is caused by trauma, manicuring, occupational or self-induced behavior. The most common disease producing fingernail onycholysis is psoriasis and pustular psoriasis. Phototoxic dermatitis, due to drugs can also produce finger onycholysis. Once the separation occurs, the environmental flora sets up temporary colonization in the available space. Finger onycholysis is most common in women. Candida albicans is often recovered from the onycholytic space. Many reports, want to associate the yeast as cause and effect, but the data are lacking and the treatment of the candida does not improve finger onycholysis. A reasonable explanation for the frequent isolation of Candida and Pseudomonas in fingernail onycholysis in women, is the close proximity the fingers have to the vaginal and gastrointestinal tract. Fifty per cent of humans harbour C. albicans in the GI tract and it is frequently carried to the vagina during hygienic practices. Finger onycholysis is best treated by drying the nail 'lytic' area with a hair blower, since all colonizing biota are moisture loving and perish in a dry environment. Toenail onycholysis has a very different etiology. It is mechanical, the result of pressure on the toes from the closed shoes, while walking, because of the ubiquitous uneven flat feet producing an asymmetric gait with more pressure on the foot with the flatter sole. PMID- 25512138 TI - Choice of approach, but not femoral head size, affects revision rate due to dislocations in THA after femoral neck fracture: results from the Lithuanian Arthroplasty Register. AB - PURPOSE: Hip dislocation after arthroplasty for femoral neck fractures (FNF) remains a serious complication. The aim of our study was to investigate FNF patients treated with THA, with a special focus of comparing the effect of surgical approach and femoral head size on the risk of revision for dislocation. METHODS: Data were derived from the Lithuanian Arthroplasty Register, and we calculated the cumulative revision rates after surgery. For survival analysis, we used revision due to dislocation as an end-point. Cox proportional hazards models were used to analyse the influence of various covariates (age, gender, femoral head size, surgical approach). RESULTS: A total of 8,813 primary THAs were registered from 1 January 2011 to 31 December 2013, of which 1,412 were due to FNF: 899 involved 28-mm femoral heads and the remaining 513 received 32-mm heads. The posterior approach was used in 1,156 cases and the anterolateral approach in 256.. At the end of the follow-up period, 74 hips had been revised for recurrent dislocation. Cox regression adjusting for age, gender and head size showed that the posterior approach had 2.3-times [95% confidence interval (CI): 1.0-5.0, p = 0.04] greater risk of revision for dislocation CONCLUSIONS: We conclude that in order to reduce the early dislocation rate in FNF patients treated with THA, it is more effective to use the anterolateral approach than it is to select a femoral head size of 32 mm instead of 28 mm. PMID- 25512137 TI - The management of type B1 periprosthetic femoral fractures: when to fix and when to revise. AB - The incidence of periprosthetic fractures around total hip arthroplasty is increasing as patient longevity rises and the number of patients with hip implants continues to grow. Type B1 periprosthetic femoral fractures are associated with a well-fixed stem and have traditionally been treated with internal fixation. However, there are a subset of these fractures which fare badly when internal fixation is undertaken, and revision of the femoral component to a long-stemmed implant may be more appropriate. We look at the traditional methods of fixation, and the evidence and indications for revision of these fractures. PMID- 25512141 TI - International orthopaedics today. PMID- 25512140 TI - Does electromagnetic-manual guided distal locking influence rotational alignment in antegrade femoral nailing? AB - PURPOSE: The aim of this study was to determine whether distal locking using an electromagnetic-manual guided distal locking decreases the malrotation rate in femur fractures treated with intramedullary nailing. METHODS: A total of 113 adult patients having unilateral femoral shaft fractures treated using IM nails were evaluated regarding demographic features, injury mechanism, fracture type, interval between trauma and nailing, operation time and number of image intensifier shots during the operation at least one year after nailing. Patients were divided into two groups according to distal locking technique. All patients had also undergone clinical examination for lower extremity alignment and range of motion and filled out the SF-36 questionnaire and undergone ultrasound measurement of femoral anteversion angles to reveal any rotational femoral malalignment. RESULTS: Group 1 consisted of 47 patients (41.6 %) with electromagnetic-manual targeting guided distal locking and group 2 consisted of 66 patients (58.4 %) with free-hand distal locking. Both groups were statistically similar regarding demographic features, injury mechanism, fracture type, interval between trauma and nailing, clinical examination and SF-36 results. Operation time and number of image intensifier shots were significantly less in group 1. No statistically significant difference was found between the femoral anteversion angles of injured and uninjured sides of the patients in both groups. CONCLUSIONS: Although there is no significant effect on malrotation, previously known advantages lead us to state that electromagnetic-manual guided distal interlocking is an advantageous treatment option in femoral shaft fractures. PMID- 25512139 TI - The role of growth factors in stem cell-directed chondrogenesis: a real hope for damaged cartilage regeneration. AB - PURPOSE: The use of stem cells in regenerative medicine offers hope to treat numerous orthopaedic disorders, including articular cartilage defects. Although much research has been carried out on chondrogenesis, this complicated process is still not well understood and much more research is needed. The present review provides an overview of the stages of chondrogenesis and describes the effects of various growth factors, which act during the multiple steps involved in stem cell directed differentiation towards chondrocytes. METHODS: The current literature on stem cell-directed chondrogenesis, in particular the role of members of the transforming growth factor-beta (TGF-beta) superfamily-TGF-betas, bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs)-is reviewed and discussed. RESULTS: Numerous studies have reported the chondrogenic potential of both adult- and embryonic-like stem cells and the role of growth factors in programming differentiation of these cells towards chondrocytes. Mesenchymal stem cells (MSCs) are adult multipotent stem cells, whereas induced pluripotent stem cells (iPSC) are reprogrammed pluripotent cells. Although better understanding of the processes involved in the development of cartilage tissues is necessary, both cell types may be of value in the clinical treatment of cartilage injuries or osteoarthritic cartilage lesions. CONCLUSIONS: MSCs and iPSCs both present unique characteristics. However, at present, it is still unclear which cell type is most suitable in the treatment of cartilage injuries. PMID- 25512142 TI - Attention deficit and attention training in early twentieth-century Japan. AB - Yuzero Motora (1856-1912), regarded as the first professional Japanese psychologist, tried to address students' attention difficulties through attention training methods of his own design. His reports contain the first description of ADHD-like symptoms in the history of Japan. Motora viewed "distractibility" as the irregular transition of attention. Students with low scores and attention difficulties who participated in Motora's exercises showed improvement in arithmetic, psychological testing, and certain aspects of daily life. This article describes Motora's theoretical conception of attention and attention training methodology, the history of attention deficit and attention training, and the significance of Motora's experiments. PMID- 25512143 TI - Comparison between tracheal ratio methods used by three observers at three occasions in English Bulldogs. AB - BACKGROUND: Tracheal hypoplasia is a congenital condition described in mainly brachycephalic breeds and is one component of the brachycephalic obstructive airway syndrome (BOAS). Two radiographic methods have been described to evaluate the dimensions of the tracheal diameter in dogs and to distinguish between hypoplastic and non-hypoplastic tracheas: the tracheal lumen diameter to thoracic inlet distance ratio (TD/TI) and the ratio between the thoracic tracheal luminal diameter and the width of the proximal third of the third rib (TT/3R). The purpose of this study was to compare these two published radiographic methods between observers, different measuring occasions and to investigate the effect on classification of dogs as having hypoplastic or non-hypoplastic tracheas using four previously published mean ratios as cut-offs (<0.11, <0.127 and <0.144 for the TD/TI and <2.0 for the TT/3R method). Three observers evaluated right and left lateral recumbent radiographs from 56 adult English Bulldogs independently on three different occasions. TD/TI and TT/3R ratios were calculated and correlated between measuring occasions. Kappa, observed, positive, and negative agreements were calculated between observers and measuring occasions. Number of hypoplastic and non-hypoplastic dogs for each method and occasion was determined using <0.11, <0.127 and <0.144 as cut-offs for TD/TI and <2.0 for TT/3R. RESULTS: Intraobserver agreement varied with kappa between 0.45-0.94 for the TD/TI and 0.20-0.86 for the TT/3R method. Interobserver kappa varied between 0.27-0.70 for the TD/TI method and between 0.05-0.57 for the TT/3R method. There was poor agreement in classifying English Bulldogs as tracheal hypoplastic or non hypoplastic, depending on measuring method, cut-off value and observer. CONCLUSIONS: The diagnostic value of both the TD/TI and TT/3R methods with such poor agreement is questionable, and significantly impacts their reliability for both clinical evaluation of dogs and use in health screening programs. PMID- 25512144 TI - HER2 testing in paired biopsy and excision specimens of gastric cancer: the reliability of the scoring system and the clinicopathological factors relevant to discordance. AB - BACKGROUND: Inclusion of trastuzumab in chemotherapy regimens is advantageous for patients with advanced or metastatic gastric cancer who overexpress HER2. Therefore, accurate assessment of HER2 status in tumor tissue is critical when weighing treatment options. METHODS: We examined HER2 expression in 180 paired endoscopic biopsy and surgical excision specimens of gastric cancers via immunohistochemistry (IHC). Equivocal IHC results (IHC 2+) were resolved by HER2 fluorescence in situ hybridization (FISH). The relationships of several clinical and pathological features with discordant HER2 results in paired specimens were determined. RESULTS: Fourteen biopsy specimens and surgical specimens (7.8%) were HER2-positive. Discordant HER2 IHC scores were observed in 90 paired specimens (50%) and 8 paired specimens (4.4%) had discordant results. The kappa coefficients for an HER2 diagnostic algorithm were 0.264, 0.339, and 0.690 for IHC scores, IHC categories, and final results, respectively (p < 0.001). Discordant HER2 results were significantly associated with discordant tumor differentiation in the paired biopsy and excision specimens (p = 0.01). Intratumoral heterogeneity did not predict HER2 discordance. There was no association between HER2 discordance and the number of biopsy tissue fragments (p = 0.764). CONCLUSIONS: Hofmann's HER2 scoring system is a fairly reliable tool for evaluating HER2 status in biopsy and excision specimens. Discordant HER2 results in paired specimens were observed in a small percentage of gastric cancers. Testing all available specimens should be considered in order to eliminate discrepancies, especially when discordant tumor differentiation is observed. PMID- 25512145 TI - Finding vulnerable subpopulations in the Seychelles Child Development Study: effect modification with latent groups. AB - The Seychelles Child Development Study is a research project with the objective of examining associations between prenatal exposure to low doses of methylmercury from maternal fish consumption and children's developmental outcomes. Whether methylmercury has neurotoxic effects at low doses remains unclear and recommendations for pregnant women and children to reduce fish intake may prevent a substantial number of people from receiving sufficient nutrients that are abundant in fish. The primary findings of the Seychelles Child Development Study are inconsistent with adverse associations between methylmercury from fish consumption and neurodevelopmental outcomes. However, whether there are subpopulations of children who are particularly sensitive to this diet is an open question. Secondary analysis from this study found significant interactions between prenatal methylmercury levels and both caregiver IQ and income on 19 month IQ. These results are sensitive to the categories chosen for these covariates and are difficult to interpret collectively. In this paper, we estimate effect modification of the association between prenatal methylmercury exposure and 19-month IQ using a general formulation of mixture regression. Our mixture regression model creates a latent categorical group membership variable which interacts with methylmercury in predicting the outcome. We also fit the same outcome model when in addition the latent variable is assumed to be a parametric function of three distinct socioeconomic measures. Bayesian methods allow group membership and the regression coefficients to be estimated simultaneously and our approach yields a principled choice of the number of distinct subpopulations. The results show three groups with different response patterns between prenatal methylmercury exposure and 19-month IQ in this population. PMID- 25512146 TI - A composite likelihood method for bivariate meta-analysis in diagnostic systematic reviews. AB - Diagnostic systematic review is a vital step in the evaluation of diagnostic technologies. In many applications, it involves pooling pairs of sensitivity and specificity of a dichotomized diagnostic test from multiple studies. We propose a composite likelihood (CL) method for bivariate meta-analysis in diagnostic systematic reviews. This method provides an alternative way to make inference on diagnostic measures such as sensitivity, specificity, likelihood ratios, and diagnostic odds ratio. Its main advantages over the standard likelihood method are the avoidance of the nonconvergence problem, which is nontrivial when the number of studies is relatively small, the computational simplicity, and some robustness to model misspecifications. Simulation studies show that the CL method maintains high relative efficiency compared to that of the standard likelihood method. We illustrate our method in a diagnostic review of the performance of contemporary diagnostic imaging technologies for detecting metastases in patients with melanoma. PMID- 25512149 TI - Cancer in low- and medium-income countries. PMID- 25512148 TI - A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies. AB - Pulmonary arterial hypertension (PAH) is a pathological condition characterized by a persistent and progressive elevation of pulmonary vascular resistance with devastating consequences if untreated. In the past recent years, several genes have been related to PAH, however, the molecular defect remains unknown in a significant proportion of patients with familial PAH (~20%). During the past few years, we have observed that PAH shows a particular behavior in Iberian Gypsies, with more aggressive course and frequently affecting multiple members of the same family. We studied five Gypsy families in whom at least one individual from each family developed a severe form of PAH and in whom no mutation had been identified in the common genes. We applied SNP-array-based homozygosity mapping in three families and obtained, among others, one of which included the gene EIF2AK4, recently reported in patients with PAH from group-1' pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH). Subsequently, we sequenced EIF2AK4 and found a homozygous mutation in all five families: c.3344C>T(p.P1115L). The majority of our patients required early lung transplantation. Hence, this mutation appeared with a more severe phenotype than previously reported for other EIF2AK4 mutations. The finding of this novel mutation is important for genetic counseling and calculation of population recurrence risks. PMID- 25512147 TI - Absence of a set of plasmid-encoded genes is predictive of reduced pathogenic potential in Brachyspira hyodysenteriae. AB - The gene content of 14 strains of the intestinal spirochaete Brachyspira hyodysenteriae was compared using a DNA microarray. A consistent difference occurred in a block of four genes on the ~36 Kb plasmid, with these being present in six virulent strains and absent in eight strains with reduced pathogenic potential. These genes encoded a predicted radical S-adenosylmethionine domain protein, a glycosyl transferase group 1-like protein, an NAD dependent epimerase and a dTDP-4-dehydrorhamnose 2-5 epimerase: they may be involved in rhamnose biosynthesis and glycosylation. The absence of these plasmid genes in B. hyodysenteriae isolates is predictive of reduced pathogenic potential. PMID- 25512150 TI - A diversity of cancer incidence and mortality in West Asian populations. AB - BACKGROUND: Western Asia comprises a large proportion of the world population with different ethnicities and religions inhabiting areas of diverse geographic features. The countries of this region have experienced rapid economic growth over the latter half of the 20th century, which continues to this day, resulting in major changes in lifestyle of the population. OBJECTIVES: The aim of this study was to compare the incidence and mortality of cancer in West Asia using the estimates reported by the International Agency for Research on Cancer (IARC) in Globocan-2012. METHODS: Countries with high-quality data or national data (based on the definition of the Globocan-2012) were included in the analysis. These included Bahrain, Iran, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, and Turkey. We also found high-quality cancer data from regional cancer registries in 3 Iranian and 3 Turkish provinces. Data on cancer incidence and mortality were collected and described in tables and graphs. Spearman's correlation test was used to assess the correlation between geographic coordinates and the incidence age-standardized rate (ASR; per 100,000 person-years) of cancers. FINDINGS: Nine countries and 6 regional registries were included. Cancers of the lung (ASR, 33.3), prostate (24.9), bladder (19.1), stomach (16.5), and colorectal (15.9) were the most common malignancies in men. The most common cancers in women were those of the breast (35.4), colorectal (12.1), thyroid (10.3), stomach (9.2), and lung (6.7). The incidence rates of upper gastrointestinal and lung cancers were considerably higher in the northern part of this region, including Turkey and northern Iran compared with southern countries. High incidences of breast, colorectal, prostate, and bladder cancers were found in countries located in the northwest including Jordan, Lebanon, and Turkey. CONCLUSIONS: The most common cancers differed by country. Consequently, cancer control programs must be tailored to the most common types of cancers in each country. Lack of high quality data for some West Asian countries was the major limitation of this study. Therefore, as the first step of cancer control programs, it is recommended that well-structured population-based cancer registries be established in all of these countries. PMID- 25512151 TI - Cancer burden and control in the Western Pacific region: challenges and opportunities. AB - BACKGROUND: Cancer has become a priority public health challenge in the Member States of the World Health Organization's (WHO) Western Pacific Region (WPR). Rapid and unplanned urbanization, demographic transition, and lifestyle changes are driving the increase in noncommunicable diseases (NCDs), which include cancer. The WHO Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013-2020, targets a reduction in premature mortality from NCDs by 25% by 2025. OBJECTIVES: The aim of this study was to review the epidemiology of cancer including cancer control efforts in the WPR. METHODS: Information was primarily extracted from Globocan 2012, Cancer Incidence in Five Continents Vol. X, and the NCD country capacity survey carried out by the WHO in 2013. The WPR, with one-fourth of the world's population, has one-third of all cancers globally. Cancer cases in the WPR are expected to increase from 4.5 million new cases in 2012 to 6.4 million in 2025. FINDINGS: In most of the low- and middle-income countries (LMICs) in Asia and in Pacific Island countries and areas, coverage of cancer registration is relatively low and they face many challenges in quality of cancer registry data. Eighty-five percent of LMICs have indicated the existence of a cancer control policy strategy and/or action plan. The predominance of lung, stomach, colorectal, breast, and cervical cancers makes control of the disease more amenable in the WPR. A relatively high ratio of mortality to incidence in LMICs reflects health-system limitations, especially in the diagnosis and management of cancer. CONCLUSIONS: Strengthening cancer registration, tobacco control, and promotion of a healthy diet, as well as HBV and HPV vaccination, is the priority areas to reduce cancer burden. Health-system strengthening with a defined package of services at different levels, referral care, trained human resources, and appropriate technology is necessary to improve cancer management. Pain relief and palliative care are priorities as well. A well planned national cancer control program with a strong component of surveillance and monitoring can help to reduce the cancer burden in LMICs and Pacific Island countries. PMID- 25512153 TI - Tobacco, alcohol, and cancer in low and high income countries. AB - BACKGROUND: Tobacco use is a well-established risk factor for cancers of the lung, head and neck, nasopharynx, esophagus, stomach, pancreas, liver, kidney, bladder, leukemia, and cervix. Alcohol consumption is a well-established risk factor for cancers of the head and neck, esophagus, liver, colorectum, and breast for women only. The majority of studies on tobacco and alcohol were conducted in high-income countries (HICs). OBJECTIVE: The aim of this review was to assess the extent of tobacco and alcohol usage and to compare the cancer burden between low- and high-income regions. FINDINGS: Overall, tobacco smoking is estimated to account for 21% of cancer deaths worldwide (29% in HICs and 18% in low- and middle-income countries [LMICs]). Alcohol consumption is estimated to account for 5% of all cancer deaths worldwide, with similar proportions in LMICs. Cancers of the breast, lung, stomach, liver, head and neck, esophagus, cervix, and nasopharynx, and leukemia are already diagnosed in greater numbers each year in less-developed countries compared with more developed countries. The future burden of tobacco- and alcohol-related cancers on less-developed regions is expected to increase greatly based on demographic effects, with a 69.9% increase in tobacco-related cancer cases and a 68% increase in cancers related to alcohol. Although HICs have experienced a decrease in tobacco prevalence in recent decades, LMICs are still in the early stages of the tobacco epidemic. CONCLUSION: Tobacco use and alcohol consumption will clearly remain important risk factors that must be targeted with public health efforts particularly in LMICs. PMID- 25512152 TI - Cancer burden in Latin America and the Caribbean. AB - BACKGROUND: In Latin America and the Caribbean, the epidemiological transition has been occurring in an unequal manner. Infectious-contagious diseases share space with the increase of chronic nontransmissible diseases, such as cancer, which already represents the second most common cause of death, after cardiovascular illnesses. OBJECTIVES: This study provides a global picture of the burden of cancer in Latin America and the Caribbean, as well as the challenges faced when controlling this disease in these regions. FINDINGS: Epidemiological information on cancer in Latin America originates mainly from mortality registries and from a limited number of population-based cancer registries. Estimates indicate increases of 72% in the incidence of cancer and 78% in the mortality of men between 2012 and 2030, and for women the rates are 62% and 74%, respectively. These increases in incidence rates, accompanied by disproportionally high mortality rates, when compared with other regions of the world, reveal the magnitude of the challenge of controlling cancer in Latin America and the Caribbean. Although neoplasms are among the main causes of death, the control strategies are faced with issues such as organization and development of the health system, and the public policy formulation mechanism. CONCLUSIONS: Establishing knowledge on the real impact of incidence, mortality, and survival in Latin America and the Caribbean is quite a challenge due to the lack of an updated and dynamic information system on mortality and incidence, although some improvement has been made in the information systems of some countries within the most recent decade. Other obstacles for cancer control are the uneven allocation of resources, lack of investments in equipment and infrastructure, and the concentration of health care professionals in large urban centers, which contribute to the reproduction of socioeconomic iniquities in the assistance of populations that suffer from cancer. PMID- 25512154 TI - Infection and cancer: global distribution and burden of diseases. AB - BACKGROUND: Infection is one of the main risk factors for cancer. OBJECTIVES: Epidemiology, pathogenesis, and disease burden of infection-related cancers were reviewed by infectious agents. FINDINGS: Chronic infection with Epstein-Barr virus, hepatitis B and C viruses, Kaposi sarcoma herpes virus, human immunodeficiency virus (HIV) type 1, human papillomavirus (HPV), human T-cell lymphotropic virus type 1, Helicobacter pylori, Clonorchis sinensis, Opisthorchis viverrini, and Schistosoma haematobium are associated with nasopharyngeal carcinoma; lymphoma and leukemia, including non-Hodgkin lymphoma, Hodgkin lymphoma, and Burkitt lymphoma; hepatocellular carcinoma; Kaposi sarcoma; oropharyngeal carcinoma; cervical carcinoma and carcinoma of other anogential sites; adult T-cell leukemia/lymphoma; gastric carcinoma; cholangiocarcinoma; and urinary bladder cancer. In 2008, approximately 2 million new cancer cases (16%) worldwide were attributable to infection. If these infections could be prevented and/or treated, it is estimated that there would be about 23% fewer cancers in less developed regions of the world, and about 7% fewer cancers in more developed regions. CONCLUSION: Widespread application of existing public health methods for the prevention of infection, such as vaccination, safer injection practices, quality-assured screening of all donated blood and blood components, antimicrobial treatments, and safer sex practices, including minimizing one's lifetime number of sexual partners and condom use, could have a substantial effect on the future burden of cancer worldwide. PMID- 25512155 TI - Occupational and environmental exposures and cancers in developing countries. AB - BACKGROUND: Over the past few decades, there has been a decline in cancers attributable to environmental and occupational carcinogens of asbestos, arsenic, and indoor and outdoor air pollution in high-income countries. For low- to middle income countries (LMICs), however, these exposures are likely to increase as industrialization expands and populations grow. OBJECTIVE: The aim of this study was to review the evidence on the cancer risks and burdens of selected environmental and occupational exposures in less-developed economies. FINDINGS: A causal association has been established between asbestos exposure and mesothelioma and lung cancer. For arsenic exposure, there is strong evidence of bladder, skin, lung, liver, and kidney cancer effects. Women are at the highest risk for lung cancer due to indoor air pollution exposure; however, the carcinogenic effect on the risk for cancer in children has not been studied in these countries. Cancer risks associated with ambient air pollution remain the least studied in LMICs, although reported exposures are higher than World Health Organization, European, and US standards. Although some associations between lung cancer and ambient air pollutants have been reported, studies in LMICs are weak or subject to exposure misclassification. For pulmonary cancers, tobacco smoking and respiratory diseases have a positive synergistic effect on cancer risks. CONCLUSIONS: A precise quantification of the burden of human cancer attributable to environmental and occupational exposures in LMICs is uncertain. Although the prevalence of carcinogenic exposures has been reported to be high in many such countries, the effects of the exposures have not been studied due to varying country-specific limitations, some of which include lack of resources and government support. PMID- 25512156 TI - Screening for cancer in low- and middle-income countries. AB - BACKGROUND: Screening programs involve testing asymptomatic individuals with an accurate screening test to identify those likely to have the disease of interest and to further investigate them to confirm or exclude the disease. The aim of cancer screening is to prevent cancer deaths and improve quality of life by finding cancers early and by effectively treating them. A decision to introduce a screening program in public health services depends on the evidence that the benefits outweigh the harms of screening, disease burden, availability of suitable screening test, effective treatment, adequate resources, and efficient health services. Screening programs should achieve high participation for testing, diagnosis, and treatment to be effective and efficient. OBJECTIVE: To describe the current status of cancer screening programs in low- and middle income countries (LMICs). METHOD: A review of literature and on-going cancer screening initiatives in LMICs was made to discuss cancer screening in these countries. FINDINGS: Although population-based programs offering Papanicolaou testing every 3 to 5 years have reduced cervical cancer incidence and mortality in high-income countries, such programs have been less successful in reducing cervical cancer burden in LMICs due to poor organization, lack of coverage, and lack of quality assurance. The challenges in introducing high-quality cytology screening in LMICs have led to evaluation of alternative screening approaches such as visual inspection with acetic acid (VIA), human papillomavirus (HPV) testing-based screening, and novel paradigms such as a "single-visit screen and treat" in which treatment with cryotherapy or cold coagulation is provided to screen-positive women without clinical evidence of cancer. Both HPV testing and VIA have been found to prevent cervical neoplasia and cervical cancer deaths in clinical trials. Although mammography screening reduces breast cancer mortality, associated overdiagnosis and overtreatment and the balance between benefits and harms have received much attention in recent years. Although introduction of clinical breast examination screening in LMICs should wait for evidence from ongoing trials, improving breast awareness and access to early diagnosis and treatment in health services is a valuable breast cancer control option in LMICs. Organized colorectal cancer screening programs are still evolving and are in early stages of development in many high-income countries. To date, there is insufficient evidence to support the introduction of population-based stomach, lung, ovarian, and prostate cancer screening in public health services. CONCLUSIONS: Implementation of VIA screening in several LMICs is conducive to future HPV screening programs when affordable HPV tests become widely available. Both HPV vaccination and HPV screening have a huge potential to eliminate cervical cancer in LMICs. A mammography screening program is a complex undertaking involving substantial resources and infrastructure that may not be feasible in many LMICs. PMID- 25512157 TI - Molecular and genetic epidemiology of cancer in low- and medium-income countries. AB - BACKGROUND: Genetic and molecular factors can play an important role in an individual's cancer susceptibility and response to carcinogen exposure. Cancer susceptibility and response to carcinogen exposure can be either through inheritance of high penetrance but rare germline mutations that constitute heritable cancer syndromes, or it can be inherited as common genetic variations or polymorphisms that are associated with low to moderate risk for development of cancer. These polymorphisms can interact with environmental exposures and can influence an individual's cancer risk through multiple pathways, including affecting the rate of metabolism of carcinogens or the immune response to these toxins. Thus, these genetic polymorphisms can account for some of the geographical differences seen in cancer prevalence between different populations. OBJECTIVES: This review explores the role of molecular epidemiology in the field of cancer prevention and control in low- and medium-income countries. FINDINGS: Using data from Human Genome Project and HapMap Project, genome-wide association studies have been able to identify multiple susceptibility loci for different cancers. The field of genetic and molecular epidemiology has been further revolutionized by the discovery of newer, faster, and more efficient DNA sequencing technologies including next-generation sequencing. CONCLUSIONS: The new DNA-sequencing technologies can play an important role in planning and implementation of cancer prevention and screening strategies. More research is needed in this area, especially in investigating new biomarkers and measuring gene-environment interactions. PMID- 25512158 TI - Biomechanical comparison of semi-rigid pediatric locking nail versus titanium elastic nails in a femur fracture model. AB - BACKGROUND: The treatment for length-unstable diaphyseal femur fractures among school-age children is commonly intramedullary elastic nails, with or without end caps. Another possible treatment is the semi-rigid pediatric locking nail (PLN). The purpose of this biomechanical study was to assess the stability of a length unstable oblique midshaft fracture in a synthetic femur model stabilized with different combinations of intramedullary elastic nails and with a PLN. METHODS: Twenty-four femur models with an intramedullary canal diameter of 10.0 mm were used. Three groups with various combinations of titanium elastic nails (TEN) with end caps and one group with a PLN were tested. An oblique midshaft fracture was created, and the models underwent compression, rotation, flexion/extension, and a varus/valgus test, with 50 and 100 % of the forces generated during walking in corresponding planes. RESULTS: We present the results [median (range)] from 100 % loading during walking. In axial compression, the PLN was less shortened than the combination with two 4.0-mm TEN [by 4.4 (3.4-5.4) mm vs. 5.2 (4.8-6.6) mm, respectively; p = 0.030]. No difference was found in shortening between the PLN and the four 3.0-mm TEN [by 7.0 (3.3-8.4) mm; p = 0.065]. The two 3.0-mm TEN did not withstand the maximum shortening of 10.0 mm. In external rotation, the PLN rotated 12.0 degrees (7.0-16.4 degrees ) while the TEN models displaced more than the maximum of 20.0 degrees . No model withstood a maximal rotation of 20.0 degrees internal rotation. In the four-point bending test, in the coronal and the sagittal plane, all combinations except the two 3.0-mm TEN in extension withstood the maximum angulation of 20.0 degrees . CONCLUSIONS: PLN provides the greatest stability in all planes compared to TEN models with end caps, even though the difference from the two 4.0-mm or four 3.0-mm TEN models was small. PMID- 25512159 TI - Bench-to-bedside development of agonists and antagonists of luteinizing hormone releasing hormone for treatment of advanced prostate cancer. AB - BACKGROUND: Androgen deprivation therapy (ADT) has been the standard of care for treating patients with hormone-sensitive advanced prostate cancer (PCa) for 3 decades. The agonists of luteinizing hormone-releasing hormone (LHRH), also called gonadotropin-releasing hormone, are still the most frequently used form of medical ADT. ADT AND LHRH ANALOGS: The application of agonists of LHRH has improved and modernized the treatment of advanced PCa; millions of patients have benefited from therapy with LHRH agonists as a preferred alternative to surgical castration, as the psychological effects and perpetuity of orchiectomy are undesirable for most men. Despite their efficacy, agonists of LHRH have several shortcomings, including initial surge in testosterone, producing exacerbation of clinical symptoms, and microsurges in testosterone that might occur after each administration. A new, alternate approach to ADT is emerging with the improvements in antagonists of LHRH. This class of LHRH analogues produces a direct and immediate blockade of pituitary LHRH receptors and leads to a more rapid suppression of testosterone without an initial surge or subsequent microsurges. Degarelix, a third-generation LHRH antagonist, is the only antagonist with a low histamine-releasing activity that is currently on the market for clinical use in advanced PCa with improved testosterone suppression, better control of follicle-stimulating hormone and prostate-specific antigen, and which offers a prolonged delay to progression and more favorable effects on serum alkaline phosphatase. CONCLUSIONS: Although LHRH agonists are still the mainstay for treatment of advanced PCa, antagonists of LHRH offer an alternative as a pharmacological approach. PMID- 25512160 TI - Multiparametric magnetic resonance imaging localizes established extracapsular extension of prostate cancer. AB - OBJECTIVE: To define the accuracy of multiparametric magnetic resonance imaging (MP-MRI) for identifying focal and established extracapsular extension (ECE) in various zones of the prostate. METHODS: Between 2010 and 2013, 342 patients underwent MP-MRI of the prostate (3T, no endorectal coil with axial perfusion and diffusion images). The findings of the images were reported as negative, suspicious, or positive for ECE by a single expert radiologist. Radical prostatectomy specimens were reviewed to confirm the size and the location of ECE and further defined as focal or established ECE. Established ECE included extension that was multifocal or involving more than 5 glands. The accuracy of MRI in localizing focal and established ECE to each zone of the prostate was determined. Regression analyses were performed to identify predictors of ECE. RESULTS: We identified 112 patients who underwent prostate MP-MRI and radical prostatectomy. MRI findings considered suspicious or definite for ECE accurately predicted pathologic ECE (P<0.001). MP-MRI identified established ECE but not focal ECE. Sensitivity, specificity, positive predictive value, and negative predictive value of MP-MRI for established ECE were 70.7%, 90.6%, 57.1%, and 95.1%, respectively. MRI identified ECE to the left vs. right side as well as each zone of the prostate; however, sensitivity was lowest at the apex. On multivariate analysis, MRI was a significant predictor of ECE that was independent of prostate-specific antigen level, Gleason score, and clinical stage. CONCLUSION: MP-MRI is useful for identifying established but not focal ECE in all zones of the prostate. MRI was a significant independent predictor of established ECE and may be a useful adjunct in staging prostate cancer. PMID- 25512161 TI - Surgical margin length and location affect recurrence rates after robotic prostatectomy. AB - BACKGROUND: Robotic-assisted laparoscopic radical prostatectomy is a current standard treatment for localized prostate cancer, with treatment failure defined by biochemical recurrence (BCR). Open radical prostatectomy series have identified the presence of a positive surgical margin (PSM) as a predictor of long-term recurrence, a measure that is affected by the surgeon's skill. We evaluate the effect of PSM parameters on BCR rates from robotic-assisted laparoscopic radical prostatectomy, across 3 high-volume institutions. METHODS: De-identifiable clinicopathological and histopathological data were prospectively collected for 4,001 patients with at least 3 years of follow-up. Kaplan-Meier plots and 3 statistical models were used to evaluate the effect of margin parameters on BCR, via crude rates, traditional multivariable Cox regression, and a propensity-adjusted Cox regression model. RESULTS: Overall, 37% of men with a PSM developed BCR compared with 10% of men with negative margins (hazard ratio [HR] = 1.81, 95% CI: 1.47-2.22). Length >=3 mm or a multifocal positive margin was associated with a higher risk of BCR compared with negative margin cases. On multivariable Cox regression analysis of the positive margin cohort, only apical margins significantly predicted BCR relative to basal margins (HR = 2.03, 95% CI: 1.01-4.09), whereas there was no significant difference in BCR rates for posterolateral margins relative to basal margins (HR = 1.62, 95% CI: 0.84-3.11). Propensity-adjusted modeling confirmed a greater effect of apical compared with posterolateral PSM. CONCLUSIONS: A PSM length >=3 mm is predictive of BCR, as is to a lesser extent multiple positive margins. In contrast to open prostatectomy series, posterolateral margins carry a smaller risk of BCR compared with apical margins. PMID- 25512162 TI - Advances in detection of antipsychotics in biological matrices. AB - Measuring antipsychotic concentrations in human matrices is important for both therapeutic drug monitoring and forensic toxicology. This review provides a critical overview of the analytical methods for detection and quantification of antipsychotics published in the last four years. Focus lies on advances in sample preparation, analytical techniques and alternative matrices. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is used most often for quantification of antipsychotics. This sensitive technique makes it possible to determine low concentrations not only in serum, plasma or whole blood, but also in alternative matrices like oral fluid, dried blood spots, hair, nails and other body tissues. Current literature on analytical techniques for alternative matrices is still limited and often requires a more thorough validation including a comparison between conventional and alternative results to determine their actual value. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) makes it possible to quantify a high amount of compounds within a shorter run time. This technique is widely used for multi analyte methods. Only recently, high-resolution mass spectrometry has gained importance when a combination of screening of (un)known metabolites, and quantification is required. PMID- 25512163 TI - Diagnostic and clinical significance of Crohn's disease-specific anti-MZGP2 pancreatic antibodies by a novel ELISA. AB - BACKGROUND: We developed a new IgA and IgG anti-MZGP2 antibody ELISAs based on recombinant isoform-4 of human zymogen granule protein-2 (GP2), which is the major autoantigen of Crohn's disease (CrD)-specific pancreatic autoantibodies and assessed their clinical relevance in the largest inflammatory bowel disease (IBD) cohort tested to date. METHODS: 832 sera were studied, including 617 consecutive IBD patients from 323 CrD and 294 ulcerative colitis (UC) follow-up in a tertiary centre, and 112 pathological and 103 normal controls. RESULTS: Sensitivity of IgA anti-MZGP2 for CrD in the IBD population was 15% and specificity was 98% (95, 99), while the sensitivity and specificity of IgG anti-MZGP2 were 27% and 97%. IgA and IgG anti-MZGP2 combined testing led to a sensitivity of 31% and a specificity of 96%. Positivity for either ASCA (IgA or IgG) or anti-MZGP2 (IgA or IgG) showed a sensitivity of 75% (70, 80) and a specificity of 84% (79, 89). IgA anti-MZGP2 antibodies were more prevalent in CrD patients with early disease onset (p=0.011). Also, anti-MZGP2 positive patients more frequently had extensive disease with ileal involvement. Patients with longer disease duration were more likely to have IgG anti-MZGP2 antibodies. CONCLUSIONS: Our novel ELISA confirms the high specificity of anti-MZGP2 antibodies for CrD and their association with disease severity phenotypes. PMID- 25512165 TI - Values of high sensitive troponin T in long-term survivors of childhood cancer treated with anthracyclines. AB - BACKGROUND: Cardiac biomarkers can play an important role in the early detection of subclinical heart failure. Our aims are to 1) obtain values of high sensitive cardiac troponin T (hs-cTnT) in long-term survivors of childhood cancer and 2) investigate the potential role of hs-cTnT in the detection of subclinical late onset cardiotoxicity. METHODS: Hs-cTnT and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) were measured in 64 survivors. Electrocardiography and echocardiography were performed to evaluate cardiac function. RESULTS: Mean follow-up period was 8.3 years (range of 4.5 to 34.1). All survivors were clinically asymptomatic and had no history of clinical heart failure during or immediately after anthracycline treatment. Electrocardiography (available in 59 of 64 survivors) showed no signs of myocardial injury related to ischemia or abnormal QTc. Echocardiography was performed in all survivors. Mean left ventricular shortening fraction (SF) was 34% (range of 28 to 43%); mean ejection fraction (EF) was 61% (range of 48 to 74%). Seven survivors had a mildly decreased EF between 48% and 55%. Normal hs-cTnT levels were found in all 64 survivors (range of 3 to 13 ng/L) and did not differ among different anthracycline dosage groups: <=120, 120-300 and >=300 mg/m(2). Yet, 5/64 survivors had elevated NT-pro-BNP levels (range of 7 to 25 pg/ml) with normal SF and ECG findings and only one mildly abnormal EF of 51%. CONCLUSIONS: Hs-cTnT concentrations are normal in long-term survivors of childhood cancer, even in the subpopulations with elevated NT-pro-BNP and/or a mildly decreased EF, indicating that it is not a sensitive marker for late onset subclinical anthracycline induced cardiotoxicity. PMID- 25512164 TI - Urinary C-type natriuretic peptide: an emerging biomarker for heart failure and renal remodeling. AB - The public health and economic burden of heart failure (HF) is staggering and the need for relevant pathophysiologic and clinical biomarkers to advance the field and improve HF therapy remains high. Renal dysfunction is common among HF patients and is associated with increased HF hospitalization and mortality. It is widely recognized that mechanisms contributing to HF pathogenesis include a complex bidirectional interaction between the kidney and heart, encompassed by the term cardiorenal syndrome (CRS). Among a new wave of urinary biomarkers germane to CRS, C-type natriuretic peptide (CNP) has emerged as an innovative biomarker of renal structural and functional impairment in HF and chronic renal disease states. CNP is a hormone, synthesized in the kidney, and is an important regulator of cell proliferation and organ fibrosis. Hypoxia, cytokines and fibrotic growth factors, which are inherent to both cardiac and renal remodeling processes, are among the recognized stimuli for CNP production and release. In this review we aim to highlight current knowledge regarding the biology and pathophysiological correlates of urinary CNP, and its potential clinical utility as a diagnostic and prognostic biomarker in HF and renal disease states. PMID- 25512166 TI - Interferon-gamma in foam cell formation and progression of atherosclerosis. AB - Interferon-gamma (IFN-gamma), the sole member in type II IFN predominantly secreted by macrophages and T cells, is a critical regulator of immune function and provides a robust first line of defense against invading pathogens. Binding of IFN-gamma to its receptor complex can activate a variety of downstream signaling pathways, particularly the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), to induce gene transcription within the target cells. This pro-inflammatory mediator is highly expressed in atherosclerotic lesions and promotes foam cell formation, but its effects on the atherogenesis are complex, with both pro- and anti-atherogenic properties. IFN-gamma also contributes to the development of myocardial infarction and stroke, the two main atherosclerotic diseases. Inhibition of IFN-gamma signaling may prevent the development of atherosclerosis and help treat atherosclerotic diseases. Since IFN gamma may also exert anti-atherogenic effects, the safety and efficacy of anti IFN-gamma treatment still require careful evaluation in the clinical setting. In the current review, we summarize recent progression on regulation and signaling pathways of IFN-gamma, and highlight its roles in foam cell formation, atherosclerosis, myocardial infarction as well as stroke. An increased understanding of these processes will help to develop novel IFN-gamma-centered therapies for atherosclerotic diseases. PMID- 25512167 TI - Non-destructive estimation of foliar carotenoid content of tree species using merged vegetation indices. AB - Leaf pigment content is an important indicator of plant status and can serve to assess the vigor and photosynthetic activity of plants. The application of spectral information gathered from laboratory, field and remote sensing-based spectrometers to non-destructively assess total chlorophyll (Chl) content of higher plants has been demonstrated in earlier studies. However, the precise estimation of carotenoid (Car) content with non-destructive spectral measurements has so far not reached accuracies comparable to the results obtained for Chl content. Here, we examined the potential of a recently developed angular vegetation index (AVI) to estimate total foliar Car content of three tree species. Based on an iterative search of all possible band combinations, we identified a best candidate AVIcar. The identified index showed quite close but essentially not linear relation with Car contents of the examined species with increasing sensitivity to high Car content and a lack of sensitivity to low Car content for which earlier proposed vegetation indices (VI) performed better. To make use of the advantages of both VI types, we developed a simple merging procedure, which combined the AVIcar with two earlier proposed carotenoid indices. The merged indices had close linear relationship with total Car content and outperformed all other examined indices. The merged indices were able to accurately estimate total Car content with a percental root mean square error (%RMSE) of 8.12% and a coefficient of determination of 0.88. Our findings were confirmed by simulations using the radiative transfer model PROSPECT-5. For simulated data, the merged indices again showed a quasi linear relationship with Car content. This strengthens the assumption that the proposed merged indices have a general ability to accurately estimate foliar Car content. Further examination of the proposed merged indices to estimate foliar Car content of other plant species is desirable to prove the general applicability of the index for non-destructive estimation of Car from leaf reflectance data. PMID- 25512168 TI - Idiopathic interstitial pneumonias: a radiology-pathology correlation based on the revised 2013 American Thoracic Society-European Respiratory Society classification system. AB - The idiopathic interstitial pneumonias (IIPs) are a group of diffuse lung diseases that share many similar radiologic and pathologic features. According to the revised 2013 American Thoracic Society-European Respiratory Society classification system, these entities are now divided into major IIPs (idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, and acute interstitial pneumonia), rare IIPs (idiopathic lymphoid interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis), and unclassifiable idiopathic interstitial pneumonias. Some of the encountered radiologic and histologic patterns can also be seen in the setting of other disorders, which makes them a diagnostic challenge. As such, the accurate classification of IIPs remains complex and is best approached through a collaboration among clinicians, radiologists, and pathologists, as the treatment and prognosis of these conditions vary greatly. PMID- 25512169 TI - Imaging appearances of musculoskeletal developmental variants in the pediatric population. AB - Variations in musculoskeletal development in children are commonly encountered. These variants often have a confusing appearance on imaging and may simulate pathologic conditions. However, in many instances, these normal variants have certain features that allow for confident determination of the benign nature of these entities. An awareness of the characteristic imaging features is therefore important for radiologists. In this review, we focus on 4 specific categories of variants in the development: (1) variations in the normal ossification of skeletal structures, (2) the appearance of tendinous and ligamentous insertions in the developing skeleton, (3) overlapping lines that can be confused with fractures or other pathologic conditions, and (4) variant orientation of normal bones. We review the etiology and imaging appearance of these entities and also describe methods of differentiating these benign entities from pathologic lesions. Although in certain cases, correlation with clinical parameters is needed to confidently diagnose the lesion as benign, in many cases, an appreciation of the characteristic imaging features alone would suffice and prevent a potentially costly workup. PMID- 25512171 TI - Enabling complex nanoscale pattern customization using directed self-assembly. AB - Block copolymer directed self-assembly is an attractive method to fabricate highly uniform nanoscale features for various technological applications, but the dense periodicity of block copolymer features limits the complexity of the resulting patterns and their potential utility. Therefore, customizability of nanoscale patterns has been a long-standing goal for using directed self-assembly in device fabrication. Here we show that a hybrid organic/inorganic chemical pattern serves as a guiding pattern for self-assembly as well as a self-aligned mask for pattern customization through cotransfer of aligned block copolymer features and an inorganic prepattern. As informed by a phenomenological model, deliberate process engineering is implemented to maintain global alignment of block copolymer features over arbitrarily shaped, 'masking' features incorporated into the chemical patterns. These hybrid chemical patterns with embedded customization information enable deterministic, complex two-dimensional nanoscale pattern customization through directed self-assembly. PMID- 25512170 TI - Assessment of the relationship between lipid parameters and obesity indices in non-diabetic obese patients: a preliminary report. AB - BACKGROUND: The aim of this cross-sectional study was to examine the relationship between obesity and lipid markers. MATERIAL AND METHODS: We divided 66 non diabetic adult obese patients (mean age: 55.8+/-11.6 years) into 3 groups according to body mass index (BMI). All patients were measured for waist circumference (WC), hip circumference (HC), body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), body adiposity index (BAI), and visceral adiposity index (VAI). Serum levels of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C), and triglycerides (TG) were determined, and lipid indices TC/HDL, LDL/HDL, and TG/HDL were also estimated. RESULTS: TC and LDL-C in Group III were lower than in Group I (5.0+/-1.0 vs. 6.0+/-1.0 mmol/L, and 2.9+/-0.9 vs. 3.8+/-1.2 mmol/L; p<0.05 for both). Negative correlations were found between: BMI and TC, LDL, and HDL (r=-0.291; r=-0.310, r=-0.240, respectively); and WC, WHR, VAI, and HDL (r=-0.371, r=-0.296, r=-0.376, respectively). Positive correlations were found between WC, WHR, and TG/HDL (r=0.279, r=0.244, respectively) and between VAI and: TC (r=0.327), TG (r=0.885), TC/HDL (r=0.618), LDL/HDL (r=0.480), and TG/HDL (r=0.927). CONCLUSIONS: Obesity is associated with lipid disturbances, especially with HDL-C reduction, in obese non-diabetic patients. VAI is strongly related to lipid profile and thus may be the most valuable obesity index in obese patients with dyslipidemias. PMID- 25512172 TI - Maple syrup urine disease in Brazil: a panorama of the last two decades. AB - OBJECTIVE: To characterize a sample of Brazilian patients with maple syrup urine disease (MSUD) diagnosed between 1992 and 2011. METHODS: In this retrospective study, patients were identified through a national reference laboratory for the diagnosis of MSUD and through contact with other medical genetics services across Brazil. Data were collected by means of a chart review. RESULTS: Eighty-three patients from 75 families were enrolled in the study (median age, 3 years; interquartile range [IQR], 0.57-7). Median age at onset of symptoms was 10 days (IQR 5-30), whereas median age at diagnosis was 60 days (IQR 29-240, p=0.001). Only three (3.6%) patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n=12) and without (n=71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients have some psychomotor or neurodevelopmental delay. CONCLUSION: In Brazil, patients with MSUD are usually diagnosed late and exhibit neurological involvement and poor survival even with early diagnosis. We suggest that specific public policies for diagnosis and treatment of MSUD should be developed and implemented in the country. PMID- 25512173 TI - Differences and similarities between bulimia nervosa, compulsive buying and gambling disorder. AB - AIM: The objective of the study was to analyse shared commonalities and differences between bulimia nervosa (BN) and certain impulse-related disorders, namely compulsive buying (CB) and gambling disorder (GD), with respect to general psychopathology and personality traits. METHODS: A total of 188 female patients [50 BN without comorbid CB (BN-CB), 49 BN with comorbid CB (BN+CB), 53 GD and 36 CB] and 50 comparison non-psychiatric women participated in the current study. All patients were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth revised edition, the Temperament and Character Inventory Revised, and other clinical indices. RESULTS: A positive-growing trend was observed in psychopathology and personality traits across the four clinical groups. Comorbid BN with CB was associated with highest eating psychopathology and social anxiety. On Novelty Seeking, the CB, GD and BN+CB were similar to each other, whereas BN-CB presented a distinct profile. Moreover, the BN+CB group displayed more dysfunctional personality traits and higher general psychopathology. The clinical groups demonstrated overall higher levels of psychopathology compared with the control group. CONCLUSIONS: The results of this study demonstrate that disorders with impulsive traits (CB, GD, BN+CB and BN-CB) follow a linear trend in general psychopathology and specific personality traits, but differ along specific personality and psychopathological dimensions. PMID- 25512174 TI - The usefulness of the stay suture technique in tracheostomy. AB - OBJECTIVE: Tracheostomy tube displacement may occur at any time in the course of patient management. Although an infrequent occurrence, such displacement is potentially serious. The purpose of this study was to evaluate the advantages and complications of the stay suture technique in tracheostomy. STUDY DESIGN: Prospective cohort study. METHODS: The SST involves the placement of sutures between the anterior tracheal wall and the skin in order to hasten the formation of a mature stoma. The study patients were divided into two groups. One group underwent tracheostomy with the SST (n =104), and the other group was treated with a conventional tracheostomy (n = 101). The postoperative complications for each group were then reviewed. RESULTS: The most common indication for tracheostomy was prolonged endotracheal intubation (79.3%), and the most common complication in each group was postoperative stoma infection. Unexpected decannulation occurred in three patients from the conventional tracheostomy group, causing death of the patients. However, the SST group did not show any occurrence of unexpected decannulation. CONCLUSIONS: Unexpected decannulation was a fatal complication. Because this complication was not observed in any patients who underwent the SST, our study recommends use of this method as a countermeasure for unexpected decannulation. LEVEL OF EVIDENCE: 4. PMID- 25512175 TI - Differences in brachial and femoral artery responses to prolonged sitting. AB - INTRODUCTION: It is unknown if there are limb differences in vascular function during prolonged sitting. PURPOSE: This study was designed to test whether the effects of prolonged sitting on brachial artery (BA) and the superficial femoral artery (SFA) are similar. METHODS: Twelve men (24.2 +/- 4 yrs.) participated in a 3 hr prolonged sitting trial (SIT). SFA and BA flow mediated dilation (FMD) and respective flow patterns were measured at baseline, 1 hr, 2 hr and 3 hr. RESULTS: By a one-way ANOVA there was a significant decline in SFA FMD during 3 hrs of SIT (p < 0.001). Simultaneously, there was a significant decline in antegrade (p = 0.04) and mean (0.037) shear rates. By a one way ANOVA there were no significant differences in BA FMD during 3 hrs of sitting. There were no changes in the shear rates in the BA except for a significant decrease in antegrade shear rate (p = 0.029) and a significant increase in oscillatory shear index (p = 0.034) during 3 hrs of sitting. Furthermore, there was no correlation between BA and SFA FMD measurements. CONCLUSION: Three hours of sitting resulted in impaired SFA FMD but not BA FMD. Although 3 hours of sitting did not impair BA FMD, it impaired shear patterns in the BA. PMID- 25512176 TI - Transanal minimal invasive surgery for rectal lesions: should the defect be closed? AB - AIM: Transanal minimal invasive surgery (TAMIS) of rectal lesions is increasingly being used, but the technique is not yet standardized. The aims of this study were to evaluate peri-operative complications and long-term functional outcome of the technique and to analyse whether or not the rectal defect needs to be closed. METHOD: Consecutive patients undergoing TAMIS using the SILS port (Covidien) and standard laparoscopic instruments were studied. RESULTS: Seventy-five patients (68% male) of mean age 67 (+/- 15) years underwent single-port transanal surgery at three different centres for 37 benign lesions and 38 low-risk cancers located at a mean of 6.4 +/- 2.3 cm from the anal verge. The median operating time was 77 (25-245) min including a median time for resection of 36 (15-75) min and for closure of the rectal defect of 38 (9-105) min. The defect was closed in 53% using interrupted (75%) or a running suture (25%). Intra-operative complications occurred in six (8%) patients and postoperative morbidity was 19% with only one patient requiring reoperation for Grade IIIb local infection. There was no difference in the incidence of complications whether the rectal defect was closed or left open. Patients were discharged after 3.4 (1-21) days. At a median follow up of 12.8 (2-29) months, the continence was normal (Vaizey score of 1.5; 0-16). CONCLUSION: Transanal rectal resection can be safely and efficiently performed by means of a SILS port and standard laparoscopic instruments. The rectal defect may be left open and at 1 year continence is not compromised. PMID- 25512177 TI - Temporal dynamics of contingency extraction from tonal and verbal auditory sequences. AB - Consecutive sound events are often to some degree predictive of each other. Here we investigated the brain's capacity to detect contingencies between consecutive sounds by means of electroencephalography (EEG) during passive listening. Contingencies were embedded either within tonal or verbal stimuli. Contingency extraction was measured indirectly via the elicitation of the mismatch negativity (MMN) component of the event-related potential (ERP) by contingency violations. MMN results indicate that structurally identical forms of predictability can be extracted from both tonal and verbal stimuli. We also found similar generators to underlie the processing of contingency violations across stimulus types, as well as similar performance in an active-listening follow-up test. However, the process of passive contingency extraction was considerably slower (twice as many rule exemplars were needed) for verbal than for tonal stimuli These results suggest caution in transferring findings on complex predictive regularity processing obtained with tonal stimuli directly to the speech domain. PMID- 25512178 TI - Time course for the recovery of physical performance, blood hemoglobin, and ferritin content after blood donation. AB - BACKGROUND: It is widely accepted that blood donation negatively affects endurance performance, but data on physical recovery after a standard blood donation are scarce. This study aimed to elucidate the temporary impact of blood donation on endurance performance, measured as peak oxygen uptake (VO2peak ) and time trial (TT) performance. STUDY DESIGN AND METHODS: VO2peak , TT performance, blood, iron, and anthropometric variables were determined before (baseline) and 3, 7, 14, and 28 days after blood donation in 19 healthy men. RESULTS: VO2peak was reduced by 6.5% from 49.7 +/- 2 mL/kg/min at baseline to 46.3 +/- 2 mL/kg/min on Day 3 (p < 0.001), and TT performance was reduced by 5.2% from 13:31 +/- 00:42 to 14:13 +/- 00:50 min:sec (p < 0.001). Both VO2peak and TT performance were back to baseline 14 days after blood donation. Blood hemoglobin (Hb) concentration declined 7.9% from 9.3 +/- 0.11 mmol/L at baseline to 8.6 +/- 0.1 mmol/L on Day 3 (p < 0.001) and was not different from baseline 28 days after blood donation. The hematocrit (Hct) was reduced from 43.8 +/- 0.5% at baseline to 40.6 +/- 0.6% on Day 3 (p < 0.001). On Day 28 Hct was 42.8 +/- 0.5% and still reduced below baseline (p = 0.028). Ferritin concentration was reduced 46% from 113 +/- 23 MUg/L at baseline to a minimum of 61 +/- 14 MUg/L on Day 14 (p = 0.008). CONCLUSION: The individual recovery was variable, but physical performance was recovered 14 days after a standard blood donation, despite blood Hb concentration remaining lower than at baseline. PMID- 25512179 TI - Couple-based HIV counseling and testing: a risk reduction intervention for US drug-involved women and their primary male partners. AB - To help reduce the elevated risk of acquiring HIV for African-American and Latina women drug users in primary heterosexual relationships, we developed a brief couple-based HIV counseling and testing prevention intervention. The intervention was based on an integrated HIV risk behavior theory that incorporated elements of social exchange theory, the theory of gender and power, the stages-of-change model, and the information-motivation-behavior skills model. In this article, we describe the development, content, and format of the couple-based HIV testing and counseling intervention, and its delivery to 110 couples (220 individuals) in a randomized effectiveness trial, the Harlem River Couples Project, conducted in New York City from 2005 to 2007. Components of the couple-based intervention included a personalized dyadic action plan based on the couple's risk profile and interactive exercises designed to help build interpersonal communication skills, and facilitated discussion of social norms regarding gender roles. The couple based HIV testing and counseling intervention significantly reduced women's overall HIV risk compared to a standard-of-care individual HIV testing and counseling intervention. Experiences and perceptions of the intervention were positive among both clients and interventionists. The study was the first to demonstrate the effectiveness and feasibility of delivering a brief couple-based HIV counseling and testing intervention to reduce risk among drug-using heterosexual couples in high HIV prevalent urban communities in the USA. The intervention can be expanded to include new HIV prevention strategies, such as pre-exposure prophylaxis. Further research is needed to evaluate cost effectiveness and implementation of the intervention in clinical settings. PMID- 25512180 TI - Hydrolysis of hydrophobic esters in a bicontinuous microemulsion catalysed by lipase B from Candida antarctica. AB - Selective enzyme-catalysed biotransformations offer great potential in organic chemistry. However, special requirements are needed to achieve optimum enzyme activity and stability. A bicontinuous microemulsion is proposed as reaction medium because of its large connected interface between oil and water domains at which a lipase can adsorb and convert substrates in the oil phase of the microemulsion. Herein, a microemulsion consisting of buffer-n-octane-nonionic surfactant Ci Ej was used to investigate the key factors that determine hydrolyses of p-nitrophenyl esters catalysed by the lipase B from Candida antarctica (CalB). The highest CalB activity was found around 44 degrees C in the absence of NaCl and substrates with larger alkyl chains were better hydrolysed than their short-chained homologues. The CalB activity was determined using two different co-surfactants, namely the phospholipid 1,2-dioleoyl-sn glycero-3-phosphocholine (DOPC) and the sugar surfactant decyl beta-D glucopyranoside (beta-C10 G1 ). The results show the CalB activity as linear function of both enzyme and substrate concentration with an enhanced activity when the sugar surfactant is used as co-surfactant. PMID- 25512182 TI - Expression, purification and characterization of an atypical 2-Cys peroxiredoxin from the silkworm, Bombyx mori. AB - Peroxiredoxins (Prxs) play important roles in protecting organisms against damage caused by reactive oxygen species (ROS). In this study, we cloned a cDNA of Bombyx mori peroxiredoxin 5 (BmPrx5), which contained a 565-bp open reading frame for a 188-residue protein. Sequence analysis indicated that BmPrx5 belongs to the atypical 2-Cys peroxiredoxin family. Recombinant BmPrx5 purified from Escherichia coli showed antioxidant activity that removes H2 O2 and protects DNA from oxidative damage. Quantitative real-time PCR showed that the level of BmPrx5 mRNA in haemocytes increased early and decreased by 24 h after injection of H2 O2 whereas, in the fat body, the transcript level decreased at 6 h and increased at 12 h. Pseudomonas aeruginosa and Staphylococcus aureus infection resulted in higher levels of H2 O2 in the haemolymph and of BmPrx5 mRNA in haemocytes at 8 h postinfection. These data suggest that BmPrx5 acts as an antioxidant enzyme to protect the silkworm from oxidative damage induced by bacterial infection. Further study is needed to elucidate the exact role of BmPrx5 in the silkworm immune system. PMID- 25512181 TI - Wild boar populations up, numbers of hunters down? A review of trends and implications for Europe. AB - Across Europe, wild boar numbers increased in the 1960s-1970s but stabilised in the 1980s; recent evidence suggests that the numbers and impact of wild boar has grown steadily since the 1980s. As hunting is the main cause of mortality for this species, we reviewed wild boar hunting bags and hunter population trends in 18 European countries from 1982 to 2012. Hunting statistics and numbers of hunters were used as indicators of animal numbers and hunting pressure. The results confirmed that wild boar increased consistently throughout Europe, while the number of hunters remained relatively stable or declined in most countries. We conclude that recreational hunting is insufficient to limit wild boar population growth and that the relative impact of hunting on wild boar mortality had decreased. Other factors, such as mild winters, reforestation, intensification of crop production, supplementary feeding and compensatory population responses of wild boar to hunting pressure might also explain population growth. As populations continue to grow, more human-wild boar conflicts are expected unless this trend is reversed. New interdisciplinary approaches are urgently required to mitigate human-wild boar conflicts, which are otherwise destined to grow further. PMID- 25512183 TI - Splenectomy as a treatment for adults with relapsed hemophagocytic lymphohistiocytosis of unknown cause. AB - Our aim was to evaluate the clinical value of splenectomy as a treatment for relapsed hemophagocytic lymphohistiocytosis (HLH) of unknown cause in adults. We retrospectively reviewed the clinical data from medical records of 19 adults with relapsed HLH of unknown cause treated with splenectomy in our institution from June 2007 to March 2014. To rule out possible underlying diseases, including infection, autoimmune disease, neoplasms, and primary HLH, the patients had undergone examinations including F18 fluoro-2-deoxyglucose positron emission tomography/computed tomography, HLH-associated gene defects, and lymph node biopsies. Twelve patients (63.2%) achieved partial responses (PR), whereas seven patients (36.8%) had no response (NR) prior to splenectomy. Infection and hemorrhage were the main complications of splenectomy. Eighteen cases were evaluable after follow-up. Seven cases with histopathologic diagnoses of lymphoma had received chemotherapy, four of whom had achieved complete responses (CR), one PR, and two NR. Maintenance treatment was ceased 2 or 3 months after splenectomy in the other 11 cases, five of whom had CR, four PR, and two NR. Eleven of 18 cases (61.1%) survived with a median follow-up of 25 months (range 3-79 months) for survivors. Twelve- and 36-month progression-free survival rates were 48 and 24%, respectively; 12- and 36-month overall survival rates were 57 and 25%, respectively. Median survival time was 22 months. Our results indicate splenectomy may be an effective means of diagnosis and treatment of relapsed HLH of unknown cause. Further study is required to establish the mechanism and value of splenectomy in this disease. PMID- 25512184 TI - Reduced IL-35 levels are associated with increased platelet aggregation and activation in patients with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. AB - Acute graft-versus-host disease (aGVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Interleukin (IL) 35 is a novel anti-inflammatory cytokine that suppresses the immune response. This prospective study explored IL-35 plasma levels in 65 patients after HSCT. The results revealed that the peripheral blood of patients with grades III-IV aGVHD (23.46 ng/ml) had reduced IL-35 compared to transplanted patients with grades I-II aGVHD (40.26 ng/ml, p < 0.01) or patients without aGVHD (41.40 ng/ml, p < 0.05). Allografts, including granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood progenitor cell (PBPC) and G-CSF-primed bone marrow (GBM), from 38 patients were analyzed for IL-35 levels with respect to aGVHD. The patients who received lower levels of IL-35 cells in the GBM (28.0 ng/ml, p = 0.551) or lower levels of IL-35 in PBPC (53.46 ng/ml, p = 0.03) exhibited a higher incidence of aGVHD. Patients with aGVHD have increased platelet aggregation. IL-35 was added to patient blood in vitro, and platelet aggregation was inhibited by IL-35 in a dose-dependent manner. The markers of platelet activation (CD62P/PAC-1) can also be inhibited by IL-35. The results indicate that IL-35 may affect the development of aGVHD by inhibiting platelet activation and aggregation. Our data suggests that IL-35 represents a potentially effective therapeutic agent against aGVHD after allo-HSCT. PMID- 25512185 TI - Molecular epidemiology of hepatitis B virus in primitive tribes of Odisha, eastern India. AB - BACKGROUND AND OBJECTIVE: Among the indigenous population of India, Primitive Tribal Groups (PTGs) are vulnerable to various health related events and some of the PTGs are showing a decline in population associated with high mortality rates. The present study was undertaken to define the prevalence of Hepatitis B Virus (HBV) infection, its genetic characterization and possible risk factors for transmission in five PTGs in Odisha, India. METHODS: Cross-sectional observational studies were carried out in the Lodha, Saora, Khadia, Mankidia, and Juanga tribes residing in different parts of Odisha between 2006 and 2010. RESULTS: Hepatitis B surface antigen (HBsAg) prevalence was 0.8%, 0.9%, 0.9%, 3.7%, and 1.7% in Lodha, Saora, Khadia, Mankidia, and Juanga tribes, respectively. While 54.8% of seropositive (HBsAg) cases demonstrated HBV DNA, occult HBV infection was observed in 19.48% of cases. High viral load with detectable 'e' antigen was found in 29% of HBsAg-positive individuals. All HBV isolates (n=17) were genotype D without pre-core mutants. Only 15.6% of HBV positive individuals had symptoms of hepatic disease, though none had severe manifestations. Multivariate analysis of the prevailing risk factors indicated that shaving by the village barber was significantly associated with HBV transmission in males. Tattooing was found to be significantly associated with females. INTERPRETATION AND CONCLUSION: This is the first report on HBV infection in PTGs of Odisha that suggests a high potential for transmission of HBV infection in two PTGs (Mankidia and Juanga). It warrants early public health attention in tribal populations vulnerable to HBV infection. PMID- 25512186 TI - Assessment of polyphenol coated nano zero valent iron for hexavalent chromium removal from contaminated waters. AB - Alternative plant extracts were examined as raw materials for the synthesis of nZVI from ferric solutions. Four plants were selected for evaluation, i.e. Camellia sinensis (green tea, GT), Syzygium aromaticum (clove, CL), Mentha spicata (spearmint, SM) and Punica granatum (pomegranate, PG). Based on the results obtained, it was concluded that the reduction of Fe(III) with the herb extracts is not complete. Using the GT extract, approximately 28 mM of the initial 66 mM of Fe (42.4 %) are reduced to the elemental state Fe(0). The highest reduction of Fe(III), about 53 %, was achieved with PG and the lowest, only 15.6 %, with the SM extract. Additional batch experiments have been carried out to evaluate the effectiveness of nZVI, synthesized with GT, CL, SM and PG, for the removal of hexavalent chromium from a 0.96 mM solution. The highest reduction of Cr(VI) (96 %) was obtained using the nZVI suspension produced with PG juice. The other three nZVI suspensions, i.e. CL-nZVI, GT-nZVI, and SM-nZVI, had a comparable effectiveness corresponding to 70 % reduction of chromate. PMID- 25512187 TI - Relationship between serum uric acid and electrocardiographic alterations in a large sample of general population: data from the Brisighella Heart Study. AB - INTRODUCTION: Serum uric acid (SUA) may contribute to the increased cardiovascular damage through direct injury to the endothelium and alteration of cardiovascular function. AIM: To evaluate the association of SUA with the presence of the most recurrent electrographic alterations and with the length of the main ECG intervals in a large sample of general population. METHODS: For this study, on the database of the Brisighella Heart Study, we evaluated the available data of 790 men and 849 women, excluding subjects affected by gout or taking antihyperuricemic agents, those taking drug increasing the QT interval and those using beta-blockers or non-dihydropyridine calcium channel blockers at the moment of the ECG registration. Multiple ascending stepwise regression analyses were carried out to determine the independent predictors of the predefined ECG alterations. RESULTS: The prevalence of predefined ECG alterations was comparable between genders, with the exception of sinus bradicardia, left-anterior fascicular block, atrio-ventricular blocks and left ventricular hypertrophy (LVH), which appeared to be more frequent in men. The multivariate analysis revealed that SUA was associated to ischaemic alterations, LVH, sinus tachycardia and tachyarrhytmias. Age was associated to all evaluated ECG alterations beyond sinus tachycardia and LVH. Male sex was associated to sinus bradicardia, atrio ventricular blocks, anterior-left fascicular block and LVH. Blood pressure was associated to different ECG alterations, but with clinically relevant OR with ischaemic alterations and LVH. CONCLUSION: SUA level is related the prevalence of both organic and rhythm ECG alterations in a wide sample of general population. PMID- 25512189 TI - A wider view on gastric erosion: detailed evaluation of complex somatic and behavioral changes in rats treated with indomethacin at gastric ulcerogenic dose. AB - OBJECTIVE: Gastric erosion is widespread side effect of nonsteroidal anti inflammatory drugs. To examine the complexity of the brain-gut axis regulation, indomethacin-induced gastric erosion formation was studied in connection with somatic and behavioral changes. METHODS: During a constant telemetric recording of heart rate, body temperature, and locomotion of male rats we examined the effects of 24 h fasting, indomethacin (35 mg/kg s.c.) injection, and refeeding at 4 h. Behavior was analyzed on elevated plus maze (EPM) at 24 h and somatic changes at 72 h. RESULTS: Gastric erosion developed 4 h after indomethacin injection, healed 72 h later contrasted by large injury in the small intestine. As classical signs of chronic stress, body and thymus weight were reduced while adrenal weight was enhanced 72 h after indomethacin injection. Fasting by itself changed all telemetrically recorded parameters with most prominent decrease in heart rate. Indomethacin induced similar diminishing effects with earliest and strongest temperature decrease. As a sign of more anxious phenotype locomotion reducing effect of indomethacin injection was detected on EPM. The EPM-induced temperature elevation was missing in indomethacin-treated animals. CONCLUSIONS: Fasting by itself induce somatic changes, which can make the animals more vulnerable to ulcerogenic stimuli. Development of indomethacin-induced gastrointestinal lesions happened in parallel with disturbances of heart rate, core body temperature, and chronic stress-like somatic changes as well as anxiety like behavior. We have to be more aware of the existence of the brain-gut axis and should study changes in the whole body rather than focusing on a specific organ. elevated plus maze. PMID- 25512188 TI - Evidence for acoustic communication among bottom foraging humpback whales. AB - Humpback whales (Megaptera novaeangliae), a mysticete with a cosmopolitan distribution, demonstrate marked behavioural plasticity. Recent studies show evidence of social learning in the transmission of specific population level traits ranging from complex singing to stereotyped prey capturing behaviour. Humpback whales have been observed to employ group foraging techniques, however details on how individuals coordinate behaviour in these groups is challenging to obtain. This study investigates the role of a novel broadband patterned pulsed sound produced by humpback whales engaged in bottom-feeding behaviours, referred to here as a 'paired burst' sound. Data collected from 56 archival acoustic tag deployments were investigated to determine the functional significance of these signals. Paired burst sound production was associated exclusively with bottom feeding under low-light conditions, predominantly with evidence of associated conspecifics nearby suggesting that the sound likely serves either as a communicative signal to conspecifics, a signal to affect prey behaviour, or possibly both. This study provides additional evidence for individual variation and phenotypic plasticity of foraging behaviours in humpback whales and provides important evidence for the use of acoustic signals among foraging individuals in this species. PMID- 25512190 TI - Prognostic factors of survival and recurrence pattern in differentiated thyroid cancer: a retrospective study from Western Turkey. AB - OBJECTIVES: The aim of this study was to determine prognostic factors in patients with well-differentiated thyroid cancer (WDTC). METHODS: This retrospective study included 181 well-differentiated thyroid cancer patients who were operated between Decembers 1996-2007. Total of 181 patients [139 (76.8%) women and 42 (23.2%) men with a mean age of 46.3 years] who were subjected to a complete follow-up, were enrolled in the study. The mean follow-up period was 7.1 years (range 3.1 to 14.9 years). Medical records were reviewed regarding to age, gender, extent of surgery, tumor size, multifocality, clinical stage, capsule infiltration, extracapsular invasion, histological type, lymph node metastasis, distant metastasis, radioactive iodine treatment and prognosis. RESULTS: During follow-up, in 41 (22.6%) patients locoregional recurrences were detected and 5 (2.7%) patients passed away. Determined statistically significant prognostic factors were as follows; tumor size (histopathologically), extent of surgery, histological type, lymph node metastasis, tumor invasion (capsule and extracapsular) and clinical stage. CONCLUSIONS: Well-differentiated thyroid cancer is a disease with good prognosis when detected early and appropriate treatment applied. Despite the prognosis, it is good to apply the right treatment and reduce recurrence and mortality rates, prognostic factors are well known and must be considered in patient management. PMID- 25512191 TI - Assessment of mean platelet volume (MPV) in primary hyperparathyroidism: effects of successful parathyroidectomy on MPV levels. AB - OBJECTIVE: A determinant of platelet function - mean platelet volume (MPV), is newly emerging risk factor for atherothrombosis. The aim of this study is to evaluate MPV in patients with primary hyperparathyroidism (PHPT) before parathyroidectomy (PTX) and six months after successful PTX in a retrospective study. METHODS: We analyzed the changes in serum biochemical, parathyroid hormone (PTH) and MPV before and six months after PTX in 66 patients with PHPT and 44 healthy controls, age- and sex-matched. RESULTS: Sixty-six patients (18 men, 48 women) with mean age 53.8 +/- 12.7 years were analyzed. MPV was significantly higher in the patients with PHPT before PTX than in the same group after PTX (9.26 +/- 1.20 fl vs. 7.99 +/- 0.80 fl, p<0.0001). MPV levels were positively correlated with PTH (r=0.888, p<0.0001), calcium (r=0.292, p=0.017) in the preoperative phase. Postoperative (after 6 months) MPV showed a significant positive correlation with postoperative PTH (r=0.381, p=0.002) and calcium levels (r=0.324, p=0.008). CONCLUSIONS: These results suggest that subjects with PHPT lead to have increased platelet activation. PMID- 25512192 TI - Blood pressure is a risk factor for progression of diabetic retinopathy in normotensive patients with type 2 diabetes: correlation with carotid intima-media thickness. AB - OBJECTIVE: Carotid atherosclerotic lesions have been described more frequently in patients with diabetes and microvascular disease than in those with uncomplicated diabetes. In this study, we investigated the role of blood pressure as a risk factor of diabetic retinopathy in normotensive patients with type 2 diabetes. We also assessed the correlation of carotid intima-media thickness with both blood pressure and diabetic retinopathy. METHODS: The study group consisted of 140 normotensive patients (68 males and 72 females) with type 2 diabetes and diabetic retinopathy. Carotid intima-media thickness was evaluated using high-resolution B mode ultrasonography. Diabetic retinopathy was assessed and graded, using colored fundus photography and fundus fluorescein angiography, as either non proliferative or proliferative. RESULTS: Patients with proliferative diabetic retinopathy showed a higher systolic and diastolic blood pressure (p<0.01). Carotid intima-media thickness was higher in patients with proliferative than non proliferative diabetic retinopathy ones (1.094 +/- 0.142 vs. 0.842 +/- 0.134 mm, respectively; p<0.001) Carotid intima-media thickness showed positive correlation with both systolic (p<0.001) and diastolic blood pressures (p<0.01). No significant differences were found between males and females in any of the studied parameters. CONCLUSION: Our study proves that both systolic and diastolic blood pressures are important risk factors for the progression of retinopathy in normotensive patients with type 2 diabetes. We also demonstrate that carotid intima-media thickness, as a marker of atherosclerosis, is strongly correlated with both blood pressure and diabetic retinopathy in those patients. PMID- 25512193 TI - Herbicide acetochlor interferes with proliferation activity of MCF-7 cells enhanced by estradiol. AB - It is well documented that pesticides used in agricultural processes may have detrimental effects upon human health. Moreover, many of these compounds have been indicated as potential endocrine and reproductive disruptors. In the present study, the ability of herbicide acetochlor to affect a growth of estrogen sensitive MCF-7 mammary epithelial carcinoma cells was studied using E-screen test. Acetochlor alone did not affect proliferation of MCF-7 cells. Significant inhibition of estradiol-induced (10-14-10-8 M) MCF-7 cell growth by the action of acetochlor (10-5 M) and interaction between these chemicals were observed. Estradiol-stimulated MCF-7 cell proliferation was decreased by 41% of positive control (17beta-estradiol, 10-8 M, 100%) in the presence of acetochlor (10-5 M). Our results demonstrate that acetochlor might interfere with estradiol signaling conducted to altered proliferation activity of MCF-7 cells and might support endocrine disruptive effects of acetochlor. PMID- 25512194 TI - Impact of endocrine disruptors on ovarian steroidogenesis. AB - Production of steroid hormones by the ovary plays a key role in the female phenotype maintenance, as well as is critical for regular ovarian processes, including follicle growth, oocyte maturation and ovulation. Thus, optimal ovarian steroid synthesis is an indispensable requisite for the female reproductive health. In the past decades, along with an increased incidence of female reproductive disorders, an increasing concern for the potential reproductive impact of exogenous factors, particularly of environmental pollutants with endocrine disrupting properties, has risen. The scientific studies report that ovarian steroid hormone production is being recognized as an important target for the action of endocrine disrupting chemicals (EDCs). The fact that these chemicals have been detected in the biological samples of general population, and even directly in the follicular fluid of women, emphasizes the demands for testing the influence of EDCs on ovarian steroidogenesis. For these purposes, different methodological approaches have been employed, from in vivo studies on female rodents to in vitro experimental procedures using steroidogenically active follicular cells. In the present review, the effects of selected EDCs (pesticides, phthalate and phenol derivatives, and halogenated arylhydrocarbons) on the processes of ovarian steroidogenesis are summarized, and possible mechanisms of action of these agents are outlined. PMID- 25512195 TI - Clinical characteristics of definite or suspected isolated cardiac sarcoidosis: application of cardiac magnetic resonance imaging and 18F-Fluoro-2-deoxyglucose positron-emission tomography/computerized tomography. AB - BACKGROUND: Isolated cardiac sarcoidosis (iCS) is difficult to diagnose in patients without histologic evidence of sarcoidosis. We aimed to clarify the clinical characteristics of iCS, including imaging features on cardiac magnetic resonance imaging (MRI) and (18)F-fluoro-2-deoxyglucose positron-emission tomography/computerized tomography (FDG-PET/CT) scans. We also reviewed the therapeutic effect of corticosteroids and determined the long-term prognosis. METHODS AND RESULTS: We retrospectively reviewed 83 consecutive patients with suspicious CS from 1997 to 2013. Systemic sarcoidosis with CS (sCS, n = 30) and iCS (n = 11) were diagnosed according to clinical criteria. In iCS cases, sarcoidosis was not detected in any other organs. The clinical features did not significantly differ between sCS and iCS cases, except for ejection fraction, which was lower in iCS (P = .025). Nine sCS and 4 iCS cases showed late gadolinium enhancement, and the lesions tended to be on the epicardial side (76.9% P = .011) and septal wall (52.9% P < .001). The coefficient of variance for the myocardial standardized uptake value of FDG-PET/CT was higher in sCS (0.32 +/- 0.13; n = 19) and iCS (0.32 +/- 0.09; n = 7) than in control cases (n = 31; P < .001). B-Type natriuretic peptide level was improved after prednisolone treatment in both groups. Kaplan-Meier curve indicated that prognosis was not different between sCS and iCS cases. CONCLUSIONS: The clinical cardiac characteristics of iCS cases were similar to those of sCS. Cardiac MRI and FDG PET, noninvasive imaging modalities, could be useful modalities to detect myocardial involvement in the cases with definite or suspected iCS. PMID- 25512196 TI - Fluoroquinolone and Ovariectomy in the Bitch: Physiology of the Immune System as to CD56 and CD16 Expression. AB - Natural killer (NK) cells are innate lymphoid cells which act against a variety of pathogens and tumours. Phenotypically they are characterized by surface markers named cluster designation (CD) antigens. CD56 and CD16 are recognized as specific NK markers in the dogs as well as in humans. Surgical interventions suppress NK cells both in rats and humans. In this direction, it has been shown that an antibiotic regimen (amoxicillin, benzylpenicillin/dihydrostreptomycin, sulfametazine/sulfamerazine/ sulfathiazole, enrofloxacin, lincomycin/spectinomycin) administered only twice is effective in preventing infections after laparatomic ovariectomy, in the bitch. On these grounds, this research will show that the administration of a fluoroquinolone (5 mg/kg of enrofloxacin, Baytril(r), Bayer, Milan, Italy) one hour before and at the end of ovariectomy is able to increase CD56 and CD16 expression levels. Moreover, the antibiotic administration modifies the relative expression levels of the two CD; thus suggesting that the fluoroquinolone employed enhances the activation of a specific subset of NK cells mainly involved in body recovering during the post operative period as already observed in humans. PMID- 25512198 TI - Health professionals' detection of depression and anxiety in their patients with diabetes: The influence of patient, illness and psychological factors. AB - This study examines how often depression and anxiety, in patients with diabetes, are detected by health professionals; and whether detection is influenced by patient characteristics (age, gender), illness factors (duration of illness, diabetes control), and self-reported levels of depression and anxiety. Prevalence rates of clinically significant depression and anxiety were high (57% and 36%, respectively); however, of those identified, only 44 and 36 per cent, respectively, were detected by staff as depressed or anxious. The only significant predictors of detection were severity of depressive and anxious symptoms. Patient and illness characteristics did not influence whether professionals identified emotional problems in their patients. PMID- 25512199 TI - The associations between objective numeracy and colorectal cancer screening knowledge, attitudes and defensive processing in a deprived community sample. AB - We examined associations between numeracy and sociocognitive factors associated with colorectal cancer screening uptake (n = 964). Nearly half (45.7%) of the respondents incorrectly answered a numeracy question (low numeracy). Low numeracy respondents were less knowledgeable about colorectal cancer (p < .001), less positive towards screening (emotional, p < .001 and practical, p = .001) and less likely to intend to participate in screening (p = .001). They also reported greater defensive processing of cancer information (p = .001). Sociocognitive factors fully mediated the relationship between numeracy and screening intention. Addressing numeracy issues may reduce inequalities in CRC screening participation, but communication strategies could be limited by the tendency process cancer information defensively. PMID- 25512200 TI - Pediatric Cerebellar Tumors: Does ADC Analysis of Solid, Contrast-Enhancing Tumor Components Correlate Better with Tumor Grade than ADC Analysis of the Entire Tumor? AB - BACKGROUND: Apparent diffusion coefficient (ADC) values assist differentiating malignancy grades in pediatric cerebellar tumors. Previous studies reported the significance of ADC measurements within the solid, contrast-enhancing tumor component (SCT). These measurements take into account only a part of the tumor. In this study, we compared ADC measurements of the SCT versus entire tumor (ET). METHODS: ADC values were measured in the SCT and ET. Absolute tumor ADC values and cerebellar and thalamic ratios were compared across tumor grades. RESULTS: Thirty-two children with 16 low-grade and 16 high-grade tumors were included. The median age at presurgical MRI was 7.66 years (range .08-17.38 years). In the SCT, absolute ADC values, cerebellar ratio, and thalamic ratio were higher in low- versus high-grade tumors (P < .001). In the ET, absolute ADC values, cerebellar ratio, and thalamic ratio were also higher in low- versus high-grade tumors (P < .005). Cut-off absolute ADC values of .9 * 10(-3) mm/s2 (sensitivity 94%, specificity 100%) and 1.5 * 10(-3) mm/s2 (sensitivity 88%, specificity 75%) were calculated for measurement in the SCT and ET, respectively, to differentiate between tumors grades. CONCLUSION: A rigorous ADC measurement of the SCT has a higher sensitivity and specificity in predicting tumor grade compared to ADC measurement of the ET. PMID- 25512201 TI - Evaluation of oxidative stress in the anemia of dogs with chronic kidney disease. AB - BACKGROUND: Anemia and systemic oxidative stress may occur in dogs with chronic kidney disease (CKD). Only scarce information regarding the intraerythrocytic redox status under these conditions is available at this time. OBJECTIVE: The aim of this study was to evaluate the indicators of oxidative stress and intraerythrocytic antioxidant defense in dogs with anemia of CKD. METHODS: Thirty dogs with CKD in stages 3 or 4 with nonregenerative anemia (HCT <= 37%) were compared to 20 healthy dogs. Complete blood count, reticulocyte %, blood smear evaluation, intraerythrocytic concentrations of total (GSHt), reduced (GSH), and oxidized glutathione (GSSH), and activities of glutathione peroxidase, glutathione reductase and superoxide dismutase (SOD), as well as plasma concentrations of thiobarbituric acid-reactive substances (TBAR) were determined. RESULTS: Anemia of CKD dogs was nonregenerative (reticulocytes <= 0.2% with scarce anisocytosis and poikilocytosis). Intraerythrocytic GSSH and SOD, and plasma TBAR were higher in dogs with CKD. There was a positive correlation between the creatinine concentration and TBAR, and negative correlations between creatinine concentration and HCT, as well as between HCT and TBAR. In CKD dogs with a higher degree of anemia, SOD levels were higher and GSSH concentrations were lower. Despite the evidence of increased systemic oxidative stress, the compensatory response of SOD and the sustained intraerythrocytic concentrations of GSSH in CKD dogs with anemia indicated that the erythrocytes maintained the antioxidant defense. CONCLUSIONS: There was no strong evidence that oxidative stress was associated with higher degrees of anemia in dogs with CKD. PMID- 25512197 TI - Inhibitor of differentiation 4 (ID4): From development to cancer. AB - Highly conserved Inhibitors of DNA-Binding (ID1-ID4) genes encode multi functional proteins whose transcriptional activity is based on dominant negative inhibition of basic helix-loop-helix (bHLH) transcription factors. Initial animal models indicated a degree of compensatory overlap between ID genes such that deletion of multiple ID genes was required to generate easily recognizable phenotypes. More recently, new model systems have revealed alterations in mice harboring deletions in single ID genes suggesting complex gene and tissue specific functions for members of the ID gene family. Because ID genes are highly expressed during development and their function is associated with a primitive, proliferative cellular phenotype there has been significant interest in understanding their potential roles in neoplasia. Indeed, numerous studies indicate an oncogenic function for ID1, ID2 and ID3. In contrast, the inhibitor of differentiation 4 (ID4) presents a paradigm shift in context of well established role of ID1, ID2 and ID3 in development and cancer. Apart from some degree of functional redundancy such as HLH dependent interactions with bHLH protein E2A, many of the functions of ID4 are distinct from ID1, ID2 and ID3: ID4 proteins a) regulate distinct developmental processes and tissue expression in the adult, b) promote stem cell survival, differentiation and/or timing of differentiation, c) epigenetic inactivation/loss of expression in several advanced stage cancers and d) increased expression in some cancers such as those arising in the breast and ovary. Thus, in spite of sharing the conserved HLH domain, ID4 defies the established model of ID protein function and expression. The underlying molecular mechanism responsible for the unique role of ID4 as compared to other ID proteins still remains largely un-explored. This review will focus on the current understanding of ID4 in context of development and cancer. PMID- 25512203 TI - Clinical and immunologic predictors of scleroderma renal crisis in Japanese systemic sclerosis patients with anti-RNA polymerase III autoantibodies. AB - OBJECTIVE: To identify predictive factors for scleroderma renal crisis (SRC) in patients with anti-RNA polymerase III (anti-RNAP III) antibodies. METHODS: A total of 583 adult Japanese patients with systemic sclerosis (SSc) were screened for anti-RNAP III using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. RNAP subsets were further identified by immunoprecipitation (IP) assays. The association of clinical and immunologic factors with SRC was examined by logistic analyses. RESULTS: In this cohort, 37 patients (6%) were positive for anti-RNAP III, as determined by anti-RNAP III-specific ELISA. Further IP assays revealed that 19 patients were positive for anti-RNAP I/III, 17 for anti-RNAP I/II/III, and 1 for anti-RNAP III. SRC occurred in a total of 17 (2.9%) of 583 patients, with a significantly higher frequency in anti-RNAP III positive SSc patients (9 of 37 [24%]) than those without anti-RNAP III (8 of 546 [1%]) (odds ratio [OR] 21.6 [95% confidence interval (95% CI) 7.8-60.3], P < 0.00001). Our multivariate analyses using the Cox proportional hazards regression model revealed that anti-RNAP I/II/III positivity (OR 11.0 [95% CI 1.6-222.8], P = 0.0118) and an ELISA index for anti-RNAP III of >=157 (OR 2.4 * 10(9) [95% CI 2.1-uncalculated], P = 0.0093) were independent factors associated with the development of SRC. CONCLUSION: Our findings indicate that anti-RNAP III is associated with SRC, as reported previously. In addition, the presence of anti RNAP II in combination with anti-RNAP I/III (anti-RNAP I/II/III) and a higher ELISA index for anti-RNAP III may be associated with the development of SRC in SSc patients with anti-RNAP III. PMID- 25512202 TI - The multiple sclerosis visual pathway cohort: understanding neurodegeneration in MS. AB - BACKGROUND: Multiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations. FINDINGS: The MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-aged MS population in Barcelona, Spain. We started the recruitment of patients in the early phase of MS in 2010 and it remains permanently open. All patients undergo a complete neurological and ophthalmological examination including measurements of physical and disability (Expanded Disability Status Scale; Multiple Sclerosis Functional Composite and neuropsychological tests), disease activity (relapses) and visual function testing (visual acuity, color vision and visual field). The MS-VisualPath protocol also assesses the presence of anxiety and depressive symptoms (Hospital Anxiety and Depression Scale), general quality of life (SF-36) and visual quality of life (25-Item National Eye Institute Visual Function Questionnaire with the 10 Item Neuro-Ophthalmic Supplement). In addition, the imaging protocol includes both retinal (Optical Coherence Tomography and Wide-Field Fundus Imaging) and brain imaging (Magnetic Resonance Imaging). Finally, multifocal Visual Evoked Potentials are used to perform neurophysiological assessment of the visual pathway. DISCUSSION: The analysis of the visual pathway with advance imaging and electrophysilogical tools in parallel with clinical information will provide significant and new knowledge regarding neurodegeneration in MS and provide new clinical and imaging biomarkers to help monitor disease progression in these patients. PMID- 25512205 TI - Radiotherapy: Rotation correction for prostate tumours. PMID- 25512204 TI - Investigating the anti-leishmanial effects of linear peptoids. AB - Peptoids, a class of peptide mimetics, have emerged as promising anti-infective agents against a range of bacterial infections. Herein we present the first study of the antiparasitic and specifically the anti-leishmanial properties of linear peptoids. Peptoids were identified as having promising activity against Leishmania mexicana axenic amastigotes, a causative agent of cutaneous leishmaniasis. PMID- 25512206 TI - Bladder cancer: Could MPDL3280A offer a therapeutic breakthrough in metastatic bladder cancer? PMID- 25512208 TI - Bladder cancer: Urinary tract infection increases risk. PMID- 25512209 TI - Urothelial carcinoma: PECULIAR, but promising. PMID- 25512207 TI - Targeting heat shock proteins in metastatic castration-resistant prostate cancer. AB - The survival of malignant cells is constantly threatened by a myriad of cellular insults. In the context of such proteotoxic stress, cancer cells activate cytoprotective adaptive pathways. Heat shock proteins (HSPs) are highly conserved molecular chaperones that are expressed at low levels under normal conditions, but upregulated by cellular stress. As molecular chaperones, HSPs control the stability and function of client proteins, preventing aggregation of misfolded proteins, facilitating intracellular protein trafficking, maintaining protein conformation to enable ligand binding, phosphorylating proteins in signalling complexes and degrading severely damaged proteins via the ubiquitin-proteasome pathway. A key client protein of several HSPs is the androgen receptor (AR). HSPs facilitate binding of dihydrotestosterone to the AR, and enhance AR-mediated transcriptional activity. The integral role of HSPs in AR function speaks to their potential utility as therapeutic targets in castration-resistant prostate cancer (CRPC), a disease state characterized by persistent activation of the androgen-AR axis. Inhibition of HSPs has the additional benefit of potentially modulating signalling and transcriptional networks that are associated with HSP client proteins in CRPC cells. As a consequence, HSPs represent highly attractive targets in the development of treatments for CRPC. PMID- 25512210 TI - Molecular characterisation of Sarcocystis lutrae n. sp. and Toxoplasma gondii from the musculature of two Eurasian otters (Lutra lutra) in Norway. AB - Sarcocysts were detected in routinely processed histological sections of skeletal muscle, but not cardiac muscle, of two adult male otters (Lutra lutra; Mustelidae) from northern Norway following their post-mortem examination in 1999 and 2000. The sarcocysts were slender, spindle-shaped, up to 970 MUm long and 35 70 MUm in greatest diameter. The sarcocyst wall was thin (~ 0.5 MUm) and smooth with no visible protrusions. Portions of unfixed diaphragm of both animals were collected at the autopsies and kept frozen for about 14 years pending further examination. When the study was resumed in 2013, the thawed muscle samples were examined for sarcocysts under a stereo microscope, but none could be found. Genomic DNA was therefore extracted from a total of 36 small pieces of the diaphragm from both otters, and samples found to contain Sarcocystidae DNA were used selectively for PCR amplification and sequencing of the nuclear 18S and 28S ribosomal (r) RNA genes and internal transcribed spacer 1 (ITS1) region, as well as the mitochondrial cytochrome b (cytb) and cytochrome c oxidase subunit 1 (cox1) genes. Sequence comparisons revealed that both otters were infected by the same Sarcocystis sp. and that there was no genetic variation (100 % identity) among sequenced isolates at the 18S and 28S rRNA genes (six identical isolates at both loci) or at cox1 (13 identical isolates). PCR products comprising the ITS1 region, on the other hand, had to be cloned before sequencing due to intraspecific sequence variation. A total of 33 clones were sequenced, and the identities between them were 97.9-99.9 %. These sequences were most similar (93.7 96.0 % identity) to a sequence of Sarcocystis kalvikus from the wolverine in Canada, but the phylogenetic analyses placed all of them as a monophyletic sister group to S. kalvikus. Hence, they were considered to represent a novel species, which was named Sarcocystis lutrae. Sequence comparisons and phylogenetic analyses based on sequences of the 18S and 28S rRNA genes and cox1, for which little or no sequence data were available for S. kalvikus, revealed that S. lutrae otherwise was most closely related to various Sarcocystis spp. using birds or carnivores as intermediate hosts. The cox1 sequences of S. lutrae from the otters were identical to two sequences from an arctic fox, which in a previous study had been assigned to Sarcocystis arctica due to a high identity (99.4 %) with the latter species at this gene and a complete identity with S. arctica at three other loci when using the same DNA samples as templates for PCR reactions. Additional PCR amplifications and sequencing of cox1 (ten sequences) and the ITS1 region (four sequences) using four DNA samples from this fox as templates again generated cox1 sequences exclusively of S. lutrae, but ITS1 sequences of S. arctica, and thus confirmed that this arctic fox had acted as intermediate host for both S. arctica and S. lutrae. Based on the phylogenetic placement of S. lutrae, the geographical location of infected animals (otters, arctic fox) and the distribution of carnivores/raptors which may have interacted with them, the white-tailed eagle (Haliaeetus albicilla) seems to be a possible definitive host of S. lutrae. Some of the muscle samples from both otters were shown to harbour stages of Toxoplasma gondii through PCR amplification and sequencing of the entire ITS1 region (five isolates) and/or the partial cytb (eight isolates) and cox1 (one isolate). These sequences were identical to several previous sequences of T. gondii in GenBank. Thus, both otters had a dual infection with S. lutrae and T. gondii. PMID- 25512213 TI - The IOM report on dying in America: a call to action for nursing homes. PMID- 25512211 TI - The molecular characterization and RNAi silencing of SjZFP1 in Schistosoma japonicum. AB - During development, Schistosoma japonicum undergoes many morphological and physiological transformations as a result of profound changes in gene expression. Proteins containing zinc finger motifs usually play an important role in DNA recognition, RNA packaging, and transcriptional activation. In our current study, we cloned the open reading frame (ORF) of SjZFP1 of S. japonicum, which encodes a zinc finger protein. We analyzed the complementary DNA (cDNA) sequence of SjZFP1 and examined the expression of SjZFP1 messenger RNA (mRNA) at various developmental stages. We also tested the effects of RNA interference (RNAi) silencing on worm burden, spawning, and egg hatching. The ORF in the SjZFP1 cDNA was 1017 bp in length and was predicted to encode a 338-aa protein with a molecular mass of approximately 38.5 kDa and theoretical isoelectric point (pI) of 7.08. Several conserved regions, including a B-box-type zinc-binding domain, two bipartite nuclear localization signal domains, a paired amphipathic helix repeat, and overlapping RING and PHD finger domains, were identified in the predicted amino acid sequence of SjZFP1. Using real-time PCR, we showed that the SjZFP1 mRNA was expressed across all of the developmental stages of the parasite and that the level of transcription was highest in the cercariae, eggs, schistosomula, and mature adult worms. The level of SjZFP1 mRNA expression in cultured schistosomula treated with one of two SjZFP1-specific small interfering RNAs (siRNAs; AY770 and AY546) was reduced by over 80 %, compared with that in the controls. In RNAi experiments in BALB/c mice, the level of SjZFP1 mRNA increased significantly when the mice were treated with the same SjZFP1-specific siRNAs during the early stages of infection. By contrast, the level of SjZFP1 mRNA decreased significantly when the mice were treated with the SjZFP1-specific siRNAs during the middle to late stages of infection. In four independent experiments, fewer worms were recovered from mice treated with the SjZFP1 specific siRNAs, compared with the number of worms recovered from the control mice. Both the average number and hatching rates of liver eggs recovered from mice treated with the SjZFP1-specific siRNAs during the middle to late stages of infection were significantly lower than those of the liver eggs recovered from the control mice. Our results suggest that the SjZFP1 gene might be important for parasite development, spawning in the vertebrate host, and egg hatching. PMID- 25512214 TI - Evaluations of home care interventions for frail older persons using the interRAI Home Care instrument: a systematic review of the literature. AB - BACKGROUND/OBJECTIVES: This systematic review describes the use of the interRAI Home Care (interRAI HC) instrument, an internationally validated comprehensive geriatric assessment, as a base for the evaluation of home care projects. Because of the evidence base of the instrument and its widespread use, researchers can make a thorough evaluation of projects and interventions in home care and can also have insight in international comparisons. The aim of this systematic review is to identify research that evaluates interventions in the home care setting using this comprehensive geriatric assessment and to describe these evaluations and report the results of the use of this instrument. DESIGN: Two independent reviewers constructed a comprehensive list of Medical Subject Headings, which was designed for 5 explicit categories: (1) interventions; (2) evaluation; (3) home care; (4) interRAI HC; and (5) older person. A systematic literature search was then performed in the main electronic databases Web of Science, EMBASE, MEDLINE, Cochrane, PsycInfo, and CINAHL for the years 1990 to 2013. SETTING: Home care. MEASUREMENTS: Studies were described and the following information was extracted from the articles: mean age and proportion of gender of participants; sample size; location of the study; goal of the study; main findings; main limitations; and results of the evaluation of the interRAI HC instrument. RESULTS: A total of 349 articles were identified. Eighteen studies met our inclusion criteria describing 18 interventions in home care evaluated with the interRAI HC instrument. CONCLUSIONS: This systematic review can help researchers to plan evaluation of interventions in home care. The interRAI HC instrument proves to be a comprehensive tool to measure outcomes and can serve as an evaluation instrument for interventions. It can also be used as an intervention itself, when caregivers use the tool and its outcome measures to implement a care plan. PMID- 25512215 TI - AMDA, much more than a rose by another name.... PMID- 25512216 TI - Phenotype of osteosarcopenia in older individuals with a history of falling. AB - OBJECTIVES: In older persons, the combination of osteopenia/osteoporosis and sarcopenia has been proposed as a subset of frailer individuals at higher risk of institutionalization, falls, and fractures. However, the particular clinical, biochemical, and functional characteristics of the osteosarcopenic (OS) patients remain unknown. In this study, we used a clinical definition of osteosarcopenia aiming to determine the clinical, functional, and biochemical features that are unique to these patients within a population of older people who fall. DESIGN: Cross-sectional study. SETTING: Falls and Fractures Clinic, Nepean Hospital (Penrith, NSW, Australia). PARTICIPANTS: A total of 680 people (mean age = 79, 65% women) assessed between 2009 and 2013. MEASUREMENTS: Assessment included medical history, physical examination, bone densitometry and body composition by dual-energy X-ray absorptiometry, posturography, grip strength, gait parameters (GaitRITE), and blood tests for nutrition and secondary causes of sarcopenia and osteoporosis. Patients were divided into 4 groups: (1) osteopenic (BMD <-1.0 SD), (2) sarcopenic, (3) OS, and (4) nonsarcopenic/nonosteopenic. Difference between groups was assessed with 1-way ANOVA and chi(2) analysis. Multivariable linear regression evaluated the association between the groups and measures of physical function. Multivariable logistic regression evaluated risk factors for being in the OS group. RESULTS: Mean age of the OS patients was 80.4 +/- 7.0 years. Our analyses showed that OS patients are older, mostly women, are at high risk for depression and malnutrition, have body mass index lower than 25, and showed a higher prevalence of peptic disease, inflammatory arthritis, maternal hip fracture, history of atraumatic fracture, and impaired mobility. CONCLUSION: We have reported a set of characteristics that are highly prevalent in OS patients. This study could be used to inform the design of future trials and to develop interventions to prevent institutionalization and poor outcomes in this particular set of high-risk patients. PMID- 25512218 TI - Prediction of endoscopic third ventriculostomy (ETV) success with 3D-SPACE technique. PMID- 25512217 TI - Hospitalization and aesthetic health in older adults. AB - OBJECTIVES: To assess the impact of hospitalization on arts engagement among older people; and to assess perceptions of whether hospitals are aesthetically deprived environments. METHODS: A Survey of Aesthetic and Cultural Health was developed to explore the role of aesthetics before, during and after hospital. Study participants were n = 150 hospital in-patients aged >65. Descriptive and inferential statistics were used to analyze the data. MAIN FINDINGS: Attendance at arts events was an important part of life for this sample and a large drop off was noted in continuation of these activities in the year post-hospital stay. Physical health issues were the main causes but also loss of confidence and transport issues. Film, dance, and music were the most popular arts for this sample prior to hospital stay. Noise pollution caused by other patients, lack of control over TV/radio, and access to receptive arts in hospital (reading and listening to music) were important issues for patients in hospital. CONCLUSIONS: This study identifies a trend for decreasing exposure to arts beginning with a hospital stay and concludes that older people may need encouragement to resume engagement in arts following a hospital stay. There is relatively limited evidence regarding the nature of, and potential benefit from, aesthetics in healthcare and limited studies with rigorous methodology, and further research is needed to understand the aesthetic preferences of older people in hospital. PMID- 25512219 TI - Diabetes educator mentorship program: mentors requested. AB - PURPOSE: The purpose of this article is to describe the Diabetes Educator Mentorship Program, communicate mentors' experiences and perceptions during the first 3 years following implementation, and provide strategies to encourage mentoring. CONCLUSIONS: Creation of this collaborative program has fostered successful attainment of additional certified diabetes educators who obtained diabetes self-management education and support (DSMES) practice requirement hours through a voluntary Diabetes Educator Mentorship Program. There is a significant need for additional mentors to meet the growing need for mentoring partnerships. Increasing the number of mentors will provide more opportunities to those seeking to gain DSMES experience and will ultimately expand the number of health professionals available to educate those with diabetes or prediabetes. PMID- 25512220 TI - Experience with the Enlite sensor in a multicenter pediatric study. AB - PURPOSE: The purpose of this article is to outline the experience of certified diabetes educators (CDEs) using the Enlite continuous glucose monitoring sensor system in a pediatric multicenter randomized controlled trial. Continuous glucose monitoring (CGM) is becoming popular as a tool for educators and families to improve glycemic control. CGM can be a valuable educational tool to demonstrate to the user the impact of insulin dosing and effects of physical activity, food intake, and other life events such as work, illness, and stress on their glycemic control. The authors will share education tips and practical applications for diabetes educators to facilitate education and sustained use of Enlite glucose sensors in children and adolescents using insulin pump therapy. CONCLUSIONS: The Enlite glucose sensor is a comfortable and user-friendly device. Improvements to both the insertion device and the Enlite glucose sensor have resulted in improved level of comfort on insertion and with ongoing wear, which may translate into greater adherence and effectiveness. PMID- 25512221 TI - Classification of lung cancer using ensemble-based feature selection and machine learning methods. AB - Lung cancer is one of the leading causes of death worldwide. There are three major types of lung cancers, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and carcinoid. NSCLC is further classified into lung adenocarcinoma (LADC), squamous cell lung cancer (SQCLC) as well as large cell lung cancer. Many previous studies demonstrated that DNA methylation has emerged as potential lung cancer-specific biomarkers. However, whether there exists a set of DNA methylation markers simultaneously distinguishing such three types of lung cancers remains elusive. In the present study, ROC (Receiving Operating Curve), RFs (Random Forests) and mRMR (Maximum Relevancy and Minimum Redundancy) were proposed to capture the unbiased, informative as well as compact molecular signatures followed by machine learning methods to classify LADC, SQCLC and SCLC. As a result, a panel of 16 DNA methylation markers exhibits an ideal classification power with an accuracy of 86.54%, 84.6% and a recall 84.37%, 85.5% in the leave-one-out cross-validation (LOOCV) and independent data set test experiments, respectively. Besides, comparison results indicate that ensemble based feature selection methods outperform individual ones when combined with the incremental feature selection (IFS) strategy in terms of the informative and compact property of features. Taken together, results obtained suggest the effectiveness of the ensemble-based feature selection approach and the possible existence of a common panel of DNA methylation markers among such three types of lung cancer tissue, which would facilitate clinical diagnosis and treatment. PMID- 25512223 TI - Abstracts of the Annual British Paediatric Neurology Association Meeting, 21-23 January 2015, Gateshead, Newcastle. PMID- 25512222 TI - Expression of NALPs in adipose and the fibrotic progression of non-alcoholic fatty liver disease in obese subjects. AB - BACKGROUND: Visceral obesity is often accompanied by non-alcoholic fatty liver disease (NAFLD). Activation of NACHT, LRR and PYD domains-containing proteins (NALPs) may contribute to the release of pro-inflammatory cytokines by adipose and the obesity-associated progression of NAFLD to non-alcoholic steatohepatitis (NASH). METHODS: We analyzed visceral adipose expression of various NALPs and its downstream effectors caspase-1, ASC (Apoptosis-associated speck-like protein containing a CARD), IL-18 (Interleukin-18) and IL-1beta (Interleukin- 1Beta) in obese subjects (BMI >= 35) with biopsy proven NAFLD. RESULTS: In adipose samples collected from NASH and pericellular fibrosis patients cohorts, expression levels of NALPs and IL-1beta were lower than that in non-NASH patients. In portal fibrosis, the levels of mRNA encoding anti-inflammatory NALP6 were upregulated. The expression levels of all NALPs were significantly co-correlated. Circulating IL-18 levels were associated with increased liver injury markers AST and ALT and portal fibrosis. CONCLUSION: Our observations point at a possible shift in inflammation and fibrotic response from adipose tissue to liver and a possible negative feedback regulation of tissue inflammation that may instigate NAFLD severity. PMID- 25512224 TI - Measurement of maternal cerebral tissue hemoglobin on near-infrared time-resolved spectroscopy in the peripartum period. AB - AIM: To measure cerebral tissue hemoglobin in uncomplicated and complicated pregnant women during the peripartum period. METHODS: Time-resolved spectroscopy (TRS-20) can measure absolute concentration of oxygenated, deoxygenated, and total tissue hemoglobin based on the transit time of individual photons. Therefore, we used TRS-20 to measured tissue hemoglobin in the hemi-prefrontal lobes of normotensive pregnant women with (n = 51) or without (n = 19) epidural anesthesia, hypertensive pregnant women with pre-eclampsia (n = 10), a pregnant woman with acute onset of hypertension soon after delivery, and a hypertensive woman after hemorrhagic stroke in delivery. RESULTS: Cyclic labor concomitant with intra-abdominal pressure caused synergistic elevation in cerebral tissue hemoglobin. In contrast, epidural anesthesia reduced the amplitude of the cyclic increase of cerebral tissue hemoglobin in normotensive pregnant women. Hypertension in labor due to pre-eclampsia increased the amplitude of synergistic elevation of cerebral tissue hemoglobin caused by cyclic labor and intra abdominal pressure. A prolonged high basal level of cerebral tissue hemoglobin was observed in a case of acute onset of hypertension soon after delivery. A decrease in cerebral tissue hemoglobin in the hemi-prefrontal lobe was observed in a woman 2 h after the onset of hemorrhagic stroke in labor. CONCLUSIONS: TRS 20 can detect specific changes in maternal cerebral tissue hemoglobin level in response to physiological and pathophysiological changes in delivery. Thus, it represents a promising new conventional tool for maternal cerebral monitoring in the peripartum period. PMID- 25512225 TI - Environmental effects on resistance gene expression in milk stage popcorn kernels and associations with mycotoxin production. AB - Like other forms of maize, popcorn is subject to increased levels of contamination by a variety of different mycotoxins under stress conditions, although levels generally are less than dent maize under comparable stress. Gene array analysis was used to determine expression differences of disease resistance associated genes in milk stage kernels from commercial popcorn fields over 3 years. Relatively lower expression of resistance gene types was noted in years with higher temperatures and lower rainfall, which was consistent with prior results for many previously identified resistance response-associated genes. The lower rates of expression occurred for genes such as chitinases, protease inhibitors, and peroxidases; enzymes involved in the synthesis of cell wall barriers and secondary metabolites; and regulatory proteins. However, expression of several specific resistance genes previously associated with mycotoxins, such as aflatoxin in dent maize, was not affected. Insect damage altered the spectrum of resistance gene expression differences compared to undamaged ears. Correlation analyses showed expression differences of some previously reported resistance genes that were highly associated with mycotoxin levels and included glucanases, protease inhibitors, peroxidases, and thionins. PMID- 25512226 TI - Ebola crisis in the United States: a glimpse of its larger shadow. AB - This article is about readiness of the U.S. health care system to deal with crises. Using the Ebola crisis as a reference, first it examines the response to the current challenge. However, that is the smaller objective of the article. Lately, we are also being challenged to deal with other kinds of epidemics like obesity, mental health diseases, and violence. These crises are not dramatic like the Ebola crisis. However, these are no less insidious than Ebola. If we are not ready for them, then these crises have the potential to undermine the long-term health and prosperity of our society. In this context, and therefore mainly, this article is about two major long-standing systemic problems in the U.S. health care system that the unfolding of the Ebola crisis has bared. One is about how the inherent problem in the design of American federalist system regarding state autonomy on health matters is creating a dysfunctional health care system. The other is about the inertia of the research industry in the health care system in clinging to an archaic outdated inefficient mind-set and methodology that fails to generate the right information required for an appropriate decision making in matters of health care delivery, including crises. These problems are not small, nor their solutions easy. However, no matter how uncomfortable and tedious, facing them is necessary and inevitable. The discussions and arguments in this article are to outline their nature broadly and to make a call to further a dialogue. PMID- 25512227 TI - Could pharmacological curtailment of the RhoA/Rho-kinase pathway reverse the endothelial barrier dysfunction associated with Ebola virus infection? AB - Activation of the RhoA/Rho-kinase (ROCK) pathway induces endothelial barrier dysfunction and increased vascular permeability, which is a hallmark of various life-threatening vascular pathologies. Therapeutic approaches aimed at inhibiting the RhoA/ROCK pathway have proven effective in the attenuation of vascular leakage observed in animal models of endotoxin-induced lung injury/sepsis, edema, autoimmune disorders, and stroke. These findings suggest that treatments targeting the ROCK pathway might be of benefit in the management of the Ebola virus disease (EVD), which is characterized by severe vascular leak, likely involving pro-inflammatory cytokines, such as tumor necrosis factor-alpha, released from virus-infected macrophages. In this paper, we review evidence from in vivo and in vitro models of vascular leakage, suggesting that the RhoA/ROCK pathway is an important therapeutic target for the reversal of the vascular permeability defects associated with EVD. Future studies should explore the efficacy of pharmacological inhibition of RhoA/ROCK pathway on reversing the endothelial barrier dysfunction in animal models of EVD and other hemorrhagic fever virus infections as part of an adjunctive therapy. Such experimental studies should focus, in particular, on the small molecule fasudil (HA-1077), a derivative of isoquinoline, which is a safe and clinically approved inhibitor of ROCK, making it an excellent candidate in this context. PMID- 25512228 TI - Flavivirus reverse genetic systems, construction techniques and applications: a historical perspective. AB - The study of flaviviruses, which cause some of the most important emerging tropical and sub-tropical human arbovirus diseases, has greatly benefited from the use of reverse genetic systems since its first development for yellow fever virus in 1989. Reverse genetics technology has completely revolutionized the study of these viruses, making it possible to manipulate their genomes and evaluate the direct effects of these changes on their biology and pathogenesis. The most commonly used reverse genetics system is the infectious clone technology. Whilst flavivirus infectious clones provide a powerful tool, their construction as full-length cDNA molecules in bacterial vectors can be problematic, laborious and time consuming, because they are often unstable, contain unwanted induced substitutions and may be toxic for bacteria due to viral protein expression. The incredible technological advances that have been made during the past 30years, such as the use of PCR or new sequencing methods, have allowed the development of new approaches to improve preexisting systems or elaborate new strategies that overcome these problems. This review summarizes the evolution and major technical breakthroughs in the development of flavivirus reverse genetics technologies and their application to the further understanding and control of these viruses and their diseases. PMID- 25512230 TI - Development of plants resistant to tomato geminiviruses using artificial trans acting small interfering RNA. AB - RNA interference (RNAi), a conserved RNA-mediated gene regulatory mechanism in eukaryotes, plays an important role in plant growth and development, and as an antiviral defence system in plants. As a counter-strategy, plant viruses encode RNAi suppressors to suppress the RNAi pathways and consequently down-regulate plant defence. In geminiviruses, the proteins AC2, AC4 and AV2 are known to act as RNAi suppressors. In this study, we have designed a gene silencing vector using the features of trans-acting small interfering RNA (tasiRNA), which is simple and can be used to target multiple genes at a time employing a single-step cloning procedure. This vector was used to target two RNAi suppressor proteins (AC2 and AC4) of the geminivirus, Tomato leaf curl New Delhi virus (ToLCNDV). The vector containing fragments of ToLCNDV AC2 and AC4 genes, on agro-infiltration, produced copious quantities of AC2 and AC4 specific siRNA in both tobacco and tomato plants. On challenge inoculation of the agro-infiltrated plants with ToLCNDV, most plants showed an absence of symptoms and low accumulation of viral DNA. Transgenic tobacco plants were raised using the AC2 and AC4 tasiRNA generating constructs, and T1 plants, obtained from the primary transgenic plants, were tested for resistance separately against ToLCNDV and Tomato leaf curl Gujarat virus. Most plants showed an absence of symptoms and low accumulation of the corresponding viruses, the resistance being generally proportional to the amounts of siRNA produced against AC2 and AC4 genes. This is the first report of the use of artificial tasiRNA to generate resistance against an important plant virus. PMID- 25512229 TI - Permissive changes in the neuraminidase play a dominant role in improving the viral fitness of oseltamivir-resistant seasonal influenza A(H1N1) strains. AB - Permissive neuraminidase (NA) substitutions such as R222Q, V234M and D344N have facilitated the emergence and worldwide spread of oseltamivir-resistant influenza A/Brisbane/59/2007 (H1N1)-H275Y viruses. However, the potential contribution of genetic changes in other viral segments on viral fitness remains poorly investigated. A series of recombinant A(H1N1)pdm09 and A/WSN/33 7:1 reassortants containing the wild-type (WT) A/Brisbane/59/2007 NA gene or its single (H275Y) and double (H275Y/Q222R, H275Y/M234V and H275Y/N344D) variants were generated and their replicative properties were assessed in vitro. The Q222R reversion substitution significantly reduced viral titers when evaluated in both A(H1N1)pdm09 and A/WSN/33 backgrounds. The permissive role of the R222Q was further confirmed using A/WSN/33 7:1 reassortants containing the NA gene of the oseltamivir-susceptible or oseltamivir-resistant influenza A/Mississippi/03/2001 strains. Therefore, NA permissive substitutions play a dominant role for improving viral replication of oseltamivir-resistant A (H1N1)-H275Y viruses in vitro. PMID- 25512231 TI - Tandem MS: it's now the norm. PMID- 25512232 TI - HepaRG culture in tethered spheroids as an in vitro three-dimensional model for drug safety screening. AB - Conventional two-dimensional (2D) monolayer cultures of HepaRG cells allow in vitro maintenance of many liver-specific functions. However, cellular dedifferentiation and functional deterioration over an extended culture period in the conventional 2D HepaRG culture have hampered its applications in drug testing. To address this issue, we developed tethered spheroids of HepaRG cells on Arg-Gly-Asp (RGD) and galactose-conjugated substratum with an optimized hybrid ratio as an in vitro three-dimensional (3D) human hepatocyte model. The liver specific gene expression level and drug metabolizing enzyme activities in HepaRG tethered spheorids were markedly higher than those in 2D cultures throughout the culture period of 7 days. The inducibility of three major cytochrome P450 (CYP) enzymes, namely CYP1A2, CYP2B6 and CYP3A4, was improved in both mRNA and activity level in tethered spheroids. Drug-induced cytotoxic responses to model hepatotoxins (acetaminophen, chlorpromazine and ketoconazole) in tethered spheroids were comparable to 2D cultures as well as other studies in the literature. Our results suggested that the HepaRG-tethered spheroid would be an alternative in vitro model suitable for drug safety screening. PMID- 25512233 TI - PI3K signaling in the pathogenesis of obesity: The cause and the cure. AB - With the steady rise in the incidence of obesity and its associated comorbidities, in the last decades research aimed at understanding molecular mechanisms that control body weight has gained new interest. Fat gain is frequently associated with chronic adipose tissue inflammation and with peripheral as well as central metabolic derangements, resulting in an impaired hypothalamic regulation of energy homeostasis. Recent attention has focused on the role of phosphatidylinositol 3-kinase (PI3K) in both immune and metabolic response pathways, being involved in the pathophysiology of obesity and its associated metabolic diseases. In this review, we focus on distinct PI3K isoforms, especially class I PI3Ks, mediating inflammatory cells recruitment to the enlarged fat as well as intracellular responses to key hormonal regulators of fat storage, both in adipocytes and in the central nervous system. This integrated view of PI3K functions may ultimately help to develop new therapeutic interventions for the treatment of obesity. PMID- 25512234 TI - Solid residues from Italian municipal solid waste incinerators: A source for "critical" raw materials. AB - The incineration of municipal solid wastes is an important part of the waste management system along with recycling and waste disposal, and the solid residues produced after the thermal process have received attention for environmental concerns and the recovery of valuable metals. This study focuses on the Critical Raw Materials (CRM) content in solid residues from two Italian municipal waste incinerator (MSWI) plants. We sampled untreated bottom ash and fly ash residues, i.e. the two main outputs of common grate-furnace incinerators, and determined their total elemental composition with sensitive analytical techniques such as XRF and ICP-MS. After the removal of a few coarse metallic objects from bottom ashes, the corresponding ICP solutions were obtained using strong digestion methods, to ensure the dissolution of the most refractory components that could host significant amounts of precious metals and CRM. The integration of accurate chemical data with a substance flow analysis, which takes into account the mass balance and uncertainties assessment, indicates that bottom and fly ashes can be considered as a low concentration stream of precious and high-tech metals. The magnesium, copper, antimony and zinc contents are close to the corresponding values of a low-grade ore. The distribution of the elements flow between bottom and fly ash, and within different grain size fractions of bottom ash, is appraised. Most elements are enriched in the bottom ash flow, especially in the fine grained fractions. However, the calculated transfer coefficients indicate that Sb and Zn strongly partition into the fly ashes. The comparison with available studies indicates that the CRM concentrations in the untreated solid residues are comparable with those residues that undergo post-treatment beneficiations, e.g. separation between ferrous and non-ferrous fractions. The suggested separate collection of "fresh" bottom ash, which could be processed for further mineral upgrading, can constitute an attractive option of the waste management system, when physical-mechanical devices are not available or could not be implemented in old MSWI systems. The suggested procedure may lead to the improvement of recovery efficiency up to 83% for CRM and 94% for other valuable metals. PMID- 25512235 TI - Cerebriform connective tissue nevus of lumbar. AB - Connective tissue nevi represents a kind of hamartoma, and coalescence of the lesions in a cerebriform mode in the lumbar region without Proteus syndrome is rarely seen. Here, we report a 26-year-old woman presenting with nodules and plaques in her left lumbar region of 26 years in duration. Histopathological examination and Masson-trichrome stain showed increased dermal collagen bundles in a haphazard array. The diagnosis of connective tissue nevi was made. This is the first case report on cerebriform connective tissue nevi without Proteus syndrome in the lumbar region. PMID- 25512236 TI - Can you identify the genodermatosis? PMID- 25512237 TI - Electrochemotherapy in the treatment of melanoma skin metastases: a report on 31 cases. AB - INTRODUCTION AND OBJECTIVES: Electrochemotherapy is indicated for the treatment of unresectable cutaneous and subcutaneous tumors. The technique involves the synergistic use of electroporation of cell membranes to increase the cytotoxicity of anticancer drugs delivered to the tumor cells. The aim of this study was to analyze the clinical effectiveness and safety of electrochemotherapy in the treatment of unresectable locoregional recurrent or metastatic melanomas. MATERIAL AND METHODS: We studied 31 patients treated between January 2007 and December 2012. The European Standard Operating Procedures of Electrochemotherapy (ESOPE) were applied in all cases. Treatment response was analyzed as overall patient response (mean response based on results for all lesions treated in a given patient). RESULTS: Response was classified as partial in 49% of patients and complete in 23%. At 1 year, the level of response achieved had been maintained in 17 patients. Disease progression was observed in 28% of the series. Immediate local complications (pain, swelling, erythema) were mild and resolved within 48hours in most cases. Eight patients developed subsequent local complications, such as ulcers and secondary infections associated with necrosis of the lesions. These complications were brought under control with topical treatments. CONCLUSIONS: Electrochemotherapy is a very effective, safe, and efficient treatment for advanced locoregional disease in patients with unresectable melanoma lesions. PMID- 25512238 TI - Small molecular amine mediated synthesis of hydrophilic CdS nanorods and their photoelectrochemical water splitting performance. AB - Photoelectrochemical (PEC) water splitting is a promising route for solar energy harvesting and storage, but it has been highly limited by the performance of the semiconductor photoelectrodes. Herein, we report a small molecular amine-mediated solvothermal method for synthesizing CdS nanorods. The obtained CdS nanorods are hydrophilic and can be easily dispersed in water. Furthermore, the small molecular amine, activating elemental sulfur and mediating the growth of CdS, all play a role similar to that of long-chain surfactant molecules in "non-aqueous" systems. Thus, the obtained CdS nanorods show uniform shape with monodispersed size, the length of which can be tuned by the sulfur dosage. In addition, the CdS nanorods show a broader light absorption than CdS nanoparticles. Their photoelectrochemical water splitting performances were then tested. Under light irradiation of lambda > 200 nm, the photocurrent density of CdS nanorods at -0.2 V bias potential (vs. Ag/AgCl) is found to be 25 times of that obtained with CdS nanoparticles. The present finding demonstrates that small amine molecules could be efficient mediators for the synthesis of hydrophilic sulfides with high quality. The simple synthesis method and the good photoelectrochemical properties illustrate the hydrophilic CdS nanorods are potential candidate for photoelectrochemical applications. PMID- 25512239 TI - Are sarcopenia, obesity and sarcopenic obesity predictive of outcome in patients with colorectal liver metastases? AB - BACKGROUND: The impact of body composition on outcomes after surgery for colorectal liver metastases (CRLM) remains unclear. The aim of the present study was to determine the influence of sarcopenia, obesity and sarcopenic obesity on morbidity, disease-free (DFS) and overall survival (OS). METHOD: Between 2005 and 2012, all patients undergoing a partial liver resection for CRLM in the Maastricht University Medical Centre, and who underwent computed tomography (CT) imaging within 3 months before liver surgery, were included. Body composition was primarily based on pre-operative CT measurements. Sarcopenia was based on total muscle area at the level of the third lumbar vertebra and predefined body mass index (BMI)- and gender-specific cut-off values for sarcopenia were used. Body fat percentages were calculated and the top 40% for men and women were considered obese. RESULTS: Of the 171 included patients undergoing liver surgery for CRLM, 80 (46.8%) patients were sarcopenic, 69 (40.4%) obese and 49 (28.7%) sarcopenic obese. The presence of sarcopenia, obesity or sarcopenic obesity did not affect the complication rates. However, readmission rates were significantly increased in patients with (sarcopenic) obesity (P < 0.05). Surprisingly, obesity seemed to prolong OS (P = 0.021) and was identified as an independent predictor [hazard ratio (HR):0.58 and P = 0.046] for better OS. Sarcopenia and sarcopenic obesity did not affect DFS or OS. CONCLUSION: Sarcopenia, obesity and sarcopenic obesity did not worsen DFS, OS and complication rates after a partial liver resection for CRLM. PMID- 25512240 TI - Sleep characteristics, exercise capacity and physical activity in patients with chronic fatigue syndrome. AB - PURPOSE: Unrefreshing sleep and lowered physical activity are commonly observed in chronic fatigue syndrome (CFS) patients, but how they might influence each other remains unexplored. Therefore, this study simultaneously examined the exercise capacity, sleep characteristics and physical activity in CFS patients. METHODS: Handgrip strength and cycle exercise capacity were assessed in 42 female CFS patients and 24 inactive control subjects. During four consecutive days and nights, energy expenditure, activity and sleep-wake pattern were objectively registered using a Sensewear Armband. RESULTS: Exercise capacity was significantly lower in CFS patients. In both groups VO2peak correlated with the time subjects were physically active. In CFS patients only, VO2peak correlated negatively with sleeping during the day whilst physical activity level and energy expenditure correlated negatively with sleep latency and lying awake at night. CONCLUSIONS: In the present study, CFS patients with higher VO2peak tend to sleep less over day. Occupation in physical activities was negatively associated with sleep latency and lying awake at night. Increased physical activity potentially has beneficial effects on sleep quality in CFS. However, a close monitoring of the effects of increasing physical activity is essential to avoid negative effects on the health status of patients. IMPLICATIONS FOR REHABILITATION: Female patients with chronic fatigue syndrome (CFS) have normal sleep latency and sleep efficiency, but sleep more and spent more time in bed as compared to healthy inactive women. Female CFS patients have lower exercise capacity, and a lower physical activity level as compared to healthy inactive women. CFS patients appear to be more sensitive for sleep quality (sleep latency and lying awake at night), which is associated with a low physical activity level. PMID- 25512241 TI - Early reconstruction of the leaking ileal pouch-anal anastomosis: a novel solution to an old problem. AB - AIM: The study aimed to determine the effectiveness and direct medical costs of early surgical closure of the anastomotic defect after a short course of Endo sponge(r) therapy of the presacral cavity, compared with conventional treatment in patients with anastomotic leakage after ileal pouch-anal anastomosis (IPAA). METHOD: Patients with anastomotic leakage after IPAA undergoing early surgical closure of the anastomotic defect after a short Endo-sponge(r) treatment were prospectively followed and compared with a consecutive cohort of patients with an anastomotic leak treated by creation of a loop ileostomy and occasional drainage of the presacral cavity. RESULTS: A total of 15 patients were treated with early surgical closure and 29 were treated conventionally. In the early surgical closure group, the Endo-sponge(r) treatment was continued for a median of 12 days [interquartile range (IQR) 7-15 days] with a median of 3 (IQR 2-4) Endo-sponge(r) changes. Secondary anastomotic healing was achieved in all patients (n = 15) in the early surgical closure group compared with 52% (n = 16) in the conventional treatment group (P = 0.003). Closure of the anastomotic defect was achieved after a median of 48 (25-103) days in the early surgical closure group compared with 70 (IQR 49-175) days in the conventional treatment group (P = 0.013). A functional pouch was seen in 93% and 86% of the patients in each group. There was no significant difference in direct medical cost. CONCLUSION: Early surgical closure after a short period of Endo-sponge(r) treatment is highly effective in treating anastomotic leakage after IPAA without increasing cost. PMID- 25512244 TI - Differentiating climate- and human-induced drivers of grassland degradation in the Liao River Basin, China. AB - Quantitatively distinguishing grassland degradation due to climatic variations from that due to human activities is of great significance to effectively governing degraded grassland and realizing sustainable utilization. The objective of this study was to differentiate these two types of drivers in the Liao River Basin during 1999-2009 using the residual trend (RESTREND) method and to evaluate the applicability of the method in semiarid and semihumid regions. The relationship between the normalized difference vegetation index (NDVI) and each climatic factor was first determined. Then, the primary driver of grassland degradation was identified by calculating the change trend of the normalized residuals between the observed and the predicted NDVI assuming that climate change was the only driver. We found that the RESTREND method can be used to quantitatively and effectively differentiate climate and human drivers of grassland degradation. We also found that the grassland degradation in the Liao River Basin was driven by both natural processes and human activities. The driving factors of grassland degradation varied greatly across the study area, which included regions having different precipitation and altitude. The degradation in the Horqin Sandy Land, with lower altitude, was driven mainly by human activities, whereas that in the Kungl Prairie, with higher altitude and lower precipitation, was caused primarily by climate change. Therefore, the drivers of degradation and local conditions should be considered in an appropriate strategy for grassland management to promote the sustainability of grasslands in the Liao River Basin. PMID- 25512242 TI - The role of thyroid and parathyroid metabolism disorders in the etiology of sudden onset dizziness. AB - BACKGROUND: The aim of this study was to evaluate thyroid and parathyroid functions as a cause of sudden onset dizziness (SOD) in patients who were admitted to the Emergency Department (ED). MATERIAL AND METHODS: This study was conducted prospectively in 100 patients with sudden onset dizziness (SOD) admitted to the ED. Neurologic, ear-nose-throat, detailed neck examinations, serum calcium levels, thyroid function tests (TFT), and parathormone and thyroid ultrasounds were performed on all patients in our study. RESULTS: Thirty-seven (37%) females and 63 (63%) males were included in this study. Four patients (4%) had elevated serum TSH levels, 6 (6%) had decreased serum fT3 levels, 10 (10%) had decreased serum fT4 levels, 2 (2%) had elevated serum fT4 levels, and 2 (2%) had elevated serum parathormone levels. In 4 (4%) patients, the serum calcium levels were lower than normal, and 2 (50%) of these patients had symptomatic hypocalcemia. Thyroid ultrasound examinations showed multinodular goiter in 28 (28%) patients, 2 (2%) patients had thyroiditis, 12 (12%) had an isolated unilateral nodule, and 58 (58%) had normal thyroid tissues. CONCLUSIONS: We suggest that detailed neck examination, TFT, and thyroid ultrasound examination should be considered in the diagnostic algorithms of SOD to provide rapid diagnosis and proper treatment for a patient in the ED. PMID- 25512245 TI - Variation of arsenic concentration on surfaces of in-service CCA-treated wood planks in a park and its influencing field factors. AB - Wood preservatives can protect wood from dry rot, fungi, mould and insect damage, and chromated copper arsenate (CCA) has been used as an inorganic preservative for many years. However, wood treated with CCA has been restricted from residential uses in the EU from June 30, 2004, due to its potential toxicity. Such a regulation is not in place in China yet, and CCA-treated wood is widely used in public parks. A portable XRF analyser was used to investigate arsenic (As) concentration on surfaces of in-service CCA-treated wood planks in a popular park as well as the influencing field factors of age in-service, immersion and human footfall. With a total of 1207 readings, the observed As concentrations varied from below the detection limit (<10 mg/kg) to 15,746 mg/kg with a median of 1160 mg/kg. Strong variation of As concentrations were observed in different wood planks of the same age, on the surface of the same piece of wood, inside the same piece of wood, and different surfaces of walkway planks, hand rails and poles in the field. The oldest planks exhibited high As concentrations, which was related to its original treatment with high retention of CCA preservative. The effect of immersion in the field for about 4 months was insignificant for As concentration on the surfaces. However, a significant reduction of As was observed for immersion combined with human footfall (wiping by shoes). Human traffic in general caused slightly reduced and more evenly distributed As concentrations on the wood surfaces. The strong variation, slow aging and relatively weak immersion effects found in this study demonstrate that the in service CCA-treated wood poses potential health risks to the park users, due to easy dermal contact especially when the wood is wet after rainfall. It is suggested that further comprehensive investigations and risk assessments of CCA treated wood in residential areas in China are needed, and precautionary measures should be considered to reduce the potential risks to residents and visitors, especially children. PMID- 25512246 TI - Effects of ouabain on respiratory rhythm generation in brainstem-spinal cord preparation from newborn rats and in decerebrate and arterially perfused in situ preparation from juvenile rats. AB - The significance of Na/K-ATPase on respiratory rhythm generation is not well understood. We investigated the effects of the Na/K-ATPase blocker, ouabain, on respiratory rhythm. Experiments were performed with brainstem-spinal cord preparation from 0 to 3-day-old Wistar rats and with decerebrate and arterially perfused in situ preparation from juvenile rats (postnatal day 11-13). Newborn rat preparations were superfused at a rate of 3.0 ml/min with artificial cerebrospinal fluid, equilibrated with 95% O2 and 5% CO2, pH 7.4, at 26-27 degrees C. Inspiratory activity was monitored from the fourth cervical ventral root (C4). Application of ouabain (15-20 min) resulted in a dose-dependent increase in the burst rate of C4 inspiratory activity. After washout, the burst rate further increased to reach quasi-maximum values under each condition (e.g. 183% of control in 1 MUM, 253% in 10 MUM, and 303% in 20 MUM at 30 min washout). Inspiratory or pre-inspiratory neurons in the rostral ventrolateral medulla were depolarized. We obtained similar results (i.e. increased phrenic burst rate) in an in situ perfused preparation of juvenile rats. Genes encoding the Na/K-ATPase alpha subunit were expressed in the region of the parafacial respiratory group (pFRG) in neonatal rats, suggesting that cells (neurons and/or glias) in the pFRG were one of the targets of ouabain. We concluded that Na/K-ATPase activity could be an important factor in respiratory rhythm modulation. PMID- 25512247 TI - Brooding rumination and cardiovascular reactivity to a laboratory-based interpersonal stressor. AB - There is a well-known link between stress and depression, but diathesis-stress models suggest that not all individuals are equally susceptible to stress. The current study examined if brooding rumination, a known risk factor for depression, influences cardiovascular reactivity to a laboratory-based interpersonal stressor. Sixty-five women watched a baseline video and were exposed to an interpersonal stressor while high frequency heart rate variability (HRV) was collected. We found that women who endorsed higher levels of brooding rumination exhibited greater HRV withdrawal from baseline to stressor, an effect that was maintained when we controlled for levels of depression. This physiological vulnerability, when combined with high levels of stress, may be one mechanism underlying how brooding rumination increases depression risk. PMID- 25512248 TI - Stimuli-responsive lipidic cubic phase: triggered release and sequestration of guest molecules. AB - New stimuli-responsive nanomaterials, made up of host-guest lipidic cubic phases (LCPs) are presented. These biocompatible, stable, transparent and water insoluble LCPs are composed of monoolein (MO) as a neutral host, and small amounts of one of three judiciously designed and synthesized designer lipids as guest that preserve the structure and stability of LCPs, but render them specific functionalities. Efficient pH- and light-induced binding, release and sequestration of hydrophilic dyes are demonstrated. Significantly, these processes can be performed sequentially, thereby achieving both temporal and dosage control, opening up the possibility of using such LCPs as effective carriers to be used in drug delivery applications. Specifically, because of the inherent optical transparency and molecular isotropy of LCPs they can be envisaged as light-induced drug carriers in ophthalmology. The results presented here demonstrate the potential of molecular design in creating new functional materials with predicted operating mode. PMID- 25512249 TI - Genome-wide and molecular evolution analysis of the subtilase gene family in Vitis vinifera. AB - BACKGROUND: Vitis vinifera (grape) is one of the most economically significant fruit crops in the world. The availability of the recently released grape genome sequence offers an opportunity to identify and analyze some important gene families in this species. Subtilases are a group of subtilisin-like serine proteases that are involved in many biological processes in plants. However, no comprehensive study incorporating phylogeny, chromosomal location and gene duplication, gene organization, functional divergence, selective pressure and expression profiling has been reported so far for the grape. RESULTS: In the present study, a comprehensive analysis of the subtilase gene family in V. vinifera was performed. Eighty subtilase genes were identified. Phylogenetic analyses indicated that these subtilase genes comprised eight groups. The gene organization is considerably conserved among the groups. Distribution of the subtilase genes is non-random across the chromosomes. A high proportion of these genes are preferentially clustered, indicating that tandem duplications may have contributed significantly to the expansion of the subtilase gene family. Analyses of divergence and adaptive evolution show that while purifying selection may have been the main force driving the evolution of grape subtilases, some of the critical sites responsible for the divergence may have been under positive selection. Further analyses of real-time PCR data suggested that many subtilase genes might be important in the stress response and functional development of plants. CONCLUSIONS: Tandem duplications as well as purifying and positive selections have contributed to the functional divergence of subtilase genes in V. vinifera. The data may contribute to a better understanding of the grape subtilase gene family. PMID- 25512253 TI - Widom line and dynamical crossovers as routes to understand supercritical water. AB - Supercritical water is fundamental in many fields of applications and a precise characterization of the supercritical state is of uttermost importance for this liquid. In a fluid, when moving from the critical point into the single-phase region, the thermodynamic response functions show maxima reminiscent of the critical divergence. Here we study the thermodynamic properties of water in the supercritical region by analysing both available experimental data and our computer simulation results. We find that the lines connecting the maxima of the response functions converge on approaching the critical point in a single line, the Widom line. We further show that the Widom line coincides with a crossover from a liquid-like to a gas-like behaviour clearly visible in the transport properties. These thermodynamic and dynamic features show that the supercritical state in water is far more complex than what was so far believed, indicating a new perspective in the characterization of the thermodynamics of this state. PMID- 25512250 TI - Comparative genomic profiling of synovium versus skin lesions in psoriatic arthritis. AB - OBJECTIVE: To our knowledge, there is no broad genomic analysis comparing skin and synovium in psoriatic arthritis (PsA). Also, there is little understanding of the relative levels of cytokines and chemokines in skin and synovium. The purpose of this study was to better define inflammatory pathways in paired lesional skin and affected synovial tissue in patients with PsA. METHODS: We conducted a comprehensive analysis of cytokine and chemokine activation and genes representative of the inflammatory processes in PsA. Paired PsA synovial tissue and skin samples were obtained from 12 patients on the same day. Gene expression studies were performed using Affymetrix HGU133 Plus 2.0 arrays. Confirmatory quantitative real-time polymerase chain reaction (PCR) was performed on selected transcripts. Cell populations were assessed by immunohistochemistry and immunofluorescence. RESULTS: Globally, gene expression in PsA synovium was more closely related to gene expression in PsA skin than to gene expression in synovium in other forms of arthritis. However, PsA gene expression patterns in skin and synovium were clearly distinct, showing a stronger interleukin-17 (IL 17) gene signature in skin than in synovium and more equivalent tumor necrosis factor (TNF) and interferon-gamma gene signatures in both tissues. These results were confirmed with real-time PCR. CONCLUSION: This is the first comprehensive molecular comparison of paired lesional skin and affected synovial tissue samples in PsA. Our results support clinical trial data showing that PsA skin and joint disease are similarly responsive to TNF antagonists, while IL-17 antagonists have better results in PsA skin than in PsA joints. Genes selectively expressed in PsA synovium might direct future therapies for PsA. PMID- 25512255 TI - Pediatric spinal trauma. AB - Pediatric spinal trauma is unique. The developing pediatric spinal column and spinal cord deal with direct impact and indirect acceleration/deceleration or shear forces very different compared to adult patients. In addition children are exposed to different kind of traumas. Moreover, each age group has its unique patterns of injury. Familiarity with the normal developing spinal anatomy and kind of traumas is essential to correctly diagnose injury. Various imaging modalities can be used. Ultrasound is limited to the neonatal time period; plain radiography and computer tomography are typically used in the acute work-up and give highly detailed information about the osseous lesions. Magnetic resonance imaging is more sensitive for disco-ligamentous and spinal cord injuries. Depending on the clinical presentation and timing of trauma the various imaging modalities will be employed. In the current review article, a summary of the epidemiology and distribution of posttraumatic lesions is discussed in the context of the normal anatomical variations due to progressing development of the child. PMID- 25512254 TI - Decoding odor quality and intensity in the Drosophila brain. AB - To internally reflect the sensory environment, animals create neural maps encoding the external stimulus space. From that primary neural code relevant information has to be extracted for accurate navigation. We analyzed how different odor features such as hedonic valence and intensity are functionally integrated in the lateral horn (LH) of the vinegar fly, Drosophila melanogaster. We characterized an olfactory-processing pathway, comprised of inhibitory projection neurons (iPNs) that target the LH exclusively, at morphological, functional and behavioral levels. We demonstrate that iPNs are subdivided into two morphological groups encoding positive hedonic valence or intensity information and conveying these features into separate domains in the LH. Silencing iPNs severely diminished flies' attraction behavior. Moreover, functional imaging disclosed a LH region tuned to repulsive odors comprised exclusively of third-order neurons. We provide evidence for a feature-based map in the LH, and elucidate its role as the center for integrating behaviorally relevant olfactory information. PMID- 25512256 TI - "Optimized" delivery of intracoronary supersaturated oxygen in acute anterior myocardial infarction: a feasibility and safety study. AB - OBJECTIVES: We sought to evaluate the feasibility and safety of catheter-based supersaturated oxygen (SSO2 ) delivery via the left main coronary artery (LMCA) following primary percutaneous coronary intervention (PCI). BACKGROUND: In the multicenter, randomized AMIHOT-II trial, SSO2 delivered into the proximal or mid left anterior descending (LAD) artery via an indwelling intracoronary infusion catheter in patients with acute anterior ST-segment elevation myocardial infarction (STEMI) following primary PCI significantly reduced infarct size but resulted in a numerically higher incidence of safety events. METHODS: Patients with acute anterior STEMI presenting within 6 hr of symptom onset were enrolled at three centers. Following successful LAD stenting, SSO2 was infused into the LMCA via a diagnostic catheter for 60 min. The primary safety endpoint was the 30 day rate of target vessel failure (composite of death, reinfarction, or target vessel revascularization). Cardiac magnetic resonance imaging (cMRI) was performed at 3-5 and 30 days to assess infarct size. RESULTS: Twenty patients with acute anterior STEMI were enrolled. The infarct lesion was located in the proximal LAD in 7 cases (35%) and the mid LAD in 13 cases (65%). Following primary PCI, SSO2 was delivered successfully in all cases. Target vessel failure within 30 days occurred in 1 patient (5%). Median [interquartile range] infarct size was 13.7% [5.4-20.6%] at 3-5 days and 9.6% [2.1-14.5%] at 30 days. CONCLUSIONS: Following primary PCI in acute anterior STEMI, infusion of SSO2 via the LMCA is feasible, and is associated with a favorable early safety and efficacy profile. PMID- 25512257 TI - SLC6A2 variants may predict remission from major depression after venlafaxine treatment in Han Chinese population. AB - OBJECTIVE: Venlafaxine, an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) type, is used to treat patients with major depressive disorder (MDD). Much evidence suggests that genetic polymorphisms may modulate serotonergic and noradrenergic function, thereby affecting the treatment efficacy of venlafaxine. The aim of this study was to examine whether polymorphisms in the norepinephrine transporter gene (SLC6A2) associate with remission after venlafaxine treatment for MDD. METHOD: An 8-week naturalistic treatment study with venlafaxine was carried out in 243 Han Chinese patients with MDD. The patients were screened for seven single-nucleotide polymorphisms of the SLC6A2 gene. Of the enrolled patients, 161 completed the 8-week treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was used to assess the improvement of depressive symptoms in each subject from baseline to the endpoint. For better presentation of time-course change of remission status, a Cox regression analysis for remission incidence during the 8-week treatment was conducted. RESULTS: Between remitters and non-remitters, significant differences in genotype frequencies were observed in five of the investigated SLC6A2 variants (rs28386840, rs1532701, rs40434, rs13333066, rs187714). GCG haplotype (rs40434 - rs13333066 - rs187714) in the SLC6A2 gene showed a association with non remission. A Cox regression analysis for remission incidence during the 8-week treatment course significantly depends on SLC6A2 variants (rs28386840, rs40434, and rs187714). CONCLUSION: Our results suggest that the variation of the SLC6A2 gene is associated with treatment remission after venlafaxine in patients with MDD. PMID- 25512259 TI - Malignant paraganglioma of the bladder: a case report and review of the literature. AB - Although paragangliomas of the bladder are uncommon, malignant paragangliomas of this anatomic site are exceedingly rare, with a mere 37 previously reported cases. We report the case of a 58-year-old man with a malignant paraganglioma of the bladder who sought care secondary to gross hematuria; however, misdiagnosis of this tumor resulted in hypertensive crisis during cystoprostatectomy. Not only does this case present a unique malignant paraganglioma of the bladder, but also it discusses the clinical ramifications when misdiagnosed. Like pheochromocytomas, extra-adrenal paragangliomas can manifest with similar sympathetic stimulation; this becomes a serious complication for clinicians resecting these tumors in unusual locations without proper histologic diagnosis. Additionally, we discuss the unique clinical and pathologic findings of our patient and comprehensively review the previously published cases comparing clinical and pathologic features. Several interesting findings are identified including average age at diagnosis, gender predilection, presenting symptoms, size at diagnosis, and common sites of metastasis. PMID- 25512258 TI - Autophagy is related to the hedgehog signaling pathway in human gastric adenocarcinoma: prognostic significance of Beclin-1 and Gli2 expression in human gastric adenocarcinoma. AB - Beclin-1 induces autophagy, which is known to be involved in many physiopathological processes such as cell development, aging, stress response, immune response and cancer. Several studies showed that Beclin-1 expression is associated with several prognostic factors of gastric carcinomas. Recently, the connection between autophagy and the hedgehog (HH) signaling pathway has been studied. Here, we investigated the relationship between the autophagy and hedgehog (HH) signaling pathways in gastric adenocarcinoma. We evaluated Beclin-1 and Gli2 expression in 108 gastric adenocarcinoma tissues via immunohistochemical analysis, using a tissue microarray, in relation to survival and other prognostic factors. Our results show that increased Beclin-1 expression is correlated with favorable clinicopathological variables including histologic grade, tumor size, primary tumor (T) stage, lymph node metastasis, lymphatic invasion, neural invasion, and tumor recurrence. Furthermore, increased Gli-2 expression was correlated with several favorable clinicopathological variables including primary tumor (T) stage, lymphatic invasion, and tumor recurrence. Increased Beclin-1 expression was significantly correlated with increased Gli2. Univariate analyses for disease-free survival and overall survival revealed that the higher Beclin-1 and Gli2 expression group had a more favorable prognosis compared with the lower Beclin-1 and Gli2 expression group. Our results suggest that progressively increased Beclin-1 and Gli2 expression contributes to the inhibition of tumor growth and metastasis in gastric adenocarcinoma and Beclin-1 acts as a tumor suppressor by regulating the HH signaling pathway through Gli2 expression in gastric adenocarcinoma. PMID- 25512260 TI - Follicular dendritic cell sarcoma of the tonsil. AB - Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm that occurs extranodally and nodally. The following case report describes a 24-year-old male patient who suffered from FDCS of the tonsil. He presented at the ENT Department of the University Hospital Magdeburg with throat pain that had lasted for 3 months. There were neither B symptoms nor abnormal fatigue. An extended tonsillectomy was performed. The morphological and immunohistochemical findings confirmed the diagnosis of FDCS. FDCS should be considered as an important differential diagnosis in spindle cell tumors of the tonsil. PMID- 25512261 TI - Electrochemical and mARC-catalyzed enzymatic reduction of para-substituted benzamidoximes: consequences for the prodrug concept "amidoximes instead of amidines". AB - The mitochondrial amidoxime reducing component (mARC) activates amidoxime prodrugs by reduction to the corresponding amidine drugs. This study analyzes relationships between the chemical structure of the prodrug and its metabolic activation and compares its enzyme-mediated vs. electrochemical reduction. The enzyme kinetic parameters KM and Vmax for the N-reduction of ten para-substituted derivatives of the model compound benzamidoxime were determined by incubation with recombinant proteins and subcellular fractions from pig liver followed by quantification of the metabolites by HPLC. A clear influence of the substituents at position 4 on the chemical properties of the amidoxime function was confirmed by correlation analyses of (1) H NMR chemical shifts and the redox potentials of the 4-substituted benzamidoximes with Hammett's sigma. However, no clear relationship between the kinetic parameters for the enzymatic reduction and Hammett's sigma or the lipophilicity could be found. It is thus concluded that these properties as well as the redox potential of the amidoxime can be largely ignored during the development of new amidoxime prodrugs, at least regarding prodrug activation. PMID- 25512262 TI - The diffusion of minimally invasive radical prostatectomy in the United States: a case study of the introduction of new surgical devices. AB - BACKGROUND: The diffusion of minimally invasive radical prostatectomy (MIRP) in the United States may have led to adverse patient outcomes due to rapid surgeon adoption and collective inexperience. We hypothesized that throughout the early period of minimally invasive surgery, MIRP patients had inferior outcomes as compared with those who had open radical prostatectomy (ORP). METHODS: We used the Surveillance, Epidemiology and End RESULTS-Medicare dataset and identified men who had ORP and MIRP for prostate cancer from 2003-2009. Study endpoints were receipt of subsequent cancer treatment, and evidence of postoperative voiding dysfunction, erectile dysfunction (ED) and bladder outlet obstruction. We used proportional hazards regression to estimate the impact of surgical approach on each endpoint, and included an interaction term to test for modification of the effect of surgical approach by year of surgery. RESULTS: ORP (n=5362) and MIRP (n=1852) patients differed in their clinical and demographic characteristics. Controlling for patient characteristics and surgeon volume, there was no difference in subsequent cancer treatments (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76-1.05), although MIRP was associated with a higher risk of voiding dysfunction (HR 1.31, 95% CI 1.20-1.43) and ED (HR 1.43, 95% CI 1.31-1.56), but a lower risk of bladder outlet obstruction (HR 0.86, 95% CI 0.75 0.97). There was no interaction between approach and year for any outcome. When stratifying the analysis by year, MIRP consistently had higher rates of ED and voiding dysfunction with no substantial improvement over time. CONCLUSIONS: MIRP patients had adverse urinary and sexual outcomes throughout the diffusion of minimally invasive surgery. This may have been a result of the rapid adoption of robotic surgery with inadequate surgeon preparedness. PMID- 25512263 TI - The regulation of methyl jasmonate on hyphal branching and GA biosynthesis in Ganoderma lucidum partly via ROS generated by NADPH oxidase. AB - Ganoderma lucidum is one of the best known medicinal basidiomycetes because it produces many pharmacologically active compounds, and methyl jasmonate (MeJA) was previously reported to induce the biosynthesis of ganoderic acids (GA) in G. lucidum. In this study, we found that MeJA not only increased the amount of GA but also increased the distance between hyphal branches by approximately 1.2 fold. Further analysis showed that MeJA could increase the intracellular ROS (reactive oxygen species) content by approximately 2.2-2.7-fold. Furthermore, the hyphal branching and GA biosynthesis regulated by MeJA treatment could be abolished by ROS scavengers to a level similar to or lower than that of the control group. These results indicated that the regulation of hyphal branching and GA biosynthesis by MeJA might occur via a ROS signaling pathway. Further analysis revealed that NADPH oxidase (NOX) plays an important role in MeJA regulated ROS generation. Importantly, our results highlight that NOX functions in signaling cross-talk between ROS and MeJA. In addition, these findings provide an excellent opportunity to identify potential pathways linking ROS networks to MeJA signaling in fungi and suggest that plants and fungi share a conserved signaling-crosstalk mechanism. PMID- 25512265 TI - Marine natural products that interfere with multiple cytoskeletal protein interactions. AB - Various marine natural products that target cytoskeletal proteins have been discovered. A few of these compounds have recently been shown to induce or inhibit protein-protein interactions. Lobophorolide, an actin filament-disrupting macrolide, binds to actin with a unique 2 : 2 stoichiometry in which two lobophorolide molecules cooperate to stabilize an actin dimer. Adociasulfates, merotriterpenoid derivatives, inhibit microtubule-stimulated ATPase activity of a motor protein kinesin by blocking both the binding of microtubules and the processive motion of kinesin along microtubules. The antitumor macrolide aplyronine A synergistically binds to tubulin in association with actin, and prevents spindle formation and mitosis. In this highlight, we address recent chemical biology studies on these mechanistically-attractive marine natural products. These findings may be useful for the design and development of new pharmacological tools and therapeutic agents. PMID- 25512266 TI - Real-time tracking, retrieval and gene expression analysis of migrating human T cells. AB - Dynamical analysis of single-cells allows assessment of the extent and role of cell-to-cell variability, however traditional dish-and-pipette techniques have hindered single-cell analysis in quantitative biology. We developed an automated microfluidic cell culture system that generates stable diffusion-based chemokine gradients, where cells can be placed in predetermined positions, monitored via single-cell time-lapse microscopy, and subsequently be retrieved based on their migration speed and directionality for further off-chip gene expression analysis, constituting a powerful platform for multiparameter quantitative studies of single-cell chemotaxis. Using this system we studied CXCL12-directed migration of individual human primary T cells. Spatiotemporally deterministic retrieval of T cell subsets in relation to their migration speed, and subsequent analysis with microfluidic droplet digital-PCR showed that the expression level of CXCR4 - the receptor of CXCL12 - underlies enhanced human T cell chemotaxis. PMID- 25512267 TI - Functional Status and Search for Meaning After Percutaneous Coronary Intervention. AB - The purpose of this study was to determine the differences in the search for meaning and functional status (psychological and physical) between persons who undergo percutaneous coronary intervention and have recurrent angina symptoms and those who do not have recurrent symptoms. Participants (224; 147 male, 77 female) who underwent PCI completed the following study materials: Meaning in Heart Disease instrument, Hospital Anxiety and Depression Scale, and SF36v2TM. Persons with recurrent angina symptoms (40% of the sample) were more likely to have higher disrupted meaning, greater anxiety, greater depression, lower physical functioning, and greater use of meaning-based coping (searching for answers and refocusing global meaning) compared with individuals without recurrent symptoms. Interventions are needed to identify the risk of recurrent symptoms after percutaneous coronary intervention and provide coping and cognitive behavioral interventions focused on managing the psychological and physical disruptions. PMID- 25512268 TI - [Myocardial protection of remote ischemic postconditioning during primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction]. AB - OBJECTIVE: To evaluate the cardioprotection of remote ischemic postconditioning (RIPostC) in patients with acute ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI). METHODS: Forty-six STEMI patients undergoing primary PCI at Peking University Third Hospital from January to April 2014 were randomized to RIPostC group (n=23) and control group (n=23).The RIPostC protocol was started within 1 min after reflow by thrombus aspiration or balloon inflation and consisted of 3 cycles of 5 min/5 min ischemia/reperfusion by cuff inflation/deflation of the lower left limb. The enzymatic infarct size, rate of complete ST segment resolution, corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) in infarct related artery (IRA) and plasma levels of malondialdehyde(MDA), endothelin-1(ET 1), tumor necrosis factor alpha (TNFalpha) of the two groups were compared. RESULTS: There was no significant difference in enzymatic infarct size between the two groups (P>0.05). The rate of complete ST-segment resolution was significantly higher in RIPostC group than in control group (60.9%vs. 30.4%,P=0.04). There was a trend toward lower CTFC in RIPostC group than that in control group, but the difference was not statistically significant(28 +/- 11 vs. 33 +/- 11, P = 0.10). However, in the subgroup of anterior wall myocardial infarction CTFC in RIPostC group was significantly lower, compared with control group (25+/-9 vs. 39+/-10, P=0.01).There were lower plasma levels of MDA,ET 1,TNFalpha in RIPostC group than in control group at different time points after primary PCI (P<0.05). CONCLUSION: In STEMI patients undergoing primary PCI, RIPostC may improve myocardial perfusion and attenuate ischemia reperfusion injury with the underlying mechanisms involving reduction of oxidative stress, protection of endothelial function and inhibition of inflammatory response. PMID- 25512264 TI - Heart rate variability and DNA methylation levels are altered after short-term metal fume exposure among occupational welders: a repeated-measures panel study. AB - BACKGROUND: In occupational settings, boilermakers are exposed to high levels of metallic fine particulate matter (PM2.5) generated during the welding process. The effect of welding PM2.5 on heart rate variability (HRV) has been described, but the relationship between PM2.5, DNA methylation, and HRV is not known. METHODS: In this repeated-measures panel study, we recorded resting HRV and measured DNA methylation levels in transposable elements Alu and long interspersed nuclear element-1 (LINE-1) in peripheral blood leukocytes under ambient conditions (pre-shift) and right after a welding task (post-shift) among 66 welders. We also monitored personal PM2.5 level in the ambient environment and during the welding procedure. RESULTS: The concentration of welding PM2.5 was significantly higher than background levels in the union hall (0.43 mg/m3 vs. 0.11 mg/m3, p < 0.0001). The natural log of transformed power in the high frequency range (ln HF) had a significantly negative association with PM2.5 exposure (beta = -0.76, p = 0.035). pNN10 and pNN20 also had a negative association with PM2.5 exposure (beta = -0.16%, p = 0.006 and beta = -0.13%, p = 0.030, respectively). PM2.5 was positively associated with LINE-1 methylation [beta = 0.79%, 5-methylcytosince (%mC), p = 0.013]; adjusted for covariates. LINE 1 methylation did not show an independent association with HRV. CONCLUSIONS: Acute decline of HRV was observed following exposure to welding PM2.5 and evidence for an epigenetic response of transposable elements to short-term exposure to high-level metal-rich particulates was reported. PMID- 25512269 TI - [Comparison of angiography-guided and fractional flow reserve-guided management strategy of percutaneous coronary intervention for intermediate coronary lesions]. AB - OBJECTIVE: To compare the consistency of angiography-guided and fractional flow reserve (FFR)-guided management strategy for intermediate coronary lesions. METHODS: The patients whose coronary intermediate lesions were assessed by measuring FFR from November 2012 to August 2014. The stenosis percentage and value of FFR during the procedure were collected. All the image data were collected and four experienced interventional cardiologists were invited to assess the target lesions and make a management strategy independently. The consistency of angiography-guided and fractional flow reserve-guided management strategy were analyzed. RESULTS: In the study, 151 patients were included, of whom, 70.2% were male, the average age was (62.7+/-9.6) years, 169 vessels were assessed by measuring FFR, 1 being left main, 116 left anterior descending, 27 left circumflex branch, and 25 right coronary artery. There were some correlationship between the stenosis percentage judged by four interventional cardiologists and the stenosis percentage judged during the procedure (r=0.29 0.38, P<0.001), but the difference was significant. When 0.80 was used as FFR threshold value, the consistency rates of angiography-guided management strategy decision made by the four cardiologists with fractional flow reserve-guided management strategy were 72.78%, 71.60%, 75.15%, and 72.78%, respectively. CONCLUSION: Angiography-guided management strategy decision is unreliable, FFR is recommended for management strategy decision for intermediate coronary lesions. PMID- 25512270 TI - [Correlation between epicardial adipose tissue and coronary flow reserve in coronary heart disease patients with no chest pain]. AB - OBJECTIVE: To assess whether epicardial adipose tissue (EAT) thickness is associated with coronary flow reserve (CFR) and could be used to detect coronary microvascular dysfunction. METHODS: We enrolled 62 nondiabetic patients who underwent computed tomography angiography or invasive coronary angiography and had no obstructive coronary artery disease. CFR and EAT thickness were measured by transthoracic Doppler echocardiography (TTDE). RESULTS: In the study, a total of 62 patients were enrolled, echocardiographic coronary flow reserve were obtained in 61 of the patients with a mean age of (59+/-10) years. 34 patients (56%) had reduced CFR (CFR<3, 2.52+/-0.32) suggesting microvascular dysfunction and 27 patients (44%) had normal CFR (CFR>=3, 3.56+/-0.52). EAT thickness was significantly increased in the patients with microvascular dysfunction as compared with those without [(3.4+/-0.8) mm vs. (2.3+/-0.6) mm, P<0.001]. EAT thickness was strongly related to CFR (r=-0.668, P<0.001). By Logistic regression analysis, EAT thickness was the independent predictor of coronary microvascular dysfunction (OR=7.78, 95%CI: 2.44-24.79). EAT thickness>2.9 mm had 82.4% sensitivity and 92.3% specificity to detect CFR<3 (area under ROC curve 0.860, P<0.001). CONCLUSION: EAT thickness was significantly increased in patients with coronary microvascular dysfunction. EAT thickness was independently associated with impaired CFR. EAT>2.9 mm had high sensitivity and specificity to detect coronary microvascular dysfunction. PMID- 25512271 TI - [Correlation between body composition and exercise capacity in patients with coronary heart disease]. AB - OBJECTIVE: To provide the evidence for more accurately assessing the patient's body composition, predicting exercise capacity and guiding rehabilitation exercise by analyzing the body compositions in patients with coronary heart disease, and to study the correlation between body compositions and exercise capacity. METHODS: The study enrolled 663 patients with coronary heart disease in NYHA I-II stages, who underwent coronary intervention therapy between December 2013 and August 2014. Between 15th and 20th days of the onset, cardiopulmonary exercising testing (CPET, Bruce Protocol) was conducted, and the body composition was measured with the Inboby720 body composition analyzer before CPET. RESULTS: All the patients completed the body composition evaluation and the CPET. According to the three indicators of body mass index (BMI), percentage of body fat (PBF), waist-hip ratio (WHR), the diagnostic rate of obesity was 22.8%, 63.3%, and 72.7%, respectively. There was a good negative correlation between PBF and exercise capacity (r=-0.306, P<0.001). Compared with non-obesity patients, the exercise capacity of obesity group decreased according to PBF (P<0.01). The patients were divided into low, moderate and high exercise capacity groups according to METs, and the difference was only the PBF among the three groups (P<0.05). CONCLUSION: PBF, measured by body composition, is a more accurate diagnosis of obesity and has a good negative correlation with exercise capacity, which can be used as an important indicator to predict the exercise capacity in patients with coronary heart disease and guide the rehabilitation exercise. PMID- 25512272 TI - [Status analysis of patients with hypertension in 22 community health centers of Shenzhen Futian District]. AB - OBJECTIVE: To investigate current situation of blood pressure control in patients with hypertension in 22 community health centers of Shenzhen Futian District, and to find out related factors which affect blood pressure control. METHODS: In the study, 10 020 cases with essential hypertension that had been registered in 22 Community Health Centers were selected as cases for the survey. The questionnaires, physical examinations, and laboratory tests were used to obtain the patients' baseline data. RESULTS: The mean blood pressure (median) levels were 142/86 mmHg (1 mmHg=0.133 kPa). Those of the males were higher than those of the females (142/86 mmHg vs. 140/85 mmHg, ZSBP=-6.14,ZDBP=-9.93,P<0.001), the systolic blood pressure increased with age. The overall blood pressure control rate was 40.2%. The blood control rates were different with different gender, body mass index (BMI) and waist circumference. The majority of the patients took single antihypertensive drug, and the proportion accounted to 54.4%. Regression analysis showed that gender, age, hyperlipidemia, smoking, and waist circumference were the main factors that affected blood pressure control. CONCLUSION: The blood control rate was low in these communities. Patients with high blood pressure often merge a variety of factors that affect blood pressure control, and at the same time of antihypertensive therapy for the patients, we should pay attention to the control of these factors. PMID- 25512273 TI - [Effects of myocardial performance index on assessing left ventricular function in patients with primary hypertension]. AB - OBJECTIVE: To investigate the value of myocardial performance index (MPI) in assessing LV function in patients with primary hypertension (HP). METHODS: We studied 130 patients with HP (mean age 54.9+/-13.3 years)and 155 healthy control subjects (mean age 52.4+/-11.6 years). MPI was determined by tissue doppler imaging using the following formula: MPI=(isovolumic contraction time + isovolumic relaxation time)/ ejection time. The HP group was divided into hypertrophy subgroup( LVMI>=115 g/m(2) in males, or >=95 g/m(2) in females) and normal mass subgroup(LVMI <115 g/m(2) in males, or<95 g/m(2) in females). RESULTS: MPI was significantly different in control group, normal mass subgroup and hypertrophy subgroup(0.72+/-0.23 vs. 0.54+/- 0.17 vs. 0.45+/-0.11, P<0.001). Hypertrophy subgroup had significant higher MPI than normal mass subgroup(P =0.046), and both the groups had significant higher MPI than control group(all P<0.001). MPI was positively associated with age(r=0.369,P<0.001), Left ventricular end diastolic diameter(r=0.169, P<0.05), Sm(r=-0.211, P<0.001) and Em(r=-0.383, P<0.001) in control group. In multiple linear regression analysis, MPI was independently related to age (beta=0.492, t=7.222,P<0.001) in control group. Among the HP patients, MPI was positively associated with left atrial area (r=0.293, P<0.001),intra ventricular septum(IVS) diameter (r=0.453, P<0.001), LVMI (r=0.453, P<0.001), relative wall thickness(r=0.458, P<0.001), and negatively associated with Sm(r=-0.414, P<0.001), Em(r=-0.508, P<0.001), left ventricular ejection fraction (r=-0.305, P<0.001) in bivariate analysis. In the multiple linear regression analysis, MPI was independently related to Em (beta=0.401, t=4.256,P<0.001) and IVS diameter (beta=-0.365, t=-3.878,P<0.001) in the HP patients. CONCLUSION: The HP patients had elevated MPI, especially in the ones with LV hypertrophy. Tissue doppler imaging (TDI) derived MPI could be a useful index to evaluate the overall cardiac function in HP patients. PMID- 25512274 TI - [Targeted effect of microRNA on nerve growth factor pathway and its functional network in patients with unstable angina]. AB - OBJECTIVE: To study microRNA profile alteration in unstable angina (UA) patients and its functional network via nerve growth factor (NGF) signaling pathway. METHODS: Whole blood microRNAs were isolated from individuals with angiographically negative report (n=6) and UA patients (n=6), Taqman low-density microRNA array was performed to detect the microRNA profile, and SAM tool was conducted to calculate the differential expressed microRNA. Bioinformatic prediction tools (Targetsan, Miranda, Diana-microT) were used to obtain microRNA target genes. Targets'enriched pathways were analyzed by DAVID and biological function clusters were figured out by Panther database. The functional network of microRNAs by Cytoscape was costructed. RESULTS: In the study, 20 microRNAs were significantly upregulated in the UA group were observed. Their main target signaling pathways were NGF, their target genes' functional clusters were in signal transduction, cell proliferation and differentiation, cell cycles, immunity and inflammation, neurogenesis, neuronal activity and apoptosis. CONCLUSION: To upregulate microRNAs in UA patients is a major way to inhibit NGF signaling pathways, whose function is to suppress cell proliferation and differentiation, immunity and inflammation, neuronal growth, etc., and to stabilize the vulnerable atherosclerotic plaque. PMID- 25512275 TI - [Relationship between serum histamine levels and ST-segment resolution in patients with acute myocardial infarction treated with primary percutaneous coronary intervention]. AB - OBJECTIVE: To investigate the dynamic changes in serum histamine levels and their association with ST-segment resolution in patients with acute ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). METHODS: A total of 84 consecutive STEMI patients who received primary PCI were enrolled in this study. The dynamic changes in serum histamine levels were observed from before PCI to 1 week after PCI. Factors associated with ST-segment resolution were identified by multivariate regression analysis. RESULTS: The serum histamine levels of STEMI patients decreased during the first week after PCI. Multivariate regression analysis showed that the factors associated with ST-segment resolution 2 h after PCI were: the histamine level 2 h after PCI (r=-0.361, P=0.001), pain to balloon time, infarct related artery, and thrombolysis in myocardial infarction (TIMI) flow grade after PCI. CONCLUSION: The higher histamine level 2 h after PCI was independently associated with poor myocardial reperfusion in STEMI patients. PMID- 25512276 TI - [Long-term effect of different right ventricular apex pacing ratio on heart structure and function of patients with dual chamber pacemaker]. AB - OBJECTIVE: To evaluate Long-term effect of different right ventricular apex pacing ratio for heart structure and function of patients with dual chamber pacemakers. METHODS: Patients who were implanted with dual chamber pacemakers at Department of Cardiology, Peking University Third Hospital were collected. The electrodes were put in right ventricular apex. All the patients, last pacemaker programming control and echocardiography results were followed up and collected.Patients with 10%-40% pacing ratio were rejected. RESULTS: The total of 83 patients were enrolled in this study. The mean duration of the follow-up was (38+/-23) months. The morbility rates of moderate-severe mitral regurgitation (MR) and tricuspid regurgitation (TR) all significantly increased after implantation compared with those before implantation (6.2% vs. 2.6%, 11.1% vs. 4.9%, all P<0.01). There were 9 patients with moderate-severe TR after pacemaker implantation. They had higher pulmonary artery systolic pressure (PASP) and mitral diastolic early flow peak velocity/lateral mitral annulus diastolic early velocity (E/Em) [(49.6+/-10.5) mmHg vs. (33.8+/-12.0) mmHg, P<0.01, 1 mmHg=0.133 kPa; and 11+/-5 vs.9+/-3, P<0.05]. And 52 patients had less than 10% pacing ratio (group A) and 31 patients had more than 40% pacing ratio (group B). The right atrium area and right ventricular diastolic diameter were bigger after implantation than those before implantation in group B [(17.7+/-4.0) cm(2) vs. (15.6+/-3.2) cm(2), (21.5+/-4.4) mm vs. (19.9+/-3.4) mm, all P<0.05]. The morbility of pulmonary artery systolic pressure (PASP) >=50 mmHg was higher after implantation than that before implantation in group B (9.7% vs. 3.2%, P<0.05). The left atrium area and right atrium area were bigger in group B than those in group A [(21.8+/-5.5) cm(2) vs. (20.2+/-4.6) cm(2), (17.7+/-4.0) cm(2) vs. (16.1+/-3.8) cm(2), all the P<0.05] after implantation, and lower left ventricular ejection fraction (LVEF) in group B than that in group A (68%+/-6% vs. 70%+/-6%, P<0.05). CONCLUSION: Patients with higher right ventricular apex pacing ratio have bigger left atrium, right atrium and right ventricular, higher PASP and lower LVEF in the long term. PMID- 25512277 TI - [Effects of simvastatin nano-liposomes on osteogenic differentiation of bone marrow stromal cells]. AB - OBJECTIVE: To investigate the effects of liposomal formulation on simvastatin nano-liposomes (SMV-liposome) promoting the osteogenic differentiation of mice bone marrow stromal cells (BMSC) analyzed by the expressions of bone morphogenetic protein 2 (BMP-2) and alkaline phosphatase (ALP). METHODS: Primary BMDC were cultured in vitro using adherence and culture of whole bone marrow method. SMV dosage was set as control group and had two different dosages in this group on the basis of the concentration of SMV. 1 MUmol/L and 2 MUmol/L SMV concentration were represented by SMV low dosage group (S1) and SMV high dosage group (S2), respectively. Similarly, SMV-liposome dosage was set as experimental group including two different dosages, 1 MUmol/L SMV capsuled concentration as SMV-liposome low dosage group (SL1) and 2 MUmol/L SMV capsuled concentration as SMV-liposome high dosage group (SL2). Besides, groups with no drug intervention in the experiments were set as blank. BMSC were treated with different concentrations of SMV and SMV-liposome for 48 h, the activity of ALP was measured using p-nitropheny-phosate method, and ALP expression in the BMSC cells was stained by BCIP/NBT alkaline phosphatase color development kit (BCIP/NBT Kit). Furthermore, BMP-2 expression in the BMSC was determined by Western Blot. RESULTS: MTT assay showed, after incubated with different concentrations of SMV and SMV-liposome, the cell viabilities of BMSC were all above 85% and had no significant difference in the groups. Compared with the same dosage of SMV in these groups, control group and experimental group had significantly elevated the specific activity of ALP, the staining of BCIP/NBTKit as well as the protein expression of BMP-2. Besides, the data showed dose-dependent elevation in the control group and experimental group, namely the high dose group had better results than the low dose group. CONCLUSION: Nano-liposomal formulation significantly enhanced SMV effects on the osteogenetic differentiation of BMSC. PMID- 25512278 TI - [Activation of transcription factor NF-kappaB in a rat model of cardiac fibrosis induced by beta-adrenoceptor stimulation]. AB - OBJECTIVE: To establish a model of cardiac fibrosis induced by isoproterenol (ISO), the non-selective beta adrenoceptor agonist, injected subcutaneously for 7 days in rats, and to observe changes of transcription factor NF-kappaB in the model. METHODS: Male SD rats weighing 280-320 g were injected with ISO (0.25 mg/kg/d) subcutaneously for 7 days to induce cardiac fibrosis. The collagen volume fraction was determined by quantitative morphometry of picrosirius red stained left ventricular sections. Collagen types I/III and IL-6 mRNA expressions were analyzed by real time PCR. The pathological changes of the heart were investigated by Hematoxylin and Eosin staining. NF-kappaB was localized by immunohistochemistry (IHC) and phosphorylated NF-kappaB levels were assessed by Western blot analysis. RESULTS: Compared with the controls, ISO significantly elevated the sirius red stained area and collagen volume fraction (12.01+/-1.644 vs. 0.95+/-0.067, P<0.001). Similarly, ISO increased the mRNA expressions of collagen Iand collagen III of the heart compared with the controls (10.51+/-0.47 vs. 0.98+/-0.02,P<0.001 for collagen I; 9.58+/-1.33 vs. 1.02+/-0.02, P<0.001 for collagen III). The number of nuclei was increased and nuclear accumulation was presented in myocardial tissue induced by ISO. The mRNA expression of IL-6 increased in ISO group (1.64+/-0.18 vs. 1.04+/-0.07, P<0.01). ISO induced NF kappaB nuclear translocation, accompanied by an increase in phosphorylation of NF kappaB (10.83+/-2.05 vs. 1.05+/-0.27, P<0.001). CONCLUSION: We conclude that the model of cardiac fibrosis can be successfully induced by ISO injected subcutaneously for 7 days in rats and the activation of nuclear factor NF-kappaB increased by beta-adrenoceptor stimulation. PMID- 25512279 TI - [microRNA-126 delivered by microparticles mediates intercellular signal transmission]. AB - OBJECTIVE: To investigate the role of microRNAs (miRNAs) in mediating intercellular signaling. METHODS: Microparticles (MP) from HUVEC and 293T were isolated by sequential centrifugation. THP-1 was co-cultured with microparticles. And then the migration of THP-1 was measured by transwell. real-time PCR and Western blotting were used to study the related mechanisms. RESULTS: Compared with the microparticles from 293T, MP from HUVEC could promote the migration of monocytes (P<0.05) and upregulate the expression of CXCR4 mRNA and protein (P<0.05). MiRNA-126 deficient MP could downregulate the migration of monocytes (P<0.05) and the expression of CXCR4 mRNA and protein (P<0.05) compared with miRNA-126 abundant MP. CONCLUSION: Microparticles from HUVEC could promote the migration of monocytes. As carriers, microparticles could mediate intercellular signaling. PMID- 25512280 TI - [Decline of ATP-binding cassette transporter G1 expressions with a liver X receptor-independent pathway in patients with type 2 diabetes]. AB - OBJECTIVE: To examine the cholesterol efflux and the expressions of ATP-binding cassette transporter G1 (ABCG1) in macrophages of diabetic patients and the roles of liver-X receptor (LXR) in regulation of ABCG1 expressions. METHODS: Blood was collected from patients with type 2 diabetes mellitus and healthy controls. The peripheral blood monocytes were differentiated into macrophages with macrophage colony stimulating factor (M-CSF). The cells were radio labeled with [(3)H] cholesterol and were performed with cholesterol efflux assays. Quantitative real time PCR (qRT PCR) and Western blot were performed to measure the mRNA and protein expressions of ABCA1 and ABCG1. To test the effects of LXR on ABCG1 expressions, inhibition of LXRalpha and LXRbeta by siRNA were performed. The DNA protein complex of LXR and LXR element (LXRE) located in the promoter region of ABCG1 gene were detected with electrophery mobility supershift assay (EMSA). RESULTS: Macrophage ABCG1 expressions and high-density lipoprotein (HDL) induced cholesterol efflux were significantly reduced (19.0%+/-1.2% vs. 12.8%+/-3.6%, t=2.532, P=0.016) in the diabetic subjects whereas ABCA1 expressions and apolipoprotein A1 (ApoA1) induced cholesterol efflux were comparable (12.0%+/ 1.2% vs. 10.2%+/-2.3%, t=1.771, P=0.109) between the diabetic patients and healthy subjects. The mRNA expressions of LXRalpha and LXRbeta had no changes between the diabetes subjects and healthy controls (t=1.025, P=0.315; t=-0.531, P=0.600). The LXR-LXRE DNA-protein complex detected by EMSA were also similar between the diabetes subjects and healthy controls (t=1.483, P=0.164). Moreover, ABCG1 expressions were not altered by inhibition of LXRalpha/beta siRNA (t=2.143, P=0.061). CONCLUSION: Our data indicated that expression of ABCG1 and HDL induced cholesterol efflux were reduced in type 2 diabetic patients. However, the LXR mRNA expression and binding complex of LXR and ABCG1 promoter were not changed. The impairment of cholesterol efflux and ABCG1 gene expressions might be regulated via an LXR-independent pathway. PMID- 25512281 TI - [Establishment of a FVB/N mouse model of cardiac hypertrophy by isoprenaline]. AB - OBJECTIVE: To investigate the condition of isoprenaline (ISO)-induced cardiac hypertrophy in the FVB/N mouse. METHODS: ISO (30 mg/kg/d) was administered either by daily subcutaneous injection, or by continuous infusion via an implanted osmotic minipump. The mice in each mode of administration were randomly divided into two groups. For subcutaneous injection: the mice received ISO or saline through daily subcutaneous injection for 2 weeks. The mice for minipump: the mice received continuous infusion of ISO via an implanted osmotic minipump for 2 weeks, or received sham operation as the control to mimipump. The ratio of heart weight to tibia length (HW/TI), the diastolic left ventricular posterior wall thickness (dLVPW) were used to indicate cardiac hypertrophy. Interstitial fibrosis was examined with picrosirius red staining. RESULTS: ISO (30 mg/kg/d) administered by daily subcutaneous injection did not lead to cardiac hypertrophy or fibrosis in the FVB/N mice, and 50% of the mice died before the end point. The mice receiving ISO via minipumps showed significant increase in HW/TI [(10.60+/ 0.40 ) mg/mm vs. (7.93+/-0.19) mg/mm,P<0.001] and dLVPW [(0.87+/-0.03) mm vs. (0.68+/-0.06)mm,P=0.0116]. ISO administered via minipumps did not induce cardiac fibrosis. All the mice in this group survived to the end point. CONCLUSION: ISO (30 mg/kg/d) administered by continuous infusion via a minipump for 2 weeks can lead to significant cardiac hypertrophy. PMID- 25512282 TI - [Analysis of risk factors associated with weaning from mechanical ventilation in critical patients with major abdominal surgery]. AB - OBJECTIVE: To analyze the risk factors involved in the weaning from mechanical ventilation in critical patients who underwent major abdominal surgery. METHODS: This retrospective study was conducted at Department of Critical Care Medicine in Peking University People's Hospital. The subjects included all critical ill patients who underwent major abdominal surgery from January 2011 to December 2013. Clinical and laboratory parameters in perioperative period were investigated for the risk factors involved in the weaning from mechanical ventilation. RESULTS: In this study, 381 patients were included, of whom, 274 were successfully weaned. We found old age, lower left ventricular ejection fraction (LVEF) before surgery, with the complication of myocardial injury after noncardiac surgery (MINS) and lower serum albumin level after surgery were the independent risk factors of weaning from mechanical ventilation. And the days of intensive care unit and 28-day mortality of patients who successfully weaned were better than patients who failed to wean. CONCLUSION: Old age, lower LVEF before surgery, with the complication of MINS and lower serum albumin level after surgery were independent risk factors of weaning in critical patients who underwent major abdominal surgery. PMID- 25512283 TI - [Prognosis of embolization of internal iliac artery during the endovascular repair for abdominal aortic aneurysm]. AB - OBJECTIVE: To study the importance of the internal iliac artery (IIA) during the endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA). METHODS: Forty-six consecutive cases of AAA treated by EVAR were retrospectively analyzed. The complications after exclusion of the IIA were analyzed. RESULTS: The bilateral IIAs were reserved in 18 cases, in which the follow-up was achieved in 16 cases and no complication was observed. The IIAs were excluded in 28 (60.9%) cases, in which the bilateral, right and left IIAs were excluded in 7 (15.2%), 14 (30.4%) and 7 (15.2%) cases respectively. The follow-up was achieved in 26 cases. Buttock claudication was observed in 12 (46.2%) cases, altered bowel habit was observed in 8 (32.0%) cases, erectile dysfunction was observed in 3 (12.0%) cases, and bloody stool was observed in 2 (8.0%) cases. Comparing the bilateral and unilateral IIA exclusions, the rates of buttock claudication were 50.0% vs. 45.0%, altered bowel habit 33.3% vs. 31.6%, and erectile dysfunction 33.3% vs. 5.3% respectively. And the average duration of buttock claudication of bilateral IIAs exclusion (8.3 months) was longer than that of unilateral exclusion (4.7 months). Moreover, comparing the left and right IIA exclusions, the rates of buttock claudication were 57.1% vs. 38.5%, altered bowel habit 57.1% vs. 16.7%, and bloody stool 28.6% vs. 0 respectively. And the average duration of buttock claudication of left IIA exclusion (6.0 months) was longer than that of right exclusion (3.7 months). CONCLUSION: The IIAs, especially the left IIA, should be reserved during the EVAR for AAA. PMID- 25512284 TI - [Correlation between urinary sediment spectra and pathological patterns of renal biopsies]. AB - OBJECTIVE: To investigate the clinical value of urinary sediment analysis, a non invasive diagnostic means, in the evaluation of pathological patterns of renal diseases. METHODS: A total of 1 140 pairs of matched renal biopsies and fresh fasting morning urine specimens were collected from hospitalized patients in Peking University First Hospital. Their urinary sediments were examined with phase-contrast microscopy; the 24 h urine proteins were measured. Based on urinary sediment features combined with urine protein amount, the spectra of the urine sediments were classified into four types, Type I: hematuria-dominant, with multiple cells and casts; Type II: proteinuria-dominant, with hyaline or fine granular casts but scanty cells; Type III: renal tubular epithelial cell(RTEC) dominant, minor proteinuria; Type IV: non-specificurine sediments,minor proteinuria. According to the pathological lesions detected in renal biopsies, the renal diseases were classified into three patterns: proliferative glomerulopathy(P-GP), non-proliferative glomerulopathy (NP-GP) and tubulointerstitial nephropathy(TIN). The urinary sediment spectra of different pathological patterns and the correlation between urinary sediment types and pathological patterns were analyzed. Statistical analyses were performed using kappa test, and chi(2) test, and significance was accepted at P<0.05. RESULTS: (1) Of the 840 cases of matched urine samples and renal biopsies, 419 cases were diagnosed with P-GP; 375 cases with NP-GP; 46 cases with TIN respectively. (2) The spectra of urine sediments were associated with pathological patterns of the renal biopsies, and 84.0% of the patients with P-GP manifested type I urine sediments; 93.1% of the patients with NP-GP had type II urine sediments; 67.4% of the patients with TIN had type III urine sediments. (3) The correlation between the urinary sediment types and renal pathological patterns was validated in an additional 300 matched samples. The positive predictive values of urinary sediment spectra in predicting renal pathological lesions were 84.8% for typeI to P-GP, 86.0% for type II to NP-GP and 73.7% for type III to TIN, respectively. CONCLUSION: As a non-invasive diagnostic means, the urinary sediment analysis is valuable in the evaluation of pathological patterns of renal diseases. PMID- 25512285 TI - [Clinical significance of high expression with UTX in renal cell carcinoma]. AB - OBJECTIVE: To investigate the expression and significance of ubiquitously transcribed TPR gene on the X chromosome (UTX) in renal cell carcinoma (RCC) tissues, then to explore the relationship between UTX expression and renal cancer pathologic characteristics. METHODS: In the study, 45 patients with dignosed renal cell carcinoma clinical samples were collected in Peking University Shenzhen Hospital. Total RNA and protein were extracted from the cancer tissues and adjacent normal tissues. UTX expression of cancer tissues and adjacent normal tissues was detected on both mRNA and protein levels using real time-PCR and IHC, respectively. And the relationship between UTX expression and the 45 patients' clinical characteristics was analyzed. RESULTS: The mRNA level of UTX in cancer tissues(C) was 4.4 folds, higher than that of the adjacent normal tissues(N) [ 0.883 2+/-0.703 8 vs. 0.199 7+/-0.140 0, P<0.05]. The protein expression of UTX in cancer tissues was up-regulated, and the protein score of cancer tissues was 4 folds, change compared with adjacent normal tissues[12+/-4 vs. 3+/-3, P<0.05].The expression of UTX was associated with pathological grade(P=0.004)but without gender, age, tumor size and TNM stage. CONCLUSION: UTX is up-regulated in RCC tissues and the expression of UTX is associated with pathological grade, illustrating that UTX may play an important role in renal cancer progression. PMID- 25512286 TI - [Influence of in vitro fertilization and embryo transfer on the physical and intellectual development of the children at pre-school age]. AB - OBJECTIVE: To study whether the assisted reproductive technology [ in vitro fertilization and embryo transfer (IVF-ET)] has influence on the physical and intellectual development of the children at the preschool age. METHODS: The study group included 50 IVF-ET children, and the control group was a match cohort of 48 children born after being naturally conceived. A matched retrospective cohort study was performed on physical and intellectual development of the two children groups. The control group was matched according to home economics situation, parents' educational level, etc. RESULTS: In the adjusted analysis, the differences of the physical and the intellectual development between the two groups were not statistically significant (P>0.05). In the language test, the scores of the IVF-ET group was 1.35, 1.05, 1.32, 1.32 higher than those of the control group in the subject of general knowledge, words, synonyms, understanding ability. The IVF-ET group was 1.21 lower than that of the control group in the subject of arithmetics, 1.91 lower than that of the control group in the language subject, 5.5 higher than that of the control group in the operation subject, and 0.40, 0.38 higher than those of the control group in the subject of the maze and geometry. The scores of the control group were 1.04, 0.54, and 0.68 higher than those of the IVF-ET group in the animal house, drawing of vacancy, and block pattern, respectively. The final results of the IVF-ET group and the control group was 115.8 and 114.6, respectively. The ratio of the above medium height of the IVF-ET group and the control group was 30% and 31%, respectively. The ratio of the above medium weight was 30% and 23%, respectively. The IVF-ET group was a little fatter. There was no statistical difference between the two groups in the body development. CONCLUSION: The assisted reproduction technology is not associated with poorer physical and intellectual development. The family pay more attention to the children may promote their development. PMID- 25512287 TI - [Analysis of the control level and the affecting factors in 4-11 years old children with asthma]. AB - OBJECTIVE: To assess the control level of 4-11 years old children with asthma and to explore the correlative factors affecting the control level of asthma. METHODS: One cross-sectional study was conducted of the 4-11 years old children with asthma from Pediatrics Outpatient Department of Peking University Third Hospital from October 2013 to February 2014. According to asthma control test (ACT), the control levels of asthma children could be divided into three levels: fully controlled, partly controlled and non-controlled. The partly controlled group and the non-controlled group were merged into the non-full controlled group. Life quality was compared between the full controlled group and the non full controlled group. The correlative factors affecting the controlled level of asthma were analyzed by Logistic regression. The correlative case information was collected and the data were entered with EpiData software and analyzed with SPSS 17.0 software. RESULTS: Ninety asthma children were enrolled.The children from the full controlled group and the non-full controlled group accounted for 61.1% (55/90) and 38.9% (35/90), respectively. Life quality of the full controlled group was higher than that of the non-fully controlled group. There was no significant difference between the two groups on body mass index (BMI), education level of parents, parents or relative smoking, times of respiratory tract infection within 3 months, using asthma control drugs within 4 weeks before seeing a doctor and regularly taking medicine according to the doctor's advice (P>0.05). The binary Logistic regression analysis obtained three correlative factors affecting the control level of asthma: non-regular follow-up (OR=8.364, 95%CI: 1.816-38.532, P<0.05), being diagnosed with or suffering from allergic rhinitis (OR=6.728, 95% CI: 1.699-26.644, P<0.05) and accompanying with other allergic diseases (OR=3.926, 95%CI: 1.210-12.744, P<0.05). CONCLUSION: The results from the single center have shown that the asthma full-controlled rate of 4-11 years old children with asthma is not high. The higher control level, the better the life quality. Non-regular follow-up and being diagnosed with or suffering from allergic rhinitis are the correlative factors affecting the control level of 4-11 years old children with asthma. Meanwhile, accompanying with other allergic diseases, such as atopic dermatitis and food allergy is the protective factor for asthma control. The data from the multi-center and further study will be needed to demonstrate the results of this study. PMID- 25512288 TI - [Effects and clinical significance of virus load on red blood cell parameters in different stage of hepatitis B]. AB - OBJECTIVE: To evaluate the effect of the viral load on the red blood cell parameters in chronic hepatitis B patients and its clinical significance. METHODS: In the study, 373 chronic hepatitis B patients were recruited, including 123 alanine transaminase (ALT) normal patients (ALT<40 U/L),128 ALT greater than or equal to the upper limit of normal, and less than 2 times higher than the upper limit of normal patients(40 U/L <=ALT<80 U/L), and 122 ALT greater than or equal to 2 times higher than the upper limit of normal patients (ALT>=80 U/L). The blood routine parameters were measured by automatic blood cell counter. The liver function parameters were measured by automatic biochemical analyzer, the hepatitis B virus loads were measured by quantitative PCR analyzer and the results were analyzed by covariance analysis. RESULTS: In the ALT normal chronic hepatitis B patients group, the viral load had minor effects on the red blood cell parameters.But in the ALT abnormal chronic hepatitis B patients group, the viral load had a significant effect on the red blood cell parameters, and the effect was most manifest in the ALT>= double upper limit of normal group. The specific performance was that with the viral load increasing, the red blood cell [low copies group (4.10+/-0.67)*10(12)/L,medium copies group (3.92+/ 0.69)*10(12)/L,high copies group (3.54+/-0.90) *10(12)/L], the hemoglobin[low copies group (129.66+/-21.12 ) g/L, medium copies group (126.23+/-23.38) g/L, high copies group (112.98+/-27.77) g/L], the hematocrit (low copies group 37.66+/ 5.68, medium copies group 37.03+/-6.03, high copies group 33.34+/-8.15) decreased(P=0.006,0.007,0.010),the mean corpuscular volume [low copies group (92.17+/-6.53) fL, medium copies group (94.85+/-7.95) fL, high copies group (101.63+/-11.33) fL], the mean corpuscular hemoglobin [low copies group (31.70+/ 2.22) pg, medium copies group (33.11+/-3.62) pg, high copies group (34.65+/-3.13) pg], the mean corpuscular hemoglobin concentration [low copies group (344.28+/ 17.17) g/L, medium copies group (351.33+/-16.90) g/L, high copies group (358.12+/ 15.67) g/L], and the red blood cell distribution width-standard deviation [low copies group (52.49+/-9.04) fL, medium copies group (56.96+/-7.19) fL, high copies group (61.23 +/-7.23) fL] increased(P=0.000,0.000,0.002,0.000). CONCLUSION: Observing the effect of the viral load on the red blood cell parameters in chronic hepatitis B patients can reflect the effect of hepatitis B virus on the immune response and liver function in the different pathological stages, providing theoretical support for the clinical antiviral treatment. PMID- 25512289 TI - [Establishment of bisphosphonate-related osteonecrosis of the jaw model in rats and preliminary analysis of its etiological mechanism]. AB - OBJECTIVE: To establish bisphosphonate-related osteonecrosis of the jaw (BRONJ) model in rats and to make preliminary analysis of its etiological mechanisms. METHODS: A BRONJ model was established in rats using pamidronate, dexamethasone combined with alveolar bone trauma (tooth extraction) method, and the ratios of CD4+ and CD90+ lymphocytes in splenocytes were also analyzed by flow cytometry in each group. For in vitro studies, the effects of pamidronate and dexamethasone on the proliferation of human osteosarcoma cell line MG-63 and mouse pre-osteoclasts cell line Raw 264.7 were investigated using CCK-8 assay. RESULTS: The rat BRONJ model was successfully established using the method described above. Flow cytometry results showed that the ratios of CD4+ and CD90+ lymphocytes in splenocytes were much lower in the pamidronate and dexamethasone-treated rats than those in either pamidronte alone- or dexamethasone alone-treated rats. CCK-8 assay results showed that pamidronate could inhibit the proliferation of both MG 63 and Raw 264.7 cell lines, while dexamethasone could enhance the inhibitory effect of pamidronate on Raw 264.7 cells. CONCLUSION: This study successfully established the BRONJ model in rats and verified that dexamethasone could enhance the inhibitory effect of pamidronate on pre-osteoclasts in vitro. At least three factors including alveolar bone trauma, infection and immune response induced by dexamethasone could be involved in the process of BRONJ. PMID- 25512290 TI - [Esthetic outcome evaluation for soft tissue of implant restored anterior teeth lost from periodontal destruction: a case series]. AB - OBJECTIVE: To evaluate the soft tissue esthetic outcome of implant restored anterior teeth lost from periodontal destruction. METHODS: In the present study, 20 teeth extracted for severe periodontal destruction from 15 patients were involved. All the recruited patients received initial periodontal therapy. The implants were inserted with routine flap surgery 2-3 months after teeth extraction, and the guided bone regeneration technique was used when indicated. The extent of alveolar bone deficiency and the depth of implant placement (the distance from implant shoulder to the line connecting cemento-enamel junction of mesial and distal neighbor teeth) were recorded. The second-stage exposure and restoration were conducted after 3-month sub-mucosal healing. Pink esthetic score (PES) was used to evaluate the soft tissue esthetic outcome 1-3 months after final restoration. RESULTS: All the implants obtained osseointegration successfully. The mean PES value was 9.6+/-2.4, ranging from 5 to 13. The PES values of the 3 prostheses were lower than 7. The mean PES value of the 13 sites with only horizontal bone defect was 10.5+/-1.9, and was significantly higher than that of the 7 sites with combined horizontal and vertical bone defect (7.9+/ 2.3, P<0.05). The negative correlation was observed between the PES value and depth of implant placement (r=-0.608, P<0.01). CONCLUSION: High esthetic risk exists when restoring missing teeth lost from periodontal destruction by implant treatment. Alveolar bone defect especially vertical bone loss may mainly contribute to the soft tissue esthetic outcome deficiency. PMID- 25512291 TI - [Clinical observation of the reliability of gingival contour by using temporary crown after loading 1 year]. AB - OBJECTIVE: To observe the gingival contour and its variation following application of implant-supported temporary crowns on gingival contour in maxillary single tooth implant procedure after loading 1 year and to explore the reliability of soft tissue intervention using temporary crowns. METHODS: In 78 (37 males and 41 females) patients with anterior maxillary single tooth loss from the Department of Second Dental Center, Peking University School and Hospital of Stomatology, the gingival contour was induced by using implant-supported temporary crowns prior to maxillary tooth implant till permanent restoration from March 2010 to November 2011. The gingival papilla height and labial gingival margin level were measured immediately after the permanent restoration and 1 year later. RESULTS: In all the cases after loading 1 year, the average mesial and distal gingival papilla heights in the implant area increased by (0.16+/-0.58) mm and (0.10+/-0.53) mm, respectively. The labial gingival margin level was changed by (0.10+/-0.41) mm averagely. The difference in gingival contour shaped by temporary crown was not statistically significant after 1 year (P>0.05). CONCLUSION: The soft tissue shaping technique on aesthetic rehabilitation in maxillary single tooth implant is clinically feasible with a good recent aesthetic effect under the condition that the complications are controlled stringently. PMID- 25512293 TI - [Evaluation method with radiographic image quality indicator for internal defects of dental casting metallic restoration]. AB - OBJECTIVE: To develop a new kind of dental radiographic image quality indicator (IQI) for internal quality of casting metallic restoration to influence on its usage life. METHODS: Radiographic image quality indicator method was used to evaluate the depth of the defects region and internal quality of 127 casting metallic restoration and the accuracy was compared with that of conventional callipers method. RESULTS: In the 127 cases of casting metallic restoration, 9 were found the thickness less than 0.7 mm and the thinnest thickness only 0.2 mm in 26 casting metallic crowns or bridges' occlusal defects region. The data measured by image quality indicator were consistent with those measured by conventional gauging. Two metal inner crowns were found the thickness less than 0.3 mm in 56 porcelain crowns or bridges. The thickness of casting removable partial denture was more than 1.0 mm, but thinner regions were not found. It was found that in a titanium partial denture, the X-ray image of clasp was not uniform and there were internal porosity defects in the clasp. CONCLUSION: Special dental image quality indicator can solve the visual error problems caused by different observing backgrounds and estimate the depth of the defects region in the casting. PMID- 25512292 TI - [Cone-beam computed tomography was used for study of root and canal morphology of maxillary first and second molars]. AB - OBJECTIVE: To investigate the root and canal morphology of maxillary first and second molars by using Cone-beam computed tomography (CBCT). METHODS: The data of patients who underwent the CBCT scan for dental or periodontal diseases between May and September 2012 were analyzed retrospectively. In the study, 630 maxillary first molars, 519 maxillary second molars which were well-developed and without treatment were included. The number of roots, the number of root canals, and the canal configuration according to Vertucci's classification were determined. The vertucci type I was regarded as the conventional form. Other types were the variation forms and the mutation rate was calculated. RESULTS: 2.38% of the maxillary first molars and 15.22% of the maxillary second molars had 2 separated roots; 97.14% of the maxillary first molars and 73.60% of the maxillary second molars had 3 roots; 10.41% of the maxillary second molars had one single root; 0.77% of the maxillary second molars had 4 roots. In 612 3-rooted maxillary first molars, additional canals were found in 30.88% of the mesiobuccal (MB) roots. In 519 3-rooted maxillary second molars, additional canals were found in 13.87% of the MB roots. CONCLUSION: CBCT scans show the root and canal anatomy accurately, with the potential of improving the outcome of endodontic treatment. PMID- 25512294 TI - [Clinical outcome evaluation of midpalatal mini-implant anchorage system in orthodontic treatment]. AB - OBJECTIVE: To evaluate the effect of midpalatal mini-implant anchorage system in fixed appliance treatment. METHODS: In this study, 14 adolescents who had skeletal class I or II malocclusions were involved. Maximal anchorage was required during orthodontic treatment. Maxillary first premolars of the selected individuals were extracted and the individuals were treated by fixed appliance. One mini-implant was inserted in the midpalatal suture region and a transpalatal arch (TPA) made of 0.019 inch*0.022 inch(1 inch=2.54 cm) stainless steel was adhered to the mini-implant and upper first molars. Cephalometric radiographs taken after mini-implants inserted (T0) and before mini-implants removing (T1) were traced and measured. SN-7 plane and PP plane were used as reference planes. Student's t-test was used. RESULTS: The successful rate of midpalatal mini implant was 73.9%. All the items measured were found with no significant difference between the two groups. CONCLUSION: This mini-implant system as orthodontic anchorage in midpalatal region can be an alternative method of maximal anchorage during orthodontic treatment. PMID- 25512295 TI - [Accuracy analysis of cone beam computed tomography in assessing furcation involvements of mandibular molars]. AB - OBJECTIVE: To evaluate the accuracy of cone beam computed tomography (CBCT) in assessing furcation involvements of mandibular molars. METHODS: In the study, 38 furcation involvements of 22 mandibular molars which would accept furcation surgery were included. Pre-surgical examination, CBCT and periapical radiograph were performed. Then, intra-surgical furcation assessments were compared with those data. RESULTS: Intra-surgical findings confirmed 86.8% of the CBCT data, with a weighed kappa of 0.976. Of the four parameters tested of detailed root anatomy and furcation morphology, the vertical bone loss, the mesial-distal bone loss and the length of the root trunk revealed by CBCT were consistent with their respective intra-surgical values (P>0.05): about vertical bone loss, CBCT was (4.03+/-2.27) mm, but in surgery was (4.32+/-2.31) mm; about mesial-distal bone loss, CBCT was (2.05+/-0.89) mm, but in surgery was (2.07+/-0.97) mm; about length of the root trunk, CBCT was (2.35+/-0.88) mm, but in surgery was (2.24+/- 0.75) mm. The horizontal bone loss revealed by CBCT [(3.40+/-1.27) mm] was significantly smaller than that by surgery [(3.72+/-1.19) mm]. However, the mean difference was only 0.32 mm. Periapical radiograph could only obtain vertical bone loss [(2.17+/-1.32) mm] and mesial-distal bone loss [(1.46+/- 0.88) mm], which was significantly different from that obtained in surgery. CONCLUSION: CBCT proved high accuracy in assessing the furcation involvement of mandibular molars. PMID- 25512296 TI - [Hyperkalemia-induced failure of pacemaker capture and sensing: a case report]. AB - Hyperkalemia may induce serious cardiac arrhythmia, with possible life threatening effects. It may cause cardiac pacemaker (PMK) malfunctioning due to a reduction of the electronegativity of the resting myocardial potential. We report the case of a 71-year-old woman who had a previous history of chronic heart failure, chronic renal failure and DDI pacemaker. She was admitted for disturbance of consciousness. During hospitalization, she was observed for extreme hypotension, acute hyperkalemia, ventricular escape rhythm, associated with failure of pacemaker capture and sensing. She was treated with calcium chloride injection, followed by insulin/glucose and sodium bicarbonate infusions; the electrocardiogram recordings showed an correction of the PMK malfunctioning and serial improvement of the intraventricular conduction. This case supports that hyperkalemia should be closely monitored in the chronic heart failure patients combined with chronic renal failure. PMID- 25512297 TI - [A case report of cerebral resuscitation by surface cooling in a patient with cardiac arrest]. AB - Therapeutic hypothermia is an important treatment for cerebral resuscitation in patients after cardiac arrest. But it is rarely used for comatose survivor post cardiac arrest in China. The patient was the first case who was in coma post cardiac arrest caused by acute myocardial infarction and given hypothermia therapy in our hospital. After coronary reperfusion and therapeutic hypothermia, the patient's sneurologic function was recovered to normal. The paper discussed the indications, contraindications, cooling methods and complications of therapeutic hypothermia. PMID- 25512298 TI - [Eisenmenger's syndrome in pregnancy: a case report and literature review]. AB - OBJECTIVE: To investigate the clinical presentation, diagnosis and treatment of the Eisenmenger's syndrome in pregnancy. METHODS: One case of Eisenmenger's syndrome in pregnancy in our hospital was retrospectively analyzed and the literature reviewed. RESULTS: This patient who received antenatal care irregularly in other hospital was diagnosed with Eisenmenger's syndrome with the symptoms of chest distress. The other hospital suggested her to terminate pregnancy, but the patient refused. She was admitted to our hospital in her late pregnancy, received the treatment of rest, oxygen, blood gas and pulmonary artery pressure monitoring. Considering perioperative pulmonary hypertension crisis likely to occur, pulmonary artery catheter was placed preoperatively. In general anesthesia, the cesarean was performed. After operation, the patient was transferred to the intensive care unit, with the treatment of expanding blood vessels, reducing pulmonary artery pressure, administering anticoagulation and preventing infection. One week later, the patient was discharged from hospital with smooth condition. CONCLUSION: Eisenmenger's syndrome in pregnancy is associated with extremely poor maternal and fetal outcome. Termination of pregnancy should be offered to such patients. When interruption of pregnancy is refused, the early hospital admission is needed. The patients should be managed in a high-risk pregnancy unit by a multidisciplinary team from obstetrics, cardiology, anesthesia and pediatrics for improving pregnancy outcomes. PMID- 25512299 TI - Tissue mechanics and adhesion during embryo development. AB - During development cells interact mechanically with their microenvironment through cell-cell and cell-matrix adhesions. Many proteins involved in these adhesions serve both mechanical and signaling roles. In this review we will focus on the mechanical roles of these proteins and their complexes in transmitting force or stress from cell to cell or from cell to the extracellular matrix. As forces operate against tissues they establish tissue architecture, extracellular matrix assembly, and pattern cell shapes. As tissues become more established, adhesions play a major role integrating cells with the mechanics of their local environment. Adhesions may serve as both a molecular-specific glue, holding defined populations of cells together, and as a lubricant, allowing tissues to slide past one another. We review the biophysical principles and experimental tools used to study adhesion so that we may aid efforts to understand how adhesions guide these movements and integrate their signaling functions with mechanical function. As we conclude we review efforts to develop predictive models of adhesion that can be used to interpret experiments and guide future efforts to control and direct the process of tissue self-assembly during development. PMID- 25512300 TI - Ascl1 and Helt act combinatorially to specify thalamic neuronal identity by repressing Dlxs activation. AB - The mammalian thalamus is an essential diencephalic derivative that plays unique roles in processing and relaying sensory and motor information to and from the cerebral cortex. The profile of transcription factors and lineage tracing experiments revealed a spatiotemporal relationship between diencephalic progenitor domains and discrete differentiated neurons contributing to thalamic nuclei. However, the precise molecular mechanisms by which heterogeneous thalamic neurons become specified and assemble into distinct thalamic nuclei are still poorly understood. Here, we show that a combinatorial interaction between the bHLH transcription factors Ascl1 and Helt is required for acquiring thalamic progenitor identity. Surprisingly, in the combined absence of Ascl1 and Helt, rostral thalamic progenitors (TH-R) adopt a molecular profile of a more rostral diencephalic derivative, the prethalamus. Furthermore, we show that the prethalamic factors Dlxs upregulated by Ascl1/Helt deficiency play unique roles in regulating thalamic progenitor specification, and that derepression of Dlx2 and Dlx5 suppress generation of TH-R neurons. Taken together, our results suggest a model whereby the combined activity of two distinct bHLH factors plays a key role in the development of discrete classes of thalamic interneurons. PMID- 25512301 TI - Loss of Npn1 from motor neurons causes postnatal deficits independent from Sema3A signaling. AB - The correct wiring of neuronal circuits is of crucial importance for the function of the vertebrate nervous system. Guidance cues like the neuropilin receptors (Npn) and their ligands, the semaphorins (Sema) provide a tight spatiotemporal control of sensory and motor axon growth and guidance. Among this family of guidance partners the Sema3A-Npn1 interaction has been shown to be of great importance, since defective signaling leads to wiring deficits and defasciculation. For the embryonic stage these defects have been well described, however, also after birth the organism can adapt to new challenges by compensational mechanisms. Therefore, we used the mouse lines Olig2 Cre;Npn1(cond) and Npn1(Sema-) to investigate how postnatal organisms cope with the loss of Npn1 selectively from motor neurons or a systemic dysfunctional Sema3A-Npn1 signaling in the entire organism, respectively. While in Olig2 Cre(+);Npn1(cond-/-) mice clear anatomical deficits in paw posturing, bone structure, as well as muscle and nerve composition became evident, Npn1(Sema-) mutants appeared anatomically normal. Furthermore, Olig2-Cre(+);Npn1(cond) mutants revealed a dysfunctional extensor muscle innervation after single-train stimulation of the N.radial. Interestingly, these mice did not show obvious deficits in voluntary locomotion, however, skilled motor function was affected. In contrast, Npn1(Sema-) mutants were less affected in all behavioral tests and able to improve their performance over time. Our data suggest that loss of Sema3A Npn1 signaling is not the only cause for the observed deficits in Olig2 Cre(+);Npn1(cond-/-) mice and that additional, yet unknown binding partners for Npn1 may be involved that allow Npn1(Sema-) mutants to compensate for their developmental deficits. PMID- 25512302 TI - Maternal-zygotic knockout reveals a critical role of Cdx2 in the morula to blastocyst transition. AB - The first lineage segregation in the mouse embryo generates the inner cell mass (ICM), which gives rise to the pluripotent epiblast and therefore the future embryo, and the trophectoderm (TE), which will build the placenta. The TE lineage depends on the transcription factor Cdx2. However, when Cdx2 first starts to act remains unclear. Embryos with zygotic deletion of Cdx2 develop normally until the late blastocyst stage leading to the conclusion that Cdx2 is important for the maintenance but not specification of the TE. In contrast, down-regulation of Cdx2 transcripts from the early embryo stage results in defects in TE specification before the blastocyst stage. Here, to unambiguously address at which developmental stage Cdx2 becomes first required, we genetically deleted Cdx2 from the oocyte stage using a Zp3-Cre/loxP strategy. Careful assessment of a large cohort of Cdx2 maternal-zygotic null embryos, all individually filmed, examined and genotyped, reveals an earlier lethal phenotype than observed in Cdx2 zygotic null embryos that develop until the late blastocyst stage. The developmental failure of Cdx2 maternal-zygotic null embryos is associated with cell death and failure of TE specification, starting at the morula stage. These results indicate that Cdx2 is important for the correct specification of TE from the morula stage onwards and that both maternal and zygotic pools of Cdx2 are required for correct pre-implantation embryogenesis. PMID- 25512303 TI - Dorsomedial hypothalamic lesions counteract decreases in locomotor activity in male Syrian hamsters transferred from long to short day lengths. AB - The dorsomedial nucleus (DMN) of the hypothalamus has been implicated in seasonal control of reproduction. Syrian hamsters with DMN lesions, unlike control hamsters, do not undergo testicular regression after transfer from a long day length (14 h of light per day; LD) to a short day length (8 h of light per day; SD). SDs also markedly reduce hamster locomotor activity (LMA). To assess whether the DMN is a component of the neural circuitry that mediates seasonal variation in LMA, neurologically intact males (controls) and hamsters that had sustained lesions of the DMN (DMNx) were housed in an LD or SD photoperiod for 26 weeks. DMNx that prevented testicular regression counteracted decreases in LMA during 8 to10 weeks of SD treatment; steroid-independent effects of SDs did not override high levels of LMA in DMNx males. As in previous studies, testosterone (T) restoration increased LMA in LD but not SD castrated control males. In the present study, T also failed to increase LMA in SD-DMNx hamsters. The DMN is not necessary to maintain decreased responsiveness of locomotor activity systems to T in SDs, which presumably is mediated by other central nervous system androgen target tissues. Finally, DMNx did not interfere with the spontaneous increase in LMA exhibited by photorefractory hamsters after 26 weeks of SD treatment. We propose that DMN is an essential part of the substrate that mediates seasonal decreases in LMA as day length decreases but is not required to sustain decreased SD responsiveness to T or for development of refractoriness to SDs. PMID- 25512304 TI - Impaired circadian photosensitivity in mice lacking glutamate transmission from retinal melanopsin cells. AB - Intrinsically photoreceptive retinal ganglion cells (ipRGCs) contain the photopigment melanopsin and convey retinal light inputs to the circadian system via the retinohypothalamic tract (RHT) projection to the suprachiasmatic nucleus (SCN). The principal neurotransmitter of this projection is glutamate, and ipRGCs use the vesicular glutamate transporter 2 (VGLUT2) to package glutamate into synaptic vesicles. However, these neurons contain other potential neurotransmitters, such as pituitary adenylate cyclase activating polypeptide (PACAP). To test the role of glutamate in mediating ipRGC light inputs into the SCN, we crossed mice in which Cre-recombinase expression is driven by the melanopsin promotor (Opn4(Cre/+)) with mice in which the second exon of VGLUT2 is flanked by loxP sites (VGLUT2(fl/fl)), producing ipRGCs that are unable to package glutamate into synaptic vesicles. Such mice had free-running circadian rhythms that did not entrain to a 12:12 light-dark (12:12 LD) cycle, nor did they show a phase delay after a 45-min light pulse administered at circadian time (CT) 14. A small subset of the mice did appear to entrain to the 12:12 LD cycle with a positive phase angle to lights-off; a similar entrainment pattern could be achieved in free-running mice if they were exposed to a 12:12 LD cycle with light of a greater intensity. Glutamate transmission from the ipRGCs is necessary for normal light entrainment of the SCN at moderate (0.35 W/m(2)) light levels, but residual transmission (possibly by PACAP in ipRGCs or by other RGCs) can weakly entrain animals, particularly at very high (6.53 W/m(2)) light levels, although it may be less effective at suppressing locomotor activity (light masking). PMID- 25512306 TI - Identification of a second two-component signal transduction system that controls fosfomycin tolerance and glycerol-3-phosphate uptake. AB - Particular interest in fosfomycin has resurfaced because it is a highly beneficial antibiotic for the treatment of refractory infectious diseases caused by pathogens that are resistant to other commonly used antibiotics. The biological cost to cells of resistance to fosfomycin because of chromosomal mutation is high. We previously found that a bacterial two-component system, CpxAR, induces fosfomycin tolerance in enterohemorrhagic Escherichia coli (EHEC) O157:H7. This mechanism does not rely on irreversible genetic modification and allows EHEC to relieve the fitness burden that results from fosfomycin resistance in the absence of fosfomycin. Here we show that another two-component system, TorSRT, which was originally characterized as a regulatory system for anaerobic respiration utilizing trimethylamine-N-oxide (TMAO), also induces fosfomycin tolerance. Activation of the Tor regulatory pathway by overexpression of torR, which encodes the response regulator, or addition of TMAO increased fosfomycin tolerance in EHEC. We also show that phosphorylated TorR directly represses the expression of glpT, a gene that encodes a symporter of fosfomycin and glycerol-3 phosphate, and activation of the TorR protein results in the reduced uptake of fosfomycin by cells. However, cells in which the Tor pathway was activated had an impaired growth phenotype when cultured with glycerol-3-phosphate as a carbon substrate. These observations suggest that the TorSRT pathway is the second two component system to reversibly control fosfomycin tolerance and glycerol-3 phosphate uptake in EHEC, and this may be beneficial for bacteria by alleviating the biological cost. We expect that this mechanism could be a potential target to enhance the utility of fosfomycin as chemotherapy against multidrug-resistant pathogens. PMID- 25512305 TI - Circadian rhythms, the molecular clock, and skeletal muscle. AB - Circadian rhythms are the approximate 24-h biological cycles that function to prepare an organism for daily environmental changes. They are driven by the molecular clock, a transcriptional:translational feedback mechanism that in mammals involves the core clock genes Bmal1, Clock, Per1/2, and Cry1/2. The molecular clock is present in virtually all cells of an organism. The central clock in the suprachiasmatic nucleus (SCN) has been well studied, but the clocks in the peripheral tissues, such as heart and skeletal muscle, have just begun to be investigated. Skeletal muscle is one of the largest organs in the body, comprising approximately 45% of total body mass. More than 2300 genes in skeletal muscle are expressed in a circadian pattern, and these genes participate in a wide range of functions, including myogenesis, transcription, and metabolism. The circadian rhythms of skeletal muscle can be entrained both indirectly through light input to the SCN and directly through time of feeding and activity. It is critical for the skeletal muscle molecular clock not only to be entrained to the environment but also to be in synchrony with rhythms of other tissues. When circadian rhythms are disrupted, the observed effects on skeletal muscle include fiber-type shifts, altered sarcomeric structure, reduced mitochondrial respiration, and impaired muscle function. Furthermore, there are detrimental effects on metabolic health, including impaired glucose tolerance and insulin sensitivity, which skeletal muscle likely contributes to considering it is a key metabolic tissue. These data indicate a critical role for skeletal muscle circadian rhythms for both muscle and systems health. Future research is needed to determine the mechanisms of molecular clock function in skeletal muscle, identify the means by which skeletal muscle entrainment occurs, and provide a stringent comparison of circadian gene expression across the diverse tissue system of skeletal muscle. PMID- 25512307 TI - Genome instability mediates the loss of key traits by Acinetobacter baylyi ADP1 during laboratory evolution. AB - Acinetobacter baylyi ADP1 has the potential to be a versatile bacterial host for synthetic biology because it is naturally transformable. To examine the genetic reliability of this desirable trait and to understand the potential stability of other engineered capabilities, we propagated ADP1 for 1,000 generations of growth in rich nutrient broth and analyzed the genetic changes that evolved by whole genome sequencing. Substantially reduced transformability and increased cellular aggregation evolved during the experiment. New insertions of IS1236 transposable elements and IS1236-mediated deletions led to these phenotypes in most cases and were common overall among the selected mutations. We also observed a 49-kb deletion of a prophage region that removed an integration site, which has been used for genome engineering, from every evolved genome. The comparatively low rates of these three classes of mutations in lineages that were propagated with reduced selection for 7,500 generations indicate that they increase ADP1 fitness under common laboratory growth conditions. Our results suggest that eliminating transposable elements and other genetic failure modes that affect key organismal traits is essential for improving the reliability of metabolic engineering and genome editing in undomesticated microbial hosts, such as Acinetobacter baylyi ADP1. PMID- 25512309 TI - The flagellar set Fla2 in Rhodobacter sphaeroides is controlled by the CckA pathway and is repressed by organic acids and the expression of Fla1. AB - Rhodobacter sphaeroides has two different sets of flagellar genes. Under the growth conditions commonly used in the laboratory, the expression of the fla1 set is constitutive, whereas the fla2 genes are not expressed. Phylogenetic analyses have previously shown that the fla1 genes were acquired by horizontal transfer from a gammaproteobacterium and that the fla2 genes are endogenous genes of this alphaproteobacterium. In this work, we characterized a set of mutants that were selected for swimming using the Fla2 flagella in the absence of the Fla1 flagellum (Fla2(+) strains). We determined that these strains have a single missense mutation in the histidine kinase domain of CckA. The expression of these mutant alleles in a Fla1(-) strain allowed fla2-dependent motility without selection. Motility of the Fla2(+) strains is also dependent on ChpT and CtrA. The mutant versions of CckA showed an increased autophosphorylation activity in vitro. Interestingly, we found that cckA is transcriptionally repressed by the presence of organic acids, suggesting that the availability of carbon sources could be a part of the signal that turns on this flagellar set. Evidence is presented showing that reactivation of fla1 gene expression in the Fla2(+) background strongly reduces the number of cells with Fla2 flagella. PMID- 25512310 TI - Variations in O-antigen biosynthesis and O-acetylation associated with altered phage sensitivity in Escherichia coli 4s. AB - The O polysaccharide of the lipopolysaccharide (O antigen) of Gram-negative bacteria often serves as a receptor for bacteriophages that can make the phage dependent on a given O-antigen type, thus supporting the concept of the adaptive significance of the O-antigen variability in bacteria. The O-antigen layer also modulates interactions of many bacteriophages with their hosts, limiting the access of the viruses to other cell surface receptors. Here we report variations of O-antigen synthesis and structure in an environmental Escherichia coli isolate, 4s, obtained from horse feces, and its mutants selected for resistance to bacteriophage G7C, isolated from the same fecal sample. The 4s O antigen was found to be serologically, structurally, and genetically related to the O antigen of E. coli O22, differing only in side-chain alpha-D-glucosylation in the former, mediated by a gtr locus on the chromosome. Spontaneous mutations of E. coli 4s occurring with an unusually high frequency affected either O-antigen synthesis or O-acetylation due to the inactivation of the gene encoding the putative glycosyltransferase WclH or the putative acetyltransferase WclK, respectively, by the insertion of IS1-like elements. These mutations induced resistance to bacteriophage G7C and also modified interactions of E. coli 4s with several other bacteriophages conferring either resistance or sensitivity to the host. These findings suggest that O-antigen synthesis and O-acetylation can both ensure the specific recognition of the O-antigen receptor following infection by some phages and provide protection of the host cells against attack by other phages. PMID- 25512308 TI - Cyclic di-GMP riboswitch-regulated type IV pili contribute to aggregation of Clostridium difficile. AB - Clostridium difficile is an anaerobic Gram-positive bacterium that causes intestinal infections with symptoms ranging from mild diarrhea to fulminant colitis. Cyclic diguanosine monophosphate (c-di-GMP) is a bacterial second messenger that typically regulates the switch from motile, free-living to sessile and multicellular behaviors in Gram-negative bacteria. Increased intracellular c di-GMP concentration in C. difficile was recently shown to reduce flagellar motility and to increase cell aggregation. In this work, we investigated the role of the primary type IV pilus (T4P) locus in c-di-GMP-dependent cell aggregation. Inactivation of two T4P genes, pilA1 (CD3513) and pilB1 (CD3512), abolished pilus formation and significantly reduced cell aggregation under high c-di-GMP conditions. pilA1 is preceded by a putative c-di-GMP riboswitch, predicted to be transcriptionally active upon c-di-GMP binding. Consistent with our prediction, high intracellular c-di-GMP concentration increased transcript levels of T4P genes. In addition, single-round in vitro transcription assays confirmed that transcription downstream of the predicted transcription terminator was dose dependent and specific to c-di-GMP binding to the riboswitch aptamer. These results support a model in which T4P gene transcription is upregulated by c-di GMP as a result of its binding to an upstream transcriptionally activating riboswitch, promoting cell aggregation in C. difficile. PMID- 25512311 TI - Bright fluorescent Streptococcus pneumoniae for live-cell imaging of host pathogen interactions. AB - Streptococcus pneumoniae is a common nasopharyngeal resident in healthy people but, at the same time, one of the major causes of infectious diseases such as pneumonia, meningitis, and sepsis. The shift from commensal to pathogen and its interaction with host cells are poorly understood. One of the major limitations for research on pneumococcal-host interactions is the lack of suitable tools for live-cell imaging. To address this issue, we developed a generally applicable strategy to create genetically stable, highly fluorescent bacteria. Our strategy relies on fusing superfolder green fluorescent protein (GFP) or a far-red fluorescent protein (RFP) to the abundant histone-like protein HlpA. Due to efficient translation and limited cellular diffusion of these fusions, the cells are 25-fold brighter than those of the currently best available imaging S. pneumoniae strain. These novel bright pneumococcal strains are fully virulent, and the GFP reporter can be used for in situ imaging in mouse tissue. We used our reporter strains to study the effect of the polysaccharide capsule, a major pneumococcal virulence factor, on different stages of infection. By dual-color live-cell imaging experiments, we show that unencapsulated pneumococci adhere significantly better to human lung epithelial cells than encapsulated strains, in line with previous data obtained by classical approaches. We also confirm with live-cell imaging that the capsule protects pneumococci from neutrophil phagocytosis, demonstrating the versatility and usability of our reporters. The described imaging tools will pave the way for live-cell imaging of pneumococcal infection and help further understanding of the mechanisms of pneumococcal pathogenesis. PMID- 25512312 TI - Genomic, proteomic, and biochemical analysis of the organohalide respiratory pathway in Desulfitobacterium dehalogenans. AB - Desulfitobacterium dehalogenans is able to grow by organohalide respiration using 3-chloro-4-hydroxyphenyl acetate (Cl-OHPA) as an electron acceptor. We used a combination of genome sequencing, biochemical analysis of redox active components, and shotgun proteomics to study elements of the organohalide respiratory electron transport chain. The genome of Desulfitobacterium dehalogenans JW/IU-DC1(T) consists of a single circular chromosome of 4,321,753 bp with a GC content of 44.97%. The genome contains 4,252 genes, including six rRNA operons and six predicted reductive dehalogenases. One of the reductive dehalogenases, CprA, is encoded by a well-characterized cprTKZEBACD gene cluster. Redox active components were identified in concentrated suspensions of cells grown on formate and Cl-OHPA or formate and fumarate, using electron paramagnetic resonance (EPR), visible spectroscopy, and high-performance liquid chromatography (HPLC) analysis of membrane extracts. In cell suspensions, these components were reduced upon addition of formate and oxidized after addition of Cl-OHPA, indicating involvement in organohalide respiration. Genome analysis revealed genes that likely encode the identified components of the electron transport chain from formate to fumarate or Cl-OHPA. Data presented here suggest that the first part of the electron transport chain from formate to fumarate or Cl-OHPA is shared. Electrons are channeled from an outward-facing formate dehydrogenase via menaquinones to a fumarate reductase located at the cytoplasmic face of the membrane. When Cl-OHPA is the terminal electron acceptor, electrons are transferred from menaquinones to outward-facing CprA, via an as-yet-unidentified membrane complex, and potentially an extracellular flavoprotein acting as an electron shuttle between the quinol dehydrogenase membrane complex and CprA. PMID- 25512315 TI - Heteroleptic cationic iridium(III) complexes bearing naphthalimidyl substituents: synthesis, photophysics and reverse saturable absorption. AB - Three heteroleptic cationic iridium(iii) complexes containing a cyclometalating 2 [3-(7-naphthalimidylfluoren-2'-yl)phenyl]pyridine ligand and different diimine (N^N) ligands (N^N = 2,2'-bipyridine (bpy, ), 1,10-phenanthroline (phen, ), and 5,5'-bis[7-(benzothiazol-2'-yl)fluoren-2'-yl]-2,2'-bipyridine (BTF-bpy, )) were synthesized and characterized. The photophysics of these complexes was systematically investigated via spectroscopic methods and by time-dependent density functional theory (TDDFT). All complexes possess a very weak charge transfer tail at ca. 450-570 nm; and two intense absorption bands in the region of 290-350 nm and 350-450 nm, respectively. The emission of in CH2Cl2 emanates predominantly from the C^N ligand-localized (3)pi,pi* state. These emitting excited states also give rise to broadband triplet excited-state absorption in the visible to the near-IR region (i.e. 420-800 nm for and , and 460-800 nm for ). The kinetics of fs transient absorption (TA) reveals that the lowest singlet excited-state lifetimes of these complexes vary from 1.43 ps to 142 ps. The stronger excited-state absorption of compared to their respective ground-state absorption in the visible spectral range leads to strong reverse saturable absorption (RSA) at 532 nm for ns laser pulses. The trend of transmission signal decrease follows > > . Extending the pi-conjugation of the N^N ligand increases the strength of RSA. In addition, the naphthalimidyl (NI) substitution at the cyclometalating ligand dramatically increases the triplet excited-state lifetimes and broadens the triplet excited-state absorption to the NIR region compared to the respective Ir(iii) complexes with a benzothiazolyl substituent on the cyclometalating ligand. PMID- 25512313 TI - The identification and functional characterization of WxL proteins from Enterococcus faecium reveal surface proteins involved in extracellular matrix interactions. AB - The WxL domain recently has been identified as a novel cell wall binding domain found in numerous predicted proteins within multiple Gram-positive bacterial species. However, little is known about the function of proteins containing this novel domain. Here, we identify and characterize 6 Enterococcus faecium proteins containing the WxL domain which, by reverse transcription-PCR (RT-PCR) and genomic analyses, are located in three similarly organized operons, deemed WxL loci A, B, and C. Western blotting, electron microscopy, and enzyme-linked immunosorbent assays (ELISAs) determined that genes of WxL loci A and C encode antigenic, cell surface proteins exposed at higher levels in clinical isolates than in commensal isolates. Secondary structural analyses of locus A recombinant WxL domain-containing proteins found they are rich in beta-sheet structure and disordered segments. Using Biacore analyses, we discovered that recombinant WxL proteins from locus A bind human extracellular matrix proteins, specifically type I collagen and fibronectin. Proteins encoded by locus A also were found to bind to each other, suggesting a novel cell surface complex. Furthermore, bile salt survival assays and animal models using a mutant from which all three WxL loci were deleted revealed the involvement of WxL operons in bile salt stress and endocarditis pathogenesis. In summary, these studies extend our understanding of proteins containing the WxL domain and their potential impact on colonization and virulence in E. faecium and possibly other Gram-positive bacterial species. PMID- 25512314 TI - Resuscitation-promoting factors are cell wall-lytic enzymes with important roles in the germination and growth of Streptomyces coelicolor. AB - Dormancy is a common strategy adopted by bacterial cells as a means of surviving adverse environmental conditions. For Streptomyces bacteria, this involves developing chains of dormant exospores that extend away from the colony surface. Both spore formation and subsequent spore germination are tightly controlled processes, and while significant progress has been made in understanding the underlying regulatory and enzymatic bases for these, there are still significant gaps in our understanding. One class of proteins with a potential role in spore associated processes are the so-called resuscitation-promoting factors, or Rpfs, which in other actinobacteria are needed to restore active growth to dormant cell populations. The model species Streptomyces coelicolor encodes five Rpf proteins (RpfA to RfpE), and here we show that these proteins have overlapping functions during growth. Collectively, the S. coelicolor Rpfs promote spore germination and are critical for growth under nutrient-limiting conditions. Previous studies have revealed structural similarities between the Rpf domain and lysozyme, and our in vitro biochemical assays revealed various levels of peptidoglycan cleavage capabilities for each of these five Streptomyces enzymes. Peptidoglycan remodeling by enzymes such as these must be stringently governed so as to retain the structural integrity of the cell wall. Our results suggest that one of the Rpfs, RpfB, is subject to a unique mode of enzymatic autoregulation, mediated by a domain of previously unknown function (DUF348) located within the N terminus of the protein; removal of this domain led to significantly enhanced peptidoglycan cleavage. PMID- 25512316 TI - Update on intra-arterial thrombolysis in patients with lower limb ischemia. AB - Intra-arterial thrombolysis has become the most important minimally-invasive treatment option to treat acute lower limb ischemia. Although hemorrhagic stroke is a dreaded complication, intra-arterial thrombolysis is considered beneficial to many fragile and elderly patients where vascular surgery is not an option. This review outlines current results after intra-arterial thrombolysis with low dose recombinant tissue plasminogen activator (rtPA) from 2001 to 2012 in two large vascular centers in Sweden. There was an increasing number of thrombolysis of occluded endoprosthesis and decreasing thrombolysis of occluded bypasses during this time period. Technical success rate for thrombolysis of occluded endoprostheses, bypasses and native artery occlusion was 91%, 89% and 73%, respectively. Amputation-free survival rate at one year was 73%. Popliteal arterial aneurysm and anemia were independently associated with dismal amputation free survival at 30 days. Independent factors associated with dismal amputation free survival at long-term were foot ulcers, motor deficit, renal insufficiency and anemia. Major hemorrhage occurred in 104 procedures (13.9%); 43 (5.7%) were so severe that thrombolysis was discontinued in advance. All three (0.4%) hemorrhagic strokes were fatal. Preoperative severe limb ischemia with motor deficit was the only independent risk factor for major bleeding. Simultaneous heparin infusion was not associated with increased risk of major bleeding or improved leg salvage or survival. In conclusion, intra-arterial thrombolysis with rtPA for lower limb ischemia was effective, with few major bleeding complications. Simultaneous heparin infusion offered no advantage. Thrombolysis in embolism due to popliteal artery aneurysm is the most important step to improve run-off and a prerequisite to succeed with operative treatment. PMID- 25512317 TI - Common iliac and hypogastric aneurysms: open and endovascular repair. AB - Currently, there are a variety of open surgical, endovascular, and hybrid options to treat iliac artery aneurysms (IAA). Anatomy of the common iliac artery (CIA) with regard to proximal and distal neck, involvement of the iliac bifurcation, and choice to preserve the ipsilateral internal iliac artery (IIA) all play a role in the decision process towards the preferred treatment method. This manuscript describes the available open surgical and endovascular techniques for the treatment of IAA. Indications, advantages and limitations, and outcomes of each technique are discussed. PMID- 25512325 TI - One in 10 women in England takes antidepressants, survey shows. PMID- 25512327 TI - People with poorer numeracy feel more negative about bowel cancer screening. PMID- 25512328 TI - Utility of Hippocrates' prognostic aphorism to predict death in the modern era: prospective cohort study. AB - OBJECTIVE: To determine if one of Hippocrates' aphorisms, identifying good cognition and good appetite as two prognostic factors, predicts death in community living older adults in the modern era. DESIGN: Secondary analysis of an existing population based cohort study. SETTING: Manitoba Study of Health and Aging. PARTICIPANTS: 1751 community living adults aged more than 65 enrolled in the Manitoba Study of Health and Aging in 1991 and followed over five years. MAIN OUTCOME MEASURE: Time to death. METHODS: We recreated the hippocratic prognosticator using an item that measures appetite drawn from the Center for Epidemiologic Studies-depression subscale, and the mini-mental state examination, with a score of >25 being considered as normal. People with normal cognition and appetite were compared with those with either poor cognition or poor appetite. We constructed Cox regression models, adjusted for age, sex, education, and functional status. RESULTS: The prognostic aphorism predicted death, with an unadjusted hazard ratio of 2.37 (95% confidence interval 1.93 to 2.88) and a hazard ratio of 1.71 (1.37 to 2.12) adjusted for age, sex, and education. Both poor appetite and poor cognition predicted death. The sensitivity and specificity were not, however, sufficient for the measure to be used alone. CONCLUSION: An aphorism devised by Hippocrates millennia ago can predict death in the modern era. PMID- 25512329 TI - New horizons in therapeutic antibody discovery: opportunities and challenges versus small-molecule therapeutics. AB - Antibody drugs have become an increasingly significant component of the therapeutic landscape. Their success has been driven by some of their unique properties, in particular their very high specificity and selectivity, in contrast to the off-target liabilities of small molecules (SMs). Antibodies can bring additional functionality to the table with their ability to interact with the immune system, and this can be further manipulated with advances in antibody engineering. This review summarizes what antibody therapeutics have achieved to date and what opportunities and challenges lie ahead. The target landscape for large molecules (LMs) versus SMs and some of the challenges for antibody drug development are discussed. Effective penetration of membrane barriers and intracellular targeting is one challenge, particularly across the highly resistant blood-brain barrier. The expanding pipeline of antibody-drug conjugates offers the potential to combine SM and LM modalities in a variety of creative ways, and antibodies also offer exciting potential to build bi- and multispecific molecules. The ability to pursue more challenging targets can also be further exploited but highlights the need for earlier screening in functional cell-based assays. I discuss how this might be addressed given the practical constraints imposed by high-throughput screening sample type and process differences in antibody primary screening. PMID- 25512331 TI - Imbalance of power between patients and doctors. PMID- 25512330 TI - Using the BioAssay Ontology for analyzing high-throughput screening data. AB - High-throughput screening (HTS) is the main starting point for hit identification in drug discovery programs. This has led to a rapid increase of available screening data both within pharmaceutical companies and the public domain. We have used the BioAssay Ontology (BAO) 2.0 for assay annotation within AstraZeneca to enable comparison with external HTS methods. The annotated assays have been analyzed to identify technology gaps, evaluate new methods, verify active hits, and compare compound activity between in-house and PubChem assays. As an example, the binding of a fluorescent ligand to formyl peptide receptor 1 (FPR1, involved in inflammation, for example) in an in-house HTS was measured by fluorescence intensity. In total, 155 active compounds were also tested in an external ligand binding flow cytometry assay, a method not used for in-house HTS detection. Twelve percent of the 155 compounds were found active in both assays. By the annotation of assay protocols using BAO terms, internal and external assays can easily be identified and method comparison facilitated. They can be used to evaluate the effectiveness of different assay methods, design appropriate confirmatory and counterassays, and analyze the activity of compounds for identification of technology artifacts. PMID- 25512332 TI - Kinetic and thermodynamic studies on the disulfide-bond reducing potential of hydrogen sulfide. AB - The significance of persulfide species in hydrogen sulfide biology is increasingly recognized. However, the molecular mechanisms of their formation remain largely elusive. The obvious pathway of the reduction of biologically abundant disulfide moieties by sulfide was challenged on both thermodynamic and kinetic grounds. Using DTNB (5,5'-dithiobis-(2-nitrobenzoic acid), also known as Ellman's reagent) as a model disulfide we conducted a comprehensive kinetic study for its reaction with sulfide. The bimolecular reaction is relatively fast with a second-order rate constant of 889 +/- 12 M(-1)s(-1) at pH = 7.4. pH dependence of the rate law revealed that the reaction proceeds via the bisulfide anion species with an initial nucleophilic thiol-disulfide exchange reaction to give 5-thio-2 nitrobenzoic acid (TNB) and TNB-persulfide with a pH independent second-order rate constant of 1090 +/- 12 M(-1)s(-1). However, kinetic studies and stoichiometric analyses in a wide range of reactant ratios together with kinetic simulations revealed that it is a multistep process that proceeds via kinetically driven, practically irreversible reactions along the disulfide -> persulfide -> inorganic polysulfides axis. The kinetic model postulated here, which is fully consistent with the experimental data, suggests that the TNB-persulfide is further reduced by sulfide with a second-order rate constant in the range of 5 * 10(3) - 5 * 10(4) M(-1)s(-1) at pH 7.4 and eventually yields inorganic polysulfides and TNB. The reactions of cystine and GSSG with sulfide were found to be significantly slower and to occur via more complicated reaction schemes. (1)H NMR studies suggest that these reactions also generate Cys-persulfide and inorganic polysulfide species, but in contrast with DTNB, in consecutive equilibrium processes that are sensitive to changes in the reactant and product ratios. Collectively, our results demonstrate that the reaction of disulfides with sulfide is a highly system specific process from both thermodynamic and kinetic aspects, which together with the considerable steady-state concentrations of the reactants in biological systems signifies physiological relevance. PMID- 25512333 TI - pyroGlu-Leu inhibits the induction of inducible nitric oxide synthase in interleukin-1beta-stimulated primary cultured rat hepatocytes. AB - Pyroglutamyl leucine (pyroGlu-Leu), which is a peptide isolated from wheat gluten hydrolysate, has been reported to be a hepatoprotective compound in acute liver failure. In inflamed liver, proinflammatory cytokines including interleukin (IL) 1beta and tumor necrosis factor (TNF)-alpha stimulate the induction of inducible nitric oxide synthase (iNOS). Excess production of nitric oxide (NO) by iNOS is an inflammatory biomarker in liver injury. We examined proinflammatory cytokine stimulated hepatocytes as a simple "in vitro inflammation model" to determine liver protective effects of pyroGlu-Leu and its mechanisms of action. We hypothesized that pyroGlu-Leu inhibits the induction of iNOS gene expression, resulting in the attenuation of hepatic inflammation. Hepatocytes were isolated from rats by collagenase perfusion and cultured. Primary cultured cells were treated with IL-1beta in the presence or absence of pyroGlu-Leu. The induction of iNOS and its signaling pathway were analyzed. IL-1beta stimulated the enhancement of NO production in hepatocytes and this effect was inhibited by pyroGlu-Leu. pyroGlu-Leu decreased the expression of iNOS protein and its mRNA. Transfection experiments with iNOS-luciferase constructs revealed that pyroGlu-Leu inhibited both of iNOS promoter transactivation and its mRNA stabilization. pyroGlu-Leu also decreased the expression of an iNOS gene antisense transcript, which is involved in iNOS mRNA stability. However, pyroGlu-Leu had no effects on IkappaB degradation and NF-kappaB activation. Results demonstrate that pyroGlu-Leu inhibited the induction of iNOS gene expression at transcriptional and post transcriptional steps through IkappaB/NF-kappaB-independent pathway, leading to the prevention of NO production. pyroGlu-Leu may have therapeutic potential for liver injury through the suppression of iNOS. PMID- 25512334 TI - Retromer and the dynamin Vps1 cooperate in the retrieval of transmembrane proteins from vacuoles. AB - Endosomes are dynamic organelles that need to combine the ability to successfully deliver proteins and lipids to the lysosome-like vacuole, and recycle others to the Golgi or the plasma membrane. We now show that retromer, which is implicated in retrieval of proteins from endosomes to the Golgi or to the plasma membrane, can act on vacuoles. We explore its function using an assay that allows us to dissect the required cofactors during recycling. We demonstrate that recycling of the transmembrane receptor Vps10 from vacuoles requires the retromer, the dynamin like Vps1, and the Rab7 GTPase Ypt7. Retromer and Vps1 leave the vacuole together with the cargo, whereas Ypt7 stays behind, in agreement with its regulatory function. Recycled cargo then accumulates at endosomes and later at the Golgi, implying consecutive sorting steps to the final destination. Our data further suggest that retromer and Vps1 are essential to maintain vacuole membrane organization. Taken together, our data demonstrate that retromer can cooperate with Vps1 and the Rab Ypt7 to clear the vacuole of selected membrane proteins. PMID- 25512335 TI - Btn3 regulates the endosomal sorting function of the yeast Ent3 epsin, an adaptor for SNARE proteins. AB - Ent3 and Ent5 are yeast epsin N-terminal homology (ENTH) domain-containing proteins involved in protein trafficking between the Golgi and late endosomes. They interact with clathrin, clathrin adaptors at the Golgi (AP-1 and GGA) and different SNAREs (Vti1, Snc1, Pep12 and Syn8) required for vesicular transport at the Golgi and endosomes. To better understand the role of these epsins in membrane trafficking, we performed a protein-protein interaction screen. We identified Btn3 (also known as Tda3), a putative oxidoreductase, as a new partner of both Ent3 and Ent5. Btn3 is a negative regulator of the Batten-disease-linked protein Btn2 involved in the retrieval of specific SNAREs (Vti1, Snc1, Tlg1 and Tlg2) from the late endosome to the Golgi. We show that Btn3 endosomal localization depends on the epsins Ent3 and Ent5. We demonstrated that in btn3Delta mutant cells, endosomal sorting of ubiquitylated cargos and endosomal recycling of the Snc1 SNARE are delayed. We thus propose that Btn3 regulates the sorting function of two adaptors for SNARE proteins, the epsin Ent3 and the Batten-disease-linked protein Btn2. PMID- 25512336 TI - Correction: MR-guided focused ultrasound technique in functional neurosurgery: targeting accuracy. AB - [This corrects the article on p. 3 in vol. 1, PMID: 24761224.]. PMID- 25512337 TI - Controversial Saatchi bill passes report stage in House of Lords. PMID- 25512339 TI - In Vitro Fertilization Is Successful in Women With Ulcerative Colitis and Ileal Pouch Anal Anastomosis. AB - BACKGROUND: Women with ulcerative colitis (UC), who require ileal pouch anal anastomosis (IPAA), have up to a threefold increased incidence of infertility. To better counsel patients who require colectomy, we examined the success rates of in vitro fertilization (IVF) among women who have undergone IPAA. METHODS: This was a retrospective cohort study conducted at the Brigham and Women's Hospital and Beth Israel Deaconess Medical Center. Female patients with UC were identified via ICD-9 codes and cross-referenced with those presenting for IVF from 1998 through 2011. UC patients with IPAA were compared with the following two unexposed groups that underwent IVF: (1) patients with UC, who had not undergone IPAA, and (2) patients without inflammatory bowel disease (IBD). The primary outcome was the cumulative live birth rate. Secondary outcomes included number of oocytes retrieved, proportion of patients who underwent embryo transfer, pregnancy rate, and live birth rate at first cycle. RESULTS: There were 22 patients with UC and IPAA, 49 patients with UC and without IPAA, and 470 patients without IBD. The cumulative live birth rate after six cycles in the UC and IPAA groups was 64% (95% confidence interval (CI): 44-83%). This rate did not differ from the cumulative live birth rate in the UC without IPAA group (71%, 95% CI: 59 83%; P=0.63) or the group without IBD (53%, 95% CI: 48-57%; P=0.57). CONCLUSIONS: This study demonstrates that in our cohort, women who undergo IPAA achieve live births following IVF at comparable rates to women with UC without IPAA and to women without IBD. PMID- 25512338 TI - The risks of thromboembolism vs. recurrent gastrointestinal bleeding after interruption of systemic anticoagulation in hospitalized inpatients with gastrointestinal bleeding: a prospective study. AB - OBJECTIVES: Anticoagulants carry a significant risk of gastrointestinal bleeding (GIB). Data regarding the safety of anticoagulation continuation/cessation after GIB are limited. We sought to determine the safety and risk of continuation of anticoagulation after GIB. METHODS: We conducted a prospective observational cohort study on consecutive patients admitted to the hospital who had GIB while on systemic anticoagulation. Patients were classified into two groups at hospital discharge after GIB: those who resumed anticoagulation and those who had anticoagulation discontinued. Patients in both groups were contacted by phone 90 days after discharge to determine the following outcomes: (i) thromboembolic events, (ii) hospital readmissions related to GIB, and (iii) mortality. Univariate and multivariate Cox proportional hazards were used to determine factors associated with thrombotic events, rebleeding, and death. RESULTS: We identified 197 patients who developed GIB while on systemic anticoagulation (n=145, 74% on warfarin). Following index GIB, anticoagulation was discontinued in 76 patients (39%) at discharge. In-hospital transfusion requirements, need for intensive care unit care, and etiology of GIB were similar between the two groups. During the follow-up period, 7 (4%) patients suffered a thrombotic event and 27 (14%) patients were readmitted for GIB. Anticoagulation continuation was independently associated on multivariate regression with a lower risk of major thrombotic episodes within 90 days (hazard ratio (HR)=0.121, 95% confidence interval (CI)=0.006-0.812, P=0.03). Patients with any malignancy at time of GIB had an increased risk of thromboembolism in follow-up (HR=6.1, 95% CI=1.18-28.3, P=0.03). Anticoagulation continuation at discharge was not significantly associated with an increased risk of recurrent GIB at 90 days (HR=2.17, 95% CI=0.861-6.67, P=0.10) or death within 90 days (HR=0.632, 95% CI=0.216-1.89, P=0.40). CONCLUSIONS: Restarting anticoagulation at discharge after GIB was associated with fewer thromboembolic events without a significantly increased risk of recurrent GIB at 90 days. The benefits of continuing anticoagulation at discharge may outweigh the risks of recurrent GIB. PMID- 25512340 TI - Spore formation in plants: sporocyteless and more. AB - Plant reproduction is initiated by the specification of sporocytes that form haploid spores through meiosis. A new study in Arabidopsis published in Cell Research shows how the product of sporocyteless/nozzle, a key gene in this process, partners with co-repressors and transcription factors to promote spore formation, and draws interesting parallels with fungi. PMID- 25512342 TI - US malaria patients have often not taken chemoprophylactic drugs, CDC report finds. PMID- 25512341 TI - The p53-induced lincRNA-p21 derails somatic cell reprogramming by sustaining H3K9me3 and CpG methylation at pluripotency gene promoters. AB - Recent studies have boosted our understanding of long noncoding RNAs (lncRNAs) in numerous biological processes, but few have examined their roles in somatic cell reprogramming. Through expression profiling and functional screening, we have identified that the large intergenic noncoding RNA p21 (lincRNA-p21) impairs reprogramming. Notably, lincRNA-p21 is induced by p53 but does not promote apoptosis or cell senescence in reprogramming. Instead, lincRNA-p21 associates with the H3K9 methyltransferase SETDB1 and the maintenance DNA methyltransferase DNMT1, which is facilitated by the RNA-binding protein HNRNPK. Consequently, lincRNA-p21 prevents reprogramming by sustaining H3K9me3 and/or CpG methylation at pluripotency gene promoters. Our results provide insight into the role of lncRNAs in reprogramming and establish a novel link between p53 and heterochromatin regulation. PMID- 25512344 TI - Leukotrienes induce the migration of Th17 cells. AB - Th17 cell trafficking in response to leukotriene signaling is poorly understood. Here we showed that Th17 cells express high levels of leukotriene B4 receptor 1 (LTB4R1) and cysteinyl leukotriene receptor 1 (CysLTR1). Th17 cells migrated under the guidance of leukotriene B4 and D4. The migration of Th17 cells was more efficient than that of Th1 and Th2 cells, and it was blocked by specific inhibitors of LTB4R1 or CysLTR1. Studies in an animal model of experimental autoimmune encephalomyelitis revealed that treatment with montelukast alleviated disease symptoms and inhibited the recruitment of Th17 cells to the central nervous system. Thus, leukotrienes may act as chemoattractants for Th17 cells. PMID- 25512345 TI - Reciprocal regulation of insulin and plasma 5'-AMP in glucose homeostasis in mice. AB - A previous investigation has demonstrated that plasma 5'-AMP (pAMP) exacerbates and causes hyperglycemia in diabetic mice. However, the crosstalk between pAMP and insulin signaling to regulate glucose homeostasis has not been investigated in depth. In this study, we showed that the blood glucose level was more dependent on the ratio of insulin to pAMP than on the absolute level of these two factors. Administration of 5'-AMP significantly attenuated the insulin-stimulated insulin receptor (IR) autophosphorylation in the liver and muscle tissues, resulting in the inhibition of downstream AKT phosphorylation. A docking analysis indicated that adenosine was a potential inhibitor of IR tyrosine kinase. Moreover, the 5'-AMP treatment elevated the ATP level in the pancreas and in the isolated islets, stimulating insulin secretion and increasing the plasma level of insulin. The insulin administration decreased the 5'-AMP-induced hyper-adenosine level by the up-regulation of adenosine kinase activities. Our results indicate that blood glucose homeostasis is reciprocally regulated by pAMP and insulin. PMID- 25512349 TI - Sexual health and science. PMID- 25512343 TI - A specific CD4 epitope bound by tregalizumab mediates activation of regulatory T cells by a unique signaling pathway. AB - CD4(+)CD25(+) regulatory T cells (Tregs) represent a specialized subpopulation of T cells, which are essential for maintaining peripheral tolerance and preventing autoimmunity. The immunomodulatory effects of Tregs depend on their activation status. Here we show that, in contrast to conventional anti-CD4 monoclonal antibodies (mAbs), the humanized CD4-specific monoclonal antibody tregalizumab (BT-061) is able to selectively activate the suppressive properties of Tregs in vitro. BT-061 activates Tregs by binding to CD4 and activation of signaling downstream pathways. The specific functionality of BT-061 may be explained by the recognition of a unique, conformational epitope on domain 2 of the CD4 molecule that is not recognized by other anti-CD4 mAbs. We found that, due to this special epitope binding, BT-061 induces a unique phosphorylation of T-cell receptor complex-associated signaling molecules. This is sufficient to activate the function of Tregs without activating effector T cells. Furthermore, BT-061 does not induce the release of pro-inflammatory cytokines. These results demonstrate that BT-061 stimulation via the CD4 receptor is able to induce T-cell receptor independent activation of Tregs. Selective activation of Tregs via CD4 is a promising approach for the treatment of autoimmune diseases where insufficient Treg activity has been described. Clinical investigation of this new approach is currently ongoing. PMID- 25512346 TI - Testosterone reduces AGTR1 expression to prevent beta-cell and islet apoptosis from glucotoxicity. AB - Hypogonadism in men is associated with an increased incidence of type 2 diabetes. Supplementation with testosterone has been shown to protect pancreatic beta-cell against apoptosis due to toxic substances including streptozotocin and high glucose. One of the pathological mechanisms of glucose-induced pancreatic beta cell apoptosis is the induction of the local rennin-angiotensin-aldosterone system (RAAS). The role of testosterone in regulation of the pancreatic RAAS is still unknown. This study aims to investigate the protective action of testosterone against glucotoxicity-induced pancreatic beta-cell apoptosis via alteration of the pancreatic RAAS pathway. Rat insulinoma cell line (INS-1) cells or isolated male mouse islets were cultured in basal and high-glucose media in the presence or absence of testosterone, losartan, and angiotensin II (Ang II), then cell apoptosis, cleaved caspase 3 expression, oxidative stress, and expression of angiotensin II type 1 receptor (AGTR1) and p47(phox) mRNA and protein were measured. Testosterone and losartan showed similar effects in reducing pancreatic beta-cell apoptosis. Testosterone significantly reduced expression of AGTR1 protein in INS-1 cells cultured in high-glucose medium or high-glucose medium with Ang II. Testosterone decreased the expression of AGTR1 and p47(phox) mRNA and protein in comparison with levels in cells cultured in high-glucose medium alone. Furthermore, testosterone attenuated superoxide production when co-cultured with high-glucose medium. In contrast, when cultured in basal glucose, supplementation of testosterone did not have any effect on cell apoptosis, oxidative stress, and expression of AGT1R and p47(phox). In addition, high-glucose medium did not increase cleaved caspase 3 in AGTR1 knockdown experiments. Thus, our results indicated that testosterone prevents pancreatic beta-cell apoptosis due to glucotoxicity through reduction of the expression of ATGR1 and its signaling pathway. PMID- 25512350 TI - SRH commissioning in England: moving beyond transition. PMID- 25512351 TI - A tool to improve patient and public engagement in commissioning sexual and reproductive health and HIV services. PMID- 25512352 TI - A missed opportunity for excellence: the NICE guideline on the diagnosis and initial management of ectopic pregnancy and miscarriage. PMID- 25512353 TI - Complexities and challenges of transition to adult services in adolescents with vertically transmitted HIV infection. PMID- 25512354 TI - 'Whether ... or not?' Our on-and-off affair with pubic hair. PMID- 25512355 TI - Catholics for choice. PMID- 25512356 TI - Medical students' knowledge and perceptions regarding contraception in Karachi, Pakistan. PMID- 25512357 TI - Observation on previous comments on incomplete IUS removal. PMID- 25512358 TI - Fractured Nexplanon(r) implant. PMID- 25512360 TI - Familial-Environmental Risk Factors in South African Children With Attention Deficit Hyperactivity Disorder (ADHD): A Case-Control Study. AB - We investigated familial and environmental risk factors in a cohort of South African children diagnosed with attention-deficit hyperactivity disorder (ADHD). A prospective, hospital-based case control study was conducted comprising 50 children diagnosed with ADHD and 50 matched non-ADHD controls. The adjusted effect of familial-environmental risk factors on ADHD was determined by systematic assessment. Birth complications, parental psychiatric disorder, maternal ADHD, early childhood trauma, and nonmaternal child care were significant risk factors for ADHD. Prolonged breastfeeding was found to be protective. In a multivariable logistic regression model, 5 criteria (birth complications, breastfeeding <3 months, at least 1 parent with tertiary education, presence of parental psychiatric disorder, and nonmaternal primary caregiver) differentiated ADHD from non-ADHD controls with a sensitivity and specificity of 74% and 86%, respectively. We found a correlation between certain familial and environmental risk factors and ADHD. A 5-criterion multivariable logistic regression model may offer clinical guidance in ADHD diagnosis. PMID- 25512359 TI - Pregnancy desire and dual method contraceptive use among people living with HIV attending clinical care in Kenya, Namibia and Tanzania. AB - AIM: To describe factors associated with pregnancy desire and dual method use among people living with HIV in clinical care in sub-Saharan Africa. DESIGN: Sexually active HIV-positive adults were enrolled in 18 HIV clinics in Kenya, Namibia and Tanzania. Demographic, clinical and reproductive health data were captured by interview and medical record abstraction. Correlates of desiring a pregnancy within the next 6 months, and dual method use [defined as consistent condom use together with a highly effective method of contraception (hormonal, intrauterine device (IUD), permanent)], among those not desiring pregnancy, were identified using logistic regression. RESULTS: Among 3375 participants (median age 37 years, 42% male, 64% on antiretroviral treatment), 565 (17%) desired a pregnancy within the next 6 months. Of those with no short-term fertility desire (n=2542), 686 (27%) reported dual method use, 250 (10%) highly effective contraceptive use only, 1332 (52%) condom use only, and 274 (11%) no protection. Respondents were more likely to desire a pregnancy if they were from Namibia and Tanzania, male, had a primary education, were married/cohabitating, and had fewer children. Factors associated with increased likelihood of dual method use included being female, being comfortable asking a partner to use a condom, and communication with a health care provider about family planning. Participants who perceived that their partner wanted a pregnancy were less likely to report dual method use. CONCLUSIONS: There was low dual method use and low use of highly effective contraception. Contraceptive protection was predominantly through condom-only use. These findings demonstrate the importance of integrating reproductive health services into routine HIV care. PMID- 25512361 TI - Pathophysiology and Management of Moderate and Severe Traumatic Brain Injury in Children. AB - Traumatic brain injury remains a leading cause of morbidity and mortality in children. Key pathophysiologic processes of traumatic brain injury are initiated by mechanical forces at the time of trauma, followed by complex excitotoxic cascades associated with compromised cerebral autoregulation and progressive edema. Acute care focuses on avoiding secondary insults, including hypoxia, hypotension, and hyperthermia. Children with moderate or severe traumatic brain injury often require intensive monitoring and treatment of multiple parameters, including intracranial pressure, blood pressure, metabolism, and seizures, to minimize secondary brain injury. Child neurologists can play an important role in acute and long-term care. Acutely, as members of a multidisciplinary team in the intensive care unit, child neurologists monitor for early signs of neurological change, guide neuroprotective therapies, and transition patients to long-term recovery. In the longer term, neurologists are uniquely positioned to treat complications of moderate and severe traumatic brain injury, including epilepsy and cognitive and behavioral issues. PMID- 25512362 TI - The Association of Cytokine Levels With Cognitive Function in Children With Sickle Cell Disease and Normal MRI Studies of the Brain. AB - Children with sickle cell disease, including those without evidence for cerebral infarcts, are at increased risk for cognitive deficits that can contribute to difficulties in academic and social functioning. Chronic inflammatory processes are endemic to sickle cell disease and are apparent in common comorbidities including asthma. Cytokines mediating inflammatory processes can influence cognition. The authors examined the relationship between plasma levels of cytokines commonly associated with asthma and cognitive functioning using standardized neuropsychological measures in 25 children with sickle cell disease with normal magnetic resonance imaging studies of the brain. Children with sickle cell disease performed significantly below the normative mean on tests of cognitive function. Pearson correlations indicated significant negative relations between cytokines (IL-4, IL-5, IL-8, and IL-13) and standardized tests of executive function (r = -.54 to -.74). Preliminary evidence suggests an association between cytokine levels and executive function in children with sickle cell disease, indicating a potential role for inflammatory processes in cognitive outcomes in these children. PMID- 25512363 TI - Characteristic neuroradiologic features in hemorrhagic shock and encephalopathy syndrome. AB - Hemorrhagic shock and encephalopathy syndrome is a devastating disease, but the pathogenesis remains unclear. The aim of this study was to examine the usefulness of neuroimaging in establishing a diagnosis and elucidating the pathogenesis. We analyzed the neuroradiologic features of 22 patients who fulfilled the Levin criteria. All patients underwent brain computed tomography (CT), and 14 patients underwent brain magnetic resonance imaging (MRI) including diffusion-weighted imaging in 10 patients. Initial CT showed normal findings in 14 of 18 (78%) patients, but subsequently hypodensities appeared in bilateral watershed zones and progressed to whole brain edema. MRI revealed cytotoxic edema, showing hyperintensities in bilateral watershed zones on diffusion-weighted imaging with a low apparent diffusion coefficient. Serial neuroimaging showed characteristic features of a widespread brain ischemic event mainly in watershed zones in hemorrhagic shock and encephalopathy syndrome. PMID- 25512365 TI - Rural living in India is linked to lower risk of breast cancer, study finds. PMID- 25512364 TI - Gender differences in the association between stop-signal reaction times, body mass indices and/or spontaneous food intake in pre-school children: an early model of compromised inhibitory control and obesity. AB - BACKGROUND: Poor inhibitory control is associated with overeating and/or obesity in school-age children, adolescents and adults. The current study examined whether an objective and reliable marker of response inhibition, the stop-signal reaction time (SSRT), is associated with body mass index (BMI) z-scores and/or food intake during a snack test in pre-school children. METHODS: The current sample consisted of 193 pre-school children taking part in a longitudinal study of early brain development (Maternal Adversity, Vulnerability and Neurodevelopment (the MAVAN project)). Linear mixed-effect models were used to examine whether the SSRT measured at age 48 months associated with BMI z-scores and/or dietary intake during a laboratory-based snack test. RESULTS: After controlling for significant covariates including maternal BMI, there was a significant gender by SSRT interaction effect in predicting 48-month BMI z scores. Post-hoc analysis revealed an association between longer SSRTs (poor response inhibition) and higher BMIs in girls but not boys. Across both girls and boys, longer SSRTs were associated with greater intake of carbohydrates and sugars during the snack test. The association between SSRT scores and BMI z scores in girls was not statistically mediated by carbohydrate or sugar intake. CONCLUSIONS: At 48 months of age, slower response inhibition on the Stop-Signal Task associates with higher BMI z-scores in girls, and with higher intake of carbohydrates and sugars during a snack test across both genders. Ongoing follow up of these children will help clarify the implications of these associations for longer term macronutrient intake, eating-related pathology and/or pathological weight gain over time. PMID- 25512366 TI - S6K is a morphogenic protein with a mechanism involving Filamin-A phosphorylation and phosphatidic acid binding. AB - Change of cell shape in vivo plays many roles that are central to life itself, such as embryonic development, inflammation, wound healing, and pathologic processes such as cancer metastasis. Nonetheless, the spatiotemporal mechanisms that control the concerted regulation of cell shape remain understudied. Here, we show that ribosomal S6K, which is normally considered a protein involved in protein translation, is a morphogenic protein. Its presence in cells alters the overall organization of the cell surface and cell circularity [(4pi * area)/(perimeter)(2)] from 0.47 +/- 0.06 units in mock-treated cells to 0.09 +/- 0.03 units in S6K-overexpressing macrophages causing stellation and arborization of cell shape. This effect was partially reversed in cells expressing a kinase inactive S6K mutant and was fully reversed in cells silenced with small interference RNA. Equally important is that S6K is itself regulated by phospholipids, specifically phosphatidic acid, whereby 300 nM 1,2-dioleoyl-sn glycero-3-phosphate (DOPA), but not the control 1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC), binds directly to S6K and causes an ~ 2.9-fold increase in S6K catalytic activity. This was followed by an increase in Filamin A (FLNA) functionality as measured by phospho-FLNA (S(2152)) expression and by a subsequent elevation of actin nucleation. This reliance of S6K on phosphatidic acid (PA), a curvature-inducing phospholipid, explained the extra-large perimeter of cells that overexpressed S6K. Furthermore, the diversity of the response to S6K in several unrelated cell types (fibroblasts, leukocytes, and invasive cancer cells) that we report here indicates the existence of an underlying common mechanism in mammalian cells. This new signaling set, PA-S6K-FLNA-actin, sheds light for the first time into the morphogenic pathway of cytoskeletal structures that are crucial for adhesion and cell locomotion during inflammation and metastasis. PMID- 25512368 TI - US could recycle 10 million unused prescription drugs a year, report says. PMID- 25512369 TI - Thrombopoietin receptor agonists protect human cardiac myocytes from injury by activation of cell survival pathways. AB - Thrombopoietin confers immediate protection against injury caused by ischemia/reperfusion in the rat heart. Eltrombopag is a small molecule agonist of the thrombopoietin receptor, the physiologic target of thrombopoietin. However, the ability of eltrombopag and thrombopoietin to protect human cardiac myocytes against injury and the mechanisms underlying myocyte protection are not known. Human cardiac myocytes (n = 6-10/group) were treated with eltrombopag (0.1-30.0 uM) or thrombopoietin (0.1-30.0 ng/ml) and then subjected to 5 hours of hypoxia (95% N2/5% CO2) and 16 hours of reoxygenation to determine their ability to confer resistance to myocardial injury. The thrombopoietin receptor c-Mpl was detected in unstimulated human cardiac myocytes by Western blotting. Eltrombopag and thrombopoietin confer immediate protection to human cardiac myocytes against injury from hypoxia/reoxygenation by decreasing necrotic and apoptotic cell death in a concentration-dependent manner, with an optimal concentration of 3 uM for eltrombopag and 1.0 ng/ml for thrombopoietin. The extent of protection conferred with eltrombopag is equivalent to that of thrombopoietin. Eltrombopag and thrombopoietin activate multiple prosurvival pathways; inhibition of Janus kinase 2, proto-oncogene tyrosine-protein kinase, protein kinase B/phosphatidylinositol 3 kinase, p44/42 mitogen-activated protein kinase (MAPK), and p38 MAPK abolished cardiac myocyte protection by eltrombopag and thrombopoietin. Eltrombopag and thrombopoietin may represent important and potent agents for immediately and substantially increasing protection of human cardiac myocytes, and may offer a long-lasting benefit through activation of prosurvival pathways during ischemia. PMID- 25512367 TI - PIN1 inhibition suppresses osteoclast differentiation and inflammatory responses. AB - Inflammatory responses and osteoclast differentiation play pivotal roles in the pathogenesis of osteolytic bone diseases such as periodontitis. Although overexpression or inhibition of peptidyl-prolyl cis/trans isomerase NIMA interacting 1 (PIN1) offers a possible therapeutic strategy for chronic inflammatory diseases, the role of PIN1 in periodontal disease is unclear. The aim of the present study was to evaluate PIN1 expression in periodontitis patients as well as the effects of PIN1 inhibition by juglone or PIN1 small interfering RNA (siRNA) and of PIN1 overexpression using a recombinant adenovirus encoding PIN1 (Ad-PIN1) on the inflammatory response and osteoclastic differentiation in lipopolysaccharide (LPS)- and nicotine-stimulated human periodontal ligament cells (PDLCs). PIN1 was up-regulated in chronically inflamed PDLCs from periodontitis patients and in LPS- and nicotine-exposed PDLCs. Inhibition of PIN1 by juglone or knockdown of PIN1 gene expression by siRNA markedly attenuated LPS- and nicotine-stimulated prostaglandin E2 (PGE2) and nitric oxide (NO) production, as well as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, whereas PIN1 overexpression by Ad-PIN1 increased it. LPS- and nicotine-induced nuclear factor (NF)-kappaB activation was blocked by juglone and PIN1 siRNA but increased by Ad-PIN1. Conditioned medium prepared from LPS- and nicotine-treated PDLCs increased the number of tartrate resistant acid phosphatase-stained osteoclasts and osteoclast-specific gene expression. These responses were blocked by PIN1 inhibition and silencing but stimulated by Ad-PIN1. Furthermore, juglone and PIN1 siRNA inhibited LPS- and nicotine-induced osteoclastogenic cytokine expression in PDLCs. This study is the first to demonstrate that PIN1 inhibition exhibits anti-inflammatory effects and blocks osteoclastic differentiation in LPS- and nicotine-treated PDLCs. PIN1 inhibition may be a therapeutic strategy for inflammatory osteolysis in periodontal disease. PMID- 25512371 TI - Another time: England, 1936. PMID- 25512370 TI - Mechanistic basis of altered morphine disposition in nonalcoholic steatohepatitis. AB - Morphine is metabolized in humans to morphine-3-glucuronide (M3G) and the pharmacologically active morphine-6-glucuronide (M6G). The hepatobiliary disposition of both metabolites relies upon multidrug resistance-associated proteins Mrp3 and Mrp2, located on the sinusoidal and canalicular membrane, respectively. Nonalcoholic steatohepatitis (NASH), the severe stage of nonalcoholic fatty liver disease, alters xenobiotic metabolizing enzyme and transporter function. The purpose of this study was to determine whether NASH contributes to the large interindividual variability and postoperative adverse events associated with morphine therapy. Male Sprague-Dawley rats were fed a control diet or a methionine- and choline-deficient diet to induce NASH. Radiolabeled morphine (2.5 mg/kg, 30 uCi/kg) was administered intravenously, and plasma and bile (0-150 or 0-240 minutes), liver and kidney, and cumulative urine were analyzed for morphine and M3G. The antinociceptive response to M6G (5 mg/kg) was assessed (0-12 hours) after direct intraperitoneal administration since rats do not produce M6G. NASH caused a net decrease in morphine concentrations in the bile and plasma and a net increase in the M3G/morphine plasma area under the concentration-time curve ratio, consistent with upregulation of UDP glucuronosyltransferase Ugt2b1. Despite increased systemic exposure to M3G, NASH resulted in decreased biliary excretion and hepatic accumulation of M3G. This shift toward systemic retention is consistent with the mislocalization of canalicular Mrp2 and increased expression of sinusoidal Mrp3 in NASH and may correlate to increased antinociception by M6G. Increased metabolism and altered transporter regulation in NASH provide a mechanistic basis for interindividual variability in morphine disposition that may lead to opioid-related toxicity. PMID- 25512372 TI - Obesity is associated with visit-to-visit systolic blood pressure variability in the US adults. AB - BACKGROUND: Evidence has accumulated showing that blood pressure variability is associated with cardiovascular disease. A substantial increase in the prevalence of obesity has been documented globally. Our objective was to examine the relation of total and central obesity on visit-to-visit blood pressure variability. METHODS: We used data collected from the cross-sectional Third National Health and Nutrition Examination Survey, to examine the association of visit-to-visit blood pressure variability with body mass index and waist circumference. RESULTS: The analysis included 14,988 participants. The participants' mean age was 43.45 years. Visit-to-visit systolic blood pressure variability was associated with a body mass index >=30 and a large waist circumference (beta coefficients were 0.25 and 0.31, respectively, P-values < 0.01). Neither the bivariate nor the multivariable analyses showed significant relationships between the obesity indicators and diastolic blood pressure variability. CONCLUSIONS: Obesity is associated with visit-to-visit systolic blood pressure variability. Additional research is required to replicate the reported results in prospective studies and evaluate approaches to reduce blood pressure variability observed in clinical settings among obese persons to reduce its subsequent complications. PMID- 25512373 TI - An active immune defense with a minimal CRISPR (clustered regularly interspaced short palindromic repeats) RNA and without the Cas6 protein. AB - The prokaryotic immune system CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated) is a defense system that protects prokaryotes against foreign DNA. The short CRISPR RNAs (crRNAs) are central components of this immune system. In CRISPR-Cas systems type I and III, crRNAs are generated by the endonuclease Cas6. We developed a Cas6b-independent crRNA maturation pathway for the Haloferax type I-B system in vivo that expresses a functional crRNA, which we termed independently generated crRNA (icrRNA). The icrRNA is effective in triggering degradation of an invader plasmid carrying the matching protospacer sequence. The Cas6b-independent maturation of the icrRNA allowed mutation of the repeat sequence without interfering with signals important for Cas6b processing. We generated 23 variants of the icrRNA and analyzed them for activity in the interference reaction. icrRNAs with deletions or mutations of the 3' handle are still active in triggering an interference reaction. The complete 3' handle could be removed without loss of activity. However, manipulations of the 5' handle mostly led to loss of interference activity. Furthermore, we could show that in the presence of an icrRNA a strain without Cas6b (Deltacas6b) is still active in interference. PMID- 25512374 TI - Angiotensin II type I and prostaglandin F2alpha receptors cooperatively modulate signaling in vascular smooth muscle cells. AB - The angiotensin II type I (AT1R) and the prostaglandin F2alpha (PGF2alpha) F prostanoid (FP) receptors are both potent regulators of blood pressure. Physiological interplay between AT1R and FP has been described. Abdominal aortic ring contraction experiments revealed that PGF2alpha-dependent activation of FP potentiated angiotensin II-induced contraction, whereas FP antagonists had the opposite effect. Similarly, PGF2alpha-mediated vasoconstriction was symmetrically regulated by co-treatment with AT1R agonist and antagonist. The underlying canonical Galphaq signaling via production of inositol phosphates mediated by each receptor was also regulated by antagonists for the other receptor. However, binding to their respective agonists, regulation of receptor-mediated MAPK activation and vascular smooth muscle cell growth were differentially or asymmetrically regulated depending on how each of the two receptors were occupied by either agonist or antagonist. Physical interactions between these receptors have never been reported, and here we show that AT1R and FP form heterodimeric complexes in both HEK 293 and vascular smooth muscle cells. These findings imply that formation of the AT1R/FP dimer creates a novel allosteric signaling unit that shows symmetrical and asymmetrical signaling behavior, depending on the outcome measured. AT1R/FP dimers may thus be important in the regulation of blood pressure. PMID- 25512375 TI - The B-type channel is a major route for iron entry into the ferroxidase center and central cavity of bacterioferritin. AB - Bacterioferritin is a bacterial iron storage and detoxification protein that is capable of forming a ferric oxyhydroxide mineral core within its central cavity. To do this, iron must traverse the bacterioferritin protein shell, which is expected to occur through one or more of the channels through the shell identified by structural studies. The size and negative electrostatic potential of the 24 B-type channels suggest that they could provide a route for iron into bacterioferritin. Residues at the B-type channel (Asn-34, Glu-66, Asp-132, and Asp-139) of E. coli bacterioferritin were substituted to determine if they are important for iron core formation. A significant decrease in the rates of initial oxidation of Fe(II) at the ferroxidase center and subsequent iron mineralization was observed for the D132F variant. The crystal structure of this variant shows that substitution of residue 132 with phenylalanine caused a steric blockage of the B-type channel and no other material structural perturbation. We conclude that the B-type channel is a major route for iron entry into both the ferroxidase center and the iron storage cavity of bacterioferritin. PMID- 25512376 TI - Inhibited insulin signaling in mouse hepatocytes is associated with increased phosphatidic acid but not diacylglycerol. AB - Although an elevated triacylglycerol content in non-adipose tissues is often associated with insulin resistance, the mechanistic relationship remains unclear. The data support roles for intermediates in the glycerol-3-phosphate pathway of triacylglycerol synthesis: diacylglycerol (DAG), which may cause insulin resistance in liver by activating PKCepsilon, and phosphatidic acid (PA), which inhibits insulin action in hepatocytes by disrupting the assembly of mTOR and rictor. To determine whether increases in DAG and PA impair insulin signaling when produced by pathways other than that of de novo synthesis, we examined primary mouse hepatocytes after enzymatically manipulating the cellular content of DAG or PA. Overexpressing phospholipase D1 or phospholipase D2 inhibited insulin signaling and was accompanied by an elevated cellular content of total PA, without a change in total DAG. Overexpression of diacylglycerol kinase-theta inhibited insulin signaling and was accompanied by an elevated cellular content of total PA and a decreased cellular content of total DAG. Overexpressing glycerol-3-phosphate acyltransferase-1 or -4 inhibited insulin signaling and increased the cellular content of both PA and DAG. Insulin signaling impairment caused by overexpression of phospholipase D1/D2 or diacylglycerol kinase-theta was always accompanied by disassociation of mTOR/rictor and reduction of mTORC2 kinase activity. However, although the protein ratio of membrane to cytosolic PKCepsilon increased, PKC activity itself was unaltered. These data suggest that PA, but not DAG, is associated with impaired insulin action in mouse hepatocytes. PMID- 25512377 TI - Amyloid form of ovalbumin evokes native antigen-specific immune response in the host: prospective immuno-prophylactic potential. AB - Amyloids are highly organized protein aggregates that arise from inappropriately folded versions of proteins or polypeptides under both physiological as well as simulated ambiences. Once thought to be irreversible assemblies, amyloids have begun to expose their more dynamic and reversible attributes depending upon the intrinsic properties of the precursor protein/peptide and experimental conditions such as temperature, pressure, structural modifications in proteins, or presence of chemicals in the reaction mixture. It has been repeatedly proposed that amyloids undergo transformation to the bioactive peptide/protein forms under specific conditions. In the present study, amyloids assembled from the model protein ovalbumin (OVA) were found to release the precursor protein in a slow and steady manner over an extended time period. Interestingly, the released OVA from amyloid depot was found to exhibit biophysical characteristics of native protein and reacted with native-OVA specific monoclonal as well as polyclonal antibodies. Moreover, antibodies generated upon immunization of OVA amyloidal aggregates or fibrils were found to recognize the native form of OVA. The study suggests that amyloids may act as depots for the native form of the protein and therefore can be exploited as vaccine candidates, where slow antigen release over extended time periods is a pre-requisite for the development of desired immune response. PMID- 25512378 TI - Oxidative stress-induced inhibition of Sirt1 by caveolin-1 promotes p53-dependent premature senescence and stimulates the secretion of interleukin 6 (IL-6). AB - Oxidative stress can induce premature cellular senescence. Senescent cells secrete various growth factors and cytokines, such as IL-6, that can signal to the tumor microenvironment and promote cancer cell growth. Sirtuin 1 (Sirt1) is a class III histone deacetylase that regulates a variety of physiological processes, including senescence. We found that caveolin-1, a structural protein component of caveolar membranes, is a direct binding partner of Sirt1, as shown by the binding of the scaffolding domain of caveolin-1 (amino acids 82-101) to the caveolin-binding domain of Sirt1 (amino acids 310-317). Our data show that oxidative stress promotes the sequestration of Sirt1 into caveolar membranes and the interaction of Sirt1 with caveolin-1, which lead to inhibition of Sirt1 activity. Reactive oxygen species stimulation promotes acetylation of p53 and premature senescence in wild-type but not caveolin-1 null mouse embryonic fibroblasts (MEFs). Either down-regulation of Sirt1 expression or re-expression of caveolin-1 in caveolin-1 null MEFs restores reactive oxygen species-induced acetylation of p53 and premature senescence. In addition, overexpression of caveolin-1 induces stress induced premature senescence in p53 wild-type but not p53 knockout MEFs. Phosphorylation of caveolin-1 on tyrosine 14 promotes the sequestration of Sirt1 into caveolar membranes and activates p53/senescence signaling. We also identified IL-6 as a caveolin-1-specific cytokine that is secreted by senescent fibroblasts following the caveolin-1-mediated inhibition of Sirt1. The caveolin-1-mediated secretion of IL-6 by senescent fibroblasts stimulates the growth of cancer cells. Therefore, by inhibiting Sirt1, caveolin-1 links free radicals to the activation of the p53/senescence pathway and the protumorigenic properties of IL-6. PMID- 25512379 TI - Cytidine deaminase motifs within the DYW domain of two pentatricopeptide repeat containing proteins are required for site-specific chloroplast RNA editing. AB - In angiosperm organelles, cytidines are converted to uridines by a deamination reaction in the process termed RNA editing. The C targets of editing are recognized by members of the pentatricopeptide repeat (PPR) protein family. Although other members of the editosome have begun to be identified, the enzyme that catalyzes the C-U conversion is still unknown. The DYW motif at the C terminus of many PPR editing factors contains residues conserved with known cytidine deaminase active sites; however, some PPR editing factors lack a DYW motif. Furthermore, in many PPR-DYW editing factors, the truncation of the DYW motif does not affect editing efficiency, so the role of the DYW motif in RNA editing is unclear. Here, a chloroplast PPR-DYW editing factor, quintuple editing factor 1 (QED1), was shown to affect five different plastid editing sites, the greatest number of chloroplast C targets known to be affected by a single PPR protein. Loss of editing at the five sites resulted in stunted growth and accumulation of apparent photodamage. Adding a C-terminal protein tag to QED1 was found to severely inhibit editing function. QED1 and RARE1, another plastid PPR DYW editing factor, were discovered to require their DYW motifs for efficient editing. To identify specific residues critical for editing, conserved deaminase residues in each PPR protein were mutagenized. The mutant PPR proteins, when expressed in qed1 or rare1 mutant protoplasts, could not complement the editing defect. Therefore, the DYW motif, and specifically, the deaminase residues, of QED1 and RARE1 are required for editing efficiency. PMID- 25512382 TI - Kinetic and structural characterization of the interaction between the FMN binding domain of cytochrome P450 reductase and cytochrome c. AB - Cytochrome P450 reductase (CPR) is a diflavin enzyme that transfers electrons to many protein partners. Electron transfer from CPR to cyt c has been extensively used as a model reaction to assess the redox activity of CPR. CPR is composed of multiple domains, among which the FMN binding domain (FBD) is the direct electron donor to cyt c. Here, electron transfer and complex formation between FBD and cyt c are investigated. Electron transfer from FBD to cyt c occurs at distinct rates that are dependent on the redox states of FBD. When compared with full-length CPR, FBD reduces cyt c at a higher rate in both the semiquinone and hydroquinone states. The NMR titration experiments reveal the formation of dynamic complexes between FBD and cyt c on a fast exchange time scale. Chemical shift mapping identified residues of FBD involved in the binding interface with cyt c, most of which are located in proximity to the solvent-exposed edge of the FMN cofactor along with other residues distributed around the surface of FBD. The structural model of the FBD-cyt c complex indicates two possible orientations of complex formation. The major complex structure shows a salt bridge formation between Glu 213/Glu-214 of FBD and Lys-87 of cyt c, which may be essential for the formation of the complex, and a predicted electron transfer pathway mediated by Lys-13 of cyt c. The findings provide insights into the function of CPR and CPR-cyt c interaction on a structural basis. PMID- 25512383 TI - Mechanistic analysis of the role of bromodomain-containing protein 4 (BRD4) in BRD4-NUT oncoprotein-induced transcriptional activation. AB - NUT midline carcinoma (NMC) is a rare but highly aggressive cancer typically caused by the translocation t(15;19), which results in the formation of the BRD4 NUT fusion oncoprotein. Previous studies have demonstrated that fusion of the NUT protein with the double bromodomains of BRD4 may significantly alter the cellular gene expression profile to contribute to NMC tumorigenesis. However, the mechanistic details of this BRD4-NUT function remain poorly understood. In this study, we examined the NUT function in transcriptional regulation by targeting it to a LacO transgene array integrated in U2OS 2-6-3 cells, which allow us to visualize how NUT alters the in situ gene transcription dynamic. Using this system, we demonstrated that the NUT protein tethered to the LacO locus recruits p300/CREB-binding protein (CBP), induces histone hyperacetylation, and enriches BRD4 to the transgene array chromatin foci. We also discovered that, in BRD4-NUT expressed in NMC cells, the NUT moiety of the fusion protein anchored to chromatin by the double bromodomains also stimulates histone hyperacetylation, which causes BRD4 to bind tighter to chromatin. Consequently, multiple BRD4 interacting factors are recruited to the NUT-associated chromatin locus to activate in situ transgene expression. This gene transcription function was repressed by either expression of a dominant negative inhibitor of the p300-NUT interaction or treatment with (+)-JQ1, which dissociates BRD4 from the LacO chromatin locus. Our data support a model in which BRD4-NUT-stimulated histone hyperacetylation recruits additional BRD4 and interacting partners to support transcriptional activation, which underlies the BRD4-NUT oncogenic mechanism in NMC. PMID- 25512385 TI - West African countries plan to strengthen health systems after Ebola. PMID- 25512381 TI - Protein kinase A rescues microtubule affinity-regulating kinase 2-induced microtubule instability and neurite disruption by phosphorylating serine 409. AB - Microtubule affinity-regulating kinase 2 (MARK2)/PAR-1b and protein kinase A (PKA) are both involved in the regulation of microtubule stability and neurite outgrowth, but whether a direct cross-talk exists between them remains unclear. Here, we found the disruption of microtubule and neurite outgrowth induced by MARK2 overexpression was blocked by active PKA. The interaction between PKA and MARK2 was confirmed by coimmunoprecipitation and immunocytochemistry both in vitro and in vivo. PKA was found to inhibit MARK2 kinase activity by phosphorylating a novel site, serine 409. PKA could not reverse the microtubule disruption effect induced by a serine 409 to alanine (Ala) mutant of MARK2 (MARK2 S409A). In contrast, mutation of MARK2 serine 409 to glutamic acid (Glu) (MARK2 S409E) did not affect microtubule stability and neurite outgrowth. We propose that PKA functions as an upstream inhibitor of MARK2 in regulating microtubule stability and neurite outgrowth by directly interacting and phosphorylating MARK2. PMID- 25512380 TI - Salivary mucin 19 glycoproteins: innate immune functions in Streptococcus mutans induced caries in mice and evidence for expression in human saliva. AB - Saliva functions in innate immunity of the oral cavity, protecting against demineralization of teeth (i.e. dental caries), a highly prevalent infectious disease associated with Streptococcus mutans, a pathogen also linked to endocarditis and atheromatous plaques. Gel-forming mucins are a major constituent of saliva. Because Muc19 is the dominant salivary gel-forming mucin in mice, we studied Muc19(-/-) mice for changes in innate immune functions of saliva in interactions with S. mutans. When challenged with S. mutans and a cariogenic diet, total smooth and sulcal surface lesions are more than 2- and 1.6-fold higher in Muc19(-/-) mice compared with wild type, whereas the severity of lesions are up to 6- and 10-fold higher, respectively. Furthermore, the oral microbiota of Muc19(-/-) mice display higher levels of indigenous streptococci. Results emphasize the importance of a single salivary constituent in the innate immune functions of saliva. In vitro studies of S. mutans and Muc19 interactions (i.e. adherence, aggregation, and biofilm formation) demonstrate Muc19 poorly aggregates S. mutans. Nonetheless, aggregation is enhanced upon adding Muc19 to saliva from Muc19(-/-) mice, indicating Muc19 assists in bacterial clearance through formation of heterotypic complexes with salivary constituents that bind S. mutans, thus representing a novel innate immune function for salivary gel forming mucins. In humans, expression of salivary MUC19 is unclear. We find MUC19 transcripts in salivary glands of seven subjects and demonstrate MUC19 glycoproteins in glandular mucous cells and saliva. Similarities and differences between mice and humans in the expression and functions of salivary gel-forming mucins are discussed. PMID- 25512386 TI - Use of Google Translate in medical communication: evaluation of accuracy. PMID- 25512384 TI - The proangiogenic effect of iroquois homeobox transcription factor Irx3 in human microvascular endothelial cells. AB - Angiogenesis is a dynamic process required for embryonic development. However, postnatal vascular growth is characteristic of multiple disease states. Despite insights into the multistep process in which adhesion molecules, extracellular matrix proteins, growth factors, and their receptors work in concert to form new vessels from the preexisting vasculature, there remains a lack of insight of the nuclear transcriptional mechanisms that occur within endothelial cells (ECs) in response to VEGF. Iroquois homeobox gene 3 (Irx3) is a transcription factor of the Iroquois family of homeobox genes. Irx homeodomain transcription factors are involved in the patterning and development of several tissues. Irx3 is known for its role during embryogenesis in multiple organisms. However, the expression and function of Irx3 in human postnatal vasculature remains to be investigated. Here we show that Irx3 is expressed in human microvascular endothelial cells, and expression is elevated by VEGF stimulation. Genetic Irx3 gain and loss of function studies in human microvascular endothelial cells resulted in the modulation of EC migration during wound healing, chemotaxis and invasion, and tubulogenesis. Additionally, we observed increased delta-like ligand 4 (Dll4) expression, which suggests an increase in EC tip cell population. Finally, siRNA screening studies revealed that transient knockdown of Hey1, a downstream Notch signaling mediator, resulted in increased Irx3 expression in response to VEGF treatment. Strategies to pharmacologically regulate Irx3 function in adult endothelial cells may provide new therapies for angiogenesis. PMID- 25512388 TI - FL118 induces p53-dependent senescence in colorectal cancer cells by promoting degradation of MdmX. AB - Anticancer agent FL118 was recently identified in screening of small-molecule inhibitors of human survivin expression. Although FL118 is a camptothecin analogue, its antitumor potency is much superior to other FDA-approved camptothecin analogues (irinotecan and topotecan). The mechanism of action (MOA) underlying the antitumor effects of FL118 remains to be fully elucidated. Here, we report that FL118 activates tumor suppressor p53 as a novel MOA in p53 wild type cancer cells. Our studies show that this MOA involves an induction of proteasomal degradation of MdmX, a critical negative regulator of p53, in a manner largely independent of ATM-dependent DNA damage signaling pathway but dependent on E3-competent Mdm2. FL118 inhibits p53 polyubiquitination and monoubiquitination by Mdm2-MdmX E3 complex in cells and in cell-free systems. In contrast, FL118 stimulates Mdm2-mediated MdmX ubiquitination. Coimmunoprecipitation revealed that FL118 slightly decreases Mdm2-p53 interactions and moderately increases Mdm2-MdmX interactions, suggesting a change of targeting specificity of Mdm2-MdmX E3 complex from p53 to MdmX, resulting in accelerated MdmX degradation. As a result, p53 ubiquitination by Mdm2-MdmX E3 complex is reduced, which in turn activates p53 signaling. Activation of the p53 pathway by FL118 induces p53-dependent senescence in colorectal cancer cells. However, in the absence of p53 or in the presence of MdmX overexpression, FL118 promotes p53-independent apoptosis. These two distinct cellular consequences collectively contribute to the potent effects of FL118 to inhibit clonogenic potential of colon cancer cells. This study identifies a potential application of FL118 as an MdmX inhibitor for targeted therapies. PMID- 25512390 TI - Remodeling of secretory compartments creates CUPS during nutrient starvation. AB - Upon starvation, Grh1, a peripheral membrane protein located at endoplasmic reticulum (ER) exit sites and early Golgi in Saccharomyces cerevisiae under growth conditions, relocates to a compartment called compartment for unconventional protein secretion (CUPS). Here we report that CUPS lack Golgi enzymes, but contain the coat protein complex II (COPII) vesicle tethering protein Uso1 and the Golgi t-SNARE Sed5. Interestingly, CUPS biogenesis is independent of COPII- and COPI-mediated membrane transport. Pik1- and Sec7 mediated membrane export from the late Golgi is required for complete assembly of CUPS, and Vps34 is needed for their maintenance. CUPS formation is triggered by glucose, but not nitrogen starvation. Moreover, upon return to growth conditions, CUPS are absorbed into the ER, and not the vacuole. Altogether our findings indicate that CUPS are not specialized autophagosomes as suggested previously. We suggest that starvation triggers relocation of secretory and endosomal membranes, but not their enzymes, to generate CUPS to sort and secrete proteins that do not enter, or are not processed by enzymes of the ER-Golgi pathway of secretion. PMID- 25512391 TI - KIF4A and PP2A-B56 form a spatially restricted feedback loop opposing Aurora B at the anaphase central spindle. AB - The mitotic kinase Aurora B is concentrated at the anaphase central spindle by the kinesin MKlp2 during mitotic exit and cytokinesis. This pool of Aurora B phosphorylates substrates including the kinesin KIF4A to regulate central spindle length. In this paper, we identify a counteracting system in which PP2A-B56gamma and -epsilon, but not PP2A-B56alpha, -beta, and -delta, are maintained at the central spindle by KIF4A. Biochemical assays show that PP2A-B56gamma can dephosphorylate the T799 Aurora B site on KIF4A and thereby counteract the Aurora B- and microtubule-stimulated ATPase activity of KIF4A. In agreement with these observations, combined silencing of PP2A-B56gamma and -epsilon resulted in increased phosphorylation of KIF4A T799 and decreased central spindle growth in anaphase B. Furthermore, reduced turnover of regulatory phosphorylation on another Aurora B substrate MKlp1 was observed, suggesting that PP2A-B56gamma and epsilon play a general role opposing Aurora B at the central spindle. KIF4A and PP2A-B56gamma and -epsilon therefore create a spatially restricted negative feedback loop counteracting Aurora B in anaphase. PMID- 25512392 TI - Thyroid hormone regulates muscle fiber type conversion via miR-133a1. AB - It is known that thyroid hormone (TH) is a major determinant of muscle fiber composition, but the molecular mechanism by which it does so remains unclear. Here, we demonstrated that miR-133a1 is a direct target gene of TH in muscle. Intriguingly, miR-133a, which is enriched in fast-twitch muscle, regulates slow to-fast muscle fiber type conversion by targeting TEA domain family member 1 (TEAD1), a key regulator of slow muscle gene expression. Inhibition of miR-133a in vivo abrogated TH action on muscle fiber type conversion. Moreover, TEAD1 overexpression antagonized the effect of miR-133a as well as TH on muscle fiber type switch. Additionally, we demonstrate that TH negatively regulates the transcription of myosin heavy chain I indirectly via miR-133a/TEAD1. Collectively, we propose that TH inhibits the slow muscle phenotype through a novel epigenetic mechanism involving repression of TEAD1 expression via targeting by miR-133a1. This identification of a TH-regulated microRNA therefore sheds new light on how TH achieves its diverse biological activities. PMID- 25512394 TI - Lung ultrasound-guided emergency pneumothorax needle aspiration in a very preterm infant. AB - Pneumothorax is a frequent critical situation in the neonatal intensive care unit. Diagnosis relies on clinical judgement, transillumination and chest radiogram. We report the case of a very preterm infant suddenly developing significant and persistent desaturation and bradycardia. Re-intubation and cardiopulmonary resuscitation were performed. Clinical and cold light examination were not suggestive of pneumothorax according to two experienced neonatologists. A lung ultrasound scan showed evidence of right pneumothorax that was promptly aspirated. Approximately 20 min later, a chest radiogram confirmed the ultrasound diagnosis. Point-of-care lung ultrasound is a useful tool for detecting symptomatic pneumothorax and accelerating its treatment. PMID- 25512395 TI - Congenital sideroblastic anaemia with a novel frameshift mutation in SLC25A38. PMID- 25512396 TI - A novel clinical entity: the Campbell-Trachter syndrome. PMID- 25512397 TI - Endoscopic extraction of proximally migrated biliary stent by intrastent balloon inflation. AB - Endoscopically placed bile duct stents are commonly used to relieve obstruction in patients with benign or malignant biliary disease. These stents may become dislodged and migrate in about 5-10% of patients. Distally migrated stents can be managed expectantly, allowing the foreign body to pass through the rectum. However, proximal migration of biliary stents usually necessitates endoscopic stent removal. We present a case of a proximally migrated stent that was extracted successfully with intrastent balloon inflation during endoscopic retrograde cholangiopancreatography (ERCP). PMID- 25512398 TI - An unusual aetiology of abdominal pain: the forgotten bullet. PMID- 25512401 TI - Development and validation of an in vitro pharmacokinetic/pharmacodynamic model to test the antibacterial efficacy of antibiotic polymer conjugates. AB - This study describes the use of a novel, two-compartment, static dialysis bag model to study the release, diffusion, and antibacterial activity of a novel, bioresponsive dextrin-colistin polymer conjugate against multidrug resistant (MDR) wild-type Acinetobacter baumannii. In this model, colistin sulfate, at its MIC, produced a rapid and extensive drop in viable bacterial counts (<2 log10 CFU/ml at 4 h); however, a marked recovery was observed thereafter, with regrowth equivalent to that of control by 48 h. In contrast, dextrin-colistin conjugate, at its MIC, suppressed bacterial growth for up to 48 h, with 3 log10 CFU/ml lower bacterial counts after 48 h than those of controls. Doubling the concentration of dextrin-colistin conjugate (to 2* MIC) led to an initial bacterial killing of 3 log10 CFU/ml at 8 h, with a similar regrowth profile to 1* MIC treatment thereafter. The addition of colistin sulfate (1* MIC) to dextrin-colistin conjugate (1* MIC) resulted in undetectable bacterial counts after 4 h, followed by suppressed bacterial growth (3.5 log10 CFU/ml lower than that of control at 48 h). Incubation of dextrin-colistin conjugates with infected wound exudate from a series of burn patients (n = 6) revealed an increasing concentration of unmasked colistin in the outer compartment (OC) over time (up to 86.3% of the initial dose at 48 h), confirming that colistin would be liberated from the conjugate by endogenous alpha-amylase within the wound environment. These studies confirm the utility of this model system to simulate the pharmacokinetics of colistin formation in humans administered dextrin-colistin conjugates and further supports the development of antibiotic polymer conjugates in the treatment of MDR infections. PMID- 25512402 TI - Multilaboratory testing of antifungal drug combinations against Candida species and Aspergillus fumigatus: utility of 100 percent inhibition as the endpoint. AB - Four laboratories tested three isolates of Candida species and two isolates of Aspergillus fumigatus using 96-well plates containing combinations of amphotericin B, anidulafungin, caspofungin, micafungin, fluconazole, itraconazole, posaconazole, and voriconazole. The majority of summation fractional inhibitory concentration indices (SigmaFICI) based on the Lowe additivity formula suggested indifferent drug interactions (SigmaFICI > 0.5 and <=4.0) and no instance of drug antagonism (SigmaFICI > 4.0). The intra- and interlaboratory agreement rates were superior when MIC100 readings were used as endpoints (at a 99% confidence interval [CI]). PMID- 25512403 TI - Efficacy and safety of faldaprevir, deleobuvir, and ribavirin in treatment-naive patients with chronic hepatitis C virus infection and advanced liver fibrosis or cirrhosis. AB - Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n=362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.). PMID- 25512404 TI - In vivo pharmacokinetics and pharmacodynamics of the lantibiotic NAI-107 in a neutropenic murine thigh infection model. AB - NAI-107 is a novel lantibiotic compound with potent in vitro activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The purpose of this study was to examine the activity of NAI-107 against S. aureus strains, including MRSA, in the neutropenic murine thigh infection model. Serum pharmacokinetics were determined and time-kill studies were performed following administration of single subcutaneous doses of 5, 20, and 80 mg/kg body weight. The dose fractionation included total doses ranging from 1.56 to 400 mg/kg/72 h, divided into 1, 2, 3, or 6 doses. Studies of treatment effects against 9 S. aureus strains (4 methicillin-susceptible Staphylococcus aureus [MSSA] and 5 MRSA) using a 12-h dosing interval and total dose range of 1.56 to 400 mg/kg/72 h were also performed. A maximum effect (Emax) model was used to determine the pharmacokinetic/pharmacodynamic (PK/PD) index that best described the dose-response data and to estimate the doses required to achieve a net bacteriostatic dose (SD) and a 1-log reduction in CFU/thigh. The pharmacokinetic studies demonstrated an area under the concentration-time curve (AUC) range of 26.8 to 276 mg.h/liter and half-lives of 4.2 to 8.2 h. MICs ranged from 0.125 to 0.5 MUg/ml. The 2 highest single doses produced more than a 2-log kill and prolonged postantibiotic effects (PAEs) ranging from 36 to >72 h. The dose fractionation-response curves were similar, and the AUC/MIC ratio was the most predictive PD index (AUC/MIC, coefficient of determination [R2]=0.89; maximum concentration of drug in serum [Cmax]/MIC, R2=0.79; time [T]>MIC, R2=0.63). A >=2 log kill was observed against all 9 S. aureus strains. The total drug 24-h AUC/MIC values associated with stasis and a 1-log kill for the 9 S. aureus strains were 371+/-130 and 510+/-227, respectively. NAI-107 demonstrated concentration-dependent killing and prolonged PAEs. The AUC/MIC ratio was the predictive PD index. Extensive killing was observed for S. aureus organisms, independent of the MRSA status. The AUC/MIC target should be useful for the design of clinical dosing regimens. PMID- 25512405 TI - AbuO, a TolC-like outer membrane protein of Acinetobacter baumannii, is involved in antimicrobial and oxidative stress resistance. AB - Although Acinetobacter baumannii is well accepted as a nosocomial pathogen, only a few of the outer membrane proteins (OMPs) have been functionally characterized. In this study, we demonstrate the biological functions of AbuO, a homolog of TolC from Escherichia coli. Inactivation of abuO led to increased sensitivity to high osmolarity and oxidative stress challenge. The DeltaabuO mutant displayed increased susceptibility to antibiotics, such as amikacin, carbenicillin, ceftriaxone, meropenem, streptomycin, and tigecycline, and hospital-based disinfectants, such as benzalkonium chloride and chlorhexidine. The reverse transcription (RT)-PCR analysis indicated increased expression of efflux pumps (resistance nodulation cell division [RND] efflux pump acrD, 8-fold; SMR-type emrE homolog, 12-fold; and major facilitator superfamily [MFS]-type ampG homolog, 2.7-fold) and two-component response regulators (baeR, 4.67-fold; ompR, 10.43 fold) in the DeltaabuO mutant together with downregulation of rstA (4.22-fold) and the pilin chaperone (9-fold). The isogenic mutant displayed lower virulence in a nematode model (P<0.01). Experimental evidence for the binding of MerR-type transcriptional regulator SoxR to radiolabeled abuO promoter suggests regulation of abuO by SoxR in A. baumannii. PMID- 25512406 TI - Pharmacodynamic target evaluation of a novel oral glucan synthase inhibitor, SCY 078 (MK-3118), using an in vivo murine invasive candidiasis model. AB - Echinocandins inhibit the synthesis of beta-1,3-D-glucan in Candida and are the first-line therapy in numerous clinical settings. Their use is limited by poor oral bioavailability, and they are available only as intravenous therapies. Derivatives of enfumafungin are novel orally bioavailable glucan synthase inhibitors. We performed an in vivo pharmacodynamic (PD) evaluation with a novel enfumafungin derivative, SCY-078 (formerly MK-3118), in a well-established neutropenic murine model of invasive candidiasis against C. albicans, C. glabrata, and C. parapsilosis. The SCY-078 MICs varied 8-fold. Oral doses of 3.125 to 200 mg/kg SCY-078 salt in sterile water produced peak levels of 0.04 to 2.66 MUg/ml, elimination half-lives of 5.8 to 8.5 h, areas under the concentration-time curve from 0 to 24 h (AUC0-24 h) of 0.61 to 41.10 MUg.h/ml, and AUC from 0 to infinity (AUC0-infinity) values of 0.68 to 40.31 MUg.h/ml. The pharmacokinetics (PK) were approximately linear over the dose range studied. Maximum response (Emax) and PK/PD target identification studies were performed with 4 C. albicans, 4 C. glabrata, and 3 C. parapsilosis isolates. The PD index AUC/MIC was explored by using total (tAUC) and free (fAUC) drug concentrations. The maximum responses were 4.0, 4.0, and 4.3 log10 CFU/kidney reductions for C. albicans, C. glabrata, and C. parapsilosis, respectively. The AUC/MIC was a robust predictor of efficacy (R2, 0.53 to 0.91). The 24-h PD targets were a static dose of 63.5 mg/kg, a tAUC/MIC of 500, and an fAUC/MIC of 1.0 for C. albicans; a static dose of 58.4 mg/kg, a tAUC/MIC of 315, and an fAUC/MIC of 0.63 for C. glabrata; and a static dose of 84.4 mg/kg, a tAUC/MIC of 198, and an fAUC/MIC of 0.40 for C. parapsilosis. The mean fAUC/MIC values associated with a 1-log kill endpoint against these species were 1.42, 1.26, and 0.91 for C. albicans, C. glabrata, and C. parapsilosis, respectively. The static and 1-log kill endpoints were measured relative to the burden at the start of therapy. The static and 1-log kill doses, as well as the total and free drug AUC/MIC PD targets, were not statistically different between species but were numerically lower than those observed for echinocandins. SCY-078 is a promising novel oral glucan synthase inhibitor against Candida species, and further investigation is warranted. PMID- 25512407 TI - Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects. AB - This study evaluated the safety, tolerability, and pharmacokinetics of a posaconazole i.v. (intravenous) solution. This was a single-center, 2-part, randomized, rising single- and multiple-dose study in healthy adults. In part 1, subjects received 0 (vehicle), 50, 100, 200, 250, or 300 mg posaconazole in a single dose i.v. by 30-min peripheral infusion (6 cohorts of 12 subjects each [9 active and 3 placebo], making a total of 72 subjects). Blood samples were collected until 168 h postdose. In part 2, subjects were to receive 2 peripheral infusions at a 12-h interval on day 1 followed by once-daily infusion for 9 days. However, part 2 was terminated early because of high rates of infusion site reactions with multiple dosing at the same infusion site. The pharmacokinetics results for part 1 (n=45 subjects) showed that the mean posaconazole exposure (area under the concentration-time curve from time zero to infinity [AUC0 infinity]) ranged from 4,890 to 46,400 ng . h/ml (range of coefficient of variation values, 26 to 50). The dose-proportionality slope estimate (90% confidence interval) for AUC0-infinity was 1.30 (1.19 to 1.41), indicating a greater-than-dose-proportional increase. The data for safety in part 1 show that 29/72 subjects had >=1 adverse event. Infusion site reactions were reported in 2/9 vehicle subjects, 0/18 placebo subjects, and 7/45 i.v. posaconazole subjects. The data for safety in part 2 show that infusion site reactions were reported in 1/4 (25%) placebo subjects, 3/9 (33%) vehicle control subjects, and 4/5 (80%) i.v. posaconazole (100 mg) subjects (3 posaconazole recipients subsequently developed thrombophlebitis and were discontinued from treatment). In conclusion, the posaconazole i.v. solution showed a greater-than-dose-proportional increase in exposure, primarily at doses below 200 mg. When administered peripherally at the same infusion site, multiple dosing of i.v. posaconazole led to unacceptably high rates of infusion site reactions. Intravenous posaconazole was otherwise well tolerated. Single doses of i.v. posaconazole were tolerated when given through a peripheral vein over 30 min. PMID- 25512409 TI - Detection of QnrB54 and its novel genetic context in Citrobacter freundii isolated from a clinical case. PMID- 25512408 TI - Identification of a new amide-containing thiazole as a drug candidate for treatment of Chagas' disease. AB - Although the parasitic infection Chagas' disease was described over 100 years ago, even now there are not suitable drugs. The available drugs nifurtimox and benznidazole have limited efficacies and tolerances, with proven mutagenic effects. Attempting to find appropriate drugs to deal with this problem, here we report on the development and pharmacological characterization of new amide containing thiazoles. In the present study, we evaluated the in vitro and in vivo effects of new candidates against Trypanosoma cruzi, the etiological agent of Chagas' disease. The lead amide-containing thiazole derivative had potent in vitro activity, an absence of both in vitro mutagenic and in vivo clastogenic effects, and excellent in vitro selectivity and in vivo tolerance. The compound suppressed parasitemia in mice, modifying the anti-T. cruzi antibodies like the reference drug, benznidazole, and displayed the lowest mortality among the tested drugs. The present evidence suggests that this compound is a promising anti-T. cruzi agent surpassing the lead optimization stage in drug development and leading to a candidate for preclinical study. PMID- 25512410 TI - Do formulation differences between the reference listed drug and generic piperacillin-tazobactam impact reconstitution? AB - Pharmaceutical differences between the reference listed drug (RLD) and generic formulations of piperacillin-tazobactam may impact the reconstitution process for intravenous administration. This study evaluated the RLD against three generic formulations and measured their reconstitution times using a standardized process. The mean (standard deviation [SD]) reconstitution time for one generic formulation was 5.57 (1.49) min, which was 35% to 42% longer (P < 0.002) than that for the RLD and two other formulations. Observable microscopic differences in powder particle morphology may explain these findings. PMID- 25512411 TI - Subinhibitory concentrations of LFF571 reduce toxin production by Clostridium difficile. AB - LFF571 is a novel semisynthetic thiopeptide antibacterial that is undergoing investigation for safety and efficacy in patients with moderate Clostridium difficile infections. LFF571 inhibits bacterial protein synthesis by interacting with elongation factor Tu (EF-Tu) and interrupting complex formation between EF Tu and aminoacyl-tRNA. Given this mechanism of action, we hypothesized that concentrations of LFF571 below those necessary to inhibit bacterial growth would reduce steady-state toxin levels in C. difficile cultures. We investigated C. difficile growth and toxin A and B levels in the presence of LFF571, fidaxomicin, vancomycin, and metronidazole. LFF571 led to strain-dependent effects on toxin production, including decreased toxin levels after treatment with subinhibitory concentrations, and more rapid declines in toxin production than in inhibition of colony formation. Fidaxomicin, which is an RNA synthesis inhibitor, conferred a similar pattern to LFF571 with respect to toxin levels versus viable cell counts. The incubation of two toxigenic C. difficile strains with subinhibitory concentrations of vancomycin, a cell wall synthesis inhibitor, increased toxin levels in the supernatant over those of untreated cultures. A similar phenomenon was observed with one metronidazole-treated strain of C. difficile. These studies indicate that LFF571 and fidaxomicin generally result in decreased C. difficile toxin levels in culture supernatants, whereas treatment of some strains with vancomycin or metronidazole had the potential to increase toxin levels. Although the relevance of these findings remains to be studied in patients, reducing toxin levels with sub-growth-inhibitory concentrations of an antibiotic is hypothesized to be beneficial in alleviating symptoms. PMID- 25512412 TI - Penicillinase-encoding gene blaTEM-1 may be plasmid borne or chromosomally located in Kingella kingae species. PMID- 25512413 TI - The novel immunotherapeutic oligodeoxynucleotide IMT504 protects neutropenic animals from fatal Pseudomonas aeruginosa bacteremia and sepsis. AB - IMT504 is a novel immunomodulatory oligonucleotide that has shown immunotherapeutic properties in early preclinical and clinical studies. IMT504 was tested in a neutropenic rat model of Pseudomonas aeruginosa bacteremia and sepsis. This animal system recapitulates many of the pathological processes found in neutropenic patients with Gram-negative, bacterial infections. The research was conducted in the setting of an academic research laboratory. The test subjects were Sprague-Dawley rats. Animals were rendered neutropenic by administration of cyclophosphamide, colonized with P. aeruginosa by oral feeding, and then randomized to receive IMT504 over a range of doses and treatment regimens representing early and late therapeutic interventions. IMT504 immunotherapy conferred a significant survival advantage over the 12-day study period compared with the results seen with placebo-treated animals when the therapy was administered at the onset of neutropenia and even in the absence of antibiotics and after the onset of fever and systemic infection. Notably, even late salvage IMT504 monotherapy was highly effective (13/14 surviving rats with IMT504 therapy versus 2/14 controls, P=<0.001). Moreover, late salvage IMT504 monotherapy was as effective as antibiotic therapy (13/14 surviving rats versus 21/21 rats, P=0.88). In addition, no antagonism or loss of therapeutic efficacy was noted with combination therapy of IMT504 plus antibiotics. IMT504 immunotherapy provides a remarkable survival advantage in bacteremia and sepsis in neutropenic animals and deserves further study as a new treatment option in patients with, or at risk for, severe Gram-negative bacterial infections and sepsis. PMID- 25512414 TI - Comparison of the accuracy and precision of pharmacokinetic equations to predict free meropenem concentrations in critically ill patients. AB - Population pharmacokinetic analyses can be applied to predict optimized dosages for individual patients. The aim of this study was to compare the prediction performance of the published population pharmacokinetic models for meropenem in critically ill patients. We coded the published population pharmacokinetic models with covariate relationships into dosing software to predict unbound meropenem concentrations measured in a separate cohort of critically ill patients. The agreements between the observed and predicted concentrations were evaluated with Bland-Altman plots. The absolute and relative bias and precision of the models were determined. The clinical implications of the results were evaluated according to whether dose adjustments were required from the predictions to achieve a meropenem concentration of >2 mg/liter throughout the dosing interval. A total of 157 free meropenem concentrations from 56 patients were analyzed. Eight published population pharmacokinetic models were compared. The models showed an absolute bias in predicting the unbound meropenem concentrations from a mean percent difference (95% confidence interval [CI]) of -108.5% (-119.9% to 97.3%) to 19.9% (7.3% to 32.7%), while absolute precision ranged from -249.1% ( 263.4% to -234.8%) to 31.9% (17.6% to 46.2%) and -178.9% (-196.9% to -160.9%) to 175.0% (157.0% to 193.0%). A dose change was required in 44% to 64% of the concentration results. Seven of the eight equations evaluated underpredicted free meropenem concentrations. In conclusion, the overall accuracy of these models supports their inclusion in dosing software and application for individualizing meropenem doses in critically ill patients to increase the likelihood of achievement of optimal antibiotic exposures. PMID- 25512415 TI - Therapeutic responses of Plasmodium vivax malaria to chloroquine and primaquine treatment in northeastern Myanmar. AB - Chloroquine-primaquine (CQ-PQ) continues to be the frontline therapy for radical cure of Plasmodium vivax malaria. Emergence of CQ-resistant (CQR) P. vivax parasites requires a shift to artemisinin combination therapies (ACTs), which imposes a significant financial, logistical, and safety burden. Monitoring the therapeutic efficacy of CQ is thus important. Here, we evaluated the therapeutic efficacy of CQ-PQ for P. vivax malaria in northeast Myanmar. We recruited 587 patients with P. vivax monoinfection attending local malaria clinics during 2012 to 2013. These patients received three daily doses of CQ at a total dose of 24 mg of base/kg of body weight and an 8-day PQ treatment (0.375 mg/kg/day) commencing at the same time as the first CQ dose. Of the 401 patients who finished the 28 day follow-up, the cumulative incidence of recurrent parasitemia was 5.20% (95% confidence interval [CI], 3.04% to 7.36%). Among 361 (61%) patients finishing a 42-day follow-up, the cumulative incidence of recurrent blood-stage infection reached 7.98% (95% CI, 5.20% to 10.76%). The cumulative risk of gametocyte carriage at days 28 and 42 was 2.21% (95% CI, 0.78% to 3.64%) and 3.93% (95% CI, 1.94% to 5.92%), respectively. Interestingly, for all 15 patients with recurrent gametocytemia, this was associated with concurrent asexual stages. Genotyping of recurrent parasites at the merozoite surface protein 3alpha gene locus from 12 patients with recurrent parasitemia within 28 days revealed that 10 of these were the same genotype as at day 0, suggesting recrudescence or relapse. Similar studies in 70 patients in the same area in 2007 showed no recurrent parasitemias within 28 days. The sensitivity to chloroquine of P. vivax in northeastern Myanmar may be deteriorating. PMID- 25512418 TI - Secular trends associated with Enterobacteriaceae with a cefepime susceptible dose-dependent MIC. PMID- 25512416 TI - STING agonists induce an innate antiviral immune response against hepatitis B virus. AB - Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon (IFN) genes (STING), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), was found to induce a robust cytokine response in macrophages that efficiently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Profiling of cytokines induced by DMXAA and agonists of representative Toll-like receptors (TLRs) in mouse macrophages revealed that, unlike TLR agonists that induced a predominant inflammatory cytokine/chemokine response, the STING agonist induced a cytokine response dominated by type I IFNs. Moreover, as demonstrated in an HBV hydrodynamic mouse model, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of mice. This study thus proves the concept that activation of the STING pathway induces an antiviral cytokine response against HBV and that the development of small-molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted. PMID- 25512417 TI - Enantiospecific reassessment of the pharmacokinetics and pharmacodynamics of oral eflornithine against late-stage Trypanosoma brucei gambiense sleeping sickness. AB - This study aimed to characterize the stereoselective pharmacokinetics of oral eflornithine in 25 patients with late-stage Trypanosoma brucei gambiense sleeping sickness. A secondary aim was to determine the concentrations of L- and D eflornithine required in plasma or cerebrospinal fluid (CSF) for an efficient eradication of the T. brucei gambiense parasites. Patients were randomly allocated to receive either 100 (group I, n=12) or 125 (group II, n=13) mg/kg of body weight of drug every 6 h for 14 days. The concentrations of L- and D eflornithine in the plasma and CSF samples were measured using a stereospecific liquid chromatographic method. Nonlinear mixed-effects modeling was used to characterize the plasma pharmacokinetics. The plasma concentrations of L eflornithine were on average 52% (95% confidence interval [CI], 51, 54%; n=321) of the D-enantiomer concentrations. The typical oral clearances of L- and D eflornithine were 17.4 (95% CI, 15.5, 19.3) and 8.23 (95% CI, 7.36, 9.10) liters/h, respectively. These differences were likely due to stereoselective intestinal absorption. The distributions of eflornithine enantiomers to the CSF were not stereoselective. A correlation was found between the probability of cure and plasma drug exposure, although it was not more pronounced for the L enantiomer than for that of total eflornithine. This study may explain why oral treatment for late-stage human African trypanosomiasis (HAT) patients with racemic eflornithine has previously failed; the more potent L-enantiomer is present at much lower concentrations in both plasma and CSF than those of the D enantiomer. Eflornithine stereoselective pharmacokinetics needs to be considered if an oral dosage regimen is to be explored further. PMID- 25512419 TI - Postexposure prophylactic effect of hepatitis B virus (HBV)-active antiretroviral therapy against HBV infection. AB - Retrospective study indicates that hepatitis B virus (HBV)-active nucleoside (nucleotide) analogues (NAs) used for antiretroviral therapy reduce the incidence of acute HBV infections in human immunodeficiency virus (HIV)-infected patients. Learning from HIV postexposure prophylaxis (PEP), we explored the possibility of using NAs in PEP following HBV exposure, if preexposure prophylaxis is feasible clinically. Using freshly isolated primary human hepatocytes cultured in vitro, we analyzed the effect of HBV-active tenofovir and lamivudine in primary HBV infection and also the effect of treatment with these NAs after HBV infection. HBV-active NAs applied from 24 h before inoculation could not prevent the secretion of hepatitis B surface antigen into the culture medium, and cessation of the NAs after inoculation allowed the cells to establish an apparent HBV infection. In contrast, hepatitis B immune globulin was able to prevent HBV infection completely. NA treatment before infection, however, can control the spread of HBV infection, as detected by immunohistochemistry. Practically, starting NA treatment within 2 days of primary HBV infection inhibited viral spread effectively, as well as preexposure treatment. We demonstrated that preexposure NA treatment was not able to prevent the acquisition of HBV infection but prevented viral spread by suppressing the production of mature progeny HBV virions. The effect of postexposure treatment within 2 days was similar to the effect of preexposure treatment, suggesting the possibility of HBV PEP using HBV active NAs in HIV- and HBV-susceptible high-risk groups. PMID- 25512420 TI - First detection of conjugative plasmid-borne fosfomycin resistance gene fosA3 in Salmonella isolates of food origin. PMID- 25512422 TI - Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects. AB - This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331.). PMID- 25512421 TI - Potent Plasmodium falciparum gametocytocidal activity of diaminonaphthoquinones, lead antimalarial chemotypes identified in an antimalarial compound screen. AB - Forty percent of the world's population is threatened by malaria, which is caused by Plasmodium parasites and results in an estimated 200 million clinical cases and 650,000 deaths each year. Drug resistance has been reported for all commonly used antimalarials and has prompted screens to identify new drug candidates. However, many of these new candidates have not been evaluated against the parasite stage responsible for transmission, gametocytes. If Plasmodium falciparum gametocytes are not eliminated, patients continue to spread malaria for weeks after asexual parasite clearance. Asymptomatic individuals can also harbor gametocyte burdens sufficient for transmission, and a safe, effective gametocytocidal agent could also be used in community-wide malaria control programs. Here, we identify 15 small molecules with nanomolar activity against late-stage gametocytes. Fourteen are diaminonaphthoquinones (DANQs), and one is a 2-imino-benzo[d]imidazole (IBI). One of the DANQs identified, SJ000030570, is a lead antimalarial candidate. In contrast, 94% of the 650 compounds tested are inactive against late-stage gametocytes. Consistent with the ineffectiveness of most approved antimalarials against gametocytes, of the 19 novel compounds with activity against known anti-asexual-stage targets, only 3 had any strong effect on gametocyte viability. These data demonstrate the distinct biology of the transmission stages and emphasize the importance of screening for gametocytocidal activity. The potent gametocytocidal activity of DANQ and IBI coupled with their efficacy against asexual parasites provides leads for the development of antimalarials with the potential to prevent both the symptoms and the spread of malaria. PMID- 25512424 TI - Imipenem-susceptible, meropenem-resistant Klebsiella pneumoniae producing OXA-181 in Japan. PMID- 25512423 TI - Detailed mutational analysis of Vga(A) interdomain linker: implication for antibiotic resistance specificity and mechanism. AB - Detailed mutational analysis examines the roles of individual residues of the Vga(A) linker in determining the antibiotic resistance phenotype. It defines a narrowed region of residues 212 to 220 whose composition determines the resistance specificity to lincosamides, pleuromutilins, and/or streptogramins A. From the analogy with the recently described function of the homologous ABC-F protein EttA as a translational factor, we infer that the Vga(A) linker interacts with the ribosome and directly or indirectly affects the binding of the respective antibiotic. PMID- 25512425 TI - Vancomycin-variable enterococci can give rise to constitutive resistance during antibiotic therapy. AB - Vancomycin-resistant enterococci (VRE) are notorious clinical pathogens restricting the use of glycopeptide antibiotics in the clinic setting. Routine surveillance to detect VRE isolated from patients relies on PCR bioassays and chromogenic agar-based test methods. In recent years, we and others have reported the emergence of enterococcal strains harboring a "silent" copy of vancomycin resistance genes that confer a vancomycin-susceptible phenotype (vancomycin susceptible enterococci [VSE]) and thus escape detection using drug sensitivity screening tests. Alarmingly, these strains are able to convert to a resistance phenotype (VSE->VRE) during antibiotic treatment, severely compromising the success of therapy. Such strains have been termed vancomycin-variable enterococci (VVE). We have investigated the molecular mechanisms leading to the restoration of resistance in VVE isolates through the whole-genome sequencing of resistant isolates, measurement of resistance gene expression, and quantification of the accumulation of drug-resistant peptidoglycan precursors. The results demonstrate that VVE strains can revert to a VRE phenotype through the constitutive expression of the vancomycin resistance cassette. This is accomplished through a variety of changes in the DNA region upstream of the resistance genes that includes both a deletion of a likely transcription inhibitory secondary structure and the introduction of a new unregulated promoter. The VSE->VRE transition of VVE can occur in patients during the course of antibiotic therapy, resulting in treatment failure. These VVE strains therefore pose a new challenge to the current regimen of diagnostic tests used for VRE detection in the clinic setting. PMID- 25512426 TI - Synergistic activity of chloroquine with fluconazole against fluconazole resistant isolates of Candida species. AB - The in vitro activity of chloroquine and the interactions of chloroquine combined with fluconazole against 37 Candida isolates were tested using the broth microdilution, disk diffusion, and Etest susceptibility tests. Synergistic effect was detected with 6 of 9 fluconazole-resistant Candida albicans isolates, with Candida krusei ATCC 6258, and with all 12 fluconazole-resistant Candida tropicalis isolates. PMID- 25512427 TI - Antimalarial iron chelator FBS0701 blocks transmission by Plasmodium falciparum gametocyte activation inhibition. AB - Reducing the transmission of the malarial parasite by Anopheles mosquitoes using drugs or vaccines remains a main focus in the efforts to control malaria. Iron chelators have been studied as potential antimalarial drugs due to their activities against different stages of the parasite. The iron chelator FBS0701 affects the development of Plasmodium falciparum early gametocytes and lowers blood-stage parasitemia. Here, we tested the effect of FBS0701 on stage V gametocyte infectivity for mosquitoes. The incubation of stage V gametocytes for up to 3 days with increasing concentrations of FBS0701 resulted in a significant dose-related reduction in mosquito infectivity, as measured by the numbers of oocysts per mosquito. The reduction in mosquito infectivity was due to the inhibition of male and female gametocyte activation. The preincubation of FBS0701 with ferric chloride restored gametocyte infectivity, showing that the inhibitory effect of FBS0701 was quenched by iron. Deferoxamine, another iron chelator, also reduced gametocyte infectivity but to a lesser extent. Finally, the simultaneous administration of drug and gametocytes to mosquitoes without previous incubation did not significantly reduce the numbers of oocysts. These results show the importance of gametocyte iron metabolism as a potential target for new transmission-blocking strategies. PMID- 25512428 TI - Biochemical characterization of the POM-1 metallo-beta-lactamase from Pseudomonas otitidis. AB - The POM-1 metallo-beta-lactamase is a subclass B3 resident enzyme produced by Pseudomonas otitidis, a pathogen causing otic infections. The enzyme was overproduced in Escherichia coli BL21(DE3), purified by chromatography, and subjected to structural and functional analysis. The purified POM-1 is a tetrameric enzyme of broad substrate specificity with higher catalytic activities with penicillins and carbapenems than with cephalosporins. PMID- 25512429 TI - Small-molecule xenomycins inhibit all stages of the Plasmodium life cycle. AB - Widespread resistance to most antimalaria drugs in use has prompted the search for novel candidate compounds with activity against Plasmodium asexual blood stages to be developed for treatment. In addition, the current malaria eradication programs require the development of drugs that are effective against all stages of the parasite life cycle. We have analyzed the antimalarial properties of xenomycins, a novel subclass of small molecule compounds initially isolated for anticancer activity and similarity to quinacrine in biological effects on mammalian cells. In vitro studies show potent activity of Xenomycins against Plasmodium falciparum. Oral administration of xenomycins in mouse models result in effective clearance of liver and blood asexual and sexual stages, as well as effective inhibition of transmission to mosquitoes. These characteristics position xenomycins as antimalarial candidates with potential activity in prevention, treatment and elimination of this disease. PMID- 25512430 TI - Direct and indirect costs of smoking in Vietnam. AB - OBJECTIVE: To estimate the direct and indirect costs of active smoking in Vietnam. METHOD: A prevalence-based disease-specific cost of illness approach was utilised to calculate the costs related to five smoking-related diseases: lung cancer, cancers of the upper aerodigestive tract, chronic obstructive pulmonary disease, ischaemic heart disease and stroke. Data on healthcare came from an original survey, hospital records and official government statistics. Morbidity and mortality due to smoking combined with the average per capita income were used to calculate the indirect costs of smoking by applying the human capital approach. The smoking-attributable fraction was calculated using the adjusted relative risk values from phase II of the American Cancer Society Cancer Prevention Study (CPS-II). Costs were classified as personal, governmental and health insurance costs. RESULTS: The total economic cost of smoking in 2011 was estimated at 24 679.9 billion Vietnamese dong (VND), equivalent to US$1173.2 million or approximately 0.97% of the 2011 gross domestic product. The direct costs of inpatient and outpatient care reached 9896.2 billion VND (US$470.4 million) and 2567.2 billion VND (US$122.0 million), respectively. The government's contribution to these costs was 4534.3 billion VND (US$215.5 million), which was equivalent to 5.76% of its 2011 healthcare budget. The indirect costs (productivity loss) due to morbidity and mortality were 2652.9 billion VND (US$126.1 million) and 9563.5 billion VND (US$454.6 million), respectively. These indirect costs represent about 49.5% of the total costs of smoking. CONCLUSIONS: Tobacco consumption has large negative consequences on the Vietnamese economy. PMID- 25512431 TI - The impact of the 2009/2010 enhancement of cigarette health warning labels in Uruguay: longitudinal findings from the International Tobacco Control (ITC) Uruguay Survey. AB - BACKGROUND: Framework Convention on Tobacco Control (FCTC) Article 11 Guidelines recommend that health warning labels (HWLs) should occupy at least 50% of the package, but the tobacco industry claims that increasing the size would not lead to further benefits. This article reports the first population study to examine the impact of increasing HWL size above 50%. We tested the hypothesis that the 2009/2010 enhancement of the HWLs in Uruguay would be associated with higher levels of effectiveness. METHODS: Data were drawn from a cohort of adult smokers (>=18 years) participating in the International Tobacco Control (ITC) Uruguay Survey. The probability sample cohort was representative of adult smokers in five cities. The surveys included key indicators of HWL effectiveness. Data were collected in 2008/09 (prepolicy: wave 2) and 2010/11 (postpolicy: wave 3). RESULTS: Overall, 1746 smokers participated in the study at wave 2 (n=1379) and wave 3 (n=1411). Following the 2009/2010 HWL changes in Uruguay (from 50% to 80% in size), all indicators of HWL effectiveness increased significantly (noticing HWLs: OR=1.44, p=0.015; reading HWLs: OR=1.42, p=0.002; impact of HWLs on thinking about risks of smoking: OR=1.66, p<0.001; HWLs increasing thinking about quitting: OR=1.76, p<0.001; avoiding looking at the HWLs: OR=2.35, p<0.001; and reports that HWLs stopped smokers from having a cigarette 'many times': OR=3.42, p<0.001). CONCLUSIONS: The 2009/2010 changes to HWLs in Uruguay, including a substantial increment in size, led to increases of key HWL indicators, thus supporting the conclusion that enhancing HWLs beyond minimum guideline recommendations can lead to even higher levels of effectiveness. PMID- 25512432 TI - The importance of product definitions in US e-cigarette laws and regulations. AB - BACKGROUND: How electronic cigarettes and similar products (e-cigarettes) are defined affects how they are regulated, particularly whether existing laws for cigarettes apply, including sales and marketing, youth access, smoke-free and taxation laws. METHODS: We examined the text of 46 bills that define e-cigarettes enacted in 40 states and characterised how e-cigarettes and similar products were defined. RESULTS: States enact laws creating new product categories for e cigarettes separate from the 'tobacco product' category (eg, 'alternative nicotine product,' 'vapour product,' 'electronic nicotine device'), with four states explicitly excluding e-cigarettes from 'tobacco products.' Twenty-eight states do not include e-cigarettes in their definitions of 'tobacco products' or 'smoking,' eight include e-cigarettes as 'tobacco products,' three include e cigarettes in 'smoking.' Sixteen states' definitions of e-cigarettes require nicotine, and five states pre-empt more stringent local laws. Tobacco and e cigarette industry representatives tried to shape laws that benefit their interests. CONCLUSIONS: Definitions separating e-cigarettes from other tobacco products are common. Similar to past 'Trojan horse' policies, e-cigarette policies that initially appear to restrict sales (eg, limit youth access) may actually undermine regulation if they establish local pre-emption or create definitions that divide e-cigarettes from other tobacco products. Comparable issues are raised by the European Union Tobacco Products Directive and e cigarette regulations in other countries. Policymakers should carefully draft legislation with definitions of e-cigarettes that broadly define the products, do not require nicotine or tobacco, do not pre-empt stronger regulations and explicitly include e-cigarettes in smoke-free and taxation laws. PMID- 25512433 TI - Traffic control bundling is essential for protecting healthcare workers and controlling the 2014 Ebola epidemic. PMID- 25512434 TI - Randomized phase 2 trial of intracoronary nitrite during acute myocardial infarction. AB - RATIONALE: Preclinical evidence demonstrates that inorganic nitrite, after its in situ conversion to nitric oxide, attenuates consequent myocardial reperfusion injury. OBJECTIVE: We investigated whether intracoronary injection of nitrite during primary percutaneous coronary intervention might improve infarct size in ST-elevated myocardial infarction. METHODS AND RESULTS: Patients undergoing primary percutaneous coronary intervention (n=80) were randomized to receive intracoronary (10 mL) sodium nitrite (1.8 MUmol) or NaCl (placebo) before balloon inflation. The primary end point was infarct size assessed by measuring creatine kinase release. Secondary outcomes included infarct size assessed by troponin T release and by cardiac MRI on day 2. Baseline characteristics were similar between the groups. No evidence of differences in creatine kinase release (P=0.92), troponin T (P=0.85), or cardiac MRI-assessed infarct size (P=0.254) were evident. In contrast, there was an improvement [corrected] in myocardial salvage index (P=0.05) and reduction in [corrected] major adverse cardiac event at 1 year (2.6% versus 15.8%; P=0.04) in the nitrite group. In a 66-patient subgroup with thrombolysis in myocardial infarction <=1 flow, there was reduced serum creatine kinase (P=0.030) and a 19% reduction in cardiac MRI-determined infarct size (P=0.034) with nitrite. No adverse effects of nitrite were detected. CONCLUSIONS: In this phase II study, intracoronary nitrite infusion did not alter infarct size, although a trend to improved myocardial salvage index and a significant reduction in major adverse cardiac event was evident. In a subgroup of patients with thrombolysis in myocardial infarction flow <=1, nitrite reduced infarct size and major adverse cardiac event and improved myocardial salvage index, indicating that a phase III clinical trial assessing intracoronary nitrite administration as an adjunct to percutaneous coronary intervention in ST-elevated myocardial infarction patients is warranted. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01584453. PMID- 25512435 TI - CrossTalk proposal: The dominant mechanism causing disuse muscle atrophy is decreased protein synthesis. PMID- 25512436 TI - CrossTalk opposing view: The dominant mechanism causing disuse muscle atrophy is proteolysis. PMID- 25512437 TI - Rebuttal from Stuart M. Phillips and Chris McGlory. PMID- 25512438 TI - Rebuttal from Michael B. Reid, Andrew R. Judge and Sue C. Bodine. PMID- 25512439 TI - The lymphangion: a not so 'primitive' heart. PMID- 25512440 TI - HOSPEX in the antipodes. AB - The Australian Army recently adopted the British concept of hospital exercise (HOSPEX) as a means of evaluating the capabilities of its deployable NATO Role 2E hospital, the 2nd General Health Battalion. The Australian approach to HOSPEX differs from the original UK model. This article describes the reasons why the Australian Army needed to adopt the HOSPEX concept, how it was adapted to suit local circumstances and how the concept may evolve to meet the needs of the wider Australian Defence Force and our allies. PMID- 25512441 TI - Surgical advances during the First World War: the birth of modern orthopaedics. AB - The First World War (1914-1918) was the first truly industrial conflict in human history. Never before had rifle fire and artillery barrage been employed on a global scale. It was a conflict that over 4 years would leave over 750,000 British troops dead with a further 1.6 million injured, the majority with orthopaedic injuries. Against this backdrop, the skills of the orthopaedic surgeon were brought to the fore. Many of those techniques and systems form the foundation of modern orthopaedic trauma management. On the centenary of 'the War to end all Wars', we review the significant advances in wound management, fracture treatment, nerve injury and rehabilitation that were developed during that conflict. PMID- 25512443 TI - Is it all determined at menarche? PMID- 25512442 TI - Sexual activity and counseling in the first month after acute myocardial infarction among younger adults in the United States and Spain: a prospective, observational study. AB - BACKGROUND: United States and European cardiovascular society guidelines recommend physicians counsel patients about resuming sexual activity after acute myocardial infarction (AMI), but little is known about patients' experience with counseling about sexual activity after AMI. METHODS AND RESULTS: The prospective, longitudinal Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients (VIRGO) study, conducted at 127 hospitals in the United States and Spain, was designed, in part, to evaluate gender differences in baseline sexual activity, function, and patient experience with physician counseling about sexual activity after an AMI. This study used baseline and 1-month data collected from the 2:1 sample of women (N=2349) and men (N=1152) ages 18 to 55 years with AMI. Median age was 48 years. Among those who reported discussing sexual activity with a physician in the month after AMI (12% of women, 19% of men), 68% were given restrictions: limit sex (35%), take a more passive role (26%), and/or keep the heart rate down (23%). In risk-adjusted analyses, factors associated with not discussing sexual activity with a physician included female gender (relative risk, 1.07; 95% confidence interval, 1.03-1.11), age (relative risk, 1.05 per 10 years; 95% confidence interval, 1.02-1.08), and sexual inactivity at baseline (relative risk, 1.11; 95% confidence interval, 1.08-1.15). Among patients who received counseling, women in Spain were significantly more likely to be given restrictions than U.S. women (relative risk; 1.36, 95% confidence interval, 1.11 1.66). CONCLUSIONS: Very few patients reported counseling for sexual activity after AMI. Those who did were commonly given restrictions not supported by evidence or guidelines. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00597922. PMID- 25512445 TI - DNMT1-microRNA126 epigenetic circuit contributes to esophageal squamous cell carcinoma growth via ADAM9-EGFR-AKT signaling. AB - PURPOSE: MicroRNAs (miRNA) are involved in and are controlled by epigenetic regulation, and thereby form a reciprocal regulatory circuit. Using next generation sequencing (NGS)-based miRNA profiling, this study aimed to discover esophageal squamous cell carcinoma (ESCC)-specific miRNAs and miRNA-related epigenetic modulations. EXPERIMENTAL DESIGN: NGS-based miRNA profiles were generated for four pairs of ESCC tissues and adjacent normal tissues. In situ hybridization was used to assess miRNA expression and its correlation with prognosis. miRNA-related DNA methylations were identified using bisulfite genomic sequencing, and the role of DNA methyltransferase 1 (DNMT1) was investigated using RNA interference. miRNA targets were screened by mRNA sequencing, and functional validation was performed in vitro and in vivo. RESULTS: NGS-based miRNA profiling identified 78 differentially expressed miRNAs in ESCC. Among them, microRNA126-3p (miR-126) was significantly downregulated, and its downregulation correlated with poor ESCC prognosis. Downregulation of miR-126 was due to promoter hypermethylation of its host gene, Egfl7. DNMT1 was aberrantly upregulated in ESCC and responsible for the hypermethylation of Egfl7. Intriguingly, DNMT1 was suppressed by overexpression of miR-126, indicating the existence of a regulatory feedback circuit. ADAM9 was identified as a key target of miR-126. Ectopic expression of miR-126 or silencing of ADAM9 reduced ESCC cell proliferation and migration by inhibiting epidermal growth factor receptor-AKT signaling. CONCLUSIONS: Our results indicate that miR-126 is a potential prognostic indicator for ESCC and suggest that a novel "DNMT1-miR-126 epigenetic circuit" is involved in ESCC progression. Consequently, miR-126-based epigenetic modulations may provide a basic rationale for new approaches to antitumor therapeutics. PMID- 25512446 TI - Crossover study of proportional assist versus assist control ventilation. AB - OBJECTIVE: To test the hypothesis that in very prematurely born infants remaining ventilated beyond the first week, proportional assist ventilation (PAV) compared with assist control ventilation (ACV) would be associated with reduced work of breathing, increased respiratory muscle strength and less ventilator-infant asynchrony which would be associated with improved oxygenation. DESIGN: Randomised crossover study. SETTING: Tertiary neonatal unit. PATIENTS: 12 infants with a median gestational age of 25 (range 24-26) weeks were studied at a median of 43 (range 8-86) days. INTERVENTIONS: Infants were studied for 1 h each on PAV and ACV in random order. MAIN OUTCOME MEASURES: At the end of each hour, the work of breathing (assessed by measuring the diaphragmatic pressure time product), thoracoabdominal asynchrony and respiratory muscle strength (maximal inspiratory pressure, maximal expiratory pressure (Pemax) and maximal transdiaphragmatic pressure (Pdimax)) were assessed. Blood gas analysis was performed and the oxygenation index (OI) calculated. RESULTS: After 1 h on PAV compared with 1 h on ACV, the median OI (5.55 (range 5-11) vs 10.10 (range 7-16), p=0.002) and PTP levels were lower (217 (range 59-556) cm H2O.s/min vs 309 (range 55-544) cm H2O.s/min, p=0.005), while Pdimax (44.26 (range 21-66) cm H2O vs 37.9 (range 19 45) cm H2O, p=0.002) and Pemax (25.6 (range 6.5-42) cm H2O vs 15.9 (range 3-35) cm H2O levels p=0.010) were higher. CONCLUSIONS: These results suggest that PAV compared with ACV may have physiological advantages for prematurely born infants who remain ventilated after the first week after birth. PMID- 25512451 TI - Should adjuvant weekly paclitaxel be considered less efficacious than anthracyclines plus cyclophosphamide for lower-risk patients with early-stage breast cancer? PMID- 25512444 TI - Age at menarche and risks of coronary heart and other vascular diseases in a large UK cohort. AB - BACKGROUND: Early menarche has been associated with increased risk of coronary heart disease (CHD), but most studies were relatively small and could not assess risk across a wide range of menarcheal ages; few have examined associations with other vascular diseases. We examined CHD, cerebrovascular disease, and hypertensive disease risks by age at menarche in a large prospective study of UK women. METHODS AND RESULTS: In 1.2 million women (mean+/-SD age, 56+/-5 years) without previous heart disease, stroke, or cancer, menarcheal age was reported to be 13 years by 25%, <=10 years by 4%, and >=17 years by 1%. After 11.6 years of follow-up, 73 378 women had first hospitalization for or death from CHD, 25 426 from cerebrovascular disease, and 249 426 from hypertensive disease. Using Cox regression, we calculated relative risks for each vascular outcome by single year of menarcheal age. The relationship was U-shaped for CHD. Compared with women with menarche at 13 years, the adjusted relative risk for CHD for menarche at <=10 years of age was 1.27 (95% confidence interval, 1.22-1.31; P<0.0001) and for menarche at >=17 years of age was 1.23 (95% confidence interval, 1.16-1.30; P<0.0001). U-shaped relationships were also seen for cerebrovascular and hypertensive disease, although the magnitudes of these risks for early and late menarche were smaller than those for CHD. CONCLUSIONS: In this cohort, the relation of age at menarche to vascular disease risk was U shaped, with both early and late menarche being associated with increased risk. Associations were weaker for cerebrovascular and hypertensive disease than for CHD. PMID- 25512452 TI - Reply to L. Cabel et al. PMID- 25512455 TI - E-mail anonymous: a physician's addiction. PMID- 25512453 TI - Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. AB - PURPOSE: Most patients with hepatocellular carcinoma (HCC) have associated chronic liver disease, the severity of which is currently assessed by the Child Pugh (C-P) grade. In this international collaboration, we identify objective measures of liver function/dysfunction that independently influence survival in patients with HCC and then combine these into a model that could be compared with the conventional C-P grade. PATIENTS AND METHODS: We developed a simple model to assess liver function, based on 1,313 patients with HCC of all stages from Japan, that involved only serum bilirubin and albumin levels. We then tested the model using similar cohorts from other geographical regions (n = 5,097) and other clinical situations (patients undergoing resection [n = 525] or sorafenib treatment for advanced HCC [n = 1,132]). The specificity of the model for liver (dys)function was tested in patients with chronic liver disease but without HCC (n = 501). RESULTS: The model, the Albumin-Bilirubin (ALBI) grade, performed at least as well as the C-P grade in all geographic regions. The majority of patients with HCC had C-P grade A disease at presentation, and within this C-P grade, ALBI revealed two classes with clearly different prognoses. Its utility in patients with chronic liver disease alone supported the contention that the ALBI grade was indeed an index of liver (dys)function. CONCLUSION: The ALBI grade offers a simple, evidence-based, objective, and discriminatory method of assessing liver function in HCC that has been extensively tested in an international setting. This new model eliminates the need for subjective variables such as ascites and encephalopathy, a requirement in the conventional C P grade. PMID- 25512454 TI - Treatment-associated musculoskeletal and vasomotor symptoms and relapse-free survival in the NCIC CTG MA.27 adjuvant breast cancer aromatase inhibitor trial. AB - PURPOSE: Treatment-emergent symptoms with adjuvant tamoxifen and aromatase inhibitors (AIs) have been associated with superior recurrence-free survival (RFS). We hypothesized that MA.27 anastrozole- or exemestane-treated patients with new or worsening vasomotor and/or joint symptoms would have improved RFS. PATIENTS AND METHODS: MA.27 randomly assigned 7,576 postmenopausal women with breast cancer to 5 years of anastrozole or exemestane. Patient-reported symptoms were collected using the Common Terminology Criteria for Adverse Events version 3.0 at protocol-specified baseline and 6- and 12-month clinical visits. Symptoms were considered present with either vasomotor and/or joint complaints. Associations between symptoms and baseline patient characteristics were examined with chi(2) and Fisher's exact tests. Subsequent effects of new or worsening symptoms on RFS were examined with landmark analyses and stratified univariable and multivariable Cox models. We examined the effects of 3-month symptoms arising from unplanned clinic visits as a result of severe toxicity. RESULTS: Patients were assessable if eligible for the MA.27 trial, received some trial therapy, and had no disease recurrence at the end of a symptom assessment period; 96% of patients (n = 7,306 patients) were included at 6 months, and 96% (n = 7,246) were included at 12 months. Thirty-four percent of patients had baseline symptoms. For patients without baseline symptoms, 25% and 52% had new symptoms by 6 and 12 months, respectively. Neither treatment-emergent nor baseline symptoms significantly impacted RFS (P > .10) in patients with or without baseline symptoms. CONCLUSION: In MA.27, anastrozole or exemestane treatment-emergent symptoms were not associated with improved RFS. Women should be supported through treatment and encouraged to remain on their AI regardless of their symptoms. PMID- 25512457 TI - Reply to V. Amoroso et al. PMID- 25512456 TI - American Society of Clinical Oncology policy statement update: the critical role of phase I trials in cancer research and treatment. PMID- 25512459 TI - No pain, no gain: a fallacy so far. PMID- 25512460 TI - Addressing the interplay of liver disease and hepatocellular carcinoma on patient survival: the ALBI scoring model. PMID- 25512458 TI - Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. AB - PURPOSE: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. METHODS: Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome associated cancers. RESULTS: The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis. CONCLUSION: CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks. PMID- 25512463 TI - Evolution of genetic testing for inherited susceptibility to breast cancer. PMID- 25512462 TI - Prognosis of t1ab node-negative human epidermal growth factor receptor 2-positive breast carcinomas. PMID- 25512461 TI - Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer. AB - PURPOSE: TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. RESULTS: Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation. CONCLUSION: PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979). PMID- 25512464 TI - Long-term active surveillance for prostate cancer: answers and questions. PMID- 25512465 TI - Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. AB - PURPOSE: Active surveillance is increasingly accepted as a treatment option for favorable-risk prostate cancer. Long-term follow-up has been lacking. In this study, we report the long-term outcome of a large active surveillance protocol in men with favorable-risk prostate cancer. PATIENTS AND METHODS: In a prospective single-arm cohort study carried out at a single academic health sciences center, 993 men with favorable- or intermediate-risk prostate cancer were managed with an initial expectant approach. Intervention was offered for a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression, or unequivocal clinical progression. Main outcome measures were overall and disease specific survival, rate of treatment, and PSA failure rate in the treated patients. RESULTS: Among the 819 survivors, the median follow-up time from the first biopsy is 6.4 years (range, 0.2 to 19.8 years). One hundred forty-nine (15%) of 993 patients died, and 844 patients are alive (censored rate, 85.0%). There were 15 deaths (1.5%) from prostate cancer. The 10- and 15-year actuarial cause-specific survival rates were 98.1% and 94.3%, respectively. An additional 13 patients (1.3%) developed metastatic disease and are alive with confirmed metastases (n = 9) or have died of other causes (n = 4). At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance. The cumulative hazard ratio for nonprostate-to-prostate cancer mortality was 9.2:1. CONCLUSION: Active surveillance for favorable-risk prostate cancer is feasible and seems safe in the 15-year time frame. In our cohort, 2.8% of patients have developed metastatic disease, and 1.5% have died of prostate cancer. This mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention. PMID- 25512467 TI - Intestinal associations of a single umbilical artery. PMID- 25512466 TI - Maternal allopurinol administration during suspected fetal hypoxia: a novel neuroprotective intervention? A multicentre randomised placebo controlled trial. AB - OBJECTIVE: To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage. DESIGN: A randomised double-blind placebo controlled multicentre trial. PATIENTS: We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery. SETTING: Delivery rooms of 11 Dutch hospitals. INTERVENTION: When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT). MAIN OUTCOME MEASURES: Primary endpoint was the difference in cord S100beta, a tissue-specific biomarker for brain damage. RESULTS: 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100beta was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% CI -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100beta value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -24.6 to -1.64)). CONCLUSIONS: Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls. TRIAL REGISTRATION NUMBER: NCT00189007, Dutch Trial Register NTR1383. PMID- 25512468 TI - Loss of the Notch effector RBPJ promotes tumorigenesis. AB - Aberrant Notch activity is oncogenic in several malignancies, but it is unclear how expression or function of downstream elements in the Notch pathway affects tumor growth. Transcriptional regulation by Notch is dependent on interaction with the DNA-binding transcriptional repressor, RBPJ, and consequent derepression or activation of associated gene promoters. We show here that RBPJ is frequently depleted in human tumors. Depletion of RBPJ in human cancer cell lines xenografted into immunodeficient mice resulted in activation of canonical Notch target genes, and accelerated tumor growth secondary to reduced cell death. Global analysis of activated regions of the genome, as defined by differential acetylation of histone H4 (H4ac), revealed that the cell death pathway was significantly dysregulated in RBPJ-depleted tumors. Analysis of transcription factor binding data identified several transcriptional activators that bind promoters with differential H4ac in RBPJ-depleted cells. Functional studies demonstrated that NF-kappaB and MYC were essential for survival of RBPJ-depleted cells. Thus, loss of RBPJ derepresses target gene promoters, allowing Notch independent activation by alternate transcription factors that promote tumorigenesis. PMID- 25512469 TI - Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity. AB - Allergic contact dermatitis and its animal model, contact hypersensitivity (CHS), are T cell-mediated inflammatory skin diseases induced by contact allergens. Though numerous cellular and molecular players are known, the mechanism of chemical-induced sensitization remains poorly understood. Here, we identify neutrophils as crucial players in the sensitization phase of CHS. Genetic deficiency of neutrophils caused by myeloid-specific deletion of Mcl-1 or antibody-mediated depletion of neutrophils before sensitization abrogated the CHS response. Neutrophil deficiency reduced contact allergen-induced cytokine production, gelatinase release, and reactive oxygen species production in naive mice. Mast cell deficiency inhibited neutrophil accumulation at the site of sensitization. In turn, neutrophils were required for contact allergen-induced release of further neutrophil-attracting chemokines, migration of DCs to the draining lymph nodes, and priming of allergen-specific T cells. Lymph node cells from mice sensitized in the absence of neutrophils failed to transfer sensitization to naive recipients. Furthermore, no CHS response could be induced when neutrophils were depleted before elicitation or when normally sensitized lymph node cells were transferred to neutrophil-deficient recipients, indicating an additional role for neutrophils in the elicitation phase. Collectively, our data identify neutrophils to be critically involved in both the sensitization and elicitation phase of CHS. PMID- 25512472 TI - The SAPHO syndrome: a single-center study of 41 adult patients. AB - OBJECTIVE: The SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) is a rare disease and only a few series have been published about it. We describe the experience of a rheumatology department with a focus on the therapeutic aspects. METHODS: All cases of SAPHO fulfilling the Benhamou criteria and seen between 1992 and 2013 in our unit were retrospectively included. RESULTS: Forty-one patients (11 men and 30 women) were included. The average age was 45 years (20-80 yrs) at the time of diagnosis. Nineteen patients had palmoplantar pustulosis, 3 had psoriasis vulgaris, 3 had severe acne, and 15 had no dermatological involvement. Bone symptoms involved mainly the anterior chest wall (n = 28, 68%), followed by the spine (n = 16, 39%) and sacroiliac joints (n = 12, 29%). Four patients had peripheral osteitis and 2 had mandibular osteitis. Ten patients had peripheral arthritis affecting mainly the knees and wrists. None of the 36 patients tested was HLA-B27-positive. At least a partial response was achieved with colchicine, methotrexate, or sulfasalazine in 0/6, 2/4, and 1/6 of patients, respectively. Antibiotic therapy (azithromycin, n = 7; doxycycline, n = 2) was effective in 2/9 patients. Pamidronate was prescribed in 26 patients with bone involvement and 18/22 patients evaluable at 6 months responded to this therapy. Two patients were treated with tumor necrosis factor blockers: 1 with infliximab and 1 with adalimumab, followed by etanercept. CONCLUSION: Based on our experience, SAPHO can be diagnosed in the elderly. It was not associated with HLA-B27. Soft tissue involvement was common and the bisphosphonates were generally effective on bone involvement. PMID- 25512470 TI - Lineage-specific compaction of Tcrb requires a chromatin barrier to protect the function of a long-range tethering element. AB - Gene regulation relies on dynamic changes in three-dimensional chromatin conformation, which are shaped by composite regulatory and architectural elements. However, mechanisms that govern such conformational switches within chromosomal domains remain unknown. We identify a novel mechanism by which cis elements promote long-range interactions, inducing conformational changes critical for diversification of the TCRbeta antigen receptor locus (Tcrb). Association between distal Vbeta gene segments and the highly expressed DbetaJbeta clusters, termed the recombination center (RC), is independent of enhancer function and recruitment of V(D)J recombinase. Instead, we find that tissue-specific folding of Tcrb relies on two distinct architectural elements located upstream of the RC. The first, a CTCF-containing element, directly tethers distal portions of the Vbeta array to the RC. The second element is a chromatin barrier that protects the tether from hyperactive RC chromatin. When the second element is removed, active RC chromatin spreads upstream, forcing the tether to serve as a new barrier. Acquisition of barrier function by the CTCF element disrupts contacts between distal Vbeta gene segments and significantly alters Tcrb repertoires. Our findings reveal a separation of function for RC flanking regions, in which anchors for long-range recombination must be cordoned off from hyperactive RC landscapes by chromatin barriers. PMID- 25512473 TI - Facilitators and barriers to adherence in the initiation phase of Disease modifying Antirheumatic Drug (DMARD) use in patients with arthritis who recently started their first DMARD treatment. AB - OBJECTIVE: To explore themes associated with adherence in the initiation phase for first-time use of disease-modifying antirheumatic drugs (DMARD) in patients with inflammatory arthritis using focus groups and individual interviews. METHODS: Thirty-three patients were interviewed in focus groups and individual interviews. Interviews were transcribed verbatim and imported into ATLAS.ti software (Scientific Software Development GmbH). Responses that included reasons for adherence or nonadherence in the initiation phase were extracted and coded by 2 coders separately. The 2 coders conferred until consensus on the codes was achieved. Codes were classified into overarching themes. RESULTS: Five themes emerged: (1) symptom severity, (2) experiences with medication, (3) perceptions about medication and the illness, (4) information about medication, and (5) communication style and trust in the rheumatologist. CONCLUSION: Perceptions about medication and the communication style with, and trust in, the rheumatologist were mentioned the most in relation to starting DMARD. The rheumatologist plays a crucial role in influencing adherence behavior by addressing perceptions about medication, providing information, and establishing trust in the treatment plan. PMID- 25512474 TI - The Interleukin 33/ST2 axis in patients with primary Sjogren syndrome: expression in serum and salivary glands, and the clinical association. AB - OBJECTIVE: To evaluate the expression of interleukin 33 (IL-33) and its receptor in sera and salivary tissues of patients with primary Sjogren syndrome (pSS), and to investigate the association with clinical profiles. METHODS: Serum IL-33 and soluble ST2 (sST2) of 55 patients with pSS and 48 controls were determined by ELISA and assessed for clinical correlation. The expression of IL-33/ST2 in salivary tissues was investigated by immunohistochemical staining and was further characterized by confocal microscopy. We also measured IL-33 production in salivary glandular epithelial cells by proinflammatory stimuli. RESULTS: Serum levels of IL-33 and sST2 were higher in patients with pSS compared to those in controls (p = 0.018 and p < 0.0001, respectively). Among patients with pSS, sST2 concentration was associated with thrombocytopenia (p = 0.029) and correlated with disease duration (p = 0.013) and the European League Against Rheumatism Sjogren Syndrome Disease Activity Index (p = 0.042). The expression of IL-33 and ST2 was elevated in salivary glands of patients with pSS with grade 2 inflammation, and diminished in advanced inflammation. In patients with pSS, IL 33 was mainly observed in epithelial and endothelial cells of glandular tissue. The production of IL-33 mRNA by salivary gland epithelial cell line increased under stimulation with interferon-gamma. CONCLUSION: The expression of IL-33 and its receptor was elevated in sera and salivary tissues of patients with pSS. These results suggest that the IL-33/ST2 axis might have a role in the pathogenesis of pSS. PMID- 25512475 TI - Cartilage thickness of the knee joint in juvenile idiopathic arthritis: comparative assessment by ultrasonography and magnetic resonance imaging. AB - OBJECTIVE: The functional disability experienced in juvenile idiopathic arthritis (JIA) is primarily caused by joint effusion, synovial membrane hypertrophy, and periarticular soft tissue edema, leading to the degeneration of the osteocartilaginous structures because of the inflammatory process in the synovium. The ability to visualize the inflammatory changes and hence the ensuing osteocartilaginous degeneration is, therefore, of great importance in pediatric rheumatology. Ultrasonography (US) has been validated as a tool for measuring cartilage thickness in healthy children and, previously, we have found good agreement with the measures obtained by magnetic resonance imaging (MRI). Our aim is to validate and compare US with MRI measurements of distal femoral cartilage thickness in the knee joint at the medial condyle, lateral condyle, and intercondylar spots in children with JIA, and to locate the best spot for imaging comparisons. METHODS: One knee from each of 23 children with oligoarticular JIA were investigated by both MRI and US. Outcome measures of imaging procedures were distal femoral cartilage thickness. RESULTS: We found a high level of agreement between MRI and US measurements of mean cartilage thickness, and Rho values between modalities were high (between 0.70 and 0.86, p < 0.05 for all). We found a thinner cartilage thickness at the medial condyle in comparison to the other investigated points. Evaluation of anatomical landmarks for optimal measurement of cartilage thickness was found to be the intercondylar spot, which was easier to locate in addition to a smaller variance around the mean for that anatomical measuring point. CONCLUSION: US measurements of distal femoral cartilage thickness are highly correlated to MRI measurements. The intercondylar notch of the distal femoral cartilage may be the best anatomical point for cartilage thickness measurements of the knee. US is a reliant and nonexpensive, non invasive modality for visualization of childhood femoral cartilage. PMID- 25512476 TI - Switching from intravenous to subcutaneous formulation of abatacept: a single center Italian experience on efficacy and safety. AB - OBJECTIVE: Subcutaneous (SC) abatacept (ABA) is comparable to intravenous (IV) formulation in terms of efficacy and safety profile. Our work analyzed the switch to SC formulation from IV administration in patients with rheumatoid arthritis. METHODS: Fifty-one patients treated with SC ABA were included. Clinical data were obtained from clinical charts. RESULTS: Fourteen patients relapsed and needed to return to the IV administration. Neither clinical and laboratory features nor the previous therapies were identified as risk factors for SC formulation inefficacy. Disease activity decreased after the return to IV infusions. CONCLUSION: SC ABA showed a risk of relapse in 27% of cases. The reinsertion of the IV administration quickly reinstated disease control. PMID- 25512477 TI - Is statin exposure associated with occurrence or better outcome in giant cell arteritis? Results from a French population-based study. AB - OBJECTIVE: To investigate the potential association between statin use and giant cell arteritis (GCA) course. METHODS: Using the French National Health Insurance system, we included patients with incident GCA from the Midi-Pyrenees region, southern France, from January 2005 to December 2008 and randomly selected 6 controls matched by age, sex, and date of diagnosis. Statin exposure was compared between patients with GCA and their controls before GCA occurrence with a logistic regression. Influence of statin exposure on prednisone requirements during GCA course was explored with a Cox model, considering statin exposure as a time-varying variable. RESULTS: The cohort included 103 patients (80 women, mean age 74.8 +/- 9 yrs, mean followup 48.9 +/- 14.8 mos), compared to 606 controls. Statin exposure (27.2% of patients with GCA and 23.4% of controls) was not associated with GCA occurrence (adjusted OR 1.2, 95% CI 0.76-1.96; p = 0.41). Diabetes mellitus was significantly associated to GCA occurrence (adjusted OR 0.38, 95% CI 0.11-0.72; p = 0.008). After diagnosis, exposure to statins up to 20 months was associated with maintenance while taking low prednisone doses (p = 0.01). CONCLUSION: Statin exposure was not associated with GCA occurrence in the general population. However, exposure to statins up to 20 months may favor a quicker corticosteroid tapering. Based on those results, statin effect on GCA course should not be definitively ruled out. PMID- 25512478 TI - Elevated serum levels of syndecan-1 are associated with renal involvement in patients with systemic lupus erythematosus. AB - OBJECTIVE: Syndecan-1 (SDC-1) is a major constituent of the endothelial glycocalyx, which plays a role in maintaining vascular homeostasis and functions as a glomerular filtration barrier. SDC-1 is readily shed into the blood under various conditions, but the clinical implication of circulating SDC-1 in patients with systemic lupus erythematosus (SLE) remains unclear. We aimed to investigate the association of serum SDC-1 level with certain clinical manifestations of SLE. METHODS: We measured serum SDC-1 levels by ELISA in 111 patients with SLE, 18 with rheumatoid arthritis (RA), and 20 healthy subjects, and investigated its association with clinical manifestations and laboratory variables. RESULTS: Serum SDC-1 levels were higher in patients with SLE than in those with RA and healthy controls (both p < 0.001) and were positively correlated with SLE Disease Activity Index (SLEDAI; r = 0.367, p < 0.001) and anti-dsDNA antibody level (r = 0.259, p = 0.007), but inversely correlated with serum C3 and CH50 levels (r = 0.305, p = 0.001 and r = -0.244, p = 0.012). Patients with active nephritis had higher serum SDC-1 levels than patients with inactive nephritis and those without nephritis (both p < 0.001). In addition, serum SDC-1 levels were correlated with renal SLEDAI score (r = 0.540, p < 0.001) and excretion of proteinuria as measured by spot urine protein/creatinine ratio (r = 0.538, p < 0.001). In 14 patients with lupus nephritis (LN) whose serum samples were obtained at the time of renal biopsy, there was a positive correlation between serum SDC-1 levels and activity index (r = 0.632, p = 0.015). CONCLUSION: Serum SDC-1 levels are increased in SLE patients with nephritis, indicating that SDC-1 might be a useful serum biomarker for active LN. PMID- 25512479 TI - Modifiable factors associated with allopurinol adherence and outcomes among patients with gout in an integrated healthcare system. AB - OBJECTIVE: To identify modifiable patient and provider factors associated with allopurinol adherence and the achievement of a serum urate acid (SUA) goal in gout. METHODS: We identified a retrospective cohort of patients with gout, newly treated with allopurinol. All patient data came from administrative datasets at a large integrated health delivery system. Patients were >= 18 years old at time of initial allopurinol dispensing, and had 12 months or more of membership and drug eligibility prior to the index date. Allopurinol adherence was defined as a proportion of days covered >= 0.80, evaluated during the first 12 months of observation after the initial dispensing. Multivariable logistic regression was used to examine factors associated with allopurinol nonadherence and attaining an SUA concentration < 6.0 mg/dl. RESULTS: We identified 13,341 patients with gout with incident allopurinol use (mean age 60 yrs, 78% men). Of these, 9581 patients (72%) had SUA measured both at baseline and during followup. Only 3078 patients (32%) attained an SUA target of < 6.0 mg/dl during followup. Potentially modifiable factors associated with treatment adherence and obtaining the SUA goal in the multivariable analysis included concomitant diuretic use, prescriber specialty, and allopurinol dosing practices. Adherent patients were 2.5-fold more likely than nonadherent patients to achieve an SUA < 6.0 mg/dl during observation. CONCLUSION: Among patients with gout initiating allopurinol in our study, 68% did not reach the SUA goal and 57% of patients were nonadherent. Modifiable factors, including allopurinol dose escalation, treatment adherence, rheumatology referral, and concomitant medication use, could be important factors to consider in efforts aimed at optimizing gout treatment outcomes. PMID- 25512480 TI - Bone lineage proteins in the entheses of the midfoot in patients with spondyloarthritis. AB - OBJECTIVE: Patients with juvenile-onset spondyloarthritis (SpA) may develop ankylosis of the midfoot resembling the spinal changes seen in patients with ankylosing spondylitis (AS). The study of the histopathology of the feet of patients with tarsitis could help us understand the pathogenesis of bone formation in affected structures in the SpA. The objective of our study was to describe the histopathologic characteristics of the midfoot in patients with tarsitis associated with SpA. METHODS: We obtained synovial sheaths, entheses, and bone samples from 20 patients with SpA with midfoot pain/tenderness and swelling. Tissue samples underwent H&E staining; immunohistochemistry for CD3, CD4, CD8, CD68, and CD20 cell identification; and immunofluorescence for bone lineage proteins, including osteocalcin, osteopontin, parathyroid hormone-related protein, bone sialoprotein, and alkaline phosphatase. RESULTS: Slight edema and hyalinization were found in some tendon sheaths, and few inflammatory cells were detected in the entheses. In bones, we found some changes suggesting osteoproliferation, including endochondral and intramembranous ossification, but no inflammatory cells. In entheses showing bone proliferation, we detected osteocalcin and osteopontin in cells with a fibroblast-mesenchymal phenotype, suggesting the induction of entheseal cells toward an osteoblast phenotype. CONCLUSION: Osteoproliferation and abnormal expression of bone lineage proteins, but no inflammatory infiltration, characterize midfoot involvement in patients with SpA. In this sense, tarsitis (or ankylosing tarsitis) resembles the involvement of the spine in patients with AS. Ossification may be in part explained by the differentiation of mesenchymal entheseal cells toward the osteoblastic lineage. PMID- 25512481 TI - Visual manifestations in giant cell arteritis: trend over 5 decades in a population-based cohort. AB - OBJECTIVE: To evaluate clinical characteristics, treatment, and outcomes of patients with visual changes from giant cell arteritis (GCA) and to examine trends over the last 5 decades. METHODS: We reviewed the medical records of a population-based cohort of patients with GCA diagnosed between 1950 and 2004. The clinical, ophthalmological, and laboratory features of patients with visual manifestations attributable to GCA were compared to patients without visual complications. Trends over time were examined using logistic regression modeling adjusted for age and sex. RESULTS: In a cohort of 204 cases of GCA (mean age 76.0 +/- 8.2 yrs, 80% female), visual changes from GCA were observed in 47 patients (23%), and 4.4% suffered complete vision loss. A higher proportion of patients with visual manifestations reported jaw claudication than did patients without visual changes (55% vs 38%, p = 0.04). Over a period of 55 years, we observed a significant decline in the incidence of visual symptoms due to GCA. There was a lower incidence of ischemic optic neuropathy in the 1980-2004 cohort vs 1950-1979 (6% vs 15%, p = 0.03). Patients diagnosed in later decades were more likely to recover from visual symptoms (HR 1.34, 95% CI 1.06-1.71). Chances of recovery were poor in patients with anterior ischemic optic neuropathy or complete vision loss. CONCLUSION: Incidence of visual symptoms has declined over the past 5 decades, and chances of recovery from visual symptoms have improved. However, complete loss of vision is essentially irreversible. Jaw claudication is associated with higher likelihood of development of visual symptoms. PMID- 25512482 TI - Outcome of takayasu arteritis with inactive disease at diagnosis: the extent of vascular involvement as a predictor of activation. AB - OBJECTIVE: Some patients with Takayasu arteritis (TA) have inactive disease at the time of diagnosis. The objective of our study was to investigate the clinical outcomes and factors that predict disease activation in patients with clinically inactive TA. METHODS: The medical records of patients diagnosed with TA between 1990 and 2012 were reviewed. At the time of diagnosis, patients were identified as having inactive disease according to the National Institutes of Health definition. Patients who went on to develop active disease during followup were classified as the "activation group". The pattern of vascular involvement was classified according to the International Conference on TA, 1994. RESULTS: A total of 59 patients with TA were classified as having inactive disease at the time of diagnosis. During the followup, 13 (22.0%) of these experienced TA activation (median followup, 37.0 mos; activation group). The remaining 46 (78.0%) did not experience disease activation (stable group). Renovascular hypertension was more common in the activation group than in the stable group (5/13, 38.5% vs 4/46, 8.7%, p = 0.019). Further, type V, which is the most extensive, was more common in the activation group (12/13, 92.3%) than in the stable group (18/46, 39.1%, p = 0.008). Multivariate analysis identified type V disease (OR 10.969, 95% CI 1.144-105.182, p = 0.038) as being significantly associated with an increased risk of disease activation. CONCLUSION: Substantial portions of patients with clinically inactive TA at the time of diagnosis experienced disease activation during followup. Type V disease may be an important predictive factor for disease activation in patients with clinically inactive TA. PMID- 25512483 TI - Remission in nonradiographic axial spondyloarthritis treated with anti-tumor necrosis factor-alpha drugs: an Italian multicenter study. AB - OBJECTIVE: To investigate the possibility of achieving partial remission (PR) in patients with nonradiographic axial spondyloarthritis (nr-axSpA) versus ankylosing spondylitis (AS) treated with anti-tumor necrosis factor (TNF)-alpha antagonists, such as adalimumab (ADA), etanercept (ETN), and infliximab (IFX), in a real clinical practice setting. The Assessment of SpondyloArthritis international Society (ASAS) 20, ASAS40, and Ankylosing Spondylitis Disease Activity Score were also calculated. METHODS: A retrospective study was conducted in patients with axSpA treated with ADA, ETN, and IFX from 2000 to 2013. All patients fulfilled the ASAS or the modified New York criteria. PR was reached when the score was < 20 mm (on a visual analog scale of 0-100 mm) in each of these domains: (1) patient global assessment, (2) pain, (3) function, and (4) inflammation. RESULTS: A total of 321 patients with axSpA were treated. Among them, 62 were nr-axSpA while the remaining 259 were AS. Log-rank test to compare survival curves showed that the probability of obtaining PR in nr-axSpA and AS during treatment with anti-TNF-alpha was not significantly different. At 12 weeks of exposure to the first anti-TNF-alpha drug, PR was achieved in 7 patients with nr-axSpA (11.3%) and in 68 patients with AS (26.2%). CONCLUSION: Our results, obtained from clinical practice, showed that PR is an achievable target of anti TNF-alpha treatment in nr-axSpA. The PR rate, as a reliable indicator of sustained effectiveness, is similar in nr-axSpA and in AS. PMID- 25512484 TI - Prevalence and significance of persistently positive antiphospholipid antibodies in women with preeclampsia. AB - OBJECTIVE: To determine the prevalence of antiphospholipid antibodies (aPL) and their association with obstetric outcomes in women with preeclampsia. METHODS: The study included 150 patients. Clinical variables, risk factors, and severity criteria for preeclampsia and aPL were analyzed. RESULTS: We found aPL in 4% of patients without risk factors for preeclampsia and in no women with risk factors (p = 0.03). Fifty percent of aPL-positive patients had a fetus with intrauterine growth restriction versus 13.9% (p = 0.04). No relation between aPL and severe preeclampsia was found. CONCLUSION: The prevalence of aPL among women with preeclampsia is low. aPL can predispose women without risk factors to preeclampsia. PMID- 25512485 TI - Evaluation of left atrial function by real-time 3-D echocardiography in patients with systemic lupus erythematosus. AB - OBJECTIVE: Left atrial function plays a key role in maintaining an optimal cardiac output. Left ventricular diastolic dysfunction has been reported in systemic lupus erythematosus (SLE), but its effect on left atrial function has been largely overlooked. Our aim was to assess left atrial performance using real time 3-D echocardiography (RT3DE) technology in patients with SLE. METHODS: Our study included 102 patients with SLE without any cardiac symptoms, and 32 healthy controls. According to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), all subjects were classified into 3 groups: healthy controls, patients with an SDI = 0, and patients with an SDI >= 1. RESULTS: Left atrial volume indexed to body surface area was dilated in subjects with SLE, whereas the left atrial passive emptying fraction (EF) was lower. Left atrial active EF was significantly higher in the SDI = 0 group than in controls (46.4 +/- 9.1% vs 30.0 +/- 10.3%, p < 0.05); however, it was significantly lower in the SDI >= 1 group than in the SDI = 0 group (41.2 +/- 9.8% vs 46.4 +/- 9.1%, p < 0.05). By multivariate linear analysis, the SDI was independently and positively associated with left atrial volume index and inversely associated with left atrial total function. CONCLUSION: Our study demonstrated that left atrial mechanical function and volume are impaired in SLE, particularly in patients with an SDI >= 1 and disease activity. RT3DE may have better diagnostic value than traditional echo indexes in detecting subclinical cardiac dysfunction in patients with SLE. PMID- 25512486 TI - Cardiovascular disease-related hospital admissions of patients with inflammatory arthritis. AB - OBJECTIVE: Patients with inflammatory arthritis (IA) have an increased risk of cardiovascular diseases (CVD), suggesting a high rate of CVD-related hospitalizations, but data on this topic are limited. Our study addressed hospital admissions for CVD in a primary care-based population of patients with IA and controls. METHODS: All newly diagnosed patients with IA between 2001 and 2010 were selected from electronic medical records of the Netherlands Institute for Health Services Research Primary Care database, representing a national network of general practices. Two control patients matched for age, sex, and practice were selected for each patient with IA. Hospital admission data for all patients was retrieved from the Dutch Hospital Data. RESULTS: There were 2615 patients with IA and 5555 controls included in our study. CVD-related hospital admissions were observed more frequently among patients with IA as compared with control patients: 48% versus 36% (p < 0.001) in a followup period of 4 years. Patients with IA were more often hospitalized because of ischemic heart disease (OR 1.7, 95% CI 1.2-2.2) and for day-care admission because of cerebrovascular disease (OR 2.2, 95% CI 1.0-4.9). CONCLUSION: Increased hospital admission rates confirm the higher CVD burden among patients with IA compared with controls, and underscore the need for proper CVD risk management in patients with IA. PMID- 25512487 TI - Structure of a pantothenate transporter and implications for ECF module sharing and energy coupling of group II ECF transporters. AB - Energy-coupling factor (ECF) transporters are a unique group of ATP-binding cassette (ABC) transporters responsible for micronutrient uptake from the environment. Each ECF transporter is composed of an S component (or EcfS protein) and T/A/A' components (or EcfT/A/A' proteins; ECF module). Among the group II ECF transporters, several EcfS proteins share one ECF module; however, the underlying mechanism remains unknown. Here we report the structure of a group II ECF transporter-pantothenate transporter from Lactobacillus brevis (LbECF-PanT), which shares the ECF module with the folate and hydroxymethylpyrimidine transporters (LbECF-FolT and LbECF-HmpT). Structural and mutational analyses revealed the residues constituting the pantothenate-binding pocket. We found that although the three EcfS proteins PanT, FolT, and HmpT are dissimilar in sequence, they share a common surface area composed of the transmembrane helices 1/2/6 (SM1/2/6) to interact with the coupling helices 2/3 (CH2/3) of the same EcfT. CH2 interacts mainly with SM1 via hydrophobic interactions, which may modulate the sliding movement of EcfS. CH3 binds to a hydrophobic surface groove formed by SM1, SM2, and SM6, which may transmit the conformational changes from EcfA/A' to EcfS. We also found that the residues at the intermolecular surfaces in LbECF PanT are essential for transporter activity, and that these residues may mediate intermolecular conformational transmission and/or affect transporter complex stability. In addition, we found that the structure of EcfT is conformationally dynamic, which supports its function as a scaffold to mediate the interaction of the ECF module with various EcfS proteins to form different transporter complexes. PMID- 25512489 TI - Cost-effective targeting of conservation investments to reduce the northern Gulf of Mexico hypoxic zone. AB - A seasonally occurring summer hypoxic (low oxygen) zone in the northern Gulf of Mexico is the second largest in the world. Reductions in nutrients from agricultural cropland in its watershed are needed to reduce the hypoxic zone size to the national policy goal of 5,000 km(2) (as a 5-y running average) set by the national Gulf of Mexico Task Force's Action Plan. We develop an integrated assessment model linking the water quality effects of cropland conservation investment decisions on the more than 550 agricultural subwatersheds that deliver nutrients into the Gulf with a hypoxic zone model. We use this integrated assessment model to identify the most cost-effective subwatersheds to target for cropland conservation investments. We consider targeting of the location (which subwatersheds to treat) and the extent of conservation investment to undertake (how much cropland within a subwatershed to treat). We use process models to simulate the dynamics of the effects of cropland conservation investments on nutrient delivery to the Gulf and use an evolutionary algorithm to solve the optimization problem. Model results suggest that by targeting cropland conservation investments to the most cost-effective location and extent of coverage, the Action Plan goal of 5,000 km(2) can be achieved at a cost of $2.7 billion annually. A large set of cost-hypoxia tradeoffs is developed, ranging from the baseline to the nontargeted adoption of the most aggressive cropland conservation investments in all subwatersheds (estimated to reduce the hypoxic zone to less than 3,000 km(2) at a cost of $5.6 billion annually). PMID- 25512488 TI - Structural basis for the auxin-induced transcriptional regulation by Aux/IAA17. AB - Auxin is the central hormone that regulates plant growth and organ development. Transcriptional regulation by auxin is mediated by the auxin response factor (ARF) and the repressor, AUX/IAA. Aux/IAA associates with ARF via domain III-IV for transcriptional repression that is reversed by auxin-induced Aux/IAA degradation. It has been known that Aux/IAA and ARF form homo- and hetero oligomers for the transcriptional regulation, but what determines their association states is poorly understood. Here we report, to our knowledge, the first solution structure of domain III-IV of Aux/IAA17 (IAA17), and characterize molecular interactions underlying the homotypic and heterotypic oligomerization. The structure exhibits a compact beta-grasp fold with a highly dynamic insert helix that is unique in Aux/IAA family proteins. IAA17 associates to form a heterogeneous ensemble of front-to-back oligomers in a concentration-dependent manner. IAA17 and ARF5 associate to form homo- or hetero-oligomers using a common scaffold and binding interfaces, but their affinities vary significantly. The equilibrium dissociation constants (KD) for homo-oligomerization are 6.6 MUM and 0.87 MUM for IAA17 and ARF5, respectively, whereas hetero-oligomerization reveals a ~ 10- to ~ 100-fold greater affinity (KD = 73 nM). Thus, individual homo oligomers of IAA17 and ARF5 spontaneously exchange their subunits to form alternating hetero-oligomers for transcriptional repression. Oligomerization is mainly driven by electrostatic interactions, so that charge complementarity at the interface determines the binding affinity. Variable binding affinity by surface charge modulation may effectively regulate the complex interaction network between Aux/IAA and ARF family proteins required for the transcriptional control of auxin-response genes. PMID- 25512490 TI - PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility. AB - Without a fully developed initial segment, the most proximal region of the epididymis, male infertility results. Therefore, it is important to understand the development and regulation of this crucial region. In addition to distinctively high activity levels of the components of the ERK pathway, which are essential for initial-segment differentiation, the initial segment exhibits high protein and activity levels of phosphatase and tensin homolog (PTEN). To understand the role of PTEN in the regulation of the initial segment, we generated a mouse model with a conditional deletion of Pten from the epithelial cells of the proximal epididymis from postnatal day 17 (P17) onward. Shortly after Pten deletion, hypertrophy of the proximal epididymis became evident. Loss of Pten resulted in activation of the AKT (protein kinase B) pathway components from P28 onward, which in turn gradually suppressed RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK signaling through the interaction between AKT and RAF1. Consistent with progressive changes in RAF1/ERK signaling, loss of Pten progressively altered cell shape, size, organization, proliferation, and survival in the initial-segment epithelium and resulted in dedifferentiation and extensive epithelial folding. Most importantly, knockout males progressively lost fertility and became infertile from 6 to 12 mo. Spermatozoa from older knockout mice showed a lower percentage of motility and a higher percentage of flagellar angulation compared with controls, suggesting compromised sperm maturation. Therefore, under normal physiological conditions, PTEN suppresses AKT activity to maintain activation of the RAF1/ERK signaling pathway, which in turn maintains normal function of the initial segment and therefore, normal sperm maturation. PMID- 25512491 TI - Identification of S-nitroso-CoA reductases that regulate protein S-nitrosylation. AB - Coenzyme A (CoA) mediates thiol-based acyl-group transfer (acetylation and palmitoylation). However, a role for CoA in the thiol-based transfer of NO groups (S-nitrosylation) has not been considered. Here we describe protein S nitrosylation in yeast (heretofore unknown) that is mediated by S-nitroso-CoA (SNO-CoA). We identify a specific SNO-CoA reductase encoded by the alcohol dehydrogenase 6 (ADH6) gene and show that deletion of ADH6 increases cellular S nitrosylation and alters CoA metabolism. Further, we report that Adh6, acting as a selective SNO-CoA reductase, protects acetoacetyl-CoA thiolase from inhibitory S-nitrosylation and thereby affects sterol biosynthesis. Thus, Adh6-regulated, SNO-CoA-mediated protein S-nitrosylation provides a regulatory mechanism paralleling protein acetylation. We also find that SNO-CoA reductases are present from bacteria to mammals, and we identify aldo-keto reductase 1A1 as the mammalian functional analog of Adh6. Our studies reveal a novel functional class of enzymes that regulate protein S-nitrosylation from yeast to mammals and suggest that SNO-CoA-mediated S-nitrosylation may subserve metabolic regulation. PMID- 25512492 TI - Myosin binding protein-C activates thin filaments and inhibits thick filaments in heart muscle cells. AB - Myosin binding protein-C (MyBP-C) is a key regulatory protein in heart muscle, and mutations in the MYBPC3 gene are frequently associated with cardiomyopathy. However, the mechanism of action of MyBP-C remains poorly understood, and both activating and inhibitory effects of MyBP-C on contractility have been reported. To clarify the function of the regulatory N-terminal domains of MyBP-C, we determined their effects on the structure of thick (myosin-containing) and thin (actin-containing) filaments in intact sarcomeres of heart muscle. We used fluorescent probes on troponin C in the thin filaments and on myosin regulatory light chain in the thick filaments to monitor structural changes associated with activation of demembranated trabeculae from rat ventricle by the C1mC2 region of rat MyBP-C. C1mC2 induced larger structural changes in thin filaments than calcium activation, and these were still present when active force was blocked with blebbistatin, showing that C1mC2 directly activates the thin filaments. In contrast, structural changes in thick filaments induced by C1mC2 were smaller than those associated with calcium activation and were abolished or reversed by blebbistatin. Low concentrations of C1mC2 did not affect resting force but increased calcium sensitivity and reduced cooperativity of force and structural changes in both thin and thick filaments. These results show that the N-terminal region of MyBP-C stabilizes the ON state of thin filaments and the OFF state of thick filaments and lead to a novel hypothesis for the physiological role of MyBP C in the regulation of cardiac contractility. PMID- 25512494 TI - Targeting osteosarcoma. PMID- 25512493 TI - Regulation of the Rhp26ERCC6/CSB chromatin remodeler by a novel conserved leucine latch motif. AB - CSB/ERCC6 (Cockayne syndrome B protein/excision repair cross-complementation group 6), a member of a subfamily of SWI2/SNF2 (SWItch/sucrose nonfermentable) related chromatin remodelers, plays crucial roles in gene expression and the maintenance of genome integrity. Here, we report the mechanism of the autoregulation of Rhp26, which is the homolog of CSB/ERCC6 in Schizosaccharomyces pombe. We identified a novel conserved protein motif, termed the "leucine latch," at the N terminus of Rhp26. The leucine latch motif mediates the autoinhibition of the ATPase and chromatin-remodeling activities of Rhp26 via its interaction with the core ATPase domain. Moreover, we found that the C terminus of the protein counteracts this autoinhibition and that both the N- and C-terminal regions of Rhp26 are needed for its proper function in DNA repair in vivo. The presence of the leucine latch motif in organisms ranging from yeast to humans suggests a conserved mechanism for the autoregulation of CSB/ERCC6 despite the otherwise highly divergent nature of the N- and C-terminal regions. PMID- 25512495 TI - Wolbachia small noncoding RNAs and their role in cross-kingdom communications. AB - In prokaryotes, small noncoding RNAs (snRNAs) of 50-500 nt are produced that are important in bacterial virulence and response to environmental stimuli. Here, we identified and characterized snRNAs from the endosymbiotic bacteria, Wolbachia, which are widespread in invertebrates and cause reproductive manipulations. Most importantly, some strains of Wolbachia inhibit replication of several vector borne pathogens in insects. We demonstrate that two abundant snRNAs, WsnRNA-46 and WsnRNA-49, are expressed in Wolbachia from noncoding RNA transcripts that contain precursors with stem-loop structures. WsnRNAs were detected in Aedes aegypti mosquitoes infected with the wMelPop-CLA strain of Wolbachia and in Drosophila melanogaster and Drosophila simulans infected with wMelPop and wAu strains, respectively, indicating that the WsnRNAs are conserved across species and strains. In addition, we show that the WsnRNAs may potentially regulate host genes and Wolbachia genes. Our findings provide evidence for the production of functional snRNAs by Wolbachia that play roles in cross-kingdom communication between the endosymbiont and the host. PMID- 25512497 TI - The role of self-interest in elite bargaining. AB - One of the best-known and most replicated laboratory results in behavioral economics is that bargainers frequently reject low offers, even when it harms their material self-interest. This finding could have important implications for international negotiations on many problems facing humanity today, because models of international bargaining assume exactly the opposite: that policy makers are rational and self-interested. However, it is unknown whether elites who engage in diplomatic bargaining will similarly reject low offers because past research has been based almost exclusively on convenience samples of undergraduates, members of the general public, or small-scale societies rather than highly experienced elites who design and bargain over policy. Using a unique sample of 102 policy and business elites who have an average of 21 y of practical experience conducting international diplomacy or policy strategy, we show that, compared with undergraduates and the general public, elites are actually more likely to reject low offers when playing a standard "ultimatum game" that assesses how players bargain over a fixed resource. Elites with more experience tend to make even higher demands, suggesting that this tendency only increases as policy makers advance to leadership positions. This result contradicts assumptions of rational self-interested behavior that are standard in models of international bargaining, and it suggests that the adoption of global agreements on international trade, climate change, and other important problems will not depend solely on the interests of individual countries, but also on whether these accords are seen as equitable to all member states. PMID- 25512498 TI - Nonrandom, diversifying processes are disproportionately strong in the smallest size classes of a tropical forest. AB - A variety of ecological processes influence diversity and species composition in natural communities. Most of these processes, whether abiotic or biotic, differentially filter individuals from birth to death, thereby altering species' relative abundances. Nonrandom outcomes could accrue throughout ontogeny, or the processes that generate them could be particularly influential at certain stages. One long-standing paradigm in tropical forest ecology holds that patterns of relative abundance among mature trees are largely set by processes operating at the earliest life cycle stages. Several studies confirm filtering processes at some stages, but the longevity of large trees makes a rigorous comparison across size classes impossible without long-term demographic data. Here, we use one of the world's longest-running, plot-based forest dynamics projects to compare nonrandom outcomes across stage classes. We considered a cohort of 7,977 individuals in 186 species that were alive in 1971 and monitored in 13 mortality censuses over 42 y to 2013. Nonrandom mortality with respect to species identity occurred more often in the smaller rather than the larger size classes. Furthermore, observed nonrandom mortality in the smaller size classes had a diversifying influence; species richness of the survivors was up to 30% greater than expected in the two smallest size classes, but not greater than expected in the larger size classes. These results highlight the importance of early life cycle stages in tropical forest community dynamics. More generally, they add to an accumulating body of evidence for the importance of early-stage nonrandom outcomes to community structure in marine and terrestrial environments. PMID- 25512496 TI - Large-scale topology and the default mode network in the mouse connectome. AB - Noninvasive functional imaging holds great promise for serving as a translational bridge between human and animal models of various neurological and psychiatric disorders. However, despite a depth of knowledge of the cellular and molecular underpinnings of atypical processes in mouse models, little is known about the large-scale functional architecture measured by functional brain imaging, limiting translation to human conditions. Here, we provide a robust processing pipeline to generate high-resolution, whole-brain resting-state functional connectivity MRI (rs-fcMRI) images in the mouse. Using a mesoscale structural connectome (i.e., an anterograde tracer mapping of axonal projections across the mouse CNS), we show that rs-fcMRI in the mouse has strong structural underpinnings, validating our procedures. We next directly show that large-scale network properties previously identified in primates are present in rodents, although they differ in several ways. Last, we examine the existence of the so called default mode network (DMN)--a distributed functional brain system identified in primates as being highly important for social cognition and overall brain function and atypically functionally connected across a multitude of disorders. We show the presence of a potential DMN in the mouse brain both structurally and functionally. Together, these studies confirm the presence of basic network properties and functional networks of high translational importance in structural and functional systems in the mouse brain. This work clears the way for an important bridge measurement between human and rodent models, enabling us to make stronger conclusions about how regionally specific cellular and molecular manipulations in mice relate back to humans. PMID- 25512499 TI - Conformational activation of ADAMTS13. AB - A disintegrin and metalloprotease with thrombospondin motifs 13 (ADAMTS13) is a metalloprotease that regulates von Willebrand factor (VWF) function. ADAMTS13 mediated proteolysis is determined by conformational changes in VWF, but also may depend on its own conformational activation. Kinetic analysis of WT ADAMTS13 revealed ~ 2.5-fold reduced activity compared with ADAMTS13 lacking its C terminal tail (MDTCS) or its CUB1-2 domains (WTDeltaCUB1-2), suggesting that the CUB domains naturally limit ADAMTS13 function. Consistent with this suggestion, WT ADAMTS13 activity was enhanced ~ 2.5-fold by preincubation with either an anti CUB mAb (20E9) or VWF D4CK (the natural binding partner for the CUB domains). Furthermore, the isolated CUB1-2 domains not only bound MDTCS, but also inhibited activity by up to 2.5-fold. Interestingly, a gain-of-function (GoF) ADAMTS13 spacer domain variant (R568K/F592Y/R660K/Y661F/Y665F) was ~ 2.5-fold more active than WT ADAMTS13, but could not be further activated by 20E9 mAb or VWF D4CK and was unable to bind or to be inhibited by the CUB1-2 domains, suggesting that the inhibitory effects of the CUB domains involve an interaction with the spacer domain that is disrupted in GoF ADAMTS13. Electron microscopy demonstrated a "closed" conformation of WT ADAMTS13 and suggested a more "open" conformation for GoF ADAMTS13. The cryptic spacer domain epitope revealed by conformational unfolding also represents the core antigenic target for autoantibodies in thrombotic thrombocytopenic purpura. We propose that ADAMTS13 circulates in a closed conformation, which is maintained by a CUB-spacer domain binding interaction. ADAMTS13 becomes conformationally activated on demand through interaction of its C-terminal CUB domains with VWF, making it susceptible to immune recognition. PMID- 25512500 TI - Forests, fields, and the edge of sustainability at the ancient Maya city of Tikal. AB - Tikal has long been viewed as one of the leading polities of the ancient Maya realm, yet how the city was able to maintain its substantial population in the midst of a tropical forest environment has been a topic of unresolved debate among researchers for decades. We present ecological, paleoethnobotanical, hydraulic, remote sensing, edaphic, and isotopic evidence that reveals how the Late Classic Maya at Tikal practiced intensive forms of agriculture (including irrigation, terrace construction, arboriculture, household gardens, and short fallow swidden) coupled with carefully controlled agroforestry and a complex system of water retention and redistribution. Empirical evidence is presented to demonstrate that this assiduously managed anthropogenic ecosystem of the Classic period Maya was a landscape optimized in a way that provided sustenance to a relatively large population in a preindustrial, low-density urban community. This landscape productivity optimization, however, came with a heavy cost of reduced environmental resiliency and a complete reliance on consistent annual rainfall. Recent speleothem data collected from regional caves showed that persistent episodes of unusually low rainfall were prevalent in the mid-9th century A.D., a time period that coincides strikingly with the abandonment of Tikal and the erection of its last dated monument in A.D. 869. The intensified resource management strategy used at Tikal-already operating at the landscape's carrying capacity-ceased to provide adequate food, fuel, and drinking water for the Late Classic populace in the face of extended periods of drought. As a result, social disorder and abandonment ensued. PMID- 25512502 TI - Links that speak: the global language network and its association with global fame. AB - Languages vary enormously in global importance because of historical, demographic, political, and technological forces. However, beyond simple measures of population and economic power, there has been no rigorous quantitative way to define the global influence of languages. Here we use the structure of the networks connecting multilingual speakers and translated texts, as expressed in book translations, multiple language editions of Wikipedia, and Twitter, to provide a concept of language importance that goes beyond simple economic or demographic measures. We find that the structure of these three global language networks (GLNs) is centered on English as a global hub and around a handful of intermediate hub languages, which include Spanish, German, French, Russian, Portuguese, and Chinese. We validate the measure of a language's centrality in the three GLNs by showing that it exhibits a strong correlation with two independent measures of the number of famous people born in the countries associated with that language. These results suggest that the position of a language in the GLN contributes to the visibility of its speakers and the global popularity of the cultural content they produce. PMID- 25512501 TI - Hedgehog-induced phosphorylation by CK1 sustains the activity of Ci/Gli activator. AB - Hedgehog (Hh) signaling governs many developmental processes by regulating the balance between the repressor (Ci(R)/Gli(R)) and activator (Ci(A)/Gli(A)) forms of Cubitus interruptus (Ci)/glioma-associated oncogene homolog (Gli) transcription factors. Although much is known about how Ci(R)/Gli(R) is controlled, the regulation of Ci(A)/Gli(A) remains poorly understood. Here we demonstrate that Casein kinase 1 (CK1) sustains Hh signaling downstream of Costal2 and Suppressor of fused (Sufu) by protecting Ci(A) from premature degradation. We show that Hh stimulates Ci phosphorylation by CK1 at multiple Ser/Thr-rich degrons to inhibit its recognition by the Hh-induced MATH and BTB domain containing protein (HIB), a substrate receptor for the Cullin 3 family of E3 ubiquitin ligases. In Hh-receiving cells, reduction of CK1 activity accelerated HIB-mediated degradation of Ci(A), leading to premature loss of pathway activity. We also provide evidence that Gli(A) is regulated by CK1 in a similar fashion and that CK1 acts downstream of Sufu to promote Sonic hedgehog signaling. Taken together, our study not only reveals an unanticipated and conserved mechanism by which phosphorylation of Ci/Gli positively regulates Hh signaling but also provides the first evidence, to our knowledge, that substrate recognition by the Cullin 3 family of E3 ubiquitin ligases is negatively regulated by a kinase. PMID- 25512503 TI - Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering. AB - The dementia of Alzheimer's disease (AD) results primarily from degeneration of neurons that furnish glutamatergic corticocortical connections that subserve cognition. Although neuron death is minimal in the absence of AD, age-related cognitive decline does occur in animals as well as humans, and it decreases quality of life for elderly people. Age-related cognitive decline has been linked to synapse loss and/or alterations of synaptic proteins that impair function in regions such as the hippocampus and prefrontal cortex. These synaptic alterations are likely reversible, such that maintenance of synaptic health in the face of aging is a critically important therapeutic goal. Here, we show that riluzole can protect against some of the synaptic alterations in hippocampus that are linked to age-related memory loss in rats. Riluzole increases glutamate uptake through glial transporters and is thought to decrease glutamate spillover to extrasynaptic NMDA receptors while increasing synaptic glutamatergic activity. Treated aged rats were protected against age-related cognitive decline displayed in nontreated aged animals. Memory performance correlated with density of thin spines on apical dendrites in CA1, although not with mushroom spines. Furthermore, riluzole-treated rats had an increase in clustering of thin spines that correlated with memory performance and was specific to the apical, but not the basilar, dendrites of CA1. Clustering of synaptic inputs is thought to allow nonlinear summation of synaptic strength. These findings further elucidate neuroplastic changes in glutamatergic circuits with aging and advance therapeutic development to prevent and treat age-related cognitive decline. PMID- 25512504 TI - Bifurcation analysis of single-cell gene expression data reveals epigenetic landscape. AB - We present single-cell clustering using bifurcation analysis (SCUBA), a novel computational method for extracting lineage relationships from single-cell gene expression data and modeling the dynamic changes associated with cell differentiation. SCUBA draws techniques from nonlinear dynamics and stochastic differential equation theories, providing a systematic framework for modeling complex processes involving multilineage specifications. By applying SCUBA to analyze two complementary, publicly available datasets we successfully reconstructed the cellular hierarchy during early development of mouse embryos, modeled the dynamic changes in gene expression patterns, and predicted the effects of perturbing key transcriptional regulators on inducing lineage biases. The results were robust with respect to experimental platform differences between RT-PCR and RNA sequencing. We selectively tested our predictions in Nanog mutants and found good agreement between SCUBA predictions and the experimental data. We further extended the utility of SCUBA by developing a method to reconstruct missing temporal-order information from a typical single-cell dataset. Analysis of a hematopoietic dataset suggests that our method is effective for reconstructing gene expression dynamics during human B-cell development. In summary, SCUBA provides a useful single-cell data analysis tool that is well suited for the investigation of developmental processes. PMID- 25512505 TI - The N- and C-terminal autolytic fragments of CAPN3/p94/calpain-3 restore proteolytic activity by intermolecular complementation. AB - CAPN3/p94/calpain-3, a calpain protease family member predominantly expressed in skeletal muscle, possesses unusually rapid and exhaustive autolytic activity. Mutations in the human CAPN3 gene impairing its protease functions cause limb girdle muscular dystrophy type 2A (LGMD2A); yet, the connection between CAPN3's autolytic activity and the enzyme's function in vivo remain unclear. Here, we demonstrated that CAPN3 protease activity was reconstituted by intermolecular complementation (iMOC) between its two autolytic fragments. Furthermore, the activity of full-length CAPN3 active-site mutants was surprisingly rescued through iMOC with autolytic fragments containing WT amino acid sequences. These results provide evidence that WT CAPN3 can be formed by the iMOC of two different complementary CAPN3 mutants. The finding of iMOC-mediated restoration of calpain activity indicates a novel mechanism for the genotype-phenotype links in LGMD2A. PMID- 25512506 TI - TSPAN12 is a critical factor for cancer-fibroblast cell contact-mediated cancer invasion. AB - Communication between cancer cells and their microenvironment controls cancer progression. Although the tumor suppressor p53 functions in a cell-autonomous manner, it has also recently been shown to function in a non-cell-autonomous fashion. Although functional defects have been reported in p53 in stromal cells surrounding cancer, including mutations in the p53 gene and decreased p53 expression, the role of p53 in stromal cells during cancer progression remains unclear. We herein show that the expression of alpha-smooth muscle actin (alpha SMA), a marker of cancer-associated fibroblasts (CAFs), was increased by the ablation of p53 in lung fibroblasts. CAFs enhanced the invasion and proliferation of lung cancer cells when cocultured with p53-depleted fibroblasts and required contact between cancer and stromal cells. A comprehensive analysis using a DNA chip revealed that tetraspanin 12 (TSPAN12), which belongs to the tetraspanin protein family, was derepressed by p53 knockdown. TSPAN12 knockdown in p53 depleted fibroblasts inhibited cancer cell proliferation and invasion elicited by coculturing with p53-depleted fibroblasts in vitro, and inhibited tumor growth in vivo. It also decreased CXC chemokine ligand 6 (CXCL6) secretion through the beta catenin signaling pathway, suggesting that cancer cell contact with TSPAN12 in fibroblasts transduced beta-catenin signaling into fibroblasts, leading to the secretion of CXCL6 to efficiently promote invasion. These results suggest that stroma-derived p53 plays a pivotal role in epithelial cancer progression and that TSPAN12 and CXCL6 are potential targets for lung cancer therapy. PMID- 25512508 TI - Thermotropic liquid crystals from biomacromolecules. AB - Complexation of biomacromolecules (e.g., nucleic acids, proteins, or viruses) with surfactants containing flexible alkyl tails, followed by dehydration, is shown to be a simple generic method for the production of thermotropic liquid crystals. The anhydrous smectic phases that result exhibit biomacromolecular sublayers intercalated between aliphatic hydrocarbon sublayers at or near room temperature. Both this and low transition temperatures to other phases enable the study and application of thermotropic liquid crystal phase behavior without thermal degradation of the biomolecular components. PMID- 25512507 TI - Expression and prognostic impact of lncRNAs in acute myeloid leukemia. AB - Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis, and cell cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged >=60 y) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. An independent set of 71 untreated older patients with CN-AML was used to validate the outcome scores using RNA sequencing. Distinctive lncRNA profiles were found associated with selected mutations, such as internal tandem duplications in the FLT3 gene (FLT3-ITD) and mutations in the NPM1, CEBPA, IDH2, ASXL1, and RUNX1 genes. Using the lncRNAs most associated with event-free survival in a training cohort of 148 older patients with CN-AML, we derived a lncRNA score composed of 48 lncRNAs. Patients with an unfavorable compared with favorable lncRNA score had a lower complete response (CR) rate [P < 0.001, odds ratio = 0.14, 54% vs. 89%], shorter disease free survival (DFS) [P < 0.001, hazard ratio (HR) = 2.88] and overall survival (OS) (P < 0.001, HR = 2.95). The validation set analyses confirmed these results (CR, P = 0.03; DFS, P = 0.009; OS, P = 0.009). Multivariable analyses for CR, DFS, and OS identified the lncRNA score as an independent marker for outcome. In conclusion, lncRNA expression in AML is closely associated with recurrent mutations. A small subset of lncRNAs is correlated strongly with treatment response and survival. PMID- 25512510 TI - Life cycle air quality impacts of conventional and alternative light-duty transportation in the United States. AB - Commonly considered strategies for reducing the environmental impact of light duty transportation include using alternative fuels and improving vehicle fuel economy. We evaluate the air quality-related human health impacts of 10 such options, including the use of liquid biofuels, diesel, and compressed natural gas (CNG) in internal combustion engines; the use of electricity from a range of conventional and renewable sources to power electric vehicles (EVs); and the use of hybrid EV technology. Our approach combines spatially, temporally, and chemically detailed life cycle emission inventories; comprehensive, fine-scale state-of-the-science chemical transport modeling; and exposure, concentration response, and economic health impact modeling for ozone (O3) and fine particulate matter (PM2.5). We find that powering vehicles with corn ethanol or with coal based or "grid average" electricity increases monetized environmental health impacts by 80% or more relative to using conventional gasoline. Conversely, EVs powered by low-emitting electricity from natural gas, wind, water, or solar power reduce environmental health impacts by 50% or more. Consideration of potential climate change impacts alongside the human health outcomes described here further reinforces the environmental preferability of EVs powered by low-emitting electricity relative to gasoline vehicles. PMID- 25512509 TI - TORC1 regulators Iml1/GATOR1 and GATOR2 control meiotic entry and oocyte development in Drosophila. AB - In single-cell eukaryotes the pathways that monitor nutrient availability are central to initiating the meiotic program and gametogenesis. In Saccharomyces cerevisiae an essential step in the transition to the meiotic cycle is the down regulation of the nutrient-sensitive target of rapamycin complex 1 (TORC1) by the increased minichromosome loss 1/ GTPase-activating proteins toward Rags 1 (Iml1/GATOR1) complex in response to amino acid starvation. How metabolic inputs influence early meiotic progression and gametogenesis remains poorly understood in metazoans. Here we define opposing functions for the TORC1 regulatory complexes Iml1/GATOR1 and GATOR2 during Drosophila oogenesis. We demonstrate that, as is observed in yeast, the Iml1/GATOR1 complex inhibits TORC1 activity to slow cellular metabolism and drive the mitotic/meiotic transition in developing ovarian cysts. In iml1 germline depletions, ovarian cysts undergo an extra mitotic division before meiotic entry. The TORC1 inhibitor rapamycin can suppress this extra mitotic division. Thus, high TORC1 activity delays the mitotic/meiotic transition. Conversely, mutations in Tor, which encodes the catalytic subunit of the TORC1 complex, result in premature meiotic entry. Later in oogenesis, the GATOR2 components Mio and Seh1 are required to oppose Iml1/GATOR1 activity to prevent the constitutive inhibition of TORC1 and a block to oocyte growth and development. To our knowledge, these studies represent the first examination of the regulatory relationship between the Iml1/GATOR1 and GATOR2 complexes within the context of a multicellular organism. Our data imply that the central role of the Iml1/GATOR1 complex in the regulation of TORC1 activity in the early meiotic cycle has been conserved from single cell to multicellular organisms. PMID- 25512511 TI - Occurrence of pristine aerosol environments on a polluted planet. AB - Natural aerosols define a preindustrial baseline state from which the magnitude of anthropogenic aerosol effects on climate are calculated and are a major component of the large uncertainty in anthropogenic aerosol-cloud radiative forcing. This uncertainty would be reduced if aerosol environments unperturbed by air pollution could be studied in the present--day atmosphere, but the pervasiveness of air pollution makes identification of unperturbed regions difficult. Here, we use global model simulations to define unperturbed aerosol regions in terms of two measures that compare 1750 and 2000 conditions-the number of days with similar aerosol concentrations and the similarity of the aerosol response to perturbations in model processes and emissions. The analysis shows that the aerosol system in many present-day environments looks and behaves like it did in the preindustrial era. On a global annual mean, unperturbed aerosol regions cover 12% of the Earth (16% of the ocean surface and 2% of the land surface). There is a strong seasonal variation in unperturbed regions of between 4% in August and 27% in January, with the most persistent conditions occurring over the equatorial Pacific. About 90% of unperturbed regions occur in the Southern Hemisphere, but in the Northern Hemisphere, unperturbed conditions are transient and spatially patchy. In cloudy regions with a radiative forcing relative to 1750, model results suggest that unperturbed aerosol conditions could still occur on a small number of days per month. However, these environments are mostly in the Southern Hemisphere, potentially limiting the usefulness in reducing Northern Hemisphere forcing uncertainty. PMID- 25512512 TI - Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis. AB - Sepsis is characterized by overlapping phases of excessive inflammation temporally aligned with an immunosuppressed state, defining a complex clinical scenario that explains the lack of successful therapeutic options. Here we tested whether the formyl-peptide receptor 2/3 (Fpr2/3)--ortholog to human FPR2/ALX (receptor for lipoxin A4)--exerted regulatory and organ-protective functions in experimental sepsis. Coecal ligature and puncture was performed to obtain nonlethal polymicrobial sepsis, with animals receiving antibiotics and analgesics. Clinical symptoms, temperature, and heart function were monitored up to 24 h. Peritoneal lavage and plasma samples were analyzed for proinflammatory and proresolving markers of inflammation and organ dysfunction. Compared with wild-type mice, Fpr2/3(-/-) animals exhibited exacerbation of disease severity, including hypothermia and cardiac dysfunction. This scenario was paralleled by higher levels of cytokines [CXCL1 (CXC receptor ligand 1), CCL2 (CC receptor ligand 2), and TNFalpha] as quantified in cell-free biological fluids. Reduced monocyte recruitment in peritoneal lavages of Fpr2/3(-/-) animals was reflected by a higher granulocyte/monocyte ratio. Monitoring Fpr2/3(-/-) gene promoter activity with a GFP proxy marker revealed an over threefold increase in granulocyte and monocyte signals at 24 h post-coecal ligature and puncture, a response mediated by TNFalpha. Treatment with a receptor peptido-agonist conferred protection against myocardial dysfunction in wild-type, but not Fpr2/3( /-), animals. Therefore, coordinated physio-pharmacological analyses indicate nonredundant modulatory functions for Fpr2/3 in experimental sepsis, opening new opportunities to manipulate the host response for therapeutic development. PMID- 25512513 TI - Treacher Collins syndrome TCOF1 protein cooperates with NBS1 in the DNA damage response. AB - The signal transduction pathway of the DNA damage response (DDR) is activated to maintain genomic integrity following DNA damage. The DDR promotes genomic integrity by regulating a large network of cellular activities that range from DNA replication and repair to transcription, RNA splicing, and metabolism. In this study we define an interaction between the DDR factor NBS1 and TCOF1, a nucleolar protein that regulates ribosomal DNA (rDNA) transcription and is mutated in Treacher Collins syndrome. We show that NBS1 relocalizes to nucleoli after DNA damage in a manner dependent on TCOF1 and on casein kinase II and ATM, which are known to modify TCOF1 by phosphorylation. Moreover, we identify a putative ATM phosphorylation site that is required for NBS1 relocalization to nucleoli in response to DNA damage. Last, we report that TCOF1 promotes cellular resistance to DNA damaging agents. Collectively, our findings identify TCOF1 as a DDR factor that could cooperate with ATM and NBS1 to suppress inappropriate rDNA transcription and maintain genomic integrity after DNA damage. PMID- 25512514 TI - Stable, uncleaved HIV-1 envelope glycoprotein gp140 forms a tightly folded trimer with a native-like structure. AB - The HIV-1 envelope spike [trimeric (gp160)3, cleaved to (gp120/gp41)3] is the mediator of viral entry and the principal target of humoral immune response to the virus. Production of a recombinant preparation that represents the functional spike poses a challenge for vaccine development, because the (gp120/gp41)3 complex is prone to dissociation. We have reported previously that stable HIV-1 gp140 trimers, the uncleaved ectodomains of (gp160)3, have nearly all of the antigenic properties expected for native viral spikes. Because of recent claims that uncleaved gp140 proteins may adopt a nonnative structure with three gp120 moieties "dangling" from a trimeric gp41 ectodomain in its postfusion conformation, we have inserted a long, flexible linker between gp120 and gp41 in our stable gp140 trimers to assess their stability and to analyze their conformation in solution. The modified trimer has biochemical and antigenic properties virtually identical to those of its unmodified counterpart. Both forms bind a single CD4 per trimer, suggesting that the trimeric conformation occludes two of the three CD4 sites even when a flexible linker has relieved the covalent constraint between gp120 and gp41. In contrast, an artificial trimer containing three gp120s flexibly tethered to a trimerization tag binds three CD4s and has antigenicity nearly identical to that of monomeric gp120. Moreover, the gp41 part of both modified and unmodified gp140 trimers has a structure very different from that of postfusion gp41. These results show that uncleaved gp140 trimers from suitable isolates have compact, native-like structures and support their use as candidate vaccine immunogens. PMID- 25512515 TI - Electrically pumped semiconductor laser with monolithic control of circular polarization. AB - We demonstrate surface emission of terahertz (THz) frequency radiation from a monolithic quantum cascade laser with built-in control over the degree of circular polarization by "fishbone" gratings composed of orthogonally oriented aperture antennas. Different grating concepts for circularly polarized emission are introduced along with the presentation of simulations and experimental results. Fifth-order gratings achieve a degree of circular polarization of up to 86% within a 12 degrees -wide core region of their emission lobes in the far field. For devices based on an alternative transverse grating design, degrees of circular polarization as high as 98% are demonstrated for selected far-field regions of the outcoupled THz radiation and within a collection half-angle of about 6 degrees . Potential and limitations of integrated antenna gratings for polarization-controlled emission are discussed. PMID- 25512517 TI - Soil surface acidity plays a determining role in the atmospheric-terrestrial exchange of nitrous acid. AB - Nitrous acid (HONO) is an important hydroxyl (OH) radical source that is formed on both ground and aerosol surfaces in the well-mixed boundary layer. Recent studies report the release of HONO from nonacidic soils, although it is unclear how soil that is more basic than the pKa of HONO (~ 3) is capable of protonating soil nitrite to serve as an atmospheric HONO source. Here, we used a coated-wall flow tube and chemical ionization mass spectrometry (CIMS) to study the pH dependence of HONO uptake onto agricultural soil and model substrates under atmospherically relevant conditions (1 atm and 30% relative humidity). Experiments measuring the evolution of HONO from pH-adjusted surfaces treated with nitrite and potentiometric titrations of the substrates show, to our knowledge for the first time, that surface acidity rather than bulk aqueous pH determines HONO uptake and desorption efficiency on soil, in a process controlled by amphoteric aluminum and iron (hydr)oxides present. The results have important implications for predicting when soil nitrite, whether microbially derived or atmospherically deposited, will act as a net source or sink of atmospheric HONO. This process represents an unrecognized mechanism of HONO release from soil that will contribute to HONO emissions throughout the day. PMID- 25512516 TI - In silico selection of therapeutic antibodies for development: viscosity, clearance, and chemical stability. AB - For mAbs to be viable therapeutics, they must be formulated to have low viscosity, be chemically stable, and have normal in vivo clearance rates. We explored these properties by observing correlations of up to 60 different antibodies of the IgG1 isotype. Unexpectedly, we observe significant correlations with simple physical properties obtainable from antibody sequences and by molecular dynamics simulations of individual antibody molecules. mAbs viscosities increase strongly with hydrophobicity and charge dipole distribution and decrease with net charge. Fast clearance correlates with high hydrophobicities of certain complementarity determining regions and with high positive or high negative net charge. Chemical degradation from tryptophan oxidation correlates with the average solvent exposure time of tryptophan residues. Aspartic acid isomerization rates can be predicted from solvent exposure and flexibility as determined by molecular dynamics simulations. These studies should aid in more rapid screening and selection of mAb candidates during early discovery. PMID- 25512518 TI - Proteogenomic analysis and global discovery of posttranslational modifications in prokaryotes. AB - We describe an integrated workflow for proteogenomic analysis and global profiling of posttranslational modifications (PTMs) in prokaryotes and use the model cyanobacterium Synechococcus sp. PCC 7002 (hereafter Synechococcus 7002) as a test case. We found more than 20 different kinds of PTMs, and a holistic view of PTM events in this organism grown under different conditions was obtained without specific enrichment strategies. Among 3,186 predicted protein-coding genes, 2,938 gene products (>92%) were identified. We also identified 118 previously unidentified proteins and corrected 38 predicted gene-coding regions in the Synechococcus 7002 genome. This systematic analysis not only provides comprehensive information on protein profiles and the diversity of PTMs in Synechococcus 7002 but also provides some insights into photosynthetic pathways in cyanobacteria. The entire proteogenomics pipeline is applicable to any sequenced prokaryotic organism, and we suggest that it should become a standard part of genome annotation projects. PMID- 25512520 TI - Carbon-bearing iron phases and the carbon isotope composition of the deep Earth. AB - The carbon budget and dynamics of the Earth's interior, including the core, are currently very poorly understood. Diamond-bearing, mantle-derived rocks show a very well defined peak at delta(13)C ~ -5 +/- 30/00 with a very broad distribution to lower values (~-400/00). The processes that have produced the wide delta(13)C distributions to the observed low delta(13)C values in the deep Earth have been extensively debated, but few viable models have been proposed. Here, we present a model for understanding carbon isotope distributions within the deep Earth, involving Fe-C phases (Fe carbides and C dissolved in Fe-Ni metal). Our theoretical calculations show that Fe and Si carbides can be significantly depleted in (13)C relative to other C-bearing materials even at mantle temperatures. Thus, the redox freezing and melting cycles of lithosphere via subduction upwelling in the deep Earth that involve the Fe-C phases can readily produce diamond with the observed low delta(13)C values. The sharp contrast in the delta(13)C distributions of peridotitic and eclogitic diamonds may reflect differences in their carbon cycles, controlled by the evolution of geodynamical processes around 2.5-3 Ga. Our model also predicts that the core contains C with low delta(13)C values and that an average delta(13)C value of the bulk Earth could be much lower than ~-50/00, consistent with those of chondrites and other planetary body. The heterogeneous and depleted delta(13)C values of the deep Earth have implications, not only for its accretion-differentiation history but also for carbon isotope biosignatures for early life on the Earth. PMID- 25512519 TI - Epigenetic targeting of activation-induced cytidine deaminase. AB - Activation-induced cytidine deaminase (AID) initiates class switch recombination (CSR) and somatic hypermutation (SHM) by deaminating cytosine residues in immunoglobulin genes (Igh, Igkappa, and Iglambda). At a lower frequency, AID also causes collateral DNA damage at non-Ig loci, including genes that are rearranged or mutated in B-cell lymphoma. Precisely how AID is recruited to these off-target sites is not entirely understood. To gain further insight into how AID selects its targets, we compared AID-mediated translocations in two different cell types, B cells and mouse embryonic fibroblasts (MEFs). AID targets a distinct set of hotspots in the two cell types. In both cases, hotspots are concentrated in highly transcribed but stalled genes. However, transcription alone is insufficient to recruit AID activity. Comparison of genes similarly transcribed in B cells and MEFs but targeted in only one of the two cell types reveals a common set of epigenetic features associated with AID recruitment in both cells. AID target genes are enriched in chromatin modifications associated with active enhancers (such as H3K27Ac) and marks of active transcription (such as H3K36me3) in both fibroblasts and B cells, indicating that these features are universal mediators of AID recruitment. PMID- 25512521 TI - Mechanical resilience and cementitious processes in Imperial Roman architectural mortar. AB - The pyroclastic aggregate concrete of Trajan's Markets (110 CE), now Museo Fori Imperiali in Rome, has absorbed energy from seismic ground shaking and long-term foundation settlement for nearly two millenia while remaining largely intact at the structural scale. The scientific basis of this exceptional service record is explored through computed tomography of fracture surfaces and synchroton X-ray microdiffraction analyses of a reproduction of the standardized hydrated lime volcanic ash mortar that binds decimeter-sized tuff and brick aggregate in the conglomeratic concrete. The mortar reproduction gains fracture toughness over 180 d through progressive coalescence of calcium-aluminum-silicate-hydrate (C-A-S-H) cementing binder with Ca/(Si+Al) ~ 0.8-0.9 and crystallization of stratlingite and siliceous hydrogarnet (katoite) at >= 90 d, after pozzolanic consumption of hydrated lime was complete. Platey stratlingite crystals toughen interfacial zones along scoria perimeters and impede macroscale propagation of crack segments. In the 1,900-y-old mortar, C-A-S-H has low Ca/(Si+Al) ~ 0.45-0.75. Dense clusters of 2- to 30-um stratlingite plates further reinforce interfacial zones, the weakest link of modern cement-based concrete, and the cementitious matrix. These crystals formed during long-term autogeneous reaction of dissolved calcite from lime and the alkali-rich scoriae groundmass, clay mineral (halloysite), and zeolite (phillipsite and chabazite) surface textures from the Pozzolane Rosse pyroclastic flow, erupted from the nearby Alban Hills volcano. The clast-supported conglomeratic fabric of the concrete presents further resistance to fracture propagation at the structural scale. PMID- 25512522 TI - Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH cytochrome P450 oxidoreductase. AB - The diurnal variation in acetaminophen (APAP) hepatotoxicity (chronotoxicity) reportedly is driven by oscillations in metabolism that are influenced by the circadian phases of feeding and fasting. To determine the relative contributions of the central clock and the hepatocyte circadian clock in modulating the chronotoxicity of APAP, we used a conditional null allele of brain and muscle Arnt-like 1 (Bmal1, aka Mop3 or Arntl) allowing deletion of the clock from hepatocytes while keeping the central and other peripheral clocks (e.g., the clocks controlling food intake) intact. We show that deletion of the hepatocyte clock dramatically reduces APAP bioactivation and toxicity in vivo and in vitro because of a reduction in NADPH-cytochrome P450 oxidoreductase gene expression, protein, and activity. PMID- 25512524 TI - A divergent Pumilio repeat protein family for pre-rRNA processing and mRNA localization. AB - Pumilio/feminization of XX and XO animals (fem)-3 mRNA-binding factor (PUF) proteins bind sequence specifically to mRNA targets using a single-stranded RNA binding domain comprising eight Pumilio (PUM) repeats. PUM repeats have now been identified in proteins that function in pre-rRNA processing, including human Puf A and yeast Puf6. This is a role not previously ascribed to PUF proteins. Here we present crystal structures of human Puf-A that reveal a class of nucleic acid binding proteins with 11 PUM repeats arranged in an "L"-like shape. In contrast to classical PUF proteins, Puf-A forms sequence-independent interactions with DNA or RNA, mediated by conserved basic residues. We demonstrate that equivalent basic residues in yeast Puf6 are important for RNA binding, pre-rRNA processing, and mRNA localization. Thus, PUM repeats can be assembled into alternative folds that bind to structured nucleic acids in addition to forming canonical eight repeat crescent-shaped RNA-binding domains found in classical PUF proteins. PMID- 25512527 TI - Exoplanet orbital eccentricity: multiplicity relation and the Solar System. AB - The known population of exoplanets exhibits a much wider range of orbital eccentricities than Solar System planets and has a much higher average eccentricity. These facts have been widely interpreted to indicate that the Solar System is an atypical member of the overall population of planetary systems. We report here on a strong anticorrelation of orbital eccentricity with multiplicity (number of planets in the system) among cataloged radial velocity (RV) systems. The mean, median, and rough distribution of eccentricities of Solar System planets fits an extrapolation of this anticorrelation to the eight-planet case rather precisely despite the fact that no more than two Solar System planets would be detectable with RV data comparable to that in the exoplanet sample. Moreover, even if regarded as a single or double planetary system, the Solar System lies in a reasonably heavily populated region of eccentricity-multiplicity space. Thus, the Solar System is not anomalous among known exoplanetary systems with respect to eccentricities when its multiplicity is taken into account. Specifically, as the multiplicity of a system increases, the eccentricity decreases roughly as a power law of index -1.20. A simple and plausible but ad hoc and model-dependent interpretation of this relationship implies that ~ 80% of the one-planet and 25% of the two-planet systems in our sample have additional, as yet undiscovered, members but that systems of higher observed multiplicity are largely complete (i.e., relatively rarely contain additional undiscovered planets). If low eccentricities indeed favor high multiplicities, habitability may be more common in systems with a larger number of planets. PMID- 25512525 TI - Maize SBP-box transcription factors unbranched2 and unbranched3 affect yield traits by regulating the rate of lateral primordia initiation. AB - The separation of male and female flowers in maize provides the potential for independent regulation of traits that affect crop productivity. For example, tassel branch number controls pollen abundance and length of shedding time, whereas ear row number directly affects kernel yield. Mutations in duplicate SBP box transcription factor genes unbranched2 (ub2) and ub3 affect both of these yield traits. Double mutants display a decrease in tassel branch number and an increase in ear row number, both of which are enhanced by loss of a related gene called tasselsheath4 (tsh4). Furthermore, triple mutants have more tillers and leaves-phenotypes seen in Corngrass1 mutants that result from widespread repression of SBP-box genes. Immunolocalization of UB2 and UB3 proteins revealed accumulation throughout the meristem but absence from the central domain of the meristem where cells regenerate. Thus, ub2, ub3, and tsh4 function as redundant factors that limit the rate of cell differentiation to the lateral domains of meristems. When these genes are mutated, cells are allocated to lateral primordia at a higher rate, causing a net loss of cells from the central domain and premature termination of the inflorescence. The ub3 locus is tightly linked to quantitative trait loci (QTL) for ear row number and tassel branch number in both the nested association mapping (NAM) and intermated B73 by Mo17 (IBM) populations of maize recombinant inbreds, indicating that this gene may be agronomically important. Analysis of ear and tassel QTL across biparental families suggests that multiple mutations in ub3 independently regulate male and female inflorescence development. PMID- 25512523 TI - Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. AB - Osteosarcoma is the most common primary bone tumor, yet there have been no substantial advances in treatment or survival in three decades. We examined 59 tumor/normal pairs by whole-exome, whole-genome, and RNA-sequencing. Only the TP53 gene was mutated at significant frequency across all samples. The mean nonsilent somatic mutation rate was 1.2 mutations per megabase, and there was a median of 230 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the intertumor heterogeneity, the extent of genomic instability, and the difficulty in acquiring a large sample size in a rare tumor, we used several methods to identify genomic events contributing to osteosarcoma survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach, and an shRNA screen converged on the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo. PMID- 25512526 TI - pH modulates the activity and synergism of the airway surface liquid antimicrobials beta-defensin-3 and LL-37. AB - The pulmonary airways are continuously exposed to bacteria. As a first line of defense against infection, the airway surface liquid (ASL) contains a complex mixture of antimicrobial factors that kill inhaled and aspirated bacteria. The composition of ASL is critical for antimicrobial effectiveness. For example, in cystic fibrosis an abnormally acidic ASL inhibits antimicrobial activity. Here, we tested the effect of pH on the activity of an ASL defensin, human beta defensin-3 (hBD-3), and the cathelicidin-related peptide, LL-37. We found that reducing pH from 8.0 to 6.8 reduced the ability of both peptides to kill Staphylococcus aureus. An acidic pH also attenuated LL-37 killing of Pseudomonas aeruginosa. In addition, we discovered synergism between hBD-3 and LL-37 in killing S. aureus. LL-37 and lysozyme were also synergistic. Importantly, an acidic pH reduced the synergistic effects of combinations of ASL antibacterials. These results indicate that an acidic pH reduces the activity of individual ASL antimicrobials, impairs synergism between them, and thus may disrupt an important airway host defense mechanism. PMID- 25512529 TI - Existence of isostatic, maximally random jammed monodisperse hard-disk packings. AB - We generate jammed packings of monodisperse circular hard-disks in two dimensions using the Torquato-Jiao sequential linear programming algorithm. The packings display a wide diversity of packing fractions, average coordination numbers, and order as measured by standard scalar order metrics. This geometric-structure approach enables us to show the existence of relatively large maximally random jammed (MRJ) packings with exactly isostatic jammed backbones and a packing fraction (including rattlers) of [Formula: see text]. By contrast, the concept of random close packing (RCP) that identifies the most probable packings as the most disordered misleadingly identifies highly ordered disk packings as RCP in 2D. Fundamental structural descriptors such as the pair correlation function, structure factor, and Voronoi statistics show a strong contrast between the MRJ state and the typical hyperstatic, polycrystalline packings with [Formula: see text] that are more commonly obtained using standard packing protocols. Establishing that the MRJ state for monodisperse hard disks is isostatic and qualitatively distinct from commonly observed polycrystalline packings contradicts conventional wisdom that such a disordered, isostatic packing does not exist due to a lack of geometrical frustration and sheds light on the nature of disorder. This prompts the question of whether an algorithm may be designed that is strongly biased toward generating the monodisperse disk MRJ state. PMID- 25512528 TI - Allosteric activation of ADAMTS13 by von Willebrand factor. AB - The metalloprotease ADAMTS13 cleaves von Willebrand factor (VWF) within endovascular platelet aggregates, and ADAMTS13 deficiency causes fatal microvascular thrombosis. The proximal metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains of ADAMTS13 recognize a cryptic site in VWF that is exposed by tensile force. Another seven T and two complement C1r/C1s, sea urchin epidermal growth factor, and bone morphogenetic protein (CUB) domains of uncertain function are C-terminal to the MDTCS domains. We find that the distal T8-CUB2 domains markedly inhibit substrate cleavage, and binding of VWF or monoclonal antibodies to distal ADAMTS13 domains relieves this autoinhibition. Small angle X-ray scattering data indicate that distal T-CUB domains interact with proximal MDTCS domains. Thus, ADAMTS13 is regulated by substrate-induced allosteric activation, which may optimize VWF cleavage under fluid shear stress in vivo. Distal domains of other ADAMTS proteases may have similar allosteric properties. PMID- 25512530 TI - Genetic modifiers of EGFR dependence in non-small cell lung cancer. AB - Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFR dependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFR-independent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival. PMID- 25512531 TI - Mice deficient in Rbm38, a target of the p53 family, are susceptible to accelerated aging and spontaneous tumors. AB - RNA-binding motif protein 38 (Rbm38), also called RNPC1 [RNA-binding region (RNP1, RRM) containing 1], is a target of the p53 family and modulates p53 expression via mRNA translation. To investigate the biological function of Rbm38 in vivo, we generated an Rbm38-null mouse model. We showed that mice deficient in Rbm38 exhibit signs of accelerated aging and are prone to hematopoietic defects and spontaneous tumors. To determine the biological significance of the p53-Rbm38 loop, we showed that Rbm38 deficiency enhances accumulation of p53 induced by ionizing radiation (IR) and sensitizes mice to IR-induced lethality in a p53 dependent manner. Most importantly, Rbm38 deficiency markedly decreases the tumor penetrance in mice heterozygous for p53 via enhanced p53 expression. Interestingly, we found that Rbm38 deficiency shortens the life span of, and promotes lymphomagenesis in, mice deficient in p53. These results provide genetic evidence that Rbm38 is necessary for normal hematopoiesis and for suppressing accelerated aging and tumorigenesis. Thus, the p53-Rbm38 axis might be explored for extending longevity and for tumor suppression. PMID- 25512532 TI - Identification of a pheromone that increases anxiety in rats. AB - Chemical communication plays an important role in the social lives of various mammalian species. Some of these chemicals are called pheromones. Rats release a specific odor into the air when stressed. This stress-related odor increases the anxiety levels of other rats; therefore, it is possible that the anxiety-causing molecules are present in the stress-related odorants. Here, we have tried to identify the responsible molecules by using the acoustic startle reflex as a bioassay system to detect anxiogenic activity. After successive fractionation of the stress-related odor, we detected 4-methylpentanal and hexanal in the final fraction that still possessed anxiogenic properties. Using synthetic molecules, we found that minute amounts of the binary mixture, but not either molecule separately, increased anxiety in rats. Furthermore, we determined that the mixture increased a specific type of anxiety and evoked anxiety-related behavioral responses in an experimental model that was different from the acoustic startle reflex. Analyses of neural mechanisms proposed that the neural circuit related to anxiety was only activated when the two molecules were simultaneously perceived by two olfactory systems. We concluded that the mixture is a pheromone that increases anxiety in rats. To our knowledge, this is the first study identifying a rat pheromone. Our results could aid further research on rat pheromones, which would enhance our understanding of chemical communication in mammals. PMID- 25512533 TI - Revealing bacterial targets of growth inhibitors encoded by bacteriophage T7. AB - Today's arsenal of antibiotics is ineffective against some emerging strains of antibiotic-resistant pathogens. Novel inhibitors of bacterial growth therefore need to be found. The target of such bacterial-growth inhibitors must be identified, and one way to achieve this is by locating mutations that suppress their inhibitory effect. Here, we identified five growth inhibitors encoded by T7 bacteriophage. High-throughput sequencing of genomic DNA of resistant bacterial mutants evolving against three of these inhibitors revealed unique mutations in three specific genes. We found that a nonessential host gene, ppiB, is required for growth inhibition by one bacteriophage inhibitor and another nonessential gene, pcnB, is required for growth inhibition by a different inhibitor. Notably, we found a previously unidentified growth inhibitor, gene product (Gp) 0.6, that interacts with the essential cytoskeleton protein MreB and inhibits its function. We further identified mutations in two distinct regions in the mreB gene that overcome this inhibition. Bacterial two-hybrid assay and accumulation of Gp0.6 only in MreB-expressing bacteria confirmed interaction of MreB and Gp0.6. Expression of Gp0.6 resulted in lemon-shaped bacteria followed by cell lysis, as previously reported for MreB inhibitors. The described approach may be extended for the identification of new growth inhibitors and their targets across bacterial species and in higher organisms. PMID- 25512534 TI - Interspecific introgressive origin of genomic diversity in the house mouse. AB - We report on a genome-wide scan for introgression between the house mouse (Mus musculus domesticus) and the Algerian mouse (Mus spretus), using samples from the ranges of sympatry and allopatry in Africa and Europe. Our analysis reveals wide variability in introgression signatures along the genomes, as well as across the samples. We find that fewer than half of the autosomes in each genome harbor all detectable introgression, whereas the X chromosome has none. Further, European mice carry more M. spretus alleles than the sympatric African ones. Using the length distribution and sharing patterns of introgressed genomic tracts across the samples, we infer, first, that at least three distinct hybridization events involving M. spretus have occurred, one of which is ancient, and the other two are recent (one presumably due to warfarin rodenticide selection). Second, several of the inferred introgressed tracts contain genes that are likely to confer adaptive advantage. Third, introgressed tracts might contain driver genes that determine the evolutionary fate of those tracts. Further, functional analysis revealed introgressed genes that are essential to fitness, including the Vkorc1 gene, which is implicated in rodenticide resistance, and olfactory receptor genes. Our findings highlight the extent and role of introgression in nature and call for careful analysis and interpretation of house mouse data in evolutionary and genetic studies. PMID- 25512536 TI - Mothers know best. PMID- 25512535 TI - Detergent-free isolation, characterization, and functional reconstitution of a tetrameric K+ channel: the power of native nanodiscs. AB - A major obstacle in the study of membrane proteins is their solubilization in a stable and active conformation when using detergents. Here, we explored a detergent-free approach to isolating the tetrameric potassium channel KcsA directly from the membrane of Escherichia coli, using a styrene-maleic acid copolymer. This polymer self-inserts into membranes and is capable of extracting membrane patches in the form of nanosize discoidal proteolipid particles or "native nanodiscs." Using circular dichroism and tryptophan fluorescence spectroscopy, we show that the conformation of KcsA in native nanodiscs is very similar to that in detergent micelles, but that the thermal stability of the protein is higher in the nanodiscs. Furthermore, as a promising new application, we show that quantitative analysis of the co-isolated lipids in purified KcsA containing nanodiscs allows determination of preferential lipid-protein interactions. Thin-layer chromatography experiments revealed an enrichment of the anionic lipids cardiolipin and phosphatidylglycerol, indicating their close proximity to the channel in biological membranes and supporting their functional relevance. Finally, we demonstrate that KcsA can be reconstituted into planar lipid bilayers directly from native nanodiscs, which enables functional characterization of the channel by electrophysiology without first depriving the protein of its native environment. Together, these findings highlight the potential of the use of native nanodiscs as a tool in the study of ion channels, and of membrane proteins in general. PMID- 25512537 TI - Laser altimetry reveals complex pattern of Greenland Ice Sheet dynamics. AB - We present a new record of ice thickness change, reconstructed at nearly 100,000 sites on the Greenland Ice Sheet (GrIS) from laser altimetry measurements spanning the period 1993-2012, partitioned into changes due to surface mass balance (SMB) and ice dynamics. We estimate a mean annual GrIS mass loss of 243 +/- 18 Gt ? y(-1), equivalent to 0.68 mm ? y(-1) sea level rise (SLR) for 2003 2009. Dynamic thinning contributed 48%, with the largest rates occurring in 2004 2006, followed by a gradual decrease balanced by accelerating SMB loss. The spatial pattern of dynamic mass loss changed over this time as dynamic thinning rapidly decreased in southeast Greenland but slowly increased in the southwest, north, and northeast regions. Most outlet glaciers have been thinning during the last two decades, interrupted by episodes of decreasing thinning or even thickening. Dynamics of the major outlet glaciers dominated the mass loss from larger drainage basins, and simultaneous changes over distances up to 500 km are detected, indicating climate control. However, the intricate spatiotemporal pattern of dynamic thickness change suggests that, regardless of the forcing responsible for initial glacier acceleration and thinning, the response of individual glaciers is modulated by local conditions. Recent projections of dynamic contributions from the entire GrIS to SLR have been based on the extrapolation of four major outlet glaciers. Considering the observed complexity, we question how well these four glaciers represent all of Greenland's outlet glaciers. PMID- 25512538 TI - Economic optimization of a global strategy to address the pandemic threat. AB - Emerging pandemics threaten global health and economies and are increasing in frequency. Globally coordinated strategies to combat pandemics, similar to current strategies that address climate change, are largely adaptive, in that they attempt to reduce the impact of a pathogen after it has emerged. However, like climate change, mitigation strategies have been developed that include programs to reduce the underlying drivers of pandemics, particularly animal-to human disease transmission. Here, we use real options economic modeling of current globally coordinated adaptation strategies for pandemic prevention. We show that they would be optimally implemented within 27 y to reduce the annual rise of emerging infectious disease events by 50% at an estimated one-time cost of approximately $343.7 billion. We then analyze World Bank data on multilateral "One Health" pandemic mitigation programs. We find that, because most pandemics have animal origins, mitigation is a more cost-effective policy than business-as usual adaptation programs, saving between $344.0.7 billion and $360.3 billion over the next 100 y if implemented today. We conclude that globally coordinated pandemic prevention policies need to be enacted urgently to be optimally effective and that strategies to mitigate pandemics by reducing the impact of their underlying drivers are likely to be more effective than business as usual. PMID- 25512539 TI - Structural dynamics inside a functionalized metal-organic framework probed by ultrafast 2D IR spectroscopy. AB - The structural elasticity of metal-organic frameworks (MOFs) is a key property for their functionality. Here, we show that 2D IR spectroscopy with pulse-shaping techniques can probe the ultrafast structural fluctuations of MOFs. 2D IR data, obtained from a vibrational probe attached to the linkers of UiO-66 MOF in low concentration, revealed that the structural fluctuations have time constants of 7 and 670 ps with no solvent. Filling the MOF pores with dimethylformamide (DMF) slows the structural fluctuations by reducing the ability of the MOF to undergo deformations, and the dynamics of the DMF molecules are also greatly restricted. Methodology advances were required to remove the severe light scattering caused by the macroscopic-sized MOF particles, eliminate interfering oscillatory components from the 2D IR data, and address Forster vibrational excitation transfer. PMID- 25512540 TI - A long noncoding RNA connects c-Myc to tumor metabolism. AB - Long noncoding RNAs (lncRNAs) have been implicated in a variety of physiological and pathological processes, including cancer. In prostate cancer, prostate cancer gene expression marker 1 (PCGEM1) is an androgen-induced prostate-specific lncRNA whose overexpression is highly associated with prostate tumors. PCGEM1's tumorigenic potential has been recently shown to be in part due to its ability to activate androgen receptor (AR). Here, we report a novel function of PCGEM1 that provides growth advantages for cancer cells by regulating tumor metabolism via c Myc activation. PCGEM1 promotes glucose uptake for aerobic glycolysis, coupling with the pentose phosphate shunt to facilitate biosynthesis of nucleotide and lipid, and generates NADPH for redox homeostasis. We show that PCGEM1 regulates metabolism at a transcriptional level that affects multiple metabolic pathways, including glucose and glutamine metabolism, the pentose phosphate pathway, nucleotide and fatty acid biosynthesis, and the tricarboxylic acid cycle. The PCGEM1-mediated gene regulation takes place in part through AR activation, but predominantly through c-Myc activation, regardless of hormone or AR status. Significantly, PCGEM1 binds directly to target promoters, physically interacts with c-Myc, promotes chromatin recruitment of c-Myc, and enhances its transactivation activity. We also identified a c-Myc binding domain on PCGEM1 that contributes to the PCGEM1-dependent c-Myc activation and target induction. Together, our data uncover PCGEM1 as a key transcriptional regulator of central metabolic pathways in prostate cancer cells. By being a coactivator for both c Myc and AR, PCGEM1 reprograms the androgen network and the central metabolism in a tumor-specific way, making it a promising target for therapeutic intervention. PMID- 25512542 TI - Absolute position total internal reflection microscopy with an optical tweezer. AB - A noninvasive, in situ calibration method for total internal reflection microscopy (TIRM) based on optical tweezing is presented, which greatly expands the capabilities of this technique. We show that by making only simple modifications to the basic TIRM sensing setup and procedure, a probe particle's absolute position relative to a dielectric interface may be known with better than 10 nm precision out to a distance greater than 1 MUm from the surface. This represents an approximate 10* improvement in error and 3* improvement in measurement range over conventional TIRM methods. The technique's advantage is in the direct measurement of the probe particle's scattering intensity vs. height profile in situ, rather than relying on assumptions, inexact system analogs, or detailed knowledge of system parameters for calibration. To demonstrate the improved versatility of the TIRM method in terms of tunability, precision, and range, we show our results for the hindered near-wall diffusion coefficient for a spherical dielectric particle. PMID- 25512541 TI - Estrogen-related receptor alpha is required for efficient human cytomegalovirus replication. AB - An shRNA-mediated screen of the 48 human nuclear receptor genes identified multiple candidates likely to influence the production of human cytomegalovirus in cultured human fibroblasts, including the estrogen-related receptor alpha (ERRalpha), an orphan nuclear receptor. The 50-kDa receptor and a 76-kDa variant were induced posttranscriptionally following infection. Genetic and pharmacological suppression of the receptor reduced viral RNA, protein, and DNA accumulation, as well as the yield of infectious progeny. In addition, RNAs encoding multiple metabolic enzymes, including enzymes sponsoring glycolysis (enolase 1, triosephosphate isomerase 1, and hexokinase 2), were reduced when the function of ERRalpha was inhibited in infected cells. Consistent with the effect on RNAs, a substantial number of metabolites, which are normally induced by infection, were either not increased or were increased to a reduced extent in the absence of normal ERRalpha activity. We conclude that ERRalpha is needed for the efficient production of cytomegalovirus progeny, and we propose that the nuclear receptor contributes importantly to the induction of a metabolic environment that supports optimal cytomegalovirus replication. PMID- 25512544 TI - Topological sensitivity analysis for systems biology. AB - Mathematical models of natural systems are abstractions of much more complicated processes. Developing informative and realistic models of such systems typically involves suitable statistical inference methods, domain expertise, and a modicum of luck. Except for cases where physical principles provide sufficient guidance, it will also be generally possible to come up with a large number of potential models that are compatible with a given natural system and any finite amount of data generated from experiments on that system. Here we develop a computational framework to systematically evaluate potentially vast sets of candidate differential equation models in light of experimental and prior knowledge about biological systems. This topological sensitivity analysis enables us to evaluate quantitatively the dependence of model inferences and predictions on the assumed model structures. Failure to consider the impact of structural uncertainty introduces biases into the analysis and potentially gives rise to misleading conclusions. PMID- 25512543 TI - Auxin depletion from leaf primordia contributes to organ patterning. AB - Stem cells are responsible for organogenesis, but it is largely unknown whether and how information from stem cells acts to direct organ patterning after organ primordia are formed. It has long been proposed that the stem cells at the plant shoot apex produce a signal, which promotes leaf adaxial-abaxial (dorsoventral) patterning. Here we show the existence of a transient low auxin zone in the adaxial domain of early leaf primordia. We also demonstrate that this adaxial low auxin domain contributes to leaf adaxial-abaxial patterning. The auxin signal is mediated by the auxin-responsive transcription factor MONOPTEROS (MP), whose constitutive activation in the adaxial domain promotes abaxial cell fate. Furthermore, we show that auxin flow from emerging leaf primordia to the shoot apical meristem establishes the low auxin zone, and that this auxin flow contributes to leaf polarity. Our results provide an explanation for the hypothetical meristem-derived leaf polarity signal. Opposite to the original proposal, instead of a signal derived from the meristem, we show that a signaling molecule is departing from the primordium to the meristem to promote robustness in leaf patterning. PMID- 25512545 TI - STAT3 promotes survival of mutant photoreceptors in inherited photoreceptor degeneration models. AB - Inherited photoreceptor degenerations (IPDs), a group of incurable progressive blinding diseases, are caused by mutations in more than 200 genes, but little is known about the molecular pathogenesis of photoreceptor (PR) death. Increased retinal expression of STAT3 has been observed in response to many retinal insults, including IPDs, but the role of this increase in PR death is unknown. Here, we show that the expression of Stat3 is increased in PRs of the Tg(RHO P347S) and Prph2(rds) (/+) mouse models of IPD and is activated by tyrosine phosphorylation. PR-specific deletion of Stat3 substantially accelerated PR degeneration in both mutant strains. In contrast, increased PR-specific expression of ROSA26 (R26) alleles encoding either WT STAT3 (Stat3(wt)) or the gain-of-function variant STAT3(C) (Stat3(C)) improved PR survival in both models. Moreover, PR signaling in Tg(RHO P347S) mice carrying either a R26-Stat3(wt) or R26-Stat3(C) allele demonstrated increased a-wave amplitude of the scotopic electroretinogram. Phosphorylation of STAT3 at tyrosine 705 was required for the prosurvival effect because an R26-Stat3(Y705F) allele was not protective. The prosurvival role of enhanced Stat3 activity was validated using recombinant adenoassociated virus (rAAV) vector-mediated PR Stat3 expression in Tg(RHO P347S) mice. Our findings (i) establish that the increase in endogenous PR Stat3 expression is a protective response in IPDs, (ii) suggest that therapeutic augmentation of PR Stat3 expression has potential as a common neuroprotective therapy for these disorders, and (iii) indicate that prosurvival molecules whose expression is increased in mutant PRs may have promise as novel therapies for IPDs. PMID- 25512546 TI - Essential role for autophagy during invariant NKT cell development. AB - Autophagy is an evolutionarily conserved cellular homeostatic pathway essential for development, immunity, and cell death. Although autophagy modulates MHC antigen presentation, it remains unclear whether autophagy defects impact on CD1d lipid loading and presentation to invariant natural killer T (iNKT) cells and on iNKT cell differentiation in the thymus. Furthermore, it remains unclear whether iNKT and conventional T cells have similar autophagy requirements for differentiation, survival, and/or activation. We report that, in mice with a conditional deletion of the essential autophagy gene Atg7 in the T-cell compartment (CD4 Cre-Atg7(-/-)), thymic iNKT cell development--unlike conventional T-cell development--is blocked at an early stage and mature iNKT cells are absent in peripheral lymphoid organs. The defect is not due to altered loading of intracellular iNKT cell agonists; rather, it is T-cell-intrinsic, resulting in enhanced susceptibility of iNKT cells to apoptosis. We show that autophagy increases during iNKT cell thymic differentiation and that it developmentally regulates mitochondrial content through mitophagy in the thymus of mice and humans. Autophagy defects result in the intracellular accumulation of mitochondrial superoxide species and subsequent apoptotic cell death. Although autophagy-deficient conventional T cells develop normally, they show impaired peripheral survival, particularly memory CD8(+) T cells. Because iNKT cells, unlike conventional T cells, differentiate into memory cells while in the thymus, our results highlight a unique autophagy-dependent metabolic regulation of adaptive and innate T cells, which is required for transition to a quiescent state after population expansion. PMID- 25512548 TI - Phytochrome controls alternative splicing to mediate light responses in Arabidopsis. AB - Plants monitor the ambient light conditions using several informational photoreceptors, including red/far-red light absorbing phytochrome. Phytochrome is widely believed to regulate the transcription of light-responsive genes by modulating the activity of several transcription factors. Here we provide evidence that phytochrome significantly changes alternative splicing (AS) profiles at the genomic level in Arabidopsis, to approximately the same degree as it affects steady-state transcript levels. mRNA sequencing analysis revealed that 1,505 and 1,678 genes underwent changes in their AS and steady-state transcript level profiles, respectively, within 1 h of red light exposure in a phytochrome dependent manner. Furthermore, we show that splicing factor genes were the main early targets of AS control by phytochrome, whereas transcription factor genes were the primary direct targets of phytochrome-mediated transcriptional regulation. We experimentally validated phytochrome-induced changes in the AS of genes that are involved in RNA splicing, phytochrome signaling, the circadian clock, and photosynthesis. Moreover, we show that phytochrome-induced AS changes of SPA1-RELATED 3, the negative regulator of light signaling, physiologically contributed to promoting photomorphogenesis. Finally, photophysiological experiments demonstrated that phytochrome transduces the signal from its photosensory domain to induce light-dependent AS alterations in the nucleus. Taking these data together, we show that phytochrome directly induces AS cascades in parallel with transcriptional cascades to mediate light responses in Arabidopsis. PMID- 25512547 TI - Prehistoric genomes reveal the genetic foundation and cost of horse domestication. AB - The domestication of the horse ~ 5.5 kya and the emergence of mounted riding, chariotry, and cavalry dramatically transformed human civilization. However, the genetics underlying horse domestication are difficult to reconstruct, given the near extinction of wild horses. We therefore sequenced two ancient horse genomes from Taymyr, Russia (at 7.4- and 24.3-fold coverage), both predating the earliest archeological evidence of domestication. We compared these genomes with genomes of domesticated horses and the wild Przewalski's horse and found genetic structure within Eurasia in the Late Pleistocene, with the ancient population contributing significantly to the genetic variation of domesticated breeds. We furthermore identified a conservative set of 125 potential domestication targets using four complementary scans for genes that have undergone positive selection. One group of genes is involved in muscular and limb development, articular junctions, and the cardiac system, and may represent physiological adaptations to human utilization. A second group consists of genes with cognitive functions, including social behavior, learning capabilities, fear response, and agreeableness, which may have been key for taming horses. We also found that domestication is associated with inbreeding and an excess of deleterious mutations. This genetic load is in line with the "cost of domestication" hypothesis also reported for rice, tomatoes, and dogs, and it is generally attributed to the relaxation of purifying selection resulting from the strong demographic bottlenecks accompanying domestication. Our work demonstrates the power of ancient genomes to reconstruct the complex genetic changes that transformed wild animals into their domesticated forms, and the population context in which this process took place. PMID- 25512549 TI - Outward-facing conformers of LacY stabilized by nanobodies. AB - The lactose permease of Escherichia coli (LacY), a highly dynamic polytopic membrane protein, catalyzes stoichiometric galactoside/H(+) symport by an alternating access mechanism and exhibits multiple conformations, the distribution of which is altered by sugar binding. We have developed single domain camelid nanobodies (Nbs) against a LacY mutant in an outward (periplasmic) open conformation to stabilize this state of the WT protein. Twelve purified Nbs inhibit lactose transport in right-side-out membrane vesicles, indicating that the Nbs recognize epitopes on the periplasmic side of LacY. Stopped-flow kinetics of sugar binding by WT LacY in detergent micelles or reconstituted into proteoliposomes reveals dramatic increases in galactoside-binding rates induced by interaction with the Nbs. Thus, WT LacY in complex with the great majority of the Nbs exhibits varied increases in access of sugar to the binding site with an increase in association rate constants (kon) of up to ~ 50-fold (reaching 10(7) M(-1) ? s(-1)). In contrast, with the double-Trp mutant, which is already open on the periplasmic side, the Nbs have little effect. The findings are clearly consistent with stabilization of WT conformers with an open periplasmic cavity. Remarkably, some Nbs drastically decrease the rate of dissociation of bound sugar leading to increased affinity (greater than 200-fold for lactose). PMID- 25512550 TI - Reinstatement of distributed cortical oscillations occurs with precise spatiotemporal dynamics during successful memory retrieval. AB - Reinstatement of neural activity is hypothesized to underlie our ability to mentally travel back in time to recover the context of a previous experience. We used intracranial recordings to directly examine the precise spatiotemporal extent of neural reinstatement as 32 participants with electrodes placed for seizure monitoring performed a paired-associates episodic verbal memory task. By cueing recall, we were able to compare reinstatement during correct and incorrect trials, and found that successful retrieval occurs with reinstatement of a gradually changing neural signal present during encoding. We examined reinstatement in individual frequency bands and individual electrodes and found that neural reinstatement was largely mediated by temporal lobe theta and high gamma frequencies. Leveraging the high temporal precision afforded by intracranial recordings, our data demonstrate that high-gamma activity associated with reinstatement preceded theta activity during encoding, but during retrieval this difference in timing between frequency bands was absent. Our results build upon previous studies to provide direct evidence that successful retrieval involves the reinstatement of a temporal context, and that such reinstatement occurs with precise spatiotemporal dynamics. PMID- 25512551 TI - Licensed human natural killer cells aid dendritic cell maturation via TNFSF14/LIGHT. AB - Interactions between natural killer (NK) cells and dendritic cells (DCs) aid DC maturation and promote T-cell responses. Here, we have analyzed the response of human NK cells to tumor cells, and we identify a pathway by which NK-DC interactions occur. Gene expression profiling of tumor-responsive NK cells identified the very rapid induction of TNF superfamily member 14 [TNFSF14; also known as homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT)], a cytokine implicated in the enhancement of antitumor responses. TNFSF14 protein expression was induced by three primary mechanisms of NK cell activation, namely, via the engagement of CD16, by the synergistic activity of multiple target cell sensing NK-cell activation receptors, and by the cytokines IL-2 and IL-15. For antitumor responses, TNFSF14 was preferentially produced by the licensed NK-cell population, defined by the expression of inhibitory receptors specific for self MHC class I molecules. In contrast, IL-2 and IL-15 treatment induced TNFSF14 production by both licensed and unlicensed NK cells, reflecting the ability of proinflammatory conditions to override the licensing mechanism. Importantly, both tumor- and cytokine-activated NK cells induced DC maturation in a TNFSF14 dependent manner. The coupling of TNFSF14 production to tumor-sensing NK-cell activation receptors links the tumor immune surveillance function of NK cells to DC maturation and adaptive immunity. Furthermore, regulation by NK cell licensing helps to safeguard against TNFSF14 production in response to healthy tissues. PMID- 25512552 TI - Correlated variation and population differentiation in satellite DNA abundance among lines of Drosophila melanogaster. AB - Tandemly repeating satellite DNA elements in heterochromatin occupy a substantial portion of many eukaryotic genomes. Although often characterized as genomic parasites deleterious to the host, they also can be crucial for essential processes such as chromosome segregation. Adding to their interest, satellite DNA elements evolve at high rates; among Drosophila, closely related species often differ drastically in both the types and abundances of satellite repeats. However, due to technical challenges, the evolutionary mechanisms driving this rapid turnover remain unclear. Here we characterize natural variation in simple sequence repeats of 2-10 bp from inbred Drosophila melanogaster lines derived from multiple populations, using a method we developed called k-Seek that analyzes unassembled Illumina sequence reads. In addition to quantifying all previously described satellite repeats, we identified many novel repeats of low to medium abundance. Many of the repeats show population differentiation, including two that are present in only some populations. Interestingly, the population structure inferred from overall satellite quantities does not recapitulate the expected population relationships based on the demographic history of D. melanogaster. We also find that some satellites of similar sequence composition are correlated across lines, revealing concerted evolution. Moreover, correlated satellites tend to be interspersed with each other, further suggesting that concerted change is partially driven by higher order structure. Surprisingly, we identified negative correlations among some satellites, suggesting antagonistic interactions. Our study demonstrates that current genome assemblies vastly underestimate the complexity, abundance, and variation of highly repetitive satellite DNA and presents approaches to understand their rapid evolutionary divergence. PMID- 25512554 TI - Simple insoluble cues specify stem cell differentiation. PMID- 25512553 TI - GDM-associated insulin deficiency hinders the dissociation of SERT from ERp44 and down-regulates placental 5-HT uptake. AB - Serotonin (5-HT) transporter (SERT) regulates the level of 5-HT in placenta. Initially, we found that in gestational diabetes mellitus (GDM), whereas free plasma 5-HT levels were elevated, the 5-HT uptake rates of trophoblast were significantly down-regulated, due to impairment in the translocation of SERT molecules to the cell surface. We sought to determine the factors mediating the down-regulation of SERT in GDM trophoblast. We previously reported that an endoplasmic reticulum chaperone, ERp44, binds to Cys200 and Cys209 residues of SERT to build a disulfide bond. Following this posttranslational modification, before trafficking to the plasma membrane, SERT must be dissociated from ERp44; and this process is facilitated by insulin signaling and reversed by the insulin receptor blocker AGL2263. However, the GDM-associated defect in insulin signaling hampers the dissociation of ERp44 from SERT. Furthermore, whereas ERp44 constitutively occupies Cys200/Cys209 residues, one of the SERT glycosylation sites, Asp208 located between the two Cys residues, cannot undergo proper glycosylation, which plays an important role in the uptake efficiency of SERT. Herein, we show that the decrease in 5-HT uptake rates of GDM trophoblast is the consequence of defective insulin signaling, which entraps SERT with ERp44 and impairs its glycosylation. In this regard, restoring the normal expression of SERT on the trophoblast surface may represent a novel approach to alleviating some GDM-associated complications. PMID- 25512555 TI - tRNA-derived G-quadruplex protects motor neurons. PMID- 25512557 TI - PTIP associates with Artemis to dictate DNA repair pathway choice. AB - PARP inhibitors (PARPis) are being used in patients with BRCA1/2 mutations. However, doubly deficient BRCA1(-/-)53BP1(-/-) cells or tumors become resistant to PARPis. Since 53BP1 or its known downstream effectors, PTIP and RIF1 (RAP1 interacting factor 1 homolog), lack enzymatic activities directly implicated in DNA repair, we decided to further explore the 53BP1-dependent pathway. In this study, we uncovered a nuclease, Artemis, as a PTIP-binding protein. Loss of Artemis restores PARPi resistance in BRCA1-deficient cells. Collectively, our data demonstrate that Artemis is the major downstream effector of the 53BP1 pathway, which prevents end resection and promotes nonhomologous end-joining and therefore directly competes with the homologous recombination repair pathway. PMID- 25512556 TI - Pioneer transcription factors in cell reprogramming. AB - A subset of eukaryotic transcription factors possesses the remarkable ability to reprogram one type of cell into another. The transcription factors that reprogram cell fate are invariably those that are crucial for the initial cell programming in embryonic development. To elicit cell programming or reprogramming, transcription factors must be able to engage genes that are developmentally silenced and inappropriate for expression in the original cell. Developmentally silenced genes are typically embedded in "closed" chromatin that is covered by nucleosomes and not hypersensitive to nuclease probes such as DNase I. Biochemical and genomic studies have shown that transcription factors with the highest reprogramming activity often have the special ability to engage their target sites on nucleosomal DNA, thus behaving as "pioneer factors" to initiate events in closed chromatin. Other reprogramming factors appear dependent on pioneer factors for engaging nucleosomes and closed chromatin. However, certain genomic domains in which nucleosomes are occluded by higher-order chromatin structures, such as in heterochromatin, are resistant to pioneer factor binding. Understanding the means by which pioneer factors can engage closed chromatin and how heterochromatin can prevent such binding promises to advance our ability to reprogram cell fates at will and is the topic of this review. PMID- 25512558 TI - A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential. AB - The Sox2 transcription factor must be robustly transcribed in embryonic stem (ES) cells to maintain pluripotency. Two gene-proximal enhancers, Sox2 regulatory region 1 (SRR1) and SRR2, display activity in reporter assays, but deleting SRR1 has no effect on pluripotency. We identified and functionally validated the sequences required for Sox2 transcription based on a computational model that predicted transcriptional enhancer elements within 130 kb of Sox2. Our reporter assays revealed three novel enhancers--SRR18, SRR107, and SRR111--that, through the formation of chromatin loops, form a chromatin complex with the Sox2 promoter in ES cells. Using the CRISPR/Cas9 system and F1 ES cells (Mus musculus(129) * Mus castaneus), we generated heterozygous deletions of each enhancer region, revealing that only the distal cluster containing SRR107 and SRR111, located >100 kb downstream from Sox2, is required for cis-regulation of Sox2 in ES cells. Furthermore, homozygous deletion of this distal Sox2 control region (SCR) caused significant reduction in Sox2 mRNA and protein levels, loss of ES cell colony morphology, genome-wide changes in gene expression, and impaired neuroectodermal formation upon spontaneous differentiation to embryoid bodies. Together, these data identify a distal control region essential for Sox2 transcription in ES cells. PMID- 25512560 TI - The scaffold protein WRAP53beta orchestrates the ubiquitin response critical for DNA double-strand break repair. AB - The WD40 domain-containing protein WRAP53beta (WD40 encoding RNA antisense to p53; also referred to as WDR79/TCAB1) controls trafficking of splicing factors and the telomerase enzyme to Cajal bodies, and its functional loss has been linked to carcinogenesis, premature aging, and neurodegeneration. Here, we identify WRAP53beta as an essential regulator of DNA double-strand break (DSB) repair. WRAP53beta rapidly localizes to DSBs in an ATM-, H2AX-, and MDC1 dependent manner. We show that WRAP53beta targets the E3 ligase RNF8 to DNA lesions by facilitating the interaction between RNF8 and its upstream partner, MDC1, in response to DNA damage. Simultaneous binding of MDC1 and RNF8 to the highly conserved WD40 scaffold domain of WRAP53beta facilitates their interaction and accumulation of RNF8 at DSBs. In this manner, WRAP53beta controls proper ubiquitylation at DNA damage sites and the downstream assembly of 53BP1, BRCA1, and RAD51. Furthermore, we reveal that knockdown of WRAP53beta impairs DSB repair by both homologous recombination (HR) and nonhomologous end-joining (NHEJ), causes accumulation of spontaneous DNA breaks, and delays recovery from radiation induced cell cycle arrest. Our findings establish WRAP53beta as a novel regulator of DSB repair by providing a scaffold for DNA repair factors. PMID- 25512561 TI - The progenitor state is maintained by lysine-specific demethylase 1-mediated epigenetic plasticity during Drosophila follicle cell development. AB - Progenitors are early lineage cells that proliferate before the onset of terminal differentiation. Although widespread, the epigenetic mechanisms that control the progenitor state and the onset of differentiation remain elusive. By studying Drosophila ovarian follicle cell progenitors, we identified lysine-specific demethylase 1 (lsd1) and CoRest as differentiation regulators using a GAL4?GFP variegation assay. The follicle cell progenitors in lsd1 or CoRest heterozygotes prematurely lose epigenetic plasticity, undergo the Notch-dependent mitotic endocycle transition, and stop dividing before a normal number of follicle cells can be produced. Simultaneously reducing the dosage of the histone H3K4 methyltransferase Trithorax reverses these effects, suggesting that an Lsd1/CoRest complex times progenitor differentiation by controlling the stability of H3K4 methylation levels. Individual cells or small clones initially respond to Notch; hence, a critical level of epigenetic stabilization is acquired cell autonomously and initiates differentiation by making progenitors responsive to pre-existing external signals. PMID- 25512559 TI - HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. AB - Cellular senescence is a stable proliferation arrest that suppresses tumorigenesis. Cellular senescence and associated tumor suppression depend on control of chromatin. Histone chaperone HIRA deposits variant histone H3.3 and histone H4 into chromatin in a DNA replication-independent manner. Appropriately for a DNA replication-independent chaperone, HIRA is involved in control of chromatin in nonproliferating senescent cells, although its role is poorly defined. Here, we show that nonproliferating senescent cells express and incorporate histone H3.3 and other canonical core histones into a dynamic chromatin landscape. Expression of canonical histones is linked to alternative mRNA splicing to eliminate signals that confer mRNA instability in nonproliferating cells. Deposition of newly synthesized histones H3.3 and H4 into chromatin of senescent cells depends on HIRA. HIRA and newly deposited H3.3 colocalize at promoters of expressed genes, partially redistributing between proliferating and senescent cells to parallel changes in expression. In senescent cells, but not proliferating cells, promoters of active genes are exceptionally enriched in H4K16ac, and HIRA is required for retention of H4K16ac. HIRA is also required for retention of H4K16ac in vivo and suppression of oncogene-induced neoplasia. These results show that HIRA controls a specialized, dynamic H4K16ac decorated chromatin landscape in senescent cells and enforces tumor suppression. PMID- 25512562 TI - Histone acetyltransferase Enok regulates oocyte polarization by promoting expression of the actin nucleation factor spire. AB - KAT6 histone acetyltransferases (HATs) are highly conserved in eukaryotes and have been shown to play important roles in transcriptional regulation. Here, we demonstrate that the Drosophila KAT6 Enok acetylates histone H3 Lys 23 (H3K23) in vitro and in vivo. Mutants lacking functional Enok exhibited defects in the localization of Oskar (Osk) to the posterior end of the oocyte, resulting in loss of germline formation and abdominal segments in the embryo. RNA sequencing (RNA seq) analysis revealed that spire (spir) and maelstrom (mael), both required for the posterior localization of Osk in the oocyte, were down-regulated in enok mutants. Chromatin immunoprecipitation showed that Enok is localized to and acetylates H3K23 at the spir and mael genes. Furthermore, Gal4-driven expression of spir in the germline can largely rescue the defective Osk localization in enok mutant ovaries. Our results suggest that the Enok-mediated H3K23 acetylation (H3K23Ac) promotes the expression of spir, providing a specific mechanism linking oocyte polarization to histone modification. PMID- 25512563 TI - beta-Pix directs collective migration of anterior visceral endoderm cells in the early mouse embryo. AB - Collective epithelial migration is important throughout embryonic development. The underlying mechanisms are poorly understood but likely involve spatially localized activation of Rho GTPases. We previously reported that Rac1 is essential for generating the protrusive activity that drives the collective migration of anterior visceral endoderm (AVE) cells in the early mouse embryo. To identify potential regulators of Rac1, we first performed an RNAi screen of Rho family exchange factors (guanine nucleotide exchange factor [GEF]) in an in vitro collective epithelial migration assay and identified beta-Pix. Genetic deletion of beta-Pix in mice disrupts collective AVE migration, while high-resolution live imaging revealed that this is associated with randomly directed protrusive activity. We conclude that beta-Pix controls the spatial localization of Rac1 activity to drive collective AVE migration at a critical stage in mouse development. PMID- 25512564 TI - Spatial genome organization: contrasting views from chromosome conformation capture and fluorescence in situ hybridization. AB - Although important for gene regulation, most studies of genome organization use either fluorescence in situ hybridization (FISH) or chromosome conformation capture (3C) methods. FISH directly visualizes the spatial relationship of sequences but is usually applied to a few loci at a time. The frequency at which sequences are ligated together by formaldehyde cross-linking can be measured genome-wide by 3C methods, with higher frequencies thought to reflect shorter distances. FISH and 3C should therefore give the same views of genome organization, but this has not been tested extensively. We investigated the murine HoxD locus with 3C carbon copy (5C) and FISH in different developmental and activity states and in the presence or absence of epigenetic regulators. We identified situations in which the two data sets are concordant but found other conditions under which chromatin topographies extrapolated from 5C or FISH data are not compatible. We suggest that products captured by 3C do not always reflect spatial proximity, with ligation occurring between sequences located hundreds of nanometers apart, influenced by nuclear environment and chromatin composition. We conclude that results obtained at high resolution with either 3C methods or FISH alone must be interpreted with caution and that views about genome organization should be validated by independent methods. PMID- 25512567 TI - Refined secondary-structure models of the core of yeast and human telomerase RNAs directed by SHAPE. AB - Telomerase catalyzes the addition of nucleotides to the ends of chromosomes to complete genomic DNA replication in eukaryotes and is implicated in multiple diseases, including most cancers. The core enzyme is composed of a reverse transcriptase and an RNA subunit, which provides the template for DNA synthesis. Despite extensive divergence at the sequence level, telomerase RNAs share several structural features within the catalytic core, suggesting a conserved enzyme mechanism. We have investigated the structure of the core of the human and yeast telomerase RNAs using SHAPE, which interrogates flexibility of each nucleotide. We present improved secondary-structure models, refined by addition of five base triples within the yeast pseudoknot and an alternate pairing within the human specific element J2a.1 in the human pseudoknot, both of which have implications for thermodynamic stability. We also identified a potentially structured CCC region within the template that may facilitate substrate binding and enzyme mechanism. Overall, the SHAPE findings reveal multiple similarities between the Saccharomyces cerevisiae and Homo sapiens telomerase RNA cores. PMID- 25512568 TI - Blood biomarkers and functional disability among extremely longevous individuals: a population-based study. AB - BACKGROUND: Several blood biomarkers have been linked to functional disability, a health problem in general populations. However, there are limited data for evaluating the potential association of biomarkers with functional disability in an extremely longevous (95+) population. METHODS: We used data from 420 extremely longevous individuals from the Rugao longevity cohort, a population-based association study conducted in Rugao, a longevity town in China. Functional disability was assessed by the Katz Index of Independence in activities of daily living. Blood biomarkers, including serum lipid, lipoprotein cholesterol, serum albumin, and lymphocyte count, were correlated with activities of daily living. RESULTS: Among extremely longevous women, following the degree of functional disability, serum albumin and lymphocyte count decreased significantly (all p for trend < .001). In a univariate model, serum albumin (beta = -0.279, p < .001), lymphocyte count (beta = -0.187, p < .001), and neutrophil count (beta = 0.140, p = .012) were found to be significantly associated with activities of daily living in women. After adjustment for other covariates, the significance remained. Notably, multivariate regression analysis revealed independent effects of all the three biomarkers on activities of daily living (beta = -0.242, -0.185, and 0.143, all p < .05). We did not observe any association in men. CONCLUSIONS: We found significant associations between serum albumin, lymphocyte count, and neutrophil count and physical disability even after adjustment for potential confounders in extremely longevous women, which call for further study. The findings provide preliminary but crucial clues for future studies specifically aimed at exploring the longitudinal relationships of interest before proceeding with interventions. PMID- 25512569 TI - Predictive validity and responsiveness of patient-reported and performance-based measures of function in the Boston RISE study. AB - BACKGROUND: Patient-reported and performance-based measures (PBMs) are commonly used to measure physical function in studies of older adults. Selection of appropriate measures to address specific research questions is complex and requires knowledge of relevant psychometric properties. The aim of this study was to examine the predictive validity for adverse outcomes and responsiveness of a widely used patient-reported measure, the Late-Life Function and Disability Instrument (LLFDI), compared with PBMs. METHODS: We analyzed 2 years of follow-up data from Boston RISE, a cohort study of 430 primary care patients aged >=65 years. Logistic and linear regression models were used to examine predictive validity for adverse outcomes and effect size and minimal detectable change scores were computed to examine responsiveness. Performance-based functional measures included the Short Physical Performance Battery, 400-m walk, gait speed, and stair-climb power test. RESULTS: The LLFDI and PBMs showed high predictive validity for poor self-rated health, hospitalizations, and disability. The LLFDI function scale was the only measure that predicted falls. Absolute effect size estimates ranged from 0.54 to 0.64 for the LLFDI and from 0.34 to 0.63 for the PBMs. From baseline to 2 years, the percentage of participants with a change >= minimal detectable change was greatest for the LLFDI scales (46-59%) followed by the Short Physical Performance Battery (44%), gait speed (35%), 400-m walk (17%), and stair-climb power test (9%). CONCLUSIONS: The patient-reported LLFDI showed comparable psychometric properties to PBMs. Our findings support the use of the LLFDI as a primary outcome in gerontological research. PMID- 25512570 TI - Volunteerism: Social Network Dynamics and Education. AB - OBJECTIVES: . We examine how changes in social networks influence volunteerism through bridging (diversity) and bonding (spending time) mechanisms. We further investigate whether social network change substitutes or amplifies the effects of education on volunteerism. METHODS: . Data (n = 543) are drawn from a two-wave survey of Social Relations and Health over the Life Course (SRHLC). Zero-inflated negative binomial regressions were conducted to test competing hypotheses about how changes in social network characteristics alone and in conjunction with education level predict likelihood and frequency of volunteering. RESULTS: . Changes in social networks were associated with volunteerism: as the proportion of family members decreased and the average number of network members living within a one-hour drive increased over time, participants reported higher odds of volunteering. The substitution hypothesis was supported: social networks that exhibited more geographic proximity and greater contact frequency over-time compensated for lower levels of education to predict volunteering more hours. DISCUSSION: . The dynamic role of social networks and the ways in which they may work through bridging and bonding to influence both likelihood and frequency of volunteering are discussed. The potential benefits of volunteerism in light of longer life expectancies and smaller families are also considered. PMID- 25512571 TI - Immediate-early gene transcriptional activation in hippocampus CA1 and CA3 does not accurately reflect rapid, pattern completion-based retrieval of context memory. AB - No studies to date have examined whether immediate-early gene (IEG) activation is driven by context memory recall. To address this question, we utilized the context preexposure facilitation effect (CPFE) paradigm. In CPFE, animals acquire contextual fear conditioning through hippocampus-dependent rapid retrieval of a previously formed contextual representation. Despite differences in behavior, we did not find any difference in CA1 or CA3 IEG activity associated with this rapid recall phase when comparing context preexposed and non-pre-exposed groups. These findings indicate that IEG activation in CA1 and CA3 is not an accurate readout of the neural activity associated with hippocampus-dependent rapid memory retrieval. PMID- 25512572 TI - Hippocampus contributes to the maintenance but not the quality of visual information over time. AB - The hippocampus has recently been implicated in the brief representation of visual information, but its specific role is not well understood. We investigated this role using a paradigm that distinguishes quantity and quality of visual memory as described in a previous study. We found that amnesic patients with bilateral hippocampal damage (N = 5) were less likely to remember test stimuli than comparison participants despite a brief maintenance interval (900 msec). However, estimates of memory quality were similar for all groups. Our findings suggest that the hippocampus contributes to brief maintenance of visual information but does not contribute to the quality of that information. PMID- 25512574 TI - Fractionating the neural substrates of incidental recognition memory. AB - Familiar stimuli are typically accompanied by decreases in neural response relative to the presentation of novel items, but these studies often include explicit instructions to discriminate old and new items; this creates difficulties in partialling out the contribution of top-down intentional orientation to the items based on recognition goals. Here, we used an incidental recognition functional MRI paradigm to compare response to repetition of novel and familiar stimuli in the absence of any ongoing memory task demand. The inferior frontal gyrus and hippocampus both displayed enhanced response to novelty and suppressed response to familiar stimuli, notably, under conditions which did not encourage intentional orientation to recognize novel or old items. Functional connectivity analyses additionally suggested that familiarity processing is associated with a network incorporating the hippocampus and prefrontal cortex. We conclude that recognition memory substrates can be fractionated even in the absence of memory goals. PMID- 25512575 TI - Potent attenuation of context fear by extinction training contiguous with acquisition. AB - Studies on the behavioral mechanisms underlying contextual fear conditioning (CFC) have demonstrated the importance of preshock context exposure in the formation of aversive context memories. However, there has been comparatively little investigation of the effects of context exposure immediately after the shock. Some models predict that nonreinforced context exposure at the end of the acquisition session will strongly influence the strength of conditioning and/or recruit distinct neural mechanisms relative to extinction after acquisition. Here we investigate the effects of manipulating postshock context exposure on CFC in mice. Prolonging the period of context exposure immediately following the shock caused a significant and durable reduction in conditioned fear. This immediate postshock context exposure was more effective at attenuating conditioned fear than was an equivalent amount of context exposure a day or more after acquisition. The results suggest that nonreinforced exposure to the context influences conditioned fear through distinct mechanisms depending on whether it occurs during acquisition or after it. The superiority of immediate postshock context exposure was specific to single-shock CFC; in two-shock CFC, immediate and delayed postshock context exposure had similar effects. Consistent with previous reports, we hypothesize that the effectiveness of extinction is modulated by emotional state, and procedures engendering higher postshock freezing (such as two-shock CFC) are associated with weaker immediate extinction. PMID- 25512573 TI - Transcriptional analysis of a whole-body form of long-term habituation in Aplysia californica. AB - Habituation is the simplest form of learning, but we know little about the transcriptional mechanisms that encode long-term habituation memory. A key obstacle is that habituation is relatively stimulus-specific and is thus encoded in small sets of neurons, providing poor signal/noise ratios for transcriptional analysis. To overcome this obstacle, we have developed a protocol for producing whole-body long-term habituation of the siphon-withdrawal reflex (SWR) of Aplysia californica. Specifically, we constructed a computer-controlled brushing apparatus to apply low-intensity tactile stimulation over the entire dorsal surface of Aplysia at regular intervals. We found that 3 d of training (10 rounds of stimulation/day; each round = 15 min brushing at a 10-sec ISI; 15-min rest between rounds) produces habituation with several characteristics favorable for mechanistic investigation. First, habituation is widespread, with SWR durations reduced whether the reflex is evoked by tactile stimulation to the head, tail, or the siphon. Second, long-term habituation is sensitive to the pattern of training, occurring only when brushing sessions are spaced out over 3 d rather than massed into a single session. Using a custom-designed microarray and quantitative PCR, we show that long-term habituation produces long-term up regulation of an apparent Aplysia homolog of cornichon, a protein important for glutamate receptor trafficking. Our training paradigm provides a promising starting point for characterizing the transcriptional mechanisms of long-term habituation memory. PMID- 25512576 TI - The role of the medial prefrontal cortex in trace fear extinction. AB - The extinction of delay fear conditioning relies on a neural circuit that has received much attention and is relatively well defined. Whether this established circuit also supports the extinction of more complex associations, however, is unclear. Trace fear conditioning is a better model of complex relational learning, yet the circuit that supports extinction of this memory has received very little attention. Recent research has indicated that trace fear extinction requires a different neural circuit than delay extinction; trace extinction requires the participation of the retrosplenial cortex, but not the amygdala, as noted in a previous study. Here, we tested the roles of the prelimbic and infralimbic regions of the medial prefrontal cortex in trace and delay fear extinction by blocking NMDA receptors during extinction learning. We found that the prelimbic cortex is necessary for trace, but not for delay fear extinction, whereas the infralimbic cortex is involved in both types of extinction. These results are consistent with the idea that trace fear associations require plasticity in multiple cortical areas for successful extinction. Further, the infralimbic cortex appears to play a role in extinction regardless of whether the animal was initially trained in trace or delay conditioning. Together, our results provide new information about how the neural circuits supporting trace and delay fear extinction differ. PMID- 25512579 TI - A novel immune regulator links malaria and inflammatory bowel disease. PMID- 25512577 TI - Experience-dependent regulation of presynaptic NMDARs enhances neurotransmitter release at neocortical synapses. AB - Sensory experience can selectively alter excitatory synaptic strength at neocortical synapses. The rapid increase in synaptic strength induced by selective whisker stimulation (single-row experience/SRE, where all but one row of whiskers has been removed from the mouse face) is due, at least in part, to the trafficking of AMPA receptors (AMPARs) to the post-synaptic membrane, and is developmentally regulated. How enhanced sensory experience can alter presynaptic release properties in the developing neocortex has not been investigated. Using paired-pulse stimulation at layer 4-2/3 synapses in acute brain slices, we found that presynaptic release probability progressively increases in the spared whisker barrel column over the first 24 h of SRE. Enhanced release probability can be at least partly attributed to presynaptic NMDA receptors (NMDARs). We find that the influence of presynaptic NMDARs in enhancing EPSC amplitude markedly increases during SRE. This occurs at the same time when recently potentiated synapses become highly susceptible to a NMDAR-dependent form of synaptic depression, during the labile phase of plasticity. Thus, these data show that augmented sensory stimulation can enhance release probability at layer 4-2/3 synapses and enhance the function of presynaptic NMDARs. Because presynaptic NMDARs have been linked to synaptic depression at layer 4-2/3 synapses, we propose that SRE-dependent up-regulation of presynaptic NMDARs is responsible for enhanced synaptic depression during the labile stage of plasticity. PMID- 25512578 TI - A conditioned visual orientation requires the ellipsoid body in Drosophila. AB - Orientation, the spatial organization of animal behavior, is an essential faculty of animals. Bacteria and lower animals such as insects exhibit taxis, innate orientation behavior, directly toward or away from a directional cue. Organisms can also orient themselves at a specific angle relative to the cues. In this study, using Drosophila as a model system, we established a visual orientation conditioning paradigm based on a flight simulator in which a stationary flying fly could control the rotation of a visual object. By coupling aversive heat shocks to a fly's orientation toward one side of the visual object, we found that the fly could be conditioned to orientate toward the left or right side of the frontal visual object and retain this conditioned visual orientation. The lower and upper visual fields have different roles in conditioned visual orientation. Transfer experiments showed that conditioned visual orientation could generalize between visual targets of different sizes, compactness, or vertical positions, but not of contour orientation. Rut-Type I adenylyl cyclase and Dnc phosphodiesterase were dispensable for visual orientation conditioning. Normal activity and scb signaling in R3/R4d neurons of the ellipsoid body were required for visual orientation conditioning. Our studies established a visual orientation conditioning paradigm and examined the behavioral properties and neural circuitry of visual orientation, an important component of the insect's spatial navigation. PMID- 25512580 TI - T cells require DOCK8 for flexibility and function. PMID- 25512581 TI - Lymphocyte called home: beta2-adreneric neurotransmission confines T cells to lymph nodes to suppress inflammation. PMID- 25512582 TI - Sleeping our Alzheimer's risk away. PMID- 25512583 TI - CCR4 drives ATLL jail break. PMID- 25512584 TI - Second-order statistics and 'designer' waves for violent free-surface motion around multi-column structures. AB - Extreme wave-structure interactions are investigated using second-order diffraction theory. The statistics of surface elevation around a multi-column structure are collected using Monte Carlo-type simulations for severe sea states. Within the footprint of a realistic four-column structure, we find that the presence of the structure can give rise to extreme crest elevations greater than twice those at the same return period in the incident wave field. Much of this extra elevation is associated with the excitation of second-order near-trapped modes. A 'designer' incident wave can be defined at each point around the structure for a given sea state as the average input wave to produce extreme crest elevations at a given return period, and we show that this wave can be simply vertically scaled to estimate the response at other return periods. PMID- 25512585 TI - Hydroelastic behaviour of a structure exposed to an underwater explosion. AB - The hydroelastic interaction between an underwater explosion and an elastic plate is investigated num- erically through a domain-decomposition strategy. The three dimensional features of the problem require a large computational effort, which is reduced through a weak coupling between a one-dimensional radial blast solver, which resolves the blast evolution far from the boundaries, and a three dimensional compressible flow solver used where the interactions between the compression wave and the boundaries take place and the flow becomes three dimensional. The three-dimensional flow solver at the boundaries is directly coupled with a modal structural solver that models the response of the solid boundaries like elastic plates. This enables one to simulate the fluid-structure interaction as a strong coupling, in order to capture hydroelastic effects. The method has been applied to the experimental case of Hung et al. (2005 Int. J. Impact Eng. 31, 151-168 (doi:10.1016/j.ijimpeng.2003.10.039)) with explosion and structure sufficiently far from other boundaries and successfully validated in terms of the evolution of the acceleration induced on the plate. It was also used to investigate the interaction of an underwater explosion with the bottom of a close-by ship modelled as an orthotropic plate. In the application, the acoustic phase of the fluid-structure interaction is examined, highlighting the need of the fluid-structure coupling to capture correctly the possible inception of cavitation. PMID- 25512586 TI - Vortex-induced vibrations of a flexible cylinder at large inclination angle. AB - The free vibrations of a flexible circular cylinder inclined at 80 degrees within a uniform current are investigated by means of direct numerical simulation, at Reynolds number 500 based on the body diameter and inflow velocity. In spite of the large inclination angle, the cylinder exhibits regular in-line and cross-flow vibrations excited by the flow through the lock-in mechanism, i.e. synchronization of body motion and vortex formation. A profound reconfiguration of the wake is observed compared with the stationary body case. The vortex-induced vibrations are found to occur under parallel, but also oblique vortex shedding where the spanwise wavenumbers of the wake and structural response coincide. The shedding angle and frequency increase with the spanwise wavenumber. The cylinder vibrations and fluid forces present a persistent spanwise asymmetry which relates to the asymmetry of the local current relative to the body axis, owing to its in-line bending. In particular, the asymmetrical trend of flow-body energy transfer results in a monotonic orientation of the structural waves. Clockwise and counter-clockwise figure eight orbits of the body alternate along the span, but the latter are found to be more favourable to structure excitation. Additional simulations at normal incidence highlight a dramatic deviation from the independence principle, which states that the system behaviour is essentially driven by the normal component of the inflow velocity. PMID- 25512587 TI - A theoretical model of asymmetric wave ripples. AB - The time development of ripples under sea waves is investigated by means of the weakly nonlinear stability analysis of a flat sandy bottom subjected to the viscous oscillatory flow that is present in the boundary layer at the bottom of propagating sea waves. Second-order effects in the wave steepness are considered, to take into account the presence of the steady drift generated by the surface waves. Hence, the work of Vittori & Blondeaux (1990 J. Fluid Mech. 218, 19-39 (doi:10.1017/S002211209000091X)) is extended by considering steeper waves and/or less deep waters. As shown by the linear analysis of Blondeaux et al. (2000 Eur. J. Mech. B 19, 285-301 (doi:10.1016/S0997-7546(90)00106-I)), because of the presence of a steady velocity component in the direction of wave propagation, ripples migrate at a constant rate that depends on sediment and wave characteristics. The weakly nonlinear analysis shows that the ripple profile is no longer symmetric with respect to ripple crests and troughs and the symmetry index is computed as a function of the parameters of the problem. In particular, a relationship is determined between the symmetry index and the strength of the steady drift. A fair agreement between model results and laboratory data is obtained, albeit further data and analyses are necessary to determine the behaviour of vortex ripples and to be conclusive. PMID- 25512588 TI - The interaction between steep waves and a surface-piercing column. AB - Experimental observations are presented of a single surface-piercing column subject to a wide range of surface gravity waves. With the column diameter, D, chosen such that the flow lies within the drag-inertia regime, two types of high frequency wave scattering are identified. The first is driven by the run-up and wash-down on the surface of the column in the vicinity of the upstream and downstream stagnation points. The second concerns the circulation of fluid around the column, leading to the scattering of a pair of non-concentric wavefronts. The phasing of the wave cycle at which this second mode evolves is dependent upon the time taken for fluid to move around the column. This introduces an additional time-scale, explaining why existing diffraction solutions, based upon a harmonic analysis of the incident waves, cannot describe this scattered component. The interaction between the scattered waves and the next (steep) incident wave can produce a large amplification of the scattered waves, particularly the second type. Evidence is provided to show that these interactions can produce highly localized free-surface effects, including vertical jetting, with important implications for the setting of deck elevations, the occurrence of wave slamming and the development of large run-up velocities. PMID- 25512589 TI - Insights on the design of free-spanning pipelines. AB - The design of free-spanning pipelines is performed with the aim of ensuring their integrity against permanent loads generated by seabed roughness, functional loads induced by internal pressure and temperature, and dynamic loads induced by marine currents and direct wave action. In particular, a load and resistance factored design is applied that focuses on extreme environmental loads, and a fatigue limit state approach is applied as a consequence of free-span dynamics due to vortex shedding-induced vibration and direct wave action. The pipeline free-span scenario can be permanent, when generated by seabed roughness, or characterized by short- to long-term evolution, when generated by seabed mobility and scouring in shallow waters. Free-span analysis is generally a task involving a number of disciplines and should be carried out using a multidisciplinary approach. The paper illustrates various themes related to free-span analysis: (i) free-span scenarios, (ii) characterization of the environment from deep to shallow water related to proper seabed properties, (iii) hydrodynamic load regimes, (iv) pipeline free-span design assessment aiming to reduce overstress and fatigue damage, (v) erodible seabed mobility and local scour, and (vi) some experiences of inspection surveys chosen as representative of a free-spanning pipeline in sandy soils. PMID- 25512590 TI - Influence of motion coupling and nonlinear effects on parametric roll for a floating production storage and offloading platform. AB - Occurrence and features of parametric roll (PR) on a weather-vaning floating production storage and offloading (FPSO) platform with a turret single-point mooring-line system are examined. The main focus is on the relevance of motions coupling and nonlinear effects on this phenomenon and on more general unstable conditions as well as on the occurrence and severity of water on deck. This work was motivated by recent experiments on an FPSO model without mooring systems highlighting the occurrence of parametric resonance owing to roll-yaw coupling. A three-dimensional numerical hybrid potential-flow seakeeping solver was able to capture this behaviour. The same method, extended to include the mooring lines, is adopted here to investigate the platform behaviour for different incident wavelengths, steepnesses, headings, locations of the turret and pretensions. From the results, sway and yaw tend to destabilize the system, also bringing chaotic features. The sway-roll-yaw coupling widens the existence region of PR resonance and increases PR severity; it also results in a larger amount of shipped water, especially at smaller wavelength-to-ship length ratio and larger steepness. The chaotic features are excited when a sufficiently large yaw amplitude is reached. Consistently, a simplified stability analysis showed the relevance of nonlinear restoring coefficients, first those connected with the sway-yaw coupling then those associated with the roll-yaw coupling, both destabilizing. From the stability analysis, the system is unstable for all longitudinal locations of the turret and pre-tensions examined, but the instability weakens as the turret is moved forward, and the pre-tension is increased. The use of a suitable dynamic positioning system can control the horizontal motions, avoiding the instability. PMID- 25512591 TI - Advances in fluid mechanics for offshore engineering: a modelling perspective. PMID- 25512592 TI - Stability of subsea pipelines during large storms. AB - On-bottom stability design of subsea pipelines transporting hydrocarbons is important to ensure safety and reliability but is challenging to achieve in the onerous metocean (meteorological and oceanographic) conditions typical of large storms (such as tropical cyclones, hurricanes or typhoons). This challenge is increased by the fact that industry design guidelines presently give no guidance on how to incorporate the potential benefits of seabed mobility, which can lead to lowering and self-burial of the pipeline on a sandy seabed. In this paper, we demonstrate recent advances in experimental modelling of pipeline scour and present results investigating how pipeline stability can change in a large storm. An emphasis is placed on the initial development of the storm, where scour is inevitable on an erodible bed as the storm velocities build up to peak conditions. During this initial development, we compare the rate at which peak near-bed velocities increase in a large storm (typically less than 10(-3) m s( 2)) to the rate at which a pipeline scours and subsequently lowers (which is dependent not only on the storm velocities, but also on the mechanism of lowering and the pipeline properties). We show that the relative magnitude of these rates influences pipeline embedment during a storm and the stability of the pipeline. PMID- 25512593 TI - Resonance of a tension leg platform exited by third-harmonic force in nonlinear regular waves. AB - The resonance of a floating tension leg platform (TLP) excited by the third harmonic force of a regular wave is investigated based on fully nonlinear theory with a higher order boundary element method (BEM). The total wave elevation and the total velocity potential are separated into two parts, based on the incoming wave from infinity and the disturbed potential by the body. A numerical radiation condition is then applied at the far field to absorb the disturbed potential without affecting the incident potential. The BEM mesh on the free surface is generated only once at the initial time and the element nodes are rearranged subsequently without changing their connectivity by using a spring analysis method. Through some auxiliary functions, the mutual dependence of fluid/structure motions is decoupled, which allows the body acceleration to be obtained without the knowledge of the pressure distribution. Numerical simulation is carried out for the interaction of a floating TLP with waves. The focus is on the motion principally excited by higher harmonic wave forces. In particular, the resonance of the ISSC TLP generated by the third-order force at the triple wave frequency in regular waves is investigated, together with the tensions of the tendons. PMID- 25512594 TI - Wave-induced response of a floating two-dimensional body with a moonpool. AB - Regular wave-induced behaviour of a floating stationary two-dimensional body with a moonpool is studied. The focus is on resonant piston-mode motion in the moonpool and rigid-body motions. Dedicated two-dimensional experiments have been performed. Two numerical hybrid methods, which have previously been applied to related problems, are further developed. Both numerical methods couple potential and viscous flow. The semi-nonlinear hybrid method uses linear free-surface and body-boundary conditions. The other one uses fully nonlinear free-surface and body-boundary conditions. The harmonic polynomial cell method solves the Laplace equation in the potential flow domain, while the finite volume method solves the Navier-Stokes equations in the viscous flow domain near the body. Results from the two codes are compared with the experimental data. The nonlinear hybrid method compares well with the data, while certain discrepancies are observed for the semi-nonlinear method. In particular, the roll motion is over-predicted by the semi-nonlinear hybrid method. Error sources in the semi-nonlinear hybrid method are discussed. The moonpool strongly affects heave motions in a frequency range around the piston-mode resonance frequency of the moonpool. No resonant water motions occur in the moonpool at the piston-mode resonance frequency. Instead large moonpool motions occur at a heave natural frequency associated with small damping near the piston-mode resonance frequency. PMID- 25512595 TI - Numerical investigation of flow and scour around a vertical circular cylinder. AB - Flow and scour around a vertical cylinder exposed to current are investigated by using a three-dimensional numerical model based on incompressible Reynolds averaged Navier-Stokes equations. The model incorporates (i) k-omega turbulence closure, (ii) vortex-shedding processes, (iii) sediment transport (both bed and suspended load), as well as (iv) bed morphology. The influence of vortex shedding and suspended load on the scour are specifically investigated. For the selected geometry and flow conditions, it is found that the equilibrium scour depth is decreased by 50% when the suspended sediment transport is not accounted for. Alternatively, the effects of vortex shedding are found to be limited to the very early stage of the scour process. Flow features such as the horseshoe vortex, as well as lee-wake vortices, including their vertical frequency variation, are discussed. Large-scale counter-rotating streamwise phase-averaged vortices in the lee wake are likewise demonstrated via numerical flow visualization. These features are linked to scour around a vertical pile in a steady current. PMID- 25512597 TI - Paul F. Cranefield award to Matthew Trudeau. PMID- 25512596 TI - Obsessive-Compulsive Disorder, Psychosis, and Bipolarity: A Longitudinal Cohort and Multigenerational Family Study. AB - Obsessive-compulsive disorder (OCD) often co-occurs with psychotic and bipolar disorders; this comorbidity complicates the clinical management of these conditions. In this population-based longitudinal and multigenerational family study, we examined the patterns of comorbidity, longitudinal risks, and shared familial risks between these disorders. Participants were individuals with a diagnosis of OCD (n = 19,814), schizophrenia (n = 58,336), bipolar disorder (n = 48,180), and schizoaffective disorder (n = 14,904) included in the Swedish Patient Register between January 1969 and December 2009; their first-, second-, and third-degree relatives; and population-matched (1:10 ratio) unaffected comparison individuals and their relatives. The Swedish Prescribed Drug Register was used to control for the potential effect of medication in the longitudinal analyses. Individuals with OCD had a 12-fold increased risk of having a comorbid diagnosis of schizophrenia and a 13-fold increased risk of bipolar disorder and schizoaffective disorder. Longitudinal analyses showed that individuals first diagnosed with OCD had an increased risk for later diagnosis of all other disorders, and vice versa. The risk of bipolar disorder was reduced, but not eliminated, when the use of selective serotonin reuptake inhibitors was adjusted for. OCD-unaffected first-, second-, and third-degree relatives of probands with OCD had a significantly increased risk for all 3 disorders; the magnitude of this risk decreased as the genetic distance increased. We conclude that OCD is etiologically related to both schizophrenia spectrum and bipolar disorders. The results have implications for current gene-searching efforts and for clinical practice. PMID- 25512599 TI - Structural model of the open-closed-inactivated cycle of prokaryotic voltage gated sodium channels. AB - In excitable cells, the initiation of the action potential results from the opening of voltage-gated sodium channels. These channels undergo a series of conformational changes between open, closed, and inactivated states. Many models have been proposed for the structural transitions that result in these different functional states. Here, we compare the crystal structures of prokaryotic sodium channels captured in the different conformational forms and use them as the basis for examining molecular models for the activation, slow inactivation, and recovery processes. We compare structural similarities and differences in the pore domains, specifically in the transmembrane helices, the constrictions within the pore cavity, the activation gate at the cytoplasmic end of the last transmembrane helix, the C-terminal domain, and the selectivity filter. We discuss the observed differences in the context of previous models for opening, closing, and inactivation, and present a new structure-based model for the functional transitions. Our proposed prokaryotic channel activation mechanism is then compared with the activation transition in eukaryotic sodium channels. PMID- 25512600 TI - Accessories assist AMPA receptors to close pockets. PMID- 25512598 TI - Modulation of CFTR gating by permeant ions. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) is unique among ion channels in that after its phosphorylation by protein kinase A (PKA), its ATP dependent gating violates microscopic reversibility caused by the intimate involvement of ATP hydrolysis in controlling channel closure. Recent studies suggest a gating model featuring an energetic coupling between opening and closing of the gate in CFTR's transmembrane domains and association and dissociation of its two nucleotide-binding domains (NBDs). We found that permeant ions such as nitrate can increase the open probability (Po) of wild-type (WT) CFTR by increasing the opening rate and decreasing the closing rate. Nearly identical effects were seen with a construct in which activity does not require phosphorylation of the regulatory domain, indicating that nitrate primarily affects ATP-dependent gating steps rather than PKA-dependent phosphorylation. Surprisingly, the effects of nitrate on CFTR gating are remarkably similar to those of VX-770 (N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline 3-carboxamide), a potent CFTR potentiator used in clinics. These include effects on single-channel kinetics of WT CFTR, deceleration of the nonhydrolytic closing rate, and potentiation of the Po of the disease-associated mutant G551D. In addition, both VX-770 and nitrate increased the activity of a CFTR construct lacking NBD2 (DeltaNBD2), indicating that these gating effects are independent of NBD dimerization. Nonetheless, whereas VX-770 is equally effective when applied from either side of the membrane, nitrate potentiates gating mainly from the cytoplasmic side, implicating a common mechanism for gating modulation mediated through two separate sites of action. PMID- 25512601 TI - Immune complexes suppress IFN-gamma-induced responses in monocytes by activating discrete members of the SRC kinase family. AB - The regulation of the innate and the adaptive immune responses are extensively intertwined and tightly regulated. Ag-driven immune responses that are modulated by immune complexes (ICs) are known to inhibit IFN-gamma-dependent MHC class II expression. We have previously demonstrated that ICs dramatically inhibit IFN gamma-induced activation of human monocytes through the activation of the FcgammaRI signaling pathway. In the present study we further explore the mechanisms by which ICs regulate IFN-gamma activation of human monocytes. We demonstrate that members of the SRC kinase family (SKF) are key mediators of IFN gamma pathway suppression: inhibitors of the SKF reverse the ability of ICs to suppress IFN-gamma signaling. Small interfering RNA was used to target specific members of the SKF. The data indicate that SRC and LYN are both required for ICs to elicit their immunosuppressive activity, whereas FYN does not appear to contribute to this function. Similarly, the kinase SYK, though not a member of the SKF, is also demonstrated to be involved in this IC-mediated immunosuppression. Our data suggest a mechanism whereby ICs directly inhibit inflammatory signals by crosslinking FcgammaRI, resulting in the activation of the specific phosphotyrosine kinases SRC, LYN, and SYK and the concomitant suppression of the IFN-gamma signaling pathway. PMID- 25512602 TI - Adenosine 5'-monophosphate-activated protein kinase regulates IL-10-mediated anti inflammatory signaling pathways in macrophages. AB - AMP-activated protein kinase (AMPK) is a conserved serine/threonine kinase with a critical function in the regulation of metabolic pathways in eukaryotic cells. Recently, AMPK has been shown to play an additional role as a regulator of inflammatory activity in leukocytes. Treatment of macrophages with chemical AMPK activators, or forced expression of a constitutively active form of AMPK, results in polarization to an anti-inflammatory phenotype. In addition, we reported previously that stimulation of macrophages with anti-inflammatory cytokines such as IL-10, IL-4, and TGF-beta results in rapid activation of AMPK, suggesting that AMPK contributes to the suppressive function of these cytokines. In this study, we investigated the role of AMPK in IL-10-induced gene expression and anti inflammatory function. IL-10-stimulated wild-type macrophages displayed rapid activation of PI3K and its downstream targets Akt and mammalian target of rapamycin complex (mTORC1), an effect that was not seen in macrophages generated from AMPKalpha1-deficient mice. AMPK activation was not impacted by treatment with either the PI3K inhibitor LY294002 or the JAK inhibitor CP-690550, suggesting that IL-10-mediated activation of AMPK is independent of PI3K and JAK activity. IL-10 induced phosphorylation of both Tyr(705) and Ser(727) residues of STAT3 in an AMPKalpha1-dependent manner, and these phosphorylation events were blocked by inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase beta, an upstream activator of AMPK, and by the mTORC1 inhibitor rapamycin, respectively. The impaired STAT3 phosphorylation in response to IL-10 observed in AMPKalpha1-deficient macrophages was accompanied by reduced suppressor of cytokine signaling 3 expression and an inadequacy of IL-10 to suppress LPS induced proinflammatory cytokine production. Overall, our data demonstrate that AMPKalpha1 is required for IL-10 activation of the PI3K/Akt/mTORC1 and STAT3 mediated anti-inflammatory pathways regulating macrophage functional polarization. PMID- 25512603 TI - The alpha-tocopherol form of vitamin E reverses age-associated susceptibility to streptococcus pneumoniae lung infection by modulating pulmonary neutrophil recruitment. AB - Streptococcus pneumoniae infections are an important cause of morbidity and mortality in older patients. Uncontrolled neutrophil-driven pulmonary inflammation exacerbates this disease. To test whether the alpha-tocopherol (alpha-Toc) form of vitamin E, a regulator of immunity, can modulate neutrophil responses as a preventive strategy to mitigate the age-associated decline in resistance to S. pneumoniae, young (4 mo) and old (22-24 mo) C57BL/6 mice were fed a diet containing 30-PPM (control) or 500-PPM (supplemented) alpha-Toc for 4 wk and intratracheally infected with S. pneumoniae. Aged mice fed a control diet were exquisitely more susceptible to S. pneumoniae than young mice. At 2 d postinfection, aged mice suffered 1000-fold higher pulmonary bacterial burden, 2.2-fold higher levels of neutrophil recruitment to the lung, and a 2.25-fold higher rate of lethal septicemia. Strikingly, alpha-Toc supplementation of aged mice resulted in a 1000-fold lower bacterial lung burden and full control of infection. This alpha-Toc-induced resistance to pneumococcal challenge was associated with a 2-fold fewer pulmonary neutrophils, a level comparable to S. pneumoniae-challenged, conventionally fed young mice. alpha-Toc directly inhibited neutrophil egress across epithelial cell monolayers in vitro in response to pneumococci or hepoxilin-A3, an eicosanoid required for pneumococcus elicited neutrophil trans-epithelial migration. alpha-Toc altered expression of multiple epithelial and neutrophil adhesion molecules involved in migration, including CD55, CD47, CD18/CD11b, and ICAM-1. These findings suggest that alpha Toc enhances resistance of aged mice to bacterial pneumonia by modulating the innate immune response, a finding that has potential clinical significance in combating infection in aged individuals through nutritional intervention. PMID- 25512604 TI - Computational modeling predicts IL-10 control of lesion sterilization by balancing early host immunity-mediated antimicrobial responses with caseation during mycobacterium tuberculosis infection. AB - Although almost a third of the world's population is infected with the bacterial pathogen Mycobacterium tuberculosis, our understanding of the functions of many immune factors involved in fighting infection is limited. Determining the role of the immunosuppressive cytokine IL-10 at the level of the granuloma has proven difficult because of lesional heterogeneity and the limitations of animal models. In this study, we take an in silico approach and, through a series of virtual experiments, we predict several novel roles for IL-10 in tuberculosis granulomas: 1) decreased levels of IL-10 lead to increased numbers of sterile lesions, but at the cost of early increased caseation; 2) small increases in early antimicrobial activity cause this increased lesion sterility; 3) IL-10 produced by activated macrophages is a major mediator of early antimicrobial activity and early host induced caseation; and 4) increasing levels of infected macrophage derived IL-10 promotes bacterial persistence by limiting the early antimicrobial response and preventing lesion sterilization. Our findings, currently only accessible using an in silico approach, suggest that IL-10 at the individual granuloma scale is a critical regulator of lesion outcome. These predictions suggest IL-10-related mechanisms that could be used as adjunctive therapies during tuberculosis. PMID- 25512605 TI - Novel long noncoding RNAs (lncRNAs) in myogenesis: a miR-31 overlapping lncRNA transcript controls myoblast differentiation. AB - Transcriptome analysis allowed the identification of new long noncoding RNAs differentially expressed during murine myoblast differentiation. These transcripts were classified on the basis of their expression under proliferating versus differentiated conditions, muscle-restricted activation, and subcellular localization. Several species displayed preferential expression in dystrophic (mdx) versus wild-type muscles, indicating their possible link with regenerative processes. One of the identified transcripts, lnc-31, even if originating from the same nuclear precursor of miR-31, is produced by a pathway mutually exclusive. We show that lnc-31 and its human homologue hsa-lnc-31 are expressed in proliferating myoblasts, where they counteract differentiation. In line with this, both species are more abundant in mdx muscles and in human Duchenne muscular dystrophy (DMD) myoblasts, than in their normal counterparts. Altogether, these data suggest a crucial role for lnc-31 in controlling the differentiation commitment of precursor myoblasts and indicate that its function is maintained in evolution despite the poor sequence conservation with the human counterpart. PMID- 25512606 TI - Transcriptional expression of myelin basic protein in oligodendrocytes depends on functional syntaxin 4: a potential correlation with autocrine signaling. AB - Myelination of axons by oligodendrocytes is essential for saltatory nerve conduction. To form myelin membranes, a coordinated synthesis and subsequent polarized transport of myelin components are necessary. Here, we show that as part of the mechanism to establish membrane polarity, oligodendrocytes exploit a polarized distribution of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) machinery components syntaxins 3 and 4, localizing to the cell body and the myelin membrane, respectively. Our data further reveal that the expression of myelin basic protein (MBP), a myelin specific protein that is synthesized "on site" after transport of its mRNA, depends on the correct functioning of the SNARE machinery, which is not required for mRNA granule assembly and transport per se. Thus, downregulation and overexpression of syntaxin 4 but not syntaxin 3 in oligodendrocyte progenitor cells but not immature oligodendrocytes impeded MBP mRNA transcription, thereby preventing MBP protein synthesis. The expression and localization of another myelin-specific protein, proteolipid protein (PLP), was unaltered. Strikingly, conditioned medium obtained from developing oligodendrocytes was able to rescue the block of MBP mRNA transcription in syntaxin 4-downregulated cells. These findings indicate that the initiation of the biosynthesis of MBP mRNA relies on a syntaxin 4-dependent mechanism, which likely involves activation of an autocrine signaling pathway. PMID- 25512607 TI - Promoter occupancy of STAT1 in interferon responses is regulated by processive transcription. AB - Interferons regulate immunity by inducing DNA binding of the transcription factor STAT1 through Y701 phosphorylation. Transcription by STAT1 needs to be restricted to minimize the adverse effects of prolonged immune responses. It remains unclear how STAT1 inactivation is regulated such that the transcription output is adequate. Here we show that efficient STAT1 inactivation in macrophages is coupled with processive transcription. Ongoing transcription feeds back to reduce the promoter occupancy of STAT1 and, consequently, the transcriptional output. Once released from the promoter, STAT1 is ultimately inactivated by Y701 dephosphorylation. We observe similar regulation for STAT2 and STAT3, suggesting a conserved inactivation mechanism among STATs. These findings reveal that STAT1 promoter occupancy in macrophages is regulated such that it decreases only after initiation of the transcription cycle. This feedback control ensures the fidelity of cytokine responses and provides options for pharmacological intervention. PMID- 25512608 TI - Spatiotemporal cascade of transcription factor binding required for promoter activation. AB - Promoters often contain multiple binding sites for a single factor. The yeast HO gene contains nine highly conserved binding sites for the SCB (Swi4/6-dependent cell cycle box) binding factor (SBF) complex (composed of Swi4 and Swi6) in the 700-bp upstream regulatory sequence 2 (URS2) promoter region. Here, we show that the distal and proximal SBF sites in URS2 function differently. Chromatin immunoprecipitation (ChIP) experiments show that SBF binds preferentially to the left side of URS2 (URS2-L), despite equivalent binding to the left-half and right half SBF sites in vitro. SBF binding at URS2-L sites depends on prior chromatin remodeling events at the upstream URS1 region. These signals from URS1 influence chromatin changes at URS2 but only at sites within a defined distance. SBF bound at URS2-L, however, is unable to activate transcription but instead facilitates SBF binding to sites in the right half (URS2-R), which are required for transcriptional activation. Factor binding at HO, therefore, follows a temporal cascade, with SBF bound at URS2-L serving to relay a signal from URS1 to the SBF sites in URS2-R that ultimately activate gene expression. Taken together, we describe a novel property of a transcription factor that can have two distinct roles in gene activation, depending on its location within a promoter. PMID- 25512610 TI - Glycolysis controls plasma membrane glucose sensors to promote glucose signaling in yeasts. AB - Sensing of extracellular glucose is necessary for cells to adapt to glucose variation in their environment. In the respiratory yeast Kluyveromyces lactis, extracellular glucose controls the expression of major glucose permease gene RAG1 through a cascade similar to the Saccharomyces cerevisiae Snf3/Rgt2/Rgt1 glucose signaling pathway. This regulation depends also on intracellular glucose metabolism since we previously showed that glucose induction of the RAG1 gene is abolished in glycolytic mutants. Here we show that glycolysis regulates RAG1 expression through the K. lactis Rgt1 (KlRgt1) glucose signaling pathway by targeting the localization and probably the stability of Rag4, the single Snf3/Rgt2-type glucose sensor of K. lactis. Additionally, the control exerted by glycolysis on glucose signaling seems to be conserved in S. cerevisiae. This retrocontrol might prevent yeasts from unnecessary glucose transport and intracellular glucose accumulation. PMID- 25512609 TI - TORC1 inhibition induces lipid droplet replenishment in yeast. AB - Lipid droplets (LDs) are intracellular structures that regulate neutral lipid homeostasis. In mammals, LD synthesis is inhibited by rapamycin, a known inhibitor of the mTORC1 pathway. In Saccharomyces cerevisiae, LD dynamics are modulated by the growth phase; however, the regulatory pathways involved are unknown. Therefore, we decided to study the role of the TORC1 pathway on LD metabolism in S. cerevisiae. Interestingly, rapamycin treatment resulted in a fast LD replenishment and growth inhibition. The discovery that osmotic stress (1 M sorbitol) also induced LD synthesis but not growth inhibition suggested that the induction of LDs in yeast is not a secondary response to reduced growth. The induction of LDs by rapamycin was due to increased triacylglycerol but not sterol ester synthesis. Induction was dependent on the TOR downstream effectors, the PP2A-related phosphatase Sit4p and the regulatory protein Tap42p. The TORC1 controlled transcriptional activators Gln3p, Gat1p, Rtg1p, and Rtg3p, but not Msn2p and Msn4p, were required for full induction of LDs by rapamycin. Furthermore, we show that the deletion of Gln3p and Gat1p transcription factors, which are activated in response to nitrogen availability, led to abnormal LD dynamics. These results reveal that the TORC1 pathway is involved in neutral lipid homeostasis in yeast. PMID- 25512611 TI - A posttranscriptional mechanism that controls Ptbp1 abundance in the Xenopus epidermis. AB - The output of alternative splicing depends on the cooperative or antagonistic activities of several RNA-binding proteins (RBPs), like Ptbp1 and Esrp1 in Xenopus. Fine-tuning of the RBP abundance is therefore of prime importance to achieve tissue- or cell-specific splicing patterns. Here, we addressed the mechanisms leading to the high expression of the ptbp1 gene, which encodes Ptbp1, in Xenopus epidermis. Two splice isoforms of ptbp1 mRNA differ by the presence of an alternative exon 11, and only the isoform including exon 11 can be translated to a full-length protein. In vivo minigene assays revealed that the nonproductive isoform was predominantly produced. Knockdown experiments demonstrated that Esrp1, which is specific to the epidermis, strongly stimulated the expression of ptbp1 by favoring the productive isoform. Consequently, knocking down esrp1 phenocopied ptbp1 inactivation. Conversely, Ptbp1 repressed the expression of its own gene by favoring the nonproductive isoform. Hence, a complex posttranscriptional mechanism controls Ptbp1 abundance in Xenopus epidermis: skipping of exon 11 is the default splicing pattern, but Esrp1 stimulates ptbp1 expression by favoring the inclusion of exon 11 up to a level that is limited by Ptbp1 itself. These results decipher a posttranscriptional mechanism that achieves various abundances of the ubiquitous RBP Ptbp1 in different tissues. PMID- 25512613 TI - Stabilization of ATF5 by TAK1-Nemo-like kinase critically regulates the interleukin-1beta-stimulated C/EBP signaling pathway. AB - Interleukin-1beta (IL-1beta) is a key proinflammatory cytokine that initiates several signaling cascades, including those involving CCAAT/enhancer binding proteins (C/EBPs). The mechanism by which IL-1beta propagates a signal that activates C/EBP has remained elusive. Nemo-like kinase (NLK) is a mitogen activated protein kinase (MAPK)-like kinase associated with many pathways and phenotypes that are not yet well understood. Using a luciferase reporter screen, we found that IL-1beta-induced C/EBP activation was positively regulated by NLK. Overexpression of NLK activated C/EBP and potentiated IL-1beta-triggered C/EBP activation, whereas knockdown or knockout of NLK had the opposite effect. NLK interacted with activating transcription factor 5 (ATF5) and inhibited the proteasome-dependent degradation of ATF5 in a kinase-independent manner. Consistently, NLK deficiency resulted in decreased levels of ATF5. NLK cooperated with ATF5 to activate C/EBP, whereas NLK could not activate C/EBP upon knockdown of ATF5. Moreover, TAK1, a downstream effector of IL-1beta that acts upstream of NLK, mimicked the ability of NLK to stabilize ATF5 and activate C/EBP. Thus, our findings reveal the TAK1-NLK pathway as a novel regulator of basal or IL-1beta triggered C/EBP activation though stabilization of ATF5. PMID- 25512614 TI - Anti-peptide monoclonal antibodies generated for immuno-multiple reaction monitoring-mass spectrometry assays have a high probability of supporting Western blot and ELISA. AB - Immunoaffinity enrichment of peptides coupled to targeted, multiple reaction monitoring-mass spectrometry (immuno-MRM) has recently been developed for quantitative analysis of peptide and protein expression. As part of this technology, antibodies are generated to short, linear, tryptic peptides that are well-suited for detection by mass spectrometry. Despite its favorable analytical performance, a major obstacle to widespread adoption of immuno-MRM is a lack of validated affinity reagents because commercial antibody suppliers are reluctant to commit resources to producing anti-peptide antibodies for immuno-MRM while the market is much larger for conventional technologies, especially Western blotting and ELISA. Part of this reluctance has been the concern that affinity reagents generated to short, linear, tryptic peptide sequences may not perform well in traditional assays that detect full-length proteins. In this study, we test the feasibility and success rates of generating immuno-MRM monoclonal antibodies (mAbs) (targeting tryptic peptide antigens) that are also compatible with conventional, protein-based immuno-affinity technologies. We generated 40 novel, peptide immuno-MRM assays and determined that the cross-over success rates for using immuno-MRM monoclonals for Western blotting is 58% and for ELISA is 43%, which compare favorably to cross-over success rates amongst conventional immunoassay technologies. These success rates could most likely be increased if conventional and immuno-MRM antigen design strategies were combined, and we suggest a workflow for such a comprehensive approach. Additionally, the 40 novel immuno-MRM assays underwent fit-for-purpose analytical validation, and all mAbs and assays have been made available as a resource to the community via the Clinical Proteomic Tumor Analysis Consortium's (CPTAC) Antibody (http://antibodies.cancer.gov) and Assay Portals (http://assays.cancer.gov), respectively. This study also represents the first determination of the success rate (92%) for generating mAbs for immuno-MRM using a recombinant B cell cloning approach, which is considerably faster than the traditional hybridoma approach. PMID- 25512612 TI - A zebrafish model of myelodysplastic syndrome produced through tet2 genomic editing. AB - The ten-eleven translocation 2 gene (TET2) encodes a member of the TET family of DNA methylcytosine oxidases that converts 5-methylcytosine (5mC) to 5 hydroxymethylcytosine (5hmC) to initiate the demethylation of DNA within genomic CpG islands. Somatic loss-of-function mutations of TET2 are frequently observed in human myelodysplastic syndrome (MDS), which is a clonal malignancy characterized by dysplastic changes of developing blood cell progenitors, leading to ineffective hematopoiesis. We used genome-editing technology to disrupt the zebrafish Tet2 catalytic domain. tet2(m/m) (homozygous for the mutation) zebrafish exhibited normal embryonic and larval hematopoiesis but developed progressive clonal myelodysplasia as they aged, culminating in myelodysplastic syndromes (MDS) at 24 months of age, with dysplasia of myeloid progenitor cells and anemia with abnormal circulating erythrocytes. The resultant tet2(m/m) mutant zebrafish lines show decreased levels of 5hmC in hematopoietic cells of the kidney marrow but not in other cell types, most likely reflecting the ability of other Tet family members to provide this enzymatic activity in nonhematopoietic tissues but not in hematopoietic cells. tet2(m/m) zebrafish are viable and fertile, providing an ideal model to dissect altered pathways in hematopoietic cells and, for small-molecule screens in embryos, to identify compounds with specific activity against tet2 mutant cells. PMID- 25512615 TI - p53 Mutation Directs AURKA Overexpression via miR-25 and FBXW7 in Prostatic Small Cell Neuroendocrine Carcinoma. AB - Prostatic small cell neuroendocrine carcinoma (SCNC) is a rare but aggressive form of prostate cancer that is negative for androgen receptor (AR) and not responsive to hormonal therapy. The molecular etiology of this prostate cancer variant is not well understood; however, mutation of the p53 (TP53) tumor suppressor in prostate neuroendocrine cells inactivates the IL8-CXCR2-p53 pathway that normally inhibits cellular proliferation, leading to the development of SCNC. SCNC also overexpresses Aurora kinase A (AURKA) which is considered to be a viable therapeutic target. Therefore, the relationship of these two molecular events was studied, and we show that p53 mutation leads to increased expression of miR-25 and downregulation of the E3 ubiquitin ligase FBXW7, resulting in elevated levels of Aurora kinase A. This study demonstrates an intracellular pathway by which p53 mutation leads to Aurora kinase A expression, which is critically important for the rapid proliferation and aggressive behavior of prostatic SCNC. IMPLICATIONS: The pathogenesis of prostatic SCNC involves a p53 and Aurora Kinase A signaling mechanism, both potentially targetable pathways. PMID- 25512617 TI - A novel photodynamic therapy targeting cancer cells and tumor-associated macrophages. AB - Tumor-associated macrophages (TAM) in cancer stroma play important roles for cancer cell growth, invasion, angiogenesis, and metastases. We synthesized a novel photosensitizer, mannose-conjugated chlorin (M-chlorin), designed to bind mannose receptors highly expressed on TAMs. We evaluated the newly available photodynamic therapy (PDT) with M-chlorin against gastric and colon cancer. We evaluated PDT with M-chlorin for in vitro cytotoxicity and apoptosis induction in cancer cells compared with chlorin alone and glucose-conjugated chlorin (G chlorin). The subcellular localization of M-chlorin was observed by confocal microscopy, and the M-chlorin PDT effects against TAMs including THP-1-induced M2 polarized macrophages were evaluated. Anticancer effects were also investigated in an allograft model where cytotoxic effects against TAMs in the cancer cell stroma were analyzed by immunohistochemistry. M-chlorin PDT strongly induced cell death in cancer cells to almost the same extent as G-chlorin PDT by inducing apoptosis. M-chlorin was incorporated into cancer cells where it localized mainly in lysosomes and endoplasmic reticula. M-chlorin PDT revealed strong cytotoxicity for M2 macrophages induced from THP-1 cell lines, and it induced stronger cytotoxicity than G-chlorin PDT in the allograft model through killing both cancer cells and TAMs in the cancer stroma. The M-chlorin PDT produced strong cytotoxicity against cancer tissue by inducing apoptosis of both cancer cells and TAMs in the cancer stroma. This novel PDT thus stands as a new candidate for very effective, next-generation PDT. PMID- 25512616 TI - Tumor-suppressor role of Notch3 in medullary thyroid carcinoma revealed by genetic and pharmacological induction. AB - Notch1-3 are transmembrane receptors that appear to be absent in medullary thyroid cancer (MTC). Previous research has shown that induction of Notch1 has a tumor-suppressor effect in MTC cell lines, but little is known about the biologic consequences of Notch3 activation for the progression of the disease. We elucidate the role of Notch3 in MTC by genetic (doxycycline-inducible Notch3 intracellular domain) and pharmacologic [AB3, novel histone deacetylase (HDAC) inhibitor] approaches. We find that overexpression of Notch3 leads to the dose dependent reduction of neuroendocrine tumor markers. In addition, Notch3 activity is required to suppress MTC cell proliferation, and the extent of growth repression depends on the amount of Notch3 protein expressed. Moreover, activation of Notch3 induces apoptosis. The translational significance of this finding is highlighted by our observation that MTC tumors lack active Notch3 protein and reinstitution of this isoform could be a therapeutic strategy to treat patients with MTC. We demonstrate, for the first time, that overexpression of Notch3 in MTC cells can alter malignant neuroendocrine phenotype in both in vitro and in vivo models. In addition, our study provides a strong rationale for using Notch3 as a therapeutic target to provide novel pharmacologic treatment options for MTC. PMID- 25512619 TI - Tumor-associated hyaluronan limits efficacy of monoclonal antibody therapy. AB - Despite tremendous progress in cancer immunotherapy for solid tumors, clinical success of monoclonal antibody (mAb) therapy is often limited by poorly understood mechanisms associated with the tumor microenvironment (TME). Accumulation of hyaluronan (HA), a major component of the TME, occurs in many solid tumor types, and is associated with poor prognosis and treatment resistance in multiple malignancies. In this study, we describe that a physical barrier associated with high levels of HA (HA(high)) in the TME restricts antibody and immune cell access to tumors, suggesting a novel mechanism of in vivo resistance to mAb therapy. We determined that approximately 60% of HER2(3+) primary breast tumors and approximately 40% of EGFR(+) head and neck squamous cell carcinomas are HA(high), and hypothesized that HA(high) tumors may be refractory to mAb therapy. We found that the pericellular matrix produced by HA(high) tumor cells inhibited both natural killer (NK) immune cell access to tumor cells and antibody dependent cell-mediated cytotoxicity (ADCC) in vitro. Depletion of HA by PEGPH20, a pegylated recombinant human PH20 hyaluronidase, resulted in increased NK cell access to HA(high) tumor cells, and greatly enhanced trastuzumab- or cetuximab dependent ADCC in vitro. Furthermore, PEGPH20 treatment enhanced trastuzumab and NK cell access to HA(high) tumors, resulting in enhanced trastuzumab- and NK cell mediated tumor growth inhibition in vivo. These results suggest that HA(high) matrix in vivo may form a barrier inhibiting access of both mAb and NK cells, and that PEGPH20 treatment in combination with anticancer mAbs may be an effective adjunctive therapy for HA(high) tumors. PMID- 25512618 TI - Identification of novel radiosensitizers in a high-throughput, cell-based screen for DSB repair inhibitors. AB - Most cancer therapies involve a component of treatment that inflicts DNA damage in tumor cells, such as double-strand breaks (DSBs), which are considered the most serious threat to genomic integrity. Complex systems have evolved to repair these lesions, and successful DSB repair is essential for tumor cell survival after exposure to ionizing radiation (IR) and other DNA-damaging agents. As such, inhibition of DNA repair is a potentially efficacious strategy for chemo- and radiosensitization. Homologous recombination (HR) and nonhomologous end-joining (NHEJ) represent the two major pathways by which DSBs are repaired in mammalian cells. Here, we report the design and execution of a high-throughput, cell-based small molecule screen for novel DSB repair inhibitors. We miniaturized our recently developed dual NHEJ and HR reporter system into a 384-well plate-based format and interrogated a diverse library of 20,000 compounds for molecules that selectively modulate NHEJ and HR repair in tumor cells. We identified a collection of novel hits that potently inhibit DSB repair, and we have validated their functional activity in a comprehensive panel of orthogonal secondary assays. A selection of these inhibitors was found to radiosensitize cancer cell lines in vitro, which suggests that they may be useful as novel chemo- and radio sensitizers. Surprisingly, we identified several FDA-approved drugs, including the calcium channel blocker mibefradil dihydrochloride, that demonstrated activity as DSB repair inhibitors and radiosensitizers. These findings suggest the possibility for repurposing them as tumor cell radiosensitizers in the future. Accordingly, we recently initiated a phase I clinical trial testing mibefradil as a glioma radiosensitizer. PMID- 25512623 TI - RealAmp Loop-Mediated Isothermal Amplification as a Point-of-Care Test for Diagnosis of Malaria: Neither Too Close nor Too Far. PMID- 25512620 TI - Detection of alternative splice and gene duplication by RNA sequencing in Japanese flounder, Paralichthys olivaceus. AB - Japanese flounder (Paralichthys olivaceus) is one of the economic important fish in China. Sexual dimorphism, especially the different growth rates and body sizes between two sexes, makes this fish a good model to investigate mechanisms responsible for such dimorphism for both fundamental questions in evolution and applied topics in aquaculture. However, the lack of "omics" data has hindered the process. The recent advent of RNA-sequencing technology provides a robust tool to further study characteristics of genomes of nonmodel species. Here, we performed de novo transcriptome sequencing for a double haploid Japanese flounder individual using Illumina sequencing. A single lane of paired-end sequencing produced more than 27 million reads. These reads were assembled into 107,318 nonredundant transcripts, half of which (51,563; 48.1%) were annotated by blastx to public protein database. A total of 1051 genes that had potential alternative splicings were detected by Chrysalis implemented in Trinity software. Four of 10 randomly picked genes were verified truly containing alternative splicing by cloning and Sanger sequencing. Notably, using a doubled haploid Japanese flounder individual allow us to analyze gene duplicates. In total, 3940 "single-nucleotide polymorphisms" were detected form 1859 genes, which may have happened gene duplicates. This study lays the foundation for structural and functional genomics studies in Japanese flounder. PMID- 25512625 TI - Streptococcus pneumoniae-Induced Oxidative Stress in Lung Epithelial Cells Depends on Pneumococcal Autolysis and Is Reversible by Resveratrol. AB - BACKGROUND: Streptococcus pneumoniae is the most common cause of community acquired pneumonia worldwide. During pneumococcal pneumonia, the human airway epithelium is exposed to large amounts of H2O2 as a product of host and pathogen oxidative metabolism. Airway cells are known to be highly vulnerable to oxidant damage, but the pathophysiology of oxidative stress induced by S. pneumoniae and the role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant systems of the host are not well characterized. METHODS: For gluthation/gluthathion disulfide analysis BEAS-2B cells, primary broncho epithelial cells (pBEC), explanted human lung tissue and mouse lungs were infected with different S. pneumoniae strains (D39, A66, R6x, H2O2/pneumolysin/LytA- deficient mutants of R6x). Cell death was proven by LDH assay and cell viability by IL-8 ELISA. The translocation of Nrf2 and the expression of catalase were shown via Western blot. The binding of Nrf2 at the catalase promoter was analyzed by ChIP. RESULTS: We observed a significant induction of oxidative stress induced by S. pneumoniae in vivo, ex vivo, and in vitro. Upon stimulation, the oxidant-responsive transcription factor Nrf2 was activated, and catalase was upregulated via Nrf2. The pneumococci-induced oxidative stress was independent of S. pneumoniae-derived H2O2 and pneumolysin but depended on the pneumococcal autolysin LytA. The Nrf2 inducer resveratrol, as opposed to catalase, reversed oxidative stress in lung epithelial cells. CONCLUSIONS: These observations indicate a H2O2-independent induction of oxidative stress in lung epithelial cells via the release of bacterial factors of S. pneumoniae. Resveratrol might be an option for prevention of acute lung injury and inflammatory responses observed in pneumococcal pneumonia. PMID- 25512627 TI - Reply to Goyal et al. PMID- 25512624 TI - Hospitalization Rates and Reasons Among HIV Elite Controllers and Persons With Medically Controlled HIV Infection. AB - BACKGROUND: Elite controllers spontaneously suppress human immunodeficiency virus (HIV) viremia but also demonstrate chronic inflammation that may increase risk of comorbid conditions. We compared hospitalization rates and causes among elite controllers to those of immunologically intact persons with medically controlled HIV. METHODS: For adults in care at 11 sites from 2005 to 2011, person-years with CD4 T-cell counts >=350 cells/mm(2) were categorized as medical control, elite control, low viremia, or high viremia. All-cause and diagnostic category-specific hospitalization rates were compared between groups using negative binomial regression. RESULTS: We identified 149 elite controllers (0.4%) among 34 354 persons in care. Unadjusted hospitalization rates among the medical control, elite control, low-viremia, and high-viremia groups were 10.5, 23.3, 12.6, and 16.9 per 100 person-years, respectively. After adjustment for demographic and clinical factors, elite control was associated with higher rates of all-cause (adjusted incidence rate ratio, 1.77 [95% confidence interval, 1.21-2.60]), cardiovascular (3.19 [1.50-6.79]) and psychiatric (3.98 [1.54-10.28]) hospitalization than was medical control. Non-AIDS-defining infections were the most common reason for admission overall (24.1% of hospitalizations) but were rare among elite controllers (2.7%), in whom cardiovascular hospitalizations were most common (31.1%). CONCLUSIONS: Elite controllers are hospitalized more frequently than persons with medically controlled HIV and cardiovascular hospitalizations are an important contributor. PMID- 25512628 TI - Antiretroviral therapy in the elite controller: justified or premature? PMID- 25512626 TI - Association of Cytokines With Exosomes in the Plasma of HIV-1-Seropositive Individuals. AB - Human immunodeficiency virus (HIV)-infected and viremic individuals exhibit elevated levels of plasma cytokines. Here we show that most cytokines are not in free form but appear associated with exosomes that are distinct from virions. Purified exosomes were analyzed to determine the levels of 21 cytokines and chemokines and compared with exosome-depleted plasma. Most cytokines were markedly enriched in exosomes from HIV-positive individuals relative to negative controls and to plasma. Moreover, exposure of naive peripheral blood mononuclear cells to exosomes purified from HIV-positive patients induced CD38 expression on naive and central memory CD4(+) and CD8(+) T cells, probably contributing to inflammation and viral propagation via bystander cell activation. PMID- 25512629 TI - Role of the Flagellar Hook-Length Control Protein FliK and sigma28 in cagA Expression in Gastric Cell-Adhered Helicobacter pylori. AB - Adherence of Helicobacter pylori to the gastric epithelial cell line AGS strongly induces expression of fliK encoding a flagellar hook-length control protein. FliK has a role in triggering dissociation of the alternate sigma factor, sigma(28), from a nonfunctional sigma(28)-FlgM complex, releasing free, functional sigma(28). The sigma(28)-RNA polymerase initiates transcription of cagA, the major virulence gene, from a promoter identified in this study. Consequently, significant up-regulation of cagA was observed in AGS-adhered H. pylori. Direct binding of sigma(28) to the cagA promoter was demonstrated by chromatin immunoprecipitation and the transcription start site was identified by 5' RACE (rapid amplification of complementary DNA ends). The sigma(28)-dependent cagA promoter was active specifically in AGS-adhered H. pylori, and this motif might be associated with high cagA expression and severity of disease. These results also indicate that H. pylori has evolved to integrate expression of the major virulence gene cagA with the flagellar regulatory circuit, essential for colonization of the human host. PMID- 25512632 TI - A CGTase with high coupling activity using gamma-cyclodextrin isolated from a novel strain clustering under the genus Carboxydocella. AB - Cyclodextrin glucanotransferases (CGTases; EC 2.4.1.19) have mainly been characterized for their ability to produce cyclodextrins (CDs) from starch in an intramolecular transglycosylation reaction (cyclization). However, this class of enzymes can also catalyze intermolecular transglycosylation via disproportionation or coupling reactions onto a wide array of acceptors and could therefore be valuable as a tool for glycosylation.In this paper, we report the gene isolation, via the CODEHOP strategy, expression and characterization of a novel CGTase (CspCGT13) from a Carboxydocella sp. This enzyme is the first glycoside hydrolase isolated from the genus, indicating starch degradation via cyclodextrin production in the Carboxydocella strain. The fundamental reactivities of this novel CGTase are characterized and compared with two commercial CGTases, assayed under identical condition, in order to facilitate interpretation of the results. The comparison showed that the enzyme, CspCGT13, displayed high coupling activity using gamma-CD as donor, despite preferentially forming alpha- and beta-CD in the cyclization reaction using wheat starch as substrate. Comparison of subsite conservation within previously characterized CGTases showed significant sequence variation in subsites -3 and -7, which may be important for the coupling activity. PMID- 25512630 TI - Intrahepatic and Peripheral CXCL10 Expression in Hepatitis C Virus-Infected Patients Treated With Telaprevir, Pegylated Interferon, and Ribavirin. AB - We assessed peripheral and liver CXCL10 levels in 15 patients treated with telaprevir/pegylated interferon/ribavirin. Induction of peripheral CXCL10 messenger RNA (mRNA) peaked (mean fold-induction [+/-SD], 3.1 +/- 1.9) between treatment hour 6 and day 2, while induction of intrahepatic CXCL10 mRNA peaked (mean fold-induction [+/-SD], 1.3 +/- 0.54) at hour 10 or day 4. Peripheral CXCL10 levels were higher at treatment hour 10 (P = .032) and day 2 (P = .009) in patients with undetectable virus 2 weeks after treatment initiation. Treatment hour 10 (P = .023) and peak (P = .034) intrahepatic CXCL10 levels were also higher in these patients. CXCL10 did not distinguish treatment responders from nonresponders. In conclusion, CXCL10 identified very rapid virological response in patients treated with a direct-acting antiviral. CLINICAL TRIALS REGISTRATION: NCT00892697. PMID- 25512631 TI - Global Dispersal Pattern of HIV Type 1 Subtype CRF01_AE: A Genetic Trace of Human Mobility Related to Heterosexual Sexual Activities Centralized in Southeast Asia. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) subtype CRF01_AE originated in Africa and then passed to Thailand, where it established a major epidemic. Despite the global presence of CRF01_AE, little is known about its subsequent dispersal pattern. METHODS: We assembled a global data set of 2736 CRF01_AE sequences by pooling sequences from public databases and patient-cohort studies. We estimated viral dispersal patterns, using statistical phylogeographic analysis run over bootstrap trees estimated by the maximum likelihood method. RESULTS: We show that Thailand has been the source of viral dispersal to most areas worldwide, including 17 of 20 sampled countries in Europe. Japan, Singapore, Vietnam, and other Asian countries have played a secondary role in the viral dissemination. In contrast, China and Taiwan have mainly imported strains from neighboring Asian countries, North America, and Africa without any significant viral exportation. DISCUSSION: The central role of Thailand in the global spread of CRF01_AE can be probably explained by the popularity of Thailand as a vacation destination characterized by sex tourism and by Thai emigration to the Western world. Our study highlights the unique case of CRF01_AE, the only globally distributed non-B clade whose global dispersal did not originate in Africa. PMID- 25512635 TI - Melanoma BRAF fusions--letter. PMID- 25512634 TI - Molecular pathways: microRNAs, cancer cells, and microenvironment. AB - One of the most unexpected discoveries in molecular oncology over the last decade is the interplay between abnormalities in protein-coding genes and short noncoding microRNAs (miRNA) that are causally involved in cancer initiation, progression, and dissemination. This phenomenon was initially defined in malignant cells; however, in recent years, more data have accumulated describing the active participation of miRNAs produced by microenvironment cells. As hormones, miRNAs can be released by a donor cell in various forms of vesicles or as "free" molecules secreted by active mechanisms. These miRNAs spread as signaling molecules that are uptaken either as exosomes or as "free" RNAs, by cells located in other parts of the organism. Here, we discuss the communication between cancer cells and the microenvironment through miRNAs. We further expand this in a more translational context and present miRNAs as predictors of treatment response, as crucial agents in targeted therapeutics, and as significant molecules to target. PMID- 25512636 TI - Melanoma BRAF fusions--response. PMID- 25512637 TI - Prognostic serum cytokines in classical Hodgkin lymphoma--letter. PMID- 25512639 TI - Ten-year incidence of colorectal cancer following a negative screening sigmoidoscopy: an update from the Colorectal Cancer Prevention (CoCaP) programme. AB - OBJECTIVE: To examine the rates of colorectal cancer (CRC) following a negative screening sigmoidoscopy. DESIGN: Cohort study. SETTING: An integrated healthcare delivery organisation in California, USA. PARTICIPANTS: 72,483 men and women aged 50 years and above who had a negative screening sigmoidoscopy between 1994 and 1996. Those at elevated risk of CRC due to inflammatory bowel disease, prior polyps or CRC, or a strong family history of CRC were excluded. MAIN OUTCOME MEASURES: Incidence rates of distal and proximal CRC. Standardised Incidence Ratios were used to compare annual incidence rates of distal and proximal CRC in the cohort to expected rates based on Surveillance, Epidemiology, and End Results data. Additionally, rate ratios (RR) and rate differences (RD) comparing the incidence rate of distal CRC in years 6+ postscreening with that in years 1-5 were calculated. RESULTS: Incidence rates of distal CRC were lower than those in the San Francisco Bay area population at large during each of the first 10 years postsigmoidoscopy screening. However, the incidence of distal CRC rose steadily, from 3 per 100,000 in the first year of follow-up to 40 per 100,000 in the 10th year. During the second half of follow-up, the rate of distal CRC was twice as high as in the first half (RR 2 .08, 95% CI 1.38 to 3.16; RD 14 per 100,000 person-years, 95% CI 6 to 22). CONCLUSIONS: Though still below population levels, the incidence of CRC during years 6-10 following a negative sigmoiodoscopy is appreciably higher than during the first 5 years. PMID- 25512640 TI - Comment on impact on colorectal cancer mortality of screening programmes based on the faecal immunochemical test. PMID- 25512641 TI - Digital microfluidic platform for the detection of rubella infection and immunity: a proof of concept. AB - BACKGROUND: Whereas disease surveillance for infectious diseases such as rubella is important, it is critical to identify pregnant women at risk of passing rubella to their offspring, which can be fatal and can result in congenital rubella syndrome (CRS). The traditional centralized model for diagnosing rubella is cost-prohibitive in resource-limited settings, representing a major obstacle to the prevention of CRS. As a step toward decentralized diagnostic systems, we developed a proof-of-concept digital microfluidic (DMF) diagnostic platform that possesses the flexibility and performance of automated immunoassay platforms used in central facilities, but with a form factor the size of a shoebox. METHODS: DMF immunoassays were developed with integrated sample preparation for the detection of rubella virus (RV) IgG and IgM. The performance (sensitivity and specificity) of the assays was evaluated with serum and plasma samples from a commercial antirubella mixed-titer performance panel. RESULTS: The new platform performed the essential processing steps, including sample aliquoting for 4 parallel assays, sample dilution, and IgG blocking. Testing of performance panel samples yielded diagnostic sensitivity and specificity of 100% and 100% for both RV IgG and RV IgM. With 1.8 MUL sample per assay, 4 parallel assays were performed in approximately 30 min with <10% mean CV. CONCLUSIONS: This proof of concept establishes DMF-powered immunoassays as being potentially useful for the diagnosis of infectious disease. PMID- 25512642 TI - Quantitative charge-tags for sterol and oxysterol analysis. AB - BACKGROUND: Global sterol analysis is challenging owing to the extreme diversity of sterol natural products, the tendency of cholesterol to dominate in abundance over all other sterols, and the structural lack of a strong chromophore or readily ionized functional group. We developed a method to overcome these challenges by using different isotope-labeled versions of the Girard P reagent (GP) as quantitative charge-tags for the LC-MS analysis of sterols including oxysterols. METHODS: Sterols/oxysterols in plasma were extracted in ethanol containing deuterated internal standards, separated by C18 solid-phase extraction, and derivatized with GP, with or without prior oxidation of 3beta hydroxy to 3-oxo groups. RESULTS: By use of different isotope-labeled GPs, it was possible to analyze in a single LC-MS analysis both sterols/oxysterols that naturally possess a 3-oxo group and those with a 3beta-hydroxy group. Intra- and interassay CVs were <15%, and recoveries for representative oxysterols and cholestenoic acids were 85%-108%. By adopting a multiplex approach to isotope labeling, we analyzed up to 4 different samples in a single run. Using plasma samples, we could demonstrate the diagnosis of inborn errors of metabolism and also the export of oxysterols from brain via the jugular vein. CONCLUSIONS: This method allows the profiling of the widest range of sterols/oxysterols in a single analytical run and can be used to identify inborn errors of cholesterol synthesis and metabolism. PMID- 25512643 TI - Trends in incidence, treatment and survival of aggressive B-cell lymphoma in the Netherlands 1989-2010. AB - Only a small number of patients with aggressive B-cell lymphoma take part in clinical trials, and elderly patients in particular are under-represented. Therefore, we studied data of the population-based nationwide Netherlands Cancer Registry to determine trends in incidence, treatment and survival in an unselected patient population. We included all patients aged 15 years and older with newly diagnosed diffuse large B-cell lymphoma or Burkitt lymphoma in the period 1989-2010 and mantle cell lymphoma in the period 2001-2010, with follow up until February 2013. We examined incidence, first-line treatment and survival. We calculated annual percentage of change in incidence and carried out relative survival analyses. Incidence remained stable for diffuse large B-cell lymphoma (n=23,527), while for mantle cell lymphoma (n=1,634) and Burkitt lymphoma (n=724) incidence increased for men and remained stable for women. No increase in survival for patients with aggressive B-cell lymphoma was observed during the period 1989-1993 and the period 1994-1998 [5-year relative survival 42% (95%CI: 39%-45%) and 41% (38%-44%), respectively], but increased to 46% (43%-48%) in the period 1999-2004 and to 58% (56%-61%) in the period 2005-2010. The increase in survival was most prominent in patients under 65 years of age, while there was a smaller increase in patients over 75 years of age. However, when untreated patients were excluded, patients over 75 years of age had a similar increase in survival to younger patients. In the Netherlands, survival for patients with aggressive B-cell lymphoma increased over time, particularly in younger patients, but also in elderly patients when treatment had been initiated. The improvement in survival coincided with the introduction of rituximab therapy and stem cell transplantation into clinical practice. PMID- 25512645 TI - Is fluid overload as measured by bioimpedance spectroscopy harmful in CKD-if so, why? PMID- 25512648 TI - Ethical approval for all studies involving human participants. PMID- 25512646 TI - Association of fluid overload with cardiovascular morbidity and all-cause mortality in stages 4 and 5 CKD. AB - BACKGROUND AND OBJECTIVES: Fluid overload is a common characteristic associated with renal progression in CKD. Additionally, fluid overload is an independent predictor of all-cause or cardiovascular mortality in patients on dialysis, but its influence on patients not on dialysis is uncertain. The aim of the study was to assess the relationship between the severity of fluid status and clinical outcomes in an advanced CKD cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In total, 478 predialysis patients with stages 4 and 5 CKD in the integrated CKD care program were enrolled from January of 2011 to December of 2011 and followed-up until August of 2013. The clinical outcomes included cardiovascular morbidity and all-cause mortality. The relative hydration status (overhydration/extracellular water) was used as the presentation of the severity of fluid status and measured using a body composition monitor. Overhydration/extracellular water >7% was defined as fluid overload. RESULTS: Over a median follow-up period of 23.2 (12.6-26.4) months, 66 (13.8%) patients reached all-cause mortality or cardiovascular morbidity. The adjusted hazard ratio of the combined outcome of all-cause mortality or cardiovascular morbidity for every 1% higher overhydration/extracellular water was 1.08 (95% confidence interval, 1.04 to 1.12; P<0.001). The adjusted overhydration/extracellular water for the combined outcome of all-cause mortality or cardiovascular morbidity in participants with overhydration/extracellular water >=7% compared with those with overhydration/extracellular water <7% was 1.93 (95% confidence interval, 1.01 to 3.69; P=0.04). In subgroup analysis, higher overhydration/extracellular water was consistently associated with increased risk for the combined outcome independent of diabetes, cardiovascular disease, and serum albumin. There was no significant interaction between all subgroups. CONCLUSIONS: These findings suggest that fluid overload is an independent risk factor of the combined outcome of all-cause mortality or cardiovascular morbidity in patients with advanced CKD. PMID- 25512644 TI - Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia. AB - B-cell acute lymphoblastic leukemia is the most common type of pediatric leukemia. Despite improved remission rates, current treatment regimens for pediatric B-cell acute lymphoblastic leukemia are often associated with adverse effects and central nervous system relapse, necessitating more effective and safer agents. Bafilomycin A1 is an inhibitor of vacuolar H(+)-ATPase that is frequently used at high concentration to block late-phase autophagy. Here, we show that bafilomycin A1 at a low concentration (1 nM) effectively and specifically inhibited and killed pediatric B-cell acute lymphoblastic leukemia cells. It targeted both early and late stages of the autophagy pathway by activating mammalian target of rapamycin signaling and by disassociating the Beclin 1-Vps34 complex, as well as by inhibiting the formation of autolysosomes, all of which attenuated functional autophagy. Bafilomycin A1 also targeted mitochondria and induced caspase-independent apoptosis by inducing the translocation of apoptosis-inducing factor from mitochondria to the nucleus. Moreover, bafilomycin A1 induced the binding of Beclin 1 to Bcl-2, which further inhibited autophagy and promoted apoptotic cell death. In primary cells from pediatric patients with B-cell acute lymphoblastic leukemia and a xenograft model, bafilomycin A1 specifically targeted leukemia cells while sparing normal cells. An in vivo mouse toxicity assay confirmed that bafilomycin A1 is safe. Our data thus suggest that bafilomycin A1 is a promising candidate drug for the treatment of pediatric B-cell acute lymphoblastic leukemia. PMID- 25512647 TI - Anal cancer and intraepithelial neoplasia: epidemiology, screening and prevention of a sexually transmitted disease. PMID- 25512649 TI - CIHR excludes Aboriginal health in review. PMID- 25512650 TI - 10 stories that mattered: Dec. 6-12. PMID- 25512651 TI - Infoway is shifting, not shuttering: Alvarez. PMID- 25512653 TI - Effect of lung-protective ventilation with lower tidal volumes on clinical outcomes among patients undergoing surgery: a meta-analysis of randomized controlled trials. AB - BACKGROUND: In anesthetized patients undergoing surgery, the role of lung protective ventilation with lower tidal volumes is unclear. We performed a meta analysis of randomized controlled trials (RCTs) to evaluate the effect of this ventilation strategy on postoperative outcomes. METHODS: We searched electronic databases from inception through September 2014. We included RCTs that compared protective ventilation with lower tidal volumes and conventional ventilation with higher tidal volumes in anesthetized adults undergoing surgery. We pooled outcomes using a random-effects model. The primary outcome measures were lung injury and pulmonary infection. RESULTS: We included 19 trials (n=1348). Compared with patients in the control group, those who received lung-protective ventilation had a decreased risk of lung injury (risk ratio [RR] 0.36, 95% confidence interval [CI] 0.17 to 0.78; I2=0%) and pulmonary infection (RR 0.46, 95% CI 0.26 to 0.83; I2=8%), and higher levels of arterial partial pressure of carbon dioxide (standardized mean difference 0.47, 95% CI 0.18 to 0.75; I2=65%). No significant differences were observed between the patient groups in atelectasis, mortality, length of hospital stay, length of stay in the intensive care unit or the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen. INTERPRETATION: Anesthetized patients who received ventilation with lower tidal volumes during surgery had a lower risk of lung injury and pulmonary infection than those given conventional ventilation with higher tidal volumes. Implementation of a lung-protective ventilation strategy with lower tidal volumes may lower the incidence of these outcomes. PMID- 25512654 TI - Identifying and treating group A streptococcal pharyngitis in children. PMID- 25512655 TI - Ebola-free in Africa's most populous nation. PMID- 25512656 TI - CIHR reforms contradict consultant reports. PMID- 25512657 TI - Intramuscular hemangioma with turkey wattle sign. PMID- 25512658 TI - Corrigendum. PMID- 25512663 TI - Training activities and injuries in English youth academy and schools rugby union. AB - BACKGROUND: All rugby training activities carry an injury risk, but in the training environment these injury risks should be more controllable than during matches. PURPOSE: To (1) describe the incidence, severity, anatomic location, and type of youth rugby training injuries; (2) determine the injury events and type of training activities associated with injuries; and (3) compare 2 levels of play (professional academy vs school) within English youth rugby union. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A 2-season (2006-2007 and 2007-2008) study recorded exposure to training activities and time-loss injuries in male youth rugby union players (age range, 16-18 years) from 12 English Premiership academies (250 player-seasons) and 7 schools (222 player-seasons). Players from the Premiership academies, associated with the top-level professional clubs in England, represented the elite level of youth rugby; the school players were from established rugby-playing schools but were overall considered at a lower level of play. RESULTS: There was a trend for training injury incidence to be lower for the academy group (1.4/1000 player-hours; 95% CI, 1.0-1.7) compared with the school group (2.1/1000 player-hours; 95% CI, 1.4-2.9) (P = .06). Injuries to the ankle/heel and thigh were most common in academy players and injuries to the lumbar spine and ankle/heel region most common in school players. The training activities responsible for injury differed between the 2 groups: technical skills (scrummaging) for school players and contact skills (defense and ruck/maul drills) for academy players. CONCLUSION: For injury risk management in youth rugby, coaches of school players should focus on the development of the correct technique during practice of technical skills such as scrummaging, weight training, and skills training, and coaches of academy players should consider the extent to which contact drills are necessary during training. PMID- 25512664 TI - Altered lower extremity movement variability in female soccer players during side step cutting after anterior cruciate ligament reconstruction. AB - BACKGROUND: Anterior cruciate ligament (ACL) reconstruction (ACLR) is common after an ACL tear and is thought to restore functional stability to the knee. A recent investigation demonstrated that individuals who have undergone ACLR exhibited increased lower extremity coupling variability during gait, suggestive of altered dynamic stability. However, little is known about whether they exhibit alterations in lower extremity variability during dynamic sport-specific tasks. PURPOSE: To determine if female soccer players who have had an ACLR demonstrate differences in lower extremity coupling variability as compared with athletes with no history of knee injury during a side-step cutting maneuver. STUDY DESIGN: Controlled laboratory study. METHODS: Ten female soccer players who had undergone ACLR served as the experimental group, and 10 female soccer players with no history of knee ligament injury composed the control group (CON). Three dimensional kinematics and ground-reaction forces were collected while each participant performed a side-step cutting maneuver. Based on known ACL loading patterns, 7 lower extremity intralimb couplings were created. With use of a vector-coding technique, the coordination variability was calculated for each coupling. Independent t tests were used to determine group differences in variability for each coupling (P <= .05). RESULTS: Individuals who had undergone ACLR exhibited increased lower extremity variability during side-step cutting as compared with control subjects in the following couplings: hip rotation/knee abduction-adduction (27.2 degrees +/- 11.5 degrees [ACLR] vs 19.7 degrees +/- 6.8 degrees [CON]; P = .04), hip flexion-extension/knee abduction-adduction (26.0 degrees +/- 13.3 degrees [ACLR] vs 18.6 degrees +/- 5.3 degrees [CON]; P = .05), knee abduction-adduction/knee flexion-extension (13.5 degrees +/- 5.7 degrees [ACLR] vs 7.3 degrees +/- 2.7 degrees [CON]; P < .01), and knee abduction-adduction/knee rotation (26.4 degrees +/- 10.8 degrees [ACLR] vs 19.3 degrees +/- 4.5 degrees [CON]; P = .03). In addition, there was a trend toward increased variability in the hip rotation/ankle inversion-eversion coupling (22.9 degrees +/- 9.3 degrees [ACLR] vs 18.0 degrees +/- 6.7 degrees [CON]; P = .09) and knee abduction-adduction/ankle inversion-eversion coupling (25.9 degrees +/- 10.0 degrees [ACLR] vs 20.2 degrees +/- 9.7 degrees [CON]; P = .10). CONCLUSION: Female soccer players who have undergone ACLR and returned to sports participation exhibit altered lower extremity coupling variability during side step cutting. CLINICAL RELEVANCE: While individuals who have had an ACLR exhibit mechanical knee stability before returning to sports, the observed increased movement variability during side-step cutting is likely reflective of altered neuromuscular control and may contribute to the known increased risk for ACL reinjury and knee osteoarthritis after return to sports participation. Improving the understanding of altered lower extremity coupling variability after ACLR will aid in the development of more effective rehabilitation programs. PMID- 25512665 TI - Biomechanical analysis of articular-sided partial-thickness rotator cuff tear and repair. AB - BACKGROUND: Articular-sided partial-thickness rotator cuff tears are common injuries in throwing athletes. The superior shoulder capsule beneath the supraspinatus and infraspinatus tendons works as a stabilizer of the glenohumeral joint. PURPOSE: To assess the effect of articular-sided partial-thickness rotator cuff tear and repair on shoulder biomechanics. The hypothesis was that shoulder laxity might be changed because of superior capsular plication in transtendon repair of articular-sided partial-thickness rotator cuff tears. STUDY DESIGN: Controlled laboratory study. METHODS: Nine fresh-frozen cadaveric shoulders were tested by using a custom shoulder-testing system at the simulated late-cocking phase and acceleration phase of throwing motion. Maximum glenohumeral external rotation angle, anterior translation, position of the humeral head apex with respect to the glenoid, internal impingement area, and glenohumeral and subacromial contact pressures were measured. Each specimen underwent 3 stages of testing: stage 1, with the intact shoulder; stage 2, after creation of articular sided partial-thickness tears of the supraspinatus and infraspinatus tendons; and stage 3, after transtendon repair of the torn tendons by using 2 suture anchors. RESULTS: Articular-sided partial-thickness tears did not significantly change any of the shoulder biomechanical measurements. In the simulated late-cocking phase, transtendon rotator cuff repair resulted in decreased maximum external rotation angle by 4.2 degrees (P = .03), posterior shift of the humeral head (1.1-mm shift; P = .02), decreased glenohumeral contact pressure by 1.7 MPa (56%; P = .004), and decreased internal impingement area by 26.4 mm(2) (65%; P < .001) compared with values in the torn shoulder. In the acceleration phase, the humeral head shifted inferiorly (1.2-mm shift; P = .03 vs torn shoulder), and glenohumeral anterior translation (1.5-mm decrease; P = .03 vs torn shoulder) and subacromial contact pressure (32% decrease; P = .004 vs intact shoulder) decreased significantly after transtendon repair. CONCLUSION: Transtendon repair of articular-sided partial-thickness supraspinatus and infraspinatus tears decreased glenohumeral and subacromial contact pressures at time zero; these changes might lead to reduced secondary subacromial and internal impingements and consequently progression to full-thickness rotator cuff tear. However, repair of the tendons decreased anterior translation and external rotation and changed the positional relationship between the humeral head and the glenoid. CLINICAL RELEVANCE: Careful attention should be paid to shoulder laxity and range of motion when transtendon repair is chosen to treat articular-sided partial thickness rotator cuff tears, specifically in throwing athletes. PMID- 25512666 TI - Human biomonitoring of chromium and nickel from an experimental exposure to manual metal arc welding fumes of low and high alloyed steel. AB - OBJECTIVES: The uptake and elimination of metals from welding fumes is currently not fully understood. In the Aachen Workplace Simulation Laboratory (AWSL) it is possible to investigate the impact of welding fumes on human subjects under controlled exposure conditions. In this study, the uptake and elimination of chromium or chromium (VI) respectively as well as nickel was studied in subjects after exposure to the emissions of a manual metal arc welding process using low or high alloyed steel. METHODS: In this present study 12 healthy male non smokers, who never worked as welders before, were exposed for 6h to welding fumes of a manual metal arc welding process. In a three-fold crossover study design, subjects were exposed in randomized order to either clean air, emissions from welding low alloyed steel, and emissions from welding high alloyed steel. Particle mass concentration of the exposure aerosol was 2.5mg m(-3). The content of chromium and nickel in the air was determined by analysing air filter samples on a high emission scenario. Urine analysis for chromium and nickel was performed before and after exposure using methods of human biomonitoring. RESULTS: There were significantly elevated chromium levels after exposure to welding fumes from high alloyed steel compared to urinary chromium levels before exposure to high alloyed welding fumes, as well as compared to the other exposure scenarios. The mean values increased from 0.27 ug l(-1) to 18.62 ug l(-1). The results were in good agreement with already existing correlations between external and internal exposure (German exposure equivalent for carcinogenic working materials EKA). The variability of urinary chromium levels was high. For urinary nickel no significant changes could be detected at all. CONCLUSIONS: Six-hour exposure to 2.5mg m(-3) high alloyed manual metal arc welding fumes lead to elevated urinary chromium levels far higher (7.11-34.16 ug l(-1)) than the German biological exposure reference value (BAR) of 0.6 ug l(-1) directly after exposure. On the other hand mean urinary nickel concentrations slightly increased, but did not exceed background levels due to lower bioavailability. We could underline with our single exposure experiment that a welding work related chromium exposure can be measured immediately after the work shift, while the same is not possible for nickel exposure due to lower nickel bioavailability. The data provide useful information for real occupational welding work places. PMID- 25512667 TI - Internalised homophobia is differentially associated with sexual risk behaviour by race/ethnicity and HIV serostatus among substance-using men who have sex with men in the United States. AB - OBJECTIVES: There is a continuing need to identify factors associated with risk for HIV transmission among men who have sex with men (MSM), including a need for further research in the ongoing scientific debate about the association of internalised homophobia and sexual risk due partly to the lack of specificity in analysis. We assess the association of internalised homophobia by race/ethnicity within HIV serostatus for a large sample of substance-using MSM at high risk of HIV acquisition or transmission. METHODS: Convenience sample of substance-using (non-injection) MSM reporting unprotected anal sex in the prior 6 months residing in Chicago, Los Angeles, New York and San Francisco. The analytic sample included HIV-negative and HIV-positive black (n=391), Latino (n=220), and white (n=458) MSM. Internalised homophobia was assessed using a published four-item scale focusing on negative self-perceptions and feelings of their own sexual behaviour with men, or for being gay or bisexual. Analyses tested associations of internalised homophobia with recent risk behaviour, stratified by laboratory confirmed HIV serostatus within race/ethnicity, and controlling for other demographic variables. RESULTS: In multivariate analysis, internalised homophobia was inversely associated (p<0.05) with recent unprotected anal sex among black MSM, and not significantly associated with sexual risk behaviour among white and Latino MSM. CONCLUSIONS: More research is needed to further identify nuanced differences in subpopulations of MSM, but these results suggest differentially targeted intervention messages for MSM by race/ethnicity. PMID- 25512668 TI - Psychological effects of diagnosis and treatment of cervical intraepithelial neoplasia: a systematic review. AB - BACKGROUND: Treatment of cervical intraepithelial neoplasia (CIN) is a common minor surgical procedure to prevent uterine cervical cancer. However, news of an abnormality detected at screening for cancer might cause the woman to worry. OBJECTIVES: To investigate the psychological consequences of CIN diagnosis and treatment in a systematic review. DATA SOURCES: We searched PubMed using Medical Subject Headings (MeSH) terms for articles published from January 1990 to February 2013. We also examined the reference lists of retrieved articles. SELECTION CRITERIA: Quantitative studies measuring psychological outcomes in women with a histological diagnosis or treatment of CIN, and in women having an outcome other than CIN at cervical screening. DATA COLLECTION AND ANALYSIS: We abstracted the data using a pre-specified list of study characteristics and measured outcomes. For studies not reporting statistical testing, we estimated the statistical significance of the differences between the compared groups using unpaired t tests. MAIN RESULTS: From 5099 retrieved abstracts, 16 studies were included. Diagnosis and treatment of CIN were associated with worse psychological outcomes than normal cytology test results, but the impact decreased over time. In several but not all studies, CIN appeared to have similar psychological consequences to abnormal smears. No study showed a difference in psychological outcomes between CIN and cervical cancer diagnosis when these were measured some years after diagnosis. CONCLUSIONS: The studies suggested that CIN diagnosis and treatment have a negative psychological impact. However, this conclusion should be viewed in the context of a paucity of rigorously designed studies. PMID- 25512669 TI - Revised simulation model does not predict rebound in gonorrhoea prevalence where core groups are treated in the presence of antimicrobial resistance. AB - OBJECTIVES: To determine the effects of using discrete versus continuous quantities of people in a compartmental model examining the contribution of antimicrobial resistance (AMR) to rebound in the prevalence of gonorrhoea. METHODS: A previously published transmission model was reconfigured to represent the occurrence of gonorrhoea in discrete persons, rather than allowing fractions of infected individuals during simulations. RESULTS: In the revised model, prevalence only rebounded under scenarios reproduced from the original paper when AMR occurrence was increased by 10(5) times. In such situations, treatment of high-risk individuals yielded outcomes very similar to those resulting from treatment of low-risk and intermediate-risk individuals. Otherwise, in contrast with the original model, prevalence was the lowest when the high-risk group was treated, supporting the current policy of targeting treatment to high-risk groups. CONCLUSIONS: Simulation models can be highly sensitive to structural features. Small differences in structure and parameters can substantially influence predicted outcomes and policy prescriptions, and must be carefully considered. PMID- 25512671 TI - Risk-taking behaviours and HIV infection among sex workers in Portugal: results from a cross-sectional survey. AB - OBJECTIVES: Sex workers (SW) are key populations at an increased risk of HIV infection. This study aimed to characterise risk-taking behaviours and assess HIV prevalence among SW in Portugal. METHODS: A cross-sectional survey was conducted with 1040 SW using a participatory research approach. SW were recruited in sex work locations and community-based organisation offices. Data were collected through a questionnaire with trained interviewers. An HIV rapid test was performed in 213 respondents. RESULTS: Reported HIV prevalence was 8%: 17.6% of man-to-woman transgenders, 7.4% of women and 5% of men. Of SW reportedly living with HIV, 52.2% reported ever injecting drug use. Inconsistent condom use with clients in the last month was higher among male SW (26.5%) and with non-paying partners in the last year was higher among women (71.3%). Among reported HIV positive SW, the proportions of inconsistent condom use were high. In multivariate regression analysis, reported HIV infection remained significantly higher among transgenders (OR 6.4; 95% CI 1.7 to 24.3), those older (OR 5.1; 95% CI 1.3 to 21.1), working outdoors (OR 5.4; 95% CI 1.9 to 15.6), having ever used psychoactive substances (OR 4.1; 95% CI 2.2 to 7.7) and earning <=?1000 per month (OR 2.6; 95% CI 1.2 to 5.9). Of those who had an HIV rapid test, 8.9% were reactive; 73.7% were unaware of their seropositivity. CONCLUSIONS: The HIV infection burden in SW is high. Efforts to promote HIV testing must be sustained in order to reduce undiagnosed infection. The diverse risk profiles of SW must be addressed in targeted HIV interventions. Prevention interventions should be systematically implemented within most-at-risk subgroups of SW. PMID- 25512670 TI - Exploring the costs and outcomes of sexually transmitted infection (STI) screening interventions targeting men in football club settings: preliminary cost consequence analysis of the SPORTSMART pilot randomised controlled trial. AB - BACKGROUND: The objective of this study was to compare the costs and outcomes of two sexually transmitted infection (STI) screening interventions targeted at men in football club settings in England, including screening promoted by team captains. METHODS: A comparison of costs and outcomes was undertaken alongside a pilot cluster randomised control trial involving three trial arms: (1) captain led and poster STI screening promotion; (2) sexual health advisor-led and poster STI screening promotion and (3) poster-only STI screening promotion (control/comparator). For all study arms, resource use and cost data were collected prospectively. RESULTS: There was considerable variation in uptake rates between clubs, but results were broadly comparable across study arms with 50% of men accepting the screening offer in the captain-led arm, 67% in the sexual health advisor-led arm and 61% in the poster-only control arm. The overall costs associated with the intervention arms were similar. The average cost per player tested was comparable, with the average cost per player tested for the captain-led promotion estimated to be L88.99 compared with L88.33 for the sexual health advisor-led promotion and L81.87 for the poster-only (control) arm. CONCLUSIONS: Costs and outcomes were similar across intervention arms. The target sample size was not achieved, and we found a greater than anticipated variability between clubs in the acceptability of screening, which limited our ability to estimate acceptability for intervention arms. Further evidence is needed about the public health benefits associated with screening interventions in non clinical settings so that their cost-effectiveness can be fully evaluated. PMID- 25512672 TI - Time trends in ophthalmia neonatorum and dacryocystitis of the newborn in England, 2000-2011: database study. AB - AIMS: To investigate English national trends in ophthalmia neonatorum and dacryocystitis (ON) of the newborn and the completeness of statutory notification of this serious infection. DESIGN: Analysis of hospital episode statistics (HES) from 2000 to 2011. MATERIALS AND METHODS: Using linked HES, numbers of neonates hospitalised with ON were identified from 2000 to 2011. The numbers of hospitalised cases were compared with numbers of statutory notifications for ON published by the Notifications of Infectious Diseases (NOIDS). RESULTS: The national incidence rate of hospitalised cases showed a gradual decline from 464 (95% CI 447 to 482) per 100,000 live births in 2000 to 216 (204 to 228) per 100,000 live births in 2005. It then gradually increased to 471 (455 to 487) per 100,000 live births in 2010, but dropped to 257 (245 to 269) per 100,000 in 2011. From 2000 to 2009, when NOIDS data were available, the NOIDS data showed only 1006 cases compared with 20,505 cases in HES, and thus the notification system captured only about 1 case in 20. CONCLUSIONS: As shown by hospital statistics, there were marked cyclical fluctuations in ON over the study period. The annual figures for ON reported during the study period, under statutory health protection regulations, underestimated the actual occurrence of this disease by a very substantial amount. Linked hospital data should be used routinely to monitor the national incidence of ON. PMID- 25512673 TI - Confirmatory assays are essential when using molecular testing for Neisseria gonorrhoeae in low-prevalence settings: insights from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). AB - OBJECTIVES: To investigate the occurrence of unconfirmed positive gonorrhoea results when using molecular testing within a large population-based survey. DESIGN, SETTING AND PARTICIPANTS: Between 2010 and 2012, we did a probability sample survey of 15,162 men and women aged 16-74 years in Britain. Urine from participants aged 16-44 years reporting >=1 lifetime sexual partner was tested for Neisseria gonorrhoeae and Chlamydia trachomatis using the Aptima Combo 2 (AC2) assay, with positive or equivocal results confirmed with molecular assays using different nucleic acid targets. RESULTS: A total of 4550 participants aged 16-44 years had urine test results (1885 men; 2665 women). For gonorrhoea, 18 samples initially tested positive and eight were equivocal. Only five out of 26 confirmed, giving a positive predictive value (PPV) for the initial testing of 19% (95% CI 4% to 34%). Most (86% (18/21)) participants with unconfirmed positive results for gonorrhoea reported zero or one sexual partner without condoms in the past year and none had chlamydia co-infection, whereas all five with confirmed gonorrhoea reported at least two recent sexual partners without condoms, and four had chlamydia co-infection. The weighted prevalence for gonorrhoea positivity fell from 0.4% (0.3% to 0.7%) after initial screening to <0.1% (0.0% to 0.1%) after confirmatory testing. By comparison, 103 samples tested positive or equivocal for chlamydia and 98 were confirmed (PPV=95% (91% to 99%)). CONCLUSIONS: We highlight the low PPV for gonorrhoea of an unconfirmed reactive test when deploying molecular testing in a low-prevalence population. Failure to undertake confirmatory testing in low-prevalence settings may lead to inappropriate diagnoses, unnecessary treatment and overestimation of population prevalence. PMID- 25512674 TI - The SPORTSMART study: a pilot randomised controlled trial of sexually transmitted infection screening interventions targeting men in football club settings. AB - BACKGROUND: Uptake of chlamydia screening by men in England has been substantially lower than by women. Non-traditional settings such as sports clubs offer opportunities to widen access. Involving people who are not medically trained to promote screening could optimise acceptability. METHODS: We developed two interventions to explore the acceptability and feasibility of urine-based sexually transmitted infection (STI) screening interventions targeting men in football clubs. We tested these interventions in a pilot cluster randomised control trial. Six clubs were randomly allocated, two to each of three trial arms: team captain-led and poster STI screening promotion; sexual health adviser led and poster STI screening promotion; and poster-only STI screening promotion (control/comparator). Primary outcome was test uptake. RESULTS: Across the three arms, 153 men participated in the trial and 90 accepted the offer of screening (59%, 95% CI 35% to 79%). Acceptance rates were broadly comparable across the arms: captain-led: 28/56 (50%); health professional-led: 31/46 (67%); and control: 31/51 (61%). However, rates varied appreciably by club, precluding formal comparison of arms. No infections were identified. Process evaluation confirmed that interventions were delivered in a standardised way but the control arm was unintentionally 'enhanced' by some team captains actively publicising screening events. CONCLUSIONS: Compared with other UK-based community screening models, uptake was high but gaining access to clubs was not always easy. Use of sexual health advisers and team captains to promote screening did not appear to confer additional benefit over a poster-promoted approach. Although the interventions show potential, the broader implications of this strategy for UK male STI screening policy require further investigation. PMID- 25512676 TI - Two-dimensional lattice gauge theories with superconducting quantum circuits. AB - A quantum simulator of [Formula: see text] lattice gauge theories can be implemented with superconducting circuits. This allows the investigation of confined and deconfined phases in quantum link models, and of valence bond solid and spin liquid phases in quantum dimer models. Fractionalized confining strings and the real-time dynamics of quantum phase transitions are accessible as well. Here we show how state-of-the-art superconducting technology allows us to simulate these phenomena in relatively small circuit lattices. By exploiting the strong non-linear couplings between quantized excitations emerging when superconducting qubits are coupled, we show how to engineer gauge invariant Hamiltonians, including ring-exchange and four-body Ising interactions. We demonstrate that, despite decoherence and disorder effects, minimal circuit instances allow us to investigate properties such as the dynamics of electric flux strings, signaling confinement in gauge invariant field theories. The experimental realization of these models in larger superconducting circuits could address open questions beyond current computational capability. PMID- 25512675 TI - MRI assessment of early response to certolizumab pegol in rheumatoid arthritis: a randomised, double-blind, placebo-controlled phase IIIb study applying MRI at weeks 0, 1, 2, 4, 8 and 16. AB - OBJECTIVES: To identify the first time point of an MRI-verified response to certolizumab pegol (CZP) therapy in patients with rheumatoid arthritis (RA). METHODS: Forty-one patients with active RA despite disease-modifying antirheumatic drug therapy were randomised 2:1 to CZP (CZP loading dose 400 mg every 2 weeks at weeks 0-4; CZP 200 mg every 2 weeks at weeks 6-16) or placebo >CZP (placebo at weeks 0-2; CZP loading dose at weeks 2-6; CZP 200 mg every 2 weeks at weeks 8-16). Contrast-enhanced MRI of one hand and wrist was acquired at baseline (week 0) and weeks 1, 2, 4, 8 and 16. All six time points were read simultaneously, blinded to time, using the Outcome Measures in Rheumatology Clinical Trials RA MRI scoring system. Primary outcome was change in synovitis score in the CZP group; secondary outcomes were change in bone oedema (osteitis) and erosion scores and clinical outcome measures. RESULTS: Forty patients were treated (27 CZP, 13 placebo->CZP), and 36 (24 CZP, 12 placebo->CZP) completed week 16. In the CZP group, there were significant reductions from baseline synovitis (Hodges-Lehmann estimate of median change, -1.5, p=0.049) and osteitis scores (-2.5, p=0.031) at week 16. Numerical, but statistically insignificant, MRI inflammation reductions were observed at weeks 1-2 in the CZP group. No significant change was seen in bone erosion score. Improvements across all clinical outcomes were seen in the CZP group. CONCLUSIONS: CZP reduced MRI synovitis and osteitis scores at week 16, despite small sample size and the technical challenge of reading six time points simultaneously. This study provides essential information on optimal MRI timing for subsequent trials. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT01235598. PMID- 25512677 TI - Degree of host susceptibility in the initial disease outbreak influences subsequent epidemic spread. AB - Disease epidemics typically begin as an outbreak of a relatively small, spatially explicit population of infected individuals (focus), in which disease prevalence increases and rapidly spreads into the uninfected, at-risk population. Studies of epidemic spread typically address factors influencing disease spread through the at-risk population, but the initial outbreak may strongly influence spread of the subsequent epidemic.We initiated wheat stripe rust Puccinia striiformis f. sp. tritici epidemics to assess the influence of the focus on final disease prevalence when the degree of disease susceptibility differed between the at-risk and focus populations.When the focus/at-risk plantings consisted of partially genetic resistant and susceptible cultivars, final disease prevalence was statistically indistinguishable from epidemics produced by the focus cultivar in monoculture. In these experimental epidemics, disease prevalence was not influenced by the transition into an at-risk population that differed in disease susceptibility. Instead, the focus appeared to exert a dominant influence on the subsequent epidemic.Final disease prevalence was not consistently attributable to either the focus or the at-risk population when focus/at-risk populations were planted in a factorial set-up with a mixture (~28% susceptible and 72% resistant) and susceptible individuals. In these experimental epidemics, spatial heterogeneity in disease susceptibility within the at-risk population appeared to counter the dominant influence of the focus.Cessation of spore production from the focus (through fungicide/glyphosate application) after 1.3 generations of stripe rust spread did not reduce final disease prevalence, indicating that the focus influence on disease spread is established early in the epidemic.Synthesis and applications. Our experiments indicated that outbreak conditions can be highly influential on epidemic spread, even when disease resistance in the at risk population is greater than that of the focus. Disease control treatments administered shortly after the initial outbreak within the focus may either prevent an epidemic from occurring or reduce its severity. PMID- 25512678 TI - The effect of US signalling and the US-CS interval on backward conditioning in mice. AB - The effect of US signalling and the US-CS interval in backward conditioning was assessed in mice. For one group of mice the presentation of food was signalled by a tone and for another group, food was unsignalled. For half of the mice, within each group, the presentation of food preceded a visual cue by 10 s. For the other half, food was presented at the start of the visual cue (0-s US-CS interval), resulting in simultaneous pairings of these events. A summation test and a subsequent retardation test were used to assess the inhibitory effects of backward conditioning in comparison to training with a non-reinforced visual cue that controlled for the possible effects of latent inhibition and conditioned inhibition caused as a consequence of differential conditioning. In the summation test unsignalled presentations of the US resulted in inhibition when the US-CS interval was 10 s, but not 0 s. Signalled presentations of the US resulted in inhibition, independent of the US-CS interval. In the retardation test, independent of US signalling, a US-CS interval of 10 s failed to result in inhibition, but an interval of 0 s resulted in greater conditioned responding to the backward CS than the control CS. A generalisation decrement account of the effect of signalling the US with a 0-s US-CS interval, which resulted in reduced responding in the summation test and faster acquisition in the retardation test, is discussed. PMID- 25512679 TI - Enhancing computer self-efficacy and attitudes in multi-ethnic older adults: a randomised controlled study. AB - Several studies have documented the health-related benefits of older adults' use of computer technology, but before they can be realised, older individuals must be positively inclined and confident in their ability to engage in computer-based environments. To facilitate the assessment of computer technology attitudes, one aim of the longitudinal study reported in this paper was to test and refine a new 22-item measure of computer technology attitudes designed specifically for older adults, as none such were available. Another aim was to replicate, on a much larger scale, the successful findings of a preliminary study that tested a computer technology training programme for older adults (Lagana 2008). Ninety-six older men and women, mainly from non-European-American backgrounds, were randomly assigned to the waitlist/control or the experimental group. The same six-week one on-one training was administered to the control subjects at the completion of their post-test. The revised (17-item) version of the Older Adults' Computer Technology Attitudes Scale (OACTAS) showed strong reliability: the results of a factor analysis were robust, and two analyses of covariance demonstrated that the training programme induced significant changes in attitudes and self-efficacy. Such results encourage the recruitment of older persons into training programmes aimed at increasing computer technology attitudes and self-efficacy. PMID- 25512680 TI - Cortical Activity during Perception of Musical Rhythm; Comparing Musicians and Non-musicians. AB - This study investigates the effects of musical training on brain activity to violations of rhythmic expectancies. We recorded behavioral and event-related brain potential (ERP) responses of musicians and non-musicians to discrepancies of rhythm between pairs of unfamiliar melodies based on Western classical rules. Rhythm deviations in the second melody involved prolongation of a note, thus creating a delay in the subsequent note; the duration of the second note was consequently shorter because the offset time was unchanged. In the first melody, on the other hand, the two notes were of equal duration. Musicians detected rhythm deviations significantly better than non-musicians. A negative auditory cortical potential in response to the omitted stimulus was observed at a latency of 150-250 ms from where the note should have been. There were no significant differences of amplitude or latency between musicians and non-musicians. In contrast, the N100 and P200 to the delayed note after the omission were significantly greater in amplitude in musicians compared to non-musicians especially in frontal and frontal-central areas. These findings indicate that long term musical training enhances brain cortical activities involved in processing temporal irregularities of unfamiliar melodies. PMID- 25512681 TI - Anti-fungal resistance in candida isolated from oral and diaper rash candidiasis in neonates. AB - The purpose of the present study is to evaluate the sensitivity of Candida species isolated from oral candidiasis and diaper dermatitis infections in children. The children referring to private and public clinics in Ilam, Iran were exmined for oral candidiasis and diaper dermatitis. In this study, 248 oral candidiasis and diaper dermatitis samples were collected and cultured.Candida species were identified by using standard methods. Resistance and sensitivity to amphotericin B, nystatin, ketoconazole, fluconazole, itraconazole, clotrimazole, and posaconazole were determined using the CLSI M44-A standard disk diffusion method. From the 248 studied samples, 149 were positive for Candida, among which the Candida albicans was the most prevalent (64.4%). The resistance of different Candida species to nystatin, itraconazole, fluconazole, ketoconazole, clotrimazole, voriconazole, and posaconazole were 4, 43, 34.2, 34.9, 21.5, 6, and 6.7%, respectively. No resistance to amphotericin B was observed. Considering rather low resistance to nystatin, this drug is the best choice for oral candidiasis and diaper dermatitis. PMID- 25512683 TI - Molecular screening of insecticides with sigma glutathione S-transferases (GST) in cotton aphid Aphis gossypii using docking. AB - Glutathione S-transferases (GSTs) are one of the major families of detoxifying enzymes that detoxifies different chemical compounds including insecticides in different insect species. Among the GST subclasses, sigma GSTs are found to be the most abundant and conserved among different insect orders. These GSTs are found to play an important role in lipid peroxidation as well as detoxification. Cotton aphid, Aphis gossypii is the most damaging sucking pest with a wide range of hosts and vector of more than 50 plant viruses. Resistance to insecticides in A. gossypii is reported in India and in other countries. Glutathione S transferases (GSTs), an oxidative enzyme is understood to have a role in insecticide resistance and plant resistance breakdown. In relation to this, we have focused on the sigma 1 (GenBank Accession No: JN989964.1) and sigma 2 (GenBank Accession No: JN989965.1) GSTs of A. gossypii and their interaction with plant natural compounds and insecticides. Molecular screening of different insecticides (Chlorphinamidine, Mevinphos, Nitenpyrum, Piperonyl butoxide, Tetrachlorovinphos, Pyrethrins, Resmetrin, Pirimicarb and Dinotefuran) and known plant derived natural compounds (Catechin, Gossypol, Myrcene, Kaempferol, P coumaric acid, Quercetin, Tannins, alpha-mangostin, Capsaicin, Cinnamic acid, Citronellal, Curcumin, Dicumarol, Ellagic acid, Eugenol, Geriniol, Isoeugenol, Juglone, Menadione, Methyl jasmonate, Morin, Myricetin, Myristicin, Piperine, Plumbagin, Tangitinin C, Thymol, Vanillin, Alpha pipene, alpha-terpineol Apigenin and beta-Caryophyllene) with sigma 1 and sigma 2 GST protein models was completed using Maestro 9.3 (Schrodinger, USA). This exercise showed the binding of piperonyl butoxide with sigma 1 GST and tannin with sigma 2 GST for further consideration. PMID- 25512682 TI - Pattern of the evolution of HIV-1 ennu gene in Cote d'Ivoire. AB - Cete d'Ivoire continues to have the highest HIV-1 prevalence rate in West Africa, although the infection number is in constant decline. The external envelope protein of the viruses is a likely site of selection, and responsible for receptor binding and entry into host cells, and therefore constitutes an ideal region with which to investigate the evolutionary processes acting on HIV-1. In this study, we analyse 189 envelope glycoprotein V3 loop region sequences of viruse isolates from 1995 to 2009, from HIV-1 untreated patients living in Cete d'Ivoire, to decipher the temporal relationship between disease diversity, divergence and selection. Our analyses show that the nonsynonymous and synonymous ratio (dN/dS) was lower than 1 for viral populations analysed within 15 years, which showed the sequences did not undergo adequate immune pressure. The phylogenetic tree of the sequences analysed demonstrated distinctly long internal branches and short external branches, suggesting that only a small number of viruses infected the new host cell at each transmission. In addition to identifying sites under purifying selection, we also identified neutral sites that can cause false positive inference of selection. These sites presented form a resource for future studies of selection pressures acting on HIV-1 ennu gene in Cete d'Ivoire and other West African countries. PMID- 25512684 TI - Elucidation of molecular targets of bioactive principles of black cumin relevant to its anti-tumour functionality - An Insilico target fishing approach. AB - Black cumin (Nigella sativa) is a spice having medicinal properties with pungent and bitter odour. It is used since thousands of years to treat various ailments, including cancer mainly in South Asia and Middle Eastern regions. Substantial evidence in multiple research studies emphasizes about the therapeutic importance of bioactive principles of N. sativa in cancer bioassays; however, the exact mechanism of their anti-tumour action is still to be fully comprehended. The current study makes an attempt in this direction by exploiting the advancements in the Insilico reverse screening technology. In this study, three different Insilico Reverse Screening approaches have been employed for identifying the putative molecular targets of the bioactive principles in Black cumin (thymoquinone, alpha-hederin, dithymoquinone and thymohydroquinone) relevant to its anti-tumour functionality. The identified set of putative targets is further compared with the existing set of experimentally validated targets, so as to estimate the performance of insilico platforms. Subsequently, molecular docking simulations studies were performed to elucidate the molecular interactions between the bioactive compounds & their respective identified targets. The molecular interactions of one such target identified i.e. VEGF2 along with thymoquinone depicted one H-bond formed at the catalytic site. The molecular targets identified in this study need further confirmatory tests on cancer bioassays, in order to justify the research findings from Insilico platforms. This study has brought to light the effectiveness of usage of Insilico Reverse Screening protocols to characterise the un-identified target-ome of poly pharmacological bioactive agents in spices. PMID- 25512685 TI - Study of the inhibitory effect of Quercus Coccifera's aqueous extract on Staphylococcus aureus and Pseudomonas aeruginosa In vitro. AB - The use of therapeutic herbs has become of great importance these days due to the increase in drug resistance. From a long time ago the Venus' navel plant has been used to treat infections. In this study the antibacterial effect of the aqueous extract from the Quercus coccifera (jaft) herb, under laboratory conditions. This study was carried out experimentally. After collecting the Venus navel herb, it was dried in a warm dry environment away from direct sunlight in the shade. The alcoholic extract was prepared using a standard method. Clinical samples of staphylococcus aureus and pseudomonas aeruginosa were acquired from Ilam's health care institutes. The inhibitory effect of the extracts was analysed in the Mueller Hinton using the disk diffusion method for both bacteria. Then MIC and MBC of the extracts was determined using the Macro broth dilution method. At its highest concentration the aqueous extract had an inhibition zone of 27.2 and 23.7 mm on staphylococcus aureus and pseudomonas aeruginosa consecutively. The MIC and MBC for staphylococcus aureus were 10 and 12.5 ug/ml and for pseudomonas aeruginosa they were 10 and 17.5 ug/m consecutively. The results of this study show the strong antimicrobial effect of jaft's aqueous extract on staphylococcus aureus and pseudomonas aeruginosa and if more studies are based on this topic it could be a substitute for common antibiotics. PMID- 25512686 TI - Evaluation of dairy allergy among ulcerative colitis patients. AB - The intestine is the largest mucosal organ of the body and also the first line immune homeostasis. Inflammatory bowel disease or IBD is divided into ulcerative colitis and Crohn's disease. One of the problems that can occur with UC is dietary allergy to some foods. This study aimed to evaluated the dairy allergy among patients with ulcerative colitis. This study is a Case - control study, that studied 72 patients with Ulcerative Colitis, after recording history of the disease, colonoscopy and confirmed by biopsy and 72 person without history of colitis. In this study, in order to investigate of food allergy, used of the EUROMMUM kit with an international code number DP3420-1601-11E. We used chi square and Monte Carlo method for analysis of data. Among UC patients, 30.6% mild, 52.8% moderate and 16.6% of cases were in sever stage. 9.7% of them reported a history of abdominal surgery due to disease. According to the chi square and Monte Carlo methods, dairy allergy (including: cow milk, cow milk UHT and casein) in UC group was significant (P=0.00). This study indicated that there is significant relationship between UC and cow milk, cow milk UHT and casein. UC patients who are allergic to dairy products and the use of dairy products can increase the severity of UC. PMID- 25512687 TI - Structure based virtual screening to identify inhibitors against MurE Enzyme of Mycobacterium tuberculosis using AutoDock Vina. AB - The Mur E enzyme of Mur pathway of Mycobacterium tuberculosis is an attractive drug target as it is unique to bacteria and is absent in mammalian cells. The virtual screening of large libraries of drug like molecules against a protein target is a common strategy used to identify novel inhibitors. However, the method has a large number of pitfalls, with large variations in accuracy caused in part by inaccurate protocols, use of improper standards and libraries, and system dependencies such as the potential for nonspecific docking from large active-site cavities. The screening of drug-like small molecules from diversity sets can, however, be used to short-list potential fragments as building blocks to generate leads with improved specificity. We describe a protocol to implement this strategy, which involves an analysis of the active site and known inhibitors to identify orthospecific determinants, virtual screening of a drug-like diversity library to identify potential drug primitives, and inspection of the potential docked fragments for both binding potential and toxicity. The protocol is implemented on the M.tb Mur E protein which has a large active site with poor enrichment of known positives and a set of drug-like molecules that meets this criteria is presented for further analysis. ABBREVIATIONS: MTB - Mycobacterium tuberculosis, NCI - National Cancer Institute, PDB - Protein Databank. PMID- 25512688 TI - Development of tumor lysis syndrome (TLS): A potential risk factor in cancer patients receiving anticancer therapy. AB - Tumor lysis syndrome (TLS) is characterized by hyperuricaemia, hyperphosphatemia, hyperkalaemia, as well as hypocalcaemia due to the breakdown of tumor cells undergoing cancer therapy (chemo/radio). Therefore it is of interest to evaluate oxidative stress using selective biological markers [Malondialdehyde (MDA), Superoxide Dismutase (SOD), Glutathione (GSH) and Catalase (CAT)] in TLS. We report the marked differences (statistically significant with control) observed among a selected set of biomarkers of oxidative stress (MDA = 8.66+/-1.37; SOD = 0.15+/-0.11; GSH = 2.25+/-.77; CAT = 0.76+/-.57) in TLS patients in addition to other conventional biomarkers. Moreover, correlation was investigated among the parameters of oxidative stress and other circulating biomarkers of TLS. Data suggest the use of SOD, MDA, and GSH as potential diagnostic biomarker for TLS with other biomarkers. PMID- 25512689 TI - PubstractHelper: A Web-based Text-Mining Tool for Marking Sentences in Abstracts from PubMed Using Multiple User-Defined Keywords. AB - While a huge amount of information about biological literature can be obtained by searching the PubMed database, reading through all the titles and abstracts resulting from such a search for useful information is inefficient. Text mining makes it possible to increase this efficiency. Some websites use text mining to gather information from the PubMed database; however, they are database-oriented, using pre-defined search keywords while lacking a query interface for user defined search inputs. We present the PubMed Abstract Reading Helper (PubstractHelper) website which combines text mining and reading assistance for an efficient PubMed search. PubstractHelper can accept a maximum of ten groups of keywords, within each group containing up to ten keywords. The principle behind the text-mining function of PubstractHelper is that keywords contained in the same sentence are likely to be related. PubstractHelper highlights sentences with co-occurring keywords in different colors. The user can download the PMID and the abstracts with color markings to be reviewed later. The PubstractHelper website can help users to identify relevant publications based on the presence of related keywords, which should be a handy tool for their research. AVAILABILITY: http://bio.yungyun.com.tw/ATM/PubstractHelper.aspx and http://holab.med.ncku.edu.tw/ATM/PubstractHelper.aspx. PMID- 25512690 TI - SNPAAMapperT2K: A genome-wide SNP downstream analysis and annotation pipeline for species annotated with NCBI.tbl data files. AB - SNPAAMapper, a genome-wide SNP downstream analysis and annotation pipeline, was designed to classify detected variants according to genomic regions and report the mutation class by processing whole-genome and/or whole-exome sequencing data. A widely used sequence and data annotation table format "knownGene.txt" has not yet been created for many popular model organisms (e.g. Arabidopsis). Instead, NCBI .tbl annotation format files are provided for these species. Therefore, it is of interest to describe SNPAAMapperT2K, a genome-wide SNP downstream analysis and annotation pipeline for species annotated with NCBI .tbl data files (e.g. Arabidopsis). The pipeline is tested with a deeply sequenced Arabidopsis thaliana strain (Seattle-0). The SNPAAMapperT2K can also annotate and report SNP classes for other species, whose chromosome files are annotated as NCBI .tbl format, but do not have their annotated knownGene.txt files available. AVAILABILITY: Perl scripts and required input files are available on the web at http://isu.indstate.edu/ybai2/SNPAAMapperT2K. PMID- 25512692 TI - Antigenic Variation in H5N1 clade 2.1 Viruses in Indonesia From 2005 to 2011. AB - Influenza A (H5N1) virus, has spread to several countries in the world and has a high mortality rate. Meanwhile, the virus has evolved into several clades. The human influenza A (H5N1) virus circulating in Indonesia is a member of clade 2.1, which is different in antigenicity from other clades of influenza A (H5N1). An analysis of the antigenic variation in the H5 hemagglutinin gene (HA) of the influenza A (H5N1) virus strains circulating in Indonesia has been undertaken. Several position of amino acid mutations, including mutations at positions 35, 53, 141, 145, 163, 174, 183, 184, 189, and 231, have been identified. The mutation Val-174-Iso appears to play an important role in immunogenicity and cross-reactivity with rabbit antisera. This study shows that the evolution of the H5HA antigenic variation of the influenza A (H5N1) virus circulating in Indonesia from 2005 to 2011 may affect the immunogenicity of the virus. PMID- 25512693 TI - High Rate of Non-detectable HIV-1 RNA Among Antiretroviral Drug Naive HIV Positive Individuals in Nigeria. AB - Plasma HIV-1 RNA concentration, or viral load, is an indication of the magnitude of virus replication and largely correlates with disease progression in an infected person. It is a very useful guide for initiation of therapy and monitoring of response to antiretroviral drugs. Although the majority of patients who are not on antiretroviral therapy (ART) have a high viral load, a small proportion of ART naive patients are known to maintain low levels or even undetectable viral load levels. In this study, we determined the rate of undetectable HIV-1 RNA among ART naive HIV positive patients who presented for treatment at the University College Hospital (UCH), Ibadan, Nigeria from 2005 to 2011. Baseline viral load and CD4 lymphocyte cell counts of 14,662 HIV positive drug naive individuals were determined using the Roche Amplicor version 1.5 and Partec easy count kit, respectively. The detection limits of the viral load assay are 400 copies/mL and 750,000 copies/mL for lower and upper levels, respectively. A total of 1,399 of the 14,662 (9.5%) HIV-1 positive drug naive individuals had undetectable viral load during the study period. In addition, the rate of non detectable viral load increased over the years. The mean CD4 counts among HIV-1 infected individuals with detectable viral load (266 cells/MUL; range = 1 to 2,699 cells/MUL) was lower than in patients with undetectable viral load (557 cells/MUL; range = 1 to 3,102 cells/MUL). About 10% of HIV-1 infected persons in our study population had undetectable viral load using the Roche Amplicor version 1.5. PMID- 25512695 TI - Molecular characteristics of rotavirus isolated from a diarrhea outbreak in october 2008 in bintuni bay, papua, indonesia. AB - BACKGROUND: Viral diarrhea continues to be a health problem in Indonesia that often causes outbreaks; in particular, acute viral diarrhea in young children. Rotavirus is the leading cause of severe diarrhea in children under two years of age. This study aimed to determine the genotypes of rotavirus in Bintuni Bay, Papua. METHODS: Stool specimens from 15 patients were collected and analyzed for rotavirus using an enzyme immunosorbent assay (EIA) and reverse transcriptase polymerase chain reaction (RT-PCR). Subsequently, we sequenced the genetic material of rotavirus positive samples by RT-PCR and analyzed the results using Mega-4 software. RESULTS: Two rotavirus serotypes were identified from the diarrhea outbreak in Bintuni, Papua in October 2008: serotype G1 with G1P[6] (50%) and G1P[8] (16.7%) strains, and serotype G2 with G2P[4] (23.3%) strain. Phylogenetic tree analyses of VP7 protein showed that rotavirus-infected diarrhea in Bintuni Bay, Papua at that time was dominated by the G1 serotype (83%). CONCLUSION: The laboratory results showed that G1 serotype rotavirus was a cause of the outbreak of diarrhea in October 2008 in Bintuni, Papua. PMID- 25512697 TI - Ruptured thoracic aortic aneurysm infected with listeria monocytogenes: a case report and a review of literature. AB - A 75-year-old male with a history of alcoholic liver cirrhosis, sigmoid colon cancer, and metastatic liver cancer was admitted to our institution with a complaint of a prickly feeling in his chest. On admission, a chest radiograph revealed a normal cardio-thoracic ratio of 47%. Echocardiography revealed pericardial effusion and blood chemical analyses revealed elevated C-reactive protein levels (14.7 mg/dL). On day 3, chest radiography revealed cardiomegaly with a cardio-thoracic ratio of 58% and protrusion of the left first arch. Contrast-enhanced chest computed tomography revealed a saccular aneurysm in the aortic arch with surrounding hematoma; thus, a ruptured thoracic aortic aneurysm was suspected. Emergency surgery was performed, which revealed a ruptured aortic aneurysm with extensive local inflammation. The diagnosis of an infected aortic rupture was therefore confirmed. The aneurysm and abscess were resected, followed by prosthetic graft replacement and omental packing. Histopathology of the resected aneurysm revealed gram-positive bacilli; and Listeria monocytogenes was confirmed as the causative organism by culture. Postoperative course was uneventful; on postoperative day 60, the patient was ambulatory and was discharged. Here we report the case of a male with a ruptured thoracic aortic aneurysm infected with L. monocytogenes. PMID- 25512696 TI - Epidemiology and associated risk factors of hepatitis e virus infection in plateau state, Nigeria. AB - A cross-sectional study in Nigeria was undertaken to determine the epidemiology, seroprevalence, and associated risk factors, of hepatitis E virus (HEV). A total of 462 subjects were used for the study, categorized into four groups: apparently healthy persons, pregnant women, HIV positive subjects, and animal handlers. Information was obtained from subjects using interviewer-administered questionnaire. Blood samples were collected and analyzed for HEV antibodies (IgG and IgM) using enzyme-linked immunosorbent assay (ELISA) technique. Results obtained were analyzed using Statistical Package for Social Sciences (SPSS) version 17.0 statistical software. The overall seroprevalence of IgG and IgM was 42.7 and 0.9%, respectively. Animal handlers had the highest seroprevalence (66.7%). The associated risk factors for IgM seroprevalence were rural dwelling (P = 0.039, odds ratio (OR) 3.3, 95% confidence interval (CI) 0.7-15.4), blood transfusion (P < 0.001, OR 9.6, 95% CI 2.6-35.6), attending to animals (P = 0.032, OR 4.9, 95% CI 0.9-26.6), and waste disposal (P < 0.001). Factors associated with IgG were age (P = 0.044), location (P < 0.001), marital status (P < 0.001), formal education (P < 0.001), farming as occupation (P < 0.001), rural dwelling (P = 0.001), waste disposal (P < 0.001), alcohol consumption (P = 0.001, OR 2.4, 95% CI 1.4-4.0), open defecation (P < 0.001, OR 2.9, 95% CI 1.4-5.7), attending to animals (P < 0.001, OR 2.3, 95% CI 1.6-3.4), consuming unwashed fruits/vegetables (P < 0.001, OR 4.2, 95% CI 0.3-54.1), and stream/river as a source of drinking water (P < 0.001, OR 3.6, 95% CI 1.6-7.8). Preventive public health measures should be reinforced among all communities, particularly domestic animal handlers and pregnant women. Potable water should be provided for all communities. Data suggest that HEV remains an under-recognized and significant public health problem, warranting further attention and research. PMID- 25512694 TI - Animal Models Utilized in HTLV-1 Research. AB - Since the isolation and discovery of human T-cell leukemia virus type 1 (HTLV-1) over 30 years ago, researchers have utilized animal models to study HTLV-1 transmission, viral persistence, virus-elicited immune responses, and HTLV-1 associated disease development (ATL, HAM/TSP). Non-human primates, rabbits, rats, and mice have all been used to help understand HTLV-1 biology and disease progression. Non-human primates offer a model system that is phylogenetically similar to humans for examining viral persistence. Viral transmission, persistence, and immune responses have been widely studied using New Zealand White rabbits. The advent of molecular clones of HTLV-1 has offered the opportunity to assess the importance of various viral genes in rabbits, non-human primates, and mice. Additionally, over-expression of viral genes using transgenic mice has helped uncover the importance of Tax and Hbz in the induction of lymphoma and other lymphocyte-mediated diseases. HTLV-1 inoculation of certain strains of rats results in histopathological features and clinical symptoms similar to that of humans with HAM/TSP. Transplantation of certain types of ATL cell lines in immunocompromised mice results in lymphoma. Recently, "humanized" mice have been used to model ATL development for the first time. Not all HTLV-1 animal models develop disease and those that do vary in consistency depending on the type of monkey, strain of rat, or even type of ATL cell line used. However, the progress made using animal models cannot be understated as it has led to insights into the mechanisms regulating viral replication, viral persistence, disease development, and, most importantly, model systems to test disease treatments. PMID- 25512691 TI - Dendritic Cells in HIV-1 and HCV Infection: Can They Help Win the Battle? AB - Persistent infections with human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) are a major cause of morbidity and mortality worldwide. As sentinels of our immune system, dendritic cells (DCs) play a central role in initiating and regulating a potent antiviral immune response. Recent advances in our understanding of the role of DCs during HIV-1 and HCV infection have provided crucial insights into the mechanisms employed by these viruses to impair DC functions in order to evade an effective immune response against them. Modulation of the immunological synapse between DC and T-cell, as well as dysregulation of the crosstalk between DCs and natural killer (NK) cells, are emerging as two crucial mechanisms. This review focuses on understanding the interaction of HIV-1 and HCV with DCs not only to understand the immunopathogenesis of chronic HIV-1 and HCV infection, but also to explore the possibilities of DC-based immunotherapeutic approaches against them. Host genetic makeup is known to play major roles in infection outcome and rate of disease progression, as well as response to anti-viral therapy in both HIV-1 and HCV-infected individuals. Therefore, we highlight the genetic variations that can potentially affect DC functions, especially in the setting of chronic viral infection. Altogether, we address if DCs' potential as critical effectors of antiviral immune response could indeed be utilized to combat chronic infection with HIV-1 and HCV. PMID- 25512699 TI - Heart surgery in end-stage renal disease: is outcome worse for african american patients? AB - General results of open heart surgery in end-stage renal disease patients (ESRD) have been well-documented. However, it is unknown if the African American subgroup with known decreased access to advanced healthcare services and a higher prevalence rate of ESRD have a worse long-term survival after heart surgery. Thirty of 150 African American patients who underwent open heart surgery by a single surgeon at an urban community hospital between 1996 and 2010 were identified to have ESRD and were on chronic maintenance hemodialysis prior to surgery. Clinical and outcome data from both groups were retrospectively analyzed. There were no significant differences in the baseline demographic characteristics of the patients, but the ESRD cohort showed a significantly higher prevalence of peripheral vascular and cardiovascular diseases [P < 0.001]. Compared to the non-ESRD subjects, the predicted logistic EuroSCORE was 16.4% vs. 9.4%, [P < 0.001], while the observed 30 days operative mortality was 16.6% vs. 4.2% [P < 0.02], respectively. In isolated coronary artery bypass graft cases, operative mortality was 20.8% and 3.0%, respectively. The 5- and 10-year post surgery survival was 40% and 25% vs. 72% and 57% [P < 0.01], respectively, in the ESRD and non-ESRD groups. Operative mortality and survival was worse in ESRD patients compared to non-ESRD patients based on their preoperative risk scores. Although the operative mortality of our ESRD patients was high, long-term survival was comparable to reports from both the United States Renal Data System and a Japanese ESRD cohort. PMID- 25512698 TI - Deep sternal wound complications: an overview of old and new therapeutic options. AB - Deep sternal wound complications represent a significant problem in current open heart surgery and still pose a tremendous challenge to surgeons. Over the years, many treatment modalities have been proposed, but only few found their way into daily clinical practice of cardiothoracic surgeons. A gold standard has not been defined yet. This review was designed to give an overview of the preferred surgical strategies. PMID- 25512701 TI - Retraction: "Bedside surgery to treat patent ductus arteriosus in low-birth weight premature infants". PMID- 25512700 TI - Bedside surgery to treat patent ductus arteriosus in low-birth-weight premature infants. AB - BACKGROUND: Patent ductus arteriosus (PDA) is commonly seen in premature infants with low birth weights (LBW). It is a condition that has high mortality and morbidity rates. Early closure of the ductus arteriosus may require surgery or medical treatment. However, the decision of first medical approach for symptomatic PDA closure is still debated. In this study, we compared the surgical and medical treatments for the closure of PDA in premature LBW infants. METHODS: This study included 27 premature infants whose birth weights were lower than 1500 g, who were born in the period between 2011 and 2013 and had symptomatic PDA. Patients were separated into two groups: groups A and B. Group A included patients whose PDAs were closed with medical treatment (n = 16), and group B included patients who had undergone surgical operations for PDA closure (n = 11). RESULTS: There were no statistically significant differences between groups A and B when the groups were compared in terms of birth weight, gestational age, respiratory distress syndrome (RDS), necrotizing enterocolitis (NEC), sepsis, intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and pneumothorax. Although the mortality rate was determined to be lower in group B (2 out of 11, 18.1%) than in group A (7 out of 16, 43.7%), no statistically significant difference was found between the two groups. A statistically significant increase was determined in the incidence of kidney function loss in patient group that received Ibuprofen, a medical treatment, in comparison to the patients who had surgery. CONCLUSION: In conclusion, surgery is a safe method to repair PDA in premature LBW infants. Although there is no remarkable difference between surgery and medical treatment, we suggest that a surgical approach may be used as a first choice to repair PDA considering the lower rate of mortality and morbidity and higher rate of closure compared to medical treatment. PMID- 25512702 TI - Acute psychosocial stress-mediated changes in the expression and methylation of perforin in chronic fatigue syndrome. AB - Perforin (PRF1) is essential for immune surveillance and studies report decreased perforin in chronic fatigue syndrome (CFS), an illness potentially associated with stress and/or infection. We hypothesize that stress can influence regulation of PRF1 expression, and that this regulation will differ between CFS and non fatigued (NF) controls. We used the Trier Social Stress Test (TSST) as a standardized acute psychosocial stress, and evaluated its effect on PRF1 expression and methylation in CFS (n = 34) compared with NF (n = 47) participants. During the TSST, natural killer (NK) cells increased significantly in both CFS (P = <0.0001) and NF subjects (P = <0.0001). Unlike previous reports, there was no significant difference in PRF1 expression at baseline or during TSST between CFS and NF. However, whole blood PRF1 expression increased 1.6 fold during the TSST in both CFS (P = 0.0003) and NF (P = <0.0001). Further, the peak response immediately following the TSST was lower in CFS compared with NF (P = 0.04). In addition, at 1.5 hours post TSST, PRF1 expression was elevated in CFS compared with NF (whole blood, P = 0.06; PBMC, P = 0.02). Methylation of seven CpG sites in the methylation sensitive region of the PRF1 promoter ranged from 38%-79% with no significant differences between CFS and NF. Although, the average baseline methylation of all seven CpG sites did not differ between CFS and NF groups, it showed a significant negative correlation with PRF1 expression at all TSST time points in both CFS (r = -0.56, P = <0.0001) and NF (r = -0.38, P = <0.0001). Among participants with high average methylation (>=65%), PRF1 expression was significantly lower in CFS than NF subjects immediately following TSST. These findings suggest methylation could be an important epigenetic determinant of inter-individual differences in PRF1 expression and that the differences in PRF1 expression and methylation between CFS and NF in the acute stress response require further investigation. PMID- 25512703 TI - Epigenetic effect of chronic stress on dopamine signaling and depression. AB - Because of the complex causal factors leading to depression, epigenetics is of considerable interest for the understanding effect of stress in depression. Dopamine is a key neurotransmitter important in many physiological functions, including motor control, mood, and the reward pathway. These factors lead many drugs to target Dopamine receptors in treating depressive disorders. In this review, we try to portray how chronic stress as an epigenetic factor changes the gene regulation pattern by interrupting Dopamine signaling mechanism. PMID- 25512704 TI - Loss of Imprinting of IGF2 Gene in the Chorionic Tissues of Spontaneously Eliminated Human Embryos. AB - Insulin-like growth factor-2 (IGF-2) is a mitogen, growth and differentiation modulator for many cell types. It is mainly expressed during the prenatal development, and its activity strongly depends on the genomic imprinting. Genomic imprinting in the chorionic tissues of spontaneously eliminated human embryos has been studied on the model of 820-AG (Apa1) of the IGF-2 gene locus. Molecular and genetic analysis was performed on the polymorphic 820-AG IGF2 locus in 107 samples of DNA extracted from the chorionic tissues of spontaneously eliminated human embryos within 5-10 weeks of gestation. Presence of AG genotype Apa1 single nucleotide polymorphisms of the IGF-2 was shown to cause more than a 7-fold increase in the risk of embryo elimination. Thus, the loss of genomic imprinting of the IGF-2 gene may be an important cause of the miscarriages in human. PMID- 25512706 TI - DNA demethylation pathways: recent insights. AB - DNA methylation is a major epigenetic regulatory mechanism for gene expression and cell differentiation. Until recently, it was still unclear how unmethylated regions in mammalian genomes are protected from de novo methylation and whether or not active demethylating activity is involved. Even the role of molecules and the mechanisms underlying the processes of active demethylation itself is blurred. Emerging sequencing technologies have led to recent insights into the dynamic distribution of DNA methylation during development and the role of this epigenetic mark within a distinct genome context, such as the promoters, exons, or imprinted control regions. This review summarizes recent insights on the dynamic nature of DNA methylation and demethylation, as well as the mechanisms regulating active DNA demethylation in mammalian cells, which have been fundamental research interests in the field of epigenomics. PMID- 25512707 TI - Changes in methylation patterns of kiss1 and kiss1r gene promoters across puberty. AB - The initiation of mammalian puberty is underpinned by an increase in Kisspeptin (Kiss1) signaling via its receptor (Kiss1r/GPR54) on gonadotropin-releasing hormone (GnRH) neurons. Animals and humans with loss-of-function mutations in Kiss1 or Kiss1r fail to go through puberty. The timing of puberty is dependent on environmental factors, and malleability in puberty timing suggests a mechanism that can translate environmental signals into patterns of Kiss1/Kiss1r gene expression. Epigenetics is a powerful mechanism that can control gene expression in an environment-dependent manner. We investigated whether epigenetic DNA methylation is associated with gene expression changes at puberty. We used bisulfite-PCR-pyrosequencing to define the methylation in the promoters of Kiss1 and Kiss1r before and after puberty in female rats. Both Kiss1 and Kiss1r showed highly significant puberty-specific differential promoter methylation patterns. By identifying key differentially methylated residues associated with puberty, these findings will be important for further studies investigating the control of gene expression across the pubertal transition. PMID- 25512705 TI - Unexplored potentials of epigenetic mechanisms of plants and animals-theoretical considerations. AB - Morphological and functional changes of cells are important for adapting to environmental changes and associated with continuous regulation of gene expressions. Genes are regulated-in part-by epigenetic mechanisms resulting in alternating patterns of gene expressions throughout life. Epigenetic changes responding to the environmental and intercellular signals can turn on/off specific genes, but do not modify the DNA sequence. Most epigenetic mechanisms are evolutionary conserved in eukaryotic organisms, and several homologs of epigenetic factors are present in plants and animals. Moreover, in vitro studies suggest that the plant cytoplasm is able to induce a nuclear reassembly of the animal cell, whereas others suggest that the ooplasm is able to induce condensation of plant chromatin. Here, we provide an overview of the main epigenetic mechanisms regulating gene expression and discuss fundamental epigenetic mechanisms and factors functioning in both plants and animals. Finally, we hypothesize that animal genome can be reprogrammed by epigenetic factors from the plant protoplast. PMID- 25512708 TI - Epigenetics of autoantigens: new opportunities for therapy of autoimmune diseases. AB - The field of epigenetics requires that traditional divisions between scientific disciplines give way to cross-fertilization of concepts and ideas from different areas of investigation. Such is the case with research in autoimmunity. Recent discoveries of stimuli that induce autoimmunity reveal that epigenetic marks of autoantigens are recognized by autoreactive B and T cell receptors. Thus, insights into the initiation of autoimmunity, its prevention and therapy will arise from understanding the biochemistry, cell biology and microbiology of autoantigen epigenetics. Here, we highlight potential benefits from the inhibition of a histone modifying enzyme and the administration of a phosphorylated, spliceosome-derived peptide, in the treatment of autoimmunity. PMID- 25512709 TI - Bioinformatic Dissecting of TP53 Regulation Pathway Underlying Butyrate-induced Histone Modification in Epigenetic Regulation. AB - Butyrate affects cell proliferation, differentiation, and motility. Butyrate inhibits histone deacetylase (HDAC) activities and induces cell-cycle arrest and apoptosis. TP53 is one of the most active upstream regulators discovered by ingenuity pathways analysis (IPA) in our RNA-sequencing data set. TP53 signaling pathway plays key role in many cellular processes. TP53 pathway and their involvement in cellular functions modified by butyrate treatment were scrutinized in this report by data mining the RNA-sequencing data using IPA (Ingenuity System((r))). The TP53 mechanistic pathway targets more than 600 genes. Downstream analysis predicted the activation of the TP53 pathway after butyrate treatment. The data mining also revealed that nine transcription factors are downstream regulators in TP53 signaling pathways. The analysis results also indicated that butyrate not only inhibits the HDAC activities, but also regulates genes encoding the HDAC enzymes through modification of histones and epigenomic landscape. PMID- 25512711 TI - Effect of FTO Gene and Physical Activity Interaction on Trunk Fat Percentage Among the Newfoundland Population. AB - OBJECTIVE: To explore the effect of FTO gene and physical activity interaction on trunk fat percentage. DESIGN AND METHODS: Subjects are 3,004 individuals from Newfoundland and Labrador whose trunk fat percentage and physical activity were recorded, and who were genotyped for 11 single-nucleotide polymorphisms (SNPs) in the FTO gene. Subjects were stratified by gender. Multiple tests and multiple regressions were used to analyze the effects of physical activity, variants of FTO, age, and their interactions on trunk fat percentage. Dietary information and other environmental factors were not considered. RESULTS: Higher levels of physical activity tend to reduce trunk fat percentage in all individuals. Furthermore, in males, rs9939609 and rs1421085 were significant (alpha = 0.05) in explaining central body fat, but no SNPs were significant in females. For highly active males, trunk fat percentage varied significantly between variants of rs9939609 and rs1421085, but there is no significant effect among individuals with low activity. The other SNPs examined were not significant in explaining trunk fat percentage. CONCLUSIONS: Homozygous male carriers of non-obesity risk alleles at rs9939609 and rs1421085 will have significant reduction in central body fat from physical activity in contrast to homozygous males of the obesity risk alleles. The additive effect of these SNPs is found in males with high physical activity only. PMID- 25512710 TI - Use of epigenetic drugs in disease: an overview. AB - Epigenetic changes such as DNA methylation and histone methylation and acetylation alter gene expression at the level of transcription by upregulating, downregulating, or silencing genes completely. Dysregulation of epigenetic events can be pathological, leading to cardiovascular disease, neurological disorders, metabolic disorders, and cancer development. Therefore, identifying drugs that inhibit these epigenetic changes are of great clinical interest. In this review, we summarize the epigenetic events associated with different disorders and diseases including cardiovascular, neurological, and metabolic disorders, and cancer. Knowledge of the specific epigenetic changes associated with these types of diseases facilitates the development of specific inhibitors, which can be used as epigenetic drugs. In this review, we discuss the major classes of epigenetic drugs currently in use, such as DNA methylation inhibiting drugs, bromodomain inhibitors, histone acetyl transferase inhibitors, histone deacetylase inhibitors, protein methyltransferase inhibitors, and histone methylation inhibitors and their role in reversing epigenetic changes and treating disease. PMID- 25512712 TI - Copy Number Variation of TLR-7 Gene and its Association with the Development of Systemic Lupus Erythematosus in Female Patients from Yucatan Mexico. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies against self-antigens, which occurs most often in women between 15 and 40 years of age. The innate immunity is involved in the pathogenesis of SLE through TLR- 7. Genetic factors such as copy number variation (CNV) of target genes may contribute to disease development, but this possible risk has not yet been studied in SLE patients from Yucatan, Mexico. The CNV of TLR-7 gene was determined by quantitative polymerase chain reaction assay using TaqMan probes in 80 SLE women and 150 control subjects. The results showed that 10% of SLE patients exhibited more than two copies of TLR-7 gene, whereas no mRNA overexpression was detected. These data suggested that increased CNV of the TLR-7 gene in Yucatan SLE women can be a risk factor for this disease. PMID- 25512714 TI - Idiopathic thrombocytopenia with iron deficiency anemia. AB - We report a rare case of anemia and thrombocytopenia as a result of uterine fibroid and adenomyosis, complicated by immune thrombocytopenic purpura (ITP). Symptoms were presented as menorrhagia and metrorrhagia in a 34-year-old African American woman, who was later treated with blood and platelet transfusion and iron therapy with steroids. Uterine fibroids are commonly found to cause hematologic disturbances such as anemia and reactive thrombocytosis and, less commonly, thrombocytopenia. Moreover, such hematologic disturbances are secondary to heavy and irregular uterine bleeding, which is typically presented. A previous uterine fibroid diagnosis was made and reconfirmed by pelvic and transvaginal ultrasound to exclude other locoregional pathologies. ITP was suggested by Coombs test and several other serologies, leading to confirmation via bone marrow biopsy. In a previous case study, we reported positive responses in hemotecrit and platelet count after the introduction of iron therapy to an iron-depleted middle-aged female presenting severe anemia and thrombocytopenia.1. PMID- 25512713 TI - Maternal stress, preterm birth, and DNA methylation at imprint regulatory sequences in humans. AB - In infants exposed to maternal stress in utero, phenotypic plasticity through epigenetic events may mechanistically explain increased risk of preterm birth (PTB), which confers increased risk for neurodevelopmental disorders, cardiovascular disease, and cancers in adulthood. We examined associations between prenatal maternal stress and PTB, evaluating the role of DNA methylation at imprint regulatory regions. We enrolled women from prenatal clinics in Durham, NC. Stress was measured in 537 women at 12 weeks of gestation using the Perceived Stress Scale. DNA methylation at differentially methylated regions (DMRs) associated with H19, IGF2, MEG3, MEST, SGCE/PEG10, PEG3, NNAT, and PLAGL1 was measured from peripheral and cord blood using bisulfite pyrosequencing in a sub sample of 79 mother-infant pairs. We examined associations between PTB and stress and evaluated differences in DNA methylation at each DMR by stress. Maternal stress was not associated with PTB (OR = 0.98; 95% CI, 0.40-2.40; P = 0.96), after adjustment for maternal body mass index (BMI), income, and raised blood pressure. However, elevated stress was associated with higher infant DNA methylation at the MEST DMR (2.8% difference, P < 0.01) after adjusting for PTB. Maternal stress may be associated with epigenetic changes at MEST, a gene relevant to maternal care and obesity. Reduced prenatal stress may support the epigenomic profile of a healthy infant. PMID- 25512716 TI - Nonsteroidal Anti-inflammatory Drug Induced Thrombotic Thrombocytopenic Purpura. AB - A 21-year-old male presented to the emergency department after a 5-day history of recurrent vomiting and decreased urine output. History revealed ingestion of ibuprofen. During the diagnostic workup, the following was identified: white blood cell count 13.4 (*10(3)/mcL), hemoglobin 11.9 (*10(6)/mcL) with an MCV of 73 fL, hematocrit 34% and platelets were 31,000/mcL, sodium of 130 mmol/L, potassium of 5.1 mmol/L, chloride of 83 mmol/L, bicarbonate of 21 mmol/L, blood urea nitrogen of 184 mg/dL and creatinine of 19.1 mg/dL. He was later diagnosed with thrombotic thrombocytopenic purpura (TTP) based on the fact that he presented with most components of the TTP pentad (except for fever), which included altered mental status, acute kidney injury, thrombocytopenia, and evidence of red cell fragmentation and his ADAMTS13 level was found to be less than 10% prior to therapy. The patient then received plasma exchange, oral corticosteroids, and hemodialysis, which led to a full recovery of platelet count and renal function. PMID- 25512715 TI - Hemoglobinuria misidentified as hematuria: review of discolored urine and paroxysmal nocturnal hemoglobinuria. AB - Discolored urine is a common reason for office visits to a primary care physician and urology referral. Early differentiation of the type or cause of discolored urine is necessary for accurate diagnosis and prompt management. Paroxysmal nocturnal hemoglobinuria is a clonal disorder caused by acquired somatic mutations in the PIG-A gene on the X- chromosome of hemopoietic stem cells and leads to deficiency of surface membrane anchor proteins. The deficiency of these proteins leads to an increased risk of hemolysis of erythrocytes and structural damage of platelets, resulting in a clinical syndrome characterized by complement mediated intravascular hemolytic anemia, bone marrow failure, and venous thrombosis. Patients with this clinical syndrome present with paroxysms of hemolysis, causing hemoglobinuria manifesting as discolored urine. This can be easily confused with other common causes of discolored urine and result in extensive urologic work-up. Three commonly confused entities of discolored urine include hematuria, hemoglobinuria, and myoglobinuria. Specific characteristics in a dipstick test or urinalysis can guide differentiation of these three causes of discolored urine. This article begins with a case summary of a woman presenting with cranberry-colored urine and a final delayed diagnosis of paryxysmal nocturnal hemoglobinuria. Her hemoglobinuria was misdiagnosed as hematuria, leading to extensive urologic work-up. The article also gives an overview of the approach to diagnosing and treating discolored urine. PMID- 25512717 TI - Clinical Characteristics and Risk of Relapse for Patients with Stage I-II Diffuse Large B-cell Lymphoma Treated in First Line with Immunochemotherapy. AB - Diffuse large b-cell lymphoma (DLBCL) is an aggressive and potentially curable lymphoma that presents itself as stage I-II in 30% of all cases. It is known that in these localized stages, 15-20% of patients treated without rituximab eventually relapse, but less data exist regarding rituximab era. We have analyzed clinico-pathological features and risk of relapse in 98 patients with I-II stage DLBCL in complete response (CR) or unconfirmed CR (CRu) after first-line treatment consisting of immunochemotherapy. Twelve patients (12.2%) eventually relapsed. Late relapse, more than two years after diagnosis, occurred in three patients, and early relapse, less than two years after diagnosis, was documented in nine patients. Median time from diagnosis to relapse was 0.61 years for patients with early relapse and 3.66 years for patients with late relapse. The second CR rate obtained was similar in the late and in early relapsing patients, being 33% versus 44% (p = 0.072), respectively. Three-year overall survival (OS) was 22% for early relapsing patients and 33% for late relapsing patients (p = 0.65). In conclusion, patients who are diagnosed with stage I-II DLBCL and achieve a CR/CRu with first line immunochemotherapy have a good prognosis. However, a proportion of patients relapse, and this is less frequent in patients treated with first line with immunochemotherapy. These patients have a poor prognosis. PMID- 25512718 TI - Risk factors for thrombosis in an african population. AB - SUMMARY: Little is known about the biological, epidemiological, and clinical risk factors for thrombosis and venous thromboembolism (VTE) among Black Africans. We undertook a study of the prevalence of VTE risk factors for thrombosis in a Senegalese population. A three-year cross-sectional and case-control study involving 105 cases and 200 controls was conducted in various hospitals in Dakar (Senegal). Our results demonstrate that oral contraception, immobilization by casts, surgery, and blood group were significantly associated with VTE occurrence. Additionally, 16 cases and 2 controls had protein S (PS) values of less than 48.4% (M-2SD), exhibiting a highly significant difference (P < 1 * 10( 4)). The number of cases with a low protein C (PC) level was significantly higher than the respective number of controls. Using logistic regression methods, we established a correlation between significantly associated variables and deep venous thrombosis (DVT) occurrence. Age, obesity, sickle cell disease, and PC deficiency were not significantly associated with thrombosis. In contrast, gender, PS deficiency, varicose veins, surgery, non-O blood type, and the presence of antiphospholipid antibodies were significantly and independently associated with DVT. These findings are extremely useful for clinical management of patients suffering from DVT and can help to reduce the high recurrence rate observed in our study. PMID- 25512720 TI - Effects of long-term repeated topical fluoride applications and adhesion promoter on shear bond strengths of orthodontic brackets. AB - OBJECTIVE: The purpose of this study was to assess the effects of long-term repeated topical application of fluoride before bonding and an adhesion promoter on the bond strength of orthodontic brackets. MATERIALS AND METHODS: A total of 76 bovine incisors were collected and divided equally into four groups. In group 1, the brackets were bonded without topical fluoride application or adhesion promoter. In group 2, before bonding, the adhesion promoter was applied to nonfluoridated enamel. In group 3, the brackets were bonded without the application of the adhesion promoter to enamel, which had undergone long-term repeated topical fluoride treatments. Teeth in group 4 received the long-term repeated topical applications of fluoride, and the brackets were bonded using the adhesion promoter. All the brackets were bonded using BeautyOrtho Bond self etching adhesive. The shear bond strength was measured and the bond failure modes were evaluated with the use of the adhesive remnant index (ARI) after debonding. RESULTS: The mean shear bond strength was significantly lower in group 3 than in groups 1, 2, and 4, and there were no significant differences between the groups except for group 3. There were significant differences in the distribution of ARI scores between groups 2 and 3, and between groups 3 and 4. CONCLUSIONS: The adhesion promoter can recover the bond strength reduced by the long-term repeated topical applications of fluoride to the prefluoridation level and had a significantly great amount of adhesives left on either fluoridated or nonfluoridated enamel. PMID- 25512721 TI - Evaluation of the marginal fit of full ceramic crowns by the microcomputed tomography (micro-CT) technique. AB - OBJECTIVE: To evaluate the marginal gap (MG) and absolute marginal discrepancy (MD) of full ceramic crowns with two finish line designs, shoulder and chamfer, using microcomputed tomography (micro-CT) before and after cementation. MATERIALS AND METHODS: Sixty extracted human maxillary premolar teeth were divided into two groups based on the finish line design: Group I: 90 degrees shoulder and Group II: 135 degrees chamfer. The specimens were further grouped based on the type of full ceramic crown they received: Group A: Feldspathic Cerec inLab ceramic system, Group B: Cerec inLab aluminum oxide ceramic system and Group C: Lithium disilicate press ceramic system. Before cementation, five crowns from each group were scanned using micro-CT in two sections, sagittal and coronal, to determine the MG and MD values for four regions of the crown (sagittal buccal, sagittal lingual, coronal mesial and coronal distal). After cementation and thermal cycling, the scanning was repeated. Measurements were obtained from 10 points for each region, 80 points totally, to evaluate the MG and MD values. Files were processed using NRecon and CTAn software. Results were statistically analyzed using one- and two-way ANOVA and Tukey HSD tests (P = 0.05). RESULTS: Full ceramic systems showed clinically acceptable marginal adaptation values. The Feldspathic Cerec inLab ceramic system generally presented the lowest variance, except in the MG values of the coronal mesial region. The MG and MD values of all ceramics increased significantly after cementation, except in the shoulder preparation design (sagittal buccal region) for MG and in the chamfer preparation design (sagittal lingual region) for MD values. CONCLUSIONS: Full-ceramic crowns showed clinically acceptable marginal adaptation values. The Feldspathic Cerec inLab ceramic system (Vitablocs Mark II) generally presented the lowest variance when compared with the other ceramics, except for the MG values on the mesial surface of the coronal section. PMID- 25512722 TI - Fracture resistance of cementum-extended composite fillings in severely damaged deciduous incisors: An in vitro study. AB - OBJECTIVE: The aim of this study was to comparatively assess the fracture resistance of the cementum-extended and conventional composite fillings with or without intracanal composite posts in severely damaged deciduous incisors. MATERIALS AND METHODS: This in vitro study was performed on 60 extracted deciduous maxillary incisors that were randomly divided into four groups: Group 1: Composite filling (CF); Group 2: Composite filling with composite posts (CF + CP); Group 3: Composite filling extended 0.5 mm to cementum (ceCF); Group 4: Composite filling extended 0.5 mm to cementum with composite posts (ceCF + CP). The fracture resistance was assessed by exerting a progressively increasing load with a cross-head speed of 0.5 mm/min in a Universal Testing Machine. STATISTICAL ANALYSIS: Data were analyzed by SPSS-18 using one-way analysis of variance at alpha < 0.05. RESULTS: The mean fracture resistance (MFR) values of the experimental groups were 410.57 +/- 139.44 N, 564.44 +/- 92.63 N, 507.5 +/- 76.37 N and 601.08 +/- 96.04 N. A significant difference was found between the MFR of Groups 1 and 2, Groups 1 and 4 and Groups 3 and 4 (P < 0.05). CONCLUSION: A superior outcome was achieved by intracanal composite posts in both conventional and cementum-extended composite fillings. PMID- 25512719 TI - Ribosomopathies: mechanisms of disease. AB - Ribosomopathies are diseases caused by alterations in the structure or function of ribosomal components. Progress in our understanding of the role of the ribosome in translational and transcriptional regulation has clarified the mechanisms of the ribosomopathies and the relationship between ribosomal dysfunction and other diseases, especially cancer. This review aims to discuss these topics with updated information. PMID- 25512723 TI - Comparative evaluation of microleakage of nano-filled resin-modified glass ionomer: An in vitro study. AB - OBJECTIVE: This in vitro study evaluated the microleakage of a nano-filled resin modified glass ionomer and a high viscosity glass-ionomer restorations in class V cavities. MATERIALS AND METHODS: Thirty-two class V cavities prepared on the buccal and lingual surfaces of 16 sound, third molar teeth were randomly assigned into two groups and restored by one of the glass ionomer material; Group A: A high viscosity (Ketac Molar, 3M ESPE) Group B: A nano-filled resin-modified (Ketac N100, 3M ESPE) glass ionomer. One clinician prepared all the cavities. The materials were used according to the manufacturers' recommendations. The restored teeth were then stored in distilled water at 37 degrees C for 24 h, thermocycled at 5-55 degrees C for 1000 cycles. The specimens were immersed in aqueous solution of Indian ink dye for 48 h at room temperature. They were embedded in resin polyester and sectioned longitudinally in a buccolingual direction. Microleakage was assessed according to the depth of dye penetration along the restoration. The extent of dye penetration at the occlusal and gingival margins was assessed using a stereo microscope. Randomly selected samples from each group were prepared for scanning electron microscope evaluation. The data were statistically analyzed with Friedman and Wilcoxon signed ranks tests. RESULTS: There were statistically significant differences between the microleakage scores of the two groups for both occlusal and gingival scores (P = 0.001). Occlusal and gingival scores for high viscosity glass ionomer (P = 0.024) and nanoionomer (P = 0.021) using Wilcoxon signed ranks tests showed statistically significant differences. High viscosity glass ionomer showed significantly less microleakage compared to the nano-filled resin-modified glass-ionomer (RMGIs) at occlusal margin (P = 0.001). No significant differences were found between the groups at gingival margin (P = 0.0317). CONCLUSION: Within the limitations of this in vitro study, nano-filled RMGIs restorations did not perform better than high viscosity glass ionomer in class V cavities in terms of microleakage assessment. PMID- 25512724 TI - Nanoclay addition to a conventional glass ionomer cements: Influence on physical properties. AB - OBJECTIVE: The objective of the present study is to investigate the reinforcement effect of polymer-grade montmorillonite (PGN nanoclay) on physical properties of glass ionomer cement (GIC). MATERIALS AND METHODS: The PGN nanoclay was dispersed in the liquid portion of GIC (HiFi, Advanced Healthcare, Kent, UK) at 1%, 2% and 4% (w/w). Fourier-transform infrared (FTIR) spectroscopy was used to quantify the polymer liquid of GICs after dispersion of nanoclay. The molecular weight (Mw) of HiFi liquid was determined by gel permeation chromatography. The compressive strength (CS), diametral-tensile strength, flexural strength (FS) and flexural modulus (Ef) of cements (n = 20) were measured after storage for 1 day, 1 week and 1 month. Fractured surface was analyzed by scanning electron microscopy. The working and setting time (WT and ST) of cements was measured by a modified Wilson's rheometer. RESULTS: The FTIR results showed a new peak at 1041 cm(-1) which increased in intensity with an increase in the nanoclay content and was related to the Si-O stretching mode in PGN nanoclay. The Mw of poly (acrylic acid) used to form cement was in the range of 53,000 g/mol. The nanoclay reinforced GICs containing <2% nanoclays exhibited higher CS and FS. The Ef cement with 1% nanoclays was significantly higher. The WT and ST of 1% nanoclay reinforced cement were similar to the control cement but were reduced with 2% and 4% nanoclay addition. CONCLUSION: The dispersion of nanoclays in GICs was achieved, and GIC containing 2 wt% nanoclay is a promising restorative materials with improved physical properties. PMID- 25512725 TI - Rapid tissue dissolution efficiency of electrically-activated sodium hypochlorite on bovine muscle. AB - OBJECTIVE: Sodium hypochlorite (NaOCl) is a common antimicrobial and tissue dissolving irrigant. The aim of this in vitro study is to evaluate and compare dissolution capacities of sodium hypochlorite solutions after electrically activation (E-NaOCl) on bovine muscle specimens at various time periods and concentrations. MATERIALS AND METHODS: Three sodium hypochlorite solutions of 1.25%, 2.5%, and 5% were tested at 3-min. and 5-min. with and without activation by electrically. Distilled water and NaOCl solutions without electrically activation were used as controls. Pieces of bovine muscle tissue (34 +/- 2 mg) were placed in 10 mL of each solution at room temperature. In the group of E NaOCl, electrically activation was performed through the potentiostat. The tissue specimens were weighed before and after treatment, and the percentage of weight loss was calculated. RESULTS: Weight loss of the tissue increased with the concentration of E-NaOCl and NaOCl. Higher concentration and electrically activation considerably enhanced the efficacy of sodium hypochlorite. The effect of electrically activation on tissue dissolution was much greater than that of same concentrations in the groups of NaOCl (P < 0.001). Tissue weight loss was significantly higher in 2.5% and 5% E-NaOCl at 3 min. than in 2.5% and 5% NaOCl at 5 min. (P < 0.05). There were not any significant differences between the 2.5% E-NaOCl and 5% NaOCl at 5 min. (P > 0.05). CONCLUSION: Electrically activation can improve the tissue-dissolving effectiveness of sodium hypochlorite. PMID- 25512726 TI - Antimicrobial effect of ozonated water, sodium hypochlorite and chlorhexidine gluconate in primary molar root canals. AB - OBJECTIVE: The aim was to determine the antimicrobial effect of ozonated water, ozonated water with ultrasonication, sodium hypochloride and chlorhexidine (CHX) in human primary root canals contaminated by Enterococcus faecalis (E. faecalis). MATERIALS AND METHODS: Fifty-eight extracted human primary molar teeth were used. Crowns were cut off using a diamond saw under water-cooling. One hundred roots were obtained and mechanically prepared. The roots were then sterilized by autoclaving in water for 15 min at 121 degrees C. All samples were contaminated with E. faecalis for 24 h and the root canals were randomly divided into five groups (n = 20). Group I: 25 mg/L of Ozonated water (O3aq), Group II: 25 mg/L of O3aq with ultrasonication, Group III: 2.5% Sodium hypochloride (NaOCl), Group IV: 2% CHX and Group V: Positive control. The canal of each specimen was irrigated for 4 min and positive control was untreated. All root canals were agitated with sterile saline solution. The saline solution was collected from canals with sterile paper points. For each specimen, the paper points were transposed to eppendorf vials containing 2 ml of brain heart infusion. According to bacterial proliferation, the mean values of optical density were achieved by ELISA (Biotek EL *800, Absorbance Microplate Reader, ABD) and the data were analyzed. RESULTS: NaOCI, CHX and two types of O3aq were found statistically different than positive control group. NaOCI irrigation was found significantly most effective. CONCLUSIONS: NaOCl, CHX and O3aq applications provide antibacterial effect in vitro conditions in primary root canals. PMID- 25512727 TI - Correlation between International Normalized Ratio values and sufficiency of two different local hemostatic measures in anticoagulated patients. AB - OBJECTIVES: The management of patients receiving oral anticoagulant therapy (OAT) undergoing minor oral surgeries is controversial. This study was designed to evaluate the correlation between International Normalized Ratio (INR) values and the sufficiency of two different local hemostatic measures in controlling postextraction bleeding in anticoagulated patients. MATERIALS AND METHODS: One hundred and sixty patients receiving Warfarin OAT were included in this study. Patients were selected so that 80 patients have INR values of <=2, whereas the remaining patients have the INR values ranging from 2 to 3. Forty patients were then randomly selected from each category to form two equal groups. Forty-five patients who had never been on OAT were selected as a negative control group (group 1). Failure to achieve hemostasis using a pressure pack was managed using either tranexamic acid (group 2) or Ankaferd Blood Stopper (ABS) (group 3). RESULTS: The INR values of patients included in group 2 and 3 ranged from 1.5 to 3, with a mean of 2.2. No significant difference was recorded between the use of either tranexamic acid or ABS in achieving hemostasis in anticoagulated patients with INR values ranging between 2 and 3 (P = 0.93). CONCLUSION: Based on our findings, ABS is a hemostatic agent of good efficacy. The effect of ABS in controlling post-extraction bleeding in anticoagulated patients with INR values <=3 is comparable to tranexamic acid with no evidence to support the superiority of tranexamic acid over ABS. PMID- 25512728 TI - Hand hygiene practices in a dental teaching center: Measures and improve. AB - OBJECTIVE: To measure the compliance and the quality of HH practices and the knowledge of the healthcare workers' of the university dental care center. MATERIALS AND METHODS: All educators and students present were eligible for inclusion in the study. Each healthcare professional was observed in care situation over a period of 30 min. The knowledge, attitudes and opinions were collected through a questionnaire. RESULTS: Number of healthcare professionals included was 190 (64.4%). Study group consisted of 151 students (74.4%) and 39 educators (42.4%). Out of a total number of expected disinfection of hands (993), 396 were made (39.9%). Educators had a higher compliance rates than students (63.7-35.8%, P = 10(-9)). Large differences were found between care situations (compliance higher before the first care to a patient and lower during installation of patient in dental X-ray area or at exit of dental X-ray area). Concerning hand rubbing (HR), 36.6% were performed correctly, and the main error was all steps of HR not observed (54.4%), and shorter duration (46.7%). The observance and the quality of HR were associated with better knowledge. CONCLUSION: This data suggests areas of improvement: (1) A comprehensive intervention including care organization/clinic ergonomics/planning/anticipation of materials needed for care; (2) the development of HH education program should include the educators, since the behavior of students is strongly influenced and formed by their mentor's attitude and behaviors. PMID- 25512729 TI - An in-vitro evaluation of mechanical and esthetic properties of orthodontic sealants. AB - OBJECTIVE: To evaluate mechanical and esthetic Properties of two commercially available orthodontic sealants: Opal((r))Seal (OS) and L.E.D. Pro Seal (PS). MATERIALS AND METHODS: Discs of each sealant were prepared to test the following properties: Micro hardness, wear resistance and color stability. Samples were randomly selected after the wear test for SEM imaging to analyze surface morphology. RESULTS: OS was significantly harder than PS (P < 0.001). PS was significantly more wear resistant than OS (P < 0.05). PS showed a greater ?E*ab (increased staining) when placed in wine or coffee showing a significant difference (P < 0.05). SEM showed particle size, shape and distribution were different for PS and OS reflecting the pattern seen on wear surfaces. CONCLUSION: Both orthodontic sealants are beneficial for protecting enamel. However with better wear properties PS was superior in resisting mechanical stresses. OS was more color stable. PMID- 25512730 TI - Effectiveness of teaching International Caries Detection and Assessment System II and its e-learning program to freshman dental students on occlusal caries detection. AB - OBJECTIVE: To assess the feasibility of teaching International Caries Detection and Assessment System (ICDAS) II and its e-learning program as tools for occlusal caries detection to freshmen dental students in comparison to dental graduates with 2 years of experience. MATERIALS AND METHODS: Eighty-four freshmen and 32 dental graduates examined occlusal surfaces of molars/premolars (n = 72) after a lecture and a hands-on workshop. The same procedure was repeated after 1 month following the training with ICDAS II e-learning program. Validation of ICDAS II codes was done histologically. Intra- and inter-examiner reproducibility of ICDAS II severity scores were assessed before and after e-learning using (Fleiss's kappa). RESULTS: The kappa values showed inter-examiner reproducibility ranged from 0.53 (ICDAS II code cut off >= 1) to 0.70 (ICDAS II code cut off >= 3) by undergraduates and 0.69 (ICDAS II code cut off >= 1) to 0.95 (ICDAS II code cut off >= 3) by graduates. The inter-examiner reproducibility ranged from 0.64 (ICDAS II code cut off >= 1) to 0.89 (ICDAS II code cut off >= 3). No statistically significant difference was found between both groups in intra examiner agreements for assessing ICDAS II codes. A high statistically significant difference (P <= 0.01) in correct identification of codes 1, 2, and 4 from before to after e-learning were observed in both groups. The bias indices for the undergraduate group were higher than those of the graduate group. CONCLUSIONS: Early exposure of students to ICDAS II is a valuable method of teaching caries detection and its e-learning program significantly improves their caries diagnostic skills. PMID- 25512731 TI - Shear bond strength of novel calcium aluminate-based cement (EndoBinder) to root dentine. AB - OBJECTIVE: To evaluate the shear bond strength of a novel calcium aluminate-based cement, EndoBinder (EB), to dentine in comparison with Grey and White Mineral Trioxide Aggregate (MTA). MATERIALS AND METHODS: Root canal hemi-sections obtained from 30 extracted molar teeth were embedded in self-polymerized acrylic resin and were grounded wet in order to obtain a flat dentine surface. Next, the roots were randomly assigned into three groups (n = 10), according to the cement used, as follows: EB: EndoBinder; WMTA: White MTA and GMTA: Grey MTA. The shear bond strength test was performed using a Universal Testing Machine (0.5 mm/min) and the data were submitted to statistical analysis (1-way ANOVA and Tukey tests, P < 0.05). RESULTS: EB presented the highest shear bond strength values; however, there was no statistically significant difference in comparison with GMTA (P > 0.05). WMTA presented the lowest mean values, which were significant in comparison with EB (P < 0.05). CONCLUSIONS: The novel calcium aluminate-based cement presented higher shear bond strength than WMTA, and should be considered as a promising alternative in endodontic therapy. PMID- 25512732 TI - Quantitative evaluation of apically extruded debris during root canal instrumentation with ProTaper Universal, ProTaper Next, WaveOne, and self adjusting file systems. AB - OBJECTIVES: The aim of this study was to compare the amount of apically extruded debris during preparation with ProTaper Universal (Dentsply Maillefer, Ballaigues, Switzerland), ProTaper Next (Dentsply Maillefer), a reciprocating single-file (WaveOne; VDW GmbH, Munich, Germany), and a self-adjusting file (SAF; ReDent Nova, Ra'anna, Israel). MATERIALS AND METHODS: Fifty-six intact mandibular premolar teeth were randomly assigned to four groups. The root canals were prepared according to the manufacturers' instructions using the ProTaper Universal, ProTaper Next, WaveOne, and SAF. Apically extruded debris was collected in preweighted Eppendorf tubes during instrumentation. The net weight of the apically extruded debris was determined by subtracting the preweights and postweights of the tubes. The data were statistically analyzed using the one-way analysis of variance and the least significant difference tests at a significance level of P < 0.05. RESULTS: A measurable amount of debris was apically extruded in all groups, and the amounts of debris extrusion in the groups were statistically significant (P < 0.001). The ProTaper Next and WaveOne groups resulted in less debris extrusion than the ProTaper Universal group (P < 0.05), and the SAF group resulted in the least debris extrusion. CONCLUSIONS: Within the limitations of the present study, it can be concluded that all systems extruded debris beyond the apical foramen. PMID- 25512733 TI - Comparative evaluation of photodynamic therapy using LASER or light emitting diode on cariogenic bacteria: An in vitro study. AB - OBJECTIVE: The aim of this study was to evaluate in vitro the effect of photodynamic therapy (PDT) using LASER or light emitting diode (LED) on cariogenic bacteria (Streptococcus mutans [SM] and Lactobacillus casei [LC]) in bovine dentin. MATERIALS AND METHODS: Twenty five fragments of dentin were contaminated with SM and LC strands and divided into five experimental groups according to the therapy they received (n = 5): C - control (no treatment), SCLED - no dye/LED application (94 J/cm(2)), SCLASER - no dye/LASER application (94 J/cm(2)), CCLED - dye/LED application (94 J/cm(2)) and CCLASER - dye/LASER application (94 J/cm(2)). The dye used was methylene blue at 10 mM. Dentin scrapes were harvested from each fragment and prepared for counts of colony forming units (CFU)/mL. The data were analyzed using Kruskal-Wallis, followed by Student-Newman-Keuls (alpha =0.05). RESULTS: Regarding SM, groups CCLASER and CCLED showed a significant reduction in CFU/mL, which was statistically superior to the SCLASER, SCLED and C groups. Regarding LC, the groups CCLASER and CCLED caused a significant reduction in CFU/mL when compared with SCLASER, which showed intermediate values. SCLED and C had a lesser effect on reducing CFU/mL, where the former showed values similar to those of SCLASER. CONCLUSIONS: In conclusion, PDT combined with LASER or LED and methylene blue had a significant antimicrobial effect on cariogenic bacteria in the dentin. PMID- 25512734 TI - Geometric analysis of root canals prepared by single twisted file in three different operation modes. AB - OBJECTIVE: The aim of this study was to evaluate and compare the effects of a single twisted file (TF) instrument in three different operation modes on the preparation of curved root canals in human molars and to explore a new possible method in canal shaping in the clinic setting. MATERIALS AND METHODS: A total of 105 selected root canals with an angle of curvature ranging from 20 degrees to 35 degrees were divided into the following three groups with 35 samples each according to the different operation mode in canal preparation: "continuous rotation-500" (CR, 500 rpm), reciprocating movement-300 (RM-300 rpm) and CR-300 rpm. Root canals were prepared by single file (a size 25/0.06 TF). The pre- and post-instrumented images of the sections were scanned using a cone-beam computed tomography scanner to measure the root transportation and centering ratio. The data were evaluated at 1.5 mm, 3.0 mm and 6.0 mm positions from the apex. The significance level was set at P < 0.05. RESULTS: The results showed a statistically significant difference in root transportation that was only found in cross-sections 3.0 mm from the anatomic apex between group "CR-500" and group "CR-300." In addition, a significant difference in centering ratio was found between group "RM-300" and group "CR-300." There was no significant difference in the two indices among the three groups at cross-sections 1.5 mm and 6 mm from the apex. CONCLUSIONS: Under the three conditions of this study, the continuous rotation mode has better shaping ability in root canal preparation than the RM mode when used with a TF single file (size 25/0.06). PMID- 25512735 TI - The use of traditional and novel techniques to determine the hardness and indentation properties of immature radicular dentin treated with antibiotic medicaments followed by ethylenediaminetetraacetic acid. AB - OBJECTIVE: The objective was to investigate the effect of intracanal antibiotic medicaments followed by ethylenediaminetetraacetic acid (EDTA) on the indentation properties and hardness of radicular dentin using a BioDent reference point indenter and a traditional microhardness technique, respectively. MATERIALS AND METHODS: Specimens with intact root canal dentin surfaces and polished radicular dentin specimens were obtained from immature human premolars. Each type of specimen was randomly assigned (n = 10 per group) and treated with either double antibiotic paste (DAP) for 4-week followed by EDTA for 5 min, triple antibiotic paste (TAP) for 4-week followed by EDTA for 5 min, EDTA for 5 min or Hank's balanced salt solution (control). The BioDent reference point indentor and Vickers microhardness tester were used to measure the indentation properties of root canal surfaces and the hardness of polished dentin specimens, respectively. One-way ANOVA followed by Fisher's protected least significant differences were used for statistical analyses. RESULTS: Both types of radicular dentin treated with antibiotic pastes and/or EDTA had a significant increase in the majority of indentation properties and a significant reduction in hardness compared to the untreated dentin. Furthermore, treatment of dentin with antibiotic pastes and EDTA caused significant increases in indentation properties and a significant reduction in hardness compared to EDTA-treated dentin. However, the RPI technique was not able to significantly differentiate between DAP + EDTA and TAP + EDTA treated dentin. CONCLUSION: Dentin treated with antibiotic medicaments followed by EDTA had a significant increase the indentation properties and significantly reduction in hardness of radicular dentin. PMID- 25512736 TI - Identification of a novel heterozygous truncation mutation in exon 1 of ARHGAP29 in an Indian subject with nonsyndromic cleft lip with cleft palate. AB - OBJECTIVE: Mutations in exon 1 of ARHGAP29, a RhoA specific GTPase have been identified in North American and Filipino subjects with nonsyndromic cleft palate and cleft lip with or without cleft palate. Since the genetic status of ARHGAP29 in Indian subjects with nonsyndromic oral clefts is not known, we designed the present study to investigate the occurrence of the above mutations in them. MATERIALS AND METHODS: Total genomic DNA extracted from peripheral blood of 60 subjects with nonsyndromic cleft palate and cleft lip with or without cleft palate, and equal number of control healthy subjects were amplified with primers flanking exon 1 of ARHGAP29 gene and subjected to direct sequencing. RESULTS: Sequencing analysis identified a nonsense mutation in exon 1 of ARHGAP29 that caused substitution of lysine to stop codon at codon position 32 in a subject with nonsyndromic cleft lip with cleft palate. The mutation, however, occurred in heterozygous condition. None of the other subjects carried mutation in this region. CONCLUSION: The study has thus identified a rare but novel truncation mutation in ARHGAP29 gene for the first time in nonsyndromic oral clefts. PMID- 25512737 TI - Effect of sodium hypochlorite and peracetic acid on the surface roughness of acrylic resin polymerized by heated water for short and long cycles. AB - OBJECTIVE: To evaluate the surface roughness of acrylic resin submitted to chemical disinfection via 1% sodium hypochlorite (NaClO) or 1% peracetic acid (C2H4O3). MATERIALS AND METHODS: The disc-shaped resin specimens (30 mm diameter *4 mm height) were polymerized by heated water using two cycles (short cycle: 1 h at 74 degrees C and 30 min at 100 degrees C; conventional long cycle: 9 h at 74 degrees C). The release of substances by these specimens in water solution was also quantified. Specimens were fabricated, divided into four groups (n = 10) depending on the polymerization time and disinfectant. After polishing, the specimens were stored in distilled deionized water. Specimens were immersed in 1% NaClO or 1% C2H4O3 for 30 min, and then were immersed in distilled deionized water for 20 min. The release of C2H4O3 and NaClO was measured via visual colorimetric analysis. Roughness was measured before and after disinfection. Roughness data were subjected to two-way ANOVA and Tukey's test. RESULTS: There was no interaction between polymerization time and disinfectant in influencing the average surface roughness (Ra, P = 0.957). Considering these factors independently, there were significant differences between short and conventional long cycles (P = 0.012), but no significant difference between the disinfectants hypochlorite and C2H4O3 (P = 0.366). Visual colorimetric analysis did not detect release of substances. CONCLUSION: It was concluded that there was the difference in surface roughness between short and conventional long cycles, and disinfection at acrylic resins polymerized by heated water using a short cycle modified the properties of roughness. PMID- 25512738 TI - Spectrophotometric and computerized evaluation of tooth bleaching employing 10 different home-bleaching procedures: In-vitro study. AB - OBJECTIVE: The aim of this in-vitro study was to evaluate the efficacy of bleaching products, determine the applicability and validation of the measurement methods. MATERIALS AND METHODS: Freshly extracted 110 human incisor teeth were stained with whole blood and hemolysate solution prior to the application of 10 different home-bleaching products. Spectrophotometric measurements of the tooth shades were performed for each specimen before and after bleaching at the 1(st), 3(rd), 7(th), and 14 days. Differences in lightness (Deltal), chroma (Deltac), hue (Deltah) values and shade changes were measured to evaluate process. Computerized digital imaging analyses to determine the color changes were performed with Photoshop CS4 software (Adobe, San Jose, CA, USA). Statistical analyses were performed with analysis of variance, Scheffe and Tukey tests. RESULTS: In all of the test groups regardless of the material used, a significant increase in lightness and hue, and decrease of chroma were observed, as compared to the control group. After recommended bleaching applications, Deltal and Deltah values respectively increased in group Zaris White and Brite (ZWB) and group Pola Night and Deltac values showed significant decrease in groups ZWB and Rembrandt REM3 (P < 0.05). At the end of the procedure both spectrophotometric and digital imaging analysis showed ZWB was the most effective product among the others while Yotuel and Happy Smile were the least (P < 0.05). CONCLUSIONS: Home-bleaching systems showed slower but almost permanent bleaching effect likewise office-based methods. Both software and spectrophotometric analyses have advantages such as evaluating the results objectively and numerically, also treatment outcomes could be preserved. PMID- 25512739 TI - Clinical findings and long-term managements of patients with amelogenesis imperfecta. AB - The aim of this clinical case series is to present a diagnosis and different treatment methods of patients in different ages with amelogenesis imperfecta (AI) as well as further treatments during a 3-6 years follow-up period. A number of 31 patients (16 female, 15 male with a mean age of 10.77 +/- 2.65 years) with AI have been examined for the study group between 2007 and 2010 years. A detailed anamnesis was recorded, followed by a clinical and radiological assessment of oral health. The types of AI classified for each patient according to clinical and radiographic evaluation. The main complaints of patients, presence of dental caries and dental anomalies were noted. Necessary treatments had been planned for the individual cases of AI. A number of 19 patients had hypoplastic (HP) form, and 10 patients showed hypomaturation (HM) form of AI, while one patient showed hypocalcified form of AI and one patient had HM-HP form with taurodontism. Main complaints were chiefly related to dissatisfactory esthetics and dental sensitivity. Caries prevalence index was 93.5%. Mean decayed, missing, filling permanent teeth (DMF) and DMF surface (DMFS) were found as 2.74 +/- 1.71 and 6.23 +/- 3.99; df (decayed, filling primary teeth) and dfs (decayed, filling primary teeth surface) were found as 3.12 +/- 2.85 and 5.24 +/- 4.97, respectively. All patients received individual clinical care, including preventive, restorative, and prosthetic treatments. Patients have scheduled for regular follow-up in every 3 months. Composite restorations were used as the most common treatment (25 patients, 80.6%). The treatment plan should be based on patient's age, type of defects and individual needs of the patients. Necessary treatment plan is essential, not only due to functional and aesthetic reasons, but also for the positive psychological impact on young patients. PMID- 25512740 TI - Coalescence of inter: Osteotomy bone graft material inserted via separate transcrestal sinus osteotomies: A case report and concise review of the literature. AB - When multiple implants are to be placed, and a pneumatized sinus exists, the published reports suggest that the lateral window approach (LWA) is favored for sinus floor augmentation. Simultaneously, if a transcrestal sinus floor augmentation has been carried out (bone-added osteotome sinus floor elevation), the reports are restricted to single implant placement at any site. The aim of this study was to evaluate the clinical and radiographic outcomes at adjacent transcrestal sinus augmentation grafts using deproteinized bovine bone material, with the immediate placement of submerged adjacent implants, and so determining the fate of the graft material. The progressive loss of the inter-implant graft is reported for the LWA Technique. However, this novel coalescence method has shown a progressive increase in the inter-implant graft region, thus inferring a positive bony regeneration and remodelling at the region. These results indicate that the carrying out of a large scale study is warranted to confirm the efficacy of this technique. PMID- 25512741 TI - Fifteen months follow-up of a hopeless tooth treated with two-step procedure involving intentional replantation and free gingival graft. AB - The aim of the report is to document 15-month results of mucogingival surgery applied following intentional replantation (IntR). A mandibular left lateral incisor with severe periodontitis and malposition was replanted and splinted following root canal treatment. Three months after IntR, a free gingival graft (FGG) was placed. Fifteen months follow-up of the case demonstrated significant improvement in periodontal healing parameters and significant bone fill was detected around the root apex. As a conclusion, IntR may be speculated as a convenient alternative to keep the periodontally hopeless teeth and supportive approaches such as FGGs may improve the outcomes following IntR. PMID- 25512742 TI - Screw-retained crown restorations of single implants: A step-by-step clinical guide. AB - This paper shows the clinical steps for preparing a screw-retained crown for the restoration of a single implant. Impression-taking using open-tray technique and delivery of the crown is presented in a step-by-step manner elucidated by detailed photographs. Furthermore, the advantages and disadvantages of screw retained crowns are discussed in comparison with the cemented restorations. PMID- 25512744 TI - Superposition-Enhanced Estimation of Optimal Temperature Spacings for Parallel Tempering Simulations. AB - Effective parallel tempering simulations rely crucially on a properly chosen sequence of temperatures. While it is desirable to achieve a uniform exchange acceptance rate across neighboring replicas, finding a set of temperatures that achieves this end is often a difficult task, in particular for systems undergoing phase transitions. Here we present a method for determination of optimal replica spacings, which is based upon knowledge of local minima in the potential energy landscape. Working within the harmonic superposition approximation, we derive an analytic expression for the parallel tempering acceptance rate as a function of the replica temperatures. For a particular system and a given database of minima, we show how this expression can be used to determine optimal temperatures that achieve a desired uniform acceptance rate. We test our strategy for two atomic clusters that exhibit broken ergodicity, demonstrating that our method achieves uniform acceptance as well as significant efficiency gains. PMID- 25512743 TI - The effect of surface roughness on ceramics used in dentistry: A review of literature. AB - Long term clinical success of modern dental ceramics depends on a number of factors. These factors include the physical properties of the material, the laboratory fabrication process, the laboratory fabrication technique and clinical procedures that may damage these brittle materials. The surface structure and composition of a dental restorative material influences the initial bacterial adhesion, and a rough material surface will accumulate more plaque. Biomaterials for the restoration of oral function are prone to biofilm formation, affecting oral health. An up to date online database search was performed using the keywords "bacterial biofilm," "ceramic strength," "dental ceramics" and "surface roughness." The searches were performed on Medline/PubMed, and Scopus and the cross references were further searched in the databases to verify further studies. The relevant papers included original articles, systemic reviews, case reports and letters to the editor. All the papers were reviewed, and the most relevant studies were selected for referencing by the author. The aim of this paper is to highlight the influence of rougher surfaces on the ceramic strength and plaque accumulation leading to bacterial biofilm formation. PMID- 25512745 TI - The influence of commercial energy shots on response time and power output in recreational cyclists. AB - BACKGROUND: Caffeine based energy shot products accounted for $1.3 billion in sales in 2011. Caffeine has been shown to confer numerous benefits during exercise and is oftentimes combined with ingredients such as carbohydrates and taurine in the hope of further performance improvement. The purpose of this project was to compare auditory response time, power output, and physiological responses between the ingestion of a CHO, PRO, caffeine supplement (CPC), a caffeine-taurine-niacin based supplement (CTN), and a placebo (PL) in commercially formulated products that make claims as to improving performance. METHODS: Fourteen subjects cycled an interval exercise of 70% VO2max for 13 minutes and 90% of VO2max for two minutes for a total of 120 minutes which was then followed by a six-minute power output (PO) task. Subjects ingested a total of 45 g CHO, 7.5 g PRO, and 375 mg caffeine for CPC while 512 mg caffeine and 1200 mg taurine were ingested for CTN throughout the exercise. The treatments were administered in a double blind, randomly assigned protocol. Response time was assessed by auditory response. Significance was set at p < 0.05. RESULTS: Average PO was significantly greater for CPC: 309 +/- 60 W than CTN: 290 +/- 57 W and PL: 282 +/- 63 W. Response time was significantly faster for the CPC: 0.219 +/- .049 s than CTN: 0.232 +/- .060 s and PL: 0.228 +/- .047 s. HR was significantly greater for CTN: 143 +/- 16 bpm than CPC: 139 +/- 16 bpm. RPE was significantly lower for CPC: 13.0 +/- 1.7 than CTN: 13.5 +/- 1.2 and PL: 13.8 +/- 1.9. Blood glucose was greater for CPC: 5.5 +/- 0.8 mM/L than CTN: 4.9 +/- 0.7 mM/L and PL: 4.6 +/- 1.1 mM/L. No significant differences were observed for RER. CONCLUSIONS: The co-ingestion of CPC improved both cycling power output and auditory response time following 2 hours of moderate and high intensity interval cycling compared to CTN and PL. It is possible that the CPC treatment conferred not only a positive peripheral effect, but also a central effect. Even with a large caffeine dose, the combination of caffeine, taurine, niacin led to an inhibitory pattern which did not improve power output or response time performances over a PL. PMID- 25512746 TI - Comparison of the mandibular bone densitometry measurement between normal, osteopenic and osteoporotic postmenopausal women. AB - OBJECTIVE: This study was conducted to compare the mandibular bone density between postmenopausal women with normal skeletal bone mass density (BMD) and those with low skeletal BMD using digital panoramic radiographs. MATERIALS AND METHODS: One hundred fifteen postmenopausal women were divided into normal and osteoporotic/osteopenic groups. Digital panoramic radiographs were prepared using Digora PCT Sorodex equipment and Promax panoramic X-ray unit (Planmeca, Helsinki, Finland, Kvp=68 and mA=9). The mandibular bone density of an area (approximately 4*4 mm), exactly near the distal edge of the right mental foramen was determined in digital panoramic radiographs using Digora for Windows (DfW) Software. RESULTS: There was no statistically significant difference in mandibular bone density between the normal and osteoporotic/osteopenic participants (P >0.05). Mandibular bone density was not statistically different in normal and osteoporotic individuals with SBMD or FBMD T-score -2.5 (P >0.05). Density of the region of interest differed significantly between the normal and the osteoporotic group with SBMD and FBMD T-score -2.5 (P <0.05). The same results also gained in women who were osteoporotic only in the femoral region (P <0.05). CONCLUSION: Mandibular bone density in subjects with low BMD was related to FBMD. So, digital panoramic radiographs could be beneficial in the diagnosis of postmenopausal women who are at risk of osteoporosis. PMID- 25512747 TI - Comparison of natural head position in different anteroposterior malocclusions. AB - OBJECTIVE: The facial esthetics after orthodontic treatment and orthognathic surgery may be affected by the patient's natural head position. The purpose of this study was to evaluate the natural head position for the three skeletal classes of malocclusion. MATERIALS AND METHODS: Our sample consisted of 102 lateral cephalometric radiographs of patients aged 15 to 18 years; class I (n=32), class II (n=40) and class III (n=30). Nine landmarks of the craniofacial skeleton and three landmarks of the cervical vertebrae were determined. Variables consisted of two angles for cervical posture (OPT/Hor and CVT/Hor), three angles for craniofacial posture (SN/Ver, PNS-ANS/Ver, and ML/Ver ) and five for craniofacial angulation (SN/OPT, SN/CVT, PNS-ANS/OPT, PNS-ANS/CVT, ML/CVT). The data were analyzed statistically using ANOVA and post hoc tests. RESULTS: PNS ANS/Ver and SN/Ver differed significantly (p<0.05) among the three groups. There were no significant differences between class I and class II malocclusions for the indicator angles of cranial posture except for ML/Ver. The SN/CVT was significantly different for class I compared to class III patients. A head posture camouflaging the underlying skeletal class III was observed in our population. CONCLUSION: A more forward head posture was observed in skeletal class III participants compared to skeletal class I and II and that class III patients tended to incline their head more ventral compared to class I participants. These findings may have implications for the amount of jaw movements during surgery particularly in patients with a class III malocclusion. PMID- 25512748 TI - Butterfly arch: a device for precise controlling of the upper molars in three planes of space. AB - Intra-oral appliances such as transpalatal arch and Nance appliance fail to resist against forces that tend to loosen the anchorage. The infirmity arises due to the long lever arm and the mesial force that is perpendicular to the long axis of the appliance. The butterfly arch is presented here as an intra-oral appliance that withstands the mesially directed forces with a mechanism that puts strain on a stiff wire along its long axis. The unique shape of the butterfly arch is advantageous in maximum anchorage cases, cases in which arch width preservation is critical and cases with a vertical growth pattern. With the aid of the butterfly arch, clinical concerns such as patient cooperation, wearing extra-oral appliances, complicated mechanics in extraction cases and control of the arch length, arch width and vertical dimension would be greatly diminished. PMID- 25512749 TI - Sealant microleakage after using nano-filled bonding agents on saliva contaminated enamel. AB - OBJECTIVE: The efficacy of correctly applied fissure sealants has been revealed in the prevention of caries. Saliva and moisture contamination of the etched enamel surface before sealant placement can decrease the bonding strength of the sealant to the enamel. The aim of this study was to test the new bonding agents containing nano-fillers in order to reduce the negative effect of saliva contamination on the sealant micro leakage. MATERIALS AND METHODS: Seventy five sound human premolars were randomly assigned to five equal groups as follows: Group A: etching, sealant; Group B: etching, saliva contamination, sealant; Group C: etching, saliva contamination, Single bond, sealant; Group D: etching, saliva contamination, Adper Single bond 2, sealant; Group E: etching, saliva contamination, N Bond, sealant. The samples were thermo-cycled and immersed in basic fuchsine 0.5% by weight. Then, the teeth were sectioned bucco-lingually and parallel to the long axis into two segments. Finally, the length of dye penetration at the sealant-tooth interface was scored according to a four-point scale. RESULTS: Micro-leakage was higher in group B compared to the other groups, while there were no differences among the evaluated dentin adhesives. CONCLUSION: The use of nano-filled bonding agents as an intermediate layer between the etched enamel and the sealant can reduce sealant micro-leakage after saliva contamination at the level of the uncontaminated enamel. PMID- 25512750 TI - Portable dental chairs and their role in assisting the community outreach program a qualitative approach. AB - OBJECTIVE: Certain conditions limit the independence of deprived people. However, those conditions do not limit the right of these people to receive dental care. Portable dental units may make it possible for the deprived and elderly to receive the care they deserve in more areas. This study aimed to explore dentists' perceptions of the use of portable dental units in community outreach programs as a precursor to our quantitative study in the future. MATERIALS AND METHODS: Qualitative semi-structured interviews were conducted by one interviewer, seven dentists, two specialists, and 11 final-year dental students who had experience with portable dental units in Isfahan, Iran. The qualitative research method was chosen first due to the rarity of information readily available about the units and second due to their specialist application; with which only certain members of the dental community have experience. RESULTS: Participants described a range of observations they had made whilst using the portable dental units in different locations. The qualitative data were primarily concerned with the range of ideas the interviewers distinguished as relevant when describing the portable dental units. The predominant view most noted within interviews was that the portable units are very useful for the community outreach programs, with two subcategories of serviceability and access to oral health. Other factors mentioned were the competence of the portable dental unit and the factors affecting each individual patient. CONCLUSION: Our findings illustrate a number of features that may enhance the reputation of portable dental units, due to their useful nature. PMID- 25512751 TI - Assessing the amount of interdental bone in posterior areas of the mandible for placing orthodontic mini-implants. AB - Objective : The aim of this study was to assess the amount of interdental bone in posterior areas of the mandible for placing orthodontic mini-implants to provide and control anchorage in orthodontic treatment. Materials and Methods : The amount of interdental bone in areas between the second premolars and first molars, first and second molars on the right and left sides of the mandible were determined in fifty patients by RVG using periapical radiographs. The images were assessed using Cygnus Media Software to determine the mesio-distal width of the interdental bone, starting at the crest of the alveolar bone (2 mm below the CEJ) every one millimeter up to 12 mm from the CEJ. The actual amount of interdental bone and the effect of related factors were assessed using chi-square test at a 95% confidence interval. Results : The minimum desired interdental bone width for placing mini-implants, 3 mm from the CEJ, between the second premolar and first molar and the first and second molars of the mandible on both sides were significantly different (p<0.01): 1.8 mm (31%) more apical in the area between the second premolar and the first molar. There was also a statistically significant difference between the areas under study on the right side (p<0.002), which was 2.2 mm (44%) more apical in the area of the second premolar and the first molar. Conclusion : The most secure site for placing orthodontic mini implants in the mandible is between the first and second molars at the height of 5.8 mm from the CEJ. PMID- 25512752 TI - The Effects of One-Stage Full-Mouth Disinfection and Qua-drant-Wise Scaling and Root Planing on Serum Levels of IL-17 and IL-1beta and Clinical Parameters (A randomized Controlled Trial Study). AB - OBJECTIVE: One-stage full-mouth disinfection technique (FMD) has been introduced to avoid cross-contamination between the treated and untreated regions between treatment sessions. Considering the role of inflammatory mediators in periodontitis, the aim of the present study was to compare the effects of FMD with the quadrant-wise scaling and root planing (Q-SRP) on serum levels of IL-17 and IL-1beta in patients with moderate-to-severe chronic periodontitis. MATERIALS AND METHODS: Twenty patients with chronic periodontitis were selected randomly and based on inclusion criteria in each group. In order to evaluate the periodontal status, the clinical parameters of bleeding on probing (BOP), clinical attachment level (CAL), probing depth (PD) and modified gingival index (MGI) were measured and recorded before treatment and at 2- and 4-month intervals after treatment. Immunologic parameters of the study such as IL-17 and IL-1beta serum levels were determined by special laboratory kits at the same intervals. Data were analyzed by SPSS 15 statistical software. Statistical significance was defined at p<0.05. RESULTS: The results showed a decrease in the means of IL-17 and IL-1beta serum levels in both treatment modalities, with no statistically significant differences between the two study groups at the two time intervals (p>0.05). In the evaluation of periodontal parameters, all parameters exhibited clinical improvements in both groups, with no statistically significant differences between the two study groups (p>0.05). CONCLUSION: Based on the results of the present study it was concluded that both FMD and Q-SRP techniques result in improvements in periodontal indexes and decreases in the serum levels of IL-17 and IL-1beta inflammatory mediators. PMID- 25512753 TI - Prosthetic management of an extensive maxillary alveolar defect with an implant supported restoration. AB - Despite the recent developments in peri-implant surgical regenerative procedures, re-establishing the hard and soft tissue contour is still a challenge in cases with severe ridge deficiency. It becomes more difficult when incorrectly placed implants cause screw connections to come out onto the labial surfaces of the teeth. A two-part maxillary implant supported fixed restoration was constructed. The first part was consisted of a screw retained sub-structure that replaced gingival portions of the deficient maxilla and the second part was a cement retained super-structure that reconstructed the anatomical crowns of the lost teeth. In this way awkwardly placed implants did not interfere with the desired esthetic result. Another great advantage was that the alterations or repairs on cemented crowns can easily be carried out without compromising the entire construction. PMID- 25512754 TI - Effect of low level laser therapy on orthodontic tooth movement: a review article. AB - Increased duration of fixed orthodontic treatments leads to increased tooth root degeneration, gum inflammation and tooth caries. To decrease the time period of orthodontic treatment, it is essential to facilitate tooth movement or in other words increase the speed of bone remodeling. Use of low level laser therapy is a method for achieving this goal. PMID- 25512755 TI - An evidence-based review literature about risk indicators and management of unknown-origin xerostomia. AB - This evidence-based article reviews risk indicators and management of unknown origin xerostomia. Xerostomia and hyposalivation refer to different aspects of dry mouth. Xerostomia is a subjective sensation of dry mouth, whilst hyposalivation is defined as an objective assessment of reduced salivary flow rate. About 30% of the elderly (65 years and older) experience xerostomia and hyposalivation. Structural and functional factors, or both may lead to salivary gland dysfunction. The EBM literature search was conducted by using the medical literature database MEDLINE via PubMed and OvidMedline search engines. Results were limited to English language articles (1965 to present) including clinical trials (CT), randomized controlled trials (RCT), systematic reviews and review articles. Case control or cohort studies were included for the etiology. Neuropathic etiology such as localized oral alteration of thermal sensations, saliva composition change (for example higher levels of K, Cl, Ca, IgA, amylase, calcium, PTH and cortisol), lower levels of estrogen and progesterone, smaller salivary gland size, and illnesses such as lichen planus, are risk indicators for unknown-origin xerostomia. The management is palliative and preventative. Management of symptoms includes drug administration (systemic secretogogues, saliva substitutes and bile secretion-stimulator), night guard, diet and habit modifications. Other managements may be indicated to treat adverse effects. Neuropathic etiology, saliva composition change, smaller salivary gland size, and illnesses such as oral lichen planus can be suggestive causes for unknown-origin xerostomia. However, longitudinal studies will be important to elucidate the causes of unknown-origin xerostomia. PMID- 25512756 TI - Full mouth rehabilitation of an ectodermal dysplasia patient with implant supported prostheses: a clinical report. AB - Full mouth rehabilitation in patients with ectodermal dysplasia (ED) is difficult to manage, especially because the afflicted individuals are quite young when they are evaluated for treatment; therefore, esthetics is an important concern. This clinical report describes the rehabilitation of a 19-year-old girl diagnosed with ectodermal dysplasia. Eleven implants were placed in the maxilla and mandible along with bone grafting to the upper jaw and both arches were constructed by metal-ceramic implant-supported fixed prostheses. This treatment plan seems to be favorable for ED patients. PMID- 25512757 TI - Conservative management of invasive cervical resorption: a case report. AB - Invasive cervical resorption is a condition that affects the root surface area below the epithelial attachment. Multiple treatment modalities are advocated, involving exposure of the invasive defect, removal of the granulation tissue and sealing with various restorative materials. This report demonstrates conservative treatment of a patient presenting with peri-apical periodontitis in upper right central and lateral incisors, along with Class II invasive resorption defect cervically on the mesial aspect of the central incisor, as a result of trauma. As the patient was not willing for any surgical intervention, only ortho-grade root canal treatment was carried out in both teeth, with Calcium hydroxide as intra canal medicament. At three year follow-up, the patient remains asymptomatic demonstrating radiographic evidence of infilling of defect with bone-like tissue. Within the limitations of this report, it was seen that this conservative method for halting the progression of invasive cervical resorption could be under taken in patients who are un-willing for surgical intervention or in whom surgery is contra-indicated. PMID- 25512758 TI - Age-related differences in polyfunctional T cell responses. AB - BACKGROUND: A reduced number of naive T cells along with an accumulation of differentiated cell types in aging have been described but little is known about the polyfunctionality of the T cell responses. In this study we compared the individual and polyfunctional expression of IFN-gamma, MIP-1alpha, TNF-alpha, perforin, and IL-2 by T cell subsets, including the newly described stem cell like memory T cells (TSCM), in response to stimulation with superantigen staphylococcal enterotoxin B (SEB) in older (median age 80, n = 23) versus younger (median age 27; n = 23) adults. RESULTS: Older age was associated with a markedly lower frequency of CD8+ naive T cells (11% vs. 47%; p < 0.0001) and an expansion in memory T cell subsets including central memory (p < 0.05), effector memory and effector T cells (p < 0.001 for both). There was also a decline in CD4+ naive T cells in older subjects (33% vs. 45%; p = 0.02). There were no differences in frequencies or polyfunctional profiles of TSCM between groups. CD8+ naive cells in the older group had increased expression of all functional parameters measured compared to the younger subjects and exhibited greater polyfunctionality (p = 0.04). CD4+ naive T cells in the older group also showed greater polyfunctionality with a TNF-alpha and IL-2 predominance (p = 0.005). CD8+ effector memory and effector T cells exhibited increased polyfunctionality in the older group compared with younger (p = 0.01 and p = 0.003). CONCLUSIONS: These data suggest that aging does not have a negative effect on polyfunctionality and therefore this is likely not a major contributor to the immunesenescence described with aging. PMID- 25512759 TI - Characterization of recovery, repair, and inflammatory processes following contusion spinal cord injury in old female rats: is age a limitation? AB - BACKGROUND: Although the incidence of spinal cord injury (SCI) is steadily rising in the elderly human population, few studies have investigated the effect of age in rodent models. Here, we investigated the effect of age in female rats on spontaneous recovery and repair after SCI. Young (3 months) and aged (18 months) female rats received a moderate contusion SCI at T9. Behavioral recovery was assessed, and immunohistocemical and stereological analyses performed. RESULTS: Aged rats demonstrated greater locomotor deficits compared to young, beginning at 7 days post-injury (dpi) and lasting through at least 28 dpi. Unbiased stereological analyses revealed a selective increase in percent lesion area and early (2 dpi) apoptotic cell death caudal to the injury epicenter in aged versus young rats. One potential mechanism for these differences in lesion pathogenesis is the inflammatory response; we therefore assessed humoral and cellular innate immune responses. No differences in either acute or chronic serum complement activity, or acute neutrophil infiltration, were observed between age groups. However, the number of microglia/macrophages present at the injury epicenter was increased by 50% in aged animals versus young. CONCLUSIONS: These data suggest that age affects recovery of locomotor function, lesion pathology, and microglia/macrophage response following SCI. PMID- 25512761 TI - Evaluation of the Back College for nursing staff. AB - BACKGROUND: Work-related musculoskeletal pain- particularly back pain - is an important individual and socioeconomic problem. The Back College for the insurance holders of the Institution for Statutory Accident Insurance and Prevention in the Health and Welfare Services (BGW) is based on a multimodal concept and has been evaluated with respect to pain relief and continuing in the nursing profession. METHODS: In a retrospective cohort study, the participants in the Back College from 2009 to 2011 were surveyed in writing. Besides demographic data, the survey covered information on qualification, length of employment, institution, employment status, periods of inability to work, applicability of working techniques and continuation in the profession. Back pain was recorded at three time points - T1 (before the Back College), T2 (directly after the Back College) and T3 (at the time of the survey). Pain changes were submitted to tests for paired samples. Multivariate logistic analysis was applied to determine potential factors influencing unfavourable changes in pain or leaving nursing due to back pain. RESULTS: The survey covered 1,282 insurance holders, with a response rate of 80%. Statistically significant reductions in pain were found for the whole group and for all subgroups. For persons who predominantly worked in old people's homes and who did not take part in refresher services, an increased odds ratio was found for unfavourable changes in pain (OR: 1.9 or 1.4, respectively). Persons with a qualification in geriatric nursing or in intensive care/OP/anaesthesia had an increased risk of leaving nursing due to back pain (OR: 2.5 in each case). An increased risk of leaving was also found for persons who did not take part in workplace support (OR: 2.9). CONCLUSION: Within the context of the study design, the multimodal concept of the Back College is clearly related to relief of back pain. The Back College appears to be less successful for geriatric nurses and persons with qualifications in intensive care/OP/anaesthesia. Further studies are needed to ascertain why some participants experience less relief in stress from the working techniques they have learnt. PMID- 25512760 TI - Possible role of ABO system in age-related diseases and longevity: a narrative review. AB - ABO blood group antigens are expressed either on the surface of red blood cells either on a variety of other cells. Based on the available knowledge of the genes involved in their biosynthesis and their tissue distribution, their polymorphism has been suggested to provide intraspecies diversity allowing to cope with diverse and rapidly evolving pathogens. Accordingly, the different prevalence of ABO group genotypes among the populations has been demonstrated to be driven by malaria selection. In the similar manner, a particular ABO blood group may contribute to favour life-extension via biological mechanisms important for surviving or eluding serious disease. In this review, we will suggest the possible association of ABO group with age-related diseases and longevity taking into account the biological role of the ABO glycosyltransferases on some inflammatory mediators as adhesion molecules. PMID- 25512762 TI - Chemistry Central Journal themed issue: Current Topics in Chemical Crystallography. PMID- 25512764 TI - Effects of Fiber-reinforced Composite Bases on Microleakage of Composite Restorations in Proximal Locations. AB - OBJECTIVES: The aim of this study was to evaluate the microleakage of direct restorative composite resin upon the addition of an intermediate glass fiber reinforced composite (GFRC) layer of various fiber orientations between tooth and particulate filler composite resin (PFRC). MATERIALS AND METHODS: Cavities were prepared both on the mesial and distal surfaces of sixty extracted human molars with one margin placed below and the other above the cementoenamel junction (CEJ). Teeth were assigned to five different groups. Four of the groups received a layer of semi-interpenetrating polymer network (semi-IPN) resin system impregnated E-glass GFRC at the bottom of the cavity: Group 1; unidirectional continuous GFRC (EVS) in buccolingual direction (EVS-BL), Group 2; EVS in mesiodistal direction (EVS-MD), Group 3; bidirectional woven GFRC (EVN), Group 4; multidirectional short GFRC (EXP-MLT), Group 5; PRFC only (control). After acid etching and priming of the cavities and insertion of GFRC layer with the adhesive resin (Scotchbond Multipurpose 3M-ESPE), the cavities were filled incrementally with PRFC (Filtek Z250, 3M-ESPE) and each layer was light cured for 20 s. After finishing and polishing, the restored teeth were water-stored for 24 h at 37 degrees C and then thermocycled for 6000 cycles between 5-55 degrees C, before immersion in 0.5 % basic fuchsin dye for 24 h. After sectioning by 3-5 sagittal cuts, each sequential section was imaged and digitally analyzed to determine the stain depth. RESULTS: All GFRC groups in dentin revealed significantly lower microleakage compared to control (p<0.05). The orientation of FRC intermediate layer did not reveal significant differences in microleakage (p>0.05). The microleakeage in enamel was not different between the groups (p>0.05). CONCLUSION: Use of intermediate GFRC layer between tooth and PFRC could provide alternative method to minimize microleakage. CLINICAL RELEVANCE: Use of GFRC intermediate layer underneath the particulate filler composite can be used to minimize the leakeage of the restorations. PMID- 25512763 TI - Abnormal daytime sleepiness in dementia with Lewy bodies compared to Alzheimer's disease using the Multiple Sleep Latency Test. AB - INTRODUCTION: Excessive daytime sleepiness is a commonly reported problem in dementia with Lewy bodies (DLB). We examined the relationship between nighttime sleep continuity and the propensity to fall asleep during the day in clinically probable DLB compared to Alzheimer's disease (AD) dementia. METHODS: A full-night polysomnography was carried out in 61 participants with DLB and 26 with AD dementia. Among this group, 32 participants with DLB and 18 with AD dementia underwent a daytime Multiple Sleep Latency Test (MSLT). Neuropathologic examinations of 20 participants with DLB were carried out. RESULTS: Although nighttime sleep efficiency did not differentiate diagnostic groups, the mean MSLT initial sleep latency was significantly shorter in participants with DLB than in those with AD dementia (mean 6.4 +/- 5 minutes vs 11 +/- 5 minutes, P <0.01). In the DLB group, 81% fell asleep within 10 minutes compared to 39% of the AD dementia group (P <0.01), and 56% in the DLB group fell asleep within 5 minutes compared to 17% in the AD dementia group (P <0.01). Daytime sleepiness in AD dementia was associated with greater dementia severity, but mean MSLT latency in DLB was not related to dementia severity, sleep efficiency the night before, or to visual hallucinations, fluctuations, parkinsonism or rapid eye movement sleep behavior disorder. These data suggest that abnormal daytime sleepiness is a unique feature of DLB that does not depend on nighttime sleep fragmentation or the presence of the four cardinal DLB features. Of the 20 DLB participants who underwent autopsy, those with transitional Lewy body disease (brainstem and limbic) did not differ from those with added cortical pathology (diffuse Lewy body disease) in dementia severity, DLB core features or sleep variables. CONCLUSIONS: Daytime sleepiness is more likely to occur in persons with DLB than in those with AD dementia. Daytime sleepiness in DLB may be attributed to disrupted brainstem and limbic sleep-wake physiology, and further work is needed to better understand the underlying mechanisms. PMID- 25512765 TI - Percutaneous transcatheter embolization of gastrointestinal bleeding in a child with polyarteritis nodosa. AB - BACKGROUND: Polyarteritis nodosa is a form of necrotizing vasculitis of small and medium-sized arteries. Major gastrointestinal complications are ulceration, perforation, hemorrhage, and obstruction. CASE REPORT: We report on a clinical case of a 16-year-old female patient with massive hematemesis, who was successfully treated with embolization with a 1:2 dilution of N-butyl cyanoacrylate glue. CONCLUSIONS: To the best of our knowledge, this is the youngest child reported on with massive GI bleeding secondary to PAN, treated with successful percutaneous transcatheter embolization under emergency conditions. PMID- 25512767 TI - Myths, fallacies and practical pearls in GI lab. AB - Many prevalent practices and guidelines related to Gastrointestinal endoscopy and procedural sedation are at odds with the widely available scientific physiological and clinical outcome data. In many institutions, strict policy of pre-procedural extended fasting is still rigorously enforced, despite no evidence of increased incidence of aspiration after recent oral intake prior to sedation. Supplemental oxygen administration in the setting of GI procedural sedation has been increasingly adopted as reported in the medical journals, despite clear evidence that supplemental oxygen blunts the usefulness of pulse oximetry in timely detection of sedation induced hypoventilation, leading to increased number of adverse cardiopulmonary outcomes. Use of Propofol by Gastroenterologist-Nurse team is erroneously considered dangerous and often prohibited in various institutions, at the same time worldwide reports of remarkable safety and patient satisfaction continue to be published, dating back more than a decade. Of patient monitoring practices that have been advocated to be standard, many merely add cost, not value. Advances in the technology often are not incorporated in a timely manner in guidelines or clinical practices, e.g., Capsule endoscopy or electrocautery during GI procedures do not interfere with proper functioning of the current pacemakers or defibrillators. Orthopedic surgeons have continued to recommend prophylactic antibiotics for joint replacement patients prior to GI procedures, without any evidence of need. These myths are explored for a succint review to prompt a change in clinical practices and institutional policies. PMID- 25512766 TI - Quality indicators for colonoscopy: Current insights and caveats. AB - Colonoscopy is the diagnostic modality of choice for investigation of symptoms suspected to be related to the colon and for the detection of polyps and colorectal cancer (CRC). Colonoscopy with removal of detected polyps has been shown to reduce the incidence and mortality of subsequent CRC. In many countries, population screening programs for CRC have been initiated, either by selection of patients for colonoscopy with fecal occult blood testing or by offering colonoscopy directly to average-risk individuals. Several endoscopy societies have formulated quality indicators for colonoscopy. These quality indicators are almost always incorporated as process indicators, rather than outcome measures. This review focuses on the quality indicators bowel preparation, cecal intubation rate, withdrawal time, adenoma detection rate, patient comfort, sedation and complication rate, and discusses the scientific evidence supporting them, as well as their potential shortcomings and issues that need to be addressed. For instance, there is still no clear and generally accepted definition of adequate bowel preparation, no robust scientific evidence is available supporting a cecal intubation rate >= 90% and the association between withdrawal time and occurrence of interval cancers has not been clarified. Adenoma detection rate is currently the only quality indicator that has been shown to be associated with interval colorectal cancer, but as an indicator it does not differentiate between subjects with one or more adenoma detected. PMID- 25512768 TI - Endoscopic resection of subepithelial tumors. AB - Management of subepithelial tumors (SETs) remains challenging. Endoscopic ultrasound (EUS) has improved differential diagnosis of these tumors but a definitive diagnosis on EUS findings alone can be achieved in the minority of cases. Complete endoscopic resection may provide a reasonable approach for tissue acquisition and may also be therapeutic in case of malignant lesions. Small SET restricted to the submucosa can be removed with established basic resection techniques. However, resection of SET arising from deeper layers of the gastrointestinal wall requires advanced endoscopic methods and harbours the risk of perforation. Innovative techniques such as submucosal tunneling and full thickness resection have expanded the frontiers of endoscopic therapy in the past years. This review will give an overview about endoscopic resection techniques of SET with a focus on novel methods. PMID- 25512769 TI - Narrow-band imaging observation of colorectal lesions using NICE classification to avoid discarding significant lesions. AB - AIM: To assess the risk of failing to detect diminutive and small colorectal cancers with the "resect and discard" policy. METHODS: Patients who received colonoscopy and polypectomy were recruited in the retrospective study. Probable histology of the polyps was predicted by six colonoscopists by the use of NICE classification. The incidence of diminutive and small colorectal cancers and their endoscopic features were assessed. RESULTS: In total, we found 681 cases of diminutive (1-5 mm) lesions in 402 patients and 197 cases of small (6-9 mm) lesions in 151 patients. Based on pathology of the diminutive and small polyps, 105 and 18 were non-neoplastic polyps, 557 and 154 were low-grade adenomas, 18 and 24 were high-grade adenomas or intramucosal/submucosal (SM) scanty invasive carcinomas, 1 and 1 were SM-d carcinoma, respectively. The endoscopic features of invasive cancer were classified as NICE type 3 endoscopically. CONCLUSION: The risk of failing to detect diminutive and small colorectal invasive cancer with the "resect and discard" strategy might be avoided through the use of narrow-band imaging observation with the NICE classification scheme and magnifying endoscopy. PMID- 25512770 TI - Comparison of split-dosing vs non-split (morning) dosing regimen for assessment of quality of bowel preparation for colonoscopy. AB - AIM: To compare (using the Ottawa Bowel Preparation Scale) the efficacy of split dose vs morning administration of polyethylene glycol solution for colon cleansing in patients undergoing colonoscopy, and to assess the optimal preparation-to-colonoscopy interval. METHODS: Single-centre, prospective, randomized, investigator-blind stud in an academic tertiary-care centre. Two hundred patients requiring elective colonoscopy were assigned to receive one of the two preparation regimens (split vs morning) prior to colonoscopy. Main outcome measurements were bowel preparation quality and patient tolerability. RESULTS: Split-dose regimen resulted in better bowel preparation compared to morning regimen [Ottawa score mean 5.52 (SD 1.23) vs 6.02 (1.34); P = 0.017]. On subgroup analysis, for afternoon procedures, both the preparations were equally effective (P = 0.756). There was no difference in tolerability and compliance between the two regimens. CONCLUSION: Overall, previous evening - same morning split-dosing regimen results in better bowel cleansing for colonoscopy compared to morning preparation. For afternoon procedures, both schedules are equally effective; morning preparation may be more convenient to the patient. PMID- 25512771 TI - Small bowel ulcerative lesions are common in elderly NSAIDs users with peptic ulcer bleeding. AB - AIM: To determine the frequency of small bowel ulcerative lesions in patients with peptic ulcer and define the significance of those lesions. METHODS: In our prospective study, 60 consecutive elderly patients with upper gastrointestinal bleeding from a peptic ulceration (cases) and 60 matched patients with a non bleeding peptic ulcer (controls) underwent small bowel capsule endoscopy, after a negative colonoscopy (compulsory in our institution). Controls were evaluated for non-bleeding indications. Known or suspected chronic inflammatory conditions and medication that could harm the gut were excluded. During capsule endoscopy, small bowel ulcerative lesions were counted thoroughly and classified according to Graham classification. Other small bowel lesions were also recorded. Peptic ulcer bleeding was controlled endoscopically, when adequate, proton pump inhibitors were started in both cases and controls, and Helicobacter pylori eradicated whenever present. Both cases and controls were followed up for a year. In case of bleeding recurrence upper gastrointestinal endoscopy was repeated and whenever it remained unexplained it was followed by repeat colonoscopy and capsule endoscopy. RESULTS: Forty (67%) cases and 18 (30%) controls presented small bowel erosions (P = 0.0001), while 22 (37%) cases and 4 (8%) controls presented small bowel ulcers (P < 0.0001). Among non-steroidal anti-inflammatory drug (NSAID) consumers, 39 (95%) cases and 17 (33%) controls presented small bowel erosions (P < 0.0001), while 22 (55%) cases and 4 (10%) controls presented small bowel ulcers (P < 0.0001). Small bowel ulcerative lesions were infrequent among patients not consuming NSAIDs. Mean entry hemoglobin was 9.3 (SD = 1.4) g/dL in cases with small bowel ulcerative lesions and 10.5 (SD = 1.3) g/dL in those without (P = 0.002). Cases with small bowel ulcers necessitate more units of packed red blood cells. During their hospitalization, 6 (27%) cases with small bowel ulcers presented bleeding recurrence most possibly attributed to small bowel ulcers, nevertheless 30-d mortality was zero. Presence of chronic obstructive lung disease and diabetes was related with unexplained recurrence of hemorrhage in logistic regression analysis, while absence of small bowel ulcers was protective (relative risk 0.13, P = 0.05). CONCLUSION: Among NSAID consumers, more bleeders than non-bleeders with peptic ulcers present small bowel ulcers; lesions related to more severe bleeding and unexplained episodes of bleeding recurrence. PMID- 25512772 TI - Novel endoscopic management for pancreatic pseudocyst with fistula to the common bile duct. AB - Pancreatic pseudocyst formation is a well-known complication of pancreatitis. It represents about 75% of the cystic lesions of the pancreas and might be located within or surrounding the pancreatic tissue. Sixty percent of the occurrences resolve spontaneously and only persistent, symptomatic or complicated cysts need to be treated. Complications include infection, hemorrhage, gastric outlet obstruction, splenic infarction and rupture. The formation of fistulas to other viscera is rare and most commonly occurs within the stomach, duodenum or colon. We report a case of a patient with a pancreatic pseudocyst in communication with the common bile duct. There have been only few cases reported in the literature. We successfully managed our case by performing an endoscopic ultrasound-guided drainage of the pancreatic collection and a contemporaneous stenting of the common bile duct. Performed independently, both drainages are effective, safe and well-coded and the expertise on these procedures is widespread. By our knowledge this therapeutic approach was never reported in literature but we retain this is the most correct treatment for this very rare condition. PMID- 25512773 TI - Life threatening bleeding from duodenal ulcer after Roux-en-Y gastric bypass: Case report and review of the literature. AB - Acute upper gastrointestinal bleeding is a rare, but serious complication of gastric bypass surgery. The inaccessibility of the excluded stomach restrains postoperative examination and treatment of the gastric remnant and duodenum, and represents a major challenge, especially in the emergency setting. A 59-year-old patient with previous history of peptic ulcer disease had an upper gastrointestinal bleeding from a duodenal ulcer two years after having a gastric bypass procedure for morbid obesity. After negative upper endoscopy finding, he was urgently evaluated for gastrointestinal bleeding. At emergency laparotomy, the bleeding duodenal ulcer was identified by intraoperative endoscopy through gastrotomy. The patient recovered well after surgical hemostasis, excision of the duodenal ulcer and completion of the remnant gastrectomy. Every general practitioner, gastroenterologist and general surgeon should be aware of growing incidence of bariatric operations and coherently possible complications after such procedures, which modify patient's anatomy and physiology. PMID- 25512774 TI - Endoscopic therapy for esophageal hematoma with blue rubber bleb nevus syndrome. AB - A 57-year-old woman previously diagnosed with blue rubber bleb nevus syndrome (BRBNS) reported hematemesis. BRBNS is a rare vascular anomaly syndrome consisting of multifocal hemangiomas of the skin and gastrointestinal (GI) tract but her GI tract had never been examined. An upper gastrointestinal endoscopy revealed a large bleeding esophageal hematoma positioned between the thoracic esophagus and the gastric cardia. An endoscopic injection of polidocanol was used to stop the hematoma from bleeding. The hematoma was incised using the injection needle to reduce the pressure within it. Finally, argon plasma coagulation (APC) was applied to the edge of the incision. The esophageal hematoma disappeared seven days later. Two months after the endoscopic therapy, the esophageal ulcer healed and the hemangioma did not relapse. This rare case of a large esophageal hematoma originating from a hemangioma with BRBNS was treated using a combination of endoscopic therapy with polidocanol injection, incision, and APC. PMID- 25512776 TI - B7-H4 as a protective shield for pancreatic islet beta cells. AB - Auto- and alloreactive T cells are major culprits that damage beta-cells in type 1 diabetes (T1D) and islet transplantation. Current immunosuppressive drugs can alleviate immune-mediated attacks on islets. T cell co-stimulation blockade has shown great promise in autoimmunity and transplantation as it solely targets activated T cells, and therefore avoids toxicity of current immunosuppressive drugs. An attractive approach is offered by the newly-identified negative T cell co-signaling molecule B7-H4 which is expressed in normal human islets, and its expression co-localizes with insulin. A concomitant decrease in B7-H4/insulin co localization is observed in human type 1 diabetic islets. B7-H4 may play protective roles in the pancreatic islets, preserving their function and survival. In this review we outline the protective effect of B7-H4 in the contexts of T1D, islet cell transplantation, and potentially type 2 diabetes. Current evidence offers encouraging data regarding the role of B7-H4 in reversal of autoimmune diabetes and donor-specific islet allograft tolerance. Additionally, unique expression of B7-H4 may serve as a potential biomarker for the development of T1D. Future studies should continue to focus on the islet specific effects of B7-H4 with emphasis on mechanistic pathways in order to promote B7-H4 as a potential therapy and cure for T1D. PMID- 25512775 TI - Saliva as a non-invasive diagnostic tool for inflammation and insulin-resistance. AB - Saliva has been progressively studied as a non-invasive and relatively stress free diagnostic alternative to blood. Currently, saliva testing is used for clinical assessment of hormonal perturbations, detection of HIV antibodies, DNA analysis, alcohol screening, and drug testing. Recently, there has been increasing interest in evaluating the diagnostic potential of saliva in obesity, inflammation, and insulin-resistance. Current literature has demonstrated elevated levels of inflammatory biomarkers including C-reactive protein, tumor necrosis factor-alpha, interleukin-6, and interferon-gamma in saliva of obese/overweight children and adults. Salivary antioxidant status has also been studied as a measure of oxidative stress in individuals with type 2 diabetes. Further, several studies have demonstrated correlations of salivary markers of stress and insulin resistance including cortisol, insulin, adiponectin, and resistin with serum concentrations. These findings suggest the potential diagnostic value of saliva in health screening and risk stratification studies, particularly in the pediatric population, with implications for inflammatory, metabolic and cardiovascular conditions. However, additional studies are required to standardize saliva collection and storage procedures, validate analytical techniques for biomarker detection, and establish reference ranges for routine clinical use. The purpose of this review is to summarize and evaluate recent advancements in using saliva as a diagnostic tool for inflammation and insulin resistance. PMID- 25512777 TI - Is the present cut-point to define type 2 diabetes appropriate in Latin Americans? AB - The diagnosis of diabetes mellitus type 2 (DM2) is based either on increased plasma glucose or Glycated hemoglobin levels. Since these measures are the only means for diagnosis of DM2, they must be well adapted to each population according to their metabolic characteristics, given that these may vary in each population. The World Health Organization (WHO) determined the cut-points of plasma glucose levels for the diagnosis of DM2 by associating hyperglycemia with the risk of a specific microvascular complication-retinopathy. Cardiovascular diseases are however the principal causes of mortality in patients with DM2 and we reported that in the Colombo-Ecuadorian population impaired fasting glucose and impaired glucose tolerance are both risk markers for myocardial infarction. We propose that the current cut-points accepted by the WHO need to be revaluated in populations such as Latin America and that there should be lower cut points for glycaemia in this population, to reduce the prevalence of cardiovascular complications associated with DM2. PMID- 25512778 TI - Recent advances on the association of apoptosis in chronic non healing diabetic wound. AB - Generally, wounds are of two categories, such as chronic and acute. Chronic wounds takes time to heal when compared to the acute wounds. Chronic wounds include vasculitis, non healing ulcer, pyoderma gangrenosum, and diseases that cause ischemia. Chronic wounds are rapidly increasing among the elderly population with dysfunctional valves in their lower extremity deep veins, ulcer, neuropathic foot and pressure ulcers. The process of the healing of wounds has several steps with the involvement of immune cells and several other cell types. There are many evidences supporting the hypothesis that apoptosis of immune cells is involved in the wound healing process by ending inflammatory condition. It is also involved in the resolution of various phases of tissue repair. During final steps of wound healing most of the endothelial cells, macrophages and myofibroblasts undergo apoptosis or exit from the wound, leaving a mass that contains few cells and consists mostly of collagen and other extracellular matrix proteins to provide strength to the healing tissue. This review discusses the various phases of wound healing both in the chronic and acute wounds especially during diabetes mellitus and thus support the hypothesis that the oxidative stress, apoptosis, connexins and other molecules involved in the regulation of chronic wound healing in diabetes mellitus and gives proper understanding of the mechanisms controlling apoptosis and tissue repair during diabetes and may eventually develop therapeutic modalities to fasten the healing process in diabetic patients. PMID- 25512779 TI - Biomarkers in diabetic nephropathy: Present and future. AB - Diabetic nephropathy (DN) is the leading cause of end stage renal disease in the Western world. Microalbuminuria (MA) is the earliest and most commonly used clinical index of DN and is independently associated with cardiovascular risk in diabetic patients. Although MA remains an essential tool for risk stratification and monitoring disease progression in DN, a number of factors have called into question its predictive power. Originally thought to be predictive of future overt DN in 80% of patients, we now know that only around 30% of microalbuminuric patients progress to overt nephropathy after 10 years of follow up. In addition, advanced structural alterations in the glomerular basement membrane may already have occurred by the time MA is clinically detectable.Evidence in recent years suggests that a significant proportion of patients with MA can revert to normoalbuminuria and the concept of nonalbuminuric DN is well-documented, reflecting the fact that patients with diabetes can demonstrate a reduction in glomerular filtration rate without progressing from normo-to MA. There is an unmet clinical need to identify biomarkers with potential for earlier diagnosis and risk stratification in DN and recent developments in this field will be the focus of this review article. PMID- 25512780 TI - Diabetes mellitus and cellular replacement therapy: Expected clinical potential and perspectives. AB - Diabetes mellitus (DM) is the most prevailing disease with progressive incidence worldwide. Despite contemporary treatment type one DM and type two DM are frequently associated with long-term major microvascular and macrovascular complications. Currently restoration of failing beta-cell function, regulation of metabolic processes with stem cell transplantation is discussed as complements to contemporary DM therapy regimens. The present review is considered paradigm of the regenerative care and the possibly effects of cell therapy in DM. Reprogramming stem cells, bone marrow-derived mononuclear cells; lineage specified progenitor cells are considered for regenerative strategy in DM. Finally, perspective component of stem cell replacement in DM is discussed. PMID- 25512781 TI - Linking uric acid metabolism to diabetic complications. AB - Hyperuricemia have been thought to be caused by the ingestion of large amounts of purines, and prevention or treatment of hyperuricemia has intended to prevent gout. Xanthine dehydrogenase/xanthine oxidase (XDH/XO) is rate-limiting enzyme of uric acid generation, and allopurinol was developed as a uric acid (UA) generation inhibitor in the 1950s and has been routinely used for gout prevention since then. Serum UA levels are an important risk factor of disease progression for various diseases, including those related to lifestyle. Recently, other UA generation inhibitors such as febuxostat and topiroxostat were launched. The emergence of these novel medications has promoted new research in the field. Lifestyle-related diseases, such as metabolic syndrome or type 2 diabetes mellitus, often have a common pathological foundation. As such, hyperuricemia is often present among these patients. Many in vitro and animal studies have implicated inflammation and oxidative stress in UA metabolism and vascular injury because XDH/XO act as one of the major source of reactive oxygen species Many studies on UA levels and associated diseases implicate involvement of UA generation in disease onset and/or progression. Interventional studies for UA generation, not UA excretion revealed XDH/XO can be the therapeutic target for vascular injury and renal dysfunction. In this review, the relationship between UA metabolism and diabetic complications is highlighted. PMID- 25512782 TI - Psychological aspects of diabetes care: Effecting behavioral change in patients. AB - Patients with diabetes mellitus (DM) need psychological support throughout their life span from the time of diagnosis. The psychological make-up of the patients with DM play a central role in self-management behaviors. Without patient's adherence to the effective therapies, there would be persistent sub-optimal control of diseases, increase diabetes-related complications, causing deterioration in quality of life, resulting in increased healthcare utilization and burden on healthcare systems. However, provision of psychosocial support is generally inadequate due to its challenging nature of needs and demands on the healthcare systems. This review article examines patient's psychological aspects in general, elaborates in particular about emotion effects on health, and emotion in relation to other psychological domains such as cognition, self-regulation, self-efficacy and behavior. Some descriptions are also provided on willpower, resilience, illness perception and proactive coping in relating execution of new behaviors, coping with future-oriented thinking and influences of illness perception on health-related behaviors. These psychological aspects are further discussed in relation to DM and interventions for patients with DM. Equipped with the understanding of the pertinent nature of psychology in patients with DM; and knowing the links between the psychological disorders, inflammation and cardiovascular outcomes would hopefully encourages healthcare professionals in giving due attention to the psychological needs of patients with DM. PMID- 25512783 TI - Association of genetic variants with diabetic nephropathy. AB - Diabetic nephropathy accounts for the most serious microvascular complication of diabetes mellitus. It is suggested that the prevalence of diabetic nephropathy will continue to increase in future posing a major challenge to the healthcare system resulting in increased morbidity and mortality. It occurs as a result of interaction between both genetic and environmental factors in individuals with both type 1 and type 2 diabetes. Genetic susceptibility has been proposed as an important factor for the development and progression of diabetic nephropathy, and various research efforts are being executed worldwide to identify the susceptibility gene for diabetic nephropathy. Numerous single nucleotide polymorphisms have been found in various genes giving rise to various gene variants which have been found to play a major role in genetic susceptibility to diabetic nephropathy. The risk of developing diabetic nephropathy is increased several times by inheriting risk alleles at susceptibility loci of various genes like ACE, IL, TNF-alpha, COL4A1, eNOS, SOD2, APOE, GLUT, etc. The identification of these genetic variants at a biomarker level could thus, allow the detection of those individuals at high risk for diabetic nephropathy which could thus help in the treatment, diagnosis and early prevention of the disease. The present review discusses about the various gene variants found till date to be associated with diabetic nephropathy. PMID- 25512784 TI - Incretin-based therapies in prediabetes: Current evidence and future perspectives. AB - The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless beta cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on beta-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater beta-cell mass and function are preserved and the possibility of beta-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on beta-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D. PMID- 25512786 TI - Transdifferentiation of pancreatic alpha-cells into insulin-secreting cells: From experimental models to underlying mechanisms. AB - Pancreatic insulin-secreting beta-cells are essential regulators of glucose metabolism. New strategies are currently being investigated to create insulin producing beta cells to replace deficient beta cells, including the differentiation of either stem or progenitor cells, and the newly uncovered transdifferentiation of mature non-beta islet cell types. However, in order to correctly drive any cell to adopt a new beta-cell fate, a better understanding of the in vivo mechanisms involved in the plasticity and biology of islet cells is urgently required. Here, we review the recent studies reporting the phenomenon of transdifferentiation of alpha cells into beta cells by focusing on the major candidates and contexts revealed to be involved in adult beta-cell regeneration through this process. The possible underlying mechanisms of transdifferentiation and the interactions between several key factors involved in the process are also addressed. We propose that it is of importance to further study the molecular and cellular mechanisms underlying alpha- to beta-cell transdifferentiation, in order to make beta-cell regeneration from alpha cells a relevant and realizable strategy for developing cell-replacement therapy. PMID- 25512785 TI - Risks of rapid decline renal function in patients with type 2 diabetes. AB - Progressive rising population of diabetes and related nephropathy, namely, diabetic kidney disease and associated end stage renal disease has become a major global public health issue. Results of observational studies indicate that most diabetic kidney disease progresses over decades; however, certain diabetes patients display a rapid decline in renal function, which may lead to renal failure within months. Although the definition of rapid renal function decline remained speculative, in general, it is defined by the decrease of estimated glomerular filtration rate (eGFR) in absolute rate of loss or percent change. Based on the Kidney Disease: Improving Global Outcomes 2012 clinical practice guidelines, a rapid decline in renal function is defined as a sustained decline in eGFR of > 5 mL/min per 1.73 m(2) per year. It has been reported that potential factors contributing to a rapid decline in renal function include ethnic/genetic and demographic causes, smoking habits, increased glycated hemoglobin levels, obesity, albuminuria, anemia, low serum magnesium levels, high serum phosphate levels, vitamin D deficiency, elevated systolic blood pressure, pulse pressure, brachial-ankle pulse wave velocity values, retinopathy, and cardiac autonomic neuropathy. This article reviews current literatures in this area and provides insight on the early detection of diabetic subjects who are at risk of a rapid decline in renal function in order to develop a more aggressive approach to renal and cardiovascular protection. PMID- 25512787 TI - Place of sodium-glucose co-transporter type 2 inhibitors for treatment of type 2 diabetes. AB - Inhibitors of sodium-glucose co-transporter type 2 (SGLT2), such as canagliflozin and dapagliflozin, are recently approved for treatment of type 2 diabetes. These agents lower blood glucose mainly by increasing urinary glucose excretion. Compared with placebo, SGLT2 inhibitors reduce hemoglobin A1c (HbA1c) levels by an average of 0.5%-0.8% when used as monotherapy or add-on therapy. Advantages of this drug class include modest weight loss of approximately 2 kg, low risk of hypoglycemia, and decrease blood pressure of approximately 4 mmHg systolic and 2 mmHg diastolic. These characteristics make these agents potential add-on therapy in patients with HbA1c levels close to 7%-8.0%, particularly if these patients are obese, hypertensive, and/or prone for hypoglycemia. Meanwhile, these drugs are limited by high frequency of genital mycotic infections. Less common adverse effects include urinary tract infections, hypotension, dizziness, and worsening renal function. SGLT2 inhibitors should be used with caution in the elderly because of increased adverse effects, and should not be used in chronic kidney disease due to decreased or lack of efficacy and nephrotoxicity. Overall, SGLT2 inhibitors are useful addition for treatment of select groups of patients with type 2 diabetes, but their efficacy and safety need to be established in long term clinical trials. PMID- 25512788 TI - Molecular mechanisms of AGE/RAGE-mediated fibrosis in the diabetic heart. AB - Chronic hyperglycemia is one of the main characteristics of diabetes. Persistent exposure to elevated glucose levels has been recognized as one of the major causal factors of diabetic complications. In pathologies, like type 2 diabetes mellitus (T2DM), mechanical and biochemical stimuli activate profibrotic signaling cascades resulting in myocardial fibrosis and subsequent impaired cardiac performance due to ventricular stiffness. High levels of glucose nonenzymatically react with long-lived proteins, such as collagen, to form advanced glycation end products (AGEs). AGE-modified collagen increase matrix stiffness making it resistant to hydrolytic turnover, resulting in an accumulation of extracellular matrix (ECM) proteins. AGEs account for many of the diabetic cardiovascular complications through their engagement of the receptor for AGE (RAGE). AGE/RAGE activation stimulates the secretion of numerous profibrotic growth factors, promotes increased collagen deposition leading to tissue fibrosis, as well as increased RAGE expression. To date, the AGE/RAGE cascade is not fully understood. In this review, we will discuss one of the major fibrotic signaling pathways, the AGE/RAGE signaling cascade, as well as propose an alternate pathway via Rap1a that may offer insight into cardiovascular ECM remodeling in T2DM. In a series of studies, we demonstrate a role for Rap1a in the regulation of fibrosis and myofibroblast differentiation in isolated diabetic and non-diabetic fibroblasts. While these studies are still in a preliminary stage, inhibiting Rap1a protein expression appears to down-regulate the molecular switch used to activate the zeta isotype of protein kinase C thereby promote AGE/RAGE-mediated fibrosis. PMID- 25512789 TI - Cardiac adipose tissue and its relationship to diabetes mellitus and cardiovascular disease. AB - Type-2 diabetes mellitus (T2DM) plays a central role in the development of cardiovascular disease (CVD). However, its relationship to epicardial adipose tissue (EAT) and pericardial adipose tissue (PAT) in particular is important in the pathophysiology of coronary artery disease. Owing to its close proximity to the heart and coronary vasculature, EAT exerts a direct metabolic impact by secreting proinflammatory adipokines and free fatty acids, which promote CVD locally. In this review, we have discussed the relationship between T2DM and cardiac fat deposits, particularly EAT and PAT, which together exert a big impact on the cardiovascular health. PMID- 25512790 TI - Intensive diabetes management and goal setting are key aspects of improving metabolic control in children and young people with type 1 diabetes mellitus. AB - Diabetes control in children remains poor in spite of advances in treatment for last 10 years. The aim of this review was to look at various aspects of intensive therapy in the management of type 1 diabetes such as insulin regimes, role of target setting, psycho-educational approaches and self-management. To achieve good metabolic control, clear goal setting with adequate support for self management are essential. Psycho-educational and behavioural interventions aimed at specific areas of management have shown significant improvement in quality of life and diabetes control. PMID- 25512791 TI - Diagnosis of hepatic glycogenosis in poorly controlled type 1 diabetes mellitus. AB - Hepatic glycogenosis (HG) in type 1 diabetes is a underrecognized complication. Mauriac firstly described the syndrome characterized by hepatomegaly with altered liver enzymes, growth impairment, delay puberty and Cushingoid features, during childhood. HG in adulthood is characterized by the liver disorder (with circulating aminotransferase increase) in the presence of poor glycemic control (elevation of glycated hemoglobin, HbA1c levels). The advances in the comprehension of the metabolic pathways driving to the hepatic glycogen deposition point out the role of glucose transporters and insulin mediated activations of glucokinase and glycogen synthase, with inhibition of glucose-6 phosphatase. The differential diagnosis of HG consists in the exclusion of causes of liver damage (infectious, metabolic, obstructive and autoimmune disease). The imaging study (ultrasonography and/or radiological examinations) gives information about the liver alterations (hepatomegaly), but the diagnosis needs to be confirmed by the liver biopsy. The main treatment of HG is the amelioration of glycemic control that is usually accompanied by the reversal of the liver disorder. In selected cases, more aggressive treatment options (transplantation) have been successfully reported. PMID- 25512792 TI - Type 2 diabetes mellitus and Alzheimer's disease. AB - Epidemiological and biological evidences support a link between type 2 diabetes mellitus (DM2) and Alzheimer's disease (AD). Persons with diabetes have a higher incidence of cognitive decline and an increased risk of developing all types of dementia. Cognitive deficits in persons with diabetes mainly affect the areas of psychomotor efficiency, attention, learning and memory, mental flexibility and speed, and executive function. The strong epidemiological association has suggested the existence of a physiopathological link. The determinants of the accelerated cognitive decline in DM2, however, are less clear. Increased cortical and subcortical atrophy have been evidenced after controlling for diabetic vascular disease and inadequate cerebral circulation. Most recent studies have focused on the role of insulin and insulin resistance as possible links between diabetes and AD. Disturbances in brain insulin signaling mechanisms may contribute to the molecular, biochemical, and histopathological lesions in AD. Hyperglycemia itself is a risk factor for cognitive dysfunction and dementia. Hypoglycemia may also have deleterious effects on cognitive function. Recurrent symptomatic and asymptomatic hypoglycemic episodes have been suggested to cause sub-clinical brain damage, and permanent cognitive impairment. Future trials are required to clarify the mechanistic link, to address the question whether cognitive decline may be prevented by an adequate metabolic control, and to elucidate the role of drugs that may cause hypoglycemic episodes. PMID- 25512793 TI - Sirtuins as novel players in the pathogenesis of diabetes mellitus. AB - Diabetes mellitus (DM) is a systemic and complex disease with micro and macrovascular complications that result from impaired metabolic pathways and genetic susceptibilities. DM has been accepted as an epidemic worldwide during the last two decades. A substantial gap in our knowledge exists regarding the pathophysiology of this metabolic disorder despite the improved diagnostic tools and therapeutic approaches. Sirtuins are a group of NAD(+) dependent enzymes that are involved in cellular homeostasis due to their deacetylating activity. In the present review, we aimed to discuss the role of associated sirtuins in the pathogenesis and treatment of diabetes mellitus. PMID- 25512794 TI - Diabetes mellitus and hypothyroidism: Strange bedfellows or mutual companions? AB - Clinicians should be cognizant of the close relationship that exists between two of the most common endocrine disorders, primary hypothyroidism and diabetes mellitus. This applies to patients with both type 1 and type 2 diabetes mellitus (T1DM and T2DM respectively). However, the association is greater in T1DM, probably because of the shared autoimmune predisposition. In patients with T2DM, the relationship is somewhat weaker and the explanation less clear-cut. Factors such as dietary iodine deficiency, metformin-induced thyroid stimulating hormone suppression and poor glycemic control may all be implicated. Further translational research is required for greater clarification. Biochemical screening for abnormal thyroid function in individuals who have diabetes is warranted, particularly in females with T1DM, and therapy with L-thyroxine appropriately instituted if hypothyroidism is confirmed. PMID- 25512795 TI - Diabetes mellitus in Nigeria: The past, present and future. AB - Diabetes mellitus (DM) is a diverse group of metabolic disorders that is often associated with a high disease burden in developing countries such as Nigeria. In the early nineties, not much was known about DM in Nigeria and traditionally, people related DM to "curses" or "hexes" and diagnosis was made based on blood or urinary tests for glucose. Currently, oral hypoglycaemic agents but not insulin are readily accessible and acceptable to persons with DM. The cost of diabetes care is borne in most instances by individuals and often payment is "out of pocket"-this being a sequel of a poorly functional national health insurance scheme. An insulin requiring individual on a minimum wage would spend 29% of his monthly income on insulin. Complementary and alternative medicines are widely used by persons with DM and form an integral component of DM care. Towards reducing the burden of DM in Nigeria, we suggest that there be concerted efforts by healthcare professionals and stakeholders in the health industry to put in place preventative measures, a better functioning health insurance scheme and a structured DM program. PMID- 25512796 TI - Possible contribution of (pro)renin receptor to development of gestational diabetes mellitus. AB - (Pro)renin receptor [(P)RR], a receptor for renin and prorenin, was first cloned in 2002. Since then, the pathophysiological roles of (P)RR have been growing concerns. (P)RR binds renin and prorenin, with two important consequences, nonproteolytic activation of prorenin, leading to the tissue renin-angiotensin system activation and the intracellular signalings. It is now also known to play an important role as vacuolar H(+)-ATPase associated protein, involving in Wnt signaling, main component of embryonic development. Extracellular domain of full length (P)RR is cleaved in golgi-complex forming soluble (P)RR [s(P)RR]. The s(P)RR is now possible to be measured in human blood and urine. It is now measured in different pathophysiological states, and recent study showed that elevated plasma s(P)RR levels in the early stage of pregnancies are associated with higher incidence of gestational diabetes mellitus later in the pregnancies. Plasma s(P)RR levels of neonates are known to be higher than that of adults. It was also shown that, increased s(P)RR concentrations in cord blood, associated with a lower small for gestational age birth likelihood. These data suggests the involvement of (P)RR in embryo's growth. In this review article, we attempt to figure out the possible pathophysiological roles of the (P)RR in maternal glucose intolerance and embryo's growth, through reviewing previous studies. PMID- 25512797 TI - Nonalcoholic steatohepatitis and insulin resistance in children. AB - Various pathological conditions can cause fatty liver in children. Nonalcoholic steatohepatitis (NASH) in children has been known since 1983. However, NASH diagnosed in childhood does not have a favorable outcome. The pathological characteristics of NASH are significantly different between children and adults. Nonalcoholic fatty liver disease (NAFLD)/NASH is accompanied by insulin resistance, which plays a pivotal role in its pathophysiology in both children and adults. In NASH, a "two-hit" model involving triglyceride accumulation (first hit) and liver damage (second hit) has been accepted. Insulin resistance was found to correlate with changes in fat levels; however, it did not correlate with fibrosis or NAFLD activity score in children. Therefore, insulin resistance may be important in the first hit. Because there is obvious familial clustering in NASH, genetic predisposition as well as environmental factors including diet might be the second hit of NAFLD/NASH. PMID- 25512799 TI - Risk factors for mortality in children with diabetic keto acidosis from developing countries. AB - Diabetic keto acidosis (DKA) is the major cause for mortality in children with Diabetes mellitus (DM). With increasing incidence of type 1 DM worldwide, there is an absolute increase of DM among children between 0-14 year age group and overall incidence among less than 30 years remain the same. This shift towards younger age group is more of concern especially in developing countries where mortality in DKA is alarmingly high. Prior to the era of insulin, DKA was associated with 100% mortality and subsequently mortality rates have come down and is now, 0.15%-0.31% in developed countries. However the scenario in developing countries like India, Pakistan, and Bangladesh are very different and mortality is still high in children with DKA. Prospective studies on DKA in children are lacking in developing countries. Literature on DKA related mortality are based on retrospective studies and are very recent from countries like India, Pakistan and Bangladesh. There exists an urgent need to understand the differences between developed and developing countries with respect to mortality rates and factors associated with increased mortality in children with DKA. Higher mortality rates, increased incidence of cerebral edema, sepsis, shock and renal failure have been identified among DKA in children from developing countries. Root cause for all these complications and increased mortality in DKA could be delayed diagnosis in children from developing countries. This necessitates creating awareness among parents, public and physicians by health education to identify symptoms of DM/DKA in children, in order to decrease mortality in DKA. Based on past experience in Parma, Italy it is possible to prevent occurrence of DKA both in new onset DM and in children with established DM, by simple interventions to increase awareness among public and physicians. PMID- 25512798 TI - Effect of periodontal treatment on adipokines in type 2 diabetes. AB - The association between adipokines and inflammatory periodontal diseases has been studied over the last two decades. This review was intended to explore the observation that periodontal therapy may lead to an improvement of adipokines in diabetic patients. In summary, substantial evidence suggests that diabetes is associated with increased prevalence, extent and severity of periodontitis. Numerous mechanisms have been elucidated to explain the impact of diabetes on the periodontium. However, current knowledge concerning the role of major adipokines indicates only some of their associations with the pathogenesis of periodontitis in type 2 diabetes. Conversely, treatment of periodontal disease and reduction of oral inflammation may have positive effects on the diabetic condition, although evidence for this remains somewhat equivocal. PMID- 25512800 TI - Type 2 diabetes is associated with a worse functional outcome of ischemic stroke. AB - AIM: To assess whether ischemic stroke severity and outcome is more adverse in patients with type 2 diabetes mellitus (T2DM). METHODS: Consecutive patients hospitalized for acute ischemic stroke between September 2010 and June 2013 were studied prospectively (n = 482; 40.2% males, age 78.8 +/- 6.7 years). T2DM was defined as self-reported T2DM or antidiabetic treatment. Stroke severity was evaluated with the National Institutes of Health Stroke Scale (NIHSS) score at admission. The outcome was assessed with the modified Rankin scale (mRS) score at discharge and with in-hospital mortality. Adverse outcome was defined as mRS score at discharge >= 2 or in-hospital death. The length of hospitalization was also recorded. RESULTS: T2DM was present in 32.2% of the study population. Patients with T2DM had a larger waist circumference, higher serum triglyceride and glucose levels and lower serum high-density lipoprotein cholesterol levels as well as higher prevalence of hypertension, coronary heart disease and congestive heart failure than patients without T2DM. On the other hand, diabetic patients had lower low-density lipoprotein cholesterol levels and reported smaller consumption of alcohol than non-diabetic patients. At admission, the NIHSS score did not differ between patients with and without T2DM (8.7 +/- 8.8 and 8.6 +/- 9.2, respectively; P = NS). At discharge, the mRS score also did not differ between the two groups (2.7 +/- 2.1 and 2.7 +/- 2.2 in patients with and without T2DM, respectively; P = NS). Rates of adverse outcome were also similar in patients with and without T2DM (62.3% and 58.5%, respectively; P = NS). However, when we adjusted for the differences between patients with T2DM and those without T2DM in cardiovascular risk factors, T2DM was independently associated with adverse outcome [relative risk (RR) = 2.39; 95%CI: 1.21-4.72, P = 0.012]. In hospital mortality rates did not differ between patients with T2DM and those without T2DM (9.0% and 9.8%, respectively; P = NS). In multivariate analysis adjusting for the difference in cardiovascular risk factors between the two groups, T2DM was again not associated with in-hospital death. CONCLUSION: T2DM does not appear to affect ischemic stroke severity but is independently associated with a worse functional outcome at discharge. PMID- 25512801 TI - Risk factors for cost-related medication non-adherence among older patients with diabetes. AB - AIM: To assess the risk factors for cost-related medication non-adherence (CRN) among older patients with diabetes in the United States. METHODS: We used data from the 2010 Health and Retirement Study to assess risk factors for CRN including age, drug insurance coverage, nursing home residence, functional limitations, and frequency of hospitalization. CRN was self-reported. We conducted multivariate regression analysis to assess the effect of each risk factor. RESULTS: Eight hundred and seventy-five (18%) of 4880 diabetes patients reported CRN. Age less than 65 years, lack of drug insurance coverage, and frequent hospitalization significantly increased risk for CRN. Limitation in both activities of daily living and instrumental activities of daily living were also generally associated with increased risk of CRN. Residence in a nursing home and Medicaid coverage significantly reduced risk. CONCLUSION: These results suggest that expanding prescription coverage to uninsured, sicker, and community-dwelling individuals is likely to produce the largest decreases in CRN. PMID- 25512803 TI - Flavonoid-rich beverage effects on lipid profile and blood pressure in diabetic patients. AB - AIM: To compare freeze-dried strawberry (FDS) beverage and strawberry-flavored drink effects on lipid profile and blood pressure in type 2 diabetic (T2D) patients. METHODS: In a randomized, double-blind, controlled trial, 36 subjects with T2D (23 females; mean +/- SE age: 51.57 +/- 10 years) were randomly divided into two groups. Participants consumed two cups of either pure FDS beverage (each cup containing 25 g freeze-dried strawberry powder equivalent to one serving of fresh strawberries; intervention group) or an iso-caloric drink with strawberry flavoring (similar to the FDS drink in fiber content and color; placebo group) daily for 6 wk. Anthropometric measurements, 3 d, 24 h dietary recall, and fasting blood samples were collected at baseline and at weeks 6 intervention. After lying down and relaxing for approximately 10 min, each participant's blood pressure was recorded in triplicate with 5 min intervals; recordings were made at baseline and the trial end-point. Each participant's lipid profile was assessed before and after intervention. RESULTS: Assessment at the weeks 6 intervention showed a significant reduction from baseline in total cholesterol levels and total cholesterol to high-density lipoprotein cholesterol (HDL-C) ratio in the intervention group (179.01 +/- 31.86 to 165.9 +/- 32.4 mg/L; P = 0.00 and 3.9 +/- 0.88 to 3.6 +/- 0.082 mg/L; P = 0.00 respectively), but the change was not significantly different between the two groups (P = 0.07, P = 0.29 respectively). Systolic blood pressure levels were significantly reduced from baseline in both the FDS and placebo drink groups (129.95 +/- 14.9 to 114.3 +/- 27.5 mmHg; P = 0.02 and 127.6 +/- 15.6 to 122.9 +/- 14.47 mmHg; P = 0.00 respectively), but the reduction was not significantly different between the two groups. Diastolic blood pressure was significantly reduced post-intervention in the FDS drink group compared to placebo group (78.7 +/- 7.2 vs 84.4 +/- 5.8; P = 0.01), the reduction was also significant within the FDS drink group (84.2 +/- 8.03 to 78.7 +/- 7.2; P = 0.00). Triglycerides, HDL-C concentrations and anthropometric indices showed no significant differences between or within groups. CONCLUSION: Short-term FDS supplementation improved selected cardiovascular risk factors in subjects with T2D. Long-term effects on other metabolic biomarkers need to be investigated in future trials. PMID- 25512802 TI - Pancreas transplantation: The Wake Forest experience in the new millennium. AB - AIM: To investigate the Wake Forest experience with pancreas transplantation in the new millennium with attention to surgical techniques and immunosuppression. METHODS: A monocentric, retrospective review of outcomes in simultaneous kidney pancreas transplant (SKPT) and solitary pancreas transplant (SPT) recipients was performed. All patients underwent pancreas transplantation as intent-to-treat with portal venous and enteric exocrine drainage and received depleting antibody induction; maintenance therapy included tapered steroids or early steroid elimination with mycophenolate and tacrolimus. Recipient selection was based on clinical judgment whether or not the patient exhibited measureable levels of C peptide. RESULTS: Over an 11.25 year period, 202 pancreas transplants were performed in 192 patients including 162 SKPTs and 40 SPTs. A total of 186 (92%) were primary and 16 (8%) pancreas retransplants; portal-enteric drainage was performed in 179 cases. A total of 39 pancreas transplants were performed in African American (AA) patients; of the 162 SKPTs, 30 were performed in patients with pretransplant C-peptide levels > 2.0 ng/mL. In addition, from 2005-2008, 46 SKPT patients were enrolled in a prospective study of single dose alemtuzumab vs 3-5 doses of rabbit anti-thymocyte globulin induction therapy. With a mean follow up of 5.7 in SKPT vs 7.7 years in SPT recipients, overall patient (86% SKPT vs 87% SPT) and kidney (74% SKPT vs 80% SPT) graft survival rates as well as insulin free rates (both 65%) were similar (P = NS). Although mortality rates were nearly identical in SKPT compared to SPT recipients, patterns and timing of death were different as no early mortality occurred in SPT recipients whereas the rates of mortality following SKPT were 4%, 9% and 12%, at 1-, 3- and 5-years follow-up, respectively (P < 0.05). The primary cause of graft loss in SKPT recipients was death with a functioning graft whereas the major cause of graft loss following SPT was acute and chronic rejection. The overall incidence of acute rejection was 29% in SKPT and 27.5% in SPT recipients (P = NS). Lower rates of acute rejection and major infection were evidenced in SKPT patients receiving alemtuzumab induction therapy. Comparable kidney and pancreas graft survival rates were observed in AA and non-AA recipients despite a higher prevalence of a "type 2 diabetes" phenotype in AA. Results comparable to those achieved in insulinopenic diabetics were found in the transplantation of type 2 diabetics with detectable C peptide levels. CONCLUSION: In the new millennium, acceptable medium-term outcomes can be achieved in SKPT and SPTs as nearly 2/3rds of patients are insulin independent following pancreas transplantation. PMID- 25512804 TI - Immediate Surgical Skills Feedback in the Operating Room Using "SurF" Cards. AB - BACKGROUND: Ensuring residents develop operative skills requires application of the principles of guided learning, deliberate practice, and directed feedback. OBJECTIVE: We sought to create and implement a tool to promote procedural "key" step review and immediate feedback on surgical skills, and examined faculty and resident satisfaction with surgical skills feedback. METHODS: We created surgical skills feedback (SurF) cards for 8 gynecologic procedures. Faculty/fellows and residents completed prestudy surveys querying frequency of preoperative key step review and satisfaction with surgical skill feedback, a SurF card each time 1 of 8 procedures was performed, and poststudy surveys to evaluate for changes. RESULTS: Prestudy surveys were completed by 31 faculty/fellows and 20 residents, with 55% (17 of 31) of the faculty/fellows and 5% (1 of 20) of the residents reporting key step review before surgery. All reported low satisfaction rates with feedback frequency, quality, and timeliness. After implementation of SurF cards, preoperative key step review occurred in 78% (82 of 105) of the procedures. Twenty-one faculty/fellows (68%) and 16 residents (80%) completed our poststudy survey. Faculty/fellows reported statistically similar key step review (n = 15 [71%], P = .23), while residents reported that key step review had significantly improved (n = 6 [38%], P = .01). Resident satisfaction with feedback frequency (5% to 50%, P = .002) and quality (15% to 50%, P = .02) increased significantly. CONCLUSIONS: The SurF cards we developed facilitated procedural key step review, were associated with significantly improved resident satisfaction with surgical feedback, and could prove helpful with outcomes assessments, such as Accreditation Council for Graduate Medical Education required documentation of Milestone attainment. PMID- 25512805 TI - Resident teachers and feedback: time to raise the bar. PMID- 25512806 TI - Now You See It, Now You Don't: What Thinking Aloud Tells Us About Clinical Reasoning. PMID- 25512807 TI - Residency redesign: much to do. PMID- 25512808 TI - Quality improvement and patient safety milestones for the continuum of physician development. PMID- 25512809 TI - Report of the Korean Journal of Urology Editorial Board Meeting 2014. PMID- 25512810 TI - Medical and dietary therapy for kidney stone prevention. AB - The prevalence of kidney stone disease is increasing, and newer research is finding that stones are associated with several serious morbidities. These facts suggest that emphasis needs to be placed not only on stone treatment but also stone prevention. However, there is a relative dearth of information on dietary and medical therapies to treat and avoid nephrolithiasis. In addition, studies have shown that there are many misconceptions among both the general community and physicians about how stones should be managed. This article is meant to serve as a review of the current literature on dietary and drug therapies for stone prevention. PMID- 25512811 TI - Current status of cryotherapy for prostate and kidney cancer. AB - In terms of treating diseases, minimally invasive treatment has become a key element in reducing perioperative complications. Among the various minimally invasive treatments, cryotherapy is often used in urology to treat various types of cancers, especially prostate cancer and renal cancer. In prostate cancer, the increased incidence of low-risk, localized prostate cancer has made minimally invasive treatment modalities an attractive option. Focal cryotherapy for localized unilateral disease offers the added benefit of minimal morbidities. In renal cancer, owing to the increasing utilization of cross-sectional imaging, nearly 70% of newly detected renal masses are stage T1a, making them more susceptible to minimally invasive nephron-sparing therapies including laparoscopic and robotic partial nephrectomy and ablative therapies. This article reviews the various outcomes of cryotherapy compared with other treatments and the possible uses of cryotherapy in surgery. PMID- 25512813 TI - Histologic variability and diverse oncologic outcomes of prostate sarcomas. AB - PURPOSE: Primary prostate sarcomas are a rare type of prostate cancer that account for less than 0.1% of primary prostate malignancies. We analyzed the experience of a single institution with prostate sarcoma over 20 years. MATERIALS AND METHODS: In this case series, the medical records of 20 patients with prostate sarcoma were reviewed from June 1990 to December 2013 to identify symptoms at presentation, diagnostic procedures, metastasis presence and development, histologic subtype, French Federation Nationale des Centres de Lutte Contre le Cancer grade, primary tumor grade and size, and treatment sequence, including surgery and preoperative and postoperative therapies. The average follow-up period was 23.6 months (range, 1.4-83.3 months). RESULTS: The average patient age was 46.3 +/- 16.7 years. Most patients presented with lower urinary tract symptoms (55%). The histologic subtype was spindle cell sarcoma in five patients (25%), rhabdomyosarcoma in three patients (15%), synovial sarcoma in three patients (15%), liposarcoma in three patients (15%), stromal sarcoma in three patients (15%), and Ewing sarcoma, nerve sheath tumor, and adenocarcinoma with sarcomatoid component (5% each). For liposarcoma, two patients were alive after complete surgical resection and had a good prognosis. At last follow-up, 15 patients had died of sarcoma. The 2- and 5-year actuarial survival rates for all 20 patients were 53% and 12%, respectively (medial survival, 20 months). CONCLUSIONS: The disease-specific survival rate of prostate sarcoma is poor. However, sarcoma that is detected early shows a better result with proper management including surgical intervention with radio-chemotherapy than with no treatment. Early diagnosis and complete surgical resection offer patients the best curative chance. PMID- 25512812 TI - Overview of pediatric testicular tumors in Korea. AB - Prepubertal testicular tumors are rare compared with postpubertal testicular tumors. The incidence of prepubertal testicular tumors peaks at 2 years of age, tapers off after 4 years of age, and then begins to rise again at puberty. Prepubertal and postpubertal testicular tumors show many differences, including the typical tumor histology, molecular biological differences, and the malignant potential of tumors at different ages. Pediatric testicular tumors are classified as benign or malignant on the basis of their clinical behavior and histologically are divided into germ cell and gonadal stromal (nongerm cell) tumors. Many histological and biological studies have further confirmed the distinct nature of prepubertal and postpubertal testicular tumors. These differences have led to various management strategies for prepubertal and postpubertal tumors. Because overall about 75% of prepubertal testicular tumors are benign, a testis-sparing approach is becoming more common in children. Orchiectomy and observation with very selective use of chemotherapy has become the standard approach when a malignant tumor is identified. Retroperitoneal lymph node dissection and radiation therapy play very limited roles. PMID- 25512814 TI - Location of positive surgical margin and its association with biochemical recurrence rate do not differ significantly in four different types of radical prostatectomy. AB - PURPOSE: To analyze the location of the positive surgical margin (PSM) and its association with the biochemical recurrence (BCR) rate in cases of radical prostatectomy (RP) according to the type of surgery. MATERIALS AND METHODS: We retrospectively analyzed 1,880 cases of RP. Baseline characteristics were analyzed. Locations of the PSM were recorded in the four surgery groups as apex, anterior, posterolateral, and base and were analyzed by using chi-square test. The association of the location of the PSM with the BCR rate was analyzed by using Kaplan-Meier survival analysis according to the type of surgery, which included radical perineal prostatectomy (RPP, n=633), radical retroperitoneal prostatectomy (RRP, n=309), laparoscopic radical prostatectomy (LRP, n=164), and robot-assisted laparoscopic radical prostatectomy (RALRP, n=774). RESULTS: A PSM was found in a total of 336 cases (18%): 122 cases of RPP (18%), 67 cases of RRP (17%), 29 cases of LRP (17%), and 119 cases of RALRP (15%). The PSM rate did not differ significantly by surgical type (p=0.142). The location of the PSM was the apex in 136 cases (7.2%), anterior in 67 cases (3.5%), posterolateral in 139 cases (7.3%), and base in 95 cases (5.0%), and showed no significant difference according to surgical type (p=0.536, p=0.557, p=0.062, and p=0.109, respectively). The BCR rate according to the location of the PSM did not differ significantly for the four types of surgery (p=0.694, p=0.301, p=0.445, and p=0.309 for RPP, RRP, LRP, and RALRP, respectively). CONCLUSIONS: The location of the PSM seemed to be unrelated to type of RP. There was no significant correlation between the BCR rate and the location of the PSM for any of the RP types. PMID- 25512815 TI - Comparison of perioperative outcomes of robotic versus laparoscopic partial nephrectomy for complex renal tumors (RENAL nephrometry score of 7 or higher). AB - PURPOSE: To compare the perioperative outcomes of laparoscopic partial nephrectomy (LPN) and robotic partial nephrectomy (RPN) for moderately or highly complex tumors (RENAL nephrometry score >= 7). MATERIALS AND METHODS: A retrospective analysis was performed for 127 consecutive patients who underwent either LPN (n=38) or RPN (n=89) between 2007 and 2013. Perioperative outcomes were compared. RESULTS: There were no significant differences between the two groups with respect to patient gender, laterality, RENAL nephrometry score, or body mass index. The RPN group had a slightly higher RENAL nephrometry score (7.8 vs. 7.5, p=0.061) and larger tumor size (3.0 cm vs. 2.5 cm, p=0.044) but had a lower Charlson comorbidity index (3.7 vs. 4.4, p=0.017) than did the LPN group. There were no significant differences with respect to warm ischemia time, estimated blood loss, intraoperative complications, or operative time. Only one patient who underwent LPN had a positive surgical margin. There were statistically significant differences in surgical marginal width between the LPN and RPN groups (0.6 cm vs. 0.4 cm, p=0.001). No significant differences in postoperative complications were found between the two groups. Owing to potential baseline differences between the two groups, we performed a propensity-based matching analysis, in which differences in surgical margin width between the LPN and RPN groups remained statistically significant (0.6 cm vs. 0.4 cm, p=0.029). CONCLUSIONS: RPN provides perioperative outcomes comparable to those of LPN and has the advantage of healthy parenchymal preservation for complex renal tumors (RENAL score >= 7). PMID- 25512816 TI - Impact of metabolic syndrome on response to medical treatment of benign prostatic hyperplasia. AB - PURPOSE: To investigate the effect of metabolic syndrome (MetS) on the response to medical therapy of benign prostatic hyperplasia (BPH) after a 3-month period of treatment. MATERIALS AND METHODS: This was a cohort study of 100 patients, 47 with MetS and 53 without MetS, referred to either the primary care unit or referral hospital with BPH who had moderate lower urinary tract symptoms of prostate involvement and were candidates for medical treatment. Our main outcome was response to medical treatment with prazosin 1 mg twice a day and finasteride 5 mg daily in patients with BPH on the basis of International Prostate Symptom Score (IPSS). Multivariate analysis of covariance was used to compare BPH treatment response in patients with and without MetS before and after receiving treatment. RESULTS: The mean volume of the prostate was significantly higher in MetS patients than in patients without MetS (57 +/- 32.65 mL compared with 46.00 +/- 20.19 mL, p=0.036). The control group demonstrated an 11-unit reduction in IPSS, whereas those with MetS showed a reduction in the symptom score of only 6 units (p<0.001). Regarding the components of MetS separately, triglyceride (p<0.001), fasting blood sugar (p=0.001), and waist circumference (p=0.028) significantly affected the clinical progression of BPH. The observational nature of this study may be a limitation in comparison with an interventional study. CONCLUSIONS: The results of the present study showed that MetS can negatively affect the response to medical treatment of BPH. Therefore, it is necessary to consider MetS in selecting patients with BPH for drug therapy. PMID- 25512817 TI - Does preoperative urodynamic testing improve surgical outcomes in patients undergoing the transobturator tape procedure for stress urinary incontinence? A prospective randomized trial. AB - PURPOSE: Urodynamic studies are commonly performed as part of the preoperative work-up of patients undergoing surgery for stress urinary incontinence (SUI). We aimed to assess the extent to which these urodynamic parameters influence patient selection and postoperative outcomes. MATERIALS AND METHODS: Patients presenting with SUI were randomly assigned to two groups: one undergoing office evaluation only and the other with a preoperative urodynamic work-up. Patients with unfavorable urodynamic parameters (detrusor overactivity [DO] and/or Valsalva leak point pressure [VLPP]<60 cm H2O and/or maximum urethral closure pressure [MUCP]<20 cm H2O) were excluded from the urodynamic testing group. All patients in both groups underwent the transobturator midurethral sling procedure. Evaluation for treatment success (reductions in urogenital distress inventory and incontinence impact questionnaire scoring along with absent positive stress test) was done at 6 months and 1 year postoperatively. RESULTS: A total of 72 patients were evaluated. After 12 patients with any one or more of the abnormal urodynamic parameters were excluded, 30 patients were finally recruited in each of the "urodynamic testing" and "office evaluation only" groups. At both the 6- and the 12-month follow-ups, treatment outcomes (reduction in scores and positive provocative stress test) were significantly better in the urodynamic testing group than in the office evaluation only group (p-values significant for all outcomes). CONCLUSIONS: Our findings showed statistically significantly better treatment outcomes in the urodynamic group (after excluding those with poor prognostic indicators such as DO, low VLPP, and MUCP) than in the office evaluation only group. We recommend exploiting the prognostic value of these urodynamic parameters for patient counseling and treatment decisions. PMID- 25512818 TI - Efficacy, tolerability, and safety of oxybutynin chloride in pediatric neurogenic bladder with spinal dysraphism: a retrospective, multicenter, observational study. AB - PURPOSE: Anticholinergics are a key element in treating neurogenic detrusor overactivity, but only limited data are available in the pediatric population, thus limiting the application to children even for oxybutynin chloride (OC), a prototype drug. This retrospective study was designed to provide data regarding the efficacy, tolerability, and safety of OC in the pediatric population (0-15 years old) with spinal dysraphism (SD). MATERIALS AND METHODS: Records relevant to OC use for neurogenic bladder were gathered and scrutinized from four specialized clinics for pediatric urology. The primary efficacy outcomes were maximal cystometric capacity (MCC) and end filling pressure (EFP). Data on tolerability, compliance, and adverse events (AEs) were also analyzed. RESULTS: Of the 121 patient records analyzed, 41 patients (34%) received OC at less than 5 years of age. The range of prescribed doses varied from 3 to 24 mg/d. The median treatment duration was 19 months (range, 0.3-111 months). Significant improvement of both primary efficacy outcomes was noted following OC treatment. MCC increased about 8% even after adjustment for age-related increases in MCC. Likewise, mean EFP was reduced from 33 to 21 cm H2O. More than 80% of patients showed compliance above 70%, and approximately 50% of patients used OC for more than 1 year. No serious AEs were reported; constipation and facial flushing consisted of the major AEs. CONCLUSIONS: OC is safe and efficacious in treating pediatric neurogenic bladder associated with SD. The drug is also tolerable and the safety profile suggests that adjustment of dosage for age may not be strictly observed. PMID- 25512819 TI - Tumor-specific immunity induced by cryoablation in a murine renal cell carcinoma model. AB - PURPOSE: To evaluate tumor-specific immunity and define the mechanisms involved in the cryoimmunologic response, we compared the tumor control efficacy and immunologic responses of cryoablation with those of surgical excision in a tumor rechallenge model. MATERIALS AND METHODS: Sixty BALB/c mice with RENCA tumors that were generated in the left flank area underwent cryoablation or radical excision. The mice successfully treated were rechallenged with RENCA or an undifferentiated colon carcinoma cell line, CT26, in the contralateral right flank area. The recurrence rate after tumor rechallenge in each group was then observed. To assess the immunologic response of each treatment modality, fluorescent-activated cell sorting (FACS) analysis and a cytotoxicity assay using (51)Cr release were performed. RESULTS: After reinoculation of the RENCA cells, the rate of tumor growth was significantly higher in the surgical excision group than in the cryoablation group (94.4% vs. 11.1%, p=0.001). In the cryoablation group, the tumor growth rate was significantly increased after rechallenge of CT26 cells compared with RENCA (94.1% vs. 11.1%, p=0.001). The cryoablation group showed an elevated CD3, CD4, CD8 T, and natural killer cell count in the FACS analysis and also showed significantly increased cytotoxicity in the (51)Cr release assay compared with the excision group. CONCLUSIONS: These results showed that cryoablation, compared to surgical resection, was more effective in preventing tumor growth after rechallenge with RENCA cells and that this response was tumor-specific, because the CT26 cells did not have the same effect. PMID- 25512820 TI - Reconstruction of an amputated glans penis with a buccal mucosal graft: case report of a novel technique. AB - Penile amputation is a rare catastrophe and a serious complication of circumcision. Reconstruction of the glans penis may be indicated following amputation. Our report discusses a novel technique for reconfiguration of an amputated glans penis 1 year after a complicated circumcision. A 2-year-old male infant presented to us with glans penis amputation that had occurred during circumcision 1 year previously. The parents complained of severe meatal stenosis with disfigurement of the penis. Penis length was 3 cm. Complete penile degloving was performed. The distal part of the remaining penis was prepared by removing fibrous tissue. A buccal mucosal graft was applied to the distal part of the penis associated with meatotomy. The use of a buccal mucosal graft is a successful and simple procedure with acceptable cosmetic and functional results for late reconfiguration of the glans penis after amputation when penile size is suitable. PMID- 25512821 TI - Radiofrequency-treated recurrence of urothelial carcinoma of the upper urinary tract after nephroureterectomy. AB - Local recurrence after radical nephroureterectomy (RNU) owing to urothelial carcinoma of the upper urinary tract is rare. The usual treatment is systemic chemotherapy followed by optional resection of the mass. We introduce the case of a 73-year-old male patient with multiple comorbidities in whom retroperitoneal carcinoma recurrence of 31 mm was diagnosed via positron emission tomography computed tomography scan with 18-fluorodeoxyglucose about 5 years after he had undergone RNU owing to urothelial carcinoma of the upper urinary tract. The patient was treated with computed tomography-guided percutaneous radiofrequency ablation. Later scans with contrast controls showed lack of contrast uptake and a decrease of the lesion's size. Twenty-four months after the procedure, the patient is free of the disease. To date, this is the first case of recurrence of urothelial carcinoma that was treated with percutaneous radiofrequency ablation, thus establishing an alternative to chemotherapy in patients with substantial comorbidities. PMID- 25512822 TI - Applying professional values: the perspective of nurses of Isfahan hospitals. AB - Applying professional values is an important issue in nursing practice. It is also crucial to find out nurses' perspectives toward ethical and professional values in the clinical environment. For this purpose, we aimed to utilize a standard tool to survey perspectives on applying these values in nursing care in hospitals of Isfahan, Iran. This is a descriptive-analytical study in which 150 nurses working in hospitals of Isfahan, Iran in 2010 were recruited by quota convenience sampling, and their perspectives on professional values were assessed. Data were collected by the Nurses Professional Values Scale (NPVS) and analyzed using SPSS Software version 16 applying descriptive and interpretive statistics. In the present study, 84% of the participants were female and 88% had bachelor's degree in nursing. The average age was 34.2 (SD=7.3), and the average years of working in a hospital were 11 (SD=7.3). No significant association was present between demographic characteristics such as age, sex, educational level or work records and applying professional and ethical values. Results also demonstrated that respect for professional values is similar among nurses of different employment types. In this study, we addressed the most and the less important professional values specified by nurses with different types of employment and also different experiences. Iranian nurses believe in respecting the legal and ethical rights of patients as the most prominent value in the nursing profession. We suggest that these professional values be specified and assessed based on Iranian culture. PMID- 25512823 TI - End-of-life care ethical decision-making: Shiite scholars' views. AB - Recent advances in life-sustaining treatments and technologies, have given rise to newly-emerged, critical and sometimes, controversial questions regarding different aspects of end-of-life decision-making and care. Since religious values are among the most influential factors in these decisions, the present study aimed to examine the Islamic scholars' views on end-of-life care. A structured interview based on six main questions on ethical decision-making in end-of-life care was conducted with eight Shiite experts in Islamic studies, and was analyzed through deductive content analysis. Analysis revealed certain points in Islamic views on the definition of death and the persons making decisions about end-of life care. According to the participants, in addition to conventional criteria ('urf) such as absence of heartbeat and respiration, the irreversible cessation of human voluntary acts (as a sign that the soul has control over the body and the faculty of thinking) are considered to be the criteria in establishing death. The participants also recognized physicians as the main authorities in verifying signs of death. Furthermore, it was emphasized that life preservation and continuation of care must be sensible, and the patient can request not to have death-prolonging procedures started or continued. In the view of participants, patient's autonomy cannot be the sole basis for all measures, but Islamic ethical and jurisprudential principles should be relied upon to make correct and sensible decisions whether to continue or stop terminal patients' care. Final decisions should be made by a team of experts, and physicians must be at the center of such a team. Finally, we suggest that a guideline in keeping with Islamic norms on human life and death, purpose of life, God's will, boundaries of man's authority, and the physician's ethical duties and obligations should be developed. PMID- 25512824 TI - The relationship between moral distress, professional stress, and intent to stay in the nursing profession. AB - Moral distress and professional stress are common problems that can have adverse effects on nurses, patients, and the healthcare system as a whole. Thus, this cross-sectional study aims to examine the relationship between moral distress, professional stress, and intent to stay in the nursing profession. Two hundred and twenty full-time nurses employed at teaching hospitals in the eastern regions of Iran were studied. A 52-item questionnaire based on Corley's Moral Distress Scale, Wolfgang's Health Professions Stress Inventory and Nedd Questionnaire on Intent to Stay in the Profession was used in the study. Additionally, demographic details of the study population were collected. No significant correlation was observed between the intensity and frequency of moral distress, professional stress, and intent to stay in the profession among nurses (P > 0.05). There was a significant correlation between moral distress, professional stress, and age, number of years in service and work setting (P < 0.05). Given the important effect of moral distress and professional stress on nurses, in addition to the educational programs for familiarization of nurses with these concepts, it is recommended that strategies be formulated by the healthcare system to increase nurses' ability to combat their adverse effects. PMID- 25512825 TI - Mission impossible: upholding successfully a charge of infanticide in the Albanian legal practice. AB - Infanticide is a horrendous crime universally condemned from all ethical, juridical and moral standpoints. However, legislation on infanticide foresees mitigating circumstances for infanticidal mothers, with sentences by far disproportionate to the severity of the crime. The main justification for this abstaining from severe punishments has been the so-called post puerperal psychosis, whose diagnostic criteria and existence are still very confusing. Psychiatric experts and even jurors show excessive feelings of empathy toward defendant mothers, and fair verdicts under this setting and with this judicial tradition are questionable. Albanian courts have in some cases even denied defendant mothers the unwilling albeit necessary psychiatric treatment, thus exposing them to recidivism and to other social difficulties. Upholding the charge of infanticide in an Albanian court is hereby an impossible enterprise, with high chances for defendants to achieve acquittal on mental insanity grounds. Through describing three cases of infanticide and filicide in recent years of Albanian judicial proceedings, authors raise the concern formulated from other sources regarding the excessive empathy surrounding infanticidal mothers, a deleterious obstacle toward achieving justice. PMID- 25512826 TI - Teaching endotracheal intubation on the recently deceased: opinion of patients and families. AB - This study was done to explore the views of patients and their companions concerning endotracheal intubation training on newly deceased patients and the necessity of obtaining their consent in this regard. In this cross-sectional descriptive analytical study, we used a questionnaire to collect data through structured interviews conducted by the researcher on patient discharge day. A convenient sample of over 18 year old patients hospitalized at a teaching hospital were enrolled, and after receiving patient consent, one of each patient's companions was enrolled in the study as well. In this study, 150 of the approached patients agreed to participate (response rate = 85.0%); of those, 92 (61.3%) allowed their companions to be enrolled as well. Eighty-three persons (55.3%) in the patient group and 68 persons (73.9%) in the companion group agreed to have endotracheal intubation training on their own bodies after death. Among these consenting patients and companions, 75.9% (n = 63) and 91.2% (n = 62) believed it was necessary to acquire patient consent for this procedure. Obtaining relatives' consent was thought to be necessary by 69.9% (n = 72) of the patients and 72.1% (n = 49) of the companions, even when there was patient prior consent. Therefore it seems that asking the patient's consent for doing educational procedures on their dead body is crucial. PMID- 25512827 TI - Health care practices in ancient Greece: The Hippocratic ideal. AB - Asclepius and Hippocrates focused medical practice on the natural approach and treatment of diseases, highlighting the importance of understanding the patient's health, independence of mind, and the need for harmony between the individual, social and natural environment, as reflected in the Hippocratic Oath. The aim of this study was to present the philosophy of care provision in ancient Greece and to highlight the influence of the Hippocratic ideal in modern health care practices. A literature review was carried out using browser methods in international databases. According to the literature, "healthy mind in a healthy body" was the main component of the Hippocratic philosophy. Three main categories were observed in the Hippocratic provision of care: health promotion, interventions on trauma care, and mental care and art therapy interventions. Health promotion included physical activity as an essential part of physical and mental health, and emphasized the importance of nutrition to improve performance in the Olympic Games. Interventions on trauma care included surgical practices developed by Hippocrates, mainly due to the frequent wars in ancient Greece. Mental care and art therapy interventions were in accordance with the first classification of mental disorders, which was proposed by Hippocrates. In this category music and drama were used as management tools in the treatment of illness and in the improvement of human behavior. The role of Asclepieion of Kos was highlighted which clearly indicates a holistic health care model in care provision. Finally, all practices regarded detailed recordings and evaluation of information within the guidelines. The Hippocratic philosophy on health care provision focused on the holistic health care model, applying standards and ethical rules that are still valid today. PMID- 25512828 TI - A comparison between conflict of interest in Western and Islamic literatures in the realm of medicine. AB - In Western literatures, "conflict" is a general term that refers to discord between two or more entities. In Islamic jurisprudence, however, in addition to the term "conflict" (Taaruz), there is another term which is called tazahum. The two terms, however, have different definitions. Conflict between two concepts, for instance, indicates that one is right and the other is wrong, while tazahum does not necessarily have to be between right and wrong, and may appear between two equally right concepts. Moreover, conflict exists on a legislative level, while tazahum is a matter of obedience and adherence, meaning that in practice, both sides cannot continue to coexist. Conflict of interest is a known term in Western literatures, and according to D.F. Thompson, it refers to a situation where professional judgment regarding a primary interest is improperly and unjustifiably influenced by a secondary interest. Taking into account Thompson's definition and the distinction between "conflict" (Taaruz) and "tazahum", the English term "conflict of interest" translates to "tazahum of interest" in Islamic jurisprudence as it refers to a person's action without reflecting right or wrong, and simply concerns priority of one interest over another. The resolution to tazahum in Islamic jurisprudence lies in two principles: the principle of significance and the principle of choice. For instance, in case of conflict (the Western term) or tazahum (the Islamic term) between the interests of patient and physician, the patient's interest should be the main concern based on the principle of significance. Although Western literatures propose methods such as disclosure or prohibition in order to resolve conflict of interest, the foundation for these solutions seems to have been the principle of significance. PMID- 25512829 TI - An exploratory study on the elements that might affect medical students' and residents' responsibility during clinical training. AB - We are now more or less confronting a "challenge of responsibility" among both undergraduate and postgraduate medical students and some recent alumni from medical schools in Iran. This ethical problem calls for urgent etiologic and pathologic investigations into the problem itself and the issues involved. This study aimed to develop a thematic conceptual framework to study factors that might affect medical trainees' (MTs) observance of responsibility during clinical training. A qualitative descriptive methodology involving fifteen in-depth semi structured interviews was used to collect the data. Interviews were conducted with both undergraduate and postgraduate MTs as well as clinical experts and experienced nurses. Interviews were audio-recorded and then transcribed. The data was analyzed using thematic content analysis. The framework derived from the data included two main themes, namely "contextual conditions" and "intervening conditions". Within each theme, participants recurrently described "individual" and "non-individual or system" based factors that played a role in medical trainees' observance of responsibility. Overall, contextual conditions provide MTs with a "primary or basic responsibility" which is then transformed into a "secondary or observed responsibility" under the influence of intervening conditions. In conclusion three measures were demonstrated to be very important in enhancing Iranian MTs' observance of responsibility: a) to make and implement stricter and more exact admission policies for medical colleges, b) to improve and revise the education system in its different dimensions such as management, structure, etc. based on regular and systematic evaluations, and c) to establish, apply and sustain higher standards throughout the educational environment. PMID- 25512830 TI - Giving information to family members of patients in the intensive care unit: Iranian nurses' ethical approaches. AB - Receiving information related to patients hospitalized in the intensive care unit is among the most important needs of the family members of such patients. When health care professionals should decide whether to be honest or to give hope, giving information becomes an ethical challenge We conducted a research to study the ethical approaches of Iranian nurses to giving information to the family members of patients in the intensive care units. This research was conducted in the intensive care units of three teaching hospitals in Iran. It employed a qualitative approach involving semi-structured and in-depth interviews with a purposive sample of 12 nurses to identify the ethical approaches to giving information to family members of the intensive care unit patients. A conventional content analysis of the data produced two categories and five subcategories. The two categories were as follows: a) informational support, and b) emotional support. Informational support had 2 subcategories consisting of being honest in giving information, and providing complete and understandable information. Emotional support in giving information had 3 sub-categories consisting of gradual revelation, empathy and assurance. Findings of the study indicated that ethical approaches to giving information can be in the form of either informational support or emotional support, based on patients' conditions and prognoses, their families' emotional state, the necessity of providing a calm atmosphere in the ICU and the hospital, and other patients and their families' peace. Findings of the present study can be used as a basis for further studies and for offering ethical guidelines in giving information to the families of patients hospitalized in the ICU. PMID- 25512831 TI - The association between work ethics and attitudes towards organizational changes among the administrative, financial and support employees of general teaching hospitals. AB - In order to achieve success in today's competitive world, organizations should adapt to environmental changes. On the other hand, managers should have a set of values and ethical guidelines for their administrative and organizational functions. This study aimed to investigate the association between work ethics and attitudes towards organizational changes among the administrative, financial and support employees of general teaching hospitals affiliated to Shiraz University of Medical Sciences. This was an applied, cross-sectional and descriptive-analytic study conducted in 2013. A sample of 124 employees was selected using stratified sampling proportional to size and simple random sampling methods. Data were collected using 2 questionnaires measuring the dimensions of employees' work ethics (four dimensions) and attitudes towards organizational changes (three dimensions). The collected data were analyzed using SPSS 18.0 and statistical tests, including ANOVA, independent samples t-test, and Pearson's correlation coefficient. A P < 0.05 was considered statistically significant. The maximum and minimum score of work ethic dimensions were related to being cooperative (4.60 +/- 0.38) and dependable (4.29 +/- 0.39) respectively. On the other hand, the maximum and minimum score of attitudes towards the various dimensions of organizational changes were related to the behavioral (3.83 +/- 0.70) and the affective (3.55 +/- 0.88) dimensions respectively. Furthermore, there was a significant relationship between the work ethics and education levels of the employees in this study (P = 0.003). Also, among work s dimensions, only being considerate had a significant association with attitudes towards organizational changes (P = 0.014) and their cognitive dimension (P = 0.005). To improve employees' work ethics and attitudes towards organizational changes, the following suggestions can be offered: training hospitals managers in participative management style and its application, as well as the importance of meeting the employees' needs and expectations based on their characteristics; familiarizing employees with the Islamic work ethic; educating employees on the importance of being considerate towards their colleagues and subordinates in the workplace, and reinforcing this desirable quality; and finally, clarifying the need for changes in the organization for all employees. PMID- 25512832 TI - Breaching confidentiality: medical mandatory reporting laws in Iran. AB - Medical ethics is a realm where four important subjects of philosophy, medicine, theology and law are covered. Physicians and philosophers cooperation in this area will have great efficiency in the respective ethical rules formation. In addition to respect the autonomy of the patient, physician's obligation is to ensure that the medical intervention has benefit for the patient and the harm is minimal. There is an obvious conflict between duty of confidentiality and duty of mandatory reporting. Professional confidentiality is one of the basic components in building a constant physician-patient relationship which nowadays, beside the novelty, it is the subject of discussion. Legal obligation of confidentiality is not absolute. In physician-patient relationship, keeping patient's secrets and maintaining confidentiality is a legal and ethical duty, and disclosure of such secrets is mainly through specific statutes. Thus, there are a number of situations where breach of confidentiality is permitted in different legal systems. One of the situations where breaching confidentiality is permitted is the medical mandatory reporting to the relevant authority which is in accordance with many countries' legal systems. Some situations are considered in many countries legal systems' such as notification of births and deaths, infectious diseases, child abuse, sport and relevant events, medical errors, drug side effects and dangerous pregnancies. In this paper, we will examine and discuss medical mandatory reporting and its ethical and legal aspects in the judicial and legal system of Iran and few other countries. Finally we will suggest making Medical Mandatory Reporting Law in Iran. PMID- 25512833 TI - Ethical challenges of researchers in qualitative studies: the necessity to develop a specific guideline. AB - Considering the nature of qualitative studies, the interaction between researchers and participants can be ethically challenging for the former, as they are personally involved in different stages of the study. Therefore, formulation of specific ethical guidelines in this respect seems to be essential. The present paper aimed to discuss the necessity to develop explicit guidelines for conducting qualitative studies with regard to the researchers' role. For this purpose, a literature review was carried out in domestic and international databases by related keywords. Health care providers who carry out qualitative research have an immense responsibility. As there is no statistical analysis in qualitative studies, the researcher has to both evaluate what he or she observes and to interpret it. Providing researchers with the necessary skills and applying stringent supervision can lead to better extraction of reliable information from qualitative studies. This article presents a debate in order to illustrate how researchers could cover the ethical challenges of qualitative studies and provide applicable and trustworthy outcomes. Researchers face ethical challenges in all stages of the study, from designing to reporting. These include anonymity, confidentiality, informed consent, researchers' potential impact on the participants and vice versa. It seems of paramount importance that health care providers, educators and clinicians be well informed of all the different aspects of their roles when acting as qualitative researchers. Hence, these adroit roles need to be well defined, and the use of practical guidelines and protocols in all stages of qualitative studies should be encouraged. PMID- 25512834 TI - Psychometric properties of the Persian version of the "Hospital Ethical Climate Survey". AB - In order to improve the ethical climate in health care organizations, it is important to apply a valid measure. This study aimed to investigate the psychometric properties of the Persian version of the Hospital Ethical Climate Survey (HECS) and to assess nurses' perceptions of the ethical climate in teaching hospitals of Iran. A cross-sectional study of randomly selected nurses (n = 187) was conducted in three teaching general hospitals of Tehran, capital of Iran. Olson's Hospital Ethical Climate Survey (HECS), a self-administered questionnaire, was used to assess the nurses' perceptions of the hospital ethical climate. Descriptive statistics, confirmatory factor analysis (CFA), internal consistency, and correlation were used to analyze the data. CFA showed acceptable model fit: an standardized root mean square residual (SRMR) of 0.064, an non normalized fit index (NNFI) of 0.96, a comparative fit index (CFI) of 0.96, and an root mean square error of approximation (RMSEA) of 0.075. The Cronbach's alpha values were acceptable and ranging from 0.69 to 0.85. The overall Cronbach's alpha coefficient was 0.94. The factor loadings for all ethical climate items were between 0.50 and 0.80, which revealed good structure of the Persian version of the HECS. Survey findings showed that the "managers" subscale had the highest score and the subscale of "doctors" had the lowest score. This study shows that the Persian version of the HECS is a valid and reliable instrument for measuring nurses' perceptions of the ethical climate in hospitals of Iran. PMID- 25512835 TI - Diagnosis and treatment of cancer in medical textbooks of ancient Iran. AB - Research shows that ancient Iranians were among the pioneers of medical science, and are therefore admired and praised by non-Iranian scholars for their efforts and accomplishments in this field. Investigations of medical and historical texts indicate that between the 10(th) and the 18(th) century A.D., ancient Iran experienced a golden age of medicine. Great physicians such as Rhazes, al-Ahwazi, Avicenna and others reviewed the medical textbooks of civilizations such as Greece and India, Theories were scientifically criticized, superstitious beliefs were discarded, valuable innovations were added to pre-existing knowledge and the ultimate achievements were compiled as precious textbooks. Alhawi by Rhazes, Cannon by Avicenna, and Kamil al-Sina'ah by al-Ahwazi are among the works that were treasured by domestic and foreign scientists alike, as well as future generations who continued to appreciate them for centuries. The above-mentioned textbooks discuss diseases and conditions related to neurosurgery, ophthalmology, ear, nose and throat, gastroenterology, urology, skeletomuscular system and other specialties, as well as cancer and similar subjects. One of the richest texts on the description, diagnosis, differential diagnosis, and prognosis of cancer and therapeutic approaches is Alhawi by Mohammad ibn Zakarya al Razi (Rhazes). This article presents a brief summary of Rhazes' views about the definition of cancer, types, signs and symptoms, prevalence, complications, medical care, treatment and even surgical indications and contraindications. Moreover, his opinions are compared against the views of other physicians and theories of modern medicine. It is also recommended to review the medical heritage of Iran and evaluate the proposed treatments based on modern methodologies and scientific approaches. PMID- 25512836 TI - Development and validation of a questionnaire to evaluate medical students' and residents' responsibility in clinical settings. AB - There is a shortage of quantitative measures for assessing the concept of responsibility as a fundamental construct in medical education, ethics and professionalism in existing literature. This study aimed to develop an instrument for measuring responsibility in both undergraduate and graduate medical students during clinical training. Instrument content was based on literature review and mainly qualitative data obtained from a published grounded theory research. The draft questionnaire (Persian version) was then validated and revised with regard to face and content validity. The finalized 41-item questionnaire consists of four domains that were identified using factor analysis. Test-retest reliability and internal consistency were also assessed. Test-retest reliability was rather high, ranging between 0.70 and 0.75 for all domains. Cronbach's alpha coefficients were 0.75 - 0.76 for all domains and 0.90 for the composite scale of the whole questionnaire. Correlations between the four domains of the instrument were also satisfactory (r <= 0.47 for most domains). The correlation between each domain and the composite scale was higher than its correlation with other domains (r >= 0.79 for most domains). The instrument demonstrated good construct and internal validity, and can be suitable for measuring the concept of responsibility in practice in different groups of undergraduate and graduate medical trainees (MTs). PMID- 25512837 TI - Nurses' perspectives on breaking bad news to patients and their families: a qualitative content analysis. AB - Breaking bad news is quite often not done in an effective manner in clinical settings due to the medical staff lacking the skills necessary for speaking to patients and their families. Bad news is faced with similar reactions on the part of the news receiver in all cultures and nations. The purpose of this study was to explore the perspectives of Iranian nurses on breaking bad news to patients and their families. In this research, a qualitative approach was adopted. In depth and semi-structured interviews were conducted with 19 nurses who had at least one year work experience in the ward, and content analysis was performed to analyze the data. Five major categories emerged from data analysis, including effective communication with patients and their families, preparing the ground for delivering bad news, minimizing the negativity associated with the disease, passing the duty to physicians, and helping patients and their families make logical treatment decisions. The results of this study show that according to the participants, it is the physicians' duty to give bad news, but nurses play an important role in delivering bad news to patients and their companions and should therefore be trained in clinical and communicative skills to be able to give bad news in an appropriate and effective manner. PMID- 25512838 TI - Peptide Targeting of Fluorescein-Based Sensors to Discrete Intracellular Locales. AB - Fluorescein-based sensors are the most widely applied class of zinc probes but display adventitious localization in live cells. We present here a peptide-based localization strategy that affords precision in targeting of fluorescein-based zinc sensors. By appending the zinc-selective, reaction-based probe Zinpyr-1 diacetate (DA-ZP1) to the N-terminus of two different targeting peptides we achieve programmable localization and avoid unwanted sequestration within acidic vesicles. Furthermore, this approach can be generalized to other fluorescein based sensors. When appended to a mitochondrial targeting peptide, the esterase activated profluorophore 2',7'-dichlorofluorescein diacetate can be used effectively at concentrations four-times lower than previously reported for analogous, non-acetylated derivatives. These results demonstrate on-resin or in solution esterification of fluorescein to be an effective strategy to facilitate peptide-based targeting in live cells. PMID- 25512839 TI - Effects of massage therapy and occlusal splint therapy on electromyographic activity and the intensity of signs and symptoms in individuals with temporomandibular disorder and sleep bruxism: a randomized clinical trial. AB - INTRODUCTION: Temporomandibular disorder (TDM) is the most common source of orofacial pain of a non-dental origin. Sleep bruxism is characterized by clenching and/or grinding the teeth during sleep and is involved in the perpetuation of TMD. The aim of the present study was to investigate the effects of massage therapy, conventional occlusal splint therapy and silicone occlusal splint therapy on electromyographic activity in the masseter and anterior temporal muscles and the intensity of signs and symptoms in individuals with severe TMD and sleep bruxism. METHODS: Sixty individuals with severe TMD and sleep bruxism were randomly distributed into four treatment groups: 1) massage group, 2) conventional occlusal splint group, 3) massage + conventional occlusal splint group and 4) silicone occlusal splint group. Block randomization was employed and sealed opaque envelopes were used to conceal the allocation. Groups 2, 3 and 4 wore an occlusal splint for four weeks. Groups 1 and 3 received three weekly massage sessions for four weeks. All groups were evaluated before and after treatment through electromyographic analysis of the masseter and anterior temporal muscles and the Fonseca Patient History Index. The Wilcoxon test was used to compare the effects of the different treatments and repeated-measures ANOVA was used to determine the intensity of TMD. RESULTS: The inter-group analysis of variance revealed no statistically significant differences in median frequency among the groups prior to treatment. In the intra-group analysis, no statistically significant differences were found between pre-treatment and post treatment evaluations in any of the groups. Group 3 demonstrated a greater improvement in the intensity of TMD in comparison to the other groups. CONCLUSION: Massage therapy and the use of an occlusal splint had no significant influence on electromyographic activity of the masseter or anterior temporal muscles. However, the combination of therapies led to a reduction in the intensity of signs and symptoms among individuals with severe TMD and sleep bruxism. TRIAL REGISTRATION: This study is registered in August, 2014 in the ClinicalTrials.gov (NCT01874041). PMID- 25512840 TI - A lack of response of the financial behaviors of biodiversity conservation nonprofits to changing economic conditions. AB - The effectiveness of conservation organizations is determined in part by how they adapt to changing conditions. Over the previous decade, economic conditions in the United States (US) showed marked variation including a period of rapid growth followed by a major recession. We examine how biodiversity conservation nonprofits in the US responded to these changes through their financial behaviors, focusing on a sample of 90 biodiversity conservation nonprofits and the largest individual organization (The Nature Conservancy; TNC). For the 90 sampled organizations, an analysis of financial ratios derived from tax return data revealed little response to economic conditions. Similarly, more detailed examination of conservation expenditures and land acquisition practices of TNC revealed only one significant relationship with economic conditions: TNC accepted a greater proportion of conservation easements as donated in more difficult economic conditions. Our results suggest that the financial behaviors of US biodiversity conservation nonprofits are unresponsive to economic conditions. PMID- 25512841 TI - Top-down effects of a lytic bacteriophage and protozoa on bacteria in aqueous and biofilm phases. AB - Lytic bacteriophages and protozoan predators are the major causes of bacterial mortality in natural microbial communities, which also makes them potential candidates for biological control of bacterial pathogens. However, little is known about the relative impact of bacteriophages and protozoa on the dynamics of bacterial biomass in aqueous and biofilm phases. Here, we studied the temporal and spatial dynamics of bacterial biomass in a microcosm experiment where opportunistic pathogenic bacteria Serratia marcescens was exposed to particle feeding ciliates, surface-feeding amoebas, and lytic bacteriophages for 8 weeks, ca. 1300 generations. We found that ciliates were the most efficient enemy type in reducing bacterial biomass in the open water, but least efficient in reducing the biofilm biomass. Biofilm was rather resistant against bacterivores, but amoebae had a significant long-term negative effect on bacterial biomass both in the open-water phase and biofilm. Bacteriophages had only a minor long-term effect on bacterial biomass in open-water and biofilm phases. However, separate short-term experiments with the ancestral bacteriophages and bacteria revealed that bacteriophages crash the bacterial biomass dramatically in the open-water phase within the first 24 h. Thereafter, the bacteria evolve phage-resistance that largely prevents top-down effects. The combination of all three enemy types was most effective in reducing biofilm biomass, whereas in the open-water phase the ciliates dominated the trophic effects. Our results highlight the importance of enemy feeding mode on determining the spatial distribution and abundance of bacterial biomass. Moreover, the enemy type can be crucially important predictor of whether the rapid defense evolution can significantly affect top-down regulation of bacteria. PMID- 25512842 TI - Reduced plant competition among kin can be explained by Jensen's inequality. AB - Plants often compete with closely related individuals due to limited dispersal, leading to two commonly invoked predictions on competitive outcomes. Kin selection, from evolutionary theory, predicts that competition between relatives will likely be weaker. The niche partitioning hypothesis, from ecological theory, predicts that competition between close relatives will likely be stronger. We tested for evidence consistent with either of these predictions by growing an annual legume in kin and nonkin groups in the greenhouse. We grew plant groups in treatments of symbiotic nitrogen fixing bacteria differing in strain identity and composition to determine if differences in the microbial environment can facilitate or obscure plant competition patterns consistent with kin selection or niche partitioning. Nonkin groups had lower fitness than expected, based on fitness estimates of the same genotypes grown among kin. Higher fitness among kin groups was observed in mixtures of N-fixing bacteria strains compared to single inoculations of bacteria strains present in the soil, which increased fitness differences between kin and nonkin groups. Lower fitness in nonkin groups was likely caused by increased competitive asymmetry in nonkin groups due to genetic differences in plant size combined with saturating relationships with plant size and fitness- i.e. Jensen's inequality. Our study suggests that microbial soil symbionts alter competitive dynamics among kin and nonkin. Our study also suggests that kin groups can have higher fitness, as predicted by kin selection theory, through a commonly heritable trait (plant size), without requiring kin recognition mechanisms. PMID- 25512843 TI - Impact of global warming at the range margins: phenotypic plasticity and behavioral thermoregulation will buffer an endemic amphibian. AB - When dispersal is not an option to evade warming temperatures, compensation through behavior, plasticity, or evolutionary adaptation is essential to prevent extinction. In this work, we evaluated whether there is physiological plasticity in the thermal performance curve (TPC) of maximum jumping speed in individuals acclimated to current and projected temperatures and whether there is an opportunity for behavioral thermoregulation in the desert landscape where inhabits the northernmost population of the endemic frog Pleurodema thaul. Our results indicate that individuals acclimated to 20 degrees C and 25 degrees C increased the breath of their TPCs by shifting their upper limits with respect to when they were acclimated at 10 degrees C. In addition, even when dispersal is not possible for this population, the landscape is heterogeneous enough to offer opportunities for behavioral thermoregulation. In particular, under current climatic conditions, behavioral thermoregulation is not compulsory as available operative temperatures are encompassed within the population TPC limits. However, for severe projected temperatures under climate change, behavioral thermoregulation will be required in the sunny patches. In overall, our results suggest that this population of Pleurodema thaul will be able to endure the worst projected scenario of climate warming as it has not only the physiological capacities but also the environmental opportunities to regulate its body temperature behaviorally. PMID- 25512844 TI - Evaluating indices of body condition in two cricket species. AB - Body mass components (dry mass, lean dry mass, water mass, fat mass) in each sex correlate strongly with body mass and pronotum length in Gryllus texensis and Acheta domesticus. Ordinary least squares (OLS) regression underestimates the scaling relationship between body mass and structural size (i.e., pronotum length) in both cricket species compared with standard major axis (SMA) regression. Standardized mass components correlate more strongly with scaled mass index ([Formula: see text]) than with residual body mass (R i). R i represents the residuals from an OLS regression of log body mass against log pronotum length. Neither condition index predicts energy stores (i.e., fat content) in G. texensis. R i is not correlated with energy stores in A. domesticus whereas [Formula: see text] is negatively correlated. A comparison of condition index methods using published data showed that neither sex nor diet quality affected body condition at adulthood in G. texensis when using the scaled mass index. However, the residual index suggested that sex had a significant effect on body condition. Further, analysis of covariance (ANCOVA) suggested that diet quality significantly affects body mass while statistically controlling for body size (i.e., body condition). We conclude that the statistical assumptions of condition index methods must be met prior to use and urge caution when using methods that are based on least squares in the y -plane (i.e., residual index ANCOVA). PMID- 25512846 TI - Nest destruction elicits indiscriminate con- versus heterospecific brood parasitism in a captive bird. AB - Following nest destruction, the laying of physiologically committed eggs (eggs that are ovulated, yolked, and making their way through the oviduct) in the nests of other birds is considered a viable pathway for the evolution of obligate interspecific brood parasitism. While intraspecific brood parasitism in response to nest predation has been experimentally demonstrated, this pathway has yet to be evaluated in an interspecific context. We studied patterns of egg laying following experimental nest destruction in captive zebra finches, Taeniopygia guttata, a frequent intraspecific brood parasite. We found that zebra finches laid physiologically committed eggs indiscriminately between nests containing conspecific eggs and nests containing heterospecific eggs (of Bengalese finches, Lonchura striata vars. domestica), despite the con- and heterospecific eggs differing in both size and coloration. This is the first experimental evidence that nest destruction may provide a pathway for the evolution of interspecific brood parasitism in birds. PMID- 25512845 TI - Carryover effects and climatic conditions influence the postfledging survival of greater sage-grouse. AB - Prebreeding survival is an important life history component that affects both parental fitness and population persistence. In birds, prebreeding can be separated into pre- and postfledging periods; carryover effects from the prefledging period may influence postfledging survival. We investigated effects of body condition at fledging, and climatic variation, on postfledging survival of radio-marked greater sage-grouse (Centrocercus urophasianus) in the Great Basin Desert of the western United States. We hypothesized that body condition would influence postfledging survival as a carryover effect from the prefledging period, and we predicted that climatic variation may mediate this carryover effect or, alternatively, would act directly on survival during the postfledging period. Individual body condition had a strong positive effect on postfledging survival of juvenile females, suggesting carryover effects from the prefledging period. Females in the upper 25th percentile of body condition scores had a postfledging survival probability more than twice that (Phi = 0.51 +/- 0.06 SE) of females in the bottom 25th percentile (Phi = 0.21 +/- 0.05 SE). A similar effect could not be detected for males. We also found evidence for temperature and precipitation effects on monthly survival rates of both sexes. After controlling for site-level variation, postfledging survival was nearly twice as great following the coolest and wettest growing season (Phi = 0.77 +/- 0.05 SE) compared with the hottest and driest growing season (Phi = 0.39 +/- 0.05 SE). We found no relationships between individual body condition and temperature or precipitation, suggesting that carryover effects operated independently of background climatic variation. The temperature and precipitation effects we observed likely produced a direct effect on mortality risk during the postfledging period. Conservation actions that focus on improving prefledging habitat for sage-grouse may have indirect benefits to survival during postfledging, due to carryover effects between the two life phases. PMID- 25512847 TI - Direct and indirect selection on flowering time, water-use efficiency (WUE, delta (13)C), and WUE plasticity to drought in Arabidopsis thaliana. AB - Flowering time and water-use efficiency (WUE) are two ecological traits that are important for plant drought response. To understand the evolutionary significance of natural genetic variation in flowering time, WUE, and WUE plasticity to drought in Arabidopsis thaliana, we addressed the following questions: (1) How are ecophysiological traits genetically correlated within and between different soil moisture environments? (2) Does terminal drought select for early flowering and drought escape? (3) Is WUE plasticity to drought adaptive and/or costly? We measured a suite of ecophysiological and reproductive traits on 234 spring flowering accessions of A. thaliana grown in well-watered and season-ending soil drying treatments, and quantified patterns of genetic variation, correlation, and selection within each treatment. WUE and flowering time were consistently positively genetically correlated. WUE was correlated with WUE plasticity, but the direction changed between treatments. Selection generally favored early flowering and low WUE, with drought favoring earlier flowering significantly more than well-watered conditions. Selection for lower WUE was marginally stronger under drought. There were no net fitness costs of WUE plasticity. WUE plasticity (per se) was globally neutral, but locally favored under drought. Strong genetic correlation between WUE and flowering time may facilitate the evolution of drought escape, or constrain independent evolution of these traits. Terminal drought favored drought escape in these spring flowering accessions of A. thaliana. WUE plasticity may be favored over completely fixed development in environments with periodic drought. PMID- 25512848 TI - Under what conditions do climate-driven sex ratios enhance versus diminish population persistence? AB - For many species of reptile, crucial demographic parameters such as embryonic survival and individual sex (male or female) depend on ambient temperature during incubation. While much has been made of the role of climate on offspring sex ratios in species with temperature-dependent sex determination (TSD), the impact of variable sex ratio on populations is likely to depend on how limiting male numbers are to female fecundity in female-biased populations, and whether a climatic effect on embryonic survival overwhelms or interacts with sex ratio. To examine the sensitivity of populations to these interacting factors, we developed a generalized model to explore the effects of embryonic survival, hatchling sex ratio, and the interaction between these, on population size and persistence while varying the levels of male limitation. Populations with TSD reached a greater maximum number of females compared to populations with GSD, although this was often associated with a narrower range of persistence. When survival depended on temperature, TSD populations persisted over a greater range of temperatures than GSD populations. This benefit of TSD was greatly reduced by even modest male limitation, indicating very strong importance of this largely unmeasured biologic factor. Finally, when males were not limiting, a steep relationship between sex ratio and temperature favoured population persistence across a wider range of climates compared to the shallower relationships. The opposite was true when males were limiting - shallow relationships between sex ratio and temperature allowed greater persistence. The results highlight that, if we are to predict the response of populations with TSD to climate change, it is imperative to 1) accurately quantify the extent to which male abundance limits female fecundity, and 2) measure how sex ratios and peak survival coincide over climate. PMID- 25512849 TI - DNA barcoding reveals novel insights into pterygophagy and prey selection in distichodontid fishes (Characiformes: Distichodontidae). AB - DNA barcoding was used to investigate dietary habits and prey selection in members of the African-endemic family Distichodontidae noteworthy for displaying highly specialized ectoparasitic fin-eating behaviors (pterygophagy). Fin fragments recovered from the stomachs of representatives of three putatively pterygophagous distichodontid genera (Phago, Eugnathichthys, and Ichthyborus) were sequenced for the mitochondrial gene co1. DNA barcodes (co1 sequences) were then used to identify prey items in order to determine whether pterygophagous distichodontids are opportunistic generalists or strict specialists with regard to prey selection and, whether as previously proposed, aggressive mimicry is used as a strategy for successful pterygophagy. Our findings do not support the hypothesis of aggressive mimicry suggesting instead that, despite the possession of highly specialized trophic anatomies, fin-eating distichodontids are opportunistic generalists, preying on fishes from a wide phylogenetic spectrum and to the extent of engaging in cannibalism. This study demonstrates how DNA barcoding can be used to shed light on evolutionary and ecological aspects of highly specialized ectoparasitic fin-eating behaviors by enabling the identification of prey species from small pieces of fins found in fish stomachs. PMID- 25512850 TI - Variation in wing pattern and palatability in a female-limited polymorphic mimicry system. AB - Checkerspot butterflies in the genera Euphydryas and Chlosyne exhibit phenotypic polymorphisms along a well-defined latitudinal and elevational gradient in California. The patterns of phenotypic variation in Euphydryas chalcedona, Chlosyne palla, and Chlosyne hoffmanni suggest a mimetic relationship; in addition, the specific patterns of variation in C. palla suggest a female-limited polymorphic mimicry system (FPM). However, the existence of polymorphic models runs counter to predictions of mimicry theory. Palatability trials were undertaken to assess whether or not the different color morphs of each species were distasteful or toxic to a generalized avian predator, the European starling (Sturnus vulgaris). Results indicate that the black morph of E. chalcedona is distasteful, but not toxic, to predators, while the red morph is palatable. C . hoffmanni and both color morphs of C. palla are palatable to predators. Predators that learn to reject black E. chalcedona also reject black C. palla, suggesting that the latter is a FPM of the former. C. hoffmanni does not appear to be involved in this mimetic relationship. PMID- 25512851 TI - Herbivory drives large-scale spatial variation in reef fish trophic interactions. AB - Trophic interactions play a critical role in the structure and function of ecosystems. Given the widespread loss of biodiversity due to anthropogenic activities, understanding how trophic interactions respond to natural gradients (e.g., abiotic conditions, species richness) through large-scale comparisons can provide a broader understanding of their importance in changing ecosystems and support informed conservation actions. We explored large-scale variation in reef fish trophic interactions, encompassing tropical and subtropical reefs with different abiotic conditions and trophic structure of reef fish community. Reef fish feeding pressure on the benthos was determined combining bite rates on the substrate and the individual biomass per unit of time and area, using video recordings in three sites between latitudes 17 degrees S and 27 degrees S on the Brazilian Coast. Total feeding pressure decreased 10-fold and the composition of functional groups and species shifted from the northern to the southernmost sites. Both patterns were driven by the decline in the feeding pressure of roving herbivores, particularly scrapers, while the feeding pressure of invertebrate feeders and omnivores remained similar. The differential contribution to the feeding pressure across trophic categories, with roving herbivores being more important in the northernmost and southeastern reefs, determined changes in the intensity and composition of fish feeding pressure on the benthos among sites. It also determined the distribution of trophic interactions across different trophic categories, altering the evenness of interactions. Feeding pressure was more evenly distributed at the southernmost than in the southeastern and northernmost sites, where it was dominated by few herbivores. Species and functional groups that performed higher feeding pressure than predicted by their biomass were identified as critical for their potential to remove benthic biomass. Fishing pressure unlikely drove the large-scale pattern; however, it affected the contribution of some groups on a local scale (e.g., large-bodied parrotfish) highlighting the need to incorporate critical functions into conservation strategies. PMID- 25512854 TI - Where does hip fracture initiate? PMID- 25512853 TI - Immune regulation of bone metastasis. AB - Metastases to bone occur in about 70% of patients with metastatic prostate and breast cancers. Unfortunately, bone metastases result in significant morbidity and mortality and treatment options are limited. Thus, significant effort has focused on understanding the mechanisms that drive tumor dissemination to bone. Bone metastases are typically characterized by a self-perpetuating 'vicious' cycle wherein tumor cells and bone-resorbing cells (osteoclasts) are locked in a cycle that leads to osteoclast-driven bone destruction and the release of bone stored factors that in turn stimulate tumor cell proliferation and survival. To break this 'vicious' cycle, potent antiresorptive agents such as zoledronic acid (ZOL) have been used. However, in the clinical setting, ZOL failed to improve the overall survival of cancer patients even though it inhibited osteoclast resorptive activity. Thus, other cells in addition to osteoclasts are likely involved in modulating tumor growth in the bone. The immune system has the ability to eliminate tumor cells. Nevertheless, tumor cells can acquire the ability to escape immune control. Our recent observations indicated that a decline in the ability of the immune cells to recognize and kill the tumor drives tumor dissemination to bone even when osteoclasts are inhibited by potent antiresorptive agents. This review focuses on the antitumor and protumor effects of various immune cell populations involved in the bone metastatic process. We also discuss strategies to enhance antitumor immune responses and bypass cancer immune resistance. PMID- 25512856 TI - MatMRI and MatHIFU: software toolboxes for real-time monitoring and control of MR guided HIFU. AB - BACKGROUND: The availability of open and versatile software tools is a key feature to facilitate pre-clinical research for magnetic resonance imaging (MRI) and magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) and expedite clinical translation of diagnostic and therapeutic medical applications. In the present study, two customizable software tools that were developed at the Thunder Bay Regional Research Institute are presented for use with both MRI and MR-HIFU. Both tools operate in a MATLAB((r);) environment. The first tool is named MatMRI and enables real-time, dynamic acquisition of MR images with a Philips MRI scanner. The second tool is named MatHIFU and enables the execution and dynamic modification of user-defined treatment protocols with the Philips Sonalleve MR-HIFU therapy system to perform ultrasound exposures in MR-HIFU therapy applications. METHODS: MatMRI requires four basic steps: initiate communication, subscribe to MRI data, query for new images, and unsubscribe. MatMRI can also pause/resume the imaging and perform real-time updates of the location and orientation of images. MatHIFU requires four basic steps: initiate communication, prepare treatment protocol, and execute treatment protocol. MatHIFU can monitor the state of execution and, if required, modify the protocol in real time. RESULTS: Four applications were developed to showcase the capabilities of MatMRI and MatHIFU to perform pre-clinical research. Firstly, MatMRI was integrated with an existing small animal MR-HIFU system (FUS Instruments, Toronto, Ontario, Canada) to provide real-time temperature measurements. Secondly, MatMRI was used to perform T2-based MR thermometry in the bone marrow. Thirdly, MatHIFU was used to automate acoustic hydrophone measurements on a per-element basis of the 256-element transducer of the Sonalleve system. Finally, MatMRI and MatHIFU were combined to produce and image a heating pattern that recreates the word 'HIFU' in a tissue-mimicking heating phantom. CONCLUSIONS: MatMRI and MatHIFU leverage existing MRI and MR-HIFU clinical platforms to facilitate pre-clinical research. MatMRI substantially simplifies the real-time acquisition and processing of MR data. MatHIFU facilitates the testing and characterization of new therapy applications using the Philips Sonalleve clinical MR-HIFU system. Under coordination with Philips Healthcare, both MatMRI and MatHIFU are intended to be freely available as open source software packages to other research groups. PMID- 25512855 TI - Characterization of knee osteoarthritis-related changes in trabecular bone using texture parameters at various levels of spatial resolution-a simulation study. AB - Articular cartilage and subchondral bone are the key tissues in osteoarthritis (OA). The role of the cancellous bone increasingly attracts attention in OA research. Because of its fast adaptation to changes in the loading distribution across joints, its quantification is expected to improve the diagnosis and monitoring of OA. In this study, we simulated OA progression-related changes of trabecular structure in a series of digital bone models and then characterized the potential of texture parameters and bone mineral density (BMD) as surrogate measures to quantify trabecular bone structure. Five texture parameters were studied: entropy, global and local inhomogeneity, anisotropy and variogram slope. Their dependence on OA relevant structural changes was investigated for three spatial resolutions typically used in micro computed tomography (CT; 10 MUm), high-resolution peripheral quantitative CT (HR-pQCT) (90 MUm) and clinical whole body CT equipment (250 MUm). At all resolutions, OA-related changes in trabecular bone architecture can be quantified using a specific (resolution dependent) combination of three texture parameters. BMD alone is inadequate for this purpose but if available reduces the required texture parameter combination to anisotropy and global inhomogeneity. The results are summarized in a comprehensive analysis guide for the detection of structural changes in OA knees. In conclusion, texture parameters can be used to characterize trabecular bone architecture even at spatial resolutions below the dimensions of a single trabecula and are essential for a detailed classification of relevant OA changes that cannot be achieved with a measurement of BMD alone. PMID- 25512857 TI - High-intensity focused ultrasound provides palliation for liver metastasis causing gastric outlet obstruction: case report. AB - BACKGROUND: Surgery is the standard of care in several oncologic diseases. However, when non-surgical candidates are not suitable for radical treatment, palliation must be achieved at least. High-intensity focused ultrasound uses ultrasound power that can be sharply focused for highly localised application, as it is a completely non-invasive procedure. Its non-invasiveness appears to be of paramount importance in critically ill patients. CASE DESCRIPTION: We describe the use of ultrasound-guided high-intensity focused ultrasound for a large liver metastasis from breast cancer causing gastric outlet obstruction in a metastatic disease. The left liver deposit did not allow the stomach to empty due to its large volume, and the patient was unable to eat properly. The tumour was metastatic, resistant to chemotherapy and had a size that contraindicated an ablation percutaneous technique. To improve the patient's quality of life, ultrasound-guided high-intensity focused ultrasound ablation seemed the only and most suitable option. Therefore, a high-intensity focused ultrasound treatment was performed, no complications occurred and the patient's general condition has improved since the early post-procedural period. Three months after treatment, two body mass index points were gained, and the lesion decreased by 72% in volume as detected through multi-detector computed tomography follow-up. DISCUSSION AND CONCLUSION: Quality of life is an unquestionable goal to achieve, and palliation must be achieved while causing as little harm as possible. In this view, debulking surgery and percutaneous ablation technique seemed not appropriate for our patient. Instead, high-intensity focused ultrasound combined several advantages, no lesion size limit and a totally non-invasive treatment. Thus, this technique proved to be a clinically successful procedure, offering better disease control and quality of life. In circumstances where other alternatives clearly seem to fail or are contraindicated, high-intensity focused ultrasound can be used and can provide benefits. We recommend its use and development in several oncologic diseases, not only for therapeutic purposes but also for the improvement of patient's quality of life. PMID- 25512858 TI - Ultrasound-targeted microbubble destruction for chemotherapeutic drug delivery to solid tumors. AB - Ultrasound-targeted microbubble destruction (UTMD) is a promising technique for non-invasive, targeted drug delivery, and its applications in chemotherapeutic drug delivery to solid tumors have attracted growing interest. Ultrasound, which has been conventionally used for diagnostic imaging, has evolved as a promising tool for therapeutic applications mainly because of its ability to be focused deep inside the human body, providing a modality for targeted delivery. Although originally being introduced into clinics as ultrasound contrast agents, microbubbles (MBs) have been developed as a diagnostic and therapeutic agent that can both be tracked through non-invasive imaging and deliver therapeutic agents selectively at ultrasound-targeted locations. Whereas free drugs often possess harmful side effects, their encapsulation in MBs and subsequent local release at the targeted tissue by ultrasound triggering may help improve the margin of safety. In the past 10 years, the feasibility and safety of UTMD have been extensively tested using normal animal models. Most recently, a growing number of preclinical studies have been reported on the therapeutic benefits of UTMD in the delivery of chemotherapeutic drugs to various malignant tumors, such as brain, liver, eyelid, pancreas, and breast tumors. Increased drug concentration in tumors and reduced tumor sizes were achieved in those tumors treated with UTMD in combination with chemotherapeutic drugs, when compared to tumors treated with chemotherapy drugs alone. This review presents an overview of current preclinical applications of UTMD in chemotherapeutic drug delivery for the treatment of cancers along with a discussion of its future developments. PMID- 25512860 TI - Clinical predictors of successful magnetic resonance-guided focused ultrasound (MRgFUS) for uterine leiomyoma. AB - BACKGROUND: Magnetic resonance-guided focused ultrasound (MRgFUS) is a relatively new minimally invasive treatment, approved by the US Food and Drug Administration in 2004 for treatments of symptomatic uterine leiomyomas (fibroids). The purpose of this work is to present retrospective cohort analysis of women that underwent commercial MRgFUS treatment between 2005 and 2009 at a single center, to identify baseline patient characteristics that predict successful MRgFUS fibroid treatment. Identifying these clinical predictors of MRgFUS would be helpful to clinicians choosing the optimal patient for this treatment modality. METHODS: One hundred thirty women with symptomatic uterine leiomyomas who underwent MRgFUS were followed up with a mean length of follow up of 17.4 +/- 10.3 months. The main outcome measure of the follow-up was to identify patients who required additional fibroid treatment due to continued fibroid symptoms. Additionally, patient medical history and radiological findings obtained prior to MRgFUS were reviewed, and statistical analysis was performed to identify factors associated with reduced risk of having additional fibroid treatment. RESULTS: Twenty-nine patients (22.3%) underwent additional fibroid treatment due to continued or recurrent fibroid symptoms during the follow up. Cumulative incidence of additional fibroid treatment was 9.7%, 29.3%, and 44.7% at 1, 2, and 3 years following MRgFUS, respectively. In multivariable Cox proportional hazard regression analyses, older age (hazard ratio (HR) 0.54 per 5-year increase in age, 95% confidence interval 0.39 to 0.76, p < 0.001), greater number of fibroids (HR 0.19 for more than three vs. one fibroid, 95% CI 0.05 to 0.67, p = 0.033), and greater fibroid volume (HR 0.70 per doubling in volume, 95% CI 0.51 to 0.96, p = 0.025) were significantly associated with less risk of having additional fibroid treatment. CONCLUSIONS: Older age at treatment and having multiple fibroids with larger volume are associated with a lower risk of additional intervention following MRgFUS treatment for uterine fibroids. PMID- 25512859 TI - The road to clinical use of high-intensity focused ultrasound for liver cancer: technical and clinical consensus. AB - Clinical use of high-intensity focused ultrasound (HIFU) under ultrasound or MR guidance as a non-invasive method for treating tumors is rapidly increasing. Tens of thousands of patients have been treated for uterine fibroid, benign prostate hyperplasia, bone metastases, or prostate cancer. Despite the methods' clinical potential, the liver is a particularly challenging organ for HIFU treatment due to the combined effect of respiratory-induced liver motion, partial blocking by the rib cage, and high perfusion/flow. Several technical and clinical solutions have been developed by various groups during the past 15 years to compensate for these problems. A review of current unmet clinical needs is given here, as well as a consensus from a panel of experts about technical and clinical requirements for upcoming pilot and pivotal studies in order to accelerate the development and adoption of focused ultrasound for the treatment of primary and secondary liver cancer. PMID- 25512861 TI - In vitro parameter optimization for spatial control of focused ultrasound ablation when using low boiling point phase-change nanoemulsions. AB - BACKGROUND: Phase-shift nanoemulsions (PSNEs) provide cavitation sites when the perfluorocarbon (PFC) nanodroplets (ND) are vaporized to microbubbles by acoustic energy. Their presence lowers the power required to ablate tissue by high intensity focused ultrasound (HIFU), potentially making it a safer option for a broader range of treatment sites. However, spatial control over the ablation region can be problematic when cavitation is used to enhance heating. This study explored relationships between vaporization, ablation, and the PSNE concentration in vitro to optimize the acoustic intensity and insonation time required for spatially controlled ablation enhancement using a PSNE that included a volatile PFC component. METHODS: HIFU (continuous wave at 1 MHz; insonation times of 5, 10, 15, and 20 s; cool-down times of 2, 4, and 6 s; peak negative pressures of 2, 3, and 4 MPa) was applied to albumin-acrylamide gels containing PFC agents (1:1 mix of volatile decafluorobutane and more stable dodecafluoropentane at 10(5) to 10(8) PFC ND per milliliter) or agent-free controls. Vaporization fields (microbubble clouds) were imaged by conventional ultrasound, and ablation lesions were measured directly by calipers. Controlled ablation was defined as the production of 'cigar'-shaped lesions corresponding with the acoustic focal zone. This control was considered to be lost when ablation occurred in prefocal vaporization fields having a predominantly 'tadpole' or oblong shape. RESULTS: Changes in the vaporization field shape and location occurred on a continuum with increasing PSNE concentration and acoustic intensity. Working with the maximum concentration-intensity combinations resulting in controlled ablation demonstrated a dose-responsive relationship between insonation time and volumes of both the vaporization fields (approximately 20 to 240 mm(3)) and the ablation lesions (1 to 135 mm(3)) within them. CONCLUSIONS: HIFU ablation was enhanced by this PSNE and could be achieved using intensities <=650 W/cm(2). Although the ablation lesions were located within much larger microbubble clouds, optimum insonation times and intensities could be selected to achieve an ablation lesion of desired size and location for a given PSNE concentration. This demonstration of controllable enhancement using a PSNE that contained a volatile PFC component is another step toward developing phase-shift nanotechnology as a potential clinical tool to improve HIFU. PMID- 25512862 TI - Effects of varying duty cycle and pulse width on high-intensity focused ultrasound (HIFU)-induced transcranial thrombolysis. AB - The goal was to test the effects of various combinations of pulse widths (PW) and duty cycles (DC) on high-intensity focused ultrasound (HIFU)-induced sonothrombolysis efficacy using an in vitro flow model. An ExAblateTM 4000 HIFU headsystem (InSightec, Inc., Israel) was used. Artificial blood clots were placed into test tubes inside a human calvarium and exposed to pulsatile flow. Four different duty cycles were tested against four different pulse widths. For all study groups, an increase in thrombolysis efficacy could be seen in association with increasing DC and/or PW (p < 0.0001). Using transcranial HIFU, significant thrombolysis can be achieved within seconds and without the use of lytic drugs in vitro. Longer duty cycles in combination with longer pulse widths seem to have the highest potential to optimize clot lysis efficacy. PMID- 25512863 TI - Safety and treatment volumes achieved following new developments of the magnetic resonance-guided focused ultrasound system in the treatment of uterine fibroids: a cohort study. AB - BACKGROUND: This research investigates whether modifications to the magnetic resonance-guided focused ultrasound ablation of uterine fibroid (MRgFUS) system used resulted in improved treatment volumes of uterine fibroids, while maintaining safety. METHODS: This study is a prospective cohort analysis of 34 women undergoing the ExAblate 2100 MRgFUS treatment for their uterine fibroids. RESULTS: The percentage of non-perfused volume (NPV) achieved with the ExAblate 2100 system was 54.92% compared with 50.49 % with the ExAblate 2000 system over the preceding year (p = 0.543). The ExAblate 2100 system resulted in a greater NPV in hyper-intense fibroids compared with the ExAblate 200 system (43.20% versus 36.33%, p = 0.005). There have been no recorded hospital admissions, no skins burns, and no reported major adverse events since the introduction of this new system. CONCLUSION: Overall, the new system has thus far shown an encouraging safety record and an improvement in non-perfused volumes achieved, especially in hyper-intense fibroids. PMID- 25512864 TI - Transcranial sonothrombolysis using high-intensity focused ultrasound: impact of increasing output power on clot fragmentation. AB - BACKGROUND: The primary goal of this study was to investigate the relationship between increasing output power levels and clot fragmentation during high intensity focused ultrasound (HIFU)-induced thrombolysis. METHODS: A HIFU headsystem, designed for brain applications in humans, was used for this project. A human calvarium was mounted inside the water-filled hemispheric transducer. Artificial thrombi were placed inside the skull and located at the natural focus point of the transducer. Clots were exposed to a range of acoustic output power levels from 0 to 400 W. The other HIFU operating parameters remained constant. To assess clot fragmentation, three filters of different mesh pore sizes were used. To assess sonothrombolysis efficacy, the clot weight loss was measured. RESULTS: No evidence of increasing clot fragmentation was found with increasing acoustic intensities in the majority of the study groups of less than 400 W. Increasing clot lysis could be observed with increasing acoustic output powers. CONCLUSION: Transcranial sonothrombolysis could be achieved in vitro within seconds in the absence of tPA and without producing relevant clot fragmentation, using acoustic output powers of <400 W. PMID- 25512865 TI - Trans-cranial focused ultrasound without hair shaving: feasibility study in an ex vivo cadaver model. AB - In preparing a patient for a trans-cranial magnetic resonance (MR)-guided focused ultrasound procedure, current practice is to shave the patient's head on treatment day. Here we present an initial attempt to evaluate the feasibility of trans-cranial focused ultrasound in an unshaved, ex vivo human head model. A human skull filled with tissue-mimicking phantom and covered with a wig made of human hair was sonicated using 220- and 710-kHz head transducers to evaluate the feasibility of acoustic energy transfer. Heating at the focal point was measured by MR proton resonance shift thermometry. Results showed that the hair had a negligible effect on focal spot thermal rise at 220 kHz and a 17% drop in temperature elevation when using 710 kHz. PMID- 25512866 TI - Focused ultrasound development and clinical adoption: 2013 update on the growth of the field. AB - The field of therapeutic focused ultrasound, which first emerged in the 1940s, has seen significant growth, particularly over the past decade. The eventual widespread clinical adoption of this non-invasive therapeutic modality require continued progress, in a multitude of activities including technical, pre clinical, and clinical research, regulatory approval and reimbursement, manufacturer growth, and other commercial and public sector investments into the field, all within a multi-stakeholder environment. We present here a snapshot of the field of focused ultrasound and describe how it has progressed over the past several decades. It is assessed using metrics which include quantity and breadth of academic work (presentations, publications), funding trends, manufacturer presence in the field, number of treated patients, number of indications reaching first-in-human status, and quantity and breadth of clinical indications. PMID- 25512867 TI - Women seeking second opinion for symptomatic uterine leiomyoma: role of comprehensive fibroid center. AB - OBJECTIVE: The objective of the study was to describe our early experience with a comprehensive uterine fibroid center and report our results in women seeking a second opinion for management of symptomatic uterine leiomyoma. METHODS: We performed a HIPAA-complaint, IRB-approved retrospective study of women seeking second opinion for management of uterine fibroids at our multidisciplinary fibroid treatment center in a tertiary care facility from July 2008 to August 2011. After a review of patients' history, physical examination, and magnetic resonance imaging (MRI) findings, treatment options were discussed which included conservative management, uterine-preserving options, and hysterectomy. We performed Fisher's exact test for categorical variables between the cohort that did or did not undergo a uterine-preserving treatment. Differences were considered significant at p < 0.05. RESULTS: The mean age of the 205 patient study cohort was 43.8 years (SD 7.5). One hundred sixty-two (79.0%) patients had no prior therapy. Based on MRI, one or more fibroids were detected in 178/205 (86.8%), adenomyosis in 8/205 (3.9%), and a combination of fibroid and nonfibroid condition (i.e., adenomyosis, endometrial polyp) in 18/205 (8.8%). In those who desired to transition their care to our institution (n = 109), 85 patients underwent 90 interventions: 39 MRgFUS (magnetic resonance-guided high-intensity focused ultrasound surgery), 14 UAE (uterine artery embolization), 25 myomectomies, 8 hysterectomies, 3 polypectomies, and 1 endometrial ablation. Five patients had two procedures. Intramural and subserosal fibroids were most commonly treated with MRgFUS followed by myomectomy and then UAE; in contrast, pedunculated fibroids were frequently managed with myomectomy. CONCLUSIONS: Multidisciplinary fibroid evaluation may facilitate the increase use of less invasive options over hysterectomy for symptomatic fibroid treatment. PMID- 25512868 TI - Cost comparison between uterine-sparing fibroid treatments one year following treatment. AB - BACKGROUND: To compare one-year all-cause and uterine fibroid (UF)-related direct costs in patients treated with one of the following three uterine-sparing procedures: magnetic resonance-guided focused ultrasound (MRgFUS), uterine artery embolization (UAE) and myomectomy. METHODS: This retrospective observational cohort study used healthcare claims for several million individuals with healthcare coverage from employers in the MarketScan Database for the period 2003 2010. UF patients aged 25-54 on their first UF procedure (index) date with 366 day baseline experience, 366-day follow-up period, continuous health plan enrollment during baseline and follow-up, and absence of any baseline UF procedures were included in the final sample. Cost outcomes were measured by allowed charges (sum of insurer-paid and patient-paid amounts). UF-related cost was defined as difference in mean cost between study cohorts and propensity-score matched control cohorts without UF. Multivariate adjustment of cost outcomes was conducted using generalized linear models. RESULTS: The study sample comprised 14,426 patients (MRgFUS = 14; UAE = 4,092; myomectomy = 10,320) with a higher percent of older patients in MRgFUS cohort (71% vs. 50% vs. 12% in age-group 45 54, P < 0.001). Adjusted all-cause mean cost was lowest for MRgFUS ($19,763; 95% CI: $10,425-$38,694) followed by myomectomy ($20,407; 95% CI: $19,483-$21,381) and UAE ($25,019; 95% CI: $23,738-$26,376) but without statistical significance. Adjusted UF-related costs were also not significantly different between the three procedures. CONCLUSIONS: Adjusted all-cause and UF-related costs at one year were not significantly different between patients undergoing MRgFUS, myomectomy and UAE. PMID- 25512869 TI - First experience with MR-guided focused ultrasound in the treatment of Parkinson's disease. AB - BACKGROUND: Radiofrequency (RF) subthalamotomies have been proposed since the 1960s to treat patients suffering from Parkinson's disease (PD). Recently, the magnetic resonance (MR)-guided focused ultrasound technology (MRgFUS) offers the possibility to perform subthalamic thermocoagulations with reduced risks and optimized accuracy. We describe here the initial results of the MRgFUS pallidothalamic tractotomy (PTT), an anatomical and physiological update of the earlier subthalamotomies. METHODS: Thirteen consecutive patients suffering from chronic (mean disease duration 9.7 years) and therapy-resistant PD were treated unilaterally with an MRgFUS PTT. Primary relief assessment indicators were the score reduction of the Unified Parkinson Disease Rating Scale (UPDRS) and the patient estimation of global symptom relief (GSR) taken at 3 months follow-up. Final temperatures at target were between 52 degrees C and 59 degrees C. The MR examinations were performed before the treatment, 2 days and 3 months after it. The accuracy of the targeting was calculated on 2 days post-treatment MR pictures for each PTT lesion. RESULTS: The first four patients received a PTT using the lesional parameters applied for thalamotomies. They experienced clear-cut recurrences at 3 months (mean UPDRS relief 7.6%, mean GSR 22.5%), and their MR showed no sign of thermal lesion in T2-weighted (T2w) images. As a consequence, the treatment protocol was adapted for the following nine patients by applying repetition of the final temperatures 4 to 5 times. That produced thermocoagulations of larger volumes (172 mm(3) against 83 mm(3) for the first four patients), which remained visible at 3 months on T2w images. These nine patients enjoyed a mean UPDRS reduction of 60.9% and a GSR of 56.7%, very close to the results obtained with radiofrequency lesioning. The targeting accuracy for the whole patient group was 0.5, 0.5, and 0.6 mm for the anteroposterior (AP), mediolateral (ML), and dorsoventral (DV) dimensions, respectively. CONCLUSIONS: This study demonstrated the feasibility, safety, and accuracy of the MRgFUS PTT. To obtain similar results as the ones of RF PTT, it was necessary to integrate the fact that white matter, in this case, the pallidothalamic tract, requires repeated thermal exposition to achieve full lesioning and thus full therapeutic effect. PMID- 25512870 TI - Therapeutic ultrasound for glaucoma: clinical use of a low-frequency low-power ultrasound device for lowering intraocular pressure. AB - BACKGROUND: This is a first-in-human study to determine the efficacy and tolerability of a new method of treating glaucoma using a low-power, low frequency, focused therapeutic ultrasound for glaucoma (TUG) device designed to trigger an inflammatory reaction in the anterior chamber angle and trabecular meshwork to enhance outflow. The use of the device is anticipated for mild or moderate open-angle glaucoma as an enhancement to outflow. METHODS: In a two branch clinical trial, a total of 26 primary open-angle glaucoma patients underwent a procedure consisting of the external application of the TUG device. In branch 1, nine of these patients were naive to pharmaceutical treatment or had been off of medication for over 6 months. In branch 2, 17 patients were treated after a medication washout period. All patients in the study were followed for 12 months. RESULTS: In branch 1, there was a decrease in intraocular pressure averaging over 20% lasting at least a year in 74% of the eyes with non normotensive open-angle glaucoma. In branch 2, an average of two visits while on medication provided the comparison intraocular pressure (IOP) to the effect of the TUG treatment after washout. It was seen that the intraocular pressure over the year post-treatment was equal to or better than the pharmaceutical control in close to 80% of measurements. CONCLUSION: A novel device for lowering intraocular pressure is described with a potential for adding to our armamentarium for treating glaucoma. This is a small cohort study which indicates beneficial trends. TRIAL REGISTRATION NUMBER: The study was a registered clinical trial, #ISRCTN50904302. PMID- 25512871 TI - A microsurgical bifurcation rabbit model to investigate the effect of high intensity focused ultrasound on aneurysms: a technical note. AB - BACKGROUND: Recent clinical studies confirmed the high potential of MR-guided focused ultrasound (MRgFUS) in the field of functional neurosurgery. While its ability for precise thermo-ablation within soft tissue is widely recognized, the impact of high-intensity focused ultrasound (HIFU) on larger vessels is less explored. We used a bifurcation aneurysm model in rabbits to investigate the possible effects on the walls of vascular aneurysms and to assess the risk and prospect of this procedure for managing neurovascular disorders. METHODS: Experimental bifurcation aneurysms were microsurgically created in New Zealand white rabbits and sonicated using MRgFUS. RESULTS: A temperature of max. 54 degrees C could be achieved close to the aneurysm, and the shape and size of the aneurysm were noticeably changed, as shown by MR angiography. CONCLUSIONS: The presented rabbit model proved suitable and capable of being extended to acquire data on the effect of HIFU on aneurysms and larger vessels. The fact that HIFU led to an alteration of the aneurysm without inducing rupture encourages further investigations. PMID- 25512872 TI - Immune monitoring using the predictive power of immune profiles. AB - BACKGROUND: We have developed a novel approach to categorize immunity in patients that uses a combination of whole blood flow cytometry and hierarchical clustering. METHODS: Our approach was based on determining the number (cells/MUl) of the major leukocyte subsets in unfractionated, whole blood using quantitative flow cytometry. These measurements were performed in 40 healthy volunteers and 120 patients with glioblastoma, renal cell carcinoma, non-Hodgkin lymphoma, ovarian cancer or acute lung injury. After normalization, we used unsupervised hierarchical clustering to sort individuals by similarity into discreet groups we call immune profiles. RESULTS: Five immune profiles were identified. Four of the diseases tested had patients distributed across at least four of the profiles. Cancer patients found in immune profiles dominated by healthy volunteers showed improved survival (p < 0.01). Clustering objectively identified relationships between immune markers. We found a positive correlation between the number of granulocytes and immunosuppressive CD14(+)HLA-DR(lo/neg) monocytes and no correlation between CD14(+)HLA-DR(lo/neg) monocytes and Lin(-)CD33(+)HLA-DR(-) myeloid derived suppressor cells. Clustering analysis identified a potential biomarker predictive of survival across cancer types consisting of the ratio of CD4(+) T cells/MUl to CD14(+)HLA-DR(lo/neg) monocytes/MUL of blood. CONCLUSIONS: Comprehensive multi-factorial immune analysis resulting in immune profiles were prognostic, uncovered relationships among immune markers and identified a potential biomarker for the prognosis of cancer. Immune profiles may be useful to streamline evaluation of immune modulating therapies and continue to identify immune based biomarkers. PMID- 25512873 TI - Inflammation increases plasma angiopoietin-like protein 4 in patients with the metabolic syndrome and type 2 diabetes. AB - BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) inhibits lipoprotein lipase and associates with dyslipidemia. The expression of ANGPTL4 is regulated by free fatty acids (FFA) that activate lipid-sensing peroxisome proliferator-activated receptors (PPARs), but FFA can also activate pattern recognition receptors including Toll-like receptor 4 (TLR4) in macrophages. OBJECTIVE: To assess whether systemic low-grade inflammation is a determinant for plasma ANGPTL4 levels in patients with the metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM). DESIGN: We studied 335 male participants: healthy controls (Controls), patients with the MetS without inflammation (MetS-I) and with low grade inflammation (MetS+I), and patients with T2DM. All patients without diabetes included in the present study were initially matched for waist circumference. In plasma, ANGPTL4, C reactive protein (CRP) and metabolic parameters were determined. Underlying mechanisms were examined using human macrophages in vitro. RESULTS: As compared with Controls, plasma ANGPTL4 levels were increased in patients with MetS-I, MetS+I, and T2DM. Furthermore, ANGPTL4 was increased in T2DM compared with MetS-I. In fact, plasma CRP correlated positively with plasma ANGPTL4. In vitro studies showed that TLR 3/4 activation largely increased the expression and release of ANGPTL4 by macrophages. CONCLUSIONS: Plasma ANGPTL4 levels in humans are predicted by CRP, a marker of inflammation, and ANGPTL4 expression by macrophages is increased by inflammatory stimuli. PMID- 25512874 TI - Feasibility of overnight closed-loop therapy in young children with type 1 diabetes aged 3-6 years: comparison between diluted and standard insulin strength. AB - OBJECTIVE: To assess feasibility of overnight closed-loop therapy in young children with type 1 diabetes and contrast closed loop using diluted versus standard insulin strength. RESEARCH DESIGN AND METHODS: Eleven children (male 6; age range 3.75-6.96 years; glycated hemoglobin 60 (14) mmol/mol; body mass index SD score 1.0 (0.8); diabetes duration 2.2 (1.0) years, mean (SD); total daily dose 12.9 (10.6, 16.5) IU/day, median (IQR)) were studied at a clinical research facility on two occasions. In random order, participants received closed loop with diluted insulin aspart (CL_Dil; 20 IU/mL) or closed loop with standard aspart (CL_Std; 100 IU/mL) from 17:00 until 8:00 the following morning. Children consumed an evening meal at 17:00 (44 (12) gCHO) and an optional bedtime snack (6 (7) gCHO) identical on both occasions. Meal insulin boluses were calculated by standard pump bolus calculators. Basal rates on insulin pump were adjusted every 15 min as directed by a model-predictive-control algorithm informed by a real time glucose sensor values. RESULTS: Mean plasma glucose was 122 (24) mg/dL during CL_Dil vs 122 (23) mg/dL during CL_Std (p=0.993). The time spent in the target glucose range 70-145 mg/dL was 83 (70, 100)% vs 72 (54, 81)% (p=0.328). Time above 145 mg/dL was 13 (0, 27)% vs 19 (10, 45)% (p=0.477) and time spent below 70 mg/dL was 0.0 (0.0, 1.4)% vs 1.4 (0.0, 11.6)% (p=0.161). One asymptomatic hypoglycemia below 63 mg/dL occurred in one participant during CL_Dil versus six episodes in five participants during CL_Std (p=0.09). Glucose variability measured by CV of plasma glucose tended to be reduced during CL_Dil (20% (13, 31) vs 32% (24, 42), p=0.075). CONCLUSIONS: In this feasibility study, closed-loop therapy maintained good overnight glucose control with tendency towards reduced hypoglycemia and reduced glucose variability using diluted insulin. TRIAL REGISTRATION NUMBER: clinicaltrials.gov Identifier: NCT01557634. PMID- 25512875 TI - Trends in the incidence and prevalence of cardiac pacemaker insertions in an ageing population. AB - OBJECTIVES: To determine contemporary population estimates of the prevalence of cardiac permanent pacemaker (PPM) insertions. METHODS: A population-based observational study using linked hospital morbidity and death registry data from Western Australia (WA) to identify all incident cases of PPM insertion for adults aged 18 years or older. Prevalence rates were calculated by age and sex for the years 1995-2009 for the WA population. RESULTS: There were 9782 PPMs inserted during 1995-2009. Prevalence rose across the study period, exceeding 1 in 50 among people aged 75 or older from 2005. This was underpinned by incidence rates which rose with age, being highest in those 85 years or older; over 500/100 000 for men throughout, and over 200/100 000 for women. Rates for patients over 75 were more than double the rates for those aged 65-74 years. Women were around 40% of cases overall. The use of dual-chamber and triple-chamber pacing increased across the study period. A cardiac resynchronisation defibrillator was implanted for 58% of patients treated with cardiac resynchronisation therapy. CONCLUSIONS: Rates of insertion and prevalence of PPM continue to rise with the ageing population in WA. As equilibrium has probably not been reached, the demand for pacing services in similarly well-developed economies is likely to continue to grow. PMID- 25512876 TI - Mental health nurses' experiences of caring for patients suffering from self harm. AB - The aim of this study was to explore mental health nurses' experiences of caring for inpatients who self-harm during an acute phase. The setting was four psychiatric clinics in Norway. Fifteen mental health nurses (MHNs) were recruited. Semistructured interviews comprised the method for data collection, with content analysis used for data analysis. Two main categories emerged: challenging and collaborative nurse-patient relationship and promoting well-being through nursing interventions. The underlying meaning of the main categories was interpreted and formulated as a latent theme: promoting person-centered care to patients suffering from self-harm. How MHNs promote care for self-harm patients can be described as a person-centered nursing process. MHNs, through the creation of a collaborative nurse-patient relationship, reflect upon nursing interventions and seek to understand each unique patient. The implication for clinical practice is that MHNs are in a position where they can promote patients' recovery processes, by offering patients alternative activities and by working in partnership with patients to promote their individual strengths and life knowledge. MHNs strive to help patients find new ways of living with their problems. The actual study highlighted that MHNs use different methods and strategies when promoting the well-being of self-harm patients. PMID- 25512878 TI - Self-reported attitudes versus actual practice of oxygen therapy by ICU physicians and nurses. AB - BACKGROUND: High inspiratory oxygen concentrations are frequently administered in ventilated patients in the intensive care unit (ICU) but may induce lung injury and systemic toxicity. We compared beliefs and actual clinical practice regarding oxygen therapy in critically ill patients. METHODS: In three large teaching hospitals in the Netherlands, ICU physicians and nurses were invited to complete a questionnaire about oxygen therapy. Furthermore, arterial blood gas (ABG) analysis data and ventilator settings were retrieved to assess actual oxygen practice in the same hospitals 1 year prior to the survey. RESULTS: In total, 59% of the 215 respondents believed that oxygen-induced lung injury is a concern. The majority of physicians and nurses stated that minimal acceptable oxygen saturation and partial arterial oxygen pressure (PaO2) ranges were 85% to 95% and 7 to 10 kPa (52.5 to 75 mmHg), respectively. Analysis of 107,888 ABG results with concurrent ventilator settings, derived from 5,565 patient admissions, showed a median (interquartile range (IQR)) PaO2 of 11.7 kPa (9.9 to 14.3) [87.8 mmHg], median fractions of inspired oxygen (FiO2) of 0.4 (0.4 to 0.5), and median positive end-expiratory pressure (PEEP) of 5 (5 to 8) cm H2O. Of all PaO2 values, 73% were higher than the upper limit of the commonly self-reported acceptable range, and in 58% of these cases, neither FiO2 nor PEEP levels were lowered until the next ABG sample was taken. CONCLUSIONS: Most ICU clinicians acknowledge the potential adverse effects of prolonged exposure to hyperoxia and report a low tolerance for high oxygen levels. However, in actual clinical practice, a large proportion of their ICU patients was exposed to higher arterial oxygen levels than self-reported target ranges. PMID- 25512877 TI - PIWI proteins and their interactors in piRNA biogenesis, germline development and gene expression. AB - PIWI-interacting RNAs (piRNAs) are a complex class of small non-coding RNAs that are mostly 24-32 nucleotides in length and composed of at least hundreds of thousands of species that specifically interact with the PIWI protein subfamily of the ARGONAUTE family. Recent studies revealed that PIWI proteins interact with a number of proteins, especially the TUDOR-domain-containing proteins, to regulate piRNA biogenesis and regulatory function. Current research also provides evidence that PIWI proteins and piRNAs are not only crucial for transposon silencing in the germline, but also mediate novel mechanisms of epigenetic programming, DNA rearrangements, mRNA turnover, and translational control both in the germline and in the soma. These new discoveries begin to reveal an exciting new dimension of gene regulation in the cell. PMID- 25512879 TI - How to Score the Sexual Experiences Survey? A Comparison of Nine Methods. AB - OBJECTIVE: Although assessments of sexual assault victimization and perpetration have greatly improved, current scoring methods do not fully utilize the wealth of information they provide. The present studies assessed new methods for scoring sexual assault severity using the Sexual Experiences Survey (SES; Koss et al., 2007). METHOD: In two studies of female (n = 436) and male (n = 313) non-problem drinkers who had engaged in unprotected sex within the past year, we compared three severity ranking schemes as well as three scoring methods per severity scheme for a total of nine scoring methods. New severity ranking schemes considered tactic types separately, varied combinations of assault outcomes, and accounted for multiple types and frequencies of assaults. Measures assessing convergent validity were also administered. RESULTS: Seventy-eight percent (n = 340) of the women reported victimization, and 58% (n = 180) of the men reported perpetration. All severity scoring methods were strongly associated with convergent measures. CONCLUSIONS: Each scoring method is viable; however especially among samples with greater victimization/perpetration rates, there can be advantages to incorporating multiple types and frequencies of assault experiences into SES scores. Recent refinements of the SES necessitate commensurate improvements in its scoring methods in order to significantly advance the field of sexual assault assessment. PMID- 25512880 TI - A Pilot Intervention to Promote Safer Sex in Heterosexual Puerto Rican Couples. AB - Although the sexual transmission of HIV occurs in the context of an intimate relationship, preventive interventions with couples are scarce, particularly those designed for Hispanics. In this article, we present the effect of a pilot intervention directed to prevent HIV/AIDS in heterosexual couples in Puerto Rico. The intervention was theory-based and consisted of five three-hour group sessions. Primary goals included increasing male condom use and the practice of mutual masturbation as a safer sex method, and promoting favorable attitudes toward these behaviors. Twenty-six couples participated in this study. Fifteen were randomly assigned to the intervention group and eleven to a control group. Retention rates at post-intervention and follow-up were 82% for the whole sample. Results showed that there was a significant increase in the use of male condoms with main partners in the intervention group when compared with the control group. Couples in the intervention group also had better scores on secondary outcomes, such as attitudes toward condom use and mutual masturbation, HIV information, sexual decision-making, and social support. We found that these effects persisted over the three month follow up. A significant effect was also observed for the practice of mutual masturbation, but not for sexual negotiation. These results showed that promoting male condom use in dyadic interventions among heterosexual couples in Puerto Rico is feasible. Our findings suggest that because vaginal penetration has been constructed as the sexual script endpoint among many Hispanic couples, promoting other non-penetrative practices, such as mutual masturbation, may be difficult. PMID- 25512881 TI - Striking while the iron is hot: Understanding the biological and neurodevelopmental effects of iron deficiency to optimize intervention in early childhood. AB - Prenatal and early postnatal iron deficiency (ID) is associated with long-term neurobiological alterations and disruptions in cognitive, social, and behavioral development. Early life ID is particularly detrimental as this is a period of rapid neurodevelopment. Even after iron supplementation, cognitive and social disruptions often persist in formerly iron deficient individuals. Observational studies of the acute and long-term effects of early life ID yield different results based on the timing of ID. Further, intervention studies demonstrate some improvement for certain domains but still show residual effects years later, which are dependent on the timing of ID and treatment. This review will cover the effects of ID during infancy and early childhood on brain structure and function, cognition, and behavior in relation to preclinical models of ID and sensitive periods of human brain development. PMID- 25512883 TI - Endovascular repair of aortic dissection and intramural hematoma: indications and serial changes. AB - Thoracic aortic dissection (AD) is one of the most common aortic emergencies. It can be fatal if not promptly diagnosed and treated. Intramural hematoma (IMH) of the aorta is recognized as distinct from classic (double-barreled) AD. IMH also frequently leads to aortic emergency, which can be fatal unless rapidly diagnosed and treated. Recently, thoracic endovascular aortic repair (TEVAR) has been used for the treatment of complications caused by AD. TEVAR is also a viable option for the treatment of complicated IHM. In this article, we review the details of TEVAR as treatment options for AD and IMH, including the indications for TEVAR, imaging, and follow-up. PMID- 25512884 TI - Embryonic and larval developmental stages of African giant catfish Heterobranchus bidorsalis (Geoffroy Saint Hilaire, 1809) (Teleostei, Clariidae). AB - The dearth of African giant catfish Heterobranchus bidorsalis seeds poses great threat to its aquaculture and biodiversity, hence detailed knowledge and understanding of its embryology is indispensable for its artificial propagation and conservation programmes. Photomicrographs of extruded oocyte through all developmental cell stages of live embryo to larval stage are documented with the aid of a light microscope. The optical transparency of the developing embryo enabled us to describe its deep structures, distinctive features and characterize the stages pictorially. Extruded oocyte had a mean diameter of 1 +/- 0.1 mm, ~20% increase when hydrated, and bounded by double thin perivitelline membranes. The first mitotic cleavage occurred at 69 min post-fertilization (pf) resulting in 2, 4 (2 * 2 array of cells), 8 (2 * 4), 16 (4 * 4), 32 (4 * 8), 64 (2 * 4 * 8) blastomeres, then developed to morula, blastula and gastrula stages. Blastula was featured by formation of enveloping layer and yolk syncytial layer. Onset of epiboly at 3 h 57 min depicted the commencement of gastrula while closure of blastopore at 11 h 8 min marked its completion. Neurulation period was distinct from segmentation where organogenesis was fully active. Embryo sudden muscular contraction was noticed at ~17 h pf, increased prior to hatching with caudal locomotion firstly at 42 s interval. Heartbeat of embryo commenced at ~1 h before its unique eclosion at average of 72 beats/min while first larva emerged at 21 h at a controlled temperature of 28.5 +/- 0.5 degrees C. Mean total length (TL) of larvae and their pouch thickness were 5 +/- 1 mm and 0.05 +/- 0.02 mm respectively. 1 -day old larvae revealed 8 distinctive neuromeres and by day 3, epicanthus folds of the eyes were fully uncovered; and thereafter commenced exogenous feeding. At day 4, larvae recorded mean TL of 9 +/- 1 mm and 15 caudal fin rays. The fin bifurcation to dorsal and adipose fins was observed at third and half weeks post-hatchability with the dorsal fin length to adipose fin was 1.7:1. This study, for the first time, presents significant morpho-sequential developmental stages of H. bidorsalis and registers its unique form of eclosion. PMID- 25512882 TI - Structural basis for heterogeneous phenotype of ERG11 dependent Azole resistance in C.albicans clinical isolates. AB - Correlating antifungal Azole drug resistance and mis-sense mutations of ERG11 has been paradoxical in pathogenic yeast Candida albicans. Amino acid substitutions (single or multiple) are frequent on ERG11, a membrane bound enzyme of Ergosterol biosynthesis pathway. Presence or absence of mutations can not sufficiently predict susceptibility. To analyze role of mis-sense mutations on Azole resistance energetically optimized, structurally validated homology model of wild C.albicans ERG11 using eukaryotic template was generated. A Composite Search Approach is proposed to identify vital residues for interaction at 3D active site. Structural analysis of catalytic groove, dynamics of substrate access channels and proximity of Heme prosthetic group characterized ERG11 active site. Several mis-sense mutations of ERG11 reported in C.albicans clinical isolates were selected through a stringent criterion and modeled. ERG11 mutants subsequently subjected to a four tier comparative biophysical analysis. This study indicates (i) critical interactions occur with residues at anterior part of 3D catalytic groove and substitution of these vital residues alters local geometry causing considerable change in catalytic pocket dimension. (ii) Substitutions of vital residues lead to confirmed resistance in clinical isolates that may be resultant to changed geometry of catalytic pocket. (iii)These substitutions also impart significant energetic changes on C.albicans ERG11 and (iv) include detectable dynamic fluctuations on the mutants. (v)Mis-sense mutations on the vital residues of the active site and at the vicinity of Heme prosthetic group are less frequent compared to rest of the enzyme. This large scale mutational study can aid to characterize the mutants in clinical isolates. PMID- 25512885 TI - ITS1, 5.8S and ITS2 secondary structure modelling for intra-specific differentiation among species of the Colletotrichum gloeosporioides sensu lato species complex. AB - The Colletotrichum gloeosporioides species complex is among the most destructive fungal plant pathogens in the world, however, identification of member species which are of quarantine importance is impacted by a number of factors that negatively affect species identification. Structural information of the rRNA marker may be considered to be a conserved marker which can be used as supplementary information for possible species identification. The difficulty in using ITS rDNA sequences for identification lies in the low level of sequence variation at the intra-specific level and the generation of artificially-induced sequence variation due to errors in polymerization of the ITS array during DNA replication. Type and query ITS sequences were subjected to sequence analyses prior to generation of predicted consensus secondary structures, including the pattern of nucleotide polymorphisms and number of indel haplotypes, GC content, and detection of artificially-induced sequence variation. Data pertaining to structure stability, the presence of conserved motifs in secondary structures and mapping of all sequences onto the consensus C. gloeosporioides sensu stricto secondary structure for ITS1, 5.8S and ITS2 markers was then carried out. Motifs that are evolutionarily conserved among eukaryotes were found for all ITS1, 5.8S and ITS2 sequences. The sequences exhibited conserved features typical of functional rRNAs. Generally, polymorphisms occurred within less conserved regions and were seen as bulges, internal and terminal loops or non-canonical G-U base pairs within regions of the double stranded helices. Importantly, there were also taxonomic motifs and base changes that were unique to specific taxa and which may be used to support intra-specific identification of members of the C. gloeosporioides sensu lato species complex. PMID- 25512886 TI - Closure of small and medium size umbilical hernias with the Proceed Ventral Patch in obese patients: a single center experience. AB - Obesity is a risk factor for the development of umbilical hernia. Open hernia closure could be challenging in obese patients leading to high rates of recurrence. The aim of this study was to investigate the effectiveness and safety of hernia patches in the management of obese patients with umbilical hernias. All the patients included in this study were managed in the department of surgery of a primary care hospital in Germany. The data of patients undergoing umbilical hernia repair within a two-year period was retrospectively reviewed. Patients managed with the PVP were included for analysis. 24 obese patients were analyzed. Small and medium size patches were used in 15 and 9 patients respectively. The median duration of surgery was 40 min and the median length of hospital stay was 4d. The mean length of follow-up was 12 +/- 9 months (range: 6-30 months). The rate of recurrence was 4.1% and the rate of complication was 8.3%. Obese patients presenting with small and medium size umbilical hernias could be safely and effectively managed with prosthetic patches like the Proceed Ventral Patch. However, the limited overlap zone following hernia closure with such a patch can be an issue. PMID- 25512887 TI - A randomized controlled trial to evaluate an educational strategy involving community health volunteers in improving self-care in patients with chronic heart failure: Rationale, design and methodology. AB - BACKGROUND: Chronic heart failure (CHF) is an increasingly important health problem worldwide. Effective self-care can improve the outcomes and quality of life in patients with CHF. Acknowledging the important role of educational interventions for improving self-care, we sought to assess a new educational strategy involving community health volunteers (CHVs) that could reduce the cost and, hypothetically, increase the effectiveness of self-care education in patients with CHF. METHODS/DESIGN: In this ongoing three-arm controlled trial, approved by two human research ethics committees in Australia and Iran, 231 patients with CHF registered at a referral cardiovascular hospital in Iran were randomly allocated into three groups -trained by community health volunteers at patients' homes, rained by formal health professionals at hospital; and a control group with no formal educational exposure. Data obtained through interviewing participants and using the Persian self-care of CHF index (pSCHFI) before and two months after interventions will be analysed using SAS and SPSS. DISCUSSION: The results of this study may help health service systems, especially in countries with limited resources, make use of community volunteers to teach patients with CHF to develop self-care behaviors and skills, reducing the cost of care and improving CHF outcomes. Also, this home-based educational strategy using face-to face training, if successful, may provide psychosocial supports for patients suffering from chronic illnesses. TRIAL REGISTRATION NUMBER: ACTRN12614000788673 (Australian New Zealand Clinical Trials Registry). PMID- 25512889 TI - The grand old party - a party of values? AB - In this article we explore the semantic space spanned by self-reported statements of Republican voters. Our semantic structure analysis uses multidimensional scaling and social network analysis to extract, explore, and visualize word patterns and word associations in response to the stimulus statement "I'm a Republican, because ..." which were collected from the official website of the Republican Party. With psychological value theory as our backdrop, we examine the association of specific keywords within and across the statements, compute clusters of statements based on these associations, and explore common word sequences Republican voters use to characterize their political association with the Party. PMID- 25512888 TI - Ventilatory response to exercise in adolescents with cystic fibrosis and mild-to moderate airway obstruction. AB - Data regarding the ventilatory response to exercise in adolescents with mild-to moderate cystic fibrosis (CF) are equivocal. This study aimed to describe the ventilatory response during a progressive cardiopulmonary exercise test (CPET) up to maximal exertion, as well as to assess the adequacy of the ventilatory response for carbon dioxide (CO2) exhalation. Twenty-two adolescents with CF (12 boys and 10 girls; mean +/- SD age: 14.3 +/- 1.3 years; FEV1: 78.6 +/- 17.3% of predicted) performed a maximal CPET. For each patient, data of a sex- and age matched healthy control was included (12 boys and 10 girls; mean +/- SD age: 14.3 +/- 1.4 years). At different relative exercise intensities of 25%, 50%, 75%, and 100% of peak oxygen uptake (VO2peak), breathing pattern, estimated ventilatory dead space ventilation (VD/VT ratio), minute ventilation (VE) to CO2 production relationship (VE/VCO2-slope), partial end-tidal CO2 tension (PETCO2), and the VE to the work rate (VE/WR) ratio were examined. VO2peak was significantly reduced in CF patients (P = 0.01). We found no differences in breathing pattern between both groups, except for a significantly higher VE at rest and a trend towards a lower VE at peak exercise in patients with CF. Significantly higher values were found for the estimated VD/VT ratio throughout the CPET in CF patients (P < 0.01). VE/VCO2-slope and PETCO2 values differed not between the two groups throughout the CPET. VE/WR ratio values were significantly higher in CF during the entire range of the CPET (P < 0.01). This study found an exaggerated ventilatory response (high VE/WR ratio values), which was adequate for CO2 exhalation (normal VE/VCO2-slope and PETCO2 values) during progressive exercise up to maximal exhaustion in CF patients with mild-to-moderate airway obstruction. PMID- 25512890 TI - Cardiac echo-lab productivity in times of economic austerity. AB - The present study attempts to offer insight into the volume, cost, and productivity of the operation of a cardiac echocardiographic laboratory (echo lab) in a major public hospital of Greece and thus to contribute, on a practical level, to the widening of knowledge in the strategic field of secondary and tertiary healthcare management. The conducted research includes the basic step of the deployment of a primary data registry in the echo-lab and unfolds in three levels, i.e. the variability measurement of the quantity and cost of medical services provided to different patient populations, the assessment of operating costs and the development of productivity indexes. The results show that the mean costs of provision do change among distinct patient populations. The most important, from a financial standpoint, population cluster appears to be the one corresponding to outpatients. Productivity indices presented in this analysis constitute an essential piece of information which the public healthcare system is currently largely lacking, and which, combined with the pricing and the diagnosis-related group coding system of hospitals, can be used to improve efficiency in the management of secondary and tertiary care. PMID- 25512892 TI - Rituximab for troublesome cases of childhood nephrotic syndrome. AB - Nephrotic syndrome (NS) is the most common glomerular disease of childhood. Steroid-dependent and steroid-resistant nephrotic syndrome present challenges in their pharmaceutical management; patients may need several immunosuppressive medication for optimum control, each of which medication has its own safety profile. Rituximab (RTX) is a monoclonal antibody that targets B cells and has been used successfully for management of lymphoma and rheumatoid arthritis. Recent clinical studies showed that rituximab may be an efficacious and safe alternative for the treatment of complicated nephrotic syndrome. In this review article, we aim to review the efficacy and safety of RTX therapy in nephrotic syndrome. We reviewed the literature pertaining to this topic by searching for relevant studies on PubMed and Medline using specific keywords. The initial search yielded 452 articles. These articles were then examined to ensure their relevance to the topic of research. We focused on multicenter randomized controlled trials with relatively large numbers of patients. A total of 29 articles were finally identified and will be summarized in this review. The majority of clinical studies of RTX in complicated pediatric NS showed that rituximab is effective in approximately 80% of patients with steroid-dependent NS, as it decreases the number of relapses and steroid dosage. However, RTX is less effective at achieving remission in steroid-resistant NS. RTX use was generally safe, and most side effects were transient and infusion-related. More randomized, double-blinded clinical studies are needed to assess the role of RTX in children with nephrotic syndrome. PMID- 25512891 TI - Racial and socioeconomic disparities in heat-related health effects and their mechanisms: a review. AB - Adaptation to increasing extreme heat in a changing climate requires a precise understanding of who is most vulnerable to the health effects of extreme heat. The evidence for race, ethnicity, income, education and occupation, at the individual and area levels, as indicators of vulnerability is reviewed. The evidence for the social, behavioral and technological mechanisms by which racial and socioeconomic disparities in vulnerability exist is also reviewed. These characteristics include cardiorespiratory, renal and endocrine comorbidities; cognitive, mental or physical disabilities; medication use; housing characteristics; neighborhood characteristics such as urban heat islands, crime and safety; social isolation; and individual behaviors such as air conditioning use, opening windows and using fans and use of cooler public spaces. Pre-existing and future research identifying these more proximal indicators of vulnerability will provide information that is more generalizable across locations and time to aid in identifying who to target for prevention of heat-associated morbidity and mortality. PMID- 25512893 TI - Durability of continuous-flow left ventricular assist devices: a systematic review. AB - BACKGROUND: Left ventricular assist devices (LVADs) are becoming an increasingly viable alternative therapy for heart failure, either as a bridge to heart transplantation (BTT) or destination therapy (DT). The latter has become increasingly popular in recent years, in the face of a donor organ shortage and a rise in elderly patients ineligible for heart transplants. For these patients in particular, device durability is a key contributor to survival, morbidity, and quality of life. This systematic review aimed to assess the long-term durability of current continuous-flow LVADs. METHODS: Six electronic databases were searched from their dates of inception to August 2014 for original studies reporting on patients receiving continuous-flow LVADs. LVAD failure was defined as device malfunction necessitating exchange or explantation, or causing patient mortality. Pooled averages were calculated for outcomes and rates of device failure were reconstructed from digitized graph curves using the software, WebPlotDigitizer v3.3. RESULTS: Twelve retrospective observational studies with a total of 5,471 patients were included for analysis. The mean duration of LVAD support was 504.7 (range, 303-568) days, and the overall weighted incidence of device failure was 3.9% (range, 1-11.3%). On average, pump thrombosis was the most common cause of device failure (50.5%), followed by lead or cable damage (21.7%), mechanical pump failure (11.6%), device-related infection (11.1%), and surgical complications from implantation (2.5%). Long-term device failure rates at 2-, 6-, 12-, 18- and 24-months post-implantation were 0.5%, 1.8%, 2.9%, 4.5% and 6.5%, respectively. CONCLUSIONS: With the expected rise in LVAD usage for end-stage heart failure, particularly as a DT, the steady minority of patients experiencing device failure is likely to increase. Further investigation is required into the incidence and mechanism of major causes of failure, as well as design improvements that may address these complications. There is currently a lack of guidelines and large randomized studies reporting on the etiology and outcomes of LVAD failure. PMID- 25512894 TI - Technique for minimizing and treating driveline infections. AB - Left ventricular assist devices (LVADs) are increasingly utilized in the management of advanced heart failure. A transcutaneous driveline is necessary to power the LVAD, and although this technology has improved over the years in terms of smaller size and increased durability, driveline complications continue to develop in up to 20% of all devices implanted. Driveline infections are associated with significant morbidity and mortality. As more patients live longer with ventricular assist devices, minimizing driveline infections is paramount. A systematic, multidisciplinary approach can be used to develop a strategy to prevent, recognize and treat driveline infections. In this paper, we describe our approach to driveline management which has resulted in zero driveline infections between January 2012 and March 2014. PMID- 25512896 TI - Ventricular assist device implantation in the elderly. AB - BACKGROUND: Dramatic advances in ventricular assist device (VAD) design and patient management have made mechanical circulatory support an attractive therapeutic option for the growing pool of elderly heart failure patients. METHODS: A literature review of all relevant studies was performed. No time or language restrictions were imposed, and references of the selected studies were checked for additional relevant citations. RESULTS: In concordance with the universal trend in mechanical circulatory support, continuous flow devices appear to have particular benefits in the elderly. In addition, the literature suggests that early intervention before the development of cardiogenic shock, important in all patients, is particularly paramount in older patients. CONCLUSIONS: The ongoing refinement of patient selection, surgical technique, and post-operative care will continue to improve surgical outcomes, and absolute age may become a less pivotal criterion for mechanical circulatory support. However, clear guidelines for the use of mechanical circulatory support in the elderly remain undefined. PMID- 25512895 TI - Minimally invasive and alternative approaches for long-term LVAD placement: the Vanderbilt strategy. AB - BACKGROUND: Minimally invasive and alternative strategies for implantation have been anecdotally reported for contemporary continuous-flow left ventricular assist device (CF-LVAD) placement. METHODS: We reviewed our experience at a single center with alternative strategies for implantation of the HeartMate II and HeartWare CF-LVADs, in patients with advanced heart failure (HF). This featured article focuses on the associated surgical techniques and patient management pitfalls. RESULTS: For appropriately selected cases, our group believes that these alternative strategies allow for the development of novel and less traumatic surgical approaches for CF-LVAD implantation. With reproducible outcomes, these approaches also promise the possibility of increasing the number of high-risk surgical patients who could benefit from CF-LVAD therapies. CONCLUSIONS: This work has detailed a variety of less invasive alternative strategies for implantation of long-term LVADs. These newer approaches have the potential for significant advancements in the field of cardiothoracic surgery. Large-scale collaborative studies will be needed to clarify the potential advantages and disadvantages of these novel techniques on patient outcomes. PMID- 25512898 TI - Hemorrhage and thrombosis with different LVAD technologies: a matter of flow? AB - BACKGROUND: Much of the morbidity and mortality associated with ventricular assist devices (VADs) is due to haemorrhagic and thrombotic complications. To manage antithrombotic therapy, interactions between the patient and pump should be better understood. METHODS: We have compared the Jarvik 2000, an axial flow left ventricular assist device (LVAD), with the HeartWare ventricular assist device (HVAD) centrifugal pump, regarding conventional laboratory findings, thromboelastometric and aggregometric tests. RESULTS: Patients with the Jarvik 2000 experienced a significant reduction in platelet count following implantation, a phenomenon not seen with the HeartWare model. Conversely, we observed that levels of platelet activation, as assessed by a platelet function analyzer, and activation of the coagulation system, as assessed by thromboelastometry, were significantly greater in the HeartWare group. CONCLUSIONS: It seems that axial flow pumps, being more destructive on blood cells, tend to reduce platelet numbers. On the other hand, centrifugal flow is associated with a hypercoagulable state, possibly resulting from the activation of the coagulation system in the absence of platelet destruction. PMID- 25512897 TI - Comparison of continuous-flow and pulsatile-flow left ventricular assist devices: is there an advantage to pulsatility? AB - BACKGROUND: Continuous-flow left ventricular assist devices (CFVAD) are currently the most widely used type of mechanical circulatory support as bridge-to transplant and destination therapy for end-stage congestive heart failure (HF). Compared to the first generation pulsatile-flow left ventricular assist devices (PFVADs), CFVADs have demonstrated improved reliability and durability. However, CFVADs have also been associated with certain complications thought to be linked with decreased arterial pulsatility. Previous studies comparing CFVADs and PFVADs have presented conflicting results. It is important to understand the outcome differences between CFVAD and PFVAD in order to further advance the current VAD technology. METHODS: In this review, we compared the outcomes of CFVADs and PFVADs and examined the need for arterial pulsatility for the future generation of mechanical circulatory support. RESULTS: CVADs offer advantages of smaller size, increased reliability and durability, and subsequent improvements in survival. However, with the increasing duration of long-term support, it appears that CFVADs may have specific complications and a lower rate of left ventricular recovery associated with diminished pulsatility, increased pressure gradients on the aortic valve and decreased compliance in smaller arterial vessels. PFVAD support or pulsatility control algorithms in CFVADs could be beneficial and potentially necessary for long term support. CONCLUSIONS: Given the relative advantages and disadvantages of CFVADs and PFVADs, the ultimate solution may lie in incorporating pulsatility into current and emerging CFVADs whilst retaining their existing benefits. Future studies examining physiologic responses, end organ function and LV remodeling at varying degrees of pulsatility and device support levels are needed. PMID- 25512899 TI - Biventricular VAD versus LVAD for right heart failure. PMID- 25512900 TI - Impact of reverse remodeling on cardiac function. PMID- 25512901 TI - Present and future perspectives on total artificial hearts. AB - Due to shortages in donor organ availability, advanced heart-failure patients are at high risk of further decompensation and often death while awaiting transplantation. This shortage has led to the development of effective mechanical circulatory support (MCS). Currently, various implantable ventricular-assist devices (VADs) are able to provide temporary or long-term circulatory support for many end-stage heart-failure patients. Implantation of a total artificial heart (TAH) currently represents the surgical treatment option for patients requiring biventricular MCS as a bridge to transplant (BTT) or destination therapy (DT). However, the clinical applicability of available versions of positive displacement pumps is limited by their size and associated complications. Application of advanced technology is aimed at solving some of these issues, attempting to develop a new generation of smaller and more effective TAHs to suit a wider patient population. Particular targets for improvement include modifications to the biocompatibility of device designs and materials in order to decrease hemorrhagic and thromboembolic complications. Meanwhile, new systems to power implanted driving units which are fully operational without interruption of skin barriers represent a potential means of decreasing the risk of infections. In this review, we will discuss the history of the TAH, its development and clinical application, the implications of the existing technological solutions, published outcomes and the future outlook for TAHs. PMID- 25512902 TI - VAD therapy 20/20: moving beyond the myopic view of a nascent therapy. AB - The past five years have seen remarkable growth in the use of durable, continuous flow left ventricular assist devices (LVAD) with associated improvements in mortality, quality of life, functionality and end-organ function. To sustain the growth of this important therapy, the LVAD community must now address key issues focused around the costs of LVAD care, refined patient selection, and reducing complications associated with this therapy. In this perspective piece, we discuss many of these issues. PMID- 25512903 TI - Evolving strategies in the treatment of acute myocardial infarction-induced cardiogenic shock. AB - Despite advances in medical technology and re-vascularization interventions, the mortality rate for cardiogenic shock (CS) following acute myocardial infarction has remained at 50%. The majority of these mortalities are from left ventricular failure resulting in multi-system organ dysfunction. The field of mechanical circulatory support (MCS) has evolved within the past decade, with improved outcomes from extracorporeal membrane oxygenation as well as continuous-flow left ventricular assist devices (CF LVADs). In this paper, we discuss our institutional treatment strategies, the rationale for the protocol development, and our improved outcomes when using MCS in patients with refractory CS following acute myocardial infarction. PMID- 25512904 TI - SynCardia: the total artificial heart. AB - The SynCardia total artificial heart (TAH) currently provides the most definitive option for patients with biventricular failure who are not candidates for isolated left ventricular (LV) assist device placement. The techniques for implantation are adaptable to almost all patients with advanced heart failure, including those with severe biventricular cardiomyopathy, complex congenital heart disease, failed LV assist devices, failed transplantations, and acquired structural heart defects that have failed or are not amenable to conventional surgical treatment. Over the years, the implantation technique has evolved in order to minimize the surgical invasiveness of the procedure, in anticipation of additional future surgery. Meticulous hemostasis with double layer sutures, use of Gore-Tex sheets around the TAH and the pericardial cavity, and use of tissue expanders to avoid contraction of pericardial cavity around the device are discussed in detail in the following report. Additionally, we will provide our experience with implantation of TAH in various challenging scenarios, such as patients with a small chest cavity, congenital heart defects, and simultaneous use of extracorporeal membrane oxygenation (ECMO). PMID- 25512905 TI - Jarvik 2000: evolution of surgical implantation from conventional to minimally invasive technique. PMID- 25512906 TI - Surgical implantation of the CardioWest Total Artificial Heart. PMID- 25512907 TI - Preoperative patient optimization for mechanical circulatory support. PMID- 25512908 TI - Concomitant surgery during ventricular assist device implantation. PMID- 25512909 TI - Heart failure. PMID- 25512911 TI - Evaluation of problem-based learning in medical students' education. AB - INTRODUCTION: In traditional medical education systems much interest is placed on the cramming of basic and clinical facts without considering their applicability in the future professional career. The aim of this study is to evaluate a novice medical training method (problem-based learning) as compared to the contemporary teacher-based medical education or traditional methods. METHODS: Selection of the study subjects was done through simple sampling and according to the division of medical students introduced from Medical Faculty to the Pediatrics Department with no personal involvement. 120 medical students were assigned to 8 groups of 15 students each. For four months, 4 groups were trained with traditional method and 4 other groups underwent problem-based learning method on selected subject materials. In each method, a pre-course test at the beginning and a post-course test at the end of each course were given to each group. The questionnaire used in this study as the instrument was composed of 39 questions, 37 multiple choice questions and two short answer questions. Three professors of pediatric gastroenterologist took part in the training. Two of these professors were responsible for solving task training method. The third professor used traditional teacher-centered methodology to eliminate any possible bias. Scores obtained from these tests were analyzed using paired t-test and independent t test. P-values of less than 0.05 were considered as significant. RESULTS: The scores of the students undergoing the traditional method were 14.70+/-3.03 and 21.20+/-4.07 in the first and second test, respectively. In problem-based learning, the scores were 15.82+/-3.29 in the first and 27.52+/-4.72 in the second test. There was a significant difference between the mean scores of post course exams of the two groups (p=0.001), while no significant difference was observed between the mean scores of pre-course exams of the groups (p=0.550). CONCLUSION: It may be concluded that problem-based learning method leads to a significant increase in learning and recalling output compared to the traditional method. Given the evolving medical education in the country's medical schools toward problem-based learning, it is suggested that the grounds be laid so that this change will take place based on thought, principles and problem solving. PMID- 25512910 TI - Uncoupling protein 2 regulates palmitic acid-induced hepatoma cell autophagy. AB - Mitochondrial uncoupling protein 2 (UCP2) is suggested to have a role in the development of nonalcoholic steatohepatitis (NASH). However, the mechanism remains unclear. Autophagy is an important mediator of many pathological responses. This study aims to investigate the relationship between UCP2 and hepatoma cells autophagy in palmitic acid- (PA-) induced lipotoxicity. H4IIE cells were treated with palmitic acid (PA), and cell autophagy and apoptosis were examined. UCP2 expression, in association with LC3-II and caspase-3, which are indicators of cell autophagy and apoptosis, respectively,was measured. Results demonstrated that UCP2 was associated with autophagy during PA-induced hepatic carcinoma cells injury. Tests on reactive oxygen species (ROS) showed that UCP2 overexpression strongly decreases PA-induced ROS production and apoptosis. Conversely, UCP2 inhibition by genipin or UCP2 mRNA silencing enhances PA-induced ROS production and apoptosis. Autophagy partially participates in this progress. Moreover, UCP2 was associated with ATP synthesis during PA-induced autophagy. In conclusion, increasing UCP2 expression in hepatoma cells may contribute to cell autophagy and antiapoptotic as result of fatty acid injury. Our results may bring new insights for potential NASH therapies. PMID- 25512912 TI - Comparison of the students' satisfaction about the performance of academic advisors before and after the advisor project in Shahrekord University of Medical Sciences. AB - INTRODUCTION: Inappropriate advice interferes with the students' achievement of educational and professional goals and they may fail to use proper resources for their educational needs. The present study was carried out to compare the students' satisfaction about the performance of academic advisors before and after the advisor project in Shahrekord University of Medical Sciences. METHODS: This longitudinal study was carried out using census report on 244 students in different courses at Shahrekord University of Medical Sciences in two stages at the first semester of 2010-2011 and first semester of 2011-2012. To collect the data, we used a self-designed questionnaire including individual and educational information and 10 multiple-choice questions with Likert scale to assess the students' satisfaction about the advisors' performance. Data were analyzed in SPSS 14 using paired t-test, qui-square test. P<0.05 was considered significant. RESULTS: Of the ten items of satisfaction, there was only a significant difference in "accessibility to an advisor before and after the advisor project in students of nursing and midwifery school (p=0.010), and the difference was not significant in other items in these students. No significant difference was found in ten items of satisfaction in students at other schools before and after the advisor project (p=0.010). CONCLUSION: It seems that the implementation of advisor project could not provide a satisfactory position for students. Adequate supervision of university officials on proper implementation of the advisor project, supporting faculty advisors and strengthening their position can help to improve the process. PMID- 25512913 TI - Effect of a parenting education program on girls' life satisfaction in governmental guidance schools of Shiraz. AB - INTRODUCTION: One of the main determinants of adolescents' life satisfaction is parenting skills. Due to the lack of educational trials in this field, this research was done to evaluate the effect of a parenting education program on girls' life satisfaction in governmental guidance schools of Shiraz. METHODS: This study is an educational randomized controlled trial. At first, 152 female students in 2nd grade of governmental guidance schools and 304 parents (152 mother and 152 father) were selected by multistage random cluster sampling method. Then, they were categorized into experimental and control groups. Before and after the intervention, data were collected from two groups using multidimensional students' life satisfaction scale with stability (Cronbach's alpha=0.89), test-retest and correlation coefficient (r=0.70). Educational intervention for parents was performed in the experimental group through presentations with question and answer, discussion in small groups and distribution of educational booklets in 5 volumes. Finally, the data were analyzed using SPSS 14 and through Mann-Whitney test, Chi-square test, Fisher's Exact test, Wilcoxon test. RESULTS: Before the intervention, the experimental and control groups did not show a statistically significant difference based on the demographic variables. Thetotal of life satisfaction scores and also its subscales in the experimental and controlgroup, before and six weeks afterthe educational interventiondid showstatisticallysignificant difference (p<0.001). The scores of differences (pre-test/post-test) in total life satisfaction between the experimental and control groups were statistically significant difference (p<0.001). CONCLUSION: According to low scores of the students in the pre-test, especially in the control group which didn't undergo any educational program, holding scheduled educational intervention is necessary. This study not only supports the effectiveness of educational intervention but also recommends further educational research to develop knowledge regarding patterns of parenting education. PMID- 25512914 TI - The relationship between emotional intelligence and job stress in the faculty of medicine in Isfahan University of Medical Sciences. AB - INTRODUCTION: health care professionals especially clinicians, undergo lots of job stress (JS). Emotional intelligence (EI) is among the variables that appear to be associated with stress. It is also included among the ways adopted by the individuals in order to resist JS in the workplace. Thus, this study aims to investigate the relationship between EI and JS in the faculty members of Isfahan University of Medical Sciences (IUMS). METHODS: This was a correlational study performed on 202 faculty members of IUMS. The data was gathered through two valid and reliable questionnaires (Bradberry EI questionnaire and JS questionnaire), being analyzed by SPSS software using descriptive statistics, Pearson correlation coefficient, t-test, analysis of variance (ANOVA) and linear regression analysis (alpha=0.05). RESULTS: 142 individuals (70.30%) filled out the questionnaires. 75% of the respondents were male and 98% were married. There was an inverse correlation between the total score of EI and the level of JS (r=-0.235, p=0.005). Moreover, among the factors of EI, self-awareness and self-management scores had significant inverse relationship with the level of JS. Linear regression analysis showed that the EI factors explained approximately 7% of the variance of JS levels of the teachers. CONCLUSIONS: Individuals with high EI have less JS. Since the EI can be taught, it can be expected that the JS of faculty members can be reduced through training them on emotional intelligence. Therefore, it is recommended that short-term training courses be scheduled and designed based on the concepts of EI for teachers, particularly clinicians. PMID- 25512915 TI - Evaluation of the consultation program in Shiraz University of Medical Sciences. AB - INTRODUCTION: Consultation and guidance is a process of learning which is done through the relationship between two individuals. In this mutual relationship, the ounsellor, through his scientific and occupational skills and qualification, tries to help the students using the methods corresponding to their needs. The main objective of this study was to provide a framework for the management of the advisors' plans in the university based on the analysis of different schools. METHODS: This research is a cross-sectional and descriptive-analytic study. Data were collected both qualitatively (centralized groups at the presence of advisors in universities) and quantitatively (self-assessment of teachers and students' evaluation). Sampling was done randomly from all students of Shiraz University of Medical Sciences. All the teachers who were advisor took part in this study. RESULTS: This study was conducted in eight schools of Shiraz University of Medical Sciences simultaneously and 974 students and 125 teachers took part in it. At the time of data collection, 25.5 percent of the students declared that the advisors have provided allocated time to them and 45.4 percent believed that the advisors helped the students to understand the importance of the courses. CONCLUSION: The emergence of weaknesses and strengths of the academic advising program and the guidance through teacher's self assessment, not only may be the sign of realization of programmed objectives, but also may be the starting point for qualitative improvement of the situation. Moreover, in order to improve the advisory services and guidance, it is necessary to regard consultation as a scientific subject which needs training. PMID- 25512917 TI - Comparison between current and ideal condition of educational justice from the students' viewpoints at Jahrom Nursing and Paramedical School. AB - INTRODUCTION: Educational justice is a process by which all those involved in education are pondering and seeking to establish it in their regulatory environments. This study aimed to investigate effective factors in an ideal educational justice and the current condition of educational justice from the students' viewpoint and ultimately increase the awareness and understanding of authorities and educational planners of the existing shortcomings. METHODS: This is a descriptive-analytical study. Samples include all nursing, operating room, and anesthesia students of nursing and paramedical college who had passed at least 5 semesters. Data collection was carried out through a scholar questionnaire. Validity was assessed through content validity and reliability of the questionnaire was evaluated using a pilot study. In order to determine the status of the scores, 5 points (very high), 4 (often), 3 (moderate), 2 (low) and 1 (very low) were assigned, respectively. To determine the justice level, a 35 score interval was considered as very low, low, medium, high and very high. SPSS software, descriptive statistics, independent t-test and ANOVA were used to analyze the data. RESULTS: There was a significant difference between the ideal and the current conditions in all items (p<=0.001) and also in the total mean score of ideal condition and mean score of current condition (p=0.010). CONCLUSION: In an educational system, educational methods and aims should be regulated in a way that principles and components of justice are attainable and distribution and allocation of educational facilities of justice are considered thoroughly. PMID- 25512916 TI - Academic resilience in education: the role of achievement goal orientations. AB - INTRODUCTION: In the past 2 decades, research findings established achievement goal theory as a powerful framework for conceptualizing difference in the quality of student's engagement, persistence on task, and academic resilience. So the present study examined the relationship between achievement goal orientations and academic resilience. METHOD: Participants were 606 students (307 girls and 297 boys) selected from Shiraz high schools. They completed the Achievement Goals Questionnaire and Youth development Module Scale (RYDM). To analyze the data, the relationships between variables were examined, using Pearson product-moment correlations. Also simulanteous multiple regression was performed to investigate the prediction of academic resilience by achievement goal orientations. To examine the reliability and the validity of measures Cronbach alpha coefficient and factor analysis method were applied, respectively. RESULTS: Simultaneous multiple regression of achievement goal orientations on academic resilience showed that "mastery-approach" was a significant positive predictor of the "home care/high" and "peer care" subscales. Also, "performance-approach" was a significant, positive predictor of "home care/high", and "school/community meaningful" was predicted by "performance-avoidance" positively. CONCLUSION: According to the findings, it seems that achievement goal orientation has a critical role in students' academic achievement. Implications of the results are discussed in more details. PMID- 25512918 TI - A study on the quality of study skills of newly-admitted students of Fasa University of Medical Sciences. AB - INTRODUCTION: Some students attribute their academic failure to such factors as low aptitude, unavailability of resources, and bad luck. However, we can dare to say that the most important factor playing a role in academic success is students' little acquaintance with learning and study skills. This study aimed at examining the quality of study skills in newly-admitted students of Fasa Medical University so that the results can be used in holding teaching courses in study skills. METHODS: The present study is a cross-sectional descriptive study. The sampling was done of all the newly-admitted students in the first semester of 2012 academic year including 94 students of Medicine, Nursing and Laboratory Technology. The data were collected through a questionnaire, consisting of two parts. The first part included items on demographic information of the subjects (such as sex, field of study, number of hours dedicated to studying, student's rank in Konkour, and the National University entrance exam. The second part was composed of 19 special items on such domains as 'Time management', 'Concentration', 'Class note-taking', 'Studying' and 'Taking exams' with 4, 5, 4, 3, 3 items, respectively. The checklists were filled in using Likert Scale. The collected data was then analyzed using an SPSS 14, through which descriptive statistics as mean, standard deviation and multiple regressions were obtained. Moreover, the data were analyzed using Independent Sample t and ANOVA tests. RESULTS: The results showed that the range of the students' study skills was 2.35, being rather below the normal level; the highest mean belonged to 'concentration' (2.56), but the lowest mean was that of 'time management' (2.05).Through ANOVA test, it was also shown that there was no significant difference between the students of Medicine, Nursing and Laboratory Sciences regarding their scores on 'study skills' as (p=0.646). In addition, through independent sample t-test, it was shown that there was no significant difference between the subjects' 'sex' and 'study skills' as the p-value was 0.584. On the other hand, through multiple regressions, the results indicated that there was a significant difference between 'taking exams' and 'studying' (p=0.003), between 'class note-taking' and ''taking exams' (p=0.004), between 'concentration' and ''taking exams' (p=0.002), and between 'time management' and 'taking exams' (p=0.001). CONCLUSION: Regarding the very important role of study skills in learning, it is recommended that 'study skills' and 'study habits' courses be included in the students' curriculum formally or implemented as workshops for students. PMID- 25512919 TI - Fasa University Medical School: a novel experience in medical education. AB - INTRODUCTION: In early 1970's a combination of a shortage and misdistribution of health services and growing public dissatisfaction about the health care available, along with increasing expectations, has put great strain on the mind of the staff of the Department of Medicine Shiraz University School of Medicine. The purpose of this report is to give an account of what was originally planned and what has happened since the start of Fasa Medical School in April 1978. METHODS: This is a case report about an experience in medical education in Iran. At the time, two major problems were facing our country. The first was gross mal distribution of these healthcare facilities, which were mostly concentrated in Tehran and big cities of Iran, and the second problem was continuous exodus of Iranian Medical graduates to the Western countries. RESULTS: The main idea of creating Fasa Medical School was to create a system in which primary care in small villages are provided by VHW with the middle level health workers of "Behdar Roustaee" to be supported by local physicians who reside in small towns. CONCLUSION: For Fasa Medical School, education was emphasized on community based, student centered, and problem based medical education located in the community and based on teamwork and cooperation. PMID- 25512920 TI - Influential factors on learning through the hidden curriculum in the perspective of undergraduate baccalaureate nursing students. AB - INTRODUCTION: Nursing curriculum is not always overt; it can also exist covertly in the form of a hidden curriculum. This study aims to explain the factors influencing learning through the hidden curriculum in the perspective of undergraduate baccalaureate nursing students. METHODS: This qualitative study was conducted through purposeful sampling strategy on 24 undergraduate baccalaureate nursing students studying in the first to the fourth years of their education. The data were collected using semi-structured interviews and this process continued until data saturation and categories' emergence. Inductive content analysis was used for data analysis. RESULTS: Professional promotion as a learning factor, impact of personal characteristics on learning, educator's behavior as a learning stimulus, and feedback as a learning stimulus are the main categories emerged in this study; some of them included sub-categories as well. CONCLUSION: Professional promotion, personal characteristics, educator's behavior and feedback were the main influencing factors on learning through the hidden curriculum in undergraduate baccalaureate nursing students. The findings of this study can be used for developing strategies to promote nursing education and as a result patient care. Further studies are recommended to identify other factors. PMID- 25512921 TI - Medical genetics teaching in Iranian medical schools, especially Ahvaz, south of Iran. AB - INTRODUCTION: Physicians have to visit, diagnose and refer patients with genetic disorders, so they need to be familiar with the basics and indications of genetic tests. In other words, they should have effective theoretical and practical knowledge about medical genetics before they do their job. Medical genetics courses at Medical Universities of Iran are generally presented as a theoretical subject in the first period of medical education. METHODS: In this descriptive research, the results of interviews with teachers of medical genetics in 30 medical schools in Islamic Republic of Iran and responses to a questionnaire by 125 medical students of Ahvaz Jundishapour University of medical sciences, about presentation time, curricula and also efficacy of medical genetics courses were analyzed. The interviews with teachers were done on phone and the students' comments were collected by a researcher-made questionnaire. The data were analyzed, using SPSS software, version 14. RESULTS: In two thirds of medical universities, medical genetics is taught in the third or fourth semester and in 5 universities in the fifth semester. 86% of the students believed that the quality of genetics courses is moderate and such courses are very beneficial to medical students. CONCLUSION: This article suggests that medical genetics be offered in the second or third period of medical education (physiopathology or stagger period). Furthermore, in teaching such courses advanced educational methods (animation presentation, case-based learning, problem-based learning, etc.) should be used, together with simple genetic tests in laboratories, and the visit of genetic patients in hospitals and genetics centers. PMID- 25512922 TI - The effects of a peer-led training program on female students' self-esteem in public secondary schools in Shiraz. AB - INTRODUCTION: Low self-esteem in adolescence is one of the risk factors for negative outcomes in important domains of adulthood life. Due to the lack of trials based on modern methods of teaching in the field of self-esteem, this study aimed to investigate the effects of a peer-led training program on female second graders' self-esteem in public secondary schools in Shiraz. METHODS: The present study is an educational controlled trial. 223 public school female students in the second grade were selected with the Multi-stage random cluster sampling method. The selected Schools were assigned randomly to experimental and control groups. The data were collected before, one and six weeks after an intervention in the control and experimental group, using Pope's 5-scale test of self-esteem with Cronbach's alpha reliability of 0.85. The educational intervention in the experimental group was a peer-led approach, using discussion techniques in small groups (the group work, role play and group play) and a 5 volume training manual. The data were analyzed through SPSS, version 14, using Mann-Whitney test, Chi-square test, Wilcoxon and repeated measure Analysis of Variance (ANOVA). RESULTS: The results showed that the mean of total self-esteem scores and the sub-scales (except for family self-esteem) in the experimental groups compared to that in the control groups, one and six weeks after the peer led based approach intervention was significantly different (p<0.001). Before the intervention, the mean for self-esteem in the experimental groups was 51.80+/ 13.91 but in the first post-test and second post-test the mean increased to 73.72+/-12.94, and 69.48+/-12.63, respectively. Before the educational intervention, the frequency distribution of females' self-esteem in the experimental and control groups did not differ significantly from each other (p=0.337). But during one and six weeks after the intervention, a significant increase was observed between the two groups (p<0.001). CONCLUSION: The results of this study suggest that peer education is an effective way to promote self esteem in adolescents. Providing opportunities such as a peer-led approach can help adolescents to acquire practical ways to increase their self-esteem. PMID- 25512923 TI - Evaluation of the efficacy of peer-learning method in nutrition students of Shiraz University of Medical Sciences. AB - INTRODUCTION: One of notable initiatives in improving the academic education is to use the abilities of students to learn together in a new and effective system of peer learning. In this regard, Education Development Center in Shiraz University of Medical Sciences proceed to implementation and study of the curriculum and teaching methods course in the form of peer learning for college students of nutrition science and survey the efficacy of this implementation. METHODS: This study was conducted two parts: qualitative and quantitative survey. A quasi-experimental, pre test/post-test research was used in quantitative part. In this study, whole groups of undergraduate nutrition students in courses of study and learning techniques with the help of teachers held a course and took a part in a competition in 15 major subjects of study and learning methods. The study lasted for two-week sessions and whole of nutrition students were included. We used pair t test for comparison pre test and post test in this study. RESULTS: In the quantitative part of the study, the results showed a significant difference between pre-test (0.0346+/-0.108) and post-test scores (0.809+/-0.187) of the students. This means that the level of knowledge of students, who participated in this course, has significant difference before and after the peer learning course (pair t-test=1.010, p=0.002). The results of the quality survey of the training course also indicated satisfaction of participants and necessity of teacher's presence and control at courses. CONCLUSIONS: The results of this study confirm the results of the previous studies emphasizing numerous positive effects of the peer learning methods in the academic community. The results also suggest that peer learning is effective to enhancement of the students' confidence and learning. Peer learning also helps to develop their future responsibilities. PMID- 25512924 TI - The summer school students' viewpoints about important factors in learning, Shiraz University of Medical Sciences. AB - INTRODUCTION: The main goal of education is learning and change in behavior which has been revolutionized in the 21st century due to the rapid and widespread changes in science. The traditional approach to education does no longer meet the learners' needs, necessitating new changes in educational curricula. This study was designed to determine the factors influencing learning in the 21st century and find out the students' viewpoints on this issue. METHODS: This is a descriptive study aiming at determining the students' views on new approaches to learning in the 21st century. To do so, a researcher-made questionnaire was designed. It contained 30 questions in 3 sections including demographic data, background questions and two open questions about their suggestions and criticisms. The reliability and validity of the questionnaire was pilot-tested and measured, which proved to be describable. 150 students participating in university summer schools in Shiraz University of Medical Sciences were enrolled. The questionnaires were sent to the students in person and through electronic mails. The students were asked to return the completed questionnaires to the given email address. The data were analyzed in SPSS, version 14, using descriptive statistics of frequency, mean, percentage and standard deviation and t-test. P<0.05 was considered as statistically significant. RESULTS: 150 questionnaires were appropriately filled out and given to the researchers. The results indicated that, according to the students, 6 factors including the use of computer in teaching, enhancement of virtual learning, the use of mobile in relations, enjoyment of electronic learning contexts, the learning focus on attitudes and the facilitating role of the lectures were the most influential factors in learning. On the other hand, the government's responsibility and responsiveness, creativity and risk taking, increase in the social relationship among the learners, focus on practical skills, and management were considered as the least influential factors in learning in the 21(st) century. CONCLUSION: It seems that the students philosophically tend to approve constructivism and cooperative learning which is learner-centered as compared to conventional education which is teacher-contended. According to experts, this type of viewpoint is in the same line with new approaches to teaching and education in the present era. Moreover, it impacts the reforms, complementation and expansion of methodology greatly. PMID- 25512925 TI - Nursing students' satisfaction about their field of study. AB - INTRODUCTION: Nowadays students' opinion is considered as a necessary factor to evaluate quality in universities. This study was performed to evaluate the nursing students' satisfaction about their field of study. METHODS: The research population in this study consists of all the students of nursing studying at the second to fourth year of university (72 students). The data were collected from all the studied population. Data collection instrument was a research questionnaire. In this cross-sectional research, nursing students' satisfaction (72 students) in 6 major topics (situation of educational environment, situation of clinical environment, trainers, social image, relation to colleagues and management) was studied. The data were analyzed in SPSS, version 14, using quantitative variables and descriptive statistics including frequency distribution tables and diagrams. RESULTS: The findings indicated that 83.3% of the students had little satisfaction as to the situation of educational environment, 47.2% about situation of clinical environment, 41.7% concerning the theoretical educational method by professors, and 41.7% as to the method of clinical education by clinical trainers. Also 47.2% were not that satisfied with the method of evaluation by the school professors, 80.6% with the method of relationship with colleagues and also 62.5% with the nursing social image. Moreover, findings indicated that 33.3% of the participants in this research were dissatisfied with the method of evaluation by clinical trainers and 50% with the method of nursing management. CONCLUSION: In the present study, most students had little satisfaction concerning their field of study. So it is necessary to make an attempt for continuous development of quality services. PMID- 25512926 TI - Comparison of empathy score among medical students in both basic and clinical levels. AB - INTRODUCTION: Empathy refers to a personality character that has a great role in communication with others. Thus, proper evaluation and education of empathy in medical students is important for medical education. Because previous studies had suggested that physician's empathy may reduce with clinical trainings, in this study we decided to measure the empathy score among medical students. METHODS: This is a cross-sectional study conducted on medical students in the first to seventh years of their studies at Shiraz medical school (south of Iran) in 2010. We designed new Iranian version questionnaire of the Jefferson Scale of Physician Empathy. Sample size was 260 students and the results were analyzed in SPSS, version 11.5 (statistical tests such as descriptive methods, t-test, and ANOVA) and p<005 was considered as the significant level. RESULTS: The empathy score decreased with increase in the students' age (p=0.001) and educational level (p=0.030). The overall rate of empathy score in basic science level (65.5+/-0.84) was more than that in the clinical level (55.5+/-1.78). The lowest empathy score was seen in the seventh year students (55.51) and the highest was in the first year students (65.50). Female students had higher mean empathy score (65.53) while it was 59.02 in the male students. CONCLUSION: In general, medical students in Shiraz University of Medical Sciences had low empathy level and this may be a cause for concern; as such we suggest a possible inclusion of courses on empathy in the curriculum. PMID- 25512927 TI - Learning operational strategies in surgery training. AB - INTRODUCTION: Education and training in surgery is in the middle of apprenticeship style of learning especially in operating room with little importance of understanding on how trainees learn. METHODS: This training is one of the most difficult types of training. Medical training and expertise are the specialty of this education system. We can name these complex fields as "Operational Strategies". The strategies are includes of "what to do", "what to think" and "what to create". These strategies are good to test and train higher functions in persons who have professional's positions. RESULTS: Most of educational fields are complex. It means that the training is not limited in an area and includes of theory fields, areas of decision making and areas of handy and practical skills. These fields are the most relevant skills or expertise which individual must be informed of the performance of maintenance and repair or upgrade and make a new system. CONCLUSION: The operational strategy is a new training strategy for surgery students. It is useful to train surgery students to modify and improve their practices and doing surgeries and treating patients in best conditions. PMID- 25512928 TI - The role of critical thinking skills and learning styles of university students in their academic performance. AB - INTRODUCTION: The Current world needs people who have a lot of different abilities such as cognition and application of different ways of thinking, research, problem solving, critical thinking skills and creativity. In addition to critical thinking, learning styles is another key factor which has an essential role in the process of problem solving. This study aimed to determine the relationship between learning styles and critical thinking of students and their academic performance in Alborz University of Medical Science. METHODS: This cross-correlation study was performed in 2012, on 216 students of Alborz University who were selected randomly by the stratified random sampling. The data was obtained via a three-part questionnaire included demographic data, Kolb standardized questionnaire of learning style and California critical thinking standardized questionnaire. The academic performance of the students was extracted by the school records. The validity of the instruments was determined in terms of content validity, and the reliability was gained through internal consistency methods. Cronbach's alpha coefficient was found to be 0.78 for the California critical thinking questionnaire. The Chi Square test, Independent t test, one way ANOVA and Pearson correlation test were used to determine relationship between variables. The Package SPSS14 statistical software was used to analyze data with a significant level of p<0.05. RESULTS: Our findings indicated the significant difference of mean score in four learning style, suggesting university students with convergent learning style have better performance than other groups. Also learning style had a relationship with age, gender, field of study, semester and job. The results about the critical thinking of the students showed that the mean of deductive reasoning and evaluation skills were higher than that of other skills and analytical skills had the lowest mean and there was a positive significant relationship between the students' performance with inferential skill and the total score of critical thinking skills (p<0.05). Furthermore, evaluation skills and deductive reasoning had significant relationship. On the other hand, the mean total score of critical thinking had significant difference between different learning styles. CONCLUSION: The results of this study showed that the learning styles, critical thinking and academic performance are significantly associated with one another. Considering the growing importance of critical thinking in enhancing the professional competence of individuals, it's recommended to use teaching methods consistent with the learning style because it would be more effective in this context. PMID- 25512929 TI - Grasha-Richmann college students' learning styles of classroom participation: role of gender and major. AB - INTRODUCTION: This study aimed to investigate the male and female students' learning styles of classroom participation and these styles' differences between Humanities and Science majors. METHOD: 1039 individuals were selected through the proportional stratified random sampling method among undergraduate and graduate students in Humanities (n=421) and Science (n=618) faculties of Tehran University. In the Humanities group, there were 285 females and 136 males, and in the Science group, there were 208 females and 410 males. The participants answered the Grasha-Riechmann student learning styles scale. RESULTS: The findings indicated that the females obtained significantly higher means in collaborative, participative, and dependent styles than males, but in avoidant, and independent styles, the means for males were higher than those for females. Also, the science group's means in collaborative, participative, dependent, and competitive styles were significantly higher than those for the humanities group. CONCLUSION: According to the findings, it seems that due to psychological characteristics, female students tend to collaborate with other students of the same sex and participate in their activities. In this way, they also are more dependent on their teacher and classroom, because otherwise they will face some problems such as anxiety. In addition, it seems that science students in comparison to humanities students are more participative and collaborative because they need more collaboration in their projects and course work. PMID- 25512930 TI - Comparison of differences in performance evaluation of faculty by students with faculty's self-assessment. AB - INTRODUCTION: The present study aimed to compare self-assessment forms of coursework taught in the school of public health at undergraduate, graduate, and postgraduate levels and students' evaluation of the performance of the faculty members at these levels. METHODS: The subjects in this cross-sectional study were the faculty members and students of the School of Public Health and Nutrition, Shiraz University of Medical Sciences, Shiraz, Iran. The data were collected using a socio-demographic information form and evaluation forms of professors prepared by the Educational Development Center (EDC). The faculty members were assessed by the students in undergraduate and graduate classes. Among the study subjects, 23 faculty members filled out the self-assessment forms which were then evaluated by 23 students. Then, the data were analyzed using the SPSS statistical 14. Paired t-test was used to compare the students' evaluation of the faculty members' performance and the professors' self-assessment. RESULTS: The mean score of self-assessment of the faculty members who taught undergraduate courses was 289.7+/-8.3, while that of the students' evaluation was 281.3+/-16.1; the difference was statistically significant (t=3.56, p=0.001). Besides, the mean score of the self-assessment of the faculty members who taught graduate courses was 269.0+/-9.7, while that of the students' evaluation was 265.7+/-14.6 but the difference was not statistically significant (t=1.09, p=0.28). CONCLUSIONS: Teaching performance perceptions of the faculty were similar to those of the graduate students as compared to the undergraduate ones. This may reflect better understanding of coursework at this level compared to the undergraduate students. Faculty members may need to adjust teaching methods to improve students' performance and understanding especially in the undergraduate level. PMID- 25512931 TI - The students' viewpoint on the quality gap in educational services. AB - INTRODUCTION: Students and university community are social and human resources of the country. The students' viewpoints about the quality of educational services can be considered as a basis for planning quality promotion and improving organizational performance. This study was conducted to determine the quality gap in educational services by the students of Health and Nutrition School of Shiraz University of Medical Sciences. METHODS: In this cross-sectional study, 140 students participated voluntarily (age range=19 to 40 years). The service quality (SERVQUAL) questionnaire was used for data collection. This questionnaire measured the quality gap in 5 dimensions of educational service including assurance, responsiveness, empathy, reliability, and tangibility. The students' perception about the current conditions and their expectations as to optimal conditions can be determined, using this questionnaire. The score of the gap in quality of educational services is calculated from difference between perception and expectation scores. Due to non-normality of data, non-parametric tests were used. To this end, data were analyzed by statistical tests including Wilcoxon, Friedman, Kruskal-Wallis and Mann-Whiteny tests in SPSS 14. RESULTS: The results showed that there was quality gap in all 5 dimensions of educational services. The largest and the smallest gaps were observed in "responsiveness" with a mean+/ SD of -0.94+/-0.74 and in "reliability" with a mean+/-SD of -0.76+/-0.69, respectively. There was a significant difference in quality gap between the 5 dimensions (p<0.001). CONCLUSION: According to the results, the students' expectations were higher than their perceptions of current conditions; also, in all aspects of the services their expectations were not met. It is recommended that workshops on customer services, communication skills and personnel's technical skills development should be planned and held. Also, allocating more resources for improving educational facilities and physical environment is recommended. PMID- 25512932 TI - The evaluation of a composed program of continuing medical education for general practitioners. AB - INTRODUCTION: The execution of composed educational programs for general practitioners is one of the most common methods of continuing medical education. This research project aims to evaluate one of these programs. METHODS: For this purpose, a pre- and post-test design was developed. The subjects consisted of 45 participants. They were tested in two stages: before and after the program. A questionnaire was also used to gather the participants' views on four variables including teachers' behavior, the degree of achieving the objective of the program, objective of the learner, and satisfaction with the program. RESULTS: Based on the results of this study, the mean scores of the participants' knowledge increased from 10.05 (pre test) to 12.61 (post test), (p<0.0001). In addition, the results showed that the teachers' behavior and satisfaction with the program were rated by participants as the highest and least, respectively. CONCLUSION: The results of this research are indicative of the effectiveness of the composed educational program in continuing medical education. Nevertheless, such programs are recommended to be further evaluated with more rigorous design. PMID- 25512933 TI - Team-based assessment of professional behavior in medical students. AB - INTRODUCTION: Self and peer assessment provides important information about the individual's performance and behavior in all aspects of their professional environment work. The aim of this study is to evaluate the professional behavior and performance in medical students in the form of team based assessment. METHODS: In a cross-sectional study, 100 medical students in the 7(th) year of education were randomly selected and enrolled; for each student five questionnaires were filled out, including one self-assessment, two peer assessments and two residents assessment. The scoring system of the questionnaires was based on seven point Likert scale. After filling out the questions in the questionnaire, numerical data and written comments provided to the students were collected, analyzed and discussed. Internal consistency (Cronbach's alpha) of the questionnaires was assessed. A p<0.05 was considered as significant level. RESULTS: Internal consistency was acceptable (Cronbach's alpha 0.83). Interviews revealed that the majority of students and assessors interviewed found the method acceptable. The range of scores was 1-6 (Mean+/ SD=4.39+/-0.57) for the residents' assessment, 2-6 (Mean+/-SD= 4.49+/-0.53) for peer assessment, and 3-7 (Mean+/-SD=5.04+/-0.32) for self-assessment. There was a significant difference between self assessment and other methods of assessment. CONCLUSIONS: This study demonstrates that a team-based assessment is an acceptable and feasible method for peer and self-assessment of medical students' learning in a clinical clerkship, and has some advantages over traditional assessment methods. Further studies are needed to focus on the strengths and weaknesses. PMID- 25512934 TI - Relationship between organizational structure and creativity in teaching hospitals. AB - INTRODUCTION: Organization structure and manpower constitute two basic components of anorganization and both are necessary for stablishing an organization. The aim of this survey was to investigate the type of the organization structure (mechanic and organic) from viewpoint of senior and junior managers in Shiraz teaching hospitals and creativity in each of these two structures. METHODS: In this cross-sectional and descriptive-analytic study, organization structure and organizational creation questionnaires were filled out by hospital managers. According to the statistical consultation and due to limited target population, the entire study population was considered as sample. Thus, the sample size in this study was 84 (12 hospitals and every hospital, n = 7). For data analysis, SPSS 14 was used and Spearman correlation coefficient and t-test were used. RESULTS: RESULTS showed that there is a negative association between centralization and complexity with organizational creation and its dimensions. Also there was a negative association between formalization and 4 organizational creation dimensions: reception change, accepting ambiguity, abet new view and less control outside (p=0.001). CONCLUSION: The results of this study showed that the creation in hospitals with organic structure is more than that in hospitals with mechanic structure. PMID- 25512935 TI - Case based teaching at the bed side versus in classroom for undergraduates and residents of pediatrics. AB - INTRODUCTION: Bedside teaching is defined as teaching in the presence of a patient, it is a vital component of medical education. The aim of this study was to evaluate the effectiveness of two methods of case based teaching (at the bedside and in the classroom) in the teaching hospitals (for both undergraduates and residents of pediatrics). METHODS: Thirty undergraduates and twenty pediatric residents were asked to study a topic of their curriculum from their text then pretest was taken from learners in the two levels; then either lecture with power point or case presentation or bed side discussion were conducted. One week later post- test was taken, and then evaluation of these three methods was done by a questionnaire from learners. RESULTS: The majority of under-graduates and all of pediatric residents had evaluated case based teaching superior to bedside teaching and these two methods superior to lecture method. CONCLUSIONS: They believed that in the case based teaching they are more relaxed and have more self esteem than at the bedside of the patients. Clinician teacher must involve participants and learners in the process of bedside teaching, by preparing a comfortable situation and by using available technology. PMID- 25512936 TI - Awareness and use of evidence based medicine (EBM) in medical trainees. PMID- 25512937 TI - Validity of transactional analysis and emotional intelligence in training nursing students. AB - INTRODUCTION: Emotional intelligence (EI) is considered a critical component of a nurse's characteristic trait which is known as a significant predictor of a person's job performance and life success. Transactional Analysis (TA) plays a fundamental role in nurse-patient communication and managing emotions during difficult dialect with patients. The aim of this review is to discuss the framework of EI and TA, and how the combined theories can be utilized to further educate nurses and enhance the patient's experience. Exploring the idea of combining EI, TA, and other theories and adding these addendums to the nursing curriculum may advance the empathy and communication skills of nursing students. METHODS: The method used in this review is a literature search using databases, such as Medline, EBSCO, and Google Scholar, etc. to form a critical discussion of this area. Key words such as emotional intelligence, transactional analysis, nursing curriculum, and relating theoretical models were used to identify applicable documents. Four studies involving EI and TA were sampled. A combination of data collection tools, such as lecture series and intervention programs, were used to authenticate the results. Other instruments used were ego state questionnaires, empathy, and five point Likert scales. No study design or type of literature was excluded in healthcare to substantiate the application of EI and TA into the nursing curriculum. RESULTS: Sixteen nurses attended a six week psycho-education program using communication and empathy scales, and patient satisfaction surveys to improve their empathetic and communication skills. The result of the mean communication score (177.8+/-20) increased to (198.8+/-15) after training (p=0.001). The empathy score increased from 25.7+/-7 to 32.6+/-6 (p=0.001). The overall result reflects that training can improve emergency nurse's communication and empathy skills. CONCLUSION: The data suggests there are under-researched theories with futuristic topics that have value to the nursing community. Suitable evaluation of these theories is vital to nursing education. Implementation and training for nursing students and existing nurses may help shift the culture of medical education ahead by creating a more educated and empathetic work environment. PMID- 25512938 TI - Comparison of the effect of lecture and blended teaching methods on students' learning and satisfaction. AB - INTRODUCTION: Blended learning, a new approach in educational planning, is defined as an applying more than one method, strategy, technique or media in education. Todays, due to the development of infrastructure of Internet networks and the access of most of the students, the Internet can be utilized along with traditional and conventional methods of training. The aim of this study was to compare the students' learning and satisfaction in combination of lecture and e learning with conventional lecture methods. METHODS: This quasi-experimental study is conducted among the sophomore students of Public Health School, Tehran University of Medical Science in 2012-2013. Four classes of the school are randomly selected and are divided into two groups. Education in two classes (45 students) was in the form of lecture method and in the other two classes (48 students) was blended method with e-Learning and lecture methods. The students' knowledge about tuberculosis in two groups was collected and measured by using pre and post-test. This step has been done by sending self-reported electronic questionnaires to the students' email addresses through Google Document software. At the end of educational programs, students' satisfaction and comments about two methods were also collected by questionnaires. Statistical tests such as descriptive methods, paired t-test, independent t-test and ANOVA were done through the SPSS 14 software, and p<=0.05 was considered as significant difference. RESULTS: The mean scores of the lecture and blended groups were 13.18+/-1.37 and 13.35+/-1.36, respectively; the difference between the pre-test scores of the two groups was not statistically significant (p=0.535). Knowledge scores increased in both groups after training, and the mean and standard deviation of knowledge scores of the lectures and combined groups were 16.51+/ 0.69 and 16.18+/-1.06, respectively. The difference between the post-test scores of the two groups was not statistically significant (p=0.112). Students' satisfaction in blended learning method was higher than lecture method. CONCLUSION: The results revealed that the blended method is effective in increasing the students' learning rate. E-learning can be used to teach some courses and might be considered as economic aspects. Since in universities of medical sciences in the country, the majority of students have access to the Internet and email address, using e-learning could be used as a supplement to traditional teaching methods or sometimes as educational alternative method because this method of teaching increases the students' knowledge, satisfaction and attention. PMID- 25512939 TI - Health students' expectations of the ideal educational environment: a qualitative research. AB - INTRODUCTION: Educational environment is an important determinant of students' behavior and its elements are associated with academic achievement and course satisfaction. The aim of this study was to determine students' expectations of the ideal educational environment. METHODS: This was a qualitative study with content analysis approach. Using a theoretical sampling method, we selected eight students from Health School of Hormozgan University of Medical Sciences, studying health education, public health, environmental health, occupational health and medical entomology. To collect data, semi-structured interviews were used and continued until reaching data saturation. Qualitative content analysis was used to analyze the data. RESULTS: Students' expectations of the ideal educational environment emerged in four main themes including school atmosphere, teaching, human aspects (with three subthemes including teachers, students, and school staff) and non-human aspects (with two subthemes including educational equipment and physical environment). CONCLUSION: Educational environment is a multidimensional issue and to achieve an ideal educational environment, educational planners should meet the students' expectations of the school atmosphere, teaching, teachers, students, school staff, educational equipment and physical environment. PMID- 25512940 TI - Effects of an osteoporosis prevention training program on physical activity related stages of change and self-efficacy among university students, Shiraz, Iran: a Randomized Clinical Trial. AB - INTRODUCTION: Osteoporosis is a major problem in today's world, being characterized by decreased bone mass and bone change. Due to deficiency of theory based studies in young population, especially in students, there are significant knowledge gaps of effective planning. Thepresent study was performed in response to this need. The present study investigated the effect of an empowerment program on physical activity related stages of change and self-efficacyin preventing osteoporosis among university students. METHODS: In this randomized controlled trial (IRCT: IRCT201212016261N2), 152 female students of Shiraz University of Medical Sciences were selected through multi-stages cluster sampling and were randomly assigned to an experimental (n=76) and a control (n=76) group.The pre and post-intervention data were collected using the Stages of Exercise Change Questionnaire (SECQ) of Marcos with Cronbach's alpha reliability of 0.89 and also the self-efficacy scale with a Cronbach's alpha reliability of 0.88 and Test Retest Correlation Coefficient of 0.80. The educational intervention for the experimental group took place through problem-based learning method, small group discussion, and training manuals. In addition, training CDs and brochures were given to the subjects and short SMSs were sent to them. The data were analyzed throughSPSS, version 14, usingMann-Whitney test, Chi-square test, Wilcoxon and regression tests. RESULTS: Pre-intervention findings showed that participants had behavioral constructs below the expected levels. The results showed that the experimental group received significant statisticalincrease after the intervention in stage of change. Before the intervention, the mean scores of stages of changes in the experimental groups was 2.28+/-0.86 but this rose to 3+/ 0.84 in the first post-test and 3.22+/-0.84 in the second post-test. The control group showed a significant increase in stage of change without intervention (pre test 2.04+/-0.82, first post-test 2.18+/-0.87 and second post-test 2.3+/ 0.89).However, this increase was more significant in the experimental group (p<0.001). The mean score of self-efficacy in physical activity in the intervention group upon completion of the course showed a significant increase (p<0.001). A significant correlation was found between the construct stage of change and self-efficacy. CONCLUSION: Theory-based curriculum is effective in empowering individuals in stage of change and developing self-efficacy in physical activity of university students. PMID- 25512941 TI - The effect of written material and verbal method education on anxiety and depression in patients with myocardial infarction in selected hospitals in Iran. AB - INTRODUCTION: Myocardial infarction (MI) is the damage to the heart muscle, or myocardium, resulting from the lack of blood flow to the heart. MI patients experience mental and emotional problems such as depression and anxiety. These complications could cause delay in resuming work, decreased quality of life and increased risk of death. The role of education in facilitating adaptation is very important in these patients. The purpose of this study was to determine the effect of written material and verbal method education on anxiety and depression in patients with myocardial infarction in Urmia hospital in 2009. METHODS: This study was a quasi-experimental study, comparing the effect of education on anxiety and depression in patients with myocardial infarction in hospitals affiliated to Urmia University of Medical Science. 124 patients were selected randomly and divided into two groups. The experimental group was educated through face to face training and an educational booklet (Written Material and Verbal Method). The control group did not receive any intervention. The level of anxiety and depression was evaluated, using HADS questionnaire at 3 intervals: after 48 hours of admission, the discharge day and 2 months after discharge. RESULTS: The findings suggested that MI patients were worried about their social role, interpersonal relations and personal health. Such problems can aggravate symptoms and complicate the future care. There was no significant difference between the control and experimental groups before the intervention, but after the intervention, anxiety and depression in the experimental group was significantly less than that in the control group (p<0.05). CONCLUSION: Considering the beneficial results obtained from written materials and verbal method education on reducing anxiety and depression in cases with myocardial infarction, this may be one of the health care goals. More research on more patients is required to achieve more conclusive results. PMID- 25512942 TI - Comparison of residents' approaches to clinical decisions before and after the implementation of Evidence Based Medicine course. AB - INTRODUCTION: It has been found that the decision-making process in medicine is affected, to a large extent, by one's experience, individual mentality, previous models, and common habitual approaches, in addition to scientific principles. Evidence-based medicine is an approach attempting to reinforce scientific, systematic and critical thinking in physicians and provide the ground for optimal decision making. In this connection, the purpose of the present study is to find out to what extent the education of evidence based medicine affects clinical decision making. METHODS: The present quasi-experimental study was carried out on 110 clinical residents, who started their education in September, 2012 and finally 62 residents filled out the questionnaires. The instrument used was a researcher-made questionnaire containing items on four decision-making approaches. The questionnaire was used both as a pre-test and a post-test to assess the residents' viewpoints on decision making approaches. The validity of the questionnaire was determined using medical education and clinical professionals' viewpoints, and the reliability was calculated through Chronbach alpha; it was found to be 0.93. The results were analyzed by paired t-test using SPSS, version 14. RESULTS: The results demonstrated that evidence-based medicine workshop significantly affected the residents' decision-making approaches (p<0.001). The pre-test showed that principles-based, reference-based and routine model-based approaches were more preferred before the program (p<0.001). However, after the implementation of the program, the dominant approaches used by the residents in their decision making were evidence-based ones. CONCLUSION: To develop the evidence-based approach, it is necessary for educational programs to continue steadily and goal-orientedly. In addition, the equipment infrastructure such as the Internet, access to data bases, scientific data, and clinical guides should develop more in the medical departments. PMID- 25512943 TI - The students' intentions and satisfaction with the field of study and university. AB - INTRODUCTION: The present study aimed to find an appropriate method to inform senior high school students to correctly select their academic field of study and their intentions. METHODS: This is a descriptive-analytic and cross-sectional study. A verified questionnaire was given to a total of 2600 students selected by stratified random sampling method (ten different colleges and entrance year from the 1(st) to 4(th) are considered as the strata). The position of the present field of study (major) among the list of the fields in the entrance exam was asked. The students' methods of familiarity with different fields of study in Shiraz University of Medical Sciences (SUMS), the reasons for their selection, the students' motivation and insistence on studying in the same field and university were asked in the questionnaire. Data were analyzed using independent two samples t-test, Analysis of Variance (ANOVA) and Chi-Square test. RESULTS: The most significant references for university field selection were high school teachers, the students' parents and the adjacency of university to one's living place. Also, the results revealed the good reputation of SUMS in the first year and its downward trend during the following years. 59.4% of the 1(st) year students were satisfied with their field of study and SUMS. 31.8% were satisfied with the university but not with their fields of study. 6.4% were dissatisfied with the university but not with their fields of study. 2% of the students were dissatisfied with both their fields of study and university. Dissatisfaction with SUMS and field of study increased little by little so that the results obtained among the students who had entered the university earlier (in the 4(th) year of their study) showed nearly 16.3% dissatisfaction with both the university and the study fields. CONCLUSION: The methods for introducing the university are recommended to be revised. PMID- 25512944 TI - The role of educational technology in medical education. PMID- 25512945 TI - Method for the quantitative measurement of collecting lymphatic vessel contraction in mice. AB - Collecting lymphatic vessels are critical for the transport of lymph and its cellular contents to lymph nodes for both immune surveillance and the maintenance of tissue-fluid balance. Collecting lymphatic vessels drive lymph flow by autonomous contraction of smooth muscle cells that cover these vessels. Here we describe methods using intravital microscopy to image and quantify collecting lymphatic vessel contraction in mice. Our methods allow for the measurement of the strength of lymphatic contraction of an individual lymphangion in a mouse, which has not yet been demonstrated using other published methods. The ability to study murine collecting lymphatic vessel contraction-using the methods described here or other recently published techniques-allows the field to dissect the molecular mechanisms controlling lymphatic pumping under normal and pathological conditions using the wide variety of molecular tools and genetic models available in the mouse. We have used our methods to study lymphatic contraction in physiological and inflammatory conditions. The methods described here will facilitate the further study of lymphatic function in other pathological conditions that feature lymphatic complications. PMID- 25512946 TI - Temporal dynamics of reproduction in Hemiramphus brasiliensis (Osteichthyes: Hemiramphidae). AB - The reproductive aspects of Hemiramphus brasiliensis were analyzed with a view to verify the temporal dynamics of reproduction. This paper presents data on sex ratio, length at first sexual maturity, macroscopic and histological aspects of gonad development, gonadosomatic index (GSI), reproductive period, and fecundity of H. brasiliensis. The fishes were captured from the coastal waters of Rio Grande do Norte, northeastern Brazil. Females of this species predominated in the sampled population and were larger in size than the males. The length at the first sexual maturation of males was 20.8 cm and that of females was 21.5 cm. The macroscopic characteristics of the gonads indicated four maturation stages. Histological studies of gonads of H. brasiliensis showed six phases of oocyte development and four phases of spermatocyte development. The batch fecundity of this species was 1153 (+/-258.22) mature oocytes for 50 g body weight of female. The microscopic characteristics of gonad development indicate that H. brasiliensis is a multiple spawner, presenting a prolonged reproductive period during the whole year, with a peak in the month of April, and is considered as an opportunistic strategist. PMID- 25512947 TI - Preoperative planning of renal transplantation: a comparison of non-contrast enhanced ultrasonography, computed tomography, and magnetic resonance angiography with observations from surgery. AB - BACKGROUND: Many candidates for kidney transplantation need to undergo vessel examination before the transplantation procedure. PURPOSE: To identify the optimal preoperative modality for the examination of vessel status without the use of contrast agents in kidney transplant candidates. MATERIAL AND METHODS: Fifty-three consecutive patients were examined and 31 patients were transplanted. Ultrasonography (US), non-contrast-enhanced computed tomography (NCCT), and non contrast-enhanced magnetic resonance angiography (NCMRA) were compared using inspection during kidney transplantation (TX) as a reference standard. The sensitivity and specificity to severe arteriosclerotic changes and the accuracy were calculated. Kappa statistics were used to assess the agreement between TX and the different examination modalities, and McNemar's test was used to test for significant differences. RESULTS: US had higher sensitivity (1.0) and better agreement with observations from surgery (k = 0.89) than both NCCT (sensitivity = 0.60; k = 0.72) and NCMRA (sensitivity = 0.20; k = 0.30). No significant difference was found between TX and US (P = 0.3173) or TX and NCCT (P = 0.1573), but there was a significant difference between TX and NCMRA (P = 0.0455). US was inconclusive in 20% of cases, and the internal iliac artery could not be visualized in 69% of cases. CONCLUSION: Either US or NCCT can be used as the preferred preoperative imaging modality to examine vessel status before kidney transplantation, but a combination of the two is preferable. NCMRA should not be used as the sole imaging modality for preoperative imaging before kidney transplantation because of its low sensitivity in detecting severe arteriosclerotic disease without the presence of stenosis. PMID- 25512948 TI - A "turn-on" fluorescent sensor for ultrasensitive detection of melamine based on a new fluorescence probe and AuNPs. AB - In this study, we synthesized a new fluorescence probe which was used to detect melamine by coupling with gold nanoparticles (AuNPs). The new fluorescence probe has good optical stability and high fluorescence intensity, which can greatly improve the detection sensitivity. Compared to the traditional fluorophore, it is less dependent on the pH value. It has a very strong fluorescence emission peak at 550 nm, which has larger overlap with the absorption peak of AuNPs. When the probe incubates with the AuNPs, the fluorescence of the probe can be effectively quenched by AuNPs. Adding melamine into a probe-AuNPs mixture caused aggregation of AuNPs and released the adsorbed probe; the fluorescence intensity of the probe was recovered. By measuring the changes of the fluorescence intensity of the probe, the detection of melamine can be realized. Under optimized conditions, the linear response to melamine is in the range of 1.0 * 10(-8)-4.0 * 10(-6) mol L( 1) and lowers the detection limit down to 3.0 nmol L(-1) with the sensor. This method can detect melamine in milk and milk-based productions. PMID- 25512950 TI - Linear assembly of a porphyrin-C60 complex confined in vertical nanocylinders of amphiphilic block copolymer films. AB - Linear assemblies of a 1 : 1 porphyrin-fullerene C60 complex were formed in vertical cylindrical polyether nanodomains of amphiphilic block copolymer films by a simple spin coating-annealing method. The nanocylinder structures were retained even with high contents of the complex in the polymer films. PMID- 25512949 TI - Thiophene-fused bowl-shaped polycyclic aromatics with a dibenzo[a,g]corannulene core for organic field-effect transistors. AB - For the first time, electron-rich thiophene units were fused into the skeleton of corannulene to extend pi-surfaces and tune arrangement in single crystals. Two isomeric butterfly-like thiophene-fused dibenzo[a,g]corannulenes (3 and 5) were synthesized. Isomer 3 showed p-type transport properties, with a hole mobility of 0.06 cm(2) V(-1) s(-1). PMID- 25512951 TI - Improving the Ambulatory Patient Experience Within an Academic Department of Medicine. AB - Academic departments of medicine (ADOM) can provide an important vehicle to drive the sharing and dissemination of best practices in clinical care delivery. With the increased focus on improving the patient experience, particularly in the ambulatory setting, ADOM also should lead efforts to cultivate improvements in this arena. To address this need, the study ADOM established a Patient Experience Working Group (PEWG) that brought together physician and nonphysician leaders, set improvement goals, and created a structure for sharing and learning. Since initiation, the PEWG has implemented more than 20 performance improvement initiatives, which have resulted in measured positive changes at both the local practice settings and department-wide. Striking the right balance between top down governance, bottom-up innovation and ownership, and shared goal setting was a key to success. This model is one that could easily be adopted by other ADOM in their own efforts to improve the patient experience. PMID- 25512952 TI - Using Innovative Methodologies From Technology and Manufacturing Companies to Reduce Heart Failure Readmissions. AB - Heart failure (HF) patients have high 30-day readmission rates with high costs and poor quality of life. This study investigated the impact of a framework blending Lean Sigma, design thinking, and Lean Startup on 30-day all-cause readmissions among HF patients. This was a prospective study in an academic hospital in Baltimore, Maryland. Thirty-day all-cause readmission was assessed using the hospital's electronic medical record. The baseline readmission rate for HF was 28.4% in 2010 with 690 discharges. The framework was developed and interventions implemented in the second half of 2011. The impact of the interventions was evaluated through 2012. The rate declined to 18.9% among 703 discharges (P < .01). There was no significant change for non-HF readmissions. This study concluded that methodologies from technology and manufacturing companies can reduce 30-day readmissions in HF, demonstrating the potential of this innovations framework to improve chronic disease care. PMID- 25512953 TI - Standards, efficiency and effectiveness in consultation-liaison psychiatry. PMID- 25512954 TI - Characteristics of antidepressant medication users in a cohort of mid-age and older Australians. AB - OBJECTIVES: We aimed to investigate antidepressant use, including the class of antidepressant, in mid-age and older Australians according to sociodemographic, lifestyle and physical and mental health-related factors. METHODS: Baseline questionnaire data on 111,705 concession card holders aged ?45 years from the 45 and Up Study-a population-based cohort study from New South Wales, Australia-were linked to administrative pharmaceutical data. Current- and any-antidepressant users were those dispensed medications with Anatomical Therapeutic Chemical classification codes beginning N06A, within ?6 months and ?19 months before baseline, respectively; non-users had no antidepressants dispensed ?19 months before baseline. Multinomial logistic regression was used to calculate adjusted relative risk ratios (aRRRs) for predominantly self-reported factors in relation to antidepressant use. RESULTS: Some 19% of the study population (15% of males and 23% of females) were dispensed at least one antidepressant during the study period; 40% of participants used selective serotonin reuptake inhibitors (SSRIs) only and 32% used tricyclic antidepressants (TCAs) only. Current antidepressant use was markedly higher in those reporting: severe versus no physical impairment (aRRR 3.86(95%CI 3.67-4.06)); fair/poor versus excellent/very good self-rated health (4.04(3.83-4.25)); high/very high versus low psychological distress (7.22(6.81-7.66)); ever- versus never-diagnosis of depression by a doctor (18.85(17.95-19.79)); low-dose antipsychotic use versus no antipsychotic use (12.26(9.85-15.27)); and dispensing of ?10 versus <5 other medications (5.97(5.62 6.34)). Sociodemographic and lifestyle factors were also associated with use, although to a lesser extent. Females, older people, those with lower education and those with poorer health were more likely to be current antidepressant users than non-users and were also more likely to use TCAs-only versus SSRIs-only. CONCLUSIONS: Use of antidepressants is substantially higher in those with physical ill-health and in those reporting a range of adverse mental health measures. In addition, sociodemographic factors, including sex, age and education were also associated with antidepressant use and the class of antidepressant used. PMID- 25512955 TI - The adsorption of a mixture of particles with non-additive interactions: a Monte Carlo study. AB - The adsorption of binary mixtures with non-additive lateral interactions has been studied through grand canonical Monte Carlo simulations in the framework of the lattice-gas model. The traditional assumption of additive lateral interactions is replaced with a more general one including non-pairwise interactions. It is assumed that the energy linking a certain atom with any of its nearest neighbors strongly depends on the state of occupancy in the first coordination sphere of such an adatom. The process has been monitored through the adsorption isotherms and the differential heats of adsorption. Different combinations of both inter- and intra-species interactions have been considered in the analysis. Interesting behaviors were observed and discussed in terms of the low temperature phases formed in the system. PMID- 25512956 TI - A mechanistic study of hydrogen gas sensing by PdO nanoflake thin films at temperatures below 250 degrees C. AB - We prepared PdO nanoflake thin films on the SiO2 substrate by reactive sputter deposition, and studied their sensing response to H2 at temperatures between 25 and 250 degrees C. In addition to the oxygen ionosorption model, which is used to describe the early H2 sensing response over the temperature range studied, the H2 sensing kinetics of the PdO thin films can be separated into three temperature regimes: temperatures below 100 degrees C, around 150 degrees C and above 200 degrees C. At temperatures below 100 degrees C, PdO reduction is the dominant reaction affecting the H2 sensing behavior. At temperatures around 150 degrees C, Pd reoxidation kinetically competes with PdO reduction leading to a complicated sensing characteristic. Active PdO reduction by H2 promotes the continuing growth of Pd nanoislands, facilitating dissociative oxygen adsorption and thus the subsequent Pd reoxidation in the H2-dry air gas mixture. The kinetic competition between the PdO reduction and reoxidation at 150 degrees C leads to the observation of an inverse of the increase in the sensor conductivity. At temperatures above 200 degrees C, the PdO sensor exhibits a sensor signal monotonically increasing with the H2 concentration, and the H2 sensing behavior is consistent with the Mars-van-Krevelen redox mechanism. PMID- 25512957 TI - Oxygen reduction reaction on neighboring Fe-N4 and quaternary-N sites of pyrolized Fe/N/C catalyst. AB - We study the interaction between the TM-Nx and metal-free active sites of a pyrolized TM/N/C catalyst and its effect on their ORR activities. We particularly choose a Fe-N4-edge-graphene and a quaternary-N-doped zigzag edge as representatives of TM-Nx and the metal-free active sites, respectively. We find that the interaction of the Fe-N4 and quaternary-N-doped sites at the zigzag edge of graphene enhances the ORR free energy profile at the quaternary-N-doped site. However, the ORR free energy profile at the Fe-N4 site is not affected by this interaction. PMID- 25512959 TI - How safe is paracetamol? PMID- 25512960 TI - Surrogates, proxies and processes. PMID- 25512962 TI - Milk intake, height and body mass index in preschool children. AB - OBJECTIVES: To evaluate links between the volume of milk consumed and weight and height status in children aged 4 and 5 years. DESIGN: We analysed data from 8950 children followed up as part of the Early Childhood Longitudinal Survey, Birth cohort, a nationally representative cohort of children. We used linear and logistic regression to assess associations of daily servings of milk intake at age 4 years with z-scores of body mass index (BMI), height and weight-for-height at 4 and 5 years, adjusted for sex, race/ethnicity, socioeconomic status and type of milk consumed. RESULTS: Among children who drank milk at age 4 years, higher milk consumption was associated with higher z-scores of BMI, height and weight for-height at 4 years (all p<0.05). This corresponded to differences between children drinking <1 and >=4 milk servings daily of approximately 1 cm in height and 0.15 kg in weight. By age 5 years, only the association with height remained significant (p<0.001). At 4 years, children drinking >=3 servings of milk daily were more likely to be overweight/obese (BMI>=85th percentile) than those drinking 0.5-2 servings of milk daily (adjusted OR 1.16 (95% CI 1.02 to 1.32) p=0.02). CONCLUSIONS: In a cohort of children at age 4 years, the volume of milk consumed was associated with higher weight status and taller stature, while at 5 years, higher milk consumption continued to be associated with taller stature. Given higher odds of overweight/obesity with milk consumption >=3 servings daily, this study supports current American Academy of Pediatrics recommendations that pre-school children consume two milk servings daily. PMID- 25512963 TI - Advertisements of follow-on formula and their perception by pregnant women and mothers in Italy. AB - OBJECTIVE: To assess how follow-on formula milks for infants aged 6-12 months are presented to and understood by mothers. DESIGN: A quantitative and qualitative cross-sectional study including (1) an analysis of advertisements in three magazines for parents; (2) in-depth semistructured qualitative interviews to pregnant women on their perception of two advertisements for follow-on formula and (3) self-administered questionnaires for mothers to explore their exposure to and perception of formula advertisements. PARTICIPANTS: Eighty pregnant women 32 36 weeks of gestation with no previous children and 562 mothers of children <3 years old. SETTING: Maternal and child health centres in eight cities of Italy. RESULTS: Advertisements of formula (n=89) represented about 7% of all advertisements in the three magazines, the majority (58%) being for follow-on formula. Advertisements were parent-oriented, aimed at helping parents solve health problems of their babies or at eliciting good feelings, or both. The qualitative interviews to pregnant women showed inability to define the advertised products at first glance due to the ambiguity of the numeral 2 and the presumed age of the portrayed baby; this inability did not disappear after carefully viewing the advertisements and reading the text. When asked in the self administered questionnaires whether they had ever come across advertisements of infant formula, 81% of mothers reported that they had, despite the legal inexistence of such advertisements, and 65% thought that it was for a product to be used from birth. CONCLUSIONS: Advertisements of follow-on formula are perceived by pregnant women and mothers as promoting infant formula. PMID- 25512964 TI - A scholarly endeavour: some practical tips on completing the scholarly project. AB - OBJECTIVES: The current article aims to assist trainees to complete the scholarly project component of the 2012 Competency Based Fellowship Program. Practical tips on how to achieve competency in the scholarly project are outlined and discussed. CONCLUSION: The scholarly project provides trainees with a good opportunity to experience and enjoy academic psychiatry. It is important to set up a clear plan so that the project can be completed in a timely manner. PMID- 25512965 TI - How to survive in research: advice for the novice investigator. AB - OBJECTIVES: This paper, written by the RANZCP Committee for Research, provides an outline for how to survive in research, considering the ingredients likely to contribute to success, the role of supportive structures and the expected challenges. Learning how to survive in research is relevant for both trainees and for Fellows undertaking research at any stage of their career. CONCLUSIONS: Intellectual curiosity, perseverance, frustration tolerance, patience and humility are key for success as a researcher. Selection of the right supervisor is important, as is development and maintenance of a good working supervisor/supervisee relationship. The personal benefits of undertaking research include flexibility in work hours, and improved skills in writing, oral presentations, objectivity, critical thinking, problem solving and project management. PMID- 25512966 TI - All the world's a stage: evaluating psychiatry role-play based learning for medical students. AB - OBJECTIVE: This paper describes an evaluation of an innovative approach, role play based learning (RBL), as a vehicle for teaching psychiatry. The aim of this intervention, where medical students perform both doctor and patients roles, was to provide an interactive learning format that engaged students while developing clinical knowledge and communication skills in a structured, reflective environment. METHOD: Questionnaires were completed by 107 students from three clinical schools of the University of Melbourne. Data were analysed using descriptive and inferential statistics and thematic content analysis. RESULTS: Student evaluations of the RBL sessions were overwhelmingly positive. Respondents reported improvements in engagement, confidence and empathy, as well as in their learning, and that the sessions provided good preparation for internship as well as for exams. CONCLUSION: The RBL tutorial programme is unique and flexible and could readily be adapted for use in other specialty rotations. It is also timely, given the increased interest in simulation prompted by increasing pressure on training places across the health sciences in Australia. PMID- 25512967 TI - Smoking and mental illness. An update for psychiatrists. AB - OBJECTIVE: We aimed to review research on smoking and mental illness and provide evidence-based guidelines for psychiatrists to help smoking patients quit. METHOD: We undertook a narrative review of the literature with a special focus on the Australian context. RESULTS: Although one in three people with mental illness smoke tobacco, smoking is often neglected in psychiatric practice. Smoking is a significant contributor to the health gap between people with mental illness and the general population. Smokers with mental illness are motivated to quit and are able to do so, albeit with lower quit rates. Quitting can lead to substantial improvements in mental wellbeing and physical health and does not exacerbate pre existing mental illness. Psychiatrists should advise all smokers to quit and provide counselling, medication and support, based on the 5As framework. Approved pharmacotherapy - nicotine replacement therapy, varenicline and bupropion - is recommended for nicotine-dependent smokers. Smoking induces the metabolism of certain psychotropic drugs such as clozapine and olanzapine and dose reductions may be necessary after cessation. CONCLUSIONS: Psychiatrists have a duty of care to identify the smoking status of their patients and to provide evidence-based support to quit. PMID- 25512968 TI - Teaching psychological processes and psychotherapy to medical students. AB - OBJECTIVE: Psychiatrists are in a key position to teach medical students about psychotherapy. Whilst at first it may appear a formidable task, it need not be so. It should however, have applicability to the bulk of students, who will not go on to psychiatry training. CONCLUSIONS: We outline some potentially useful strategies to help clinicians teach aspects of psychotherapy to students: making it easy and relevant, illustrating the broad applications of psychological concepts, introducing cultural references, as well as appreciating that assessment can drive learning. PMID- 25512969 TI - Medical professionalism education for psychiatry trainees: does it meet standards? AB - OBJECTIVE: Developing professionalism is an important part of a doctor's training. Developing professional attributes is an expected part of postgraduate psychiatry training, as indicated by the curriculum. It is unknown whether this requirement is being met. Our aim was to explore whether psychiatry trainees are meeting current standards of professionalism education. METHODS: This audit and evaluation was investigated using an online survey, inviting trainees from three National Health Service Trusts in North West England. Invitations were sent by email with a link to an online survey. RESULTS: The results suggest that current standards are not being met. Trainees value professionalism education and feel it is important. However, there is a lack of formal teaching and a lack of adequate educational opportunities: 25% of trainees get any formal teaching and 78% feel this teaching is not adequate. There is also a concern that 20% of supervisors are not considered good role models. CONCLUSIONS: Recommendations to address this educational gap are presented. Recommendations include making time in trainees' academic programmes for formal educational activities for professionalism development, and further exploration of why some supervisors are not considered good role models for professionalism. PMID- 25512970 TI - Assessing the risk of imminent aggression in mentally ill young offenders. AB - OBJECTIVES: Aggression in adolescents presents a significant problem for psychiatric units. The Dynamic Appraisal of Situational Aggression (DASA) is an empirically validated measure designed to appraise the risk of imminent aggression (within the next 24 hours) in adult patients. Our aim was to examine the predictive validity of the DASA: Youth Version (DASA:YV) with youth-specific items, in young offenders hospitalised with a mental illness. METHODS: This prospective validation study involved 4440 DASA:YV ratings of mentally ill adolescents in a secure hospital. At 24 hours post-assessment, the nursing staff documented whether patients had behaved aggressively: physically, verbally or towards property. Predictive accuracy was assessed using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: The DASA:YV significantly predicted any imminent aggression (AUC = 0.754). Additional youth specific items conferred a greater predictive yield, as compared to adult-derived items (p = 0.014). CONCLUSIONS: It is possible to monitor the risk state of hospitalised mentally ill youth, so that heightened states can be detected early, thus facilitating interventions to reduce the risk of violence. PMID- 25512971 TI - Fatal torment--from psychosis-driven index offence to trauma: a case study in forensic psychotherapy, trauma therapy and matricide. AB - OBJECTIVE: This paper presents the case of a forensic inpatient who was found 'Not Guilty by Reason of Mental Illness' for the murder of his mother and illustrates how psychotic symptoms can mask trauma symptoms, leading to neglect in the treatment of trauma in psychotherapy with forensic inpatients. METHOD: A case study of a forensic inpatient diagnosed with schizophrenia that as part of his rehabilitation program received 19 sessions of therapy (i.e. grief counselling, Trauma-Focused Cognitive Behavioural Therapy (TF-CBT) and imagery rescripting). The following measures were administered pre- and post-treatment: (a) The Depression Anxiety Stress Scale (DASS), to measure symptoms of depression, anxiety and stress; (b) The Impact of Events Scale-Revised (IES-R), to measure post-traumatic stress symptoms; and (c) The Trauma Attachment and Beliefs Scale (TABS), to measure disruption in beliefs about self and others. RESULTS: At completion of therapy, he showed a reduction in Post-Traumatic Stress Disorder (PTSD), depression, anxiety and stress symptoms. CONCLUSIONS: Trauma and PTSD-related symptoms in the forensic inpatient population must be assessed and treated alongside psychotic symptoms, where relevant. TF-CBT was effective in reducing PTSD symptoms in this current case study and should be considered as an intervention in forensic inpatient populations. PMID- 25512972 TI - What can psychiatrists do to better support victims of family violence? AB - OBJECTIVE: This article aims to draw psychiatrists' attention to the problem of family violence and offer pragmatic guidance to detect and manage family violence in the psychiatric context. METHODS: Selective narrative review. RESULTS: Family violence involves complex interactions between societal, cultural, family and individual factors. Awareness and understanding of family violence is important for psychiatrists as engagement can result in enhanced opportunities for early intervention and harm reduction. CONCLUSIONS: There are barriers facing psychiatrists regarding successful family violence intervention outcomes. Concerted action is required to improve services and support to victims and perpetrators. PMID- 25512973 TI - No evidence of reaction time slowing in autism spectrum disorder. AB - A total of 32 studies comprising 238 simple reaction time and choice reaction time conditions were examined in individuals with autism spectrum disorder (n = 964) and controls (n = 1032). A Brinley plot/multiple regression analysis was performed on mean reaction times, regressing autism spectrum disorder performance onto the control performance as a way to examine any generalized simple reaction time/choice reaction time slowing exhibited by the autism spectrum disorder group. The resulting regression equation was Y (autism spectrum disorder) = 0.99 * (control) + 87.93, which accounted for 92.3% of the variance. These results suggest that there are little if any simple reaction time/choice reaction time slowing in this sample of individual with autism spectrum disorder, in comparison with controls. While many cognitive and information processing domains are compromised in autism spectrum disorder, it appears that simple reaction time/choice reaction time remain relatively unaffected in autism spectrum disorder. PMID- 25512977 TI - Author response. PMID- 25512978 TI - Author response. PMID- 25512980 TI - Turning point: Kate McAllister. PMID- 25512979 TI - Mentoring awards: focus on people. PMID- 25512981 TI - Reply. PMID- 25512985 TI - In memory of Professor Stanislaw Necek. PMID- 25512989 TI - Studies: Just a brief daily walk or run offers health benefits. PMID- 25512990 TI - Do not let the holidays ruin your healthy habits. PMID- 25512988 TI - Labeling of a NOTA mannosylated dextran with (68)Ga. PMID- 25512992 TI - Hybrid coronary revascularization for treatment of multivessel coronary artery disease. PMID- 25512994 TI - A tribute to Hugh de Wardener. PMID- 25513006 TI - Reply. PMID- 25513008 TI - 2014 annual congress of the European Respiratory Society. PMID- 25513022 TI - Association between dog guardianship and HIV clinical outcomes. AB - Despite numerous potential health outcomes of dog guardianship, their value has not been examined in the HIV-positive population. The study objective was to examine the relationship between dog guardianship and HIV clinical outcomes (antiretroviral adherence [>95% versus <95%], HIV viral load [> or =48 versus <48 copies/mL], and CD4 count) among HIV-positive individuals. The authors conducted a secondary analysis of baseline data of 370 HIV-positive men on antiretroviral regimen enrolled in the Duo Project. Generalized estimating equations were used for inferential regression analyses, while controlling for the focal dog guar- dianship variable and nonfocal covariates. Current dog guardianship was reported in 28.7% of participants. Dog guardianship may be associated with higher CD4 (coefficient = 60.6, P = .052) and adherence >95% (odds ratio [OR] = 1.80, P = .048); however, having a detectable viral load was not related to dog guardianship (OR = 0.94, P = .85). Further clinical research with detailed dog guardianship data is needed to further examine the association between dog guardianship and HIV clinical outcomes. PMID- 25513023 TI - Religion and HIV/AIDS stigma in Puerto Rico: a cultural challenge for training future physicians. AB - HIV/AIDS stigma continues to be a challenge for HIV prevention and treatment. When health professionals manifest stigma it can limit access to quality treatment. With an ever-growing epidemic among Latinos, including Puerto Ricans living on the Caribbean Island, the social and structural factors that foster HIV/AIDS stigma need to be understood. In this study, we documented the association of religion with HIV/AIDS stigma in a sample of medical students in Puerto Rico. Findings suggest that importance placed on religion, and participation in religious activities, is associated with HIV/AIDS stigma for this population. PMID- 25513024 TI - Rhodococcus equi pericarditis in a patient living with HIV/AIDS. AB - INTRODUCTION: Rhodococcus equi, previously called Corynebacterium equi, is known to cause pneumonia in foals and swine. Although it was known to cause infection rarely in humans, R equi infection in humans has increased with the advent of HIV and increased use of immunosuppressants. CASE: We report a case of a 48-year-old male patient with newly diagnosed HIV/AIDS presenting with recurrent R equi bacteremia, pericardial effusion, and pericardial cyst. The infection was treated with drainage of the pericardial effusion and cyst and 2 weeks of intravenous vancomycin and 6 months of oral azithromycin and levofloxacin. DISCUSSION: Rhodococcus equi causes pericarditis and pericardial effusion. It can be effectively treated with debridement, drainage, and a prolonged course of antibiotics. In vitro antibiotic susceptibility should be checked as resistance to antibiotics can develop, especially if drainage is inadequate. PMID- 25513025 TI - AIDS-related lymphoma: resolution with antiretroviral therapy alone. AB - Patients with HIV are at increased risk of malignancy, particularly lymphoma, which is the most common malignancy leading to death. With the advent of highly active antiretroviral therapy (HAART), patients live longer but have a longer duration of antigenic stimulation, increasing the prevalence of AIDS-related lymphoma (ARL) in the population living with HIV. Highly active antiretroviral therapy plays a direct role in preserving the immune system, helping to decrease the incidence of ARL. We present a case of a female patient with HIV (CD4 count of 576 cells/mm3) diagnosed with a stage Ill-B non-Hodgkin lymphoma in 2009 while off HAART. She was subsequently started on HAART, leading to full resolution of her lymphoma without any chemotherapeutic intervention. She was last seen in the clinic in December 2013 without any evidence of recurrence of her lymphoma. To our knowledge, this is the first case report of a stage III-B non-Hodgkin17 years and on antiretroviral therapy were recruited in clinics and community organizations and surveyed via direct interview, telephone encounter, or online. Chi-square analyses were performed with an 80% power to detect a difference of >20%. RESULTS: Of 2035 participants, 37% were women. Prevalence of self-reported CVD risk factors was 28% overall, and greater CVD risk was present in 55% of patients in North America, 12% in Africa, and 26% to 28% on other continents. Only 19% of patients ever discussed CVD with their physician, and 31% had ever discussed hypertension, hypercholesterolemia, family history of CVD, or smoking; these findings were true for HIV clinicians in all regions of the world. Forty-four percent of smokers reported never discussing smoking with their HIV clinician. CONCLUSION: We found that HIV clinicians worldwide are not sufficiently addressing CVD risk factors with their patients. Expanded training and education for HIV clinicians should include effective approaches to the mitigation of CV risk factors. PMID- 25513032 TI - The effect of depressive symptoms and CD4 count on adherence to highly active antiretroviral therapy in sub-Saharan Africa. AB - BACKGROUND: Studies have identified several programmatic and nonprogrammatic indicators that affect adherence to highly active antiretroviral therapy (HAART). Depression has been shown to impact adherence to HAART. This cross-sectional analysis of data collected from Nigeria, Uganda, Zambia, and Tanzania in 2008 examined the relationship between levels of depressive symptoms, clinical progression, and adherence to HAART. METHODS: A multinational, multicenter, observational, retrospective cross-sectional evaluation of a population of focus comprised randomly selected patients on HAART. The dependent variable was adherence to HAART. The primary variable of interest to be assessed was patients' level of depressive symptom score. A multivariable logistic regression model was used to examine the relationship between explanatory variables and adherence to HAART. RESULTS: A total of 2344 patients were recruited for adherence survey. About 70% of the study sample reported having some level of depression. Logistic regression results show that patients who reported, respectively, low, moderate, and high levels of depressive symptoms are 35% (P < .001), 56% (P < .001), and 64% (P < .001) less likely to adhere to HAART than those who reported having no depressive symptoms. At multivariate analysis, adherence to HAART was independently associated with the levels of depressive symptoms, older age, CD4 count >200 cells/mm3, Truvada (tenofovir [TDF]/emtricitabine [FTC])-based regimens, good knowledge about HAART, and longer period on therapy. CONCLUSIONS: These results indicate that mental health and clinical parameters are significant factors in determining patients' adherence to their HAART, which need to be more aggressively addressed as a critical component of care and treatment support. PMID- 25513033 TI - Ritonavir-boosted lopinavir as maintenance monotherapy in HIV-infected patients who achieved viral suppression during a second-line protease inhibitor-based regimen: a pilot randomized trial (BIDI-MONO). AB - Eligibility criteria were (I) having previously failed first-line nonnucleoside reverse transcriptase inhibitor-based regimens and (2) having achieved virologic suppression >6 months while receiving a protease inhibitor (PI)-based regimen as second-line treatment. Eligible participants were randomized to receive either (I) ritonavir-boosted lopinavir (LPV/r) monotherapy (n = 29) or (2) LPV/r with optimized background regimens (OBRs; n = 31). Median duration of viral suppression before randomization was 45 months. At week 48, viral suppression during LPV/r monotherapy was 86.2% and did not differ from the suppression achieved with LPV/r with OBRs (87.1%, P = 1.000). However, persistent viremia during LPV/r monotherapy tended to be higher than during LPV/r with OBRs (10.3% versus 3.2%, P = .346). History of viral blip during virologic suppression with second-line PI-based regimen is a predictor of achieving viral suppression at all visits (adjusted relative risk 0.255 [95% confidence interval 0.080-0.821], P = .022). Use of LPV/r monotherapy as maintenance regimen in this study produced persistent viremia that tended to be higher than LPV/r monotherapy with OBRs. PMID- 25513035 TI - Long-term outcome of second-line antiretroviral therapy in resource-limited settings. AB - There is limited information on efficacy and durability of second-line antiretroviral therapy (2NL) beyond 12 months in resource-limited settings. A total of 73 patients were enrolled into a prospective 2NL observational cohort in Nigeria. Second-line antiretroviral therapy consisted of lopinavir/ritonavir plus nucleoside reverse transcriptase inhibitors. Time on 2NL ranged from 15 to 31 months. Genotypes were retrospectively done and not available to guide second line regimen choice. At enrollment, median CD4 count was 121 cells/mm3, and median time on first-line antiretroviral therapy (ISL) was 24 months. At 6 to 9 months on 2NL, 72.6% (intention to treat [ITT]) and 88.3% (on treatment [OT]) had an undetectable viral load (UDVL). At 12 months, 65.8% (ITT) and 90.57% (OT) had UDVL. At >12 to 24 months and at >24 months, 57.5% (ITT) and 91.3% (OT) had UDVL. No statistically significant association was observed between CD4 at 2NL start, sex, genotypic sensitivity score of 2NL, or tenofovir (TDF) use in ISL and viral suppression. Two patients developed major protease inhibitor mutations while on 2NL. We observed a high degree of viral suppression at 12 months and little loss of viral suppression thereafter. PMID- 25513036 TI - "Notify your partners--it's the law": HIV providers and mandatory disclosure. AB - HIV care providers in the United States must counsel clients about disclosure to sexual partners and report anyone who is suspected of noncompliance. This study compared provider attitudes and practices in relation to counseling clients about mandatory disclosure in North Carolina and Alabama, the 2 states with similar HIV epidemiology but different laws for HIV control. Personal interviews were conducted with 20 providers in each state (n = 40). The results were analyzed in a qualitative, cross-comparison method to identify patterns of convergence or difference. Providers in both states believed that clients often failed to notify sexual partners and were secretive if questioned about disclosure. Differences in counseling styles and procedures for each state were noteworthy. Compared to Alabama, North Carolina had harsher penalties for nondisclosure, stricter and more standardized procedures for counseling, and providers expressed greater support for HIV criminalization. Although most North Carolina providers viewed the stricter standards as beneficial for HIV care and control, Alabama providers were likely to view such standards as a barrier to patient care. These results indicated a direct relation between state HIV law, provider attitudes, and counseling procedures for mandatory disclosure. PMID- 25513037 TI - Law and pediatric HIV testing: realizing the right to health in Kenya. AB - Realization of the right to health occurs along a continuum including national ratification of international treaties such as the Convention on the Rights of the Child, passage of domestic laws and policies that may specify modes of implementation and enforcement such as Kenya's Constitution and HIV and AIDS Prevention and Control Act, and actual implementation of domestic laws and policies such as through the regulation and delivery of health services. The stages heuristic theoretical framework describes the public policy continuum as consisting of marked stages: agenda setting, policy formulation, policy implementation, and evaluation. This case study illustrates the continuum in Kenya with regard to pediatric HIV testing. Kenya has made progress applying law, policy, and science to reduce vertical transmission of HIV and increase HIV testing of infants, although several challenges remain. Progress in policy implementation may reduce mother-to-child transmission and increase pediatric HIV testing. PMID- 25513048 TI - Drug rehab. PMID- 25513055 TI - Strengthening the peer review process for the International Journal of Toxicology. PMID- 25513059 TI - [In Process Citation]. PMID- 25513195 TI - Diversity: Structural approach. PMID- 25513060 TI - [In Process Citation]. PMID- 25513200 TI - Preface. PMID- 25513235 TI - Geriatric oncology: an overview. PMID- 25513263 TI - Global routine vaccination coverage, 20131. PMID- 25513294 TI - Performance of acute flaccid paralysis (AFP) surveillance and incidence of poliomyelitis, 2014. PMID- 25513272 TI - Bilateral acute depigmentation of the iris (BADI): first reported case in Brazil. PMID- 25513318 TI - Reply. PMID- 25513322 TI - Reply. PMID- 25513400 TI - [In Process Citation]. PMID- 25513444 TI - Boosting business. PMID- 25513414 TI - The other global South. PMID- 25513487 TI - Stigmatized diagnosis. PMID- 25513617 TI - Contemporary ceramics and cements. PMID- 25513611 TI - Author response. PMID- 25513631 TI - [In Process Citation]. PMID- 25513623 TI - Abstracts of the 59th Caribbean Public Health Agency Annual Scientific Meeting, May 1-3, 2014, Aruba. PMID- 25513635 TI - Iatrogenic Cushing syndrome and secondary adrenal insufficiency related to concomitant triamcinolone and ritonavir administration: a case report and review. AB - Triamcinolone is a long-acting glucocorticoid medication that can be responsible for transient suppression of the hypothalamic-pituitary-adrenal (HPA) axis. This physiologic alteration may persist for weeks after repeated or even single localized injection of this agent. However, when this glucocorticoid agent is given to patients receiving the HIV protease inhibitor (PI) ritonavir (RTV),inhibition of their shared cytochrome P450 3A4 degradation pathway leads to an increased bioavailability of triamcinolone, with subsequent heightening and prolongation of the glucocorticoid serum levels. In those instances, iatrogenic Cushing syndrome may ensue. The authors encountered such an event in an HIV infected patient on chronic treatment with an antiretroviral regimen containing RTV. The patient's clinical presentation and laboratory investigations confirmed a diagnosis of Cushing syndrome and secondary adrenal insufficiency. This was believed to have occurred in close association following cervical vertebral column facet joint injections with triamcinolone acetonide for cephalagia deemed related to cervical spine disease. The discontinuation of the RTV-boosted PI therapy alone, promoting the clearance of the elevated triamcinolone serum levels and restoration of HPAhomeostasis, proved successful in this patient. For this case, the authors review the published English medical literature relating to this uncommon phenomenon. PMID- 25513637 TI - [In process citation]. PMID- 25513636 TI - Integration of HIV and tuberculosis in the community. AB - Current strategies are insufficient to contain the growing tuberculosis (TB) epidemic in areas of high HIV prevalence such as sub-Saharan Africa. Due to the increased risk of morbidity and mortality among those coinfected, early detection is critical. However,strategies dependent on passive, facility-based case finding have failed due to severe limitations in the HIV-positive population.There is growing evidence from multiple clinical trials that early initiation of antiretroviral therapy (ART) in patients coinfected with HIV and TB reduces mortality. Integration of community-based distribution of ART and TB medicines should be considered for coinfected patients to help improve retention in care and to off-load busy health systems. Several models of integration of HIV and TB care in sub-Saharan Africa have been successful. This review article examines the concepts of HIV and TB integration of testing and treatment at the community level. PMID- 25513640 TI - Author response. PMID- 25513641 TI - Author response. PMID- 25513642 TI - Reply: re: Mariconda et al. Partial trapeziectomy and pyrocarbon interpositional arthroplasty for trapeziometacarpal joint osteoarthritis: results after minimum 2 years of follow-up. J Hand Surg Eur. 2014, 39: 604-610. PMID- 25513643 TI - Abstracts of original contributions presented at the American College of Cardiology's 59th Annual Scientific Session and i2 Summit: Innovation in Intervention, March 14-16, 2010, Atlanta, Georgia. PMID- 25513644 TI - Abstracts of the Rheumatology 2013 British Society for Rheumatology and British Health Professionals in Rheumatology Annual Meeting 2013, 23-25 April 2013, Birmingham, UK. PMID- 25513645 TI - [Committed to qualification -- to acquire qualifications]. PMID- 25513646 TI - [Right to remuneration -- ophthalmologists who are also operationally active can bill surcharges to the basic GOP 06225 EBM package]. PMID- 25513647 TI - Proceedings of the second biennial meeting of the North American Society for Comparative Endocrinology, May 22-25, 2013, Queretaro,Mexico. PMID- 25513648 TI - [Young doctors in the hospital -- balancing work and life in harmony]. PMID- 25513649 TI - [Interview -- challenging and enriching at the same time at the same time]. PMID- 25513650 TI - [A chip instead of a pill: "Intelligent" drugs and diagnostic devices]. PMID- 25513651 TI - Abstracts from the 6th Annual Meeting of the North American NeuroEndocrine Tumor Society, October 4-5, 2013, Charleston, South Carolina. PMID- 25513652 TI - special issue in honor of Edward E. Smith. PMID- 25513653 TI - Proceedings of the VIth International Workshop on Spatio-Temporal Modelling (METMAVI), September 12-14, 2012, Guimaraes, Portugal. PMID- 25513654 TI - Proceedings of the 63rd Annual Meeting of the CSPS, May 24-27, 2013, San Francisco, CA. PMID- 25513655 TI - Proceedings of the 7th International Symposium on Microdialysis, May 23-24,2013, Poitiers, France. PMID- 25513656 TI - Proceedings of the 17th European Carbohydrate Symposium, July 7-11, 2013, Tel Aviv, Jerusalem. PMID- 25513657 TI - Legionnaires' disease incidence and risk factors, New York, New York, USA, 2002 2011. PMID- 25513658 TI - In response. PMID- 25513659 TI - Digital imaging of peripheral blood identifies atypical chronic lymphocytic leukemia. PMID- 25513660 TI - Caught in transformation. PMID- 25513661 TI - Response. PMID- 25513662 TI - Response. PMID- 25513663 TI - Preface. Bacterial pangenomics. PMID- 25513664 TI - Gigantic coronary aneurysms: a late complication of Kawasaki disease. PMID- 25513665 TI - Huge ascending aortic aneurysm in a 7-year-old patient with Marfan syndrome. PMID- 25513667 TI - Authors' response. PMID- 25513666 TI - Can admission anaemia predict mortality after acute coronary syndrome? PMID- 25513668 TI - Largest patient-satisfaction measurement firms. Ranked by total number of clients in 2013. PMID- 25513669 TI - Interpersonal synchrony increases prosocial behavior in infants. AB - Adults who move together to a shared musical beat synchronously as opposed to asynchronously are subsequently more likely to display prosocial behaviors toward each other. The development of musical behaviors during infancy has been described previously, but the social implications of such behaviors in infancy have been little studied. In Experiment 1, each of 48 14-month-old infants was held by an assistant and gently bounced to music while facing the experimenter, who bounced either in-synchrony or out-of-synchrony with the way the infant was bounced. The infants were then placed in a situation in which they had the opportunity to help the experimenter by handing objects to her that she had 'accidently' dropped. We found that 14-month-old infants were more likely to engage in altruistic behavior and help the experimenter after having been bounced to music in synchrony with her, compared to infants who were bounced to music asynchronously with her. The results of Experiment 2, using anti-phase bouncing, suggest that this is due to the contingency of the synchronous movements as opposed to movement symmetry. These findings support the hypothesis that interpersonal motor synchrony might be one key component of musical engagement that encourages social bonds among group members, and suggest that this motor synchrony to music may promote the very early development of altruistic behavior. PMID- 25513670 TI - Effects of four different cooking methods on anthocyanins, total phenolics and antioxidant activity of black rice. AB - BACKGROUND: Two cultivars of black rice were investigated for the effects of different cooking methods on anthocyanins, total phenolic compounds and antioxidant activities. RESULTS: There was a significant loss of anthocyanins during cooking: roasting resulted in the greatest decrease (94%), followed by steaming (88%), pan-frying (86%) and boiling (77%). Contents of phenolic compounds decreased drastically after cooking, with significantly lower retention in the black rice cultivar that had higher amylose content. DPPH radical scavenging activity of black rice decreased after cooking. In contrast, metal chelating activity increased significantly after cooking. Anthocyanins showed a high positive correlation with total phenolic compounds (r2 = 0.936) but a significant negative correlation with metal-chelating activity (r2 = 0.6107). CONCLUSION: The results indicate that cooking degraded anthocyanins and other phenolic compounds, but with a concomitant increase in phenolics from possible degradation of anthocyanins, which resulted in the enhancement of metal-chelating activity. PMID- 25513671 TI - Meeting of the Strategic Advisory Group of Experts on immunization, October 2014 conclusions and recommendations. PMID- 25513672 TI - Accuracy of peripheral nerve assessment in junior medical staff: is our knowledge of anatomy sufficient for practice? PMID- 25513673 TI - Anatomy by whole-body dissection: what motivates surgeons to teach? PMID- 25513674 TI - How can clinical anatomy teaching be rationalized? PMID- 25513675 TI - Anatomy teaching to medical students and future trainees: the paradigm shift. PMID- 25513676 TI - Postgraduate Diploma in Surgical Anatomy: The University of Melbourne experience. PMID- 25513677 TI - Medicine in small doses. Google Glass: a new dimension in surgical education or just another gimmick? PMID- 25513679 TI - Diastereoselective osmium-catalyzed vicinal oxyamination of acyclic allylic alcohol derivatives. AB - The osmium-catalyzed oxyamination of chiral acyclic allylic alcohol derivatives bearing mono- and 1,1-di-substituted double bonds with benzyl N-(4 tosyloxy)carbamate proceeds with high regioselectivity and moderate levels of diastereoselectivity favoring the anti product. The observed stereoselectivity shows a clear and systematic trend with anti:syn ratios increasing in line with the size of substituent at both the allylic stereocenter and double bond alpha carbon. The stereoinduction is in accord with the sense of diastereoselectivity predicted by Kishi's empirical rule and a previously reported transition state model for the osmium-catalyzed dihydroxylation of allylic alcohol derivatives. In contrast, allylic alcohol derivatives bearing trisubstituted double bonds show low or no reactivity in the oxyamination reaction affording the syn product in low yield in the cases examined. PMID- 25513678 TI - Endoscopic endonasal approaches to infratemporal fossa tumors: a classification system and case series. AB - OBJECTIVES/HYPOTHESIS: To propose a clinically applicable anatomic classification system describing three progressive endoscopic endonasal approaches (EEAs) to the infratemporal fossa (ITF) and their potential sequelae. Overall feasibility and outcomes of these approaches are presented through a consecutive case series. STUDY DESIGN: Description of classification system for EEAs to the ITF and case series. METHODS: A classification system of EEAs to ITF tumors was created based on the senior author's clinical experience and cadaveric dissection. A retrospective chart review of 21 child and adult patients with primary ITF tumors treated by these approaches from 2008 to 2012 at a tertiary-care academic medical center was conducted. RESULTS: Three progressive EEAs to ITF tumors were defined: 1) a transpterygopalatine fossa approach, 2) a transmedial pterygoid plate approach, and 3) a translateral pterygoid plate approach. Twenty-one patients treated with these approaches were identified consecutively, with a mean age of 44.2 years (range, 11-79 years). Tumors primarily involving the pterygopalatine fossa and not the ITF were excluded. Pathology included three advanced juvenile nasopharyngeal angiofibromas, three adenoid cystic carcinomas, two recurrent inverted papillomas, two trigeminal schwannomas, and 11 other diverse skull base pathologies. No intraoperative or postoperative complications occurred, with a mean follow-up of 21.5 months (range, 1-55 months). Expected potential sequelae such as V2/palatal numbness, Eustachian tube dysfunction, and trismus occurred in 10/21 patients. CONCLUSIONS: EEAs to ITF tumors are technically feasible with low risk of complications for well-selected patients. The proposed classification system is useful for anticipating potential sequelae for each approach. PMID- 25513680 TI - Online sample concentration in partial-filling chiral electrokinetic chromatography - mass spectrometry. AB - The concentration sensitivity of a racemic drug (chlorpheniramine maleate) in chiral capillary electrophoresis with electrospray ionization - mass spectrometric detection was improved ~500-fold via stacking. Enantiomeric separation was achieved through the use of a neutral chiral pseudostationary phase (2-hydroxpropyl-beta-cyclodextrin), untreated fused-silica capillaries, and the application of a partial-filling technique to prevent the pseudostationary phase from entering the detector. A concentration factor of 50 resulted from field-enhanced sample injection(FESI). However, the higher concentration factor was achieved by combining FESI with micelle-to-solvent stacking (MSS) to increase sample load and focus the analyte band. MSS was achieved by injection of an ammonium lauryl sulfate micellar plug prior to sample injection. The sample diluent was a 20-fold dilution of the background electrolyte (50 mM ammonium acetate, pH 3.5) with 60% acetonitrile. This methodology provided a limit of detection (LOD) of as low as 5 ng/ml of the racemate. PMID- 25513681 TI - Distinct enantiomeric signals of ibuprofen and naproxen in treated wastewater and sewer overflow. AB - Ibuprofen and naproxen are commonly used members of a class of pharmaceuticals known as 2-arylpropionic acids (2-APAs). Both are chiral chemicals and can exist as either of two (R)- and (S)-enantiomers. Enantioselective analyses of effluents from municipal wastewater treatment plants (WWTPs) and from untreated sewage overflow reveal distinctly different enantiomeric fractions for both pharmaceuticals. The (S)-enantiomers of both were dominant in untreated sewage overflow, but the relative proportions of the (R)-enantiomers were shown to be increased in WWTP effluents. (R)-naproxen was below method detection limits (<1 ng.L(-1)) in sewage overflow, but measurable at higher concentrations in WWTP effluents. Accordingly, enantiomeric fractions (EF) for naproxen were consistently 1.0 in sewage overflow, but ranged from 0.7-0.9 in WWTP effluents. Ibuprofen EF ranged from 0.6-0.8 in sewage overflow and receiving waters, and was 0.5 in two WWTP effluents. Strong evidence is provided to indicate that chiral inversion of (S)-2-APAs to produce (R)-2-APAs may occur during wastewater treatment processes. It is concluded that this characterization of the enantiomeric fractions for ibuprofen and naproxen in particular effluents could facilitate the distinction of treated and untreated sources of pharmaceutical contamination in surface waters. PMID- 25513682 TI - Five-year hearing results with the shape memory nitinol stapes prosthesis. AB - OBJECTIVES/HYPOTHESIS: To evaluate the long-term (5-year) results of the shape memory nitinol stapes piston in the surgical treatment of otosclerosis. STUDY DESIGN: Retrospective case review in a tertiary referral center. METHODS: The patients were adults with clinically proven otosclerosis undergoing stapedotomy. Stapedotomy and ossicular chain reconstruction using a shape-memory nitinol stapes piston were performed. The main outcome measure was masked air and bone conduction audiometry. RESULTS: Forty-eight out of a potential 58 ears had complete audiometric data. The mean preoperative air-bone gap was 29.2 dB (standard deviation [SD] 9.4). The postoperative gap at 1 year was 4.6 dB (SD 3.1), and P at 5 years was 7.0 dB (SD 6.2). CONCLUSIONS: These data suggest that the Smart piston provides a stable long-term hearing result in the surgical treatment of otosclerosis. PMID- 25513683 TI - HFMA eyes wide adoption of medical-debt collection guidelines. PMID- 25513684 TI - Hospitals with best, worst 30-day readmission rates. PMID- 25513685 TI - Targeting hunger to help promote population health. PMID- 25513686 TI - Serving seniors by building new partnerships. PMID- 25513687 TI - Largest rehabilitation providers. PMID- 25513688 TI - Largest health insurers. Based on total direct premiums data from companies' 2013 annual financial filings. PMID- 25513689 TI - Critical-access hospitals by state. Ranked by total number of CAHs. PMID- 25513690 TI - CDC and hospitals hit reset on Ebola preparedness. PMID- 25513691 TI - Provider and pharmacy sector sees lively quarter. PMID- 25513692 TI - Largest post-acute companies. Ranked by net revenue for the organization's 2013 fiscal year. PMID- 25513693 TI - Medicaid budgets by state. Ranked by average spending per enrollee, 2013. PMID- 25513694 TI - Are we just teaching to the test? PMID- 25513696 TI - Popularity of safety walks surges. PMID- 25513697 TI - NSQIP program finds 44 stars. PMID- 25513698 TI - Ebola fears remain high, despite new guidelines. PMID- 25513699 TI - Emergency department hand hygiene, catheter placement remain IC challenges. PMID- 25513701 TI - Most frequently billed DRGs. Ranked by 2012 Medicare patient discharges. PMID- 25513700 TI - Transforming renal care. Dialysis providers anticipate ACOs, payment cuts and consolidation. PMID- 25513702 TI - Largest medical group practices. Ranked by number of full-time-equivalent employed physicians, per AMGA data as of Sept. 22. PMID- 25513703 TI - Preface: a new universe of RNA interactions. PMID- 25513704 TI - Retraction. Lapatinib, a dual inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2, potentiates the antitumor effects of cisplatin on esophageal carcinoma. PMID- 25513705 TI - Photocatalytic generation of N-centered hydrazonyl radicals: a strategy for hydroamination of beta,gamma-unsaturated hydrazones. AB - A visible-light photocatalytic generation of N-centered hydrazonyl radicals has been accomplished for the first time. This approach allows efficient intramolecular addition of hydrazonyl radical to terminal alkenes, thus providing hydroamination and oxyamination products in good yields. Importantly, the protocol involves deprotonation of an N-H bond and photocatalytic oxidation to an N-centered radical, thus obviating the need to prepare photolabile amine precursors or the stoichiometric use of oxidizing reagents. PMID- 25513706 TI - Dramatic improvement in water retention and proton conductivity in electrically aligned functionalized CNT/SPEEK nanohybrid PEM. AB - Nanohybrid membranes of electrically aligned functionalized carbon nanotube f CNT with sulfonated poly ether ether ketone (SPEEK) have been successfully prepared by solution casting. Functionalization of CNTs was done through a carboxylation and sulfonation route. Further, a constant electric field (500 V.cm(-2)) has been applied to align CNTs in the same direction during the membrane drying process. All the membranes are characterized chemically, thermally, and mechanically by the means of FTIR, DSC, DMA, UTM, SEM, TEM, and AFM techniques. Intermolecular interactions between the components in hybrid membranes are established by FTIR. Physicochemical measurements were done to analyze membrane stability. Membranes are evaluated for proton conductivity (30-90 degrees C) and methanol crossover resistance to reveal their potential for direct methanol fuel cell application. Incorporation of f CNT reasonably increases the ion-exchange capacity, water retention, and proton conductivity while it reduces the methanol permeability. The maximum proton conductivity has been found in the S-sCNT-5 nanohybrid PEM with higher methanol crossover resistance. The prepared membranes can be also used for electrode material for fuel cells and batteries. PMID- 25513707 TI - An early lesson. PMID- 25513708 TI - Characterization of drug-product-related impurities and variants of a therapeutic monoclonal antibody by higher energy C-trap dissociation mass spectrometry. AB - Mass spectrometry (MS) characterization of recombinant monoclonal antibody (mAb) drugs and their degraded and/or post-translationally modified counterparts, drug product-related impurities and variants, is critical for successful development of biotherapeutics. Specifically in this study, drug-product-related impurities of an anti-Clostridium difficile IgG1 mAb drug substance were profiled by cation exchange liquid chromatography (CEX) followed by the CEX peaks being fraction collected for MS characterization. A reversed-phase liquid chromatography/mass spectrometry (LC/MS) methodology was developed on a Thermo Q-Exactive orbitrap mass spectrometer for (1) accurate mass measurements of the mAb, its CEX fractionated impurities, and their respective heavy chains and light chains and (2) middle-down LC/MS/MS of the light chains and the heavy chains using higher energy C-trap dissociation (HCD). The accurate mass measurements and the HCD middle-down MS/MS experiments identify that major impurities and variants of the anti-C. difficile mAb are degradation species of the heavy chains at residue Asn101 as well as at the hinge region amino acids, including Cys222, Lys224, His226, and Thr227, with levels ranging from 0.3% to 6.2% of the total drug substance. Additional impurities were identified as light chain C-terminal truncation at Gly93 and oxidized heavy chains at Met40, Met93, and Met430. Our impurity characterization results demonstrate that the middle-down MS method allows direct and accurate identification of drug-product-related impurities of therapeutic mAbs. It is particularly useful for those low-level impurities and variants that are not suitable for further fractionation and characterization by bottom-up MS. PMID- 25513709 TI - Carrier Mediated Distribution System (CAMDIS): a new approach for the measurement of octanol/water distribution coefficients. AB - Here we present a miniaturized assay, referred to as Carrier-Mediated Distribution System (CAMDIS) for fast and reliable measurement of octanol/water distribution coefficients, log D(oct). By introducing a filter support for octanol, phase separation from water is facilitated and the tendency of emulsion formation (emulsification) at the interface is reduced. A guideline for the best practice of CAMDIS is given, describing a strategy to manage drug adsorption at the filter-supported octanol/buffer interface. We validated the assay on a set of 52 structurally diverse drugs with known shake flask log D(oct) values. Excellent agreement with literature data (r(2) = 0.996, standard error of estimate, SEE = 0.111), high reproducibility (standard deviation, SD < 0.1 log D(oct) units), minimal sample consumption (10 MUL of 100 MUM DMSO stock solution) and a broad analytical range (log D(oct) range = -0.5 to 4.2) make CAMDIS a valuable tool for the high-throughput assessment of log D(oc)t. PMID- 25513710 TI - Modelling of dissolving microneedles for transdermal drug delivery: theoretical and experimental aspects. AB - A mathematical model was developed to predict the amount of drug delivered into the skin via the dissolution of a microneedle (MN). This approach differs markedly from previous research which focused on similar phenomena but failed to include a biological membrane. Dimensionless governing equations were derived to help predict the needle height and fate of the active ingredient in the skin layer after application of the device. Simulation studies with fentanyl revealed that the drug concentration was proportional to its mass fraction in the MN. The effect of the pitch on skin permeation was mildly nonlinear. A larger amount of fentanyl was delivered from microneedle arrays with smaller pitch size. The dissolution process was independent of changes in the elimination rate constant. An optimization algorithm was applied to show how to recover this parameter from needle height--time data. PMID- 25513711 TI - Polymorphisms in key pulmonary inflammatory pathways and the development of acute respiratory distress syndrome. AB - PURPOSE/AIM: Acute Respiratory Distress Syndrome (ARDS) is an important clinical and public health problem. Why some at-risk individuals develop ARDS and others do not is unclear but may be related to differences in inflammatory and cell signaling systems. The Receptor for Advanced Glycation Endproducts (RAGE) and Granulocyte-Monocyte Stimulating Factor (GM-CSF) pathways have recently been implicated in pulmonary pathophysiology; whether genetic variation within these pathways contributes to ARDS risk or outcome is unknown. MATERIALS AND METHODS: We studied 842 patients from three centers in Utah and 14 non-Utah ARDS Network centers. We studied patients at risk for ARDS and patients with ARDS to determine whether Single Nucleotide Polymorphisms (SNPs) in the RAGE and GM-CSF pathways were associated with development of ARDS. We studied 29 SNPs in 5 genes within the two pathways and controlled for age, sepsis as ARDS risk factor, and severity of illness, while targeting a false discovery rate of <= 5%. In a secondary analysis we evaluated associations with mortality. RESULTS: Of 842 patients, 690 had ARDS, and 152 were at-risk. Sepsis was the risk factor for ARDS in 250 (30%) patients. When controlling for age, APACHE III score, sepsis as risk factor, and multiple comparisons, no SNPs were significantly associated with ARDS. In a secondary analysis, only rs743564 in CSF2 approached significance with regard to mortality (OR 2.17, unadjusted p = 0.005, adjusted p = 0.15). CONCLUSIONS: Candidate SNPs within 5 genes in the RAGE and GM-CSF pathways were not significantly associated with development of ARDS in this multi-centric cohort. PMID- 25513712 TI - Repositioning proton pump inhibitors as anticancer drugs by targeting the thioesterase domain of human fatty acid synthase. AB - Fatty acid synthase (FASN), the enzyme responsible for de novo synthesis of free fatty acids, is up-regulated in many cancers. FASN is essential for cancer cell survival and contributes to drug resistance and poor prognosis. However, it is not expressed in most nonlipogenic normal tissues. Thus, FASN is a desirable target for drug discovery. Although different FASN inhibitors have been identified, none has successfully moved into clinical use. In this study, using in silico screening of an FDA-approved drug database, we identified proton pump inhibitors (PPIs) as effective inhibitors of the thioesterase activity of human FASN. Further investigation showed that PPIs inhibited proliferation and induced apoptosis of cancer cells. Supplementation of palmitate, the end product of FASN catalysis, rescued cancer cells from PPI-induced cell death. These findings provide new evidence for the mechanism by which this FDA-approved class of compounds may be acting on cancer cells. PMID- 25513716 TI - An immunogenetic study of bullous pemphigoid with mucosal involvement in two siblings. PMID- 25513717 TI - A systems life cycle approach to managing the radiology profession: an Australian perspective. AB - OBJECTIVE: Although the medical system has expanded considerably over the past two decades in almost all countries, so too has the demand for health care. The radiology specialisation may be an early system indicator, being especially sensitive to changes in supply and demand in both rural and urban environments. The question is whether the new policies of increasing the number of radiologists can be a proper long-term solution for the imbalance of workforce supply and demand or not. METHODS: Using system dynamics modelling, we present our integrated descriptive models for the supply and demand of Australian radiologists to find the actual gap. Followed by this, we pose a prescriptive model for the supply in order to lessen the identified imbalance between supply and demand. Our system dynamics models compare the demand and supply of Australian radiologists over 40 years between 2010 and 2050. RESULTS: The descriptive model shows that even if the radiology training program grows at a higher rate than the medical training growth rate and its own historical growth, the system will never be able to meet demand. The prescriptive model also indicates that although changing some influential factors (e.g the intake rate) reduces the level of imbalance, the system will still stay unstable during the study period. CONCLUSION: We posit that Australia may need to design a new system of radiology provision to meet future demands for high-quality medical radiation services. We also suggest some strategies, such as greater development of radiographers' role, are critical for enabling sustainable change over time. What is known about the topic? Long-term workforce planning for medical services at the national level has been very challenging for policy makers of the 21st century. The current demographic imbalance in the supply and demand of the Australian radiologist workforce makes it difficult to plan the effects of extra inflow of radiology students over time. PMID- 25513718 TI - A mechanobiological model of endothelial cell migration and proliferation. AB - How angiogenesis is regulated by local environmental cues is still not fully understood despite its importance to many regenerative events. Although mechanics is known to influence angiogenesis, the specific cellular mechanisms influenced by mechanical loading are poorly understood. This study adopts a lattice-based modelling approach to simulate endothelial cell (EC) migration and proliferation in order to explore how mechanical stretch regulates their behaviour. The approach enables the explicit modelling of ECs and, in particular, their migration/proliferation (specifically, rate and directionality) in response to such mechanical cues. The model was first used to simulate previously reported experiments of EC migration and proliferation in an unloaded environment. Next, three potential effects (increased cell migration, increased cell proliferation and biased cellular migration) of mechanical stretch on EC behaviour were simulated using the model and the observed changes in cell population characteristics were compared to experimental findings. Combinations of these three potential drivers were also investigated. The model demonstrates that only by incorporating all three changes in cellular physiology (increased EC migration, increased EC proliferation and biased EC migration in the direction perpendicular to the applied strain) in response to dynamic loading, it is possible to successfully predict experimental findings. This provides support for the underlying model hypotheses for how mechanics regulates EC behaviour. PMID- 25513719 TI - Computational design and discovery of nanomolar inhibitors of IkappaB kinase beta. AB - IkappaB kinase beta (IKKbeta) is a useful target for the discovery of new medicines for cancer and inflammatory diseases. In this study, we aimed to identify new classes of potent IKKbeta inhibitors based on structure-based virtual screening, de novo design, and chemical synthesis. To increase the probability of finding actual inhibitors, we improved the scoring function for the estimation of the IKKbeta-inhibitor binding affinity by introducing proper solvation free energy and conformational destabilization energy terms for putative inhibitors. Using this modified scoring function, we have been able to identify 15 submicromolar-level IKKbeta inhibitors that possess the phenyl-(4 phenyl-pyrimidin-2-yl)-amine moiety as the molecular core. Decomposition analysis of the calculated binding free energies showed that a high biochemical potency could be achieved by lowering the desolvation cost and the conformational destabilization for the inhibitor required for binding to IKKbeta as well as by strengthening the interactions in the ATP-binding site. The formation of two hydrogen bonds with backbone amide groups of Cys99 in the hinge region was found to be necessary for tight binding of the inhibitors in the ATP-binding site. From molecular dynamics simulations of IKKbeta-inhibitor complexes, we also found that complete dynamic stability of the bidentate hydrogen bond with Cys99 was required for low nanomolar-level inhibitory activity. This implies that the scoring function for virtual screening and de novo design would be further optimized by introducing an additional energy term to measure the dynamic stability of the key interactions in enzyme-inhibitor complexes. PMID- 25513720 TI - Silver nanoparticle effects on stream periphyton during short-term exposures. AB - Silver nanoparticles (AgNP) are increasingly used as antimicrobials in consumer products. Subsequently released into aquatic environments, they are likely to come in contact with microbial communities like periphyton, which plays a key role as a primary producer in stream ecosystems. At present, however, very little is known about the effects of nanoparticles on processes mediated by periphyton communities. We assessed the effects of citrate-coated silver nanoparticles and silver ions (dosed as AgNO3) on five functional end points reflecting community and ecosystem-level processes in periphyton: photosynthetic yield, respiration potential, and the activity of three extracellular enzymes. After 2 h of exposure in experimental microcosms, AgNP and AgNO3 inhibited respiration and photosynthesis of periphyton and the activities of two of the three extracellular enzymes. Addition of a chelating ligand that complexes free silver ions indicated that, in most cases, toxicity of AgNP suspensions was caused by Ag(I) dissolved from the particles. However, these suspensions inhibited one of the extracellular enzymes (leucine aminopeptidase), pointing to a specific nanoparticle effect independent of the dissolved Ag(I). Thus, our results show that both silver nanoparticles and silver ions have potential to disrupt basic metabolic functions and enzymatic resource acquisition of stream periphyton. PMID- 25513721 TI - Bimolecular decomposition pathways for carboxylic acids of relevance to biofuels. AB - The bimolecular thermal reactions of carboxylic acids were studied using quantum mechanical molecular modeling. Previous work1 investigated the unimolecular decomposition of a variety of organic acids, including saturated, alpha,beta unsaturated, and beta,gamma-unsaturated acids, and showed that the type and position of the unsaturation resulted in unique branching ratios between dehydration and decarboxylation, [H2O]/[CO2]. In this work, the effect of bimolecular chemistry (water-acid and acid-acid) is considered with a representative of each acid class. In both cases, the strained 4-centered, unimolecular transition state, typical of most organic acids, is opened up to 6- or 8-centered bimolecular geometries. These larger structures lead to a reduction in the barrier heights (20-45%) of the thermal decomposition pathways for organic acids and an increase in the decomposition kinetics. In some cases, they even cause a shift in the branching ratio of the corresponding product slates. PMID- 25513722 TI - iDrug-Target: predicting the interactions between drug compounds and target proteins in cellular networking via benchmark dataset optimization approach. AB - Information about the interactions of drug compounds with proteins in cellular networking is very important for drug development. Unfortunately, all the existing predictors for identifying drug-protein interactions were trained by a skewed benchmark data-set where the number of non-interactive drug-protein pairs is overwhelmingly larger than that of the interactive ones. Using this kind of highly unbalanced benchmark data-set to train predictors would lead to the outcome that many interactive drug-protein pairs might be mispredicted as non interactive. Since the minority interactive pairs often contain the most important information for drug design, it is necessary to minimize this kind of misprediction. In this study, we adopted the neighborhood cleaning rule and synthetic minority over-sampling technique to treat the skewed benchmark datasets and balance the positive and negative subsets. The new benchmark datasets thus obtained are called the optimized benchmark datasets, based on which a new predictor called iDrug-Target was developed that contains four sub-predictors: iDrug-GPCR, iDrug-Chl, iDrug-Ezy, and iDrug-NR, specialized for identifying the interactions of drug compounds with GPCRs (G-protein-coupled receptors), ion channels, enzymes, and NR (nuclear receptors), respectively. Rigorous cross validations on a set of experiment-confirmed datasets have indicated that these new predictors remarkably outperformed the existing ones for the same purpose. To maximize users' convenience, a public accessible Web server for iDrug-Target has been established at http://www.jci-bioinfo.cn/iDrug-Target/ , by which users can easily get their desired results. It has not escaped our notice that the aforementioned strategy can be widely used in many other areas as well. PMID- 25513723 TI - Increased transcriptome sequencing efficiency with modified Mint-2 digestion ligation protocol. AB - The standard digestion-ligation cloning method enables synthesis of large amounts of complementary DNA (cDNA) from a model organism facilitating study of the transcriptome. Here, we used cDNA amplification of the dimorphic yeast Taphrina betulina as an example of how a library construction protocol can significantly increase sequencing throughput. Two modification steps were introduced to the Evrogen standard Mint-2 protocol to improve its suitability for next-generation sequencing projects. We performed two partial Illumina MiSeq sequencing runs with the modified protocol: one with and one without biotin-purified primers. The results demonstrated that biotinylated libraries increased both accuracy and throughput of the modified protocol. Moreover, our sequencing results indicate that a sequence-specific miscall may affect the output of Illumina's MiSeq platform. PMID- 25513724 TI - Thermodynamic study of binary mixtures of 1-butyl-1-methylpyrrolidinium dicyanamide ionic liquid with molecular solvents: new experimental data and modeling with PC-SAFT equation of state. AB - This work is concerned with thermodynamic properties of binary mixtures composed of 1-butyl-1-methylpyrrolidinium dicyanamide ionic liquid (IL) and the following molecular solvents: n-heptane, benzene, toluene, ethylbenzene, thiophene, 1 butanol, 1-hexanol, and 1-octanol. This is the very first time when experimental data on liquid-liquid equilibrium (LLE) phase diagrams and excess enthalpies of mixing (H(E)) for these systems are reported. An impact of the molecular solvent structure on LLE and H(E) is discussed. Furthermore, modeling of the properties under study is presented by using perturbed-chain statistical associating fluid theory (PC-SAFT). The equation of state is used in purely predictive and semipredictive mode. The latter one involves temperature-dependent binary corrections to combining rules employed in the PC-SAFT model determined on the basis of infinite dilution activity coefficients. The results shown indicate that such an approach can serve as an interesting modern thermodynamic tool for representation of thermodynamic data for complex ILs-based systems. PMID- 25513725 TI - Highly efficient oxidation of secondary alcohols to ketones catalyzed by manganese complexes of N4 ligands with H2O2. AB - The manganese complex Mn(S-PMB)(CF3SO3)2 was proven to be highly efficient in the catalytic oxidation of several benzylic and aliphatic secondary alcohols with H2O2 as the oxidant and acetic acid as the additive. A maximum turnover number of 4700 was achieved in the alcohol oxidation. In addition, the Hammett analysis unveiled the electrophilic nature of this manganese catalyst with N4 ligand. PMID- 25513727 TI - Single injection of the beta2-adrenergic receptor agonist, clenbuterol, into newly hatched chicks alters abdominal fat pad mass in growing birds. AB - Excessive energy is stored in white adipose tissue as triacylglycerols in birds as well as in mammals. Although beta2-adrenergic receptor agonists reduce adipose tissue mass in birds, the underlying mechanism remains unclear. The aim of the current study was to examine the effects of a single intraperitoneal injection of the beta2-adrenergic receptor agonist, clenbuterol, on the abdominal fat pad tissue development. Thirty-three chicks at 1-day-old were given a single intraperitoneal injection of clenbuterol (0.1mg/kg body weight) or phosphate buffered saline. At 2 weeks post-dose, the weight of the abdominal fat tissue was decreased in the clenbuterol-injected chicks, and small adipocyte-like cells were observed in the abdominal fat pad tissue of the clenbuterol-injected chicks. Then, the expression of mRNAs encoding genes related to avian adipogenesis was examined in the abdominal fat pat tissue. The expression of mRNAs encoding Kruppel-like zinc finger transcription factor 5 (KLF-5), KLF-15, and zinc finger protein 423 in the abdominal fat pad tissue of the clenbuterol-injected chicks was significantly lower (P<0.05) than that of the control chicks, while the expression of mRNA encoding peroxisome proliferator-activated receptor-gamma was not affected. In addition, both mRNA expression (P<0.05) and enzymatic activity (P<0.05) of fatty acid synthase (FAS) were decreased in the abdominal fat pad tissue of the clenbuterol-injected chicks, while clenbuterol injection did not affect FAS activity in liver. These results suggested that a single injection with clenbuterol into newly hatched chicks reduces their abdominal fat pad mass possibly via disrupting adipocyte development during later growth stages. PMID- 25513728 TI - Synthesis of oxaspiranic compounds through [3 + 2] annulation of cyclopropenones and donor-acceptor cyclopropanes. AB - The Sc(OTf)3-catalyzed [3 + 2]-annulation reaction between cyclopropenones and donor-acceptor cyclopropanes is described. The process leads directly to the formation of 4-oxaspiro[2.4]hept-1-ene derivatives in good to excellent reaction yields. Density functional theory calculations suggest that the [3 + 2] annulation pathway is strongly preferred over the possible [3 + 3]-process. PMID- 25513729 TI - Mass and surface fractal in supercritical dried silica aerogels prepared with additions of sodium dodecyl sulfate. AB - Silica wet gels were prepared from hydrolysis of tetraethoxysilane (TEOS) with additions of sodium dodecyl sulfate (SDS). The surfactant was removed after gelation. Wet gels exhibited mass-fractal structure with mass-fractal dimension D (typically around 2.25) in a length scale extending from a characteristic size xi (typically about 10 nm) of the mass-fractal domains to a characteristic size a0 (typically between 0.3 and 0.4 nm) of the primary particles building up the fractal domains. xi increased while D and a0 diminished slightly as the SDS quantity increased. Aerogels with typical specific surface of 1000 m(2)/g and density of 0.20 g/cm(3) were obtained by supercritical drying of the wet gels after washing with ethanol and n-hexane. The pore volume and the mean pore size increased with the increase of the SDS quantity. The aerogels presented most of the mass-fractal characteristics of the original wet gels at large length scales and exhibited at a higher resolution level at about 0.7 nm a crossover to a mass surface fractal structure, with apparent mass-fractal dimension Dm ~ 2.4 and surface-fractal dimension Ds ~ 2.6, as inferred from small-angle X-ray scattering (SAXS) and nitrogen adsorption data. PMID- 25513730 TI - Cancer cachexia syndrome: pathogenesis, diagnosis, and new therapeutic options. AB - Cancer anorexia-cachexia syndrome (CACS) is the most frequent paraneoplastic syndrome occurring in half of all oncologic patients and is considered as a poor prognosticator. Patients usually present with weight loss, lipolysis, muscle wasting, anorexia, chronic nausea, inflammation, and asthenia. The etiopathogenesis of CACS is still poorly understood, although several factors and biological pathways are known to be involved. Because of the complexity of this multifactorial condition, a single agent therapy may not be sufficient. Indeed, there is a tendency toward an integrated multiple approach including nonpharmacological and pharmacological treatments. However, despite encouraging preliminary results, currently there is not enough evidence to support a change in clinical practice. This review provides a brief and practical summary of the diagnosis, pathogenesis, and treatment of CACS. Future perspectives will also be discussed. PMID- 25513726 TI - An intracellular anion channel critical for pigmentation. AB - Intracellular ion channels are essential regulators of organellar and cellular function, yet the molecular identity and physiological role of many of these channels remains elusive. In particular, no ion channel has been characterized in melanosomes, organelles that produce and store the major mammalian pigment melanin. Defects in melanosome function cause albinism, characterized by vision and pigmentation deficits, impaired retinal development, and increased susceptibility to skin and eye cancers. The most common form of albinism is caused by mutations in oculocutaneous albinism II (OCA2), a melanosome-specific transmembrane protein with unknown function. Here we used direct patch-clamp of skin and eye melanosomes to identify a novel chloride-selective anion conductance mediated by OCA2 and required for melanin production. Expression of OCA2 increases organelle pH, suggesting that the chloride channel might regulate melanin synthesis by modulating melanosome pH. Thus, a melanosomal anion channel that requires OCA2 is essential for skin and eye pigmentation. PMID- 25513731 TI - Interfacial oxygen stabilizes composite silicon anodes. AB - Silicon can store Li(+) at a capacity 10 times that of graphite anodes. However, to harness this remarkable potential for electrical energy storage, one has to address the multifaceted challenge of volume change inherent to high capacity electrode materials. Here, we show that, solely by chemical tailoring of Si carbon interface with atomic oxygen, the cycle life of Si/carbon matrix-composite electrodes can be substantially improved, by 300%, even at high mass loadings. The interface tailored electrodes simultaneously attain high areal capacity (3.86 mAh/cm(2)), high specific capacity (922 mAh/g based on the mass of the entire electrode), and excellent cyclability (80% retention of capacity after 160 cycles), which are among the highest reported. Even at a high rate of 1C, the areal capacity approaches 1.61 mAh/cm(2) at the 500th cycle. This remarkable electrochemical performance is directly correlated with significantly improved structural and electrical interconnections throughout the entire electrode due to chemical tailoring of the Si-carbon interface with atomic oxygen. Our results demonstrate that interfacial bonding, a new dimension that has yet to be explored, can play an unexpectedly important role in addressing the multifaceted challenge of Si anodes. PMID- 25513732 TI - MIDA-vinylsilanes: selective cross-couplings and applications to the synthesis of functionalized stilbenes. AB - A rapid and stereodefined synthesis of MIDA-boryl vinylsilanes has been achieved through the hydrosilylation of an alkynylboronic ester. The E products which contain a silyl and boryl group can be selectively cross-coupled in a two-step bidirectional sequence to provide a rapid and high-yielding synthesis of complex styrenes. PMID- 25513733 TI - PTPN22 controls virally-induced autoimmune diabetes by modulating cytotoxic T lymphocyte responses in an epitope-specific manner. AB - Ptpn22 is one of the most potent autoimmunity predisposing genes and strongly associates with type 1 diabetes (T1D). Previous studies showed that non-obese diabetic mice with reduced expression levels of Ptpn22 are protected from T1D due to increased number of T regulatory (Treg) cells. We report that lack of Ptpn22 exacerbates virally-induced T1D in female rat insulin promoter lymphocytic choriomeningitis virus (RIP-LCMV-GP) mice, while maintaining higher number of Treg cells throughout the antiviral response in the blood and spleen but not in the pancreatic lymph nodes. GP33-41-specific pentamer-positive cytotoxic lymphocytes (CTLs) are numerically reduced in the absence of Ptpn22 at the expansion and contraction phase but reach wild-type levels at the memory phase. However, they show similar effector function and even a subtle increase in the production of IL-2. In contrast, NP396-404-specific CTLs develop normally at all phases but display enhanced effector function. Lack of Ptpn22 also augments the memory proinflammatory response of GP61-80 CD4 T cells. Hence, lack of Ptpn22 largely augments antiviral effector T cell responses, suggesting that caution should be taken when targeting Ptpn22 to treat autoimmune diseases where viral infections are considered environmental triggers. PMID- 25513734 TI - Antimicrobial and Antibiofilm Activity of Chitosan on the Oral Pathogen Candida albicans. AB - Oral candidiasis is particularly evident, not only in cancer patients receiving chemotherapy, but also in elderly people with xerostomy. In general, Candida is an opportunistic pathogen, causing infections in immunocompromised people and, in some cases, when the natural microbiota is altered. Chitosan, a natural derivative of chitin, is a polysaccharide that has been proven to possess a broad spectrum of antimicrobial activity that encompasses action against fungi, yeast and bacteria. While recent studies have revealed a significant antibiofilm activity upon several microorganisms, including C. albicans, little is known regarding the impact of chitosan upon the adhesive process or mature biofilms. With that in mind, the purpose of this work was to evaluate, in vitro, the capability of chitosan to inhibit C. albicans growth and biofilm formation. The results obtained showed that chitosan is capable of inhibiting C. albicans planktonic growth (HMW, 1 mg/mL; LMW, 3 mg/mL). Regarding biofilm growth, chitosan inhibited C. albicans adhesion (ca. 95%), biofilm formation (percentages above 90%) and reduced mature biofilms by ca. 65% and dual species biofilms (C. albicans and S. mutans) by ca. 70%. These results display the potential of this molecule to be used as an effective anti-Candida agent capable of acting upon C. albicans infections. PMID- 25513735 TI - Proteomic Differences between Listeria monocytogenes Isolates from Food and Clinical Environments. AB - Listeria monocytogenes is an organism associated with a wide range of foods. It causes listeriosis, a severe illness that mainly affects people with weakened immune systems. Proteomic profiles of three different L. monocytogenes isolates were studied using 1D SDS PAGE, 2DE and mass spectrometry. The protein banding patterns generated by 1D SDS PAGE of three strains of L. monocytogenes were found to be similar. Visual observations from 2DE gel maps revealed that certain spots appeared to have intensity differences. Key differences in proteins synthesis of three strains of L. monocytogenes were found using the PDQest TM 2DE Analysis software. Comparison showed that the clinical isolate (strain SB92/844) had 53.4% and 53.9% protein profile similarity with dairy isolate (strain V7) and seafood isolate (SB92/870), respectively. The identity of selected protein spots was achieved using MALDI-TOF and ion trap mass spectrometry. It was found that certain identified proteins (i.e., a major cold shock protein and superoxide dismutase) were expressed differently between two local strains of L. monocytogenes (SB92/844, SB92/870) and one strain from overseas (V7). PMID- 25513736 TI - Bronchomediastinal fistula caused by endobronchial aspergilloma. AB - RATIONALE: Endobronchial aspergilloma is a rare condition affecting immunocompromised patients. We present three cases resulting in airway fistulae. CASE PRESENTATIONS: A 68-year-old male with orthotopic heart transplantation presented with fatigue, cough, and dyspnea. A computerized tomography (CT) scan of the chest and bronchoscopy revealed an endobronchial right mainstem mass and airway fistula to the mediastinum. The mass was debrided and biopsy showed Aspergillus fumigatus. He was treated with antifungals and recovered. A 52-year old male with acquired immunodeficiency syndrome presented with cough, dyspnea, and hypoxemia. Chest CT showed a bronchus intermedius mass and fistula to the mediastinum. Bronchoscopy revealed a necrotic endobronchial mass and pseudomembranes and confirmed the presence of a fistula. The mass was resected bronchoscopically and Aspergillus fumigatus was isolated. He was treated with antifungals and the fistula healed. A 63-year-old male with chronic lymphoid leukemia was admitted for dyspnea, cough, weakness, and dysphagia. Chest CT and bronchoscopy showed a mass causing obstruction of the subglottic trachea and a fistula to the mediastinum. Biopsy showed Aspergillus fumigatus and he was treated with antifungals. The sinus healed but the patient died of leukemia. MAIN RESULTS: Risk factors for airway aspergilloma include immune deficiency, mucosal damage, and ischemia. We report airway fistula formation as a complication of this infection, which has not been previously emphasized. CONCLUSIONS: Endobronchial aspergillomas may form fistulae to the mediastinum. Aggressive treatment with antifungals and bronchoscopic interventions are required. PMID- 25513738 TI - Structural studies of 1,1-dimethyl-2-oxy-1-silacyclohexane by means of matrix isolation infrared absorption spectroscopy. AB - Infrared spectra of gaseous, liquid, and matrix-isolated samples of newly synthesized 1,1-dimethyl-2-oxy-1-silacyclohexane were recorded. Raman spectra of 1,1-dimethyl-2-oxy-1-silacyclohexane in liquid and solid states were obtained in the temperature range from 170 to 340 K. Ab initio HF and DFT B3LYP calculations were performed in order to determine the possible conformations of 1,1-dimethyl-2 oxy-1-silacyclohexane and to make accurate assignment of the vibrational spectral bands. The study confirms the existence of only one chair-type conformer of 1,1 dimethyl-2-oxy-1-silacyclohexane. PMID- 25513737 TI - Octogenarian and centenarian performance on the Fuld Object Memory Evaluation. AB - The Fuld Object Memory Evaluation (FOME) has considerable utility for cognitive assessment in older adults, but there are few normative data, particularly for the oldest old. In this study, 80 octogenarians and 244 centenarians from the Georgia Centenarian Study completed the FOME. Total and trial-to-trial performance on the storage, retrieval, repeated retrieval, and ineffective reminder indices were assessed. Additional data stratified by age group, education, and cognitive impairment are provided in the Supplemental data. Octogenarians performed significantly better than centenarians on all FOME measures. Neither age group benefitted from additional learning trials beyond Trial 3 for storage and Trial 2 for retention and retrieval. Ineffective reminders showed no change across learning trials for octogenarians, while centenarians improved only between Trials 1 and 2. This minimal improvement past Trial 2 indicates that older adults might benefit from a truncated version of the test that does not include trials three through five, with the added benefit of reducing testing burden in this population. PMID- 25513740 TI - Excitable neurofibrils and the problem of identifying the structure of central excitatory synapses in the nineteenth century. AB - Neurofibrils, identified after staining with Cajal's reduced silver nitrate, for example, were thought by many senior histologists in the nineteenth and early twentieth centuries to conduct action potentials. There was no basis for this popular idea, although it was the impetus for intense study of the "neurofibrillar network" within neurons by Golgi, Cajal, Freud, and many others. Here, I trace the way in which this "excitable neurofibrillary" hypothesis led to major problems in the attempt by histologists to identify the central excitatory synapse, postulated by Sherrington on functional grounds and eventually described by Berkley. PMID- 25513741 TI - Protocatechuic acid inhibits oleic acid-induced vascular smooth muscle cell proliferation through activation of AMP-activated protein kinase and cell cycle arrest in G0/G1 phase. AB - Protocatechuic acid (PCA) has been implicated in the progression of atherosclerosis. The proliferation of vascular smooth muscle cells (VSMC) may play a crucial role in the pathogenesis of atherosclerosis. Adenosine 5' monophosphate-activated protein kinase (AMPK) additionally exerts several beneficial effects on vascular function and improves vascular abnormalities. The current study sought to determine whether PCA has an inhibitory effect on VSMC proliferation under oleic acid (OA) treatment. A7r5 cells were treated with OA (150 MUM) or cotreated with OA and PCA (150 MUg/mL) for 24 and 48 h. PCA-treated cells were found to cause an increase in G0/G1 cell cycle arrest. Western blotting showed that PCA increased the expressions of p53 and p21Cip1, subsequently decreasing the expression of cyclin E1 and Cdk2. In addition, PCA induced phosphorylation of AMPK and inhibited the expression of fatty acid synthase, Akt-p, and Skp2 after stimulation with OA. After treatment with AMPK inhibitor, the effects of PCA mentioned above were reversed. Taken together, PCA inhibited OA-induced VSMC proliferation through AMPK activation and down regulation of FAS and AKT signals, which then blocks G0/G1 phase cell cycle progression. These findings provide a new insight into the protective properties of PCA on VSMC, which may constitute a novel effective antiatherosclerosis agent. PMID- 25513739 TI - Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases. AB - Enzyme function prediction remains an important open problem. Though structure based modeling, such as metabolite docking, can identify substrates of some enzymes, it is ill-suited to reactions that progress through a covalent intermediate. Here we investigated the ability of covalent docking to identify substrates that pass through such a covalent intermediate, focusing particularly on the haloalkanoate dehalogenase superfamily. In retrospective assessments, covalent docking recapitulated substrate binding modes of known cocrystal structures and identified experimental substrates from a set of putative phosphorylated metabolites. In comparison, noncovalent docking of high-energy intermediates yielded nonproductive poses. In prospective predictions against seven enzymes, a substrate was identified for five. For one of those cases, a covalent docking prediction, confirmed by empirical screening, and combined with genomic context analysis, suggested the identity of the enzyme that catalyzes the orphan phosphatase reaction in the riboflavin biosynthetic pathway of Bacteroides. PMID- 25513742 TI - Do early emergency calls before patient collapse improve survival after out-of hospital cardiac arrests? AB - AIM: Some out-of-hospital cardiac arrests (OHCAs) are witnessed after emergency calls. This study aimed to confirm the benefit of early emergency calls before patient collapse on survival after OHCAs witnessed by bystanders and/or emergency medical technicians (EMTs). METHODS: We analysed 278,310 witnessed OHCAs [EMT witnessed cases (n=54,172), bystander-witnessed cases (n=224,138)] without pre hospital physician involvement from all Japanese OHCA data prospectively collected between 2006 and 2012. The data were analysed for the correlation between neurologically favourable 1-month survival and the time interval between the emergency call and patient collapse. RESULTS: When emergency calls were placed earlier before patient collapse, the proportion of EMT-witnessed cases and survival rate after OHCAs witnessed by bystanders and EMTs were higher. When analysed only for bystander-witnessed cases, for earlier emergency calls placed before patient collapse, survival rate and incidences of bystander cardiopulmonary resuscitation (CPR) and dispatcher-assisted CPR decreased: 2.9%, 33.6% and 24.4%, respectively, for emergency calls placed >6min before collapse and 5.5%, 48.8% and 48.5%, respectively, for those placed 1-2min after collapse. Multivariable logistic regression showed that call-to-collapse interval (adjusted odds ratio; 95% confidence interval) (0.92; 0.90-0.94) and EMT response time after collapse (0.84; 0.82-0.86) were associated with survival after bystander witnessed OHCAs with emergency calls before collapse. CONCLUSION: Early emergency calls before patient collapse efficiently increases the proportion of EMT witnessed cases and promotes survival after witnessed OHCAs. However, early emergency call before collapse may worsen the outcome when the patient's condition deteriorates to cardiac arrest before EMT arrival. PMID- 25513743 TI - Hanging-associated left ventricular systolic dysfunction. AB - BACKGROUNDS: Although hanging injury is infrequent, its clinical course is usually devastating. Hanging patients usually need cardiopulmonary resuscitation (CPR). However, hanging-associated cardiovascular damage has not been fully established. The aim of this study was to evaluate echocardiographic findings in patients with hanging injury. METHODS: We enrolled 25 patients (nine males and 16 females with mean age of 33+/-15 years) with hanging injury. Echocardiography was performed within 2 weeks after admission. Clinical, demographic, and laboratory data as well as transthoracic echocardiographic findings were analyzed. RESULTS: Of the 25 patients, eight (two males and six females with mean age of 34+/-13 years) showed left ventricular systolic dysfunction (LVSD). Mean LV ejection fraction was 34+/-16%. Global hypokinesia was present in one patient. Apical ballooning with sparing of the basal segment was present in two patients. Basal akinesia and apical hyperkinesia were present in one patient. Four patients showed regional wall motion abnormalities unmatched with coronary territories. The duration of suspension or CPR was not significantly different according to the presence of LVSD. CONCLUSION: This study showed the echocardiographic findings in considerable numbers of patients with hanging injury for the first time. Variable patterns of LVSD were present in patients with hanging injury. PMID- 25513744 TI - Important determinants of diabetes control in insulin pump therapy in patients with type 1 diabetes mellitus. AB - BACKGROUND: Insulin pumps are equipped with advanced functions. Intensive training and adherence are required for optimum use of the technology. We aimed to assess the association of various key elements in insulin pump functions on blood glucose control. PATIENTS AND METHODS: Patients on insulin pump therapy were enrolled. Insulin pumps were downloaded (CareLink((r)) Pro 3 software; Medtronic Minimed, Northridge, CA), and data were collected over an 8-12-week period. Glycemic control of patients was classified as controlled (hemoglobin A1c [HbA1c] level of 7.5% or less in adults and 8% or less in children) and uncontrolled based on HbA1c level at enrollment. Variables studied were use of sensors and duration, frequency of blood glucose monitoring, Bolus Wizard (Medtronic Minimed) use, frequency of correction boluses, and frequency of cannula changing. RESULTS: Seventy-two patients were enrolled (50 children). Median age was 12 years for children and 27.5 years for adults. Respective median numbers of blood glucose checks were 4.4 and 3.2 for controlled and uncontrolled children (P<0.021) and 3.1 and 2.8 for controlled and uncontrolled adults, respectively. Respective frequency of Bolus Wizard use per day showed a median of 6 and 4.15 for controlled and uncontrolled children (P<0.001) and 3.8 and 3.5 for controlled and uncontrolled adults. Controlled children wore sensors for longer (5 vs. 2.9 days/week) and did more corrections (3.9 vs. 2.5). There was no difference in the frequency of changing the infusion cannula in children's or adults' groups. CONCLUSIONS: We conclude that the frequency of blood glucose monitoring and Bolus Wizard use have a favorable association with glycemic control. These observations were more significant in the children's groups. Our data shows that patients with better control tend to bolus more for correction and wear sensors longer. PMID- 25513746 TI - The Quasi-cohort approach in pharmacoepidemiology: upgrading the nested case control. AB - Observational studies of drug effects conducted using health care mega-databases often involve large cohorts with multiple time-varying exposures and covariates. These present formidable technical challenges in data analysis, necessitating sampling approaches such as nested case-control designs. The nested case-control approach is, however, baffling to medical journal readers, particularly the comparisons involving "cases" versus "controls" and the convoluted way in which forward-looking relations from exposure to outcome are extracted from backward looking data. I propose a "quasi-cohort" approach involving alternative ways of data presentation and analysis that are more in line with the underlying cohort design, including the computation of quasi-rates, rate ratios, and quasi-rate differences. I illustrate the quasi-cohort approach using data from a study of pneumonia risk associated with inhaled corticosteroid use in a cohort of 163,514 patients with chronic obstructive pulmonary disease, including 20,344 who had the outcome event of pneumonia hospitalization during more than 304 million person days of follow-up. PMID- 25513745 TI - Targeting chromatin to improve radiation response. AB - Chromatin, the structure formed by the wrapping of approximately 146 base pairs of DNA around an octamer of histones, has a profound impact on numerous DNA-based processes. Chromatin modifications and chromatin remodellers have recently been implicated in important aspects of the DNA damage response including facilitating the initial sensing of the damage as well as subsequent recruitment of repair factors. Radiation is an effective cancer therapy for a large number of tumours, and there is considerable interest in finding approaches that might further increase the efficacy of radiotherapy. The use of radiation leads to the generation of DNA damage and, therefore, agents that can affect the sensing and repair of DNA damage may have an impact on overall radiation efficacy. The chromatin modifications as well as chromatin modifiers that have been associated with the DNA damage response will be summarized in this review. An emphasis will be placed on those processes that can be pharmacologically manipulated with currently available inhibitors. The rationale for the use of these inhibitors in combination with radiation will also be described. PMID- 25513748 TI - Microbial transformation of bioactive compounds and production of ortho dihydroxyisoflavones and glycitein from natural fermented soybean paste. AB - Recently, there has been a great deal of remarkable interest in finding bioactive compounds from nutritional foods to replace synthetic compounds. In particular, ortho-dihydroxyisoflavones and glycitein are of growing scientific interest owing to their attractive biological properties. In this study, 7,8-ortho dihydroxyisoflavone, 6,7-ortho-dihydroxyisoflavone, 3',4'-ortho dihydroxyisoflavone and 7,4'-dihydroxy-6-methoxyisoflavone were characterized using microorganism screened from soybean Doenjang. Three ortho dihydroxyisoflavones and glycitein were structurally elucidated by 1H-NMR and GC MS analysis. Furthermore, bacterial strains from soybean Doenjang with the capacity of biotransformation were screened. The bacterial strain, identified as Bacillus subtilis Roh-1, was shown to convert daidzein into ortho dihydroxyisoflavones and glycitein. Thus, this study has, for the first time, demonstrated that a bacterial strain had a substrate specificity for multiple modifications of the bioactive compounds. PMID- 25513747 TI - A facile and sensitive method for quantification of cyclic nucleotide monophosphates in mammalian organs: basal levels of eight cNMPs and identification of 2',3'-cIMP. AB - A sensitive, versatile and economical method to extract and quantify cyclic nucleotide monophosphates (cNMPs) using LC-MS/MS, including both 3',5'-cNMPs and 2',3'-cNMPs, in mammalian tissues and cellular systems has been developed. Problems, such as matrix effects from complex biological samples, are addressed and have been optimized. This protocol allows for comparison of multiple cNMPs in the same system and was used to examine the relationship between tissue levels of cNMPs in a panel of rat organs. In addition, the study reports the first identification and quantification of 2',3'-cIMP. The developed method will allow for quantification of cNMPs levels in cells and tissues with varying disease states, which will provide insight into the role(s) and interplay of cNMP signalling pathways. PMID- 25513750 TI - Rehabilitation of women from the Middle East living with chronic pain- perceptions from health care professionals. AB - Meeting patients from other countries constitutes a challenge for health care. The purpose of this study was to increase knowledge about tacit understandings of treatment in practice by determining the perceptions of chronic pain and rehabilitation directed to resettled women from the Middle East, from a variety of health care professionals within primary care. Based on the results, we find a need to support and increase knowledge among health care professionals to involve the patient and consider her beliefs, expectations, background, current life situation, and spirituality, and to involve family in rehabilitation. PMID- 25513749 TI - An intervention to decrease heavy episodic drinking in college students: the effect of executive function training. AB - OBJECTIVE: To develop and test a planning-ability, executive function (EF) intervention to reduce heavy episodic drinking (HED). PARTICIPANTS: Fifty-five heavy-drinking, first-year college students, recruited from May to October 2012. METHODS: Participants were randomly allocated to an experimental or active control group and then completed the Alcohol Use Disorders Identification Test Consumption and demographic questions. Over 1 week, the experimental group completed 4 progressively harder planning tasks, whereas the control group completed 4 easier, consistent-difficulty planning tasks. Participants then recorded their daily alcohol consumption for 2 weeks. RESULTS: As hypothesized, both mean and maximum per-occasion alcohol consumption was significantly reduced in the experimental group compared with the control group. There were no significant differences in frequency of HED. CONCLUSIONS: These results provide initial support for the use of a planning-ability intervention in decreasing per occasion alcohol consumption. Future researchers can examine the mechanism of effect, the long-term efficacy, and the specific EFs involved in other aspects of alcohol consumption. PMID- 25513751 TI - High performance planar heterojunction perovskite solar cells with fullerene derivatives as the electron transport layer. AB - In this study, we report the utilization of solution-processed high electrical conductive [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM) combined with solution-processed TiO2 as the electron transport layer (ETL) to overcome extremely low electrical conductivity of solution-processed TiO2 ETL in planar heterojunction (PHJ) perovskite hybrid solar cells (pero-HSCs). Due to the much more preferable electron extraction and transportation of PC61BM at the cathode side, a tremendously boosted short-circuit current density (JSC), fill factor (FF) and enhanced power conversion efficiency (PCE) are observed. To further address the wettability issues of perovskite materials on the top of PC61BM, water-soluble fullerene derivative is applied to modulate the surface of PC61BM. Consequently, further advanced FF with slightly enlarged JSC and open-circuit voltage (VOC) are observed. The resulted PCE is comparable with the meso superstructured solar cells in which high PCEs can be produced. Our studies certainly provide a simple approach to boost the efficiency of PHJ pero-HSCs. PMID- 25513752 TI - Novel object recognition of Djungarian hamsters depends on circadian time and rhythmic phenotype. AB - Circadian rhythms have been shown to influence learning and memory. In this study, cognitive functions of Djungarian hamsters revealing different circadian phenotypes were evaluated using a novel object recognition (NOR) task. Wild type (WT) animals show a clear and well-synchronized daily activity rhythm, whereas DAO hamsters are characterized by a delayed activity onset. The phenomenon is caused by a diminished ability of photic synchronization. In arrhythmic (AR) hamsters, the suprachiasmatic nuclei (SCN) do not generate a circadian signal at all. The aim of this study was to investigate consequences of these deteriorations for learning and memory processes. Hamsters were bred and kept under standardized housing conditions with food and water ad libitum and a 14 L/10 D lighting regimen. Experimental animals were assigned to different groups (WT, DAO and AR) according to their activity pattern obtained by means of infrared motion sensors. Activity onset of DAO animals was delayed by 3 +/- 0.5 h. NOR tests were performed in an open arena and consisted of habituation, training (two identical objects) and test sessions (one of the two objects being replaced). The training-test interval was 60 min. Tests were performed at different Zeitgeber times (ZT 0 = light-on). Every hamster was tested at all times with an interval of one week between experiments. As activity onset of DAO animals is delaying continuously day by day, they could be tested at only three times (ZT 13, ZT 16 and ZT 19). The times animals did explore the novel and the familiar objects were recorded, and the discrimination index as a measure of cognitive performance was calculated. Behavioral analyzes revealed that, WT hamsters were able to discriminate between familiar and novel objects at ZT 13, ZT 16 and ZT 19, i.e. one hour before and during their activity period. In accordance with their delayed activity onset, DAO hamsters could discriminate between objects only at ZT 16 and ZT 19 what corresponds also to 1 h before and 2 h after their activity onset. In contrast, AR hamsters were not able to perform the NOR task at any time. The results show that the SCN modulate learning and memory in a circadian manner. Moreover, the loss of circadian rhythmicity results in cognitive impairments. PMID- 25513753 TI - Iodide sensing via electrochemical etching of ultrathin gold films. AB - Iodide is an essential element for humans and animals and insufficient intake is still a major problem. Affordable and accurate methods are required to quantify iodide concentrations in biological and environmental fluids. A simple and low cost sensing device is presented which is based on iodide induced electrochemical etching of ultrathin gold films. The sensitivity of resistance measurements to film thickness changes is increased by using films with a thickness smaller than the electron mean free path. The underlying mechanism is demonstrated by simultaneous cyclic voltammetry experiments and resistance change measurements in a buffer solution. Iodide sensing is conducted in buffer solutions as well as in lake water with limits of detection in the range of 1 MUM (127 MUg L(-1)) and 2 MUM (254 MUg L(-1)), respectively. In addition, nanoholes embedded in the thin films are tested for suitability of optical iodide sensing based on localized surface plasmon resonance. PMID- 25513754 TI - Relationship of impulsivity and depression during early methamphetamine withdrawal in Han Chinese population. AB - OBJECTIVE: High level of impulsivity as well as depression is thought to be involved in the maintenance and development of methamphetamine (METH) addiction. However, the relationship between impulsivity and depression has not been studied thoroughly in METH dependence subjects, especially in early METH abstinent subjects. In this study, our objective is to explore the interplay between the depressive symptoms and impulsivity in early METH abstinent subjects. METHODS: A total of 182 early abstinent METH dependent subjects (abstinence for 1-7 days) were recruited and the level of impulsivity was measured by the Barratt Impulsiveness Scale (BIS-11). Depressive symptoms and anxiety symptoms were assessed by the short 13-item Beck Depression Inventory (BDI-13) and Beck Anxiety Inventory (BAI) respectively. RESULTS: Global impulsivity of BIS-11 was significantly correlated with depressive symptoms among early METH abstinent subjects (r=0.283, p=0.001). Moreover, all subscales of BIS-11 were also found to be correlated with depressive symptoms: correlation with attentional impulsivity (r=0.202, p=0.006); correlation with motor impulsivity (r=0.267, p=0.001); and correlation with non-planning impulsivity (r=0.177, p=0.017). CONCLUSIONS: This study showed a relationship between impulsivity and depression, which may further the comprehension of motivational elements contributing to the maintenance and development of METH use disorder. Future research would be dedicated to exploring underlying mechanisms of association between impulsivity and depression. PMID- 25513757 TI - Smart design of free-standing ultrathin Co-Co(OH)2 composite nanoflakes on 3D nickel foam for high-performance electrochemical capacitors. AB - Ultrathin Co-Co(OH)2 composite nanoflakes have been fabricated through electrodeposition on 3D nickel foam. As electrochemical capacitor electrodes, they exhibit a high specific capacitance of 1000 F g(-1) at the scan rate of 5 mV s(-1) and 980 F g(-1) at the current density of 1 A g(-1), respectively, and the retention of capacitance is 91% after 5000 cycles. PMID- 25513756 TI - Cross-reactive immunity against influenza viruses in children and adults following 2009 pandemic H1N1 infection. AB - 2009 H1N1 pandemic influenza (A(H1N1)pdm09) virus infected large numbers of people worldwide. Recent studies suggest infection with A(H1N1)pdm09 virus elicited cross-reactive anti-hemagglutinin (HA) memory B cell response to conserved regions of HA. However, the breadth and magnitude of cross-reactive immunity in children and adults following A(H1N1)pdm09 infection are unknown. METHODS: We investigated serum anti-HA immunity to a number of group-1 and -2 viruses in children and adults using hemagglutination inhibition (HAI), enzyme linked immunosorbent assay and virus neutralization assay. RESULTS: Applying hemagglutination inhibition (HAI) titers ?40 against A(H1N1)pdm09 as threshold of sero-positivity, we observed significantly higher levels of anti-HA antibodies to a number of virus subtypes, including those neutralizing H5N1, in subjects with HAI titer ?40 than those with HAI <40. Adults demonstrated broader and stronger cross-reactive anti-HA antibodies than children, including cross-reactive anti HA1 and -HA2 antibodies. By comparison, individuals with serologic evidence of recent exposure to seasonal H1N1 or H3N2 did not show such broad cross-reactive immunity. CONCLUSION: Our results suggest individuals exposed to A(H1N1)pdm09 virus developed a broad and age-associated cross-reactive anti-HA immunity which may have important implications for future vaccination strategies to enable protection against a broader range of influenza viruses. PMID- 25513755 TI - Recombinant influenza virus expressing a fusion protein neutralizing epitope of respiratory syncytial virus (RSV) confers protection without vaccine-enhanced RSV disease. AB - Respiratory syncytial virus (RSV) is the leading cause of viral bronchiolitis in both children and the elderly. There is no vaccine available for the prevention of RSV infection. Here, we generated recombinant influenza virus (PR8/RSV.HA-F) expressing an RSV F243-294 neutralizing epitope in the hemagglutinin (HA) as a chimeric protein. Neutralizing antibodies specific for both RSV and influenza virus were induced by a single intranasal immunization of mice with PR8/RSV.HA-F. Mice that were immunized with PR8/RSV.HA-F were protected against RSV infection comparable with live RSV as evidenced by significant reduction of RSV lung viral loads, as well as the absence of lung eosinophilia and RSV-specific cellular immune responses. In contrast, formalin-inactivated RSV-immunized mice showed severe disease and high cellular immune responses in lungs after RSV infection. These findings support a concept that recombinant influenza virus carrying the RSV F243-294 neutralizing epitope can be developed as a promising RSV vaccine candidate which induces protective neutralizing antibodies but avoids lung immunopathology. PMID- 25513759 TI - Consequences of Decreased Light Harvesting Capability on Photosystem II Function in Synechocystis sp. PCC 6803. AB - Cyanobacteria use large pigment-protein complexes called phycobilisomes to harvest light energy primarily for photosystem II (PSII). We used a series of mutants with partial to complete reduction of phycobilisomes to examine the effects of antenna truncation on photosystem function in Synechocystis sp. PCC 6803. The antenna mutants CB, CK, and PAL expressed increasing levels of functional PSII centers to compensate for the loss of phycobilisomes, with a concomitant decrease in photosystem I (PSI). This increased PSII titer led to progressively higher oxygen evolution rates on a per chlorophyll basis. The mutants also exhibited impaired S-state transition profiles for oxygen evolution. Additionally, P700+ re-reduction rates were impacted by antenna reduction. Thus, a decrease in antenna size resulted in overall physiological changes in light harvesting and delivery to PSII as well as changes in downstream electron transfer to PSI. PMID- 25513758 TI - Looked at life from both sides now. AB - As the molecular top-down causality emerging through comparative genomics is combined with the bottom-up dynamic chemical networks of biochemistry, the molecular symbiotic relationships driving growth of the tree of life becomes strikingly apparent. These symbioses can be mutualistic or parasitic across many levels, but most foundational is the complex and intricate mutualism of nucleic acids and proteins known as the central dogma of biological information flow. This unification of digital and analog molecular information within a common chemical network enables processing of the vast amounts of information necessary for cellular life. Here we consider the molecular information pathways of these dynamic biopolymer networks from the perspective of their evolution and use that perspective to inform and constrain pathways for the construction of mutualistic polymers. PMID- 25513761 TI - Reconciling ligase ribozyme activity with Fatty Acid vesicle stability. AB - The "RNA world" and the "Lipid world" theories for the origin of cellular life are often considered incompatible due to the differences in the environmental conditions at which they can emerge. One obstacle resides in the conflicting requirements for divalent metal ions, in particular Mg2+, with respect to optimal ribozyme activity, fatty acid vesicle stability and protection against RNA strand cleavage. Here, we report on the activity of a short L1 ligase ribozyme in the presence of myristoleic acid (MA) vesicles at varying concentrations of Mg2+. The ligation rate is significantly lower at low-Mg2+ conditions. However, the loss of activity is overcompensated by the increased stability of RNA leading to a larger amount of intact ligated substrate after long reaction periods. Combining RNA ligation assays with fatty acid vesicles we found that MA vesicles made of 5 mM amphiphile are stable and do not impair ligase ribozyme activity in the presence of approximately 2 mM Mg2+. These results provide a scenario in which catalytic RNA and primordial membrane assembly can coexist in the same environment. PMID- 25513760 TI - Toward Spatially Regulated Division of Protocells: Insights into the E. coli Min System from in Vitro Studies. AB - For reconstruction of controlled cell division in a minimal cell model, or protocell, a positioning mechanism that spatially regulates division is indispensable. In Escherichia coli, the Min proteins oscillate from pole to pole to determine the division site by inhibition of the primary divisome protein FtsZ anywhere but in the cell middle. Remarkably, when reconstituted under defined conditions in vitro, the Min proteins self-organize into spatiotemporal patterns in the presence of a lipid membrane and ATP. We review recent progress made in studying the Min system in vitro, particularly focusing on the effects of various physicochemical parameters and boundary conditions on pattern formation. Furthermore, we discuss implications and challenges for utilizing the Min system for division site placement in protocells. PMID- 25513763 TI - PTSD and substance use disorder among veterans: characteristics, service utilization and pharmacotherapy. AB - OBJECTIVE: While there has been considerable concern about veterans with dually diagnosed posttraumatic stress disorder (PTSD) and comorbid substance use disorders, a national study of clinical characteristics, service utilization, and psychotropic medication use of such veterans in Veterans Affairs (VA) has yet to be conducted. We hypothesized that veterans having both PTSD and substance use disorder would have lower socioeconomic status, greater medical and psychiatric comorbidity, higher medical service utilization, and more psychotropic pharmacotherapy fills. METHODS: National VA data from fiscal year 2012 were used to compare veterans with dually diagnosed PTSD and substance use disorder to veterans with PTSD without substance use disorder on sociodemographic characteristics, psychiatric and medical comorbidities, mental health and medical service utilization, and psychotropic pharmacotherapy. Comparisons were based on bivariate and Poisson regression analyses. RESULTS: The sample included all 638,451 veterans who received the diagnosis of PTSD in the VA in fiscal year 2012: 498,720 (78.1%) with PTSD alone and 139,731 (21.9%) with dually diagnosed PTSD and a comorbid substance use disorder. Veterans with dual diagnoses were more likely to have been homeless and to have received a VA disability pension. Medical diagnoses that were more strongly associated with veterans with dual diagnosis included seizure disorders, liver disease, and human immunodeficiency virus (HIV). Psychiatric comorbidities that distinguished veterans with dual diagnoses included bipolar disorder and schizophrenia. Veterans with dually diagnosed PTSD and substance use disorder also had a greater likelihood of having had mental health inpatient treatment. There were no substantial differences in other measures of service use or prescription fills for psychotropic medications. CONCLUSIONS: Several substantial differences were observed, each of which represented more severe medical and psychiatric illness among veterans with dually diagnosed PTSD and substance use disorder compared to those with PTSD alone. However, effective treatments are available for these disorders and special efforts should be made to ensure that veterans with dual diagnoses receive them. PMID- 25513764 TI - Divide and control: split design of multi-input DNA logic gates. AB - Logic gates made of DNA have received significant attention as biocompatible building blocks for molecular circuits. The majority of DNA logic gates, however, are controlled by the minimum number of inputs: one, two or three. Here we report a strategy to design a multi-input logic gate by splitting a DNA construct. PMID- 25513766 TI - Epilepsy-related stigma in European people with epilepsy: correlations with health system performance and overall quality of life. AB - We aimed to relate the percentages of encountered epilepsy-related stigma in people with epilepsy with quantitative indicators of the quality of health systems and quality of life by country in Europe. The epilepsy-related stigma percentages were obtained from the largest population-based study in people with epilepsy available. We correlated percentages of people with perceived stigma per European country with data on the country's overall health system performance, health expenditure per capita in international dollars, and the Economist Intelligence Unit's quality-of-life index. We found a nonsignificant trend towards negative correlation between the epilepsy-related stigma percentage and the overall health system performance (r=-0.16; p=0.57), the health expenditure per capita in international dollars (r=-0.24; p=0.4), and the Economist Intelligence Unit's quality-of-life index (r=-0.33; p=0.91). Living in a European country with a better health system performance and higher health expenditure per capita does not necessarily lead to a reduction in perceived epilepsy-related discrimination, unless the public health system invests on awareness programs to increase public knowledge and reduce stigma. PMID- 25513762 TI - Regulation of Three Nitrogenase Gene Clusters in the Cyanobacterium Anabaena variabilis ATCC 29413. AB - The filamentous cyanobacterium Anabaena variabilis ATCC 29413 fixes nitrogen under aerobic conditions in specialized cells called heterocysts that form in response to an environmental deficiency in combined nitrogen. Nitrogen fixation is mediated by the enzyme nitrogenase, which is very sensitive to oxygen. Heterocysts are microxic cells that allow nitrogenase to function in a filament comprised primarily of vegetative cells that produce oxygen by photosynthesis. A. variabilis is unique among well-characterized cyanobacteria in that it has three nitrogenase gene clusters that encode different nitrogenases, which function under different environmental conditions. The nif1 genes encode a Mo-nitrogenase that functions only in heterocysts, even in filaments grown anaerobically. The nif2 genes encode a different Mo-nitrogenase that functions in vegetative cells, but only in filaments grown under anoxic conditions. An alternative V-nitrogenase is encoded by vnf genes that are expressed only in heterocysts in an environment that is deficient in Mo. Thus, these three nitrogenases are expressed differentially in response to environmental conditions. The entire nif1 gene cluster, comprising at least 15 genes, is primarily under the control of the promoter for the first gene, nifB1. Transcriptional control of many of the downstream nif1 genes occurs by a combination of weak promoters within the coding regions of some downstream genes and by RNA processing, which is associated with increased transcript stability. The vnf genes show a similar pattern of transcriptional and post-transcriptional control of expression suggesting that the complex pattern of regulation of the nif1 cluster is conserved in other cyanobacterial nitrogenase gene clusters. PMID- 25513767 TI - Enacted stigma among patients with epilepsy and intellectual impairment. AB - BACKGROUND: The limited research on stigma and its determinants in patients with epilepsy and intellectual impairment motivated our study in this area. PURPOSE: We assessed enacted stigma and its determining factors in Bulgarian patients with refractory epilepsy and intellectual impairment. METHODS: We conducted a study of 64 patients with refractory epilepsy and intellectual impairment based on a questionnaire designed for people with intellectual impairment (stigma scale) and a purposeful interview on clinical factors and real experiences of discrimination, insults and/or threats, and attacks. RESULTS: A real experience of discrimination was reported by 51 (91.07%) of the interviewed participants, 34 (60.71%) of whom had been insulted and/or threatened and attacked because of their health problems. The experience of insults and/or threats and attacks was more frequent in cases with moderate intellectual impairment (chi(2)=5.17, P<0.05). Discrimination was reported more rarely by older patients (F=3.23, P<0.05). The participants who gave a greater number of positive answers about experienced discrimination or insults and/or threats and attacks reported a more pronounced perceived stigma (F=19.30, P<0.001 and F=12.91, P<0.001, respectively). Perceived stigma and the experience of insults and/or threats and attacks proved to be predictors of discrimination on multivariate regression analysis (F=40.54, P<0.001). CONCLUSIONS: We have affirmed very frequent enacted stigmatization in Bulgarian patients with refractory epilepsy and intellectual impairment and its correlation with the degree of intellectual impairment, age, and perceived stigma. PMID- 25513768 TI - Cosmetic side effects of antiepileptic drugs in adults with epilepsy. AB - OBJECTIVE: Cosmetic side effects (CSEs) such as weight gain and alopecia are common, undesirable effects associated with several AEDs. The objective of the study was to compare the CSE profiles in a large specialty practice-based sample of patients taking both older and newer AEDs. METHODS: As part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 1903 adult patients (>=16years of age) newly started on an AED. Cosmetic side effects were determined by patient or physician report in the medical record and included acne, gingival hyperplasia, hair loss, hirsutism, and weight gain. We compared the overall rate of CSEs and intolerable CSEs (ICSEs-CSEs that led to dosage reduction or discontinuation) between different AEDs in both monotherapy and polytherapy. RESULTS: Overall, CSEs occurred in 110/1903 (5.8%) patients and led to intolerability in 70/1903 (3.7%) patients. Weight gain was the most commonly reported CSE (68/1903, 3.6%) and led to intolerability in 63 (3.3%) patients. Alopecia was the second most common patient-reported CSE (36/1903, 1.9%) and was intolerable in 33/1903 (1.7%) patients. Risk factors for CSEs included female sex (7.0% vs. 4.3% in males; p<0.05) and any prior CSE (37% vs. 2.9% in patients without prior CSE; p<0.001). Significantly more CSEs were attributed to valproic acid (59/270; 21.9%; p<0.001) and pregabalin (14/143; 9.8%; p<0.001) than to all other AEDs. Significantly less CSEs were attributed to levetiracetam (7/524; 1.3%; p=0.002). Weight gain was most frequently associated with valproic acid (35/270; 13.0%; p<0.001) and pregabalin (12/143; 8.4%; p<0.001). Hair loss was most commonly reported among patients taking valproic acid (24/270; 8.9%; p<0.001). Finally, gingival hyperplasia was most commonly reported in patients taking phenytoin (10/404; 2.5%; p<0.001). Cosmetic side effects leading to dosage change or discontinuation occurred most frequently with pregabalin and valproic acid compared with all other AEDs (13.3 and 5.6% vs. 2.3%; p<0.001). For patients who had been on an AED in monotherapy (n=677), CSEs and ICSEs were still more likely to be attributed to valproic acid (30.2% and 17.1%, respectively) than to any other AED (both p<0.001). SIGNIFICANCE: Weight gain and alopecia were the most common patient-reported CSEs in this study, and weight gain was the most likely cosmetic side effect to result in dosage adjustment or medication discontinuation. Particular attention should be paid to pregabalin, phenytoin, and valproic acid when considering cosmetic side effects. Female patients and patients who have had prior CSE(s) to AED(s) were more likely to report CSEs. Knowledge of specific CSE rates for each AED found in this study may be useful in clinical practice. PMID- 25513769 TI - Pathogens. PMID- 25513770 TI - Effector triggered immunity. AB - Pathogenic bacteria produce virulence factors called effectors, which are important components of the infection process. Effectors aid in pathogenesis by facilitating bacterial attachment, pathogen entry into or exit from the host cell, immunoevasion, and immunosuppression. Effectors also have the ability to subvert host cellular processes, such as hijacking cytoskeletal machinery or blocking protein translation. However, host cells possess an evolutionarily conserved innate immune response that can sense the pathogen through the activity of its effectors and mount a robust immune response. This "effector triggered immunity" (ETI) was first discovered in plants but recent evidence suggest that the process is also well conserved in metazoans. We will discuss salient points of the mechanism of ETI in metazoans from recent studies done in mammalian cells and invertebrate model hosts. PMID- 25513771 TI - Effector biology during biotrophic invasion of plant cells. AB - Several obligate biotrophic phytopathogens, namely oomycetes and fungi, invade and feed on living plant cells through specialized structures known as haustoria. Deploying an arsenal of secreted proteins called effectors, these pathogens balance their parasitic propagation by subverting plant immunity without sacrificing host cells. Such secreted proteins, which are thought to be delivered by haustoria, conceivably reprogram host cells and instigate structural modifications, in addition to the modulation of various cellular processes. As effectors represent tools to assist disease resistance breeding, this short review provides a bird's eye view on the relationship between the virulence function of effectors and their subcellular localization in host cells. PMID- 25513772 TI - Go in for the kill: How plants deploy effector-triggered immunity to combat pathogens. [Corrected]. AB - Plant resistance (R) proteins perceive specific pathogen effectors from diverse plant pathogens to initiate defense responses, designated effector-triggered immunity (ETI). Plant R proteins are mostly nucleotide binding-leucine rich repeat (NB-LRR) proteins, which recognize pathogen effectors directly or indirectly through sophisticated mechanisms. Upon activation by effector proteins, R proteins elicit robust defense responses, including a rapid burst of reactive oxygen species (ROS), induced biosynthesis and accumulation of salicylic acid (SA), a rapid programmed cell death (PCD) called hypersensitive response (HR) at the infection sites, and increased expression of pathogenesis-related (PR) genes. Initiation of ETI is correlated with a complex network of defense signaling pathways, resulting in defensive cellular responses and large-scale transcriptional reprogramming events. In this review, we highlight important recent advances on the recognition of effectors, regulation and activation of plant R proteins, dynamic intracellular trafficking of R proteins, induction of cell death, and transcriptional reprogramming associated with ETI. Current knowledge gaps and future research directions are also discussed in this review. PMID- 25513773 TI - The role of effectors and host immunity in plant-necrotrophic fungal interactions. AB - Fungal diseases pose constant threats to the global economy and food safety. As the largest group of plant fungal pathogens, necrotrophic fungi cause heavy crop losses worldwide. The molecular mechanisms of the interaction between necrotrophic fungi and plants are complex and involve sophisticated recognition and signaling networks. Here, we review recent findings on the roles of phytotoxin and proteinaceous effectors, pathogen-associated molecular patterns (PAMPs), and small RNAs from necrotrophic fungi. We also consider the functions of damage-associated molecular patterns (DAMPs), the receptor-like protein kinase BIK1, and epigenetic regulation in plant immunity to necrotrophic fungi. PMID- 25513774 TI - Effector triggered manipulation of host immune response elicited by different pathotypes of Escherichia coli. AB - Effectors are virulence factors that are secreted by bacteria during an infection in order to subvert cellular processes or induce the surveillance system of the host. Pathogenic microorganisms encode effectors, toxins and components of secretion systems that inject the effectors to the host. Escherichia coli is part of the innocuous commensal microbial flora of the gastrointestinal tract. However, pathogenic E. coli can cause diarrheal and extraintestinal diseases. Pathogenic E. coli uses secretion systems to inject an array of effector proteins directly into the host cells. Herein, we discuss the effectors secreted by different pathotypes of E. coli and provide an overview of strategies employed by effectors to target the host cellular and subcellular processes as well as their role in triggering host immune response. PMID- 25513777 TI - Manipulation of pro-inflammatory cytokine production by the bacterial cell penetrating effector protein YopM is independent of its interaction with host cell kinases RSK1 and PRK2. AB - The effector protein Yersinia outer protein M (YopM) of Yersinia enterocolitica has previously been identified and characterized as the first bacterial cell penetrating protein (CPP). We found that recombinant YopM (rYopM) enters different eukaryotic cell types and downregulates the expression of several pro inflammatory cytokines (e.g., tumor necrosis factor-alpha [TNF-alpha]) after autonomous translocation. After infection with Y. enterocolitica or transfection of host cells, YopM interacts with isoforms of the two kinases ribosomal S6 protein kinase (RSK) and protein kinase C-related kinase (PRK). This interaction caused sustained RSK activation due to interference with dephosphorylation. Here we demonstrate by co-immunoprecipitation that rYopM interacts with RSK and PRK following cell-penetration. We show that autonomously translocated rYopM forms a trimeric complex with different RSK and PRK isoforms. Furthermore, we constructed a series of truncated versions of rYopM to map the domain required for the formation of the complex. The C-terminus of rYopM was identified to be essential for the interaction with RSK1, whereas any deletion in rYopM's leucin-rich repeat domains abrogated PRK2 binding. Moreover, we found that the interaction of cell penetrating rYopM with RSK led to enhanced autophosphorylation of this kinase at serine 380. Finally, we investigated whether downstream signaling of the trimeric rYopM-RSK/PRK complex modulates the expression of pro-inflammatory TNF-alpha. Here, we could exclude that interaction with RSK1 and PRK2 is essential for the anti-inflammatory effects of rYopM. PMID- 25513776 TI - Proteomics of effector-triggered immunity (ETI) in plants. AB - Effector-triggered immunity (ETI) was originally termed gene-for-gene resistance and dates back to fundamental observations of flax resistance to rust fungi by Harold Henry Flor in the 1940s. Since then, genetic and biochemical approaches have defined our current understanding of how plant "resistance" proteins recognize microbial effectors. More recently, proteomic approaches have expanded our view of the protein landscape during ETI and contributed significant advances to our mechanistic understanding of ETI signaling. Here we provide an overview of proteomic techniques that have been used to study plant ETI including both global and targeted approaches. We discuss the challenges associated with ETI proteomics and highlight specific examples from the literature, which demonstrate how proteomics is advancing the ETI research field. PMID- 25513778 TI - Stoma creation for treatment of primary perianal Paget's disease. PMID- 25513779 TI - In-vivo longitudinal MRI study: an assessment of melanoma brain metastases in a clinically relevant mouse model. AB - Brain metastases are an important clinical problem. Few animal models exist for melanoma brain metastases; many of which are not clinically relevant. Longitudinal MRI was implemented to examine the development of tumors in a clinically relevant mouse model of melanoma brain metastases. Fifty thousand human metastatic melanoma (A2058) cells were injected intracardially into nude mice. Three Tesla MRI was performed using a custom-built gradient insert coil and a mouse solenoid head coil. Imaging was performed on consecutive days at four time points. Tumor burden and volumes of metastases were measured from balanced steady-state free precession image data. Metastases with a disrupted blood-tumor barrier were identified from T1-weighted spin echo images acquired after administration of gadopentetic acid (Gd-DTPA). Metastases permeable to Gd-DTPA showed signal enhancement. The number of enhancing metastases was determined by comparing balanced steady-state free precession images with T1-weighted spin echo images. After the final imaging session, ex-vivo permeability and histological analyses were carried out. Imaging showed that both enhancing and nonenhancing brain metastases coexist in the brain, and that most metastases switched from the nonenhancing to the enhancing phenotype. Small numbers of brain metastases were enhancing when first detected by MRI and remained enhancing, whereas other metastases remained nonenhancing to Gd-DTPA throughout the experiment. No clear relationship existed between the permeability of brain metastases and size, brain location and age. Longitudinal in-vivo MRI is key to studying the complex and dynamic processes of metastasis and changes in the blood-tumor barrier permeability, which may lead to a better understanding of the variable responses of brain metastases to treatments. PMID- 25513775 TI - Modulation of host adaptive immunity by hRSV proteins. AB - Globally, the human respiratory syncytial virus (hRSV) is the major cause of lower respiratory tract infections (LRTIs) in infants and children younger than 2 years old. Furthermore, the number of hospitalizations due to LRTIs has shown a sustained increase every year due to the lack of effective vaccines against hRSV. Thus, this virus remains as a major public health and economic burden worldwide. The lung pathology developed in hRSV-infected humans is characterized by an exacerbated inflammatory and Th2 immune response. In order to rationally design new vaccines and therapies against this virus, several studies have focused in elucidating the interactions between hRSV virulence factors and the host immune system. Here, we discuss the main features of hRSV biology, the processes involved in virus recognition by the immune system and the most relevant mechanisms used by this pathogen to avoid the antiviral host response. PMID- 25513781 TI - Low frequency of KRAS mutation in pancreatic ductal adenocarcinomas in Korean patients and its prognostic value. AB - OBJECTIVES: Low prevalence and prognostic relevance of KRAS mutations in Korean pancreatic ductal adenocarcinomas (PDACs) need to be validated with sensitive detection method. METHODS: Peptide nucleic acid (PNA)-mediated polymerase chain reaction (PCR) clamping was used to precisely detect KRAS mutation in 72 paraffinized tumor samples and was validated by pancreatic cell lines to compare the efficiency of direct sequencing. RESULTS: The PNA-mediated PCR clamping detected mutant allele proportions of as low as 0.5% against a background of wild type DNA and was 20-fold more sensitive than direct sequencing through the validation of pancreatic cell lines. Peptide nucleic acid-mediated PCR clamping detected KRAS mutations in 47.2% of 72 PDACs. Low tumor cellularity and low PCR amplification efficiency led to be undetected or failed by direct sequencing in pancreatic paraffinized samples.KRAS mutations were an independent worse prognostic factor predicting a reduced progression-free survival rate in the postoperative chemotherapy group. CONCLUSIONS: Peptide nucleic acid clamp real time PCR was a sensitive method for detecting KRAS status in paraffinized PDAC samples. We identified a low KRAS mutation rate among the Korean PDAC patients using PNA clamp real-time PCR, potentially implicating epidemiological characteristics. The low KRAS mutation rate and its prognostic role may suggest the further survival benefit in Korean PDAC patients. PMID- 25513783 TI - Influence of inspiration to expiration ratio on cyclic recruitment and derecruitment of atelectasis in a saline lavage model of acute respiratory distress syndrome. AB - OBJECTIVE: Cyclic recruitment and derecruitment of atelectasis can occur during mechanical ventilation, especially in injured lungs. Experimentally, cyclic recruitment and derecruitment can be quantified by respiration-dependent changes in PaO2 (DeltaPaO2), reflecting the varying intrapulmonary shunt fraction within the respiratory cycle. This study investigated the effect of inspiration to expiration ratio upon DeltaPaO2 and Horowitz index. DESIGN: Prospective randomized study. SETTING: Laboratory investigation. SUBJECTS: Piglets, average weight 30 +/- 2 kg. INTERVENTIONS: At respiratory rate 6 breaths/min, end inspiratory pressure (Pendinsp) 40 cm H2O, positive end-expiratory pressure 5 cm H2O, and FIO2 1.0, measurements were performed at randomly set inspiration to expiration ratios during baseline healthy and mild surfactant depletion injury. Lung damage was titrated by repetitive surfactant washout to induce maximal cyclic recruitment and derecruitment as measured by multifrequency phase fluorimetry. Regional ventilation distribution was evaluated by electrical impedance tomography. Step changes in airway pressure from 5 to 40 cm H2O and vice versa were performed after lavage to calculate PO2-based recruitment and derecruitment time constants (TAU). MEASUREMENTS AND MAIN RESULTS: In baseline healthy, cyclic recruitment and derecruitment could not be provoked, whereas in model acute respiratory distress syndrome, the highest DeltaPaO2 were routinely detected at an inspiration to expiration ratio of 1:4 (range, 52-277 torr [6.9 36.9 kPa]). Shorter expiration time reduced cyclic recruitment and derecruitment significantly (158 +/- 85 torr [21.1 +/- 11.3 kPa] [inspiration to expiration ratio, 1:4]; 25 +/- 12 torr [3.3 +/- 1.6 kPa] [inspiration to expiration ratio, 4:1]; p < 0.0001), whereas the PaO2/FIO2 ratio increased (267 +/- 50 [inspiration to expiration ratio, 1:4]; 424 +/- 53 [inspiration to expiration ratio, 4:1]; p < 0.0001). Correspondingly, regional ventilation redistributed toward dependent lung regions (p < 0.0001). Recruitment was much faster (TAU: fast 1.6 s [78%]; slow 9.2 s) than derecruitment (TAU: fast 3.1 s [87%]; slow 17.7 s) (p = 0.0078). CONCLUSIONS: Inverse ratio ventilation minimizes cyclic recruitment and derecruitment of atelectasis in an experimental model of surfactant-depleted pigs. Time constants for recruitment and derecruitment, and regional ventilation distribution, reflect these findings and highlight the time dependency of cyclic recruitment and derecruitment. PMID- 25513782 TI - GUIDE-seq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. AB - CRISPR RNA-guided nucleases (RGNs) are widely used genome-editing reagents, but methods to delineate their genome-wide, off-target cleavage activities have been lacking. Here we describe an approach for global detection of DNA double-stranded breaks (DSBs) introduced by RGNs and potentially other nucleases. This method, called genome-wide, unbiased identification of DSBs enabled by sequencing (GUIDE seq), relies on capture of double-stranded oligodeoxynucleotides into DSBs. Application of GUIDE-seq to 13 RGNs in two human cell lines revealed wide variability in RGN off-target activities and unappreciated characteristics of off target sequences. The majority of identified sites were not detected by existing computational methods or chromatin immunoprecipitation sequencing (ChIP-seq). GUIDE-seq also identified RGN-independent genomic breakpoint 'hotspots'. Finally, GUIDE-seq revealed that truncated guide RNAs exhibit substantially reduced RGN induced, off-target DSBs. Our experiments define the most rigorous framework for genome-wide identification of RGN off-target effects to date and provide a method for evaluating the safety of these nucleases before clinical use. PMID- 25513785 TI - Lung recruitability is better estimated according to the Berlin definition of acute respiratory distress syndrome at standard 5 cm H2O rather than higher positive end-expiratory pressure: a retrospective cohort study. AB - OBJECTIVES: The Berlin definition of acute respiratory distress syndrome has introduced three classes of severity according to PaO2/FIO2 thresholds. The level of positive end-expiratory pressure applied may greatly affect PaO2/FIO2, thereby masking acute respiratory distress syndrome severity, which should reflect the underlying lung injury (lung edema and recruitability). We hypothesized that the assessment of acute respiratory distress syndrome severity at standardized low positive end-expiratory pressure may improve the association between the underlying lung injury, as detected by CT, and PaO2/FIO2-derived severity. DESIGN: Retrospective analysis. SETTING: Four university hospitals (Italy, Germany, and Chile). PATIENTS: One hundred forty-eight patients with acute lung injury or acute respiratory distress syndrome according to the American-European Consensus Conference criteria. INTERVENTIONS: Patients underwent a three-step ventilator protocol (at clinical, 5 cm H2O, or 15 cm H2O positive end-expiratory pressure). Whole-lung CT scans were obtained at 5 and 45 cm H2O airway pressure. MEASUREMENTS AND MAIN RESULTS: Nine patients did not fulfill acute respiratory distress syndrome criteria of the novel Berlin definition. Patients were then classified according to PaO2/FIO2 assessed at clinical, 5 cm H2O, or 15 cm H2O positive end-expiratory pressure. At clinical positive end-expiratory pressure (11+/-3 cm H2O), patients with severe acute respiratory distress syndrome had a greater lung tissue weight and recruitability than patients with mild or moderate acute respiratory distress syndrome (p<0.001). At 5 cm H2O, 54% of patients with mild acute respiratory distress syndrome at clinical positive end-expiratory pressure were reclassified to either moderate or severe acute respiratory distress syndrome. In these patients, lung recruitability and clinical positive end-expiratory pressure were higher than in patients who remained in the mild subgroup (p<0.05). When patients were classified at 5 cm H2O, but not at clinical or 15 cm H2O, lung recruitability linearly increases with acute respiratory distress syndrome severity (5% [2-12%] vs 12% [7-18%] vs 23% [12-30%], respectively, p<0.001). The potentially recruitable lung was the only CT-derived variable independently associated with ICU mortality (p=0.007). CONCLUSIONS: The Berlin definition of acute respiratory distress syndrome assessed at 5 cm H2O allows a better evaluation of lung recruitability and edema than at higher positive end-expiratory pressure clinically set. PMID- 25513784 TI - Cooccurrence of and remission from general anxiety, depression, and posttraumatic stress disorder symptoms after acute lung injury: a 2-year longitudinal study. AB - OBJECTIVE: To evaluate the cooccurrence, and predictors of remission, of general anxiety, depression, and posttraumatic stress disorder symptoms during 2-year follow-up in survivors of acute lung injury treated in an ICU. DESIGN: Prospective cohort study, with follow-up at 3, 6, 12, and 24 months post-acute lung injury. SETTING: Thirteen medical and surgical ICUs in four hospitals. PATIENTS: Survivors among 520 patients with acute lung injury. MEASUREMENTS AND MAIN RESULTS: The outcomes of interest were measured using the Hospital Anxiety and Depression Scale anxiety and depression subscales (scores >= 8 indicating substantial symptoms) and the Impact of Event Scale-Revised (scores >= 1.6 indicating substantial posttraumatic stress disorder symptoms). Of the 520 enrolled patients, 274 died before 3-month follow-up; 186 of 196 consenting survivors (95%) completed at least one Hospital Anxiety and Depression Scale and Impact of Event Scale-Revised assessment during 2-year follow-up, and most completed multiple assessments. Across follow-up time points, the prevalence of suprathreshold general anxiety, depression, and posttraumatic stress disorder symptoms ranged from 38% to 44%, 26% to 33%, and 22% to 24%, respectively; more than half of the patients had suprathreshold symptoms in at least one domain during 2-year follow-up. The majority of survivors (59%) with any suprathreshold symptoms were above threshold for two or more types of symptoms (i.e., general anxiety, depression, and/or posttraumatic stress disorder). In fact, the most common pattern involved simultaneous general anxiety, depression, and posttraumatic stress disorder symptoms. Most patients with general anxiety, depression, or posttraumatic stress disorder symptoms during 2-year follow-up had suprathreshold symptoms at 24-month (last) follow-up. Higher Short-Form-36 physical functioning domain scores at the prior visit were associated with a greater likelihood of remission from general anxiety and posttraumatic stress disorder symptoms during follow-up. CONCLUSIONS: The majority of acute lung injury survivors had clinically significant general anxiety, depression, or posttraumatic stress disorder symptoms, and these symptoms tended to co-occur across domains. Better physical functioning during recovery predicted subsequent remission of general anxiety and posttraumatic stress disorder symptoms. PMID- 25513786 TI - Extravascular lung water and pulmonary vascular permeability index as markers predictive of postoperative acute respiratory distress syndrome: a prospective cohort investigation. AB - OBJECTIVE: Robust markers of subclinical perioperative lung injury are lacking. Extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index are two promising early markers of lung edema. We aimed to evaluate whether extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index would identify patients at risk for clinically significant postoperative pulmonary edema, particularly resulting from the acute respiratory distress syndrome. DESIGN: Prospective cohort study. SETTING: Tertiary care academic medical center. PATIENTS: Adults undergoing high risk cardiac or aortic vascular surgery (or both) with risk of acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index measurements were obtained intraoperatively and in the early postoperative period. We assessed the accuracy of peak extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index as predictive markers of clinically significant pulmonary edema (defined as acute respiratory distress syndrome or cardiogenic pulmonary edema) using area under the receiver-operating characteristic curves. Associations between extravascular lung water indexed to predicted body weight and pulmonary vascular permeability patient-important with important outcomes were assessed. Of 150 eligible patients, 132 patients (88%) had extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index measurements. Of these, 13 patients (9.8%) had postoperative acute respiratory distress syndrome and 15 patients (11.4%) had cardiogenic pulmonary edema. Extravascular lung water indexed to predicted body weight effectively predicted development of clinically significant pulmonary edema (area under the receiver-operating characteristic curve, 0.79; 95% CI, 0.70-0.89). Pulmonary vascular permeability index discriminated acute respiratory distress syndrome from cardiogenic pulmonary edema alone or no edema (area under the receiver-operating characteristic curve, 0.77; 95% CI, 0.62-0.93). Extravascular lung water indexed to predicted body weight was associated with the worst postoperative PaO2/FIO2, duration of mechanical ventilation, ICU stay, and hospital stay. Peak values for extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index were obtained within 2 hours of the primary intraoperative insult for the majority of patients (> 80%). CONCLUSIONS: Perioperative extravascular lung water indexed to predicted body weight is an early marker that predicts risk of clinically significant postoperative pulmonary edema in at-risk surgical patients. Pulmonary vascular permeability index effectively discriminated postoperative acute respiratory distress syndrome from cardiogenic pulmonary edema. These measures will aid in the early detection of subclinical lung injury in at-risk surgical populations. PMID- 25513787 TI - Tissue oxygen saturation and finger perfusion index in central hypovolemia: influence of pain. AB - OBJECTIVES: Tissue oxygen saturation and peripheral perfusion index are proposed as early indirect markers of hypovolemia in trauma patients. Hypovolemia is associated with increased sympathetic nervous activity. However, many other stimuli, such as pain, also increase sympathetic activity. Since pain is often present in trauma patients, its effect on the indirect measures of hypovolemia needs to be clarified. The aim of this study was, therefore, to explore the effects of hypovolemia and pain on tissue oxygen saturation (measurement sites: cerebral, deltoid, forearm, and thenar) and finger photoplethysmographic perfusion index. DESIGN: Experimental study. SETTING: University hospital clinical circulation and research laboratory. SUBJECTS: Twenty healthy volunteers. INTERVENTIONS: Central hypovolemia was induced with lower body negative pressure (-60 mm Hg) and pain by the cold pressor test (ice water exposure). Interventions were performed in a 2*2 fashion with the combination of lower body negative pressure or not (normovolemia), and ice water or not (sham). Each subject was thus exposed to four experimental sequences, each lasting for 8 minutes. MEASUREMENTS AND MAIN RESULTS: Measurements were averaged over 30 seconds. For each person and sequence, the minimal value was analyzed. Tissue oxygenation in all measurement sites and finger perfusion index were reduced during hypovolemia/sham compared with normovolemia/sham. Tissue oxygen saturation (except cerebral) and perfusion index were reduced by pain during normovolemia. There was a larger reduction in tissue oxygenation (all measurement sites) and perfusion index during hypovolemia and pain than during normovolemia and pain. CONCLUSIONS: Pain (cold pressor test) reduces tissue oxygen saturation in all measurement sites (except cerebral) and perfusion index. In the presence of pain, tissue oxygen saturation and perfusion index are further reduced by hypovolemia (lower body negative pressure, -60 mm Hg). Thus, pain must be considered when evaluating tissue oxygen saturation and perfusion index as markers of hypovolemia in trauma patients. PMID- 25513789 TI - Characteristics and outcomes of patients admitted to ICU following activation of the medical emergency team: impact of introducing a two-tier response system. AB - OBJECTIVE: To determine the impact of introducing a two-tier system for responding to deteriorating ward patients on ICU admissions after medical emergency team review. DESIGN: Retrospective database review before (2006-2009) and after (2011-2013) the introduction of a two-tier system. SETTING: Tertiary, university-affiliated hospital. PATIENTS: A total of 1,564 ICU admissions. INTERVENTIONS: Two-tier rapid response system. MEASUREMENTS AND MAIN RESULTS: The median number of medical emergency team activations/1,000 hospitalizations increased from 22 to 31 (difference [95% CI], 9 [5-10]; p<0.0001) with a decreased rate of medical emergency team activations leading to ICU admission (from median 11 to 8; difference [95% CI], 3 [3-4]; p=0.03). The median proportion of medical emergency team reviews leading to ICU admission increased for those triggered by tachypnoea (from 11% to 15%; difference [95% CI], 4 [3-5]; p<0.0001) and by hypotension (from 27% to 43%; difference [95% CI], 15 [12-19]; p<0.0001) and decreased for those triggered by reduced level of consciousness (from 20% to 17%; difference [95% CI], 3 [2-4]; p<0.0001) and by clinical concern (from 18% to 9%; difference [95% CI], 10 [9-13]; p<0.0001). The proportions of ICU admissions following medical emergency team review did not change significantly for tachycardia, seizure, or cardiorespiratory arrest. The overall ICU mortality for admissions following medical emergency team review for tachypnoea, tachycardia, and clinical concern decreased (from 29% to 9%: difference [95% CI], 20 [11-29]; p<0.0001) but did not change for the other triggers. The Acute Physiology and Chronic Health Evaluation predicted and observed ICU mortality and the proportion of patients dying with a not-for resuscitation order decreased. CONCLUSIONS: The introduction of a two-tier response to clinical deterioration increased ICU admissions triggered by cardiorespiratory criteria, whereas admissions triggered by more subjective criteria decreased. The overall ICU mortality for patients admitted following medical emergency team review decreased, suggesting that the two-tier system led to earlier recognition of reversible pathology or a decision not to escalate the level of care. PMID- 25513788 TI - Elevated plasma-free cortisol concentrations and ratios are associated with increased mortality even in the presence of statin therapy in patients with severe sepsis. AB - BACKGROUND: Dissociation between plasma-free cortisol and total cortisol profiles exists in critical illness. Data on plasma-free cortisol are based on either calculated values or immunoassay-based measurements. Both have significant limitations. Statins have been advocated as a therapy in sepsis. Whether they impact on plasma cortisol through inhibition of cholesterol synthesis is unclear. OBJECTIVES: In patients enrolled into a randomized trial of statins in sepsis (n = 250), we examined the association of mass spectrometry measured plasma-free cortisol, plasma-free cortisol/plasma total cortisol ratios, and outcome and the impact of concomitant statin therapy on cortisol profiles in 80 steroid naive patients. PATIENTS: Two hundred twenty serial measurements of plasma-free cortisol, plasma total cortisol, and interleukin-6 were collected from 80 patients (43 placebo and 37 statins). Data from 10 volunteers were used as controls. MEASUREMENTS AND MAIN RESULTS: Data are presented as median and interquartile range. Compared with controls, in severe sepsis, baseline plasma total cortisol was elevated two-fold (463 nmol/L [284-742 nmol/L] vs 245 nmol/L [200-299 nmol/L], p < 0.001), plasma-free cortisol 20-fold (75 nmol/L [20-151 nmol/L] vs 5 nmol/L [5-7 nmol/L], p < 0.001), and plasma-free cortisol/plasma total cortisol ratio six-fold (0.15 vs 0.02, p = 0.058). Baseline interleukin-6 was elevated at 121 pg/mL (65-611 pg/mL). In severe sepsis, there were no differences in plasma total cortisol (p = 0.66), plasma-free cortisol (p = 0.77), and interleukin-6 (p = 0.29) between statins and placebo groups. Plasma-free cortisol, plasma total cortisol, and plasma-free cortisol/plasma total cortisol were positively correlated with interleukin-6 (p = 0.0001, p < 0.0004, and p < 0.001, respectively) and day 90 mortality (p = 0.03, p = 0.03, and p = 0.058, respectively). Elevated plasma-free cortisol/plasma total cortisol ratios were associated with increased length of stay (p = 0.04). Baseline plasma-free cortisol, plasma total cortisol, and plasma-free cortisol/plasma total cortisol ratios were higher in nonsurvivors as compared with survivors (174 nmol/L [77-329 nmol/L] vs 57 nmol/L [17-122 nmol/L], p = 0.016; 890 nmol/L [333-1,430 nmol/L] vs 408 nmol/L [269-681 nmol/L], p = 0.035; and 0.19 [0.13-0.29] vs 0.14 [0.07-0.20]; p = 0.054, respectively). CONCLUSIONS: In severe sepsis, plasma-free cortisol increase is 10-fold greater than that of plasma total cortisol. Both are similarly associated with inflammatory response and mortality. Elevated plasma free cortisol/plasma total cortisol ratios were associated with increased length of stay. Statin therapy does not influence the plasma cortisol profiles in patients with severe sepsis. PMID- 25513790 TI - A recommended integrated mechanism to enhance OSH management of blue-collar foreign workers in Taiwan. AB - This study examines the roles and functions of businesses, labor-exporting countries' representative offices in Taiwan, religious organizations, and manpower agencies in promoting occupational safety and health (OSH). It also offers advice to Taiwanese authorities on making policies and improvements regarding the oversight mechanism mandated by the Labor Safety and Health Act, giving them an idea of what to focus on when enforcing control over blue-collar foreign workers' OSH conditions. This study also proposes that Taiwanese authorities may serve not only as an overseer/inspector of those hiring blue collar foreign workers in Taiwan, but also expand their role to lay down policies regarding a variety of OSH teaching materials in the blue-collar foreign workers' native languages (spoken or written), the qualifications of translators in blue collar foreign workers' OSH training programs, and regulations concerning the longer hours such training programs take. PMID- 25513791 TI - Patients' characteristics and healthcare providers' perceived workload in French hospital emergency wards. AB - The aim of this research is to understand how patients' characteristics increase healthcare providers' perceived workload. Patients' characteristics and dependency, technical and relational complexities of care seem to increase healthcare providers' workload. As workload is multidimensional, we examine which dimensions are affected by patients' characteristics. Our methodology is based on 121 patients assessed with the NASA task load index (NASA-TLX) and a questionnaire filled in by 57 health providers in 2 emergency wards in French hospital settings, to evaluate their attitudes to different patients' characteristics. Our results show that physical demand is the dimension most affected by patients' behaviour and characteristics. Next, we observe that workload increases more due to patients' behaviour than their social characteristics. We propose that a regulation mechanism be taken into account in further research, using methodology based on observations to identify how healthcare providers might adapt their activities to compensate for workload variations caused by patients. PMID- 25513792 TI - Safety culture in high-risk industries. AB - This paper addresses the question of whether adopting safety culture improves hazard prevention in enterprises characterized by high primary risk. To answer this question, sample underground coal mines were examined to investigate the basic elements of the safety culture of employees. This paper presents the results of a diagnosis of the basic elements of the safety culture of supervisors (midlevel managers) and blue-collar workers in 3 underground coal mines. The study used 2 techniques: a Likert-type scale and a questionnaire. The results indicate the need to introduce changes in the safety culture of underground coal mine employees. This study also presents the conditions for improvement. Special attention was paid to (a) the conditions for improving safety culture and (b) a programme for modifying risky behaviours. PMID- 25513793 TI - Evaluation of the toxic potency of selected cadmium compounds on A549 and CHO-9 cells. AB - Cytotoxicity of cadmium sulphide, oxide and chloride was tested using A549 and CHO-9 cells. Metabolic activity of cells (MTT test) and cell membrane permeability (NRU test) were used as cytotoxicity endpoints. The results revealed unexpectedly low toxicity of cadmium sulphide as compared to chloride and oxide. This preliminary report does not provide any explanation for this effect, but the result may nevertheless be interesting for future studies of toxicity mechanisms of cadmium compounds. First cadmium compounds caused damage or change in the permeability of cell membranes, then inhibition of metabolic activity of mitochondria. It cannot be ruled out that the cell lysosomes are at first exposed to the effect of cadmium. PMID- 25513794 TI - Psychometric properties of the Polish version of Karasek's Job Content Questionnaire. AB - AIM: The objective of this study was to test the psychometric properties of selected scales, namely, Decision Latitude, Psychological Job Demand, Social Support and Job Insecurity, from the Polish version of Karasek's 29-item Job Content Questionnaire (JCQ). METHOD: The study covered 2626 workers from a wide range of occupations. Estimation of internal consistency with Cronbach's alpha, and both exploratory factor analysis (with principal axis method) and confirmatory factor analysis were the main statistical methods. Predictive validity was assessed by regressing the outcomes of JCQ scales on the outcomes of Goldberg and Williams's General Health Questionnaire. RESULTS: The internal consistency of the scales was satisfactory, ranging from .60 to .85. The 4 dimensional structure of the measured version was generally confirmed; the 4 dimensions being Decision Latitude; Psychological Job Demands and Job Insecurity merged into 1 factor; Co-workers' Social Support; and Supervisors' Social Support. Fit indexes for this model were satisfactory, it was also proved that this model predicted mental health. CONCLUSIONS: The Polish version of Karasek's 29-item JCQ has satisfactory psychometric properties; it is a short, easy method for assessing psychosocial work conditions. PMID- 25513795 TI - The effects of co-ordinating postures with shoulder and elbow flexion angles on maximum grip strength and upper-limb muscle activity in standing and sitting postures. AB - Eighteen co-ordination postures with shoulder flexion angles (0 degrees , 45 degrees and 90 degrees ) and elbow flexion angles (0 degrees , 45 degrees and 90 degrees ) in standing and sitting positions were evaluated to identify the effects of co-ordination postures on maximum grip strength and muscle activities of the upper limb in this study. Thirty-nine subjects were recruited and their maximum grip strengths were measured. According to the analysis of grip strength, grip strength was shown to be stronger in a standing posture (297.4 N) than in a sitting posture (274.6 N). In addition, grip strength (293.8 N) at 90 degrees shoulder flexion angle was significantly higher than that at 0 degrees and 45 degrees shoulder angles. There was no statistically significant difference in grip strength from the effects of elbow angles in this study. The results of muscle activities for all muscle groups showed a similar trend with the results of grip strength associated with shoulder angles. PMID- 25513796 TI - Chronic musculoskeletal disorders as risk factors for reduced work ability in younger and ageing workers. AB - AIMS: The aim of the study was to assess the occurrence and intensity of musculoskeletal pain as a risk factor for reduced work ability. METHODS: In total, 1449 workers participated in the study, 64% were younger workers (<45 years old, M 31.4); 36% were ageing workers (>=45 years old, M 50.3), Their health condition was established on the basis of (a) subjective feeling of health on a 5-point scale, (b) pain in 6 parts of the body in the past year; and (c) intensity of pain on a 100-mm visual analogue scale (VAS). Work ability was assessed with the subjective work ability index (WAI). RESULTS: The results of the study showed that although in the both groups, i.e., younger and ageing workers, the occurrence and intensity of pain in the hands/wrists, neck and lower back were a significant factor which decreased WAI, in ageing workers only the occurrence of pain in the lower back generated higher risk factors for reduced work ability (WAI < 37). CONCLUSIONS: Improving physical and psychosocial working conditions to reduce musculoskeletal complaints, and identifying individuals with such complaints are important in increasing workers' work ability and thus extending their occupational activity. PMID- 25513797 TI - A quasi-experimental study of the effects of the Erggi action model of musculoskeletal symptoms and VDU working conditions among university staff. AB - PURPOSE: The aim of this study was to investigate musculoskeletal symptoms and working conditions of university workers with and without contact with an Erggi action model. METHODS: A quasi-experimental and longitudinal field study design examined effects of the Erggi action model with 3 types of questionnaires filled by 1000 university workers. The statistical analyses used logistic regression. RESULTS: Subjects who had contact with the Erggi action model had a higher probability of weekly musculoskeletal symptoms impairing their work, perceived more possibilities to influence their musculoskeletal symptoms and had lower risk for sick leave compared to those without contact with the Erggi action model. CONCLUSIONS: The Erggi action model increases the probability of influencing workers' musculoskeletal symptoms, decreases the number of sick leave and increases awareness of musculoskeletal symptoms and working conditions. PMID- 25513798 TI - The use of a global index of acoustic assessment for predicting noise in industrial rooms and optimizing the location of machinery and workstations. AB - This paper describes the results of a study aimed at developing a tool for optimizing the location of machinery and workstations. A global index of acoustic assessment of machines was developed for this purpose. This index and a genetic algorithm were used in a computer tool for predicting noise emission of machines as well as optimizing the location of machines and workstations in industrial rooms. The results of laboratory and simulation tests demonstrate that the developed global index and the genetic algorithm support measures aimed at noise reduction at workstations. PMID- 25513799 TI - Occupational exposure to natural UV radiation and premature skin ageing. AB - The skin is the part of the human body most vulnerable to ultraviolet (UV) radiation. The spectrum of the negative effects of UV radiation on the skin ranges from acute erythema to carcinogenesis. Between these extreme conditions, there are other common skin lesions, e.g., photoageing. The aim of this study was to assess the skin for signs of photoageing in a group of 52 men occupationally exposed to natural UV radiation. There were 2 types of examinations: an examination of skin condition (moisture, elasticity, sebum, porosity, smoothness, discolourations and wrinkles) with a device for diagnosing the skin, and a dermatological examination. The results of both examinations revealed a higher percentage of skin characteristics typical for photoageing in outdoor workers compared to the general population. PMID- 25513800 TI - A body characteristic index to evaluate the level of risk of heat strain for a group of workers with a test. AB - The purpose of this study was to develop a body characteristic index (BCI) based on the distribution of maximal oxygen uptake per body mass (VO2max/mass), body surface area per body mass (BSA/mass), and percentage of body fat (Fat%) to evaluate the relative level of individual physiological responses to heat strain in a group of workers. BCI was based upon the data obtained from 10 males and 10 females exercising for 60 min on a treadmill at 2 relative exercise intensities of 25% and 45% VO2max in mild, warm wet, and hot dry climate condition, separately. BCI was developed into 2 formulas, which were proved to be better predictors for heat strain responses than each individual characteristic, and more sensitive than body type to describe the distributions of individual characteristics and distinguish the differences in physiological responses to heat. PMID- 25513801 TI - Noise pollution in metalwork and woodwork industries in the Kingdom of Saudi Arabia. AB - This study was conducted in metalwork and woodwork industries in Jeddah Industrial Estate. The purpose of this study was to assess the magnitude of industrial noise exposure and to propose remedial actions. Noise was measured at different times of a day in 28 randomly selected factories and workshops. Results indicated that noise levels varied according to the type and size of a factory, and the type and number of machines used. Mean noise levels in metalwork factories were higher than those in woodwork factories. The highest noise levels were observed while manufacturing cans and forming steel reinforcement for concrete, where noise levels exceed 90 dB(A). All mean noise levels in all studied metalwork factories and in 50% of studied woodwork industries were higher than the standard level of 85 dB(A). PMID- 25513802 TI - Musculoskeletal disorders and working conditions among Iranian nursing personnel. AB - This study investigated the prevalence of musculoskeletal disorders (MSDs) and associations with organizational, physical and psychosocial working conditions among 520 nursing personnel in Tehran, Iran. The results of the cross-sectional study on aids and different educational levels of nurses showed that the participants experienced 88% of MSDs in at least one body region during the past 12 months. The 3 most prevalent body regions were the low back (65.3%), knee (56.2%) and neck (49.8%). The participants reported inflexible work schedule, poor quality of devices for transferring patients, overexertion and job dissatisfaction. Physical and psychosocial exposure revealed an elevated odds ratio (95% confidence interval) of MSDs. The results showed a combination of high physical and psychosocial work demands along with low control over the work which increased work-related stress and enhanced the risk of MSDs. This study findings could help to understand work-related MSDs among nursing personnel in a developing country where the work situation and sociocultural context differ from other countries. PMID- 25513804 TI - [The reasons for a snub--the invitation that was never sent to be part of the reform of private health insurance in Chile]. PMID- 25513803 TI - ApoD mediates binding of HDL to LDL and to growing T24 carcinoma. AB - Apolipoprotein (Apo) D is an important protein produced in many parts of the body. It is necessary for the development and repair of the brain and protection from oxidative stress. The purpose of this study was to investigate the extent to which apoD interacts with lipoproteins in human plasma. By using detergent-free ELISA, we show that immobilized monoclonal antibodies against apoD very efficiently bind to low density lipoprotein (LDL) from plasma; this binding is as equally efficient as binding to an anti-apoB monoclonal antibody. Adding detergent to the plasma inhibited the binding, suggesting that the binding is dependent on the presence of intact lipoprotein particles. Reversing the system by using immobilized anti-apoB revealed that the affinity of apoD for LDL is rather low, suggesting that multiple bindings are needed for a durable connection. Biosensor experiments using purified lipoproteins also showed that purified apoD and high density lipoprotein 3 (HDL3), a lipoprotein fraction rich in apoD, were both able to bind LDL very efficiently, indicating that the HDL3 LDL interaction may be a physiological consequence of the affinity of apoD for LDL. Furthermore, we found that apoD increases the binding of HDL to actively growing T24 bladder carcinoma cells but not to quiescent, contact-inhibited, confluent T24 cells. This result is especially intriguing given that the T24 supernatant only contained detectable levels of apoD after growth inhibition, raising the possibility that alternating the expression of apoD and a putative apoD-receptor could give direction to the flow of lipids. In the current paper, we conclude that apoD mediates binding of HDL to LDL and to growing T24 carcinomas, thereby highlighting the importance of apoD in lipid metabolism. PMID- 25513805 TI - Reply to the comments by Cucuianu A, et al. on 'Chronic granulomatous dermatosis as a presenting sign of cutaneous T-cell lymphomas'. PMID- 25513806 TI - Whiteboards and discharge traffic lights: visual management in acute care. AB - Flinders Medical Centre was experiencing issues with timely discharge and knowing the potential discharges and in-patient bed capacity for the next day. This case study describes the application of 'visual management' theory to discharge processes. The solutions developed were 'patient journey boards' and 'discharge traffic lights'. The implementation of these visual management systems has enabled the hospital to improve its discharge processes. PMID- 25513808 TI - The contribution of nearshore fish aggregating devices (FADs) to food security and livelihoods in Solomon Islands. AB - Fish aggregating devices, or FADs, are used widely in developing countries to concentrate pelagic fish, making them easier to catch. Nearshore FADs anchored close to the coast allow access for rural communities, but despite their popularity among policy makers, there is a dearth of empirical analysis of their contributions to the supply of fish and to fisheries management. In this paper we demonstrate that nearshore FADs increased the supply of fish to four communities in Solomon Islands. Estimated total annual fish catch ranged from 4300 to 12,000 kg across the study villages, with nearshore FADs contributing up to 45% of the catch. While it is clear that FADs increased the supply of fish, FAD catch rates were not consistently higher than other fishing grounds. Villages with limited access to diverse or productive fishing grounds seemingly utilized FADs to better effect. Villagers believed FADs increased household income and nutrition, as well as providing a source of fish for community events. FADs were also perceived to increase intra-household conflict and reduce fishers' participation in community activities. FADs need to be placed within a broader rural development context and treated as another component in the diversified livelihoods of rural people; as with other livelihood options they bring trade-offs and risks. PMID- 25513809 TI - Construction and analyses of human large-scale tissue specific networks. AB - Construction and analyses of tissue specific networks is crucial to unveil the function and organizational structure of biological systems. As a direct method to detect protein dynamics, human proteome-wide expression data provide an valuable resource to investigate the tissue specificity of proteins and interactions. By integrating protein expression data with large-scale interaction network, we constructed 30 tissue/cell specific networks in human and analyzed their properties and functions. Rather than the tissue specificity of proteins, we mainly focused on the tissue specificity of interactions to distill tissue specific networks. Through comparing our tissue specific networks with those inferred from gene expression data, we found our networks have larger scales and higher reliability. Furthermore, we investigated the similar extent of multiple tissue specific networks, which proved that tissues with similar functions tend to contain more common interactions. Finally, we found that the tissue specific networks differed from the static network in multiple topological properties. The proteins in tissue specific networks are interacting looser and the hubs play more important roles than those in the static network. PMID- 25513807 TI - Home-based versus mobile clinic HIV testing and counseling in rural Lesotho: a cluster-randomized trial. AB - BACKGROUND: The success of HIV programs relies on widely accessible HIV testing and counseling (HTC) services at health facilities as well as in the community. Home-based HTC (HB-HTC) is a popular community-based approach to reach persons who do not test at health facilities. Data comparing HB-HTC to other community based HTC approaches are very limited. This trial compares HB-HTC to mobile clinic HTC (MC-HTC). METHODS AND FINDINGS: The trial was powered to test the hypothesis of higher HTC uptake in HB-HTC campaigns than in MC-HTC campaigns. Twelve clusters were randomly allocated to HB-HTC or MC-HTC. The six clusters in the HB-HTC group received 30 1-d multi-disease campaigns (five villages per cluster) that delivered services by going door-to-door, whereas the six clusters in MC-HTC group received campaigns involving community gatherings in the 30 villages with subsequent service provision in mobile clinics. Time allocation and human resources were standardized and equal in both groups. All individuals accessing the campaigns with unknown HIV status or whose last HIV test was >12 wk ago and was negative were eligible. All outcomes were assessed at the individual level. Statistical analysis used multivariable logistic regression. Odds ratios and p-values were adjusted for gender, age, and cluster effect. Out of 3,197 participants from the 12 clusters, 2,563 (80.2%) were eligible (HB-HTC: 1,171; MC HTC: 1,392). The results for the primary outcomes were as follows. Overall HTC uptake was higher in the HB-HTC group than in the MC-HTC group (92.5% versus 86.7%; adjusted odds ratio [aOR]: 2.06; 95% CI: 1.18-3.60; p = 0. 011). Among adolescents and adults >= 12 y, HTC uptake did not differ significantly between the two groups; however, in children <12 y, HTC uptake was higher in the HB-HTC arm (87.5% versus 58.7%; aOR: 4.91; 95% CI: 2.41-10.0; p<0.001). Out of those who took up HTC, 114 (4.9%) tested HIV-positive, 39 (3.6%) in the HB-HTC arm and 75 (6.2%) in the MC-HTC arm (aOR: 0.64; 95% CI: 0.48-0.86; p = 0.002). Ten (25.6%) and 19 (25.3%) individuals in the HB-HTC and in the MC-HTC arms, respectively, linked to HIV care within 1 mo after testing positive. Findings for secondary outcomes were as follows: HB-HTC reached more first-time testers, particularly among adolescents and young adults, and had a higher proportion of men among participants. However, after adjusting for clustering, the difference in male participation was not significant anymore. Age distribution among participants and immunological and clinical stages among persons newly diagnosed HIV-positive did not differ significantly between the two groups. Major study limitations included the campaigns' restriction to weekdays and a relatively low HIV prevalence among participants, the latter indicating that both arms may have reached an underexposed population. CONCLUSIONS: This study demonstrates that both HB-HTC and MC-HTC can achieve high uptake of HTC. The choice between these two community-based strategies will depend on the objective of the activity: HB HTC was better in reaching children, individuals who had never tested before, and men, while MC-HTC detected more new HIV infections. The low rate of linkage to care after a positive HIV test warrants future consideration of combining community-based HTC approaches with strategies to improve linkage to care for persons who test HIV-positive. TRIAL REGISTRATION: ClinicalTrials.gov NCT01459120. Please see later in the article for the Editors' Summary. PMID- 25513810 TI - The association between body mass index and mortality in incident dialysis patients. AB - OBJECTIVES: To study the body mass index (BMI) trajectory in patients with incident end-stage kidney disease and its association with all-cause mortality. METHODS: This longitudinal cohort study included 17022 adult patients commencing hemodialysis [HD] (n = 10860) or peritoneal dialysis [PD] (n = 6162) between 2001 and 2008 and had >=6-month follow-up and >=2 weight measurements, using the Australia and New Zealand Dialysis and Transplant Registry data. The association of time-varying BMI with all-cause mortality was explored using multivariate Cox regression models. RESULTS: The median follow-up was 2.3 years. There was a non linear change in the mean BMI (kg/m2) over time, with an initial decrease from 27.6 (95% confidence interval [CI]: 27.5, 27.7) to 26.7 (95% CI: 26.6, 26.9) at 3 month, followed by increments to 27.1 (95% CI: 27, 27.2) at 1-year and 27.2 (95% CI: 26.8, 27.1) at 3-year, and a gradual decrease subsequently. The BMI trajectory was significantly lower in HD patients who died than those who survived, although this pattern was not observed in PD patients. Compared to the reference time-varying BMI category of 25.1-28 kg/m2, the mortality risks of both HD and PD patients were greater in all categories of time-varying BMI <25 kg/m2. The mortality risks were significantly lower in all categories of time-varying BMI >28.1 kg/m2 among HD patients, but only in the category 28.1-31 kg/m2 among PD patients. CONCLUSIONS: BMI changed over time in a non-linear fashion in incident dialysis patients. Time-varying measures of BMI were significantly associated with mortality risk in both HD and PD patients. PMID- 25513814 TI - Arsenite-induced pseudo-hypoxia results in loss of anchorage-dependent growth in BEAS-2B pulmonary epithelial cells. AB - Epidemiology studies have established a strong link between lung cancer and arsenic exposure. Currently, the role of disturbed cellular energy metabolism in carcinogenesis is a focus of scientific interest. Hypoxia inducible factor-1 alpha (HIF-1A) is a key regulator of energy metabolism, and it has been found to accumulate during arsenite exposure under oxygen-replete conditions. We modeled arsenic-exposed human pulmonary epithelial cells in vitro with BEAS-2B, a non malignant lung epithelial cell line. Constant exposure to 1 uM arsenite (As) resulted in the early loss of anchorage-dependent growth, measured by soft agar colony formation, beginning at 6 weeks of exposure. This arsenite exposure resulted in HIF-1A accumulation and increased glycolysis, similar to the physiologic response to hypoxia, but in this case under oxygen-replete conditions. This "pseudo-hypoxia" response was necessary for the maximal acquisition of anchorage-independent growth in arsenite-exposed BEAS-2B. The HIF 1A accumulation and induction in glycolysis was sustained throughout a 52 week course of arsenite exposure in BEAS-2B. There was a time-dependent increase in anchorage-independent growth during the exposure to arsenite. When HIF-1A expression was stably suppressed, arsenite-induced glycolysis was abrogated, and the anchorage-independent growth was reduced. These findings establish that arsenite exerts a hypoxia-mimetic effect, which plays an important role in the subsequent gain of malignancy-associated phenotypes. PMID- 25513813 TI - Testing an mHealth momentary assessment Routine Outcome Monitoring application: a focus on restoration of daily life positive mood states. AB - BACKGROUND: Routine Outcome Monitoring (ROM) is used as a means to enrich the process of treatment with feedback on patient outcomes, facilitating patient involvement and shared decision making. While traditional ROM measures focus on retrospective accounts of symptoms, novel mHealth technology makes it possible to collect real life, in-the-moment ambulatory data that allow for an ecologically valid assessment of personalized and contextualized emotional and behavioural adjustment in the flow daily life (mROM). METHOD: In a sample of 34 patients with major depressive disorder, treated with antidepressants, the combined effect of treatment and natural course was examined over a period of 18 weeks with Ecological Momentary Assessment (EMA). EMA consisted of repeated, within-subject, mini-measurements of experience (eg positive affect, negative affect, medication side effects) and context (eg stressors, situations, activities) at 10 unselected semi-random moments per day, for a period of six days, repeated three times over the 18-week period (baseline, week 6 and week 18). RESULTS: EMA measures of emotional and behavioural adjustment were sensitive to the effects of treatment and natural course over the 18-week period, particularly EMA measures focussing on positive mood states and the ability to use natural rewards (impact of positive events on positive mood states), with standardized effect sizes of 0.4 0.5. EMA measures of activities, social interaction, stress-sensitivity and negative mood states were also sensitive to change over time. CONCLUSION: This study supports the use of mROM as a means to involve the patient in the process of needs assessment and treatment. EMA data are meaningful to the patient, as they reflect daily life circumstances. Assessment of treatment response with mROM data allows for an interpretation of the effect of treatment at the level of daily life emotional and social adjustment--as an index of health, obviating the need for an exclusive focus on traditional measures of 'sickness'. PMID- 25513816 TI - Autophagy and ubiquitin-mediated proteolysis may not be involved in the degradation of spermatozoon mitochondria in mouse and porcine early embryos. AB - The mitochondrial genome is maternally inherited in animals, despite the fact that paternal mitochondria enter oocytes during fertilization. Autophagy and ubiquitin-mediated degradation are responsible for the elimination of paternal mitochondria in Caenorhabditis elegans; however, the involvement of these two processes in the degradation of paternal mitochondria in mammals is not well understood. We investigated the localization patterns of light chain 3 (LC3) and ubiquitin in mouse and porcine embryos during preimplantation development. We found that LC3 and ubiquitin localized to the spermatozoon midpiece at 3 h post fertilization, and that both proteins were colocalized with paternal mitochondria and removed upon fertilization during the 4-cell stage in mouse and the zygote stage in porcine embryos. Sporadic paternal mitochondria were present beyond the morula stage in the mouse, and paternal mitochondria were restricted to one blastomere of 4-cell embryos. An autophagy inhibitor, 3-methyladenine (3-MA), did not affect the distribution of paternal mitochondria compared with the positive control, while an autophagy inducer, rapamycin, accelerated the removal of paternal mitochondria compared with the control. After the intracytoplasmic injection of intact spermatozoon into mouse oocytes, LC3 and ubiquitin localized to the spermatozoon midpiece, but remnants of undegraded paternal mitochondria were retained until the blastocyst stage. Our results show that paternal mitochondria colocalize with autophagy receptors and ubiquitin and are removed after in vitro fertilization, but some remnants of sperm mitochondrial sheath may persist up to morula stage after intracytoplasmic spermatozoon injection (ICSI). PMID- 25513815 TI - Unprecedented therapeutic potential with a combination of A2A/NR2B receptor antagonists as observed in the 6-OHDA lesioned rat model of Parkinson's disease. AB - In Parkinson's disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy) or with (add-on therapy) the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch 58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant + Radiprodil; Istradefylline + Co-101244. Animals given monotherapy were assessed on distance traveled and rearing, whereas those given add-on therapy were assessed on contralateral rotations. Three-way mixed ANOVA were conducted to assess the main effect of each drug separately and to determine whether any interaction between two drugs was additive or synergistic. Additional post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Motor activity improved significantly and was sustained for longer when the drugs were given in combination than when administered separately at the same dose. Similarly, when tested as add-on treatment to L-Dopa, the combinations resulted in higher levels of contralateral rotation in comparison to the single drugs. Of special interest, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. The combined administration of A2A/NR2B-receptor antagonists improved motor behaviour in 6-OHDA rats. Given the proven translatability of this model such a combination may be expected to be effective in improving motor symptoms in patients. PMID- 25513817 TI - Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth. AB - Loss of Foxc1 is associated with Dandy-Walker malformation, the most common human cerebellar malformation characterized by cerebellar hypoplasia and an enlarged posterior fossa and fourth ventricle. Although expressed in the mouse posterior fossa mesenchyme, loss of Foxc1 non-autonomously induces a rapid and devastating decrease in embryonic cerebellar ventricular zone radial glial proliferation and concurrent increase in cerebellar neuronal differentiation. Subsequent migration of cerebellar neurons is disrupted, associated with disordered radial glial morphology. In vitro, SDF1alpha, a direct Foxc1 target also expressed in the head mesenchyme, acts as a cerebellar radial glial mitogen and a chemoattractant for nascent Purkinje cells. Its receptor, Cxcr4, is expressed in cerebellar radial glial cells and conditional Cxcr4 ablation with Nes-Cre mimics the Foxc1-/- cerebellar phenotype. SDF1alpha also rescues the Foxc1-/- phenotype. Our data emphasizes that the head mesenchyme exerts a considerable influence on early embryonic brain development and its disruption contributes to neurodevelopmental disorders in humans. PMID- 25513818 TI - Cerebral white matter integrity during primary HIV infection. AB - OBJECTIVE: Inflammation and infection within the central nervous system is initiated during primary HIV infection (PHI), but the association of these processes with the integrity of brain white matter during PHI is unknown. DESIGN: We used diffusion tensor imaging (DTI) in this prospective cross-sectional neuroimaging study to determine the extent of white matter involvement in early HIV infection. METHODS: Antiretroviral-naive PHI (defined as <1 year after infection, n = 62), chronic HIV infection (CHI, n = 16), and HIV-uninfected (n = 19) participants had DTI, laboratory, and neuropsychometric performance assessments. DTI metrics were examined using region of interest and whole brain voxelwise analyses. Linear mixed-effects models assessed correlations between DTI measures and laboratory and neuropsychometric performance values. RESULTS: PHI participants were assessed at a median 4.1 months after estimated infection, and had median CD4 cell count of 573 cells/MUl, and HIV-1 RNA viral load of 4.5 log10 copies/ml in plasma and 2.6 log10 copies/ml in cerebrospinal fluid (CSF). DTI metrics in PHI individuals were similar to HIV- participants and correlated with disruptions in the blood-brain barrier (indicated by CSF/plasma albumin ratio and CSF protein). CHI participants had significant loss of white matter integrity that correlated with biomarkers of infection and inflammation (blood viral load, CD4 T-cell count, and neopterin, and CSF white blood cell). Within the PHI group, DTI metrics inversely correlated with increasing days since infection. CONCLUSION: In individuals assessed during PHI, group DTI measures suggested relative preservation of white matter microstructural integrity, but were associated with disruption of the blood-brain barrier and estimated duration of infection. PMID- 25513820 TI - Analysis of radio wave propagation for ISM 2.4 GHz Wireless Sensor Networks in inhomogeneous vegetation environments. AB - The use of wireless networks has experienced exponential growth due to the improvements in terms of battery life and low consumption of the devices. However, it is compulsory to conduct previous radio propagation analysis when deploying a wireless sensor network. These studies are necessary to perform an estimation of the range coverage, in order to optimize the distance between devices in an actual network deployment. In this work, the radio channel characterization for ISM 2.4 GHz Wireless Sensor Networks (WSNs) in an inhomogeneous vegetation environment has been analyzed. This analysis allows designing environment monitoring tools based on ZigBee and WiFi where WSN and smartphones cooperate, providing rich and customized monitoring information to users in a friendly manner. The impact of topology as well as morphology of the environment is assessed by means of an in-house developed 3D Ray Launching code, to emulate the realistic operation in the framework of the scenario. Experimental results gathered from a measurement campaign conducted by deploying a ZigBee Wireless Sensor Network, are analyzed and compared with simulations in this paper. The scenario where this network is intended to operate is a combination of buildings and diverse vegetation species. To gain insight in the effects of radio propagation, a simplified vegetation model has been developed, considering the material parameters and simplified geometry embedded in the simulation scenario. An initial location-based application has been implemented in a real scenario, to test the functionality within a context aware scenario. The use of deterministic tools can aid to know the impact of the topological influence in the deployment of the optimal Wireless Sensor Network in terms of capacity, coverage and energy consumption, making the use of these systems attractive for multiple applications in inhomogeneous vegetation environments. PMID- 25513821 TI - Mobile phone middleware architecture for energy and context awareness in location based services. AB - The disruptive innovation of smartphone technology has enabled the development of mobile sensing applications leveraged on specialized sensors embedded in the device. These novel mobile phone applications rely on advanced sensor information processes, which mainly involve raw data acquisition, feature extraction, data interpretation and transmission. However, the continuous accessing of sensing resources to acquire sensor data in smartphones is still very expensive in terms of energy, particularly due to the periodic use of power-intensive sensors, such as the Global Positioning System (GPS) receiver. The key underlying idea to design energy-efficient schemes is to control the duty cycle of the GPS receiver. However, adapting the sensing rate based on dynamic context changes through a flexible middleware has received little attention in the literature. In this paper, we propose a novel modular middleware architecture and runtime environment to directly interface with application programming interfaces (APIs) and embedded sensors in order to manage the duty cycle process based on energy and context aspects. The proposed solution has been implemented in the Android software stack. It allows continuous location tracking in a timely manner and in a transparent way to the user. It also enables the deployment of sensing policies to appropriately control the sampling rate based on both energy and perceived context. We validate the proposed solution taking into account a reference location-based service (LBS) architecture. A cloud-based storage service along with online mobility analysis tools have been used to store and access sensed data. Experimental measurements demonstrate the feasibility and efficiency of our middleware, in terms of energy and location resolution. PMID- 25513819 TI - Comparing genotoxic signatures in cord blood cells from neonates exposed in utero to zidovudine or tenofovir. AB - OBJECTIVES: Zidovudine and tenofovir are the two main nucleos(t)ide analogs used to prevent mother-to-child transmission of HIV. In vitro, both drugs bind to and integrate into human DNA and inhibit telomerase. The objective of the present study was to assess the genotoxic effects of either zidovudine or tenofovir-based combination therapies on cord blood cells in newborns exposed in utero. DESIGN: We compared the aneuploid rate and the gene expression profiles in cord blood samples from newborns exposed either to zidovudine or tenofovir-based combination therapies during pregnancy and from unexposed controls (n = 8, 9, and 8, respectively). METHODS: The aneuploidy rate was measured on the cord blood T-cell karyotype. Gene expression profiles of cord blood T cells and hematopoietic stem and progenitor cells were determined with microarrays, analyzed in a gene set enrichment analysis and confirmed by real-time quantitative PCRs. RESULTS: Aneuploidy was more frequent in the zidovudine-exposed group (26.3%) than in the tenofovir-exposed group (14.2%) or in controls (13.3%; P < 0.05 for both). The transcription of genes involved in DNA repair, telomere maintenance, nucleotide metabolism, DNA/RNA synthesis, and the cell cycle was deregulated in samples from both the zidovudine and the tenofovir-exposed groups. CONCLUSION: Although tenofovir has a lower clastogenic impact than zidovudine, gene expression profiling showed that both drugs alter the transcription of DNA repair and telomere maintenance genes. PMID- 25513822 TI - Deployment-based lifetime optimization model for homogeneous Wireless Sensor Network under retransmission. AB - Sensor-deployment-based lifetime optimization is one of the most effective methods used to prolong the lifetime of Wireless Sensor Network (WSN) by reducing the distance-sensitive energy consumption. In this paper, data retransmission, a major consumption factor that is usually neglected in the previous work, is considered. For a homogeneous WSN, monitoring a circular target area with a centered base station, a sensor deployment model based on regular hexagonal grids is analyzed. To maximize the WSN lifetime, optimization models for both uniform and non-uniform deployment schemes are proposed by constraining on coverage, connectivity and success transmission rate. Based on the data transmission analysis in a data gathering cycle, the WSN lifetime in the model can be obtained through quantifying the energy consumption at each sensor location. The results of case studies show that it is meaningful to consider data retransmission in the lifetime optimization. In particular, our investigations indicate that, with the same lifetime requirement, the number of sensors needed in a non-uniform topology is much less than that in a uniform one. Finally, compared with a random scheme, simulation results further verify the advantage of our deployment model. PMID- 25513823 TI - Piezoelectric bimorphs' characteristics as in-socket sensors for transfemoral amputees. AB - Alternative sensory systems for the development of prosthetic knees are being increasingly highlighted nowadays, due to the rapid advancements in the field of lower limb prosthetics. This study presents the use of piezoelectric bimorphs as in-socket sensors for transfemoral amputees. An Instron machine was used in the calibration procedure and the corresponding output data were further analyzed to determine the static and dynamic characteristics of the piezoelectric bimorph. The piezoelectric bimorph showed appropriate static operating range, repeatability, hysteresis, and frequency response for application in lower prosthesis, with a force range of 0-100 N. To further validate this finding, an experiment was conducted with a single transfemoral amputee subject to measure the stump/socket pressure using the piezoelectric bimorph embedded inside the socket. The results showed that a maximum interface pressure of about 27 kPa occurred at the anterior proximal site compared to the anterior distal and posterior sites, consistent with values published in other studies. This paper highlighted the capacity of piezoelectric bimorphs to perform as in-socket sensors for transfemoral amputees. However, further experiments are recommended to be conducted with different amputees with different socket types. PMID- 25513824 TI - Freshness-preserving non-interactive hierarchical key agreement protocol over WHMS. AB - The digitization of patient health information (PHI) for wireless health monitoring systems (WHMSs) has brought many benefits and challenges for both patients and physicians. However, security, privacy and robustness have remained important challenges for WHMSs. Since the patient's PHI is sensitive and the communication channel, i.e., the Internet, is insecure, it is important to protect them against unauthorized entities, i.e., attackers. Otherwise, failure to do so will not only lead to the compromise of a patient's privacy, but will also put his/her life at risk. This paper proposes a freshness-preserving non interactive hierarchical key agreement protocol (FNKAP) for WHMSs. The FNKAP is based on the concept of the non-interactive identity-based key agreement for communication efficiency. It achieves patient anonymity between a patient and physician, session key secrecy and resistance against various security attacks, especially including replay attacks. PMID- 25513825 TI - Soft, comfortable polymer dry electrodes for high quality ECG and EEG recording. AB - Conventional gel electrodes are widely used for biopotential measurements, despite important drawbacks such as skin irritation, long set-up time and uncomfortable removal. Recently introduced dry electrodes with rigid metal pins overcome most of these problems; however, their rigidity causes discomfort and pain. This paper presents dry electrodes offering high user comfort, since they are fabricated from EPDM rubber containing various additives for optimum conductivity, flexibility and ease of fabrication. The electrode impedance is measured on phantoms and human skin. After optimization of the polymer composition, the skin-electrode impedance is only ~10 times larger than that of gel electrodes. Therefore, these electrodes are directly capable of recording strong biopotential signals such as ECG while for low-amplitude signals such as EEG, the electrodes need to be coupled with an active circuit. EEG recordings using active polymer electrodes connected to a clinical EEG system show very promising results: alpha waves can be clearly observed when subjects close their eyes, and correlation and coherence analyses reveal high similarity between dry and gel electrode signals. Moreover, all subjects reported that our polymer electrodes did not cause discomfort. Hence, the polymer-based dry electrodes are promising alternatives to either rigid dry electrodes or conventional gel electrodes. PMID- 25513826 TI - A Vondrak low pass filter for IMU sensor initial alignment on a disturbed base. AB - The initial alignment of the Inertial Measurement Unit (IMU) is an important process of INS to determine the coordinate transformation matrix which is used in the integration of Global Positioning Systems (GPS) with Inertial Navigation Systems (INS). In this paper a novel alignment method for a disturbed base, such as a vehicle disturbed by wind outdoors, implemented with the aid of a Vondrak low pass filter, is proposed. The basic principle of initial alignment including coarse alignment and fine alignment is introduced first. The spectral analysis is processed to compare the differences between the characteristic error of INS force observation on a stationary base and on disturbed bases. In order to reduce the high frequency noise in the force observation more accurately and more easily, a Vondrak low pass filter is constructed based on the spectral analysis result. The genetic algorithms method is introduced to choose the smoothing factor in the Vondrak filter and the corresponding objective condition is built. The architecture of the proposed alignment method with the Vondrak low pass filter is shown. Furthermore, simulated experiments and actual experiments were performed to validate the new algorithm. The results indicate that, compared with the conventional alignment method, the Vondrak filter could eliminate the high frequency noise in the force observation and the proposed alignment method could improve the attitude accuracy. At the same time, only one parameter needs to be set, which makes the proposed method easier to implement than other low-pass filter methods. PMID- 25513828 TI - Self-assembly formation of lipid bilayer coatings on bare aluminum oxide: overcoming the force of interfacial water. AB - Widely used in catalysis and biosensing applications, aluminum oxide has become popular for surface functionalization with biological macromolecules, including lipid bilayer coatings. However, it is difficult to form supported lipid bilayers on aluminum oxide, and current methods require covalent surface modification, which masks the interfacial properties of aluminum oxide, and/or complex fabrication techniques with specific conditions. Herein, we addressed this issue by identifying simple and robust strategies to form fluidic lipid bilayers on aluminum oxide. The fabrication of a single lipid bilayer coating was achieved by two methods, vesicle fusion under acidic conditions and solvent-assisted lipid bilayer (SALB) formation under near-physiological pH conditions. Importantly, quartz crystal microbalance with dissipation (QCM-D) monitoring measurements determined that the hydration layer of a supported lipid bilayer on aluminum oxide is appreciably thicker than that of a bilayer on silicon oxide. Fluorescence recovery after photobleaching (FRAP) analysis indicated that the diffusion coefficient of lateral lipid mobility was up to 3-fold greater on silicon oxide than on aluminum oxide. In spite of this hydrodynamic coupling, the diffusion coefficient on aluminum oxide, but not silicon oxide, was sensitive to the ionic strength condition. Extended-DLVO model calculations estimated the thermodynamics of lipid-substrate interactions on aluminum oxide and silicon oxide, and predict that the range of the repulsive hydration force is greater on aluminum oxide, which in turn leads to an increased equilibrium separation distance. Hence, while a strong hydration force likely contributes to the difficulty of bilayer fabrication on aluminum oxide, it also confers advantages by stabilizing lipid bilayers with thicker hydration layers due to confined interfacial water. Such knowledge provides the basis for improved surface functionalization strategies on aluminum oxide, underscoring the practical importance of surface hydration. PMID- 25513827 TI - A Phospho-SIM in the Antiviral Protein PML is Required for Its Recruitment to HSV 1 Genomes. AB - Herpes simplex virus type 1 (HSV-1) is a significant human pathogen that infects a large portion of the human population. Cells deploy a variety of defenses to limit the extent to which the virus can replicate. One such factor is the promyelocytic leukemia (PML) protein, the nucleating and organizing factor of nuclear domain 10 (ND10). PML responds to a number of stimuli and is implicated in intrinsic and innate cellular antiviral defenses against HSV-1. While the role of PML in a number of cellular pathways is controlled by post-translational modifications, the effects of phosphorylation on its antiviral activity toward HSV-1 have been largely unexplored. Consequently, we mapped phosphorylation sites on PML, mutated these and other known phosphorylation sites on PML isoform I (PML I), and examined their effects on a number of PML's activities. Our results show that phosphorylation at most sites on PML-I is dispensable for the formation of ND10s and colocalization between PML-I and the HSV-1 regulatory protein, ICP0, which antagonizes PML-I function. However, inhibiting phosphorylation at sites near the SUMO-interaction motif (SIM) of PML-I impairs its ability to respond to HSV-1 infection. Overall, our data suggest that PML phosphorylation regulates its antiviral activity against HSV-1. PMID- 25513829 TI - Residential tap water contamination following the Freedom Industries chemical spill: perceptions, water quality, and health impacts. AB - During January 2014, an industrial solvent contaminated West Virginia's Elk River and 15% of the state population's tap water. A rapid in-home survey and water testing was conducted 2 weeks following the spill to understand resident perceptions, tap water chemical levels, and premise plumbing flushing effectiveness. Water odors were detected in all 10 homes sampled before and after premise plumbing flushing. Survey and medical data indicated flushing caused adverse health impacts. Bench-scale experiments and physiochemical property predictions showed flushing promoted chemical volatilization, and contaminants did not appreciably sorb into cross-linked polyethylene (PEX) pipe. Flushing reduced tap water 4-methylcyclohexanemethanol (4-MCHM) concentrations within some but not all homes. 4-MCHM was detected at unflushed (<10 to 420 MUg/L) and flushed plumbing systems (<10 to 96 MUg/L) and sometimes concentrations differed among faucets within each home. All waters contained less 4-MCHM than the 1000 MUg/L Centers for Disease Control drinking water limit, but one home exceeded the 120 MUg/L drinking water limit established by independent toxicologists. Nearly all households refused to resume water use activities after flushing because of water safety concerns. Science based flushing protocols should be developed to expedite recovery, minimize health impacts, and reduce concentrations in homes when future events occur. PMID- 25513830 TI - Integrated perovskite/bulk-heterojunction toward efficient solar cells. AB - We successfully demonstrated an integrated perovskite/bulk-heterojunction (BHJ) photovoltaic device for efficient light harvesting and energy conversion. Our device efficiently integrated two photovoltaic layers, namely a perovskite film and organic BHJ film, into the device. The device structure is ITO/TiO2/perovskite/BHJ/MoO3/Ag. A wide bandgap small molecule DOR3T-TBDT was used as donor in the BHJ film, and a power conversion efficiency (PCE) of 14.3% was achieved in the integrated device with a high short circuit current density (JSC) of 21.2 mA cm(-2). The higher JSC as compared to that of the traditional perovskite/HTL (hole transporting layer) device (19.3 mA cm(-2)) indicates that the BHJ film absorbs light and contributes to the current density of the device. Our result further suggests that the HTL in traditional perovskite solar cell, even with good light absorption capability, cannot contribute to the overall device photocurrent, unless this HTL becomes a BHJ layer (by adding electron transporting material like PC71BM). PMID- 25513831 TI - Barcoded microchips for biomolecular assays. AB - Multiplexed assay of analytes is of great importance for clinical diagnostics and other analytical applications. Barcode-based bioassays with the ability to encode and decode may realize this goal in a straightforward and consistent manner. We present here a microfluidic barcoded chip containing several sets of microchannels with different widths, imitating the commonly used barcode. A single barcoded microchip can carry out tens of individual protein/nucleic acid assays (encode) and immediately yield all assay results by a portable barcode reader or a smartphone (decode). The applicability of a barcoded microchip is demonstrated by human immunodeficiency virus (HIV) immunoassays for simultaneous detection of three targets (anti-gp41 antibody, anti-gp120 antibody, and anti gp36 antibody) from six human serum samples. We can also determine seven pathogen specific oligonucleotides by a single chip containing both positive and negative controls. PMID- 25513832 TI - Total synthesis of clavilactone B: a radical cyclization-fragmentation strategy. AB - A new synthetic route to clavilactone B, a naturally occurring inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, is disclosed. The route features a sequential samarium-mediated radical cyclization-fragmentation of an indanone derivative, which provides rapid access to a 10-membered carbocyclic motif fused to an aromatic ring. PMID- 25513835 TI - Synthesis and properties study of the uniform nonspherical styrene/methacrylic acid copolymer latex particles. AB - A facile method to prepare the nonspherical amphiphilic random copolymer of poly(styrene-co-methacrylic acid) (poly(St-co-PMAA)) latex particles with well defined shapes and high yields by one-step batch emulsifier-free polymerization was demonstrated. In our strategy, only varying the molar ratio of styrene (St) to methacrylic acid (MAA), no seed-particles, no cross-linker, and no multistep control procedures were needed. Due to the presence of carboxyl groups on the surface of (poly(St-co-PMAA) latex particles, these latex particles can be used as templates for fabricating core-shell nonspherical functional materials, such as poly(St-co-PMAA)@SiO2 and poly(St-co-PMAA)@polypyrrole). The corresponding nonspherical hollow structures (SiO2 and polypyrrole) could be obtained after removal of the templates. In addition, poly(St-co-PMAA) latex particles exhibit interesting morphologies in ethanol. PMID- 25513834 TI - How does tunneling contribute to counterintuitive H-abstraction reactivity of nonheme Fe(IV)O oxidants with alkanes? AB - This article addresses the intriguing hydrogen-abstraction (H-abstraction) and oxygen-transfer (O-transfer) reactivity of a series of nonheme [Fe(IV)(O)(TMC)(Lax)](z+) complexes, with a tetramethyl cyclam ligand and a variable axial ligand (Lax), toward three substrates: 1,4-cyclohexadiene, 9,10 dihydroanthracene, and triphenyl phosphine. Experimentally, O-transfer-reactivity follows the relative electrophilicity of the complexes, whereas the corresponding H-abstraction-reactivity generally increases as the axial ligand becomes a better electron donor, hence exhibiting an antielectrophilic trend. Our theoretical results show that the antielectrophilic trend in H-abstraction is affected by tunneling contributions. Room-temperature tunneling increases with increase of the electron donation power of the axial-ligand, and this reverses the natural electrophilic trend, as revealed through calculations without tunneling, and leads to the observed antielectrophilic trend. By contrast, O-transfer reactivity, not being subject to tunneling, retains an electrophilic-dependent reactivity trend, as revealed experimentally and computationally. Tunneling corrected kinetic-isotope effect (KIE) calculations matched the experimental KIE values only if all of the H-abstraction reactions proceeded on the quintet state (S = 2) surface. As such, the present results corroborate the initially predicted two-state reactivity (TSR) scenario for these reactions. The increase of tunneling with the electron-releasing power of the axial ligand, and the reversal of the "natural" reactivity pattern, support the "tunneling control" hypothesis (Schreiner et al., ref 19). Should these predictions be corroborated, the entire field of C-H bond activation in bioinorganic chemistry would lay open to reinvestigation. PMID- 25513833 TI - Defective hydrophobic sliding mechanism and active site expansion in HIV-1 protease drug resistant variant Gly48Thr/Leu89Met: mechanisms for the loss of saquinavir binding potency. AB - HIV drug resistance continues to emerge; consequently, there is an urgent need to develop next generation antiretroviral therapeutics.1 Here we report on the structural and kinetic effects of an HIV protease drug resistant variant with the double mutations Gly48Thr and Leu89Met (PRG48T/L89M), without the stabilizing mutations Gln7Lys, Leu33Ile, and Leu63Ile. Kinetic analyses reveal that PRG48T/L89M and PRWT share nearly identical Michaelis-Menten parameters; however, PRG48T/L89M exhibits weaker binding for IDV (41-fold), SQV (18-fold), APV (15 fold), and NFV (9-fold) relative to PRWT. A 1.9 A resolution crystal structure was solved for PRG48T/L89M bound with saquinavir (PRG48T/L89M-SQV) and compared to the crystal structure of PRWT bound with saquinavir (PRWT-SQV). PRG48T/L89M SQV has an enlarged active site resulting in the loss of a hydrogen bond in the S3 subsite from Gly48 to P3 of SQV, as well as less favorable hydrophobic packing interactions between P1 Phe of SQV and the S1 subsite. PRG48T/L89M-SQV assumes a more open conformation relative to PRWT-SQV, as illustrated by the downward displacement of the fulcrum and elbows and weaker interatomic flap interactions. We also show that the Leu89Met mutation disrupts the hydrophobic sliding mechanism by causing a redistribution of van der Waals interactions in the hydrophobic core in PRG48T/L89M-SQV. Our mechanism for PRG48T/L89M-SQV drug resistance proposes that a defective hydrophobic sliding mechanism results in modified conformational dynamics of the protease. As a consequence, the protease is unable to achieve a fully closed conformation that results in an expanded active site and weaker inhibitor binding. PMID- 25513836 TI - Synthesis of benzofused five-ring sultams via Rh-catalyzed C-H olefination directed by an N-Ac-substituted sulfonamide group. AB - A Rh-catalyzed N-Ac-sulfonamide group directed C-H olefination-cyclization to afford benzofused five-ring sultam is described with high yield and a wide range of substrate scope. The N-acetyl group is a key for this transformation implying that N-H acidity is the major influence. The acetyl group is removed under mild conditions in excellent yield to provide NH-free sultam that can be transformed into various benzofused five-ring sultam analogues via acylation, nucleophilic substitution, and Mitsunobu alkylation. PMID- 25513837 TI - The cyclopentyl group, as a small but bulky terminal group, allows rapid and efficient active transport. AB - Secondary ammonium salts bearing a cyclopentyl terminal group rapidly formed pseudorotaxane with 1.5 equiv of DB24C8. Acylation of the pseudorotaxane with 50 equiv of benzoyl chloride in the presence of 50 equiv of triethylamine in toluene afforded rotaxane, the product of active transport, in 95% yield. The cyclopentyl group is small enough to allow rapid formation of pseudorotaxane, and bulky enough to facilitate the quantitative active transport by steric repulsion. PMID- 25513838 TI - Resistive switching memory based on bioinspired natural solid polymer electrolytes. AB - A solution-processed, chitosan-based resistive-switching memory device is demonstrated with Pt/Ag-doped chitosan/Ag structure. The memory device shows reproducible and reliable bipolar resistive switching characteristics. A memory device based on natural organic material is a promising device toward the next generation of nonvolatile nanoelectronics. The memory device based on chitosan as a natural solid polymer electrolyte can be switched reproducibly between high and low resistance states. In addition, the data retention measurement confirmed the reliability of the chitosan-based nonvolatile memory device. The transparent Ag embedded chitosan film showed an acceptable and comparable resistive switching behavior on the flexible plastic substrate as well. A cost-effective, environmentally benign memory device using chitosan satisfies the functional requirements of nonvolatile memory operations. PMID- 25513839 TI - Regulation of human mesenchymal stem cell osteogenesis by specific surface density of fibronectin: a gradient study. AB - The success of synthetic bone implants requires good interface between the material and the host tissue. To study the biological relevance of fibronectin (FN) density on the osteogenic commitment of human bone marrow mesenchymal stem cells (hBM-MSCs), human FN was adsorbed in a linear density gradient on the surface of PCL. The evolution of the osteogenic markers alkaline phosphatase and collagen 1 alpha 1 was monitored by immunohistochemistry, and the cytoskeletal organization and the cell-derived FN were assessed. The functional analysis of the gradient revealed that the lower FN-density elicited stronger osteogenic expression and higher cytoskeleton spreading, hallmarks of the stem cell commitment to the osteoblastic lineage. The identification of the optimal FN density regime for the osteogenic commitment of hBM-MSCs presents a simple and versatile strategy to significantly enhance the surface properties of polycaprolactone as a paradigm for other synthetic polymers intended for bone related applications. PMID- 25513840 TI - Proteomics of nitrogen remobilization in poplar bark. AB - Seasonal nitrogen (N) cycling in temperate deciduous trees involves the accumulation of bark storage proteins (BSPs) in phloem parenchyma and xylem ray cells. BSPs are anabolized using recycled N during autumn leaf senescence and later become a source of N during spring shoot growth as they are catabolized. Little is known about the catabolic processes involved in remobilization and reutilization of N from BSPs in trees. In this study, we used multidimensional protein identification technology (MudPIT) and spectral counting to identify protein changes that occur in the bark during BSP catabolism. A total of 4,178 proteins were identified from bark prior to and during BSP catabolism. The majority (62%) of the proteins were found during BSP catabolism, indicating extensive remodeling of the proteome during renewed shoot growth and N remobilization. Among these proteins were 30 proteases, the relative abundances of which increased during BSP catabolism. These proteases spanned a range of families including members of the papain-like cysteine proteases, serine carboxypeptidases, and aspartyl proteases. These data identify, for the first time, candidate proteases that could potentially provide hydrolase activity required for N remobilization from BSPs and provide the foundation for research to advance our knowledge of poplar N cycling. PMID- 25513841 TI - Thermodynamics of small alkali metal halide cluster ions: comparison of classical molecular simulations with experiment and quantum chemistry. AB - We evaluate the ability of selected classical molecular models to describe the thermodynamic and structural aspects of gas-phase hydration of alkali metal halide ions and the formation of small water clusters. To understand the effect of many-body interactions (polarization) and charge penetration effects on the accuracy of a force field, we perform Monte Carlo simulations with three rigid water models using different functional forms to account for these effects: (i) point charge nonpolarizable SPC/E, (ii) Drude point charge polarizable SWM4-DP, and (iii) Drude Gaussian charge polarizable BK3. Model predictions are compared with experimental Gibbs free energies and enthalpies of ion hydration, and with microscopic structural properties obtained from quantum DFT calculations. We find that all three models provide comparable predictions for pure water clusters and cation hydration but differ significantly in their description of anion hydration. None of the investigated classical force fields can consistently and quantitatively reproduce the experimental gas-phase hydration thermodynamics. The outcome of this study highlights the relation between the functional form that describes the effective intermolecular interactions and the accuracy of the resulting ion hydration properties. PMID- 25513842 TI - Needleless electrospinning with twisted wire spinneret. AB - A needleless electrospinning setup named 'Needleless Twisted Wire Electrospinning' was developed. The polymer solution is electrospun from the surface of a twisted wire set to a high voltage and collected on a cylindrical collector around the wire. Multiple Taylor cones are simultaneously self-formed on the downward flowing solution. The system is robust and simple with no moving parts aside from the syringe pump used to transport the solution to the top of the wire. The structure and process parameters of the setup and the results on the preparation of polyvinyl pyrrolidone (PVP), hydroxyapatite (HA) and bioglass fibers with the setup are presented. PVP fiber sheets with areas of 40 * 120 cm(2) and masses up to 1.15 g were prepared. High production rates of 5.23 g h( 1) and 1.40 g h(-1) were achieved for PVP and HA respectively. The major limiting factor of the setup is drying of the polymer solution on the wire during the electrospinning process which will eventually force to interrupt the process for cleaning of the wire. Possible solutions to this problem and other ways to develop the setup are discussed. The presented system provides a simple way to increase the production rate and area of fiber sheet as compared with the conventional needle electrospinning. PMID- 25513845 TI - Development of gene transfer technology. PMID- 25513844 TI - Sex Work and Motherhood: Social and Structural Barriers to Health and Social Services for Pregnant and Parenting Street and Off-Street Sex Workers. AB - Our study documents the correlates of barriers to pregnancy and mothering among sex workers in Vancouver, Canada. We used baseline data from An Evaluation of Sex Workers' Health Access (AESHA), a prospective cohort of sex workers. Among the 399 sex workers who had ever been pregnant or had a child, 35% reported having ever experienced a barrier, with lower education, homelessness, and history of injecting drugs significantly correlated with pregnancy and mothering barriers. Our findings highlight a critical need for tailored and nonjudgmental services and supports, including improved programs to address intersecting aspects of poverty, health literacy, stigma, and substance use. PMID- 25513843 TI - Blocking the maturation of OncomiRNAs using pri-miRNA-17~92 aptamer in retinoblastoma. AB - The miR-17~92. or oncomiR-1, cluster encodes oncogenic microRNAs (miRNAs), and it also promotes retinoblastoma (RB) tumor formation. Antagomir and miRNA mimics based approaches are widely tried against oncogenic and tumor suppressive miRNAs. Other methods for targeting cancer related miRNAs are still under development. In the current study, we focused on the pri-miRNA-17~92 aptamer (pri-apt), which can potentially replace the mix of five antagomirs by one aptamer that function to abrogate the maturation of miR-17, miR-18a, and miR-19b (P<0.05) for targeting RB. We used RB cell lines WERI-Rb1 and Y79 as an in vitro model. Cellular changes upon transfecting the pri-apt led to S-phase arrest in WERI-Rb1 cells and onset of apoptosis in both Y79 and WERI-Rb1 cell lines. There was increased cytotoxicity as measured by lactate dehydrogenase activity in pri-apt treated Y79 cells (P<0.05), and significant inhibition of cell proliferation was observed in both of the cell lines. Thus we showed the antiproliferative property of pri-apt in RB cell lines, which can be readily modified by developing appropriate vectors for the delivery of the aptamer specifically to cancer cells. PMID- 25513849 TI - Job stress and mental health among nonregular workers in Korea: What dimensions of job stress are associated with mental health? AB - Although nonregular workers experience higher job stress, poorer mental health, and different job stress dimensions relative to regular workers, little is known about which job stress dimensions are associated with poor mental health among nonregular workers. This study investigated the association between job stress dimensions and mental health among Korean nonregular workers. Data were collected from 333 nonregular workers in Seoul and Gyeonggi Province, and logistic regression analysis was conducted. Results of the study indicated that high job insecurity and lack of rewards had stronger associations with poor mental health than other dimensions of job stress when controlling for sociodemographic and psychosocial variables. It is important for the government and organizations to improve job security and reward systems to reduce job stress among nonregular workers and ultimately alleviate their mental health issues. PMID- 25513850 TI - Endobronchial ultrasound-guided transbronchial needle injection for local control of recurrent non-small cell lung cancer. AB - RATIONALE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) is an established technique for the diagnosis of thoracic malignancies. Non ultrasound-guided transbronchial needle injection has been used previously to deliver chemotherapeutic agents. OBJECTIVES: To use endobronchial ultrasound guided transbronchial needle injection (EBUS-TBNI) to achieve local control of recurrent early-stage lung cancer. METHODS: A 63-year-old man presented with recurrent early stage non-small cell lung carcinoma after chemotherapy and external beam radiation. We used EBUS-TBNI to deliver cisplatin into the tumor located outside the airway. This procedure was performed on three separate occasions without complication. MEASUREMENTS AND MAIN RESULTS: EBUS-TBNI resulted in resolution of fluorodeoxyglucose avidity, measured by positron emission tomography-computed tomography, in the region at 4 weeks. However, at 5 months, there was evidence of distal recurrence. CONCLUSIONS: This is the first description of EBUS-TBNI to treat local recurrence of lung cancer and one of the first reports of the use of EBUS for intratumoral therapy. Additional research is warranted to determine the clinical usefulness and safety of this therapeutic approach. PMID- 25513848 TI - Pulmonary preconditioning, injury, and inflammation modulate expression of the candidate tumor suppressor gene ECRG4 in lung. AB - PURPOSE: The human c2orf40 gene encodes a candidate tumor suppressor called Esophageal Cancer-Related Gene-4 (ECRG4) that is a cytokine-like epigenetically regulated protein that is characteristically downregulated in cancer, injury, inflammation, and infection. Here, we asked whether ECRG4 gene expression is detectable in lung epithelial cells and if its expression changes with inflammation, infection, and/or protective preconditioning. MATERIALS AND METHODS: We used immunoblotting, PCR, and quantitative PCR to measure ECRG4 and either inhalation anesthesia preconditioning, lipopolysaccharide injection, or laparotomy to modulate lung inflammation. RESULTS: Immunoblotting establishes the presence of the full-length 14 kDa ECRG4 peptide in mouse lung. Immunohistochemistry localizes ECRG4 to type l alveolar epithelial cells. Basal ECRG4 mRNA is greater than TNF-alpha, IL-1beta, and IL-6 but following inflammatory lung injury, TNF-alpha, IL-1beta, IL-6, and IL-10 are upregulated while ECRG4 gene expression is decreased. Similar findings are observed after an intravenous administration of lipopolysaccharide. In contrast, lung preconditioning with isoflurane anesthesia increases lung ECRG4 gene expression. Over-expression of ECRG4 in human lung epithelial cells in vitro decreases cell proliferation implying that a loss of ECRG4 in vivo would be permissive to cell growth. CONCLUSIONS: This study supports the hypothesis that ECRG4 acts as a sentinel growth inhibitor in lung alveolar epithelial cells. Its downregulation by injury, infection, and inflammation and upregulation by preconditioning supports a role for ECRG4 in regulating the alveolar epithelium response to injury and inflammation. By extension, the findings support a functional consequence to its inhibition by promoter hypermethylation (i.e. lung cancer) and suggest potential benefits to its upregulation. PMID- 25513852 TI - Early Observations on Facial Palsy. AB - Before Charles Bell's eponymous account of facial palsy, physicians of the Graeco Roman era had chronicled the condition. The later neglected accounts of the Persian physicians Abu al-Hasan Ali ibn Sahl Rabban al-Tabari and Abu Bakr Muhammad ibn Zakariya Razi ("Rhazes") and Avicenna in the first millennium are presented here as major descriptive works preceding the later description by Stalpart van der Wiel in the seventeenth century and those of Friedreich and Bell at the end of the eighteenth and the beginning of the nineteenth centuries. PMID- 25513851 TI - Characterisation of non-autoinducing tropodithietic Acid (TDA) production from marine sponge Pseudovibrio species. AB - The search for new antimicrobial compounds has gained added momentum in recent years, paralleled by the exponential rise in resistance to most known classes of current antibiotics. While modifications of existing drugs have brought some limited clinical success, there remains a critical need for new classes of antimicrobial compound to which key clinical pathogens will be naive. This has provided the context and impetus to marine biodiscovery programmes that seek to isolate and characterize new activities from the aquatic ecosystem. One new antibiotic to emerge from these initiatives is the antibacterial compound tropodithietic acid (TDA). The aim of this study was to provide insight into the bioactivity of and the factors governing the production of TDA in marine Pseudovibrio isolates from a collection of marine sponges. The TDA produced by these Pseudovibrio isolates exhibited potent antimicrobial activity against a broad spectrum of clinical pathogens, while TDA tolerance was frequent in non-TDA producing marine isolates. Comparative genomics analysis suggested a high degree of conservation among the tda biosynthetic clusters while expression studies revealed coordinated regulation of TDA synthesis upon transition from log to stationary phase growth, which was not induced by TDA itself or by the presence of the C10-acyl homoserine lactone quorum sensing signal molecule. PMID- 25513853 TI - Genetic and biochemical evaluation of natural rubber from Eastern Washington prickly lettuce (Lactuca serriola L.). AB - Alternative sources of natural rubber are of importance due to economic, biological, and political threats that could diminish supplies of this resource. Prickly lettuce (Lactuca serriola L.) synthesizes long-chain natural rubber and was studied to determine underlying genetic and phenotypic characteristics of rubber biosynthesis. Genotypic and phenotypic analysis of an F2 segregating population using EST-SSR markers led to the discovery of genetic regions linked to natural rubber production. Interval mapping (IM) and multiple QTL mapping (MQM) identified several QTL in the mapping population that had significance based on LOD score thresholds. The discovered QTL and the corresponding local markers are genetic resources for understanding rubber biosynthesis in prickly lettuce and could be used in marker-assisted selection (MAS) breeding. Prickly lettuce is an excellent candidate for elucidating the rubber synthesis mechanism and has potential as a crop plant for rubber production. PMID- 25513854 TI - Diagnostic Performance of Dedicated Axillary T2- and Diffusion-weighted MR Imaging for Nodal Staging in Breast Cancer. AB - PURPOSE: To evaluate the diagnostic performance of unenhanced axillary T2 weighted and diffusion-weighted (DW) magnetic resonance (MR) imaging for axillary nodal staging in patients with newly diagnosed breast cancer, with node-by-node and patient-by-patient validation. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Fifty women (mean age, 60 years; range, 22-80 years) underwent high-spatial-resolution axillary 3.0-T T2 weighted imaging without fat suppression and DW imaging (b = 0, 500, and 800 sec/mm(2)), followed by either sentinel lymph node biopsy (SLNB) or axillary lymph node dissection. Two radiologists independently scored each lymph node on a confidence level scale from 0 (benign) to 4 (malignant), first on T2-weighted MR images, then on DW MR images. Two researchers independently measured the mean apparent diffusion coefficient (ADC) of each lymph node. Diagnostic performance parameters were calculated on the basis of node-by-node and patient-by-patient validation. RESULTS: With respective node-by-node and patient-by-patient validation, T2-weighted MR imaging had a specificity of 93%-97% and 87%-95%, sensitivity of 32%-55% and 50%-67%, negative predictive value (NPV) of 88%-91% and 86%-89%, positive predictive value (PPV) of 60%-70% and 62%-75%, and area under the receiver operating characteristic curve (AUC) of 0.78 and 0.80-0.88, with good interobserver agreement (kappa = 0.70). The addition of DW MR imaging resulted in lower specificity (59%-88% and 50%-84%), higher sensitivity (45%-64% and 75%-83%), comparable NPV (89% and 90%-91%), lower PPV (23%-42% and 34%-60%), and lower AUC (0.68-0.73 and 0.70-0.86). ADC measurement resulted in a specificity of 63%-64% and 61%-63%, sensitivity of 41% and 67%, NPV of 85% and 85%-86%, PPV of 18% and 35%-36%, and AUC of 0.54-0.58 and 0.69-0.74, respectively, with excellent interobserver agreement (intraclass correlation coefficient, 0.83). CONCLUSION: Dedicated high-spatial-resolution axillary T2 weighted MR imaging showed good specificity on the basis of node-by-node and patient-by-patient validation, with good interobserver agreement. However, its NPV is still insufficient to substitute it for SLNB for exclusion of axillary lymph node metastasis. DW MR imaging and ADC measurement were of no added value. PMID- 25513855 TI - Whole-body 3D T1-weighted MR imaging in patients with prostate cancer: feasibility and evaluation in screening for metastatic disease. AB - PURPOSE: To develop and assess the diagnostic performance of a three-dimensional (3D) whole-body T1-weighted magnetic resonance (MR) imaging pulse sequence at 3.0 T for bone and node staging in patients with prostate cancer. MATERIALS AND METHODS This prospective study was approved by the institutional ethics committee; informed consent was obtained from all patients. Thirty patients with prostate cancer at high risk for metastases underwent whole-body 3D T1-weighted imaging in addition to the routine MR imaging protocol for node and/or bone metastasis screening, which included coronal two-dimensional (2D) whole-body T1 weighted MR imaging, sagittal proton-density fat-saturated (PDFS) imaging of the spine, and whole-body diffusion-weighted MR imaging. Two observers read the 2D and 3D images separately in a blinded manner for bone and node screening. Images were read in random order. The consensus review of MR images and the findings at prospective clinical and MR imaging follow-up at 6 months were used as the standard of reference. The interobserver agreement and diagnostic performance of each sequence were assessed on per-patient and per-lesion bases. RESULTS: The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were significantly higher with whole-body 3D T1-weighted imaging than with whole-body 2D T1-weighted imaging regardless of the reference region (bone or fat) and lesion location (bone or node) (P < .003 for all). For node metastasis, diagnostic performance (area under the receiver operating characteristic curve) was higher for whole body 3D T1-weighted imaging (per-patient analysis; observer 1: P < .001 for 2D T1 weighted imaging vs 3D T1-weighted imaging, P = .006 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging; observer 2: P = .006 for 2D T1-weighted imaging vs 3D T1-weighted imaging, P = .006 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging), as was sensitivity (per-lesion analysis; observer 1: P < .001 for 2D T1-weighted imaging vs 3D T1-weighted imaging, P < .001 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging; observer 2: P < .001 for 2D T1-weighted imaging vs 3D T1-weighted imaging, P < .001 for 2D T1-weighted imaging + PDFS imaging vs 3D T1-weighted imaging). CONCLUSION: Whole-body MR imaging is feasible with a 3D T1-weighted sequence and provides better SNR and CNR compared with 2D sequences, with a diagnostic performance that is as good or better for the detection of bone metastases and better for the detection of lymph node metastases. PMID- 25513856 TI - Ovine induced pluripotent stem cells are resistant to reprogramming after nuclear transfer. AB - Induced pluripotent stem cells (iPSCs) share similar characteristics of indefinite in vitro growth with embryonic stem cells (ESCs) and may therefore serve as a useful tool for the targeted genetic modification of farm animals via nuclear transfer (NT). Derivation of stable ESC lines from farm animals has not been possible, therefore, it is important to determine whether iPSCs can be used as substitutes for ESCs in generating genetically modified cloned farm animals. We generated ovine iPSCs by conventional retroviral transduction using the four Yamanaka factors. These cells were basic fibroblast growth factor (bFGF)- and activin A-dependent, showed persistent expression of the transgenes, acquired chromosomal abnormalities, and failed to activate endogenous NANOG. Nonetheless, iPSCs could differentiate into the three somatic germ layers in vitro. Because cloning of farm animals is best achieved with diploid cells (G1/G0), we synchronized the iPSCs in G1 prior to NT. Despite the cell cycle synchronization, preimplantation development of iPSC-NT embryos was lower than with somatic cells (2% vs. 10% blastocysts, p<0.01). Furthermore, analysis of the blastocysts produced demonstrated persistent expression of the transgenes, aberrant expression of endogenous SOX2, and a failure to activate NANOG consistently. In contrast, gene expression in blastocysts produced with the parental fetal fibroblasts was similar to those generated by in vitro fertilization. Taken together, our data suggest that the persistent expression of the exogenous factors and the acquisition of chromosomal abnormalities are incompatible with normal development of NT embryos produced with iPSCs. PMID- 25513857 TI - Numerical simulation of wave propagation in a realistic model of the human external ear. AB - In this study, a numerical investigation is performed to evaluate the effects of high-pressure sinusoidal and blast wave's propagation around and inside of a human external ear. A series of computed tomography images are used to reconstruct a realistic three-dimensional (3D) model of a human ear canal and the auricle. The airflow field is then computed by solving the governing differential equations in the time domain using a computational fluid dynamics software. An unsteady algorithm is used to obtain the high-pressure wave propagation throughout the ear canal which is validated against the available analytical and numerical data in literature. The effects of frequency, wave shape, and the auricle on pressure distribution are then evaluated and discussed. The results clearly indicate that the frequency plays a key role on pressure distribution within the ear canal. At 4 kHz frequency, the pressure magnitude is much more amplified within the ear canal than the frequencies of 2 and 6 kHz, for the incident wave angle of 90 degrees investigated in this study, attributable to the '4-kHz notch' in patients with noise-induced hearing loss. According to the results, the pressure distribution patterns at the ear canal are very similar for both sinusoidal pressure waveform with the frequency of 2 kHz and blast wave. The ratio of the peak pressure value at the eardrum to that at the canal entrance increases from about 8% to 30% as the peak pressure value of the blast wave increases from 5 to 100 kPa for the incident wave angle of 90 degrees investigated in this study. Furthermore, incorporation of the auricle to the ear canal model is associated with centerline pressure magnitudes of about 50% and 7% more than those of the ear canal model without the auricle throughout the ear canal for sinusoidal and blast waves, respectively, without any significant effect on pressure distribution pattern along the ear canal for the incident wave angle of 90 degrees investigated in this study. PMID- 25513859 TI - Scalp sarcoidosis mimicking organoid nevus. PMID- 25513858 TI - Multiple barriers delay care among women with abnormal cancer screening despite patient navigation. AB - BACKGROUND: While there is widespread dissemination of patient navigation programs in an effort to reduce delays in cancer care, little is known about the impact of barriers to care on timely outcomes. METHODS: We conducted a secondary analysis of the Boston Patient Navigation Research Program (PNRP) to examine the effect that the presence of barriers had on time to diagnostic resolution of abnormal breast or cervical cancer screening tests. We used multivariable Cox proportional hazards regression with time to diagnostic resolution as the outcome to examine the effect of the number of barriers, controlling for demographic covariates and clustered by patients' primary navigator. RESULTS: There were 1481 women who received navigation; mean age was 39 years; 32% were White, 27% Black, and 31% Hispanic; 28% had private health insurance; and 38% did not speak English. Overall, half (n=745, 50%) had documentation of one or more barriers to care. Women with barriers were more likely to be older, non-White, non-English language speakers, and on public or no health insurance compared with women without barriers. In multivariable analyses, we found less timely diagnostic resolution as the number of barriers increased (one barrier, adjusted hazard ratio [aHR] 0.81 [95% CI 0.56-1.17], p=0.26; two barriers, aHR 0.55 [95% CI 0.37 0.81], p=0.0025; three or more barriers, aHR 0.31 [95% CI 0.21-0.46], p<0.0001)]. CONCLUSION: Within a patient navigation program proven to reduce delays in care, we found that navigated patients with documented barriers to care experience less timely resolution of abnormal cancer screening tests. PMID- 25513861 TI - Investigation of the interaction between human serum albumin and antitumor palladium(II) complex containing 1,10-phenanthroline and dithiocarbamate ligands. AB - The interaction between [Pd(But-dtc)(phen)]NO3 (where But-dtc = butyldithiocarbamate and phen = 1,10-phenanthroline) with HSA (Human Serum Albumin) was investigated by applying fluorescence, UV-Vis and circular dichroism techniques under physiological conditions. The results of fluorescence spectra indicated that the Pd(II) complex could effectively quench the fluorescence intensity of HSA molecules via static mechanism. The number of binding sites and binding constant of HSA-Pd(II) complex were calculated. Analysis of absorption titration data on the interaction between Pd(II) complex and HSA revealed the formation of HSA-Pd(II) complex with high-binding affinity. Thermodynamic parameters indicated that hydrophobic forces play a major role in this interaction. Furthermore, CD measurements were taken to explore changes in HSA secondary structure induced by the Pd(II) complex. PMID- 25513860 TI - Design, synthesis, antiviral activity, and pre-formulation development of poly-L arginine-fatty acyl derivatives of nucleoside reverse transcriptase inhibitors. AB - The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC50 values of 1.5-16.6 MUM. FLT-CO-(CH2)12-CO-(Arg)7 exhibited EC50 values of 2.9 MUM and 3.1 MUM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to be stable in neutral and oxidative conditions and moderately stable in heated conditions. PMID- 25513862 TI - Concise and efficient synthesis of 3'-O-tetraphosphates of 2'-deoxyadenosine and 2'-deoxycytidine. AB - We describe concise and efficient synthesis of biologically very important 3'-O tetraphosphates namely 2'-deoxyadenosine-3'-O-tetraphosphate (2'-d-3'-A4P) and 2' deoxycytidine-3'-O-tetra-phosphate (2'-d-3'-C4P). N(6)-benzoyl-5'-O-levulinoyl-2' deoxyadenosine was converted into N(6)-benzoyl-5'-O-levulinoyl-2'-deoxyadenosine 3'-O-tetraphosphate in 87% yield using a one-pot synthetic methodology. One-step concurrent deprotection of N(6)-benzoyl and 5'-O-levulinoyl groups using concentrated aqueous ammonia resulted 2'-d-3'-A4P in 74% yield. The same synthetic strategy was successfully employed to convert N(4)-benzoyl-5'-O levulinoyl-2'-deoxycytidine into 2'-d-3'-C4P in 68% yield. PMID- 25513863 TI - Synthesis, spectral characterization, and pharmacological importance of new 4H 1,4-benzothiazines, their sulfone analogues, and ribofuranosides. AB - The present article describes the synthesis of new 4H-1,4-benzothiazines via condensation and oxidative cyclization of substituted 2-aminobenzenethiols with compounds containing active methylene groups. It is believed that the reaction proceeds via intermediary of the enaminoketone system. The sulfone derivatives were synthesized by oxidation of 4H-1,4-benzothiazines using 30% hydrogen peroxide in glacial acetic acid. Benzothiazines were used as bases to prepare ribofuranosides by treatment with a sugar derivative (beta-D-ribofuranosyl-1 acetate-2,3,5-tribenzoate). The pharmacological importance of the synthesized compounds was evaluated by their, antimicrobial properties against various bacterial strains and fungal species. The structures of the compounds have been confirmed by spectral and chemical analysis. PMID- 25513864 TI - Impact of anti-peroxynitrite-damaged-thymidine-monophosphate antibodies on disease activity in patients with systemic lupus erythematosus. AB - Present study probes the role of peroxynitrite (ONOO(-))-modified thymidine-5' monophosphate (TMP) in SLE patients with different disease activity scores according to the SLE Disease Activity Index (SLEDAI). Serum analysis showed significant increased number of subjects positive for anti-ONOO(-)-TMP-protein antibodies in SLE patients with different SLEDAI scores. Interestingly, the levels of these antibodies were significantly higher among SLE patients, whose SLEDAI scores were >=20. In addition, a significant correlation was observed between the levels of anti-ONOO(-)-TMP-protein antibodies and the SLEDAI score (r = 0.595, p < 0.0001). In short, this study shows a positive association between anti-ONOO(-)-TMP-protein antibodies and SLEDAI. The stronger response observed in patients with higher SLEDAI scores suggests that anti-ONOO(-)-TMP-protein antibodies may be useful in evaluating the progression of SLE and in elucidating the mechanisms of disease pathogenesis. PMID- 25513865 TI - Simultaneous determination of twenty-two components in Asari Radix et Rhizoma by ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. AB - Asari Radix et Rhizoma is a herbal medicine for the treatment of common cold, rhinitis, etc. An ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry method has been established for the rapid analysis of 22 components in 27 samples from the raw materials of Asari Radix et Rhizoma and an adulterant. A total of 5 lignans, 5 essential oils, 3 aristolochic acids, 4 alkamides, and 5 flavanoids were identified by co-chromatography of samples extracts and comparison of the retention time, UV spectra, characteristic molecular ions, and fragment ions with those of authentic standards, or tentatively identified by MS/MS determination along with MassFragment software. Moreover, the method was validated for the simultaneous quantification and semi quantification of 20 components. The samples from Asarum heterotropoides var. mandshuricum differed in the quantity of 2-methoxyl-4,5 methylenedioxypropiophenone and kakuol from those of Asarum sieboldii var. seoulense, and the chemical difference was supported by principal component analysis and orthogonal partial least squared discriminant analysis based on dataset obtained from UHPLC-QTOF/MS. In comparison with the samples from the two medicinal Asarum species mentioned above, those from A. himalaicum differed in the quality and quantity of major compounds and contained higher amounts of aristolochic acid I. PMID- 25513866 TI - The effect of radiofrequency thermal ablation method on nasal mucociliary activity in patients with inferior turbinate hypertrophy. AB - OBJECTIVES: This study aims to investigate the effect of radiofrequency thermal ablation (RFTA) treatment on nasal mucociliary activity before and after treatment in inferior turbinate hypertrophy. PATIENTS AND METHODS: Thirty-nine patients (21 males, 18 females; mean age 36.3+/-13.9 years; range 16 to 67 years) admitted to our clinic with complaint of nasal obstruction and diagnosed with stromal inferior turbinate hypertrophy were included in this study. Effect of RFTA treatment on nasal mucociliary activity was investigated by saccharine test before treatment and two months after treatment. Grade of nasal obstruction was evaluated by visual analog scale (VAS) before treatment and two months after treatment. Results were compared with paired t-test. RESULTS: Mean mucociliary activity times were 9.8+/-4.4 minutes before treatment and 9.6+/-4.1 minutes two months after treatment, and the difference between two tests was not statistically significant (p=0.3). Mean VAS scores for nasal obstruction were 6.5+/-1.2 before treatment and 3.8+/-1.0 two months after treatment, and the difference between two results was statistically significant (p=0.001). Difference between sexes in terms of saccharine transit time and VAS values before and after treatment was not statistically significant (p>0.05). CONCLUSION: It was detected that RFTA has no adverse effect on mucociliary activity in the treatment of inferior turbinate hypertrophy, and this method is notably effective in relieving the nasal obstruction caused by inferior turbinate hypertrophy. PMID- 25513867 TI - Histopathological analysis of tonsillectomy specimens: a report from Southeastern Anatolia. AB - OBJECTIVES: This study aims to evaluate the necessity of routine histopathological analyses of tonsillectomy specimens. PATIENTS AND METHODS: A retrospective review for 2,004 patients (1,048 males, 956 females; mean age 12.2 years; range 2 to 60 years) who underwent tonsillectomy between January 2009 and May 2013 was carried out at the Diyarbakir Training and Research Hospital, Turkey. Tonsillectomy specimens were fixed with formalin, and stained with hematoxylin and eosin before being sectioned and examined via light microscope. Chronic inflammation and lymphoid hyperplasia were considered non-significant pathological findings. Other pathological diagnoses including infectious processes, and benign and malignant neoplasms were regarded as significant pathological findings. RESULTS: Non-significant pathological findings -chronic inflammation, lymphoid hyperplasia or both- were observed in 1,972 patients. Significant pathological findings -epidermal cyst, mucocele, squamous papilloma, granuloma and squamous cell carcinoma- were observed in 32 patients. One patient was diagnosed with squamous cell carcinoma, and another had granulomatous disease diagnosed as tuberculosis. CONCLUSION: Histopathological examination is only necessary for patients with preoperative risk factors. Gross examination may be a good alternative since it is cost effective and not time consuming. PMID- 25513868 TI - Prevalence of allergic fungal rhinosinusitis among patients with chronic rhinosinusitis with or without nasal polyposis who underwent endonasal sinus surgery in northwestern Turkey. AB - OBJECTIVES: This study aims to evaluate the prevalence of allergic fungal rhinosinusitis in chronic rhinosinusitis patients in the northwest of Turkey. PATIENTS AND METHODS: Eighty-seven patients diagnosed with chronic rhinosinusitis and who were planned endonasal sinus surgery were enrolled in this prospective study. Patients were evaluated by detailed clinical examination, computed tomography, skin test against allergens, total serum immunoglobulin E (IgE) antibody, fungal-specific IgE antibody, and histopathologic and mycologic monitoring. RESULTS: Fungal elements showing tissue invasiveness were detected in only four patients. These patients had specific IgE against Aspergillus fumigatus (4.6%). Skin tests were positive for at least one allergen in 16 patients (18.3%). CONCLUSION: None of the patients met diagnostic criteria for allergic fungal rhinosinusitis. This result may be due to the diversity in disease prevalence based on geographical location or diagnostic methods. PMID- 25513869 TI - Complications of chronic suppurative otitis media: challenge for a developing country. AB - OBJECTIVES: This study aims to investigate the frequency and management of complications of chronic suppurative otitis media (CSOM). PATIENTS AND METHODS: Out of 376 patients with CSOM, 44 patients (25 males, 19 females; mean age 48.5+/ 3.5 years; range 21 to 76 years) meeting study criteria were enrolled in this descriptive cross sectional study which was conducted at the Department of Ear Nose and Throat, Head and Neck Surgery, Postgraduate Medical Institute, Lady Reading Hospital Peshawar. All newly diagnosed patients having CSOM with complications were enrolled. The complications were treated first. Intracranial abscesses were evacuated by neurosurgeons. Radical and modified radical mastoidectomy were performed. RESULTS: Majority of the patients presented in the second and third decade of life (21-30 years: 27.27%, 31-40 years: 18.18%). Most of the patients (59.1%) had lower socioeconomic status. Canal wall down mastoidectomy was the most common (79.5%) procedure performed. Cholesteatoma was the most common operative finding (100%). Among extracranial complications, subperiosteal abscess was the most common finding (38.63%), while extradural abscess outnumbered (22.72%) in intracranial complications. CONCLUSION: Complications of CSOM commonly affect younger people with low socioeconomic status. Collaborating with neurosurgeons may assist in the successful management of this infection. PMID- 25513870 TI - Injection laryngoplasty outcomes in vocal fold paralysis using calcium hydroxylapatite. AB - OBJECTIVES: This study aims to evaluate our injection laryngoplasty experience in patients with unilateral vocal fold paralysis. PATIENTS AND METHODS: Sixty-eight patients (32 males, 36 females; mean age 59.5 years; range 27 to 86 years) who were diagnosed with unilateral vocal fold paralysis at our clinic and who underwent injection laryngoplasty using calcium hydroxylapatite between January 2005 and June 2012 were included in this study. RESULTS: Mean follow-up period was 36 weeks (range 0-340.4 weeks). Data of 29 patients with post-injection Voice Handicap Index (VHI) scores were retrospectively analyzed. Of these patients, 16 (55%) were female, and the mean patient age was 60 (range 27 to 86 years). Seventeen patients underwent suspension laryngoscopy in the operating room, 12 patients underwent in-office percutaneous injection. Post-injection mean VHI score was 36.7 (range 4 to 87). Percutaneous injection laryngoplasty was performed to half of the 20 patients with pre- and post-injection VHI data. Mean VHI scores of these 20 patients improved by 27.9 points. Mean VHI score improved by 35.1 points in the percutaneous group, and by 20.7 points in the suspension group (p=0.29). Post-injection VHI score of one patient with lung cancer decreased, as his general health deteriorated. CONCLUSION: This study supports injection laryngoplasty in vocal fold paralysis. Calcium hydroxylapatite is a safe and effective treatment method in both percutaneous and operating room procedures. PMID- 25513871 TI - [Importance of laryngologic examination in chronic cough]. AB - OBJECTIVES: This study aims to investigate the distribution of etiologic factors related to otorhinolaryngology in chronic cough patients with normal lung examination and spirometric findings, and also highlight the importance of videolaryngostroboscopic (VLS) examination with these patients. PATIENTS AND METHODS: Seventy-six patients (31 males, 45 females; mean age 48.0+/-15.5 years; range 18 to 83 year) who applied to pulmonology outpatient clinic with cough complaint for more than two months were included in the study. After being evaluated by a pulmonologist, patients were referred to otolaryngology outpatient clinic. To detect the underlying cause of cough, patients' detailed histories, and flexible fiberoptic endoscopy and VLS findings were reviewed. Reflux symptom index (RSI) was used for the diagnosis of gastroesophageal reflux. RESULTS: In RSI >=13 group, posterior commissure edema was detected in 12 patients (42.9%), and posterior commissure hyperemia was detected in four patients (14.3%). These findings were statistically significantly higher than RSI <13 group (p=0.006 and p=0.016, respectively). No significant difference was present between the group of patients with allergic rhinitis and the group of patients without allergic rhinitis in terms of VLS findings. Mucopurulent secretion rate in posterior commissure in patients with acute sinusitis findings was statistically higher than patients without acute sinusitis findings (p<0.001). CONCLUSION: Chronic cough is a common symptom of many different diseases. Therefore, a multidisciplinary approach is important for diagnosis. Videolaryngostroboscopy is a valuable examination tool in the differential diagnosis of gastroesophageal reflux and acute sinusitis. PMID- 25513872 TI - [Foreign body aspiration: an urgent airway condition]. AB - OBJECTIVES: This study aims to investigate demographic features, type and localization of foreign bodies, mean hospitalization duration, and peri- and postoperative complication ratios of patients with foreign body aspiration. PATIENTS AND METHODS: Seventy patients (23 males, 47 females; mean age 32+/-14.5 months; range 3 months to 10 years) who were diagnosed with foreign body aspiration in our clinic between January 2007 and August 2010, and performed rigid bronchoscopy under general anesthesia were included in this study. RESULTS: Main findings were cough, wheezing, and witnessed aspiration. No foreign body was detected in 14 patients (20%). Foreign bodies in 56 patients (80%) were successfully removed. Foreign bodies were located in the left bronchial tree in 23 patients (41%), right bronchial tree in 18 patients (32%), trachea in four patients (7%), bilateral bronchial tree in three patients (5%), carina in two patients (3%), subglottic region in two patients (3%), pyriform sinus in two patients (2%), laryngeal ventricle in one patient (1.7%), and right vocal cord in one patient (1.7%). Foreign bodies were hard-shelled nuts in 23 patients (41%), beans in 14 patients (25%), plastic materials in 11 patients (19%), and other bodies in eight patients (14%). CONCLUSION: Foreign body aspiration is a risky condition particularly for children under the age of four. Bronchoscopy is still the most commonly used and reliable diagnosis and treatment method. Foreign body aspiration should be kept in mind in children with persistent cough, wheezing, and unilateral pulmonary findings in radiologic imaging. PMID- 25513873 TI - Bilateral sudden sensorineural hearing loss caused by leptomeningeal carcinomatosis: case report and review. AB - Leptomeningeal carcinomatosis is a rare condition characterized by diffuse infiltration of the meninges after the metastasis of the solid tumors. Bilateral sudden hearing loss is a rare initial symptom. In this article, we report a 44 year-old male patient with bilateral sudden hearing loss and dizziness. Magnetic resonance imaging showed involvement of the bilateral vestibulocochlear nerves. Malignant cells were detected in cerebrospinal fluid cytology. To the best of our knowledge, leptomeningeal carcinomatosis due to duodenum adenocarcinoma has not been reported before in the English literature. Leptomeningeal carcinomatosis should be kept in mind in patients who have bilateral sudden sensorineural hearing loss. PMID- 25513874 TI - Bilateral superior concha bullosa: a rare case overlooked. AB - Concha bullosa is generally defined as the pneumatization of the middle turbinate and, rarely, of the superior or the inferior turbinates. A symptomatic pneumatization of the superior turbinate is extremely rare. When symptomatic, concha bullosa may cause various problems. Concha bullosa can be easily recognized in paranasal sinus computed tomography. In this article we present a very rare case with bilateral pneumatization of the superior turbinates in a patient with relevant symptomatology. PMID- 25513875 TI - [Fracture of the glenoid fossa without mandibular condylar dislocation or fracture: two case reports]. AB - The mandibular condyle region which protects the middle cranial fossa from facial and jaw traumas has an excellent osteomuscular structure. Condylar structures reduce or limit the force of trauma. Most importantly, the condylar neck is the weakest part of the mandible and is easily fractured without dislocation. Generally, this mechanism prevents condylar penetration into the middle cranial fossa; however, there are condylar penetration into the middle cranial fossa can be rarely. Glenoid fossa fractures without mandibular condylar fracture and dislocation can be made. In this article, we present two cases to assess the isolated glenoid fossa fractures of the temporal bone. PMID- 25513876 TI - [Giant desmoid tumor in the neck]. AB - Desmoid tumor is a benign tumor which originates from musculoaponeurotic system, can reach greater sizes with local invasion among facial plans, and cause severe deformities, morbidity and even mortality by compression of adjacent structures. These tumors are rarely seen in the head and neck region. The treatment of advanced desmoid tumors of head and neck region is surgery and radiotherapy. In this paper, we present -to the best of our knowledge- the greatest desmoid tumor case of the head and neck region in the literature. PMID- 25513877 TI - [Questionnaire methods used in the psychosomatic evaluation of tinnitus]. AB - Tinnitus is a common disorder in ear, nose and throat practice. Not only muscular, vascular, neuronal, odiologic and ear pathologies, also psychological parameters contribute to the formation of tinnitus. Scales which evaluate patients' perception of tinnitus and how they are affected from tinnitus psychosomatically have gained increasing importance. Questionnaire studies are very assisting in terms of showing the degree of anxiety and depression experienced by the patients, diagnosis of the disease, evaluation of treatment efficacy, and patient follow-up. In this study, we reviewed the visual analog scale which measures the level of subjective perception in tinnitus, tinnitus evaluation questionnaires, and questionnaires measuring the level of quality of life and depression. PMID- 25513878 TI - A theoretical framework to support research of health service innovation. AB - OBJECTIVE: Health service managers and policy makers are increasingly concerned about the sustainability of innovations implemented in health care settings. The increasing demand on health services requires that innovations are both effective and sustainable; however, research in this field is limited, with multiple disciplines, approaches and paradigms influencing the field. These variations prevent a cohesive approach, and therefore the accumulation of research findings, in the development of a body of knowledge. The purpose of this paper is to provide a thorough examination of the research findings and provide an appropriate theoretical framework to examine sustainability of health service innovation. METHODS: This paper presents an integrative review of the literature available in relation to sustainability of health service innovation and provides the development of a theoretical framework based on integration and synthesis of the literature. RESULTS: A theoretical framework serves to guide research, determine variables, influence data analysis and is central to the quest for ongoing knowledge development. This research outlines the sustainability of innovation framework; a theoretical framework suitable for examining the sustainability of health service innovation. CONCLUSION: If left unaddressed, health services research will continue in an ad hoc manner, preventing full utilisation of outcomes, recommendations and knowledge for effective provision of health services. The sustainability of innovation theoretical framework provides an operational basis upon which reliable future research can be conducted. PMID- 25513880 TI - Dying in Australian hospitals: will a separate national clinical standard improve the delivery of quality care? AB - While it is commonly stated that for most people the preferred place of death is their own homes, the actual reality is that most people will die in hospitals. This is both by choice and necessity. However, for many, the care that they receive would not necessarily align with their expectations. The need to improve the quality of health care at the end of life has been acknowledged by the Australian Commission for Safety and Quality in Healthcare with the release of a recent discussion paper. It is presumed this is a prelude to the release of another quality standard specifically for end of life care. The aim of this paper is to question whether such a standard is likely to result in the hoped for improvements in care. PMID- 25513879 TI - [Profile of immune and allergic dermatoses among children at the outpatient dermatology clinic in Cotonou (Benin)]. AB - OBJECTIVE: The aim of this work was to study the profile of immune and allergic dermatoses (IAD) in children consulting at the outpatient dermatology clinic at the National University Hospital in Cotonou (Benin). METHOD: This retrospective descriptive study examined records of children consulting with this diagnosis over a 10-year period. RESULTS: IAD (902 cases, 37%) were the most common pediatric dermatosis, followed by infectious dermatosis (24%). The sex ratio of children was 0.78. The age groups most strongly affected were those aged 1-30 months (25.39%) and 150-180 months (19.73%). The main IAD were: eczema (47.9%) and prurigo simplex (40.7%). Other IADs included lichen planus (5.1%), toxicoderma (3.8%), urticaria (1.5%), and erythrodermic eczema (1%). The incidence of eczema increased from 13.5% in 2000 to 21.5% in 2009, an increase of 62.2% over 10 years. CONCLUSION: IADs are common at the Cotonou hospital clinic and are dominated by eczema, the incidence of which has increased significantly over time. PMID- 25513883 TI - Template-particle stabilized bicontinuous emulsion yielding controlled assembly of hierarchical high-flux filtration membranes. AB - A novel solvent-evaporation-based process that exploits template-particle stabilized bicontinuous emulsions for the formation of previously unreached membrane morphologies is reported in this article. Porous membranes have a wide range of applications spanning from water filtration, pharmaceutical purification, and battery separators to scaffolds for tissue engineering. Different situations require different membrane morphologies including various pore sizes and pore gradients. However, most of the previously reported membrane preparation procedures are restricted to specific morphologies and morphology alterations require an extensive optimization process. The tertiary system presented in this article, which consists of a poly(ether sulfone)/dimethylacetamide (PES/DMAc) solution, glycerol, and ZnO-nanoparticles, allows simple and exact tuning of pore diameters ranging from sub-20 nm, up to 100 nm. At the same time, the pore size gradient is controlled from 0 up to 840%/MUm yielding extreme asymmetry. In addition to structural analysis, water flux rates of over 5600 L m(-2) h(-1) are measured for membranes retaining 45 nm silica beads. PMID- 25513884 TI - A new way to find evidence quickly and efficiently. AB - Evidence coming from scientific research helps us make better decisions in relation with the care we provide to our patients. Some evidence is more reliable than other is, and systematic reviews are considered the best available evidence for answering questions that compare two or more alternatives of care, as long as they are well conducted and up-to-date. There has lately been a fast growth of the amount of available systematic reviews, so users need to choose between several possible options. Epistemonikos database is a highly efficient search resource, since it groups the larger number of systematic reviews worldwide, and allows accessing the body of evidence for a specific question in a simple and intuitive way. Additionally, it offers tools that enable the choice among different systematic reviews and for keeping the evidence for a question updated with minimal effort. PMID- 25513882 TI - Altered Actions of Memantine and NMDA-Induced Currents in a New Grid2-Deleted Mouse Line. AB - Memantine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, and is an approved drug for the treatment of moderate-to-severe Alzheimer's disease. We identified a mouse strain with a naturally occurring mutation and an ataxic phenotype that presents with severe leg cramps. To investigate the phenotypes of these mutant mice, we screened several phenotype modulating drugs and found that memantine (10 mg/kg) disrupted the sense of balance in the mutants. Moreover, the mutant mice showed an attenuated optokinetic response (OKR) and impaired OKR learning, which was also observed in wild-type mice treated with memantine. Microsatellite analyses indicated that the Grid2 gene-deletion is responsible for these phenotypes. Patch-clamp analysis showed a relatively small change in NMDA-dependent current in cultured granule cells from Grid2 gene-deleted mice, suggesting that GRID2 is important for correct NMDA receptor function. In general, NMDA receptors are activated after the activation of non-NMDA receptors, such as AMPA receptors, and AMPA receptor dysregulation also occurs in Grid2 mutant mice. Indeed, the AMPA treatment enhanced memantine susceptibility in wild-type mice, which was indicated by balance sense and OKR impairments. The present study explores a new role for GRID2 and highlights the adverse effects of memantine in different genetic backgrounds. PMID- 25513886 TI - Evaluation of nanoparticle-ligand distributions to determine nanoparticle concentration. AB - The concentration of nanoparticles in solution is an important, yet challenging, parameter to quantify. In this work, a facile strategy for the determination of nanoparticle concentration is presented. The method relies on the quantitative analysis of the inherent distribution of nanoparticle-ligand conjugates that are generated when nanoparticles are functionalized with ligands. Validation of the method was accomplished by applying it to gold nanoparticles and semiconductor nanoparticles (CdSe/ZnS; core/shell). Poly(ethylene glycol) based ligands, with functional groups that quantitatively react with the nanoparticles, were incubated with the nanoparticles at varying equivalences. Agarose gel electrophoresis was subsequently used to separate and quantify the nanoparticle ligand conjugates of varying valences. The distribution in the nanoparticle ligand conjugates agreed well with that predicted by the Poisson model. A protocol was then developed, where a series of only eight different ligand amounts could provide an estimate of the nanoparticle concentration that spans 3 orders of magnitude (1 MUM to 1 mM). For the gold nanoparticles and semiconductor nanoparticles, the measured concentrations were found to deviate by only 7% and 2%, respectively, from those determined by UV-vis spectroscopy. The precision of the assay was evaluated, resulting in a coefficient of variation of 5-7%. Finally, the protocol was used to determine the extinction coefficient of alloyed semiconductor nanoparticles (CdSxSe1-x/ZnS), for which a reliable estimate is currently unavailable, of three different emission wavelengths (525, 575, and 630 nm). The extinction coefficient of the nanoparticles of all emission wavelengths was similar and was found to be 2.1 * 10(5) M(-1)cm(-1). PMID- 25513885 TI - The sanitation ladder, what constitutes an improved form of sanitation? AB - This study aimed to assess whether the MDG classifications and JMP sanitation ladder corresponded to hygienic proxies. Latrines were purposefully sampled in urban and rural Tanzania. Three hygienic proxies were measured: E. coli on points of hand contact, helminth at point of foot contact, and number of flies. Additionally, samples were collected from comparable surfaces in the household, and a questionnaire on management and use, combined with a visual inspection of the latrine's design was conducted. In total, 341 latrines were sampled. The MDG classifications "improved" vs "unimproved" did not describe the observed differences in E. coli concentrations. Disaggregating the data into the JMP sanitation ladder, on average "shared" facilities were the least contaminated: 9.2 vs 17.7 ("improved") and 137 E. coli/100 mL ("unimproved") (p = 0.04, p < 0.001). Logistic regression analysis suggests that both the presence of a slab and sharing a facility is protective against faecal-oral exposure (OR 0.18 95% CI 0.10, 0.34 and OR 0.52, 95% CI 0.29, 0.92). The findings do not support the current assumption that shared facilities of an adequate technology should be classified for MDG purposes as "unimproved". PMID- 25513881 TI - Somatic mosaicism in the human genome. AB - Somatic mosaicism refers to the occurrence of two genetically distinct populations of cells within an individual, derived from a postzygotic mutation. In contrast to inherited mutations, somatic mosaic mutations may affect only a portion of the body and are not transmitted to progeny. These mutations affect varying genomic sizes ranging from single nucleotides to entire chromosomes and have been implicated in disease, most prominently cancer. The phenotypic consequences of somatic mosaicism are dependent upon many factors including the developmental time at which the mutation occurs, the areas of the body that are affected, and the pathophysiological effect(s) of the mutation. The advent of second-generation sequencing technologies has augmented existing array-based and cytogenetic approaches for the identification of somatic mutations. We outline the strengths and weaknesses of these techniques and highlight recent insights into the role of somatic mosaicism in causing cancer, neurodegenerative, monogenic, and complex disease. PMID- 25513887 TI - Sphere-shaped hierarchical cathode with enhanced growth of nanocrystal planes for high-rate and cycling-stable li-ion batteries. AB - High-energy and high-power Li-ion batteries have been intensively pursued as power sources in electronic vehicles and renewable energy storage systems in smart grids. With this purpose, developing high-performance cathode materials is urgently needed. Here we report an easy and versatile strategy to fabricate high rate and cycling-stable hierarchical sphered cathode Li(1.2)Ni(0.13)Mn(0.54)Co(0.13)O2, by using an ionic interfusion method. The sphere-shaped hierarchical cathode is assembled with primary nanoplates with enhanced growth of nanocrystal planes in favor of Li(+) intercalation/deintercalation, such as (010), (100), and (110) planes. This material with such unique structural features exhibits outstanding rate capability, cyclability, and high discharge capacities, achieving around 70% (175 mAh g(-1)) of the capacity at 0.1 C rate within about 2.1 min of ultrafast charging. Such cathode is feasible to construct high-energy and high-power Li-ion batteries. PMID- 25513888 TI - Approaches to polycyclic 1,4-dioxygenated xanthones. Application to total synthesis of the aglycone of IB-00208. AB - Hexacyclic xanthone natural products such as IB-00208 present a formidable challenge in organic synthesis. A new approach to polycyclic 1,4-dioxygenated xanthones from benzocyclobutenones has been developed and applied to the first total synthesis of the aglycone of IB-00208. The 22-step synthesis features an acetylide stitching process that joins an aryl aldehyde with an angularly fused benzocyclobutenone, which was prepared by a ring-closing metathesis reaction. The resulting acetylenic benzocyclobutenone diol underwent a Moore rearrangement to give an intermediate that was further elaborated to the aglycone of IB-00208 as a mixture of hydroquinone-quinone tautomers. PMID- 25513889 TI - Liposomes as chaperone mimics with controllable affinity toward heat-denatured formate dehydrogenase from Candida boidinii. AB - Chaperone machinery in living systems can catch denatured enzymes and induce their reactivation. Chaperone mimics are beneficial for applying enzymatic reactions in vitro. In this work, the affinity between liposomes and thermally denatured enzymes was controlled to stabilize the enzyme activity. The model enzyme is formate dehydrogenase from Candida boidinii (CbFDH) which is a homodimer and negatively charged in the phosphate buffer solution (pH 7.2) used. The activity of free CbFDH readily decreased at 58 degrees C following the first order kinetics with the half-life t1/2 of 27 min. The turbidity measurements showed that the denatured enzyme molecules formed aggregates. The liposomes composed of zwitterionic phosphatidylcholines (PCs) stabilized the CbFDH activity at 58 degrees C, as revealed with six different PCs. The PC liposomes were indicated to bind to the aggregate-prone enzyme molecules, allowing reactivation at 25 degrees C. The cofactor beta-reduced nicotinamide adenine dinucleotide (NADH) also stabilized the enzyme activity. The affinity between liposomes and denatured CbFDH could be modulated by incorporating cationic 1,2-dioleoyloxy-3 trimethylammonium propane chloride (DOTAP) in PC membranes. The t1/2 values significantly increased in the presence of liposomes ([lipid] = 1.5 mM) composed of PC and DOTAP at the mole fraction f(D) of 0.1. On the other hand, the DOTAP rich liposomes (f(D) >= 0.7) showed strong affinity toward denatured CbFDH, accelerating its deactivation. The liposomes with low charge density function as chaperone mimics that can efficiently catch the denatured enzymes without interfering with their intramolecular interaction for reactivation. PMID- 25513890 TI - Life in a World without Microbes. PMID- 25513891 TI - Membrane defects accelerate outer membrane beta-barrel protein folding. AB - Outer membrane beta-barrel proteins spontaneously fold into lipid bilayers with rates of folding that are strongly influenced by the physical properties of the membrane. We show that folding is accelerated when the bilayer is at the phase transition temperature, because of the coexistence of lipid phase domains and the high degree of defects present at domain boundaries. These results are consistent with previous observations of faster folding into thin and highly curved membranes, which also contain a higher prevalence of defects. The importance of defects in beta-barrel folding provides insight into the intrinsic folding process and the biological assembly pathway. PMID- 25513892 TI - Effects of hydrogen peroxide and ultrasound on biomass reduction and toxin release in the cyanobacterium, Microcystis aeruginosa. AB - Cyanobacterial blooms are expected to increase, and the toxins they produce threaten human health and impair ecosystem services. The reduction of the nutrient load of surface waters is the preferred way to prevent these blooms; however, this is not always feasible. Quick curative measures are therefore preferred in some cases. Two of these proposed measures, peroxide and ultrasound, were tested for their efficiency in reducing cyanobacterial biomass and potential release of cyanotoxins. Hereto, laboratory assays with a microcystin (MC) producing cyanobacterium (Microcystis aeruginosa) were conducted. Peroxide effectively reduced M. aeruginosa biomass when dosed at 4 or 8 mg L-1, but not at 1 and 2 mg L-1. Peroxide dosed at 4 or 8 mg L-1 lowered total MC concentrations by 23%, yet led to a significant release of MCs into the water. Dissolved MC concentrations were nine-times (4 mg L-1) and 12-times (8 mg L-1 H2O2) higher than in the control. Cell lysis moreover increased the proportion of the dissolved hydrophobic variants, MC-LW and MC-LF (where L = Leucine, W = tryptophan, F = phenylalanine). Ultrasound treatment with commercial transducers sold for clearing ponds and lakes only caused minimal growth inhibition and some release of MCs into the water. Commercial ultrasound transducers are therefore ineffective at controlling cyanobacteria. PMID- 25513894 TI - Oxygen reduction electrocatalyst of Pt on Au nanoparticles through spontaneous deposition. AB - A straightforward one-step spontaneous deposition approach for growth of Pt atomic shell on Au nanoparticles and the superior activity and durability of the resulted Pt-on-Au nanoparticles for the oxygen reduction reaction (ORR) are reported. Transmission electron microscopy, X-ray photoelectron spectroscopy, energy-dispersive spectrometry, and electrochemical measurements indicate that Pt can be spontaneously deposited on Au surface upon simply dispersing carbon supported Au nanoparticles in PtCl42--containing solution, without introducing any extraneous reducing agents or any pre/post-treatments. The deposited Pt atoms are uniformly distributed on the surface of Au nanoparticles, with coverage tunable by the concentration of PtCl42- and temperatures. An approximate monolayer of Pt forms at temperature of ca. 80 degrees C and PtCl42- concentrations of above 10-4 mol/L. The obtained Pt-on-Au core-shell nanoparticles catalyze the ORR with specific and mass activities of Pt that are 3.5 times higher than that of pure Pt nanoparticles. Moreover, they exhibit no visible activity degradation after undergoing long-term oxidization/reduction cycling in O2-saturated acid media, therefore showing great prospect as durable cathode electrocatalysts in proton-exchange membrane fuel cells. PMID- 25513895 TI - Chloro, difluoromethylation and chloro, carbomethoxydifluoromethylation: reaction of radicals derived from RfSO2Cl with unactivated alkenes under metal-free conditions. AB - Difluoromethyl and carbomethoxydifluoromethyl radicals were generated from their respective sulfonyl chlorides under mild, metal-free conditions leading to efficient atom transfer radical additions (ATRA) to unactivated alkenes to form chloro, difluoromethylated and chloro, carbomethoxydifluoromethylated products. PMID- 25513893 TI - Biosynthetic pathways of ergot alkaloids. AB - Ergot alkaloids are nitrogen-containing natural products belonging to indole alkaloids. The best known producers are fungi of the phylum Ascomycota, e.g., Claviceps, Epichloe, Penicillium and Aspergillus species. According to their structures, ergot alkaloids can be divided into three groups: clavines, lysergic acid amides and peptides (ergopeptines). All of them share the first biosynthetic steps, which lead to the formation of the tetracyclic ergoline ring system (except the simplest, tricyclic compound: chanoclavine). Different modifications on the ergoline ring by specific enzymes result in an abundance of bioactive natural products, which are used as pharmaceutical drugs or precursors thereof. From the 1950s through to recent years, most of the biosynthetic pathways have been elucidated. Gene clusters from several ergot alkaloid producers have been identified by genome mining and the functions of many of those genes have been demonstrated by knock-out experiments or biochemical investigations of the overproduced enzymes. PMID- 25513896 TI - Phase transitions in a LiMn2O4 nanowire battery observed by operando electron microscopy. AB - Fast charge-discharge process has been reported to give a high capacity loss. A nanobattery consisting of a single LiMn2O4 nanowire cathode, ionic liquid electrolyte and lithium titanium oxide anode was developed for in situ transmission electron microscopy. When it was fully charged or discharged within a range of 4 V in less than half an hour (corresponding average C rate: 2.5C), Li rich and Li-poor phases were observed to be separated by a transition region, and coexisted during whole process. The phase transition region moved reversibly along the nanowire axis which corresponds to the [011] direction, allowing the volume fraction of both phases to change. In the electron diffraction patterns, the Li-rich phase was seen to have the (100) orientation with respect to the incident electron beam, while the Li-poor phase had the (111) orientation. The orientation was changed as the transition region moved. However, the nanowire did not fracture. This suggests that a LiMn2O4 nanowire has the advantage of preventing capacity fading at high charge rates. PMID- 25513897 TI - Superacidity of closo-dodecaborate-based Bronsted acids: a DFT study. AB - The structures and intrinsic gas-phase acidities (GA) of some dodecaborane acids, the derivatives of YB12H11H (Y = PF3, NH3, NF3, NMe3), B12H12H2, and B12H12H(-) (HA, H2A, and HA(-), respectively) have been computationally explored with DFT B3LYP method at the 6-311+G** level of theory as new possible directions of creating superstrong Bronsted acids. Depending on the nature and number of the substituents different protonation geometries were investigated. In general, the GA values of the neutral systems varied according to the substituents in the following order: CF3 < F < Cl and in case of anionic acids: CF3 < Cl < F. The dodecatrifluoromethyl derivative of H2A, B12(CF3)12H1H2, emerges as the strongest among the considered acids and is expected to be in the gas phase at least as strong as the undecatrifluoromethyl carborane, CB11(CF3)11H1H. The GA values of the respective monoanionic forms of the considered acids all, but the (CF3)11 derivative, remained higher than the widely used threshold of superacidity. The HA derivatives' (Y = PF3, NF3) GA's were approximately in the same range as the H2A acids'. In the case Y = NH3 or NMe3 the GA values were significantly higher. Also, the pKa values of B12H12H2, CB11H12H, and their perfluorinated derivatives in 1,2-dichloroethane (DCE) were estimated with SMD and cluster-continuum model calculations. The obtained estimates of pKa values of the perfluorinated derivatives are by around 30 units lower than that of trifluoromethylsulfonylimide, making these acids the strongest ever predicted in solution. The derivatives of B12H12H2 are as a rule not significantly weaker acids than the respective derivatives of CB11H12H. This is important for expanding practical applicability of this type of acids and their anions, as they are synthetically much more accessible than the corresponding CB11H12(-) derivatives. PMID- 25513898 TI - Laparoscopic management of the spigelian hernia. PMID- 25513899 TI - Incidental finding of desmoplastic small round cell tumor during trauma laparotomy. PMID- 25513900 TI - Recurrent and chronic appendicitis: assessment of a new maneuver as a screening test. PMID- 25513901 TI - Bilateral lower extremity anterior compartment syndrome in a severely hypothyroid patient. PMID- 25513902 TI - Organ-sparing pancreatectomy for synchronous pancreatic intraductal papillary mucinous neoplasms. PMID- 25513903 TI - Harmonic focus compared with classic hemostasis during total parathyroidectomy in secondary hyperparathyroidism: a prospective randomized trial. PMID- 25513904 TI - Kikuchi-Fujimoto disease: a rarity in the southern states. PMID- 25513905 TI - Superior mesenteric vein aneurysm associated with necrotizing pancreatitis. PMID- 25513906 TI - Laparoscopic left hemihepatectomy for treatment of left intrahepatic duct stones. PMID- 25513907 TI - Detection of an embedded foreign object in a deep tissue space. PMID- 25513908 TI - Novel use for aquapheresis in a patient with severe volume overload post massive transfusion. PMID- 25513909 TI - Toxic colitis with megacolon in a patient with malrotation. PMID- 25513910 TI - Successful preservation of the mesenteric and bowel circulation with treatment for a ruptured superior mesenteric artery aneurysm using the HyperEye Medical System. PMID- 25513911 TI - Is chest wall reconstruction appropriate in McCune-Albright patients with impending respiratory failure? PMID- 25513912 TI - Mesh extrusion into the esophageal lumen after surgery for a giant hiatal hernia. PMID- 25513913 TI - An unusual case of severe upper gastrointestinal bleeding treated using an endovascular technique. PMID- 25513914 TI - Small bowel trauma: current approach to diagnosis and management. PMID- 25513915 TI - Theodor Billroth: A Surgeon for the 21st Century. AB - This perspective article describes unique aspects of Theodor Billroth's personality and life, which enabled him to succeed and become a leading figure of 19th century medicine. These qualities are discussed with today's developing surgeon in mind. PMID- 25513916 TI - Surgeons and their tools: a history of surgical instruments and their innovators- Part II: The surgeon's wand-evolution from knife to scalpel to electrocautery. AB - This is the second of five articles reviewing the historical origins of some of the more commonly used surgical instruments and takes "time out" to remind current surgeons about the surgical pioneers on whose shoulders they now stand and whose inventions they now use. PMID- 25513917 TI - Niels thorkild Rovsing: the surgeon behind the sign. AB - Niels Thorkild Rovsing (1862 to 1927) was a Danish surgeon. His eponyms include the Rovsing sign of acute appendicitis, the Rovsing syndrome (abdominal pain in a horseshoe kidney), the Rovsing operation I (for polycystic kidney), and the Rovsing operation II (to separate a fused "horseshoe" kidney). He received his M.D. degree in 1885 and his Ph.D. in 1889 from Copenhagen University. Rovsing practiced surgery from 1892 to 1902 at the Queen Louise Children's Hospital and the Red Cross Hospital, both located in Copenhagen. He became Professor of Surgery in 1899 and Director of Surgery at the Royal Frederiks Hospital in 1904. Rovsing earned international recognition for his innovative urological surgery. Together with his colleague, Eilert A. Tscherning, Rovsing founded the Danish Surgical Society (Dansk Kirurgisk Selskap) in 1908. His advocacy for antisepsis and Listerism advanced his notoriety and exemplified his medical leadership. His clarion call for a modern hospital led to the construction of the Copenhagen University Hospital (Rigshospitalet) that opened in 1910. Rovsing was an Honorary Member of the Edinburgh Medico-Chirurgical Society and the Association of Surgeons of Great Britain and Ireland. Rovsing served briefly as Denmark's Minister of Education in 1920. He died in 1927 from cardiac failure and laryngeal cancer. PMID- 25513918 TI - Surgical repair of ileovesical fistulas: long-term complications, quality of life, and patient satisfaction. AB - Ileovesical fistulas (IVFs) are an uncommon complication of Crohn's disease. The aim of this study is to compare long-term surgical outcomes, assess quality of life, and quantify patient satisfaction after IVF repair. A retrospective chart review followed by a prospective survey was carried out. Survey questions focused on patient satisfaction and quality of life after repair of IVF. Fifty-one patients were identified from an administrative database. Mean follow-up was 4.3 years with a response rate of 51 per cent. At the time of the study, 0 per cent mortality and 16 per cent morbidity were recorded. No recurrence was noted. There was no statistical significance in incidence of complications between laparoscopic and open surgery. Statistically significant differences in single stage versus multistage operations were found in postoperative day of discharge (P < 0.001) and patient satisfaction (P = 0.049). Ninety-eight per cent of patients reported extreme satisfaction with their surgery and an improvement in quality of life. A low incidence of morbidity and recurrence supports early surgical intervention in IVFs. PMID- 25513919 TI - Clinical features and management of pancreatic solid pseudopapillary tumor. AB - Solid pseudopapillary tumor (SPT) is a rare pancreatic tumor with low malignant potential. Between February 2006 and May 2013, six patients were affected by SPT. Two patients were male and four were female. Median age of the patients was 31.5 years (range, 13 to 47 years). One patient was preoperatively diagnosed by an endoscopic ultrasound-guided fine-needle aspiration biopsy. Pancreaticoduodenectomy was performed in two and distal pancreatectomy was done in four. One operation of those was laparoscopic distal pancreatectomy. In this series, recurrence or distant metastasis was not reported and successful outcome was achieved in all patients. In conclusion, whereas diagnosis of SPT is difficult, it can be diagnosed by endoscopic ultrasound-guided fine-needle aspiration biopsy preoperatively. It should be treated by surgery, and laparoscopic operation can be considered. PMID- 25513920 TI - Frequency of lower urinary tract injury after gastrointestinal surgery in the nationwide inpatient sample database. AB - Bladder and ureteral injury are serious iatrogenic complications during abdominal and pelvic surgery but are poorly investigated in the general surgery literature. The objective of this study was to examine rates, trends, and patient and surgical characteristics present in lower urinary tract injuries during gastrointestinal surgery using the Nationwide Inpatient Sample (NIS) database. The NIS database was queried from 2002 to 2010 for gastrointestinal surgery procedures including small/large bowel, rectal surgery, and procedures involving a combination of the two. These were crossreferenced with bladder and ureteral injury using International Classification of Diseases, 9th Revision, Clinical Modification codes. Multivariate regression analysis was used to calculate odds ratios for hypothesized risk factors. From 2002 to 2010, total average rates of bladder injury and ureteral injury were 0.15 and 0.06 per cent, respectively. Small/large bowel procedures had lower annual rates of ureteral (0.05 to 0.07%) and bladder (0.12 to 0.14%) injuries compared with ureteral (0.11 to 0.25%) and bladder (0.27 to 0.41%) injuries in rectal procedures. Presence of metastatic disease was associated with the greatest risk for bladder (odds ratio, 2.0; 95% confidence interval, 1.8 to 2.2) and ureteral (2.2; 1.9 to 2.5) injury in small/large bowel surgery, and for bladder (3.1; 2.5 to 3.9) and ureteral (4.0; 3.2 to 5.0) injury in combination procedures. Injury rates were significantly greater in open surgeries compared with laparoscopic procedures for both bladder injury (0.78 vs 0.26%, P < 0.0001) and ureteral injury (0.34 vs 0.06%, P < 0.0001). The incidence of genitourinary (GU) injury in gastrointestinal surgery is rare, less than 1.0 per cent, and is less than the incidence of GU injury reported in gynecologic surgery. This risk is increased by operations on the rectum and the presence of malignancy. PMID- 25513921 TI - The functional outcomes of coloanal and low colorectal anastomoses with reservoirs after low rectal cancer resections. AB - Nearly half of patients undergoing low anterior rectal cancer resection have a functional sequelae after straight coloanal or low colorectal anastomoses (SA), including low anterior rectal resection syndrome, which combines stool fragmentation, urge incontinence, and incontinence. SA are responsible for anastomotic leakage rates of 0 to 29.2 per cent. Adding a colonic reservoir improves the functional results while reducing anastomotic complications. These colonic reservoir techniques include the colonic J pouch (CJP), transverse coloplasty (TC), and side-to-end anastomosis (STEA) procedures. The aim of this literature review was to compare the functional outcomes of these three techniques from a high level of evidence. CJP with a 4- to 6-cm reservoir is a good surgical option because it reduces functional impairments during the first year, and probably up to 5 years, but is not always feasible. TC appears to perform as well as CJP, is achievable in over 95 per cent of patients, but still with some doubts about a higher anastomotic leakage rate and worse functional outcomes. STEA appears equivalent to CJP in terms of morbidity and even better functional outcomes. STEA, with a terminal side segment size of 3 cm, is feasible in the majority of nonobese patients, combines good functional results, has low anastomotic leakage rates, and is easy to complete. PMID- 25513922 TI - Single-center experience with live kidney donors 60 years of age or older. AB - Live donor kidney transplantation (LDKT) with elderly donors is a controversial topic. The purpose of this study was to evaluate donor and recipient outcomes involving live donors 60 years of age or older. All LDKTs performed at our institution from January 2000 to January 2011 were evaluated. Statistical analysis included t test, uni- and multivariate regression analyses, and Kaplan Meier survival analysis. Forty-seven LDKTs were performed with donors 60 years of age or older. Median donor age was 65 years. Fifty-seven per cent were female. Forty-one recipients received their first KT (seven pre-emptive). Initial graft function was documented in 45 patients (96%). After a median follow-up of 69 months, 1-, 3-, and 5-year graft and patient survival rates were 98, 98, and 95 per cent and 96, 94, and 87 per cent, respectively. Univariate Cox proportional hazard analysis showed donor body mass index and previous KT to be predictors of graft survival. Recipient comorbidity index, HLA-B mismatches, and creatinine level at 2 years post-KT were predictors of patient survival. None of these variables remained significant by multivariate analysis. Female gender was the only positive predictor of donor postoperative creatinine levels. Satisfactory long-term donor and recipient outcomes can be achieved with live kidney donors 60 years of age or older. Careful evaluation and selection remain key to success. The role of female gender in donor long-term kidney function should be further investigated. PMID- 25513923 TI - Inferior vena cava filters in trauma patients: a national practice patterns survey of U.S. Trauma centers. AB - Inferior vena cava filters (IVCFs) for thromboprophylaxis in trauma patients are being increasingly used despite a lack of strong clinical data in support of their efficacy and conflicting clinical practice guidelines. This national survey elucidates practice patterns of IVCF use across U.S. trauma centers. A web-based survey was administered to members of the Eastern Association for the Surgery of Trauma between September 2011 and October 2011. The survey queried: 1) background and professional practice; 2) trauma patient population; 3) IVCF placement; 4) IVCF retrieval and follow-up; and 5) pharmacologic prophylaxis. Two hundred eighty-one of 1059 eligible providers completed the survey (27%). Respondents were from a wide spectrum of training backgrounds and clinical practice settings. IVCFs were used by 98.9 per cent of respondents. IVCFs in patients without known venous thromboembolism were considered by 93.2 per cent of respondents. Indications and timing of IVCF retrieval vary. Follow-up care of patients with IVCFs was not uniform. An IVCF registry was maintained by 38 per cent of trauma programs. Adjunctive pharmacologic prophylaxis was used by 96.8 per cent of respondents. This study elucidates the gaps and variations in contemporary practices of IVCF use in trauma patients. Identification of best practices in IVCF use and retrieval awaits well-designed comparative effectiveness studies. PMID- 25513924 TI - Comparison of a flexible-tip laparoscope with a rigid straight laparoscope for single-incision laparoscopic cholecystectomy. AB - This study assessed whether a flexible-tip laparoscope improves operative outcomes including operative length while performing single-incision laparoscopic cholecystectomy (SILC) compared with the use of a conventional straight laparoscope. The flexible-tip laparoscope decreased the operative time compared with the straight laparoscope. Although SILC has potential benefits, surgeons experience problems for in-line viewing through a laparoscope and from contact of instruments with the laparoscope, resulting in longer operative times and the need for additional ports. The aim of this study was to determine whether a flexible-tip laparoscope improves operative outcomes, including operative length and the rate of insertion of additional ports, while performing SILC compared with the use of a conventional rigid straight laparoscope. We reviewed data on patients for whom we performed SILC at the Department of Surgery, Kansai Medical University, for the period from November 1, 2009, to February 28, 2013. The information was assessed with respect to patient characteristics, types of laparoscope used, operative data as well as postoperative outcomes. Operating time for SILC using the flexible-tip laparoscope was significantly shorter than with the straight laparoscope (81.5 +/- 23.2 vs 94.4 +/- 21.1 minutes) as a result of a better view of the operating field without contact with working instruments. Although a trend was shown toward a reduced rate of the need for extra ports in the flexible-tip laparoscope group, the difference did not reach statistical significance. Using the flexible-tip laparoscope solved the problem of in-line viewing and decreased the operative time for SILC. PMID- 25513925 TI - Old dogs and new tricks: length of stay for appendicitis improves with an acute care surgery program and transition from private surgical practice to multispecialty group practice. AB - Acute care surgery (ACS) programs have emerged mainly at academic medical centers to provide timely care for emergency general surgery and trauma patients. We hypothesized that the development of an ACS program in a multispecialty group practice would improve outcomes for patients with acute appendicitis. A retrospective analysis of patients with acute appendicitis was performed in two time periods: 18 months of private practice and the following 12 months with ACS coverage. Length of stay was the primary outcome measure. A total of 871 patients were studied (526 private practice, 345 ACS). The ACS group had a greater proportion of laparoscopic appendectomies (P < 0.001) and more transitions in care between surgeons (P < 0.001). Length of stay was shorter in the ACS group (1.6 +/- 1.5 [mean +/- standard deviation] vs 1.9 +/- 2.4 days, P = 0.01) and a greater proportion of surgeries were performed during the daytime (44.9 vs 36.6%, P = 0.02). Multivariate analysis demonstrated length of stay was related to appendicitis grade (P < 0.001), American Society of Anesthesiologists class (P < 0.001), symptom duration (P = 0.001), and laparoscopic approach (P < 0.001). The initial transition from private practice to ACS resulted in decreased length of stay with no increase in morbidity related to transitions of surgical care in patients with appendicitis. PMID- 25513926 TI - Employment and hospital support among pediatric surgeons. AB - Employment, either by an academic entity or a hospital, is increasingly becoming a feature of surgical practice. Independent practices receive indirect subsidies to support their revenue. A survey of the extent of employment and the forms of indirect subsidies by which hospitals support independent practices, not previously done, would be of interest to all clinicians. A 2012 Internet survey of pediatric surgeons, asking practice description, hospital support, governance and management, conditions of compensation, selected contractual obligations, and arrangements for part-time coverage was conducted. Response rate was 21.8 per cent (253 of 1,163). Employed surgeons comprised 80 per cent: 60 per cent academic (152 of 253) and 20 per cent nonacademic (51). Only eight per cent (19) were in private practice. Half (47% [106 of 226]) had administrative tasks. One fifth (20% [45 of 223]) was in a system without physician input in governance. The rest were in practices with physicians involved in management: on boards of directors (35% [78]), in management positions (31% [69]), and entirely physician run (14% [31]). Most salaries were independent of external benchmarks. Productivity measures, when applied to compensation (54% [117 of 218]), used relative value units (71% [83 of 117]) more often than revenue production (29% [34]). Patient contact minimums (4% [nine of 217]) and penalties were less common (20% [43 of 218]) than bonus provisions (53% [116 of 218]). Most surgeons in private practice (75% [14 of 19]) received nonsalary hospital support. Pediatric surgery reflects the current trend of physician employment and hospital subsidies. Surgeon participation in governance and strategic system decisions will be necessary as healthcare systems evolve. PMID- 25513927 TI - Gastroesophageal reflux disease-related symptom assessment in subjects with malignant dysphagia receiving esophageal stents. AB - Concerns remain over the ability to stent across of the lower esophageal sphincter (LES) for esophageal adenocarcinoma and the effects of gastroesophageal (GE) reflux. Thus, the aim of this study was to demonstrate minimal quality-of life (QOL) side effects in patients undergoing esophageal stenting across the LES. An Institutional Review Board-approved prospective clinical trial evaluated the results of the Gastrointestinal Symptom questionnaire that includes a validated GE reflux disease (GERD) assessment (GERD-HRQL) and a dysphagia assessment. Consecutive patients were enrolled in this clinical trial, with 81 per cent male, 19 per cent female, median age of 62 years, with adenocarcinoma of the GE junction as their diagnosis. The median dysphagia score was 3 (only liquids can be tolerated) prestent and was improved to a median score of 0 (ability to eat all foods) poststent (P = 0.01). The median GERD score was 0 (none) prestent and did not change with a median score of 0 (none) poststent (P = 0.2). All GERD-related questions were unchanged prestent and poststent in all categories, specifically: frequency of GERD, time of day of reflux, pain behind breastbone, and pain medications. There was also no difference in regurgitation frequency (median prestent 1 vs poststent 0, P = 0.08), texture (prestent 2 [semisolid] vs poststent 1 [liquid]). There was only a statistical change in the ability to belch (prestent 0 [no ability] to poststent 1 [ability]), P = 0.02) and the ability to vomit. Esophageal stenting across the GE junction for dysphagia relief in esophageal malignancies does not adversely effect a patient's QOL in regard to reflux-related symptoms. PMID- 25513928 TI - A simplified technique for tumor localization using preoperative endoscopic clipping and radio-opaque markers during totally laparoscopic gastrectomy. AB - Tumor localization during intracorporeal anastomosis after totally laparoscopic distal gastrectomy (TLDG) is challenging. The aim of this study was to assess the simplicity and feasibility of locating tumors in the stomach using radio-opaque markers and preoperative endoscopic clipping. The intra- and postoperative findings of 29 patients who underwent TLDG with intracorporeal anastomosis between January 2012 and March 2013 were reviewed. Preoperative endoscopic clips were applied just proximal to the tumor by specialized endoscopists, and surgical gauze with an attached radio-opaque marker (3 mm * 60 mm) was prepared. The marker was fixed to either the anterior or posterior of the stomach, above the predicted site of the tumor, using suture ties. Portable abdominal radiography was used during the laparoscopic surgery, and the stomach was resected using guidance by the radiomarker. The radio-opaque marker and the endoscopic clips were clearly visible by intraoperative abdominal radiography. All patients received curative resection. No complications or deaths were encountered. The mean distance between the endoscopic clips and the radiomarker by portable intraoperative radiography was 21.3 +/- 18.3 mm, whereas the actual in situ mean distance was 20.7 +/- 17.6 mm. This difference was not statistically significant (P > 0.05). It is imperative that preoperative endoscopic clips are applied just proximal to the tumor by specialized endoscopists. The use of a radio-opaque marker is a simple and feasible way to locate tumors during totally laparoscopic gastrectomy. PMID- 25513929 TI - Hidradenocarcinoma: a sinister diagnosis of a suspected benign condition. PMID- 25513930 TI - Scalp melanoma and in-transit metastases: a retrospective case-controlled study. PMID- 25513931 TI - Same-day discharge after laparoscopic sleeve gastrectomy: our initial experience. PMID- 25513932 TI - Gram stain can be used to safely discontinue vancomycin therapy for early pneumonia in the trauma intensive care unit. PMID- 25513933 TI - Doppler-guided hemorrhoidal artery ligation and rectoanal repair modification for the treatment of grade III and grade IV hemorrhoids: one-year follow-up. PMID- 25513934 TI - Fate of the combined adult and pediatric trauma centers: impact of increased pediatric trauma requirements. PMID- 25513935 TI - Aggregation behavior of rod-coil-rod triblock copolymers in a coil-selective solvent. AB - Recent experiments have reported that the self-assembly of conjugated polymers mimicking rod-coil-rod triblock copolymers (BCPs) in selective solvents exhibits unique aggregate morphologies. However, the nature of the arrangement of the polymers within the aggregates and the spatial organization of the aggregates remain an unresolved issue. We report the results of coarse-grained Langevin dynamics simulations, which investigated the self-assembly behavior of rod-coil rod BCPs in a coil-selective solvent. We observe a rapid formation of cylindrically shaped multichain clusters. The initial stages of formation of the aggregates was seen to be independent of the strength of the solvent selectivity. However, for higher solvent selectivities, the clusters were seen to merge into larger units at later stages. A reduction in rod to coil block ratio was observed to decrease the size and number of clusters. In the limit of a highly concentrated solution, we observe the formation of a networked system of distinct clusters, which however retain the cylindrical arrangement observed at lower polymer concentrations. PMID- 25513936 TI - A new approach for high-yield metal-molecule-metal junctions by direct metal transfer method. AB - The realization of high-yield, stable molecular junctions has been a long standing challenge in the field of molecular electronics research, and it is an essential prerequisite for characterizing and understanding the charge transport properties of molecular junctions prior to their device applications. Here, we introduce a new approach for obtaining high-yield, vertically structured metal molecule-metal junctions in which the top metal electrodes are formed on alkanethiolate self-assembled monolayers by a direct metal transfer method without the use of any additional protecting interlayers in the junctions. The fabricated alkanethiolate molecular devices exhibited considerably improved device yields (~70%) in comparison to the typical low device yields (less than a few %) of molecular junctions in which the top metal electrodes are fabricated using the conventional evaporation method. We compared our method with other molecular device fabrication methods in terms of charge transport parameters. This study suggests a potential new device platform for realizing robust, high yield molecular junctions and investigating the electronic properties of devices. PMID- 25513937 TI - Metabolic and cardiovascular responses during aquatic exercise in water at different temperatures in older adults. AB - PURPOSE: The aim of this study was to investigate the physiological responses during upper-body aquatic exercises in older adults with different pool temperatures. METHOD: Eleven older men (aged 65 years and older) underwent 2 identical aquatic exercise sessions that consisted of 3 upper-body exercises using progressive intensities (30, 35, and 40 metronome beat . min(- 1)) on separate visits. Water temperatures for the visits were 28 degrees C (cold water [CW]) and 36 degrees C (hot water [HW]), and water depth ranged from 1.2 m to 1.4 m. Measurements for heart rate (HR), blood pressure (BP), oxygen consumption (VO2), and rate of perceived exertion (RPE) were compared between the CW and HW conditions. RESULTS: The comparison between temperatures showed a higher HR response during exercise in HW, particularly when participants exercised at the highest intensities. During a 30-min postexercise period in resting conditions, HR was statistically significantly higher for the HW condition compared with the CW condition, with a large effect size (15.9%, d = 1.23). Systolic and diastolic BPs were found to be lower for the HW condition ( - 7.2%, d = - 0.60; - 10.1%, d = - 0.65), while VO2 and RPE showed no differences. The effect size between double products (HR . systolic BP) for the 2 conditions was small (CW = 8,649 +/- 1,287, HW = 9,340 +/- 1,672; d = 0.36), suggesting similar myocardial oxygen requirements. CONCLUSION: This study showed that HR response was higher in an HW condition for older men. Warmer environments may add additional stressors to the body, which may impact training strategies and should be considered when estimating the effort of performing aquatic exercise. PMID- 25513938 TI - Violence, threat, and emotional "malnourishment": an interview with Dr. Dan Gottlieb. AB - Daniel Gottlieb, Ph.D., is a psychologist and host of the National Public Radio (NPR) program Voices in the Family. He is interviewed here by Victor Schermer about his views on the increase in violence in American society. He sees violence to be partly a consequence of interpersonal "malnourishment," a lack of empathy, trust, and connectedness in our communities. Thus, the therapist's openness and non-judgmental reflection is helpful in establishing social connectedness and diminishing anger and violence. He advocates that therapists engage in social action by facilitating community meetings to bring people together to discuss their conflicts and find commonalities among them. PMID- 25513939 TI - A group therapist reflects on violence in America. AB - In this paper, the author draws on his experience as a group therapist, noting parallels between the often intense but well contained dynamics of therapy groups and what they can tell us about violence in America. He examines the tension between bearing and understanding feelings and the desire to act on them, sometimes destructively in therapy groups and in society. He notes the omnipresent desire to find scapegoats rather than bear our own discomforts and notes the same in the abuse through which those in power scapegoat those under their control. Using the ideas of Roche, Volkan, and others, he also notes that current violence emerges from threats to individual or group identities often embedded in unfinished crises in the past, whether in a therapy group or in American society. Unresolved racial tensions reaching into the past is one outstanding example. He concludes noting the important role of reparation and forgiveness in therapy groups and society to slow the forward movement of violence. PMID- 25513940 TI - The dangerous role of silence in the relationship between trauma and violence: a group response. AB - This article considers that somewhere in the space between violence and trauma is dangerous silence. Silence intensifies the impact of trauma, and trauma that goes unspoken, un-witnessed, and unclaimed too often "outs itself" as more violence to self or others. Relevant empirical evidence on the impact of civilian interpersonal violence, combat trauma, school shootings, bullying, and domestic violence confirms this tragic cycle. Crucial to addressing the danger of silence in this cycle, the article examines the centrality of silence existentially, neuropsychologically, psychologically, developmentally, interpersonally, and culturally in relation to violence. The bridge to voicing and assimilating the unspeakable is empathic connection with others. Drawing upon two different types of group programs, the article demonstrates that group can serve as that bridge. Group process has the potential to undo the dangerous role of silence in the relationship of trauma and violence. PMID- 25513941 TI - There's always a villain to punish: group processes contributing to violence and its remediation. AB - This paper considers the widespread use of violent metaphors, such as "combat" and "war," to represent the current social, psychological, and political problems within the United States. I apply Lakoff and Johnson's (1980) thesis that metaphor shapes thought, policy, and behavior. I examine how use of such metaphors inclines the national consciousness toward violence and punishment for it. In addition, I discuss shame and humiliation as psychological precursors of violence, particularly as these play out in the exclusion and extrusion via group scapegoating of individuals and whole groups from active participation in an esteemed or powerful other group. Included within the concept of "violence" are those harmful social policies that invalidate the experiences of disempowered people within the United States. I consider the role of group processes in resolving the injuries wrought by violence, particularly as these operate within such restorative justice projects as the Glencree Ex-Combatants Programme in Northern Ireland. Lessons emerge from restorative justice projects installed internationally for ameliorating conflict within and between "victim" groups in the United States. PMID- 25513942 TI - Voice of Violences video series. PMID- 25513943 TI - A cigar is sometimes just a cigar, but a dog is never just a dog. PMID- 25513944 TI - Increasing success in neurocognitively impaired patients through group therapy. AB - This eight-session support group program was presented at the American Group Psychotherapy Association's (AGPA) 2013 Spring Conference in New Orleans, Louisiana. The presentation focused on creating hope and increasing motivation in neurocognitively impaired individuals. The premise was that this standardized intervention process delivered weekly at the beginning of an individual's outpatient neurorehabilitation program would enhance commitment and success. This program was formatted to address: setting goals for recovery, relating to others, restructuring negative thinking, addressing feelings, identifying barriers to recovery, resolving grief issues, creating hope, redefining the self, rebuilding self-esteem, and exploring coping strategies. PMID- 25513945 TI - Effectiveness of skills for academic and social success (SASS) with Portuguese adolescents. AB - Social fears are common among adolescents and may considerably impair their lives. Even so, most adolescents do not seek professional help for these difficulties, making it important to promote evidence-based and preventive interventions in community samples. This research presents the effectiveness of an intervention with a group of five female adolescents who reported serious interference of their social fears in their daily life. At post-intervention, effectiveness was noticeable by high recovery, reliable individual change, and intragroup statistical change. The intervention showed impact for measures of social anxiety, avoidance, and assertiveness, and such impact was steady at 3 month follow-up. These findings add to the cumulative and transcultural evidence on the effectiveness of Skills for Academic and Social Success (SASS). PMID- 25513948 TI - The endlessly fascinating complexity of just being yourself: remembering Barbara Cohn. PMID- 25513950 TI - Toward understanding and treating violence in America: some contributions from group dynamic and group therapy perspectives: introduction to part I. AB - The co-editors introduce a two-part Special Section of the Journal devoted to understanding and treating violence in America. They examine the relevance of clinical experience for contributions that can be made by group therapists and group dynamic thinkers to the growing national dialogue about this problem. The pervasive nature, causes, and different forms of violence in the United States are compared with those found in other countries. Underlying sociocultural values and myths, historical and current cultural contexts are considered breeding grounds for potential violence. How therapists can promote healthy change in their groups and in the broader society is explored. The articles contained in part one are reviewed against this backdrop. PMID- 25513952 TI - Assessment of planning abilities in individuals with mild cognitive impairment using an open-ended problem-solving task. AB - INTRODUCTION: There is currently limited research evaluating planning abilities, a core subcomponent of executive functioning, in individuals with mild cognitive impairment (MCI). In the present study, we utilized the "Amap Task," an open ended problem-solving task, to separately evaluate the formulation and execution components of planning ability in individuals with MCI. METHOD: Thirty-seven cognitively healthy older adults and 37 individuals with MCI used a map layout of a university apartment to develop and write out a strategy (formulation stage) to successfully complete a list of tasks (e.g., retrieve and fill a water pitcher before placing it in the refrigerator). Subsequently, participants carried out the tasks in the apartment with the aid of their formulated plan (execution stage). RESULTS: MCI participants performed more poorly than older adult (OA) controls during both the formulation and execution stages on measures of task accuracy and task efficiency. However, both groups were able to adjust and improve task accuracy and efficiency from formulation to task execution. Finally, MCI participants took significantly longer to complete the task and adhered less to their formulated plans during task completion. CONCLUSIONS: Using an open ended problem-solving task, the findings revealed that individuals with MCI experienced difficulties with both the formulation and execution components of planning. Like controls, participants with MCI were able to successfully modify their plan online, improving their performance from task formulation to task execution. PMID- 25513951 TI - Comparison of CT-derived ventilation maps with deposition patterns of inhaled microspheres in rats. AB - PURPOSE: Computer models for inhalation toxicology and drug-aerosol delivery studies rely on ventilation pattern inputs for predictions of particle deposition and vapor uptake. However, changes in lung mechanics due to disease can impact airflow dynamics and model results. It has been demonstrated that non-invasive, in vivo, 4DCT imaging (3D imaging at multiple time points in the breathing cycle) can be used to map heterogeneities in ventilation patterns under healthy and disease conditions. The purpose of this study was to validate ventilation patterns measured from CT imaging by exposing the same rats to an aerosol of fluorescent microspheres (FMS) and examining particle deposition patterns using cryomicrotome imaging. MATERIALS AND METHODS: Six male Sprague-Dawley rats were intratracheally instilled with elastase to a single lobe to induce a heterogeneous disease. After four weeks, rats were imaged over the breathing cycle by CT then immediately exposed to an aerosol of ~ 1 MUm FMS for ~ 5 minutes. After the exposure, the lungs were excised and prepared for cryomicrotome imaging, where a 3D image of FMS deposition was acquired using serial sectioning. Cryomicrotome images were spatially registered to match the live CT images to facilitate direct quantitative comparisons of FMS signal intensity with the CT-based ventilation maps. RESULTS: Comparisons of fractional ventilation in contiguous, non-overlapping, 3D regions between CT-based ventilation maps and FMS images showed strong correlations in fractional ventilation (r = 0.888, p < 0.0001). CONCLUSION: We conclude that ventilation maps derived from CT imaging are predictive of the 1 MUm aerosol deposition used in ventilation-perfusion heterogeneity inhalation studies. PMID- 25513953 TI - Distribution of Heparan Sulfate Oligosaccharides in Murine Mucopolysaccharidosis Type IIIA. AB - Heparan sulfate (HS) catabolism begins with endo-degradation of the polysaccharide to smaller HS oligosaccharides, followed by the sequential action of exo-enzymes to reduce these oligosaccharides to monosaccharides and inorganic sulfate. In mucopolysaccharidosis type IIIA (MPS IIIA) the exo-enzyme, N sulfoglucosamine sulfohydrolase, is deficient resulting in an inability to hydrolyze non-reducing end glucosamine N-sulfate esters. Consequently, partially degraded HS oligosaccharides with non-reducing end glucosamine sulfate esters accumulate. We investigated the distribution of these HS oligosaccharides in tissues of a mouse model of MPS IIIA using high performance liquid chromatography electrospray ionization-tandem mass spectrometry. Oligosaccharide levels were compared to total uronic acid (UA), which was used as a measure of total glycosaminoglycan. Ten oligosaccharides, ranging in size from di- to hexasaccharides, were present in all the tissues examined including brain, spleen, lung, heart, liver, kidney and urine. However, the relative levels varied up to 10-fold, suggesting different levels of HS turnover and storage. The relationship between the di- and tetrasaccharides and total UA was tissue specific with spleen and kidney showing a different disaccharide:total UA ratio than the other tissues. The hexasaccharides showed a stronger correlation with total UA in all tissue types suggesting that hexasaccharides may more accurately reflect the storage burden in these tissues. PMID- 25513954 TI - Knowledge, attitudes, and likelihood of pre-exposure prophylaxis (PrEP) use among US women at risk of acquiring HIV. AB - Although the Food and Drug Administration (FDA) approved oral Truvada for pre exposure prophylaxis (PrEP) for women at risk of HIV infection in the US in July 2012, and the Centers for Disease Control and Prevention (CDC) issued guidance for clinicians to provide PrEP to women "at substantial risk of HIV acquisition" in May 2014, there remain no clinical trial data on efficacy among US women, and there is a dearth of research on knowledge, attitudes, and likelihood of use of PrEP among them. We conducted a qualitative focus group (FG) study with 144 at risk women in six US cities between July and September 2013, including locations in the Southern US, where HIV infections among women are most prevalent. FG questions elicited awareness of PrEP, attitudes about administration and uptake, and barriers to and facilitators of use. Women expressed anger at the fact that they had not heard of PrEP prior to the study, but once informed most found it attractive. PrEP was seen as additional, not substitute protection to condoms, and participants suggested several dissemination strategies to meet the diverse needs of women. Key barriers to PrEP uptake included distrust of the medical system, stigma, and cost. Findings suggest that US women view PrEP as an important prevention option, assuming side effects and the cost to the consumer are minimal, the efficacy of the drug is reasonable, and PrEP is delivered by trusted providers in trusted venues. PMID- 25513955 TI - Homoharringtonine increases intestinal epithelial permeability by modulating specific claudin isoforms in Caco-2 cell monolayers. AB - Homoharringtonine (HHT), a natural alkaloid produced by various Cephalotaxus species, has antileukemic activity in acute and chronic myelogenous leukemia. However, HHT can also induce unanticipated effects in the gastrointestinal tract, such as diarrhea and nausea/vomiting, but the mechanism behind these adverse effects has not been clarified. In the present study, we show that HHT affects the epithelial permeability of intestinal Caco-2 cell monolayers. HHT reduced the transepithelial electrical resistance (TER) of Caco-2 cells in a dose- and time dependent manner. The HHT effect was reversible and no cytotoxicity was observed at the concentrations used. HHT simultaneously increased the paracellular flux of the 4 kDa and 40 kDa FITC-dextrans associated with the TER reduction. Immunoblotting analysis revealed that HHT decreased the protein expression of TJ components such as claudin-3, -5, and -7. However, the transcription levels of these claudins were not repressed by HHT treatment. HHT also disturbed the cellular localization of claudin-1 and -4. These changes coincided with the reduced barrier function. Our findings suggest that HHT enhances the paracellular permeability of Caco-2 cell monolayers by modulating the protein expression and localization of claudin isoforms; these actions might be responsible for the gastrointestinal effects of HHT. PMID- 25513957 TI - Lipophilic prodrugs of apomorphine I: preparation, characterisation, and in vitro enzymatic hydrolysis in biorelevant media. AB - Apomorphine, a subcutaneously administered drug for Parkinson's disease with short half-life requires frequent administration leading to patient non compliance. This study aimed at synthesising and purifying lipophilic diesters of apomorphine, and investigating their in vitro degradation in biorelevant media before and after incorporating them into self-emulsifying drug delivery systems (SEDDS) for oral delivery. Two apomorphine diester prodrugs were synthesised: dilauroyl apomorphine (DLA) and dipalmitoyl apomorphine (DPA). The in vitro enzymatic hydrolysis of diesters was performed using biorelevant media with pancreatin to catalyse the diester degradation. The synthesised and purified diesters were found to be free from reactants as impurities confirmed by LC/MS and NMR. DLA and DPA were degraded into corresponding monoesters and free apomorphine within 5 min after adding pancreatin, leaving about 4% and 28% of the intact diester, respectively. The incorporation of the diesters into SEDDS reduced the enzymatic degradation of diesters. In addition, the chain length of diester and the type of oil used in formulations affected diester hydrolysis. The lipophilic apomorphine diesters were substrates of lipases present in pancreatin, and the degree of diester degradation can be controlled by selecting suitable lipid excipients. Therefore, diesters of apomorphine are promising prodrugs for oral delivery aiming at lymphatic transport. PMID- 25513956 TI - Micelle formulation of hexadecyloxypropyl-cidofovir (HDP-CDV) as an intravitreal long-lasting delivery system. AB - There still is an unmet need for a safe and sustained intravitreal drug delivery system. In this study we are proposing and characterizing a micelle based, clear media intravitreal drug delivery system using the lipid derivatized nucleoside analog, hexadecyloxypropyl-cidofovir (HDP-CDV, CMX 001). HDP-CDV forms micelles in water and in vitreous supernatant with the critical micelle concentration of 19 MUg/mL and 9 MUg/mL, respectively at 37 degrees C. The formed micelles had the average size of 274.7 nm and the Zeta potential of -47.1 mV. Drug release study in the excised rabbit vitreous showed a sustained release profile with a half-life of 2.7 days. The micelle formulation of HDP-CDV demonstrated a good safety profile in two animal species (rabbit and guinea pig) following intravitreal injection. The sustained efficacy was tested in a pretreatment study design and the drug potency was tested in an ongoing herpes simplex virus (HSV-1) retinitis model. The pretreatment studies using single intravitreal injection and later HSV-1 infection revealed at least 9 weeks of vitreous presence and therapeutic level of HDP-CDV, with 71% eyes protection from infection. The treatment study demonstrated that intravitreal administration halted active HSV-1 retinitis in 80% of the infected eyes while cidofovir (CDV) treatment failed to suppress active HSV-1 retinitis. In summary, lipid derivatized nucleoside analogs can be formulated as a micelle intravitreal injection and provides a sustained drug release in vitreous for chronic retinal diseases. PMID- 25513958 TI - New serine-derived gemini surfactants as gene delivery systems. AB - Gemini surfactants have been extensively used for in vitro gene delivery. Amino acid-derived gemini surfactants combine the special aggregation properties characteristic of the gemini surfactants with high biocompatibility and biodegradability. In this work, novel serine-derived gemini surfactants, differing in alkyl chain lengths and in the linker group bridging the spacer to the headgroups (amine, amide and ester), were evaluated for their ability to mediate gene delivery either per se or in combination with helper lipids. Gemini surfactant-based DNA complexes were characterized in terms of hydrodynamic diameter, surface charge, stability in aqueous buffer and ability to protect DNA. Efficient formulations, able to transfect up to 50% of the cells without causing toxicity, were found at very low surfactant/DNA charge ratios (1/1-2/1). The most efficient complexes presented sizes suitable for intravenous administration and negative surface charge, a feature known to preclude potentially adverse interactions with serum components. This work brings forward a new family of gemini surfactants with great potential as gene delivery systems. PMID- 25513959 TI - Predicting critical micelle concentration and micelle molecular weight of polysorbate 80 using compendial methods. AB - This manuscript addresses the capability of compendial methods in controlling polysorbate 80 (PS80) functionality. Based on the analysis of sixteen batches, functionality related characteristics (FRC) including critical micelle concentration (CMC), cloud point, hydrophilic-lipophilic balance (HLB) value and micelle molecular weight were correlated to chemical composition including fatty acids before and after hydrolysis, content of non-esterified polyethylene glycols and sorbitan polyethoxylates, sorbitan- and isosorbide polyethoxylate fatty acid mono- and diesters, polyoxyethylene diesters, and peroxide values. Batches from some suppliers had a high variability in functionality related characteristic (FRC), questioning the ability of the current monograph in controlling these. Interestingly, the combined use of the input parameters oleic acid content and peroxide value - both of which being monographed methods - resulted in a model adequately predicting CMC. Confining the batches to those complying with specifications for peroxide value proved oleic acid content alone as being predictive for CMC. Similarly, a four parameter model based on chemical analyses alone was instrumental in predicting the molecular weight of PS80 micelles. Improved models based on analytical outcome from fingerprint analyses are also presented. A road map controlling PS80 batches with respect to FRC and based on chemical analyses alone is provided for the formulator. PMID- 25513960 TI - Tumor necrosis factor-alpha-induced apoptosis of gastric cancer MKN28 cells: accelerated degradation of the inhibitor of apoptosis family members. AB - The role of the inhibitor of apoptosis (IAP) family members in tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis of human gastric cancer MKN28 cells was explored. TNF-alpha induced up-regulation of cIAP2, whereas cycloheximide (CHX) induced down-regulation of XIAP and survivin. Degradation of cIAP1 and XIAP, but not survivin, was accelerated by co-treatment of cells with TNF-alpha and CHX, and TNF-alpha-induced up-regulation of cIAP2 was inhibited by BMS-345541 (NF-kappaB inhibitor). Treatment of MKN28 cells with TNF-alpha plus CHX induced degradation of survivin and activation of caspase-8 and -3, followed by degradation of cIAP1 and XIAP and apoptosis. Proteasome inhibitors (MG132 and epoxomicin) suppressed TNF-alpha plus CHX-induced degradation of survivin, cIAP1, and XIAP as well as apoptosis. A caspase inhibitor (z-VAD-fmk) suppressed TNF alpha plus CHX-induced apoptosis, but allowed degradation of survivin, cIAP1 and XIAP. TNF-alpha receptor 1 and 2 were expressed on MKN28 cells. The magnitude of apoptosis induced by TNF-alpha plus BMS-345541 was much less than that induced by TNF-alpha plus CHX. These findings suggest that TNF-alpha plus CHX-induced apoptosis of gastric cancer MKN28 cells may be caused by accelerated degradation of the IAP family members (survivin, cIAP1, and XIAP), in addition to inhibition of NF-kappaB-dependent synthesis of anti-apoptotic molecules. PMID- 25513961 TI - Monoterpene (-)-citronellal affects hepatocarcinoma cell signaling via an olfactory receptor. AB - Terpenes are the major constituents of essential oils in plants. In recent years, terpenes have become of clinical relevance due to their ability to suppress cancer development. Their effect on cellular proliferation has made them promising agents in the prevention or treatment of many types of cancer. In the present study, a subset of different monoterpenes was investigated for their molecular effects on the hepatocellular carcinoma cell line Huh7. Using fluorometric calcium imaging, acyclic monoterpene (-)-citronellal was found to induce transient Ca(2+) signals in Huh7 cells by activating a cAMP-dependent signaling pathway. Moreover, we detected the (-)-citronellal-activated human olfactory receptor OR1A2 at the mRNA and protein levels and demonstrated its potential involvement in (-)-citronellal-induced calcium signaling in Huh7 cells. Furthermore, activation of OR1A2 results in phosphorylation of p38 MAPK and reduced cell proliferation, indicating an effect on hepatocellular carcinoma progression. Here, we provide for the first time data on the molecular mechanism evoked by (-)-citronellal in human hepatocellular carcinoma cells. The identified olfactory receptor could serve as a potential therapeutic target for cancer diagnosis and treatment. PMID- 25513964 TI - Programmatic and ethical challenges in the implementation of treatment-as prevention in the context of HIV and drug-resistant tuberculosis co-infection in sub-Saharan Africa. AB - There is limited literature on programmatic challenges in the implementation of a treatment-as-prevention (TasP) strategy among human immunodeficiency virus (HIV) and drug-resistant tuberculosis (DR-TB) co-infected individuals in sub-Saharan Africa (SSA). This paper highlights specific programmatic challenges surrounding the implementation of this strategy among HIV and DR-TB co-infected populations in SSA. In SSA, limitations in administrative, human and financial resources and poor health infrastructure, as well as increased duration and complexity of providing long-term treatment for HIV individuals co-infected with DR-TB, pose substantial challenges to the implementation of a TasP strategy and warrant further investigation. A comprehensive approach must be devised to implement TasP strategy, with special attention paid to the sizable HIV and DR-TB co-infected populations. We suggest that evidence-informed and human rights-based guidelines for participant protection and strategies for programme delivery must be developed and tailored to maximise the benefits to those most at risk of developing HIV and DR-TB co-infection. Assessing regional circumstances is crucial, and TasP programmes in the region should be complemented by combined prevention strategies to achieve the intended goals. PMID- 25513962 TI - Surface plasmon resonance (SPR)-based biosensor technology for the quantitative characterization of protein-carotenoid interactions. AB - The surface plasmon resonance (SPR) biosensor method is a highly sensitive, label free technique to study the non-covalent interactions of biomolecules, especially protein-protein and protein-small molecule interactions. We have explored this robust biosensor platform to study the interactions of carotenoid-binding proteins and their carotenoid ligands to assess the specificity of interaction, kinetics, affinity, and stoichiometry. These characterizations are important to further study uptake and transport of carotenoids to targeted tissues such as the macula of the human eye. In this review, we present an overview of the SPR method and optimization of assay conditions, and we discuss the particular challenges in studying carotenoid-protein interactions using SPR. PMID- 25513963 TI - Vaccination of calves against Cooperia oncophora with a double-domain activation associated secreted protein reduces parasite egg output and pasture contamination. AB - With the increasing incidence of anthelmintic resistance worldwide, immunological control of worm infections through vaccination is often put forward as a rational and cost-effective alternative for anthelmintic drugs. In this study we report on the evaluation of a double-domain activation-associated secreted protein purified from the excretory-secretory material of the adult stage of the small intestinal parasite Cooperia oncophora as a vaccine antigen against this parasite. In a first experiment, calves were vaccinated three times i.m. with activation associated secreted protein and Quil A adjuvant or with adjuvant alone, and subsequently challenged with a trickle infection of 25,000 infective larvae in total over 25 days. Vaccinated calves showed a significant reduction of 91% in their cumulative faecal egg counts and a significantly higher number of inhibited L4s present in their intestine compared with control animals. Furthermore, both female and male adult worms were significantly smaller in the vaccinated group than in the control group. In a second experiment, the vaccine antigen was further evaluated under field conditions. Calves were immunised as described above, followed by a natural challenge infection on pasture. Cooperia oncophora faecal egg counts in the vaccinated animals were reduced during the entire grazing period, resulting in a significant reduction in the cumulative faecal egg counts of 58.5%. Numbers of infective C. oncophora larvae were lower on plots grazed by vaccinated calves, with a reduction in mean pasture larval counts of 65% at housing. A significant reduction of 81.6% in total numbers of C. oncophora worms was shown in the vaccinated group compared with the control group. Taken together, the data highlight the protective capacity of the double-domain activation-associated secreted protein and the possibility of controlling C. oncophora infections through vaccination. PMID- 25513965 TI - Rationale and design of MANJUSRI trial: a randomized, open-label, active controlled multicenter study to evaluate the safety of combined therapy with ticagrelor and warfarin in AF subjects after PCI-eS. AB - BACKGROUND: Long-term oral anticoagulant treatment is obligatory in patients with atrial fibrillation (AF, score of CHA2DS2VASc>=2). When these patients undergo percutaneous coronary intervention with a drug-eluting stent (PCI-eS), there is also an indication for aspirin and clopidogrel treatment, according to the ESC Guidelines. However, triple therapy has been known to increase the risk of bleeding complications. Unfortunately, there is little prospective data available to resolve this issue. Therefore, it is imperative that an optimal therapy for AF patients with indications of both anticoagulation and antiplatelet intervention to prevent thrombotic complications without increasing the risk of bleeding is found. OBJECTIVES: This prospective, randomized, multicenter study is going to assess the hypothesis that in persistent or permanent AF patients (score of CHA2DS2VASc>=2) after PCI-eS, the combination therapy of oral anticoagulation (warfarin) and ticagrelor (90 mg/bid) could reduce the risk of bleeding events. DESIGN: A multicenter, active-controlled, open-label, randomized trial is to be performed to evaluate dual antithrombotic therapy (ticagrelor+warfarin) in persistent or permanent AF patients (score of CHA2DS2VASc>=2) after PCI-eS versus the combination of triple antithrombosis (clopidogrel+aspirin+warfarin). The primary endpoint is the overall bleeding up to 6 months, according to TIMI criteria and classifications. The secondary endpoints are the major bleeding events up to 6 months, according to TIMI criteria. The sample size is estimated at 296. CONCLUSION: This study is intended to provide information about the safety characteristics of warfarin and ticagrelor in persistent or permanent AF patients after PCI-eS. No prospective randomized study has been conducted on the issue of antithrombotic therapy using warfarin and ticagrelor in these patients. Therefore, the MANJUSRI trial will help to explore and determine a new potential therapeutic regimen for AF patients after PCI-eS. TRIAL REGISTRATION: Clinical Trials.gov # NCT02206815, registered July 30, 2014. PMID- 25513966 TI - Redox control of cardiac remodeling in atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is a potential cause of thromboembolic events. AF induces significant changes in the electrophysiological properties of atrial myocytes and causes alterations in the structure, metabolism, and function of the atrial tissue. The molecular basis for the development of structural atrial remodeling of fibrillating human atria is still not fully understood. However, increased production of reactive oxygen or nitrogen species (ROS/RNS) and the activation of specific redox-sensitive signaling pathways observed both in patients with and animal models of AF are supposed to contribute to development, progression and self-perpetuation of AF. SCOPE OF REVIEW: The present review summarizes the sources and targets of ROS/RNS in the setting of AF and focuses on key redox sensitive signaling pathways that are implicated in the pathogenesis of AF and function either to aggravate or protect from disease. MAJOR CONCLUSIONS: NADPH oxidases and various mitochondrial monooxygenases are major sources of ROS during AF. Besides direct oxidative modification of e.g. ion channels and ion handling proteins that are crucially involved in action potential generation and duration, AF leads to the reversible activation of redox-sensitive signaling pathways mediated by activation of redox-regulated proteins including Nrf2, NF-kappaB, and CaMKII. Both processes are recognized to contribute to the formation of a substrate for AF and, thus, to increase AF inducibility and duration. GENERAL SIGNIFICANCE: AF is a prevalent disease and due to the current demographic developments its socio-economic relevance will further increase. Improving our understanding of the role that ROS and redox-related (patho)-mechanisms play in the development and progression of AF may allow the development of a targeted therapy for AF that surpasses the efficacy of previous general anti-oxidative strategies. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. PMID- 25513968 TI - Novel fluoroalkyl derivatives of selective kappa opioid receptor antagonist JDTic: Design, synthesis, pharmacology and molecular modeling studies. AB - Novel N- and O-fluoroalkyl derivatives of the highly potent KOR antagonist JDTic were designed and synthesized. Their opioid receptor properties were compared in both in vitro binding assays and modeling approach. All compounds displayed nanomolar affinities for KOR. The fluoropropyl derivatives were more active than their fluoroethyl analogues. N-Fluoroalkylation was preferable to O-alkylation to keep a selective KOR binding. Compared to JDTic, the N-fluoropropyl derivative 2 bound to KOR with an only 4-fold lower affinity and a higher selectivity relative to MOR and DOR [Ki(kappa) = 1.6 nM; Ki(MU)/Ki(kappa) = 12; Ki(delta)/Ki(kappa) = 159 for 2versus Ki(kappa) = 0.42 nM; Ki(MU)/Ki(kappa) = 9; Ki(delta)/Ki(kappa) = 85 for JDTic]. Modeling studies based on the crystal structure of the JDTic/KOR complex revealed that fluorine atom in ligand 2 was involved in specific KOR binding. Ligand 2 was concluded to merit further development for KOR exploration. PMID- 25513969 TI - Bacteroides fragilis response to subinhibitory concentrations of antimicrobials includes different morphological, physiological and virulence patterns after in vitro selection. AB - As antimicrobials are introduced into the environment, microorganisms may respond in different ways, sometimes displaying alterations in cellular physiology. Considering the clinical relevance of the Bacteroides fragilis, strains were selected to investigate bacterial response after exposure to subinhibitory concentrations (SIC) of ampicillin (AMP), ampicillin-sulbactam (AMS), clindamycin (CLI), chloramphenicol (CHL), and its relationship to a host model (BALB/c mice) after experimental challenge. Morphological alterations, and biochemical physiological and genetic profiles were evaluated among drug-selected bacteria. Histopathological evaluation of the liver and spleen, and inflammatory cytokines were determined after bacterial infection in mice. AMP and AMS exposure were related to most significant cellular alterations. Decreased sensitivity to all antimicrobials was observed for all drug-selected bacteria. Down regulation in adherence properties were also observed. Spleen and liver alterations were observed in different patterns. Increased levels of TNF-alpha, IL-6 and IFN-gamma were also observed. Our results show that SICs of AMP, AMS, CLI and CHL may be related to alterations in cell physiology in B. fragilis with implications to the host-bacteria relationship. The data emphasizes the risks of inappropriate chemotherapy, and the concerns regarding ecological consequences lead by SICs of antimicrobials in resident microbiota. PMID- 25513970 TI - Protective effects of Selenium-enriched probiotics on carbon tetrachloride induced liver fibrosis in rats. AB - This study aimed to investigate the effects of Se-enriched probiotics (SP) on the liver fibrosis induced by CCl4 in rats. The results showed that SP significantly decreased serum alanine aminotransferase (87.0 +/- 1.96 U/L), aspartate aminotransferase (101 +/- 3.13 U/L), hepatic hydroxyproline (898 +/- 72.5 MUg/g), and malondialdehyde (2.39 +/- 0.34 nmol/mg) levels, but increased glutathione peroxidase (37.2 +/- 3.19 U/mg), superoxide dismutase (201 +/- 19.2 U/mg), and glutathione levels (3.32 +/- 0.25 mg/g) (P < 0.05) in rats treated by CCl4. SP suppressed hepatic inflammation and necrosis induced by CCl4. Moreover, SP significantly reduced the expression of alpha-smooth muscle actin, collagen, TGF beta1, TIMP-1, and inflammation-related gene and induced apoptosis of activated hepatic stellate cells (P < 0.05) in rats treated by CCl4. Our results suggest that SP could protect the liver from fibrosis by attenuating hepatic oxidative stress, suppressing hepatic inflammation, and inducing apoptosis of hepatic stellate cells. PMID- 25513971 TI - Metacognitive training (MCT) for schizophrenia improves cognitive insight: a randomized controlled trial in a Chinese sample with schizophrenia spectrum disorders. AB - Metacognitive training (MCT) is a group-based treatment program for people with schizophrenia that targets the cognitive biases thought to contribute to the pathogenesis and maintenance of delusions. Although effective in reducing the severity of delusions, the influence of MCT on cognitive insight, and its feasibility in Chinese culture, has yet to be investigated. The present randomized-controlled trial attempted to address these inconsistencies. A Chinese sample of 80 participants with schizophrenia spectrum disorders was randomized to the eight-module MCT program or continued treatment as usual (TAU). All participants were assessed using the Beck Cognitive Insight Scale, which assesses two components of cognitive insight (self-reflectiveness and self-certainty). Participants in the MCT condition subjectively rated their satisfaction with the training. Retention rates were high after four-weeks of MCT (n = 38) or TAU (n = 39). Clients randomized into the MCT condition rated the program favourably and showed significant improvements in cognitive insight (i.e., increased self reflectiveness), relative to TAU controls, who exhibited decreases in cognitive insight at follow-up. These findings suggest that the MCT program is not only subjectively efficacious in Chinese samples, but also improves metacognitive awareness of the processes underlying delusional symptoms. PMID- 25513973 TI - Tolerance to LSD and DOB induced shaking behaviour: differential adaptations of frontocortical 5-HT(2A) and glutamate receptor binding sites. AB - Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25 mg/kg, i.p.) induce a ketanserin sensitive (0.5 mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7* in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB sensitive [(3)H]spiroperidol and DOB induced [(35)S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT2A binding sites and 5-HT2 signalling, respectively; glutamate-sensitive [(3)H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT2 signalling and 5-HT2A binding, respectively, are not or only marginally affected, yet [(3)H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT2A (r=.80) as well as the unchanged [(3)H]glutamate binding sites (r=.84); tolerance to LSD, as opposed, shares variance with the reduction in [(3)H]glutamate binding sites only (r=.86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT2A (down )regulation, glutamate receptors (activated postsynaptic to 5-HT2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex. PMID- 25513974 TI - Abnormal spontaneous neural activity in the anterior insular and anterior cingulate cortices in anxious depression. AB - OBJECTIVE: Anxious depression is a distinct clinical subtype of major depressive disorder (MDD) characterized by palpitations, somatic complaints, altered interoceptive awareness, high risk of suicide, and poor response to pharmacotherapy. However, the neural mechanisms of anxious depression are still not well understood. In this study we investigated changes in neural oscillation during the resting-state of patients with anxious depression by measuring differences in the amplitude of low-frequency fluctuation (ALFF). METHODS: Resting-state functional magnetic resonance imaging was acquired in 31 patients with anxious depression, 18 patients with remitted depression, as well as 68 gender- and age-matched healthy participants. We compared the differences both in the ALFF and fractional ALFF (fALFF) among the three groups. We also examined the correlation between the ALFF/fALFF and the severity of anxiety as well as depression. RESULTS: Anxious depression patients showed increased ALFF/fALFF in the right dorsal anterior insular cortex and decreased ALFF/fALFF in the bilateral lingual gyrus relative to remitted depression patients and healthy controls. The increased ALFF in the dorsal anterior insula was also positively correlated with stronger anxiety in the anxious depression group. Anxious depression patients also displayed increased fALFF in the right ventral anterior cingulate cortex (ACC) compared to remitted depression patients and healthy controls. CONCLUSIONS: Our results suggest that alterations of the cortico-limbic networks, including the right dorsal anterior insula and right ventral ACC, may play a critical role in the physiopathology of anxious depression. PMID- 25513972 TI - TRPC3 channels critically regulate hippocampal excitability and contextual fear memory. AB - Memory formation requires de novo protein synthesis, and memory disorders may result from misregulated synthesis of critical proteins that remain largely unidentified. Plasma membrane ion channels and receptors are likely candidates given their role in regulating neuron excitability, a candidate memory mechanism. Here we conduct targeted molecular monitoring and quantitation of hippocampal plasma membrane proteins from mice with intact or impaired contextual fear memory to identify putative candidates. Here we report contextual fear memory deficits correspond to increased Trpc3 gene and protein expression, and demonstrate TRPC3 regulates hippocampal neuron excitability associated with memory function. These data provide a mechanistic explanation for enhanced contextual fear memory reported herein following knockdown of TRPC3 in hippocampus. Collectively, TRPC3 modulates memory and may be a feasible target to enhance memory and treat memory disorders. PMID- 25513975 TI - Cortical characterization of the perception of intelligible and unintelligible speech measured via high-density electroencephalography. AB - High-density electroencephalography was used to evaluate cortical activity during speech comprehension via a sentence verification task. Twenty-four participants assigned true or false to sentences produced with 3 noise-vocoded channel levels (1--unintelligible, 6--decipherable, 16--intelligible), during simultaneous EEG recording. Participant data were sorted into higher- (HP) and lower-performing (LP) groups. The identification of a late-event related potential for LP listeners in the intelligible condition and in all listeners when challenged with a 6-Ch signal supports the notion that this induced potential may be related to either processing degraded speech, or degraded processing of intelligible speech. Different cortical locations are identified as neural generators responsible for this activity; HP listeners are engaging motor aspects of their language system, utilizing an acoustic-phonetic based strategy to help resolve the sentence, while LP listeners do not. This study presents evidence for neurophysiological indices associated with more or less successful speech comprehension performance across listening conditions. PMID- 25513976 TI - Increased calorie intake at a specific mid-morning meal and increased intake of soft drinks are strongly associated with obesity in Mexican rural women. AB - The study investigated the dietary habits and foods that are associated with obesity in women from a rural area in Mexico. Anthropometry and body fat were measured in 580 women. Participants answered a socioeconomic and a food-frequency questionnaire; a subsample (n = 80) also answered three 24-hour-recall questionnaires. Results showed that obese women consumed more soft drinks and fat than did overweight and normal-weight women. Women who consumed more energy during a mid-morning meal had higher BMI. A strategy to decrease the prevalence of obesity in rural areas could be to encourage limiting the consumption of soft drinks and eliminating or reducing caloric intake at a mid-morning meal. PMID- 25513977 TI - Postinfectious Rhabdomyolysis in a 5-Year-Old Boy: When to Look a Little Deeper. AB - We report on a 5-year-old boy with recurrent severe postinfectious rhabdomyolysis who, after systematic stepwise evaluation, was found to have the adult form of carnitine palmityl transferase II (CPT II) deficiency directly by blood mutation analysis. Timely diagnosis of CPT II deficiency in this case prevented further potentially devastating episodes of rhabdomyolysis by avoiding triggering factors. CONCLUSION: Although most cases of rhabdomyolysis are nonrecurrent and benign, a metabolic myopathy, such as CPT II deficiency, should be suspected in children with episodic muscle necrosis and paroxysmal myoglobinuria. PMID- 25513978 TI - Venous stroke and status epilepticus due to milk-induced anemia in a child. AB - The risk factors for cerebral sinus venous thrombosis include dehydration, infection, and anemia. The clinical presentation in children of venous strokes associated with cerebral venous thrombosis is variable and may include seizures. Acute management should focus on the treatment of the primary cause and anticoagulation or antiplatelet therapy if needed. Early recognition and targeted treatment is important because survivors are at increased risk for long-term neurologic complications. We report a case of a 4-year-old girl who presented with status epilepticus and was subsequently found to have a cerebral venous sinus thrombosis in the transverse and sigmoid sinus, with venous infarction in the temporal lobe. Laboratory results were significant for a microcytic anemia caused by excessive milk intake. Although iron deficiency anemia is a common pediatric disorder, this uncommon presentation demonstrates the potential for neurologic complications secondary to anemia, as well as the need for a high index of suspicion in order to identify venous stroke as a cause in children who present to the emergency department with seizures. PMID- 25513979 TI - Fatal Anaphylactic Shock Ceftriaxone-Induced in a 4-Year-Old Child. AB - One of the most used cephalosporin in clinical practice is ceftriaxone. Anaphylaxis due to the administration of ceftriaxone is considered a rare event. Here, we report a case of fatal anaphylactic shock after the administration of ceftriaxone in a child who had tolerated the drug in past exposures. The allergic pathogenesis is sustained by the clinical data (short time between the inoculation of the drug and the onset of the symptoms; past exposure to the same molecule and probable sensitization) and the postmortem examination findings (polivisceral congestion and intense eosinophilia found in the histological examination). PMID- 25513980 TI - Outpatient Emergency Preparedness: A Survey of Pediatricians. AB - OBJECTIVE: To determine outpatient pediatricians' self-reported experience with and preparation for patient emergencies, and their awareness of the American Academy of Pediatrics (AAP) policy statement on outpatient emergency preparedness. METHODS: A 34-question cross-sectional survey of outpatient pediatric faculty and gratis faculty from the sole medical school in a metropolitan area was used to assess demographic information, training, and equipment for patient emergencies and familiarity with the AAP policy. RESULTS: Of the 57 responses from 123 surveyed physicians (46% response rate), 23% worked in academics and 70% in private practice. At least 1 emergency per month was reported by 39%; 75% referred a patient to the emergency department or hospital at least monthly. Current Pediatric Advanced Life Support (PALS) certification was maintained by 21%, and 42% had current Basic Life Support (BLS). The majority (79%) agreed that respiratory emergencies were most common. Almost all had bag valve mask (96%) in the office; however, only 65% had oropharyngeal airways. All reported feeling comfortable performing bag-valve mask ventilation, but only 68% reported the same comfort level with oropharyngeal airways. About half (44%) had intubation equipment, and about half (47%) had automated external defibrillators. Only 25% performed mock emergencies. About half of pediatricians (53%) reported awareness of the 2007 AAP policy guideline, and one quarter (23%) thought their office met guideline recommendations. CONCLUSIONS: Although emergencies occur frequently in general pediatric offices, pediatricians may not have adequate emergency equipment and training. Variable preparedness reflects the need for greater awareness of and compliance with the AAP policy. PMID- 25513981 TI - Development and characterization of monoclonal antibodies to detect klotho. AB - Although antibodies are commercially available to allow investigation into the biology of the age-regulating protein Klotho, problems with antibody specificity and application functionality are significant barriers to progress. Chief among these limitations is the inability of current tools to allow in vivo validation of binding partners originally identified through transfection of tagged proteins. To overcome this barrier, we generated a series of hybridoma cell lines by immunizing rats with a GST-KL1 fusion protein. Purified antibodies generated from these cell lines differentially detect human or mouse Klotho protein via Western blot, immunocyto/histochemistry, and immunoprecipitation. Specificity of antibody binding to Klotho was confirmed by mass spectrometry following immunoprecipitation. With this confidence in antibody specificity, co immunoprecipitation was utilized to validate the interaction of Klotho/FGFR and Klotho/wnt7a in mouse kidney lysates. PMID- 25513982 TI - Diversity and consistency: a case study of regionalised clinical placements for medical students. AB - OBJECTIVE: A major challenge for medical schools is the provision of clinical skills training for increasing student numbers. This case study describes the expansion of the clinical school network at The University of Queensland (UQ). The purpose of the study was to investigate consistency in medical education standards across a regional clinical teaching network, as measured by academic performance. METHODS: A retrospective analysis of academic records for UQ medical students (n = 1514) completing clinical rotations (2009-2012) was performed using analysis of covariance (ANCOVA) for comparisons between clinical school cohorts and linear mixed-effects modelling (LEM) to assess predictors of academic performance. RESULTS: In all, 13 036 individual clinical rotations were completed between 2009 and 2012. ANCOVA found no significant differences in rotation grades between the clinical schools except that Rural Clinical School (RCS) cohorts achieved marginally higher results than non-RCSs in the general practice rotation (5.22 vs 5.10-5.18; P = 0.03) and on the final clinical examination (objective structured clinical examination; 5.27 vs 5.01-5.09; P < 0.01). LEM indicated that the strongest predictor of academic performance on clinical rotations was academic performance in the preclinical years of medical school (= 0.38; 95% confidence interval 0.35-0.41; P < 0.001). CONCLUSIONS: The decentralised UQ clinical schools deliver a consistent standard of clinical training for medical students in all core clinical rotations across a range ofurban, regional and rural clinical settings. Further research is required to monitor the costs versus benefits of regionalised clinical schools for students, local communities and regional healthcare services. PMID- 25513983 TI - Prevalence of nonalcoholic fatty liver disease and its metabolic risk factors in women of different ages and body mass index. AB - OBJECTIVE: This study aims to investigate the prevalence of nonalcoholic fatty liver disease (NAFLD), to determine the metabolic risk factors of this disease, and to predict nonalcoholic steatohepatitis (NASH) with liver fibrosis in women of different ages and body mass index (BMI). METHODS: In 2010-2011, a cross sectional survey was conducted among 9,360 women at the health checkup center of Zhongnan Hospital (Wuhan, China). The probability of NASH with liver fibrosis was predicted using BAAT (BMI, age, alanine aminotransferase, and triglycerides) score. RESULTS: The prevalence of NAFLD increased from 5.3% to 18.8% in women younger than 45 years versus women aged 45 to 55 years and rose to 27.8% in women older than 55 years. In obese women, the prevalence of NAFLD was 48.4%. Women older than 45 years and obese women with NAFLD had more unfavorable metabolic risk factors. Multiple regression analyses showed that increased BMI and low aspartate aminotransferase-to-alanine aminotransferase ratio were closely related to NAFLD in women of different ages, whereas increasing BMI, BAAT score, age, high triglycerides, alanine aminotransferase, and low aspartate aminotransferase to-alanine aminotransferase ratio were all closely related to NAFLD in obese women. The prevalence of NASH with a BAAT index of 3 or higher was 13.2% and 14.9% in women older than 55 years and obese women with NAFLD, respectively. CONCLUSIONS: Obese and postmenopausal women have a high prevalence of NAFLD and severe metabolic disorders. The prevalence of NASH seems to be considerably higher in obese and postmenopausal women with NAFLD. PMID- 25513984 TI - Adherence to Mediterranean dietary pattern and menopausal symptoms in relation to overweight/obesity in Spanish perimenopausal and postmenopausal women. AB - OBJECTIVE: This study aims to assess the relationship of adherence to the Mediterranean dietary pattern, as well as the presence of menopausal symptoms, with overweight/obesity in Spanish perimenopausal and postmenopausal women. METHODS: Participants in this cross-sectional study were 8,954 Spanish perimenopausal or postmenopausal women. Anthropometric measurements were recorded, and all women were interviewed to assess their adherence to the Mediterranean dietary pattern, using a validated questionnaire and the Menopause and Health subscale of the validated Cervantes Scale. A logistic regression model was used to investigate the association between categories of adherence to the Mediterranean diet and the odds of being overweight/obese. Multinomial logistic regression was used to study the association between menopausal symptoms and the odds of being overweight/obese (reference categories: participants in the low adherence category and participants with no menopausal problems). RESULTS: After adjustment for relevant confounders, the odds ratio (95% CI) for being overweight/obese among women in the highest category of adherence to the Mediterranean dietary pattern was 0.68 (0.60-0.78; P for trend <0.001). The odds ratio (95% CI) for being overweight/obese was 3.05 (1.98-4.71) for the category "severe problems" in comparison with the category "no problems." CONCLUSIONS: Higher adherence to a healthy dietary pattern (Mediterranean diet) is inversely associated with overweight/obesity in perimenopausal and postmenopausal women. The occurrence of low to severe problems during perimenopause or postmenopause is positively associated with overweight/obesity. Therefore, high adherence to the Mediterranean dietary pattern and a body mass index of 25kg/m(2) or lower might improve quality of life in women at these stages. PMID- 25513985 TI - Depressed calcium cycling contributes to lower ischemia tolerance in hearts of estrogen-deficient rats. AB - OBJECTIVE: Estrogens enhance ischemia tolerance (IT) in the myocardium, the mechanism of which remains unclear. We investigated the effects of long-term estrogen deprivation on the intracellular calcium (Ca(2+)(i)) transient of the heart and its possible influence on IT. METHODS: Hearts of ovariectomized (OVX) and sham-operated (control) adult female rats (some receiving estrogen therapy) were studied 10 weeks after surgical operation: control (n = 8), OVX (n = 10), sham-operated estrogen-substituted (n = 7), and ovariectomized estrogen substituted (n = 9). In vivo heart function was assessed by echocardiography, whereas Ca(2+)(i) transients were recorded, concomitantly with left ventricular pressure and coronary flow, by Indo-1 surface fluorometry in isolated Langendorff perfused hearts. Isolated hearts were subjected to a 30-minute global ischemia-30 minute reperfusion protocol. Left ventricular expression of myocardial sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA2a), phospholamban (PLB), and Ser16-phosphorylated PLB was measured. RESULTS: Ovariectomy did not influence resting cardiac function in vivo or ex vivo. However, Ca(2+) removal was slower. During ischemia, Ca(2+)(i) elevation and ischemic contracture were more pronounced after ovariectomy. Postischemic restitution of inotropic function (developed pressure; +dP/dt(max)) and lusitropic function (-dP/dt(max)) and Ca(2+)(i) transient recovery (amplitude; +/-dCa(2+)(i)/dt(max)) were decreased in OVX hearts. Sarcoendoplasmic reticulum Ca(2+)-ATPase expression was unaltered, whereas PLB and Ser16-phosphorylated PLB levels were higher after ovariectomy. All effects of ovariectomy were restored by estrogen therapy. CONCLUSIONS: Ovariectomy impairs myocardial Ca(2+) removal by increasing the expression of the SERCA2a inhibitor PLB. Defective Ca(2+) transport causes ischemic Ca(2+)(i) overload and insufficient postischemic recovery of Ca(2+)(i) transients, which entail depressed hemodynamic restitution. Protection of intact Ca(2+) cycling in the myocardium by estrogens plays a major role in enhancing IT. PMID- 25513986 TI - Identification of a recurrent mitochondrial mutation in a Japanese family with palmoplantar keratoderma, nail dystrophy, and deafness. PMID- 25513987 TI - Getting to Normal: Women's Experiences Self-Managing Their Perceived Blood Pressure Changes. AB - BACKGROUND: In the United States, nearly 25% of all women older than 20 years have hypertension (HTN). Nearly 30% to 50% of persons with HTN experience symptoms attributed to high blood pressure (BP). Women with hypertensive symptoms may connect their symptoms to perceived BP changes and may be using their perceptions about BP changes to guide their HTN self-management. There is limited research about perceived BP changes or their use in self-management. OBJECTIVE: The purpose of this qualitative study is to describe the experiences of women with HTN self-managing their perceived BP changes. METHODS: van Manen's phenomenology methodology and method guided the inquiry. Women with HTN who believed they could tell when their BP changed based on their symptoms were recruited from community settings and were interviewed once with a semistructured guide. Interviews were digitally recorded and professionally transcribed. Textual data were analyzed using thematic analysis to identify major themes. RESULTS: Seven black and 6 white women comprised the study sample. Participants were middle aged (mean [SD], 50.5 [9.62] years), were experienced in living with HTN (mean [SD],10.76 [9.50] years), had at least a high school education, and had a limited annual income (93% <$24 000). One central theme ("getting to normal") and 4 subthemes (i.e., "I can tell," "tending to it," "the wake-up call," and "doing it right") were discovered in the data. The themes depict a process of episodic symptom-driven and day-to-day actions that the participants used to get their BP to normal. CONCLUSIONS: The study is significant as new knowledge was discovered about how women perceive their BP changes and use them to guide self-management. This study contributes to clinical practice through suggestions for improving patient assessments. Results serve as a foundation for further research of the self-management of BP changes and developing belief-based interventions with the potential to improve BP control. PMID- 25513988 TI - Predicting Heart Failure Readmissions. AB - OBJECTIVES: In this study, the effects of sociodemographic and clinical factors on heart failure (HF) readmission risk were examined. BACKGROUND: Hospitals now incur financial penalties for excessive HF readmission rates; therefore, identifying factors associated with risk is essential for designing risk reduction strategies. METHODS: A retrospective cohort study using chart reviews compared HF inpatients (N = 245) who were readmitted with those who were not readmitted. RESULTS: The sample included mostly white (64%) elderly (mean [SD] age, 69.8 [15.1] years) men (49%) and women (51%). Using Cox regression, the number of comorbidities (3-4 or 5-8) and type of comorbidities, specifically renal insufficiency (readmission ratio [RR], 1.7; P = .003), atrial fibrillation (RR, 1.7; P = .005), cardiomyopathy (RR, 1.5; P = .020), followed by a history of myocardial infarction/coronary artery disease (RR, 1.4; P = .055), were the predictors of HF readmission. CONCLUSIONS: Targeting those with high-risk comorbidities is important in designing measures to prevent or delay readmission of HF patients. PMID- 25513990 TI - A library, a nurse, and good health. PMID- 25513992 TI - Stiffness after total knee arthroplasty. AB - Stiffness after total knee arthroplasty (TKA) adversely affects outcome and impacts patient function. Various risk factors for stiffness after TKA have been identified, including reduced preoperative knee range of motion, history of prior knee surgery, etiology of arthritis, incorrect positioning or oversizing of components, and incorrect gap balancing. Mechanical and associated causes, such as infection, arthrofibrosis, complex regional pain syndrome, and heterotopic ossification, secondary gain issues have also been identified. Management of stiffness following TKA can be challenging. The condition needs to be assessed and treated in a staged manner. A nonsurgical approach is the first step. Manipulation under anesthesia may be considered within the first 3 months after the index TKA, if physical therapy fails to improve the range of motion. Beyond this point, consideration should be given to surgical intervention such as lysis of adhesions, either arthroscopically or by open arthrotomy. If the cause of stiffness is deemed to be surgical error, such as component malpositioning, revision arthroplasty is indicated. The purpose of this article is to evaluate the various aspects of management of stiffness after TKA. PMID- 25513989 TI - Characteristics of TCRzeta, ZAP-70, and FcERIgamma gene expression in patients with T- and NK/T-cell lymphoma. AB - Abnormal expression of key signaling molecules and defective T-cell function play a crucial role in the pathogenesis of T-cell immunodeficiency in hematological malignancies. To understand the molecular basis of T-cell signaling abnormalities and TCRzeta chain deficiencies in T- and NK/T-cell lymphoma, the expression level of the TCRzeta, ZAP-70, and FcERIgamma genes in peripheral blood mononuclear cells from 25 patients with T-cell lymphoma, 16 patients with NK/T-cell lymphoma (NK/T-CL), and 26 healthy individuals was determined. In addition, their relationship with disease stage and TCRzeta 3' untranslated region (3'UTR) splice variants was analyzed in this study. The expression level of all three genes was significantly altered with disease progression, and a decreasing trend was found in patients compared with healthy controls. TCRzeta and ZAP-70 were significantly positively related in all samples, and a negative relationship between TCRzeta and FcERIgamma was significantly lost in NK/T-CL patients. Moreover, distinct expression patterns were defined for patient groups with different TCRzeta 3'UTR isoforms. In conclusion, a lower expression pattern for all three genes may indicate a weaker immune status based on reduced TCRzeta and ZAP-70 expression without the complementary effects of FcERIgamma, while aberrant TCRzeta 3'UTR splicing may contribute to T-cell receptor (TCR) signaling regulation in T cells from patients with T- and NK/T-cell lymphoma. PMID- 25513993 TI - Impact of HIV-1 infection on the clinical presentation of syphilis in men who have sex with men. AB - Men who have sex with men (MSM), especially those with HIV-1 infection, are disproportionately affected by syphilis in higher income countries. The course, and some of the clinical features of the disease, especially the development of neurosyphilis, can be affected by HIV-1 co-infection. This review documents potential differences in the clinical features of syphilis in HIV-1 infected and uninfected MSM and highlights the importance of a thorough examination and high index of suspicion when seeing and treating MSM at risk of sexually transmissible infections. PMID- 25513994 TI - Transition from diffusive to subdiffusive motion in colloidal liquids. AB - In this work we report experimental and theoretical results for the motion of single colloidal particles embedded in complex fluids with different interparticle interactions. The motion of particles is found to follow a similar behavior for the different systems. In particular, the transition from the short time diffusive motion to the subdiffusive intermediate-time motion is found to occur when the square root of its mean squared displacement is in the order of 1 tenth of the neighbors' interparticle distance, thus following a quantitative criterion similar to Lindemann's criterion for melting. PMID- 25513996 TI - Comparison of Toxicity and Treatment Outcomes in HIV-positive Versus HIV-negative Patients With Squamous Cell Carcinoma of the Anal Canal. AB - PURPOSE: To compare the toxicity and treatment outcomes in human immunodeficiency virus (HIV)-positive versus HIV-negative patients with squamous cell carcinoma of the anal canal who underwent definitive concurrent chemoradiation at a single institution. MATERIALS AND METHODS: Fifty-three consecutive HIV-positive patients treated between 1987 and 2013 were compared with 205 consecutive HIV-negative patients treated between 2003 and 2013. All patients received radiotherapy at a single regional facility. The median radiation dose was 54 Gy (range, 28 to 60 Gy). Concurrent chemotherapy consisted of 2 cycles 5-FU with mitomycin-C given on day 1+/-day 29). After treatment, patients were closely followed with imaging studies, clinical examinations, and rigid proctoscopies. Outcomes assessed were toxicity rates, progression-free survival, colostomy-free survival, cancer specific survival, and overall survival. RESULTS: Median follow-up was 34 months. Compared with HIV-negative patients, HIV-positive patients were younger (median age, 48 vs. 62 y) and predominantly male sex (98% of HIV-positive patients were male vs. 22% of HIV-negative patients). Of the HIV-positive patients, 37 (70%) were on highly active antiretroviral therapy, 26 (65%) had an undetectable viral load at the time of treatment, and 36 (72%) had a CD4 count>200 (mean CD4 count, 455). There were no significant differences in acute or late nonhematologic or hematologic toxicity rates between the 2 groups. At 3 years, there was no significant difference between HIV-positive and HIV-negative patients in regards to progression-free survival (75% vs. 76%), colostomy-free survival (85% vs. 85%), or cancer-specific survival (79% vs. 88%, P=0.36), respectively. On univariate analysis, there was a trend toward worse overall survival in HIV positive patients (72% vs. 84% at 3 y, P=0.06). For the entire cohort, on multivariate analysis only male sex and stage were predictive of worse survival outcomes. HIV status was not associated with worse outcomes in Cox models. CONCLUSIONS: In the highly active antiretroviral therapy era, HIV-positive patients with anal cancer treated with standard definitive chemoradiation have equivalent toxicity and cancer-specific survival compared with HIV-negative patients. PMID- 25513995 TI - A novel enzymatic approach in the production of food with low purine content using Arxula adeninivorans endogenous and recombinant purine degradative enzymes. AB - The purine degradation pathway in humans ends with uric acid, which has low water solubility. When the production of uric acid is increased either by elevated purine intake or by impaired kidney function, uric acid will accumulate in the blood (hyperuricemia). This increases the risk of gout, a disease described in humans for at least 1000 years. Many lower organisms, such as the yeast Arxula adeninivorans, possess the enzyme, urate oxidase that converts uric acid to 5 hydroxyisourate, thus preventing uric acid accumulation. We have examined the complete purine degradation pathway in A. adeninivorans and analyzed enzymes involved. Recombinant adenine deaminase, guanine deaminase, urate oxidase and endogenous xanthine oxidoreductase have been investigated as potential additives to degrade purines in the food. Here, we review the current model of the purine degradation pathway of A. adeninivorans and present an overview of proposed enzyme system with perspectives for its further development. PMID- 25513997 TI - Exploring the relationship between changes in weight and utterances in an online weight loss forum: a content and correlational analysis study. AB - BACKGROUND: There is increasing interest in the use of online forums as a component of eHealth weight loss interventions. Although the research is mixed on the utility of online forums in general, results suggest that there is promise to this, particularly if the systems can be designed well to support healthful interactions that foster weight loss and continued engagement. OBJECTIVE: The purpose of this study was to examine the relationship between the styles of utterances individuals make on an online weight loss forum and week-to-week fluctuations in weight. This analysis was conducted to generate hypotheses on possible strategies that could be used to improve the overall design of online support groups to facilitate more healthful interactions. METHODS: A convenience sample of individuals using an online weight loss forum (N=4132) included data both on online forum use and weight check-in data. All interactions were coded utilizing the Linguistic Inquiry and Word Count (LIWC) system. Mixed model analyses were conducted to examine the relationship between these LIWC variables and weight over time. RESULTS: Results suggested that increased use of past-tense verbs (P=.05) and motion (P=.02) were associated with lower weekly weights whereas increased use of conjunctions (eg, and, but, whereas; P=.001) and exclusion words (eg, but, without, exclude; P=.07) were both associated with higher weight during the weeks when these utterances were used more. CONCLUSIONS: These results provide some insights on the styles of interactions that appear to be associated with weight fluctuations. Future work should explore the stability of these findings and also explore possibilities for fostering these types of interactions more explicitly within online weight loss forums. PMID- 25513998 TI - Alanine aminotransferase within reference range is associated with metabolic syndrome in middle-aged and elderly Chinese men and women. AB - OBJECTIVE: To investigate the association between serum ALT level within reference range (<=40 U/L) and morbidity of MetS in a large middle-aged and elderly Chinese community population. METHODS: Our study was a community-based cross-sectional survey which used cluster sampling method. From November 2011 to August 2012 a total of 16,539 subjects (males 5184; females 11,355) with serum ALT levels in the normal range aged >=40 years from Shijingshan District (Beijing, China) were included in the study. Data on demographic information, lifestyle, history of diabetes mellitus, hypertension, dyslipidemia and liver disease were collected. Body height, body weight, waist circumference, hip circumference, and blood pressure were recorded. The oral glucose tolerance test or a standard meal test and blood lipid test was performed. The determination of metabolic syndrome was according to the unified criteria published in 2009. The association between serum ALT level and metabolic syndrome was evaluated by logistic regression. The association between serum ALT level and all components of metabolic syndrome was evaluated by multiple linear regression. p < 0.05 was regarded as statistically significant. RESULTS: The prevalence of metabolic syndrome was 41.4% in males and 40.6% in females. We found ALT level was positively associated with odds of metabolic syndrome after adjustment for age, smoking, and alcohol intake. The odds ratio values of MetS in the ALT quartiles 2 4 groups were 1.920 (95%CI: 1.619-2.277), 2.853 (95%CI: 2.407-3.381), and 4.171 (95%CI: 3.510-4.956) in males; 1.889 (95%CI: 1.671-2.136), 3.490 (95%CI: 3.095 3.935), and 5.593 (95%CI: 4.957-6.311) in females, respectively, compared with the ALT quartile 1 group. CONCLUSIONS: Higher serum ALT level within the reference range was associated with increased odds of MetS in middle-aged and elderly Chinese men and women. PMID- 25513999 TI - Mobile applications for participation at the shopping mall: content analysis and usability for persons with physical disabilities and communication or cognitive limitations. AB - The aim of this exploratory study was to determine the important features in content and usability of existing mobile applications evaluating environmental barriers and facilitators (EBF) to participation for persons with physical disabilities presenting mild communication or cognitive limitations. A rigorous process based on a user-centered design approach led to the identification of two relevant mobile applications to evaluate the EBF. An accessibility expert, the research team as well as five users then tested the mobile applications in a shopping mall. A thematic content analysis of the research team's and users' comments established 10 categories of key features that adequately respond to the needs of the clientele targeted in this study. In terms of content, granularity and contextualization of the information provided were considered important. With respect to usability, relevant features were place finding, rating system, presentation of results, compatibility, user-friendliness, aesthetics, credibility of the information as well as connectivity/interactiveness. The research team and the users agreed on some aspects such as aesthetics, but had different perspectives on features such as the rating system or the connectivity/interactiveness of the application. The users proposed new features suggesting that the existing mobile applications did not correspond to all their needs. PMID- 25514001 TI - Xylem. PMID- 25514002 TI - Unconventional colour vision. AB - Butterflies and stomatopods are certainly outliers in their unconventional colour sense and despite some similarities at first glance, in fact sample the world of colour very differently. In one way, butterflies are relatively conventional, possessing either tri-or tetrachromatic colour vision, then just adding one or several task-specific sub-mechanisms onto this. It is the stomatopods so far that have really pushed the boat out into a different colour vision mechanism. Over 400 million years of independent evolution they have arrived at a solution with more in common with the way a satellite sensor examines the colours of the earth than other animals. Remember, however, that unconventional colour vision is not just the realm of the serially polychromatic. Apparently waterfleas with four classes of spectral receptors living in ponds operate a task-specific spectral sense with no need, or indeed neural processing power, to construct a complex discriminatory mechanism. It seems they have the butterfly added-extra set without the more complex comparative chromatic mechanisms, although in truth, conclusive behavioural proof is lacking. Behavioural observation of colour vision in the ecological context of each animal is vital before making the distinction between conventional and unconventional. Just counting spectral sensitivities is never enough. PMID- 25514000 TI - Formylglycine, a post-translationally generated residue with unique catalytic capabilities and biotechnology applications. AB - Formylglycine (fGly) is a catalytically essential residue found almost exclusively in the active sites of type I sulfatases. Formed by post translational oxidation of cysteine or serine side chains, this aldehyde functionalized residue participates in a unique and highly efficient catalytic mechanism for sulfate ester hydrolysis. The enzymes that produce fGly, formylglycine-generating enzyme (FGE) and anaerobic sulfatase-maturating enzyme (anSME), are as unique and specialized as fGly itself. FGE especially is structurally and mechanistically distinct, and serves the sole function of activating type I sulfatase targets. This review summarizes the current state of knowledge regarding the mechanism by which fGly contributes to sulfate ester hydrolysis, the molecular details of fGly biogenesis by FGE and anSME, and finally, recent biotechnology applications of fGly beyond its natural catalytic function. PMID- 25514003 TI - Multistepped optogenetics connects neurons and behavior. PMID- 25514004 TI - Distance-dependent defensive coloration. PMID- 25514005 TI - Animal memory: rats bind event details into episodic memories. AB - A recent study shows that rats remember multiple details of an event in a way that suggests those details are bound into episodic memories that the rats use when faced with a foraging task. PMID- 25514006 TI - Sensory biology: echolocation from click to call, mouth to wing. AB - Echolocators use echoes of sounds they produce, clicks or calls, to detect objects. Usually, these signals originate from the head. New work reveals that three species of bats use their wings to generate echolocation signals. PMID- 25514007 TI - Life history: mother-specific proteins that promote aging. AB - A yeast mother cell progressively ages with each cell division and yet produces daughter cells that are largely rejuvenated, suggesting that mothers accumulate aging factors. Two current studies address this issue by identifying mother specific long-lived proteins and, in the case of Pma1, evidence that asymmetric distribution drives mother cell aging. PMID- 25514008 TI - Neuroscience: who needs a parasol at night? AB - New measurements of nerve cells in the eye show how very dim lights are processed by night-vision pathways. PMID- 25514009 TI - Climate change: many ways to beat the heat for reef corals. AB - Reef-building corals are vulnerable to heat stress and are facing widespread losses due to climate change. A new study shows that coral heat tolerance can result from selection on a suite of genes to maintain genetic flexibility. PMID- 25514010 TI - Synaptic specificity: when the neighbors are away, sensory axons turn promiscuous. AB - A new study describes cellular mechanisms establishing synaptic specificity during development and remodeling of a zebrafish mechanosensory organ. Coordination amongst postsynaptic neurons and interactions between presynaptic and postsynaptic cells together promote the segregation of circuits responding to distinct sensory stimuli. PMID- 25514011 TI - ER morphology: sculpting with XendoU. AB - Endoplasmic reticulum (ER) sheet membranes are covered with ribosomes and RNAs that are involved in protein synthesis. A new study reveals that a calcium activated endoribonuclease of the EndoU protein family promotes the formation of tubular ER networks, contributing to dynamic shaping of the ER in cells. PMID- 25514012 TI - Symmetric development: transcriptional regulation of symmetry transition in plants. AB - Symmetry breaking and re-establishment is an important developmental process that occurs during the development of multicellular organisms. A new report determines that transcription factors regulate a symmetry transition event in plants by modifying the direction of auxin transport. This provides one of the first mechanistic descriptions of a transition from bilateral to radial symmetry in plants. PMID- 25514014 TI - Preparation and size control of sub-100 nm pure nanodrugs. AB - Pure nanodrugs (PNDs), nanoparticles consisting entirely of drug molecules, have been considered as promising candidates for next-generation nanodrugs. However, the traditional preparation method via reprecipitation faces critical challenges including low production rates, relatively large particle sizes, and batch-to batch variations. Here, for the first time, we successfully developed a novel, versatile, and controllable strategy for preparing PNDs via an anodized aluminum oxide (AAO) template-assisted method. With this approach, we prepared PNDs of an anticancer drug (VM-26) with precisely controlled sizes reaching the sub-20 nm range. This template-assisted approach has much higher feasibility for mass production comparing to the conventional reprecipitation method and is beneficial for future clinical translation. The present method is further demonstrated to be easily applicable for a wide range of hydrophobic biomolecules without the need of custom molecular modifications and can be extended for preparing all-in-one nanostructures with different functional agents. PMID- 25514013 TI - Graphene oxide interfaces in serum based autoantibody quantification. AB - A reliable quantification of protein markers will undoubtedly underpin profound developments in disease surveillance, diagnostics, and improved therapy. Although there potentially exist numerous means of achieving this, electrochemical impedimetric techniques offer scale of sensitivity, cost, convenience, and a flexibility with which few alternatives can compete. Though there have been marked developments in electroanalytical protein detection, the demands associated with accessing the inherent assay sensitivity in complex biological media largely remains. We report herein the use of cysteamine-graphene oxide modified gold microelectrode arrays in underpinning the ultrasensitive and entirely label free non-faradaic quantification of Parkinson's-relevant autoantibodies in human serum. PMID- 25514015 TI - Fluidized capacitive bioanode as a novel reactor concept for the microbial fuel cell. AB - The use of granular electrodes in Microbial Fuel Cells (MFCs) is attractive because granules provide a cost-effective way to create a high electrode surface area, which is essential to achieve high current and power densities. Here, we show a novel reactor design based on capacitive granules: the fluidized capacitive bioanode. Activated carbon (AC) granules are colonized by electrochemically active microorganisms, which extract electrons from acetate and store the electrons in the granule. Electricity is harvested from the AC granules in an external discharge cell. We show a proof-of-principle of the fluidized capacitive system with a total anode volume of 2 L. After a start-up period of 100 days, the current increased from 0.56 A/m(2) with 100 g AC granules, to 0.99 A/m(2) with 150 g AC granules, to 1.3 A/m(2) with 200 g AC granules. Contact between moving AC granules and current collector was confirmed in a control experiment without biofilm. Contribution of an electro-active biofilm to the current density with recirculation of AC granules was limited. SEM images confirmed that a biofilm was present on the AC granules after operation in the fluidized capacitive system. Although current densities reported here need further improvement, the high surface area of the AC granules in combination with external discharge offers new and promising opportunities for scaling up MFCs. PMID- 25514016 TI - A DNA-inspired synthetic ion channel based on G-C base pairing. AB - A dinucleoside containing guanosine and cytidine at the end groups has been prepared using a modular one-pot azide-alkyne cycloaddition. Single channel analysis showed that this dinucleoside predominantly forms large channels with 2.9 nS conductance for the transport of potassium ions across a phospholipid bilayer. Transmission electron microscopy, atomic force microscopy, and circular dichroism spectroscopy studies reveal that this dinucleoside can spontaneously associate through Watson-Crick canonical H-bonding and pi-pi stacking to form stable supramolecular nanostructures. Most importantly, the ion channel activity of this G-C dinucleoside can be inhibited using the nucleobase cytosine. PMID- 25514017 TI - A concise total synthesis of breitfussin A and B. AB - The first total synthesis of breitfussin A and B is described. The approach features two palladium-catalyzed cross-couplings installing the indole and pyrrole onto the oxazole core and selective lithiation/iodination of a common indole-oxazole fragment providing 2,4-diiodinated or 2-iodinated oxazoles as potential precursors for breitfussin A and B, respectively. An unexpected acid promoted deiodination was utilized in the synthesis of breitfussin B. Comparison of the synthetic material with previously reported spectral data of isolated breitfussin A and B verified the structure of the breitfussin framework. PMID- 25514018 TI - Microemulsion-controlled synthesis of one-dimensional Ir nanowires and their catalytic activity in selective hydrogenation of o-chloronitrobenzene. AB - Ultrathin iridium nanowires have been synthesized using a convenient method mediated by microemulsion via oriented attachment growth for the first time. The interconnected polycrystalline Ir nanowires possess high aspect ratio, small average diameter of 2 nm, and length up to several hundred nanometers. The 1D growth of surfactant-encapsulated primary nanoparticles, which is determined by the inherent crystal growth habit and the specific interactions of nanocrystals with surfactant molecules, accounts for the formation of Ir nanowires. The as prepared Ir nanowires show high activity and selectivity toward the hydrogenation production of industrially valuable chloroaniline from o-chloronitrobenzene. Theoretical evidence based on DFT calculation indicates that H2 could be dissociated more easily and quickly on Ir(100) surface than on Ir(111), accounting for the higher hydrogenation rate over Ir nanowires exposing both (200) and (111) crystal facets rather than only (111) facet for Ir nanoparticles. PMID- 25514020 TI - [Chilean health budget for 2015: progress, setbacks and absences]. PMID- 25514019 TI - Biochemistry that times the day. PMID- 25514021 TI - Network models of frequency modulated sweep detection. AB - Frequency modulated (FM) sweeps are common in species-specific vocalizations, including human speech. Auditory neurons selective for the direction and rate of frequency change in FM sweeps are present across species, but the synaptic mechanisms underlying such selectivity are only beginning to be understood. Even less is known about mechanisms of experience-dependent changes in FM sweep selectivity. We present three network models of synaptic mechanisms of FM sweep direction and rate selectivity that explains experimental data: (1) The 'facilitation' model contains frequency selective cells operating as coincidence detectors, summing up multiple excitatory inputs with different time delays. (2) The 'duration tuned' model depends on interactions between delayed excitation and early inhibition. The strength of delayed excitation determines the preferred duration. Inhibitory rebound can reinforce the delayed excitation. (3) The 'inhibitory sideband' model uses frequency selective inputs to a network of excitatory and inhibitory cells. The strength and asymmetry of these connections results in neurons responsive to sweeps in a single direction of sufficient sweep rate. Variations of these properties, can explain the diversity of rate-dependent direction selectivity seen across species. We show that the inhibitory sideband model can be trained using spike timing dependent plasticity (STDP) to develop direction selectivity from a non-selective network. These models provide a means to compare the proposed synaptic and spectrotemporal mechanisms of FM sweep processing and can be utilized to explore cellular mechanisms underlying experience- or training-dependent changes in spectrotemporal processing across animal models. Given the analogy between FM sweeps and visual motion, these models can serve a broader function in studying stimulus movement across sensory epithelia. PMID- 25514022 TI - Epithelial cells are active participants in vocal fold wound healing: an in vivo animal model of injury. AB - Vocal fold epithelial cells likely play an important, yet currently poorly defined, role in healing following injury, irritation and inflammation. In the present study, we sought to identify a possible role for growth factors, epidermal growth factor (EGF) and transforming growth factor-beta 1 (TGFbeta1), in epithelial regeneration during wound healing as a necessary first step for uncovering potential signaling mechanisms of vocal fold wound repair and remodeling. Using a rat model, we created unilateral vocal fold injuries and examined the timeline for epithelial healing and regeneration during early and late stages of wound healing using immunohistochemistry (IHC). We observed time dependent secretion of the proliferation marker, ki67, growth factors EGF and TGFbeta1, as well as activation of the EGF receptor (EGFR), in regenerating epithelium during the acute phase of injury. Ki67, growth factor, and EGFR expression peaked at day 3 post-injury. Presence of cytoplasmic and intercellular EGF and TGFbeta1 staining occurred up to 5 days post-injury, consistent with a role for epithelial cells in synthesizing and secreting these growth factors. To confirm that epithelial cells contributed to the cytokine secretion, we examined epithelial cell growth factor secretion in vitro using polymerase chain reaction (PCR). Cultured pig vocal fold epithelial cells expressed both EGF and TGFbeta1. Our in vivo and in vitro findings indicate that epithelial cells are active participants in the wound healing process. The exact mechanisms underlying their roles in autocrine and paracrine signaling guiding wound healing await study in a controlled, in vitro environment. PMID- 25514023 TI - Functional characterization of Corynebacterium glutamicum mycothiol S-conjugate amidase. AB - The present study focuses on the genetic and biochemical characterization of mycothiol S-conjugate amidase (Mca) of Corynebacterium glutamicum. Recombinant C. glutamicum Mca was heterologously expressed in Escherichia coli and purified to apparent homogeneity. The molecular weight of native Mca protein determined by gel filtration chromatography was 35 kDa, indicating that Mca exists as monomers in the purification condition. Mca showed amidase activity with mycothiol S conjugate of monobromobimane (MSmB) in vivo while mca mutant lost the ability to cleave MSmB. In addition, Mca showed limited deacetylase activity with N-acetyl-D glucosamine (GlcNAc) as substrate. Optimum pH for amidase activity was between 7.5 and 8.5, while the highest activity in the presence of Zn2+ confirmed Mca as a zinc metalloprotein. Amino acid residues conserved among Mca family members were located in C. glutamicum Mca and site-directed mutagenesis of these residues indicated that Asp14, Tyr137, His139 and Asp141 were important for activity. The mca deletion mutant showed decreased resistance to antibiotics, alkylating agents, oxidants and heavy metals, and these sensitive phenotypes were recovered in the complementary strain to a great extent. The physiological roles of Mca in resistance to various toxins were further supported by the induced expression of Mca in C. glutamicum under various stress conditions, directly under the control of the stress-responsive extracytoplasmic function-sigma (ECF-sigma) factor SigH. PMID- 25514024 TI - World Health organization guidelines for management of acute stress, PTSD, and bereavement: key challenges on the road ahead. AB - Wietse Tol and colleagues discuss some of the key challenges for implementation of new WHO guidelines for stress-related mental health disorders in low- and middle-income countries. Please see later in the article for the Editors' Summary. PMID- 25514025 TI - Diversity, distribution and hydrocarbon biodegradation capabilities of microbial communities in oil-contaminated cyanobacterial mats from a constructed wetland. AB - Various types of cyanobacterial mats were predominant in a wetland, constructed for the remediation of oil-polluted residual waters from an oil field in the desert of the south-eastern Arabian Peninsula, although such mats were rarely found in other wetland systems. There is scarce information on the bacterial diversity, spatial distribution and oil-biodegradation capabilities of freshwater wetland oil-polluted mats. Microbial community analysis by Automated Ribosomal Spacer Analysis (ARISA) showed that the different mats hosted distinct microbial communities. Average numbers of operational taxonomic units (OTUsARISA) were relatively lower in the mats with higher oil levels and the number of shared OTUsARISA between the mats was <60% in most cases. Multivariate analyses of fingerprinting profiles indicated that the bacterial communities in the wetland mats were influenced by oil and ammonia levels, but to a lesser extent by plant density. In addition to oil and ammonia, redundancy analysis (RDA) showed also a significant contribution of temperature, dissolved oxygen and sulfate concentration to the variations of the mats' microbial communities. Pyrosequencing yielded 282,706 reads with >90% of the sequences affiliated to Proteobacteria (41% of total sequences), Cyanobacteria (31%), Bacteriodetes (11.5%), Planctomycetes (7%) and Chloroflexi (3%). Known autotrophic (e.g. Rivularia) and heterotrophic (e.g. Azospira) nitrogen-fixing bacteria as well as purple sulfur and non-sulfur bacteria were frequently encountered in all mats. On the other hand, sequences of known sulfate-reducing bacteria (SRBs) were rarely found, indicating that SRBs in the wetland mats probably belong to yet undescribed novel species. The wetland mats were able to degrade 53-100% of C12 C30 alkanes after 6 weeks of incubation under aerobic conditions. We conclude that oil and ammonia concentrations are the major key players in determining the spatial distribution of the wetland mats' microbial communities and that these mats contribute directly to the removal of hydrocarbons from oil field wastewaters. PMID- 25514026 TI - Epidemiological characterization and risk factors of allergic rhinitis in the general population in Guangzhou City in china. AB - The prevalence of allergic rhinitis (AR) in China has increased with an apparent geographic variation. The current study aims to investigate the AR prevalence/classification, diagnosis/treatment conditions, trigger factors, and risk factors in the general population of Guangzhou, the third biggest city in China. A cross-sectional survey was performed in the citizens in Guangzhou from December 2009 to March 2010 by using a stratified multistage cluster sampling method. All subjects were asked to complete a comprehensive questionnaire via a face to face interview. A total of 9,899 questionnaires were valid. The prevalence rate of AR in the general population of Guangzhou was 6.24%, with a significant higher prevalence in urban area (8.32%) versus rural area (3.43%). Among the AR subjects, most (87%) were diagnosed with intermittent AR and 87% suffered from moderate-severe symptoms. High percentages of the AR patients did not have previously physician-based diagnosis (34%) or specific medical treatment (55%). Morning time, winter season, and cold air were the most common trigger factors of AR. Family history of AR, current living place, living place during babyhood, smoking, home renovation, and pet ownership were the significant risk factors associated with AR prevalence in the population. The study demonstrated comprehensive epidemiological and clinical information about the AR in Guangzhou population. Change of living environment and lifestyles had strong impacts on the prevalence of AR. Public health policies should help the patients benefit from a proper diagnosis/treatment and specifically target the local risk factors, in order to control the AR incidence. PMID- 25514031 TI - Propagation style controls lava-snow interactions. AB - Understanding interactions between volcanic eruptions and the cryosphere (a.k.a. glaciovolcanism) is important for climate reconstructions as well as for hazard mitigation at ice-clad volcanoes. Here we present unique field observations of interactions between snowpack and advancing basaltic lava flows during the 2012 13 eruption at Tolbachik volcano, Kamchatka, Russia. Our observations show that lava-snow heat transfer is slow, and that styles of lava propagation control snowpack responses. 'A'a and sheet lava flows advance in a rolling caterpillar track motion on top of the rigid, snowpack substrate with minor lava-snow interaction. In contrast, pahoehoe lava propagates by inflation of lobes beneath/inside the snowpack, producing rigorous lava-snow interaction via meltwater percolation down into the incandescent lava causing production of voluminous steam, rapid surface cooling and thermal shock fragmentation. The textures produced by pahoehoe-snowpack interactions are distinctive and, where observed at other sites, can be used to infer syn-eruption seasonality and climatic conditions. PMID- 25514029 TI - Liganded peroxisome proliferator-activated receptors (PPARs) preserve nuclear histone deacetylase 5 levels in endothelin-treated Sprague-Dawley rat cardiac myocytes. AB - Ligand activation of peroxisome proliferator-activated receptors (PPARs) prevents cardiac myocyte hypertrophy, and we previously reported that diacylglycerol kinase zeta (DGKzeta) is critically involved. DGKzeta is an intracellular lipid kinase that catalyzes phosphorylation of diacylglycerol; by attenuating DAG signaling, DGKzeta suppresses protein kinase C (PKC) and G-protein signaling. Here, we investigated how PPAR-DGKzeta signaling blocks activation of the hypertrophic gene program. We focused on export of histone deacetylase 5 (HDAC5) from the nucleus, a key event during hypertrophy, since crosstalk occurs between PPARs and other members of the HDAC family. Using cardiac myocytes isolated from Sprague-Dawley rats, we determined that liganded PPARs disrupt endothelin-1 (ET1) induced nuclear export of HDAC5 in a manner that is dependent on DGKzeta. When DGKzeta-mediated PKC inhibition was circumvented using a constitutively-active PKCepsilon mutant, PPARs failed to block ET1-induced nuclear retention of HDAC5. Liganded PPARs also prevented (i) activation of protein kinase D (the downstream effector of PKC), (ii) HDAC5 phosphorylation at 14-3-3 protein chaperone binding sites (serines 259 and 498), and (iii) physical interaction between HDAC5 and 14 3-3, all of which are consistent with blockade of nucleo-cytoplasmic shuttling of HDAC5. Finally, the ability of PPARs to prevent neutralization of HDAC5 activity was associated with transcriptional repression of hypertrophic genes. This occurred by first, reduced MEF2 transcriptional activity and second, augmented deacetylation of histone H3 associated with hypertrophic genes expressing brain natriuretic peptide, beta-myosin heavy chain, skeletal muscle alpha-actin, and cardiac muscle alpha-actin. Our findings identify spatial regulation of HDAC5 as a target for liganded PPARs, and to our knowledge, are the first to describe a mechanistic role for nuclear DGKzeta in cardiac myocytes. In conclusion, these results implicate modulation of HDAC5 as a mechanism by which liganded PPARs suppress the hypertrophic gene program. PMID- 25514032 TI - Differences of starch granule distribution in grains from different spikelet positions in winter wheat. AB - Wheat starch development is a complex process and is markedly difference by changes in spikelet spatial position. The present study deals with endosperm starch granule distribution and spatial position during filling development. The study was conducted with pure starch isolated from wheat (Triticum aestivum L.), Jimai20 and Shannong1391, at 7-35 days after anthesis (DAA). The results showed that grain number, spikelet weight and grain weight per spikelet in different spatial position showed parabolic changes. Upper spikelets had highest starch and amylose content followed by basal spikelets, then middle spikelets. The paper also suggested the volume percents of B-type and A-type granule in grain of middle spikelets were remarkably higher and lower than those of basal and upper spikelets, respectively. However, no significant difference occurred in the number percents of the two type granule. The ratio of amylase to amylopectin was positively correlated with the volume proportion of 22.8-42.8 um, but was negatively related to the volume proportion of <9.9 um. The results indicated that the formation and distribution of starch granules were affected significantly by spikelet position, and grains at upper and basal spikelet had the potential of increasing grain weight through increasing the volume of B-type granules. PMID- 25514033 TI - BaTiO3 supercages: unusual oriented nanoparticle aggregation and continuous ordering transition in morphology. AB - Here we report the organic-free mesocrystalline superstructured cages of BaTiO3, i.e., the BaTiO3 supercages, which are synthesized by a one-step templateless and additive-free route using molten hydrated salt as the reaction medium. An unusual three-dimensional oriented aggregation of primary BaTiO3 nanoparticles in the medium of high ionic strength, which normally favors random aggregation, is identified to take place at the early stage of the synthesis. The spherical BaTiO3 aggregates further experience a remarkable continuous ordering transition in morphology, consisting of nanoparticle faceting and nanosheet formation steps. This ordering transition in conjunction with Ostwald ripening-induced solid evacuation leads to the formation of unique supercage structure of BaTiO3. Benefiting from their structure, the BaTiO3 supercages exhibit improved microwave absorption property. PMID- 25514030 TI - Perception of odors linked to precise timing in the olfactory system. AB - While the timing of neuronal activity in the olfactory bulb (OB) relative to sniffing has been the object of many studies, the behavioral relevance of timing information generated by patterned activation within the bulbar response has not been explored. Here we show, using sniff-triggered, dynamic, 2-D, optogenetic stimulation of mitral/tufted cells, that virtual odors that differ by as little as 13 ms are distinguishable by mice. Further, mice are capable of discriminating a virtual odor movie based on an optically imaged OB odor response versus the same virtual odor devoid of temporal dynamics-independently of the sniff-phase. Together with studies showing the behavioral relevance of graded glomerular responses and the response timing relative to odor sampling, these results imply that the mammalian olfactory system is capable of very high transient information transmission rates. PMID- 25514034 TI - ERbeta1 inhibits the migration and invasion of breast cancer cells through upregulation of E-cadherin in a Id1-dependent manner. AB - ERbeta1 is a member of the nuclear receptor superfamily of ligand-regulated transcription factors. It plays an important role in regulating the progression of breast cancer. However, the mechanisms of ERbeta1 in tumorigenesis, metastasis and prognosis are still not fully clear. In this study, we showed that the expression of ERbeta1 was positively correlated with E-cadherin expression in breast cancer cell lines. In addition, we found that ERbeta1 upregulates E cadherin expression in breast cancer cell lines. Furthermore, we also found that ERbeta1 inhibits the migration and invasion of breast cancer cells and upregulated E-cadherin expression in a Id1-dependent manner. Taken together, our study provides further understanding of the molecular mechanism of ERbeta1 in tumor metastasis and suggests the feasibility of developing novel therapeutic approaches to target Id1 to inhibit breast cancer metastasis. PMID- 25514035 TI - Proteoglycan from salmon nasal cartridge [corrected] promotes in vitro wound healing of fibroblast monolayers via the CD44 receptor. AB - Proteoglycans (PGs) are involved in various cellular functions including cell growth, adhesion, and differentiation; however, their physiological roles are not fully understood. In this study, we examined the effect of PG purified from salmon nasal cartilage (SNC-PG) on wound closure using tissue-cultured cell monolayers, an in vitro wound-healing assay. The results indicated that SNC-PG significantly promoted wound closure in NIH/3T3 cell monolayers by stimulating both cell proliferation and cell migration. SNC-PG was effective in concentrations from 0.1 to 10MUg/ml, but showed much less effect at higher concentrations (100-1000MUg/ml). The effect of SNC-PG was abolished by chondroitinase ABC, indicating that chondroitin sulfates (CSs), a major component of glycosaminoglycans (GAGs) in SNC-PG, are crucial for the SNC-PG effect. Furthermore, chondroitin 6-sulfate (C-6-S), a major CS of SNC-PG GAGs, could partially reproduce the SNC-PG effect and partially inhibit the binding of SNC-PG to cells, suggesting that SNC-PG exerts its effect through an interaction between the GAGs in SNC-PG and the cell surface. Neutralization by anti-CD44 antibodies or CD44 knockdown abolished SNC-PG binding to the cells and the SNC-PG effect on wound closure. These results suggest that interactions between CS-rich GAG-chains of SNC-PG and CD44 on the cell surface are responsible for the SNC-PG effect on wound closure. PMID- 25514036 TI - Inhibition of osteoclastogenesis by osteoblast-like cells genetically engineered to produce interleukin-10. AB - Bone destruction at inflamed joints is an important complication associated with rheumatoid arthritis (RA). Interleukin-10 (IL-10) may suppress not only inflammation but also induction of osteoclasts that play key roles in the bone destruction. If IL-10-producing osteoblast-like cells are induced from patient somatic cells and transplanted back into the destructive bone lesion, such therapy may promote bone remodeling by the cooperative effects of IL-10 and osteoblasts. We transduced mouse fibroblasts with genes for IL-10 and Runx2 that is a crucial transcription factor for osteoblast differentiation. The IL-10 producing induced osteoblast-like cells (IL-10-iOBs) strongly expressed osteoblast-specific genes and massively produced bone matrix that were mineralized by calcium phosphate in vitro and in vivo. Culture supernatant of IL 10-iOBs significantly suppressed induction of osteoclast from RANKL-stimulated Raw264.7 cells as well as LPS-induced production of inflammatory cytokine by macrophages. The IL-10-iOBs may be applicable to novel cell-based therapy against bone destruction associated with RA. PMID- 25514037 TI - Rac1 modulates cardiomyocyte adhesion during mouse embryonic development. AB - Rac1, a member of the Rho subfamily of small GTPases, is involved in morphogenesis and differentiation of many cell types. Here we define a role of Rac1 in cardiac development by specifically deleting Rac1 in the pre-cardiac mesoderm using the Nkx2.5-Cre transgenic driver line. Rac1-conditional knockout embryos initiate heart development normally until embryonic day 11.5 (E11.5); their cardiac mesoderm is specified, and the heart tube is formed and looped. However, by E12.5-E13.5 the mutant hearts start failing and embryos develop edema and hemorrhage which is probably the cause for the lethality observed soon after. The hearts of Rac1-cKO embryos exhibit disorganized and thin myocardial walls and defects in outflow tract alignment. No significant differences of cardiomyocyte death or proliferation were found between developing control and mutant embryos. To uncover the role of Rac1 in the heart, E11.5 primary heart cells were cultured and analyzed in vitro. Rac1-deficient cardiomyocytes were less spread, round and loosely attached to the substrate and to each other implying that Rac1-mediated signaling is required for appropriate cell-cell and/or cellmatrix adhesion during cardiac development. PMID- 25514038 TI - The N-terminal leucine-zipper motif in PTRF/cavin-1 is essential and sufficient for its caveolae-association. AB - PTRF/cavin-1 is a protein of two lives. Its reported functions in ribosomal RNA synthesis and in caveolae formation happen in two different cellular locations: nucleus vs. plasma membrane. Here, we identified that the N-terminal leucine zipper motif in PTRF/cavin-1 was essential for the protein to be associated with caveolae in plasma membrane. It could counteract the effect of nuclear localization sequence in the molecule (AA 235-251). Deletion of this leucine zipper motif from PTRF/cavin-1 caused the mutant to be exclusively localized in nuclei. The fusion of this leucine-zipper motif with histone 2A, which is a nuclear protein, could induce the fusion protein to be exported from nucleus. Cell migration was greatly inhibited in PTRF/cavin-1(-/-) mouse embryonic fibroblasts (MEFs). The inhibited cell motility could only be rescued by exogenous cavin-1 but not the leucine-zipper motif deleted cavin-1 mutant. Plasma membrane dynamics is an important factor in cell motility control. Our results suggested that the membrane dynamics in cell migration is affected by caveolae associated PTRF/cavin-1. PMID- 25514039 TI - Tbx3 and Nr5alpha2 improve the viability of porcine induced pluripotent stem cells after dissociation into single cells by inhibiting RHO-ROCK-MLC signaling. AB - Porcine induced pluripotent stem cells (piPSCs) had been reported during the past 5years, but there were few reports on how the cell signaling works in piPSCs. In order to clarify the signaling work that dominated the characteristic difference of two types of piPSCs which were derived from Oct4, Sox2, Klf4 and c-Myc (termed 4F piPSCs) and Oct4, Sox2, Klf4, c-Myc, Tbx3 and Nr5alpha2 (termed 6F piPSCs) respectively, we performed this study. 4F piPSCs and 6F piPSCs were cultured in medium with or without the ROCK inhibitor Y27632 after dissociating into single cells, the efficiency of a single cell colony and the number of AP positive colonies were assessed. The total RhoA and GTP-bind RhoA were detected in 4F piPSCs and 6F piPSCs before and after digestion into single cells. To explore the relationship between RHO-ROCK-MLC signaling pathway and the two factors Tbx3 and Nr5alpha2, the 4F piPSCs were infected with lenti-virus Tbx3 and Nr5alpha2 (termed 4F+TND). Results showed that the viability of cells could be enhanced by Y27632 and the RHO-ROCK-MLC signaling pathway was activated after dissociation into single cells in 4F piPSCs but not in 6F piPSCs. And, the 4F+TND piPSCs could be passaged and keep in high viability after dissociation into single cells, though the morphology of colonies did not change. These results indicated that the Tbx3 and Nr5alpha2 can improve the viability of piPSCs after dissociation into single cells by inhibiting the RHO-ROCK-MLC signaling pathway. And this provides useful information for establishing porcine pluripotent cells in future study. PMID- 25514040 TI - Trps1 deficiency inhibits the morphogenesis of secondary hair follicles via decreased Noggin expression. AB - A representative phenotype of patients with tricho-rhino-phalangeal syndrome (TRPS) is sparse hair. To understand the developmental defects of these patient's hair follicles, we analyzed the development of hair follicles histologically and biochemically using Trps1 deficient (KO) mice. First, we compared the numbers of primary hair follicles in wild-type (WT) and KO embryos at different developmental stages. No differences were observed in the E14.5 skins of WT and KO mice. However, at later time points, KO fetal skin failed to properly develop secondary hair follicles, and the number of secondary hair follicles present in E18.5 KO skin was approximately half compared to that of WT skin. Sonic hedgehog expression was significantly decreased in E17.5 KO skin, whereas no changes were observed in Eda/Edar expression in E14.5 or E17.5 skins. In addition, Noggin expression was significantly decreased in E14.5 and E17.5 KO skin compared to WT skin. In parallel with the suppression of Noggin expression, BMP signaling was promoted in the epidermal cells of KO skins compared to WT skins as determined by immunohistochemistry for phosphorylated Smad1/5/8. The reduced number of secondary hair follicles was restored in skin graft cultures treated with a Noggin and BMP inhibitor. Furthermore, decreased cell proliferation, and increased apoptosis in KO skin was rescued by Noggin treatment. Taken together, we conclude that hair follicle development in Trps1 KO embryos is impaired directly or indirectly by decreased Noggin expression. PMID- 25514041 TI - Effects of molecular symmetry on quantum reaction dynamics: novel aspects of photoinduced nonadiabatic dynamics. AB - Nonadiabatic coupling terms (NACTs) between different electronic states lead to fast radiationless decay in photoexcited molecules. Using molecular symmetry, i.e., symmetry with respect to permutation of identical nuclei and inversion of the molecule in space, the irreducible representations of the NACTs can be determined with a combination of molecular symmetry arguments and quantization rules. Here, we extend these symmetry rules for electronic states and coupling elements and demonstrate the importance of molecular symmetry for nonadiabatic nuclear dynamics. As an example, we consider the NACTs related to the torsion around the CN bond in C5H4NH. We present the results of quantum dynamical simulations of the photoinduced large amplitude torsion on three coupled electronic states and show how the interference between wavepackets leads to radiationless decay, which depends on the symmetry of the NACTs. Moreover, we show that the nuclear spin of the system determines the symmetry of the initial nuclear wave function and thus influences the torsional dynamics. This may open new possibilities for nuclear spin selective laser control of nuclear dynamics. PMID- 25514042 TI - Nonlinear absorbance amplification using a diffuse reflectance cell: total organic carbon monitoring at 214 nm. AB - We present an absorption spectrometric method using a polytetrafluoroethylene (PTFE) cell as a diffuse reflector. The system was used for monitoring ultrapure water. All compounds absorb to some degree at low UV wavelengths, and the absorption at 214 nm from a zinc lamp source was monitored using a charge-coupled device (CCD) spectrometer. The absorption was interpreted in terms of total organic carbon present. The cell acts as a nonlinear absorbance amplifier, improving both the limit of detection (LOD) and the dynamic range. Potassium hydrogen phthalate (KHP) and glucose were used to evaluate the system and provided respective LODs of 46.5 ng/L and 4.5 mg/L as carbon. Although the physical path length was 25 cm, a maximum effective path length of 280 cm was observed at the lowest tested KHP concentrations. The system is intended for real time monitoring of ultrapure water. PMID- 25514043 TI - Tracking overwintering areas of fish-eating birds to identify mercury exposure. AB - Migration patterns are believed to greatly influence concentrations of contaminants in birds due to accumulation in spatially and temporally distinct ecosystems. Two species of fish-eating birds, the Double-crested Cormorant (Phalacrocorax auritus) and the Caspian Tern (Hydroprogne caspia) breeding in Lake Ontario were chosen to measure the impact of overwintering location on mercury concentrations ([Hg]). We characterized (1) overwintering areas using stable isotopes of hydrogen (delta(2)H) and band recoveries, and (2) overwintering habitats by combining information from stable isotopes of sulfur (delta(34)S), carbon (delta(13)C), nitrogen (delta(15)N), and delta(2)H in feathers grown during the winter. Overall, overwintering location had a significant effect on [Hg]. Both species showed high [Hg] in (13)C-rich habitats. In situ production of Hg (e.g., through sulfate reducing bacteria in sediments) and allochthonous import could explain high [Hg] in birds visiting (13)C-rich habitats. Higher [Hg] were found in birds with high delta(2)H, suggesting that Hg is more bioavailable in southern overwintering locations. Hotspot maps informed that higher [Hg] in birds were found at the limit of their southeastern overwintering range. Mercury concentrations in winter feathers were positively related to predicted spatial pattern of [Hg] in fish using the National Descriptive Model of Mercury in Fish (NDMMF) based on bird spatial assignment (using delta(2)H). This study indicates that the overwintering location greatly influences [Hg]. PMID- 25514044 TI - C. elegans as a model to study PTEN's regulation and function. AB - PTEN (phosphatase and tensin homolog deleted on chromosome 10) has important roles in tumor suppression, metabolism, and development, yet its regulators, effectors, and functions are not fully understood. DAF-18 is the PTEN ortholog in Caenorhabditis elegans. DAF-18's role is highly conserved to human PTEN, and can be functionally replaced by human PTEN. Thus C. elegans provides a valuable model to study PTEN. This review assesses current and emerging methods to study DAF 18's regulators and functions in C. elegans. We propose genetic modify screens to identify genes that interact with daf-18/PTEN. These genes are potential targets for anticancer drug therapies. We also provide a review on the roles DAF-18/PTEN has during C. elegans development and how studying these physiological roles can provide mechanistic insight on DAF-18/PTEN function. PMID- 25514045 TI - Deriving appropriate boundary conditions, and accelerating position-jump simulations, of diffusion using non-local jumping. AB - In this paper we explore lattice-based position-jump models of diffusion, and the implications of introducing non-local jumping; particles can jump to a range of nearby boxes rather than only to their nearest neighbours. We begin by deriving conditions for equivalence with traditional local jumping models in the continuum limit. We then generalize a previously postulated implementation of the Robin boundary condition for a non-local process of arbitrary maximum jump length, and present a novel implementation of flux boundary conditions, again generalized for a non-local process of arbitrary maximum jump length. In both these cases we validate our results using stochastic simulation. We then proceed to consider two variations on the basic diffusion model: a hybrid local/non-local scheme suitable for models involving sharp concentration gradients, and the implementation of biased jumping. In all cases we show that non-local jumping can deliver substantial time savings for stochastic simulations. PMID- 25514046 TI - Influence of IL10 gene polymorphisms on the severity of liver fibrosis and susceptibility to liver cirrhosis in HBV/HCV-infected patients. AB - BACKGROUND: Previous studies about the association of the interleukin-10 (IL-10) polymorphisms with the progression of liver fibrosis or cirrhosis susceptibility in chronic hepatitis B/C (CHB/C) disease were inconsistent. The aim of this meta analysis was to derive a more precise estimation of the association. METHODS: We searched Medline, PubMed, EMBASE and Web of Science electronic databases using the following key words: liver fibrosis/cirrhosis, IL10, and polymorphism. Statistical analyses were performed by STATA11.0 software, with odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: 12 independent studies in relation to IL10-1082A/G, -819C/T and -592C/A polymorphisms were included in our study, which consisted of 197 moderate/severe liver fibrosis cases and 426 mild fibrosis controls as well as 536 liver cirrhosis cases and 881 non-cirrhosis controls. The results indicated that a significantly decreased risk of moderate/severe fibrosis was associated with the GCC haplotype (IL10-1082G, -819C and -592C) in the overall CHB/C patients (OR: 0.547, 95% CI: 0.317-0.946, P=0.031). We did not detect any significant association between these polymorphisms and liver cirrhosis susceptibility in the total population or a subgroup of Asians. However, subgroup analyses by different aetiologies showed that the -819T heterozygotes (TC) were associated with a significantly increased risk of HCV-related liver cirrhosis in the Japanese population (OR: 1.254, 95% CI: 1.033-1.522, P=0.022). CONCLUSIONS: The putative high IL-10 production haplotype GCC is more likely to be associated with less severe liver fibrosis in CHB/C patients. Additionally, the IL10-819T allele may be a susceptible factor for HCV-related liver cirrhosis in the Japanese population. PMID- 25514048 TI - Vinpocetine attenuates MPTP-induced motor deficit and biochemical abnormalities in Wistar rats. AB - Up-regulation in phosphodiesterase 1 (PDE1) expression and decreased levels of cyclic nucleotides (cAMP and cGMP) have been reported in patients and experimental animal models of Parkinson's disease (PD). Phosphodiesterase (PDE) inhibitors have been reported to be beneficial in cognitive and motor deficit states. The present study is designed to investigate the effect of vinpocetine, a PDE1 inhibitor in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental PD-like symptoms in rats. To produce stable motor deficit, MPTP was repeatedly administered intranigrally (bilaterally) at an interval of 1 week (days 1, 7 and 14). Following development of stable motor deficit, which was observed after the third infusion of MPTP (day 14) in rats, the animals were treated with vinpocetine (5-, 10- and 20-mg/kg, i.p.) from days 15 to 28. Movement abnormalities were assessed by a battery of behavioral tests. Moreover, levels of malondialdehyde, nitrite and reduced glutathione were measured in striatal brain homogenate to confirm the role of oxidative and nitrosative stress in PD. Repeated intranigral administration of MPTP produced stable motor deficits, reduced the cyclic nucleotides and dopamine levels and caused elevation in oxidative-nitrosative stress markers. Chronic administration of vinpocetine (for 14 days) significantly and dose dependently attenuated movement disabilities and oxidative-nitrosative stress in MPTP-treated rats. Moreover, vinpocetine treatment enhances cyclic nucleotide levels and restores the dopamine level in MPTP-treated rats. The observed results of the present study are indicative of the therapeutic potential of vinpocetine in PD. PMID- 25514050 TI - A simple simulation model as a tool to assess alternative health care provider payment reform options in Vietnam. AB - Vietnam is currently considering a revision of its 2008 Health Insurance Law, including the regulation of provider payment methods. This study uses a simple spreadsheet-based, micro-simulation model to analyse the potential impacts of different provider payment reform scenarios on resource allocation across health care providers in three provinces in Vietnam, as well as on the total expenditure of the provincial branches of the public health insurance agency (Provincial Social Security [PSS]). The results show that currently more than 50% of PSS spending is concentrated at the provincial level with less than half at the district level. There is also a high degree of financial risk on district hospitals with the current fund-holding arrangement. Results of the simulation model show that several alternative scenarios for provider payment reform could improve the current payment system by reducing the high financial risk currently borne by district hospitals without dramatically shifting the current level and distribution of PSS expenditure. The results of the simulation analysis provided an empirical basis for health policy-makers in Vietnam to assess different provider payment reform options and make decisions about new models to support health system objectives. PMID- 25514049 TI - Effects of ROCK inhibitor Y27632 and EGFR inhibitor PD168393 on human neural precursors co-cultured with rat auditory brainstem explant. AB - Hearing function lost by degeneration of inner ear spiral ganglion neurons (SGNs) in the auditory nervous system could potentially be compensated by cellular replacement using suitable donor cells. Donor cell-derived neuronal development with functional synaptic formation with auditory neurons of the cochlear nucleus (CN) in the brainstem is a prerequisite for a successful transplantation. Here a rat auditory brainstem explant culture system was used as a screening platform for donor cells. The explants were co-cultured with human neural precursor cells (HNPCs) to determine HNPCs developmental potential in the presence of environmental cues characteristic for the auditory brainstem region in vitro. We explored effects of pharmacological inhibition of GTPase Rho with its effector Rho-associated kinase (ROCK) and epidermal growth factor receptor (EGFR) signaling on the co-cultures. Pharmacological agents ROCK inhibitor Y27632 and EGFR blocker PD168393 were tested. Effect of the treatment on explant penetration by green fluorescent protein (GFP)-labeled HNPCs was evaluated based on the following criteria: number of GFP-HNPCs located within the explant; distance migrated by the GFP-HNPCs deep into the explant; length of the GFP+/neuronal class III beta-tubulin (TUJ1)+ processes developed and phenotypes displayed. In a short 2-week co-culture both inhibitors had growth-promoting effects on HNPCs, prominent in neurite extension elongation. Significant enhancement of migration and in-growth of HNPCs into the brain slice tissue was only observed in Y27632 treated co-cultures. Difference between Y27632- and PD168393-treated HNPCs acquiring neuronal fate was significant, though not different from the fates acquired in control co-culture. Our data suggest the presence of inhibitory mechanisms in the graft-host environment of the auditory brainstem slice co culture system with neurite growth arresting properties which can be modulated by administration of signaling pathways antagonists. Therefore the co-culture system can be utilized for screens of donor cells and compounds regulating neuronal fate determination. PMID- 25514047 TI - Plasmodium falciparum field isolates from areas of repeated emergence of drug resistant malaria show no evidence of hypermutator phenotype. AB - Multiple transcontinental waves of drug resistance in Plasmodium falciparum have originated in Southeast Asia before spreading westward, first into the rest of Asia and then to sub-Saharan Africa. In vitro studies have suggested that hypermutator P. falciparum parasites may exist in Southeast Asia and that an increased rate of acquisition of new mutations in these parasites may explain the repeated emergence of drug resistance in Southeast Asia. This study is the first to test the hypermutator hypothesis using field isolates. Using genome-wide SNP data from human P. falciparum infections in Southeast Asia and West Africa and a test for relative rate differences we found no evidence of increased relative substitution rates in P. falciparum isolates from Southeast Asia. Instead, we found significantly increased substitution rates in Mali and Bangladesh populations relative to those in populations from Southeast Asia. Additionally we found no association between increased relative substitution rates and parasite clearance following treatment with artemisinin derivatives. PMID- 25514051 TI - Exploitation of in situ generated sugar-based olefin keto-nitrones: synthesis of carbocycles, heterocycles, and nucleoside derivatives. AB - Application of intramolecular 1,3-dipolar nitrone cycloaddition reaction on carbohydrate-derived precursors containing an olefin functionality at C-1 or C-3 or C-5 and a nitrone moiety at C-2 or C-3 as appropriate has resulted in the formation of structurally new cycloaddition products containing furanose-fused oxepane, thiepane, azepane, cyclopentane, cycloheptane, tetrahydrofuran, and pyranose-fused tetrahydrofuran rings. The structure and stereochemistry of these products have been characterized by spectral as well as single-crystal X-ray analyses. Two of the compounds have been transformed to the bicyclic nucleoside derivatives applying Vorbruggen reaction conditions. PMID- 25514052 TI - Vapour phase hydrogenation of phenol over rhodium on SBA-15 and SBA-16. AB - In the present work, mesoporous SBA-15 and SBA-16 were synthesised using classical methods, and their physicochemical properties were investigated by X ray diffraction (XRD), FTIR, TEM and N2 adsorption-desorption. Rhodium (Rh, 1 wt %) was loaded on the mesoporous SBA-15 and SBA-16 by an impregnation method. The Rh surface coverage, dispersion and crystallite size were determined by room temperature H2 chemisorption on reduced samples. The catalytic activity of Rh supported on mesoporous SBA-15 and SBA-16 was evaluated for the first time in the hydrogenation of phenol in vapour phase in a temperature range between 130 and 270 degrees C at atmospheric pressure. The reaction over Rh/SBA-15 at 180 degrees C produced cyclohexanone as the major product (about 60%) along with lower amounts of cyclohexanol (about 35%) and cyclohexane (about 15%). The influences of temperature, H2/phenol ratio, contact time and the nature of the solvent on the catalytic performance were systematically investigated. The Rh/SBA 16 system offered lower phenol conversion compared to Rh/SBA-15, but both have a very high selectivity for cyclohexanone (above 60%). PMID- 25514053 TI - Pharmacokinetics, tissue distribution and excretion of verticinone from F. hupehensis in rats. AB - Verticinone, the main active component in F. hupehensis, exhibits potent antitussive and expectorant effects. Here, a LC-MS method was developed and applied to study the pharmacokinetics, tissue distribution and excretion of verticinone in rats, and its plasma protein binding in vitro. A significant gender difference in the pharmacokinetics of verticinone in rats was observed, as its absolute oral bioavailability in male and female rats was 45.8% and 2.74%, respectively. The relative bioavailability of verticinone was significantly lower in female rats as compared to male, following intragastrical (i.g.) and intravenous (i.v.) administration. After successive i.g. administration of verticinone, accumulation was observed in female rats but not in the male ones. The tissue distribution study showed that verticinone had a good tissue penetrability and a high tissue affinity in most studied tissues, except brain. After a 2 mg/kg oral dose, less than 4% of the dose was excreted as unchanged parent compound in male rats, and less than 1% in female rats, which indicated that verticinone was metabolized more extensively in female rats than in male rats. PMID- 25514054 TI - Determination and occurrence of phenoxyacetic acid herbicides and their transformation products in groundwater using ultra high performance liquid chromatography coupled to tandem mass spectrometry. AB - A sensitive method was developed and validated for ten phenoxyacetic acid herbicides, six of their main transformation products (TPs) and two benzonitrile TPs in groundwater. The parent compounds mecoprop, mecoprop-p, 2,4-D, dicamba, MCPA, triclopyr, fluroxypr, bromoxynil, bentazone, and 2,3,6-trichlorobenzoic acid (TBA) are included and a selection of their main TPs: phenoxyacetic acid (PAC), 2,4,5-trichloro-phenol (TCP), 4-chloro-2-methylphenol (4C2MP), 2,4 dichlorophenol (DCP), 3,5,6-trichloro-2-pyridinol (T2P), and 3,5-dibromo-4 hydroxybenzoic acid (BrAC), as well as the dichlobenil TPs 2,6-dichlorobenzamide (BAM) and 3,5-dichlorobenzoic acid (DBA) which have never before been determined in Irish groundwater. Water samples were analysed using an efficient ultra-high performance liquid chromatography (UHPLC) method in an 11.9 min separation time prior to detection by tandem mass spectrometry (MS/MS). The limit of detection (LOD) of the method ranged between 0.00008 and 0.0047 ug.L(-1) for the 18 analytes. All compounds could be detected below the permitted limits of 0.1 ug.L( 1) allowed in the European Union (EU) drinking water legislation. The method was validated according to EU protocols laid out in SANCO/10232/2006 with recoveries ranging between 71% and 118% at the spiked concentration level of 0.06 ug.L(-1). The method was successfully applied to 42 groundwater samples collected across several locations in Ireland in March 2012 to reveal that the TPs PAC and 4C2MP were detected just as often as their parent active ingredients (a.i.) in groundwater. PMID- 25514055 TI - Expanding current knowledge on the chemical composition and antioxidant activity of the genus Lactarius. AB - Despite the presence of toxic compounds in inedible mushrooms, the question whether the chemical nutrients and non-nutrients compositions in edible and inedible Lactarius species are similar remains unanswered. To answer this question, Lactarius citriolens Pouzar and Lactarius turpis (Weinm.) Fr., two inedible species, were studied in order to obtain information about their chemical composition and bioactivity. Free sugars, fatty acids, tocopherols, organic and phenolic acids were analysed by chromatographic techniques coupled to different detectors. L. citriolens and L. turpis methanolic extracts were tested regarding antioxidant potential (reducing power, radical scavenging activity and lipid peroxidation inhibition). The composition of macronutrients varied among the two species, but the profiles were similar between them and among other Lactarius species; L. citriolens gave the highest energy contribution, saturated fatty acids and organic acids, while the L. turpis sample was richer in free sugars, mono- and polyunsaturated fatty acids, tocopherols and phenolic compounds. L. turpis methanolic extract showed the highest antioxidant activity. The absence of hepatoxicity of the methanolic extracts was confirmed in porcine liver primary cells (in vitro conditions). The present study provided new information about wild L. citriolens and L. turpis, comparing their chemical composition and antioxidant properties with other Lactarius species, and expanding the knowledge about this genus. PMID- 25514056 TI - Synthesis of racemic beta-chamigrene, a spiro[5.5]undecane sequiterpene. AB - The present paper describes a total synthesis of racemic beta-chamigrene, a sesquiterpene with a spiro[5.5]undecane carbon framework. Compared with previously reported beta-chamigrene syntheses, we were able to reduce the total number of reaction steps, which also resulted in a significant improvement of the overall yield. The commercially available ketone 6-methylhept-5-en-2-one was transformed by known simple procedures into 3,3-dimethyl-2 methylenecyclohexanone. This reacted with isoprene by a Diels-Alder reaction to give a spiro ketone. An olefination reaction on this compound gave the target molecule. PMID- 25514057 TI - Editorial: Special issue--Enzyme immobilization. PMID- 25514058 TI - Remarkable improvement of gas-sensing abilities in p-type oxide nanowires by local modification of the hole-accumulation layer. AB - This paper proposes a method for improving the reducing or oxidizing gas-sensing abilities of p-type oxide nanowires (NWs) by locally modifying the hole accumulation channel through the attachment of p-type nanoparticles (NPs) with different upper valence band levels. In this study, the sensing behaviors of p CuO NWs functionalized with either p-NiO or p-Co3O4 NPs were investigated as a model materials system. The attachment of p-NiO NPs greatly improved the reducing gas-sensing performance of p-CuO NWs. In contrast, the p-Co3O4 NPs improved the oxidizing gas-sensing properties of p-CuO NWs. These results are associated with the local suppression/expansion of the hole-accumulation channel of p-CuO NWs along the radial direction due to hole flow between the NWs and NPs. The approach proposed in this study provides a guideline for fabricating sensitive chemical sensors based on p-CuO NWs. PMID- 25514059 TI - Temperature determines toxicity: bisphenol A reduces thermal tolerance in fish. AB - Bisphenol A (BPA) is a ubiquitous pollutant around the globe, but whether environmental concentrations have toxic effects remains controversial. BPA interferes with a number of nuclear receptor pathways, including several that mediate animal responses to environmental input. Because thermal acclimation is regulated by these pathways in fish, we hypothesized that the toxicity of BPA would change with ambient temperature. We exposed zebrafish (Danio rerio) to ecologically relevant and artificially high concentrations of BPA at two acclimation temperatures, and tested physiological responses at two test temperatures that corresponded to acclimation temperatures. We found ecologically relevant concentrations of BPA (20 MUg l(-1)) impair swimming performance, heart rate, muscle and cardiac SERCA activity and gene expression. We show many of these responses are temperature-specific and non-monotonic. Our results suggest that BPA pollution can compound the effects of climate change, and that its effects are more dynamic than toxicological assessments currently account for. PMID- 25514060 TI - Transcriptomic resources for environmental risk assessment: a case study in the Venice lagoon. AB - The development of new resources to evaluate the environmental status is becoming increasingly important representing a key challenge for ocean and coastal management. Recently, the employment of transcriptomics in aquatic toxicology has led to increasing initiatives proposing to integrate eco-toxicogenomics in the evaluation of marine ecosystem health. However, several technical issues need to be addressed before introducing genomics as a reliable tool in regulatory ecotoxicology. The Venice lagoon constitutes an excellent case, in which the assessment of environmental risks derived from the nearby industrial activities represents a crucial task. In this context, the potential role of genomics to assist environmental monitoring was investigated through the definition of reliable gene expression markers associated to chemical contamination in Manila clams, and their subsequent employment for the classification of Venice lagoon areas. Overall, the present study addresses key issues to evaluate the future outlooks of genomics in the environmental monitoring and risk assessment. PMID- 25514062 TI - Analytical solution of cross polarization dynamics. AB - The first analytical solution under Hartman-Hahn match (omega1I=omega1S) for a stationary sample was derived by Muller et al. After the introduction of magic angle spinning (MAS), the dynamics becomes much more complicated. By transferring the Hamiltonian into a rotating frame, Stejskal et al. derived the effective Hamiltonian and the new condition of Hartman-Hahn match (omega1I omega1S=nomegar,n=+/-1,+/-2), which leads to an analytical solution of CP dynamics under very fast MAS. For both stationary and fast MAS results, the effective Hamiltonians are time-independent in the rotating frame. Under Hartman Hahn match (omega1I=omega1S) and arbitrary MAS speed condition, the Hamiltonian is no longer time-independent, making the CP dynamics very intriguing. In this work, the solution is derived analytically in the zero- and double-quantum spaces. The initial polarization in the double-quantum space is a constant of motion under strong pulse condition (|omega1I+omega1S|?|d(t)|), while the Hamiltonian in the zero-quantum space reduces to d(t)sigmaz(Delta), which is time dependent but self commuting all the time. This Hamilontian acts on the initial density matrix successively, leading to an analytical solution of CP dynamics. Based on the result, a phenomenological solution is derived. When the MAS speed omegar->0 , this solution reduces to Muller's formula except a spin-lattice relaxation time in the rotating frame (T1rho). Computer simulations and experimental results agree well with the solutions. PMID- 25514061 TI - Optimization of bicelle lipid composition and temperature for EPR spectroscopy of aligned membranes. AB - We have optimized the magnetic alignment of phospholipid bilayered micelles (bicelles) for EPR spectroscopy, by varying lipid composition and temperature. Bicelles have been extensively used in NMR spectroscopy for several decades, in order to obtain aligned samples in a near-native membrane environment and take advantage of the intrinsic sensitivity of magnetic resonance to molecular orientation. Recently, bicelles have also seen increasing use in EPR, which offers superior sensitivity and orientational resolution. However, the low magnetic field strength (less than 1 T) of most conventional EPR spectrometers results in homogeneously oriented bicelles only at a temperature well above physiological. To optimize bicelle composition for magnetic alignment at reduced temperature, we prepared bicelles containing varying ratios of saturated (DMPC) and unsaturated (POPC) phospholipids, using EPR spectra of a spin-labeled fatty acid to assess alignment as a function of lipid composition and temperature. Spectral analysis showed that bicelles containing an equimolar mixture of DMPC and POPC homogeneously align at 298 K, 20 K lower than conventional DMPC-only bicelles. It is now possible to perform EPR studies of membrane protein structure and dynamics in well-aligned bicelles at physiological temperatures and below. PMID- 25514063 TI - Complexity of illness and adjunctive benzodiazepine use in outpatients with bipolar I or II disorder: results from the Bipolar CHOICE study. AB - Benzodiazepines are widely prescribed for patients with bipolar disorders in clinical practice, but very little is known about the subtypes of patients with bipolar disorder or aspects of bipolar illness that contribute most to benzodiazepine use. We examined the prevalence of and factors associated with benzodiazepine use among 482 patients with bipolar I or II disorder enrolled in the Bipolar CHOICE study. Eighty-one subjects were prescribed benzodiazepines at study entry and were considered benzodiazepine users. Stepwise logistic regression was used to model baseline benzodiazepine use versus nonuse, using entry and exit criteria of P < 0.1. In bivariate analyses, benzodiazepine users were prescribed a significantly higher number of other psychotropic medications and were more likely to be prescribed lamotrigine or antidepressants as compared with benzodiazepine nonusers. Benzodiazepine users were more likely to have a diagnosis of bipolar I disorder and comorbid anxiety disorder, but not comorbid alcohol or substance use disorders. Benzodiazepine users also had experienced more anxiety and depressive symptoms and suicidality, but not irritability or manic symptoms, than did benzodiazepine nonusers. In the multivariate model, anxiety symptom level (regardless of diagnosis), lamotrigine use, number of concomitant psychotropic medications, college education, and high household income predicted benzodiazepine use. Benzodiazepine use in patients with bipolar disorders is associated with greater illness complexity as indicated by a higher number of concomitant psychotropic medications and higher anxiety symptom burden, regardless of a comorbid anxiety disorder diagnosis. Demographic factors were also important determinants of benzodiazepine use, which may be related to access to care and insurance coverage for benzodiazepines. PMID- 25514064 TI - Safety and tolerability of dexmecamylamine (TC-5214) adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to antidepressant therapy: results of a long-term study. AB - Safety and tolerability are important considerations when selecting patients' treatment for major depressive disorder. We report the long-term safety and tolerability of the nicotinic channel modulator dexmecamylamine (TC-5214), adjunct to selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder and who had an inadequate response to antidepressants. This 52-week, double-blind, placebo-controlled study explored the long-term safety and tolerability of dexmecamylamine. Patients were randomized 3:1 to receive flexibly dosed dexmecamylamine 1 to 4 mg adjunct to SSRI/SNRI or placebo plus SSRI/SNRI. The patient population comprised inadequate responders from 2 Phase III acute dexmecamylamine studies (NCT01157078 [study 002], NCT01153347 [study 004]) and de novo patients who responded inadequately during a 6-week open-label antidepressant treatment period preceding randomization. Safety and tolerability were assessed by monitoring adverse events, vital signs, and physical and laboratory parameters. Descriptive statistical analyses were performed on most efficacy-related end points. Sustained efficacy was analyzed using logistic regression. Overall, 813 patients were randomized (610 received dexmecamylamine, 203 received placebo). In total, 82.4% and 84.6% of patients, respectively, experienced an adverse event. Adverse events occurring more frequently with dexmecamylamine vs placebo were constipation (19.6% vs 6.0%), dizziness (12.0% vs 7.0%), and dry mouth (9.7% vs 5.0%). Back pain (2.8% vs 8.5%), weight increase (4.4% vs 7.0%), and fatigue (5.6 % vs 7.5%) occurred more frequently in placebo treated patients. No notable differences were observed between dexmecamylamine and placebo for any secondary end point. In this long-term study, safety and tolerability of dexmecamylamine were consistent with that reported in acute Phase III studies of dexmecamylamine. PMID- 25514065 TI - Simple pulmonary eosinophilia associated with clozapine treatment. PMID- 25514066 TI - Association study of GABAA alpha2 receptor subunit gene variants in antipsychotic associated weight gain. AB - Schizophrenia treatment has been hampered by undesirable adverse effects, including weight gain and associated complications. Recent candidate gene studies have been exploring the appetite regulation pathways in antipsychotic-associated weight gain (AAWG) with some promising leads. Genome-wide association studies of obesity have pointed to a number of potential candidate genes, such as MC4R, that were later found to be shared with AAWG. GABAA alpha2 receptor subunit (GABRA2) was another potential candidate gene for obesity from genome-wide association studies; however, it has not been explored in AAWG. We examined 9 single nucleotide polymorphisms across the GABRA2 gene. Prospective weight change was assessed for a total of 160 schizophrenia patients of European ancestry. The rs279858 marker was associated with percent weight change, with the patients homozygous for the TT genotype experiencing higher percentage weight gain on average than the C allele carriers (P = 0.009). When we performed the analysis considering each clinical site using a meta-analytic method, the results remained statistically significant (P = 1.4e-4). These findings became even more significant when we considered only patients taking clozapine or olanzapine, the 2 medications with higher risk for weight gain (P < 1e-10). GABRA2 genetic variants may play a role in predicting AAWG. However, replication in larger and independent samples is required. PMID- 25514068 TI - Lupin peptone as a replacement for animal-derived peptone in rich culture media for yeast. AB - Lupin peptone was shown to be a suitable replacement for traditional bacteriological peptone in the culture of Candida glabrata, Candida albicans and Saccharomyces cerevisiae. This new medium formulation allows yeast researchers to increase safety and to eliminate the use of animal products for the culture of yeast in rich medium. PMID- 25514067 TI - Weight gain on antipsychotic medication is associated with sustained use among veterans with schizophrenia. AB - OBJECTIVE: Continuous antipsychotic treatment is important in schizophrenia, and studies have shown that rates of discontinuation are high. Some studies suggest that weight gain may lead schizophrenic patients to discontinue treatment, whereas other studies show smaller effects of weight gain on medication discontinuation, and some find weight gain associated with symptom improvement. Our retrospective cohort study investigated the effect of weight change on the continued use for 1 year (persistence) of all antipsychotics, then among users of first-generation antipsychotics and second-generation antipsychotics (SGAs), and lastly subgroups of SGAs. METHODS: We identified 2130 patients with schizophrenia starting an antipsychotic that had not used 1 in the prior year. Using multivariable logistic regression adjusted for demographic and clinical variables, we determined the odds of remaining persistent on medication among patients who either gained weight or did not gain weight in the following year. RESULTS: For all antipsychotics combined, weight change was not associated with persistence. Among SGAs, weight gain was associated with a 23% increase in the adjusted odds ratio (OR) for persistence (OR, 1.23; 95% confidence interval [CI], 1.00-1.51), whereas there was a nonsignificant decrease in the adjusted odds of persistence among first-generation antipsychotic users (OR, 0.74; 95% CI, 0.43 1.28). When SGAs were divided into subgroups (clozapine/olanzapine, risperidone/quetiapine), both had increases in the likelihood of persistence, but only the association for clozapine/olanzapine was significant at a trend level (adjusted OR, 1.46; 95% CI, 0.99-2.16). CONCLUSIONS: These findings are supportive of other research that shows weight gain does not invariably lead to medication discontinuation and may be associated with clinical improvement. PMID- 25514069 TI - In vitro assessment of the acid resistance of demineralized enamel irradiated with Er, Cr:YSGG and Nd:YAG lasers. AB - PURPOSE: This study's purpose was to evaluate the acid resistance of demineralized enamel irradiated with high-intensity lasers. METHODS: Enamel fragments were demineralized and treated as follows (N=10): Group 1-no treatment; Group 2-five percent sodium fluoride (NaF) varnish; Group 3-Er, Cr:YSGG laser (8.92 J/cm2, 0.5 W, 20 Hz, 30 seconds); Group 4-NaF and Er, Cr:YSGG laser; Group 5-Er, Cr:YSGG laser and NaF; Group 6-Nd:YAG laser (84.9 J/cm2, 0.5 W, 10 Hz, 30 seconds); Group 7-NaF and Nd:YAG laser; and Group 8-Nd:YAG laser and NaF. The samples were subjected to pH-cycling and assessed by microhardness (analysis of variance; alpha equals five percent) at different depths from the outer enamel surface. Samples were observed using polarized light microscopy (PLM) and scanning electron microscopy (SEM). RESULTS: There were no significant differences among the experimental groups in any of the subsurface layers evaluated. PLM observation revealed that the extent of demineralization of the irradiated samples was similar to the samples for Group 1 (control). SEM observation showed that irradiated surfaces were ablated and presented areas of melting. CONCLUSIONS: Laser irradiation, with or without applying five percent sodium fluoride, was not capable of increasing the enamel white spot lesions' acid resistance. PMID- 25514071 TI - Complete pre-eruptive idiopathic crown resorption. AB - The purpose of this paper was to present the unique case of complete pre-eruptive idiopathic crown resorption, few of which have ever been reported, because most have concerned partial idiopathic crowns. Crown resorption affects only a part of the crown and begins when crown mineralization is complete, leading to hypomineralization of the teeth. Treatment usually consists of restorative/endodontic care or extraction. A 12-year-old-boy presented with complete idiopathic resorption of the permanent mandibular left third molar and secondary failure of eruption of the permanent mandibular left first molar. The finding was incidental during routine radiographs for orthodontic treatment and was documented using cone beam computed tomography and computed tomography (one mm slices). Follow-up, using a panoramic radiograph, occurred after one year, confirming the absence of the third molar. No preventive or therapeutic regimen is known. PMID- 25514070 TI - The Rect-spring: a new device for treating ectopically erupting permanent molars. AB - The Rect-spring, a new device that simply and effectively resolves ectopically erupting molars, may be applied in cases where the ectopically erupted molar is entrapped by more than two mm. Its design, scientifically logical for changing the direction of force, delivers a continuous distalizing and uprighting force. The Rect-spring can be easily manufactured at chairside and delivered on the same day without the need to take impressions or perform laboratory procedures. With proper activation, it can resolve a severely ectopically erupting molar within three months. It is relatively inexpensive and easy to deliver, causes little irritation, and is less time consuming for patients. It is worth utilizing before introducing Halterman or Humphrey appliances due to its simplicity and economical benefit. The purpose of this clinical report was to describe the design and the clinical application procedure for the Rect-spring and three successfully treated cases. PMID- 25514072 TI - The image gently in dentistry campaign: partnering with parents to promote the responsible use of x-rays in pediatric dentistry. PMID- 25514073 TI - Rationale for caries inhibition of debonded glass ionomer sealants: an in vitro study. AB - PURPOSE: This study's purpose was to test the hypothesis that, after glass ionomer (GI) sealant debonding, remaining GI in the deepest parts of fissures and/or the inhibition of enamel demineralization after artificial caries challenge imparts the residual cariostatic property observed in clinical studies. METHODS: Fuji IX GI sealant was placed on one tooth from 14 matched pairs of noncarious extracted human permanent molars and premolars; the other tooth was the control. Sealed teeth underwent thermocycling (4,000 cycles), and the sealant was manually debonded. The amount of remaining sealant in the fissures was determined using a stereomicroscope. All teeth were placed in lactic acid gel (pH 5.0) at 37 degrees Celsius for three weeks to simulate caries formation. The extent of demineralization was determined using the serial micro-hardness method on the cross-sectioned specimens at 0.5 mm from the depth of the central fissure. RESULTS: All teeth had GI retained in the fissures at a microscopic level. Enamel demineralization adjacent to the remaining GI was not significantly different from the control (t test; P=.88). CONCLUSIONS: The residual cariostatic property of glass ionomer sealant is most likely due to a physical barrier of remaining GI in the fissures rather than a chemical effect on demineralization inhibition. PMID- 25514074 TI - Cuspal flexure, depth-of-cure, and bond integrity of bulk-fill composites. AB - PURPOSE: Evaluate cuspal flexure caused by polymerization shrinkage stress, bond integrity, and depth-of-cure of bulk-fill composites. METHODS: Twenty-eight extracted permanent molars were mounted in stainless steel rings. Slot-shaped Class II mesio-occlusal-distal preparations (four mm deep) were restored with Filtek Supreme Ultra (control; two two-mm increments) and bulk-fill composites (Tetric EvoCeram, Venus, Filtek Bulk Fill). The teeth were digitized using a 3D scanner before and after restoration. Before- and after-restoration scans were aligned, and cuspal flexure was calculated. Bond integrity along occlusal interfaces was assessed by dye penetration and measured after overnight immersion in basic fuchsin dye and cross-sectioning. Depth-of-cure was determined on the cross-sections using Vickers hardness. Statistical analysis was performed with one-way analysis of variance. RESULTS: All composites caused inward cuspal flexure (10.4 to 13.6 MUm). No statistical difference in flexure was found among the composites (P=.07). No significant difference in microhardness at any restoration depths was found for any composite (.35=90%. Kinetic and stoichiometric characterization of the acclimated biomass was performed with biodegradation tests carried out in the bioreactor during the reaction phase. The classical and a modified four-parameter forms of the Haldane equation were applied to model the substrate inhibited kinetics. Both models provided reliable predictions with high correlation coefficients (>0.99). The biomass characterization was completed with the evaluation of the growth yield coefficient, Y (0.075 on chemical oxygen demand base) and endogenous respiration rate, b (0.054 d(-1)). The aerobic SBR, operated in the metabolic mode with a mixed culture, showed superior performance in comparison to continuous systems applied in the same range of PCP influent loads and achieved removal rates are suitable for application. PMID- 25514135 TI - A pilot plant study of the degradation of Brilliant Green dye using ozone microbubbles: mechanism and kinetics of reaction. AB - Oxidation of Brilliant Green dye was performed using ozone microbubbles in a pilot plant scale. Decolourisation was very effective at both acidic and alkaline pH. The colour of the aqueous solution was below detectable limit after 30 min at 1.7 mg/s ozone generation rate. The reaction between the dye and ozone was first order in nature with respect to both ozone and the dye. The enhancement factor increased with increasing dye concentration. The samples were analysed by the ultra-violet-visible (UV-Vis) spectrophotometry, gas chromatography-mass spectrometry (GC-MS) and Fourier transform infra-red (FTIR) spectroscopy. From the GC-MS analysis, 13 intermediates were detected as oxidation products of this dye at various stages of oxidation. The changes in the FTIR spectra showed the destruction of the dye and the formation of new compounds. The oxidation mechanism was divided into two reaction pathways. The mineralisation of Brilliant Green was up to 80% in 60 min, as determined by total organic carbon analysis. PMID- 25514137 TI - Normal contact and friction of rubber with model randomly rough surfaces. AB - We report on normal contact and friction measurements of model multicontact interfaces formed between smooth surfaces and substrates textured with a statistical distribution of spherical micro-asperities. Contacts are either formed between a rigid textured lens and a smooth rubber, or a flat textured rubber and a smooth rigid lens. Measurements of the real area of contact A versus normal load P are performed by imaging the light transmitted at the microcontacts. For both interfaces, A(P) is found to be sub-linear with a power law behavior. Comparison with two multi-asperity contact models, which extend the Greenwood-Williamson (J. Greenwood and J. Williamson, Proc. Royal Soc. London Ser. A, 295, 300 (1966)) model by taking into account the elastic interaction between asperities at different length scales, is performed, and allows their validation for the first time. We find that long range elastic interactions arising from the curvature of the nominal surfaces are the main source of the non linearity of A(P). At a shorter range, and except for very low pressures, the pressure dependence of both density and area of microcontacts remains well described by Greenwood-Williamson's model, which neglects any interaction between asperities. In addition, in steady sliding, friction measurements reveal that the mean shear stress at the scale of the asperities is systematically larger than that found for a macroscopic contact between a smooth lens and a rubber. This suggests that frictional stresses measured at macroscopic length scales may not be simply transposed to microscopic multicontact interfaces. PMID- 25514136 TI - Column experiment on activation aids and biosurfactant application to the persulphate treatment of chlorophene-contaminated soil. AB - An innovative strategy integrating the use of biosurfactant (BS) and persulphate activated by chelated iron for the decontamination of soil from an emerging pollutant chlorophene was studied in laboratory down-flow columns along with other persulphate activation aids including combined application of persulphate and hydrogen peroxide, and persulphate activation with sodium hydroxide. Although BS addition improved chlorophene removal by the persulphate treatment, the addition of chelated iron did not have a significant influence. Combined application of persulphate with hydrogen peroxide resulted in a significant (p<=.05) overall improvement of chlorophene removal compared with treatment with persulphate only. The highest removal rate (71%) of chlorophene was achieved with the base-activated persulphate, but only in the upper part (of 0.0-3.5 cm in depth) of the column. The chemicals at the applied dosages did not substantially influence the Daphnia magna toxicity of the effluent. Dehydrogenase activity (DHA) measurements indicated no substantial changes in the microbial activity during the persulphate treatment. The highest oxygen consumption and a slight increase in DHA were observed with the BS addition. The combined application of persulphate and BS at natural soil pH is a promising method for chlorophene contaminated soil remediation. Hydroquinone was identified among the by-products of chlorophene degradation. PMID- 25514138 TI - Tenosynovial Osteochondromatosis of the Flexor Hallucis Longus in a Division I Tennis Player. AB - Tenosynovial (extra-articular) chondromatosis (TC) is a condition characterized by the cartilaginous proliferation of synovial cells derived from the synovial lining of bursa and tendon sheaths. These lesions are often multinodular and most commonly present with complaints of swelling or pain. Treatment of TC primarily entails surgical excision. There are no known reports of TC in collegiate athletes. We present a case of TC in a Division I tennis player. PMID- 25514139 TI - A Randomized Clinical Trial Comparing Patellar Tendon, Hamstring Tendon, and Double-Bundle ACL Reconstructions: Patient-Reported and Clinical Outcomes at a Minimal 2-Year Follow-up. AB - OBJECTIVE: To compare 3 anatomically positioned autografts for anterior cruciate ligament (ACL) reconstruction, by measuring patient-reported disease-specific quality of life at 2 years postoperatively. DESIGN: Double-blinded, randomized clinical trial with intraoperative computer-generated treatment allocation. Patients and an independent trained evaluator were blinded. SETTING: University based orthopedic referral practice. PATIENTS: Three hundred thirty patients (14 50 years; 183 male patients) with isolated ACL deficiency were equally randomized to: (1) patellar tendon, PT: 28.7 years (SD = 9.7); (2) quadruple-stranded hamstring tendon, HT: 28.5 years (SD = 9.9); and (3) double bundle using HT, DB: 28.3 years (SD = 9.8); 322 patients completed 2-year follow-up. INTERVENTION: Anterior cruciate ligament reconstruction using PT, HT, or DB autografts. MAIN OUTCOME MEASURES: Measured at baseline, 1 and 2 years postoperatively-primary: anterior cruciate ligament quality-of-life scores; secondary: International Knee Documentation Committee (IKDC) scores, KT-1000 arthrometer, pivot shift, range of motion, Tegner activity, Cincinnati Occupational Scale, and single-leg hop. Proportions of correct graft type guesses by the patients and evaluator assessed blinding effectiveness. RESULTS: Baseline characteristics were not different. Anterior cruciate ligament quality-of-life scores increased over time for all groups (P = 0.001) but were not different at 2 years (P = 0.591): PT = 84.6 (SD = 16.6, 95% confidence interval [CI] = 81.4-87.8), HT = 82.5 (SD = 17.7, 95% CI = 79.2-85.9), and DB = 82.4 (SD = 17.5, 95% CI = 79.1-85.7). Two-year KT-1000 side to-side differences (PT = 1.86 mm; HT = 2.97 mm; DB = 2.65 mm) were statistically significant between PT-HT (P = 0.002) and PT-DB (P = 0.044). The remaining secondary outcomes were not statistically different. Correct graft type guesses occurred 51% of the time for patients and 46% for the evaluator. CONCLUSIONS: Two year disease-specific quality-of-life outcome was not different between the ACL reconstruction techniques. The PT reconstructions had significantly lower side-to side differences on static stability measures. Patient and evaluator blinding was achieved. LEVEL OF EVIDENCE: Level 1 (Therapeutic Studies). CLINICAL RELEVANCE: This high-quality, large, double-blind randomized clinical trial (RCT) addresses the insufficient evidence in the literature comparing PT, single-bundle hamstring, and DB hamstring reconstructions for ACL rupture in adults. In addition to the clinical and functional results, this RCT uniquely reports on the disease-specific, patient-reported quality-of-life outcome at 2 years postoperatively. PMID- 25514141 TI - Preliminary evaluation of a regional atmospheric chemical data assimilation system for environmental surveillance. AB - We report the progress of an ongoing effort by the Air Resources Laboratory, NOAA to build a prototype regional Chemical Analysis System (ARLCAS). The ARLCAS focuses on providing long-term analysis of the three dimensional (3D) air pollutant concentration fields over the continental U.S. It leverages expertise from the NASA Earth Science Division-sponsored Air Quality Applied Science Team (AQAST) for the state-of-science knowledge in atmospheric and data assimilation sciences. The ARLCAS complies with national operational center requirement protocols and aims to have the modeling system to be maintained by a national center. Meteorology and chemistry observations consist of land-, air- and space based observed and quality-assured data. We develop modularized testing to investigate the efficacies of the various components of the ARLCAS. The sensitivity testing of data assimilation schemes showed that with the increment of additional observational data sets, the accuracy of the analysis chemical fields also increased incrementally in varying margins. The benefit is especially noted for additional data sets based on a different platform and/or a different retrieval algorithm. We also described a plan to apply the analysis chemical fields in environmental surveillance at the Centers for Disease Control and Prevention. PMID- 25514140 TI - Inhibitory activity of the isoflavone biochanin A on intracellular bacteria of genus Chlamydia and initial development of a buccal formulation. AB - Given the established role of Chlamydia spp. as causative agents of both acute and chronic diseases, search for new antimicrobial agents against these intracellular bacteria is required to promote human health. Isoflavones are naturally occurring phytoestrogens, antioxidants and efflux pump inhibitors, but their therapeutic use is limited by poor water-solubility and intense first-pass metabolism. Here, we report on effects of isoflavones against C. pneumoniae and C. trachomatis and describe buccal permeability and initial formulation development for biochanin A. Biochanin A was the most potent Chlamydia growth inhibitor among the studied isoflavones, with an IC50 = 12 uM on C. pneumoniae inclusion counts and 6.5 uM on infectious progeny production, both determined by immunofluorescent staining of infected epithelial cell cultures. Encouraged by the permeation of biochanin A across porcine buccal mucosa without detectable metabolism, oromucosal film formulations were designed and prepared by a solvent casting method. The film formulations showed improved dissolution rate of biochanin A compared to powder or a physical mixture, presumably due to the solubilizing effect of hydrophilic additives and presence of biochanin A in amorphous state. In summary, biochanin A is a potent inhibitor of Chlamydia spp., and the in vitro dissolution results support the use of a buccal formulation to potentially improve its bioavailability in antichlamydial or other pharmaceutical applications. PMID- 25514142 TI - A critical review of an authentic and transformative environmental justice and health community--university partnership. AB - Distressed neighborhoods in North Charleston (SC, USA) are impacted by the cumulative effects of multiple environmental hazards and expansion of the Port of Charleston. The Low Country Alliance for Model Communities (LAMC) built an environmental justice partnership to address local concerns. This case study examines the process of building and sustaining a successful transformative and authentic community-university partnership. We apply the framework established by Community-Campus Partnerships for Health (CCPH), focusing on four of the nine principles of Good Practice of Community Campus Partnerships. PMID- 25514143 TI - Secondhand smoke exposure, indoor smoking bans and smoking-related knowledge in China. AB - Although previous studies have provided strong evidence that Chinese individuals are exposed to secondhand smoke (SHS) and lack knowledge of its harmful effects, there has not been an in-depth exploration of the variability in exposure and knowledge by geographic region, occupation, and socioeconomic status. The objectives of this study were to examine: (1) the demographic factors associated with the level of knowledge of the harmful effects of smoking; (2) the factors related to implementation of in-home and workplace smoking bans; and (3) geographic differences in being exposed to SHS in government buildings, healthcare facilities, restaurants, public transportations, and schools. We used data from the 2010 Global Adult Tobacco Survey-China. Chi-square tests were used for statistical analysis. The results suggested that among Chinese citizens age 15 years and older, there is poor knowledge of the harmful effects of tobacco, and knowledge varies with region and socioeconomic status. Over three-quarters of the households had no smoking restrictions, and a large percentage of workers reported working in places with no smoking ban. In public places, exposure to SHS was high, particularly in rural areas and in the Southwest. These results suggest Chinese individuals are not well informed of smoking and SHS associated risks and are regularly exposed to SHS at home, work and public places. PMID- 25514144 TI - Addressing health disparities in chronic kidney disease. AB - According to the official health statistics, Taiwan has the highest prevalence of end stage renal disease (ESRD) in the world. Each year, around 60,000 ESRD patients in Taiwan consume 6% of the national insurance budget for dialysis treatment. The prevalence of chronic kidney disease (CKD) has been climbing during 2008-2012. However, the spatial disparities and clustering of CKD at the public health level have rarely been discussed. The aims of this study are to explore the possible population level risk factors and identify any clusters of CKD, using the national health insurance database. The results show that the ESRD prevalence in females is higher than that in males. ESRD medical expenditure constitutes 87% of total CKD medical expenditure. Pre-CKD and pre-ESRD disease management might slow the progression from CKD to ESRD. After applying ordinary least-squares regression, the percentages of high education status and the elderly in the townships are positively correlated with CKD prevalence. Geographically weighted regression and Local Moran's I are used for identifying the clusters in southern Taiwan. The findings can be important evidence for earlier and targeted community interventions and reducing the health disparities of CKD. PMID- 25514146 TI - A health impact assessment framework for assessing vulnerability and adaptation planning for climate change. AB - This paper presents a detailed description of an approach designed to investigate the application of the Health Impact Assessment (HIA) framework to assess the potential health impacts of climate change. A HIA framework has been combined with key climate change terminology and concepts. The fundamental premise of this framework is an understanding of the interactions between people, the environment and climate. The diversity and complexity of these interactions can hinder much needed action on the critical health issue of climate change. The objectives of the framework are to improve the methodology for understanding and assessing the risks associated with potential health impacts of climate change, and to provide decision-makers with information that can facilitate the development of effective adaptation plans. While the process presented here provides guidance with respect to this task it is not intended to be prescriptive. As such, aspects of the process can be amended to suit the scope and available resources of each project. A series of working tables has been developed to assist in the collation of evidence throughout the process. The framework has been tested in a number of locations including Western Australia, Solomon Islands, Vanuatu and Nauru. PMID- 25514147 TI - Rat lung response to PM2.5 exposure under different cold stresses. AB - Ambient particulate matters and temperature were reported to have additive effects over the respiratory disease hospital admissions and deaths. The purpose of this study is to discuss the interactive pulmonary toxicities of cold stress and fine particulate matter (PM2.5) exposure by estimating inflammation and oxidative stress responses. 48 Wistar male rats, matched by weight and age, were randomly assigned to six groups, which were treated with cold stress alone (0 degrees C, 10 degrees C, and 20 degrees C (Normal control)) and cold stresses plus PM2.5 exposures respectively. Cold stress alone groups were intratracheal instillation of 0.25 mL normal saline, while cold stress plus PM2.5 exposure groups were intratracheal instillation of 8 mg/0.25 mL PM2.5. These procedures were carried out for three times with an interval of 48 hours for each treatment. All rats were sacrificed after 48 hours of the third treatment. The bronchoalveolar lavage fluid (BALF) was collected for analyzing inflammatory cells and cytokines, and lung homogenate MDA was determined for oxidative stress estimation. Results showed higher level of total cell and neutrophil in the BALF of PM2.5 exposed groups (p < 0.05). Negative relationships between cold stress intensity and the level of tumor necrosis factor alpha (TNF-a), C-reactive protein (CRP) interleukin-6 (IL-6) and interleukin-8 (IL-8) in BALF were indicated in PM2.5 exposure groups. Exposure to cold stress alone caused significant increase of inflammatory cytokines and methane dicarboxylic aldehyde (MDA) and decline of superoxide dismutase (SOD) and glutathione peroxidase (GSH Px) activity only in 0 degrees C exposure group (p < 0.05). The two-way ANOVA found significant interactive effects between PM2.5 exposure and cold stress in the level of neutrophil, IL-6 and IL-8 and SOD activity (p < 0.05). These data demonstrated that inflammation and oxidative stress involved in the additive effect of PM2.5 exposure and cold stress on pulmonary toxicity, providing explanation for epidemiological studies on the health effect of ambient PM2.5 and cold stress. PMID- 25514148 TI - Histological changes in gills of two fish species as indicators of water quality in Jansen Lagoon (Sao Luis, Maranhao State, Brazil). AB - Water quality of the Jansen Lagoon (Sao Luis, Maranhao State, Brazil) was assessed through histological biomarkers and microbiological parameters. To this end, 29 fish specimens (11 Centropomus undecimalis and 18 Sardinella sp) and eight water samples were collected during the rainy and dry periods of 2013. The lagoon water showed thermotolerant coliform indices above the limit set forth in CONAMA Resolution 357/2005. Histological changes observed in the gills were: lifting of the respiratory epithelium, hyperplasia of the lamellar epithelium, incomplete and complete fusion of several lamellae, disorganization of the lamellae, congestion of blood vessels, aneurysms, hypertrophy of the respiratory epithelium, hemorrhage and rupture of the lamellar epithelium and parasite. The histological alteration index (HAI) average value to Sardinella sp was 31.8 and to C. undecimalis was 22.2. The average HAI value in both species corresponds to category 21-50, with tissue injuries being classified from moderate to severe. The presence of histological injuries and the HAI values indicate that the fish sampled from the Jansen Lagoon are reacting to non-specific xenobiotics present at the site. PMID- 25514145 TI - The public health exposome: a population-based, exposure science approach to health disparities research. AB - The lack of progress in reducing health disparities suggests that new approaches are needed if we are to achieve meaningful, equitable, and lasting reductions. Current scientific paradigms do not adequately capture the complexity of the relationships between environment, personal health and population level disparities. The public health exposome is presented as a universal exposure tracking framework for integrating complex relationships between exogenous and endogenous exposures across the lifespan from conception to death. It uses a social-ecological framework that builds on the exposome paradigm for conceptualizing how exogenous exposures "get under the skin". The public health exposome approach has led our team to develop a taxonomy and bioinformatics infrastructure to integrate health outcomes data with thousands of sources of exogenous exposure, organized in four broad domains: natural, built, social, and policy environments. With the input of a transdisciplinary team, we have borrowed and applied the methods, tools and terms from various disciplines to measure the effects of environmental exposures on personal and population health outcomes and disparities, many of which may not manifest until many years later. As is customary with a paradigm shift, this approach has far reaching implications for research methods and design, analytics, community engagement strategies, and research training. PMID- 25514149 TI - Overall accessibility to traveling by rail for the elderly with and without functional limitations: the whole-trip perspective. AB - Elderly persons' perceived accessibility to railway traveling depends on their functional limitations/diseases, their functional abilities and their travel behaviors in interaction with the barriers encountered during whole trips. A survey was conducted on a random sample of 1000 city residents (65-85 years old; 57% response rate). The travels were perceived least accessible by respondents with severely reduced functional ability and by those with more than one functional limitation/disease (e.g., restricted mobility and chronic pain). Those who traveled "often", perceived the accessibility to be better than those who traveled less frequently. For travelers with high functional ability, the main barriers to more frequent traveling were travel costs and low punctuality. For those with low functional ability, one's own health was reported to be the main barrier. Our results clarify the links among existing functional limitations/functional abilities, the barriers encountered, the travel behavior, and the overall accessibility to traveling. By operationalizing the whole-trip concept as a chain of events, we deliver practical knowledge on vulnerable groups for decision-making to improve the transport environment for all. PMID- 25514150 TI - General practitioners' knowledge and concern about electromagnetic fields. AB - Our aim is to explore general practitioners' (GPs') knowledge about EMF, and to assess whether different knowledge structures are related to the GPs' concern about EMF. Random samples were drawn from lists of GPs in Germany in 2008. Knowledge about EMF was assessed by seven items. A latent class analysis was conducted to identify latent structures in GPs' knowledge. Further, the GPs' concern about EMF health risk was measured using a score comprising six items. The association between GPs' concern about EMF and their knowledge was analysed using multiple linear regression. In total 435 (response rate 23.3%) GPs participated in the study. Four groups were identified by the latent class analysis: 43.1% of the GPs gave mainly correct answers; 23.7% of the GPs answered low frequency EMF questions correctly; 19.2% answered only the questions relating EMF with health risks, and 14.0% answered mostly "don't know". There was no association between GPs' latent knowledge classes or between the number of correct answers given by the GPs and their EMF concern, whereas the number of incorrect answers was associated with EMF concern. Greater EMF concern in subjects with more incorrect answers suggests paying particular attention to misconceptions regarding EMF in risk communication. PMID- 25514151 TI - Six-month outcome in bipolar spectrum alcoholics treated with acamprosate after detoxification: a retrospective study. AB - BACKGROUND: Glutamate system is modified by ethanol and contributes both to the euphoric and the dysphoric consequences of intoxication, but there is now growing evidence that the glutamatergic system also plays a central role in the neurobiology and treatment of mood disorders, including major depressive disorders and bipolar disorders. We speculate that, using acamprosate, patients with bipolar depression (BIP-A) can take advantage of the anti-glutamate effect of acamprosate to "survive" in treatment longer than peers suffering from non bipolar depression (NBIP-A) after detoxification. METHOD: We retrospectively evaluated the efficacy of a long-term (six-month) acamprosate treatment, after alcohol detoxification, in 41 patients (19 males and 22 females), who could be classified as depressed alcoholics, while taking into account the presence/absence of bipolarity. RESULTS: During the period of observation most NBIP-A patients relapsed, whereas a majority of BIP-A patients were still in treatment at the end of their period of observation. The cumulative proportion of 'surviving' patients was significantly higher in BIP-A patients, but this finding was not related to gender or to other demographic or clinically investigated characteristics. The treatment time effect was significant in both subgroups. The treatment time-group effect was significant (and significantly better) for bipolar patients on account of changes in the severity of their illness. LIMITATIONS: Retrospective methodology and the lack of DSM criteria in diagnosing bipolarity. CONCLUSIONS: Bipolarity seems to be correlated with the efficacy of acamprosate treatment in inducing patients to refrain from alcohol use after detoxification (while avoiding relapses) in depressed alcoholics. Placebo controlled clinical trials are now warranted to check the validity of this hypothesis. PMID- 25514152 TI - Changing patterns of health in communities impacted by a bioenergy project in northern Sierra Leone. AB - Large private sector investments in low- and middle-income countries are often critically evaluated with regards to their environmental, social, human rights, and health impacts. A health impact assessment, including a baseline health survey, was commissioned by the Addax Bioenergy Sierra Leone project in 2010. As part of the monitoring, a follow-up survey was conducted three years later. A set of health indicators was assessed at six impacted and two control sites. Most of these indices improved, particularly at the impacted sites. The prevalences of stunting, wasting, and Plasmodium falciparum in children under five years of age decreased significantly at impacted sites (all p < 0.05) and non-significantly at control sites. Anemia in children and in women of reproductive age (15-49 years) decreased significantly at impacted and control sites (p < 0.05 and p < 0.001, respectively). Health facility-based deliveries increased significantly at the impacted sites (p < 0.05). The prevalences of helminth infections in children aged 10-15 years remained approximately at the same levels, although focal increases at the impacted sites were noted. Access to improved sanitation decreased significantly (p < 0.05) at control and non-significantly at impacted sites. Water quality remained poor without significant changes. The epidemiologic monitoring of a bioenergy project provides a useful contribution for evidence based decision-making. PMID- 25514153 TI - Disparities in rates of inpatient mortality and adverse events: race/ethnicity and language as independent contributors. AB - Patients with limited English proficiency have known limitations accessing health care, but differences in hospital outcomes once access is obtained are unknown. We investigate inpatient mortality rates and obstetric trauma for self-reported speakers of English, Spanish, and languages of Asia and the Pacific Islands (API) and compare quality of care by language with patterns by race/ethnicity. Data were from the United States Agency for Healthcare Research and Quality, Healthcare Cost and Utilization Project, 2009 State Inpatient Databases for California. There were 3,757,218 records. Speaking a non-English principal language and having a non-White race/ethnicity did not place patients at higher risk for inpatient mortality; the exception was significantly higher stroke mortality for Japanese-speaking patients. Patients who spoke API languages or had API race/ethnicity had higher risk for obstetric trauma than English-speaking White patients. Spanish-speaking Hispanic patients had more obstetric trauma than English-speaking Hispanic patients. The influence of language on obstetric trauma and the potential effects of interpretation services on inpatient care are discussed. The broader context of policy implications for collection and reporting of language data is also presented. Results from other countries with and without English as a primary language are needed for the broadest interpretation and generalization of outcomes. PMID- 25514154 TI - Occupational hazards education for nursing staff through web-based learning. AB - This study aims to explore the efficiency of using online education as an intervention measure to prevent occupational hazards in a clinical nursing setting. The subjects were 320 female nursing staff from two hospitals in Taiwan. The questionnaire results indicated that the subjects primarily experienced human factor occupational hazards, as well as psychological and social hazards. Specifically, 73.1% and 69.8% of the subjects suffered from poor sleep quality and low back pain, respectively. After web-based learning, the experimental group had higher post-test scores than the control group in terms of knowledge, attitudes, and practices (KAP). However, there was only a significant difference (p < 0.05) in their knowledge about the prevention of occupational hazards. It is suggested that an online discussion may enhance nursing staff's participation in web-based learning, and further facilitate their comments on negative factors. The findings can highly promote nursing staff's attitudes and practices toward preventing occupational hazards through web-based learning. PMID- 25514157 TI - Marker-free detection of progenitor cell differentiation by analysis of Brownian motion in micro-wells. AB - The kinetics of stem and progenitor cell differentiation at the single-cell level provides essential clues to the complexity of the underlying decision-making circuits. In many hematopoietic progenitor cells, differentiation is accompanied by the expression of lineage-specific markers and by a transition from a non adherent to an adherent state. Here, using the granulocyte-macrophage progenitor (GMP) as a model, we introduce a label-free approach that allows one to follow the course of this transition in hundreds of single cells in parallel. We trap single cells in patterned arrays of micro-wells and use phase-contrast time-lapse movies to distinguish non-adherent from adherent cells by an analysis of Brownian motion. This approach allowed us to observe the kinetics of induced differentiation of primary bone-marrow-derived GMPs into macrophages. The time lapse started 2 hours after addition of the cytokine M-CSF, and nearly 80% of the population had accomplished the transition within the first 20 h. The analysis of Brownian motion proved to be a sensitive and robust tool for monitoring the transition, and thus provides a high-throughput method for the study of cell differentiation at the single-cell level. PMID- 25514155 TI - Urinary concentrations of toxic and essential trace elements among rural residents in Hainan Island, China. AB - BACKGROUND: Toxic element exposure and essential trace element consumption may have changed after the Chinese economy transformed to a market-oriented system. The objectives of this study were to measure urinary concentrations of toxic (arsenic, cadmium, lead) and essential trace (selenium, zinc, copper) elements among rural residents in Hainan, China and to examine if variations in economic development are linked to differences in toxic and trace element exposure. METHODS: We conducted a questionnaire-based survey and undertook anthropometric measurements of residents aged >=20 years (n = 599). Urinary samples were collected and analyzed using inductively coupled plasma mass spectrometry. RESULTS: The median (MUg/g creatinine) element concentrations were: arsenic, 73.2; cadmium, 1.8; lead, 3.1; selenium, 36.5; zinc, 371; and copper, 11.0. Intra community variation in element concentrations was explained by age (arsenic, cadmium, zinc and copper), sex (arsenic, cadmium and selenium: higher in females; zinc: higher in males), body mass index (cadmium) and individual involvement in the market economy as indexed by agrochemical use (lead and selenium). The degree of community-level economic development, which was determined by the proportion of people living in better housing among the study communities, was positively associated with cadmium concentration. CONCLUSIONS: The degree of community-level economic development was positively associated with urinary cadmium concentration while individual involvement in the market economy was positively associated with lead and selenium. PMID- 25514156 TI - The lifestyle switch protein Bd0108 of Bdellovibrio bacteriovorus is an intrinsically disordered protein. AB - Bdellovibrio bacteriovorus is a delta-proteobacterium that preys upon Salmonella spp., E. coli, and other Gram-negative bacteria. Bdellovibrio can grow axenically (host-independent, HI, rare and mutation-driven) or subsist via a predatory lifecycle (host-dependent, HD, the usual case). Upon contact with prey, B. bacteriovorus enters the host periplasm from where it slowly drains the host cytosol of nutrients for its own replication. At the core of this mechanism is a retractile pilus, whose architecture is regulated by the protein Bd0108 and its interaction with the neighboring gene product Bd0109. Deletion of bd0108 results in negligible pilus formation, whereas an internal deletion (the one that instigates host-independence) causes mis-regulation of pilus length. These mutations, along with a suite of naturally occurring bd0108 mutant strains, act to control the entry to HI growth. To further study the molecular mechanism of predatory regulation, we focused on the apparent lifecycle switch protein Bd0108. Here we characterize the solution structure and dynamics of Bd0108 using nuclear magnetic resonance (NMR) spectroscopy complemented with additional biophysical methods. We then explore the interaction between Bd0108 and Bd0109 in detail utilizing isothermal titration calorimetry (ITC) and NMR spectroscopy. Together our results demonstrate that Bd0108 is an intrinsically disordered protein (IDP) and that the interaction with Bd0109 is of low affinity. Furthermore, we observe that Bd0108 retains an IDP nature while binding Bd0109. From our data we conclude that Bdellovibrio bacteriovorus utilizes an intrinsically disordered protein to regulate its pilus and control predation signaling. PMID- 25514158 TI - New Year's res-illusions: food shopping in the new year competes with healthy intentions. AB - OBJECTIVE: How do the holidays--and the possible New Year's resolutions that follow--influence a household's purchase patterns of healthier foods versus less healthy foods? This has important implications for both holiday food shopping and post-holiday shopping. METHODS: 207 households were recruited to participate in a randomized-controlled trial conducted at two regional-grocery chain locations in upstate New York. Item-level transaction records were tracked over a seven-month period (July 2010 to March 2011). The cooperating grocer's proprietary nutrient rating system was used to designate "healthy," and "less healthy" items. Calorie data were extracted from online nutritional databases. Expenditures and calories purchased for the holiday period (Thanksgiving-New Year's), and the post-holiday period (New Year's-March), were compared to baseline (July-Thanksgiving) amounts. RESULTS: During the holiday season, household food expenditures increased 15% compared to baseline ($105.74 to $121.83; p<0.001), with 75% of additional expenditures accounted for by less-healthy items. Consistent with what one would expect from New Year's resolutions, sales of healthy foods increased 29.4% ($13.24/week) after the holiday season compared to baseline, and 18.9% ($9.26/week) compared to the holiday period. Unfortunately, sales of less-healthy foods remained at holiday levels ($72.85/week holiday period vs. $72.52/week post holiday). Calories purchased each week increased 9.3% (450 calories per serving/week) after the New Year compared to the holiday period, and increased 20.2% (890 calories per serving/week) compared to baseline. CONCLUSIONS: Despite resolutions to eat more healthfully after New Year's, consumers may adjust to a new "status quo" of increased less-healthy food purchasing during the holidays, and dubiously fulfill their New Year's resolutions by spending more on healthy foods. Encouraging consumers to substitute healthy items for less-healthy items may be one way for practitioners and public health officials to help consumers fulfill New Year's resolutions, and reverse holiday weight gain. PMID- 25514159 TI - Recruitment via the Internet and social networking sites: the 1989-1995 cohort of the Australian Longitudinal Study on Women's Health. AB - BACKGROUND: Faced with the challenge of recruiting young adults for health studies, researchers have increasingly turned to the Internet and social networking sites, such as Facebook, as part of their recruitment strategy. As yet, few large-scale studies are available that report on the characteristics and representativeness of the sample obtained from such recruitment methods. OBJECTIVE: The intent of the study was to describe the sociodemographic and health characteristics of a national sample of young Australian women recruited mainly through the Internet and social networking sites and to discuss the representativeness of their sociodemographic, health, and lifestyle characteristics relative to the population. METHODS: A cohort of 17,069 women (born between 1989 and 1995) was recruited in 2012-13 for the Australian Longitudinal Study on Women's Health. Sociodemographic characteristics (percentages, means, and 95% confidence intervals) from the online survey data were compared with women aged 18-23 years from the 2011 Australian Census. Sample data were compared by age and education level with data from the 2011-13 Australian Health Survey (AHS). RESULTS: Compared to the Australian Census data, study participants were broadly representative in terms of geographical distribution across Australia, marital status (95.62%, 16,321/17,069) were never married), and age distribution. A higher percentage had attained university (22.52%, 3844/17,069) and trade/certificate/diploma qualifications (25.94%, 4428/17,069) compared with this age group of women in the national population (9.4% and 21.7% respectively). Among study participants, 22.05% (3721/16,877) were not in paid employment with 35.18% (5931/16,857) studying 16 or more hours a week. A higher percentage of study participants rated their health in the online survey as fair or poor (rather than good, very good, or excellent) compared with those participating in face-to-face interviews in the AHS (18.77%, 3203/17,069 vs 10.1%). A higher percentage of study participants were current smokers (21.78%, 3718/17,069 vs 16.4%) and physically active (59.30%, 10,089/17,014 were classified as sufficiently active vs 48.3%) but alcohol consumption was lower (59.58%, 9865/16,558 reported drinking alcohol at least once per month vs 65.9% in the AHS). Using self-reported height and weight to determine body mass index (BMI, kg/m(2)), 34.80% (5901/16,956) of the cohort were classified as overweight or obese (BMI of 25 or more), compared with 33.6% respectively using measured height and weight in the AHS. CONCLUSIONS: Findings indicated that using the Internet and social networking sites for an online survey represent a feasible recruitment strategy for a national cohort of young women and result in a broadly representative sample of the Australian population. PMID- 25514163 TI - A rapid and convenient method for detecting a broad spectrum of malignant cells from malignant pleuroperitoneal effusion of patients using a multifunctional NIR heptamethine dye. AB - Detection of malignant cells from malignant effusion is crucial to establish or adjust therapies of patients with cancer. The conventional qualitative detection in malignant pleuroperitoneal effusion is cytological analysis, which is time consuming and complicated. Therefore, a faster and more convenient detection strategy is urgently needed. In this study, we report a rapid method to detect malignant cells from malignant pleuroperitoneal effusion (hydrothorax and ascites) of patients using IR-808, a tumor-targeted near-infrared (NIR) fluorescent heptamethine dye (tNRI dye), which exhibited superior labeling efficacy without specific conjugation to biomarkers. The targeted imaging performance toward malignant cells using IR-808 was confirmed by comparing with normal cells, and the fluorescence stability assay of IR-808 in malignant effusion was performed from 1 h to 48 h. In order to save time and dose, the incubation time and concentration were optimized to 10 min and 5 MUM, which were used to detect malignant cells from 28 clinical samples of malignant pleuroperitoneal effusion. The results revealed that IR-808 could be internalized selectively by malignant cells of samples, and these malignant cells could be easily distinguished from normal cells under a fluorescence microscope. The positive rates between cytological analysis and the IR-808 staining method were 86% (24/28) and 79% (22/28), respectively. An excellent concordance level (Kappa = 0.752, P < 0.001) was observed between the two methods. Our results indicated that IR-808, a new NIR fluorescent heptamethine dye with unique optical imaging and tumor targeting properties, could provide a fast and simple way to detect a broad spectrum of malignant cells from malignant pleuroperitoneal effusion in patients. PMID- 25514164 TI - Distinguishing odors with high temporal precision. PMID- 25514162 TI - Serotonin/dopamine interactions in a hyperactive mouse: reduced serotonin receptor 1B activity reverses effects of dopamine transporter knockout. AB - Knockout (KO) mice that lack the dopamine transporter (SL6A3; DAT) display increased locomotion that can be attenuated, under some circumstances, by administration of drugs that normally produce psychostimulant-like effects, such as amphetamine and methylphenidate. These results have led to suggestions that DAT KO mice may model features of attention deficit hyperactivity disorder (ADHD) and that these drugs may act upon serotonin (5-HT) systems to produce these unusual locomotor decreasing effects. Evidence from patterns of brain expression and initial pharmacologic studies led us to use genetic and pharmacologic approaches to examine the influence of altered 5-HT1B receptor activity on hyperactivity in DAT KO mice. Heterozygous 5-HT1B KO and pharmacologic 5-HT1B antagonism both attenuated locomotor hyperactivity in DAT KO mice. Furthermore, DAT KO mice with reduced, but not eliminated, 5-HT1B receptor expression regained cocaine-stimulated locomotion, which was absent in DAT KO mice with normal levels of 5-HT1B receptor expression. Further experiments demonstrated that the degree of habituation to the testing apparatus determined whether cocaine had no effect on locomotion in DAT KO or reduced locomotion, helping to resolve differences among prior reports. These findings of complementation of the locomotor effects of DAT KO by reducing 5-HT1B receptor activity underscore roles for interactions between specific 5-HT receptors and dopamine (DA) systems in basal and cocaine stimulated locomotion and support evaluation of 5-HT1B antagonists as potential, non-stimulant ADHD therapeutics. PMID- 25514165 TI - Regioselective plasmonic coupling in metamolecular analogs of benzene derivatives. AB - In analogy with benzene-derived molecular structures, we construct plasmonic metamolecules by attaching Au nanospheres to specific sites on a hexagonal Au nanoplate. We employ a ligand exchange strategy that allows regioselective control of nanosphere attachment and study resulting structures using correlated electron microscopy/optical spectroscopy at the single-metamolecule level. We find that plasmonic coupling within the resulting assembly is strongly dependent on the structure of the metamolecule, in particular the site of attachment of the nanosphere(s). We also uncover a synergy in the polarizing effect of multiple nanospheres attached to the nanoplate. Regioselective control of plasmonic properties demonstrated here enables the design of novel structure-dependent electromagnetic modes and applications in three-dimensional spatial nanosensors. PMID- 25514167 TI - Heating-enabled formation of droplet interface bilayers using Escherichia coli total lipid extract. AB - Droplet interface bilayers (DIBs) serve as a convenient platform to study interactions between synthetic lipid membranes and proteins. However, a majority of DIBs have been assembled using a single lipid type, diphytanoylphosphatidylcholine (DPhPC). The work described herein establishes a new method to assemble DIBs using total lipid extract from Escherichia coli (eTLE); it is found that incubating oil-submerged aqueous droplets containing eTLE liposomes at a temperature above the gel-fluid phase transition temperature (Tg) promotes monolayer self-assembly that does not occur below Tg. Once monolayers are properly assembled via heating, droplets can be directly connected or cooled below Tg and then connected to initiate bilayer formation. This outcome contrasts immediate droplet coalescence observed upon contact between nonheated eTLE-infused droplets. Specific capacitance measurements confirm that the interface between droplets containing eTLE lipids is a lipid bilayer with thickness of 29.6 A at 25 degrees C in hexadecane. We observe that bilayers formed from eTLE or DPhPC survive cooling and heating between 25 and 50 degrees C and demonstrate gigaohm (GOmega) membrane resistances at all temperatures tested. Additionally, we study the insertion of alamethicin peptides into both eTLE and DPhPC membranes to understand how lipid composition, temperature, and membrane phase influence ion channel formation. Like in DPhPC bilayers, alamethicin peptides in eTLE exhibit discrete, voltage-dependent gating characterized by multiple open channel conductance levels, though at significantly lower applied voltages. Cyclic voltammetry measurements of macroscopic channel currents confirm that the voltage-dependent conductance of alamethicin channels in eTLE bilayers occurs at lower voltages than in DPhPC bilayers at equivalent peptide concentrations. This result suggests that eTLE membranes, via composition, fluidity, or the presence of subdomains, offer an environment that enhances alamethicin insertion. For both membrane compositions, increasing temperature reduces the lifetimes of single channel gating events and increases the voltage required to cause an exponential increase in channel current. However, the fact that alamethicin insertion in eTLE exhibits significantly greater sensitivity to temperature changes through its Tg suggests that membrane phase plays an important role in channel formation. These effects are much less severe in DPhPC, where heating from 25 to 50 degrees C does not induce a phase change. The described technique for heating-assisted monolayer formation permits the use of other high transition temperature lipids in aqueous droplets for DIB formation, thereby increasing the types of lipids that can be considered for assembling model membranes. PMID- 25514166 TI - Generation and characterization of a monoclonal antibody against prM protein of West Nile virus. AB - West Nile virus (WNV), which is an emerging pathogenic flavivirus with increasing distribution worldwide, is the cause of major human and animal health concerns. The pre-membrane (prM) protein of WNV is cleaved during maturation by the furin protease into the structural protein M and a pr-segment. In this study we generated and characterized a monoclonal antibody (MAb) against the WNV prM protein. Western blot analysis showed that the MAb reacted with WNV prM specifically. Immunohistochemistry assays demonstrated that the MAb recognized native prM protein in transfected BHK-21 cells. Preliminary studies were performed to identify the epitope recognized by the MAb using a set of synthesized overlapping peptides spanning the whole length of the prM protein. The MAb reported here may provide a valuable tool for the further exploration of the biological properties and functions of the prM protein and may also be developed for potential clinical applications. PMID- 25514168 TI - Eruptive nevi and hair depigmentation related to regorafenib. PMID- 25514169 TI - RNA-seq analysis of equine conceptus transcripts during embryo fixation and capsule disappearance. AB - Extensive studies have been conducted to characterize the unique phenomena of equine pregnancy. Most studies have focused on embryo transmigration when the embryo is covered with a mucin-like glycoprotein capsule and on the characterization of the chorionic girdle and chorionic gonadotropin (CG) secretion. However, the events preceding and following capsule disappearance have not been well studied. In this study, the mRNA expression in conceptus membranes at days 19, 21, and 25 (day 0 = day of ovulation) was analyzed by RNA-seq (SOLiD3), and transcript levels on these three days and day 13 were confirmed by real-time PCR. Of the 26,416 equine genes registered, 20,436 transcripts were aligned to sequences in the Ensembl database, from which 4,625 transcripts were registered in both Ensembl and the KEGG pathway. Each of the 4,625 transcripts was examined through KEGG pathway analysis, and 12 transcripts of integrins (ITGs) and collagens (COLs) were confirmed through real-time PCR. Our data indicated that extracellular matrix (ECM)-related mRNAs were highly expressed in day 19, 21, and 25 conceptus membranes. In combination with previous results, which confirmed a lack of laminin and fibronectin transcript expression in the endometrium, these observations suggest that in contrast to attachment through focal adhesion, conceptus chorionic membrane ECMs function as a scaffold-like structure to possibly maintain the shape of the conceptus and a separation between chorionic membranes and the uterine luminal epithelium. PMID- 25514170 TI - Adiponectin induces apoptosis in hepatocellular carcinoma through differential modulation of thioredoxin proteins. AB - Adiponectin blocks hepatocellular carcinoma (HCC) progression by inducing cell apoptosis through the modulation of C-Jun N-terminal kinase and mammalian target of rapamycin. However, the precise upstream signaling pathways or molecules remain elusive. In the present study, we analyzed the role of antioxidant protein thioredoxin (Trx) in adiponectin-induced apoptosis in HCC. Adiponectin treatment decreased the viabilities of both HepG2 and Huh7 HCC cells accompanied by increased accumulation of intracellular reactive oxygen species, as evidenced by 2',7'-dichlorodihydrofluorescein diacetate staining. Pretreatment of these cells with the deoxidant N-acetylcysteine blocked the inhibitory effect of adiponectin. Levels of Trx2 protein in both HCC cells were significantly decreased, and the level of Trx1 was significantly inhibited in Huh7 cells while unchanged in HepG2 cells. However, the redox state of Trx1 was altered from reduced to the oxidized form following adiponectin treatment in HepG2 cells. Overexpression of both Trx proteins rescued adiponectin-induced cell apoptosis, whereas mutated Trx proteins were less effective. Further analysis suggested that both ASK1 and JNK signaling are involved in this process. Trx1 and Trx2 proteins also manifested protective effects on HCC cells in response to adiponectin treatment in a xenograft tumor model. Furthermore, high levels of Trx proteins and low adiponectin expression levels were found in primary human HCC samples compared with paracancerous tissues. These results suggest that Trx proteins play important roles in mediating adiponectin-induced HCC cell apoptosis, thus providing new insights into the pathogenesis of HCC and identifying adiponectin and Trx proteins as potential combinational therapeutic targets for the treatment of HCC. PMID- 25514171 TI - Mesomartoxin, a new K(v)1.2-selective scorpion toxin interacting with the channel selectivity filter. AB - Venom-derived neurotoxins are ideal probes for the investigation of structure function relationship of ion channels and promising scaffolds for the design of ion channel-targeted drug leads as well. The discovery of highly selective toxins against a specific channel subtype facilitates the development of drugs with reduced side effects. Here, we describe the systemic characterization of a new scorpion short-chain K(+) channel blocker from Mesobuthus martensii, termed mesomartoxin (MMTX). MMTX is synthesized as a precursor comprising a signal peptide and a mature peptide of 29 residues. Nuclear magnetic resonance analysis confirmed that recombinant MMTX adopts a typical cysteine-stabilized alpha helical and beta-sheet fold. Electrophysiological experiments showed that MMTX exhibits high affinity for the Drosophila Shaker K(+) channel but differential selectivity on different members of the rat voltage-gated K(+) channel (Kv) family, with nanomolar affinity (IC50=15.6 nM) for rKv1.2, micromolar affinity for rKv1.3 (IC50=12.5 MUM) and no activity on rKv1.1 at >50 MUM. Site-directed mutagenesis of the channel pore identified a key site located on the selectivity filter of the pore, which is directly implicated in toxin binding and controls target's selectivity of the toxin. Given a key role of Kv1.2 in epilepsy, MMTX might serve as a potential drug lead for the disease. PMID- 25514172 TI - Accurate data process for nanopore analysis. AB - Data analysis for nanopore experiments remains a fundamental and technological challenge because of the large data volume, the presence of unavoidable noise, and the filtering effect. Here, we present an accurate and robust data process that recognizes the current blockades and enables evaluation of the dwell time and current amplitude through a novel second-order-differential-based calibration method and an integration method, respectively. We applied the developed data process to analyze both generated blockages and experimental data. Compared to the results obtained using the conventional method, those obtained using the new method provided a significant increase in the accuracy of nanopore measurements. PMID- 25514174 TI - Prevalence of antibiotic resistance genes and bacterial pathogens in long-term manured greenhouse soils as revealed by metagenomic survey. AB - Antibiotic resistance genes (ARGs), human pathogenic bacteria (HPB), and HPB carrying ARGs pose a high risk to soil ecology and public health. Here, we used a metagenomic approach to investigate their diversity and abundance in chicken manures and greenhouse soils collected from Guli, Pulangke, and Hushu vegetable bases with different greenhouse planting years in Nanjing, Eastern China. There was a positive correlation between the levels of antibiotics, ARGs, HPB, and HPB carrying ARGs in manures and greenhouse soils. In total, 156.2-5001.4 MUg/kg of antibiotic residues, 22 classes of ARGs, 32 HPB species, and 46 species of HPB carrying ARGs were found. The highest relative abundance was tetracycline resistance genes (manures) and multidrug resistance genes (greenhouse soils). The dominant HPB and HPB carrying ARGs in the manures were Bacillus anthracis, Bordetella pertussis, and B. anthracis (sulfonamide resistance gene, sul1), respectively. The corresponding findings in greenhouse soils were Mycobacterium tuberculosis and M. ulcerans, M. tuberculosis (macrolide-lincosamide streptogramin resistance protein, MLSRP), and B. anthracis (sul1), respectively. Our findings confirmed high levels of antibiotics, ARGs, HPB, and HPB carrying ARGs in the manured greenhouse soils compared with those in the field soils, and their relative abundance increased with the extension of greenhouse planting years. PMID- 25514173 TI - Evolution of the syphilis epidemic among men who have sex with men. AB - Syphilis has existed for millenni, but its epidemiology was only recently linked to men who have sex with men (MSM) after the introduction of penicillin in the 1940s; the syphilis epidemic became concentrated within the MSM community in subsequent decades. The HIV/AIDS epidemic in the 1980s led to a surge of new syphilis cases and revealed the potentiation between HIV and syphilis, as evidenced by a shift in the natural history of neurosyphilis. In response, MSM revolutionised their sexual behaviour by implementing community-driven seroadaptive strategies to stem HIV transmission. The Centers for Disease Control in the US called for the elimination of syphilis in the late 1990s since the rates had fallen sharply but this effort was overtaken by a resurgence of global outbreaks among MSM in the 2000s, many of which were linked to methamphetamine use and sexual networking websites. Syphilis remains highly prevalent today, especially among MSM and individuals infected with HIV, and it continues to present a significant public health conundrum. Innovative syphilis prevention strategies are warranted. MSM engaging in high-risk behaviour such as condomless anal receptive intercourse, sex with multiple partners or recreational drug use should be routinely screened for syphilis infection; they should also be counselled about the limits of seroadaptive behaviours and HIV pre-exposure prophylaxis as they relate to syphilis transmission. PMID- 25514177 TI - Field effect transistors with current saturation and voltage gain in ultrathin ReS2. AB - We report the fabrication and device characteristics of exfoliated, few-layer, dual-gated ReS2 field effect transistors (FETs). The ReS2 FETs display n-type behavior with a room temperature Ion/I(off) of 10(5). Many devices were studied with a maximum intrinsic mobility of 12 cm(2) . V(-1) . s(-1) at room temperature and 26 cm(2) . V(-1) . s(-1) at 77 K. The Cr/Au-ReS2 contact resistance determined using the transfer length method is gate-bias dependent and ranges from 175 kOmega . MUm to 5 kOmega . MUm, and shows an exponential dependence on back-gate voltage indicating Schottky barriers at the source and drain contacts. Dual-gated ReS2 FETs demonstrate current saturation, voltage gain, and a subthreshold swing of 148 mV/decade. PMID- 25514175 TI - BMP signalling regulates the pre-implantation development of extra-embryonic cell lineages in the mouse embryo. AB - Pre-implantation development requires the specification and organization of embryonic and extra-embryonic lineages. The separation of these lineages takes place when asymmetric divisions generate inside and outside cells that differ in polarity, position and fate. Here we assess the global transcriptional identities of these precursor cells to gain insight into the molecular mechanisms regulating lineage segregation. Unexpectedly, this reveals that complementary components of the bone morphogenetic protein (BMP) signalling pathway are already differentially expressed after the first wave of asymmetric divisions. We investigate the role of BMP signalling by expressing dominant negative forms of Smad4 and Bmpr2, by downregulating the pathway using RNA interference against BMP ligands and by applying three different BMP inhibitors at distinct stages. This reveals that BMP signalling regulates the correct development of both extra embryonic lineages, primitive endoderm and trophectoderm, but not the embryonic lineage, before implantation. Together, these findings indicate multiple roles of BMP signalling in the early mouse embryo. PMID- 25514176 TI - Relationship between immune parameters and organ involvement in children with Henoch-Schonlein purpura. AB - Henoch-Schonlein purpura (HSP) is the most common type of connective tissue diseases which increasingly occurs in children in recent years and its pathogenesis remains unclear. In order to explore the immune parameters and underlying pathogenesis mechanism of children with HSP, the study involved 1232 patients with HSP having different clinical symptoms and their laboratory indicators were evaluated. Th1/Th2 imbalance and overactivity of Th2 cells can cause increase in the synthesis and release of immunoglobulins in children with HSP. The number of red blood cells and white blood cells in urine was directly proportional to the level of IgA and inversely proportional to the level of serum complements (C3 and C4). Activation of these complements caused by immunoglobulin in patients with HSP plays an important role in renal injury. The urinary protein content in children with HSP along with proteinuria was positively correlated with IgE level, and IgE mediated type 1 hypersensitivity can cause increase in capillary permeability and weakened the charge barrier; hence, it could be considered as one of the causes of proteinuria in HSP. Additionally, the NK cells percentage was reduced and impaired immune function of NK cells were related to the immune injury of the digestive tract and kidney. PMID- 25514178 TI - Direct radiation effects to the amino acid side chain: EMR and periodic DFT of X irradiated L-asparagine at 6 K. AB - Radical formation in single crystals of L-asparagine monohydrate following X irradiation at 6 K has been investigated at 6 K and at elevated temperatures using various electron magnetic resonance (EMR) techniques such as electron paramagnetic resonance (EPR), electron nuclear double resonance (ENDOR), and ENDOR-induced EPR (EIE) spectroscopy. Molecular structures of the three free radicals stable at 6 K were assessed by detailed analysis of the experimental data and density functional theory (DFT) calculations in a periodic approach. Radical LI is assumed to result from one-electron reduction at the amide functional group in the asparagine side chain followed by protonation at the amide carbonyl oxygen by proton transfer from a neighboring molecule across a hydrogen bond. Radical LII is assigned to a one-electron reduction of the carboxyl group in the amino acid backbone, followed by proton transfer across a hydrogen bond between a carboxylic oxygen and a neighboring asparagine molecule. Radical LIII is suggested to be formed by a net CO2 abstraction from an initial one-electron oxidized amino acid backbone. For the DFT modeling of LIII at 6 K, it was chosen to include the CO2 group stably embedded in the crystalline lattice. The assignments made are discussed in relation to previous work on L asparagine. The relevance of these results to possible charge transfer processes in protein:DNA complexes is discussed. PMID- 25514179 TI - PINK1-PARKIN interplay: down to ubiquitin phosphorylation. AB - By using quantitative proteomics, Ordureau et al. (2014) provide a comprehensive view on the regulatory steps by which PINK1-mediated phosphorylation of PARKIN and ubiquitin triggers the recruitment of the ubiquitin ligase PARKIN to damaged mitochondria. PMID- 25514180 TI - Rewiring mitochondrial pyruvate metabolism: switching off the light in cancer cells? AB - Metabolic reprogramming is a characteristic of cancer cells. Three studies published in this month's Molecular Cell provide novel insights into the role of mitochondrial pyruvate in tumor metabolism and describe how targeting pyruvate transport and metabolism may afford therapeutic benefit. PMID- 25514181 TI - Ribosomes left in the dust: diverse strategies for Peptide-mediated translation stalling. AB - In two recent papers, Arenz et al. (2014a) and Bischoff et al. (2014) provide structural insights into drug-induced, peptide-mediated stalling of the ribosome. PMID- 25514183 TI - Nutrition knowledge and dietary intake of adolescents in Cofimvaba, Eastern Cape, South Africa. AB - The aim of the study was to assess the nutrition knowledge, nutrient intakes, and association between nutrition knowledge and dietary intakes of 98 adolescents attending five schools in rural Cofimvaba, South Africa. Measures included a socioeconomic questionnaire, two 24-hour-recall questionnaires, and food frequency and nutrition knowledge questionnaires. The overall score for the multiple-choice section on general nutrition and the South African Food-Based Dietary Guidelines was 72.9%; 75.4% for correct identification of food groups; and 41.3% for correct identification of food portions/serving sizes. Median nutrient intakes, measured by 24-hour recall, failed to meet average requirements, with the exception of protein, carbohydrates, chromium, riboflavin, pantothenate, and vitamin K among girls. A similar trend was observed for boys. Lower total carbohydrate and fat and higher protein intakes were associated with a higher quartile score for nutrition knowledge. The study provided a valuable understanding of the association between nutrition knowledge and dietary intakes of adolescents. PMID- 25514182 TI - The coilin interactome identifies hundreds of small noncoding RNAs that traffic through Cajal bodies. AB - Coilin protein scaffolds Cajal bodies (CBs)-subnuclear compartments enriched in small nuclear RNAs (snRNAs)-and promotes efficient spliceosomal snRNP assembly. The molecular function of coilin, which is intrinsically disordered with no defined motifs, is poorly understood. We use UV crosslinking and immunoprecipitation (iCLIP) to determine whether mammalian coilin binds RNA in vivo and to identify targets. Robust detection of snRNA transcripts correlated with coilin ChIP-seq peaks on snRNA genes, indicating that coilin binding to nascent snRNAs is a site-specific CB nucleator. Surprisingly, several hundred small nucleolar RNAs (snoRNAs) were identified as coilin interactors, including numerous unannotated mouse and human snoRNAs. We show that all classes of snoRNAs concentrate in CBs. Moreover, snoRNAs lacking specific CB retention signals traffic through CBs en route to nucleoli, consistent with the role of CBs in small RNP assembly. Thus, coilin couples snRNA and snoRNA biogenesis, making CBs the cellular hub of small ncRNA metabolism. PMID- 25514184 TI - Inspiratory resonant frequency of forced oscillation technique as a predictor of the composite physiologic index in interstitial lung disease. AB - The composite physiologic index (CPI), which is derived from FEV1, FVC, and diffusing capacity, has been developed to predict the extent of fibrosis on high resolution computed tomography (HRCT). However, the relevance to the forced oscillation technique (FOT) is not fully understood. We hypothesized that FOT would independently predict the CPI in interstitial lung disease (ILD). In this cross-sectional study we assessed the relationship between pulmonary function tests, forced oscillatory parameters, and the degree of fibrosis in ILD. Spirometry, evaluation of diffusing capacity for carbon monoxide, and the broadband frequency FOT were performed in 93 patients with a clinical/HRCT diagnosis of ILD. The CPI was calculated and fibrosis extent was measured by HRCT and scored. Univariate analyses revealed that, of the forced oscillatory parameters, inspiratory resonant frequency best correlated with FVC, FEV1, diffusing capacity, CPI, and fibrosis score. In multiple regression analyses, CPI was independently predicted by inspiratory resonant frequency and fibrosis score (model R(2)=0.405, p<0.0001). PMID- 25514185 TI - Phenotypic features of children with neurodevelopmental diseases in relation to biogenic amines. AB - Disruption of monoamines metabolism leads to diverse manifestations, including developmental, movement and respiratory dysfunctions. We aimed to correlate clinical phenotypes of 55 children with neurodevelopmental disorders with dopamine (HVA) and serotonin (5-HIIA) metabolites in CSF. Decreased level of at least one metabolite was documented in 49.1% patients. Both metabolites were significantly lower in progressive disorder and extrapyramidal syndrome (p<0.05). HVA was significantly lower in hypokinetic and regulatory disorders (p<0.05). In univariate analysis, only progressive course, extrapyramidal syndrome and dystonia were significantly associated with decreased 5-HIAA. In multivariate regression only progressive course remained significant (p=0.005). Progressive disease, extrapyramidal syndrome, dystonia, tremor and rigidity were positively associated with low HVA. In multivariate analysis only: progressive course and rigidity remained significant. Progressive/rigid phenotype carries a high risk of monoamines deficiency, strongly implying need for their analysis. Psychomotor delay with epilepsy and hypotonia is rarely linked to low monoamines level. Irrespective of final diagnosis, different clinical presentations may be associated with impaired monoamines turnover. PMID- 25514187 TI - Silver-mediated selective oxidative cross-coupling between C-H/P-H: a strategy to construct alkynyl(diaryl)phosphine oxide. AB - A direct oxidative cross-coupling between terminal alkynes and secondary phosphine oxides was developed. This approach provides an efficient way to construct alkynyl di(phenyl) phosphine oxides from basic materials, and in this process, the silver salts act as a key promoter. PMID- 25514188 TI - Asymmetric tandem reactions of N-sulfonylimines and alpha,beta-unsaturated aldehydes: an alternative reaction pathway to that of using saturated aldehydes. AB - An organocatalyzed asymmetric tandem reaction of cyclic N-sulfonylimines and alpha,beta-unsaturated aldehydes was developed. These substrates follow an alternative reaction pathway to that of reactions involving saturated aldehydes, affording similar piperidine derivatives. PMID- 25514186 TI - Transcriptional consequence and impaired gametogenesis with high-grade aneuploidy in Arabidopsis thaliana. AB - Aneuploidy features a numerical chromosome variant that the number of chromosomes in the nucleus of a cell is not an exact multiple of the haploid number, which may have an impact on morphology and gene expression. Here we report a tertiary trisomy uncovered by characterizing a T-DNA insertion mutant (aur2-1/+) in the Arabidopsis (Arabidopsis thaliana) AURORA2 locus. Whole-genome analysis with DNA tiling arrays revealed a chromosomal translocation linked to the aur2-1 allele, which collectively accounted for a tertiary trisomy 2. Morphologic, cytogenetic and genetic analyses of aur2-1 progeny showed impaired male and female gametogenesis to various degrees and a tight association of the aur2-1 allele with the tertiary trisomy that was preferentially inherited. Transcriptome analysis showed overlapping and distinct gene expression profiles between primary and tertiary trisomy 2 plants, particularly genes involved in response to stress and various types of external and internal stimuli. Additionally, transcriptome and gene ontology analyses revealed an overrepresentation of nuclear-encoded organelle-related genes functionally involved in plastids, mitochondria and peroxisomes that were differentially expressed in at least three if not all Arabidopsis trisomics. These observations support a previous hypothesis that aneuploid cells have higher energy requirement to overcome the detrimental effects of an unbalanced genome. Moreover, our findings extend the knowledge of the complex nature of the T-DNA insertion event influencing plant genomic integrity by creating high-grade trisomy. Finally, gene expression profiling results provide useful information for future research to compare primary and tertiary trisomics for the effects of aneuploidy on plant cell physiology. PMID- 25514190 TI - An open canvas--2D materials with defects, disorder, and functionality. AB - CONSPECTUS: While some exceptional properties are unique to graphene only (its signature Dirac-cone gapless dispersion, carrier mobility, record strength), other features are common to other two-dimensional materials. The broader family "beyond graphene" offers greater choices to be explored and tailored for various applications. Transition metal dichalcogenides (TMDCs), hexagonal boron nitride (h-BN), and 2D layers of pure elements, like phosphorus or boron, can complement or even surpass graphene in many ways and uses, ranging from electronics and optoelectronics to catalysis and energy storage. Their availability greatly relies on chemical vapor deposition growth of large samples, which are highly polycrystalline and include interfaces such as edges, heterostructures, and grain boundaries, as well as dislocations and point defects. These imperfections do not always degrade the material properties, but they often bring new physics and even useful functionality. It turns particularly interesting in combination with the sheer openness of all 2D sheets, fully exposed to the environment, which, as we show herein, can change and tune the defect structures and consequently all their qualities, from electronic levels, conductivity, magnetism, and optics to structural mobility of dislocations and catalytic activities. In this Account, we review our progress in understanding of various defects. We begin by expressing the energy of an arbitrary graphene edge analytically, so that the environment is regarded by "chemical phase shift". This has profound implications for graphene and carbon nanotube growth. Generalization of this equation to heteroelemental BN gives a method to determine the energy for arbitrary edges of BN, depending on the partial chemical potentials. This facilitates the tuning of the morphology and electronic and magnetic properties of pure BN or hybrid BN|C systems. Applying a similar method to three-atomic-layer TMDCs reveals more diverse edge structures for thermodynamically stable flakes. Moreover, CVD samples show new types of edge reconstruction, providing insight into the nonequilibrium growth process. Combining dislocation theory with first-principles computations, we could predict the dislocation cores for BN and TMDC and reveal their variable chemical makeup. This lays the foundation for the unique sensitivity to ambient conditions. For example, partial occupation of the defect states for dislocations in TMDCs renders them intrinsically magnetic. The exchange coupling between electrons from neighboring dislocations in grain boundaries further makes them half-metallic, which may find its applications in spintronics. Finally, brief discussion of monoelemental 2D-layer phosphorus and especially the structures and growth routes of 2D boron shows how theoretical assessment can help the quest for new synthetic routes. PMID- 25514189 TI - CXCR3 Requirement for the Interleukin-13-Mediated Up-Regulation of Interleukin 13Ralpha2 in Pulmonary Fibroblasts. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibrosis and abnormal vascularity. IL-13, a profibrotic cytokine that plays a role in IPF, functions through the Jak/STAT pathway after binding to the IL-13 receptor alpha1 (IL-13Ralpha1)/IL-4Ralpha complex. IL-13 also binds to IL 13Ralpha2, which has been thought to function as a nonsignaling decoy receptor, although possible signaling roles of this receptor have been proposed. CXCR3 and its IFN-inducible ligands-CXCL9, CXCL10, and CXCL11-have been implicated in vascular remodeling and fibroblast motility during the development of IPF. In this study, CXCR3 expression was demonstrated in cultured pulmonary fibroblasts from wild-type BALB/c mice and was found to be necessary for the IL-13-mediated gene and protein up-regulation of IL-13Ralpha2. In fibroblasts from CXCR3 deficient mice, STAT6 activation was prolonged. This study is the first to demonstrate the expression of CXCR3 in fibroblasts and its association with the expression of IL-13Ralpha2. Taken together, the results from this study point strongly to a requirement for CXCR3 for IL-13-mediated IL-13Ralpha2 gene expression. Understanding the function of CXCR3 in IL-13-mediated lung injury may lead to novel approaches to combat the development of pulmonary fibrosis, whether by limiting the effects of IL-13 or by manipulation of angiostatic pathways. The elucidation of the complex relationship between these antifibrotic receptors and manipulation of the CXCR3-mediated regulation of IL-13Ralpha2 may represent a novel therapeutic modality in cases of acute lung injury or chronic inflammation that may progress to fibrosis. PMID- 25514191 TI - Assessment of Arctic community wastewater impacts on marine benthic invertebrates. AB - This study sought to understand the performance of arctic treatment systems and the impact of wastewater effluent on benthic invertebrate communities in arctic receiving water habitats. Effluent quality and benthic impacts were monitored in the receiving water of five communities across Nunavut that differed in the type and level of treatment achieved by wastewater infrastructure, the volume of effluent and receiving water mixing environment. We detected minimal impacts to benthic communities (<225 m linear distance from the effluent source) in four out of the five communities (Grise Fiord, Kugaaruk, Pond Inlet, and Pangnirtung), where the population was <2000 people. In these small communities impacts were characterized by increases or decreases in species richness, diversity, evenness, and density, and some differences in benthic species composition. This was in contrast to benthic sediments in Iqaluit (population 6699), which were devoid of benthic fauna up to 580 m from the effluent source in response to sediment anoxia. Variation in benthic community response between sampling locations was attributed primarily to differences in effluent volume, with effluent quality and receiving water hydrodynamics playing secondary roles. The results of this study will help to inform the development of northern specific treatment performance standards which will aid in prioritizing community wastewater system upgrades in arctic communities. PMID- 25514192 TI - Self-organization of colloidal PbS quantum dots into highly ordered superlattices. AB - X-ray structural analysis, together with steady-state and transient optical spectroscopy, is used for studying the morphology and optical properties of quantum dot superlattices (QDSLs) formed on glass substrates by the self organization of PbS quantum dots with a variety of surface ligands. The diameter of the PbS QDs varies from 2.8 to 8.9 nm. The QDSL's period is proportional to the dot diameter, increasing slightly with dot size due to the increase in ligand layer thickness. Removal of the ligands has a number of effects on the morphology of QDSLs formed from the dots of different sizes: for small QDs the reduction in the amount of ligands obstructs the self-organization process, impairing the ordering of the QDSLs, while for large QDs the ordering of the superlattice structure is improved, with an interdot distance as low as 0.4 nm allowing rapid charge carrier transport through the QDSLs. QDSL formation does not induce significant changes to the absorption and photoluminescence spectra of the QDs. However, the luminescence decay time is reduced dramatically, due to the appearance of nonradiative relaxation channels. PMID- 25514193 TI - Patterns of women's mood after delivery: a growth curve analysis. AB - BACKGROUND: The course and predictors of women's mood following childbirth have informed clinically significant phenomena, such as postpartum depression (PPD), with some contradictory findings due to methodological limitations. It is important to further investigate mood during this unique period of time to inform assessment and improve interventions. METHODS: Recently delivered mothers (n=216) recruited from the maternity unit at a University hospital completed sociodemographic questions and the Daily Experiences Questionnaire (DEQ), a measure of Negative Affect (NA) and Positive Affect (PA), for 10 consecutive days. The Structured Clinical Interview for DSM-IV was administered to assess postpartum depression diagnosis. RESULTS: Growth curve modeling (GCM) techniques revealed average trends in mood following delivery. NA changed in a curvilinear fashion with a peak at day 5. PA declined rapidly during the days immediately following delivery and then stabilized. Women diagnosed with PPD experienced higher overall levels of NA and lower levels of PA from delivery to 10 days postpartum. Patterns of mood varied as a function of neuroticism and several well established sociodemographic variables. LIMITATIONS: Small sample size and relatively few ethnic minority participants may affect generalizability of the findings. CONCLUSIONS: NA changed in a pattern consistent with the "peaking phenomenon". Well-established risk factors of the blues had significant associations with mood from delivery to day 10. Increased understanding into the nature of NA and PA in the early postpartum, and its role in identifying women susceptible to experiencing PPD, can inform screening and therapeutic interventions for PPD. PMID- 25514194 TI - Multisite accelerometry for sleep and wake classification in children. AB - Actigraphy is a useful alternative to the gold standard polysomnogram for non invasively measuring sleep and wakefulness. However, it is unable to accurately assess sleep fragmentation due to its inability to differentiate restless sleep from wakefulness and quiet wake from sleep. This presents significant limitations in the assessment of sleep-related breathing disorders where sleep fragmentation is a common symptom. We propose that this limitation may be caused by hardware constraints and movement representation techniques. Our objective was to determine if multisite tri-axial accelerometry improves sleep and wake classification. Twenty-four patients aged 6-15 years (median: 8 years, 16 male) underwent a diagnostic polysomnogram while simultaneously recording motion from the left wrist and index fingertip, upper thorax and left ankle and great toe using a custom accelerometry system. Movement was quantified using several features and two feature selection techniques were employed to select optimal features for restricted feature set sizes. A heuristic was also applied to identify movements during restless sleep. The sleep and wake classification performance was then assessed and validated against the manually scored polysomnogram using discriminant analysis. Tri-axial accelerometry measured at the wrist significantly improved the wake detection when compared to uni-axial accelerometry (specificity at 85% sensitivity: 71.3(14.2)% versus 55.2(24.7)%, p < 0.01). Multisite accelerometry significantly improved the performance when compared to the single wrist placement (specificity at 85% sensitivity: 82.1(12.5)% versus 71.3(14.2)%, p < 0.05). Our results indicate that multisite accelerometry offers a significant performance benefit which could be further improved by analysing movement in raw multisite accelerometry data. PMID- 25514195 TI - Switching of the triplet-triplet-annihilation upconversion with photoresponsive triplet energy acceptor: photocontrollable singlet/triplet energy transfer and electron transfer. AB - A photoswitchable fluorescent triad based on two 9,10-diphenylanthracene (DPA) and one dithienylethene (DTE) moiety is prepared for photoswitching of triplet triplet annihilation upconversion. The DPA and DTE moieties in the triad were connected via Click reaction. The DPA unit in the triad was used as the triplet energy acceptor and upconverted fluorescence emitter. The fluorescence of the triad is switched ON with the DTE moiety in open form [DTE-(o)] (upconversion quantum yield PhiUC = 1.2%). Upon UV irradiation, photocyclization of the DTE-(o) moiety produces the closed form [DTE-(c)], as a result the fluorescence of DPA moiety was switched off (PhiUC is negligible). Three different mechanisms are responsible for the upconverted fluorescence photoswitching effect (i.e., the photoactivated fluorescence resonance energy transfer, the intramolecular electron transfer, as well as the photoactivated intermolecular triplet energy transfer between the photosensitizer and DTE-(c) moiety). Previously, the photoswitching of TTA upconversion was accomplished with only one mechanism (i.e., the triplet state quenching of the photosensitizer by DTE-(c) via either the intermolecular or intramolecular energy transfer). The photophysical processes involved in the photochromism and photoswitching of TTA upconversion were studied with steady-state UV-vis absorption and fluorescence emission spectroscopies, nanosecond transient absorption spectroscopy, electrochemical characterization, and DFT/TDDFT calculations. PMID- 25514196 TI - Comprehensive analysis of genes, pathways, and TFs in nonsmoking Taiwan females with lung cancer. AB - PURPOSE: The aim of this study was to investigate the molecular mechanism of lung cancer among nonsmoking Taiwan females. MATERIALS AND METHODS: By using the GSE19804 microarray data accessible from Gene Expression Omnibus (GEO) database, we identified differentially expressed genes (DEGs) between nonsmoking female lung cancer patients and healthy controls (!logFC! >1.5 and p-value < 0.05). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene ontology (GO) enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). The Search Tool for the Retrieval of Interacting Genes (STRING) tool was utilized to build a protein-protein interaction (PPI) network, followed by the construction of a transcriptional regulatory network based on Transcription factor (TRANSFAC) database. RESULTS: As a result, 320 DEGs were identified between nonsmoking female patients with lung cancer and healthy controls. Pathway enrichment analysis showed significantly enriched pathways such as extracellular matrix (ECM)-receptor interaction and peroxisome proliferator-activated receptor (PPAR) signaling pathway, both of which were enriched with genes COL11A1 (encoding collagen XI alpha-1 chain protein), COL1A1, cluster of differentiation 36(CD36). GO enrichment analysis found that DEGs were significantly related to chemotaxis, vasculature development and cell adhesion GO terms. IL-6 was the node of the PPI network. Critical transcription factors (TFs) including CCAAT/enhancer-binding protein delta (CEBPD) and Rel/NF-kappaB were also identified. CONCLUSIONS: Our study revealed that ECM-receptor interaction, PPAR signaling pathways, and important biomolecules including COL11A1, COL1A1, CD36, IL-6, CEBPD, and Rel/NF-kappaB might be involved in lung cancer. This study might pave the way for the development and application of targeted therapeutics of lung cancer irrelevant to smoking. PMID- 25514197 TI - Iridium-catalyzed silylation of aryl C-H bonds. AB - A method for the iridium-catalyzed silylation of aryl C-H bonds is described. The reaction of HSiMe(OSiMe3)2 with arenes and heteroarenes catalyzed by the combination of [Ir(cod)(OMe)]2 and 2,4,7-trimethylphenanthroline occurs with the aromatic compound as the limiting reagent and with high levels of sterically derived regioselectivity. This new catalytic system occurs with a much higher tolerance for functional groups than the previously reported rhodium-catalyzed silylation of aryl C-H bonds and occurs with a wide range of heteroarenes. The silylarene products are suitable for further transformations, such as oxidation, halogenation, and cross-coupling. Late-stage functionalization of complex pharmaceutical compounds was demonstrated. PMID- 25514198 TI - From the determination of the accurate equilibrium structure of 1-methylthymine by gas electron diffraction and coupled cluster computations to the observation of methylation and flexibility effects in pyrimidine nucleobases. AB - 1-Methylthymine is of particular interest because it can be considered as a simple model of thymidine, in which deoxyribose attaches to thymine precisely at the N1 atom. The structure of this molecule is still unknown and so far has been experimentally studied for the first time in this work. The semiexperimental equilibrium structural parameters (r(e)(se)/?(e)(se)) of 1-methylthymine have been determined by the gas electron diffraction (GED) method, taking into account vibrational corrections calculated with the use of the anharmonic (cubic) MP2/cc pVTZ force constants. The methyl torsion around the C-N bond has been treated as a large-amplitude motion. For the first time, the structure of this molecule has been optimized by the very time-consuming coupled-cluster method (CCSD(T)(ae)) with the triple-zeta (cc-pwCVTZ) basis set. The obtained results have been extrapolated to the quadruple-zeta basis set at the MP2 level. It has been revealed that the methylation of uracil, especially at the nitrogen atom, leads to an increase in the flexibility of the nucleobase as well as a noticeable deformation of the pyrimidine ring. PMID- 25514200 TI - Ultrathin beta-Ni(OH)2 nanoplates vertically grown on nickel-coated carbon nanotubes as high-performance pseudocapacitor electrode materials. AB - Various metal hydroxides/oxides grown on conductive substrates such as nickel foam have been reported and studied as supercapacitor electrode materials. However, the capacitances of these electrodes are extremely limited because of the low content of active materials grown on the limited surface of nickel foam. To achieve high capacitance, we use nickel-coated carbon nanotubes (Ni-CNTs) as the conductive substrate for the growth of beta-Ni(OH)2. By a facile chemical method, ultrathin beta-Ni(OH)2 nanoplates are vertically grown on the surface of Ni-CNTs. The density, thickness, and content of beta-Ni(OH)2 can be easily controlled by modulating the ratio of NiCl2.6H2O to Ni-CNTs. This hierarchical nanostructure can provide remarkable synergistic effects: facilitate electron and ion transport and accelerate the reversible redox reactions. As-prepared Ni CNTs@beta-Ni(OH)2 composites exhibit high specific capacitances (~1807 F g(-1) at 2 A g(-1), based on the mass of beta-Ni(OH)2; ~1283 F g(-1) at 2 A g(-1), based on the mass of composite), good rate capabilities, and excellent cycling stabilities. This strategy has potential for large-scale production and can be applied to the preparation of other hierarchical nanostructured metal hydroxide/oxide composites. PMID- 25514199 TI - Formation and stability of D-limonene organogel-based nanoemulsion prepared by a high-pressure homogenizer. AB - D-limonene organogel-based nanoemulsion was prepared by high-pressure homogenization technology. The organogelator type had a major role on the formation of the formulations, in which stearic acid has given nanoemulsions with the smallest droplet size. The surfactant type and concentration also had an appreciable effect on droplet formation, with Tween 80 giving a mean droplet diameter (d ~ 112 nm) among a range of non-ionic surfactants (Tween 20, 40, 60, 80, and 85). In addition, high-pressure homogenization conditions played a key role in the nanoemulsion preparation. The stability of d-limonene organogel-based nanoemulsion was also investigated under two different temperatures (4 and 28 degrees C) through 2 weeks of storage. Results showed a good stability of the formulations, which is maybe due to the incorporation of D-limonene into the organogel prior to homogenization. This study may have a valuable contribution for the design and use of organogel-based nanoemulsion as a delivery system in food. PMID- 25514201 TI - Integrated protocol for reliable and fast quantification and documentation of electrophoresis gels. AB - Quantitative analysis of electrophoresis gels is an important part in molecular cloning, as well as in protein expression and purification. Parallel quantifications in yield and purity can be most conveniently obtained from densitometric analysis. This communication reports a comprehensive, reliable and simple protocol for gel quantification and documentation, applicable for single samples and with special features for protein expression screens. As major component of the protocol, the fully annotated code of a proprietary open source computer program for semi-automatic densitometric quantification of digitized electrophoresis gels is disclosed. The program ("GelQuant") is implemented for the C-based macro-language of the widespread integrated development environment of IGOR Pro. PMID- 25514202 TI - Application of coupled affinity-sizing chromatography for the detection of proteolyzed HSA-tagged proteins. AB - Coupled affinity liquid chromatography and size exclusion chromatography (ALC SEC) is a technique that has been shown to successfully report product quality of proteins during cell expression and prior to the commencement of downstream processing chromatography steps. This method was applied to monitoring the degradation and subsequent partial remediation of a HSA-tagged protein which showed proteolysis, allowing for rapid cell line development to address this product quality dilemma. This paper outlines the novel application of this method for measuring and addressing protease-induced proteolysis. PMID- 25514203 TI - Isolation of the GFA1 gene encoding glucosamine-6-phosphate synthase of Sporothrix schenckii and its expression in Saccharomyces cerevisiae. AB - Glucosamine-6-phosphate synthase (GlcN-6-P synthase) is an essential enzyme involved in cell wall biogenesis that has been proposed as a strategic target for antifungal chemotherapy. Here we describe the cloning and functional characterization of Sporothrix schenckii GFA1 gene which was isolated from a genomic library of the fungus. The gene encodes a predicted protein of 708 amino acids that is homologous to GlcN-6-P synthases from other sources. The recombinant enzyme restored glucosamine prototrophy of the Saccharomyces cerevisiae gfa1 null mutant. Purification and biochemical analysis of the recombinant enzyme revealed some differences from the wild type enzyme, such as improved stability and less sensitivity to UDP-GlcNAc. The sensitivity of the recombinant enzyme to the selective inhibitor FMDP [N(3)-(4-methoxyfumaroyl)-l 2,3-diaminopropanoic acid] and other properties were similar to those previously reported for the wild type enzyme. PMID- 25514204 TI - Cloning, expression and purification of penicillin-binding protein 3 from Pseudomonas aeruginosa CMCC 10104. AB - Penicillin-binding protein 3 (PBP3) of Pseudomonas aeruginosa is the primary target of beta-lactams used to treat pseudomonas infections. Meanwhile, structure change and overproduction of PBP3 play important roles in the drug resistance of P. aeruginosa. Therefore, studies on the gene and structure of PBP3 are urgently needed. P. aeruginosa CMCC 10104 is a type culture strain common used in China. However, there is no report on its genomic and proteomic profiles. In this study, based on ftsI of P. aeruginosa PAO1, the gene encoding PBP3 was cloned from CMCC 10104. A truncated version of the ftsI gene, omitting the bases encoding the hydrophobic leader peptide (amino acids 1-34), was amplified by PCR. The cloned DNA shared 99.76% identity with ftsI from PAO1. Only four bases were different (66 C-A, 1020 T-C, 1233 T-C, and 1527 T-C). However, there were no differences between their deduced amino acid sequences. The recombinant PBP3 (rPBP3), containing a 6-histidine tag, was expressed in Escherichia coli BL21 (DE3). Immobilized metal affinity chromatography (IMAC) with Ni(2+)-NTA agarose was used for its purification. The purified rPBP3 was identified by SDS-PAGE and western blot analysis, and showed a single band at about 60kDa with purity higher than 95%. The penicillin-binding assay indicated that the obtained rPBP3 was functional and not hindered by the presence of the C-terminal His-tag. The protocol described in this study offers a method for obtaining purified recombinant PBP3 from P. aeruginosa CMCC 10104. PMID- 25514205 TI - A rare cause of protein losing enteropathy: collagenous sprue. AB - Collagenous sprue is a clinicopathological entity with an unknown etiology. Its clinical features include progressive malabsorption, diarrhea, weight loss, unresponsiveness to treatment, and high mortality rates. The age interval of collagenous sprue is quite broad and ranges between 2 and 85 years. As far as to our knowledge, the presented case is the first reported case in infancy. PMID- 25514206 TI - Porcine bocavirus: achievements in the past five years. AB - Porcine bocavirus is a recently discovered virus that infects pigs and is classified within the Bocavirus genus (family Parvoviridae, subfamily Parvovirinae). The viral genome constitutes linear single-stranded DNA and has three open reading frames that encode four proteins: NS1, NP1, VP1, and VP2. There have been more than seven genotypes discovered to date. These genotypes have been classified into three groups based on VP1 sequence. Porcine bocavirus is much more prevalent in piglets that are co-infected with other pathogens than in healthy piglets. The virus can be detected using PCR, loop-mediated isothermal amplification, cell cultures, indirect immunofluorescence, and other molecular virology techniques. Porcine bocavirus has been detected in various samples, including stool, serum, lymph nodes, and tonsils. Because this virus was discovered only five years ago, there are still many unanswered questions that require further research. This review summarizes the current state of knowledge and primary research achievements regarding porcine bocavirus. PMID- 25514207 TI - A user-friendly and scalable process to prepare a ready-to-use inactivated vaccine: the example of heartwater in ruminants under tropical conditions. AB - The use of cheap and thermoresistant vaccines in poor tropical countries for the control of animal diseases is a key issue. Our work aimed at designing and validating a process for the large-scale production of a ready-to-use inactivated vaccine for ruminants. Our model was heartwater caused by the obligate intracellular bacterium Ehrlichia ruminantium (ER). The conventional inactivated vaccine against heartwater (based on whole bacteria inactivated with sodium azide) is prepared immediately before injection, using a syringe-extrusion method with Montanide ISA50. This is a fastidious time-consuming process and it limits the number of vaccine doses available. To overcome these issues, we tested three different techniques (syringe, vortex and homogenizer) and three Montanide ISA adjuvants (50, 70 and 70M). High-speed homogenizer was the optimal method to emulsify ER antigens with both ISA70 and 70M adjuvants. The emulsions displayed a good homogeneity (particle size below 1 MUm and low phase separation), conductivity below 10 MUS/cm and low antigen degradation at 4 degrees C for up to 1 year. The efficacy of the different formulations was then evaluated during vaccination trials on goats. The inactivated ER antigens emulsified with ISA70 and ISA70M in a homogenizer resulted in 80% and 100% survival rates, respectively. A cold-chain rupture assay using ISA70M+ER was performed to mimic possible field conditions exposing the vaccine at 37 degrees C for 4 days before delivery. Surprisingly, the animal survival rate was still high (80%). We also observed that the MAP-1B antibody response was very similar between animals vaccinated with ISA70+ER and ISA70M+ER emulsions, suggesting a more homogenous antigen distribution and presentation in these emulsions. Our work demonstrated that the combination of ISA70 or ISA70M and homogenizer is optimal for the production of an effective ready-to-use inactivated vaccine against heartwater, which could easily be produced on an industrial scale. PMID- 25514208 TI - Is there something special with probabilities?--insight vs. computational ability in multiple risk combination. AB - While a wealth of evidence suggests that humans tend to rely on additive cue combination to make controlled judgments, many of the normative rules for probability combination require multiplicative combination. In this article, the authors combine the experimental paradigms on probability reasoning and multiple cue judgment to allow a comparison between formally identical tasks that involve probability vs. other task contents. The purpose was to investigate if people have cognitive algorithms for the combination, specifically, of probability, affording multiplicative combination in the context of probability. Three experiments suggest that, although people show some signs of a qualitative understanding of the combination rules that are specific to probability, in all but the simplest cases they lack the cognitive algorithms needed for multiplication, but instead use a variety of additive heuristics to approximate the normative combination. Although these heuristics are surprisingly accurate, normative combination is not consistently achieved until the problems are framed in an additive way. PMID- 25514211 TI - Reliability of force per unit cross-sectional area measurements of the first dorsal interosseus muscle. AB - The purpose of this study was to determine the reliability of maximum voluntary isometric force (MVIF), cross-sectional area (CSA) and force per unit CSA measures, of the first dorsal interosseus (FDI) muscle, using a custom-built dynamometer and ultrasonography. Twenty-seven participants completed MVIF and CSA measurements on two separate occasions under the same conditions. Reliability was determined using paired samples t-tests, systematic bias ratio and ratio limits of agreement (RLoA), intra-class correlation (ICC) and coefficient of variation (CV). MVIF of the FDI muscle (mean +/- s; 31.8 +/- 7.6 N and 31.6 +/- 7.3 N) was not different between trials (P = 0.63); RLoA between trials were 1.00 *// 1.09, ICC = 0.990 and CV = 3.22%. CSA of the FDI muscle (22.6 +/- 6.9 and 22.9 +/- 6.9 mm2) was also not different between trials (P = 0.31); RLoA between trials were 0.98 *// 1.19, ICC = 0.979 and CV = 6.61%. Force per unit CSA was not different between trials (1.49 +/- 0.43 and 1.46 +/- 0.44 N.mm2; P = 0.18), RLoA were 1.02 *// 1.17, ICC = 0.985 and CV = 5.76%. The techniques used to determine MVIF and CSA of the FDI muscle were reliable and can be combined to calculate force per unit CSA. PMID- 25514209 TI - Uric acid promotes apoptosis in human proximal tubule cells by oxidative stress and the activation of NADPH oxidase NOX 4. AB - Mild hyperuricemia has been linked to the development and progression of tubulointerstitial renal damage. However the mechanisms by which uric acid may cause these effects are poorly explored. We investigated the effect of uric acid on apoptosis and the underlying mechanisms in a human proximal tubule cell line (HK-2). Increased uric acid concentration decreased tubule cell viability and increased apoptotic cells in a dose dependent manner (up to a 7-fold increase, p<0.0001). Uric acid up-regulated Bax (+60% with respect to Ctrl; p<0.05) and down regulated X-linked inhibitor of apoptosis protein. Apoptosis was blunted by Caspase-9 but not Caspase-8 inhibition. Uric acid induced changes in the mitochondrial membrane, elevations in reactive oxygen species and a pronounced up regulation of NOX 4 mRNA and protein (p<0.05). In addition, both reactive oxygen species production and apoptosis was prevented by the NADPH oxidase inhibitor DPI as well as by Nox 4 knockdown. URAT 1 transport inhibition by probenecid and losartan and its knock down by specific siRNA, blunted apoptosis, suggesting a URAT 1 dependent cell death. In summary, our data show that uric acid increases the permissiveness of proximal tubule kidney cells to apoptosis by triggering a pathway involving NADPH oxidase signalling and URAT 1 transport. These results might explain the chronic tubulointerstitial damage observed in hyperuricaemic states and suggest that uric acid transport in tubular cells is necessary for urate-induced effects. PMID- 25514212 TI - The impact of using computer decision-support software in primary care nurse-led telephone triage: interactional dilemmas and conversational consequences. AB - Telephone triage represents one strategy to manage demand for face-to-face GP appointments in primary care. Although computer decision-support software (CDSS) is increasingly used by nurses to triage patients, little is understood about how interaction is organized in this setting. Specifically any interactional dilemmas this computer-mediated setting invokes; and how these may be consequential for communication with patients. Using conversation analytic methods we undertook a multi-modal analysis of 22 audio-recorded telephone triage nurse-caller interactions from one GP practice in England, including 10 video-recordings of nurses' use of CDSS during triage. We draw on Goffman's theoretical notion of participation frameworks to make sense of these interactions, presenting 'telling cases' of interactional dilemmas nurses faced in meeting patient's needs and accurately documenting the patient's condition within the CDSS. Our findings highlight troubles in the 'interactional workability' of telephone triage exposing difficulties faced in aligning the proximal and wider distal context that structures CDSS-mediated interactions. Patients present with diverse symptoms, understanding of triage consultations, and communication skills which nurses need to negotiate turn-by-turn with CDSS requirements. Nurses therefore need to have sophisticated communication, technological and clinical skills to ensure patients' presenting problems are accurately captured within the CDSS to determine safe triage outcomes. Dilemmas around how nurses manage and record information, and the issues of professional accountability that may ensue, raise questions about the impact of CDSS and its use in supporting nurses to deliver safe and effective patient care. PMID- 25514213 TI - Antimicrobial resistance and extended-spectrum beta-lactamases of Salmonella enterica serotypes isolated from livestock and processed food in Portugal: an update. AB - As Salmonella is a common foodborne pathogen, the present study aimed to determine the distribution of Salmonella enterica serotypes isolated during 2011 2012 from poultry, swine, cattle, and processed food in Portugal, and to characterize the antimicrobial susceptibility and the extended-spectrum beta lactamases (ESBLs). Results were also compared with data obtained before the implementation of the National Control Program in Poultry and the ban of antimicrobial agents in animal feed in the European Union (EU). A total of 14 serotypes were identified, from 258 isolates recovered, with Salmonella Typhimurium (32.6%, n=84) and Salmonella Enteritidis (10.1%, n=26) being the most common. Salmonella Enteritidis in poultry was less frequent than in previous studies, which might be associated with the implementation of the National Control Program for Salmonella in poultry. Nevertheless, other serotypes seem to occupy this biological niche, and may be more common in human salmonellosis in the future. The majority of isolates (70.2%, n=181) were resistant to at least one class of antimicrobial agent and exhibited higher frequency of resistance to tetracycline (47.7%, n=123) and ampicillin (36.0%, n=93), with Salmonella Typhimurium being the more resistant serotype. Resistance to fluoroquinolones was shown in 8% (n=21) of isolates, a lower value compared to data obtained before 2004. ESBLs producers Salmonella Typhimurium bla(CTX-M-1) and Salmonella Enteritidis bla(SHV-12) were isolated from swine and poultry, respectively. The bla(CTX-M-1) and bla(SHV-12) genes were carried on conjugative plasmids of IncHI2replicon types and IncI1, respectively. This was the first report of a bla(CTX-M-1) in Salmonella Typhimurium in Portugal. Overall, the results revealed changes in animal origin Salmonella serotypes, mainly emerging serotypes, in frequency of resistance, and in occurrence of ESBLs-producing Salmonella. The control measures taken by the EU seem to have some impact on the resistance rate of some antibiotics such as quinolones. The emergence of ESBLs and its potential spread among animal reservoirs and the food chain highlight the continuous antimicrobial surveillance at the animal level. PMID- 25514214 TI - Antibiotic prescribing in primary care: The need for interprofessional collaboration. AB - Patients with self-limiting respiratory tract infections (RTIs) are frequently seen in general practice. Although antibiotics are ineffective for these conditions, they are often prescribed by general practitioners (GPs), and perceived patient expectations for an antibiotic plays an important role in the decision to prescribe one. Superfluous use of antibiotics contributes to antimicrobial resistance. High numbers of nurse prescribers work alongside GPs and these prescribers see education and self-management advice as central to the care of these patients. Multi-faceted interventions, designed to reduce antibiotic prescribing, only exist for GPs. Such interventions should foster interprofessional collaboration and, as such, consider the needs and experiences of the different prescribers, and the views of patients. This paper outlines a research study in which a questionnaire will be distributed to patients who consult with a nurse prescriber to see whether their expectations influence their satisfaction with the consultation outcome. Findings will guide the development of an interprofessional intervention designed to promote collaborative practice and appropriate and responsible antibiotic prescribing in primary care. PMID- 25514215 TI - Modeling neuropeptide transport in various types of nerve terminals containing en passant boutons. AB - We developed a mathematical model for simulating neuropeptide transport inside dense core vesicles (DCVs) in axon terminals containing en passant boutons. The motivation for this research is a recent experimental study by Levitan and colleagues (Bulgari et al., 2014) which described DCV transport in nerve terminals of type Ib and type III as well as in nerve terminals of type Ib with the transcription factor DIMM. The goal of our modeling is validating the proposition put forward by Levitan and colleagues that the dramatic difference in DCV number in type Ib and type III terminals can be explained by the difference in DCV capture in type Ib and type III boutons rather than by differences in DCV anterograde transport and half-life of resident DCVs. The developed model provides a tool for studying the dynamics of DCV transport in various types of nerve terminals. The model is also an important step in gaining a better mechanistic understanding of transport processes in axons and identifying directions for the development of new models in this area. PMID- 25514217 TI - Photochemistry of benzotriazoles: generation of 1,3-diradicals and intermolecular cycloaddition as a new route toward indoles and dihydropyrrolo[3,4-b]indoles. AB - Irradiation of benzotriazoles 1a-e at lambda = 254 nm in acetonitrile solution generated the corresponding 1,3-diradicals which underwent intermolecular cycloaddition with maleimides to afford the corresponding dihydropyrrolo[3,4 b]indoles and with acetylene derivatives to afford indoles as the major products. This offers an interesting and simple access to such ring systems of potential synthetic and biological interest. The structures of the photoproducts were established spectroscopically and by single crystal X-ray crystallography. PMID- 25514216 TI - Synergistic radiation protective effect of purified Auricularia auricular-judae polysaccharide (AAP IV) with grape seed procyanidins. AB - The aim of this study was to investigate the synergistic antioxidant potential and protective effect of grape seed procyanidins (GSP) in combination with Auricularia auricular-judae polysaccharides (AAP IV) on radiation injury in splenocytes. Rat splenocyte irradiation resulted in significantly higher apoptosis rate, malondialdehyde (MDA) (p < 0.005), reactive oxygen species (ROS) (p < 0.01); cell viability, total superoxide dismutase (T-SOD) (p < 0.01), catalase (CAT) (p < 0.01), glutathione peroxidase (GSH-PX) (p < 0.05), activity and glutathione (GSH) (p < 0.01) levels were significantly reduced, compared with the control group. "GSP + AAP IV" treatment of rat splenocytes at doses of "GSP (0.3 MUg/mL) + AAP IV (50 MUg/mL)" displayed higher radioprotective and antioxidative effects than the administration of either GSP or AAP IV, as evident by lower levels of MDA (p < 0.001) concentration, as well as higher cell viability and T-SOD (p < 0.05), CAT (p < 0.005), GSH-PX (p < 0.01) and GSH content compared to the radiation group. In addition, in vivo studies have shown that "GSP + AAP IV" significantly ameliorated the decrease of spleen index (p < 0.005) and spleen GSH (p < 0.005) levels and significantly inhibited the increase of MDA (p < 0.005) levels of spleen with radiation-induced damage, compared with the non-treated group. The in vivo and in vitro results suggested that GSP and AAP IV have a synergistic protective effect against radiation-induced injury by improving the antioxidant and immunomodulation activities. PMID- 25514218 TI - Chemically synthesized glycosides of hydroxylated flavylium ions as suitable models of anthocyanins: binding to iron ions and human serum albumin, antioxidant activity in model gastric conditions. AB - Polyhydroxylated flavylium ions, such as 3',4',7-trihydroxyflavylium chloride (P1) and its more water-soluble 7-O-beta-d-glucopyranoside (P2), are readily accessible by chemical synthesis and suitable models of natural anthocyanins in terms of color and species distribution in aqueous solution. Owing to their catechol B-ring, they rapidly bind FeIII, weakly interact with FeII and promote its autoxidation to FeIII. Both pigments inhibit heme-induced lipid peroxidation in mildly acidic conditions (a model of postprandial oxidative stress in the stomach), the colorless (chalcone) forms being more potent than the colored forms. Finally, P1 and P2 are moderate ligands of human serum albumin (HSA), their likely carrier in the blood circulation, with chalcones having a higher affinity for HSA than the corresponding colored forms. PMID- 25514219 TI - Investigation of dendriplexes by ion mobility-mass spectrometry. AB - Highly branched polyamidoamine (PAMAM) dendrimers presenting biological activities have been envisaged as non-viral gene delivery vectors. They are known to associate with nucleic acid (DNA) in non-covalent complexes via electrostatic interactions. Although their transfection efficiency has been proved, PAMAMs present a significant cytotoxicity due to their cationic surface. To overcome such a drawback, different chemical modifications of the PAMAM surface have been reported such as the attachment of hydrophobic residues. In the present work, we studied the complexation of DNA duplexes with different low-generation PAMAM; ammonia-cored G0(N) and G1(N) PAMAM, native or chemically modified with aromatic residues, i.e., phenyl-modified-PAMAM G0(N) and phenylalanine-modified-PAMAM G1(N). To investigate the interactions involved in the PAMAM/DNA complexes, also called dendriplexes, we used electrospray ionization (ESI) coupled to ion mobility spectrometry-mass-spectrometry (IM-MS). ESI is known to allow the study of non-covalent complexes in native conditions while IM-MS is a bidimensional separation technique particularly useful for the characterization of complex mixtures. IM-MS allows the separation of the expected complexes, possible additional non-specific complexes and the free ligands. Tandem mass spectrometry (MS/MS) was also used for the structural characterization. This work highlights the contribution of IM-MS and MS/MS for the study of small dendriplexes. The stoichiometries of the complexes and the equilibrium dissociation constants were determined. The [DNA/native PAMAM] and [DNA/modified-PAMAM] dendriplexes were compared. PMID- 25514220 TI - Bio-inspired nitrile hydration by peptidic ligands based on L-cysteine, L methionine or L-penicillamine and pyridine-2,6-dicarboxylic acid. AB - Nitrile hydratase (NHase, EC 4.2.1.84) is a metalloenzyme which catalyses the conversion of nitriles to amides. The high efficiency and broad substrate range of NHase have led to the successful application of this enzyme as a biocatalyst in the industrial syntheses of acrylamide and nicotinamide and in the bioremediation of nitrile waste. Crystal structures of both cobalt(III)- and iron(III)-dependent NHases reveal an unusual metal binding motif made up from six sequential amino acids and comprising two amide nitrogens from the peptide backbone and three cysteine-derived sulfur ligands, each at a different oxidation state (thiolate, sulfenate and sulfinate). Based on the active site geometry revealed by these crystal structures, we have designed a series of small-molecule ligands which integrate essential features of the NHase metal binding motif into a readily accessible peptide environment. We report the synthesis of ligands based on a pyridine-2,6-dicarboxylic acid scaffold and L-cysteine, L-S methylcysteine, L-methionine or L-penicillamine. These ligands have been combined with cobalt(III) and iron(III) and tested as catalysts for biomimetic nitrile hydration. The highest levels of activity are observed with the L-penicillamine ligand which, in combination with cobalt(III), converts acetonitrile to acetamide at 1.25 turnovers and benzonitrile to benzamide at 1.20 turnovers. PMID- 25514222 TI - Prodrug strategies for enhancing the percutaneous absorption of drugs. AB - The transdermal application of drugs has attracted increasing interest over the last decade or so, due to the advantages it offers, compared to other delivery methods. The development of an efficient means of transdermal delivery can increase drug concentrations, while reducing their systemic distribution, thereby avoiding certain limitations of oral administration. The efficient barrier function of the skin, however, limits the use of most drugs as transdermal agents. This limitation has led to the development of various strategies to enhance drug-skin permeation, including the use of penetration enhancers. This method unfortunately has certain proven disadvantages, such as the increased absorption of unwanted components, besides the drug, which may induce skin damage and irritancy. The prodrug approach to increase the skin's permeability to drugs represents a very promising alternative to penetration enhancers. The concept involves the chemical modification of a drug into a bioreversible entity that changes both its pharmaceutical and pharmacokinetic characteristics to enhance its delivery through the skin. In this review; we report on the in vitro attempts and successes over the last decade by using the prodrug strategy for the percutaneous delivery of pharmacological molecules. PMID- 25514221 TI - Up-regulation of urotensin II and its receptor contributes to human hepatocellular carcinoma growth via activation of the PKC, ERK1/2, and p38 MAPK signaling pathways. AB - Urotensin II (UII) and its receptor (UTR) have mitogenic effects on tumor growth. Our previous study demonstrated that the UII/UTR system is up-regulated in dithyinitrosamine-induced precancerous rat liver lesions. However, its role in human hepatocellular carcinoma remains unknown. In this study, the mRNA and protein expression of UII and its receptor (UTR) in human hepatocellular carcinoma samples and in the BEL-7402 human hepatoma cell line were evaluated. In addition, the effect of exogenous UII on the pathways that regulate proliferation in BEL-7402 cells in vitro were determined. Liver sections were subjected to immunohistochemical staining. mRNA expression was detected by real-time polymerase chain reaction analysis, and protein levels were evaluated by western blotting. Proliferating cells were detected by BrdU incorporation. The expression of UII/UT mRNA and protein significantly increased in human hepatocellular carcinoma samples, and in BEL-7402 cells. Administration with UII increased the phosphorylation of protein kinase C (PKC), extracellular signal-regulated kinase (ERK1/2) and p38 mitogen-activated protein kinases (p38 MAPK). Furthermore, GF109203x, PD184352, and SB203580 partially abolished UII-induced proliferation of BEL-7402 cells. These results provide the first evidence that up-regulation of the UII/UT system may enhance proliferation of the human hepatoma cell line at least in part via PKC, ERK1/2, and p38 MAPK signaling pathways, and may provide novel therapeutic targets for inhibiting human hepatocellular carcinoma. PMID- 25514223 TI - Optimization of ultrasonic-assisted extraction of cordycepin from Cordyceps militaris using orthogonal experimental design. AB - This study reports on the optimization of the extraction conditions of cordycepin from Cordyceps militaris by using ultrasonication. For this purpose, the orthogonal experimental design was used to investigate the effects of factors on the ultrasonic-assisted extraction (UAE). Four factors: extraction time (min), ethanol concentration (%), extraction temperature ( degrees C) and extraction frequency (kHz), were studied. The results showed that the highest cordycepin yield of 7.04 mg/g (86.98% +/- 0.23%) was obtained with an extraction time of 60 min, ethanol concentration of 50%, extraction temperature of 65 degrees C and extraction frequency of 56 kHz. It was found that the cordycepin extraction yield increased with the effect of ultrasonication during the extraction process. Therefore, UAE can be used as an alternative to conventional immersion extraction with respect to the recovery of cordycepin from C. militaris, with the advantages of shorter extraction time and reduced solvent consumption. PMID- 25514224 TI - Antioxidant properties of pyroligneous acid obtained by thermochemical conversion of Schisandra chinensis Baill. AB - Sustainable development of renewable resources is a major challenge globally. Biomass is an important renewable energy source and an alternative to fossil fuels. Pyrolysis of biomass is a promising method for simultaneous production of biochar, bio-oil, pyroligneous acid (PA), and gaseous fuels. The purpose of this study was to investigate the pyrolysis process and products yields of Schisandra chinensis fruits with different pyrolysis powers. The obtained PA was extracted with organic solvents, including ethyl formate, dichloromethane, methanol and tetrahydrofuran. The antioxidant activities, including the free radical scavenging activity and ferric reducing power, of the PA extracts were investigated. The synthetic antioxidants butylated hydroxyanisole and butylated hydroxytoluene were used as positive controls. A dichloromethane extract of PA showed excellent antioxidant properties compared to the other extracts. The chemical compositions of the PA extracts were determined by GC-MS, and further proved that the dichloromethane extract had the best antioxidant characteristics among the extracts tested. PMID- 25514225 TI - Hybrid curcumin compounds: a new strategy for cancer treatment. AB - Cancer is a multifactorial disease that requires treatments able to target multiple intracellular components and signaling pathways. The natural compound, curcumin, was already described as a promising anticancer agent due to its multipotent properties and huge amount of molecular targets in vitro. Its translation to the clinic is, however, limited by its reduced solubility and bioavailability in patients. In order to overcome these pharmacokinetic deficits of curcumin, several strategies, such as the design of synthetic analogs, the combination with specific adjuvants or nano-formulations, have been developed. By taking into account the risk-benefit profile of drug combinations, as well as the knowledge about curcumin's structure-activity relationship, a new concept for the combination of curcumin with scaffolds from different natural products or components has emerged. The concept of a hybrid curcumin molecule is based on the incorporation or combination of curcumin with specific antibodies, adjuvants or other natural products already used or not in conventional chemotherapy, in one single molecule. The high diversity of such conjugations enhances the selectivity and inherent biological activities and properties, as well as the efficacy of the parental compound, with particular emphasis on improving the efficacy of curcumin for future clinical treatments. PMID- 25514226 TI - Relevance of the anti-inflammatory properties of curcumin in neurodegenerative diseases and depression. AB - This review is an attempt to summarize our current understanding of curcumin's potential as a neuroprotectant and an antidepressant. This dual property confers a unique advantage to this herbal medication, believed to be devoid of any major side effects, to combat commonly observed co-morbid conditions of a neurodegenerative and a neuropsychiatric disorder. Moreover, in line with the theme of this series, the role of inflammation and stress in these diseases and possible anti-inflammatory effects of curcumin, as well as its interaction with signal transduction proteins as a common denominator in its varied mechanisms of action, are also discussed. Thus, following a brief introduction of curcumin's pharmacology, we present research suggesting how its anti-inflammatory properties have therapeutic potential in treating a devastating neurological disorder (Parkinson's disease = PD) and a debilitating neuropsychiatric disorder (major depressive disorder = MDD). It is concluded that curcumin, or better yet, an analog with better and longer bioavailability could be of important therapeutic potential in PD and/or major depression. PMID- 25514227 TI - Two new coumarins from Talaromyces flavus. AB - Two new coumarins, talacoumarins A (1) and B (2), were isolated from the ethyl acetate extract of the wetland soil-derived fungus Talaromyces flavus BYD07-13. Their structures were elucidated by spectroscopic data (NMR, MS) analyses. The absolute configuration of C-12 in 1 was assigned using the modified Mosher's method, whereas that of C-12 in 2 was deduced via the circular dichroism data of its corresponding [Rh2(OCOCF3)4] complex. Compounds 1 and 2 were evaluated for their anti-Abeta42 aggregation, cytotoxic, and antimicrobial activities. The results showed that the two compounds had moderate anti-Abeta42 aggregation activity, and this is the first report on the Abeta42 inhibitory aggregation activity of coumarins. PMID- 25514228 TI - Combined dynamic light scattering and Raman spectroscopy approach for characterizing the aggregation of therapeutic proteins. AB - Determination of the physicochemical properties of protein therapeutics and their aggregates is critical for developing formulations that enhance product efficacy, stability, safety and manufacturability. Analytical challenges are compounded for materials: (1) that are formulated at high concentration, (2) that are formulated with a variety of excipients, and (3) that are available only in small volumes. In this article, a new instrument is described that measures protein secondary and tertiary structure, as well as molecular size, over a range of concentrations and formulation conditions of low volume samples. Specifically, characterization of colloidal and conformational stability is obtained through a combination of two well-established analytical techniques: dynamic light scattering (DLS) and Raman spectroscopy, respectively. As the data for these two analytical modalities are collected on the same sample at the same time, the technique enables direct correlation between them, in addition to the more straightforward benefit of minimizing sample usage by providing multiple analytical measurements on the same aliquot non-destructively. The ability to differentiate between unfolding and aggregation that the combination of these techniques provides enables insights into underlying protein aggregation mechanisms. The article will report on mechanistic insights for aggregation that have been obtained from the application of this technique to the characterization of lysozyme, which was evaluated as a function of concentration and pH. PMID- 25514229 TI - Total synthesis and anti-viral activities of an extract of Radix isatidis. AB - Radix isatidis (Banlangen), a famous traditional Chinese medicine, has been used for thousands of years in China due to its anti-viral activity. Through our research, we inferred that the anti-viral activity of Radix isatidis depended on the water-soluble part. Among the components of this extract, the isoquinoline derivative 1 was isolated for the first time and has shown better anti-viral activity than other constituents. In this study, to solve the problem of sourcing sufficient quantities of compound 1, a total synthesis route is described, and several analogues are also evaluated for their anti-viral activities. Among them, compound 8 shown potent anti-viral activity with an IC50 value of 15.3 ug/mL. The results suggested that isoquinoline derivatives possessed potent anti-viral activity and are worthy further development. PMID- 25514230 TI - An insecticidal compound produced by an insect-pathogenic bacterium suppresses host defenses through phenoloxidase inhibition. AB - A bioassay-guided column chromatographic strategy was adopted in the present study to fractionate the culture extract of Photorhabdus temperata M1021 to identify potential insecticidal and antimicrobial compounds. An ethyl acetate (EtOAc) culture extract of P. temperata was assayed against Galleria mellonella larvae through intra-hemocoel injection and exhibited 100% insect mortality within 60 h. The EtOAc fraction and an isolated compound exhibited phenoloxidase (PO) inhibition of up to 60% and 63%, respectively. The compound was identified as 1,2-benzenedicarboxylic acid (phthalic acid, PA) by gas chromatography-mass spectrometry and nuclear magnetic resonance. PA exhibited insecticidal activity against G. mellonella in a dose-dependent manner, and 100% insect mortality was observed at 108 h after injection of 1 M PA. In a PO inhibition assay, 0.5 and 1 M concentrations of PA were found to inhibit PO activity by 74% and 82%, respectively; and in a melanotic nodule formation assay, nodule formation was significantly inhibited (27 and 10 nodules) by PA (0.5 and 1 M, respectively). PA was furthermore found to have substantial antioxidant activity and maximum antioxidant activity was 64.7% for 0.5 M PA as compare to control. Antibacterial activity was assessed by The MIC values ranged from 0.1 M to 0.5 M of PA. This study reports a multifunctional PA, a potential insecticidal agent, could a factor of insect mortality along with other toxins produced by P. temperata M1021. PMID- 25514231 TI - The biological activities of cinnamon, geranium and lavender essential oils. AB - Acinetobacter sp. represent an important cause of nosocomial infections. Their resistance to some antibiotics, their ability to survive on inanimate surfaces in the hospital environment and their ability to produce biofilms contributes to their virulence. The aim of the study was to determine the antibacterial properties of cinnamon, lavender and geranium essential oils against bacteria of the genus Acinetobacter isolated from several clinical materials and from the hospital environment. A comprehensive evaluation of the susceptibility of Acinetobacter sp. clinical strains to recommended antibiotics was performed. The constituents of cinnamon, lavender and geranium essential oils were identified by GC-FID-MS analysis, and their Minimal Inhibitory Concentrations (MICs) against tested clinical strains were determined by the micro-dilution broth method. In addition, the effects of essential oils on the viability of human microvascular endothelial cells (HMEC-1) and glioblastoma cell line (T98G) were evaluated. Cinnamon bark oil was the most active against clinical and environmental strains of Acinetobacter baumannii with MIC values ranging from 0.5 to 2.5 uL/mL. The MIC values for geranium oil were between 7.5 and 9.5 uL/mL, and between 10.5 and 13.0 uL/mL for lavender oil. These essential oils can be best employed in the fight against infections caused by bacteria from Acinetobacter genus as components of formulations for hygiene and disinfection of hospital environment. PMID- 25514232 TI - Cross-protection conferred by filovirus virus-like particles containing trimeric hybrid glycoprotein. AB - Filoviruses are causative agents of hemorrhagic fever, and to date no effective vaccine or therapeutic has been approved to combat infection. Filovirus glycoprotein (GP) is the critical immunogenic component of filovirus vaccines, eliciting high levels of antibody after successful vaccination. Previous work has shown that protection against both Ebola virus (EBOV) and Marburg virus (MARV) can be achieved by vaccinating with a mixture of virus-like particles (VLPs) expressing either EBOV GP or MARV GP. In this study, the potential for eliciting effective immune responses against EBOV, Sudan virus, and MARV with a single GP construct was tested. Trimeric hybrid GPs were produced that expressed the sequence of Marburg GP2 in conjunction with a hybrid GP1 composed EBOV and Sudan virus GP sequences. VLPs expressing these constructs, along with EBOV VP40, provided comparable protection against MARV challenge, resulting in 75 or 100% protection. Protection from EBOV challenge differed depending upon the hybrid used, however, with one conferring 75% protection and one conferring no protection. By comparing the overall antibody titers and the neutralizing antibody titers specific for each virus, it is shown that higher antibody responses were elicited by the C terminal region of GP1 than by the N terminal region, and this correlated with protection. These data collectively suggest that GP2 and the C terminal region of GP1 are highly immunogenic, and they advance progress toward the development of a pan-filovirus vaccine. PMID- 25514233 TI - Improving teaching assistants' orientation in a school of nursing: a lean approach. AB - Newly hired teaching assistants (TAs) come to schools of nursing with varying levels of experience in academic institutions. Therefore, the orientation of TAs becomes important at a micro level (student instruction) and macro level (mission of the organization). We describe a Lean approach to strengthening TA orientation and reducing waste and inconsistency. Developed solutions and tools through the lens of quality improvement are discussed. PMID- 25514234 TI - Neurocognitive function in patients with idiopathic Restless Legs Syndrome before and after treatment with dopamine-agonist. AB - Although a huge amount of clinical evidence for Restless Legs Syndrome (RLS) is present in literature, an exhaustive account of cognitive profile in RLS patients is still lacking. In this study we evaluated the neurocognitive function in RLS patients and the effects of a three-month treatment with a dopamine agonist (pramipexole) at low doses. Clinical and polysomnographic characteristics, cognitive abilities, quality of life and psychological clinical indices were assessed in 20 RLS patients and 15 age-matched controls. The neurocognitive results, obtained by untreated RLS patients (baseline), were firstly compared to those of controls and then to those of the same RLS group after treatment (follow up). Increased Total Sleep Time, Slow Wave Sleep, Sleep Efficiency and decreased Sleep Latency, Wake After Sleep Onset and periodic leg movement index were found by polysomnographic recording after a three-month treatment. Results showed that cognitive functions, impaired at baseline when compared to control subjects, improved after the pharmacological treatment, reaching the scores of healthy subjects. Decision making, problem solving and categorizing abilities, investigated by the Iowa Gambling Task (IGT) and the Wisconsin Card Sorting Test (WCST), resulted lower in RLS patients at baseline than in controls. All these functions improved after pharmacological treatment, as well as quality of life, depressive and anxiety symptoms, and daytime sleepiness. PMID- 25514236 TI - Conundrums in merging public policy into private dentistry: experiences from Australia's recent past. AB - Oral disease continues to be a major problem in Australia impacting quality of life, the economy and broader health system. Although the understanding of caries and periodontal disease has improved along with increased government support, oral diseases continue to be the most prevalent among all health conditions. This is despite unprecedented levels of funding in the Chronic Disease Dental Scheme and the Teen Dental Plan. Access to primary care dentistry in the private sector, where the majority of dental services are provided, remains a critical issue. Under the current system of dentistry, it cannot be assumed that the practice of dentistry represents a prioritised approach to combat disease patterns based on scientific evidence in primary health and prevention. Drawing on data in relation to these two programs, the present study highlights issues impacting dental service provision. This includes issues such as access and affordability to dental care, sustainability of policy and its unintended consequences, private practice pressures and the impact of remuneration on treatment. This paper argues that without structural reform there will continue to be barriers in implementing policies capable of improving oral health. PMID- 25514235 TI - Flesh quality loss in response to dietary isoleucine deficiency and excess in fish: a link to impaired Nrf2-dependent antioxidant defense in muscle. AB - The present study explored the impact of dietary isoleucine (Ile) on fish growth and flesh quality and revealed a possible role of muscle antioxidant defense in flesh quality in relation to dietary Ile. Grass carp (weighing 256.8+/-3.5 g) were fed diets containing six graded levels of Ile (3.8, 6.6, 9.3, 12.5, 15.2 and 18.5 g/kg) for eight weeks. The results indicated that compared with Ile deficiency (3.8 g/kg diets) and excess (18.5 g/kg diets) groups, 9.3-15.2 g Ile/kg diet supplementations promoted fish growth and muscle fat deposition, whereas 6.6-15.2 g Ile/kg diets supplementation enhanced muscle nutrients (protein and total EAAs) deposition. Furthermore, muscle shear force, pH value, and hydroxyproline concentration were improved by 9.3-12.5, 9.3 and 9.3 g Ile/kg diet supplementations, respectively. However, muscle cooking loss, lactate content, and activities of cathepsin B and L were decreased by 6.6-15.2, 9.3 12.5, 9.3-12.5 and 9.3-15.2 g Ile/kg diet supplementations, respectively. Additionally, 6.6-15.2 and 6.6-12.5 g Ile/kg diet supplementations attenuated malondialdehyde and protein carbonyl contents, respectively. The activities of copper/zinc superoxide dismutase (Cu/Zn-SOD) and glutathione peroxidase (GPx), and glutathione content were enhanced by 6.6-9.3, 6.6-12.5 and 6.6-15.2 g Ile/kg diet supplementations, respectively. Moreover, the relative mRNA expressions of antioxidant enzymes, including Cu/Zn-SOD (6.6-12.5 g/kg diets) and GPx (12.5 g/kg diets), as well as antioxidant-related signaling molecules, including NF-E2 related factor 2 (Nrf2) (6.6-12.5 g/kg diets), target of rapamycin (6.6-12.5 g/kg diets), ribosomal S6 protein kinase 1 (9.3-12.5 g/kg diets) and casein kinase 2 (6.6-12.5 g/kg diets), were up-regulated when Ile diet supplementations were administered at these levels, respectively, whereas the relative mRNA expression of Kelch-like ECH-associated protein 1 was down-regulated with 9.3 g Ile/kg diet supplementations. Collectively, the present study indicated that optimum isoleucine improved flesh quality, partly due to the activation of antioxidant defense through the Nrf2 signaling pathway. PMID- 25514237 TI - Crossreactive autoantibodies directed against cutaneous and joint antigens are present in psoriatic arthritis. AB - BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease of unknown origin, characterized by erosions and new bone formation. Diagnosis of PsA is mainly clinical and there are no biomarkers available. Moreover in PsA autoantibodies have not been described so far. Indeed an autoimmune origin has been suggested but never proven. Aim of the study was to investigate the possible presence of autoantibodies typically associated with PsA. METHODS: We used pooled IgG immunoglobulins derived from 30 patients with PsA to screen a random peptide library in order to identify disease relevant autoantigen peptides. RESULTS: Among the selected peptides, one was recognised by nearly all the patients' sera. The identified peptide (PsA peptide: TNRRGRGSPGAL) shows sequence similarities with skin autoantigens, such as fibrillin 3, a constituent of actin microfibrils, desmocollin 3, a constituent of the desmosomes and keratin 78, a component of epithelial cytoskeleton. Interestingly the PsA peptide shares homology with the nebulin-related anchoring protein (N-RAP), a protein localized in the enthesis (point of insertion of a tendon or ligament to the bone), which represents the first affected site during early PsA. Antibodies affinity purified against the PsA peptide recognize fibrillin, desmocollin, keratin and N-RAP. Moreover antibodies directed against the PsA peptide are detectable in 85% of PsA patients. Such antibodies are not present in healthy donors and are present in 13/100 patients with seroposive rheumatoid arthritis (RA). In seronegative RA these antibodies are detectable only in 3/100 patients. CONCLUSIONS: Our results indicate that PsA is characterized by the presence of serum autoantibodies crossreacting with an epitope shared by skin and joint antigens. PMID- 25514238 TI - The glutaredoxin mono- and di-thiol mechanisms for deglutathionylation are functionally equivalent: implications for redox systems biology. AB - Glutathionylation plays a central role in cellular redox regulation and anti oxidative defence. Grx (Glutaredoxins) are primarily responsible for reversing glutathionylation and their activity therefore affects a range of cellular processes, making them prime candidates for computational systems biology studies. However, two distinct kinetic mechanisms involving either one (monothiol) or both (dithiol) active-site cysteines have been proposed for their deglutathionylation activity and initial studies predicted that computational models based on either of these mechanisms will have different structural and kinetic properties. Further, a number of other discrepancies including the relative activity of active-site mutants and contrasting reciprocal plot kinetics have also been reported for these redoxins. Using kinetic modelling, we show that the dithiol and monothiol mechanisms are identical and, we were also able to explain much of the discrepant data found within the literature on Grx activity and kinetics. Moreover, our results have revealed how an apparently futile side reaction in the monothiol mechanism may play a significant role in regulating Grx activity in vivo. PMID- 25514239 TI - Best of both worlds: combining pharma data and state of the art modeling technology to improve in Silico pKa prediction. AB - In a unique collaboration between a software company and a pharmaceutical company, we were able to develop a new in silico pKa prediction tool with outstanding prediction quality. An existing pKa prediction method from Simulations Plus based on artificial neural network ensembles (ANNE), microstates analysis, and literature data was retrained with a large homogeneous data set of drug-like molecules from Bayer. The new model was thus built with curated sets of ~14,000 literature pKa values (~11,000 compounds, representing literature chemical space) and ~19,500 pKa values experimentally determined at Bayer Pharma (~16,000 compounds, representing industry chemical space). Model validation was performed with several test sets consisting of a total of ~31,000 new pKa values measured at Bayer. For the largest and most difficult test set with >16,000 pKa values that were not used for training, the original model achieved a mean absolute error (MAE) of 0.72, root-mean-square error (RMSE) of 0.94, and squared correlation coefficient (R(2)) of 0.87. The new model achieves significantly improved prediction statistics, with MAE = 0.50, RMSE = 0.67, and R(2) = 0.93. It is commercially available as part of the Simulations Plus ADMET Predictor release 7.0. Good predictions are only of value when delivered effectively to those who can use them. The new pKa prediction model has been integrated into Pipeline Pilot and the PharmacophorInformatics (PIx) platform used by scientists at Bayer Pharma. Different output formats allow customized application by medicinal chemists, physical chemists, and computational chemists. PMID- 25514240 TI - Physiological adaptations to resistance training in prepubertal boys. AB - PURPOSE: The purpose of this study was to investigate the physiological adaptations of resistance training (RT) in prepubertal boys. METHODS: Eighteen healthy boys were divided into RT (n = 9, Mage = 10.4 +/- 0.5 years) and control (CTR; n = 9, Mage = 10.9 +/- 0.7 years) groups. The RT group underwent a resistance training during 12 weeks, 3 times per week, performing 3 sets of 6 to 15 repetitions at intensities ranging from 60% to 80% of maximal dynamic strength (1-repetition maximum [1-RM] values). Before and after the training, the groups were assessed in their body mass and composition (dual-energy X-ray absorptiometry), isokinetic dynamometry, 1-RM, and ergoespirometry. Moreover, force per unit of muscle volume was calculated by the quotient between 1-RM and lean mass. RESULTS: Both groups presented statistically significant (p < .05) increases in the 1-RM and force per unit of muscle volume in the knee extension and elbow flexion, but these strength increases were statistically significantly greater in the RT group (effect size [ES] = 2.83-9.00) than in the CTR group (ES = 0.72-1.00). Moreover, both groups statistically significantly increased in lean body mass variables (ES = 0.12-0.38). However, increases in the fat mass variables occurred only in the CTR group (ES = - 0.01-0.50), whereas no changes were observed in the RT group. Furthermore, there were statistically significant increases in all bone mineral content variables (ES = 0.13-0.43), without differences between groups. No cardiorespiratory changes were observed. CONCLUSION: Twelve weeks of RT was effective in improving strength and force per unit of muscle volume and prevented fat mass increases in boys. PMID- 25514241 TI - Shotgun bisulfite sequencing of the Betula platyphylla genome reveals the tree's DNA methylation patterning. AB - DNA methylation plays a critical role in the regulation of gene expression. Most studies of DNA methylation have been performed in herbaceous plants, and little is known about the methylation patterns in tree genomes. In the present study, we generated a map of methylated cytosines at single base pair resolution for Betula platyphylla (white birch) by bisulfite sequencing combined with transcriptomics to analyze DNA methylation and its effects on gene expression. We obtained a detailed view of the function of DNA methylation sequence composition and distribution in the genome of B. platyphylla. There are 34,460 genes in the whole genome of birch, and 31,297 genes are methylated. Conservatively, we estimated that 14.29% of genomic cytosines are methylcytosines in birch. Among the methylation sites, the CHH context accounts for 48.86%, and is the largest proportion. Combined transcriptome and methylation analysis showed that the genes with moderate methylation levels had higher expression levels than genes with high and low methylation. In addition, methylated genes are highly enriched for the GO subcategories of binding activities, catalytic activities, cellular processes, response to stimulus and cell death, suggesting that methylation mediates these pathways in birch trees. PMID- 25514242 TI - LRP-1: functions, signaling and implications in kidney and other diseases. AB - Low-density lipoprotein (LDL)-related protein-1 (LRP-1) is a member of LDL receptor family that is implicated in lipoprotein metabolism and in the homeostasis of proteases and protease inhibitors. Expression of LRP-1 is ubiquitous. Up-regulation of LRP-1 has been reported in numerous human diseases. In addition to its function as a scavenger receptor for various ligands, LRP-1 has been shown to transduce multiple intracellular signal pathways including mitogen-activated protein kinase (MAPK), Akt, Rho, and the integrin signaling. LRP-1 signaling plays an important role in the regulation of diverse cellular process, such as cell proliferation, survival, motility, differentiation, and transdifferentiation, and thus participates in the pathogenesis of organ dysfunction and injury. In this review, we focus on the current understanding of LRP-1 signaling and its roles in the development and progression of kidney disease. The role and signaling of LRP-1 in the nervous and cardiovascular systems, as well as in carcinogenesis, are also briefly discussed. PMID- 25514243 TI - Associations of NR5A2 gene polymorphisms with the clinicopathological characteristics and survival of gastric cancer. AB - The orphan nuclear receptor (NR5A2), which belongs to the NR5A subfamily of nuclear receptors, is expressed in developing and adult tissues of endodermal origin, and can contribute to the development of several cancers through regulating cell proliferation. NR5A2 (rs3790843 and rs3790844) single nucleotide polymorphisms (SNPs) genotyping were examined in DNA samples, extracted from paraffin-embedded cancer tissue. Clinicopathologic and follow-up data were collected from 944 patients with gastric cancer (GC). Associations of the 2 SNPs with the progression and prognosis in gastric cancer patients were analyzed using the SPSS version 18.0. We found that NR5A2 rs3790843 polymorphism was significantly associated with the risk of GC which had regional lymph node metastasis (p = 0.044) or distant metastasis (p = 0.020). Our results also indicated that rs3790844 polymorphism was associated with the increased overall survival (OS) of GC patients in the dominant model (GG vs. GA/AA, HR (hazard ratio) = 0.823, 95% CI (confidence interval) = 0.679-0.997), suggesting a potential protective role of the variant A allele. Additionally, in the stratified analysis, both NR5A2 rs3790843 and rs3790844 polymorphism were associated with significantly lower risk of death in the groups of female, tumor size >5 cm in a dominant model. Our results represent the first demonstration that the NR5A2 rs3790844 polymorphism is associated with increased OS of GC patients in the dominant model, and similar results were found among the female group and tumor size >5 cm group for NR5A2 rs3790843 polymorphism. Further validation in other larger studies with different ethnic populations and functional evaluations are needed. PMID- 25514244 TI - Dysfunction of endocytic kinase AAK1 in ALS. AB - Mechanisms of human mutant superoxide dismutase 1 (SOD1)-induced toxicity in causing the familial form of amyotrophic lateral sclerosis (ALS) remain elusive. Identification of new proteins that can selectively interact with mutant SOD1s and investigation of their potential roles in ALS are important to discover new pathways that are involved in disease pathology. Using the yeast two-hybrid system, we identified the adaptor-associated kinase 1 (AAK1), a regulatory protein in clathrin-coated vesicle endocytic pathway that selectively interacted with the mutant but not the wild-type SOD1. Using both transgenic mouse and rat SOD1-linked familial ALS (FALS) models, we found that AAK1 was partially colocalized with the endosomal and presynaptic protein markers under the normal physiological condition, but was mislocated into aggregates that contained mutant SOD1s and the neurofilament proteins in rodent models of ALS in disease. AAK1 protein levels were also decreased in ALS patients. These results suggest that dysfunction of a component in the endosomal and synaptic vesicle recycling pathway is involved in ALS pathology. PMID- 25514245 TI - Molecular genetic variability of commercial and wild accessions of passion fruit (Passiflora spp.) targeting ex situ conservation and breeding. AB - Passiflora species are distributed throughout Latin America, and Brazil and Colombia serve as the centers of diversity for this genus. We performed cross species amplification to evaluate 109 microsatellite loci in 14 Passiflora species and estimated the diversity and genetic structure of Passiflora cincinnata, Passiflora setaceae and Passiflora edulis. A total of 127 accessions, including 85 accessions of P. edulis, a commercial species, and 42 accessions of 13 wild species, were examined. The cross-species amplification was effective for obtaining microsatellite loci (average cross-amplification of 70%). The average number of alleles per locus (five) was relatively low, and the average diversity ranged from 0.52 in P. cincinnata to 0.32 in P. setacea. The Bayesian analyses indicated that the P. cincinnata and P. setacea accessions were distributed into two groups, and the P. edulis accessions were distributed into five groups. Private alleles were identified, and suggestions for core collections are presented. Further collections are necessary, and the information generated may be useful for breeding and conservation. PMID- 25514247 TI - Corrigendum. PMID- 25514246 TI - The single-breath diffusing capacity of CO and NO in healthy children of European descent. AB - RATIONALE: The diffusing capacity (DL) of the lung can be divided into two components: the diffusing capacity of the alveolar membrane (Dm) and the pulmonary capillary volume (Vc). DL is traditionally measured using a single breath method, involving inhalation of carbon monoxide, and a breath hold of 8-10 seconds (DL,CO). This method does not easily allow calculation of Dm and Vc. An alternative single-breath method (DL,CO,NO), involving simultaneous inhalation of carbon monoxide and nitric oxide, and traditionally a shorter breath hold, allows calculation of Dm and Vc and the DL,NO/DL,CO ratio in a single respiratory maneuver. The clinical utility of Dm, Vc, and DL,NO/DL,CO in the pediatric age range is currently unknown but also restricted by lack of reference values. OBJECTIVES: The aim of this study was to establish reference ranges for the outcomes of DL,CO,NO with a 5 second breath hold, including the calculated outcomes Dm, Vc, and the DL,NO/DL,CO ratio, as well as to establish reference values for the outcomes of the traditional DL,CO method, with a 10 second breath hold in children. METHODS: DL,CO,NO and DL,CO were measured in healthy children, of European descent, aged 5-17 years using a Jaeger Masterscreen PFT. The data were analyzed using the Generalized Additive Models for Location Scale and Shape (GAMLSS) statistical method. MEASUREMENTS AND MAIN RESULTS: A total of 326 children were eligible for diffusing capacity measurements, resulting in 312 measurements of DL,CO,NO and 297 of DL,CO, respectively. Reference equations were established for the outcomes of DL,CO,NO and DL,CO, including the calculated values: Vc, Dm, and the DL,NO/DL,CO ratio. CONCLUSION: These reference values are based on the largest sample of children to date and may provide a basis for future studies of their clinical utility in differentiating between alterations in the pulmonary circulation and changes in the alveolar membrane in pediatric patients. PMID- 25514248 TI - Accessibility of academic plastic surgeons as mentors to medical students. AB - BACKGROUND: Determining a field of specialty can be a difficult decision for medical students. Career plans are often fostered through exposure to the field and mentorship, but it is often hard to identify accessible mentors. The purposes of this study were to determine the prevalence of accessible mentors among academic plastic surgery faculty and to characterize predictors of accessibility. METHODS: An audit was conducted of academic plastic surgeon faculty affiliated with integrated and combined residency programs. A request for mentorship was sent from a medical student enrolled at the faculty member's affiliated medical school. Sources for e-mail addresses included residency program Web sites, the American Society of Plastic Surgeons Web site, and a manual PubMed search. Independent predictors of accessible mentors were determined. RESULTS: There were 498 e-mails delivered and 363 responses received (response rate of 73%). In total, there were 283 positive responses, resulting in 56.8% of plastic surgeons contacted identifying themselves as accessible for mentorship. Younger age [odds ratio (OR), 1.72; P = 0.005], Fellow of the American College of Surgeons (OR, 1.49; P = 0.035), and faculty members of medical schools ranked in the top 20 (OR, 1.75; P = 0.003) were associated with an increased odds of accessibility. CONCLUSIONS: Most academic plastic surgeons are accessible as mentors (78%). Medical students enrolled at a highly ranked medical school seeking younger faculty mentors may have the greatest access to research opportunities and career advice. Encouraging faculty to participate in mentorship is important in developing the next generation of plastic surgeons. PMID- 25514249 TI - Correction: Structural heterogeneity of milk casein micelles: a SANS contrast variation study. AB - Correction for 'Structural heterogeneity of milk casein micelles: a SANS contrast variation study' by Antoine Bouchoux et al., Soft Matter, 2015, DOI: 10.1039/c4sm01705f. PMID- 25514250 TI - Patient education for preventing diabetic foot ulceration. AB - BACKGROUND: Ulceration of the feet, which can result in loss of limbs and even death, is one of the major health problems for people with diabetes mellitus. OBJECTIVES: To assess the effects of patient education on the prevention of foot ulcers in patients with diabetes mellitus. SEARCH METHODS: We searched The Cochrane Wounds Group Specialised Register (searched 03 September 2014); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 8). SELECTION CRITERIA: Prospective randomised controlled trials (RCTs) that evaluated educational programmes for preventing foot ulcers in people with diabetes mellitus. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook data extraction and assessment of risk of bias. Primary end points were foot ulceration or ulcer recurrence and amputation. MAIN RESULTS: Of the 12 RCTs included, the effect of patient education on primary end points was reported in only five. Pooling of outcome data was precluded by marked, mainly clinical, heterogeneity. One of the RCTs showed reduced incidence of foot ulceration (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.14 to 0.66) and amputation (RR 0.33, 95% CI 0.15 to 0.76) during one-year follow-up of diabetes patients at high risk of foot ulceration after a one-hour group education session. However, one similar study, with lower risk of bias, did not confirm this finding (RR amputation 0.98, 95% CI 0.41 to 2.34; RR ulceration 1.00, 95% CI 0.70 to 1.44). Three other studies, also did not demonstrate any effect of education on the primary end points, but were most likely underpowered. Patients' foot care knowledge was improved in the short term in five of eight RCTs in which this outcome was assessed, as was patients' self-reported self-care behaviour in the short term in seven of nine RCTs. Callus, nail problems and fungal infections improved in only one of five RCTs. Only one of the included RCTs was at low risk of bias. AUTHORS' CONCLUSIONS: In some trials, foot care knowledge and self reported patient behaviour seem to be positively influenced by education in the short term. Yet, based on the only two sufficiently powered studies reporting the effect of patient education on primary end points, we conclude that there is insufficient robust evidence that limited patient education alone is effective in achieving clinically relevant reductions in ulcer and amputation incidence. PMID- 25514251 TI - Collaterals in endovascular therapy for stroke. AB - PURPOSE OF REVIEW: Endovascular therapy is a promising aspect of acute ischemic stroke treatment. The ideal population of patients who benefit from treatment remains undefined, and the status of collateral circulation at presentation may be a key feature in their identification. RECENT FINDINGS: Adequate collateral flow has been recently demonstrated to be associated with improved clinical status on presentation, increased likelihood of recanalization with endovascular therapy, and better functional outcome at 3 months. SUMMARY: In this review, we define the collateral circulation, review methods of its measurement, and present recent clinical data on its impact in endovascular therapy for acute ischemic stroke. We outline our current understandings and discuss their relevance in future directions with clinical stroke management. PMID- 25514252 TI - Physical therapy for persons with vestibular disorders. AB - PURPOSE OF REVIEW: Persons with vestibular disorders experience symptoms of dizziness and balance dysfunction, resulting in falls, as well as impairments of daily life. Various interventions provided by physical therapists have been shown to decrease dizziness and improve postural control. In the present review, we will focus on the role of physical therapy in the management of vestibular symptoms in patients with peripheral and central vestibular disorders. RECENT FINDINGS: Persons with both acute and chronic central and peripheral vestibular disorders improve with vestibular rehabilitation. New interventions during the past 5 years have been designed to enhance recovery from problems with balance and dizziness. Examples include the use of virtual reality, vibrotactile feedback, optokinetic flow, YouTube videos, and innovative methods to change the gain of the vestibulo-ocular reflex (VOR). SUMMARY: Patients with central and peripheral vestibular disorders benefit from physical therapy interventions. Advances in physical therapy interventions include new methods to stimulate adaptation of the VOR and the vestibulospinal systems. PMID- 25514253 TI - Micro, soft, windows: integrating super-resolution viewing capabilities into soft lithographic devices. AB - Microengineered cell culture environments afford experimentalists with the critical ability to study cells in precisely-defined, yet physiologically realistic environments. A significant, but often overlooked, feature of these technologies is the unique ability to optically probe cellular and sub-cellular processes during culture in these complex environments, thereby obtaining information that would not be possible via conventional techniques. Motivated by the recent presentation of the Nobel prizes for super-resolution imaging and more recent technological breakthroughs in lattice-based light sheet microscopy, in this research highlight we survey recent innovations in the design of microfluidic cell culture platforms, that will ultimately allow experimentalists to probe biological activity with high-spatial and temporal-resolution. These advances will provide new technology-driven windows into biological processes and mechanisms. PMID- 25514254 TI - Effect of remineralizing agents on surface microhardness of primary and permanent teeth after erosion. AB - PURPOSE: The purposes of this study were to compare the susceptibility of human primary and permanent enamel to dental erosion caused by soft drinks and to compare in vitro the remineralization potential of casein phosphopeptide amorphous calcium phosphate (CPP-ACP) paste, 1.23 percent acidulated phosphate fluoride (APF) gel, and iron supplement. METHODS: Fifteen extracted primary and permanent teeth were used for sample preparation. Samples were randomly divided into three treatment groups: CPP-ACP paste, APF gel and iron supplement. The samples were subjected to a series of demineralization and remineralization cycles and were evaluated through surface microhardness. Statistical analysis was performed using one way ANOVA and unpaired t -tests. RESULTS: After remineralization, all samples showed an increase in surface hardness, which was significantly higher with CPP-ACP paste. CONCLUSION: CPP-ACP paste was more effective at preventing dental erosion than the other products. PMID- 25514255 TI - Association between breast-feeding duration and posterior crossbites. AB - PURPOSE: The purpose of this study was to evaluate the association between breast feeding duration and the subsequent occurrence of posterior crossbite in Brazilian children. METHODS: A cross-sectional study was conducted involving 714 six- to nine-year-old children. A questionnaire was completed by mothers or guardians of the children concerning the length of time they were exclusively breast-fed and the breast-feeding duration. A clinical examination of each child was conducted to detect posterior crossbite. Data were analyzed using Pearson's chi-square test at a five percent significance level. RESULTS: There was a posterior crossbite prevalence of approximately 15 percent. There was no statistically significant association between posterior crossbite and age or gender ( P >.05). The prevalence of posterior crossbite was higher among children who were not breast-fed (28 percent) than among breast-fed children (13 percent). There was a significant association between posterior crossbite and the length of time that children were exclusively breast-fed and the breast-feeding duration ( P <.05 percent). CONCLUSION: The prevalence of posterior crossbite gradually decreased as exclusive breast-feeding duration increased, and there was a relationship between breast-feeding duration and the occurrence of posterior crossbite. PMID- 25514256 TI - Pulp chamber temperature increase from curing light units: an in vitro study. AB - PURPOSE: The purpose of this study was to compare temperature rises in the pulp chamber induced by halogen, plasma arc, and conventional light-emitting diode (LED) curing units with that induced via a new generation LED-curing unit (VALO) in extra power mode. METHODS: A Class I cavity was prepared on the occlusal surface of 80 extracted caries- free mandibular third molars, which were filled with a microhybrid composite. A thermocouple wire was inserted into the pulp chamber of each tooth to measure temperature changes. RESULTS: The greatest temperature increases were observed during polymerization of composite resin with a halogen curing unit (3.2 degrees Celsius), followed by plasma arc curing (2.07 degrees Celsius) and VALO curing (1.44 degrees Celsius); the lowest temperature rise was with conventional LED curing (1.01 degrees Celsius). CONCLUSION: There were no statistically significant differences between conventional LED and VALO curing in extra power mode regarding pulp chamber temperature increases when polymerizing composite resin. PMID- 25514257 TI - Oral habits--part 1: the dental effects and management of nutritive and non nutritive sucking. AB - Nutritive sucking and non-nutritive sucking are among the most commonly reported oral habits in children. These habits generally cease around four years of age as interaction with other children increases. However, prolonged habits may alter dento-skeletal development, leading to orthodontic problems, which may persist into the permanent dentition. Rewards, reminder therapy, and appliance therapy have been described for the management of nutritive and non-nutritive sucking habits. Reminder therapy includes the use of gloves, thumb-guards, mittens, and tastants applied to fingers. When other modes of treatment have failed, appliance therapy, such as palatal cribs or Bluegrass appliances, may be necessary to prevent the placement of the digit in its sucking position. These tools are very effective and are associated with few adverse effects; however, they must be used with the cooperation of the child and never as punishment. The purpose of this paper is to update clinicians about nutritive and non-nutritive sucking habits in children and their impact on dental/skeletal development, and management options. PMID- 25514258 TI - Oral habits--part 2: beyond nutritive and non-nutritive sucking. AB - In addition to sucking habits, a range of other habits have been associated with short- and long-term dental and orthodontic problems. These habits include tongue thrusting and atypical swallowing, lip sucking, oral self-mutilation, mouth breathing, and bruxism. Although the association between form and function continues to be controversial, if habits are of sufficient duration they may lead to dental malocclusion and impede successful management. Oral self-injury and bruxism can lead to significant problems, such as soft tissue trauma and infection. Accurate history taking and examination are essential steps in formulating a diagnosis and management plan. Although a range of treatment options are often available, clear guidelines for treatment are difficult to develop due to a lack of high quality clinical trials. Optimal management is likely to be dictated by patient and severity variability. The purpose of this paper is to review and discuss the management of tongue thrust and atypical swallowing, lip sucking, oral self-mutilation, mouth breathing and bruxism. PMID- 25514259 TI - Developmental defects of enamel in phenylketonuria patients. AB - PURPOSE: The purpose of this study was to determine the prevalence of developmental defects of enamel in patients diagnosed with phenylketonuria (PKU). METHODS: The study group consisted of 24 four- to 24-year-old subjects with PKU. The control group consisted of 24 healthy individuals. An examination for the detection of developmental defects of enamel was conducted at the university pediatric dentistry clinic by a single examiner. Data were analyzed using the chi square test (P<.05) and odds ratios. RESULTS: The prevalence of developmental defects of enamel was 36 percent in the study group and 15 percent in the control group. The maxillary central incisors were the most affected teeth in patients with PKU, while the maxillary and mandibular first molars were the most affected teeth in the control group. Patients with PKU had a 3.3-fold greater chance of exhibiting developmental defects of enamel versus the healthy controls, which was statistically significant (P<.001). CONCLUSION: The study findings suggest that PKU increases the risk of developmental defects of enamel. PMID- 25514260 TI - Pre-eruptive intracoronal resorption of a permanent first molar. AB - For the last 70 years, the phenomenon of pre-eruptive intracoronal resorption (PIR) has been described in the literature, including a number of case reports illustrating the challenges clinicians face in diagnosing and managing these resorptive defects. Pre-eruptively affected teeth can be difficult to access and posteruptively they are difficult to diagnose because the defects resemble caries. Many times, these defects are not detected until after eruption, when the majority are diagnosed as dental decay and teeth are often subjected to surgical tooth restoration. The purposes of this paper are to report a case of nonprogressive PIR that was detected early, treated with a preventive glass ionomer sealant, and monitored for 44 months, and to propose an alternative approach to management of nonprogressive defects that may help preserve tooth structure. PMID- 25514261 TI - Transalveolar repositioning of an impacted immature permanent mandibular canine. AB - The purpose of this case report is to discuss the four-year follow-up of a transalveolar transplantation of an impacted immature permanent mandibular left canine. A nine year-old-boy was referred to the dental school because of a mandibular swelling associated with the impacted canine. Under local anesthesia, the tooth was extracted and transplanted in its own space, followed by a two-week orthodontic fixation. The radiographic examination two months later revealed the presence of external inflammatory root resorption, which was treated with an apexification. The overall status of the transplanted tooth and the surrounding hard and soft tissues four years post-treatment indicates a successful outcome. PMID- 25514262 TI - Esthetic management of double tooth associated with talon cusp using a laminate veneer. AB - Double tooth and talon cusp are tooth shape anomalies with rare co-occurrences in a single tooth. Double tooth is a developmental anomaly that leads to the eruption of fused teeth and may contribute to compromised esthetics, pain, caries, and tooth crowding. Talon cusp is a rare developmental extra cusp-like projection on the cingulum area that may cause functional and esthetic problems. Differential diagnosis of these anomalies may be complicated. A multidisciplinary approach for the esthetic and functional rehabilitation of double teeth is important. Various treatment methods have been described in the literature for the different types and morphological variations of double teeth. The purpose of this paper is to report the case of an unusual combination of double tooth and talon cusp on a permanent maxillary incisor and describe its esthetic and functional rehabilitation using a porcelain laminate veneer. PMID- 25514263 TI - The association between Cri du chat syndrome and dental anomalies. AB - Cri du chat syndrome (CdcS), also known as 5p deletion syndrome is a genetic disorder caused by the partial deletion of chromatin from the short arm of chromosome 5. There is a paucity of literature on the dental manifestations in CdcS. The purposes of this report are to present the case of a nine-year-old girl with the syndrome, CdcS and to review its dental and clinical manifestations and their management in children. PMID- 25514265 TI - What's new in Shock, January 2015? PMID- 25514266 TI - The management of diabetic foot ulcers through optimal off-loading: building consensus guidelines and practical recommendations to improve outcomes. AB - BACKGROUND: We sought to develop a consensus statement for the use of off-loading in the management of diabetic foot ulcers (DFUs). METHODS: A literature search of PubMed for evidence regarding off-loading of DFUs was initially conducted, followed by a meeting of authors on March 15, 2013, in Philadelphia, Pennsylvania, to draft consensus statements and recommendations using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach to assess quality of evidence and develop strength of recommendations for each consensus statement. RESULTS: Evidence is clear that adequate off-loading increases the likelihood of DFU healing and that increased clinician use of effective off-loading is necessary. Recommendations are included to guide clinicians on the optimal use of off-loading based on an initial comprehensive patient/wound assessment and the necessity to improve patient adherence with off loading devices. CONCLUSIONS: The likelihood of DFU healing is increased with off loading adherence, and, current evidence favors the use of nonremovable casts or fixed ankle walking braces as optimum off-loading modalities. There currently exists a gap between what the evidence supports regarding the efficacy of DFU off loading and what is performed in clinical practice despite expert consensus on the standard of care. PMID- 25514267 TI - Efinaconazole topical solution, 10%: the development of a new topical treatment for toenail onychomycosis. AB - BACKGROUND: Toenail onychomycosis is a common disease with limited treatment options; treatment failure and relapse are frequently encountered. Many patients experience long-standing disease affecting multiple toenails, with substantial discomfort and pain. Although some patients might prefer a topical therapy, efficacy with ciclopirox nail lacquer has been disappointing. METHODS: Efinaconazole topical solution, 10% is the first topical triazole antifungal agent specifically developed for the treatment of onychomycosis. This paper reviews the preclinical and clinical data on efinaconazole topical solution, 10%. RESULTS: Efinaconazole has a broad spectrum of antifungal activity in vitro and is more potent than ciclopirox against common onychomycosis pathogens. It has a more optimal keratin affinity than ciclopirox, and it exhibits significantly greater in vivo activity owing to its superior nail penetration. Mycologic cure rates at week 52 were 55.2% (study 1) and 53.4% (study 2) with efinaconazole topical solution, 10% compared with 16.8% and 16.9%, respectively, with vehicle (P<.001 for both). In addition, efinaconazole is well tolerated. CONCLUSIONS: Efinaconazole topical solution, 10% may likely become a preferred topical agent for the management of mild-to-moderate onychomycosis. PMID- 25514268 TI - Podiatric medical abnormalities in a random population sample 40 years or older in Spain. AB - BACKGROUND: Podiatric medical abnormalities are highly prevalent, yet few random population studies exist that determine the presence of pathologic abnormalities in the feet, despite their importance. The aim of this study was to determine the prevalence of podiatric medical abnormalities in a random sample population 40 years or older. METHODS: An observational study was conducted of a random sample population (n = 1,002) located in A Coruna, Spain. Anthropometric variables, comorbidity (Charlson score), quality of life (36-item Short-Form Health Survey), and podiatric medical examination findings were studied. A descriptive analysis and multivariate logistic regression were performed. RESULTS: The most common diseases were claw toes (69.7%), hallux valgus (38%), and hallux extensus (15.8%), which increased with age and female sex. The most frequent metatarsal formula was index minus (40.9%), followed by index plus minus (35.0%). The most frequent digital formula was Egyptian foot (57.1%), followed by Greek foot (31.4%). In this study, although the presence of podiatric medical abnormalities reduced the probability of enjoying a better quality of life, it did not do so significantly. After taking into account age, sex, comorbidity, body mass index (BMI), and the presence of podiatric medical abnormalities, the variables with an independent effect that modified the physical component of quality of life were sex (female), comorbidity, and BMI. CONCLUSIONS: There was a high prevalence of podiatric medical abnormalities, which increased with age and female sex. Comorbidity, BMI, and sex modified quality of life independently of podiatric medical abnormalities. PMID- 25514269 TI - Chronic recurrent multifocal osteomyelitis: the prevalence of lower-limb and foot involvement. AB - BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory condition. The lesions are reported to present most frequently in the long bones. This study aimed to review the presenting features of CRMO in a cohort of children diagnosed as having CRMO and to compare the level of agreement between the clinical and published diagnostic criteria. METHODS: A case notes review was undertaken of patients with a clinical diagnosis of CRMO. Patients were younger than 16 years at the time of diagnosis. Features were identified in each patient that agreed or disagreed with the published diagnostic criteria. The location of bone lesions in the lower limb at onset and disease progression was recorded. RESULTS: A total of 37 patients were included. There was a high prevalence in white individuals. Agreement with the diagnostic criteria of Jansson et al and El-Shanti and Ferguson was poor, with levels of agreement of 40.5% and 43%, respectively, and low kappa scores (kappa = 0.07 and 0.09, respectively). The lower limb was affected in 49% of patients at onset and in 72% overall. CONCLUSIONS: This study presents one of the largest published cohorts of pediatric patients with CRMO and also presents racial/ethnic group data that have not previously been reported in other studies. Despite being a condition considered to affect the metaphysis of long bones, the ankle area and foot bones were also frequently affected. The agreement between the clinical diagnosis and the published diagnostic criteria was weak. PMID- 25514270 TI - Foot type analysis based on electronic pedobarography data in individuals with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type during upright standing. AB - BACKGROUND: Joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT) is a rheumatologic condition characterized by generalized joint hypermobility and musculoskeletal and nonmusculoskeletal findings related to congenital laxity of connective tissue. Because foot pain and other foot problems are reported to make daily life problematic to manage for individuals with JHS/EDS-HT, and thanks to the availability of modern technology, the aim of the present study was to quantitatively characterize foot type in individuals with JHS/EDS-HT during upright standing. METHODS: Forty feet of 20 women with JHS/EDS HT (mean +/- SD age, 36.03 +/- 14.01 years) were assessed clinically and with a pressure-sensitive mat during upright standing. RESULTS: Forty-five percent of feet had a high arch (pes cavus), 27.5% had a normal arch, and 27.5% had a low arch (pes planus or flatfoot). CONCLUSIONS: From a clinical perspective, the characterization of foot type in JHS/EDS-HT is important to identify, develop, and enhance the rehabilitative options. An understanding of the relationship between pes cavus and foot pain in these patients could, in fact, improve the clinical management of these patients. PMID- 25514271 TI - Forefoot varus predicts subtalar hyperpronation in young people. AB - BACKGROUND: Subtalar joint hyperpronation is a foot misalignment that has been associated with several musculoskeletal injuries. Forefoot varus is thought to result in subtalar hyperpronation during weightbearing circumstances. However, few studies have aimed to verify whether there is a significant relationship between forefoot alignment and subtalar hyperpronation. Moreover, no study has attempted to verify whether forefoot varus can predict subtalar hyperpronation in young individuals. Therefore, the purpose of this study was to verify whether forefoot varus can predict subtalar hyperpronation, measured using the rearfoot eversion angle test, the navicular drop test, and the Foot Posture Index (FPI), in young people. METHODS: Fifty-four healthy adolescents volunteered for this study (28 boys and 26 girls). A single examiner evaluated the forefoot angle, rearfoot angle, navicular drop, and FPI of each participant. Statistical analysis included the Pearson correlation test and a linear regression analysis to establish the relationship between the variables. RESULTS: These results showed a high positive correlation between forefoot varus and rearfoot angle (r = 0.86; P < .001), navicular drop (r = 0.76; P < .001), and FPI (r = 0.82; P < .001). Moreover, the forefoot varus variable was able to predict 74% of the variability in the rearfoot angle, 58% in the navicular drop, and 67% in the FPI (P < .001). CONCLUSIONS: These findings support previous assumptions that individuals with forefoot varus present subtalar hyperpronation. Clinicians should not overlook forefoot alignment when prescribing foot orthoses for treating patients with foot misalignments. PMID- 25514272 TI - Between-day reliability of a cluster-based method for multisegment kinematic analysis of the foot-ankle complex. AB - BACKGROUND: Detailed description of foot pronation-supination requires multisegment evaluation of the kinematics of the foot-ankle complex. There are noninvasive methods with independent (single) tracking markers attached directly to the skin. However, these methods are inconsistent with the usual rigid segments assumption. In contrast, using clustered markers is compatible with this assumption and is necessary for analyses that need tracking markers to be distant from the foot (eg, shod walking). This study investigated the between-day reliability of a cluster-based method for multisegment analysis of foot-ankle angles related to pronation-supination. METHODS: Ten healthy adults participated in the study. An anatomically based, three-dimensional model comprising the shank, calcaneus, and forefoot was created. Rigid clusters of tracking markers were used to determine the relative positions and motions of the segments. Mean positions were measured with the subtalar joint in neutral position during standing. Furthermore, mean angles, peaks, and timings of peaks were measured during the stance phase of walking. All of the variables were measured twice, with a 1-week interval. To evaluate reliability, intraclass correlation coefficients were calculated for discrete variables and coefficients of multiple correlation for entire gait curves. RESULTS: Intraclass correlation coefficients varied from 0.8 to 0.93 for the angles obtained when the subtalar joint was in neutral and from 0.76 to 0.9 for walking variables. Coefficients of multiple correlation varied from 0.93 to 0.97 for walking curves. CONCLUSIONS: The method described has good to high reliability and provides a systematic method for multisegment kinematic evaluation of foot-ankle pronation-supination. PMID- 25514273 TI - Effects of off-the-shelf foot orthoses on plantar foot pressures in patients with early rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) often affects feet with progressive pathologic changes to foot morphology and pressure distribution. Studies in RA suggest that reductions in forefoot peak pressures can reduce pain. We investigated the effects of off-the-shelf foot orthoses on plantar foot pressures in patients with early RA. METHODS: Thirty-five patients with early RA were recorded walking. Variables measured were forefoot peak plantar pressure (PPPft), forefoot pressure-time integral (PTIft), and hallux and lesser toe and midfoot contact areas. Patients were analyzed while walking barefoot, with shoes, and with shoes and foot orthoses. Measurements were taken at baseline and at 3 and 6 months. RESULTS: There were significantly increased PPPft values between barefoot and shod and between barefoot and orthoses (P < .01). However, there was a significant reduction in PPPft during the 6 months with orthoses compared with shoes only (P < .01). Foot orthoses significantly reduced PTIft over 6 months (P < .01). Results also demonstrated a significant increase in hallux and lesser toe (P < .01) and midfoot (P < .01) contact areas during the 6 months with foot orthoses. CONCLUSIONS: In patients with early RA, off-the-shelf foot orthoses cause a significant reduction of 22% in PPPft and 14% in PTIft as soon as insoles are worn compared with shod. Further reductions for orthoses compared with baseline were found by 3 months (15% in PPPft and 14% in PTIft) and 6 months (33% in PPPft and 33% in PTIft). These findings could contribute to reductions in foot pain. PMID- 25514274 TI - Healing efficacy and participant outcomes of chemical matrixectomies using a hydrogel containing oakin. AB - BACKGROUND: We sought to demonstrate the healing efficacy of an antimicrobial hydrogel containing Oakin, an oak extract, to heal postoperative partial and total chemical matrixectomies. METHODS: Sixty participants were eligible for this open-label prospective study by having an ingrown toenail and a willingness to have the ingrown portion of the nail or the entire toenail permanently removed. All of the participants underwent a similar nail surgery, were provided a postoperative kit that included the study hydrogel, and received the same sheet of instructions for aftercare. RESULTS: Fifty-four participants could be contacted for follow-up and final evaluation; 54% (n = 29) were men and 46% (n = 25) were women. Eighty-nine partial hallux nail avulsions with phenol matrixectomy were performed. The median +/- SD time to healing was 7.00 +/- 0.00 days for 80% of participants (n = 43) and 8.85 +/- 4.15 days for 98% (n = 53). An analysis of variance showed that the proportion healed time trend is significant (F1,53 = 79.265; P < .001). CONCLUSIONS: The study hydrogel's ability to stop phenol's caustic activity is clinically beneficial in phenol matrixectomy aftercare. Providing each participant with a kit that included the same dressing supplies yielded consistent aftercare outcomes and 98% patient satisfaction (n = 53). The findings show that the Oakin-containing hydrogel was efficacious in healing phenol matrixectomies without the need for soaking. Furthermore, we suggest that the study hydrogel could also reduce healing times. PMID- 25514275 TI - Assessing plantar pressure distribution in children with flatfoot arch: application of the Clarke angle. AB - BACKGROUND: Flatfoot, or pes planus, is one of the most common foot posture problems in children that may lead to lower-extremity pain owing to a potential increase in plantar pressure. First, we compared plantar pressure distribution between children with and without flatfoot. Second, we examined the reliability and accuracy of a simple metric for characterization of foot posture: the Clarke angle. Third, we proposed a mathematical model to predict plantar pressure magnitude under the medial arch using body mass and the Clarke angle. METHODS: Sixty children with flatfoot and 33 aged-matched controls were recruited. Measurements included in-shoe plantar pressure distribution, ground reaction force, Clarke angle, and radiography assessment. The measured Clarke angle was compared with radiographic measurements, and its test-retest reliability was determined. A mathematical model was fitted to predict plantar pressure distribution under the medial arch using easy-to-measure variables (body mass and the Clarke angle). RESULTS: A high correlation was observed between the Clarke angle and radiography measurements (r > 0.9; P < 10(-6)). Excellent between- and within-day test-retest reliability for Clarke angle measurement (intraclass correlation coefficient, >0.9) was observed. Results also suggest that pressure magnitude under the medial arch can be estimated using the Clarke angle and body mass (R(2) = 0.95; error, <0.04 N/cm(2) [2%]). CONCLUSIONS: This study suggests that the Clarke angle is a practical, reliable, and sensitive metric for quantification of medial arch height in children and could be recommended for research and clinical applications. It can also be used to estimate plantar pressure under the medial arch, which, in turn, may assist in the timely intervention and prognosis of prospective problems associated with flatfoot posture. PMID- 25514276 TI - Radiographic anatomy of the foot and ankle--part 3: the lesser tarsus. AB - BACKGROUND: The normal radiographic anatomy of the foot and ankle, aside from my previous work, has been addressed only superficially or sparingly in the medical literature. This project correlates the detailed radiographic anatomy of the entire adult foot and ankle (two-dimensional) to osteology (three-dimensional). METHODS: Each bone's position was determined after meticulous examination and correlation to an articulated skeleton relative to the image receptor and direction of the x-ray beam, with correlation to the radiograph for confirmation. RESULTS: Images of each foot and distal leg bone ("front" and "back" perspectives) are presented alongside a corresponding radiographic image for comparison. The normal gross and radiographic anatomy is correlated and described for each radiographic positioning technique. CONCLUSIONS: Foundational knowledge is provided that future researchers can use as a baseline ("normal") and that students and practitioners can use for comparison when interpreting radiographs and distinguishing abnormal findings. The results of the original project, owing to its broad scope, have been divided into five parts: the lower leg, the greater tarsus, the lesser tarsus (the focus of this article), the metatarsals, and the phalanges. PMID- 25514277 TI - Calcaneocuboid joint dislocation: a case report. AB - Tarsal bone dislocation is a rare entity. It is usually undiagnosed in the emergency department. We present the case of a 44-year-old man who was diagnosed as having calcaneocuboid joint dislocation in the emergency department. The dislocation was reduced in the emergency department, and a below-the-knee cast was applied. Successful clinical and radiologic results were obtained during follow-up. In this case, unlike the previous reports in the literature, conservative management succeeded in the treatment of calcaneocuboid joint dislocation. PMID- 25514281 TI - Soup and recycling. PMID- 25514278 TI - Complications of sodium hydroxide chemical matrixectomy: nail dystrophy, allodynia, hyperalgesia. AB - Ingrown toenails are seen most commonly in young adults, and they can seriously affect daily life. Partial nail avulsion with chemical matrixectomy, generally by using either sodium hydroxide or phenol, is one of the most effective treatment methods. Known complications of phenol matrixectomy are unpredictable tissue damage, prolonged postoperative drainage, increased secondary infection rates, periostitis, and poor cosmetic results. To our knowledge, there have been no reports about the complications related to sodium hydroxide matrixectomy. Herein, we describe three patients who developed nail dystrophy, allodynia, and hyperalgesia after sodium hydroxide matrixectomy. PMID- 25514290 TI - Untitled (composition with grey background): Wassily Kandinsky. PMID- 25514291 TI - Nobel Prize winners' research relates to brain function and neurodegenerative diseases. PMID- 25514292 TI - The challenges of reforming graduate medical education payments. PMID- 25514299 TI - A piece of my mind. The half-wall. PMID- 25514300 TI - Optimal antiviral prophylaxis against hepatitis B reactivation in patients receiving rituximab-based chemotherapy for lymphoma. PMID- 25514301 TI - Role of glycemic index in the context of an overall heart-healthy diet. PMID- 25514302 TI - Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial. AB - IMPORTANCE: Hepatitis B virus (HBV) reactivation is a serious complication for patients with lymphoma treated with rituximab-containing chemotherapies, despite lamivudine prophylaxis treatment. An optimal prophylactic antiviral protocol has not been determined. OBJECTIVE: To compare the efficacy of entecavir and lamivudine in preventing HBV reactivation in patients seropositive for the hepatitis B surface antigen with untreated diffuse large B-cell lymphoma receiving chemotherapy treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). DESIGN, SETTING, AND PATIENTS: Randomized, open-label, phase 3 study conducted from February 2008 through December 2012 at 10 medical centers in China. This study was a substudy of a parent study designed to compare a 3-week with a 2-week R-CHOP chemotherapy regimen for untreated diffuse large B-cell lymphoma. Patients enrolled in the parent study who were seropositive for the hepatitis B surface antigen and had normal liver function, serum HBV DNA levels of less than 103 copies/mL, and no prior antiviral therapy were randomized to entecavir (n = 61) or lamivudine (n = 60). INTERVENTIONS: Daily entecavir (0.5 mg) or lamivudine (100 mg) beginning 1 week before the initiation of R-CHOP treatment to 6 months after completion of chemotherapy. MAIN OUTCOMES AND MEASURES: The primary efficacy end point was the incidence of HBV related hepatitis. The secondary end points included rates of HBV reactivation, chemotherapy disruption due to hepatitis, and treatment-related adverse events. RESULTS: There were 121 patients randomly assigned to receive entecavir (n = 61) or lamivudine (n = 60). The date of last patient follow-up was May 25, 2013. The rates were significantly lower for the entecavir group vs the lamivudine group for HBV-related hepatitis (0% vs 13.3%, respectively; difference between groups, 13.3% [95% CI, 4.7% to 21.9%]; P = .003), HBV reactivation (6.6% vs 30%; difference, 23.4% [95% CI, 10.2% to 36.6%]; P = .001), and chemotherapy disruption (1.6% vs 18.3%; difference, 16.7% [95% CI, 6.4% to 27.0%]; P = .002). Of the 61 patients in the entecavir group, 15 (24.6%) experienced treatment related adverse events. Of 60 patients in the lamivudine group, 18 (30%) experienced treatment-related adverse events (difference between entecavir and lamivudine groups, 5.4% [95% CI, -10.5% to 21.3%]; P = .50). CONCLUSIONS AND RELEVANCE: Among patients seropositive for the hepatitis B surface antigen with diffuse large B-cell lymphoma undergoing R-CHOP chemotherapy, the addition of entecavir compared with lamivudine resulted in a lower incidence of HBV-related hepatitis and HBV reactivation. If replicated, these findings support the use of entecavir in these patients. TRIAL REGISTRATIONS: clinicaltrials.gov Identifier: NCT01793844; Chinese Clinical Trial Registry Identifier: CTR-TRC-11001687. PMID- 25514305 TI - Oral anticoagulants and the risk of intracranial hemorrhage. PMID- 25514303 TI - Effects of high vs low glycemic index of dietary carbohydrate on cardiovascular disease risk factors and insulin sensitivity: the OmniCarb randomized clinical trial. AB - IMPORTANCE: Foods that have similar carbohydrate content can differ in the amount they raise blood glucose. The effects of this property, called the glycemic index, on risk factors for cardiovascular disease and diabetes are not well understood. OBJECTIVE: To determine the effect of glycemic index and amount of total dietary carbohydrate on risk factors for cardiovascular disease and diabetes. DESIGN, SETTING, AND PARTICIPANTS: Randomized crossover-controlled feeding trial conducted in research units in academic medical centers, in which 163 overweight adults (systolic blood pressure, 120-159 mm Hg) were given 4 complete diets that contained all of their meals, snacks, and calorie-containing beverages, each for 5 weeks, and completed at least 2 study diets. The first participant was enrolled April 1, 2008; the last participant finished December 22, 2010. For any pair of the 4 diets, there were 135 to 150 participants contributing at least 1 primary outcome measure. INTERVENTIONS: (1) A high glycemic index (65% on the glucose scale), high-carbohydrate diet (58% energy); (2) a low-glycemic index (40%), high-carbohydrate diet; (3) a high-glycemic index, low-carbohydrate diet (40% energy); and (4) a low-glycemic index, low carbohydrate diet. Each diet was based on a healthful DASH-type diet. MAIN OUTCOMES AND MEASURES: The 5 primary outcomes were insulin sensitivity, determined from the areas under the curves of glucose and insulin levels during an oral glucose tolerance test; levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides; and systolic blood pressure. RESULTS: At high dietary carbohydrate content, the low- compared with high-glycemic index level decreased insulin sensitivity from 8.9 to 7.1 units (-20%, P = .002); increased LDL cholesterol from 139 to 147 mg/dL (6%, P <= .001); and did not affect levels of HDL cholesterol, triglycerides, or blood pressure. At low carbohydrate content, the low- compared with high-glycemic index level did not affect the outcomes except for decreasing triglycerides from 91 to 86 mg/dL (-5%, P = .02). In the primary diet contrast, the low-glycemic index, low-carbohydrate diet, compared with the high-glycemic index, high-carbohydrate diet, did not affect insulin sensitivity, systolic blood pressure, LDL cholesterol, or HDL cholesterol but did lower triglycerides from 111 to 86 mg/dL (-23%, P <= .001). CONCLUSIONS AND RELEVANCE: In this 5-week controlled feeding study, diets with low glycemic index of dietary carbohydrate, compared with high glycemic index of dietary carbohydrate, did not result in improvements in insulin sensitivity, lipid levels, or systolic blood pressure. In the context of an overall DASH-type diet, using glycemic index to select specific foods may not improve cardiovascular risk factors or insulin resistance. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00608049. PMID- 25514306 TI - Pustulonodular lesion on the nose. PMID- 25514307 TI - A stool DNA test (Cologuard) for colorectal cancer screening. PMID- 25514304 TI - The diagnosis and management of mild cognitive impairment: a clinical review. AB - IMPORTANCE: Cognitive decline is a common and feared aspect of aging. Mild cognitive impairment (MCI) is defined as the symptomatic predementia stage on the continuum of cognitive decline, characterized by objective impairment in cognition that is not severe enough to require help with usual activities of daily living. OBJECTIVE: To present evidence on the diagnosis, treatment, and prognosis of MCI and to provide physicians with an evidence-based framework for caring for older patients with MCI and their caregivers. EVIDENCE ACQUISITION: We searched PubMed for English-language articles in peer-reviewed journals and the Cochrane Library database from inception through July 2014. Relevant references from retrieved articles were also evaluated. FINDINGS: The prevalence of MCI in adults aged 65 years and older is 10% to 20%; risk increases with age and men appear to be at higher risk than women. In older patients with MCI, clinicians should consider depression, polypharmacy, and uncontrolled cardiovascular risk factors, all of which may increase risk for cognitive impairment and other negative outcomes. Currently, no medications have proven effective for MCI; treatments and interventions should be aimed at reducing cardiovascular risk factors and prevention of stroke. Aerobic exercise, mental activity, and social engagement may help decrease risk of further cognitive decline. Although patients with MCI are at greater risk for developing dementia compared with the general population, there is currently substantial variation in risk estimates (from <5% to 20% annual conversion rates), depending on the population studied. Current research targets improving early detection and treatment of MCI, particularly in patients at high risk for progression to dementia. CONCLUSIONS AND RELEVANCE: Cognitive decline and MCI have important implications for patients and their families and will require that primary care clinicians be skilled in identifying and managing this common disorder as the number of older adults increases in coming decades. Current evidence supports aerobic exercise, mental activity, and cardiovascular risk factor control in patients with MCI. PMID- 25514308 TI - Assessment of outcomes of hepatitis C treatment. PMID- 25514309 TI - Assessment of outcomes of hepatitis C treatment--reply. PMID- 25514310 TI - Causes of ferritin elevation. PMID- 25514311 TI - Prevention of noncommunicable diseases. PMID- 25514312 TI - Causes of ferritin elevation. PMID- 25514313 TI - Prevention of noncommunicable diseases. PMID- 25514315 TI - Is aspirin a dangerous drug? PMID- 25514316 TI - JAMA patient page. Breast cancer screening: benefits and harms. PMID- 25514317 TI - Co-expression of CD40/CD40L on XG1 multiple myeloma cells promotes IL-6 autocrine function. AB - Multiple myeloma (MM) is characterized by uncontrolled proliferation of malignant plasma cells in the bone marrow and peripheral blood. Here, we found that CD40 and CD40L co-expressed on XG1 MM cells and the coordinated expression of CD40 CD40L was critical for production and autocrine IL-6 in XG1 cells. Furthermore, TNF-alpha enhanced the expression of both CD40 and CD40L expression on XG1 cells. We also found that persistent CD40L/CD40 signaling was required for the constitutive activation of NF-kappaB in the cells. PMID- 25514318 TI - Directionally-controlled periodic collimated beams of surface plasmon polaritons on metal film in Ag nanowire/Al2O3/Ag film composite structure. AB - Plasmonics holds promise for the realization of miniaturized photonic devices and circuits in which light can be confined and controlled at the nanoscale using surface plasmon polaritons (SPPs), surface waves of collective oscillations of electrons at a metal/dielectric interface. However, realizing plasmonic applications fundamentally requires the ability to guide and transfer SPPs in different plasmonic structures. Here the generation and control of periodic collimated SPP-beams are reported in composite structures of silver nanowire on silver film with a dielectric spacer layer between them. It is revealed that the collimated beams on the silver film originate from the interference between film SPPs generated by two SPP modes on the nanowire. The direction of the collimated beams can be readily tuned by changing the thickness of the dielectric spacer. These findings demonstrate the transfer of nanowire SPPs to film SPPs and offer a new approach to generate nondiffracting SPP-beams, which could facilitate the design and development of complex plasmonic systems for device applications and enable the tailoring of SPP radiation and SPP-matter interactions. PMID- 25514320 TI - Ten-dimensional anthropomorphic arm control in a human brain-machine interface: difficulties, solutions, and limitations. AB - OBJECTIVE: In a previous study we demonstrated continuous translation, orientation and one-dimensional grasping control of a prosthetic limb (seven degrees of freedom) by a human subject with tetraplegia using a brain-machine interface (BMI). The current study, in the same subject, immediately followed the previous work and expanded the scope of the control signal by also extracting hand-shape commands from the two 96-channel intracortical electrode arrays implanted in the subject's left motor cortex. APPROACH: Four new control signals, dictating prosthetic hand shape, replaced the one-dimensional grasping in the previous study, allowing the subject to control the prosthetic limb with ten degrees of freedom (three-dimensional (3D) translation, 3D orientation, four dimensional hand shaping) simultaneously. MAIN RESULTS: Robust neural tuning to hand shaping was found, leading to ten-dimensional (10D) performance well above chance levels in all tests. Neural unit preferred directions were broadly distributed through the 10D space, with the majority of units significantly tuned to all ten dimensions, instead of being restricted to isolated domains (e.g. translation, orientation or hand shape). The addition of hand shaping emphasized object-interaction behavior. A fundamental component of BMIs is the calibration used to associate neural activity to intended movement. We found that the presence of an object during calibration enhanced successful shaping of the prosthetic hand as it closed around the object during grasping. SIGNIFICANCE: Our results show that individual motor cortical neurons encode many parameters of movement, that object interaction is an important factor when extracting these signals, and that high-dimensional operation of prosthetic devices can be achieved with simple decoding algorithms. ClinicalTrials.gov Identifier: NCT01364480. PMID- 25514321 TI - First evidence of a volatile sex pheromone in lady beetles. AB - To date, volatile sex pheromones have not been identified in the Coccinellidae family; yet, various studies have suggested that such semiochemicals exist. Here, we collected volatile chemicals released by virgin females of the multicolored Asian lady beetle, Harmonia axyridis (Pallas), which were either allowed or not allowed to feed on aphids. Virgin females in the presence of aphids, exhibited "calling behavior", which is commonly associated with the emission of a sex pheromone in several Coleoptera species. These calling females were found to release a blend of volatile compounds that is involved in the remote attraction (i.e., from a distance) of males. Gas Chromatography-Mass Spectrometry (GC-MS) analyses revealed that (-)-beta-caryophyllene was the major constituent of the volatile blend (ranging from 80 to 86%), with four other chemical components also being present; beta-elemene, methyl-eugenol, alpha-humulene, and alpha-bulnesene. In a second set of experiments, the emission of the five constituents identified from the blend was quantified daily over a 9-day period after exposure to aphids. We found that the quantity of all five chemicals significantly increased across the experimental period. Finally, we evaluated the activity of a synthetic blend of these chemicals by performing bioassays which demonstrated the same attractive effect in males only. The results confirm that female H. axyridis produce a volatile sex pheromone. These findings have potential in the development of more specific and efficient biological pest-control management methods aimed at manipulating the behavior of this invasive lady beetle. PMID- 25514322 TI - An adolescent with asthma presenting with worsening cough. AB - The diagnosis of systemic histoplasmosis may be delayed due to underlying pulmonary conditions in patients from an endemic area. An adolescent White male from the Midwestern United States with a history of moderate persistent asthma presented to the pulmonary clinic with a 10-day's history of cough. The patient had no response to modifications of his asthma treatment regimen and proceeded to experience worsening symptoms, including pleuritic chest pain and dysphagia. Chest imaging revealed multiple pulmonary nodules, right mainstem bronchus narrowing, bilateral hilar adenopathy, and esophageal thickening. Ophthalmologic examination revealed an ocular "histo spot", but the patient denied any ocular symptoms. Despite negative initial histoplasmosis antibody testing, the patient began oral itraconazole therapy for presumed histoplasmosis infection. Follow-up histoplasmosis antibody titers were positive, and the patient responded well to itraconazole. Disseminated histoplasmosis can have a wide range of presenting symptoms, which may delay its diagnosis among patients with pre-existing asthma. PMID- 25514323 TI - Evaluation of puberty by verifying spontaneous and stimulated gonadotropin values in girls. AB - BACKGROUND: Changes in pharmacological agents and advancements in laboratory assays have changed the gonadotropin-releasing hormone analog stimulation test. OBJECTIVE: To determine the best predictive model for detecting puberty in girls. SUBJECTS: Thirty-five girls, aged 2 years 7 months to 9 years 3 months, with central precocious puberty (CPP) (n=20) or premature thelarche/premature adrenarche (n=15). METHODS: Diagnoses were based on clinical information, baseline hormones, bone age, and pelvic sonogram. Gonadotropins and E2 were analyzed using immunochemiluminometric assay. Logistic regression for CPP was performed. RESULTS: The best predictor of CPP is the E2-change model based on 3- to 24-h values, providing 80% sensitivity and 87% specificity. Three-hour luteinizing hormone (LH) provided 75% sensitivity and 87% specificity. Basal LH lowered sensitivity to 65% and specificity to 53%. CONCLUSIONS: The E2-change model provided the best predictive power; however, 3-h LH was more practical and convenient when evaluating puberty in girls. PMID- 25514324 TI - Virilizing adrenal oncocytoma in a 9-year-old girl: rare neoplasm with an intriguing postoperative course. AB - Adrenal oncocytoma is an extremely rare neoplasm, which is mostly non-functional. Only five cases of childhood adrenal oncocytoma have been described so far, all of which were hormonally active. Currently, guidelines for management and follow up are not available. We report a 9-year-old girl with benign adrenal oncocytoma, presenting with severe short-term virilization. After diagnostic work-up the patient underwent laparoscopic unilateral adrenalectomy. For the first 2 weeks following surgery she suffered marked mood swings, irritability and fatigue. There were no other clinical and/or laboratory abnormalities except the rapid drop-down of androgen levels to normal values. Follow-up showed no signs of recurrence and in the absence of signs of adrenal insufficiency, we speculate that, the rapid drop of androgen levels after removal of the tumor might be the reason for the deteriorated psychoemotional condition of our patient. PMID- 25514325 TI - Determining abdominal obesity cut-offs and relevant risk factors for anthropometric indices in Turkish children and adolescents. AB - AIM: To determine the >=90th percentile values of waist circumference (WC) to calculate anthropometric measures, indices and relevant risk factors in 5358 Turkish children and adolescents. METHODS: This cross-sectional study was conducted in Kayseri, Turkey, from February to April 2005. Cut-offs for body weight, height, mid-upper arm circumference (MUAC), triceps skinfold thickness, body mass index (BMI), and fat percentages were calculated for >=90th percentile of WC. RESULTS: According to the results of binary multiple logistic regression analysis (the backward stepwise procedure), sleep duration (boys), maternal education (boys), elevator use (boys), and appetite (boys and girls) were revealed as significant predictors of abdominal obesity, adjusted for age. Appetite was the strongest variable to be associated with abdominal obesity for both genders. CONCLUSIONS: According to receiver operating characteristic analysis, for all age groups within both genders, the best predictors to explain abdominal obesity were BMI and MUAC, respectively. PMID- 25514326 TI - Ovotesticular disorder of sex development with unusual karyotype: patient report. AB - BACKGROUND: Ovotesticular disorder of sex development (OT-DSD) (true hermaphroditism) is an anatomopathological diagnosis based on the findings of testicular and ovarian tissues in the same subject, in the same gonad (ovotestis), or in separate gonads. OT-DSD is a rare cause of sex ambiguity, and the most common karyotype is 46,XX; mosaics and chimeras are found only in 10% 20%. AIM: To report a case of an OT-DSD patient with a rare karyotype constitution. CASE REPORT: A 2-month-old child with male sex assignment was referred to our clinic for investigation of sex ambiguity. He was the second child of healthy unrelated parents; pregnancy and labor were uneventful. On physical examination, he had a 2.3-cm phallus and perineal hypospadias (Prader grade III); the right gonad was in the labioscrotal fold and the left was found in the inguinal channel. Karyotype was 46,XX/47,XXY/48,XXYY. Anatomopathological examination of gonads revealed right testis and left ovotestis. The male sex assignment was maintained; the child underwent left gonadectomy, removal of Mullerian structures and urethroplasty. CONCLUSION: A thorough revision of literature revealed a single case of OT-DSD with the same chromosome constitution. Gonadal biopsy is necessary to establish diagnosis in cases of sex chromosome mosaicism. PMID- 25514327 TI - Effects of T3 treatment on brown adipose tissue and energy expenditure in a patient with craniopharyngioma and hypothalamic obesity. AB - OBJECTIVE: Patients treated for childhood craniopharyngioma often develop hypothalamic obesity (HO), which has a huge impact on the physical condition and quality of life of these patients. Treatment for HO thus far has been disappointing, and although several different strategies have been attempted, all interventions had only transient effects. Since thyroid hormones increase energy expenditure metabolism (thyroid hormone induced thermogenesis), it was speculated that treatment with tri-iodothyronine (T3) may be beneficial. In 2002, a case report was published on reduction of body weight after T3 treatment for HO. No studies have been reported since. Recent experimental studies in rodents showed that T3 increases brown adipose tissue (BAT) activity via (pre)sympathetic pathways between the hypothalamus and BAT. Our aim was to investigate whether T3 treatment increases BAT activity in a patient with HO resulting from (treatment of) childhood craniopharyngioma. METHODS: Thyroxine treatment for central hypothyroidism was switched to T3 monotherapy. Serum T3 and free thyroxine (FT4) concentrations were measured twice weekly for 2 months. 123I-MIBG and 18F-FDG-PET after induction of non-shivering thermogenesis for the assessment of sympathetic and metabolic activity of BAT as well as indirect calorimetry for assessment of resting energy expenditure were performed before and during T3 treatment. RESULTS: No change in sympathetic and metabolic BAT activity, energy expenditure, or BMI was seen during T3 treatment despite the expected changes in thyroid hormone plasma concentrations. CONCLUSION: We conclude that T3 monotherapy does not seem to be effective in decreasing HO in childhood craniopharyngioma. PMID- 25514328 TI - Endocrine aspects and sequel in patients with craniopharyngioma. AB - A craniopharyngioma (CP) is an embryonic malformation of the sellar and parasellar region. The annual incidence is 0.5-2.0 cases/million per year and approximately 60% of CP is seen in adulthood. The therapy of choice is surgery, followed by cranial radiotherapy in about half of the patients. Typical initial manifestations at diagnosis in children are symptoms of elevated intracranial pressure, visual disturbances and hypopituitarism. CPs have the highest mortality of all pituitary tumours. The standardised overall mortality rate varies from 2.88 to 9.28 in cohort studies. Adults with CP have a 3-19-fold higher cardiovascular mortality in comparison to the general population. Women with CP have an even higher risk. The long-term morbidity is substantial with hypopituitarism, increased cardiovascular risk, hypothalamic damage, visual and neurological deficits, reduced bone health and reduction in quality of life and cognitive function. PMID- 25514329 TI - The importance of interdisciplinary communication with patients about complex, chronic illnesses: our experiences as parents of a child with a craniopharyngioma. PMID- 25514330 TI - Morphological changes in the pancreas and glucose reduction of the aqueous extract of Costus afer leaf on alloxan-induced diabetic rats. AB - BACKGROUND: Considering the antihyperglycemic and antioxidant activities of herbs, this study has evaluated the morphological changes, hypoglycemic effect, and comparative ameliorating effects of Costus afer Ker Gawl leaf and glibenclamide on pancreatic injury induced by alloxan. METHODS: Thirty adult male albino rats that were divided into six groups of five weight-matched animals each were used in the study. Groups 1 and 2 served as controls, whereas groups 3-6 were alloxan-induced diabetic groups treated with different doses of the extract (375, 750, and 1125 mg/kg C. afer) and glibenclamide, respectively. The glucose level was measured daily, whereas the weight of the animal was monitored on a weekly basis for 21 days. The oral glucose tolerance test was measured on overnight fasted rats after glucose load at 0, 30, 60, 90, and 120 min. The histopathology of the pancreas was also investigated. RESULTS: The phytoconstituents of C. afer Ker Gawl leaves include glycosides, tannins, saponins, terpenoid, phenolic compound, flavonoids, and alkaloids. Costus afer possessed significant hypoglycemic (p<0.05) effect and reversed the histopathologic damage of pancreases in alloxan-induced diabetic rats comparable to those of glibenclamide. CONCLUSIONS: Costus afer leaves possess both antidiabetic and tissue protective properties on pancreases of investigated rats. PMID- 25514331 TI - Nonafluorobutanesulfonyl azide as a shelf-stable highly reactive oxidant for the copper-catalyzed synthesis of 1,3-diynes from terminal alkynes. AB - Nonafluorobutanesulfonyl azide is a highly efficient reagent for the copper catalyzed coupling of terminal alkynes to give symmetrical and unsymmetrical 1,3 diynes in good to excellent yields and with good functional group compatibility. The reaction is extremely fast (<10 min), even at low temperature (-78 degrees C), and requires substoichiometric amounts of a simple copper(I) or copper(II) salt (2-5 mol %) and an organic base (0.6 mol %). A possible mechanistic pathway is briefly discussed on the basis of model DFT theoretical calculations. The quantitative assessment of the safety of use and shelf stability of nonafluorobutanesulfonyl azide has confirmed that this reagent is a superior and safe alternative to other electrophilic azide reagents in use today. PMID- 25514333 TI - Geranylgeranylacetone protects against cerebral ischemia and reperfusion injury: HSP90 and eNOS phosphorylation involved. AB - Cerebral ischemia and reperfusion (I/R) can trigger a cytotoxic cascade with overflow of reactive oxygen species, paradoxically causing neurological dysfunction, redox imbalance, inflammation and apoptosis. The present study aims to investigate the effect of geranylgeranylacetone(GGA) on cerebral I/R injury and the underlying mechanism. The results demonstrated that cerebral I/R increased the neurological function abnormality, brain edema, inflammation and oxidative injury in rats as well as the cognitive impairment, which was significantly reversed by GGA in a dose-dependent manner. GGA also suppressed the cell injury and apoptosis caused by cerebral I/R. Moreover, the protective effect of GGA was found to involve heat shock protein 90 (HSP90) and phosphorylated endothelial nitric oxide synthase (eNOS) expression and activity. Both the HSP90 and eNOS inhibitor abolished the effect of GGA. The data showed that GGA could protect rats against cerebral I/R injury, which may be related to the induction of HSP90 and activation of eNOS. PMID- 25514332 TI - Coevolution drives the emergence of complex traits and promotes evolvability. AB - The evolution of complex organismal traits is obvious as a historical fact, but the underlying causes--including the role of natural selection--are contested. Gould argued that a random walk from a necessarily simple beginning would produce the appearance of increasing complexity over time. Others contend that selection, including coevolutionary arms races, can systematically push organisms toward more complex traits. Methodological challenges have largely precluded experimental tests of these hypotheses. Using the Avida platform for digital evolution, we show that coevolution of hosts and parasites greatly increases organismal complexity relative to that otherwise achieved. As parasites evolve to counter the rise of resistant hosts, parasite populations retain a genetic record of past coevolutionary states. As a consequence, hosts differentially escape by performing progressively more complex functions. We show that coevolution's unique feedback between host and parasite frequencies is a key process in the evolution of complexity. Strikingly, the hosts evolve genomes that are also more phenotypically evolvable, similar to the phenomenon of contingency loci observed in bacterial pathogens. Because coevolution is ubiquitous in nature, our results support a general model whereby antagonistic interactions and natural selection together favor both increased complexity and evolvability. PMID- 25514334 TI - The association between cortisol and the BOLD response in male adolescents undergoing fMRI. AB - MRI participation has been shown to induce subjective and neuroendocrine stress reactions. A recent aging study showed that cortisol levels during fMRI have an age-dependent effect on cognitive performance and brain functioning. The present study examined whether this age-specific influence of cortisol on behavioral and brain activation levels also applies to adolescence. Salivary cortisol as well as subjective experienced anxiety were assessed during the practice session, at home, and before, during and after the fMRI session in young versus old male adolescents. Cortisol levels were enhanced pre-imaging relative to during and post-imaging in both age groups, suggesting anticipatory stress and anxiety. Overall, a negative correlation was found between cortisol output during the fMRI experiment and brain activation magnitude during performance of a gambling task. In young but not in old adolescents, higher cortisol output was related to stronger deactivation of clusters in the anterior and posterior cingulate cortex. In old but not in young adolescents, a negative correlation was found between cortisol and activation in the inferior parietal and in the superior frontal cortex. In sum, cortisol increased the deactivation of several brain areas, although the location of the affected areas in the brain was age-dependent. The present findings suggest that cortisol output during fMRI should be considered as confounder and integrated in analyzing developmental changes in brain activation during adolescence. PMID- 25514335 TI - Cortical EEG components that reflect inverse effectiveness during visuotactile integration processing. AB - Multisensory integration is required to interpret information from multiple senses and then produce the appropriate behavioral output. Inverse effectiveness, a phenomenon in which weaker stimuli induce greater activation of multisensory neurons than do stronger stimuli, is an essential component of multisensory integration. The superior colliculus is especially abundant in multisensory neurons with properties of inverse effectiveness. However, multisensory neurons are distributed throughout the brain, suggesting that a wide range of brain regions are involved in generating multisensory behavior in addition to the superior colliculus. In this study, we aimed to use scalp EEG to elucidate the cortical responses that respond to multisensory stimuli according to the principle of inverse effectiveness. By modulating the intensity of the tactile aspect of a simultaneous visuotactile stimulus, we explored the time-frequency component of scalp EEG waveforms produced during multi-sensory stimulation. Using this method, we determined the relative values and temporal dynamics of the increment of power spectrum (event-related spectrum perturbation) and phase coherence across trials (e.g., inter-trial phase coherency) produced by multisensory stimulation compared to unisensory stimulation. In the somatosensory and anterior cingulate cortices, we observed significant differences in the inter trial phase coherence of the theta band oscillation 200-400 ms post-stimulus, in response to visuotactile (multisensory) and tactile (unisensory) stimulation, while no differences were found in later time windows and other cortical areas. These results suggest that inverse effectiveness is an important aspect of multi sensory processing in the somato-sensory and frontal cerebral cortices. PMID- 25514336 TI - Thalamocortical integration of instrumental learning and performance and their disintegration in addiction. AB - A recent focus of addiction research has been on the effect of drug exposure on the neural processes that mediate the acquisition and performance of goal directed instrumental actions. Deficits in goal-directed control and a consequent dysregulation of habit learning processes have been described as resulting in compulsive drug seeking. Similarly, considerable research has focussed on the motivational and emotional changes that drugs produce and that result in changes in the incentive processes that modulate goal-directed performance. Although these areas have developed independently, we argue that the effects they described are likely not independent. Here we hypothesize that these changes result from a core deficit in the way the learning and performance factors that support goal-directed action are integrated at a neural level to maintain behavioural control. A dorsal basal ganglia stream mediating goal-directed learning and a ventral stream mediating various performance factors find several points of integration in the cortical basal ganglia system, most notably in the thalamocortical network linking basal ganglia output to a variety of cortical control centres. Recent research in humans and other animals is reviewed suggesting that learning and performance factors are integrated in a network centred on the mediodorsal thalamus and that disintegration in this network may provide the basis for a 'switch' from recreational to dysregulated drug seeking resulting in the well documented changes associated with addiction. PMID- 25514337 TI - Patellar fractures--a review of classification, genesis and evaluation of treatment. AB - The patellar bone is involved in repetitive, load bearing motion sequences every day and functions as a vectorial force translator. A fracture rate of 1% of all skeletal fractures is reported and surgical treatment often required. beside a direct trauma mechanism, indirect mechanism but as well as fatigue fractures after reconstructive knee surgery are published. The fracture management is dependent on the soft tissue condition and a variety of surgical options are known. new generation of low profile plates show promising results but the conventional cerclage wiring technique with K-wires is widely preferred. best functional results with sustainable stability are biomechanically seen after a combined fixation technique using anterior cerclage wiring with cannulated screw fixation. A definite algorithm of treatment of patellar bone fractures is yet not defied but a review of classification and surgical techniques should give assistance in decision making. PMID- 25514338 TI - The risk of neurovascular injury in minimally invasive plate osteosynthesis (MIPO) when using a distal tibia anterolateral plate: a cadaver study. AB - PURPOSE OF THE STUDY: Percutaneous plating of the distal tibia via a limited incision is an accepted technique of osteosynthesis for extra-articular and simple intra-articular distal tibia fractures. The aim of this study was to analyze structures that are at risk during this approach. MATERIAL AND METHODS: Thirteen unpaired adult lower limbs were used for this study. Thirteen, 15-hole LCP anterolateral distal tibial plates were percutaneously inserted according to the recommended technique. Dissection was performed to examine the relation of the superficial and deep peroneal nerves and anterior tibial artery relative to the plate. RESULTS: The superficial peroneal nerve was found to cross the vertical limb of the LCP plate at a mean distance of 63 mm (screw hole five) but with a wide range of 21 to 105 mm. The neurovascular bundle (deep peroneal nerve and anterior tibial artery) crossed the plate at a mean of 76 mm (screw hole six) but also with a wide range of 38 to 138 mm. The zone of danger of the neurovascular structures ranges from 21 to 138 mm from the tibial plafond. In one specimen, a significant branch of the deep peroneal nerve was found to be entrapped under the plate. CONCLUSION: Caution is advised when using anterolateral minimally invasive technique for plate insertion and screw placement in the distal tibia due to great variability in the neurovascular structures that course distally in the lower leg and cross the ankle. PMID- 25514339 TI - [Correction of kyphotic deformity of the cervical spine in ankylosing spondylitis using pedicle subtraction osteotomy of the seventh cervical vertebra]. AB - PURPOSE OF THE STUDY: The aim of the study is to present the technique of pedicle subtraction osteotomy (PSO) of the seventh cervical vertebra (C7) for correction of rigid kyphotic deformity of the cervicothoracic junction (C/Th) in patients with severe ankylosing spondylitis (AS).. MATERIAL AND METHODS: The PSO technique for correction of rigid deformity of the C/Th spine was used in five patients with the aim to restore their ability of horizontal vision. The follow-up in all patients lasted two years at least. Clinical assessment of treatment results was based on the patients' neurological status and their satisfaction with the correction achieved. Improvement in a vertical 2) line of sight was evaluated using the angle measured between the forehead-chin line and the vertical (FCv angle) in a lateral view photograph of the standing patient. The achieved correction of kyphotic deformity was assessed by comparing the pre-operative Cobb's angle between the second cervical and the fourth thoracic vertebra with the post-operative one. RESULTS: The average operative time was 4 hours (range, 3.5 to 5 h). The average blood loss was 1600 ml (range, 800 to 2100 ml). On the average, the FCv angle was reduced by 45.2 degrees and Cobb's angle was corrected) by 54.6 degrees . All patients were satisfied with the degree of correction achieved and reported alleviation of neck pain. none of the patients showed any significant loss of correction or neurological deterioration at two year follow-up. DISCUSSION: The theoretical and technical principles of corrective osteotomy at the C7 level performed for rigid kyphotic deformity of the spine at the C/Th junction are presented in our group of patients. Our results give support to the superiority of instrumented PSO used currently over the previous techniques. In accordance with the relevant literature data, attention is drawn to a relatively higher risk of this procedure in comparison with corrective surgery performed at the other spinal levels. CONCLUSIONS: Corrective osteotomy of a rigid kyphotic deformity at the C/Th spine level in AS patients involves a complex reconstructive surgical procedure. The PSO technique reduces the risk of injury to the visceral structures ventral to the spine, and provides optimal conditions for bone healing at the site of vertebral body resection. If the patient heals well, a successful PSO procedure will markedly improve the quality of his/her life. PMID- 25514340 TI - [Surgery for degenerative spondylolisthesis of the lumbar spine using intra articular fusion. A prospective study]. AB - PURPOSE OF THE STUDY: The aim of the study is to present our surgical method of treating degenerative spondylolisthesis, which includes radical bilateral laminectomy to relieve compression on the spinal cord, transpedicular fixation of the segment and arthrodesis by bilateral intra-articular fusion. MATERIAL AND METHODS: This surgery was indicated in patients with grade I or grade II of degenerative sponylolisthesis with a 4-mm or more slippage. Our prospectively studied group consisted of 46 patients (17 men, 29 women; average age, 64.2 years; range, 39-84 years). Before surgery and at 1 year after the procedure, the intensity of axial pain and that of radicular pain were each assessed using the visual Analogue Scale (VAS). Difficulty in performing daily living activities was measured by the Oswestry Disability Index (ODI). The surgical procedure included laminectomy, partial medial facetectomy, foraminotomy to relieve pressure on the spinal nerve roots and transpedicular fixation to provide stability. Using a cutter, cartilage was separated off the cortical bone and, in order to facilitate fusion, bone cavities thus produced were filed with corticospongious grafts harvested from the removed vertebral arch with Kerrison forceps. At 1-year follow up, dynamic X-ray was used to evaluate spine alignment and, on a CT scan, the degree of intra-articular fusion was assessed. Fusion was achieved when bone density measurement showed more than 350 Hounsfield Units (HU). For the measurements, the authors used their own modified method by means of a Region of Interest (ROI) analysis. The clinical and radiographic results were statistically evaluated. RESULTS: At 1 year after surgery, lumbar flexion-extension bending X ray films revealed stability of the treated segments in all patients (100%). CT examination showed bone density higher than 350 HU at both joints, i.e., complete bone fusion, also in all 46 patients. The mean post-operative ODI score was significantly lower than its mean pre-operative value (23.6 vs 55.4), which was improvement by 57.4%. The differences in pre- and post-operative VAS scores were also statistically significant. The mean VAS score for low back pain decreased from 7.61 to 1.74, i.e., improvement by 77.1%, and the mean vAS score for radicular pain dropped from 6.98 to 1.24, i.e., improvement by 82.2%. Assessed by Odom's outcome criteria, the results were excellent in 26 patients and very good in 20 patients, and they were not related to age, gender or the spinal level treated. Any complications associated with the operative procedure or wound healing and requiring repeated surgical treatment were not recorded. DISCUSSION: The surgical technique described here has advantages over other methods in reliable achieving nerve decompression, joint fusion and spinal stability at low costs and short operative time. In addition, it avoids the necessity of harvesting bone from the iliac crest. CONCLUSIONS: At 1-year follow-up all patients showed better health conditions, with improvement in average scores for the ODI by 57%, for low back pain by 77% and for radicular and claudication pain by 82%. The technique of intra-articular fusion for treatment of degenerative spondylolisthesis resulted in solid bone fusion and spinal stability in all patients. PMID- 25514341 TI - [Femoroacetabular impingement syndrome: first experience with surgical treatment]. AB - PURPOSE OF THE STUDY: Femoroacetabular impingement syndrome (FAI) represents a mechanical conflict between acetabulum and proximal part of the femur. This disorder may gradually result in the development of the hip osteoarthritis. FAI may be caused by an acetabular retroversion, rarely by coxa profunda or by asphericity of the femoral head and missing femoral head-neck offset respectively. However, a combination of both conditions is the most frequent. Before FAI treatment was adopted as a standard technique for hip preservation at our department, detailed cadaver studies of the vascular anatomy of the hip were performed and the relevant literature was reviewed. The aim of this study was to assess the efficiency of hip preserving surgery in relation to the technique used. We hypothesized that surgical intervention helped to alleviate pain and improve hip function. MATERIAL AND METHODS: In the period from October 11, 2005 to June 30, 2012, a total of 168 patients (190 hips) had surgery for FAI. After we met exclusion criteria, 83 hips were treated by surgical hip dislocation (SHD) and 17 undergoing anterior minimally invasive surgery (AMIS). The minimum follow up was 12 months, with an average of 3 years and 4 months, and a range of 12 months to 7 years and 8 months. The subjective evaluation by the patients and the functional hip assessment were based on the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the non-Arthritic Hip Score (nAHS) questionnaires. To assess the efficiency of the techniques, the pre- and post operative scores were compared in each group (SHD group, n=83; AMIS group, n=17). A comparison of pre- and post-operative data was also made for the groups joined together to evaluate the benefit of surgery as such in FAI treatment. The results were statistically analysed using the Wilcoxon test for paired samples; the level of significance was set at 0.05. RESULTS: There was a statistically significant increase in the scores obtained after surgery, as compared with the pre-operative data, in the SHD and AMIS groups and in all patients evaluated together. Hip survival without the necessity of conversion to total hip replacement was 96.4% (80/83 hips) in the SHD group and 94.1% (16/17 hips) in the AMIS group. no serious complications were recorded. DISCUSSIOn The rate of failure in the surgical treatment of FAI syndrome in our patients was in accordance with the literature data, as was the number of the patients requiring conversion to total hip replacement. Also the other results were comparable with those of relevant studies. CONCLUSIONS: Hip preservation surgery is an issue which has slowly been gaining consensus although opinions on it, including FAI surgical treatment, still vary. As FAI syndrome is a condition leading to degenerative changes in the hip, it is important to pay attention to a thorough diagnostic evaluation and a correct, though often long-term, therapy. PMID- 25514342 TI - [Shape-memory osteosynthesis for trapeziometacarpal joint arthrodesis]. AB - PURPOSE OF THE STUDY: Arthrodesis of the trapeziometacarpal joint is the method of choice in the treatment of degenerative arthritis of this joint. This procedure was indicated most frequently in middle-age patients doing hard manual labor. Methods for achieving a solid fusion of the trapeziometacarpal joint are known and often reported in the literature. Frequently, they are associated with some failure rate, particularly as concerns bone union. Our study presents a simple and effective method verified in cadaver specimens and then currently used at our department. MATERIAL AND METHODS: The procedure for arthrodesis of the trapeziometacarpal joint was verified fist in fixed wrist and hand specimens at the Institute of Anatomy, 1 st Faculty of Medicine, Charles University in Prague. If the original shape of the basal thumb joint between the trapezium and the metacarpal is maintained, it allows for correct reduction and subsequent arthrodesis in a required position. In patients, surgical treatment included the use of implants, two DePuy shape-memory staples, which facilitate sufficient fragment compression and provide stable fixation. The staples were inserted in pre-drilled and gauged tunnels in the body of the trapezium and in the proximal metaphysis of the fist metacarpal. RESULTS: Between 2011 and 2014, the procedure was used in 14 patients diagnosed with primary arthritis of the trapeziometacarpal joint. The group comprised nine women and five men, the average age was 52 years and the range was 44 to 69 years. Surgery was most frequently carried out on the dominant upper extremity (85%); there was no bilateral surgery. The average follow-up was 18.3 months (range, 5 to 39 months). Solid fusion was recorded at 7 weeks after surgery in all patients except for the one still treated at the time of this paper submission. All patients were free of pain, ten reported satisfaction with grip strength and hand function, the rest would have preferred improvement in fine motor skills of the thumb. All of them found the cosmetic appearance of the hand satisfactory.. DISCUSSION: The methods generally used for trapeziometacarpal joint arthrodesis are reported to carry some risk of pseudarthrosis development. A lot of modifications have been described, from conventional procedures using AO lag screws or Kirschner wires to up-to-date plate systems involving angle-stable fixation. Total fusion of the trapeziometacarpal joint is disputable in patients with rheumatoid arthritis from the technical point of view as well as the relevance of indication criteria. Some authors consider this procedure a contraindication for patients with rheumatoid arthritis. The use of joint replacement in treating trapeziometacarpal joint arthritis is another complex issue. CONCLUSIONS: An arthrodesis of the trapeziometacarpal joint based on careful assessment of indication criteria proved to be a simple, effective and low-cost method of stable osteosynthesis that provided good conditions for solid fusion of the trapezium with the base of the fist metacarpal. It allowed for sufficient abduction and opposition of the thumb, thus permitting satisfactory hand grip strength and full involvement in everyday life activities and occupations. It provided stability of the thumb, its painless movement and good cosmetic looks. PMID- 25514343 TI - Is platelet-rich plasma injection an effective choice in cases of non-union? AB - PURPOSE OF THE STUDY: By the expression of several growth factors from activated thrombocytes, the application of Platelet Rich Plasma (PRP) stimulates angiogenesis and regeneration thus stimulating recovery through cell differentiation. This study aimed to evaluate the effects of PRP injection on patients who had undergone surgery for fracture and in whom delayed union or nonunion had been determined. MATERIAL AND METHODS: The study comprised 20 patients (male 17, female 3; median age 33.5 range 15-77) who had undergone lower extremity fracture surgery and were diagnosed with aseptic delayed union (8 patients) or non-union (12 patients). Blood taken from the patients was centrifuged to separate PRP, which was then activated by calcium chloride. The prepared PRP was injected into the fracture line under fluoroscopy guidance for totally three times once a week. The application of PRP was made at median 6 (range 6-8) months after fracture surgery. All patients were followed-up with clinical examinations and radiographs over a median period of 11 (range 8-12) months. RESULTS: Fracture union was achieved in six patients at median 15 (range 8-24) weeks. There was non-union of the fracture in eleven patients during the follow-up period and these patients underwent revision surgery. Sufficient union was not determined radiologically and clinically in three patients. Fracture union was achieved in six of eight patients in the delayed union group. There was no patient in the non-union group with fracture union. CONCLUSIONS: Fracture healing is a process affected by many factors. Although PRP has been reported in literature to be a biological treatment which increases healing, adequate healing was not determined in the treatment of non-union with PRP injection. However, in selected patients determined with delayed union, PRP injection can be recommended in non-surgical treatment. PMID- 25514345 TI - Leukemia inhibitory factor tips the immune balance towards regulatory T cells in multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), for which current treatments are unable to prevent disease progression. Based on its neuroprotective and neuroregenerating properties, leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is proposed as a novel candidate for MS therapy. However, its effect on the autoimmune response remains unclear. In this study, we determined how LIF modulates T cell responses that play a crucial role in the pathogenesis of MS. We demonstrate that expression of the LIF receptor was strongly increased on immune cells of MS patients. LIF treatment potently boosted the number of regulatory T cells (Tregs) in CD4(+) T cells isolated from healthy controls and MS patients with low serum levels of IL-6. Moreover, IL-6 signaling was reduced in the donors that responded to LIF treatment in vitro. Our data together with previous findings revealing that IL-6 inhibits Treg development, suggest an opposing function of LIF and IL-6. In a preclinical animal model of MS we shifted the LIF/IL-6 balance in favor of LIF by CNS-targeted overexpression. This increased the number of Tregs in the CNS during active autoimmune responses and reduced disease symptoms. In conclusion, our data show that LIF downregulates the autoimmune response by enhancing Treg numbers, providing further impetus for the use of LIF as a novel treatment for MS and other autoimmune diseases. PMID- 25514346 TI - Effectively suppressing dissolution of manganese from spinel lithium manganate via a nanoscale surface-doping approach. AB - The capacity fade of lithium manganate-based cells is associated with the dissolution of Mn from cathode/electrolyte interface due to the disproportionation reaction of Mn(III), and the subsequent deposition of Mn(II) on the anode. Suppressing the dissolution of Mn from the cathode is critical to reducing capacity fade of LiMn2O4-based cells. Here we report a nanoscale surface doping approach that minimizes Mn dissolution from lithium manganate. This approach exploits advantages of both bulk doping and surface-coating methods by stabilizing surface crystal structure of lithium manganate through cationic doping while maintaining bulk lithium manganate structure, and protecting bulk lithium manganate from electrolyte corrosion while maintaining ion and charge transport channels on the surface through the electrochemically active doping layer. Consequently, the surface-doped lithium manganate demonstrates enhanced electrochemical performance. This study provides encouraging evidence that surface doping could be a promising alternative to improve the cycling performance of lithium-ion batteries. PMID- 25514344 TI - Transcriptome analysis of chicken ES, blastodermal and germ cells reveals that chick ES cells are equivalent to mouse ES cells rather than EpiSC. AB - Pluripotent Embryonic Stem cell (ESC) lines can be derived from a variety of sources. Mouse lines derived from the early blastocyst and from primordial germ cells (PGCs) can contribute to all somatic lineages and to the germ line, whereas cells from slightly later embryos (EpiSC) no longer contribute to the germ line. In chick, pluripotent ESCs can be obtained from PGCs and from early blastoderms. Established PGC lines and freshly isolated blastodermal cells (cBC) can contribute to both germinal and somatic lineages but established lines from the former (cESC) can only produce somatic cell types. For this reason, cESCs are often considered to be equivalent to mouse EpiSC. To define these cell types more rigorously, we have performed comparative microarray analysis to describe a transcriptomic profile specific for each cell type. This is validated by real time RT-PCR and in situ hybridisation. We find that both cES and cBC cells express classic pluripotency-related genes (including cPOUV/OCT4, NANOG, SOX2/3, KLF2 and SALL4), whereas expression of DAZL, DND1, DDX4 and PIWIL1 defines a molecular signature for germ cells. Surprisingly, contrary to the prevailing view, our results also suggest that cES cells resemble mouse ES cells more closely than mouse EpiSC. PMID- 25514347 TI - Divalent folate modification on PEG: an effective strategy for improving the cellular uptake and targetability of PEGylated polyamidoamine-polyethylenimine copolymer. AB - The stability and targeting ability of nanocarrier gene delivery systems are necessary conditions to ensure the good therapeutic effect and low nonspecific toxicity of cancer treatment. Poly(ethylene glycol) (PEG) has been widely applied for improving stability and as a spacer for linking ligands and nanocarriers to improve targetability. However, the cellular uptake and endosomal escape capacity of nanocarriers has been seriously harmed due to the introduction of PEG. In the present study, we synthesized a new gene delivery vector by coupling divalent folate-PEG (PEG3.4k-FA2) onto polyamidoamine-polyethylenimine (PME) copolymer (PME-(PEG3.4k-FA2)1.72). Both PEG and monovalent folate-PEG (PEG3.4k-FA1) modified PME were prepared as control polymers, which were named as PME (PEG3.5k)1.69 and PME-(PEG3.4k-FA1)1.66, respectively. PME-(PEG3.4k-FA2)1.72 exhibited strong DNA condensation capacity like parent polymer PME which was not significantly influenced by PEG. PME-(PEG3.4k-FA2)1.72/DNA complexes at N/P = 10 had a diameter ~143 nm and zeta potential ~13 mV and showed the lowest cytotoxicity and hemolysis and the highest transfection efficiency among all tested polymers. In folate receptor positive (FR-positive) cells, the cellular uptake and transfection efficiency were increased with the increase in the number of folates coupled on PEG; the order was PME-(PEG3.4k-FA2)1.72 > PME-(PEG3.4k FA1)1.66 > PME-(PEG3.5k)1.69. Folate competition assays showed that PME-(PEG3.4k FA2)1.72 complexes had stronger targeting ability than PME-(PEG3.5k)1.69 and PME (PEG3.4k-FA1)1.66 complexes due to their higher folate density per PEG molecule. Cellular uptake mechanism study showed that the folate density on PEG could change the endocytosis pathway of PME-(PEG3.5k)1.69 from clathrin-mediated endocytosis to caveolae-mediated endocytosis, leading to less lysosomal degradation. Distribution and uptake in 3D multicellular spheroid assays showed that divalent folate could offer PME-(PEG3.4k-FA2)1.72 complexes stronger penetrating ability and higher cellular uptake. With these advantages, PME (PEG3.4k-FA2)1.72 may be a promising nonviral vector candidate for efficient gene delivery. This study also indicates that divalent folate modification on PEG can serve as an efficient strategy to improve the cellular uptake and targeting ability of PEGylated cationic polymers for gene delivery. PMID- 25514348 TI - Feasibility and reproducibility of echo planar spectroscopic imaging on the quantification of hepatic fat. AB - OBJECTIVES: 1H-MRS is widely regarded as the most accurate noninvasive method to quantify hepatic fat content (HFC). When practical period of breath holding, and acquisition of HFC over multiple liver areas is considered, a fast MR spectroscopic imaging technique is desired. The aim of this study is to examine the feasibility and reproducibility of echo planar spectroscopic imaging (EPSI) on the quantification of HFC in subject with various HFCs. METHODS: Twenty two volunteers were examined in a 3T MR system. The acquisition time of proposed EPSI protocol was 18 seconds. The EPSI scans were repeated 8 times for each subject to test reproducibility. The peak of water and individual peaks of fat including methyl, methylene, and allylic peaks at 0.9, 1.3, and 2.0 ppm were fitted. Calculated amount of water and fat content were corrected for T2 relaxation. The total HFC was defined as the combination of individual peaks. Standard deviation (SD), coefficient of variance (COV) and fitting reliability of HFC quantified by LCModel were calculated. RESULTS: Our results show that the SDs of total HFC for all subjects are less than 2.5%. Fitting reliability is mostly under 10% and positively correlates with COV. Subjects separated into three subgroups according to quantified total HFC show that improved fitting reliability and reproducibility can be achieved on subjects with higher total HFC. CONCLUSIONS: We have demonstrated feasibility of the proposed EPSI protocols on the quantification of HFC over a whole slice of liver with scan time in a single breath hold. PMID- 25514349 TI - Role of a double docking to improve lymph node dissection: when robotically assisted laparoscopy for para-aortic lymphadenectomy is associated to a pelvic procedure. AB - OBJECTIVE: The objective of this study was to demonstrate that robotically assisted laparoscopy for aortic lymph node dissection was improved when double docking (DD) of the Da Vinci system is used for combined surgical procedures [defined by the combination of a pelvic procedure and a para-aortic lymphadenectomy (PAL)]. METHODS: From February 2007 to February 2013, 41 patients underwent combined procedures including PAL up to the left renal vein in 2 cancer centers. We used 2 different approaches as follows: a single docking (SD) of the Da Vinci system (transperitoneal PAL and pelvic surgery) during the first period (22 patients) and a DD during the second period (19 patients). We recorded retrospectively the lymph node count (main criteria), operative time, estimated blood loss, hospital stay, and postoperative complications. RESULTS: We observed a statistical difference between SD and DD concerning aortic lymph node count (5.86 vs 10.89, P < 0.005). Operative time is longer in the DD group (326.1 vs 239.4 minutes, P < 0.05). No difference was observed concerning estimated blood loss. Hospital stay was longer in the DD group (4.9 vs 3.2 days, P < 0.05). Only 1 conversion to open was described in the SD group. CONCLUSIONS: In our experience of robotically assisted laparoscopy, when PAL is combined to a pelvic procedure, the use of a DD seems to improve aortic lymph node count.Despite a longer operative time compared to SD, DD seems to be a good solution to combine the advantages of robotic assistance to our quality criteria of aortic dissection. SYNOPSIS: We compare 2 techniques to realize robotic assisted para aortic lymphadenectomy combined with pelvic procedure. Double docking seems to improve histological results compared to single docking. PMID- 25514350 TI - Dkk-3 induces apoptosis through mitochondrial and Fas death receptor pathways in human mucinous ovarian cancer cells. AB - OBJECTIVE: Dkk-3 is a Wnt signaling inhibitor that is frequently inactivated in human cancers. Dkk-3 possesses an antiproliferative activity and induces apoptosis in tumor cells, suggesting that it functions as a tumor suppressor. In this study, we investigated the molecular function of Dkk-3 in human ovarian cancer cells. METHODS: We assessed the levels of Dkk-3 protein expression in human mucinous and clear cell ovarian cancer cells, and compared cell viabilities between cell lines that expressed Dkk-3 and those that did not, as well as between cells that expressed Dkk-3 and those whose expression of Dkk-3 was reduced by small interfering RNA. We also evaluated the characteristic fragmentation of DNA to detect apoptosis in Dkk-3-deficient cells. To further investigate the molecular mechanisms of apoptosis, we assessed the expression of molecules involved in apoptosis signaling pathways in Dkk-3-deficient cells. RESULTS: The expression of the Dkk-3 protein was observed in most of the ovarian cancer cell lines tested. Dkk-3-deficient cells showed faster growth than Dkk-3 replete cells. The characteristic fragmentation of DNA was not observed in Dkk-3 deficient cells, which showed decreased levels of expression in caspase-3, activated caspase-9, Bax, p53, activated caspase-8, and Fas/CD95, as well as an increase in Bcl-2 expression. CONCLUSIONS: Although Dkk-3 expression was observed in most of human ovarian cancer cell lines, Dkk-3 has a tumor-suppressive function and a proapoptotic effect, inducing apoptosis through mitochondrial and Fas death receptor pathways in human mucinous ovarian cancer MCAS cells. PMID- 25514351 TI - Acute generalized exanthematous pustulosis possibly induced by isoniazid in a patient with psoriatic erythroderma. PMID- 25514352 TI - Flexible microfabricated film sensors for the in situ quantum dot-based voltammetric detection of DNA hybridization in microwells. AB - A new flexible miniaturized integrated device was microfabricated for the in situ ultrasensitive voltammetric determination of DNA mutation in a microwell format, using quantum dots (QDs) labels. The integrated device consisted of thin Bi, Ag, and Pt films (serving as the working, reference, and counter electrode, respectively) deposited by sputtering on a flexible polyimide substrate. A DNA assay was employed in microwell format, where an immobilized complementary oligonucleotide probe hybridized with the biotinylated target oligonucleotide followed by reaction with streptavidin-conjugated PbS QDs. After the acidic dissolution of the QDs, the flexible sensor was rolled and inserted into the microwell and the Pb(II) released was determined in situ by anodic stripping voltammetry. Since the analysis took place directly in the microwell, the volume of the working solution was only 100 MUL and the target DNA could be detected at a concentration down to 1.1 fmol L(-1). The proposed flexible microdevice addresses the restrictions of conventional rigid electrodes while it provides a low cost integrated transducer for the ultrasensitive detection of important biomolecules. PMID- 25514353 TI - A hybrid open-framework structure containing different manganese phosphate chains as its building blocks. AB - An open-framework hybrid solid with two different types of manganese phosphate chains has been synthesized under solvent-free conditions. A type I chain consists of isolated Mn2O10 dimers, while a type II chain contains an infinite Mn O-Mn chain constructed from corner-sharing Mn2O10 dimers. The compound shows ferrimagnetic behavior, which is different from the antiferromagnetic behavior for its structural analogue that only contains type I manganese phosphate chains. PMID- 25514354 TI - Tailored surface-enhanced Raman nanopillar arrays fabricated by laser-assisted replication for biomolecular detection using organic semiconductor lasers. AB - Organic semiconductor distributed feedback (DFB) lasers are of interest as external or chip-integrated excitation sources in the visible spectral range for miniaturized Raman-on-chip biomolecular detection systems. However, the inherently limited excitation power of such lasers as well as oftentimes low analyte concentrations requires efficient Raman detection schemes. We present an approach using surface-enhanced Raman scattering (SERS) substrates, which has the potential to significantly improve the sensitivity of on-chip Raman detection systems. Instead of lithographically fabricated Au/Ag-coated periodic nanostructures on Si/SiO2 wafers, which can provide large SERS enhancements but are expensive and time-consuming to fabricate, we use low-cost and large-area SERS substrates made via laser-assisted nanoreplication. These substrates comprise gold-coated cyclic olefin copolymer (COC) nanopillar arrays, which show an estimated SERS enhancement factor of up to ~ 10(7). The effect of the nanopillar diameter (60-260 nm) and interpillar spacing (10-190 nm) on the local electromagnetic field enhancement is studied by finite-difference-time-domain (FDTD) modeling. The favorable SERS detection capability of this setup is verified by using rhodamine 6G and adenosine as analytes and an organic semiconductor DFB laser with an emission wavelength of 631.4 nm as the external fiber-coupled excitation source. PMID- 25514355 TI - Assembly and catalysis of molybdenum or tungsten-containing formate dehydrogenases from bacteria. AB - The global carbon cycle depends on the biological transformations of C1 compounds, which include the reductive incorporation of CO2into organic molecules (e.g. in photosynthesis and other autotrophic pathways), in addition to the production of CO2from formate, a reaction that is catalyzed by formate dehydrogenases (FDHs). FDHs catalyze, in general, the oxidation of formate to CO2and H+. However, selected enzymes were identified to act as CO2reductases, which are able to reduce CO2to formate under physiological conditions. This reaction is of interest for the generation of formate as a convenient storage form of H2for future applications. Cofactor-containing FDHs are found in anaerobic bacteria and archaea, in addition to facultative anaerobic or aerobic bacteria. These enzymes are highly diverse and employ different cofactors such as the molybdenum cofactor (Moco), FeS clusters and flavins, or cytochromes. Some enzymes include tungsten (W) in place of molybdenum (Mo) at the active site. For catalytic activity, a selenocysteine (SeCys) or cysteine (Cys) ligand at the Mo atom in the active site is essential for the reaction. This review will focus on the characterization of Mo- and W-containing FDHs from bacteria, their active site structure, subunit compositions and its proposed catalytic mechanism. We will give an overview on the different mechanisms of substrate conversion available so far, in addition to providing an outlook on bio-applications of FDHs. This article is part of a Special Issue entitled: Cofactor-dependent proteins: evolution, chemical diversity and bio-applications. PMID- 25514356 TI - Association of genetic polymorphisms of EGFR with glioma in a Chinese population. AB - OBJECTIVE: Several studies indicated that genetic polymorphisms in the epidermal growth factor receptor (EGFR) gene were associated with glioma risk. However, the relationship between EGFR genetic polymorphisms and glioma remains unclear in the Chinese population. METHODS: We designed a case-control study by selecting 300 histologically confirmed adult glioma patients and 300 cancer-free controls to analyze the distribution of EGFR genotype. Two single-nucleotide polymorphisms, rs730437 and rs1468727, were genotyped by using the polymerase chain reaction restriction fragment length polymorphism method. RESULTS: We found that the CC genotype of rs1468727 was more common in the glioma group than in the control group (p=0.021). We also found that the C allele frequency was higher in the glioma group than that in the control group (p=0.005; odds ratio [OR]=1.38, 95% confidence interval [CI]: 1.101-1.740). For rs730437, we found both the AA genotype (p=0.011) and A allele frequency (p=0.003; OR=0.703; 95% CI: 0.558 0.886) were significantly lower in the glioma patients than in the control subjects, respectively. Haplotype analysis showed that the A T haplotype frequency was higher in the control group than in the glioma group (p=0.005; OR=0.722; 95% CI: 0.575-0.908). However, the CC haplotype frequency was higher in the glioma group than in the control group (p=0.003; OR=1.423; 95% CI: 1.129 1.793). CONCLUSION: Our study indicates that polymorphisms in the EGFR gene are associated with glioma susceptibility in the Chinese population. PMID- 25514357 TI - (+/-)-Melicolones A and B, rearranged prenylated acetophenone stereoisomers with an unusual 9-oxatricyclo[3.2.1.1(3,8)]nonane core from the leaves of Melicope ptelefolia. AB - Melicolones A (1) and B (2), a pair of rearranged prenylated acetophenone epimers with an unusual 9-oxatricyclo[3.2.1.1(3,8)]nonane core, were isolated from the leaves of Melicope ptelefolia. Further chiral high-performance liquid chromatography resolution gave enantiomers (+)- and (-)-1, as well as (+)- and ( )-2, respectively. The structures and absolute configurations of the pure enantiomers were determined by extensive spectroscopic data and single crystal X ray diffraction. All the isolated enantiomers exhibited potent cell protecting activities against high glucose-induced oxidative stress in human vein endothelial cells. PMID- 25514358 TI - Encapsulation into carbon nanotubes and release of anticancer Cisplatin drug molecule. AB - Molecular dynamics simulations have been investigated to study the interactions between single-wall carbon nanotubes and an anticancer agent Pt complex (Cisplatin). The optimized diameter of the vector system has been determined to encapsulate in the best conditions the drug molecules. The simulation results show also that several drug molecules can be adsorbed inside the nanotubes, leading to an increased confinement time. Moreover, our simulations show that the release of the drug near a cell membrane model is favored, opening the way to a natural drug nanocapsule. PMID- 25514359 TI - Association between serum bilirubin and estimated glomerular filtration rate among elderly persons. AB - Chronic kidney disease (CKD) is a major public health problem. However, few studies have examined the significance of serum bilirubin as a risk factor for the development of CKD in the general Japanese population. The subjects comprised 413 men (mean age: 79+/-9 years; (range, 60-100 years) and 637 women (mean age: 81+/-8 years; range, 60-106 years) who visited the medical department of Seiyo Municipal Nomura Hospital. We examined the relationship between increased serum bilirubin and renal function that was evaluated by estimated glomerular filtration rate (eGFR) using CKD-EPI equations modified by a Japanese coefficient. Stepwise multiple regression analysis with eGFR as the objective variable, and adjusted risk factors as the explanatory variables, showed that serum bilirubin (beta = 0.11, P<0.001) was significantly and independently associated with eGFR, in addition to gender, age, prevalence of antihypertensive medication, triglycerides, prevalence of antidiabetic medication, and serum uric acid. Compared with stages 1+2 (eGFR >=60.0 ml/min/1.73 m2), mean multivariate adjusted odds ratio {95% (confidence interval (CI)} for hypobilirubinemia (first quartile, <0.52 mg/dL) was 3.52 (range: 1.88-6.59). Next, to control potential confounding factors, data were further stratified by gender, age, medication (antihypertensive, antidyslipidemic, and antidiabetic agents), and prevalence of cardiovascular disease. The standardized coefficient for eGFR was significant in both groups, and there was no interaction between the groups. Our data demonstrated an independent positive association between serum bilirubin and eGFR in both genders. Low serum bilirubin level would be useful as a potential risk factor for renal function. PMID- 25514361 TI - Rasagiline, a suicide inhibitor of monoamine oxidases, binds reversibly to alpha synuclein. AB - Rasagiline (N-propargyl-1-R-aminoindan) and selegiline (1-deprenyl) are MAO-B inhibitors which are used in the treatment of Parkinson's disease. The binding of rasagiline, selegiline, and their metabolites including 1-aminoindan, 2 aminoindan, and methamphetamine to alpha-synuclein was investigated by nanopore analysis and isothermal titration calorimetry. Blockade current histograms of alpha-synuclein alone give a peak at -86 pA which is due to translocation of the protein through the pore. In the presence of rasagiline and R-1-aminoindan, this peak shifts to about -80 pA. In the presence of selegiline and R-methamphetamine, the number of events at -86 pA is reduced and there is a higher proportion of bumping events at about -25 pA which are due to a more compact conformation. Rasagiline can also bind to sites in both the N- and C-terminal regions of alpha synuclein. The binding constants of rasagiline and selegiline were estimated by isothermal titration calorimetry to be about 5 * 10(5) and <10(4) M(-1), respectively. A model is presented in which both rasagiline and R-1-aminoindan bind to alpha-synuclein, forming a loop structure which is less likely to aggregate or form fibrils. In contrast, selegiline binds and forms a more compact structure similar to that formed by methamphetamine. PMID- 25514362 TI - Enhancing surface methane fluxes from an oligotrophic lake: exploring the microbubble hypothesis. AB - Exchange of the greenhouse gases carbon dioxide (CO2) and methane (CH4) across inland water surfaces is an important component of the terrestrial carbon (C) balance. We investigated the fluxes of these two gases across the surface of oligotrophic Lake Stechlin using a floating chamber approach. The normalized gas transfer rate for CH4 (k600,CH4) was on average 2.5 times higher than that for CO2 (k600,CO2) and consequently higher than Fickian transport. Because of its low solubility relative to CO2, the enhanced CH4 flux is possibly explained by the presence of microbubbles in the lake's surface layer. These microbubbles may originate from atmospheric bubble entrainment or gas supersaturation (i.e., O2) or both. Irrespective of the source, we determined that an average of 145 L m(-2) d(-1) of gas is required to exit the surface layer via microbubbles to produce the observed elevated k600,CH4. As k600 values are used to estimate CH4 pathways in aquatic systems, the presence of microbubbles could alter the resulting CH4 and perhaps C balances. These microbubbles will also affect the surface fluxes of other sparingly soluble gases in inland waters, including O2 and N2. PMID- 25514360 TI - Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease. AB - Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P < 9.57 * 10(-8)). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57 * 10(-8) < P <= 4.6 * 10(-6)). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57 * 10(-9)) and MYH15 (P = 1.62 * 10(-6)), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness. PMID- 25514363 TI - In vivo evaluation of a novel 'diastole-patching' algorithm for the estimation of pulse transit time: advancing the precision in pulse wave velocity measurement. AB - Carotid-to-femoral pulse wave velocity (PWV) is the gold standard for the assessment of aortic stiffness. It is calculated by the ratio of pulse transit time (PTT) between two arterial sites and the distance between them. The precision of PTT estimation depends upon the algorithm that determines characteristic points at the foot of the pulse waveforms. Different algorithms yield variable PTT values thus affecting the precision of PWV and subsequently its diagnostic and prognostic accuracy. Our aim was to apply in vivo a new 'diastole-patching' algorithm and investigate whether it improves the precision of PWV measurement. Two repeated PWV measurements were performed in a general population (340 subjects) by a reference apparatus (SphygmoCor) which uses the tangential method for PTT estimation. PTT was re-estimated by the 'diastole patching' algorithm. We computed statistical parameters of agreement, consistency, precision and variability between the two PWV measurements. The 'diastole-patching' method yielded more precise and reproducible measurements of PWV compared to the tangential method at the total population. In those cases where the reference method provided PWV measurements with difference >1 m s(-1), the 'diastole-patching' algorithm further improved the precision of PWV. These findings may have direct implications concerning the enhancement of the diagnostic and prognostic value of PWV. PMID- 25514364 TI - On the redox mechanism operating along C2H2 self-assembly at the surface of TiO2. AB - The interaction of acetylene with the TiO2 surface at room temperature entails a complex set of self-assembly reactions with the formation of products having relatively high molecular weight. In a previous paper by some of us (Jain, S. M.; et al. J. Mater. Chem. A 2014, 2, 12247-12254), the C2H2-TiO2 reaction has been monitored, essentially by Fourier transform infrared spectroscopy, at the surface of P25 (a mixture of anatase and rutile, typical benchmark material in the field of photocatalysis) in order to elucidate the nature of the products of this surface reaction. In the present paper, the same process was followed, for the first time, using electron paramagnetic resonance (EPR) and monitoring by the thermogravimetric analysis the weight loss of the material upon heating in order to further investigate the complex mechanism of the surface reaction. This was done using pure anatase and comparing the EPR results with those concerning both rutile and P25. The self-assembly mechanism occurring at the interface is accompanied by the formation of EPR visible Ti(3+) centers due to electrons injection in the TiO2 substrate. This finding clarifies that at least one of the reaction channels of this complex process (namely, the formation of polycyclic aromatic hydrocarbons) is based on the heterolytic dissociative chemisorption of acetylene, followed by a redox interaction between the adsorbate and the solid, which allows the creation of the building blocks necessary to assemble polyaromatic molecules. PMID- 25514365 TI - Vibrational spectra, theoretical calculations, and two-dimensional potential energy surface for the ring-puckering vibrations of 2,4,7-trioxa[3.3.0]octane. AB - 2,4,7-Trioxa[3.3.0]octane (247TOO) is an unusual bicyclic molecule which can exist in four different conformational forms which are determined by the directions of the two ring- puckering motions. The vibrational assignments of 247TOO have been made based on its infrared and Raman spectra and theoretical density functional theory (DFT) calculations. The two ring-puckering motions (in phase and out-of-phase) were observed in the Raman spectra of the liquid at 249 and 205 cm(-1) and these values correspond well to the DFT values of 247 and 198 cm(-1). Ab initio calculations were utilized to calculate the structures and conformational energies for the four energy minima and the barriers to interconversion and the data was utilized to generate a two-dimensional potential energy surface (PES) for the two ring-puckering motions. The resulting quantum state energies for this PES were then calculated in order to better understand the patterns that are produced when the PES has four energy minima at different energy values. The wave functions corresponding to the different quantum states were also calculated. The NMR spectrum of 247TOO showed the presence of the two lowest energy conformations, consistent with the results of the ab initio calculations. PMID- 25514366 TI - The relation between gray matter morphology and divergent thinking in adolescents and young adults. AB - Adolescence and early adulthood are developmental time periods during which creative cognition is highly important for adapting to environmental changes. Divergent thinking, which refers to generating novel and useful solutions to open ended problems, has often been used as a measure of creative cognition. The first goal of this structural neuroimaging study was to elucidate the relationship between gray matter morphology and performance in the verbal (AUT; alternative uses task) and visuo-spatial (CAT; creative ability test) domain of divergent thinking in adolescents and young adults. The second goal was to test if gray matter morphology is related to brain activity during AUT performance. Neural and behavioral data were combined from a cross-sectional study including 25 adolescents aged 15-17 and 20 young adults aged 25-30. Brain-behavior relationships were assessed without a priori location assumptions and within areas that were activated during an AUT-scanner task. Gray matter volume and cortical thickness were not significantly associated with verbal divergent thinking. However, visuo-spatial divergent thinking (CAT originality and fluency) was positively associated with cortical thickness of the right middle temporal gyrus and left brain areas including the superior frontal gyrus and various occipital, parietal, and temporal areas, independently of age. AUT brain activity was not associated with cortical thickness. The results support an important role of a widespread brain network involved in flexible visuo-spatial divergent thinking, providing evidence for a relation between cortical thickness and visuo spatial divergent thinking in adolescents and young adults. However, studies including visuo-spatial divergent thinking tasks in the scanner are warranted. PMID- 25514368 TI - Thermoset elastomers derived from carvomenthide. AB - Renewable thermoset elastomers were prepared using the plant-based monomer carvomenthide. Controlled ring-opening transesterification polymerization of carvomenthide using diethylene glycol as an initiator gave alpha,omega-dihydroxyl poly(carvomenthide) (HO-PCM-OH), which was subsequently converted to carboxy telechelic poly(carvomenthide) (HOOC-PCM-COOH) by esterification with excess succinic anhydride through a one-pot, two-step process, leading to no crystallinity, high viscosity, strong thermal resistance, and low glass transition temperature of the resulting functionalized polyester. Thermal curing processes of the resulting 3, 6, and 12 kg mol(-1) prepolymers were achieved with trifunctional aziridine to give cross-linked PCM elastomers. The thermal properties, mechanical behavior, and biocompatibility of the rubbery thermoset products were investigated by differential scanning calorimetry, thermal gravimetric analysis, dynamic mechanical analysis, tensile tests under static and cyclic loads, and cell adherence. These new materials are useful candidates to satisfy the design objective for the engineering of a variety of soft tissues. PMID- 25514367 TI - DNA methylation profile and expression of surfactant protein A2 gene in lung cancer. AB - Knowledge of the methylation profile of genes allow for the identification of biomarkers that may guide diagnosis and effective treatment of disease. Human surfactant protein A (SP-A) plays an important role in lung homeostasis and immunity, and is encoded by two genes (SFTPA1 and SFTPA2). The goal of this study was to identify differentially methylated CpG sites in the promoter region of the SFTPA2 gene in lung cancer tissue, and to determine the correlation between the promoter's methylation profile and gene expression. For this, we collected 28 pairs of cancerous human lung tissue and adjacent noncancerous (NC) lung tissue: 17 adenocarcinoma (AC), 9 squamous cell carcinoma (SCC), and 2 AC with SCC features, and we evaluated DNA methylation of the SFTPA2 promoter region by bisulfite conversion. Our results identified a higher methylation ratio in one CpG site of the SFTPA2 gene in cancerous tissue versus NC tissue (0.36 versus 0.11, p = 0.001). When assessing AC samples, we also found cancerous tissues associated with a higher methylation ratio (0.43 versus 0.10, p = 0.02). In the SCC group, although cancerous tissue showed a higher methylation ratio (0.22 versus 0.11), this difference was not statistically significant (p = 0.35). Expression of SFTPA2 mRNA and total SP-A protein was significantly lower in cancer tissue when compared to adjacent NC tissue (p < 0.001), and correlated with the hypermethylated status of an SFTPA2 CpG site in AC samples. The findings of this pilot study may hold promise for future use of SFTPA2 as a biomarker for the diagnosis of lung cancer. PMID- 25514369 TI - Multiporphyrin arrays with pi-pi interchromophore interactions. AB - A recently reported synthetic method has been employed to prepare several arrays of free base and zinc porphyrins. In the arrays, the porphyrins are arranged around a central benzene ring. The lack of aryl rings in the linkages to the central benzene ring, coupled with the presence of only one meso-aryl substituent on each porphyrin, allows strong electronic interactions between the porphyrin macrocycles. In arrays containing two or six porphyrins, a variety of evidence indicates that the porphyrins exist as twist-stacked dimers reminiscent of the special pairs of bacteriochlorophylls found in some photosynthetic bacteria. These dimers feature van der Waals contact between the macrocycles, and demonstrate excitonic splitting due to pi-pi interactions. The excitonic effects split and blue-shift the Soret absorptions, and slightly broaden the Q-band absorptions and shift them to longer wavelengths. The interactions also lower the first oxidation potentials by ca. 100 mV, and the arrays show evidence for delocalization of the radical cation over both porphyrins in the dimer. The arrays demonstrate singlet-singlet energy transfer among the chromophores. Arrays of this type will be good models for some aspects of the interactions of photosynthetic pigments, including those of reaction center special pairs and possibly quantum coherence effects. They can also be useful in artificial photosynthetic constructs. PMID- 25514372 TI - Quantitative determination of ligand densities on nanomaterials by X-ray photoelectron spectroscopy. AB - X-ray photoelectron spectroscopy (XPS) is a nearly universal method for quantitative characterization of both organic and inorganic layers on surfaces. When applied to nanoparticles, the analysis is complicated by the strong curvature of the surface and by the fact that the electron attenuation length can be comparable to the diameter of the nanoparticles, making it necessary to explicitly include the shape of the nanoparticle to achieve quantitative analysis. We describe a combined experimental and computational analysis of XPS data for molecular ligands on gold nanoparticles. The analysis includes scattering in both Au core and organic shells and is valid even for nanoparticles having diameters comparable to the electron attenuation length (EAL). To test this model, we show experimentally how varying particle diameter from 1.3 to 6.3 nm leads to a change in the measured AC/AAu peak area ratio, changing by a factor of 15. By analyzing the data in a simple computational model, we demonstrate that ligand densities can be obtained, and, moreover, that the actual ligand densities for these nanoparticles are a constant value of 3.9 +/- 0.2 molecules nm(-2). This model can be easily extended to a wide range of core-shell nanoparticles, providing a simple pathway to extend XPS quantitative analysis to a broader range of nanomaterials. PMID- 25514373 TI - Decreased tobacco-specific nitrosamines by microbial treatment with Bacillus amyloliquefaciens DA9 during the air-curing process of burley tobacco. AB - Tobacco specific nitrosamines (TSNA) mainly consisting of N-nitrosonornicotine (NNN), N-nitrosoanatabine (NAT), N-nitrosoanabasine (NAB), and 4 (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are a group of toxic components threatening human health. To inhibit TSNA formation in tobacco leaves, a high nitrite reductive strain with low nitrate reduction ability was isolated and applied to tobacco leaves in an attempt to lower the nitrite precursor of TSNA. By morphology, physiology, biochemistry, and 16S rDNA sequence analysis, the strain DA9 was identified as Bacillus amyloliquefaciens. Under the optimized fermentation parameters (glucose 40 g/L, NH4Cl 4 g/L, corn steep liquor 8 g/L, MnSO4 0.01 g/L, KH2PO4 1.0 g/L, MgSO4 0.3 g/L, initial pH 7.0, inoculum age 6 h, inoculum size 3%, temperature 37 degrees C), the maximum cell dentisity of 1.2 * 10(9) CFU/mL was obtained at 36 h. The DA9 cell suspensions were applied in the air-curing process of the Burley tobacco (Eyan 6) leaves. The treatment by DA9 cells lowered 32% of the nitrite content and 47% of total TSNA content in the tobacco leaves, and the concentrations of the NNN, NNK, and NAT were decreased by 48%, 12%, and 35%, respectively. Collectively, this study provides a promising strain and a novel strategy for decreasing TSNA during the air-curing process. PMID- 25514374 TI - Molecular characterization of interleukin 15 mRNA from rohu, Labeo rohita (Hamilton): Its prominent role during parasitic infection as indicated from infection studies. AB - Interleukin 15 (IL-15) is an important cytokine of fish immune system. Sequence characterization of IL-15 from rohu, Labeo rohita revealed a mRNA sequence of 1064 bp with coding sequence of 567 bp and signal peptide of 16 amino acids. There are four characteristic sequence features viz., presence of four out-of frame AUG initiation codons, four highly conserved cysteine residues, constitutive expression in all tissues and evolutionary similarity. The ontogeny study revealed maternal transfer of this molecule and higher expression up to 3 h post-fertilization in fertilized embryos. Its expression was down-regulated in anterior and posterior kidneys, intestine and liver tissues of rohu infected with Aeromonas hydrophila. Mild up-regulation in liver and higher expression in spleen was noticed in rohu stimulated with poly I:C (poly ionosinic:cytidylic), whereas down-regulation was observed in intestine and kidney tissues. However, a consistent higher expression was noticed in kidney and skin tissues during Argulus siamensis infection. Therefore, rohu IL-15 might possess more defensive role during early development and parasitic infection. PMID- 25514375 TI - The effects of Lactobacillus acidophilus as feed supplement on skin mucosal immune parameters, intestinal microbiota, stress resistance and growth performance of black swordtail (Xiphophorus helleri). AB - The present study evaluates the effects of different levels of dietary Lactobacillus acidophilus as feed supplement on intestinal microbiota, skin mucus immune parameters and salinity stress resistance as well as growth performance of black swordtail (Xiphophorus helleri). One-thousand and eight hundred healthy black swordtail larvae (0.03 +/- 0.001 g) were randomly distributed in 12 tanks (100 L) at a density of 150 fish per aquaria and fed different levels of dietary L. acidophilus (0, 1.5 * 10(8), 3 * 10(8) and 6 * 10(8) CFU g(-1)) for 10 weeks. At the end of trial, there were significant differences among antibacterial activity of skin mucus in probiotic fed fish and control group (P < 0.05). Furthermore, the skin mucus protein level and alkaline phosphatase activity in control group were significantly lower than those of L. acidophilus fed fish (P < 0.05). Microbiological assessments revealed that feeding with probiotic supplemented diet remarkably increased total autochthonous bacteria and autochthonous lactic acid bacteria levels (P < 0.05). The results showed that dietary administration of L. acidophilus significantly elevated black swordtail resistance against salinity stress (i.e survival %) (P < 0.05). Also, dietary administration of different levels of L. acidophilus improved weight gain, SGR, FCR compared to fish fed unsupplemented diet (P < 0.05). These results demonstrate beneficial effects of dietary L. acidophilus on mucosal immune parameters, intestinal microbiota, stress resistance and growth parameters of black swordtail and the appropriate inclusion is 6 * 10(8) CFU g(-1). PMID- 25514377 TI - Janusian peregrinations and progress. PMID- 25514370 TI - KSHV LANA--the master regulator of KSHV latency. AB - Kaposi's sarcoma associated herpesvirus (KSHV), like other human herpes viruses, establishes a biphasic life cycle referred to as dormant or latent, and productive or lytic phases. The latent phase is characterized by the persistence of viral episomes in a highly ordered chromatin structure and with the expression of a limited number of viral genes. Latency Associated Nuclear Antigen (LANA) is among the most abundantly expressed proteins during latency and is required for various nuclear functions including the recruitment of cellular machineries for viral DNA replication and segregation of the replicated genomes to daughter cells. LANA achieves these functions by recruiting cellular proteins including replication factors, chromatin modifying enzymes and cellular mitotic apparatus assembly. LANA directly binds to the terminal repeat region of the viral genome and associates with nucleosomal proteins to tether to the host chromosome. Binding of LANA to TR recruits the replication machinery, thereby initiating DNA replication within the TR. However, other regions of the viral genome can also initiate replication as determined by Single Molecule Analysis of the Replicated DNA (SMARD) approach. Recent, next generation sequence analysis of the viral transcriptome shows the expression of additional genes during latent phase. Here, we discuss the newly annotated latent genes and the role of major latent proteins in KSHV biology. PMID- 25514371 TI - Interferon induction by RNA viruses and antagonism by viral pathogens. AB - Interferons are a group of small proteins that play key roles in host antiviral innate immunity. Their induction mainly relies on host pattern recognition receptors (PRR). Host PRR for RNA viruses include Toll-like receptors (TLR) and retinoic acid-inducible gene I (RIG-I) like receptors (RLR). Activation of both TLR and RLR pathways can eventually lead to the secretion of type I IFNs, which can modulate both innate and adaptive immune responses against viral pathogens. Because of the important roles of interferons, viruses have evolved multiple strategies to evade host TLR and RLR mediated signaling. This review focuses on the mechanisms of interferon induction and antagonism of the antiviral strategy by RNA viruses. PMID- 25514376 TI - SNP detection of TLR8 gene, association study with susceptibility/resistance to GCRV and regulation on mRNA expression in grass carp, Ctenopharyngodon idella. AB - Toll-like receptor 8 (TLR8), a prototypical intracellular member of TLR family, is generally linked closely to antiviral innate immune through recognizing viral nucleic acid. In this study, 5'-flanking region of Ctenopharyngodon idella TLR8 (CiTLR8), 671bp in length, was amplified and eight SNPs containing one SNP in the intron, three SNPs in the coding region (CDS) and four SNPs in the 3' untranslated region (UTR) were identified and characterized. Of which 4062 A/T was significantly associated with the susceptibility/resistance to GCRV both in genotype and allele (P < 0.05), while 4168 C/T was extremely significantly associated with that (P < 0.01) according to the case (susceptibility)-control (resistance) analysis. Following the verification experiment, further analyses of mRNA expression, linkage disequilibrium (LD), haplotype and microRNA (miRNA) target site indicated that 4062 A/T and 4168 C/T in 3'-UTR might affect the miRNA regulation, while the exertion of antiviral effects of 4062 A/T might rely on its interaction with other SNPs. Additionally, the high-density of SNPs in 3'-UTR might reflect the specific biological functions of 3'-UTR. And also, the mutation of 747 A/G in intron changing the potential transcriptional factor-binding sites (TFBS) nearby might affect the expression of CiTLR8 transcriptionally or post transcriptionally. Moreover, as predicted, the A/G transition of the only non synonymous SNP (3846 A/G) in CDS causing threonine/alanine variation, could shorten the length of the alpha-helix and ultimately affect the integrity of the Toll-IL-1 receptor (TIR) domain. The functional mechanism of 3846 A/G might also involve a threonine phosphorylation signaling. This study may broaden the knowledge of TLR polymorphisms, lay the foundation for further functional research of CiTLR8 and provide potential markers as well as theoretical basis for resistance molecular breeding of grass carp against GCRV. PMID- 25514378 TI - Effects of forward trunk lean on hamstring muscle kinematics during sprinting. AB - This study aimed to investigate the effects of forward trunk lean on hamstring muscle kinematics during sprinting. Eight male sprinters performed maximal-effort sprints in two trunk positions: forward lean and upright. A three-dimensional musculoskeletal model was used to compute the musculotendon lengths and velocity of the biceps femoris long head, semitendinosus, and semimembranosus muscles during the sprinting gait cycle. The musculotendon lengths of all the three hamstring muscles at foot strike and toe-off were significantly greater during the forward trunk lean sprint than during the upright trunk sprint. In addition, a positive peak musculotendon lengthening velocity was observed in the biceps femoris long head and semimembranosus muscles during the late stance phase, and musculotendon lengths at that instant were significantly greater during the forward trunk lean sprint than during the upright trunk sprint. The present study provides significant evidence that a potential for hamstring muscle strain injury involving forward trunk lean sprinting would exist during the stance phase. The results also indicate that the biceps femoris long head and semimembranosus muscles are stretched during forward trunk lean sprinting while contracting eccentrically in the late stance phase; thus, the elongation load on these muscles could be increased. PMID- 25514381 TI - Impact of cyclodextrins on postprandial glycemia: evaluation in experimental animal model using the real-time continuous glucose monitoring system. AB - The impact of cyclodextrins (CDs) on postprandial glycemic response employing the real-time continuous glucose monitoring system (RT-CGMS) was investigated. For this purpose, alpha-CD, beta-CD, gamma-CD, HP-beta-CD, curdlan, and dextrin at doses of 10 and 100 mg/kg were orally administered in rats. The RT-CGMS was efficient to evaluate the impact of CDs on postprandial glycemia. The results showed that alpha-CD, beta-CD, dextrin, and curdlan did not reduce the glycemic response after the administration of starch. In contrast, the HP-beta-CD (100 mg/kg) attenuated the rise in glycemia. Moreover, the gamma-CD blunts the postprandial glycemic excursion at doses of 10 and 100 mg/kg. Therefore, gamma-CD could attenuate the rise in glycemia promoted by oral administration of starch. Considering that the treatment of postprandial hyperglycemia is necessary to prevent type 2 diabetes, this study opens the perspective of better control of postprandial glycemia by the addition of gamma-CD in food. PMID- 25514382 TI - Molecular characterization and clonal relationships among Escherichia coli strains isolated from broiler chickens with colisepticemia. AB - This study characterized 52 Escherichia coli isolates from distinct diseased organs of 29 broiler chickens with clinical symptoms of colibacillosis in the Southern Brazilian state of Rio Grande do Sul. Thirty-eight isolates were highly virulent and 14 were virtually avirulent in 1-day-old chicks, yet all isolates harbored virulence factors characteristic of avian pathogenic E. coli (APEC), including those related to adhesion, iron acquisition, and serum resistance. E. coli reference collection phylogenetic typing showed that isolates belonged mostly to group D (39%), followed by group A (29%), group B1 (17%), and group B2 (15%). Phylogenetic analyses using the Amplified Ribosomal DNA Restriction Analysis and pulse-field gel electrophoresis methods were used to discriminate among isolates displaying the same serotype, revealing that five birds were infected with two distinct APEC strains. Among the 52 avian isolates, 2 were members of the pandemic E. coli O25:H4-B2-ST131 clone. PMID- 25514379 TI - Antagonism between granulocytic maturation and deacetylase inhibitor-induced apoptosis in acute promyelocytic leukaemia cells. AB - BACKGROUND: Transcriptional repression is a key mechanism driving leukaemogenesis. In acute promyelocytic leukaemia (APL), the fusion protein promyelocytic leukaemia-retinoic acid receptor-alpha fusion (PML-RARalpha) recruits transcriptional repressors to myeloid differentiation genes. All-trans retinoic acid (ATRA) induces the proteasomal degradation of PML-RARalpha and granulocytic differentiation. Histone deacetylases (HDACs) fall into four classes (I-IV) and contribute to the transcription block caused by PML-RARalpha. METHODS: Immunoblot, flow cytometry, and May-Grunwald-Giemsa staining were used to analyze differentiation and induction of apoptosis. RESULTS: A PML-RARalpha- and ATRA dependent differentiation programme induces granulocytic maturation associated with an accumulation of the myeloid transcription factor CCAAT/enhancer binding protein (C/EBP)E and of the surface protein CD11b. While this process protects APL cells from inhibitors of class I HDAC activity, inhibition of all Zinc dependent HDACs (classes I, II, and IV) with the pan-HDACi (histone deacetylase inhibitor(s)) LBH589 induces apoptosis of immature and differentiated APL cells. LBH589 can eliminate C/EBPE and the mitochondrial apoptosis regulator B-cell lymphoma (BCL)-xL in immature and differentiated NB4 cells. Thus, BCL-xL and C/EBPE are newly identified molecular markers for the efficacy of HDACi against APL cells. CONCLUSIONS: Our results could explain the therapeutic limitations occurring with ATRA and class I HDACi combinations. Pro-apoptotic effects caused by pan-HDAC inhibition are not blunted by ATRA-induced differentiation and may provide a clinically interesting alternative. PMID- 25514383 TI - Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment. AB - Alzheimer's Disease (AD) is the major form of senile dementia, characterized by neuronal loss, extracellular deposits, and neurofibrillary tangles. It is accompanied by a loss of cholinergic tone, and acetylcholine (ACh) levels in the brain, which were hypothesized to be responsible for the cognitive decline observed in AD. Current medication is restricted to enhancing cholinergic signalling for symptomatic treatment of AD patients. The nicotinic acetylcholine receptor family (nAChR) and the muscarinic acetylcholine receptor family (mAChR) are the target of ACh in the brain. Both families of receptors are affected in AD. It was demonstrated that amyloid beta (Abeta) interacts with nAChRs. Here we discuss how Abeta activates or inhibits nAChRs, and how this interaction contributes to AD pathology. We will discuss the potential role of nAChRs as therapeutic targets. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. PMID- 25514384 TI - Pramipexole protects dopaminergic neurons through paraplegin against 6 hydroxydopamine. AB - The neurotransmitter dopamine (DA) regulates various physiological and psychological functions, such as movement, motivation, behavior, and learning. DA exerts its function through DA receptors and a series of studies have reported the role of DAergic receptors in preventing DAergic neuronal degeneration. Here, we studied the DA receptor-mediated neuroprotective effect of the D2-like receptor agonists against 6-hydroxydopamine (6-OHDA)-induced DAergic neurodegeneration. D2-like receptor agonists were administered in the substantia nigra in vivo and to primary cultured neurons. Treatment of 6-OHDA decreased tyrosine hydroxylase (TH) and paraplegin (mitochondrial regulation protein) immunoreactivity, whereas pretreatment with quinpirole (a full D2-like receptor agonist) preserved TH and paraplegin reactivity. This led us to test which DA receptors were necessary for the neuroprotective effect and whether paraplegin can be regulated by D2 or D3 receptor agonists. Pretreatment with the D2 receptor selective agonist, sumanirole, did not preserve TH and paraplegin reactivity from 6-OHDA. However, the D3 receptor agonist, pramipexole, protected TH reactivity and restored paraplegin expression to the control level in the presence of 6 OHDA. Interestingly, pretreatment with the D3 receptor antagonist GR103691 reduced TH and paraplegin expression levels. These results suggest that the D3 receptor agonist may protect DA neurons from the effect of 6-OHDA through the modulation of the mitochondrial regulation protein paraplegin. PMID- 25514380 TI - Imaging tumour hypoxia with positron emission tomography. AB - Hypoxia, a hallmark of most solid tumours, is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. Given its prominent role in oncology, accurate detection of hypoxia is important, as it impacts on prognosis and could influence treatment planning. A variety of approaches have been explored over the years for detecting and monitoring changes in hypoxia in tumours, including biological markers and noninvasive imaging techniques. Positron emission tomography (PET) is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. This review provides an overview of imaging hypoxia with PET, with an emphasis on the advantages and limitations of the currently available hypoxia radiotracers. PMID- 25514385 TI - Characterization of clinical and immunological parameters during Ebola virus infection of rhesus macaques. AB - The rhesus macaque serves as an animal model for Ebola virus (EBOV) infection. A thorough understanding of EBOV infection in this species would aid in further development of filovirus therapeutics and vaccines. In this study, pathological and immunological data from EBOV-infected rhesus macaques are presented. Changes in blood chemistries, hematology, coagulation, and immune parameters during infection, which were consistently observed in the animals, are presented. In an animal that survived challenge, a delay was observed in the detection of viral RNA and inflammatory cytokines and chemokines which may have contributed to survival. Collectively, these data add to the body of knowledge regarding EBOV pathogenesis in rhesus macaques and emphasize the reproducibility of the rhesus macaque challenge model. PMID- 25514386 TI - Topographic distribution of cortical projection cells in the rat subiculum. AB - The topographic distribution of subicular pyramidal cells, which give rise to projections to the entorhinal cortex, presubiculum, parasubiculum, and the retrosplenial granular cortex, was investigated in the rat using retrograde labeling with wheat germ agglutinin-horseradish peroxidase. Using two-dimensional unfolded maps of the entire hippocampal and parahippocampal fields, we found that the cells originating the projections to the above cortical areas were consistently observed throughout the entire septotemporal extent of the subiculum. In the transverse plane, most of the cortical projection cells were vertically located in the middle region of the subicular pyramidal cell layer. The cells giving rise to the projections to the lateral entorhinal cortex were predominantly located in the most proximal (near CA1), superficial region. Few cortical projection cells were located in the deepest (adjacent to the angular bundle) region. The distribution of cortical projection cells showed an oblique tri-laminar pattern, which was similar to the previously reported laminal pattern of subcortical projection cells in the subiculum. These results suggest that cortical projection cells in middle and superficial regions of the subiculum may correspond to layer V of the isocortex and cells in the deepest region corresponding to layer VI. PMID- 25514387 TI - Reading the Mind in the Eyes or reading between the lines? Theory of Mind predicts collective intelligence equally well online and face-to-face. AB - Recent research with face-to-face groups found that a measure of general group effectiveness (called "collective intelligence") predicted a group's performance on a wide range of different tasks. The same research also found that collective intelligence was correlated with the individual group members' ability to reason about the mental states of others (an ability called "Theory of Mind" or "ToM"). Since ToM was measured in this work by a test that requires participants to "read" the mental states of others from looking at their eyes (the "Reading the Mind in the Eyes" test), it is uncertain whether the same results would emerge in online groups where these visual cues are not available. Here we find that: (1) a collective intelligence factor characterizes group performance approximately as well for online groups as for face-to-face groups; and (2) surprisingly, the ToM measure is equally predictive of collective intelligence in both face-to-face and online groups, even though the online groups communicate only via text and never see each other at all. This provides strong evidence that ToM abilities are just as important to group performance in online environments with limited nonverbal cues as they are face-to-face. It also suggests that the Reading the Mind in the Eyes test measures a deeper, domain-independent aspect of social reasoning, not merely the ability to recognize facial expressions of mental states. PMID- 25514389 TI - Isoflavone and protein constituents of lactic acid-fermented soy milk combine to prevent dyslipidemia in rats fed a high cholesterol diet. AB - A high cholesterol diet induces dyslipidemia. This study investigated whether isoflavone aglycones in lactic acid-fermented soy milk (LFS) improve lipid metabolism in rats fed a high cholesterol diet. Male Sprague-Dawley rats aged seven weeks were fed an AIN-93G diet, a 1% cholesterol diet (a high cholesterol diet), a high-cholesterol diet containing 4% isoflavone extract of LFS (LFS extract diet), a high-cholesterol diet containing 19.4% ethanol-washed LFS (ethanol-washed LFS diet, isoflavone-poor diet), or a high cholesterol diet containing 23.2% intact LFS (intact LFS diet) for five weeks. The plasma total cholesterol (TC) level was increased in the rats fed the LFS extract diet compared with those fed the high cholesterol diet. The TC level was decreased by the intact LFS and ethanol-washed LFS diets. The cholesterol-lowering effect was stronger in the rats fed the intact LFS diet than those fed the ethanol-washed LFS diet. The plasma triglyceride (TG) level was unchanged in the rats fed the LFS extract diet, but it decreased in rats fed the intact LFS and ethanol-washed LFS diets. Although, compared with the high cholesterol diet, the LFS extract and ethanol-washed LFS diets did not reduce hepatic cholesterol and TG, both levels were remarkably lowered by the intact LFS diet. These results suggest that the improvement in lipid metabolism of rats fed a high-cholesterol diet containing LFS isoflavone aglycones is not due to an independent effect but due to a cooperative effect with soy protein. PMID- 25514388 TI - The role of dietary sugars and de novo lipogenesis in non-alcoholic fatty liver disease. AB - Dietary sugar consumption, in particular sugar-sweetened beverages and the monosaccharide fructose, has been linked to the incidence and severity of non alcoholic fatty liver disease (NAFLD). Intervention studies in both animals and humans have shown large doses of fructose to be particularly lipogenic. While fructose does stimulate de novo lipogenesis (DNL), stable isotope tracer studies in humans demonstrate quantitatively that the lipogenic effect of fructose is not mediated exclusively by its provision of excess substrates for DNL. The deleterious metabolic effects of high fructose loads appear to be a consequence of altered transcriptional regulatory networks impacting intracellular macronutrient metabolism and altering signaling and inflammatory processes. Uric acid generated by fructose metabolism may also contribute to or exacerbate these effects. Here we review data from human and animal intervention and stable isotope tracer studies relevant to the role of dietary sugars on NAFLD development and progression, in the context of typical sugar consumption patterns and dietary recommendations worldwide. We conclude that the use of hypercaloric, supra-physiological doses in intervention trials has been a major confounding factor and whether or not dietary sugars, including fructose, at typically consumed population levels, effect hepatic lipogenesis and NAFLD pathogenesis in humans independently of excess energy remains unresolved. PMID- 25514390 TI - Insights from space: potential role of diet in the spatial organization of chromosomes. AB - We can now sequence and identify genome wide epigenetic patterns and perform a variety of "genomic experiments" within relatively short periods of time-ranging from days to weeks. Yet, despite these technological advances, we have a poor understanding of the inter-relationships between epigenetics, genome structure function, and nutrition. Perhaps this limitation lies, in part, in our propensity to study epigenetics in terms of the linear arrangement of elements and genes. Here we propose that a more complete understanding of how nutrition impacts on epigenetics and cellular development resides within the inter-relationships between DNA and histone modification patterns and genome function, in the context of spatial organization of chromatin and the epigenome. PMID- 25514391 TI - Taking a low glycemic index multi-nutrient supplement as breakfast improves glycemic control in patients with type 2 diabetes mellitus: a randomized controlled trial. AB - Dietary therapy is the mainstay of treatment for diabetes. This study examined the effect of a low glycemic index (GI) multi-nutrient supplement, consumed in place of breakfast, on glycemic control in patients with type 2 diabetes mellitus (T2DM). A total of 71 participants were randomized at a 2:1 ratio into either a breakfast replacement group or a normal breakfast group for a 12-week interventional study. The primary outcome measure was change in hemoglobin A1c (HbA1c). Nutrition status and somatometry were studied as secondary outcomes. The breakfast replacement group displayed a -0.2% absolute reduction in HbA1c (95% CI (confidence interval), -0.38% to -0.07%, p = 0.004), while the HbA1c of the control group increased 0.3% (95% CI, 0.1% to 0.5%, p = 0.005). The baseline Mini Nutritional Assessment score for both groups was 26.0 and no significant changes occurred following intervention. However, there was a statistically significant difference in body mass index between the treatment and control groups (p = 0.032) due to the weight gain in the control group (increased 0.5 kg, 95% CI was 0.2 to 0.9, p = 0.007). These data suggest that breakfast replacement with a low GI multi-nutrient supplement can improve glycemic and weight control in T2DM. PMID- 25514394 TI - Evaluation of a semi-automated workflow for fragment growing. AB - Intelligent Automatic Design (IADE) is an expert system developed at Novartis to identify nonclassical bioisosteres. In addition to bioisostere searching, one could also use IADE to grow a fragment bound to a protein. Here we report an evaluation of IADE as a tool for fragment growing. Three examples from the literature served as test cases. In all three cases, IADE generated close analogues of the published compounds and reproduced their crystallographic binding modes. This exercise validated the use of the IADE system for fragment growing. We have also gained experience in optimizing the performance of IADE for this type of application. PMID- 25514392 TI - Application of coenzyme Q10 for accelerating soft tissue wound healing after tooth extraction in rats. AB - Accelerating wound healing after tooth extraction is beneficial in dental treatment. Application of antioxidants, such as reduced coenzyme Q10 (rCoQ10), may promote wound healing after tooth extraction. In this study, we examined the effects of topical application of rCoQ10 on wound healing after tooth extraction in rats. After maxillary first molars were extracted, male Fischer 344 rats (8 weeks old) (n = 27) received topical application of ointment containing 5% rCoQ10 (experimental group) or control ointment (control group) to the sockets for 3 or 8 days (n = 6-7/group). At 3 days after extraction, the experimental group showed higher collagen density and lower numbers of polymorphonuclear leukocytes in the upper part of socket, as compared to the control group (p < 0.05). Gene expression of interleukin-1beta, tumor necrosis factor-alpha and nuclear factor kappaB were also lower in the experimental group than in the control group (p < 0.05). At 8 days after tooth extraction, there were no significant differences in collagen density, number of polymorphonuclear leukocytes and bone fill between the groups. Our results suggest that topical application of rCoQ10 promotes wound healing in the soft tissue of the alveolar socket, but that rCoQ10 has a limited effect on bone remodeling in rats. PMID- 25514395 TI - Comparison of four aquatic plant treatment systems for nutrient removal from eutrophied water. AB - Nutrient removal behaviors of four aquatic plant treatment systems (Oenanthe javanica, Iris pseudacorus L., Canna lily, and Potamogeton crispus) were systematically examined and compared. The kinetics of nutrient uptake were conducted with the standard depletion method. All four aquatic species exhibited a strong preference of ammonium nitrogen (NH4(+)-N) over nitrate nitrogen (NO3(-) N) and nitrite nitrogen (NO2(-)-N). Main pathways of nutrient removal in the aquatic plant treatment system were examined in details. It was estimated that direct assimilation by plants accounted for 28.2-34.5% of N reduction and 25.2 33.4% of P reduction while substrate absorption accounted for 7.2-25.5% of N reduction and 7.3-25.0% of P reduction. The activity of urease and phosphatase in the substrates could indicate the aquatic plant treatment system's capability for reducing TN and soluble P load. PMID- 25514396 TI - A novel algal biofilm membrane photobioreactor for attached microalgae growth and nutrients removal from secondary effluent. AB - In this study, a novel algal biofilm membrane photobioreactor (BMPBR) equipped with solid carriers and submerged membrane module was developed for attached growth of Chlorella vulgaris and secondary effluent treatment. The volumetric microalgae production achieved in BMPBR was 0.072 g L(-1) d(-1), which was 1.44 fold larger than that in suspended growth membrane photobioreactor (MPBR). Furthermore, 72.4% of the total produced algal biomass was immobilized as algal biofilm in BMPBR. Advanced nutrients removal from secondary effluent was achieved both in BMPBR and MPBR, with average reduction of about 85% for PO4(3-)-P in the stable stage. Additionally, BMPBR showed better nitrogen removal performance than MPBR due to its higher algal biomass productivity. Moreover, with the filtration effect of the submerged membrane module in the reactor, suspended microalgae could be completely isolated from the effluent and a low average SS concentration of 0.28 mg L(-1) was achieved in the effluent of BMPBR. PMID- 25514397 TI - Hydrogen production using amino acids obtained by protein degradation in waste biomass by combined dark- and photo-fermentation. AB - The biological hydrogen production from amino acids obtained by protein degradation was comprehensively investigated to increase heating value conversion efficiency. The five amino acids (i.e., alanine, serine, aspartic acid, arginine, and leucine) produced limited hydrogen (0.2-16.2 mL/g) but abundant soluble metabolic products (40.1-84.0 mM) during dark-fermentation. The carbon conversion efficiencies of alanine (85.3%) and serine (94.1%) during dark-fermentation were significantly higher than those of other amino acids. Residual dark-fermentation solutions treated with zeolite for NH4(+) removal were inoculated with photosynthetic bacteria to further produce hydrogen during photo-fermentation. The hydrogen yields of alanine and serine through combined dark- and photo fermentation were 418.6 and 270.2 mL/g, respectively. The heating value conversion efficiency of alanine to hydrogen was 25.1%, which was higher than that of serine (21.2%). PMID- 25514398 TI - Free nitrous acid pretreatment of wasted activated sludge to exploit internal carbon source for enhanced denitrification. AB - Using internal carbon source contained in waste activated sludge (WAS) is beneficial for nitrogen removal from wastewater with low carbon/nitrogen ratio, but it is usually limited by sludge disintegration. This study presented a novel strategy based on free nitrous acid (FNA) pretreatment to intensify the release of organic matters from WAS for enhanced denitrification. During FNA pretreatment, soluble chemical oxygen demand (SCOD) production kept increasing when FNA increased from 0 to 2.04 mg HNO2-N/L. Compared with untreated WAS, the internal carbon source production increased by 50% in a simultaneous fermentation and denitrification reactor fed with WAS pretreated by FNA for 24 h at 2.04 mg HNO2-N/L. This also increased denitrification efficiency by 76% and sludge reduction by 87.5%. More importantly, greenhouse gas nitrous oxide production in denitrification was alleviated since more electrons could be provided by FNA pretreated WAS. PMID- 25514400 TI - Degradation of a model pollutant ferulic acid by the endophytic fungus Phomopsis liquidambari. AB - Biodegradation of ferulic acid, by an endophytic fungus called Phomopsis liquidambari was investigated in this study. This strain can use ferulic acid as the sole carbon for growth. Both in mineral salt medium and in soil, more than 97% of added ferulic acid was degraded within 48 h. The metabolites were identified and quantified using GC-MS and HPLC-MS. Ferulic acid was first decarboxylated to 4-vinyl guaiacol and then oxidized to vanillin and vanillic acid, followed by demethylation to protocatechuic acid, which was further degraded through the beta-ketoadipate pathway. During degradation, ferulic acid decarboxylase, laccase and protocatechuate 3,4-dioxygenase activities and their gene transcription levels were significantly affected by the variation of substrate and product concentrations. Moreover, ferulic acid degradation was determined to some extent by P. liquidambari laccase. This study is the first report of an endophytic fungus that has a great potential for practical application in ferulic acid-contaminated environments. PMID- 25514399 TI - Anolyte recirculation effects in buffered and unbuffered single-chamber air cathode microbial fuel cells. AB - Two identical microbial fuel cells (MFCs) with a floating air-cathode were operated under either buffered (MFC-B) or bufferless (MFC-BL) conditions to investigate anolyte recirculation effects on enhancing proton transfer. With an external resistance of 50 Omega and recirculation rate of 1.0 ml/min, MFC-BL had a 27% lower voltage (9.7% lower maximal power density) but a 64% higher Coulombic efficiency (CE) than MFC-B. MFC-B had a decreased voltage output, batch time, and CE with increasing recirculation rate resulting from more oxygen transfer into the anode. However, increasing the recirculation rate within a low range significantly enhanced proton transfer in MFC-BL, resulting in a higher voltage output, a longer batch time, and a higher CE. A further increase in recirculation rate decreased the batch time and CE of MFC-BL due to excess oxygen transfer into anode outweighing the proton-transfer benefits. The unbuffered MFC had an optimal recirculation rate of 0.35 ml/min. PMID- 25514401 TI - Enhancement of anaerobic acidogenesis by integrating an electrochemical system into an acidogenic reactor: effect of hydraulic retention times (HRT) and role of bacteria and acidophilic methanogenic Archaea. AB - In this study, an acidogenic reactor packed with a pair of Fe-carbon electrodes (R1) was developed to enhance anaerobic acidogenesis of organic wastewater at short hydraulic retention times. The results indicated that the acidogenic efficiency was improved by settling a bio-electrochemical system. When hydraulic retention times decreased from 12 to 3h, R1 showed 18.9% more chemical oxygen demand removal and 13.8% more acidification efficiency. After cutting off the voltage of R1, the COD removal decreased by about 5%. Coupling of Fe(2+) leaching and electric field accelerated the hydrolysis of polysaccharide, relieving its accumulation in the sludge phase. Several acidophilic methanogenic Archaea such as Methanosarcina sp. were enriched in R1, which was favorable for consuming organic acids and preventing excessive pH decline. Thus, the developed acidogenic reactor with Fe-carbon electrodes is expected to be potentially effective and useful for wastewater treatment. PMID- 25514402 TI - Simultaneous pretreatment and saccharification: green technology for enhanced sugar yields from biomass using a fungal consortium. AB - Two different biomasses were subjected to simultaneous pretreatment and saccharification (SPS) using a cocktail of hydrolytic and oxidizing enzymes. Application of a novel laccase as a detoxifying agent caused the removal of 49.8% and 32.6% of phenolic contents from the soaked rice straw and willow, respectively. Hydrolysis of soaked substrates using a newly developed fungal consortium resulted in saccharification yield of up to 74.2% and 63.6% for rice straw and willow, respectively. A high saccharification yield was obtained with soaked rice straw and willow without using any hazardous chemicals. The efficiency of each step related to SPS was confirmed by atomic force microscopy. The suitability of the developed SPS process was further confirmed by converting the hydrolysate from the process into bioethanol with 72.4% sugar conversion efficiency. To the best of our knowledge, this is the first report on the development of a less tedious, single-pot, and eco-friendly SPS methodology. PMID- 25514403 TI - A Preliminary Model of Motivation for Pornography Consumption Among Men Participating in Zoophilic Virtual Environments. AB - Although zoophilic blogs and websites attract the attention of zoophiles and others who are curious about this sexual activity, the motivations for consuming this type of pornography are not clear. This study aimed to confirm the factorial validity of the Pornography Consumption Inventory in an online sample of men with sexual interest in animals, and to construct an association model between motivations for pornography consumption and the following psychological variables: depression, sexual impulsiveness, and strength of sexual interest in animals. In this cross-sectional study, we located a website that catered to a network of people with a sexual interest in animals. Subsequently, a questionnaire was made available online to members of this network. Results support the 4-factor model of the Pornography Consumption Inventory. Depression and strength of sexual interest in animals were negatively and positively correlated with the sexual curiosity factor, respectively. Sexual impulsiveness was positively associated with the emotional avoidance, excitement seeking, and sexual pleasure factors. Depression and sexual impulsiveness were positively correlated. Psychological factors can differently motivate the consumption of pornography among men who visit zoophilic blogs and websites. With these preliminary data, we can identify some characteristics of this population. PMID- 25514404 TI - Should central venous catheter be systematically removed in patients with suspected catheter related infection? AB - INTRODUCTION: Best clinical practice for patients with suspected catheter-related infection (CRI) remains unclear according to the latest Infectious Diseases Society of America (IDSA) guidelines. Thus, the objective of this study was to analyze clinical practice concerning the central venous catheter (CVC) and its impact on prognosis in patients with suspected CRI. METHODS: We performed a prospective, multicenter, observational study in 18 Spanish Intensive Care Units (ICUs). Inclusion criteria were patients with CVC and suspected CRI. The following exclusion criteria were used: age less than 18 years; pregnancy; lactation; human immunodeficiency virus; neutropenia; solid or haematological tumor; immunosuppressive or radiation therapy; transplanted organ; intravascular foreign body; haemodynamic instability; suppuration or frank erythema/induration at the insertion site of the CVC, and patients with bacteremia or fungemia. The end-point of the study was mortality at 30 days of CRI suspicion. RESULTS: The study included 384 patients. In 214 (55.8%) patients, CVC was removed at the moment of CRI suspicion, in 114 (29.7%) CVC was removed later and in 56 (14.6%) CVC was not removed. We did not find significant differences between survivors (n =311) and non-survivors (n =73) at 30 days according to CVC decision (P =0.26). The rate of confirmed catheter-related bloodstream infection (CRBSI) was higher in survivors than in non-survivors (14.5% versus 4.1%; P =0.02). Mortality rate was lower in patients with CRBSI than in the group of patients whose clinical symptoms were due to other causes (3/48 (6.25%) versus 70/336 (20.8%); P =0.02). We did not find significant differences in mortality in patients with confirmed CRBSI according to CVC removal at the moment of CRI suspicion (n =38) or later (n =10) (7.9% versus 0; P =0.99). CONCLUSION: In patients with suspected CRI, immediate CVC removal may be not necessary in all patients. Other aspects should be taken into account in the decision-making, such as vascular accessibility, the risk of mechanical complications during new cannulation that may be life threatening, and the possibility that the CVC may not be the origin of the suspected CRI. PMID- 25514405 TI - Modulation of induced cytotoxicity of doxorubicin by using apoferritin and liposomal cages. AB - Doxorubicin is an effective chemotherapeutic drug, however, its toxicity is a significant limitation in therapy. Encapsulation of doxorubicin inside liposomes or ferritin cages decreases cardiotoxicity while maintaining anticancer potency. We synthesized novel apoferritin- and liposome-encapsulated forms of doxorubicin ("Apodox" and "lip-8-dox") and compared its toxicity with doxorubicin and Myocet on prostate cell lines. Three different prostatic cell lines PNT1A, 22Rv1, and LNCaP were chosen. The toxicity of the modified doxorubicin forms was compared to conventional doxorubicin using the MTT assay, real-time cell impedance-based cell growth method (RTCA), and flow cytometry. The efficiency of doxorubicin entrapment was 56% in apoferritin cages and 42% in the liposome carrier. The accuracy of the RTCA system was verified by flow-cytometric analysis of cell viability. The doxorubicin half maximal inhibition concentrations (IC50) were determined as 170.5, 234.0, and 169.0 nM for PNT1A, 22Rv1, and LNCaP, respectively by RTCA. Lip8-dox is less toxic on the non-tumor cell line PNT1A compared to doxorubicin, while still maintaining the toxicity to tumorous cell lines similar to doxorubicin or epirubicin (IC50 = 2076.7 nM for PNT1A vs. 935.3 and 729.0 nM for 22Rv1 and LNCaP). Apodox IC50 was determined as follows: 603.1, 1344.2, and 931.2 nM for PNT1A, 22Rv1, and LNCaP. PMID- 25514406 TI - A comparative study of sodium houttuyfonate and 2-undecanone for their in vitro and in vivo anti-inflammatory activities and stabilities. AB - Houttuynia cordata Thunb. (H. cordata) is an anti-inflammatory herbal drug that is clinically used in Asia. The essential oil obtained from H. cordata is known to contain 2-undecanone (2-methyl nonyl ketone). In addition, sodium houttuyfonate is a compound that can be derived from H. cordata and has important clinical uses as an anti-inflammatory agent. Sodium houttuyfonate can be converted to decanoyl acetaldehyde (houttuynin) and then to 2-undecanone. Therefore, the experiments described here explore the comparative anti inflammatory activities of these compounds. Sodium houttuyfonate showed more potent anti-inflammatory activities than that of 2-undecanone at the same dosage, both in vitro and in vivo, although both compounds significantly inhibited the production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL 1beta) and the expression of toll-like receptor 4 (TLR4), but increased the secretion of interleukin-10 (IL-10) in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. In addition, both compounds showed dose-dependent inhibitory effects on xylene-induced mouse ear edema. In a previous study, we found sodium houttuyfonate to be transformed to 2-undecanone during steam distillation (SD). Optimum therapeutic effects are related to the stability and pharmacological activity of the drugs. Consequently, we studied the stability of sodium houttuyfonate under a simulated gastrointestinal environment with the main influencing factors being solvent, temperature and pH effects. For the first time, sodium houttuyfonate and 2-undecanone were detected simultaneously in the mouse serum and the gastrointestinal tissue after oral administration. Sodium houttuyfonate is detected within a short period of time in the systemic circulation and tissues without conversion to 2-undecanone. PMID- 25514407 TI - Antimicrobial and hypoglycemic activities of novel N-Mannich bases derived from 5 (1-adamantyl)-4-substituted-1,2,4-triazoline-3-thiones. AB - The reaction of 5-(1-adamantyl)-4-ethyl or allyl-1,2,4-triazoline-3-thione with formaldehyde solution and various 1-substituted piperazines yielded the corresponding N-Mannich bases. The newly synthesized N-Mannich bases were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram negative bacteria and the yeast-like pathogenic fungus Candida albicans. Six compounds showed potent antibacterial activity against one or more of the tested microorganisms, while two compounds exhibited moderate activity against the tested Gram-positive bacteria. None of the newly synthesized compounds were proved to possess marked activity against Candida albicans. The oral hypoglycemic activity of six compounds was determined in streptozotocin (STZ)-induced diabetic rats. Four compounds produced significant strong dose-dependent reduction of serum glucose levels, compared to gliclazide at 10 mg/kg dose level (potency ratio > 75%). PMID- 25514408 TI - Effect of hydrogen peroxide on the biosynthesis of heme and proteins: potential implications for the partitioning of Glu-tRNA(Glu) between these pathways. AB - Glutamyl-tRNA (Glu-tRNA(Glu)) is the common substrate for both protein translation and heme biosynthesis via the C5 pathway. Under normal conditions, an adequate supply of this aminoacyl-tRNA is available to both pathways. However, under certain circumstances, Glu-tRNA(Glu) can become scarce, resulting in competition between the two pathways for this aminoacyl-tRNA. In Acidithiobacillus ferrooxidans, glutamyl-tRNA synthetase 1 (GluRS1) is the main enzyme that synthesizes Glu-tRNA(Glu). Previous studies have shown that GluRS1 is inactivated in vitro by hydrogen peroxide (H2O2). This raises the question as to whether H2O2 negatively affects in vivo GluRS1 activity in A. ferrooxidans and whether Glu-tRNA(Glu) distribution between the heme and protein biosynthesis processes may be affected by these conditions. To address this issue, we measured GluRS1 activity. We determined that GluRS1 is inactivated when cells are exposed to H2O2, with a concomitant reduction in intracellular heme level. The effects of H2O2 on the activity of purified glutamyl-tRNA reductase (GluTR), the key enzyme for heme biosynthesis, and on the elongation factor Tu (EF-Tu) were also measured. While exposing purified GluTR, the first enzyme of heme biosynthesis, to H2O2 resulted in its inactivation, the binding of glutamyl-tRNA to EF-Tu was not affected. Taken together, these data suggest that in A. ferrooxidans, the flow of glutamyl-tRNA is diverted from heme biosynthesis towards protein synthesis under oxidative stress conditions. PMID- 25514409 TI - Anti-vascular endothelial growth factor therapy in breast cancer. AB - Neo-angiogenesis is a critical process for tumor growth and invasion and has become a promising target in cancer therapy. This manuscript reviews three currently relevant anti-angiogenic agents targeting the vascular endothelial growth factor system: bevacizumab, ramucirumab and sorafenib. The efficacy of anti-angiogenic drugs in adjuvant therapy or as neo-adjuvant treatment has been estimated in clinical trials of advanced breast cancer. To date, the overall observed clinical improvements are unconvincing, and further research is required to demonstrate the efficacy of anti-angiogenic drugs in breast cancer treatments. The outcomes of anti-angiogenic therapy have been highly variable in terms of tumor response. New methods are needed to identify patients who will benefit from this regimen. The development of biomarkers and molecular profiling are relevant research areas that may strengthen the ability to focus anti-angiogenic therapy towards suitable patients, thereby increase the cost-effectiveness, currently estimated to be inadequate. PMID- 25514410 TI - Regulation of photochemical energy transfer accompanied by structural changes in thylakoid membranes of heat-stressed wheat. AB - Photosystems of higher plants alleviate heat-induced damage in the presence of light under moderate stressed conditions; however, in the absence of light (i.e., in the dark), the same plants are damaged more easily. (Yamauchi and Kimura, 2011) We demonstrate that regulating photochemical energy transfer in heat treated wheat at 40 degrees C with light contributed to heat tolerance of the photosystem. Chlorophyll fluorescence analysis using heat-stressed wheat seedlings in light showed increased non-photochemical quenching (NPQ) of chlorophyll fluorescence, which was due to thermal dissipation that was increased by state 1 to state 2 transition. Transmission electron microscopy revealed structural changes in thylakoid membranes, including unstacking of grana regions under heat stress in light. It was accompanied by the phosphorylation of thylakoid proteins such as D1 and D2 proteins and the light harvesting complex II proteins Lhcb1 and Lhcb2. These results suggest that heat stress at 40 degrees C in light induces state 1 to state 2 transition for the preferential excitation of photosystem I (PSI) by phosphorylating thylakoid proteins more strongly. Structural changes of thylakoid membrane also assist the remodeling of photosystems and regulation of energy distribution by transition toward state 2 probably contributes to plastoquione oxidation; thus, light-driven electrons flowing through PSI play a protective role against PSII damage under heat stress. PMID- 25514411 TI - L-cystathionine inhibits the mitochondria-mediated macrophage apoptosis induced by oxidized low density lipoprotein. AB - This study was designed to investigate the regulatory role of l-cystathionine in human macrophage apoptosis induced by oxidized low density lipoprotein (ox-LDL) and its possible mechanisms. THP-1 cells were induced with phorbol 12-myristate 13-acetate (PMA) and differentiated into macrophages. Macrophages were incubated with ox-LDL after pretreatment with l-cystathionine. Superoxide anion, apoptosis, mitochondrial membrane potential, and mitochondrial permeability transition pore (MPTP) opening were examined. Caspase-9 activities and expression of cleaved caspase-3 were measured. The results showed that compared with control group, ox LDL treatment significantly promoted superoxide anion generation, release of cytochrome c (cytc) from mitochondrion into cytoplasm, caspase-9 activities, cleavage of caspase-3, and cell apoptosis, in addition to reduced mitochondrial membrane potential as well as increased MPTP opening. However, 0.3 and 1.0 mmol/L l-cystathionine significantly reduced superoxide anion generation, increased mitochondrial membrane potential, and markedly decreased MPTP opening in ox-LDL + l-cystathionine macrophages. Moreover, compared to ox-LDL treated-cells, release of cytc from mitochondrion into cytoplasm, caspase-9 activities, cleavage of caspase-3, and apoptosis levels in l-cystathionine pretreated cells were profoundly attenuated. Taken together, our results suggested that l-cystathionine could antagonize mitochondria-mediated human macrophage apoptosis induced by ox LDL via inhibition of cytc release and caspase activation. PMID- 25514412 TI - Expression of the MT1 melatonin receptor in ovarian cancer cells. AB - Ovarian cancer (OC) is the leading cause of death among women with genital tract disorders. Melatonin exhibits oncostatic properties which it may effect through binding to its membrane receptor, MT1. The aim of this study was to determine the expression of MT1 in OC cells and to correlate this with clinical and pathological data. Immunohistochemistry was performed on 84 cases of OC. Normal ovarian epithelial (IOSE 364) and OC (SK-OV-3, OVCAR-3) cell lines were used to examine the MT1 expression at protein level using the western blot and immunofluorescence technique. The expression of MT1 was observed as cytoplasmic membrane (MT1(CM)) and membrane (MT1(M)) reactions. A positive correlation between MT1(CM) and MT1(M) was found in all the studied cases. There were no significant differences between the expression of MT1(CM), MT1(M), and histological type, staging, grading, presence of residual disease, or overall survival time. Immunofluorescence showed both MT1(M) and MT1(CM) expression in all the tested cell lines. Western blot illustrated the highest protein level of MT1 in IOSE 364 and the lowest in the OVCAR-3. The results indicate the limited prognostic significance of MT1 in OC cells. PMID- 25514414 TI - Plant-pathogen interaction, circadian rhythm, and hormone-related gene expression provide indicators of phytoplasma infection in Paulownia fortunei. AB - Phytoplasmas are mycoplasma-like pathogens of witches' broom disease, and are responsible for serious yield losses of Paulownia trees worldwide. The molecular mechanisms of disease development in Paulownia are of considerable interest, but still poorly understood. Here, we have applied transcriptome sequencing technology and a de novo assembly approach to analyze gene expression profiles in Paulownia fortunei infected by phytoplasmas. Our previous researches suggested that methyl methane sulfonated (MMS) could reverse the effects of the infection. In this study, leaf samples from healthy, infected, and both infected and methyl methane sulfonate treated plants were analyzed. The results showed that the gene expression profile of P. fortunei underwent dramatic changes after Paulownia witches' broom (PaWB) phytoplasma infection. Genes that encoded key enzymes in plant-pathogen interaction processes were significantly up-regulated in the PaWB infected Paulownia. Genes involved in circadian rhythm and hormone-related genes were also altered in Paulownia after PaWB infection. However, after the PaWB infected plants were treated with MMS, the expression profiles of these genes returned to the levels in the healthy controls. The data will help identify potential PaWB disease-resistance genes that could be targeted to inhibit the growth and reproduction of the pathogen and to increase plant resistance. PMID- 25514416 TI - Crosstalk between Edc4 and mammalian target of rapamycin complex 1 (mTORC1) signaling in mRNA decapping. AB - The mammalian target of rapamycin complex 1 (mTORC1) is involved in the cellular transcription and translation processes. The undertaken study characterized the enhancer of mRNA decapping protein 4 (Edc4) as mTORC1 interacting protein. Human T lymphoblast (CCRF-CEM) cells were used for mTORC1 purification. Co immunoprecipitation coupled with immunoblotting analysis was used to confirm the interaction of Edc4 in mTORC1 specific purifications. Further assays were incorporated to conclude the role of mTORC1 in mRNA decapping via Edc4. Edc4 was identified as a new interacting protein with mTORC1 in both the endogenous and myc-tag raptor component mTORC1 specific purifications. Quantitative co localization using confocal microscopy demonstrated that raptor component of mTORC1 coexists with Edc4 in processing (P) bodies, a site for mRNA degradation. Incubation of cells with rapamycin, a known inhibitor of mTOR kinase activity, increased the total Edc4 protein expression but at the same time decreased the Edc4 interaction with mTORC1. Moreover, rapamycin treatment resulted in a significant decrease in total serine phosphorylated Edc4 protein signal and the total 5'-capped mRNA. These findings provide the first evidence for the pivotal role of mTORC1 in Edc4 regulation. Further in-depth studies are required to get a complete understanding of molecular crosstalk between mTORC1 signaling and mRNA decapping pathway. PMID- 25514415 TI - Irisin, a link among fatty liver disease, physical inactivity and insulin resistance. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in industrialized countries. The increasing prevalence of NAFLD mirrors the outbreak of obesity in western countries, highlighting the connection between these two conditions. Nevertheless, there is currently no specific pharmacotherapy for its treatment. Accepted management begins with weight loss and exercise. Moreover, exercise can provide metabolic benefits independently of weight loss. It is known how long-term aerobic training produces improvements in hepatic triglycerides, visceral adipose tissue and free fatty acids, even if there is no weight reduction. A recent study from Bostrom et al. unravels a potential molecular mechanism that may explain how exercise, independently of weight loss, can potentially improve metabolic parameters through a new messenger system (irisin) linking muscle and fat tissue. Irisin has been proposed to act as a hormone on subcutaneous white fat cells increasing energy expenditure by means of a program of brown-fat-like development. Moreover, it was also shown that irisin plasma concentration was higher in people who exercise, suggesting a molecular mechanism by which exercise may improve metabolism. The present systematic review is based on the possibility that irisin might represent a hypothetical connection between NAFLD pathogenesis and disease progression. PMID- 25514417 TI - Characterization and expression of genes encoding three small heat shock proteins in Sesamia inferens (Lepidoptera: Noctuidae). AB - The pink stem borer, Sesamia inferens (Walker), is a major pest of rice and is endemic in China and other parts of Asia. Small heat shock proteins (sHSPs) encompass a diverse, widespread class of stress proteins that have not been characterized in S. inferens. In the present study, we isolated and characterized three S. inferens genes that encode members of the alpha-crystallin/sHSP family, namely, Sihsp21.4, Sihsp20.6, and Sihsp19.6. The three cDNAs encoded proteins of 187, 183 and 174 amino acids with calculated molecular weights of 21.4, 20.6 and 19.6 kDa, respectively. The deduced amino acid sequences of the three genes showed strong similarity to sHSPs identified in other lepidopteran insects. Sihsp21.4 contained an intron, but Sihsp20.6 and Sihsp19.6 lacked introns. Real time quantitative PCR analyses revealed that Sihsp21.4 was most strongly expressed in S. inferens heads; Whereas expression of Sihsp20.6 and Sihsp19.6 was highest in eggs. The three S. inferens sHSP genes were up-regulated during low temperature stress. In summary, our results show that S. inferens sHSP genes have distinct regulatory roles in the physiology of S. inferens. PMID- 25514419 TI - Impact of the Medicare Chronic Disease Management program on the conduct of Australian dietitians' private practices. AB - OBJECTIVE: This study explored private practice dietitians' perceptions of the impact of the Australian Chronic Disease Management (CDM) program on the conduct of their private practice, and the care provided to patients. METHODS: Twenty five accredited practising dietitians working in primary care participated in an individual semistructured telephone interview. Interview questions focussed on dietitians' perceptions of the proportion of patients receiving care through the CDM program, fee structures, adhering to reporting requirements and auditing. Transcript data were thematically analysed using a process of open coding. RESULTS: Half of the dietitians (12/25) reported that most of their patients (>75%) received care through the CDM program. Many dietitians (19/25) reported providing identical care to patients using the CDM program and private patients, but most (17/25) described spending substantially longer on administrative tasks for CDM patients. Dietitians experienced pressure from doctors and patients to keep their fees low or to bulk-bill patients using the CDM program. One-third of interviewed dietitians (8/25) expressed concern about the potential to be audited by Medicare. Recommendations to improve the CDM program included increasing the consultation length and subsequent rebate available for dietetic consultations, and increasing the number of consultations to align with dietetic best-practice guidelines. CONCLUSIONS: The CDM program creates challenges for dietitians working in primary care, including how to sustain the quality of patient-centred care and yet maintain equitable business practices. To ensure the CDM program appropriately assists patients to receive optimal care, further review of the CDM program within the scope of dietetics is required. PMID- 25514413 TI - What macromolecular crowding can do to a protein. AB - The intracellular environment represents an extremely crowded milieu, with a limited amount of free water and an almost complete lack of unoccupied space. Obviously, slightly salted aqueous solutions containing low concentrations of a biomolecule of interest are too simplistic to mimic the "real life" situation, where the biomolecule of interest scrambles and wades through the tightly packed crowd. In laboratory practice, such macromolecular crowding is typically mimicked by concentrated solutions of various polymers that serve as model "crowding agents". Studies under these conditions revealed that macromolecular crowding might affect protein structure, folding, shape, conformational stability, binding of small molecules, enzymatic activity, protein-protein interactions, protein nucleic acid interactions, and pathological aggregation. The goal of this review is to systematically analyze currently available experimental data on the variety of effects of macromolecular crowding on a protein molecule. The review covers more than 320 papers and therefore represents one of the most comprehensive compendia of the current knowledge in this exciting area. PMID- 25514418 TI - Sodium hydrosulfide prevents myocardial dysfunction through modulation of extracellular matrix accumulation and vascular density. AB - The aim was to examine the role of exogenous hydrogen sulfide (H2S) on cardiac remodeling in post-myocardial infarction (MI) rats. MI was induced in rats by ligation of coronary artery. After treatment with sodium hydrosulfide (NaHS, an exogenous H2S donor, 56 MUM/kg.day) for 42 days, the effects of NaHS on left ventricular morphometric features, echocardiographic parameters, heme oxygenase-1 (HO-1), matrix metalloproteinases-9 (MMP-9), type I and type III collagen, vascular endothelial growth factor (VEGF), CD34, and alpha-smooth muscle actin (alpha-SMA) in the border zone of infarct area were analyzed to elucidate the protective mechanisms of exogenous H2S on cardiac function and fibrosis. Forty two days post MI, NaHS-treatment resulted in a decrease in myocardial fibrotic area in association with decreased levels of type I, type III collagen and MMP-9 and improved cardiac function. Meanwhile, NaHS administration significantly increased cystathionine gamma-lyase (CSE), HO-1, alpha-SMA, and VEGF expression. This effect was accompanied by an increase in vascular density in the border zone of infarcted myocardium. Our results provided the strong evidences that exogenous H2S prevented cardiac remodeling, at least in part, through inhibition of extracellular matrix accumulation and increase in vascular density. PMID- 25514420 TI - The comparative cytotoxic effects of different local anesthetics on a human neuroblastoma cell line. AB - BACKGROUND: Although local anesthetics (LAs) are generally accepted as being safe, incidental neuronal damage has been reported for all LAs in humans. Therefore, in this study, we compared the dose corresponding to 50% cell lethality (LD50) of articaine, lidocaine, mepivacaine, bupivacaine, prilocaine, and ropivacaine in human neuroblastoma cells. METHODS: Undifferentiated SH-SY5Y cells were exposed for 20 minutes to different concentrations of each LA. Metabolic activity of viable cells was assessed by a cell viability test with a tetrazolium dye (WST-1) followed by optical density quantification. LD50 was determined by extrapolation of curve response. RESULTS: As expected, all LAs induced cell death in a concentration-dependent manner. The bupivacaine, lidocaine, prilocaine, mepivacaine, articaine, and ropivacaine LD50 were 0.95 +/- 0.08, 3.35 +/- 0.33, 4.32 +/- 0.39, 4.84 +/- 1.28, 8.98 +/- 2.07, and 13.43 +/- 0.61 mM, respectively, after 20 minutes of incubation on SH-SY5Y cells. Ropivacaine LD50 was significantly different from the bupivacaine, lidocaine, mepivacaine, and prilocaine LD50 (all P <= 0.009). No significant difference was obtained between ropivacaine and articaine LD50 and between prilocaine, lidocaine, and mepivacaine LD50. Articaine LD50 was significantly different from lidocaine LD50 (P = 0.03). Bupivacaine LD50 was significantly lower compared with all LAs (all P <= 0.003). CONCLUSIONS: LA neurotoxicity was tested in a validated in vitro model SH-SY5Y, a human neuroblastoma cell line. Three groups of LAs were identified in terms of toxicity: (1) the less (ropivacaine, articaine); (2) medium (mepivacaine, prilocaine, lidocaine); and (3) the high (bupivacaine). Among dental anesthetics, articaine is the least neurotoxic in SH-SY5Y cells. PMID- 25514422 TI - Systematic conservation planning for groundwater ecosystems using phylogenetic diversity. AB - Aquifer ecosystems provide a range of important services including clean drinking water. These ecosystems, which are largely inaccessible to humans, comprise a distinct invertebrate fauna (stygofauna), which is characterized by narrow distributions, high levels of endemism and cryptic species. Although being under enormous anthropogenic pressure, aquifers have rarely been included in conservation planning because of the general lack of knowledge of species diversity and distribution. Here we use molecular sequence data and phylogenetic diversity as surrogates for stygofauna diversity in aquifers of New South Wales, Australia. We demonstrate how to incorporate these data as conservation features in the systematic conservation planning software Marxan. We designated each branch of the phylogenetic tree as a conservation feature, with the branch length as a surrogate for the number of distinct characters represented by each branch. Two molecular markers (nuclear 18S ribosomal DNA and mitochondrial cytochrome oxidase subunit I) were used to evaluate how marker variability and the resulting tree topology affected the site-selection process. We found that the sites containing the deepest phylogenetic branches were deemed the most irreplaceable by Marxan. By integrating phylogenetic data, we provide a method for including taxonomically undescribed groundwater fauna in systematic conservation planning. PMID- 25514424 TI - Rhinogenic and nonrhinogenic headaches. AB - PURPOSE OF REVIEW: To review the present knowledge and the recent publications on the cause, characteristics, course and treatment of chronic and recurring facial pain and headaches. Facial pain is amongst the commonest complaints in ear, nose and throat clinics. Recent articles have presented important evidence-based approach to this common problem. RECENT FINDINGS: Recent publications in the fields of otolaryngology and neurology have better defined the differences between rhinogenic and nonrhinogenic facial pain, and place this symptom in the context of rhinosinusitis. Although chronic facial pain has conventionally been considered to be due to sinusitis because of anatomical proximity, there is increasing evidence to support the contrary. Published literature has identified that only 16-20% of patients with sinusitis (purulent or with polyposis) confirmed by nasal endoscopy actually declared symptoms of facial pain. More pertinently, surgical series have shown that up to 40% of patients had persistent postoperative facial pain despite resolution of sinusitis on nasal endoscopy and computed tomography (CT). Rhinogenic pain is generally unilateral, severe, located on the same side and related to rhinogenic symptoms, and almost always accompanied by endoscopic and CT abnormalities. Incidental CT mucosal disease can be noted in 30% of asymptomatic patients. SUMMARY: Traditionally, facial pain has often been considered to be caused by chronic rhinosinusitis. Increasing evidence has shown that the commonest cause for chronic facial pain is of nonrhinogenic origin. As otorhinolaryngologists, we deal with facial pain on a daily basis and therefore need to be aware of the different causes for this common symptom. PMID- 25514425 TI - Role of immunotherapy in allergic fungal rhinosinusitis. AB - PURPOSE OF REVIEW: Our understanding of the pathogenesis and treatment of allergic fungal rhinosinusitis (AFRS) continues to evolve. This article serves to update the reader on the diagnosis and management of AFRS and pays particular attention to the recent literature regarding efficacy and safety of immunotherapy in this patient population. RECENT FINDINGS: The mainstay of treatment of AFRS remains a thorough surgery; however, adjunctive medical management is also critical to achieve optimal outcomes. Oral steroid use in AFRS remains recommended. Immunotherapy, both fungal and nonfungal, may be considered for patients exhibiting a type I hypersensitivity to specific allergens. To date, limited studies do show improvement with reduction of postoperative exacerbations and revision surgeries. There remains no evidence of unusual side-effects or formation of immune complexes from immunotherapy in AFRS patients. Double-blind placebo controlled trials on immunotherapy and AFRS are lacking, and ultimately, conclusive evidence of efficacy is not present to date. SUMMARY: Treatment of AFRS requires multimodality therapy with immunotherapy playing a significant, yet inconclusive, role. Further studies remain warranted. PMID- 25514426 TI - Rhinology and skull base surgery: key updates in our field. PMID- 25514423 TI - Oxidative stress influences positive strand RNA virus genome synthesis and capping. AB - Flaviviruses are 5' capped positive-stranded RNA viruses that replicate their genomes within endoplasmic reticulum-derived vesicles. Flaviviruses are well known to induce oxidative stress late in infection but it is unknown if oxidative stress plays a positive role in the viral RNA replication cycle. We therefore examined how oxidation affects flavivirus RNA replication. We found that antioxidant treatment reduced virus production, reduced the viral positive-to negative strand RNA ratio, and resulted in the accumulation of uncapped positive sense viral RNAs. Treatment of the NS5 RNA capping enzyme in vitro with oxidizing agents enhanced guanylyltransferase activity, indicating that the guanylyltransferase function of the flavivirus NS5 RNA capping enzyme is activated by oxidative conditions. Antioxidant treatment also reduced alphavirus RNA replication and protein expression while enhancing nsP1 capping activity. These findings suggest that RNA viruses may utilize oxidative stress induced during infection to help temporally control genome RNA capping and genome replication. PMID- 25514427 TI - Predictive Value of IL-8 for Sepsis and Severe Infections After Burn Injury: A Clinical Study. AB - The inflammatory response induced by burn injury contributes to increased incidence of infections, sepsis, organ failure, and mortality. Thus, monitoring postburn inflammation is of paramount importance but, so far, there are no reliable biomarkers available to monitor and/or predict infectious complications after burn. As interleukin 8 (IL-8) is a major mediator for inflammatory responses, the aim of our study was to determine whether IL-8 expression can be used to predict postburn sepsis, infections, and mortality. Plasma cytokines, acute-phase proteins, constitutive proteins, and hormones were analyzed during the first 60 days after injury from 468 pediatric burn patients. Demographics and clinical outcome variables (length of stay, infection, sepsis, multiorgan failure [MOF], and mortality) were recorded. A cutoff level for IL-8 was determined using receiver operating characteristic analysis. Statistical significance is set at P < 0.05. Receiver operating characteristic analysis identified a cutoff level of 234 pg/mL for IL-8 for survival. Patients were grouped according to their average IL-8 levels relative to this cutoff and stratified into high (H) (n = 133) and low (L) (n = 335) groups. In the L group, regression analysis revealed a significant predictive value of IL-8 to percent of total body surface area burned and incidence of MOF (P < 0.001). In the H group, IL-8 levels were able to predict sepsis (P < 0.002). In the H group, elevated IL-8 was associated with increased inflammatory and acute-phase responses compared with the L group (P < 0.05). High levels of IL-8 correlated with increased MOF, sepsis, and mortality. These data suggest that serum levels of IL-8 may be a valid biomarker for monitoring sepsis, infections, and mortality in burn patients. PMID- 25514428 TI - WNT Agonist Decreases Tissue Damage and Improves Renal Function After Ischemia Reperfusion. AB - Renal ischemia-reperfusion (IR) injury (IRI) after shock states or transplantation causes tissue damage and delayed graft function, respectively. The Wnt/beta-catenin signaling pathway plays a critical role in nephrogenesis. We therefore hypothesized that pharmacological activation of the Wnt/beta-catenin signaling by the Wnt agonist, a synthetic pyrimidine, could protect kidneys from IRI. Adult male rats were subjected to bilateral clamping of the renal pedicles with microvascular clips for 60 min, followed by reperfusion. The Wnt agonist (5 mg/kg body weight) or vehicle (20% dimethyl sulfoxide in saline) was administered intravenously 1 h before ischemia. Blood and renal tissues were collected 24 h after IR for evaluation. Renal IR caused a significant reduction of beta-catenin and its downstream target gene cyclin D1 by 65% and 39%, respectively, compared with the sham, whereas the Wnt agonist restored them to sham levels. The number and intensity of cells staining with the proliferation marker Ki67 in ischematized kidneys were enhanced by the Wnt agonist. The integrity of the renal histological architecture in the Wnt agonist group was better preserved than the vehicle group. The Wnt agonist significantly lowered serum levels of creatinine, aspartate aminotransferase, and lactate dehydrogenase and inhibited the production of interleukin 6 and interleukin 1beta and myeloperoxidase activities. Lastly, the Wnt agonist reduced inducible nitric oxide synthase, nitrotyrosine proteins, and 4-hydroxynonenal in the kidneys by 60%, 47%, and 21%, respectively, compared with the vehicle. These results indicate that the Wnt agonist improves renal regeneration and function while attenuating inflammation and oxidative stress in the kidneys after IR. Thus, pharmacologic stimulation of the Wnt/beta catenin signaling provides a beneficial effect on the prevention of renal IRI. PMID- 25514429 TI - Alpha-lipoic acid prevents endotoxic shock and multiple organ dysfunction syndrome induced by endotoxemia in rats. AB - Alpha-lipoic acid (ALA), a naturally occurring disulfide derivative of octanoic acid, serves as a strong antioxidant and has been reported to possess anti inflammatory effects. The aim of the present study is to investigate the preventive and therapeutic effects of ALA on multiple organ dysfunction syndrome (MODS) caused by endotoxemia in rats. Male Wistar rats were intravenously infused with lipopolysaccharide (LPS) (10 mg/kg) to induce endotoxemia. Alpha-lipoic acid 10, 20, or 40 mg/kg was administered intravenously 60 min before (pretreatment) LPS challenge, and ALA 40 mg/kg was administered intravenously 30 min after (posttreatment) LPS challenge. Pretreatment and posttreatment with ALA significantly improved the deleterious hemodynamic changes 8 h after LPS challenge, including hypotension and bradycardia. Alpha-lipoic acid reduced the plasma levels of glutamic pyruvic transaminase, blood urea nitrogen, lactate dehydrogenase, tumor necrosis factor-alpha, nitric oxide metabolites, and thrombin-antithrombin complex, which increased markedly after LPS challenge. The induction of inducible nitric oxide synthase both in the liver and the lung and vascular superoxide anion production were also significantly suppressed by ALA. Moreover, ALA significantly attenuated LPS-induced caspase-3 activation in cardiomyocytes and improved survival rate. In conclusion, ALA effectively attenuated LPS-induced acute inflammatory response and improved MODS. The antioxidant and anti-inflammatory effects of ALA may contribute to these beneficial effects. Alpha-lipoic acid might be considered as a novel therapeutic strategy in the prevention of sepsis-induced MODS and inflammatory vascular diseases. PMID- 25514430 TI - Significance of Traumatic Macroamputation in Severely Injured Patients: An Analysis of the Traumaregister DGU(r). AB - Treatment of patients with traumatic macroamputations is challenging. The aim of this study is to analyze the significance of this type of injury in TraumaRegister DGU(r) (TR-DGU) and to depict the rate of formal surgical ablation of the traumatically induced amputation, epidemiologic data, as well as outcome in severely injured patients with amputations. We acquired data from the TR-DGU of the German Trauma Society (DGU). The inclusion criteria for our study were Injury Severity Score (ISS) greater than 9, macroamputation, and available data about the Abbreviated Injury Scale (AIS) code. A total of 48,908 of 67,425 patients had an ISS greater than 9 and available data about the AIS code. In total, 926 (1.9%) of 48,908 patients had an immediate traumatic macroamputation on-scene. Thereof, 298 patients (32.2%) had a macroamputation of the arms, 605 patients (65.3%) had an amputation of the legs, and 23 patients (2.5%) had both. Among them, 457 patients (49.4%) with a macroamputation had monotrauma. In total, 126 patients (13.6%) underwent replantation and 800 patients (86.4%) underwent formal surgical ablation of the traumatically induced amputation. Seventy-six (23.7%) of 321 patients with upper-extremity amputations and 53 (8.4%) of 628 patients with lower-extremity amputations underwent replantation. Mortality in patients with replantation was lower (5.6% vs. 19.6%, P < 0.001). Standardized mortality rate was lower for patients with replantation (0.71, 95% confidence interval, 0.20-1.21 vs. 0.94, 95% confidence interval, 0.80-1.10; P = 0.26). Glasgow Outcome Scale (GOS) was significantly better for patients with replantation (34.0%; GOS score 5) as compared with patients without replantation (20.7%; GOS score 5; P < 0.001). In borderline patients (defined according to the orthopedic damage control principles), 91.5% received formal surgical ablation of the traumatically induced amputation and 8.5% underwent replantation. The rate of formal surgical ablation of the traumatically induced amputation is higher when principles of damage control surgery are applied. The replantation rate in the upper extremity is higher than in the lower extremity. The less ISS and base excess and the higher blood pressure, hemoglobin value, and thromboplastin time are, the safer the decision for replantation seems to be. PMID- 25514432 TI - Investigating Biological Assumptions through Radical Reimplementation. AB - An important goal in both artificial life and biology is uncovering the most general principles underlying life, which might catalyze both our understanding of life and engineering lifelike machines. While many such general principles have been hypothesized, conclusively testing them is difficult because life on Earth provides only a singular example from which to infer. To circumvent this limitation, this article formalizes an approach called radical reimplementation. The idea is to investigate an abstract biological hypothesis by intentionally reimplementing its main principles to diverge maximally from existing natural examples. If the reimplementation successfully exhibits properties resembling biology, it may support the underlying hypothesis better than an alternative example inspired more directly by nature. The approach thereby provides a principled alternative to a common tradition of defending and minimizing deviations from nature in artificial life. This work reviews examples that can be interpreted through the lens of radical reimplementation to yield potential insights into biology despite having purposely unnatural experimental setups. In this way, radical reimplementation can help renew the relevance of computational systems for investigating biological theory and can act as a practical philosophical tool to help separate the fundamental features of terrestrial biology from the epiphenomenal. PMID- 25514433 TI - Creating and maintaining chemical artificial life by robotic symbiosis. AB - We present a robotic platform based on the open source RepRap 3D printer that can print and maintain chemical artificial life in the form of a dynamic, chemical droplet. The robot uses computer vision, a self-organizing map, and a learning program to automatically categorize the behavior of the droplet that it creates. The robot can then use this categorization to autonomously detect the current state of the droplet and respond. The robot is programmed to visually track the droplet and either inject more chemical fuel to sustain a motile state or introduce a new chemical component that results in a state change (e.g., division). Coupling inexpensive open source hardware with sensing and feedback allows for replicable real-time manipulation and monitoring of nonequilibrium systems that would be otherwise tedious, expensive, and error-prone. This system is a first step towards the practical confluence of chemical, artificial intelligence, and robotic approaches to artificial life. PMID- 25514431 TI - Systems biology investigation of cAMP modulation to increase SMN levels for the treatment of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA), a leading genetic cause of infant death worldwide, is an autosomal recessive disorder caused by the loss of SMN1 (survival motor neuron 1), which encodes the protein SMN. The loss of SMN1 causes a deficiency in SMN protein levels leading to motor neuron cell death in the anterior horn of the spinal cord. SMN2, however, can also produce some functional SMN to partially compensate for loss of SMN1 in SMA suggesting increasing transcription of SMN2 as a potential therapy to treat patients with SMA. A cAMP response element was identified on the SMN2 promoter, implicating cAMP activation as a step in the transcription of SMN2. Therefore, we investigated the effects of modulating the cAMP signaling cascade on SMN production in vitro and in silico. SMA patient fibroblasts were treated with the cAMP signaling modulators rolipram, salbutamol, dbcAMP, epinephrine and forskolin. All of the modulators tested were able to increase gem formation, a marker for SMN protein in the nucleus, in a dose dependent manner. We then derived two possible mathematical models simulating the regulation of SMN2 expression by cAMP signaling. Both models fit well with our experimental data. In silico treatment of SMA fibroblasts simultaneously with two different cAMP modulators resulted in an additive increase in gem formation. This study shows how a systems biology approach can be used to develop potential therapeutic targets for treating SMA. PMID- 25514434 TI - Lambda and the edge of chaos in recurrent neural networks. AB - The idea that there is an edge of chaos, a region in the space of dynamical systems having special meaning for complex living entities, has a long history in artificial life. The significance of this region was first emphasized in cellular automata models when a single simple measure, lambdaCA, identified it as a transitional region between order and chaos. Here we introduce a parameter lambdaNN that is inspired by lambdaCA but is defined for recurrent neural networks. We show through a series of systematic computational experiments that lambdaNN generally orders the dynamical behaviors of randomly connected/weighted recurrent neural networks in the same way that lambdaCA does for cellular automata. By extending this ordering to larger values of lambdaNN than has typically been done with lambdaCA and cellular automata, we find that a second edge-of-chaos region exists on the opposite side of the chaotic region. These basic results are found to hold under different assumptions about network connectivity, but vary substantially in their details. The results show that the basic concept underlying the lambda parameter can usefully be extended to other types of complex dynamical systems than just cellular automata. PMID- 25514435 TI - A would-be nervous system made from a slime mold. AB - The slime mold Physarum polycephalum is a huge single cell that has proved to be a fruitful material for designing novel computing architectures. The slime mold is capable of sensing tactile, chemical, and optical stimuli and converting them to characteristic patterns of its electrical potential oscillations. The electrical responses to stimuli may propagate along protoplasmic tubes for distances exceeding tens of centimeters, as impulses in neural pathways do. A slime mold makes decisions about its propagation direction based on information fusion from thousands of spatially extended protoplasmic loci, similarly to a neuron collecting information from its dendritic tree. The analogy is distant yet inspiring. We speculate on whether alternative-would-be-nervous systems can be developed and practically implemented from the slime mold. We uncover analogies between the slime mold and neurons, and demonstrate that the slime mold can play the roles of primitive mechanoreceptors, photoreceptors, and chemoreceptors; we also show how the Physarum neural pathways develop. The results constituted the first step towards experimental laboratory studies of nervous system implementation in slime molds. PMID- 25514437 TI - Sustainable responsible research and innovation through secure, private data. PMID- 25514438 TI - Pd-catalyzed cross-coupling of aryllithium reagents with 2-alkoxy-substituted aryl chlorides: mild and efficient synthesis of 3,3'-diaryl BINOLs. AB - Palladium-catalyzed cross-coupling of aryllithium reagents with 2-alkoxy substituted aryl chlorides is described. The reactions proceed under mild conditions with short reaction times and provide a wide range of 2-alkoxy substituted biaryls. This new methodology is applied to the efficient preparation of 3,3'-diaryl BINOLs and represents the first synthesis of this important class of chiral compounds from the corresponding 3,3'-dichloro BINOLs. PMID- 25514439 TI - Towards high-energy and durable lithium-ion batteries via atomic layer deposition: elegantly atomic-scale material design and surface modification. AB - Targeted at fueling future transportation and sustaining smart grids, lithium-ion batteries (LIBs) are undergoing intensive investigation for improved durability and energy density. Atomic layer deposition (ALD), enabling uniform and conformal nanofilms, has recently made possible many new advances for superior LIBs. The progress was summarized by Liu and Sun in their latest review [1], offering many insightful views, covering the design of nanostructured battery components (i.e., electrodes and solid electrolytes), and nanoscale modification of electrode/electrolyte interfaces. This work well informs peers of interesting research conducted and it will also further help boost the applications of ALD in next-generation LIBs and other advanced battery technologies. PMID- 25514436 TI - Genetics of microstructure of the corpus callosum in older adults. AB - The current study sought to examine the relative influence of genetic and environmental factors on corpus callosum (CC) microstructure in a community sample of older adult twins. Analyses were undertaken in 284 healthy older twins (66% female; 79 MZ and 63 DZ pairs) from the Older Australian Twins Study. The average age of the sample was 69.82 (SD = 4.76) years. Brain imaging scans were collected and DTI measures were estimated for the whole CC as well as its five subregions. Parcellation of the CC was performed using Analyze. In addition, white matter lesion (WMLs) burden was estimated. Heritability and genetic correlation analyses were undertaken using the SOLAR software package. Age, sex, scanner, handedness and blood pressure were considered as covariates. Heritability (h(2)) analysis for the DTI metrics of whole CC, indicated significant h(2) for fractional anisotropy (FA) (h(2) = 0.56; p = 2.89*10(-10)), mean diffusivity (MD) (h(2) = 0.52; p = 0.30*10(-6)), radial diffusivity (RD) (h(2) = 0.49; p = 0.2*10(-6)) and axial diffusivity (AD) (h(2) = 0.37; p = 8.15*10(-5)). We also performed bivariate genetic correlation analyses between (i) whole CC DTI measures and (ii) whole CC DTI measures with total brain WML burden. Across the DTI measures for the whole CC, MD and RD shared 84% of the common genetic variance, followed by MD-AD (77%), FA-RD (52%), RD-AD (37%) and FA MD (11%). For total WMLs, significant genetic correlations indicated that there was 19% shared common genetic variance with whole CC MD, followed by CC RD (17%), CC AD (16%) and CC FA (5%). Our findings suggest that the CC microstructure is under moderate genetic control. There was also evidence of shared genetic factors between the CC DTI measures. In contrast, there was less shared genetic variance between WMLs and the CC DTI metrics, suggesting fewer common genetic variants. PMID- 25514440 TI - Emergence of a KPC-3-Producing Escherichia coli ST69 as a Cause of Bloodstream Infections in Italy. AB - The spread of carbapenem-resistant gram negatives is a global emergency, and surveillance of new resistant clones is critical from both public health and clinical standpoints. Herein, we describe the emergence of a KPC-3-producing Escherichia coli ST69 as a cause of bloodstream infection in two Italian patients. PMID- 25514441 TI - Finding a way through the forest: A Biopsychosocial model of hot flashes. PMID- 25514442 TI - Chronic lung injury in the neonatal rat: up-regulation of TGFbeta1 and nitration of IGF-R1 by peroxynitrite as likely contributors to impaired alveologenesis. AB - Postnatal alveolarization is regulated by a number of growth factors, including insulin-like growth factor-I (IGF-I) acting through the insulin-like growth factor receptor-1 (IGF-R1). Exposure of the neonatal rat lung to 60% O2 for 14 days results in impairments of lung cell proliferation, secondary crest formation, and alveologenesis. This lung injury is mediated by peroxynitrite and is prevented by treatment with a peroxynitrite decomposition catalyst. We hypothesized that one of the mechanisms by which peroxynitrite induces lung injury in 60% O2 is through nitration and inactivation of critical growth factors or their receptors. Increased nitration of both IGF-I and IGF-R1 was evident in 60% O2-exposed lungs, which was reversible by concurrent treatment with a peroxynitrite decomposition catalyst. Increased nitration of the IGF-R1 was associated with its reduced activation, as assessed by IGF-R1 phosphotyrosine content. IGF-I displacement binding plots were conducted in vitro using rat fetal lung distal epithelial cells which respond to IGF-I by an increase in DNA synthesis. When IGF-I was nitrated to a degree similar to that observed in vivo there was minimal, if any, effect on IGF-I displacement binding. In contrast, nitrating cell IGF-R1 to a similar degree to that observed in vivo completely prevented specific binding of IGF-I to the IGF-R1, and attenuated an IGF-I mediated increase in DNA synthesis. Additionally, we hypothesized that peroxynitrite also impairs alveologenesis by being an upstream regulator of the growth inhibitor, TGFbeta1. That 60% O2-induced impairment of alveologenesis was mediated in part by TGFbeta1 was confirmed by demonstrating an improvement in secondary crest formation when 60% O2-exposed pups received concurrent treatment with the TGFbeta1 activin receptor-like kinase, SB 431542. That the increased TGFbeta1 content in lungs of pups exposed to 60% O2 was regulated by peroxynitrite was confirmed by its attenuation by concurrent treatment with a peroxynitrite decomposition catalyst. We conclude that peroxynitrite contributes to the impaired alveologenesis observed following the exposure of neonatal rats to 60% O2 both by preventing binding of IGF-I to the IGF-R1, secondary to nitration of the IGF-R1, and by causing an up-regulation of the growth inhibitor, TGFbeta1. PMID- 25514445 TI - Comment on "tympanometry screening criteria in children ages 5-7 yr" by Swanepoel et al. PMID- 25514444 TI - Alpha band cortico-muscular coherence occurs in healthy individuals during mechanically-induced tremor. AB - The present work aimed at investigating the effects of mechanically amplified tremor on cortico-muscular coherence (CMC) in the alpha band. The study of CMC in this specific band is of particular interest because this coherence is usually absent in healthy individuals and it is an aberrant feature in patients affected by pathological tremors; understanding its mechanisms is therefore important. Thirteen healthy volunteers (23+/-4 years) performed elbow flexor sustained contractions both against a spring load and in isometric conditions at 20% of maximal voluntary isometric contraction (MVC). Spring stiffness was selected to induce instability in the stretch reflex servo loop. 64 EEG channels, surface EMG from the biceps brachii muscle and force were simultaneously recorded. Contractions against the spring resulted in greater fluctuations of the force signal and EMG amplitude compared to isometric conditions (p<.05). During isometric contractions CMC was systematically found in the beta band and sporadically observed in the alpha band. However, during the contractions against the spring load, CMC in the alpha band was observed in 12 out of 13 volunteers. Partial directed coherence (PDC) revealed an increased information flow in the EMG to EEG direction in the alpha band (p<.05). Therefore, coherence in the alpha band between the sensory-motor cortex and the biceps brachii muscle can be systematically induced in healthy individuals by mechanically amplifying tremor. The increased information flow in the EMG to EEG direction may reflect enhanced afferent activity from the muscle spindles. These results may contribute to the understanding of the presence of alpha band CMC in tremor related pathologies by suggesting that the origin of this phenomenon may not only be at cortical level but may also be affected by spinal circuit loops. PMID- 25514446 TI - Tympanometry screening criteria in children ages 5-7 yr. AB - BACKGROUND: Despite its value as a diagnostic measure of middle-ear function, recommendations for tympanometry as a screening test for middle-ear disorders have been tentative. This is primarily due to concerns related to over-referrals, cost-effectiveness, variability in referral criteria and protocols, variable reported screen performance, and influence of demographic and environmental factors. PURPOSE: The current study assessed tympanometry in a large population of children between 5-7 yr old in terms of normative ranges, performance of current recommended referral criteria, and associations with independent demographic and environmental variables. RESEARCH DESIGN: Retrospective cohort study. STUDY SAMPLE: A total of 2868 children and their families were originally enrolled in the Raine Cohort Study in Western Australia. Of these, 1469 children between 5-7 yr old (average age = 5.97 yr, SD = 0.17 yr) were evaluated with tympanometry and pure-tone audiometry screening. DATA COLLECTION AND ANALYSIS: Tympanometry was conducted using a 226 Hz probe tone with screening ipsilateral acoustic reflexes recorded using a 1000 Hz stimulus. Hearing screening was conducted using pure tones at 20 dB HL for 1000, 2000, and 4000 Hz. Relationships among normative ranges (90% and 95% ranges) for tympanometric indices, age, gender, and month of test were determined. Associations were also explored between tympanometry referrals and month of test, gender, and absence of acoustic reflexes. RESULTS: Normative 90% ranges for tympanometric peak pressure was -275 to 15 daPa, 60-150 daPa for peak compensated tympanometric width, 0.2 and 1.0 mmho for peak compensated static admittance, and 0.7-1.3 cm3 for ear canal volume. Current screening guidelines result in high referral rates for children 5 7 yr old (13.3% and 11.5% using the American Speech-Language-Hearing Association [ASHA] and American Academy of Audiology [AAA] guidelines, respectively). The subgroup of children 6-7 yr old had referral rates (for ears tested) of only 3.3% and 2.7%, respectively, according to ASHA and AAA guidelines. The prevalence of middle-ear effusion (admittance <0.1 mmho) was significantly different across seasons, with the highest (13.5%) in September and lowest (3.8%) in January. Month of test was associated with a general decrease in tympanometric peak pressure across the population. CONCLUSIONS: An 80% reduction in tympanometry referrals for children ages 6 and 7 yr compared with children age 5 yr argues for tympanometry as a first-tier screening method in older children only. The impact of regional seasonal influences, representing an increase in referrals as high as 3.5 times from one month to another, should also inform and direct pediatric screening programs for middle-ear functioning and/or hearing loss. PMID- 25514448 TI - Subjective assessment of cochlear implant users' signal-to-noise ratio requirements for different levels of wireless device usability. AB - BACKGROUND: In order to better inform the development and revision of the American National Standards Institute C63.19 and American National Standards Institute/Telecommunications Industry Association-1083 hearing aid compatibility standards, a previous study examined the signal strength and signal (speech)-to noise (interference) ratio needs of hearing aid users when using wireless and cordless phones in the telecoil coupling mode. This study expands that examination to cochlear implant (CI) users, in both telecoil and microphone modes of use. PURPOSE: The purpose of this study was to evaluate the magnetic and acoustic signal levels needed by CI users for comfortable telephone communication and the users' tolerance relative to the speech levels of various interfering wireless communication-related noise types. RESEARCH DESIGN: Design was a descriptive and correlational study. Simulated telephone speech and eight interfering noise types presented as continuous signals were linearly combined and were presented together either acoustically or magnetically to the participants' CIs. The participants could adjust the loudness of the telephone speech and the interfering noises based on several assigned criteria. STUDY SAMPLE: The 21 test participants ranged in age from 23-81 yr. All used wireless phones with their CIs, and 15 also used cordless phones at home. There were 12 participants who normally used the telecoil mode for telephone communication, whereas 9 used the implant's microphone; all were tested accordingly. DATA COLLECTION AND ANALYSIS: A guided-intake questionnaire yielded general background information for each participant. A custom-built test control box fed by prepared speech-and-noise files enabled the tester or test participant, as appropriate, to switch between the various test signals and to precisely control the speech-and noise levels independently. The tester, but not the test participant, could read and record the selected levels. Subsequent analysis revealed the preferred speech levels, speech (signal)-to-noise ratios, and the effect of possible noise measurement weighting functions. RESULTS: The participants' preferred telephone speech levels subjectively matched or were somewhat lower than the level that they heard from a 65 dB SPL wideband reference. The mean speech (signal)-to-noise ratio requirement for them to consider their telephone experience "acceptable for normal use" was 20 dB, very similar to the results for the hearing aid users of the previous study. Significant differences in the participants' apparent levels of noise tolerance among the noise types when the noise level was determined using A-weighting were eliminated when a CI-specific noise-measurement weighting was applied. CONCLUSIONS: The results for the CI users in terms of both preferred levels for wireless and cordless phone communication and signal-to-noise requirements closely paralleled the corresponding results for hearing aid users from the previous study, and showed no significant differences between the microphone and telecoil modes of use. Signal-to-noise requirements were directly related to the participants' noise audibility threshold and were independent of noise type when appropriate noise-measurement weighting was applied. Extending the investigation to include noncontinuous interfering noises and forms of radiofrequency interference other than additive audiofrequency noise could be areas of future study. PMID- 25514447 TI - Validation of a screening test of auditory function using the telephone. AB - BACKGROUND: Several European countries have demonstrated successful use of telephone screening tests for auditory function. The screening test consists of spoken three-digit sequences presented in a noise background. The speech-to-noise ratios of the stimuli are determined by an adaptive tracking method that converges on the level required to achieve 50% correct recognition. PURPOSE: A version of the three-digit telephone screening protocol for the United States was developed: the US National Hearing Test (NHT). The objective of the current study was to determine the sensitivity and specificity as well as the feasibility of the NHT for use within the Department of Veterans Affairs (VA). Research Design and Study Sample: Using a multisite study design with convenience sampling, we used the NHT to collect data from 693 participants (1379 ears) from three geographical areas of the United States (Florida, Tennessee, and California). DATA COLLECTION AND ANALYSIS: The NHT procedures were as follows: the participants (1) called a toll-free telephone number, (2) entered their assigned ear-specific identification code, (3) listened to 40-sets of digit triplets presented in speech-spectrum background noise, and (4) entered in the numbers that they heard on the telephone key pad. The NHT was performed on each ear, either at home or in a VA clinic. In addition to collecting data from the experimental task, we gathered demographic data and the data from other standard of-care tests (i.e., audiometric thresholds and speech recognition tests in quiet and in noise). RESULTS: A total of 505 participants completed the NHT at a VA clinic, whereas 188 completed the test at home. Although the ear-specific NHT and mean pure-tone threshold all correlated significantly (p < 0.001), there were more modest correlations in the low- and high-frequency ranges with the highest correlation seen with the 2000 Hz mean pure-tone threshold. When the NHT 50% point or threshold was compared with the three-frequency PTA at 500, 1000, and 2000 Hz, the sensitivity was 0.87 and specificity was 0.54. When comparing the NHT with the four-frequency PTA at 500, 1000, 2000, and 4000 Hz, the sensitivity was 0.81 and specificity increased to 0.65. The NHT also correlated strongly with other speech-in-noise measures. CONCLUSIONS: The NHT was found to correlate with other audiometric measures, including pure-tone thresholds and speech recognition tests in noise, at sufficiently high correlation values to support its use as a screening test of auditory function. PMID- 25514449 TI - Does electrode impedance affect the recording of ocular vestibular-evoked myogenic potentials? AB - BACKGROUND: In evoked potential testing, it is common practice to abrade the skin surface as a means of reducing and balancing electrode impedance. The effects of skin preparation and electrode impedance on ocular vestibular-evoked myogenic potential (oVEMP) prevalence and amplitudes are not known. PURPOSE: We sought to determine whether comparable oVEMP waveforms could be recorded without excessive skin preparation. RESEARCH DESIGN: This was a prospective study with a repeated measures (within-subjects) design. STUDY SAMPLE: The study group comprised 20 healthy participants (12 females and 8 males) ages 21-57 yr. DATA COLLECTION AND ANALYSIS: oVEMP reflexes were recorded in response to air-conducted and bone conducted (AC and BC) stimuli in three conditions. In the first condition (no skin preparation), electrodes were simply placed over the skin surface. For the second condition (moderate skin preparation), oVEMP testing was repeated after the skin had been prepared with 70% isopropyl alcohol swabs. oVEMPs recorded in these two conditions were then compared with those recorded using a third conventional protocol whereby the skin was abraded with skin preparation gel until electrode impedances were low and balanced. For BC stimuli, reflex amplitudes and latencies were compared using a repeated-measures general linear model. For AC stimuli, rates of reflex detection were analyzed using a generalized estimating equation. Nonparametric Friedman tests were used to compare AC oVEMP amplitudes across the three conditions. RESULTS: There was no significant effect of electrode impedance on reflex amplitudes, latencies, or rates of detection (p > 0.05). The results indicated significant stimulus-related artifact (>=3 MUV) in 25 of 40 recordings under the high-impedance condition in response to BC stimulation. The stimulus artifact was detectable in 12 of 40 recordings after moderate skin preparation and in 5 recordings after skin abrasion. CONCLUSIONS: Comparable rates of reflex detection and oVEMP amplitudes were recorded in the three conditions, implying that rigorous rubbing of the facial skin is largely unnecessary in clinical oVEMP testing. However, for oVEMPs recorded in response to a single-polarity stimulus, reducing and balancing electrode impedances with either isopropyl alcohol wipes or skin abrasion may help reduce unwanted stimulus artifact. PMID- 25514450 TI - Cognition and speech-in-noise recognition: the role of proactive interference. AB - BACKGROUND: Complex working memory (WM) span tasks have been shown to predict speech-in-noise (SIN) recognition. Studies of complex WM span tasks suggest that, rather than indexing a single cognitive process, performance on such tasks may be governed by separate cognitive subprocesses embedded within WM. Previous research has suggested that one such subprocess indexed by WM tasks is proactive interference (PI), which refers to difficulties memorizing current information because of interference from previously stored long-term memory representations for similar information. PURPOSE: The aim of the present study was to investigate phonological PI and to examine the relationship between PI (semantic and phonological) and SIN perception. RESEARCH DESIGN: A within-subjects experimental design was used. STUDY SAMPLE: An opportunity sample of 24 young listeners with normal hearing was recruited. DATA COLLECTION AND ANALYSIS: Measures of resistance to, and release from, semantic and phonological PI were calculated alongside the signal-to-noise ratio required to identify 50% of keywords correctly in a SIN recognition task. The data were analyzed using t-tests and correlations. RESULTS: Evidence of release from and resistance to semantic interference was observed. These measures correlated significantly with SIN recognition. Limited evidence of phonological PI was observed. CONCLUSIONS: The results show that capacity to resist semantic PI can be used to predict SIN recognition scores in young listeners with normal hearing. On the basis of these findings, future research will focus on investigating whether tests of PI can be used in the treatment and/or rehabilitation of hearing loss. PMID- 25514452 TI - Electrophysiological gap detection thresholds: effects of age and comparison with a behavioral measure. AB - BACKGROUND: Temporal processing ability has been linked to speech understanding ability and older adults often complain of difficulty understanding speech in difficult listening situations. Temporal processing can be evaluated using gap detection procedures. There is some research showing that gap detection can be evaluated using an electrophysiological procedure. However, there is currently no research establishing gap detection threshold using the N1-P2 response. PURPOSE: The purposes of the current study were to 1) determine gap detection thresholds in younger and older normal-hearing adults using an electrophysiological measure, 2) compare the electrophysiological gap detection threshold and behavioral gap detection threshold within each group, and 3) investigate the effect of age on each gap detection measure. DESIGN: This study utilized an older adult group and younger adult group to compare performance on an electrophysiological and behavioral gap detection procedure. STUDY SAMPLE: The subjects in this study were 11 younger, normal-hearing adults (mean = 22 yrs) and 11 older, normal-hearing adults (mean = 64.36 yrs). DATA COLLECTION: All subjects completed an adaptive behavioral gap detection procedure in order to determine their behavioral gap detection threshold (BGDT). Subjects also completed an electrophysiologic gap detection procedure to determine their electrophysiologic gap detection threshold (EGDT). RESULTS: Older adults demonstrated significantly larger gap detection thresholds than the younger adults. However, EGDT and BGDT were not significantly different in either group. The mean difference between EGDT and BGDT for all subjects was 0.43 msec. CONCLUSIONS: Older adults show poorer gap detection ability when compared to younger adults. However, this study shows that gap detection thresholds can be measured using evoked potential recordings and yield results similar to a behavioral measure. PMID- 25514451 TI - Paired comparisons of nonlinear frequency compression, extended bandwidth, and restricted bandwidth hearing aid processing for children and adults with hearing loss. AB - BACKGROUND: Preference for speech and music processed with nonlinear frequency compression (NFC) and two controls (restricted bandwidth [RBW] and extended bandwidth [EBW] hearing aid processing) was examined in adults and children with hearing loss. PURPOSE: The purpose of this study was to determine if stimulus type (music, sentences), age (children, adults), and degree of hearing loss influence listener preference for NFC, RBW, and EBW. RESEARCH DESIGN: Design was a within-participant, quasi-experimental study. Using a round-robin procedure, participants listened to amplified stimuli that were (1) frequency lowered using NFC, (2) low-pass filtered at 5 kHz to simulate the RBW of conventional hearing aid processing, or (3) low-pass filtered at 11 kHz to simulate EBW amplification. The examiner and participants were blinded to the type of processing. Using a two alternative forced-choice task, participants selected the preferred music or sentence passage. STUDY SAMPLE: Participants included 16 children (ages 8-16 yr) and 16 adults (ages 19-65 yr) with mild to severe sensorineural hearing loss. INTERVENTION: All participants listened to speech and music processed using a hearing aid simulator fit to the Desired Sensation Level algorithm v5.0a. RESULTS: Children and adults did not differ in their preferences. For speech, participants preferred EBW to both NFC and RBW. Participants also preferred NFC to RBW. Preference was not related to the degree of hearing loss. For music, listeners did not show a preference. However, participants with greater hearing loss preferred NFC to RBW more than participants with less hearing loss. Conversely, participants with greater hearing loss were less likely to prefer EBW to RBW. CONCLUSIONS: Both age groups preferred access to high-frequency sounds, as demonstrated by their preference for either the EBW or NFC conditions over the RBW condition. Preference for EBW can be limited for those with greater degrees of hearing loss, but participants with greater hearing loss may be more likely to prefer NFC. Further investigation using participants with more severe hearing loss may be warranted. PMID- 25514453 TI - The Ling 6(HL) test: typical pediatric performance data and clinical use evaluation. AB - BACKGROUND: The Ling 6(HL) test offers a calibrated version of naturally produced speech sounds in dB HL for evaluation of detection thresholds. Aided performance has been previously characterized in adults. PURPOSE: The purpose of this work was to evaluate and refine the Ling 6(HL) test for use in pediatric hearing aid outcome measurement. RESEARCH DESIGN: This work is presented across two studies incorporating an integrated knowledge translation approach in the characterization of normative and typical performance, and in the evaluation of clinical feasibility, utility, acceptability, and implementation. STUDY SAMPLE: A total of 57 children, 28 normally hearing and 29 with binaural sensorineural hearing loss, were included in Study 1. Children wore their own hearing aids fitted using Desired Sensation Level v5.0. Nine clinicians from The Network of Pediatric Audiologists participated in Study 2. DATA COLLECTION AND ANALYSIS: A CD-based test format was used in the collection of unaided and aided detection thresholds in laboratory and clinical settings; thresholds were measured clinically as part of routine clinical care. Confidence intervals were derived to characterize normal performance and typical aided performance according to hearing loss severity. Unaided-aided performance was analyzed using a repeated measures analysis of variance. The audiologists completed an online questionnaire evaluating the quality, feasibility/executability, utility/comparative value/relative advantage, acceptability/applicability, and interpretability, in addition to recommendation and general comments sections. RESULTS: Ling 6(HL) thresholds were reliably measured with children 3-18 yr old. Normative and typical performance ranges were translated into a scoring tool for use in pediatric outcome measurement. In general, questionnaire respondents generally agreed that the Ling 6(HL) test was a high-quality outcome evaluation tool that can be implemented successfully in clinical settings. CONCLUSIONS: By actively collaborating with pediatric audiologists and using an integrated knowledge translation framework, this work supported the creation of an evidence-based clinical tool that has the potential to be implemented in, and useful to, clinical practice. More research is needed to characterize performance in alternative listening conditions to facilitate use with infants, for example. Future efforts focused on monitoring the use of the Ling 6(HL) test in daily clinical practice may help describe whether clinical use has been maintained across time and if any additional adaptations are necessary to facilitate clinical uptake. PMID- 25514454 TI - Evaluation of wideband frequency responses and nonlinear frequency compression for children with cookie-bite audiometric configurations. AB - BACKGROUND: Previous research has suggested that use of nonlinear frequency compression (NLFC) can improve audibility for high-frequency sounds and speech recognition of children with moderate to profound high-frequency hearing loss. Furthermore, previous studies have generally found no detriment associated with the use of NLFC. However, there have been no published studies examining the effect of NLFC on the performance of children with cookie-bite audiometric configurations. For this configuration of hearing loss, frequency-lowering processing will likely move high-frequency sounds to a lower frequency range at which a greater degree of hearing loss exists. PURPOSE: The purpose of this study was to evaluate and compare the effects of wideband amplification and NLFC on high-frequency audibility and speech recognition of children with cookie-bite audiometric configurations. RESEARCH DESIGN: This study consisted of a within participant design with repeated measures across test conditions. STUDY SAMPLE: Seven children, ages 6-13 yr, with cookie-bite audiometric configurations and normal hearing or mild hearing loss at 6000 and 8000 Hz, were recruited. INTERVENTION: Participants were fitted with Phonak Nios S H2O III behind-the-ear hearing aids and Oticon Safari 300 behind-the-ear hearing aids. DATA COLLECTION: The participants were evaluated after three 4-to 6-wk intervals: (1) Phonak Nios S H2O III without NLFC, (2) Phonak Nios S H2O III with NLFC, and (3) Oticon Safari 300 with wideband frequency response extending to 8000 Hz. The order in which each technology was used was counterbalanced across participants. High frequency audibility was evaluated by assessing aided thresholds (dB SPL) for warble tones and the high-frequency phonemes /sh/ and /s/. Speech recognition in quiet was measured with the University of Western Ontario (UWO) Plurals Test, the UWO Distinctive Features Difference (DFD) Test, and the Phoneme Perception Test vowel-consonant-vowel nonsense syllable test. Sentence recognition in noise was evaluated with the Bamford-Kowal-Bench Speech-In-Noise (BKB-SIN) Test. ANALYSIS: Repeated-measures analyses of variance were used to analyze the data collected in this study. The results across the three different conditions were compared. RESULTS: No difference in performance across conditions was observed for detection of high-frequency warble tones and the speech sounds /sh/ and /s/. No significant difference was seen across conditions for speech recognition in quiet when measured with the UWO Plurals Test, the UWO-DFD Test, and the Phoneme Perception Test vowel-consonant-vowel nonsense syllable test. Finally, there were also no differences across conditions on the BKB-SIN Test. CONCLUSIONS: These results suggest that NLFC does not degrade or improve audibility for and recognition of high-frequency speech sounds as well as sentence recognition in noise when compared with wideband amplification for children with cookie-bite audiometric configurations. PMID- 25514455 TI - Time for a change: a note on hearing loss terminology. PMID- 25514457 TI - Base-mediated cascade rearrangements of aryl-substituted diallyl ethers. AB - Two base-mediated cascade rearrangement reactions of diallyl ethers were developed leading to selective [2,3]-Wittig-oxy-Cope and isomerization-Claisen rearrangements. Both diaryl and arylsilyl-substituted 1,3-substituted propenyl substrates were examined, and each exhibits unique reactivity and different reaction pathways. Detailed mechanistic and computational analysis was conducted, which demonstrated that the role of the base and solvent was key to the reactivity and selectivity observed. Crossover experiments also suggest that these reactions proceed with a certain degree of dissociation, and the mechanistic pathway is highly complex with multiple competing routes. PMID- 25514458 TI - Chromatographic evidence of silyl ether formation (SEF) in supercritical fluid chromatography. AB - In this article, we propose that silyl ether formation (SEF) is a major contribution to retention and selectivity variation over time for supercritical fluid chromatography (SFC). In the past, the variations were attributed to instrumentation, but high performance SFC systems have shed new light on the source of variation. As silyl ethers form on the particle surface, the hydrophilicity is decreased, significantly altering the retention and selectivity observed. SEF is expected to occur with any chromatographic particle containing silanols but is slowed on hybrid inorganic/organic particles. The SEF reaction is between alcohols on the particle surface and in the mobile phase solvent. We have found that storage conditions of a column are paramount, which can either prevent or accelerate the process. Because SEF exists as an equilibrium between the liquid phase and the particle surface, the process is also reversible. The silanols can be hydroxylated (regenerated) to their original state upon exposure to water. The next generation of stationary phases will either advantageously utilize SEF or effectively mitigate its effects. Mitigation of SEF would be a significant improvement in SFC that has the potential to vault their performance to levels of similar reproducibility and reliability observed for high performance liquid chromatography (HPLC). Further research in SEF may lead to a better understanding of the mechanism of interaction between the solutes and chromatographic surface. PMID- 25514459 TI - Interaction effects of temperature and ozone on lung function and markers of systemic inflammation, coagulation, and fibrinolysis: a crossover study of healthy young volunteers. AB - BACKGROUND: Trends in climate suggest that extreme weather events such as heat waves will become more common. High levels of the gaseous pollutant ozone are associated with elevated temperatures. Ozone has been associated with respiratory diseases as well as cardiovascular morbidity and mortality and can reduce lung function and alter systemic markers of fibrinolysis. The interaction between ozone and temperature is unclear. METHODS: Sixteen healthy volunteers were exposed in a randomized crossover study to 0.3 ppm ozone and clean air for 2 hr at moderate (22 degrees C) temperature and again at an elevated temperature (32.5 degrees C). In each case lung function was performed and blood taken before and immediately after exposure and the next morning. RESULTS: Ozone exposure at 22 degrees C resulted in a decrease in markers of fibrinolysis the next day. There was a 51.8% net decrease in PAI-1 (plasminogen activator inhibitor-1), a 12.1% net decrease in plasminogen, and a 17.8% net increase in D-dimer. These significantly differed from the response at 32.5 degrees C, where there was a 44.9% (p = 0.002) and a 27.9% (p = 0.001) increase in PAI-1 and plasminogen, respectively, and a 12.5% (p = 0.042) decrease in D-dimer. In contrast, decrements in lung function following ozone exposure were comparable at both moderate and elevated temperatures (forced expiratory volume in 1 sec, -12.4% vs. -7.5%, p > 0.05). No changes in systemic markers of inflammation were observed for either temperature. CONCLUSION: Ozone-induced systemic but not respiratory effects varied according to temperature. Our study suggests that at moderate temperature ozone may activate the fibrinolytic pathway, while at elevated temperature ozone may impair it. These findings provide a biological basis for the interaction between temperature and ozone on mortality observed in some epidemiologic studies. PMID- 25514461 TI - ROS production, intracellular HSP70 levels and their relationship in human neutrophils: effects of age. AB - ROS production and intracellular HSP70 levels were measured in human neutrophils for three age groups: young (20-59 years), elders (60-89 years) and nonagenarians (90 years and older). Elders showed higher levels of spontaneous intracellular ROS content compared with young and nonagenarian groups, which had similar intracellular ROS levels. Zymosan-induced (non-spontaneous) extracellular ROS levels were also similar for young and nonagenarians but were lower in elders. However, spontaneous extracellular ROS production increased continuously with age. Correlation analysis revealed positive relationships between HSP70 levels and zymosan-stimulated ROS production in the elder group. This was consistent with a promoting role for HSP70 in ROS-associated neutrophils response to pathogens. No positive correlation between ROS production and intracellular HSP70 levels was found for groups of young people and nonagenarians. In contrast, significant negative correlations of some ROS and HSP70 characteriscics were found for neutrophils from young people and nonagenarians. The observed difference in ROS and HSP70 correlations in elders and nonagenarians might be associated with an increased risk of mortality in older individuals less than 90 years old. PMID- 25514462 TI - Claudin-7 promotes the epithelial-mesenchymal transition in human colorectal cancer. AB - In colorectal cancer (CoCa) EpCAM is frequently associated with claudin-7. There is evidence that tumor-promoting EpCAM activities are modulated by the association with claudin-7. To support this hypothesis, claudin-7 was knocked down (kd) in HT29 and SW948 cells. HT29-cld7kd and SW948-cld7kd cells display decreased anchorage-independent growth and the capacity for holoclone-, respectively, sphere-formation is reduced. Tumor growth is delayed and cld7kd cells poorly metastasize. In line with this, migratory and invasive potential of cld7kd clones is strongly impaired, migration being inhibited by anti-CD49c, but not anti-EpCAM, although motility is reduced in EpCAM siRNA-treated cells. This is due to claudin-7 recruiting EpCAM in glycolipid-enriched membrane fractions towards claudin-7-associated TACE and presenilin2, which cleave EpCAM. The cleaved intracellular domain, EpIC, promotes epithelial-mesenchymal transition (EMT)-associated transcription factor expression, which together with fibronectin and vimentin are reduced in claudin-7kd cells. But, uptake of HT29wt and SW948wt exosomes by the claudin-7kd lines sufficed for transcription factor upregulation and for restoring motility. Thus, claudin-7 contributes to motility and invasion and is required for recruiting EpCAM towards TACE/presenilin2. EpIC generation further supports motility by promoting a shift towards EMT. Notably, EMT features of cld7-competent metastatic CoCa cells can be transferred via exosomes to poorly metastatic cells. PMID- 25514460 TI - TAp73 promotes anabolism. AB - Metabolic adaptation has emerged as a hallmark of cancer and a promising therapeutic target, as rapidly proliferating cancer cells adapt their metabolism increasing nutrient uptake and reorganizing metabolic fluxes to support biosynthesis. The transcription factor p73 belongs to the p53-family and regulates tumorigenesis via its two N-terminal isoforms, with (TAp73) or without (DeltaNp73) a transactivation domain. TAp73 acts as tumor suppressor, at least partially through induction of cell cycle arrest and apoptosis and through regulation of genomic stability. Here, we sought to investigate whether TAp73 also affects metabolic profiling of cancer cells. Using high throughput metabolomics, we unveil a thorough and unexpected role for TAp73 in promoting Warburg effect and cellular metabolism. TAp73-expressing cells show increased rate of glycolysis, higher amino acid uptake and increased levels and biosynthesis of acetyl-CoA. Moreover, we report an extensive TAp73-mediated upregulation of several anabolic pathways including polyamine and synthesis of membrane phospholipids. TAp73 expression also increases cellular methyl-donor S adenosylmethionine (SAM), possibly influencing methylation and epigenetics, and promotes arginine metabolism, suggestive of a role in extracellular matrix (ECM) modeling. In summary, our data indicate that TAp73 regulates multiple metabolic pathways that impinge on numerous cellular functions, but that, overall, converge to sustain cell growth and proliferation. PMID- 25514465 TI - Cs8[Fe4S10] and Cs7[Fe4S8], two new sulfido ferrates with different tetrameric anions. AB - The two new cesium sulfido ferrates Cs(8)[Fe(4)S(10)] and Cs(7)[Fe(4)S(8)] were synthesized at a maximum temperature of 1070 K in corundum crucibles from stoichiometric samples containing elemental Fe and S together with cesium disulfide, Cs(2)S(2). Their crystal structures have been determined by means of single-crystal X-ray diffraction. Cs(8)[Fe(III)(4)S(10)] crystallizes in the triclinic Cs(6)[Ga(4)Se(10)]-type structure and is thus isotypic to the corresponding rubidium salt. The structure exhibits tetramers [Fe(4)S(10)](8-) of edge-sharing tetrahedra, which represent segments of the well-known chain compounds A[FeS(2)]. The monoclinic mixed-valent iron(II/III) sulfido ferrate Cs(7)[Fe(4)S(8)], which is isotypic to the cesium tellurido ferrate, likewise contains oligomeric tetramers of four edge-sharing [FeS(4)] tetrahedra, in this case resulting in only slightly distorted tetrahedral [Fe(4)S(8)](7-) anions with a Fe(4)S(4) cubane core resembling the prominent [Fe(4)(MU(3)-S(4))](+) cluster, e.g., in the active site of ferredoxins. These sulfido ferrate anions are surrounded by 26 Cs cations, which are located at the 8 corners, 6 faces, and 12 edges of a cube. A dense stacking of these cubes, which ultimately results in the overall seven cesium countercations per cluster anion, describes the overall crystal structure completely. According to this arrangement of cluster-centered cubes, a relationship of the packing of Cs cations and cluster anions with the simple cubic packing (alpha-Po-type structure) can be established by applying the crystallographic group-subgroup formalism. FP-LAPW band-structure calculations applying antiferromagnetic spin ordering of the high-spin Fe ions in the two tetramers predict a small band gap of 1 eV associated with a L -> M-CT for Cs(8)[Fe(III)(4)S(10)] and a tiny energy gap of 0.1 eV resulting from a d-d transition for the mixed-valent cluster compound Cs(7)[Fe(II/III)(4)S(8)]. PMID- 25514463 TI - The Na+/H+ exchanger (NHE1) as a novel co-adjuvant target in paclitaxel therapy of triple-negative breast cancer cells. AB - Dysregulation of Na+/H+ exchanger isoform one (NHE1) activity is a hallmark of cells undergoing tumorigenesis and metastasis, the leading cause of patient mortality. The acidic tumor microenvironment is thought to facilitate the development of resistance to chemotherapy drugs and to promote extracellular matrix remodeling leading to metastasis. Here, we investigated NHE1 as a co adjuvant target in paclitaxel chemotherapy of metastatic breast cancer. We generated a stable NHE1-knockout of the highly invasive, triple-negative, MDA-MB 231 breast cancer cells. The NHE1-knockout cells proliferated comparably to parental cells, but had markedly lower rates of migration and invasion in vitro. In vivo xenograft tumor growth in athymic nude mice was also dramatically decreased compared to parental MDA-MB-231 cells. Loss of NHE1 expression also increased the susceptibility of knockout cells to paclitaxel-mediated cell death. NHE1 inhibition, in combination with paclitaxel, resulted in a dramatic decrease in viability, and migratory and invasive potential of triple-negative breast cancer cells, but not in hormone receptor-positive, luminal MCF7 cells. Our data suggest that NHE1 is critical in triple-negative breast cancer metastasis, and its chemical inhibition boosts the efficacy of paclitaxel in vitro, highlighting NHE1 as a novel, potential co-adjuvant target in breast cancer chemotherapy. PMID- 25514464 TI - A novel antisense long noncoding RNA regulates the expression of MDC1 in bladder cancer. AB - Antisense long noncoding RNAs (lncRNAs) play important roles in regulating the expression of coding genes in post-transcriptional level. However, detailed expression profile of lncRNAs and functions of antisense lncRNAs in bladder cancer remains unclear. To investigate regulation of lncRNAs in bladder cancer and demonstrate their functions, we performed lncRNAs microarray analysis in 3 paired bladder cancer tissues. Further molecular assays were conducted to determine the potential role of identified antisense lncRNA MDC1-AS. As a result, a series of lncRNAs were differentially expressed in bladder cancer tissues in microarray screen. In a larger size of samples validation, we found that the expression levels of MDC1-AS and MDC1 was down-regulated in bladder cancer. After over-expression of MDC1-AS, increased levels of MDC1 were observed in bladder cancer cells. We also found a remarkably inhibitory role of antisense lncRNA MDC1 AS on malignant cell behaviors in bladder cancer cells EJ and T24. Subsequently, knockdown of MDC1 revealed that suppressing role of MDC1-AS was attributed to up regulation of MDC1. In summary, we have identified a novel antisense lncRNA MDC1 AS, which may participate in bladder cancer through up-regulation of its antisense tumor-suppressing gene MDC1. Further studies should be conducted to demonstrate detailed mechanism of our findings. PMID- 25514467 TI - The utility of the International Classification of Functioning, Disability and Health checklist for evaluating disability in a community-dwelling geriatric population sample. AB - The aim of this study was to investigate disability in community-dwelling individuals aged 65 years and over using the International Classification of Functioning, Disability and Health (ICF) checklist and the World Health Organization Disability Assessment Schedule II (WHODAS-II) and to compare how these two ICF-based instruments measured disability in an attempt to show the utility of the ICF checklist in a field setting to describe disability. In this population-based, cross-sectional and descriptive study, data on the ICF checklist and the WHODAS-II were collected from 200 selected participants who lived in a small town. Both the ICF checklist and the WHODAS-II identified a considerable proportion of the elderly with a disability in life areas relevant to cognition and domestic life in a similar manner, the proportions ranging from 52.5 to 68.5%. However, the proportions of those with a disability showed a statistically significant difference in the domains of the two instruments relevant to mobility, self-care, and participation in society. Although the absolute intrarater agreement for matching items of the instruments ranged from 40.5 to 87.5%, kappa statistics showed slight to moderate agreement for the original ICF qualifier and mostly moderate agreement with reduced response options. ICF qualifiers were found to discriminate between the WHODAS-II domain scores in those with no, mild-moderate and severe-complete difficulty. The disparity between the data obtained from the ICF checklist and the WHODAS-II in some domains may have resulted from differing interpretations of the items of the ICF checklist, lower reliability of some of the items, and the current feature of the qualifiers used without any adaptations. The ICF checklist has the potential to be used in a field setting, provided that some modifications are made. PMID- 25514468 TI - Next generation carbon nanoparticles for efficient gene therapy. AB - In a pursuit to develop a commercially exploitable and traceable gene delivery vehicle, here, we develop next generation carbon nanoparticle-DNA complex (CNPLex). CNPLexes were used to transfect green fluorescent protein (GFP) reporter gene containing plasmid DNA (pDNA) pEGFP-N1 targeting breast cancer cells MCF-7 and MDA-MB231. Prepared CNPs were optimized for particle size, surface potential, polymer surface decoration, absorbance efficiency, fluorescence efficiency, IR spectroscopic signatures, and DNA loading and release efficiencies. Rigorous biophysical methods were employed to determine the variations in physicochemical properties of CNPs after surface decoration with polymers followed by complexation with pDNA. Optimized CNPLexes were used to deliver pEGFP-N1 plasmid and efficiency of GFP was followed by fluorescence microscopy and quantified by flow assisted cell sorting. Lipofectamine2000 was used as positive control according to manufacturer's protocol and found to be comparative in transfection efficiency with one of our novel formulations. Further evaluation of cell toxicity and cell viability was performed by LDH activity and MTT assay, respectively. It was found that cell toxicity furnished by polymer decorated carbon nanoparticles was significantly low compared to the parent polymer (polyethylenimine, PEI). Similarly cell viability was found to be much higher with CNPLexes compared to PEI alone. This established the developed particles as better transfecting agents for reporter gene plasmid pEGFP-N1 compared to PEI and showed similar efficacy to one of the best known commercial transfection agents Liofectamine2000 in breast cancer cells MCF-7 and MDA-MB231. PMID- 25514466 TI - The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer. AB - Prostate cancer is the second leading cause of cancer death in the United States. Treatment of localized high-risk disease and de novo metastatic disease frequently leads to relapse. These metastatic castration resistant prostate cancers (mCRPC) claim a high mortality rate, despite the extended survival afforded by the growing armamentarium of androgen deprivation, radiation and immunotherapies. Here, we review two studies of neoadjuvant treatment of high risk localized prostate cancer prior to prostatectomy, the total androgen pathway suppression (TAPS) trial and the neoadjuvant abiraterone acetate (AA) trial. These two trials assessed the efficacy of the non-specific P450c17 inhibitor, ketoconazole and the specific P450c17 inhibitor, AA, to inhibit tissue and serum androgen levels. Furthermore, a novel and validated stable isotope dilution liquid chromatography electrospray ionization selected reaction monitoring mass spectrometry assay was used to accurately quantify adrenal and gonadal androgens in circulation during the course of these trials. The adrenal androgens, Delta(4) androstene-3,17-dione, dehydroepiandrosterone and dehydroepiandrosterone sulfate were significantly reduced in the patients receiving ketoconazole or AA compared to those who did not. However, in both trials, a significant amount of DHEA-S (~20 MUg/dL) persists and thus may serve as a depot for intratumoral conversion to the potent androgen receptor ligands, testosterone (T) and 5alpha dihydrotestosterone (DHT). The final step in conversion of Delta(4)-androstene 3,17-dione and 5alpha-androstanedione to T and DHT, respectively, is catalyzed by AKR1C3. We therefore present the case that in the context of the DHEA-S depot, P450c17 and AKR1C3 inhibition may be an effective combinatorial treatment strategy. PMID- 25514470 TI - Measuring forces and spatiotemporal evolution of thin water films between an air bubble and solid surfaces of different hydrophobicity. AB - A combination of atomic force microscopy (AFM) and reflection interference contrast microscopy (RICM) was used to measure simultaneously the interaction force and the spatiotemporal evolution of the thin water film between a bubble in water and mica surfaces with varying degrees of hydrophobicity. Stable films, supported by the repulsive van der Waals-Casimir-Lifshitz force were always observed between air bubble and hydrophilic mica surfaces (water contact angle, theta(w) < 5 degrees ) whereas bubble attachment occurred on hydrophobized mica surfaces. A theoretical model, based on the Reynolds lubrication theory and the augmented Young-Laplace equation including the effects of disjoining pressure, provided excellent agreement with experiment results, indicating the essential physics involved in the interaction between air bubble and solid surfaces can be elucidated. A hydrophobic interaction free energy per unit area of the form: WH(h) = -gamma(1 - cos theta(w))exp(-h/D(H)) can be used to quantify the attraction between bubble and hydrophobized solid substrate at separation, h, with gamma being the surface tension of water. For surfaces with water contact angle in the range 45 degrees < theta(w) < 90 degrees , the decay length DH varied between 0.8 and 1.0 nm. This study quantified the hydrophobic interaction in asymmetric system between air bubble and hydrophobic surfaces, and provided a feasible method for synchronous measurements of the interaction forces with sub nN resolution and the drainage dynamics of thin films down to nm thickness. PMID- 25514471 TI - Langerhans cell histiocytosis involving the skin and the thymus. PMID- 25514469 TI - A structural model of the genome packaging process in a membrane-containing double stranded DNA virus. AB - Two crucial steps in the virus life cycle are genome encapsidation to form an infective virion and genome exit to infect the next host cell. In most icosahedral double-stranded (ds) DNA viruses, the viral genome enters and exits the capsid through a unique vertex. Internal membrane-containing viruses possess additional complexity as the genome must be translocated through the viral membrane bilayer. Here, we report the structure of the genome packaging complex with a membrane conduit essential for viral genome encapsidation in the tailless icosahedral membrane-containing bacteriophage PRD1. We utilize single particle electron cryo-microscopy (cryo-EM) and symmetry-free image reconstruction to determine structures of PRD1 virion, procapsid, and packaging deficient mutant particles. At the unique vertex of PRD1, the packaging complex replaces the regular 5-fold structure and crosses the lipid bilayer. These structures reveal that the packaging ATPase P9 and the packaging efficiency factor P6 form a dodecameric portal complex external to the membrane moiety, surrounded by ten major capsid protein P3 trimers. The viral transmembrane density at the special vertex is assigned to be a hexamer of heterodimer of proteins P20 and P22. The hexamer functions as a membrane conduit for the DNA and as a nucleating site for the unique vertex assembly. Our structures show a conformational alteration in the lipid membrane after the P9 and P6 are recruited to the virion. The P8-genome complex is then packaged into the procapsid through the unique vertex while the genome terminal protein P8 functions as a valve that closes the channel once the genome is inside. Comparing mature virion, procapsid, and mutant particle structures led us to propose an assembly pathway for the genome packaging apparatus in the PRD1 virion. PMID- 25514472 TI - Manifestation of unconventional biexciton states in quantum dots. AB - Although semiconductor excitons consist of a fermionic subsystem (electron and hole), they carry an integer net spin similar to Cooper-electron-pairs. While the latter cause superconductivity by forming a Bose-Einstein-condensate, excitonic condensation is impeded by, for example, a fast radiative decay of the electron hole pairs. Here, we investigate the behaviour of two electron-hole pairs in a quantum dot with wurtzite crystal structure evoking a charge carrier separation on the basis of large spontaneous and piezoelectric polarizations, thus reducing carrier overlap and consequently decay probabilities. As a direct consequence, we find a hybrid-biexciton complex with a water molecule-like charge distribution enabling anomalous spin configurations. In contrast to the conventional-biexciton complex with a net spin of s=0, the hybrid-biexciton exhibits s=+/-3, leading to completely different photoluminescence signatures in addition to drastically enhanced charge carrier-binding energies. Consequently, the biexcitonic cascade via the dark exciton can be enhanced on the rise of temperature as approved by photon cross-correlation measurements. PMID- 25514473 TI - Rationally Engineering Phototherapy Modules of Eosin-Conjugated Responsive Polymeric Nanocarriers via Intracellular Endocytic pH Gradients. AB - Spatiotemporal switching of respective phototherapy modes at the cellular level with minimum side effects and high therapeutic efficacy is a major challenge for cancer phototherapy. Herein we demonstrate how to address this issue by employing photosensitizer-conjugated pH-responsive block copolymers in combination with intracellular endocytic pH gradients. At neutral pH corresponding to extracellular and cytosol milieu, the copolymers self-assemble into micelles with prominently quenched fluorescence emission and low (1)O2 generation capability, favoring a highly efficient photothermal module. Under mildly acidic pH associated with endolysosomes, protonation-triggered micelle-to-unimer transition results in recovered emission and enhanced photodynamic (1)O2 efficiency, which synergistically actuates release of encapsulated drugs, endosomal escape, and photochemical internalization processes. PMID- 25514474 TI - Cobalt-catalyzed enantioselective directed C-H alkylation of indole with styrenes. AB - A cobalt-chiral phosphoramidite catalyst promotes enantioselective imine-directed C2-alkylation of Boc-protected indoles with styrenes. The reaction affords 1,1 diarylethane products in moderate to good yields with good enantioselectivities under mild conditions. A deuterium-labeling experiment suggests that the enantioselectivity is controlled by both the styrene insertion and the C-C reductive elimination steps. PMID- 25514475 TI - Increased IL-22 level in allergic rhinitis significantly correlates with clinical severity. AB - BACKGROUND: IL-22 regulates various processes and has been linked to diverse effects. However, the importance of IL-22 in the pathogenesis of allergic rhinitis (AR) remains poorly understood. This study sought to evaluate the levels of IL-22 and IL-17A in AR patients and their association with clinical severity ofN AR. METHODS: Thirty-six AR patients and 22 normal controls were enrolled in this study. The frequencies of IL-22(+), IL-17A(+), and IL-9(+) T helper (Th) cells in peripheral blood of AR patients and normal controls were examined by flow cytometry. Serum levels of IL-22 and IL-17A in AR patients and normal controls were determined by ELISA. The clinical relevance of the percentages of IL-22(+) and IL-17A(+) Th cells as well as serum IL-22 and IL-17A levels were evaluated. RESULTS: The frequencies of IL-22(+) and IL-17A(+) Th cells, but not IL-9(+) Th cells, were significantly increased compared with those in normal controls (p < 0.05). Frequencies of IL-22(+) and IL-17A(+) Th cells in peripheral blood of AR patients significantly correlated with visual analog scale scores of nasal symptoms (nasal congestion and rhinorrhea; p < 0.05). Moreover, the serum levels of IL-22 and IL-17A were significantly increased compared with those in normal controls (p < 0.05) and significantly correlated with the levels of Dermatophagoides pteronyssinus and Dermatophagoides farinae specific IgE in AR patients. CONCLUSION: Our findings suggested that IL-22 as well as IL-17A may play an important role in the regulation of Th2-skewed inflammation in AR patients. PMID- 25514476 TI - Combined use of scoring incisions and 2-octylcyanoacrylate adhesive during endonasal septoplasty to correct cartilaginous deviations. AB - BACKGROUND: Applying 2-octylcyanoacrylate (2-OCA) tissue adhesive onto scoring incisions may increase efficacy and prevent concavity recurrence after septal deviation treatment. The present study evaluates the utility of 2-OCA adhesive application during endonasal septoplasty. METHODS: The postoperative outcomes were compared between two consecutive periods in a single surgical department. Between March 2011 and March 2012, 23 consecutive patients underwent septoplasty using scoring incisions without 2-OCA application (scoring alone group), and between April 2012 and April 2013, the scoring incision gaps were filled with 2 OCA in 27 patients (scoring + CA group). The patients were followed up for more than six months. RESULTS: A straight septum was achieved in 37.0% of patients in the scoring alone group versus 58.3% in the scoring + CA group. The postoperative symptom score for nasal obstruction was significantly improved in both groups. Persistent septal swelling developed in three (12.5%) patients in the scoring + CA group. Neither group experienced major complications such as septal hematoma, abscess, or septal perforation. CONCLUSIONS: Application of 2-OCA adhesive onto scoring incisions appears to be a reliable and effective technique to correct deviated cartilage during endonasal septoplasty. However, the volume of 2-OCA applied onto the septum should be minimized to avoid potential foreign body reaction. A long-term follow-up study is warranted. PMID- 25514477 TI - Allergic rhinitis phenotypes based on bronchial hyperreactivity to methacholine. AB - BACKGROUND: Allergic rhinitis (AR) and asthma may be associated, bronchial hyperreactivity (BHR) is quite common in AR patients. Methacholine (MCH) is a stimulus able to elicit BHR, as many other ones. Phenotyping AR is an up-to-date issue. OBJECTIVE: The aim of this study was to evaluate whether MCH bronchial challenge is able to differentiate patients with AR. METHODS: A total of 298 patients (277 males, mean age 28.9 years), suffering from AR were evaluated. Sensitization, rhinitis duration, values for bronchial function (forced vital capacity [FVC], forced expiratory volume [FEV]1, forced expiratory flow [FEF]25 75, and FEV1/FVC ratio), MCH bronchial challenge, visual analog scale (VAS) for nasal and bronchial symptoms perception, and fractioned exhaled nitric oxide (FeNO) were evaluated. RESULTS: BHR-positive patients (22.8%) had significantly more frequent mite allergy (p = 0.025), longer AR duration (p < 0.001), lower FEV1 (p = 0.003), FEV1/FVC (p < 0.001), FEF25-75 (p < 0.001), higher (p < 0.001), and higher VAS values for both nasal and bronchial symptoms (p < 0.001 for both) in comparison with BHR-negative patients. FeNO can be considered a good predictor for BHR in AR patients (area under the curve, 0.90) with 27.0 ppb as cutoff. CONCLUSIONS: The present study demonstrates that BHR to MCH could define two distinct phenotypes in AR patients. It could be clinically relevant as BHR positive patients have initial impairment of lung function, impaired FeNO values, and worsening of respiratory symptoms perception. PMID- 25514478 TI - A report on 15 years of clinical negligence claims in rhinology. AB - BACKGROUND: This study was designed to determine the characteristics of medical negligence claims in rhinology. In 2010-2011 the National Health Service (NHS) litigation bill surpassed 1 billion Great British Pounds (GBP; 1.52 billion U.S. dollars [US$]). Systematic analysis of malpractice complaints allows for the identification of errors and can thereby improve patient safety and reduce the burden of litigation claims on health services. METHODS: Claims relating to ear, nose, and throat between 1995 and 2010 were obtained from the NHS Litigation Authority and were analyzed. RESULTS: The series contains 65 closed claims that resulted in payment totaling 3.1 million GBP (US$4.7 million). Fifty claims were related to surgical complications. Functional endoscopic sinus surgery and septoplasty were the procedures most commonly associated with successful claims. There were 11 cases of orbital injury including 6 cases of visual loss and 5 cases of diplopia. The most common cause of a claim was failure to recognize the complication or manage it appropriately. Lack of informed consent was claimed in eight cases. Other claims arose because of errors in outpatient procedures (two), diagnosis (six), delayed surgery (one), and errors in medical management (three). CONCLUSION: This is the first study to report the outcomes of negligence claims in rhinology in the United Kingdom. Claims in rhinology are associated with a high success rate. Steps that can be taken to reduce litigation include careful patient workup and ensuring adequate informed consent. Where there is a suspicion of orbital damage early recognition and intervention is needed to reduce long term injury to the patient. PMID- 25514479 TI - Editorial: Studying the spectrum of allergic and rhinologic disease. PMID- 25514480 TI - Th2 cytokines differentially regulate psoriasin expression in human nasal epithelia. AB - BACKGROUND: Psoriasin is known to be expressed in diverse organs, where it exerts antimicrobial activity. Psoriasin is also involved in the local host defense mechanism against pathogens. We hypothesized that allergy-related T-helper cell type 2 (Th2) cytokines may regulate the expression of psoriasin. METHODS: We treated normal human nasal epithelial (NHNE) cells with IL-4 or IL-13. Using human nasal tissues, we compared the expression level of psoriasin. We performed real-time polymerase chain reaction and Western blot assays using NHNE cells. Immunohistochemical staining and Western blot assays were performed with human nasal tissues. Furthermore, we studied the antimicrobial activity of nasal secretions from normal and allergic rhinitis patients. RESULTS: IL-13 markedly down-regulated psoriasin expression at the gene and protein levels in NHNE cells, and it also decreased the amount of psoriasin protein that was secreted into the extracellular compartment in NHNE cells. IL-4 had no statistically significant effect. Results from immunohistochemical staining and Western blot assays showed that psoriasin expression was decreased in allergic rhinitis patients compared with control subjects. Nasal secretions of allergic rhinitis patients exhibited decreased antimicrobial activity compared with control subjects. CONCLUSION: We found that Th2 cytokines regulated psoriasin expression in NHNE cells, and psoriasin expression was decreased in allergic rhinitis patients compared with control subjects. The decreased expression of psoriasin may be related to the reduction in antimicrobial capacity of nasal secretions under allergic conditions, resulting in an increase in susceptibility to viruses or bacterial infections. PMID- 25514481 TI - The effect of drugs and other compounds on the ciliary beat frequency of human respiratory epithelium. AB - BACKGROUND: Cilia in the human respiratory tract play a critical role in clearing mucus and debris from the airways. Their function can be affected by a number of drugs or other substances, many of which alter ciliary beat frequency (CBF). This has implications for diseases of the respiratory tract and nasal drug delivery. This article is a systematic review of the literature that examines 229 substances and their effect on CBF. METHODS: MEDLINE was the primary database used for data collection. Eligibility criteria based on experimental design were established, and 152 studies were ultimately selected. Each individual trial for the substances tested was noted whenever possible, including concentration, time course, specific effect on CBF, and source of tissue. RESULTS: There was a high degree of heterogeneity between the various experiments examined in this article. Substances and their general effects (increase, no effect, decrease) were grouped into six categories: antimicrobials and antivirals, pharmacologics, human biological products, organisms and toxins, drug excipients, and natural compounds/other manipulations. CONCLUSION: Organisms, toxins, and drug excipients tend to show a cilioinhibitory effect, whereas substances in all other categories had mixed effects. All studies examined were in vitro experiments, and application of the results in vivo is confounded by several factors. The data presented in this article should be useful in future respiratory research and examination of compounds for therapeutic and drug delivery purposes. PMID- 25514482 TI - Development of Aspergillus protease with ovalbumin-induced allergic chronic rhinosinusitis model in the mouse. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a multifactorial inflammatory disease. Particularly, eosinophilic CRS is often recalcitrant to treatment, so an appropriate animal model is required to evaluate the pathogenesis of, and to develop therapies for, recalcitrant eosinophilic CRS. This study aimed to improve the ovalbumin (OVA)-induced mouse model of eosinophilic/allergic CRS by combining OVA with Aspergillus protease, which is known to trigger allergic reactions in mouse lungs. METHODS: In a model of allergic CRS, mice were challenged intranasally with Aspergillus protease combined with OVA. Local and systemic responses were measured. Protease (0.54 U) from Aspergillus oryzae, prepared with or without OVA (75 micrograms), OVA alone, or saline, was administered intranasally to wild-type mice for 5 weeks. Sinonasal complex samples were evaluated histologically, and interleukin (IL)-4, IL-5, IL-6, macrophage inflammatory protein (MIP) 2, and tumor necrosis factor (TNF) alpha were measured in nasal lavage fluid. A differential white blood cell count was also performed. RESULTS: OVA alone induced minimal eosinophilic inflammation in sinonasal mucosa, while protease + OVA and protease alone induced moderate eosinophilic inflammation. Protease + OVA elevated eosinophil counts in blood comparable with controls, but not compared with OVA alone. Although IL-4, IL-5, IL-6, MIP-2, and TNF-alpha were increased in all study mice, the levels of IL-4 and IL-6 were higher in mice treated with protease + OVA than in mice treated with OVA alone. Protease alone excessively elevated the levels of IL-6, MIP-2, and TNF-alpha, not Th2 cytokines, compared with OVA alone and protease + OVA. CONCLUSION: Aspergillus protease combined with OVA induced more severe allergic inflammation in sinonasal mucosa compared with OVA alone and similar eosinophilia. This model could be more relevant to recalcitrant eosinophilic CRS in humans than OVA induced allergic CRS. PMID- 25514483 TI - Markers of increased aeration in the paranasal sinuses and along the skull base: association between anatomic variants. AB - BACKGROUND: There may be substantial variation in paranasal sinus pneumatization across patients and between right and left sides. Patients with extensive sinus aeration, especially of the sphenoid sinus and along the skull base, often have protrusion of critical structures into the pneumatized sinus cavities, which potentially places these structures at risk during sinus surgery. OBJECTIVE: To evaluate associations between anatomic markers of increased paranasal sinus aeration along the skull base and to determine whether the presence of certain markers predicts other critical anatomic variants. METHODS: Submillimeter axial computed tomography (CT) scans and associated triplanar reconstructions from 100 subjects were reviewed for the presence of 22 anatomic variants by two separate evaluators. Twelve of these variants were selected as markers of increased pneumatization. Average numbers of markers were compared with t-tests; associations between markers were evaluated by logistic regression analyses. The Holm-Bonferroni method was used to correct for multiple tests. RESULTS: Five anatomic variants were associated with increased paranasal sinus pneumatization, as defined by total number of markers of pneumatization: anterior ethmoid artery below the skull base, dehiscent/protruding internal carotid artery (ICA), dehiscent/protruding optic nerve (ON), pneumatized pterygoid recess, and middle turbinate (MT) concha bullosa (all p < .02). Significant associations were found between pneumatized pterygoid recesses and dehiscent or protruding ONs (odds ratio [OR] 3.06, p = .0120), dehiscent or protruding ICAs (OR 6.64, p < .0001), and anterior ethmoid arteries below the skull base (OR 2.65, p = .0189). Significant association was also found between dehiscent or protruding ONs and dehiscent or protruding ICAs (OR 3.57, p = .0047). CONCLUSION: The markers of increased pneumatization and anatomic associations identified in this study have important implications for surgeons planning and undertaking operative approaches in and around the sinuses. PMID- 25514484 TI - Objective radiographic density measurements of sinus opacities are not strong predictors of noninvasive fungal disease. AB - BACKGROUND: High-density paranasal sinus opacities are often deemed consistent with fungal elements. No studies of objective quantitative radiographic density measures have been performed to support this assertion. METHODS: A consecutive series of 120 patients with chronic rhinosinusitis who underwent maxillary antrostomy with microbiological evaluation of contents within 60 days of sinus computed tomography scanning was investigated. Radiographic density characteristics of opacities in cultured maxillary sinuses (minimum, maximum, average, and standard deviation of Hounsfield units [HUstd]) were recorded. Receiver operator characteristic (ROC) curves were used to analyze the accuracy of radiographic characteristics in predicting fungal opacities. RESULTS: Of 133 maxillary sinus opacities, 22 were ultimately consistent with noninvasive fungal disease: 11 allergic fungal rhinosinusitis and 11 fungal balls. Fungal balls had higher-density components and were more heterogeneous and allergic fungal mucin was generally more radiodense. These findings were reflected by statistically significant ROC curves for maximum HU (p = 0.019) and HUstd (p = 0.023) for fungal balls and for average HU (p = 0.002) for allergic fungal mucin. A maximum HU cutoff of 334.0 detected fungal balls with 90.9% sensitivity and 72.7% specificity. An average HU cutoff of 42.9 HU detected allergic fungal mucin with 100% sensitivity and 46.3% specificity, although specificity improved to 73.2% with inclusion of nasal polyposis as a second requirement. CONCLUSION: Higher average HU more accurately predicts allergic fungal mucin whereas heterogeneity/high-density components more accurately predict fungal balls. No objective radiographic density measure, in isolation, is both sensitive and specific in predicting noninvasive fungal sinusitis. PMID- 25514485 TI - Societal and physician perspectives on sinonasal diagnosis and treatment. AB - BACKGROUND: Sinusitis is diagnosed in 31 million individuals annually and has a significant impact on health care expenditures. Otolaryngologists understand that patient expectations, health knowledge, and the use of therapeutic options by patients and primary care physicians (PCPs) vary greatly. The intent of this study was to elucidate differences in the perspectives of patients, PCPs and otolaryngologists regarding the diagnosis and treatment of sinonasal disease. METHODS: Three surveys were developed with questions targeting sinonasal infections: specifically, prevalence, diagnosis, physician prescribing patterns, treatment alternatives, and referral patterns to tertiary level physicians. Surveys were distributed to adult patients (n = 113) at general health fairs, whereas surveys for PCPs (n = 54) and otolaryngologists (n = 40) were obtained from teaching conferences and professional networking events. RESULTS: In a description of viral upper respiratory tract infections (URIs), 43% of patients attributed symptoms to allergic rhinitis, 28% to URIs, and 28% to sinus infections. Despite this, 37% of patients still expected anti-bacterial agents. In patients with acute rhinosinusitis (ARS), 44% of patients would wait <1 week to see a physician whereas 82% of otolaryngologists and 57% of PCPs felt waiting 1 week or more was appropriate. In an ambulatory care setting, 45% of PCPs would chose to treat patients with 5 days of ARS symptoms whereas 32% of otolaryngologists would treat patients (p = .22). For ARS, 70% of patients expected antibiotics. Seventy percent of PCPs stated that they would refer a patient to an otolaryngologist after a single episode of sinusitis. CONCLUSION: Patients with sinonasal symptoms confuse URIs for sinusitis and expect unnecessary treatment with antibiotics. PCPs and otolaryngologists vary regarding indications for presentation to a physician, approaches to therapy, and indications for referral to a tertiary provider in their respective practices. PMID- 25514486 TI - State of the art: a systematic review of the surgical management of aspirin exacerbated respiratory disease. AB - BACKGROUND: Endoscopic sinus surgery is an important modality to the armamentarium of the otolaryngologist managing chronic rhinosinusitis (CRS). Within the spectrum of CRS, there exists a subset of patients who are recalcitrant to conventional treatment strategies, including those with aspirin exacerbated respiratory disease (AERD). Although surgery is frequently undertaken in this group, there has been no general consensus on the efficacy or optimal extent of surgery. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic review of published studies was conducted. Inclusion criteria included original publications of adult patients with AERD undergoing surgery, cohorts of greater than five subjects, a minimum follow-up of 3 months, and measurable clinical outcomes. An electronic search was performed using OVID MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science. RESULTS: Sixteen studies met the criteria for analysis. For our primary objective, sinus surgery appeared to improve patient-reported quality of life (QoL) and symptom profile in AERD. Overall, most studies reported a decrease in radiographic grading, endoscopy scores, and asthma severity. Compared with aspirin-tolerant asthmatic patients, AERD patients may have worse objective measures of disease severity both pre- and postoperatively; however, patient-reported QoL and symptom improvement may be similar after sinus surgery. Finally, this review showed that patients with AERD required revision surgeries sooner and more frequently compared with other subtypes of CRS. We also discussed the role of maximal surgical techniques and additional benefit of postoperative adjunctive therapies in the management of this disease entity. CONCLUSION: The state of the art in the management of AERD patients suggests that surgery does play an important role in helping establish symptomatic control. In the future, more rigorous studies evaluating the comprehensiveness of surgery and postoperative adjuncts are required to understand their impact on long-term patient outcomes. PMID- 25514487 TI - Clinical effects of middle turbinate resection after endoscopic sinus surgery: a systematic review. AB - BACKGROUND: The middle turbinate (MT) is a structure that is often carefully preserved during endoscopic sinus surgery (ESS) in an effort to preserve nasal physiology and serve as an anatomic landmark. However, resection is performed in select cases because of involvement of the MT in the inflammatory process, obstruction, or instability. Therefore, significant controversy exists among surgeons regarding the indications for proceeding with MT resection in ESS. This study evaluates clinical outcomes of MT resection after ESS. METHODS: An English language search of the PubMed and Ovid databases was conducted for publications examining clinical outcomes of MT resection after ESS performed for chronic rhinosinusitis. Two authors independently examined the articles to identify those meeting inclusion criteria. Any differences over which studies to include were resolved by discussion and consensus. Bias assessment was conducted using the Cochrane Collaboration bias tool for randomized controlled trials and the Newcastle-Ottawa bias tool for cohort and case-control studies. RESULTS: After initial screening, search results revealed 71 articles that warranted detailed evaluation. After applying inclusion criteria, 9 studies were selected. A total of 2123 patients were included among the studies. All studies were controlled. Within the limited available data, olfaction scores may be improved in the MT resection patients compared with MT preservation patients. No difference between the groups was noted for quality of life outcomes, nasal airway resistance, or rates of postoperative frontal sinusitis. In regard to postoperative endoscopic examinations, some studies note greater improvement in the MT resection group compared with the MT preservation group, while others were equivalent. CONCLUSION: Although some studies show outcome benefit in MT resection patients compared with MT preservation patients, several others show no difference. When MT resection was appropriately indicated, no studies showed detrimental effects compared with MT preservation in their designated outcomes. Additional more stringent studies are warranted. PMID- 25514488 TI - Outcomes in primary powered endoscopic dacryocystorhinostomy: comparison between experienced versus less experienced surgeons. AB - BACKGROUND: This study compares the anatomic and functional outcomes of primary powered endoscopic dacryocystorhinostomy (DCR) in surgeons of differing levels of experience. METHODS: A retrospective interventional study was performed of all consecutive powered endoscopic DCRs performed at a tertiary institution over a period of 10 years from 2002 to 2012. All patients completed a minimum of 3 months follow-up after stent removal. Patient records were reviewed for demographic data, clinical and surgical profiles, adjunctive procedures, complications, and success rates at last follow-up. The level of surgeon's experience performing the DCR was also documented. Anatomic success was defined as patent ostium on irrigation and functional success as free flow of dye into ostium on functional endoscopic dye test and resolution of epiphora. RESULTS: Among the 160 DCRs performed by the consultant, all except four underwent intubation; 54.4% (68/125) of these patients required adjunctive procedures. There were no major complications in this group and at a long-term mean follow-up of 14.2 months, the anatomic and functional success rates were 98.1 and 95.6%, respectively. Among the 100 DCRs performed by the fellows, all underwent intubation and 40.8% (29/71) of the patients required adjunctive procedures. The complications include three cases of ostium granulomas and two patients each with postoperative bleeding, stent prolapse, and turbinoseptal synechiae. At the mean follow-up of 10.9 months, the final anatomic success was achieved in 95% of the cases and functional success in 89% of the cases. CONCLUSION: Powered endoscopic dacryocystorhinostomy is an effective procedure and offers excellent results in the hands of experienced surgeons. A good transfer of knowledge and skills along with supervision when required ensures a good surgical success rate, even when the training fellows operate. PMID- 25514489 TI - Olfactory outcomes after endoscopic pituitary surgery with nasoseptal "rescue" flaps: electrocautery versus cold knife. AB - BACKGROUND: Olfaction has been shown to have a large impact on patients' lives. Endoscopic pituitary surgery is associated with potentially significant damage to olfactory tissues. The objective of this study was to determine the effect of cauterization on olfactory function when performing endoscopic pituitary surgery with a nasoseptal "rescue" flap. METHODS: A retrospective review was performed of prospectively collected data. Olfaction was the primary outcome and was measured using the subjective visual analog scale (VAS; 0-100) and Cross-Cultural Smell Identification Test (CC-SIT) before and 3 months after surgery. Significant olfactory deficit was defined as >20% loss compared with preoperative functions. Patients who underwent an endoscopic transsphenoidal approach with NSRFs for pituitary adenoma from June 2012 to March 2013 were included. Included patients were divided into two groups; group 1 underwent rescue flaps raised by monopolar cautery and group 2 underwent rescue flaps by cold knife. RESULTS: Forty-nine patients were included in this study. There were 19 patients in group 1 and 30 patients in group 2. There was no significant difference in subjective olfactory change between the two groups (p = 0.386; group 1, 13.68 +/- 17.7, versus group 2, 6.83 +/- 8.25). However, 5 of 19 patients (26.3%) had significant olfactory loss in group 1 and 1 of 30 (3.3%) in group 2. This difference was statistically significant (p = 0.027). None of the patients showed a significant decrease in CC SIT score. CONCLUSION: Raising the rescue flap by cold knife could reduce the rate of hyposmia compared with using an electrocautery postoperatively. PMID- 25514490 TI - Efficacy of lidocaine with or without epinephrine in rigid nasal endoscopy. AB - BACKGROUND: This study evaluates if there is any benefit of adding epinephrine to lidocaine in patients undergoing diagnostic rigid nasal endoscopy. A prospective, randomized, double-blinded study was performed. METHODS: Seventy patients were randomized to receive either 2% lidocaine or 2% lidocaine with 0.2% epinephrine before rigid nasal endoscopy examination. Patients were asked to report the intensity of pain and discomfort they experienced using visual analog scale. An endoscopist recorded the ease to perform the procedure using the same scale. Intranasal structures visualized were also reported. RESULTS: There were no significant differences in pain, discomfort or ease of exam, or in the percentage of visualized nasal structures between the two groups. In the whole series, there were no significant differences in the studied variables based on gender or indication to perform endoscopy. CONCLUSION: Adding epinephrine to lidocaine has no advantages in patients undergoing diagnostic rigid nasal endoscopy. PMID- 25514492 TI - Quercetin inhibits proliferation and drug resistance in KB/VCR oral cancer cells and enhances its sensitivity to vincristine. AB - Quercetin has been confirmed to possess antihistamine, anti-inflammatory, antiviral, immunomodulatory, and antioxidant properties. Herein, we evaluated their antitumor activity in vitro by using KB/VCR oral cancer cells. We found that quercetin at 25 to 100 MUmol/L effectively inhibited the migration and invasion of KB/VCR cells. Quercetin at dose ranging from 25 to 100 MUmol/L significantly inhibited the growth of the KB/VCR cells and at 50 MUmol/L arrested cells at the G1 phase and decreased the amount of cells in the S and G2 phase. Apoptosis analysis showed that quercetin at 50 or 100 MUmol/L induced apoptosis of KB/VCR cells by suppressing expression of Bax and inducing the expression of Caspase-3 and Bcl-2. Furthermore, we also confirmed that quercetin from 25 to 100 MUmol/L reversed gene-encoded Pglycoprotein (P-gp)-mediated MDR in KB/VCR cells by inhibiting the expression of P-gp. For combination treatment with vincristin (0.375 MUmol/L) and quercetin (50 MUmol/L), the proliferation rate significantly decreased and apoptosis rate significantly increased. This study provided evidence that quercetin induced apoptosis and reversed drug resistance in oral tumor cells and may be a potential candidate for other tumors treatment. PMID- 25514494 TI - Development of a Clinically Applicable Protocol for Assessment of Hypoxic Response Through Measurement of the Endogenous Gasotransmitter Hydrogen Sulfide in Human Plasma. AB - BACKGROUND: Gasotransmitters are endogenously made, biologically active gases with unique physiological properties. In addition to participation in the hypoxic respiratory reflex of the carotid body, the gasotransmitter hydrogen sulfide (H(2)S) is thought to play a role in more localized vasodilatory hypoxic tissue responses. This pilot project describes a methodology suitable to the clinical environment that allows for H(2)S gas capture in human plasma utilizing the fluorescent trapping agent dansyl azide. METHODS: Under an IRB-approved pilot project, 10 healthy male volunteers were spontaneously ventilated on room air, hypoxic (15% oxygen, 85% nitrogen), and hyperoxic (100%) gas mixtures through a nonrebreather system. Venous whole-blood samples were collected at both internal jugular and antecubital sites following 7 minutes of exposure to the tested oxygen environments. Resultant plasma aliquots were treated with dansyl azide and submitted to fluorescence reading (excitation 340 nm, emission 517 nm). RESULTS: Compiled mean data from volunteer plasma samples demonstrated statistically significant findings (P<0.05) in measurement of increased fluorescent intensity between those samples collected under mildly hypoxic conditions compared with normoxic and hyperoxic samples submitted to the same laboratory criteria. CONCLUSIONS: To study the role of H(2)S as a marker of hypoxic response in humans, a reliable, robust, and safe protocol amenable to standard hospital laboratory procedures is needed. Through modification to methodologies described in the biochemistry literature, this pilot project demonstrates the feasibility of utilizing a fluorescent H2S gas trapping agent for assessment of hypoxic response in humans within the confines of a typical clinical collection and analysis environment. PMID- 25514493 TI - Pokemon (FBI-1) interacts with Smad4 to repress TGF-beta-induced transcriptional responses. AB - Pokemon, an important proto-oncoprotein, is a transcriptional repressor that belongs to the POK (POZ and Kruppel) family. Smad4, a key component of TGF-beta pathway, plays an essential role in TGF-beta-induced transcriptional responses. In this study, we show that Pokemon can interact directly with Smad4 both in vitro and in vivo. Overexpression of Pokemon decreases TGF-beta-induced transcriptional activities, whereas knockdown of Pokemon increases these activities. Interestingly, Pokemon does not affect activation of Smad2/3, formation of Smads complex, or DNA binding activity of Smad4. TGF-beta1 treatment increases the interaction between Pokemon and Smad4, and also enhances the recruitment of Pokemon to Smad4-DNA complex. In addition, we also find that Pokemon recruits HDAC1 to Smad4 complex but decreases the interaction between Smad4 and p300/CBP. Taken together, all these data suggest that Pokemon is a new partner of Smad4 and plays a negative role in TGF-beta pathway. PMID- 25514495 TI - Novel Method of Identifying Intraoperative Cuff Leak and its Treatment While Monitoring Cuff Pressure. PMID- 25514496 TI - On the Incidence of Stroke Following Antiplatelet/Anithrombotic Drug Cessation. PMID- 25514498 TI - Effect of benzimidazole configuration in polybenzimidazole chain on interaction with phosphoric acid: a DFT study. AB - Polybenzimidazole doped with phosphoric acid (PA) is a candidate for polymer electrolyte membranes in fuel cells. Understanding the interaction of benzimidazole in polybenzimidazole with PA is important for fuel-cell applications. Herein, the interaction of a PA-benzimidazole complex was investigated using density functional theory, with calculations performed at the omegaB97X-D/6-311G(d,p) level of theory, with an aim to investigate the effects of bibenzimidazole configuration on the interaction energy. Benzimidazole and three different bibenzimidazole configurations (2,2'-bibenzo[d]imidazole (1), 2,5'-bibenzo[d]imidazole (2), and 5,5'-bibenzo[d]imidazole (3)) were used as models for bulk polybenzimidazole. Calculation of various types of hydrogen bond interaction showed that the interaction between the imino moiety of the monomer and the hydroxyl group of PA is the strongest, which agrees with previous studies. Our calculations indicated that pi-H interactions between the hydrogen atoms of the PA molecule and the benzene rings should be considered, and these contribute to the interaction energy for some interaction complexes. The interaction energy between the monomer and PA is smaller than that of the PA dimer. However, the interaction energy between bibenzimidazole and PA is comparable to that of the PA dimer for bibenzimidazole configurations 1 and 2, highlighting the importance of considering the adjacent monomer unit. PMID- 25514497 TI - Early developability screen of therapeutic antibody candidates using Taylor dispersion analysis and UV area imaging detection. AB - Therapeutic antibodies represent one of the fastest growing segments in the pharmaceutical market. They are used in a broad range of disease fields, such as autoimmune diseases, cancer, inflammation and infectious diseases. The growth of the segment has necessitated development of new analytical platforms for faster and better antibody selection and characterization. Early quality control and risk assessment of biophysical parameters help prevent failure in later stages of antibody development, and thus can reduce costs and save time. Critical parameters such as aggregation, conformational stability, colloidal stability and hydrophilicity, are measured during the early phase of antibody generation and guide the selection process of the best lead candidates in terms of technical developability. We report on the use of a novel instrument (ActiPix/Viscosizer) for measuring both the hydrodynamic radius and the absolute viscosity of antibodies based on Taylor dispersion analysis and UV area imaging. The looped microcapillary-based method combines low sample consumption, fast throughput and high precision compared to other conventional methods. From a random panel of 130 antibodies in the early selection process, we identified some with large hydrodynamic radius outside the normal distribution and others with non-Gaussian Taylor dispersion profiles. The antibodies with such abnormal properties were confirmed later in the selection process to show poor developability profiles. Moreover, combining these results with those of the viscosity measurements at high antibody concentrations allows screening, with limited amounts of materials, candidates with potential issues in pre-formulation development. PMID- 25514499 TI - Chloride Channel 3 Channels in the Activation and Migration of Human Blood Eosinophils in Allergic Asthma. AB - Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is responsible for respiratory burst in immune cells. Chloride channel 3 (CLC3) has been linked to the respiratory burst in eosinophils and neutrophils. The effect of cytokines and the involvement of CLC3 in the regulation of NADPH-dependent oxidative stress and on cytokine-mediated migration of eosinophils are not known. Human peripheral blood eosinophils were isolated from healthy individuals and from individuals with asthma by negative selection. Real-time PCR was used to detect the expression of NADPH oxidases in eosinophils. Intracellular reactive oxygen species (ROS) measurement was done with flow cytometry. Superoxide generation was measured with transforming growth factor (TGF)-beta, eotaxin, and CLC3 blockers. CLC3 dependence of eosinophils in TGF-beta- and eotaxin-induced migration was also examined. The messenger RNA (mRNA) transcripts of NADPH oxidase (NOX) 2, dual oxidase (DUOX) 1, and DUOX2 were detected in blood eosinophils, with very low expression of NOX1, NOX3, and NOX5 and no NOX4 mRNA. The level of NOX2 mRNA transcripts increased with disease severity in the eosinophils of subjects with asthma compared with healthy nonatopic volunteers. Change in granularity and size in eosinophils, but no change in intracellular ROS, was observed with phorbol myristate acetate (PMA). PMA, TGF-beta, and eotaxin used the CLC3-dependent pathway to increase superoxide radicals. TGF-beta and eotaxin induced CLC3 dependent chemotaxis of eosinophils. These findings support the requirement of CLC3 in the activation and migration of human blood eosinophils and may provide a potential novel therapeutic target to regulate eosinophil hyperactivity in allergic airway inflammation in asthma. PMID- 25514501 TI - Monitoring molecules: insights and progress. AB - In August, 2014, neuroscientists and physical scientists gathered together on the campus of the University of California, Los Angeles to discuss how to monitor molecules in neuroscience. This field has seen significant growth since its inception in the 1970s. Here, the advances in this field are documented, including its advance into understanding the actions that specific neurotransmitters mediate during behavior. PMID- 25514500 TI - A simplified score to quantify comorbidity in COPD. AB - IMPORTANCE: Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes. MATERIALS AND METHODS: Using the COPDGene study (GOLD II-IV COPD), we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1) simple count, 2) weighted score, and 3) weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC) and calibration statistics to validate scores internally with outcomes of respiratory disease-specific quality of life (St. George's Respiratory Questionnaire, SGRQ), six minute walk distance (6MWD), modified Medical Research Council (mMRC) dyspnea score and exacerbation risk, ultimately choosing one score for external validation in SPIROMICS. RESULTS: Associations between comorbidities and all outcomes were comparable across the three scores. All scores added predictive ability to models including age, gender, race, current smoking status, pack-years smoked and FEV1 (p<0.001 for all comparisons). Area under the curve (AUC) was similar between all three scores across outcomes: SGRQ (range 0.7624-0.7676), MMRC (0.7590-0.7644), 6MWD (0.7531 0.7560) and exacerbation risk (0.6831-0.6919). Because of similar performance, the comorbidity count was used for external validation. In the SPIROMICS cohort, the comorbidity count performed well to predict SGRQ (AUC 0.7891), MMRC (AUC 0.7611), 6MWD (AUC 0.7086), and exacerbation risk (AUC 0.7341). CONCLUSIONS: Quantifying comorbidity provides a more thorough understanding of the risk for patient-centered outcomes in COPD. A comorbidity count performs well to quantify comorbidity in a diverse population with COPD. PMID- 25514502 TI - Soil contamination in China: current status and mitigation strategies. AB - China faces great challenges in protecting its soil from contamination caused by rapid industrialization and urbanization over the last three decades. Recent nationwide surveys show that 16% of the soil samples, 19% for the agricultural soils, are contaminated based on China's soil environmental quality limits, mainly with heavy metals and metalloids. Comparisons with other regions of the world show that the current status of soil contamination, based on the total contaminant concentrations, is not worse in China. However, the concentrations of some heavy metals in Chinese soils appear to be increasing at much greater rates. Exceedance of the contaminant limits in food crops is widespread in some areas, especially southern China, due to elevated inputs of contaminants, acidic nature of the soil and crop species or cultivars prone to heavy metal accumulation. Minimizing the transfer of contaminants from soil to the food chain is a top priority. A number of options are proposed, including identification of the sources of contaminants to agricultural systems, minimization of contaminant inputs, reduction of heavy metal phytoavailability in soil with liming or other immobilizing materials, selection and breeding of low accumulating crop cultivars, adoption of appropriate water and fertilizer management, bioremediation, and change of land use to grow nonfood crops. Implementation of these strategies requires not only technological advances, but also social economic evaluation and effective enforcement of environmental protection law. PMID- 25514503 TI - Characterization of the aggregates formed by various bacterial lipopolysaccharides in solution and upon interaction with antimicrobial peptides. AB - The biophysical analysis of the aggregates formed by different chemotypes of bacterial lipopolysaccharides (LPS) before and after challenge by two different antiendotoxic antimicrobial peptides (LL37 and bovine lactoferricin) was performed in order to determine their effect on the morphology of LPS aggregates. Small-angle neutron scattering (SANS) and cryogenic transmission electron microscopy (cryoTEM) were used to examine the structures formed by both smooth and rough LPS chemotypes and the effect of the peptides, by visualization of the aggregates and analysis of the scattering data by means of both mathematical approximations and defined models. The data showed that the structure of LPS determines the morphology of the aggregates and influences the binding activity of both peptides. The morphologies of the worm-like micellar aggregates formed by the smooth LPS were relatively unaltered by the presence of the peptides due to their pre-existing high degree of positive curvature being little affected by their association with either peptide. On the other hand, the aggregates formed by the rough LPS chemotypes showed marked morphological changes from lamellar structures to ordered micellar networks, induced by the increase in positive curvature engendered upon association with the peptides. The combined use of cryoTEM and SANS proved to be a very useful tool for studying the aggregation properties of LPS in solution at biologically relevant concentrations. PMID- 25514504 TI - On the risk of aortic valve replacement surgery assessed by heart rate variability parameters. AB - In recent years the number of arterial stenosis (AS) patients has grown rapidly and valvular disease is expected to be the next great epidemic. We studied a group of 385 arterial valve replacement (AVR) surgery patients, of whom 16 had died in the postoperational period (up to 30 d after the operation). Each patient had a heart rate variability (HRV) recording made prior to the operation in addition to a full set of medical diagnostics including echocardiography. We formed 16 age, sex, New York Heart Association (NYHA) class, and BMI adjusted control pairs for each person who died in the perioperative period. Our aim was to find indications of the risk from AVR surgery based on the medical data and HRV properties. Besides standard, linear HRV methods, we used indexes of time irreversibility introduced by Guzik (G%), Porta (P%), Ehlers (index E) and Hou (index D). In addition, we analyzed the multiscale multifractal properties of HRV calculating the Hurst surface. The nonlinear analysis methods show statistically significant indications of the risk of AVR surgery in an increase of multifractality and an increase of time irreversibility of the HRV measured prior to the operation. PMID- 25514505 TI - On surface order and disorder of alpha-pinene-derived secondary organic material. AB - The surfaces of secondary organic aerosol particles are notoriously difficult to access experimentally, even though they are the key location where exchange between the aerosol particle phase and its gas phase occurs. Here, we overcome this difficulty by applying standard and sub- 1 cm(-1) resolution vibrational sum frequency generation (SFG) spectroscopy to detect C-H oscillators at the surfaces of secondary organic material (SOM) prepared from the ozonolysis of alpha-pinene at Harvard University and at the University of California, Irvine, that were subsequently collected on Teflon filters as well as CaF2 windows using electrostatic deposition. We find both samples yield comparable SFG spectra featuring an intense peak at 2940 cm(-1) that are independent of spectral resolution and location or method of preparation. We hypothesize that the SFG spectra are due to surface-active C-H oscillators associated with the four membered ring motif of alpha-pinene, which produces an unresolvable spectral continuum of approximately 50 cm(-1) width reminiscent of the similar, albeit much broader, O-H stretching continuum observed in the SFG spectra of aqueous surfaces. Upon subjecting the SOM samples to cycles in relative humidity (RH) between <2% RH and ~95% RH, we observe reversible changes in the SFG signal intensity across the entire spectral range surveyed for a polarization combination probing components of the vibrational transition dipole moments that are oriented parallel to the plane of incidence, but no signal intensity changes for any other polarization combination investigated. These results support the notion that the C-H oscillators at the surfaces of alpha-pinene-derived SOM deposited on CaF2 windows shift back and forth between two different molecular orientation distributions as the RH is lowered (more ordered) or raised (less ordered). The findings thus point toward the presence of a reversible surface switch for hindering (more ordered, <2%RH) and promoting (less ordered, ~95%RH) exchange between the aerosol particle phase and its gas phase. PMID- 25514506 TI - Intake of cooked tomato sauce preserves coronary endothelial function and improves apolipoprotein A-I and apolipoprotein J protein profile in high-density lipoproteins. AB - Intake of tomatoes has been linked with healthy diets (eg, Mediterranean diet). However, it remains unknown whether tomato intake exerts protective effects on the vasculature. The aim of this study was to determine whether medium-term supplementation with cooked tomato sauce (CTS) Mediterranean style (sofrito) attenuates diet-induced coronary endothelial dysfunction in an animal model with clinical impact and explore the mechanisms behind the effects. Pigs (N = 18) were fed a 10-day hypercholesterolemic diet. Half of the animals were given a supplement of 100 g/d of CTS (21.5 mg lycopene per day). Coronary responses to escalating doses of vasoactive drugs (acetylcholine, calcium ionophore, and sodium nitroprusside) and L-NG-monomethylarginine (endothelial nitric oxide synthase [eNOS] inhibitor) were measured using flow Doppler. In the coronary arteries, we investigated eNOS gene expression and activation, monocyte chemoattractant protein 1 (MCP-1) expression, and oxidative DNA damage. In the circulation, we investigated lipoprotein resistance to oxidation and the differential proteomic protein profile. In dyslipidemic animals, CTS intake prevented diet-induced impairment of receptor-operated and nonreceptor-operated endothelial-dependent coronary vasodilation. These beneficial effects were associated with enhanced eNOS transcription and activation and diminished DNA damage in the coronary arteries. CTS-fed animals showed lower lipid peroxidation, higher high-density lipoprotein (HDL) antioxidant potential and plasma lycopene levels of 0.16 mg/L. Interestingly, improved HDL functionality was associated with protein profile changes in apolipoprotein A-I and apolipoprotein J. Lipids levels and MCP-1 expression were not affected by CTS. We report that CTS intake protects against low-density lipoprotein-induced coronary endothelial dysfunction by reducing oxidative damage, enhancing eNOS expression and activity, and improving HDL functionality. PMID- 25514507 TI - The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology, for which there is no curative pharmacological therapy. Bleomycin, an anti neoplastic agent that causes lung fibrosis in human patients has been used extensively in rodent models to mimic IPF. In this review, we compare the pathogenesis and histological features of human IPF and bleomycin-induced pulmonary fibrosis (BPF) induced in rodents by intratracheal delivery. We discuss the current understanding of IPF and BPF disease development, from the contribution of alveolar epithelial cells and inflammation to the role of fibroblasts and cytokines, and draw conclusions about what we have learned from the intratracheal bleomycin model of lung fibrosis. PMID- 25514508 TI - Bicuspid aortic disease and decision making under uncertainty - The limitations of clinical guidelines. PMID- 25514509 TI - Photochromism of diarylethene molecules and crystals: memories, switches, and actuators. PMID- 25514510 TI - Bayesian inference on the effect of density dependence and weather on a guanaco population from Chile. AB - Understanding the mechanisms that drive population dynamics is fundamental for management of wild populations. The guanaco (Lama guanicoe) is one of two wild camelid species in South America. We evaluated the effects of density dependence and weather variables on population regulation based on a time series of 36 years of population sampling of guanacos in Tierra del Fuego, Chile. The population density varied between 2.7 and 30.7 guanaco/km2, with an apparent monotonic growth during the first 25 years; however, in the last 10 years the population has shown large fluctuations, suggesting that it might have reached its carrying capacity. We used a Bayesian state-space framework and model selection to determine the effect of density and environmental variables on guanaco population dynamics. Our results show that the population is under density dependent regulation and that it is currently fluctuating around an average carrying capacity of 45,000 guanacos. We also found a significant positive effect of previous winter temperature while sheep density has a strong negative effect on the guanaco population growth. We conclude that there are significant density dependent processes and that climate as well as competition with domestic species have important effects determining the population size of guanacos, with important implications for management and conservation. PMID- 25514512 TI - Influence of metal-MoS2 interface on MoS2 transistor performance: comparison of Ag and Ti contacts. AB - In this work, we compare the electrical characteristics of MoS2 field-effect transistors (FETs) with Ag source/drain contacts with those with Ti and demonstrate that the metal-MoS2 interface is crucial to the device performance. MoS2 FETs with Ag contacts show more than 60 times higher ON-state current than those with Ti contacts. In order to better understand the mechanism of the better performance with Ag contacts, 5 nm Au/5 nm Ag (contact layer) or 5 nm Au/5 nm Ti film was deposited onto MoS2 monolayers and few layers, and the topography of metal films was characterized using scanning electron microscopy and atomic force microscopy. The surface morphology shows that, while there exist pinholes in Au/Ti film on MoS2, Au/Ag forms a smoother and denser film. Raman spectroscopy was carried out to investigate the metal-MoS2 interface. The Raman spectra from MoS2 covered with Au/Ag or Au/Ti film reveal that Ag or Ti is in direct contact with MoS2. Our findings show that the smoother and denser Au/Ag contacts lead to higher carrier transport efficiency. PMID- 25514511 TI - Mechanistic insights into a classic wonder drug--aspirin. AB - Aspirin, one of the oldest and most common anti-inflammatory agents, has recently been shown to reduce cancer risks. The principal pharmacological effects of aspirin are known to arise from its covalent modification of cyclooxygenase-2 (COX-2) through acetylation of Ser530, but the detailed mechanism of its biochemical action and specificity remains to be elucidated. In this work, we have filled this gap by employing a state-of-the-art computational approach, Born Oppenheimer molecular dynamics simulations with ab initio quantum mechanical/molecular mechanical potential and umbrella sampling. Our studies have characterized a substrate-assisted inhibition mechanism for aspirin acetylating COX: it proceeds in two successive stages with a metastable tetrahedral intermediate, in which the carboxyl group of aspirin serves as the general base. The computational results confirmed that aspirin would be 10-100 times more potent against COX-1 than against COX-2, and revealed that this inhibition specificity between the two COX isoforms can be attributed mainly to the difference in kinetics rate of the covalent inhibition reaction, not the aspirin binding step. The structural origin of this differential inhibition of the COX enzymes by aspirin has also been elucidated. PMID- 25514513 TI - Beta-carotene chemical stability in Nanoemulsions was improved by stabilized with beta-lactoglobulin-catechin conjugates through free radical method. AB - Beta-lactoglobulin (BLG)-catechin conjugates were prepared by a free radical method and investigated with sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), electrospray ionization-mass spectrometry (ESI-MS), and far-UV circular dichroism (CD). Covalent binding between BLG and catechin were confirmed with SDS-PAGE and ESI-MS. About 93% of beta-lactoglobulin was conjugated with catechin or catecin fragments according to the gel intensity analysis software. Far-UV CD results showed that the content of beta-sheet decreased with a corresponding increase in unordered structures after grafting. Both nanoemulsions with mean particle size between 160 and 170 nm were prepared. Both the rate of particle growth and the total beta-carotene (BC) loss at 50 degrees C were significantly greater than at 4 and 25 degrees C. The retention rates of BC in nanoemulsions were 27.8% and 48.6% for BLG and BLG-catechin conjugates, respectively, after 30 days of storage at 50 degrees C. The BC retention encapsulated in nanoemulsion was significantly improved using BLG catechin conjugates, compared with BLG alone. The increase of BC retention in nanoemulsions encapsulated with BLG-catechin conjugates was due to the significant improvement of antioxidative properties (reducing power, free radical scavenging activity, and hydroxyl radical scavenging activity) of BLG after covalent binding with catechin. The results indicated that the proteins modified with polyphenols can be widely used in a labile bioactive compounds encapsulation delivery system. PMID- 25514515 TI - Daily iTBS worsens hand motor training--a combined TMS, fMRI and mirror training study. AB - INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) is used to increase regional excitability to improve motor function in combination with training after neurological diseases or events such as stroke. We investigated whether a daily application of intermittent theta burst stimulation (iTBS; a short-duration rTMS that increases regional excitability) improves the training effect compared with sham stimulation in association with a four-day hand training program using a mirror (mirror training, MT). The right dorsal premotor cortex (dPMC right) was chosen as the target region for iTBS because this region has recently been emphasized as a node within a network related to MT. METHODS: Healthy subjects were randomized into the iTBS group or sham group (control group CG). In the iTBS group, iTBS was applied daily over dPMC right, which was functionally determined in an initial fMRI session prior to starting MT. MT involved 20 min of hand training daily in a mirror over four days. The hand tests, the intracortical excitability and fMRI were evaluated prior to and at the end of MT. RESULTS: The results of the hand training tests of the iTBS group were surprisingly significantly poorer compared with those from the CG group. Both groups showed a different course of excitability in both M1 and a different course of fMRI activation within the supplementary motor area and M1 left. CONCLUSION: We suggest the inter-regional functional balance was affected by daily iTBS over dPMC right. Maybe an inter-regional connectivity within a network is differentially balanced. An excitability increase within an inhibitory balanced network would therefore disturb the underlying network. PMID- 25514516 TI - How to detect the Granger-causal flow direction in the presence of additive noise? AB - Granger-causality metrics have become increasingly popular tools to identify directed interactions between brain areas. However, it is known that additive noise can strongly affect Granger-causality metrics, which can lead to spurious conclusions about neuronal interactions. To solve this problem, previous studies have proposed the detection of Granger-causal directionality, i.e. the dominant Granger-causal flow, using either the slope of the coherency (Phase Slope Index; PSI), or by comparing Granger-causality values between original and time-reversed signals (reversed Granger testing). We show that for ensembles of vector autoregressive (VAR) models encompassing bidirectionally coupled sources, these alternative methods do not correctly measure Granger-causal directionality for a substantial fraction of VAR models, even in the absence of noise. We then demonstrate that uncorrelated noise has fundamentally different effects on directed connectivity metrics than linearly mixed noise, where the latter may result as a consequence of electric volume conduction. Uncorrelated noise only weakly affects the detection of Granger-causal directionality, whereas linearly mixed noise causes a large fraction of false positives for standard Granger causality metrics and PSI, but not for reversed Granger testing. We further show that we can reliably identify cases where linearly mixed noise causes a large fraction of false positives by examining the magnitude of the instantaneous influence coefficient in a structural VAR model. By rejecting cases with strong instantaneous influence, we obtain an improved detection of Granger-causal flow between neuronal sources in the presence of additive noise. These techniques are applicable to real data, which we demonstrate using actual area V1 and area V4 LFP data, recorded from the awake monkey performing a visual attention task. PMID- 25514517 TI - Associations between age, motor function, and resting state sensorimotor network connectivity in healthy older adults. AB - Aging is associated with impaired motor performance across a range of tasks. Both primary neural representations of movement and potential compensatory cognitive mechanisms appear to be disrupted in older age. Here we determined how age is associated with resting state sensorimotor functional connectivity, and whether connectivity strength is associated with motor performance. We investigated the association between age and resting state functional connectivity of several sensorimotor networks in 191 healthy older, right-handed individuals. Regions of interest were defined in the left motor cortex, left putamen, and right cerebellar lobules V and VIII. Analyses were adjusted for head motion, gray matter volume, diastolic blood pressure, and smoker status; we then evaluated whether connectivity is associated with participants' manual motor performance. We found both increased and decreased connectivity within portions of the motor cortical and cerebellar networks after adjusting for covariates. We observed that connectivity increased with age for the motor cortex and cerebellar lobule VIII with the putamen, providing evidence of greater interactivity across networks with age. Higher tapping frequency and greater grip force were associated with stronger connectivity between the motor cortex during resting state, putamen, cerebellar lobule VIII and the insular cortex, suggesting that greater network interactivity may protect against age declines in performance. PMID- 25514514 TI - Assessing dynamic brain graphs of time-varying connectivity in fMRI data: application to healthy controls and patients with schizophrenia. AB - Graph theory-based analysis has been widely employed in brain imaging studies, and altered topological properties of brain connectivity have emerged as important features of mental diseases such as schizophrenia. However, most previous studies have focused on graph metrics of stationary brain graphs, ignoring that brain connectivity exhibits fluctuations over time. Here we develop a new framework for accessing dynamic graph properties of time-varying functional brain connectivity in resting-state fMRI data and apply it to healthy controls (HCs) and patients with schizophrenia (SZs). Specifically, nodes of brain graphs are defined by intrinsic connectivity networks (ICNs) identified by group independent component analysis (ICA). Dynamic graph metrics of the time-varying brain connectivity estimated by the correlation of sliding time-windowed ICA time courses of ICNs are calculated. First- and second-level connectivity states are detected based on the correlation of nodal connectivity strength between time varying brain graphs. Our results indicate that SZs show decreased variance in the dynamic graph metrics. Consistent with prior stationary functional brain connectivity works, graph measures of identified first-level connectivity states show lower values in SZs. In addition, more first-level connectivity states are disassociated with the second-level connectivity state which resembles the stationary connectivity pattern computed by the entire scan. Collectively, the findings provide new evidence about altered dynamic brain graphs in schizophrenia, which may underscore the abnormal brain performance in this mental illness. PMID- 25514520 TI - A catastrophe of caring? PMID- 25514519 TI - Real-time MEG neurofeedback training of posterior alpha activity modulates subsequent visual detection performance. AB - It has been demonstrated that alpha activity is lateralized when attention is directed to the left or right visual hemifield. We investigated whether real-time neurofeedback training of the alpha lateralization enhances participants' ability to modulate posterior alpha lateralization and causes subsequent short-term changes in visual detection performance. The experiment consisted of three phases: (i) pre-training assessment, (ii) neurofeedback phase and (iii) post training assessment. In the pre- and post-training phases we measured the threshold to covertly detect a cued faint Gabor stimulus presented in the left or right hemifield. During magnetoencephalography (MEG) neurofeedback, two face stimuli superimposed with noise were presented bilaterally. Participants were cued to attend to one of the hemifields. The transparency of the superimposed noise and thus the visibility of the stimuli were varied according to the momentary degree of hemispheric alpha lateralization. In a double-blind procedure half of the participants were provided with sham feedback. We found that hemispheric alpha lateralization increased with the neurofeedback training; this was mainly driven by an ipsilateral alpha increase. Surprisingly, comparing pre- to post-training, detection performance decreased for a Gabor stimulus presented in the hemifield that was un-attended during neurofeedback. This effect was not observed in the sham group. Thus, neurofeedback training alters alpha lateralization, which in turn decreases performances in the untrained hemifield. Our findings suggest that alpha oscillations play a causal role for the allocation of attention. Furthermore, our neurofeedback protocol serves to reduce the detection of unattended visual information and could therefore be of potential use for training to reduce distractibility in attention deficit patients, but also highlights that neurofeedback paradigms can have negative impact on behavioral performance and should be applied with caution. PMID- 25514521 TI - No end to caring? AB - In a recent issue of Politics and the Life Sciences Mark Walker presented a compelling proposition for reducing evil in the world via an interdisciplinary program he calls the "Genetic Virtue Project" (GVP). As Walker explains, the purpose of the GVP is "to discover and enhance human ethics using biotechnology genetic correlates of virtuous behavior." PLS subsequently published several critiques of this proposal. While most of these critiques focused on conventional doubts about the technical feasibility or the ethics of such interventions, the more fundamental concern revealed by both Walker's proposal and its critiques is in the largely unquestioned assumption that more morality is necessarily better. Human history is marked by a gradual if uneven extension of moral concern to increasingly distant others, which many take as evidence of the rationality of morality. There is substantial evidence, though, that this expansion is fundamentally biological in origin and therefore not ultimately limited by rationality. Because these expanding moral feelings feel so good to us, we are incapable of perceiving the danger from their ever-expanding focus, in particular from the sincere but increasingly maladaptive collective policies they will engender. Utilizing the philosophy of Friedrich Nietzsche as a platform, the feasibility of different natural and cultural responses to this impending crisis of caring are examined, none of which are found capable of counteracting this expanding morality. Instead, the best hope for a successful response to this dangerous expansion of caring is actually a sort of reverse GVP, in which the biological mechanisms for this unchecked moral expansion are manipulated via genetic engineering to dial back this expansion. However, the likelihood of actually implementing such an admittedly counterintuitive and controversial program within an increasingly democratized world is doubtful. Ultimately, if we are unable to overcome this betrayal by our best intentions, where does that leave us as a species? PMID- 25514522 TI - Evolutionary preferences for physical formidability in leaders. AB - This research uses evolutionary theory to evaluate followers' preferences for physically formidable leaders and to identify conditions that stimulate those preferences. It employs a population-based survey experiment (N >= 760), which offers the advantages to internal validity of experiments and external validity of a highly heterogeneous sample drawn from a nationally representative subject pool. The theoretical argument proffered here is followers tend to prefer leaders with greater physical formidability because of evolutionary adaptations derived from humans' violent ancestral environment. In this environment, individuals who allied with and ultimately followed physically powerful partners were more likely to acquire and retain important resources necessary for survival and reproduction because the presence of the physically powerful partner cued opponents to avoid a challenge for the resources or risk a costly confrontation. This argument suggests and the results indicate that threatening (war) and nonthreatening (peace, cooperation, and control) stimuli differentially motivate preferences for physically formidable leaders. In particular, the findings suggest threatening conditions lead to preferences for leaders with more powerful physical attributes, both anthropometric (i.e., weight, height, and body mass index) and perceptual (i.e., attributes of being "physically imposing or intimidating" and "physically strong"). Overall, this research offers a theoretical framework from which to understand this otherwise seemingly irrational phenomenon. Further, it advances the emerging but long-neglected investigation of biological effects on political behavior and has implications for a fundamental process in democratic society, leader selection. PMID- 25514518 TI - The effects of age on resting state functional connectivity of the basal ganglia from young to middle adulthood. AB - The basal ganglia nuclei are critical for a variety of cognitive and motor functions. Much work has shown age-related structural changes of the basal ganglia. Yet less is known about how the functional interactions of these regions with the cerebral cortex and the cerebellum change throughout the lifespan. Here, we took advantage of a convenient sample and examined resting state functional magnetic resonance imaging data from 250 adults 18 to 49 years of age, focusing specifically on the caudate nucleus, pallidum, putamen, and ventral tegmental area/substantia nigra (VTA/SN). There are a few main findings to report. First, with age, caudate head connectivity increased with a large region of ventromedial prefrontal/medial orbitofrontal cortex. Second, across all subjects, pallidum and putamen showed negative connectivity with default mode network (DMN) regions such as the ventromedial prefrontal cortex and posterior cingulate cortex, in support of anti-correlation of the "task-positive" network (TPN) and DMN. This negative connectivity was reduced with age. Furthermore, pallidum, posterior putamen and VTA/SN connectivity to other TPN regions, such as somatomotor cortex, decreased with age. These results highlight a distinct effect of age on cerebral functional connectivity of the dorsal striatum and VTA/SN from young to middle adulthood and may help research investigating the etiologies or monitoring outcomes of neuropsychiatric conditions that implicate dopaminergic dysfunction. PMID- 25514523 TI - Suffodit inguina. AB - When Julius Caesar was stabbed, 23 times, on the Ides of March, at least one of the daggers is supposed to have gone into his groin. He wasn't the last Roman to have his privates attacked. And he wasn't the last primate. In competition for sexual access, gonads are occasionally targeted: canine incisions in monkey and ape scrota are not uncommon; and rumors had a number of Roman emperors--from Caligula and Nero, to Galba, Vitellius, Domitian, Commodus, Caracalla, Elagabalus, to Balbinus, Pupienus and Valerian over the course of the third century crisis--done in with their genitals at risk, or with their genitals cut off. PMID- 25514524 TI - Towards effective emerging infectious disease surveillance. AB - In this plenary talk given at the annual meeting of the Association for Politics and the Life Sciences at Texas Tech University last October, Professor Sophal Ear, then of the U.S. Naval Postgraduate School in Monterey, discussed his research on the political economy of emerging infectious disease (EID) surveillance programs. His talk reviews lessons learned for U.S. military medical research laboratories collaborating with developing countries and is comprised of three case studies: Cambodia (U.S. Naval Area Medical Research Unit 2 or NAMRU 2), Indonesia (also NAMRU-2 in the context of H5N1 or Highly Pathogenic Avian Influenza), (1) and Mexico (that country's handling of A/H1N1 or Swine Flu in 2009). (2) Professor Ear's research provides policymakers with tools for improving the effectiveness of new or existing EID surveillance programs. His work also offers host countries the opportunity to incorporate ideas, provide opinions, and debate the management of political and economic constraints facing their programs. In this analysis, constraints are found for each case study and general recommendations are given for improving global emerging infectious disease surveillance across political, economic, and cultural dimensions. PMID- 25514525 TI - Federalism and bioethics. AB - The absence of comprehensive federal oversight of human biotechnologies in the United States continues to stimulate academic discourse on the relative merits of European-style regulatory agencies as compared to the current, decentralized approach. Many American bioethicists support the latter, maintaining that the key features of federalism--policy experimentation and moral pluralism--allows for the efficient regulation of these complex and contentious issues. This paper examines state-level regulation of oocyte donation to assess claims regarding the superiority of this decentralized regulatory approach. Further, this paper introduces an additional element to this examination of state law, which concerns the degree to which the health and safety of key participants is addressed at the state level. This inquiry assesses one facet of fertility medicine and biomedical research law, oocyte donation, an analysis that can be used to inform the broader discourse regarding the regulation of human biotechnologies and bioethical issues by the states. PMID- 25514530 TI - Welcome to PLS. PMID- 25514531 TI - Jamie's Ministry of Food: quasi-experimental evaluation of immediate and sustained impacts of a cooking skills program in Australia. AB - OBJECTIVE: To evaluate the immediate and sustained effectiveness of the first Jamie's Ministry of Food Program in Australia on individuals' cooking confidence and positive cooking/eating behaviours. METHODS: A quasi- experimental repeated measures design was used incorporating a wait-list control group. A questionnaire was developed and administered at baseline (T1), immediately post program (T2) and 6 months post completion (T3) for participants allocated to the intervention group, while wait -list controls completed it 10 weeks prior to program commencement (T1) and just before program commencement (T2). The questionnaire measured: participants' confidence to cook, the frequency of cooking from basic ingredients, and consumption of vegetables, vegetables with the main meal, fruit, ready-made meals and takeaway. Analysis used a linear mixed model approach for repeated measures using all available data to determine mean differences within and between groups over time. SUBJECTS: All adult participants (>=18 years) who registered and subsequently participated in the program in Ipswich, Queensland, between late November 2011- December 2013, were invited to participate. RESULTS: In the intervention group: 694 completed T1, 383 completed T1 and T2 and 214 completed T1, T2 and T3 assessments. In the wait-list group: 237 completed T1 and 149 completed T1 and T2 assessments. Statistically significant increases within the intervention group (P<0.001) and significant group*time interaction effects (P<0.001) were found in all cooking confidence measures between T1 and T2 as well as cooking from basic ingredients, frequency of eating vegetables with the main meal and daily vegetable intake (0.52 serves/day increase). Statistically significant increases at T2 were sustained at 6 months post program in the intervention group. CONCLUSIONS: Jamie's Ministry of Food Program, Australia improved individuals' cooking confidence and cooking/eating behaviours contributing to a healthier diet and is a promising community-based strategy to influence diet quality. PMID- 25514532 TI - Total and differential white blood cell counts predict eight-year incident coronary heart disease in elderly Japanese-American men: the Honolulu Heart Program. AB - BACKGROUND: Previous studies have reported an association between total and differential white blood cell (WBC) counts and incident coronary heart disease (CHD), but data from elderly populations are scarce. The purpose of this study was to examine the association between total and differential WBC counts and incident CHD in an elderly Japanese-American population. METHODS: Total and differential WBC counts were examined at a baseline examination from 1991 to 1993 in the Honolulu Heart Program. Subjects were Japanese-American men aged 71-93 years free of CHD at baseline (N = 2879), who were divided into quartiles of total and differential WBC counts for analysis, and were followed for incident CHD for 8 years. RESULTS: During the follow up period, 279 men developed CHD. Hazard ratio for incident CHD for each quartile of total and differential WBC counts were obtained by Cox regression using the lowest quartile as the reference group. After full adjustment including age, cardiovascular risk factors, chronic diseases and medication use, the hazard ratios in the highest quartiles of total WBC, granulocyte and neutrophil counts were 1.75 (95% confidence interval [CI], 1.18-2.62; P = 0.006), 1.66 (95%CI, 1.11-2.48; P = 0.01), and 1.57 (95%CI, 1.06 2.34; P = 0.03), respectively. No significant associations were found between lymphocyte or monocyte counts and incident CHD. CONCLUSIONS: Higher total WBC, granulocyte and neutrophil counts were associated with higher risk of incident CHD in a population of elderly Japanese-American men. Further studies are needed to establish cut-points and treatment options with anti-inflammatory medications. PMID- 25514533 TI - A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation. AB - There is a poor understanding of how the physiology of polymicrobial communities in cystic fibrosis (CF) lungs contributes to pulmonary exacerbations and lung function decline. In this study, a microbial culture system based on the principles of the Winogradsky column (WinCF system) was developed to study the physiology of CF microbes. The system used glass capillary tubes filled with artificial sputum medium to mimic a clogged airway bronchiole. Chemical indicators were added to observe microbial physiology within the tubes. Characterization of sputum samples from seven patients showed variation in pH, respiration, biofilm formation and gas production, indicating that the physiology of CF microbial communities varied among patients. Incubation of homogenized tissues from an explant CF lung mirrored responses of a Pseudomonas aeruginosa pure culture, supporting evidence that end-stage lungs are dominated by this pathogen. Longitudinal sputum samples taken through two exacerbation events in a single patient showed that a two-unit drop in pH and a 30% increase in gas production occurred in the tubes prior to exacerbation, which was reversed with antibiotic treatment. Microbial community profiles obtained through amplification and sequencing of the 16S rRNA gene showed that fermentative anaerobes became more abundant during exacerbation and were then reduced during treatment where P. aeruginosa became the dominant bacterium. Results from the WinCF experiments support the model where two functionally different CF microbial communities exist, the persistent Climax Community and the acute Attack Community. Fermentative anaerobes are hypothesized to be the core members of the Attack Community and production of acidic and gaseous products from fermentation may drive developing exacerbations. Treatment targeting the Attack Community may better resolve exacerbations and resulting lung damage. PMID- 25514534 TI - Bacteria-bacteria interactions within the microbiota of the ancestral metazoan Hydra contribute to fungal resistance. AB - Epithelial surfaces of most animals are colonized by diverse microbial communities. Although it is generally agreed that commensal bacteria can serve beneficial functions, the processes involved are poorly understood. Here we report that in the basal metazoan Hydra, ectodermal epithelial cells are covered with a multilayered glycocalyx that provides a habitat for a distinctive microbial community. Removing this epithelial microbiota results in lethal infection by the filamentous fungus Fusarium sp. Restoring the complex microbiota in gnotobiotic polyps prevents pathogen infection. Although mono-associations with distinct members of the microbiota fail to provide full protection, additive and synergistic interactions of commensal bacteria are contributing to full fungal resistance. Our results highlight the importance of resident microbiota diversity as a protective factor against pathogen infections. Besides revealing insights into the in vivo function of commensal microbes in Hydra, our findings indicate that interactions among commensal bacteria are essential to inhibit pathogen infection. PMID- 25514535 TI - Metatranscriptomics of N2-fixing cyanobacteria in the Amazon River plume. AB - Biological N2 fixation is an important nitrogen source for surface ocean microbial communities. However, nearly all information on the diversity and gene expression of organisms responsible for oceanic N2 fixation in the environment has come from targeted approaches that assay only a small number of genes and organisms. Using genomes of diazotrophic cyanobacteria to extract reads from extensive meta-genomic and -transcriptomic libraries, we examined diazotroph diversity and gene expression from the Amazon River plume, an area characterized by salinity and nutrient gradients. Diazotroph genome and transcript sequences were most abundant in the transitional waters compared with lower salinity or oceanic water masses. We were able to distinguish two genetically divergent phylotypes within the Hemiaulus-associated Richelia sequences, which were the most abundant diazotroph sequences in the data set. Photosystem (PS)-II transcripts in Richelia populations were much less abundant than those in Trichodesmium, and transcripts from several Richelia PS-II genes were absent, indicating a prominent role for cyclic electron transport in Richelia. In addition, there were several abundant regulatory transcripts, including one that targets a gene involved in PS-I cyclic electron transport in Richelia. High sequence coverage of the Richelia transcripts, as well as those from Trichodesmium populations, allowed us to identify expressed regions of the genomes that had been overlooked by genome annotations. High-coverage genomic and transcription analysis enabled the characterization of distinct phylotypes within diazotrophic populations, revealed a distinction in a core process between dominant populations and provided evidence for a prominent role for noncoding RNAs in microbial communities. PMID- 25514537 TI - Influence of biochar application methods on the phytostabilization of a hydrophobic soil contaminated with lead and acid tar. AB - A hardwood biochar was examined for its potential use as an amendment to aid in the phytostabilization of a severely-contaminated soil at a former sulfuric acid recycling factory site. The soil, which has remained unvegetated for nearly a century, contained high pseudo-total concentrations of lead, arsenic and antimony and was both highly acidic and hydrophobic due to the presence of petroleum-based acid tar. Three application approaches were tested with 10 and 20% (vol/vol) biochar: Incorporation into soil, top-dressing on the surface, and layering within the soil. The results suggest that the homogeneous mixing of the hardwood biochar into soil would not promote the long-term restoration at this site due to its inherently low alkalinity relative to the very high net acidity of the existing soil. In contrast, surface application of biochar resulted in the most successful growth of Canada wild-rye grass by exploiting the properties inherent to biochar alone. PMID- 25514536 TI - Correlates of virulence in a frog-killing fungal pathogen: evidence from a California amphibian decline. AB - The fungal pathogen Batrachochytrium dendrobatidis (Bd) has caused declines and extinctions in amphibians worldwide, and there is increasing evidence that some strains of this pathogen are more virulent than others. While a number of putative virulence factors have been identified, few studies link these factors to specific epizootic events. We documented a dramatic decline in juvenile frogs in a Bd-infected population of Cascades frogs (Rana cascadae) in the mountains of northern California and used a laboratory experiment to show that Bd isolated in the midst of this decline induced higher mortality than Bd isolated from a more stable population of the same species of frog. This highly virulent Bd isolate was more toxic to immune cells and attained higher density in liquid culture than comparable isolates. Genomic analyses revealed that this isolate is nested within the global panzootic lineage and exhibited unusual genomic patterns, including increased copy numbers of many chromosomal segments. This study integrates data from multiple sources to suggest specific phenotypic and genomic characteristics of the pathogen that may be linked to disease-related declines. PMID- 25514538 TI - Effect of citric acid and bacteria on metal uptake in reeds grown in a synthetic acid mine drainage solution. AB - The effect of citric acid (CA), rhizosphere acidophilic heterotrophs and/or Fe(II) oxidizing bacteria (Fe(II)OB) on plaque formation and metal accumulation in Phragmites australis L. (common reed) from acid mine drainage (AMD) solution were investigated. Reeds were grown in different hydroponic solutions that contained AMD, CA and/or rhizosphere bacteria for three months. Triplicate experiments were conducted for each experimental condition. Fe(II)OB enhanced the formation of Fe plaque which decreased Fe and Mn uptake in reeds, while it had no significant influence on Al accumulation. CA inhibited the growth of Fe(II)OB, decreased the formation of metal plaque and increased Fe and Mn accumulation in reeds. Acidophilic heterotrophs consumed CA and made the environment more suitable for the growth of Fe(II)OB. Reeds are a good candidate for phytoextraction while CA is a useful chelator to enhance metal uptake in plants. More research may be needed to investigate the influence of CA on microbial community. Further investigations are required to study the effect of CA on phytoremediation of AMD contaminated fields. PMID- 25514539 TI - Public awareness of aesthetic and other forest values associated with sustainable forest management: a cross-cultural comparison among the public in four countries. AB - Korea, China, Japan and Canada are all members of the Montreal Process (MP). However, there has been little comparative research on the public awareness of forest values within the framework of Sustainable Forest Management, not only between Asia and Canada, but also among these three Asian countries. This is true of aesthetic values, especially as the MP framework has no indicator for aesthetic values. We conducted surveys to identify similarities and differences in the perceptions of various forest values, including aesthetic values, between residents of the four countries: university student groups in Korea, China, Japan and Canada, as well as a more detailed assessment of the attitudes of Koreans by including two additional groups, Korean office workers, and Koreans living in Canada. A multivariate analysis of variance test across the four university student groups revealed significant differences in the rating of six forest functions out of 31. However the same test across the three Korean groups indicated no significant differences indicating higher confidence in the generalizability of our university student comparisons. For the forest aesthetic values, an analysis of variance test showed no significant differences across all groups. The forest aesthetic value was rated 6.95 to 7.98 (out of 10.0) depending on the group and rated relatively highly among ten social values across all the groups. Thurstone scale rankings and relative distances of six major forest values indicated that climate change control was ranked as the highest priority and scenic beauty was ranked the lowest by all the groups. Comparison tests of the frequencies of preferred major forest values revealed no significant differences across the groups with the exception of the Japanese group. These results suggest that public awareness of aesthetic and other forest values are not clearly correlated with the cultural backgrounds of the individuals, and the Korean university students' awareness could potentially be representative of the Koreans general public's opinion. We expect this research to contribute to the development of aesthetic and social indicators, and to the enhancement of balancing social with environmental and economic values within the SFM framework. PMID- 25514540 TI - From the Editor-in-Chief's Desk. PMID- 25514541 TI - Temperament and behavior in toddlers of mothers with bipolar disorder: a preliminary investigation of a population at high familial risk for psychopathology. AB - OBJECTIVE: There are no published studies examining concurrent associations between temperament and behavior during toddlerhood in offspring of parents with bipolar disorder (OBD), a population at high familial risk for psychopathology. Better understanding of early determinants contributing to well-being or mental illness in this high-risk population has the potential to aid in the identification of problem domains to be targeted clinically, and facilitate the development of early intervention and prevention initiatives for an appropriate subgroup of children at the youngest possible age. METHODS: A total of 30 offspring of mothers with BD (mean age=25.4+/-4.9 months) participated in this study at Emory University. The mothers completed the Early Childhood Behavior Questionnaire (ECBQ) and the Child Behavior Checklist (CBCL). RESULTS: The results of the correlational analyses indicated that the broad temperament dimension Negative Affectivity and the individual ECBQ scales Sadness and Shyness were positively associated with the broad CBCL dimension Internalizing Problems, whereas Sociability was negatively associated with Internalizing Problems. In addition, the temperament scales Soothability and Frustration were negatively and positively associated with Internalizing Problems, respectively. All ECBQ scales included in the broad temperament dimension Effortful Control, except for Cuddliness, were significantly negatively associated with the broad CBCL dimension Externalizing Problems. A significant sex difference was found for the ECBQ scale Positive Anticipation and the CBCL scale Sleep Problems, with a higher mean rank score for girls than for boys. CONCLUSIONS: This is the first systematic investigation of temperament and behavior and concurrent associations between these two domains in toddlers of mothers with BD. The present findings provide a platform for future investigations of the contribution of temperament and early behavior to potential well-being or mental illness in OBD. PMID- 25514543 TI - Treatment of aggressive behavior problems in boys with intellectual disabilities using zuclopenthixol. AB - OBJECTIVE: Disruptive or challenging behavior problems pose a threat to children and adolescents with intellectual disabilities and their caregivers. Psychopharmacological treatment is mostly studied with new-generation antipsychotics and has been criticized for adverse side effects. This study examined the effect of the classic antipsychotic zuclopenthixol. METHODS: A total of 39 boys (ages 8.0-17.11 years) with learning disabilities were included and examined for a response to zuclopenthixol during a 6 week period of open label treatment. Doses started low and were adapted individually. From responders, zuclopenthixol was randomly withdrawn for 12 weeks. Responses to withdrawal were observed by external raters using the Modified Overt Aggression Scale. RESULTS: Of all patients included into the study, 15 were not randomized because of insufficient therapeutic effect, adverse event, or noncompliance. Kaplan-Meier estimations showed less aggressive behavior problems for the continuing subgroup (n=9) than in the placebo group (n=15). Individual doses stayed <10 mg/day. CONCLUSIONS: Zuclopenthixol proved to be effective in reducing challenging behavior in boys even at low doses. PMID- 25514542 TI - Single-dose pharmacokinetics of methylphenidate extended-release multiple layer beads administered as intact capsule or sprinkles versus methylphenidate immediate-release tablets (Ritalin((r))) in healthy adult volunteers. AB - OBJECTIVES: The purpose of this study was to evaluate the relative bioavailability and safety of a multilayer extended-release bead methylphenidate (MPH) hydrochloride 80 mg (MPH-MLR) capsule or sprinkles (37% immediate-release [IR]) versus MPH hydrochloride IR(Ritalin((r))) tablets, and to develop a pharmacokinetic (PK) model simulating MPH concentration-time data for different MPH-MLR dosage strengths. METHODS: This was a single-center, randomized, open label, three-period crossover study conducted in 26 fasted healthy adults (mean weight+/-standard deviation, 70.4+/-11.7 kg) assigned to single-dose oral MPH-MLR 80 mg capsule or sprinkles with applesauce, or Ritalin IR 25 mg (1*5 mg and 1*20 mg tablet) administered at 0, 4, and 8 hours. RESULTS: MPH-MLR 80 mg capsule and sprinkles were bioequivalent; ratios for maximum concentration (Cmax), area under plasma drug concentration versus time curve (AUC)0-t, and AUC0-inf were 1.04 (95% confidence interval [CI], 96.3-112.4), 0.99 (95% CI, 95.3-102.8), and 0.99 (95% CI, 95.4-103.0), respectively. MPH-MLR capsule/sprinkles produced highly comparable, biphasic profiles of plasma MPH concentrations characterized by rapid initial peak, followed by moderate decline until 5 hours postdose, and gradual increase until 7 hours postdose, culminating in an attenuated second peak. Based on 90% CIs, total systemic exposure to MPH-MLR 80 mg capsule/sprinkles was similar to that for Ritalin IR 25 mg three times daily, but marked differences in Cmax values indicated that MPH-MLR regimens were not bioequivalent to Ritalin. MPH Cmax and total systemic exposure over the first 4 hours postdose with MPH-MLR capsule/sprinkles was markedly higher than that associated with the first dose of Ritalin. All study drugs were safe and well tolerated. The PK modeling in adults suggested that differences in MPH pharmacokinetics between MPH-MLR and Ritalin are the result of dosage form design attributes and the associated absorption profiles of MPH. CONCLUSIONS: MPH-MLR 80 mg provides a long-acting biphasic pattern of plasma MPH concentrations with one less peak and trough than Ritalin IR. PMID- 25514544 TI - Emotional dysregulation in a child with attention-deficit/hyperactivity disorder and anxiety: psychopharmacological stategies. PMID- 25514545 TI - Neuroprotective effect of prenylated arylbenzofuran and flavonoids from morus alba fruits on glutamate-induced oxidative injury in HT22 hippocampal cells. AB - A prenylated arylbenzofuran and six flavonoids were isolated from the fruits of Morus alba L. through silica gel, octadecyl silica gel, and Diaion HP-20 column chromatography. Based on the nuclear magnetic resonance, mass spectrometry, and infrared spectroscopic data, the chemical structures of the compounds were determined to be artoindonesianin O (1), isobavachalcone (2), morachalcone A (3), quercetin (4), astragalin (5), isoquercetin (6), and rutin (7). The isolated compounds were evaluated for protection of HT22-immortalized hippocampal cells against glutamate-induced oxidative stress. Compounds 1 and 3 exhibited protective effects with EC(50) values of 19.7+/-1.2 and 35.5+/-2.1 MUM, respectively. The major compounds 1-3 and 7 were quantified using liquid chromatography/mass spectrometry analysis and were determined to be 1.88+/-2.1, 1.90+/-1.8, 0.78+/-1.5, and 37.29+/-2.2 mg/kg, respectively, in the ethanol extract of M. alba L. fruits. PMID- 25514546 TI - Seasonal influenza vaccination among Mexican migrants traveling through the Mexico-US border region. AB - OBJECTIVE: Mobile populations are at high risk for communicable diseases and can serve as a bridge between sending and receiving communities. The objective of this study is to determine the rates of, and factors associated with, seasonal influenza vaccination among Mexican migrants traveling through the US-Mexico border. METHODS: We used a 2013 cross-sectional population-based survey of adult mobile Mexican migrants traveling through the Mexico-US border region (N=2313; weighted N=652,500). We performed a multivariable logistic regression analysis to model the odds of receiving an influenza vaccination in the past year by sociodemographics, migration history, health status, and access to health care. RESULTS: The seasonal influenza vaccination rate in this population was 18.6%. Gender, health status, and health insurance were associated with the likelihood to receive an influenza vaccination. CONCLUSION: Overall, the rates of seasonal influenza vaccination in circular Mexican migrants are low compared to adults in Mexico and the US Efforts are needed to increase influenza vaccination among this highly mobile population, particularly in adults with chronic conditions. PMID- 25514547 TI - Effectiveness of brief interventions in primary health care settings to decrease alcohol consumption by adult non-dependent drinkers: a systematic review of systematic reviews. AB - OBJECTIVE: To evaluate the effectiveness of brief interventions in the primary health care setting to decrease alcohol consumption in non-alcoholic adult drinkers. METHOD: Systematic review of systematic reviews and meta-analyses of randomized clinical trials published in English and Spanish and indexed in EMBASE, MEDLINE (PubMed), Web of Science, Scopus, and The Cochrane Library, from their inception to January 2014. The quality of the studies was evaluated with the AMSTAR instrument. RESULTS: Seven studies, published from 1999 to 2011, were included in the review (six meta-analyses, one systematic review). These studies were heterogeneous in terms of design, type and length of interventions analyzed, participants, responsible professionals, and results. Five studies reported a moderate decrease in alcohol consumption and four showed a decrease in the number of participants who consumed alcohol above the established risk level. CONCLUSION: Brief interventions have a moderate effect on reducing alcohol consumption among excessive drinkers or people who consume excessive amounts of alcohol and as a consequence these interventions increased the number of people drinking alcohol below established limits of risk. Brief interventions with multiple contacts or follow-up sessions are the most effective. PMID- 25514549 TI - Perspectives on super-shedding of Escherichia coli O157:H7 by cattle. AB - Escherichia coli O157:H7 is a foodborne pathogen that causes illness in humans worldwide. Cattle are the primary reservoir of this bacterium, with the concentration and frequency of E. coli O157:H7 shedding varying greatly among individuals. The term "super-shedder" has been applied to cattle that shed concentrations of E. coli O157:H7 >= 104 colony-forming units/g feces. Super shedders have been reported to have a substantial impact on the prevalence and transmission of E. coli O157:H7 in the environment. The specific factors responsible for super-shedding are unknown, but are presumably mediated by characteristics of the bacterium, animal host, and environment. Super-shedding is sporadic and inconsistent, suggesting that biofilms of E. coli O157:H7 colonizing the intestinal epithelium in cattle are intermittently released into feces. Phenotypic and genotypic differences have been noted in E. coli O157:H7 recovered from super-shedders as compared to low-shedding cattle, including differences in phage type (PT21/28), carbon utilization, degree of clonal relatedness, tir polymorphisms, and differences in the presence of stx2a and stx2c, as well as antiterminator Q gene alleles. There is also some evidence to support that the native fecal microbiome is distinct between super-shedders and low-shedders and that low-shedders have higher levels of lytic phage within feces. Consequently, conditions within the host may determine whether E. coli O157:H7 can proliferate sufficiently for the host to obtain super-shedding status. Targeting super shedders for mitigation of E. coli O157:H7 has been proposed as a means of reducing the incidence and spread of this pathogen to the environment. If super shedders could be easily identified, strategies such as bacteriophage therapy, probiotics, vaccination, or dietary inclusion of plant secondary compounds could be specifically targeted at this subpopulation. Evidence that super-shedder isolates share a commonality with isolates linked to human illness makes it imperative that the etiology of this phenomenon be characterized. PMID- 25514548 TI - Assessment of an interactive voice response system for identifying falls in a statewide sample of older adults. AB - OBJECTIVE: Interactive voice response (IVR) systems offer great advantages for data collection in large, geographically dispersed samples involving frequent contact. We assessed the quality of IVR data collected from older respondents participating in a statewide falls prevention program evaluation in Pennsylvania in 2010-12. METHOD: Participants (n=1834) were followed up monthly for up to 10 months to compare respondents who completed all, some, or no assessments in the IVR system. Validity was assessed by examining IVR-reported falls incidence relative to baseline in-person self-report and performance assessment of balance. RESULTS: While a third of the sample switched from IVR to in-person calls over follow-up, IVR interviews were successfully used to complete 68.1% of completed monthly assessments (10,511/15,430). Switching to in-person interviews was not associated with measures of participant function or cognition. Both self-reported (p<.0001) and performance assessment of balance (p=.05) at baseline were related to falls incidence. CONCLUSION: IVR is a productive modality for falls research among older adults. Future research should establish what level of initial personal research contact is optimal for boosting IVR completion rates and what research domains are most appropriate for this kind of contact. PMID- 25514550 TI - [The absence of stewardship in the Chilean health authority after the 2004 health reform]. AB - Stewardship is the most important political function of a health system. It is a government responsibility carried out by the health authority. Among other dimensions, it is also a meta-function that includes conduction and regulation. The Health Authority and Management Act, which came about from the health reform of 2004, separated the functions of service provision and stewardship with the aim of strengthening the role of the health authority. However, the current structure of the health system contains overlapping functions between the different entities that leads to lack of coordination and inconsistencies, and a greater weight on individual health actions at the expense of collective ones. Consequently, a properly funded national health strategy to improve the health of the population is missing. Additionally, the components of citizen participation and governance are weak. It is necessary, therefore, to revisit the Chilean health structure in order to develop one that truly enables the exercise of the health authority?s stewardship role. PMID- 25514551 TI - The value of fluorine-18 fluorodeoxyglucose PET/MRI in the diagnosis of head and neck carcinoma: a meta-analysis. AB - OBJECTIVES: Fluorine-18 fluorodeoxyglucose (18F-FDG) PET/MRI has been used in the diagnosis of head and neck carcinoma. The aim of this study was to systematically review and perform a meta-analysis of published data on the performance of F PET/MRI in the diagnosis of head and neck carcinoma. MATERIALS AND METHODS: We conducted a comprehensive review of the literature on the role of soft-based fusion and integrated 18F-FDG PET/MRI in the diagnosis of head and neck carcinoma. Pooled sensitivity, specificity, and area under the receiver-operating characteristic curve of soft-based fusion and integrated 18F-FDG PET/MRI in the diagnosis of head and neck carcinoma were calculated. RESULTS: Ten studies comprising 421 patients, which included 1879 head and neck primary carcinoma and metastatic lesions, were included in this meta-analysis. 18F-FDG PET/MRI had a pooled sensitivity of 91%, a pooled specificity of 63%, and an area under the receiver-operating characteristic curve of 0.96 on a per lesion-based analysis in detecting head and neck carcinoma lesions. Soft-based fusion and integrated 18F FDG PET/MRI had a pooled sensitivity of 92 and 90%, a pooled specificity of 53 and 87%, and an area under the receiver-operating characteristic curve of 0.95 and 0.96, respectively, on a per lesion-based analysis in detecting head and neck carcinoma lesions. CONCLUSION: 18F-FDG PET/MRI demonstrated high sensitivity and moderate specificity in the diagnosis of head and neck carcinoma lesions. 18F-FDG PET/MRI is an accurate method in the diagnosis of head and neck carcinoma. PMID- 25514552 TI - The feasibility of low-dose CT protocols for coronary artery calcium scoring and PET attenuation correction in cardiac PET/CT. AB - INTRODUCTION: The purpose of this study was to investigate the feasibility of using low-dose computed tomography (CT) in coronary artery calcium scoring and PET attenuation correction for patients in different weight categories undergoing cardiac PET/CT examinations. MATERIALS AND METHODS: Calcium scoring computed tomography (CSCT) scans and PET scans of anthropomorphic cardiac phantoms simulating normal-weight, mildly obese, and severely obese patients were acquired with a hybrid PET/CT scanner. CSCT images were acquired at 120 kVp, with tube current ranging from 10 to 550 mA. PET scans were performed in three-dimensional mode, with acquisition time of 3 min/bed position. The image quality of cardiac PET/CT was evaluated by assessing the signal-to-noise ratio. CT-based coronary artery calcium quantification was performed using the Agatston scoring system. RESULTS: On the basis of our results, the CSCT protocols using tube currents of 50 and 150 mA should be able to achieve the lowest possible radiation dose while maintaining the desired image quality for normal-weight and mildly obese patients undergoing cardiac PET/CT examinations, respectively. When the proposed low-dose CSCT protocols were performed, radiation dose could be reduced by 83.34 and 50% compared with those from CSCT scans acquired with standard tube current settings for normal-weight and mildly obese patients, respectively. In the scanning of severely obese patients, an increase in tube voltage or current would help improve the reliability of image information provided by cardiac PET/CT. CONCLUSION: Our study demonstrated the feasibility of low-dose CT protocols for coronary artery calcium scoring and PET attenuation correction in cardiac PET/CT to examine patients in different weight categories. The calculations performed in this work should be able to provide practical information to achieve necessary diagnostic information while keeping radiation dose as low as reasonably achievable. PMID- 25514553 TI - Short-term kinesthetic training for sensorimotor rhythms: effects in experts and amateurs. AB - The authors' aim was to examine whether short-term kinesthetic training affects the level of sensorimotor rhythm (SMR) in different frequency band: alpha (8-12 Hz), lower beta (12.5-16 Hz) and beta (16.5-20 Hz) during the execution of a motor imagery task of closing and opening the right and the left hand by experts (jugglers, practicing similar exercises on an everyday basis) and amateurs (individuals not practicing any sports). It was found that the performance of short kinesthetic training increases the power of alpha rhythm when executing imagery tasks only in the group of amateurs. Therefore, kinesthetic training may be successfully used as a method increasing the vividness of motor imagery, for example, in tasks involving the control of brain-computer interfaces based on SMR. PMID- 25514554 TI - Real-time shear-wave elastography: applicability, reliability and accuracy for clinically significant portal hypertension. AB - BACKGROUND & AIMS: Real-time shear wave elastography (RT-SWE) might be useful to assess the severity of portal hypertension; reliability criteria for measurement are needed. METHODS: We prospectively included 88 consecutive patients undergoing hepatic venous pressure gradient measurement (HVPG, reference standard) for portal hypertension. Liver stiffness (LS) was measured by RT-SWE and by transient elastography (TE). Spleen stiffness (SS) was measured by RT-SWE. Reliability criteria for RT-SWE were searched, and the accuracy of these techniques to identify HVPG ?10mmHg (clinically significant portal hypertension, CSPH) was tested and internally validated by bootstrapping analysis. RESULTS: LS and SS by RT-SWE were feasible respectively in 87 (99%) and 58 (66%) patients. Both correlated with HVPG (LS: R=0.611, p<0.0001 and SS: R=0.514, p<0.0001). LS performed well for diagnosing CSPH (optimism corrected AUROC=0.858). Reliability of measurements was influenced by standard deviation (SD)/median ratio and depth. SD/median ?0.10 and depth of measurement <5.6cm were associated to 96.3% well classified for CSPH, while when one or none of the criteria were fulfilled the rates were 76.4% and 44.4%, respectively. Measurements fulfilling at least one criterion were considered acceptable; in these patients, RT-SWE performance to detect CSPH was excellent (AUROC=0.939; 95% CI: 0.865-1.000; p<0.0001; best cut off: 15.4kPa). LS by RT-SWE and by TE were strongly correlated (R=0.795, p<0.0001) and performed similarly both in "per protocol" and in "intention-to diagnose" analysis after applying reliability criteria. CONCLUSIONS: LS by RT-SWE is an accurate method to diagnose CSPH if reliability criteria (SD/median ?0.10 and/or depth <5.6cm) are fulfilled. PMID- 25514555 TI - Mirtoselect, an anthocyanin-rich bilberry extract, attenuates non-alcoholic steatohepatitis and associated fibrosis in ApoE(*)3Leiden mice. AB - BACKGROUND & AIMS: Anthocyanins may have beneficial effects on lipid metabolism and inflammation and are demonstrated to have hepatoprotective properties in models of restraint-stress- and chemically-induced liver damage. However, their potential to protect against non-alcoholic steatohepatitis (NASH) under conditions relevant for human pathogenesis remains unclear. Therefore, we studied the effects of the standardised anthocyanin-rich extract Mirtoselect on diet induced NASH in a translational model of disease. METHODS: ApoE(*)3Leiden mice were fed a Western-type cholesterol-containing diet without (HC) or with 0.1% (w/w) Mirtoselect (HCM) for 20weeks to study the effects on diet-induced NASH. RESULTS: Mirtoselect attenuated HC-induced hepatic steatosis, as observed by decreased macro- and microvesicular hepatocellular lipid accumulation and reduced hepatic cholesteryl ester content. This anti-steatotic effect was accompanied by local anti-inflammatory effects in liver, as demonstrated by reduced inflammatory cell clusters and reduced neutrophil infiltration in HCM. On a molecular level, HC diet significantly induced hepatic expression of pro-inflammatory genes Tnf, Emr1, Ccl2, Mpo, Cxcl1, and Cxcl2 while this induction was less pronounced or significantly decreased in HCM. A similar quenching effect was observed for HC induced pro-fibrotic genes, Acta2 and Col1a1 and this anti-fibrotic effect of Mirtoselect was confirmed histologically. Many of the pro-inflammatory and pro fibrotic parameters positively correlated with intrahepatic free cholesterol levels. Mirtoselect significantly reduced accumulation and crystallisation of intrahepatic free cholesterol, providing a possible mechanism for the observed hepatoprotective effects. CONCLUSIONS: Mirtoselect attenuates development of NASH, reducing hepatic lipid accumulation, inflammation and fibrosis, possibly mediated by local anti-inflammatory effects associated with reduced accumulation and crystallisation of intrahepatic free cholesterol. PMID- 25514556 TI - Baseline interpatient hepatitis B viral diversity differentiates HBsAg outcomes in patients treated with tenofovir disoproxil fumarate. AB - BACKGROUND AND AIMS: HBsAg loss is a desired, but rare, treatment-induced clinical endpoint in chronic hepatitis B (CHB). Few studies have evaluated viral factors contributing to HBsAg loss. METHODS: This study evaluated baseline interpatient sequence diversity across the HBV genome in tenofovir disoproxil fumarate-treated patients who lost HBsAg and compared it to that of control patients with high HBsAg levels throughout therapy. Twenty-one HBeAg+ patients (14 genotype (GT) A and 7 GT D) who achieved HBsAg loss and 27 controls (17 GT A and 10 GT D), were analyzed. Population sequencing was performed on baseline samples and pairwise genetic distances were calculated for 17 overlapping regions across the HBV genome as a measure of interpatient viral diversity. RESULTS: Overall, viral diversity was up to 10-fold higher across GT D patients compared to GT A patients throughout the HBV genome. Within the pol/RT and HBs genes, interpatient viral diversity was significantly lower among HBsAg loss patients for both GT A and D, with the difference driven largely by a reduction in diversity in the small S gene. Conversely, interpatient viral diversity was generally higher in HBsAg loss patients across the HBx gene regulatory elements and precore region. CONCLUSION: In HBsAg loss patients, less interpatient viral diversity was observed within structural-coding regions while specific regions across the HBx and precore genes encoding nonstructural regulatory elements generally displayed higher interpatient viral diversity. These distinct patterns may reflect different responses to adaptive pressure for HBV genomic structural and nonstructural elements. PMID- 25514558 TI - Use of mouse liver mesothelial cells to prevent postoperative adhesion and promote liver regeneration after hepatectomy. AB - BACKGROUND & AIMS: Repeated hepatectomy is widely accepted as one of the most effective curative treatment for recurrent hepatocellular carcinoma or liver metastasis from colorectal cancer. It has, however, two critical issues; postoperative adhesion and decrease of liver regenerative capacity. Postoperative adhesion makes surgical operations technically more demanding, leading to increased mortality and morbidity rates. Although the liver has a remarkable regenerative ability, volume and functional restoration after multiple repeated hepatectomy is not generally complete. So a new procedure that overcomes these two issues is required. We examined if a fetal liver mesothelial cells (FL-MCs) sheet could solve these two clinical issues simultaneously. METHODS: We established a novel mouse hepatectomy model that reproduces postoperative adhesion on the resected liver surface. We isolated FL-MCs from mouse fetal liver and prepared a cell sheet. The FL-MCs sheet was then transplanted to the resected liver surface. RESULTS: The FL-MCs sheet effectively prevented postoperative adhesion by expressing PCLP1, one of the transmembrane sialomucin family proteins and by activating the fibrinolytic system. Furthermore, the FL-MCs sheet facilitated liver regeneration by providing growth factors for hepatocytes, allowing quick recovery of liver weight and function. Additionally, we showed that an allogeneic FL-MCs sheet was as effective as a syngeneic cell sheet. CONCLUSIONS: We demonstrate that the FL-MCs sheet is able to not only prevent postoperative adhesion but also promote liver regeneration in both syngeneic and allogeneic transplantation, and hence FL-MCs may serve as a potentially useful cell source for regenerative medicine after hepatectomy. PMID- 25514557 TI - Sorafenib therapy for hepatocellular carcinoma with extrahepatic spread: treatment outcome and prognostic factors. AB - BACKGROUND & AIMS: Sorafenib is recommended as the treatment of choice for hepatocellular carcinoma (HCC) with extrahepatic spread (EHS). However, early discontinuation of sorafenib treatment is not uncommon because of adverse events, deterioration of liver function and/or performance. This study aimed to investigate the treatment outcome and prognostic factors of sorafenib treatment in HCC patients with EHS in which sorafenib was administered for at least 8 weeks. METHODS: From May 2007 to December 2012, a total of 254 HCC patients with EHS were treated with sorafenib monotherapy for at least 8 weeks. The treatment outcome, risk factors for disease progression, and overall survival were retrospectively analyzed. RESULTS: The median duration of radiologic progression and overall survival after sorafenib was 2.5 and 9.6 months, respectively. Prognostic factors for radiologic progression were intrahepatic tumor with macrovascular invasion (MVI) (hazard ratio (HR) 2.38, p<0.001), intrahepatic tumor without MVI (HR 2.37, p<0.001), age <60 years (HR 1.44, p=0.008), peritoneal involvement (HR 1.57, p=0.03), and underlying hepatitis B (HR 1.46, p=0.05). Prognostic factors for overall survival were lack of disease control with sorafenib (HR 2.98, p<0.001), intrahepatic tumor with MVI (HR 2.23, p<0.001), intrahepatic tumor without MVI (HR 1.70, p=0.003), Child-Pugh class B (HR 1.90, p=0.009), serum AFP ?200ng/ml (HR 1.45, p=0.009), and ALT ?40U/L (HR 1.34, p=0.041). In patients with chronic hepatitis B, the use of antiviral treatment was associated with favorable overall survival after sorafenib therapy (HR 0.64, p=0.003). CONCLUSION: Sorafenib prolonged survival in HCC patients with EHS who achieved disease control. Intrahepatic tumor is a poor prognostic factor for both disease progression and overall survival in HCC patients with EHS treated with sorafenib. PMID- 25514559 TI - Effect of tea theaflavins and catechins on microvascular function. AB - Beneficial effects of flavonoid-rich black and green tea on macrocirculation have been well established. Theaflavins are unique to black tea as they are formed from catechins during the enzymatic oxidation of tea leaves. The study was performed to gain more insight into the effects of theaflavins on microcirculation and to compare effects with another important flavonoid class, the green tea derived catechins, which have been reported to improve vascular function. Twenty-four healthy subjects were included in a double-blind, placebo controlled, randomised, cross-over study. On six different days, subjects received capsules with a single dose of catechins (500 mg), four varying doses of theaflavins (100 to 500 mg) or placebo. Microcirculation was assessed after each treatment by Pulse Amplitude Tonometry (EndoPAT) at baseline and 2, 4 and 6 h after test product intake. The EndoPAT reactive hyperemia response was improved by 500 mg catechins (reactive hyperemia index (RHI): 0.2; p = 0.04) and by 500 mg theaflavins (RHI: 0.19; p = 0.06) compared to placebo. Also, 300 mg theaflavins increased the RHI (0.28; p = 0.02), but no effects were observed at lower doses. The study suggests moderate effects of single doses of catechins and theaflavins on peripheral microcirculation. PMID- 25514561 TI - Urban-rural differences explain the association between serum 25-hydroxyvitamin D level and insulin resistance in Korea. AB - An increasing number of studies report associations between low serum 25 hydroxyvitamin D [25(OH)D] level and insulin resistance; however, whether low vitamin D levels directly contribute to increased insulin resistance is unclear. We investigated the impact of residential area on the association between 25(OH)D and insulin resistance in elderly Koreans. Using data from the Korean Urban Rural Elderly study, we conducted cross-sectional analyses in 1628 participants (505 men and 1123 women). Serum 25(OH)D was analyzed as both continuous and categorized variables. Homeostasis model assessment for insulin resistance (HOMA IR) was calculated using fasting blood glucose and insulin levels. In men, 25(OH)D level was inversely associated with HOMA-IR (standardized beta = -0.133, p < 0.001) after adjustment for age, body mass index, waist circumference, smoking, alcohol intake, exercise, and study year. However, we noted significant urban-rural differences in 25(OH)D level (43.4 versus 65.6 nmol/L; p < 0.001) and HOMA-IR (1.2 versus 0.8 mmol . pmol/L2; p < 0.001). When we additionally adjusted for residential area, the association between 25(OH)D and HOMA-IR was attenuated (standardized beta = -0.063, p = 0.115). In women, the association between 25(OH)D and HOMA-IR was not significant before or after adjustment for residential area. Environmental or lifestyle differences in urban and rural areas may largely explain the inverse association between serum 25(OH)D and insulin resistance. PMID- 25514560 TI - Dysbiotic events in gut microbiota: impact on human health. AB - The human body is colonized by a large number of microbes coexisting peacefully with their host. The most colonized site is the gastrointestinal tract (GIT). More than 70% of all the microbes in the human body are in the colon. The microorganism population is 10 times larger of the total number of our somatic and germ cells. Two bacterial phyla, accounting for more than 90% of the bacterial cells, dominate the healthy adult intestine: Firmicutes and Bacteroidetes. Considerable variability in the microbiota compositions between people is found when we look at the taxonomic level of species, and strains within species. It is possible to assert that the human microbiota could be compared to a fingerprint. The microbiota acts as a barrier from pathogens, exerts important metabolic functions, and regulates inflammatory response by stimulating the immune system. Gut microbial imbalance (dysbiosis), has been linked to important human diseases such as inflammation related disorders. The present review summarizes our knowledge on the gut microbiota in a healthy context, and examines intestinal dysbiosis in inflammatory bowel disease (IBD) patients; the most frequently reported disease proven to be associated with changes in the gut microbiota. PMID- 25514562 TI - Astaxanthin supplementation delays physical exhaustion and prevents redox imbalances in plasma and soleus muscles of Wistar rats. AB - Astaxanthin (ASTA) is a pinkish-orange carotenoid commonly found in marine organisms, especially salmon. ASTA is a powerful antioxidant and suggested to provide benefits for human health, including the inhibition of LDL oxidation, UV photoprotection, and prophylaxis of bacterial stomach ulcers. Exercise is associated to overproduction of free radicals in muscles and plasma, with pivotal participation of iron ions and glutathione (GSH). Thus, ASTA was studied here as an auxiliary supplement to improve antioxidant defenses in soleus muscles and plasma against oxidative damage induced by exhaustive exercise. Long-term 1 mg ASTA/kg body weight (BW) supplementation in Wistar rats (for 45 days) significantly delayed time to exhaustion by 29% in a swimming test. ASTA supplementation increased scavenging/iron-chelating capacities (TEAC/FRAP) and limited exercise-induced iron overload and its related pro-oxidant effects in plasma of exercising animals. On the other hand, ASTA induced significant mitochondrial Mn-dependent superoxide dismutase and cytosolic glutathione peroxidase antioxidant responses in soleus muscles that, in turn, increased GSH content during exercise, limited oxidative stress, and delayed exhaustion. We also provided significant discussion about a putative "mitochondrial-targeted" action of ASTA based on previous publications and on the positive results found in the highly mitochondrial populated (oxidative-type) soleus muscles here. PMID- 25514563 TI - A novel role of Eruca sativa Mill. (rocket) extract: antiplatelet (NF-kappaB inhibition) and antithrombotic activities. AB - BACKGROUND: Epidemiological studies have shown the prevention of cardiovascular diseases through the regular consumption of vegetables. Eruca sativa Mill., commonly known as rocket, is a leafy vegetable that has anti-inflammatory activity. However, its antiplatelet and antithrombotic activities have not been described. METHODS: Eruca sativa Mill. aqueous extract (0.1 to 1 mg/mL), was evaluated on human platelets: (i) P-selectin expression by flow cytometry; (ii) platelet aggregation induced by ADP, collagen and arachidonic acid; (iii) IL 1beta, TGF-beta1, CCL5 and thromboxane B2 release; and (iv) activation of NF kappaB and PKA by western blot. Furthermore, (v) antithrombotic activity (200 mg/kg) and (vi) bleeding time in murine models were evaluated. RESULTS: Eruca sativa Mill. aqueous extract (0.1 to 1 mg/mL) inhibited P-selectin expression and platelet aggregation induced by ADP. The release of platelet inflammatory mediators (IL-1beta, TGF-beta1, CCL5 and thromboxane B2) induced by ADP was inhibited by Eruca sativa Mill. aqueous extract. Furthermore, Eruca sativa Mill. aqueous extract inhibited NF-kappaB activation. Finally, in murine models, Eruca sativa Mill. aqueous extract showed significant antithrombotic activity and a slight effect on bleeding time. CONCLUSION: Eruca sativa Mill. presents antiplatelet and antithrombotic activity. PMID- 25514565 TI - Proteomic changes during tuber dormancy release process revealed by iTRAQ quantitative proteomics in potato. AB - Given that limited information is available with regard to tuber dormancy release related proteome, we conducted proteome analysis of tuber dormancy release process at dormant tuber (DT), dormancy release tuber (DRT) and sprouting tuber (ST) using the iTRAQ technology. A total of 1,752 proteins were identified. Among them, a subset of 316 proteins was screened as significant up- (137) and down regulated (179) between DT vs DRT. A subset of 120 proteins experienced significant up- (40) or down-regulation (80) between DRT vs ST. The differentially expressed proteins were grouped into 11 functional categories. Proteins enriched in functional categories of major carbohydrate (CHO) metabolism, glycolysis, fermentation, amino acid metabolism, protein and transport were highly up-regulated, while functional categories of photosynthesis and RNA were down-regulated between DT vs DRT. Proteins enriched in functional groups of protein, cell wall, lipid metabolism, miscellaneous, and signaling were strongly up-regulated, while functional categories of photosynthesis, hormone metabolism and protein were down-regulated between DRT vs ST. Consistent with previous documented differentially expressed genes, most of differentially expressed proteins were also identified between DT and DRT, indicating the metabolism shift from growth suspension to growth activation as tubers dormancy breaking. The changes in protein profiles showed lower concordance with corresponding alterations in transcript levels, indicating possible transcriptional and posttranscriptional regulation. Furthermore, the possible mechanism of tuber dormancy release was discussed in relation to what was known in transcripts change and other plant models from carbohydrate metabolism, protein metabolism, stress response, redox regulation, transcription regulation, DNA metabolism, amino acid metabolism, development, signaling as well as hormone metabolism. PMID- 25514566 TI - The Association Between Female Sexual Dysfunction and the Husband's Erectile Dysfunction: Evidence from Married Couples in Hong Kong. AB - Little is known about the association between the sexual functioning of each partner in a heterosexual married couple. By using a community-based survey of Hong Kong Chinese couples in 2012, this study attempted to examine the relation between female sexual dysfunction and their husbands' erectile dysfunction. Among the 1,518 female and 1,059 male respondents, 944 sexually active couples were eligible for the analysis, with mean age of 39.3 +/- 6.8 years (range = 21-50) for the wives and 43.6 +/- 8.6 years (range = 18-80) for the husbands. Of the wives, 27.0% reported at least one form of female sexual dysfunction and 5.0% of the husbands reported erectile dysfunction. After adjusting for the female's age and other risk factors, the total and domain scores of female sexual dysfunction were not associated with her husband's erectile dysfunction except for physical pain during sexual intercourse. Therefore, whether to screen the partner's sexual function depends on the age of the female clients. PMID- 25514564 TI - The protective effect of Rhizoma Dioscoreae extract against alveolar bone loss in ovariectomized rats via regulating Wnt and p38 MAPK signaling. AB - AIM: The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy induced bone loss. METHODS: Female Wistar rats were subjected to either ovariectomy or a sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX) or RDE by oral gavage or with 17beta-estradiol (E2) subcutaneously. After treatments, the bone mineral density (BMD), the three dimensional bone architecture of the alveolar bone and the plasma biomarkers of bone turnover were analyzed to assess bone metabolism, and the histomorphometry of the alveolar bone was observed. Microarrays were used to evaluate gene expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of genes was further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using real-time quantitative RT PCR (qRT-PCR). RESULTS: Our results showed that RDE inhibited alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 207 genes and downregulated expression levels of 176 genes in the alveolar bone. The IPA showed that several genes had the potential to code for proteins that were involved in the Wnt/beta-catenin signaling pathway (Wnt7a, Fzd2, Tcf3, Spp1, Frzb, Sfrp2 and Sfrp4) and the p38 MAPK signaling pathway (Il1rn and Mapk14). CONCLUSION: These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti osteopenic effect in alveolar bone may be involved in the reduced abnormal bone remodeling, which is associated with the modulation of the Wnt/beta-catenin and the p38 MAPK signaling pathways via gene regulation. PMID- 25514567 TI - Effects of hemoglobin-based oxygen carriers on blood coagulation. AB - For many decades, Hemoglobin-based oxygen carriers (HBOCs) have been central in the development of resuscitation agents that might provide oxygen delivery in addition to simple volume expansion. Since 80% of the world population lives in areas where fresh blood products are not available, the application of these new solutions may prove to be highly beneficial (Kim and Greenburg 2006). Many improvements have been made to earlier generation HBOCs, but various concerns still remain, including coagulopathy, nitric oxide scavenging, platelet interference and decreased calcium concentration secondary to volume expansion (Jahr et al. 2013). This review will summarize the current challenges faced in developing HBOCs that may be used clinically, in order to guide future research efforts in the field. PMID- 25514568 TI - A better way to do this? Views of mental health nursing directors about preparation for mental health nursing practice. AB - OBJECTIVE: Nursing directors in mental health services hold important leadership positions that include responsibility for the nursing workforce. The comprehensive or generalist approach to undergraduate nursing education consistently poses significant recruitment problems. Specialisation in mental health within Bachelor of Nursing programs has been suggested as a potential solution. This paper presents the views and opinions of mental health nursing directors regarding undergraduate specialisation. METHODS: A qualitative exploratory study was undertaken. Thirteen nursing directors from Queensland Mental Health Services participated in an in-depth telephone interview. The data were analysed thematically. RESULTS: Nursing directors were very supportive of specialisation in mental health at the undergraduate level. Thematic analysis revealed four main themes: perceived advantages of the specialist stream; knowledge and experience; increased recruitment; and commitment. CONCLUSIONS: Nursing directors are important stakeholders in educational preparation for practice in mental health settings. The research participants described many potential benefits to undergraduate specialisation. Their voice provides an important contribution to this issue. PMID- 25514570 TI - Motivational effects of coronary artery calcium scores on statin adherence and weight loss. AB - AIM: The aim of this study was to assess the effect on adherence to statin therapy and assess the effect of beneficial changes in behavior that resulted in weight loss in patients who underwent coronary artery calcium (CAC) scoring with cardiac computed tomography. BACKGROUND: Despite convincing data demonstrating the benefits of HmGCoA inhibitors for both primary and secondary prevention of coronary heart disease, they remain underused. Also, despite convincing data demonstrating the benefits of weight loss for both primary and secondary prevention of coronary heart disease, it remains difficult to motivate behavioral changes resulting in weight loss. In this study, we assess whether higher CAC scores are associated with increased compliance with statin medication and whether higher CAC scores are associated with beneficial lifestyle behaviors resulting in weight loss. METHODS: We retrospectively analyzed patients that had undergone baseline CAC testing and returned for a follow-up scan. All patients had weight documented and were administered a questionnaire regarding compliance to medications. The primary endpoint was measurable weight loss between visit one and visit two and the self-reported compliance to statin use. RESULTS: The study population with data regarding statin compliance consisted of 2608 individuals (72% men, mean age 58+/-8 years) who were followed for a mean of 4.1+/-3.2 years after an initial CAC scan. Overall, statin compliance was lowest (27.4%) among those with CAC=0, and gradually increased with higher CAC scores (1-99, 39.2%; 100-399, 53.6%; >=400, 58.8%; P<0.001 for trend). In the group analyzed for weight loss the study population consisted of 1078 individuals (68% men, mean age 60+/-8 years) who were followed for a mean of 4.1+/-3.2 years after an initial CAC scan. CONCLUSION: Overall, behavioral modification resulting in weight loss was lowest (19.8%) among those with CAC=0, and gradually increased with higher CAC scores (1-99, 23.4%; 100-399, 30.8%; >=400, 33.6%; P<0.001 for trend). In addition to being a robust risk stratification tool, a higher rate of adherences with statin therapy was observed in patients with higher CAC scores. PMID- 25514569 TI - Optimal protective hypothermia in arrested mammalian hearts. AB - Many therapeutic hypothermia recommendations have been reported, but the information supporting them is sparse, and reveals a need for the data of target therapeutic hypothermia (TTH) from well-controlled experiments. The core temperature <=35 degrees C is considered as hypothermia, and 29 degrees C is a cooling injury threshold in pig heart in vivo. Thus, an optimal protective hypothermia (OPH) should be in the range 29-35 degrees C. This study was conducted with a pig cardiopulmonary bypass preparation to decrease the core temperature to 29-35 degrees C range at 20 minutes before and 60 minutes during heart arrest. The left ventricular (LV) developed pressure, maximum of the first derivative of LV (dP/dtmax), cardiac power, heart rate, cardiac output, and myocardial velocity (Vmax) were recorded continuously via an LV pressure catheter and an aortic flow probe. At 20 minutes of off-pump during reperfusion after 60 minutes arrest, 17 hypothermic hearts showed that the recovery of Vmax and dP/dtmax established sigmoid curves that consisted of two plateaus: a good recovery plateau at 29-30.5 degrees C, the function recovered to baseline level (BL) (Vmax=118.4%+/-3.9% of BL, LV dP/dtmax=120.7%+/-3.1% of BL, n=6); another poor recovery plateau at 34-35 degrees C (Vmax=60.2%+/-2.8% of BL, LV dP/dtmax=28.0%+/-5.9% of BL, p<0.05, n=6; ), which are similar to the four normothermia arrest (37 degrees C) hearts (Vmax=55.9%+/-4.8% of BL, LV dP/dtmax=24.5%+/-2.1% of BL, n=4). The 32-32.5 degrees C arrest hearts showed moderate recovery (n=5). A point of inflection (around 30.5-31 degrees C) existed at the edge of a good recovery plateau followed by a steep slope. The point presented an OPH that should be the TTH. The results are concordant with data in the mammalian hearts, suggesting that the TTH should be initiated to cool core temperature at 31 degrees C. PMID- 25514572 TI - Negative association between serum parathyroid hormone levels and urinary perchlorate, nitrate, and thiocyanate concentrations in U.S. adults: the National Health and Nutrition Examination Survey 2005-2006. AB - OBJECTIVES: Perchlorate, nitrate, and thiocyanate are well-known inhibitors of the sodium-iodide symporter and may disrupt thyroid function. This exploratory study investigated the association among urinary perchlorate, nitrate, and thiocyanate concentrations and parathyroid hormone (PTH) levels in the general U.S. population. METHODS: We analyzed data on 4265 adults (aged 20 years and older) from the National Health and Nutrition Examination Survey in 2005 through 2006 to evaluate the relationship among urinary perchlorate, nitrate, and thiocyanate concentration and PTH levels and the presence of hyperparathyroidism cross-sectionally. RESULTS: The geometric means and 95% confidence interval (95% CI) concentrations of urinary perchlorate, nitrate, and thiocyanate were 3.38 (3.15-3.62), 40363 (37512-43431), and 1129 (1029-1239) ng/mL, respectively. After adjusting for confounding variables and sample weights, creatinine-corrected urinary perchlorate was negatively associated with serum PTH levels in women (P = 0.001), and creatinine-corrected urinary nitrate and thiocyanate were negatively associated with serum PTH levels in both sex groups (P = 0.001 and P<0.001 for men, P = 0.018 and P<0.001 for women, respectively). Similar results were obtained from sensitivity analyses performed for exposure variables unadjusted for creatinine with urinary creatinine added as a separate covariate. There was a negative relationship between hyperparathyroidism and urinary nitrate and thiocyanate [odds ratio (95% CI) = 0.77 (0.60-0.98) and 0.69 (0.61-0.79), respectively]. CONCLUSIONS: A higher urinary concentration of perchlorate, nitrate, and thiocyanate is associated with lower serum PTH levels. Future studies are needed to determine the pathophysiological background of the observation. PMID- 25514575 TI - Pelvic inflammatory disease in the adolescent: a poignant, perplexing, potentially preventable problem for patients and physicians. AB - PURPOSE OF REVIEW: The present review considers recent pelvic inflammatory disease literature. It remains a difficult condition to accurately diagnose and manage in the adolescent woman. Failure of accurate diagnosis and prompt management leads to complications, including chronic pelvic pain and infertility. RECENT FINDINGS: Annual chlamydia screening of sexually active adolescents is an important method for early identification of this common cause of this disorder. Youth with positive screens can be lost for treatment if effective follow-up plans are not in place in clinical practice. The intrauterine device is not a risk factor for this condition in adolescents and is a recommended contraceptive device in sexually active adolescent women. A variety of chlamydial antigens are being used to help differentiate lower genital infection from upper genital disorder. Clinicians are not following established protocols for its diagnosis and management. SUMMARY: Sequelae can be reduced in adolescent women if clinicians continue with regular chlamydia screening in sexually active adolescent women, have a low index of suspicion for pelvic inflammatory disease, carefully follow accepted treatment protocols, and teach youth comprehensive sexuality education including regular condom use. Funded research is needed to develop improved diagnosis and management tools as well as a chlamydia vaccine. PMID- 25514574 TI - Importance of viruses in acute otitis media. AB - PURPOSE OF REVIEW: Acute otitis media occurs as a complication of viral upper respiratory tract infection. Bacterial otopathogens and respiratory viruses interact and play important roles in acute otitis media development. A better understanding of viral and bacterial interactions may lead to innovative ways to lessen the burden of this common childhood disease. RECENT FINDINGS: There has been increasing evidence that acute otitis media occurs during upper respiratory infection, even in the absence of nasopharyngeal bacterial colonization. Among the types of viruses associated with acute otitis media, respiratory syncytial virus continues to be the most commonly detected. It is still unclear whether viral load plays an important role in acute otitis media development, but symptomatic upper respiratory tract infection (as opposed to asymptomatic viral infection) is crucial. Widespread use of bacterial and viral vaccines in young children, including pneumococcal conjugate and influenza vaccines, has led to the reduction in otitis media-related healthcare use between 2001 and 2011. There has been no new vaccine against respiratory viruses other than influenza. SUMMARY: Progress has been made toward the reduction of the burden of acute otitis media in the last decade. Success in reducing acute otitis media incidence will rely mainly on prevention of nasopharyngeal otopathogen colonization, as well as reduction in the incidence of viral upper respiratory tract infection. PMID- 25514573 TI - Identification of a polyomavirus microRNA highly expressed in tumors. AB - Polyomaviruses (PyVs) are associated with tumors including Merkel cell carcinoma (MCC). Several PyVs encode microRNAs (miRNAs) but to date no abundant PyV miRNAs have been reported in tumors. To better understand the function of the Merkel cell PyV (MCPyV) miRNA, we examined phylogenetically-related viruses for miRNA expression. We show that two primate PyVs and the more distantly-related raccoon PyV (RacPyV) encode miRNAs that share genomic position and partial sequence identity with MCPyV miRNAs. Unlike MCPyV miRNA in MCC, RacPyV miRNA is highly abundant in raccoon tumors. RacPyV miRNA negatively regulates reporters of early viral (T antigen) transcripts, yet robust viral miRNA expression is tolerated in tumors. We also identify raccoon miRNAs expressed in RacPyV-associated neuroglial brain tumors, including several likely oncogenic miRNAs (oncomiRs). This work describes the first PyV miRNA abundantly expressed in tumors and is consistent with a possible role for both host and viral miRNAs in RacPyV-associated tumors. PMID- 25514576 TI - A device for dried blood microsampling in quantitative bioanalysis: overcoming the issues associated blood hematocrit. AB - AIMS: A cross-laboratory experiment has been performed on a novel dried blood sampler in order to investigate whether it overcomes issues associated with blood volume and hematocrit (HCT) that are observed when taking a subpunch from dried blood spot samples. MATERIALS & METHODS: An average blood volume of 10.6 MUl was absorbed by the samplers across the different HCTs investigated (20-65%). RESULTS: No notable change of volume absorbed was noted across the HCT range. Furthermore, the variation in blood sample volumes across six different laboratories was within acceptable limits. CONCLUSION: The novel volumetric absorptive microsampling device has the potential to deliver the advantages of dried blood spot sampling while overcoming some of the issues associated with the technology. PMID- 25514577 TI - Jealousy-induced sex differences in eye gaze directed at either emotional- or sexual infidelity-related mobile phone messages. PMID- 25514578 TI - Author response to letter. Ref: Madsen et al. "Unnecessary work tasks and mental health: a prospective analysis of Danish human service workers". AB - We read with interest the letter from Drs Durand-Moreau, Lodde, and Dewitte (1) regarding our article on unnecessary work tasks and mental health (2). The authors argue that: (i) the article is flawed by an imprecise one-item exposure measurement, (ii) the results may be affected by reverse causality, and (iii) ultimately the elimination of unnecessary work tasks may increase "psychic suffering". We would like to take this opportunity to address their concerns. We acknowledge, as we did in the article itself, that measuring unnecessary work tasks using only one item is less than ideal and could have increased measurement error in our analyses. The item we used to measure unnecessary work tasks assesses the employee's overall evaluation regarding the extent to which they must conduct work tasks that they, for whatever reason, deem unnecessary. We are unconvinced by the claim by Drs Durand-Moreau, Lodde, and Dewitte that this phenomenon is somehow unrelated to Semmer's definition of unnecessary tasks (3, 4), regardless of the sense-making processes underlying an individual employee's evaluation of a particular work task as unnecessary. Regarding the issue of reverse causality, the analyses were longitudinal and the effect estimates were adjusted for the baseline mental health level of the participants. Consequently, we examined changes in mental health over time, and our results cannot be explained by poorer mental health making workers think "that what they're doing is useless" as claimed in the commentary. Although causal inference is always a delicate issue when applying observational research methods, the adjustment for baseline mental health should account for reverse causality at least. Drs Durand Moreau, Lodde, and Dewitte question that our findings suggest that the elimination of unnecessary work tasks may be beneficial to employee mental health. Instead they propose that unnecessary work tasks may be conducive to mental health because "some tasks may seem unnecessary or bothersome, but may correspond to work periods that allow for temporary rest". We find this suggestion curious and are not aware of any empirical studies to support this claim. Consequently, we encourage the authors of the commentary to test their hypothesis empirically. Any such empirical evidence would be a welcome advancement to the scientific knowledge concerning the mental health consequences of unnecessary work tasks. As the results of our study do not indicate that unnecessary work tasks could be beneficial to mental health, but indeed that they could be harmful, we find no reason to modify the conclusions of our article. References 1. Durand-Moreau Q, Lodde B, Dewitte J-D. Ref: Madsen et al. "Unnecessary work tasks and mental health: a prospective analysis of Danish human service workers". Scand J Work Environ Health - online first. http://dx.doi.org/10.5271/sjweh.3473. 2. Madsen IEH, Tripathi M, Borritz M, Rugulies R, Unnecessary work tasks and mental health: a prospective analysis of Danish human service workers, Scand J Work Environ Health. 2014;40(6):631-8. http://dx.doi.org/10.5271/sjweh.3453. 3. Semmer NK, Tschan F, Meier LL, Facchin S, Jacobshagen N, Illegitimate tasks and counterproductive work behavior, Appl Psychol. 2010;59:70-96. http://dx.doi.org/10.1111/j.1464-0597.2009.00416.x. 4. Durand MJ, Vezina N, Baril R, Loisel P, Richard MC, Ngomo S, Margin of manoeuvre indicators in the workplace during the rehabilitation process: a qualitative analysis, J Occup Rehab. 2009;19:194-202. http://dx.doi.org/10.1007/s10926-009 9173-4. PMID- 25514579 TI - Synthesis and stability of boratriazaroles. AB - We describe the synthesis and stability analysis of novel boratriazaroles that can be viewed as bioisosteres of imidazoles or pyrazoles. These heterocycles could conveniently be obtained by condensing a boronic acid and amidrazone 1 in various solvents. A detailed stability analysis of selected compounds at different pH values as a function of time led to the identification of steric hindrance around the boron atom as a key element for stabilization. PMID- 25514580 TI - Elegant design of electrode and electrode/electrolyte interface in lithium-ion batteries by atomic layer deposition. AB - Lithium-ion batteries (LIBs) are very promising power supply systems for a variety of applications, such as electric vehicles, plug-in hybrid electric vehicles, grid energy storage, and microelectronics. However, to realize these practical applications, many challenges need to be addressed in LIBs, such as power and energy density, cycling lifetime, safety, and cost. Atomic layer deposition (ALD) is emerging as a powerful technique for solving these problems due to its exclusive advantages over other film deposition counterparts. In this review, we summarize the state-of-the-art progresses of employing ALD to design novel nanostructured electrode materials and solid-state electrolytes and to tailor electrode/electrolyte interface by surface coatings in order to prevent unfavorable side reactions and achieve optimal performance of the electrode. Insights into the future research and development of the ALD technique for LIB applications are also discussed. We expect that this review article will provide resourceful information to researchers in both fields of LIBs and ALD and also will stimulate more insightful studies of using ALD for the development of next generation LIBs. PMID- 25514581 TI - Substitutions of Ser83Leu in GyrA and Ser80Leu in ParC Associated with Quinolone Resistance in Acinetobacter pittii. AB - To investigate the prevalence and the mechanism of quinolone-resistant Acinetobacter pittii, 634 Acinetobacter calcoaceticus-Acinetobacter baumannii complex isolates were collected throughout Zhejiang Province. Identification of isolates was conducted by matrix-assisted laser desorption ionization/time of flight mass spectrometry (MALDI-TOF MS), blaOXA-51-like gene, and partial RNA polymerase beta-subunit (rpoB) amplification. Twenty-seven isolates of A. pittii were identified. Among the 634 isolates, A. baumannii, A. pittii, Acinetobacter nosocomialis, and A. calcoaceticus counted for 87.22%, 4.26%, 8.20%, and 0.32%, respectively. Antimicrobial susceptibility of nalidixic acid, ofloxacin, enoxacin, ciprofloxacin, lomefloxacin, levofloxacin, sparfloxacin, moxifloxacin, and gatifloxacin for 27 A. pittii were determined by the agar dilution method. Detection of quinolone-resistant determining regions of gyrA, gyrB, parC, and parE was performed for the A. pittii isolates. In addition, plasmid-mediated quinolone resistance (PMQR) determinants (qnrA, qnrB, qnrS, qnrC, qnrD, aac(6') Ib-cr, qepA, oqxA, and oqxB) were investigated. All the 27 isolates demonstrated a higher minimum inhibitory concentration (MIC) to old quinolones than the new fluoroquinolones. No mutation in gyrA, gyrB, parC, or parE was detected in 20 ciprofloxacin-susceptible isolates. Seven ciprofloxacin-resistant A. pittii were identified with a Ser83Leu mutation in GyrA. Among them, six isolates with simultaneous Ser83Leu amino acid substitution in GyrA and Ser80Leu in ParC displayed higher MIC values against ciprofloxacin. Additionally, three were identified with a Met370Ile substitution in ParE, and two were detected with a Tyr317His mutation in ParE, which were reported for the first time. No PMQR determinants were identified in the 27 A. pittii isolates. In conclusion, mutations in chromosome play a major role in quinolone resistance in A. pittii, while resistance mechanisms mediated by plasmid have not been found. Ser83Leu substitution in GyrA and Ser80Leu substitution in ParC are associated with quinolone resistance in A. pittii. Whether Met370Ile and Tyr317His substitutions in ParE play a minor role requires further investigation. PMID- 25514582 TI - Effects of perinatal methylphenidate (MPH) treatment on postweaning behaviors of male and female Sprague-Dawley rats. AB - Methylphenidate (MPH) is a common treatment for adult Attention Deficit Hyperactivity Disorder (ADHD). However, little information exists regarding its safety during pregnancy and thus, women with ADHD face difficult decisions regarding continued use during pregnancy. Thus, Sprague-Dawley rats were orally treated 3*/day with 0 (control), 6 (low), 18 (mid), or 42 (high) mg MPH/kg/day (i.e., 0, 2, 6, or 14mg/kg at each treatment time) on gestational days 6-21. All offspring/litter were orally treated with the same dose their dam had received on postnatal days (PNDs) 1-21. After weaning, offspring were assessed for adolescent play behavior, locomotor activity, motor coordination, Barnes maze performance, acoustic startle response, novel object recognition, residential running wheel activity, flavored solution intake, home cage behavior, water maze performance, elevated plus maze behavior, locomotor response to an MPH challenge, and passive avoidance. At euthanasia, whole brain and striatal weights as well as serum hormone levels were measured. Body weights of the high MPH group were reduced in both sexes. Males of the high MPH group were less active than control males in open field assessments on PNDs 40-42. Latency to maximum acoustic startle was significantly altered in females of the medium and high MPH groups and residential running wheel activity of females of the low and medium MPH groups was lower than control females. Open arm entries in the elevated plus maze were increased in subjects of the medium MPH group. Females of the low MPH group were less sensitive to the locomotor-increasing effects of an acute 5mg/kg MPH challenge. Serum hormone levels and whole brain and striatal weights were not altered by prior MPH treatment. These results indicate that MPH treatment during development has sporadic effects on postweaning behaviors and those effects were generally exhibited by females. PMID- 25514585 TI - Feasibility of "Standardized Clinician" Methodology for Patient Training on Hospital-to-Home Transitions. AB - INTRODUCTION: Patient engagement in health care is increasingly recognized as essential for promoting the health of individuals and populations. This study pilot tested the standardized clinician (SC) methodology, a novel adaptation of standardized patient methodology, for teaching patient engagement skills for the complex health care situation of transitioning from a hospital back to home. METHODS: Sixty-seven participants at heightened risk for hospitalization were randomly assigned to either simulation exposure-only or full-intervention group. Both groups participated in simulation scenarios with "standardized clinicians" around tasks related to hospital discharge and follow-up. The full-intervention group was also debriefed after scenario sets and learned about tools for actively participating in hospital-to-home transitions. Measures included changes in observed behaviors at baseline and follow-up and an overall program evaluation. RESULTS: The full-intervention group showed increases in observed tool possession (P = 0.014) and expression of their preferences and values (P = 0.043). The simulation exposure-only group showed improvement in worksheet scores (P = 0.002) and fewer engagement skills (P = 0.021). Both groups showed a decrease in telling an SC about their hospital admission (P < 0.05). Open-ended comments from the program evaluation were largely positive. CONCLUSIONS: Both groups benefited from exposure to the SC intervention. Program evaluation data suggest that simulation training is feasible and may provide a useful methodology for teaching patient skills for active engagement in health care. Future studies are warranted to determine if this methodology can be used to assess overall patient engagement and whether new patient learning transfers to health care encounters. PMID- 25514583 TI - delta-Aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter 2*2 haplotype (hPEPT2*2) differently influence neurobehavior in low-level lead exposed children. AB - Delta-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter haplotype 2*2 (hPEPT2*2) through different pathways can increase brain levels of delta-aminolevulinic acid and are associated with higher blood lead burden in young children. Past child and adult findings regarding ALAD2 and neurobehavior have been inconsistent, and the possible association of hPEPT2*2 and neurobehavior has not yet been examined. Mean blood lead level (BLL), genotype, and neurobehavioral function (fine motor dexterity, working memory, visual attention and short-term memory) were assessed in 206 males and 215 females ages 5.1-11.8years. Ninety-six percent of children had BLLs<5.0MUg/dl. After adjusting for covariates (sex, age and mother's level of education) and sibling exclusion (N=252), generalized linear mixed model analyses showed opposite effects for the ALAD2 and hPEPT2*2 genetic variants. Significant effects for ALAD2 were observed only as interactions with BLL and the results suggested that ALAD2 was neuroprotective. As BLL increased, ALAD2 was associated with enhanced visual attention and enhanced working memory (fewer commission errors). Independent of BLL, hPEPT2*2 predicted poorer motor dexterity and poorer working memory (more commission errors). BLL alone predicted poorer working memory from increased omission errors. The findings provided further substantiation that (independent of the genetic variants examined) lowest-level lead exposure disrupted early neurobehavioral function, and suggested that common genetic variants alter the neurotoxic potential of low-level lead. ALAD2 and hPEPT2*2 may be valuable markers of risk, and indicate novel mechanisms of lead induced neurotoxicity. Longitudinal studies are needed to examine long-term influences of these genetic variants on neurobehavior. PMID- 25514586 TI - The Template of Events for Applied and Critical Healthcare Simulation (TEACH Sim): a tool for systematic simulation scenario design. AB - Simulation-based training (SBT) affords practice opportunities for improving the quality of clinicians' technical and nontechnical skills. However, the development of practice scenarios is a process plagued by a set of challenges that must be addressed for the full learning potential of SBT to be realized. Scenario templates are useful tools for assisting with SBT and navigating its inherent challenges. This article describes existing SBT templates, explores considerations in choosing an appropriate template, and introduces the Template of Events for Applied and Critical Healthcare Simulation (TEACH Sim) as a tool for facilitating the formation of practice scenarios in accordance with an established evidence-based simulation design methodology. TEACH Sim's unique contributions are situated within the landscape of previously existing templates, and each of its component sections is explained in detail. PMID- 25514584 TI - Recombinant Treponema pallidum protein Tp0965 activates endothelial cells and increases the permeability of endothelial cell monolayer. AB - The recombinant Treponema pallidum protein Tp0965 (rTp0965), one of the many proteins derived from the genome of T. pallidum subsp. pallidum, shows strong immunogenicity and immunoreactivity. In this study, we investigated the effects of rTp0965 on the endothelial barrier. Treatment of human umbilical vein endothelial cells (HUVECs) with rTp0965 resulted in increased levels of ICAM-1, E selectin, and MCP-1 mRNA and protein expression. These increases contributed to the adhesion and chemataxis of monocytes (THP-1 cells) to HUVECs preincubated with rTp0965. In addition, rTp0965 induced reorganization of F-actin and decreased expression of claudin-1 in HUVECs. Interestingly, inhibition of the RhoA/ROCK signal pathway protected against rTp0965-induced higher endothelial permeability as well as transendothelial migration of monocytes. These data indicate that Tp0965 protein may play an important role in the immunopathogenesis of syphilis. PMID- 25514588 TI - Neurosurgical endoscopic training via a realistic 3-dimensional model with pathology. AB - INTRODUCTION: Training in intraventricular endoscopy is particularly challenging because the volume of cases is relatively small and the techniques involved are unlike those usually used in conventional neurosurgery. Present training models are inadequate for various reasons. Using 3-dimensional (3D) printing techniques, models with pathology can be created using actual patient's imaging data. This technical article introduces a new training model based on a patient with hydrocephalus secondary to a pineal tumour, enabling the models to be used to simulate third ventriculostomies and pineal biopsies. METHODS: Multiple models of the head of a patient with hydrocephalus were created using 3D rapid prototyping technique. These models were modified to allow for a fluid-filled ventricular system under appropriate tension. The models were qualitatively assessed in the various steps involved in an endoscopic third ventriculostomy and intraventricular biopsy procedure, initially by 3 independent neurosurgeons and subsequently by 12 participants of an intraventricular endoscopy workshop. RESULTS: All 3 surgeons agreed on the ease and usefulness of these models in the teaching of endoscopic third ventriculostomy, performing endoscopic biopsies, and the integration of navigation to ventriculoscopy. Their overall score for the ventricular model realism was above average. The 12 participants of the intraventricular endoscopy workshop averaged between a score of 4.0 to 4.6 of 5 for every individual step of the procedure. DISCUSSION: Neurosurgical endoscopic training currently is a long process of stepwise training. These 3D printed models provide a realistic simulation environment for a neuroendoscopy procedure that allows safe and effective teaching of navigation and endoscopy in a standardized and repetitive fashion. PMID- 25514587 TI - Development and validation of a virtual human vignette to compare nurses' assessment and intervention choices for pain in critically ill children. AB - INTRODUCTION: As virtual experiences are increasingly used in health care training and research, it is important that adequate processes are applied for developing valid scenarios. We describe the development and validation of virtual human (VH) vignettes, computer-generated scenarios with animated patients and clinical information, for a mixed-methods study regarding nurses' assessment and intervention choices for critically ill children's pain. METHODS: We followed the case development and review process for high-fidelity simulation case scenarios, including the use of validated written vignettes and content experts. Forty nurses described their pain assessment and intervention choices for the newly derived VH vignettes and completed a pain questionnaire. Nurses' reports of VH vignette consistency with their professional experience and recognition of VH facial expressions were evaluated to establish face validity. Their pain ratings for the VH and written (questionnaire) vignettes were evaluated for convergent validity. Qualitative content analysis, descriptive statistics, correlations, and paired t tests were used. RESULTS: Most nurses (68.4%) supported vignette consistency with their professional experience. Facial expression recognition was 98.4%. Smiling children's pain was rated significantly lower than grimacing children in both VH and written vignettes. Pain was rated significantly lower for grimacing children in the VH vignettes than the written vignettes. Virtual human vignette pain ratings were strongly correlated with their written counterparts. CONCLUSIONS: This process was effective for developing VH vignettes that demonstrated good face validity with participants and convergent validity with written vignettes. Virtual human vignettes may be useful in studying the influence of facial actions on nurses' choices for children's pain assessment and treatment. PMID- 25514589 TI - Advancing surgical simulation in gynecologic oncology: robotic dissection of a novel pelvic lymphadenectomy model. AB - INTRODUCTION: Pelvic lymphadenectomy is a key component of the surgical treatment of several gynecologic cancers and involves mastery of complex anatomic relationships. Our aim was to demonstrate that the anatomy relevant to robotic pelvic lymphadenectomy can be modeled using low-cost techniques, thereby enabling simulation focused on surgical dissection, a task that integrates technical skills and anatomic knowledge. METHODS: A model of pelvic lymphadenectomy was constructed through experimentation with several different materials and a number of prototypes. In the final version, blood vessels were simulated by rubber tubing stented with wire and lymph nodes by cotton balls. Adipose and areolar tissue were simulated by a gelatin solution poured into the model and then allowed to cool and semisolidify. Three gynecologic oncologists and 2 gynecologic oncology fellows dissected the model using the surgical robot (da Vinci Surgical System) and completed a structured questionnaire. Five additional gynecologic oncologists assessed the model at a national conference. RESULTS: The model received high ratings for face and content validity. Median ratings were almost all 4 of 5 or higher (range, 3-5). Participants who dissected the model (n = 5) unanimously rated it as "useful for training throughout residency and fellowship." CONCLUSIONS: A novel low-cost inanimate model of pelvic lymphadenectomy has been developed and rated highly for face and content validity. This model may permit more regular simulation sessions compared with alternatives such as cadaveric dissection and animal laboratories, thereby complementing them and facilitating distributed practice. PMID- 25514590 TI - Chemical-free lysis and fractionation of cells by use of surface acoustic waves for sensitive protein assays. AB - We exploit the mechanical action of surface acoustic waves (SAW) to differentially lyse human cancer cells in a chemical-free manner. The extent to which cells were disrupted is reported for a range of SAW parameters, and we show that the presence of 10 MUm polystyrene beads is required to fully rupture cells and their nuclei. We show that SAW is capable of subcellular fractionation through the chemical-free isolation of nuclei from whole cells. The concentration of protein was assessed in lysates with a sensitive microfluidic antibody capture (MAC) chip. An antibody-based sandwich assay in a microfluidic microarray format was used to detect unlabeled human tumor suppressor protein p53 in crude lysates, without any purification step, with single-molecule resolution. The results are digital, enabling sensitive quantification of proteins with a dynamic range >4 orders of magnitude. For the conditions used, the efficiency of SAW-induced mechanical lysis was determined to be 12.9% +/- 0.7% of that for conventional detergent-based lysis in yielding detectable protein. A range of possible loss mechanisms that could lead to the drop in protein yield are discussed. Our results show that the methods described here are amenable to an integrated point of-care device for the assessment of tumor protein expression in fine needle aspirate biopsies. PMID- 25514591 TI - The association between childhood environmental exposures and the subsequent development of Crohn's disease in the Western Cape, South Africa. AB - BACKGROUND: Environmental factors during childhood are thought to play a role in the aetiolgy of Crohn's Disease (CD). However the association between age at time of exposure and the subsequent development of CD in South Africa is unknown. METHODS: A case control study of all consecutive CD patients seen at 2 large inflammatory bowel disease (IBD) referral centers in the Western Cape, South Africa between September 2011 and January 2013 was performed. Numerous environmental exposures during 3 age intervals; 0-5, 6-10 and 11-18 years were extracted using an investigator administered questionnaire. An agreement analysis was performed to determine the reliability of questionnaire data for all the relevant variables. RESULTS: This study included 194 CD patients and 213 controls. On multiple logistic regression analysis, a number of childhood environmental exposures during the 3 age interval were significantly associated with the risk of developing CD. During the age interval 6-10 years, never having had consumed unpasteurized milk (OR = 5.84; 95% CI, 2.73-13.53) and never having a donkey, horse, sheep or cow on the property (OR = 2.48; 95% CI, 1.09-5.98) significantly increased the risk of developing future CD. During the age interval 11-18 years, an independent risk-association was identified for; never having consumed unpasteurized milk (OR = 2.60; 95% CI, 1.17-6.10) and second-hand cigarette smoke exposure (OR = 1.93; 95% CI, 1.13-3.35). CONCLUSION: This study demonstrates that both limited microbial exposures and exposure to second-hand cigarette smoke during childhood is associated with future development of CD. PMID- 25514592 TI - Echinococcus granulosus genomics: a new dawn for improved diagnosis, treatment, and control of echinococcosis. AB - Cystic echinococcosis (CE) is a cosmopolitan disease caused by the dog tapeworm Echinococcus granulosus. The disease is difficult to diagnose, treat, and control and is responsible for considerable human morbidity and mortality globally. There is an urgent need for new diagnostic tests and new drugs for treatment of CE and the development of a vaccine against adult worms of E. granulosus in dogs. We recently presented a draft genomic sequence for the worm comprising 151.6 Mb encoding 11,325 proteins. We undertook an extensive comparative analysis of the E. granulosus transcriptome using representative life stages (protoscoleces, cyst germinal cells and membranes, adult worms, and oncospheres) to explore different aspects of tapeworm biology and parasitism. The genome and transcriptome of E. granulosus provide a unique platform for post-genomic research and to facilitate the development of new, effective treatments and interventions for echinococcosis control. PMID- 25514593 TI - Efficiency of colored modified box traps for sampling of tabanids. AB - The efficiency of ten differently colored modified box traps for collecting tabanids was studied in the Monjoros Forest in eastern Croatia. A total of 5,436 specimens belonging to 16 species of tabanids grouped into six genera were collected. The genus Tabanus was the most represented with 98% of all collected tabanids. Tabanus bromius comprised 90% of tabanids collected, and was the most abundant species collected in all box traps. The majority of tabanids (74%) were collected from black, brown, bordeaux, red, and blue traps (dark group), whereas 26% were collected from green, light violet, white, orange, and yellow traps (light group). The black modified trap was the most successful and collected 20% of all collected tabanids, whereas the yellow trap was the least effective with 1%. The number of collected specimens of species T. bromius differed significantly between the dark and light group of traps. Traps with lower reflectance from green color collected 77% of T. bromius. The most species of tabanids (12) was collected in the brown trap, whereas the least number of species (6) was collected in the yellow trap. PMID- 25514594 TI - Notes on the genus Tunga (Siphonaptera: Tungidae) II--neosomes, morphology, classification, and other taxonomic notes. AB - This review focuses on the neosomes, morphology, and taxonomy of adult species of the genus Tunga, complementing the previously published data on the phylogeny, ecology, and pathogenic role. Neosomes are structures formed after penetration of adult females into the skin of hosts resulting in significant enlargement, being the most characteristic and most frequently observed form in hosts. Neosomes can be differentiated by shape, measurements, and sites of attachment to principal hosts. The taxonomic value and morphometric data of the most widely used characteristics to separate species - such as frontal curvature, head chaetotaxy, preoral internal sclerotization, ventral and dorsal genal lobes, eyes, maxillary palps, fusion of pronotum and mesonotum, metacoxae, metatarsi chaetotaxy, spermatheca (females), manubrium, basimere, telomere, and phallosome (males) - are comparatively analyzed. The sexes, individual variations, undescribed species, higher taxa, as well as a proposal for division of the genus into two subgenera (Tunga and Brevidigita) are presented (as previously given by Wang). A key for females, males, and gravid females (neosomes) also is included for identifying the 13 known species. Data on host specificity and geographical distribution may also support the identification of Tunga species because some sand fleas and their hosts may have co-evolved. PMID- 25514595 TI - A novel mouse model of advanced diabetic kidney disease. AB - Currently available rodent models exhibit characteristics of early diabetic nephropathy (DN) such as hyperfiltration, mesangial expansion, and albuminuria yet features of late DN (hypertension, GFR decline, tubulointerstitial fibrosis) are absent or require a significant time investment for full phenotype development. Accordingly, the aim of the present study was to develop a mouse model of advanced DN with hypertension superimposed (HD mice). Mice transgenic for human renin cDNA under the control of the transthyretin promoter (TTRhRen) were employed as a model of angiotensin-dependent hypertension. Diabetes was induced in TTRhRen mice through low dose streptozotocin (HD-STZ mice) or by intercrossing with OVE26 diabetic mice (HD-OVE mice). Both HD-STZ and HD-OVE mice displayed more pronounced increases in urinary albumin levels as compared with their diabetic littermates. Additionally, HD mice displayed renal hypertrophy, advanced glomerular scarring and evidence of tubulointerstitial fibrosis. Both HD OVE and HD-STZ mice showed evidence of GFR decline as FITC-inulin clearance was decreased compared to hyperfiltering STZ and OVE mice. Taken together our results suggest that HD mice represent a robust model of type I DN that recapitulates key features of human disease which may be significant in studying the pathogenesis of DN and in the assessment of putative therapeutics. PMID- 25514596 TI - Increased number of negative lymph nodes is associated with improved cancer specific survival in pathological IIIB and IIIC rectal cancer treated with preoperative radiotherapy. AB - Preoperative radiation significantly decreases the number of retrieved lymph nodes (LNs) in rectal cancer, but little is known with respect to the prognostic significance of negative LN (NLN) counts under these circumstances. In this study, Surveillance, Epidemiology, and End Results Program (SEER)-registered ypIII stage rectal cancer patients, and patients from Fudan University Shanghai Cancer Center (FDSCC) were combined and analyzed. The results showed that the survival rate of patients with n (cutoff) or more NLNs increased gradually when n ranged from two to nine. After n reached 10 or greater, survival rates were approximately equivalent. Furthermore, the optimal cutoff value of 10 was validated as an independent prognostic factor in stage ypIIIB and ypIIIC patients by both univariate and multivariate analysis (P < 0.001); the number of NLNs could also stratify the prognosis of ypN(+) patients in more detail. Patients in the FDSCC set validated these findings and confirmed that NLN count was not decreased in the good tumor regression group relative to the poor tumor regression group. These results suggest that NLN count is an independent prognostic factor for ypIIIB and ypIIIC rectal cancer patients, and, together with the number of positive LNs, this will provide better prognostic information than the number of positive LNs alone. PMID- 25514597 TI - Elevated endoplasmic reticulum stress reinforced immunosuppression in the tumor microenvironment via myeloid-derived suppressor cells. AB - The role of endoplasmic reticulum (ER) stress in cancer has been studied in detail, and ER stress is known to increase tumor cell apoptosis, and thus, reduce tumor growth. However, in our study, persistent ER stress induced by multiple administrations of low-dose thapsigargin (Tg) accelerated tumor growth in mice. Tg-mediated ER stress increased the generation of Ly6G+CD11b+ myeloid cells, but did not alter anti-tumor effector T cells. 4-Phenylbutyric acid (4-PBA), a chemical chaperone widely used as an ER stress reducer, attenuated Tg-induced myeloid-derived suppressor cell (MDSC) expansion and tumor growth. Tg-mediated ER stress enhanced the immunosuppressive capacity of tumor-infiltrating MDSCs by increasing expression of ARG1, iNOS, and NOX2, although splenic MDSCs were not affected. Consistent with these results, 4-PBA restored the anti-tumor immune response by regulating inflammatory cytokines such as TNF-alpha and CXCL1/KC, and activated tumor-infiltrating CD8+ T cells that were inhibited by Tg-mediated ER stress. These results suggest that significant ER stress in a tumor-bearing host might induce tumor growth mediated by enhancement of MDSC-mediated suppression. Therefore, ER stress reducers such as 4-PBA could restore anti-tumor immunity by inhibiting suppressive MDSCs that are exacerbated by ER stress. PMID- 25514598 TI - Cell type specific gene expression analysis of prostate needle biopsies resolves tumor tissue heterogeneity. AB - A lack of cell surface markers for the specific identification, isolation and subsequent analysis of living prostate tumor cells hampers progress in the field. Specific characterization of tumor cells and their microenvironment in a multi parameter molecular assay could significantly improve prognostic accuracy for the heterogeneous prostate tumor tissue. Novel functionalized gold-nano particles allow fluorescence-based detection of absolute mRNA expression levels in living cells by fluorescent activated flow cytometry (FACS). We use of this technique to separate prostate tumor and benign cells in human prostate needle biopsies based on the expression levels of the tumor marker alpha-methylacyl-CoA racemase (AMACR). We combined RNA and protein detection of living cells by FACS to gate for epithelial cell adhesion molecule (EPCAM) positive tumor and benign cells, EPCAM/CD45 double negative mesenchymal cells and CD45 positive infiltrating lymphocytes. EPCAM positive epithelial cells were further sub-gated into AMACR high and low expressing cells. Two hundred cells from each population and several biopsies from the same patient were analyzed using a multiplexed gene expression profile to generate a cell type resolved profile of the specimen. This technique provides the basis for the clinical evaluation of cell type resolved gene expression profiles as pre-therapeutic prognostic markers for prostate cancer. PMID- 25514599 TI - PKM2 promotes metastasis by recruiting myeloid-derived suppressor cells and indicates poor prognosis for hepatocellular carcinoma. AB - Pyruvate kinase M2 (PKM2) is a member of the pyruvate kinase family. Recent work has defined the "non-metabolic" functions of PKM2. However, the role of PKM2 in HCC remains unclear. To investigate the role of PKM2 in tumor growth, invasion and the prognosis of hepatocellular carcinoma (HCC), PKM2 expression was measured in HCC cell lines and tissues using qRT-PCR, western blot, and immunofluorescence assays. In in vitro experiments, PKM2 was knocked down using a short hairpin RNA lentivirus vector, and tumor cell behavior and the downstream signaling pathways and chemokine were analyzed. For the analysis of in vivo tumor growth, intratumoral and peritumoral lymphocyte infiltration were examined in nude mice. The prognostic value of PKM2 was analyzed by immunohistochemistry in two cohorts including 721 HCC patients. Together, our data obtained from cell lines, tumorigenicity studies, and primary HCC samples illustrate an oncogenic role for PKM2 in tumors. Moreover, PKM2 may serve as a novel prognostic indicator for HCC patients after curative resection, targeted therapy aimed at PKM2 may represent an effective treatment approach for HCC. PMID- 25514602 TI - Strategies to control alkoxy radical-initiated relay cyclizations for the synthesis of oxygenated tetrahydrofuran motifs. AB - Radical relay cyclizations initiated by alkoxy radicals are a powerful tool for the rapid construction of substituted tetrahydrofurans. The scope of these relay cyclizations has been dramatically increased with the development of two strategies that utilize an oxygen atom in the substrate to accelerate the desired hydrogen atom transfer (HAT) over competing pathways. This has enabled a chemoselective 1,6-HAT over a competing 1,5-HAT. Furthermore, this allows for a chemoselective 1,5-HAT over competing direct cyclizations and beta fragmentations. Oxygen atom incorporation leads to a general increase in cyclization diastereoselectivity over carbon analogues. This chemoselective relay cyclization strategy was utilized in the improved synthesis of the tetrahydrofuran fragment in (-)-amphidinolide K. PMID- 25514600 TI - Expression of sulfotransferase SULT1A1 in cancer cells predicts susceptibility to the novel anticancer agent NSC-743380. AB - The small molecule anticancer agent NSC-743380 modulates functions of multiple cancer-related pathways and is highly active in a subset of cancer cell lines in the NCI-60 cell line panel. It also has promising in vivo anticancer activity. However, the mechanisms underlying NSC-743380's selective anticancer activity remain uncharacterized. To determine biomarkers that may be used to identify responders to this novel anticancer agent, we performed correlation analysis on NSC-743380's anticancer activity and the gene expression levels in NCI-60 cell lines and characterized the functions of the top associated genes in NSC-743380 mediated anticancer activity. We found sulfotransferase SULT1A1 is causally associated with NSC-743380's anticancer activity. SULT1A1 was expressed in NSC 743380-sensitive cell lines but was undetectable in resistant cancer cells. Ectopic expression of SULT1A1 in NSC743380 resistant cancer cells dramatically sensitized the resistant cells to NSC-743380. Knockdown of the SULT1A1 in the NSC 743380 sensitive cancer cell line rendered it resistance to NSC-743380. The SULT1A1 protein levels in cell lysates from 18 leukemia cell lines reliably predicted the susceptibility of the cell lines to NSC-743380. Thus, expression of SULT1A1 in cancer cells is required for NSC-743380's anticancer activity and can be used as a biomarker for identification of NSC-743380 responders. PMID- 25514601 TI - Comparative effects of di(n-butyl) phthalate exposure on fetal germ cell development in the rat and in human fetal testis xenografts. AB - BACKGROUND: Phthalate exposure induces germ cell effects in the fetal rat testis. Although experimental models have shown that the human fetal testis is insensitive to the steroidogenic effects of phthalates, the effects on germ cells have been less explored. OBJECTIVES: We sought to identify the effects of phthalate exposure on human fetal germ cells in a dynamic model and to establish whether the rat is an appropriate model for investigating such effects. METHODS: We used immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction to examine Sertoli and germ cell markers on rat testes and human fetal testis xenografts after exposure to vehicle or di(n-butyl) phthalate (DBP). Our study included analysis of germ cell differentiation markers, proliferation markers, and cell adhesion proteins. RESULTS: In both rat and human fetal testes, DBP exposure induced similar germ cell effects, namely, germ cell loss (predominantly undifferentiated), induction of multinucleated gonocytes (MNGs), and aggregation of differentiated germ cells, although the latter occurred rarely in the human testes. The mechanism for germ cell aggregation and MNG induction appears to be loss of Sertoli cell-germ cell membrane adhesion, probably due to Sertoli cell microfilament redistribution. CONCLUSIONS: Our findings provide the first comparison of DBP effects on germ cell number, differentiation, and aggregation in human testis xenografts and in vivo in rats. We observed comparable effects on germ cells in both species, but the effects in the human were muted compared with those in the rat. Nevertheless, phthalate effects on germ cells have potential implications for the next generation, which merits further study. Our results indicate that the rat is a human-relevant model in which to explore the mechanisms for germ cell effects. PMID- 25514604 TI - Biodegradable poly-l-lactide based microparticles as controlled release delivery system for filarial vaccine candidate antigens. AB - Modern recombinant vaccines are less immunogenic than conventional vaccines which require adjuvants to enhance the effect of a vaccine. Alum is being used as a standard adjuvant for protein based vaccines to augment immune response in several diseases. However, the problem associated with alum is it requires multiple doses at specific time intervals to achieve the adequate level of immunity. Currently the adjuvanticity of Poly-l-lactide microparticles as single dose immunization was explored to overcome multiple immunization and reported to be effective for several diseases. In this regard we adsorbed filarial recombinant chimeric multivalent vaccine candidates such as TV and FEP on to PLA by double emulsion method and analyzed the characterization of PLA encapsulated microparticles and evaluated its immune responses in mice. The efficacy of single dose of PLA encapsulated proteins was investigated in comparison with single dose of alum or protein alone. In mice, single dose of PLA encapsulated antigens such as TV and FEP elicited significantly high antibody titer of 50,000 and 64,000 respectively than single dose of alum adsorbed TV/FEP (6000/9000) and single dose of protein TV/FEP (3000/4000) alone. Further PLA encapsulated antigens induced higher levels of cellular proliferation together with significant (P<0.0001) levels of cytokine response [PLA-TV induced high levels of IL-4(Th2) and IFN gamma (Th1) cytokines whereas PLA-FEP showed high levels of IL-5(Th2) and IFN gamma (Th1)] indicating a balanced response elicited by PLA antigens. Overall strong humoral and cellular responses were observed for PLA encapsulated antigens compared with single dose of alum adsorbed or protein alone. PMID- 25514603 TI - Chemically synthesized molecules with the targeting and effector functions of antibodies. AB - This article reports the design, synthesis, and evaluation of a novel class of molecules of intermediate size (approximately 7000 Da), which possess both the targeting and effector functions of antibodies. These compounds-called synthetic antibody mimics targeting prostate cancer (SyAM-Ps)-bind simultaneously to prostate-specific membrane antigen and Fc gamma receptor I, thus eliciting highly selective cancer cell phagocytosis. SyAMs have the potential to combine the advantages of both small-molecule and biologic therapies, and may address many drawbacks associated with available treatments for cancer and other diseases. PMID- 25514605 TI - Nicotine facilitates reinnervation of phenol-injured perivascular adrenergic nerves in the rat mesenteric resistance artery. AB - Nicotine has been shown to have neuroprotective and neurotrophic actions in the central nervous system. To elucidate the peripheral neurotrophic effects of nicotine, we determined whether nicotine affected the reinnervation of mesenteric perivascular nerves following a topical phenol treatment. A topical phenol treatment was applied to the superior mesenteric artery proximal to the abdominal aorta in Wistar rats. We examined the immunohistochemistry of the distal small arteries 7 days after the treatment. The topical phenol treatment markedly reduced the density of tyrosine hydroxylase (TH)-LI and calcitonin gene-related peptide (CGRP)-LI fibers in these arteries. The administration of nicotine at a dose of 3 mg/kg/day (1.5 mg/kg/injection, twice a day), but not once a day or its continuous infusion using a mini-pump significantly increased the density of TH LI nerves without affecting CGRP-LI nerves. A pretreatment with nicotinic acetylcholine receptor antagonists hexamethonium, mecamylamine, and methyllycaconitine, but not dextrometorphan, canceled the TH-LI nerve reinnervation induced by nicotine. Nicotine significantly increased NGF levels in the superior cervical ganglia (SCG) and mesenteric arteries, but not in the dorsal root ganglia, and also up-regulated the expression of NGF receptors (TrkA) in the SCG, which were canceled by hexamethonium. These results suggested that nicotine exhibited neurotrophic effects that facilitated the reinnervation of adrenergic TH-LI nerves by activating alpha7 nicotinic acetylcholine receptor and NGF in the SCG. PMID- 25514606 TI - Quality of life of psoriatic patients evaluated by a new psychometric assessment tool: PsoDisk. AB - BACKGROUND: Psoriasis is a chronic skin disorder which negatively impacts a patient's quality of life (QoL). A recently published assessment tool, PsoDisk, has been proposed to evaluate patient's QoL. OBJECTIVE: The aim of this study was to test PsoDisk as a QoL assessment tool in psoriatic patients undergoing treatment with adalimumab. METHODS: A retrospective, monocentric study, including patients who completed at least 48 weeks of both adalimumab therapy and PsoDisk assessment. PASI was assessed by the physician whereas the PsoDisk test was self performed by the patient. Both were evaluated at each control visit throughout the study-period in order to detect changes in disease severity and the impact of quality of life, respectively. RESULTS: In total, we evaluated 31 patients selected from our database. At baseline, all aspects of patients' psycho emotional and social lives were impaired. PASI score reduction correlated with a PsoDisk score decrease (r = 0.97; p = 0.02), reflecting an overall improvement of patient's QoL. CONCLUSION: PsoDisk was found to be easy to administer and intuitive for interpreting clinical results. PMID- 25514607 TI - Prolactin variations during risperidone therapy in a sample of drug-naive children and adolescents. AB - The aim of this prospective observational study was to investigate the variations of serum prolactin hormone (PRL) in a sample of 34 drug-naive patients (mean age 13 years) who started risperidone therapy assuming that several factors may favor the increase in serum PRL. Serum PRL and hyperprolactinemia clinical signs were examined at baseline (T0) and after almost 3 months of treatment (T1). We considered sex, pubertal status, risperidone dosage, psychiatric diagnosis, and any personal/family history of autoimmune diseases. The mean serum PRL value increased between T0 and T1 (P=0.004). The mean serum PRL was higher in females in the pubertal/postpubertal stage and for risperidone dosage up 1 mg/day. Hyperprolactinemia was found in 20% of patients at T0 and in 38% of patients at T1 (P=0.03). The mean serum PRL increase was greater in early-onset schizophrenia spectrum psychosis patients compared with no-early-onset schizophrenia spectrum psychosis patients (P=0.04). The increase in PRL was higher in patients with a personal and a family history of autoimmune diseases. This study suggests that the increase in serum PRL in patients treated with risperidone may be linked not only to the drug and its dosage but also to several risk factors such as sex, pubertal stage, psychiatric disease, and autoimmune disorders. PMID- 25514612 TI - Gold-catalyzed intermolecular nitrene transfer from 2H-azirines to ynamides: a direct approach to polysubstituted pyrroles. AB - An effective gold-catalyzed intermolecular nitrene transfer by the reaction of 2H azirines and ynamides is reported, which provides highly substituted pyrroles in a straightforward manner. This transformation proceeds under mild conditions and gives the polysubstituted pyrroles in good-to-excellent yields. Preliminary results indicate that a nongold carbenoid pathway is preferred for current pyrrole synthesis. PMID- 25514608 TI - Bacteria can mobilize nematode-trapping fungi to kill nematodes. AB - In their natural habitat, bacteria are consumed by bacterivorous nematodes; however, they are not simply passive preys. Here we report a defensive mechanism used by certain bacteria to mobilize nematode-trapping fungi to kill nematodes. These bacteria release urea, which triggers a lifestyle switch in the fungus Arthrobotrys oligospora from saprophytic to nematode-predatory form; this predacious form is characterized by formation of specialized cellular structures or 'traps'. The bacteria significantly promote the elimination of nematodes by A. oligospora. Disruption of genes involved in urea transport and metabolism in A. oligospora abolishes the urea-induced trap formation. Furthermore, the urea metabolite ammonia functions as a signal molecule in the fungus to initiate the lifestyle switch to form trap structures. Our findings highlight the importance of multiple predator-prey interactions in prey defense mechanisms. PMID- 25514613 TI - Unilateral and bilateral pedicle screw fixation in transforaminal lumbar interbody fusion: radiographic and clinical analysis. AB - BACKGROUND: Transforaminal lumbar interbody fusion with bilateral segmental pedicle screw (PS) fixation is a widely used and well-recognized technique that provides fixation and load-bearing capacity, while restoring morphometric spine parameters and relieving symptoms in patients with degenerative disc disease. A supplemental interspinous process fixation plate (ISFP) as an adjunct to unilateral PS fixation allows for reduced invasiveness of this technique compared with bilateral PS placement. The biomechanical comparison results have been previously reported, but the significance of these findings has not been studied in clinical settings. METHODS: A prospective cohort study with a supplemental retrospective chart review and radiographic analysis was performed. Patients were divided into 2 groups: bilateral PS fixation (n = 75) or unilateral PS fixation + ISFP (n = 96). Lateral lumbar standing radiographs were obtained for preoperative and postoperative foraminal height (FH), disc height, segmental sagittal alignment, and lumbar sagittal alignment measurements. Standardized questionnaires were used to compare postoperative clinical outcomes. RESULTS: The estimated blood loss, duration of procedure, and length of hospital stay were significantly lower for 1-level and 2-level procedures in the unilateral PS + ISFP group. A statistically significant mean disc height increase was observed in both groups. Regardless of the disc height increase, a statistically significant FH loss was detected in the bilateral PS group (from 17.1 mm to 16.3 mm; 4.7% loss; P = 0.04) compared with FH height loss in the unilateral PS + ISFP group that was not statistically significant (from 19.0 mm to 18.4 mm; 3.2% loss; P = 0.1). The analysis of segmental sagittal alignment, lumbar sagittal alignment, clinical outcomes, and fusion rates did not demonstrate any statistically significant differences. CONCLUSIONS: Significantly reduced surgical invasiveness was associated with unilateral PS + ISFP fixation, which represents the major advantage of this technique. Unilateral fixation was also associated with a slightly lower reduction in FH and was equally effective as bilateral PS fixation in regard to fusion rates, clinical outcomes, and other radiographic outcomes studied. PMID- 25514610 TI - Frequency of COL4A3/COL4A4 mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing. AB - Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies. PMID- 25514614 TI - Biomechanical comparison of cervical fixation via transarticular facet screws without rods versus lateral mass screws with rods. AB - OBJECTIVE: Transarticular facet screws restore biomechanical stability to the cervical spine when posterior cervical anatomy has been compromised. This study compares the more recent, less invasive, and briefer transarticular facet screw system without rods with the lateral mass screw system with rods. METHODS: For this study, 6 human cervical spines were obtained from cadavers. Transarticular facet screws without rods were inserted bilaterally into the inferior articular facets at the C5-C6 and C5-C6-C7 levels. Lateral mass screws with rods were inserted bilaterally at the same levels using Magerl's technique. All specimens underwent range of motion (ROM) testing by a material testing machine for flexion, extension, lateral bending, and axial rotation. RESULTS: Both fixation methods, transarticular facet screws without rods and lateral mass screws with rods, reduced all ROM measurements and increased spinal stiffness. No statistically significant differences between the 2 stabilization methods were found in ROM measurements for 1-level insertions. However, in 2-level insertions, ROM for the nonrod transarticular facet screw group was significantly increased for flexion-extension and lateral bending. CONCLUSIONS: Transarticular facet screws without rods and lateral mass screws with rods had similar biomechanical stability in single-level insertions. For 2-level insertions, transarticular facet screws without rods are a valid option in cervical spine repair. PMID- 25514615 TI - High prevalence of pituitary dysfunction after aneurysmal subarachnoid hemorrhage: a long-term prospective study using dynamic endocrine testing. AB - OBJECTIVE: Impaired systemic hormonal activity caused by hypothalamic and pituitary injury may contribute to neuropsychologic disturbances and poor quality of life after aneurysmal subarachnoid hemorrhage (SAH). This prospective study was designed to longitudinally evaluate long-term clinical outcome and pituitary function after SAH using dynamic tests for adrencorticotropic and somatotropic secretory capacity. METHODS: Endocrine function was assessed by basal hormonal concentrations at 6-12 months and 12-24 months after SAH. At the 12-24 months follow-up, dynamic provocative evaluation of adrenocorticotropic hormone (ACTH) and growth hormone (GH) was performed using the insulin tolerance test (ITT). In patients where ITT was contraindicated, an ACTH stimulation test was used to assess ACTH capacity, and a growth hormone releasing hormone (GHRH)-arginine stimulation test was used to assess GH capacity. RESULTS: Of 60 patients with SAH screened, 51 were included in the study, and 44 remained to be tested at the two follow-up visits. As assessed by basal hormone concentrations alone, the prevalence of pituitary dysfunction was 34% at 6-12 months and 41% at 12-24 months. When using dynamic tests (12-24 months), impaired pituitary function was detected in 43%. The ITT detected more cases of central hypoadrenalism and GH deficiency compared with the ACTH- and GHRH-arginine-stimulation tests, respectively. CONCLUSIONS: Application of dynamic endocrine tests revealed a high frequency of long-term hypothalamic-pituitary dysfunction after aneurysmal SAH. The role of pituitary dysfunction in the recovery after SAH merits further evaluation. PMID- 25514616 TI - Meta-analysis of the efficacy and safety of therapeutic hypothermia in children with acute traumatic brain injury. AB - OBJECTIVE: To evaluate the efficacy and safety of therapeutic hypothermia in children with acute traumatic brain injury (TBI). METHODS: A systematic literature review using PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, VIP, and Chinese Biomedical Database was performed to retrieve studies of randomized controlled trials (RCTs) on therapeutic hypothermia for children with TBI published before March 2014. Data extraction and quality evaluation of RCTs were performed by 2 investigators independently. A meta-analysis was performed by RevMan 5.2.7. RESULTS: There were 7 RCTs comprising 442 children (218 in hypothermia group and 224 in normothermia group). Meta-analysis showed therapeutic hypothermia could increase mortality compared with the normothermia group (relative risk [RR] = 1.84, 95% confidence interval [CI] = 1.15-2.93, P = 0.01). On the Glasgow Outcome Scale (GOS), the following scores did not differ between the hypothermia group and normothermia group: 3-month GOS 4-5 (RR = 0.89, 95% CI = 0.68-1.16, P = 0.39), 3-month GOS 1-3 (RR = 1.19, 95% CI = 0.80-1.76, P = 0.39), 6-month GOS 4-5 (RR = 0.91, 95% CI = 0.78-1.07, P = 0.26), and 6-month GOS 1-3 (RR = 1.18, 95% CI = 0.88-1.59, P = 0.27). Hypothermia did not increase the rate of pneumonia (RR = 0.84, 95% CI = 0.63-1.12, P = 0.23) or bleeding (RR = 0.94, 95% CI = 0.39-2.26, P = 0.89), but the incidence of arrhythmias was higher in the hypothermia group (RR = 2.60, 95% CI = 1.06-6.41, P = 0.04). CONCLUSIONS: No benefit of therapeutic hypothermia in children with TBI is shown in this study; therapeutic hypothermia may increase the risk of mortality and arrhythmia. There is no evidence that therapeutic hypothermia improves prognosis of children with TBI; there is also no evidence that therapeutic hypothermia increases the risk of pneumonia and coagulation dysfunction. These results are limited by the quality of the included studies and need to be considered with caution. Further large-scale, well-designed RCTs on this topic are needed. PMID- 25514617 TI - Cerebrospinal fluid leaks and encephaloceles of temporal bone origin: nuances to diagnosis and management. AB - OBJECTIVE: Temporal bone encephalocele has become less common as the incidence of chronic mastoid infection and surgery for this condition has decreased. As a result, the diagnosis is often delayed, and the encephalocele is often an incidental finding. This situation can result in serious neurologic complications with patients presenting with cerebrospinal fluid leak and meningitis. We review the occurrence of, characteristics of, and repair experience with temporal encephaloceles from 2000-2012. METHODS: We conducted a retrospective review of 32 patients undergoing combined mastoidectomy and middle cranial fossa craniotomy for the treatment of temporal encephalocele. RESULTS: The diagnosis of temporal encephalocele was made in all patients using high-resolution temporal bone computed tomography and magnetic resonance imaging. At the time of diagnosis, 12 patients had confirmed cerebrospinal fluid leak; other common presenting symptoms included hearing loss and ear fullness. Tegmen defect was most commonly due to chronic otitis media (n = 14). Of these patients, 8 had undergone prior mastoidectomy, suggesting an iatrogenic cause. Other etiologies included radiation exposure, congenital defects, and spontaneous defects. Additionally, 2 patients presented with meningitis; 1 patient had serious neurologic deficits resulting from venous infarction. CONCLUSIONS: The risk of severe neurologic complications after the herniation of intracranial contents through a tegmen defect necessitates prompt recognition and appropriate management. Computed tomography and magnetic resonance imaging aid in definitive diagnosis. A combined mastoid/middle fossa approach allows for sustainable repair with adequate exposure of defects and support of intracranial contents. PMID- 25514618 TI - Chemopreventive and therapeutic potential of "naringenin," a flavanone present in citrus fruits. AB - Cancer is one of the major causes of deaths in developed countries and is emerging as a major public health burden in developing countries too. Changes in cancer prevalence patterns have been noticed due to rapid urbanization and changing lifestyles. One of the major concerns is an influence of dietary habits on cancer rates. Approaches to prevent cancer are many and chemoprevention or dietary cancer prevention is one of them. Therefore, nutritional practices are looked at as effective types of dietary cancer prevention strategies. Attention has been given to identifying plant-derived dietary agents, which could be developed as a promising chemotherapeutic with minimal toxic side effects. Naringenin, a phytochemical mainly present in citrus fruits and tomatoes, is a frequent component of the human diet and has gained increasing interest because of its positive health effects not only in cancer prevention but also in noncancer diseases. In the last few years, significant progress has been made in studying the biological effects of naringenin at cellular and molecular levels. This review examines the cancer chemopreventive/therapeutic effects of naringenin in an organ-specific format, evaluating its limitations, and its considerable potential for development as a cancer chemopreventive/therapeutic agent. PMID- 25514619 TI - Safety and efficacy of parenteral fish oil-containing lipid emulsions in premature neonates. AB - OBJECTIVE: The aim of the study was to evaluate the safety and efficacy of fish oil-containing (FO) lipid emulsions that are rich in omega-3 fatty acids for parenteral nutrition in preterm neonates by using data retrieved from randomized controlled trials. METHODS: We performed a meta-analysis of 8 randomized controlled trials representing 483 premature neonates to compare FO with control (CO) lipid emulsions. RESULTS: This meta-analysis revealed that the levels of omega-3 fatty acids in the form of docosahexaenoic acid, eicosapentaenoic acid, and arachidonic acid (% of total fatty acids) in plasma were statistically higher in FO groups (mean difference [MD] -0.7%, 95% confidence interval [CI] -1.05 to 0.36, P < 0.001; MD -1.31%, 95% CI -1.40 to -1.21, P < 0.001). The differences were found in red blood cell (RBC) membranes. The levels of arachidonic acid (% of total fatty acids) as omega-6 fatty acid in plasma and red blood cell membranes were significantly lower in FO groups (MD 1.27%, 95% CI 1.12-1.42, P < 0.001) (MD 0.92%, 95% CI 0.12-1.72, P = 0.02). The mean body weight, serum level of bilirubin, triglycerides or C-reactive protein, all-cause mortality, and rate of lipid emulsion-associated complications were, however, not different between FO and CO groups. CONCLUSIONS: The level of docosahexaenoic acid is efficiently improved by FO lipid emulsions. The changes observed in eicosapentaenoic acid and arachidonic acid, and the associated safety issue, however, remain to be clarified. Any clinical benefit or detrimental effect of using FO in premature neonates cannot be demonstrated by the present study. PMID- 25514621 TI - NO3(-) coordination in aqueous solutions by (15)N/(14)N and (18)O/(nat)O isotopic substitution: what can we learn from molecular simulation? AB - We explore the deconvolution of water-nitrate correlations by the first-order difference approach involving neutron diffraction of heavy- and null-aqueous solutions of KNO3 under (14)N/(15)N and (nat)O(N)/(18)O(N) substitutions to achieve a full characterization of the first water coordination around the nitrate ion. For that purpose we performed isobaric-isothermal simulations of 3.5 m KNO3 aqueous solutions at ambient conditions to generate the relevant radial distribution functions required in the analysis (a) to identify the individual partial contributions to the total neutron-weighted distribution function, (b) to isolate and assess the contribution of NO3(-)...K(+) pair formation, (c) to test the accuracy of the neutron diffraction with isotope substitution based coordination calculations and X-ray diffraction based assumptions, and (d) to describe the water coordination around both the nitrogen and oxygen sites of the nitrate ion. PMID- 25514620 TI - Discriminant score for celiac disease based on immunohistochemical analysis of duodenal biopsies. AB - OBJECTIVES: Celiac disease (CD) represents a spectrum, which includes cases with minor histological abnormalities (potential CD). The aim of this work is to evaluate the contribution of immunohistochemical analysis of duodenal biopsies to the diagnosis of gluten-related minor enteropathy. METHODS: Duodenal biopsies from 56 patients with untreated CD and 56 controls were analyzed for CD3 and gammadelta intraepithelial lymphocyte number, gammadelta/CD3 ratio, and density of CD25+ lamina propria cells. A discriminant equation was obtained by which 61 more biopsies with normal villous architecture were blindly evaluated. RESULTS: All of the immunohistochemical parameters were significantly different between patients with CD and controls. None of the single parameters showed sufficient specificity for CD. The combination of all of the 4 markers resulted in the following discriminant equation: discriminant score (Dscore) = (CD3 * 0.06) - (gammadelta * 0.119) + (CD25 * 0.012) + (gammadelta/CD3 * 0.131) - 4.709. Using this Dscore, patients were correctly classified as celiac or controls in 97.3% of the cases. When this equation was applied to a validation set of 61 patients with normal villous architecture and unknown diagnosis, 92.9% of those with a positive score turned out to be patients with potential CD. A normal score, however, did not exclude this condition. CONCLUSIONS: Immunohistochemistry represents a specific tool for the diagnosis of CD, but does lack sensitivity in detecting all of the potential CD cases. PMID- 25514622 TI - Interpreting chemical neurotransmission in vivo: techniques, time scales, and theories. AB - Monitoring neurotransmitter levels is a major research strategy for determining the functions of neuronal systems, specifically the ascending neuromodulator systems. In this Viewpoint, we consider the impact of different methods for recording extracellular neurotransmitter levels in vivo on theories concerning the signaling mode(s) and functions of these neuronal systems. As exemplified by evidence from experiments using different methods to measure acetylcholine (ACh) signaling, both neuromodulatory and deterministic functions have been attributed to cholinergic activity. Technical and experimental advances now allow determination of the validity of such dual-signaling theories. PMID- 25514623 TI - Measuring central airway obstruction. What do bronchoscopists do? AB - RATIONALE: All bronchoscopists will encounter, at some point, central airway obstruction (CAO) and will face the problem of documenting its severity. Axial imaging is suggested as the gold standard for assessing CAO, but anecdotal evidence indicates that many bronchoscopists use visual estimation. The prevalence and reliability of this method have not been extensively studied. OBJECTIVES: This study aimed to determine bronchoscopists' opinions about assessing CAO and to assess the variability of visual estimation. METHODS: All 438 members of the American Association of Bronchology and Interventional Pulmonology were invited to participate in an online questionnaire. In addition to reporting opinions and practice in measuring CAO, participants estimated degree of obstruction for 10 bronchoscopic photos of abnormal central airway lesions using a sliding scale from 0 to 100%. MEASUREMENTS AND MAIN RESULTS: Responses were obtained from 118 individuals with varied interventional bronchoscopy experience. Most participants reported using visual estimation of CAO (91%) and largely by numeric estimates (87%). A total of 55 participants volunteered additional methods they employed, and their comments reflected discontent with the dependability of those. When shown the same 10 bronchoscopic photos, estimates varied considerably, with very large ranges of responses for all images. Most (86%) agreed that measurement of airway narrowing should be standardized. CONCLUSIONS: Although limited by sample size and static photos of abnormal airways, this study supports the tenet that most bronchoscopists use a subjective and variable method of estimating CAO, which is anecdotally pervasive in the absence of a clinically practical alternative. PMID- 25514624 TI - Comparison between direct measurements and modeled estimates of external radiation exposure among school children 18 to 30 months after the Fukushima nuclear accident in Japan. AB - After a major radioactive incident, accurate dose reconstruction is important for evaluating health risks and appropriate radiation protection policies. After the 2011 Japan Fukushima nuclear incident, we assessed the level of agreement between the modeled and directly measured dose and estimated the uncertainties. The study population comprised 520 school children from Minamisoma city, located 20 km north of the nuclear plant. The annual dose 18-30 months after the incident was assessed using two approaches: estimation using the model proposed by the Japanese government and direct measurement by radiation dosemeters. The ratio of the average of modeled and measured doses was 3.0 (standard deviation (SD): 2.0). The reduction coefficient, an index for radiation attenuation properties, was 0.3 (SD: 0.1) on average, whereas the value used in the government model was 0.6. After adjusting for covariates, the coefficient had a significant negative correlation with the air dose rate in the dwelling location (p < 0.001), indicating that stronger building shielding effects are valuable in areas with higher air contamination levels. The present study demonstrated that some overestimation may have been related to uncertainties in radiation reduction effects, and that the air contamination level might provide a more important indicator of these effects. PMID- 25514625 TI - Understanding Stober silica's pore characteristics measured by gas adsorption. AB - Controversial reports regarding Stober silica's microporosity and specific surface area remain in the literature despite decades of widespread applications. In this work, Stober silica samples prepared under controlled reaction time and postsynthesis washing/drying conditions were characterized by nitrogen adsorption at 77 K, transmission electron microscopy, elemental analysis, Fourier transform infrared spectroscopy, thermal analysis, and evolved gas analysis. Our experimental results demonstrated the important but often overlooked effects of reaction time and postsynthesis treatments on Stober silica's pore characteristics, as evidenced by the strikingly large range of BET specific surface area (11.3-309.7 m(2)/g). A simple micropore filling and blocking mechanism compatible with an existing Stober silica growth model incorporating both aggregation and monomer addition steps was proposed to explain all our experimental findings. The carbon and nitrogen contents appear to serve well as the indicative link between our experimental variables and the resulting pore blocking by TEOS and its derivatives. A suitable combination of experimental conditions is recommended in order to make microporous Stober silica samples with large specific surface area, including a short reaction time, water washing, and drying at moderate temperature preferably under vacuum. PMID- 25514626 TI - Accurate standard hydrogen electrode potential and applications to the redox potentials of vitamin C and NAD/NADH. AB - We computationally evaluated the standard hydrogen electrode (SHE) potential in aqueous phase and the Gibbs energy of a proton from the experimental pKa values of alcohol molecules. From the "golden standard" CCSD(T)/aug-cc-pVTZ level calculation, we estimated the SHE potential as 4.48 V, which is very close to the IUPAC-recommended experimental value of 4.44 V. As applications to the Gaussian-3 (G3) methods, which also reproduce the "golden standard" level calculations, we computed various pKa values and redox potentials for a vitamin series. For vitamin C, we support the experimental result of +0.35 V and predict the pKa value of d-ascorbic acid to be 3.7-3.9. Using a model molecule for nicotinamide adenine dinucleotide (NAD), we reproduced the redox potential and determined the order of the proton/electron addition, based on both the proton affinity and redox potential. PMID- 25514627 TI - Selecting the optimal anti-aliasing filter for multichannel biosignal acquisition intended for inter-signal phase shift analysis. AB - The availability of microcomputer-based portable devices facilitates the high volume multichannel biosignal acquisition and the analysis of their instantaneous oscillations and inter-signal temporal correlations. These new, non-invasively obtained parameters can have considerable prognostic or diagnostic roles. The present study investigates the inherent signal delay of the obligatory anti aliasing filters. One cycle of each of the 8 electrocardiogram (ECG) and 4 photoplethysmogram signals from healthy volunteers or artificially synthesised series were passed through 100-80-60-40-20 Hz 2-4-6-8th order Bessel and Butterworth filters digitally synthesized by bilinear transformation, that resulted in a negligible error in signal delay compared to the mathematical model of the impulse- and step responses of the filters. The investigated filters have as diverse a signal delay as 2-46 ms depending on the filter parameters and the signal slew rate, which is difficult to predict in biological systems and thus difficult to compensate for. Its magnitude can be comparable to the examined phase shifts, deteriorating the accuracy of the measurement. As a conclusion, identical or very similar anti-aliasing filters with lower orders and higher corner frequencies, oversampling, and digital low pass filtering are recommended for biosignal acquisition intended for inter-signal phase shift analysis. PMID- 25514628 TI - Hypoxia-induced acute lung injury is aggravated in streptozotocin diabetic mice. AB - PURPOSE: Hypoxia is an inevitable consequence of many respiratory diseases resulting from inadequate alveolar ventilation. As pulmonary dysfunction is recently recognized as one of the many clinical features associated with diabetes, this study aims to investigate the effect of streptozotocin (STZ) induced diabetes on hypoxia-induced lung injury. MATERIALS AND METHODS: Mice were randomly allocated to four groups (Control, Hypoxia, Diabetes, Diabetes+Hypoxia). Control and type I diabetic (100 mg/kg STZ-treated) mice were followed for 4 weeks and finally exposed to normoxia or hypoxia (8% O2). Twelve hours later, lung tissues were collected for histopathologic examination, and determination of interleukin (IL)-1beta, IL-6, myeloperoxidase (MPO), malondialdehyde (MDA), total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, and Toll-like receptor (TLR)4 expression. RESULTS: STZ-induced diabetes aggravated histopathological changes in the lung exposed to acute hypoxia. Hypoxia increased lung MDA level but decreased T-AOC and SOD activity. STZ-induced diabetic mice presented significant increases in MDA level and SOD activity in the lung. Moreover, no difference was found in the levels of both oxidant index (MDA) and anti-oxidant indexes (T-AOC and SOD) between "Hypoxia" group and "Hypoxia plus Diabetes" group. On the other hand, STZ-induced diabetic mice presented significant increases in pulmonary neutrophil infiltration, pro-inflammatory cytokines (IL-1beta and IL-6) production, as well as TLR4 expression. Although acute hypoxia alone had no significant effect on pulmonary inflammatory markers, it profoundly increased STZ-diabetes-induced neutrophil infiltration, pro inflammatory cytokine production, and TLR4 expression in lung tissues. CONCLUSIONS: STZ-induced diabetes may aggravate acute hypoxia-induced lung injury through enhancing pulmonary inflammatory responses. PMID- 25514630 TI - Coordination among thigh muscles including the vastus intermedius and adductor magnus at different cycling intensities. AB - Although many studies have been focused on muscle synergies in the lower limbs, synergies of the thigh muscles during cycling have not been investigated in detail. We examined synergies of the thigh muscles including the vastus intermedius (VI) and adductor magnus (AM) while cycling. Eight healthy men pedaled at 20%, 40%, 60%, 80% and 100% of maximal aerobic power output at a constant cadence of 60 rpm. Surface electromyography (EMG) recorded signals from the deep VI and the three superficial quadriceps femoris (QF) muscles, the two hamstrings and the AM. The root mean square of the EMG signal was averaged every 2 degrees of crank rotation and normalized by the peak value for each muscle. We used factor analysis to assess normalized EMG recordings while cycling and to identify thigh muscle synergies. The VI, the superficial QF muscles and the AM dominated the first muscle synergy at all power output levels. The AM also formed a second synergy with the two hamstrings at all power output levels. These results suggest that the VI coordinates with the other QF and AM muscles, and that the AM coordinates with the QF and hamstring muscles while cycling. PMID- 25514629 TI - A putatively functional polymorphism in the HTR2C gene is associated with depressive symptoms in white females reporting significant life stress. AB - Psychosocial stress is well known to be positively associated with subsequent depressive symptoms. Cortisol response to stress may be one of a number of biological mechanisms that links psychological stress to depressive symptoms, although the precise causal pathway remains unclear. Activity of the x-linked serotonin 5-HTR2C receptor has also been shown to be associated with depression and with clinical response to antidepressant medications. We recently demonstrated that variation in a single nucleotide polymorphism on the HTR2C gene, rs6318 (Ser23Cys), is associated with different cortisol release and short term changes in affect in response to a series of stress tasks in the laboratory. Based on this observation, we decided to examine whether rs6318 might moderate the association between psychosocial stress and subsequent depressive symptoms. In the present study we use cross-sectional data from a large population-based sample of young adult White men (N = 2,366) and White women (N = 2,712) in the United States to test this moderation hypothesis. Specifically, we hypothesized that the association between self-reported stressful life events and depressive symptoms would be stronger among homozygous Ser23 C females and hemizygous Ser23 C males than among Cys23 G carriers. In separate within-sex analyses a genotype by-life stress interaction was observed for women (p = .022) but not for men (p = .471). Homozygous Ser23 C women who reported high levels of life stress had depressive symptom scores that were about 0.3 standard deviations higher than female Cys23 G carriers with similarly high stress levels. In contrast, no appreciable difference in depressive symptoms was observed between genotypes at lower levels of stress. Our findings support prior work that suggests a functional SNP on the HTR2C gene may confer an increased risk for depressive symptoms in White women with a history of significant life stress. PMID- 25514631 TI - Acute effects of dynamic exercises on the relationship between the motor unit firing rate and the recruitment threshold. AB - The aim of this study was to compare the acute effects of concentric versus eccentric exercise on motor control strategies. Fifteen men performed six sets of 10 repetitions of maximal concentric exercises or eccentric isokinetic exercises with their dominant elbow flexors on separate experimental visits. Before and after the exercise, maximal strength testing and submaximal trapezoid isometric contractions (40% of the maximal force) were performed. Both exercise conditions caused significant strength loss in the elbow flexors, but the loss was greater following the eccentric exercise (t=2.401, P=.031). The surface electromyographic signals obtained from the submaximal trapezoid isometric contractions were decomposed into individual motor unit action potential trains. For each submaximal trapezoid isometric contraction, the relationship between the average motor unit firing rate and the recruitment threshold was examined using linear regression analysis. In contrast to the concentric exercise, which did not cause significant changes in the mean linear slope coefficient and y-intercept of the linear regression line, the eccentric exercise resulted in a lower mean linear slope and an increased mean y-intercept, thereby indicating that increasing the firing rates of low-threshold motor units may be more important than recruiting high-threshold motor units to compensate for eccentric exercise-induced strength loss. PMID- 25514632 TI - Kinetics of thermal activation of an ultraviolet cone pigment. AB - Visual pigments can be thermally activated via isomerization of the retinyl chromophore and hydrolysis of the Schiff base (SB) through which the retinyl chromophore is bound to the opsin protein. Here, we present the first combined experimental and theoretical study of the thermal activation of a Siberian hamster ultraviolet (SHUV) pigment. We measured the rates of thermal isomerization and hydrolysis in the SHUV pigment and bovine rhodopsin. We found that these rates were significantly faster in the UV pigment than in rhodopsin due to the difference in the structural and electrostatic effects surrounding the unprotonated Schiff base (USB) retinyl chromophore in the UV pigment. Theoretical (DFT-QM/MM) calculations of the cis-trans thermal isomerization revealed a barrier of ~23 kcal/mol for the USB retinyl chromophore in SHUV compared to ~40 kcal/mol for protonated Schiff base (PSB) chromophore in rhodopsin. The lower barrier for thermal isomerization in the SHUV pigment is attributed to the (i) lessening of the steric restraints near the beta-ionone ring and SB ends of the chromophore, (ii) displacement of the transmembrane helix 6 (TM6) away from the binding pocket toward TM5 due to absence of the salt bridge between the USB and the protonated E113 residue, and (iii) change in orientation of the hydrogen bonding networks (HBNs) in the extracellular loop 2 (EII). The results in comparing thermal stability of UV cone pigment and rhodopsin provide insight into molecular evolution of vertebrate visual pigments in achieving low discrete dark noise and high photosensitivity in rod pigments for dim-light vision. PMID- 25514633 TI - Effective adsorption and enhanced removal of organophosphorus pesticides from aqueous solution by Zr-based MOFs of UiO-67. AB - Though many efforts have been devoted to the adsorptive removal of hazardous materials of organophosphorus pesticides (OPs), it is still highly desirable to develop novel adsorbents with high adsorption capacities. In the current work, the removal of two representative OPs, glyphosate (GP) and glufosinate (GF), was investigated by the exceptionally stable Zr-based MOFs of UiO-67. The abundant Zr OH groups, resulting from the missing-linker induced terminal hydroxyl groups and the inherent bridging ones in Zr-O clusters of UiO-67 particles, served as natural anchorages for efficient GP and GF capture in relation with their high affinity toward phosphoric groups in OPs. The correlation between the most significant parameters such as contact time, OPs concentration, adsorbent dose, pH, as well as ionic strength with the adsorption capacities was optimized, and the effects of these parameters on the removal efficiency of GP and GF from the polluted aqueous solution were investigated. The adsorption of GP on UiO-67 was faster than that of GF, and a pseudo-second-order rate equation effectively described the uptake kinetics. The Langmuir model exhibited a better fit to adsorption isotherm than the Freundlich model. Thanks to the strong affinity and adequate pore size, the adsorption capacities in UiO-67 approached as high as 3.18 mmol (537 mg) g(-1) for GP and 1.98 mmol (360 mg) g(-1) for GF, which were much higher than those of many other reported adsorbents. The excellent adsorption characteristics of the current adsorbents toward OPs were preserved in a wide pH window and high concentration of the background electrolytes. These prefigured the promising potentials of UiO-67 as novel adsorbent for the efficient removal of OPs from aqueous solution. PMID- 25514635 TI - Effect of Gibberellin on the biosynthesis of tocopherols in Oilseed rape (Brassica napus L.) and arabidopsis. AB - Elevating the yield and altering the composition of seed tocopherols (Toc's) are important to rapeseed breeding and production. However, little is known about the biosynthesis of Toc's in response to environmental signals. In this study, we investigated the effects of exogenous gibberellin (GA3) and paclobutrazol (PAC) on Toc biosynthesis. We also explored the interactive effects between the two plant growth regulators (PGRs) and other factors, such as PGR treatment duration, genotype, and growing location on the total Toc yield and composition in oilseed rape seed. GA3 significantly enhanced the production of Toc's and elevated the alpha-/gamma-Toc ratio in a time- and genotype-dependent manner. By contrast, PAC significantly reduced Toc yield. Genotypic differences were observed in the effects of GA3 on Toc yield and composition in the seeds. GA3 significantly increased the Toc yield and alpha-/gamma-Toc ratio in Zheyou-50, a genotype with a low proportion of very long chain fatty acids (VLCFAs). However, GA3 did not significantly influence these parameters in Jiu-Er-13Xi, a genotype with a high VLCFA proportion. The increased Toc yield induced by GA3 was mediated by the upregulation of genes (BnPDS1 and BnVTE1) that catalyze the production of Toc precursors. Therefore, applying GA3 can improve rapeseed quality by increasing Toc yield and improving Toc composition. PMID- 25514634 TI - Proangiogenic compositions of microvesicles derived from human umbilical cord mesenchymal stem cells. AB - INTRODUCTION & OBJECTIVE: Microvesicles (MVs) derived from mesenchymal stem cells (MSCs) have been shown to promote angiogenesis. This study was aimed to shed a light on the mechanisms by analyzing the angiogenesis-promoting compositions of MSC-MVs. Also we try to figure out the impact of hypoxia on angiogenesis. METHODS: MVs were isolated from the culture supernatants of MSCs under hypoxia/normoxia and serum-deprivation condition. The morphological features of MVs were revealed by an electron microscope and the origin of the MVs was identified by a bead-bound assay. An antibody array was used to analyze the expression of angiogenic cytokines from MVs and the parent MSCs as well. The major candidate factors were screened and the results were validated by immune blotting. RESULTS: MSC-MVs were around 80 nm in diameter. They expressed CD29, CD44, and CD73, but not CD31 and CD45. Antibody array showed that both MSCs and MVs expressed many angiogenesis-promoting biomolecules, including interleukin-6 (IL-6), basic fibroblast growth factors (bFGF), and recptor of urokinase-type plasminogen activator (UPAR). MSC-MVs contained angiogenin, vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1) and the receptor-2 for vascular endothelial growth factor at higher levels than the parent MSCs. Under hypoxic condition most cytokines were expressed in greater quantity than normoxic in MSCs while in MVs there was no significant difference between hypoxic and normoxic conditions except UPAR, Angiogenin, VEGF, IGF, Tie-2/TEK, and IL-6 which were higher in MVs under hypoxic conditions than those in normoxic condition. CONCLUSION: Upon serum-deprivation condition, MSCs could secrete MVs that contain a variety of factors contributing to their angiogenesis-promoting function. And among them, Angiogenin, VEGF, MCP-1, VEGF R2 might be of greater importance than the other cytokines. Also UPAR, Angiogenin, VEGF, IGF, Tie-2/TEK, IL-6 might be responsible for hypoxia-augmented proangiogenic effects of MVs. PMID- 25514636 TI - Toward improved anti-cryptococcal drugs: Novel molecules and repurposed drugs. AB - Cryptococcosis is one of the most important fungal infections of humans. It primarily, but not exclusively, afflicts people with compromised immune function. Cryptococcosis is most commonly caused by Cryptococcus neoformans var. grubii with C. neoformans var. neoformans and C. gatti also contributing to the disease. Cryptococcosis is primarily manifested as meningoencephalitis although pneumonia occurs frequently as well. Globally, the burden of disease is highest among those living with HIV/AIDS and is one of the most common causes of death in this patient population. Cryptococcal meningitisis almost invariably fatal if untreated. The current gold standard therapy is amphotericin B combined with 5 flucytosine. Unfortunately, this therapy has significant toxicity and is not widely available in resource-limited regions. Fluconazole, which is associated with poorer outcomes, is frequently as an alternative. Here, I present the characteristics of an ideal anti-cryptococcal agent and review recent progress toward identifying both novel and repurposed drugs as potential new therapies. PMID- 25514638 TI - Asp48 function in the hydrogen-bonding network involving Asp52 of hen egg-white lysozyme. AB - To characterize the hydrogen-bonding network in lysozyme, we focused on the residue of Asp48 located at the active site in hen egg-white lysozyme. We constructed a mutant lysozyme (D48A) and analyzed using (GlcNAc)3 and chitin affinity chromatography. The substrate binding of subsites D-F in D48A and the activity against (GlcNAc)5 were decreased. The parameters of substrate binding and rate constants obtained from computer simulations confirmed these changes. In the crystal structure, (GlcNAc)4 was located at the same position as wildtype. However, the side chains of Arg45 and Thr47 at subsites E-F were moved by the replacement. Further, the loss of the hydrogen bond between Asp48 and Ser50 changed the hydrogen-bonding network, and this resulted in an alteration of the side chain of Asn59. This result suggests that the hydrogen-bonding network plays a crucial in the function of Asp52 and of transglycosylation at subsites E-F. PMID- 25514642 TI - Sol-gel synthesis of mesoporous anatase-brookite and anatase-brookite-rutile TiO2 nanoparticles and their photocatalytic properties. AB - TiO2 photocatalysts with a mixture of different TiO2 crystal polymorphs have customarily been synthesized hydrothermally at high temperatures using complicated and expensive equipment. In this study TiO2 nanoparticles with a mixture of TiO2 crystals were synthesized using a modified sol-gel method at low temperature. In order to form nanoparticles with different polymorphs a series of samples were obtained at pH 2, 4, 7 and 9. Raw samples were calcined at different temperatures ranging from 200 to 800 degrees C to evaluate the effect of the calcination temperature on the physico-chemical properties of the samples. XRD results revealed that a mixture of anatase and brookite can be obtained in the as synthesized samples and in those calcined up to 800 degrees C depending on the pH used to obtain the final product. Indeed, a mixture of anatase brookite and rutile; or a sample with only rutile phase can be yielded through further calcination of the as-prepared samples at temperatures ?600 degrees C due to phase transformation. The photocatalytic performance of the samples with a mixture of anatase-brookite; anatase-brookite-rutile; and anatase-rutile (Degussa P25 TiO2) was exquisitely investigated in the degradation of methylene blue solutions. The samples obtained at pH 2 and calcined at 200 degrees C possessed the highest activity of all due to its superior properties. This study elucidates a facile method suitable for the synthesis of TiO2 with different mixtures of TiO2 polymorphs with desirable properties for various applications. PMID- 25514637 TI - Transcriptional profiling of adult neural stem-like cells from the human brain. AB - There is a great potential for the development of new cell replacement strategies based on adult human neural stem-like cells. However, little is known about the hierarchy of cells and the unique molecular properties of stem- and progenitor cells of the nervous system. Stem cells from the adult human brain can be propagated and expanded in vitro as free floating neurospheres that are capable of self-renewal and differentiation into all three cell types of the central nervous system. Here we report the first global gene expression study of adult human neural stem-like cells originating from five human subventricular zone biopsies (mean age 42, range 33-60). Compared to adult human brain tissue, we identified 1,189 genes that were significantly up- and down-regulated in adult human neural stem-like cells (1% false discovery rate). We found that adult human neural stem-like cells express stem cell markers and have reduced levels of markers that are typical of the mature cells in the nervous system. We report that the genes being highly expressed in adult human neural stem-like cells are associated with developmental processes and the extracellular region of the cell. The calcium signaling pathway and neuroactive ligand-receptor interactions are enriched among the most differentially regulated genes between adult human neural stem-like cells and adult human brain tissue. We confirmed the expression of 10 of the most up-regulated genes in adult human neural stem-like cells in an additional sample set that included adult human neural stem-like cells (n = 6), foetal human neural stem cells (n = 1) and human brain tissues (n = 12). The NGFR, SLITRK6 and KCNS3 receptors were further investigated by immunofluorescence and shown to be heterogeneously expressed in spheres. These receptors could potentially serve as new markers for the identification and characterisation of neural stem- and progenitor cells or as targets for manipulation of cellular fate. PMID- 25514643 TI - Electrokinetic mixing at high zeta potentials: ionic size effects on cross stream diffusion. AB - The electrokinetic phenomena at high zeta potentials may show several unique features which are not normally observed. One of these features is the ionic size (steric) effect associated with the solutions of high ionic concentration. In the present work, attention is given to the influences of finite ionic size on the cross stream diffusion process in an electrokinetically actuated Y-shaped micromixer. The method consists of a finite difference based numerical approach for non-uniform grid which is applied to the dimensionless form of the governing equations, including the modified Poisson-Boltzmann equation. The results reveal that, neglecting the ionic size at high zeta potentials gives rise to the overestimation of the mixing length, because the steric effects retard liquid flow, thereby enhancing the mixing efficiency. The importance of steric effects is found to be more intense for channels of smaller width to height ratio. It is also observed that, in sharp contrast to the conditions that the ions are treated as point charges, increasing the zeta potential improves the cross stream diffusion when incorporating the ionic size. Moreover, increasing the EDL thickness decreases the mixing length, whereas the opposite is true for the channel aspect ratio. PMID- 25514644 TI - Residence time and pH effects on the bonding configuration of orthophosphate surface complexes at the goethite/water interface as examined by Extended X-ray Absorption Fine Structure (EXAFS) spectroscopy. AB - Identifying the mechanisms by which P is bound to soils and soil constituents is ultimately important as they provide information on the stability of bound species and their reactivity in the environment. EXAFS studies were carried out to provide information on how the local chemical environment of sorbed P changes as an effect of pH and time. Goethite was reacted with orthophosphate at a P concentration of 0.8mmolL(-1) P at pH 3.0, 4.5 and 6.0. The residence time effect on the mechanisms of P sorption on goethite was also evaluated for two different reaction times, 5 and 18days, on goethite suspensions reacted at pH 4.5. The objective of this study was to understand how P sorption mechanisms change over a wide pH range when subjected to P concentrations above the P saturation ratio of goethite. Phosphorus K-edge EXAFS spectra were collected at 2150eV in fluorescence mode and the structural parameters were obtained through the fits of sorption data using Artemis. The monodentate surface complex was shown to be the predominant mechanism by which P sorbs at the goethite surface under the experimental conditions. The lack of a discrete Fe-P shell and the presence of highly disordered structures, particularly, at R-space ?3.5 suggested the formation of P surface precipitates at the goethite/water interface. PMID- 25514646 TI - Preparation and characterization of bifunctional Ti-Fe kaolinite composite for Cr(VI) removal. AB - A novel bifunctional Ti-Fe kaolinite composite with excellent adsorption and photocatalytic properties was synthesized by a simple precipitation method. X-ray diffraction analysis and high-resolution transmission electron microscope analysis confirmed the existence of rutile phase TiO2 and amorphous iron in the composite. The specific surface area of the Ti-Fe kaolinite composite is 5.5 times higher than that of the original kaolinite. The composite was used as an adsorbent as well as photocatalyst for Cr(VI) removal. The results indicate that the low pH is favorable to the Cr(VI) removal by the composite and the removal rate of Cr(VI) reached 87% at pH 3.0. Visible light irradiation obviously increased the removal of Cr(VI) by the composite and greatly shortened reaction equilibrium time, which may be attributed to the photocatalytic reduction of Cr(VI) to Cr(III) by TiO2 associated with simultaneous redox cycle of Fe(III)/Fe(II). Various common co-existing ions did not show obvious effects on the removal of Cr(VI) by the composite. The composite exhibited very high stability for the Cr(VI) removal. The adsorption models and thermodynamics of Cr(VI) onto the composite were studied. PMID- 25514645 TI - Vanillin-molecularly targeted extraction of stir bar based on magnetic field induced self-assembly of multifunctional Fe3O4@Polyaniline nanoparticles for detection of vanilla-flavor enhancers in infant milk powders. AB - A molecularly imprinted stir bar was constructed based on Fe3O4@Polyaniline nanoparticles with magnetic field-induced self-assembly process. The monomer, methacrylic acid, was pre-assembled into the pre-polymers with vanillin as template by the formation of hydrogen bonds. After that, the magnetic complexes were generated by the hydrogen bonding, the hydrophobic and pi-pi interaction between the pre-polymers and Fe3O4@Polyaniline. The complexes were adsorbed on the surface of magnetic stir bar under the magnetic induction, and the coating of vanillin-molecularly imprinted polymers was generated by the one-step copolymerization basing on the cross linking of ethylene glycol dimethacrylate. The molecular imprinting stir bar showed superior selectivity and fast binding kinetics for vanillin, and was used for the enrichment of vanilla-flavor enhancers (vanillin, ethyl maltol and methyl vanillin) in infant milk powders. The results measured by HPLC-UV exhibited good linear ranges of 0.01-100, 0.02 100 and 0.03-100MUgmL(-1) with the limit of detection of 2.5-10.0ngmL(-1), and the recoveries were 94.7-98.9%, 82.1-96.7% and 84.5-93.2% with RSD<7.2% for the three enhancers, respectively. PMID- 25514647 TI - Alternative use of cross-linked polyallylamine (known as Sevelamer pharmaceutical compound) as biosorbent. AB - In this study, an alternative use of Sevelamer carbonate (SEV, a cross-linked polyallylamine which is a widely known pharmaceutical compound) was suggested. The existence of primary and secondary amino groups (with different ratios) in its molecule increases its adsorption potential and use as biosorbent material. SEV was tested as biosorbent material aiming the removal of heavy metals and dyes from simulated effluents. As heavy metals and dyes, hexavalent chromium (Cr(VI)) and Remazol Brilliant Blue RN (RB) were used, respectively. A full adsorption study was done confirming the strong adsorption capability of SEV. The maximum theoretical adsorption capacity (Qm) was 772 and 485mg/g for single-component solutions of RB and Cr(VI), respectively; the respective values for binary mixtures of the same concentration (200mg/L) were 445 and 309mg/g respectively (calculated after fitting to Langmuir-Freundlich isotherm model at 25 degrees C). The same experiments were also done at increasing temperatures (45 and 65 degrees C) concluding thermodynamic remarks (DeltaH(0)>0; DeltaG(0)<0; DeltaS(0)>0). The effect of contact time was analyzed running kinetic adsorption experiments and fitting them to pseudo-second order kinetic equation. The reusability was evaluated completing successfully 20 cycles of reuse (adsorption/desorption). The adsorption mechanism among SEV molecules and Cr(VI) or/and RB was clarified using FTIR spectroscopy before and after adsorption in line with a detailed theoretical modeling which provided important calculations. SEV was also characterized using swelling experiments, BET, SEM, XRD, TGA techniques. PMID- 25514648 TI - Photocatalytic reduction of carbon dioxide over ZnFe2O4/TiO2 nanobelts heterostructure in cyclohexanol. AB - A series of ZnFe2O4/TiO2 heterostructure photocatalysts with different mass percentages of ZnFe2O4 were synthesized through hydrothermal deposition method. The photocatalysts were characterized by SEM, TEM, XRD, XPS, and UV-vis DRS techniques. It is observed that ZnFe2O4 nanoparticles grew on the TiO2 nanobelts, and the obtained nanocomposites have ordered nanobelt structure with a high crystallinity. The photocatalytic activities of the nanocomposites were tested by photocatalytic reduction of CO2 in cyclohexanol under UV light (main wave length at 360nm) irradiation. The experimental results showed that the main products were cyclohexanone (CH) and cyclohexyl formate (CF). Compared with pure TiO2 and ZnFe2O4 samples, the obtained ZnFe2O4/TiO2 nanocomposites showed much higher photocatalytic performance. The loading amount of ZnFe2O4 was an important factor affecting the generation yields of the products. When the loading amount of ZnFe2O4 reached 9.78%, the ZnFe2O4/TiO2 heterostructure sample displayed the highest activity. The Z-scheme system reaction mechanism was proposed to explain the photocatalytic activity of the ZnFe2O4/TiO2 heterostructure sample. PMID- 25514649 TI - Targeting Hepatitis B Virus With CRISPR/Cas9. AB - Hepatitis B virus persistence in infected hepatocytes is due to the presence of covalently closed circular DNA (cccDNA), the template for the transcription of viral RNAs. Antiviral therapies with nucleoside analogues inhibit replication of HBV DNA in capsids present in the cytoplasm of infected cells, but do not reduce or destroy nuclear cccDNA. To investigate whether cccDNA derived from infectious HBV could be directly targeted for destruction, we used the CRISPR/Cas9 system in HepG2 cells expressing the HBV receptor sodium taurocholate cotransporting polypeptide (NTCP). We tested different HBV-specific guide RNAs and demonstrated that they could inhibit HBV infections up to eightfold. Inhibition was due to mutations and deletions in cccDNA similar to those observed with chromosomal DNA cleaved by Cas9 and repaired by nonhomologous end joining (NHEJ). Interferon alpha (IFN-alpha) did not have a measurable effect on the antiviral activity of the CRISPR/Cas9 system, suggesting that Cas9 and NHEJ activities are not affected by induction of an innate immune response with the cytokine. Taken together, our results demonstrated that Cas9 can be recruited to cccDNA, opening the possibility for the development of future antiviral strategies aimed at targeting cccDNA for endonucleolytic cleavage with small molecules. PMID- 25514650 TI - Identification and Characterization of an eIF4e DNA Aptamer That Inhibits Proliferation With High Throughput Sequencing. AB - Development of DNA aptamer screens that are both simple and informative can increase the success rate of DNA aptamer selection and induce greater adoption. High eIF4e levels contribute to malignancies, thus eIF4e presents itself as a valuable target for DNA aptamer-based inhibition screen. Here, we demonstrate a method for the rapid selection of looped DNA aptamers against eIF4e by combining negative selection and purification in a single step, followed by characterization with high throughput sequencing. The resulting aptamers show functional binding to eIF4e and inhibit translation initiation in biochemical assays. When transfected into cells, eIF4e aptamers cause a dramatic loss of cell proliferation in tumor cells as seen with eIF4e knockdown with antisense oligonucleotides, shRNAs, and siRNAs, hinting at therapeutic possibilities. With the large data set provided by high throughput sequencing, we demonstrate that selection happens in waves and that sequencing data can be used to infer aptamer structure. Lastly, we show that ligation of looped aptamers can enhance their functional effects. These results demonstrate a rapid protocol to screen and optimize aptamers against macromolecules of interest. PMID- 25514651 TI - Photocatalytic applications of paper-like poly(vinylidene fluoride)-titanium dioxide hybrids fabricated using a combination of electrospinning and electrospraying. AB - A paper-like photocatalyst was fabricated by electrospraying an N,N' dimethylformamide (DMF) dispersion of titanium dioxide (TiO2) nanoparticles (NPs) on a poly(vinylidene fluoride) nanofiber (PVDF NF) mat prepared by electrospinning. Morphological studies revealed that the TiO2 NPs uniformly deposited as clusters on the surface of the PVDF NF mat. The immobilized amount of TiO2 was found to be 2.08, 2.44, 3.80, and 4.73 mg per 45 cm(2) of PVDF-TiO2 hybrids for the electrospraying of 10, 20, 40, and 60 ml of TiO2-DMF, respectively. The hybrid photocatalysts were effective in degrading bisphenol A (BPA), 4-chlorophenol (4-CP), and cimetidine (CMT), which dissolved in both deionized water and secondary wastewater effluents, with activity being proportional to the quantity of TiO2 NPs immobilized. For the highest loading amount of TiO2, BPA, 4-CP, and CMT degraded completely within 100, 100, and 40 min of UV irradiation, respectively. Stable photo-oxidation of CMT was maintained through 10 repeated cycles. During these cycles, it was confirmed that there was no loss of TiO2 NPs by inductively coupled plasma optical emission spectrometry. Our results suggest that effective and stable PVDF-TiO2 hybrid photocatalysts can be fabricated on a large scale by combining electrospinning and electrospraying techniques. PMID- 25514652 TI - Disentangling the Role of Cortico-Basal Ganglia Loops in Top-Down and Bottom-Up Visual Attention: An Investigation of Attention Deficits in Parkinson Disease. AB - It is solidly established that top-down (goal-driven) and bottom-up (stimulus driven) attention mechanisms depend on distributed cortical networks, including prefrontal and frontoparietal regions. On the other hand, it is less clear whether the BG also contribute to one or the other of these mechanisms, or to both. The current study was principally undertaken to clarify this issue. Parkinson disease (PD), a neurodegenerative disorder primarily affecting the BG, has proven to be an effective model for investigating the contribution of the BG to different brain functions; therefore, we set out to investigate deficits of top-down and bottom-up attention in a selected cohort of PD patients. With this objective in mind, we compared the performance on three computerized tasks of two groups of 12 parkinsonian patients (assessed without any treatment), one otherwise pharmacologically treated and the other also surgically treated, with that of a group of controls. The main behavioral tool for our study was an attentional capture task, which enabled us to tap the competition between top down and bottom-up mechanisms of visual attention. This task was suitably combined with a choice RT and a simple RT task to isolate any specific deficit of attention from deficits in motor response selection and initiation. In the two groups of patients, we found an equivalent increase of attentional capture but also comparable delays in target selection in the absence of any salient distractor (reflecting impaired top-down mechanisms) and movement initiation compared with controls. In contrast, motor response selection processes appeared to be prolonged only in the operated patients. Our results confirm that the BG are involved in both motor and cognitive domains. Specifically, damage to the BG, as it occurs in PD, leads to a distinct deficit of top-down control of visual attention, and this can account, albeit indirectly, for the enhancement of attentional capture, reflecting weakened ability of top-down mechanisms to antagonize bottom-up control. PMID- 25514653 TI - Choice-related Activity in the Anterior Intraparietal Area during 3-D Structure Categorization. AB - The anterior intraparietal area (AIP) of macaques contains neurons that signal the depth structure of disparity-defined 3-D shapes. Previous studies have suggested that AIP's depth information is used for sensorimotor transformations related to the efficient grasping of 3-D objects. We trained monkeys to categorize disparity-defined 3-D shapes and examined whether neuronal activity in AIP may also underlie pure perceptual categorization behavior. We first show that neurons with a similar 3-D shape preference cluster in AIP. We then demonstrate that the monkeys' 3-D shape discrimination performance depends on the position in depth of the stimulus and that this performance difference is reflected in the activity of AIP neurons. We further reveal correlations between the neuronal activity in AIP and the subject's subsequent choices and RTs during 3-D shape categorization. Our findings propose AIP as an important processing stage for 3-D shape perception. PMID- 25514654 TI - Short-term Motor Training, but Not Observational Training, Alters Neurocognitive Mechanisms of Action Processing in Infancy. AB - The role of motor experience in the processing of perceived actions is hotly debated on both behavioral (e.g., action understanding) and neural (e.g., activation of the motor system) levels of interpretation. Whereas some researchers focus on the role of motor experience in the understanding of and motor activity associated with perceived actions, others emphasize the role of visual experience with the perceived actions. The question of whether prior firsthand motor experience is critical to motor system activation during perception of actions performed by others is best addressed through studies with infants who have a limited repertoire of motor actions. In this way, infants can receive motor or visual training with novel actions that are not mere recombinations of previously acquired actions. In this study, 10-month-old infants received active training with a motorically unfamiliar action that resulted in a distinct sound effect. They received observational experience with a second, similarly unfamiliar action. Following training, we assessed infants' neural motor activity via EEG while they listened to the sounds associated with the actions relative to a novel sound. We found a greater decrease in mu power to sounds associated with the motorically learned action than to those associated with the observed action that the infants had never produced. This effect was directly related to individual differences in the degree of motor learning via motor training. These findings indicate a unique effect of active experience on neural correlates of action perception. PMID- 25514655 TI - The allocation of attention and working memory in visual crowding. AB - When the distance between a visual target and nearby flankers falls below a critical distance, target discrimination declines precipitously. This is called "crowding." Many researchers have proposed that selective attention plays a role in crowding. However, although some research has examined the effects of directing attention toward versus away from the targets, no previous research has assessed how attentional allocation varies as a function of target-flanker distance in crowding. Here, we used ERPs to assess the operation of attention during crowding, focusing on the attention-related N2pc component. We used a typical crowding task in which participants were asked to report the category (vowel/consonant) of a lateralized target letter flanked by distractor letters at different distances. We tested the hypothesis that attention fails when the target-flanker distance becomes too small for attention to operate effectively. Consistent with this hypothesis, we found that N2pc amplitude was maximal at intermediate target-flanker distances and decreased substantially when crowding became severe. In addition, we examined the sustained posterior contralateral negativity (SPCN), which reflects the amount of information being maintained in working memory. Unlike the N2pc component, the SPCN increased in amplitude at small target-flanker distances, suggesting that observers stored information about the target and flankers in working memory when attention failed to select the target. Together, the N2pc and SPCN results suggest that attention and working memory play distinctive roles in crowding: Attention operates to minimize interference from the flankers at intermediate target-flanker distances, whereas working memory may be recruited when attention fails to select the target at small target-flanker distances. PMID- 25514657 TI - Delay Period Activity of the Substantia Nigra during Proactive Control of Response Selection as Determined by a Novel fMRI Localization Method. AB - The ability to proactively control motor responses, particularly to overcome overlearned or automatic actions, is an essential prerequisite for adaptive, goal oriented behavior. The substantia nigra (SN), an element of the BG, has figured prominently in current models of response selection. However, because of its small size and proximity to functionally distinct subcortical structures, it has been challenging to test the SN's involvement in response selection using conventional in vivo functional neuroimaging approaches. We developed a new fMRI localization method for directly distinguishing, on echo-planar images, the SN BOLD signal from that of neighboring structures, including the subthalamic nucleus (STN). Using this method, we tested the hypothesis that the SN supports the proactive control of response selection. We acquired high-resolution EPI volumes at 3 T from 16 healthy participants while they completed the Preparing to Overcome Prepotency task of proactive control. There was significantly elevated delay period signal selectively during high- compared with low-control trials in the SN. The STN did not show delay period activity in either condition. SN delay period signal was significantly inversely associated with task performance RTs across participants. These results suggest that our method offers a novel means for measuring SN BOLD responses, provides unique evidence of SN involvement in cognitive control in humans, and suggests a novel mechanism for proactive response selection. PMID- 25514656 TI - High-resolution 7T fMRI of Human Hippocampal Subfields during Associative Learning. AB - Examining the function of individual human hippocampal subfields remains challenging because of their small sizes and convoluted structures. Previous human fMRI studies at 3 T have successfully detected differences in activation between hippocampal cornu ammonis (CA) field CA1, combined CA2, CA3, and dentate gyrus (DG) region (CA23DG), and the subiculum during associative memory tasks. In this study, we investigated hippocampal subfield activity in healthy participants using an associative memory paradigm during high-resolution fMRI scanning at 7 T. We were able to localize fMRI activity to anterior CA2 and CA3 during learning and to the posterior CA2 field, the CA1, and the posterior subiculum during retrieval of novel associations. These results provide insight into more specific human hippocampal subfield functions underlying learning and memory and a unique opportunity for future investigations of hippocampal subfield function in healthy individuals as well as those suffering from neurodegenerative diseases. PMID- 25514658 TI - Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4 oxo-4H-chromene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3Kbeta and PI3Kdelta for the treatment of PTEN-deficient cancers. AB - Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kbeta activity and specific inhibition of PI3Kdelta has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kbeta/delta inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen 4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials. PMID- 25514659 TI - An update on the rotenone models of Parkinson's disease: their ability to reproduce the features of clinical disease and model gene-environment interactions. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder that is characterized by two major neuropathological hallmarks: the degeneration of dopaminergic neurons in the substantia nigra (SN) and the presence of Lewy bodies in the surviving SN neurons, as well as other regions of the central and peripheral nervous system. Animal models have been invaluable tools for investigating the underlying mechanisms of the pathogenesis of PD and testing new potential symptomatic, neuroprotective and neurorestorative therapies. However, the usefulness of these models is dependent on how precisely they replicate the features of clinical PD with some studies now employing combined gene-environment models to replicate more of the affected pathways. The rotenone model of PD has become of great interest following the seminal paper by the Greenamyre group in 2000 (Betarbet et al., 2000). This paper reported for the first time that systemic rotenone was able to reproduce the two pathological hallmarks of PD as well as certain parkinsonian motor deficits. Since 2000, many research groups have actively used the rotenone model worldwide. This paper will review rotenone models, focusing upon their ability to reproduce the two pathological hallmarks of PD, motor deficits, extranigral pathology and non-motor symptoms. We will also summarize the recent advances in neuroprotective therapies, focusing on those that investigated non-motor symptoms and review rotenone models used in combination with PD genetic models to investigate gene-environment interactions. PMID- 25514660 TI - UV irradiation and UV-H2O2 advanced oxidation of the roxarsone and nitarsone organoarsenicals. AB - Roxarsone (ROX) and nitarsone (NIT) are used as additives in animal feeding operations and have been detected in animal manure, agricultural retention ponds, and adjacent surface waters. This work investigates treatment of organoarsenicals using UV-based treatment processes, namely UV irradiation at 253.7 nm and the UV H2O2 advanced oxidation process. The apparent molar absorptivity was mapped for ROX and NIT across pH and wavelength. For UV irradiation at 253.7 nm, the fluence based pseudo-first order rate constant (kp(')) and effective quantum yield (Phi) for ROX were 8.10-29.7 * 10(-5) cm(2)/mJ and 2.34-8.37 * 10(-3) mol/E, respectively; the corresponding constants were slightly lower for NIT. The observed rate constants are higher during advanced oxidation (e.g., kp,ROX(')=3.92(+/-0.19)-217(+/-48) * 10(-4) cm(2)/mJ). Second order rate constants for organoarsenical transformation by hydroxyl radicals were determined to be 3.40(+/-0.45) * 10(9) and 8.28(+/-0.49) * 10(8) M(-1)s(-1) for ROX and NIT, respectively. Solution pH and nitrate concentration did not significantly impact ROX transformation during advanced oxidation; however, bicarbonate and dissolved organic matter from chicken litter reduced ROX transformation through hydroxyl radical scavenging. Inorganic arsenic was the predominant transformation product of ROX during UV-H2O2 treatment. PMID- 25514661 TI - Modifying the high rate algal pond light environment and its effects on light absorption and photosynthesis. AB - The combined use of high rate algal ponds (HRAPs) for wastewater treatment and commercial algal production is considered to be an economically viable option. However, microalgal photosynthesis and biomass productivity is constrained in HRAPs due to light limitation. This paper investigates how the light climate in the HRAP can be modified through changes in pond depth, hydraulic retention time (HRT) and light/dark turnover rate and how this impacts light absorption and utilisation by the microalgae. Wastewater treatment HRAPs were operated at three different pond depth and HRT during autumn. Light absorption by the microalgae was most affected by HRT, significantly decreasing with increasing HRT, due to increased internal self-shading. Photosynthetic performance (as defined by Pmax, Ek and alpha), significantly increased with increasing pond depth and decreasing HRT. Despite this, increasing pond depth and/or HRT, resulted in decreased pond light climate and overall integrated water column net oxygen production. However, increased light/dark turnover was able to compensate for this decrease, bringing the net oxygen production in line with shallower ponds operated at shorter HRT. On overcast days, modelled daily net photosynthesis significantly increased with increased light/dark turnover, however, on clear days such increased turnover did not enhance photosynthesis. This study has showed that light absorption and photosynthetic performance of wastewater microalgae can be modified through changes to pond depth, HRT and light/dark turnover. PMID- 25514662 TI - NBO, HOMO-LUMO, UV, NLO, NMR and vibrational analysis of veratrole using FT-IR, FT-Raman, FT-NMR spectra and HF-DFT computational methods. AB - This work deals with FT-IR, FT-Raman and FT-NMR spectral analysis and NBO, NLO, HOMO-LUMO and electronic transitions studies on veratrole. The molecular structure, fundamental vibrational frequencies and intensity of the vibrational bands were interpreted with the aid of structure optimizations and geometrical parameter calculations based on Hartree-Fock (HF) and density functional theory (DFT) method with 6-311++G(d, p) basis set. A study on the electronic properties, such as HOMO and LUMO energies were performed by time independent DFT approach. In addition, molecular electrostatic potential (MEP), Natural Bond-Orbital (NBO) analysis and thermodynamic properties were performed. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by gauge independent atomic orbital (GIAO) method and compared with experimental chemical shift. PMID- 25514663 TI - A Rapidly Enlarging Recurrent Eyebrow Pilomatrixoma in a Nonagenarian. AB - A rapidly growing, large (horizontal diameter of 3.1 cm) eyebrow lesion in a nonagenarian patient was found on pathologic examination to demonstrate an admixture of islands of anucleated, washed out eosinophilic "ghost" cells with surrounding nucleated, small germinal basaloid cells. Further analysis disclosed adipophilin granular positivity in the necrotic zones, negative nuclear staining for androgen receptor and strong nuclear positivity for Ki67 in the basaloid cells (proliferation index of 50%). These findings are consistent with a highly mitotically active pilomatrixoma. The lesion recurred after initial resection but returned the same histopathologic features as the primary. Several clinical features were notably atypical for pilomatrixoma-specifically, the age of the patient, rapid lesion growth and recurrence, and clinical appearance and large size of the mass. The immunohistochemical findings can help to distinguish this tumor from other skin neoplasms, especially sebaceous carcinoma in an older individual. PMID- 25514664 TI - Upper Eyelid Coloboma Repair Using Accessory Preauricular Cartilage in a Patient With Goldenhar Syndrome: Technique Revisited. AB - We present an unusual case of upper eyelid coloboma repair in a patient with Goldenhar syndrome. We describe the use of a modified Cutler-Beard flap with concurrent inlay graft using cartilage from a preauricular appendage. This technique provides the benefits of autologous tissue, while minimizing donor site morbidity and reducing the risk of upper eyelid retraction. PMID- 25514666 TI - [Trigeminal neuralgia]. PMID- 25514665 TI - Clinical relevance of regulatory T cells monitoring in the peripheral blood of ovarian cancer patients. AB - BACKGROUND: Tregs play a suppressive role in the control of antitumour immunity. In this study we evaluated the relevance of prospective monitoring of peripheral blood regulatory T cells (Tregs) as a potential prognostic marker of future outcome of epithelial ovarian cancer in patients with or without a metronomic chemotherapy. METHODS: 46 patients diagnosed with the ovarian cancer were enrolled in the study and divided into groups according to the stage of the disease, outcome of the surgery and treatment received. Proportions of Tregs in the peripheral blood samples were evaluated using flow cytometry. RESULTS: We show that the early stage of the disease and absence of the tumor residuum after radical surgery are the most important factors predicting a favourable clinical outcome in the ovarian cancer. We did not show any significant effect of consolidation chemotherapy with metronomic doses of etoposide or cyclophosphamide on the peripheral blood Tregs and on the clinical outcome. The slope of the Tregs trend line was a significant predictor of an early relapse, even after controlling for stage and tumor residuum after the surgical debulking by using the Cox proportional hazard model. CONCLUSIONS: This study shows that the faster kinetics of Tregs increase in the peripheral blood, expressed as the slope of the Tregs trend line, is a significant predictor of ovarian cancer early relapse hazard. However, due to its relatively low specificity, the informative value of regular monitoring of Tregs kinetics in the peripheral blood for the subsequent clinical outcome is limited. PMID- 25514667 TI - [Intracranial pressure targeted treatment in acute bacterial meningitis increased survival]. AB - To evaluate the efficacy of intracranial pressure (ICP)-targeted treatment, compared to standard intensive care, in adults with community acquired acute bacterial meningitis (ABM) and severely impaired consciousness, a prospectively designed intervention-control comparison study was performed. Included were patients with confirmed ABM and severely impaired mental status on admission. Fifty-two patients, given ICP-targeted treatment at a neuro-intensive care unit, and 53 control cases, treated with conventional intensive care, were included. All patients received intensive care with me-chanical ventilation, sedation, antibiotics and corticosteroids according to current guidelines. ICP-targeted treatment was performed in the intervention group, aiming at ICP 50 mmHg. The mortality was significantly lower in the intervention group compared to controls, 5/52 (10%) versus 16/53 (30%). Furthermore, only 17 patients (32%) in the control group fully recovered, compared to 28 (54%) in the intervention group. Early neuro-intensive care using ICP-targeted therapy reduces mortality and improves the overall outcome in adult patients with ABM and severely impaired mental status on admission. PMID- 25514668 TI - [Now there are national strategies against zoonotic intestinal infections. Combined efforts by five government agencies should lead to fewer cases of illness]. PMID- 25514669 TI - [Changes in prescription patterns to patients with bipolar syndromes. Increased use of lamotrigine and decreased use of lithium]. AB - Lithium is a first line option in the maintenance treatment of bipolar disorder, but several alternative treatment regimens have been introduced in recent years, among them treatment with antiepileptic compounds and atypical antipsychotic drugs. Little is known about if and how this has changed the prescription patterns of mood stabilizers. We analysed trends in prescription of mood stabilisers in Sweden using the national quality register for bipolar disorder (BipolaR), the Prescribed Drug Register, and the Patient Register during the years 2007-2011. We found that lithium use decreased while lamotrigine use increased in bipolar patients. These changes could not be ex-plained by differences in bipolar subtypes; lithium use decreased in both bipolar type I and type II, and the use of lamotrigine increased in bipolar type II. Lithium use was more common in men, whereas lamotrigine use was more common in women. The prescription of other mood stabilisers did not change during these years. PMID- 25514670 TI - [Broad injury panorama in children who swallowed a battery]. AB - Most ingested batteries in children pass through the gastrointestinal canal without problems. The risk for complications is at its highest if the battery gets stuck in the esophagus or if the child is less than 6 years of age or the size of the battery exceeds 15 mm. Thorough database searches only identified a limited number of articles, all were considered to provide low-grade evidence. PMID- 25514672 TI - Optimized brain extraction for pathological brains (optiBET). AB - The study of structural and functional magnetic resonance imaging data has greatly benefitted from the development of sophisticated and efficient algorithms aimed at automating and optimizing the analysis of brain data. We address, in the context of the segmentation of brain from non-brain tissue (i.e., brain extraction, also known as skull-stripping), the tension between the increased theoretical and clinical interest in patient data, and the difficulty of conventional algorithms to function optimally in the presence of gross brain pathology. Indeed, because of the reliance of many algorithms on priors derived from healthy volunteers, images with gross pathology can severely affect their ability to correctly trace the boundaries between brain and non-brain tissue, potentially biasing subsequent analysis. We describe and make available an optimized brain extraction script for the pathological brain (optiBET) robust to the presence of pathology. Rather than attempting to trace the boundary between tissues, optiBET performs brain extraction by (i) calculating an initial approximate brain extraction; (ii) employing linear and non-linear registration to project the approximate extraction into the MNI template space; (iii) back projecting a standard brain-only mask from template space to the subject's original space; and (iv) employing the back-projected brain-only mask to mask-out non-brain tissue. The script results in up to 94% improvement of the quality of extractions over those obtained with conventional software across a large set of severely pathological brains. Since optiBET makes use of freely available algorithms included in FSL, it should be readily employable by anyone having access to such tools. PMID- 25514671 TI - Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis. AB - Gulf War illness (GWI) is a chronic disease of unknown etiology characterized by persistent symptoms such as cognitive impairment, unexplained fatigue, pervasive pain, headaches, and gastrointestinal abnormalities. Current reports suggest that as many as 200,000 veterans who served in the 1990-1991 Persian Gulf War were afflicted. Several potential triggers of GWI have been proposed including chemical exposure, toxins, vaccines, and unknown infectious agents. However, a definitive cause of GWI has not been identified and a specific biological marker that can consistently delineate the disease has not been defined. Myalgic encephalomyelitis (ME) is a disease with similar and overlapping symptomology, and subjects diagnosed with GWI typically fit the diagnostic criteria for ME. For these reasons, GWI is often considered a subgroup of ME. To explore this possibility and identify immune parameters that may help to understand GWI pathophysiology, we measured 77 serum cytokines in subjects with GWI and compared these data to that of subjects with ME as well as healthy controls. Our analysis identified a group of cytokines that identified ME and GWI cases with sensitivities of 92.5% and 64.9%, respectively. The five most significant cytokines in decreasing order of importance were IL-7, IL-4, TNF-alpha, IL-13, and IL-17F. When delineating GWI and ME cases from healthy controls, the observed specificity was only 33.3%, suggesting that with respect to cytokine expression, GWI cases resemble control subjects to a greater extent than ME cases across a number of parameters. These results imply that serum cytokines are representative of ME pathology to a greater extent than GWI and further suggest that the two diseases have distinct immune profiles despite their overlapping symptomology. PMID- 25514673 TI - The role of pulse shape in motor cortex transcranial magnetic stimulation using full-sine stimuli. AB - A full-sine (biphasic) pulse waveform is most commonly used for repetitive transcranial magnetic stimulation (TMS), but little is known about how variations in duration or amplitude of distinct pulse segments influence the effectiveness of a single TMS pulse to elicit a corticomotor response. Using a novel TMS device, we systematically varied the configuration of full-sine pulses to assess the impact of configuration changes on resting motor threshold (RMT) as measure of stimulation effectiveness with single-pulse TMS of the non-dominant motor hand area (M1). In young healthy volunteers, we (i) compared monophasic, half-sine, and full-sine pulses, (ii) applied two-segment pulses consisting of two identical half-sines, and (iii) manipulated amplitude, duration, and current direction of the first or second full-sine pulse half-segments. RMT was significantly higher using half-sine or monophasic pulses compared with full-sine. Pulses combining two half-sines of identical polarity and duration were also characterized by higher RMT than full-sine stimuli resulting. For full-sine stimuli, decreasing the amplitude of the half-segment inducing posterior-anterior oriented current in M1 resulted in considerably higher RMT, whereas varying the amplitude of the half segment inducing anterior-posterior current had a smaller effect. These findings provide direct experimental evidence that the pulse segment inducing a posterior anterior directed current in M1 contributes most to corticospinal pathway excitation. Preferential excitation of neuronal target cells in the posterior anterior segment or targeting of different neuronal structures by the two half segments can explain this result. Thus, our findings help understanding the mechanisms of neural stimulation by full-sine TMS. PMID- 25514674 TI - Inactivation of pathogenic Listeria monocytogenes in raw milk by high hydrostatic pressure. AB - The aim of this work was to investigate the mechanisms underlying the inactivation of Listeria monocytogenes in raw milk under high hydrostatic pressure (HHP). The results showed that a 450-MPa treatment for 5 min could completely eliminate 108 colony-forming units/mL of viable bacteria, as indicted by increased uptake of propidium iodide. Morphological damage to the cell wall, cell membrane, and cytoplasmic components by HHP treatments was observed on scanning and transmission electron micrographs. The protein bands on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels differed between HHP treated and untreated L. monocytogenes, in that HHP decreased the protein content and caused partial protein degradation. Therefore, our results indicate that HHP inactivates L. monocytogenes by causing morphological changes in the internal and external cellular structures, as well as through membrane damage, cell wall rupture, and membrane protein degradation. PMID- 25514675 TI - Multimeric scaffolds displaying the HIV-1 envelope MPER induce MPER-specific antibodies and cross-neutralizing antibodies when co-immunized with gp160 DNA. AB - Developing a vaccine that overcomes the diversity of HIV-1 is likely to require a strategy that directs antibody (Ab) responses toward conserved regions of the viral Envelope (Env). However, the generation of neutralizing Abs (NAbs) targeting these regions through vaccination has proven to be difficult. One conserved region of particular interest is the membrane proximal external region (MPER) of Env located within the gp41 ectodomain. In order to direct the immune response to this region, the MPER and gp41 ectodomain were expressed separately as N-terminal fusions to the E2 protein of Geobacillus stearothermophilus. The E2 protein acts as a scaffold by self-assembling into 60-mer particles, displaying up to 60 copies of the fused target on the surface. Rabbits were immunized with E2 particles displaying MPER and/or the gp41 ectodomain in conjunction with DNA encoding full-length gp160. Only vaccines including E2 particles displaying MPER elicited MPER-specific Ab responses. NAbs were elicited after two immunizations that largely targeted the V3 loop. To overcome V3 immunodominance in the DNA component, E2 particles displaying MPER were used in conjunction with gp160 DNA lacking hypervariable regions V2, V3, or combined V1V2V3. All rabbits had HIV binding Ab responses and NAbs following the second vaccination. Using HIV-2/HIV-1 MPER chimeric viruses as targets, NAbs were detected in 12/16 rabbits after three immunizations. Low levels of NAbs specific for Tier 1 and 2 viruses were observed in all groups. This study provides evidence that co-immunizing E2 particles displaying MPER and gp160 DNA can focus Ab responses toward conserved regions of Env. PMID- 25514677 TI - Use of sensory information during postural control in children with cerebral palsy: systematic review. AB - Impairments in sensory processing in children with cerebral palsy (CP) appear to be a cause of the postural control deficits they present and may affect function and participation in daily activities. Understanding the role of sensory processing in postural control can better inform their rehabilitation. Thus, the authors aimed to systematically review the literature concerning effects of sensory information manipulation on postural control in children with CP. A tailored search strategy in relevant databases identified 11 full-text reports that fulfilled the predefined inclusion and exclusion criteria. Sensory information affects postural control in children with CP. These children are less responsive to sensory input, and therefore are less able to perform adjustments during sensory perturbation. They exhibit less postural stability in the presence of sensory conflicts. The most commonly studied sources of sensory data are visual and somatosensory information, particularly when processed under static conditions. There are no studies addressing sensory information manipulation on postural control during the performance of functional activities. Further studies addressing manipulation of new sources of sensory cues on postural control are required. PMID- 25514676 TI - TAM receptors support neural stem cell survival, proliferation and neuronal differentiation. AB - Tyro3, Axl and Mertk (TAM) receptor tyrosine kinases play multiple functional roles by either providing intrinsic trophic support for cell growth or regulating the expression of target genes that are important in the homeostatic regulation of immune responses. TAM receptors have been shown to regulate adult hippocampal neurogenesis by negatively regulation of glial cell activation in central nervous system (CNS). In the present study, we further demonstrated that all three TAM receptors were expressed by cultured primary neural stem cells (NSCs) and played a direct growth trophic role in NSCs proliferation, neuronal differentiation and survival. The cultured primary NSCs lacking TAM receptors exhibited slower growth, reduced proliferation and increased apoptosis as shown by decreased BrdU incorporation and increased TUNEL labeling, than those from the WT NSCs. In addition, the neuronal differentiation and maturation of the mutant NSCs were impeded, as characterized by less neuronal differentiation (beta-tubulin III+) and neurite outgrowth than their WT counterparts. To elucidate the underlying mechanism that the TAM receptors play on the differentiating NSCs, we examined the expression profile of neurotrophins and their receptors by real-time qPCR on the total RNAs from hippocampus and primary NSCs; and found that the TKO NSC showed a significant reduction in the expression of both nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), but accompanied by compensational increases in the expression of the TrkA, TrkB, TrkC and p75 receptors. These results suggest that TAM receptors support NSCs survival, proliferation and differentiation by regulating expression of neurotrophins, especially the NGF. PMID- 25514680 TI - Absence of filaggrin mutation in a patient affected by pachyonychia congenita and mild atopic dermatitis. PMID- 25514681 TI - The plant microbiome at work. AB - Plants host distinct microbial communities on and inside their tissues designated the plant microbiota. Microbial community profiling enabled the description of the phylogenetic structure of the plant microbiota to an unprecedented depth, whereas functional insights are largely derived from experiments using individual microorganisms. The binary interplay between isolated members of the plant microbiota and host plants ranges from mutualistic to commensalistic and pathogenic relationships. However, how entire microbial communities capable of executing both growth-promoting and growth-compromising activities interfere with plant fitness remains largely unknown. Ultimately, unravelling the net result of microbial activities encoded in the extended plant genome-the plant microbiome will be key to understanding and exploiting the full yield potential of a crop plant. In this perspective, we summarize first achievements of plant-microbiome research, we discuss future research directions, and we provide ideas for the translation of basic science to application to capitalize on the plant microbiome at work. PMID- 25514679 TI - Surfactant-derived proteins as markers of alveolar membrane damage in heart failure. AB - BACKGROUND: In heart failure (HF) alveolar-capillary membrane is abnormal. Surfactant-derived proteins (SPs) and plasma receptor for advanced-glycation-end products (RAGE) have been proposed as lung damage markers. METHODS: Eighty-nine chronic HF and 17 healthy subjects were evaluated by echocardiography, blood parameters, carbon monoxide lung diffusion (DLCO) and cardiopulmonary exercise test. We measured immature SP-B, mature SP-B, SP-A, SP-D and RAGE plasma levels. RESULTS: Immature SP-B (arbitrary units), mature SP-A (ng/ml) and SP-D (ng/ml), but not mature SP-B (ng/ml) and RAGE (pg/ml) levels, were higher in HF than in controls [immature SP-B: 15.6 (13.1, 75th-25th interquartile range) Vs. 11.1 (6.4), p<0.01; SP-A, 29.6 (20.1) Vs. 18.3 (13.5), p = 0.01; SP-D: 125 (90) Vs. 78 (58), p<0.01]. Immature SP-B, SP-A, SP-D and RAGE values were related to DLCO, peak oxygen consumption, ventilatory efficiency, and brain natriuretic peptide (BNP), whereas plasma mature SP-B was not. The DLCO Vs. immature SP-B correlation was the strongest one. At multivariate analysis, RAGE was associated to age and creatinine, SP-A to DLCO and BNP, SP-D to BNP, mature SP-B to DLCO and creatinine, and immature SP-B only but strongly to DLCO. CONCLUSIONS: Immature SP B is the most reliable biological marker of alveolar-capillary membrane function in HF. PMID- 25514682 TI - Population Genomics Analysis of Legume Host Preference for Specific Rhizobial Genotypes in the Rhizobium leguminosarum bv. viciae Symbioses. AB - Rhizobium leguminosarum bv. viciae establishes root nodule symbioses with several legume genera. Although most isolates are equally effective in establishing symbioses with all host genera, previous evidence suggests that hosts select specific rhizobial genotypes among those present in the soil. We have used population genomics to further investigate this observation. Pisum sativum, Lens culinaris, Vicia sativa, and V. faba plants were used to trap rhizobia from a well-characterized soil, and pooled genomic DNA from 100 isolates from each plant were sequenced. Sequence reads were aligned to the R. leguminosarum bv. viciae 3841 reference genome. High overall conservation of sequences was observed in all subpopulations, although several multigenic regions were absent from the soil population. A large fraction (16 to 22%) of sequence reads could not be recruited to the reference genome, suggesting that they represent sequences specific to that particular soil population. Although highly conserved, the 16S to 23S ribosomal RNA gene region presented single nucleotide polymorphisms (SNP) regarding the reference genome, but no striking differences could be found among plant-selected subpopulations. Plant-specific SNP patterns were, however, clearly observed within the nod gene cluster, supporting the existence of a plant preference for specific rhizobial genotypes. This was also shown after genome wide analysis of SNP patterns. PMID- 25514683 TI - Evidence of efficacy in outcomes of complementary integrative therapies. PMID- 25514684 TI - Complementary and integrative modalities in addiction treatment. PMID- 25514685 TI - Yoga as an alternative intervention for promoting a healthy lifestyle among college students. AB - Substance use and abuse continues to plague U.S. college campuses. The literature is replete with information from various disciplines on how to identify and intervene in this public health dilemma impacting college students. Identifications, treatments, and interventions are often based on Western medicine, but there is a growing movement and evidence supporting the effectiveness, value, and usefulness of Eastern therapies to combat this problem. Yoga is one Eastern intervention that has proven beneficial for promoting quality of life and wellness relationship to several acute and chronic illnesses. As a result of advocating for the inclusion of yoga in traditional college settings, two college campuses in Central Illinois introduced yoga courses for students, faculty, and staff. The courses are reviewed, and the positive results reported by students are shared. The information and evidence of yoga's benefits collected in this study warrant consideration by college campuses to initiate this practice enhancing primary, secondary, and tertiary prevention in their populations. PMID- 25514686 TI - Effects of music therapy on drug avoidance self-efficacy in patients on a detoxification unit: a three-group randomized effectiveness study. AB - Self-efficacy is a component of Bandura's social cognitive theory and can lead to abstinence and a reduction of relapse potential for people who have substance abuse disorders. To date, no music therapy researcher has utilized this theoretical model to address abstinence and reduce the likelihood of relapse in people who have addictions. The purpose of this study was to determine the effects of music therapy on drug avoidance self-efficacy in a randomized three group wait-list control design with patients on a detoxification unit. Participants (N = 131) were cluster randomized to one of three single-session conditions: music therapy, verbal therapy, or wait-list control. Music therapy participants received a group lyric analysis intervention, verbal therapy participants received a group talk therapy session, and wait-list control participants eventually received a group recreational music therapy intervention. Although there was no significant between-group difference in drug avoidance self efficacy, participants in the music therapy condition tended to have the highest mean drug avoidance self-efficacy scores. Posttest written comments supported the use of both music therapy and verbal therapy sessions. Two music therapy participants specifically noted that their initial skepticism had dissipated after receiving music therapy. Despite a lack of significant differences, the theoretical support of self-efficacy for substance abuse rehabilitation suggests that this may be an area of continued clinical focus and empirical investigation. Clinical anecdotes, limitations of the study, and suggestions for future research are provided. PMID- 25514687 TI - NADA protocol: integrative acupuncture in addictions. AB - National Acupuncture Detoxification Association (NADA) acupuncture is a simple, standardized, 1- to 5-point auricular needling protocol that originated as a grass-roots response to the opiate epidemic of the 1970s. NADA acupuncture is increasingly recognized as a universally useful intervention in the treatment of addictions specifically and in behavior health more generally. It is recognized as a best practice in the treatment of substance use disorders. Integrative programs using the NADA protocol are likely to see improvements in engagement, retention, decreased drug cravings, anxiety, and less physical symptoms. PMID- 25514690 TI - Lighting the darkness of addiction: can phototherapy enhance contingency management-based treatment of substance-related and addictive disorders? AB - Maladaptive patterns of substance use are serious social problems. Both pharmacological and nonpharmacological treatments are available, but nondrug options may be preferable because they avoid the expense and adverse side effects of psychotropic medication. Contingency management (CM) and nondrug social and recreational activities (NDSRAs) are based on operant conditioning principles and seek to decrease substance use by means of nondrug rewards. However, their efficacy may be hindered where brain reward circuitry is dysfunctional. Research shows that substance abuse biases neural reward systems in favor of drug-induced highs, while disrupting circadian-based rhythms. Circadian systems also have been found to influence human reward pathways. Possibly, a bidirectional relationship exists between circadian disturbance and substance abuse effects. If so, repair of abnormal circadian rhythms might help normalize reward response in substance abusers, with positive effects on CM or NDSRA treatment outcomes. Phototherapy has been effective in repairing circadian rhythms in persons with seasonal affective disorder and other chronobiological conditions. This article proposes that it similarly may repair circadian response in substance abusers, thereby normalizing brain reward systems. By doing so, it would enhance the efficacy of CM and NDSRA therapies and may also help prevent relapse. Given its low cost and ease of administration, phototherapy seems a promising avenue to pursue. PMID- 25514689 TI - The use of art and music therapy in substance abuse treatment programs. AB - Although the implementation of evidence-based practices in the treatment of substance use disorders has attracted substantial research attention, little consideration has been given to parallel implementation of complementary and alternative medical (CAM) practices. Using data from a nationally representative sample (N = 299) of U.S. substance abuse treatment programs, this study modeled organizational factors falling in the domains of patient characteristics, treatment ideologies, and structural characteristics, associated with the use of art therapy and music therapy. We found that 36.8% of treatment programs offered art therapy and 14.7% of programs offered music therapy. Programs with a greater proportion of women were more likely to use both therapies, and programs with larger proportions of adolescents were more likely to offer music therapy. In terms of other treatment ideologies, programs' use of Motivational Enhancement Therapy was positively related to offering art therapy, whereas use of contingency management was positively associated with offering music therapy. Finally, our findings showed a significant relationship between requiring 12-step meetings and the use of both art therapy and music therapy. With increasing use of CAM in a diverse range of medical settings and recent federal legislation likely to reduce barriers in accessing CAM, the inclusion of CAM in addiction treatment is growing in importance. Our findings suggest treatment programs may be utilizing art and music therapies to address unique patient needs of women and adolescents. PMID- 25514691 TI - The impact of a sleep hygiene intervention on residents of a private residential facility for individuals with co-occurring mental health and substance use disorders: results of a pilot study. AB - An increasing number of Americans are experiencing sleep problems. There is evidence of a complex, bidirectional relationship between sleep disorders, substance abuse, and mental health symptoms. Institutional settings have been shown to elicit sleep problems as well. This pilot study was conducted with 28 patients in private, residential, dual-diagnosis treatment for addiction and mental health disorders. Upon admission, consenting patients were administered the Addiction Severity Index to assess pretreatment substance use and mental health symptoms. Patients followed a normal course of treatment as well as participated in a nightly sleep hygiene group that included relaxation suggestions. Evaluations with the Addiction Severity Index were completed again 30 days after discharge from treatment. Significant improvements in some substance use patterns as well as mental health symptoms were noted. Although results cannot be directly attributed to the use of a sleep hygiene group, this pilot study lays the foundation for future investigations of interventions supporting sleep in the dual-diagnosis population. PMID- 25514692 TI - Pharmacology corner. Methadone. PMID- 25514693 TI - Interview with Julie Viveros, RN, Director of Nursing, Charlotte Rescue Mission, Rebound men's program. Interview by Joan Kub. AB - The Charlotte Rescue Mission is a 90-day residential program that serves approximately 530 men and 365 women experiencing the disease of addiction annually. It has a long rich history and has been serving the Charlotte community for over 75 years for men and almost 25 years for women. "The men's program provides a five-fold, client-centered treatment approach addressing spiritual, mental, physical, social, and vocational needs to battle addiction. The objective is to help individuals fighting addiction and homelessness to accomplish spiritual, mental, physical, social, and vocational goals and be free of addiction." "Dove's Nest, Charlotte Rescue Mission's women's recovery program, opened its doors in 1992. The program provides a structured, yet loving and stable living environment, with a dedicated staff aimed at helping women understand and deal with the core issues of addiction as a disease". (Web site: http:// charlotterescuemission.org/). I had the privilege of interviewing Julie Viveros, RN, the Director of Nursing for the Rebound men's program, about her unique role at the Rescue Mission. PMID- 25514697 TI - Mentoring: a personal perspective from academia and industry. PMID- 25514698 TI - Positive and Negative Affect During Sexual Activity: Differences Between Homosexual and Heterosexual Men and Women, With and Without Sexual Problems. AB - Empirical research suggests that emotional response during sexual activity discriminates between sexually functional and dysfunctional heterosexual men and women, with clinics presenting lower positive and higher negative affect. However, there is no evidence about the role of emotions in gay men and lesbian women with sexual problems. The present study analyzed affective states during sexual activity in homosexual and heterosexual men and women, with and without sexual problems. Participants in this study were 156 men and 168 women. A 2 (group) * 2 (sexual orientation) multivariate analysis of variance was performed. Participants completed a web-survey assessing sexual functioning and the Positive Affect-Negative Affect Scale. Findings indicated a main effect of group, with groups with sexual problems reporting significantly more negative and lower positive affect compared with men and women without sexual problems, regardless of sexual orientation. However, findings have also shown an interaction effect in the male sample with gay men, contrary to heterosexual men, reporting similar affective responses regardless of having a sexual dysfunction or not. Overall, findings emphasize the role of affective responses during sexual activity in men and women with sexual problems, suggesting the importance of addressing emotional responses in assessment and treatment of sexual problems in individuals with different sexual orientations. PMID- 25514696 TI - Syntheses and biological studies of marine terpenoids derived from inorganic cyanide. AB - Isocyanoterpenes (ICTs) are marine natural products biosynthesized through an unusual pathway that adorns terpene scaffolds with nitrogenous functionality derived from cyanide. The appendage of nitrogen functional groups - isonitriles in particular - onto stereochemically-rich carbocyclic ring systems provides enigmatic, bioactive molecules that have required innovative chemical syntheses. This review discusses the challenges inherent to the synthesis of this diverse family and details the development of the field. We also present recent progress in isolation and discuss key aspects of the remarkable biological activity of these compounds. PMID- 25514699 TI - Multimodality imaging of obliterative portal venopathy: what every radiologist should know. AB - Obliterative portal venopathy (OPV) is an important cause of non-cirrhotic portal hypertension, which is often erroneously misdiagnosed as cryptogenic cirrhosis. It has a worldwide distribution with majority of cases hailing from the Asian subcontinent. However, recently the disease has gained global attention particularly because of its association with human immunodeficiency virus infection and use of antiretroviral drug therapy (didanosine). As the name suggests, the disorder is characterized by sclerosis and obliteration of the intrahepatic portal vein branches (with attendant periportal fibrosis) leading to portal hypertension amid intriguingly little liver dysfunction. It primarily affects young adults who present with clinically significant portal hypertension in the form of episodes of variceal bleed; however, contrasting liver cirrhosis, the liver function and liver structure remain normal or near normal until late in the disease process. Radiological findings during advanced disease are often indistinguishable from cirrhosis often warranting a liver biopsy. Nevertheless, recent studies have suggested that certain imaging manifestations, if present, can help us to prospectively suggest the possibility of OPV. At imaging, OPV is characterized by a wide range of intrahepatic and/or extrahepatic portal venous abnormalities with attendant changes in liver and splenic volume and stiffness. We shall, through this pictorial review, appraise the literature and illustrate the germane radiological manifestations of OPV that can be seen using different imaging modalities including ultrasonography, CT, MRI, elastography and hepatic haemodynamic studies. PMID- 25514700 TI - Prospective evaluation of hypromellose 2% for punctal occlusion in patients with dry eye. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of punctal occlusion using hypromellose 2% in patients with dry eye. METHODS: In this prospective, randomized single-blinded clinical trial, we evaluated 76 eyes of 38 patients (36 women and 2 men) with dry eye secondary to rheumatic diseases. In each patient, the lower lacrimal punctum of 1 eye was occluded using hypromellose 2%, whereas the contralateral eye underwent a simulation of the procedure (control group). Patients' eyes were assessed for burning, itching, redness, foreign body sensation, and tearing based on a visual scale questionnaire (score, 0-10). We also performed objective tests for evaluation of dry eye using a Schirmer test with anesthesia (basal tear secretion test), the tear film break-up time test, and fluorescein and rose bengal staining tests at 0, 28, and 56 days after treatment. RESULTS: Fluorescein and rose bengal staining tests showed that there was a significant reduction in signs after occlusion using hypromellose. The symptoms measured by the visual scale were significantly reduced. The values of the Schirmer test with anesthesia and the break-up time test increased significantly. The effects persisted for up to 8 weeks. There were no dropouts or reported side effects during the 24-month follow-up. CONCLUSIONS: Our results suggest that punctal occlusion using hypromellose 2% is a low-cost and safe additional treatment for dry eye. PMID- 25514701 TI - Clinical outcomes and risk factors for graft failure after deep anterior lamellar keratoplasty and penetrating keratoplasty for macular corneal dystrophy. AB - PURPOSE: The aim of this study was to compare visual acuity, clinical outcomes, complications, and risk factors for graft failure after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PK) for macular corneal dystrophy. METHODS: Retrospective comparative case series. RESULTS: The PK group consisted of 109 eyes of 84 patients and the DALK group consisted of 21 eyes of 20 patients. The mean logarithm of the minimum angle of resolution best-corrected visual acuity at 3 and 12 months was 0.5 versus 0.5 (P = 0.285) and 0.4 versus 0.4 (P = 0.67) in the DALK and PK groups, respectively. There was no significant statistical difference in astigmatism and spherical equivalent between the 2 groups at 12 months. In the PK group, graft rejection that was the most common cause of graft failure was seen in 27 eyes (25%), of which 55% occurred within 1 year. In the DALK group, Descemet membrane microperforation occurred in 5 eyes (24%) intraoperatively, and early postoperative Descemet membrane detachment with double anterior chamber occurred in 9 eyes (43%). Kaplan-Meier estimate of graft survival in PK versus DALK groups were 93% versus 80% at 1 year and 78% versus 70% at 4 years, respectively. CONCLUSIONS: Visual and refractive outcomes are comparable between DALK and PK groups. DALK was superior to PK in its safety against postoperative complications such as endothelial rejection and secondary glaucoma. Graft failure in DALK was mostly associated with either intraoperative or early postoperative complications. DALK is a viable surgical option in cases with macular corneal dystrophy. PMID- 25514702 TI - Measurement of central corneal thickness with optical low-coherence reflectometry and ultrasound pachymetry in normal and post-femtosecond laser in situ keratomileusis eyes. AB - PURPOSE: To determine the repeatability and reproducibility of measurements of central corneal thickness (CCT) using optical low-coherence reflectometry (Lenstar LS900; Haag Streit) in normal eyes and post-femtosecond laser in situ keratomileusis (post-FS-LASIK) eyes and evaluate their agreement with ultrasound (US) pachymetry. METHODS: CCT was measured using Lenstar and US pachymetry sequentially in normal and post-FS-LASIK eyes by 2 experienced observers. Intraoperator repeatability and interoperator reproducibility were assessed by within-subject standard deviation, test-retest repeatability, coefficient of variation (CoV), and intraclass correlation coefficient. Paired t-tests and Bland Altman plots were used for analyzing agreement between the 2 devices. RESULTS: In this study, 55 healthy subjects and 50 post-FS-LASIK patients were recruited. Test-retest repeatability of Lenstar was within 10 MUm, CoV was less than 1.0%, and intraclass correlation coefficient was more than 0.9 in both normal and post FS-LASIK groups. Mean difference between these methods was 1.4 +/- 4.2 MUm and 1.7 +/- 5.4 MUm, respectively. Moreover, measurements of CCT showed narrow 95% limits of agreement (range, normal group: -6.8 and 9.6 MUm; post-FS-LASIK group: 12.4 and 8.9 MUm), which implied good agreement. CONCLUSIONS: Measurements of CCT using Lenstar showed excellent intraoperator repeatability and interoperator reproducibility both in normal eyes and post-FS-LASIK eyes. Measurements of CCT using Lenstar and US pachymetry showed good agreement and both can be used interchangeably. PMID- 25514703 TI - Stromal demarcation line induced by corneal cross-linking in eyes with keratoconus and nonkeratoconic asymmetric topography. AB - PURPOSE: To evaluate stromal demarcation lines following corneal cross-linking (CXL) using anterior segment optical coherence tomography in patients with keratoconus and nonkeratoconic asymmetric topography. METHODS: Fifth-nine eyes of 59 patients were enrolled in a retrospective comparative case series, of which 19 eyes had keratoconus and 40 eyes had asymmetric topography. Eyes with asymmetric topography were treated in preparation for photorefractive keratectomy. One month after CXL, a stromal demarcation line was evaluated at 5 standardized corneal points using anterior segment optical coherence tomography. RESULTS: Mean stromal demarcation line depths were measured at 5 points on the cornea, namely, centrally, 3.0 mm temporally, 1.5 mm temporally, 3.0 mm nasally, and 1.5 mm nasally. For the keratoconus group, the values were 178 +/- 47, 123 +/- 15, 152 +/- 47, 125 +/- 23, and 160 +/- 43 MUm, respectively. For the asymmetric corneal topography group (without keratoconus), they were 305 +/- 64, 235 +/- 57, 294 +/- 50, 214 +/- 54, and 285 +/- 58 MUm, respectively. There was no correlation between central corneal pachymetry and stromal demarcation line depth in all 5 measured corneal points in both groups. CONCLUSIONS: CXL treatment profiles are similar in keratoconic and nonkeratoconic eyes with asymmetric topography. PMID- 25514704 TI - Joseph E. Parrillo, MD, MCCM: Editor-in-Chief, 1997-2014: an appreciation. PMID- 25514705 TI - Male-predominant plasma transfusion strategy for preventing transfusion-related acute lung injury: a systematic review. AB - OBJECTIVES: To assess 1) the effectiveness of male-predominant plasma transfusion strategy for preventing transfusion-related acute lung injury and related mortality; and 2) whether this effect varies across different patient subgroups. DESIGN: Systematic Review and meta-analysis: Data were identified by querying MEDLINE and EMBASE (including proceedings of major conferences on blood transfusions), searching the Internet for hemovigilance reports, reviewing reference lists of eligible articles and contacting experts in the field. Eligible were all studies reporting transfusion-related acute lung injury incidence, all-cause mortality (primary outcomes), hospital length of stay, time to extubation, PaO2/FIO2-ratio or blood pressure changes (secondary outcomes) in recipients of plasma transfusions containing relatively more plasma from individuals at low risk of carrying leukocyte-antibodies ("male plasma") than those receiving comparator plasma ("control plasma"). No limits were placed on study design, population or language. The only exclusion criteria were non-human subjects and lack of control group. Prespecified study quality indicators (including risk of bias assessment) and potential effect modifiers were tested using Cochran's Q Test. Final analyses using random-effects models and I2 to assess heterogeneity were performed in the subset of studies judged to provide the best evidence and separately for significantly different subgroups using STATA 12.1 (StataCorp, College Station, TX). SETTING: As per primary studies. PATIENTS/SUBJECTS: As per primary studies. INTERVENTIONS: As per primary studies (generally: exposure to plasma containing relatively more male plasma than comparator plasma). MEASUREMENTS AND MAIN RESULTS: From a total of 850 retrieved records, we identified 45 eligible studies. For transfusion-related acute lung injury incidence, final analysis was restricted to 13 cohort studies and one randomized controlled trial in which transfusion-related acute lung injury cases only involved plasma transfusions. Risk of transfusion-related acute lung injury and mortality in plasma recipients exposed to men when compared with control plasma were 0.27 (95% CI, 0.20-0.38; p < 0.001; I = 0%; n = 14; 286 events) and 0.89 (95% CI, 0.80-1.00; p = 0.04; I = 79%; n = 7; 5, 710 events), respectively. No other significant interactions were found. Secondary outcomes showed similar results but were less reported and the studies were more heterogeneous. Sensitivity analyses did not alter the results. There was no evidence of publication bias. DISCUSSION: More than 800 million people in 17 countries are subject to male-predominant plasma transfusion policy and at least three more countries are planning or considering adoption of this strategy. On the basis of most observational data, judged to be of high quality, male-predominant plasma transfusion strategy reduces plasma-related transfusion-related acute lung injury incidence and possibly mortality. There was no evidence that the effect differs across patient subgroups, but power to detect such differences was low. PMID- 25514706 TI - The curious case of the missing sepsis patients. PMID- 25514707 TI - Ventilator-associated pneumonia and ventilator-associated conditions: apples are not oranges (mix only in a salade de fruits!). PMID- 25514708 TI - Alternative lipid emulsions as a new standard of care for total parenteral nutrition: finally available in the United States?. PMID- 25514709 TI - Risk factors for delirium: are systematic reviews enough?. PMID- 25514710 TI - Microcirculation in the ICU: a small step for monitoring, a giant leap for tissue viability. PMID- 25514711 TI - Sadly, pyridoxalated hemoglobin polyoxyethylene is more a dodo than a PHOENIX. PMID- 25514712 TI - Elucidating the known unknowns of sepsis. PMID- 25514713 TI - Mitigating maternal mortality in the developed world. PMID- 25514714 TI - The true obesity paradox: obese and malnourished?. PMID- 25514715 TI - Finding a needle in the haystack: leveraging bioinformatics to identify a functional genetic risk factor for sepsis death. PMID- 25514716 TI - A step-up approach to managing acute pancreatitis-associated fluid collections. PMID- 25514717 TI - Extracorporeal Co2 removal for chronic obstructive pulmonary disease: too risky or ready for a trial?. PMID- 25514718 TI - Is it time to reprioritize our research focus in critical care medicine? A call for more collaboration between cardiologists and intensive care specialists. PMID- 25514719 TI - When perception may not meet reality: sleep and delirium in the ICU. PMID- 25514720 TI - Neuroprotective properties of xenon in traumatic brain injury. PMID- 25514721 TI - Strength by sheer numbers: electroencephalogram gathers momentum as a positive predictor. PMID- 25514722 TI - Intracranial pressure after aneurysmal subarachnoid hemorrhage: time to revisit. PMID- 25514723 TI - Simulation: why not, when it feels so good?. PMID- 25514724 TI - Pharmacologic approach for delirium after cardiac surgery: there is no magic bullet. PMID- 25514725 TI - Tourniqueting the limbs, the new chest compression in cardiopulmonary resuscitation. PMID- 25514727 TI - Hemodynamic deterioration during extracorporeal membrane oxygenation weaning in a patient with a total artificial heart. AB - OBJECTIVES: The Total Artificial Heart (Syncardia, Tucson, AZ) is approved for use as a bridge-to-transplant or destination therapy in patients who have irreversible end-stage biventricular heart failure. We present a unique case, in which the inferior vena cava compression by a total artificial heart was initially masked for days by the concurrent placement of an extracorporeal membrane oxygenation cannula. PATIENT: This is the case of a 33-year-old man admitted to our institution with recurrent episodes of ventricular tachycardia requiring emergent total artificial heart and venovenous extracorporeal membrane oxygenation placement. CONCLUSION: This interesting scenario highlights the importance for critical care physicians to have an understanding of exact anatomical localization of a total artificial heart, extracorporeal membrane oxygenation, and their potential interactions. In total artificial heart patients with hemodynamic compromise or reduced device filling, consideration should always be given to venous inflow compression, particularly in those with smaller body surface area. Transesophageal echocardiogram is a readily available diagnostic tool that must be considered standard of care, not only in the operating room but also in the ICU, when dealing with this complex subpopulation of cardiac patients. PMID- 25514728 TI - Corticosteroids and transition to delirium in acute lung injury: multinomial logistic regression analysis accounting for multiple States. PMID- 25514729 TI - The authors reply. PMID- 25514730 TI - Why did poisoned patients eventually die long after their ICU stay? PMID- 25514731 TI - The authors reply. PMID- 25514732 TI - Balancing between benefit and harm-what is the best solution in fluid resuscitation? PMID- 25514733 TI - The authors reply. PMID- 25514734 TI - Cerebral perfusion pressure versus intracranial pressure-driven therapy on outcomes. PMID- 25514735 TI - The authors reply. PMID- 25514736 TI - Effect of prior weight loss on mortality in the critically ill obese. PMID- 25514737 TI - The authors reply. PMID- 25514738 TI - Angiogenic factors as promising therapeutic targets in sepsis: where are we now? PMID- 25514739 TI - The authors reply. PMID- 25514740 TI - Short- and long-term neurologic outcome of elderly patients with out-of-hospital cardiac arrest. PMID- 25514741 TI - The authors reply. PMID- 25514742 TI - Inconsistent reporting of findings. PMID- 25514743 TI - Can soluble CD73 predict the persistent organ failure in patients with acute pancreatitis? PMID- 25514744 TI - Hepcidin as a target of therapy in the treatment of anemia after trauma. PMID- 25514745 TI - The author replies. PMID- 25514746 TI - Advanced glycation endproducts increase proliferation, migration and invasion of the breast cancer cell line MDA-MB-231. AB - Diabetic patients have increased likelihood of developing breast cancer. Advanced glycation endproducts (AGEs) underlie the pathogenesis of diabetic complications but their impact on breast cancer cells is not understood. This study aims to determine the effects of methylglyoxal-derived bovine serum albumin AGEs (MG-BSA AGEs) on the invasive MDA-MB-231 breast cancer cell line. By performing cell counting, using wound-healing assay, invasion assay and zymography analysis, we found that MG-BSA-AGEs increased MDA-MB-231 cell proliferation, migration and invasion through MatrigelTM associated with an enhancement of matrix metalloproteinase (MMP)-9 activities, in a dose-dependent manner. Using Western blot and flow cytometry analyses, we demonstrated that MG-BSA-AGEs increased expression of the receptor for AGEs (RAGE) and phosphorylation of key signaling protein extracellular signal-regulated kinase (ERK)-1/2. Furthermore, in MG-BSA AGE-treated cells, phospho-protein micro-array analysis revealed enhancement of phosphorylation of the ribosomal protein 70 serine S6 kinase beta 1 (p70S6K1), which is known to be involved in protein synthesis, the signal transducer and activator of transcription (STAT)-3 and the mitogen-activated protein kinase (MAPK) p38, which are involved in cell survival. Blockade of MG-BSA-AGE/RAGE interactions using a neutralizing anti-RAGE antibody inhibited MG-BSA-AGE-induced MDA-MB-231 cell processes, including the activation of signaling pathways. Throughout the study, non-modified BSA had a negligible effect. In conclusion, AGEs might contribute to breast cancer development and progression partially through the regulation of MMP-9 activity and RAGE signal activation. The up regulation of RAGE and the concomitant increased phosphorylation of p70S6K1 induced by AGEs may represent promising targets for drug therapy to treat diabetic patients with breast cancer. PMID- 25514748 TI - Scientific evaluation of spinal implants: an ethical necessity. AB - The clinical introduction of novel medical devices often occurs without evidence of good methodological quality and with relatively little oversight and regulation. As a consequence, the safety, efficacy, and long-term effects of devices are frequently insufficiently known upon device approval. Recent controversies surrounding the Poly Implant Prothese (PIP) breast implants, metal on-metal hip implants, and interspinous implants underscore the need to reconsider how innovation in medical devices can adhere to sound ethical standards without inhibiting surgical research and development. In this article, the introduction of spinal implants is taken as an example to firstly discuss the scientific and ethical challenges of developing, testing, and introducing novel medical devices and to secondly identify avenues for improving the existing regulatory frameworks for such innovation. Two measures for improvement are most feasible in the short term: demanding prospective studies before device introduction and developing registries to monitor and evaluate new medical devices. Level of evidence: 5. PMID- 25514747 TI - Time course study of blood pressure in term and preterm infants immediately after birth. AB - OBJECTIVE: To describe temporal changes in systolic, diastolic, and mean blood pressure (SBP, DBP, and MBP, respectively) in term and preterm infants immediately after birth. METHODS: Prospective observational two-center study. In term infants SBP, DBP, and MBP were assessed non-invasively every minute for the first 15 minutes, and in preterm infants every minute for the first 15 minutes, as well as at 20, 25, 30, 45, and 60 minutes after birth. Regression analyses were performed by gender and respiratory support in all neonates; and by mode of delivery, cord clamping time, and development of ultrasound-detected brain injury in preterm neonates. RESULTS: Term infants (n = 54) had a mean (SD) birth weight of 3298 (442) g and gestational age of 38 (1) weeks, and preterm infants (n = 94) weighed 1340 (672) g and were 30 (3) weeks gestation. Term infants' SBP, DBP and MBP within the first 15 minutes after birth were independent of gender or respiratory support. Linear mixed regression analysis showed that preterm infants, who were female, born vaginally, had delayed cord clamping and did not require positive pressure ventilation nor develop periventricular injury or ventriculomegaly, had significantly higher SBP, DBP, and MBP at some measurement points within the first hour after birth. CONCLUSIONS: We present novel reference ranges of BP immediately after birth in a cohort of term and preterm neonates. They may aid in optimization of cardiovascular support during early transition at all gestations. PMID- 25514749 TI - Novel expression vectors enabling induction of gene expression by small interfering RNAs and microRNAs. AB - Small-interfering RNAs and microRNAs are small ~21-22 nucleotide long RNAs capable of posttranscriptional suppression of gene expression. The synthetic siRNAs are especially designed to target pre-specified genes and are common molecular biology tools. The miRNAs are endogenous regulators of gene expression found in a wide variety of eukaryotes. miRNAs are currently utilized for diagnostics applications. Therapeutically, various miRNA-antagonizing tools are being explored and miRNAs are also utilized for cell-specific inhibition of the expression of gene therapy vectors harboring target sites for specific miRNAs. Here we show, for the first time, that siRNAs and miRNAs can be harnessed to induce gene expression. We designed special expression vectors in which target sites for artificial siRNAs or endogenous miRNAs are located between the transgene and an Upstream Inhibitory Region (UIR). We hypothesized that cleavage of the mRNA by siRNAs or miRNAs will separate the transgene from the UIR and the resulting uncapped mRNA will be capable of being translated. A UIR composed of seven open reading frames was found to be the most efficient inhibitor of the translation of the downstream transgene. We show that under such a configuration both artificial siRNAs and endogenous miRNAs were capable of inducing transgene expression. We show that using the diphtheria toxin A-chain gene, in combination with target sites for highly expressed miRNAs, specific induction of cell-death can be achieved, setting the stage for application to cancer therapy. PMID- 25514750 TI - Systemic inflammatory response and calcification markers in patients with long lasting moderate-severe chronic spontaneous urticaria. AB - BACKGROUND: Low grade inflammation is associated with both chronic spontaneous urticaria (CSU) and atherosclerosis. Data regarding an association between urticarial inflammation and atherosclerosis and subsequent cardiovascular events are scarce. It has been demonstrated that matrix GLA protein (MGP), a biomarker of arterial calcification, is increased in patients with atherosclerosis. OBJECTIVES: To evaluate circulating levels of markers of arterial calcification and acute phase response (APR) in patients with CSU. METHODS: Concentrations of MGP and IL-6 were measured in venous blood samples of patients with long-lasting moderate-severe CSU. RESULTS: There were no significant differences in serum MGP concentration between healthy subjects and CU patients. Serum IL-6 concentration was significantly higher in CSU patients as compared with healthy subjects. CONCLUSIONS: The results confirm that CSU is accompanied by a low grade systemic inflammatory state. However, the long lasting urticarial inflammation was not paralleled by an increased circulating level of the calcification marker matrix Gla protein. PMID- 25514752 TI - Identification of tetrahydrocarbazoles as novel multifactorial drug candidates for treatment of Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most frequent cause of dementia. To date, there are only a few approved drugs for AD, which show little or no effect on disease progression. Impaired intracellular calcium homeostasis is believed to occur early in the cascade of events leading to AD. Here, we examined the possibility of normalizing the disrupted calcium homeostasis in the endoplasmic reticulum (ER) store as an innovative approach for AD drug discovery. High-throughput screening of a small molecule compound library led to the identification of tetrahydrocarbazoles, a novel multifactorial class of compounds that can normalize the impaired ER calcium homeostasis. We found that the tetrahydrocarbazole lead structure, first, dampens the enhanced calcium release from ER in HEK293 cells expressing familial Alzheimer's disease (FAD)-linked presenilin 1 mutations. Second, the lead structure also improves mitochondrial function, measured by increased mitochondrial membrane potential. Third, the same lead structure also attenuates the production of amyloid-beta (Abeta) peptides by decreasing the cleavage of amyloid precursor protein (APP) by beta-secretase, without notably affecting alpha- and gamma-secretase cleavage activities. Considering the beneficial effects of tetrahydrocarbazoles addressing three key pathological aspects of AD, these compounds hold promise for the development of potentially effective AD drug candidates. PMID- 25514754 TI - Assessment of human health risk associated with pyaemia in Danish finisher pigs when conducting visual-only inspection of the lungs. AB - The most important lesion to be overlooked when performing visual-only inspection of the lungs is embolic pneumonia. The aim of the present study was to assess the additional human health risk represented by overlooking cases of pyaemia represented by embolic pneumonia in finisher pigs, when conducting visual-only compared to palpation of the lungs, as is the traditional meat inspection procedure. An examination of bacteria isolated from 19 finisher pigs identified with embolic pneumonia at traditional meat inspection was undertaken. From each pig samples were taken from various organs (lungs, spleen, heart, liver and kidney), from the carpal joints (A. carpi) and flexor muscle (M. flexor digitorum superficialis) on the right foreleg. These data were included in a risk assessment following OIE guidelines. Bacteria were isolated from 78 out of 127 tissue and swap samples taken (61% positive samples). Staphylococcus aureus (N=37) was the most frequently isolated bacterium. The predominant site of S. aureus was the lung. S. aureus was detected although less frequently in low numbers in some organs (<100CFU/sample) and muscle samples (<10CFU/sample). Only one MRSA isolate was found. Staphylococcus warneri (N=24) was the second most commonly found bacterium. There was no predominant site and the number of S. warneri was less than 50CFU per sample. The risk of a food-borne intoxication from S. aureus in relation to pyaemia in pigs was considered very low due to the low quantitative numbers of S. aureus in muscle tissue samples. Implementing visual-only inspection will reduce the exposure of S. aureus due to less cross contamination and handling of the plucks by the meat inspectors. The human health risk associated with S. warneri was considered very low, due to the limited zoonotic potential of this bacterium. In conclusion, the additional human health risk in relation to possibly overlooking pyaemia in Danish finisher pigs was considered negligible when conducting visual-only compared to traditional meat inspection. PMID- 25514753 TI - The functional -1019C/G HTR1A polymorphism and mechanisms of fear. AB - Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12 sessions of manualized cognitive-behavioural therapy (CBT) and were genotyped for HTR1A rs6295. In four subsamples of this multicentre trial, exposure behaviour (n=185), defensive reactivity measured using a behavioural avoidance test (BAT; before CBT: n=245; after CBT: n=171) and functional magnetic resonance imaging (fMRI) data during fear conditioning were acquired before and after CBT (n=39). HTR1A risk genotype (GG) carriers more often escaped during the BAT before treatment. Exploratory fMRI results suggest increased activation of the amygdala in response to threat as well as safety cues before and after treatment in GG carriers. Furthermore, GG carriers demonstrated reduced effects of CBT on differential conditioning in regions including the bilateral insulae and the anterior cingulate cortex. Finally, risk genotype carriers demonstrated reduced self-initiated exposure behaviour to aversive situations. This study demonstrates the effect of HTR1A variation on defensive behaviour, amygdala activity, CBT induced neural plasticity and normalization of defence behaviour in PD/AG. Our results, therefore, translate evidence from animal studies to humans and suggest a central role for HTR1A in differentiating subgroups of patients with anxiety disorders. PMID- 25514755 TI - Metabolic depression in cunner (Tautogolabrus adspersus) is influenced by ontogeny, and enhances thermal tolerance. AB - To examine the effect of ontogeny on metabolic depression in the cunner (Tautogolabrus adspersus), and to understand how ontogeny and the ability to metabolically depress influence this species' upper thermal tolerance: 1) the metabolic rate of 9 degrees C-acclimated cunner of three size classes [0.2-0.5 g, young of the year (YOY); 3-6 g, small; and 80-120 g, large (adult)] was measured during a 2 degrees C per day decrease in temperature; and 2) the metabolic response of the same three size classes of cunner to an acute thermal challenge [2 degrees C h(-1) from 10 degrees C until Critical Thermal Maximum, CTMax] was examined, and compared to that of the Atlantic cod (Gadus morhua). The onset temperature for metabolic depression in cunner increased with body size, i.e. from 5 degrees C in YOY cunner to 7 degrees C in adults. In contrast, the extent of metabolic depression was ~80% (Q10 = ~15) for YOY fish, ~65% (Q10 = ~8) for small fish and ~55% (Q10 = ~5) for adults, and this resulted in the metabolic scaling exponent (b) gradually increasing from 0.84 to 0.92 between 9 degrees C to 1 degrees C. All size classes of cunner had significantly (approximately 60%) lower routine metabolic rates at 10 degrees C than Atlantic cod. However, there was no species' difference in the temperature-induced maximum metabolic rate, and this resulted in factorial metabolic scope values that were more than two-fold greater for cunner, and CTMax values that were 6-9 degrees C higher (~21 vs. 28 degrees C). These results: 1) show that ontogeny influences the temperature of initiation and the extent of metabolic depression in cunner, but not O2 consumption when in a hypometabolic state; and 2) suggest that the evolution of cold-induced metabolic depression in this northern wrasse species has not resulted in a trade-off with upper thermal tolerance, but instead, an enhancement of this species' metabolic plasticity. PMID- 25514751 TI - Inflammation and lithium: clues to mechanisms contributing to suicide-linked traits. AB - Suicide is one of the leading causes of death in the United States, yet it remains difficult to understand the mechanistic provocations and to intervene therapeutically. Stress is recognized as a frequent precursor to suicide. Psychological stress is well established to cause activation of the inflammatory response, including causing neuroinflammation, an increase of inflammatory molecules in the central nervous system (CNS). Neuroinflammation is increasingly recognized as affecting many aspects of CNS functions and behaviors. In particular, much evidence demonstrates that inflammatory markers are elevated in traits that have been linked to suicidal behavior, including aggression, impulsivity and depression. Lithium is recognized as significantly reducing suicidal behavior, is anti-inflammatory and diminishes aggression, impulsivity and depression traits, each of which is associated with elevated inflammation. The anti-inflammatory effects of lithium result from its inhibition of glycogen synthase kinase-3 (GSK3). GSK3 has been demonstrated to strongly promote inflammation, aggressive behavior in rodents and depression-like behaviors in rodents, whereas regulation of impulsivity by GSK3 has not yet been investigated. Altogether, evidence is building supporting the hypothesis that stress activates GSK3, which in turn promotes inflammation, and that inflammation is linked to behaviors associated with suicide, including particularly aggression, impulsivity and depression. Further investigation of these links may provide a clearer understanding of the causes of suicidal behavior and provide leads for the development of effective preventative interventions, which may include inhibitors of GSK3. PMID- 25514758 TI - Identifying Continuous Quality Improvement Priorities in Maternal, Infant, and Early Childhood Home Visiting. AB - OBJECTIVE: The purpose of this article was to describe a methodology to identify continuous quality improvement (CQI) priorities for one state's Maternal, Infant, and Early Childhood Home Visiting program from among the 40 required constructs associated with 6 program benchmarks. The authors discuss how the methodology provided consensus on system CQI quality measure priorities and describe variation among the 3 service delivery models used within the state. DESIGN: Q sort methodology was used by home visiting (HV) service delivery providers (home visitors) to prioritize HV quality measures for the overall state HV system as well as their service delivery model. RESULTS: There was general consensus overall and among the service delivery models on CQI quality measure priorities, although some variation was observed. Measures associated with Maternal, Infant, and Early Childhood Home Visiting benchmark 1, Improved Maternal and Newborn Health, and benchmark 3, Improvement in School Readiness and Achievement, were the highest ranked. CONCLUSIONS: The Q-sort exercise allowed home visitors an opportunity to examine priorities within their service delivery model as well as for the overall First Teacher HV system. Participants engaged in meaningful discussions regarding how and why they selected specific quality measures and developed a greater awareness and understanding of a systems approach to HV within the state. The Q-sort methodology presented in this article can easily be replicated by other states to identify CQI priorities at the local and state levels and can be used effectively in states that use a single HV service delivery model or those that implement multiple evidence-based models for HV service delivery. PMID- 25514757 TI - Lessons Learned From Transitioning PEPFAR Track 1.0 Care and Treatment Programs: Case Studies in Financial Management Capacity Building in Zambia and Botswana. AB - In 2008, the United States government mandated transition of internationally managed HIV care and treatment programs to local country ownership. Three case studies illustrate the US Health Resources Services Administration's fiscal assessment and technical assistance (TA) processes to strengthen local organizations' capabilities to absorb and manage United States government funding. Review of initial, TA and follow-up reports reveal that the 1 Botswanan and 2 Zambian organizations closed 10 of 17 financial capacity gaps, with Health Resources Services Administration assisting on 2. Zambian organizations requested and absorbed targeted TA on the basis of the consultant's desk review, their finance staff revised fiscal policies and procedures, and accordingly trained other staff. In Botswana, delays in integrating recommendations necessitated on site TA for knowledge building and role modeling. Organizational maturity may explain differences in responsiveness, ownership, and required TA approaches. Clarifying expectations of capacity building, funding agreement, and nonmonetary donor involvement can help new organizations determine and act on intervening actions. PMID- 25514756 TI - A new companion of elongating RNA Polymerase II: TINTIN, an independent sub module of NuA4/TIP60 for nucleosome transactions. AB - Multiple factors are involved in the elongation stage of transcription regulation to ensure the passing of RNA polymerases while preserving appropriate nucleosome structure thereafter. The recently reported trimeric sub-module of NuA4 histone acetyltransferase complex involved in this process provides more insight into the sophisticated modulation of transcription elongation. PMID- 25514759 TI - Antibiotic suppression of intestinal microbiota reduces heme-induced lipoperoxidation associated with colon carcinogenesis in rats. AB - Epidemiological studies show that heme iron from red meat is associated with increased colorectal cancer risk. In carcinogen-induced-rats, a heme iron-rich diet increases the number of precancerous lesions and raises associated fecal biomarkers. Heme-induced lipoperoxidation measured by fecal thiobarbituric acid reagents (TBARs) could explain the promotion of colon carcinogenesis by heme. Using a factorial design we studied if microbiota could be involved in heme induced carcinogenesis, by modulating peroxidation. Rats treated or not with an antibiotic cocktail were given a control or a hemoglobin-diet. Fecal bacteria were counted on agar and TBARs concentration assayed in fecal water. The suppression of microbiota by antibiotics was associated with a reduction of crypt height and proliferation and with a cecum enlargement, which are characteristics of germ-free rats. Rats given hemoglobin diets had increased fecal TBARs, which were suppressed by the antibiotic treatment. A duplicate experiment in rats given dietary hemin yielded similar results. These data show that the intestinal microbiota is involved in enhancement of lipoperoxidation by heme iron. We thus suggest that microbiota could play a role in the heme-induced promotion of colorectal carcinogenesis. PMID- 25514760 TI - Registration of in-vivo to ex-vivo MRI of surgically resected specimens: a pipeline for histology to in-vivo registration. AB - BACKGROUND: Advances in MRI have the potential to improve surgical treatment of epilepsy through improved identification and delineation of lesions. However, validation is currently needed to investigate histopathological correlates of these new imaging techniques. The purpose of this work is to develop and evaluate a protocol for deformable image registration of in-vivo to ex-vivo resected brain specimen MRI. This protocol, in conjunction with our previous work on ex-vivo to histology registration, completes a registration pipeline for histology to in vivo MRI, enabling voxel-based validation of novel and existing MRI techniques with histopathology. NEW METHOD: A combination of image-based and landmark-based 3D registration was used to register in-vivo MRI and the ex-vivo MRI from patients (N=10) undergoing epilepsy surgery. Target registration error (TRE) was used to assess accuracy and the added benefit of deformable registration. RESULTS: A mean TRE of 1.35+/-0.11 and 1.41+/-0.33mm was found for neocortical and hippocampal specimens respectively. Statistical analysis confirmed that the deformable registration significantly improved the registration accuracy for both specimens. COMPARISON WITH EXISTING METHODS: Image registration of surgically resected brain specimens is a unique application which presents numerous technical challenges and that have not been fully addressed in previous literature. Our computed TRE are comparable to previous attempts tackling similar applications, as registering in-vivo MRI to whole brain or serial histology. CONCLUSION: The presented registration pipeline finds dense and accurate spatial correspondence between in-vivo MRI and histology and allows for the spatially local and quantitative assessment of pathological correlates in MRI. PMID- 25514761 TI - Clinical characteristics and outcomes of patients with stage I epithelial ovarian cancer compared with fallopian tube cancer. AB - OBJECTIVE: The purpose of this study was to compare clinical characteristics and survival between patients with stage I epithelial ovarian cancer and fallopian tube cancer. STUDY DESIGN: We identified women with stage I epithelial ovarian cancer and fallopian tube cancer who underwent treatment from 2000-2010. Correlation between categoric variables was assessed with chi2 test. The Kaplan Meier survival analysis was used to generate overall survival data. Factors predictive of outcome were compared with the use of the log-rank test and Cox proportional hazards model. RESULTS: The study group consisted of 385 women with epithelial ovarian cancer and 43 women with fallopian tube cancer. Patients with fallopian tube cancer had a higher rate of stage IA disease (65% vs 48%; P=.02) and grade 3 tumors (60.4% vs 30.9%; P<.001). Patients with fallopian tube cancer had a significantly higher rate of breast cancer (25.6% vs 5.7%; P<.001) and BRCA 1 mutations (45.8% vs 9.1%; P<.001). There was no difference in the rates of platinum-based and paclitaxel chemotherapy between the groups. Women with fallopian tube cancer were more likely to have received >=6 cycles of chemotherapy (58.1% vs 44.1%; P=.02). The 5-year disease-free survival rates were 100% in women with fallopian tube cancer and 93% in patients with epithelial ovarian cancer (P=.04). The 5-year overall survival rates were 100% and 95% for fallopian tube cancer and epithelial ovarian cancer, respectively (P=.7). CONCLUSION: We found a higher rate of stage IA, grade 3, and serous carcinoma in fallopian tube cancer. Women with fallopian tube cancer had a higher rate of breast cancer. There was no difference in overall survival between the groups. PMID- 25514763 TI - Spatial and seasonal variations of PM2.5 mass and species during 2010 in Xi'an, China. AB - PM2.5 mass and selected chemical species are measured in 24-h integrated PM2.5 samples collected simultaneously at the urban and rural regions of Xi'an (six sites in total), China in the four seasons of 2010. The analytes include organic carbon and elemental carbon (OC+EC = total carbon, TC), seven water-soluble inorganic ions (NH4(+), K(+), Mg(2+), Ca(2+), Cl(-), SO4(2-), NO3(-)) and six trace elements (Ti, Mn, Fe, Zn, As, Pb). The average PM2.5 mass for the entire measurement period is 142.6 +/- 102.7 MUg m(-3), which is more than four times that of the Chinese national ambient air quality standard. Spatial variations in PM2.5 mass are not pronounced. The PM2.5 mass and those species measured show a similar seasonal pattern in all six measurement sites, i.e., in the order of winter > autumn > spring > summer. The dominant PM2.5 composition is OC in winter, soil dust in spring, and sulfate, nitrate, and ammonium in summer and autumn. Seasonal variations of TC/PM2.5 and OC/EC ratios follow the PM2.5 changes. Seasonal distributions of (SO4(2-)+NO3(-)+NH4(+))/PM2.5 showed increase in autumn and decrease in winter, while NO3(-)/SO4(2-) ratios increased in autumn and decreased in summer. Eight main PM2.5 sources are identified based on the positive matrix factorization (PMF) analysis and emissions from fossil fuel combustion (traffic and coal burning) are founded to be the main source responsible for the fine particle pollution in Xi'an. In addition, a decreasing trend in OC/PM2.5 is observed in comparison with previous studies in Xi'an. PMID- 25514762 TI - Depressive symptoms and risk of uterine leiomyomata. AB - OBJECTIVE: Uterine leiomyomata (UL) are a major source of gynecologic morbidity and the primary indication for hysterectomy. Depression can cause dysregulation of the hypothalamic-pituitary-adrenal axis, which may affect the synthesis of reproductive hormones involved in UL pathogenesis. We assessed the association between depressive symptoms and UL among 15,963 premenopausal women. STUDY DESIGN: Data were derived from the Black Women's Health Study, a prospective cohort study. In 1999 and 2005, the Center for Epidemiologic Studies Depression Scale (CES-D) was used to ascertain depressive symptoms. On biennial follow-up questionnaires from 1999 through 2011, women reported physician-diagnosed depression, antidepressant use, and UL diagnoses. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression. RESULTS: There were 4722 incident UL cases diagnosed by ultrasound (n=3793) or surgery (n=929) during 131,262 person-years of follow-up. Relative to baseline CES-D scores<16, IRRs were 1.05 (95% CI, 0.98-1.13) for CES-D scores 16 24 and 1.16 (95% CI, 1.06-1.27) for CES-D scores>=25 (P-trend=.001). IRRs for current and past physician-diagnosed depression relative to no depression were 1.15 (95% CI, 0.98-1.34) and 1.25 (95% CI, 1.13-1.39), respectively. Results persisted after further control for antidepressant use. IRRs for current and past use of antidepressants (any indication) relative to never use were 1.11 (95% CI, 0.97-1.28) and 1.32 (95% CI, 1.14-1.52), respectively. CONCLUSION: In this cohort of black women, greater depressive symptoms were associated with UL, independent of antidepressant use, supporting the hypothesis that dysregulation of the hypothalamic-pituitary-adrenal axis increases UL risk. PMID- 25514764 TI - River chloride trends in snow-affected urban watersheds: increasing concentrations outpace urban growth rate and are common among all seasons. AB - Chloride concentrations in northern U.S. included in this study have increased substantially over time with average concentrations approximately doubling from 1990 to 2011, outpacing the rate of urbanization in the northern U.S. Historical data were examined for 30 monitoring sites on 19 streams that had chloride concentration and flow records of 18 to 49 years. Chloride concentrations in most studied streams increased in all seasons (13 of 19 in all seasons; 16 of 19 during winter); maximum concentrations occurred during winter. Increasing concentrations during non-deicing periods suggest that chloride was stored in hydrologic reservoirs, such as the shallow groundwater system, during the winter and slowly released in baseflow throughout the year. Streamflow dependency was also observed with chloride concentrations increasing as streamflow decreased, a result of dilution during rainfall- and snowmelt-induced high-flow periods. The influence of chloride on aquatic life increased with time; 29% of sites studied exceeded the concentration for the USEPA chronic water quality criteria of 230 mg/L by an average of more than 100 individual days per year during 2006-2011. The rapid rate of chloride concentration increase in these streams is likely due to a combination of possible increased road salt application rates, increased baseline concentrations, and greater snowfall in the Midwestern U.S. during the latter portion of the study period. PMID- 25514765 TI - The mechanics of ribosomal translocation. AB - The ribosome translates the sequence of codons of an mRNA into the corresponding sequence of amino acids as it moves along the mRNA with a codon-step width of about 10 A. The movement of the million-dalton complex ribosome is triggered by the universal elongation factor G (EF2 in archaea and eukaryotes) and is termed translocation. Unraveling the molecular details of translocation is one of the most challenging tasks of current ribosome research. In the last two years, enormous progress has been obtained by highly-resolved X-ray and cryo-electron microscopic structures as well as by sophisticated biochemical approaches concerning the trigger and control of the movement of the tRNA2.mRNA complex inside the ribosome during translocation. This review inspects and surveys these achievements. PMID- 25514768 TI - [In Process Citation]. PMID- 25514769 TI - [In Process Citation]. PMID- 25514770 TI - [In Process Citation]. PMID- 25514767 TI - PI3K signalling in inflammation. AB - PI3Ks regulate several key events in the inflammatory response to damage and infection. There are four Class I PI3K isoforms (PI3Kalpha,beta,gamma,delta), three Class II PI3K isoforms (PI3KC2alpha, C2beta, C2gamma) and a single Class III PI3K. The four Class I isoforms synthesise the phospholipid 'PIP3'. PIP3 is a 'second messenger' used by many different cell surface receptors to control cell movement, growth, survival and differentiation. These four isoforms have overlapping functions but each is adapted to receive efficient stimulation by particular receptor sub-types. PI3Kgamma is highly expressed in leukocytes and plays a particularly important role in chemokine-mediated recruitment and activation of innate immune cells at sites of inflammation. PI3Kdelta is also highly expressed in leukocytes and plays a key role in antigen receptor and cytokine-mediated B and T cell development, differentiation and function. Class III PI3K synthesises the phospholipid PI3P, which regulates endosome-lysosome trafficking and the induction of autophagy, pathways involved in pathogen killing, antigen processing and immune cell survival. Much less is known about the function of Class II PI3Ks, but emerging evidence indicates they can synthesise PI3P and PI34P2 and are involved in the regulation of endocytosis. The creation of genetically-modified mice with altered PI3K signalling, together with the development of isoform-selective, small-molecule PI3K inhibitors, has allowed the evaluation of the individual roles of Class I PI3K isoforms in several mouse models of chronic inflammation. Selective inhibition of PI3Kdelta, gamma or beta has each been shown to reduce the severity of inflammation in one or more models of autoimmune disease, respiratory disease or allergic inflammation, with dual gamma/delta or beta/delta inhibition generally proving more effective. The inhibition of Class I PI3Ks may therefore offer a therapeutic opportunity to treat non-resolving inflammatory pathologies in humans. This article is part of a Special Issue entitled Phosphoinositides. PMID- 25514771 TI - [In Process Citation]. PMID- 25514766 TI - Detection and manipulation of phosphoinositides. AB - Phosphoinositides (PIs) are minor components of cell membranes, but play key roles in cell function. Recent refinements in techniques for their detection, together with imaging methods to study their distribution and changes, have greatly facilitated the study of these lipids. Such methods have been complemented by the parallel development of techniques for the acute manipulation of their levels, which in turn allow bypassing the long-term adaptive changes implicit in genetic perturbations. Collectively, these advancements have helped elucidate the role of PIs in physiology and the impact of the dysfunction of their metabolism in disease. Combining methods for detection and manipulation enables the identification of specific roles played by each of the PIs and may eventually lead to the complete deconstruction of the PI signaling network. Here, we review current techniques used for the study and manipulation of cellular PIs and also discuss advantages and disadvantages associated with the various methods. This article is part of a Special Issue entitled Phosphoinositides. PMID- 25514772 TI - [In Process Citation]. PMID- 25514773 TI - [In Process Citation]. PMID- 25514774 TI - [In Process Citation]. PMID- 25514775 TI - [In Process Citation]. PMID- 25514776 TI - [In Process Citation]. PMID- 25514777 TI - [In Process Citation]. PMID- 25514778 TI - [National second opinion network for testicular cancer patients - transferring guidelines into practice!]. AB - The second opinion network for testicular cancer is an internet-based platform addressed to physicians treating testicular cancer patients. They are offered a second opinion before determining further therapy after orchiectomy and completion of staging procedures. The platform has been used in more than 3,000 cases of testicular cancer to date. The rate of discrepancies between first and second opinions is higher than 30%. This suggests a deficit in the implementation of published therapy guidelines. According to our present interim analysis, the second opinion platform helps in avoiding overtreatment of testicular cancer. The high acceptance of the project and the encouraging results of this interim analysis open the door for expansion of the second opinion model to other diseases, e. g., penile carcinoma. PMID- 25514779 TI - [Robot-assisted radical prostatectomy - review of the literature concerning oncological and functional outcome of patients]. AB - In 2000, the first robot-assisted radical prostatectomy (RARP) worldwide for treatment of prostate cancer (PCa) was performed in Frankfurt/Main (Germany). Since then, this surgical method has broadly dispersed. In the US, RARP currently already represents the most frequently applied surgical technique for treatment of localized PCa, although until now the potential benefits of RARP in comparison to alternative surgical procedures have still not been evaluated in prospective randomized trials. Against the background that also in Germany a continuously and fast growing number of patients are treated by RARP, the present article provides a comprehensive and critical review of internationally published data concerning oncological and functional results of RARP. The main focus represents evaluation of the safety of this procedure with respect to achieving Pentafecta criteria (i.e. no biochemical recurrence, complete urinary continence and erectile function, negative surgical margins, and no postoperative complications), which were primarily described by Patel et al. in 2011. PMID- 25514780 TI - [In Process Citation]. PMID- 25514781 TI - [In Process Citation]. PMID- 25514782 TI - Immunotargeted photodynamic therapy for cholesteatoma: in vitro results with anti EGFR-coated indocyanine green nanocapsules. AB - HYPOTHESIS: The objective was to test the hypothesis that immunotargeted photodynamic therapy (IT-PDT) using anti-epithelial growth factor receptor (EGFR) coated indocyanine green (ICG) nanocapsules would selectively kill cholesteatoma derived keratinocytes while sparing middle ear-derived mucosa cells in vitro. BACKGROUND: Rates of residual cholesteatoma caused by incomplete microsurgical removal are unacceptably high; thus, development of an adjuvant therapy to safely destroy undetected residual cholesteatoma cells would be desirable. IT-PDT is a possible means to achieve this end. METHODS: ICG nanocapsules coated with anti EGFR were synthesized and applied to cholesteatoma-derived keratinocytes and middle ear mucosa cells in vitro. Selective binding to keratinocytes was evaluated by fluorescence microscopy. Activation of ICG was undertaken by applying near-infrared light (810 nm) at an applied energy dose of 1,080 J/cm. Cell death was evaluated 2 hours after treatment with trypan blue staining. RESULTS: Selective and robust nanocapsule binding to keratinocytes, but not mucosa cells, was confirmed by preapplication and postapplication fluorescence measurements. A keratinocyte cell death rate of 70.12% +/- 2.50% was achieved, whereas negligible mucosa cell death was observed. Negligible cell death was also observed for both cell types with application of the nanocapsules alone or with application of near-infrared light alone. CONCLUSION: Anti-EGFR ICG nanocapsules applied topically and activated as part of an IT-PDT scheme results in a high rate of cholesteatoma-derived keratinocyte cell death while negligibly affecting middle ear mucosal cells in vitro. These preliminary findings suggest that this is a feasible concept and that further investigation is warranted. PMID- 25514783 TI - Changes in the jugular bulb associated with sacrifice of the internal jugular vein. AB - OBJECTIVE: To determine whether sacrifice of the internal jugular vein (IJV) causes subsequent changes in the jugular bulb. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: Patients were selected by CPT code for neck dissection and were included in the study if they had undergone unilateral neck dissection and had preoperative and postoperative computed tomographic scans through the temporal bone. INTERVENTIONS: The jugular bulb was measured in the axial plane for anteroposterior and mediolateral diameters. MAIN OUTCOME MEASURES: Cross-sectional area of the jugular bulb was calculated, and comparison was made between preoperative and postoperative studies in patients with or without ligation of the IJV. RESULTS: After unilateral neck dissection, the mean change in the size of the jugular bulb ipsilateral to surgery with sacrifice of the IJV was found to be -10.4 mm (95% confidence interval [95% CI], +/- 8.54 mm); ipsilateral to surgery without sacrifice of the internal jugular, 0.2 mm (95% CI, +/- 3.24 mm); contralateral to surgery with sacrifice of the IJV, +1.9 mm (95% CI, +/- 11.12 mm); and contralateral to surgery without sacrifice of the IJVa, +1.0 mm (95% CI, +/- 2.66 mm). Analysis of variance demonstrated a significant difference for changes in the jugular bulb area ipsilateral to surgery with sacrifice of the IJV (p = 0.03) when compared with contralateral to surgery without sacrifice of the IJV. CONCLUSION: Changes in size of the jugular bulb occur with surgical manipulation of the jugular vein. This study demonstrates a decrease in the size of the jugular bulb with ipsilateral IJV sacrifice. PMID- 25514784 TI - Surgical outcomes after cochlear implantation in children with incomplete partition type I: comparison with deaf children with a normal inner ear structure. AB - OBJECTIVE: To compare audiologic performance after cochlear implantation (CI) in children with incomplete partition (IP) Type I and age-matched children with normal cochleae. STUDY DESIGN: Retrospective chart review. SETTING: Academic center. PATIENTS: Twenty-three children (25 ears) with IP Type I and 230 age matched deaf children (230 ears) with nonsyndromic normal inner ears who underwent CI between January 2000 and June 2013. INTERVENTION CI MAIN OUTCOME MEASURE: The Categories of Auditory Performance (CAP) Scale score and the Meaningful Auditory Integration Scale (MAIS) score. RESULTS: The mean age of IP Type I patients at the time of CI was 5.3 years (standard deviation, 5.4 yr; range, 0.9-17.7 yr). The mean duration of follow-up was 4.7 years (standard deviation, 3.5 yr; range, 1.1-11.2 yr). Fourteen of the 25 IP Type I ears (56%) had cerebrospinal fluid gusher during the cochleostomy. In the IP type ears, the number of inserted electrodes was 16.3 +/- 3.2 (range, 11-22), and the insertion angle was 236.5 +/- 41.2 degrees (range, 180-305 degrees). The cochlear nerve was assessed in 17 of the 25 IP type ears, and hypoplasia was present in nine (53%). Facial nerve stimulation occurred in 15 of the 25 IP type ears. IP Type I patients younger than 3 years at CI had significantly lower CAP Scale and MAIS scores than age-matched controls at 12 and 24 months after CI, but similar CAP Scale and MAIS scores as age-matched controls at 42 and 72 months after CI. IP Type I patients aged 3 to 18 years at CI had similar CAP Scale and MAIS scores as age-matched controls at all post-CI time points. CONCLUSION: Children with IP Type I who underwent CI performed as well as children with normal cochlea in the long-term. PMID- 25514786 TI - The origins of children's metamemory: the role of theory of mind. AB - The relation between preschoolers' theory of mind (ToM) and declarative metamemory (DM) was investigated in two studies. The first study focused on 4 year-old children's (N=106) cognitive and affective ToM and their DM. The data showed a significant association between cognitive (but not affective) ToM and DM, independent of verbal ability, non-verbal ability, and working memory. The second study involved 83 children tested at 4 years 6 months of age (and 6 months later) for cognitive ToM and DM. Here, results showed that early cognitive ToM, in particular false-belief understanding, predicts later DM independent of early verbal ability. These data support a view considering cognitive ToM as a precursor of children's DM. PMID- 25514785 TI - From local to global processing: the development of illusory contour perception. AB - Global visual processing is important for segmenting scenes, extracting form from background, and recognizing objects. Local processing involves attention to the local elements, contrast, and boundaries of an image at the expense of extracting a global percept. Previous work is inconclusive regarding the relative development of local and global processing. Some studies suggest that global perception is already present by 8 months of age, whereas others suggest that the ability arises during childhood and continues to develop during adolescence. We used a novel method to assess the development of global processing in 3- to 10 year-old children and an adult comparison group. We used Kanizsa illusory contours as an assay of global perception and measured responses on a touch sensitive screen while monitoring eye position with a head-mounted eye tracker. Participants were tested using a similarity match-to-sample paradigm. Using converging measures, we found a clear developmental progression with age such that the youngest children performed near chance on the illusory contour discrimination, whereas 7- and 8-year-olds performed nearly perfectly, as did adults. There was clear evidence of a gradual shift from a local processing strategy to a global one; young children looked predominantly at and touched the "pacman" inducers of the illusory form, whereas older children and adults looked predominantly at and touched the middle of the form. These data show a prolonged developmental trajectory in appreciation of global form, with a transition from local to global visual processing between 4 and 7 years of age. PMID- 25514788 TI - Novel role for NFAT3 in ERK-mediated regulation of CXCR4. AB - The G-protein coupled chemokine (C-X-C motif) receptor CXCR4 is linked to cancer, HIV, and WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome. While CXCR4 is reported to be overexpressed in multiple human cancer types and many hematological cancer cell lines, we have observed poor in vitro cell surface expression of CXCR4 in many solid tumor cell lines. We explore further the possible factors and pathways involved in regulating CXCR4 expression. Here, we showed that MEK-ERK signaling pathway and NFAT3 transcriptional factor plays a novel role in regulating CXCR4 expression. When cultured as 3D spheroids, HeyA8 ovarian tumor cells showed a dramatic increase in surface CXCR4 protein levels as well as mRNA transcripts. Furthermore, HeyA8 3D spheroids showed a decrease in phospho-ERK levels when compared to adherent cells. The treatment of adherent HeyA8 cells with an inhibitor of the MEK-ERK pathway, U0126, resulted in a significant increase in surface CXCR4 expression. Additional investigation using the PCR array assay comparing adherent to 3D spheroid showed a wide range of transcription factors being up-regulated, most notably a > 20 fold increase in NFAT3 transcription factor mRNA. Finally, chromatin immunoprecipitation (ChIP) analysis showed that direct binding of NFAT3 on the CXCR4 promoter corresponds to increased CXCR4 expression in HeyA8 ovarian cell line. Taken together, our results suggest that high phospho-ERK levels and NFAT3 expression plays a novel role in regulating CXCR4 expression. PMID- 25514789 TI - Wild mallards have more "goose-like" bills than their ancestors: a case of anthropogenic influence? AB - Wild populations of the world's most common dabbling duck, the mallard (Anas platyrhynchos), run the risk of genetic introgression by farmed conspecifics released for hunting purposes. We tested whether bill morphology of free-living birds has changed since large-scale releases of farmed mallards started. Three groups of mallards from Sweden, Norway and Finland were compared: historical wild (before large-scale releases started), present-day wild, and present-day farmed. Higher density of bill lamellae was observed in historical wild mallards (only males). Farmed mallards had wider bills than present-day and historical wild ones. Present-day wild and farmed mallards also had higher and shorter bills than historical wild mallards. Present-day mallards thus tend to have more "goose like" bills (wider, higher, and shorter) than their ancestors. Our study suggests that surviving released mallards affect morphological traits in wild population by introgression. We discuss how such anthropogenic impact may lead to a maladapted and genetically compromised wild mallard population. Our study system has bearing on other taxa where large-scale releases of conspecifics with 'alien genes' may cause a cryptic invasive process that nevertheless has fitness consequences for individual birds. PMID- 25514790 TI - The shared crosstalk of multiple pathways involved in the inflammation between rheumatoid arthritis and coronary artery disease based on a digital gene expression profile. AB - Rheumatoid arthritis (RA) and coronary artery disease (CAD) are both complex inflammatory diseases, and an increased prevalence of CAD and a high rate of mortality have been observed in RA patients. But the molecular mechanism of inflammation that is shared between the two disorders is unclear. High-throughput techniques, such as transcriptome analysis, are becoming important tools for genetic biomarker discovery in highly complex biological samples, which is critical for the diagnosis, prognosis, and treatment of disease. In the present study, we reported one type of transcriptome analysis method: digital gene expression profiling of peripheral blood mononuclear cells of 10 RA patients, 10 CAD patients and 10 healthy people. In all, 213 and 152 differently expressed genes (DEGs) were identified in RA patients compared with normal controls (RA vs. normal) and CAD patients compared with normal controls (CAD vs. normal), respectively, with 73 shared DEGs between them. Using this technique in combination with Ingenuity Pathways Analysis software, the effects on inflammation of four shared canonical pathways, three shared activated predicted upstream regulators and three shared molecular interaction networks were identified and explored. These shared molecular mechanisms may provide the genetic basis and potential targets for optimizing the application of current drugs to more effectively treat these diseases simultaneously and for preventing one when the other is diagnosed. PMID- 25514792 TI - Calcium--a central regulator of keratinocyte differentiation in health and disease. AB - Regular keratinocyte differentiation is crucial for the formation of an intact epidermal barrier and is triggered by extracellular calcium. Disturbances of epidermal barrier formation and aberrant keratinocyte differentiation are involved in the pathophysiology of several skin diseases, such as psoriasis, atopic dermatitis, basal and squamous skin cancer, and genetic skin diseases such as Darier's disease and Olmstedt syndrome. In this review, we summarize current knowledge about the underlying molecular mechanisms of calcium-induced differentiation in keratinocytes. We provide an overview of calcium's genomic and non-genomic mechanisms to induce differentiation and discuss the calcium gradient in the epidermis, giving rise to cornified skin and lipid envelope formation. We focus on the calcium-sensing receptor, transient receptor potential channels, and STIM/Orai as the major constituents of calcium sensing and calcium entry in the keratinocytes. Finally, skin diseases linked to impaired differentiation will be discussed, paying special attention to disturbed TRP channel expression and TRP channel mutations. PMID- 25514793 TI - Innate activation of MDC and NK cells in high-risk HIV-1-exposed seronegative IV drug users who share needles when compared with low-risk nonsharing IV-drug user controls. AB - BACKGROUND: Previous studies have described increased innate immune activation in HIV-1-exposed seronegative intravenous drug users (HESN-IDU), but have not addressed the independent role of injected drugs and/or repeated injections in driving immune activation. METHODS: In this study, we investigated innate [natural killer (NK) cells and dendritic cells] and adaptive (HIV-specific antibody and CD8 T cell) immune parameters among a high-risk cohort of needle sharing HESN-IDU subjects and compared them with low-risk nonsharing IDU subjects (NS-IDU) and non-drug-user controls. RESULTS: We observed that HIV-specific antibody and CD8 T-cell responses were not detected in HESN-IDU subjects, yet innate immune cell activation was found to be significantly increased on NK cells (CD69 and CD107a upregulation) and myeloid dendritic cells (CD40 and CD83 upregulation) when compared with NS-IDU subjects or non-drug-user controls (P < 0.01 and P < 0.05, respectively). HESN-IDU subjects maintained strong NK-cell CD107a degranulation and cytokine (IFN-gamma, TNF-alpha, and MIP-1 beta) production after target cell incubation suggesting that constitutive innate activation does not induce functional exhaustion of innate cells in HESN-IDU subjects. NK activation in HESN-IDU subjects was independent of drug use patterns but was durable over time and correlated with plasma levels of IP-10 by Luminex analysis (rho = 0.5073, P = 0.0059, n = 28). CONCLUSIONS: Our results indicate that heightened innate immune cell activation in HESN-IDU subjects is not the result of the IV drugs and repeated injection practice itself, but to repeated exposure to factors intrinsic to sharing needles (ie, exposure to pathogens or heterologous cells among donor blood). PMID- 25514794 TI - Rosuvastatin reduces vascular inflammation and T-cell and monocyte activation in HIV-infected subjects on antiretroviral therapy. AB - BACKGROUND: Despite suppressive antiretroviral therapy (ART), increased levels of immune activation persist in HIV-infected subjects. Statins have anti inflammatory effects and may reduce immune activation in HIV disease. METHODS: Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN in HIV (SATURN-HIV) is a randomized, double-blind placebo-controlled trial assessing the effect of rosuvastatin (10 mg daily) on markers of cardiovascular risk and immune activation in ART-treated patients. T-cell activation was measured by expression of CD38, HLA-DR, and PD1. Monocyte activation was measured with soluble markers (sCD14 and sCD163) and by enumeration of monocyte subpopulations and tissue factor expression. Markers of systemic and vascular inflammation and coagulation were also measured. SATURN-HIV is registered on clinicaltrials.gov (identifier: NCT01218802). RESULTS: Rosuvastatin, compared with placebo, reduced sCD14 (-10.4% vs 0.5%, P = 0.006), lipoprotein-associated phospholipase A2 (-12.2% vs -1.7%, P = 0.0007), and IP-10 (-27.5 vs -8.2%, P = 0.03) levels after 48 weeks. The proportion of tissue factor-positive patrolling (CD14CD16) monocytes was also reduced by rosuvastatin (-41.6%) compared with placebo (-18.8%, P = 0.005). There was also a greater decrease in the proportions of activated (CD38HLA-DR) T cells between the arms (-38.1% vs -17.8%, P = 0.009 for CD4 cells, and -44.8% vs 27.4%, P = 0.003 for CD8 cells). CONCLUSIONS: Forty-eight weeks of rosuvastatin treatment reduced significantly several markers of inflammation and lymphocyte and monocyte activation in ART-treated subjects. PMID- 25514795 TI - Clinical and radiological spectrum of posterior reversible encephalopathy syndrome: does age make a difference?--A retrospective comparison between adult and pediatric patients. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a serious and increasingly recognized disorder, but data from observational studies on clinicoradiological differences between etiologies and age groups are limited. In this study, we aimed to investigate the clinical and imaging characteristics of PRES in children compared to adults in a large cohort. METHODS: We retrospectively reviewed the radiological report data bases between January 1999 and August 2012 for patients with PRES (total of 110 patients). Patients fulfilling the criteria for PRES after detailed investigation of clinical charts and imaging studies were separated into children (<18 years) and adults (>=18 years). Various imaging features at onset of symptoms and on follow-up as well as clinical and paraclinical data were analyzed. RESULTS: A total of 19 pediatric and 91 adult patients with PRES were included into the study. In pediatric PRES patients, seizures were significantly more frequent as initial PRES-related symptom (p = 0.01). In addition, in children the superior frontal sulcus topographic lesion pattern occurred as frequent as the parieto-occipital one and was significantly more prevalent than in adults (p = 0.02). In contrast, in adults visual disturbances tended to occur more frequently than in children (p = 0.05). Also, severity of edema tended to be greater in adults than in children (p = 0.07). CONCLUSION: In our PRES cohort, we found relevant clinicoradiological differences between pediatric and adult PRES patients. However, prospective studies are warranted to establish factors that are specifically associated with pediatric PRES. PMID- 25514796 TI - Trimodal speech perception: how residual acoustic hearing supplements cochlear implant consonant recognition in the presence of visual cues. AB - OBJECTIVES: As cochlear implant (CI) acceptance increases and candidacy criteria are expanded, these devices are increasingly recommended for individuals with less than profound hearing loss. As a result, many individuals who receive a CI also retain acoustic hearing, often in the low frequencies, in the nonimplanted ear (i.e., bimodal hearing) and in some cases in the implanted ear (i.e., hybrid hearing) which can enhance the performance achieved by the CI alone. However, guidelines for clinical decisions pertaining to cochlear implantation are largely based on expectations for postsurgical speech-reception performance with the CI alone in auditory-only conditions. A more comprehensive prediction of postimplant performance would include the expected effects of residual acoustic hearing and visual cues on speech understanding. An evaluation of auditory-visual performance might be particularly important because of the complementary interaction between the speech information relayed by visual cues and that contained in the low frequency auditory signal. The goal of this study was to characterize the benefit provided by residual acoustic hearing to consonant identification under auditory alone and auditory-visual conditions for CI users. Additional information regarding the expected role of residual hearing in overall communication performance by a CI listener could potentially lead to more informed decisions regarding cochlear implantation, particularly with respect to recommendations for or against bilateral implantation for an individual who is functioning bimodally. DESIGN: Eleven adults 23 to 75 years old with a unilateral CI and air-conduction thresholds in the nonimplanted ear equal to or better than 80 dB HL for at least one octave frequency between 250 and 1000 Hz participated in this study. Consonant identification was measured for conditions involving combinations of electric hearing (via the CI), acoustic hearing (via the nonimplanted ear), and speechreading (visual cues). RESULTS: The results suggest that the benefit to CI consonant-identification performance provided by the residual acoustic hearing is even greater when visual cues are also present. An analysis of consonant confusions suggests that this is because the voicing cues provided by the residual acoustic hearing are highly complementary with the mainly place-of articulation cues provided by the visual stimulus. CONCLUSIONS: These findings highlight the need for a comprehensive prediction of trimodal (acoustic, electric, and visual) postimplant speech-reception performance to inform implantation decisions. The increased influence of residual acoustic hearing under auditory-visual conditions should be taken into account when considering surgical procedures or devices that are intended to preserve acoustic hearing in the implanted ear. This is particularly relevant when evaluating the candidacy of a current bimodal CI user for a second CI (i.e., bilateral implantation). Although recent developments in CI technology and surgical techniques have increased the likelihood of preserving residual acoustic hearing, preservation cannot be guaranteed in each individual case. Therefore, the potential gain to be derived from bilateral implantation needs to be weighed against the possible loss of the benefit provided by residual acoustic hearing. PMID- 25514798 TI - Insights into fisheries management practices: using the theory of planned behavior to explain fish stocking among a sample of Swiss anglers. AB - Using inadequate management tools often threatens the natural environment. This study focuses on the example of Swiss recreational fishermen (hereafter called "anglers") as recreational fisheries management stakeholders. In recreational fisheries, fish stocking conducted by anglers has been identified as one important factor associated with declining fish catches. We therefore aimed to a) gain insights into why anglers want to maintain fish stocking and b) identify entry points for interventions to promote more pro-ecological management practices. Results (N = 349) showed that the majority of anglers think very uncritically about stocking and that they frequently engage in it. We conclude that outcome expectancies and beliefs about risks, in combination with a lack of stocking success controls are the main reasons that anglers retain stocking measures. We suggest that providing anglers with direct experience and feedback about stocking success is suitable to change their intentions regarding stocking and their actual stocking behavior, and thus, to promote more pro-ecological management methods. From a more general perspective, the results of this study are likely to help improve pro-ecological ecosystem management in other domains where problems similar to those in recreational fisheries management might exist. PMID- 25514797 TI - LOX-1 plays an important role in ischemia-induced angiogenesis of limbs. AB - LOX-1, lectin-like oxidized low-density lipoprotein (LDL) receptor-1, is a single transmembrane receptor mainly expressed on endothelial cells. LOX-1 mediates the uptake of oxidized LDL, an early step in atherosclerosis; however, little is known about whether LOX-1 is involved in angiogenesis during tissue ischemia. Therefore, we examined the role of LOX-1 in ischemia-induced angiogenesis in the hindlimbs of LOX-1 knockout (KO) mice. Angiogenesis was evaluated in a surgically induced hindlimb ischemia model using laser Doppler blood flowmetry (LDBF) and histological capillary density (CD) and arteriole density (AD). After right hindlimb ischemia, the ischemic/nonischemic hindlimb blood flow ratio was persistently lower in LOX-1 KO mice than in wild-type (WT) mice. CD and AD were significantly smaller in LOX-1 KO mice than in WT mice on postoperative day 14. Immunohistochemical analysis revealed that the number of macrophages infiltrating ischemic tissues was significantly smaller in LOX-1 KO mice than in WT mice. The number of infiltrated macrophages expressing VEGF was also significantly smaller in LOX-1 KO mice than in WT mice. Western blot analysis and ROS production assay revealed that LOX- KO mice show significant decrease in Nox2 expression, ROS production and HIF-1alpha expression, the phosphorylation of p38 MAPK and NF kappaB p65 subunit as well as expression of redox-sensitive vascular cell adhesion molecule-1 (VCAM-1) and LOX-1 itself in ischemic muscles, which is supposed to be required for macrophage infiltration expressing angiogenic factor VEGF. Reduction of VEGF expression successively suppressed the phosphorylation of Akt and eNOS, which accelerated angiogenesis, in the ischemic leg of LOX-1 KO mice. Our findings indicate that LOX-1 plays an important role in ischemia induced angiogenesis by 1) Nox2-ROS-NF-kappaB activation, 2) upregulated expression of adhesion molecules: VCAM-1 and LOX-1 and 3) promoting macrophage infiltration, which expresses angiogenic factor VEGF. PMID- 25514799 TI - The internalization of weight bias is associated with severe eating pathology among lean individuals. AB - OBJECTIVE: The internalization of weight bias is associated with clinically significant eating pathology among overweight adults. However, these relationships have not yet been assessed in lean individuals, who may perceive themselves to be overweight and subsequently internalize weight bias. The aim of the present study, therefore, was to determine whether lean individuals internalize weight bias and if the internalization of weight bias among lean respondents is associated with eating pathology. METHOD: Participants were 197 lean (mean BMI: 22.28+/-1.89, range 15.80-24.98) adults who completed the Weight Bias Internalization Scale (WBIS) and measures of disordered eating behaviors and attitudes via an anonymous online survey. RESULTS: Based on convergence of responses from the EDE-Q and QEWP-R, and using DSM-5 behavioral criteria, 10% and 15% of participants were classified into a binge eating and binge/purge group, respectively. WBIS scores were significantly higher among those with binge and/or purge behaviors compared to those without eating pathology. Bivariate correlations revealed positive associations between WBIS score and BMI, depression, and all EDE-Q subscales (restraint, eating concern, shape concern, weight concern). Logistic regressions indicated that internalized weight bias was significantly associated with binge/purge behaviors (OR=4.67, 95% CI: 2.38-9.17, p<.001) and binge eating (OR=2.29, 95% CI: 1.26-4.19, p<.01). DISCUSSION: These novel findings suggest that lean individuals may internalize weight bias. Importantly, the internalization of weight bias among lean individuals is associated with clinically significant eating pathology. PMID- 25514800 TI - Mitosis trumps T stage and proposed international association for the study of lung cancer/american thoracic society/european respiratory society classification for prognostic value in resected stage 1 lung adenocarcinoma. AB - INTRODUCTION: We investigated whether a group of pathologists could reproducibly apply the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) classification for lung adenocarcinoma to a cohort of stage 1 tumors and whether this architectural classification and/or other parameters could demonstrate survival advantage. METHODS: A total of 145 cases of 7 edition of tumor, node, metastasis stage 1 adenocarcinoma were retrospectively reviewed for predominant architectural pattern, including cribriform pattern, nuclear grade, mitotic index, and necrosis. The parameters were assessed for reproducibility and survival and using multivariate analysis, compared with stage, age, and sex. RESULTS: The majority of tumors had a mixed architecture with the acinar pattern being the most common predominant architecture. Micropapillary and cribriform architecture were the least frequent patterns. This study demonstrated that a group of five pathologists could reproducibly apply the IASLC/ATS/ERS classification. Although there were insufficient cribriform-predominant adenocarcinomas for assessment, when the percentage of all cribriform was combined with other architectures, it was associated with a worse prognosis. The majority of the parameters assessed demonstrated significance with univariate analysis but only mitotic index, as assessed by the highest count/10 high-power fields remained significant with multivariate analysis. CONCLUSION: In this study of resected stage 1 primary lung adenocarcinoma, we found mitotic index to be the only independent prognostic marker. It was more closely associated with outcome than either pathologic T stage or IASLC/ATS/ERS architecture-based classification. Further validation of concordance and reproducibility in reporting mitotic index, as well as validation of prognostic significance, needs to be undertaken in independent data sets. PMID- 25514801 TI - Dynamic plasma EGFR mutation status as a predictor of EGFR-TKI efficacy in patients with EGFR-mutant lung adenocarcinoma. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) mutation status in lung cancer can effectively predict EGFR-tyrosine kinase inhibitor (TKI) efficacy. We evaluated the role of dynamic plasma cell-free DNA EGFR mutation status in outcome prediction. METHODS: Advanced lung adenocarcinoma patients were enrolled and prospectively observed for outcomes of EGFR-TKI treatment. Peptide nucleic acid-zip nucleic acid polymerase chain reaction clamp method was developed to assess EGFR mutations in matched tumor and serial plasma cell-free DNA specimens. RESULTS: A total of 72 patients were enrolled in this study, of which 62 patients (86.1%) had EGFR-mutant tumors (34 patients with exon 19 deletions, and 28 patients with L858R). Pretreatment plasma used for EGFR mutation testing showed a sensitivity of 59.7% and a specificity of 100%. Detection sensitivity was significantly higher in stage IV-M1b patients compared with stage IIIb and IV-M1a patients (78.0% versus 23.8%, p < 0.001). All patients who presented with EGFR mutant tumors received first-line EGFR-TKI therapy. The objective response rate and disease control rate were 74.2% and 82.3%, respectively. Median progression free survival and overall survival were 8.8 months (95% CI: 6.6-11.0) and 20.5 months (95% CI 15.1-26.0), respectively. Failure to clear plasma EGFR mutations after EGFR-TKI treatment was an independent predictor of lower disease control rate (odds ratio 5.26 [95% CI: 1.13-24.44]; p = 0.034), shorter progression-free survival (hazard ratio: 1.97 [95% CI: 1.33-2.91]; p = 0.001), and shorter overall survival (hazard ratio: 1.82 [95% CI: 1.04-3.18], p = 0.036). CONCLUSION: Changes in plasma EGFR mutation status can be successfully assessed using the peptide nucleic acid-zip nucleic acid polymerase chain reaction clamp method and can serve as an independent outcome predictor. PMID- 25514802 TI - ALK testing in lung adenocarcinoma: technical aspects to improve FISH evaluation in daily practice. AB - INTRODUCTION: Anaplastic lymphoma kinase (ALK) gene rearrangement characterizes a subgroup of patients with lung adenocarcinoma who may benefit from ALK inhibitors. Fluorescence in situ hybridization (FISH) with a break-apart/split signal strategy is the gold standard to investigate ALK. The cutoff to define ALK positivity has been settled at 15% or greater. A subset of patients has ALK borderline status, showing 15% +/- 5% positive cells. Several aspects, both biological and technical, might influence signals evaluation, making FISH interpretation a challenging task. To improve ALK evaluation, we classified the different FISH patterns on the basis of the type of the split signals, namely short, long, far away, and deleted. METHODS: We investigated ALK gene status by FISH in 244 lung adenocarcinomas and in a series of ALK negative cell lines samples, collected in three Institutions. RESULTS: ALK positive profile was found in 12% of patients; long, deleted, and far-away splits were the primary patterns observed. ALK borderline profile characterized 10% of samples; long and deleted splits were significantly more frequent in those borderline finally classified as ALK positive, whereas short split were mostly detected in those borderline patients finally classified as ALK negative (p = 3.4 * 10). In the ALK negative control series, short split was the predominant pattern. Concordance was observed among different operators and probes for both samples and controls. CONCLUSIONS: Difficulties in ALK FISH signal interpretation might be bypassed using this detailed scoring system, which is highly reproducible, helps clarify borderline samples (according to split type), and provides experimental evidence that 15% is a reasonable cutoff to overcome the assay-dependent background noise. PMID- 25514803 TI - Targeted next-generation sequencing of cancer genes in advanced stage malignant pleural mesothelioma: a retrospective study. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare malignant disease, and the understanding of molecular pathogenesis has lagged behind other malignancies. METHODS: A series of 123 formalin-fixed, paraffin-embedded tissue samples with clinical annotations were retrospectively tested with a commercial library kit (Ion AmpliSeq Cancer Hotspot Panel v.2, Life Technologies, Grand Island, NY) to investigate 50 genes plus other two, BRCA1-associated protein-1 (BAP-1) and neurofibromatosis-2 (NF2), frequently altered in MPM. DNA was obtained from tissues after manual microdissection and enriched for at least 50% cancer cells. Variations affecting protein stability or previously correlated to cancer, more frequently identified (>= 25 patients with at least 10% of allelic frequency), were subsequently evaluated by Sanger sequencing. Immunohistochemistry staining for BAP1 and NF2 proteins was also performed. RESULTS: The commonest genetic variations were clustered in two main pathways: the p53/DNA repair (TP53, SMACB1, and BAP1) and phosphatidylinositol 3-kinase-AKT pathways (PDGFRA, KIT, KDR, HRAS, PIK3CA, STK11, and NF2). PIK3CA:c.1173A>G mutation, STK11:rs2075606 (T>C), or TP53:rs1042522 (Pro/Pro) was significantly associated with time to progressive disease (TTPD; all p values < 0.01). Furthermore, the accumulation of genetic alterations correlated with shorter TTPD and reduced overall survival (TTPD p value = 0.02, overall survival p value = 0.04). BAP1 genetic variations identified were mainly located in exons 13 and 17, and BAP1 nonsynonymous variations were significantly correlated with BAP1 protein nuclear localization. CONCLUSION: Next-generation sequencing was applied to a relatively large retrospective series of MPM using formalin-fixed, paraffin embedded archival material. Our results indicate a complex mutational landscape with a higher number of genetic variations in the p53/DNA repair and phosphatidylinositol 3-kinase pathways, some of them with prognostic value. PMID- 25514804 TI - Phase II study of afatinib, an irreversible ErbB family blocker, in EGFR FISH positive non-small-cell lung cancer. AB - INTRODUCTION: Afatinib, an oral irreversible ErbB Family Blocker, has demonstrated efficacy and safety in epidermal growth factor receptor (EGFR) mutation-positive advanced lung adenocarcinoma. It is unknown whether such activity also occurs in patients with EGFR gene overexpression, regardless of mutation status. This phase II study investigated the activity and safety of afatinib in advanced non-small-cell lung cancer with increased EGFR gene copy number and/or gene amplification by fluorescence in situ hybridization (FISH), with or without EGFR mutation. METHODS: EGFR gene overexpression was assessed by FISH analysis; patients with high polysomy or gene amplification were considered FISH positive. Patients received daily afatinib less than or equal to 50 mg (monotherapy). Endpoints included objective response rate (ORR; primary), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 223 patients screened, 69 patients were FISH-positive and met eligibility criteria for treatment. The ORR was 13.0% overall (n =9 of 69). Higher ORRs were observed in patients with gene amplification (20.0%; n =5 of 25) and EGFR mutation-positive tumors (25.0%; n =3 of 12). The DCR was 50.7% overall (n = 35 of 69; median duration: 24.9 weeks) with higher DCRs observed in patients with gene amplification 64.0%; (n = 16 of 25), and in patients with EGFR mutation positive tumors 66.7% (n = 8 of 12). In the overall population, median PFS was 8.4 weeks and median OS was 50.4 weeks. The most common afatinib-related adverse events were rash/acne (83%) and diarrhea (78%). CONCLUSIONS: First- or second line afatinib demonstrated preliminary activity and manageable safety in EGFR FISH-positive patients with advanced non-small-cell lung cancer. PMID- 25514805 TI - Genome-wide hypomethylation and specific tumor-related gene hypermethylation are associated with esophageal squamous cell carcinoma outcome. AB - INTRODUCTION: Esophageal squamous cell carcinoma (ESCC) is a cancer of variable outcomes with limited effective treatments resulting in poor overall survival (OS). Epigenetic alterations contributing to this deadly cancer type that can be used as novel therapeutic or diagnostic targets are still poorly understood. METHODS: We explored genome-wide DNA methylation data from The Cancer Genome Atlas project and identified a panel of tumor-related genes hypermethylated in ESCC. The methylation statuses of RASSF1, RARB, CDKN2A (p16INK4a, p14ARF), APC, and RUNX3 genes and long interspersed nucleotide element-1 (LINE-1) were validated in a large cohort (n = 140) of clinically well-annotated ESCC specimens and esophageal normal mucosa (n = 28) using a quantitative methylation-specific polymerase chain reaction. RESULTS: Hypermethylation of RARB, p16INK4a, RASSF1, APC, RUNX3, and p14ARF were observed in 55%, 24%, 20%, 19%, 14%, and 8% of specimens, respectively. Hypermethylation of APC was significantly associated with tumor depth (p = 0.02) and American Joint Committee on Cancer stage (p = 0.03). Global DNA methylation level, assessed by LINE-1, was significantly lower in ESCC than in normal mucosa (p < 0.0001), and lower in greater than or equal to T2 (n = 69) than T1 tumors (n = 45; p = 0.03). There was a significant inverse correlation between LINE-1 and RARB methylation (p = 0.008). Importantly, hypermethylation of RASSF1 and APC genes was significantly associated with overall survival (OS; p = 0.006 and p = 0.007, respectively). In addition, patients with tumors containing a higher number of methylated genes (greater than two genes) presented worse OS (p = 0.003). CONCLUSIONS: This study demonstrates that epigenetic alterations of a panel of tumor-related genes and the noncoding region LINE-1 can be used as prognostic indicators and help in clinical management of ESCC patients. PMID- 25514806 TI - Perception of lung cancer among the general population and comparison with other cancers. AB - INTRODUCTION: To evaluate the perception of lung cancer in the general population to identify obstacles in patient-doctor communications. METHODS: A prospective nationwide survey was conducted using a questionnaire and lexical approaches given to 2200 healthy subjects selected within a representative polling database. RESULTS: Of the 1469 subjects eligible for full analysis, most were well informed regarding the epidemiological changes to lung cancer and the main risk factors. The overall survival of patients with lung cancer (32%) was overestimated, and the survival of patients with early stages of lung cancer was underestimated (52%). Lung cancer was identified as a severe disease (82%) with a worse prognosis than other cancers. Most of the population was aware of the main treatments available, except for targeted therapy. Using lexical analyses, we observed that a major proportion considered lung cancer to be a tobacco-induced, life-threatening disease that involved major treatment, and a minor proportion considered it to be an environmentally induced disease. Compared with breast cancer, lung cancer was characterized by a greater feeling of guilt and was more frequently associated with lifestyle. CONCLUSIONS: We have identified knowledge gaps in the perception of lung cancer and have highlighted a need for a public information campaign on lung-cancer screening to promote the good survival rate from early-stage disease and the progress achieved with new therapeutic strategies. PMID- 25514807 TI - Stereotactic ablative radiotherapy for centrally located early stage non-small cell lung cancer: what we have learned. AB - Image-guided stereotactic ablative radiotherapy (SABR; also called stereotactic body radiotherapy or radiosurgery) has become a standard treatment for medically inoperable peripherally located stage I non-small-cell lung cancer (NSCLC) and can achieve local control rates in excess of 90%. However, the role of SABR for centrally located lesions remains controversial because of concerns about the potential for severe toxic effects. When cutting-edge technologies and knowledge based optimization of SABR planning that considers both target coverage and normal tissue sparing are used, some patients with central lesions can be safely and effectively cured of early stage NSCLC. However, delivery of ablative doses of radiation to critical structures such as bronchial tree, esophagus, major vessels, heart, and the brachial plexus/phrenic nerve could produce severe, potentially lethal toxic effects. Here, we address the current understanding of indications, dose regimens, planning optimization, and normal tissue dose-volume constraints for using SABR to treat central NSCLC. PMID- 25514809 TI - [In Process Citation]. PMID- 25514810 TI - Authors' response. PMID- 25514808 TI - Shoc2/Sur8 protein regulates neurite outgrowth. AB - The Shoc2 protein has been implicated in the positive regulation of the Ras-ERK pathway by increasing the functional binding interaction between Ras and Raf, leading to increased ERK activity. Here we found that Shoc2 overexpression induced sustained ERK phosphorylation, notably in the case of EGF stimulation, and Shoc2 knockdown inhibited ERK activation. We demonstrate that ectopic overexpression of human Shoc2 in PC12 cells significantly promotes neurite extension in the presence of EGF, a stimulus that induces proliferation rather than differentiation in these cells. Finally, Shoc2 depletion reduces both NGF induced neurite outgrowth and ERK activation in PC12 cells. Our data indicate that Shoc2 is essential to modulate the Ras-ERK signaling outcome in cell differentiation processes involved in neurite outgrowth. PMID- 25514811 TI - Electronic cigarettes and alternative nicotine products. AB - (1) Electronic cigarettes currently are not regulated by the FDA. (2) Ingredients and design of electronic cigarettes and vaporizers vary. (3) States are taking action to regulate electronic cigarettes in various ways. PMID- 25514812 TI - Treating hepatitis C. AB - (1) New treatments for hepatitis C are curing more people than before. (2) Baby boomers make up an estimated 75 percent of all cases of hepatitis C. (3) Medicare and some insurance plans cover screening for hepatitis C as a preventive service without a copayment. PMID- 25514813 TI - Reducing state employee health insurance costs. AB - (1) States and their employees spent $30.7 billion on health insurance premiums for state employees in 2013. (2) State employee health plan cost-sharing arrangements and premiums vary widely by state. (3) Across all sectors, employer provided health insurance costs doubled from 1992 to 2012. PMID- 25514814 TI - Disability insurance and retirement around the world. PMID- 25514815 TI - The Affordable Care Act young adult mandate and use of inpatient care. PMID- 25514816 TI - In memoriam: Robert G. "Bob" Gallaghar (1924-2014) [corrected]. PMID- 25514817 TI - Correction to Design and Synthesis of Orally Bioavailable Benzimidazole Reverse Amides as Pan RAF Kinase Inhibitors. AB - [This corrects the article DOI: 10.1021/ml5002272.]. PMID- 25514818 TI - Fruit-localized photoreceptors increase phenolic compounds in berry skins of field-grown Vitis vinifera L. cv. Malbec. AB - Sunlight exposure has multiple effect on fruits, as it affects the light climate perceived by fruit photoreceptors and fruit tissue temperature. In grapes (Vitis vinifera L.), light exposure can have a strong effect on fruit quality and commercial value; however, the mechanisms of light action are not well understood. The role of fruit-localized photoreceptors in the control of berry quality traits was evaluated under field conditions in a commercial vineyard in Mendoza (Argentina). Characterization of the diurnal dynamics of the fruit light environment in a vertical trellis system indicated that clusters were shaded by leaves during most of the photoperiod. Supplementation of the fruit light environment from 20 days before veraison until technological harvest showed that red (R, 660 nm) and blue (B, 470 nm) light strongly increased total phenolic compound levels at harvest in the berry skins without affecting sugar content, acidity or berry size. Far-red (FR, 730 nm) and green (G, 560 nm) light supplementation had relatively small effects. The stimulation of berry phytochromes and cryptochromes favored accumulation of flavonoid and non flavonoid compounds, including anthocyanins, flavonols, flavanols, phenolic acids and stilbenes. These results demonstrate that the chemical composition of grape berries is modulated by the light quality received by the clusters under field conditions, and that fruit photoreceptors are not saturated even in areas of high insolation and under management systems that are considered to result in a relatively high exposure of fruits to solar radiation. Therefore, manipulation of the light environment or the light sensitivity of fruits could have significant effects on critical grape quality traits. PMID- 25514819 TI - Incessant tachycardic bursts: what is the mechanism? PMID- 25514820 TI - A cohort study to define the age-specific incidence and risk factors of Shigella diarrhoeal infections in Vietnamese children: a study protocol. AB - BACKGROUND: Shigella spp. are one of the most common causes of paediatric dysentery globally, responsible for a substantial proportion of diarrhoeal disease morbidity and mortality, particularly in industrialising regions. Alarming levels of antimicrobial resistance are now reported in S. flexneri and S. sonnei, hampering treatment options. Little is known, however, about the burden of infection and disease due to Shigella spp. in the community. METHODS/DESIGN: In order to estimate the incidence of this bacterial infection in the community in Ho Chi Minh City, Vietnam we have designed a longitudinal cohort to follow up approximately 700 children aged 12-60 months for two years with active and passive surveillance for diarrhoeal disease. Children will be seen at 6 month intervals for health checks where blood and stool samples will be collected. Families will also be contacted every two weeks for information on presence of diarrhoea in the child. Upon report of a diarrhoeal disease episode, study nurses will either travel to the family home to perform an evaluation or the family will attend a study hospital at a reduced cost, where a stool sample will also be collected. Case report forms collected at this time will detail information regarding disease history, risk factors and presence of disease in the household.Outcomes will include (i) age-specific incidence of Shigella spp. and other agents of diarrhoeal disease in the community, (ii) risk factors for identified aetiologies, (iii) rates of seroconversion to a host of gastrointestinal pathogens in the first few years of life. Further work regarding the longitudinal immune response to a variety of Shigella antigens, host genetics and candidate vaccine/diagnostic proteins will also be conducted. DISCUSSION: This is the largest longitudinal cohort with active surveillance designed specifically to investigate Shigella infection and disease. The study is strengthened by the active surveillance component, which will likely capture a substantial proportion of episodes not normally identified through passive or hospital-based surveillance. It is hoped that information from this study will aid in the design and implementation of Shigella vaccine trials in the future. PMID- 25514821 TI - Effects of a strength-training program for shoulder complaint prevention in female team handball athletes. A pilot study. AB - AIM: Very little is known about the potential for preventing the prevalence of shoulder complaints in handball players, particularly younger players. The aim of the present pilot study was to evaluate shoulder-strengthening program on shoulder complaints during a season of team handball. METHODS: Seven teams, consisting of 15 to 20 players each, were randomized into two groups throughout their competition seasons. Three teams (N.=53) participated in a six-month, three times-a-week shoulder-muscle strength-training program while four teams (N.=56) participated in a comparable handball training program but did not conduct any specific upper-body strength training. Effects of this strength-training program were evaluated by comparing pre- and post-training data from a survey on shoulder complaints based on a self-report questionnaire, and from maximal strength test data. RESULTS: Overall, the shoulder strength-training showed positive effects on shoulder complaints prevalence; in the exercise group, the prevalence of players with shoulder pain decreased from 34 to 11%, while the control group increased the prevalence from 23 to 36%. The exercise group increased the shoulder-muscle strength significantly, compared to the control group. CONCLUSION: By increasing shoulder-muscle strength, this pilot program potentially decreases the risk for shoulder complaints in handball athletes. PMID- 25514822 TI - Effect of EMG-triggered stimulation combined with comprehensive rehabilitation training on muscle tension in poststroke hemiparetic patients. AB - AIM: The aim of this study was to investigate the effect of electromyography stimulation (EMGS) combined with comprehensive rehabilitation training on muscle tension of paretic limb in poststroke hemiparetic patients. METHODS: Forty poststroke hemiparetic patients were randomly divided into 2 groups (N.=20 each): control group that received conventional therapy and experimental group that underwent EMGS combined with comprehensive rehabilitation training in addition to conventional therapy. The outcome was assessed by Fugl-Meyer Score, functional ambulation category (FAC) Scale and integrated electromyography (iEMG) for both pretreatment and post-treatment. The results were analyzed using paired t-test and group t-test. RESULTS: No statistical significance was observed for Fugl Meyer Score, FAC Score and iEMG values between control and experimental groups prior to the treatment (P>0.05). However, Fugl-Meyer and FAC scores were improved and iEMG values of gastrocnemius muscle were significantly decreased (P<0.05) in experimental group post-treatment. Thus, EMGS combined with comprehensive rehabilitation training show statistically significant interaction effect on Fugl Meyer Score, FAC score and iEMG values (P<0.05), suggesting a positive effect of this combined therapy on functional recovery of post-stroke hemiparetic patients. The iEMG values in both groups were also consistent with the Fugl-Meyer and FAC scores. CONCLUSION: EMGS combined with comprehensive rehabilitation training can synergistically reduce muscle tension and relieve muscular spasticity of paretic limb in post-stroke patients. The iEMG proved to be a potential candidate for the evaluation of motor function in these patients. PMID- 25514823 TI - Expression of transforming growth factor-beta after different non-invasive facial rejuvenation modalities. AB - BACKGROUND: Transforming growth factor-beta (TGF-beta) is a major regulator of the synthesis of extracellular matrix (ECM) proteins in human skin as it stimulates fibroblast proliferation and collagen production. Perturbed TGF-beta expression may play a key role in the pathogenesis of skin aging. OBJECTIVES: This study was conducted to objectively evaluate the effects of different modalities of non-invasive facial rejuvenation on TGF-beta expression and to correlate its level with that of newly synthesized collagen. METHODS: A total of 36 patients with Fitzpatrick skin types III and IV were divided into six groups. Each group of six patients was subjected to a different non-invasive modality for the treatment of skin aging, including radiofrequency (RF), Nd:YAG 1320-nm laser and Er:YAG 2940-nm laser mini-peels, intense pulsed light (IPL), mesotherapy injection, and electro-optical synergy (ELOS). Skin biopsies were obtained before treatment, at the end of treatment, and at three months post-treatment. In addition, biopsies were obtained from 30 control subjects. Levels of TGF-beta were quantitatively evaluated using computerized image analysis of immunostained sections. RESULTS: The expression of TGF-beta was statistically significantly increased (P < 0.05) at the end of Nd:YAG 1320-nm and Er:YAG 2940-nm mini-peel treatments compared with baseline levels, and at three months post-treatment with RF and ELOS compared with pretreatment and end-of-treatment levels. However, no significant differences (P > 0.05) were observed in TGF-beta level in response to IPL or mesotherapy treatments in comparison with baseline. The level of TGF-beta was positively correlated (P < 0.05) to that of newly synthesized collagen at the end of Nd:YAG 1320-nm laser and Er:YAG 2940-nm laser mini-peels, as well as at three months after RF and ELOS treatments. CONCLUSIONS: Radiofrequency, ELOS, and Nd:YAG 1320-nm laser and Er:YAG 2940-nm laser mini-peels resulted in an increase in TGF-beta expression, which may mediate the effects of these modalities in enhancing dermal collagen expression through the activation of fibroblasts and thereby reverse the photoaging of skin. PMID- 25514824 TI - Photoresistance switching of plasmonic nanopores. AB - Fast and reversible modulation of ion flow through nanosized apertures is important for many nanofluidic applications, including sensing and separation systems. Here, we present the first demonstration of a reversible plasmon controlled nanofluidic valve. We show that plasmonic nanopores (solid-state nanopores integrated with metal nanocavities) can be used as a fluidic switch upon optical excitation. We systematically investigate the effects of laser illumination of single plasmonic nanopores and experimentally demonstrate photoresistance switching where fluidic transport and ion flow are switched on or off. This is manifested as a large (~ 1-2 orders of magnitude) increase in the ionic nanopore resistance and an accompanying current rectification upon illumination at high laser powers (tens of milliwatts). At lower laser powers, the resistance decreases monotonically with increasing power, followed by an abrupt transition to high resistances at a certain threshold power. A similar rapid transition, although at a lower threshold power, is observed when the power is instead swept from high to low power. This hysteretic behavior is found to be dependent on the rate of the power sweep. The photoresistance switching effect is attributed to plasmon-induced formation and growth of nanobubbles that reversibly block the ionic current through the nanopore from one side of the membrane. This explanation is corroborated by finite-element simulations of a nanobubble in the nanopore that show the switching and the rectification. PMID- 25514828 TI - Kaposi's sarcoma-associated herpesvirus G-protein coupled receptor activates the canonical Wnt/beta-catenin signaling pathway. AB - BACKGROUND: KSHV is a tumorigenic gamma-herpesvirus that has been identified as the etiologic agent of Kaposi's sarcoma (KS), a multifocal highly vascularized neoplasm that is the most common malignancy associated with acquired immunodeficiency syndrome (AIDS). The virus encodes a constitutively active chemokine receptor homologue, vGPCR that possesses potent angiogenic and tumorigenic properties, and is critical for KSHV pathobiology. To date, a number of signaling pathways have been identified as key in mediating vGPCR oncogenic potential. FINDINGS: In this study, we identify a novel pathway, the Wnt/beta catenin pathway, which is dysregulated by vGPCR expression in endothelial cells. Expression of vGPCR in endothelial cells enhances the nuclear accumulation of beta-catenin, that correlates with an increase in beta-catenin transcriptional activity. Activation of beta-catenin signaling by vGPCR is dependent on the PI3K/Akt pathway, as treatment of vGPCR-expressing cells with a pharmacological inhibitor of PI3K, leads to a decreased activation of a beta-catenin-driven reporter, a significant decrease in expression of beta-catenin target genes, and reduced endothelial tube formation. CONCLUSIONS: Given the critical role of Wnt/beta-catenin signaling in angiogenesis and tumorigenesis, the findings from this study suggest a novel mechanism in KSHV-induced malignancies. PMID- 25514829 TI - High-resolution direct 3D printed PLGA scaffolds: print and shrink. AB - Direct three-dimensional printing (3DP) produces the final part composed of the powder and binder used in fabrication. An advantage of direct 3DP is control over both the microarchitecture and macroarchitecture. Prints which use porogen incorporated in the powder result in high pore interconnectivity, uniform porosity, and defined pore size after leaching. The main limitations of direct 3DP for synthetic polymers are the use of organic solvents which can dissolve polymers used in most printheads and limited resolution due to unavoidable spreading of the binder droplet after contact with the powder. This study describes a materials processing strategy to eliminate the use of organic solvent during the printing process and to improve 3DP resolution by shrinking with a non solvent plasticizer. Briefly, poly(lactic-co-glycolic acid) (PLGA) powder was prepared by emulsion solvent evaporation to form polymer microparticles. The printing powder was composed of polymer microparticles dry mixed with sucrose particles. After printing with a water-based liquid binder, the polymer microparticles were fused together to form a network by solvent vapor in an enclosed vessel. The sucrose is removed by leaching and the resulting scaffold is placed in a solution of methanol. The methanol acts as a non-solvent plasticizer and allows for polymer chain rearrangement and efficient packing of polymer chains. The resulting volumetric shrinkage is ~80% at 90% methanol. A complex shape (honey-comb) was designed, printed, and shrunken to demonstrate isotropic shrinking with the ability to reach a final resolution of ~400 MUm. The effect of type of alcohol (i.e. methanol or ethanol), concentration of alcohol, and temperature on volumetric shrinking was studied. This study presents a novel materials processing strategy to overcome the main limitations of direct 3DP to produce high resolution PLGA scaffolds. PMID- 25514830 TI - Understanding the challenges of palliative care in everyday clinical practice: an example from a COPD action research project. AB - Palliative care seeks to improve the quality of life for patients suffering from the impact of life-limiting illnesses. Palliative care encompasses but is more than end-of-life care, which is defined as care during the final hours/days/weeks of life. Although palliative care policies increasingly require all healthcare professionals to have at least basic or non-specialist skills in palliative care, international evidence suggests there are difficulties in realising such policies. This study reports on an action research project aimed at developing respiratory nursing practice to address the palliative care needs of patients with advanced chronic obstructive pulmonary disease (COPD). The findings suggest that interlevel dynamics at individual, team, interdepartmental and organisational levels are an important factor in the capacity of respiratory nurses to embed non-specialist palliative care in their practice. At best, current efforts to embed palliative care in everyday practice may improve end-of life care in the final hours/days/weeks of life. However, embedding palliative care in everyday practice requires a more fundamental shift in the organisation of care. PMID- 25514831 TI - A successful unrelated peripheral blood stem cell transplantation with reduced intensity-conditioning regimen in a patient with late-onset purine nucleoside phosphorylase deficiency. AB - PNP deficiency is a rare combined immunodeficiency with autosomal recessive mode of inheritance. The immunodeficiency is progressive with normal immune functions at birth, but then, T-cell deficiency with variable B-cell functions usually presents by the age of two yr. The only curative treatment for PNP deficiency is hematopoietic stem cell transplantation. Here, we present a 13-yr-old girl with late-onset PNP deficiency. Despite many complications of infections, she was successfully transplanted with a reduced intensity-conditioning regimen from an HLA-identical unrelated donor. PMID- 25514832 TI - GABARAP is a determinant of apoptosis in growth-arrested chicken embryo fibroblasts. AB - Nutrient depletion triggers a series of adaptive processes as part of the unfolded protein response or UPR. These processes reduce stress to the endoplasmic reticulum by enhancing its protein folding capacity or ability to promote the degradation of dysfunctional proteins. Failure to restore ER homeostasis causes the activation of lethal pathways. The expression of a dominant negative mutant of C/EBPbeta (Delta184-C/EBPbeta) alters this balance in chicken embryo fibroblasts (CEF). As a result, CEF display enhanced survival upon prolonged nutrient depletion. Starved Delta184-C/EBPbeta-expressing CEF display pronounced features of autophagy characterized by the appearance of large vesicles containing amorphous material, the formation of smaller double-membrane vesicles (autophagosomes) and processing of LC3 and GABARAP. However, there were marked differences in the expression and processing of these proteins. In both normal and Delta184-C/EBPbeta expressing CEF, the lipidated form of LC3 (form II) accumulated during starvation but was detectable even when cells were actively dividing in complete medium. In contrast, GABARAP expression and lipidation were strongly stimulated in response to starvation. Inhibition of LC3 expression by RNA interference led to apoptosis in normal CEF even in the absence of starvation but stable and near complete repression of GABARAP was tolerated. Moreover, the inhibition of GABARAP enhanced CEF survival and abolished the expression of the pro-apoptotic CHOP factor in conditions of starvation, suggesting a reduced level of ER stress. Therefore, GABARAP is a determinant of apoptosis in CEF subjected to prolonged nutrient depletion. PMID- 25514833 TI - Immune-mediated diseases: what can be found in the oral cavity? AB - Immune-mediated diseases frequently affect oral mucosa, which may often be the first site of clinical manifestation. In this review, we describe the most important oral lesions related to inflammatory disorders and present their management and novel therapies. The review is based on an open PubMed literature search from 1980 to 2012 with relevant keywords. Pemphigus vulgaris, oral lichen planus, cicatricial pemphigoid, erythema multiforme, Stevens-Johnson syndrome, systemic lupus erythematosus, Sjogren's syndrome, and linear IgA dermatosis are the immune-mediated diseases with oral manifestations discussed. Etiology is unknown in most of these diseases, but recently some of them have been found to share common genes. Modern treatment of these diseases is based on drugs that interfere along the pathogenic mechanisms instead of the still commonly used palliative measures. However, the immunomodulatory drugs may also cause oral side effects, complicating the clinical picture. Therefore, consulting dental or oral medicine specialists can be necessary in some cases with various immune-mediated diseases. PMID- 25514834 TI - Facile one-pot synthesis of MoS2 quantum dots-graphene-TiO2 composites for highly enhanced photocatalytic properties. AB - We reported a simple one-pot solvothermal approach to fabricate a MoS2 quantum dots (QDs)-graphene-TiO2 (MGT) composite photocatalyst with significantly improved photocatalysis properties, which is caused by the increased charge separation, visible-light absorbance, specific surface area and reaction sites upon the introduction of MoS2 QDs. PMID- 25514835 TI - Clinicopathologic evaluation of cardiofaciocutaneous syndrome: overcoming the challenges of diagnosing a rare genodermatosis. AB - We report the case of a 2-year-old boy from a family with limited financial resources who presented with cutaneous abnormalities, a history of congenital heart defect, and a presumptive diagnosis of Noonan syndrome. Genetic testing had been deferred because of a lack of funds. Skin findings were characteristic of cardiofaciocutaneous syndrome, including keratosis pilaris, ichthyosis, sparse eyebrows, and multiple nevi. A biopsy of a perifollicular thick papule with background hyperpigmentation was obtained to further characterize the cutaneous findings. Clinical evaluation allowed rapid, cost-effective, specific diagnosis in this patient with a RASopathy-spectrum genetic disorder who did not have access to genetic testing. This time-honored clinical approach is adequate for providing information important for prognosis, follow-up, and counseling. We will also discuss available resources for genetic testing and specialized care for patients with RASopathies. PMID- 25514836 TI - Biosynthesis of integric acid isolated from the wood-decay fungus Xylaria feejeensis 2FB-PPM08M. AB - The biosynthesis of integric acid, a secondary metabolite of the wood-decay fungus Xylaria feejeensis strain 2FB-PPM08M, has been studied. Labeling experiments using [1-(13)C], [2-(13)C] and [1,2-(13)C2] acetate and L-methionine (methyl-(13)C) were separately performed with fungal culture. The labeling patterns of these metabolites indicated the same origin, and determined that integric acid was formed through the condensation of a sesquiterpene and a polyketide. These experiments showed that side chain of compounds would be synthesized by the polyketide pathway, while the ring carbon indicated the biosynthesis of compounds via the mevalonate pathway. PMID- 25514837 TI - Population-based estimates of still birth, induced abortion and miscarriage in the Indian state of Bihar. AB - BACKGROUND: We report population-based data on still birth, induced abortion and miscarriage from the Indian state of Bihar to assess the magnitude of the problem and to inform corrective action. METHODS: A representative sample of women from all districts of Bihar with a pregnancy outcome in the last 12 months was obtained through multistage sampling in early 2012. Still birth rate was calculated as fetuses born with no sign of life at 7 or more months of gestation per 1,000 births. Induced abortion and miscarriage rates were defined as expulsion of dead fetuses at less than 7 months of gestation induced by any means or without inducement, respectively, per 1000 pregnancies that had an outcome. Multiple regression models were used to explore possible associations with stillbirths, induced abortions and miscarriages. Multi-level models were developed for the relatively less developed north zone and for the south zone of Bihar to examine contextual factors associated with still births, induced abortions and miscarriages. RESULTS: Still birth rate was estimated as 20 per 1,000 births (95% CI 15.6-24.5), and induced abortion and miscarriage rates as 8.6 (6.6-10.6), and 46 (40.8-51.3) per 1,000 pregnancies with outcome, respectively. The odds of induced abortion and miscarriage were significantly higher in the south zone (odds ratio 2.53 [95% CI 1.79-3.57] and 1.27 [95% CI 1.10-1.47], respectively). In the multi-level model for the north zone, the odds of induced abortion were higher for women with husband's having mean years of education higher than the state mean (2.62; 95% CI 1.47-4.69). Among the nine divisions of Bihar, comprising of groups of districts, higher induced abortion rate was associated with lower neonatal mortality rate (R(2) = 0.68, p = 0.01). CONCLUSIONS: These population-based data show a significant burden of still births in Bihar, suggesting that addressing these must become an important part of maternal and child health initiatives. The higher induced abortion in the more developed districts, and the inverse trend between induced abortion and neonatal mortality rates, have programmatic implications. PMID- 25514839 TI - Dietary intake in infants with complex congenital heart disease: a case-control study on macro- and micronutrient intake, meal frequency and growth. AB - BACKGROUND: Children with severe congenital heart disease (CHD) need considerable nutritional support to reach normal growth. The actual intake of macro- and micronutrients in outpatient CHD infants over a 6-month period in infancy is not described in the literature. The present study aimed to prospectively investigate the distribution between macro- and micronutrient intake, meal frequency and growth in children with CHD. METHODS: At 6, 9 and 12 months of age, a 3-day food diary and anthropometric data were collected in 11 infants with severe CHD and 22 healthy age- and feeding-matched controls. Macro- and micronutrient intake, meal frequency and growth were calculated. RESULTS: Compared to the healthy controls, CHD infants had a statistically significantly higher intake of fat at 9 months of age (4.8 versus 3.6 g kg(-1) day(-1) ), a higher percentage energy (E%) from fat, (40.6% versus 34.5%) and a lower E% from carbohydrates (46.1% versus 39.6%) at 12 months of age, and a lower intake of iron (7.22 versus 9.28 mg day(-1) ) at 6 months of age. Meal frequency was significantly higher at 6 and 9 months of age (P < 0.01). Mean Z-score weight for height, weight for age and body mass index for age were significant lower (P < 0.01) at all time points. CONCLUSIONS: Despite a higher intake of energy from fat and a higher meal frequency, the intake does not meet the needs for growth, and the results may indicate a low intake of micronutrients in CHD infants. PMID- 25514838 TI - WP1066 sensitizes oral squamous cell carcinoma cells to cisplatin by targeting STAT3/miR-21 axis. AB - Accumulating evidence reveals that activation of STAT3 and miR-21 contributes to chemoresistance in multiple tumors. We examined the expression of STAT3 and miR 21 in 43 oral squamous cell carcinoma (OSCC) tumors and classified them into cisplatin sensitive or resistant group. Tca8113 and Tca8113/DDP cells were treated with cisplatin (DDP), WP1066 (STAT3 inhibitor) or in combination. MTT, colony formation, wound healing, 3-D culture, and transwell chamber assays were used to evaluate the malignant phenotype of OSCC cells. We evaluated the effect of WP1066 on the expression of STAT3 and miR-21. A Tca8113/DDP OSCC xenograft tumor model was established to evaluate the therapeutic effect of WP1066 in combination with DDP. The expression of STAT3/miR-21 was significantly increased in DDP-resistant OSCC samples and Tca8113/DDP cells compared to its parental cell. Treatment of DDP combined with WP1066 efficiently inhibited Tca8113 and Tca8113/DDP cell proliferation, migration and invasion. STAT3 mediated OSCC cell survival and DDP resistance through upregulating the expression of miR-21 and downregulating miR-21 downstream targets, including PTEN, TIMP3 and PDCD4. WP1066 plus DDP treatment could inhibit Tca8113 and Tca8113/DDP cell growth by inhibiting STAT3 phosphorylation and miR-21 expression. These results indicated that STAT3/miR-21 axis could be a candidate therapeutic target for OSCC chemoresistance. PMID- 25514840 TI - Characterization of single amino acid substitutions in the beta2 integrin subunit of patients with leukocyte adhesion deficiency (LAD)-1. AB - Leukocyte adhesion deficiency 1 (LAD-1) is caused by defects in the beta2 integrin subunit. We studied 18 missense mutations, 14 of which fail to support the surface expression of the beta2 integrins. Integrins with the beta2-G150D mutation fail to bind ligands, possibly due to the failure of the alpha1 segment of the betaI domain to assume an alpha-helical structure. Integrins with the beta2-G716A mutation are not maintained in their resting states, and the patient has the severe phenotype of LAD-1. The beta2-S453N and beta2-P648L mutants support the expression of integrins and adhesion functions. They should be re classified as polymorphic variants. PMID- 25514841 TI - Losing images in digital radiology: more than you think. AB - It is a common belief that the shift to digital imaging some 20 years ago helped medical image exchange and got rid of any potential image loss that was happening with printed image films. Unfortunately, this is not the case: despite the most recent advances in digital imaging, most hospitals still keep losing their imaging data, with these losses going completely unnoticed. As a result, not only does image loss affect the faith in digital imaging but it also affects patient diagnosis and daily quality of clinical work. This paper identifies the origins of invisible image losses, provides methods and procedures to detect image loss, and demonstrates modes of action that can be taken to stop the problem from happening. PMID- 25514843 TI - RNA interference-mediated silencing of G protein-coupled receptor 137 inhibits human gastric cancer cell growth. AB - G protein-coupled receptor 137 (GPR137) is an integral membrane protein, which belongs to the GPR137 family of cell surface mediators of signal transduction. GPF137 was recently identified; however, its role in human disease onset has remained to be elucidated. GPR137 is highly expressed in multiple human gastric cancer cell lines. A GPR137 short hairpin RNA (shRNA)-expressing vector was transfected into AGS and MGC80-3 gastric cancer cells, and the subsequent depletion of GPR137 resulted in a significant reduction in cell proliferation and colony formation, as determined by MTT and colony formation assays. In addition, cell cycle analysis indicated that GPR137 knockdown arrested MGC80-3 cells in G2/M phase. To the best of our knowledge, the present study was the first to investigate the role of GPR137 in gastric tumorigenesis and revealed that knockdown of GPR137 by lentivirus-mediated shRNA transfection inhibited the growth of gastric cancer cells in vitro. These results indicated that GPR137 may present a novel target for the development of pharmacological therapeutics for human gastric cancer. PMID- 25514844 TI - Early integration of bilateral touch in the primary somatosensory cortex. AB - Animal, as well as behavioural and neuroimaging studies in humans have documented integration of bilateral tactile information at the level of primary somatosensory cortex (SI). However, it is still debated whether integration in SI occurs early or late during tactile processing, and whether it is somatotopically organized. To address both the spatial and temporal aspects of bilateral tactile processing we used magnetoencephalography in a tactile repetition-suppression paradigm. We examined somatosensory evoked-responses produced by probe stimuli preceded by an adaptor, as a function of the relative position of adaptor and probe (probe always at the left index finger; adaptor at the index or middle finger of the left or right hand) and as a function of the delay between adaptor and probe (0, 25, or 125 ms). Percentage of response-amplitude suppression was computed by comparing paired (adaptor + probe) with single stimulations of adaptor and probe. Results show that response suppression varies differentially in SI and SII as a function of both spatial and temporal features of the stimuli. Remarkably, repetition suppression of SI activity emerged early in time, regardless of whether the adaptor stimulus was presented on the same and the opposite body side with respect to the probe. These novel findings support the notion of an early and somatotopically organized inter-hemispheric integration of tactile information in SI. PMID- 25514845 TI - Directed evolution of cell size in Escherichia coli. AB - BACKGROUND: In bacteria, cell size affects chromosome replication, the assembly of division machinery, cell wall synthesis, membrane synthesis and ultimately growth rate. In addition, cell size can also be a target for Darwinian evolution for protection from predators. This strong coupling of cell size and growth, however, could lead to the introduction of growth defects after size evolution. An important question remains: can bacterial cell size change and/or evolve without imposing a growth burden? RESULTS: The directed evolution of particular cell sizes, without a growth burden, was tested with a laboratory Escherichia coli strain. Cells of defined size ranges were collected by a cell sorter and were subsequently cultured. This selection-propagation cycle was repeated, and significant changes in cell size were detected within 400 generations. In addition, the width of the size distribution was altered. The changes in cell size were unaccompanied by a growth burden. Whole genome sequencing revealed that only a few mutations in genes related to membrane synthesis conferred the size evolution. CONCLUSIONS: In conclusion, bacterial cell size could evolve, through a few mutations, without growth reduction. The size evolution without growth reduction suggests a rapid evolutionary change to diverse cell sizes in bacterial survival strategies. PMID- 25514846 TI - Measurement of monocyte-platelet aggregates by imaging flow cytometry. AB - Platelets are subcellular blood elements with a well-established role in haemostasis. Upon activation platelets express P-Selectin (CD62P) on the cell membrane and bind to P-Selectin glycoprotein ligand 1 expressing monocytes, influencing them toward a pro-adhesive and inflammatory phenotype. It is well established that elevated circulating monocyte-platelet aggregates (MPAs) are linked to atherothrombosis in high risk patients. However, whole blood flow cytometry (FCM) has recently shown that circulating MPAs may also occur in the absence of platelet activation, particularly in healthy children. A potential limitation of conventional FCM is the potential for coincident events to resemble monocyte platelet aggregates. Here we report a novel imaging cytometry approach to further characterize monocyte-platelet aggregate formation by P-Selectin dependent and P-Selectin independent mechanisms and distinguish circulating MPAs from coincidental events. Monocytes were identified by expression of the lipopolysachharide receptor (CD14 BV421), while platelets were identified by expression of the glycoprotein Ib (CD42b APC). Differentiation of P-Selectin dependent and P-Selectin independent binding was achieved with AF488 labeled CD62P. Overall analysis of circulating and in vitro generated MPAs by conventional and imaging cytometry methods showed very strong correlation (r(2) = >0.99, P < 0.01). The Bland-Altman bias of -1.72 was not significantly different to zero. However, when measuring only P-Selectin negative MPAs, a lack of correlation (r(2) = 0.27, P = n.s.) likely reflects better discrimination of coincidence events using imaging cytometry. Our data demonstrate that IFC is more accurate in enumerating MPAs than conventional FCM, which over-estimates the number of MPAs due to the presence of coincident events. PMID- 25514847 TI - A mild copper-catalyzed aerobic oxidative thiocyanation of arylboronic acids with TMSNCS. AB - A facile and efficient transformation of arylboronic acids to their corresponding aryl thiocyanates has been successfully developed. Based on the CuCl-catalyzed oxidative cross-coupling reaction between arylboronic acids and trimethylsilylisothiocyanate (TMSNCS) under oxygen atmosphere, the transformation can be readily conducted at ambient temperature. The newly-developed protocol provided a competitive synthetic approach to aryl thiocyanates that can tolerate a broad range of reactive functional groups and/or strong electron-withdrawing groups. PMID- 25514848 TI - A label-free fluorescence sensing approach for selective and sensitive detection of 2,4,6-trinitrophenol (TNP) in aqueous solution using graphitic carbon nitride nanosheets. AB - An effective and facile fluorescence sensing approach for the determination of 2,4,6-trinitrophenol (TNP) using the chemically oxidized and liquid exfoliated graphitic carbon nitride (g-C3N4) nanosheets was developed. The strong inner filter effect and molecular interactions (electrostatic, pi-pi, and hydrogen bonding interactions) between TNP and the g-C3N4 nanosheets led to the fluorescence quenching of the g-C3N4 nanosheets with efficient selectivity and sensitivity. Under optimal conditions, the limit of detection for TNP was found to be 8.2 nM. The proposed approach has potential application for visual detection of TNP in natural water samples for public safety and security. PMID- 25514849 TI - A new chapter for China's public health security--aids offered to Africa to combat Ebola. PMID- 25514850 TI - ATOH8: a novel marker in human muscle fiber regeneration. AB - Regenerating muscle fibers emerge from quiescent satellite cells, which differentiate into mature multinuclear myofibers upon activation. It has recently been found that ATOH8, a bHLH transcription factor, is regulated during myogenic differentiation. In this study, expression and localization of ATOH8, the other well-described regeneration markers, vimentin, nestin and neonatal myosin, and the satellite cell marker Pax7 were analyzed on protein level in human myopathy samples by immunofluorescence studies. On mRNA level, expression levels of ATOH8 and vimentin were studied by quantitative real-time PCR. ATOH8 is expressed in activated satellite cells and proliferating myoblasts of human skeletal muscle tissue. Quantitative analyses of ATOH8+, Pax7+, vimentin+, nestin+ and neonatal myosin+ muscle fibers showed the highest amount of regenerating muscle fibers in inflammatory myopathies, followed by muscular dystrophy. The relative co expression of ATOH8 with the above-mentioned markers did not vary among the disorders. These results show that the novel regeneration marker ATOH8 contributes to muscle cell differentiation in healthy and diseased human muscle tissue. PMID- 25514852 TI - Search for the global minimum structures of AlB3H(2n) (n = 0 - 6) clusters. AB - The global minimum structures of AlB3H2n (n = 0-6) clusters are determined using the stochastic search method at the B3LYP/6-31G level of theory. These initially specified geometries are recalculated using B3LYP and CCSD(T) methods using the 6 311++G(**) basis set. The structural and electronic properties of the two lowest lying isomers are presented. The structural parameters obtained for aluminum borohydride are compared with the experimental and theoretical results. The H2 fragmentation energies of the most stable isomers are investigated. Chemical bonding analyses for the global minimum of AlB3H2n (n = 0-6) clusters are performed using the adaptive natural density partitioning method. PMID- 25514851 TI - Determining the quality and complexity of next-generation sequencing data without a reference genome. AB - We describe an open-source kPAL package that facilitates an alignment-free assessment of the quality and comparability of sequencing datasets by analyzing k mer frequencies. We show that kPAL can detect technical artefacts such as high duplication rates, library chimeras, contamination and differences in library preparation protocols. kPAL also successfully captures the complexity and diversity of microbiomes and provides a powerful means to study changes in microbial communities. Together, these features make kPAL an attractive and broadly applicable tool to determine the quality and comparability of sequence libraries even in the absence of a reference sequence. kPAL is freely available at https://github.com/LUMC/kPAL webcite. PMID- 25514853 TI - Proposal of a magnetic resonance technique for the evaluation of the calcaneofibular ligament minimizing false positive results. AB - BACKGROUND: Magnetic resonance (MR) techniques used to detect lesions of the ligament complex for articulation of the ankle lack the desired accuracy for the study of the calcaneofibular ligament (CFL). The lack of sensitivity of the conventional techniques is due to variations in the dimensions of the CFL. The best results are obtained when the image plane is oriented parallel to the ligament. This study aims to develop a model that addresses the width, length and angle parameters of the CFL and the orientation of the MR image plane, and thus determine a technique in the oblique transversal plane with the foot in anatomical flexion, that is adequate for the majority of patients. METHOD: To determine this orientation and adapt it to the majority of people, images of the articulation of the ankle in the 3D isotropic, volumetric, sagittal plane of 100 volunteers were taken using the MR technique. None of the volunteers had a clinical history of ligament lesions, serious pathologies, or surgeries. A measurement of the length, width, and angle of the CFL relative to the sole of the foot was performed using the MR tools. A virtual model was developed that simulated the visualization of the CFL in the oblique transversal image plane from 35 degrees to 45 degrees using the CFL dimensions of 100 volunteers. The comparison of the simulations with the reconstructed images validated the model and permitted the calculation of the agreement and sensitivity of each technique in the detection of the complete CFL. RESULTS: Using the simulator, it was possible to obtain the limit angle for complete CFL visualization as a function of its dimensions for any angle of the oblique transversal image plane of the MR. CONCLUSION: The results suggest that a single image acquisition technique in the oblique transversal plane at 38 degrees with the foot in anatomical flexion would serve the majority of patients. PMID- 25514854 TI - Acupuncture promotes white adipose tissue browning by inducing UCP1 expression on DIO mice. AB - BACKGROUND: To study the influence of acupuncture and its possible mechanism on white adipose tissue of high fat diet-induced obese. METHODS: Four-week-old C57BL/6 J mice were randomly divided into a normal diet group and a high-fat diet (HFD) group. After 8 weeks, the HFD mice were randomly divided into Electro acupuncture (EA) group and control group. Mice in the EA group were electro acupunctured, under physical restraint, on Zusanli (ST36) and Neiting (ST44) acupoints, while the mice in the control group were under physical restraint only. Body weight and food intake were monitored, and serum leptin, cholesterol and triglyceride levels were measured by using biochemistrical methods. The effect of EA on white adipose tissues (WAT) was assessed by qPCR, immunoblotting, immunohistochemistry (IHC), immunoprecipitation and cold endurance experiment. RESULTS: The WAT/body weight ratio decreased (P < 0.05) in the EA group, albeit no significant difference on food consumption between EA and control groups. The difference in the darkness of Epi-WAT between EA and control groups could be distinguished visually. HE staining indicated that the EA mice had an increased number of UCP1-immunoreactive paucilocular adipocytes in their WAT. The expressions of brown adipose tissue (BAT) markers, including UCP1, COX4il and Nrtf1 were increased in the WAT of EA mice, acetylation of Ppargamma was decreased by electro-acupuncture. CONCLUSION: EA can remodel WAT to BAT through inducing UCP1 expression, and this may be one of the mechanisms by which acupuncture affects weight loss. PMID- 25514855 TI - The contribution of trees outside forests to national tree biomass and carbon stocks--a comparative study across three continents. AB - In contrast to forest trees, trees outside forests (TOF) often are not included in the national monitoring of tree resources. Consequently, data about this particular resource is rare, and available information is typically fragmented across the different institutions and stakeholders that deal with one or more of the various TOF types. Thus, even if information is available, it is difficult to aggregate data into overall national statistics. However, the National Forest Monitoring and Assessment (NFMA) programme of FAO offers a unique possibility to study TOF resources because TOF are integrated by default into the NFMA inventory design. We have analysed NFMA data from 11 countries across three continents. For six countries, we found that more than 10% of the national above-ground tree biomass was actually accumulated outside forests. The highest value (73%) was observed for Bangladesh (total forest cover 8.1%, average biomass per hectare in forest 33.4 t ha(-1)) and the lowest (3%) was observed for Zambia (total forest cover 63.9%, average biomass per hectare in forest 32 t ha(-1)). Average TOF biomass stocks were estimated to be smaller than 10 t ha(-1). However, given the large extent of non-forest areas, these stocks sum up to considerable quantities in many countries. There are good reasons to overcome sectoral boundaries and to extend national forest monitoring programmes on a more systematic basis that includes TOF. Such an approach, for example, would generate a more complete picture of the national tree biomass. In the context of climate change mitigation and adaptation, international climate mitigation programmes (e.g. Clean Development Mechanism and Reduced Emission from Deforestation and Degradation) focus on forest trees without considering the impact of TOF, a consideration this study finds crucial if accurate measurements of national tree biomass and carbon pools are required. PMID- 25514856 TI - Hydrochemical characterization and quality assessment of groundwater for drinking and irrigation purposes: a case study of Meenachil River Basin, Western Ghats, Kerala, India. PMID- 25514857 TI - Multivariate statistical analysis of temporal-spatial variations in water quality of a constructed wetland purification system in a typical park in Beijing, China. AB - Using discriminant analysis (DA) and principal component analysis/factor analysis (PCA/FA), we described the variations in the water quality of a constructed wetland (CW) purification system in Olympic Park supplied with reclaimed water (RW). The analyses were conducted across three seasons (spring, summer, and autumn) and four functional zones (composite vertical flow constructed wetland [CVW], plant oxidation pond [POP], mixed oxidation pond [MOP], and main lake [ML]). The results demonstrated the relatively high water quality of the CW, which was suitable for landscape reuse. The most severe contamination occurred in autumn and in the ML/MOP. Chemical oxygen demand (CODMn), NO3(-)-N, oxidation reduction potential (ORP), and total nitrogen (TN) caused 91.8% of the temporal variations while DO, cyanobacteria (PCY), and pH caused 70.8% of the spatial variations. The low accuracy of the DA indicated that the four functional areas exhibited similar pollution characteristics. Internal pollution was the major pollutant source in all selected seasons/functional zones. In spring, the CW was largely affected by organic matters. In summer, the CW was contaminated chiefly by nutrient pollutants (N and P), particularly in the CVW and POP. In autumn, the major threat became eutrophication. Enhancing water circulation and shortening hydraulic retention time can effectively weaken the effect of nutrient salts and organic pollutants. PMID- 25514858 TI - Trace elements contamination and human health risk assessment in drinking water from Shenzhen, China. AB - The levels of seven essential trace elements (Mn, Co, Ni, Cu, Zn, Se, and Mo) and six non-essential trace elements (Cr, As, Cd, Sb, Hg, and Pb) in a total of 89 drinking water samples collected in Shenzhen, China were determined using inductively coupled plasma mass spectrometry (ICP-MS) in the present study. Both the essential and non-essential trace elements were frequently detectable in the different kinds of drinking waters assessed. Remarkable temporal and spatial variations were observed among most of the trace elements in the tap water collected from two tap water treatment plants. Meanwhile, potential human health risk from these non-essential trace elements in the drinking water for local residents was also assessed. The median values of cancer risks associated with exposure to carcinogenic metals via drinking water consumption were estimated to be 6.1 * 10(-7), 2.1 * 10(-8), and 2.5 * 10(-7) for As, Cd, and Cr, respectively; the median values of incremental lifetime for non-cancer risks were estimated to be 6.1 * 10(-6), 4.4 * 10(-5), and 2.2 * 10(-5) for Hg, Pb, and Sb, respectively. The median value of total incremental lifetime health risk induced by the six non essential trace elements for the population was 3.5 * 10(-5), indicating that the potential health risks from non-carcinogenic trace elements in drinking water also require some attention. Sensitivity analysis indicates that the most important factor for health risk assessment should be the levels of heavy metal in drinking water. PMID- 25514859 TI - Trends in renal function after radical cystectomy and ileal conduit diversion: new insights regarding estimated glomerular filtration rate variations. AB - INTRODUCTION: Our objectives were to evaluate the long-term renal function after radical cystectomy (RC) and ileal conduit diversion (ICD) and to analyze year-by year the estimated glomerular filtration rate (eGFR) and morphologic upper urinary tract changes. PATIENTS AND METHODS: We retrospectively identified 226 patients who had undergone RC and ICD from 1980 to 2008, with regular postoperative follow-up visits. The eGFR was calculated using the Modification of Diet in Renal Disease equation at baseline and during follow-up. A decrease in renal function was defined as > 1 mL/min/1.73 m(2) annually. RESULTS: The median follow-up period after RC was 91 months (range, 61-235 months). The median eGFR decreased from 66 mL/min/1.73 m(2) (range, 17-139 mL/min/1.73 m(2)) to 59 mL/min/1.73 m(2) (range, 33-102 mL/min/1.73 m(2)). A rapid decline in renal function occurred during the first 2 postoperative years (-9 mL/min/1.73 m(2) and -4 mL/min/1.73 m(2) in the first and second year, respectively), with a moderate to slight decrease in the subsequent years. Urinary obstruction was diagnosed in 51 patients (23%). Among the patients who underwent prompt surgical treatment, we did not find any association with the eGFR decline (P = .8). CONCLUSION: Patients with urinary ICD have a lifelong risk of chronic kidney disease. Regular monitoring of renal function and the morphologic upper urinary tract will permit early diagnosis and treatment of modifiable factors, avoiding irreversible kidney damage. PMID- 25514860 TI - Electron transport dynamics in redox-molecule-terminated branched oligomer wires on Au(111). AB - Dendritic bis(terpyridine)iron(II) wires with terminal ferrocene units were synthesized on a Au(111) surface by stepwise coordination using a three-way terpyridine ligand, a ferrocene-modified terpyridine ligand, and Fe(II) ions. Potential-step chronoamperometry, which applied overpotentials to induce the redox of the terminal ferrocene, revealed an unusual electron-transport phenomenon. The current-time profile did not follow an exponential decay that is common for linear molecular wire systems. The nonexponentiality was more prominent in the forward electron-transport direction (from the terminal ferrocene to the gold electrode, oxidation) than in the reverse direction (from the gold electrode to the terminal ferrocenium, reduction). A plateau and a steep fall were observed in the former. We propose a simple electron transport mechanism based on intrawire electron hopping between two adjacent redox-active sites, and the numerical simulation thereof reproduced the series of "asymmetric" potential-step chronoamperometry results for both linear and branched bis(terpyridine)iron(II) wires. PMID- 25514862 TI - Urtica dioica leaves modulates muscarinic cholinergic system in the hippocampus of streptozotocin-induced diabetic mice. AB - Diabetes mellitus is a chronic metabolic disorder and has been associated with cognitive dysfunction. In our earlier study, chronic Urtica dioica (UD) treatment significantly ameliorated diabetes induced associative and spatial memory deficit in mice. The present study was designed to explore the effect of UD leaves extract on muscarinic cholinergic system, which has long been known to be involved in cognition. Streptozotocin (STZ) (50 mg/kg, i.p., consecutively for 5 days) was used to induce diabetes followed by treatment with UD extract (50 mg/kg, oral) or rosiglitazone (5 mg/kg, oral) for 8 weeks. STZ-induced diabetic mice showed significant reduction in hippocampal muscarinic acetylcholine receptor-1 and choline acetyltransferase expressions. Chronic diabetes significantly up-regulated the protein expression of acetylcholinesterase associated with oxidative stress in hippocampus. Besides, STZ-induced diabetic mice showed hypolocomotion with up-regulation of muscarinic acetylcholine receptor-4 expression in striatum. Chronic UD treatment significantly attenuated the cholinergic dysfunction and oxidative stress in the hippocampus of diabetic mice. UD had no effect on locomotor activity and muscarinic acetylcholine receptor-4 expression in striatum. In conclusion, UD leaves extract has potential to reverse diabetes mediated alteration in muscarinic cholinergic system in hippocampus and thereby improve memory functions. PMID- 25514861 TI - PET and MR imaging of neuroinflammation in hepatic encephalopathy. AB - Neurological or psychiatric abnormalities associated with hepatic encephalopathy (HE) range from subclinical findings to coma. HE is commonly accompanied with the accumulation of toxic substances in bloodstream. The toxicity effect of hyperammonemia on astrocyte, such as the alteration in neurotransmission, oxidative stress, astrocyte swelling, is considered as an important factor in the pathogenesis of HE. Besides, neuroinflammation has captured more attention in the process of HE, but the mechanism of neuroinflammation leading to HE remains unclear. Molecular imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) targeting activated microglia and/ or other mediators appear to be promising noninvasive approaches to assess HE. This review focuses on novel imaging and therapy strategies of neuroinflammation in HE. PMID- 25514863 TI - Ovarian Sertoli Leydig cell tumours in children and adolescents: an analysis of the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT). AB - OBJECTIVE: To analyse ovarian Sertoli-Leydig cell tumours (SLCTs) for potential prognostic markers and their use for treatment stratification. PATIENTS: Forty four patients were included. Patients were prospectively reported to the German MAKEI (Maligne Keimzelltumoren) studies (n=23), French TGM protocols (n=10), Italian Rare Tumour Project (TREP) registry (n=6), and the Polish Pediatric Rare Tumour Study group (n=5). Tumours were classified according to World Health Organisation (WHO) and staged according to International Federation of Gynecological Oncology (FIGO). RESULTS: Median age was 13.9 (0.5-17.4) years. All patients underwent resection by tumour enucleation (n=8), ovariectomy (n=17), adenectomy isolated (n=18) or with hysterectomy (n=1). FIGO-stage: Ia 24pts., Ic 17pts., II/III 3pts. One patient had bilateral tumours. Four patients (stage Ia: 3, stage Ic: 1) developed a metachronous contralateral tumour. Otherwise, all stage Ia patients remained in complete remission. Among 20 patients with incomplete resection or tumour spread (stage Ic-III), eight relapsed, and five patients died. Eleven patients were initially treated with two to sixcycles of cisplatin-based chemotherapy. Of these, seven patients are in continuous remission. Poor histological differentiation was associated with higher relapse rate (5/13) compared to intermediate (3/18) and high differentiation (0/4). Tumours with retiform pattern or heterologous elements showed a high relapse rate, too (5/11). After a median follow-up of 62 months, event-free survival is 0.70+/-0.07, relapse-free survival 0.81+/-0.06 and overall survival 0.87+/-0.05. CONCLUSIONS: Prognosis of SLCTs is determined by stage and histopathologic differentiation. Complete resection with careful avoidance of spillage is a prerequisite of cure. The impact of chemotherapy in incompletely resected and advanced stage tumours remains to be evaluated. PMID- 25514864 TI - Agriculture, health, and wealth convergence: bridging traditional food systems and modern agribusiness solutions. AB - The causes of many vexing challenges facing 21st-century society are at the nexus of systems involved in agriculture, health and wealth production, consumption, and distribution. Using food as a test bed, and on the basis of emerging roadmaps that set achievable objectives over a 1- to 3-year horizon, we introduce this special feature with convergence thinking and practice at its core. Specifically, we discuss academic papers structured around four themes: (1) evidence for a need for convergence and underlying mechanisms at the individual and societal levels; (2) strategy for mainstreaming convergence as a driver of business engagement and innovation; (3) convergence in policy and governance; (4) convergence in metrics and methods. Academic papers under each theme are accompanied by a roadmap paper reporting on the current status of concrete transformative convergence-building projects associated with that theme. We believe that the insights provided by these papers have the potential to enable all actors throughout society to singly and collectively work to build supply and demand for nutritious food, in both traditional and modern food systems, while placing the burdens of malnutrition and ill health on their core strategic agendas. PMID- 25514865 TI - Improving complementary feeding in Ghana: reaching the vulnerable through innovative business--the case of KOKO Plus. AB - Reaching vulnerable populations in low-resource settings with effective business solutions is critical, given the global nature of food and nutrition security. Over a third of deaths of children under 5 years of age are directly or indirectly caused by undernutrition. The Lancet series on malnutrition (2013) estimates that over 220,000 lives of children under 5 years of age can be saved through the implementation of an infant and young child feeding and care package. A unique project being undertaken in Ghana aims to bring in two elements of innovation in infant and young child feeding. The first involves a public-private partnership (PPP) to develop and test the efficacy and effectiveness of the delivery of a low-cost complementary food supplement in Ghana called KOKO PlusTM. The second involves the testing of the concepts of social entrepreneurship and social business models in the distribution and delivery of the product. This paper shares information on the ongoing activities in the testing of concepts of PPPs, social business, social marketing, and demand creation using different delivery platforms to achieve optimal nutrition in Ghanaian infants and young children in the first 2 years of life. It also focuses on outlining the concept of using PPP and base-of-the-pyramid approaches toward achieving nutrition objectives. PMID- 25514866 TI - A nutrition/health mindset on commercial Big Data and drivers of food demand in modern and traditional systems. AB - Building greater reciprocity between traditional and modern food systems and better convergence of human and economic development outcomes may enable the production and consumption of accessible, affordable, and appealing nutritious food for all. Information being key to such transformations, this roadmap paper offers a strategy that capitalizes on Big Data and advanced analytics, setting the foundation for an integrative intersectoral knowledge platform to better inform and monitor behavioral change and ecosystem transformation. Building upon the four P's of marketing (product, price, promotion, placement), we examine digital commercial marketing data through the lenses of the four A's of food security (availability, accessibility, affordability, appeal) using advanced consumer choice analytics for archetypal traditional (fresh fruits and vegetables) and modern (soft drinks) product categories. We demonstrate that business practices typically associated with the latter also have an important, if not more important, impact on purchases of the former category. Implications and limitations of the approach are discussed. PMID- 25514867 TI - Cerebellar retraction and hearing loss after microvascular decompression for hemifacial spasm. AB - BACKGROUND: This retrospective study evaluated the length of cerebellar retraction and the changes of intraoperative brainstem auditory evoked potential (BAEP) during microvascular decompression (MVD), and assessed the predictive value of the hearing loss as a prognostic indicator for the treatment outcome of hemifacial spasm (HFS). METHODS: This series included 1,518 consecutive patients affected with HFS who underwent MVD, during which BAEP was monitored. Patients were divided into two groups based on whether hearing loss occurred following decompression or not. Each patient underwent a similar procedure performed by one neurosurgeon. The two patients groups were matched with regard to sex, age, and degree of spasm. RESULTS: Among the 1,518 patients, 106 (6.98 %) displayed functional hearing changes. Hearing loss was permanent in 12 patients (0.79 %). Of the 1,412 patients with stationary hearing compared with preoperative audiometry, 96 patients were selected who were individually matched with respect to sex, age, and degree of spasm. BAEP changed immediately after cerebellar retraction in 7 of 12 hearing-loss patients, suggesting the importance of retraction on hearing outcomes. The distance from the cerebellar surface of the petrous temporal bone to the neurovascular compression point was measured. The median distance of cerebellar retraction in the hearing-loss group was 13.77 mm, which was longer than the median distance in the control group. CONCLUSIONS: Preoperative measurement of the cerebellar retraction distance can be a valuable clue to predict and prevent postoperative hearing loss in MVD for HFS. PMID- 25514868 TI - Radiosurgery for unruptured cerebral arteriovenous malformations in pediatric patients. AB - BACKGROUND: Unruptured cerebral arteriovenous malformations (AVMs) in pediatric patients (age <18 years) were excluded from A Randomized Trial of Unruptured AVMs (ARUBA). Therefore, the efficacy of radiosurgery for unruptured pediatric AVMs is poorly understood. The goal of this study is to determine the outcomes and define the predictors of obliteration following radiosurgery for unruptured AVMs in pediatric patients. METHODS: We evaluated a prospective database, from 1989 to 2013, of AVM patients treated with radiosurgery at our institution. Patients with age less than 18 years at the time of radiosurgery, unruptured nidi, and at least 2 years of radiologic follow-up or AVM obliteration were selected for analysis. Statistical analyses were performed to determine actuarial obliteration rates and identify factors associated with obliteration. RESULTS: In the 51 unruptured pediatric AVM patients included for analysis, the median age was 13 years, and the most common presentation was seizure in 53 %. The median nidus volume and radiosurgical margin dose were 3.2 cm(3) and 21.5 Gy, respectively. The median radiologic follow-up was 45 months. The actuarial AVM obliteration rates at 3, 5, and 10 years were 29 %, 54 %, and 72 %, respectively. In the multivariate Cox proportional hazards regression analysis, higher margin dose (P = 0.002), fewer draining veins (P = 0.038), and lower Virginia Radiosurgery AVM Scale (P = 0.003) were independent predictors of obliteration. Obliteration rates were significantly higher with a margin dose of at least 22 Gy (P = 0.003) and for nidi with 2 or fewer draining veins (P = 0.001). The incidences of radiologically evident, symptomatic, and permanent radiation-induced changes were 55 %, 16 %, and 2 %, respectively. The annual post-radiosurgery hemorrhage rate was 1.3 %, and the incidence of post-radiosurgery cyst formation was 2 %. CONCLUSION: Radiosurgery affords a favorable risk to benefit profile for unruptured pediatric AVMs. Pediatric patients with unruptured AVMs merit further study to define an optimal management approach. PMID- 25514869 TI - Intraoperative neurophysiological monitoring during resection of intradural extramedullary spinal cord tumors: experience with 100 cases. AB - BACKGROUND: Intradural-extramedullary spinal cord tumor surgery is common. Unlike intramedullary spinal cord tumor surgery, where intraoperative neurophysiological monitoring (IONM) has been described extensively, the application of IONM has not been described in this context, and its relevance has not been investigated. METHODS: From 2001 to 2012, 100 patients underwent intradural-extramedullary spinal cord tumor resection with IONM. Preoperative and postoperative clinical evaluations were completed retrospectively, using a modified McCormick grading scale and correlated with IONM monitorability and dynamics. IONM consisted of transcranial motor evoked potentials (tcMEP), spinal (D wave) and muscle generators, somatosensory evoked potentials (SSEP), and electromyography (EMG). Both short-term and long-term clinical evaluations were performed. Patient demographics, tumor type, span, location, and morphologic complexity were analyzed. RESULTS: Surgeries were performed for resection of schwannomas (33 %), meningiomas (22 %), ependymomas (12 %), and other pathologies (20 %); pathology was unknown in 13 % of patients. Tumor locations were cervical in 21 %, thoracic in 46 %, thoracolumbar in 7 %, lumbar 20 %, and not specified in 6 %. Tumors spanned an average of 2.2 spinal levels. Monitorability was 97 and 67 % with tcMEP and SSEP modalities respectively. D waves were monitorable in 73 % of attempts. Intraoperative tcMEP changes were reported in 29 cases with 14 resolved intraoperatively, There were one false-negative outcome and five true-positive outcomes. For SSEP, 13 changes were noted and three resolved; there were three false-negative results and one true-positive result. For D wave monitoring there were two intraoperative changes with none resolved leading to one false negative and one true positive result. With a multimodality approach incorporating any change in evoked potential, IONM demonstrated sensitivity of 0.82, specificity of 0.95, positive predictive value of 0.82, and a negative predictive value of 0.95. CONCLUSIONS: IONM is feasible and useful in the context of intradural extramedullary spinal cord surgery for identifying iatrogenic injury to the spinal cord. PMID- 25514870 TI - A computational fluid dynamics comparison between different outflow graft anastomosis locations of Left Ventricular Assist Device (LVAD) in a patient specific aortic model. AB - Left ventricular assist devices (LVADs) are mechanical supports used in case of heart failure. Little is known as the height of the anastomosis in aorta might influence the hemodynamic. The aim of the study was to evaluate the fluid dynamic behavior due to the outflow graft placement of a continuous flow LVAD in ascending aorta and to identify the insertion site with the best hemodynamic profile. Computational fluid dynamic studies were carried out to analyze 4 different anastomosis locations in a patient-specific aorta 3D model coupled with a lumped parameters model: 1 cm (case 1), 2 cm (case 2), 3 cm (case 3) and 4 cm (case 4) above the ST junction. In cases 1 and 2, epiaortic vessels presented a steady flow, while in cases 3 and 4 the flow was whirling. Moreover, maximum velocity occurred before: brachiocephalic trunk (case 1), brachiocephalic and left carotid arteries (case 2), left carotid and left subclavian artery (case 3) and left subclavian vessel and upper wall of aortic arch (case 4). Maximum time averaged wall shear stress (TAWSS) was located in: the ascending aorta (cases 1 and 2), the inferior curvature of the arch (case 3); at the origin of epiaortic vessels (case 4). Furthermore, a flow recirculation (cases 1 and 2), a blood stagnation and chaotic flow (cases 3 and 4) occurred above the aortic valve. The results suggested that the placement of the outflow graft at 2 cm above the ST junction gave the most favorable hemodynamic profile. PMID- 25514871 TI - Epidermal growth factor receptor variant III renders glioma cancer cells less differentiated by JAGGED1. AB - Glioblastoma is a highly aggressive primary brain tumor in which the majority of cancer cells are undifferentiated. One of the most common oncogenic drivers for this malignancy is the epidermal growth factor receptor variant III (EGFRvIII), which lacks a portion of the extracellular ligand-binding domain due to deletion of exons 2-7 of the EGFR gene. EGFRvIII plays a critical role in tumor progression, promoting acquisition of stem cell-like features including an undifferentiated state and therapy resistance. However, the molecular mechanisms by which EGFRvIII contributes to cancer cell aggressiveness remain poorly understood. Here, we show that EGFR expression correlates with JAGGED1 expression in glioblastoma patients. Overexpression of EGFRvIII in glioma cell lines augmented JAGGED1 expression at the transcriptional level through the mitogen activated protein kinase signaling pathway. Consequently, EGFRvIII overexpression drove partial dedifferentiation of glioma cells, as determined by tumorsphere forming ability and expression of stem cell markers, through JAGGED1 induction. EGFRvIII-mediated radioresistance, but not chemoresistance, was also modulated by JAGGED1. Taken together, our results provide new insight into the mechanism underlying EGFRvIII-driven glioblastoma aggressiveness. PMID- 25514872 TI - TFF3 and HER2 expression and their correlation with survival in gastric cancer. AB - The molecular biomarkers human epidermal growth factor receptor-2 (HER2) and trefoil factor 3 (TFF3) are reported to play important roles in the pathogenesis of gastric cancer (GC). In this study, we investigated the clinicopathological and prognostic significance of TFF3 and HER2 expression in GC and explored the correlation between these two biomarkers. Ninety-two patients who were diagnosed with GC were enrolled. TFF3 and HER2 expression was determined on tumor tissues. The results showed that TFF3 and HER2 were positively expressed in 42.7 and 10.9% of the cases, respectively. There were significantly higher rates of TFF3 positivity in patients with deep invasive tumors and advanced stage ones. Patients with negative TFF3 staining survived longer than those with the presence of TFF3, with 5-year overall survival (OS) rates of 57.1 +/- 7.1 and 39.5 +/- 7.5%, respectively (P = 0.033). However, HER2 positivity was not significantly associated with OS (P = 0.262). Multivariate analysis demonstrated TFF3 expression to be an independent indicator for short-term survival, with a hazard ratio of 2.327 (95% confidence interval (CI), 1.202-4.507, P = 0.012). There was a trend that the expression of TFF3 was more frequent in HER2 negative tumors than in HER2 positive ones (positive rates: 16.3 vs. 4.7%, P = 0.098). Patients with HER2-negative/TFF3-negative GC presented higher OS than those with other phenotypes (P = 0.009). This study suggests that TFF3 is an independent indicator for survival in GC, while HER2 is not associated with the outcome. Patients with HER2-negative/TFF3-negative GC have the best outcome. PMID- 25514873 TI - Contribution of susceptibility locus at HLA class I region and environmental factors to occurrence of nasopharyngeal cancer in Northeast India. AB - High incidence of nasopharyngeal carcinoma (NPC) has been reported from China, Southeast Asia and Northeast (NE) region of India. Populations at geographic regions having higher incidence of NPC display human leukocyte antigen (HLA) distribution patterns different from areas having low incidence. The current study has investigated the contribution of environmental risk factors and ethnic variation of microsatellite markers in HLA region for the high incidence of NPC in NE India. Genotyping of HLA region using 33 microsatellite markers by fragment length analysis was done in 220 study subjects (120 NPC patients and 100 healthy controls). Association analysis showed two adjacent microsatellite markers HL003 (allele 121) and D6S2704 (allele 218) in the HLA class I region having association with high risk of NPC while allele 127 of HL003 and allele 255 of D6S2678 conferred a protective effect. The environmental factors mainly use of firewood (odds ratio (OR) = 3.797385, confidence interval (CI) = 1.97-7.30, P < 0), living in mud house (OR = 3.46, CI = 1.19-10.08, P = 0.022) and consumption of alcohol (OR = 2.11, CI = 1.02-4.37, P = 0.043) were found as major risk factors for NPC. Higher-order interaction showed combination of smoked food consumption and firewood use for cooking in multifactor dimensionality reduction (MDR) analysis and interaction of non-firewood users, non-ventilated houses and residence in mud houses in classification and regression tree (CART) analysis as the significant risk factors for NPC. Expression of Epstein-Barr virus (EBV) RNA was found in 92% (23/25) of NPC cases suggesting its significant role in NPC aetiopathogenesis. This study identified association of NPC with a susceptibility locus in the HLA class I region which has complex interaction with viral DNA and environmental factors. PMID- 25514874 TI - Factors influencing antibiotic prescribing in long-term care facilities: a qualitative in-depth study. AB - BACKGROUND: Insight into factors that influence antibiotic prescribing is crucial when developing interventions aimed at a more rational use of antibiotics. We examined factors that influence antibiotic prescribing in long-term care facilities, and present a conceptual model that integrates these factors. METHODS: Semi-structured qualitative interviews were conducted with physicians (n = 13) and nursing staff (n = 13) in five nursing homes and two residential care homes in the central-west region of the Netherlands. An iterative analysis was applied to interviews with physicians to identify and categorize factors that influence antibiotic prescribing, and to integrate these into a conceptual model. This conceptual model was triangulated with the perspectives of nursing staff. RESULTS: The analysis resulted in the identification of six categories of factors that can influence the antibiotic prescribing decision: the clinical situation, advance care plans, utilization of diagnostic resources, physicians' perceived risks, influence of others, and influence of the environment. Each category comprises several factors that may influence the decision to prescribe or not prescribe antibiotics directly (e.g. pressure of patients' family leading to antibiotic prescribing) or indirectly via influence on other factors (e.g. unfamiliarity with patients resulting in a higher physician perceived risk of non treatment, in turn resulting in a higher tendency to prescribe antibiotics). CONCLUSIONS: Our interview study shows that several non-rational factors may affect antibiotic prescribing decision making in long-term care facilities, suggesting opportunities to reduce inappropriate antibiotic use. We developed a conceptual model that integrates the identified categories of influencing factors and shows the relationships between those categories. This model may be used as a practical tool in long-term care facilities to identify local factors potentially leading to inappropriate prescribing, and to subsequently intervene at the level of those factors to promote appropriate antibiotic prescribing. PMID- 25514875 TI - Effects of phototherapy on muscle activity and pain in individuals with temporomandibular disorder: a study protocol for a randomized controlled trial. AB - BACKGROUND: According to the International Association for the Study of Pain (IASP), the term temporomandibular disorder (TMD) regards a subgroup of orofacial pain, the symptoms of which include pain or discomfort in the temporomandibular joint, ears, masticatory muscles and neck on one or both sides, as well as joint sounds, limited mandibular movements or mandibular deviation and difficulties chewing. Phototherapy, such as low-level laser therapy (LLLT) and light-emitting diode (LED) therapy, is one of the resources used to treatment muscle pain. Thus, there is a need to investigate therapeutic resources that combine different wavelengths as well as different light sources (LLLT and LED) in the same apparatus. The aim of the proposed study is to evaluate the effects of four different doses of phototherapy on pain, activity of the masticatory muscles (masseter and bilateral anterior temporal) and joint mobility in individuals with temporomandibular disorder. A further aim is to determine the cumulative effect 24 and 48 hours after a single session. METHODS/DESIGN: A placebo-controlled, double-blind, randomized, clinical trial will be carried out involving 72 women between 18 and 40 years of age with a diagnosis of myogenous TMD. The participants will then be randomly allocated to four groups totaling 18 individuals per group. Three groups will be submitted to a single session of phototherapy with different light sources, and one group will receive placebo therapy: Group A (2.62 Joules); Group B (5.24 Joules); Group C (7.86 Joules); and Group D (0 Joules). The following assessment tools will be administered on four separate occasions (baseline and immediately after, 24 h after and 48 h after phototherapy). Pain intensity will be assessed using the visual analog scale for pain, while pain thresholds will be determined using algometer, and electromyographic (EMG) analysis on the masseter and anterior temporal muscles. DISCUSSION: The study will contribute to the practice of the evidence-based use of phototherapy in individuals with a myogenous TMD. Data will be published after the study is completed. TRIAL REGISTRATION: This study is registered with the Brazilian Registry of Clinical Trials, NCT02018770, date of registration: 7 December 2013. PMID- 25514876 TI - A gene-derived SNP-based high resolution linkage map of carrot including the location of QTL conditioning root and leaf anthocyanin pigmentation. AB - BACKGROUND: Purple carrots accumulate large quantities of anthocyanins in their roots and leaves. These flavonoid pigments possess antioxidant activity and are implicated in providing health benefits. Informative, saturated linkage maps associated with well characterized populations segregating for anthocyanin pigmentation have not been developed. To investigate the genetic architecture conditioning anthocyanin pigmentation we scored root color visually, quantified root anthocyanin pigments by high performance liquid chromatography in segregating F2, F3 and F4 generations of a mapping population, mapped quantitative trait loci (QTL) onto a dense gene-derived single nucleotide polymorphism (SNP)-based linkage map, and performed comparative trait mapping with two unrelated populations. RESULTS: Root pigmentation, scored visually as presence or absence of purple coloration, segregated in a pattern consistent with a two gene model in an F2, and progeny testing of F3-F4 families confirmed the proposed genetic model. Purple petiole pigmentation was conditioned by a single dominant gene that co-segregates with one of the genes conditioning root pigmentation. Root total pigment estimate (RTPE) was scored as the percentage of the root with purple color.All five anthocyanin glycosides previously reported in carrot, as well as RTPE, varied quantitatively in the F2 population. For the purpose of QTL analysis, a high resolution gene-derived SNP-based linkage map of carrot was constructed with 894 markers covering 635.1 cM with a 1.3 cM map resolution. A total of 15 significant QTL for all anthocyanin pigments and for RTPE mapped to six chromosomes. Eight QTL with the largest phenotypic effects mapped to two regions of chromosome 3 with co-localized QTL for several anthocyanin glycosides and for RTPE. A single dominant gene conditioning anthocyanin acylation was identified and mapped.Comparative mapping with two other carrot populations segregating for purple color indicated that carrot anthocyanin pigmentation is controlled by at least three genes, in contrast to monogenic control reported previously. CONCLUSIONS: This study generated the first high resolution gene-derived SNP-based linkage map in the Apiaceae. Two regions of chromosome 3 with co-localized QTL for all anthocyanin pigments and for RTPE, largely condition anthocyanin accumulation in carrot roots and leaves. Loci controlling root and petiole anthocyanin pigmentation differ across diverse carrot genetic backgrounds. PMID- 25514878 TI - Clinicopathological and immunohistochemical characteristics of surgically treated primary carcinoma of the nasal vestibule - an evaluation of 30 cases. AB - OBJECTIVES/HYPOTHESIS: Squamous cell carcinoma of the nasal vestibule (SCCNV) is a rare tumour entity. Treatment modality, particularly indication of neck dissection, is still a controversial subject of debate. We sought to evaluate the occurrence of lymph node metastases, the prognosis and the immunohistochemical characteristics of SCCNV. STUDY DESIGN: Retrospective cohort study. METHODS: This study included 30 consecutive patients with SCCNV treated with primary tumour resection and neck dissection in cases of suspicious lymph nodes between 2003 and 2013. According to therapeutical standard adjuvant radiotherapy or chemotherapy were applied in some cases. Clinicopathological data and immunohistochemical expression of CK5/6, EGFR, Ki-67, MMP-2, MMP-9, p53 and VEGFR were analysed. RESULTS: The median follow-up period was 47.1 months. Five-year disease-free (5 year DFS) and 5-year overall survival (5-year OS) were 91.7% and 92.3%. Five-year OS in low-grade tumours (G1, G2) was 100.0%, in high-grade tumours (G3) 75.0% (P = 0.028), respectively. We did not detect any lymph node metastases in the neck dissections. Overexpression of p53 showed a trend for better 5-year OS (p53 positive 100% versus p53-negative 77.8%, n.s.). We found a positive correlation between p53 and EGFR (P = 0.0001). There was no significant relationship between the expression rates of the markers and tumour stage and grading. CONCLUSIONS: We propose no prophylactic neck dissection in small-sized SCCNV. Subtile endoscopic follow-up and periodic ultrasound examination of the cervical lymph nodes after surgical treatment are recommended. Further evaluation of the p53- and EGFR pathways might pave the way to identify possible molecular targets in an attempt to tailor tumour management. PMID- 25514877 TI - Parent-reported distress in children under 3 years old during preventive medical and dental care. AB - PURPOSE: This study examined factors related to young children's distress during preventive oral health visits. Additionally, associations between parent-reported child behaviour during the dental visit and during previous medical visits were tested. METHODS: One hundred twenty-two children under 3 years of age enrolled in a government insurance programme for low-income children were seen for examination, prophylaxis, and fluoride application at a university-based dental clinic. Child distress was rated by parents on a numerical rating scale. RESULTS: The average age of children enrolled was 23.5 +/- 7.3 months. The majority (55.7 %) were judged to have little or no distress pre-examination. Mild or no distress during the examination was reported for 42.6 % of the children and severe distress was reported for 39.4 %. Intensity of distress during the examination was not associated with the child's age, gender, dental health, or previous experience with dental care. Distress was also unrelated to the caregiver's education level or own dental health. Intensity of distress was associated with the child's pre-dental examination distress and distress during prior medical examinations and injections. CONCLUSIONS: Dental professionals can better anticipate child distress by assessing children before a dental examination and enquiring about previous medical experiences. Strategies to prepare parents and alleviate distress may help children cope with the preventive dental visit. PMID- 25514879 TI - Screening of lactic acid bacteria that can form mixed-species biofilm with Saccharomyces cerevisiae. AB - The abilities of lactic acid bacteria (LAB) to form mixed-species biofilm with Saccharomyces cerevisiae in a static co-culture were investigated out of 168 LAB stock cultures, and two Lactobacillus plantarum strains (D71 and E31) and one Leuconostoc mesenteroides strain K01 were found to form mixed-species biofilm with S. cerevisiae BY4741. SEM observation showed that there was no significant difference in morphological properties among these three mixed-species biofilms and they resembled that formed by S. cerevisiae with L. plantarum ML11-11 previously isolated from a brewing sample of Fukuyama pot vinegar. The co aggregation assays showed that L. plantarum D71 and L. plantarum E31 could co aggregate with S. cerevisiae similarly to L. plantarum ML11-11, while L. mesenteroides K01 had no ability to co-aggregate with yeast. The above results indicate that aggregation followed by direct cell-to-cell contact is required for mixed-species biofilm formation between these L. plantarum strains and S. cerevisiae, though some different mechanism may be involved in biofilm formation between L. mesenteroides strain and S. cerevisiae. PMID- 25514880 TI - The blind spot in risk ethics: managing natural hazards. AB - Many risk scholars recognize the importance of including ethical considerations in risk management. Risk ethics can provide in-depth ethical analysis so that ethical considerations can be part of risk-related decisions, rather than an afterthought to those decisions. In this article, I present a brief sketch of the field of risk ethics. I argue that risk ethics has a bias toward technological hazards, thereby overlooking the risks that stem from natural and semi-natural hazards. In order to make a contribution to the field of risk research, risks ethics should broaden its scope to include natural and semi-natural hazards and develop normative distribution criteria that can support decision making on such hazards. PMID- 25514882 TI - Evaluation of a membrane filtration method for the rapid enumeration of confirmed Clostridium perfringens from water. AB - A modification of the UK reference and ISO 14189 TSCA medium for the enumeration of Clostridium perfringens from water coupled with a membrane filter transfer technique for testing for production of acid phosphatase was evaluated. The new tryptose cycloserine agar (TCA) medium, which lacks sodium metabisulphite but contains sodium pyruvate to improve recovery, allows the isolation and confirmation of Cl. perfringens within 18-24 h of sample processing. Data from a multilaboratory study analysed according to ISO 17994 showed that TCA was equivalent to TSCA for the enumeration of Cl. perfringens. The identification of acid phosphatase-negative isolates revealed a false-negative rate for the TCA method of 0.8%. The TCA membrane filter transfer procedure provides confirmed Cl. perfringens counts in half the time of the TSCA method and is simple to undertake. SIGNIFICANCE AND IMPACT OF THE STUDY: The testing of drinking water for Clostridium perfringens is a regulatory parameter in Europe and the UK. Current UK and ISO methods employ membrane filtration (MF) and TSCA medium followed by subculture and confirmation of isolates by testing for acid phosphatase. This takes 48 h. We present here the results of a multilaboratory evaluation of a MF method that features a simplified isolation medium (TCA) and a membrane transfer procedure for the acid phosphatase test resulting in confirmed results being available in 18-24 h. This development significantly reduces the time to confirmed results for Cl. perfringens from water samples. PMID- 25514883 TI - Biology of the cell cycle inhibitor p21(CDKN1A): molecular mechanisms and relevance in chemical toxicology. AB - The cell cycle inhibitor p21(CDKN1A) is a protein playing multiple roles not only in the DNA damage response, but also in many cellular processes during unperturbed cell growth. The main, well-known function of p21 is to arrest cell cycle progression by inhibiting the activity of cyclin-dependent kinases. In addition, p21 is involved in the regulation of transcription, apoptosis, DNA repair, as well as cell motility. However, p21 appears to a have a dual-face behavior because, in addition to its tumor suppressor functions, it may act as an oncogene, depending on the cell type and on the cellular localization. As a biomarker of the cell response to different toxic stimuli, p21 expression and functions have been analyzed in an impressive number of studies investigating the activity of several types of chemicals, in order to determine their possible harmful effects on human cells. Here, we review these studies in order to highlight the different roles p21 may play in the cell response to chemical exposure and to better evaluate the information provided by this biomarker. PMID- 25514884 TI - A two-and-a-half-year-old breastfed toddler presenting with anemia: a case report. AB - BACKGROUND: Anemia is a common presentation in children but the differential diagnosis of iron deficiency and beta-thalassemia remains a diagnostic challenge. Red blood cell indices have been shown to perform weakly in such scenarios. One potential cause is breastfeeding, but the evidence for unusually prolonged exclusive breastfeeding as a cause of iron deficiency anemia in older (>2 years) toddlers is sparse and the association of breastfeeding with iron deficiency in this age group of older toddlers is not unequivocally established. In this case we describe an unusual cause of nutritional iron deficiency anemia in the age group of 2-3 years. CASE PRESENTATION: We describe a two-and-a-half-year-old Turkish boy who presented to our outpatient clinic with recurrent diarrhea and anemia. The patient was febrile (99.1 degrees F) with pale skin and signs of mild dehydration. A reduced nutritional status with a weight of 11.5 kg between the 3rd and 10th percentile was noted. Nutritional evaluation revealed that the boy was still exclusively breastfed with more than 6 times breastfeedings per day. Iron supplementation ameliorated the anemia and reduced hypochromic red blood cells. CONCLUSION: The case demonstrates that unusually prolonged (longer than two years) exclusive breastfeeding is a potential cause of iron deficiency anemia in older toddlers. We discuss a simple combination of laboratory tests with ferritin and red cell distribution width that together with a nutritional evaluation provide a quick diagnosis and show that even at such an advanced stage of nutritional iron deficiency oral iron supplementation is an effective treatment. PMID- 25514885 TI - Should All Children Admitted with Community Acquired Pneumonia have Blood Cultures Taken? Correspondence. PMID- 25514886 TI - Should All Children Admitted with Community Acquired Pneumonia have Blood Cultures Taken? Authors' Reply. PMID- 25514888 TI - Erratum to: study of ventilator-associated pneumonia in a pediatric intensive care unit. PMID- 25514889 TI - Advances in pediatric cancer therapy: potential applicability in Indian scenario. PMID- 25514891 TI - Insight into luminescence enhancement of coordinated water-containing lanthanide metal-organic frameworks by guest molecules. AB - A series of isostructural lanthanide three-dimensional compounds [Ln(HL)(H2O)2].guest (Ln = Tb or Eu, = 2-(N,N-bis(4-methylbenzoic acid)amino)benzoic-1,4-dioic acid, guest = NMP, DMA, DMF or H2O) were assembled and characterized. Their luminescence intensities and quantum yields increase in the order of the guest molecules: NMP > DMA > DMF > H2O (NMP = N-methyl-2 pyrrolidone, DMA = N,N-dimethylacetamide, DMF = N,N-dimethylformamide). The investigation reveals that the hydrogen-bond formed between the metal-organic frameworks should be responsible for the luminescence enhancement of the compounds. PMID- 25514892 TI - Research gaps in the care of women with female genital mutilation: an analysis. AB - Female genital mutilation (FGM) includes procedures involving the partial or total removal of the external female genitals for non-therapeutic reasons. They can have negative psychosexual and health consequences that need specific care. In this paper, we review some key knowledge gaps in the clinical care of women with FGM, focusing on obstetric outcomes, surgical interventions (defibulation and clitoral reconstruction), and the skills and training of healthcare professionals involved in the prevention and management of FGM. We identify research priorities to improve the evidence necessary to establish guidelines for the best multidisciplinary care, communication, and prevention, and to improve health-promotion measures for women with FGM. PMID- 25514894 TI - Use of aripiprazole for delirium in the elderly: a short review. AB - The effects and tolerability of antipsychotics in delirium treatment remain controversial. Compared to other antipsychotics, aripiprazole differs in pharmacological activity because it exerts its effect as a dopamine D2 partial agonist. The guidelines of the American Psychiatric Association rank aripiprazole highly among antipsychotics with regard to safety, and this drug is likely to be useful for delirium treatment. Here, we reviewed the efficacy and safety of aripiprazole for delirium. The results of our literature review on the efficacy and safety of delirium treatments suggest that aripiprazole is an effective treatment option for delirium in the elderly. Aripiprazole is as effective as other antipsychotics in improving delirium symptoms, and it is safer because it is less likely to cause extrapyramidal symptoms, excessive sedation, and weight gain. However, these findings are based on only a few clinical studies of elderly patients with delirium. Therefore, further investigations are necessary. PMID- 25514893 TI - Effects of an outdoor bicycle-based intervention in healthy rural Indian men with normal and low birth weight. AB - Physical inactivity and low birth weight (LBW) may lead to an increased risk for developing type 2 diabetes. The extent to which LBW individuals may benefit from physical exercise training when compared with those with normal birth weight (NBW) controls is uncertain. We assessed the impact of an outdoor exercise intervention on body composition, insulin secretion and action in young men born with LBW and NBW in rural India. A total of 61 LBW and 56 NBW healthy young men were recruited into the study. The individuals were instructed to perform outdoor bicycle exercise training for 45 min every day. Fasting blood samples, intravenous glucose tolerance tests and bioimpedance body composition assessment were carried out. Physical activity was measured using combined accelerometry and heart rate monitoring during the first and the last week of the intervention. Following the exercise intervention, the LBW group displayed an increase in physical fitness [55.0 ml (O2)/kg min (52.0-58.0)-57.5 ml (O2)/kg min (54.4 60.5)] level and total fat-free mass [10.9% (8.0-13.4)-11.4% (8.0-14.6)], as well as a corresponding decline in the ratio of total fat mass/fat-free mass. In contrast, an increase in total fat percentage as well as total fat mass was observed in the NBW group. After intervention, fasting plasma insulin levels, homoeostasis model assessments (HOMA) of insulin resistance (HOMA-IR) and insulin secretion (HOMA-IS), improved to the same extent in both the groups. In summary, young men born with LBW in rural India benefit metabolically from exercise training to an extent comparable with NBW controls. PMID- 25514895 TI - Nano metal-organic framework (NMOF)-based strategies for multiplexed microRNA detection in solution and living cancer cells. AB - MiRNAs are an emerging type of biomarker for diagnostics and prognostics. A reliable sensing strategy that can monitor miRNA expression in living cancer cells would be critical in view of its extensive advantages for fundamental research related to miRNA-associated bioprocesses and biomedical applications. Conventional miRNA sensing methods include northern blot, microarrays and real time quantitative PCR. However, none of them is able to monitor miRNA levels expressed in living cancer cells in a real-time fashion. Some fluorescennt biosensors developed recently from carbon nanomaterials, such as single-walled carbon nanotubes (SWNTs), graphene oxide (GO), and carbon nanoparticles, have been successfully used for assaying miRNA in vitro; however the preparation processes are often expensive, complicated and time-consuming, which have motivated the research on other substitute and novel materials. Herein we present a novel sensing strategy based on peptide nucleic acid (PNA) probes labeled with fluorophores and conjugated with an NMOF vehicle to monitor multiplexed miRNAs in living cancer cells. The NMOF works as a fluorescence quencher of the labelled PNA that is firmly bound with the metal center. In the presence of a target miRNA, PNA is hybridized and released from the NMOF leading to the recovery of fluorescence. This miRNA sensor not only enables the quantitative and highly specific detection of multiplexed miRNAs in living cancer cells, but it also allows the precise and in situ monitoring of the spatiotemporal changes of miRNA expression. PMID- 25514890 TI - Role of membrane contact sites in protein import into mitochondria. AB - Mitochondria import more than 1,000 different proteins from the cytosol. The proteins are synthesized as precursors on cytosolic ribosomes and are translocated by protein transport machineries of the mitochondrial membranes. Five main pathways for protein import into mitochondria have been identified. Most pathways use the translocase of the outer mitochondrial membrane (TOM) as the entry gate into mitochondria. Depending on specific signals contained in the precursors, the proteins are subsequently transferred to different intramitochondrial translocases. In this article, we discuss the connection between protein import and mitochondrial membrane architecture. Mitochondria possess two membranes. It is a long-standing question how contact sites between outer and inner membranes are formed and which role the contact sites play in the translocation of precursor proteins. A major translocation contact site is formed between the TOM complex and the presequence translocase of the inner membrane (TIM23 complex), promoting transfer of presequence-carrying preproteins to the mitochondrial inner membrane and matrix. Recent findings led to the identification of contact sites that involve the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. MICOS plays a dual role. It is crucial for maintaining the inner membrane cristae architecture and forms contacts sites to the outer membrane that promote translocation of precursor proteins into the intermembrane space and outer membrane of mitochondria. The view is emerging that the mitochondrial protein translocases do not function as independent units, but are embedded in a network of interactions with machineries that control mitochondrial activity and architecture. PMID- 25514896 TI - A systematic methodology to estimate added sugar content of foods. AB - BACKGROUND/OBJECTIVES: The effect of added sugar on health is a topical area of research. However, there is currently no analytical or other method to easily distinguish between added sugars and naturally occurring sugars in foods. This study aimed to develop a systematic methodology to estimate added sugar values on the basis of analytical data and ingredients of foods. SUBJECTS/METHODS: A 10 step, stepwise protocol was developed, starting with objective measures (six steps) and followed by more subjective estimation (four steps) if insufficient objective data are available. The method developed was applied to an Australian food composition database (AUSNUT2007) as an example. RESULTS: Out of the 3874 foods available in AUSNUT2007, 2977 foods (77%) were assigned an estimated value on the basis of objective measures (steps 1-6), and 897 (23%) were assigned a subjectively estimated value (steps 7-10). Repeatability analysis showed good repeatability for estimated values in this method. CONCLUSIONS: We propose that this method can be considered as a standardised approach for the estimation of added sugar content of foods to improve cross-study comparison. PMID- 25514897 TI - Body composition through adult life: Swedish reference data on body composition. AB - BACKGROUND/OBJECTIVES: The prevalence of obesity, defined as body mass index (BMI) ?30 kg/m(2), differs between populations; however, there is a need for data on description on body composition in reference populations of different ages and from different countries. The objective of this study was to pool dual-energy X ray absorptiometry (DXA) body composition reference data from population-based Swedish cohorts. SUBJECTS/METHODS: Four population-based cross-sectional cohort studies including 1424 adult Swedes were divided into five age groups (20-29, 30 39, 40-49, 50-61 and 75 years of age); BMI 24.6+/-3.9 kg/m(2) were pooled. Body composition was measured with DXA. RESULTS: The difference in BMI from the youngest to the oldest age group was 3.2 and 4.3 kg/m(2) in men and women, respectively (P<0.001, both sexes), and fat mass (FM) was 9.9 and 9.1% higher in the oldest compared with the youngest men and women (P<0.001, both sexes). Fat free mass (FFM) remained stable up to 60 years of age in men (P=0.83) and was lower at 75 years of age compared with the younger ages. In women, FFM was lower from age 60. From youngest to oldest age groups, height-adjusted FM differed from 4.6 to 7.8 kg/m(2) in men and from 6.8 to 10.8 kg/m(2) in women (P<0.001, both sexes). CONCLUSIONS: Our results provide reference data on body composition in Swedish populations. BMI and FM were higher among older age groups compared with the younger ones. FFM remained stable up to 60 years of age and was lower first among the 75 years of age. PMID- 25514898 TI - Vitamin D and thyroid disease: to D or not to D? AB - The main role of vitamin D is to maintain calcium and phosphorus homeostasis, thus preserving bone health. Recent evidence has demonstrated that vitamin D may also have a role in a variety of nonskeletal disorders such as endocrine diseases and in particular type 1 diabetes, type 2 diabetes, adrenal diseases and polycystic ovary syndrome. Low levels of vitamin D have also been associated with thyroid disease, such as Hashimoto's thyroiditis. Similarly, patients with new onset Graves' disease were found to have decreased 25-hydroxyvitamin D concentrations. Impaired vitamin D signaling has been reported to encourage thyroid tumorigenesis. This review will focus on the role of vitamin D in thyroid diseases, both autoimmune diseases and thyroid cancer, and will summarize the results of vitamin D supplementation studies performed in patients with thyroid disorders. Although observational studies support a beneficial role of vitamin D in the management of thyroid disease, randomized controlled trials are required to provide insight into the efficacy and safety of vitamin D as a therapeutic tool for this dysfunction. PMID- 25514899 TI - Validity and reliability of the new Canadian Nutrition Screening Tool in the 'real-world' hospital setting. AB - BACKGROUND/OBJECTIVES: Nutrition screening should be initiated on hospital admission by non-dietitians. This research aimed to validate and assess the reliability of the Canadian Nutrition Screening Tool (CNST) in the 'real-world' hospital setting. SUBJECTS/METHODS: Adult patients were admitted to surgical and medical wards only (no palliative patients). Study 1--Nutrition Care in Canadian Hospitals (n=1014): development of the CNST (3 items: weight loss, decrease food intake, body mass index (BMI)) and exploratory assessment of its criterion and predictive validity. Study 2--Inter-rater reliability and criterion validity assessment of the tool completed by untrained nursing personnel or diet technician (DT) (n=150). Subjective Global Assessment performed by site coordinators was used as a gold standard for comparison. RESULTS: Study 1: The CNST completed by site coordinators showed good sensitivity (91.7%) and specificity (74.8%). Study 2: In the subsample of untrained personnel (160 nurses; one DT), tool's reliability was excellent (Kappa=0.88), sensitivity was good (>90%) but specificity was low (47.8%). However, using a two-item ('yes' on both weight change and food intake) version of the tool improved the specificity (85.9%). BMI was thus removed to promote feasibility. The final two-item tool (study 1 sample) has a good predictive validity: length of stay (P<0.001), 30-day readmission (P=0.02; X(2) 5.92) and mortality (P<0.001). CONCLUSIONS: The simple and reliable CNST shows good sensitivity and specificity and significantly predicts adverse outcomes. Completion by several untrained nursing personnel confirms its utility in the nursing admission assessment. PMID- 25514900 TI - Fructose consumption in the Netherlands: the Dutch National Food Consumption Survey 2007-2010. AB - BACKGROUND/OBJECTIVES: Despite the worldwide scientific and media attention, the actual fructose consumption in many non-US populations is not clear. The aim of this study was to estimate the fructose consumption and its main food sources in a representative sample of the general Dutch population. SUBJECTS/METHODS: In all, 3817 children and adults aged 7-69 years from the Dutch National Food Consumption Survey 2007-2010 were studied. Values for fructose content of the products were assigned using several food composition tables. Diet was assessed with two nonconsecutive 24-h dietary recalls. The Multiple Source Method was used to take into account day-to-day variation and to estimate the habitual fructose consumption. RESULTS: Median habitual fructose intake was 46 g/day, with an interquartile range of 35-60 g/day. In boys, the highest median intake was observed among 14- to 18-year olds: 61 g/day. In girls, those aged 9-13 years reported the highest median intake: 56 g/day. Of total fructose intake, 67% was consumed in the form of sucrose and 33% was consumed as free fructose. Soft drinks constituted the main food source of total fructose (13-29% across age and sex categories), followed by juices (9-12%), fruit (9-18%), cake and cookies (9 11%) and dairy products (6-10%). CONCLUSIONS: Fructose comprised 9% of the mean daily energy intake in the general Dutch population aged 7-69 years. The fructose consumption was somewhat lower than most recent figures from the US. The main food sources of fructose were soft drinks, juices and fruit. PMID- 25514901 TI - Relationship of maternal grain intake and serum triglyceride levels with infant birth weight: Mothers and Children's Environmental Health (MOCEH) study. AB - BACKGROUND/OBJECTIVES: Maternal serum triglyceride (TG) level is known to be associated with neonatal birth weight. Although Koreans traditionally consume relatively high amounts of grain and grain products, mainly in the form of white rice, and the consumption is positively associated with serum TG levels, no study has investigated the relationship between dietary grain intake, serum TG levels and neonatal birth weight in pregnant women. This study was conducted to identify the association between infant birth weight and maternal intake of grain, as well as serum TG levels. SUBJECTS/METHODS: Subjects were 1011 pregnant women at 12-28 weeks' gestational age and their offspring. Maternal serum TG levels, dietary intake and infant birth weight were measured. RESULTS: Serum TG levels were positively related to neonatal birth weight both at mid-pregnancy (P=0.0015) and at late pregnancy (P<0.0001). Such an association only existed in subjects with the highest tertile of grain intake at mid-pregnancy (P=0.0055) but was observed in all tertiles at late pregnancy (1st P=0.0186, 2nd P=0.0146, 3rd P=0.0099). CONCLUSIONS: The relationship between maternal TG levels and infant birth weight may depend on dietary grain intake and stages of pregnancy in Korean pregnant women. PMID- 25514902 TI - Cardiovascular risk factors and the risk of Parkinson's disease. AB - BACKGROUND/OBJECTIVES: The objective of this study was to investigate whether serum triglycerides (S-TG), cholesterol, blood pressure and waist/height ratio are risk factors for Parkinson's disease (PD). SUBJECTS AND METHODS: A population based sample within the Northern Sweden Health and Disease Study (NSHDS) was used in this study (n=101 790 subjects). Cases with PD were identified prospectively in a community-based study of idiopathic Parkinsonism in the period 2004-2009 in the county of Vasterbotten in northern Sweden. The case database obtained was crosslinked to the NSHDS. Eighty-four of 147 patients with PD had visited the primary health care 2-8 years before diagnosis for participation in the NSHDS. For each case, four referents from the NSHDS population were selected, matched for sex, age, year of health survey, subcohort and geographic area. RESULTS: Cases had lower mean S-TG levels (P=0.007). After stratification for sex, the lower S-TG remained significant for men (P=0.006) but not for women (P=0.450), and these were confirmed by the conditional logistic regression for all cases, none adjusted (hazard ratio (HR): 0.65; 95% confidence interval (CI): 0.42, 0.99) and after adjusting for age, body mass index (BMI) and physical activity (HR: 0.61; 95% CI: 0.39, 0.96). Systolic blood pressure (SBP) was negatively associated with PD risk after adjustments for age, BMI and physical activity (HR: 0.98; 95% CI: 0.97-0.99). Smoking and former smoking were associated with a reduced risk for PD. CONCLUSIONS: We found lower S-TG and SBP 2-8 years before a diagnosis of PD. Smoking was confirmed to be negatively associated with PD, whereas recreational activity indicates a risk for women. PMID- 25514903 TI - Genetic variability in CYP2E1 and catalase gene among currently and formerly alcohol-dependent male subjects. AB - AIMS: The present study explored whether specific single-nucleotide polymorphisms in alcohol metabolic pathway are associated with alcohol dependence or alcohol related psychopathological symptoms. METHODS: Three groups of male unrelated subjects were included: 101 currently alcohol-dependent patients, 100 formerly alcohol-dependent subjects and 97 healthy controls. The following questionnaires were implemented: AUDIT, Zung Depression and Anxiety scale, Brief Social Phobia Scale, Yale-Brown Obsessive Compulsive Scale, Obsessive Compulsive Drinking Scale and Buss-Durkee Hostility Inventory. All the subjects were genotyped for CYP2E1 c.-1053C>T and CAT c.-262C>T. RESULTS: Statistically significant differences in the distribution of genotypes and alleles for CAT c.-262C>T polymorphism were observed among the three investigated groups. We observed a higher frequency of CAT -262T allele in alcohol-dependent subjects (OR = 1.74, 95% CI = 1.164-2.610). Among currently dependent patients CAT -262T allele carriers had higher AUDIT scores (P = 0.023), while CYP2E1-1053T allele carriers had significantly higher YBOCS-obsession subscale scores (P = 0.005) and Zung Anxiety Scale scores (P = 0.011). CONCLUSIONS: Our findings suggest that the CAT c.-262C>T genetic polymorphism influences the susceptibility to alcohol dependence and severity of alcohol dependence, while CYP2E1 c.-1053C>T polymorphism influences the expression of obsessive-compulsive and anxiety symptoms. PMID- 25514905 TI - Transmissibility of the Ice Bucket Challenge among globally influential celebrities: retrospective cohort study. AB - OBJECTIVES: To estimate the transmissibility of the Ice Bucket Challenge among globally influential celebrities and to identify associated risk factors. DESIGN: Retrospective cohort study. SETTING: Social media (YouTube, Facebook, Twitter, Instagram). PARTICIPANTS: David Beckham, Cristiano Ronaldo, Benedict Cumberbatch, Stephen Hawking, Mark Zuckerberg, Oprah Winfrey, Homer Simpson, and Kermit the Frog were defined as index cases. We included contacts up to the fifth generation seeded from each index case and enrolled a total of 99 participants into the cohort. MAIN OUTCOME MEASURES: Basic reproduction number R0, serial interval of accepting the challenge, and odds ratios of associated risk factors based on fully observed nomination chains; R0 is a measure of transmissibility and is defined as the number of secondary cases generated by a single index in a fully susceptible population. Serial interval is the duration between onset of a primary case and onset of its secondary cases. RESULTS: Based on the empirical data and assuming a branching process we estimated a mean R0 of 1.43 (95% confidence interval 1.23 to 1.65) and a mean serial interval for accepting the challenge of 2.1 days (median 1 day). Higher log (base 10) net worth of the participants was positively associated with transmission (odds ratio 1.63, 95% confidence interval 1.06 to 2.50), adjusting for age and sex. CONCLUSIONS: The Ice Bucket Challenge was moderately transmissible among a group of globally influential celebrities, in the range of the pandemic A/H1N1 2009 influenza. The challenge was more likely to be spread by richer celebrities, perhaps in part reflecting greater social influence. PMID- 25514906 TI - A means of measuring serial changes in anal sphincter tone in patients with spinal cord compression. PMID- 25514904 TI - KSRP is critical in governing hepatic lipid metabolism through controlling Per2 expression. AB - Hepatic lipid metabolism is controlled by integrated metabolic pathways. Excess accumulation of hepatic TG is a hallmark of nonalcoholic fatty liver disease, which is associated with obesity and insulin resistance. Here, we show that KH type splicing regulatory protein (KSRP) ablation reduces hepatic TG levels and diet-induced hepatosteatosis. Expression of period 2 (Per2) is increased during the dark period, and circadian oscillations of several core clock genes are altered with a delayed phase in Ksrp(-/-) livers. Diurnal expression of some lipid metabolism genes is also disturbed with reduced expression of genes involved in de novo lipogenesis. Using primary hepatocytes, we demonstrate that KSRP promotes decay of Per2 mRNA through an RNA-protein interaction and show that increased Per2 expression is responsible for the phase delay in cycling of several clock genes in the absence of KSRP. Similar to Ksrp(-/-) livers, both expression of lipogenic genes and intracellular TG levels are also reduced in Ksrp(-/-) hepatocytes due to increased Per2 expression. Using heterologous mRNA reporters, we show that the AU-rich element-containing 3' untranslated region of Per2 is responsible for KSRP-dependent mRNA decay. These findings implicate that KSRP is an important regulator of circadian expression of lipid metabolism genes in the liver likely through controlling Per2 mRNA stability. PMID- 25514907 TI - Insulin resistance, non-alcoholic fatty liver disease and hepatitis C virus infection. AB - Due to their high prevalence, non-alcoholic fatty liver disease (NAFLD), insulin resistance (IR) and hepatitis C virus (HCV) infection are bound to cohabit. However, the relationship between these 3 entities is complex and multilayered. HCV, particularly genotype 3, may induce a "viral" steatosis, morphologically indistinguishable from the steatosis of NAFLD but with different implications and prognosis. On the other hand, epidemiological and experimental data show that patients with HCV have a higher risk of developing IR and, in susceptible individuals, type 2 diabetes (T2D). In patients with HCV, T2D increases fibrosis progression rate, increases the incidence of HCC, worsens liver-related outcomes and worsens response to interferon-alpha based therapy. We conclude by discussing a possible increased incidence of cardiovascular events in HCV patients. PMID- 25514908 TI - The role of liver biopsy to assess non-alcoholic fatty liver disease. AB - Liver biopsy, since 1883, when were first performed, became the gold standard to confirm the earlier stages of fibrosis and grading of non-alcoholic fatty liver disease (NAFLD) and for distinguishing simple steatosis from non- alcoholic steatohepatitis (NASH). General limitations of liver biopsy are sampling error and inter- and intraobserver variability. Also procedure is invasive and that's why associated with some potential adverse effects and complications which may be minor (pain or vagal reactions, transient hypotension) or major such as visceral perforation, bile peritonitis or significant bleeding. Presence of steatosis, hepatocellular injury in the form of ballooning, lobular inflammation and perisinusoidal fibrosis, usually with a zone 3 distribution are considered to be most important histological features of adult NAFLD which may differ from bariatric surgery or pediatric patients. In addition, grading and staging and current semiquantitative systems for NAFLD assessment are discussed. PMID- 25514909 TI - Role of adipokines and cytokines in non-alcoholic fatty liver disease. AB - One of the most common hepatic manifestations of the metabolic syndrome is non alcoholic fatty liver disease (NAFLD). This disease varies from simple steatosis to cirrhosis and hepatocellular carcinoma. Different molecules secreted from adipose tissue such as adiponectin, leptin, resistin and visfatin and pro inflammatory cytokines such as tumour necrosis factor-alpha, and interleukins, can be involved in the pathogenesis of NAFLD. In this review we describe the role of these adipokines and cytokines in the pathogenesis of NAFLD. We comment on their potential use as non-invasive biomarkers of steatosis and fibrosis, and their potential therapeutic role. PMID- 25514910 TI - Common features of the metabolic syndrome and nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is an important cause of chronic liver disease; including simple steatosis, steatohepatitis, fibrosis, or cirrhosis. The metabolic syndrome (MS) is the existence of metabolic alterations that confer an increased risk for developing cardiovascular disease and diabetes. NAFLD and MS frequently coexist and 90% of NAFLD patients have more than one manifestation of the MS. In addition, both entities are related to other comorbid conditions. Scientific advances in the understanding of the association between NAFLD and the MS have identified insulin resistance as a key aspect in the pathophysiology of both diseases. Knowledge gained from these advances can be applied clinically in the management and prevention of NAFLD, the MS, and associated metabolic alterations. Cardiovascular disease is the leading cause of death in patients with NAFLD and the MS, therefore adequate diagnosis and effective treatment are critical. This review analyzes current evidence of the association between NAFLD and the MS. The growing prevalence of both entities is highlighted. Next, the common mechanisms leading to insulin resistance are discussed. Manifestations and diagnosis of the MS and NAFLD are reviewed, pointing out the associated comorbid conditions shared by both diseases. Finally, a brief overview regarding NAFLD treatment is presented. PMID- 25514911 TI - Intestinal permeability in non-alcoholic fatty liver disease: the gut-liver axis. AB - The gut-liver axis model has helped to explain the liver steatosis (NAFLD) and steatohepatitis (NASH) etiopathogenesis. The discovery of a key role for an altered intestinal permeability (IP) in this pathophysioligcal framework has closed the link between gut lumen antigenic/toxic substances and systemic and liver inflammation in NAFLD and obesity, metabolic syndrome. Recent evidence from the literature show how IP can be modulated by several non-pharmacological and pharmacological agents and be the target for future preventive and curative treatment of NAFLD and NASH. In this review we describe the concept of IP, its ultrastructural basis, its role in the NALFD pathophysiology and emerging evidence on non-pharmacological and pharmacological agents able to favourably modulate it. PMID- 25514912 TI - Use of liver breath tests to assess severity of nonalcoholic fatty liver disease. AB - As the prevalence of obesity and insulin-resistance continues to increase in the general population, nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions, thus becoming one of the leading causes of chronic liver disease worldwide. It may present as simple steatosis (NAFL) or steatohepatitis (NASH), which in turn may develop fibrosis and ultimately cirrhosis. Conventional biochemical liver test and radiological investigations are not able to provide reliable information on liver functional reserve, and liver biopsy remains the gold standard to stage NAFLD, differentiate simple steatosis from NASH, and grade fibrosis. However, liver biopsy has some limitations, and is not preferred by patients due to its invasiveness. Thus, non-invasive assessment of disease stage by using liver breath tests - which are based on hepatic clearance of non radioactive stable (13)C-labelled drugs - may be of interest to stage disease and assess patients prognosis due to good accuracy and repeatability. These substrates are orally administered and are cleaved by enzymes specifically located in the liver thus reflecting either the microsomal, cytosolic, or mitochondrial functions. (13)C-Breath Tests have been initially oriented to differentiate broad categories of patients and more recently to refine stage differentiation in patients with early stages of liver disease. In NAFLD patients, (13)C-BTs were able to distinguish simple steatosis from NASH and had good correlation with both histological fibrosis stage and biochemical markers of fibrogenesis. Although promising results have been achieved in this field, their use in clinical practice is still restricted to a specialized niche. However, concordant data from literature conferred to (13)C-Breath Tests a potential role in providing punctual and longitudinal evaluation of patients, identifying those patients where liver biopsy may selectively be performed to stage disease, monitoring and predicting therapeutic response. PMID- 25514913 TI - Orthotopic liver transplantation in non-alcoholic fatty liver disease patients. AB - Non-alcoholic fatty liver disease (NAFLD) is a frequent etiology of liver disease in Western Countries and non-alcoholic steato-hepatitis (NASH) is becoming a leading indication for liver transplantation in US, with constant increase overtime. Specific co-morbidities correlated to the presence of obesity and associated with metabolic syndrome should always be ruled out in patients affected by NASH-related end-stage liver disease, who are potential candidates for liver transplantation. Patients transplanted for NAFLD present similar outcomes compared with patients transplanted for other indications. With regards to post-transplant outcomes in obese patients, available data are contradictory, with reported increased mortality only in patients with BMI >40. A new multidisciplinary protocol of liver transplantation and sleeve gastrectomy seems to be effective and safe in obese patients who were not able to lose weight before liver transplantation. However prospective studies are needed. The NASH recurrence rate after liver transplantation ranges between 20-40%, but its variability largely depends on the methodology used for the diagnosis (i.e. liver tests, liver histology or imaging technique). PMID- 25514914 TI - Phytotherapy and NAFLD--from goals and challenges to clinical practice. AB - Non-alcoholic fatty liver disease (NAFLD) is a global problem and one of the most common liver diseases in the world. Various pharmacological and non pharmacological therapies seem to be non-effective and the patients are often advised not to expect a positive outcome. Hence, even in the modern Western society many patients reach for traditional herbal products. Silymarin, a lipophilic extract derived from milk thistle (Silybum marianum) has been used in liver and bile disorders for centuries. Strong antifibrotic, antioxidant, antiviral and anti-inflammatory activities of silymarin joined with its metabolic effect proven in vitro make it ideal as a drug candidate in the therapy of NAFLD. Several recent randomized clinical studies have demonstrated that silymarin versus placebo significantly contributes to amelioration of the liver condition affected by NAFLD since it reduces steatosis severity, liver ballooning and fibrosis, followed by lowered aminotransferase levels in both short and long lasting therapies. Silymarin is also as efficient as an insulin sensitizer in the NAFLD therapy, but with less adverse effects. Phase III clinical trials have confirmed silymarin to be currently the best medication for the NAFLD patients, but the problems associated with its standardization, formulation and dosage are yet to be solved. However, green tea (Camellia sinensis) and licorice (Glycyrrhiza glabra) root extracts have also been studied in the clinical trials in the therapy of NAFLD patients. Some other herbal products, which have been tested on animals and have the potential to be used in clinical trials, are briefly summarized in this paper. PMID- 25514915 TI - Treatment strategies for fatty liver diseases. AB - Hepatic steatosis, a hallmark of non-alcoholic fatty liver diseases (NAFLD), is an early marker as well as a cause of the cardiometabolic syndrome, prediabetes and NIDDM. Its high prevalence in the general population and its many causes and complex mechanisms make it a pathology which must be treated and requires careful diagnosis also in terms of underlying causes, which may strongly vary among subjects. The recent awareness of the commonness of NAFLD has prompted intensive research which unraveled many different mechanisms causing hepatic steatosis, from diet to intestinal diseases and liver receptors. Epigenetic factors must be added to this list. A variety of causes and mechanisms open many different potential therapeutic approaches. This review aims at summarizing the effects of a selected series of old and new treatments for which there exist at least a reasonable amount of data. Many show efficacy in animals but human data are less convincing largely because of poor amount of data and generally they lack histological confirmation. Many drugs either induce undesirable side-effects or have tight therapeutic dose windows. The recent recognition of a key role of intestinal microbiota in NAFLD and metabolic syndrome may represent a major therapeutic breakthrough by the modulation of bacteria in the gut. Performing randomized long-term clinical studies including liver biopsies appears as prerequisite to determine which treatment is the most valuable, however not ignoring that the therapeutic choice may require individualization among subjects as a function of the origins of NAFLD. PMID- 25514916 TI - Non alcoholic fatty liver: epidemiology and natural history. AB - Non Alcoholic Fatty Liver Disease (NAFLD), defined as the presence of a significant amount of lipid accumulation in the liver (at least in 5% of hepatocytes), represents a challenging issue for the Hepatologists. NAFLD is not represented by a single entity, but rather by two different entities that have different natural history and evolution that range from simple fat accumulation in the liver (without any consequence), to necroinflammation, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The reason of these differences has to be found in the host characteristics and associated risk factors. Globally, its prevalence among liver diseases, and in the general population, is rising in the recent years along with its associated conditions: obesity, insulin resistance, metabolic syndrome and diabetes. This increment, together with the reported clinical conditions, may be accounted for changes in dietary habits and the increase of sedentary lifestyle. Its diffusion seems to be pandemic, given that it is beginning to affect the populations in the developing world due to the spread of Western lifestyle. This is particularly worrying in young adults and children in what seems to have become the main cause of liver disease. Even if the real rate of global incidence of NAFLD are not known, its worldwide prevalence in general population is estimated to be 20-30% in Western Countries and 5-18% in Asia and it is increasing over time. In this review we will report on the global and regional prevalence of NAFLD, the principal risk factors and the natural history of its different presentations. PMID- 25514917 TI - Non-invasive assessment of non-alcoholic fatty liver disease: ultrasound and transient elastography. AB - Non-alcoholic fatty liver disease (NAFLD) is extremely prevalent in the Western world. Non-invasive diagnostic methods should be able to reflect the presence and severity of liver fatty changes and the presence and severity of hepatic inflammation and fibrosis (features of non-alcoholic steato-hepatitis), since these are related to the risk of progression and clinical complications. This article will: a) review the rational basis for the use of ultrasound and transient elastography in patients with NAFLD; b) summarize available data regarding the diagnostic performance of these two widely used non-invasive imaging methods in patients with NAFLD; and c) give an overview of newer sonographic applications that might be used in clinical practice in the near future in this field. PMID- 25514918 TI - Geobacillus icigianus sp. nov., a thermophilic bacterium isolated from a hot spring. AB - A Gram-reaction-positive, motile, thermophilic spore-forming strain, G1w1(T), was isolated from a hot spring of the Valley of Geysers, Kamchatka (Russia). Based on data from the present polyphasic taxonomic study, including phylogenetic analysis of 16S rRNA and spo0A gene sequences, the strain is considered to represent a novel species of the genus Geobacillus, for which the name Geobacillus icigianus sp. nov. is proposed. The type strain is G1w1(T) ( = VKM B-2853(T) = DSM 28325(T)). PMID- 25514919 TI - Influence of dosemeter position for the assessment of eye lens dose during interventional cardiology. AB - The equivalent dose limit for the eye lens for occupational exposure recommended by the ICRP has been reduced to 20 mSv y(-1) averaged over defined periods of 5 y, with no single year exceeding 50 mSv. The compliance with this new requirement could not be easy in some workplace such as interventional radiology and cardiology. The aim of this study is to evaluate different possible approaches in order to have a good estimate of the eye lens dose during interventional procedures. Measurements were performed with an X-ray system Philips Allura FD 10, using a PMMA phantom to simulate the patient scattered radiation and a Rando phantom to simulate the cardiologist. Thermoluminescence (TL) whole-body and TL eye lens dosemeters together with Philips DoseAware active dosemeters were located on different positions of the Rando phantom to estimate the eye lens dose in typical cardiology procedures. The results show that, for the studied conditions, any of the analysed dosemeter positions are suitable for eye lens dose assessment. However, the centre of the thyroid collar and the left ear position provide a better estimate. Furthermore, in practice, improper use of the ceiling-suspended screen can produce partial protection of some parts of the body, and thus large differences between the measured doses and the actual exposure of the eye could arise if the dosemeter is not situated close to the eye. PMID- 25514920 TI - Design of 3D printed insert for hanging culture of Caco-2 cells. AB - A Caco-2 cell culture on Transwell, an alternative testing to animal or human testing used in evaluating drug intestinal permeability, incorrectly estimated the absorption of actively transported drugs due to the low expression of membrane transporters. Similarly, three-dimensional (3D) cultures of Caco-2 cells, which have been recommended to be more physiological relevant, were not superior to the Transwell culture in either accuracy or convenience in drug permeability testing. Using rapid 3D printing prototyping techniques, this study proposed a hanging culture of Caco-2 cells that performed with high accuracy in predicting drug permeability in humans. As found, hanging cultured Caco-2 cells formed a confluent monolayer and maintained high cell viability on the 3D printed insert. Compared with the normal culture on Transwell, the Caco-2 cells on the 3D printed insert presented ~30-100% higher brush border enzyme activity and ~2-7 folds higher activity of P-glycoprotein/multidrug resistance-associated protein 2 during 21 days of incubation. For the eight membrane transporter substrates, the predictive curve of the 3D printing culture exhibited better linearity (R(2) = 0.92) to the human oral adsorption than that of the Transwell culture (R(2) = 0.84), indicating better prediction by the 3D printing culture. In this regard, the 3D printed insert for hanging culture could be potentially developed as a convenient and low-cost tool for testing drug oral absorption. PMID- 25514921 TI - Paracrine factors from mesenchymal stem cells attenuate epithelial injury and lung fibrosis. AB - Paracrine factors are currently considered to be the major mechanism through which mesenchymal stem cells (MSCs) exert their actions. The aim of this study was to investigate the protective effects of conditioned medium (CM) from bone marrow mesenchymal stem cells (MSC) on bleomycin (BLM)-induced lung injury and fibrosis, both in vitro and in vivo. A549 human non-small cell lung cancer epithelial cells were cultured in serum-free medium, or MSC-CM, both with or without BLM. The protective effects of MSC-CM was determined by MTT assay to assess cell viability and Annexin V-PE to assess apoptosis. Rats were intratracheally injected with MSC-CM, saline, or conditioned medium from fibroblasts on day 0 and day 3 after intratracheal administration of BLM, and were sacrificed on day 28. Lung injury and fibrosis were assessed by histological assessment, Ashcroft score, and hydroxyproline assay; lung cell apoptosis was detected using terminal deoxynucleotidyl transferase dUTP nick end labeling assay. In comparison to the control group (0.17+/-0.01), 8 and 16% MSC-CM had a significant stimulatory effect on A549 cellular proliferation (0.24+/-0.03 and 0.24+/-0.04, respectively, P<0.01). A549 cells cultured with MSC-CM were protected from BLM-induced apoptosis, 23.43+/-3.76% vs. 38.06+/-4.32%; (P<0.05). In the BLM-challenged rats, MSC-CM was shown to protect against lung fibrosis in terms of lung inflammation, fibrotic scores, collagen deposition, and cell apoptosis. This data suggests that MSCs are capable of protecting against lung injury and fibrosis both in vitro and in vivo through a paracrine anti inflammatory mechanism. MSC-CM may provide a novel approach for the treatment of lung fibrosis. PMID- 25514922 TI - Beneficial effects of the micronized purified flavonoid fraction (MPFF, Daflon(r) 500 mg) on microvascular damage elicited by sclerotherapy. AB - OBJECTIVES: To evaluate if the micronized purified flavonoid fraction (MPFF) treatment could reduce the side effects of sclerotherapy (a procedure frequently used to treat venous disease manifestations) by minimizing the inflammatory response within the surrounding tissues. METHOD: Twenty-two male New Zealand rabbits were treated by gavage with micronized purified flavonoid fraction (MPFF; 300 mg/kg/day) or vehicle (10% lactose solution) during 21 consecutive days, starting 7 days before sclerotherapy. The sclerotherapy consisted of an injection containing 5% ethanolamine oleate solution in the rabbit's dorsal ear vein. Before and after sclerotherapy, venular and arteriolar diameters, microvascular permeability, functional capillary density (FCD), number of rolling and sticking leukocytes were evaluated on ear microcirculation. Images of the sclerotherapy site were taken before and after the procedure. RESULTS: Compared to placebo, MPFF treatment prevented the increase in venular diameter, preserved FCD (P < 0.001) and reduced the number of leaky sites (P < 0.001) and sticking leukocytes (P < 0.001). Imaging confirmed these effects on thrombosis and perivascular edema of the sclerosed vein, 14 days after procedure. CONCLUSION: MPFF treatment limited the postsclerotherapy inflammation in surrounding microvascular network, suggesting that MPFF may prevent undesirable secondary effects of the procedure in this animal model. This study warrants further investigation for its use in clinical conditions. PMID- 25514923 TI - Air contamination in the sclerosing foam for the treatment of varicose veins. AB - BACKGROUND: Fluids and drugs formulated for intravenous infusion may potentially promote the growth of microorganisms that can cause infections. The aim of this study is to test the sterility of sclerosing foam. METHODS: Polidocanol was used for the production of the foam. The Tessari method was used in order to generate the foam. The preparation was carried out both in the operating theater and in an outpatient room. A validation test with microorganisms was also performed. RESULTS: The measurements showed no evident growth of microorganisms and in the validation tests the foam appeared to even display bacteriostatic and/or bactericide properties. CONCLUSIONS: Sclerosing foam seems to be safe from a microbiological point of view. PMID- 25514924 TI - NERF encodes a RING E3 ligase important for drought resistance and enhances the expression of its antisense gene NFYA5 in Arabidopsis. AB - NFYA5 is an important drought-stress inducible transcription factor gene that is targeted by miR169 in Arabidopsis. We show here that the cis-natural antisense transcript gene of NFYA5, NFYA5 Enhancing RING FINGER (NERF), can produce siRNAs from their overlapping region (OR) and affect NFYA5 transcripts by functioning together with miR169. The NERF protein functions as an E3 ligase for ubiquitination. Overexpression of NERF or OR cDNA leads to siRNANERF accumulation, miR169 repression, and NFYA5 transcript enhancement; knock-down of NERF transcripts by an artificial miRNA enhances miR169 abundance and reduces NFYA5 transcripts. Overexpression of NFYA5 does not affect the NERF mRNA level. Deep sequencing of the small RNA library from 35S::OR plants identifies 960 sequences representing 323 unique siRNAs that originate from OR; the sequences of some siRNANERF are similar/complementary to those of miR169. Overexpression of the 195- to 280-bp OR cDNA-containing siRNAs similar/complementary to miR169 also leads to the accumulation of NFYA5 transcripts. Analysis of NERF knock-down plants and NERF overexpression lines showed that, like NFYA5, NERF is important for controlling stomatal aperture and drought resistance. This regulatory model might apply to other natural antisense transcripts with positively correlated expression patterns. PMID- 25514925 TI - Multilayer regulatory mechanisms control cleavage factor I proteins in filamentous fungi. AB - Cleavage factor I (CFI) proteins are core components of the polyadenylation machinery that can regulate several steps of mRNA life cycle, including alternative polyadenylation, splicing, export and decay. Here, we describe the regulatory mechanisms that control two fungal CFI protein classes in Magnaporthe oryzae: Rbp35/CfI25 complex and Hrp1. Using mutational, genetic and biochemical studies we demonstrate that cellular concentration of CFI mRNAs is a limited indicator of their protein abundance. Our results suggest that several post transcriptional mechanisms regulate Rbp35/CfI25 complex and Hrp1 in the rice blast fungus, some of which are also conserved in other ascomycetes. With respect to Rbp35, these include C-terminal processing, RGG-dependent localization and cleavage, C-terminal autoregulatory domain and regulation by an upstream open reading frame of Rbp35-dependent TOR signalling pathway. Our proteomic analyses suggest that Rbp35 regulates the levels of proteins involved in melanin and phenylpropanoids synthesis, among others. The drastic reduction of fungal CFI proteins in carbon-starved cells suggests that the pre-mRNA processing pathway is altered. Our findings uncover broad and multilayer regulatory mechanisms controlling fungal polyadenylation factors, which have profound implications in pre-mRNA maturation. This area of research offers new avenues for fungicide design by targeting fungal-specific proteins that globally affect thousands of mRNAs. PMID- 25514927 TI - Silent myocardial infarction and stroke: findings of multimodality imaging. PMID- 25514926 TI - PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. AB - PhosphoSitePlus((r)) (PSP, http://www.phosphosite.org/), a knowledgebase dedicated to mammalian post-translational modifications (PTMs), contains over 330,000 non-redundant PTMs, including phospho, acetyl, ubiquityl and methyl groups. Over 95% of the sites are from mass spectrometry (MS) experiments. In order to improve data reliability, early MS data have been reanalyzed, applying a common standard of analysis across over 1,000,000 spectra. Site assignments with P > 0.05 were filtered out. Two new downloads are available from PSP. The 'Regulatory sites' dataset includes curated information about modification sites that regulate downstream cellular processes, molecular functions and protein protein interactions. The 'PTMVar' dataset, an intersect of missense mutations and PTMs from PSP, identifies over 25,000 PTMVars (PTMs Impacted by Variants) that can rewire signaling pathways. The PTMVar data include missense mutations from UniPROTKB, TCGA and other sources that cause over 2000 diseases or syndromes (MIM) and polymorphisms, or are associated with hundreds of cancers. PTMVars include 18 548 phosphorlyation sites, 3412 ubiquitylation sites, 2316 acetylation sites, 685 methylation sites and 245 succinylation sites. PMID- 25514928 TI - History taking as a diagnostic test in patients with syncope: developing expertise in syncope. PMID- 25514929 TI - Corrigendum to: cardiovascular disease in Europe 2014: epidemiological update. PMID- 25514930 TI - Impaired P2X signalling pathways in renal microvascular myocytes in genetic hypertension. AB - AIMS: P2X receptors (P2XRs) mediate sympathetic control and autoregulation of renal circulation triggering preglomerular vasoconstriction, which protects glomeruli from elevated pressures. Although previous studies established a casual link between glomerular susceptibility to hypertensive injury and decreased preglomerular vascular reactivity to P2XR activation, the mechanisms of attenuation of the P2XR signalling in hypertension remained unknown. We aimed to analyse molecular mechanisms of the impairment of P2XR signalling in renal vascular smooth muscle cells (RVSMCs) in genetic hypertension. METHODS AND RESULTS: We compared the expression of pertinent genes and P2XR-linked Ca(2+) entry and Ca(2+) release mechanisms in RVSMCs of spontaneously hypertensive rats (SHRs) and their normotensive controls, Wistar Kyoto (WKY) rats. We found that, in SHR RVSMCs, P2XR-linked Ca(2+) entry and Ca(2+) release from the sarcoplasmic reticulum (SR) are both significantly reduced. The former is due to down regulation of the P2X1 subunit. The latter is caused by a decrease of the SR Ca(2+) load. The SR Ca(2+) load reduction is caused by attenuated Ca(2+) uptake via down-regulated sarco-/endoplasmic reticulum Ca(2+)-ATPase 2b and elevated Ca(2+) leak from the SR via ryanodine receptors (RyRs) and inositol 1,4,5 trisphosphate receptors. Spontaneous activity of these Ca(2+)-release channels is augmented due to up-regulation of RyR type 2 and elevated IP3 production by up regulated phospholipase C-beta1. CONCLUSIONS: Our study unravels the cellular and molecular mechanisms of attenuation of P2XR-mediated preglomerular vasoconstriction that elevates glomerular susceptibility to harmful hypertensive pressures. This provides an important impetus towards understanding of the pathology of hypertensive renal injury. PMID- 25514931 TI - Uncoupling protein 3 mediates H2O2 preconditioning-afforded cardioprotection through the inhibition of MPTP opening. AB - AIMS: Uncoupling protein 3 (UCP3), located in the mitochondrial inner membrane, is cardioprotective, but its mechanisms of preserving mitochondrial function during ischaemia/reperfusion (I/R) are not fully understood. This study investigated whether UCP3 mediates/mimics the cardioprotection of H2O2 preconditioning (H2O2PC) against I/R injury and the downstream pathway that mediates H2O2PC- and UCP3-afforded cardioprotection. METHODS AND RESULTS: H2O2PC at 20 uM for 5 min significantly improved post-ischaemic functional recovery and reduced lactate dehydrogenase (LDH) release and infarct size with concurrently up regulated UCP3 expressions in perfused rat hearts subjected to global no-flow I/R. These protections were blocked by UCP3 knockdown with short hairpin RNA but mimicked by UCP3 overexpression. Consistently, H2O2PC-attenuated I/R-induced cytosolic and mitochondrial Ca(2+) overload, Ca(2+) transient suppression, mitochondrial reactive oxygen species burst, and loss of mitochondrial inner membrane potential were reversed by UCP3 knockdown but mimicked by UCP3 overexpression. Moreover, co-immunoprecipitation assay revealed an interaction of UCP3 with the mitochondrial permeability transition pore (mPTP) component, adenine nucleotide translocator (ANT), while the cardioprotection induced by H2O2PC- and UCP3 overexpression in mitochondria, cardiac function, and cell survival was abolished by atractyloside, a mPTP opener binding to ANT, and partially inhibited by a PI3K/Akt inhibitor wortmannin. Furthermore, H2O2PC up regulated the phosphorylation of Akt, and glycogen synthase kinase 3beta was blocked by UCP3 knockdown but mimicked by UCP3 overexpression. CONCLUSION: UCP3 mediates the cardioprotection of H2O2PC against I/R injury by preserving the mitochondrial function through inhibiting mPTP opening via the interaction with ANT and the PI3K/Akt pathway. Our findings reveal novel mechanisms of UCP3 in the cardioprotection. PMID- 25514932 TI - Optogenetic release of norepinephrine from cardiac sympathetic neurons alters mechanical and electrical function. AB - AIMS: Release of norepinephrine (NE) from sympathetic neurons enhances heart rate (HR) and developed force through activation of beta-adrenergic receptors, and this sympathoexcitation is a key risk for the generation of cardiac arrhythmias. Studies of beta-adrenergic modulation of cardiac function typically involve the administration of exogenous beta-adrenergic receptor agonists to directly elicit global beta-adrenergic receptor activation by bypassing the involvement of sympathetic nerve terminals. In this work, we use a novel method to activate sympathetic fibres within the myocardium of Langendorff-perfused hearts while measuring changes in electrical and mechanical function. METHODS AND RESULTS: The light-activated optogenetic protein channelrhodopsin-2 (ChR2) was expressed in murine catecholaminergic sympathetic neurons. Sympathetic fibres were then photoactivated to examine changes in contractile force, HR, and cardiac electrical activity. Incidence of arrhythmia was measured with and without exposure to photoactivation of sympathetic fibres, and hearts were optically mapped to detect changes in action potential durations and conduction velocities. Results demonstrate facilitation of both developed force and HR after photostimulated release of NE, with increases in contractile force and HR of 34.5 +/- 5.5 and 25.0 +/- 9.3%, respectively. Photostimulation of sympathetic fibres also made hearts more susceptible to arrhythmia, with greater incidence and severity. In addition, optically mapped action potentials displayed a small but significant shortening of the plateau phase (-5.5 +/- 1.0 ms) after photostimulation. CONCLUSION: This study characterizes a powerful and clinically relevant new model for studies of cardiac arrhythmias generated by increasing the activity of sympathetic nerve terminals and the resulting activation of myocyte beta-adrenergic receptors. PMID- 25514934 TI - Hypoxia induces autophagy in human vascular endothelial cells in a hypoxia inducible factor 1-dependent manner. AB - Hypoxia has been widely implicated in numerous pathological conditions, including those associated with inflammation and tumorigenesis. A number of recent studies have implicated hypoxia in the control of microvascular damage, the basis for which is not fully understood. In the present study, it was identified that autophagy was induced in human umbilical vein endothelial cells (HUVECs) post treatment with hypoxia, and the induction of autophagy by hypoxia was enhanced by hypoxia-inducible factor 1 (HIF-1) gene overexpression and inhibited by HIF-1 knockout. Furthermore, the autophagy induced by overexpression of HIF-1 was associated with a reduction of HUVEC cell viability. Therefore, HIF-1 reduced HUVEC cell viability by inducing autophagy. These findings provide evidence of an important link between hypoxia and microvascular damage associated with HIF-1 related autophagy. PMID- 25514933 TI - Na+ ions as spatial intracellular messengers for co-ordinating Ca2+ signals during pH heterogeneity in cardiomyocytes. AB - AIMS: Contraction of the heart is regulated by electrically evoked Ca(2+) transients (CaTs). H(+) ions, the end products of metabolism, modulate CaTs through direct interactions with Ca(2+)-handling proteins and via Na(+)-mediated coupling between acid-extruding proteins (e.g. Na(+)/H(+) exchange, NHE1) and Na(+)/Ca(2+) exchange. Restricted H(+) diffusivity in cytoplasm predisposes pH sensitive Ca(2+) signalling to becoming non-uniform, but the involvement of readily diffusible intracellular Na(+) ions may provide a means for combatting this. METHODS AND RESULTS: CaTs were imaged in fluo3-loaded rat ventricular myocytes paced at 2 Hz. Cytoplasmic [Na(+)] ([Na(+)]i) was imaged using SBFI. Intracellular acidification by acetate exposure raised diastolic and systolic [Ca(2+)] (also observed with acid-loading by ammonium prepulse or CO2 exposure). The systolic [Ca(2+)] response correlated with a rise in [Na(+)]i and sarcoplasmic reticulum Ca(2+) load, and was blocked by the NHE1 inhibitor cariporide (CO2/HCO3(-)-free media). Exposure of one half of a myocyte to acetate using dual microperfusion (CO2/HCO3(-)-free media) raised diastolic [Ca(2+)] locally in the acidified region. Systolic [Ca(2+)] and CaT amplitude increased more uniformly along the length of the cell, but only when NHE1 was functional. Cytoplasmic Na(+) diffusivity (DNa) was measured in quiescent cells, with strophanthidin present to inhibit the Na(+)/K(+) pump. With regional acetate exposure to activate a local NHE-driven Na(+)-influx, DNa was found to be sufficiently fast (680 um(2)/s) for transmitting the pH-systolic Ca(2+) interaction over long distances. CONCLUSIONS: Na(+) ions are rapidly diffusible messengers that expand the spatial scale of cytoplasmic pH-CaT interactions, helping to co-ordinate global Ca(2+) signalling during conditions of intracellular pH non-uniformity. PMID- 25514935 TI - The insulinotrophic effect of insulin-like peptide 5 in vitro and in vivo. AB - Insulin-like peptide 5 (INSL5), a member of the insulin/relaxin superfamily, can activate the G-protein-coupled receptor relaxin/insulin-like family peptide receptor 4 (RXFP4), but its precise biological functions are largely unknown. Recent studies suggest that INSL5/RXFP4 is involved in the control of food intake and glucose homoeostasis. We report in the present study that RXFP4 is present in the mouse insulinoma cell line MIN6 and INSL5 augments glucose-stimulated insulin secretion (GSIS) both in vitro and in vivo. RXFP4 is also expressed in the mouse intestinal L-cell line GLUTag and INSL5 is capable of potentiating glucose dependent glucagon-like peptide-1 (GLP-1) secretion in GLUTag cells. We propose that the insulinotrophic effect of INSL5 is probably mediated through stimulation of insulin/GLP-1 secretion and the INSL5/RXFP4 system may be a potential therapeutic target for Type 2 diabetes. PMID- 25514936 TI - The sound of one hand clapping: overdetermination and the pansensory nature of communication. AB - Two substantive issues are relevant to discussions of the evolution of acoustic communication and merit further consideration here. The first is the importance of communicative ontogeny and the impact of the proximal social environment on the early development of communication and language. The second is the emerging evidence for a number of non-linguistic roles of FOXP2 and its orthologs. PMID- 25514937 TI - Comparative analyses of speech and language converge on birds. AB - Unlike nonhuman primates, thousands of bird species have articulatory capabilities that equal or surpass those of humans, and they develop their vocalizations through vocal imitation in a way that is very similar to how human infants learn to speak. An understanding of how speech mechanisms have evolved is therefore unlikely to yield key insights into how the human brain is special. PMID- 25514938 TI - Beyond cry and laugh: toward a multilevel model of language production. AB - Language production is a multilevel phenomenon, and human capacities to communicate vocally progress from early forms, based on projections of motor cortex to brainstem nuclei, to complex elaborations, mediated by high-order cognition and fostered by socially mediated feedback. PMID- 25514939 TI - The evolution of coordinated vocalizations before language. AB - Ackermann et al. briefly point out the potential significance of coordinated vocal behavior in the dual pathway model of acoustic communication. Rhythmically entrained and articulated pre-linguistic vocal activity in early hominins might have set the evolutionary stage for later refinements that manifest in modern humans as language-based conversational turn-taking, joint music-making, and other behaviors associated with prosociality. PMID- 25514940 TI - Environments organize the verbal brain. AB - FOXP2 expression in the evolution of language derives from its role in allowing vocal articulation that is sensitive to its consequences. The discrete verbal discourse it allows must have evolved recently relative to affective features of vocal behavior such as tone of voice. Because all organ systems must have evolved in the service of behavior, attention is given to ways in which environments may have driven brain organization. PMID- 25514941 TI - Evolution of affective and linguistic disambiguation under social eavesdropping pressures. AB - Contradicting new dual-pathway models of language evolution, cortico-striatal thalamic circuitry disambiguate uncertainties in affective prosody and propositional linguistic content of language production and comprehension, predictably setting limits on useful complexity of articulate phonic and/or signed speech. Such limits likely evolved to ensure public information is discriminated by intended communicants and safeguarded against the ecological pressures of social eavesdropping within and across phylogenetic boundaries. PMID- 25514942 TI - Physical mechanisms may be as important as brain mechanisms in evolution of speech. AB - We present two arguments why physical adaptations for vocalization may be as important as neural adaptations. First, fine control over vocalization is not easy for physical reasons, and modern humans may be exceptional. Second, we present an example of a gorilla that shows rudimentary voluntary control over vocalization, indicating that some neural control is already shared with great apes. PMID- 25514943 TI - Very young infants' responses to human and nonhuman primate vocalizations. AB - Recent evidence from very young human infants' responses to human and nonhuman primate vocalizations offers new insights - and brings new questions - to the forefront for those who seek to integrate primate-general and human-specific mechanisms of acoustic communication with theories of language acquisition. PMID- 25514944 TI - Functional neuroimaging of human vocalizations and affective speech. AB - Neuroimaging studies have verified the important integrative role of the basal ganglia during affective vocalizations. They, however, also point to additional regions supporting vocal monitoring, auditory-motor feedback processing, and online adjustments of vocal motor responses. For the case of affective vocalizations, we suggest partly extending the model to fully consider the link between primate-general and human-specific neural components. PMID- 25514945 TI - Functions of the cortico-basal ganglia circuits for spoken language may extend beyond emotional-affective modulation in adults. AB - We support Ackermann et al.'s proposal that the cortico-basal ganglia circuits may play essential roles in the evolution of spoken language. Here we discuss further evidence indicating that the cortico-basal ganglia circuits may contribute to various aspects of spoken language including planning, learning, and controlling of speech in adulthood. PMID- 25514946 TI - Does it talk the talk? On the role of basal ganglia in emotive speech processing. AB - Ackermann et al.'s phylogenetic account of speech argues that the basal ganglia imbue speech with emotive content. However, a body of work on auditory/emotive processing is inconsistent with attributing this function exclusively to these structures. The account further overlooks the possibility that the emotion integration function may be at least in part mediated by the cortico-ponto cerebellar system. PMID- 25514948 TI - Neanderthals did speak, but FOXP2 doesn't prove it. AB - Ackermann et al. treat both genetic and paleoanthropological data too superficially to support their conclusions. The case of FOXP2 and Neanderthals is a prime example, which I will comment on in some detail; the issues are much more complex than they appear in Ackermann et al. PMID- 25514947 TI - Differences in auditory timing between human and nonhuman primates. AB - The gradual audiomotor evolution hypothesis is proposed as an alternative interpretation to the auditory timing mechanisms discussed in Ackermann et al.'s article. This hypothesis accommodates the fact that the performance of nonhuman primates is comparable to humans in single-interval tasks (such as interval reproduction, categorization, and interception), but shows differences in multiple-interval tasks (such as entrainment, synchronization, and continuation). PMID- 25514949 TI - The forgotten role of consonant-like calls in theories of speech evolution. AB - Ackermann et al. provide an informative neurological road-map to primate call communication. However, the proposed model for speech evolution inadequately integrates comparative primate evidence. Critically, great ape voiceless calls are explicitly rendered unimportant, leaving the proposed model deprived of behavioral feedstock and proximate selective drivers capable of triggering the neurological transformations described by the authors in the primate brain. PMID- 25514950 TI - Early human communication helps in understanding language evolution. AB - Building a theory on extant species, as Ackermann et al. do, is a useful contribution to the field of language evolution. Here, I add another living model that might be of interest: human language ontogeny in the first year of life. A better knowledge of this phase might help in understanding two more topics among the "several building blocks of a comprehensive theory of the evolution of spoken language" indicated in their conclusion by Ackermann et al., that is, the foundation of the co-evolution of linguistic motor skills with the auditory skills underlying speech perception, and the possible phylogenetic interactions of protospeech production with referential capabilities. PMID- 25514951 TI - Why we can talk, debate, and change our minds: neural circuits, basal ganglia operations, and transcriptional factors. AB - Ackermann et al. disregard attested knowledge concerning aphasia, Parkinson disease, cortical-to-striatal circuits, basal ganglia, laryngeal phonation, and other matters. Their dual-pathway model cannot account for "what is special about the human brain." Their human cortical-to-laryngeal neural circuit does not exist. Basal ganglia operations, enhanced by mutations on FOXP2, confer human motor-control, linguistic, and cognitive capabilities. PMID- 25514952 TI - En route to disentangle the impact and neurobiological substrates of early vocalizations: learning from Rett syndrome. AB - Research on acoustic communication and its underlying neurobiological substrates has led to new insights about the functioning of central pattern generators (CPGs). CPG-related atypicalities may point to brainstem irregularities rather than cortical malfunctions for early vocalizations/babbling. The "vocal pattern generator," together with other CPGs, seems to have great potential in disentangling neurodevelopmental disorders and potentially predict neurological development. PMID- 25514953 TI - Speech as a breakthrough signaling resource in the cognitive evolution of biological complex adaptive systems. AB - In self-adapting dynamical systems, a significant improvement in the signaling flow among agents constitutes one of the most powerful triggering events for the emergence of new complex behaviors. Ackermann and colleagues' comprehensive phylogenetic analysis of the brain structures involved in acoustic communication provides further evidence of the essential role which speech, as a breakthrough signaling resource, has played in the evolutionary development of human cognition viewed from the standpoint of complex adaptive system analysis. PMID- 25514954 TI - Voluntary and involuntary processes affect the production of verbal and non verbal signals by the human voice. AB - We argue that a comprehensive model of human vocal behaviour must address both voluntary and involuntary aspects of articulate speech and non-verbal vocalizations. Within this, plasticity of vocal output should be acknowledged and explained as part of the mature speech production system. PMID- 25514955 TI - Why vocal production of atypical sounds in apes and its cerebral correlates have a lot to say about the origin of language. AB - Ackermann et al. mention the "acquisition of species-atypical sounds" in apes without any discussion. In our commentary, we demonstrate that these atypical sounds in chimpanzees not only include laryngeal sounds, but also have a major significance regarding the origins of language, if we consider looking at their context of use, their social properties, their relations with gestures, their lateralization, and their neurofunctional correlates as well. PMID- 25514956 TI - Speech, vocal production learning, and the comparative method. AB - The faith that "comparative analysis of the behaviour of modern primates, in conjunction with an accurate phylogenetic tree of relatedness, has the power to chart the early history of human cognitive evolution" (Byrne 2000 p. 543) runs afoul of the fact that no other primate besides humans is capable of vocal production learning. This basic enabling adaptation for articulate speech bears crucially on the reconstruction of language origins. PMID- 25514957 TI - Phonation takes precedence over articulation in development as well as evolution of language. AB - Early human vocal development is characterized first by emerging control of phonation and later by prosodic and supraglottal articulation. The target article has missed the opportunity to use these facts in the characterization of evolution in language-specific brain mechanisms. Phonation appears to be the initial human-specific brain change for language, and it was presumably a key target of selection in early hominin evolution. PMID- 25514958 TI - The basal ganglia within a cognitive system in birds and mammals. AB - The primate basal ganglia are fundamental to Ackermann et al.'s proposal. However, primates and rodents are models for human cognitive functions involving basal ganglia circuits, and links between striatal function and vocal communication come from songbirds. We suggest that the proposal is better integrated in cognitive and/or motor theories on spoken language origins and with more analogous nonhuman animal models. PMID- 25514959 TI - The sensorimotor and social sides of the architecture of speech. AB - Speech is a complex skill to master. In addition to sophisticated phono articulatory abilities, speech acquisition requires neuronal systems configured for vocal learning, with adaptable sensorimotor maps that couple heard speech sounds with motor programs for speech production; imitation and self-imitation mechanisms that can train the sensorimotor maps to reproduce heard speech sounds; and a "pedagogical" learning environment that supports tutor learning. PMID- 25514960 TI - Vocal learning, prosody, and basal ganglia: don't underestimate their complexity. AB - Ackermann et al.'s arguments in the target article need sharpening and rethinking at both mechanistic and evolutionary levels. First, the authors' evolutionary arguments are inconsistent with recent evidence concerning nonhuman animal rhythmic abilities. Second, prosodic intonation conveys much more complex linguistic information than mere emotional expression. Finally, human adults' basal ganglia have a considerably wider role in speech modulation than Ackermann et al. surmise. PMID- 25514961 TI - Perceptual elements in brain mechanisms of acoustic communication in humans and nonhuman primates. AB - Ackermann et al. outline a model for elaboration of subcortical motor outputs as a driving force for the development of the apparently unique behaviour of language in humans. They emphasize circuits in the striatum and midbrain, and acknowledge, but do not explore, the importance of the auditory perceptual pathway for evolution of verbal communication. We suggest that understanding the evolution of language will also require understanding of vocalization perception, especially in the auditory cortex. PMID- 25514962 TI - Vocal communication is multi-sensorimotor coordination within and between individuals. AB - Speech is an exquisitely coordinated interaction among effectors both within and between individuals. No account of human communication evolution that ignores its foundational multisensory characteristics and cooperative nature will be satisfactory. Here, we describe two additional capacities - rhythmic audiovisual speech and cooperative communication - and suggest that they may utilize the very same or similar circuits as those proposed for vocal learning. PMID- 25514963 TI - Speech prosody, reward, and the corticobulbar system: an integrative perspective. AB - Speech prosody is essential for verbal communication. In this commentary I provide an integrative overview, arguing that speech prosody is subserved by the same anatomical and neurochemical mechanisms involved in the processing of reward/affective outcomes. PMID- 25514965 TI - Contribution of the basal ganglia to spoken language: is speech production like the other motor skills? AB - Two of the roles assigned to the basal ganglia in spoken language parallel very well their contribution to motor behaviour: (1) their role in sequence processing, resulting in syntax deficits, and (2) their role in movement "vigor," leading to "hypokinetic dysarthria" or "hypophonia." This is an additional example of how the motor system has served the emergence of high-level cognitive functions, such as language. PMID- 25514966 TI - 3D vasculature segmentation using localized hybrid level-set method. AB - BACKGROUND: Intensity inhomogeneity occurs in many medical images, especially in vessel images. Overcoming the difficulty due to image inhomogeneity is crucial for the segmentation of vessel image. METHODS: This paper proposes a localized hybrid level-set method for the segmentation of 3D vessel image. The proposed method integrates both local region information and boundary information for vessel segmentation, which is essential for the accurate extraction of tiny vessel structures. The local intensity information is firstly embedded into a region-based contour model, and then incorporated into the level-set formulation of the geodesic active contour model. Compared with the preset global threshold based method, the use of automatically calculated local thresholds enables the extraction of the local image information, which is essential for the segmentation of vessel images. RESULTS: Experiments carried out on the segmentation of 3D vessel images demonstrate the strengths of using locally specified dynamic thresholds in our level-set method. Furthermore, both qualitative comparison and quantitative validations have been performed to evaluate the effectiveness of our proposed model. CONCLUSIONS: Experimental results and validations demonstrate that our proposed model can achieve more promising segmentation results than the original hybrid method does. PMID- 25514967 TI - At the brink of eusociality: transcriptomic correlates of worker behaviour in a small carpenter bee. AB - BACKGROUND: There is great interest in understanding the genomic underpinnings of social evolution, in particular, the evolution of eusociality (caste-containing societies with non-reproductives that care for siblings). Subsociality is a key precursor for the evolution of eusociality and characterized by prolonged parental care and parent-offspring interaction. Here, we provide the first transcriptomic data for the small carpenter bee, Ceratina calcarata. This species is of special interest because it is subsocial and in the same family as the highly eusocial honey bee, Apis mellifera. In addition, some C. calcarata females demonstrate alloparental care without reproduction, which provides a unique opportunity to study worker behaviour in a non-eusocial species. RESULTS: We uncovered similar gene expression patterns related to maternal care and sibling care in different groups of females. This agrees with the maternal heterochrony hypothesis, specifically, that changes in timing of offspring care gene expression are related to worker behaviour in incipient insect societies. In addition, we also detected some similarity to caste-related gene expression patterns in highly eusocial honey bees, and uncovered large lifetime changes in gene expression that accompany shifts in reproductive and maternal care behaviour. CONCLUSIONS: For Ceratina calcarata, we found that transcript expression profiles were most similar between sibling care and maternal care females. The maternal care behaviour exhibited post-reproductively by Ceratina mothers is concordant in terms of transcript expression with the alloparental care exhibited by workers. In line with theoretical predictions, our data are consistent with the maternal heterochrony hypothesis for the evolutionary development of worker behaviour in subsocial bees. PMID- 25514969 TI - Imidazo[1,2-a]pyridines as cholesterol 24-hydroxylase (CYP46A1) inhibitors: a patent evaluation (WO2014061676). AB - A series of imidazo[1,2-a]pyridine analogs that effectively inhibit cholesterol 24-hydroxylase (CYP46A1) was reported in WO2014061676. The treatment or prophylaxis of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, by these novel CYP46A1 inhibitors is claimed in the patent. These compounds represent a novel pharmacophore that is different from other structural motifs described in the prior patent publications by Takeda Pharmaceutical Company Ltd. PMID- 25514968 TI - Predictors of urinary incontinence in community-dwelling frail older adults with diabetes mellitus in a cross-sectional study. AB - BACKGROUND: Diabetes mellitus is a potent risk factor for urinary incontinence. Previous studies of incontinence in patients with diabetes have focused on younger, healthier patients. Our objective was to characterize risk factors for urinary incontinence among frail older adults with diabetes mellitus in a real world clinical setting. METHODS: We performed a cross-sectional analysis on enrollees at On Lok (the original Program for All-Inclusive Care of the Elderly) between October 2004 and December 2010. Enrollees were community-dwelling, nursing home-eligible older adults with diabetes mellitus (N = 447). Our outcome was urinary incontinence measures (n = 2602) assessed every 6 months as "never incontinent", "seldom incontinent" (occurring less than once per week), or "often incontinent" (occurring more than once per week). Urinary incontinence was dichotomized ("never" versus "seldom" and "often" incontinent). We performed multivariate mixed effects logistic regression analysis with demographic (age, gender and ethnicity), geriatric (dependence on others for ambulation or transferring; cognitive impairment), diabetes-related factors (hemoglobin A1c level; use of insulin and other glucose-lowering medications; presence of renal, ophthalmologic, neurological and peripheral vascular complications), depressive symptoms and diuretic use. RESULTS: The majority of participants were 75 years or older (72%), Asian (65%) and female (66%). Demographic factors independently associated with incontinence included older age (OR for age >85, 3.13, 95% CI: 2.15-4.56; Reference: Age <75) and African American or other race (OR 2.12, 95% CI: 1.14-3.93; Reference: Asian). Geriatric factors included: dependence on others for ambulation (OR 1.48, 95% CI: 1.19-1.84) and transferring (OR 2.02, 95% CI: 1.58-2.58) and being cognitively impaired (OR 1.41, 95% CI: 1.15-1.73). Diabetes-related factors associated included use of insulin (OR 2.62, 95% CI: 1.67-4.13) and oral glucose-lowering agents (OR 1.81, 95% CI: 1.33-2.45). Urinary incontinence was not associated with gender, hemoglobin A1c level or depressive symptoms. CONCLUSIONS: Geriatric factors such as the inability to ambulate or transfer independently are important predictors of urinary incontinence among frail older adults with diabetes mellitus. Clinicians should address mobility and cognitive impairment as much as diabetes-related factors in their assessment of urinary incontinence in this population. PMID- 25514972 TI - Supported gold nanoparticle-catalyzed hydration of alkynes under basic conditions. AB - TiO2-supported nanosize gold particles catalyze the hydration of alkynes using morpholine as a basic cocatalyst. Unlike most homogeneous cationic gold catalysts, the TiO2-Au/morpholine system is weakly basic and is compatible with acid-sensitive functional groups (e.g., silyl ethers, ketals) or with a strongly coordinating group such as pyridine. What's more, this gold catalyst can be recycled by simple filtration and works well in flow reactors. PMID- 25514970 TI - Why do doctors emigrate from Sri Lanka? A survey of medical undergraduates and new graduates. AB - BACKGROUND: Migration of medical professionals is a long recognized problem in Sri Lanka, but it has not been studied in depth. Undergraduate and postgraduate medical education in Sri Lanka is state sponsored, and loss of trained personnel is a loss of investment. This study assessed the intention to migrate among medical students and newly passed out graduates from the largest medical school in Sri Lanka. METHODS: A cross sectional descriptive study was conducted in the Faculty of Medicine, University of Colombo in September 2013 with the participation of first and fourth year medical students and pre-intern medical graduates. Data was collected using a self administered, pre-tested questionnaire that collected data on socio-demographic details, intention to migrate and factors influencing a decision for or against migration. RESULTS: There were 374 respondents, 162 from first year (females; 104, 64.2%), 159 from fourth year (females; 85, 53.5%) and 53 pre interns (females; 22, 41.5%). Of the entire sample, 89 (23.8%) had already decided to migrate while another 121 (32.3%) were not sure of their decision. The most cited reasons for migration were a perceived better quality of life, better earnings and more training opportunities in the host country. There were no socio-demographic characteristics that had a significant association with the intention to migrate, indicating that it is a highly individualized decision. CONCLUSIONS: The rate of intention to migrate in this sample is low when compared to international studies from Africa and South Asia, but is still significant. The core reasons which prompt doctors to migrate should be addressed by a multipronged approach to prevent brain drain. PMID- 25514971 TI - Multiplex PCR analysis of clusters of unexplained viral respiratory tract infection in Cambodia. AB - BACKGROUND: Fevers of unknown origin constitute a substantial disease burden in Southeast Asia. In majority of the cases, the cause of acute febrile illness is not identified. METHODS: We used MassTag PCR, a multiplex assay platform, to test for the presence of 15 viral respiratory agents from 85 patients with unexplained respiratory illness representing six disease clusters that occurred in Cambodia between 2009 and 2012. RESULTS: We detected a virus in 37 (44%) of the cases. Human rhinovirus, the virus detected most frequently, was found in both children and adults. The viruses most frequently detected in children and adults, respectively, were respiratory syncytial virus and enterovirus 68. Sequence analysis indicated that two distinct clades of enterovirus 68 were circulating during this time period. CONCLUSIONS: This is the first report of enterovirus 68 in Cambodia and contributes to the appreciation of this virus as an important respiratory pathogen. PMID- 25514973 TI - Improved nutrient intake following implementation of the consensus standardised parenteral nutrition formulations in preterm neonates--a before-after intervention study. AB - BACKGROUND: New standardised parenteral nutrition (SPN) formulations were implemented in July 2011 in many neonatal intensive care units in New South Wales following consensus group recommendations. The aim was to evaluate the efficacy and safety profile of new consensus formulations in preterm infants born less than 32 weeks. METHODS: A before-after intervention study conducted at a tertiary neonatal intensive care unit. Data from the post-consensus cohort (2011 to 2012) were prospectively collected and compared retrospectively with a pre-consensus cohort of neonates (2010). RESULTS: Post-consensus group commenced parenteral nutrition (PN) significantly earlier (6 v 11 hours of age, p 0.005). In comparison to the pre-consensus cohort, there was a higher protein intake from day 1 (1.34 v 0.49 g/kg, p 0.000) to day 7 (3.55 v 2.35 g/kg, p 0.000), higher caloric intake from day 1 (30 v 26 kcal/kg, p 0.004) to day 3 (64 v 62 kcal/kg, p 0.026), and less daily fluid intake from day 3 (105.8 v 113.8 mL/kg, p 0.011) to day 7 (148.8 v 156.2 mL/kg, p 0.025), and reduced duration of lipid therapy (253 v 475 hr, p 0.011). This group also had a significantly greater weight gain in the first 4 weeks (285 v 220 g, p 0.003). CONCLUSIONS: New consensus SPN solutions provided better protein intake in the first 7 days and were associated with greater weight gain in the first 4 weeks. However, protein intake on day 1 was below the consensus goal of 2 g/kg/day. PMID- 25514974 TI - Attenuation of inflammatory-mediated neurotoxicity by Saururus chinensis extract in LPS-induced BV-2 microglia cells via regulation of NF-kappaB signaling and anti-oxidant properties. AB - BACKGROUND: A Saururus chinensis Baill (SC) has been used by Native Americans, early colonists and practitioners of Korean traditional medicine for treating several diseases including cancer, rheumatoid arthritis and edema. The objective of this study was to evaluate the effects of SC extract in lipopolysaccharide (LPS)-stimulated neuroinflammatory responses in BV-2 microglial cells. METHODS: The effects of SC on the LPS-induced neuroinflammatory responses in BV-2 microglial cells were assessed by Western blotting, RT-PCR and immunofluorescence labeling techniques. DPPH and alkyl radical scavenging assay was performed to evaluate the anti-oxidant effects. Comparisons between groups were analyzed using one-way analysis of variance followed by Dunnett's multiple comparisons test using GraphPad Prism V5.01 software. RESULTS: Pre-treatment with SC extract (1, 5 and 10 MUg/mL) significantly (p < 0.001 at 10 MUg/mL) and concentration dependently inhibited LPS-induced production of nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and suppressed the inflammatory cytokine levels such as tumor necrosis factor-alpha and interleukin (IL)-6 in BV 2 microglial cells (p < 0.001 at 10 MUg/mL). Further, SC suppressed the nuclear factor-kappa B (NF-kappaB) activation by blocking the degradation of IkappaB alpha. SC also exhibited profound anti-oxidant effects by scavenging 1, 1 diphenyl-2-picrylhydrazyl (DPPH) (IC50: 0.055 mg/mL) and alkyl radicals (IC50: 0.349 mg/mL). High performance liquid chromatography finger printing analysis of SC revealed quercetin (QCT) as one of the major constituents compared with reference standard. QCT also inhibited the excessive release of NO, and inhibited the increased expressional levels of IL-6, iNOS and COX-2 in LPS-stimulated BV-2 cells. CONCLUSIONS: Our results indicated that SC inhibited the LPS-stimulated neuroinflammatory responses in BV-2 microglia via regulation of NF-kappaB signaling. The antioxidant active constituents of SC might be partly involved in delivering such effects. Based on the traditional claims and our present results SC can be potentially used in treating inflammatory-mediated neurodegenerative diseases. PMID- 25514975 TI - Identification of differentially expressed genes regulated by transcription factors in glioblastomas by bioinformatics analysis. AB - The present study aimed to identify differentially expressed genes (DEGs) regulated by transcription factors (TFs) in glioblastoma, by conducting a bioinformatics analysis. The results of the present study may provide potential therapeutic targets that are involved in the development of glioblastoma. The GSE4290 raw data set was downloaded from the Gene Expression Omnibus database, and consisted of 23 non-tumor samples and 77 glioblastoma (grade 4) tumor samples. Robust Multichip Averaging was used to identify DEGs between the glioblastoma and non-tumor samples. Functional enrichment analysis of the DEGs was also performed. Based on the TRANSFAC(r) database, TFs associated with the glioblastoma gene expression profile were used to construct a regulatory network. Furthermore, trimmed subnets were identified according to calculated Z-scores. A total of 676 DEGs were identified, of which 190 were upregulated and 496 were downregulated. Gene Ontology analysis demonstrated that the majority of these DEGs were functionally enriched in synaptic transmission, regulation of vesicle mediated transport and ion-gated channel activity. In addition, the enriched Kyoto Encyclopedia of Genes and Genomes pathway included neuroactive ligand receptor interaction, calcium signaling pathway, p53 signaling pathway and cell cycle. Based on the TRANSFAC(r) database, transcriptional regulatory networks with 2,246 nodes and 4,515 regulatory pairs were constructed. According to the Z scores, the following candidate TFs were identified: TP53, SP1, JUN, STAT3 and SPI1; alongside their downstream DEGs. TP53 was the only differentially expressed TF. These candidate TFs and their downstream DEGs may have important roles in the progression of glioblastoma, and could be potential biomarkers for clinical treatment. PMID- 25514977 TI - Identification and characterization of the interactive proteins with cytotoxic T lymphocyte antigen-2alpha. AB - Cytotoxic T-lymphocyte antigen-2alpha (CTLA-2alpha) is a potent inhibitor of cathepsin L-like cysteine proteases. Recombinant CTLA-2alpha is known to be a potent, competitive inhibitor of cathepsin L-like cysteine proteases. In this study, cathepsin L, cathepsin C, and tubulointerstitial nephritis antigen-related protein 1 (TINAGL1) were identified as novel interactive proteins of CTLA-2alpha by the yeast two-hybrid screening system. The direct interactions and co localization of these proteins with CTLA-2alpha were confirmed using co immunoprecipitation and immunofluorescence staining, respectively. The disulfide bonded CTLA-2alpha/cathepsin L complex was isolated from mouse tissue. CTLA 2alpha was found to be specific and consistently expressed on the maternal side of the mouse placenta. Double immunofluorescence analysis showed that CTLA-2alpha was co-localized with cathepsin L, cathepsin C, and TINAGL1 in placenta. A simple cell-based fluorescence assay revealed that CTLA-2alpha exhibited inhibitory activity toward cathepsin C in live cells, which indicated that CTLA-2alpha is a novel endogenous inhibitor of cathepsin C. PMID- 25514976 TI - Development of a risk-adjusted in-hospital mortality prediction model for community-acquired pneumonia: a retrospective analysis using a Japanese administrative database. AB - BACKGROUND: Community-acquired pneumonia (CAP) is a common cause of patient hospitalization and death, and its burden on the healthcare system is increasing in aging societies. Here, we develop and internally validate risk-adjustment models and scoring systems for predicting mortality in CAP patients to enable more precise measurements of hospital performance. METHODS: Using a multicenter administrative claims database, we analyzed 35,297 patients hospitalized for CAP who had been discharged between April 1, 2012 and September 30, 2013 from 303 acute care hospitals in Japan. We developed hierarchical logistic regression models to analyze predictors of in-hospital mortality, and validated the models using the bootstrap method. Discrimination of the models was assessed using c statistics. Additionally, we developed scoring systems based on predictors identified in the regression models. RESULTS: The 30-day in-hospital mortality rate was 5.8%. Predictors of in-hospital mortality included advanced age, high blood urea nitrogen level or dehydration, orientation disturbance, respiratory failure, low blood pressure, high C-reactive protein levels or high degree of pneumonic infiltration, cancer, and use of mechanical ventilation or vasopressors. Our models showed high levels of discrimination for mortality prediction, with a c-statistic of 0.89 (95% confidence interval: 0.89-0.90) in the bootstrap-corrected model. The scoring system based on 8 selected variables also showed good discrimination, with a c-statistic of 0.87 (95% confidence interval: 0.86-0.88). CONCLUSIONS: Our mortality prediction models using administrative data showed good discriminatory power in CAP patients. These risk adjustment models may support improvements in quality of care through accurate hospital evaluations and inter-hospital comparisons. PMID- 25514978 TI - Genome-wide and single-base resolution DNA methylomes of the Pacific oyster Crassostrea gigas provide insight into the evolution of invertebrate CpG methylation. AB - BACKGROUND: Studies of DNA methylomes in a wide range of eukaryotes have revealed both conserved and divergent characteristics of DNA methylation among phylogenetic groups. However, data on invertebrates particularly molluscs are limited, which hinders our understanding of the evolution of DNA methylation in metazoa. The sequencing of the Pacific oyster Crassostrea gigas genome provides an opportunity for genome-wide profiling of DNA methylation in this model mollusc. RESULTS: Homologous searches against the C. gigas genome identified functional orthologs for key genes involved in DNA methylation: DNMT1, DNMT2, DNMT3, MBD2/3 and UHRF1. Whole-genome bisulfite sequencing (BS-seq) of the oyster's mantle tissues revealed that more than 99% methylation modification was restricted to cytosines in CpG context and methylated CpGs accumulated in the bodies of genes that were moderately expressed. Young repeat elements were another major targets of CpG methylation in oysters. Comparison with other invertebrate methylomes suggested that the 5'-end bias of gene body methylation and the negative correlation between gene body methylation and gene length were the derived features probably limited to the insect lineage. Interestingly, phylostratigraphic analysis showed that CpG methylation preferentially targeted genes originating in the common ancestor of eukaryotes rather than the oldest genes originating in the common ancestor of cellular organisms. CONCLUSIONS: Comparative analysis of the oyster DNA methylomes and that of other animal species revealed that the characteristics of DNA methylation were generally conserved during invertebrate evolution, while some unique features were derived in the insect lineage. The preference of methylation modification on genes originating in the eukaryotic ancestor rather than the oldest genes is unexpected, probably implying that the emergence of methylation regulation in these 'relatively young' genes was critical for the origin and radiation of eukaryotes. PMID- 25514979 TI - Biomimetic kinetic resolution: highly enantio- and diastereoselective transfer hydrogenation of aglain ketones to access flavagline natural products. AB - We have previously reported asymmetric syntheses and absolute configuration assignments of the aglains (+)-ponapensin and (+)-elliptifoline and proposed a biosynthetic kinetic resolution process to produce enantiomeric rocaglamides and aglains. Herein, we report a biomimetic approach for the synthesis of enantiomerically enriched aglains and rocaglamides via kinetic resolution of a bridged ketone utilizing enantioselective transfer hydrogenation. The methodology has been employed to synthesize and confirm the absolute stereochemistries of the pyrimidone rocaglamides (+)-aglaiastatin and (-)-aglaroxin C. Additionally, the enantiomers and racemate of each metabolite were assayed for inhibition of the heat-shock response, cytotoxicity, and translation inhibition. PMID- 25514984 TI - Detecting and predicting balance decline in Parkinson disease: a prospective cohort study. AB - BACKGROUND: The natural progression of balance decline in individuals with Parkinson disease (PD) is not well understood. OBJECTIVES: We aimed to: 1) compare the utility of three standardized clinical measures for detecting balance decline over 1-year, 2) identify components of balance susceptible to decline, and 3) identify factors useful for predicting future balance decline. METHODS: Eighty people with PD (59% male; mean age 68.2 +/- 9.3; Hoehn & Yahr range I-IV) completed Balance Evaluation Systems Test (BESTest), Mini-BESTest, and Berg Balance Scale (BBS) assessments. Baseline predictor variables included the MDS UPDRS III sub-score, presence of freezing, 6-month fall history, age, gender, and physical activity. Balance and MDS-UPDRS III assessments were repeated at 6 (n = 51) and 12 months (n = 44). RESULTS: BESTest and Mini-BESTest score declined over 6 and 12 months (P < 0.01). Postural responses, stability limits, and sensory orientation were most susceptible to decline. BBS score did not change (P > 0.01). MDS-UPDRS III score was unchanged over 6 months (P > 0.01), but declined over 12 months (P < 0.01). Change in BESTest score over 6 months was related to baseline MDS-UPDRS III, H&Y, freezing, and fall history (P < 0.05). Change in BESTest score over 12 months was related to baseline MDS-UPDRS III and freezing (P < 0.05). Change in Mini-BESTest over 12 months was related to baseline MDS UPDRS III and age (P < 0.05). CONCLUSIONS: The BESTest and Mini-BESTest were responsive to balance decline in individuals with PD and helped to identify decline in underlying balance components. Disease severity and freezing most consistently predicted balance decline in persons with PD. PMID- 25514986 TI - African histoplasmosis: the first report of an indigenous case in India. AB - OBJECTIVES: African histoplasmosis, caused by Histoplasma capsulatum var. duboisii, is an invasive fungal infection endemic in Central and West Africa. Cases seen outside Africa are generally imported. We report a disseminated purely cutaneous form of this infection in an otherwise healthy person from Kerala, in southern India. METHODS: A 59-year-old farmer presented with asymptomatic, generalized, reddish skin lesions of five months in duration. Dermatologic examination revealed multiple erythematous papules and plaques of varying sizes, predominantly over the trunk and upper limbs. The patient was otherwise in good health. Systemic examination including the pulmonary and musculoskeletal systems revealed no abnormalities. RESULTS: Skin biopsy was performed from a lesion on the thigh. Histopathologic examination revealed epithelioid and suppurative granulomas in the upper dermis, with lymphocytes, neutrophils, and plenty of giant cells. Fite-Faraco staining for Mycobacterium leprae was negative. Fungus cultured from the specimen was identified as H. capsulatum var. duboisii, the rarer variant of H. capsulatum. The patient was treated with ketoconazole 200 mg/day for four months and attained complete clearance. No relapse has been detected over two years of follow-up. CONCLUSIONS: To the best of our knowledge, this case represents the first instance of African histoplasmosis to be reported from India. The occurrence of such a rare infection in an immunocompetent individual, who had not travelled elsewhere, raises the possibility of the indigenous existence of H. capsulatum var. duboisii in Kerala. Further studies of the ecology and epidemiology of this rare infection are essential. PMID- 25514985 TI - Educational silos in nursing education: a critical review of practical nurse education in Canada. AB - Changes to practical nurse education (with expanded scopes of practice) align with the increasing need for nurses and assistive personnel in global acute care contexts. A case in point is this critical exploration of Canadian practical nursing literature, undertaken to reveal predominating discourses and relationships to nursing disciplinary knowledge. The objectives of this poststructural critical review were to identify dominant discourses in practical nurse education literature and to analyze these discourses to uncover underlying beliefs, constructed truths, assumptions, ambiguities and sources of knowledge within the discursive landscape. Predominant themes in the discourses surrounding practical nurse education included conversations about the nurse shortage, expanded roles, collaboration, evidence-based practice, role confusion, cost/efficiency, the history of practical nurse education and employer interests. The complex relationships between practical nursing and the disciplinary landscape of nursing are revealed in the analysis of discourses related to the purpose(s) of practical nurse education, curricula/educational programming, relationships between RN and PN education and the role of nursing knowledge. Power dynamics related to employer needs and interests, as well as educational silos and the nature of women's work, are also revealed within the intersection of various discourses. PMID- 25514964 TI - Modification of spectral features by nonhuman primates. AB - Ackermann et al. discuss the lack of evidence for vocal control in nonhuman primates. We suggest that nonhuman primates may be capable of achieving greater vocal control than previously supposed. In support of this assertion, we discuss new evidence that nonhuman primates are capable of modifying spectral features in their vocalizations. PMID- 25514987 TI - Sudden cardiac arrest during sex in patients with either catecholaminergic polymorphic ventricular tachycardia or long-QT syndrome: a rare but shocking experience. AB - BACKGROUND: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) and long-QT syndrome (LQTS) are susceptible to cardiac events during sympathetic nervous system activation. Herein, we sought to determine the risk of cardiac events associated with sex in CPVT and LQTS patients. METHODS AND RESULTS: We reviewed the electronic medical record of patients seen in the Genetic Heart Rhythm Clinic. There were 445 patients >= 18 years diagnosed with LQTS (N = 402, age at diagnosis 30 +/- 16 years) or CPVT (N = 43, age at diagnosis 25 +/- 15 years). No sex-induced cardiac events occurred in the LQTS population, and 2 occurred in the CPVT population. Sex-induced events were more likely in CPVT (2/43, 4.7%) than LQTS (0/402, 0%, P = 0.008). One case involved a 22-year-old CPVT1 female with prior cardiac arrest, who experienced several appropriate implantable cardioverter defibrillator shocks during intercourse while taking beta-blockers. The second case was a 52-year-old CPVT1 male with history of recurrent exercise-triggered syncope, who had syncope during sex in the setting of beta-blocker noncompliance. Extrapolating from published estimates of intercourse frequency by age, the overall event rate was only 0.0004%, and 0.005% among the CPVT cohort. CONCLUSIONS: Potentially life-threatening cardiac events during sex in patients with CPVT are rare and even rarer in LQTS. Overall, the cardiac event per intercourse rate is extremely low. Patients and their partners should be reassured that sex is a low-risk activity from a cardiac standpoint. PMID- 25514988 TI - Panatrophy of Gowers is a rare disease: case reports and review of the literature. AB - BACKGROUND: Panatrophy of Gowers (PG) is a very rare disorder. It is characterized by a sharply defined and localized area of atrophy involving subcutaneous tissue and, on rare occasions, bone. The etiopathogenesis of this disorder is an enigma. A limited number of patients have been described in single case reports. OBJECTIVES: This article describes the clinical features and histopathological findings of PG with the aim of indicating that PG may not be as rare as it is assumed to be. METHODS: We studied patients with lesions resembling those of PG between the years 2007 and 2012. Diagnoses of PG were based on clinical and histopathological findings. RESULTS: Four female and three male patients presented with clinically and histologically identical lesions. CONCLUSIONS: This disorder is not as rare as it is assumed to be, probably because it is misdiagnosed as post-steroid atrophy; thus PG requires more attention. Seven patients with PG are reported here to counteract the supposed rarity of this disorder and to highlight findings of hypopigmentation mimicking steroid-induced atrophy. PMID- 25514989 TI - Aneurysmal bone cyst does not hinder the success of kidney transplantation. A case report. AB - Uremic osteodystrophy is an expected complication in subjects with chronic renal insufficiency. It develops gradually and progressively already during the conservative treatment and then during the dialysis treatment. It can present a wide histopathological spectrum including typical alterations (from osteitis fibrosa to osteomalacia and/or mixed lesions) or, more rarely, isolated bone lesions indicative of a brown tumor of the bone. These conditions must be clearly identified in the pretransplant phase, especially if a bone lesion indicative of a pathological condition possibly evolving into a neoplasm is detected fortuitously. We report the case of a 19-yr-old boy with renal insufficiency and candidate for a pre-emptive renal transplantation from a living donor, in whom the diagnosis of ABC of the pubic symphysis - asymptomatic and fortuitously detected while performing instrumental investigations - was suspected through the imaging studies (CT scan, MRI) and was confirmed by the histological examination. This made it possible to perform the renal transplant. The immunosuppressive treatment, which was subsequently administered, was based on steroids, calcineurin inhibitors (tacrolimus), and mycophenolate and did not determine any modification in the radiological aspect of the bone lesion, even after more than one yr from the transplant. PMID- 25514991 TI - Linear cutaneous lupus erythematosus with calcinosis cutis and milia. AB - Linear cutaneous lupus erythematosus (LCLE) is an unusual manifestation of cutaneous lupus erythematosus in which erythematous, atrophic, dyschromic lesions are located along the lines of Blaschko. Calcinosis cutis and secondary milia are very uncommon in lupus erythematosus. We present a rare case of LCLE with calcinosis cutis and milia. PMID- 25514992 TI - Inhibition of Alzheimer's amyloid-beta peptide aggregation and its disruption by a conformationally restricted alpha/beta hybrid peptide. AB - Insertion of an anthranilic acid in an amyloidogenic peptide sequence generates a novel conformationally restricted alpha/beta-hybrid peptide that inhibits amyloid formation of Abeta(1-40) and disrupts preformed fibrillar aggregates in vitro. Such beta-sheet breaker hybrid peptides (BSBHps) may be useful for designing novel physiologically important compounds relevant to diverse amyloidoses and for studying the process of aggregation. PMID- 25514990 TI - A role for nonapeptides and dopamine in nest-building behaviour. AB - During nest building in zebra finches (Taeniopygia guttata), several regions in the social behaviour network and the dopaminergic reward system, which are two neural circuits involved in social behaviour, appear to be active in male and female nest-building finches. Because the nonapeptides, mesotocin and vasotocin and the neurotransmitter, dopamine, play important roles in avian social behaviour, we tested the hypothesis that mesotocinergic-vasotocinergic and dopaminergic neuronal populations in the social behaviour network and dopaminergic reward system, respectively, are active during nest building. We combined immunohistochemistry for Fos (an indirect marker of neuronal activity) and vasotocin, mesotocin or tyrosine hydroxylase on brain tissue from nest building and non-nest-building male and female zebra finches and compared Fos immunoreactivity in these neuronal populations with the variation in nest building behaviour. Fos immunoreactivity in all three types of neuronal populations increased with some aspect of nest building: (i) higher immunoreactivity in a mesotocinergic neuronal population of nest-building finches compared to controls; (ii) increased immunoreactivity in the vasotocinergic neuronal populations in relation to the amount of material picked up by nest building males and the length of time that a male spent in the nest with his mate; and (iii) increased immunoreactivity in a dopaminergic neuronal population in relation to the length of time that a male nest-building finch spent in the nest with his mate. Taken together, these findings provide evidence for a role of the mesotocinergic-vasotocinergic and dopaminergic systems in avian nest building. PMID- 25514993 TI - Simulation in laryngology training; what should we invest in? Our experience with 64 porcine larynges and a literature review. PMID- 25514996 TI - Empirical analysis of farmers' drought risk perception: objective factors, personal circumstances, and social influence. AB - Drought-induced water shortage and salinization are a global threat to agricultural production. With climate change, drought risk is expected to increase as drought events are assumed to occur more frequently and to become more severe. The agricultural sector's adaptive capacity largely depends on farmers' drought risk perceptions. Understanding the formation of farmers' drought risk perceptions is a prerequisite to designing effective and efficient public drought risk management strategies. Various strands of literature point at different factors shaping individual risk perceptions. Economic theory points at objective risk variables, whereas psychology and sociology identify subjective risk variables. This study investigates and compares the contribution of objective and subjective factors in explaining farmers' drought risk perception by means of survey data analysis. Data on risk perceptions, farm characteristics, and various other personality traits were collected from farmers located in the southwest Netherlands. From comparing the explanatory power of objective and subjective risk factors in separate models and a full model of risk perception, it can be concluded that farmers' risk perceptions are shaped by both rational and emotional factors. In a full risk perception model, being located in an area with external water supply, owning fields with salinization issues, cultivating drought-/salt-sensitive crops, farm revenue, drought risk experience, and perceived control are significant explanatory variables of farmers' drought risk perceptions. PMID- 25514994 TI - The natural history of levator avulsion one year following childbirth: a prospective study. AB - OBJECTIVE: To explore the natural history of levator avulsion in primipara 1 year postpartum and correlate this to pelvic floor dysfunction (PFD). DESIGN: Observational longitudinal cohort study. SETTING: District General University Hospital. POPULATION OR SAMPLE: Nullipara at 36 weeks of gestation, 3 months and 1 year postpartum. METHODS: Validated methods assessed muscle strength, prolapse, ultrasound measurements of levator hiatus and avulsion, and questionnaires for sexual function, and urinary and anal incontinence. Pattern differences over time were evaluated using linear mixed models. MAIN OUTCOME MEASURES: Natural history of levator avulsion and relationship with PFD. RESULTS: Of the 269 nullipara, 191 returned at 3 months and 147 (55%) at 1 year postpartum; 109 had a vaginal delivery and 38 had a caesarean delivery. Sixty-two percent (n = 13/21; 95% CI 41 79%) of levator avulsions diagnosed 3 months postpartum were no longer evident at 1 year. Following vaginal delivery, nine women (8%, 95% CI 4.2-15.1%) had persistent levator avulsion. Most changes in PFD occurred between the antenatal and first postnatal visit, without improvement at 1 year. Women with persistent levator avulsion had significantly worse deterioration patterns of muscle strength, hiatus measurements and vaginal symptoms (loose vagina/lump sensation). However, evidence of PFD was also related to no longer evident levator avulsion. CONCLUSIONS: Sixty-two percent of levator avulsions were no longer evident 1 year postpartum. Partial avulsion has a tendency to improve over time, which seems to be less common for complete levator avulsions. Women with no longer evident and persistent levator avulsion had PFD, with worse patterns in presence of persistent avulsion. PMID- 25514997 TI - Marine antimicrobial peptide tachyplesin as an efficient nanocarrier for macromolecule delivery in plant and mammalian cells. AB - Membrane-active peptides can be classified as cell-penetrating peptides and antimicrobial peptides (AMPs) that are known to play interchangeable roles. In this study, this dual behaviour was studied for the marine AMP, tachyplesin. It is a well-established cyclic peptide known to possess antimicrobial properties and was investigated for its cell-penetrating property and cargo delivery ability. Because of its derivation from a marine organism as well as cyclic nature, it has been shown to possess higher stability in vitro. In this study, its internalization as a cell-penetrating peptide was established and characterized in both plant and mammalian systems. It was shown to deliver cargo molecules in both living systems, emerging as an efficient nonviral macromolecule nanocarrier. PMID- 25514999 TI - Long-term efficacy of donepezil for relapse of visual hallucinations in patients with dementia with Lewy bodies. AB - BACKGROUND: The use of cholinesterase inhibitors is recommended for the treatment of dementia with Lewy bodies (DLB) in the guidelines of the DLB Consortium. However, no consensus regarding therapeutic approaches for DLB-related visual hallucinations has been reached. To the best of our knowledge, an appropriate dose of donepezil for the treatment of DLB at each stage has not been discussed. METHODS: Eight patients suffering from DLB with visual hallucinations were treated with donepezil. We summarize the effects of donepezil on these visual hallucinations chronologically in all cases and discuss its efficacy and characteristics. RESULTS: Donepezil contributed to the complete disappearance of visual hallucinations in all cases, and its effects were maintained for more than 6 months. However, relapses of visual hallucinations also occurred in all cases. Against these relapses, an increased dose of donepezil was very effective in resolving them again in almost all cases in this study. CONCLUSIONS: Donepezil was highly effective against visual hallucinations in DLB patients, but there were some issues regarding pharmacotherapy for DLB. PMID- 25514998 TI - The effect of solid fuel use on childhood mortality in Nigeria: evidence from the 2013 cross-sectional household survey. AB - BACKGROUND: In Nigeria, approximately 69% of households use solid fuels as their primary source of domestic energy for cooking. These fuels produce high levels of indoor air pollution. This study aimed to determine whether Nigerian children residing in households using solid fuels at <5 years of age were at higher risk of death. METHODS: The 2013 Nigeria Demographic and Health Survey data were analysed in Cox regression analyses to examine the effects of solid fuel use on deaths of children aged 0-28 days (neonatal), 1-11 months (post-neonatal), and 12 59 months (child). RESULTS: The results indicated that approximately 0.8% of neonatal deaths, 42.9% of post-neonatal deaths, and 36.3% of child deaths could be attributed to use of solid fuels. The multivariable analyses found that use of solid fuel was associated with post-neonatal mortality (hazard ratio [HR] =1.92, 95% confidence interval [CI]: 1.42-2.58) and child mortality (HR = 1.63, CI: 1.09 2.42), but was not associated with neonatal mortality (HR = 1.01, CI: 0.73-1.26). Living in rural areas and poor households were associated with an increased risk of death during the three mortality periods. CONCLUSION: Living in a rural area and poor households were strongly associated with an increased risk of a child > 1 to < 60 months dying due to use of solid fuels. The health effects of household use of solid fuels are a major public health threat that requires increased research and policy development efforts. Research should focus on populations in rural areas and low socioeconomic households so that child survival in Nigeria can be improved. PMID- 25515001 TI - Normal weight individuals who develop type 2 diabetes: the personal fat threshold. AB - Type 2 diabetes (T2DM) is frequently regarded as a disease of obesity and its occurrence in individuals of normal body mass index (BMI) is often regarded as indicating a non-obesity-related subtype. However, the evidence for such a distinct, common subtype is lacking. The United Kingdom Prospective Diabetes Study (UKPDS) cohort of people diagnosed with T2DM in the 1970s and 1980s had a median BMI of only 28 kg/m2. UKPDS data form the basis of current understanding of the condition even though one in three of those studied had a BMI of less than 25 kg/m2. BMI, though, is a population measure and not a rigid personal guide. Weight loss is considered de rigueur for treating obese diabetic individuals, but it is not usually considered for those deemed to have a normal BMI. Given the new evidence that early T2DM can be reversed to normal glucose tolerance by substantial weight loss, it is important to explain why non-overweight people respond to this intervention as well as obese individuals. We hypothesize that each individual has a personal fat threshold (PFT) which, if exceeded, makes likely the development of T2DM. Subsequent weight loss to take the individual below their level of susceptibility should allow return to normal glucose control. Crucially, the hypothesized PFT is independent of BMI. It allows both understanding of development of T2DM in the non-obese and remission of diabetes after substantial weight loss in people who remain obese by definition. To illustrate this concept, we present the distribution curve of BMI at diagnosis for the UKPDS cohort, together with a diagram explaining individual behaviour within the population. The concept of PFT is of practical benefit in explaining the onset of diabetes and its logical management to the non-obese majority of people with T2DM. PMID- 25515002 TI - Ebola: who is responsible for the political failures? PMID- 25515000 TI - Role of NADPH oxidase in the regulation of autophagy in cardiomyocytes. AB - In the past several years, it has been demonstrated that the reactive oxygen species (ROS) may act as intracellular signalling molecules to activate or inhibit specific signalling pathways and regulate physiological cellular functions. It is now well-established that ROS regulate autophagy, an intracellular degradation process. However, the signalling mechanisms through which ROS modulate autophagy in a regulated manner have only been minimally clarified. NADPH oxidase (Nox) enzymes are membrane-bound enzymatic complexes responsible for the dedicated generation of ROS. Different isoforms of Nox exist with different functions. Recent studies demonstrated that Nox-derived ROS can promote autophagy, with Nox2 and Nox4 representing the isoforms of Nox implicated thus far. Nox2- and Nox4-dependent autophagy plays an important role in the elimination of pathogens by phagocytes and in the regulation of vascular- and cancer-cell survival. Interestingly, we recently found that Nox is also important for autophagy regulation in cardiomyocytes. We found that Nox4, but not Nox2, promotes the activation of autophagy and survival in cardiomyocytes in response to nutrient deprivation and ischaemia through activation of the PERK (protein kinase RNA-like endoplasmic reticulum kinase) signalling pathway. In the present paper, we discuss the importance of Nox family proteins and ROS in the regulation of autophagy, with a particular focus on the role of Nox4 in the regulation of autophagy in the heart. PMID- 25515003 TI - A novel myostatin mutation in double-muscled German Gelbvieh. PMID- 25515004 TI - The effect of stabilizer on the mechanical response of double-emulsion-templated polymersomes. AB - Recent studies have shown that polymersomes templated by microfluidic double emulsion possess several advantages such as high monodispersity and encapsulation efficiency compared with those generated based on thin-film rehydration and electroformation. Stabilizers, including bovine serum albumin (BSA) and polyvinyl alcohol (PVA), have been used to enhance the formation and stability of double emulsions that are used as templates for the generation of polymersomes. In this work, the effect of stabilizers on the mechanical response of double-emulsion templated polymersomes using micropipette aspiration is investigated. It is demonstrated that the existence of stabilizers results in the inelastic response in poly-mersomes in the early stage of solvent removal. However, aged polymersomes that have little residual solvent show elastic behavior. Polymersomes prepared from PVA-stabilized double emulsions have noticeably lower area expansion moduli than polymersomes prepared from stabilizer-free and BSA stabilized double emulsions, suggesting that PVA is incorporated in the bilayer membrane of polymersomes. PMID- 25515005 TI - On optimal treatment regimes selection for mean survival time. AB - In clinical studies with time-to-event as a primary endpoint, one main interest is to find the best treatment strategy to maximize patients' mean survival time. Due to patient's heterogeneity in response to treatments, great efforts have been devoted to developing optimal treatment regimes by integrating individuals' clinical and genetic information. A main challenge arises in the selection of important variables that can help to build reliable and interpretable optimal treatment regimes as the dimension of predictors may be high. In this paper, we propose a robust loss-based estimation framework that can be easily coupled with shrinkage penalties for both estimation of optimal treatment regimes and variable selection. The asymptotic properties of the proposed estimators are studied. Moreover, a model-free estimator of restricted mean survival time under the derived optimal treatment regime is developed, and its asymptotic property is studied. Simulations are conducted to assess the empirical performance of the proposed method for parameter estimation, variable selection, and optimal treatment decision. An application to an AIDS clinical trial data set is given to illustrate the method. PMID- 25515006 TI - Gel-aided sample preparation (GASP)--a simplified method for gel-assisted proteomic sample generation from protein extracts and intact cells. AB - We describe a "gel-assisted" proteomic sample preparation method for MS analysis. Solubilized protein extracts or intact cells are copolymerized with acrylamide, facilitating denaturation, reduction, quantitative cysteine alkylation, and matrix formation. Gel-aided sample preparation has been optimized to be highly flexible, scalable, and to allow reproducible sample generation from 50 cells to milligrams of protein extracts. This methodology is fast, sensitive, easy-to-use on a wide range of sample types, and accessible to nonspecialists. PMID- 25515007 TI - Normal values of exhaled carbon monoxide in healthy subjects: comparison between two methods of assessment. AB - BACKGROUND: In a previous study, exhaled carbon monoxide (eCO) has been assessed in healthy non-smokers with a photo acoustic spectrometer Bruel&Kjaer 1312. Unexpectedly, values were higher than those reported in literature, which were mostly obtained with electrochemical analysers. This study was aimed to compare eCO values obtained with Bruel&Kjaer 1312 and PiCO + Smokerlyzer, a largely utilized electrochemical analyser. METHODS: Thirty-four healthy subjects, 15 non smokers and 19 smokers, underwent eCO assessment with Bruel&Kjaer 1312 and PiCO + Smokerlyzer during a prolonged expiration (15 seconds). Bruel&Kjaer 1312 assessed CO concentration 7 and 12 seconds after the beginning of expiration and displayed the mean value. PiCO + Smokerlyzer was utilized according to the manufacturer's recommendations. In vitro, the two devices were tested with standard concentrations of CO in nitrogen (5, 9.9, 20, and 50 ppm), and the time needed by PiCO + Smokerlyzer readings to stabilize was assessed at different gas flows. RESULTS: Both Bruel&Kjaer 1312 and PiCO + Smokerlyzer presented very good internal consistency. The values provided were strictly correlated, but at low test concentrations, the Bruel&Kjaer 1312 readings were greater than the PiCO + Smokerlyzer, and vice versa. PiCO + Smokerlyzer overestimated the CO standard concentrations at 5 and 9.9 ppm by 20%, while Bruel&Kjaer 1312 measures were correct. PiCO + Smokerlyzer readings stabilized in 12 seconds during in vitro tests and in 15 seconds during in vivo measurements, suggesting that the values displayed corresponded to the initial phase of expiration. CONCLUSIONS: Differences between Bruel&Kjaer 1312 and PiCO + Smokerlyzer may be explained because Bruel&Kjaer 1312 measured CO levels in the middle and at the end of expiration while PiCO + Smokerlyzer assessed them in the initial part of expiration. PMID- 25515013 TI - Chromatographic and spectroscopic analysis of the components present in the phenanthridinium trypanocidal agent isometamidium. AB - The chromatographic isolation and characterisation of the four compounds present in the quaternary phenanthridine veterinary trypanocidal agent, isometamidium chloride hydrochloride (ISM), is reported. The isolated compounds were unambiguously characterised using spectroscopic (NMR, UV, IR and MS) methods as 3 amino-8-[3-(3-carbamimidoyl-phenyl)-triazenyl]-5-ethyl-6-phenylethidium (1a) and related isomers, 8-amino-3-[3-(3-carbamimidoyl-phenyl)-triazenyl]-5-ethyl-6 phenylethidium, 3,-8-diamino-7-[3-(3-carbamimidoyl-phenyl)-triazenyl]-5-ethyl-6 phenylethidium and 3,-8-bis[3-(3-carbamimidoyl-phenyl)-triazenyl]-5-ethyl-6 phenylethidium. During the course of this study, it was realised that the nature of the solvent used in the NMR study was critical as in DMSO-d6 the quaternary group in the compounds was reduced to dihydro forms (e.g. 2a). PMID- 25515008 TI - Establishment of a primed pluripotent epiblast stem cell in FGF4-based conditions. AB - Several mouse pluripotent stem cell types have been established either from mouse blastocysts and epiblasts. Among these, embryonic stem cells (ESCs) are considered to represent a "naive", epiblast stem cells (EpiSCs) a "primed" pluripotent state. Although EpiSCs form derivatives of all three germ layers during in vitro differentiation, they rarely incorporate into the inner cell mass of blastocysts and rarely contribute to chimera formation following blastocyst injection. Here we successfully established homogeneous population of EpiSC lines with efficient chimera-forming capability using a medium containing fibroblast growth factor (FGF)-4. The expression levels of Rex1 and Nanog was very low although Oct4 level is comparable to ESCs. EpiSCs also expressed higher levels of epiblast markers, such as Cer1, Eomes, Fgf5, Sox17, and T, and further showed complete DNA methylation of Stella and Dppa5 promoters. However, the EpiSCs were clustered separately from E3 and T9 EpiSC lines and showed a completely different global gene expression pattern to ESCs. Furthermore, the EpiSCs were able to differentiate into all three germ layers in vitro and efficiently formed teratomas and chimeric embryos (21.4%) without germ-line contribution. PMID- 25515014 TI - Intraocular pressure decreases after muscle union surgery for highly myopic strabismus. AB - PURPOSE: To analyze the relationship between changes in the intraocular pressure (IOP) and dislocation angle in highly myopic strabismus patients who had undergone muscle union surgery. METHODS: Medical data were examined of eight eyes of seven consecutive patients with highly myopic strabismus, who had some limitation in abduction, received muscle union surgery and undergone pre- and postoperative IOP evaluation with a noncontact tonometer, and were retrospectively reviewed. In addition, 15 eyes of 15 patients with comitant horizontal strabismus who underwent unilateral recess-resect procedure as well as pre- and postoperative IOP evaluation were also included. The correlation between IOP changes after strabismus surgery and the dislocation angle of the globe was analyzed. RESULTS: The IOP was significantly reduced in the highly myopic strabismus group (-5.6 mmHg) but not in the fellow eye or in comitant horizontal strabismus patients. The decrease in IOP after surgery was significantly correlated with the preoperative dislocation angle of the globe (r = -0.725, p = 0.042). CONCLUSIONS: IOP is often higher in highly myopic strabismus patients than perceived, and it may indicate abnormal anatomy of the orbit rather than glaucoma. In that case, muscle union surgery can improve eye position and normalizes the IOP. PMID- 25515015 TI - A comparative study on genetic effects of artificial and natural habitat fragmentation on Loropetalum chinense (Hamamelidaceae) in Southeast China. AB - Elucidating the demographic and landscape features that determine the genetic effects of habitat fragmentation has become fundamental to research in conservation and evolutionary biology. Land-bridge islands provide ideal study areas for investigating the genetic effects of habitat fragmentation at different temporal and spatial scales. In this context, we compared patterns of nuclear microsatellite variation between insular populations of a shrub of evergreen broad-leaved forest, Loropetalum chinense, from the artificially created Thousand Island Lake (TIL) and the Holocene-dated Zhoushan Archipelago of Southeast China. Populations from the TIL region harboured higher levels of genetic diversity than those from the Zhoushan Archipelago, but these differences were not significant. There was no correlation between genetic diversity and most island features, excepting a negative effect of mainland-island distance on allelic richness and expected heterozygosity in the Zhoushan Archipelago. In general, levels of gene flow among island populations were moderate to high, and tests of alternative models of population history strongly favoured a gene flow-drift model over a pure drift model in each region. In sum, our results showed no obvious genetic effects of habitat fragmentation due to recent (artificial) or past (natural) island formation. Rather, they highlight the importance of gene flow (most likely via seed) in maintaining genetic variation and preventing inter-population differentiation in the face of habitat 'insularization' at different temporal and spatial scales. PMID- 25515017 TI - gammaH2AX responses in human buccal cells exposed to ionizing radiation. AB - DNA double strand breaks are induced by ionizing radiation (IR), leading to the phosphorylation of the core histone protein H2AX (termed gammaH2AX). The understanding of the gammaH2AX responses in irradiated human buccal cells is still very limited. We used visual scoring and laser scanning cytometry (LSC) methods to investigate gammaH2AX signaling following exposure of human buccal cells (from six individuals) to ionizing radiation at 0-4 Gy. The frequency of nuclei containing 15-30 gammaH2AX foci was significantly elevated 30 min post-IR exposure (by visual scoring). Concomitantly, there was a significant decrease in the frequency of cells without foci following exposure to IR. IR-induced gammaH2AX signal as determined by laser scanning cytometry (which included gammaH2AX integral and MaxPixel value) increased significantly in all individual's 2N nuclei 30 min post-IR and was similar for all three nuclear shapes identified. Individuals with the lowest baseline gammaH2AX integral (i.e., in nonirradiated cells) showed the greatest fold stimulation of gammaH2AX and significant dose-responses to IR doses of 1, 2, and 4 Gy. In 5 out of 6 individuals, the frequency of visually scored gammaH2AX in nuclei showed a strong correlation (up to r = 0.999) with LSC scored gammaH2AX integrals. The gammaH2AX response and subsequent decline varied between individuals but remained elevated above baseline levels 24 h post IR exposure. gammaH2AX response in irradiated human buccal cells has potential to be used as an index of baseline DNA damage in population studies. The variable response to IR exposure between individuals should be taken into consideration when using the gammaH2AX assay for radiation biodosimetry. PMID- 25515018 TI - Estimation of hand and wrist muscle capacities in rock climbers. AB - PURPOSE: This study investigated the hand and wrist muscle capacities among expert rock climbers and compared them with those of non-climbers. The objective was to identify the adaptations resulting from several years of climbing practice. METHODS: Twelve climbers (nine males and three females) and 13 non climber males participated in this study. Each subject performed a set of maximal voluntary contractions about the wrist and the metacarpo-phalengeal joints during which net joint moments and electromyographic activities were recorded. From this data set, the muscle capacities of the five main muscle groups of the hand (wrist flexors, wrist extensors, finger flexors, finger extensors and intrinsic muscles) were estimated using a biomechanical model. This process consisted in adjusting the physiological cross-sectional area (PCSA) and the maximal muscle stress value from an initial generic model. RESULTS: Results obtained from the model provided several new pieces of information compared to the analysis of only the net joint moments. Particularly, the capacities of the climbers were 37.1 % higher for finger flexors compared to non-climbers and were similar for finger extensor and for the other muscle groups. Climbers thus presented a greater imbalance between flexor and extensor capacities which suggests a potential risk of pathologies. CONCLUSIONS: The practice of climbing not only increased the strength of climbers but also resulted in specific adaptations among hand muscles. The proposed method and the obtained data could be re-used to optimize the training programs as well as the rehabilitation processes following hand pathologies. PMID- 25515016 TI - A linkage disequilibrium perspective on the genetic mosaic of speciation in two hybridizing Mediterranean white oaks. AB - We analyzed the genetic mosaic of speciation in two hybridizing Mediterranean white oaks from the Iberian Peninsula (Quercus faginea Lamb. and Quercus pyrenaica Willd.). The two species show ecological divergence in flowering phenology, leaf morphology and composition, and in their basic or acidic soil preferences. Ninety expressed sequence tag-simple sequence repeats (EST-SSRs) and eight nuclear SSRs were genotyped in 96 trees from each species. Genotyping was designed in two steps. First, we used 69 markers evenly distributed over the 12 linkage groups (LGs) of the oak linkage map to confirm the species genetic identity of the sampled genotypes, and searched for differentiation outliers. Then, we genotyped 29 additional markers from the chromosome bins containing the outliers and repeated the multilocus scans. We found one or two additional outliers within four saturated bins, thus confirming that outliers are organized into clusters. Linkage disequilibrium (LD) was extensive; even for loosely linked and for independent markers. Consequently, score tests for association between two-marker haplotypes and the 'species trait' showed a broad genomic divergence, although substantial variation across the genome and within LGs was also observed. We discuss the influence of several confounding effects on neutrality tests and review the evolutionary processes leading to extensive LD. Finally, we examine how LD analyses within regions that contain outlier clusters and quantitative trait loci can help to identify regions of divergence and/or genomic hitchhiking in the light of predictions from ecological speciation theory. PMID- 25515019 TI - Energetics and biomechanics of double poling in regional and high-level cross country skiers. AB - PURPOSE: The aim of this study was to evaluate the energetics and the biomechanics of double poling technique (DP) in two groups of cross-country skiers. METHODS: Eight high-level (HLG) and eight regional-level (RLG) skiers performed a 5-min sub-maximal DP trial, roller skiing on a treadmill at 14 km h( 1) and 2 degrees . Energetic cost (ECDP), center of mass (COM) vertical displacement range, body inclination (theta, i.e., the angle between the vertical line and the line passing through COM and a fixed pivot point identified at feet level) and mechanical work associated to COM motion were analyzed. Pole and joint kinematics, poling forces and cycle timing were also considered. RESULTS: HLG showed lower ECDP than RLG, smaller COM vertical displacement range and mechanical work, whereas higher theta during the early part of the poling phase (P < 0.05). In HLG, pole inclination was higher, poling forces greater and cycle duration longer (P < 0.05). Considering all skiers, a forward multiple regression revealed that the maximum value of theta (theta max) and the minimum value of COM vertical displacement resulted the COM-related parameters that better predict ECDP (AdjR (2) = 0.734; P < 0.001). Moreover, theta max positively related to poling force integrals and cycle duration (P < 0.05). CONCLUSIONS: A pronounced body inclination during the early poling phase and a reduced COM vertical displacement range concur in explaining the differences in ECDP found between the groups and among the skiers. A mechanically advantageous motion of COM during DP improves poling effectiveness, reduces cycle frequency and the mechanical work sustained. PMID- 25515020 TI - Renal thromboembolism during treatment with recombinant activated factor VII (rFVIIa) in a child with hemophilia B with factor IX inhibitors. AB - BACKGROUND: Serious thromboembolic events connected with rFVIIa therapy in hemophilia patients are rare. Only three cases are reported in children, all of them with hemophilia A. CASE PRESENTATION: We present unique case of patient with hemophilia B and high titer inhibitors to coagulation FIX, who developed severe renal damage due to thromboembolic event during rFVIIa therapy, associated with unsuspected renovascular anomalies. CONCLUSION: Caution is necessary if hematuria B requires administration of rFVIIa. US color doppler renal imaging before and after drug administration should be sufficient as an early warning. PMID- 25515021 TI - Beaver-mediated methane emission: The effects of population growth in Eurasia and the Americas. AB - Globally, greenhouse gas budgets are dominated by natural sources, and aquatic ecosystems are a prominent source of methane (CH(4)) to the atmosphere. Beaver (Castor canadensis and Castor fiber) populations have experienced human-driven change, and CH(4) emissions associated with their habitat remain uncertain. This study reports the effect of near extinction and recovery of beavers globally on aquatic CH4 emissions and habitat. Resurgence of native beaver populations and their introduction in other regions accounts for emission of 0.18-0.80 Tg CH(4) year(-1) (year 2000). This flux is approximately 200 times larger than emissions from the same systems (ponds and flowing waters that became ponds) circa 1900. Beaver population recovery was estimated to have led to the creation of 9500-42 000 km(2) of ponded water, and increased riparian interface length of >200 000 km. Continued range expansion and population growth in South America and Europe could further increase CH(4) emissions. PMID- 25515022 TI - Reading speed and phonological awareness deficits among Arabic-speaking children with dyslexia. AB - Although reading accuracy of isolated words and phonological awareness represent the main criteria of subtyping developmental dyslexia, there is increasing evidence that reduced reading speed also represents a defining characteristic. In the present study, reading speed and accuracy were measured in Arabic-speaking phonological and mixed dyslexic children matched with controls of the same age. Participants in third and fourth grades, aged from 9-10 to 9-8 years, were given single frequent and infrequent word and pseudo-word reading and phonological awareness tasks. Results showed that the group with dyslexia scored significantly lower than controls in accuracy and speed in reading tasks. Phonological and mixed dyslexic subgroups differed in infrequent and frequent word reading accuracy, the latter being worse. In contrast, the subgroups were comparable in pseudo-word identification and phonological awareness. Delayed phonological and recognition processes of infrequent and frequent words, respectively, were placed in the context of the dual route model of reading and the specific orthographic features of the Arabic language. PMID- 25515023 TI - Posterior fossa tuberculoma in a Huichol native Mexican child: a case report. AB - BACKGROUND: Tuberculosis is a major health concern in Mexico, especially among the native population. Tuberculomas are a frequent and severe complication of pediatric tuberculosis, these are observed as tumors in neuroimaging studies but are often not diagnosed adequately. CASE PRESENTATION: We present a case of a 12 year-old native Mexican girl Huichol ethnicity diagnosed with a large posterior fossa tuberculoma found by imaging. This tuberculoma was surgically removed. Histopathologic examination and staining with hematoxylin and eosin, and Ziehl Neelsen techniques of the surgical specimen were performed. Cerebrospinal fluid was analyzed by using the newly available Xpert(r) MTB/RIF assay (Cepheid, Sunnyvale CA, USA). Granulomatous inflammation with central caseous necrosis surrounded by edematous brain with reactive gliosis and acid-fast bacilli were revealed on histopathologic analysis. Mycobacterium tuberculosis DNA susceptible to rifampicin was detected in the patient's cerebrospinal fluid and the patient was started on anti-tuberculosis treatment. The girl continued to show severe neurologic damage despite surgery and anti-tuberculosis treatment, and she eventually died of respiratory complications. CONCLUSION: Our case highlights the need for early confirmation of tuberculoma diagnosis by molecular assay so that timely treatment can be initiated to prevent severe brain damage. Furthermore, it emphasizes the need to consider tuberculomas in the differential diagnosis of children with neurologic symptoms living in areas of high tuberculosis incidence and those belonging to native populations in developing countries. PMID- 25515025 TI - Dependency of magnetic microwave absorption on surface architecture of Co20Ni80 hierarchical structures studied by electron holography. AB - To design and fabricate rational surface architecture of individual particles is one of the key factors that affect their magnetic properties and microwave absorption capability, which is still a great challenge. Herein, a series of Co20Ni80 hierarchical structures with different surface morphologies, including flower-, urchin-, ball-, and chain-like morphologies, were obtained using structure-directing templates via a facile one-step solvothermal treatment. The microwave reflection loss (RL) of urchin-like Co20Ni80 hierarchical structures reaches as high as -33.5 dB at 3 GHz, with almost twice the RL intensity of the ball- and chain-like structures, and the absorption bandwidth (<-10 dB) is about 5.5 GHz for the flower-like morphology, indicating that the surface nanospikes and nanoflakes on the Co20Ni80 microsphere surfaces have great influences on their magnetic microwave absorption properties. Electron holography analysis reveals that the surface nanospikes and nanoflakes could generate a high density of stray magnetic flux lines and contribute a large saturation magnetization (105.62 emu g(-1) for urchin-like and 96.41 emu g(-1) for flower-like morphology), leading the urchin-like and flower-like Co20Ni80 to possess stronger microwave RL compared with the ball-like and chain-like Co20Ni80 alloys. The eddy current absorption mechanism MU''(MU')(-2)(f)(-1) is dominant in the frequency region above 8 GHz, implying that eddy-current loss is a vital factor for microwave RL in the high frequency range. It can be supposed from our findings that different surface morphologies of magnetic hierarchical structures might become an effective path to achieve high-performance microwave absorption for electromagnetic shielding and stealth camouflage applications. PMID- 25515024 TI - Analysis of codon usage bias of mitochondrial genome in Bombyx mori and its relation to evolution. AB - BACKGROUND: Synonymous codon usage bias (SCUB) is an inevitable phenomenon in organismic taxa, generally referring to differences in the occurrence frequency of codons across different species or within the genome of the same species. SCUB happens in various degrees under pressure from nature selection, mutation bias and other factors in different ways. It also attaches great significance to gene expression and species evolution, however, a systematic investigation towards the codon usage in Bombyx mori (B. mori) has not been reported yet. Moreover, it is still indistinct about the reasons contributing to the bias or the relationship between the bias and the evolution of B. mori. RESULTS: The comparison of the codon usage pattern between the genomic DNA (gDNA) and the mitochondrial DNA (mtDNA) from B. mori suggests that mtDNA has a higher level of codon bias. Furthermore, the correspondence analysis suggests that natural selection, such as gene length, gene function and translational selection, dominates the codon preference of mtDNA, while the composition constraints for mutation bias only plays a minor role. Additionally, the clustering results of the silkworm superfamily suggest a lack of explicitness in the relationship between the codon usage of mitogenome and species evolution. CONCLUSIONS: Among the complicated influence factors leading to codon bias, natural selection is found to play a major role in shaping the high bias in the mtDNA of B. mori from our current data. Although the cluster analysis reveals that codon bias correlates little with the species evolution, furthermore, a detailed analysis of codon usage of mitogenome provides better insight into the evolutionary relationships in Lepidoptera. However, more new methods and data are needed to investigate the relationship between the mtDNA bias and evolution. PMID- 25515026 TI - Angiostrongylus chabaudi Biocca, 1957: a new parasite for domestic cats? AB - BACKGROUND: Natural infection with a species of Angiostrongylus has been reported only once in wildcats from central Italy by Biocca in 1957. The causative species of this infection was identified as Angiostrongylus chabaudi. Following this report, this parasite had never been found in either wild or domestic cats. FINDINGS: The lungs and the pulmonary arteries of an adult female cat (Felis silvestris catus), road-killed in Sardinia, Italy, were macroscopically examined and dissected under a light microscope for the presence of parasites. A slender nematode was detected and its morphometrical features were consistent with those of A. chabaudi. Morphological data were supplemented by sequencing of the partial cytochrome oxidase c subunit 1 (cox1) gene, as well as the internal transcribed spacer 2 (ITS2) of the rDNA. Nucleotide sequences displayed 99% homology with the ITS2 sequence [GenBank KM216825.1] of a specimen of Angiostrongylus sp. recovered recently from the pulmonary artery of a wildcat in Germany and 91% with cox1 sequence [GenBank GU138118.1] of Angiostrongylus vasorum. CONCLUSION: The results of the present study indicate, for the first time, that A. chabaudi may also infect domestic cats, and thus should be considered in the diagnosis of metastrongyloid species infecting their cardio-pulmonary system. PMID- 25515028 TI - An alternative construction of internodons: the emergence of a multi-level tree of life. AB - Internodons are a formalization of Hennig's concept of species. We present an alternative construction of internodons imposing a tree structure on the genealogical network. We prove that the segments (trivial unary trees) from this tree structure are precisely the internodons. We obtain the following spin-offs. First, the generated tree turns out to be an organismal tree of life. Second, this organismal tree is homeomorphic to the phylogenetic Hennigian species tree of life, implying the discovery of a multi-level tree of life: this phylogenetic tree can be obtained by zooming out from the organismal tree, or conversely, the organismal tree of life can be generated by expanding the phylogenetic nodes into unary trees. Finally, the definition of the organismal tree allows an efficient algorithmic transformation of a given genealogical network into its corresponding phylogenetic species tree of life. The latter will be presented in a separate paper. PMID- 25515027 TI - ADAMTS2 gene dysregulation in T/myeloid mixed phenotype acute leukemia. AB - BACKGROUND: Mixed phenotype acute leukemias (MPAL) include acute leukemias with blasts that express antigens of more than one lineage, with no clear evidence of myeloid or lymphoid lineage differentiation. T/myeloid (T/My) MPAL not otherwise specified (NOS) is a rare leukemia that expresses both T and myeloid antigens, accounting for less than 1% of all leukemias but 89% of T/My MPAL. From a molecular point of view, very limited data are available on T/My MPAL NOS. CASE PRESENTATION: In this report we describe a T/My MPAL NOS case with a complex rearrangement involving chromosomes 5 and 14, resulting in overexpression of the ADAM metallopeptidase with thrombospondin type 1 motif, 2 (ADAMTS2) gene due to its juxtaposition to the T cell receptor delta (TRD) gene segment. CONCLUSION: Detailed molecular cytogenetic characterization of the complex rearrangement in the reported T/My MPAL case allowed us to observe ADAMTS2 gene overexpression, identifying a molecular marker that may be useful for monitoring minimal residual disease. To our knowledge, this is the first evidence of gene dysregulation due to a chromosomal rearrangement in T/My MPAL NOS. PMID- 25515029 TI - Asymptotic analysis of first passage time problems inspired by ecology. AB - A hybrid asymptotic-numerical method is formulated and implemented to accurately calculate the mean first passage time (MFPT) for the expected time needed for a predator to locate small patches of prey in a 2-D landscape. In our analysis, the movement of the predator can have both a random and a directed component, where the diffusivity of the predator is isotropic but possibly spatially heterogeneous. Our singular perturbation methodology, which is based on the assumption that the ratio [Formula: see text] of the radius of a typical prey patch to that of the overall landscape is asymptotically small, leads to the derivation of an algebraic system that determines the MFPT in terms of parameters characterizing the shapes of the small prey patches together with a certain Green's function, which in general must be computed numerically. The expected error in approximating the MFPT by our semi-analytical procedure is smaller than any power of [Formula: see text], so that our approximation of the MFPT is still rather accurate at only moderately small prey patch radii. Overall, our hybrid approach has the advantage of eliminating the difficulty with resolving small spatial scales in a full numerical treatment of the partial differential equation (PDE). Similar semi-analytical methods are also developed and implemented to accurately calculate related quantities such as the variance of the mean first passage time (VMFPT) and the splitting probability. Results for the MFPT, the VMFPT, and splitting probability obtained from our hybrid methodology are validated with corresponding results computed from full numerical simulations of the underlying PDEs. PMID- 25515031 TI - Influence of seasonal fluctuation and loading rates on microbial and chemical indicators during semi-continuous anaerobic digestion. AB - Minimal attention is paid towards the performance of the 40 million small-scale digesters which frequently operate at psychrophilic temperatures. Understanding the levels of microbial and chemical indicators at various loading rates and temperatures is useful for improving treatment efficiency and management strategies for small-scale digesters. In this study, semi-continuous anaerobic digesters were operated in replicate at four different loading rates (control, 0.3, 0.8 and 1.3 kg VS/m(3)/day) and housed in an environment that simulated seasonal change (27.5 degrees C,10 degrees C and 27.5 degrees C). The results illustrate that class B quality biosolids were generated for all treatments as per guidelines from the United States Environmental Protection Agency (USEPA). The simulated seasonal change did not influence Escherichia coli or faecal coliform levels, while it did appear to have an effect upon levels of Enterococci. Reduced loading rates led to a more stable environment (in terms of pH, levels of volatile fatty acids (VFAs) and total inorganic carbonate (TIC)) as well as lower levels of indicator bacteria, but generated slightly lower biogas volumes (high--53.23 L vs. low--53.19 L) over the course of the study. The results provide important data to improve the performance of small-scale psychrophilic digesters, specifically by reducing loading rates to prevent souring during winter months. PMID- 25515030 TI - Reproducibility of Her2/neu scoring in gastric cancer and assessment of the 10% cut-off rule. AB - The application of Trastuzumab on gastric cancer patients is based on Her2/neu immunostaining. The testing method relies on visual estimation of both membranous staining intensity, and positive tumor ratio with respect to a 10% cutoff. We evaluated the effect of inter- and intraobserver variations of both factors on therapeutic decision, especially if the positive tumor ratio hovers around the 10% cutoff. Ten pathologists scored 12 Her2/neu immunohistologically stained whole sections of gastric cancer. Applying the common rules for Her2/neu testing for gastric cancer, they separately noted the strongest identifiable staining intensity and the corresponding positive tumor ratio. Scoring was done repeatedly using the microscope, plain virtual microscopy, and virtual microscopy with a manual outline drawing function. Agreements on the strongest identified staining intensities were moderate. Overall concordance correlation coefficients of positive tumor ratios ranged from 0.55 to 0.81. Reproducibility was not improved by virtual microscopy. Pathologists have a good ability to estimate ratios of clearly demarcated areas, but gradients in staining intensities hinder reproducible visual demarcation of positive tumor areas. When hovering around the 10% positive tumor ratio cutoff there is a risk of misinterpretation of the staining results. This could lead to a denial of Trastuzumab therapy. Assessment of Her2/neu expression should be carried out by experienced pathologists because they can more reproducibly rate membranous staining intensities. The low reproducibility of positive tumor ratio is inherent in the testing method and cannot be improved by virtual microscopy. Therefore, we propose to reconsider the 10% cut-off limit. PMID- 25515033 TI - POSS as building-blocks for the preparation of polysilsesquioxanes through an innovative synthetic approach. AB - A novel solvent-free solid-state synthesis was used to prepare a non-crystalline polysilsesquioxane sample, with a peculiar viscous form. The material was synthesized through direct self-condensation of a partially condensed polyhedral oligomeric silsesquioxane (POSS) and its physico-chemical properties, in terms of composition/structure, thermal stability and hydrophobicity, were investigated. PMID- 25515032 TI - The future disease burden of hepatitis C virus infection in Sweden and the impact of different treatment strategies. AB - OBJECTIVE. Recently, new highly effective direct-acting antivirals (DAAs) against hepatitis C virus (HCV) were introduced. Whether these will alleviate the anticipated increase of liver disease burden in Sweden is unknown, partly because high costs may restrict the use. The objectives were to model the HCV epidemic in Sweden, the burden of disease, and the potential impact of different treatment strategies. MATERIAL AND METHODS: HCV disease progression was modeled to 2030. Scenarios were simulated using new DAAs with sustained annual treatment rate (n = 1130), reduced treatment rate (n = 380) to maintain budget, and increased treatment rates (n = 1430 or 2260) to reduce HCV infections. RESULTS: With today's triple therapies, the estimated number of serious liver complications and death are expected to peak in 2021. Using new DAAs among F0-F4 patients, an unchanged annual treatment rate can reduce the number of HCV infections by 10% by 2030; however, hepatocellular carcinoma (HCC) and mortality will remain unchanged. By reducing to 380 treatments annually and focusing on patients with advanced fibrosis (F3-F4), serious complications will remain constant but the total number of HCV infections will increase. By doubling the number of DAA treatments, HCC-incidence and liver-related deaths would decrease by 65-70% by 2030. CONCLUSION: Mortality and HCC can be reduced with new DAAs and sustained treatment uptake when restricted to F2-F4 patients, or with increased uptake in F0-F4 patients. Treatment restrictions to limit cost may reduce the positive effects and increase the burden of HCV infection. These results may be important for the future strategies of HCV management. PMID- 25515034 TI - Hypovitaminosis D is associated with endothelial dysfunction in patients with non dialysis chronic kidney disease. AB - OBJECTIVE: Cardiovascular events are highly prevalent in chronic kidney disease (CKD). Hypovitaminosis D and vascular endothelial dysfunction are risk factors for cardiovascular morbidity and mortality and they both are common in CKD patients. This study aimed to investigate the association between hypovitaminosis D and endothelial dysfunction in non-dialysis CKD patients. METHODS: In 117 non dialysis CKD patients, we assessed endothelial function by brachial artery flow mediated dilation (FMD), soluble vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin. 25-hydroxyvitamin D [25(OH)D] was measured by electrochemiluminescence immunoassay. RESULTS: Brachial artery FMD was lower in vitamin D-deficient and -insufficient versus vitamin D-sufficient groups, with the lowest value observed in the vitamin D-deficient group. Conversely, sVCAM-1 and sE-selectin were higher in vitamin D-deficient and -insufficient groups versus vitamin D-sufficient, and the highest value was observed in the vitamin D deficient group. There was a positive association between FMD and 25(OH)D (r = 0.556, p < 0.001) and negative correlations between both sVCAM-1 (r = -0.549, p < 0.001) and sE-selectin (r = -0.360, p < 0.001) and 25(OH)D. These associations remained significant after adjusting for confounders. CONCLUSIONS: Hypovitaminosis D is associated with endothelial dysfunction in non-dialysis CKD patients. Further studies are needed to confirm whether vitamin D supplementation can improve endothelial function and reduce cardiovascular events in these patients. PMID- 25515035 TI - Gypenosides attenuate cholesterol-induced DNA damage by inhibiting the production of reactive oxygen species in human umbilical vein endothelial cells. AB - Previous studies have demonstrated that DNA damage induces atherosclerosis and that oxidative stress has an important role in DNA damage. Gypenosides (Gps), the main ingredient of Gynostemma Pentaphylla (Thunb.) Makino, have been recognized as specific antioxidants and have previously been reported to inhibit high-fat diet-induced atherosclerosis in rats. However, whether or not Gps attenuate DNA damage through their antioxidant effects remains to be elucidated. The current study was performed to clarify whether or not Gps can inhibit cholesterol-induced DNA damage through antioxidation. The present study provided new insights into the pharmacological effects of Gps on atherosclerosis. HUVECs were treated with Gps at various concentrations (1, 10 and 100 ug/ml) for 1 h. The protective effects of Gps on cholesterol-induced DNA damage were determined using immunofluorescence, western blotting, reverse-transcription quantitative polymerase chain reaction and flow cytometry. Pretreatment with Gps (1, 10 and 100 ug/ml) effectively attenuated cholesterol-induced DNA damage in HUVECs by inhibiting phosphorylation of H2AX, a member of the histone family. Furthermore, Gps (100 ug/ml) pretreatment inhibited cholesterol-induced transcription and activity of nicotinamide adenine dinucleotide phosphate-oxidase 4 and reduced intracellular ROS levels. In conclusion, Gps attenuated cholesterol-induced DNA damage by inhibiting ROS production in HUVECs, suggesting that the inhibitory effect of Gps on atherogenesis is correlated with the alleviation of DNA damage. PMID- 25515037 TI - Stereoselective preparation of spiro[4.4] cyclic compounds by the photochemical activation of oxazoles. AB - A novel photocyclization of 2-aryloxazole derivatives linked with an alkene moiety through a three-atom spacer at the 5-position gave a range of functionalized spiro[4.4] cyclic compounds that included cyclopentane, tetrahydrofuran, and pyrrolidine moieties in moderate to high yields with excellent diastereoselectivity. PMID- 25515036 TI - Alkane hydroxylase genes in psychrophile genomes and the potential for cold active catalysis. AB - BACKGROUND: Psychrophiles are presumed to play a large role in the catabolism of alkanes and other components of crude oil in natural low temperature environments. In this study we analyzed the functional diversity of genes for alkane hydroxylases, the enzymes responsible for converting alkanes to more labile alcohols, as found in the genomes of nineteen psychrophiles for which alkane degradation has not been reported. To identify possible mechanisms of low temperature optimization we compared putative alkane hydroxylases from these psychrophiles with homologues from nineteen taxonomically related mesophilic strains. RESULTS: Seven of the analyzed psychrophile genomes contained a total of 27 candidate alkane hydroxylase genes, only two of which are currently annotated as alkane hydroxylase. These candidates were mostly related to the AlkB and cytochrome p450 alkane hydroxylases, but several homologues of the LadA and AlmA enzymes, significant for their ability to degrade long-chain alkanes, were also detected. These putative alkane hydroxylases showed significant differences in primary structure from their mesophile homologues, with preferences for specific amino acids and increased flexibility on loops, bends, and alpha-helices. CONCLUSION: A focused analysis on psychrophile genomes led to discovery of numerous candidate alkane hydroxylase genes not currently annotated as alkane hydroxylase. Gene products show signs of optimization to low temperature, including regions of increased flexibility and amino acid preferences typical of psychrophilic proteins. These findings are consistent with observations of microbial degradation of crude oil in cold environments and identify proteins that can be targeted in rate studies and in the design of molecular tools for low temperature bioremediation. PMID- 25515038 TI - An examination of competition and efficiency for hospital industry in Turkey. AB - The two particular reforms that have been undertaken under the Health Transformation Program in Turkey are enhancing efficiency and increasing competition. However, there is a lack of information about the relationship between competition and hospital efficiency. The purpose of this paper is to analyze the effect of competition on technical efficiency for the hospital industry in Turkey. The target population included all public and private general hospitals that were open in 2010 in Turkey (n = 1,224). From these, 1,103 hospitals met the selection criteria and were included in the study. Data were obtained from the Turkish Statistical Institute, the Ministry of Health, and through a field survey. Technical efficiency of hospitals was estimated using Data Envelopment Analysis with five outputs and five inputs. The intensity of competition among hospitals was measured by objective and subjective measures. Objective competition was measured using the Hirschman-Herfindahl Index, and subjective competition was measured based on the perceptions of top level hospital managers. Multivariate Tobit regression was used to investigate the relationship between competition and efficiency while controlling the effects of demand and supply characteristics of the market and the hospital traits. Efficiency results showed that 17% of hospitals were technically efficient. Regression analyses portrayed that the degree of competition among general hospitals did not have a statistically significant relationship with hospitals' technical efficiency. To conclude, hospital efficiency in Turkey does not seem to be affected by the intensity of competition among hospitals. PMID- 25515039 TI - Raising multiples: mental health of mothers and fathers in early parenthood. AB - The rate of twin and higher-order gestation births has risen dramatically in recent decades in the United States as well as other Western countries. Although the obstetrical and neonatal risks of multiple gestation pregnancies are well documented, much less is known regarding the mental health impact on parents of multiples during the perinatal and early parenthood period. Given that parents of multiples face greater functional demands, as well as other pressures (financial, medical) this population may be at risk for heightened distress. We conducted a systematic review of quantitative, English language studies that assessed mental health outcomes of parents of multiples during pregnancy, in the first postpartum year, and in the period of early parenthood, including depression, anxiety, stress, and related constructs. Twenty-seven articles published between 1989 and 2014 met selection criteria and were included in the review. Studies utilized a wide range of methods and outcome constructs, often making comparisons difficult. Although some studies found no differences, most investigations that compared mental health outcomes in parents of multiples versus parents of singletons found that parents of multiples experience heightened symptoms of depression, anxiety, and parenting stress. We discuss gaps in the existing body of literature on parental mental health related to multiple gestation birth and conclude by discussing the need for novel intervention strategies to meet the needs of this growing population. Parents of multiples may experience worse mental health outcomes than parents of singletons. More research is needed, and future work should explore potential treatment and support options. PMID- 25515041 TI - Visual identification of skin cancer in beachgoers: a need for improved education on non-melanoma skin cancer in the general population and melanoma in the African American population. PMID- 25515042 TI - WITHDRAWN: Clinical effectiveness of neoadjuvant chemotherapy in advanced gastric cancer: An updated meta-analysis of 12 randomized controlled trials. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 25515040 TI - Short telomere length in peripheral blood leukocyte predicts poor prognosis and indicates an immunosuppressive phenotype in gastric cancer patients. AB - Compelling evidences indicate that relative telomere length (RTL) in peripheral blood leukocytes (PBLs) can predict the clinical outcome of several cancers. However, to date, the prognostic value of leukocyte RTL in gastric cancer (GC) patients has not been explored. In this study, relative telomere length (RTL) in peripheral blood leukocytes (PBLs) was measured using a real-time PCR-based method in a total of 693 GC patients receiving surgical resection. The prognostic value of leukocyte RTL was first explored in the training set (112 patients) using Kaplan-Meier and Cox proportional hazards regression analyses. Then an independent cohort of 581 patients was used as a validation set. To explore potential mechanism, we detected the immunophenotypes of peripheral blood mononuclear cells and plasma concentrations of several cytokines in GC patients. Patients with short RTL showed significantly worse overall survival (OS) and relapse-free survival (RFS) than those with long RTL in all patient sets. Furthermore, leukocyte RTL and TNM stage exhibited a notable joint effect in prognosis prediction. Integration of TNM stage and leukocyte RTL significantly improved the prognosis prediction efficacy for GC. In addition, we found that patients with short RTL had a higher CD4(+) T cell percentage in PBMCs, CD19(+)IL 10(+) Breg percentage in B cells and plasma IL-10 concentration, indicating an enhanced immunosuppressive status with short leukocyte RTL. In conclusion, our study for the first time demonstrates that leukocyte RTL is an independent prognostic marker complementing TNM stage and associated with an immunosuppressive phenotype in the peripheral blood lymphocytes in GC patients. PMID- 25515043 TI - Improving patient access to prevent sight loss: ophthalmic electronic referrals and communication (Scotland). AB - INTRODUCTION: With the number of people with sight loss predicted to double to four million people in the UK by the year 2050, preventable visual loss is a significant public health issue. Sight loss is associated with an increased risk of falls, accidents and depression and evidence suggests that 50% of sight loss can be avoided. Timely diagnosis is central to the prevention of sight loss. Access to care can be a limiting factor in preventable cases. By improving referrals and access to hospital eye services it is possible to treat and minimise the number of patients with preventable sight loss and the impact this has on wider society. CLINICAL PILOT STUDY: In 2005, NHS Fife took part in a flagship pilot funded by the Scottish government e-health department to evaluate the feasibility, safety, clinical effectiveness, and cost of electronic referral with images of patients directly from community optometrists to Hospital Eye Service (HES). The pilot study showed that electronic referral was feasible, fast, safe, and obviated the need for outpatient appointments in 128 (37%) patients with a high patient satisfaction. CENTRALISED OPHTHALMIC ELECTRONIC REFERRAL UNIT: The results of the pilot study were presented and in May 2007, the electronic referral system was rolled out regionally in southeast Scotland. Referrals were accepted at a single site with vetting by a trained team and appointments were allocated within 48 hours. Following the implementation of electronic referral, waiting times were reduced from a median of 14 to 4 weeks. Significantly fewer new patients were seen (7462 vs 8714 [p < 0.001]). There were also fewer casualties (1984 vs 2671 [p < 0.001]) and 'did not arrive' (DNA) new patients (503 vs 635 [p < 0.001]). EYE CARE INTEGRATION PROJECT (SCOTLAND): In 2010 the Scottish Government Health Department committed L 6.6 million to community and hospital ophthalmic services forming the Eyecare Integration Project in 2011. The main aim of this project was to create electronic communication between community optometry practices and hospital eye departments. Five electronic forms were specifically designed for cataract, glaucoma, macula, paediatric and general ophthalmic disease. A Virtual Private Network was created which enabled optometrists to connect to the Scottish clinical information gateway system and send referrals to hospital and receive referral status feedback. Numerous hurdles have been encountered and overcome in order to deliver this project. DISCUSSION: An efficient unique system has been described within the NHS whereby the provision of eye care has been modernised by creating a user friendly electronic interface between the community and HES. This system ensures patients are vetted into the correct specialist clinic and thus will be less likely to go blind from treatable conditions. Urgent conditions will continue to be prioritised and savings made with efficiencies gained can be re-invested towards better overall patient care. PMID- 25515044 TI - Defining migration and its health impact in China. AB - The scale and rapid expansion of urbanization resulting from socio-economic transformation in China at the beginning of the 21st century has accelerated rural-urban migration. Public health concerns from this increasing internal population mobility are now receiving attention from researchers. The health problems from internal migration pose particular demands on healthcare systems and relate to its demographic characteristics, with many younger and older people being left behind in the rural countryside. A review of literature, census, policy reports, government documents and media was undertaken to look at the classification system and health characteristics of China's internal migrants. It suggests that public health bears the consequences of political and economic decisions made elsewhere in society. PMID- 25515045 TI - Periorbital indurated lesions in a 67-year-old female patient. PMID- 25515047 TI - Sapocribrum chincoteaguense n. gen. n. sp.: A Small, Scale-bearing Amoebozoan with Flabellinid Affinities. AB - The isolate American Type Culture Collection (ATCC)(r) 50979TM is a small amoebozoan whose actin gene was previously characterized, but did not allow a stable phylogenetic placement. This isolate was originally mis-identified upon deposition, and subsequently mis-illustrated in a recent publication. Here, we provide both a detailed morphological description as well as additional molecular analyses in order to clarify the isolate's phylogenetic relationships. The amoeba is minute (less than 5 MUm), and presents the behavior of staying in a fixed location, while emitting one or two thin pseudopods. Transmission electron microscopy reveals that the cell is covered in a layer with embedded scales, giving the cell an armored appearance. Molecular phylogenetic analyses of data (actin, alpha- and beta-tubulin, elongation factor 2, and 14-3-3) from transcriptomes of this and four other isolates reveals that ATCC(r) 50979(TM) is closely related to the recently described Squamamoeba japonica and in a novel, stable clade. Due to the unique nature of the scale covering, as well as other gross morphological characters and the molecular phylogenetic analyses, we formally describe the isolate as Sapocribrum chincoteaguense n. gen. n. sp. PMID- 25515048 TI - Anton-Babinski syndrome in an old patient: a case report and literature review. AB - Anton-Babinski syndrome is a rare disease featuring bilateral cortical blindness and anosognosia with visual confabulation, but without dementia or any memory impairment. It has a unique neuropsychiatric presentation and should be highly suspected in those with odd visual loss and imaging evidence of occipital lobe injury. In the case discussed herein, a 90-year-old man presented with bilateral blindness, obvious anosognosia, and vivid visual confabulation, which he had had for 3 days. Brain computed tomography demonstrated recent hypodense infarctions at the bilateral occipital lobes. Thus, the patient was diagnosed with Anton Babinski syndrome. Because of his age and the thrombolytic therapy during the golden 3 hours after ischemic stroke, the patient received aspirin therapy rather than tissue plasminogen activator or warfarin. He gradually realized he was blind during the following week, but died of pneumonia 1 month later. In the literature, it is difficult to establish awareness of blindness in patients with Anton-Babinski syndrome, but optimistically, in one report, a patient was aware of blindness within 2 weeks, without vision improvement. Our case illustrates that elderly patients with Anton-Babinski syndrome can partially recover and that 1 week is the shortest time for the establishment of awareness of blindness for sufferers without vision improvement. PMID- 25515050 TI - An efficient data preprocessing approach for large scale medical data mining. AB - BACKGROUND: The size of medical datasets is usually very large, which directly affects the computational cost of the data mining process. Instance selection is a data preprocessing step in the knowledge discovery process, which can be employed to reduce storage requirements while also maintaining the mining quality. This process aims to filter out outliers (or noisy data) from a given (training) dataset. However, when the dataset is very large in size, more time is required to accomplish the instance selection task. OBJECTIVE: In this paper, we introduce an efficient data preprocessing approach (EDP), which is composed of two steps. The first step is based on training a model over a small amount of training data after preforming instance selection. The model is then used to identify the rest of the large amount of training data. METHODS: Experiments are conducted based on two medical datasets for breast cancer and protein homology prediction problems that contain over 100000 data samples. In addition, three well-known instance selection algorithms are used, IB3, DROP3, and genetic algorithms. On the other hand, three popular classification techniques are used to construct the learning models for comparison, namely the CART decision tree, k nearest neighbor (k-NN), and support vector machine (SVM). RESULTS: The results show that our proposed approach not only reduces the computational cost by nearly a factor of two or three over three other state-of-the-art algorithms, but also maintains the final classification accuracy. CONCLUSIONS: To perform instance selection over large scale medical datasets, it requires a large computational cost to directly execute existing instance selection algorithms. Our proposed EDP approach solves this problem by training a learning model to recognize good and noisy data. To consider both computational complexity and final classification accuracy, the proposed EDP has been demonstrated its efficiency and effectiveness in the large scale instance selection problem. PMID- 25515051 TI - Self-management of hypertension using technology enabled interventions in primary care settings. AB - BACKGROUND: Self-management of hypertension by controlling Blood Pressure (BP) through technology-based interventions can effectively reduce the burden of high BP, which affects one out of every three adults in the United States. OBJECTIVE: The primary aim of this study is to explore the role of technology enabled interventions to improve or enhance self-management among individuals with hypertension. METHODS: We conducted a systematic review of the literature published between July 2008 and June 2013 on the MEDLINE database (via PubMed interface) during July 2013. The search words were "hypertension" and "primary care" in combination with each of the terms of "technology", "internet", "computer" and "cell phone". Our inclusion criteria consisted of: (a) Randomized Controlled Trials (RCTs) (b) conducted on human subjects; (c) technology-based interventions (d) to improve self-management (e) of hypertension and if the (f) final results of the study were published in the study. Our exclusion criteria included (a) management of other conditions and (b) literature reviews. RESULTS: The initial search resulted in 108 results. After applying the inclusion and exclusion criteria, a total of 12 studies were analyzed. Various technologies implemented in the studies included internet-based telemonitoring and education, telephone-based telemonitoring and education, internet-based education, telemedicine via videoconferencing, telehealth kiosks and automated modem device. Some studies also involved a physician intervention, in addition to patient intervention. The outcomes of proportion of subjects with BP control and change in mean SBP and DBP were better for the group of subjects who received combined physician and patient interventions. CONCLUSION: Interventions to improve BP control for self-management of hypertension should be aimed at both physicians as well as the patients. More interventions should utilize the JNC-7 guidelines and cost-effectiveness of the intervention should also be assessed. PMID- 25515053 TI - Cortical bone drilling: An experimental and numerical study. AB - BACKGROUND: Bone drilling is a common surgical procedure in orthopedics, dental and neurosurgeries. In conventional bone drilling process, the surgeon exerts a considerable amount of pressure to penetrate the drill into the bone tissue. Controlled penetration of drill in the bone is necessary for safe and efficient drilling. OBJECTIVE: Development of a validated Finite Element (FE) model of cortical bone drilling. METHODS: Drilling experiments were conducted on bovine cortical bone. The FE model of the bone drilling was based on mechanical properties obtained from literature data and additionally conducted microindentation tests on the cortical bone. RESULTS: The magnitude of stress in bone was found to decrease exponentially away from the lips of the drill in simulations. Feed rate was found to be the main influential factor affecting the force and torque in the numerical simulations and experiments. The drilling thrust force and torque were found to be unaffected by the drilling speed in numerical simulations. Simulated forces and torques were compared with experimental results for similar drilling conditions and were found in good agreement.CONCLUSIONS: FE schemes may be successfully applied to model complex kinematics of bone drilling process. PMID- 25515049 TI - Lavender oil suppresses indoleamine 2,3-dioxygenase activity in human PBMC. AB - BACKGROUND: Lavender remedies have been used in traditional medicine because of antimicrobial, anti-inflammatory and mood alleviating effects, but underlying molecular mechanisms are not yet fully elucidated. Recently, studies investigating the effects of lavender oil in the context of psychiatric disorders have indicated potent pharmacological properties. Metabolism of tryptophan by indoleamine 2,3-dioxygenase (IDO) was found to provide a biochemical link between immunology and neuroendocrinology and to be a frequent target of natural products. METHODS: In this in vitro study, interferences of lavender oil and constituents (-)-linalool, (+)-alpha-pinene and (+)-limonene with tryptophan catabolism by IDO and formation of neopterin via guanosine triphosphate (GTP) cyclohydrolase-I and of interferon-gamma have been investigated using unstimulated and phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear cells (PBMC). RESULTS: Treatment with lavender oil dose-dependently suppressed PHA-induced tryptophan breakdown and kynurenine formation. Similar effects were observed for the three constituents. In parallel, formation of neopterin and interferon-gamma was diminished upon lavender oil treatment. In unstimulated PBMC, effect of lavender oil treatment was similar, but less pronounced. CONCLUSION: Data from this in vitro study suggest that lavender oil treatment might contribute to the modulation of the immune and neuroendocrine system by interfering with activation-induced tryptophan breakdown and IDO activity. PMID- 25515052 TI - Effectiveness of a telemedicine programme for patients with metabolic syndrome. AB - BACKGROUND: There is a high prevalence of metabolic syndrome in Western societies, and it is therefore an example of chronic disease whose follow-up could be enhanced by telemedicine. OBJECTIVE: The objective of this study was to assess the effectiveness of a telemedicine programme for the follow-up and control of patients with metabolic syndrome in a primary-care setting. METHODS: Semi-experimental study in which 82 patients with metabolic syndrome were included in a telemedicine programme and compared to 82 patients routinely followed up at health-care facilities. The programme consisted of the teletransmission of analytical parameters via the PITES technological platform for chronic and dependent patients. Other study variables were lifestyle, treatment compliance, perceived health status and satisfaction with the programme. RESULTS: Follow-up showed that 68 patients (82.9%) continued in the programme after 6 months and 45 (54.9%) after one year, with a mean stay of 39.7 weeks. Comparison of the parameters obtained for the telemedicine and control group patients indicated that the former registered significantly lower mean values for systolic blood pressure (125.5 +/- 10.6 SD vs. 136.7 +/- 12.0 SD), diastolic blood pressure (81.0 +/- 6.3 SD vs. 84.0 +/- 6.8 SD), total cholesterol (177.4 +/- 34.5 SD vs. 202.4 +/- 31.7 SD) and cLDL (106.0 +/- 28.1 SD vs. 121.3 +/- 30.6 SD). By the end of follow-up, the health status scores of the patients monitored by telemedicine had risen significantly (69.2 vs. 64.2; p=0.04), and 86.6% stated that they were satisfied. CONCLUSIONS: Telemedicine allows for better control of some of the defining parameters of metabolic syndrome than is achieved by routine clinical practice. Teletransmission is viable and satisfactory, and constitutes a novel contribution to the clinical management of these patients. PMID- 25515054 TI - Correlation of serum- and glucocorticoid-regulated kinase 1 expression with ischemia-reperfusion injury after heart transplantation. AB - IRI of a transplanted heart may result in serious early and late disadvantageous effects such as increased allograft immunogenicity, primary graft dysfunction, and initiation of fibroproliferative cascades that compromise the survival of the recipient. Sgk-1 has recently been linked to cell growth and survival. It has been reported that through a renal transplantation model, Dexa increases Sgk-1 expression and therefore protects from renal IRI. In our current study, we aim to assess the expression of Sgk-1 and its protective effects on cardiomyocyte IRI after heart transplantation. Heart allograft model was performed from Wistar into Lewis, and isograft model was from Lewis into Lewis. Grafts were then harvested at one, six, 12, or 24 h post-transplantation for Sgk-1 expression analyses. In some groups, part donors were treated with Dexa 2 h prior at doses of 0.05, 0.5 and 2 mg/BWkg, respectively. Sgk-1 expression was markedly increased in grafted heart 6-12 h post-transplantation in both the allogenic and isogenic models. Immunostaining experiments confirmed that Sgk-1 was expressed in cardiomyocytes rather than infiltrated immune cells. Furthermore, Dexa treatment significantly increased Sgk-1 expression and the donor cardiomyocyte injury was greatly minimized by Dexa treatment. These results suggest that induction of Sgk-1 might explain some of the beneficial impact of corticosteroids in IRI and hence might have therapeutic implications. PMID- 25515057 TI - Thermal C-H borylation using a CO-free iron boryl complex. AB - New CO-free iron boryl complexes, CpFe(PR3)2(Bpin), are described. The CpFe(PEt3)2(Bpin) derivative is uniquely capable of UV-free arene borylation at 70 degrees C via a dissociative pathway. Catalytic C-H borylation does not proceed using either monometallic or heterobimetallic schemes, and this failure is rationalized through analysis of relative pKa values for the corresponding iron hydride species. PMID- 25515056 TI - Comparison on therapeutic effect of plasma exchange and intravenous immunoglobulin for Guillian-Barre syndrome. AB - OBJECTIVES: To observe and compare the clinical curative effect of the plasma exchange (PE) and intravenous immunoglobulin (IVIg) for Guillian-Barre Syndrome (GBS). METHODS: Overall, 64 adult patients with GBS for PE and IVIg treatment, respectively, and nerve function were observed pre-treatment and at 1 week/2 weeks after completion of treatment; the blood immunoglobulin, complement, fibrinogen (Fib) and monocyte percentage (MON%) were detected simultaneously. RESULTS: After PE treatment, nerve function defect appeared to improve better than the IVIg group and clinical effect was better than the IVIg group. Treatment effective rates of the two groups after 2 weeks, respectively, are 96 and 79%. PE and IVIg can significantly reduce the GBS patients' blood immunoglobulin IgG, IgA, IgM, C3 and C4, but these were significantly lower in the PE group than in the IVIg group. Fib and MON% were significantly lower in the PE group than in the IVIg group. CONCLUSION: Both PE and IVIg have a high response as therapy and are reasonable therapeutic options for GBS. However, PE treatment has a more significantly curative effect, as it can effectively improve symptoms and be helpful in the early rehabilitation of patients. PMID- 25515058 TI - Medical eponyms: taxonomies, natural history, and the evidence. PMID- 25515059 TI - Post-tonsillectomy haemorrhage rates are related to technique for dissection and for haemostasis. An analysis of 15734 patients in the National Tonsil Surgery Register in Sweden. AB - OBJECTIVES: To analyse post-tonsillectomy haemorrhage (PTH) rates related to technique for dissection and haemostasis. STUDY DESIGN: Register study from the National Tonsil Surgery Register in Sweden (NTSRS). METHODS: All patients, subjected to tonsillectomy (TE) without adenoidectomy from 1 March 2009 to 26 April 2013, were included in the study. The surgeon reports data about technique and early PTH, while late PTH is reported by the patient in a questionnaire 30 days after surgery. RESULTS: 15734 patients with complete data concerning technique for dissection and for haemostasis were identified in the NTSRS. Techniques used were cold steel dissection with uni- or bipolar diathermy haemostasis (65.3%), diathermy scissors (15.7%), coblation (9.1%), cold steel dissection with cold haemostasis (7.4%) and ultrascision (2.5%). Early and late PTH were reported in 3.2% and 9.4% of the cases, respectively, and return to theatre (RTT) in 2.7%. The rates for PTH and RTT related to technique were analysed. Compared with cold dissection+ cold haemostasis, late PTH rate was 2.8 times higher after cold dissection + hot haemostasis, 3.2 times higher after coblation, 4.3 times higher after diathermy scissors and 5.6 times higher after ultrascision. The risk for RTT was higher for all hot techniques except for coblation, while ultrascision resulted in a lower risk for early PTH. CONCLUSIONS: All hot techniques resulted in a higher risk for late PTH compared with cold steel dissection +cold haemostasis. The risk for RTT was higher for all hot techniques except for coblation, while ultrascision resulted in a lower risk for early PTH. An early PTH was associated with an increased risk for late PTH. PMID- 25515060 TI - Obstetrics in the time of Ebola: challenges and dilemmas in providing lifesaving care during a deadly epidemic. PMID- 25515061 TI - Human Delta3,Delta2-enoyl-CoA isomerase, type 2: a structural enzymology study on the catalytic role of its ACBP domain and helix-10. AB - The catalytic domain of the trimeric human Delta(3),Delta(2)-enoyl-CoA isomerase, type 2 (HsECI2), has the typical crotonase fold. In the active site of this fold two main chain NH groups form an oxyanion hole for binding the thioester oxygen of the 3E- or 3Z-enoyl-CoA substrate molecules. A catalytic glutamate is essential for the proton transfer between the substrate C2 and C4 atoms for forming the product 2E-enoyl-CoA, which is a key intermediate in the beta oxidation pathway. The active site is covered by the C-terminal helix-10. In HsECI2, the isomerase domain is extended at its N terminus by an acyl-CoA binding protein (ACBP) domain. Small angle X-ray scattering analysis of HsECI2 shows that the ACBP domain protrudes out of the central isomerase trimer. X-ray crystallography of the isomerase domain trimer identifies the active site geometry. A tunnel, shaped by loop-2 and extending from the catalytic site to bulk solvent, suggests a likely mode of binding of the fatty acyl chains. Calorimetry data show that the separately expressed ACBP and isomerase domains bind tightly to fatty acyl-CoA molecules. The truncated isomerase variant (without ACBP domain) has significant enoyl-CoA isomerase activity; however, the full-length isomerase is more efficient. Structural enzymological studies of helix-10 variants show the importance of this helix for efficient catalysis. Its hydrophobic side chains, together with residues from loop-2 and loop-4, complete a hydrophobic cluster that covers the active site, thereby fixing the thioester moiety in a mode of binding competent for efficient catalysis. PMID- 25515062 TI - HLA-DRB1*11:106, a variant of HLA-DRB1*11, discovered in a Chinese bone marrow donor. AB - HLA-DRB1*11:106 has 1 nucleotide change from HLA-DRB1*11:01:01 at nucleotide 155 (G -> A). PMID- 25515063 TI - Effect and tolerability of blonanserin in severe delusion with various types of dementia. AB - Low-dose blonanserin was effective for treating severe delusions in six patients with various types of dementia, and it was also well tolerated. Delusion and hallucination scores, as measured by the Neuropsychiatric Inventory, improved, and extrapyramidal symptom scores, as measured by the Drug-Induced Extrapyramidal Symptoms Scale, were unchanged. Blonanserin has strong dopamine D2 receptor-, 5 hydroxytryptamine 2A receptor-, and dopamine D3 receptor-blocking activities and weak 5-hydroxytryptamine-2C, alpha1 -, histamine H1 -, and muscarinic M1 blocking activities. Its unique characteristics may make it suitable for treating severe delusions and hallucination in patients with dementia. PMID- 25515065 TI - Integrated Direct and Indirect Flood Risk Modeling: Development and Sensitivity Analysis. AB - In this article, we propose an integrated direct and indirect flood risk model for small- and large-scale flood events, allowing for dynamic modeling of total economic losses from a flood event to a full economic recovery. A novel approach is taken that translates direct losses of both capital and labor into production losses using the Cobb-Douglas production function, aiming at improved consistency in loss accounting. The recovery of the economy is modeled using a hybrid input output model and applied to the port region of Rotterdam, using six different flood events (1/10 up to 1/10,000). This procedure allows gaining a better insight regarding the consequences of both high- and low-probability floods. The results show that in terms of expected annual damage, direct losses remain more substantial relative to the indirect losses (approximately 50% larger), but for low-probability events the indirect losses outweigh the direct losses. Furthermore, we explored parameter uncertainty using a global sensitivity analysis, and varied critical assumptions in the modeling framework related to, among others, flood duration and labor recovery, using a scenario approach. Our findings have two important implications for disaster modelers and practitioners. First, high-probability events are qualitatively different from low-probability events in terms of the scale of damages and full recovery period. Second, there are substantial differences in parameter influence between high-probability and low-probability flood modeling. These findings suggest that a detailed approach is required when assessing the flood risk for a specific region. PMID- 25515064 TI - Potential effects of polychlorinated biphenyls (PCBs) and selected organochlorine pesticides (OCPs) on immune cells and blood biochemistry measures: a cross sectional assessment of the NHANES 2003-2004 data. AB - BACKGROUND: Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) are widely distributed in the environment and may have adverse effects on the immune system. METHODS: Lipid adjusted serum levels of 19 Dioxin Like (DL), 17 Non Dioxin Like (NDL) PCBs, 5 OCPs, and measures of complete blood count and routine biochemistry profile were obtained from the NHANES 2003-2004 cycle. For each of the PCB/OCP variables, individuals were put into four exposure groups and blood markers were compared across these groups. RESULTS: Serum levels of PCBs and OCPs increased with age. Total white blood cell (WBC) count, red blood cells (RBC), hemoglobin, and hematocrit measures were lowest in the group with the highest serum PCBs. Results for the OCPs varied. For Mirex, WBC declined in the highest exposure; no significant differences were observed for p-p'-DDT or p-p' DDE; and higher levels of WBC were observed at the highest exposure groups of serum trans-nonachlor and oxychlordane. Liver enzymes (AST, ALT, and GGT) were significantly higher in the highest exposure groups of PCBs/OCPs. CONCLUSIONS: We observed significant associations between PCB/OCP levels and blood markers in the general population. All of the levels were within normal ranges but the consistency of results is remarkable and may reflect subclinical effects. Largest differences were observed for NDL PCBs. Thus, routine application of toxic equivalency factors, which assume dioxin like mechanisms and aryl hydrocarbon receptor involvement, may not adequately reflect the effects of NDL PCBs in the mixture. PMID- 25515066 TI - Genetic markers that influence feed efficiency phenotypes also affect cattle temperament as measured by flight speed. AB - Flight speed is a predictive indicator of cattle temperament and is associated with feed efficiency phenotypes. Genetic markers associated with both traits may assist with selection of calmer animals with improved economic value. A preliminary genome-wide association study determined chromosomal regions on BTA9, and 17 were associated with flight speed. The genes quaking (QKI), glutamate receptor, ionotropic, AMPA 2 (GRIA2) and glycine receptor beta (GLRB) were identified in these regions as potential functional candidates. Beef steers (n = 1057) were genotyped with SNPs located within and flanking these genes. One SNP located near QKI and one near GRIA2 were nominally associated with flight speed (P <= 0.05) although neither was significant after Bonferroni correction. Several studies have shown a correlation between flight speed and feed intake or gain; therefore, we also analyzed SNPs on BTA6:38-39 Mb known to be associated with average daily gain (ADG) and average daily feed intake (ADFI) for association with flight speed. Several SNPs on BTA6 were associated with flight speed (P <= 0.005), and three were significant after Bonferroni correction. These results suggest that the genes tested are unlikely to contribute to flight speed variation for our cattle population, but SNPs on BTA6 associated with ADG and ADFI may influence temperament. Use of these markers to select for economically important feed efficiency phenotypes may produce cattle with more desirable temperaments. PMID- 25515068 TI - Therapeutic strategies in Parkinson's disease: what we have learned from animal models. AB - Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by a loss of dopaminergic neurons in the substantia nigra, as well as in other brain areas. The currently available dopamine replacement therapy provides merely symptomatic benefit and is ineffective because habituation and side effects arise relatively quickly. Studying the genetic forms of PD in animal models provides novel insight that allows targeting of specific aspects of this heterogenic disease more specifically. Among others, two important cellular deficits are associated with PD; these deficits relate to (1) synaptic transmission and vesicle trafficking, and (2) mitochondrial function, relating respectively to the dominant and recessive mutations in PD-causing genes. With increased knowledge of PD, the possibility of identifying an efficient, long lasting treatment is becoming more conceivable, but this can only be done with an increased knowledge of the specific affected cellular mechanisms. This review discusses how discoveries in animal models of PD have clarified the therapeutic potential of pathways disrupted in PD, with a specific focus on synaptic transmission, vesicle trafficking, and mitochondrial function. PMID- 25515069 TI - Mitochondrial mutations associated with aminoglycoside ototoxicity and hearing loss susceptibility identified by meta-analysis. AB - BACKGROUND: Genetic variations, including mitochondrial mutations, are important contributors to hearing loss, especially in children, and newborn genetic screens for hearing loss mutations are becoming increasingly common. Mitochondrial mutations have been linked with ototoxic responses to common antibiotics, therefore understanding the association of these mutations with hearing loss is of special importance. To address the usefulness of screening for these mutations in a clinical setting, we formed a collaboration of clinicians and geneticists to analyse the association of mitochondrial mutations with non-syndromic hearing loss, including the effect of ethnicity, audiological test methods and aminoglycoside exposure. METHODS: This survey identified 122 variants in 43 studies that have been assessed for an association with hearing loss, and meta analysis was performed on clinically relevant subsets. RNA folding and conservation analysis further explored possible relevance of these variants. RESULTS: Among all studies, eight variants were found to have significant associations with hearing loss. A partially overlapping set of six variants had significant association with hearing loss when aminoglycoside exposure was assessed. Five of these variants predictive of sensitivity to aminoglycoside spatially co-localise in an RNA folding model. There was little effect of the audiological test method used to assess hearing loss on the association with the variants. CONCLUSIONS: Our results found a small set of studied variants had reproducible association with hearing loss, which will help clarify mutations useful in genetic screens for hearing loss. Several of the aminoglycoside exposure-associated mutations may co-localise on folded 12S rRNA, suggesting a functional association between these loci and aminoglycoside-induced hearing loss. PMID- 25515070 TI - Mendelian randomisation applied to drug development in cardiovascular disease: a review. AB - Despite increased expenditure, productivity of the pharmaceutical industry has decreased and currently 90% of developed molecules entering phase II and phase III clinical trials fail to gain regulatory approval. Most of these failures are due to lack of therapeutic efficacy rather than lack of safety, suggesting that drug development failures may often be due to poor drug target validation. Currently, drug targets are largely validated using in vitro assays and animal models which may not translate well to human disease. Emerging methods from human genetics, such as Mendelian randomisation (MR), can enable the validation of putative biomarker drug targets in humans prior to the initiation of clinical trials. MR studies can provide evidence as to whether genetically determined levels of a biomarker influence disease aetiology, enabling investigators to infer whether the biomarker is causal. We review the extent to which MR techniques may be helpful in biomarker validation by assessing the concordance between the results from MR studies and phase III clinical trials for lipid therapy in cardiovascular disease. Our findings show that concordance is highest when MR provides evidence suggesting that a biomarker is not causal. In contrast, there are many examples of clinical trials that still failed despite targeting confirmed causal biomarkers. We discuss why such trials may not succeed, despite evidence for causality in MR studies, and outline important limitations when using MR for biomarker validation in drug development. Nonetheless, given the current inefficiencies in drug development, MR methods have potential to improve the success rate of drug development and ultimately the delivery of new molecules to clinical care. PMID- 25515071 TI - A simple and highly repeatable viral plaque assay for enterovirus 71. AB - The classic plaque assay is a method for counting infectious viral particles, however its complexity limits its use in a variety of virological experiments. To simplify the operation and to improve the repeatability, we employed an improved plaque assay procedure based on Avicel to make the whole experiment easier and optimize the results on a model of Vero cells infection with Enterovirus 71(EV71). Clear plaques visible to the naked eyes can be formed on a 24-well plate or a 96-well plate without immunostaining. Following further improvement, this plaque assay procedure could be applied to other viruses, being both simple and repeatable. PMID- 25515072 TI - Symptoms of depression impact the course of lung function in adolescents and adults with cystic fibrosis. AB - BACKGROUND: Epidemiological studies report high rates of depression among patients with cystic fibrosis (CF). Assuming a causal relationship between depression and the progression of CF, our hypothesis is that elevated symptoms of depression would be a predictor of worse lung function after two years. METHODS: In the context of the TIDES study, 473 German patients with CF (age 12-53 years, FEV1% predicted M = 66.2, range 13-137) completed the Hospital Anxiety and Depression Scale (HADS). Lung function (FEV1% predicted) was assessed at baseline and followed up two years later. Repeated measures analysis was performed involving the level of FEV1% and the level of depressive symptoms at baseline as independent factors and FEV1% at the 2-year follow-up as the dependent variable. RESULTS: Interaction between lung function and depression at baseline significantly affected the change in lung function at the 2-years observation interval. The largest decline in FEV1% occurred in depressed patients with good lung function at baseline. In contrast, patients without any clinically relevant depressive symptoms and with poor lung function at baseline showed a slight increase two years later. CONCLUSION: The findings emphasise the need to screen patients with CF for symptoms of depression and to treat co-morbid depression. PMID- 25515073 TI - Self-assembled monolayers and nanocomposite hydrogels of functional nanomaterials for tissue engineering applications. AB - In biotechnology, SAMs and NC hydrogels of functional nanomaterials are of high interest as 2D and 3D cell culture systems, respectively, to mimic natural ECM and to control cell behaviors. Advanced biotechnological approaches often use nanoscale topography together with suitable surface functionalization, as a model of ECM, to control cell behaviors and tissue formation. SAMs of NMs are effective ECM models as 2D surfaces due to their larger nanostructured surface areas which provide higher molecular density by functionalization on a planar substrate than molecular SAMs. Additionally, NC hydrogels, produced by cross-linking of organic polymers with NMs, are excellent candidates as 3D cell culture systems owing to their optical, cell-compatibility and the extraordinary mechanical properties. PMID- 25515074 TI - Long-run relative importance of temperature as the main driver to malaria transmission in Limpopo Province, South Africa: a simple econometric approach. AB - Malaria in Limpopo Province of South Africa is shifting and now observed in originally non-malaria districts, and it is unclear whether climate change drives this shift. This study examines the distribution of malaria at district level in the province, determines direction and strength of the linear relationship and causality between malaria with the meteorological variables (rainfall and temperature) and ascertains their short- and long-run variations. Spatio-temporal method, Correlation analysis and econometric methods are applied. Time series monthly meteorological data (1998-2007) were obtained from South Africa Weather Services, while clinical malaria data came from Malaria Control Centre in Tzaneen (Limpopo Province) and South African Department of Health. We find that malaria changes and pressures vary in different districts with a strong positive correlation between temperature with malaria, r = 0.5212, and a weak positive relationship for rainfall, r = 0.2810. Strong unidirectional causality runs from rainfall and temperature to malaria cases (and not vice versa): F (1, 117) = 3.89, rho = 0.0232 and F (1, 117) = 20.08, P < 0.001 and between rainfall and temperature, a bi-directional causality exists: F (1, 117) = 19.80; F (1,117) = 17.14, P < 0.001, respectively, meaning that rainfall affects temperature and vice versa. Results show evidence of strong existence of a long-run relationship between climate variables and malaria, with temperature maintaining very high level of significance than rainfall. Temperature, therefore, is more important in influencing malaria transmission in Limpopo Province. PMID- 25515075 TI - Detection of Mycobacterium tuberculosis Complex in New World Monkeys in Peru. AB - The Mycobacterium tuberculosis complex causes tuberculosis in humans and nonhuman primates and is a global public health concern. Standard diagnostics rely upon host immune responses to detect infection in nonhuman primates and lack sensitivity and specificity across the spectrum of mycobacterial infection in these species. We have previously shown that the Oral Swab PCR (OSP) assay, a direct pathogen detection method, can identify the presence of M. tuberculosis complex in laboratory and free-ranging Old World monkeys. Addressing the current limitations in tuberculosis diagnostics in primates, including sample acquisition and pathogen detection, this paper furthers our understanding of the presence of the tuberculosis-causing bacteria among New World monkeys in close contact with humans. Here we use the minimally invasive OSP assay, which includes buccal swab collection followed by amplification of the IS6110 repetitive nucleic acid sequence specific to M. tuberculosis complex subspecies, to detect the bacteria in the mouths of Peruvian New World monkeys. A total of 220 buccal swabs from 16 species were obtained and positive amplification of the IS6110 sequence was observed in 30 (13.6%) of the samples. To our knowledge, this is the first documentation of M. tuberculosis complex DNA in a diverse sample of Peruvian Neotropical primates. PMID- 25515082 TI - The neonatal sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA1b): a neglected pump in scope. AB - The neonatal isoform of the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase (SERCA1b) is formed by developmental splicing and expressed fully only in developing muscle. As a major Ca(2+) pump in myotubes, SERCA1b must be detected in excitation contraction coupling or in store-operated calcium entry. The available pan SERCA1 antibodies also recognise SERCA1b but these are more frequently used to detect SERCA1a, the adult muscle-specific isoform characteristically expressed in fast fibres of skeletal muscle. In such applications, the pan SERCA1 antibodies are frequently claimed to be SERCA1a antibodies without proving it. Realistically, such an antibody cannot be made since it should recognise a single glycine at the C-terminal, the only part of SERCA1a that is different from SERCA1b. The false interpretation of the antibody specificity created inconsistence in the literature and led to false conclusions attributing features only to SERCA1a although those at least are also shared by SERCA1b. In contrast, a SERCA1b antibody has been made against the eight amino acid peptide tail that replaces the glycine of SERCA1a at the C-terminal. Therefore, the expression of SERCA1b can be specifically demonstrated, unlike that of SERCA1a, in various stages and conditions of skeletal muscle. This review argues against misbeliefs related to the distinction, expressions and functions of the two muscle-specific SERCA1 isoforms. PMID- 25515084 TI - Image-based cell-resolved screening assays in flow. AB - A parallel microfluidic cytometer (PMC) is based on a one-dimensional (1D) scanning detector, a parallel array of flow channels, and new multiparameter analysis algorithms that operate on low-pixel-count 1D images. In this article, we explore a series of image-based live- and fixed-cell screening assays, including two NF-kB nuclear translocations and T-cell capping. We then develop a new multiparametric linear weighted classifier that achieves a Z' factor sufficient for scaled pharmaceutical discovery with Jurkat cells in suspension. We conclude that the PMC should have the throughput and statistical power to permit a new capability for image-based high-sample-number pharmaceutical screening with suspension samples. PMID- 25515083 TI - Soybean Fe-S cluster biosynthesis regulated by external iron or phosphate fluctuation. AB - KEY MESSAGE: Iron and phosphorus are essential for soybean nodulation. Our results suggested that the deficiency of Fe or P impairs nodulation by affecting the assembly of functional iron-sulfur cluster via different mechanisms. Iron (Fe) and phosphorus (P) are important mineral nutrients for soybean and are indispensable for nodulation. However, it remains elusive how the pathways of Fe metabolism respond to the fluctuation of external Fe or P. Iron is required for the iron-sulfur (Fe-S) cluster assembly in higher plant. Here, we investigated the expression pattern of Fe-S cluster biosynthesis genes in the nodulated soybean. Soybean genome encodes 42 putative Fe-S cluster biosynthesis genes, which were expressed differently in shoots and roots, suggesting of physiological relevance. Nodules initiated from roots of soybean after rhizobia inoculation. In comparison with that in shoots, iron concentration was three times higher in nodules. The Fe-S cluster biosynthesis genes were activated and several Fe-S protein activities were increased in nodules, indicating that a more effective Fe S cluster biosynthesis is accompanied by nodulation. Fe-S cluster biosynthesis genes were massively repressed and some Fe-S protein activities were decreased in nodules by Fe deficiency, leading to tiny nodules. Notably, P deficiency induced a similar Fe-deficiency response in nodules, i.e, certain Fe-S enzyme activity loss and tiny nodules. However, distinct from Fe-deficient nodules, higher iron concentration was accumulated and the Fe-S cluster biosynthesis genes were not suppressed in the P-deficiency-treated nodules. Taken together, our results showed that both Fe deficiency and P deficiency impair nodulation, but they affect the assembly of Fe-S cluster maybe via different mechanisms. The data also suggested that Fe-S cluster biosynthesis likely links Fe metabolism and P metabolism in root and nodule cells of soybean. PMID- 25515085 TI - Feature-rich magnetic quantization in sliding bilayer graphenes. AB - The generalized tight-binding model, based on the subenvelope functions of distinct sublattices, is developed to investigate the magnetic quantization in sliding bilayer graphenes. The relative shift of two graphene layers induces a dramatic transformation between the Dirac-cone structure and the parabolic band structure, and thus leads to drastic changes of Landau levels (LLs) in the spatial symmetry, initial formation energy, intergroup anti-crossing, state degeneracy and semiconductor-metal transition. There exist three kinds of LLs, i.e., well-behaved, perturbed and undefined LLs, which are characterized by a specific mode, a main mode plus side modes, and a disordered mode, respectively. Such LLs are clearly revealed in diverse magneto-optical selection rules. Specially, the undefined LLs frequently exhibit intergroup anti-crossings in the field-dependent energy spectra, and show a large number of absorption peaks without optical selection rules. PMID- 25515086 TI - Placebo interventions for nausea: a systematic review. AB - BACKGROUND: Expectancy often predicts nausea, but the extent to which placebo interventions can alter nausea is less clear. PURPOSE: We conducted a systematic review to determine 1) if placebo interventions can affect nausea and 2) which features of these interventions are effective. METHODS: Articles were identified via PsychInfo, Medline, and PubMed databases. We targeted instructional and conditioning interventions aimed at altering nausea via the placebo effect. RESULTS: Fourteen studies were identified, nine instructional and five conditioning. Many found evidence suggesting that placebo interventions could alter nausea, but a few found no evidence or 'reverse' effects. Effective interventions tended to be those that were aimed at participants with high initial expectancies, with evidence that combined or conditioning manipulations were more effective than instructions. CONCLUSIONS: These findings suggest that placebo interventions can alter nausea and that these may serve as a useful way of reducing the burden of nausea in practice. PMID- 25515081 TI - Renal acid-base regulation: new insights from animal models. AB - Because majority of biological processes are dependent on pH, maintaining systemic acid-base balance is critical. The kidney contributes to systemic acid base regulation, by reabsorbing HCO3 (-) (both filtered by glomeruli and generated within a nephron) and acidifying urine. Abnormalities in those processes will eventually lead to a disruption in systemic acid-base balance and provoke metabolic acid-base disorders. Research over the past 30 years advanced our understanding on cellular and molecular mechanisms responsible for those processes. In particular, a variety of transgenic animal models, where target genes are deleted either globally or conditionally, provided significant insights into how specific transporters are contributing to the renal acid-base regulation. Here, we broadly overview the mechanisms of renal ion transport participating to acid-base regulation, with emphasis on data obtained from transgenic mice models. PMID- 25515087 TI - Fatigue-related electromyographic coherence and phase synchronization analysis between antagonistic elbow muscles. AB - The aim of this study was to examine coherence and phase synchronization between antagonistic elbow muscles and thus to explore the coupling and common neural inputs of antagonistic elbow muscles during sustained submaximal isometric fatiguing contraction. Fifteen healthy male subjects sustained an isometric elbow flexion at 20 % maximal level until exhaustion, while surface electromyographic signals (sEMG) were collected from biceps brachii (BB) and triceps brachii (TB). sEMG signals were divided into the first half (stage 1 with minimal fatigue) and second half (stage 2 with severe fatigue) of the contraction. Coherence and phase synchronization analysis was conducted between sEMG of BB and TB, and coherence value and phase synchronization index in alpha (8-12 Hz), beta (15-35 Hz) and gamma (35-60 Hz) frequency bands were obtained. Significant increase in EMG-EMG coherence and phase synchronization index in alpha and beta frequency bands between antagonistic elbow flexion muscles was observed all increased in stage 2 compared to stage 1. Coupling of EMG activities between antagonistic muscles increased as a result of fatigue caused by 20 % maximal level sustained isometric elbow flexion, indicating the increased interconnection between synchronized cortical neurons and the motoneuron pool of BB and TB, which may be cortical in origin. This increased coupling may help to maintain coactivation level so as to ensure joint stability on the basis of maintaining the joint force output. PMID- 25515089 TI - New antioxidant sesquiterpenes from a culture broth of Coprinus echinosporus. PMID- 25515088 TI - Short-term fluoxetine treatment induces neuroendocrine and behavioral anxiogenic like responses in adolescent male rats. AB - Fluoxetine (FLX) is prescribed to treat depression and anxiety in adolescent patients. However, FLX has anxiogenic effects during the acute phase of treatment, and caution has been raised due to increased suicidal thinking and behavior. Herein, we sought to study in adolescent (35-day-old) male rats, the effects of short-term FLX treatment (10 mg/kg/day, i.p. for 3-4 days) on hypothalamic-pituitary-adrenal axis activity, serotonin (5-hidroxytriptamine, 5 HT) transporter (SERT) mRNA expression in the dorsal raphe nucleus (DRN), energy balance-related variables and behavioral profiles in the holeboard. Our results revealed that daily FLX administration increased plasma corticosterone (B) concentrations without affecting basal gene expression of corticotrophin releasing hormone in the hypothalamic paraventricular nucleus (PVN) nor of pro opiomelanocortin in the anterior pituitary. However, FLX had significant effects increasing the mRNA expression of PVN arginine vasopressin (AVP) and reducing SERT mRNA levels in the dorsolateral subdivision of the DRN. In the holeboard, FLX-induced anxiety/emotionality-like behaviors. As expected, FLX treatment was endowed with anorectic effects and reduced body weight gain. Altogether, our study shows that short-term FLX treatment results in physiological, neuroendocrine and behavioral stress-like effects in adolescent male rats. More importantly, considering that the AVP- and 5-HTergic systems: (1) are intimately involved in regulation of the stress response; (2) are regulated by sex hormones and (3) are related to regulation of aggressive behaviors, our results highlight the potential significance of these systems mediating the anxiogenic/emotionality/stress-like responses of adolescent male rats to short term FLX treatment. PMID- 25515090 TI - Association of apolipoprotein A5 genetic polymorphisms with steroid-induced osteonecrosis of femoral head in a Chinese Han population. AB - BACKGROUND: Previous studies suggested that apolipoprotein A5 (ApoA5) genetic polymorphisms (SNPs) may result in lipid metabolism disorders. Therefore, genetic polymorphisms in ApoA5 may be associated with the occurrence of osteonecrosis of femoral head (ONFH). METHODS: We designed a case-control study including 223 patients of osteonecrosis and 201 age- and sex-matched control subjects to analyze the association between ApoA5 polymorphisms and susceptibility of steroid induced ONFH. We utilized polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to genotype two SNPs (rs662799 and rs3135506) in ApoA5 gene. RESULTS: We found both rs662799 and rs3135506 were associated with the risk of ONFH in codominant, dominant, and recessive model, respectively. Haplotype analyses suggested that T-C haplotype was associated with decreased risk of ONFH, whereas the haplotype C-C was significantly associated with an increased risk of ONFH. CONCLUSION: Our study suggested that ApoA5 genetic polymorphisms were associated with susceptibility to ONFH in Chinese population. However, our results need further investigation with large sample size and various populations. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_229. PMID- 25515093 TI - Are antagonists at bradykinin 1 receptors promising analgesic drugs? PMID- 25515094 TI - Author's reply to the commentary by Gilpin et al. PMID- 25515091 TI - Suicide risk in Veterans Health Administration patients with mental health diagnoses initiating lithium or valproate: a historical prospective cohort study. AB - BACKGROUND: Lithium has been reported in some, but not all, studies to be associated with reduced risks of suicide death or suicidal behavior. The objective of this nonrandomized cohort study was to examine whether lithium was associated with reduced risk of suicide death in comparison to the commonly-used alternative treatment, valproate. METHODS: A propensity score-matched cohort study was conducted of Veterans Health Administration patients (n=21,194/treatment) initiating lithium or valproate from 1999-2008. RESULTS: Matching produced lithium and valproate treatment groups that were highly similar in all 934 propensity score covariates, including indicators of recent suicidal behavior, but recent suicidal ideation was not able to be included. In the few individuals with recently diagnosed suicidal ideation, a significant imbalance existed with suicidal ideation more prevalent at baseline among individuals initiating lithium than valproate (odds ratio (OR) 1.30, 95% CI 1.09, 1.54; p=0.003). No significant differences in suicide death were observed over 0-365 days in A) the primary intent-to-treat analysis (lithium/valproate conditional odds ratio (cOR) 1.22, 95% CI 0.82, 1.81; p=0.32); B) during receipt of initial lithium or valproate treatment (cOR 0.86, 95% CI 0.46, 1.61; p=0.63); or C) after such treatment had been discontinued/modified (OR 1.51, 95% CI 0.91, 2.50; p=0.11). Significantly increased risks of suicide death were observed after the discontinuation/modification of lithium, compared to valproate, treatment over the first 180 days (OR 2.72, 95% CI 1.21, 6.11; p=0.015). CONCLUSIONS: In this somewhat distinct sample (a predominantly male Veteran sample with a broad range of psychiatric diagnoses), no significant differences in associations with suicide death were observed between lithium and valproate treatment over 365 days. The only significant difference was observed over 0-180 days: an increased risk of suicide death, among individuals discontinuing or modifying lithium, compared to valproate, treatment. This difference could reflect risks either related to lithium discontinuation or higher baseline risks among lithium recipients (i.e., confounding) that became more evident when treatment stopped. Our findings therefore support educating patients and providers about possible suicide-related risks of discontinuing lithium even shortly after treatment initiation, and the close monitoring of patients after lithium discontinuation, if feasible. If our findings include residual confounding biasing against lithium, however, as suggested by the differences observed in diagnosed suicidal ideation, then the degree of beneficial reduction in suicide death risk associated with active lithium treatment would be underestimated. Further research is urgently needed, given the lack of interventions against suicide and the uncertainties concerning the degree to which lithium may reduce suicide risk during active treatment, increase risk upon discontinuation, or both. PMID- 25515096 TI - A review of cardiovascular outcomes in the treatment of people with type 2 diabetes. AB - INTRODUCTION: Cardiovascular disease (CVD) is a common and serious complication of type 2 diabetes mellitus (T2DM) often linked to the increased morbidity and mortality associated with T2DM. Monitoring and treating risk factors for CVD are important elements of diabetes management. This review aims to examine CV risk in people with relatively early and mild diabetes who are at substantial risk of CVD; it considers the impact of insulin therapy on this risk by focusing on key studies in patients with diabetes. METHODS: A literature search was carried out using PubMed to identify key publications, between 2008 and 2013, related to insulin and its possible effect on CVD. This review examines CV risk in diabetes and the impact of insulin therapy on this risk. RESULTS: Studies have shown that treatment with insulin glargine is associated with marked improvement in the lipid profile of people with T2DM. Intensive insulin therapy has been shown to lower mortality rates in people with diabetes following acute myocardial infarction after 1 year. Retrospective data also indicate that insulin reduces the risk of CVD events, regardless of whether people had comorbidities known to increase CV risk. The prospective ORIGIN (Outcome Reduction with Initial Glargine Intervention) trial found that treatment with insulin glargine had a neutral effect with regard to CV outcomes in people with prediabetes or early diabetes, compared with standard care. CONCLUSIONS: Other ongoing, large-scale studies of insulin therapy should provide further insights into whether or not insulin therapy can influence long-term CV outcomes. PMID- 25515097 TI - Central and peripheral metabolic changes induced by gamma-hydroxybutyrate. AB - STUDY OBJECTIVES: Gamma-hydroxybutyrate (GHB) was originally introduced as an anesthetic but was first abused by bodybuilders and then became a recreational or club drug.1 Sodium salt of GHB is currently used for the treatment of cataplexy in patients with narcolepsy. The mode of action and metabolism of GHB is not well understood. GHB stimulates growth hormone release in humans and induces weight loss in treated patients, suggesting an unexplored metabolic effect. In different experiments the effect of GHB administration on central (cerebral cortex) and peripheral (liver) biochemical processes involved in the metabolism of the drug, as well as the effects of the drug on metabolism, were evaluated in mice. DESIGN: C57BL/6J, gamma-aminobutyric acid B (GABAB) knockout and obese (ob/ob) mice were acutely or chronically treated with GHB at 300 mg/kg. MEASUREMENTS AND RESULTS: Respiratory ratio decreased under GHB treatment, independent of food intake, suggesting a shift in energy substrate from carbohydrates to lipids. GHB-treated C57BL/6J and GABAB null mice but not ob/ob mice gained less weight than matched controls. GHB dramatically increased the corticosterone level but did not affect growth hormone or prolactin. Metabolome profiling showed that an acute high dose of GHB did not increase the brain GABA level. In the brain and the liver, GHB was metabolized into succinic semialdehyde by hydroxyacid-oxoacid transhydrogenase. Chronic administration decreased glutamate, s-adenosylhomocysteine, and oxidized gluthathione, and increased omega-3 fatty acids. CONCLUSIONS: Our findings indicate large central and peripheral metabolic changes induced by GHB with important relevance to its therapeutic use. PMID- 25515098 TI - Bilateral thalamic stimulation induces insomnia in patients treated for intractable tremor. AB - STUDY OBJECTIVES: To explore the influence of acute bilateral ventral intermediate thalamic nucleus (VIM) stimulation on sleep. DESIGN: Three consecutive full-night polysomnography recordings were made in the laboratory. After the habituation night, a random order for night ON-stim and OFF-stim was applied for the second and third nights. SETTING: Sleep disorders unit of a university hospital. PATIENTS: Eleven patients with bilateral stimulation of the ventral intermediate nucleus of the thalamus (VIM) for drug-resistant tremor. MEASUREMENTS: Sleep measures on polysomnography. RESULTS: Total sleep time was reduced during night ON-stim compared to OFF- stim, as well as rapid eye movement sleep percentage while the percentage of N2 increased. Wakefulness after sleep onset time was increased. CONCLUSION: Our results show that bilateral stimulation of the VIM nuclei reduces sleep and could be associated with insomnia. PMID- 25515099 TI - Sleep deprivation and time-on-task performance decrement in the rat psychomotor vigilance task. AB - STUDY OBJECTIVES: The rat psychomotor vigilance task (rPVT) was developed as a rodent analog of the human psychomotor vigilance task (hPVT). We examined whether rPVT performance displays time-on-task effects similar to those observed on the hPVT. DESIGN: The rPVT requires rats to respond to a randomly presented light stimulus to obtain a water reward. Rats were water deprived for 22 h prior to each 30-min rPVT session to motivate performance. We analyzed rPVT performance over time on task and as a function of the response-stimulus interval, at baseline and after sleep deprivation. SETTING: The study was conducted in an academic research vivarium. PARTICIPANTS: Male Long-Evans rats were trained to respond to a 0.5 sec stimulus light within 3 sec of stimulus onset. Complete data were available for n = 20 rats. INTERVENTIONS: Rats performed the rPVT for 30 min at baseline and after 24 h total sleep deprivation by gentle handling. MEASUREMENTS AND RESULTS: Compared to baseline, sleep deprived rats displayed increased performance lapses and premature responses, similar to hPVT lapses of attention and false starts. However, in contrast to hPVT performance, the time-on task performance decrement was not significantly enhanced by sleep deprivation. Moreover, following sleep deprivation, rPVT response times were not consistently increased after short response-stimulus intervals. CONCLUSIONS: The rPVT manifests similarities to the hPVT in global performance outcomes, but not in post-sleep deprivation effects of time on task and response-stimulus interval. PMID- 25515100 TI - Psychomotor vigilance task performance during and following chronic sleep restriction in rats. AB - STUDY OBJECTIVES: Chronic sleep restriction (CSR) impairs sustained attention in humans, as commonly assessed with the psychomotor vigilance task (PVT). To further investigate the mechanisms underlying performance deficits during CSR, we examined the effect of CSR on performance on a rat version of PVT (rPVT). DESIGN: Adult male rats were trained on a rPVT that required them to press a bar when they detected irregularly presented, brief light stimuli, and were then tested during CSR. CSR consisted of 100 or 148 h of continuous cycles of 3-h sleep deprivation (using slowly rotating wheels) alternating with a 1-h sleep opportunity (3/1 protocol). MEASUREMENTS AND RESULTS: After 28 h of CSR, the latency of correct responses and the percentages of lapses and omissions increased, whereas the percentage of correct responses decreased. Over 52-148 h of CSR, all performance measures showed partial or nearly complete recovery, and were at baseline levels on the first or second day after CSR. There were large interindividual differences in the magnitude of performance impairment during CSR, suggesting differential vulnerability to the effects of sleep loss. Wheel running controls showed no changes in performance. CONCLUSIONS: A 28-h period of the 3/1 chronic sleep restriction (CSR) protocol disrupted performance on a sustained attention task in rats, as sleep deprivation does in humans. Performance improved after longer periods of CSR, suggesting allostatic adaptation, contrary to some reports of progressive deterioration in psychomotor vigilance task performance during CSR in humans. However, as observed in humans, there were individual differences among rats in the vulnerability of their attention performance to CSR. PMID- 25515101 TI - Alcohol and sleep restriction combined reduces vigilant attention, whereas sleep restriction alone enhances distractibility. AB - STUDY OBJECTIVES: Alcohol and sleep loss are leading causes of motor vehicle crashes, whereby attention failure is a core causal factor. Despite a plethora of data describing the effect of alcohol and sleep loss on vigilant attention, little is known about their effect on voluntary and involuntary visual attention processes. DESIGN: Repeated-measures, counterbalanced design. SETTING: Controlled laboratory setting. PARTICIPANTS: Sixteen young (18-27 y; M = 21.90 +/- 0.60 y) healthy males. INTERVENTIONS: Participants completed an attention test battery during the afternoon (13:00-14:00) under four counterbalanced conditions: (1) baseline; (2) alcohol (0.05% breath alcohol concentration); (3) sleep restriction (02:00-07:00); and (4) alcohol/sleep restriction combined. This test battery included a Psychomotor Vigilance Task (PVT) as a measure of vigilant attention, and two ocular motor tasks-visually guided and antisaccade-to measure the involuntary and voluntary allocation of visual attention. MEASUREMENTS AND RESULTS: Only the combined condition led to reductions in vigilant attention characterized by slower mean reaction time, fastest 10% responses, and increased number of lapses (P < 0.05) on the PVT. In addition, the combined condition led to a slowing in the voluntary allocation of attention as reflected by increased antisaccade latencies (P < 0.05). Sleep restriction alone however increased both antisaccade inhibitory errors [45.8% errors versus < 28.4% all others; P < 0.001] and the involuntary allocation of attention, as reflected by faster visually guided latencies (177.7 msec versus > 185.0 msec all others) to a peripheral target (P < 0.05). CONCLUSIONS: Our data reveal specific signatures for sleep related attention failure: the voluntary allocation of attention is impaired, whereas the involuntary allocation of attention is enhanced. This provides key evidence for the role of distraction in attention failure during sleep loss. PMID- 25515102 TI - A new model to study sleep deprivation-induced seizure. AB - BACKGROUND AND STUDY OBJECTIVES: A relationship between sleep and seizures is well-described in both humans and rodent animal models; however, the mechanism underlying this relationship is unknown. Using Drosophila melanogaster mutants with seizure phenotypes, we demonstrate that seizure activity can be modified by sleep deprivation. DESIGN: Seizure activity was evaluated in an adult bang sensitive seizure mutant, stress sensitive B (sesB(9ed4)), and in an adult temperature sensitive seizure mutant seizure (sei(ts1)) under baseline and following 12 h of sleep deprivation. The long-term effect of sleep deprivation on young, immature sesB(9ed4) flies was also assessed. SETTING: Laboratory. PARTICIPANTS: Drosophila melanogaster. INTERVENTIONS: Sleep deprivation. MEASUREMENTS AND RESULTS: Sleep deprivation increased seizure susceptibility in adult sesB(9ed4)/+ and sei(ts1) mutant flies. Sleep deprivation also increased seizure susceptibility when sesB was disrupted using RNAi. The effect of sleep deprivation on seizure activity was reduced when sesB(9ed4)/+ flies were given the anti-seizure drug, valproic acid. In contrast to adult flies, sleep deprivation during early fly development resulted in chronic seizure susceptibility when sesB(9ed4)/+ became adults. CONCLUSIONS: These findings show that Drosophila is a model organism for investigating the relationship between sleep and seizure activity. PMID- 25515103 TI - Targeted Memory Reactivation during Sleep Depends on Prior Learning. AB - STUDY OBJECTIVES: When sounds associated with learning are presented again during slow-wave sleep, targeted memory reactivation (TMR) can produce improvements in subsequent location recall. Here we used TMR to investigate memory consolidation during an afternoon nap as a function of prior learning. PARTICIPANTS: Twenty healthy individuals (8 male, 19-23 y old). MEASUREMENTS AND RESULTS: Participants learned to associate each of 50 common objects with a unique screen location. When each object appeared, its characteristic sound was played. After electroencephalography (EEG) electrodes were applied, location recall was assessed for each object, followed by a 90-min interval for sleep. During EEG verified slow-wave sleep, half of the sounds were quietly presented over white noise. Recall was assessed 3 h after initial learning. A beneficial effect of TMR was found in the form of higher recall accuracy for cued objects compared to uncued objects when pre-sleep accuracy was used as an explanatory variable. An analysis of individual differences revealed that this benefit was greater for participants with higher pre-sleep recall accuracy. In an analysis for individual objects, cueing benefits were apparent as long as initial recall was not highly accurate. Sleep physiology analyses revealed that the cueing benefit correlated with delta power and fast spindle density. CONCLUSIONS: These findings substantiate the use of targeted memory reactivation (TMR) methods for manipulating consolidation during sleep. TMR can selectively strengthen memory storage for object-location associations learned prior to sleep, except for those near-perfectly memorized. Neural measures found in conjunction with TMR-induced strengthening provide additional evidence about mechanisms of sleep consolidation. PMID- 25515104 TI - Coronary heart disease incidence in sleep disordered breathing: the Wisconsin Sleep Cohort Study. AB - STUDY OBJECTIVES: The aim of the study was to determine the association of objectively measured sleep disordered breathing (SDB) with incident coronary heart disease (CHD) or heart failure (HF) in a nonclinical population. DESIGN: Longitudinal analysis of a community-dwelling cohort followed up to 24 y. SETTING: Sleep laboratory at the Clinical Research Unit of the University of Wisconsin Hospital and Clinics. PARTICIPANTS: There were 1,131 adults who completed one or more overnight polysomnography studies, were free of CHD or HF at baseline, were not treated by continuous positive airway pressure (CPAP), and followed over 24 y. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: In-laboratory overnight polysomnography was used to assess SDB, defined by the apnea-hypopnea index (AHI) using apnea and hypopnea events per hour of sleep. Incident CHD or HF was defined by new reports of myocardial infarction, coronary revascularization procedures, congestive heart failure, and cardiovascular deaths. We used baseline AHI as the predictor variable in survival analysis models predicting CHD or HF incidence adjusted for traditional confounders. The incidence of CHD or HF was 10.9/1,000 person-years. The mean time to event was 11.2 +/- 5.8 y. After adjusting for age, sex, body mass index, and smoking, estimated hazard ratios (95% confidence interval) of incident CHD or HF were 1.5 (0.9-2.6) for AHI > 0-5, 1.9 (1.05-3.5) for AHI 5 <= 15, 1.8 (0.85-4.0) for AHI 15 <= 30, and 2.6 (1.1 6.1) for AHI > 30 compared to AHI = 0 (P trend = 0.02). CONCLUSIONS: Participants with untreated severe sleep disordered breathing (AHI > 30) were 2.6 times more likely to have an incident coronary heart disease or heart failure compared to those without sleep disordered breathing. Our findings support the postulated adverse effects of sleep disordered breathing on coronary heart disease and heart failure. PMID- 25515106 TI - Treating Acute Insomnia: A Randomized Controlled Trial of a "Single-Shot" of Cognitive Behavioral Therapy for Insomnia. AB - STUDY OBJECTIVES: Despite considerable evidence supporting cognitive behavioral therapy for insomnia (CBT-I) for chronic insomnia, it remains untested within the context of acute insomnia. This study examined the efficacy of a single session of CBT-I, with an accompanying self-help pamphlet, for individuals with acute insomnia. DESIGN: A pragmatic parallel group randomized controlled trial. SETTING: Community. PARTICIPANTS: Forty adults (mean age 32.9 +/- 13.72 y) with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) defined insomnia disorder, except a self-reported duration of less than 3 mo (i.e., acute insomnia), who reported no previous exposure to CBT-I and were not currently taking medication for sleep. INTERVENTIONS: A single 60- to 70-min session of CBT-I (n = 20), with an accompanying self-help pamphlet, or wait list control group (n = 20). All subjects were offered a full individual course of CBT I on completion of the study, regardless of group allocation. MEASUREMENTS AND RESULTS: Subjects completed sleep diaries and the Insomnia Severity Index (ISI) pretreatment and 1 mo following treatment. There were no between-group differences on baseline ISI scores or subjective sleep continuity. The intervention group reported significantly lower ISI scores than controls (t(38) 2.24, P < 0.05) at follow-up. Further, using proposed ISI scores for identifying insomnia caseness (i.e., >= 10), 60% of those in the CBT-I group had remitted by 1 mo compared to 15% of those in the control group. CONCLUSIONS: This single session of cognitive behavioral therapy for insomnia (CBT-I) is sufficiently efficacious for a significant proportion of those with acute insomnia. The results are discussed in terms of integrating this brief form of CBT-I into the "stepped care" model of insomnia. TRIAL REGISTRATION: Testing the efficacy of an early intervention for acute insomnia (SRCTN05891695) http://www.controlled trials.com/ISRCTN05891695. PMID- 25515105 TI - Feedback Blunting: Total Sleep Deprivation Impairs Decision Making that Requires Updating Based on Feedback. AB - STUDY OBJECTIVES: To better understand the sometimes catastrophic effects of sleep loss on naturalistic decision making, we investigated effects of sleep deprivation on decision making in a reversal learning paradigm requiring acquisition and updating of information based on outcome feedback. DESIGN: Subjects were randomized to a sleep deprivation or control condition, with performance testing at baseline, after 2 nights of total sleep deprivation (or rested control), and following 2 nights of recovery sleep. Subjects performed a decision task involving initial learning of go and no go response sets followed by unannounced reversal of contingencies, requiring use of outcome feedback for decisions. A working memory scanning task and psychomotor vigilance test were also administered. SETTING: Six consecutive days and nights in a controlled laboratory environment with continuous behavioral monitoring. SUBJECTS: Twenty six subjects (22-40 y of age; 10 women). INTERVENTIONS: Thirteen subjects were randomized to a 62-h total sleep deprivation condition; the others were controls. MEASUREMENTS AND RESULTS: Unlike controls, sleep deprived subjects had difficulty with initial learning of go and no go stimuli sets and had profound impairment adapting to reversal. Skin conductance responses to outcome feedback were diminished, indicating blunted affective reactions to feedback accompanying sleep deprivation. Working memory scanning performance was not significantly affected by sleep deprivation. And although sleep deprived subjects showed expected attentional lapses, these could not account for impairments in reversal learning decision making. CONCLUSIONS: Sleep deprivation is particularly problematic for decision making involving uncertainty and unexpected change. Blunted reactions to feedback while sleep deprived underlie failures to adapt to uncertainty and changing contingencies. Thus, an error may register, but with diminished effect because of reduced affective valence of the feedback or because the feedback is not cognitively bound with the choice. This has important implications for understanding and managing sleep loss-induced cognitive impairment in emergency response, disaster management, military operations, and other dynamic real-world settings with uncertain outcomes and imperfect information. PMID- 25515107 TI - An Integrative Model of Physiological Traits Can be Used to Predict Obstructive Sleep Apnea and Response to Non Positive Airway Pressure Therapy. AB - STUDY OBJECTIVES: Both anatomical and nonanatomical traits are important in obstructive sleep apnea (OSA) pathogenesis. We have previously described a model combining these traits, but have not determined its diagnostic accuracy to predict OSA. A valid model, and knowledge of the published effect sizes of trait manipulation, would also allow us to predict the number of patients with OSA who might be effectively treated without using positive airway pressure (PAP). DESIGN, PARTICIPANTS AND INTERVENTION: Fifty-seven subjects with and without OSA underwent standard clinical and research sleep studies to measure OSA severity and the physiological traits important for OSA pathogenesis, respectively. The traits were incorporated into a physiological model to predict OSA. The model validity was determined by comparing the model prediction of OSA to the clinical diagnosis of OSA. The effect of various trait manipulations was then simulated to predict the proportion of patients treated by each intervention. MEASUREMENTS AND RESULTS: The model had good sensitivity (80%) and specificity (100%) for predicting OSA. A single intervention on one trait would be predicted to treat OSA in approximately one quarter of all patients. Combination therapy with two interventions was predicted to treat OSA in ~50% of patients. CONCLUSIONS: An integrative model of physiological traits can be used to predict population-wide and individual responses to non-PAP therapy. Many patients with OSA would be expected to be treated based on known trait manipulations, making a strong case for the importance of non-anatomical traits in OSA pathogenesis and the effectiveness of non-PAP therapies. PMID- 25515108 TI - Effect of Placebo Conditions on Polysomnographic Parameters in Primary Insomnia: A Meta-Analysis. AB - STUDY OBJECTIVES: Little is known about the role of placebo response in the pharmacotherapy of primary insomnia, especially about the effect of placebo intake on objectively assessed outcome variables. Our aim was therefore to conduct an effect-size analysis of placebo conditions in randomized controlled drug trials addressing primary insomnia also including polysomnography. DESIGN: We conducted a comprehensive literature search using PubMed, PsycINFO, PSYNDEX, PQDT OPEN, OpenGREY, ISI Web of Knowledge, Cochrane Clinical Trials, and the World Health Organization International Clinical Trials Registry Platform. The meta-analysis used a random effects model and was based on 32 studies reporting 82 treatment conditions covering a total of 3,969 participants. Special emphasis was given to the comparison of objective and subjective outcomes and the proportion of the placebo response to the drug response. MEASUREMENTS AND RESULTS: Effect sizes estimates (Hedges g) suggest that there is a small to moderate yet significant and robust placebo response reducing the symptoms of insomnia in terms of sleep onset latency (-0.35), total sleep time (0.42), wake after sleep onset (-0.29), sleep efficiency (0.31), subjective sleep onset latency (-0.29), subjective total sleep time (0.43), subjective wake after sleep onset (-0.32), subjective sleep efficiency (0.25) and sleep quality (0.31). Thus, the placebo response was also evident in objective, physiological (polysomnographic) variables. Our results indicate that 63.56% of the drug responses are achieved even in the placebo groups. CONCLUSIONS: In light of these strong placebo responses, future studies should investigate how to exploit placebo mechanisms in clinical practice. PMID- 25515109 TI - Sleep and Respiration in 100 Healthy Caucasian Sleepers--A Polysomnographic Study According to American Academy of Sleep Medicine Standards. AB - STUDY OBJECTIVES: Despite differences between American Academy of Sleep Medicine (AASM) and Rechtschaffen and Kales scoring criteria, normative values following the current AASM criteria are lacking. We investigated sleep and respiratory variables in healthy adults over the lifespan, and established polysomnographic normative values according to current standards. DESIGN: Prospective polysomnographic investigation. SETTING: Academic referral hospital sleep laboratory. PARTICIPANTS: One hundred healthy sleepers aged 19-77 y were selected from a representative population sample by a two-step screening. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: All subjects underwent one full-night polysomnography. Sleep and arousals were scored according to AASM standards. Respiration was scored according to AASM 2007 and 2012 criteria in order to compare both methods. Percentile curves showed age-related differences in sleep architecture: a decrease was found for sleep efficiency [<= 30 y: 87.0 (71.9 94.1)% versus > 60 y: 79.7 (44.5-90.9)%], total sleep time [<= 30 y: 413.5 (345.6 451.9) min versus > 60 y: 378.3 (216.0-440.0) min], the percentages of N3 [<= 30 y 20.7 (15.2-37.5)% versus > 60 y: 14.9 (2.4-35.6)%] and rapid eye movement sleep [<= 30 y 15.5 (7.5-23.6)% versus. > 60 y: 10.3 (1.9-21.9)%], whereas the percentage of wake time after sleep onset increased with age [<= 30 y 6.0 (1.9 22.8)% versus > 60 y: 15.2 (6.3-48.7)%]. The apnea-hypopnea index (AHI) was higher when applying the AASM 2012 criteria [AHI AASM 2007 0.7 (0.0-21.5)/h versus 2012: 1.7 (0.0-25)/h; P < 0.001]. Eight percent of subjects had an AHI > 15/h. CONCLUSIONS: This study provides normative data on sleep macrostructure, microstructure, and respiration in adults following AASM standards. Furthermore, we demonstrated that respiration scoring according to AASM 2012 results in higher AHIs, and challenge the use of age-independent respiratory cutoff values. PMID- 25515110 TI - Cav2.3 E-/R-type voltage-gated calcium channels modulate sleep in mice. PMID- 25515111 TI - HLA-DQ allele competition in narcolepsy: where is the evidence? PMID- 25515112 TI - Natural history and management of pediatric obstructive sleep apnea-emerging concepts. PMID- 25515113 TI - Are we ready for "unisomnography"? PMID- 25515114 TI - Sleep duration: a consensus conference. PMID- 25515116 TI - Gaps between calcium recommendations to prevent pre-eclampsia and current intakes in one hospital in Argentina. AB - BACKGROUND: Hypertensive disorders are a major cause of maternal mortality. In Latin America and the Caribbean, pre-eclampsia accounts for approximately one in every four maternal deaths. The World Health Organization recommends calcium supplementation during pregnancy for the prevention and treatment of pre eclampsia and eclampsia in locations where dietary calcium intake is low. Calcium intake in Argentina is reported to be below WHO recommended levels; however, calcium intake from supplements and water has not been fully evaluated. The objective of this study was to evaluate calcium intake from supplements and water in a group of pregnant women. METHODS: This cross-sectional study was conducted at a maternity hospital in the city of Buenos Aires, Argentina. Questionnaires were verbally administered to women attending a routine antenatal care visit. Participants were 18 years of age or older and in their third trimester of pregnancy. Participants were first interviewed to evaluate nutritional supplement consumption and a subgroup was invited to undergo a 24-hour dietary recall. RESULTS: 137 women meeting inclusion criteria consented to participate. The average participant age was 27 years (SD+/-5.9), and all resided in an urban setting. None of the subjects took calcium supplements specifically, although 24 (17%) recalled taking supplements or antacids which contributed to their calcium intake. Mean calcium intake was 663 mg SD+/-389 for those women completing the 24 hour dietary recall,. This value increased to 706 mg SD+/-387 upon considering water intake and measuring chemical composition of water from the areas where women lived at the time of the interview and was further increased to 719 mg (SD+/-392) when calcium from supplements was taken into consideration. CONCLUSIONS: None of the subjects were consuming calcium supplements. Taking into account the low calcium intake in this population, diverse strategies would be required to comply with recommendations. PMID- 25515115 TI - Effects of cognitive behavioral therapy for insomnia on suicidal ideation in veterans. AB - OBJECTIVE: To examine the effects of cognitive behavioral therapy for insomnia (CBT-I) on suicidal ideation among Veterans with insomnia. DESIGN: Longitudinal data collected in the course of an uncontrolled evaluation of a large-scale CBT-I training program. SETTING: Outpatient and residential treatment facilities. PARTICIPANTS: Four hundred five Veterans presenting for treatment of insomnia. INTERVENTIONS: Cognitive behavioral therapy for insomnia (CBT-I). MEASUREMENT AND RESULTS: At baseline, 32% of patients, compared with 21% at final assessment, endorsed some level of suicidal ideation [chi(2)(df = 1) = 125; P < 0.001]. After adjusting for demographic variables and baseline insomnia severity, each 7-point decrease in Insomnia Severity Index (ISI) score achieved during CBT-I treatment was associated with a 65% (OR = 0.35; 95% CI = 0.24 to 0.52) reduction in odds of suicidal ideation. The effect of change in insomnia severity on change in depression severity was also significant. After controlling for change in depression severity and other variables in the model, the effect of change in insomnia severity on change in suicidal ideation remained significant. CONCLUSION: This evaluation of the largest dissemination of CBT-I in the United States found a clinically meaningful reduction in suicidal ideation among Veterans receiving CBT-I. The mechanisms by which effective treatment of insomnia with CBT-I reduces suicide risk are unknown and warrant investigation. The current results may have significant public health implications for preventing suicide among Veterans. PMID- 25515117 TI - A case of child death caused by intestinal volvulus following magnetic toy ingestion. AB - An 8-year boy was admitted to the ER of one of Warsaw's pediatric hospitals with a history of having bloody vomiting the day before. During admission the boy collapsed and lost consciousness. CPR was unsuccessful. On medico-legal autopsy, two foreign objects (small magnetic spheres--0.5 cm in diameter) were found in two different places in the small and large intestines and were notably attracted magnetically one to another. A loop of approximately 1-m length with features of small intestinal hemorrhagic necrosis and small intestinal mechanical obstruction was found. The cause of death was intestinal volvulus and small intestinal mechanical obstruction caused by ingestion of foreign objects (two neodymium magnets). Most likely these small magnetic spheres were part of a popular toy, the safety of which, lately, has been widely discussed. PMID- 25515118 TI - Plasminogen activation by staphylokinase enhances local spreading of S. aureus in skin infections. AB - BACKGROUND: Staphylococcus aureus (S. aureus) is a frequent cause of skin and soft tissue infections. A unique feature of S. aureus is the combined presence of coagulases that trigger fibrin formation and of the plasminogen activator staphylokinase (SAK). Whereas the importance of fibrin generation for S. aureus virulence has been established, the role of SAK remains unclear. We studied the role of plasminogen activation by SAK in a skin infection model in mice and evaluated the impact of alpha-2-antiplasmin (alpha2AP) deficiency on the spreading and proteolytic activity of S. aureus skin infections. The species selectivity of SAK was overcome by adenoviral expression of human plasminogen. Bacterial spread and density was assessed non-invasively by imaging the bioluminescence of S. aureus Xen36. RESULTS: SAK-mediated plasmin activity increased the local invasiveness of S. aureus, leading to larger lesions with skin disruption as well as decreased bacterial clearance by the host. Even though fibrin and bacterial surfaces protected SAK-mediated plasmin activity from inhibition by alpha2AP, the deficiency of alpha2AP resulted in increased bacterial spreading. SAK-mediated plasmin also induced secondary activation of gelatinases, shown both in vitro and in lesions from the in vivo model. CONCLUSION: SAK contributes to the phenotype of S. aureus skin infections by enhancing bacterial spreading as a result of fibrinolytic and proteolytic activation. PMID- 25515121 TI - [Perioperative antibiotic prophylaxis during standard interventions in ear, nose and throat medicine]. AB - BACKGROUND: The majority of standard interventions in otorhinolaryngology are classified as "clean contaminated" according to international classifications; correspondingly, no generally accepted recommendations regarding perioperative antibiotic prophylaxis (pAP) exist. The value of such pAP for these interventions remains unclear. Aim of the study was to assess the effects of pAP in selected standard otorhinolaryngologic procedures. MATERIALS AND METHODS: In August 2012 a standard operating procedure (SOP) was implemented, which lead to termination of routine pAP for the majority of standard operations. All patients included in this retrospective study had undergone a standard procedure (tonsil, septum or paranasal sinus surgery) during a period either 6 months before or 6 months after the inauguration of the SOP. The charts were reviewed for demographic factors, postoperative complications and length of hospital stay. RESULTS: The group before the inauguration of the SOP consisted of 316 patients (132 female, 184 male), aged 30+/-20 years. The group after the inauguration comprised 308 patients (128 female, 180 male), aged 31+/-19 years. For the entire patient collective, the termination of pAP led to a statistically significant increase in postoperative antibiotic treatment for all types of interventions tested. A statistically significant change in noninflammatory complications or the length of hospital stay was not detected. DISCUSSION: The termination of pAP during standard procedures in otorhinolaryngology is associated with an increase in postoperative antibiotic treatment but has no effect on other postoperative complications tested or the length of hospital stay. PMID- 25515122 TI - [Clinical otorhinolaryngological symptoms of metamizole-induced agranulocytosis]. AB - BACKGROUND: Despite the controversial international debate on the use of metamizole as a standard analgesic, the prescription figures for Germany have increased constantly during recent years. However, metamizole can lead to the rare and severe medical condition called agranulocytosis. MATERIALS AND METHODS: Between January 2009 and January 2014, 5 patients with metamizole-induced agranulocytosis presented themselves at the Interdisciplinary Emergency Center of the University Clinic Bonn. According to their leading ENT symptoms, they were transferred to the otorhinolaryngological department. We retrospectively evaluated metamizole medication, all general patient data and previous diseases, as well as disease course and the respective therapies. RESULTS: Within the scope of the different treatments--surgery after trauma (n=2), elective orthopedic surgery (n=2), tonsillitis treatment (n=1)--the patients (n=5; mean age 30 years) had made regular ambulant use of metamizole for several days or weeks (4-28 days, mean 16.8 days). Daily oral dose ranged from 625 to 2000 mg/d (mean 1500 mg/d). Subsequently, patients required treatment for clinical symptoms of agranulocytosis (e.g. tonsillitis with severe odynophagia and significantly reduced general condition). All patients were monitored in an intermediate or intensive care unit (3-14 days, mean 10 days). No patients died. DISCUSSION: As our cases show, when using metamizole as a standard analgesic, the treating otolaryngologist should look for clinical symptoms of agranulocytosis and inform patients about possible adverse effects. We recommend strict indication setting, regular blood analyses during long-term medication and consideration of alternative analgesics (e.g. NSAR). PMID- 25515123 TI - [Speech perception with electric-acoustic stimulation : Comparison with bilateral cochlear implant users in different noise conditions]. AB - BACKGROUND: Cochlear implantation with the aim of hearing preservation for combined electric-acoustic stimulation (EAS) is the therapy of choice for patients with residual low-frequency hearing. Preserved residual acoustic hearing has a positive effect on speech intelligibility in difficult noise conditions. OBJECTIVES: The goal of this study was to assess speech reception thresholds in various complex noise conditions for patients with EAS in comparison with patients using bilateral cochlear implants (CI). MATERIALS AND METHODS: Speech perception in noise was measured for bilateral CI and EAS patient groups. A total of 22 listeners with normal hearing served as a control group. Speech reception thresholds (SRT) were measured using a closed-set sentence matrix test. Speech was presented with a single source in frontal position; noise was presented in frontal position or in a multisource noise field (MSNF) consisting of a four loudspeaker array with independent noise sources. Modulated speech-simulating noise and pseudocontinuous noise served respectively as interference signal with different temporal characteristics. RESULTS: The average SRTs in the EAS group were significantly better in all test conditions than those of the group with bilateral CI. Both user groups showed significant improvement in the MSNF condition compared with the frontal noise condition as a result of bilateral interaction. The normal-hearing control group was able to use short temporal gaps in modulated noise to improve speech perception in noise (gap listening). This effect was absent in both implanted user groups. CONCLUSION: Patients with combined EAS in one ear and a hearing aid in the contralateral ear show significantly improved speech perception in complex noise conditions compared with bilateral CI recipients. PMID- 25515124 TI - [Targeting p16(INK4a) by therapeutic vaccination : Concept and status of clinical investigations in HPV-associated head and neck cancers]. AB - BACKGROUND: Up to 70% of oropharyngeal cancers are attributable to human papillomavirus (HPV) infection; however, a therapy specific for patients with HPV associated cancers is currently not available. Overexpression of the viral oncogenes E6 and E7 results in cellular alterations that represent interesting targets for novel therapies. One consequence of E6/E7 overexpression is strong expression of the cellular protein p16(INK4a). The elimination of p16(INK4a) expressing tumor cells by the immune system could be achieved through a therapeutic p16(INK4a) vaccine. OBJECTIVE: The current article provides an overview of HPV-associated head and neck cancers and the associated p16(INK4a) expression. Based on this overview, the concept and status of the clinical investigation of therapeutic p16(INK4a) vaccination is described. MATERIAL AND METHODS: In addition to discussing published literature, a clinical study is described. In this phase I/IIa study, patients with advanced HPV-associated p16(INK4a)-expressing tumors were vaccinated with a p16(INK4a) peptide. RESULTS: HPV-associated head and neck cancers continuously display strong overexpression of the cellular protein p16(INK4a). Vaccination with p16(INK4a) could represent a novel therapy for patients with HPV-associated carcinomas. CONCLUSION: Further studies will evaluate the clinical efficacy of therapeutic p16(INK4a) vaccination. Combinations with other immunotherapeutic approaches are interesting considering the modulating role of the immune system, particularly in HPV associated tumors. PMID- 25515125 TI - [Development of a questionnaire for the assessment of the voice self-concept]. AB - BACKGROUND: Common self-assessment questionnaires on voice diagnostics focus mostly on functionality of the voice and the impact on the quality of life. Personal aspects such as the relationship with one's own voice and its self perception are for the most part not taken into consideration. OBJECTIVES: In this article a questionnaire for the assessment of the voice self-concept (Fragebogen zur Erfassung des stimmlichen Selbstkonzepts, FESS) is introduced. MATERIALS AND METHODS: Reliability and validity were tested with a sample of 308 student teachers. For external validity, the scales were correlated with standardized questionnaires of vocal, physical, and mental health. The scale reliability was also retested in 94 participants. RESULTS: The principal component analysis confirmed the internal consistency of three subscales on the relationship with one's own voice, the awareness of the use of one's own voice, and the perception of the connection between voice and emotional changes. CONCLUSION: The FESS questionnaire was shown to be a reliable and valid instrument which supplements existing voice questionnaires by self-related aspects of the voice. PMID- 25515126 TI - [Importance of cellular tight junction complexes in the development of periprosthetic leakage after prosthetic voice rehabilitation]. AB - BACKGROUND: The use of voice prostheses is currently the gold standard in voice rehabilitation after total laryngectomy. This method combines low complication rates and excellent rehabilitation results; however, approximately 30% of patients show periprosthetic leakage or severe fistula enlargement after laryngectomy and prosthetic voice restoration within the first 4 years. The development of this enlargement is controversially discussed in the literature but recently published studies have shown that high esophageal reflux plays a key role in this process, which leads to an inflammatory reaction and disturbs the intercellular tight junctions in the sense of an epithelial mesenchymal transition (EMT). MATERIAL AND METHODS: A total of 44 patients underwent 24 h pH monitoring, a sample biopsy from the region of the fistula and a subsequent biomolecular examination for intracellular junction proteins as well as a correlation between the severity of reflux and tracheoesophageal fistula problems before and after antireflux therapy with proton pump inhibitors (PPI). RESULTS: Immunohistochemical staining revealed decreases in membrane E-cadherin and beta catenin and a significant increase in the cytoplasmic fraction, depending on the severity of inflammation in the fistula tissue. In patients with an improvement of clinical fistula problems under oral PPI treatment an increase of membrane E cadherin could be shown, whereas patients with persisting fistula enlargement demonstrated a further decrease of E-cadherin. CONCLUSION: The data indicate a central role of EMT in the development of fistula enlargement after total laryngectomy. Patients with periprosthetic leakage showed a loss of membrane bound E-cadherin and beta-catenin with an up-regulation of vimentin expression. In patients with mild or no leakage problems EMT could be resolved by aggressive antireflux treatment, whereas patients without any effect of PPI treatment on the fistula showed no reversal of EMT. These data contribute to the understanding of treatment resistant fistula enlargement after total laryngectomy. PMID- 25515128 TI - [Facets of facial plastic surgery]. PMID- 25515127 TI - [Influence of the psyche on cosmetic treatments]. AB - The wish for an attractive appearance is evident in many people. Aesthetic, cosmetic and surgical treatment is willingly made use of in order to fit into the current beauty ideal. A considerable portion of people who decide to follow this path show signs of psychological problems. One has to recognize and evaluate these for the planning or, if necessary, refusal of further treatment. In this article, the most common psychological problems in the cosmetic and aesthetic field of work are presented. A guideline for handling these patients is explained. Thus, a productive and relaxed cooperation will be possible which enables psychological and physical satisfaction for the medical team and the patients. PMID- 25515130 TI - Lithium-induced cortical atrophy and cognitive dysfunction. PMID- 25515129 TI - [Interpretation of ultrasound findings in otorhinolaryngology : Skin, soft tissue of the neck, lymph nodes, and oncologic follow-up]. AB - A major advantage of head and neck sonography over other imaging methods is that the attending physician performs the examination himself/herself and can directly compare the imaging findings with other clinical and endoscopic findings. Given the "big picture," the physician is thus able to interpret the sonographic findings correctly. The first part of this article gives an exemplary overview of lesions of the skin, neck, and lymph nodes as well as the ensuing oncologic follow-up with ultrasound. In the second part the focus lies on salivary glands, paragangliomas, the esophagus, and vascular pathologies. PMID- 25515131 TI - Severe resistant maternal hypotension following tocolysis with nifedipine. AB - An 18-year-old woman, gravida 3, para 2, presented at 24 weeks of gestation with preterm premature rupture of membranes. She was started on nifedipine for tocolysis and to facilitate administration of steroids. Two and a half hours later, the patient developed tachycardia and hypotension. Sepsis from chorioamnionitis, acute cardiac event and pulmonary embolism were considered as differential diagnoses. Laboratory and radiological investigations, however, ruled out these possible causes of haemodynamic instability. Her clinical condition deteriorated and hypotension remained intractable despite aggressive fluid resuscitation. An emergency caesarean section at 24 weeks of gestation was carried out in the interest of saving the mother's life. The haemodynamic status of the patient recovered rapidly postcaesarean section. This case report highlights the rare but potentially serious adverse effects of hypotension in administration of nifedipine; and thus reminds us of the importance of judicious prescription and careful titration of nifedipine as a tocolytic. PMID- 25515132 TI - Multifunctional magnetic and fluorescent core-shell nanoparticles for bioimaging. AB - Novel magnetic and fluorescent core-shell nanoparticles have been fabricated, which exhibit superparamagnetic behavior and emit strong near-infrared fluorescence. The nanoparticles are highly biocompatible and can be internalized into cells with nucleic accumulation via strong interaction with nucleic acids, implying potential applications in the biomedical field. PMID- 25515133 TI - Prevalence and genotyping of Toxoplasma gondii in naturally-infected synanthropic rats (Rattus norvegicus) and mice (Mus musculus) in eastern China. AB - BACKGROUND: Synanthropic rats and mice share the same environment with humans and play an important role in epidemiology of toxoplasmosis; however, there is limited information about prevalence and genetic characterization of Toxoplasma gondii in synanthropic rats and mice in China. FINDINGS: In the present study, the prevalence and genetic characterization of T. gondii naturally infected synanthropic rodents (Rattus norvegicus and Mus musculus) were investigated in the urban area of Xuzhou city, Eastern China between June 2013 and August 2014. DNA from the brain of each animal was prepared and screened by specific PCR assay targeting 35-fold repeated B1 gene (B1-PCR). PCR positive DNA samples were further genotyped by multi-locus PCR-RFLP. Overall, out of 123 synanthropic rodents, 29 samples were positive by B1 gene-targeted PCR (23.6%). Of these, 7 out of 31 (22.3%) M. musculus were positive, whereas the positive rate of R. norvegicus was 23.9% (22/92). Multi-locus PCR-RFLP analysis reveals that seven PCR-positive samples were completely genotyped and they were identified as type China 1 (ToxoDB# 9). CONCLUSION: To our knowledge, this is the first report of molecular detection and genetic characterization of T. gondii infection in synanthropic rodents in Eastern China. The results of the present study showed a high infection pressure of T. gondii exists in the environment and synanthropic rodents infected by T. gondii may be an important source of infection for cats and other animals. PMID- 25515134 TI - Sunitinib-induced severe toxicities in a Japanese patient with the ABCG2 421 AA genotype. AB - BACKGROUND: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects. CASE PRESENTATION: A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient. CONCLUSION: The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib. PMID- 25515120 TI - Mars atmosphere. Mars methane detection and variability at Gale crater. AB - Reports of plumes or patches of methane in the martian atmosphere that vary over monthly time scales have defied explanation to date. From in situ measurements made over a 20-month period by the tunable laser spectrometer of the Sample Analysis at Mars instrument suite on Curiosity at Gale crater, we report detection of background levels of atmospheric methane of mean value 0.69 +/- 0.25 parts per billion by volume (ppbv) at the 95% confidence interval (CI). This abundance is lower than model estimates of ultraviolet degradation of accreted interplanetary dust particles or carbonaceous chondrite material. Additionally, in four sequential measurements spanning a 60-sol period (where 1 sol is a martian day), we observed elevated levels of methane of 7.2 +/- 2.1 ppbv (95% CI), implying that Mars is episodically producing methane from an additional unknown source. PMID- 25515137 TI - The sister Mary Joseph nodule. PMID- 25515136 TI - Provider perspectives on essential functions for care management in the collaborative treatment of hypertension: the P.A.R.T.N.E.R. framework. AB - BACKGROUND: Care management has become a widespread strategy for improving chronic illness care. However, primary care provider (PCP) participation in programs has been poor. Because the success of care management relies on provider engagement, understanding provider perspectives is necessary. OBJECTIVE: Our goal was to identify care management functions most valuable to PCPs in hypertension treatment. DESIGN: Six focus groups were conducted to discuss current challenges in hypertension care and identify specific functions of care management that would improve care. PARTICIPANTS: The study included 39 PCPs (participation rate: 83 %) representing six clinics, two of which care for large African American populations and four that are in underserved locations, in the greater Baltimore metropolitan area. APPROACH: This was a qualitative analysis of focus groups, using grounded theory and iterative coding. KEY RESULTS: Providers desired achieving blood pressure control more rapidly. Collaborating with care managers who obtain ongoing patient data would allow treatment plans to be tailored to the changing life conditions of patients. The P.A.R.T.N.E.R. framework summarizes the care management functions that providers reported were necessary for effective collaboration: Partner with patients, providers, and the community; Arrange follow-up care; Resolve barriers to adherence; Track treatment response and progress; Navigate the health care system with patients; Educate patients & Engage patients in self-management; Relay information between patients and/or provider(s). CONCLUSIONS: The P.A.R.T.N.E.R. framework is the first to offer a checklist of care management functions that may promote successful collaboration with PCPs. Future research should examine the validity of this framework in various settings and for diverse patient populations affected by chronic diseases. PMID- 25515119 TI - Mars atmosphere. The imprint of atmospheric evolution in the D/H of Hesperian clay minerals on Mars. AB - The deuterium-to-hydrogen (D/H) ratio in strongly bound water or hydroxyl groups in ancient martian clays retains the imprint of the water of formation of these minerals. Curiosity's Sample Analysis at Mars (SAM) experiment measured thermally evolved water and hydrogen gas released between 550 degrees and 950 degrees C from samples of Hesperian-era Gale crater smectite to determine this isotope ratio. The D/H value is 3.0 (+/-0.2) times the ratio in standard mean ocean water. The D/H ratio in this ~3-billion-year-old mudstone, which is half that of the present martian atmosphere but substantially higher than that expected in very early Mars, indicates an extended history of hydrogen escape and desiccation of the planet. PMID- 25515135 TI - Diet drink consumption and the risk of cardiovascular events: a report from the Women's Health Initiative. AB - BACKGROUND: Data are limited regarding the influence of diet drink consumption on cardiovascular disease (CVD) outcomes. OBJECTIVE: We aimed to evaluate the relationship between diet drink intake and cardiovascular events. DESIGN: We conducted a retrospective cohort study, utilizing data from the national, multicenter Women's Health Initiative Observational Study (WHI OS), recruiting subjects from 1993 to 1998. PATIENTS: Post-menopausal women with available diet drink intake data, without pre-existing CVD and who survived >= 60 days were included in the study. MAIN MEAURES: A composite of incident coronary heart disease, heart failure, myocardial infarction, coronary revascularization procedure, ischemic stroke, peripheral arterial disease and CVD death was used as the primary outcome. CVD death and all-cause mortality were secondary outcomes. Adjusted Cox proportional hazards models were used to compare primary and secondary outcomes across diet drink intake strata. KEY RESULTS: In all, 59,614 women, mean age 62.8 years, were included for analysis. In unadjusted analysis over a follow-up of 8.7 +/- 2.7 years, the primary outcome occurred in 8.5 % of the women consuming >= 2 diet drinks/day, compared to 6.9 %, 6.8 % and 7.2 % in the 5-7/week, 1-4/week and 0-3/month groups, respectively. After controlling for other CVD risk factors, women who consumed >= 2 drinks/day had a higher adjusted risk of CVD events (HR 1.3, 95 % CI 1.1-1.5), CVD mortality (HR 1.5, 95 % CI 1.03 2.3) and overall mortality (HR 1.3, 95 % CI 1.04-1.5) compared to the reference group (0-3 drinks/month). CONCLUSIONS: This analysis demonstrates an association between high diet drink intake and CVD outcomes and mortality in post-menopausal women in the WHI OS. PMID- 25515138 TI - The patient diarist in the digital age. PMID- 25515139 TI - Role of bifidobacteria in the hydrolysis of chlorogenic acid. AB - This study aimed to explore the capability of potentially probiotic bifidobacteria to hydrolyze chlorogenic acid into caffeic acid (CA), and to recognize the enzymes involved in this reaction. Bifidobacterium strains belonging to eight species occurring in the human gut were screened. The hydrolysis seemed peculiar of Bifidobacterium animalis, whereas the other species failed to release CA. Intracellular feruloyl esterase activity capable of hydrolyzing chlorogenic acid was detected only in B. animalis. In silico research among bifidobacteria esterases identified Balat_0669 as the cytosolic enzyme likely responsible of CA release in B. animalis. Comparative modeling of Balat_0669 and molecular docking studies support its role in chlorogenic acid hydrolysis. Expression, purification, and functional characterization of Balat_0669 in Escherichia coli were obtained as further validation. A possible role of B. animalis in the activation of hydroxycinnamic acids was demonstrated and new perspectives were opened in the development of new probiotics, specifically selected for the enhanced bioconversion of phytochemicals into bioactive compounds. PMID- 25515140 TI - The effect of body position on postprandial perceptions, gastric emptying, and intragastric meal distribution: an ultrasonographic study in reclining healthy subjects. AB - OBJECTIVE: Postprandial dyspepsia is common and may be associated with abnormal intragastric distribution of food. We aimed to determine the effect of body position on gastric emptying, meal distribution, and postprandial perceptions in healthy subjects. MATERIAL AND METHODS: Eight adolescents (4 females and 4 males aged 14 years) were investigated using three-dimensional ultrasonography. The subjects were studied twice in a random order: once in the right lateral recumbent (RLR) position and once in the left lateral recumbent (LLR) position. Postprandial perceptions, gastric volumes, and antral areas were recorded immediately after the ingestion of 500 ml of a low-caloric meat soup over 4 min, and at 10 and 20 min following the meal. RESULTS: Postprandial perceptions (epigastric pain, nausea, and fullness) were more pronounced in the RLR position compared to the LLR position, particularly at the end of the meal ingestion (p < 0.01). Gastric volumes were significantly smaller in the RLR position compared to the LLR position at 10 min (p < 0.01) and 20 min (p < 0.05). Antral areas were significantly wider in the RLR position compared to the LLR position at 10 min (p < 0.05) and 20 min (p < 0.01). CONCLUSION: Postprandial perceptions are more pronounced, gastric emptying is faster, and antral area is wider in the RLR position compared to the LLR position. The results suggest that lying on the left side after a meal may be a measure to reduce postprandial dyspeptic sensations. PMID- 25515141 TI - Rhenium and technetium complexes that bind to amyloid-beta plaques. AB - Alzheimer's disease is associated with the presence of insoluble protein deposits in the brain called amyloid plaques. The major constituent of these deposits is aggregated amyloid-beta peptide. Technetium-99m complexes that bind to amyloid beta plaques could provide important diagnostic information on amyloid-beta plaque burden using Single Photon Emission Computed Tomography (SPECT). Tridentate ligands with a stilbene functional group were used to form complexes with the fac-[M(I)(CO)3](+) (M = Re or (99m)Tc) core. The rhenium carbonyl complexes with tridentate co-ligands that included a stilbene functional group and a dimethylamino substituent bound to amyloid-beta present in human frontal cortex brain tissue from subjects with Alzheimer's disease. This chemistry was extended to make the analogous [(99m)Tc(I)(CO)3](+) complexes and the complexes were sufficiently stable in human serum. Whilst the lipophilicity (log D7.4) of the technetium complexes appeared ideally suited for penetration of the blood brain barrier, preliminary biodistribution studies in an AD mouse model (APP/PS1) revealed relatively low brain uptake (0.24% ID g(-1) at 2 min post injection). PMID- 25515142 TI - Iodine-131 induces apoptosis in HTori-3 human thyrocyte cell line and G2/M phase arrest in a p53-independent pathway. AB - Iodine-131 is known to destroy residual thyroid tissue following surgical resection of differentiated thyroid carcinoma and is widely used to treat hyperthyroidism. However, the mechanism by which iodine-131 induces apoptosis and cell cycle arrest in the human thyrocyte cell line, Htori-3, remains to be elucidated. In the present study, the cytotoxic effect of iodine-131 on the HTori 3 cell line and the underlying mechanism of iodine-131-induced cell apoptosis were investigated. Cell viability was analyzed using an MTT assay, while cell apoptosis and cell cycle arrest were determined using flow cytometry. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analyses were performed to determine the changes in the expression levels of p53, B-cell lymphoma 2 (Bcl-2), Fas and growth arrest and DNA damage-inducible 45 (GADD45), following iodine-131 treatment. The results demonstrated that iodine 131 may inhibit HTori-3 cell growth via cell apoptosis and G2/M phase arrest in a time- and dose-dependent manner. The iodine-131 dose required for 50% growth inhibition of HTori-3 cell viability 48 h after treatment was 27.75+/-2.22 MBq/ml. Upregulation of Fas and downregulation of Bcl-2 expression levels were observed following iodine-131 treatment. The results of RT-qPCR revealed an increase in the GADD45 mRNA expression following HTori-3 cell exposure to iodine 131. Notably, the mRNA and protein expression levels of p53 were not altered following iodine-131 treatment. In conclusion, iodine-131 may induce apoptosis in HTori-3 cells by downregulating the expression of Bcl-2 and upregulating the expression of Fas. In addition, iodine-131 may upregulate GADD45 mRNA expression in HTori-3 cells, resulting in G2/M phase arrest in a p53-independent pathway. PMID- 25515143 TI - Darwin: German mystic or French rationalist? AB - The notion that Charles Darwin embraced the German Romantic tradition seems plausible, given the early influence of Alexander von Humboldt. But this view fails to do justice to other scientific traditions. Darwin was a protege of the Englishman John Stevens Henslow and was a follower of the Scott Charles Lyell. He had important debts to French scientists, notably Henri Milne-Edwards, Etienne and Isidore Geoffroy Saint-Hilaire, and Alphonse de Candolle. Many Germans were quite supportive of Darwin, but not all of these were encumbered by idealistic metaphysical baggage. Both Darwin and Anton Dohrn treated science as very much a cosmopolitan enterprise. PMID- 25515145 TI - Marine biology, intertidal ecology, and a new place for biology. AB - At the present time, there is considerable interest for the physical setting of science, that is, its actual 'place' of practice. Among historians of biology, place has been considered to be a crucial component for the study of ecology. Other historians have noted the 'built' environments (laboratories) for the study of biology along the seashore, even referring to these places in terms more applicable to vacation sites. In this paper, I examine the place of intertidal ecology investigations, both in terms of the physical space and the built space. Part of the examination will investigate the aesthetic aspect of the Pacific Coast, part will evaluate the unique character of the intertidal zone, and part will consider the construction of natural laboratories and built laboratories as characteristic places for biology. PMID- 25515144 TI - [The Essen-based steel producer Alfred Krupp (1812-1887) as a reader of the flora and fauna of the Gulf of Naples. A look at the relationship of Anton Dohrn (1840 1909) to the house Krupp]. AB - A unfavourable notice written by industrial magnate Alfred Krupp (1812-1887) has been discovered on the posterior cover sheet of the first volume of the monumental series Fauna und Flora des Golfes von Neapel, edited by the Zoological Station at Naples (1880) Krupp's handwritten statement affords the opportunity to discuss in more detail the intricate relationship between the founder of the first marine biology station, Anton Dohrn (1840-1909), and the owner of the greatest steel factory in Europe, the Krupp-family at Essen. Although Anton Dohrn did not know about Krupp's disapproving comment he had a fine unerring instinct for the mentality of his negotiating partner, whose way of thinking rather aimed at the practical success and completion of armament factory, preventing thus a the serious rapprochement between the two personalities. Even when the Krupp heir, Friedrich Alfred Krupp, later devoted to questions about marine biology in his new built house at Capri, and was willing to support the Zoological Station with high sponsoring, Anton Dohrn maintained a reserved attitude towards the Krupp's offer to support the marine research financially. Likewise, he remained unimpressed, when the steel magnate was shook by the smear campaign in Capri that ultimately led to Krupp's death in November 1902. PMID- 25515146 TI - Is there such a thing as "group selection" in the, contextual analysis framework? AB - This paper argues that the contextual approach to natural selection does not offer an estimation of the contributions of individual and group selection to evolutionary change in multi-level selection scenarios, and that this is so because the term "group selection", as defined by the contextual approach, does not refer to a process taking place at the group level. In the contextual analysis framework, this term simply denotes an evolutionary change that takes place due to the fact that, overall, individual types do not share similar contexts or environments, and the only way to claim that such an evolutionary change is a result of selection is by admitting that "group selection" is in fact a kind of frequency-dependent selection, i.e. a selection process taking place at the individual level. Therefore, under the names "individual selection" and "group selection", the contextual approach actually isolates two aspects of the relation between individual types and their environment, and not two distinct levels of selection. PMID- 25515147 TI - A soul of truth in things erroneous: Popper's "amateurish" evolutionary philosophy in light of contemporary biology. AB - This paper will critically assess Popper's evolutionary philosophy. There exists a rich literature on the topic with which we have many reservations. We believe that Popper's evolutionary philosophy should be assessed in light of the intriguing theoretical insights offered, during the last 10 years or so, by the philosophy of biology, evolutionary biology and molecular biology. We will argue that, when analysed in this manner, Popper's ideas concerning the nature of selection, Lamarckism and the theoretical limits of neo-Darwinism can be appreciated in their full biological and philosophical value. PMID- 25515148 TI - A mild, three-component one-pot synthesis of 2,4,5-trisubstituted imidazoles using Mo(IV) salen complex in homogeneous catalytic system and Mo(IV) salen complex nanoparticles onto silica as a highly active, efficient, and reusable heterogeneous nanocatalyst. AB - Mo(IV) salen complex (2.5 mol%) was found to be a highly efficient catalyst for the one-pot synthesis of 2,4,5-triarylimidazoles via a three-component reaction using benzil or benzoin, aryl aldehydes, and ammonium acetate as a nitrogen source under mild conditions. In order to recover and the reuse of the catalyst, a new Mo(IV) salen-silica nanoparticle as heterogeneous catalyst was prepared by simple and successful immobilization of the catalyst onto silica (3-aminopropyl functionalized silica gel). This procedure can be applied to large-scale conditions with high efficiency. Experimental evidence showed that the catalyst is stable and can be easily recovered and reused for at least five times without significant loss of activity. The nanocatalyst was characterized using FT-IR spectroscopy, scanning electron microscopy, atomic force microscopy, powder X-ray diffraction , transmission electron microscopy, thermogravimetric instrument for analysis of nitrogen adsorption, and inductively coupled plasma spectrometer. PMID- 25515149 TI - Rh(III)-catalyzed selenylation of arenes with selenenyl chlorides/diselenides via C-H activation. AB - Rh(III)-catalyzed, chelation-assisted C-H activation and selenylation of arenes has been achieved. Arenes bearing oxime, azo, pyridyl, and N-oxide chelating groups are viable substrates, and electrophilic selenyl chlorides and diselenides are used as selenylating reagents. The catalytic system is highly efficient under mild conditions over a broad range of substrates with excellent functional group tolerance. PMID- 25515150 TI - Cronobacter, the emergent bacterial pathogen Enterobacter sakazakii comes of age; MLST and whole genome sequence analysis. AB - BACKGROUND: Following the association of Cronobacter spp. to several publicized fatal outbreaks in neonatal intensive care units of meningitis and necrotising enterocolitis, the World Health Organization (WHO) in 2004 requested the establishment of a molecular typing scheme to enable the international control of the organism. This paper presents the application of Next Generation Sequencing (NGS) to Cronobacter which has led to the establishment of the Cronobacter PubMLST genome and sequence definition database (http://pubmlst.org/cronobacter/) containing over 1000 isolates with metadata along with the recognition of specific clonal lineages linked to neonatal meningitis and adult infections RESULTS: Whole genome sequencing and multilocus sequence typing (MLST) has supports the formal recognition of the genus Cronobacter composed of seven species to replace the former single species Enterobacter sakazakii. Applying the 7-loci MLST scheme to 1007 strains revealed 298 definable sequence types, yet only C. sakazakii clonal complex 4 (CC4) was principally associated with neonatal meningitis. This clonal lineage has been confirmed using ribosomal-MLST (51-loci) and whole genome-MLST (1865 loci) to analyse 107 whole genomes via the Cronobacter PubMLST database. This database has enabled the retrospective analysis of historic cases and outbreaks following re-identification of those strains. CONCLUSIONS: The Cronobacter PubMLST database offers a central, open access, reliable sequence-based repository for researchers. It has the capacity to create new analysis schemes 'on the fly', and to integrate metadata (source, geographic distribution, clinical presentation). It is also expandable and adaptable to changes in taxonomy, and able to support the development of reliable detection methods of use to industry and regulatory authorities. Therefore it meets the WHO (2004) request for the establishment of a typing scheme for this emergent bacterial pathogen. Whole genome sequencing has additionally shown a range of potential virulence and environmental fitness traits which may account for the association of C. sakazakii CC4 pathogenicity, and propensity for neonatal CNS. PMID- 25515151 TI - Pre-treatment options for halophytic microalgae and associated methane production. AB - Methane production from lipid extracted, pre-treated disrupted and non-pretreated Tetraselmis spp. microalgae was investigated. The results demonstrated that 122 mL per g VS methane was produced for the lipid extracted Tetraselmis spp., demonstrating that lipid free Tetraselmis can be effectively digested in an anaerobic environment. A total of 252 mL per g VS and 248 mL per g VS of methane was reported for non-disrupted and pre-treated disrupted Tetraselmis sp. respectively. It was also observed that the microbial community caused cell lysis of Tetraselmis spp. during the anaerobic digestion process. Cell lyses can offer a direct conversion pathway of intact Tetraselmis spp. for energy production, thus negating the need for pre-treatment. PMID- 25515154 TI - Size-resolved infrared spectroscopic study of structural transitions in sodium doped (H2O)n clusters containing 10-100 water molecules. AB - In water clusters containing 10-100 water molecules the structural transition takes place between "all surface" structures without internally solvated water molecules to amorphous water clusters with a three dimensionally structured interior. This structural evolution is explored with rigorous size selection by IR excitation modulated photoionization spectroscopy of sodium-doped (H2O)n clusters. The emergence of fully coordinated interior water molecules is observed by an increased relative absorption from 3200 to 3400 cm(-1) in agreement with theoretical predictions and earlier experimental studies. The analysis has also shown that the intermediate-sized water clusters (n = 40-65) do not smoothly link the structures in the largest and smallest analyzed size regions (n = 15-35 and n = 100-150) in line with previous reports suggesting the appearance of exceptionally stable water cluster isomers at n = 51, 53, 55, and 57. In the size range from n = 49 to n = 55 a reduced ion yield, a plateau in the total IR signal gain and signatures in the distribution of free OH stretch oscillator absorption have been observed. Recently reported putative global minima structures for n = 51 and n = 54 point to the presence of periplanar interior rings in odd-numbered clusters in this size range, which may affect cluster (surface) stability and the shape of the free OH stretch absorption peak. Potential links between pure and sodium-doped water cluster structures and the signatures of solvated electrons in photoelectron spectra of anionic water clusters are discussed. PMID- 25515153 TI - Early post-partum hematological changes in Holstein dairy cows with retained placenta. AB - Retained placenta (RP) occurs frequently in dairy cattle but little is known about the pathogenic or prognostic role of the hematological changes in this disease. This retrospective study was designed to investigate the hematological changes associated with RP in the immediate post-partum period and to assess whether these changes are associated with an acute phase reaction. Data concerning hematology, acute phase proteins, markers of inflammation and serum biochemistry performed on cows at 3+/-1 days in milk (DIM) from two intensive farms were extracted from the database of the ProZoo project, a research project aimed to investigate the relationship between genomic traits and bovine health and production. After application of restrictive inclusion criteria, data from 45 cows, 22 with RP and 23 controls, were statistically compared. RBC count, d-ROMs concentration, and AST activity were significantly higher in the RP group than controls. Conversely, neutrophils, thiol groups, and serum zinc concentration were significantly lower in the RP group than controls. In conclusion, although retained placenta has to be considered as a syndrome with multifactorial causes, neutropenia may be a co-factor involved in its pathogenesis. Further studies are needed to clarify whether neutropenia acts as a contributor in the pathogenesis of RP or if it is a very early consequence of the syndrome, preceding any other inflammatory changes in blood. PMID- 25515152 TI - Evidence of clinical efficacy of counterpulsation therapy methods. AB - Although heart transplantation remains the ultimate treatment for end-stage heart failure, its epidemiological impact is limited by donor organ availability. Surgical and device-based approaches have been introduced with the aim of increasing systemic perfusion and in some circumstances promoting left ventricular recovery by inducing reverse remodelling. Innovative counterpulsation devices based on the established principle of the intra-aortic balloon pump have been developed, and of these, the CardioVad and the C-Pulse System have been introduced in clinical practice with convincing evidence of haemodynamic efficacy. The evolution from pulsatile to continuous-flow left ventricular assist devices has been associated with improved survival rates during the first 2 years of support with the potential of matching heart transplantation outcomes. However, blood contact with the device remains a significant challenge despite the highly sophisticated technology currently available. Innovative extra vascular counterpulsation devices have been shown to overcome the limitations of the intra-aortic balloon pump and rend the device suitable for prolonged support. Monitoring of the performance of these novel devices is essential, and carotid Doppler ultrasonography is of utility in assessing the haemodynamic performance of the devices in a clinical setting. Computational modelling has played a role in the simulation of these devices and should continue to assist with their optimisation and implementation in clinical practice. PMID- 25515156 TI - Neutrophilic dermatosis of the dorsal hands: a localized variant of Sweet's syndrome or a distinct entity? PMID- 25515155 TI - The impact of LRP5 polymorphism (rs556442) on calcium homeostasis, bone mineral density, and body composition in Iranian children. AB - Failure to achieve optimal bone mass in childhood is the primary cause of decreased adult bone mineral density (BMD) and increased bone fragility in later life. Activating and inactivating LRP5 gene mutations has been associated with extreme bone-related phenotypes. Our aim was to investigate the role of LRP5 polymorphism on BMD, mineral biochemical parameters, and body composition in Iranian children. This cross-sectional study was performed on 9-18 years old children (125 boys, 137 girls). The serum level of calcium, phosphorous, alkaline phosphatase, and vitamin D parameters were checked. The body composition and BMD variables were measured by the Hologic system DXA. The rs566442 (V1119V) coding polymorphism in exon 15 of LRP5 was performed using PCR-RFLP method. Linear regression analysis, with adjustment for age, gender, body size parameters, and pubertal status was used to determine the association between LRP5 polymorphism (rs556442) and bone and body composition parameters. The allele frequency of the rs566442 gene was 35.5 % A and 63.9 % G. Our study revealed that LRP5 (rs556442) has not any significant influence on serum calcium, phosphorus, 25OHvitD, and serum alkaline phosphatase (P > 0.05). Total lean mass was greater in GG genotype (P = 0.028). Total body less head area (P = 0.044), spine BMD (P = 0.04), and total femoral BMC (P = 0.049) were lower in AG heterozygote genotype. This study show LRP5 polymorphism may associate with body composition and BMD in Iranian children. However, further investigations should be done to evaluate the role of other polymorphism. PMID- 25515157 TI - Total body photography for skin cancer screening. AB - BACKGROUND: Total body photography may aid in melanoma screening but is not widely applied due to time and cost. We hypothesized that a near-simultaneous automated skin photo-acquisition system would be acceptable to patients and could rapidly obtain total body images that enable visualization of pigmented skin lesions. METHODS: From February to May 2009, a study of 20 volunteers was performed at the University of Virginia to test a prototype 16-camera imaging booth built by the research team and to guide development of special purpose software. For each participant, images were obtained before and after marking 10 lesions (five "easy" and five "difficult"), and images were evaluated to estimate visualization rates. Imaging logistical challenges were scored by the operator, and participant opinion was assessed by questionnaire. RESULTS: Average time for image capture was three minutes (range 2-5). All 55 "easy" lesions were visualized (sensitivity 100%, 90% CI 95-100%), and 54/55 "difficult" lesions were visualized (sensitivity 98%, 90% CI 92-100%). Operators and patients graded the imaging process favorably, with challenges identified regarding lighting and positioning. CONCLUSIONS: Rapid-acquisition automated skin photography is feasible with a low-cost system, with excellent lesion visualization and participant acceptance. These data provide a basis for employing this method in clinical melanoma screening. PMID- 25515158 TI - Optimal resources for children's surgical care: a global perspective. PMID- 25515159 TI - Omitted variable bias and the risk of incisional hernia after partial colectomy for diverticular disease. PMID- 25515160 TI - Diverticulosis and colon cancer: in reply to Prasad and colleagues. PMID- 25515161 TI - Resident exposure to complex surgery while ensuring patient safety. PMID- 25515163 TI - Novel esophageal speech therapy method in total laryngectomized patients: biofeedback by intraesophageal impedance. AB - The loss of the best communication port after total laryngectomy surgery makes speech rehabilitation an important goal. Our aim was to improve the quality of esophageal speech (ES) using online esophageal multichannel intra-luminal impedance (MII) as a new biofeedback method. Twenty-six total laryngectomized patients were included. Before ES therapy, an esophageal motility test was carried out. MII catheters were placed in all subjects who were then randomized into two groups. Group 1 included 13 cases, who were retrained according to the classical method. Group 2 included 13 cases, who were retrained according to the simplified animation of air movements within the esophagus and upper stomach resulting from the modifications of intra-esophageal air kinetics gained by MII. The level of speech proficiency was evaluated relative to pretraining levels using perceptual scales in the third and sixth months. Acoustic voice was analyzed. The number of syllables read per minute and the intelligibility of monosyllabic and dissyllabic words were calculated. In this study, MII was used for the first time in alaryngeal speech rehabilitation as a biofeedback method; an overall sufficient speech level was achieved by 68.4% at the end of therapy, whereas attendance was 90%. A statistically significant improvement was found in both groups in terms of ES level compared with the pretraining period although there was no significant difference between groups. Although we did not observe the expected difference between groups suggested by our hypothesis, MII may be used as an objective tool to show patients how to swallow and regurgitate air during training, and may thus expedite ES therapy both for the speech therapist and the patient in the future. PMID- 25515164 TI - Alcohol withdrawal delirium manifested by manic symptoms in an elderly patient. AB - Alcohol withdrawal syndrome is a commonly seen problem in psychiatric practice. Alcohol withdrawal delirium is associated with significant morbidity and mortality. Withdrawal symptoms usually include tremulousness, psychotic and perceptual symptoms, seizures, and consciousness disturbance. Herein, we report a case involving a 63-year-old man who had alcohol withdrawal delirium that was manifested mainly by manic symptoms. PMID- 25515166 TI - Additive interaction in the presence of a mismeasured outcome. PMID- 25515165 TI - Changing use of traditional healthcare amongst those dying of HIV related disease and TB in rural South Africa from 2003 - 2011: a retrospective cohort study. AB - BACKGROUND: In 2011 there were 5.5 million HIV infected people in South Africa and 71% of those requiring antiretroviral therapy (ART) received it. The effective integration of traditional medical practitioners and biomedical providers in HIV prevention and care has been demonstrated. However concerns remain that the use of traditional treatments for HIV-related disease may lead to pharmacokinetic interactions between herbal remedies and ART drugs and delay ART initiation. Here we analyse the changing prevalence and determinants of traditional healthcare use amongst those dying of HIV-related disease, pulmonary tuberculosis and other causes in a rural South African community between 2003 and 2011. ART was made available in this area in the latter part of this period. METHODS: Data was collected during household visits and verbal autopsy interviews. InterVA-4 was used to assign causes of death. Spatial analyses of the distribution of traditional healthcare use were performed. Logistic regression models were developed to test associations of determinants with traditional healthcare use. RESULTS: There were 5929 deaths in the study population of which 47.7% were caused by HIV-related disease or pulmonary tuberculosis (HIV/AIDS and TB). Traditional healthcare use declined for all deaths, with higher levels throughout for those dying of HIV/AIDS and TB than for those dying of other causes. In 2003-2005, sole use of biomedical treatment was reported for 18.2% of HIV/AIDS and TB deaths and 27.2% of other deaths, by 2008-2011 the figures were 49.9% and 45.3% respectively. In bivariate analyses, higher traditional healthcare use was associated with Mozambican origin, lower education levels, death in 2003-2005 compared to the later time periods, longer illness duration and moderate increases in prior household mortality. In the multivariate model only country of origin, time period and illness duration remained associated. CONCLUSIONS: There were large decreases in reported traditional healthcare use and increases in the sole use of biomedical treatment amongst those dying of HIV/AIDS and TB. No associations between socio-economic position, age or gender and the likelihood of traditional healthcare use were seen. Further qualitative and quantitative studies are needed to assess whether these figures reflect trends in healthcare use amongst the entire population and the reasons for the temporal changes identified. PMID- 25515167 TI - Trends in diabetes incidence among 7 million insured adults, 2006-2011: the SUPREME-DM project. AB - An observational cohort analysis was conducted within the Surveillance, Prevention, and Management of Diabetes Mellitus (SUPREME-DM) DataLink, a consortium of 11 integrated health-care delivery systems with electronic health records in 10 US states. Among nearly 7 million adults aged 20 years or older, we estimated annual diabetes incidence per 1,000 persons overall and by age, sex, race/ethnicity, and body mass index. We identified 289,050 incident cases of diabetes. Age- and sex-adjusted population incidence was stable between 2006 and 2010, ranging from 10.3 per 1,000 adults (95% confidence interval (CI): 9.8, 10.7) to 11.3 per 1,000 adults (95% CI: 11.0, 11.7). Adjusted incidence was significantly higher in 2011 (11.5, 95% CI: 10.9, 12.0) than in the 2 years with the lowest incidence. A similar pattern was observed in most prespecified subgroups, but only the differences for persons who were not white were significant. In 2006, 56% of incident cases had a glycated hemoglobin (hemoglobin A1c) test as one of the pair of events identifying diabetes. By 2011, that number was 74%. In conclusion, overall diabetes incidence in this population did not significantly increase between 2006 and 2010, but increases in hemoglobin A1c testing may have contributed to rising diabetes incidence among nonwhites in 2011. PMID- 25515168 TI - Improving propensity score estimators' robustness to model misspecification using super learner. AB - The consistency of propensity score (PS) estimators relies on correct specification of the PS model. The PS is frequently estimated using main-effects logistic regression. However, the underlying model assumptions may not hold. Machine learning methods provide an alternative nonparametric approach to PS estimation. In this simulation study, we evaluated the benefit of using Super Learner (SL) for PS estimation. We created 1,000 simulated data sets (n = 500) under 4 different scenarios characterized by various degrees of deviance from the usual main-term logistic regression model for the true PS. We estimated the average treatment effect using PS matching and inverse probability of treatment weighting. The estimators' performance was evaluated in terms of PS prediction accuracy, covariate balance achieved, bias, standard error, coverage, and mean squared error. All methods exhibited adequate overall balancing properties, but in the case of model misspecification, SL performed better for highly unbalanced variables. The SL-based estimators were associated with the smallest bias in cases of severe model misspecification. Our results suggest that use of SL to estimate the PS can improve covariate balance and reduce bias in a meaningful manner in cases of serious model misspecification for treatment assignment. PMID- 25515169 TI - Spatial-temporal modeling of neighborhood sociodemographic characteristics and food stores. AB - The literature on food stores, neighborhood poverty, and race/ethnicity is mixed and lacks methods of accounting for complex spatial and temporal clustering of food resources. We used quarterly data on supermarket and convenience store locations from Nielsen TDLinx (Nielsen Holdings N.V., New York, New York) spanning 7 years (2006-2012) and census tract-based neighborhood sociodemographic data from the American Community Survey (2006-2010) to assess associations between neighborhood sociodemographic characteristics and food store distributions in the Metropolitan Statistical Areas (MSAs) of 4 US cities (Birmingham, Alabama; Chicago, Illinois; Minneapolis, Minnesota; and San Francisco, California). We fitted a space-time Poisson regression model that accounted for the complex spatial-temporal correlation structure of store locations by introducing space-time random effects in an intrinsic conditionally autoregressive model within a Bayesian framework. After accounting for census tract-level area, population, their interaction, and spatial and temporal variability, census tract poverty was significantly and positively associated with increasing expected numbers of supermarkets among tracts in all 4 MSAs. A similar positive association was observed for convenience stores in Birmingham, Minneapolis, and San Francisco; in Chicago, a positive association was observed only for predominantly white and predominantly black tracts. Our findings suggest a positive association between greater numbers of food stores and higher neighborhood poverty, with implications for policy approaches related to food store access by neighborhood poverty. PMID- 25515170 TI - Pharmacological Potential of Tetrahydrofurano/Pyrano Quinoline and Benzo[b]furoindolyl Derivatives in Acute Inflammation, Pain and Oxidative Stress. AB - OBJECTIVE: Investigation of the pharmacological potential of Tetrahydrofurano/pyrano quinoline and Benzo [b]furoindolyl derivatives in acute inflammation, pain and oxidative stress. METHODS: Tetrahydrofurano/ pyrano quinoline and Benzo[b]furoindolyl were evaluated for anti-inflammatory activity by carrageenan-induced hind paw edema in rats. Analgesic activity in mice was assessed by both peripheral and central analgesic models. The free radical scavenging activity of the synthetic compound was analyzed by the in vivo antioxidant assays, by measuring the antioxidant enzymes such as Superoxide dismutase (SOD), Catalase and Peroxidase from the liver homogenate and the in vitro antioxidant activity was evaluated by DPPH photometric assay, Hydroxyl radical scavenging and Lipid Peroxidation assay. RESULTS: The compounds had substantially inhibited the inflammation induced by subcutaneous carrageenan injection. The same compounds had demonstrated remarkable central and peripheral analgesic activity with potent free radical scavenging activity as evident from both in vitro and in vivo antioxidant assays. CONCLUSION: Tetrahydrofurano/pyrano quinoline and Benzo[b]furoindolyl derivatives exhibit varied pharmacological activities that include anti-inflammatory, analgesic and antioxidant activity. PMID- 25515173 TI - Soldier rehabilitation. PMID- 25515171 TI - Normolipidic dietary fat modifies circulating Renin-Angiotensin system-regulating aminopeptidase activities in rat with breast cancer. AB - HYPOTHESIS: Renin-angiotensin system (RAS) has been considered not only as a regulator of systemic volume and electrolyte balance but also has been recently involved in various pathological processes such as cancer. In the etiology of breast cancer, dietary factors have been analyzed and especially the influence of dietary fat has been studied, but the underlying mechanisms remain unclear. In this study, we analyzed RAS-regulating enzymes in serum of rats with N-methyl nitrosourea (NMU)-induced breast cancer fed with different diets. STUDY DESIGN: Four groups of rats were injected intraperitoneally with 3 doses of 50 mg/kg body weight of NMU at different days after birth and were fed with an AIN-93 commercial diet or AIN-93 diets with 4% fat constituted respectively by extra virgin olive oil, refined sunflower oil, and refined sunflower oil enriched to 50% with oleic acid. METHOD: After sacrifice, blood and tumor samples were collected by spectrophotometric determinations of RAS-regulating enzymes in plasma and histopathology studies. RESULTS: We show that the type of dietary fat does not influence latency period, incidence of animals with tumors, incidence of mortality, or tumor yield per rat. However, changes were observed in tumor volume and the histopathology. The type of dietary fat also differently modified the enzymes involved in RAS regulation. CONCLUSIONS: It might suggest that one of the mechanisms by which dietary fat affects breast cancer is the modification of the RAS system, which may be consider as a new target for integrative therapies. PMID- 25515174 TI - Computer-based cognitive rehabilitation research in a military treatment facility: Recruitment, compliance, and lessons learned. AB - BACKGROUND: Evidence-based approaches to cognitive rehabilitation are limited; however, new technologies such as brain-training computer programs provide opportunities for novel interventions. OBJECTIVE: This paper describes a randomized controlled training study in a military treatment facility with service members who had combat-related cognitive symptoms. It examines challenges in study design and implementation, and provides "lessons learned" with proposed solutions. METHODS: Participants were randomly assigned to one of two 6-week computer-based cognitive training (CBCT) programs or a treatment-as-usual (TAU) control group. Feasibility assessments included reasons for consent refusal, compliance, and drop-out rates. RESULTS: The intended sample size for the study was 114 participants before attrition. Of 291 patients referred over 2.5 years, 120 were eligible, 38 consented to participate, and 18 completed the study. Forty two percent of the participants assigned to CBCT groups completed the required 30 sessions in 6.5 to 32 weeks. Study-design factors that affected enrollment and compliance included eligibility restrictions, lack of a computer-based control condition, and inflexible scheduling. CONCLUSIONS: Successful implementation of a high-dose computer-based clinical trial will require design changes such as expanded inclusion criteria, control by sham computer program or wait-list, dosing flexibility, and web-based options. PMID- 25515175 TI - A new method to prevent degradation of lithium-oxygen batteries: reduction of superoxide by viologen. AB - Lithium-oxygen battery development is hampered by degradation reactions initiated by superoxide, which is formed in the pathway of oxygen reduction to peroxide. This work demonstrates that the superoxide lifetime is drastically decreased upon addition of ethyl viologen, which catalyses the reduction of superoxide to peroxide. PMID- 25515176 TI - Epidemiology of blood component recipients in hospitals of Yazd, Iran. AB - BACKGROUND AND OBJECTIVES: Blood recipient and blood product utilisation data are needed for assessment of current transfusion practice in hospitals. Such data can help monitoring blood use, improving blood transfusion practice and estimating future blood use. MATERIALS AND METHODS: In this cross sectional study, the rate of blood consumption has been evaluated in three randomly selected hospitals of Yazd, Iran in 2011-2012. Data of blood recipients including patient identification number, age, sex, principal diagnoses, date of transfusion, type and number of transfused blood components and indication for transfusion were prospectively collected. RESULTS: The dataset included information about 814 patients (53% males) who received 1110 RBCs, 410 plasma and 1484 platelet (PLT) units. Transfusion rate per 1000 population per year was 24, 10 and 15 for red blood cells (RBCs), plasma and PLT units, respectively. Age group 17-64 years had the highest consumption of blood components (55%). Most of the RBCs and PLT units were transfused to patients with neoplasm (42 and 82%, respectively). Cardiovascular surgery was the diagnosis category with most plasma usage (32%). The category with highest haemoglobin level before transfusion was surgery; Orthopaedic and ENT surgeries were at the top of ranking (11.96 +/- 1.85 g dL( 1)). PLT count before transfusion was 11.160 +/- 5.282 * 10(9) L(-1) in neoplasm category and 12.3637 +/- 6.2267 * 10(10) L(-1) in neonatal disease. CONCLUSION: Study results showed the first epidemiological data of blood recipients on a regional basis in Iran. It is suggested to study blood utilisation at the national level to assist in improving transfusion practice in hospitals. PMID- 25515177 TI - A novel approach for quantitation of nonderivatized sialic acid in protein therapeutics using hydrophilic interaction chromatographic separation and nano quantity analyte detection. AB - This paper describes a novel approach for the quantitation of nonderivatized sialic acid in glycoproteins, separated by hydrophilic interaction chromatography, and detection by Nano Quantity Analyte Detector (NQAD). The detection technique of NQAD is based on measuring change in the size of dry aerosol and converting the particle count rate into chromatographic output signal. NQAD detector is suitable for the detection of sialic acid, which lacks sufficiently active chromophore or fluorophore. The water condensation particle counting technology allows the analyte to be enlarged using water vapor to provide highest sensitivity. Derivatization-free analysis of glycoproteins using HPLC/NQAD method with PolyGLYCOPLEXTM amide column is well correlated with HPLC method with precolumn derivatization using 1, 2-diamino-4, 5 methylenedioxybenzene (DMB) as well as the Dionex-based high-pH anion-exchange chromatography (or ion chromatography) with pulsed amperometric detection (HPAEC PAD). With the elimination of derivatization step, HPLC/NQAD method is more efficient than HPLC/DMB method. HPLC/NQAD method is more reproducible than HPAEC PAD method as HPAEC-PAD method suffers high variability because of electrode fouling during analysis. Overall, HPLC/NQAD method offers broad linear dynamic range as well as excellent precision, accuracy, repeatability, reliability, and ease of use, with acceptable comparability to the commonly used HPAEC-PAD and HPLC/DMB methods. PMID- 25515178 TI - Seeing the unseen: Charles Bonnet syndrome revisited. AB - Charles Bonnet syndrome (CBS) is a rare condition that encompasses three clinical features: complex visual hallucinations, ocular pathology causing visual deterioration, and preserved cognitive status. Common associated ocular pathologies include age-related macular degeneration, glaucoma, and cataracts. Several theories have been proposed to try to explain the visual hallucinations. However, the pathophysiology remains poorly understood, and treatment is largely based on anecdotal data. The lack of awareness of CBS among medical professionals often leads to inappropriate diagnosis and medication. In a country like India, where awareness of mental health is not widespread, cultural myths and stigma prevent patients from seeking professional help. Here we describe two cases of CBS and revisit different ocular morbidities that have been reported to occur in conjunction with CBS. Psychiatrists and ophthalmologists alike must be sensitive to this clinical condition to ensure prompt diagnosis and treatment. PMID- 25515179 TI - The SPOTLIGHT virtual audit tool: a valid and reliable tool to assess obesogenic characteristics of the built environment. AB - BACKGROUND: A lack of physical activity and overconsumption of energy dense food is associated with overweight and obesity. The neighbourhood environment may stimulate or hinder the development and/or maintenance of a healthy lifestyle. To improve research on the obesogenicity of neighbourhood environments, reliable, valid and convenient assessment methods of potential obesogenic characteristics of neighbourhood environments are needed. This study examines the reliability and validity of the SPOTLIGHT-Virtual Audit Tool (S-VAT), which uses remote sensing techniques (Street View feature in Google Earth) for desk-based assessment of environmental obesogenicity. METHODS: A total of 128 street segments in four Dutch urban neighbourhoods - heterogeneous in socio-economic status and residential density - were assessed using the S-VAT. Environmental characteristics were categorised as walking related items, cycling related items, public transport, aesthetics, land use-mix, grocery stores, food outlets and physical activity facilities. To assess concordance of inter- and intra-observer reliability of the Street View feature in Google Earth, and validity scores with real life audits, percentage agreement and Cohen's Kappa (k) were calculated. RESULTS: Intra-observer reliability was high and ranged from 91.7% agreement (k = 0.654) to 100% agreement (k = 1.000) with an overall agreement of 96.4% (k = 0.848). Inter-observer reliability results ranged from substantial agreement 78.6% (k = 0.440) to high agreement, 99.2% (k = 0.579), with an overall agreement of 91.5% (k = 0.595). Criterion validity was substantial to high for most of the categories ranging from 87.3% agreement (k = 0.539) to 99.9% agreement (k = 0.887) with an overall score of 95.6% agreement (k = 0.747). CONCLUSION: These study results suggest that the S-VAT is a highly reliable and valid remote sensing tool to assess potential obesogenic environmental characteristics. PMID- 25515180 TI - Is it reasonable to use 1 and 8 kHz anchor points in the medico-legal diagnosis and estimation of noise-induced hearing loss? AB - BACKGROUND: In the United Kingdom, use of 1 and 8 kHz as anchor point frequencies has been recommended for the medico-legal diagnosis and estimation of noise induced hearing loss. There appear to be four assumptions behind the use of 1 and 8 kHz anchor point approach: (i) The frequencies of 1 and 8 kHz are not damaged by noise; therefore, the measured hearing thresholds at the said frequencies solely reflect age-related hearing loss, even in the noise-exposed; (ii) The hearing thresholds at 1 and 8 kHz are a valid predictor of the likely age-related hearing loss thresholds at the other frequencies; (iii) Age and noise damage are always completely additive; (iv) Individual's susceptibility to age and noise damage is not proportionate. Doubts have been expressed in the medical circles about the legitimacy and validity of their use as anchor points. OBJECTIVE OF REVIEW: Is it reasonable to use 1 and 8 kHz anchor points in the medico-legal diagnosis and estimation of noise-induced hearing loss? TYPE OF REVIEW: Medico legal. SEARCH STRATEGY: Literature search; Medline, Embase, Internet, and medico legal records. EVALUATION METHOD: Equating and comparing the assumptions in the anchor point approach with the information in medical literature. RESULTS: Based upon the information in medical literature, technical reports, and professional statements, the assumptions behind the use of anchor point approach cannot be reliably substantiated. CONCLUSIONS: 'Carte Blanche' use of 1 and 8 kHz anchor points is probably unreasonable and may well be unsafe in the medico-legal diagnosis and estimation of noise-induced hearing loss. PMID- 25515182 TI - ScatterJ: An ImageJ plugin for the evaluation of analytical microscopy datasets. AB - We present ScatterJ, an ImageJ plugin that allows for extracting qualitative as well as quantitative information from analytical microscopy datasets. A large variety of analytical microscopy methods are used to obtain spatially resolved chemical information. The resulting datasets are often large and complex, and can contain information that is not obvious or directly accessible. ScatterJ extends and complements existing methods to extract information on correlation and colocalization from pairs of species-specific or element-specific maps. We demonstrate the possibilities to extract information using example datasets from biogeochemical studies, although the plugin is not restricted to this type of research. The information that we could extract from our existing data helped to further our understanding of biogeochemical processes such as mineral formation or heavy metal sorption. ScatterJ can be used for a variety of different two dimensional (2D) and three-dimensional (3D) datasets such as energy-dispersive X ray spectroscopy maps, 3D confocal laser scanning microscopy maps, and 2D scanning transmission X-ray microscopy maps. PMID- 25515183 TI - The full length genomic sequence of a novel HLA-C*03 allele: HLA-C*03:219. AB - HLA-C*03:219 differs from HLA-C*03:04:01:01 by a non-synonymous substitution in the alpha3 domain (T216I). PMID- 25515184 TI - Developmental milestones in children born post-term in the Danish National Birth Cohort: a main research article. AB - OBJECTIVE: To examine the timing of reaching developmental milestones in children born post-term. DESIGN: Cohort study. SETTING: The Danish National Birth Cohort: children born between 1997 and 2003. POPULATION: Data were obtained from a cohort of 92 892 pregnancies participating in the first pregnancy interview. All singletons born in gestational weeks 39-45 were identified. The study was then restricted to children who participated in an interview at the age of approximately 18 months and had information on at least one developmental milestone. We excluded children of mothers with chronic diseases from the final analysis. The remaining study population constituted of 43 915 singletons (27 503 born at term; 16 412 born post-term). METHODS: Logistic regression was used to calculate odds ratios of late achievement of these developmental milestones, adjusted for potential confounding factors. MAIN OUTCOME MEASURES: Achieving developmental milestones at the time of interview or at a certain age. RESULTS: More children born post-term achieved the assessed developmental milestones compared with children born at term (39-40 weeks). A test for trend for gestational ages 39, 40, and 41 weeks also showed a positive trend at achieving developmental milestones with gestational age at birth in nine out of 14 milestone items. CONCLUSIONS: Children born post-term appear to reach the main developmental milestones at an earlier age than children born at term. The association could also result from bias related to a longer time between conception and interviewing, misclassification of end points, or selection bias. PMID- 25515185 TI - Genome-wide association study for jumping performances in French sport horses. AB - A genome-wide association study was performed to identify single nucleotide polymorphisms (SNPs) associated with jumping performances of warmbloods in France. The 999 horses included in the study for jumping performances were sport horses [mostly Selle Francais (68%), Anglo-Arabians (13%) and horses from the other European studbooks]. Horses were genotyped using the Illumina EquineSNP50 BeadChip. Of the 54,602 SNPs available on this chip, 44,424 were retained after quality testing. Phenotypes were obtained by deregressing official breeding values for jumping competitions to use all available information, that is, the performances of each horse as well as those of its relatives. Two models were used to test the effects of the genotypes on deregressed phenotypes: a single marker mixed model and a haplotype-based mixed model (significant: P < 1E-05; suggestive: P < 1E-04). Both models included a polygenic effect to take into account familial structures. For jumping performances, one suggestive quantitative trait locus (QTL) located on chromosome 1 (BIEC2_31196 and BIEC2_31198) was detected with both models. This QTL explains 0.7% of the phenotypic variance. RYR2, a gene encoding a major calcium channel in cardiac muscle in humans and mice, is located 0.55 Mb from this potential QTL. PMID- 25515181 TI - Diagnosis and pharmacotherapy of stable chronic obstructive pulmonary disease: the finnish guidelines. AB - The Finnish Medical Society Duodecim initiated and managed the update of the Finnish national guideline for chronic obstructive pulmonary disease (COPD). The Finnish COPD guideline was revised to acknowledge the progress in diagnosis and management of COPD. This Finnish COPD guideline in English language is a part of the original guideline and focuses on the diagnosis, assessment and pharmacotherapy of stable COPD. It is intended to be used mainly in primary health care but not forgetting respiratory specialists and other healthcare workers. The new recommendations and statements are based on the best evidence available from the medical literature, other published national guidelines and the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. This guideline introduces the diagnostic approach, differential diagnostics towards asthma, assessment and treatment strategy to control symptoms and to prevent exacerbations. The pharmacotherapy is based on the symptoms and a clinical phenotype of the individual patient. The guideline defines three clinically relevant phenotypes including the low and high exacerbation risk phenotypes and the neglected asthma-COPD overlap syndrome (ACOS). These clinical phenotypes can help clinicians to identify patients that respond to specific pharmacological interventions. For the low exacerbation risk phenotype, pharmacotherapy with short-acting beta2 -agonists (salbutamol, terbutaline) or anticholinergics (ipratropium) or their combination (fenoterol-ipratropium) is recommended in patients with less symptoms. If short-acting bronchodilators are not enough to control symptoms, a long-acting beta2 -agonist (formoterol, indacaterol, olodaterol or salmeterol) or a long-acting anticholinergic (muscarinic receptor antagonists; aclidinium, glycopyrronium, tiotropium, umeclidinium) or their combination is recommended. For the high exacerbation risk phenotype, pharmacotherapy with a long-acting anticholinergic or a fixed combination of an inhaled glucocorticoid and a long-acting beta2 -agonist (budesonide-formoterol, beclomethasone dipropionate-formoterol, fluticasone propionate-salmeterol or fluticasone furoate-vilanterol) is recommended as a first choice. Other treatment options for this phenotype include combination of long-acting bronchodilators given from separate inhalers or as a fixed combination (glycopyrronium indacaterol or umeclidinium-vilanterol) or a triple combination of an inhaled glucocorticoid, a long-acting beta2 -agonist and a long-acting anticholinergic. If the patient has severe-to-very severe COPD (FEV1 < 50% predicted), chronic bronchitis and frequent exacerbations despite long-acting bronchodilators, the pharmacotherapy may include also roflumilast. ACOS is a phenotype of COPD in which there are features that comply with both asthma and COPD. Patients belonging to this phenotype have usually been excluded from studies evaluating the effects of drugs both in asthma and in COPD. Thus, evidence-based recommendation of treatment cannot be given. The treatment should cover both diseases. Generally, the therapy should include at least inhaled glucocorticoids (beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate or mometasone) combined with a long-acting bronchodilator (beta2 -agonist or anticholinergic or both). PMID- 25515187 TI - Seeing is Believing? Evidence from Property Prices in Inundated Areas. AB - We use hedonic property models to estimate the changes in implicit flood risk premium following a large flood event. Previous studies have used flood hazard maps to proxy flood risk. In addition to knowing whether a property lies in the floodplain, we use a unique data set with the flood inundation map. We find that the price discount for properties in the inundated area is substantially larger than in comparable properties in the floodplain that did not get inundated. This suggests that, in addition to capturing an information effect, the larger discount in inundated properties reflects potential uninsurable flood damages, and supports a hypothesis that homeowners respond better to what they have visualized ("seeing is believing"). PMID- 25515186 TI - GSTM1, GSTP1, and GSTT1 genetic variability in Turkish and worldwide populations. AB - OBJECTIVE: Glutathione S-transferase (GST) variants have been widely investigated to better understand their role in several pathologic conditions. To our knowledge, no data about these genetic polymorphisms within the Turkish population are currently available. The aim of this study was to analyze GSTM1 positive/null, GSTT1 positive/null, GSTP1*I105V (rs1695), and GSTP1*A114V (rs1138272) variants in the general Turkish population, to provide information about its genetic diversity, and predisposition to GST-related diseases. METHODS: Genotyping was performed in 500 Turkish individuals using the Sequenom MassARRAY platform. A comparative analysis was executed using the data from the HapMap and Human Genome Diversity Projects (HGDP). Sequence variation was deeply explored using the Phase 1 data of the 1,000 Genomes Project. RESULTS: The variability of GSTM1, GSTT1, and GSTP1 polymorphisms in the Turkish population was similar to that observed in Central Asian, European, and Middle Eastern populations. The high linkage disequilibrium between GSTP1*I105V and GSTP1*A114V in these populations may have a confounding effect on GSTP1 genetic association studies. In analyzing GSTM1, GSTT1, and GSTP1 sequence variation, we observed other common functional variants that may be candidates for associated studies of diseases related to GST genes (e.g., cancer, cardiovascular disease, and allergy). CONCLUSIONS: This study provides novel data about GSTM1 positive/null, GSTT1 positive/null, GSTP1*I105V, and GSTP1*A114V variants in the Turkish population, and other functional variants that may affect GSTM1, GSTT1, and GSTP1 functions among worldwide populations. This information can assist in the design of future genetic association studies investigating oxidative stress-related diseases. PMID- 25515188 TI - Comparative pharmacokinetics and tissue distribution of quinocetone in crucian carp (Carassius auratus), common carp (Cyprinus carpio L.), and grass carp (Ctenopharyngodon idella) following the same experimental conditions. AB - The pharmacokinetics and tissue distribution of quinocetone (QCT) in crucian carp (Carassius auratus), common carp (Cyprinus carpio L.), and grass carp (Ctenopharyngodon idella) were compared after oral administration of QCT (50 mg/kg body weight) at water temperature of 24 +/- 1 degrees C. Similar QCT plasma concentration-time profiles were found in the three species of cyprinid fish at the same dosage regimen and water temperature, which were all fitted two compartment open pharmacokinetic model. However, different pharmacokinetic parameters were observed in crucian carp, common carp, and grass carp. The absorption rate constants (K(a)) of QCT were 1.65, 1.40 and 1.74/h, respectively and absorption half-lives (t(1/2kalpha)) were 0.42, 0.49, and 0.40/h, respectively. The distribution half-life (t(1/2alpha)) was 2.83, 0.67, and 0.88 h, respectively, and elimination half-lives (t(1/2beta)) of QCT were 133.97, 63.55, and 40.76 h, respectively. The maximum concentrations (C(max)) of QCT in plasma were 0.315, 0.182, and 0.139 MUg/mL and the time to peak concentrations (T(p)) were 1.45, 0.96, and 1.08 h, respectively. The area under the plasma concentration-time curves (AUC) were 12.35, 5.99, and 4.52 MUg.h/mL, respectively. The distribution volumes (V(d)/F) of QCT were calculated as 117.81, 128.71, and 220.10 L/kg, respectively. The tissue analysis showed that a similar regularity was obtained in the three species of cyprinids with a single dose of 50 mg/kg body weight after oral administration at the same water temperature. The tissue concentration of QCT in each fish was in order of liver>kidney>muscle, while the residues of QCT in the three species of cyprinid fish were in order of crucian carp>common carp>grass carp. PMID- 25515189 TI - Deciphering the factors associated with the colonization of rice plants by cyanobacteria. AB - Cyanobacteria-rice plant interactions were analyzed using a hydroponics experiment. The activity of plant defense and pathogenesis-related enzymes, scanning electron microscopy, growth, nitrogen fixation (measured as ARA), and DNA fingerprinting assays proved useful in illustrating the nature of associations of cyanobacteria with rice plants. Microscopic analyses revealed the presence of short filaments and coiled masses of filaments of cyanobacteria near the epidermis and cortex of roots and shoot tissues. Among the six cyanobacterial strains employed, Calothrix sp. (RPC1), Anabaena laxa (RPAN8), and Anabaena azollae (C16) were the best performing strains, in terms of colonization in roots and stem. These strains also enhanced nitrogen fixation and stimulated the activity of plant defense/cell wall-degrading enzymes. A significantly high correlation was also recorded between the elicited plant enzymes, growth, and ARA. DNA fingerprinting using highly iterated palindromic sequences (HIP-TG) further helped in proving the establishment of inoculated organisms in the roots/shoots of rice plants. This study illustrated that the colonization of cyanobacteria in the plant tissues is facilitated by increased elicitation of plant enzymes, leading to improved plant growth, nutrient mobilization, and enhanced plant fitness. Such strains can be promising candidates for developing "cyanobacteria colonized-nitrogen-fixing rice plants" in the future. PMID- 25515190 TI - Don't look away now. PMID- 25515191 TI - Oklahoma doctor faces prison after billing for abortions when patients were not pregnant. PMID- 25515193 TI - Effect of silicon on wheat seedlings (Triticum turgidum L.) grown in hydroponics and exposed to 0 to 30 uM Cu. AB - MAIN CONCLUSION: Aqueous Si limits Cu uptake by a Si-accumulating plant via physicochemical mechanisms occurring at the root level. Sufficient Si supply may alleviate Cu toxicity in Cu-contaminated soils. Little information is available on the role of silicon (Si) in copper (Cu) tolerance while Cu toxicity is widespread in crops grown on Cu-contaminated soils. A hydroponic study was set up to investigate the influence of Si on Cu tolerance in durum wheat (Triticum turgidum L.) grown in 0, 0.7, 7.0 and 30 uM Cu without and with 1.0 mM Si, and to identify the mechanisms involved in mitigation of Cu toxicity. Si supply alleviated Cu toxicity in durum wheat at 30 uM Cu, while Cu significantly increased Si concentration in roots. Root length, photosynthetic pigments concentrations, macroelements, and organic anions (malate, acetate and aconitate) in roots, were also increased. Desorption experiments, XPS analysis of the outer thin root surface (<=100 A) and uXRF analyses showed that Si increased adsorption of Cu at the root surface as well as Cu accumulation in the epidermis while Cu was localised in the central cylinder when Si was not applied. Copper was not detected in phytoliths. This study provides evidences for Si-mediated alleviation of Cu toxicity in durum wheat. It also shows that Si supplementation to plants exposed to increasing levels of Cu in solution induces non-simultaneous changes in physiological parameters. We propose a three-step mechanism occurring mainly at the root level and limiting Cu uptake and translocation to shoots: (i) increased Cu adsorption onto the outer thin layer root surface and immobilisation in the vicinity of root epidermis, (ii) increased Cu complexation by both inorganic and organic anions such as aconitate and, (iii) limitation of translocation through an enhanced thickening of a Si-loaded endodermis. PMID- 25515192 TI - Short-term functional versus patient-reported outcome of the bicruciate stabilized total knee arthroplasty: prospective consecutive case series. AB - BACKGROUND: The main goals of the standard treatment for advanced symptomatic knee osteoarthritis, total knee arthroplasty (TKA), are pain reduction and restoration of knee motion.The aim of this study was to analyse the outcome of the patient-based Knee Injury and Osteoarthritis Outcome Score (KOOS), and the surgeon-based Knee Society Score (KSS) and its Knee Score (KS) and Knee Functional Score (KFS) components after (TKA) using the Journey knee prosthesis, and to assess the correlation of these scores with range of motion (ROM). METHODS: In a prospective case series study between August 1st 2008 and May 31st 2011, 99 patients, all operated by a single surgeon, received Journey bicruciate stabilized total knee prostheses. The female/male ratio was 53/34, the mean patient age at surgery was 68 years (range 41-83 years), and the left/right knee ratio was 55/44. The KOOS, range of motion, and KS and KFS were obtained preoperatively and at 1-year follow-up. The pre- and postoperative levels of the outcome measures were compared using the Wilcoxon signed-rank test. Correlation between ROM and patient outcomes was analysed with the Spearman coefficient. RESULTS: All KOOS subscores improved significantly. Ninety percent of patients improved by at least the minimum clinically relevant difference of 10 points in stiffness and other symptoms, 94.5% in pain, 94.5% in activities of daily living, 84.9% in sports and recreation, and 90% in knee-related quality of life. The mean passive and active ROM improved from 122.4 degrees (range 90-145 degrees ) and 120.4 degrees (range 80-145 degrees ) preoperatively to 129.4 degrees (range 90 145 degrees ) and 127.1 degrees (range 100-145 degrees ) postoperatively. The highest correlation coefficients for ROM and KOOS were observed for the activity and pain subscores. Very low or no correlation was seen for the sport subscore.There was a significant and clinically relevant improvement of KSS (preop/postop 112.2/174.5 points), and its KS (preop/postop 45.6/86.8 points) and KFS (preop/postop 66.6/87.8 points) components. CONCLUSIONS: The Journey bicruciate stabilized knee prosthesis showed good 1-year postoperative results in terms of both functional and patient-based outcome. However, higher knee ROM correlates only moderately with patient-based outcome, implying that functionality afforded by the Journey bicruciate TKA is not equivalent to patient satisfaction. PMID- 25515195 TI - Teens and indoor tanning: time to act on the US Food and Drug Administration's black-box warning. PMID- 25515194 TI - Trichome differentiation on leaf primordia of Helianthus annuus (Asteraceae): morphology, gene expression and metabolite profile. AB - MAIN CONCLUSION: Sunflower trichomes fully develop on embryonic plumula within 3 days after start of germination. Toxic sesquiterpene lactones are produced immediately thereafter thus protecting the apical bud of the seedling against herbivory. Helianthus annuus harbors non-glandular and two different types of multicellular glandular trichomes, namely the biseriate capitate glandular trichomes and the uniseriate linear glandular trichomes. The development of capitate glandular trichomes is well known from anther tips on sunflower disk florets, but not from leaves and no information is yet available on the development of the linear glandular trichomes. Scanning electron microscopy of sunflower seedlings unravelled that within the first 40 h of seed germination all three types of trichomes started to emerge on primordia of the first true leaves. Within the following 20-30 h trichomes developed from trichoblasts to fully differentiated hairs. Gene expression studies showed that genes involved in the trichome-based sesquiterpene lactone formation were up-regulated between 72 and 96 h after start of germination. Metabolite profiling with HPLC confirmed the synthesis of sesquiterpene lactones which may contribute to protect the germinating seedlings from herbivory. The study has shown that sunflower leaf primordia can serve as a fast and easy to handle model system for the investigation of trichome development in Asteraceae. PMID- 25515196 TI - A Prospective Evaluation of Lymphedema-Specific Quality-of-Life Outcomes Following Vascularized Lymph Node Transfer. AB - BACKGROUND: Microsurgical techniques for the treatment of lymphedema rapidly increased in popularity. Although surgical success with vascularized lymph node (VLN) transfer has been demonstrated, limited studies have investigated the influence of microsurgical treatments on health-related quality-of-life (HRQoL) parameters. The aim of this study was to prospectively evaluate changes in HRQoL following VLN transfer for upper- and lower-extremity lymphedema using a validated instrument. METHODS: An Institutional Review Board-approved prospective study was performed of patients who underwent VLN transfer for symptomatic upper- or lower-limb lymphedema. A validated lymphedema-specific questionnaire lymphoedema quality-of-life study-was utilized to assess specific quality-of-life parameters at multiple time points during the 12-month perioperative period. For a comparison with HRQoL metrics, limb circumference measurements were obtained to assess circumference differentiation. RESULTS: Twenty-five patients met the study criteria. Limb circumference analysis revealed significant early improvements following VLN transfer, with continued improvement during the study period (upper limb lymphedema: 24.4 %; lower-limb lymphedema: 35.2 %). These improvements were mirrored by improvements in all HRQoL domains and overall quality of life (p < 0.01). The function, body appearance, symptom, and mood domains were all found to be significantly improved during the postoperative evaluation, with continued improvement being reported throughout the study period (p < 0.01 within each domain). CONCLUSIONS: Microsurgical treatment of lymphedema with VLN transfer procedures effectively decrease limb circumference. This improvement is mirrored by improvements in patient-reported outcomes and quality of life. These changes can be observed as soon as 1 month postoperatively, and continued steady improvement can be expected. PMID- 25515197 TI - Second Axillary Sentinel Lymph Node Biopsy for Breast Tumor Recurrence: Experience of the European Institute of Oncology. AB - PURPOSE: This retrospective study aimed to determine the feasibility, accuracy, and recurrence rates of lymphoscintigraphy and the new sentinel lymph node biopsy (SLNB) for patients with ipsilateral breast tumor recurrences who were treated previously with conservative surgery and had negative SLNB results. METHODS: The study was conducted at the European Institute of Oncology in Milan and included 212 patients with the diagnosis of operable local breast cancer recurrence. They had been treated previously with conservative surgery and showed negative SLNB results. They subsequently underwent additional breast surgery and a second SLNB between May 2001 and December 2011. RESULTS: Preoperative lymphoscintigraphy demonstrated at least one new axillary sentinel lymph node (SLN) in 207 patients (97.7 %), whereas no drainage was observed in five patients (2.3 %). One or more SLNs were surgically removed from 196 of the 207 patients. Isolation of SLNs from the remaining 11 patients could not be accomplished. The success rate for the SLNB was 92.5 %. Extra-axillary drainage pathways were visualized in 17 patients (8 %). The annual axillary recurrence rate after a median follow-up period of 48 months was 0.8 %, and the cumulative incidence of axillary recurrence at 5 years was 3.9 %. CONCLUSIONS: A second SLNB should be considered for patients with operable local breast tumor recurrence who underwent conservative surgery and had negative SLNB results. The procedure is technically feasible and accurate for selected patients. PMID- 25515198 TI - Deviation from the Standard of Care for Early Breast Cancer in the Elderly: What are the Consequences? AB - BACKGROUND: For elderly patients with early-stage breast cancer, the standards of care often are not strictly followed due to either clinician biases or patient preferences. The authors hypothesized that forgoing radiation and lymph node (LN) staging for elderly patients with early-stage breast cancer would have a negative impact on survival. METHODS: From the Surveillance, Epidemiology, and End Results Program database, 53,619 women older than 55 years with stage 1 breast cancer who underwent breast conservation surgery were identified. Analyses were performed to compare the characteristics and outcomes of patients who received the standards of care with LN sampling and radiation and those of patients who did not, with control used for confounders. To account for selection bias from covariate imbalance, propensity score matching was performed. Survival was analyzed using the Kaplan-Meier method. RESULTS: Older patients were less likely to receive radiation and LN sampling. These standards of care were associated with improved overall survival rates of 15.8 and 27.1 % after 10 years, respectively (p <= 0.0001). This survival advantage persisted after propensity score matching, with a 7.4 % higher survival rate for patients who received radiation and a 16.8 % higher survival rate for those who underwent LN staging (p < 0.0001). Lymph node sampling and radiation therapy also conferred a statistically significant improvement in breast cancer-specific survival, with 1.3 and 2.6 % lower mortality rates respectively in the radiated and LN biopsy groups (p < 0.0001). CONCLUSIONS: As patients age, they are less likely to receive the standard of care for stage 1 breast cancer. Even after controlling for other factors, the study showed that failure to adhere to the standards of LN sampling and radiation therapy may have a negative impact in survival. PMID- 25515199 TI - Loss of Lean Body Mass as an Independent Risk Factor for Continuation of S-1 Adjuvant Chemotherapy for Gastric Cancer. AB - BACKGROUND AND AIMS: Compliance with S-1 adjuvant chemotherapy is not satisfactory, and the aim of the present study was to clarify risk factors for the continuation of S-1 after gastrectomy. METHODS: This retrospective study selected patients who underwent curative D2 surgery for gastric cancer, were diagnosed with stage II/III disease, had a creatinine clearance >60 ml/min, and received adjuvant S-1 at our institution between June 2010 and March 2014. The time to S-1 treatment failure (TTF) was calculated. RESULTS: Fifty-eight patients were selected for the present study. When the TTF curves stratified by each clinical factor were compared using the log-rank test, lean body-mass loss (LBL) of 5 % was regarded as a critical cutoff point. Univariate Cox's proportional hazard analyses demonstrated that LBL was a significant independent risk factor for continuation. The 6-month continuation rate was 91.7 % in patients with an LBL < 5 %, and 66.3 % for patients with an LBL > 5 % (p = 0.031). CONCLUSIONS: The present study demonstrated that LBL might be an important risk factor for a decrease in compliance to adjuvant chemotherapy with S-1 in patients with stage II/III gastric cancer who underwent D2 gastrectomy. A multicenter, double blinded, prospective cohort study is necessary to confirm whether LBL would affect adjuvant S-1 continuation. PMID- 25515200 TI - Serious Postoperative Complications Affect Early Recurrence After Cytoreductive Surgery and HIPEC for Colorectal Peritoneal Carcinomatosis. AB - BACKGROUND: The prognosis of patients with peritoneally metastasized colorectal cancer has improved significantly with the introduction of cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Although a macroscopically complete resection is achieved in nearly every patient, recurrence rates are high. This study aims to identify risk factors for early recurrence, thereby offering ways to reduce its occurrence. METHODS: All patients with colorectal peritoneal carcinomatosis treated with CRS + HIPEC and a minimum follow-up of 12 months, in April 2014, were analyzed. Patient data were compared between patients with or without recurrence within 12 months after CRS + HIPEC. Risk factors were determined using logistic regression analysis. Postoperative complications were graded according to the serious adverse events (SAEs) score, with grade 3 or higher indicating complications requiring intervention. RESULTS: A complete macroscopic cytoreduction was achieved in 96 % of all patients treated with CRS + HIPEC. Forty-six of 133 patients (35 %) developed recurrence within 12 months. An SAE >=3 after CRS + HIPEC was the only significant risk factor found for early recurrence (odds ratio 2.3; p = 0.046). Median survival in the early recurrence group was 19.3 months compared with 43.2 months in the group without early recurrence (p < 0.001). Patients with an SAE >=3 showed a reduced survival compared with patients without such complications (22.1 vs. 31.0 months, respectively; p = 0.02). CONCLUSIONS: Early recurrence after CRS + HIPEC is associated with a significant reduction in overall survival. This study identifies postoperative complications requiring intervention as the only significant risk factor for early recurrence, independent of the extent of peritoneal disease, highlighting the importance of minimizing the risk of postoperative complications. PMID- 25515201 TI - MiR-92a Promotes Cell Metastasis of Colorectal Cancer Through PTEN-Mediated PI3K/AKT Pathway. AB - BACKGROUND: MicroRNAs regulate gene expression at the posttranscriptional level and play important roles in tumor development, progression, and metastasis. The aim of this study was to investigate the role of microRNA-92a (miR-92a) in metastasis of colorectal cancer (CRC). METHODS: One hundred fifty-eight CRC patients were enrolled. The expression of miR-92a, PTEN, and E-cadherin was analyzed by real-time PCR. Univariate (Kaplan-Meier) analysis was used to analyze primary outcomes included 5-year overall survival and tumor recurrence. CRC cell model studies were used to analyze the miR-92a-involved CRC metastasis. RESULTS: The expression of miR-92a in tumor tissues was significantly positively correlated with lymph node metastasis in CRC patients (p = 0.012). After adjusting for age, sex, and disease differentiation, this correlation remained significant (p = 0.01). In addition, there was a negative correlation between levels of miR-92a and the PTEN gene (p < 0.0001). No any association of miR-92a and E-cadherin was found (p = 0.128). Patients with high miR-92a/low PTEN had poorer overall survival and disease-free survival rates than those with high miR 92a/high PTEN, low miR-92a/high PTEN, and low miR-92a/low PTEN. The association of levels of miR-92a and PTEN with tumor cell migration in CRC was also confirmed in CRC cell models. CONCLUSIONS: We suggest that miR-92a is involved in lymph node metastasis of CRC patients through PTEN-regulated PI3K/AKT signaling pathway. PMID- 25515202 TI - Case report: a balance training program using the Nintendo Wii Fit to reduce fall risk in an older adult with bilateral peripheral neuropathy. AB - A recent systematic review supported the use of strength and balance training for older adults at risk for falls, and provided preliminary evidence for those with peripheral neuropathy (PN). However, the role of gaming systems in fall risk reduction was not explored. The purpose of this case report was to describe the use of the Nintendo(r) WiiTM Fit gaming system to train standing balance in a community-dwelling older adult with PN and a history of recurrent near falls. A 76-year-old patient with bilateral PN participated in 1 h of Nintendo(r) WiiTM Fit balance training, two times a week for 6 weeks. Examination was conducted using a Computerized Dynamic Posturography system (i.e. Sensory Organization Test (SOT), Limits of Stability (LOS), Adaptation Test (ADT) and Motor Control Test (MCT) and clinical testing with the Berg Balance Scale (BBS), Timed Up and Go (TUG), Activities-specific Balance Confidence (ABC) scale and 30-s Chair Stand. Following training, sensory integration scores on the SOT were unchanged. Maximum excursion abilities improved by a range of 37-86% on the LOS test. MCT scores improved for amplitude with forward translations and ADT scores improved for downward platform rotations. Clinical scores improved on the BBS (28/56-34/56), ABC (57.5-70.6%) and TUG (14.9-10.9 s) which indicated reduced fall risk. Balance training with a gaming system showed promise as a feasible, objective and enjoyable method to improve physical performance and reduce fall risk in an individual with PN. PMID- 25515203 TI - PEG-Poly(L-alanine) thermogel as a 3D scaffold of bone-marrow-derived mesenchymal stem cells. AB - Bone-marrow-derived mesenchymal stem cells (BMSCs) were cultured in three dimensional (3D) scaffolds formed by temperature-sensitive sol-to-gel transition of BMSC-suspended poly(ethylene glycol)-poly(L-alanine) (PEG-PA) aqueous solutions. A commercialized thermogelling 3D scaffold of MatrigelTM was used for the comparative study. The cells maintained their spherical shapes in the PEG-PA thermogel, whereas fibrous cell morphologies were observed in the MatrigelTM. Type II collagen and myogenic differentiation factor 1 were dominantly expressed in the PEG-PA thermogel. On the other hand, a significant extent of type III beta tubulin was expressed in the MatrigelTM in addition to type II collagen and myogenic differentiation factor 1. After confirming the dominant chondrogenic differentiation of the BMSCs in the PEG-PA thermogel in in vitro study, in vivo study was performed for injectable tissue engineering application of the BMSCs/PEG-PA system. The cell-growing implant was formed in situ by subcutaneous injection of the BMSC-suspended PEG-PA aqueous solution to mice. In vivo study also proved the excellent expressions of chondrogenic biomarkers including collagen type II and sulfated glycosaminoglycan in the mouse model. This paper suggests that the PEG-PA thermogel is a very promising as a 3D culture matrix as well as an injectable tissue-engineering system for preferential chondrogenic differentiation of the BMSCs. PMID- 25515204 TI - Chest CT using spectral filtration: radiation dose, image quality, and spectrum of clinical utility. AB - OBJECTIVES: To determine the radiation dose, image quality, and clinical utility of non-enhanced chest CT with spectral filtration. METHODS: We retrospectively analysed 25 non-contrast chest CT examinations acquired with spectral filtration (tin-filtered Sn100 kVp spectrum) compared to 25 examinations acquired without spectral filtration (120 kV). Radiation metrics were compared. Image noise was measured. Contrast-to-noise-ratio (CNR) and figure-of-merit (FOM) were calculated. Diagnostic confidence for the assessment of various thoracic pathologies was rated by two independent readers. RESULTS: Effective chest diameters were comparable between groups (P = 0.613). In spectral filtration CT, median CTDIvol, DLP, and size-specific dose estimate (SSDE) were reduced (0.46 vs. 4.3 mGy, 16 vs. 141 mGy*cm, and 0.65 vs. 5.9 mGy, all P < 0.001). Spectral filtration CT had higher image noise (21.3 vs. 13.2 HU, P < 0.001) and lower CNR (47.2 vs. 75.3, P < 0.001), but was more dose-efficient (FOM 10,659 vs. 2,231/mSv, P < 0.001). Diagnostic confidence for parenchymal lung disease and osseous pathologies was lower with spectral filtration CT, but no significant difference was found for pleural pathologies, pulmonary nodules, or pneumonia. CONCLUSIONS: Non-contrast chest CT using spectral filtration appears to be sufficient for the assessment of a considerable spectrum of thoracic pathologies, while providing superior dose efficiency, allowing for substantial radiation dose reduction. KEY POINTS: * Spectral filtration enables non-contrast chest CT with very high dose efficiency. * This approach reduces CTDI vol , DLP, and SSDE (effective chest diameter 28 cm). * Lung nodules, pneumonia, and pleural pathologies can be assessed with uncompromised confidence. PMID- 25515205 TI - Differential leukocyte counting and immunophenotyping in cryopreserved ex vivo whole blood. AB - Absolute cell counts are typically measured in fresh samples, but this is impractical in large field studies. We compared quantification of leukocyte proportions and absolute counts using reference real-time methods (stain and lyse/no-wash (LNW) or hematology analyser) with a novel assay that allows long term cryopreservation of fixed leukocytes for later counting (DLC-ICE: differential leukocyte count and immunophenotype in cryopreserved ex vivo whole blood). For the LNW method, whole blood (WB) was stained with fluorescent antibodies, then erythrocytes were lysed, and leukocytes fixed prior to flow cytometry. Alternatively, our novel DLC-ICE method entailed erythrocyte lysis and leukocyte fixation, cryopreservation and later staining of permeabilized cells prior to flow cytometry. Outcomes were proportions and absolute counts of granulocytes, lymphocytes, monocytes, T cells, B cells, and activated T cells within the leukocyte population. We also compared leukocyte subset counts in fresh WB from 51 healthy infants measured by hematology analyser at a rural clinical site or by DLC-ICE method after 2 years of cryopreservation. We observed excellent agreement and strong correlations between absolute counts or cell proportions measured by the LNW and DLC-ICE methods on fresh WB from 10 healthy adults. Compared to LNW, DLC-ICE yielded similar or brighter staining even after cryopreservation. Duration of cryopreservation, assessed monthly for 1 year, had little effect on cell enumeration: median coefficients of variation were below 15% for all outcomes. Under field site conditions, we observed strong correlations between infant leukocyte numbers measured in fresh samples by hematology analyser and those measured by DLC-ICE up to 2 years of cryopreservation. Our novel DLC-ICE method allows accurate flow cytometric quantification of cell subsets from fixed WB even after long-term cryopreservation. This method is ideal for batched, retrospective analysis of samples from large field studies, or when advanced flow cytometry equipment is not available for clinical research purposes. (c) 2014 International Society for Advancement of Cytometry. PMID- 25515206 TI - Application of the modified chi-square ratio statistic in a stepwise procedure for cascade impactor equivalence testing. AB - Equivalence testing of aerodynamic particle size distribution (APSD) through multi-stage cascade impactors (CIs) is important for establishing bioequivalence of orally inhaled drug products. Recent work demonstrated that the median of the modified chi-square ratio statistic (MmCSRS) is a promising metric for APSD equivalence testing of test (T) and reference (R) products as it can be applied to a reduced number of CI sites that are more relevant for lung deposition. This metric is also less sensitive to the increased variability often observed for low deposition sites. A method to establish critical values for the MmCSRS is described here. This method considers the variability of the R product by employing a reference variance scaling approach that allows definition of critical values as a function of the observed variability of the R product. A stepwise CI equivalence test is proposed that integrates the MmCSRS as a method for comparing the relative shapes of CI profiles and incorporates statistical tests for assessing equivalence of single actuation content and impactor sized mass. This stepwise CI equivalence test was applied to 55 published CI profile scenarios, which were classified as equivalent or inequivalent by members of the Product Quality Research Institute working group (PQRI WG). The results of the stepwise CI equivalence test using a 25% difference in MmCSRS as an acceptance criterion provided the best matching with those of the PQRI WG as decisions of both methods agreed in 75% of the 55 CI profile scenarios. PMID- 25515207 TI - Long-lived and well-resolved Mn2+ ion emissions in CuInS-ZnS quantum dots. AB - CuInS2 (CIS) quantum dots (QDs) have tunable photoluminescence (PL) behaviors in the visible and near infrared spectral range with markedly lower toxicity than the cadmium-based counterparts, making them very promising applications in light emitting and solar harvesting. However, there still remain material- and fabrication- related obstacles in realizing the high-performance CIS-based QDs with well-resolved Mn(2+) d-d emission, long emission lifetimes as well as high efficiencies. Here, we demonstrate the growth of high-quality Mn(2+)-doped CuInS ZnS (CIS-ZnS) QDs based on a multi-step hot-injection strategy. The resultant QDs exhibit a well-resolved Mn(2+) d-d emission with a high PL quantum yield (QY) up to 66% and an extremely long excited state lifetime up to ~3.78 ms, which is nearly two times longer than the longest one of "green" QDs ever reported. It is promising that the synthesized Mn(2+)-doped CIS-ZnS QDs might open new doors for their practical applications in bioimaging and opto/electronic devices. PMID- 25515208 TI - Effects of adding chymosin to milk on calcium homeostasis: a randomized, double blind, cross-over study. AB - Calcium intake and absorption is important for bone health. In a randomized double-blind cross-over trial, we investigated effects of adding chymosin to milk on the intestinal calcium absorption as measured by renal calcium excretion and indices of calcium homeostasis. The primary outcome of the study was 24-h renal calcium excretion that is considered a proxy measure of the amount of calcium absorbed from the intestine. We studied 125 healthy men and women, aged 34 (25 45) years on two separate days. On each day, a light breakfast was served together with 500 ml of semi-skimmed milk to which either chymosin or similar placebo was added. Compared with placebo, chymosin did not affect 24-h urinary calcium, calcium/creatinine ratio, plasma parathyroid hormone, calcitonin or ionized calcium levels. However, during the first 4 h after intake of milk with chymosin, urinary calcium-creatinine ratio was significantly increased (17%) compared with placebo. Stratification by daily calcium intake showed effect of chymosin in participant with a habitual intake above the median (>1,050 mg/day) in whom both urinary calcium and calcium/creatinine ratio were significantly increased compared with placebo. Effects did not depend on plasma 25 hydroxyvitamin D levels. Chymosin added to milk increases renal calcium excretion in the hours following intake without affecting plasma levels of calcium or calciotropic hormones. The effect most likely represents enhanced intestinal calcium absorption shortly after intake. Further studies are warranted on whether intake of milk-added chymosin may cause beneficial effects on bone. www.ClinicalTrials.gov no. NCT01370941. PMID- 25515209 TI - Evaluation of cerebrovascular impedance and wave reflection in mouse by ultrasound. AB - Genetic and surgical mouse models are commonly used to study cerebrovascular disease, but their size makes invasive hemodynamic testing technically challenging. The purpose of this study was to demonstrate a noninvasive measurement of cerebrovascular impedance and wave reflection in mice using high frequency ultrasound in the left common carotid artery (LCCA), and to examine whether microvascular changes associated with hypercapnia could be detected with such an approach. Ten mice (C57BL/6J) were studied using a high-frequency ultrasound system (40 MHz). Lumen area and blood flow waveforms were obtained from the LCCA and used to calculate pulse-wave velocity, input impedance, and reflection amplitude and transit time under both normocapnic and hypercapnic (5% CO2) ventilation. With hypercapnia, vascular resistance was observed to decrease by 87%+/-12%. Although the modulus of input impedance was unchanged with hypercapnia, a phase decrease indicative of increased total arterial compliance was observed at low harmonics together with an increased reflection coefficient in both the time (0.57+/-0.08 versus 0.68+/-0.08, P=0.04) and frequency domains (0.62+/-0.08 versus 0.73+/-0.06, P=0.02). Interestingly, the majority of LCCA blood flow was found to pass into the internal carotid artery (range=76% to 90%, N=3), suggesting that hemodynamic measurements in this vessel are a good metric for intracerebral reactivity in mouse. PMID- 25515210 TI - Increased cerebral vascular reactivity in the tau expressing rTg4510 mouse: evidence against the role of tau pathology to impair vascular health in Alzheimer's disease. AB - Vascular abnormalities are a key feature of Alzheimer's disease (AD). Imaging of cerebral vascular reactivity (CVR) is a powerful tool to investigate vascular health in clinical populations although the cause of reduced CVR in AD patients is not fully understood. We investigated the specific role of tau pathology in CVR derangement in AD using the rTg4510 mouse model. We observed an increase in CVR in cortical regions with tau pathology. These data suggest that tau pathology alone does not produce the clinically observed decreases in CVR and implicates amyloid pathology as the dominant etiology of impaired CVR in AD patients. PMID- 25515211 TI - Myeloperoxidase propagates damage and is a potential therapeutic target for subacute stroke. AB - Few effective treatment options exist for stroke beyond the hyperacute period. Radical generation and myeloperoxidase (MPO) have been implicated in stroke. We investigated whether pharmacologic reduction or gene deletion of this highly oxidative enzyme reduces infarct propagation and improves outcome in the transient middle cerebral artery occlusion mouse model (MCAO). Mice were treated with 4-aminobenzoic acid hydrazide (ABAH), a specific irreversible MPO inhibitor. Three treatment regimens were used: (1) daily throughout the 21-day observational period, (2) during the acute stage (first 24 hours), or (3) during the subacute stage (daily starting on day 2). We found elevated MPO activity in ipsilateral brain 3 to 21 days after ischemia. 4-Aminobenzoic acid hydrazide reduced enzyme activity by 30% to 40% and final lesion volume by 60% (P<0.01). The MPO-knockout (KO) mice subjected to MCAO also showed a similar reduction in the final lesion volume (P<0.01). The ABAH treatment or MPO-KO mice also improved neurobehavioral outcome (P<0.001) and survival (P=0.01), but ABAH had no additional beneficial effects in MPO-KO mice, confirming specificity of ABAH. Interestingly, inhibiting MPO activity during the subacute stage recapitulated most of the therapeutic benefit of continuous MPO inhibition, suggesting that MPO-targeted therapies could be useful when given after 24 hours of stroke onset. PMID- 25515212 TI - Premyelinated central axons express neurotoxic NMDA receptors: relevance to early developing white-matter injury. AB - Ischemic-type injury to developing white matter is associated with the significant clinical condition cerebral palsy and with the cognitive deficits associated with premature birth. Premyelinated axons are the major cellular component of fetal white matter and loss of axon function underlies the disability, but the cellular mechanisms producing ischemic injury to premyelinated axons have not previously been described. Injury was found to require longer periods of modelled ischemia than at latter developmental points. Ischemia produced initial hyperexcitability in axons followed by loss of function after Na(+) and Ca(2+) influx. N-methyl-D-aspartate- (NMDA) type glutamate receptor (GluR) agonists potentiated axon injury while antagonists were protective. The NMDA GluR obligatory Nr1 subunit colocalized with markers of small premyelinated axons and expression was found at focal regions of axon injury. Ischemic injury of glial cells present in early developing white matter was NMDA GluR independent. Axons in human postconception week 18 to 23 white matter had a uniform prediameter expansion phenotype and postembedded immuno-gold labelling showed Nr1 subunit expression on the membrane of these axons, demonstrating a shared key neuropathologic feature with the rodent model. Premyelinated central axons therefore express high levels of functional NMDA GluRs that confer sensitivity to ischemic injury. PMID- 25515213 TI - Intracranial pressure elevation after ischemic stroke in rats: cerebral edema is not the only cause, and short-duration mild hypothermia is a highly effective preventive therapy. AB - In both the human and animal literature, it has largely been assumed that edema is the primary cause of intracranial pressure (ICP) elevation after stroke and that more edema equates to higher ICP. We recently demonstrated a dramatic ICP elevation 24 hours after small ischemic strokes in rats, with minimal edema. This ICP elevation was completely prevented by short-duration moderate hypothermia soon after stroke. Here, our aims were to determine the importance of edema in ICP elevation after stroke and whether mild hypothermia could prevent the ICP rise. Experimental stroke was performed in rats. ICP was monitored and short duration mild (35 degrees C) or moderate (32.5 degrees C) hypothermia, or normothermia (37 degrees C) was induced after stroke onset. Edema was measured in three studies, using wet-dry weight calculations, T2-weighted magnetic resonance imaging, or histology. ICP increased 24 hours after stroke onset in all normothermic animals. Short-duration mild or moderate hypothermia prevented this rise. No correlation was seen between DeltaICP and edema or infarct volumes. Calculated rates of edema growth were orders of magnitude less than normal cerebrospinal fluid production rates. These data challenge current concepts and suggest that factors other than cerebral edema are the primary cause of the ICP elevation 24 hours after stroke onset. PMID- 25515214 TI - Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing multiple targets to inhibit NF-kappaB activation. AB - Pro-inflammatory cytokine-induced activation of nuclear factor, NF-kappaB has an important role in leukocyte adhesion to, and subsequent migration across, brain endothelial cells (BECs), which is crucial for the development of neuroinflammatory disorders such as multiple sclerosis (MS). In contrast, microRNA-146a (miR-146a) has emerged as an anti-inflammatory molecule by inhibiting NF-kappaB activity in various cell types, but its effect in BECs during neuroinflammation remains to be evaluated. Here, we show that miR-146a was upregulated in microvessels of MS-active lesions and the spinal cord of mice with experimental autoimmune encephalomyelitis. In vitro, TNFalpha and IFNgamma treatment of human cerebral microvascular endothelial cells (hCMEC/D3) led to upregulation of miR-146a. Brain endothelial overexpression of miR-146a diminished, whereas knockdown of miR-146a augmented cytokine-stimulated adhesion of T cells to hCMEC/D3 cells, nuclear translocation of NF-kappaB, and expression of adhesion molecules in hCMEC/D3 cells. Furthermore, brain endothelial miR-146a modulates NF-kappaB activity upon cytokine activation through targeting two novel signaling transducers, RhoA and nuclear factor of activated T cells 5, as well as molecules previously identified, IL-1 receptor-associated kinase 1, and TNF receptor-associated factor 6. We propose brain endothelial miR-146a as an endogenous NF-kappaB inhibitor in BECs associated with decreased leukocyte adhesion during neuroinflammation. PMID- 25515215 TI - Cortical spreading depolarization stimulates gliogenesis in the rat entorhinal cortex. AB - Recently, we showed that cortical spreading depolarizations (CSDs) are a potent trigger of hippocampal neurogenesis. Here, we evaluated CSD-induced cytogenesis in the entorhinal cortex (EC), which provides the major afferent input to the dentate gyrus. Cortical spreading depolarizations were induced by epidural application of 3 mol/L KCl, controls received equimolar NaCl. Cytogenesis was analyzed at different time points thereafter by means of intraperitoneal 5 bromodeoxyuridine injections (day 2, 4, or days 1 to 7) and immunohistochemistry. Recurrent CSD significantly increased numbers of newborn cells in the ipsilateral EC. The majority of these cells expressed glial markers. Microglia proliferation was maximal at day 2, whereas NG2 glia and astrocytes responded for a prolonged period of time (days 2 to 4). Newborn glia remained detectable for 6 weeks after CSD. Whereas we furthermore detected newborn cells immunopositive for doublecortin, a marker for immature neuronal cells, we found no evidence for the generation of new neurons in the EC. Our results indicate that CSD is a potent gliogenic stimulus, leading to rapid and enduring changes in the glial cellular composition of the affected brain tissue. Thus, CSD facilitates ongoing structural remodeling of the directly affected cortex that might contribute to the pathophysiology of CSD-related brain pathologies. PMID- 25515216 TI - Noninvasive assessment of arterial compliance of human cerebral arteries with short inversion time arterial spin labeling. AB - A noninvasive method of assessing cerebral arterial compliance (AC) is introduced in which arterial spin labeling (ASL) is used to measure changes in arterial blood volume (aBV) occurring within the cardiac cycle. Short inversion time pulsed ASL (PASL) was performed in healthy volunteers with inversion times ranging from 250 to 850 ms. A model of the arterial input function was used to obtain the cerebral aBV. Results indicate that aBV depends on the cardiac phase of the arteries in the imaging volume. Cerebral AC, estimated from aBV and brachial blood pressure measured noninvasively in systole and diastole, was assessed in the flow territories of the basal cerebral arteries originating from the circle of Willis: right and left middle cerebral arteries (RMCA and LMCA), right and left posterior cerebral arteries (RPCA and LPCA), and the anterior cerebral artery (ACA). Group average AC values calculated for the RMCA, LMCA, ACA, RPCA, and LPCA were 0.56%+/-0.2%, 0.50%+/-0.3%, 0.4%+/-0.2%, 1.1%+/-0.5%, and 1.1%+/-0.3% per mm Hg, respectively. The current experiment has shown the feasibility of measuring AC of cerebral arteries with short inversion time PASL. PMID- 25515218 TI - The conformation of a catalytic loop is central to GTPase activity on the ribosome. AB - The translational GTPases hydrolyze GTP on the ribosome at several stages of the protein synthesis cycle. Because of the strong conservation of their catalytic center, these enzymes are expected to operate through a universal hydrolysis mechanism, in which a critical histidine residue together with the sarcin-ricin loop of the large ribosomal subunit is necessary for GTPase activation. Here we examine different possible pathways for GTP hydrolysis by EF-Tu through extensive computer simulations. We show that a conformational change of the peptide plane preceding this histidine has a decisive effect on the energetics of the reaction. This transition was predicted earlier by us and has recently been confirmed experimentally. It is found to promote early proton transfer from water to the gamma-phosphate group of GTP, followed by nucleophilic attack by hydroxide ion. The calculated reaction energetics is in good agreement with available kinetic data, for both wild-type and mutant versions of EF-Tu, and indicates that the latter may enforce a change in mechanism toward more concerted pathways. PMID- 25515217 TI - A multifaceted quality improvement intervention for CVD risk management in Australian primary healthcare: a protocol for a process evaluation. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. Despite the widespread availability of evidence-based clinical guidelines and validated risk predication equations for prevention and management of CVD, their translation into routine practice is limited. We developed a multifaceted quality improvement intervention for CVD risk management which incorporates electronic decision support, patient risk communication tools, computerised audit and feedback tools, and monthly, peer-ranked performance feedback via a web portal. The intervention was implemented in a cluster randomised controlled trial in 60 primary healthcare services in Australia. Overall, there were improvements in risk factor recording and in prescribing of recommended treatments among under-treated individuals, but it is unclear how this intervention was used in practice and what factors promoted or hindered its use. This information is necessary to optimise intervention impact and maximally implement it in a post-trial context. In this study protocol, we outline our methods to conduct a theory-based, process evaluation of the intervention. Our aims are to understand how, why, and for whom the intervention produced the observed outcomes and to develop effective strategies for translation and dissemination. METHODS/DESIGN: We will conduct four discrete but inter-related studies taking a mixed methods approach. Our quantitative studies will examine (1) the longer term effectiveness of the intervention post-trial, (2) patient and health service level correlates with trial outcomes, and (3) the health economic impact of implementing the intervention at scale. The qualitative studies will (1) identify healthcare provider perspectives on implementation barriers and enablers and (2) use video ethnography and patient semi-structured interviews to understand how cardiovascular risk is communicated in the doctor/patient interaction both with and without the use of intervention. We will also assess the costs of implementing the intervention in Australian primary healthcare settings which will inform scale-up considerations. DISCUSSION: This mixed methods evaluation will provide a detailed understanding of the process of implementing a quality improvement intervention and identify the factors that might influence scalability and sustainability. TRIALS REGISTRATION: 12611000478910. PMID- 25515220 TI - Electron transfer reduction of the diazirine ring in gas-phase peptide ions. On the peculiar loss of [NH4O] from photoleucine. AB - Electron transfer to gas-phase peptide ions with diazirine-containing amino acid residue photoleucine (L*) triggers diazirine ring reduction followed by cascades of residue-specific radical reactions. Upon electron transfer, substantial fractions of (GL*GGR +2H)(+[Symbol: see text]) cation-radicals undergo elimination of [NH(4)O] radicals and N(2)H(2) molecules from the side chain. The side-chain dissociations are particularly prominent on collisional activation of long-lived (GL*GGR +2H)(+[Symbol: see text]) cation-radicals formed by electron transfer dissociation of noncovalent peptide-18-crown-6-ether ion complexes. The ion dissociation products were characterized by multistage tandem mass spectrometry (MS(n)) and ion mobility measurements. The elimination of [NH(4)O] was elucidated with the help of (2)H, (15) N, and (18)O-labeled peptide ions and found to specifically involve the amide oxygen of the N-terminal residue. The structures, energies, and electronic states of the peptide radical species were elucidated by a combination of near-UV photodissociation experiments and electron structure calculations combining ab initio and density functional theory methods. Electron transfer reaching the ground electronic states of charge reduced (GL*GGR +2H)(+[Symbol: see text]) cation-radicals was found to reduce the diazirine ring. In contrast, backbone N - Calpha bond dissociations that represent a 60%-75% majority of all dissociations because of electron transfer are predicted to occur from excited electronic states. PMID- 25515219 TI - CaMKII content affects contractile, but not mitochondrial, characteristics in regenerating skeletal muscle. AB - BACKGROUND: The multi-meric calcium/calmodulin-dependent protein kinase II (CaMKII) is the main CaMK in skeletal muscle and its expression increases with endurance training. CaMK family members are implicated in contraction-induced regulation of calcium handling, fast myosin type IIA expression and mitochondrial biogenesis. The objective of this study was to investigate the role of an increased CaMKII content for the expression of the contractile and mitochondrial phenotype in vivo. Towards this end we attempted to co-express alpha- and beta CaMKII isoforms in skeletal muscle and characterised the effect on the contractile and mitochondrial phenotype. RESULTS: Fast-twitch muscle m. gastrocnemius (GM) and slow-twitch muscle m. soleus (SOL) of the right leg of 3 month old rats were transfected via electro-transfer of injected expression plasmids for native alpha/beta CaMKII. Effects were identified from the comparison to control-transfected muscles of the contralateral leg and non transfected muscles. alpha/beta CaMKII content in muscle fibres was 4-5-fold increased 7 days after transfection. The transfection rate was more pronounced in SOL than GM muscle (i.e. 12.6 vs. 3.5%). The overexpressed alpha/beta CaMKII was functional as shown through increased threonine 287 phosphorylation of beta CaMKII after isometric exercise and down-regulated transcripts COXI, COXIV, SDHB after high-intensity exercise in situ. alpha/beta CaMKII overexpression under normal cage activity accelerated excitation-contraction coupling and relaxation in SOL muscle in association with increased SERCA2, ANXV and fast myosin type IIA/X content but did not affect mitochondrial protein content. These effects were observed on a background of regenerating muscle fibres. CONCLUSION: Elevated CaMKII content promotes a slow-to-fast type fibre shift in regenerating muscle but is not sufficient to stimulate mitochondrial biogenesis in the absence of an endurance stimulus. PMID- 25515221 TI - Aerobic exercise training facilitates the effectiveness of cognitive behavioral therapy in panic disorder. AB - BACKGROUND: Physical activity has been discussed as a therapeutic alternative or add-on for the treatment of anxiety disorders. We studied whether aerobic exercise compared to physical activity with low impact can improve the effect of cognitive behavioral therapy (CBT) in patients with panic disorder (PD) with/without agoraphobia. METHODS: Forty-seven patients received group CBT treatment over 1 month, which was augmented with an 8-week protocol of either aerobic exercise (three times/week, 30 min, 70% VO(2) max; n = 24) or a training program including exercises with very low intensity (n = 23) in a randomized controlled double-blind design. The primary outcome measure was the total score on the Hamilton Anxiety Scale (Ham-A). A 2 * 3 analysis of covariance (ANCOVA) with baseline value as a covariate was conducted for data analysis. RESULTS: Time * group interaction for the Ham-A revealed a significant effect (P = .047, eta(2) p = .072), which represented the significant group difference at a 7-month follow up. For the other clinical outcome measures no statistical significance emerged, although improvement was more sustained in the exercise group. CONCLUSIONS: For patients with PD, regular aerobic exercise adds an additional benefit to CBT. This supports previous results and provides evidence about the intensity of exercise that needs to be performed. PMID- 25515222 TI - In vitro method for assessing the biomechanics of the patellofemoral joint following total knee arthroplasty. AB - The patellofemoral joint is a common site of pain and failure following total knee arthroplasty. A contributory factor may be adverse patellofemoral biomechanics. Cadaveric investigations are commonly used to assess the biomechanics of the joint, but are associated with high inter-specimen variability and often cannot be carried out at physiological levels of loading. This study aimed to evaluate the suitability of a novel knee simulator for investigating patellofemoral joint biomechanics. This simulator specifically facilitated the extended assessment of patellofemoral joint biomechanics under physiological levels of loading. The simulator allowed the knee to move in 6 degrees of freedom under quadriceps actuation and included a simulation of the action of the hamstrings. Prostheses were implanted on synthetic bones and key soft tissues were modelled with a synthetic analogue. In order to evaluate the physiological relevance and repeatability of the simulator, measurements were made of the quadriceps force and the force, contact area and pressure within the patellofemoral joint using load cells, pressure-sensitive film, and a flexible pressure sensor. The results were in agreement with those previously reported in the literature, confirming that the simulator is able to provide a realistic physiological loading situation. Under physiological loading, average standard deviations of force and area measurements were substantially lower and comparable to those reported in previous cadaveric studies, respectively. The simulator replicates the physiological environment and has been demonstrated to allow the initial investigation of factors affecting patellofemoral biomechanics following total knee arthroplasty. PMID- 25515223 TI - Automated fit quantification of tibial nail designs during the insertion using computer three-dimensional modelling. AB - Intramedullary nailing is the standard fixation method for displaced diaphyseal fractures of the tibia. An optimal nail design should both facilitate insertion and anatomically fit the bone geometry at its final position in order to reduce the risk of stress fractures and malalignments. Due to the nonexistence of suitable commercial software, we developed a software tool for the automated fit assessment of nail designs. Furthermore, we demonstrated that an optimised nail, which fits better at the final position, is also easier to insert. Three dimensional models of two nail designs and 20 tibiae were used. The fitting was quantified in terms of surface area, maximum distance, sum of surface areas and sum of maximum distances by which the nail was protruding into the cortex. The software was programmed to insert the nail into the bone model and to quantify the fit at defined increment levels. On average, the misfit during the insertion in terms of the four fitting parameters was smaller for the Expert Tibial Nail Proximal bend (476.3 mm(2), 1.5 mm, 2029.8 mm(2), 6.5 mm) than the Expert Tibial Nail (736.7 mm(2), 2.2 mm, 2491.4 mm(2), 8.0 mm). The differences were statistically significant (p <= 0.05). The software could be used by nail implant manufacturers for the purpose of implant design validation. PMID- 25515224 TI - Does cam osteochondroplasty compromise proximal femur strength? AB - Little is known about the effect on load bearing ability of cam-type femurs following osteochondroplasty. The aim of this study was to compare the change in deformation undergone by cam-type femoral acetabular impingement femur models after resection of different volumes. Dry-bone replicas (N = 10) of two cam-type femurs (cam A and B) underwent resections of increasing volume (Surgery I, II and III) representing conservative, adequate and radical resections. Deformation under cyclic loading of 700 N for five cycles after each surgery was compared. The 360 degrees alpha angle and the change in head to neck ratio at four equidistant points along the femoral neck were used as measures of surgical efficacy and volume resected. Intact cam A and B replicas had a maximum alpha angle of 88 degrees and 90 degrees , respectively, which were reduced to 55 degrees and 54 degrees post Surgery I. Cam A replicas showed a significant reduction (p < 0.01) in mean axial displacement after Surgery I (up to 10% reduction in neck volume) and an increase after Surgery III (~20%-40% reduction in neck volume) compared to unresected controls (p < 0.01). Surgery II (~10%-15% reduction in neck volume) produced no significant change in mean displacement (p > 0.05). Cam B models exhibited lower mean displacement after Surgery I, II and III (p < 0.01) compared to unresected controls. Conservative surgery appears to improve the axial load bearing ability of dry-bone models. Radical resections may significantly decrease the fracture-resistant properties of bone following osteochondroplasty which should be noted when planning such a procedure. PMID- 25515225 TI - Automatic and accurate reconstruction of distal humerus contours through B-Spline fitting based on control polygon deformation. AB - The strong advent of computer-assisted technologies experienced by the modern orthopedic surgery prompts for the expansion of computationally efficient techniques to be built on the broad base of computer-aided engineering tools that are readily available. However, one of the common challenges faced during the current developmental phase continues to remain the lack of reliable frameworks to allow a fast and precise conversion of the anatomical information acquired through computer tomography to a format that is acceptable to computer-aided engineering software. To address this, this study proposes an integrated and automatic framework capable to extract and then postprocess the original imaging data to a common planar and closed B-Spline representation. The core of the developed platform relies on the approximation of the discrete computer tomography data by means of an original two-step B-Spline fitting technique based on successive deformations of the control polygon. In addition to its rapidity and robustness, the developed fitting technique was validated to produce accurate representations that do not deviate by more than 0.2 mm with respect to alternate representations of the bone geometry that were obtained through different-contact based-data acquisition or data processing methods. PMID- 25515226 TI - The relationship between maximal hip abductor strength and resultant loading at the knee during walking. AB - The peak external knee adduction moment (KAM) is implicated in progression of knee osteoarthritis (OA). Recently, hip abductor weakness has also been found in patients with knee OA; however, it remains unknown as to how or if this weakness is a consequence of OA, or a predisposing factor. If it is the latter, a direct relationship between hip strength and KAM magnitude would be expected. The purpose of this study was to evaluate the relationship between hip abductor strength and KAM magnitude during walking. In fourteen adults, maximal isometric hip abductor strength was measured, and the KAM was quantified during gait. Additionally, internal hip abductor moments, vertical and medial ground-reaction forces (GRFs), and GRF to knee joint center lever-arms were quantified during gait. The relationship between hip strength and GRFs, lever-arms and KAM were assessed using correlation. Internal hip abductor moments were compared to maximum hip strength by paired samples t-test. Correlations between hip strength and the vertical GRF (r = -0.05, p = 0.87), medial GRF (r = -0.24, p = 0.41), lever arm (r = -0.01, p = 0.97), and KAM (r = -0.24, p = 0.41) were not statistically significant. Peak internal hip abductor moments during gait (1.1 +/ 0.2 Nm/kg) were significantly lower than maximal hip abductor strength (1.8 +/- 0.3 Nm/kg, p < 0.001). It is concluded that hip abductor strength is not related to KAM magnitude. It seems more likely that hip abductor weakness is a consequence of OA rather than a predisposing factor. PMID- 25515227 TI - Characterization of a pressure measuring system for the evaluation of medical devices. AB - The purpose of this study is to evaluate the possible use of four "FSA" thin and flexible resistive pressure mapping systems, designed by Vista Medical (Winnipeg, Manitoba, Canada), for the measurement of interface pressure exerted by lumbar belts onto the trunk. These sensors were originally designed for the measurement of low pressure applied by medical devices on the skin. Two types of tests were performed: standard metrology tests such as linearity, hysteresis, repeatability, reproducibility and drift, and specific tests for this application such as curvature, surface condition and mapping system superposition. The linear regression coefficient is between 0.86 and 0.98; hysteresis is between 6.29% and 9.41%. Measurements are repeatable. The location, time and operator, measurement surface condition and mapping system superposition have a statistically significant influence on the results. A stable measure is verified over the period defined in the calibration procedure, but unacceptable drift is observed afterward. The measurement stays suitable on a curved surface for an applied pressure above 50 mmHg. To conclude, the sensor has acceptable linearity, hysteresis and repeatability. Calibration must be adapted to avoid drift. Moreover, when comparing different measurements with this sensor, the location, the time, the operator and the measurement surface condition should not change; the mapping system must not be superimposed. PMID- 25515228 TI - The impact of proximal femoral morphology on failure strength with a mid-head resection short-stem hip arthroplasty. AB - Mid-head resection short-stem hip arthroplasty is a conservative alternative to conventional total hip replacement and addresses proximal fixation challenges in patients not suitable for hip resurfacing. It is unclear whether proximal femoral morphology impacts the ultimate failure load of mid-head resection implanted femurs, thus the aim of this study was to investigate the effect of native neck shaft angle (NSA) and coronal implant alignment on proximal femoral strength. In total, 36 synthetic femurs with two different proximal femoral morphologies were utilized in this study. Of them, 18 femurs with a varus NSA of 120 degrees and 18 femurs with a valgus NSA of 135 degrees were each implanted with a mid-head resection prosthesis. Femurs within the two different femoral morphology groups were divided into three equal coronal implant alignment groups: 10 degrees valgus, 10 degrees varus or neutral alignment. Prepared femurs were tested for stiffness and to failure in axial compression. There was no significant difference in stiffness nor failure load between femurs implanted with valgus-, varus- or neutrally aligned implants in femurs with a NSA of 120 degrees (p = 0.396, p = 0.111, respectively). Femurs implanted in valgus orientation were significantly stiffer and failed at significantly higher loads than those implanted in varus alignment in femurs with a NSA of 135 degrees (p = 0.001, p = 0.007, respectively). A mid-head resection short-stem hip arthroplasty seems less sensitive to clinically relevant variations of coronal implant alignment and may be more forgiving upon implantation in some femoral morphologies, however, a relative valgus component alignment is recommended. PMID- 25515229 TI - An in silico parametric model of vertebrae trabecular bone based on density and microstructural parameters to assess risk of fracture in osteoporosis. AB - Osteoporosis is a progressive bone disease characterized by deterioration in the quantity and quality of bone, leading to inferior mechanical properties and an increased risk of fracture. Current assessment of osteoporosis is typically based on bone densitometry tools such as Quantitative Computed Tomography (QCT) and Dual Energy X-ray absorptiometry (DEXA). These assessment modalities mainly rely on estimating the bone mineral density (BMD). Hence present densitometry tools describe only the deterioration of the quantity of bone associated with the disease and not the affected morphology or microstructural changes, resulting in potential incomplete assessment, many undetected patients, and unexplained fractures. In this study, an in-silico parametric model of vertebral trabecular bone incorporating both material and microstructural parameters was developed towards the accurate assessment of osteoporosis and the consequent risk of bone fracture. The model confirms that the mechanical properties such as strength and stiffness of vertebral trabecular tissue are highly influenced by material properties as well as morphology characteristics such as connectivity, which reflects the quality of connected inter-trabecular parts. The FE cellular solid model presented here provides a holistic approach that incorporates both material and microstructural elements associated with the degenerative process, and hence has the potential to provide clinical practitioners and researchers with more accurate assessment method for the degenerative changes leading to inferior mechanical properties and increased fracture risk associated with age and/or disease such as Osteoporosis. PMID- 25515231 TI - Opportunities-and hard work-ahead. PMID- 25515230 TI - Translational cancer research: balancing prevention and treatment to combat cancer globally. AB - Cancer research is drawing on the human genome project to develop new molecular targeted treatments. This is an exciting but insufficient response to the growing, global burden of cancer, particularly as the projected increase in new cases in the coming decades is increasingly falling on developing countries. The world is not able to treat its way out of the cancer problem. However, the mechanistic insights from basic science can be harnessed to better understand cancer causes and prevention, thus underpinning a complementary public health approach to cancer control. This manuscript focuses on how new knowledge about the molecular and cellular basis of cancer, and the associated high-throughput laboratory technologies for studying those pathways, can be applied to population based epidemiological studies, particularly in the context of large prospective cohorts with associated biobanks to provide an evidence base for cancer prevention. This integrated approach should allow a more rapid and informed translation of the research into educational and policy interventions aimed at risk reduction across a population. PMID- 25515233 TI - Different conceptual constructs for modelling sedentary behaviour and physical activity: the impact on the correlates of behaviour. AB - BACKGROUND: Research on the correlates of physical activity (PA) and sedentary behaviour (SB) to date has used independent prediction equations for each behaviour, without considering that they are both part of the same continuum of movement. This assumption of independence might lead to inaccurate estimates because common underlying latent variables may simultaneously influence the propensity to engage in PA and SB. This study tests empirically the interdependent nature of PA and SB by comparing independent equations (current approach in the literature), and joint estimators (a novel but unexplored approach). Using Health Survey for England 2008 data, accelerometry-accessed PA and SB were separately modelled (using ordinary least squared regressions-OLS) and then jointly (using seemingly unrelated regressions-SUR). We tested for diagonality, specification, and goodness of fit. FINDINGS: The best fit models were the ones that allowed for interdependence of the two movement-related behaviours (rho=-0.156; p<0.001). The SUR showed more favourable properties compared to OLS models; producing lower standard errors and more consistent and efficient coefficients. The efficiency gain was more pronounced in the SB equation (Chi2=92.75; p<0.001). CONCLUSION: Evidence from a large national population-wide accelerometry study suggests that accounting for the interdependent nature of PA and SB in prediction equations leads to more efficient modelling estimates. Further research using different samples is, however, required to fully understand the magnitude of efficiency gains accruable from using the joint estimators. PMID- 25515232 TI - Costs, effectiveness, and workload impact of management strategies for women with an adnexal mass. AB - BACKGROUND: We compared the estimated clinical outcomes, costs, and physician workload resulting from available strategies for deciding which women with an adnexal mass should be referred to a gynecologic oncologist. METHODS: We used a microsimulation model to compare five referral strategies: 1) American Congress of Obstetricians and Gynecologists (ACOG) guidelines, 2) Multivariate Index Assay (MIA) algorithm, 3) Risk of Malignancy Algorithm (ROMA), 4) CA125 alone with lowered cutoff values to prioritize test sensitivity over specificity, 5) referral of all women (Refer All). Test characteristics and relative survival were obtained from the literature and data from a biomarker validation study. Medical costs were estimated using Medicare reimbursements. Travel costs were estimated using discharge data from Surveillance, Epidemiology and End Results Medicare and State Inpatient Databases. Analyses were performed separately for pre- and postmenopausal women (60 000 "subjects" in each), repeated 10 000 times. RESULTS: Refer All was cost-effective compared with less expensive strategies in both postmenopausal (incremental cost-effectiveness ratio [ICER] $9423/year of life saved (LYS) compared with CA125) and premenopausal women (ICER $10 644/YLS compared with CA125), but would result in an additional 73 cases/year/subspecialist. MIA was more expensive and less effective than Refer All in pre- and postmenopausal women. If Refer All is not a viable option, CA125 is an optimal strategy in postmenopausal women. CONCLUSIONS: Referral of all women to a subspecialist is an efficient strategy for managing women with adnexal masses requiring surgery, assuming sufficient capacity for additional surgical volume. If a test-based triage strategy is needed, CA125 with lowered cutoff values is a cost-effective strategy. PMID- 25515235 TI - Ultrasound assisted enzyme catalyzed degradation of Cetirizine dihydrochloride. AB - Cetirizine dihydrochloride, a pharmaceutical drug of the class antihistamines is frequently detected in wastewater samples. In the present work, the degradation of Cetirizine dihydrochloride is carried out using a novel technique of laccase enzyme as a catalyst under the influence of ultrasound irradiation. Effect of various process parameters such as enzyme loading, temperature, power, duty cycle, frequency and speed of agitation has been studied along with identification of the degradation intermediates. The maximum degradation of 91% is achieved at optimized experimental parameters such as 0.02% enzyme loading (w/v), 50 degrees C temperature, power input of 100 W, 25 kHz frequency and 50% duty cycle with agitation speed of 200 rpm. It is observed that enzymatic degradation of Cetirizine dihydrochloride under the influence of ultrasound irradiation not only enhances the degradation but also reduces the time of degradation as compared to conventional enzymatic degradation technique. PMID- 25515234 TI - Comparative analysis of the human saliva microbiome from different climate zones: Alaska, Germany, and Africa. AB - BACKGROUND: Although the importance of the human oral microbiome for health and disease is increasingly recognized, variation in the composition of the oral microbiome across different climates and geographic regions is largely unexplored. RESULTS: Here we analyze the saliva microbiome from native Alaskans (76 individuals from 4 populations), Germans (10 individuals from 1 population), and Africans (66 individuals from 3 populations) based on next-generation sequencing of partial 16S rRNA gene sequences. After quality filtering, a total of 67,916 analyzed sequences resulted in 5,592 OTUs (defined at >=97% identity) and 123 genera. The three human groups differed significantly by the degree of diversity between and within individuals (e.g. beta diversity: Africans > Alaskans > Germans; alpha diversity: Germans > Alaskans > Africans). UniFrac, network, ANOSIM, and correlation analyses all indicated more similarities in the saliva microbiome of native Alaskans and Germans than between either group and Africans. The native Alaskans and Germans also had the highest number of shared bacterial interactions. At the level of shared OTUs, only limited support for a core microbiome shared across all three continental regions was provided, although partial correlation analysis did highlight interactions involving several pairs of genera as conserved across all human groups. Subsampling strategies for compensating for the unequal number of individuals per group or unequal sequence reads confirmed the above observations. CONCLUSION: Overall, this study illustrates the distinctiveness of the saliva microbiome of human groups living under very different climatic conditions. PMID- 25515236 TI - Smooth muscle 22alpha facilitates angiotensin II-induced signaling and vascular contraction. AB - Smooth muscle 22alpha (SM22alpha) is involved in stress fiber formation and enhances contractility in vascular smooth muscle cells (VSMCs). In many cases, SM22alpha acts as an adapter protein to assemble signaling complexes and regulate signaling, but whether SM22alpha regulates contractile signaling induced by angiotensin II (AngII) remains unclear. To address this issue, we established a hypertension model of Sm22alpha(-/-) mice, and demonstrated that hypertension induced by AngII was attenuated in Sm22alpha(-/-) mice. A decreased vasoconstriction was observed in aortic rings from Sm22alpha(-/-) mice. Furthermore, loss of SM22alpha resulted in a reduced contractile response to AngII in VSMCs in vitro. The phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) induced by AngII was impaired following depletion of SM22alpha, in parallel with a reduced contractility. The decay of ERK1/2 activity was associated with increased expression of mitogen-activated protein kinase phosphatase 3 (MKP3). Inhibition of MKP3 activity rescued ERK1/2 activity. SM22alpha depletion caused an enhanced interaction of MKP3 with ERK1/2, and a reduced ubiquitination and degradation of MKP3. Knockdown of SM22alpha extended the half-life of MKP3. In conclusion, SM22alpha promotes AngII-induced contraction by maintenance of ERK1/2 signaling cascades through facilitating ubiquitination and degradation of MKP3. KEY MESSAGE: The vasoconstriction is attenuated in aortic rings from Sm22alpha(-/-) mice. MKP3 mediates dephosphorylation of ERK1/2 in AngII-induced VSMC contraction. SM22alpha inhibits the interaction of ERK1/2 with MKP3. SM22alpha promotes ubiquitination and degradation of MKP3. SM22alpha facilitates AngII-induced contraction by maintenance of ERK1/2 signaling. PMID- 25515238 TI - High performance multi-core iron oxide nanoparticles for magnetic hyperthermia: microwave synthesis, and the role of core-to-core interactions. AB - The adoption of magnetic hyperthermia as either a stand-alone or adjunct therapy for cancer is still far from being optimised due to the variable performance found in many iron oxide nanoparticle systems, including commercially available formulations. Herein, we present a reproducible and potentially scalable microwave-based method to make stable citric acid coated multi-core iron oxide nanoparticles, with exceptional magnetic heating parameters, viz. intrinsic loss parameters (ILPs) of up to 4.1 nH m(2) kg(-1), 35% better than the best commercial equivalents. We also probe the core-to-core magnetic interactions in the particles via remanence-derived Henkel and DeltaM plots. These reveal a monotonic dependence of the ILP on the magnetic interaction field Hint, and show that the interactions are demagnetising in nature, and act to hinder the magnetic heating mechanism. PMID- 25515237 TI - The cognitive defects of neonatally irradiated mice are accompanied by changed synaptic plasticity, adult neurogenesis and neuroinflammation. AB - BACKGROUND/PURPOSE OF THE STUDY: Epidemiological evidence suggests that low doses of ionising radiation (<=1.0 Gy) produce persistent alterations in cognition if the exposure occurs at a young age. The mechanisms underlying such alterations are unknown. We investigated the long-term effects of low doses of total body gamma radiation on neonatally exposed NMRI mice on the molecular and cellular level to elucidate neurodegeneration. RESULTS: Significant alterations in spontaneous behaviour were observed at 2 and 4 months following a single 0.5 or 1.0 Gy exposure. Alterations in the brain proteome, transcriptome, and several miRNAs were analysed 6-7 months post-irradiation in the hippocampus, dentate gyrus (DG) and cortex. Signalling pathways related to synaptic actin remodelling such as the Rac1-Cofilin pathway were altered in the cortex and hippocampus. Further, synaptic proteins MAP-2 and PSD-95 were increased in the DG and hippocampus (1.0 Gy). The expression of synaptic plasticity genes Arc, c-Fos and CREB was persistently reduced at 1.0 Gy in the hippocampus and cortex. These changes were coupled to epigenetic modulation via increased levels of microRNAs (miR-132/miR-212, miR-134). Astrogliosis, activation of insulin-growth factor/insulin signalling and increased level of microglial cytokine TNFalpha indicated radiation-induced neuroinflammation. In addition, adult neurogenesis within the DG was persistently negatively affected after irradiation, particularly at 1.0 Gy. CONCLUSION: These data suggest that neurocognitive disorders may be induced in adults when exposed at a young age to low and moderate cranial doses of radiation. This raises concerns about radiation safety standards and regulatory practices. PMID- 25515239 TI - Nocturnal activities and host preferences of Phlebotomus orientalis in extra domestic habitats of Kafta-Humera lowlands, Kala-azar endemic, Northwest Ethiopia. AB - BACKGROUND: Phlebotomus orientalis feeds on a variety of wild and domestic animals and transmits Leishmania donovani from hitherto unknown reservoir hosts to humans in extra-domestic habitats in the Metema-Humera lowlands. The aim of this study was to determine the nocturnal activities of P. orientalis and its preferred blood meal hosts. METHODS: Collections of Phlebotomus orientalis were made by using CDC light traps to determine the density as P. orientalis/hour CDC trap and preference to rodents by using Turner's traps in agricultural fields, animal shelters and thickets of Acacia seyal in Baeker site-1 and Gelanzeraf site 2. The blood meal sources were detected by Reverse Line Blot (RLB) of cytochrome b polymerase chain reaction (PCR) amplification in August, 2012 from collections of sand flies in thickets of A. seyal (March 2011) and dense mixed forest (July 2011) in Baeker site 1. RLB PCR involved first amplification of animal specific sequences of cytochrome b using PCR techniques. Then the amplified sequence was hybridized with 11 species-specific probes for domestic animals adsorbed on nitrocellulose membrane for calorimetric color detection. RESULTS: A total of 6,083 P. orientalis (2,702 males and 3,381 females) were collected at hourly intervals using 22 CDC traps from January to May 2013. The peak activities of P. orientalis were at 1.00 a.m (134.0 +/- 7.21) near animal shelters, 3.00 a.m (66.33 +/- 46.40) in agricultural fields and 21:00 pm (40.6 +/- 30.06) in thickets of A. seyal. This species was not attracted to the different species of rodents in trials carried out in March and April 2013. RLB PCR identified 7 human (28%), 9 mixed (human and cattle) (36%) and 2 cattle (8%) blood meals while 7 were unknown (28%). CONCLUSION: Female P. orientalis can bite humans in extra domestic habitats of Kafta-Humera lowlands at any hour of the night with peak biting after midnight. PMID- 25515241 TI - The risk of colorectal cancer in inflammatory bowel disease: a hospital-based cohort study from Korea. AB - OBJECTIVE: Limited data are available on the incidence and risk factors of colorectal cancer (CRC) in Asian patients with inflammatory bowel disease (IBD). MATERIAL AND METHODS: Information on 5212 Korean patients with IBD (2414 with Crohn's disease [CD] and 2798 with ulcerative colitis [UC]) was retrieved from the IBD registry of Asan Medical Center. Data on CRC incidence for the entire Korean population were derived from the Korean Statistical Information Service. RESULTS: During 39,951 person-years of follow-up (17,679 for CD and 22,272 for UC), 30 patients (12 with CD and 18 with UC) developed CRC. The standardized incidence ratio (SIR) of CRC was 6.0 (95% confidence interval [CI], 3.10-10.48) for CD and 1.68 (95% CI, 1.00-2.66) for UC; it was 9.69 (95% CI, 5.01-16.93) for CD with colonic involvement and 4.31 (95% CI, 2.46-7.00) for extensive UC. The SIR was also increased in patients diagnosed with IBD at younger than 30 years old. CRC location was the low rectum in 11 of 12 CD patients (91.7%). The cumulative probability of rectal cancer was higher in CD patients with a perianal fistula than in those without a perianal fistula (p = 0.02). CONCLUSIONS: A high prevalence of perianal fistulas in Korean CD patients may be the cause of the predominance of low rectal cancer in this population and the higher SIR of CRC in Koreans than in Westerners. In contrast, the SIR of CRC in Korean UC patients may be similar to that in Western UC patients. PMID- 25515240 TI - DEK is a potential marker for aggressive phenotype and irinotecan-based therapy response in metastatic colorectal cancer. AB - BACKGROUND: DEK is a transcription factor involved in stabilization of heterochromatin and cruciform structures. It plays an important role in development and progression of different types of cancer. This study aims to analyze the role of DEK in metastatic colorectal cancer. METHODS: Baseline DEK expression was firstly quantified in 9 colorectal cell lines and normal mucosa by WB. SiRNA-mediated DEK inhibition was carried out for transient DEK silencing in DLD1 and SW620 to dissect its role in colorectal cancer aggressiveness. Irinotecan response assays were performed with SN38 over 24 hours and apoptosis was quantified by flow cytometry. Ex-vivo assay was carried out with 3 fresh tumour tissues taken from surgical resection and treated with SN38 for 24 hours. DEK expression was determined by immunohistochemistry in 67 formalin-fixed paraffin-embedded tumour samples from metastatic colorectal cancer patients treated with irinotecan-based therapy as first-line treatment. RESULTS: The DEK oncogene is overexpressed in all colorectal cancer cell lines. Knock-down of DEK on DLD1 and SW620 cell lines decreased cell migration and increased irinotecan induced apoptosis. In addition, low DEK expression level predicted irinotecan based chemotherapy response in metastatic colorectal cancer patients with KRAS wild-type. CONCLUSIONS: These data suggest DEK overexpression as a crucial event for the emergence of an aggressive phenotype in colorectal cancer and its potential role as biomarker for irinotecan response in those patients with KRAS wild-type status. PMID- 25515242 TI - Early invasive pulmonary aspergillosis in a kidney transplant recipient caused by Aspergillus lentulus: first Brazilian report. AB - We report the first Brazilian case of pulmonary invasive aspergillosis caused by Aspergillus lentulus, a new opportunistic Aspergillus species included in the section fumigati that is usually resistant to amphotericin B and azoles. PMID- 25515243 TI - Human serum potentiates the expression of genes associated with antifungal drug resistance in C. albicans biofilms on central venous catheters. AB - Candida albicans is a major agent of fungaemias and frequently causes systemic disease through seeded, blood stream dissemination. These infections, particularly common in hospitalized patients with central venous catheters (CVCs), appear to persevere due to biofilm reservoirs of the yeast that tend to develop on the device. Although it is known that candidal biofilms are intrinsically resistant to antifungals compared with their planktonic counterparts, there is a paucity of data on the expression of antifungal drug resistance genes (DRGs) in candidal biofilms in CVC reservoirs. Furthermore, notwithstanding the fact that CVCs are constantly bathed in human serum, there are no studies on the effect of the latter on the DRG expression in candidal biofilms. Hence, we developed in vitro biofilms of three different C. albicans strains on silicone CVC discs immersed in human serum and evaluated the temporal expression of nine antifungal DRGs. In an attempt to evaluate the effect of hyphal elements on DRG expression, we incorporated a hyphal mutant (HM) and its wild-type (WT) counterpart, as well as a fresh clinical isolate in the studies. Human serum significantly up-regulated DRG transcripts in Candida biofilms on CVCs, at different stages of biofilm growth, while the WT strain over-expressed more DRGs than the HM strain. Here, we report, for the first time, that both human serum and the hyphal elements of the yeast have a profound modulatory effect on DRG expression in C. albicans biofilms on CVCs. PMID- 25515244 TI - A double-blind randomized placebo-controlled clinical trial of squalamine ointment for tinea capitis treatment. AB - BACKGROUND: Novel treatments against for tinea capitis are needed, and the natural aminosterol squalamine is a potential topical antidermatophyte drug candidate. OBJECTIVES: This phase II randomized double-blind placebo-controlled clinical trial aimed at testing the efficacy and safety of a three-week squalamine ointment regimen for the treatment of tinea capitis. PATIENTS: Males aged 6-15 years presenting with tinea capitis were treated with either topical squalamine ointment or placebo for 3 weeks. The primary endpoint was complete clinical cure. The secondary endpoints were the occurrence of local and/or systemic adverse events, mycological cure, and partial clinical response. Prospective follow-up of clinical adverse events was performed daily. RESULTS: Five patients were treated with 1% squalamine ointment and 15 with placebo. No complete cure was observed. No clinical or biological adverse event was recorded. A significantly (p = 0.03) better hair-growth score, indicating a partial clinical improvement of the tinea capitis lesion, was observed in the patients treated with squalamine compared to those treated with placebo. CONCLUSION: This three-week squalamine ointment regimen was well tolerated and showed an encouraging partial clinical activity for the treatment of tinea capitis. Further studies are needed to evaluate the efficacy of topical squalamine alone against tinea corporis or in combination with a systemic antidermatophyte drug against tinea capitis. PMID- 25515245 TI - 2-(benzylideneamino)phenol: a promising hydroxyaldimine with potent activity against dermatophytoses. AB - Infections caused by dermatophytes, mainly Trichophyton rubrum,are often vulnerable to relapses upon cessation of antifungal therapy, reinforcing the need of new antifungals. Aldimines have potential biological activities, but there are few reports on their antifungal profile. The aim of this study was to evaluate the antifungal activity of 2-(benzylideneamino)phenol (3A3) and 4 (benzylideneamino)phenol (3A4) against dermatophytes. We determined the minimum inhibitory concentration, minimum fungicidal concentration, time-kill curves and fractional inhibitory concentration of the combination of 3A3, 3A4 and itraconazole against a set of isolates of T. rubrum and T. interdigitale. 3A3 was tested in a murine model of dermatophytoses caused by T. rubrum, and the effect on phagocytosis was assessed. The MIC values ranged from 8 to 32 MUg/mL for 3A3 and from 64 to 256 MUg/mL for 3A4. The interaction between 3A3 and 3A4 with itraconazole proved to be synergistic and indifferent, respectively. 3A3 was as efficient as itraconazole in reducing the fungal burden on the skin of mice, being this effect associated with the influx of neutrophil and macrophage. Also, 3A3 was able to increase the internalization of conidia by macrophages. Altogether, our data encourage future clinical studies with 3A3 to treat dermatophytoses. PMID- 25515246 TI - Establishment of oct4:gfp transgenic zebrafish line for monitoring cellular multipotency by GFP fluorescence. AB - The establishment of induced pluripotent stem (iPS) cell technology in fish could facilitate the establishment of novel cryopreservation techniques for storing selected aquaculture strains as frozen cells. In order to apply iPS cell technology to fish, we established a transgenic zebrafish line, Tg(Tru.oct4:EGFP), using green fluorescent protein (GFP) expression under the control of the oct4 gene promoter as a marker to evaluate multipotency in iPS cell preparations. We used the oct4 promoter from fugu (Takifugu rubripes) due to the compact nature of the fugu genome and to facilitate future applications of this technology in marine fishes. During embryogenesis, maternal GFP fluorescence was observed at the cleavage stage and zygotic GFP expression was observed from the start of the shield stage until approximately 24 h after fertilization. gfp messenger RNA (mRNA) was expressed by whole embryonic cells at the shield stage, and then restricted to the caudal neural tube in the latter stages of embryogenesis. These observations showed that GFP fluorescence and the regulation of gfp mRNA expression by the exogenous fugu oct4 promoter are well suited for monitoring endogenous oct4 mRNA expression in embryos. Bisulfite sequencing revealed that the rate of CpG methylation in the transgenic oct4 promoter was high in adult cells (98%) and low in embryonic cells (37%). These findings suggest that, as with the endogenous oct4 promoter, demethylation and methylation both take place normally in the transgenic oct4 promoter during embryogenesis. The embryonic cells harvested at the shield stage formed embryonic body-like cellular aggregates and maintained GFP fluorescence for 6 d when cultured on Transwell-COL Permeable Supports or a feeder layer of adult fin cells. Loss of GFP fluorescence by cultured cells was correlated with cellular differentiation. We consider that the Tg(Tru.oct4:EGFP) zebrafish line established here is well suited for monitoring multipotency in multipotent zebrafish cell cultures and for iPS cell preparation. PMID- 25515247 TI - Differentiation of human CD146-positive endometrial stem cells to adipogenic-, osteogenic-, neural progenitor-, and glial-like cells. AB - The aim of this study was to investigate the potential differentiation of CD146(+) endometrial stem cells to several lineages. Endometrial stromal cells were cultured using Dulbecco's modified Eagle's medium/Hams F-12 (DMEM/F-12) and were passaged every 7-10 d when cultures reached 80-100% of confluency. The immunophenotypes of single endometrial cells were analyzed using flow cytometry at fourth passage. Then the CD146(+) cells were sorted using magnetic-activated cell sorting, and they were cultured and analyzed for in vitro differentiation to several lineages. Detection of adipocyte- and osteocyte-like cells were assessed by oil red O and alizarin red staining, respectively. For detection of neural progenitor and oligodendrocyte-like cells, the cells were immunostained by neurofilament 68 and oligo2, respectively. The rates of CD90, CD105, CD146, CD31, CD34, and CD9 of cultured endometrial cells were 94.98 +/- 3%, 95.77 +/- 2.5%, 27.61 +/- 2%, 0.79 +/- 0.05%, 1.43 +/- 0.1%, and 1.01 +/- 0.06%, respectively. CD146(+) cells were isolated to high purity. CD146(+)-differentiated cells to adipogenic cell with typical lipid-rich vacuoles and osteogenic cells were observed and confirmed their mesenchymal origin. They also differentiated into neural progenitor and glial differentiation by retinoic acid, basic fibroblast growth factor, and epidermal growth factor signaling molecules, respectively, and confirmed by neurofilament 68 and oligo2 immunocytochemistry. The efficiency of differentiation to neural progenitor and oligodendrocyte-like cells was 90 +/- 3.4% and 79 +/- 2.8%, respectively. This study showed that CD146(+) cells from human endometrium after in vitro cultivation can differentiate into adipogenic-, osteogenic-, neural progenitor-, and glial-like cells. They may provide available alternative source of stem cells for future cell-based therapies and tissue engineering applications. PMID- 25515248 TI - Chondroprotective potential of Phyllanthus amarus Schum. & Thonn. in experimentally induced cartilage degradation in the explants culture model. AB - Phyllanthus amarus Schum. & Thonn. (P. amarus) has been reported to exhibit anti inflammation and antiarthritis properties leading to our interest to examine its beneficial effect in osteoarthritis. Thus, this study aimed to explore the chondroprotective potential of P. amarus extract (PAE) and its major compounds, phyllanthin and hypophyllanthin, in a cartilage explant model. Various concentrations of P. amarus extract, phyllanthin and hypophyllanthin, were treated on porcine articular cartilage explants induced with 25 ng/ml of interleukin-1 beta (IL-1beta). After 4 days of incubation, the culture medium was measured for the release of sulfate glycosaminoglycans (s-GAGs) and matrix metalloproteinase-2 (MMP-2) activity by DMMB binding assay and zymography, respectively. The explant tissues were analyzed for the remaining of uronic acid content by colorimetric assay and stained with safranin-O for investigation of proteoglycan content. Cell viability of this model was evaluated by lactate dehydrogenase (LDH) assay. Chondroprotective potential of PAE and the major components against IL-1beta-induced cartilage explant degradation were revealed by the decreased s-GAGs level and MMP-2 activity in culture medium consistent with an increase in uronic acid and proteoglycan contents in the explants when compared to the IL-1beta treatment. These results agreed with those of diacerein and sesamin which used as positive controls. In addition, better chondroprotective activities of P. amarus crude extracts than those of the purified components were disclosed in this study. Hence, this is a pioneering study presenting the chondroprotective potential of PAE which may augment its application for therapeutic use as an antiarthritic agent. PMID- 25515249 TI - Retinoic acid promotes primary fetal alveolar epithelial type II cell proliferation and differentiation to alveolar epithelial type I cells. AB - Retinoic acid (RA) plays an important role in lung development and maturation. Many stimuli can induce alveolar epithelial cell damage which will result in the injury of lung parenchyma. The aim of this study was to observe the effect of RA on the proliferation and differentiation of primary fetal alveolar epithelial type II cells (fAECIIs). Primary fAECIIs were isolated from fetal rats at 19 d of gestation and purified by a differential centrifugation and adhesion method. The cells were randomly divided into control (dimethyl sulfoxide, DMSO) and RA groups. Cell proliferation, viability, apoptosis, cycle, and expression of target protein were examined at 24, 48, and 72 h. We found that the proliferation and viability of cells in the RA-exposed group significantly increased compared with the DMSO control group. The proportion (%) of cells in the G2 and S phases in the RA group was significantly higher than that in control group cells. The proportion (%) of both early apoptotic cells and late apoptotic cells decreased significantly in cells exposed to RA compared with cells exposed to DMSO. RA significantly enhanced the expression of aquaporin 5 (AQP5). The expression level of pulmonary surfactant C (SPC) was elevated after cells were exposed to RA for 24 and 72 h but was inhibited when cells were exposed to RA for 48 h. These results suggest that RA promotes fAECII proliferation by improving cell viability, promoting S phase entry and inhibiting apoptosis and RA promotes fAECIIs differentiation to alveolar epithelial type I cells (AECIs). PMID- 25515250 TI - Aquaporin 3 promotes prostate cancer cell motility and invasion via extracellular signal-regulated kinase 1/2-mediated matrix metalloproteinase-3 secretion. AB - Aquaporins (AQPs) are known to be important in cancer progression. The present study used a cDNA microarray to demonstrate that AQP3, a member of the AQP family, was overexpressed in prostate cancer cells. In order to determine the role of AQP3 in prostate cancer, AQP3 expression was silenced by transfection with small interfering RNA, following which wound healing and invasion assays were conducted in DU-145 and PC-3 cells. Notably, the results showed that silencing of AQP3 suppressed prostate cancer cell motility and invasion. The possible mechanisms underlying the AQP3-enhanced motility and invasion of prostate cancer cells was also investigated. Knockdown of AQP3 expression was shown to reduce extracellular signal-regulated kinase 1/2 (ERK1/2) activation in DU-145 and PC-3 cells. Blocking the ERK pathway inhibited AQP3-mediated motility and invasion of these cells. Finally, the results demonstrated that AQP3 upregulated matrix metalloproteinase-3 (MMP-3) expression and secretion in prostate cancer cells via activation of the ERK pathway. In conclusion, the present study suggests that AQP3 induces ERK1/2 activation, thereby increasing MMP-3 expression and secretion, which in turn promotes prostate cancer cell motility and invasion. Thus, AQP3 may be considered to be a potential therapeutic target for prostate cancer. PMID- 25515251 TI - Structural and luminescence studies of the new nitridomagnesoaluminate CaMg2AlN3. AB - CaMg(2)AlN(3) was synthesized in a closed system by solid state reaction from binary nitrides. Structure refinements based on powder X-ray diffraction data suggested ambiguity about the occupancy of magnesium and aluminum tetrahedral sites. Solid-state (27)Al and (25)Mg NMR studies were used to adjudicate amongst possible space groups. With reference to projector augmented wave calculations of the quadrupolar coupling constants, the measured values of CQ and the numbers of crystallographically inequivalent Al and Mg sites indicate that CaMg(2)AlN(3) crystallizes in the space group P6(3)/mmc with partial occupancy of the distorted tetrahedral Al site and possibly also mixing of Mg(2+) and Al(3+) ions on opposite sites. The compound obtained by synthesis with a flux shows orange defect-related luminescence at room temperature. PMID- 25515260 TI - Editorial. PMID- 25515252 TI - The evolution of Jen3 proteins and their role in dicarboxylic acid transport in Yarrowia. AB - Jen proteins in yeast are involved in the uptake of mono/dicarboxylic acids. The Jen1 subfamily transports lactate and pyruvate, while the Jen2 subfamily transports fumarate, malate, and succinate. Yarrowia lipolytica has six JEN genes: YALI0B19470g, YALI0C15488g, YALI0C21406g, YALI0D20108g, YALI0D24607g, and YALI0E32901g. Through phylogenetic analyses, we found that these genes represent a new subfamily, Jen3 and that these three Jen subfamilies derivate from three putative ancestral genes. Reverse transcription-PCR. revealed that only four YLJEN genes are expressed and they are upregulated in the presence of lactate, pyruvate, fumarate, malate, and/or succinate, suggesting that they are able to transport these substrates. Analysis of deletion mutant strains revealed that Jen3 subfamily proteins transport fumarate, malate, and succinate. We found evidence that YALI0C15488 encodes the main transporter because its deletion was sufficient to strongly reduce or suppress growth in media containing fumarate, malate, or succinate. It appears that the other YLJEN genes play a minor role, with the exception of YALI0E32901g, which is important for malate uptake. However, the overexpression of each YLJEN gene in the sextuple-deletion mutant strain DeltaYLjen1-6 revealed that all six genes are functional and have evolved to transport different substrates with varying degrees of efficacy. In addition, we found that YALI0E32901p transported succinate more efficiently in the presence of lactate or fumarate. PMID- 25515261 TI - Introduction: the plurality of modeling. AB - Philosophers of science have recently focused on the scientific activity of modeling phenomena, and explicated several of its properties, as well as the activities embedded into it. A first approach to modeling has been elaborated in terms of representing a target system: yet other epistemic functions, such as producing data or detecting phenomena, are at least as relevant. Additional useful distinctions have emerged, such as the one between phenomenological and mechanistic models. In biological sciences, besides mathematical models, models now come in three forms: in vivo, in vitro and in silico. Each has been investigated separately, and many specific problems they raised have been laid out. Another relevant distinction is disciplinary: do models differ in significant ways according to the discipline involved-medicine or biology, evolutionary biology or earth science? Focusing on either this threefold distinction or the disciplinary boundaries reveals that they might not be sufficient from a philosophical perspective. On the contrary, focusing on the interaction between these various kinds of models, some interesting forms of explanation come to the fore, as is exemplified by the papers included in this issue. On the other hand, a focus on the use of models, rather than on their content, shows that the distinction between biological and medical models is theoretically sound. PMID- 25515262 TI - What good are abstract and what-if models? Lessons from the Gaia hypothesis. AB - This article on the epistemology of computational models stems from an analysis of the Gaia hypothesis (GH). It begins with James Kirchner's criticisms of the central computational model of GH: Daisyworld. Among other things, the model has been criticized for being too abstract, describing fictional entities (fictive daisies on an imaginary planet) and trying to answer counterfactual (what-if) questions (how would a planet look like if life had no influence on it?). For these reasons the model has been considered not testable and therefore not legitimate in science, and in any case not very interesting since it explores non actual issues. This criticism implicitly assumes that science should only be involved in the making of models that are "actual" (by opposition to what-if) and "specific" (by opposition to abstract). I challenge both of these criticisms in this article. First by showing that although the testability-understood as the comparison of model output with empirical data-is an important procedure for explanatory models, there are plenty of models that are not testable. The fact that these are not testable (in this restricted sense) has nothing to do with their being "abstract" or "what-if" but with their being predictive models. Secondly, I argue that "abstract" and "what-if" models aim at (respectable) epistemic purposes distinct from those pursued by "actual and specific models". Abstract models are used to propose how-possibly explanation or to pursue theorizing. What-if models are used to attribute causal or explanatory power to a variable of interest. The fact that they aim at different epistemic goals entails that it may not be accurate to consider the choice between different kinds of model as a "strategy". PMID- 25515263 TI - Model organisms in evo-devo: promises and pitfalls of the comparative approach. AB - Evolutionary developmental biology (evo-devo) is a rapidly growing discipline whose ambition is to address questions that are of relevance to both evolutionary biology and developmental biology. This field has been increasingly progressing as a new and independent comparative science. However, we argue that evo-devo's comparative approach is challenged by several metaphysical, methodological and socio-disciplinary issues related to the foundation of heuristic functions of model organisms and the possible criteria to be adopted for their selection. In addition, new tools have to be developed to deal with newly chosen model organisms. Therefore, we present a modelling framework suitable to integrate data on individual variation into evo-devo studies on new model organisms and thus to compensate for current idealization practices deliberately suppressing variation. PMID- 25515264 TI - Mapping an expanding territory: computer simulations in evolutionary biology. AB - The pervasive use of computer simulations in the sciences brings novel epistemological issues discussed in the philosophy of science literature since about a decade. Evolutionary biology strongly relies on such simulations, and in relation to it there exists a research program (Artificial Life) that mainly studies simulations themselves. This paper addresses the specificity of computer simulations in evolutionary biology, in the context (described in Sect. 1) of a set of questions about their scope as explanations, the nature of validation processes and the relation between simulations and true experiments or mathematical models. After making distinctions, especially between a weak use where simulations test hypotheses about the world, and a strong use where they allow one to explore sets of evolutionary dynamics not necessarily extant in our world, I argue in Sect. 2 that (weak) simulations are likely to represent in virtue of the fact that they instantiate specific features of causal processes that may be isomorphic to features of some causal processes in the world, though the latter are always intertwined with a myriad of different processes and hence unlikely to be directly manipulated and studied. I therefore argue that these simulations are merely able to provide candidate explanations for real patterns. Section 3 ends up by placing strong and weak simulations in Levins' triangle, that conceives of simulations as devices trying to fulfil one or two among three incompatible epistemic values (precision, realism, genericity). PMID- 25515265 TI - The role of models in the process of epistemic integration: the case of the Reichardt motion detector. AB - Recent work on epistemic integration in the life sciences has emphasized the importance of integration in thinking about explanatory practice in science, particularly for articulating a robust alternative to reductionism and anti reductionism. This paper analyzes the role of models in balancing the relative contributions of lower- and higher-level epistemic resources involved in this process. Integration between multiple disciplines proceeds by constructing a problem agenda (Love, Philos Sci 75(5): 874-886, 2008), a set of interrelated problems that structures the problem space of a complex phenomenon that is investigated by many disciplines. The usage of models, it is argued, mark changes in a phenomenon's problem agenda depending on the task that is expected of it. Particularly, it emphasizes the sensitivity of a problem agenda to changing attitudes in the solutions to the conceptual and empirical items constituting that agenda. The analysis will proceed by means of a case study, the Reichardt motion detector, a model that has been vital to the methodological and conceptual development of research on motion detection, especially in invertebrates. As will be seen, the history of the Reichardt model will exemplify the dynamic changes that occur in the interdisciplinary negotiations that comprise the active efforts of various sciences working to integrate their resources. PMID- 25515266 TI - From replica to instruments: animal models in biomedical research. AB - The ways in which other animal species can be informative about human biology are not exhausted by the traditional picture of the animal model. In this paper, I propose to distinguish two roles which laboratory organisms can have in biomedical research. In the more traditional case, organisms act as surrogates for human beings, and as such are expected to be more manageable replicas of humans. However, animal models can inform us about human biology in a much less straightforward way, by being used as measuring devices-what I call their instrumental role. I first characterize this role and provide criteria for it, before illustrating it with some examples from biomedical research, especially cancer research. In such an instrumental role, phenotypes are not expected to phenocopy human phenomena, but instead have the purely instrumental value of detecting or measuring differences. I argue that the instrumental role is more prevalent than might first be suspected, and that some characteristics of contemporary biomedical research are increasingly shifting the use of laboratory organisms to the instrumental role. Finally, in light of the distinction proposed, I discuss the meaning of the expression "animal model". PMID- 25515267 TI - Wechsler Adult Intelligence Scale-III profile in the early stages of Alzheimer's disease: performance in subtests sensitive to and resistant to normal decline with ageing. AB - AIM: This study examined the significance of age-related subtest scores from the Japanese version of the Wechsler Adult Intelligence Scale-III in patients in the early stages of Alzheimer's disease (AD). METHODS: The subjects of this study included 58 elderly Japanese persons classified into two groups: AD group (n = 29) and control group (n = 29). These groups did not differ in age, years of education, gender ratio, Hasegawa's Dementia Scale-Revised score, or Full-Scale IQ score. No subject scored below the cut-off point on Hasegawa's Dementia Scale Revised, a frequently used dementia screen test in Japan. RESULTS: At the index score level, General Ability Index scores were the only scores that differed significantly between the groups, with the AD group scoring significantly lower than the control group (P < 0.05, Hedges' g = 0.54). At the subtest level, information scores were the only scores that differed significantly between the groups, with the AD group significantly lower than the control group (P < 0.01, Hedges' g = 0.74). CONCLUSION: The General Ability Index is a composite score that deducts components of working memory and processing speed, which are sensitive to decline with normal ageing, from the Full-Scale IQ. It also served as a subtest measuring crystallized intelligence, especially of acquired knowledge of general and factual information. Therefore, the results of this study seem to suggest that Wechsler Adult Intelligence Scale-III profile of very early AD may be characterized by weak performance on subtests normally resistant to decline with ageing. PMID- 25515268 TI - Prevalence, patterns, associated factors and severity of substance use among psychotic patients in southern Thailand. AB - Co-occurring substance use in psychotic patients causes many subsequences including increased illness severity, decreased medication compliance, higher relapse rates, more hospitalizations, and legal problems. We aim to investigate the prevalence, patterns, associated factors and severity of substance use risk among psychotic patients in southern Thailand. Psychotic out-patients were screened with the Alcohol, Smoking, Substance Involvement Screening Test (ASSIST) for their history of substance use in the past three months and categorized as None-to-Low Risk (NLR) or Moderate-to-High Risk (MHR) levels. Multivariate logistic regression was used to examine the associated factors of substance use risk-level. The associations between substance use risk-level and emotional and behavioural symptoms, functional status and family functional status were examined using multivariate linear regression analysis. Of 663 participants screened, 322 (48.6%) used at least one substance in the past three months. Tobacco was the most common substance used (47.2%). The factors associated with a higher risk of any substance use were male gender, young age group, low level of education, being employed and being diagnosed with schizophrenia. A higher number of emotional and behavioural symptoms was significantly associated with higher substance use risk-level. In conclusion, the prevalence of substance use in psychotic patients was high and associated with their emotional and behavioural symptoms. Recommendations for implementation of screening and early intervention programs of substance-related problems in psychotic patients are important for preventing unwanted outcomes. PMID- 25515269 TI - Cylindroma: an update. AB - This paper reviews the recent literature on cylindroma, a rare tumor originating from the cutaneous adnexal structures of the scalp and face. Benign cylindroma is more frequent in women, and there are solitary and multiple forms, which are autosomal. Malignant cylindroma can occur in the Brooke-Spiegler syndrome, and malignant transformation is more frequent in multiple variants than in solitary tumors. Its histopathological basis is controversial, and its origin is unknown, although it is known that there is a genetic basis for onset of these tumors in Brooke-Spiegler syndrome. PMID- 25515271 TI - Prevalence and quantitative analysis of Epstein-Barr virus DNA and Porphyromonas gingivalis associated with Japanese chronic periodontitis patients. AB - OBJECTIVE: A number of studies have recently suggested Epstein-Barr virus (EBV) involvement in the pathogenesis of periodontitis. In this study, we investigated the association between major periodontopathic bacteria Porphyromonas gingivalis (P. gingivalis) and EBV in Japanese chronic periodontitis (CP) patients. MATERIALS AND METHODS: A group of 25 patients with CP participated in the study along with 13 individuals without periodontitis. Subgingival samples were obtained with paper points. Quantitative real-time polymerase chain reaction (PCR) was used to detect EBV DNA and P. gingivalis. RESULTS: In the CP patients, EBV DNA and P. gingivalis were detected in both 80 % of sites with probing pocket depths (PPD) of >=5 mm and in 40 and 36 % of sites with PPD <=3 mm, respectively. EBV DNA and P. gingivalis were detected in 50 and 27 % of the sites in periodontally healthy individuals. Coexistence of EBV DNA and P. gingivalis was significantly higher in the deeper PPD sites of CP patients (68 %) than in the PPD sites of the healthy controls (15 %) and shallow PPD sites of CP patients (12 %). PCR-positive deeper PPD sites of CP patients for EBV DNA and P. gingivalis range between 3.74 * 10(3)~2.83 * 10(9) and 2.73 * 10(5)~6.65 * 10(9) (copies/ml), respectively. CONCLUSION: These results suggest an association between EBV DNA, P. gingivalis, and CP in Japanese individuals. Further studies are required to clarify this association; however, we believe that our enhanced understanding of the pathogenesis of periodontal diseases involving viral infections will lead to new treatments. PMID- 25515272 TI - Does this pediatric patient meet criteria for a polysomnogram? PMID- 25515270 TI - In Vitro Neutrophil Migration Requires Protein Kinase C-Delta (delta-PKC) Mediated Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) Phosphorylation. AB - Dysregulated release of neutrophil reactive oxygen species and proteolytic enzymes contributes to both acute and chronic inflammatory diseases. Therefore, molecular regulators of these processes are potential targets for new anti inflammatory therapies. We have shown previously that myristoylated alanine-rich C-kinase substrate (MARCKS), a well-known actin binding protein and protein kinase C (PKC) substrate, is a key regulator of neutrophil functions. In the current study, we investigate the role of PKC-mediated MARCKS phosphorylation in neutrophil migration and adhesion in vitro. We report that treatment of human neutrophils with the delta-PKC inhibitor rottlerin significantly attenuates f-Met Leu-Phe (fMLF)-induced MARCKS phosphorylation (IC50=5.709 MUM), adhesion (IC50=8.4 MUM), and migration (IC50=6.7 MUM), while alpha-, beta-, and zeta-PKC inhibitors had no significant effect. We conclude that delta-PKC-mediated MARCKS phosphorylation is essential for human neutrophil migration and adhesion in vitro. These results implicate delta-PKC-mediated MARCKS phosphorylation as a key step in the inflammatory response of neutrophils. PMID- 25515273 TI - Asthma, allergic rhinitis, and sleep problems in urban children. AB - OBJECTIVES: In this study, we examine the association of asthma (asthma symptoms, asthma control, lung function) and sleep problems in a group of urban children. The role of allergic rhinitis (AR), a comorbid condition of asthma, on children's sleep problems is also examined. Finally, we investigate whether sleep hygiene moderates the association between asthma and sleep problems, and whether there are differences in these associations based on ethnic background. METHODS: Non Latino White, Latino, and African American urban children with asthma (n = 195) ages 7-9 (47% female) and their primary caregivers participated in a baseline visit involving interview-based questionnaires on demographics, asthma and rhinitis control, and caregiver report of children's sleep problems and sleep hygiene. Children and their caregivers participated in a clinical evaluation of asthma and AR, followed by a month monitoring period of children's asthma using objective and subjective methods. RESULTS: Total sleep problem scores were higher in children of the sample who were from African American and Latino backgrounds, compared to non-Latino white children. Poor asthma control was predictive of higher levels of sleep problems in the entire sample. Poorer AR control also was related to more sleep problems, over and above children's asthma in the sample. This association was more robust in non-Latino white children. Poor sleep hygiene heightened the association between poor asthma control and sleep problems in the entire sample and in African American children. CONCLUSIONS: Multidisciplinary interventions integrating the co-management of asthma, AR, and the effects of both illnesses on children's sleep, need to be developed and tailored to children and their families' ethnic background. PMID- 25515274 TI - Sleep disturbances among medical students: a global perspective. AB - Medical students carry a large academic load which could potentially contribute to poor sleep quality above and beyond that already experienced by modern society. In this global literature review of the medical students' sleep experience, we find that poor sleep is not only common among medical students, but its prevalence is also higher than in non-medical students and the general population. Several factors including medical students' attitudes, knowledge of sleep, and academic demands have been identified as causative factors, but other potential mechanisms are incompletely understood. A better understanding about the etiology of sleep problems in medical trainees is essential if we hope to improve the overall quality of medical students' lives, including their academic performance. Sleep self-awareness and general knowledge appear insufficient in many studied cohorts, so increasing education for students might be one beneficial intervention. We conclude that there is ample evidence for a high prevalence of the problem, and research in this area should now expand towards initiatives to improve general sleep education for medical students, identify students at risk, and target them with programs to improve sleep. PMID- 25515275 TI - Poor sleep quality is independently associated with physical disability in older adults. AB - STUDY OBJECTIVE: We aimed to evaluate the association between sleep quality and physical disability in community-dwelling older adults. METHODS: There were 213 community-dwelling adults (76 men and 137 women) aged 65 years and above participated into this investigation. The Groningen Activity Restriction Scale and the Pittsburgh Sleep Quality Index were utilized to evaluate physical disability and subjective sleep quality, respectively. Global functional capacity was measured by the 6-minute walk test (6MWT). The Mini Mental State Examination and the Chinese Geriatric Depression Screening Scale were used to evaluate cognitive function and depression. RESULTS: Univariate analysis revealed a correlation between physical disability and poor sleep quality, older age, 2 or more comorbidities, depression, functional capacity, and poor cognitive function. However, in the multivariate analyses, depression failed to show significant association with physical disability. In contrast, an independent association was observed between poor sleep quality and physical disability (OR = 2.03; 95% CI: 1.02-4.05). CONCLUSIONS: In community-dwelling older adults, subjective poor sleep was significantly associated with physical disability, even after controlling for the effects of other established risk factors. PMID- 25515276 TI - Sleep position trainer versus tennis ball technique in positional obstructive sleep apnea syndrome. AB - STUDY OBJECTIVE: Positional therapy (PT) is an effective therapy in positional obstructive sleep apnea syndrome (POSAS) when used, but the compliance of PT is low. The objective of this study was to investigate whether a new kind of PT is effective and can improve compliance. METHODS: 29 patients were treated with the Sleep Position Trainer (SPT), 26 patients with the Tennis Ball Technique (TBT). At baseline and 1 month polysomnography, Epworth Sleepiness Scale (ESS) and the Quebec Sleep Questionnaire (QSQ) were taken. Daily compliance was objectively measured in both groups. RESULTS: Both therapies prevent supine sleep position to a median of 0% (min-max: SPT 0.0% to 67%, TBT 0.0% to 38.9%), resulting in a treatment success (AHI <5) in 68.0% of the SPT and 42.9% of the TBT patients. The ESS at baseline was <10 in both groups. Sleep quality parameters as wake after sleep onset (WASO; p = 0.001) and awakenings (p = 0.006) improved more in the SPT group. Total QSQ scores (0.4+/-0.2, p = 0.03) and the QSQ domains nocturnal symptoms (0.7+/-0.2, p = 0.01) and social interactions (0.8+/-0.3, p = 0.02) changed in favor of the SPT group. Effective compliance (>=4 h/night + >=5 days/week) was 75.9% for the SPT and 42.3% for the TBT users (p = 0.01). CONCLUSION: In mild POSAS with normal EES the new SPT device and the standard TBT are equally effective in reducing respiratory indices. However, compared to the TBT, sleep quality, quality of life, and compliance improved significantly more in the SPT group. PMID- 25515277 TI - Academic performance among adolescents with behaviorally induced insufficient sleep syndrome. AB - STUDY OBJECTIVES: The present study investigated academic performance among adolescents with behaviorally induced insufficient sleep syndrome (BISS) and attempted to identify independent predictors of academic performance among BISS related factors. METHODS: A total of 51 students with BISS and 50 without BISS were recruited from high schools in South Korea based on self-reported weekday sleep durations, weekend oversleep, and the Epworth Sleepiness Scale (ESS). Participants reported their academic performance in the form of class quartile ranking. The Korean version of the Composite Scale (KtCS) for morningness/eveningness, the Beck Depression Inventory (BDI) for depression, and the Barratt Impulsiveness Scale-II (BIS-II) for impulsivity were administered. RESULTS: Adolescents with BISS reported poorer academic performance than adolescents without BISS (p = 0.02). Adolescents with BISS also exhibited greater levels of eveningness (p < 0.001), depressive symptoms (p < 0.001), and impulsiveness (p < 0.01). Longer weekend oversleep predicted poorer academic performance among adolescents with BISS even after controlling for ESS, KtCS, BDI, and BIS-II (beta = 0.42, p < 0.01). CONCLUSIONS: BISS among adolescents is associated with poor academic performance and that sleep debt, as represented by weekend oversleep, predicts poorer academic performance independent of depression, impulsiveness, weekday sleep duration, daytime sleepiness, and morningness/eveningness among adolescents with BISS. PMID- 25515278 TI - Sleep pattern in Charcot-Marie-Tooth disease type 2: report of family case series. AB - OBJECTIVES: Charcot-Marie-Tooth (CMT) disease is the most prevalent hereditary motor and sensory polyneuropathy, and a condition in which sleep has rarely been studied, particularly in relation to the type 2 (CMT2). Thus, we aimed to characterize the sleep patterns of a family affected by CMT2 disease. METHODS: Sixteen volunteers with CMT2 from the same multigenerational family agreed to participate in the study (refusal rate = 31%). All participants answered sleep questionnaires and came to the sleep laboratory to perform a diagnostic polysomnography (PSG). Clinical manifestation and severity of the disease were also evaluated. RESULTS: 56% of the sample were male and 44% female, with a mean age of 32 +/- 17 years, of normal weight (body mass index 21 +/- 3 kg/m(2)); 64% presented moderate to severe CMT2. Regarding subjective sleep, 31% had excessive daytime sleepiness and 75% reported poor sleep quality. The PSG results revealed that CMT2 patients had an increase in stage N3 and a reduction in REM sleep, in addition to a high arousal index. Although 81% of the sample were snorers, only 13% had an apnea-hypopnea index (AHI) > 5. However, a positive correlation was found between the severity of disease and the AHI. CONCLUSIONS: Taken together, these data show that CMT2 disease is characterized by important changes in sleep architecture, probably due to sleep fragmentation. Although these alterations may worsen with disease severity, it seems that they are not related to sleep breathing or movement disorders. PMID- 25515279 TI - Shorter Mandibular Length is Associated with a Greater Fall in AHI with Weight Loss. AB - RATIONALE: Obesity is a major risk factor towards the development of obstructive sleep apnea, while significant weight loss (both conservatively managed and surgically assisted) has a variable effect upon its severity. Differences in the effect of weight loss on obstructive sleep apnea may be due to underlying craniofacial characteristics. OBJECTIVES: To determine whether craniofacial characteristics can predict OSA treatment response to significant weight loss. METHODS: We analyzed craniofacial measurements from lateral cephalograms performed at baseline on 57 patients enrolled in a previously reported 2-year randomized clinical weight loss trial (laparoscopic adjustable gastric band surgery versus conservatively [dietician and very low calorie diet] treated). Group mean weight loss was ~ 13% (mean weight loss 131 to 114 kg), with corresponding reduction in mean apnea-hypopnea index (AHI) from 61 to 41 events/h. Computer assisted lateral cephalogram analysis was undertaken by three trained staff blinded to treatment. We analyzed lateral cephalogram and demographic data at baseline (cross-sectional) and change over two years (interventional) in 54 patients. MEASUREMENTS AND MAIN RESULTS: Baseline cross sectional analysis indicated no cephalometric measurement correlated significantly with baseline AHI when corrected for neck circumference. The percentage change in AHI over 2 years correlated with a shorter menton-gonion distance (i.e., mandibular body length). The % change in AHI correlated with the % weight change (R(2) = 0.25, p < 0.001) and mandibular body length (R(2) = 0.19, p = 0.002). The % change in AHI correlated with combined weight change and mandibular body length (combined R(2) = 0.31, p < 0.001). CONCLUSIONS: Weight loss as a therapeutic option for severe OSA with severe obesity may be predicted by shorter mandibular body length as measured by lateral cephalometry. PMID- 25515280 TI - Sleep patterns, sleep instability, and health related quality of life in parents of ventilator-assisted children. AB - STUDY OBJECTIVES: Parents of children with chronic illnesses have poorer health related quality of life (HRQoL), shorter sleep duration, and poorer sleep quality than parents of healthy children. However, night-to-night variability of sleep in parents has not previously been considered. This study compared the sleep patterns of parents of ventilator-assisted children (VENT) and healthy, typically developing children (HEALTHY), and examined the relationship between sleep variability and perceived HRQoL. METHODS: Seventy-nine mothers and 33 fathers from 42 VENT families (n = 56) and 40 HEALTHY (n = 56) families completed the SF 36 and wore an actigraph for 2 weeks. Reported bedtime and wake time, along with actigraphic total sleep time (TST), wake after sleep onset (WASO), and sleep efficiency (SE) were examined using both average values and night-tonight instability (mean square successive differences). RESULTS: VENT parents showed significantly later bedtimes, shorter TST, longer WASO, and lower SE than HEALTHY parents. VENT parents also exhibited greater instability in their reported wake time, WASO, and SE. Adjusting for family type and gender, greater instability of wake times, WASO and SE were related to poorer SF-36 subscale scores, while averaged sleep values were not. CONCLUSIONS: Many parents of ventilator-assisted children experience deficient sleep and show significant instability in their sleep, which was related to HRQoL. Similar to shift workers, variable sleep schedules that may result from caregiving responsibilities or stress may impact parental caregivers' health and well-being. Additional studies are needed to determine how support and other interventions can reduce sleep disruptions in parental caregivers. PMID- 25515281 TI - Obstructive sleep apnea pretreatment and posttreatment in symptomatic children with congenital craniofacial malformations. AB - STUDY OBJECTIVES: Obstructive sleep symptoms are common in children with craniofacial malformations (CFM). However objective data about obstructive sleep apnea (OSA) is still limited. The aims of this study were to investigate the frequency of OSA in symptomatic children with CFM and to determine improvement in severity of OSA after treatment. METHODS: Symptomatic children with CFM referred for a diagnostic polysomnogram (PSG) were identified. Obstructive sleep apnea was defined as an apnea/hypopnea index (AHI) >= 1, with moderate/severe OSA as an AHI >= 5. RESULTS: Overall, 151 symptomatic children were identified; 87% were diagnosed with OSA, of whom 24% had moderate-to-severe OSA. Children with syndromic CFM, compared to non-syndromic CFM, were more likely to have an AHI >= 5 (syndromic 33% vs. non-syndromic 15%, p = 0.02). Of the 131 children with OSA, 64 were treated and 32 returned for a posttreatment PSG, with 22 treated with either positive airway pressure (PAP) or adenotonsillectomy (AT). Children treated with PAP demonstrated a decrease in AHI from 6.2 to 3.5 (p = 0.057) and an increase in SpO2 from 89.1% to 91.1% (p = 0.091). There were no significant improvements for those in the AT group for either AHI (2.5 to 1.8, p = 0.19) or SpO2 (90.4% to 91.3%, p = 0.46). Normalization of the AHI (AHI < 1) occurred in only one child in each group (7% and 14% of the PAP and AT groups, respectively). CONCLUSIONS: The vast majority of children with CFM referred for OSA evaluation are found to have objective evidence of OSA and a quarter of children have moderate-to-severe OSA. It is likely that many children with underlying OSA are not identified and referred for evaluation. Residual OSA after treatment is common in children with CFM. PMID- 25515282 TI - Sleep disorders in adult sickle cell patients. AB - STUDY OBJECTIVES: While sleep apnea has been studied in children with sickle cell disease (SCD), little is known about sleep disorders in adult sickle cell patients. The objective of this study was to evaluate sleep disordered breathing and its polysomnographic characteristics in adult patients with sickle cell disease. METHODS: The analysis cohort included 32 consecutive adult SCD patients who underwent a comprehensive sleep evaluation and overnight polysomnography in an accredited sleep center after reporting symptoms suggesting disordered sleep or an Epworth Sleepiness Scale score >= 10. Epworth score, sleep parameters, comorbid conditions, and narcotic use were reviewed and compared in patients with and without sleep disordered breathing. SCD complication rates in the two groups also were compared. RESULTS: In adult SCD patients who underwent overnight polysomnography, we report a high prevalence (44%) of sleep disordered breathing. Disease severity was mild to moderate (mean apnea-hypopnea index = 17/h (95% CI: 10-24/h). Concomitant sleep disorders, including insomnia complaints (57%) and delayed sleep-phase syndrome (57%), also were common in this population. In this limited cohort, we did not find increased SCD complications associated with sleep disordered breathing in adult patients with sickle cell disease. CONCLUSIONS: A high burden of sleep disordered breathing and other sleep-related complaints were identified in the adult sickle cell population. Our results provide important information on this unique population. PMID- 25515284 TI - Trichotillomania and non-epileptic seizures as sleep-related dissociative phenomena. AB - ABSTRACT: The occurrence of non-epileptic seizures (NES) and trichotillomania during sleep is rare. We describe the case of an adult woman with a personal history of childhood maltreatment and psychiatric morbidity (major depression, trichotillomania, and conversion disorder), who was referred to the sleep unit because of nocturnal hair-pulling and psychomotor agitation during sleep. An all night PSG recording with audiovisual monitoring documented seven episodes of trichotillomania and one NES, all of which arose from unequivocal wakefulness. Improvement of nocturnal behaviors was observed after long-term psychotherapy. This case illustrates that nocturnal trichotillomania and NES may be symptoms of a sleep-related dissociative disorder. PMID- 25515283 TI - Postoperative CPAP use impacts long-term weight loss following bariatric surgery. AB - INTRODUCTION: Obstructive sleep apnea (OSA) is common among bariatric surgery candidates. After surgical weight loss, OSA frequently persists and untreated OSA can lead to weight gain. Long-term continuous positive airway pressure (CPAP) adherence is unclear and poor adherence may worsen weight loss outcomes. We sought to determine the impact of CPAP use on long-term weight-loss outcomes in a cohort of bariatric patients. METHODS: Long-term observational study of bariatric surgery patients with OSA. Patients were evaluated with polysomnography preoperatively and one-year postoperatively. The cohort was again evaluated a mean of 7.2 years later to determine the relationship between long-term CPAP use and subsequent regain of weight. RESULTS: Twenty-four consecutive patients (aged 48.5 +/- 9.4 years at time of surgery; 73% female) were included in the initial assessment, and long-term outcome data were available on 22 subjects. Persistent OSA was documented in 21 of 22 subjects (95%) one year postoperatively. Final evaluation occurred 7.2 +/- 2.3 years following surgery. Weight (213.3 +/- 39.1 to 235.3 +/- 47.1 lb, p = 0.10) and BMI (32.5 +/- 5.4 to 37.3 +/- 8.2 kg/m(2), p = 0.03) increased in most (n = 19, 86.4%) from postoperative to final evaluation. CPAP use declined from 83.3% (preoperatively) to 38.1% (one year) and to 23.8% (final evaluation). BMI increased among those not using CPAP at long-term follow up compared to those with continued CPAP use (6.8% v -1.8%, p = 0.05). CONCLUSIONS: In our cohort of bariatric patients with OSA, long-term adherence to CPAP therapy was poor, and non-adherence was associated with weight gain. Ongoing follow-up of OSA in this population may help to preserve initial achievements after surgical weight loss. PMID- 25515285 TI - A 42-year-old female with well-controlled atrial fibrillation and mild obstructive sleep apnea. PMID- 25515286 TI - A 14-year-old girl with excessive daytime sleepiness and facial twitching. PMID- 25515287 TI - The ICSD-3 NREM parasomnia section is evidence based resulting from international collaboration, consensus and best practices. PMID- 25515288 TI - In memoriam: Dr. William C. Kohler. PMID- 25515289 TI - Treating nightmares--sleep medicine and posttraumatic stress disorder. PMID- 25515290 TI - Thanks to Dr. Quan and the next chapter for JCSM. PMID- 25515291 TI - Sleep duration: a consensus conference. PMID- 25515292 TI - Correlation of esophageal pressure-flow analysis findings with bolus transit patterns on videofluoroscopy. AB - Pressure-flow analysis quantifies the interactions between bolus transport and pressure generation. We undertook a pilot study to assess the interrelationships between pressure-flow metrics and fluoroscopically determined bolus clearance and bolus transport across the esophagogastric junction (EGJ). We hypothesized that findings of abnormal pressure-flow metrics would correlate with impaired bolus clearance and reduced flow across the EGJ. Videofluoroscopic images, impedance, and pressure were recorded simultaneously in nine patients with dysphagia (62-82 years, seven male) tested with liquid barium boluses. A 3.6 mm diameter solid state catheter with 25 * 1 cm pressure/12 * 2 cm impedance was utilized. Swallowed bolus clearance was assessed using a validated 7-point radiological bolus transport scale. The cumulative period of bolus flow across the EGJ was also fluoroscopically measured (EGJ flow time). Pressure only parameters included the length of breaks in the 20 mmHg iso-contour and the 4 second integrated EGJ relaxation pressure (IRP4s). Pressure-flow metrics were calculated for the distal esophagus, these were: time from nadir impedance to peak pressure (TNadImp to PeakP) to quantify bolus flow timing; pressure flow index (PFI) to integrate bolus pressurization and flow timing; and impedance ratio (IR) to assess bolus clearance. When compared with controls, patients had longer peristaltic breaks, higher IRs, and higher residual EGJ relaxation pressures (break length of 8 [2, 13] vs. 2 [0, 2] cm, P = 0.027; IR 0.5 +/- 0.1 vs. 0.3 +/- 0.0, P = 0.019; IRP4s 11 +/- 2 vs. 6 +/- 1 mmHg, P = 0.070). There was a significant positive correlation between higher bolus transport scores and longer peristaltic breaks (Spearman correlation r = 0.895, P < 0.001) and with higher IRs (r = 0.661, P < 0.05). Diminished EGJ flow times correlated with a shorter TNadImp to PeakP (r = 0.733, P < 0.05) and a higher IR (r = -0.750, P < 0.05). Longer peristaltic breaks and higher IR correlate with failed bolus clearance on videofluoroscopy. The metric TNadImp to PeakP appears to be a marker of the period of time over which the bolus flows across the EGJ. PMID- 25515293 TI - HOX-7 suppresses body weight gain and adipogenesis-related gene expression in high-fat-diet-induced obese mice. AB - BACKGROUND: HOX-7 is a newly developed dietary formula composed of traditional oriental herbal medicines. The formula was developed with the aim of improving weight control. We investigated the anti-obesity effect of HOX-7 on high-fat-diet (HFD)-induced obesity in C57BL/6 mice. METHODS: The mice were divided into four groups and were fed a normal diet (ND), HFD, or HFD with oral administration of HOX-7 at 100 or 200 mg/kg/day for 12 weeks. Body and fat weight, histological changes of fat tissue, and the expression of key adipogenic transcription factors were investigated. RESULTS: The body weight of mice fed the HFD with HOX-7 was significantly decreased compared to the HFD group. There were no obvious differences in weekly food intake among the 4 groups. The weight of the epididymal and total fat pads was reduced in mice fed the HFD with HOX-7. Treatment with HOX-7 also substantially attenuated the expression of key adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein alpha, sterol regulatory element binding protein 1c, adipocyte P2, liver X receptor, and lipoprotein lipase in the epididymal adipose tissue. CONCLUSION: Overall, this study highlighted the anti obesity effects of HOX-7, a finding that could contribute to the development of natural anti-obesity herbal medicines. PMID- 25515294 TI - Publication rate of abstracts presented at the Canadian society of otolaryngology head and neck surgery annual meetings: a five year study 2006-2010. AB - BACKGROUND: To determine the rate of publication in a peer-reviewed journal for all oral presentations made at the Canadian Society for Otolaryngology- Head and Neck Surgery's Annual Meetings from 2006-2010. METHODS: All abstracts were searched by keywords and authors' names in Medline via PubMed and Google Scholar. Authors of presented abstracts not found to be published were contacted directly for further information. RESULTS: 50.5% of presented abstracts (n = 198) were subsequently published with an average time to publication of 21 months. For those abstracts found not to be published 74.6% (n = 167) of authors responded with further information about their research, 66% (n = 89) of abstracts with author response that were not published were never submitted for publication. Authors' main reasons for not publishing were that the research was still in process (34%, n = 21) or that a resident or fellow working on the project "had moved on" (26%, n = 16). CONCLUSION: The publication rate for the Canadian Society for Otolaryngology- Head and Neck Surgery's Annual Meetings from 2006 2010 is within the range reported by other conferences and specifically other Canadian conferences in different specialties; however, roughly half of presentations went on to be published. The main barrier to publication was bringing projects to the submission stage and not rejection by journals. Resources such as more time for research or personnel to coordinate projects may result in a greater rate of project completion. PMID- 25515295 TI - Why are there fewer obese children in France than in other Western European countries? PMID- 25515297 TI - X-linked dominant protoporphyria: response to "Cutaneous porphyrias part 1". PMID- 25515298 TI - Methodological and clinical aspects of alloimmunization after granulocyte transfusion in patients undergoing allogeneic stem cell transplantation. AB - In allogeneic hematopoietic stem cell transplantation (HSCT), granulocyte transfusions (GT) may be required in immunocompromised, neutropenic patients. In this context, alloimmunization against alloantigens may occur and affect HSCT outcome. Anti-human leukocyte antigen (HLA) and -MHC class I chain related antigens A (MICA) antibody response after the administration of GT in 29 patients undergoing allogeneic HSCT (n = 27) encompassing 109 sera was investigated by multianalyte microbead assay before and up to 6 month after HSCT. Anti-HLA class I and II antibodies emerged de novo in 11 (38%) and 4 (14%) patients, respectively. Similarly, preformed antibodies were observed in four cases (14%) for anti-HLA class I and also four patients for anti-HLA class II antibodies. Anti-MICA antibodies were observed in eight granulocyte recipients of which three patients developed anti-MICA antibodies after GT, whereas preformed antibodies were seen in five patients. The conversion to positivity for any of the investigated antibodies did not significantly affect overall survival or the incidence of GVHD. GT-associated alloantibody conversion observed did not significantly correlate with outcome. Thus, surveillance of anti-HLA antibodies in the course of GT in the context of HSCT may not be required routinely. The role of MICA antibodies in HSCT and GT, however, requires further study. PMID- 25515299 TI - Use of inhaled and oral corticosteroids in pregnancy and the risk of malformations or miscarriage. AB - Corticosteroids are potent anti-inflammatory and immunosuppressive drugs, which sometimes must be given to pregnant women. Corticosteroids have been suspected to be teratogenic for many years; however, there is conflicting evidence regarding the association. Based on a literature review of three databases, this MiniReview provides an overview of inhaled and oral corticosteroid use in pregnancy with specific emphasis on the association between use of corticosteroids during pregnancy and risk of miscarriage and congenital malformations in offspring. The use of corticosteroids among pregnant women ranged from 0.2% to 10% and increased nearly two times in recent years. Taken together, the evidence suggests that the use of corticosteroids in early pregnancy is not associated with an increased risk of congenital malformations overall or oral clefts in offspring; at the same time, published estimates are inconsistent. The use of inhaled corticosteroids was associated with a slightly increased risk of miscarriage, whereas the use of oral corticosteroids was not; however, confounding by indication could not be ruled out. PMID- 25515300 TI - Whole genome sequencing confirms KIT insertions in a white cat. PMID- 25515296 TI - Cholesterol-cholate-butterfat diet offers multi-organ dysfunction in rats. AB - BACKGROUND: Comparable to commercial expensive high-fat diets, cholesterol cholate-butterfat (CCB) diet has also been used to induce hyperlipidemia in rats. Our objective was to explore its influence on multiple organs. Consequence of fasting was also analysed. METHODS: Rats in groups 1 and 2 received normal diet (ND) whereas groups 3 and 4 received CCB-diet. Food was withdrawn daily for two hours from groups 2 (ND-F) and 4 (CCB-F). Blood was collected at fourth and sixth week for biochemical estimation; Morris water maze was done in the sixth week for learning ability and memory; after which aortae were isolated for vascular reactivity. RESULTS: Apart from hyperlipidemia, CCB also induced hyperglycemia with marked increase in hepatic enzymes: gamma-glutamyl transferase (GGT), alanine and aspartate aminotransferase (ALT and AST); and vascular biomarkers: uric acid (UA), phosphorus and alkaline phosphatase (ALP). Isolated aortae, pre contracted with phenylephrine, were less responsive to acetylcholine indicating endothelial dysfunction--serum nitric oxide (NO) production was limited with subsequent inhibition of endothelial NO synthase. CCB diet also compromised learning ability. CCB-coupled fasting potentiated hyperlipidemia but prevented memory-loss. CONCLUSION: We introduce CCB-diet for multi-organ dysfunction in rats, and propose its use for research on cardiovascular diseases and associated manifestations involving immense interplay of integrated pathways. PMID- 25515301 TI - Technology in the field of molecular ecology continues to advance rapidly. Introduction. PMID- 25515302 TI - The effects of dabigatran on lupus anticoagulant, diluted plasma thrombin time, and other specialized coagulation assays. PMID- 25515303 TI - Bacterial communities in the phylloplane of Prunus species. AB - Bacterial populations in the phylloplane of four different Prunus species were investigated by 16 S rRNA pyrosequencing. Bioinformatic analysis identified an average of 510 operational taxonomic units belonging to 159 genera in 76 families. The two genera, Sphingomonas and Methylobacterium, were dominant in the phylloplane of four Prunus species. Twenty three genera were commonly identified in the four Prunus species, indicating a high level of bacterial diversity dependent on the plant species. Our study based on 16 S rRNA sequencing reveals the complexity of bacterial diversity in the phylloplane of Prunus species in detail. PMID- 25515304 TI - Tooth discolouration and internal bleaching after the use of triple antibiotic paste. AB - AIM: To assess the discolouration of teeth with closed and open apices after placement of triple antibiotic paste (TAP, ciprofloxacin, metronidazole and minocycline) in the pulp chamber and whether discolouration could be reversed by internal bleaching procedures. METHODOLOGY: Twenty extracted human mandibular premolars were divided into 2 groups (n = 10): teeth with closed apices (CA) and teeth with open apices (OA). After conventional access, the TAP was sealed in the pulp chamber for 3 weeks. The paste was removed by a rinse with sodium hypochlorite (NaOCl) and a mixture of sodium perborate and distilled water was sealed in the pulp chamber for 1, 2 and 3 weeks. The shade was measured by a spectrophotometer at six time periods: baseline (T0), after 3 weeks of placement of TAP (T1), after removal of TAP with a NaOCl rinse (T2) and after 1 (T3), 2 (T4) and 3 (T5) weeks of internal bleaching with sodium perborate paste. Data were collected based on the CIELAB-CIE1976 (L*a*b*) system and analysed using t tests and anova. RESULTS: A significant decrease in the mean values of L* (lightness) was observed after treatment with TAP (T1, P < 0.05). Considerable increases in these values after bleaching with sodium perborate (T3 < T4 < T5) were found in both groups. The only significant difference in the intergroup analysis was between T1 and T2, in which DeltaE values in the OA group were higher (P = 0.04). CONCLUSIONS: TAP discoloured the tooth structure, but discolouration could be reversed with sodium perborate paste. In general, teeth with closed and open apices had the same rates of discolouration and bleaching. PMID- 25515305 TI - In-vitro evidence of enhanced breast cancer resistance protein-mediated intestinal urate secretion by uremic toxins in Caco-2 cells. AB - OBJECTIVES: It has been reported that intestinal urate excretion is increased at chronic kidney disease (CKD) state. In this report, whether uremic toxins are involved in the upregulation of intestinal breast cancer resistance protein (BCRP), an intestinal urate exporter, was examined. METHODS: Uremic toxins that were increased at least 15-fold at CKD state were selected for investigation. Caco-2 cells were exposed to these uremic toxins at clinically relevant concentrations. mRNA was quantified by real-time PCR, and flow cytometry was utilized to measure BCRP protein and function in Caco-2 cells. Transcellular secretory transport of [(14) C]urate was determined utilizing Transwell studies after uremic toxin exposure. KEY FINDINGS: Indoxyl sulfate (IS) treatment alone resulted in ~ 3-fold increase in BCRP mRNA in Caco-2 cells. Membrane protein expression of BCRP in Caco-2 cells also was increased by 1.8-fold after treatment with IS. Intracellular accumulation of pheophorbide A, a selective BCRP substrate, was decreased by 22% after IS treatment for 3 days. Consistent with these findings, transcellular secretory transport of urate across Caco-2 cell monolayers was increased by 22%. CONCLUSION: Intestinal urate secretion may be increased at CKD state partially by upregulation of intestinal BCRP by uremic toxins such as IS. PMID- 25515306 TI - Risk Policies in the United States: Definition and Characteristics Based on a Scoping Review of the Literature. AB - The concept of "risk policy" is used with increasing frequency by decisionmakers, researchers, and the media. However, there is no precise, generally accepted definition of what is covered by policies in this area. Based on a scoping review of the literature published in key journals in the sector, we have identified the main characteristics of public risk policies drawn up and implemented in the United States. The sample comprised 21 articles published in six multidisciplinary journals between 2000 and 2010. PMID- 25515307 TI - Olfactory function in elderly people and patients with Alzheimer's disease. AB - BACKGROUND: Olfactory function is an important sensory perception function that helps us detect the smell of spoiled food, dirty clothing, and gas leaks. If ageing and Alzheimer's disease (AD) are accompanied by a decline in olfactory function, this might reduce the ability to sense danger, placing the safety and hygiene of elderly people at risk. METHODS: Subjects in this study included 113 healthy subjects aged 20-89 years and 12 persons with AD aged 62-85 years. The healthy subjects were divided into three groups according to age: young-adult group (20-43 years), middle-adult group (45-69 years), and old-adult group (70-89 years). The Hasegawa Dementia Scale-Revised score of AD subjects ranged from 15 to 26. We developed and implemented an odour identification ability test and a situational judgement test using an odour stick to examine the impact of ageing and AD on olfactory function from the perspective of sensing danger. To examine the impact of mild AD on the olfactory function, we compared the scores between the AD group and the age-matched control group. RESULTS: The scores for the situational judgement and odour identification ability tests were significantly lower in an old-adult group than in the young-adult and middle-adult groups. A significant correlation was found between age and scores for both tests in the control group. The AD group exhibited significantly lower total scores on both tests compared with the age-matched controls. CONCLUSIONS: These results suggest that ageing and mild AD may reduce the ability to identify odours and judge situations based on odours. PMID- 25515309 TI - Alteration in global motor strategy following lateral ankle sprain. AB - BACKGROUND: Lateral ankle sprain (LAS) has often been considered an injury leading to localized joint impairments affecting the musculoskeletal system. Persistent chronic ankle instability and bilateral alterations in motor control after a first ankle sprain episode suggest that the origin of relapses might be a maladaptive reorganization of central motor commands. The objectives of this study were (1) to compare the quality of motor control through motor strategy variables of two groups (with and without LAS) from a military population (n = 10/group), (2) to evaluate the contribution of the lower limbs and the trunk to global body strategy and (3) to identify which global variable best estimates performance on the Star Excursion Balance Test (SEBT) for each group, reaching direction, and lower limb. METHODS: Personal and clinical characteristics of the participants of both groups were collected. Their functional ability was measured using questionnaires and they performed a series of functional tests including the SEBT. During this test, the maximal reach distance (MRD) and biomechanical data were collected to characterize whole body and segmental strategies using a 3D motion capture system. RESULTS: At maximal lower limb reach, participants with LAS had a smaller variation in their vertical velocity in lowering-straightening and lowered the body centre of mass less for all injured limb conditions and some conditions with the uninjured lower limb. The global body centre of mass variables were significantly correlated to SEBT performance (MRD). CONCLUSION: Modifications in global motor strategies were found in participants with LAS as well as a decreased performance on the SEBT for the injured and uninjured lower limbs. These results support the hypothesis that following LAS, there may be a maladaptive reorganization of the central motor commands. LEVEL OF EVIDENCE: 3b. PMID- 25515310 TI - Enhanced efficacy of pluronic copolymer micelle encapsulated SCR7 against cancer cell proliferation. AB - 5,6-Bis(benzylideneamino)-2-mercaptopyrimidin-4-ol (SCR7) is a new anti cancer molecule having capability to selectively inhibit non-homologous end joining (NHEJ), one of the DNA double strand break (DSB) repair pathways inside the cells. In spite of the promising potential as an anticancer agent, hydrophobicity of SCR7 decreases its bioavailability. Herein the entrapment of SCR7 in Pluronic copolymer is reported. The size of the aggregates was determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS) which yields an average diameter of 23 nm. SCR7 encapsulated micelles (ES) were also characterized by small-angle neutron scattering (SANS). Evaluation of its biological properties by using a variety of techniques, including Trypan blue, MTT and Live-dead cell assays, reveal that encapsulated SCR7 can induce cytotoxicity in cancer cell lines, being more effective in breast cancer cell line. Encapsulated SCR7 treatment resulted in accumulation of DNA breaks within the cells, resulting in cell cycle arrest at G1 phase and activation of apoptosis. More importantly, we found ~ 5 fold increase in cell death, when encapsulated SCR7 was used in comparison with SCR7 alone. PMID- 25515308 TI - Robust hippocampal responsivity during retrieval of consolidated associative memory. AB - A contentious point in memory research is whether or not the hippocampus plays a time-limited role in the consolidation of declarative memories. A widely held view is that declarative memories are initially encoded in the hippocampus, then transferred to the neocortex for long-term storage. Alternate views argue instead that the hippocampus continues to play a role in remote memory recall. These competing theories are largely based on human amnesic and animal lesion/inactivation studies. However, in vivo electrophysiological evidence supporting these views is scarce. Given that other studies examining the role of the hippocampus in remote memory retrieval using lesion and imaging techniques in human and animal models have provided mixed results, it would be particularly useful to gain insight at the in vivo electrophysiological level. Here we report hippocampal single-neuron and theta activity recorded longitudinally during acquisition and remote retrieval of trace eyeblink conditioning. Results from conditioned rabbits were compared to those obtained from yoked pseudo-conditioned control rabbits. Results reveal continued learning-specific hippocampal activity one month after initial acquisition of the task. Our findings yield insight into the normal physiological responses of the hippocampus during memory processes and provide compelling in vivo electrophysiological evidence that the hippocampus is involved in both acquisition and retrieval of consolidated memories. PMID- 25515311 TI - Sensory encoding in Neuregulin 1 mutants. AB - Schizophrenic patients show altered sensory perception as well as changes in electrical and magnetic brain responses to sustained, frequency-modulated sensory stimulation. Both the amplitude and temporal precision of the neural responses differ in patients as compared to control subjects, and these changes are most pronounced for stimulation at gamma frequencies (20-40 Hz). In addition, patients display enhanced spontaneous gamma oscillations, which has been interpreted as 'neural noise' that may interfere with normal stimulus processing. To investigate electrophysiological markers of aberrant sensory processing in a model of schizophrenia, we recorded neuronal activity in primary somatosensory cortex of mice heterozygous for the schizophrenia susceptibility gene Neuregulin 1. Sensory responses to sustained 20-70 Hz whisker stimulation were analyzed with respect to firing rates, spike precision (phase locking) and gamma oscillations, and compared to baseline conditions. The mutants displayed elevated spontaneous firing rates, a reduced gain in sensory-evoked spiking and gamma activity, and reduced spike precision of 20-40 Hz responses. These findings present the first in vivo evidence of the linkage between a genetic marker and altered stimulus encoding, thus suggesting a novel electrophysiological endophenotype of schizophrenia. PMID- 25515313 TI - The excitatory amino acid carrier 1 (EAAC1) in the rat nucleus of the solitary tract: subcellular localization suggests no major role in glutamate clearance. AB - The excitatory amino acid carrier 1 (EAAC1) is a sodium-dependent glutamate transporter widely found in the mammalian brain and mainly localized in the somatodendritic compartment of neurons. The present study was performed to determine whether EAAC1 is present in the rat nucleus of the solitary tract (NST, a sensory brainstem nucleus involved in visceroception) and to document its subcellular localization. Using fluorescent immunolabeling, peroxidase immunostaining and quantitative immunogold labeling, we showed that both intracellular and plasma membrane-associated pools of EAAC1 transporters existed in dendrites of NST neurons. Although plasma membrane-associated transporters were more concentrated in the vicinity of synapses, no labeling was found at the axon-dendrite interface, suggesting that EAAC1 was not (or barely) expressed in this portion of dendritic membrane. Using computer simulation, we next showed that the ability of EAAC1 to efficiently take up synaptically released glutamate was very low outside the axon-dendrite interface. These data suggest that EAAC1 transporters present on NST dendrites may play a minor role if any in glutamate clearance. PMID- 25515315 TI - Bioengineered Scaffolds for 3D Analysis of Glioblastoma Proliferation and Invasion. AB - The invasion of malignant glioblastoma (GBM) cells into healthy brain is a primary cause of tumor recurrence and associated morbidity. Here, we describe a high-throughput method for quantitative measurement of GBM proliferation and invasion in three-dimensional (3D) culture. Optically clear hydrogels composed of thiolated hyaluronic acid and gelatin were chemically crosslinked with thiol reactive poly(ethylene glycol) polymers to form an artificial 3D tumor microenvironment. Characterization of the viscoelasticity and aqueous stability indicated the hydrogels were mechanically tunable with stiffness ranging from 18 Pa to 18.2 kPa and were resistant to hydrolysis for at least 30 days. The proliferation, dissemination and subsequent invasion of U118 and U87R GBM spheroids cultured on the hydrogels were tracked in situ with repeated fluorescence confocal microscopy. Using custom automated image processing, cells were identified and quantified through 500 um of gel over 14 days. Proliferative and invasive behaviors were observed to be contingent on cell type, gel stiffness, and hepatocyte growth factor availability. These measurements highlight the utility of this platform for performing quantitative, fluorescence imaging analysis of the behavior of malignant cells within an artificial, 3D tumor microenvironment. PMID- 25515312 TI - Rapid treatment-induced brain changes in pediatric CRPS. AB - To date, brain structure and function changes in children with complex regional pain syndrome (CRPS) as a result of disease and treatment remain unknown. Here, we investigated (a) gray matter (GM) differences between patients with CRPS and healthy controls and (b) GM and functional connectivity (FC) changes in patients following intensive interdisciplinary psychophysical pain treatment. Twenty-three patients (13 females, 9 males; average age +/- SD = 13.3 +/- 2.5 years) and 21 healthy sex- and age-matched controls underwent magnetic resonance imaging. Compared to controls, patients had reduced GM in the primary motor cortex, premotor cortex, supplementary motor area, midcingulate cortex, orbitofrontal cortex, dorsolateral prefrontal cortex (dlPFC), posterior cingulate cortex, precuneus, basal ganglia, thalamus, and hippocampus. Following treatment, patients had increased GM in the dlPFC, thalamus, basal ganglia, amygdala, and hippocampus, and enhanced FC between the dlPFC and the periaqueductal gray, two regions involved in descending pain modulation. Accordingly, our results provide novel evidence for GM abnormalities in sensory, motor, emotional, cognitive, and pain modulatory regions in children with CRPS. Furthermore, this is the first study to demonstrate rapid treatment-induced GM and FC changes in areas implicated in sensation, emotion, cognition, and pain modulation. PMID- 25515314 TI - Engineering myocardial tissue patches with hierarchical structure-function. AB - Complex hierarchical organization is a hallmark of tissues and their subsequent integration into organs. A major challenge in tissue engineering is to generate arrays of cells with defined structural organization that display appropriate functional properties. Given what is known about cellular responses to physiochemical cues from the surrounding environment, we can build tissue structures that mimic these microenvironments and validate these platforms using both experimental and computational approaches. Tissue generation encompasses many methods and tissue types, but here we review layering cell sheets to create scaffold-less myocardial patches. We discuss surgical criteria that can drive the design of myocardial cell sheets and the methods used to fabricate, mechanically condition, and functionally test them. We also focus on how computational and experimental approaches could be integrated to optimize tissue mechanical properties by using measurements of biomechanical properties and tissue anisotropy to create predictive computational models. Tissue anisotropy and dynamic mechanical stimuli affect cell phenotype in terms of protein expression and secretion, which in turn, leads to compositional and structural changes that ultimately impact tissue function. Therefore, a combinatorial approach of design, fabrication, testing, and modeling can be carried out iteratively to optimize engineered tissue function. PMID- 25515316 TI - Commentary: China's changing health system: implications for sexual and reproductive health. PMID- 25515317 TI - Abnormal erythroid maturation leads to microcytic anemia in the TSAP6/Steap3 null mouse model. AB - Genetic ablation of the ferrireductase STEAP3, also known as TSAP6, leads to severe microcytic and hypochromic red cells with moderate anemia in the mouse. However, the mechanism leading to anemia is poorly understood. Previous results indicate that TSAP6/Steap3 is a regulator of exosome secretion. Using TSAP6/Steap3 knockout mice, we first undertook a comprehensive hematologic characterization of the red cell compartment, and confirmed a dramatic decrease in the volume and hemoglobin content of these erythrocytes. We observed marked anisocytosis as well as the presence of fragmenting erythrocytes. Consistent with these observations, we found by ektacytometry decreased membrane mechanical stability of knockout red cells. However, we were unable to document significant changes in the expression levels of the major skeletal and transmembrane proteins to account for this decrease in the membrane stability. Furthermore, there were no differences in red cell survival between wild type and knockout animals. However, when we monitored erythropoiesis, we found a decreased number of proerythroblasts in the bone marrow of TSAP6/Steap3(-/-) animals. In addition, progression from the proerythroblastic to the orthochromatic stage was affected, with accumulation of cells at the polychromatic stage. Altogether, our findings demonstrate that abnormal erythroid maturation is the main cause of anemia in these mice. PMID- 25515318 TI - Cytometric characterization of circulating tumor cells captured by microfiltration and their correlation to the CellSearch((r)) CTC test. AB - Recent studies reporting hundreds, to thousands, of circulating tumor cells (CTCs) in the blood of cancer patients have raised questions regarding the prevalence of CTCs, as enumerated by the CellSearch((r)) CTC Test. Although CellSearch has been shown to consistently detect clinically relevant CTCs; the ability to only capture EpCAM positive cells has led to speculation that it captures limited subsets of CTCs. In contrast, alternative approaches to CTC isolation are often cited as capturing large numbers of CTCs from patient blood. Not surprisingly the number of cells isolated by alternative approaches show poor correlations when compared to CellSearch, even when accounting for EpCAM presence or absence. In an effort to address this discrepancy, we ran an exploratory method comparison study to characterize and compare the CTC subgroups captured from duplicate blood samples from 30 breast and prostate cancer patients using a microfiltration system (CellSieveTM) and CellSearch. We then categorized the CellSieve Cytokeratin(CK)+/CD45-/DAPI+ cells into five morphologically distinct subpopulations for correlative analysis. Like other filtration techniques, CellSieve isolated greater numbers of CK+/CD45- cells than CellSearch. Furthermore, analysis showed low correlation between the total CK+/CD45- cells captured by these two assays, regardless of EpCAM presence. However, subgrouping of CK+/CD45-/DAPI+ cells based on distinct cytokeratin staining patterns and nuclear morphologies elucidated a subpopulation correlative to CellSearch. Using method comparison analyses, we identified a specific CTC morphology which is highly correlative between two distinct capture methods. These data suggests that although various morphologic CTCs with similar phenotypic expressions are present in the blood of cancer patients, the clinically relevant cells isolated by CellSearch can potentially be identified using non-EpCAM dependent isolation. (c) 2014 The Authors. Published by Wiley Periodicals, Inc. PMID- 25515319 TI - The increased transglutaminase 2 expression levels during initial tumorigenesis predict increased risk of metastasis and decreased disease-free and cancer specific survivals in renal cell carcinoma. AB - PURPOSE: The aim of this study was to investigate the role of transglutaminase 2(TG2) in renal cell carcinoma (RCC) by comparing the immunohistochemistry staining of primary and metastatic tumor tissues. METHODS: A total of 33 metastatic RCC(mRCC) and 33 non-metastatic RCC (nmRCC) patients who were matched as closely as possible based on gender, age, nuclear grade and pathologic T stage were retrospectively investigated. TG2 immunohistochemistry staining was performed on paraffin-embedded primary tumor tissues from both patient groups and on metastatic tissues from mRCC patients. The tissues were scored from 0 to 7 according to the TG2 staining. Furthermore, the patients were stratified into two groups using median primary tumor staining score as the cutoff value: Group 1 (high risk, n = 41) and Group 2(low risk, n = 22). The clinical, histopathological and survival outcomes were compared between these risk groups using Chi-square test, t test, Mann-Whitney U test and Kaplan-Meier survival analyses. RESULTS: The median TG2 score for primary tumor was 5 for the entire study population. The median primary tumor TG2 score of the mRCC patients was significantly higher compared to the nmRCC patients (6 vs. 4, p < 0.001). The TG2 score between the primary and metastatic tissues of mRCC patients was not significantly different (6 vs. 7, p = 0.086). The percentage of metastatic patients was significantly higher in Group 1 compared to Group 2 (68.3 vs. 18.2 %, p < 0.001). Kaplan-Meier analyses showed that 5-year disease-free (34.9 vs. 92.9 %, p = 0.001) and cancer-specific (47.4 vs. 86.5 %, p = 0.04) survival rates were significantly lower in high-risk group. CONCLUSIONS: The increased expression of TG2 in primary tumor predicts metastasis in RCC patients and is also associated with a decrease in disease-free and cancer-specific survival outcomes. PMID- 25515320 TI - Qualitative study of the impact of an authentic electronic portfolio in undergraduate medical education. AB - BACKGROUND: Portfolios are increasingly used in undergraduate and postgraduate medical education. Four medical schools have collaborated with an established NHS electronic portfolio provider to develop and implement an authentic professional electronic portfolio for undergraduate students. We hypothesized that using an authentic portfolio would have significant advantages for students, particularly in familiarizing them with the tool many will continue to use for years after graduation. This paper describes the early evaluation of this undergraduate portfolio at two participating medical schools. METHODS: To gather data, a questionnaire survey with extensive free text comments was used at School 1, and three focus groups were held at School 2. This paper reports thematic analysis of students' opinions expressed in the free text comments and focus groups. RESULTS: Five main themes, common across both schools were identified. These concerned the purpose, use and acceptability of the portfolio, advantages of and barriers to the use of the portfolio, and the impacts on both learning and professional identity. CONCLUSIONS: An authentic portfolio mitigated some of the negative aspects of using a portfolio, and had a positive effect on students' perception of themselves as becoming past of the profession. However, significant barriers to portfolio use remained, including a lack of understanding of the purpose of a portfolio and a perceived damaging effect on feedback. PMID- 25515321 TI - Loop electrosurgical excision procedure and risk of vaginal infections during pregnancy: an observational study. AB - OBJECTIVE: To investigate the risk for preterm birth associated with vaginal infections in pregnancies after a loop electrosurgical excision procedure (LEEP), compared with women with no prior LEEP. DESIGN: Multicentre retrospective cohort study. SETTING: USA. POPULATION: Women with LEEP between 1996 and 2006 were compared with two unexposed groups who had cervical biopsy or Pap test, without any other cervical procedure, in the same calendar year. METHODS: The first pregnancy progressing beyond 20 weeks of gestation in women with prior LEEP was compared with pregnancy in women without LEEP. Stratified analysis according to the presence or the absence of vaginal infection during pregnancy was used to investigate whether the risk for preterm birth differed according to the presence or the absence of infection. The interaction between LEEP and vaginal infection was investigated using multivariable logistic regression with interaction terms, as well as the Mantel-Haenszel test for homogeneity. MAIN OUTCOME MEASURES: Spontaneous preterm birth (<37 and <34 weeks of gestation). RESULTS: Of 1727 patients who met the inclusion criteria, 34.4% (n = 598) underwent LEEP prior to an index pregnancy. There was no increased risk for vaginal infections among women with LEEP compared with women without LEEP. Chlamydia infection and LEEP demonstrated significant interaction, suggesting that the presence of chlamydia infection in women with a history of LEEP augments the risk for preterm birth, compared with women with no history of LEEP. CONCLUSIONS: Vaginal infections during pregnancy in women with a history of LEEP may be associated with an increased risk for preterm birth, compared with women with no history of LEEP. PMID- 25515322 TI - Management of bone disease in Gaucher disease type 1: clinical practice. AB - Gaucher disease is a rare autosomal recessive disorder of glycosphingolipid metabolism resulting from deficient activity of the lysosomal enzyme beta glucocerebrosidase that causes accumulation of glucosylceramide in tissue macrophage with damage to hematological, visceral, and skeletal organ systems. Severity and progression may vary independently among these domains, necessitating individualized therapy. Skeletal involvement is highly prevalent and often associated with intense pain, impaired mobility, and reduced quality of life. Enzyme replacement therapy improves parameters in all affected domains, but skeletal involvement requires longer treatment and higher dosages to obtain significant results. Despite numerous papers on bone complications in patients with Gaucher disease, there are no specific indications on how to assess properly bone involvement in such condition, the frequency of assessment, the use of markers for osteoblast and osteoclast activity, or the administration of bisphosphonates or other symptomatic drugs in adult and pediatric patients. Starting from a re-evaluation of cases with bone involvement, we have identified some common errors in the diagnostic approach and management. The aim of this paper was to propose a methodological and critical approach to the diagnosis, follow-up and treatment of bone disease in patients with Gaucher disease type 1. PMID- 25515323 TI - Mind your binomials: a guide to microbial nomenclature and spelling in sexually transmitted infections. PMID- 25515324 TI - Synthesis of poly(meth)acrylates with thioether and tertiary sulfonium groups by ARGET ATRP and their use as siRNA delivery agents. AB - The field of RNA interference depends on the development of safe and efficient carriers for short interfering ribonucleic acid (siRNA) delivery. Conventional cationic monomers for siRNA delivery have utilized the nitrogen heteroatom to produce cationic charges. Here, we polymerized cationic sulfonium (meth)acrylate by activators regenerated by electron transfer (ARGET) atom transfer radical polymerization (ATRP) to form polymers with narrow molecular weight distributions for siRNA delivery. The tertiary sulfonium species was stable toward dealkylation in water but less stable in the polar aprotic solvent dimethyl sulfoxide. Block copolymers poly(ethylene oxide) with poly(meth)acrylate containing sulfonium moieties were prepared as an siRNA delivery platform. Results suggested block copolymers were biocompatible up to 50 MUg/mL in vitro and formed polyplexes with siRNA. Additionally, block copolymers protected siRNAs against endonuclease digestion and facilitated knockdown of glyceraldehyde 3-phosphate dehydrogenase (Gapdh) mRNA expression in murine calvarial preosteoblasts. The versatility, biocompatibility, and cationic nature of these tertiary sulfonium groups are expected to find widespread biological applications. PMID- 25515325 TI - A novel method of achieving haemostasis in transfusion-dependent small bowel malignancy-related bleeding. PMID- 25515326 TI - A retrospective study of external beam radiation, neutron brachytherapy, and concurrent chemotherapy for patients with localized advanced carcinoma of the esophagus. AB - PURPOSE: The aim of this study was to retrospectively observe and analyze the long-term treatment outcomes of a total of 140 esophageal cancer patients who were treated with californium-252 ((252)Cf) neutron brachytherapy (NBT) in combination with external beam radiotherapy (EBRT) and concurrent chemotherapy (CCT). METHODS AND MATERIALS: From January 2002 to November 2012, 140 patients with esophageal cancer underwent NBT in combination with EBRT and CCT. The distribution of the patient numbers over the various cancer stages of IIA, IIB, and III were 43, 7, and 90, respectively. The total radiation dose to the reference point via NBT was 8-25 Gy-eq in two to five fractions with one fraction per week. The total dose via EBRT was 50-60 Gy, which was delivered over a period of five to six weeks with normal fractionation. Fifty-four and 86 patients received tegafur suppositories (TS) and continuous infusion of fluorouracil (5 Fu) with cisplatin (CDDP), respectively. RESULTS: The median follow-up time was 42 months. The minimum follow-up was three months, and the maximum was 106 months. The overall median survival including death from all causes was 29.5 months. The five-year overall survival rate (OS) and local control (LC) were 33.4% and 55.9%, respectively. The chemotherapy regimen was a factor that was significantly associated with OS (p = 0.025) according to univariate analysis. The five-year OSs were 27.4% and 44.3% for the PF and TS chemotherapy regimens, respectively. Regarding acute toxicity, no incidences of fistula or massive bleeding were observed during this treatment period. The incidence of severe, late complications was related to the PF chemotherapy regimen (p = 0.080). CONCLUSIONS: The clinical data indicated that NBT in combination with EBRT and CRT produced favorable local control and long-term survival rates for patients with esophageal cancer and that the side effects were tolerable. A reasonable CRT regimen can decrease the rate of severe, late complications. PMID- 25515327 TI - "Appropriate" diagnostic testing: supporting diagnostics with evidence-based medicine and shared decision making. AB - BACKGROUND: Evidence-based medicine is an important approach to avoiding care that is unlikely to benefit patients in both the treatment and the diagnostic context. The medical evidence alone may not determine the most appropriate care decision. Patient interests are best served when the advantages and risks of a diagnostic test are viewed through the lens of the patient's values. That is, the paradigm of evidence-based medicine should be complemented by the paradigm of shared decision making. ANALYSIS: Diagnostic testing may offer physiological and psychological benefits. Clinicians should also discuss the potential harms, however, which may be physiological (e.g. radiation or scarring), psychological (e.g. anxiety), and financial (e.g. cost-sharing burdens). All three of these concerns are compounded by the risk of false positives or incidental findings that are not serious, but which require decisions about further testing or treatment. CONCLUSION: We suggest that patient-centered decision making around diagnostic testing involves a two-step inquiry:(1) Is the test medically appropriate? Does the available evidence documenting short- and long-term risk and benefits support the test for its intended use, given the patient's characteristics and symptoms?(2) Is the test appropriate for this patient? Has the provider initiated a conversation about tradeoffs that helps the patient evaluate whether the balance of risks and benefits is consonant with the patient's own values and preferences? Potential benefits and harms to consider include the physiological, the psychological, and the financial. PMID- 25515328 TI - New potential solutions for the chemolysis of urinary phosphate calculi determined by an in vitro study. AB - To find a more efficient solution for chemolysis of urinary calculi, several organic acids were chosen to form solutions by consulting the composition of a classic solution, Suby G. The solutions together with Renacidin, another classic solution, were designed to react with the 4 phosphate components of urinary stone. The processes were real-time measured and analysed by a focused beam reflectance measurement, and the efficiency factors were investigated and discussed in detail. The results show that several organic acids, e.g. hydroxyacetic acid, lactic acid and alpha-ketoglutaric acid, are more efficient than citric acid in dissolving urinary phosphate calculus. The new solutions containing the organic acids are promising for improving chemolysis treatment. PMID- 25515329 TI - Genetic predictor of working memory and prefrontal function in women with HIV. AB - The Val158Met (rs4680) single-nucleotide polymorphism (SNP) of the catechol-O methyltransferase gene (COMT) influences executive function and prefrontal function through its effect on dopamine (DA) metabolism. Both HIV and the Val allele of the Val158Met SNP are associated with compromised executive function and inefficient prefrontal function. The present study used behavioral and neuroimaging techniques to determine independent and interactive associations between HIV serostatus and COMT genotype on working memory and prefrontal function in women. For the behavioral study, 54 HIV-infected and 33 HIV uninfected women completed the 0-, 1-, and 2-back conditions of the verbal N back, a working memory test. For the imaging study, 36 women (23 HIV-infected, 13 HIV-uninfected) underwent functional magnetic resonance imaging (fMRI) assessments while completing the N-back task. HIV-infected women demonstrated significantly worse N-back performance compared with HIV-uninfected women (p < 0.05). A significant serostatus by genotype interaction (p < 0.01) revealed that, among Val/Val, but not Met allele carriers, HIV-infected women performed significantly worse than HIV-uninfected controls across N-back conditions (p < 0.01). Analogous to behavioral findings, a serostatus by genotype interaction revealed that HIV-infected Val/Val carriers showed significantly greater prefrontal activation compared with HIV-uninfected Val/Val carriers (p < 0.01). Conversely, HIV-uninfected Met allele carriers demonstrated significantly greater prefrontal activation compared with HIV-infected Met allele carriers. Findings suggest that the combination of HIV infection and the Val/Val COMT genotype leads to working memory deficits and altered prefrontal function in HIV-infected individuals. PMID- 25515330 TI - Tracking surface glycans on live cancer cells with single-molecule sensitivity. AB - Using a combination of metabolically labeled glycans, a bioorthogonal copper(I) catalyzed azide-alkyne cycloaddition, and the controlled bleaching of fluorescent probes conjugated to azide- or alkyne-tagged glycans, a sufficiently low spatial density of dye-labeled glycans was achieved, enabling dynamic single-molecule tracking and super-resolution imaging of N-linked sialic acids and O-linked N acetyl galactosamine (GalNAc) on the membrane of live cells. Analysis of the trajectories of these dye-labeled glycans in mammary cancer cells revealed constrained diffusion of both N- and O-linked glycans, which was interpreted as reflecting the mobility of the glycan rather than to be caused by transient immobilization owing to spatial inhomogeneities on the plasma membrane. Stochastic optical reconstruction microscopy (STORM) imaging revealed the structure of dynamic membrane nanotubes. PMID- 25515331 TI - Molecular characterization of the piggyBac-like element, a candidate marker for phylogenetic research of Chilo suppressalis (Walker) in China. AB - BACKGROUND: Transposable elements (TEs, transposons) are mobile genetic DNA sequences. TEs can insert copies of themselves into new genomic locations and they have the capacity to multiply. Therefore, TEs have been crucial in the shaping of hosts' current genomes. TEs can be utilized as genetic markers to study population genetic diversity. The rice stem borer Chilo suppressalis Walker is one of the most important insect pests of many subtropical and tropical paddy fields. This insect occurs in all the rice-growing areas in China. This research was carried out in order to find diversity between C. suppressalis field populations and detect the original settlement of C. suppressalis populations based on the piggyBac-like element (PLE). We also aim to provide insights into the evolution of PLEs in C. suppressalis and the phylogeography of C. suppressalis. RESULTS: Here we identify a new piggyBac-like element (PLE) in the rice stem borer Chilo suppressalis Walker, which is called CsuPLE1.1 (GenBank accession no. JX294476). CsuPLE1.1 is transcriptionally active. Additionally, the CsuPLE1.1 sequence varied slightly between field populations, with polymorphic indels (insertion/deletion) and hyper-variable regions including the identification of the 3' region outside the open reading frame (ORF). CsuPLE1.1 insertion frequency varied between field populations. Sequences variation was found between CsuPLE1 copies and varied within and among field populations. Twenty-one different insertion sites for CsuPLE1 copies were identified with at least two insertion loci found in all populations. CONCLUSIONS: Our results indicate that the initial invasion of CsuPLE1 into C. suppressalis occurred before C. suppressalis populations spread throughout China, and suggest that C. suppressalis populations have a common ancestor in China. Additionally, the lower reaches of the Yangtze River are probably the original settlement of C. suppressalis in China. Finally, the CsuPLE1 insertion site appears to be a candidate marker for phylogenetic research of C. suppressalis. PMID- 25515332 TI - An anatomical and histological study of the structures surrounding the proximal attachment of the hamstring muscles. AB - INTRODUCTION: The proximal attachment of hamstring muscles has a very high incidence of injuries due to a wide number of factors and its morphology may be one of the underlying factors as scientific literature points out. The connective tissue component of the attachment of hamstring muscles is not well known. For this reason the aim of this study is to describe the anatomy and histology surrounding the proximal attachment of the hamstring muscles (PAHM) and its direct anatomic relations. METHODS: Forty-eight cryopreserved lower limbs have sequentially been studied by means of dissection, anatomical sections and histology. RESULTS: All specimens studied presented an annular connective tissue structure that resembles a retinaculum, which covers and adapts to the attachment of hamstring muscles on the ischial tuberosity. CONCLUSION: The results show how this retinaculum is continuous with the long head of biceps femoris muscle, however there is a layer of loose connective tissue between the retinaculum and the semitendinosus muscle. Furthermore, this structure receives expansions of the anterior epimysium of the gluteus maximus muscle (GIM). PMID- 25515334 TI - Glycosuria medicated with ipragliflozin and nifedipine or ipragliflozin and candesartan: a case report. AB - INTRODUCTION: Animal studies have reported that treatment with angiotensin II receptor blockers reduced kidney sodium-dependent glucose cotransporter expression. We therefore hypothesized that patients with hypertension treated with an angiotensin II receptor blocker (candesartan) would probably have an increased response to sodium-dependent glucose cotransporter inhibitor therapy (ipragliflozin) compared with patients treated with alternative hypertensive medications such as calcium channel blockers (nifedipine). Although sodium dependent glucose cotransporter inhibitor (ipragliflozin) is a new anti-diabetic medicine, the clinical efficacy in the Japanese population has not been fully evaluated. We compared the combined effect of angiotensin II receptor blocker candesartan plus ipragliflozin with nifedipine plus ipragliflozin therapy and found that the combination of candesartan plus ipragliflozin was more effective in increasing glycosuria and lowering plasma glucose. CASE PRESENTATION: A 57 year-old Japanese man with essential hypertension was treated with candesartan. Candesartan was switched to nifedipine for the initial 10 days of an observation period and 5 days later he was started on ipragliflozin (day 6 of nifedipine treatment) with nifedipine for the next 5 days. Thereafter (from day 11 to day 20), candesartan was started instead of nifedipine and ipragliflozin was continued. In the last 5 days ipragliflozin was stopped and he was treated with candesartan alone. Neither nifedipine alone (0.038+/-0.004) nor candesartan alone (0.048+/-0.006) produce any trace amount of glycosuria. However, the extent of glycosuria under ipragliflozin with candesartan treatment (37.5+/-8.45) was significantly greater than that of ipragliflozin with nifedipine (23.75+/-0.35; P<0.05). CONCLUSION: Candesartan demonstrated additive actions with ipragliflozin to increase glycosuria compared to ipragliflozin with nifedipine treatment. PMID- 25515333 TI - Nicotine exposure and transgenerational impact: a prospective study on small regulatory microRNAs. AB - Early developmental stages are highly sensitive to stress and it has been reported that pre-conditioning with tobacco smoking during adolescence predisposes those youngsters to become smokers as adults. However, the molecular mechanisms of nicotine-induced transgenerational consequences are unknown. In this study, we genome-widely investigated the impact of nicotine exposure on small regulatory microRNAs (miRNAs) and its implication on health disorders at a transgenerational aspect. Our results demonstrate that nicotine exposure, even at the low dose, affected the global expression profiles of miRNAs not only in the treated worms (F0 parent generation) but also in two subsequent generations (F1 and F2, children and grandchildren). Some miRNAs were commonly affected by nicotine across two or more generations while others were specific to one. The general miRNA patterns followed a "two-hit" model as a function of nicotine exposure and abstinence. Target prediction and pathway enrichment analyses showed daf-4, daf-1, fos-1, cmk-1, and unc-30 to be potential effectors of nicotine addiction. These genes are involved in physiological states and phenotypes that paralleled previously published nicotine induced behavior. Our study offered new insights and further awareness on the transgenerational effects of nicotine exposed during the vulnerable post-embryonic stages, and identified new biomarkers for nicotine addiction. PMID- 25515335 TI - [The term mental disease in psychiatry and psychotherapy]. PMID- 25515336 TI - [Medical and vocational rehabilitation in rehabilitation facilities for people with mental illnesses in Germany: Analysis of admission and discharge data]. AB - BACKGROUND: Integrative medical and vocational rehabilitation has been implemented in Germany in rehabilitation facilities for people with mental illnesses (RPK). MATERIAL AND METHODS: In all 52 RPK facilities in Germany the admission and discharge data of all rehabilitation patients are collected and accumulated at facility level before they are combined at the registration office of the Federal Association of RPKs (BAG RPK). This study is based on a descriptive analysis of admission and discharge data of 1311 rehabilitation patients in the year 2010. RESULTS: Nearly two thirds of the 1311 RPK rehabilitation patients met the diagnostic criteria for schizophrenia or affective disorders. A subgroup of 39.1 % of all patients participated in vocational RPK measures (programs for participation in working life, LTA) after having received medical RPK measures. After completion of the vocational RPK measures 38 % of the rehabilitation patients were employed and 26 % were in education and retraining, i.e. 64 % of the patients were employed in the labor market or in educational measures. The housing and living conditions of the majority of patients changed in the direction of increased autonomy after completion of the RPK measures. DISCUSSION AND CONCLUSION: For people with severe mental illnesses, RPKs can be a place of successful rehabilitative measures facilitating participation in community life. Future studies need to investigate predictors of outcome. PMID- 25515337 TI - Feasibility and related outcome of intraluminal pulmonary artery banding. AB - OBJECTIVES: This retrospective study evaluated the feasibility and related outcome of intraluminal pulmonary artery banding (I-PAB). METHODS: Thirty-two children underwent I-PAB between July 2006 and April 2014. The median age and weight were 60 days (range: 5 days to 4.2 years) and 3.7 kg (range: 2.6-13.0 kg), respectively. Cardiac diagnoses included single ventricle morphology (n = 11), complex ventricular septal defects (n = 11), balanced atrioventricular septal defects (n = 3), congenitally corrected transposition of the great arteries (n = 2) and aortic arch hypoplasia with ventricular septal defects (n = 5). On cardiopulmonary bypass (CPB), 2 I-PAB modifications with either 1 (n = 24) or 2 ('hour-glass-technique', n = 8) fenestrated pericardial patches were performed. RESULTS: The median fenestration size was 5 mm (range: 4-6.5 mm). In 18 patients I-PAB was a solitary procedure; in 3 of them the decision was made intraoperatively. There was no hospital mortality. The median interval to debanding was 189 days (range: 112 days to 2.6 years). During this period, we observed a significant increase in the pressure gradient over I-PAB (P < 0.01), whereas arterial saturations remained stable. Four patients received balloon dilatation of I-PAB to prolong the palliation period. No patient experienced band occlusion, pulmonary hypertension related to I-PAB, coronary or pulmonary valve impairment. Debanding was performed in 27 patients and one of them required pulmonary patch arterioplasty due to I-PAB-associated pulmonary trunk distortion. Three patients are still awaiting further surgery. There were 2 late deaths prior to, and 3 after debanding, all not related to I-PAB. CONCLUSIONS: I-PAB with an exactly defined internal orifice is feasible and effective. Although arterial saturations seem to remain stable, balloon dilatation of I-PAB can be performed safely and efficiently in order to prolong the palliation period. The rate of I PAB-related complications is low, which might improve the long-term patient outcome. Therefore, despite requiring CPB, I-PAB is our institutional preference for children who require pulmonary artery banding. PMID- 25515339 TI - New developments at the Annals of Occupational Hygiene. PMID- 25515338 TI - Forces in yeast flocculation. AB - In the baker's yeast Saccharomyces cerevisiae, cell-cell adhesion ("flocculation") is conferred by a family of lectin-like proteins known as the flocculin (Flo) proteins. Knowledge of the adhesive and mechanical properties of flocculins is important for understanding the mechanisms of yeast adhesion, and may help controlling yeast behaviour in biotechnology. We use single-molecule and single-cell atomic force microscopy (AFM) to explore the nanoscale forces engaged in yeast flocculation, focusing on the role of Flo1 as a prototype of flocculins. Using AFM tips labelled with mannose, we detect single flocculins on Flo1 expressing cells, showing they are widely exposed on the cell surface. When subjected to force, individual Flo1 proteins display two distinct force responses, i.e. weak lectin binding forces and strong unfolding forces reflecting the force-induced extension of hydrophobic tandem repeats. We demonstrate that cell-cell adhesion bonds also involve multiple weak lectin interactions together with strong unfolding forces, both associated with Flo1 molecules. Single molecule and single-cell data correlate with microscale cell adhesion behaviour, suggesting strongly that Flo1 mechanics is critical for yeast flocculation. These results favour a model in which not only weak lectin-sugar interactions are involved in yeast flocculation but also strong hydrophobic interactions resulting from protein unfolding. PMID- 25515340 TI - Pancreatic beta-cell glucose toxicity in type 2 diabetes mellitus. AB - Pancreatic beta-cells secrete insulin when blood glucose levels become high. However, when beta-cells are chronically exposed to hyperglycemia, their function gradually deteriorates. Although such phenomena are called as beta-cell glucose toxicity, its molecular mechanism remained unclear. This manuscript describes the possible mechanism for such beta-cell dysfunction. In the diabetic state, nuclear expression levels of pancreatic transcription factors PDX-1 and MafA are decreased. In addition, incretin receptor expression in beta- cells is decreased, which is likely involved in the impairment of incretin effects in diabetes. Taken together, it is likely that down-regulation of pancreatic transcription factors and/or incretin receptors are involved in beta-cell dysfunction observed in type 2 diabetes. PMID- 25515342 TI - A Christmas carousel. PMID- 25515341 TI - Eilat virus displays a narrow mosquito vector range. AB - BACKGROUND: Most alphaviruses are arthropod-borne and utilize mosquitoes as vectors for transmission to susceptible vertebrate hosts. This ability to infect both mosquitoes and vertebrates is essential for maintenance of most alphaviruses in nature. A recently characterized alphavirus, Eilat virus (EILV), isolated from a pool of Anopheles coustani s.I. is unable to replicate in vertebrate cell lines. The EILV host range restriction occurs at both attachment/entry as well as genomic RNA replication levels. Here we investigated the mosquito vector range of EILV in species encompassing three genera that are responsible for maintenance of other alphaviruses in nature. METHODS: Susceptibility studies were performed in four mosquito species: Aedes albopictus, A. aegypti, Anopheles gambiae, and Culex quinquefasciatus via intrathoracic and oral routes utilizing EILV and EILV expressing red fluorescent protein (-eRFP) clones. EILV-eRFP was injected at 10(7) PFU/mL to visualize replication in various mosquito organs at 7 days post infection. Mosquitoes were also injected with EILV at 10(4)-10(1) PFU/mosquito and virus replication was measured via plaque assays at day 7 post-infection. Lastly, mosquitoes were provided bloodmeals containing EILV-eRFP at doses of 10(9), 10(7), 10(5) PFU/mL, and infection and dissemination rates were determined at 14 days post-infection. RESULTS: All four species were susceptible via the intrathoracic route; however, replication was 10-100 fold less than typical for most alphaviruses, and infection was limited to midgut-associated muscle tissue and salivary glands. A. albopictus was refractory to oral infection, while A. gambiae and C. quinquefasciatus were susceptible only at 10(9) PFU/mL dose. In contrast, A. aegypti was susceptible at both 10(9) and 10(7) PFU/mL doses, with body infection rates of 78% and 63%, and dissemination rates of 26% and 8%, respectively. CONCLUSIONS: The exclusion of vertebrates in its maintenance cycle may have facilitated the adaptation of EILV to a single mosquito host. As a consequence, EILV displays a narrow vector range in mosquito species responsible for the maintenance of other alphaviruses in nature. PMID- 25515343 TI - A pilot study examining measures of balance and mobility in children with unilateral lower-limb amputation. AB - BACKGROUND: Individuals with unilateral lower-limb amputation (LLA) have altered structure and physiology of their lower limbs which impairs their balance, mobility, physical function and participation in physical activities. As part of (re)habilitation, focus is given to improving gait and balance in order to enhance overall mobility, function, self-efficacy, and independence. However, the relationships amongst body impairments and physical activity limitations remain unclear, particularly in the pediatric population. OBJECTIVE: To provide an examination of the relationships among balance and mobility measures in children with unilateral lower-limb amputation and able-bodied children. STUDY DESIGN: Cross-sectional prospective comparative pilot study. METHODS: Spatiotemporal gait parameters and standing postural control were evaluated in children with lower limb amputation (n = 10) and age-matched able-bodied children (n = 10) in a laboratory-based setting. Clinical tests for mobility and balance consisted of the 10-m walk test, the 6-min walk test, and the Community Balance and Mobility scale. Energy expenditure was estimated during the 6-min walk test using the Physiological Cost Index. Analysis included comparing variables between able bodied and lower-limb amputation groups, as well as examining the correlations among them. RESULTS: Walking speed, distance, and functional balance (p < 0.05) were significantly diminished in children with lower-limb amputation compared to able-bodied children. For children with lower-limb amputation, reduced energy expenditure was associated with narrower step width and more symmetrical gait; better postural control and balance were associated with faster walking speeds (p < 0.05). CONCLUSION: A greater clinical understanding of gait and balance deficits in this population may help to improve rehabilitation outcomes and overall functional mobility. CLINICAL RELEVANCE: Improved understanding of deficits in children with lower-limb amputation (LLA) may lead to more targeted interventions and facilitate clinical decision-making in rehabilitation settings for this population. The findings contribute to the limited literature and provide a basis to further examine suitable clinical outcome measures to be used in children with LLA. PMID- 25515344 TI - Origin and stability of exomoon atmospheres: implications for habitability. AB - We study the origin and escape of catastrophically outgassed volatiles (H2O, CO2) from exomoons with Earth-like densities and masses of 0.1, 0.5 and 1 M? orbiting an extra-solar gas giant inside the habitable zone of a young active solar-like star. We apply a radiation absorption and hydrodynamic upper atmosphere model to the three studied exomoon cases. We model the escape of hydrogen and dragged dissociation products O and C during the activity saturation phase of the young host star. Because the soft X-ray and EUV radiation of the young host star may be up to ~100 times higher compared to today's solar value during the first 100 Myr after the system's origin, an exomoon with a mass < 0.25 M? located in the HZ may not be able to keep an atmosphere because of its low gravity. Depending on the spectral type and XUV activity evolution of the host star, exomoons with masses between ~0.25 and 0.5 M? may evolve to Mars-like habitats. More massive bodies with masses >0.5 M?, however, may evolve to habitats that are a mixture of Mars like and Earth-analogue habitats, so that life may originate and evolve at the exomoon's surface. PMID- 25515345 TI - Organic compounds in star forming regions. AB - The influence of complex dust composition on the general chemical evolution of a prestellar core and the content of complex organic compounds is studied. It is shown that various component groups respond differently to the presence of a small dust population. At early stages the difference is determined primarily by changes in the balance of photo processes due to effective absorption of ultraviolet photons by small dust grains of the second population and collisional reactions with dust particles. At later stages differences are also caused by the growing dominance of additional reaction channels related to surface organic synthesis. PMID- 25515346 TI - Radiotherapy-induced mesorectum alterations: histological evaluation of 90 consecutive cases. AB - OBJECTIVE: In order to identify the radiotherapy-induced histological modifications in the mesorectum, we reviewed the surgical specimens of 90 rectal resections comprehensive of the total mesorectal excision (23 cases radiologically classified as cT2N0M0 and 67 as cT3N0M0). All patients were preoperative treated with radiotherapy: 20 with 50 Gy, 20 with 20 Gy and 50 Gy irradiation associated to FOLFOX scheme chemotherapy. MATERIAL AND METHODS: Routine hematoxylin and eosin stained serial slides at 5 mm of intervals were obtained from surgical specimens and included the tumor site and the adjacent irradiated mucosa, the submucosa and the muscular layers of the rectal wall and the mesorectal adipose tissue, completely removed until to the mesorectal fascia. Ten subjects (eight cT2N0M0 and two cT3N0M0), who did not received preoperative oncological treatments were adopted as controls. RESULTS: Histologically, examination revealed fibrosis of the adipose tissue in 86 cases (95%), vascular damage including vasculities and fibrotic thickening wall of arteries and veins in 46 cases (51%), sclero-hyalinosis of lymph nodes with pericapsular fibrosis in 22 cases (23%) and perineural deposition of fibrosis in 12 (13%). These findings were ubiquitously observed in the whole mesorectum. Fibrosis of the adipose tissue and vasculitis were mainly associated to the combination of 50 Gy radiations plus chemotherapy (p < 0.05). CONCLUSION: The detection of histopathological alterations in the mesorectum can give reason of the well-known postoperative complications and long-term sequels. PMID- 25515349 TI - Dissociating prefrontal circuitry in intelligence and memory: neuropsychological correlates of magnetic resonance and diffusion tensor imaging. AB - We examined intelligence and memory in 25 healthy participants who had both prior magnetic resonance imaging (MRI) of gray matter volumes of medial orbital frontal cortex (mOFC) and rostral anterior cingulate cortex (rACC), along with diffusion tensor imaging (DTI) of posterior and anterior mOFC-rACC white matter microstructure, as assessed by fractional anisotropy (FA). Results showed distinct relationships between these basic structural brain parameters and higher cognition, highlighted by a highly significant correlation of left rACC gray matter volume with memory, and to a lesser extent, though still statistically significant, correlation of left posterior mOFC-rACC FA with intelligence. Regression analyses showed that left posterior mOFC-rACC connections and left rACC gray matter volume each contributed to intelligence, with left posterior mOFC-rACC FA uniquely accounting for between 20.43 and 24.99% of the variance in intelligence, in comparison to 13.54 to 17.98% uniquely explained by left rACC gray matter volume. For memory, only left rACC gray matter volume explained neuropsychological performance, uniquely accounting for a remarkably high portion of individual variation, ranging from 73.61 to 79.21%. These results pointed to differential contributions of white mater microstructure connections and gray matter volumes to individual differences in intelligence and memory, respectively. PMID- 25515347 TI - Current and recent clinical trials for perioperative systemic therapy for muscle invasive bladder cancer: a systematic review. AB - BACKGROUND: Although Muscle Invasive Bladder Cancer (MIBC) is increasing in incidence, treatment has largely remained limited to radical cystectomy with or without cisplatin-based neoadjuvant and/or adjuvant chemotherapy. We reviewed the current and recent clinical trials evaluating perioperative chemotherapy, targeted therapy, and novel therapeutic regimens for MIBC patients undergoing radical cystectomy. METHODS: An overview of perioperative MIBC management was conducted initially using MEDLINE. The Clinical Trials Registry and MEDLINE were further searched specifically for perioperative MIBC chemotherapy, targeted therapy, and other novel therapeutic approaches. Trials involving non perioperative management, operative management other than radical cystectomy, multiple tumors, or purely superficial or metastatic disease were excluded from selection. These criteria were not specifically fulfilled for mTOR inhibitor and immune therapy trials. Only phase III chemotherapy and phase II targeted therapy trials found in the Clinical Trials Registry were selected. MEDLINE searches of specific treatments were limited to January 2009 to January 2014 whereas the Clinical Trials Registry search had no timeline. Systematic MEDLINE searches had no phase restrictions. Trials known by the authors to fulfill search criteria but were not found via searches were also selected. RESULTS: Twenty-five trials were selected from the Clinical Trials Registry including 7 phase III chemotherapy trials, 11 Phase II targeted therapy trials, 3 immune therapy trials, 1 mammalian target of rapamycin (mTOR) inhibitor trial, and 3 gene and vaccine therapy trials. Nine trials have been completed and 5 have been terminated early or withdrawn. Nine trials have data available when individually searched using MEDLINE and/or Google. Systematic searches of MEDLINE separately found 12 trials in the past 5 years. Two phase III chemotherapy trials were selected based on knowledge by the authors. No phase III trials of targeted therapy have been registered or published. CONCLUSIONS: New trials are currently being conducted that may revolutionize MIBC treatment preceding or following cystectomy. Head-to head phase III trials of perioperative chemotherapy and further phase II and phase III trials of targeted therapy and other therapeutic approaches are necessary before the current cisplatin-based perioperative chemotherapy paradigm is altered. PMID- 25515348 TI - Right is not always wrong: DTI and fMRI evidence for the reliance of reading comprehension on language-comprehension networks in the right hemisphere. AB - The Simple View theory suggests that reading comprehension relies on automatic recognition of words combined with language comprehension. The goal of the current study was to examine the structural and functional connectivity in networks supporting reading comprehension and their relationship with language comprehension within 7-9 year old children using Diffusion Tensor Imaging (DTI) and fMRI during a Sentence Picture Matching task. Fractional Anisotropy (FA) values in the left and right Inferior Longitudinal Fasciculus (ILF) and Superior Longitudinal Fasciculus (SLF), known language-related tracts, were correlated from DTI data with scores from the Woodcock-Johnson III (WJ-III) Passage Comprehension sub-test. Brodmann areas most proximal to white-matter regions with significant correlation to Passage Comprehension scores were chosen as Regions-of Interest (ROIs) and used as seeds in a functional connectivity analysis using the Sentence Picture Matching task. The correlation between percentile scores for the WJ-III Passage Comprehension subtest and the FA values in the right and left ILF and SLF indicated positive correlation in language-related ROIs, with greater distribution in the right hemisphere, which in turn showed strong connectivity in the fMRI data from the Sentence Picture Matching task. These results support the participation of the right hemisphere in reading comprehension and may provide physiologic support for a distinction between different types of reading comprehension deficits vs difficulties in technical reading. PMID- 25515350 TI - Self-enhanced electrogenerated chemiluminescence of ruthenium(II) complexes conjugated with Schiff bases. AB - In this work, we obtain two ruthenium(ii) complexes with Schiff base cavities that exhibit significantly enhanced electrochemiluminescence (ECL) intensity and quantum efficiency due to Ru(bpy)3(2+) in aqueous solution, without the addition of tri-n-propylamine (TPrA). The great increase in ECL intensity is confirmed to be due to the electrochemical oxidation of phenolic hydroxyl groups and the resonant structure of imino radicals. Thus, the electrons are transferred intramolecularly to the Ru(iii) center, leading to efficient generation of the excited state of Ru(ii)*. Subsequently, we find that Co(2+) bonding with the salen cavity can selectively and quickly quench the ECL signal. Furthermore, we study the mechanism of the process by which Co(2+) hinders the oxidation of phenolic groups and blocks the electron transfer from imino radicals to the Ru center. Thus, a highly sensitive and selective ECL probe for the recognition of Co(2+) was developed with a stable response over a concentration range of 0.9 MUM to 6.3 MUM and a detection limit as low as 21 nM. PMID- 25515352 TI - Ginsenoside Rg1 attenuates invasion and migration by inhibiting transforming growth factor-beta1-induced epithelial to mesenchymal transition in HepG2 cells. AB - Ginseng has become one of the most commonly used alternative herbal medicines and its active component, ginsenoside Rg1, possesses known pharmacological effects, including anticancer properties. However, the effects of ginsenoside Rg1 on metastasis have not been investigated. The present study demonstrated that ginsenoside Rg1 was able to suppress transforming growth factor-beta1 (TGF-beta1) induced invasion and migration in HepG2 liver cancer cells. This suppression was associated with the inhibition of TGF-beta1-induced epithelial to mesenchymal transition (EMT). Furthermore, TGF-beta1 induced HepG2 cells to undergo EMT and significantly promoted cell invasion and migration. When cells were pretreated with ginsenoside Rg1 for 24 h and subsequently exposed to TGF-beta1 for 24 h, the results demonstrated that ginsenoside Rg1 inhibited the initiation of TGF-beta1 induced EMT. In addition, HepG2 cells exhibited a mesenchymal phenotype when exposed to TGF-beta1, but when exposed to ginsenoside Rg1 this effect was reversed and the cells exhibited a classical epithelial morphology. Ginsenoside Rg1 also increased the expression of the epithelial phenotype marker E-cadherin and repressed the expression of the mesenchymal phenotype marker vimentin. In conclusion, the results of the present study suggest that ginsenoside Rg1 may suppress liver cancer invasion and migration in vitro through inhibiting TGF beta1-induced EMT. PMID- 25515351 TI - Linking regional variation of epibiotic bacterial diversity and trophic ecology in a new species of Kiwaidae (Decapoda, Anomura) from East Scotia Ridge (Antarctica) hydrothermal vents. AB - We analyzed the diversity of bacterial epibionts and trophic ecology of a new species of Kiwa yeti crab discovered at two hydrothermal vent fields (E2 and E9) on the East Scotia Ridge (ESR) in the Southern Ocean using a combination of 454 pyrosequencing, Sanger sequencing, and stable isotope analysis. The Kiwa epibiont communities were dominated by Epsilon- and Gammaproteobacteria. About 454 sequencing of the epibionts on 15 individual Kiwa specimen revealed large regional differences between the two hydrothermal vent fields: at E2, the bacterial community on the Kiwa ventral setae was dominated (up to 75%) by Gammaproteobacteria, whereas at E9 Epsilonproteobacteria dominated (up to 98%). Carbon stable isotope analysis of both Kiwa and the bacterial epibionts also showed distinct differences between E2 and E9 in mean and variability. Both stable isotope and sequence data suggest a dominance of different carbon fixation pathways of the epibiont communities at the two vent fields. At E2, epibionts were putatively fixing carbon via the Calvin-Benson-Bassham and reverse tricarboxylic acid cycle, while at E9 the reverse tricarboxylic acid cycle dominated. Co-varying epibiont diversity and isotope values at E2 and E9 also present further support for the hypothesis that epibionts serve as a food source for Kiwa. PMID- 25515353 TI - An organic surface modifier to produce a high work function transparent electrode for high performance polymer solar cells. AB - Modification of an ITO electrode with small-molecule organic surface modifier, 4 chloro-benzoic acid (CBA), via a simple spin-coating method produces a high-work function electrode with high transparency and a hydrophobic surface. As an alternative to PEDOT:PSS, CBA modification achieves efficiency enhancement up to 8.5%, which is attributed to enhanced light absorption within the active layer and smooth hole transport from the active layer to the anode. PMID- 25515354 TI - Impact of bone marrow pathology on the clinical management of Philadelphia chromosome-negative myeloproliferative neoplasms. AB - Philadelphia chromosome-negative myeloproliferative neoplasms include primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET). Although these 3 entities share many pathogenic characteristics, such as dysregulated Janus kinase (JAK)/signal transducer and activator of transcription signaling, they differ substantially regarding prognosis, progression to myelofibrosis (MF), risk of leukemic transformation, and specific medical needs. Accurate diagnosis and classification of myeloproliferative neoplasms are prerequisites for appropriate risk-based therapy and should be based on an integrated approach following the World Health Organization guidelines that, in addition to clinical, molecular, and cytogenetic evaluation, includes the examination of bone marrow morphology. Reticulin fibrosis at presentation in ET and PV is associated with increased risk of myelofibrotic transformation, and higher fibrosis grade in patients with MF is associated with worse prognosis. Additional assessment of collagen deposition and osteosclerosis may further increase diagnostic and prognostic precision. Moreover, the evaluation of bone marrow pathology has become very important in the new era of disease-modifying agents. In randomized controlled phase 3 studies, the JAK1/JAK2 inhibitor ruxolitinib provided rapid and lasting improvement in MF-related splenomegaly and symptom burden as well as a survival advantage compared with placebo or best available therapy. Follow-up for up to 5 years of patients who participated in a phase 1/2 study of ruxolitinib, revealed stabilization or reversal of bone marrow fibrosis in a proportion of patients with MF. Combinations of JAK inhibitors with other therapies, including agents with antifibrotic and/or anti-inflammatory properties, may possibly decrease bone marrow fibrosis further and favorably influence clinical outcomes. PMID- 25515355 TI - Antipsychotic polypharmacy among elderly patients with schizophrenia and dementia during hospitalization at a Taiwanese psychiatric hospital. AB - BACKGROUND: This study was to investigate the prescribing patterns for antipsychotic drugs in elderly hospitalized patients with a diagnosis of schizophrenia or dementia at a psychiatric hospital in Taiwan from 2007 to 2012. This study also explored the predictors of antipsychotic polypharmacy (APP). METHODS: We collected patients' demographic data, including year of admission, age, gender, and length of hospital stay, and drug-related information. RESULTS: Second-generation antipsychotic (SGA) monotherapy was the most common type of therapy in both those with dementia and with schizophrenia, and quetiapine and risperidone were the most commonly prescribed drugs for these conditions, respectively. In late-life schizophrenia, 33.8% of the patients used first generation antipsychotics (FGA) alone. Regarding APP, a combination of FGA and SGA and combinations of SGA were most commonly noted in schizophrenia patients and dementia patients, respectively. Overall, APP increased from 2007 to 2012. It was significantly more common in patients with dementia (odds ratio: 3.49, 95% confidence interval: 1.29-9.39, P = 0.014), less concurrent use of hypnotics and sedatives (odds ratio: 0.41, 95% confidence interval: 0.17-0.99, P = 0.046), and a higher-than-recommended dose of antipsychotic drugs (odds ratio: 4.98, 95% confidence interval: 2.75-9.02, P < 0.001). CONCLUSIONS: FGA are still commonly used for the late-life schizophrenia at our hospital. Given their potentially hazardous side effects, FGA must be employed with caution. The use of APP involving SGA increased over the 6 years of the study period, especially among patients with dementia. However, the use of SGA in dementia began to decline after the US Food and Drug Administration's 2005 warning about SGA being associated with increased mortality in dementia patients, which contrasts with the trends examined in this study. Further controlled trials exploring the efficacy, safety, and tolerability of APP in this population are warranted to gain an additional insight into this practice. PMID- 25515356 TI - Images of cell trees, cell lines, and cell fates: the legacy of Ernst Haeckel and August Weismann in stem cell research. AB - Stem cells did not become a proper research object until the 1960 s. Yet the term and the basic mind-set--namely the conception of single undifferentiated cells, be they embryonic or adult, as the basic units responsible for a directed process of development, differentiation and increasing specialisation--were already in place at the end of the nineteenth century and then transmitted on a non-linear path in the form of tropes and diagrams. Ernst Haeckel and August Weismann played a special role in this story. The first coined the term Stammzelle (stem cell), the second was the author of the first cellular stem-tree diagram. Even today, I shall argue, the understanding of stem cells, especially the popular perception, is to a large extent a Haeckelian-Weismannian one. After having demonstrated this, by analysing the terminology, in this essay I will focus on the use of cytogenetic tree diagrams between 1892 and 1925 and on the tacit understanding of stem cells that they transmit. PMID- 25515357 TI - Mendel's use of mathematical modelling: ratios, predictions and the appeal to tradition. AB - The seventh section of Gregor Mendel's famous 1866 paper contained a peculiar mathematical model, which predicted the expected ratios between the number of constant and hybrid types, assuming self-pollination continued throughout further generations. This model was significant for Mendel's argumentation and was perceived as inseparable from his entire theory at the time. A close examination of this model reveals that it has several perplexing aspects which have not yet been systematically scrutinized. The paper analyzes those aspects, dispels some common misconceptions regarding the interpretation of the model, and re-evaluates the role of this model for Mendel himself. In light of the resulting analysis, Mendel's position between nineteenth-century hybridist tradition and twentieth century population genetics is reassessed, and his sophisticated use of mathematics to legitimize his innovative theory is uncovered. PMID- 25515358 TI - "The awe in which biologists hold physicists": Frits Went's first phytotron at Caltech, and an experimental definition of the biological environment. AB - After Darwin, experimental biology sought to unravel organisms. By the early twentieth century, organisms were broadly conceived as the product of their heredity and their environment. Much historical work has explored the scientific attack on the genotype, particularly through the new science of genetics. This article explores the tandem efforts to assert experimental control over the environment in which plants grew and developed. The case described here concerns the creation of the first phytotron at Caltech by botanist and plant physiologist Frits Went. Opening in 1949, the phytotron was a plant laboratory that, across a series of rooms and chambers, kept genes constant while regulating and maintaining defined ranges of known environments. This article details the context in which the phytotron emerged, how the phytotron gained its sobriquet, and how it served to cement the "environment" as a category of biological knowledge. Describing the institutional context of Caltech, its interdisciplinary culture, and its encouragement of adopting technology into biological science, I argue that the phytotron and the commensurate category of the "environment", were the product of the familiar movement to integrate the physical and biological sciences. In addition, however, the creation of the phytotron was also a broader story of plant physiologists establishing a definition of the "environment" in both physical and technological terms. PMID- 25515359 TI - The life of concepts: Georges Canguilhem and the history of science. AB - Twelve years after his famous Essay on Some Problems Concerning the Normal and the Pathological (1943), the philosopher Georges Canguilhem (1904-1995) published a book-length study on the history of a single biological concept. Within France, his Formation of the Reflex Concept in the Seventeenth and Eighteenth Centuries (1955) contributed significantly to defining the "French style" of writing on the history of science. Outside of France, the book passed largely unnoticed. This paper re-reads Canguilhem's study of the reflex concept with respect to its historiographical and epistemological implications. Canguilhem defines concepts as complex and dynamic entities combining terms, definitions, and phenomena. As a consequence, the historiography of science becomes a rather complex task. It has to take into account textual and contextual aspects that develop independently of individual authors. In addition, Canguilhem stresses the connection between conceptual activities and other functions of organic individuals in their respective environments. As a result, biological concepts become tied to a biology of conceptual thinking, analogical reasoning, and technological practice. The paper argues that this seemingly circular structure is a major feature in Canguilhem's philosophical approach to the history of the biological sciences. PMID- 25515360 TI - Errant life, molecular biology, and biopower: Canguilhem, Jacob, and Foucault. AB - This paper considers the theoretical circumstances that urged Michel Foucault to analyse modern societies in terms of biopower. Georges Canguilhem's account of the relations between science and the living forms an essential starting point for Foucault's own later explorations, though the challenges posed by the molecular revolution in biology and Francois Jacob's history of it allowed Foucault to extend and transform Canguilhem's philosophy of error. Using archival research into his 1955-1956 course on "Science and Error," I show that, for Canguilhem, it is inauthentic to treat a living being as an error, even if living things are capable of making errors in the domain of knowledge. The emergent molecular biology in the 1960s posed a grave challenge, however, since it suggested that individuals could indeed be errors of genetic reproduction. The paper discusses how Canguilhem and Foucault each responded to this by examining, among other texts, their respective reviews of Jacob's The Logic of the Living. For Canguilhem this was an opportunity to reaffirm the creativity of life in the living individual, which is not a thing to be evaluated, but the source of values. For Foucault, drawing on Jacob's work, this was the opportunity to develop a transformed account of valuation by posing biopower as the DNA of society. Despite their disagreements, the paper examines these three authors as different iterations of a historical epistemology attuned to errancy, error, and experimentation. PMID- 25515361 TI - Lederberg on bacterial recombination, Haldane, and cold war genetics: an interview. AB - Joshua Lederberg (1925-2008), was one of the pioneers of molecular genetics perhaps best known for his discovery of genetic recombination in bacteria which earned him a Nobel Prize in 1958 (shared with George Beadle and Edward Tatum). Lederberg's interests were broad including the origin of life, exobiology (a term that he coined) and emerging diseases and artificial intelligence in his, later years. This article contains the transcription of an interview in excerpts, docu- menting the interactions between Lederberg and fellow biologist J.B.S. Haldane wlich lasted from 1946 until Haldane's death in Kolkata (then Calcutta) in 1964. PMID- 25515362 TI - Inappropriate management conditions, especially for the regressed class, are related to sperm quality in Prochilodus lineatus. AB - The aims of this study were to evaluate the characteristics of the reproductive classes and semen quality in curimbata (Prochilodus lineatus) breeders maintained in two different rearing systems. To achieve this goal, cages (Cs) and earthen ponds (EPs) were used as experimental systems to provide unsuitable and suitable conditions, respectively. The fish were maintained under the experimental conditions for 18 months. During this period, males were randomly sampled every 2 months for biometric analysis (n = 30 per sample) and for an evaluation of selected characteristics of the testes (n = 5 per sample). After this period, males maintained in EPs and males maintained in Cs (CMs) were evaluated in induced breeding experiments. We observed that rearing P. lineatus in a C at a high stocking density for the long 18-month period of study produced reductions in growth, testis development, gonadosomatic index values, and sperm quality in the fish. We found differences between the groups in all the reproductive classes examined, especially in the regression class, which showed a pronounced accumulation of immature germ cells in the CMs. In this group, we also noted a less intense transition from a continuous to discontinuous germinal epithelium, with an extended and abnormal but less intense spermatogenic period resulting in decreases in semen volume and sperm concentration in the breeding season. Together, such dysfunctions resulted in the production of low-quality sperm in the CMs, as demonstrated by lower-quality DNA (as evaluated by the comet assay), low fertilization success, and low hatching success. In conclusion, to ensure high-quality semen in P. lineatus, appropriate management conditions must be provided throughout the reproductive cycle, especially for the regressed class, even in winter, two seasons before the breeding season. PMID- 25515363 TI - Effect of vaccination with a multivalent modified-live viral vaccine on reproductive performance in synchronized beef heifers. AB - Prebreeding vaccination should provide fetal and abortive protection against bovine viral diarrhea virus (BVDV) and bovine herpesvirus 1 (BoHV-1) but not impede reproduction when administered to cattle before estrus synchronization and breeding. The objective was to assess reproductive performance when naive beef heifers were vaccinated with modified-live viral (MLV) vaccine 2 days after unsynchronized estrus, and then revaccinated with MLV vaccine at 10 or 31 days before synchronized natural breeding. Sixty beef heifers naive to BVDV and BoHV-1 were randomly assigned to one of four treatment groups. Groups A and B (n = 20 per group) were vaccinated with MLV vaccine containing BVDV and BoHV-1 at 2 days after initial detected estrus, and then revaccinated 30 days later, which corresponded to 10 days (group A) or 31 days (group B) before synchronized natural breeding. Groups C and D (n = 10 per group) served as controls and were vaccinated with an inactivated vaccine that did not contain BVDV or BoHV-1 at the same time points as groups A and B, respectively. Estrous behavior was assessed using radio frequency technology. Estrus synchronization was performed, with initiation occurring at revaccination (groups A and C) or 21 days after revaccination (groups B and D). After synchronization, heifers were submitted to a bull breeding pasture for 45 days. At the end of the breeding period, heifers were assessed for pregnancy using ultrasonography. Progesterone concentrations were evaluated at estrus and 10 days after unsynchronized and synchronized estrus, at initial pregnancy check, and at the end of the study. All pregnant heifers in groups A and B and five pregnant heifers in group C were euthanized between 44 and 62 days of gestation and ovarian and conceptus tissues were assayed for BVDV and BoHV-1. Vaccination with MLV vaccine did not result in significant negative reproductive impact based on the duration of interestrus intervals, proportion of heifers exhibiting estrus within 5 days after synchronization, serum progesterone concentrations, pregnancy rates, and pregnancies in the first 5 days of the breeding season. Bovine viral diarrhea virus and BoHV-1 were not detected in luteal tissue, ovarian tissue, or fetal tissues. Use of MLV vaccine did not impede reproduction, when revaccination was performed at 10 or 31 days before synchronized natural breeding. PMID- 25515364 TI - Ram seminal plasma proteins contribute to sperm capacitation and modulate sperm zona pellucida interaction. AB - Incubation of ram spermatozoa in capacitating conditions with cAMP-elevating agents promotes a progressive time-dependent increase in the capacitated sperm subpopulation. In this study, the fertilizing capacity of ram spermatozoa (ability to bind to the zona pellucida, ZBA rate) capacitated in these conditions was determined. The results showed an increase (P < 0.001) in ZBA rate related to control samples in basal medium that contained BSA, calcium, and bicarbonate (1.97 +/- 0.19 vs. 1.31 +/- 0.09 sperm bound/oocyte, respectively). A significant correlation between protein tyrosine phosphorylation and ZBA rate (P < 0.05, r = 0.501) corroborated that incubation in a "high-cAMP" environment improves the fertilizing ability of ram spermatozoa. Likewise, the presence of two seminal plasma (SP) proteins able to protect sperm against cold shock (RSVP14 and RSVP20) was evidenced in both SP and the ram sperm surface, and their influence in the fertilizing ability of spermatozoa capacitated in basal medium or with cAMP elevating agents was determined. The results verified that RSVP14 and RSVP20 act as decapacitating factors given that their addition to SP-free sperm samples previously to capacitation maintained high proportions of the noncapacitated sperm pattern with no increase in protein tyrosine phosphorylation. However, the obtained ZBA rate in the high-cAMP-containing samples was increased in the presence of RSVP20 (P < 0.05). These findings would indicate that the stimulating effect exerted by this protein on the sperm-oocyte binding occurs downstream from the cAMP generation and that the mechanisms by which RSVP20 promotes the zona pellucida binding might be independent of protein tyrosine phosphorylation. PMID- 25515366 TI - A giant lump on the shoulder. PMID- 25515365 TI - The effect of COX-2-selective meloxicam on the myocardial, vascular and renal risks: a systematic review. AB - PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) are known to increase the risk of cardiovascular (CV) and renal incidences, especially at higher doses and upon long term use. However, the available reports are criticized for lack of specificity, grouping of vastly different outcomes together and ignoring the heterogeneity among NSAIDs. In this systematic review, we are reporting CV/renal risks associated with meloxicam, stratified into myocardial, vascular, renal risk categories, to address the differential nature of NSAIDs effects on different body systems. We are also reporting composite CV/renal risk to present overall risk associated with various covariates. METHODS: We searched the online healthcare databases for observational studies or randomized controlled trials, reporting myocardial or all-cause mortality outcome (>90 days exposure) and/or vascular/renal outcomes (any exposure) after meloxicam use, published until April 2014. The combined odd ratio values (OR'; 95% CI) were calculated using the random effect inverse variance model. RESULTS: We found 19 eligible studies out of 2,422 reports. Meloxicam demonstrated a low increase in composite risk (OR' 1.14; CI 1.04-1.25) which was mainly vascular in nature (OR' 1.35; CI 1.18-1.55] as it did not elevate myocardial (OR' 1.13; CI 0.98-1.32) or renal (OR', 0.99; CI 0.72-1.35) risks. Relative to meloxicam, other NSAIDs increased the composite risk, in a dose-dependent fashion, in the following order: rofecoxib > indomethacin > diclofenac > celecoxib > naproxen > ibuprofen. OR' was also influenced by type of disease and the comparator used, and acetylsalicylic acid. CONCLUSION: NSAIDs are heterogeneous in increasing CV/renal risks. The low increased risk associated with meloxicam is mainly vascular in origin. PMID- 25515368 TI - Development of a SCAR (sequence-characterised amplified region) marker for acid resistance-related gene in Lactobacillus plantarum. AB - A sequence characterised amplified region marker was developed to determine an acid resistance-related gene in Lactobacillus plantarum. A random amplified polymorphic DNA marker named S116-680 was reported to be closely related to the acid resistance of the strains. The DNA band corresponding to this marker was cloned and sequenced with the induction of specific designed PCR primers. The results of PCR test helped to amplify a clear specific band of 680 bp in the tested acid-resistant strains. S116-680 marker would be useful to explore the acid-resistant mechanism of L. plantarum and to screen desirable malolactic fermentation strains. PMID- 25515367 TI - Temperature and pH control on lipid composition of silica sinters from diverse hot springs in the Taupo Volcanic Zone, New Zealand. AB - Microbial adaptations to environmental extremes, including high temperature and low pH conditions typical of geothermal settings, are of interest in astrobiology and origin of life investigations. The lipid biomarkers preserved in silica deposits associated with six geothermal areas in the Taupo Volcanic Zone were investigated and variations in lipid composition as a function of temperature and pH were assessed. Lipid analyses reveal highly variable abundances and distributions, reflecting community composition as well as adaptations to extremes of pH and temperature. Biomarker profiles reveal three distinct microbial assemblages across the sites: the first in Champagne Pool and Loop Road, the second in Orakei Korako, Opaheke and Ngatamariki, and the third in Rotokawa. Similar lipid distributions are observed in sinters from physicochemically similar springs. Furthermore, correlation between lipid distributions and geothermal conditions is observed. The ratio of archaeol to bacterial diether abundance, bacterial diether average chain length, degree of GDGT cyclisation and C31 and C32 hopanoic acid indices typically increase with temperature. At lower pH, the ratio of archaeol to bacterial diethers, degree of GDGT cyclisation and C31 and C32 hopanoic acid indices are typically higher. No trends in fatty acid distributions with temperature or pH are evident, likely reflecting overprinting due to population influences. PMID- 25515369 TI - High oxygen tension increases global methylation in bovine 4-cell embryos and blastocysts but does not affect general retrotransposon expression. AB - Retrotransposons are transposable elements that insert extra copies of themselves throughout the genome via an RNA intermediate using a 'copy and paste' mechanism. They account for more than 44% of the bovine genome and have been reported to be functional, especially during preimplantation embryo development. In the present study, we tested whether high oxygen tension (20% O2) influences global DNA methylation analysed by immunofluorescence staining of developing bovine embryos and whether this has an effect on the expression of some selected retrotransposon families. High oxygen tension significantly increased global DNA methylation in 4 cell embryos and blastocysts. A significant expression difference was observed for ERV1-1-I_BT in female blastocysts, but no significant changes were observed for the other retrotransposon families tested. Therefore, the study indicates that global DNA methylation is not necessarily correlated with retrotransposon expression in bovine preimplantation embryos. PMID- 25515370 TI - Does the site of anastomosis for esophagectomy affect long-term quality of life? AB - Long-term survival after esophagectomy is improving, and hence, quality of life (QOL) of these patients has become a priority. There has been extensive debate regarding the optimal site of surgical anastomosis (cervical or intrathoracic). We aimed to evaluate the impact of anastomotic site on long-term QOL postesophagectomy. Quality of life questionnaires (European Organisation for Research and Treatment of Cancer [EORTC] C-30 and OG-25) were sent to patients surviving over 3 years following esophagectomy. The data were analyzed by site of esophagogastric anastomosis: intrathoracic or cervical. EORTC C-30 data were compared against the reference population data. Of the patients, 62 responded (82%) with a median time postsurgery of 6.1 years (range 3-12 years). Patient demographics were comparable. There was no significant difference between cervical or intrathoracic anastomosis groups for functional or symptom scores, focusing on dysphagia (cervical = 8.8 vs. intrathoracic = 17.6, P = 0.24), odynophagia (cervical = 13.4 vs. intrathoracic = 16.1, P = 0.68) and swallowing problems (cervical = 8.1 vs. intrathoracic = 13.4, P = 0.32). There was no difference in overall health score between groups (cervical = 70.5 vs. intrathoracic = 71.6, P = 0.46). Overall general health score was comparable with the reference population (esophagectomy group P = 70.9 +/- 22.1 vs. reference population = 71.2 +/- 22.4, P = 0.93). There is no difference in long-term QOL after esophagectomy between patients with a cervical or intrathoracic anastomosis. Scores compare favorably with EORTC reference data. Survival after esophagectomy is associated with recovery of QOL in the long term, regardless of site of anastomosis and despite worse gastrointestinal-related symptoms. PMID- 25515371 TI - Compartment Syndrome After Varicose Vein Surgery Evidenced by CT Images. AB - A 21-year-old man developed compartment syndrome after a varicose vein surgery. Because of a lack of appropriate diagnostic apparatus, it was not possible to measure calf pressure. The only diagnostic tool available was computed tomography (CT). With the aid of CT, faster diagnosis of the compartment syndrome was possible, leading to appropriate management. By providing unique CT images of a patient before and after having compartment syndrome and after a fasciotomy, this study could add valuable references for diagnosis of compartment syndrome using CT. PMID- 25515372 TI - Innovation, Translation, and Cooperation. AB - The 9th Wound Healing and Tissue Repair and Regeneration Annual Meeting of Chinese Tissue Repair Society was hold in Wuhan, China. This meeting was focused on the innovation, translation application, and cooperation in wound care both in China and other countries. More than 400 delegates took part in this meeting and communicated successfully. PMID- 25515373 TI - Staphylococcus aureus-Related Diabetic Osteomyelitis: Medical or Surgical Management? A French and Spanish Retrospective Cohort. AB - Staphylococcus aureus is the main cause of diabetic foot osteomyelitis (DFO) and can be treated medically or by surgery. We investigated the outcome of consecutive patients with a diagnosis of S aureus DFO retrospectively in 4 hospitals according to the type of management, medical (including debridement at bedside) or surgical. The outcome was classified as either favorable or failure (relapse, impaired wound healing, or amputation). Seventy-four patients with S aureus DFO, including 26 with methicillin-resistant S aureus, were included with a mean duration of follow-up of 21 +/- 1 months. As part of the initial treatment, 47% underwent bone surgery followed with a short course of antibiotic. Others were treated with antibiotic therapy alone with bedside debridement. The outcome was favorable for 84% of these patients, with similar rates in the surgical and medical groups (80% vs 87%, P > .05). Patients in the medical group were less frequently hospitalized (49% vs 94%, P < .001) and had a shorter length of hospital stay (17 +/- 3 vs 50 +/- 12 days, P = .004). Patients in the surgery group received a shorter course of antibiotic therapy (10 +/- 2 vs 11 +/- 1 weeks, P = .001) with fewer side effects (9% vs 33%, P = .01). The type of management was not associated with subsequent new episode of noncontiguous DFO, which developed in 32% of cases. In conclusion, except significant differences in duration of hospitalization and antibiotic therapy, medical and surgical management of S aureus DFO had similar outcomes with a cure rate >80%. PMID- 25515374 TI - Infective endocarditis caused by Finegoldia magna following aortic dissection repair: a case report and data evaluation. AB - BACKGROUND: Finegoldia magna (F. magna) is a rare pathogen causing infective endocarditis (IE). Only 7 cases are documented in the literature. CASE REPORT: We report a case of infective endocarditis in a 45-year-old male due to F. magna 2 months after a Bentall procedure. He presented with fever, dyspnea, and chest pain. Aerobic and anaerobic blood samples were drawn before empirical antibiotic treatment was initiated. A transesophageal echocardiogram (TEE) demonstrated several findings involving the prosthetic valve, including a vegetation. The patient underwent a second aortic repair procedure. Tissue cultures obtained from 2 sources in the infected area during the operation were positive for F. magna. The antibiotic regimen was changed in accordance with susceptibility testing to piperacillin/tazobactam. Two weeks after the operation, the patient was released with a recommendation for antibiotic treatment for 8 weeks. CONCLUSIONS: We report this case because F. magna in a rare pathogen causing endocarditis. This was a case of prosthetic valve F. magna IE in which the definitive diagnosis was based on tissue cultures following sterile blood cultures. Data evaluation of all F. magna IE reported cases illustrated that tissue cultures were the predominant microbiologic diagnostic tool used. PMID- 25515375 TI - Transmission through air as a possible route of exposure for MRSA. AB - Livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) is highly prevalent in pigs and veal calves. The environment and air in pig and veal calf barns is often contaminated with LA-MRSA, and can act as a transmission source for humans. This study explores exposure-response relationships between sequence type 398 (ST398) MRSA air exposure level and nasal ST398 MRSA carriage in people working and/or living on farms. Samples and data were used from three longitudinal field studies in pig and veal calf farm populations. Samples consisted of nasal swabs from the human participants and electrostatic dust fall collectors capturing airborne settled dust in barns. In both multivariate and mutually adjusted analyses, a strong association was found between nasal ST398 MRSA carriage in people working in the barns for >20 h per week and MRSA air levels. In people working in the barns < 20 h per week there was a strong association between nasal carriage and number of working hours. Exposure to ST398 MRSA in barn air seems to be an important determinant for nasal carriage, especially in the highly exposed group of farmers, next to duration of contact with animals. Intervention measures should therefore probably also target reduction of ST398 MRSA air levels. PMID- 25515376 TI - Reliability of concentrations of organophosphate pesticide metabolites in serial urine specimens from pregnancy in the Generation R Study. AB - The widespread use of organophosphate (OP) pesticides has resulted in ubiquitous exposure in humans, primarily through their diet. Exposure to OP pesticides may have adverse health effects, including neurobehavioral deficits in children. The optimal design of new studies requires data on the reliability of urinary measures of exposure. In the present study, urinary concentrations of six dialkyl phosphate (DAP) metabolites, the main urinary metabolites of OP pesticides, were determined in 120 pregnant women participating in the Generation R Study in Rotterdam. Intra-class correlation coefficients (ICCs) across serial urine specimens taken at <18, 18-25, and >25 weeks of pregnancy were determined to assess reliability. Geometric mean total DAP metabolite concentrations were 229 (GSD 2.2), 240 (GSD 2.1), and 224 (GSD 2.2) nmol/g creatinine across the three periods of gestation. Metabolite concentrations from the serial urine specimens in general correlated moderately. The ICCs for the six DAP metabolites ranged from 0.14 to 0.38 (0.30 for total DAPs), indicating weak to moderate reliability. Although the DAP metabolite levels observed in this study are slightly higher and slightly more correlated than in previous studies, the low to moderate reliability indicates a high degree of within-person variability, which presents challenges for designing well-powered epidemiological studies. PMID- 25515378 TI - Pressure-induced molten globule state of human acetylcholinesterase: structural and dynamical changes monitored by neutron scattering. AB - We used small-angle neutron scattering (SANS) to study the effects of high hydrostatic pressure on the structure of human acetylcholinesterase (hAChE). At atmospheric pressure, our SANS results obtained on D11 at ILL (Grenoble, France) give a radius of gyration close to that calculated for a mixture of monomers, dimers and tetramers of the enzyme, suggesting a good agreement between hAChE crystal structure and its conformation in solution. Applying high pressure to the sample we found a global compression of about 11% of the enzyme up to a pressure of 900 bar and then again an extension up to 2.1 kbar indicating unfolding of the tertiary structure due to a molten globule (MG) state. On the other hand, we studied the influence of pressure up to 6 kbar on the dynamics of this enzyme, on the backscattering spectrometer IN13 at ILL. For the first time, we used elastic incoherent neutron scattering (EINS) to probe the differences between hAChE in its folded state (N), its high-pressure induced MG state and its unfolded state (U). Especially around the MG state at 1750 bar we found a significant increase in the dynamics, indicating a partial unfolding. A four-step-model is suggested to describe the changes in the protein. PMID- 25515377 TI - Prenatal exposure to pyrethroid insecticides and birth outcomes in Rural Northern China. AB - Although pyrethroid insecticides are widely used, little is known about potential adverse effects on fetal growth. Participating 454 mother-infant pairs were recruited from a prospective birth cohort in rural northern China between September 2010 and 2012. We measured five non-specific pyrethroid metabolites in maternal urine at delivery and examined their association with birth outcomes including birth weight, length, head circumference, and gestational duration. The creatinine-adjusted medians of pyrethroid metabolites in urine were 0.51 MUg/g for cis-DCCA, 0.65 MUg/g for trans-DCCA, and 0.68 MUg/g for 3-PBA. The pregnant women had substantially higher levels of urinary pyrethroid metabolites compared with those reported in developed countries. A increase in total (the sum of cis DCCA, trans-DCCA, and 3-PBA) but not individual urinary metabolite levels was associated with a decrease in birth weight (adjusted beta=-96.76 g per log10 unit increase, 95% confidence interval=-173.15 to -20.37). No associations were found between individual or total metabolite levels and birth length, head circumference, or gestational duration. We report an adverse association of prenatal exposure to pyrethroids as measured by urinary metabolites with birth weight. More studies are warranted in China given the relatively high levels of urinary metabolites in our study population. PMID- 25515379 TI - How doctors learn and perform sustained inflations with a self-inflating bag: a manikin study with a newborn lung simulator. AB - AIM: Sustained inflations during initial resuscitation may help a depressed infant make a more efficient transition to air-filled lungs. This study examined whether doctors could perform sustained inflations with a self-inflating bag in high and low compliance settings and with an open or blocked pressure-relief valve. METHODS: We asked 43 doctors to carry out sustained inflations for more than 5-sec in a manikin connected to a newborn lung simulator with randomised compliance settings. Tidal volume, inflation time, peak and mean inflating pressure were measured, and 34 were retested 3 months later. RESULTS: The majority of the doctors - 72% in the initial study and 62% in the retest - managed sustained inflations within three ventilation attempts, irrespective of lung compliance setting and years of work experience. Using a blocked pressure relief valve produced higher tidal volume (27.8 versus 22.6 mL, p < 0.001), inflation time (8.9 versus 8.1 sec, p = 0.025), peak inflating pressure (34.0 versus 28.0 cmH2O; p = 0.012) and mean inflating pressure (28.1 versus 22.8 cmH2O; p < 0.001). CONCLUSION: The majority of doctors could deliver sustained inflation with a self-inflating bag in a newborn lung simulator for more than 5 sec. Using a blocked pressure-relief valve resulted in higher inflation time, tidal volume and inflation pressure. PMID- 25515380 TI - Spectrum of skin diseases presented at LAUTECH Teaching Hospital, Osogbo, southwest Nigeria. AB - BACKGROUND: Patterns of skin disease in developing nations are changing as frequencies of non-communicable diseases continue to increase. Appraisal of the current status of the disease profile is of utmost importance for health planning and resource allocation. METHODS: A prospective analysis of 895 cases of outpatient consultation during the years 2005-2010 was conducted. RESULTS: The mean +/- standard deviation age of patients was 31.1 +/- 19.1 years. Non infectious skin diseases accounted for 80.9% of all cases. Eczemas/dermatitis (27.0%), urticarias/erythemas (11.0%), fungal infections (9.5%), skin appendage disorders (8.9%), papulosquamous diseases (8.2%), pigmentary diseases (8.2%), viral infections (6.8%), and tumors and malignant skin lesions (5.4%) represented the most common presentations. Atopic dermatitis was the most common type of eczema (29.8%) among children (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.09-2.13; P = 0.013), in whom cornification disorders (OR 3.90, 95% CI 1.73 8.92; P < 0.001) and viral infections (OR 1.80, 95% CI 1.09-3.25; P = 0.021) were also frequent. Adults were more likely to be diagnosed with drug eruptions (OR 3.58, 95% CI 1.09-11.80; P = 0.003), tumors/malignancy (OR 4.97, 95% CI 1.53 16.10; P = 0.030), or autoimmune connective tissue disorders (OR 8.13, 95% CI 1.09-60.20; P = 0.015). Female subjects were significantly affected by urticarias (OR 1.53, 95% CI 1.00-2.33; P = 0.030) and papulosquamous diseases (OR 1.80, 95% CI 1.09-3.03; P = 0.019). CONCLUSIONS: The present pattern shows that non infectious skin diseases are predominant. Occurrences of eczemas and urticarias are increasing at similar rates, whereas infectious skin diseases are decreasing in frequency. Resources and research should be directed towards the prevention of non-infectious skin diseases at this time as the campaign for a cleaner environment continues. PMID- 25515381 TI - Electronic structure and optical signatures of semiconducting transition metal dichalcogenide nanosheets. AB - CONSPECTUS: Two-dimensional (2D) crystals derived from transition metal dichalcogenides (TMDs) are intriguing materials that offer a unique platform to study fundamental physical phenomena as well as to explore development of novel devices. Semiconducting group 6 TMDs such as MoS2 and WSe2 are known for their large optical absorption coefficient and their potential for high efficiency photovoltaics and photodetectors. Monolayer sheets of these compounds are flexible, stretchable, and soft semiconductors with a direct band gap in contrast to their well-known bulk crystals that are rigid and hard indirect gap semiconductors. Recent intense research has been motivated by the distinct electrical, optical, and mechanical properties of these TMD crystals in the ultimate thickness regime. As a semiconductor with a band gap in the visible to near-IR frequencies, these 2D MX2 materials (M = Mo, W; X = S, Se) exhibit distinct excitonic absorption and emission features. In this Account, we discuss how optical spectroscopy of these materials allows investigation of their electronic properties and the relaxation dynamics of excitons. We first discuss the basic electronic structure of 2D TMDs highlighting the key features of the dispersion relation. With the help of theoretical calculations, we further discuss how photoluminescence energy of direct and indirect excitons provide a guide to understanding the evolution of the electronic structure as a function of the number of layers. We also highlight the behavior of the two competing conduction valleys and their role in the optical processes. Intercalation of group 6 TMDs by alkali metals results in the structural phase transformation with corresponding semiconductor-to-metal transition. Monolayer TMDs obtained by intercalation-assisted exfoliation retains the metastable metallic phase. Mild annealing, however, destabilizes the metastable phase and gradually restores the original semiconducting phase. Interestingly, the semiconducting 2H phase, metallic 1T phase, and a charge-density-wave-like 1T' phase can coexist within a single crystalline monolayer sheet. We further discuss the electronic properties of the restacked films of chemically exfoliated MoS2. Finally, we focus on the strong optical absorption and related exciton relaxation in monolayer and bilayer MX2. Monolayer MX2 absorbs as much as 30% of incident photons in the blue region of the visible light despite being atomically thin. This giant absorption is attributed to nesting of the conduction and valence bands, which leads to diversion of optical conductivity. We describe how the relaxation pathway of excitons depends strongly on the excitation energy. Excitation at the band nesting region is of unique significance because it leads to relaxation of electrons and holes with opposite momentum and spontaneous formation of indirect excitons. PMID- 25515382 TI - A delay discounting task produces a greater likelihood of waiting than a deferred gratification task. AB - A first-person-shooter video game was adapted for the study of choice between smaller sooner and larger later outcomes to compare the behavioral patterns produced by deferred gratification (DG) and delay discounting (DD) tasks. Participants played a game in which they could either fire their weapon sooner and do a small amount of damage or wait a few seconds to fire their weapon and do a larger amount of damage. For the DD task, a failure to fire within one second committed the player to waiting for the larger later outcome thus removing the opportunity to defect during the delay that is present in the DG task. The incentive structure changed multiple times during game play so that at times the optimal decision was to choose the smaller sooner outcome whereas at other times the optimal decision was to wait for the larger later outcome. Players assigned to the DD task showed a greater tendency to wait and lower sensitivity to the changing incentives. PMID- 25515383 TI - Extinction of aversive classically conditioned human sexual response. AB - INTRODUCTION: Research has shown that acquired subjective likes and dislikes are quite resistant to extinction. Moreover, studies on female sexual response demonstrated that diminished genital arousal and positive affect toward erotic stimuli due to aversive classical conditioning did not extinguish during an extinction phase. Possible resistance to extinction of aversive conditioned sexual responses may have important clinical implications. However, resistance to extinction of aversive conditioned human sexual response has not been studied using extensive extinction trials. AIM: This article aims to study resistance to extinction of aversive conditioned sexual responses in sexually functional men and women. METHODS: A differential conditioning experiment was conducted, with two erotic pictures as conditioned stimulus (CSs) and a painful stimulus as unconditioned stimuli (USs). Only one CS (the CS+) was followed by the US during the acquisition phase. Conditioned responses were assessed during the extinction phase. MAIN OUTCOME MEASURE: Penile circumference and vaginal pulse amplitude were assessed, and ratings of affective value and subjective sexual arousal were obtained. Also, a stimulus response compatibility task was included to assess automatic approach and avoidance tendencies. RESULTS: Men and women rated the CS+ more negative as compared with the CS-. During the first trials of the extinction phase, vaginal pulse amplitude was lower in response to the CS+ than in response to the CS-, and on the first extinction trial women rated the CS+ as less sexually arousing. Intriguingly, men did not demonstrate attenuated genital and subjective sexual response. CONCLUSIONS: Aversive conditioning, by means of painful stimuli, only affects sexual responses in women, whereas it does not in men. Although conditioned sexual likes and dislikes are relatively persistent, conditioned affect eventually does extinguish. PMID- 25515384 TI - [The quality institute for doctors]. AB - The mission of the Quality Institute, which is part of the Dutch National Health Care Institute, is to promote quality of healthcare. It is cooperating with all parties within healthcare to improve quality and insight into quality. Input from all stakeholders, including healthcare providers, clients, and providers of healthcare insurance, is important for the realisation of quality standards and measuring instruments. The starting point is the demands of the client. The Quality Institute has drawn up a framework to test criteria with which quality standards and measuring instruments must comply. This promotes the development of good quality standards and measuring instruments that deliver useful and reliable information. The current practice of parallel registration of patient data, for the care process and to deliver quality-information, causes high administrative burdens and is not future-proof. For that reason the Quality Institute, together with other parties in healthcare, is developing the concept of an 'information standard'. This should eventually lead to multiple use of unambiguous data registered at source. PMID- 25515385 TI - [Video consultation in general practice: need and feasibility]. AB - OBJECTIVE: To study whether patients require video consultations in general practice and whether or not video consultation is feasible. DESIGN: Semi structured interviews and a pilot study in practice. METHOD: We interviewed 25 visitors to the general practice on their views on video consultations in a health centre in the eastern part of the Netherlands. Furthermore, we studied and evaluated the feasibility of video consultation for 21 patients. RESULTS: Patients' opinions on video consultations differed. Few patients felt that video consultation was suitable for a first contact in a disease episode, and hardly any patient saw possibilities for video consultations from their work station. Many patients favoured the possibility of specialists or family members joining the consultation from a remote location. Although technical problems occurred in more than 80% of consultations, over 80% of patients were satisfied after the video consultation had taken place. CONCLUSION: The need for video consultation in general practice is limited. Although many technical problems occurred, video consultations are feasible and can be conducted satisfactorily in practice. PMID- 25515386 TI - [Doctor, know that your patient has Googled: Internet and reason for medical consultation]. AB - The internet is increasingly used as a source of medical information, not only by healthcare professionals but by patients as well. We describe the case of Patient A, a 32-year-old male with symptoms of sinusitis. He found a treatment on the internet and was informed when to consult a general practitioner. We also describe Patient B, a 31-year-old female with symptoms of fatigue after the delivery of her second child. Her search on the internet led to several referrals to a medical specialist due to her conviction that her symptoms were caused by a hormonal imbalance. We conclude that medical information on the internet can support both the doctor and the patient, or it can present an obstacle to proper communication during a consultation. Awareness by medical professionals of the Googling behaviour of their patients may be helpful in detecting the underlying question and worries of the patient. PMID- 25515387 TI - [E-health for all: are we reaching the patients who really need it?]. AB - The introduction and implementation of e-health into our healthcare system may have great benefits. E-health as a means of improving health and lowering healthcare expenditure may be especially efficacious when aimed specifically at older patients and those in lower income groups. However, older patients may not generally feel as comfortable using e-health as younger patients do, and sometimes lack the necessary skills. In addition, patients from lower income groups may not have the necessary access to e-health. New cost-effectiveness analyses of e-health should take into account costs necessary for improving computer skills as well as access to e-health. PMID- 25515388 TI - [Point-of-care testing in family practices: present use and need for tests in the future]. AB - OBJECTIVE: To provide insight into the current use, future needs, and attitudes towards point-of-care testing among Dutch family practitioners. DESIGN: Cross sectional online survey. METHOD: We performed a survey among 2129 Dutch family practitioners. We asked respondents to report on the current and desired use of point-of-care tests, frequency of use, their opinions on aspects of point-of-care tests and consequences of point-of-care tests on their practice, acceptable waiting times for test results to come in, the desire for point-of-care tests at out-of-hours services, and conditions for which a point-of-care test could assist in diagnosis. RESULTS: 639 family practitioners completed the survey (response rate: 30%). The most common point-of-care tests currently used by family physicians were: blood glucose (96%), urine leucocytes or nitrite (96%), urine pregnancy (94%), haemoglobin (58%), and CRP (48%). The most commonly desired point-of-care tests were: D-dimer (70%), troponin (65%), BNP (62%), chlamydia (60%), and INR (54%). Family practitioners expected point-of-care tests to have a positive effect on patient satisfaction (93%), diagnostic certainty (89%), antibiotics use (84%), and substitution to primary care (78%). They considered the proven effect on clinical management (46%) and the tests' reliability (35%) to be important aspects of point-of-care tests. Respondents wanted point-of-care tests to help them diagnose acute conditions, such as acute thromboembolic disorders (D-dimers), cardiac disorders (troponin, BNP), and infections (CRP, chlamydia). CONCLUSION: The current use of point-of-care testing in family practice is restricted to a limited number of tests. In the future, Dutch family practitioners wish to use more point-of-care tests, especially in acute conditions in which a diagnostic decision needs to be made immediately. PMID- 25515389 TI - [Virtual paediatric medicine]. AB - Health information technology (eHealth) can be cost-effective if it replaces existing care services. The introduction of eHealth has provided the opportunity to directly support and improve care for children with chronic diseases. We show an example of this in children with diabetes mellitus. Giving patients direct feedback on their glucose levels results in better outcomes of patient care. Accessing data from electronic patient files and using them effectively, however, is not yet possible in a number of health care institutions. PMID- 25515390 TI - [Telemedicine for patients with chronic intestinal failure]. AB - Telemedicine is a valuable extension of the ways in which patients with chronic diseases can be contacted. Patients can easily contact their caregivers within the safe environment of the digital waiting room. Telemedicine especially offers an advantage for those forms of care where the visual aspect is important. Care should be taken with respect to its implementation into the disease management process with careful synchronisation between all involved parties, e.g. patient, caregiver, and organisation. The effectiveness of telemedicine and the savings that can be achieved should be properly established in order to justify the funding of a telemedicine project. Rather than focusing on the possible drawbacks of telemedicine, e.g. safety concerns and the user-friendliness of the system, we should highlight the possibilities that information technology offers. PMID- 25515391 TI - [What do you think of Thuisarts.nl? Experiences after 3 years of www.Thuisarts.nl]. AB - Many people need information on health and disease, but the internet is a maze of medical information. In order to offer patients reliable medical information, and to support general practitioners, the Dutch College of General Practitioners (NHG) set up the public website Thuisarts.nl in 2011, which was later followed by an app. The NHG members survey amongst general practitioners from June 2013 showed that 90% of the general practitioners used Thuisarts.nl. The number of visitors was on average 60,000 a day. Information is also available from questionnaires filled in by the NIVEL Health Care Consumer Panel (n = 2846) and participants in a study on information technology and independence (n = 25). Thuisarts.nl meets an important need and is highly valued by doctors and patients. There are plans for the further development of Thuisarts.nl including short videos, illustrations, searchable anatomical structures and information from other reliable organisations such as associations of specialist doctors. PMID- 25515392 TI - [A legal perspective on trends in eHealth]. AB - eHealth aims to support and enhance citizens' health and healthcare in general using information technology. Medical confidentiality and protection of personal data play an important role in most eHealth applications. In July 2014, the Dutch Lower House adopted a bill that imposes conditions on electronic provision of patient data. When using social media, healthcare professionals would be prudent to observe the guidelines of the professional group. A European quality mark is required for medical apps that fall under the European Medical Devices Directive, but that does not dispel doubts about the reliability of medical apps. PMID- 25515393 TI - [E-health and the GP as gatekeeper; are the two compatible?]. AB - Within the Dutch healthcare system the general practitioner functions as a "gatekeeper", deciding whether or not to refer the patient for specialist care. The introduction of e-health makes it easier for medical specialists to inform patients about their abilities in their own field. When they also offer to help the patient via e-health consultation they are, in practical terms, bypassing the gatekeeper. At the moment the Dutch healthcare system has no way of regulating payment for these services. Irrespective of the many advantages of e-health in the collaboration between primary and specialist care, we should carefully consider whether we want the gatekeeper to be bypassed in this way. This will be even more important if it results in extra costs for the healthcare system. PMID- 25515394 TI - [Not Available]. AB - A Dutch research group has calculated how much cancer in the Netherlands can be prevented and how much the incidence of cancer deaths could be diminished by reducing pathogenic factors associated with behaviour. This has been known for a long time, but that does not change the behaviour that is driven by habits, environment and addiction. Health lobbies are necessary that infiltrate the political parties. We also need more research into the origins and reduction of addictions. PMID- 25515395 TI - [E-health within the Dutch mental health services: what is the current situation?]. AB - The 'e-mental health' currently available, which also covers m-health and i health, varies from psycho-education and self-tests to self-help, treatment and contact with fellow sufferers. Many programs are based on cognitive behavioural therapy, but other types of therapy are also used. Research shows that online programs for depression, alcohol problems and anxiety can reduce these symptoms and can be cost effective. This applies to both self-help and treatment programs. Many e-programs in the Netherlands have been developed for the Dutch Association of Mental Health and Addiction Care (GGZ) and for treatment of addiction problems. One problem with e-mental-health is that provision is fragmented, and there is no national overview, while insight into quality is important for patients and professionals. The quality hallmark 'Onlinehulpstempel.nl' ('Online help hallmark') provides this insight. The use of e-mental-health within Dutch healthcare services is still in its infancy. New financing methods are stimulating general practitioners to use it. The consolidation of online and face to-face care ('blended e-health') provides an opportunity for patients and GGZ support personnel within general practice to start to use e-health. PMID- 25515396 TI - [Web-based education: learning surgical procedures step-by-step with 3D visualization]. AB - There is a need for more uniform, structured education focused on surgical procedures. We offer a standardized, step-by-step, web-based procedural training method with which surgeons can train more interns efficiently. The basis of this learning method is formed by 3D films in which surgical procedures are performed in clearly defined steps and the anatomic structures behind the surgical operating planes are further dissected. This basis is supported by online modules in which, aside from the operation, preparation and postoperative care are also addressed. Registrars can test their knowledge with exams. Trainers can see what the registrars studied, how they scored and how they progressed with their clinical skills. With the online portfolio we offer building blocks for certification and accreditation. With this clearly structured research method of constant quality, registrars are less dependent on the local trainer. In addition, through better preparation, the operation capacity can be used more efficiently for the training. PMID- 25515397 TI - [Contribution of lifestyle factors to cancer: secondary analysis of Dutch data over 2010 and a projection for 2020]. AB - OBJECTIVE: To calculate the proportion of cancer cases in the Netherlands in 2010 that were attributable to lifestyle factors by using the most recent data. DESIGN: Secondary analysis. METHOD: Lifestyle risk factors studied were tobacco smoking, alcohol consumption, overweight, lack of physical exercise, and six elements of diet (consumption of vegetables, fruit, processed meat and red meat, and calcium and fibre intake). The lifestyle factors were organised so that the group with the highest risk (e.g. smokers) could be compared with the groups with the lowest risk (e.g. ex-smokers, non-smokers). Cut-off points were in line with Dutch public health messages. We obtained prevalence data on risk factors from national databases. Relative risks for the relationship between lifestyle and cancer were based on the international literature. Incidence and mortality data for cancer in 2010 were obtained through the Netherlands Cancer Registry. We calculated percentages of new cancer cases and deaths for men and women and for each type of cancer individually; these were then summed. RESULTS: We estimated that of the 98,971 newly-diagnosed cases of cancer among persons aged >= 20 years in the Netherlands in 2010, 29,938 (30%) were attributable to the above-mentioned lifestyle factors. Smoking was the most important contributory risk factor (19% of all new cancer cases), followed by sub-optimal dietary habits (10%), overweight (4%), alcohol consumption (3%), and lack of physical activity (2%). Of cancer deaths in 2010, an estimated 38% were attributable to lifestyle factors. Projections for 2020 show that lack of exercise and consumption of alcohol and meat will contribute less to the development of cancer while overweight and a reduction in inadequate dietary fibre intake and inadequate fruit and vegetable consumption will contribute more. CONCLUSION: Almost one-third of all cases of cancer and almost 40% of deaths from cancer can be attributed to a less healthy lifestyle. PMID- 25515399 TI - Comparison of whole-genome (13X) and capture (87X) resequencing methods for SNP and genotype callings. AB - The number of polymorphisms identified with next-generation sequencing approaches depends directly on the sequencing depth and therefore on the experimental cost. Although higher levels of depth ensure more sensitive and more specific SNP calls, economic constraints limit the increase of depth for whole-genome resequencing (WGS). For this reason, capture resequencing is used for studies focusing on only some specific regions of the genome. However, several biases in capture resequencing are known to have a negative impact on the sensitivity of SNP detection. Within this framework, the aim of this study was to compare the accuracy of WGS and capture resequencing on SNP detection and genotype calling, which differ in terms of both sequencing depth and biases. Indeed, we have evaluated the SNP calling and genotyping accuracy in a WGS dataset (13X) and in a capture resequencing dataset (87X) performed on 11 individuals. The percentage of SNPs not identified due to a sevenfold sequencing depth decrease was estimated at 7.8% using a down-sampling procedure on the capture sequencing dataset. A comparison of the 87X capture sequencing dataset with the WGS dataset revealed that capture-related biases were leading with the loss of 5.2% of SNPs detected with WGS. Nevertheless, when considering the SNPs detected by both approaches, capture sequencing appears to achieve far better SNP genotyping, with about 4.4% of the WGS genotypes that can be considered as erroneous and even 10% focusing on heterozygous genotypes. In conclusion, WGS and capture deep sequencing can be considered equivalent strategies for SNP detection, as the rate of SNPs not identified because of a low sequencing depth in the former is quite similar to SNPs missed because of method biases of the latter. On the other hand, capture deep sequencing clearly appears more adapted for studies requiring great accuracy in genotyping. PMID- 25515398 TI - Acute effects of feeding fructose, glucose and sucrose on blood lipid levels and systemic inflammation. AB - BACKGROUND: Recent studies have demonstrated a relationship between fructose consumption and risk of developing metabolic syndrome. Mechanisms by which dietary fructose mediates metabolic changes are poorly understood. This study compared the effects of fructose, glucose and sucrose consumption on post postprandial lipemia and low grade inflammation measured as hs-CRP. METHODS: This was a randomized, single blinded, cross-over trial involving healthy subjects (n=14). After an overnight fast, participants were given one of 3 different isocaloric drinks, containing 50 g of either fructose or glucose or sucrose dissolved in water. Blood samples were collected at baseline, 30, 60 and 120 minutes post intervention for the analysis of blood lipids, glucose, insulin and high sensitivity C-reactive protein (hs-CRP). RESULTS: Glucose and sucrose supplementation initially resulted in a significant increase in glucose and insulin levels compared to fructose supplementation and returned to near baseline values within 2 hours. Change in plasma cholesterol, LDL and HDL-cholesterol (measured as area under curve, AUC) was significantly higher when participants consumed fructose compared with glucose or sucrose (P<0.05). AUC for plasma triglyceride levels however remained unchanged regardless of the dietary intervention. Change in AUC for hs-CRP was also significantly higher in subjects consuming fructose compared with those consuming glucose (P<0.05), but not sucrose (P=0.07). CONCLUSION: This study demonstrates that fructose as a sole source of energy modulates plasma lipids and hsCRP levels in healthy individuals. The significance of increase in HDL-cholesterol with a concurrent increase in LDL cholesterol and elevated hs-CRP levels remains to be delineated when considering health effects of feeding fructose-rich diets. REGISTRATION NUMBER FOR CLINICAL TRIALS: ACTRN12614000431628. PMID- 25515400 TI - Squamous cell carcinoma presenting as a refilled thin-walled cavity in lung: a case report. AB - Thin-walled cavity with air-fluid level is often considered radiographically benign-looking lesion. We recently encountered a patient with a rare lung cavity. A 58-year-old male presented with intermittent fever, chest pain and hemoptysis. A large thin-walled cavity, with a smooth inner surface and a clear air-fluid level, occupied the left upper lobe on the chest computerized tomography (CT) scan. After intravenous antibiotics was administrated, the air-fluid level in the cavity disappeared, and the cavity was gradually fluid refilled unexpectedly. However, the cavitary lesion kept the previous contour. Then CT-guided percutaneous needle lung biopsy was performed, revealing a squamous cell carcinoma of the lung. Although it is rare, a refilled thin-walled cavity in lung may be malignant, which should be kept in mind by clinician. PMID- 25515401 TI - A new HLA-B allele, B*44:203, sequenced in a Spanish Caucasian cord blood unit. AB - HLA-B*44:203 shows one nucleotide difference to B*44:03:01 at codon 171 (TAC>CAC, Y171>H171). PMID- 25515402 TI - Orally administered novel cyclic pentapeptide P-317 alleviates symptoms of diarrhoea-predominant irritable bowel syndrome. AB - OBJECTIVE: The aim of our study was to characterize the effect of P-317, a novel cyclic derivative of morphiceptin, on gastrointestinal (GI) motility and abdominal pain in mouse models mimicking symptoms of diarrhoea-predominant irritable bowel syndrome (IBS-D). METHODS: The effect of P-317 on mouse intestinal motility was characterized in vitro and in vivo in physiological and pathophysiological conditions. The antinociceptive action of P-317 was characterized in the mustard oil-induced abdominal pain model and the writhing test. Locomotor activity and grip-strength tests were used to evaluate the effect of P-317 in the central nervous system (CNS). To translate our study to clinical conditions, the semi-quantitative expression of MU-opioid receptors (MOP) and kappa-opioid receptors (KOP) messenger RNA (mRNA) in human colonic samples from IBS-D patients was quantified. KEY FINDINGS: In vitro, P-317 (10(-10) -10(-6) M) inhibited colonic and ileal smooth muscle contractions in a concentration dependent, beta-funaltrexamine and nor-binaltorphimine-reversible manner. In vivo, P-317 (0.1 mg/kg, i.p. and 1 mg/kg, p.o.) inhibited GI transit, displayed a potent antinociceptive action in abdominal pain tests and did not influence the CNS. CONCLUSION: P-317 produced a potent analgesic and antidiarrhoeal action in the mouse GI tract after oral administration. Given lower expression of MOP and KOP mRNA in IBS-D patients, P-317 is a promising peptide-based drug candidate for IBS-D therapy. PMID- 25515403 TI - Antimicrobial activity of Chlorhexidine, Peracetic acid and Sodium hypochlorite/etidronate irrigant solutions against Enterococcus faecalis biofilms. AB - AIM: To evaluate the antimicrobial effect of 2.5% sodium hypochlorite alone (NaOCl) and associated with 9% HEBP (NaOCl/HEBP), 2% peracetic acid (PAA) and 2% chlorhexidine (CHX), on the viability of Enterococcus faecalis biofilms attached to dentine. METHODOLOGY: Biofilms of E. faecalis were grown on the surface of dentine blocks for 5 days and then exposed to the irrigating solutions for 3 min. Distilled water was used as the control. The total biovolume and the percentage of dead cells of the infected dentine were measured by means of confocal microscopy and the live/dead technique. Nonparametric tests were used to determine statistical differences (P < 0.05). RESULTS: NaOCl and the NaOCl/HEBP mixture were associated with a significantly greater percentage of dead cells, followed by PAA (P < 0.05). No significant antimicrobial effect of CHX was observed in comparison with the control group. Total biovolume decreased significantly in NaOCl, NaOCl/HEBP and PAA solutions in comparison with the CHX and control groups. CONCLUSIONS: NaOCl alone or associated with HEBP were the most effective irrigant solutions in dissolving and killing E. faecalis biofilms. PMID- 25515404 TI - Which variable is the strongest adjusted predictor of quality of life in caregivers of patients with dementia? AB - BACKGROUND: The central role of family in caregiving for patients with dementia is now widely acknowledged. However, in playing this role, caregivers may neglect their health and quality of life (QOL). The purposes of present study were to measure caregivers' QOL and to determine its adjusted predictors via multiple regression models. METHODS: We used sequential sampling to recruit 153 patients and their caregivers from the Iran Alzheimer Association in our cross-sectional study. A single-item question with a Likert scale was applied to measure QOL. A multiple linear regression model was used to determine the adjusted predictors of QOL. RESULTS: Of the responding caregivers, 22.8% reported their QOL as poor or very poor. Caregiver burden, the main caregiver's age, the Global Deterioration Scale, and the number of caregivers were introduced as adjusted predictors of QOL. CONCLUSIONS: Caregiver burden was proposed as the strongest adjusted predictor for caregivers' poor QOL. Therefore, it seems that interventions to reduce caregiver burden can be effective in enhancing caregivers' QOL. PMID- 25515405 TI - Authors' reply to Timimi. PMID- 25515406 TI - The canonical Notch pathway effector RBP-J regulates neuronal plasticity and expression of GABA transporters in hippocampal networks. AB - Activation of the Notch pathway in neurons is essential for learning and memory in various species from invertebrates to mammals. However, it remains unclear how Notch signaling regulates neuronal plasticity, and whether the transcriptional regulator and canonical pathway effector RBP-J plays a role. Here, we report that conditional disruption of RBP-J in the postnatal hippocampus leads to defects in long-term potentiation, long-term depression, and in learning and memory. Using gene expression profiling and chromatin immunoprecipitation, we identified two GABA transporters, GAT2 and BGT1, as putative Notch/RBP-J pathway targets, which may function downstream of RBP-J to limit the accumulation of GABA in the Schaffer collateral pathway. Our results reveal an essential role for canonical Notch/RBP-J signaling in hippocampal synaptic plasticity and suggest that role, at least in part, is mediated by the regulation of GABAergic signaling. PMID- 25515407 TI - Elevated VEGF levels contribute to the pathogenesis of osteoarthritis. AB - BACKGROUND: The aim of our meta-analysis is to understand the relationship between the pathogenesis of osteoarthritis and the expression levels of vascular endothelial growth factor (VEGF) in multiple disease tissues in osteoarthritis patients. METHODS: The following electronic databases were searched, without language restrictions, to retrieve published studies relevant to VEGF and osteoarthritis: MEDLINE (1966 ~ 2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), Web of Science (1945 ~ 2013) and the Chinese Biomedical Database (CBM) (1982 ~ 2013). Meta-analysis of the extracted data was performed using the STATA statistical software. Standardized mean difference (SMD) with its corresponding 95% confidence interval (95% CI) was calculated. RESULTS: A total of 11 case-control studies, containing 302 osteoarthritis patients and 195 healthy controls, met our selection criteria for this meta-analysis. Our analyses of the data available from multiple disease tissues demonstrate that VEGF expression levels in osteoarthritis patients are significantly higher than healthy controls (SMD = 1.18, 95% CI: 4.91 ~ 9.11, P < 0.001). A subgroup analysis based on ethnicity revealed that both Asian and Caucasian osteoarthritis patients had higher levels of VEGF expression compared to their respective healthy counterparts (Asians: SMD = 5.49, 95% CI: 3.44 ~ 7.54, P < 0.001; Caucasians: SMD = 15.17, 95% CI: 5.21 ~ 25.13, P = 0.003; respectively). We also performed other subgroup analyses based on country, language and sample source, and the results showed that, in all these subgroups, osteoarthritis patients had higher levels of VEGF expression than healthy controls (all P > 0.05). CONCLUSION: Our meta-analysis provides evidence that higher VEGF expression levels strongly correlate with the pathogenesis of osteoarthritis. PMID- 25515408 TI - Systematic evaluation of cancer risk associated with DNMT3B polymorphisms. AB - PURPOSE: The aim of our study is to provide a precise quantification for the association between DNA methyltransferase 3B (DNMT3B) variations (rs2424913 C/T, rs1569686 G/T, rs6087990 T/C and rs2424908 T/C) and the risk of cancer. METHODS: We performed a systematic literature review and assessed the methodological quality of included case-control designed studies based on Newcastle-Ottawa Scale. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were calculated to assess the strengths of the associations. RESULTS: We identified 34 studies for pooled analyses. Overall, the results demonstrated that rs2424913 polymorphism was significantly associated with negative cancer risk in the African population (CT vs TT: OR 0.10, 95% CI 0.02-0.63, P = 0.01; CT+CC vs TT: OR 0.14, 95% CI 0.03-0.76, P = 0.02), and the rs1569686 polymorphism was significantly associated with a subtly decreased cancer risk (GT vs TT: OR 0.80, 95% CI 0.72-0.90, P < 0.01; GT+GG vs TT: OR 0.84, 95% CI 0.76-0.94, P < 0.01), particularly in the Asian population (GT vs TT: OR 0.79, 95% CI 0.66-0.96, P < 0.01) and in colorectal cancer subgroup (G vs T: OR 0.69, 95% CI 0.54-0.88, P < 0.01). In addition, the rs6087990 polymorphism was associated with decreased risk in Asian population (T vs C: OR 0.77, 95% CI 0.62-0.96, P = 0.02). Similarly, the rs2424908 polymorphism was observed as a protective factor for cancer in the Asian population (CT+CC vs TT: OR 0.79, 95% CI 0.66-0.95, P = 0.01). CONCLUSIONS: DNMT3B polymorphisms might be associated with decreased cancer risk especially in the Asian population and for colorectal cancer. Further multicentric studies are still needed to confirm the results. PMID- 25515410 TI - 'Mediator-ing' messenger RNA processing. AB - Pre-messenger RNA (mRNA) processing, generally including capping, mRNA splicing, and cleavage-polyadenylation, is physically and functionally associated with transcription. The reciprocal coupling between transcription and mRNA processing ensures the efficient and regulated gene expression and editing. Multiple transcription factors/cofactors and mRNA processing factors are involved in the coupling process. This review focuses on several classic examples and recent advances that enlarge our understanding of how the transcriptional factors or cofactors, especially the Mediator complex, contribute to the RNA Pol II elongation, mRNA splicing, and polyadenylation. PMID- 25515411 TI - Myroides injenensis sp. nov., a new member isolated from human urine. AB - A Gram-negative, yellow-pigmented, rod-shaped bacteria, designated M09-0166(T)and M09-1053 were isolated from human urine samples. 16S rRNA gene sequence analysis revealed that the isolates belong to the Myroides cluster and were closely related to Myroides phaeus DSM 23313(T) (96.3 %), Myroides odoratimimus KCTC 23053(T) (96.1 %), Myroides profundi KCTC 23066(T) (96.0 %), Myroides odoratus KCTC 23054(T) (95.4 %) and Myroides pelagicus KCTC 12661(T) (95.2 %). The major mena quinone was identified as MK-6. The major polar lipids were identified as phosphatidylethanolamine, amino lipids, and several unknown lipids, and the major fatty acids as iso-C15:0 and iso-C17:0 3-OH. Phenotypic and chemotaxonomic data supported the affiliation of the isolates with the genus Myroides and clearly indicated that two isolates represent novel species, for which the name Myroides injenensis sp. nov. (type strain, M09-0166(T) = KCTC 23367(T) = JCM 17451(T)) is proposed. PMID- 25515409 TI - Differential diagnosis between metastatic and non-metastatic lymph nodes using DW MRI: a meta-analysis of diagnostic accuracy studies. AB - PURPOSES: The purpose of our meta-analysis was to assess the overall diagnostic value of diffusion-weighted magnetic resonance imaging (DW-MRI) in detecting node metastases and investigate whether the apparent diffusion coefficient (ADC) value could be used to discriminate between metastatic and non-metastatic lymph nodes in patients with primary tumors. MATERIALS AND METHODS: The meta-analysis included a total of 1,748 metastatic and 6,547 non-metastatic lymph nodes from 39 studies, including 8 different tumor types with lymph node metastases. RESULTS: The pooled sensitivity and specificity of DW-MRI were 0.82 (95 % CI 0.76-0.87) and 0.92 (95 % CI 0.88-0.94), respectively. The positive likelihood ratio (PLR), negative likelihood ratio (NLR), and the area under the curve were 9.8 (95 % CI 6.9-14.0), 0.20 (95 % CI 0.15-0.26) and 0.93 (95 % CI 0.91-0.95), respectively. The probability of 42 % can be viewed as the cutoff pretest probability for DW MRI to diagnosis lymph node metastases; when the more chance of metastatic increased from 42 % that the pretest probability was estimated, it was more suitable to emphasize on "ruling in," on the contrary, and when the more chance of metastatic decreased from 42 %, it was more suitable to emphasize on "ruling out." Furthermore, the mean ADC value of metastatic lymph nodes was significantly lower than that of non-metastatic (P = 0.001). CONCLUSIONS: DW-MRI is useful for differentiation between metastatic and non-metastatic lymph nodes. However, DW MRI has a moderate diagnostic value for physician's decision making when PLR and NLR took into consideration, while a superior ability for nodal metastases confirmation, but an inferior ability for ruling out. In the future, large-scale, high-quality trials are necessary to evaluate, respectively, their clinical value in different tumor types with nodal metastases. PMID- 25515412 TI - Chryseobacterium rhizoplanae sp. nov., isolated from the rhizoplane environment. AB - A slightly yellow pigmented strain (JM-534(T)) isolated from the rhizoplane of a field-grown Zea mays plant was investigated using a polyphasic approach for its taxonomic allocation. Cells of the isolate were observed to be rod-shaped and to stain Gram-negative. Comparative 16S rRNA gene sequence analysis showed that the isolate had the highest sequence similarities to Chryseobacterium lactis (98.9 %), Chryseobacterium joostei and Chryseobacterium indologenes (both 98.7 %), and Chryseobacterium viscerum (98.6 %). Sequence similarities to all other Chryseobacterium species were 98.5 % or below. The fatty acid analysis of the strain resulted in a Chryseobacterium typical pattern consisting mainly of the fatty acids C15:0 iso, C15:0 iso 2-OH, C17:1 iso omega9c, and C17:0 iso 3-OH. DNA DNA hybridizations with the type strains of C. lactis, C. joostei, C. viscerum and C. indologenes resulted in values below 70 %. Genomic fingerprinting showed that the isolate was very different to the type strains of these species. Differentiating biochemical and chemotaxonomic properties showed that the isolate JM-534(T) represents a novel species, for which the name Chryseobacterium rhizoplanae sp. nov. (type strain JM-534(T) = LMG 28481(T) = CCM 8544(T) = CIP 110828(T)) is proposed. PMID- 25515413 TI - Deinococcus radioresistens sp. nov., a UV and gamma radiation-resistant bacterium isolated from mountain soil. AB - Two Gram-negative, non-motile, short rod-shaped bacterial strains, designated as 8A(T) and 28A, were isolated from Mount Deogyusan, Jeonbuk Province, South Korea. The isolates were analyzed by a polyphasic approach, revealing variations in their phenotypic characters but high DNA-DNA hybridisation values reciprocally, confirming that they belong to the same species. Both the isolates also showed a high resistance to UV compared with Deinococcus radiodurans, and a gamma radiation resistance similar to other members of the genus Deinococcus. Phylogenetic analysis with the 16S rRNA gene sequences of closely related species indicated their similarities were below 97 %. Chemotaxonomic data showed the most abundant fatty acids to be C16:1omega7c and C16:0. The strains can be distinguished from closely related species by the production of esterase (C4) and alpha-galactosidase, and by their ability to assimilate L-alanine, L-histidine and N-acetyl-D-glucosamine. Based on the phenotypic, phylogenetic, and chemotaxonomic data, the isolates represent a novel species of the genus Deinococcus, for which the name Deinococcus radioresistens sp. nov. is proposed. The type strain is 8A(T) (KEMB 9004-109(T) = JCM 19777(T)), and a second strain is 28A (KEMB 9004-113 = JCM 19778). PMID- 25515414 TI - The diversity and extracellular enzymatic activities of yeasts isolated from water tanks of Vriesea minarum, an endangered bromeliad species in Brazil, and the description of Occultifur brasiliensis f.a., sp. nov. AB - The diversity of yeast species collected from the bromeliad tanks of Vriesea minarum, an endangered bromeliad species, and their ability to produce extracellular enzymes were studied. Water samples were collected from 30 tanks of bromeliads living in a rupestrian field site located at Serrada Piedade, Minas Gerais state, Brazil, during both the dry and rainy seasons. Thirty-six species were isolated, representing 22 basidiomycetous and 14 ascomycetous species. Occultifur sp., Cryptococcus podzolicus and Cryptococcus sp. 1 were the prevalent basidiomycetous species. The yeast-like fungus from the order Myriangiales, Candida silvae and Aureobasidium pullulans were the most frequent ascomycetous species. The diversity of the yeast communities obtained between seasons was not significantly different, but the yeast composition per bromeliad was different between seasons. These results suggest that there is significant spatial heterogeneity in the composition of populations of the yeast communities within bromeliad tanks, independent of the season. Among the 352 yeast isolates tested, 282 showed at least one enzymatic activity. Protease activity was the most widely expressed extracellular enzymatic activity, followed by xylanase, amylase, pectinase and cellulase activities. These enzymes may increase the carbon and nitrogen availability for the microbial food web in the bromeliad tank of V. minarum. Sequence analyses revealed the existence of 10 new species, indicating that bromeliad tanks are important sources of new yeasts. The novel species Occultifur brasiliensis, f.a., sp. nov., is proposed to accommodate the most frequently isolated yeast associated with V. minarum. The type strain of O. brasiliensis, f.a., sp. nov. is UFMG-CM-Y375(T) (= CBS 12687(T)). The Mycobank number is MB 809816. PMID- 25515415 TI - Commentary: Accelerating the quest for integrated and comprehensive sexual and reproductive health services in Nigeria. PMID- 25515416 TI - Morphology of the ampullae of Lorenzini in juvenile freshwater Carcharhinus leucas. AB - Ampullae of Lorenzini were examined from juvenile Carcharhinus leucas (831-1,045 mm total length) captured from freshwater regions of the Brisbane River. The ampullary organ structure differs from all other previously described ampullae in the canal wall structure, the general shape of the ampullary canal, and the apically nucleated supportive cells. Ampullary pores of 140-205 um in diameter are distributed over the surface of the head region with 2,681 and 2,913 pores present in two sharks that were studied in detail. The primary variation of the ampullary organs appears in the canal epithelial cells which occur as either flattened squamous epithelial cells or a second form of pseudostratified contour ridged epithelial cells; both cell types appear to release material into the ampullary lumen. Secondarily, this ampullary canal varies due to involuted walls that form a clover-like canal wall structure. At the proximal end of the canal, contour-ridged cells abut a narrow region of cuboidal epithelial cells that verge on the constant, six alveolar sacs of the ampulla. The alveolar sacs contain numerous receptor and supportive cells bound by tight junctions and desmosomes. Pear-shaped receptor cells that possess a single apical kinocilium are connected basally by unmyelinated neural boutons. Opposed to previously described ampullae of Lorenzini, the supportive cells have an apical nucleus, possess a low number of microvilli, and form a unique, jagged alveolar wall. A centrally positioned centrum cap of cuboidal epithelial cells overlies a primary afferent lateral line nerve. PMID- 25515417 TI - The other side of the coin: time-domain fluorescence lifetime in flow. PMID- 25515418 TI - [Use of hospital data for ophthalmological research : A feasibility study]. AB - AIMS: This study was carried out to investigate whether ophthalmology hospitals can exchange patient data for research purposes, i.e. whether this is technically and legally feasible and whether it is worthwhile, i.e. whether the data are useful for answering important medical questions. METHODS: In-depth interviews were conducted with experts and a literature search was carried out. RESULTS: Patient data were found to be fundamentally well-suited for research purposes and there is a corresponding need for research. There are also specific scientific question which need to be answered, e.g. development of visual acuity after various surgical procedures for glaucoma. There are also legal and technical difficulties but it is possible to solve these problems. Potential solutions are described. DISCUSSION: The results of this study show that it is basically feasible for hospitals and hospital personnel to exchange patient data and to combine them. As opposed to earlier attempts which tried to collect as much data as possible and then analyzed what to do with the data afterwards, it is recommended that a medical question should first be defined followed by a search for data afterwards. Furthermore, researching would be facilitated by an improved exchange of data by information systems. PMID- 25515419 TI - Mapping the rapid expansion of India's medical education sector: planning for the future. AB - BACKGROUND: India has witnessed rapid growth in its number of medical schools over the last few decades, particularly in recent years. One dominant feature of this growth has been expansion in the private medical education sector. At this point it is relevant to trace historically and geographically the changing role of public and private sectors in Indian medical education system. METHODS: The information on medical schools and sociodemographic indicators at provincial, district and sub-district (taluks) level were retrieved from available online databases. A digital map of medical schools was plotted on a geo-referenced map of India. The growth of medical schools in public and private sectors was tracked over last seven decades using line diagrams and thematic maps. The growth of medical schools in context of geographic distribution and access across the poorer and relatively richer provinces as well as the country's districts and taluks was explored using geographic information system. Finally candidate geographic areas, identified for intervention from equity perspective were plotted on the map of India. RESULTS: The study presents findings of 355 medical schools in India that enrolled 44250 students in 2012. Private sector owned 195 (54.9%) schools and enrolled 24205 (54.7%) students in the same year. The 18 poorly performing provinces (population 620 million, 51.3%) had only 94 (26.5%) medical schools. The presence of the private sector was significantly lower in poorly performing provinces where it owned 38 (40.4%) medical schools as compared to 157 (60.2%) schools in better performing provinces. The distances to medical schools from taluks in poorly performing provinces were longer [median 65.1 kilometres (km)] than from taluks in better performing provinces (median 41.2 km). Taluks farthest from a medical school were, situated in economically poorer districts with poor health indicators, a lower standard of living index and low levels of urbanization. CONCLUSIONS: The distribution of medical schools in India is skewed in the favour of areas (provinces, districts and taluks) with better indicators of health, urbanization, standards of living and economic prosperity. This particular distribution was most evident in the case of private sector schools set up in recent decades. PMID- 25515420 TI - Uses and misuses of causal language. PMID- 25515421 TI - Influence of respiratory motion correction on quantification of myocardial perfusion SPECT. AB - BACKGROUND: Respiratory-related cardiac motion could have considerable effects on myocardial perfusion imaging, leading to misinterpretation of the images. In this study, we examined the influence of respiratory correction on ECG-gated myocardial perfusion SPECT (RC-GSPECT) concerning regional myocardial perfusion and function. MATERIALS AND METHODS: Using the NCAT phantom, a typical torso phantom was generated. SimSET, a Monte Carlo simulator, was used to image the photon emerging from the phantom. Twenty-six patients underwent a 2-day stress rest ECG-gated myocardial perfusion SPECT (GSPECT) imaging. A separate study was also performed by simultaneous respiratory and cardiac triggering with the real time position management (RPM) for respiratory correction (RC). RESULTS: In simulation study, count density in the inferior and inferoseptal walls increased in the lower bin of the respiratory cycle. On the other hand, there was a higher correlation between RC-GSPECT and echocardiography for left ventricular ejection fraction (LVEF) (r = 0.95, P < .01 vs r = 0.88, P < .01 for GSPECT). CONCLUSION: We proposed a new approach for respiratory and cardiac-gated SPECT to eliminate respiratory motion artifacts. RC-GSPECT is a feasible method in MPI studies and may play an important role to improve the quality of MPI images, particularly in the inferior wall. PMID- 25515423 TI - Case report: paravalvular leak as a complication of percutaneous catheter ablation for atrial fibrillation. AB - An increasing number of reports reveal the safety and efficacy of catheter ablation for atrial fibrillation therapy even in patients with a history of prosthetic heart valve. This case report presents a 60 year old female patient who had a prosthetic mitral paravalvular leak as a complication of radiofrequency ablation. Surgery revealed a 15 mm hole and three broken knots in the posterolateral mitral annulus. This report demonstrates radiofrequency ablation for atrial fibrillation in patients with prosthetic mitral valve may cause a paravalvular leak likely as a result of thermal injury. Moreover, patient can be asymptomatic at first. The clinician should keep in mind such complication and the patient should be evaluated in terms of paravalvular leakage. PMID- 25515424 TI - The Effects of Temperature Variation on the Sensitivity to Pesticides: a Study on the Slime Mould Dictyostelium discoideum (Protozoa). AB - Slime moulds live in agricultural ecosystems, where they play an important role in the soil fertilization and in the battle against crop pathogens. In an agricultural soil, the amoebae are exposed to different stress factors such as pesticides and weather conditions. The use of pesticides increased up from 0.49 kg per hectare in 1961 to 2 kg in 2004, and the global greenhouse gas emission has grown 70% between 1970 and 2004 leading to a global fluctuation of average surface temperature. Therefore, the European Directive 2009/128/EC has led to a new approach to agriculture, with the transition from an old concept based on high use of pesticides and fossil fuels to an agriculture aware of biodiversity and health issues. We studied the effects of temperature variations and pesticides on Dictyostelium discoideum. We measured the fission rate, the ability to differentiate and the markers of stress such as the activity and presence of pseudocholinesterase and the presence of heat shock protein 70. Our results highlight how the sensitivity to zinc, aluminium, silver, copper, cadmium, mercury, diazinon and dicofol changes for a 2 degrees C variation from nothing/low to critical. Our work suggests considering, in future regulations, about the use of pesticides as their toxic effect on non-target organisms is strongly influenced by climate temperatures. In addition, there is a need for a new consideration of the protozoa, which takes into account recent researches about the presence in this microorganism of classical neurotransmitters that, similar to those in animals, make protozoa an innocent target of neurotoxic pesticides in the battle against the pest crops. PMID- 25515425 TI - Effects of light and autochthonous carbon additions on microbial turnover of allochthonous organic carbon and community composition. AB - The fate of allochthonous dissolved organic carbon (DOC) in aquatic systems is primarily controlled by the turnover of heterotrophic bacteria. However, the roles that abiotic and biotic factors such as light and DOC release by aquatic primary producers play in the microbial decomposition of allochthonous DOC is not well understood. We therefore tested if light and autochthonous DOC additions would increase allochthonous DOC decomposition rates and change bacterial growth efficiencies and community composition (BCC). We established continuous growth cultures with different inocula of natural bacterial communities and alder leaf leachates (DOCleaf) with and without light exposure before amendment. Furthermore, we incubated DOCleaf together with autochthonous DOC from lysed phytoplankton cultures (DOCphyto). Our results revealed that pretreatments of DOCleaf with light resulted in a doubling of bacterial growth efficiency (BGE), whereas additions of DOCphyto or combined additions of DOCphyto and light had no effect on BGE. The change in BGE was not accompanied by shifts in the phylogenetic structure of the BCC, but BCC was influenced by the DOC source. Our results highlight that a doubling of BGE is not necessarily accompanied by a shift in BCC and that BCC is more strongly affected by resource properties. PMID- 25515426 TI - Hydroxytyrosol: lack of clastogenicity in a bone marrow chromosome aberration study in rats. AB - BACKGROUND: Hydroxytyrosol is naturally found in olives, olive oil and wine, and is consumed as part of a normal diet. The substance may have utility as a preservative in a wide variety of foods due to its antioxidant, antimicrobial and amphipathic properties. The potential for hydroxytyrosol to cause chromosome aberrations in vitro had been tested previously, with positive results at high concentrations. An OECD Guideline 475 study (mammalian bone marrow chromosome aberration test) was conducted in rats with the oral limit dose of 2000 mg/kg bw to determine whether hydroxytyrosol is a clastogen in vivo. RESULTS: The oral limit dose of 2000 mg/kg hydroxytyrosol was well tolerated by most rats; however, some rats exhibited clinical signs that abated within 24 hours. Treatment with hydroxytyrosol did not significantly enhance the number of aberrant cells or the mitotic index 24 or 48 hours post-dose. The positive control (cyclophosphamide) induced the expected increase in chromosomal aberrations and a decrease in the mitotic index, confirming the validity of the assay. CONCLUSION: An oral limit dose of 2000 mg/kg hydroxytyrosol does not induce chromosome aberrations in bone marrow cells of the rat. Accordingly, hydroxytyrosol is not a clastogen in vivo. PMID- 25515427 TI - Speech and swallow rehabilitation following partial glossectomy: a systematic review. AB - PURPOSE: Tongue cancer is known to negatively affect both speech and swallowing function; however this is the first review to report speech-language pathology (SLP) intervention for both functions following partial glossectomy. METHOD: Using a PRISMA approach, systematic screening of nine databases was undertaken. Original studies reporting SLP rehabilitation for speech and/or swallowing dysfunction with participants following partial glossectomy as primary cancer treatment were included. RESULT: These studies are discussed in terms of SLP assessment and intervention trends as well as quality according to current research method standards (levels of evidence, Pedro-P, SCED) in order to determine suitability for guiding current clinical practice. CONCLUSION: Publications were few (n = 7) and mostly of non-experimental design. This review highlights the gap in evidence and questions the rationale of current SLP rehabilitation following partial glossectomy. PMID- 25515428 TI - Asymmetric dual-reagent catalysis: Mannich-type reactions catalyzed by ion pair. AB - The combination of a new bifunctional phosphine and an acrylate generate a zwitterion in situ and it serves as an efficient catalyst for asymmetric reactions through a homogeneous ion-pairing mode. This new catalytic system has been successfully applied to Mannich-type reactions to give excellent results and it demonstrates a broad substrate scope. Such reactivity is not accessible with general organophosphine catalytic modes. Preliminary investigations into the mechanism are also presented. PMID- 25515429 TI - Patient safety skills in primary care: a national survey of GP educators. AB - BACKGROUND: Clinicians have a vital role in promoting patient safety that goes beyond their technical competence. The qualities and attributes of the safe hospital doctor have been explored but similar work within primary care is lacking. Exploring the skills and attributes of a safe GP may help to inform the development of training programmes to promote patient safety within primary care. This study aimed to determine the views of General Practice Educational Supervisors (GPES) regarding the qualities and attributes of a safe General Practitioner (GP) and the perceived trainability of these 'safety skills' and to compare selected results with those generated by a previous study of hospital doctors. METHODS: This was a two-stage study comprising content validation of a safety skills questionnaire (originally developed for hospital doctors) (Stage 1) and a prospective survey of all GPES in Scotland (n = 691) (Stage 2). RESULTS: Stage 1: The content-validated questionnaire comprised 66 safety skills/attributes across 17 broad categories with an overall content validation index of 0.92. Stage 2: 348 (50%) GPES completed the survey. GPES felt the skills/attributes most important to being a safe GP were honesty (93%), technical clinical skills (89%) and conscientiousness (89%). That deemed least important/relevant to being a safe GP was leadership (36%). This contrasts sharply with the views of hospital doctors in the previous study. GPES felt the most trainable safety skills/attributes were technical skills (93%), situation awareness (75%) and anticipation/preparedness (71%). The least trainable were honesty (35%), humility (33%) and patient awareness/empathy (30%). Additional safety skills identified as relevant to primary care included patient advocacy, negotiation skills, accountability/ownership and clinical intuition ('listening to that worrying little inner voice'). CONCLUSIONS: GPES believe a broad range of skills and attributes contribute to being a safe GP. Important but subtle differences exist between what primary care and secondary care doctors perceive as core safety attributes. Educationalists, GPs and patient safety experts should collaborate to develop and implement training in these skills to ensure that current and future GPs possess the necessary competencies to engage and lead in safety improvement efforts. PMID- 25515431 TI - Deviating to the right: using eyetracking to study the role of attention in navigation asymmetries. AB - The ability to navigate accurately through the environment and avoid obstacles is essential for effective interactions with the environment. It is therefore surprising that systematic rightward errors are observed when neurologically intact participants navigate through doorways-most likely due to the operation of biases in spatial attention. These rightward errors may arise due to the operation of an extinction-like process, whereby participants overattend to the left doorpost and collide with the right one. Alternatively, rightward biases might reflect a bisection bias, such that the extrapersonal nature of the aperture causes participants to misbisect the aperture slightly to the right of true center. Because eye movements and spatial attention are closely related, in this study we used eyetracking to test the extinction and bisection models in a remote wheelchair navigation task. University students (n = 16) made rightward errors when navigating the wheelchair through a doorway, and fixated more frequently toward the right side of the aperture throughout the trial. These results are inconsistent with an extinction-based theory of navigation asymmetry, which predicts a leftward bias in eye position due to participants overattending to the left side of the doorway. Instead, the observed rightward bias in eye movements strongly supports a bisection-based theory of navigation asymmetry, whereby participants mentally "mark" the midpoint of a doorway toward the right and then head toward that point, resulting in rightward deviations. The rightward nature of participants' navigation errors and eye positions is consistent with the existence of a rightward attentional bias for extrapersonal stimuli. PMID- 25515430 TI - Synthesis of Au/graphene oxide composites for selective and sensitive electrochemical detection of ascorbic acid. AB - In this work, we present a novel ascorbic acid (AA) sensor applied to the detection of AA in human sera and pharmaceuticals. A series of Au nanoparticles (NPs) and graphene oxide sheets (Au NP/GO) composites were successfully synthesized by reduction of gold (III) using sodium citrate. Then the Au NP/GO composites were used to construct nonenzymatic electrodes in practical AA measurement. The electrode that has the best performance presents attractive analytical features, such as a low working potential of +0.15 V, a high sensitivity of 101.86 MUA mM(-1) cm(-2) to AA, a low detection limit of 100 nM, good reproducibility and excellent selectivity. And more,it was also employed to accurately and practically detect AA in human serum and clinical vitamin C tablet with the existence of some food additive. The enhanced AA electrochemical properties of the Au NP/GO modified electrode in our work can be attributed to the improvement of electroactive surface area of Au NPs and the synergistic effect from the combination of Au NPs and GO sheets. This work shows that the Au NP/GO/GCEs hold the prospect for sensitive and selective determination of AA in practical clinical application. PMID- 25515432 TI - Remote haptic perception of slanted surfaces shows the same scale expansion as visual perception. AB - Previous work has shown that overestimates of geographic slant depend on the modality used (verbal or haptic). Recently, that line of reasoning has come into question for many reasons, not the least of which is that the typical method used for measuring "action" has been the use of a palm board, which is not well calibrated to any type of action toward slanted surfaces. In the present work, we investigated how a remote haptic task that has been well calibrated to action in previous work is related to verbal overestimates of slanted surfaces that are out of reach. The results show that haptic estimates are perceptually equivalent to the verbal overestimates that have been found in numerous previous studies. This work shows that the haptic perceptual system is scaled in the same way as the visual perceptual system for estimating the orientation of slanted surfaces that are out of reach. PMID- 25515433 TI - A novel method for identifying a graph-based representation of 3-D microvascular networks from fluorescence microscopy image stacks. AB - A novel approach to determine the global topological structure of a microvasculature network from noisy and low-resolution fluorescence microscopy data that does not require the detailed segmentation of the vessel structure is proposed here. The method is most appropriate for problems where the tortuosity of the network is relatively low and proceeds by directly computing a piecewise linear approximation to the vasculature skeleton through the construction of a graph in three dimensions whose edges represent the skeletal approximation and vertices are located at Critical Points (CPs) on the microvasculature. The CPs are defined as vessel junctions or locations of relatively large curvature along the centerline of a vessel. Our method consists of two phases. First, we provide a CP detection technique that, for junctions in particular, does not require any a priori geometric information such as direction or degree. Second, connectivity between detected nodes is determined via the solution of a Binary Integer Program (BIP) whose variables determine whether a potential edge between nodes is or is not included in the final graph. The utility function in this problem reflects both intensity-based and structural information along the path connecting the two nodes. Qualitative and quantitative results confirm the usefulness and accuracy of this method. This approach provides a mean of correctly capturing the connectivity patterns in vessels that are missed by more traditional segmentation and binarization schemes because of imperfections in the images which manifest as dim or broken vessels. PMID- 25515434 TI - The genetic basis of resistance to barley grass yellow rust (Puccinia striiformis f. sp. pseudo-hordei) in Australian barley cultivars. AB - KEY MESSAGE: Resistance to Puccinia striiformis in 18 barleys was conferred by one or more genes. In two genotypes, resistance mapped to chromosomes 5HL and 7HL (seedling), and 5HS (adult plant). Twenty barley genotypes were assessed for resistance to a variant of P. striiformis [barley grass yellow rust (BGYR)] that is adapted to wild Hordeum sp. (barley grass) and is known to be virulent on several Australian barley cultivars. With the exception of Biosaline-19, all of the genotypes tested were resistant to BGYR. Genetic analyses of 16 Australian and three exotic barley lines indicated that each carried at least a single gene for resistance. Seedling resistance genes identified in the doubled haploid population developed from a cross between Franklin and Yerong were mapped to the long arm of chromosomes 5H and 7H, respectively. These genes were given the temporary designations of Rpsp-hFranklin and Rpsp-hYerong. Three QTL were detected in the same population when tested at the adult plant stage, two of them being in a similar position to Rpsp-hFranklin and Rpsp-hYerong and the third one was mapped to 5HS. Allelism tests between genotypes that exhibited seedling infection type responses to BGYR that were similar to Franklin and Yerong revealed that resistance in most were genetically independent of Rpsp-hFranklin and Rpsp-hYerong. PMID- 25515436 TI - Nurses deterred by grim realities of senior roles. AB - Who would want to be a nurse director at an NHS trust? Not many of you, it would seem, given the findings of a study by think tank The King's Fund involving 134 organisations across England. Its report on the study reveals that it takes an average of more than nine months to replace nursing directors, which is much longer than the time taken to fill other board-level vacancies. PMID- 25515435 TI - Warfarin and boceprevir interaction causing subtherapeutic international normalized ratio: a case report. AB - INTRODUCTION: Chronic hepatitis C is a leading cause of severe liver disease. Protease inhibitors used to treat these patients are known to have many drug interactions, although there is limited data available between boceprevir and warfarin. This case report is the first in vivo drug interaction reported in the literature. CASE PRESENTATION: A 73-year-old African American man was diagnosed with hepatitis C in 2004, and had decided to not initiate therapy. In 2006, he was diagnosed with deep vein thrombosis and pulmonary embolism and was started on warfarin. His international normalized ratio had been stable on a dose of 13.75 mg to 20mg/week over a period of 6 years. A liver biopsy in 2012 revealed marked fibrosis, leading the patient to start hepatitis C treatment with peginterferon alfa-2a, ribavirin and boceprevir. Three weeks after starting boceprevir, his international normalized ratio became subtherapeutic at 1.2. Upon increasing the warfarin dose by 16%, his international normalized ratio remained at 1.2 6 days later. Two months after initiating boceprevir, he reached a therapeutic international normalized ratio. His warfarin dose had been increased by 75% from his dose prior to starting boceprevir, from 15 mg/week to 26.25mg/week. His hepatitis C treatment was discontinued at week 39 of the intended 48 weeks of treatment due to severe thrombocytopenia. Upon discontinuation of boceprevir, his warfarin dose was prophylactically decreased by 17%, which resulted in a subtherapeutic international normalized ratio of 1.48 1 week later. The warfarin dose was subsequently increased by 10% which resulted, 2 weeks later, in a therapeutic international normalized ratio of 2.8. Once stabilized, his new warfarin dose was 23.75 mg/week, 37% higher than his original maintenance dose of 15 mg/week prior to starting boceprevir. CONCLUSIONS: The co-administration of boceprevir and warfarin resulted in a subtherapeutic international normalized ratio. Upon starting boceprevir, his warfarin dose was increased by 75% over 2 months to achieve a therapeutic international normalized ratio. After discontinuing boceprevir, his maintenance dose of warfarin was 37% greater than his original dose. This is an original case report which demonstrates the significant effects of this drug interaction and the importance of monitoring international normalized ratio. PMID- 25515438 TI - Potential nursing directors might be put off by 'old boys' culture'. AB - A 'macho, old boys' culture' and fear of being in the spotlight could be deterring nurses from applying for director jobs in England, a major new report claims. PMID- 25515439 TI - Ward rounding approach will undergo research. AB - The effectiveness of the intentional rounding system, championed by prime minister David Cameron, is being investigated in a L450,000 study. PMID- 25515443 TI - London still short of thousands of nurses despite increase in posts. AB - More than 8,000 nursing posts in London remain unfilled as the capital's nurse shortage worsens, research by the RCN has revealed. PMID- 25515447 TI - Injuries at work vastly reduced by moving and handling course. AB - A university's innovative moving and handling course has seen injuries to students on placement decline by more than 90 per cent. PMID- 25515449 TI - Chocolates last less than an hour on wards, so try another option. PMID- 25515452 TI - Catholic nurse wins religious discrimination case at tribunal. AB - A critical care nurse from Northern Ireland has been awarded L9,900 after an employment tribunal upheld his claim of religious discrimination. PMID- 25515454 TI - A year of honours, remembrance and a historic strike over pay. PMID- 25515460 TI - Lessons in great care. PMID- 25515461 TI - PCOS. AB - Essential facts Polycystic ovary syndrome (PCOS) is a common disorder that affects millions of women in the UK. It can affect a woman's menstrual cycle, fertility and aspects of her appearance. The three main features of the condition are cysts that develop in the ovaries, ovaries that do not regularly release eggs, and having high levels of androgens, the group of male hormones. A diagnosis of PCOS is usually made if someone has two of these features. PMID- 25515475 TI - The powers that be will only respond to assertive action. PMID- 25515474 TI - Mental health provision needs to be at the heart of nursing. PMID- 25515476 TI - Let's prune nursing's four branches down to two, but widen their focus. PMID- 25515478 TI - Correction. AB - The feature 'Shaping the future of epilepsy care' in the December 10 issue of Nursing Standard incorrectly stated that some people with epilepsy 'may find it safer to use baths rather than showers'. This should have read: 'Some may find it safer to use showers rather than baths'. We apologise for the error which occurred during the production process. PMID- 25515479 TI - Lessons to be learned from Malawi nursing pioneer. PMID- 25515480 TI - Expression of your religious beliefs may be inappropriate. PMID- 25515481 TI - Retired reps can do bank work and then regain accreditation. PMID- 25515482 TI - Development of learning facilitation roles for unregistered practitioners. AB - This article describes how unregistered practitioners, such as healthcare assistants and community-based mental health workers, can contribute to the learning, support and development of pre-registration nursing students in clinical practice. It presents the results of an unregistered practitioner co mentoring scheme piloted in a mental health trust, and demonstrates its benefits for nursing students, unregistered practitioners and nurse mentors. The scheme delivers training and supervision for unregistered practitioners who are starting a formal role in clinical learning. It aims to recognise and develop the contribution of unregistered practitioners to student learning, and to enhance the learning environments in which nursing students train. PMID- 25515483 TI - How nurse leaders are connected internationally. AB - AIM: To determine whether communication networks exist in a diverse and competitively selected cohort of nurse leaders, and to identify variables that explain any patterns of connection. METHOD: Twenty seven nurse leaders completed a form to ascertain the presence and strength of communication between participants. Data were analysed using social network analysis, generating a visualisation of the network and associated quantitative measures. RESULTS: Participants were poorly connected. Those connections that did exist centred on geographic proximity and participation in regional and global bodies. CONCLUSION: These results help improve understanding of how nurse leaders are connected internationally, and prompt inquiry in to how connections might be strengthened. PMID- 25515484 TI - Promoting better care for stigmatised patients. AB - This article discusses the role of nurses and nurse leaders in the prevention and resolution of patient stigmatisation. The multiple nurse, patient and environmental factors that contribute to difficulties in nurse-patient interactions are outlined. The antecedents and consequences of patient stigmatisation are discussed and leadership strategies for counteracting and preventing patient stigmatisation are explored. The reader is encouraged to reflect on the role of patient stigmatisation in nursing practice and consider ways to promote better care of stigmatised patients. PMID- 25515485 TI - Nursing research. AB - As a registered nurse working in a community setting, I encounter a diverse range of patient healthcare needs every day. Holistic assessment and individualised care plans are essential to meet patients' needs. PMID- 25515486 TI - Leave it to Florence. AB - There are four practice nurses at Heatherlands Medical Centre in Woodchurch, Cheshire--and one 'intelligent system' named Florence. With a voice like a car satnav, 'she' is a software robot, or Artificial Intelligence (AI). PMID- 25515488 TI - Making a world of difference. AB - Volunteering on hospital ships that take health care to the world's poorest people has given Elaine Gordon extraordinary new experiences, as well as skills and experience to bring back to the NHS. PMID- 25515489 TI - Getting documentation right. AB - Between medication administration, care tasks and communication with colleagues and patients' families, documentation often gets put on the back-burner. However, it is a critical aspect of nursing care that provides a precise account of your actions that is vital for your legal protection and that of your employer. Below are a few suggestions to ensure your documentation is accurate and timely. PMID- 25515490 TI - Guiding star or reluctant mentor. AB - University students Alanna Webster and Caitlin Bowron led a study examining the effects of role models in clinical placements. They share their findings. PMID- 25515491 TI - The secondary drying and the fate of organic solvents for spray dried dispersion drug product. AB - PURPOSE: To understand the mechanisms of secondary drying of spray-dried dispersion (SDD) drug product and establish a model to describe the fate of organic solvents in such a product. METHODS: The experimental approach includes characterization of the SDD particles, drying studies of SDD using an integrated weighing balance and mass spectrometer, and the subsequent generation of the drying curve. The theoretical approach includes the establishment of a Fickian diffusion model. RESULTS: The kinetics of solvent removal during secondary drying from the lab scale to a bench scale follows Fickian diffusion model. Excellent agreement is obtained between the experimental data and the prediction from the modeling. CONCLUSIONS: The diffusion process is dependent upon temperature. The key to a successful scale up of the secondary drying is to control the drying temperature. The fate of primary solvents including methanol and acetone, and their potential impurity such as benzene can be described by the Fickian diffusion model. A mathematical relationship based upon the ratio of diffusion coefficient was established to predict the benzene concentration from the fate of the primary solvent during the secondary drying process. PMID- 25515492 TI - Cluster of Differentiation 44 Targeted Hyaluronic Acid Based Nanoparticles for MDR1 siRNA Delivery to Overcome Drug Resistance in Ovarian Cancer. AB - PURPOSE: Approaches for the synthesis of biomaterials to facilitate the delivery of "biologics" is a major area of research in cancer therapy. Here we designed and characterized a hyaluronic acid (HA) based self-assembling nanoparticles that can target CD44 receptors overexpressed on multidrug resistance (MDR) ovarian cancer. The nanoparticle system is composed of HA-poly(ethyleneimine)/HA poly(ethylene glycol) (HA-PEI/HA-PEG) designed to deliver MDR1 siRNA for the treatment of MDR in an ovarian cancer model. METHODS: HA-PEI/HA-PEG nanoparticles were synthesized and characterized, then the cellular uptake and knockdown efficiency of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles was further determined. A human xenograft MDR ovarian cancer model was established to evaluate the effects of the combination of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles and paclitaxel on MDR tumor growth. RESULTS: Our results demonstrated that HA-PEI/HA-PEG nanoparticles successfully targeted CD44 and delivered MDR1 siRNA into OVCAR8TR (established paclitaxel resistant) tumors. Additionally, HA-PEI/HA-PEG nanoparticles loaded with MDR1 siRNA efficiently down-regulated the expression of MDR1 and P-glycoprotein (Pgp), inhibited the functional activity of Pgp, and subsequently increased cell sensitivity to paclitaxel. HA-PEI/HA-PEG/MDR1 siRNA nanoparticle therapy followed by paclitaxel treatment inhibited tumor growth in MDR ovarian cancer mouse models. CONCLUSIONS: These findings suggest that this CD44 targeted HA-PEI/HA-PEG nanoparticle platform may be a clinicaly relevant gene delivery system for systemic siRNA-based anticancer therapeutics for the treatment of MDR cancers. PMID- 25515494 TI - The overexpression of genes of thiol metabolism contribute to drug resistance in clinical isolates of visceral leishmaniasis (kala azar) in India. AB - BACKGROUND: Visceral leishmaniasis (VL), also called Kala Azar (KA) or black fever in India, claims around 20,000 lives every year. Chemotherapy remains one of the most important tools in the control of VL. Current chemotherapy for Kala Azar in India relies on a rather limited arsenal of drugs including sodium antimony gluconate and amphotericin B in addition to the very expensive drug miltefosine. Pentavalent antimonials have been used for more than half a century in the therapy of leishmaniasis as it is relatively safe and inexpensive, however, the spread of resistance to this drug is forcing clinicians in India to abandon this treatment. Consequently, improvement of antimonial chemotherapy has become a major challenging area of study by leishmaniacs worldwide. The alarming emergence of resistance to the commonly used antleishmanial drug, sodium antimony gluconate, in India, has led us to elucidate the resistance mechanism(s) in clinical isolates. Studies on laboratory mutants have shown that resistance to antimonials is highly dependent on thiol levels. The parasite evades cytotoxic effects of antimonial therapy by enhanced efflux of drug upon conjugation with thiols, through overexpressed membrane proteins belonging to the superfamily of ABC transporters. METHODS: We have carried out functional studies to determine the activity of the efflux pumps in antimonial resistant clinical isolates collected from disease endemic areas in India and also carried out molecular characterization of thiol levels in these parasites. RESULTS: Overexpression of the gene coding for gamma glutamylcysteine synthetase was observed in these resistant clinical isolates thereby establishing that thiols represent the key determinants of antimonial resistance. The SbIII/thiol conjugates can be sequestered by ABC transporter multidrug resistance protein A (MRPA) into intracellular organelles or can be directly pumped out by an uncharacterized transporter. CONCLUSIONS: Our studies investigating antimonial resistance in different L. donovani clinical isolates suggest that over functioning of MRP plays a role in generation of antimony resistance phenotype in some L. donovani clinical isolates. PMID- 25515495 TI - Composition and antioxidant activity of Senecio nudicaulis Wall. ex DC. (Asteraceae): a medicinal plant growing wild in Himachal Pradesh, India. AB - The composition of essential oil isolated from Senecio nudicaulis Wall. ex DC. growing wild in Himachal Pradesh, India, was analysed, for the first time, by capillary gas chromatography (GC) and GC-mass spectrometry. A total of 30 components representing 95.3% of the total oil were identified. The essential oil was characterised by a high content of oxygenated sesquiterpenes (54.97%) with caryophyllene oxide (24.99%) as the major component. Other significant constituents were humulene epoxide-II (21.25%), alpha-humulene (18.75%), beta caryophyllene (9.67%), epi-alpha-cadinol (2.90%), epi-alpha-muurolol (2.03%), beta-cedrene (1.76%), longiborneol (1.76%), 1-tridecene (1.16%) and citronellol (1.13%). The oil was screened for antioxidant activity using DPPH, ABTS and nitric oxide-scavenging assay. The oil was found to exhibit significant antioxidant activity by scavenging DPPH, ABTS and nitric oxide radicals with IC50 values of 10.61 +/- 0.14 MUg mL(- 1), 11.85 +/- 0.28 MUg mL(- 1) and 11.29 +/- 0.42 MUg mL(- 1), respectively. PMID- 25515497 TI - Non-symmetrical aryl- and arylethynyl-substituted thioalkyl-porphyrazines for optoelectronic materials: synthesis, properties, and computational studies. AB - A series of novel non-symmetrically substituted mono beta-aryl and beta arylethynyl (alkylsulfanyl)porphyrazines and the corresponding Ni(ii) complexes have been prepared by the Suzuki-Miyaura and Sonogashira cross-coupling reactions with the aim to investigate substituent effects on their electronic and aggregation properties. Spectroscopic, electrochemical and computational investigations show that in both aryl and arylethynyl compounds efficient electron transfer between the aryl and macrocycle moieties occurs. The highest perturbation of the porphyrazine pi-electron core is provided by strong electron donating (NMe2) and electron withdrawing (NO2) aryl substituents, which increase and decrease the macrocycle electron density, respectively. Moreover, while in most of the compounds the LUMOs and HOMOs are mainly localized on the porphyrazine ring, in the amino-substituted derivatives the HOMO is localized on the peripheral aryl moieties and the LUMO is localized on the macrocycle. Charge transfer electronic excitations give rise to absorptions in UV-Vis spectra of both amino- and nitro-substituted compounds. In the former such excitations occur from aryl-localized to macrocycle-localized orbitals, while backward excitations occur in the latter. Therefore, the porphyrazine ring shows an ambivalent behavior, acting as an electron acceptor in the case of the NMe2-substituted compounds and as an electron donor in the NO2-substituted derivative. In these derivatives, even macrocycle mono-substitution provides unconventional "push pull" systems suitable for NLO. Columnar discotic mesophases are also shown by thio-octyl arylethynyl derivatives, allowing us to envisage the possibility to achieve compounds both suitable for optoelectronic applications and endowed with self-aggregation properties. PMID- 25515496 TI - Case series: indoor-photosensitivity caused by fluorescent lamps in patients treated with vemurafenib for metastatic melanoma. AB - BACKGROUND: Vemurafenib, a selective inhibitor of genetically activated BRAF, is registered for unresectable stage III and stage IV melanomas harboring a BRAF mutation. Photosensitivity related to exposure to sunlight is a common side effect. We here present three cases of indoor-photosensitivity due to fluorescent lamps, whilst undergoing treatment with vemurafenib. CASE PRESENTATION: Patient A is a 45-year-old Caucasian female, patient B a 32-year-old Caucasian male and patient C a 53-year-old male. They are all undergoing treatment with vemurafenib for metastatic melanoma. Patient A developed indoor-photosensitivity due to fluorescent lamps at work. Her employer changed the lighting to LED light and her complaints disappeared. Patient B is a biology teacher and in classrooms he is exposed to fluorescent lamps. He developed alopecia and subsequently indoor photosensitivity. This was solved by wearing a baseball cap at work during the day. Patient C developed red and burning skin after working under fluorescent lamps in his shed. This side-effect disappeared completely after avoiding the lamps. CONCLUSION: Photosensitivity is a known adverse event of vemurafenib. This is known to be an UVA-depended photosensitivity. Until now it was thought to be solely related to sunlight exposure. These cases illustrate that patients, whilst undergoing treatment with vemurafenib, can develop indoor-photosensitivity as a result of exposure to fluorescent lamps with a relatively high UV content of the emitted spectrum (low permissible exposure time). Awareness of this side-effect is important to take appropriate measures in the future. PMID- 25515498 TI - Morbidly "Healthy" Obese Are Not Metabolically Healthy but Less Metabolically Imbalanced Than Those with Type 2 Diabetes or Dyslipidemia. AB - BACKGROUND: We have investigated the differences between metabolically "healthy" morbidly obese patients and those with comorbidities. MATERIALS AND METHODS: Thirty-two morbidly obese patients were divided by the absence ("healthy": DM-DL ) or presence of comorbidities (dyslipidemic: DM-DL+, or dyslipidemic and with type 2 diabetes: DM+DL+). We have studied various plasma parameters and gene expression adipose tissue, before and after gastric bypass. RESULTS: The group DM+DL+ tends to have lower values than the other two groups for anthropometric parameters. Regarding the satiety parameters, only leptin (p = 0.0024) showed a significant increase with comorbidities. Lipid parameters showed significant differences among groups, except for phospholipids and NEFA. For insulin resistance parameters, only glucose (p < 0.0001) was higher in DM+DL+ patients, but not insulin or homeostasis model assessment of insulin resistance (HOMA-IR). The gene expression of adiponectin, insulin receptor (INSR) and glucose receptor 4 (GLUT4), in the subcutaneous fat, decreased in all groups vs. a non-obese control. Interleukin-6 (IL6) and the inhibitor of plasminogen activator type 1 (PAI-1) genes decreased only in DM-DL+ and DM+DL+, but not in "healthy" patients. Leptin increased in all groups vs. the non-obese control. The visceral fat from DM+DL+ patients showed a sharp decrease in adiponectin, GLUT4, IL6 and PAI-1. All parameters mentioned above improved very significantly by surgery, independent of the occurrence of comorbidities. CONCLUSIONS: The morbidly obese "healthy" individual is not really metabolically healthy, but morbidly obese individuals with diabetes and dyslipidemia are more metabolically imbalanced. PMID- 25515499 TI - The Impact of Bariatric Surgery on Diabetic Retinopathy: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Significant reductions in glucose control immediately post bariatric surgery in patients with longstanding poor glycemic control can lead to the paradoxical progression of diabetic retinopathy (DR) in susceptible individuals. Bariatric surgery results in dramatic and immediate diabetic control postoperatively. We aimed to systematically review the literature to assess the effect of bariatric surgery on DR. METHODS: A comprehensive search of electronic databases (e.g., MEDLINE, EMBASE, SCOPUS, Web of Science, and the Cochrane Library) was completed. All randomized controlled trials, non-randomized comparison study, and case series were included. Inclusion criteria included English-speaking studies, enrolling >= 5 patients, and contained ophthalmological data on outcome of DR pre- and post bariatric surgery. Two independently reviewers screened abstracts, reviewed full text versions of all studies classified, and extracted data. All comparison studies included in the meta analysis were assessed independently by two reviewers for methodological quality using the Cochrane Risk of Bias (RoB) tools. Disagreements were resolved by re extraction, or third-party adjudication. Where possible and appropriate, a meta analysis was conducted. RESULTS: A total of 277 studies were identified using our search criteria for screening. Four primary studies (n = 148 patients) met our inclusion criteria and were included in the systematic review. These included no randomized controlled trials and four non-randomized case series. Patients with no preoperative DR (n = 80), following bariatric surgery, an average of 92.5 +/- 7.4 % remained disease free, while 7.5 +/- 7.4 % of patients progressed to DR. Patients with diabetic retinopathy preoperatively (n = 68), following bariatric surgery, an average of 57.4 +/- 18.5 % of patients had no change, 23.5 +/- 18.7 % of patients had progression, and 19.2 +/- 2.9 % of patients had improvement in their disease. CONCLUSIONS: Progression of diabetic retinopathy is a significant issue postoperatively following bariatric surgery. Patients with a diagnosis of DR prior to surgery are at increased risk of further progression in their disease and should receive adequate counseling and evaluation prior to undergoing a surgical procedure. However, the few primary studies in this systematic review limit any conclusion. Further studies are needed to further evaluate these results. PMID- 25515500 TI - Systematic review of definitions of failure in revisional bariatric surgery. AB - BACKGROUND: There are no agreed definitions as to what constitutes a 'failure' of the primary bariatric procedure in relation to weight loss. METHODS: The MEDLINE database for primary research articles was searched using obesity [title] or bariatric [title] and revision [title] or revisional [title]. RESULTS: The MEDLINE search retrieved 174 studies. After duplicates and exclusions were removed, 60 articles underwent analysis. Fifty-one studies included inadequate weight loss or weight regain as an indication for revision: 31/51 (61 %) gave no definition of failure, 7/20 quoted <50 % of excess weight loss at 18 months and 6/20 used <25 % excess weight loss. CONCLUSIONS: The majority of published studies do not define failure of bariatric surgery, and <50 % excess weight loss at 18 months was the most frequent definition identified. PMID- 25515501 TI - Modelling the natural history of Huntington's disease progression. AB - BACKGROUND: The lack of reliable biomarkers to track disease progression is a major problem in clinical research of chronic neurological disorders. Using Huntington's disease (HD) as an example, we describe a novel approach to model HD and show that the progression of a neurological disorder can be predicted for individual patients. METHODS: Starting with an initial cohort of 343 patients with HD that we have followed since 1995, we used data from 68 patients that satisfied our filtering criteria to model disease progression, based on the Unified Huntington's Disease Rating Scale (UHDRS), a measure that is routinely used in HD clinics worldwide. RESULTS: Our model was validated by: (A) extrapolating our equation to model the age of disease onset, (B) testing it on a second patient data set by loosening our filtering criteria, (C) cross-validating with a repeated random subsampling approach and (D) holdout validating with the latest clinical assessment data from the same cohort of patients. With UHDRS scores from the past four clinical visits (over a minimum span of 2 years), our model predicts disease progression of individual patients over the next 2 years with an accuracy of 89-91%. We have also provided evidence that patients with similar baseline clinical profiles can exhibit very different trajectories of disease progression. CONCLUSIONS: This new model therefore has important implications for HD research, most obviously in the development of potential disease-modifying therapies. We believe that a similar approach can also be adapted to model disease progression in other chronic neurological disorders. PMID- 25515502 TI - Intravenous immunoglobulin response in treatment-naive chronic inflammatory demyelinating polyradiculoneuropathy. AB - OBJECTIVE: There is no consensus on which treatment should be used preferentially in individual patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Patients unlikely to respond to intravenous immunoglobulin (IVIg) could be prescribed corticosteroids first to avoid high cost and a delayed treatment response. We investigated which factors determined a response to IVIg. METHODS: Treatment-naive patients with CIDP initially treated with at least one full course of IVIg (2 g/kg) at one of two neuromuscular disease centres were included. Patients fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society clinical criteria for CIDP. Significant improvement following IVIg was defined as an improvement (>= 1 grade) on the modified Rankin scale. Difference in weakness between arms and legs was defined as >= 2 grades on the Medical Research Council scale between ankle dorsiflexion and wrist extension. Clinical predictors with a p value <0.15 in univariate analysis were analysed in multivariate logistic regression. RESULTS: Of a total of 281 patients, 214 patients (76%) improved. In univariate analysis, the presence of pain, other autoimmune disease, difference in weakness between arms and legs, and a myelin-associated glycoprotein negative IgM monoclonal gammopathy of undetermined significance were associated with no response to IVIg. In multivariate analysis no pain (p=0.018) and no difference in weakness between arms and legs (p=0.048) were independently associated with IVIg response. Of IVIg non-responders, 66% improved with plasma exchange and 58% with corticosteroids. CONCLUSIONS: IVIg is a very effective first-line treatment. Patients with CIDP presenting with pain or a difference in weakness between arms and legs are less likely to respond to IVIg. PMID- 25515504 TI - Modulation of friction dynamics in water by changing the combination of the loop- and graft-type poly(ethylene glycol) surfaces. AB - A Velcro-like poly(ethylene glycol) (PEG) interface was prepared in order to control the friction dynamics of material surfaces. Graft- and loop-type PEGs were formed on mirror-polished Ti surfaces using an electrodeposition method with mono- and di-amine functionalized PEGs. The friction dynamics of various combinations of PEG surfaces (i.e., graft-on-graft, loop-on-loop, graft-on-loop, and loop-on-graft) were investigated by friction testing. Here, only the Velcro like combinations (graft-on-loop and loop-on-graft) exhibited a reversible friction behavior (i.e., resetting the kinetic friction coefficient and the reappearance of the maximum static friction coefficient) during the friction tests. The same tendency was observed when the molecular weights of loop- and graft-type PEGs were tested at 1 k and 10 k, respectively. This indicates that a Velcro-like friction behavior could be induced by simply changing the conformation of PEGs, which suggests a novel concept of altering polymer surfaces for the effective control of friction dynamics. PMID- 25515503 TI - Impaired imitation of gestures in mild dementia: comparison of dementia with Lewy bodies, Alzheimer's disease and vascular dementia. AB - INTRODUCTION: To examine whether imitation of gestures provided useful information to diagnose early dementia in elderly patients. METHODS: Imitation of finger and hand gestures was evaluated in patients with mild dementia; 74 patients had dementia with Lewy bodies (DLB), 100 with Alzheimer's disease (AD) and 52 with subcortical vascular dementia (SVaD). RESULTS: Significantly, more patients with DLB (32.4%) compared with patients with AD (5%) or SVaD (11.5%) had an impaired ability to imitate finger gestures bilaterally. Also, significantly, more patients with DLB (36.5%) compared with patients with AD (5%) or SVaD (15.4%) had lower mean scores of both hands. In contrast, impairment of the imitation of bimanual gestures was comparable among the three patient groups (DLB 50%, AD 42%, SVaD 42.3%). DISCUSSION: Our study revealed that imitation of bimanual gestures was impaired non-specifically in about half of the patients with mild dementia, whereas imitation of finger gestures was significantly more impaired in patients with early DLB than in those with AD or SVaD. Although the sensitivity was not high, the imitation tasks may provide additional information for diagnosis of mild dementia, especially for DLB. PMID- 25515505 TI - Purinergic P2X Receptors: Physiological and Pathological Roles and Potential as Therapeutic Targets. PMID- 25515506 TI - Editorial. Bioactivation of drugs: enzymes, reactive metabolites and adverse reactions. PMID- 25515507 TI - Synthesis Of Pyrido-Annelated Seven-Membered N-Containing Heterocycles. AB - Pharmaceutical industry is struggling with a lack of potential drugs in the pipe line. However, there is still a great opportunity to elaborate interesting scaffolds for medicinal chemistry. Various scaffolds that hold promise are rarely described in the literature. The last couple of decades, the wide range of biological activities of benzodiazepine derivatives have been investigated thoroughly and make the benzodiazepine scaffold, particularly the 1,4 benzodiazepine system, one of the most important structures for drug discovery. The substantial research on benzodiazepines has led to the synthesis of heterocycle-fused azepine derivatives with potentially new pharmacological activity. Some pyridoazepines are known to be active in the central nervous system and have a comparable activity to the well-known benzodiazepine scaffolds, which make the synthesis and study of pyridoazepines an important research topic. PMID- 25515508 TI - Bacterial beta-ketoacyl-acyl carrier protein synthase III (FabH) as a target for novel antibacterial agents design. AB - In bacterial type II fatty acid biosynthesis (FAS-II), beta-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) initiates the first condensation of acyl-CoA and malonyl-ACP to form acetoacetyl-ACP. Its key role for organism survival and specificity to bacteria make it as an essential target for the discovery of novel antibacterial agents. Over the last decade, several structures of FabH from diverse microorganisms have been solved, giving detailed information about the three-dimensional features of the catalytic pocket. This has facilitated the rational design of FabH inhibitors, which provides a framework for future development of antibiotics against multi-drug resistant strains. This review covers recent advances in the biochemical and structural research of FabH and updates the main families of related inhibitors. PMID- 25515509 TI - Benzothiazoles - scaffold of interest for CNS targeted drugs. AB - Benzothiazole compounds represent heterocyclic systems comprising a benzene ring fused with a thiazole ring containing nitrogen and sulphur in its structure. Besides the presence of a benzothiazole core in naturally occurring molecules, synthesized compounds containing a benzothiazole moiety in their structure proved to be a significant class of potential therapeutics, as they exhibit biological effects such as antitumor, antibacterial, antitubercular, antiviral, anthelmintic, antidiabetic and many others. Apart from the aforementioned peripheral or microbial active sites, benzothiazole analogues are also biologically active compounds in the central nervous system, where some approved drugs containing a benzothiazole moiety have already been identified and are used in the treatment of various neurological disorders. New benzothiazole molecules are currently under development and are being evaluated for several uses including diagnostics and as therapeutic drug candidates for the treatment of epilepsy and neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis amongst others. PMID- 25515511 TI - Role of the microenvironment in tumourigenesis: focus on virus-induced tumors. AB - Tumor microenvironment can differ considerably in various types of tumors in terms of cellular and cytokine networks and molecular drivers. The well known link between inflammation and cancer has recently found a number of genetic and molecular confirmations. In this respect, numerous reports have revealed that infection and chronic inflammation can contribute to cancer development, progression and control. Adhesion molecules, chemokines and proinflammatory cytokines, that enroll leukocytes, are persistently present in cancer microenvironment, thus increasing the risk for developing tumors. In this respect, cancer-derived microvescicles, in particular exosomes, exert an important role in the recruitment and reprogramming of components of tumor microenvironment. The relationship between cancer and virus infection has generated, in recent years, a great interest for studies aiming to better understand the role of the immune system in the control of these infections and of the immune cofactors in the promotion of the virus-induced neoplastic transformation. This suggests that virus-induced immune alterations may play a role to create an immunotolerogenic microenvironment during the carcinogenesis process. PMID- 25515510 TI - Involvement of the P2X7 purinergic receptor in inflammation: an update of antagonists series since 2009 and their promising therapeutic potential. AB - The purinergic receptor P2X7 is highly expressed in immune peripheral and central cells suggesting its important role in numerous diseases characterized by inflammatory processes like cancer, or neurodegenerative pathologies in relation with modulation of the immune system. Thereby, antagonization of this receptor may be a hopeful therapeutic strategy to treat a large range of diseases. Indeed, selective P2X7 antagonists display beneficial anti-inflammatory, analgesic, and in some cases, anticancer properties. This article will review the involvement of P2X7 in the immune system, the update of P2X7 antagonists series since 2009 and their promising therapeutic potential for the treatment of several immune- related diseases. PMID- 25515513 TI - Oleanolic acid and related triterpenoids from olives on vascular function: molecular mechanisms and therapeutic perspectives. AB - Oleanolic acid and related triterpenoids from olives modulate different signaling pathways, showing a wide range of pharmacological activities against inflammation, cancer or cardiovascular diseases. In particular, emerging evidences reveal the potential of oleanolic acid to restore vascular disorders associated to cardiovascular risk factors, i.e. hypertension, obesity and diabetes, and atherosclerosis. During the previous years, in vitro and in vivo studies with these triterpenoids have positioned them as being mainly responsible for cardiovascular risk protection traditionally associated to olive oil. This review updates recent investigations in olive oil triterpenoids function related to cardiovascular diseases, as well as the underlying mechanisms and structural implications. Important aspects of olive oil triterpenoids such as bioavailability and clinical perspectives on cardiovascular disorder are also extensively analyzed. All these investigations evidence the potential of triterpenoids from olive oil as a promising therapeutic strategy against vascular function, thus efficiently preventing the progression of cardiovascular diseases. PMID- 25515512 TI - Flavonoids and dementia: an update. AB - Dementia is a strongly age-related syndrome due to cognitive decline that can be considered a typical example of the combination of physiological and pathological aging-associated changes occurring in old people; it ranges from intact cognition to mild cognitive impairment, which is an intermediate stage of cognitive deterioration, and dementia. The spread of this syndrome has induced to study and try to reduce dementia modifiable risk factors. They include insulin resistance and hyperinsulinaemia, high blood pressure, obesity, smoking, depression, cognitive inactivity or low educational attainment as well as physical inactivity and incorrect diet, which can be considered one of the most important factors. One emerging strategy to decrease the prevalence of mild cognitive impairment and dementia may be the use of nutritional interventions. In the last decade, prospective data have suggested that high fruit and vegetable intakes are related to improved cognitive functions and reduced risks of developing a neurodegenerative process. The protective effects against neurodegeneration could be in part due to the intake of flavonoids that have been associated with several health benefits such as antioxidant and anti-inflammatory activities, increased neuronal signaling, and improved metabolic functions. The present article is aimed at reviewing scientific studies that show the protective effects of flavonoid intake against mild cognitive impairment and dementia. PMID- 25515514 TI - Biodegradation Aspects of Carbendazim and Sulfosulfuron: Trends, Scope and Relevance. AB - A large amount of pesticides are being used now-a-days in crop protection which has resulted in buildup of such harmful compounds in the environment, proving a menace to humans, animal life as well as to soil microbes. Residues of these pesticides have been reported in soil, water and foods. Carbendazim and sulfosulfuron are among the most widely used pesticides for treating fungal diseases and unwanted herbs in crops respectively. Carbendazim is a benzimidazole fungicide which can harm liver as well as the endocrine system and suspected to have mutagenic and tumorigenic effects. On similar lines sulfosulfuron, a sulfonylurea herbicide may result in the development of resistant herbs displaying its carry-over effects to the next crop cultivated. These pesticides possess large half-lives and thus remain persistent in the environment which may lead to harmful consequences in near future. Besides chemical and photo-catalytic degradation of pesticides, microbial degradation has now been evolved as a much effective and safer way to eradicate these harmful compounds from the environment. However a limited literature is available on the microbial degradation of such compounds. The present review emphasizes mainly upon the chemical properties of Carbendazim and Sulfosulfuron, detection of their residues, harmful effects and insights into their degradation studies. Further, the use of efficient microbes for remediation of pesticides from the environment has been discussed. PMID- 25515515 TI - Medicinal chemistry of P2X receptors: agonists and orthosteric antagonists. AB - In this work, we have highlighted data reported in the literature trying to draw a complete picture of the structures and biological activity of agonists and orthosteric antagonists of P2X receptors. Actually, only few P2X receptor agonists have been found and most of them are derived from modification of the natural ligand ATP and they are P2X receptor subtype unselective. In particular, BzATP (9) is one of the most potent P2X receptor agonists with EC50 value in the nanomolar range at some subtypes. Differently from agonists, P2X receptor antagonists belong to different chemical classes such as high molecular weight aryl polysulfonate molecules like suramin and its simplified derivatives and anthraquinone compounds. All these molecules proved to be non selective at P2X receptors, and they are endowed with micromolar activity and not favourable pharmacokinetic properties due to the presence of several charged groups. Also modification of the natural ligand ATP led to the discovery of P2X receptor antagonists like TNP-ATP (29), which, although not selective, showed high potency at P2X1, P2X3 (IC50 of 0.006 uM and 0.001 uM, respectively), and heteromeric P2X2/3 receptors. Also the dinucleotide inosine polyphosphate Ip5I (33) was found to be a potent and selective antagonist at P2X1 vs P2X3 receptors with IC50 = 0.003 uM. A significant improvement has been gained from the interest of pharmaceutical companies that in the last years discovered, through the use of high-throughput screening, potent and selective antagonists endowed with novel structures, some of which are currently in clinical trials for several therapeutic applications. PMID- 25515516 TI - P2X receptors in the cardiovascular system and their potential as therapeutic targets in disease. AB - This review considers the expression and roles of P2X receptors in the cardiovascular system in health and disease and their potential as therapeutic targets. P2X receptors are ligand gated ion channels which are activated by the endogenous ligand ATP. They are formed from the assembly of three P2X subunit proteins from the complement of seven (P2X1-7), which can associate to form homomeric or heteromeric P2X receptors. The P2X1 receptor is widely expressed in the cardiovascular system, being located in the heart, in the smooth muscle of the majority of blood vessels and in platelets. P2X1 receptors expressed in blood vessels can be activated by ATP coreleased with noradrenaline as a sympathetic neurotransmitter, leading to smooth muscle depolarisation and contraction. There is evidence that the purinergic component of sympathetic neurotransmission is increased in hypertension, identifying P2X1 receptors as a possible therapeutic target in this disorder. P2X3 and P2X2/3 receptors are expressed on cardiac sympathetic neurones and may, through positive feedback of neuronal ATP at this prejunctional site, amplify sympathetic neurotransmission. Activation of P2X receptors expressed in the heart increases cardiac myocyte contractility, and an important role of the P2X4 receptor in this has been identified. Deletion of P2X4 receptors in the heart depresses contractile performance in models of heart failure, while overexpression of P2X4 receptors has been shown to be cardioprotective, thus P2X4 receptors may be therapeutic targets in the treatment of heart disease. P2X receptors have been identified on endothelial cells. Although immunoreactivity for all P2X1-7 receptor proteins has been shown on the endothelium, relatively little is known about their function, with the exception of the endothelial P2X4 receptor, which has been shown to mediate endothelium dependent vasodilatation to ATP released during shear stress. The potential of P2X receptors as therapeutic targets in the treatment of cardiovascular disease is discussed. PMID- 25515517 TI - The role of P2X receptors in bone biology. AB - Bone is a highly dynamic organ, being constantly modeled and remodeled in order to adapt to the changing need throughout life. Bone turnover involves the coordinated actions of bone formation and bone degradation. Over the past decade great effort has been put into the examination of how P2X receptors regulate bone metabolism and especially for the P2X7 receptor an impressive amount of evidence has now documented its expression in osteoblasts, osteoclasts, and osteocytes as well as important functional roles in proliferation, differentiation, and function of the cells of bone. Key evidence has come from studies on murine knockout models and from pharmacologic studies on cells and animals. More recently, the role of P2X receptors in human bone diseases has been documented. Loss-of-functions polymorphisms in the P2X7 receptorare associated with bone loss and increased fracture risk. Very recently a report from a genetic study in multiple myeloma demonstrated that decreased P2X7 receptor function was associated with increased risk of developing multiple myeloma. In contrast, the risk of developing myeloma bone disease and subsequent vertebral fractures was increased in subjects carrying P2X7 receptor gain-of-function alleles as compared to subjects only carrying loss-of-function or normal functioning alleles. It is evident that P2X receptors are important in regulating bone turnover and maintaining bone mass, and thereby holding great potential as novel drug targets for treatment of bone diseases. However, further research is needed before we fully understand the roles and effects of P2X receptors in bone. PMID- 25515518 TI - Melatonin, its metabolites and its synthetic analogs as multi-faceted compounds: antioxidant, prooxidant and inhibitor of bioactivation reactions. AB - It is known that melatonin (MLT) and some of its metabolites act as antioxidants by scavenging free radicals as well as increasing the activity of antioxidant enzymes in the body. MLT is suggested to exert beneficial effects via various mechanisms in the treatment of many diseases, such as cancer, neurodegenerative diseases, epilepsy, diabetes mellitus and obesity. People working in nightshift exhibit decreased MLT levels that are suggested to be related with increased risk of hormone-related diseases. Similarly blind people were found to have increased MLT levels protecting against many diseases. This review briefly summarizes the published reports supporting these beneficial effects of MLT. Furthermore the present review involves recent developments related to the antioxidant effect of remarkable and multi-faceted molecule MLT as well as its metabolites and its synthesized analogues. The role of MLT as an inhibitor of bioactivation reactions is also discussed. PMID- 25515519 TI - Dis-organizing centrosomal clusters: specific cancer therapy for a generic spread? AB - Cancer is a leading cause of mortality and the annual incidence of new cancer cases is rising worldwide. Due to the frequent development of resistance and the side effects of established anti-cancer drugs, the quest for new drugs with improved therapeutic features goes on. In contrast to cytotoxic chemotherapy of the past, the concept of targeted chemotherapy attempts to increase specificity of therapy by attacking tumor-related mechanisms. A novel emerging treatment concept represents the inhibition of centrosomal clustering. The centrosome regulates mitotic spindle formation assuring uniform separation of chromosomes to daughter cells. Many tumors contain supernumerary centrosomes, which contribute to aneuploidy induction via multipolar mitotic spindle formation. As spindle multipolarity leads to cell death, tumor cells developed centrosomal clustering mechanism to prevent multipolar spindle formation by coalescence of multiple centrosomes into two functional spindle poles. Inhibition of centrosome clustering represents a novel strategy for drug development and leads to the formation of multipolar spindles and subsequent cell death. In the present review, we report advances in understanding the biology of centrosomal clustering as well as enlist compounds capable of inducing the formation of multipolar spindles such as indolquinolizines, integrin-linked kinase inhibitors (QLT-0267), noscapinoids (EM011), phthalamide derivatives (TC11), griseofulvin, phenanthridines (PJ-34), CCC1-01, CW069 GF-15, colcemid, nocodazole, paclitaxel, and vinblastine. We also present in silico result of compounds that bind to gamma tubulin under the ambit of centrosomal clustering inhibition. We observed maximum binding efficacy in GF-15, CW069, paclitaxel and larotaxel with GF-15 exhibiting least energy of -8.4 Kcal/mol and 0.7 MUM Pki value. PMID- 25515520 TI - The Aeromonas caviae AHA0618 gene modulates cell length and influences swimming and swarming motility. AB - Aeromonas caviae is motile via a polar flagellum in liquid culture, with a lateral flagella system used for swarming on solid surfaces. The polar flagellum also has a role in cellular adherence and biofilm formation. The two subunits of the polar flagellum, FlaA and FlaB, are posttranslationally modified by O-linked glycosylation with pseudaminic acid on 6-8 serine and threonine residues within the central region of these proteins. This modification is essential for the formation of the flagellum. Aeromonas caviae possesses the simplest set of genes required for bacterial glycosylation currently known, with the putative glycosyltransferase, Maf1, being described recently. Here, we investigated the role of the AHA0618 gene, which shares homology (37% at the amino acid level) with the central region of a putative deglycosylation enzyme (HP0518) from the human pathogen Helicobacter pylori, which also glycosylates its flagellin and is proposed to be part of a flagellin deglycosylation pathway. Phenotypic analysis of an AHA0618 A. caviae mutant revealed increased swimming and swarming motility compared to the wild-type strain but without any detectable effects on the glycosylation status of the polar flagellins when analyzed by western blot analysis or mass spectroscopy. Bioinformatic analysis of the protein AHA0618, demonstrated homology to a family of l,d-transpeptidases involved in cell wall biology and peptidoglycan cross-linking (YkuD-like). Scanning electron microscopy (SEM) and fluorescence microscopy analysis of the wild-type and AHA0618-mutant A. caviae strains revealed the mutant to be subtly but significantly shorter than wild-type cells; a phenomenon that could be recovered when either AHA0618 or H. pylori HP0518 were introduced. We can therefore conclude that AHA0618 does not affect A. caviae behavior by altering polar flagellin glycosylation levels but is likely to have a role in peptidoglycan processing at the bacterial cell wall, consequently altering cell length and hence influencing motility. PMID- 25515521 TI - Effect of a 12-day balneotherapy programme on pain, mood, sleep, and depression in healthy elderly people. AB - BACKGROUND: The main purpose of this study is to analyze the effect of a 12-day balneotherapy programme on pain, mood state, sleep, and depression in older adults. METHODS: In this study, 52 elderly adults from different areas of Spain participated in a social hydrotherapy programme created by the government's Institute for Elderly and Social Services, known as IMSERSO; participants included 23 men (age, 69.74 +/- 5.19 years) and 29 women (age, 70.31 +/- 6.76 years). Pain was analyzed using the visual analogue scale. Mood was assessed using the Profile of Mood Status. Sleep was assessed using the Oviedo Sleep Questionnaire. Depression was assessed using the Geriatric Depression Scale. The balneotherapy programme was undertaken at Balneario San Andres (Jaen, Spain). The water at Balneario San Andres, according to the Handbook of Spanish Mineral Water, is a hypothermic (>=20 degrees C) hard water of medium mineralization, with bicarbonate, sulfate, sodium, and magnesium as the dominant ions. RESULTS: Balneotherapy produced significant improvements (P < 0.05) for all variables (pain, mood state, sleep, and depression) in the total sample. A differential effect was found between the sexes regarding pain improvement, with men, but not women, having significantly improvement (P < 0.01) after treatment. With regard to improving mood, sex differences were also shown, with women, but not men, significantly improved (P < 0.05) in both depression and fatigue. CONCLUSIONS: In conclusion, a 12-day balneotherapy programme has a positive effect on pain, mood, sleep quality, and depression in healthy older people. PMID- 25515522 TI - MSC-regulated microRNAs converge on the transcription factor FOXP2 and promote breast cancer metastasis. AB - Mesenchymal stem/stromal cells (MSCs) are progenitor cells shown to participate in breast tumor stroma formation and to promote metastasis. Despite expanding knowledge of their contributions to breast malignancy, the underlying molecular responses of breast cancer cells (BCCs) to MSC influences remain incompletely understood. Here, we show that MSCs cause aberrant expression of microRNAs, which, led by microRNA-199a, provide BCCs with enhanced cancer stem cell (CSC) properties. We demonstrate that such MSC-deregulated microRNAs constitute a network that converges on and represses the expression of FOXP2, a forkhead transcription factor tightly associated with speech and language development. FOXP2 knockdown in BCCs was sufficient in promoting CSC propagation, tumor initiation, and metastasis. Importantly, elevated microRNA-199a and depressed FOXP2 expression levels are prominent features of malignant clinical breast cancer and are associated significantly with poor survival. Our results identify molecular determinants of cancer progression of potential utility in the prognosis and therapy of breast cancer. PMID- 25515523 TI - Glucocorticoids induce autophagy in rat bone marrow mesenchymal stem cells. AB - Glucocorticoid-induced osteoporosis (GIOP) is a widespread clinical complication following glucocorticoid therapy. This irreversible damage to bone-forming and resorbing cells is essential in the pathogenesis of osteoporosis. Autophagy is a physiological process involved in the regulation of cells and their responses to diverse stimuli, however, the role of autophagy in glucocorticoid-induced damage to bone marrow mesenchymal stem cells (BMSCs) remains unclear. The current study confirmed that glucocorticoid administration impaired the proliferation of BMSCs. Transmission electron microscopy, immunohistochemistry and western blot analysis detected autophagy in vitro and in GIOP model rats (in vivo). With the addition of the autophagy inhibitor 3-methyladenine, the proliferative ability of BMSCs was further reduced, while the number of apoptotic BMSCs was significantly increased. The data suggests that in response to glucocorticoid administration, induced autophagy aids to maintain proliferation and prevent apoptosis of BMSCs. Thus, it is hypothesized that autophagy may be a novel target in the treatment or prevention of osteoporosis. PMID- 25515524 TI - A spinal tumor showing mixed features of ependymoma and hemangioblastoma: a case report and literature review. AB - We report an intramedullary spinal tumor consisting of an ependymoma and a hemangioblastoma (HB). A 37-year-old woman presented with progressive bilateral lower limb sensory and motor deficits. Magnetic resonance imaging showed a single intramedullary mass in the thoracic cord (T4-T6 level). Clinically, the patient had no von Hippel-Lindau disease and neurofibromatosis type 2. Metastatic carcinomas including renal cell carcinoma were altogether negative. Complete surgical resection was performed. Histologically, the tumor consisted of a mixed ependymoma and HB. Tumor cells of ependymoma displayed a rather uniform appearance with round to oval nuclei having salt-and-pepper-like chromatin, forming perivascular pseudorosette structures with radially arranged, tapering cell processes extending to intratumoral blood vessels. Stromal cells of HB had vacuolated or homogeneously eosinophilic cytoplasm and variable sized hyperchromatic nuclei within a background of capillaries. Immunohistochemically, tumor cells of ependymoma were strongly positive for glial fibrillary acidic protein (GFAP), focally positive for epithelial membrane antigen (EMA) and D2-40 in a dot-like or ring-like pattern. Stromal cells of HB showed immunoreactivity for S100, vimentin, inhibin-alpha, D2-40, EMA and cytokeratins (CK: AE1/AE3, CK19). A review of the literature, in conjunction with the present case, shows that ependymomas and HBs may have a close relationship with each other. PMID- 25515525 TI - Nintendo related injuries and other problems: review. AB - OBJECTIVE: To identify all reported cases of injury and other problems caused by using a Nintendo video gaming system. DESIGN: Review. DATA SOURCES AND REVIEW METHODS: Search of PubMed and Embase in June 2014 for reports on injuries and other problems caused by using a Nintendo gaming system. RESULTS: Most of the 38 articles identified were case reports or case series. Injuries and problems ranged from neurological and psychological to surgical. Traditional controllers with buttons were associated with tendinitis of the extensor of the thumb. The joystick on the Nintendo 64 controller was linked to palmar ulceration. The motion sensitive Wii remote was associated with musculoskeletal problems and various traumas. CONCLUSIONS: Most problems are mild and prevalence is low. The described injuries were related to the way the games are controlled, which varies according to the video game console. PMID- 25515526 TI - Bubble-surface interactions with graphite in the presence of adsorbed carboxymethylcellulose. AB - The adsorption of carboxymethylcellulose (CMC), and the subsequent effect on bubble-surface interactions, has been studied for a graphite surface. CMC adsorbs on highly oriented pyrolytic graphite (HOPG) in specific patterns: when adsorbed from a solution of low concentration it forms stretched, isolated and sparsely distributed chains, while upon adsorption from a solution of higher concentration, it forms an interconnected network of multilayer features. The amount and topography of the adsorbed CMC affect the electrical properties as well as the wettability of the polymer-modified HOPG surface. Adsorption of CMC onto the HOPG surface causes the zeta potential to be more negative and the modified surface becomes more hydrophilic. This increase in both the absolute value of zeta potential and the surface hydrophilicity originates from the carboxymethyl groups of the CMC polymer. The effect of the adsorbed polymer layer on wetting film drainage and bubble-surface/particle attachment was determined using high speed video microscopy to monitor single bubble-surface collision, and single bubble Hallimond tube flotation experiments. The time of wetting film drainage and the time of three-phase contact line spreading gets significantly longer for polymer-modified HOPG surfaces, indicating that the film rupture and three-phase contact line expansion were inhibited by the presence of polymer. The effect of longer drainage times and slower dewetting correlated with reduced flotation recovery. The molecular kinetic (MK) model was used to quantify the effect of the polymer on dewetting dynamics, and showed an increase in the jump frequency for the polymer adsorbed at the higher concentration. PMID- 25515528 TI - Derivation of Endothelial Cells and Pericytes from Human Pluripotent Stem Cells. AB - Blood vessels serve as the lifeline of nearly all living tissue. Vascular cells derived from human pluripotent stem cells hold great potential for clinical use in the regeneration of diseased vasculature and construction of blood vessels in engineered tissue. By deriving these cells in a controllable and clinically relevant manner harnessing physiological cues, we can obtain populations of cells amenable for transplantation. In this chapter, we describe methods to differentiate human pluripotent stem cells toward a bicellular population of early vascular cells using low oxygen cues, guide these subpopulations into mature endothelial cells and pericytes, and expand the vascular derivatives. PMID- 25515527 TI - Dietary self-control is related to the speed with which attributes of healthfulness and tastiness are processed. AB - We propose that self-control failures, and variation across individuals in self control abilities, are partly due to differences in the speed with which the decision-making circuitry processes basic attributes, such as tastiness, versus more abstract attributes, such as healthfulness. We tested these hypotheses by combining a dietary-choice task with a novel form of mouse tracking that allowed us to pinpoint when different attributes were being integrated into the choice process with temporal resolution at the millisecond level. We found that, on average, tastiness was processed about 195 ms earlier than healthfulness during the choice process. We also found that 13% to 39% of observed individual differences in self-control ability could be explained by differences in the relative speed with which tastiness and healthfulness were processed. PMID- 25515529 TI - Psoriasis-associated IgA nephropathy under infliximab therapy. PMID- 25515530 TI - Up-regulation of semaphorin 4A expression in human retinal pigment epithelial cells by PACAP released from cocultured neural cells. AB - Development and homeostasis of multicellular organisms require interactions between neighbouring cells. We recently established an in vitro model of cell cell interaction based on a collagen vitrigel membrane. We have now examined the role of neural cells in retinal homeostasis by coculture of human retinal pigment epithelial (RPE) cells and neural cells on opposite sides of such a membrane. The neural cells (differentiated PC12 cells) induced up-regulation of semaphorin 4A (Sema4A), a member of the semaphorin family of neural guidance proteins, in RPE (ARPE19) cells. This effect of the neural cells was mimicked by the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) and was abolished by the PACAP antagonist PACAP(6-38). Coculture with neural cells or stimulation with PACAP also induced the phosphorylation of extracellular-signal-regulated kinase in ARPE19 cells, and this effect of the neural cells was inhibited by PACAP(6 38). Finally, among various cytokines examined, only the amount of interleukin-6 released by cocultures of ARPE19 and neural cells differed from that released by ARPE19 cells cultured alone. Interleukin-6 was not detected in culture supernatants of neural cells, and the reduction in the amount of interleukin-6 released by the cocultures compared with that released by ARPE19 cells alone was prevented by PACAP(6-38). Our findings suggest that PACAP released from retinal neural cells (photoreceptors or optic nerve cells) may regulate Sema4A expression in RPE cells and thereby contribute to the maintenance of retinal structure and function. Development and homeostasis of multicellular organisms require interactions between neighbouring cells. With the use of a coculture system based on a collagen vitrigel membrane, we have now shown that neural cells induce up regulation of the neural guidance protein Sema4A in RPE cells. This effect of neural cells appears to be mediated by the neuropeptide PACAP. PACAP released from retinal neural cells (photoreceptors or optic nerve cells) may thus regulate Sema4A expression in RPE cells and thereby contribute to the maintenance of retinal structure and function. PMID- 25515531 TI - Synergistic concurrent enhancement of charge generation, dissociation, and transport in organic solar cells with plasmonic metal-carbon nanotube hybrids. AB - Plasmonic nanostructures are synthesized by decorating B- or N-doped carbon nanotubes (CNTs) with Au nanoparticles. While the plasmonic nanoparticles promote exciton generation and dissociation, the B- and N-doped CNTs enable charge selective transport enhancement in the organic active layer. Such concurrent enhancements of all the principal energy-harvesting steps improve the device efficiency up to 9.98% for organic single-junction solar cells. PMID- 25515532 TI - Revisiting germinal vesicle transfer as a treatment for aneuploidy in infertile women with diminished ovarian reserve. AB - The maturation and meiotic competence of human oocyte requires both healthy cytoplasmic and nuclear compartments. Germinal vesicle (GV) transfer techniques have represented useful tools for studying the interaction between the nucleus and the cytoplasm in oocyte maturation process in mammals. This report summarizes an update on the recent findings on GV transfer pertaining to improving meiotic resumption and ability of immature oocytes to mature. It also addresses mitochondrial DNA heteroplasmy as a challenge in GV transfer technology. Altogether, data to date indicate that GV transfer could improve the quality of human oocytes especially in women with advanced maternal age who usually have high rates of spindle abnormality and chromosomal misalignment. Although experimental, this technique represents a viable therapeutic option for women with diminished ovarian reserve who do not produce mature oocytes or good embryos during IVF treatment. PMID- 25515533 TI - Prospective assessment of the diagnostic utility of esophageal brushings in adults with eosinophilic esophagitis. AB - Patients with eosinophilic esophagitis (EoE) undergo multiple endoscopies with biopsy for both diagnosis and assessment of treatment response, which is inconvenient and costly. Brush cytology has been examined in Barrett's esophagus to reduce the need for repeated endoscopic biopsies. The aim of this pilot study was to evaluate the ability of brush cytology to detect mucosal eosinophilia in patients with EoE. This prospective study included adults with untreated and treated esophageal eosinophilia undergoing endoscopy at a tertiary care center. Patients received paired brushings and biopsies at the proximal and distal esophagus. A blinded pathologist quantified the number of eosinophils and epithelial cells per high-power field (hpf) on the cytology slides. The ratio of eosinophils/epithelial cells was used to normalize the cytology specimens for density of cells collected. The main outcome measures were sensitivity and specificity of brush cytology, and correlation between cytology and histology. Twenty-eight patients enrolled. The average age of the cohort was 37.7 +/- 10.4 years; 75% of subjects were male. The sensitivity of cytology was 67-69% at the proximal esophagus and 70-72% at the distal esophagus. The specificity was 61-67% proximally and 70-75% distally. Histology was not significantly correlated with the max ratio of eosinophils/epithelial cells per hpf or the absolute number of eosinophils on cytology slides. Cytology using esophageal brushing has limited sensitivity and specificity for the detection of esophageal mucosal eosinophilia. The presence of exudates on endoscopy increased the detection of eosinophilia, which could make cytology useful in pediatric EoE, which often has a more exudative presentation. Diagnostic yield may improve with alternative acquisition techniques or the incorporation of eosinophil degranulation proteins. PMID- 25515534 TI - Embryonic developmental plasticity in the long-snouted seahorse (Hippocampus reidi, Ginsburg 1933) in relation to parental preconception diet. AB - The aim of the present study was to investigate the hypothesis that parental periconception nutrition in adult seahorses affects the development and growth of their offspring. We tested the hypothesis that because seahorse embryos develop inside the male's brood pouch, manipulation of the male's diet would affect offspring growth and development independently of the female's diet. Adult males and females were fed separately with either wild-caught crustaceans or commercial aquarium diet for 1 month before conception to influence the periconception environment. Approximately 10000 offspring were obtained from four different treatment groups (Male/Wild or Male/Commercial*Female/Wild or Female/Commercial). Weights, physical dimensions and fatty acid profiles of the newborns were determined. Offspring produced when the males receiving commercial diet were mated with wild-fed females were larger (P<0.05) than those produced by wild-fed males. When both males and females were fed with commercial diet, their offspring were significantly smaller than those from the other treatment groups. When commercial diet-fed females were mated with wild-fed males, the offspring showed distortion of the snout:head length ratio. These results support the view that the preconception diet received by males and females differentially affects embryonic development. PMID- 25515535 TI - Efficacy of artesunate-amodiaquine for the treatment of acute uncomplicated falciparum malaria in southern Mauritania. AB - BACKGROUND: A regular evaluation of therapeutic efficacy in sentinel sites and a system of surveillance are required to establish treatment guidelines and adapt national anti-malarial drug policy to the rapidly changing epidemiology of drug resistant malaria. The current anti-malarial treatment guideline in Mauritania, officially recommended since 2006, is based on artemisinin-based combination therapy. The aim of the present study was to evaluate clinical efficacy and tolerance of artesunate-amodiaquine, the first-line treatment for acute uncomplicated malaria, in Mauritanian paediatric and adult patients to validate its continued use in the country. METHODS: Plasmodium falciparum-infected symptomatic patients aged > six months were enrolled in Kobeni and Timbedra in southern Mauritania in September to October 2013. Co-formulated artesunate amodiaquine was administered at the recommended dose over three days. Patients were followed until day 28. Parasitological and clinical response was classified according to the standard 2009 World Health Organization protocol. RESULTS: A total of 130 patients (65 in Kobeni and 65 in Timbedra) were enrolled in the study. Seventeen patients (13.1%) were either excluded (before PCR correction) or lost to follow-up. Based on the per protocol analysis, artesunate-amodiaquine efficacy (i.e., the proportion of adequate clinical and parasitological response) was 96.6% in Kobeni and 98.2% in Timbedra before PCR correction. Late clinical failure was observed in two patients in Kobeni and one patient in Timbedra. After PCR correction, the efficacy rate in the two study sites was 98.2%. On day 3, all patients were afebrile and had negative smears. Treatment was well tolerated. CONCLUSIONS: Artesunate-amodiaquine is well tolerated and highly efficacious for the treatment of uncomplicated P. falciparum malaria. In the majority of patients, fever and parasitaemia were rapidly cleared before day 3. The results support the national anti-malarial drug guideline for a continued use of artesunate-amodiaquine as a first-line drug for uncomplicated malaria in southern Mauritania. PMID- 25515536 TI - HSP70 mediates degradation of the p65 subunit of nuclear factor kappaB to inhibit inflammatory signaling. AB - The nuclear PDZ-LIM domain protein PDLIM2 acts as a ubiquitin E3 ligase that targets the p65 subunit of the transcription factor nuclear factor kappaB (NF kappaB) for degradation, thus preventing excessive inflammatory responses. We found that the chaperone protein HSP70 (heat shock protein of 70 kD) was required for the PDLIM2-mediated degradation of p65 and suppression of NF-kappaB signaling in lipopolysaccharide (LPS)-treated dendritic cells. In response to LPS, HSP70 translocated to the nucleus where it associated with PDLIM2 and the proteasome associated protein BAG-1 (BCL2-associated athanogene 1) and promoted the transport of the NF-kappaB-PDLIM2 complex to the proteasome, thereby facilitating the degradation of p65. Consistent with these data, mouse dendritic cells deficient in either HSP70 or BAG-1 had more nuclear p65 and produced more proinflammatory cytokines than did wild-type dendritic cells. Furthermore, HSP70 deficient mice had more sustained inflammatory responses to bacterial infection than did wild-type mice. These data suggest that in addition to acting as a chaperone during protein folding, HSP70 plays a role in inhibiting proinflammatory NF-kappaB signaling by acting as a bridge between a ubiquitin E3 ligase and the proteasome. PMID- 25515538 TI - A systems-wide screen identifies substrates of the SCFbetaTrCP ubiquitin ligase. AB - Cellular proteins are degraded by the ubiquitin-proteasome system (UPS) in a precise and timely fashion. Such precision is conferred by the high substrate specificity of ubiquitin ligases. Identification of substrates of ubiquitin ligases is crucial not only to unravel the molecular mechanisms by which the UPS controls protein degradation but also for drug discovery purposes because many established UPS substrates are implicated in disease. We developed a combined bioinformatics and affinity purification-mass spectrometry (AP-MS) workflow for the system-wide identification of substrates of SCF(betaTrCP), a member of the SCF family of ubiquitin ligases. These ubiquitin ligases are characterized by a multisubunit architecture typically consisting of the invariable subunits Rbx1, Cul1, and Skp1 and one of 69 F-box proteins. The F-box protein of this member of the family is betaTrCP. SCF(betaTrCP) binds, through the WD40 repeats of betaTrCP, to the DpSGXX(X)pS diphosphorylated motif in its substrates. We recovered 27 previously reported SCF(betaTrCP) substrates, of which 22 were verified by two independent statistical protocols, thereby confirming the reliability of this approach. In addition to known substrates, we identified 221 proteins that contained the DpSGXX(X)pS motif and also interacted specifically with the WD40 repeats of betaTrCP. Thus, with SCF(betaTrCP), as the example, we showed that integration of structural information, AP-MS, and degron motif mining constitutes an effective method to screen for substrates of ubiquitin ligases. PMID- 25515539 TI - Exposure science and its places in environmental health sciences and risk assessment: why is its application still an ongoing struggle in 2014? PMID- 25515537 TI - Npr2 inhibits TORC1 to prevent inappropriate utilization of glutamine for biosynthesis of nitrogen-containing metabolites. AB - Cells must be capable of switching between growth and autophagy in unpredictable nutrient environments. The conserved Npr2 protein complex (comprising Iml1, Npr2, and Npr3; also called SEACIT) inhibits target of rapamycin complex 1 (TORC1) kinase signaling, which inhibits autophagy in nutrient-rich conditions. In yeast cultured in media with nutrient limitations that promote autophagy and inhibit growth, loss of Npr2 enables cells to bypass autophagy and proliferate. We determined that Npr2-deficient yeast had a metabolic state distinct from that of wild-type yeast when grown in minimal media containing ammonium as a nitrogen source and a nonfermentable carbon source (lactate). Unlike wild-type yeast, which accumulated glutamine, Npr2-deficient yeast metabolized glutamine into nitrogen-containing metabolites and maintained a high concentration of S-adenosyl methionine (SAM). Moreover, in wild-type yeast grown in these nutrient-limited conditions, supplementation with methionine stimulated glutamine consumption for synthesis of nitrogenous metabolites, demonstrating integration of a sulfur containing amino acid cue and nitrogen utilization. These data revealed the metabolic basis by which the Npr2 complex regulates cellular homeostasis and demonstrated a key function for TORC1 in regulating the synthesis and utilization of glutamine as a nitrogen source. PMID- 25515540 TI - Urinary creatinine adjustment for uranium and kidney outcomes from lead workers. PMID- 25515541 TI - Cadmium exposure in inhabitants living in non-polluted area. PMID- 25515542 TI - Flavoring exposure in food manufacturing. PMID- 25515544 TI - The importance of the supratrochlear foramen of the humerus in humans: an anatomical study. AB - BACKGROUND: The supratrochlear foramen (STF) is an important and relatively common anatomic variation in the lower end of the humerus in humans. Its structure has received increased attention in recent years. Anatomical knowledge of STF is useful for anatomists, anthropologists, orthopedic surgeons, and radiologists. This aperture is of great interest to anthropologists who claim it as one of the points in establishing a relationship between humans and lower animals. The goal of this study was to describe the features of STF of the humerus in the Turkish population. MATERIAL AND METHODS: All bones were obtained from the Department of Anatomy, Faculty of Medicine and Department of Antrophology, University of Mustafa Kemal, Hatay. A total of 166 dried humeri (83 right side and 83 left side), of which 78 belonged to males and 88 to females, were examined to determine the presence of supratrochlear foramen. Digital vernier calipers were used to measure the maximum width (transverse) and height (vertical) of the STF. RESULTS: Out of 166 bones, the foramen was present in 18 humeri (4 right side and 14 left side), showing the incidence as 10.8% with unpaired humeri. We observed 4 types of shape: oval, round, triangular, and sieve like. The average diameter of the long (transverse) axis was 5.93+/-1.68 mm and the short (vertical) axis was 4.06+/-0.89 mm. Some of the bones showed translucency of the bony septum, found in 17 (20.5%) on both sides of the humeri. CONCLUSIONS: There are few studies about STF in the Turkish population. Knowledge of supratrochlear foramen in the distal humerus in humans is important in diagnostic orthopedics, in intramedullary nailing of the humerus, and in possibly increasing the risk of future low-energy fractures. In addition, STF is a radiolucent area in radiographs and may be misinterpreted as an osteolytic or cystic lesion. PMID- 25515545 TI - Formation of complex organic molecules in methanol and methanol-carbon monoxide ices exposed to ionizing radiation--a combined FTIR and reflectron time-of-flight mass spectrometry study. AB - The radiation induced chemical processing of methanol and methanol-carbon monoxide ices at 5.5 K exposed to ionizing radiation in the form of energetic electrons and subsequent temperature programmed desorption is reported in this study. The endogenous formation of complex organic molecules was monitored online and in situ via infrared spectroscopy in the solid state and post irradiation with temperature programmed desorption (TPD) using highly sensitive reflectron time-of-flight (ReTOF) mass spectrometry coupled with single photoionization at 10.49 eV. Infrared spectroscopic analysis of the processed ice systems resulted in the identification of simple molecules including the hydroxymethyl radical (CH2OH), formyl radical (HCO), methane (CH4), formaldehyde (H2CO), carbon dioxide (CO2), ethylene glycol (HOCH2CH2OH), glycolaldehyde (HOCH2CHO), methyl formate (HCOOCH3), and ketene (H2CCO). In addition, ReTOF mass spectrometry of subliming molecules following temperature programmed desorption definitely identified several closed shell C/H/O bearing organics including ketene (H2CCO), acetaldehyde (CH3COH), ethanol (C2H5OH), dimethyl ether (CH3OCH3), glyoxal (HCOCOH), glycolaldehyde (HOCH2CHO), ethene-1,2-diol (HOCHCHOH), ethylene glycol (HOCH2CH2OH), methoxy methanol (CH3OCH2OH) and glycerol (CH2OHCHOHCH2OH) in the processed ice systems. Additionally, an abundant amount of molecules yet to be specifically identified were observed sublimating from the irradiated ices including isomers with the formula C3H(x=4,6,8)O, C4H(x=8,10)O, C3H(x=4,6,8)O2, C4H(x=6,8)O2, C3H(x=4,6)O3, C4H8O3, C4H(x=4,6,8)O4, C5H(x=6,8)O4 and C5H(x=6,8)O5. The last group of molecules containing four to five oxygen atoms observed sublimating from the processed ice samples include an astrobiologically important class of sugars relevant to RNA, phospholipids and energy storage. Experiments are currently being designed to elucidate their chemical structure. In addition, several reaction pathways were identified in the irradiated ices of mixed isotopes based upon the results of both in situ FTIR analysis and TPD ReTOF gas phase analysis. In general, the results of this study provide crucial information on the formation of a variety of classes of organics including alcohols, ketones, aldehydes, esters, ethers, and sugars within the bulk ices upon exposure to ionizing radiation that are relevant to the molecular clouds within the interstellar medium. PMID- 25515547 TI - The pathogenesis of herpes zoster duplex bilateralis symmetricus. PMID- 25515546 TI - The effects of building-related factors on classroom relative humidity among North Carolina schools participating in the 'Free to Breathe, Free to Teach' study. AB - Both high and low indoor relative humidity (RH) directly impact Indoor Air Quality (IAQ), an important school health concern. Prior school studies reported a high prevalence of mold, roaches, and water damage; however, few examined associations between modifiable classroom factors and RH, a quantitative indicator of dampness. We recorded RH longitudinally in 134 North Carolina classrooms (n = 9066 classroom-days) to quantify the relationships between modifiable classroom factors and average daily RH below, within, or above levels recommended to improve school IAQ (30-50% or 30-60% RH). The odds of having high RH (>60%) were 5.8 [95% Confidence Interval (CI): 2.9, 11.3] times higher in classrooms with annual compared to quarterly heating, ventilating, and air conditioning (HVAC) system maintenance and 2.5 (95% CI: 1.5, 4.2) times higher in classrooms with HVAC economizers compared to those without economizers. Classrooms with direct-expansion split systems compared to chilled water systems had 2.7 (95% CI: 1.7, 4.4) times higher odds of low RH (<30%). When unoccupied, classrooms with thermostat setbacks had 3.7 (95% CI: 1.7, 8.3) times the odds of high RH (>60%) of those without setbacks. This research suggests actionable decision points for school design and maintenance to prevent high or low classroom RH. PRACTICAL IMPLICATIONS: This study combines longitudinal measurements of classroom relative humidity with school inspection data from several schools to describe the problem of relative humidity control in schools. Our findings on how maintenance and mechanical factors affect classroom humidity provide suggestions on building operations policies and heating, ventilating, and air-conditioning (HVAC) design considerations that may improve classroom relative humidity control. PMID- 25515548 TI - Cyclic (alkyl)(amino)carbenes (CAACs): stable carbenes on the rise. AB - CONSPECTUS: Carbenes are compounds that feature a divalent carbon atom with only six electrons in its valence shell. In the singlet state, they possess a lone pair of electrons and a vacant orbital and therefore exhibit Lewis acidic and Lewis basic properties, which explains their very high reactivity. Following the preparation by our group in 1988 of the first representative, a variety of stable carbenes are now available, the most popular being the cyclic diaminocarbenes. In this Account, we discuss another class of stable cyclic carbenes, namely, cyclic (alkyl)(amino)carbenes (CAACs), in which one of the electronegative and pi-donor amino substituents of diaminocarbenes is replaced by a sigma-donating but not pi donating alkyl group. As a consequence, CAACs are more nucleophilic (sigma donating) but also more electrophilic (pi-accepting) than diaminocarbenes. Additionally, the presence of a quaternary carbon in the position alpha to the carbene center provides steric environments that differentiate CAACs dramatically from all other ligands. We show that the peculiar electronic and steric properties of CAACs allow for the stabilization of unusual diamagnetic and paramagnetic main group element species. As examples, we describe the preparation of room temperature stable phosphorus derivatives in which the heteroatom is in the zero oxidation state, nucleophilic boron compounds, and phosphorus-, antimony , boron-, silicon-, and even carbon-centered neutral and cationic radicals. CAACs are also excellent ligands for transition metal complexes. The most recent application is their use for the stabilization of paramagnetic complexes, in which the metal is often in a formal zero oxidation state. Indeed, bis(CAAC)M complexes in which the metal is gold, copper, cobalt, iron, nickel, manganese, and zinc have been isolated. Depending on the metal, the majority of spin density can reside either on the metal or on the carbene carbons and the nitrogen atoms of the CAAC ligand. In contrast to diaminocarbenes, the higher basicity of CAACs makes them poor leaving groups, and thus they cannot be used for classical organocatalysis. However, because of their superior electrophilicity and smaller singlet-triplet gap, CAACs can activate small molecules at room temperature, such as CO, H2, and P4, as well as enthalpically strong bonds, such as B-H, Si-H, N-H, and P-H. Lastly, excellent results have been obtained in palladium, ruthenium, and gold catalysis. CAAC-metal complexes are extremely thermally robust, which allows for their utilization in harsh conditions. This property has been used to perform a variety of gold-catalyzed reactions in the presence of basic amines, including ammonia and hydrazine, which usually deactivate catalysts. PMID- 25515549 TI - Nutritional epidemiology--there's life in the old dog yet! AB - Consideration is given to the idea that the nutritional epidemiology of cancer is dead, as some in the media have claimed. The basis for the claim does not lie in science nor has anyone with relevant knowledge made such a statement-although that, too, has been claimed. Evidence is adduced for the importance of past achievements of nutritional epidemiology. Attention is similarly drawn to recent contributions. In particular, I note the state of play of cancer and plant foods, fat and breast cancer, meat and cancer, vegetarians, intervention studies, migrant studies, and westernization of diet and lifestyle. Some next steps and some currently important questions are outlined. PMID- 25515551 TI - Compensatory smoking from gradual and immediate reduction in cigarette nicotine content. AB - Reducing the addictiveness of cigarettes by reducing their nicotine content can potentially have a profound impact on public health. Two different approaches to nicotine reduction have been proposed: gradual and immediate. To determine if either of these approaches results in significant compensatory smoking behavior, which might lead to safety concerns, we performed a secondary analysis of data from studies that have utilized these two approaches. The number of cigarettes smoked per day, carbon monoxide exposure, and cotinine levels in plasma or urine were assessed while participants smoked reduced nicotine content cigarettes and compared with when they smoked their usual brand cigarettes. The results showed that in general, these two approaches led to minimal compensatory smoking and reduced levels of cotinine over the course of the experimental period, suggesting that neither of these approaches poses a major safety concern. PMID- 25515550 TI - Tobacco and alcohol in relation to male breast cancer: an analysis of the male breast cancer pooling project consortium. AB - BACKGROUND: The etiology of male breast cancer is poorly understood, partly due to its relative rarity. Although tobacco and alcohol exposures are known carcinogens, their association with male breast cancer risk remains ill-defined. METHODS: The Male Breast Cancer Pooling Project consortium provided 2,378 cases and 51,959 controls for analysis from 10 case-control and 10 cohort studies. Individual participant data were harmonized and pooled. Unconditional logistic regression was used to estimate study design-specific (case-control/cohort) ORs and 95% confidence intervals (CI), which were then combined using fixed-effects meta-analysis. RESULTS: Cigarette smoking status, smoking pack-years, duration, intensity, and age at initiation were not associated with male breast cancer risk. Relations with cigar and pipe smoking, tobacco chewing, and snuff use were also null. Recent alcohol consumption and average grams of alcohol consumed per day were also not associated with risk; only one subanalysis of very high recent alcohol consumption (>60 g/day) was tentatively associated with male breast cancer (ORunexposed referent = 1.29; 95% CI, 0.97-1.71; OR>0-<7 g/day referent = 1.36; 95% CI, 1.04-1.77). Specific alcoholic beverage types were not associated with male breast cancer. Relations were not altered when stratified by age or body mass index. CONCLUSIONS: In this analysis of the Male Breast Cancer Pooling Project, we found little evidence that tobacco and alcohol exposures were associated with risk of male breast cancer. IMPACT: Tobacco and alcohol do not appear to be carcinogenic for male breast cancer. Future studies should aim to assess these exposures in relation to subtypes of male breast cancer. PMID- 25515552 TI - Dietary inflammatory index and risk of pancreatic cancer in an Italian case control study. AB - Previous studies have shown that various dietary components may be implicated in the aetiology of pancreatic cancer. However, the possible relationship between diet-related inflammation and the risk of pancreatic cancer has not yet been investigated. We examined the ability of a newly developed literature-derived dietary inflammatory index (DII) to predict the risk of pancreatic cancer in a case-control study conducted in Italy between 1991 and 2008. This included 326 incident cases and 652 controls admitted to the major teaching and general hospitals for non-neoplastic diseases, frequency-matched to cases by study centre, sex and age. The DII was computed based on dietary intake assessed using a validated and reproducible seventy-eight-item FFQ. Logistic regression models were used to estimate multivariable OR adjusted for age, sex, study centre, education, BMI, smoking status, alcohol drinking and history of diabetes. Energy adjustment was performed using the residual method. Subjects with higher DII scores (i.e., representing a more pro-inflammatory diet) had a higher risk of pancreatic cancer, with the DII being used as both a continuous variable (ORcontinuous 1.24, 95% CI 1.11, 1.38) and a categorical variable (i.e., compared with the subjects in the lowest quintile of the DII, those in the second, third, fourth and fifth quintiles had, respectively, OR(quintile2 v. 1) 1.70, 95% CI 1.02, 2.80; OR(quintile3 v. 1) 1.91, 95% CI 1.16, 3.16; OR(quintile4 v. 1) 1.98, 95% CI 1.20, 3.27; OR(quintile5 v. 1) 2.48, 95% CI 1.50, 4.10; P trend= 0.0015). These data suggest that a pro-inflammatory diet increases the risk of pancreatic cancer. PMID- 25515554 TI - Elevated circulating microRNA-122 is associated with obesity and insulin resistance in young adults. AB - OBJECTIVE: MicroRNAs (miRNAs) are involved in the regulation of adiposity, but functional studies have yielded inconclusive results. Examining the associations of circulating miRNAs levels with obesity and insulin sensitivity in humans may lead to improved insights. DESIGN AND METHODS: Serum samples collected from 112 obese and control subjects (50.0% men) were randomly divided and combined into four pools (28 samples in each obese or control pool). The genome-wide circulating miRNA profiles were detected via microarray. Elevated miR-122 was selected and validated in individual serum samples from 123 obese (46.7% men) and 107 control (50.0% men) young adults. Associations between circulating miR-122 levels and parameters related to adiposity, insulin resistance, lipid profiles and hepatic enzymes were further assessed. RESULTS: Thirty-four miRNAs were found to be expressed differently in the sera of obese patients compared with control subjects (P<0.001). Further analyses confirmed that obese patients had 3.07-fold higher circulating miR-122 levels than controls (P<0.001). Serum miR-122 levels were correlated with BMI (r=0.469), alanine aminotransferase (r=0.634), triglycerides (r=0.448), HDL-cholesterol (r=-0.351) and homeostasis model assessment of insulin resistance (r=0.401, all P<0.01). After controlling for confounding factors, miR-122 remained as an independent risk factor for insulin resistance (OR=3.379, 95% CI=1.141-10.007, P=0.028). CONCLUSIONS: Elevated circulating miR-122 is positively associated with obesity and insulin resistance in young adults. These findings provide a better understanding regarding the role of miRNAs in adiposity and insulin sensitivity. PMID- 25515553 TI - The impact of polyunsaturated fatty acid-based dietary supplements on disease biomarkers in a metabolic syndrome/diabetes population. AB - BACKGROUND: Ingestion of polyunsaturated fatty acids (PUFAs) has been proposed to influence several chronic diseases including coronary heart disease (CHD) and type-2 diabetes (T2D).There is strong evidence that omega-3 (n-3) PUFAs provide protection against CHD and biomarkers of atherosclerosis. In contrast, there is more limited and inconsistent data for T2D. Few studies have examined the impact of n-3 PUFA-containing botanical oils on T2D. METHODS: Fifty-nine subjects with early-stageT2D or metabolic syndrome participated in an 8-week, randomized, single-blind, parallel intervention study and were provided PUFA-containing oils. Individuals received either corn oil (CO), a botanical oil (BO) combination (borage [Borago officinalis L.]/echium oil [Echium plantagineum L.]) or fish oil (FO). The BO combination was enriched in alpha-linolenic, gamma-linolenic, and stearidonic acids and the FO in eicosapentaenoic and docosahexaenoic acids. Serum fatty acids and other serum lipids(triglycerides and total, HDL and LDL cholesterol), as well as markers of inflammation (leptin, and C-reactive protein) and glucose regulation (glucose and hemoglobin A1c) were assessed from fasting participants at baseline and after the intervention. RESULTS: Compliance was verified by expected increases in specific PUFAs in each of the three oil arms. Participants in the CO group showed no differences in serum lipids, markers of inflammation or glucose regulation between pre- and post-treatment measures. Supplementation with BO significantly lowered total and LDL cholesterol levels and FO reduced serum triglycerides, hemoglobin A1c and increased HDL-cholesterol. CONCLUSION: Short-term dietary supplementation with BO and FO improved biomarkers associated with T2D/metabolic syndrome. TRIAL REGISTRATION: Clinicaltrial.gov NCT01145066. PMID- 25515556 TI - Genomic regions influencing coat color saturation and facial markings in Fleckvieh cattle. AB - Genomic regions associated with coat color and pigmented areas of the head were identified for Fleckvieh (dual-purpose Simmental), a red-spotted and white-headed cattle breed. Coat color was measured with a chromameter, implementing the CIELAB color space and resulting in numerical representation of lightness, color intensity, red/green and blue/yellow color components, rather than subjective classification. Single marker regression analyses with fixed effects of the sex and barn were applied, and significant regions were determined with the local false discovery rate methodology. The PMEL and ERBB3 genes on chromosome 5 were in the most significant region for the color measurements. In addition to the blue/yellow color component and color intensity, the AP3B2 gene on chromosome 21 was identified. Its function was confirmed for similar traits in a range of model species. The KIT gene on chromosome 6 was found to be strongly associated with the inhibition of circum-ocular pigmentation and pigmented spots on the cheek. PMID- 25515555 TI - RET Cys634Arg mutation confers a more aggressive multiple endocrine neoplasia type 2A phenotype than Cys634Tyr mutation. AB - OBJECTIVE: Specific germline mutations in the RET proto-oncogene are correlated with clinical features in multiple endocrine neoplasia type 2A (MEN2A); however, data are scarce regarding differences in clinical profiles dependent on the type of nucleotide and amino acid substitution at the same codon. We aimed to analyse differences in clinical risk profiles and outcomes among different amino acids encoded by codon 634. DESIGN: The study was retrospective and multicentric. METHODS: We collected data included in the Spanish Online National Database from patients with MEN2A carrying a RET proto-oncogene mutation on codon 634. The mean follow-up time was 7.6+/-6.9 years (1-32). RESULTS: Patients (n=173) from 49 unrelated families were C634Y carriers, and 26 patients from eight different families had C634R mutation. We found higher penetrance of medullary thyroid carcinoma, phaeochromocytoma and hyperparathyroidism (P<0.001, P=0.007 and P<0.001 respectively) in C634R carriers than in C634Y carriers. The Kaplan-Meier estimate of cumulative lymph node and distant metastases rates showed that these events occurred earlier in patients harbouring the C634R mutation (P<0.001). A multivariate adjusted Cox regression analysis indicated that the C634R mutation was an independent factor for persistent/recurrent disease (hazard ratio, 3.17; 95% CI: 1.66-6.03; P<0.001). CONCLUSIONS: Our results suggest that there could be clinical differences caused by different amino acid substitutions at codon 634; specifically, the C634R mutation was associated with a more aggressive MEN2A phenotype than the C634Y mutation. PMID- 25515557 TI - Functional vesicles formed by anticancer drug assembly. AB - In this Letter, a new type of nitrogen mustard conjugate vesicles is developed to improve the stability and efficiency of anticancer drug. Benzoic acid nitrogen mustard-peptide (AAAK) conjugate was designed and synthesized, which was found to self-assemble into vesicles in water. The formation of the vesicles was confirmed by dynamic light scattering (DLS), transmission electron microscopy (TEM) and circular dichroism (CD). The degradation data revealed that the benzoic acid nitrogen mustard peptide (AAAK) conjugate vesicles are more stable than the parent drug in aqueous solution. Furthermore, MTT assay revealed that the free drug conjugate has similar antitumor activity against MCF-7, Hela, HepG-2 cell lines compared with the parent drug. The benzoic acid nitrogen mustard-peptide conjugate vesicles may have potential in the treatment of cancers. PMID- 25515558 TI - A prodrug strategy for the oral delivery of a poorly soluble HCV NS5B thumb pocket 1 polymerase inhibitor using self-emulsifying drug delivery systems (SEDDS). AB - A prodrug approach was developed to address the low oral bioavailability of a poorly soluble (<0.1MUg/mL in pH 6.8 buffer) but highly permeable thumb pocket 1 HCV NS5B polymerase inhibitor. Bioconversion rates of structurally diverse prodrug derivatives were evaluated in a panel of in vitro assays using microsomes, from either liver or intestinal tissues, simulated intestinal fluids, simulated gastric fluids or plasma. In vivo bioconversion of promising candidates was evaluated following oral administration to rats. The most successful strategy involved modification of the parent drug carboxylic acid moiety to glycolic amide esters which improved solubility in lipid-based self-emulsifying drug delivery systems (SEDDS). Crystalline prodrug analog 36 (mp 161 degrees C) showed good solubility in individual SEDDS components (up to 80mg/mL) compared to parent 2 (<3mg/mL; mp 267 degrees C) and cross-species bioconversions which correlated with in vitro stability in liver microsomes. PMID- 25515559 TI - Role of the ERK1/2 pathway in tumor chemoresistance and tumor therapy. AB - Chemotherapy is one of the important methods for treatment in tumors. However, many tumor patients may experience tumor recurrence because of treatment failure due to chemoresistance. Although many signaling pathways could influence chemoresistance of tumor cells, the extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathway has gained significant attention because of its implications in signaling and which has crosstalk with other signaling pathways. Extensive studies conclude that ERK1/2 pathway is responding to chemoresistance in many kinds of malignant tumors. The aim of this review is to discuss on the role of ERK1/2 pathway in chemoresistance and therapy of tumors. A comprehensive understanding of ERK1/2 pathway in chemoresistance of tumors could provide novel avenues for treatment strategies of tumors. PMID- 25515560 TI - Synthesis and quantitative structure-activity relationship (QSAR) analysis of some novel oxadiazolo[3,4-d]pyrimidine nucleosides derivatives as antiviral agents. AB - We have synthesized a series of 4H,6H-[1,2,5]oxadiazolo[3,4-d]pyrimidine-5,7 dione 1-oxide nucleoside and their anti-vesicular stomatitis virus (VSV) activities in Wish cell were also investigated in vitro. It was found that most compounds showed obvious anti-VSV activities and compound 9 with ribofuranoside improved the anti-VSV activity by approximately 10 times and 18 times compared to didanosine (DDI) and acyclovir, respectively. A quantitative structure-activity relationship (QSAR) study of these compounds as well as previous reported oxadiazolo[3,4-d]pyrimidine nucleoside derivatives indicated that compounds with high activity should have small values of logP(o/w), vsurf_G and a large logS value. These findings and results provide a base for further investigations. PMID- 25515561 TI - Curcumolide, a unique sesquiterpenoid with anti-inflammatory properties from Curcuma wenyujin. AB - Curcumolide, a novel sesquiterpenoid with a unique 5/6/5 tricyclic skeleton, was isolated from Curcuma wenyujin. The structure and absolute configuration were elucidated by extensive NMR, ECD data analysis, and a single-crystal X-ray study. This molecule exhibited significant anti-inflammatory effects in LPS-induced RAW 264.7 macrophages. It suppressed LPS-induced NF-kappaB activation, including the nuclear translocation and DNA binding activity of NF-kappaB, and decreased tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-1beta (IL 1beta), nitric oxide (NO) and reactive oxygen species (ROS) production. Therefore, Curcumolide may have therapeutic potential for treating inflammatory diseases by inhibiting NF-kappaB activation and pro-inflammatory mediator production. PMID- 25515562 TI - Carcinosarcoma of the parotid: investigating its biology with morphoproteomics. AB - Carcinosarcoma of the parotid is a rare biphasic malignant neoplasm comprised of both carcinomatous and sarcomatous components representing approximately 0.4% of all malignant salivary gland neoplasms. We report a case of a 55-year-old Caucasian man who presented with a progressively enlarging left facial mass. Histopathological evaluation of the tumoral tissue revealed a high grade, mixed epithelial and mesenchymal malignant tumor, most consistent with a carcinosarcoma of the parotid. Morphoproteomic analysis was performed and revealed expression of secreted protein acidic and rich in cysteine (SPARC); glioma-associated oncogen protein 2 (Gli2); and phosphorylated signal transducer and activator of transcription (p-STAT3 [Tyr705]) in the carcinomatous and malignant mesenchymal components. These aforementioned markers have been linked to the epithelial mesenchymal transition in which epithelial cells lose their characteristics and phenotypically become mesenchymal cells. This finding allows us to further understand the biology of the 2 cellular components of the carcinosarcoma as having a monoclonal origin. PMID- 25515563 TI - Identification of Wolbachia-responsive microRNAs in the two-spotted spider mite, Tetranychus urticae. AB - BACKGROUND: The two-spotted spider mite, Tetranychus urticae, is infected with Wolbachia, which have the ability to manipulate host reproduction and fitness. MicroRNAs (miRNAs) are small non-coding RNAs that are involved in many biological processes such as development, reproduction and host-pathogen interactions. Although miRNA was observed to involve in Wolbachia-host interactions in the other insect systems, its roles have not been fully deciphered in the two-spotted spider mite. RESULTS: Small RNA libraries of infected and uninfected T. urticae for both sexes (in total four libraries) were constructed. By integrating the mRNA data originated from the same samples, the target genes of the differentially expressed miRNAs were predicted. Then, GO and pathway analyses were performed for the target genes. Comparison of libraries showed that Wolbachia infection significantly regulated 91 miRNAs in females and 20 miRNAs in males, with an overall suppression of miRNAs in Wolbachia-infected libraries. A comparison of the miRNA and mRNA data predicted that the differentially expressed miRNAs negatively regulated 90 mRNAs in females and 9 mRNAs in males. An analysis of target genes showed that Wolbachia-responsive miRNAs regulated genes with function in sphingolipid metabolism, lysosome function, apoptosis and lipid transporting in both sexes, as well as reproduction in females. CONCLUSION: Comparisons of the miRNA and mRNA data can help to identify miRNAs and miRNA target genes involving in Wolbachia-host interactions. The molecular targets identified in this study should be useful in further functional studies. PMID- 25515564 TI - SMC3 may play an important role in atopic asthma development. AB - INTRODUCTION: As a common disease with a complex risk, including genetic and environmental factors, atopic asthma is prevalent but treatable. The aim of the study was to predict the underlying mechanism of asthma and identify target genes for the disease. METHODS: The affymetrix chip data, GSE18965, were available from Gene Expression Omnibus and the differentially expressed genes (DEGs) between nine atopic asthmatic specimens and seven healthy nonatopic samples were identified by R. Then Gene Ontology and pathway enrichment analyses were performed to these DEGs. Further, search tool for the retrieval of interacting genes/proteins (STRING) was used to select protein-protein interaction (PPI) for DEGs, and then the network was visualized by Cytoscape. Finally, transcription factor binding site analysis was conducted to the hot gene. RESULTS: Total 565 DEGs were identified, including 535 upregulated and 30 downregulated genes. The upregulated genes, such as structural maintenance of chromosome (SMC)3, significantly affected cellular component of extracellular matrix (P = 1.56E-04). Otherwise, DEGs were remarkably enriched in three pathways, including transforming growth factor-beta signaling pathway (P = 0.005252649). Further, SMC3 was detected as hot gene in PPI network, and NET (Elk3) was predicted as the significant transcription factor for this gene. CONCLUSION: SMC3 may play an important role in atopic asthma development; therefore, it has the potential to be the target for the disease. Moreover, our findings provide more knowledge about the mechanism of atopic asthma and help the researchers to explore it in future. PMID- 25515565 TI - Identification of a novel HLA-A*24 allele, A*24:289, in a Chinese individual. AB - The new allele, A*24:289 is different to A*24:03:01 at codons 151, 152 and 156 at exon 3. PMID- 25515566 TI - How reliable are case formulations? A systematic literature review. AB - OBJECTIVES: This systematic literature review investigated the inter-rater and test-retest reliability of case formulations. We considered the reliability of case formulations across a range of theoretical modalities and the general quality of the primary research studies. METHODS: A systematic search of five electronic databases was conducted in addition to reference list trawling to find studies that assessed the reliability of case formulation. This yielded 18 studies for review. A methodological quality assessment tool was developed to assess the quality of studies, which informed interpretation of the findings. RESULTS: Results indicated inter-rater reliability mainly ranging from slight (.1 .4) to substantial (.81-1.0). Some studies highlighted that training and increased experience led to higher levels of agreement. In general, psychodynamic formulations appeared to generate somewhat increased levels of reliability than cognitive or behavioural formulations; however, these studies also included methods that may have served to inflate reliability, for example, pooling the scores of judges. Only one study investigated the test-retest reliability of case formulations yielding support for the stability of formulations over a 3-month period. CONCLUSIONS: Reliability of case formulations is varied across a range of theoretical modalities, but can be improved; however, further research is required to strengthen our conclusions. PRACTITIONER POINTS: Clinical implications: The findings from the review evidence some support for case formulation being congruent with the scientist-practitioner approach. The reliability of case formulation is likely to be improved through training and clinical experience. Limitations: The broad inclusion criteria may have introduced heterogeneity into the sample, which may have affected the results. Studies reviewed were limited to peer-reviewed journal articles written in the English language, which may represent a source of publication and selection bias. PMID- 25515567 TI - Health-related quality of life in male patients with congenital hypogonadotropic hypogonadism. PMID- 25515568 TI - Intranasal and intravenous administration of octa-arginine modified poly(lactic co-glycolic acid) nanoparticles facilitates central nervous system delivery of loperamide. AB - OBJECTIVES: The potential of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) surface modified with octa-arginine (R8) for central nervous system (CNS) delivery was investigated. METHODS: PLGA NPs containing coumarin-6 or loperamide were surface modified using R8 and characterised for size, zeta potential, drug loading and release. We examined the cellular uptake of NPs in Madin-Darby Canine Kidney (MDCK) cells and CNS delivery of loperamide in a mouse model following intranasal (i.n.) and intravenous (i.v.) administration. KEY FINDINGS: NPs were 300-350 nm in diameter and of negative zeta potential which neutralised on R8 conjugation. Cellular uptake of R8-PLGA NPs was rapid compared with PLGA NPs and correlated with a high antinociceptive effect in mice by both the i.n. and i.v. routes. Little antinociceptive effect for PLGA NPs was observed reflecting their slow uptake in the in-vitro cell model. CONCLUSION: This study demonstrates the potential of R8-PLGA NPs as carriers of therapeutic agents to the CNS. PMID- 25515569 TI - The dementia diagnosis: a literature review of information, understanding, and attributions. AB - This review examines how people understand and make sense of a dementia diagnosis. The review explores how lay frameworks and information presented at diagnosis may inform a caregiver's understanding of dementia in a family member. Existing qualitative research exploring how caregivers understand and make sense of dementia is reviewed. A literature search was conducted, and the results indicated that family carers often receive little or unclear information about dementia, with diagnostic information often delivered in euphemistic terms. Lack of clarity regarding diagnosis and prognosis creates uncertainty for caregivers and impacts future care planning. Caregiver's understandings of the condition vary, with some symptoms often not attributed to the condition. The literature highlights significant gaps and misconceptions in public knowledge regarding dementia, which raises questions about how family caregivers understand the condition. Further research is required to explore how information is presented to family carers at the time of diagnosis and how this is used to understand the condition. PMID- 25515570 TI - Correlation of outer nuclear layer thickness with cone density values in patients with retinitis pigmentosa and healthy subjects. AB - PURPOSE: We studied the correlation between outer nuclear layer (ONL) thickness and cone density in normal eyes and eyes with retinitis pigmentosa (RP). METHODS: Spectral-domain optical coherence tomography (SD-OCT) scans were acquired using a displaced pupil entry position of the scanning beam to distinguish Henle's fiber layer from the ONL in 20 normal eyes (10 subjects) and 12 eyes with RP (7 patients). Cone photoreceptors were imaged using adaptive optics scanning laser ophthalmoscopy. The ONL thickness and cone density were measured at 0.5 degrees intervals along the horizontal meridian through the fovea nasally and temporally. The ONL thickness and cone density were correlated using Spearman's rank correlation coefficient r. RESULTS: Cone densities averaged over the central 6 degrees were lower in eyes with RP than normal, but showed high variability in both groups. The ONL thickness and cone density were significantly correlated when all retinal eccentricities were combined (r = 0.74); the correlation for regions within 0.5 degrees to 1.5 degrees eccentricity was stronger (r = 0.67) than between 1.5 degrees and 3.0 degrees eccentricity (r = 0.23). Although cone densities were lower between 0.5 degrees and 1.5 degrees in eyes with RP, ONL thickness measures at identical retinal locations were similar in the two groups (P = 0.31), and interindividual variation was high for ONL and cone density measures. Although ONL thickness and retinal eccentricity were important predictors of cone density, eccentricity was over 3 times more important. CONCLUSIONS: The ONL thickness and cone density were correlated in normal eyes and eyes with RP, but both were strongly correlated with retinal eccentricity, precluding estimation of cone density from ONL thickness. (ClinicalTrials.gov number, NCT00254605.). PMID- 25515572 TI - Lutein and zeaxanthin supplementation and association with visual function in age related macular degeneration. AB - PURPOSE: To evaluate the effects of lutein and zeaxanthin on visual function in randomized controlled trials (RCTs) of AMD patients. METHODS: Relevant studies were identified by searches on PubMed, EMBASE, Web of Science, and Cochrane Library database up to April 2014. Three investigators independently determined the eligibility of RCTs, which compared lutein and zeaxanthin intervention with placebo. The adjusted weighted mean differences (WMDs) from each study were extracted to calculate a pooled estimate with its corresponding 95% confidence interval (CI). The main outcome measurements included visual acuity (VA), contrast sensitivity (CS), glare recovery time (GRT), and subjective perception of visual quality. RESULTS: Eight RCTs involving 1176 AMD patients were included in the meta-analysis. Xanthophyll carotenoids supplementation was associated with significant decrease in logMAR levels compared with the placebo group (WMD, 0.04; 95% CI, -0.06 to -0.03), and during intervention, each 1-mg/day increase in these carotenoids supplementation was related to a 0.003 reduction in logMAR level of VA. Remarkable benefit was also observed at all four spatial frequencies of CS (WMD ranging from 0.08-0.18; all P < 0.05) in contrast to placebo. Furthermore, association was observed between the postintervention increase in macular pigment optical density and improvements in VA (r = -0.58; P = 0.02), and in CS at 12 cycles/degree as well (r = 0.94; P < 0.001). CONCLUSIONS: Lutein and zeaxanthin supplementation is a safe strategy for improving visual performance of AMD patients, which mainly showed in a dose-response relationship. PMID- 25515571 TI - Identification of the WNK-SPAK/OSR1 signaling pathway in rodent and human lenses. AB - PURPOSE: To identify whether the kinases that regulate the activity of cation chloride cotransporters (CCC) in other tissues are also expressed in rat and human lenses. METHODS: The expression of with-no-lysine kinase (WNK 1, 3, 4), oxidative stress response kinase 1 (OSR1), and Ste20-like proline alanine rich kinase (SPAK) were determined at either the transcript or protein levels in the rat and human lenses by reverse-transcriptase PCR and/or Western blotting, respectively. Selected kinases were regionally and subcellularly characterized in rat and human lenses. The transparency, wet weight, and tissue morphology of lenses extracted from SPAK knock-out animals was compared with wild-type lenses. RESULTS: WNK 1, 3, 4, SPAK, and OSR1 were identified at the transcript level in rat lenses and WNK1, 4, SPAK, and OSR1 expression confirmed at the protein level in both rat and human lenses. SPAK and OSR1 were found to associate with membranes as peripheral proteins and exhibited distinct subcellular and region specific expression profiles throughout the lens. No significant difference in the wet weight of SPAK knock-out lenses was detected relative to wild-type lenses. However, SPAK knock-out lenses showed an increased susceptibility to opacification. CONCLUSIONS: Our results show that the WNK 1, 3, 4, OSR1, and SPAK signaling system known to play a role in regulating the phosphorylation status, and hence activity of the CCCs in other tissues, is also present in the rat and human lenses. The increased susceptibility of SPAK lenses to opacification suggests that disruption of this signaling pathway may compromise the ability of the lens to control its volume, and its ability to maintain its transparency. PMID- 25515573 TI - Levels of blood CD1c+ mDC1 and CD1chi mDC1 subpopulation reflect disease activity in noninfectious uveitis. AB - PURPOSE: Myeloid dendritic cells (mDCs) play an important role in autoimmune diseases. However, the role of blood CD1c(+) myeloid dendritic cells 1 (mDC1s), the subset of human blood mDCs, is not well understood in noninfectious uveitis. METHODS: Fresh peripheral blood samples from human noninfectious uveitis patients (n = 32) and healthy controls (HCs) (n = 64) were stained with FITC-Lineage 1 (Lin1), PERCP-HLADR, and PE-CD1c antibodies. The levels of mDC1 were quantified by using flow cytometric analysis. Longitudinal data from patients (n = 16) were analyzed to correlate the levels of mDC1 with disease activity. RESULTS: Blood CD1c(+) mDC1 and its subpopulation, CD1c(hi) mDC1, were increased in uveitis patients compared with HCs. Longitudinal data demonstrated that both the CD1c(+) mDC1 and CD1c(hi) mDC1 subpopulation reflected a dynamic change in clinical uveitis activity: CD1c expression was increased in active uveitis but decreased when uveitis became inactive. CONCLUSIONS: Given these observations, an alteration in blood CD1c(+) mDC1 and the CD1c(hi) mDC1 subpopulation could be a potential biomarker to monitor clinical uveitis activity within patients. PMID- 25515574 TI - The penny pusher: a cellular model of lens growth. AB - PURPOSE: The mechanisms that regulate the number of cells in the lens and, therefore, its size and shape are unknown. We examined the dynamic relationship between proliferative behavior in the epithelial layer and macroscopic lens growth. METHODS: The distribution of S-phase cells across the epithelium was visualized by confocal microscopy and cell populations were determined from orthographic projections of the lens surface. RESULTS: The number of S-phase cells in the mouse lens epithelium fell exponentially, to an asymptotic value of approximately 200 cells by 6 months. Mitosis became increasingly restricted to a 300-MUm-wide swath of equatorial epithelium, the germinative zone (GZ), within which two peaks in labeling index were detected. Postnatally, the cell population increased to approximately 50,000 cells at 4 weeks of age. Thereafter, the number of cells declined, despite continued growth in lens dimensions. This apparently paradoxical observation was explained by a time-dependent increase in the surface area of cells at all locations. The cell biological measurements were incorporated into a physical model, the Penny Pusher. In this simple model, cells were considered to be of a single type, the proliferative behavior of which depended solely on latitude. Simulations using the Penny Pusher predicted the emergence of cell clones and were in good agreement with data obtained from earlier lineage-tracing studies. CONCLUSIONS: The Penny Pusher, a simple stochastic model, offers a useful conceptual framework for the investigation of lens growth mechanisms and provides a plausible alternative to growth models that postulate the existence of lens stem cells. PMID- 25515576 TI - Posterior pole retinal abnormalities in mild asymptomatic FEVR. AB - PURPOSE: To describe the posterior retinal abnormalities in asymptomatic mild familial exudative vitreoretinopathy (FEVR) individuals who are normal in conventional clinical examination. METHODS: Thirty-eight asymptomatic mild FEVR individuals (38 eyes) and 38 controls (38 eyes) were included in this cross sectional study. The posterior retinas in each individual appeared normal. The diagnosis of FEVR was made based on a positive FEVR family history and the presence of retinal peripheral avascular zone with other vessel abnormalities. Biometric data from fundus photographs and fluorescein fundus angiography of all subjects were studied. The diameter of the optic disc (DD), the disc-to-macula distance (DM), the ratio of DM/DD, and numbers of retinal vessels radiated from the optic disc were measured. RESULTS: Significant anatomic differences were identified in the eyes of patients with asymptomatic FEVR compared with those of the control subjects. In individuals with stage I or II FEVR, DD was smaller (1605.34 +/- 250.60 vs. 1733.39 +/- 163.79 MUm), DM was larger (5434.08 +/- 824.82 vs. 4696.29 +/- 257.34 MUm), and DM/DD was higher (3.49 +/- 0.93 vs. 2.73 +/- 0.28) than those of the controls. Peripapillary retinal vessels were increased significantly in FEVR compared with the controls (24.53 +/- 3.10 vs. 21.39 +/- 2.65). CONCLUSIONS: Asymptomatic individuals with stage I or II FEVR had several abnormalities in the posterior pole noted with more retinal vessels, a significantly larger disc-to-macula distance as well as a remarkably smaller optic disc with a decreased horizontal diameter. These findings will facilitate the early diagnosis of FEVR and are important for adequate genetic counseling as well as the prevention and treatment of this disease. PMID- 25515575 TI - The effect of TIMP-1 on the cone mosaic in the retina of the rat model of retinitis pigmentosa. AB - PURPOSE: The array of photoreceptors found in normal retinas provides uniform and regular sampling of the visual space. In contrast, cones in retinas of the S334ter-line-3 rat model for RP migrate to form a mosaic of rings, leaving large holes with few or no photoreceptors. Similar mosaics appear in human patients with other forms of retinal dystrophy. In the current study, we aimed to investigate the effect of tissue inhibitor of metalloproteinase-1 (TIMP-1) on the mosaic of cones in S334ter-line-3 rat retinas. We focused on TIMP-1 because it is one of the regulators of the extracellular matrix important for cellular migration. METHODS: Immunohistochemistry was performed to reveal M-opsin cone cells (M-cone) and the results were quantified to test statistically whether or not TIMP-1 restores the mosaics to normal. In particular, the tests focused on the Voronoi and nearest-neighbor distance analyses. RESULTS: Our tests indicated that TIMP-1 led to significant disruption of the M-opsin cone rings in S334ter line-3 rat retinas and resulted in almost complete homogeneous mosaics. In addition, TIMP-1 induced the M-cone spatial distribution to become closer to random with decreased regularity in S334ter-line-3 rat retinas. CONCLUSIONS: These findings confirm that TIMP-1 induced M-cone mosaics in S334ter-line-3 to gain homogeneity without reaching the degree of regularity seen in normal retinal mosaics. Even if TIMP-1 fails to promote regularity, the effects of this drug on homogeneity appear to be so dramatic that TIMP-1 may be a potential therapeutic agent. TIMP-1 improves sampling of the visual field simply by causing homogeneity. PMID- 25515577 TI - Longitudinal change and stability of refractive, keratometric, and internal astigmatism in childhood. AB - PURPOSE: To assess longitudinal change in refractive, keratometric, and internal astigmatism in a sample of students from a population with a high prevalence of with-the-rule (WTR) astigmatism and to determine the optical origins of changes in refractive astigmatism. METHODS: A retrospective analysis of longitudinal measurements of right eye refractive and keratometric astigmatism in Tohono O'odham Native American children was conducted. Changes in refractive and keratometric astigmatism per year were compared in a younger cohort (n = 1594, 3 to <11 years old) and an older cohort (n = 648, 11 to <19 years old). Data were analyzed in clinical notation (Cyl) and vector notation (J0, J45). RESULTS: On average, refractive astigmatism (means: 1.19 diopters [D] Cyl, +0.54 J0, +0.03 J45) resulted primarily from WTR corneal astigmatism (means: +0.85 J0, -0.02 J45) and against-the-rule (ATR) internal astigmatism (means: -0.31 J0, +0.05 J45). Mean longitudinal changes in astigmatism were statistically significant (younger cohort -0.02 D/y Cyl; older cohort +0.06 D/y Cyl). In the younger cohort, astigmatism decreased with age in low and moderate astigmats (<3.00 D) and increased with age in high astigmats (>=3.00 D). In the older cohort, astigmatism increased with age across all levels of astigmatism. Longitudinal changes in keratometric and internal astigmatism were negatively correlated in both cohorts. CONCLUSIONS: Cross-sectional data suggest the presence of a constant ATR contribution from internal astigmatism (0.60 D Cyl) that is close to the 0.50 D ATR constant reported by Javal and others. Highly astigmatic 3- to <11-year-old children and children older than age 11 years show a small (not clinically significant) increase in astigmatism with age. A negative correlation between changes in keratometric astigmatism and internal astigmatism suggests an active compensation that may contribute to the stability of astigmatism in Tohono O'odham children. PMID- 25515578 TI - Microperimetry of nascent geographic atrophy in age-related macular degeneration. AB - PURPOSE: To determine the microperimetric retinal sensitivity in areas with nascent geographic atrophy (nGA) compared with other pathological features in eyes with intermediate AMD. METHODS: Participants with bilateral intermediate AMD underwent microperimetry examinations and high-resolution spectral-domain optical coherence tomography (SD-OCT) scans in a prospective study. Twenty-two participants (24 eyes) identified as having a microperimetric stimulus sampling an atrophic area (nGA or drusen-associated atrophy detected on SD-OCT) in an eye were analyzed, using three neighboring nonatrophic regions (with or without AMD associated features) in the same eye as reference areas. RESULTS: On average, the mean microperimetric retinal sensitivity was worse in areas with nGA than nonatrophic reference areas (P <= 0.008), but better than areas with drusen associated atrophy (P = 0.008). Considering all the microperimetry points in an eye, there were only 6 out of 16 eyes (37.5%) where the retinal sensitivity over nGA was the worst performing point in the eye, while all eight out of eight eyes (100.0%) with an area of drusen-associated atrophy detected on SD-OCT had the worst-performing point over that area. CONCLUSIONS: Areas of nGA were characterized by worse microperimetric retinal sensitivity compared with nonatrophic areas in eyes with intermediate AMD, but better retinal sensitivity compared with areas of drusen-associated atrophy detected on SD-OCT. Areas of nGA were also not always the worst performing point in an eye. These findings further our understanding of the functional changes occurring in novel SD-OCT identified pathological changes in intermediate AMD. PMID- 25515579 TI - Corneal inflammation after miniature keratoprosthesis implantation. AB - PURPOSE: To compare corneal inflammation after syngeneic and allogeneic penetrating keratoplasty (PK) with miniature Keratoprosthesis (m-KPro) implantation in mice. METHODS: BALB/C (syngeneic) or C57BL/6 (allogeneic) corneas were transplanted onto BALB/C host beds as part of PK or m-KPro implantation. Corneal inflammation was assessed by determining the frequencies of CD45(+) leukocytes, CD4(+) T cells, CD11b(+) cells, and Gr-1(+) granulocytes/monocytes by flow cytometry at 2, 4, and 8 weeks post transplantation. In addition, expression levels of the proinflammatory cytokines TNF-alpha and IL-1beta were analyzed using real-time qPCR at 8 weeks post transplantation. RESULTS: Cell frequencies in the syngeneic (syn) and allogeneic (allo) m-KPro groups were higher compared with the syngeneic and allogeneic PK groups, respectively, at all time points. However, after week 4, frequencies of all analyzed immune cells were higher in the alloPK group as compared with synKPro group. At 8 weeks, the expression of TNF-alpha was higher in synKPro, alloPK, and alloKPro groups compared with the naive and synPK groups. The expression of IL-1beta was significantly higher in both KPro groups as compared with PK groups. CONCLUSIONS: Although the m-KPro device augments the inflammatory response in the cornea after its implantation, allogenicity (of the carrier tissue) is also a significant contributor to corneal inflammation. These data suggest that using syngeneic or decellularized corneal tissue as a Boston-KPro carrier could reduce the postoperative inflammation response. PMID- 25515580 TI - Estimating the critical duration for temporal summation of standard achromatic perimetric stimuli. AB - PURPOSE: To estimate the critical duration of temporal summation for achromatic Goldmann III stimuli under the conditions of standard automated perimetry (SAP) and quantify response variability for short-duration stimuli. METHODS: Contrast thresholds were gathered using the method of constant stimuli for seven circular (0.48 degrees diameter) incremental stimuli of varying duration (sum-of-frames equivalent: 8.3-198.3 ms), at an eccentricity of 8.8 degrees along the four principal meridians of the visual field in two healthy, psychophysically experienced observers. Stimuli were presented on a high-resolution cathode ray tube display with a background luminance of 10 cd/m(2). Psychometric functions were fitted using a probit model and nonparametric local-linear analysis. The critical duration was estimated using iterative two-phase regression analysis, the results also being compared with values produced using previously published methods of analysis. RESULTS: The median critical duration estimated using iterative two-phase regression analysis was 27.7 ms (IQR 22.5-29.8). A slight steepening of the psychometric function slope (lower variability) was observed for longer stimulus durations, using both probit and local-linear analysis techniques, but this was not statistically significant. CONCLUSIONS: Critical duration estimates in this study are substantially shorter than those previously reported for a Goldmann III stimulus, under the conditions of SAP. Further work is required to firmly establish the relationship between measurement variability and the degree of local temporal and spatial summation. PMID- 25515581 TI - A new small molecule for treating inflammation and chorioretinal neovascularization in relapsing-remitting and chronic experimental autoimmune uveitis. AB - PURPOSE: We investigated the effect of PP-001, a new small molecule inhibitor of dihydro-orotate dehydrogenase in two experimental rat experimental autoimmune uveitis (EAU) models: a spontaneously relapsing-remitting model and a monophasic/chronic disease model that results in late chorioretinal neovascularization. Both of the diseases are induced by immunization with autoantigen peptides. METHODS: Prevention was tested using daily oral applications of PP-001 after immunization with the retinal S-antigen peptide PDSAg (for induction of monophasic uveitis and neovascularization) or the interphotoreceptor retinoid-binding protein peptide R14 (for induction of spontaneously relapsing-remitting EAU). Treatment to inhibit relapses and neovascularization was tested using PP-001 daily after the first attack of R14 induced or after onset of PDSAg-induced EAU. Uveitis was graded clinically and histologically. The effect of PP-001 on cytokine secretion and proliferation was evaluated using rat T-cell lines. RESULTS: Preventive feeding of PP-001 abrogated both types of EAU. Starting treatment after the resolution of the first attack led to a significant reduction of the number and intensity of relapses in R14 induced EAU. PP-001-treatment initiated after onset or after peak of PDSAg induced EAU significantly reduced neovascularization (as determined by histology). Proliferation of antigen-specific T-cell lines and secretion of IFN gamma, IL-17, IL-10, IP-10, and VEGF were efficiently suppressed by PP-001. CONCLUSIONS: We investigated a new dihydroorotate dehydrogenase inhibitor as treatment for primary and recurrent disease in relapsing-remitting and chronic rat models of experimental autoimmune uveitis. The small molecule compound PP-001 suppressed proliferation and cytokine secretion of autoreactive T cells (i.e., IFN-g, IL-17, and VEGF) and chorioretinal neovascularization in chronic EAU. PMID- 25515583 TI - Targeting the fibronectin type III repeats in tenascin-C inhibits epithelial mesenchymal transition in the context of posterior capsular opacification. AB - PURPOSE: Posterior capsular opacification (PCO) is a common complication following extracapsular surgery, associated with fibrosis, opacification, and contraction of the posterior lens capsule. It is characterized by increased expression of extracellular matrix proteins such as tenascin-C, fibronectin, collagens, and proteoglycans. Tenascin-C is known to be critical for injury induced epithelial-mesenchymal transition (EMT) in the lens epithelium. We aimed to target fibronectin type III repeats 1-5 within tenascin-C (TNfnIII 1-5) using an scFv (single-chain variable fragment) antibody, and to evaluate its effectiveness in the context of lens epithelial cells. METHODS: Phage display library screening was used to generate an antibody against TNfnIII 1-5. Lens epithelial cells were cultured in the presence of the scFv antibodies to evaluate the effects on cell proliferation, migration, fibronectin polymerization and deposition, matrix metalloprotease (MMP) regulation, actin stress fiber distribution, and expression of EMT markers. The effect on SMAD-dependent and SMAD-independent pathways was also examined. RESULTS: The scFv TN64 was found to be effective in regulating the proliferation, migration, and expression of MMP-2 and MMP-9, fibronectin polymerization and deposition, and expression of EMT markers. TN64 did not interfere with SMAD3 phosphorylation. Altered localization of beta-catenin, as well as downregulation of phosphorylation of mitogen activated protein (MAP) kinases and focal adhesion kinase (FAK), was involved. CONCLUSIONS: Our data suggest that the TNfnIII 1-5 repeats play an important role in PCO pathology. The inhibition of EMT by TN64 is mediated by SMAD-independent, integrin-beta-catenin-FAK signaling pathway, and is therefore proposed as a novel antifibrotic therapeutic candidate. PMID- 25515582 TI - Whole exome sequencing reveals GUCY2D as a major gene associated with cone and cone-rod dystrophy in Israel. AB - PURPOSE: The Israeli population has a unique genetic make-up, with a high prevalence of consanguineous marriages and autosomal recessive diseases. In rod dominated phenotypes, disease-causing genes and mutations that differ from those identified in other populations often are incurred. We used whole exome sequencing (WES) to identify genetic defects in Israeli families with cone dominated retinal phenotypes. METHODS: Clinical analysis included family history, detailed ocular examination, visual function testing, and retinal imaging. Whole exome sequencing, followed by segregation analysis, was performed in 6 cone dominated retinopathy families in which prior mutation analysis did not reveal the causative gene. Based on the WES findings, we screened 106 additional families with cone-dominated phenotypes. RESULTS: The WES analysis revealed mutations in known retinopathy genes in five of the six families: two pathogenic mutations in the GUCY2D gene in three families, and one each in CDHR1 and C8orf37. Targeted screening of additional cone-dominated families led to identification of GUCY2D mutations in four other families, which included two highly probable novel disease-causing variants. CONCLUSIONS: Our study suggested that GUCY2D is a major cause of autosomal dominant cone and cone-rod dystrophies in Israel; this is similar to other Caucasian populations and is in contrast with retinitis pigmentosa (primary rod disease), where the genetic make-up of the Israeli population is distinct from other ethnic groups. We also conclude that WES permits more comprehensive and rapid analyses that can be followed by targeted screens of larger samples to delineate the genetic structure of retinal disease in unique population cohorts. PMID- 25515584 TI - Tackling obesity among the medical profession. PMID- 25515585 TI - Using the California Q-sort Measure of Life History Strategy to Predict Sexual Behavioral Outcomes. AB - The validity of the California Q-set measure of life history (LH) strategy was examined by conducting secondary analyses on longitudinal data that included the Q-sort measure of LH strategy at multiple ages (base year N = 106) and six measures of reproductive behavior. LH strategy Q-sort ratings showed stability from ages 14-23. Additionally, the ratings were found to be good prospective and age concurrent predictors of six reproductive behaviors. LH strategy as rated at age 14 was found to be a significant predictor of age of sexual debut, number of sexual partners, frequency of intercourse, number of abortions, age at birth of first child, and likelihood for having contracted venereal disease as measured up to age 32. Future research should test the further utility of the measure focusing on ways to reduce its cumbersomeness without reducing its ability to predict behavioral outcomes. PMID- 25515587 TI - Commentary: Sustaining progress towards comprehensive reproductive health services in Bangladesh. PMID- 25515589 TI - An event-related potential investigation of error monitoring in adults with a history of psychosis. AB - OBJECTIVE: Previous research suggests that deficits in error monitoring contribute to psychosis and poor functioning. Consistent with the NIMH Research Domain Criteria initiative, this study examined electrophysiological brain activity, appraisal of self-performance, and personality traits related to psychosis during error monitoring in individuals with and without a history of psychosis across disorders. METHODS: Error-related negativity (ERN), correct response negativity (CRN), error positivity (Pe), and correct response positivity (Pc) were recorded in 14 individuals with a history of psychosis (PSY) and 12 individuals with no history of psychosis (CTR) during a flanker task. Participants continuously rated their performance and completed the Schizotypal Personality Questionnaire-Brief Revised (SPQ-BR). RESULTS: Compared with CTR, PSY exhibited reduced ERN and Pe amplitudes and was also less accurate at evaluating their performance. Group differences were specific to error trials. Across all participants, smaller Pe amplitudes were associated with greater scores on the SPQ-BR Cognitive-Perceptual factor and less accuracy in subjective identification of errors. CONCLUSIONS: Individuals with a history of psychosis, regardless of diagnosis, demonstrated abnormal neural activity and imprecise confidence in response during error monitoring. SIGNIFICANCE: Results suggest that disruptions in neural circuitry may underlie specific clinical symptoms across diagnostic categories. PMID- 25515590 TI - Disclosure of congenital cleft lip and palate to Japanese patients: reported patient experiences and relationship to self-esteem. AB - BACKGROUND: The present study investigated when and how Japanese people with cleft lip and palate (CL/P) learn that their condition is congenital; the perceived effects of withholding the CL/P diagnosis on patients; and whether the resulting social experience and self-esteem are related. A questionnaire survey was conducted in 71 adults with CL/P recruited through a hospital, a patients' association, and by snowball sampling. RESULTS: The participants became aware of their physical difference in childhood, but many reported difficulty in understanding their condition. Participants reported that their families avoided the topic of diagnosis. Participants who understood their condition during childhood rather than in adulthood were significantly more likely to consider this scenario as positive (p < 0.001). Although stigmatising experiences were extremely painful, most patients hid their suffering, making it more difficult to obtain social support. Participants with high self-esteem were more likely to feel that they received adequate support. CONCLUSIONS: It is important to explain the congenital nature of CL/P sufficiently and early. In addition, openness by the family about the diagnosis, rather than avoidance, may improve patients' self esteem. Sufficient support from family, health care providers, and significant others is needed for patients to develop adequate self-esteem. PMID- 25515588 TI - Unexpected biotic resilience on the Japanese seafloor caused by the 2011 Tohoku Oki tsunami. AB - On March 11(th), 2011 the Mw 9.0 2011 Tohoku-Oki earthquake resulted in a tsunami which caused major devastation in coastal areas. Along the Japanese NE coast, tsunami waves reached maximum run-ups of 40 m, and travelled kilometers inland. Whereas devastation was clearly visible on land, underwater impact is much more difficult to assess. Here, we report unexpected results obtained during a research cruise targeting the seafloor off Shimokita (NE Japan), shortly (five months) after the disaster. The geography of the studied area is characterized by smooth coastline and a gradually descending shelf slope. Although high-energy tsunami waves caused major sediment reworking in shallow-water environments, investigated shelf ecosystems were characterized by surprisingly high benthic diversity and showed no evidence of mass mortality. Conversely, just beyond the shelf break, the benthic ecosystem was dominated by a low-diversity, opportunistic fauna indicating ongoing colonization of massive sand-bed deposits. PMID- 25515591 TI - Inter-response-time reinforcement and relative reinforcer frequency control choice. AB - In Conditions 1 and 3 of our Experiment 1, rats pressed levers for food in a two component multiple schedule. The first component was concurrent variable-ratio (VR) 20 variable-interval (VI) 90 s, and the second was concurrent yoked VI (its reinforcement rate equaled that of the prior component's VR) VI 90 s. In Condition 2, the VR was changed to tandem VR 20, differential reinforcement of low rates (DRL) 0.8 s. Local response rates were higher in the VR than in the yoked VI schedule, and this difference disappeared between tandem VR DRL and yoked VI. The relative time allocations to VR and yoked VI, as well as to tandem VR DRL and yoked VI, were approximately the same across conditions. In Experiment 2, rats chose in a single session between five different VI pairs, each lasting for 12 reinforcer presentations (variable-environment procedure). The across schedule hourly reinforcement rates were 120 and 40, respectively, in Conditions 1-3 and 4-6. During Conditions 2 and 5, one lever's VI was changed to tandem VI, DRL 2 s. High covariation between relative time allocations and relative reinforcer frequencies, as well as invariance in local response rates to the schedules, was evident in all conditions. In addition, the relative local response rates were biased toward the unchanged VI in Conditions 2 and 5. These results demonstrate two-process control of choice: Inter-response-time reinforcement controls the local response rate, and relative reinforcer frequency controls relative time allocations. PMID- 25515593 TI - Connective tissue problems and attention deficit and hyperactivity. PMID- 25515592 TI - Histone deacetylase 4 alters cartilage homeostasis in human osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is the most common degenerative joint disorder, and a major cause of pain and disability among the elderly. Histone deacetylase 4 (HDAC4) has been shown to be a key regulator of chondrocyte hypertrophy during skeletogenesis. The aims of present study were to investigate the expression of HDAC4 in normal and OA cartilage and its potential roles during OA pathogenesis. METHODS: The knee cartilage specimen (a total of 18, 12 female and 6 male) were obtained from primary OA patients undergoing total knee arthroplasty (TKA) and normal donors. By using immunohistochemistry staining, we detected the expression patterns of HDAC4 in OA cartilage and normal cartilage respectively. To assess the potential roles of HDAC4, HDAC4 expression in human chondrosarcoma cells (SW1353) was down-regulated by transfecting small interference RNA (siRNA), thereafter, cells were treated with IL-1beta or TNF-alpha, and the expressions of several matrix-degrading enzymes and anabolic factors were examined by using quantitative PCR. RESULTS: The expression of HDAC4 was observed in the OA cartilage, whereas it was barely detected in the normal cartilage. The extent of HDAC4 expression had a statistically negative correlation with OA severity. We further explored that the reduction of HDAC4 level led to a significant repression of proinflammation cytokines induced up-regulated expressions of matrix-degrading enzymes (MMP1 (Matrix metalloproteinase 1), MMP3 (Matrix metalloproteinase 3) , MMP13 (Matrix metalloproteinase 13), ADAMTS4 (aggrecanase 1) and ADAMTS5 (aggrecanase 2)) in SW1353 in vitro. Moreover, knockdown of HDAC4 inhibited the expression of some anabolic genes (such as aggrecan). CONCLUSIONS: In this study, our findings suggest that the abnormal expression of HDAC4 in osteoarthritic cartilage might be implicated in promoting catabolic activity of chondrocyte, which is associated with OA pathogenesis. Thus, our findings give a new insight into the mechanism of articular cartilage damage, and indicate that HDAC4 might be a potential target for the therapeutic interventions of OA. PMID- 25515586 TI - Computational challenges, tools, and resources for analyzing co- and post transcriptional events in high throughput. AB - Co- and post-transcriptional regulation of gene expression is complex and multifaceted, spanning the complete RNA lifecycle from genesis to decay. High throughput profiling of the constituent events and processes is achieved through a range of technologies that continue to expand and evolve. Fully leveraging the resulting data is nontrivial, and requires the use of computational methods and tools carefully crafted for specific data sources and often intended to probe particular biological processes. Drawing upon databases of information pre compiled by other researchers can further elevate analyses. Within this review, we describe the major co- and post-transcriptional events in the RNA lifecycle that are amenable to high-throughput profiling. We place specific emphasis on the analysis of the resulting data, in particular the computational tools and resources available, as well as looking toward future challenges that remain to be addressed. PMID- 25515594 TI - Biomechanics of hearing in katydids. AB - Animals have evolved a vast diversity of mechanisms to detect sounds. Auditory organs are thus used to detect intraspecific communicative signals and environmental sounds relevant to survival. To hear, terrestrial animals must convert the acoustic energy contained in the airborne sound pressure waves into neural signals. In mammals, spectral quality is assessed by the decomposition of incoming sound waves into elementary frequency components using a sophisticated cochlear system. Some insects like katydids (or bushcrickets) have evolved biophysical mechanisms for auditory processing that are remarkably equivalent to those of mammals. Located on their front legs, katydid ears are small, yet are capable of performing several of the tasks usually associated with mammalian hearing. These tasks include air-to-liquid impedance conversion, signal amplification, and frequency analysis. Impedance conversion is achieved by a lever system, a mechanism functionally analogous to the mammalian middle ear ossicles, yet morphologically distinct. In katydids, the exact mechanisms supporting frequency analysis seem diverse, yet are seen to result in dispersive wave propagation phenomenologically similar to that of cochlear systems. Phylogenetically unrelated katydids and tetrapods have evolved remarkably different structural solutions to common biophysical problems. Here, we discuss the biophysics of hearing in katydids and the variations observed across different species. PMID- 25515595 TI - Melatonin adjusts the expression pattern of clock genes in the suprachiasmatic nucleus and induces antidepressant-like effect in a mouse model of seasonal affective disorder. AB - Recently, we have shown that C57BL/6J mice exhibit depression-like behavior under short photoperiod and suggested them as an animal model for investigating seasonal affective disorder (SAD). In this study, we tested if manipulations of the circadian clock with melatonin treatment could effectively modify depression like and anxiety-like behaviors and brain serotonergic system in C57BL/6J mice. Under short photoperiods (8-h light/16-h dark), daily melatonin treatments 2 h before light offset have significantly altered the 24-h patterns of mRNA expression of circadian clock genes (per1, per2, bmal1 and clock) within the suprachiasmatic nuclei (SCN) mostly by increasing amplitude in their expressional rhythms without inducing robust phase shifts in them. Melatonin treatments altered the expression of genes of serotonergic neurotransmission in the dorsal raphe (tph2, sert, vmat2 and 5ht1a) and serotonin contents in the amygdala. Importantly, melatonin treatment reduced the immobility in forced swim test, a depression-like behavior. As a key mechanism of melatonin-induced antidepressant like effect, the previously proposed phase-advance hypothesis of the circadian clock could not be confirmed under conditions of our experiment. However, our findings of modest adjustments in both the amplitude and phase of the transcriptional oscillators in the SCN as a result of melatonin treatments may be sufficient to associate with the effects seen in the brain serotonergic system and with the improvement in depression-like behavior. Our study confirmed a predictive validity of C57BL/6J mice as a useful model for the molecular analysis of links between the clock and brain serotonergic system, which could greatly accelerate our understanding of the pathogenesis of SAD, as well as the search for new treatments. PMID- 25515597 TI - Compact coupled graphene and porous polyaryltriazine-derived frameworks as high performance cathodes for lithium-ion batteries. AB - It is highly desirable to develop electroactive organic materials and their derivatives as green alternatives of cathodes for sustainable and cost-effective lithium-ion batteries (LIBs) in energy storage fields. Herein, compact two dimensional coupled graphene and porous polyaryltriazine-derived frameworks with tailormade pore structures are fabricated by using various molecular building blocks under ionothermal conditions. The porous nanosheets display nanoscale thickness, high specific surface area, and strong coupling of electroactive polyaryltriazine-derived frameworks with graphene. All these features make it possible to efficiently depress the dissolution of redox moieties in electrolytes and to boost the electrical conductivity of whole electrode. When employed as a cathode in LIBs, the two-dimensional porous nanosheets exhibit outstanding cycle stability of 395 mAh g(-1) at 5 A g(-1) for more than 5100 cycles and excellent rate capability of 135 mAh g(-1) at a high current density of 15 A g(-1). PMID- 25515596 TI - Intrinsic excitability changes induced by acute treatment of hippocampal CA1 pyramidal neurons with exogenous amyloid beta peptide. AB - Accumulation of beta-amyloid (Abeta) peptides in the human brain is a canonical pathological hallmark of Alzheimer's disease (AD). Recent work in Abeta overexpressing transgenic mice indicates that increased brain Abeta levels can be associated with aberrant epileptiform activity. In line with this, such mice can also exhibit altered intrinsic excitability (IE) of cortical and hippocampal neurons: these observations may relate to the increased prevalence of seizures in AD patients. In this study, we examined what changes in IE are produced in hippocampal CA1 pyramidal cells after 2-5 h treatment with an oligomeric preparation of synthetic human Abeta 1-42 peptide. Whole cell current clamp recordings were compared between Abeta-(500 nM) and vehicle-(DMSO 0.05%) treated hippocampal slices obtained from mice. The soluble Abeta treatment did not produce alterations in sub-threshold intrinsic properties, including membrane potential, input resistance, and hyperpolarization activated "sag". Similarly, no changes were noted in the firing profile evoked by 500 ms square current supra threshold stimuli. However, Abeta 500 nM treatment resulted in the hyperpolarization of the action potential (AP) threshold. In addition, treatment with Abeta at 500 nM depressed the after-hyperpolarization that followed both a single AP or 50 Hz trains of a number of APs between 5 and 25. These data suggest that acute exposure to soluble Abeta oligomers affects IE properties of CA1 pyramidal neurons differently from outcomes seen in transgenic models of amyloidopathy. However, in both chronic and acute models, the IE changes are toward hyperexcitability, reinforcing the idea that amyloidopathy and increased incidence in seizures might be causally related in AD patients. PMID- 25515598 TI - Kindler syndrome with severe mucosal involvement in a large Palestinian pedigree. AB - BACKGROUND: Kindler syndrome (KS) is a rare autosomal recessive disease of skin fragility, photosensitivity and progressive poikiloderma. Mucous membranes may also be involved. KS is caused by mutations in the FERMT1 gene encoding kindlin 1. OBJECTIVES: We report the clinical and molecular features of the largest kindred with KS to date, comprising 18 affected family members (age range: 12-63 years) from the Gaza Strip. MATERIALS AND METHODS: All the affected family members were clinically examined. In addition a skin biopsy for immunofluorescence testing was obtained from the index case. Molecular analysis of the FERMT1 gene was performed on genomic DNA extracted from peripheral blood of 5 patients. RESULTS: All patients presented skin and eye photosensitivity, cutaneous atrophy, dyschromia and poikiloderma, oral cavity involvement, dysphagia and constipation with anal fissures. In addition, nail dystrophy and digit webbing were observed in most of them. Ocular manifestations detected in all patients comprised ectropion and keratoconjunctivitis, with early development of symblepharon in 17 out of 18 cases and blindness in one. Of note, 17 out of 18 affected family members also suffered from urethral strictures since childhood. Diagnosis was supported by immunofluorescence findings and definitely confirmed by FERMT1 sequencing which identified the homozygous frame-shift mutation c.137_140delTAGT. CONCLUSIONS: The high rate of mucosal involvement, its early onset and progressive course are noticeable features of our kindred. Also noteworthy is the lack of muco-cutaneous malignancies, despite the sunny habitat. PMID- 25515599 TI - The cerebellar nodulus: perceptual and ocular processing of graviceptive input. AB - Current concepts postulate a decisive role of the cerebellar nodulus in the processing of otolith input. We hypothesized that nodular lesions abolish otolith perceptual integration, predicting alignment of perceived direction of earth vertical with the z-axis of the head and not with gravity. In an 80-year-old patient with acute heminodular infarction, the subjective visual vertical deviated contralesionally by -21.1 degrees when the patient was upright. After subtracting this offset, perceived vertical closely matched the patient's head orientation when the patient was roll-tilted. Otolith-ocular reflexes remained normal. This is the first report on abolished earth verticality perception in heminodular stroke and underlines the importance of the nodulus in spatial orientation. PMID- 25515602 TI - Speeding up image cytometry. PMID- 25515600 TI - Peptide-induced formation of a tethered lipid bilayer membrane on mesoporous silica. AB - Tethered bilayer lipid membranes (tBLMs) on solid supports have substantial advantages as models of artificial cell membranes for such biomedical applications as drug delivery and biosensing. Compared with untethered lipid membranes, tBLMs have more space between substrate and the bilayer and greater stability. The purpose of this work was to use these properties to fabricate and characterize a zwitterionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine lipid tBLM containing 2 mol% 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N maleimide(poly(ethylene glycol))-2000 (DSPE-PEG2000-NHS) lipid tethers on a 3 aminopropyltrimethoxysilane-modified mesoporous silica substrate. A quartz crystal microbalance with dissipation monitoring was used to monitor the process of vesicle adsorption and tBLM self-assembly, and atomic force microscopy was performed to characterize the structural properties of the tBLM obtained. Whereas tether-containing lipid vesicles ruptured neither spontaneously nor as a result of osmotic shock, introduction of an amphipathic alpha-helical (AH) peptide induced vesicle rupture and subsequent tBLM formation. Taken together, our findings suggest that the AH peptide is an efficient means of rupturing vesicles of both simple and complex composition, and is, therefore, useful for formation of tBLMs on solid and mesoporous materials for applications in biotechnology. PMID- 25515603 TI - Alkaloid extracts of Ficus species and palm oil-derived tocotrienols synergistically inhibit proliferation of human cancer cells. AB - Tocotrienols have been reported to possess anticancer effects other than anti inflammatory and antioxidant activities. This study explored the potential synergism of antiproliferative effects induced by individual alkaloid extracts of Ficus fistulosa, Ficus hispida and Ficus schwarzii combined with delta- and gamma tocotrienols against human brain glioblastoma (U87MG), lung adenocarcinoma (A549) and colorectal adenocarcinoma (HT-29) cells. Cell viability and morphological results demonstrated that extracts containing a mixture of alkaloids from the leaves and bark of F. schwarzii inhibited the proliferation of HT-29 cells, whereas the alkaloid extracts of F. fistulosa inhibited the proliferation of both U87MG and HT-29 cells and showed synergism in combined treatments with either delta- or gamma-tocotrienol resulting in 2.2-34.7 fold of reduction in IC50 values of tocotrienols. The observed apoptotic cell characteristics in conjunction with the synergistic antiproliferative effects of Ficus species derived alkaloids and tocotrienols assuredly warrant future investigations towards the development of a value-added chemotherapeutic regimen against cancers. PMID- 25515604 TI - The Christmas tree sign: a diagnostic tool for ECG connoisseurs. PMID- 25515605 TI - Is an unfavourable cardiovascular risk profile a risk factor for vasomotor menopausal symptoms? Results of a population-based cohort study. AB - OBJECTIVE: Evidence suggests an association between vasomotor menopausal symptoms (VMSs), i.e. hot flushes and night sweats, and cardiovascular disease. However, the causal pathway is unclear. We investigated whether an unfavourable cardiovascular risk profile is a risk factor for VMS later in life. DESIGN: Retrospective cohort study. SETTING: Women aged 50-70 from the general population. POPULATION: The Prospect-European Prospective Investigation into Cancer and Nutrition (Prospect-EPIC) cohort is a population-based cohort of women who enrolled between 1993 and 1997. Follow-up questionnaires were sent at 5-year intervals for 15 years. Women who returned the third questionnaire, answered questions regarding lifetime VMS and did not report VMS prior to baseline were included in this study (n = 1295). METHODS: At baseline, the Framingham Risk Score (FRS) was determined. We used logistic regression analysis to calculate odds ratios (ORs) for the association between baseline FRS and incident VMS. MAIN OUTCOME MEASURE: Incident VMS. RESULTS: At baseline (mean age +/- standard deviation, 52.2 +/- 3.6 years), 21.2% had a FRS > 10%. During follow-up, 40.2% of women reported the onset of VMS. Adjusted for body mass index, physical activity, education and alcohol consumption, each point increase in FRS was associated with a decreased incidence of VMS [OR, 0.94 (95% CI, 0.91-0.97)]. Additional adjustment for menopausal status attenuated the OR to null [OR, 0.98 (95% CI, 0.95-1.01)]. None of the separate FRS variables were associated with VMS after adjustment for age. CONCLUSIONS: In our cohort, an unfavourable cardiovascular risk profile was not associated with VMS, and therefore we found no evidence for the involvement of a vascular mechanism in the etiology of VMS. PMID- 25515606 TI - Does receipt of 5As services have implications for patients' satisfaction in India? AB - BACKGROUND: The 5As model for behavior change counseling is an evidence-based counseling approach. This study aims to explore the relationship between patient satisfaction with counseling services and 5As interventions in tobacco cessation. We also investigated the impact of satisfaction with counseling services on patients' intention to quit and recommendation of those services to other tobacco users. METHODS: Two cross-sectional surveys were administered among patients and physicians working in primary health care facilities in 12 districts of two states in India. Health facilities and patients were recruited by systematic random and simple random sampling respectively. We limited our analyses to only those patients who were asked about their tobacco consumption. We used multivariable logistic regression to investigate associations between individual components of 5As interventions and patients' satisfaction with the counseling services. RESULTS: Patients who reported that they were 'advised' to quit (OR: 9.56; 95% CI: 1.89-48.28), 'assessed' for readiness to quit (OR 2.1, 95% CI: 1.07 4.15) and offered cessation 'assistance' (OR 2.2, 95% CI: 1.17-4.29) were more satisfied with the counseling services. Patients who were satisfied with the counseling services were five times more likely to have an intention to quit tobacco (OR: 5.45, 95% CI: 3.59 to 8.27) and four times as likely to recommend counseling to other tobacco users (OR 3.83; 95% CI:2.46 -5.96). CONCLUSIONS: Incorporating 5As interventions in the delivery of primary care would likely increase patients' satisfaction with physicians' delivered counseling services. Patients' recommendation of counseling services will aid in demand generation for cessation services in primary care. PMID- 25515607 TI - Male Ebola Survivors: Do Not Forget to Use a Condom! PMID- 25515608 TI - Traditional and religious healers in the pathway to care for people with mental disorders in Africa: a systematic review and meta-analysis. AB - PURPOSE: In resource-limited contexts in low- and middle-income countries (LMICs), a considerable proportion of individuals seeking care for mental disorders consult traditional and religious healers in their pathway to mental health care. Reports from Africa suggest that early involvement of healers may result in delays in the care pathway; a potential barrier to early identification and intervention. METHODS: A systematic review was conducted to evaluate the proportion of patients attending formal health services after making first contact for treatment of mental disorders with traditional or religious healers or other informal and formal care providers within published research in Africa. Electronic databases were searched for the period from January 1990 to February 2014. Quality assessment of included studies was conducted the SAQOR tool. RESULTS: Fourteen papers were identified with data on category of first care provider. Utilizing random effects modelling with inverse variance method, the pooled proportion of participants making first contact for treatment of mental disorders with two broadly categorised providers (informal and formal) was 48.1 % (95 % CI 36.4-60.0 %) and 49.2 % (95 % CI 38.0-60.4 %), respectively. The pooled proportion of participants making first contact with specific providers was: traditional healers (17.0 %, 95 % CI 10.9-24.1 %); religious healers (26.2 %, 95 % CI 18.1-35.1 %); general health services (24.3 %, 95 % CI 16.9-32.5 %); and mental health services (13.0 %, 95 % CI 5.1-23.5 %). Substantial regional variation in patterns of first provider choice was evident. CONCLUSIONS: Conclusions of this review must be qualified in the light of several limitations. Approximately half of individuals seeking formal health care for mental disorders in Africa, choose traditional and religious healers as their first care provider. Previous reports suggest that this choice is associated with delays in accessing formal mental health services. Strategies to improve pathways to mental health care in Africa must include innovative programmes aimed at fostering collaboration between biomedical mental health services and these key community based providers. PMID- 25515609 TI - Anti-inflammatory and antifibrotic effects of resveratrol in the lung. AB - Resveratrol, a natural polyphenolic molecule with several biological activities, is a well recognized anti-oxidant, anti-aging and cancer chemopreventive agent. Moreover, resveratrol anti-inflammatory and antifibrotic properties have been demonstrated both in vitro and in different animal models of inflammatory pathologies, including bowel and liver diseases. We review the evidence of resveratrol protective role in respiratory diseases such as acute lung injury, asthma, chronic obstructive pulmonary disease and lung fibrosis. We conclude that resveratrol and its derivatives may act as a therapeutic agents in respiratory diseases and pertinent clinical trials should be performed. PMID- 25515610 TI - Human convection flow in spaces with and without ventilation: personal exposure to floor-released particles and cough-released droplets. AB - The effects of the human convective boundary layer (CBL), room airflow patterns, and their velocities on personal exposure are examined. Two pollutants are studied which simulate particles released from the feet and generated at distances of 2 and 3 m by a human cough. A thermal manikin whose body shape, size, and surface temperatures correspond to those of an average person is used to simulate the CBL. The findings of the study reveal that for accurate predictions of personal exposure, the CBL needs to be considered, as it can transport the pollution around the human body. The best way to control and reduce personal exposure when the pollution originates at the feet is to employ transverse flow from in front and from the side, relative to the exposed occupant. The flow from the above opposing the CBL create the most unfavorable velocity field that can increase personal exposure by 85%, which demonstrates a nonlinear dependence between the supplied flow rate and personal exposure. In the current ventilation design, it is commonly accepted that an increased amount of air supplied to the rooms reduces the exposure. The results of this study suggest that the understanding of air patterns should be prioritized. PRACTICAL IMPLICATIONS: A human convective boundary layer plays an important role in pollution transport around the human body. It interacts with the surrounding airflows which modifies air movement around the human body and personal exposure. Understanding the influence of this interaction on the pollution spread around the human can be used to control and reduce personal exposure and improve HVAC design. PMID- 25515611 TI - Two-year follow-up of revision total hip arthroplasty using a ceramic revision head with a retained well-fixed femoral component: a case series. AB - INTRODUCTION: It is known that a well-fixed stem can be left in situ when only the acetabular component and femoral head have to be changed. However, in a revision case, the use of a ceramic head on an existing taper is not recommended. Slight damages of the taper may increase the risk of a ceramic fracture. Until now in a revision case a primary ceramic-on-ceramic or ceramic-on-polyethylene pairing was changed to a metal-on-polyethylene pairing or the well-fixed stem was removed as well. During the past several years, a ceramic head with a metallic sleeve has been introduced as an option for revisions with a stem left in situ. We report short-term results of a ceramic revision head in this clinical setting. METHODS: Eight patients with a ceramic revision head were clinically and radiologically followed up two years after revision surgery. Their Harris Hip Score and visual analogue scale scores for pain and satisfaction were recorded, and their radiographs were checked for osteolysis and heterotopic ossifications. RESULTS: The mean Harris Hip Score increased from 46.5 points before surgery to 88.3 points 2 years after surgery. The mean visual analogue scale score for pain improved from 6.7 to 1.1, and the mean visual analogue scale for satisfaction rose from 5.1 to 8.3. The radiological results did not show osteolysis in any of the patients. Grade I heterotopic ossification according to the Brooker classification system was seen in one patient. CONCLUSIONS: The early clinical and radiological results in this case series are in agreement with previously published studies. Ceramic revision heads with a metallic sleeve are a promising approach in the revision of a ceramic head with a well-fixed stem which can be left in situ. This solution avoids an unnecessary exchange of a well-fixed stem and thereby shortens the surgical time of the revision and may reduce the peri operative complications. PMID- 25515613 TI - A porous metal-organic framework containing multiple active Cu(2+) sites for highly efficient cross dehydrogenative coupling reaction. AB - A novel 3D porous metal-organic framework was constructed from imidazole carboxylate linkers and copper(ii) nodes, which in situ generates multiple active Cu(II) sites in the nanosized channel walls for highly efficient cross dehydrogenative coupling reaction between 1,2,3,4-tetrahydroisoquinoline derivatives and nitroalkanes that are superior to the simple copper salts. PMID- 25515612 TI - Endoscopic balloon dilatation of benign esophageal strictures in childhood: a 15 year experience. AB - The study aims to evaluate the effectiveness and safety of endoscopic balloon dilatation (EBD) in childhood benign esophageal strictures. The medical records of 38 patients who underwent EBD from 1999 to 2013 were retrospectively reviewed. Demographic features, diagnoses, features of strictures, frequency and number of EBD, complications, outcome, and recurrence data were recorded. Median age was 1.5 years (0-14), and female/male ratio was 17/21 (n = 38). Primary diagnoses were corrosive esophageal stricture (n = 19) and esophageal atresia (n = 19). The length of strictures were less than 5 cm in 78.9% (n = 30). No complication was seen in 86.8% (n = 33). Perforation was seen in 10.5% (n = 4), and recurrent fistula was seen in 2.7% (n = 1). Total treatment lasted for 1 year (1-11). Dysphagia was relieved in 60.5% (n = 23). Recurrence was seen in 31.6% (n = 12). Treatment effectiveness was higher, and complication rates were lower in strictures shorter than 5 cm compared with longer ones (70% vs. 25%, P < 0.05, and 3.4% vs. 37.5%, P < 0.05). Although there was no statistical difference, treatment effectiveness rates were lower and complication and recurrence rates were higher in corrosive strictures compared with anastomotic ones (P > 0.05). EBD is a safe and efficient treatment choice in esophageal strictures, especially in strictures shorter than 5 cm and anastomotic strictures. PMID- 25515614 TI - Unpredictable drug reaction in a child with Cornelia de Lange syndrome. AB - CASE DESCRIPTION: Preoperative use of midazolam sedation is mandatory during induction of anesthesia in noncooperative and hyperactive children to prevent possible obstacles. Unusual drug reactions rarely occur in patients undergoing anesthesia or in intensive care unit. This report describes an unpredictable drug reaction after a routine midazolam premedication in a patient with no history of allergy. There has been no literature data yet to show that midazolam can provoke respiratory problems in patients with Cornelia de Lange Syndrome. CONCLUSION: In our opinion midazolam should be avoided in patients with Cornelia de Lange Syndrome, which we enforced after first unpredictable reaction. PMID- 25515615 TI - Observational study to compare antithrombin and thrombomodulin for disseminated intravascular coagulation. AB - BACKGROUND: There have been no studies comparing the effects of antithrombin (AT III) and recombinant human soluble thrombomodulin (rhs-TM) on outcomes in patients with disseminated intravascular coagulation (DIC) associated with infectious diseases. OBJECTIVE: The aim of this observational study is to compare AT-III and rhs-TM in terms of outcomes such as mortality, length of hospitalization, and medical costs in patients with DIC associated with infectious diseases based on a Japanese administrative database. SETTING: A total of 7,535 patients with DIC associated with infectious diseases in 886 hospitals from 2010 to 2012 in Japan. Methods We collected patients' data from the administrative database to compare clinical and medical economic outcomes of patients with DIC. Patients were divided into two groups according to treatment of DIC: AT-III (n = 3,601) and rhs-TM (n = 3,934). MAIN OUTCOMES MEASURE: In hospital mortality (within 14 days, within 28 days, and overall mortality), length of stay (LOS), and medical costs during hospitalization. RESULTS: Multilevel logistic regression analysis showed that there were no significant differences with regard to in-hospital mortality between AT-III and rhs-TM within 14 days (odds ratio (OR) of rhs-TM 0.97, 95 % confidence interval (CI) 0.85-1.11, p = 0.744), within 28 days (OR 1.00, 95 % CI 0.89-1.13, p = 0.919), and overall (OR 0.95, 95 % CI 0.85-1.07, p = 0.470). However, multilevel linear regression analysis revealed that use of rhs-TM significantly decreased LOS and medical costs during hospitalization. The coefficient for LOS was -2.92 days (95 % CI 4.79 to -1.04 days; p = 0.002) whereas that for medical costs during hospitalization was -798.3 Euro (95 % CI -1,515.7 to -81.0 Euro; p = 0.029). CONCLUSION: This study demonstrated no significant difference in in-hospital mortality between AT-III and rhs-TM. However, use of rhs-TM was significantly associated with decreased LOS and medical costs during hospitalization in patients with DIC associated with infectious diseases. PMID- 25515616 TI - Drug-induced anaemia: a decade review of reporting to the Italian Pharmacovigilance data-base. AB - BACKGROUND: Studies investigating drug-induced anaemia are relatively scarce and mostly related to specific drugs or patients with specific pathologies. OBJECTIVE: To analyse all reports of suspected drug-induced anaemias recorded in the National Pharmacovigilance Database of the Italian Medicines Agency. METHOD: The cases of suspected drug-induced anaemias analysed were those retrieved from the Italian National Pharmacovigilance Database from January 2001 to December 2013. RESULTS: The active substances involved were 375 in 3,305 reports of drug induced anaemia; of these, 72 % were reported as serious. In 35 % of the reports patients were in polytherapy. In 24.3 % of the cases relevant DDIs were identified. We found a PRR value of 57.29 for peginterferon alfa-2a, of 12.57 for ribavirin, of 13 for flu vaccine for the occurrence of autoimmune haemolytic anaemia. The drugs mostly involved in the cases where the Naranjo causality was probable or possible were acetylsalicylic acid, warfarin, ribavirin, peginterferon alfa-2a, carboplatin and acenocoumarol. CONCLUSIONS: A possible signal was detected for peginterferon alfa-2a, ribavirin and flu vaccine in the occurrence of autoimmune haemolytic anaemia. A great involvement of clopidogrel, enoxaparin, warfarin, ticlopidine and acetylsalicylic acid in preventable DDI induced anaemia was detected, highlighting a poor awareness among healthcare providers on this issue. PMID- 25515617 TI - Qualitative exploration of the views of healthy living champions from pharmacies in England. AB - BACKGROUND: In England, the 'Healthy Living Pharmacy (HLP)' initiative has been trialed; positive outcomes led to national roll-out across England to 20 pathfinder sites. A HLP provides health promotion/prevention services through a structured framework to meet local population need. Non-pharmacist staff receive additional training so that they can provide these services, and are known as Healthy Living Champions (HLCs). OBJECTIVES: To explore HLCs views on their role and to identify any barriers or facilitators in performing the role. METHODS: Fourteen semi-structured face-to-face interviews were conducted during February and March 2013 in NHS Dudley, and analysed using the principles of content analysis. RESULTS: Three themes emerged from the interviews; HLC job role; training; and public awareness. HLC staff showed high levels of motivation, a strong desire to help people and felt a sense of personal reward, resulting in increased levels of job satisfaction. Training had improved their confidence but they still had reservations in offering services such as alcohol intervention and weight management. All believed that public awareness was low despite advertising. CONCLUSION: HLCs were positive toward their new role and derived job satisfaction from helping people to improve their health, although on-going training and support was perceived as important. PMID- 25515618 TI - Malaria's contribution to World War One - the unexpected adversary. AB - Malaria in the First World War was an unexpected adversary. In 1914, the scientific community had access to new knowledge on transmission of malaria parasites and their control, but the military were unprepared, and underestimated the nature, magnitude and dispersion of this enemy. In summarizing available information for allied and axis military forces, this review contextualizes the challenge posed by malaria, because although data exist across historical, medical and military documents, descriptions are fragmented, often addressing context specific issues. Military malaria surveillance statistics have, therefore, been summarized for all theatres of the War, where available. These indicated that at least 1.5 million solders were infected, with case fatality ranging from 0.2 -5.0%. As more countries became engaged in the War, the problem grew in size, leading to major epidemics in Macedonia, Palestine, Mesopotamia and Italy. Trans-continental passages of parasites and human reservoirs of infection created ideal circumstances for parasite evolution. Details of these epidemics are reviewed, including major epidemics in England and Italy, which developed following home troop evacuations, and disruption of malaria control activities in Italy. Elsewhere, in sub-Saharan Africa many casualties resulted from high malaria exposure combined with minimal control efforts for soldiers considered semi-immune. Prevention activities eventually started but were initially poorly organized and dependent on local enthusiasm and initiative. Nets had to be designed for field use and were fundamental for personal protection. Multiple prevention approaches adopted in different settings and their relative utility are described. Clinical treatment primarily depended on quinine, although efficacy was poor as relapsing Plasmodium vivax and recrudescent Plasmodium falciparum infections were not distinguished and managed appropriately. Reasons for this are discussed and the clinical trial data summarized, as are controversies that arose from attempts at quinine prophylaxis (quininization). In essence, the First World War was a vast experiment in political, demographic, and medical practice which exposed large gaps in knowledge of tropical medicine and unfortunately, of malaria. Research efforts eventually commenced late in the War to address important clinical questions which established a platform for more effective strategies, but in 1918 this relentless foe had outwitted and weakened both allied and axis powers. PMID- 25515619 TI - Resveratrol induces cell cycle arrest via a p53-independent pathway in A549 cells. AB - Resveratrol, a non-flavone polyphenol compound, has a chemopreventive and chemotherapeutic effect against the progression of multiple types of cancer, including lung cancer. However, the molecular mechanism underlying the effects of resveratrol on cancer remain to be elucidated. In the present study, using an MTT assay, it was demonstrated that resveratrol inhibited cell proliferation in a concentration- and time-dependent manner. In addition, morphological features were observed in the A549, human lung cancer cell line, which included cell shrinkage, cells became distorted, certain cells became rounded and there was a concentration-dependent increase in the number of sloughed cells. Cell cycle analysis revealed that resveratrol may induce cell cycle arrest in the G0/G1 phase by downregulating the expression levels of cyclin D1, cyclin-dependent kinase (CDK)4 and CDK6, and upregulating the expression levels of the CDK inhibitors, p21 and p27. The immunofluorescence and western blot analysis results revealed that resveratrol upregulated the nuclear expression of p53 in A549 cells. Further studies have demonstrated that p53 downregulation did not contribute to the G0/G1 cell cycle arrest induced by resveratrol. In addition, resveratrol had no effect on the expression of p21, through use of the p53 inhibitor, pifithrin-alpha. The present study may offer a scientific basis for the further in-depth evaluation of resveratrol in the association of p53 and cell cycle arrest. PMID- 25515621 TI - Assessment of tuberculosis infection during treatment with biologic agents in a BCG-vaccinated pediatric population. AB - Biologic therapies, such as tumor necrosis factor-alpha (TNF-alpha) blockers, are commonly used to treat rheumatological diseases in childhood. Screening patients for tuberculosis (TB) is highly recommended before starting therapy with TNF alpha blockers. Despite appropriate screening, TB still remains a problem in patients receiving anti-TNF therapy in countries where TB is not endemic. TB in anti-TNF-treated patients is often diagnosed late due to altered presentation, and this delay results in high morbidity and mortality with a high proportion of extrapulmonary and disseminated disease. The aim of this study is to show the course of TB disease in children who are on biologic therapy, in an era where many of the children are BCG-vaccinated and TB is intermediately endemic. We recruited 71 patients with several types of inflammatory diseases. Six of them had a positive test result during TB screening and began taking isoniazid (INH) prophylactically. During the 3 years of follow-up, none of these patients developed TB disease. Biologic agents can be safely used in a BCG-vaccinated pediatric population, as long as patients are closely monitored to ensure that any cases of TB will be detected early. PMID- 25515620 TI - Cardio-metabolic risk screening among adolescents: understanding the utility of body mass index, waist circumference and waist to height ratio. AB - BACKGROUND: Few studies have assessed how well body mass index (BMI), waist circumference (WC), or waist to height ratio (WtHR) perform in identifying cardio metabolic risk among youth. OBJECTIVE: The objective of this study was to evaluate the utility of BMI and WC percentiles and WtHR to distinguish adolescents with and without cardio-metabolic risk. METHODS: A cross-sectional analysis of data from 6097 adolescents aged 10-13 years who participated in the HEALTHY study was conducted. Receiver operating characteristic curves determined the discriminatory ability of BMI and WC percentiles and WtHR. RESULTS: The discriminatory ability of BMI percentile was good (area under the curve [AUC] >= 0.80) for elevated insulin and clustering of >=3 risk factors, with optimal cut points of 96 and 95, respectively. BMI percentile performed poor to fair (AUC = 0.57-0.75) in identifying youth with the majority of individual risk factors examined (elevated glucose, total cholesterol, low-density lipoprotein, blood pressure, triglycerides and high-density lipoprotein). WC percentile and WtHR performed similarly to BMI percentile. CONCLUSIONS: The current definition of obesity among US children performs well at identifying adolescents with elevated insulin and a clustering of >=3 cardio-metabolic risk factors. Evidence does not support WC percentile or WtHR as superior screening tools compared with BMI percentile for identifying cardio-metabolic risk. PMID- 25515623 TI - Abstraction and addition kinetics of C2H radicals with CH4, C2H6, C3H8, C2H4, and C3H6: CVT/SCT/ISPE and hybrid meta-DFT methods. AB - Rate coefficients for the reactions of C2H radicals with methane (k1), ethane (k2), propane (k3), ethylene (k4), and propylene (k5) were computed using canonical variational transition state theory (CVT) coupled with hybrid-meta density functional theory (DFT) over a wide range of temperatures from 150 to 5000 K. The quantum chemical tunneling effect was corrected by the small curvature tunneling (SCT) method. The dynamic calculations are performed using the variational transition state theory (VTST) with the interpolated single-point energies (ISPE) method at the CCSD(T)/cc-pVTZ//M06-2X/6-31+G(d,p) level of theory. Intrinsic reaction coordinate (IRC) calculations were performed to verify that the transition states are connected to the reactants and products. The rate coefficients obtained over the studied temperature range yield the following Arrhenius expressions (cm(3) molecule(-1) s(-1)): k1 = 4.69 * 10(-19)T(2.44) exp[331/T], k2 = 4.29 * 10(-17)T(2.11) exp[432/T], k3 = 4.81 * 10(-17)T(1.98) exp[697/T], k4 = 7.54 * 10(-21)T(2.96) exp[1942/T], and k5 = 8.04 * 10( 23)T(3.44) exp[3011/T] cm(3) molecule(-1) s(-1). Branching ratio calculation for the reactions of C2H radicals with ethylene and propylene shows that the abstraction reactions are not important at lower temperatures. However, as the temperature increases, abstraction reactions become more important. PMID- 25515622 TI - Trichostatin A modulates intracellular reactive oxygen species through SOD2 and FOXO1 in human bone marrow-mesenchymal stem cells. AB - Engraft cells are often exposed to oxidative stress and inflammation; therefore, any factor that can provide the stem cells resistance to these stresses may yield better efficacy in stem cell therapy. Studies indicate that histone deacetylase (HDACs) inhibitors alleviate damage induced by oxidative stress. In this study, we investigated whether regulation of reactive oxygen species (ROS) occurs through the HDAC inhibitor trichostatin A (TSA) in human bone marrow-mesenchymal stem cells (hBM-MSCs). Intracellular ROS levels increased following exposure to hydrogen peroxide (H2 O2 ), and were suppressed by TSA treatment. Levels of the antioxidant enzyme superoxide dismutase 2 (SOD2) increased following treatment with 200 nM TSA and to a lesser level at 1-5 MUM TSA. Cell protective effects against oxidative stress were significantly increased in TSA-MSCs after treatment with low doses of TSA (50-500 nM) and decreased with high doses of TSA (5-10 MUM). Consistent results were obtained with immunoblot analysis for caspase3. Investigation of Forkhead box O1 (FOXO1), superoxide dismutase 2 (SOD2), and p53 levels to determine intracellular signaling by TSA in oxidative stress-induced MSCs demonstrated that expression of phosphorylated-FOXO1 and phosphorylated-SOD2 decreased in H2 O2 -treated MSCs while levels of p53 increased. These effects were reversed by the treatment of 200 nM TSA. These results suggest that the main function of ROS modulation by TSA is activated through SOD2 and FOXO1. Thus, optimal treatment with TSA may protect hBM-MSCs against oxidative stress. PMID- 25515625 TI - Teledermatology: a possible reality in rural India. PMID- 25515624 TI - Comparing the motivational interviewing integrity in two prevalent models of brief intervention service delivery for primary care settings. AB - This quasi experimental study compared the motivational interviewing (MI) integrity in two prevalent brief intervention (BI) service delivery models for drug abuse. Routine primary care providers (RCPs) and non-routine care providers (NRCPs) performed BIs using an MI style within the same medical setting, patient population, and Screening, Brief Intervention, and Referral for Treatment (SBIRT) protocol. Interventionists (9 RCPs and 6 NRCPs) underwent similar MI training and performed a total of 423 audiorecorded BIs. We compared the MI integrity scores for all audio recorded sessions from these two SBIRT models for up to 40 months post MI training. Both groups met the lower standard (beginning proficiency in MI) on 4 of 5 MI integrity scores, but NRCPs met more of the higher standards (competency in MI) than RCPs. There may be limitations with regards to MI fidelity when using RCPs to conduct BIs in some primary care settings. Further experimental investigation is warranted to replicate this finding and identify casual factors of observed differences in MI fidelity. PMID- 25515626 TI - New evidence of melatonin receptor contribution to ram sperm functionality. AB - The present study analysed the involvement of melatonin, acting via its receptors (MT1 and MT2), in ram sperm functionality. Indirect immunofluorescence assays revealed no changes in the distribution or intensity of MT1 receptors, whereas different subpopulations were established for MT2 receptors in control, in vitro capacitated and acrosome-reacted ram spermatozoa. Chlortetracycline staining revealed the following correlations between the pattern of staining for MT2 receptors in: (1) non-capacitated (NC) sperm rate and the proportion of spermatozoa with equal immunostaining intensity in the acrosome and post-acrosome (r=0.59, P<0.001); (2) in capacitated (C) sperm rate and the proportion of spermatozoa with stronger reactivity in the acrosome (r=0.60, P<0.001); and (3) in acrosome-reacted (AR) sperm rate and the proportion of spermatozoa with more intense staining on the post-acrosome (r=0.67, P<0.001). Incubation of swim-up selected samples with either 1MUM melatonin or MT1 and MT2 receptor agonists (2 phenylmelatonin 1uM and 8-Methoxy-2-propionamidotetralin (8M-PDOT) 1uM and 10nM) at 39 degrees C and 5% CO2 for 3h resulted in a higher proportion of the NC pattern compared with the control group (P<0.05), whereas treatment with MT1 and MT2 receptor antagonists (luzindole 1uM and 4-phenyl-2-propionamidotetralin (4P PDOT) 1uM and 10nM) decreased the proportion of spermatozoa exhibiting the NC pattern (P<0.001) concomitant with an increase in those exhibiting the C pattern (P<0.01). In conclusion, melatonin exerts a modulating effect on ram sperm functionality, primarily via activation of the MT2 receptor. PMID- 25515627 TI - Seroprevalence screening for the West Nile virus in Malaysia's Orang Asli population. AB - BACKGROUND: West Nile virus (WNV) infection is an emerging zoonotic disease caused by an RNA virus of the genus Flavivirus. WNV is preserved in the environment through cyclic transmission, with mosquitoes, particularly Culex species, serving as a vector, birds as an amplifying host and humans and other mammals as dead-end hosts. To date, no studies have been carried out to determine the prevalence of the WNV antibody in Malaysia. The aim of this study was to screen for the seroprevalence of the WNV in Malaysia's Orang Asli population. METHODS: Serum samples of 742 Orang Asli were collected in seven states in peninsular Malaysia. The samples were assessed to determine the seroprevalence of WNV immunoglobulin (Ig)G with the WNV IgG enzyme-linked immunosorbent assay (ELISA) method. For each individual, we documented the demographic factors. Anti dengue and anti-tick-borne encephalitis virus IgG ELISA were also performed to rule out a cross reaction. All statistical analyses were performed using the GraphPad Prism 6 (GraphPad Software, Inc.); p values of less than 0.05 were considered significant. RESULTS: The serosurvey included 298 men (40.16%) and 444 women (59.84%) of Malaysia's Orang Asli. Anti-WNV IgG was found in 9 of the 742 samples (1.21%). The seroprevalence was 0.67% (2 of 298) in men and 1.58% (7 of 444) in women. The presence of anti-WNV IgG was found not to be associated with gender but, however, did correlate with age. The peak seroprevalence was found to be 2.06% (2 of 97) in individuals between 30 to 42 years of age. CONCLUSIONS: No previous studies have examined the seroprevalence of the WNV antibody in the human population in Malaysia, and no clinical reports of infections have been made. Screening for the WNV seroprevalence is very significant because of many risk factors contribute to the presence of WNV in Malaysia, such as the abundance of Culex mosquitoes as the main vector and a high degree of biodiversity, including migratory birds that serve as a reservoir to the virus. PMID- 25515628 TI - Thymic stromal lymphopoietin (TSLP) secretion from human nasal epithelium is a function of TSLP genotype. AB - Recent candidate gene and genome-wide association studies have identified "protective" associations between the single-nucleotide polymorphism (SNP) rs1837253 in the TSLP gene and risk for allergy, asthma, and airway hyperresponsiveness. The absence of linkage disequilibrium of rs1837253 with other SNPs in the region suggests it is likely a causal polymorphism for these associations, having functional consequences. We hypothesized that rs1837253 genotype would influence TSLP secretion from mucosal surfaces. We therefore evaluated the secretion of TSLP protein from primary nasal epithelial cells (NECs) of atopic and nonatopic individuals and its association with rs1837253 genotype. We found that although atopic sensitization does not affect the secretion of TSLP from NECs, there was decreased TSLP secretion in NECs obtained from heterozygous (CT; 1.8-fold) and homozygous minor allele (TT; 2.5-fold) individuals, as compared with NECs from homozygous major allele individuals (CC; P<0.05), after double-stranded RNA (dsRNA) stimulation (50 MUg ml(-1)). Our novel results show that rs1837253 polymorphism may be directly involved in the regulation of TSLP secretion. This may help explain the protective association of this genetic variant with asthma and related traits. Identifying functional consequences of SNPs in genes with previously reported clinical associations is critical in understanding and targeting allergic inflammation. PMID- 25515629 TI - A critical role for the TLR signaling adapter Mal in alveolar macrophage-mediated protection against Bordetella pertussis. AB - Bordetella pertussis causes whooping cough, an infectious disease of the respiratory tract that is re-emerging despite high vaccine coverage. Here we examined the role of Toll-like receptor (TLR) adapter protein Mal in the control of B. pertussis infection in the lungs. We found that B. pertussis bacterial load in the lungs of Mal-defective (Mal(-/-)) mice exceeded that of wild-type (WT) mice by up to 100-fold and bacteria disseminated to the liver in Mal(-/-) mice and 50% of these mice died from the infection. Macrophages from Mal(-/-) mice were defective in an early burst of pro-inflammatory cytokine production and in their ability to kill or constrain intracellular growth of B. pertussis. Importantly, the B. pertussis bacterial load in the lungs inversely correlated with the number of alveolar macrophages. Despite the maintenance and expansion of other cell populations, alveolar macrophages were completely depleted from the lungs of infected Mal(-/-) mice, but not from infected WT mice. Our findings define for the first time a role for a microbial pattern-recognition pathway in the survival of alveolar macrophages and uncover a mechanism of macrophage mediated immunity to B. pertussis in which Mal controls intracellular survival and dissemination of bacteria from the lungs. PMID- 25515631 TI - Imputation accuracy is robust to cattle reference genome updates. AB - Genotype imputation is routinely applied in a large number of cattle breeds. Imputation has become a need due to the large number of SNP arrays with variable density (currently, from 2900 to 777,962 SNPs). Although many authors have studied the effect of different statistical methods on imputation accuracy, the impact of a (likely) change in the reference genome assembly on imputation from lower to higher density has not been determined so far. In this work, 1021 Italian Simmental SNP genotypes were remapped on the three most recent reference genome assemblies. Four imputation methods were used to assess the impact of an update in the reference genome. As expected, the four methods behaved differently, with large differences in terms of accuracy. Updating SNP coordinates on the three tested cattle reference genome assemblies determined only a slight variation on imputation results within method. PMID- 25515630 TI - Prevalence of human papillomavirus in head and neck cancers in European populations: a meta-analysis. AB - BACKGROUND: Infection with human papillomavirus (HPV) is necessary for the development of cervical carcinoma. By contrast, the role of HPV in the pathogenesis of other malignancies, such as head and neck cancers, is less well characterised. This study aimed to address key information gaps by conducting a systematic review and meta-analysis of the prevalence of HPV infection in head and neck cancers, focusing on data for European populations. METHODS: MEDLINE, Embase and grey literature sources were systematically searched for primary studies that were published in English between July 2002 and July 2012, and which reported on the prevalence of HPV infection in head and neck cancers in European populations. Studies on non-European populations, those not published in English, and those assessing patients co-infected with human immunodeficiency virus were excluded. Eligible studies were combined in a meta-analysis. In addition, the potential statistical association between the head and neck cancers and certain HPV types was investigated. RESULTS: Thirty-nine publications met the inclusion criteria. The prevalence of HPV of any type in 3,649 patients with head and neck cancers was 40.0% (95% confidence interval, 34.6% to 45.5%), and was highest in tonsillar cancer (66.4%) and lowest in pharyngeal (15.3%) and tongue (25.7%) cancers. There were no statistically significant associations between the HPV types analysed and the geographical setting, type of sample analysed or type of primer used to analyse samples in head and neck cancers. CONCLUSIONS: The prevalence of HPV infection in European patients with head and neck cancers is high but varies between the different anatomical sites of these malignancies. There appears to be no association between HPV type and geographical setting, type of samples analysed or type of primer used to analyse samples in such cancers. PMID- 25515636 TI - New statistics on the cost of new drug development and the trouble with CNS drugs. PMID- 25515638 TI - Possible benefits of robot-assisted rectal cancer surgery regarding urological and sexual dysfunction: a systematic review and meta-analysis. AB - AIM: Robot-assisted surgery for rectal cancer may result in lower rates of urogenital dysfunction compared with laparoscopic surgery. A systematic review was conducted of studies reporting urogenital dysfunction after robot-assisted rectal cancer surgery. METHOD: PubMed, Embase and the Cochrane Library were systematically searched in February 2014. All studies investigating urogenital function after robot-assisted rectal cancer surgery were identified. The inclusion criteria for meta-analysis studies required comparison of robot assisted with laparoscopic surgery and the evaluation of urological and sexual function by validated questionnaire. The outcome was evaluated using the International Prostate Symptom Score (IPSS), the International Index of Erectile Function (IIEF) and the Female Sexual Function Index. RESULTS: Ten studies including 689 patients were included. For the meta-analysis this fell to four including 152 patients in the robotic group and 161 in the laparoscopic group, without heterogeneity. The IPSS score at 3 and 12 months favoured robot-assisted surgery [mean difference (MD) -1.58; 95% CI (-3.1, -0.0), [P = 0.04; and MD -0.90 (-1.81, -0.02), P = 0.05]. IIEF scores at 3 months' follow-up [MD -2.59 (-4.25, 0.94),] P = 0.002] and 6 months' follow-up [MD -3.06 (-4.53, -1.59), P = 0.0001] were better after robot-assisted than laparoscopic surgery. CONCLUSION: Although there were few data and no randomized controlled trials the results of the review suggested that robot-assisted surgery resulted in improved urogenital function than after laparoscopy. PMID- 25515639 TI - App-etite for change. PMID- 25515640 TI - Impact of voluntary food fortification practices in Ireland: trends in nutrient intakes in Irish adults between 1997-9 and 2008-10. AB - Because of the discretionary nature of voluntary food fortification in the European Union, there is a need to monitor fortification practices and consumption of fortified foods in order to assess the efficacy and safety of such additions on an ongoing basis. The present study aimed to investigate the nutritional impact of changes in voluntary fortification practices in adults aged 18-64 years using dietary intake data from two nationally representative cross sectional food consumption surveys, the North/South Ireland Food Consumption Survey (NSIFCS) (1997-9) and the National Adult Nutrition Survey (NANS) (2008 10). The supply of fortified foods increased between 1997-9 and 2008-10, resulting in a higher proportion of adults consuming fortified foods (from 67 to 82 ) and a greater contribution to mean daily energy intake (from 4.6 to 8.4%). The overall nutrient profile of fortified foods consumed remained favourable, i.e. higher in starch and dietary fibre and lower in fat and saturated fat, with polyunsaturated fat, sugars and Na in proportion to energy. Women, particularly those of childbearing age, remained the key beneficiaries of voluntary fortification practices in Ireland. Continued voluntary fortification of foods has increased protection against neural tube defect-affected pregnancy by folic acid and maintained the beneficial impact on the adequacy of Fe intake. Increased consumption of fortified foods did not contribute to an increased risk of intakes exceeding the tolerable upper intake level for any micronutrient. Recent increases in voluntary fortification of foods in Ireland have made a favourable nutritional impact on the diets of adults and have not contributed to an increased risk of adverse effects. PMID- 25515641 TI - Sleep disturbances and dementia. AB - Sleep is a complex behavioural state, the ultimate functions of which remain poorly understood. It becomes more fragmented as we age, with more night-time awakenings and greater tendency for daytime sleep. The magnitude of disordered sleep among individuals affected by dementia has been clearly demonstrated, and disturbed sleep is a major clinical problem in dementia. Comorbid insomnia and other sleep disturbances are common in patients with neurodegenerative disorders, such Alzheimer's disease and other dementing disorders. How and when sleep problems manifest themselves can depend on the type of dementia involved as well as the stage of the dementia. However, differences in sleep pattern presentation show more variation during the initial stages of dementias than they do during the later stages. Effective, pragmatic interventions are largely anecdotal and untested. PMID- 25515644 TI - Celebrating Soft Matter's 10th anniversary: stimuli-responsive Pickering emulsion polymerized smart fluids. AB - The Pickering emulsion process is an important and interesting way of forming hybrid soft matter particles stabilized by solid particles as surfactants instead of the extensive use of conventionally available organic surfactant molecules. This Highlight briefly reviews stimuli-responsive polymer/inorganic hybrid materials fabricated by Pickering emulsion polymerization along with the rheological characteristics of their electrorheological and magnetorheological smart fluids under electric and magnetic fields, respectively. PMID- 25515643 TI - Metastatic breast cancer mimicking a hilar cholangiocarcinoma: case report and review of the literature. AB - BACKGROUND/AIMS: Breast cancer is the most common tumor in women and the first cause of death for malignancy in the female population. Bile ducts are not among the common sites of metastasis from breast cancer; few cases of obstructive jaundice due to metastatic breast cancer have been described in the literature and they mostly resulted from widespread liver metastases that eventually involved the bile ducts. We report an exceptional case of metastatic infiltration of the extrahepatic bile ducts in absence of liver metastases. CASE PRESENTATION: A 56-year-old woman who had undergone a right mastectomy 13 years earlier due to infiltrating ductal breast cancer and had remained tumor free, presented at a follow-up examination with obstructive jaundice.Imaging (computed tomography, magnetic resonance and endoscopic retrograde cholangiopancreatography) scans showed features that were suggestive of a primary tumor of the extrahepatic bile duct. At surgery, the intraoperative findings were also those of a tumor of the bile duct, however, an histological examination showed no evidence of malignancy in the mucosa, but did shown an infiltration of the external wall from adenocarcinoma. Immunohistochemistry analysis demonstrated that the tumor was metastatic breast cancer. CONCLUSIONS: Indeterminate stenosis of the extrahepatic bile ducts should be examined with suspicion in women with a history of breast cancer, and bile duct metastases are to be considered among the possible diagnoses. A differential diagnosis from cholangiocarcinoma is of paramount importance and mainly relies on pathology. PMID- 25515642 TI - Transcription factor MrpC binds to promoter regions of hundreds of developmentally-regulated genes in Myxococcus xanthus. AB - BACKGROUND: Myxococcus xanthus is a bacterium that undergoes multicellular development when starved. Cells move to aggregation centers and form fruiting bodies in which cells differentiate into dormant spores. MrpC appears to directly activate transcription of fruA, which also codes for a transcription factor. Both MrpC and FruA are crucial for aggregation and sporulation. The two proteins bind cooperatively in promoter regions of some developmental genes. RESULTS: Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) and bioinformatic analysis of cells that had formed nascent fruiting bodies revealed 1608 putative MrpC binding sites. These sites included several known to bind MrpC and they were preferentially distributed in likely promoter regions, especially those of genes up-regulated during development. The up-regulated genes include 22 coding for protein kinases. Some of these are known to be directly involved in fruiting body formation and several negatively regulate MrpC accumulation. Our results also implicate MrpC as a direct activator or repressor of genes coding for several transcription factors known to be important for development, for a major spore protein and several proteins important for spore formation, for proteins involved in extracellular A- and C-signaling, and intracellular ppGpp-signaling during development, and for proteins that control the fate of other proteins or play a role in motility. We found that the putative MrpC binding sites revealed by ChIP seq are enriched for DNA sequences that strongly resemble a consensus sequence for MrpC binding proposed previously. MrpC2, an N-terminally truncated form of MrpC, bound to DNA sequences matching the consensus in all 11 cases tested. Using longer DNA segments containing 15 of the putative MrpC binding sites from our ChIP-seq analysis as probes in electrophoretic mobility shift assays, evidence for one or more MrpC2 binding site was observed in all cases and evidence for cooperative binding of MrpC2 and FruA was seen in 13 cases. CONCLUSIONS: We conclude that MrpC and MrpC2 bind to promoter regions of hundreds of developmentally-regulated genes in M. xanthus, in many cases cooperatively with FruA. This binding very likely up-regulates protein kinases, and up- or down regulates other proteins that profoundly influence the developmental process. PMID- 25515645 TI - Quality of care in breast cancer centers: results of benchmarking by the German Cancer Society and German Society for Breast Diseases. AB - A total of 218 breast cancer centers, with 274 operating sites, have been certified since 2003 in accordance with the criteria set out by the German Cancer Society (Deutsche Krebsgesellschaft) and the German Society for Breast Diseases (Deutsche Gesellschaft fur Senologie). Most of these centers are located in Germany, but centers in Austria, Switzerland, and Italy have also been certified. This paper presents the results for quality indicators (QIs) from 2009 to 2012, based on data from 195,342 primary breast cancer patients, in order to illustrate the development and progress of these centers. Descriptive results on interdisciplinary collaboration (6 QIs), guideline adherence (15 QIs), and specialist expertise (7 QIs) are reported over time. Fulfillment of the certification requirements was high and remained relatively stable over time, with the extent of variation between sites declining. Sites that do not reach the target values are asked to comment on the discrepancies, and their comments, as well as the QI results, are used by centers and auditors during an on-site auditing process and to constantly revise the QIs set out by the guideline and the certification commission. PMID- 25515646 TI - Postural sway and motor control in trans-tibial amputees as assessed by electroencephalography during eight balance training tasks. AB - BACKGROUND: The purpose of this study was to investigate the changes in the Power Spectral Density (PSD) of the electroencephalogram (EEG) during 8 common sensorimotor balance training tasks of varying difficulty in single-limb trans tibial amputees. MATERIAL AND METHODS: Eight sensorimotor balance exercises, including alteration in vision, base of support, and surface compliance, were used to test postural control and how it related to the electroencephalogram (EEG). A control group was compared to a group of people with trans-tibial amputation of 1 leg to see how the brain responds to loss of a single limb during progressively harder balance testing. Postural sway and EEG changes of the alpha, beta, and sigma wave bands were measured in 20 participants (10 controls, 10 amputees) during 8 balance tasks of varying difficulty with eyes open and closed, feet in tandem or apart, and on a foam or a firm surface. RESULTS: The power of alpha, beta, and sigma bands increased significantly in most tests when comparing the amputees to the control subjects. Balance was significantly worse in the amputees even when standing on both legs. In amputees, balance required more cortical activity than in the controls. CONCLUSIONS: This study demonstrated that amputees have considerably more difficulty in motor control for the brain during balance tasks. Balance was impaired even when standing feet apart on 2 legs and EEG showed more spectral power in all areas of the brain in the amputees. PMID- 25515647 TI - The relationship between sleep quality and functional exercise capacity in COPD. AB - BACKGROUND: Poor sleep is often associated with a series of health problems in patients with chronic obstructive pulmonary disease (COPD), but the relationship between sleep quality and functional exercise capacity has not been previously investigated. AIMS: To evaluate the relationship between quality of sleep and functional exercise capacity in clinically stable COPD. METHODS: One hundred three consecutive subjects with stable COPD were recruited. The subjects were assessed with the Pittsburgh Sleep Quality Index (PSQI) and divided into poor sleep group (PSQI >5) and good sleep group (PSQI <=5). Subjects were also assessed with spirometry, 6-min walk distance (6MWD), oxygen saturation (SP O2 ), the Epworth Sleepiness Scale, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, COPD Assessment Test (CAT), Modified Medical Research Council dyspnea scale and quadriceps muscle function. RESULTS: Poor sleep was present in 43.69% of the patients with COPD. Subjects with poor sleep had shorter 6MWD (t = 3.588, P < 0.001), greater age (t = 2.519, P = 0.013), worse quality of life (t = 5.487, P < 0.001) and more depression (t = 6.576, P < 0.001) or anxiety (t = 4.245, P < 0.001) symptoms. 6MWD showed significant negative correlations with the PSQI global score (r = -0.373, P < 0.001). Multiple stepwise regresion analysis showed that PSQI global score was an independent psychological predictor of 6MWD, and 6MWD was the only physical predictor of PSQI total score in patients with COPD. CONCLUSION: There is a close relationship between sleep quality and functional exercise capacity in patients with COPD. PMID- 25515648 TI - Eccrine porocarcinoma: epidemiologic and histopathologic characteristics. AB - BACKGROUND: Porocarcinoma is a rare tumor, representing 0.005% of all malignant epithelial neoplasms. The majority of publications are single case reports. The objective of this study was to describe the epidemiologic and histopathologic characteristics of patients diagnosed with eccrine porocarcinoma. METHODS: A retrospective study was carried out from January 1994 to December 2010. Cases with a histopathological diagnosis of eccrine porocarcinoma were included. The investigated variables were frequency, gender, age, time of evolution, localization, morphology, referral clinical diagnosis, and histopathology patterns. The information was analyzed using descriptive statistics. RESULTS: During this 17-year period, 33 cases diagnosed with eccrine porocarcinoma were detected. Female gender was predominant with 64% cases. The average age was 74 +/ 12 years. The most frequent location was the head with 37% cases; the most common observed morphology was nodular, in 46%. The main referral diagnosis was squamous cell carcinoma in 67% of cases. With regard to the histopathology characteristics, necrosis predominated in 64% cases, comedonecrosis in 45% cases, squamous differentiation in 42% cases, and melanocyte colonization in 21%. CONCLUSIONS: Our series presents some clinical and histopathology differences with previously reported, such as the most frequent localization in the head and the presence of melanocyte colonization. PMID- 25515649 TI - HLA-A*24:287, a novel variant of HLA-A*24:02:01:01, discovered in a Taiwanese hematopoietic stem cell donor. AB - One nucleotide replacement in codon 182 of HLA-A*24:02:01:01 results in a novel allele, HLA-A*24:287. PMID- 25515650 TI - Genetic analysis of the 'uveal melanoma' C918 cell line reveals atypical BRAF and common KRAS mutations and single tandem repeat profile identical to the cutaneous melanoma C8161 cell line. PMID- 25515652 TI - Comparison of molar intrusion efficiency and bone density by CT in patients with different vertical facial morphology. AB - The purpose of this study is to examine the relationship between molar intrusion efficiency and bone density in patients with different vertical facial morphology. Thirty-six female patients, with overerupted upper first molars, were divided into two groups according to mandiblular plane angle (FH-MP): hyperdivergent, FH-MP>30 degrees (G1), hypodivergent, FH-MP<22 degrees (G2). Mini-screw implants with elastic chains were used to intrude upper first molars. Spiral CT was used to measure the intrusion degree of upper first molar and bone density, and molar intrusion efficiency was calculated as amount/duration (mm month(-1) ). In addition, each tooth was divided into three portions (cervical, furcation and apical) to measure the bone density. It was found in this study that treatment duration was 3.13 and 4.71 months in G1 and G2 and that the intrusion efficiency was 1.57 and 0.81 in G1 and G2 with significant difference (P < 0.05). There were significant differences in cervical, furcation and apical bone density between two groups (P < 0.05). The bone density was significantly reduced after molar intrusion. In addition, the bone density change was greater in G1 than in G2 (P < 0.05). It was concluded that molars were more easily to be intruded in hyperdivergent than in hypodivergent patients. The difference of bone density and bone density changes during intrusion may account for the variation of molar intrusion efficiency. PMID- 25515651 TI - Alcohol-induced changes in opioid peptide levels in adolescent rats are dependent on housing conditions. AB - BACKGROUND: Endogenous opioids are implicated in the mechanism of action of alcohol and alcohol affects opioids in a number of brain areas, although little is known about alcohol's effects on opioids in the adolescent brain. One concern, in particular when studying young animals, is that alcohol intake models often are based on single housing that may result in alcohol effects confounded by the lack of social interactions. The aim of this study was to investigate short- and long-term alcohol effects on opioids and the influence of housing conditions on these effects. METHODS: In the first part, opioid peptide levels were measured after one 24-hour session of single housing and 2-hour voluntary alcohol intake in adolescent and adult rats. In the second part, a model with a cage divider inserted during 2-hour drinking sessions was tested and the effects on opioids were examined after 6 weeks of adolescent voluntary intake in single-and pair housed rats, respectively. RESULTS: The effects of single housing were age specific and affected Met-enkephalin-Arg(6) Phe(7) (MEAP) in particular. In adolescent rats, it was difficult to distinguish between effects induced by alcohol and single housing, whereas alcohol-specific effects were seen in dynorphin B (DYNB), beta-endorphin (BEND), and MEAP levels in adults. Voluntary drinking affected several brain areas and the majority of alcohol-induced effects were not dependent on housing. However, alcohol effects on DYNB and BEND in the amygdala were dependent on housing. Housing alone affected MEAP in the cingulate cortex. CONCLUSIONS: Age-specific housing- and alcohol-induced effects on opioids were found. In addition, prolonged voluntary alcohol intake under different housing conditions produced several alcohol-induced effects independent of housing. However, housing-dependent effects were found in areas implicated in stress, emotionality, and alcohol use disorder. Housing condition and age may therefore affect the reasons and underlying mechanisms for drinking and could potentially affect the outcome of a number of end points in research on alcohol intake. PMID- 25515653 TI - Development and validation of a new performance-based measurement of instrumental activities of daily living in Taiwan. AB - BACKGROUND: The performance-based instrumental activities of daily living (IADL) measurement is thought to improve the validity and reliability of conventional tools that rely on proxy reports. The aims of this study were to develop and validate a performance-based measurement of IADL for use in elderly patients with cognitive impairment in Taiwan and other Chinese-speaking communities. METHODS: Referring to current versions of performance-based IADL, we developed the new Taiwan Performance-Based IADL (TPIADL) measurement to minimize literacy dependency and render it compatible with local culture. Participants performed tasks, including finding a telephone number, calculating the correct amount of change, reading the ingredients on a tin of food, finding food items on a shelf, and reading instructions on a medicine container. The internal consistency and convergent and criteria validity of the TPIADL were examined. RESULTS: Altogether, 117 elderly subjects were invited to participate in this study, including 39 patients with dementia due to Alzheimer's disease, 29 with amnestic mild cognitive impairment, and 49 without cognitive impairment. The internal consistency of the TPIADL was 0.82. The TPIADL scores were significantly correlated with the Lawton Instrumental Activities of Daily Living Scale (r = 0.76, P < 0.001). The area under the relative operating characteristic curve was 0.90 (95% confidence interval = 0.84-0.97) to differentiate dementia due to Alzheimer's disease and others. The optimal cut-off point for the TPIADL was 6/7, which gives a sensitivity of 84.6% and a specificity of 75.6%. CONCLUSIONS: The TPIADL is a validated instrument for the measurement of IADL in elderly subjects. It might replace conventional assessment as a valid and easily administered measurement. PMID- 25515654 TI - Vaginal prolapse in a pregnant Maine coon cat: a case report. AB - Vaginal prolapse is a condition characterised by excessive accumulation of mucosal oedema and protrusion of hyperplastic tissue through the vulva. It has been reported in ruminants and canines, but has not been characterised in felines. This report describes the history, clinical signs and treatment of a pregnant Maine coon cat with a Type III vaginal prolapse diagnosed approximately 54 days after the first day of mating. Prior to queening, the prolapse was reduced and retained using a vulvar cruciate suture. Due to the risk of dystocia and recurrence, a caesarean section with ovariohysterectomy was performed. Postoperatively, a stay suture was maintained in the vulva for 2 weeks, resulting in permanent reduction of the vaginal prolapse. To the authors' knowledge, this case represents the first report of the successful management of vaginal prolapse in a pregnant cat. PMID- 25515655 TI - Mass Spectral and Chromatographic Studies on Some Halogenatedphenyl-2 Piperazinopropanones. AB - Gas chromatography-mass spectrometry (GC-MS) studies on the halogenatedphenyl-2 piperazinopropanones (XPPPOs): Twelve XPPPOs were subdivided into four groups of compounds and studied using GC-MS. The four studied groups include the three ring substituted fluorophenylpiperazinopropanones, chlorophenylpiperazinopropanones, bromophenylpiperazinopropanones and trifluoromethylphenylpiperazinopropanones. The three compounds in each group have equal mass and many common mass spectral fragment ions. Perfluoroacylation of the secondary amine nitrogen of these isomeric piperazines gave mass spectra with differences in relative abundance of some fragment ions but acylation did not alter the fragmentation pathway and did not provide additional MS fragments of discrimination among these isomers. The perfluoroacyl derivatives of these piperazines were resolved on a stationary phase of 100% trifluoropropyl methyl polysiloxane (Rtx-200). PMID- 25515656 TI - Role of circulating tumor cells as prognostic marker in resected stage III colorectal cancer. AB - BACKGROUND: The prognostic role of circulating tumor cells (CTC) in early colorectal cancer (CRC) has not been determined yet. We evaluated the potential prognostic value of CTC in stage III CRC patients. PATIENTS AND METHODS: Prospective multicenter study of 519 patients with stage III CRC recruited between January 2009 and June 2010. CTC were enumerated with the CellSearch System after primary tumor resection and before the start of adjuvant therapy. A total of 472 patients were included in the analysis. RESULTS: CTC >=1, >=2, >=3 and >=5 were detected in 166 (35%), 93 (20%), 57 (12%) and 34 (7%) patients, respectively. Median follow-up was 40 months. In the overall population, CTC >=1 (disease-free survival (DFS): HR 0.97, P = 0.85; overall survival (OS): HR 1.03, P = 0.89), >=2 (DFS: HR 1.07, P = 0.76; OS: HR 1.02, P = 0.95), >=3 (DFS: HR 0.96, P = 0.87; OS: HR 0.74, P = 0.41) and >=5 (DFS: HR 0.72, P = 0.39; OS: HR 0.48, P = 0.21) were not associated with worse DFS and OS. No clinicopathological characteristics were significantly associated with the presence of CTC. In patients with disease relapse, the proportion with CTC >=1 was not significantly different between those with single versus multiple metastatic locations (37.9% versus 31.4%, P = 0.761). In the multivariate analysis, CTC >=1 was not an independent prognostic factor for DFS (HR 0.97, P = 0.87) and OS (HR 0.96, P = 0.89). CONCLUSION: CTC detection was not associated with worse DFS and OS in patients with stage III CRC. Given the scarcity of CTC in these patients, it is likely that CTC determined by CellSearch system does not have a prognostic role in this setting. However, a longer follow-up is needed. PMID- 25515657 TI - Neutrophil-to-lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials. AB - BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a marker of host inflammation, has been associated with poor outcome in several solid tumors. Here, we investigated associations of the derived NLR (dNLR) and duration of initial androgen deprivation therapy (ADT) with survival of men with metastatic castration-resistant prostate cancer (mCRPC) receiving first-line chemotherapy. PATIENTS AND METHODS: Data from the multinational randomized phase III studies VENICE and TAX327 included a total of 2230 men with mCRPC randomized to receive first-line chemotherapy, and were used as training and validation sets, respectively. Associations of dNLR and duration of initial ADT with overall survival (OS) were evaluated by multivariable Cox regression analysis in the training set stratified for performance status and treatment arm. The model was then tested in the validation set. Subsequently, we investigated the treatment effect of docetaxel on OS in subgroups according to dNLR and duration of initial ADT. RESULTS: In the training set, both dNLR >=median (2) and duration of initial ADT =2) was associated with shorter survival irrespective of the received treatment. This readily available biomarker may serve for risk stratification in future clinical trials and could be incorporated into prognostic nomograms. CLINICAL TRIALS NUMBER: NCT00519285. PMID- 25515658 TI - Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA-N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy. AB - BACKGROUND: This study compared prophylactic cranial irradiation (PCI) with observation in patients with resected stage IIIA-N2 non-small-cell lung cancer (NSCLC) and high risk of cerebral metastases after adjuvant chemotherapy. PATIENTS AND METHODS: In this open-label, randomized, phase III trial, patients with fully resected postoperative pathologically confirmed stage IIIA-N2 NSCLC and high cerebral metastases risk without recurrence after postoperative adjuvant chemotherapy were randomly assigned to receive PCI (30 Gy in 10 fractions) or observation. The primary end point was disease-free survival (DFS). The secondary end points included the incidence of brain metastases, overall survival (OS), toxicity and quality of life. RESULTS: This trial was terminated early after the random assignment of 156 patients (81 to PCI group and 75 to control group). The PCI group had significantly lengthened DFS compared with the control group, with a median DFS of 28.5 months versus 21.2 months [hazard ratio (HR), 0.67; 95% confidence interval (CI) 0.46-0.98; P = 0.037]. PCI was associated with a decrease in risk of brain metastases (the actuarial 5-year brain metastases rate, 20.3% versus 49.9%; HR, 0.28; 95% CI 0.14-0.57; P < 0.001). The median OS was 31.2 months in the PCI group and 27.4 months in the control group (HR, 0.81; 95% CI 0.56-1.16; P = 0.310). While main toxicities were headache, nausea/vomiting and fatigue in the PCI group, they were generally mild. CONCLUSION: In patients with fully resected postoperative pathologically confirmed stage IIIA-N2 NSCLC and high risk of cerebral metastases after adjuvant chemotherapy, PCI prolongs DFS and decreases the incidence of brain metastases. PMID- 25515661 TI - Improving livestock for agriculture - technological progress from random transgenesis to precision genome editing heralds a new era. AB - Humans have a long history in shaping the genetic makeup of livestock to optimize production and meet growing human demands for food and other animal products. Until recently, this has only been possible through traditional breeding and selection, which is a painstakingly slow process of accumulating incremental gains over a long period. The development of transgenic livestock technology offers a more direct approach with the possibility for making genetic improvements with greater impact and within a single generation. However, initially the technology was hampered by technical difficulties and limitations, which have now largely been overcome by progressive improvements over the past 30 years. Particularly, the advent of genome editing in combination with homologous recombination has added a new level of efficiency and precision that holds much promise for the genetic improvement of livestock using the increasing knowledge of the phenotypic impact of genetic sequence variants. So far not a single line of transgenic livestock has gained approval for commercialization. The step change to genome-edited livestock with precise sequence changes may accelerate the path to market, provided applications of this new technology for agriculture can deliver, in addition to economic incentives for producers, also compelling benefits for animals, consumers, and the environment. PMID- 25515660 TI - Beneficial effects of melatonin in a rat model of sporadic Alzheimer's disease. AB - Melatonin synthesis is disordered in patients with Alzheimer's disease (AD). To determine the role of melatonin in the pathogenesis of AD, suitable animal models are needed. The OXYS rats are an experimental model of accelerated senescence that has also been proposed as a spontaneous rat model of AD-like pathology. In the present study, we demonstrate that disturbances in melatonin secretion occur in OXYS rats at 4 months of age. These disturbances occur simultaneously with manifestation of behavioral abnormalities against the background of neurodegeneration and alterations in hormonal status but before the signs of amyloid-beta accumulation. We examined whether oral administration of melatonin could normalize the melatonin secretion and have beneficial effects on OXYS rats before progression to AD-like pathology. The results showed that melatonin treatment restored melatonin secretion in the pineal gland of OXYS rats as well as the serum levels of growth hormone and IGF-1, the level of BDNF in the hippocampus and the healthy state of hippocampal neurons. Additionally, melatonin treatment of OXYS rats prevented an increase in anxiety and the decline of locomotor activity, of exploratory activity, and of reference memory. Thus, melatonin may be involved in AD progression, whereas oral administration of melatonin could be a prophylactic strategy to prevent or slow down the progression of some features of AD pathology. PMID- 25515659 TI - Spontaneous development of hepatocellular carcinoma with cancer stem cell properties in PR-SET7-deficient livers. AB - PR-SET7-mediated histone 4 lysine 20 methylation has been implicated in mitotic condensation, DNA damage response and replication licensing. Here, we show that PR-SET7 function in the liver is pivotal for maintaining genome integrity. Hepatocyte-specific deletion of PR-SET7 in mouse embryos resulted in G2 phase arrest followed by massive cell death and defect in liver organogenesis. Inactivation at postnatal stages caused cell duplication-dependent hepatocyte necrosis, accompanied by inflammation, fibrosis and compensatory growth induction of neighboring hepatocytes and resident ductal progenitor cells. Prolonged necrotic regenerative cycles coupled with oncogenic STAT3 activation led to the spontaneous development of hepatic tumors composed of cells with cancer stem cell characteristics. These include a capacity to self-renew in culture or in xenografts and the ability to differentiate to phenotypically distinct hepatic cells. Hepatocellular carcinoma in PR-SET7-deficient mice displays a cancer stem cell gene signature specified by the co-expression of ductal progenitor markers and oncofetal genes. PMID- 25515662 TI - Simultaneous targeting of two ligand-binding sites on VEGFR2 using biparatopic Affibody molecules results in dramatically improved affinity. AB - Angiogenesis plays an important role in cancer and ophthalmic disorders such as age-related macular degeneration and diabetic retinopathy. The vascular endothelial growth factor (VEGF) family and corresponding receptors are regulators of angiogenesis and have been much investigated as therapeutic targets. The aim of this work was to generate antagonistic VEGFR2-specific affinity proteins having adjustable pharmacokinetic properties allowing for either therapy or molecular imaging. Two antagonistic Affibody molecules that were cross-reactive for human and murine VEGFR2 were selected by phage and bacterial display. Surprisingly, although both binders independently blocked VEGF A binding, competition assays revealed interaction with non-overlapping epitopes on the receptor. Biparatopic molecules, comprising the two Affibody domains, were hence engineered to potentially increase affinity even further through avidity. Moreover, an albumin-binding domain was included for half-life extension in future in vivo experiments. The best-performing of the biparatopic constructs demonstrated up to 180-fold slower dissociation than the monomers. The new Affibody constructs were also able to specifically target VEGFR2 on human cells, while simultaneously binding to albumin, as well as inhibit VEGF-induced signaling. In summary, we have generated small antagonistic biparatopic Affibody molecules with high affinity for VEGFR2, which have potential for both future therapeutic and diagnostic purposes in angiogenesis-related diseases. PMID- 25515664 TI - The adhesive properties of the Staphylococcus lugdunensis multifunctional autolysin AtlL and its role in biofilm formation and internalization. AB - Although it belongs to the group of coagulase-negative staphylococci, Staphylococcus lugdunensis has been known to cause aggressive courses of native and prosthetic valve infective endocarditis with high mortality similar to Staphylococcus aureus. In contrast to S. aureus, only little is known about the equipment of S. lugdunensis with virulence factors including adhesins and their role in mediating attachment to extracellular matrix and plasma proteins and host cells. In this study, we show that the multifunctional autolysin/adhesin AtlL of S. lugdunensis binds to the extracellular matrix and plasma proteins fibronectin, fibrinogen, and vitronectin as well as to human EA.hy926 endothelial cells. Furthermore, we demonstrate that AtlL also plays an important role in the internalization of S. lugdunensis by eukaryotic cells: The atlL-deficient mutant Mut17 adheres to and becomes internalized by eukaryotic cells to a lesser extent than the isogenic wild-type strain Sl253 and the complemented mutant Mut17 (pCUatlL) shows an increased internalization level in comparison to Mut17. Thus, surface localized AtlL that exhibits a broad binding spectrum also mediates the internalization of S. lugdunensis by eukaryotic cells. We therefore propose an internalization pathway for S. lugdunensis, in which AtlL plays a major role. Investigating the role of AtlL in biofilm formation of S. lugdunensis, Mut17 shows a significantly reduced ability for biofilm formation, which is restored in the complemented mutant. Thus, our data provide evidence for a significant role for AtlL in adherence and internalization processes as well as in biofilm formation of S. lugdunensis. PMID- 25515665 TI - Characterization of three active transposable elements recently inserted in three independent DFR-A alleles and one high-copy DNA transposon isolated from the Pink allele of the ANS gene in onion (Allium cepa L.). AB - Intact retrotransposon and DNA transposons inserted in a single gene were characterized in onions (Allium cepa) and their transcription and copy numbers were estimated in this study. While analyzing diverse onion germplasm, large insertions in the DFR-A gene encoding dihydroflavonol 4-reductase (DFR) involved in the anthocyanin biosynthesis pathway were found in two accessions. A 5,070-bp long terminal repeat (LTR) retrotransposon inserted in the active DFR-A (R4) allele was identified from one of the large insertions and designated AcCOPIA1. An intact ORF encoded typical domains of copia-like LTR retrotransposons. However, AcCOPIA1 contained atypical 'TG' and 'TA' dinucleotides at the ends of the LTRs. A 4,615-bp DNA transposon was identified in the other large insertion. This DNA transposon, designated AcCACTA1, contained an ORF coding for a transposase showing homology with the CACTA superfamily transposable elements (TEs). Another 5,073-bp DNA transposon was identified from the DFR-A (TRN) allele. This DNA transposon, designated AchAT1, belonged to the hAT superfamily with short 4-bp terminal inverted repeats (TIRs). Finally, a 6,258-bp non autonomous DNA transposon, designated AcPINK, was identified in the ANS-p allele encoding anthocyanidin synthase, the next downstream enzyme to DFR in the anthocyanin biosynthesis pathway. AcPINK also possessed very short 3-bp TIRs. Active transcription of AcCOPIA1, AcCACTA1, and AchAT1 was observed through RNA Seq analysis and RT-PCR. The copy numbers of AcPINK estimated by mapping the genomic DNA reads produced by NextSeq 500 were predominantly high compared with the other TEs. A series of evidence indicated that these TEs might have transposed in these onion genes very recently, providing a stepping stone for elucidation of enormously large-sized onion genome structure. PMID- 25515666 TI - Does surgery followed by physiotherapy improve short and long term outcome for patients with atraumatic shoulder instability compared with physiotherapy alone? protocol for a randomized controlled clinical trial. AB - BACKGROUND: Shoulder instability is a common problem affecting young adults. Stabilization surgery followed by physiotherapy rehabilitation has been shown to reduce the chance of further episodes of shoulder dislocation and to improve quality of life in patients who sustain a shoulder dislocation as a result of a high collision trauma, but it is unclear if surgical intervention is beneficial for patients with atraumatic shoulder instability who have structural damage at the shoulder. The aim of this randomized controlled clinical trial is to determine if the addition of surgical intervention to physiotherapy rehabilitation improves outcomes for patients with atraumatic shoulder instability who have sustained soft tissue damage at their joint. METHODS/DESIGN: 140 participants will be recruited. Patients with feelings of insecurity (apprehension) at their shoulder joint, which is not the result of a collision injury, with physical signs of shoulder joint instability will be invited to participate. Consenting participants will undergo arthroscopic investigation of the shoulder joint. Patients with capsulolabral damage will be randomly allocated using a concealed allocation procedure to either stabilization surgery immediately following the arthroscopic examination or no additional surgical procedure. All participants will then receive the same postoperative physiotherapy protocol for up to 6 months. Outcomes (pain, functional impairment and number of shoulder dislocations sustained) will be evaluated prior to surgery and, together with participant-reported improvement, again at 6, 12 and 24 months after randomization. The primary endpoint will be pain and functional impairment at 2 years. Participants, clinical staff (but not surgeons) and assessors will be blind to whether stabilization surgery was performed. Data analysis will be conducted on an intention-to-treat basis with the focus on estimation of the effect. DISCUSSION: This trial will have a direct and immediate impact on clinical decision making by establishing if patients presenting with soft tissue shoulder damage associated with atraumatic shoulder instability should be referred for stabilization surgery before commencing physiotherapy rehabilitation in order to ensure optimal outcome. This in turn will ensure effective, efficient use of scarce health resources to manage this common often disabling musculoskeletal condition. TRIAL REGISTRATION: Study was registered with National Institutes of Health Clinical Trials Protocol Registration System in December 2012.ClinicalTrials.gov Identifier: NCT01751490. PMID- 25515667 TI - DK mini-culotte stenting in the treatment of true coronary bifurcation lesions: a propensity score matching comparison with T-provisional stenting. AB - The conventional culotte technique remains not to be widely used for the treatment of coronary bifurcation lesions due to its inherent drawbacks. Here, we developed a double kissing mini-culotte stenting (DK mini-culotte) and assessed its efficacy and safety by a propensity score matching comparison (PSM) with T provisional stenting. From June 2010 to June 2012, a total of 223 consecutive patients with true coronary bifurcation lesions (TCBLs) were treated with DK mini culotte (91 patients with 92 lesions) or T-provisional stenting (132 patients with 135 lesions). We performed a PSM to correct the confounders from clinical and lesion's characteristics. The primary endpoint was cumulative major adverse cardiac event (MACE) at 1 year including cardiac death, myocardial infarction, and target vessel revascularization or target lesion revascularization (TVR/TLR). The secondary endpoint was the rate of side branch (SB) restenosis at 12 months. After a PSM, there were 66 patients in each group. Additional SB stenting in the T-provisional group was performed in 10 (15.2 %) lesions. The incidence of 1-year cumulative MACE was 4.55 % for the DK mini-culotte versus 13.6 % for T provisional stenting (P = 0.127), the rate of TVR/TLR was 1.52 % for DK mini culotte versus 12.12 % for T-provisional stenting (P = 0.033). The SB binary restenosis rate was 5.6 % in the DK mini-culotte group and 22.4 % in the T provisional group (P = 0.014). In summary, despite that there is no difference in MACE between groups, DK mini-culotte significantly reduce TVR/TLR and SB restenosis in the treatment of true coronary bifurcation lesions. PMID- 25515668 TI - Longitudinal measurement of airway inflammation over one year in children and adults with intermittent asthma. AB - BACKGROUND: Asthma is an inflammatory disease of the airways, but in clinical practice inflammation is rarely monitored. The aim of this study was to assess the level of airway inflammation in steroid naive adult and pediatric patients with intermittent asthma over one year. METHODS: 54 children and 50 adults with intermittent asthma (GINA step 1) were included. On up to 6 visits lung function, airway hyperresponsiveness to methacholine (PC20FEV1), sputum eosinophils and exhaled nitric oxide (FeNO) were assessed. RESULTS: 36 pediatric and 34 adult patients were able to produce at least three adequate sputum samples over the study period and were included into the analysis.In 8 children (22%) the percentage of sputum eosinophils was always below 2.5%. A higher level of eosinophils (>2.5%) was found on at least one visit in 16 (44%) and always >2.5% in 12 children (33%). In the adult group the respective numbers were 14 patients (41%) with always low (<2.5%), 17 (50%) with at least once over 2.5% and three patients (9%) were always above the threshold of 2.5% sputum eosinophils. CONCLUSION: These results demonstrate that a substantial number of children and adults with intermittent asthma under beta-agonist treatment only, have variable or persistently high levels of eosinophilic airway inflammation. Long-term studies are needed to observe the progression of asthma severity in such patient populations. PMID- 25515669 TI - Pharmacodynamic studies of nitrofurantoin against common uropathogens. AB - OBJECTIVES: To determine the pharmacokinetic/pharmacodynamic index that best correlates to nitrofurantoin's antibacterial effect, we studied nitrofurantoin activity against common causative pathogens in uncomplicated urinary tract infection (UTI). METHODS: Five isolates [two Escherichia coli (one isolate producing the ESBL CTX-M-15), two Enterococcus faecium (including one that was vancomycin resistant) and one Staphylococcus saprophyticus] were used. The MICs of nitrofurantoin were determined by Etest. Time-kill curves with different concentrations of nitrofurantoin (based on multiples of isolate-specific MICs) were followed over 24 h. An in vitro kinetic model was used to simulate different time-concentration profiles, exposing E. coli to nitrofurantoin for varying proportions of the dosing interval. The outcome parameters reduction in cfu 0-24 h (Deltacfu0-24) and the area under the bactericidal curve (AUBC), were correlated with time over MIC (T>MIC) and area under the antibiotic concentration curve divided by the MIC (AUC/MIC). RESULTS: A bactericidal effect at varying static drug concentrations was achieved for all isolates. All isolates showed similar kill curve profiles. In the kinetic model, the effect of nitrofurantoin on E. coli displayed a 4 log reduction in cfu/mL within 6 h at 8 * MIC. The outcome parameters Deltacfu0-24 and AUBC had a good correlation with T>MIC (R ~ 0.83 and R ~ 0.67, respectively), whereas log(AUC/MIC) was significantly poorer (R ~ 0.39 and R ~ 0.53, respectively). CONCLUSIONS: Nitrofurantoin was highly effective against E. coli and S. saprophyticus isolates; the killing effect against E. faecium was not as rapid, but still significant. Against E. coli, nitrofurantoin was mainly associated with a concentration-dependent action; this was confirmed in the kinetic model, in which T>MIC displayed the best correlation. PMID- 25515670 TI - Silent night: retrospective database study assessing possibility of "weekend effect" in palliative care. AB - OBJECTIVE: To compare the mortality of patients in a palliative care unit on working days with that on weekends and public holidays. DESIGN: Retrospective database study. SETTING: Palliative care unit in Germany. POPULATION: All admissions to palliative care unit between 1 January 1997 and 31 December 2008. MAIN OUTCOME MEASURE: The impact of day type (working days or weekends and public holidays) on mortality was analysed using Poisson regression models. RESULTS: A total of 2565 admitted patients and 1325 deaths were recorded. Of the deaths, 448 (33.8%) occurred on weekends and public holidays. The mortality rate on weekends and public holidays was 18% higher than that on working days (mortality rate ratio 1.18, 95% confidence interval 1.05 to 1.32; P=0.005). CONCLUSION: Patients in the palliative care unit were at higher risk of dying on weekends and public holidays. In the absence of a prospective study, the exact reasons for this correlation are unclear. PMID- 25515671 TI - Inattentional blindness reflects limitations on perception, not memory: Evidence from repeated failures of awareness. AB - Perhaps the most striking phenomenon of visual awareness is inattentional blindness (IB), in which a surprisingly salient event right in front of you may go completely unseen when unattended. Does IB reflect a failure of perception, or only of subsequent memory? Previous work has been unable to answer this question, due to a seemingly intractable dilemma: ruling out memory requires immediate perceptual reports, but soliciting such reports fuels an expectation that eliminates IB. Here we introduce a way of evoking repeated IB in the same subjects and the same session: we show that observers fail to report seeing salient events' not only when they have no expectation, but also when they have the wrong expectations about the events nature. This occurs when observers must immediately report seeing anything unexpected, even mid-event. Repeated IB thus demonstrates that IB is aptly named: it reflects a genuine deficit in moment-by moment conscious perception, rather than a form of inattentional amnesia. PMID- 25515672 TI - Why does the sense of smell vanish in the mouth? Testing predictions from two accounts. AB - When participants perceive flavor they do not recognise the role of smell. We examined two possible accounts of why: (1) a common attentional channel activated by taste; and (2) prior learning between taste and smell. Participants were asked to sniff food-related odors with a fluid in their mouth and profile each odor after expectorating. This process was later repeated for each odor, with some odors experienced with water on both occasions, and others with water on one occasion and sucrose (weak or strong) on the other. We investigated how reliable these odor profiles were and whether they were influenced by prior odor-taste learning (indexed by odor sweetness). For non-sweet smells, the presence of a tastant significantly improved profile reliability relative to water in the mouth. For sweet smells, tastant had no effect, which we suggest represents a cancelling out of the beneficial effects of the common attentional channel by the detrimental effects of prior learning. Thus, both mechanisms may contribute to masking the modal identity of smell thereby contributing to flavor binding. PMID- 25515673 TI - Pressure-induced metathesis reaction to sequester Cs. AB - We report here a pressure-driven metathesis reaction where Ag-exchanged natrolite (Ag16Al16Si24O80.16H2O, Ag-NAT) is pressurized in an aqueous CsI solution, resulting in the exchange of Ag(+) by Cs(+) in the natrolite framework forming Cs16Al16Si24O80.16H2O (Cs-NAT-I) and, above 0.5 GPa, its high-pressure polymorph (Cs-NAT-II). During the initial cation exchange, the precipitation of AgI occurs. Additional pressure and heat at 2 GPa and 160 degrees C transforms Cs-NAT-II to a pollucite-related, highly dense, and water-free triclinic phase with nominal composition CsAlSi2O6. At ambient temperature after pressure release, the Cs remains sequestered in a now monoclinic pollucite phase at close to 40 wt % and a favorably low Cs leaching rate under back-exchange conditions. This process thus efficiently combines the pressure-driven separation of Cs and I at ambient temperature with the subsequent sequestration of Cs under moderate pressures and temperatures in its preferred waste form suitable for long-term storage at ambient conditions. The zeolite pollucite CsAlSi2O6.H2O has been identified as a potential host material for nuclear waste remediation of anthropogenic (137)Cs due to its chemical and thermal stability, low leaching rate, and the large amount of Cs it can contain. The new water-free pollucite phase we characterize during our process will not display radiolysis of water during longterm storage while maintaining the Cs content and low leaching rate. PMID- 25515675 TI - A cautionary note in the interpretation of human papillomavirus E6 immunohistochemistry in focal cortical dysplasia. PMID- 25515677 TI - Screening for the ADHD Phenotype Using the Strengths and Difficulties Questionnaire in a Clinical Sample of Newly Referred Children and Adolescents. AB - OBJECTIVE: To examine the screening ability of the Strengths and Difficulties Questionnaire (SDQ) for ADHD subtypes in a clinical sample. METHOD: Parents of 523 children (3 to 17 years old) referred to Child and Adolescent Mental Health Services completed the Spanish version of the SDQ and the ADHD Rating Scale-IV. Receiver operating curve (ROC) curve analyses and likelihood ratios (LRs) were conducted. RESULTS: The LR results indicated that the 8/10 cutoff showed the highest diagnostic accuracy. The sensitivity of the SDQ 8/10 cutoff for the three subtypes was significantly different: 84.0% (95% confidence interval [CI] = [75.58, 89.90]) of ADHD combined subtype (ADHD-Co), 25.0% (95% CI = [17.55, 34.30]) of ADHD predominantly inattentive subtype (ADHD-I), and 77.8% (95% CI = [68.71, 84.83]) of ADHD predominantly hyperactive/impulsive subtype (ADHD-H). Sex and age differences were found. These screening differences were also found when using the 7/10 cutoff or the SDQ predictive algorithm. CONCLUSION: Our study supports the use of the SDQ in the screening for ADHD. However, not all ADHD subtypes are equally screened. PMID- 25515676 TI - Does diffusion-weighted imaging improve therapy response evaluation in patients with hepatocellular carcinoma after radioembolization? comparison of MRI using Gd EOB-DTPA with and without DWI. AB - PURPOSE: To investigate whether additional diffusion-weighted imaging (DWI) improves therapy response evaluation by Gd-EOB magnetic resonance imaging (MRI) in hepatocellular carcinoma (HCC) after radioembolization. MATERIALS AND METHODS: Fifty patients with radioembolization for HCC underwent gadobutrol and Gd-EOB MRI with DWI prior to and 30, 90, and 180 days after radioembolization. A combination of gadobutrol MRI, alpha-fetoprotein, and imaging follow-up served as the reference standard. Two radiologists reviewed Gd-EOB alone (Gd-EOB), DWI alone (DWI), and the combination of both (Gd-EOB+DWI) separately and in consensus using a 4-point-scale: 1 = definitely no tumor progression (TP), 2 = probably no TP, 3 = probably TP, 4 = definitely TP. Receiver operating characteristic (ROC) and kappa analysis were performed. RESULTS: Kappa values for Gd-EOB, DWI, and Gd EOB+DWI ranged between 0.712 and 0.892 (P < 0.001). 30 days after radioembolization three out of 38 patients showed TP, which was missed by DWI in one case. No significant area under the curve (AUC) difference between Gd-EOB (1.0, P = 0.004), DWI (0.881, P = 0.030), and Gd-EOB+DWI (1.0, P = 0.004) was found (P = 0.320). 90 days after radioembolization six out of 28 patients showed TP, which was detected in one patient only by DWI and Gd-EOB+DWI. The AUC did not differ significantly (P = 0.319) between Gd-EOB (0.890, P = 0.004), DWI (1.0, P < 0.001), and Gd-EOB+DWI (1.0, P < 0.001). 180 days after radioembolization five patients showed TP, which in one case was missed by DWI. The AUC did not differ significantly (P1 = 0.322, P2 = 0.369, P3 = 0.350) between Gd-EOB (1.0, P = 0.003), DWI (0.913, P = 0.016), and Gd-EOB+DWI (0.963, P = 0.007). CONCLUSION: Additional DWI does not substantially improve therapy response evaluation by Gd EOB MRI in HCC after radioembolization but proved helpful in single cases. PMID- 25515678 TI - ADHD Dimensions and Sluggish Cognitive Tempo Symptoms in Relation to Self-Report and Laboratory Measures of Neuropsychological Functioning in College Students. AB - OBJECTIVE: This study examined ADHD and sluggish cognitive tempo (SCT) symptoms in relation to self-report and laboratory measures of neuropsychological functioning in college students. METHOD: College students ( N = 298, aged 17-25, 72% female) completed self-reports of ADHD, SCT, depression, sleep, functional impairment, and executive functioning (EF). Participants also completed a visual working memory task, a Stroop test, and the Conners' Continuous Performance Test II (CPT-II). RESULTS: ADHD inattentive and SCT symptoms were strong predictors of self-reported EF, with inattention the strongest predictor of Time Management and Motivation and SCT the strongest predictor of Self-Organization/Problem Solving. SCT (but not inattention) was associated with Emotion Regulation. No relationships were found between self-reported symptoms and laboratory task performance. Between-group analyses were largely consistent with regression analyses. CONCLUSION: Self-reported ADHD and SCT symptoms are strongly associated with college students' self-reported EF, but relationships with laboratory task measures of neuropsychological functioning are limited. PMID- 25515679 TI - Temperament and Character Traits of Parents of Children With ADHD. AB - OBJECTIVE: This study investigates the relationship between ADHD and the personalities of parents of children with ADHD. METHOD: Personality traits of parents of children with ADHD (study group; n = 135) and parents of children without ADHD (control group; n = 122) were compared. Psychiatric comorbidities were excluded with Structured Clinical Interview for DSM-IV Axis I Disorders, Clinical Version [SCID-I-CV]. Personality is assessed with Temperament and Character Inventory, and inattention (IA) and hyperactivity (HI) are assessed with Turgay Scale. RESULTS: Harm avoidance and persistence scores were higher, and self-directedness (SD) scores were lower in the study group than the control group. Being in ADHD group predicted lower SD scores. Positive correlations were found between harm avoidance and IA and HI, and between persistence and HI. Negative correlations were found between SD and both IA and HI. CONCLUSION: Our data suggest that there is relationship between ADHD in children's and parents' personalities. Common etiologic properties and personalized psychoeducation and treatment options for families should be discussed. PMID- 25515680 TI - Sex dependent risk factors for mortality after myocardial infarction: individual patient data meta-analysis. AB - BACKGROUND: Although a number of risk factors are known to predict mortality within the first years after myocardial infarction, little is known about interactions between risk factors, whereas these could contribute to accurate differentiation of patients with higher and lower risk for mortality. This study explored the effect of interactions of risk factors on all-cause mortality in patients with myocardial infarction based on individual patient data meta analysis. METHODS: Prospective data for 10,512 patients hospitalized for myocardial infarction were derived from 16 observational studies (MINDMAPS). Baseline measures included a broad set of risk factors for mortality such as age, sex, heart failure, diabetes, depression, and smoking. All two-way and three-way interactions of these risk factors were included in Lasso regression analyses to predict time-to-event related all-cause mortality. The effect of selected interactions was investigated with multilevel Cox regression models. RESULTS: Lasso regression selected five two-way interactions, of which four included sex. The addition of these interactions to multilevel Cox models suggested differential risk patterns for males and females. Younger women (age<50) had a higher risk for all-cause mortality than men in the same age group (HR 0.7 vs. 0.4), while men had a higher risk than women if they had depression (HR 1.4 vs. 1.1) or a low left ventricular ejection fraction (HR 1.7 vs. 1.3). Predictive accuracy of the Cox model was better for men than for women (area under the curves: 0.770 vs. 0.754). CONCLUSIONS: Interactions of well-known risk factors for all-cause mortality after myocardial infarction suggested important sex differences. This study gives rise to a further exploration of prediction models to improve risk assessment for men and women after myocardial infarction. PMID- 25515681 TI - Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. AB - Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P-glycoprotein) and can reduce the efficacy of co-administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses >= 200 mg/day) and perampanel (at doses >= 8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen-containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs. PMID- 25515682 TI - Tumor necrosis factor mediates temporomandibular joint bone tissue resorption in rheumatoid arthritis. AB - OBJECTIVE: To investigate if TNF, IL-1 or their endogenous controls, in relation to ACPA, are associated with radiological signs of ongoing temporomandibular joint (TMJ) bone tissue resorption and disc displacement in RA patients. METHODS: Twenty-two consecutive outpatients with TMJ of RA were included. Systemic inflammatory activity was assessed by DAS28. The number of painful regions in the body and ESR, CRP, RF and ACPA were analyzed. TMJ synovial fluid and blood samples were obtained and analyzed for TNF, TNFsRII, IL-1ra, IL-1sRII and ACPA. The ratios between the mediators and their endogenous control receptors were used in the statistical analysis. Magnetic resonance imaging was performed in closed- and open-mouth positions and evaluated regarding disc position and presence of condylar and temporal erosions of the TMJ. RESULTS: A high TNF level in relation to TNFsRII in TMJ synovial fluid correlated to the degree of TMJ condylar erosion. A high IL-1ra level in relation to TNF in TMJ synovial fluid was also correlated to the degree of TMJ condylar erosion. The total degree of TMJ condylar erosion was correlated with the number of painful regions. CONCLUSION: This study indicates that TNF in TMJ synovial fluid mediates TMJ cartilage and bone tissue resorption in RA. The study also suggests that the degree of endogenous cytokine control is of importance for development of bone tissue destruction. PMID- 25515683 TI - Biotransformation of agallochaexcoerin A by Aspergillus flavus. AB - Agallochaexcoerin A (1), a seco-manoyl oxide diterpenoid was metabolised by pathogenic fungus, Aspergillus flavus, in growth media to yield a new metabolite, termed agallochaexcoerin G (2). It was confirmed by using IR, UV, (1)H NMR and HR ESI-MS techniques. This microbial bioconversion was achieved by unusual dehydration at C-4 position. PMID- 25515686 TI - Reconstruction of limnology and microbialite formation conditions from carbonate clumped isotope thermometry. AB - Quantitative tools for deciphering the environment of microbialite formation are relatively limited. For example, the oxygen isotope carbonate-water geothermometer requires assumptions about the isotopic composition of the water of formation. We explored the utility of using 'clumped' isotope thermometry as a tool to study the temperatures of microbialite formation. We studied microbialites recovered from water depths of 10-55 m in Pavilion Lake, and 10-25 m in Kelly Lake, spanning the thermocline in both lakes. We determined the temperature of carbonate growth and the (18)O/(16)O ratio of the waters that microbialites grew in. Results were then compared to current limnological data from the lakes to reconstruct the history of microbialite formation. Modern microbialites collected at shallow depths (11.7 m) in both lakes yield clumped isotope-based temperatures of formation that are within error of summer water temperatures, suggesting that clumped isotope analyses may be used to reconstruct past climates and to probe the environments in which microbialites formed. The deepest microbialites (21.7-55 m) were recovered from below the present-day thermoclines in both lakes and yield radioisotope ages indicating they primarily formed earlier in the Holocene. During this time, pollen data and our reconstructed water (18)O/(16)O ratios indicate a period of aridity, with lower lake levels. At present, there is a close association between both photosynthetic and heterotrophic communities, and carbonate precipitation/microbialite formation, with biosignatures of photosynthetic influences on carbonate detected in microbialites from the photic zone and above the thermocline (i.e., depths of generally <20 m). Given the deeper microbialites are receiving <1% of photosynthetically active radiation (PAR), it is likely these microbialites primarily formed when lower lake levels resulted in microbialites being located higher in the photic zone, in warm surface waters. PMID- 25515684 TI - 454 screening of individual MHC variation in an endemic island passerine. AB - Genes of the major histocompatibility complex (MHC) code for receptors that are central to the adaptive immune response of vertebrates. These genes are therefore important genetic markers with which to study adaptive genetic variation in the wild. Next-generation sequencing (NGS) has increasingly been used in the last decade to genotype the MHC. However, NGS methods are highly prone to sequencing errors, and although several methodologies have been proposed to deal with this, until recently there have been no standard guidelines for the validation of putative MHC alleles. In this study, we used the 454 NGS platform to screen MHC class I exon 3 variation in a population of the island endemic Berthelot's pipit (Anthus berthelotii). We were able to characterise MHC genotypes across 309 individuals with high levels of repeatability. We were also able to determine alleles that had low amplification efficiencies, whose identification within individuals may thus be less reliable. At the population level we found lower levels of MHC diversity in Berthelot's pipit than in its widespread continental sister species the tawny pipit (Anthus campestris), and observed trans-species polymorphism. Using the sequence data, we identified signatures of gene conversion and evidence of maintenance of functionally divergent alleles in Berthelot's pipit. We also detected positive selection at 10 codons. The present study therefore shows that we have an efficient method for screening individual MHC variation across large datasets in Berthelot's pipit, and provides data that can be used in future studies investigating spatio-temporal patterns and scales of selection on the MHC. PMID- 25515687 TI - Acquired superoxide-scavenging ability of ceria nanoparticles. AB - Ceria nanoparticles (nanoceria) are well known as a superoxide scavenger. However, inherent superoxide-scavenging ability has only been found in the nanoceria with sizes of less than 5 nm and with very limited shape diversity. Reported herein is a strategy to significantly improve the superoxide-scavenging activity of nanoceria sized at greater than 5 nm. The nanoceria with sizes of greater than 5 nm, with different shapes, and with a negligible Ce(3+)/Ce(4+) ratio can acquire remarkable superoxide-scavenging abilities through electron transfer. This method will make it possible to develop nanoceria-based superoxide scavengers with long-acting activity and tailorable characteristics. PMID- 25515685 TI - Inhibitory effects of astaxanthin on azoxymethane-induced colonic preneoplastic lesions in C57/BL/KsJ-db/db mice. AB - BACKGROUND: Obesity and related metabolic abnormalities, including excess oxidative stress and chronic inflammation, are associated with colorectal carcinogenesis. Astaxanthin, a xanthophyll carotenoid found in aquatic animals, is known to possess antioxidant, anti-inflammatory, and antineoplastic properties. The present study examined the effects of astaxanthin on the development of azoxymethane (AOM)-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. METHOD: Male db/db mice were administered 4 weekly subcutaneous injections of AOM (15 mg/kg body weight) from 5 weeks of age and subsequently, from 1 week after the last injection of AOM, were fed a diet containing 200 ppm astaxanthin throughout the experiment (8 weeks). RESULT: The development of colonic premalignant lesions, i.e., aberrant crypt foci and beta catenin accumulated crypts, was significantly inhibited in mice treated with astaxanthin than in mice fed the basal diet. Astaxanthin administration markedly reduced urinary levels of 8-OHdG and serum levels of d-ROMs, which are oxidative stress markers, while increasing the expression of mRNA for the antioxidant enzymes GPx1, SOD1, and CAT in the colonic mucosa of AOM-treated db/db mice. The expression levels of IL-1beta, IL-6, F4/80, CCL2, and CXCL2 mRNA in the colonic mucosa of AOM-treated mice were significantly decreased by astaxanthin. Dietary feeding with astaxanthin also resulted in a reduction in the numbers of NF-kappaB and PCNA-positive cells that were increased by AOM exposure, in the colonic epithelium. CONCLUSION: These findings suggest that astaxanthin inhibits the development of colonic premalignant lesions in an obesity-related colorectal carcinogenesis model by reducing oxidative stress, attenuating chronic inflammation, and inhibiting NF-kappaB activation and cell proliferation in the colonic mucosa. Astaxanthin, therefore, may be a potential candidate as a chemoprevention agent against colorectal carcinogenesis in obese individuals. PMID- 25515688 TI - Hemoglobinopathy screening by osmotic fragility test based on flow cytometer or naked eye. AB - BACKGROUND: Diagnosis of hemoglobin (Hb) disorders is based mostly on abnormal red blood cell (RBC) indices, elevated levels of HbA2, HbF, or any other Hb on the Variant high performance liquid chromatography (HPLC) system, and confirmation by molecular methods. However, large scale population screening is of prime importance and requires a simple, accurate, and cost effective technique. We have tried to compare the sensitivity of the widely used Naked Eye Single Tube Red Cell Osmotic Fragility Test (NESTROFT) and the osmotic fragility described as % residual RBCs through flow cytometry for population screening. METHODS: The count of residual red cells was measured sequentially in real-time using flow cytometry. NESTROFT was performed using a 0.36% buffered saline. HbA2 and HbF levels along with other abnormal Hbs were determined on the Variant HPLC System. Molecular studies were done to confirm the diagnosis. RESULTS: The normal group showed a significantly lower percentage of residual RBCs (48.08 +/- 11.87) as compared to cases (beta thalassemia trait-82.97 +/- 12.20, alpha thalassemia trait-72.58 +/- 8.34, and HbS trait-85.00 +/- 4.05). The sensitivity and specificity of NESTROFT was high for both beta thalassemia traits (98.33 and 96.72%, respectively) and alpha thalassemia traits (100 and 96.72%, respectively) but very low sensitivity for HbS traits (54.84%). CONCLUSION: Flow cytometric osmotic fragility was a more sensitive method to discriminate normal from the group of hemoglobinopathy carriers as compared to NESTROFT which missed majority of HbS carriers. However, in view of feasibility and cost effectiveness, NESTROFT could still be used for population screening of thalassemia. (c) 2014 International Clinical Cytometry Society. PMID- 25515689 TI - Electronic cigarettes for smoking cessation and reduction. AB - BACKGROUND: Electronic cigarettes (ECs) are electronic devices that heat a liquid - usually comprising propylene glycol and glycerol, with or without nicotine and flavours, stored in disposable or refillable cartridges or a reservoir - into an aerosol for inhalation. Since ECs appeared on the market in 2006 there has been a steady growth in sales. Smokers report using ECs to reduce risks of smoking, but some healthcare organisations have been reluctant to encourage smokers to switch to ECs, citing lack of evidence of efficacy and safety. Smokers, healthcare providers and regulators are interested to know if these devices can reduce the harms associated with smoking. In particular, healthcare providers have an urgent need to know what advice they should give to smokers enquiring about ECs. OBJECTIVES: To examine the efficacy of ECs in helping people who smoke to achieve long-term abstinence; to examine the efficacy of ECs in helping people reduce cigarette consumption by at least 50% of baseline levels; and to assess the occurrence of adverse events associated with EC use. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Groups Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and two other databases for relevant records from 2004 to July 2014, together with reference checking and contact with study authors. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which current smokers (motivated or unmotivated to quit) were randomized to EC or a control condition, and which measured abstinence rates or changes in cigarette consumption at six months or longer. As the field of EC research is new, we also included cohort follow-up studies with at least six months follow-up. We included randomized cross-over trials and cohort follow-up studies that included at least one week of EC use for assessment of adverse events. DATA COLLECTION AND ANALYSIS: One review author extracted data from the included studies and another checked them. Our main outcome measure was abstinence from smoking after at least six months follow-up, and we used the most rigorous definition available (continuous, biochemically validated, longest follow-up). For reduction we used a dichotomous approach (no change/reduction < 50% versus reduction by 50% or more of baseline cigarette consumption). We used a fixed-effect Mantel-Haenszel model to calculate the risk ratio (RR) with a 95% confidence interval (CI) for each study, and where appropriate we pooled data from these studies in meta-analyses. MAIN RESULTS: Our search identified almost 600 records, from which we include 29 representing 13 completed studies (two RCTs, 11 cohort). We identified nine ongoing trials. Two RCTs compared EC with placebo (non-nicotine) EC, with a combined sample size of 662 participants. One trial included minimal telephone support and one recruited smokers not intending to quit, and both used early EC models with low nicotine content. We judged the RCTs to be at low risk of bias, but under the GRADE system the overall quality of the evidence for our outcomes was rated 'low' or 'very low' because of imprecision due to the small number of trials. A 'low' grade means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. A 'very low' grade means we are very uncertain about the estimate. Participants using an EC were more likely to have abstained from smoking for at least six months compared with participants using placebo EC (RR 2.29, 95% CI 1.05 to 4.96; placebo 4% versus EC 9%; 2 studies; GRADE: low). The one study that compared EC to nicotine patch found no significant difference in six-month abstinence rates, but the confidence intervals do not rule out a clinically important difference (RR 1.26, 95% CI: 0.68 to 2.34; GRADE: very low). A higher number of people were able to reduce cigarette consumption by at least half with ECs compared with placebo ECs (RR 1.31, 95% CI 1.02 to 1.68, 2 studies; placebo: 27% versus EC: 36%; GRADE: low) and compared with patch (RR 1.41, 95% CI 1.20 to 1.67, 1 study; patch: 44% versus EC: 61%; GRADE: very low). Unlike smoking cessation outcomes, reduction results were not biochemically verified.None of the RCTs or cohort studies reported any serious adverse events (SAEs) that were considered to be plausibly related to EC use. One RCT provided data on the proportion of participants experiencing any adverse events. Although the proportion of participants in the study arms experiencing adverse events was similar, the confidence intervals are wide (ECs vs placebo EC RR 0.97, 95% CI 0.71 to 1.34; ECs vs patch RR 0.99, 95% CI 0.81 to 1.22). The other RCT reported no statistically significant difference in the frequency of AEs at three- or 12-month follow-up between the EC and placebo EC groups, and showed that in all groups the frequency of AEs (with the exception of throat irritation) decreased significantly over time. AUTHORS' CONCLUSIONS: There is evidence from two trials that ECs help smokers to stop smoking long-term compared with placebo ECs. However, the small number of trials, low event rates and wide confidence intervals around the estimates mean that our confidence in the result is rated 'low' by GRADE standards. The lack of difference between the effect of ECs compared with nicotine patches found in one trial is uncertain for similar reasons. ECs appear to help smokers unable to stop smoking altogether to reduce their cigarette consumption when compared with placebo ECs and nicotine patches, but the above limitations also affect certainty in this finding. In addition, lack of biochemical assessment of the actual reduction in smoke intake further limits this evidence. No evidence emerged that short-term EC use is associated with health risk. PMID- 25515690 TI - Total mercury content in cultured oysters from NW Mexico: health risk assessment. AB - The total mercury (Hg) content of the soft tissues of cultured oysters of the genus Crassostrea obtained during the dry and rainy seasons at sampling sites of NW Mexico with different degrees of urbanization, was determined by cold vapor atomic absorption spectrophotometry. Hg levels ranged from 0.05 to 0.37 ug/g (dry weight) and no significant differences (p > 0.05) related to season and sampling site were observed. The values did not exceed the limit of 1.0 ug/g (wet weight) established by Mexican legislation and by the Food and Drug Agency (FDA), and the hazard quotient was between 0.001 and 0.002. The estimated hazard quotient for MeHg ranged approximately from 0.002 to 0.01. PMID- 25515691 TI - Polycyclic aromatic hydrocarbons (PAHs) and n-alkanes in beaked sea snake Enhydrina schistose (Daudin, 1803) from the Mandovi estuary, Goa. AB - An ecotoxicological study were conducted to evaluate the concentrations of PAHs and n-alkanes, in gut, liver and kidney tissues of two individuals of Enhydrina schistose (Daudin, 1803), using gas chromatography/mass spectrometry. The concentrations of PAHs (0.10 ug/g) and n-alkanes (8.12 ug/g) were elevated in the gut, and liver (PAHs 0.05 ug/g tissue, n-alkanes 29.16 ug/g tissue). In kidney of both specimen-A and B the PAHs (0.01 and 0.1 ug/g) and n-alkanes (0.22 and 2.06 ug/g) concentration was detected. This was an initial survey (n = 2) and the main goal was to know accumulation and distribution of PAHs and n-alkanes in the sea snakes. This study indicates high accumulation of petroleum hydrocarbon in gut, liver and kidney of sea snake. Since, this species also act as pray for sea eagles and some predatory fishes such as tiger shark, there is high possibilities of PAHs being circulated in marine food chain. PMID- 25515692 TI - Pseudoephedrine and circadian rhythm interaction on neuromuscular performance. AB - This study analyzed the effects of pseudoephedrine (PSE) provided at different time of day on neuromuscular performance, side effects, and violation of the current doping cut-off threshold [World Anti-Doping Agency (WADA)]. Nine resistance-trained males carried out bench press and full squat exercises against four incremental loads (25%, 50%, 75%, and 90% one repetition maximum [1RM]), in a randomized, double-blind, cross-over design. Participants ingested either 180 mg of PSE (supra-therapeutic dose) or placebo in the morning (7:00 h; AM(PLAC) and AM(PSE)) and in the afternoon (17:00 h; PM(PLAC) and PM(PSE)). PSE enhanced muscle contraction velocity against 25% and 50% 1RM loads, only when it was ingested in the mornings, and only in the full squat exercise (4.4-8.7%; P < 0.05). PSE ingestion raised urine and plasma PSE concentrations (P < 0.05) regardless of time of day; however, cathine only increased in the urine samples. PSE ingestion resulted in positive tests occurring in 11% of samples, and it rose some adverse side effects such us tachycardia and heart palpitations. Ingestion of a single dose of 180 mg of PSE results in enhanced lower body muscle contraction velocity against low and moderate loads only in the mornings. These mild performance improvements are accompanied by undesirable side effects and an 11% risk of surpassing the doping threshold. PMID- 25515693 TI - Right ventricular myxoma obstructing the right ventricular outflow tract: a case report. AB - INTRODUCTION: Primary cardiac tumors are uncommon during infancy and childhood. Myxomas originating from the right ventricle are even less common in pediatric patients. CASE PRESENTATION: Here we describe a case of an 11-year-old Tunisian boy who was referred for syncope. Transthoracic echocardiography revealed a large mobile mass attached to his right ventricle, obstructing his right ventricular outflow tract. Complete surgical excision of the mass with preservation of the pulmonary valve was performed. The diagnosis of myxoma was histologically confirmed. CONCLUSION: Cardiac myxomas located in the right ventricular outflow tract are rare and can present unusual diagnostic and therapeutic challenges. PMID- 25515695 TI - Transition metal complex assisted Csp3-F bond formation. AB - Fluoroorganic compounds have attracted significant attention in various fields, such as pharmaceutical, agricultural chemistry, and materials science, as a result of their unique physical, chemical, and physiological properties. Consequently, extensive efforts have been devoted to the site-specific synthesis of organofluorine compounds. In recent years, transition-metal-mediated C-F bond formation has emerged as a powerful method for fabrication of these compounds. this Perspective mainly focuses on the most recent advances in transition-metal assisted synthesis of alkyl fluorides. PMID- 25515694 TI - Totally minimally invasive Ivor-Lewis esophagectomy with single-utility incision video-assisted thoracoscopic surgery for treatment of mid-lower esophageal cancer. AB - The study aims to evaluate the safety and availability of totally minimally invasive Ivor-Lewis esophagectomy (MIIE) with single-utility incision video assisted thoracoscopic surgery. Forty-one patients with mid-lower thoracic esophageal cancer were prospectively treated with totally MIIE. Two stages of laparoscopic-thoracoscopic procedures were performed. The first 29 patients were treated with four-port video-assisted thoracoscopic surgery (Group 1); the others were treated with single-utility incision video-assisted thoracoscopic surgery (Group 2). Short-term clinicopathological outcomes were examined. All patients had negative tumor margins and were pathologically staged from T1N0M0 to T3N2M0. Among Group 1, there was one conversion to open surgery. The mean duration of surgery was 268.4 +/- 37.8 minutes, and mean blood loss was 207.2 +/- 74.1 mL without significant differences between groups. The average thoracic or abdominal lymph node yield was 12.6 +/- 7.1 or 6 +/- 5.8, respectively. The median postoperative hospital stay was 7 days. No mortalities occurred. Minor morbidity complicated by late-stage gastroparesis occurred in two patients (4.9%) after discharge. Major morbidities, including intestinal obstruction and anastomotic leakage, occurred in three patients (7.3%) after discharge. Among Group 2, the average operative duration was 275.4 +/- 31.2 minutes, and the mean blood loss was 220 +/- 94.9 mL. One patient developed late-stage anastomotic leakage. The average thoracic or abdominal lymph node yield was 14.7 +/- 8.8 and 6.3 +/- 5.7, respectively. No statistically significant differences were identified between Group 1 and Group 2. MIIE with single-utility incision video-assisted thoracoscopic surgery is feasible in patients with mid-lower thoracic esophageal cancer without compromising the extent of surgical resection and perioperative outcomes. PMID- 25515696 TI - Rice phenylalanine ammonia-lyase gene OsPAL4 is associated with broad spectrum disease resistance. AB - Most agronomically important traits, including resistance against pathogens, are governed by quantitative trait loci (QTL). QTL-mediated resistance shows promise of being effective and long-lasting against diverse pathogens. Identification of genes controlling QTL-based disease resistance contributes to breeding for cultivars that exhibit high and stable resistance. Several defense response genes have been successfully used as good predictors and contributors to QTL-based resistance against several devastating rice diseases. In this study, we identified and characterized a rice (Oryza sativa) mutant line containing a 750 bp deletion in the second exon of OsPAL4, a member of the phenylalanine ammonia lyase gene family. OsPAL4 clusters with three additional OsPAL genes that co localize with QTL for bacterial blight and sheath blight disease resistance on rice chromosome 2. Self-pollination of heterozygous ospal4 mutant lines produced no homozygous progeny, suggesting that homozygosity for the mutation is lethal. The heterozygous ospal4 mutant line exhibited increased susceptibility to three distinct rice diseases, bacterial blight, sheath blight, and rice blast. Mutation of OsPAL4 increased expression of the OsPAL2 gene and decreased the expression of the unlinked OsPAL6 gene. OsPAL2 function is not redundant because the changes in expression did not compensate for loss of disease resistance. OsPAL6 co-localizes with a QTL for rice blast resistance, and is down-regulated in the ospal4 mutant line; this may explain enhanced susceptibility to Magnoporthe oryzae. Overall, these results suggest that OsPAL4 and possibly OsPAL6 are key contributors to resistance governed by QTL and are potential breeding targets for improved broad spectrum disease resistance in rice. PMID- 25515699 TI - Contribution of neovascularization and intraplaque haemorrhage to atherosclerotic plaque progression and instability. AB - Atherosclerosis is a continuous pathological process that starts early in life and progresses frequently to unstable plaques. Plaque rupture leads to deleterious consequences such as acute coronary syndrome, stroke and atherothrombosis. The vulnerable lesion has several structural and functional hallmarks that distinguish it from the stable plaque. The unstable plaque has large necrotic core (over 40% plaque volume) composed of cholesterol crystals, cholesterol esters, oxidized lipids, fibrin, erythrocytes and their remnants (haeme, iron, haemoglobin), and dying macrophages. The fibrous cap is thin, depleted of smooth muscle cells and collagen, and is infiltrated with proinflammatory cells. In unstable lesion, formation of neomicrovessels is increased. These neovessels have weak integrity and leak thereby leading to recurrent haemorrhages. Haemorrhages deliver erythrocytes to the necrotic core where they degrade promoting inflammation and oxidative stress. Inflammatory cells mostly presented by monocytes/macrophages, neutrophils and mast cells extravagate from bleeding neovessels and infiltrate adventitia where they support chronic inflammation. Plaque destabilization is an evolutionary process that could start at early atherosclerotic stages and whose progression is influenced by many factors including neovascularization, intraplaque haemorrhages, formation of cholesterol crystals, inflammation, oxidative stress and intraplaque protease activity. PMID- 25515698 TI - Fixed dose artesunate amodiaquine - a phase IIb, randomized comparative trial with non-fixed artesunate amodiaquine. AB - BACKGROUND: Pharmacokinetic (PK) and pharmacodynamic (PD) data are limited for artesunate (AS) and amodiaquine (AQ) in uncomplicated Plasmodium falciparum. METHODS: From 2007-8, 54 P. falciparum-infected, Kenyan adults were assigned randomly fixed dose (FD) ASAQ (n = 26) or non-fixed (NF) ASAQ (n = 28). Total doses were 600 mg AS (both arms) + 1,620 mg (FD) or 1,836 mg (NF)AQ. Follow-up extended over 28 days. PK data were collected for AS, dihydroartemisinin (DHA), AS + DHA combined as DHA equivalents (DHAeq), AQ, desethylamodiaquine (DAQ),and their relationships assessed against the PD collected data consisting of parasitological efficacy, adverse events (AEs), and the Bazett's corrected QTinterval (QTcB). RESULTS: Mean AUC 0-72 of dihydroartemisinin equivalents (DHAeq) when administered as a fixed dose (FD) compared to NF dose were similar: 24.2 +/-4.6 vs 26.4+/-6.9 umol*h/L (p = 0.68) Parasite clearance rates were also similar after 24 hrs: 17/25 (68%) vs 18/28(64.3%) (p = 0.86),as well as at 48 hrs: 25/8 (100%)vs 26 (92.9%)/28 (p = 0.49). Mean FD vs NF DAQ AUC0-28 were 27.6+/-3.19 vs 32.7+/-5.53 mg*h/L (p = 0.0005). Two PCR-proven new infections occurred on Day (D) 28 for estimated, in vivo, DAQ minimum inhibitory concentrations of 15.2 and 27.5 ng/mL. Combining the FD and NF arms, the mean QTcB at D2+4 hrs increased significantly (p = 0.0059) vs baseline: 420 vs410 ms (? = 9.02 (95% confidence interval 2.72-15.31 ms), explained by falling heart rates, increasing DAQ concentrations and female sex in a general linear mixed effects model. Ten of 108 (9.26%) AEs (5/arm) reported by 37/54 (68.5%) patients were possibly or probably drug related. Severe, asymptomatic neutropaenia developed in 2/47 (4.25%) patients on D28: 574/uL (vsD0: 5,075/uL), and 777/uL (vsD0: 3,778/uL). CONCLUSIONS: Tolerability of both formulations was good. For QTcB, a parameter for ECG modifications, increases were modest and due to rising DAQ concentrations and falling heart rates as malaria resolved. Rapid parasite clearance rates and no resistant infections suggest effective pharmacokinetics of both formulations. PMID- 25515700 TI - MiR-203 sensitizes glioma cells to temozolomide and inhibits glioma cell invasion by targeting E2F3. AB - Glioma is the most common malignant and fatal primary tumor in the central nervous system in adults. Recent data has suggested a profound role for microRNAs (miRs) in cancer progression. The present study demonstrated, via quantitative polymerase chain reaction (qPCR) analysis, that miR-203 expression was markedly lower in highly invasive U87MG glioma cells and glioma tissues. Wound healing and Transwell assays demonstrated that restoration of miR-203 expression inhibited U87MG cell migration and invasion. Restoration of miR-203 expression additionally sensitized the cells to temozolomide (TMZ) as determined by MTS assay. By contrast, miR-203 inhibition in A172 cells exerted opposite effects. Bioinformatic analysis combined with experimental analysis revealed that miR-203 directly targeted E2F3 via the conserved miR-203 target site within the E2F3 3' untranslational region. E2F3 knockdown with specific small hairpin RNA also inhibited U87MG cell migration and invasion, and sensitized them to TMZ. Importantly, miR-203 and E2F3 showed inverse expression patterns in invasive glioma tissues, as demonstrated by qPCR and luciferase assay. These results suggested that miR-203 may function as a tumor suppressor in glioma progression and that the miR-203/E2F3 axis may be a novel candidate in the development of rational therapeutic strategies for glioma. PMID- 25515697 TI - Biomechanical aspects of the muscle-bone interaction. AB - There is growing interest in the interaction between skeletal muscle and bone, particularly at the genetic and molecular levels. However, the genetic and molecular linkages between muscle and bone are achieved only within the context of the essential mechanical coupling of the tissues. This biomechanical and physiological linkage is readily evident as muscles attach to bone and induce exposure to varied mechanical stimuli via functional activity. The responsiveness of bone cells to mechanical stimuli, or their absence, is well established. However, questions remain regarding how muscle forces applied to bone serve to modulate bone homeostasis and adaptation. Similarly, the contributions of varied, but unique, stimuli generated by muscle to bone (such as low-magnitude, high frequency stimuli) remains to be established. The current article focuses upon the mechanical relationship between muscle and bone. In doing so, we explore the stimuli that muscle imparts upon bone, models that enable investigation of this relationship, and recent data generated by these models. PMID- 25515701 TI - The role of placenta growth factor in the hyperoxia-induced acute lung injury in an animal model. AB - Prolonged exposure to hyperoxia leads to acute lung injury. Alveolar type II cells are main target of hyperoxia-induced lung injury. However, the cellular and molecular mechanisms remain unknown. Here, we aimed to investigate the role of placental growth factor (PLGF) in hyperoxia-induced lung injury. Using experimental hyperoxia-induced lung injury model of neonatal rat and mouse lung epithelial type II cells (MLE-12), we examined the levels of PLGF in bronchoalveolar lavage fluid and in the supernatants of MLE-12 cells. Our results revealed that exogenous PLGF induced hyperoxia-induced lung injury. Furthermore, PLGF triggered a shift of vinculin from insoluble to soluble cell fraction, similar to the observation under hyperoxia stimulation. Moreover, we observed significantly reduced phosphorylation of focal adhesion kinase and increased permeability in MLE-12 cells treated with PLGF. These results suggest that PLGF triggers focal adhesion disassembly in alveolar type II cells via inhibiting the activation of focal adhesion kinase. Our findings reveal a novel role of PLGF in hyperoxia-induced lung injury and provide a potential target for the management of hyperoxia-induced acute lung injury. PMID- 25515702 TI - Erratum to: Something worth remembering: visual discrimination in sharks. PMID- 25515704 TI - Blending of reactive prepolymers to control the morphology and polarity of polyglycidol based microgels. AB - The compartmentalization of microgels is a challenging task for synthetic polymer chemistry. Although the complexation with low molecular weight compounds or the use of microfluidic techniques offer attractive possibilities for other length scales, it is difficult to implement compartments in the mesoscale range of 10 100 nm. Herein we show how simple blending of reactive prepolymers is suitable to design new microgel morphologies with tailored compartments. We use poly(EEGE) block-poly(AGE) as crosslinkable, pro-hydrophilic prepolymer in blends with varying amounts of crosslinkable, yet hydrophobic poly(THF-stat-AllylEHO) or inert and hydrophobic polystyrene, and crosslink the allyl functional prepolymer(s) in a thiol-ene click-type reaction after miniemulsification. Our strategy shows how arrested versus free nanophase separation can be used to control easily the morphology and polarity of microgel particles. PMID- 25515703 TI - Liver enzymes and clustering cardiometabolic risk factors in European adolescents: the HELENA study. AB - OBJECTIVES: This study aimed to explore the associations of liver biomarkers with cardiometabolic risk factors and their clustering, and to provide reference values (percentiles) and cut-off points for liver biomarkers associated with high cardiometabolic risk in European adolescents. METHODS: Alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), aspartate aminotransferase to ALT ratio (AST/ALT), waist circumference, blood pressure, triglycerides, high-density lipoprotein cholesterol and insulin were measured in 1084 adolescents. We computed a continuous cardiometabolic risk score and defined the high cardiometabolic risk. RESULTS: Higher ALT and GGT and lower AST/ALT were associated with adiposity and with the number of adverse cardiometabolic risk factors (Ps < 0.05). Higher GGT and lower AST/ALT were associated with higher cardiometabolic risk score (Ps < 0.001) in males and females, and ALT only in males (Ps < 0.001). Gender- and age-specific percentiles for liver biomarkers were provided. Receiver operating characteristic analyses showed a significant discriminatory accuracy of AST/ALT in identifying the low/high cardiometabolic risk (Ps < 0.01) and thresholds were provided. CONCLUSIONS: Higher GGT and lower AST/ALT are associated with higher cardiometabolic risk factors and their clustering in male and female European adolescents, whereas the associations of ALT were gender dependent. Our results suggest the usefulness of AST/ALT as a screening test in the assessment of adolescents with high cardiometabolic risk and provide gender- and age-specific thresholds that might be of clinical interest. PMID- 25515705 TI - Photoelectron spectroscopy and theoretical studies of anion-pi interactions: binding strength and anion specificity. AB - Proposed in theory and then their existence confirmed, anion-pi interactions have been recognized as new and important non-covalent binding forces. Despite extensive theoretical studies, numerous crystal structural identifications, and a plethora of solution phase investigations, anion-pi interaction strengths that are free from complications of condensed-phase environments have not been directly measured in the gas phase. Herein we present a joint photoelectron spectroscopic and theoretical study on this subject, in which tetraoxacalix[2]arene[2]triazine 1, an electron-deficient and cavity self-tunable macrocyclic, was used as a charge-neutral molecular host to probe its interactions with a series of anions with distinctly different shapes and charge states (spherical halides Cl(-), Br(-), I(-), linear thiocyanate SCN(-), trigonal planar nitrate NO3(-), pyramidic iodate IO3(-), and tetrahedral sulfate SO4(2-)). The binding energies of the resultant gaseous 1 : 1 complexes (1.Cl(-), 1.Br(-), 1.I(-), 1.SCN(-), 1.NO3(-), 1.IO3(-) and 1.SO4(2-)) were directly measured experimentally, exhibiting substantial non-covalent interactions with pronounced anion-specific effects. The binding strengths of Cl(-), NO3(-), IO3(-) with 1 are found to be strongest among all singly charged anions, amounting to ca. 30 kcal mol(-1), but only about 40% of that between 1 and SO4(2-). Quantum chemical calculations reveal that all the anions reside in the center of the cavity of 1 with an anion-pi binding motif in the complexes' optimized structures, where 1 is seen to be able to self-regulate its cavity structure to accommodate anions of different geometries and three-dimensional shapes. Electron density surface and charge distribution analyses further support anion-pi binding formation. The calculated binding energies of the anions and 1 nicely reproduce the experimentally estimated electron binding energy increase. This work illustrates that size-selective photoelectron spectroscopy combined with theoretical calculations represents a powerful technique to probe anion-pi interactions and has potential to provide quantitative guest-host molecular binding strengths and unravel fundamental insights in specific anion recognitions. PMID- 25515707 TI - Luteotropic and luteolytic factors regulate mRNA and protein expression of progesterone receptor isoforms A and B in the bovine endometrium. AB - The aim of the present study was to examine the effects of luteotropic and luteolytic factors on the mRNA and protein levels of progesterone receptor isoforms A (PGRA) and B (PGRB) in the bovine endometrium. Endometrial slices from Days 6-10 and 17-20 of the oestrous cycle were treated with LH (100ngmL-1), oestradiol (E2; 1*10-8M), prostaglandin (PG) E2 (1*10-6M) and PGF2alpha (1*10-6M) and the nitric oxide donor NONOate (1*10-4M); these treatments lasted for 6h for mRNA expression analysis and 24h for protein expression analysis. On Days 6-10 of the oestrous cycle PGRAB (PGRAB; the entire PGRA mRNA sequence is common to the PGRB mRNA sequence) mRNA expression in endometrial slices was enhanced by E2 treatment (P<0.001), whereas PGRB mRNA expression was increased by LH (P<0.001), E2 (P<0.05) and NONOate (P<0.05) treatment. On Days 17-20, PGRAB mRNA expression increased after E2 (P<0.001) and PGE2 (P<0.05) treatment; PGRB mRNA expression was increased by PGE2 (P<0.05) and PGF2alpha (P<0.01) treatment, but decreased by LH (P<0.05). On Days 6-10 protein levels of PGRA were stimulated by E2 (P<0.01), whereas PGRB protein levels were increased by LH (P<0.05) and E2 (P<0.05). On Days 17-20 of the oestrous cycle, PGRA protein levels were enhanced by E2 (P<0.05) and PGF2alpha (P<0.05), whereas PGRB protein levels were stimulated by PGE2 (P<0.05) and PGF2alpha (P<0.001). These data suggest that luteotropic and luteolytic factors affect PGRA and PGRB mRNA and protein levels, and this may regulate the effects of progesterone on endometrial cells. PMID- 25515706 TI - Genotypic and sex differences in anxiety-like behavior and alcohol-induced anxiolysis in High Drinking in the Dark selected mice. AB - Alcohol use disorders and anxiety disorders are highly comorbid in humans. In rodent lines selected for alcohol drinking, differences in anxiety-like behavior are also seen. The High Drinking in the Dark (HDID) lines of mice are selectively bred for drinking to intoxication during limited access to alcohol, and these mice represent a genetic model of risk for binge-like drinking. The present studies investigated whether these selected lines differ from control (HS) mice in basal anxiety behavior or in anxiolytic response to alcohol. We also assessed the genetic correlation between alcohol drinking in the dark (DID) and basal anxiety-like behavior using existing inbred strain data. Mice of both sexes and HDID replicates (HDID-1 and HDID-2) were tested on an elevated zero maze immediately following a DID test. In general, HDID mice showed more time spent in the open arms after drinking alcohol than HS mice, and open-arm time was significantly correlated with blood alcohol concentration. HDID-1 male mice also showed less anxiety-like behavior at baseline (water-drinking controls). In a separate experiment, HDID-1 and HS mice were tested for anxiolytic dose-response to acute alcohol injections. Both genotypes showed increasing time spent in the open arms with increasing alcohol doses, and HDID-1 and female mice had greater open-arm time across all doses. HDID-1 control males showed lower anxiety-like behavior than the HS control males. Inbred strain data analysis also showed no significant genetic relationship between alcohol DID and anxiety. These findings suggest that HDID selection has not produced systematic changes in anxiety-like behavior or sensitivity to alcohol-induced anxiolysis, though there is a tendency in the male mice of the first replicate toward reduced basal anxiety-like behavior. Therefore, anxiety state and sensitivity to alcohol's anxiolytic effects do not appear to contribute significantly to the high drinking behavior of the HDID mice. PMID- 25515708 TI - Long pulsed 1064 nm Nd:YAG laser treatment for wrinkle reduction and skin laxity: evaluation of new parameters. AB - INTRODUCTION: Among non-ablative devices for wrinkle reduction and skin laxity, long pulsed 1064 nm Nd:YAG laser (LPND) has considerable effectiveness. It can penetrate to deep dermis due to its longer wavelength. This study assesses the efficacy and safety of LPND applying new parameters for skin rejuvenation in Korean subjects. METHODS: A prospective randomized split-faced study was done (n = 20). Half of the face was treated with three passes of LPND at a spot size of 12 mm, 20-24 J/cm(2) fluence, 12 ms width, and frequency of 2 Hz, for three sessions, every four weeks. Outcomes were measured by wrinkle evaluation of blinded investigators, subjects' self-assessment, objective measurements of elasticity, and skin biopsy. RESULTS: Four weeks after the final treatment sessions, the average wrinkle grades of the treated side were reduced by 45.1%. Skin elasticity was significantly increased. The increment of collagen and elastic fiber in papillary dermis was confirmed histologically. No adverse reaction was reported. Pain on the treated side was mild without needing anesthesia. DISCUSSION: The authors studied new parameters for LPND for improvement of wrinkles and skin laxity with fewer treatment sessions without serious complications. Histologic findings corresponded to clinical improvement. CONCLUSION: New parameters of LPND can achieve wrinkle improvement with few side effects. PMID- 25515710 TI - Detecting signatures of selection in nine distinct lines of broiler chickens. AB - Modern commercial chickens have been bred for one of two specific purposes: meat production (broilers) or egg production (layers). This has led to large phenotypic changes, so that the genomic signatures of selection may be detectable using statistical techniques. Genetic differentiation between nine distinct broiler lines was calculated using Weir and Cockerham's pairwise FST estimator for 11 003 genome-wide markers to identify regions showing evidence of differential selection across lines. Differentiation measures were averaged into overlapping sliding windows for each line, and a permutation approach was used to determine the significance of each window. A total of 51 regions were found to show significant differentiation between the lines. Several lines were consistently found to share significant regions, suggesting that the pattern of line divergence is related to selection for broiler traits. The majority of the 51 regions contain QTL relating to broiler traits, but only five of them were found to be significantly enriched for broiler QTL, including a region on chromosome 27 containing 39 broiler QTL and 114 genes. Additionally, a number of these regions have been identified by other selection mapping studies. This study has identified a large number of potential selection signatures, and further tests with higher-density marker data may narrow these regions down to individual genes. PMID- 25515711 TI - First report of monepantel Haemonchus contortus resistance on sheep farms in Uruguay. AB - BACKGROUND: On two farms it was noted that after routine treatment with monepantel, fecal egg counts failed to drop. This was accompanied by lambs mortality due to Haemonchus contortus infection. The aim of this work was to evaluate the efficacy of monepantel to control gastrointestinal nematodes (GIN) in two sheep farms, in Uruguay. FINDINGS: A Fecal Egg Count Reduction Test (FECRT) was subsequently performed at the Experimental Stations Glencoe of INIA Tacuarembo (Farm 1) and Sheep Unit of INIA La Estanzuela (Farm 2) using the World Association for the Advancement of Veterinary Parasitology guidelines. On Farm 1 the FECRT was performed using 6-8 month old Corriedale or Merino Dohne x Corriedale male lambs naturally infected with GIN. On day 0 pre-treatment, three groups of 15 lambs each were selected, blocked by fecal egg count level (FEC) and randomly assigned to one of the following: Group 0 = untreated control, Group 1 = treated with monepantel (Zolvix(r), Novartis Animal Health Inc.) from stock previously purchased; Group 2 = treated with monepantel from stock provided by the supplier, at the recommended dose of 2.5 mg/kg of body weight. Fecal samples were collected directly from the rectum from each lamb on day 0 and on day 9 post treatment. On Farm 2, the FECRT was conducted on a group of 8 month old male lambs Milchschaff x Finn. At this farm, 10 lambs were randomly allocated to be treated with monepantel (Group 1) and 10 lambs were randomly allocated to remain as untreated control (Group 0) using the same protocols as Farm 1. On farm 1 the FECR was 0.0% (95% CI = 0.0-49.0) and 42.0% (95% CI = 0.0-75.0) for Group 1 and Group 2 respectively. For Farm 2, the FECR was 82.1% (95% CI = 36.0-99.0). Haemonchus spp was the resistant genus. CONCLUSIONS: Poor effcicacy of monepantel in treating GIN parasites was demonstrated on both farms. PMID- 25515712 TI - A hyporeflective space between hyperreflective materials in pigment epithelial detachment and Bruch's membrane in neovascular age-related macular degeneration. AB - BACKGROUND: The purpose of this study was to investigate the clinical characteristics of a hyporeflective space between hyperreflective materials in pigment epithelial detachment (PED) and Bruch's membrane in neovascular age related macular degeneration (AMD) using spectral-domain optical coherence tomography (SD-OCT) or swept source optical coherence tomography (SS-OCT). METHODS: Among 223 patients with neovascular AMD, 227 eyes were studied retrospectively. Using SD-OCT or SS-OCT, we reviewed clinical characteristics of the space. RESULTS: Twenty-two (10%) of the 227 eyes showed a space between hyperreflective materials in PED and Bruch's membrane. In all spaces, fibrovascular changes of the choroidal neovascularization (CNV) membrane were seen on funduscopy, with OCT images showing the retinal pigment epithelium (RPE) above the space adhering tightly and continuously to the CNV membranes. Nineteen (86%) of the 22 eyes with this cleft also had serous retinal detachment or cystoid macular edema. Five eyes (23%) had an RPE tear during follow-up. CONCLUSIONS: A hyporeflective space between hyperreflective materials in PED and Bruch's membrane sometimes appears in neovascular AMD. The appearance of such a space may indicate residual activities of the hyperreflective materials. PMID- 25515709 TI - Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates. AB - G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in beta-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the G(M2) gangliosidoses, we tested the potential of systemically delivered adeno associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or -LacZ and monitored for serum beta-hexosaminidase activity, motor function, and survival. Brain G(M2) ganglioside, beta-hexosaminidase activity, and inflammation were assessed at experimental week 43, or an earlier humane end point. SD mice injected with AAV9-LacZ died by 17 weeks of age, whereas all neonatal AAV9-HexB-treated SD mice survived until 43 weeks (P < 0.0001) with only three exhibiting neurological dysfunction. SD mice treated as adults with AAV9 HexB died between 17 and 35 weeks. Neonatal SD-HexB-treated mice had a significant increase in brain beta-hexosaminidase activity, and a reduction in G(M2) ganglioside storage and neuroinflammation compared to adult SD-HexB- and SD LacZ-treated groups. However, at 43 weeks, 8 of 10 neonatal-HexB injected control and SD mice exhibited liver or lung tumors. This study demonstrates the potential for long-term correction of SD and other G(M2) gangliosidoses through early rAAV9 based systemic gene therapy. PMID- 25515713 TI - Isolation of flavonoids and triterpenoids from the fruits of Alphitonia neocaledonica and evaluation of their anti-oxidant, anti-tyrosinase and cytotoxic activities. AB - INTRODUCTION: Alphitonia neocaledonica (Rhamnaceae) is an endemic tree of New Caledonia. Although three flavonoids have been identified in the leaves, the secondary metabolite profile of the fruits has never been investigated. OBJECTIVE: Phytochemical investigation of A. neocaledonica fruits and evaluation of their anti-oxidant, anti-tyrosinase and cytotoxic activities. METHODS: A hydromethanolic extract was fractionated by liquid-liquid extraction to obtain ethyl acetate and n-butanolic fractions. The ethyl-acetate-soluble part was purified by silica-gel column chromatography and high-performance liquid chromatography (HPLC). The n-butanol-soluble part was fractionated by centrifugal partition extraction (CPE) and the collected fractions were further purified by centrifugal partition chromatography (CPC) and HPLC. The chemical structures of the purified compounds were identified by nuclear magnetic resonance and mass spectrometry. RESULTS: Three triterpenoids and one flavonoid were isolated from the ethyl-acetate-soluble part. Fractions enriched in triterpenoids, flavonoids and catechin derivatives were obtained from the n-butanol-soluble part. Gallocatechin and flavonoids were obtained as pure compounds by further CPC and HPLC purification. The n-butanolic-soluble part showed anti-oxidant and anti tyrosinase activities due to the presence of tannins and gallocatechin. The triterpenoid alphitolic acid showed a moderate cytotoxic activity against KB cell line (median inhibition concentration = 8.5 MUM). CONCLUSIONS: Nine known compounds including three triterpenes, five flavonoids and (+) gallocatechin, as well as a new 3-O-(6-E-feruloyl)-beta-D-glucopyranosyl-(1 -> 2)-[beta-D xylopyranosyl-(1 -> 2)-]alpha-L-rhamnopyranosyl-quercetin, were isolated from A. neocaledonia fruits. The hydromethanolic extract possesses a potential cytotoxic activity due to the presence of triterpenes, and it can also be valuable as a cosmetic ingredient for its anti-oxidant and anti-tyrosinase activities. PMID- 25515714 TI - Cumulative effect of IFIH1 variants and increased gene expression associated with type 1 diabetes. AB - AIMS: IFIH1 (Interferon Induced with Helicase C domain 1) gene encodes a sensor of double-stranded RNA, which initiates antiviral activity. Recent studies have indicated the association of rare and common IFIH1 variants with type 1 diabetes mellitus (T1D). The aim of this study was to investigate whether polymorphisms in the IFIH1 locus are a risk factor for T1D in Caucasian patients from Poland. METHODS: We genotyped 514 T1D patients and 713 healthy control individuals for rs3747517, rs1990760, rs2111485 and rs13422767 variants. Cumulative genetic risk score (CGRS) was calculated using unweighted and weighted approaches. We also examined the expression of IFIH1 gene in a cohort of 90 T1D patients. RESULTS: All studied polymorphisms showed significant association with type 1 diabetes. The risk alleles G of rs3747517, rs2111485, rs13422767 and A of rs1990760 were observed more frequently in T1D group with P values and allelic odds ratio OR (95%CI) < 0.0001, 1.742 (1.428-2.126); 0.001, 1.336 (1.125-1.588); < 0.0001, 1.799 (1.416-2.285); 0.0005, 1.359 (1.144-1.616), respectively. The risk for type 1 diabetes increased with the growing number of the risk alleles. OR (95%CI) for carriers of >= 6 risk alleles reached 2.387 (1.552-3.670) for unweighted CGRS and 3.132 (1.928-5.089) for weighted CGRS. Furthermore, IFIH1 gene expression levels in unstimulated peripheral blood mononuclear cells of T1D patients were significantly higher compared to healthy individuals (mean +/- SEM mRNA copy number 163.8 +/- 15.7 vs. 117.8 +/- 7.2; P = 0.046). CONCLUSIONS: This study confirms the association of the IFIH1 locus with susceptibility to T1D in the Polish population. The cumulative effect of rs3747517, rs1990760, rs2111485 and rs13422767 variants on type 1 diabetes risk was observed. PMID- 25515716 TI - Plasma metabolic profiling of mild cognitive impairment and Alzheimer's disease using liquid chromatography/mass spectrometry. AB - OBJECTIVES: Alzheimer's disease (AD) is the main cause of gradual cognitive impairment in elderly individuals. This highlights the need of obtaining biomarkers to identify features that are different among mild cognitive impairment (MCI), AD and cognitively normal (CN) individuals. DESIGN AND METHODS: Ultra-performance liquid chromatography (UPLC)/mass spectrometry (MS) was employed to find the metabolic changes in plasma samples obtained from AD, MCI and CN individuals. Based on principal component analysis (PCA), the metabolic differences among AD, MCI and CN subjects were identified. RESULTS: The PCA of UPLC/MS spectra indicated metabolic differences among AD, MCI and CN subjects. The peak intensities of progesterone, lysophos- phatidylcholines (LPCs), tryptophan, L-phenylalanine, dihydrosphingosine and phytosphingosine in the plasma of the MCI and AD subjects were significantly different from the CN subjects. Furthermore, the peak intensities of tryptophan, LPCs, dihydrosphingosine in the plasma of the AD subjects were significantly lower compared to the MCI subjects. CONCLUSION: Our data provide a link between metabolite imbalance and AD, and suggest that metabolomics can be used to reveal the early disease mechanisms occurred in the progression from CN to MCI and AD. PMID- 25515715 TI - CARTOONS KILL: casualties in animated recreational theater in an objective observational new study of kids' introduction to loss of life. AB - OBJECTIVES: To assess the risk of on-screen death of important characters in children's animated films versus dramatic films for adults. DESIGN: Kaplan-Meier survival analysis with Cox regression comparing time to first on-screen death. SETTING: Authors' television screens, with and without popcorn. PARTICIPANTS: Important characters in 45 top grossing children's animated films and a comparison group of 90 top grossing dramatic films for adults. MAIN OUTCOME MEASURES: Time to first on-screen death. RESULTS: Important characters in children's animated films were at an increased risk of death compared with characters in dramatic films for adults (hazard ratio 2.52, 95% confidence interval 1.30 to 4.90). Risk of on-screen murder of important characters was higher in children's animated films than in comparison films (2.78, 1.02 to 7.58). CONCLUSIONS: Rather than being the innocuous form of entertainment they are assumed to be, children's animated films are rife with on-screen death and murder. PMID- 25515718 TI - Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: american society of clinical oncology endorsement of the college of american pathologists/international association for the study of lung cancer/association for molecular pathology guideline. PMID- 25515717 TI - Population-based assessment of cancer survivors' financial burden and quality of life: a prospective cohort study. AB - PURPOSE: The impact of financial burden among patients with cancer has not yet been measured in a way that accounts for inter-relationships between quality of life, perceived quality of care, disease status, and sociodemographic characteristics. PATIENTS AND METHODS: In a national, prospective, observational, population- and health care systems-based cohort study, patients with colorectal or lung cancer were enrolled from 2003 to 2006 within 3 months of diagnosis. For this analysis, surviving patients who were either disease free or had advanced disease were resurveyed a median 7.3 years from diagnosis. Structural equation modeling was used to investigate relationships between financial burden, quality of life, perceived quality of care, and sociodemographic characteristics. RESULTS: Among 1,000 participants enrolled from five geographic regions, five integrated health care systems, or 15 Veterans Administration Hospitals, 89% (n = 889) were cancer free, and 11% (n = 111) had advanced cancer. Overall, 48% (n = 482) reported difficulties living on their household income, and 41% (n = 396) believed their health care to be "excellent." High financial burden was associated with lower household income (adjusted odds ratio [OR] = 0.61 per $20k per year, P < .001) and younger age (adjusted OR = 0.63 per 10 years; P < .001). High financial burden was also associated with poorer quality of life (adjusted beta = -0.06 per burden category; P < .001). Better quality of life was associated with fewer perceptions of poorer quality of care (adjusted OR = 0.85 per 0.10 EuroQol units; P < .001). CONCLUSION: Financial burden is prevalent among cancer survivors and is related to patients' health-related quality of life. Future studies should consider interventions to improve patient education and engagement with regard to financial burden. PMID- 25515719 TI - Reply to a. Small et al. PMID- 25515720 TI - In response to L.N. Newcomer et al. PMID- 25515721 TI - Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an american society of clinical oncology guideline adaptation. PMID- 25515723 TI - Erratum to: MuRF1 activity is present in cardiac mitochondria and regulates reactive oxygen species production in vivo. PMID- 25515722 TI - Breast cancer treatment delays in a majority minority community: is there a difference? AB - PURPOSE: Recent studies from large nationwide cancer databases have consistently shown that Hispanic women with breast cancer have delays in treatment initiation compared with non-Hispanic white women. However, time to treatment initiation has not been studied in a community where Hispanics are the majority. PATIENTS AND METHODS: We conducted a retrospective, observational study of 362 female patients with breast cancer treated at a large National Cancer Institute (NCI) -designated cancer center with a largely Hispanic population. We examined the relationship between race/ethnicity and time from mammogram to biopsy as well as time from biopsy to treatment initiation using Kaplan-Meier analyses and multivariable Cox proportional hazards regression. RESULTS: Half of the female patients with breast cancer were of Hispanic descent (50.0%; n = 181). Hispanic patients were more likely to be obese, have an Eastern Cooperative Oncology Group functional status >= 1, and have higher histologic grade disease (all P <= .05); no differences in American Joint Committee on Cancer stage at diagnosis were observed. After comprehensive adjustment for demographic and clinical characteristics, we found no significant differences between Hispanic versus non-Hispanic white patients in time from mammogram to biopsy (hazard ratio [HR], 0.91; 95% CI, 0.68 to 1.21) or time from biopsy to treatment (HR, 1.13; 95% CI, 0.69 to 1.88). CONCLUSION: Hispanic women and Non-Hispanic white women with breast cancer treated at an NCI designated cancer center had similar times to biopsy and treatment initiation. These findings suggest that in majority minority communities with large cancer centers, racial disparities can be reduced. With a growing Hispanic population throughout the United States, future studies should examine the long-term impact on improved breast cancer survival in this population. PMID- 25515724 TI - Synthesis of unsaturated phosphatidylinositol 4-phosphates and the effects of substrate unsaturation on SopB phosphatase activity. AB - In this paper evidence is presented that the fatty acid component of an inositide substrate affects the kinetic parameters of the lipid phosphatase Salmonella Outer Protein B (SopB). A succinct route was used to prepare the naturally occurring enantiomer of phosphatidylinositol 4-phosphate (PI-4-P) with saturated, as well as singly, triply and quadruply unsaturated, fatty acid esters, in four stages: (1) The enantiomers of 2,3:5,6-O-dicyclohexylidene-myo-inositol were resolved by crystallisation of their di(acetylmandelate) diastereoisomers. (2) The resulting diol was phosphorylated regio-selectively exclusively on the 1-O using the new reagent tri(2-cyanoethyl)phosphite. (3) With the 4-OH still unprotected, the glyceride was coupled using phosphate tri-ester methodology. (4) A final phosphorylation of the 4-O, followed by global deprotection under basic then acidic conditions, provided PI-4-P bearing a range of sn-1-stearoyl, sn-2 stearoyl, -oleoyl, -gamma-linolenoyl and arachidonoyl, glycerides. Enzymological studies showed that the introduction of cis-unsaturated bonds has a measurable influence on the activity (relative Vmax) of SopB. Mono-unsaturated PI-4-P exhibited a five-fold higher activity, with a two-fold higher KM, over the saturated substrate, when presented in DOPC vesicles. Poly-unsaturated PI-4-P showed little further change with respect to the singly unsaturated species. This result, coupled with our previous report that saturated PI-4-P has much higher stored curvature elastic stress than PI, supports the hypothesis that the activity of inositide phosphatase SopB has a physical role in vivo. PMID- 25515726 TI - Influence of halophytic hosts on their parasites-the case of Plicosepalus acaciae. AB - Halophytes develop various morphological and physiological traits that enable them to grow successfully on saline substrates. Parasitic plants on halophytic hosts may also encounter salt stress. We investigated the mistletoe Plicosepalus acaciae (syn: Loranthus acacia; Loranthaceae), which occurs on 5 halophytic and at least 10 non-halophytic hosts in the Southern Arava Valley (Israel). Plicosepalus acaciae is a common parasite north of Eilat to the Dead Sea area and in the Jordan Valley. Morphological and physiological responses of P. acaciae to salinity were investigated by comparison of plants on halophytic with those on non-halophytic hosts. Ion patterns of different host-parasite associations were determined as was the development of leaf succulence at different growth stages. The leaf water content of P. acaciae increased and leaves developed succulence when growing on halophytic hosts, especially on Tamarix species, where leaf water content was three times higher than that on non-halophytic hosts and the leaf volume increased four to five times. The reason for increased succulence was a higher ion concentration of, and osmotic adjustment with, Na(+) and Cl(-). Plicosepalus acaciae showed a high morphological and ecophysiological plasticity, enabling it to cope with salt stress, and can be classified as a facultative eu halophyte, which increases its halo-succulence according to the host. Host parasite associations are a model system for the investigation of halophytes under different salt stress conditions. PMID- 25515725 TI - In-hospital switching between adenosine diphosphate receptor inhibitors in patients with acute myocardial infarction treated with percutaneous coronary intervention: Insights into contemporary practice from the TRANSLATE-ACS study. AB - AIMS: While randomized clinical trials have compared clopidogrel with higher potency adenosine diphosphate (ADP) receptor inhibitors among patients with acute myocardial infarction, little is known about the frequency, effectiveness and safety of switching between ADP receptor inhibitors in routine clinical practice. METHODS AND RESULTS: We studied 11,999 myocardial infarction patients treated with percutaneous coronary intervention at 230 hospitals from April 2010 to October 2012 in the TRANSLATE-ACS study. Multivariable Cox regression was used to compare six-month post-discharge risks of major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, or unplanned revascularization) and Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-defined bleeding between in-hospital ADP receptor inhibitor switching versus continuation of the initially selected therapy. Among 8715 patients treated initially with clopidogrel, 994 (11.4%) were switched to prasugrel or ticagrelor; switching occurred primarily after percutaneous coronary intervention (60.9%) and at the time of hospital discharge (26.7%). Among 3284 patients treated initially with prasugrel or ticagrelor, 448 (13.6%) were switched to clopidogrel; 48.2% of switches occurred after percutaneous coronary intervention and 48.0% at hospital discharge. Switching to prasugrel or ticagrelor was not associated with increased bleeding when compared with continuation on clopidogrel (2.7% vs. 3.3%, adjusted hazard ratio 0.96, 95% confidence interval 0.64-1.42, p=0.82). Switching from prasugrel or ticagrelor to clopidogrel was not associated with increased MACE (8.9% vs. 7.7%, adjusted hazard ratio 1.06, 95% confidence interval 0.75-1.49, p=0.76) when compared with continuation on the higher potency agent. CONCLUSIONS: In-hospital ADP receptor inhibitor switching occurs in more than one in 10 myocardial infarction patients in contemporary practice. In this observational study, ADP receptor inhibitor switching does not appear to be significantly associated with increased hazard of MACE or bleeding. PMID- 25515727 TI - Author's reply to Vautrey. PMID- 25515728 TI - Canine ocular protothecosis: A review of 14 cases. AB - PURPOSE: To examine a series of 14 cases of canine ocular protothecosis from archived cases from the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW), and compare gross and histologic findings. METHODS: Archival records from COPLOW were searched for canine cases of ocular protothecosis. Fourteen cases that contained matching criteria were identified, and gross and histologic findings, and clinical records for each case were tabulated, examined, and compared (2001-2013). RESULTS: Of the 14 cases identified, six had evidence of systemic disease, as per clinical history. Two of the 14 cases had Prototheca identified via cytology of ocular fluid or retinal exudate; in the remainder of cases, Prototheca identified via cytology of ocular fluid or retinal exudate in the remaining 12 cases, Prototheca was identified upon histologic examination of the submitted globe(s). Presenting ocular clinical signs were variable and nonspecific. Duration of ocular clinical signs varied from days to months. Fundoscopically, white membranes or plaques were identified on or around the retina in five cases. Retinal detachment was identified in 13 of the 14 submitted globes on gross examination following fixation and sectioning. The predominant histologic finding was granulomatous chorioretinitis with retinal detachment, with variable numbers of Prototheca within the inflammatory infiltrate. CONCLUSIONS: Due to the nonspecific nature of the ocular signs, a diagnosis of protothecosis generally is not made until enucleation and histopathologic examination of the globe(s). Retinal detachment and blindness were common. Cytologic sampling of retinal plaques and exudate may provide a rapid way to identify Prototheca. PMID- 25515729 TI - Carbohydrates and obesity: from evidence to policy in the UK. AB - Carbohydrates provide the major source of energy in the diet and hence the type and amount of carbohydrate consumed is an important consideration for weight control. Recent risk assessments have shown that there is no consistent association between the proportions of energy consumed as carbohydrate and body weight and reinforce the dominance of total energy intake as the primary determinant of body weight. However, they have highlighted evidence that different types of carbohydrate have specific effects on the risk of obesity. Short-term experimental studies suggest that some types of dietary fibre may be linked to increased satiation and cohort studies are supportive of an association between low intakes of fibre-rich, whole-grain foods and weight gain. But these observations are not supported by evidence of effects on body weight in randomised controlled trials, suggesting that high-fibre or whole-grain intake may simply be a marker of a broader dietary pattern. Recent attention has focused on the growing evidence of a positive association between the intake of free sugars and weight gain and particularly the risks linked to consumption of sugar sweetened beverages (SSB). Given the high population-level intake of free sugars the challenge is to identify actions that will successfully reduce consumption to contribute to reductions in the prevalence of obesity. The present paper considers the range of policy options available, using the Nuffield ladder of intervention to provide a framework for risk management, with a focus on the consumption of SSB. Current policy interventions are largely based around consumer education and encouragement to industry to renovate products to reduce the sugar content of food and drinks and/or reduce portion size, but dietary change has been slow. Further measures, including the use of specific incentives/disincentives may be needed to change consumption patterns, some of which may infringe personal or commercial freedom. For these policies to be implemented will require sustained efforts to create a climate in which such interventions are acceptable or even welcomed by society as an appropriate protection against obesity and other diet-related ill-health. PMID- 25515730 TI - Tumour-associated fibroblasts contribute to neoangiogenesis in human parathyroid neoplasia. AB - Components of the tumour microenvironment initiate and promote cancer development. In this study, we investigated the stromal component of parathyroid neoplasia. Immunohistochemistry for alpha-smooth muscle actin (alpha-SMA) showed an abundant periacinar distribution of alpha-SMA(+) cells in normal parathyroid glands (n=3). This pattern was progressively lost in parathyroid adenomas (PAds; n=6) where alpha-SMA(+)cells were found to surround new microvessels, as observed in foetal parathyroid glands (n=2). Moreover, in atypical adenomas (n=5) and carcinomas (n=4), alpha-SMA(+) cells disappeared from the parenchyma and accumulated in the capsula and fibrous bands. At variance with normal glands, parathyroid tumours (n=37) expressed high levels of fibroblast-activation protein (FAP) transcripts, a marker of tumour-associated fibroblasts. We analysed the ability of PAd-derived cells to activate fibroblasts using human bone-marrow mesenchymal stem cells (hBM-MSCs). PAd-derived cells induced a significant increase in FAP and vascular endothelial growth factor A (VEGFA) mRNA levels in co-cultured hBM-MSCs. Furthermore, the role of the calcium-sensing receptor (CASR) and of the CXCL12/CXCR4 pathway in the PAd-induced activation of hBM-MSCs was investigated. Treatment of co-cultures of hBM-MSCs and PAd-derived cells with the CXCR4 inhibitor AMD3100 reduced the stimulated VEGFA levels, while CASR activation by the R568 agonist was ineffective. PAd-derived cells co-expressing parathyroid hormone (PTH)/CXCR4 and PTH/CXCL12 were identified by FACS, suggesting a paracrine/autocrine signalling. Finally, CXCR4 blockade by AMD3100 reduced PTH gene expression levels in PAd-derived cells. In conclusion, i) PAd derived cells activated cells of mesenchymal origin; ii) PAd-associated fibroblasts were involved in tumuor neoangiogenesis and iii) CXCL12/CXCR4 pathway was expressed and active in PAd cells, likely contributing to parathyroid tumour neoangiogenesis and PTH synthesis modulation. PMID- 25515731 TI - SSTR3 is a putative target for the medical treatment of gonadotroph adenomas of the pituitary. AB - Gonadotroph pituitary adenomas (GPAs) often present as invasive macroadenomas not amenable to complete surgical resection. Radiotherapy is the only post-operative option for patients with large invasive or recurrent lesions. No medical treatment is available for these patients. The somatostatin analogs (SSAs) octreotide and lanreotide that preferentially target somatostatin receptor type 2 (SSTR2) have little effect on GPAs. It is widely accepted that the expression of specific SSTR subtypes determines the response to SSAs. Given that previous studies on mRNA and protein expression of SSTRs in GPAs have generated conflicting results, we investigated the expression of SSTR2, SSTR3, and SSTR5 (the main targets of available SSAs) in a clinically and pathologically well characterized cohort of 108 patients with GPAs. A total of 118 samples were examined by immunohistochemistry using validated and specific MABs. Matched primary and recurrent tissues were available for ten patients. The results obtained were validated in an independent cohort of 27 GPAs. We observed that SSTR3 was significantly more abundant than SSTR2 (P<0.0001) in GPAs, while full length SSTR5 was only expressed in few tumors. Expression of SSTR3 was similar in primary and recurrent adenomas, was high in potentially aggressive lesions, and did not change significantly in adenomas that recurred after irradiation. In conclusion, low levels of expression of SSTR2 may account for the limited response of GPAs to octreotide and lanreotide. Given the potent anti proliferative, pro-apoptotic, and anti-angiogenic activities of SSTR3, targeting this receptor with a multireceptor ligand SSA such as pasireotide may be indicated for potentially aggressive GPAs. PMID- 25515733 TI - Hepatitis B and C virus prevalence and association with demographics: report of population screening in Nigeria. AB - Hepatitis B and C remain a major cause of chronic liver disease worldwide with its attendant consequences. The burden of these viral infections in sub-Saharan Africa including Nigeria rely on estimates based on small population studies in some select populations. We present the report of a population survey in Nigeria during the period 2010-2012. A total of 5,558 adults participated in the screening exercise. The minimum age recorded was 18 years, while the maximum age was 75 years. The mean +/- S.D. was 36.07 +/- 8.76 years. The prevalence of hepatitis B (HBsAg) among the adults screened was determined to be 6.7% while that of hepatitis C (HCV) was 0.9%. The peak prevalence for HBsAg carriage was in the third to fourth decade in keeping with childhood acquisition while of HCV antibody was in the sixth to seventh decade. Male gender was significantly associated with HBsAg carriage while we noted a higher prevalence in those within the lower socioeconomic status. Overall our findings suggest that hepatitis B is endemic in Nigeria, much less than previously reported, while the prevalence for HCV is low although reports of pockets of high prevalence exist in select populations (hospital patients including those living with HIV). PMID- 25515732 TI - A scoping review of training and deployment policies for human resources for health for maternal, newborn, and child health in rural Africa. AB - BACKGROUND: Most African countries are facing a human resources for health (HRH) crisis, lacking the required workforce to deliver basic health care, including care for mothers and children. This is especially acute in rural areas and has limited countries' abilities to meet maternal, newborn, and child health (MNCH) targets outlined by Millennium Development Goals 4 and 5. To address the HRH challenges, evidence-based deployment and training policies are required. However, the resources available to country-level policy makers to create such policies are limited. To inform future HRH planning, a scoping review was conducted to identify the type, extent, and quality of evidence that exists on HRH policies for rural MNCH in Africa. METHODS: Fourteen electronic health and health education databases were searched for peer-reviewed papers specific to training and deployment policies for doctors, nurses, and midwives for rural MNCH in African countries with English, Portuguese, or French as official languages. Non-peer reviewed literature and policy documents were also identified through systematic searches of selected international organizations and government websites. Documents were included based on pre-determined criteria. RESULTS: There was an overall paucity of information on training and deployment policies for HRH for MNCH in rural Africa; 37 articles met the inclusion criteria. Of these, the majority of primary research studies employed a variety of qualitative and quantitative methods. Doctors, nurses, and midwives were equally represented in the selected policy literature. Policies focusing exclusively on training or deployment were limited; most documents focused on both training and deployment or were broader with embedded implications for the management of HRH or MNCH. Relevant government websites varied in functionality and in the availability of policy documents. CONCLUSIONS: The lack of available documentation and an apparent bias towards HRH research in developed areas suggest a need for strengthened capacity for HRH policy research in Africa. This will result in enhanced potential for evidence uptake into policy. Enhanced alignment between policy-makers' information needs and the independent research agenda could further assist knowledge development and uptake. The results of this scoping review informed an in-depth analysis of relevant policies in a sub-set of African countries. PMID- 25515734 TI - Hyaluronidase in ophthalmic evisceration surgery. AB - BACKGROUND: To research the effectiveness of hyaluronidase in evisceration surgery. METHODS: A total of 34 patients were studied as three groups: conventional surgery group (n = 13); isotonic fluid group (n = 8); and hyaluronidase group (n = 13). Hyaluronidase and isotonic fluid were introduced into the uveo-scleral space. Intraocular content was removed, if possible by a one-scoop method, with the aid of a spoon. RESULTS: Removing all the intraocular content as a one-scoop method was achieved in 10 of 13 (77%) in the hyaluronidase group and four of eight (50%) in the isotonic fluid group. The one-scoop method was not possible in any case without the introduction of fluid. The mean durations for the evisceration procedure were 32, 36.6 and 40.5 min in the three groups, respectively (P < 0.05). CONCLUSIONS: Using hyaluronidase in evisceration surgery greatly facilitates and speeds up the removal of all the intraocular content in ophthalmic evisceration surgery. PMID- 25515735 TI - Microscopic haematuria: A rare presentation of typhoid fever. AB - Typhoid fever can cause a number of renal manifestations heretofore dubbed 'nephrotyphoid'. Haematuria in the absence of renal impairment is extremely rare among typhoid patients. We report a case of an adult who presented with a prolonged febrile illness and microscopic haematuria. Blood culture confirmed the diagnosis of typhoid and the patient was treated successfully with ceftriaxone. PMID- 25515736 TI - Prevalence of hepatitis C virus infection among pregnant women in a rural district in Egypt. AB - BACKGROUND: Egypt has the highest prevalence of hepatitis C virus (HCV) infection in the world. Screening of HCV during pregnancy is not as routinely done in Egypt compared with many other countries, although pregnancy is an important period where screening of HCV infection is important owing to low immunity, the possibility of vertical transmission and possible horizontal transmission to the baby or other household contacts at a later stage. AIM: To determine the seroprevalence of HCV antibodies (HCV-Ab) and risk factors associated with infection among pregnant women in Egypt. PATIENTS AND METHOD: A total of 360 pregnant women visiting the healthcare units for routine antenatal care were tested using third generation ELISA test for detection of HCV-Ab. Polymerase chain reaction (PCR) was done for seropositive cases. RESULTS: A total of 6.1% (22/360) of pregnant women were HCV seropositive; of them only 45% (9/20) had viraemia. Risk factors were their age, the age of their husband and the presence of chronic liver disease in the husband. CONCLUSION: The prevalence of HCV infection in pregnant women in Egypt appears to be lower than previously reported. The detected risk factors are old age of the pregnant women and their husbands, and chronic liver disease in the husbands. None of the other known risk factors was found to be significantly associated with HCV infection in pregnant women. PMID- 25515738 TI - MicroRNAs in melanocyte and melanoma biology. AB - The importance of microRNAs as key molecular components of cellular processes is now being recognized. Recent reports have shown that microRNAs regulate processes as diverse as protein expression and nuclear functions inside cells and are able to signal extracellularly, delivered via exosomes, to influence cell fate at a distance. The versatility of microRNAs as molecular tools inspires the design of novel strategies to control gene expression, protein stability, DNA repair and chromatin accessibility that may prove very useful for therapeutic approaches due to the extensive manageability of these small molecules. However, we still lack a comprehensive understanding of the microRNA network and its interactions with the other layers of regulatory elements in cellular and extracellular functions. This knowledge may be necessary before we exploit microRNA versatility in therapeutic settings. To identify rules of interactions between microRNAs and other regulatory systems, we begin by reviewing microRNA activities in a single cell type: the melanocyte, from development to disease. PMID- 25515739 TI - Parity of esteem for mental and physical health is a red herring. PMID- 25515741 TI - A novel approach to detect respiratory phases from pulmonary acoustic signals using normalised power spectral density and fuzzy inference system. AB - BACKGROUND: Monitoring respiration is important in several medical applications. One such application is respiratory rate monitoring in patients with sleep apnoea. The respiratory rate in patients with sleep apnoea disorder is irregular compared with the controls. Respiratory phase detection is required for a proper monitoring of respiration in patients with sleep apnoea. AIMS: To develop a model to detect the respiratory phases present in the pulmonary acoustic signals and to evaluate the performance of the model in detecting the respiratory phases. METHODS: Normalised averaged power spectral density for each frame and change in normalised averaged power spectral density between the adjacent frames were fuzzified and fuzzy rules were formulated. The fuzzy inference system (FIS) was developed with both Mamdani and Sugeno methods. To evaluate the performance of both Mamdani and Sugeno methods, correlation coefficient and root mean square error (RMSE) were calculated. RESULTS: In the correlation coefficient analysis in evaluating the fuzzy model using Mamdani and Sugeno method, the strength of the correlation was found to be r = 0.9892 and r = 0.9964, respectively. The RMSE for Mamdani and Sugeno methods are RMSE = 0.0853 and RMSE = 0.0817, respectively. CONCLUSION: The correlation coefficient and the RMSE of the proposed fuzzy models in detecting the respiratory phases reveals that Sugeno method performs better compared with the Mamdani method. PMID- 25515740 TI - Proteomic profile in glomeruli of type-2 diabetic KKAy mice using 2-dimensional differential gel electrophoresis. AB - BACKGROUND: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. To search for glomerular proteins associated with early-stage DN, glomeruli of spontaneous type 2 diabetic KKAy mice were analyzed by 2-dimensional differential gel electrophoresis (2D-DIGE). MATERIAL AND METHODS: Glomeruli of 20 week spontaneous type 2 diabetic KKAy mice and age-matched C57BL/6 mice were isolated by kidney perfusion with magnetic beads. Proteomic profiles of glomeruli were investigated by using 2D-DIGE and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Western blot analysis was used to confirm the results of proteomics. Immunohistochemical and semi-quantitative analysis were used to confirm the differential expression of prohibitin and annexin A2 in glomeruli. RESULTS: We identified 19 differentially expressed proteins - 17 proteins were significantly up-regulated and 2 proteins were significantly down-regulated in glomeruli of diabetic KKAy mice. Among them, prohibitin and annexin A2 were up-regulated and Western blot analysis validated the same result in proteomics. Immunohistochemical analysis also revealed up regulation of prohibitin and annexin A2 in glomeruli of KKAy mice. CONCLUSIONS: Our findings suggest that prohibitin and annexin A2 may be associated with early stage DN. Further functional research might help to reveal the pathogenesis of DN. PMID- 25515742 TI - Different patterns of A*80:01:01:01 allele generation based on exon or intron sequences. AB - Generation of the HLA-A*80:01:01:01 allele has been analysed using its complete sequence. Direct comparison of the sequences and phylogenetic trees using the human leukocyte antigen (HLA)-A representative alleles and the major histocompatibility complex (MHC)-A sequences of non-human primates has been made. Results based on exon sequences confirm previously published, but considering only the sequences of the introns, two distinct regions can be differentiated. The first one comprises from the 5' untranslated region region to the first part of intron 3 sequence (shared with A2 family), and the second one includes the sequence from the end of intron 3 to intron 7 (shared with A1/A3/A11/A36/A30 family). Each of them clusters with Gorilla and Chimpanzee MHC-A sequences, respectively, suggesting an origin coming from a common ancestor to Gorilla and Chimpanzee. PMID- 25515743 TI - Editorial :Chemistry Bordering Biology: highlights from the XXXIV Biennial Meeting of the RSEQ. PMID- 25515744 TI - Poly(epsilon-caprolactone) films with favourable properties for neural cell growth. AB - The regeneration of brain tissue is one of the major challenges in regenerative medicine due to the lack of viable grafts to support the re-growth of functional tissue after a traumatic injury. The development of biocompatible and biodegradable structures with appropriate morphology for the interaction with neural tissue is required. The objective pursued in this work is to develop a biodegradable 2D scaffold structure for neural tissue engineering. Poly(epsilon caprolactone) (PCL) was the selected material due to its biocompatibility and biodegradability in the long term. PCL (15%w/w) was dissolved in N methylpyrrolidone and the film was fabricated by phase inversion casting technique employing ethanol and isopropanol as coagulation baths. The physical structure, morphology and topography of the flat scaffolds were characterized using different techniques. The two different scaffolds presented homogeneous structure with high porosity (higher than 85%), contact angles higher than 90(o), high roughness (Ra> 0.6 MUm) and superficial pore sizes of 0.7 and 1.7 MUm, respectively. Permeance tests showed high water permeabilities (~350-590 mL m(-1) bar(-1) h(-1)) indicative of promising nutrients supply to the cells. Finally, in vitro human glioblastoma cells cultures after 48 hours showed good cell attachment, proliferation and penetration in the scaffolds. Detailed evaluation of the interaction between the surface morphology and the properties of the scaffolds with the cell response has been done. Thus, the PCL films herein fabricated show promising results as scaffolds for neural tissue regeneration. PMID- 25515745 TI - Triplet excited States as a source of relevant (bio)chemical information. AB - The properties of triplet excited states are markedly medium-dependent, which turns this species into valuable tools for investigating the microenvironments existing in protein binding pockets. Monitoring of the triplet excited state behavior of drugs within transport proteins (serum albumins and alpha1-acid glycoproteins) by laser flash photolysis constitutes a valuable source of information on the strength of interaction, conformational freedom and protection from oxygen or other external quenchers. With proteins, formation of spatially confined triplet excited states is favored over competitive processes affording ionic species. Remarkably, under aerobic atmosphere, the triplet decay of drug@protein complexes is dramatically longer than in bulk solution. This offers a convenient dynamic range for assignment of different triplet populations or for stereochemical discrimination. In this review, selected examples of the application of the laser flash photolysis technique are described, including drug distribution between the bulk solution and the protein cavities, or between two types of proteins, detection of drug-drug interactions inside proteins, and enzyme-like activity processes mediated by proteins. Finally, protein encapsulation can also modify the photoreactivity of the guest. This is illustrated by presenting an example of retarded photooxidation. PMID- 25515746 TI - The use of citrullinated peptides for the diagnosis and prognosis of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint inflammation and extra-articular manifestations. To prevent progressive and irreversible structural damage, early diagnosis of RA is of paramount importance. Antibodies directed against citrullinated proteins and peptides (ACPAs) are the most specific serological markers available for diagnosing RA. ACPAs may be detected several years before symptoms appear, and their presence at disease onset is a good predictor of the development of erosive joint lesions. Synthetic peptides can replace cognate proteins in solid-phase assays for specific autoantibody recognition in RA patients. The use of synthetic peptides instead of proteins represents an advantage in terms of the reproducibility of such immunoassays. They give absolute control over the exact epitopes presented. Furthermore, it is difficult to prepare sufficient amounts of high-quality antigenic proteins with a well-defined degree of citrullination. Synthetic citrullinated peptides, in contrast, are easily obtained in a pure form with a well-defined chemical structure and the epitopes can be precisely oriented in the plate by covalent binding of the peptides. We have recently obtained and highlighted the application of chimeric peptides bearing different citrullinated protein domains for the design of RA diagnosis systems. Our results indicate that more than one serological test is required to classify RA patients based on the presence or absence of ACPAs. Each of the target molecules reported (fibrin, vimentin and filaggrin) helps to identify a particular subset of RA patients. PMID- 25515747 TI - Synthesis and biological evaluation of 1,5-naphthyridines as topoisomerase I inhibitors. A new family of antiproliferative agents. AB - The synthesis of a variety of phenyl- and indeno-1,5-naphthyridine derivatives as new substrates with anticancer activity is described. Several of the prepared products were addressed to in vitro anticancer screening which indicated that some of them exhibited inhibitory effect of Top1 and antiproliferative activity against human colon cancer cells (COLO 205). PMID- 25515748 TI - Conformational analysis of peptides and glycopeptides derived from the consensus sequence for beta-O-glucosylation. AB - Cys-Xxx-Ser-Xxx-Pro-Cys (Xxx= any amino acid but Pro) is the most common sequence present in naturally occurring peptides and proteins glycosylated with beta-O glucose (beta-O-Glc). Taking into account the lack of studies concerning the spatial disposition of this sequence, we have synthesized and analyzed, in aqueous solution, the conformational behavior of peptides and a glycopeptide derived from the particular fragment Cys-Ala-Ser-Ser-Pro-Cys. This sequence is found in the crystal structure of the complex of blood coagulation factor VIIa with soluble tissue factor. Our studies, based on the use of NOESY experiments in combination with molecular dynamics (MD) simulations, indicate that for this particular fragment, initially characterized by a type I beta-turn motif, the glycosylation with beta-O-Glc forces the peptide backbone into an extended conformation. This conformation is stabilized by the presence of both hydrogen bonds and water pockets between the peptide and the sugar moieties. PMID- 25515749 TI - Chemoenzymatic synthesis of carbohydrates as antidiabetic and anticancer drugs. AB - Different chemoenzymatic strategies for the preparation of carbohydrates and analogues possessing antidiabetic or anticancer activity are summarized. In this sense, some examples illustrating the use of enzymes such as aldolases, lipases or glycosidases (in some cases improved by genetic engineering techniques) are presented, showing the advantages of the implementation of chemoenzymatic protocols, which combine the flexibility of chemical synthesis with the efficiency, selectivity and sustainability of biotransformations to obtain diverse complex carbohydrates, glycoconjugates and glycomimetics. PMID- 25515750 TI - Choline kinase active site provides features for designing versatile inhibitors. AB - Choline kinase (CK) is a homodimeric enzyme that catalyses the transfer of the ATP gamma-phosphate to choline, generating phosphocholine and ADP in the presence of magnesium. Several isoforms of CK are present in humans but only the HsCKalpha has been associated with cancer and validated as a drug target to treat this disease. As a consequence a large number of compounds based on Hemicholinium (HC 3) have been described. Two compounds, previously reported to inhibit the human enzyme, have recently been shown to inhibit P. falciparum CK (PfCK) and therefore their potential applications might be anticipated to other pathogens. Herein, using molecular dynamic simulations, we have firstly observed that the ATP and the choline binding site of different CK in pathogens and human are conserved, suggesting that previous compounds inhibiting the human enzyme may also interact with CKs from different pathogens. We have substantiated such observation with experimental assays showing that HsCKalpha1, PfCK and CpCK bind to two compounds with distinct structural features in the low MUM range. Collectively, these results uncover similarities among the choline kinase binding site from different pathogenic species and the human enzyme, highlighting the feasibility of designing novel inhibitors based on the choline binding pocket. PMID- 25515751 TI - Modulation of toll-like receptor 4. Insights from x-ray crystallography and molecular modeling. AB - Toll-like receptors (TLRs) are a family of proteins with a key role in the innate immune system. They are specialized in the recognition of molecular patterns present in microbial components, through mechanisms not yet unraveled at atomic level. Improvement in the understanding of the molecular mechanisms that drive TLR signaling is of paramount importance to grasp key aspects of immunity, potentially leading to the design of new molecules able to modulate their functions. Toll-like receptor 4 (TLR4), along with its accessory protein myeloid differentiation factor 2 (MD-2), builds a heterodimeric complex that specifically recognizes lipopolysaccharides (LPS), which are present on the cell wall of gramnegative bacteria, activating the immune response. Some TLR4 modulators are undergoing preclinical and clinical evaluation for the treatment of sepsis, inflammatory diseases, cancer, and rheumatoid arthritis. Reported X-ray crystal structures together with molecular modeling studies, not reviewed before in the literature, have recently contributed to the elucidation of key interactions at atomic level of the binding between the TLR4/MD-2 system and different TLR4/MD-2 ligands. The purpose of this review is to summarize these reported studies which may account for the SAR rationalization of natural/ synthetic agonist/antagonist TLR4 binders and may also guide further design of novel TLR4 modulators. PMID- 25515752 TI - Glutathione-triggered drug release from nanostructures. AB - The delivery of drugs can be improved with the use of different carriers, such as those based on nanoparticles. The nanostructures loaded with the therapeutic molecules should be able to reach the target cells and, what is more, release the drugs efficiently. Ideally, the drugs should be delivered only in the target cells, and not along their way to the cells. For these reasons several approaches have been developed to control the release of the drugs at the desired sites. In this review article we have summarized the reports that describe the use of glutathione to trigger the release of the therapeutic molecules from different nanostructures. PMID- 25515753 TI - Membrane-targeted self-assembling cyclic peptide nanotubes. AB - Peptide nanotubes are novel supramolecular nanobiomaterials that have a tubular structure. The stacking of cyclic components is one of the most promising strategies amongst the methods described in recent years for the preparation of nanotubes. This strategy allows precise control of the nanotube surface properties and the dimensions of the tube diameter. In addition, the incorporation of 3- aminocycloalkanecarboxylic acid residues in the nanotube forming peptides allows control of the internal properties of the supramolecular tube. The research aimed at the application of membrane-interacting self assembled cyclic peptide nanotubes (SCPNs) is summarized in this review. The cyclic peptides are designed to interact with phospholipid bilayers to induce nanotube formation. The properties and orientation of the nanotube can be tuned by tailoring the peptide sequence. Hydrophobic peptides form transmembrane pores with a hydrophilic orifice, the nature of which has been exploited to transport ions and small molecules efficiently. These synthetic ion channels are selective for alkali metal ions (Na(+), K(+) or Cs(+)) over divalent cations (Ca(2+)) or anions (Cl(-)). Unfortunately, selectivity was not achieved within the series of alkali metal ions, for which ion transport rates followed the diffusion rates in water. Amphipathic peptides form nanotubes that lie parallel to the membrane. Interestingly, nanotube formation takes place preferentially on the surface of bacterial membranes, thus making these materials suitable for the development of new antimicrobial agents. PMID- 25515754 TI - Phospholipid bilayer nanodiscs: a powerful tool to study the structural organization and biochemical reactivity of proteins in membrane-like environments. AB - Nanodiscs are disc-like structures formed by two copies of a membrane scaffold protein, engineered from apolipoprotein A-I, surrounding a phospholipid mixture that can incorporate membrane proteins preserving their natural properties. They behave as soluble entities allowing the use of high-resolution structural techniques to determine the structural organization of the embedded membrane protein, and the use of solution biochemical-biophysical tools to measure its activity, assembly and interactions with other proteins in membranelike environments. In addition, nanodiscs are biocompatible which makes them an attractive technology to be used in therapy, drug discovery, and other biotechnological applications. PMID- 25515755 TI - Metabolomics as a tool for drug discovery and personalised medicine. A review. AB - Studying the effects of drugs on the metabolome constitutes a huge part of the metabolomics discipline. Whether the approach is associated with drug discovery (altered pathways due to the disease that provide future targets and information into the mechanism of action or resistance, etc.) or pharmacometabolomics (studying the outcome of treatment), there have been many aspiring published articles in this area. With specific experimental design, including fingerprinting analysis with different analytical platforms in a non-targeted way, the approach is advancing towards the discovery of markers for the implication of personalised medicine, while also providing information that could help to improve the efficacy and reduce the side effects associated with a treatment. In this review, the evolution of pharmacometabolomics from other areas of drug efficacy metabolomics studies is explored. PMID- 25515757 TI - Gardening Activities and Physical Health Among Older Adults: A Review of the Evidence. AB - Few studies have examined the health-related consequences of gardening among older adults. This scoping review summarizes and characterizes current research that examines the relationship between physical health and participation in planned gardening activities, including establishing, maintaining, or caring for plants. Six databases were searched. Eligible studies were published between 2000 and 2013, were published in English, and assessed different aspects of physical health (e.g., functional ability, energy expenditure, injury) for older adults who had participated in a planned gardening activity. Of the eight eligible studies identified with these criteria, four assessed energy expenditures and four assessed physical functioning. Studies assessing energy expenditures documented that the majority of gardening tasks were classified into low-to moderate intensity physical activity. The current literature does not provide sufficient evidence of the physical functioning consequences of gardening. Future studies should consider how specific gardening interventions help older adults meet physical activity guidelines. PMID- 25515756 TI - LocNES: a computational tool for locating classical NESs in CRM1 cargo proteins. AB - MOTIVATION: Classical nuclear export signals (NESs) are short cognate peptides that direct proteins out of the nucleus via the CRM1-mediated export pathway. CRM1 regulates the localization of hundreds of macromolecules involved in various cellular functions and diseases. Due to the diverse and complex nature of NESs, reliable prediction of the signal remains a challenge despite several attempts made in the last decade. RESULTS: We present a new NES predictor, LocNES. LocNES scans query proteins for NES consensus-fitting peptides and assigns these peptides probability scores using Support Vector Machine model, whose feature set includes amino acid sequence, disorder propensity, and the rank of position specific scoring matrix score. LocNES demonstrates both higher sensitivity and precision over existing NES prediction tools upon comparative analysis using experimentally identified NESs. AVAILABILITY AND IMPLEMENTATION: LocNES is freely available at http://prodata.swmed.edu/LocNES CONTACT: yuhmin.chook@utsouthwestern.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25515759 TI - When locums can earn as much as partners, general practice is in trouble. PMID- 25515758 TI - Nursing Home Perspectives on the Admission of Morbidly Obese Patients From Hospitals to Nursing Homes. AB - PURPOSE OF THE STUDY: Care challenges have been described for hospitalized morbidly obese (MO) patients. These challenges likely persist post discharge. As a result, nursing homes (NHs) may be reluctant to admit these patients, potentially leaving them "stranded in hospitals". This study identified issues NHs consider in admission decisions for MO patients transitioning from hospitals. DESIGN AND METHOD: Approved surveys were mailed to nursing directors at federally certified NHs in Arkansas (n = 234) and Pennsylvania (n = 710) to collect NH experience in the admission of patients weighing >= 325 pounds. Analyses included descriptive and inferential statistics to summarize and identify predictors of MO patient admission decisions. RESULTS: In total, 360 surveys were returned (38.1% response rate). Although two-thirds of respondents reported patient size as an admission barrier, only 6% reported that MO patients were always refused admission. Adjusted analysis showed that NHs with adequate staff were significantly (p = .04) less likely to report obesity as an admission barrier whereas NHs reporting concerns about availability of bariatric equipment were significantly (p < .0001) more likely to report obesity as a barrier. IMPLICATIONS: Lack of staff and bariatric equipment in NHs appears to negatively affect the transition of MO patients out of the hospital to NHs. Additional research, including examination of current regulations and reimbursement policies, should be undertaken to understand NH staffing and equipment acquisition decisions in light of the current obesity epidemic. Such research has implications for the optimal care of obese individuals during times of transition. PMID- 25515760 TI - Orexin A upregulates the protein expression of OX1R and enhances the proliferation of SGC-7901 gastric cancer cells through the ERK signaling pathway. AB - Orexins are hypothalamic peptides that regulate food intake, wakefulness, the reward system and energy metabolism. Recent studies have demonstrated the ability of orexins to promote a robust apoptosis and subsequent inhibition of cell growth in various types of cancer cells. The present study was conducted to investigate the effects of orexin A on the survival of human gastric cancer cells, SGC-7901, and the possible mechanisms. SGC-7901 cells were exposed to various concentrations of orexin A in vitro in the presence or absence of the orexin receptor 1 (OX1R) antagonist (SB334867), extracellular signal-regulated kinases 1 and 2 (ERK1/2) antagonist (U0126) or a combination of the two antagonists. The amount of cell proliferation, viability and apoptosis, caspase-8 and caspases-9 activities, OX1R protein expression and ERK1/2 protein levels were determined. The expression of OX1R in SGC-7901 cells was observed. Orexin A (10-10 to 10-6 M) stimulated SGC-7901 cell proliferation and viability, reduced the pro-apoptotic activity of caspase-9 and protected the cells from apoptosis in a dose-dependent manner. Additionally, ERK1/2 phosphorylation was stimulated by orexin A (10-10 to 10-6 M). However, the OX1R antagonist SB334867 (10-6 M), ERK1/2 antagonist U0126 (30 uM) or the combination of antagonists blocked the effects of orexin A to a certain extent. These results suggest that stimulation of OX1R induces the growth of SGC-7901 gastric cancer cells through activation of ERK1/2 signaling pathway. These findings add a new dimension to the biological activities of orexin, which may have important implications in health and disease, in particular gastric cancer. PMID- 25515762 TI - Rapid serial processing of natural scenes: color modulates detection but neither recognition nor the attentional blink. AB - The exact function of color vision for natural-scene perception has remained puzzling. In rapid serial visual presentation (RSVP) tasks, categorically defined targets (e.g., animals) are detected typically slightly better for color than for grayscale stimuli. Here we test the effect of color on animal detection, recognition, and the attentional blink. We present color and grayscale RSVP sequences with up to two target images (animals) embedded. In some conditions, we modify either the hue or the intensity of each pixel. We confirm a benefit of color over grayscale images for animal detection over a range of stimulus onset asynchronies (SOAs), with improved hit rates from 50 to 120 ms and overall improved performance from 90 to 120 ms. For stimuli in which the hue is inverted, performance is similar to grayscale for small SOAs and indistinguishable from original color only for large SOAs. For subordinate category discrimination, color provides no additional benefit. Color and grayscale sequences show an attentional blink, but differences between color and grayscale are fully explained by single-target differences, ruling out the possibility that the color benefit is purely attentional. PMID- 25515761 TI - Mediation analysis of gestational age, congenital heart defects, and infant birth weight. AB - BACKGROUND: In this study we assessed the mediation role of the gestational age on the effect of the infant's congenital heart defects (CHD) on birth-weight. METHODS: We used secondary data from the Baltimore-Washington Infant Study (1981 1989). Mediation analysis was employed to investigate whether gestational age acted as a mediator of the association between CHD and reduced birth-weight. We estimated the mediated effect, the mediation proportion, and their corresponding 95% confidence intervals (CI) using several methods. RESULTS: There were 3362 CHD cases and 3564 controls in the dataset with mean birth-weight of 3071 (SD = 729) and 3353 (SD = 603) grams, respectively; the mean gestational age was 38.9 (SD = 2.7) and 39.6 (SD = 2.2) weeks, respectively. After adjusting for covariates, the estimated mediated effect by gestational age was 113.5 grams (95% CI, 92.4-134.2) and the mediation proportion was 40.7% (95% CI, 34.7%-46.6%), using the bootstrap approach. CONCLUSIONS: Gestational age may account for about 41% of the overall effect of heart defects on reduced infant birth-weight. Improved prenatal care and other public health efforts that promote full term delivery, particularly targeting high-risk families and mothers known to be carrying a fetus with CHD, may therefore be expected to improve the birth-weight of these infants and their long term health. PMID- 25515763 TI - Surround-contingent tilt aftereffect. AB - We investigated whether aftereffects can be contingent on surroundings. Gabor patches tilted clockwise and counterclockwise were presented in alternation. Each patch was surrounded by an open circle or an open square. After prolonged exposure to these stimuli, tilt aftereffects were found to be contingent upon the surrounding frames: Vertical test patches appeared tilted clockwise when surrounded by the frame that was presented in conjunction with the adaptation patch tilted counterclockwise. The effect lasted 24 hours and was observed only when adaptation and test stimuli were presented at the same retinotopic position, but not observed at the same spatiotopic position. These results indicate that the aftereffect would be influenced not only by stimulus features but also by their surroundings. PMID- 25515764 TI - Binocular visual performance with aberration correction as a function of light level. AB - The extent to which monocular visual performance of subjects with normal amounts of ocular aberrations can be improved with adaptive optics (AO) depends on both the pupil diameter and the luminance for visual testing. Here, the benefit of correction of higher order aberrations for binocular visual performance was assessed over a range of luminances for natural light-adapted pupil sizes with a binocular AO visual simulator. Results show that binocular aberration correction benefits for visual acuity and contrast sensitivity increase with decreasing luminances. Also, the advantage of binocular over monocular viewing increases when visual acuity becomes worse. The findings suggest that binocular summation mitigates poor visual performance under low luminance conditions. PMID- 25515765 TI - Sustained improvement in urticaria pigmentosa and pruritus in a case of indolent systemic mastocytosis treated with cladribine. AB - Systemic mastocytosis (SM) is a myeloproliferative disorder, characterized by a clonal proliferation of abnormal mast cells accumulating in internal organs and sometimes in the skin, leading to cutaneous and systemic symptoms. Mutations within the gene KIT, which encodes the receptor tyrosine kinase (KIT) on mast cells, is found in most patients with SM. We report a case of a 62-year-old woman presenting with a pruritic rash on her limbs and trunk. Several years later she developed gastrointestinal symptoms, associated with raised serum tryptase. Skin and bone marrow biopsies confirmed a diagnosis of SM, initially presenting with urticaria pigmentosa. Responses to multiple therapies, including potent topical steroids, oral antihistamines, phototherapy and the tyrosine kinase inhibitor, nilotinib, were inadequate. Treatment with cladribine (2-chlorodeoxyadenosine) produced a marked and sustained reduction in her symptoms and serum tryptase level. PMID- 25515766 TI - Depressive symptoms associated with dabigatran: a case report. AB - Several studies have reported that depression and anxiety are very common in atrial fibrillation due to impaired quality of life. Dabigatran is an anti aggregation agent used for the treatment of atrial fibrillation. In terms of drug interactions during treatment with dabigatran, patients suffering from minor depression are reported to be a population at risk. This report is about a 68 year-old man whose depressive symptoms were aggravated after taking dabigatran for atrial fibrillation. The case is discussed in terms of his aggravated depressive symptoms and the interaction between his prescription medications. PMID- 25515767 TI - Oxidative stress as a pharmacological target for medicinal chemistry: synthesis and evaluation of compounds with redox activity - part 1. PMID- 25515768 TI - Orientation of B798 BChl a Q y transition dipoles in Chloroflexus aurantiacus chlorosomes: polarized transient absorption spectroscopy studies. AB - Isotropic and anisotropic pump-probe spectra of Cfx. aurantiacus chlorosomes were measured on the fs-through ps-time scales for the B798 BChl a Q y band upon direct excitation of the B798 band at T = 293 K and T = 90 K. Upon direct excitation of the B798 band, the anisotropy parameter value r(lambda) was constant within the whole BChl a Q y band at any delay time at both temperatures. The value of the anisotropy parameter r decayed from r = 0.4 at both temperatures (at 200 fs delay time after excitation) to the steady-state values r = 0.1 at T = 293 K and to r = 0.09 at T = 90 K (at 30 / 100 ps delay time after excitation). The results were considered within the framework of the model of uniaxial orientation distribution of BChl-a transition dipoles within a single Cfx. aurantiacus chlorosome. This implies that the B798 BChl a Q y transition dipoles, randomly distributed around the normal to the baseplate plane, form the angle theta with the plane. For this model, the theoretical dependence of the steady state anisotropy parameter r on the angle theta was derived. According to the theoretical dependence r(theta), the angle theta corresponding to the experimental steady-state value r = 0.1 at T = 293 K was found to equal 55 degrees . As the temperature drops to 90 K, the angle theta decreases to 54 degrees . PMID- 25515771 TI - Diagnostic accuracy of clinical tests for the diagnosis of hip femoroacetabular impingement/labral tear: a systematic review with meta-analysis. AB - BACKGROUND: Surgery for hip femoroacetabular impingement/acetabular labral tear (FAI/ALT) is exponentially increasing despite lacking investigation of the accuracy of various diagnostic measures. Useful clinical utility of these measures is necessary to support diagnostic imaging and subsequent surgical decision-making. OBJECTIVE: Summarise/evaluate the current diagnostic accuracy of various clinical tests germane to hip FAI/ALT pathology. METHODS: A computer assisted literature search of MEDLINE, CINAHL and EMBASE databases using keywords related to diagnostic accuracy of the hip joint, as well as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for the search and reporting phases of the study. Quality assessment of bias and applicability was conducted using the Quality of Diagnostic Accuracy Studies 2 (QUADAS-2). Random effects models were used to summarise sensitivities (SN), specificities (SP), diagnostic odds ratio (DOR) and respective confidence intervals (CI). RESULTS: The employed search strategy revealed 21 potential articles, with one demonstrating high quality. Nine articles qualified for meta analysis. The meta-analysis demonstrated that flexion-adduction-internal rotation (pooled SN ranging from 0.94 (95% CI 0.90 to 0.97) to 0.99 (95% CI 0.98 to 1.00); DOR 5.71 (95% CI 0.84 to 38.86) to 7.82 (95% CI 1.06 to 57.84)) and flexion internal rotation (pooled SN 0.96 (95% CI 0.81 to 0.99); DOR 8.36 (95% CI 0.41 to 171.3) tests possess only screening accuracy. CONCLUSIONS: Few hip physical examination tests for diagnosing FAI/ALT have been investigated in enough studies of substantial quality to direct clinical decision-making. Further high-quality studies across a wider spectrum of hip pathology patients are recommended to discern the confirmed clinical utility of these tests. TRIALS REGISTRATION NUMBER: PROSPERO Registration # CRD42014010144. PMID- 25515769 TI - Challenges of metagenomics and single-cell genomics approaches for exploring cyanobacterial diversity. AB - Cyanobacteria have played a crucial role in the history of early earth and continue to be instrumental in shaping our planet, yet applications of cutting edge technology have not yet been widely used to explore cyanobacterial diversity. To provide adequate background, we briefly review current sequencing technologies and their innovative uses in genomics and metagenomics. Next, we focus on current cell capture technologies and the challenges of using them with cyanobacteria. We illustrate the utility in coupling breakthroughs in DNA amplification with cell capture platforms, with an example of microfluidic isolation and subsequent targeted amplicon sequencing from individual terrestrial thermophilic cyanobacteria. Single cells of thermophilic, unicellular Synechococcus sp. JA-2-3-B'a(2-13) (Syn OS-B') were sorted in a microfluidic device, lysed, and subjected to whole genome amplification by multiple displacement amplification. We amplified regions from specific CRISPR spacer arrays, which are known to be highly diverse, contain semi-palindromic repeats which form secondary structure, and can be difficult to amplify. Cell capture, lysis, and genome amplification on a microfluidic device have been optimized, setting a stage for further investigations of individual cyanobacterial cells isolated directly from natural populations. PMID- 25515772 TI - Radiation-resistant Macrococcus caseolyticus (A) isolated from radiation processed semidried prawns. AB - A radiation-resistant bacterial isolate from gamma-radiation-processed (5 kGy) semidried prawns was identified as a new strain of Macrococcus caseolyticus and was designated as M. caseolyticus (A) on the basis of morphological and biochemical characterization and 16S rRNA sequencing. DNA-DNA hybridization studies with M. caseolyticus DSM 20597(T) further confirmed the isolate as M. caseolyticus. Major fatty acids present in M. caseolyticus (A) were C14:0, C16:1omega11c, and C18:1omega9c, whereas C15:0anteiso, C16:0iso, and C18:0iso were absent. The closest match for the isolate, as per fatty acid methyl ester analysis, was M. caseolyticus DSM 20597(T). However, the similarity index was significantly low (0.112), which indicates that the isolate could be a new strain of M. caseolyticus. The decimal reduction dose (D10) for M. caseolyticus (A), M. caseolyticus JCSC5402, and Staphylococcus aureus MTCC96 was 1.18, 0.607, and 0.19 kGy, respectively. This is the first report on radiation resistance of M. caseolyticus. Macrococcus caseolyticus (A) is more resistant to gamma and UV radiation stress than are M. caseolyticus JCSC5402 and S. aureus MTCC96; however, it is sensitive to heat as well as desiccation stress. PMID- 25515770 TI - Temperature responses of the Rubisco maximum carboxylase activity across domains of life: phylogenetic signals, trade-offs, and importance for carbon gain. AB - Temperature response of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) catalytic properties directly determines the CO2 assimilation capacity of photosynthetic organisms as well as their survival in environments with different thermal conditions. Despite unquestionable importance of Rubisco, the comprehensive analysis summarizing temperature responses of Rubisco traits across lineages of carbon-fixing organisms is lacking. Here, we present a review of the temperature responses of Rubisco carboxylase specific activity (c(cat)(c)) within and across domains of life. In particular, we consider the variability of temperature responses, and their ecological, physiological, and evolutionary controls. We observed over two-fold differences in the energy of activation (DeltaH(a)) among different groups of photosynthetic organisms, and found significant differences between C3 plants from cool habitats, C3 plants from warm habitats and C4 plants. According to phylogenetically independent contrast analysis, DeltaH(a) was not related to the species optimum growth temperature (T growth), but was positively correlated with Rubisco specificity factor (S(c/o)) across all organisms. However, when only land plants were analyzed, DeltaH(a) was positively correlated with both T(growth) and S(c/o), indicating different trends for these traits in plants versus unicellular aquatic organisms, such as algae and bacteria. The optimum temperature (T(opt)) for k(cat)(c) correlated with S(c/o) for land plants and for all organisms pooled, but the effect of T growth on T(opt) was driven by species phylogeny. The overall phylogenetic signal was significant for all analyzed parameters, stressing the importance of considering the evolutionary framework and accounting for shared ancestry when deciphering relationships between Rubisco kinetic parameters. We argue that these findings have important implications for improving global photosynthesis models. PMID- 25515773 TI - [Complex reconstruction in Charcot arthropathy using the Ilizarov ring fixator]. AB - BACKGROUND: From the foot surgeon's point of view, the surgical treatment of Charcot neuro-osteopathy is considered challenging. Conservative treatment using plaster and orthoses is used to treat Charcot arthropathy, especially in the acute stage of a treatment strategy. Surgical treatment using the Ilizarov ring fixator is established for the correction of residual misalignments and also in the acute stage. Advantages of the ring fixator are great stability of the apparatus, low loading of the soft tissues caused by foreign material, and possible long-term treatment. OBJECTIVES: The aim of this work is to explain the indication, planning of correction, assembly of Ilizarov ring fixator, and the postoperative treatment with respect to the literature and the authors' experience. The aim of treatment with the Ilizarov ring fixator is a plantigrade, resilient, ulcer-free foot. Treatment is lengthy for both the affected patients and the attending orthopedic surgeon, and great attention is required to achieve the desired corrections and a good result for the patient. DISCUSSION: According to the literature and the authors' experience, the results indicate that the Ilizarov ring fixator represents a viable method for the preservation of the affected limb in patients with Charcot neuro-osteopathy. The assembly of the apparatus must follow the principles of Ilizarov in order to avoid failure. Corrective osseous and soft tissue interventions require a detailed preoperative analysis. PMID- 25515774 TI - Effect of micro-patterning on bacterial adhesion on polyethylene terephthalate surface. AB - Bacterial adhesion on surfaces commonly used in medicine and food industry could lead to infections and illnesses. Topographically patterned surfaces recently have shown to be a promising alternative to chemical antibacterial methods, which might release cytotoxin and promote antibiotic resistance. In this study, we fabricated micro-patterned polyethylene terephthalate surfaces, and quantitatively explored the amount and localization of Escherichia coli MG1655 cells attached on a series of defined topographies. The adhesion was conducted in static conditions and under a weak flow, in both physiological buffer and nutritious solutions. The results showed that in the presence of weak shear force, live bacteria could still maintain sensing ability in nutritious culture, but not in buffer solution. The finely textured surface, which could inhibit bacterial adhesion in the early stage of attachment, reversed its effect to enhance the adhesion after 24 h incubation, indicating that microbial cells seemed to be able to sense the disadvantageous condition and eventually overcome it. In terms of adhesion localization, bacteria exhibited preferential adhesion onto the edges of topographic features. The patterned substrates that have the most even (homogeneous) bacterial localization on topographic features retained the least attachment after 24 h exposure. PMID- 25515776 TI - Cytosolic dsDNA triggers apoptosis and pro-inflammatory cytokine production in normal human melanocytes. AB - Considerable evidence implicates that viral infection might be a participant factor in the pathogenesis of vitiligo. However, it is still unclear how viral infection leads to the melanocyte destruction. To elucidate the effects of viral dsDNA on the viability and cytokine synthesis of normal human melanocytes and to explore the underlying mechanisms, primary cultured normal human melanocytes were transfected with poly(dA:dT). The results demonstrated that poly(dA:dT) triggered apoptosis instead of pyroptosis in melanocytes. Knocking down AIM2 or RIG-I by RNA interference partially reduced the poly(dA:dT)-induced LDH release, suggesting the involvement of both nucleic acid sensors in the process of melanocyte death. Poly(dA:dT) induced the expression of pro-inflammatory cytokine genes including IFN-beta, TNF-alpha, IL-6 and IL-8 as well, whereas the pro inflammatory cytokine production was suppressed by RIG-I siRNA, but not by AIM2 siRNA. Poly(dA:dT) treatment increased the phosphorylation of p38 and JNK and NFkappaB. Accordingly, NFkappaB inhibitor Bay 11-7082 and JNK inhibitor SP600125 blocked the induction of the cytokine genes except IFN-beta. The production of IL6 and IL8 was also suppressed by p38 inhibitor SB203580. On the contrary, the Poly(dA:dT)-induced melanocyte death was only decreased by SP600125. This study provides the possible mechanism of melanocyte destruction and immuno-stimulation in vitiligo by innate immune response following viral infection. PMID- 25515775 TI - Pharmacotherapies for cannabis dependence. AB - BACKGROUND: Cannabis is the most prevalent illicit drug in the world. Demand for treatment of cannabis use disorders is increasing. There are currently no pharmacotherapies approved for treatment of cannabis use disorders. OBJECTIVES: To assess the effectiveness and safety of pharmacotherapies as compared with each other, placebo or supportive care for reducing symptoms of cannabis withdrawal and promoting cessation or reduction of cannabis use. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (to 4 March 2014), MEDLINE (to week 3 February 2014), EMBASE (to 3 March 2014) and PsycINFO (to week 4 February 2014). We also searched reference lists of articles, electronic sources of ongoing trials and conference proceedings, and contacted selected researchers active in the area. SELECTION CRITERIA: Randomised and quasi randomised controlled trials involving the use of medications to reduce the symptoms and signs of cannabis withdrawal or to promote cessation or reduction of cannabis use, or both, in comparison with other medications, placebo or no medication (supportive care) in participants diagnosed as cannabis dependent or who were likely to be dependent. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Two review authors assessed studies for inclusion and extracted data. All review authors confirmed the inclusion decisions and the overall process. MAIN RESULTS: We included 14 randomised controlled trials involving 958 participants. For 10 studies the average age was 33 years; two studies targeted young people; and age data were not available for two studies. Approximately 80% of study participants were male. The studies were at low risk of selection, performance, detection and selective outcome reporting bias. Three studies were at risk of attrition bias.All studies involved comparison of active medication and placebo. The medications included preparations containing tetrahydrocannabinol (THC) (two studies), selective serotonin reuptake inhibitor (SSRI) antidepressants (two studies), mixed action antidepressants (three studies), anticonvulsants and mood stabilisers (three studies), an atypical antidepressant (two studies), an anxiolytic (one study), a norepinephrine reuptake inhibitor (one study) and a glutamatergic modulator (one study). One study examined more than one medication. Diversity in the medications and the outcomes reported limited the extent that analysis was possible. Insufficient data were available to assess the utility of most of the medications to promote cannabis abstinence at the end of treatment.There was moderate quality evidence that completion of treatment was more likely with preparations containing THC compared to placebo (RR 1.29, 95% CI 1.08 to 1.55; 2 studies, 207 participants, P = 0.006). There was some evidence that treatment with preparations containing THC was associated with reduced cannabis withdrawal symptoms and craving, but this latter outcome could not be quantified. For mixed action antidepressants compared with placebo (2 studies, 179 participants) there was very low quality evidence on the likelihood of abstinence from cannabis at the end of follow-up (RR 0.82, 95% CI 0.12 to 5.41), and moderate quality evidence on the likelihood of treatment completion (RR 0.93, 95% CI 0.71 to 1.21). For this same outcome there was very low quality evidence for the effects of SSRI antidepressants (RR 0.82, 95% CI 0.44 to 1.53; 2 studies, 122 participants), anticonvulsants and mood stabilisers (RR 0.78, 95% CI 0.42 to 1.46; 2 studies, 75 participants), and the atypical antidepressant, bupropion (RR 1.06, 95% CI 0.67 to 1.67; 2 studies, 92 participants). Available evidence on gabapentin (anticonvulsant) and N-acetylcysteine (glutamatergic modulator) was insufficient for quantitative estimates of their effectiveness, but these medications may be worth further investigation. AUTHORS' CONCLUSIONS: There is incomplete evidence for all of the pharmacotherapies investigated, and for many of the outcomes the quality was downgraded due to small sample sizes, inconsistency and risk of attrition bias. The quantitative analyses that were possible, combined with general findings of the studies reviewed, indicate that SSRI antidepressants, mixed action antidepressants, atypical antidepressants (bupropion), anxiolytics (buspirone) and norepinephrine reuptake inhibitors (atomoxetine) are probably of little value in the treatment of cannabis dependence. Preparations containing THC are of potential value but, given the limited evidence, this application of THC preparations should be considered still experimental. Further studies should compare different preparations of THC, dose and duration of treatment, adjunct medications and therapies. The evidence base for the anticonvulsant gabapentin and the glutamatergic modulator N acetylcysteine is weak, but these medications are also worth further investigation. PMID- 25515777 TI - The dosage of Patz1 modulates reprogramming process. AB - The acquisition of pluripotent cells can be achieved by combined overexpression of transcription factors Oct4, Klf4, Sox2 and c-Myc in somatic cells. This cellular reprogramming process overcomes various barriers to re-activate pluripotency genes and re-acquire the highly dynamic pluripotent chromatin status. Many genetic and epigenetic factors are essentially involved in the reprogramming process. We previously reported that Patz1 is required for maintenance of ES cell identity. Here we report that Patz1 plays an inhibitory role in OKSM-induced reprogramming process since more iPS colonies can be induced from Patz1(+/-) MEFs than wild type MEFs; while the addition of Patz1 significantly repressed reprogramming efficiency. Patz1(+/-) MEFs can surpass the senescence barrier of Ink4a/Arf locus, thus enhancing iPS colonies formation. Moreover, Patz1(+/-) MEFs displayed higher levels of acetylated histone H3, H3K4me2, H3K4me3, H3K36me3 and lower levels of histone H3K9me3 and HP1alpha, indicating that heterozygous knockout of Patz1 results in a globally open chromatin which is more accessible for transcriptional activation. However, Patz1(-/-) MEFs gave the lowest reprogramming efficiency which may result from cell senescence trigged by up-regulated Ink4a/Arf locus. Together, we have demonstrated that the dosage of Patz1 modulates reprogramming process via significantly influencing cell senescence, proliferation and chromatin structure. PMID- 25515778 TI - The specific role of FAM20C in dentinogenesis. AB - FAM20C is an evolutionarily reserved molecule highly expressed in mineralized tissues. Previously we demonstrated that Sox2-Cre;Fam20C(fl/fl) mice, in which Fam20C was ubiquitously inactivated, had dentin and enamel defects as well as hypophosphatemic rickets. We also showed that K14-Cre;Fam20C(fl/fl) mice, in which Fam20C was specifically inactivated in the epithelium, had enamel defects but lacked hypophosphatemia and defects in the bone and dentin. These results indicated that the enamel defects in the Sox2-Cre;Fam20C(fl/fl) mice were independent of dentin defects and hypophosphatemia. To determine if the dentin defects in the Sox2-Cre;Fam20C(fl/fl) mice were associated with the enamel defects and hypophosphatemia, we crossed Fam20C(fl/fl) mice with Wnt1-Cre and Osr2-Cre transgenic mice to inactivate Fam20C in the craniofacial mesenchymal cells that form dentin and alveolar bone. The resulting Wnt1-Cre;Fam20C(fl/fl) and Osr2-Cre;Fam20C(fl/fl) mice showed remarkable dentin and alveolar bone defects, while their enamel did not show apparent defects. The serum FGF23 levels in these mice were higher than normal but lower than those in the Sox2 Cre;Fam20C(fl/fl) mice; they developed a mild type of hypophosphatemia that did not cause major defects in long bones. These results indicate that the dentin defects in the Sox2-Cre;Fam20C(fl/fl) mice were independent of the enamel defects. PMID- 25515779 TI - Self-Reported and Interviewer-Rated Oral Health in Patients With Schizophrenia, Bipolar Disorder, and Major Depressive Disorder. AB - PURPOSE: To compare self-reported (SR) and interviewer-rated (IR) oral health between schizophrenia (SZ), bipolar disorder (BP), and major depressive disorder (MDD) patients. DESIGN AND METHODS: 356 patients with SZ, BP, or MDD underwent assessments of psychopathology, side effects, SR, and IR oral health status. FINDINGS: 118 patients (33.1%) reported poor oral health; the corresponding proportion was 36.4% in BP, 34.8% in SZ, and 25.5% in MD (p = .21). SR and IR oral health correlated only modestly (r = 0.17-0.36) in each group. PRACTICE IMPLICATIONS: Psychiatric patients need to be assessed for both SR and IR oral health. PMID- 25515780 TI - Was there really any evidence that rosiglitazone increased the risk of myocardial infarction or death from cardiovascular causes? AB - Rosiglitazone has previously been widely used to treat patients with type 2 diabetes mellitus, but its safety in terms of cardiovascular morbidity and mortality had been called into question. Recently, there have been doubts raised about the meta-analytic evidence with the regulatory authorities relaxing its restrictions. We hypothesized that the original analyses may have produced exaggerated results because of the small baseline risks involved. To demonstrate this, we replicated the meta-analysis of four randomized trials of greater than 12-month follow-up that made use of a randomized control group not receiving rosiglitazone and reported outcome data for all occurrences of the complementary outcomes (no myocardial infarction, no death from cardiovascular causes, and no heart failure). Data were combined by means of a fixed-effects model. In the rosiglitazone group, as compared with the control group, the relative risk for no myocardial infarction was 0.997 (95% confidence interval [CI], 0.994 to 1.000), and the relative risk for no death from cardiovascular causes was 1.001 (95%CI, 0.999 to 1.003). Finally, no heart failure had a relative risk of 0.995 (95%CI, 0.993 to 0.998). Rosiglitazone does not seem to have any significant increase in the risk of myocardial infarction or of death from cardiovascular causes associated with its use. Regulatory authorities should revisit this issue of the appropriate measure for reporting of adverse events with low baseline risks as this has implications well beyond rosiglitazone. PMID- 25515781 TI - Outcomes after cervical laminectomy with instrumented fusion versus expansile laminoplasty: a propensity matched study of 3185 patients. AB - The aim of this study was to compare reoperation, complication rates, and healthcare resource utilization of expansile laminectomies with instrumented fusion versus laminoplasty. Using the MarketScan database (Truven Health Analytics, Ann Arbor, MI, USA), we selected patients aged >18 years who underwent either cervical laminoplasty or laminectomy with fusion between 2000-2009. Propensity score modeling produced a matched cohort balanced for age, sex, comorbidities, and other relevant factors. A total of 3185 patients meeting our inclusion criteria also had 2 year follow-up available. Of these, 2927 (91.90%) and 258 (8.10%) had laminectomy with fusion and laminoplasty, respectively. Laminoplasty patients had significantly lower complication rates during index hospitalization (5.81 versus 9.62%, adjusted odds ratio [aOR]: 0.556, 95% confidence interval [CI]: 0.418-0.740, p<0.0002), during 30 day (6.87 versus 11.12%, aOR: 0.568, 95% CI: 0.436-0.740, p<0.0002) and 90 day (7.61 versus 11.78%, aOR: 0.593, 95% CI: 0.460-0.764, p<0.0002) postoperative periods. They also had lower costs (United States dollars) during index hospitalization ($26,129 versus $35,483, p<0.0004), and overall during the 2 year postoperative period ($77,960 versus $106,453, p<0.0001). Two year reoperation rates were similar between both groups (9.77% versus 7.36%, p=0.20). Our study suggests that cervical laminoplasty has significantly lower complication rates, similar long term reoperation rates and lower healthcare resource utilization after 2 years than laminectomy with fusion. PMID- 25515782 TI - Epidemiology of exposure to HIV/AIDS risky conditions in healthcare settings: the case of health facilities in Gondar City, North West Ethiopia. AB - BACKGROUND: It has been estimated that every year more than quarter a million health care workers exposed to HIV risky conditions in health care settings, more so in developing countries, with high incidence of HIV/AIDS and unsafe practices. Particularly, Sub-Saharan African countries share at least half of these occupational exposures to HIV risky conditions among health care workers. The aim of this study was to determine the epidemiology of health care workers' exposure to HIV/AIDS risky conditions and associated factors in the healthcare settings in Gondar city. METHODS: Institution based quantitative cross sectional study was conducted from April 1-20, 2014. The study included 401 health care workers who were selected from the source population by simple random sampling technique. Data were collected by interviewing health care workers using structured and pretested questionnaire. After the collected data entered to EPI INFO version 3.5.3 statistical software and exported to SPSS version 20.0 for analysis, both binary and multivariable logistic regressions were done to identify factors associated with exposure to HIV/AIDS risky conditions. RESULTS: From a total of 401 health care workers involved in this study, 162(40.4%) reported at least one history of occupational exposure to HIV/AIDS risky conditions in the last one year. More than half (52.31%) of physicians and 47.62% of anesthetists were exposed to HIV/AIDS risky conditions within one year. Lack of training on infection prevention, 5-10 years work experience, long working hours per week, absence of work guidelines, and dissatisfaction with current job were significantly associated with accidental occupational exposure to HIV/AIDS risky conditions. CONCLUSION: This study found quite high prevalence of health care workers exposure to HIV/AIDS risky conditions in the health care settings in Gondar city. Therefore, effective and goal oriented educational programmes targeting at health care workers and establishment of surveillance systems for registering, reporting and management of occupational exposures in health care settings are quite important. PMID- 25515783 TI - GP funding formula masks major inequalities for practices in deprived areas. PMID- 25515784 TI - Progesterone receptor isoform A may regulate the effects of neoadjuvant aglepristone in canine mammary carcinoma. AB - BACKGROUND: Progesterone receptors play a key role in the development of canine mammary tumours, and recent research has focussed on their possible value as therapeutic targets using antiprogestins. Cloning and sequencing of the progesterone receptor gene has shown that the receptor has two isoforms, A and B, transcribed from a single gene. Experimental studies in human breast cancer suggest that the differential expression of progesterone receptor isoforms has implications for hormone therapy responsiveness. This study examined the effects of the antiprogestin aglepristone on cell proliferation and mRNA expression of progesterone receptor isoforms A and B in mammary carcinomas in dogs treated with 20 mg/Kg of aglepristone (n = 22) or vehicle (n = 5) twice before surgery. RESULTS: Formalin-fixed, paraffin-embedded tissue samples taken before and after treatment were used to analyse total progesterone receptor and both isoforms by RT-qPCR and Ki67 antigen labelling. Both total progesterone receptor and isoform A mRNA expression levels decreased after treatment with aglepristone. Furthermore, a significant decrease in the proliferation index (percentage of Ki67-labelled cells) was observed in progesterone-receptor positive and isoform-A positive tumours in aglepristone-treated dogs. CONCLUSIONS: These findings suggest that the antiproliferative effects of aglepristone in canine mammary carcinomas are mediated by progesterone receptor isoform A. PMID- 25515785 TI - Mitochondrial reactive oxygen species production mediates ursolic acid-induced mitochondrial uncoupling and glutathione redox cycling, with protection against oxidant injury in H9c2 cells. AB - Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid, is a ubiquitous compound widely distributed in many plants, fruits and medicinal herbs worldwide. A previous study in our laboratory has shown that UA can increase the mitochondrial ATP generation capacity (ATP-GC) and a glutathione-dependent antioxidant response, thereby protecting against oxidant injury in H9c2 cells in vitro and rat hearts ex vivo. However, the mechanism underlying the cellular protective effects induced by UA remains largely unknown. The present study has shown that pre-incubation with UA produces a transient increase in the mitochondrial membrane potential in H9c2 cells, which was accompanied by increases in mitochondrial reactive oxygen species (ROS) production. Studies using an antioxidant (dimethylthiourea) indicated that the suppression of mitochondrial ROS completely abrogated the UA-induced enhancement of mitochondrial uncoupling and glutathione reductase (GR)-mediated glutathione redox cycling, as well as protection against menadione cytotoxicity in H9c2 cells. Co-incubation with specific inhibitors of uncoupling proteins and GR almost completely prevented the cytoprotection afforded by UA against menadione induced cytotoxicity in H9c2 cells. The results obtained so far suggest that UA induced mitochondrial ROS production can elicit mitochondrial uncoupling and glutathione-dependent antioxidant responses, which offer cytoprotection against oxidant injury in H9c2 cells. PMID- 25515786 TI - The validation of an Italian version of the Freezing of Gait Questionnaire. AB - Freezing of gait (FOG) is a common and disabling symptom in Parkinson's disease (PD) and its staging is complex because of its episodic nature. Patient-reported assessments are essential in evaluating this disabling symptom. The Freezing of Gait Questionnaire (FOG-Q) is considered a valid and reliable tool for the assessment of FOG severity. The aim of our study was to validate the Italian version of FOG-Q and to investigate for its association with several clinical aspects of PD. Fifty-one PD patients were administered the FOG-Q and the timed up and go test. Moreover, patients were evaluated for the unified PD rating scale (UPDRS), the Hoehn and Yahr Scale (H&Y) and the falls-efficacy scale [FES(S)]. Mean (SD) FOG-Q item scores ranged between 1.5 and 2.7 (1.0-1.4); corrected item total correlations ranged between 0.63 and 0.86. The total FOG-Q score ranged between 0 and 24, with a mean + SD of 12.6 (6.2) and a median (q1-q3) of 12 (9 17). Reliability was 0.91. FOG-Q correlated with H&Y (0.36, p = 0.0091), UPDRS part III (rS = 0.27, p = 0.054), PD duration (rS = 0.35, p < 0.01), FES(S) (rS = 0.58, p < 0.001) and the timed up and go test (rS = 0.51, p = 0.001). Non significant positive correlations were observed for dyskinesia and motor fluctuations. Our study validates the Italian version of the FOG-Q, in that it results being a reliable instrument for assessing FOG in PD patients. PMID- 25515787 TI - Familial Creutzfeldt-Jakob disease with M232R mutation presented with corticobasal syndrome. PMID- 25515788 TI - Corticobasal syndrome-like variant of Creutzfeldt-Jakob disease: clinical description of two cases. PMID- 25515790 TI - Renalase is removed by kidneys and during dialysis - excess related to CKD complications? AB - BACKGROUND: The most common complications of chronic kidney disease (CKD) are hypertension and cardiovascular (CV) disorders. Renalase is produced and released by the kidney and also cardiomyocytes. Renalase deficiency was claimed to be responsible for hypertension and CV complication in CKD. There are contradictory data about serum renalase because of low activity and high levels revealed in hypertensive patients with CKD. We assessed serum renalase concentration in objects with CKD after one-side and both-side nephrectomy (on haemodialysis [HD]), or hemodiafiltration (HDF), in urine and ultrafiltrate in hemodialysis objects. We also evaluated the influence of hemodialysis sessions on renalase concentrations. METHODS: The concentration of renalase in plasma, ultrafiltrate and urine of 100 hemodialysis patients was assessed by commercially accessible test. We evaluated renalase in 17 HDF objects and 24 healthy controls. Western Blot test was also used to assess renalase concentration. RESULTS: Ultrafiltrate in hemodialysis objects contained renalase and there was no impact of dialysers' type (high-flux and low-flux). Renalase concentration of urine in control group was higher than in hemodialysis objects (n=60). The anuric group had higher renalase concentration comparing to those with remaining diuresis (p<0.001). Univariate analysis revealed the correlation between renalase concentration in plasma and in urine (r=-0.28, p<0.05) and ultrafiltrate renalase in hemodialysis group and between renalase in urine in the control group (r=0.61, p<0.01). There was a correlation between urinary renalase and residual diuresis, hemodialysis sessions non-significantly lowered renalase, the type of heparin had no effect on serum renalase levels. HDF patients had significantly lower renalase than HD patients. In Western blot analysis we found that patients after bilateral nephrectomy had the highest renalase, followed by unilateral nephrectomy. CONCLUSION: Kidneys eliminate renalase and it is possible that the increased renalase has the impact on cardiovascular diseases in chronic kidney disease. PMID- 25515789 TI - Curcumin attenuates opioid tolerance and dependence by inhibiting Ca2+/calmodulin dependent protein kinase II alpha activity. AB - Chronic use of opioid analgesics has been hindered by the development of opioid addiction and tolerance. We have reported that curcumin, a natural flavonoid from the rhizome of Curcuma longa, attenuated opioid tolerance, although the underlying mechanism remains unclear. In this study, we tested the hypothesis that curcumin may inhibit Ca(2+)/calmodulin-dependent protein kinase II alpha (CaMKIIalpha), a protein kinase that has been previously proposed to be critical for opioid tolerance and dependence. In this study, we used state-of-the-art polymeric formulation technology to produce poly(lactic-co-glycolic acid) (PLGA) curcumin nanoparticles (nanocurcumin) to overcome the drug's poor solubility and bioavailability, which has made it extremely difficult for studying in vivo pharmacological actions of curcumin. We found that PLGA-curcumin nanoparticles reduced the dose requirement by 11- to 33-fold. Pretreatment with PLGA-curcumin (by mouth) prevented the development of opioid tolerance and dependence in a dose dependent manner, with ED50 values of 3.9 and 3.2 mg/kg, respectively. PLGA curcumin dose-dependently attenuated already-established opioid tolerance (ED50 = 12.6 mg/kg p.o.) and dependence (ED50 = 3.1 mg/kg p.o.). Curcumin or PLGA curcumin did not produce antinociception by itself or affect morphine (1-10 mg/kg) antinociception. Moreover, we found that the behavioral effects of curcumin on opioid tolerance and dependence correlated with its inhibition of morphine-induced CaMKIIalpha activation in the brain. These results suggest that curcumin may attenuate opioid tolerance and dependence by suppressing CaMKIIalpha activity. PMID- 25515791 TI - Mild hypothermia induces incomplete left ventricular relaxation despite spontaneous bradycardia in pigs. AB - AIM: Mild hypothermia (MH) decreases left ventricular (LV) end-diastolic capacitance. We sought to clarify whether this results from incomplete relaxation. METHODS: Ten anaesthetized pigs were cooled from normothermia (NT, 38 degrees C) to MH (33 degrees C). LV end-diastolic pressure (LVPed), volume (LVVed) and pressure-volume relationships (EDPVRs) were determined during stepwise right atrial pacing. LV capacitance (i.e. LVVed at LVPed of 10 mmHg, LV VPed10) was derived from the EDPVR. Pacing-induced changes of diastolic indices (LVPed, LVVed and LV VPed10) were analysed as a function of (i) heart rate and (ii) the ratio between diastolic time interval (t-dia) and LV isovolumic relaxation constant tau, which was calculated using a logistic fit (tauL ) and monoexponential fit with zero asymptote (tauZ ) and nonzero asymptote (tauNZ ). RESULTS: Mild hypothermia decreased heart rate (85 +/- 4 to 68 +/- 3 bpm), increased tauL (22 +/- 1 to 57 +/- 4 ms), tauZ (26 +/- 2 to 56 +/- 5 ms) and tauNZ (41 +/- 1 to 96 +/- 5 ms), decreased t-dia/tau ratios, and shifted the EDPVR leftwards compared to NT (all P < 0.05). During NT, pacing at >=140 bpm shifted the EDPVR progressively leftwards. During MH, relationships between diastolic indices and heart rate were shifted towards lower heart rates compared to NT. However, relationships between diastolic indices and t-dia/tau during NT and MH were superimposable. CONCLUSION: We conclude that the loss of LV end diastolic capacitance during MH can be explained at least in part by slowed LV relaxation. MH thereby is an example of incomplete LV relaxation at a spontaneous low heart rate. Caution may be advised, when heart rate is increased in patients treated with MH. PMID- 25515792 TI - Idiopathic pulmonary haemosiderosis: spectrum of thoracic imaging findings in the adult patient. AB - Idiopathic pulmonary haemosiderosis (IPH) is a rare disease characterized by alveolar capillary haemorrhage resulting in deposition and accumulation of haemosiderin in the lungs. Although its precise pathophysiology remains unclear, several hypotheses have been proposed to explain the aetiology of the disorder, including autoimmune, environmental, allergic, and genetic theories. IPH is typically diagnosed in childhood, usually before the age of 10 years; however, this entity may be encountered in older patients given the greater awareness of the diagnosis, availability and utilization of advanced imaging techniques, and improved treatment and survival. The classic presentation of IPH consists of the triad of haemoptysis, iron-deficiency anaemia, and pulmonary opacities on chest radiography. The diagnosis is usually confirmed via bronchoscopy with bronchoalveolar lavage (BAL), at which time haemosiderin-laden macrophages referred to as siderophages, considered pathognomonic for IPH, may be identified. However, lung biopsy may ultimately be necessary to exclude other disease processes. For children with IPH, the disease course is severe and the prognosis is poor. However, adults generally have a longer disease course with milder symptoms and the prognosis is more favourable. Specific imaging features, although non-specific in isolation, may be identified on thoracic imaging studies, principally chest radiography and CT, depending on the phase of disease (acute or chronic). Recognition of these findings is important to guide appropriate clinical management. PMID- 25515793 TI - Paediatric parotid neoplasms: a 10 year retrospective imaging and pathology review of these rare tumours. AB - AIM: To determine the relative incidence of benign and malignant paediatric parotid gland tumours and whether particular presenting symptoms or imaging characteristics were more likely to predict malignancy. MATERIALS AND METHODS: Hospital records were reviewed for all patients <18 years with histopathology proven parotid neoplasms over the 10 year period from 2003-2013. Infantile haemangiomas and patients with neurofibromatosis type I were excluded. The presenting clinical symptoms for each patient were recorded. All available CT and MRI examinations for these patients were evaluated for tumour imaging characteristics. RESULTS: Seventeen patients (nine boys, eight girls; age range 2 17 years) were identified with neoplastic parotid masses; 11 tumours were malignant (65%) and six were benign (35%). The malignant tumours consisted of three acinic cell carcinomas, two mucoepidermoid carcinomas, one alveolar rhabdomyosarcoma, one poorly differentiated carcinoma, one low-grade adenocarcinoma, and three metastases (two melanoma, one orbital medulloepithelioma). The benign tumours consisted of five pleomorphic adenomas and one schwannoma. Presenting clinical symptoms were similar between benign and malignant tumours. Twelve MRI and six CT examinations were available for review with five patients undergoing both techniques. MRI features commonly identified with malignant tumours included: hypointense T2 signal, restricted diffusion, ill defined borders, and focal necrosis. Only four of the six tumours imaged at CT were visualized, and of those, the margins were indeterminate in three patients. CONCLUSION: Paediatric parotid masses are more likely to be malignant than benign. Presenting clinical symptoms and CT are not helpful for distinguishing benign and malignant disease. MRI features such as T2 hypointensity, restricted diffusion, ill-defined borders, and focal necrosis, although not specific, should raise concern for malignancy. PMID- 25515794 TI - MRI appearances of pure epithelial papillary serous borderline ovarian tumours. AB - Borderline epithelial ovarian tumours (BOT) represent 15-20% of all non-benign ovarian epithelial neoplasms. Compared to malignant ovarian tumours, they usually present at a younger age and carry a far superior prognosis. Fertility-conserving surgery is an important treatment option for patients with BOT. Ultrasound and CT are both widely available and play roles in the initial investigation and staging of BOT, respectively. However, lack of soft-tissue contrast limits their ability to characterize BOT. MRI can facilitate recognition of pure epithelial serous BOT (SBOT), including the cystic papillary and surface papillary subtypes. An abundance of hyperintense papillary projections with low signal internal branching and ovarian stroma preservation with a hypointense ovarian capsular margin on T2-weighted imaging are features strongly suggestive of SBOT. In this review we will discuss the general morphological features of SBOT, the benefits and drawbacks of ultrasound and CT in the initial work-up, and the principal MRI features enabling recognition of surface papillary and cystic papillary SBOT. PMID- 25515796 TI - Making metabolism accessible and meaningful: is the definition of a central metabolic dogma within reach? AB - Intermediary metabolism, a dominant research area before the emergence of molecular biology, is attracting renewed interest for fundamental and applied reasons as documented here. Nonetheless, the field may appear to be a thicket precluding entry to all but the most determined. Here we present a metabolic overview that makes this important and fascinating area accessible to a broad range of the molecular biological and biotechnological communities that are being attracted to biological problems crying out for metabolic solutions. This is accomplished by identifying seven key concepts, a so-called metabolic central dogma, that provide a core understanding analogous to the "Central Dogma of Molecular Biology" which focused upon maintenance and flow of genetic information. PMID- 25515795 TI - CXCL10/XCL1 fusokine elicits in vitro and in vivo chemotaxis. AB - Fusokines are proteins formed by the fusion of two cytokines. They have greater bioavailability and therapeutic potential than individual cytokines or a combination of different cytokines. Interferon-gamma-inducible protein 10 (CXCL10) and lymphotactin (XCL1) are members of the chemotactic family of cytokines, which induce tumor regression by eliciting immune-system cell chemotaxis. We engineered a replication-deficient adenoviral system expressing CXCL10/XCL1 fusokine (Ad FIL) and assessed its chemotactic response in vitro and in vivo. The CXCL10/XCL1 fusokine elicited a greater chemotactic effect in IL-2 stimulated lymphocytes than individual or combined cytokines in vitro. CXCL10/XCL1 fusokine biological activity was demonstrated in vivo by intratumoral chemoattraction of CXCR3+ cells. Thus, this novel CXCL10/XCL1 fusokine may represent a potential tool for gene therapy treatment of cancer and other illnesses that require triggering immune-system cell recruitment. PMID- 25515797 TI - Enhanced cadaverine production from L-lysine using recombinant Escherichia coli co-overexpressing CadA and CadB. AB - The effect of fusing the PelB signal sequence to lysine/cadaverine antiporter (CadB) on the bioconversion of L-lysine to cadaverine was investigated. To construct a whole-cell biocatalyst for cadaverine production, four expression plasmids were constructed for the co-expression of lysine decarboxylase (CadA) and lysine/cadaverine antiporter (CadB) in Escherichia coli. Expressing CadB with the PelB signal sequence increased cadaverine production by 12%, and the optimal expression plasmid, pETDuet-pelB-CadB-CadA, contained two T7 promoter-controlled genes, CadA and the PelB-CadB fusion protein. Based on pETDuet-pelB-CadB-CadA, a whole-cell system for the bioconversion of L-lysine to cadaverine was constructed, and three strategies for L-lysine feeding were evaluated to eliminate the substrate inhibition problem. A cadaverine titer of 221 g l(-1) with a molar yield of 92% from lysine was obtained. PMID- 25515798 TI - Improvement on the thermal stability and activity of plant cytosolic ascorbate peroxidase 1 by tailing hyper-acidic fusion partners. AB - Cytosolic ascorbate peroxidase 1 (APX1) plays a crucial role in regulating the level of plant cellular reactive oxygen species and its thermolability is proposed to cause plant heat-susceptibility. Herein, several hyper-acidic fusion partners, such as the C-terminal peptide tails, were evaluated for their effects on the thermal stability and activity of APX1 from Jatropha curcas and Arabidopsis. The hyper-acidic fusion partners efficiently improved the thermostability and prevented thermal inactivation of APX1 in both plant species with an elevated heat tolerance of at least 2 degrees C. These hyper-acidified thermostable APX1 fusion variants are of considerable biotechnological potential and can provide a new route to enhance the heat tolerance of plant species especially of inherent thermo-sensitivity. PMID- 25515799 TI - Enhanced extracellular production of alpha-amylase in Bacillus subtilis by optimization of regulatory elements and over-expression of PrsA lipoprotein. AB - alpha-Amylase was used as a heterologous model protein to investigate the effects of promoters, signal peptides and over-expression of an extra-cytoplasmic molecular chaperone, PrsA lipoprotein, on enhancing the secretion of alpha amylase in Bacillus subtilis. Four promoters and six signal peptides were compared, successively, and the highest yield of alpha-amylase was achieved under the promotion mediated by PAprE, a strong constitutive promoter, and secretion by SPnprE, a signal peptide from B. subtilis. Moreover, under conditions of overexpressed PrsA lipoprotein, the secretion production and activity of alpha amylase increased to 2.5-fold. The performance of the recombinant B. subtilis 1A751PL31 was evaluated with a fed-batch fermentation in a 7.5 l fermentor. Optimization of regulatory elements and over-expression of PrsA lipoprotein had a significant effect on enhancing the production of alpha-amylase in B. subtilis. PMID- 25515800 TI - Effectiveness of coping strategies intervention on caregiver burden among caregivers of elderly patients with dementia. AB - BACKGROUND: Coping strategies are a potential way to improve interventions designed to manage the caregiver burden of dementia. The purpose of this study was to develop an intervention targeted towards improving coping strategies and to examine its effectiveness on reducing caregiver burden. METHODS: A controlled study design was used. Fifty-seven caregivers of dementia patients were enrolled. Coping strategies were assessed with the Revised Ways of Coping Checklist (WCCL R) and caregiver burden was assessed with the Chinese version of the Caregiver Burden Inventory. The participants were randomly divided into two groups. The intervention group was offered a series of five interventions in which problem solving skills, knowledge of dementia, social resources, and emotional support were taught every 2 weeks, and the control group was telephoned every 2 weeks for the usual clinical management. Two weeks after the end of the intervention, we again administered the WCCL-R and the Caregiver Burden Inventory. Two-way repeated-measure anova was used to evaluate the changes in coping strategies and caregiver burden. RESULTS: Forty-six participants completed the study. No statistically significant differences were noted in the demographic data between the two groups. On the problem-focused coping subscale on the WCCL-R, the intervention group's mean score increased by 3.8 points, and the control group's decreased by 5.1 points (F = 7.988, P = 0.007). On the seeking social support coping subscale on the WCCL-R, the intervention group's mean score increased by 3.8 points, and the control group's decreased by 3.1 points (F = 4.462, P = 0.04). On the Caregiver Burden Inventory, the intervention group's mean score decreased by 7.2 points, and the control group's increased by 2.2 points (F = 6.155, P = 0.017). CONCLUSIONS: Psychosocial intervention can help caregivers to adopt more problem-focused and social support coping strategies, which are beneficial in terms of reducing the caregiver burden. PMID- 25515801 TI - Wernicke encephalopathy in children and adolescents. AB - BACKGROUND: Wernicke encephalopathy is caused by thiamine (vitamin B1) deficiency. It is generally considered to be a disease of adult alcoholics. However, it is known to occur in the pediatric population and in non-alcoholic conditions. DATA SOURCES: We searched PubMed with the key words Wernicke, thiamine, pediatric, children and adolescents and selected publications that were deemed appropriate. RESULTS: The global prevalence rates of hunger, poverty and resultant nutrient deprivation have decreased in the 21st century. However, several scenarios which may predispose to Wernicke encephalopathy may be increasingly prevalent in children and adolescents such as malignancies, intensive care unit stays and surgical procedures for the treatment of obesity. Other predisposing conditions include magnesium deficiency and defects in the SLC19A3 gene causing thiamine transporter-2 deficiency. The classic triad consists of encephalopathy, oculomotor dysfunction and gait ataxia but is not seen in a majority of patients. Treatment should be instituted immediately when the diagnosis is suspected clinically without waiting for laboratory confirmation. Common magnetic resonance findings include symmetric T2 hyperintensities in dorsal medial thalamus, mammillary bodies, periaqueductal gray matter, and tectal plate. CONCLUSIONS: Wernicke encephalopathy is a medical emergency. Delay in its recognition and treatment may lead to significant morbidity, irreversible neurological damage or even death. This article aims to raise the awareness of this condition among pediatricians. PMID- 25515802 TI - Complementary and alternative medicine in pediatrics in Turkey. AB - BACKGROUND: Complementary and alternative medicine (CAM) is applied both to children and adults widely throughout the world. A previous pan-European survey showed a surprisingly high CAM-use in Turkish children. This review aimed to survey information on the use of CAM in pediatrics in Turkey. DATA SOURCES: A narrative, non-systematic review was conducted by melding expert opinions with a thorough and balanced review of available evidence. An unrestricted literature search using the key words, "alternative", "complementary", "integrative", "prevalence" and "pediatric" or "children" and "Turkey" was performed by internet search in March, 2012 using PubMed and Google Scholar. RESULTS: CAM use was examined in general pediatrics, pediatric oncology, patients with asthma, and patients with diabetes. A frequency of CAM use was 87% in Turkish pediatric patients, with a mean of 60%. The primary sources of information about CAM are family and friends. Communication with patients/parents and health care professionals showed that most parents do not speak about CAM use with their physicians or nurses. CONCLUSIONS: CAM is extensively used in Turkish pediatric patients. This might be due to Turkey's status as a developing country in which a traditional medical system still dominates in comparison to developed countries. Thus, larger studies are required to prove an extensive use of CAM in Turkey, as this review article does not have the capacity for in-depth analysis. Knowledge about CAM and its related topics is essential for physicians and nurses in order to meet the patients' wish for a competent consultation concerning all aspects of a possible therapy. PMID- 25515803 TI - Ontogeny of the mammalian kidney: expression of aquaporins 1, 2, 3, and 4. AB - BACKGROUND: Determining the expression and functions of aquaporins (AQPs) in the adult kidney has generated important information about the roles of this protein family in the renal regulation of water homeostasis. However, limited information describes the expression of AQPs in fetal kidneys, and most reports on fetal renal AQPs originate from animal studies. Although there are the maturation and regulation of the renal-concentrating mechanism, the ways in which changes in the expression of AQPs contribute to the formation of urine during the perinatal period remain unclear. DATA SOURCES: This review summarizes current knowledge about the spatial and temporal expression patterns of AQP1, AQP2, AQP3, and AQP4 in the fetal and postnatal kidneys in different animal species and in human beings. RESULTS: AQP1 and AQP2 expression can be detected earlier in gestation in human beings and sheep compared with mice and rats. AQP1 expression is detected earlier in the proximal tubules than the expression of AQP2, AQP3, and AQP4 in the collecting ducts. CONCLUSION: Further studies investigating the regulation of AQPs during kidney development may provide insights into normal water-handling mechanisms and the pathophysiology of fetal kidneys, which may determine new directions for the clinical treatment of kidney diseases. PMID- 25515804 TI - Topical treatment with propranolol gel as a supplement to the existing treatment of hemangiomas. AB - BACKGROUND: Systemic treatment with propranolol is proven to be effective for patients with hemangiomas with less side-effect. We used a propranolol gel for topical use on hemangiomas. METHODS: In this retrospective study, we analyzed 148 patients who had been treated topically with propranolol gel for 12 weeks. We analyzed the data of patients and clinically gave each hemangioma a "hemangioma score" to determine the treatment success. RESULTS: In 147 of the 148 patients, strong signs of resolution under treatment included lightening, paling, and less vascularization. The hemangioma score showed a significant decrease during the treatment. Relevant serum levels of propranolol were not found. Adverse effects were rare and not related to propranolol. CONCLUSION: Topical treatment with propranolol gel is suitable for specific hemangiomas in addition to cryotherapy and systemic treatment with propranolol. PMID- 25515805 TI - Anthropometric assessment of a Middle Eastern group of autistic children. AB - BACKGROUND: Growth abnormalities are uniquely associated with autism spectrum disorders (ASD); however, the extent to which growth abnormalities are present has hardly been investigated. The current study aims to compare the differences in anthropometric parameters in a group of autistic Egyptian children and the healthy normal population. METHODS: We recruited 100 children with ASD from the Outpatient Clinic for "Autistic Children" at the Medical Research Hospital of Excellence, National Research Centre in Cairo, Egypt. They were diagnosed by DSM IV criteria of the American Psychiatric Association, Autism Diagnostic Interview Revised, and Childhood Autism Rating Scale. Of these children at age of 3-10 years, 71 were males and 29 females. Eight anthropometric parameters were assessed in view of data of the healthy Egyptians of pertinent sex and age. RESULTS: Weight and body mass index increased because of a significant increase in subcutaneous fat thickness. This tendency with a probable decrease in muscle mass was more evident in male or in older children, likely resulting from sedentary life style and food selectivity. CONCLUSIONS: The Z head circumference score and its variance significantly increased especially in males or older children, suggesting the relative overgrowth of the brain in a substantial percentage of Egyptian children with autism. We concluded that increased fat composition in Egyptian autistic children with decreased muscle mass necessitates tailoring a specially designed food supplementation program to ameliorate the severity of autism symptoms. PMID- 25515806 TI - Novel and functional DNA sequence variants within the GATA5 gene promoter in ventricular septal defects. AB - BACKGROUND: Congenital heart disease (CHD) is the most common human birth defect. Genetic causes for CHD remain largely unknown. GATA transcription factor 5 (GATA 5) is an essential regulator for the heart development. Mutations in the GATA5 gene have been reported in patients with a variety of CHD. Since misregulation of gene expression have been associated with human diseases, we speculated that changed levels of cardiac transcription factors, GATA5, may mediate the development of CHD. METHODS: In this study, GATA5 gene promoter was genetically and functionally analyzed in large cohorts of patients with ventricular septal defect (VSD) (n=343) and ethnic-matched healthy controls (n=348). RESULTS: Two novel and heterozygous DNA sequence variants (DSVs), g.61051165A>G and g.61051463delC, were identified in three VSD patients, but not in the controls. In cultured cardiomyocytes, GATA5 gene promoter activities were significantly decreased by DSV g.61051165A>G and increased by DSV g.61051463delC. Moreover, fathers of the VSD patients carrying the same DSVs had reduced diastolic function of left ventricles. Three SNPs, g.61051279C>T (rs77067995), g.61051327A>C (rs145936691) and g.61051373G>A (rs80197101), and one novel heterozygous DSV, g.61051227C>T, were found in both VSD patients and controls with similar frequencies. CONCLUSION: Our data suggested that the DSVs in the GATA5 gene promoter may increase the susceptibility to the development of VSD as a risk factor. PMID- 25515807 TI - Antenatal use of bosentan and/or sildenafil attenuates pulmonary features in rats with congenital diaphragmatic hernia. AB - BACKGROUND: Lung hypoplasia, pulmonary persistent hypertension of the newborn and its morphological changes are the main features in congenital diaphragmatic hernia (CDH). This study was undertaken to investigate if antenatal use of sildenafil and/or bosentan attenuates vascular remodeling, promotes branching, and improves alveolarization in experimental nitrofeninduced CDH. METHODS: Nitrofen (100 mg) was gavage-fed to pregnant rats at post conception day (PCD) 9 to induce CDH. The rats were randomized to 5 groups: 1) control; 2) nitrofen; 3) nitrofen+sildenafil 100 mg/kg per day at PCD 16-20; 4) nitrofen+bosentan 30 mg/kg per day, at PCD 16-20, and 5) nitrofen+bosentan+sildenafil, same doses and administration days. After cesarean delivery, the offsprings were sacrificed. The diaphragmatic defect and pulmonary hypoplasia were identified, and the lungs were dissected. Arterial wall thickness, bronchiolar density and alveolarization were assessed. RESULTS: The offsprings with CDH were characterized by severe pulmonary hypoplasia (lung weight-to-body weight ratio: 0.0263 [95% confidence interval (CI) 0.0242-0.0278)] in the nitrofen group versus 0.0385 (95% CI 0.0355-0.0424) in the control group (P=0.0001). Pulmonary arterial wall thickness was decreased to 3.0 (95% CI 2.8-3.7) MUm in the nitrofen+sildenafil group versus 5.0 (95% CI 4.1-4.9) MUm in the nitrofen group (P=0.02). Terminal bronchioles increased to 13.7 (95% CI 10.7-15.2) MUm in the nitrofen+bosentan group in contrast to 8.7 (95% CI 7.2-9.4) MUm in the nitrofen group (P=0.002). More significant differences (P=0.0001) were seen in terminal bronchioles in the nitrofen+sildenafil+bosentan group than in the nitrofen group [14.0 (95% CI 12.5 15.4) MUm versus 8.5 (95% CI 7.1-9.3) MUm]. Pulmonary arterial wall thickness was also decreased in the former group. CONCLUSIONS: In this rat model, antenatal treatment with sildenafil attenuates vascular remodeling. Bosentan promotes the development of terminal bronchioles in nitrofen-induced CDH. PMID- 25515808 TI - Clinical characteristics and risk factors of severe respiratory syncytial virus associated acute lower respiratory tract infections in hospitalized infants. AB - BACKGROUND: To investigate the clinical characteristics and analyze risk factors for severe respiratory syncytial virus (RSV) infection in hospitalized infants with acute lower respiratory tract infections (ALRIs). METHODS: A retrospective review of the medical records of infants with RSV-associated ALRIs between March 1st, 2011 and February 29th, 2012 was conducted. Subjects were followed up over the phone or by outpatient visit six and twelve months after discharge. RESULTS: Among 913 RSV-associated ALRIs infants, 288 (31.5%) had severe infections, which accounted for 4.2% of hospitalized children. The hospital RSV mortality rate was 1.0%. The proportions of cases with tachypnea, apnea, cyanosis, and fine rales were significantly higher in the severe ALRIs group (all P<0.001). Multivariate logistic regression showed that low-birth-weight [1.698 (1.028-2.805)], age less than 3 months old [3.385 (2.174-5.271)], congenital heart disease [1.667 (1.149 2.418)], bronchopulmonary dysplasia [8.505 (1.731-41.780)], and airway abnormalities [2.246 (1.008-5.005)] were independent risk factors for severe ALRIs. The incidence of bronchitis, pneumonia and readmission in the severe group was significantly higher than that of the non-severe group during the one-year follow-up (all P<0.001). CONCLUSIONS: Younger age, low birth weight and underlying disease are associated with severe RSVassociated ALRIs. Furthermore, severe RSV infections may be associated with a higher frequency of subsequent bronchitis, pneumonia and re-hospitalization in the following year. PMID- 25515809 TI - Cutaneous bronchogenic cyst in the left scapular region of a boy. AB - BACKGROUND: Scapular bronchogenic cyst (SBC) is rare. METHODS: A sinus on a boy's left scapula was excised. RESULTS: Histopathological analysis showed the epithelium with scattered PAS-positive goblet cells was positive for CEA and CK7. CONCLUSION: SBC should be suspected of a superficial scapular skin lesion in children. PMID- 25515810 TI - Imaging findings of multiple infantile hepatic hemangioma associated with cardiac insufficiency. AB - BACKGROUND: Infantile hepatic hemangioma (IHH) as a benign liver tumor in infancy and childhood is commonly associated with high output cardiac failure. The present study aims to describe the imaging findings in a patient who was diagnosed as having multiple IHH with congestive cardiac insufficiency. METHODS: The imaging findings and clinical manifestations of the patient with multiple IHH associated with cardiac insufficiency were retrospectively reviewed. RESULTS: Ultrasonography showed multiple intrahepatic lesions with mixed echoes and markedly expanded hepatic veins and the inferior vena cava of the patient. Echocardiography revealed right heart insufficiency and pulmonary hypertension. Contrast-enhanced MRI showed early mild enhancement of lesions and more obvious delayed enhancement. The patient died after combined therapy of surgery and hormone. CONCLUSIONS: The imaging findings of multiple IHH associated with cardiac insufficiency are typical and diagnostic. Early imaging assessment may facilitate the diagnosis and treatment of the disease. PMID- 25515811 TI - Moyamoya disease associated with aortic coarctation. PMID- 25515812 TI - Metabolic engineering of Escherichia coli for the biosynthesis of flavonoid-O glucuronides and flavonoid-O-galactoside. AB - Most flavonoids are glycosylated and the nature of the attached sugar can strongly affect their physiological properties. Although many flavonoid glycosides have been synthesized in Escherichia coli, most of them are glucosylated. In order to synthesize flavonoids attached to alternate sugars such as glucuronic acid and galactoside, E. coli was genetically modified to express a uridine diphosphate (UDP)-dependent glycosyltransferase (UGT) specific for UDP glucuronic acid (AmUGT10 from Antirrhinum majus or VvUGT from Vitis vinifera) and UDP-galactoside (PhUGT from Petunia hybrid) along with the appropriate nucleotide biosynthetic genes to enable simultaneous production of their substrates, UDP glucuronic acid and UDP-galactose. To engineer UDP-glucuronic acid biosynthesis, the araA gene encoding UDP-4-deoxy-4-formamido-L-arabinose formyltransferase/UDP glucuronic acid C-4" decarboxylase, which also used UDP-glucuronic acid as a substrate, was deleted in E. coli, and UDP-glucose dehydrogenase (ugd) gene was overexpressed to increase biosynthesis of UDP-glucuronic acid. Using these strategies, luteolin-7-O-glucuronide and quercetin-3-O-glucuronide were biosynthesized to levels of 300 and 687 mg/L, respectively. For the synthesis of quercetin 3-O-galactoside, UGE (encoding UDP-glucose epimerase from Oryza sativa) was overexpressed along with a glycosyltransferase specific for quercetin and UDP galactose. Using this approach, quercetin 3-O-galactoside was successfully synthesized to a level of 280 mg/L. PMID- 25515813 TI - Selection of a novel FGF23-binding peptide antagonizing the inhibitory effect of FGF23 on phosphate uptake. AB - Fibroblast growth factor 23 (FGF23) is a bone-derived endocrine regulator of phosphate homeostasis and has been considered as a potential therapeutic target for hypophosphatemic disorders. Herein, we isolated a novel FGF23-binding peptide by screening a phage display library with FGF23180-205, the minimal epitope of FGF23 binding to the binary fibroblast growth factor receptor (FGFR)-Klotho complex. The corresponding peptide (referred to as 23-b6) showed high homology to the immunoglobulin-like (Ig-like) domain III (D3) of FGFR1c, the predominant receptor mediating the phosphaturic activity of FGF23. The 23-b6 peptide and panning target FGF23180-205 carried opposite charges and shared similar hydrophilic profiles. Functional analysis indicated that synthetic 23-b6 peptide exhibited antagonistic effect on the inhibition of phosphate uptake by FGF23 in opossum kidney cells (OK cells). The mechanisms of 23-b6 peptide impairing the bioactivity of FGF23 involved blockade of the activation of Erk cascade and up regulation of NaPi-2a and NaPi-2c expression in OK cells. Our results demonstrate that the 23-b6 peptide is a potent FGF23 antagonist with increased effect on phosphate uptake in kidney cells and might have therapeutic potentials in hypophosphatemic disorders characterized by an abnormally high level of FGF23. PMID- 25515814 TI - The response of Chlamydomonas reinhardtii to nitrogen deprivation: a systems biology analysis. AB - Drastic alteration in macronutrients causes large changes in gene expression in the photosynthetic unicellular alga Chlamydomonas reinhardtii. Preliminary data suggested that cells follow a biphasic response to this change hinging on the initiation of lipid accumulation, and we hypothesized that drastic repatterning of metabolism also followed this biphasic modality. To test this hypothesis, transcriptomic, proteomic, and metabolite changes that occur under nitrogen (N) deprivation were analyzed. Eight sampling times were selected covering the progressive slowing of growth and induction of oil synthesis between 4 and 6 h after N deprivation. Results of the combined, systems-level investigation indicated that C. reinhardtii cells sense and respond on a large scale within 30 min to a switch to N-deprived conditions turning on a largely gluconeogenic metabolic state, which then transitions to a glycolytic stage between 4 and 6 h after N depletion. This nitrogen-sensing system is transduced to carbon- and nitrogen-responsive pathways, leading to down-regulation of carbon assimilation and chlorophyll biosynthesis, and an increase in nitrogen metabolism and lipid biosynthesis. For example, the expression of nearly all the enzymes for assimilating nitrogen from ammonium, nitrate, nitrite, urea, formamide/acetamide, purines, pyrimidines, polyamines, amino acids and proteins increased significantly. Although arginine biosynthesis enzymes were also rapidly up regulated, arginine pool size changes and isotopic labeling results indicated no increased flux through this pathway. PMID- 25515816 TI - Role of toll-like receptors in myocardial infarction. AB - Toll-like receptors (TLRs) play a pivotal role in both innate and adaptive immunity, and TLRs recognize invading pathogens through molecular pattern recognition, and ultimately lead to the activation of transcription factors and inflammatory responses. Myocardial infarction leads to changes in the remodeling of the left ventricle of the heart, and the degree and type of remodeling provides important diagnostic information for the therapeutic management of ischemic heart disease. Innate immune takes a most important role in myocardial infarction. There are some studies reporting that TLRs play an important role in the myocardial infarction. The literatures were searched extensively and this review was performed to review the role of TLRs in myocardial infarction. PMID- 25515817 TI - Nutrition affects Sertoli cell function but not Sertoli cell numbers in sexually mature male sheep. AB - We tested whether the reversible effects of nutrition on spermatogenesis in sexually mature sheep were mediated by Sertoli cells. Rams were fed with diets designed to achieve a 10% increase (High), no change (Maintenance) or a 10% decrease (Low) in body mass after 65 days. At the end of treatment, testes were lighter in the Low than the High group (PP<0.05) in the expression of seven Sertoli cell-specific genes. Under-nutrition appeared to reverse cellular differentiation leading to disruption of tight-junction morphology. In conclusion, in sexually mature sheep, reversible reductions in testis mass and spermatogenesis caused by under-nutrition were associated with impairment of basic aspects of Sertoli cell function but not with changes in the number of Sertoli cells. PMID- 25515815 TI - Complete mitochondrial genomes of the human follicle mites Demodex brevis and D. folliculorum: novel gene arrangement, truncated tRNA genes, and ancient divergence between species. AB - BACKGROUND: Follicle mites of the genus Demodex are found on a wide diversity of mammals, including humans; surprisingly little is known, however, about the evolution of this association. Additional sequence information promises to facilitate studies of Demodex variation within and between host species. Here we report the complete mitochondrial genome sequences of two species of Demodex known to live on humans--Demodex brevis and D. folliculorum--which are the first such genomes available for any member of the genus. We analyzed these sequences to gain insight into the evolution of mitochondrial genomes within the Acariformes. We also used relaxed molecular clock analyses, based on alignments of mitochondrial proteins, to estimate the time of divergence between these two species. RESULTS: Both Demodex genomes shared a novel gene order that differs substantially from the ancestral chelicerate pattern, with transfer RNA (tRNA) genes apparently having moved much more often than other genes. Mitochondrial tRNA genes of both species were unusually short, with most of them unable to encode tRNAs that could fold into the canonical cloverleaf structure; indeed, several examples lacked both D- and T-arms. Finally, the high level of sequence divergence observed between these species suggests that these two lineages last shared a common ancestor no more recently than about 87 mya. CONCLUSIONS: Among Acariformes, rearrangements involving tRNA genes tend to occur much more often than those involving other genes. The truncated tRNA genes observed in both Demodex species would seem to require the evolution of extensive tRNA editing capabilities and/or coevolved interacting factors. The molecular machinery necessary for these unusual tRNAs to function might provide an avenue for developing treatments of skin disorders caused by Demodex. The deep divergence time estimated between these two species sets a lower bound on the time that Demodex have been coevolving with their mammalian hosts, and supports the hypothesis that there was an early split within the genus Demodex into species that dwell in different skin microhabitats. PMID- 25515818 TI - Eosinophilic annular erythema in a patient with metastatic prostate adenocarcinoma. PMID- 25515819 TI - Case for cultural adaptation of psychological interventions for mental healthcare in low and middle income countries. PMID- 25515820 TI - Relationship of impaired-driving enforcement intensity to drinking and driving on the roads. AB - BACKGROUND: It is principally the area of enforcement that offers the greatest opportunity for reducing alcohol-impaired driving in the near future. How much of a reduction in drinking and driving would be achieved by how much improvement in enforcement intensity? METHODS: We developed logistic regression models to explore how enforcement intensity (6 different measures) related to the prevalence of weekend nighttime drivers in the 2007 National Roadside Survey who had been drinking (blood alcohol concentration [BAC] >= 0.00 g/dl), who had BACs >= 0.05 g/dl, and who were driving with an illegal BAC >= 0.08 g/dl. RESULTS: Drivers on the roads in our sample of 30 communities who were exposed to fewer than 228 traffic stops per 10,000 population aged 18 and older had 2.4 times the odds of being BAC positive, 3.6 times the odds of driving with a BAC >= 0.05, and 3.8 times the odds of driving with a BAC >= 0.08 compared to those drivers on the roads in communities with more than 1,275 traffic stops per 10,000 population. Drivers on the roads in communities with fewer than 3.7 driving under the influence (DUI) arrests per 10,000 population had 2.7 times the odds of BAC positive drivers on the roads compared to communities with the highest intensity of DUI arrest activity (>38 DUI arrests per 10,000 population). CONCLUSIONS: The number of traffic stops and DUI arrests per capita were significantly associated with the odds of drinking and driving on the roads in these communities. This might reflect traffic enforcement visibility. The findings in this study may help law enforcement agencies around the country adjust their traffic enforcement intensity to reduce impaired driving in their community. PMID- 25515821 TI - Metabonomic analysis of the anti-inflammatory effects of volatile oils of Angelica sinensis on rat model of acute inflammation. AB - Metabonomics based on GC-MS was used to study the possible anti-inflammatory mechanisms of volatile oils of Angelica sinensis (VOAS) in rats with acute inflammation. Acute inflammation was induced by subcutaneous injection of carrageenan in rats. The levels of prostaglandin E2 (PGE2 ), histamine (HIS) and 5-hydroxytryptamine (5-HT) in the inflammatory fluid were detected. Principal component analysis and orthogonal partial least squares-discriminant analysis models were performed for pattern recognition analysis. After the administration of VOAS, the levels of PGE2 , HIS, and 5-HT returned to levels observed in normal group. According to GC-MS analysis, the intervention of VOAS in rats with acute inflammation induced substantial and characteristic changes in their metabolic profiles. Fourteen metabolite biomarkers, namely, lactic acid, malic acid, citric acid, trans-dehydroandrosterone, aldosterone, linoleic acid, hexadecanoic acid, pregnenolone, octadecenoic acid, myristic acid, l-histidine, octadecanoic acid, arachidonic acid (AA) and l-tryptophan, were detected in the inflammatory fluid. The levels of all biomarkers either increased or decreased significantly in model groups. VOAS possibly intervened in the metabolic process of inflammation by altering histidine metabolism, tryptophan metabolism, AA metabolism, steroid hormone biosynthesis, fatty acid metabolism and energy metabolism. Metabonomics was used to reflect an organism's physiological and metabolic state comprehensively, and it is a potentially powerful tool that reveals the anti acute-inflammatory mechanism of VOAS. PMID- 25515822 TI - Type of retirement as a determinant of pre- and post-retirement hospital in patient care use: a prospective study. AB - BACKGROUND: We examined prospectively the use of all-cause hospital in-patient care among public sector employees by using a 3-year pre- and post-retirement study window. METHODS: A total of 5269 participants of the Finnish Longitudinal Study of Municipal Employees had retired during January 1984 and July 2000. They had register-based data on retirement (non-disability retirement n = 3411, men 40%, and diagnose-specific disability retirement n = 1858, men 50%) and all-cause hospital in-patient admissions and discharges. Analyses were conducted using Generalized Estimating Equation model. RESULTS: The prevalence of hospital care use for non-disability retirees remained stable during the 6-year study window. The rate ratio (RR) for hospital care use increased in the year prior to retirement for men and women who transitioned into disability retirement due to cardiovascular disease and for women with disability due to mental disease. The RRs for hospital care use in the post-retirement year decreased for men who retired due to cardiovascular disease or mental disorders and for women who retired due to cardiovascular or musculoskeletal diseases. CONCLUSIONS: An increase in hospital care preceding retirement in major diagnosis-specific disability retirement groups was followed by various patterns of decrease in the need of care indicated a beneficial health effect of retirement. PMID- 25515824 TI - Alcohol sensors and their potential for improving clinical care. PMID- 25515823 TI - Port-a-Cath extravasation of vesicant cytotoxics: surgical options for a rare complication of cancer chemotherapy. AB - BACKGROUND: Although implantation of a central venous device such as a Port-a Cath was initially considered safe, extravasation rates up to 4.7% have been reported. Therefore, the objective of this study was to propose a structured procedure for the management of extravasation of a cytotoxic treatment. METHODS: A total of eight patients were evaluated after port extravasation of epirubicin (n = 3), platinum compounds (n = 3), paclitaxel (n = 1), or trabectedin (n = 1) into the subcutaneous space. Immediate explantation of the port was performed in combination with a "Subcutaneous Wash-Out Procedure" (SWOP). When removal of the port was delayed, debridement and flap coverage were performed as necessary. Epirubicin concentrations present in the samples obtained during surgical intervention were subsequently analysed using high-performance liquid chromatography (HPLC). Patients were followed for at least six months and were examined for sequelae such as pain, induration, redness, and limited movement. RESULTS: All three patients whose extravasation event was detected during chemotherapy administration benefited from SWOP with acceptable side effects (e.g., erythema). The analysis of epirubicin concentrations demonstrated the active removal of relevant amounts of the compound by wound rinsing. In contrast, late detection of extravasation led to major debridement and flap coverage in four out of five patients. A high body mass index (BMI) value was associated with all of the patients that experienced port extravasation. CONCLUSION: Depending on when Port-a-Cath extravasations into subcutaneous tissue are detected, different treatments are appropriate. When extravasation is detected early, the SWOP was found to be beneficial. PMID- 25515825 TI - Handling the fragile vase of scientific practices. PMID- 25515826 TI - Ten reasons why journals must review manuscripts before results are known. PMID- 25515827 TI - We need more research on causes and consequences, as well as on solutions. PMID- 25515828 TI - Commentary on Hall (2015): The health effects of recreational cannabis use. PMID- 25515829 TI - Commentary on Zhou et al. (2015): Treating psychiatric comorbidity in adolescents -an important problem. PMID- 25515830 TI - Commentary on Nelson et al. (2015): Challenges of adopting and implementing effective alcohol policies. PMID- 25515831 TI - Commentary on Lundholm et al. (2015): What came first, the steroids or the violence? PMID- 25515832 TI - Subgroup analysis as a source of spurious findings: an illustration using new data on alcohol intake and coronary heart disease. PMID- 25515833 TI - Large increase in adolescent marijuana use in Chile. PMID- 25515837 TI - De rerum natura: a case of irritant phytodermatitis from Ranunculus bulbosus. PMID- 25515836 TI - Sodium channel slow inactivation as a therapeutic target for myotonia congenita. AB - OBJECTIVE: Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. In patients, muscle stiffness lessens with exercise, a change known as the warmup phenomenon. Our goal was to identify the mechanism underlying warmup and to use this information to guide development of novel therapy. METHODS: To determine the mechanism underlying warmup, we used a recently discovered drug to eliminate muscle contraction, thus allowing prolonged intracellular recording from individual muscle fibers during induction of warmup in a mouse model of myotonia congenita. RESULTS: Changes in action potentials suggested slow inactivation of sodium channels as an important contributor to warmup. These data suggested that enhancing slow inactivation of sodium channels might offer effective therapy for myotonia. Lacosamide and ranolazine enhance slow inactivation of sodium channels and are approved by the US Food and Drug Administration for other uses in patients. We compared the efficacy of both drugs to mexiletine, a sodium channel blocker currently used to treat myotonia. In vitro studies suggested that both lacosamide and ranolazine were superior to mexiletine. However, in vivo studies in a mouse model of myotonia congenita suggested that side effects could limit the efficacy of lacosamide. Ranolazine produced fewer side effects and was as effective as mexiletine at a dose that produced none of mexiletine's hypoexcitability side effects. INTERPRETATION: We conclude that ranolazine has excellent therapeutic potential for treatment of patients with myotonia congenita. PMID- 25515838 TI - Assessing segmentation processes by click detection: online measure of statistical learning, or simple interference? AB - Statistical learning can be used to extract the words from continuous speech. Gomez, Bion, and Mehler (Language and Cognitive Processes, 26, 212-223, 2011) proposed an online measure of statistical learning: They superimposed auditory clicks on a continuous artificial speech stream made up of a random succession of trisyllabic nonwords. Participants were instructed to detect these clicks, which could be located either within or between words. The results showed that, over the length of exposure, reaction times (RTs) increased more for within-word than for between-word clicks. This result has been accounted for by means of statistical learning of the between-word boundaries. However, even though statistical learning occurs without an intention to learn, it nevertheless requires attentional resources. Therefore, this process could be affected by a concurrent task such as click detection. In the present study, we evaluated the extent to which the click detection task indeed reflects successful statistical learning. Our results suggest that the emergence of RT differences between within and between-word click detection is neither systematic nor related to the successful segmentation of the artificial language. Therefore, instead of being an online measure of learning, the click detection task seems to interfere with the extraction of statistical regularities. PMID- 25515839 TI - Qualitative modeling of the decision-making process using electrooculography. AB - A novel method based on electrooculography (EOG) has been introduced in this work to study the decision-making process. An experiment was designed and implemented wherein subjects were asked to choose between two items from the same category that were presented within a limited time. The EOG and voice signals of the subjects were recorded during the experiment. A calibration task was performed to map the EOG signals to their corresponding gaze positions on the screen by using an artificial neural network. To analyze the data, 16 parameters were extracted from the response time and EOG signals of the subjects. Evaluation and comparison of the parameters, together with subjects' choices, revealed functional information. On the basis of this information, subjects switched their eye gazes between items about three times on average. We also found, according to statistical hypothesis testing-that is, a t test, t(10) = 71.62, SE = 1.25, p < .0001-that the correspondence rate of a subjects' gaze at the moment of selection with the selected item was significant. Ultimately, on the basis of these results, we propose a qualitative choice model for the decision-making task. PMID- 25515840 TI - Partial segmental thrombosis of the corpus cavernosum (PSTCC) diagnosed by contrast-enhanced ultrasound: a case report. AB - BACKGROUND: Partial segmental thrombosis of the corpus cavernosum (PSTCC) is a rare disease predominantly occurring in young men. Cardinal symptoms are pain and perineal swelling. Although several risk factors are described in the literature, the exact etiology of penile thrombosis remains unclear in most cases. MRI or ultrasound (US) is usually used for diagnosing this condition. CASE PRESENTATION: We report a case of penile thrombosis after left-sided varicocele ligature in a young patient. The diagnosis was established using contrast-enhanced ultrasound (CEUS) and was confirmed by contrast-enhanced magnetic resonance imaging (ceMRI). Successful conservative treatment consisted of systemic anticoagulation using low molecular weight heparin and acetylsalicylic acid. CONCLUSION: PSTCC is a rare condition in young men and appears with massive pain and perineal swelling. In case of suspected PSTCC utilization of CEUS may be of diagnostic benefit. PMID- 25515841 TI - High reproducibility of adenosine stress cardiac MR myocardial perfusion imaging in patients with non-ischaemic dilated cardiomyopathy. AB - OBJECTIVE: To evaluate the reproducibility of first-pass contrast-enhanced cardiac MR (CMR) myocardial perfusion imaging in patients with non-ischaemic dilated cardiomyopathy (NIDCM). DESIGN: Prospective observational study. SETTING: Single centre, tertiary care hospital. PARTICIPANTS: 6 outpatient participants with NIDCM. OUTCOME: Reproducibility of semiquantitative myocardial perfusion analysis by CMR. METHOD: 6 patients with NIDCM were studied twice using first pass of contrast transit through the left ventricular (LV) myocardium with a saturation-recovery gradient echo sequence at rest and during adenosine-induced hyperaemia. The anterior wall was divided into endocardial (Endo) and epicardial (Epi) segments. The Myocardial Perfusion Index (MPI) was calculated as the myocardial signal augmentation rate normalised to the LV cavity rate. The Myocardial Perfusion Reserve Index (MPRI) was calculated as hyperaemic/resting MPI. RESULTS: Between study 1 and 2, median MPI was similar for resting Endo (0.076 vs 0.077), hyperaemic Endo (0.143 vs 0.143), resting Epi (0.073 vs 0.074), and hyperaemic Epi (0.135 vs 0.134). Median MPRI was similar for Endo (1.84 vs 1.87) and Epi (1.90 vs 2.00). Combining Endo and Epi MPI (N=12), there was excellent agreement between Study 1 and 2 for resting MPI (r=0.998, intraclass correlation coefficient (ICC) 0.998, coefficients of variation (CoV) 1.4%), hyperaemic MPI (r=0.979, ICC 0.963, CoV 3.3%) and MPRI (r=0.989, ICC 0.94, CoV 3.8%). CONCLUSIONS: Resting and hyperaemic myocardial perfusion using a normalised upslope analysis during adenosine CMR is a highly reproducible technique in patients with NIDCM. TRIAL REGISTRATION NUMBER: Clinical Trials.Gov ID NCT00574119. PMID- 25515842 TI - Health-related quality of life in partners of persons with MS: a longitudinal 10 year perspective. AB - OBJECTIVES: Multiple sclerosis (MS) impacts the health-related quality of life (HRQL) in partners, but knowledge on the longitudinal perspective is needed. The aim was to analyse HRQL in partners of persons with MS living in Sweden a decade ago and after 10 years. MATERIALS AND METHODS: Partners were identified through a population-based study of persons with MS in Stockholm. Information on HRQL (the Sickness Impact profile), personal factors and disease-specific factors, and measures of functioning of persons with MS was collected at both time points mainly by home visits. RESULTS: Some 64 of 102 identified partners (63%) agreed to participate at baseline, and at 10 years 40 of 54 eligible partners were included (74%). HRQL in partners was worse than in a Swedish, aged-grouped reference population at both baseline and follow-up. Depressive symptoms in persons with MS were independently associated with worse HRQL in partners. CONCLUSIONS: Depressive symptoms in persons with MS were associated with worse HRQL in their partners, and HRQL of partners was continuously impacted in the longitudinal perspective. This knowledge needs to be accounted for in the planning of MS care, together with the development of evidence-based support for depressive symptoms, and engagement in recreational life in both partners and persons with MS. PMID- 25515844 TI - Low-flow veno-venous extracorporeal carbon dioxide removal in the management of severe status asthmatics: a case report. AB - Status asthmaticus is a life-threatening condition that requires intensive care management. Most of these patients have severe hypercapnic acidosis that requires lung protective mechanical ventilation. A small proportion of these patients do not respond to conventional lung protective mechanical ventilation or pharmacotherapy. Such patients have an increased mortality and morbidity. Successful use of extracorporeal membrane oxygenation (ECMO) is reported in such patients. However, the use of ECMO is invasive with its associated morbidity and is limited to specialised centres. In this report, we report the use of a novel, minimally invasive, low-flow extracorporeal carbon dioxide removal device in management of severe hypercapnic acidosis in a patient with life threatening status asthmaticus. PMID- 25515843 TI - The design and user-testing of a question prompt list for attention deficit/hyperactivity disorder. AB - OBJECTIVES: This study involved the development of a question prompt list (QPL) booklet designed to facilitate communication and shared decision-making between parents/carers of children diagnosed with attention-deficit/hyperactivity disorder (ADHD) and their clinicians; and user-testing of the QPL to assess its usability. DESIGN: Best practice in information writing and design was used to format the QPL content into a 16-page booklet. We then applied user-testing, which uses mixed methods to assess document performance with small cohorts of participants and then improves it in an iterative process. Individual interviews assessed the ability of QPL users to locate and understand key points of information, followed by a semistructured questionnaire, to ascertain their general views about the booklet. SETTING AND PARTICIPANTS: Testing was undertaken with two cohorts of 10 parents/carers of children with ADHD (n=20); matched on age, gender and educational attainment. TESTED DOCUMENTS: In round 1, we tested 15 key points of information related to the QPL. Participant responses and feedback from round 1 informed a revised version of the booklet, tested in a subsequent round. PRIMARY OUTCOME MEASURE: The target was for 8/10 of the participants to be able to find and demonstrate an understanding of all key information points, in accordance with European guidelines for medicine leaflet testing. RESULTS: After round 1, problems related to 4/15 information points were identified (booklet purpose; preparing for appointments; asking about a second medical opinion; selecting which questions to ask). Participants also made suggestions regarding the booklet's layout and design. After round 2, all information points were located and understood by at least 8/10 participants. CONCLUSIONS: This is the first study to have developed a usable ADHD-specific QPL for use by parents/carers of children with ADHD during clinical consultations, and the first demonstration of the utility of user-testing methods in ensuring QPL usability. PMID- 25515845 TI - Calcium dynamics in microbialite-forming exopolymer-rich mats on the atoll of Kiritimati, Republic of Kiribati, Central Pacific. AB - Microbialite-forming microbial mats in a hypersaline lake on the atoll of Kiritimati were investigated with respect to microgradients, bulk water chemistry, and microbial community composition. O2, H2S, and pH microgradients show patterns as commonly observed for phototrophic mats with cyanobacteria dominated primary production in upper layers, an intermediate purple layer with sulfide oxidation, and anaerobic bottom layers with sulfate reduction. Ca(2+) profiles, however, measured in daylight showed an increase of Ca(2+) with depth in the oxic zone, followed by a sharp decline and low concentrations in anaerobic mat layers. In contrast, dark measurements show a constant Ca(2+) concentration throughout the entire measured depth. This is explained by an oxygen-dependent heterotrophic decomposition of Ca(2+)-binding exopolymers. Strikingly, the daylight maximum in Ca(2+) and subsequent drop coincides with a major zone of aragonite and gypsum precipitation at the transition from the cyanobacterial layer to the purple sulfur bacterial layer. Therefore, we suggest that Ca(2+) binding exopolymers function as Ca(2+) shuttle by their passive downward transport through compression, triggering aragonite precipitation in the mats upon their aerobic microbial decomposition and secondary Ca(2+) release. This precipitation is mediated by phototrophic sulfide oxidizers whose action additionally leads to the precipitation of part of the available Ca(2+) as gypsum. PMID- 25515846 TI - Biomineral coating increases bone formation by ex vivo BMP-7 gene therapy in rapid prototyped poly(L-lactic acid) (PLLA) and poly(epsilon-caprolactone) (PCL) porous scaffolds. AB - Porousbiodegradable polymer scaffolds are widely utilized for bone tissue engineering, but are not osteoconductive like calcium phosphate scaffolds. We combine indirect solid freeform fabrication (SFF), ex vivo gene therapy, with biomineral coating to compare the effect of biomineral coating on bone regeneration for Poly (L-lactic acid) (PLLA) and Poly (epsilon-caprolactone) (PCL) scaffolds with the same porous architecture. Scanning electron microscope (SEM) and micro-computed tomography (MU-CT) demonstrate PLLA and PCL scaffolds have the same porous architecture and are completely coated. All scaffolds are seeded with human gingival fibroblasts (HGF) transduced with adenovirus encoded with either bone morphogenetic protein 7 (BMP-7) or green fluorescent protein (GFP), and implanted into mice subcutaneously for 3 and 10 weeks. Only scaffolds with BMP-7 transduced HGFs show mineralized tissue formation. At 3 weeks some blood vessel-like structures are observed in coated PLLA and PCL scaffolds, but there is no significant difference in bone ingrowth between the coated and uncoated scaffolds for either PLLA or PCL. At 10 weeks, however, coated scaffolds (both PLLA and PCL) have significantly more bone ingrowth than uncoated scaffolds, which have more fibrous tissue. Coated PLLA scaffolds have improved mechanical properties compared with uncoated PLLA scaffolds due to increased bone ingrowth. PMID- 25515847 TI - Endovascular retreatment of a splenic artery aneurysm refilled by collateral branches of the left gastric artery: a case report. AB - INTRODUCTION: A rare case of a splenic artery aneurysm refilled by a hypertrophic branch originating from the left gastric artery retreated with an endovascular approach is reported. To the best of our knowledge, this is the first such case reported in the literature. CASE PRESENTATION: A hilum splenic artery aneurysm of a 43-year-old Caucasian woman was treated with endovascular ligature. Contrast enhanced computed tomography performed after 1 month revealed reperfusion of the aneurysm and a new angiogram demonstrated a hypertrophic vessel from her left gastric artery supplying the sac of the aneurysm. It was catheterized by splenic hilum branches and it was embolized with coil and glue. Contrast-enhanced computed tomography performed after 3 months confirmed complete exclusion of the sac of the aneurysm. CONCLUSIONS: Our patient represents the first rare case of a splenic artery aneurysm refilled from a branch of her left gastric artery not visible at first at angiography or at contrast-enhanced computed tomography performed after 1 month; it was revealed at the second angiography and it was definitively embolized. These eventualities and possibilities of treatment, although rare, should be kept in mind for each patient with similar presentation. PMID- 25515848 TI - Enhancing the effects of a narrative message through experiential information processing: An experimental study. AB - First-person narratives are becoming a popular means to communicate health risk information. Although studies show they can increase risk perception and motivate health behaviours compared to statistical messages, more research on the conditions in which they are particularly likely to have effects is needed. In this study, we tested a moderator related to how information is processed. Specifically, we hypothesised that thinking in terms of emotions and personal experiences - known as experiential information processing - would increase people's responsiveness to a narrative. Female college students (N = 138) who reported indoor tanning were randomly assigned to read a first-person narrative message or a statistical message about the risks of skin cancer. Prior to reading the message, the women received instructions that would activate either experiential or rational information processing. Participants then reported their risk perceptions of skin cancer, worry about skin cancer and behaviour intentions related to skin cancer. Analyses showed that message type and information processing interacted to influence risk perceptions and worry. Consistent with hypotheses, participants reported the highest risk perception and worry when they used an experiential information system prior to reading the narrative message. There were no effects on behaviour intentions. Implications of these findings are discussed. PMID- 25515849 TI - How has early testicular cancer affected your life? A study of sexual function in men attending active surveillance for stage one testicular cancer. AB - PURPOSE: Testicular cancer is the most common cancer in young men, it is frequently diagnosed at key times in relationship formation. In early stage disease the vast majority of tumours will be cured by surgery alone with patients being offered active surveillance rather than adjuvant therapies. To date, research has not evaluated how surveillance alone impacts on sexual function. METHODS: The aim of this quantitative longitudinal study was to ascertain the sexual function of men with stage one disease at 3 and 12 months post diagnosis and to compare with normative data. Additional data was collected on the information men sought regarding sexual function and media they used to access this. RESULTS: This study shows that men's sexual function is altered at diagnosis and improves by 3 months. At 12 months, whilst not statistically significant, sexual function improves but not to the same level as normative data comparison. Men appear to find verbal information useful at 3 months, however men appear to be seeking written and online information at 12 months. CONCLUSION: The intricacies of sexual function together with the low number of participants may have been best met with a qualitative approach. However, the information data indicates the importance of further research into the effects of early stage testicular cancer on sexual function. Therefore, further qualitative research is recommended to explore the effects of early stage testicular cancer in relation to sexual function. PMID- 25515850 TI - Evaluating the efficacy of biological and conventional insecticides with the new 'MCD bottle' bioassay. AB - BACKGROUND: Control of mosquitoes requires the ability to evaluate new insecticides and to monitor resistance to existing insecticides. Monitoring tools should be flexible and low cost so that they can be deployed in remote, resource poor areas. Ideally, a bioassay should be able to simulate transient contact between mosquitoes and insecticides, and it should allow for excito-repellency and avoidance behaviour in mosquitoes. Presented here is a new bioassay, which has been designed to meet these criteria. This bioassay was developed as part of the Mosquito Contamination Device (MCD) project and, therefore, is referred to as the MCD bottle bioassay. METHODS: Presented here are two experiments that serve as a proof-of-concept for the MCD bottle bioassay. The experiments used four insecticide products, ranging from fast-acting, permethrin-treated, long-lasting insecticide nets (LLINs) that are already widely used for malaria vector control, to the slower acting entomopathogenic fungus, Beauveria bassiana, that is currently being evaluated as a prospective biological insecticide. The first experiment used the MCD bottle to test the effect of four different insecticides on Anopheles stephensi with a range of exposure times (1 minute, 3 minutes, 1 hour). The second experiment is a direct comparison of the MCD bottle and World Health Organization (WHO) cone bioassay that tests a subset of the insecticides (a piece of LLIN and a piece of netting coated with B. bassiana spores) and a further reduced exposure time (5 seconds) against both An. stephensi and Anopheles gambiae. Immediate knockdown and mortality after 24 hours were assessed using logistic regression and daily survival was assessed using Cox proportional hazards models. RESULTS: Across both experiments, fungus performed much more consistently than the chemical insecticides but measuring the effect of fungus required monitoring of mosquito mortality over several days to a week. Qualitatively, the MCD bottle and WHO cone performed comparably, although knockdown and 24 hour mortality tended to be higher in some, but not all, groups of mosquitoes exposed using the WHO cone. CONCLUSION: The MCD bottle is feasible as a flexible, low-cost method for testing insecticidal materials. It is promising as a tool for testing transient contact and for capturing the effects of mosquito behavioural responses to insecticides. PMID- 25515851 TI - A rare case: testicular exstrophy or scrotoschisis? A report and discussion. AB - Anomalies of testicular descent are very common but scrotal wall deformity leading to extrusion of testes is very rare. This anomaly is described as scrotoschisis or testicular exstrophy. In English literature less than 15 cases were reported till date to the best of our knowledge. A rare case of unilateral testicular exstrophy in a full term 3-day-old neonate is reported here along with review of literature and discussions on probable etiology. PMID- 25515852 TI - The formal oxidation states of iridium now run from -III to +IX. PMID- 25515853 TI - Detailed imaging and genetic analysis reveal a secondary BRAF(L505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib. AB - Resistance to treatment is the main problem of targeted treatment for cancer. We followed ten patients during treatment with vemurafenib, by three-dimensional imaging. In all patients, only a subset of lesions progressed. Next-generation DNA sequencing was performed on sequential biopsies in four patients to uncover mechanisms of resistance. In two patients, we identified mutations that explained resistance to vemurafenib; one of these patients had a secondary BRAF L505H mutation. This is the first observation of a secondary BRAF mutation in a vemurafenib-resistant patient-derived melanoma sample, which confirms the potential importance of the BRAF L505H mutation in the development of therapy resistance. Moreover, this study hints toward an important role for tumor heterogeneity in determining the outcome of targeted treatments. PMID- 25515855 TI - Universality in surface mixing rule of adsorption strength for small adsorbates on binary transition metal alloys. AB - Understanding the adsorption phenomena of small adsorbates involved in surface reactions on transition metals is important because their adsorption strength can be a descriptor for predicting the catalytic activity. To explore adsorption energies on a wide range of binary transition metal alloys, however, tremendous computational efforts are required. Using density functional theory (DFT) calculations, here we suggest a "surface mixing rule" to predict the adsorption energies of H, O, S, CO and OH on bimetallic alloys, based on the linear interpolation of adsorption energies on each pure surface. As an application, the activity of CO oxidation on various bimetallic alloys is predicted from the adsorption energies of CO and O easily obtained by the surface mixing rule. Our results provide a useful tool for rapidly estimating adsorption energies, and furthermore, catalytic activities on multi-component metal alloy surfaces. PMID- 25515854 TI - Hypersomnia subtypes, sleep and relapse in bipolar disorder. AB - BACKGROUND: Though poorly defined, hypersomnia is associated with negative health outcomes and new-onset and recurrence of psychiatric illness. Lack of definition impedes generalizability across studies. The present research clarifies hypersomnia diagnoses in bipolar disorder by exploring possible subgroups and their relationship to prospective sleep data and relapse into mood episodes. METHOD: A community sample of 159 adults (aged 18-70 years) with bipolar spectrum diagnoses, euthymic at study entry, was included. Self-report inventories and clinician-administered interviews determined features of hypersomnia. Participants completed sleep diaries and wore wrist actigraphs at home to obtain prospective sleep data. Approximately 7 months later, psychiatric status was reassessed. Factor analysis and latent profile analysis explored empirical groupings within hypersomnia diagnoses. RESULTS: Factor analyses confirmed two separate subtypes of hypersomnia ('long sleep' and 'excessive sleepiness') that were uncorrelated. Latent profile analyses suggested a four-class solution, with 'long sleep' and 'excessive sleepiness' again representing two separate classes. Prospective sleep data suggested that the sleep of 'long sleepers' is characterized by a long time in bed, not long sleep duration. Longitudinal assessment suggested that 'excessive sleepiness' at baseline predicted mania/hypomania relapse. CONCLUSIONS: This study is the largest of hypersomnia to include objective sleep measurement, and refines our understanding of classification, characterization and associated morbidity. Hypersomnia appears to be comprised of two separate subgroups: long sleep and excessive sleepiness. Long sleep is characterized primarily by long bedrest duration. Excessive sleepiness is not associated with longer sleep or bedrest, but predicts relapse to mania/hypomania. Understanding these entities has important research and treatment implications. PMID- 25515857 TI - Editorial: Novel microRNAs as Putative Therapeutic Targets in Cardiovascular Diseases. PMID- 25515856 TI - High-definition endoscopy with iScan and Lugol's solution for the detection of inflammation in patients with nonerosive reflux disease: histologic evaluation in comparison with a control group. AB - Nonerosive reflux disease (NERD) is commonly diagnosed in patients with symptoms of reflux. The aim of the present study was to determine whether high-definition endoscopy (HD) plus equipped with the iScan function or chromoendoscopy with Lugol's solution might permit the differentiation of NERD patients from those without reflux symptoms, proven by targeted biopsies of endoscopic lesions. A total of 100 patients without regular intake of proton pump inhibitors and with a normal conventional upper endoscopy were prospectively divided into NERD patients and controls. A second upper endoscopy was performed using HD+ with additional iScan function and then Lugol's solution was applied. Biopsy specimens were taken from the gastroesophageal junction in all patients. A total of 65 patients with reflux symptoms and 27 controls were included. HD(+) endoscopy with iScan revealed subtle mucosal breaks in 52 patients; the subsequent biopsies confirmed esophagitis in all cases. After Lugol's solution, 58 patients showed mucosal breaks. Sensitivity for the iScan procedure was 82.5%, whereas that for Lugol's solution was 92.06%. Excellent positive predictive values of 100% and 98.3%, respectively, were noted. The present study suggests that the majority of patients with NERD and typical symptoms of reflux disease can be identified by iScan or Lugol's chromoendoscopy as minimal erosive reflux disease (ERD) patients. PMID- 25515858 TI - FcRgamma promotes contact hypersensitivity to oxazolone without affecting the contact sensitisation process in B6 mice. AB - The process of sensitisation by specific contact allergens is indispensable for the induction of allergic contact dermatitis. Oxazolone is a well-characterised contact allergen. Previous studies suggested that immune cells bearing the FcRgamma subunit are essential for oxazolone-induced contact hypersensitivity, but the biological functions of the FcRgamma subunit in the process of sensitisation to oxazolone remain unknown. In this study, we show that FcRgamma deficiency decreases ear-swelling responses to oxazolone in mice. However, we found that oxazolone-sensitised FcRgamma(-/-) mice and oxazolone-sensitised wild type (WT) mice have comparable numbers of CD11c(+) MHCII(hi) dendritic cells (DCs) in their draining lymph nodes (LNs). In addition, oxazolone-sensitised LN cells from both FcRgamma(-/-) and WT mice showed considerable production of interferon-gamma (IFNgamma), interleukin-4 (IL-4) and IL-17A upon oxazolone keyhole limpet haemocyanin loading. Consistent with these data, oxazolone sensitised FcRgamma(-/-) and FcRgamma(+/+) LN cells conferred contact hypersensitivity to WT naive mice challenged with the hapten. Our findings clearly indicate that, in an experimental mouse model, the FcRgamma subunit positively regulates contact hypersensitivity to oxazolone without affecting the contact sensitisation process. PMID- 25515859 TI - Comparative transcriptome analysis of the Asteraceae halophyte Karelinia caspica under salt stress. AB - BACKGROUND: Much attention has been given to the potential of halophytes as sources of tolerance traits for introduction into cereals. However, a great deal remains unknown about the diverse mechanisms employed by halophytes to cope with salinity. To characterize salt tolerance mechanisms underlying Karelinia caspica, an Asteraceae halophyte, we performed Large-scale transcriptomic analysis using a high-throughput Illumina sequencing platform. Comparative gene expression analysis was performed to correlate the effects of salt stress and ABA regulation at the molecular level. RESULTS: Total sequence reads generated by pyrosequencing were assembled into 287,185 non-redundant transcripts with an average length of 652 bp. Using the BLAST function in the Swiss-Prot, NCBI nr, GO, KEGG, and KOG databases, a total of 216,416 coding sequences associated with known proteins were annotated. Among these, 35,533 unigenes were classified into 69 gene ontology categories, and 18,378 unigenes were classified into 202 known pathways. Based on the fold changes observed when comparing the salt stress and control samples, 60,127 unigenes were differentially expressed, with 38,122 and 22,005 up and down-regulated, respectively. Several of the differentially expressed genes are known to be involved in the signaling pathway of the plant hormone ABA, including ABA metabolism, transport, and sensing as well as the ABA signaling cascade. CONCLUSIONS: Transcriptome profiling of K. caspica contribute to a comprehensive understanding of K. caspica at the molecular level. Moreover, the global survey of differentially expressed genes in this species under salt stress and analyses of the effects of salt stress and ABA regulation will contribute to the identification and characterization of genes and molecular mechanisms underlying salt stress responses in Asteraceae plants. PMID- 25515860 TI - Heritability and genome-wide analyses of problematic peer relationships during childhood and adolescence. AB - Peer behaviour plays an important role in the development of social adjustment, though little is known about its genetic architecture. We conducted a twin study combined with a genome-wide complex trait analysis (GCTA) and a genome-wide screen to characterise genetic influences on problematic peer behaviour during childhood and adolescence. This included a series of longitudinal measures (parent-reported Strengths-and-Difficulties Questionnaire) from a UK population based birth-cohort (ALSPAC, 4-17 years), and a UK twin sample (TEDS, 4-11 years). Longitudinal twin analysis (TEDS; N <= 7,366 twin pairs) showed that peer problems in childhood are heritable (4-11 years, 0.60 < twin-h(2) <= 0.71) but genetically heterogeneous from age to age (4-11 years, twin-r(g) = 0.30). GCTA (ALSPAC: N <= 5,608, TEDS: N <= 2,691) provided furthermore little support for the contribution of measured common genetic variants during childhood (4-12 years, 0.02 < GCTA-h(2)(Meta) <= 0.11) though these influences become stronger in adolescence (13-17 years, 0.14 < GCTA-h (2)(ALSPAC) <= 0.27). A subsequent cross sectional genome-wide screen in ALSPAC (N <= 6,000) focussed on peer problems with the highest GCTA-heritability (10, 13 and 17 years, 0.0002 < GCTA-P <= 0.03). Single variant signals (P <= 10(-5)) were followed up in TEDS (N <= 2835, 9 and 11 years) and, in search for autism quantitative trait loci, explored within two autism samples (AGRE: N Pedigrees = 793; ACC: N Cases = 1,453/N Controls = 7,070). There was, however, no evidence for association in TEDS and little evidence for an overlap with the autistic continuum. In summary, our findings suggest that problematic peer relationships are heritable but genetically complex and heterogeneous from age to age, with an increase in common measurable genetic variation during adolescence. PMID- 25515862 TI - A Framework to Move Forward on the Path to Eco-innovation in the Construction Industry: Implications to Improve Firms' Sustainable Orientation. AB - This paper examines key aspects in the innovative behavior of the construction firms that determine their environmental orientation while innovating. Structural equation modeling was used and data of 222 firms retrieved from the Spanish Technological Innovation Panel (PITEC) for 2010 to analyse the drivers of environmental orientation of the construction firms during the innovation process. The results show that the environmental orientation is positively affected by the product and process orientation of construction firms during the innovation process. Furthermore, the positive relation between the importance of market information sources and environmental orientation, mediated by process and product orientation, is discussed. Finally, a model that explains these relations is proposed and validated. Results have important managerial implications for those companies worried about their eco-innovative focus as the types of actions and relations within firms most suitable for improving their eco-innovative orientation are highlighted. PMID- 25515861 TI - Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C. AB - Cytopenia during interferon-based (IFN-based) therapy for chronic hepatitis C (CHC) often necessitates reduction of doses of drugs and premature withdrawal from therapy resulting in poor response to treatment. To identify genetic variants associated with IFN-induced neutropenia, we conducted a genome-wide association study (GWAS) in 416 Japanese CHC patients receiving IFN-based therapy. Based on the results, we selected 192 candidate single nucleotide polymorphisms (SNPs) to carry out a replication analysis in an independent set of 404 subjects. The SNP rs2305482, located in the intron region of the PSMD3 gene on chromosome 17, showed a strong association when the results of GWAS and the replication stage were combined (OR = 2.18, P = 3.05 * 10(-7) in the allele frequency model). Logistic regression analysis showed that rs2305482 CC and neutrophil count at baseline were independent predictive factors for IFN-induced neutropenia (OR = 2.497, P = 0.0072 and OR = 0.998, P < 0.0001, respectively). Furthermore, rs2305482 genotype was associated with the doses of pegylated interferon (PEG-IFN) that could be tolerated in hepatitis C virus genotype 1 infected patients treated with PEG-IFN plus ribavirin, but not with treatment efficacy. Our results suggest that genetic testing for this variant might be useful for establishing personalized drug dosing in order to minimize drug induced adverse events. PMID- 25515863 TI - Ledipasvir-sofosbuvir: interferon-/ribavirin-free regimen for chronic hepatitis C virus infection. AB - OBJECTIVES: To review the pharmacology, efficacy, and safety of ledipasvir sofosbuvir for the treatment of chronic hepatitis C virus (HCV). DATA SOURCES: A literature search through clinicaltrials.gov, EMBASE, and PubMed was conducted (January 1966 to October 2014) using the terms ledipasvir, sofosbuvir, GS-5885, and GS-7977. References from retrieved articles and abstracts presented at recent meetings were reviewed for any additional material. The prescribing information was also reviewed. STUDY SELECTION/DATA EXTRACTION: Phase 1, 2, and 3 human and animal studies describing the pharmacology, pharmacokinetics, efficacy, and safety of ledipasvir and sofosbuvir for HCV were identified. DATA SYNTHESIS: Ledipasvir-sofosbuvir, a fixed-dose combination (FDC) tablet inhibiting nonstructural (NS) 5A and 5B proteins, without peginterferon and ribavirin is indicated for adult patients with genotype 1 HCV infection who are treatment naive or experienced, with or without cirrhosis. Pivotal trials (n = 1952) have demonstrated that once-daily administration of ledipasvir-sofosbuvir for 12 or 24 weeks is effective at achieving sustained virological response (SVR) rates (94% 99%) in treatment-naive patients (12 weeks), treatment-experienced patients without cirrhosis (12 weeks), and treatment-experienced patients with cirrhosis (24 weeks). Treatment-naive patients without cirrhosis and baseline viral levels of less than 6 million IU/mL may be considered for 8 weeks of treatment. The most common adverse drug events (ADEs) associated with ledipasvir-sofosbuvir include headache, fatigue, insomnia, nausea, and diarrhea. CONCLUSIONS: Ledipasvir sofosbuvir is the first interferon- and ribavirin-free FDC agent that has SVR rates much greater than 94%, with minimal ADEs, for the treatment of chronic HCV genotype 1 in naive and treatment-experienced patients. PMID- 25515864 TI - Clinical experience with prophylactic fondaparinux in critically ill patients with moderate to severe renal impairment or renal failure requiring renal replacement therapy. AB - BACKGROUND: Fondaparinux has an increased bleeding risk in patients with a CrCl <= 50 mL/min and is contraindicated if CrCl < 30 mL/min. Data regarding dosing and anti-Xa monitoring are lacking in this population. OBJECTIVE: To describe dosing, monitoring, and safety outcomes of prophylactic fondaparinux in critically ill patients with moderate to severe renal impairment, including renal replacement therapy (RRT). METHODS: Retrospective analysis from October 2006 to November 2012 of patients >= 18 years old who received fondaparinux for >= 72 hours with >= 1 dose in an intensive care unit and a CrCl <= 50 mL/min or RRT during therapy. Participants were divided into 4 cohorts: moderate impairment (CrCl = 30-50 mL/min), severe impairment (CrCl < 30 mL/min), hemodialysis (HD), or continuous venovenous hemofiltration (CVVH). Outcomes included the incidence of clinically significant bleeding and thromboembolic events. Fondaparinux dose, dosing frequency, and anti-Xa level monitoring are described. Pharmacokinetic modeling was performed to assess drug accumulation. RESULTS: In all, 95 patients met inclusion criteria: 64 (67.4%) with moderate impairment, 10 (10.5%) with severe impairment, 5 (5.3%) with HD, and 16 (16.8%) with CVVH. The median defined daily doses in the moderate, severe, HD, and CVVH cohorts were 2.5, 2.5, 0.9, and 1.9 mg. Anti-Xa monitoring occurred in 19 (20%) patients, although few concentrations were peaks. Clinically significant bleeding occurred in 4 (4.2%) patients. A pharmacokinetic model demonstrated drug accumulation. CONCLUSIONS: Empirical dose adjustments may be prudent in critically ill patients with renal dysfunction; however, the optimal fondaparinux dosage in this population remains unknown. Peak anti-Xa concentrations may help guide therapy. PMID- 25515865 TI - Efficacy and safety of argatroban and bivalirudine in patients with suspected heparin-induced thrombocytopenia. AB - BACKGROUND: Argatroban is the only commercially available Food and Drug Administration (FDA)-approved anticoagulant for managing heparin-induced thrombocytopenia (HIT). However, bivalirudin may be an attractive alternative. OBJECTIVE: To assess the efficacy and safety of argatroban and bivalirudin in patients with suspected HIT. METHODS: This single-center, retrospective analysis included patients who received argatroban or bivalirudin for at least 24 hours between January 1, 2000, and June 30, 2012. The primary end point assessed anticoagulation goals, specifically time to therapeutic activated partial thromboplastin time (aPTT) goal and percentage of aPTT values within therapeutic range. Secondary end points included new thromboembolic events, bleeding, and mortality. RESULTS: Of the 68 patients who met the inclusion criteria, 48 received argatroban and 20 received bivalirudin. Baseline characteristics were similar between the 2 groups except for age, percentage of patients with liver dysfunction, aPTT immediately prior to drug initiation, and the serotonin release assay results. The mean +/- SD times to reach therapeutic aPTT goal for argatroban and bivalirudin were 14 +/- 15 and 7 +/- 8 hours, respectively (P = 0.024). The mean +/- SD percentage of aPTT values within therapeutic aPTT goal was 69% +/- 23% for argatroban and 84% +/- 18% for bivalirudin (P = 0.005). Rates of thromboembolic events were similar between the 2 groups, as were the rates of bleeding and all-cause mortality. CONCLUSIONS: Bivalirudin appears to reach therapeutic aPTT goal faster with more aPTT values within therapeutic aPTT goal while achieving similar clinical outcomes. Although not approved by the FDA for managing HIT, bivalirudin may be an attractive alternative anticoagulant. PMID- 25515866 TI - Treatment of hypertension with chronotherapy: is it time of drug administration? AB - OBJECTIVE: To review evidence for dosing antihypertensives at bedtime and possible cardiovascular risk reduction. DATA SOURCES: A PubMed, EMBASE, and Cochrane Controlled Trials database literature search (1990-September 2014) limited to human subjects was performed using the search terms hypertension, chronotherapy, ambulatory blood pressure, morning administration, evening administration, and antihypertensives. Additional references were identified from literature citations. STUDY SELECTION: All prospective studies assessing cardiovascular outcomes or comparing morning to evening administration of antihypertensives were selected. DATA SYNTHESIS: Compared with morning administration, dosing one or more antihypertensive medications at bedtime helps induce a normal circadian blood pressure pattern and reduces the risk of cardiovascular disease morbidity and mortality in individuals with hypertension. Similar results have been reported in high-risk individuals with diabetes, chronic kidney disease, and resistant hypertension. A lack of diversity among studied populations and reliance on subgroup analyses are among the limitations of these data. All antihypertensive medications have not been studied in chronotherapy and do not uniformly achieve desired results. The most substantial evidence exists for medications affecting the renin-angiotensin-aldosterone system. CONCLUSIONS: Despite growing evidence and promise as a cost-effective strategy for reducing cardiovascular risk, chronotherapy is not uniformly recommended in the treatment of hypertension. Careful selection of patients and antihypertensives for chronotherapy is required. Further investigation is needed to evaluate the definitive impact of chronotherapy on cardiovascular outcomes. PMID- 25515867 TI - Linezolid bladder irrigation as adjunctive treatment for a vancomycin-resistant Enterococcus faecium catheter-associated urinary tract infection. AB - OBJECTIVE: To describe the first reported successful use of adjunctive linezolid bladder irrigation. CASE SUMMARY: An 89-year-old woman with 10% TBSA burns developed septic shock and anuric acute kidney insufficiency. She acquired a urinary tract infection caused by vancomycin-resistant Enterococcus faecium (VREfm). Based on clinical status, a linezolid bladder irrigation was initiated in addition to high-dose intravenous linezolid and demonstrated microbiological cure with 7 days of treatment. DISCUSSION: Linezolid is primarily hepatically cleared and has no labeled indication for urinary tract infections. Anuria adds an additional complication of potentially reduced urinary drug concentrations. Bladder irrigation offers the benefit of achieving high local drug concentrations, but there are no data regarding such a route for linezolid. This case report is the first demonstrating the use, stability, safety, and efficacy of linezolid as a continuous bladder irrigation. CONCLUSIONS: Linezolid use as a bladder irrigation may be a feasible route of administration in anuric, critically ill patients with VREfm and few antimicrobial options. Further studies are warranted. PMID- 25515868 TI - Safety of novel oral anticoagulants compared with uninterrupted warfarin for catheter ablation of atrial fibrillation. AB - BACKGROUND: The novel oral anticoagulants (NOACs) are used for stroke prevention in atrial fibrillation (AF), but their safety and efficacy in the periablation period are not well established. Additionally, no standard procedure for managing periprocedural and intraprocedural anticoagulation has been established. OBJECTIVE: To evaluate the frequency of hemorrhagic and thrombotic events as well as periprocedural management strategies of NOACs compared with warfarin as anticoagulation therapy for AF ablation. METHODS: This was a retrospective cohort study from a prospective AF ablation registry maintained at a large, academic medical center. RESULTS: A total of 374 cases (173 warfarin, 123 dabigatran, 61 rivaroxaban, and 17 apixaban) were included in the analysis. The overall hemorrhagic/thrombotic event rate was 14.2 % (major hemorrhage 2.7%, minor hemorrhage 11.2%, thrombotic stroke 0.5%). The frequency of minor hemorrhage was significantly higher with warfarin compared with dabigatran (15% vs 5.7%, P = 0.012). The average heparin dose required to reach the goal activated clotting time (ACT) was 5600 units for warfarin, 12 900 units for dabigatran (P < 0.001), 15 100 units for rivaroxaban (P < 0.001), and 14 700 units for apixaban (P < 0.001). The average time in minutes to reach the goal ACT was significantly longer, compared with warfarin, for dabigatran (57 vs 28, P < 0.001), rivaroxaban (63 vs 28, P < 0.001), and apixaban (72 vs 28, P < 0.001). CONCLUSIONS: Compared with warfarin, periprocedural anticoagulation with dabigatran resulted in fewer minor hemorrhages and total adverse events after AF ablation. Patients anticoagulated with NOACs required larger doses of heparin and took longer to reach the goal ACT compared with patients anticoagulated with warfarin. PMID- 25515870 TI - Remote-controlled experiments with cloud chemistry. PMID- 25515869 TI - Regional variation in use of a new class of antidiabetic medication among medicare beneficiaries: the case of incretin mimetics. AB - BACKGROUND: When incretin mimetic (IM) medications were introduced in 2005, their effectiveness compared with other less-expensive second-line diabetes therapies was unknown, especially for older adults. Physicians likely had some uncertainty about the role of IMs in the diabetes treatment armamentarium. Regional variation in uptake of IMs may be a marker of such uncertainty. OBJECTIVE: To investigate the extent of regional variation in the use of IMs among beneficiaries and estimate the cost implications for Medicare. METHODS: This was a cross-sectional analysis of 2009-2010 claims data from a nationally representative sample of 238 499 Medicare Part D beneficiaries aged >=65 years, who were continuously enrolled in fee-for-service Medicare and Part D and filled >=1 antidiabetic prescription. Beneficiaries were assigned to 1 of 306 hospital-referral regions (HRRs) using ZIP codes. The main outcome was adjusted proportion of antidiabetic users in an HRR receiving an IM. RESULTS: Overall, 29 933 beneficiaries (12.6%) filled an IM prescription, including 26 939 (11.3%) for sitagliptin or saxagliptin and 3718 (1.6%) for exenatide or liraglutide. The adjusted proportion of beneficiaries using IMs varied more than 3-fold across HRRs, from 5th and 95th percentiles of 5.2% to 17.0%. Compared with non-IM users, IM users faced a 155% higher annual Part D plan ($1067 vs $418) and 144% higher patient ($369 vs $151) costs for antidiabetic prescriptions. CONCLUSION: Among older Part D beneficiaries using antidiabetic drugs, substantial regional variation exists in the use of IMs, not accounted for by sociodemographics and health status. IM use was associated with substantially greater costs for Part D plans and beneficiaries. PMID- 25515871 TI - A molecule with a ring to it. PMID- 25515878 TI - Natural product biosynthesis: the road to L. PMID- 25515879 TI - Metal-halide bond activation: a chloride shift in the spotlight. PMID- 25515880 TI - Molecular self-assembly: Searching sequence space. PMID- 25515881 TI - Nanotechnology: deadly DNA. PMID- 25515884 TI - All manner of antimony. PMID- 25515885 TI - Systems chemistry: Selecting complex behaviour. PMID- 25515886 TI - Towards greener and more sustainable batteries for electrical energy storage. AB - Ever-growing energy needs and depleting fossil-fuel resources demand the pursuit of sustainable energy alternatives, including both renewable energy sources and sustainable storage technologies. It is therefore essential to incorporate material abundance, eco-efficient synthetic processes and life-cycle analysis into the design of new electrochemical storage systems. At present, a few existing technologies address these issues, but in each case, fundamental and technological hurdles remain to be overcome. Here we provide an overview of the current state of energy storage from a sustainability perspective. We introduce the notion of sustainability through discussion of the energy and environmental costs of state-of-the-art lithium-ion batteries, considering elemental abundance, toxicity, synthetic methods and scalability. With the same themes in mind, we also highlight current and future electrochemical storage systems beyond lithium ion batteries. The complexity and importance of recycling battery materials is also discussed. PMID- 25515889 TI - Covalent functionalization of monolayered transition metal dichalcogenides by phase engineering. AB - Chemical functionalization of low-dimensional materials such as nanotubes, nanowires and graphene leads to profound changes in their properties and is essential for solubilizing them in common solvents. Covalent attachment of functional groups is generally achieved at defect sites, which facilitate electron transfer. Here, we describe a simple and general method for covalent functionalization of two-dimensional transition metal dichalcogenide nanosheets (MoS2, WS2 and MoSe2), which does not rely on defect engineering. The functionalization reaction is instead facilitated by electron transfer between the electron-rich metallic 1T phase and an organohalide reactant, resulting in functional groups that are covalently attached to the chalcogen atoms of the transition metal dichalcogenide. The attachment of functional groups leads to dramatic changes in the optoelectronic properties of the material. For example, we show that it renders the metallic 1T phase semiconducting, and gives it strong and tunable photoluminescence and gate modulation in field-effect transistors. PMID- 25515890 TI - Solvating additives drive solution-mediated electrochemistry and enhance toroid growth in non-aqueous Li-O2 batteries. AB - Given their high theoretical specific energy, lithium-oxygen batteries have received enormous attention as possible alternatives to current state-of-the-art rechargeable Li-ion batteries. However, the maximum discharge capacity in non aqueous lithium-oxygen batteries is limited to a small fraction of its theoretical value due to the build-up of insulating lithium peroxide (Li2O2), the battery's primary discharge product. The discharge capacity can be increased if Li2O2 forms as large toroidal particles rather than as a thin conformal layer. Here, we show that trace amounts of electrolyte additives, such as H2O, enhance the formation of Li2O2 toroids and result in significant improvements in capacity. Our experimental observations and a growth model show that the solvating properties of the additives prompt a solution-based mechanism that is responsible for the growth of Li2O2 toroids. We present a general formalism describing an additive's tendency to trigger the solution process, providing a rational design route for electrolytes that afford larger lithium-oxygen battery capacities. PMID- 25515887 TI - Exploring the sequence space for (tri-)peptide self-assembly to design and discover new hydrogels. AB - Peptides that self-assemble into nanostructures are of tremendous interest for biological, medical, photonic and nanotechnological applications. The enormous sequence space that is available from 20 amino acids probably harbours many interesting candidates, but it is currently not possible to predict supramolecular behaviour from sequence alone. Here, we demonstrate computational tools to screen for the aqueous self-assembly propensity in all of the 8,000 possible tripeptides and evaluate these by comparison with known examples. We applied filters to select for candidates that simultaneously optimize the apparently contradicting requirements of aggregation propensity and hydrophilicity, which resulted in a set of design rules for self-assembling sequences. A number of peptides were subsequently synthesized and characterized, including the first reported tripeptides that are able to form a hydrogel at neutral pH. These tools, which enable the peptide sequence space to be searched for supramolecular properties, enable minimalistic peptide nanotechnology to deliver on its promise. PMID- 25515888 TI - Copper-catalysed selective hydroamination reactions of alkynes. AB - The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, alpha-chiral branched alkylamines and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio- and stereoselectivity. This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine and tolterodine. PMID- 25515891 TI - Substrate control in stereoselective lanthionine biosynthesis. AB - Enzymes are typically highly stereoselective catalysts that enforce a reactive conformation on their native substrates. We report here a rare example in which the substrate controls the stereoselectivity of an enzyme-catalysed Michael-type addition during the biosynthesis of lanthipeptides. These natural products contain thioether crosslinks formed by a cysteine attack on dehydrated Ser and Thr residues. We demonstrate that several lanthionine synthetases catalyse highly selective anti-additions in which the substrate (and not the enzyme) determines whether the addition occurs from the re or si face. A single point mutation in the peptide substrate completely inverted the stereochemical outcome of the enzymatic modification. Quantum mechanical calculations reproduced the experimentally observed selectivity and suggest that conformational restraints imposed by the amino-acid sequence on the transition states determine the face selectivity of the Michael-type cyclization. PMID- 25515892 TI - Spatially resolved analysis of short-range structure perturbations in a plastically bent molecular crystal. AB - The exceptional mechanical flexibility observed with certain organic crystals defies the common perception of single crystals as brittle objects. Here, we describe the morphostructural consequences of plastic deformation in crystals of hexachlorobenzene that can be bent mechanically at multiple locations to 360 degrees with retention of macroscopic integrity. This extraordinary plasticity proceeds by segregation of the bent section into flexible layers that slide on top of each other, thereby generating domains with slightly different lattice orientations. Microscopic, spectroscopic and diffraction analyses of the bent crystal showed that the preservation of crystal integrity when stress is applied on the (001) face requires sliding of layers by breaking and re-formation of halogen-halogen interactions. Application of stress on the (100) face, in the direction where pi...pi interactions dominate the packing, leads to immediate crystal disintegration. Within a broader perspective, this study highlights the yet unrecognized extraordinary malleability of molecular crystals with strongly anisotropic supramolecular interactions. PMID- 25515893 TI - Screening and classifying small-molecule inhibitors of amyloid formation using ion mobility spectrometry-mass spectrometry. AB - The search for therapeutic agents that bind specifically to precursor protein conformations and inhibit amyloid assembly is an important challenge. Identifying such inhibitors is difficult because many protein precursors of aggregation are partially folded or intrinsically disordered, which rules out structure-based design. Furthermore, inhibitors can act by a variety of mechanisms, including specific or nonspecific binding, as well as colloidal inhibition. Here we report a high-throughput method based on ion mobility spectrometry-mass spectrometry (IMS-MS) that is capable of rapidly detecting small molecules that bind to amyloid precursors, identifying the interacting protein species and defining the mode of inhibition. Using this method we have classified a variety of small molecules that are potential inhibitors of human islet amyloid polypeptide (hIAPP) aggregation or amyloid-beta 1-40 aggregation as specific, nonspecific, colloidal or non-interacting. We also demonstrate the ability of IMS-MS to screen for inhibitory small molecules in a 96-well plate format and use this to discover a new inhibitor of hIAPP amyloid assembly. PMID- 25515895 TI - Platelet apoptosis in patients with acute coronary syndromes. AB - Platelet apoptosis occurs commonly under various conditions such as physical and chemical stimuli. Acute coronary syndrome (ACS), one of most important cardiovascular and cerebrovascular diseases, severely threats people's health and is usually accompanied with various complications especially bleeding. There might be platelet apoptosis in ACS, which might be responsible for the complication of bleeding. The objective of the present study was to explore whether there were apoptotic platelets in ACS patients. Vein blood was drawn from eleven ACS patients and eleven health people. Platelet-rich plasma was prepared and subjected to apoptotic events analysis including increased expression of pro apoptotic proteins and decreased expression of anti-apoptotic proteins, exposure of phosphatidylserine (PS), mitochondrial inner membrane potential depolarization and caspase-3 activation by Western blot and flow cytometry. In addition, washed platelets from the normal people were prepared and treated with the platelet-poor plasma (PPP) of the ACS patients, and were further examined apoptotic cascades. Paired Student's t test was used in the data comparisons. There were more platelets with depolarized mitochondrial inner membrane potential in the ACS patients than those of the health donors. Levels of Bax and Bak increased, while expression of Bcl-2 and Bcl-XL decreased in platelets from ACS patients. Caspase 3 activation was observed in platelets from the patients with ACS. Interestingly, there were significant differences in PS exposure between the platelets from the ACS patients and the normal controls. Furthermore, apoptotic events were observed in the normal platelets incubated with PPP from the ACS patients. In addition, pretreatment of healthy platelets with anti-oxidants N-acetyl cysteine (NAC) or dithiothreitol (DTT) significantly reduced ACS patients-derived PPP-induced platelet apoptosis. Platelets from the ACS patients are incurred apoptosis. Antioxidants NAC or DTT can reduce ACS patients-derived PPP-induced platelet apoptosis in vitro. PMID- 25515894 TI - Pseudopterosin synthesis from a chiral cross-conjugated hydrocarbon through a series of cycloadditions. AB - The pseudopterosins are a family of diterpene marine natural products, which, by virtue of their interesting anti-inflammatory and analgesic properties, have attracted the attentions of many synthetic chemists. The most efficient syntheses reported to date are 14 and 20 steps in the longest linear sequence for chiral pool and enantioselective approaches, respectively, and all start with precursors that are easily mapped onto the natural product structure. Here, we describe an unconventional approach in which a chiral cross-conjugated hydrocarbon is used as the starting material for a series of three cycloadditions. Our approach has led to a significant reduction in the step count required to access these interesting natural products (10 steps chiral pool and 11 steps enantioselective). Furthermore it demonstrates that cross-conjugated hydrocarbons, erroneously considered by many to be too unstable and difficult to handle, are viable precursors for natural product synthesis. PMID- 25515897 TI - [The consent and its ethical conditions]. PMID- 25515896 TI - Effect of tea tree (Melaleuca alternifolia) oil as a natural antimicrobial agent in lipophilic formulations. AB - There has been increased interest surrounding the use of tea tree oil (TTO) as a natural antimicrobial. In this study, the antimicrobial activity of TTO and its components were investigated in vitro and in a predominantly lipid-based personal care formulation. In vitro, TTO showed minimal inhibitory concentrations of 0.2% (for Saccharomyces cerevisiae and Pythium sulcatum), 0.4% (for Escherichia coli, Bacillus subtilis, and Rhizopus stolonifer), and 0.8% (for Botrytis cinerea). TTO at 0.08%-0.8% was often as efficient as parabens. Comparison of the antimicrobial activities of TTO components showed that terpinen-4-ol and gamma-terpinene were generally most effective in inhibiting microbial growth. TTO activity in a personal care product was evaluated through air and water exposure, artificial inoculation, and shelf life studies. While TTO did not increase shelf life of unopened products, it decreased microbial load in products exposed to water and air. Results from this study support that antimicrobial activity of TTO can be attributed to varying levels of its components and that low levels of TTO were effective in reducing microbial growth during the use of the product. This study showed that TTO can act as a suitable preservative system within an oil-based formulation. PMID- 25515898 TI - [Intervention of mobile palliative care team on nursing homes: retrospective study]. AB - BACKGROUND: Interventions of mobile palliative care teams in nursing homes have been the subject special consideration, however very little data are available on this subject. OBJECTIVES: To determine the proportion of patients followed and consultations conducted in nursing homes for the dependent elderly by a mobile palliative care team, to describe the patients followed and to analyze the various aspects of this intervention. METHOD: Retrospective study on the interventions carried out by a mobile palliative care team in nursing homes between January 1st and December 31st, 2012. RESULTS: The interventions in nursing homes targeted, 7.2% of the followed patients and represented 8.7% of the total activity of the mobile team. Intervention requests were made primarily by the family physician. The followed patients were mostly women (63%), with a mean age of 84 years, presenting non-cancerous diseases (78.2%), and had an average of 4.4 consultations. Half of the patients died during follow-up. Three quarters of the patients presented pain, neuro-psychological symptoms and verbal communication disorders. Four out of ten patients met with the occupational therapist and one of ten, the psychologist. DISCUSSION: The activity of mobile palliative care teams remains marginal, although steadily (on the rise. The collected data illustrate the specificity of geriatric palliative care, while certain characteristics inherent to nursing homes require establishing appropriate therapy proposals. CONCLUSION: Although quantitatively limited, the activity of mobile palliative care teams in nursing homes appears important as these interventions are likely meet the needs of both patients and staff in addition to enabling patients in palliative care to remain at their current place of residence. PMID- 25515899 TI - [Morpho-epidemiological profile of elderly subject cancer in Dakar]. AB - The elderly is defined by WHO as any individual who has a chronological age greater than or equal to 60 years. The number of elderly is growing. The scarcity of work on malignant tumor pathology elderly contrasting with the difficulty of support have raised the interest of this work. MATERIALS AND METHODS: This is a descriptive and retrospective study carried out on a periode of 5 years based on the reported analyses of all public laboratories of anatomical pathology and cytology in Dakar. RESULTS: During the five years of our study on 1,264 cases of tumors of the elderly we identified 699 cases of cancer. The average age of patients was 68.82 years with a discreet male predominance (sex ratio=1.07). The most common malignant tumors were cancers of the prostate (23.74%), cancers of the cervix (16.88%), cancer of the breast (10.72%) and cancers of the skin and soft tissues (9.15%). Some tumor sites (stomach, larynx, esophagus, ganglion, sinus, bladder, liver, lungs and bronchi, vulva, eye, jaw, pancreas, bone) had always proved malignant. Tumor location was primitive in 97.56% and metastatic in 2.44%. The histological type of primary cancer was met by far dominated by carcinomas (91.20%) followed by lymphoma (3.81%), sarcomas (3.66%) and melanoma (1.31%). All cases of metastatic were carcinomas. PMID- 25515900 TI - [Arthritis of the thumb (rhizarthrosis) in the elderly]. AB - Osteoarthritis of the base of the thumb is a common and painful condition, mostly observed in post menopausal women. This paper proposes a critical review of the recent papers in the point of view of geriatric medicine. The basal joint of the thumb is formed by the trapeziometacarpal joint and the carpometacarpal joint of the thumb. The trapeziometacarpal joint is a saddle joint with a wide mobility. The trapezium is most important bone which authorizes movement of rotation towards every finger of the hand. Carpometacarpal allows the strength of the hand. Antalgesic drugs are the first treatments. NSAIDs can be applied and reduced pain. Resting hand splint have a significant pain relief, without any side effects. This advantage is appropriate to treatment in elderly subjects. Flexible orthosis is adapted to maintaining activities of daily living in moderate pain. Chirurgical ligament reconstruction tendon interposition is the most common technics used. In elderly subject, trapeziectomy achieved pain relief and adapted to frail elderly. PMID- 25515901 TI - [Management of behavioral symptoms in dementia in a specialized unit care]. AB - The project "Plan Alzheimer 2008-2012" allowed the development of units specialized in management of behavioral disorders in dementia, by favoring pharmacological and non-pharmacological approaches. OBJECTIVES: Our article analyses the evolution of behavioral symptoms, autonomy and prescription of psychotropic drugs, in "Cognitive and Behavioral Unit" of Toulouse (France). Second outcome is the analysis of early unplanned readmission for behavioral reasons. RESULTS: 199 patients are included over 2 years of study. Behavioral symptoms are significantly improved during the follow-up with a persistent effect after discharge. The global autonomy, particular for walking, is not altered. The prescriptions of psychotropics, among others antipsychotics, is significantly lower at discharge. Early unplanned readmissions at hospital, in spite of cognitive disorders of our patients, are not more important than in global geriatric population. CONCLUSION: We show the efficiency of global care in behavioral disruptive symptoms in dementia, favoring non pharmacological approaches, in specialized units. Those cognitive and behavioral units have a role for care of demented patients with behavioral disruptive symptoms. PMID- 25515902 TI - [Construct and validation of a quality of life's scale for older French people]. AB - Given changing and subjective aspects of quality of life, the current assessment scales are often encompassing and not very adapted for older people. Thus, the present validation study has several objectives: 1) To elaborate a specific measure of the quality of life of older people, given the characteristics and problems of this population; 2) To propose a simple scale to use for any health care professional and fast passation to encourage the inclusion of such measures in the framework of a comprehensive care of the elderly; 3) To validate this scale in a large cohort of retired older farmers. This scale resulted in 14 items illustrating the various dimensions of quality of life of older people. It was then proposed for validation in a large cohort of retired elderly farmers of 65 years and over, and living at home. After exploratory factor analysis of subjects' responses to the EQVPA, five items were extracted explaining 48.8% of the total variance. Its internal consistency was satisfactory (Cronbach's alpha=0.72). The five items permitted to assess daily and social activities in environment, social and familial relationships, physical and functional health and mental health. The results showed that quality of life is significantly correlated with greater life satisfaction, more social support and social network, higher level of subjective health, lower level of functional impairments, lower level of anxious and depressive symptoms, and lower level of routinization. Validation of the tools such as EQVPA seems important for the prevention and preservation of the quality of life of older people. PMID- 25515903 TI - [Study on knowledge and practices related to malnutrition in the elderly to the nursing home]. AB - The prevalence of malnutrition in nursing homes varies between 50% and 90% in Belgium. There are multiple causes of malnutrition and one of the consequences is the impact on the workload of nursing home staff. The purpose of this study is to better understand the knowledge and the practices of the nursing home staff who would influence the nutritional status of elderly in nursing homes. This study is divided into a quantitative approach with a self-administered questionnaire and a qualitative approach by non-participant observation. We observed that 29% of nursing home staff have good knowledge about the malnutrition and that 64% have good practices in providing nutrition to the elderly. People with good knowledge tend to have better practices. 38% of the nursing home staff engage in continued professional development in the field. There is no systematic screening, nutritional assessment and nutritional intervention in nursing homes. It is of great importance to ensure nursing home staff are aware of this problem through training. PMID- 25515904 TI - [Activity and cost related to hospital management of herpes zoster in France: focus on ophthalmic herpes zoster]. AB - OBJECTIVES: Herpes zoster secondary to reactivation and replication of the varicella zoster virus (VZV) caused a painful disease which impact the quality of life. Among the complications, herpes zoster ophtalmicus was responsible to post herpetic neuralgia and lesions of the ocular globus. The aim of this study is to evaluated the burden and cost of herpes zoster in secondary care in France with focus on herpes zoster ophtalmicus (HZO). METHODS: This retrospective analysis was performed using data extracted from the French medical information system during the year 2012. The diagnosis are coded using the international classification of diseases as primary, related or significant associated diagnosis. RESULTS: During the year 2012, 2,509 patients 50 years old and more were admitted secondary to HZ. Among them, 495 were admitted with an HZO (19.7%). The mean age of patients hospitalized were 77 years. The average cost per stay varied between 3,370 euros and 9,191 euros respectively for zoster without complications and for encephalitis. The overall total hospitalization due to HZ and its complications was around 10.2 million euros in France in 2012, 18% of these costs were attributable to hospitalizations for HZO. CONCLUSION: This study evaluated the cost of hospitalization due to zoster for the French health insurance. This total costs were probably underestimate because the non exhaustiveness of CIM coding. This study shows the burden of zoster and his cost particularly heavy when ophtalmicus or neurological complications were associated to HZ. PMID- 25515905 TI - [Does the brain have a gender? A literature review in younger and older adults]. AB - There are no longer doubts about the existence of gender's differences in cognition, only their origin is still controversial. The literature provides evidence of differences in cognitive performance and brain activation patterns and links these differences in men and women with biological, social and psychological measures. To date, the favored hypothesis explaining these differences is the cognitive style hypothesis according to which women and men would favor different strategies while resolving some tasks. Some of these tasks are autobiographical memory tasks, which are also the most sensitive to the effects of age but very few studies had explored the impact of aging on the differences in cognition between men and women. We discuss the importance of such studies about the gender's differences in aging. A better understanding of gender differences in cognition in pathological aging as in health would provide the opportunity to offer a more personalized care. PMID- 25515906 TI - [Interest and role of brain scintigraphy in the diagnosis of dementia in 2014]. AB - Isotopic functional brain imaging is an important tool for the diagnosis and assessment of Alzheimer's disease and related disorders. This paper is a review of currently available radiotracers for PET and SPECT imaging, making a distinction between so-called topographical and pathophysiological markers. The respective indications and limitations of the ligands are presented. PMID- 25515907 TI - [An integrative model of the psychological benefits of gardening in older adults]. AB - This review of the literature tackles the question of the psychological benefits linked to gardening in older adults. First, the current data on these benefits are reviewed, and the findings reveal that gardening is linked to feelings of accomplishment, well-being and peace, a decrease of depressive symptoms, a protective effect on cognitive functions as well as to the development of social links for community living older adults. In institutionalized older adults, gardening promotes internal locus of control and well-being, and is related to a decrease of sadness and anxiety. Second, several explanatory theories are discussed. All of them postulate an action on the cognitive and/or emotional spheres, which were included into a integrated model that must be tested in future research. In conclusion, gardening appears to be a beneficial activity for promoting older adults' functioning but the current knowledge still has to be extended to understand the specific mechanisms of action. This deeper understanding is necessary in order to improve the future actions depending on this activity. PMID- 25515908 TI - [Role of context recall in destination memory decline in normal aging]. AB - Until recently, little was known about destination memory, or memory for the destination of outputted information. In the present work, this memory was evaluated in 32 older adults and 36 younger adults, who had to associate proverbs to pictures of famous people and decide, on a subsequent recognition task, whether they had previously told that proverb to that face or not. When deciding about the destination, participants had to provide contextual judgment, that is, whether each picture had been previously exposed in color or in black and white. Participants also performed a neuropsychological battery tapping episodic memory and executive functions. Findings showed poor destination recall in older participants. Destination recall in older adults was reliably predicted by with their context recall. Destination memory seems to be particularly affected by aging, a deterioration that can be related to deficits in processing contextual features during encoding. PMID- 25515909 TI - [Assessment of verbal episodic memory by a new memory test with self-initiated items (MAI test)]. AB - The assessment of episodic memory is a critical aspect of psychometric assessment in elderly people, particularly for the diagnosis of dementia. However, evaluation of episodic memory in these subjects is not easy in subjects with non native language, different culture, visual impairment or fatigability. To overcome these difficulties, a rapid assessment of episodic memory, the Auto initiated memory test (MAI test) has been developed. The goal of our research is to validate and standardize this test. To achieve the standards, we included 84 non-demented older participants (74.24+/-6.9 years). Moreover, we included 171 older participants with cognitive impairment and 33 older participants with Mild cognitive impairment. The results showed that the MAI test (phase 2 of the test) has good psychometric properties in MCI patients (sensitivity=76%, specificity=100%). Thus it appears to be an useful screening tool for detection of pre-dementia in subjects who are not able to pass usual standard tests of episodic memory. PMID- 25515910 TI - [Relationship between two models of personality in old individuals]. AB - The relationships between the seven dimensions of the Cloninger psychobiological model and the five factors of the Costa and McCrae model were examined in 54 elderly subjects from the French general population. The dimensions of temperament (novelty seeking, harm avoidance, reward dependence) and character (determination, cooperation, transcendence) from the Cloninger's model were measured by the temperament and character inventory whereas the five factors of Costa and McCrae model (neuroticism, extraversion, openness to experience, agreeableness and conscientiousness) were evaluated using the NEO PI-R. Multiple regression analyses show that some dimensions of the temperament and character inventory predict some dimensions of the Big five and vice versa. Therefore we suggest that the Big five model could be related to brain monoaminergic activities. PMID- 25515912 TI - Haplotype diversity in autochthonous Balkan cattle breeds. PMID- 25515911 TI - Diagnostic accuracy of high resolution melting analysis for detection of KRAS mutations: a systematic review and meta-analysis. AB - Increasing evidence points to a negative correlation between KRAS mutations and patients' responses to anti-EGFR monoclonal antibody treatment. Therefore, patients must undergo KRAS mutation detection to be eligible for treatment. High resolution melting analysis (HRM) is gaining increasing attention in KRAS mutation detection. However, its accuracy has not been systematically evaluated. We conducted a meta-analysis of published articles, involving 13 articles with 1,520 samples, to assess its diagnostic accuracy compared with DNA sequencing. The quality of included articles was assessed using the revised Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2) tools. Random effects models were applied to analyze the performance of pooled characteristics. The overall sensitivity and specificity of HRM were 0.99 (95% confidence interval [CI]: 0.98-1.00) and 0.96 (95%CI: 0.94-0.97), respectively. The area under the summary receiver operating characteristic curve was 0.996. High sensitivity and specificity, less labor, rapid turn-around and the closed-tube format of HRM make it an attractive choice for rapid detection of KRAS mutations in clinical practice. The burden of DNA sequencing can be reduced dramatically by the implementation of HRM, but positive results still need to be sequenced for diagnostic confirmation. PMID- 25515913 TI - Development of the Informing Relatives Inventory (IRI): Assessing Index Patients' Knowledge, Motivation and Self-Efficacy Regarding the Disclosure of Hereditary Cancer Risk Information to Relatives. AB - BACKGROUND: Despite the use of genetic services, counselees do not always share hereditary cancer information with at-risk relatives. Reasons for not informing relatives may be categorized as a lack of: knowledge, motivation, and/or self efficacy. PURPOSE: This study aims to develop and test the psychometric properties of the Informing Relatives Inventory, a battery of instruments that intend to measure counselees' knowledge, motivation, and self-efficacy regarding the disclosure of hereditary cancer risk information to at-risk relatives. METHOD: Guided by the proposed conceptual framework, existing instruments were selected and new instruments were developed. We tested the instruments' acceptability, dimensionality, reliability, and criterion-related validity in consecutive index patients visiting the Clinical Genetics department with questions regarding hereditary breast and/or ovarian cancer or colon cancer. RESULTS: Data of 211 index patients were included (response rate = 62%). The Informing Relatives Inventory (IRI) assesses three barriers in disclosure representing seven domains. Instruments assessing index patients' (positive) motivation and self-efficacy were acceptable and reliable and suggested good criterion-related validity. Psychometric properties of instruments assessing index patients knowledge were disputable. These items were moderately accepted by index patients and the criterion-related validity was weaker. CONCLUSION: This study presents a first conceptual framework and associated inventory (IRI) that improves insight into index patients' barriers regarding the disclosure of genetic cancer information to at-risk relatives. Instruments assessing (positive) motivation and self-efficacy proved to be reliable measurements. Measuring index patients knowledge appeared to be more challenging. Further research is necessary to ensure IRI's dimensionality and sensitivity to change. PMID- 25515914 TI - Facilitating Sunscreen Use Among Chinese Young Adults: Less-Motivated Persons Benefit from a Planning Intervention. AB - BACKGROUND: The effect of a self-regulatory intervention with its focus on planning sunscreen use is evaluated in comparison to a standard educational condition. PURPOSE: This paper studied whether planning mediates between the experimental conditions and the behavioral outcome. Further, it is examined who benefits more: already motivated or unmotivated individuals. METHOD: College students (N = 253) were randomly assigned to two groups: a self-regulatory and a standard-care condition. Sunscreen use, intention to use sunscreen, and planning were assessed at two points in time, 1 month apart. RESULTS: The self-regulatory intervention improved planning to use sunscreen but not the behavior directly. Planning emerged as the mediator between conditions and later sunscreen use, controlling for baseline behavior. Moreover, participants who were less motivated benefited more from the intervention. CONCLUSIONS: Although it is generally assumed that planning interventions are best designed for already motivated persons, the present findings suggest that less prepared individuals might have more to gain from a brief self-regulatory intervention. PMID- 25515915 TI - HIV patients with latent tuberculosis living in a low-endemic country do not develop active disease during a 2 year follow-up; a Norwegian prospective multicenter study. AB - BACKGROUND: Interferon-gamma release assays (IGRA) serve as immunodiagnostics of tuberculosis (TB) infection to identify individuals with latent TB infection (LTBI) eligible for preventive anti-TB therapy. In this longitudinal study of HIV infected LTBI patients we have observed for possible progression to active TB as well as evaluated repeated IGRA testing in a TB low-endemic setting. METHODS: QuantiFERON TB-Gold In-tube(r) assay (QFT), TB-SPOT.TB(r) (TSPOT) and tuberculin skin test (TST) were performed on 298 HIV-patients recruited from seven out patient clinics in Norway. Patients with active TB, LTBI and negative IGRA were followed with repeat QFTs and clinical evaluation over a period of 24 months. RESULTS: Seven HIV-patients (median CD4 count 270; IQR 50-340) were diagnosed with active TB at inclusion, all IGRA positive. Sixty-four (21%) HIV-patients (median CD4 count 471; IQR 342-638) were diagnosed with LTBI and of these 39 (61%) received TB preventive treatment. Neither treated nor untreated HIV infected LTBI patients developed active TB during the 24 months. At baseline, the median interferon-gamma (INF-gamma) level measured by QFT was 3.48 IU/ml (IQR 0.94-8.91 IU/ml) for treated LTBI compared to 1.13 IU/ml (IQR 0.47-4.25 IU/ml) for untreated LTBI patients (p = 0.029). The QFT reversion rates were 75% for active TB, 23% for treated LTBI and 44% for untreated LTBI, whereas the conversion rate for the non-TB group was 7% despite no new TB exposure. There was no significant difference in the trend of INF-gamma levels over time between treated and untreated LTBI patients. CONCLUSION: The prevalence of LTBI is high among HIV-patients, but the risk of developing active TB seems to be low in patients with high CD4 counts in this TB low-endemic setting. In several patients, especially with baseline IFN-gamma levels close to cut-offs, the QFT tests reverted to negative independent of preventive anti-TB treatment indicating possibly false positive tests. This highlights the importance of defining reliable cut-offs for immunodiagnostic tests and deferring preventive therapy in selected patients. Randomized studies with longer follow-up time are needed to identify HIV-patients that would benefit from LTBI treatment in a TB low-endemic setting. PMID- 25515917 TI - A longitudinal pigmented band on the right index fingernail. PMID- 25515916 TI - Qualitative and quantitative analysis of Potentilla fulgens roots by NMR, matrix assisted laser desorption/ionisation with time-of-flight MS, electrospray ionisation MS/MS and HPLC/UV. AB - INTRODUCTION: Potentilla fulgens is a commonly used folk medicine by natives of northeast India, Nepal and Bhutan and is rich in polyphenolic and triterpene constituents. OBJECTIVE: To identify chemomarkers in the roots of P. fulgens by an interplay of (13)C-NMR, matrix-assisted laser desorption/ionisation with time of-flight (MALDI/TOF) MS, electrospray ionisation (ESI) MS/MS and HPLC/UV. MATERIAL AND METHODS: The (13)C-NMR spectrum of crude methanolic extract was recorded in deuterated dimethyl sulphoxide. For MALDI/TOF/MS analysis, 2,5 dihydroxybenzoic acid was used as the matrix. For determination of chemical constituents, two independent simple isocratic HPLC/UV methods for monomeric/oligomeric flavanols and triterpene acids were developed and validated. RESULTS: The (13)C-NMR spectrum of the methanolic extract indicated the presence of B-type oligomeric polyphenolics containing mainly epicatechin/catechin (epicat/cat) and epiafzelechin/afzelechin (epiafz/afz) as the monomeric units. Several isobaric monomeric and oligomeric flavanols and triterpenoids were tentatively identified by MALDI/TOF/MS and ESI/MS/MS. Fourteen compounds (four monomeric and five dimeric flavanols and five triterpene acids) were isolated using repeated column chromatography and semi-preparative HPLC, and were quantitated using HPLC/UV. CONCLUSION: It is evident from these analyses that roots of P. fulgens contain flavans, including oligomeric flavanols, as major constituents followed by triterpene acids. The methods described can be applied to other Potentilla species to identify their constituents. PMID- 25515918 TI - Role of fetal DNA in preeclampsia (review). AB - Preeclampsia is an autoimmune disorder characterized by hypertension. It begins with abnormal cytotrophoblast apoptosis, which leads to inflammation and an increase in the levels of anti-angiogenic factors followed by the disruption of the angiogenic status. Increased levels of fetal DNA and RNA coming from the placenta, one of the most commonly affected organs in pregnancies complicated by preeclampsia, have been found in pregnant women with the condition. However, it remains unknown as to whether this is a cause or a consequence of preeclampsia. Few studies have been carried out on preeclampsia in which an animal model of preeclampsia was induced by an injection of different types of DNA that are mimic fetal DNA and provoke inflammation through Toll-like receptor 9 (TLR9) or cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). The specific mechanisms involved in the development of preeclampsia are not yet fully understood. It is hypothesized that the presence of different fragments of fetal DNA in maternal plasma may cause for the development of preeclampsia. The function of DNase during preeclampsia also remains unresolved. Studies have suggested that its activity is decreased or the DNA is protected against its effects. Further research is required to uncover the pathogenesis of preeclampsia and focus more on the condition of patients with the condition. PMID- 25515919 TI - An arthroscopic-assisted minimal invasive method for the reconstruction of the scapho-lunate ligament using a bone-ligament-bone graft. AB - We report the outcomes of an arthroscopic-assisted minimally invasive technique to reconstruct the scapho-lunate ligament using a bone-ligament-bone graft in 11 patients (11 wrists). The mean follow-up time was 29 months (range 20 to 38). The preoperative mean wrist flexion, extension, grip strength and patient-rated wrist evaluation score values were 61 degrees , 54 degrees , 115 N and 54, respectively. The postoperative mean values were 64 degrees , 58 degrees , 142 N and 15, respectively. There were no statistical differences between the pre- and postoperative wrist flexion and extension, whereas changes in grip strength and patient-rated wrist evaluation score were significant. Scapho-lunate angles decreased significantly from 69 degrees to 60 degrees . Based on our clinical outcomes, this method provides a reliable alterative for the reconstruction of the scapho-lunate ligament in patients with persistent Geissler type 3 and 4 lesions in the short-term. LEVEL OF EVIDENCE: IV. PMID- 25515920 TI - The value of post-operative radiographs in clinical management of AO type A distal radius fractures. AB - The value of post-operative radiographs following stabilization of Arbeitsgemeinschaft fur Osteosynthesefragen (AO) type A distal radius fractures with volar locking plates is unclear. We examined the value of post-operative radiographs of type A fractures treated with volar locking plates. A retrospective review was performed on all AO type A distal radius fractures treated with volar locking plates between 2007 and 2010 at two institutions. A total of 158 patients receiving 446 sets of post-operative radiographs were included. Reviewing all clinic, emergency, and operative notes, we found that 94% of radiographs were performed as routine follow-up, with no set of post-operative radiographs demonstrating findings of hardware/fracture site complications. All cases requiring further workup or interventions were heralded by patient complaints. Routine post-operative radiographs following volar locking plates for extra-articular distal radius fractures did not demonstrably alter clinical decision making; this is an area where a reduction in resource utilization would not seem to alter clinical quality care, but further studies with larger populations are needed to establish the incidence of radiographic problems prior to symptom occurrence. Level of evidence: Diagnostic III. PMID- 25515921 TI - Overexpression of Lin28 inhibits the proliferation, migration and cell cycle progression and induces apoptosis of BGC-823 gastric cancer cells. AB - Lin28 plays important roles in the development, maintenance of pluripotency and progression of various types of cancers. Lin28 represses the biogenesis of let-7 microRNAs and is implicated in both development and tumorigenesis. Oncogenic regulation of let-7 microRNAs has been demonstrated in several human malignancies, yet their correlation with Lin28 has not yet been studied in gastric cancer. Therefore, in the present study, we explored the possible mechanisms involved in the effects by Lin28 on the proliferation, migration, cell cycle arrest and apoptosis in gastric cancer cells via alteration of let-7 miRNA. The expression levels of Lin28 and let-7 were detected by real-time PCR in gastric cancer cell lines in vitro. Lin28 was overexpressed in the BGC-823 cells via lentiviral transfection, and let-7 expression was assessed. Cell proliferation and migration capabilities were investigated by MTT and Transwell assays, while cell cycle distribution and the apoptosis rate were detected using flow cytometry. The expression of Lin28 was moderately expressed in the GES cells while underexpressed in the BGC-823, SGC-7901 and HGC-27 cells. Let-7a miRNA was highly expressed in the GES, BGC-823, SGC-7901 and HGC-27 cells. Overexpression of Lin28 was inversely correlated with the downregulated expression of let-7a, and markedly suppressed the proliferation, migration, cell cycle progression and induced apoptosis in the BGC-823 cells. These findings demonstrated that overexpression of Lin28 can suppress the biological behavior of gastric cancer in vitro, and let-7 miRNA may play an important role in the process. We suggest that Lin28 may be a candidate predictor or an anticancer therapeutic target for gastric cancer patients. PMID- 25515922 TI - Doctors in all specialties need more training in mental health. PMID- 25515923 TI - Synthetic biology's self-fulfilling prophecy--dangers of confinement from within and outside. AB - A too narrow focus on engineering and application may confine the development of synthetic biology: this Forum article provides reasons to suggest that knowledge could remain related to intended functions and applications, and not flow back from application to (deeper biological) understanding. Concurrently, such an engineering/application focus may 'attract' and feed strategic policy schemes, in turn enhancing the need for applicability as a prerequisite of knowledge production. This self-reinforcing loop--driven from within and outside the field- could ultimately restrict future knowledge and benefits from synthetic biology. PMID- 25515924 TI - Re-examining antidepressant risk of self-injury in children and adolescents. PMID- 25515925 TI - Origin of the exotic blue color of copper-containing historical pigments. AB - The study of chemical factors that influence pigment coloring is a field of fundamental interest that is still dominated by many uncertainties. In this Article, we investigate, by means of ab initio calculations, the origin of the unusual bright blue color displayed by historical Egyptian Blue (CaCuSi4O10) and Han Blue (BaCuSi4O10) pigments that is surprisingly not found in other compounds like BaCuSi2O6 or CaCuO2 containing the same CuO4(6-) chromophore. We show that the differences in hue between these systems are controlled by a large red-shift (up to 7100 cm(-1)) produced by an electrostatic field created by a lattice over the CuO4(6-) chromophore from the energy of the 3z(2)-r(2) -> x(2)-y(2) transition, a nonlocal phenomenon widely ignored in the realm of transition metal chemistry and strongly dependent upon the crystal structure. Along this line, we demonstrate that, although SiO4(4-) units are not involved in the chromophore itself, the introduction of sand to create CaCuSi4O10 plays a key role in obtaining the characteristic hue of the Egyptian Blue pigment. The results presented here demonstrate the opportunity for tuning the properties of a given chromophore by modifying the structure of the insulating lattice where it is located. PMID- 25515926 TI - Exposure to alcohol outlets in rural towns. AB - BACKGROUND: Lower-income populations are exposed to excess risks related to the presence of greater concentrations of alcohol outlets in their communities. Theory from economic geography suggests this is due to dynamic processes that shape urban retail markets (as outlets are attracted to areas of higher population density due to the increased demand but are excluded from higher income areas due to land and structure rents). This mechanism may explain increased exposure to alcohol outlets for lower-income populations in rural areas. This study tests the hypothesis that the distribution of outlets between rural towns will reflect these market dynamics, such that outlets are concentrated in towns with (i) greater resident and temporary populations, (ii) with lower income, and (iii) which are adjacent to towns with higher income. METHOD: Bayesian conditional autoregressive Poisson models examined counts of bars, restaurants, and off-premise outlets within 353 discrete towns of rural Victoria, Australia (mean population = 4,236.0, SD = 15,754.1). Independent variables were each town's total resident population, net changes to population (due to commuter flow, visitors, and the flow of local residents to other towns [spatial interaction]), and income for the local and adjacent towns. RESULTS: Lower local income and increased income in adjacent towns were associated with more outlets of all types. Greater resident populations and greater net population due to commuters also predicted greater numbers of all outlets. Bars and restaurants were positively related to greater net population due to visitors and negatively related to spatial interaction. CONCLUSIONS: The economic geographic processes that lead to greater concentrations of alcohol outlets in lower-income areas are common to all retail markets. Lower-income populations are exposed to increased risk associated with the presence of additional outlets that service demand from nonresidents. In rural areas, these processes appear to operate between discrete towns. PMID- 25515927 TI - Ten-year prognosis in multiple sclerosis: a better outcome in relapsing-remitting patients but not in primary progressive patients. AB - BACKGROUND AND PURPOSE: Multiple sclerosis (MS) prognosis remains a challenge for both patients and physicians. Complementary to natural history studies, updated population-based data from the first event suggestive of MS, at the time of the first approved disease modifying drug (DMD), are needed. Our objective was to provide a 10-year history of MS from clinical onset at time of first approved DMDs in a population-based cohort. METHODS: A population-based cohort of patients whose first clinical event suggestive of MS had occurred in Brittany between 2000 and 2001 was prospectively selected. History of relapses, treatments and disability up to 10 years after onset were collected. RESULTS: In all, 278 patients with either attack-onset (n = 244) or progressive-onset (n = 34) were recruited. Amongst attack-onset patients, 30% remained as clinically isolated syndrome and 70% had a second relapse after a median time of 1.7 years (95% confidence interval 1.2-2.4). 80% of relapsing-remitting MS patients received DMDs for at least 6 months. 29% reached disability status scale (DSS) 3 and 8% DSS 6. Amongst progressive-onset patients, 100% reached DSS 3 and 59% DSS 6. CONCLUSION(S): Our population-based study reports a lower risk of disability progression at 10-year follow-up in the relapsing-remitting MS group than previously reported. This better prognosis was not observed in the progressive onset MS group. This finding impacts the prognosis given to patients in clinical practice. PMID- 25515928 TI - Effective gene delivery into human stem cells with a cell-targeting Peptide modified bioreducible polymer. AB - Stem cells are poorly permissive to non-viral gene transfection reagents. In this study, we explored the possibility of improving gene delivery into human embryonic (hESC) and mesenchymal (hMSC) stem cells by synergizing the activity of a cell-binding ligand with a polymer that releases nucleic acids in a cytoplasm responsive manner. A 29 amino acid long peptide, RVG, targeting the nicotinic acetylcholine receptor (nAchR) was identified to bind both hMSC and H9-derived hESC. Conjugating RVG to a redox-sensitive biodegradable dendrimer-type arginine grafted polymer (PAM-ABP) enabled nanoparticle formation with plasmid DNA without altering the environment-sensitive DNA release property and favorable toxicity profile of the parent polymer. Importantly, RVG-PAM-ABP quantitatively enhanced transfection into both hMSC and hESC compared to commercial transfection reagents like Lipofectamine 2000 and Fugene. ~60% and 50% of hMSC and hESC were respectively transfected, and at increased levels on a per cell basis, without affecting pluripotency marker expression. RVG-PAM-ABP is thus a novel bioreducible, biocompatible, non-toxic, synthetic gene delivery system for nAchR expressing stem cells. Our data also demonstrates that a cell-binding ligand like RVG can cooperate with a gene delivery system like PAM-ABP to enable transfection of poorly-permissive cells. PMID- 25515929 TI - Networks of neuroblastoma cells on porous silicon substrates reveal a small world topology. AB - The human brain is a tightly interweaving network of neural cells where the complexity of the network is given by the large number of its constituents and its architecture. The topological structure of neurons in the brain translates into its increased computational capabilities, low energy consumption, and nondeterministic functions, which differentiate human behavior from artificial computational schemes. In this manuscript, we fabricated porous silicon chips with a small pore size ranging from 8 to 75 nm and large fractal dimensions up to Df ~ 2.8. In culturing neuroblastoma N2A cells on the described substrates, we found that those cells adhere more firmly to and proliferate on the porous surfaces compared to the conventional nominally flat silicon substrates, which were used as controls. More importantly, we observed that N2A cells on the porous substrates create highly clustered, small world topology patterns. We conjecture that neurons with a similar architecture may elaborate information more efficiently than in random or regular grids. Moreover, we hypothesize that systems of neurons on nano-scale geometry evolve in time to form networks in which the propagation of information is maximized. PMID- 25515930 TI - A novel minimal in vitro system for analyzing HIV-1 Gag-mediated budding. AB - A biomimetic minimalist model membrane was used to study the mechanism and kinetics of cell-free in vitro HIV-1 Gag budding from a giant unilamellar vesicle (GUV). Real-time interaction of Gag, RNA, and lipid, leading to the formation of mini-vesicles, was measured using confocal microscopy. Gag forms resolution limited punctae on the GUV lipid membrane. Introduction of the Gag and urea to a GUV solution containing RNA led to the budding of mini-vesicles on the inside surface of the GUV. The GUV diameter showed a linear decrease in time due to bud formation. Both bud formation and decrease in GUV size were proportional to Gag concentration. In the absence of RNA, addition of urea to GUVs incubated with Gag also resulted in subvesicle formation. These observations suggest the possibility that clustering of GAG proteins leads to membrane invagination even in the absence of host cell proteins. The method presented here is promising, and allows for systematic study of the dynamics of assembly of immature HIV and help classify the hierarchy of factors that impact the Gag protein initiated assembly of retroviruses such as HIV. PMID- 25515932 TI - Deployed communication between the Role 3 and Role 1. AB - INTRODUCTION: The discharge summary is the most common method for documenting a patient's diagnostic findings, hospital management and arrangements for post discharge follow up. After being discharged from hospital, patients are routinely reviewed without a discharge summary being available. A recent review revealed that a significant proportion of patients discharged from the Role 3 had no evidence of their admission on their permanent medical record. The aim of this audit was to assess the transition of discharge summaries from Role 3 to Role 1 during Op HERRICK 18. The intention was to review where errors in the transfer of discharge information between Role 3 and Role 1 might be occurring with a view to implementing improvements. METHODS: Two audits assessed the delivery of discharge information. A re-audit was performed 1 month after a system was implemented. RESULTS: The transfer of discharge information was poor with only 1/40 (2.5%) summaries arriving from R3 to R1. Following implementation of a system the transfer of discharge information improved to 24/30 (80%). CONCLUSIONS: The adoption of a system to transit discharge information from R3 to R1 resulted in a drastic improvement. Ideally, a future electronic patient record system used by all facets of Defence Medical Services would limit the potential for future adverse events due to communication failure. Regular audits assessing the transfer of discharge information should form part of standard audit cycles in future contingency operations. PMID- 25515931 TI - Regulation of cell survival by HUNK mediates breast cancer resistance to HER2 inhibitors. AB - Breast cancer patients who are HER2-positive receive targeted inhibitors to HER2, including trastuzumab and lapatinib. While patients benefit from the use of HER2 inhibitors, many fail therapy and almost all patients become resistant to treatment, indicating a critical need to prevent treatment failure. Several recent studies indicate that activation of autophagy contributes to trastuzumab and lapatinib resistance and demonstrate that impairing autophagy in breast cancer cells is therapeutically beneficial. Moreover, autophagy is mechanistically linked through signaling crosstalk to apoptotic pathways, where activation of one process impacts the other. Therefore, understanding the molecular mechanisms that control these processes may uncover novel areas of therapeutic intervention to combat or prevent resistance in breast cancer. We previously characterized the protein kinase HUNK as a breast cancer-promoting factor in HER2/neu-induced mammary tumor models, in which HUNK supported the survival of HER2/neu-positive tumor cells, likely through the regulation of apoptosis. Because significant crosstalk exists between apoptotic and autophagy proteins, we now examine if HUNK is also able to regulate cell survival through modulation of autophagy using HER2 inhibitor sensitive and resistant breast cancer models. Furthermore, we investigate whether inhibiting HUNK impairs in vivo tumor growth that is initiated by HER2 inhibitor-resistant breast cancer cells. Our findings indicate that therapeutically targeting HUNK is a potential strategy for overcoming resistance and that resistant breast cancer cells maintain HUNK expression to drive tumorigenesis, an observation that is consistent with a pro-survival role for this kinase. PMID- 25515933 TI - Unveiling the triplet state of a 4-amino-7-nitrobenzofurazan derivative in cyclohexane. AB - The nitrobenzofurazan (NBD) moiety has gained tremendous popularity over the last decades due to its fluorogenic nature. Indeed, upon interaction with aliphatic amines, it generates a stable fluorescent adduct, which has been used for protein and lipid labeling. In fact the 4-amino substituted NBD belongs to the broad family of intramolecular charge transfer molecules, with the amino group acting as an electron donor upon photoexcitation, and the nitro group as an electron acceptor. Although the singlet excited state of 4-amino NBD derivatives has been abundantly studied, investigation of its triplet manifold is scarce and even the absence of intersystem crossing for this type of molecules has been suggested. However, intramolecular charge transfer molecules are known to undergo intersystem crossing and high phosphorescence quantum yields have been reported in a nonpolar solvent. In the present paper, we have investigated the photophysical and photochemical properties of N-hexyl-7 nitrobenzo[c][1,2,5]xadiazole-4-amine. We have shown the existence of a triplet state for this molecule in cyclohexane via nanosecond laser flash photolysis. Interestingly, deactivation of the triplet state leads to photoproducts formation, which are only present in the absence of oxygen. PMID- 25515934 TI - Unlicensed personnel administering medications to older persons living at home: a challenge for social and care services. AB - BACKGROUND: Administration of medication to care recipients is delegated to home care assistants working in the municipal social care, alongside responsibility for providing personal assistance for older people. Home-care assistants have practical administration skills, but lack formal medical knowledge. AIM: The aim of this study was to explore how home-care assistants perceive administration of medication to older people living at home, as delegated to them in the context of social care. METHODS: Four focus groups consisting of 19 home-care assistants were conducted. Data were analysed using qualitative content analysis. RESULTS: According to home-care assistants, health and social care depends on delegation arrangements to function effectively, but in the first place it relieves a burden for district nurses. Even when the delegation had expired, administration of medication continued, placing the statutes of regulation in a subordinate position. There was low awareness among home-care assistants about the content of the statutes of delegation. Accepting delegation to administer medications has become an implicit prerequisite for social care work in the municipality. CONCLUSIONS: Accepting the delegation to administer medication was inevitable and routine. In practice, the regulating statute is made subordinate and consequently patient safety can be threatened. The organisation of health and social care relies on the delegation arrangement to meet the needs of a growing number of older home-care recipients. IMPLICATIONS FOR PRACTICE: This is a crucial task which management within both the healthcare professions and municipal social care needs to address, to bridge the gap between statutes and practice, to create arenas for mutual collaboration in the care recipients' best interest and to ensure patient safety. PMID- 25515935 TI - The Worst Itch Numeric Rating Scale for patients with moderate to severe plaque psoriasis or psoriatic arthritis. AB - Plaque psoriasis (PP) and psoriatic arthritis (PsA) are autoinflammatory chronic conditions associated with skin involvement. Pruritus, or itching, is a prevalent and bothersome symptom in patients with PP and is associated with reduced health related quality of life. The Worst Itch Numeric Rating Scale (WI-NRS) has been developed as a simple, single item with which to assess the patient-reported severity of this symptom at its most intense during the previous 24-hour period. Qualitative research was undertaken to assess the content validity of the WI-NRS. Patients with moderate to severe PP and patients with PsA were recruited from clinical sites in the USA. The qualitative research entailed two-part interviews, which began with concept elicitation to gain understanding of patients' experiences of itching, followed by cognitive debriefing of the WI-NRS to assess the instrument's understandability, clarity, and degree of appropriateness from the patient's perspective. Twelve patients with PP and 22 with PsA participated in the study. Patients reported that itching was an important and relevant symptom of their psoriatic disease. The WI-NRS was reported to be complete and easy to understand; the recall period was considered appropriate, the response scale was familiar, and, overall, the instrument was found to be appropriate for assessing itching severity. Patient responses support the content validity of the WI-NRS. The psychometric properties of the tool will be evaluated in future studies. PMID- 25515937 TI - Impact of superovulation and mating on the wellbeing of juvenile and adult C57BL/6N mice. AB - Superovulation of mice is routinely used to increase the number of obtainable ova per female. Because of the better outcome, prepubescent females are preferentially used. Here, we provide results of the impact of superovulation and mating on the wellbeing of juvenile compared with adult C57BL/6N mice. Two groups of mice (3-4 weeks vs 7-8 weeks old) were superovulated and mated. Observation of mating behaviour showed that reluctant adult females tended to fight the male's approach, whereas juveniles preferred to take flight. Faeces were collected daily for the analysis of stress hormones. There was no difference in the levels of glucocorticoid metabolites either between age groups or between treated animals and their controls. Histology after mating revealed intact vaginal mucosa without any detectable lesions in all animals regardless of age. In contrast to adults, almost all juveniles were synchronised in oestrus and produced significantly more ova. Taken together, our results reveal no increased welfare problem from using juvenile mice for superovulation and mating. Considering the higher yield of fertilisable oocytes and zygotes, it is advisable to use C57BL/6N prepubescent mice in order to reduce the number of donor females required. PMID- 25515936 TI - Efficacy of a smoking prevention programme in Catalan secondary schools: a cluster-randomized controlled trial in Spain. AB - AIMS: To evaluate the efficacy of a school-based educational programme in reducing the incidence and prevalence of smoking in secondary school students (compulsory secondary education: CSE) in Catalonia (Spain). DESIGN: Cluster randomized controlled trial. SETTING: Schools in the Tarragona Health Care Region of Spain. PARTICIPANTS: All students enrolled in the first year of CSE during the 2007-08 school year in the 29 participating schools (n = 2245); 1583 students completed the follow-up over the 4-year study period (804 and 779 in the control and intervention groups, respectively). MEASURES: Self-reported questionnaires were administered during the first quarter of the 2007, 2008, 2009 and 2010 school years. A smoker was defined as 'smoking cigarettes daily or occasionally within the past 30 days'. Multi-level logistic regression analysis was conducted to analyse the prevalence and incidence of smoking between the intervention and control groups. INTERVENTION: A school-based educational programme comprising seven modules, each with a different approach to smoking habits. Each module included activities, work-shops and/or class sessions. FINDINGS: The initial prevalence of smokers in the control and intervention groups who completed the follow-up was 3.9% and 4.2%, respectively. At the end of the study, the prevalence of smokers was 24.4% in the control group and 19.9% in the intervention group. The accumulated incidence of new smokers was 230.57/1000 in the control group and 183.65/1000 in the intervention group. The adjusted odds ratio (OR) comparing the intervention group with the control group was 0.75 [95% confidence interval (CI) = 0.49, 1.15] for smoking prevalence, and 0.74 (95% CI = 0.48, 1.14) for smoking incidence. CONCLUSIONS: A school-based educational intervention for secondary school students in Catalonia, Spain was not found to lead to a statistically significant reduction of smoking prevalence and incidence. PMID- 25515938 TI - Effective use of mirtazapine for refractory pruritus associated with carcinoma en cuirasse. AB - Pruritus is a debilitating symptom that can be associated with cutaneous involvement by an underlying malignancy. We report the case of a 68-year-old woman with a history of triple-negative breast cancer who presented with extensive, localised cutaneous metastasis complicated by incapacitating, treatment-refractory pruritus localised to the anatomic regions involved by her metastatic disease. Physical examination revealed an indurated, ecchymotic, ulcerated plaque circumferentially encasing her thorax. Histopathological examination revealed substantial dermal lymphatic involvement and dilation as well as dermal collagen infiltration by tumour cells and nodules. The clinical and pathological findings were consistent with a diagnosis of carcinoma en cuirasse. Mirtazapine, a noradrenergic antidepressant with antiserotonin and antihistamine activity, was started and led to rapid, sustained relief of the patient's pruritus. Mirtazapine may be a useful systemic agent for the palliative relief of pruritus associated with cutaneous infiltration by an underlying malignancy. PMID- 25515939 TI - Improvement of the trigger of a ventilator for non-invasive ventilation in children: bench and clinical study. AB - BACKGROUND AND AIMS: Even though numerous ventilators are licensed for a use in children, very few have been specifically developed for this age range. Therefore, home ventilators may not be able to adequately synchronize with the child's respiratory effort, and the inspiratory triggers (ITs) of assist modes are not always appropriate for children. The aim of the study was to test the improvement of the IT of a ventilator on a pediatric bench and in pediatric patients. METHODS: A classical IT (ITc) and an improved IT [non-invasive ventilation (NIV) + IT] were tested on a bench with six pediatric profiles and in six young patients (mean age 14.1 +/- 2.7 years old) requiring long-term NIV. RESULTS: On the bench, trigger time delays (DeltaT) and trigger pressures (DeltaP) were reduced with the NIV + IT as compared with the ITc (DeltaT: 0.481 +/- 0.332 vs 0.079 +/- 0.022 s for ITc and NIV + IT, respectively, P = 0.027; DeltaP: -1.40 +/- 0.70 vs -0.42 +/- 0.28 cmH2 O for ITc and NIV + IT, respectively, P = 0.046). The clinical study confirmed the decrease in DeltaT (0.267 +/- 0.061 vs 0.178 +/- 0.074 s for ITc and NIV + IT, respectively, P = 0.024) and DeltaP (-0.68 +/- 0.26 vs -0.39 +/- 0.11 cmH2 O for ITc and NIV + IT, respectively, P = 0.030). CONCLUSIONS: The sensitivity of the IT of a ventilator can be improved for pediatric use. The improvements observed on the bench study were confirmed in pediatric patients. PMID- 25515940 TI - Separation and analysis of triazine herbcide residues by capillary electrophoresis. AB - Triazines are widely used in agriculture around the world as selective pre- and post-emergence herbicides for the control of broad leaf and grassy weeds. With high toxicity and persistence, triazines can contaminate the environment and crops, so the development of rapid and sensitive methods for the determination of different triazines is necessary. Capillary electrophoresis comprises a group of techniques used to separate chemical mixtures. Analytical separation is based on different electrophoretic mobilities. This review focuses on the analysis of triazine herbicides with different modes of capillary electrophoresis, including capillary zone electrophoresis, micellar electrokinetic capillary electrophoresis, capillary electrochromatography and nonaqueous capillary electrophoresis. Determinations of triazines in various matrices such as surface water, groundwater, vegetables, soil and grains are emphasized. PMID- 25515941 TI - Learning feature representations with a cost-relevant sparse autoencoder. AB - There is an increasing interest in the machine learning community to automatically learn feature representations directly from the (unlabeled) data instead of using hand-designed features. The autoencoder is one method that can be used for this purpose. However, for data sets with a high degree of noise, a large amount of the representational capacity in the autoencoder is used to minimize the reconstruction error for these noisy inputs. This paper proposes a method that improves the feature learning process by focusing on the task relevant information in the data. This selective attention is achieved by weighting the reconstruction error and reducing the influence of noisy inputs during the learning process. The proposed model is trained on a number of publicly available image data sets and the test error rate is compared to a standard sparse autoencoder and other methods, such as the denoising autoencoder and contractive autoencoder. PMID- 25515942 TI - [Provision of services and demand for care support centers. Results of the evaluation of all care support centers in Baden-Wurttemberg]. AB - BACKGROUND: The counseling infrastructure for elderly and vulnerable people is characterized by overuse, underuse and misuse. According to the German care reform, care support centers should solve this problem by putting all relevant counseling services under one roof. OBJECTIVE: The aim of this study was to analyze the type of services and demand of German care support centers 5 years after the German care reform came into force. MATERIAL AND METHODS: The study was based on an analysis of the documentation of all 48 care support centers in Baden Wurttemberg after the German care reform came into force and of counseling services for elderly and vulnerable people. RESULTS AND CONCLUSION: The results of the evaluation of all care support centers in Baden-Wurttemberg showed that they offer a wide range of services ranging from counseling services for simple assistance to promoting self-help, up to comprehensive case management. The wide variety of counseling services offered also showed that these care support centers can meet the many different needs and requirements of the clientele. Findings from this study enabled a positive conclusion about the demand to be drawn. It became clear that the services offered are used by many people of all ages who are already in need of care or who are trying to prevent this need from occurring. A consensus about the conceptual development of care provision models employed by care support centers has not yet been achieved in Germany. Findings from this study could be useful in highlighting the need to further develop the care support centers. PMID- 25515944 TI - Does the ingrowth surface make a difference? A retrieval study of 423 cementless acetabular components. AB - The effect of factors such as design, alloy and coating type on bony or fibrous tissue ingrowth was evaluated in a study of 423 retrieved cementless acetabular shells representing 16 shell designs. Small-beaded (250MUm) porous coatings, either with or without hydroxyapatite (HA) coatings, proved to be the superior porous surface for bone ingrowth. Small-beaded shells that were Duofix coated had predominantly fibrous tissue ingrowth. In addition to bead size, alloy type and surface type have significant effect on bone ingrowth. In contrast, there is no significant association between bone ingrowth and time in situ, with most bone ingrowth occurring early. Although roughened, press-fit shells have acceptable clinical and Registry data, they showed some of the lowest ingrowth/ongrowth scores of all the shells tested. PMID- 25515943 TI - The duration of Plasmodium falciparum infections. AB - Plasmodium vivax and Plasmodium ovale are often considered the malaria parasites best adapted to long-term survival in the human host because of their latent exo erythrocytic forms. The prevailing opinion until the middle of the last century was that the maximum duration of Plasmodium falciparum infections was less than two years. Case reports and series investigating blood donors following accidental malaria infection of blood transfusion recipients and other sporadic malaria cases in non-endemic countries have shown clearly that asymptomatic P. falciparum infections may persist for up to a decade or longer (maximum confirmed 13 years). Current policies in malaria-free countries of excluding blood donors who have lived in malarious areas are justified. Vigilance for longer than three years after declaring elimination in an area may be needed. PMID- 25515945 TI - Effects of CYP3A4 polymorphisms on the plasma concentration of voriconazole. AB - Voriconazole is frequently utilized for the prevention and treatment of invasive fungal infections (IFIs), and is extensively metabolized by the cytochrome P450 (CYP) system. The impact of activity of the genes encoding CYP3A4, CYP3A5, and CYP2C9 on the pharmacokinetics of voriconazole cannot be ignored because, second to CYP2C19, they are the most important enzymes involved in voriconazole metabolism. The influence of genetic polymorphisms in CYP3A4, CYP3A5, and CYP2C9 on the plasma concentrations of voriconazole was evaluated in the present study. The study cohort comprised 158 patients with IFIs in whom 22 single-nucleotide polymorphisms (SNPs) in CYP3A4, CYP3A5, and CYP2C9 were genotyped using the Sequenom MassARRAY RS1000 system, and voriconazole plasma concentrations were measured by high-performance liquid chromatography (HPLC). 40, 91, and 27 patients presented with low (<1 mg/L), normal (1-4 mg/L), and high (>4 mg/L) plasma voriconazole concentrations, respectively. Correlation analysis between polymorphisms and the plasma voriconazole concentration revealed an association between the presence of the rs4646437 T allele and a higher plasma voriconazole concentration [p = 0.033, odds ratio (OR) = 2.832, 95% confidence interval (CI) = 1.086-7.384]. This study has identified a new SNP related to the metabolism of voriconazole, potentially providing novel insight into the influence of CYP3A4 on the pharmacokinetics of this antifungal agent. PMID- 25515947 TI - Ephedrine for myasthenia gravis, neonatal myasthenia and the congenital myasthenic syndromes. AB - BACKGROUND: Myasthenia is a condition in which neuromuscular transmission is affected by antibodies against neuromuscular junction components (autoimmune myasthenia gravis, MG; and neonatal myasthenia gravis, NMG) or by defects in genes for neuromuscular junction proteins (congenital myasthenic syndromes, CMSs). Clinically, some individuals seem to benefit from treatment with ephedrine, but its effects and adverse effects have not been systematically evaluated. OBJECTIVES: To assess the effects and adverse effects of ephedrine in people with autoimmune MG, transient neonatal MG, and the congenital myasthenic syndromes. SEARCH METHODS: On 17 November 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. We also searched reference lists of articles, conference proceedings of relevant conferences, and prospective trial registers. In addition, we contacted manufacturers and researchers in the field. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) and quasi-RCTs comparing ephedrine as a single or add-on treatment with any other active treatment, placebo, or no treatment in adults or children with autoimmune MG, NMG, or CMSs. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study design and quality, and extracted data. We contacted study authors for additional information. We collected information on adverse effects from included articles, and contacted authors. MAIN RESULTS: We found no RCTs or quasi-RCTs, and therefore could not establish the effect of ephedrine on MG, NMG and CMSs. We describe the results of 53 non-randomised studies narratively in the Discussion section, including observations of endurance, muscle strength and quality of life. Effects may differ depending on the type of myasthenia. Thirty-seven studies were in participants with CMS, five in participants with MG, and in 11 the precise form of myasthenia was unknown. We found no studies for NMG. Reported adverse effects included tachycardia, sleep disturbances, nervousness, and withdrawal symptoms. AUTHORS' CONCLUSIONS: There was no evidence available from RCTs or quasi-RCTs, but some observations from non randomised studies are available. There is a need for more evidence from suitable forms of prospective RCTs, such as series of n-of-one RCTs, that use appropriate and validated outcome measures. PMID- 25515946 TI - Antiviral, antifungal, and antiparasitic activities of fluoroquinolones optimized for treatment of bacterial infections: a puzzling paradox or a logical consequence of their mode of action? AB - This review summarizes evidence that commercially available fluoroquinolones used for the treatment of bacterial infections are active against other non-bacterial infectious agents as well. Any of these fluoroquinolones exerts, in parallel to its antibacterial action, antiviral, antifungal, and antiparasitic actions at clinically achievable concentrations. This broad range of anti-infective activities is due to one common mode of action, i.e., the inhibition of type II topoisomerases or inhibition of viral helicases, thus maintaining the selective toxicity of fluoroquinolones inhibiting microbial topoisomerases at low concentrations but mammalian topoisomerases at much higher concentrations. Evidence suggests that standard doses of the fluoroquinolones studied are clinically effective against viral and parasitic infections, whereas higher doses administered topically were active against Candida spp. causing ophthalmological infections. Well-designed clinical studies should be performed to substantiate these findings. PMID- 25515948 TI - Pretransplant urinary proteome analysis does not predict development of chronic kidney disease after liver transplantation. AB - BACKGROUND & AIMS: Chronic kidney disease (CKD) is a common complication after liver transplantation. Kidney biopsies cannot be easily performed before liver transplantation to predict patients at high risk for CKD. The aim of our study was to determine whether pre-, peri- and post-transplant factors, as well as peptides present in preliver transplant urine samples were associated with loss in kidney function at 6 months post-transplantation using proteome analysis. METHODS: Eighty patients who underwent a liver transplantation and that had pretransplant glomerular filtration rate (GFR) value of >=60 mL/min/1.73 m2 (MDRD) were included in the study. RESULTS: GFR decreased significantly after transplantation. At month 6 post-transplantation, 40 patients displayed a CKD, i.e. eGFR of <60 mL/min/1.73 m2, while the other 40 patients did not. Although thousands of peptides were identified, none was significantly associated with the development of CKD at 6 months after liver transplantation. Moreover, using a urinary peptidome classifier to detect preexisting CKD, no difference was found in CKD scores between the 2 groups. After analysis of a large number of pre-, peri- and post-transplant parameters, viral hepatitis as a cause for liver transplantation was the sole independent predictive factor for CKD. No difference in peptides with differential urinary abundance between patients who received a graft for virus related liver disease vs. all other causes of liver disease was observed. CONCLUSION: Urinary peptidome analysis before liver transplantation failed to identify a peptide pattern associated with the development of CKD at 6 months after liver transplantation. PMID- 25515950 TI - Health-related quality of life, personality and choice of coping are related in renal cell carcinoma patients. AB - OBJECTIVE: To investigate whether health-related quality of life (HRQoL) depends on psychosocial factors, rather than on factors related to the cancer treatment, this study explored the associations between HRQoL, personality, choice of coping and clinical parameters in surgically treated renal cell carcinoma (RCC) patients. MATERIALS AND METHODS: After exclusions (e.g. death, dementia), 260 patients were found to be eligible and invited to participate. The response rate was 71%. HRQoL was determined by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), personality by the Eysenck Personality Inventory and coping by the COPE Questionnaire. Given tumour treatment, TNM stage and patient-reported comorbidity were also determined. The HRQoL indices were also summarized in general quality of life/health, functional sum and symptom sum scores. RESULTS: EORTC C30 sum scores were negatively associated with the personality trait of neuroticism [common variance (CV) 19-36%]. Avoidant choice of coping inversely accounted for 9-18% of the total HRQoL variance, while reported coping by humour was to some extent negatively associated with HRQoL score (CVmax 4%). Indeed, all of the quality of life indices except for one were significantly negatively correlated with neuroticism and avoidance coping. Patients with low HRQoL due to treatment, secondary to flank or open surgery, reported a closer association between problem focused choice of coping and HRQoL than the other patients. Moreover, present comorbidities were uniquely associated with a lowered HRQoL. CONCLUSIONS: HRQoL is related to treatment-related factors in RCC patients, but shown here to be more strongly associated with psychological factors and present comorbidity. These findings suggest that attention should be paid to supportive treatment of RCC patients. PMID- 25515949 TI - Graftless sinus augmentation technique with contextual placement of implants: a case report. AB - INTRODUCTION: The positioning of implants in the jaw bones with contextual graftless lateral approach sinus lifting is finding an increasingly broad consensus in the literature. Since the 1970s, various clinical research projects have been conducted on applications of biological and synthetic biomaterials in bone regenerative surgery, both in sinus lift procedures and in cystic cavity filling after cystectomy or in bone defects in regenerative periodontal surgery. Currently, we are finding that there is an increasing trend of clinicians aiming to adopt graftless techniques, with satisfactory results in terms of implant survival in the long term. In our study, through a case report, we describe a variant of graftless sinus augmentation technique with contextual implant placement, emphasizing the role of the blood clot, combined with collagen sponges, as a natural scaffold and the osteogenic potential of the subantral membrane in guided bone regeneration, with reduced morbidity of the patient. CASE PRESENTATION: To describe the surgical technique, the clinical case of a 38-year old Caucasian woman with a lateral posterior edentulism was selected. The rehabilitation was solved by a graftless sinus augmentation technique with a contextual implant placement. For each implant, a resonance frequency analysis evaluation was reported as implant stability quotient values. The performance of the implant stability quotient values followed a gradual increase from time zero to the sixth month, as the clot was differentiated into osteoid tissue and then into bone tissue, due to the scaffold effect conferred by the equine collagen sponge. The stabilization phase took place between the fourth and the sixth month, according to the implant stability quotient values. CONCLUSIONS: Our graftless sinus augmentation technique seems to be very predictable thanks to the osteoconductive principles on which it is based, and in association with the proper management of peri-implant soft tissue, so as to increase the amount of keratinized tissue, which could represent the new gold standard for this type of rehabilitation in the future. PMID- 25515951 TI - Sleep and partner-specific quality of life in partners of men with lower urinary tract symptoms compared with partners of men from the general population. AB - OBJECTIVE: The aims of this study were to examine differences between partners of men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO) and partners of men from the population regarding sleep and two aspects of quality of life, partner-specific quality of life and health-related quality of life (HRQoL), and to identify factors related to the partner-specific quality of life and the parameter sleep efficiency. MATERIALS AND METHODS: The design was descriptive and comparative. The subjects were partners of men with LUTS suggestive of BPO (n = 126) and partners of randomly selected men from the general population (n = 131). Self-administered questionnaires about demography, comorbidity, sleep, sexuality, partner-specific quality of life and HRQoL were used. RESULTS: Partners of men with LUTS suggestive of BPO were significantly more affected in all variables measuring partner-specific quality of life compared with partners from the population. The most impaired aspects were compassion and worry about an operation or cancer. In logistic regression, the only explanatory factors were having a partner belonging to the LUTS group for impaired partner-specific quality of life and having a bed partner for high sleep efficiency. There were no significant differences between the two groups regarding the quantity and quality of sleep or the HRQoL. CONCLUSIONS: The partner-specific quality of life was impaired in partners of men with LUTS suggestive of BPO. Sleep and HRQoL did not differ between partners of men with LUTS and partners from the population. PMID- 25515952 TI - Changes in prostate-specific antigen, markers of bone metabolism and bone scans after treatment with radium-223. AB - OBJECTIVE: The aim of this study was to assess treatment-related changes in prostate-specific antigen (PSA), total and bone alkaline phosphatase (total ALP, bone ALP), and changes on conventional bone scans in patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases who received six cycles of radium-223 (Ra-223). MATERIALS AND METHODS: Changes in PSA, total ALP and bone ALP (>=30% increase or decrease), and changes on bone scans were assessed before and after six monthly cycles of Ra-223 therapy (50 kBq/kg body weight) in 14 patients with mCRPC with bone metastases and four patients on placebo. RESULTS: Post-treatment PSA increased by at least 30% in 11 out of 14 patients and remained stable in three. Total ALP and bone ALP decreased in six and nine patients, respectively. In 10 out of 12 evaluable patients the uptake on post-treatment bone scan was reduced in lesions with high pretreatment uptake, in 11 patients accompanied by the development of new or expanded bone lesions. FACBC position emission tomography/computed tomography scans confirmed the growth of new or expanded bone metastases in two patients. CONCLUSIONS: These observations support the notion that Ra-223 kills tumour cells in metastases surrounded by highly proliferating osteoblasts, consistent with the reported survival benefit. The radiation effect in small tumour deposits not surrounded by increased osteoblast activity seems, however, insufficient, thus allowing continuous tumour growth. Long-lasting PSA reductions are the exception rather than the rule during Ra-223 treatment, whereas alkaline phosphatases decrease more frequently. To improve the overall anticancer effect, Ra-223 might be a valuable component of combination treatment. PMID- 25515953 TI - Antibacterial activity of novel benzopolycyclic amines. AB - Staphylococcus aureus, especially strains resistant to multiple antibiotics, is a major pathogen for humans and animals. In this paper we have synthesized and evaluated the antibacterial activity of a new series of benzopolycyclic amines. Some of them exhibited MUM MIC values against Staphylococcus aureus and other bacteria, including methicillin-resistant S. aureus MRSA. Compound 8 that displayed a good selectivity index, showed to be active in eliminating bacterial cells forming a preexisting biofilm. PMID- 25515954 TI - Synthesis, SAR study, and biological evaluation of novel quinoline derivatives as phosphodiesterase 10A inhibitors with reduced CYP3A4 inhibition. AB - A novel class of phosphodiesterase 10A inhibitors with potent PDE10A inhibitory activity and reduced CYP3A4 inhibition was designed and synthesized starting from 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1). Replacement of pyridine ring of 1 with N-methyl pyridone ring drastically improved CYP3A4 inhibition, and further optimization of these quinoline analogues identified 1-methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4 yl)pyridin-2(1H)-one (42b), which showed potent PDE10A inhibitory activity and a good CYP3A4 inhibition profile. A PET study with (11)C-labeled 42b indicated that 42b exhibited good brain penetration and specifically accumulated in the rodent striatum. Further, oral administration of 42b dose-dependently attenuated phencyclidine-induced hyperlocomotion in mice with an ED50 value of 2.0mg/kg and improved visual-recognition memory impairment at 0.1 and 0.3mg/kg in mice novel object recognition test. PMID- 25515955 TI - Design, synthesis and structure-activity relationship studies of novel sirtuin 2 (SIRT2) inhibitors with a benzamide skeleton. AB - Human sirtuin 2 (SIRT2) is an attractive target molecule for development of drugs to treat neurodegenerative diseases and cancer, because SIRT2 inhibitors have a protective effect against neurodegeneration and an anti-proliferative effect on cancer stem cells. We designed and synthesized a series of benzamide derivatives as SIRT2 inhibitor candidates. Among them, compound 17k showed the most potent SIRT2-inhibitory activity (IC50=0.60MUM), with more than 150-fold selectivity over SIRT1 and SIRT3 isoforms (IC50 >100MUM). PMID- 25515956 TI - New synthetic sulfone derivatives inhibit growth, adhesion and the leucine arylamidase APE2 gene expression of Candida albicans in vitro. AB - The successful preventing and effective treatment of invasive Candida albicans infections required research focused on synthesis of new classes of agents and antifungal activity studies. Bromodichloromethyl-4-chloro-3-nitrophenyl sulfone (named compound 6); dichloromethyl-4-chloro-3-nitrophenyl sulfone (named 7); and chlorodibromomethyl-4-hydrazino-3-nitrophenyl sulfone (named 11) on inhibition of planktonic cells' growth, leucine arylamidase APE2 gene expression, and adhesion to epithelial cells were investigated. In vitro anti-Candida activities were determined against wild-types, and the morphogenesis mutants: Deltaefg1 and Deltacph1. MICs of compounds 6, 7 and 11 (concentrated at 0.25-16MUg/ml) were determined using the Clinical and Laboratory Standards Institute Broth Microdilution Method (M27-A3 Document). APE2 expression was analyzed using RT PCR; relative quantification was normalized against ACT1 in cells growth in YEPD and on Caco-2 cell line. Adherence assay of C. albicans to Caco-2 was performed in 24-well-plate. The structure activity relationship suggested that sulfone containing hydrazine function at C-1 (compound 11) showed higher antifungal activity (cell inhibition%=100 at 1-16MUg/ml) than the remaining sulfones with chlorine at C-1. Deltacph1/Deltaefg1 was highly sensitive to compound 11, while the sensitivity was reduced in Deltacph1/Deltaefg1::EFG1 (%=100 at 16-fold higher concentration). Compound 11 significantly affected adherence to epithelium (P ?0.05) and hyphae formation. The APE2 up-regulation plays role in sulfones' resistance on MAP kinase pathway. Either CPH1 or EFG1 play a role in the resistance mechanism in sulfones. The strain-dependent phenomenon is a factor in the sulfone resistance mechanism. Sulfones' mode of action was attributed to reduced virulence arsenal in terms of adhesiveness and pathogenic potential related to the APE2 expression and morphogenesis. PMID- 25515957 TI - Design, synthesis and evaluation of novel 5-phenylpyridin-2(1H)-one derivatives as potent reversible Bruton's tyrosine kinase inhibitors. AB - A series of novel reversible Btk inhibitors has been designed based on the structure of the recently reported preclinical drug RN486. The synthesis and SAR of these compounds are described. Among these derivatives, compound 16b was identified to be a potent and orally available reversible agent with satisfactory Btk enzymatic and cellular inhibition in vitro, as well as favorable PK properties and inhibition of arthritis in vivo. PMID- 25515959 TI - Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. AB - Current guidelines for heparin-induced thrombocytopenia (HIT) management recommend heparin cessation and switching to a nonheparin anticoagulant (ie, argatroban, danaparoid) upon clinical suspicion. Fondaparinux may be effective but information supporting its use is limited. We retrospectively evaluated 239 patients who received a nonheparin anticoagulant (fondaparinux = 133, danaparoid = 59, and argatroban = 47) for suspected or confirmed HIT. A propensity score was constructed based on age, gender, creatinine, 4T scores, and comorbidity index, and used to match 133 patients to 60 controls. Outcomes were thrombosis or thrombosis-related death and major bleeding. In the matched population there were 22 (16.5%) episodes of thromboses in the fondaparinux group and 13 (21.4%) in the control group (chi(2) P = .424). Bleeding was observed in 28 (21.1%) patients in the fondaparinux group compared with 12 (20%) in the control group (chi(2) P = .867). Survival analysis, and subgroup and unmatched analyses showed similar results. In the fondaparinux group, 60% of patients received prophylactic doses. Fondaparinux has similar effectiveness and safety as argatroban and danaparoid in patients with suspected HIT. Prophylactic fondaparinux doses seem to be effective if no indication for full anticoagulation exists. PMID- 25515958 TI - Genome-wide identification of vegetative phase transition-associated microRNAs and target predictions using degradome sequencing in Malus hupehensis. AB - BACKGROUND: A long juvenile period between germination and flowering is a common characteristic among fruit trees, including Malus hupehensis (Pamp.) Rehd., which is an apple rootstock widely used in China. microRNAs (miRNAs) play an important role in the regulation of phase transition and reproductive growth processes. RESULTS: M. hupehensis RNA libraries, one adult and one juvenile phase, were constructed using tree leaves and underwent high-throughput sequencing. We identified 42 known miRNA families and 172 novel miRNAs. We also identified 127 targets for 25 known miRNA families and 168 targets for 35 unique novel miRNAs using degradome sequencing. The identified miRNA targets were categorized into 58 biological processes, and the 123 targets of known miRNAs were associated with phase transition processes. The KEGG analysis revealed that these targets were involved in starch and sucrose metabolism, and plant hormone signal transduction. Expression profiling of miRNAs and their targets indicated multiple regulatory functions in the phase transition. The higher expression level of mdm-miR156 and lower expression level of mdm-miR172 in the juvenile phase leaves implied that these two small miRNAs regulated the phase transition. mdm-miR160 and miRNA393, which regulate genes involved in auxin signal transduction, could also be involved in controlling this process. The identification of known and novel miRNAs and their targets provides new information on this regulatory process in M. hupehensis, which will contribute to the understanding of miRNA functions during growth, phase transition and reproduction in woody fruit trees. CONCLUSIONS: The combination of sRNA and degradome sequencing can be used to better illustrate the profiling of hormone-regulated miRNAs and miRNA targets involving complex regulatory networks, which will contribute to the understanding of miRNA functions during growth, phase transition and reproductive growth in perennial woody fruit trees. PMID- 25515960 TI - The role of the Janus-faced transcription factor PAX5-JAK2 in acute lymphoblastic leukemia. AB - PAX5-JAK2 has recently been identified as a novel recurrent fusion gene in B-cell precursor acute lymphoblastic leukemia, but the function of the encoded chimeric protein has not yet been characterized in detail. Herein we show that the PAX5 JAK2 chimera, which consists of the DNA-binding paired domain of PAX5 and the active kinase domain of JAK2, is a nuclear protein that has the ability to bind to wild-type PAX5 target loci. Moreover, our data provide compelling evidence that PAX5-JAK2 functions as a nuclear catalytically active kinase that autophosphorylates and in turn phosphorylates and activates downstream signal transducers and activators of transcription (STATs) in an apparently noncanonical mode. The chimeric protein also enables cytokine-independent growth of Ba/F3 cells and therefore possesses transforming potential. Importantly, the kinase activity of PAX5-JAK2 can be efficiently blocked by JAK2 inhibitors, rendering it a potential target for therapeutic intervention. Together, our data show that PAX5-JAK2 simultaneously deregulates the PAX5 downstream transcriptional program and activates the Janus kinase-STAT signaling cascade and thus, by interfering with these two important pathways, may promote leukemogenesis. PMID- 25515962 TI - Affinity of FVIII-specific antibodies reveals major differences between neutralizing and nonneutralizing antibodies in humans. AB - Recently, we reported that distinct immunoglobulin (Ig) isotypes and IgG subclasses of factor VIII (FVIII)-specific antibodies are found in different cohorts of patients with hemophilia A and in healthy individuals. Prompted by these findings, we further investigated the distinguishing properties among the different populations of FVIII-specific antibodies. We hypothesized that the affinity of antibodies would discriminate between the neutralizing and nonneutralizing antibodies found in different study cohorts. To test this idea, we established a competition-based enzyme-linked immunosorbent assay technology to assess the apparent affinities for each isotype and IgG subclass of FVIII specific antibodies without the need for antibody purification. We present a unique data set of apparent affinities of FVIII-specific antibodies found in healthy individuals, patients with congenital hemophilia A with and without FVIII inhibitors, and patients with acquired hemophilia A. Our data indicate that FVIII specific antibodies found in patients with FVIII inhibitors have an up to 100 fold higher apparent affinity than that of antibodies found in patients without inhibitors and in healthy individuals. High-affinity FVIII-specific antibodies could be retrospectively detected in longitudinal samples of an individual patient with FVIII inhibitors 543 days before the first positive Bethesda assay. This finding suggests that these antibodies might serve as potential biomarkers for evolving FVIII inhibitor responses. PMID- 25515961 TI - MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors. AB - MicroRNAs (miRNAs) are key regulators of hematopoietic cell differentiation and may contribute to altered growth of leukemic stem cells. Using microarray-based miRNA profiling, we found that miRNA 486 (miR-486) is significantly upregulated in chronic myeloid leukemia (CML) compared with normal CD34(+) cells, particularly in the megakaryocyte-erythroid progenitor population. miR-486-5p expression increased during erythroid differentiation of both CML and normal CD34(+) cells. Ectopic miR-486-5p expression enhanced in vitro erythroid differentiation of normal CD34(+) cells, whereas miR-486-5p inhibition suppressed normal CD34(+) cell growth in vitro and in vivo and inhibited erythroid differentiation and erythroid cell survival. The effects of miR-486-5p on hematopoietic cell growth and survival are mediated at least in part via regulation of AKT signaling and FOXO1 expression. Using gene expression and bioinformatics analysis, together with functional screening, we identified several novel miR-486-5p target genes that may modulate erythroid differentiation. We further show that increased miR-486-5p expression in CML progenitors is related to both kinase-dependent and kinase-independent mechanisms. Inhibition of miR-486-5p reduced CML progenitor growth and enhanced apoptosis following imatinib treatment. In conclusion, our studies reveal a novel role for miR-486-5p in regulating normal hematopoiesis and of BCR-ABL-induced miR 486-5p overexpression in modulating CML progenitor growth, survival, and drug sensitivity. PMID- 25515963 TI - How I treat the older patient with acute myeloid leukemia. AB - Acute myeloid leukemia (AML) in older patients presents a notable therapeutic challenge to the clinical hematologist. The clinical biology of AML among patients is highly heterogeneous. Interpatient variations are relevant for prognosis and treatment choice. Outcome of treatment for patients of advanced age is often compromised by comorbid conditions and an enhanced susceptibility to toxicities from therapy. Here we present selected clinical vignettes that highlight distinct representative situations derived from clinical practice. The vignettes are specifically discussed in light of the perspective of treating older patients with leukemia. We review the clinical significance of various cytogenetic and molecular features of the disease, and we examine the various currently available treatment options as well as the emerging prognostic algorithms that may offer guidance in regard to personalized therapy recommendations. The dilemmas in tailoring treatment selection in this category of patients with AML are the central theme in this discussion. PMID- 25515964 TI - Retrospective Case Series of Patients with Diabetes or Prediabetes Who Were Switched from Omega-3-Acid Ethyl Esters to Icosapent Ethyl. AB - INTRODUCTION: Patients with diabetes and prediabetes are at increased risk of dyslipidemia and cardiovascular disease. To reduce this risk, statins and additional therapies may be considered. Omega-3 fatty acids offer an option to reduce triglycerides (TG) and potentially improve other lipid parameters, although products that contain docosahexaenoic acid (DHA) may increase low density lipoprotein cholesterol (LDL-C) while eicosapentaenoic acid (EPA) does not. Prescription formulations include omega-3-acid mixtures (combination of predominantly EPA and DHA), and icosapent ethyl (high-purity prescription form of EPA ethyl ester); prescription omega-3 products are indicated as an adjunct to diet to reduce TGs in adult patients with severe hypertriglyceridemia at a dose of 4 g/day. METHODS: This was a retrospective analysis of records from a private endocrinology practice of patients who received omega-3-acid ethyl esters (OM3EE) (4 g/day) and were subsequently switched to icosapent ethyl (IPE; 4 g/day) due to the potential of OM3EE to raise LDL-C and/or cause gastrointestinal upset. Patient records were analyzed for LDL-C, TG, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and non-HDL-C measured before and after the switch to IPE. RESULTS: The records of ten patients met the criteria for this analysis and were included. All patients had taken OM3EE for >=1 year prior to their last lipid measurement before switching to IPE, and all had been taking IPE for >3 months at the time of their subsequent lipid measurement. Nine of the ten patients were on concomitant statin therapy throughout. Reductions in LDL-C, TC, and non-HDL-C were observed in eight patients, reductions or no changes in TG were observed in eight patients, and increases or no changes in HDL-C were observed in eight patients. No gastrointestinal adverse events were observed. CONCLUSION: In most patients with prediabetes or diabetes who switched from OM3EE to IPE, LDL-C and other lipid parameters improved. IPE was well tolerated. PMID- 25515965 TI - Percutaneous Mechanical Ventricular Support in Acute Cardiac Care: A UK Quaternary Centre Experience Using 2.5L, 3.8L and 5.0L Impella Catheters. AB - AIMS: The Impella is a percutaneous ventricular assist device. The majority of published data describes the 2.5L and 5.0L devices, and little data is available for the newer 3.8L device. We examined the indications and outcomes from our single-centre "real-world" registry at The Queen Elizabeth Hospital, Birmingham, UK, using all three pump sizes. METHODS AND RESULTS: Records from all patients who underwent attempted Impella-assisted procedures at our centre were examined retrospectively. Impella implantation was attempted in 49 patients (mean age 72 +/- 13 years; 80% male) and was successful in 48 (98%). 45 patients underwent high-risk percutaneous coronary intervention (PCI), one patient underwent balloon aortic valvuloplasty and 3 patients had Impella as a bridge to cardiac transplantation. The 2.5L and 3.8L devices were used in 36 (75%) and 11 (23%) patients, respectively, while one patient (2%) had the 5L device. Vascular complications occurred in only one patient (2%) and stroke and peri-procedural myocardial infarction occurred in one patient (2%), while in-hospital mortality was 20% (10/49). CONCLUSIONS: In this large real-world registry, we have demonstrated the safety and feasibility of the Impella device for a wide range of indications. This includes the first series of the 3.8L device which provides superior support with no increase in vascular complications. PMID- 25515966 TI - Subjective neck pain or foreign body sensation and the true location of foreign bodies in the pharynx. AB - CONCLUSION: The location of the foreign body did not correspond well to the location of pain reported by patients. When patients present with foreign bodies in the pharynx, in addition to recording the location of pain and foreign body sensation, clinicians should perform a comprehensive and thorough oropharyngeal examination to avoid misdiagnosis. OBJECTIVES: Physicians are often guided by patient-indicated locations of pharyngeal foreign bodies. In this study, we aimed to determine the correlation between the location of the subjective neck pain or foreign body sensation and the true location of the foreign body. METHODS: We prospectively studied 90 patients who had pharyngeal foreign bodies removed at MacKay Memorial Hospital. We divided the head and neck into 10 zones according to the superficial anatomy. Subjective location, examination findings, and actual foreign body location were recorded and compared. RESULTS: The overall subjective and true locations of the foreign body were poorly correlated (kappa 0.27, p = 0.003). The positive predictive value (PPV) for the midline neck was 68%, which was higher than that on either lateral side of the neck. PPV above cricoid cartilage level was 66%. PMID- 25515967 TI - Systematic review of treatments for chronic spontaneous urticaria with inadequate response to licensed first-line treatments. AB - BACKGROUND: Patients with chronic spontaneous urticaria (CSU) are sometimes unresponsive to nonsedating, second-generation, H1 antihistamines; this study summarizes published clinical evidence for patients who remain symptomatic despite treatment. OBJECTIVE: To evaluate, via a systematic literature review, clinical evidence of management strategies for patients with CSU who remain symptomatic despite approved use of nonsedating H1 antihistamines. METHODS: Using a prespecified protocol, we searched MEDLINE, Embase, the Cochrane Library (1 January 1960-20 December 2011), and published conference abstracts (2010-2012). Rigorous criteria identified trials in patients with CSU who had a history of inadequate response to previous treatment or had used combination treatments. Trials evaluating treatment-naive patients or first-line therapies were excluded. RESULTS: Qualitative data synthesized from 26 randomized, controlled trials, four prospective studies, and one retrospective study showed cyclosporine, desloratadine plus dapsone or dipyridamole, montelukast, and omalizumab reduced urticaria activity scores, weals, and pruritus, versus placebo. Optimal treatment doses and durations were unclear due to varying trial durations, outcome measurement scales, and assessment timings. No safety concerns were reported. CONCLUSIONS: This review confirms that available evidence to guide treatment choice for patients with CSU with inadequate response to H1 antihistamines varies in quality. Further research is warranted due to low-quality trials with methodological and reporting limitations. PMID- 25515968 TI - Effectiveness of preoperative pelvic floor muscle training for urinary incontinence after radical prostatectomy: a meta-analysis. AB - BACKGROUND: Radical prostatectomy (RP) is the most common treatment for patients with localized prostate cancer. Urinary incontinence (UI) is a significant bothersome sequela after radical prostatectomy that may dramatically worsen a patient's quality of life. Pelvic floor muscle training (PFMT) is the main conservation treatment for men experiencing urinary incontinence; however, whether additional preoperative PFMT can hasten the reestablishment of continence is still unclear. The objective of this meta-analysis is to determine whether the effectiveness of preoperative plus postoperative PFMT is better than postoperative PFMT only for the re-establishment of continence after RP. METHODS: A meta-analysis was performed after a comprehensive search of available randomized controlled trials (RCTs). Quality of the included studies was assessed by the Cochrane Risk of Bias tool. Efficacy data were pooled and analyzed using Review Manager (RevMan) Version 5.0. Pooled analyses of continence rates 1, 3, 6, and 12 months postoperatively, using relative risk (RR) and 95% confidence intervals (CIs), were conducted. For data deemed not appropriate for synthesis, a narrative overview was conducted. RESULTS: Five eligible studies were ultimately included in this analysis. No significant differences in continence rates were detected at the early (1- and 3-month) time points: RR = 1.21, 95% CI = 0.71 2.08, P = 0.48; RR = 1.1, 95% CI = 0.09-1.34, P = 0.34, respectively), interim (6 month time point: RR = 0.98, 95% CI = 0.93-1.04, P = 0.59), or late recovery stage (RR = 0.93, 95% CI = 0.67-1.29, P = 0.66). Outcomes reported were time to continence in two trials and quality of life in three, but results were inconclusive because of insufficient data. CONCLUSION: According to this meta analysis, additional preoperative PFMT did not improve the resolution of UI after RP at early (<=3-month), interim (6-month), or late (1-year) recovery stages. However, the results of time to continence and quality of life were inconclusive because of insufficient data. More high-quality RCTs are needed for better evaluation of the effectiveness of preoperative PFMT on post-prostatectomy UI. PMID- 25515969 TI - Applying gamma-substituted prolines in the foldon peptide: polarity contradicts preorganization. AB - Rational choice of chemical modifications to proline residues allows the preorganization principle to be exploited for more stable assembly of the foldon domain as a tag for trimerization. With systematic knowledge of how chemical and steric variations of the ring substituents affect the relative stabilities of exo and endo puckers, the preorganization principle should then be usable in biotechnologically synthesized foldon mutants and applicable for protein tagging elsewhere. PMID- 25515970 TI - Constrained control landscape for population transfer in a two-level system. AB - The growing success of controlling the dynamics of quantum systems has been ascribed to the favorable topology of the quantum control landscape, which represents the physical observable as a function of the control field. The landscape contains no suboptimal trapping extrema when reasonable physical assumptions are satisfied, including that no significant constraints are placed on the control resources. A topic of prime interest is understanding the effects of control field constraints on the apparent landscape topology, as constraints on control resources are inevitable in the laboratory. This work particularly explores the effects of constraining the control field fluence on the topology and features of the control landscape for pure-state population transfer in a two level system through numerical simulations, where unit probability population transfer in the system is only accessible in the strong coupling regime within the model explored here. With the fluence and three phase variables used for optimization, no local optima are found on the landscape, although saddle features are widespread at low fluence values. Global landscape optima are found to exist at two disconnected regions of the fluence that possess distinct topologies and structures. Broad scale connected optimal level sets are found when the fluence is sufficiently large, while the connectivity is reduced as the fluence becomes more constrained. These results suggest that seeking optimal fields with constrained fluence or other resources may encounter complex landscape features, calling for sophisticated algorithms that can efficiently find optimal controls. PMID- 25515971 TI - Sleep duration and associated factors in a community sample of elderly individuals in Korea. AB - BACKGROUND: This study estimates the duration of sleep and its relationships with clinical correlates in a community sample of elderly individuals in Korea. METHODS: A total of 1924 individuals aged 65 and over were interviewed in Korea. Sleep durations were classified into five categories: 5.00 h or less, 6.00 h per day, 7.00 h per day, 8.00 h per day, and 9.00 h or more per day. Sleep disturbance was classified into four sleep complaints: difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening, and non-restorative sleep. The Mini-Mental Status Examination, the Geriatric Depression Scale, and questionnaires about the presence of cardiovascular disease were employed. RESULTS: The most frequent self-reported sleep duration was 7.00 h. The mean sleep duration was 6.46 h. Female subjects, subjects between the ages of 75 and 79, and subjects with current depression were associated with sleeping for 6.00 h or less or 9.00 h or more. Subjects who lived alone and those with cardiovascular disease were associated with sleeping for 5.00 h or less. Subjects aged 80 and over, formally educated subjects, current smokers, and subjects with cognitive dysfunction were associated with sleeping for 9.00 h or more. Sleep disturbances according to sleep duration has a U-shaped distribution. We found that all sleep disturbances were significantly related to sleep durations of 6.00 h or less compared to sleep durations of 7.00 h. We also found that non-restorative sleep was significantly related to sleep durations of 8.00 h or more compared to sleep durations of 7.00 h. CONCLUSION: A relatively high prevalence of short or long sleep duration was identified. Various sociodemographic variables influenced sleep duration. Depression, cognitive dysfunction, and cardiovascular disease were associated with short or long sleep duration. Careful attention should be paid to the health of elderly individuals who are short or long sleepers. PMID- 25515972 TI - Changes in modified Glasgow prognostic score after neoadjuvant chemotherapy is a prognostic factor in clinical stage II/III esophageal cancer. AB - The inflammation-based modified Glasgow prognostic score (mGPS) has been shown to be a prognostic factor for esophageal cancer, but its changes in relation to neoadjuvant chemotherapy (NAC) have never been discussed. The purpose of this study was to evaluate the potential prognostic role of mGPS with regard to NAC. mGPS was evaluated on the basis of admission blood samples taken before chemotherapy and before surgery. Patients with elevated C-reactive protein (CRP) serum levels (>10 mg/L) and hypoalbuminemia (<35 g/L) were allocated a score of 2, patients with elevated CRP serum levels without hypoalbuminemia were allocated a score of 1, and patients with normal CRP serum levels with or without hypoalbuminemia were allocated a score of 0. A total of 100 patients with clinical stage II/III squamous cell esophageal cancer, who underwent NAC and esophagectomy between January 2007 and August 2012, were investigated. From the multivariate analysis, the grade of response to chemotherapy and post-NAC mGPS level was found to be independent prognostic factors. The overall survival rate was significantly higher in the conserved mGPS group than in the worse mGPS group (P = 0.030). Changes in mGPS during chemotherapy affected the prognosis of patients, and post-NAC mGPS is an independent prognostic factor in patients with clinical stage II/III thoracic esophageal squamous cell cancer. PMID- 25515973 TI - Searching for Medical Substances Safe for Mother and Child, Facilitating the Delivery of Pain Management and Decreasing Exhaustion--Evaluation of Obstetric Gel by Pregnant Women. AB - The aim of the present study was to determine whether applying obstetric gel, a noninvasive method of pain management that is safe both for the mother and the child, during labor influences delivery satisfaction by facilitating pain management and decreasing exhaustion. Forty-seven primiparous women were included in the study: 23 on whom during the delivery gel was used and 24 whose delivery proceeded without the use of a gel (control group). The following research tools were used for the evaluation of satisfaction with the course of the delivery: Visual Analogue Scale (VAS), self-authorship survey, and the State-Trait Anxiety Inventory. There were no significant differences in intensification of pain in the first and second periods of delivery, exhaustion after delivery and intensification of pain in the second period of delivery, and increased anxiety between the study group and the control group. Our results suggest that application of obstetric gel during the first and second period of delivery does not significantly influence women's satisfaction with the course of delivery. PMID- 25515974 TI - Minor physical anomalies and craniofacial measures in patients with treatment resistant schizophrenia. AB - BACKGROUND: Schizophrenia patients have higher rates of minor physical anomalies (MPAs) than controls, particularly in the craniofacial region; this difference lends support to the neurodevelopmental model of schizophrenia. Whether MPAs are associated with treatment response in schizophrenia remains unknown. The aim of this case-control study was to investigate whether more MPAs and specific quantitative craniofacial features in patients with schizophrenia are associated with operationally defined treatment resistance. METHOD: A comprehensive scale, consisting of both qualitatively measured MPAs and quantitative measurements of the head and face, was applied in 108 patients with treatment-resistant schizophrenia (TRS) and in 104 non-TRS patients. Treatment resistance was determined according to the criteria proposed by Conley & Kelly (2001; Biological Psychiatry 50, 898-911). RESULTS: Our results revealed that patients with TRS had higher MPA scores in the mouth region than non-TRS patients, and the two groups also differed in four quantitative measurements (facial width, lower facial height, facial height, and length of the philtrum), after controlling for multiple comparisons using the false discovery rate. Among these dysmorphological measurements, three MPA item types (mouth MPA score, facial width, and lower facial height) and earlier disease onset were further demonstrated to have good discriminant validity in distinguishing TRS from non-TRS patients in a multivariable logistic regression analysis, with an area under the curve of 0.84 and a generalized R 2 of 0.32. CONCLUSIONS: These findings suggest that certain MPAs and craniofacial features may serve as useful markers for identifying TRS at early stages of the illness. PMID- 25515975 TI - Anatomy of nasolacrimal canal in congenital nasolacrimal duct obstruction - 18 cases retrospective study. PMID- 25515976 TI - Efficacy of metal and plastic stents for transmural drainage of pancreatic fluid collections: a systematic review. AB - BACKGROUND AND AIM: Metal stents are being used more frequently for transmural endoscopic drainage of pancreatic fluid collections (PFC) despite lack of data. The present systematic review was conducted to compare the rates of treatment success, adverse events and recurrence between patients undergoing metal versus plastic stent placement for endoscopic transmural drainage of PFC. METHODS: MEDLINE and EMBASE were searched to identify all published manuscripts that evaluated metal stents for endoscopic transmural drainage of PFC. All published studies from the same period involving plastic stent placement for PFC drainage that included >50 patients were also identified. Main outcome measures were to compare the rates of treatment success, adverse events and recurrence between the metal and plastic stent cohorts. RESULTS: Seventeen studies (881 patients) met inclusion criteria. There was no difference in overall treatment success between patients treated with plastic and metal stents (81% [95% CI, 77-84%] vs 82% [95% CI, 74-88%]) for both pseudocysts (85% [95% CI, 81-89%] vs 83% [95% CI, 74-89%]) and walled-off necrosis (70% [95% CI, 62-76%] vs 78% [95% CI, 50-93%]). Also, there was no difference in the rates of adverse events (16% [95% CI, 14-39%] vs 23% [95% CI, 16-33%]) or recurrence (10% [95% CI, 8-13%] vs 9% [95% CI, 4-19%]) between plastic and metal stents. CONCLUSIONS: Current evidence does not support routine placement of metal stents for transmural drainage of PFC. Randomized trials are needed to justify the use of metal stents for PFC drainage. PMID- 25515978 TI - Totally laparoscopic ALPPS in the treatment of cirrhotic hepatocellular carcinoma. AB - BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a breakthrough in the field of hepatobiliary surgery [1], resulting in the growth of remnant liver volume by 74-87.2% in 9-13 days [2, 3]. However, patients required to undergo two open operations in a short period of time [2-5]. To our knowledge, this video is the first description of the technical aspects of totally laparoscopic ALPPS for the treatment of cirrhotic hepatocellular carcinoma (HCC). METHODS: A patient with 6-cm cirrhotic HCC in the right liver was referred for surgical treatment. Preoperative examination confirmed that the remnant liver volume to standard liver volume ratio was 27%. Therefore, a totally laparoscopic ALPPS was planned. In the first stage of the operation, the right portal vein was ligated after laparoscopic cholecystectomy. A tape was passed along the retrohepatic avascular space and the liver was suspended during parenchymal transection, resulting in the successful completion of liver partition using the anterior approach, which conformed to the "No Touch" principle. Thirteen days after the first stage, the ratio had reached 40.6%. The second stage involved the transections of the right hepatic pedicle and the right hepatic vein. RESULTS: The operative times were 255 min for the first stage and 210 min for the second stage. Pathology confirmed the diagnosis of HCC. A complication, pleural effusion, occurred after the second stage. Following pleural puncture drainage, the patient was discharged 9 days postoperatively. Follow-up 4 months after surgery was uneventful. Comparing with our open ALPPS results in two patients, the laparoscopic approach reduced the rate of postoperative complications and peritoneal adhesions, which often complicate the second stage of the operation, thus contributing to more rapid recovery. CONCLUSION: Totally laparoscopic ALPPS is feasible, with satisfactory short-term efficacy, conforming to the "No Touch" principle. ALPPS may be safe for the treatment of HCC in cirrhotic patients, but the interval between the two stages may be extended. PMID- 25515977 TI - The loose evolutionary relationships between transcription factors and other gene products across prokaryotes. AB - BACKGROUND: Tests for the evolutionary conservation of associations between genes coding for transcription factors (TFs) and other genes have been limited to a few model organisms due to the lack of experimental information of functional associations in other organisms. We aimed at surmounting this limitation by using the most co-occurring gene pairs as proxies for the most conserved functional interactions available for each gene in a genome. We then used genes predicted to code for TFs to compare their most conserved interactions against the most conserved interactions for the rest of the genes within each prokaryotic genome available. RESULTS: We plotted profiles of phylogenetic profiles, p-cubic, to compare the maximally scoring interactions of TFs against those of other genes. In most prokaryotes, genes coding for TFs showed lower co-occurrences when compared to other genes. We also show that genes coding for TFs tend to have lower Codon Adaptation Indexes compared to other genes. CONCLUSIONS: The co occurrence tests suggest that transcriptional regulation evolves quickly in most, if not all, prokaryotes. The Codon Adaptation Index analyses suggest quick gene exchange and rewiring of transcriptional regulation across prokaryotes. PMID- 25515979 TI - Ergon-trial: ergonomic evaluation of single-port access versus three-port access video-assisted thoracic surgery. AB - BACKGROUND: Single-port access video-assisted thoracic surgery (VATS), a technique progressively developed from the standard three-port approach in minimally invasive surgery, offers ergonomic advantages but also new challenges for the surgeon. We compared the ergonomics of three-port versus single-port VATS. METHODS: Posture analysis of surgeons was evaluated during 100 consecutive VATS wedge resections (50 triportal vs. 50 uniportal). Technically demanding procedures (major lung resection) were excluded. Operating table height, monitor height, distance and inclination were adjusted according to operator preference. Body posture was assessed by measuring head-trunk axial rotation and head flexion. Perceived physical strain was self-evaluated on the Borg Category Ratio (CR-10) scale. Mental workload was assessed with the National Aeronautics Space Administration-Task Load indeX (NASA-TLX), a multidimensional tool that rates workloads on six scales (mental, physical and temporal demand; effort; performance; frustration). RESULTS: All procedures were completed without complications. Head-trunk axial rotation was significantly reduced and neck flexion significantly improved in uniportal VATS. Viewing direction significantly declined (p = 0.01), body posture as measured on the Borg CR-10 scale was perceived as more stressful and the NASA-TLX score for overall workload was higher (p = 0.04) during triportal VATS. The NASA-TLX score for frustration was higher with uniportal VATS (p = 0.02), but the score for physical demand was higher in triportal VATS (p = 0.006). CONCLUSIONS: The surgeon can maintain a more neutral body posture during uniportal VATS by standing straight and facing the monitor with only minimal neck extension/rotation; however, frustration is greater than with triportal VATS. PMID- 25515980 TI - A pilot study assessing tolerance safety and feasibility of diagnostic transnasal esophagogastroduodenoscopy using an improved larger caliber endoscope and an adapted topical anesthesia. AB - BACKGROUND: Transnasal esophagogastroduodenoscopy (TN-EGDS) is well tolerated by patients and the examination is perceived comfortable without the need of a sedative drug. Conversely, mainly in Western literature, some authors report limitations in illumination, image quality, and working channel as affecting TN EGDS diffusion. To overcome these disadvantages, a new transnasal endoscope (TNE) was tested but, due to its larger diameter, we have no evidence of its clinical safety and tolerability. A new adapted nasal anesthesia could be useful to improve TNE tolerance. In an independent, not sponsored, pilot prospective study we enrolled, in a busy clinical hospital setting, 30 adult patients receiving nasal atomized Lidocaine and Xylometazoline (XAL) to undergo a diagnostic TN-EGDS with TNE to evaluate its tolerance, safety, and feasibility. METHODS: Three physicians enrolled inpatients and outpatients with indication to diagnostic EGDS during a 6-month period. Main outcome measures were cardio-pulmonary monitoring data and patients' answers to an adapted questionnaire investigating pain, anxiety level, willingness to repeat the examination, operators' scores about endoscopy quality, examination conduction and anesthesia-related complications. RESULTS: The examination was completed by the transnasal route in 100 % of the enrolled patients, endoscopy satisfaction and feasibility were scored to nearly the highest levels by the three different physicians. A total of 29/30 patients (96.6 %) declared the willingness to repeat the same examination if needed. The mean patients' score for overall pain was 3.7 +/- 1 SD (range 1-10 by Visual Analog Scale). Mean endoscopy duration was 11.1 +/- 2.6 min (range 5.0-19.0). In a total of 17/30 TN-EGDS that lasted more than 11 min, higher heart frequency variations and worse tolerance scores were found (p < 0.05). CONCLUSION: Our pilot study demonstrates that TN-EGDS with TNE and NA is safe, well tolerated, and feasible. The best clinical tolerance is reached when TN-EGDS lasts <11 min. PMID- 25515981 TI - Peritonitis related to percutaneous endoscopic gastrostomy using the direct method for cancer patients. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) using the direct method is generally indicated for cancer patients. However, there are little available data about peritonitis related to this method. The aim of this retrospective analysis was to assess peritonitis related to PEG using the direct method in patients with cancer. METHODS: We assessed the prevalence of peritonitis and the relationship between peritonitis and patients' backgrounds, as well as the clinical course after peritonitis. RESULTS: Between December 2008 and December 2011, peritonitis was found in 9 (2.1 %) of 421 patients. Of the 9 patients with peritonitis, 4 had received PEG prior to chemoradiotherapy. Emergency surgical drainage was required in 1 patient, and the remaining 8 recovered with conservative treatment. Peritonitis occurred within 8 days of PEG for 8 of the 9 patients and occurred within 2 days of suture removal for 4 of the 9 patients. CONCLUSION: Peritonitis related to PEG using the direct method was less frequent for cancer patients. Peritonitis tended to occur within a few days after removal of securing suture and in patients with palliative stage. PMID- 25515982 TI - Complications of endoscopic dilation for esophageal stenosis after endoscopic submucosal dissection of superficial esophageal cancer. AB - BACKGROUND: Endoscopic dilation (ED) is used for the treatment of benign strictures caused by reflux esophagitis or anastomotic stenosis after esophagectomy. Esophageal stenosis is a major complication after endoscopic submucosal dissection (ESD) of large superficial esophageal cancer, but little is known regarding the incidence of complications of ED for stenosis caused by esophageal ESD. METHODS: This was a retrospective study conducted at a single institution. From September 2002 to December 2012, a total of 1,337 ED procedures were performed for stenosis after esophageal ESD in 121 patients. The incidence of complications of ED and related clinical characteristics were analyzed. RESULTS: The incidence of bleeding was 0.8 % (1/121) per patient and 0.07 % (1/1,337) per procedure. The incidence of perforation was 4.1 % (5/121) per patient and 0.37 % (5/1,337) per procedure. Perforation occurred at a median of third time of ED procedures (range 2-9 procedures) and at a median of 18 days (range 8-29 days) after ESD. There were no significant characteristics correlated to perforation, such as location, circumferential extent, or diameter of mucosal defect after ESD. The total number of ED procedures was significantly larger among perforation cases (37, range 6-57) compared with those without perforation (7, range 1-70) (p = 0.01), and the treatment duration tended to be longer (190 vs. 69 days, respectively). CONCLUSIONS: The incidence of bleeding caused by ED for esophageal stenosis after ESD was very low. Relevant risk of perforation should be considered for patients requiring multiple ED procedures. PMID- 25515983 TI - Role of intraoperative fluids on hospital length of stay in laparoscopic bariatric surgery: a retrospective study in 224 consecutive patients. AB - BACKGROUND: Studies are unclear regarding optimal intraoperative fluid management during laparoscopic bariatric surgery. The purpose of this 1-year study was to investigate the role of intraoperative fluid administration on hospital length of stay (hLOS) and postoperative complications in laparoscopic bariatric surgery. METHODS: Patient data analyzed included previously reported demographics, comorbidities, and intraoperative fluid administration on the duration of hLOS and incidence of postoperative complications. RESULTS: Logistic regression analysis of demographic and comorbidity variables revealed that BMI (P = 0.0099) and history of anemia (P = 0.0084) were significantly associated with hLOS (C index statistic, 0.7). Lower rates of intraoperative fluid administration were significantly associated with longer hLOS (P = 0.0005). Recursive partitioning observed that patients who received <1,750 ml of intraoperative fluids resulted in longer hLOS when compared to patients who received >= 1,750 ml (LogWorth = 0.5). When intraoperative fluid administration rates were defined by current hydration guidelines for major abdominal surgery, restricted rates (<5 ml/kg/h) were associated with the highest incidence of extended hLOS (>1 postoperative day) at 54.1 % when compared to 22.9 % with standard rates (5-7 ml/kg/h) and were lowest at 14.5 % in patients receiving liberal rates (>7 ml/kg/h) (P < 0.0001). Finally, lower rates of intraoperative fluid administration were significantly associated with delayed wound healing (P = 0.03). CONCLUSIONS: The amount of intravenous fluids administered during laparoscopic bariatric surgery plays a significant role on hLOS and on the incidence of delayed wound healing. PMID- 25515984 TI - A feasibility study of chemically assisted endoscopic submucosal mechanical dissection using mesna for superficial esophageal squamous cell carcinomas. AB - BACKGROUND: Injection of mesna into submucosal layers was recently reported to chemically soften connective tissue and facilitate the gastric endoscopic submucosal dissection (ESD) procedure. This study aimed to evaluate the safety and feasibility of similarly using mesna for esophageal ESD (mesna ESD). METHODS: We performed mesna ESD in 20 consecutive patients with superficial esophageal squamous cell carcinomas (SESCCs). To do this, a submucosal fluid cushion was initially formed using sodium hyaluronate, and the esophageal lesion was circumferentially isolated with a short blade needle-knife. Mesna solution was then injected into the submucosal layer, which was dissected mechanically by cleavage using the tip of a cap-fitted endoscope. The number of electrosurgical incisions was recorded by computer software in real time. The data from 20 conventional ESD procedures without mesna (consecutive 10 SESCCs pre and post the 20 consecutive mesna ESD) were used for comparison to evaluate the mesna ESD. RESULTS: The mesna ESDs achieved en bloc and R0 resection success rates of 100 and 95 %, respectively. There was no perforation or uncontrollable hemorrhage during and after mesna ESD, and the median procedural time of submucosal dissection was significantly less with mesna ESD than with conventional ESD (median; 8 vs. 15 min, P < 0.05). There were also significantly fewer electrosurgical incisions made during the mesna ESD than with conventional ESDs (median; 65 vs. 183 times, P < 0.01). CONCLUSIONS: Mesna ESD for SESCCs is a safe procedure with the potential to facilitate esophageal ESD. PMID- 25515985 TI - Face, content, and construct validity of the EndoViS training system for objective assessment of psychomotor skills of laparoscopic surgeons. AB - BACKGROUND: The aim of this study is to present face, content, and constructs validity of the endoscopic orthogonal video system (EndoViS) training system and determines its efficiency as a training and objective assessment tool of the surgeons' psychomotor skills. METHODS: Thirty-five surgeons and medical students participated in this study: 11 medical students, 19 residents, and 5 experts. All participants performed four basic skill tasks using conventional laparoscopic instruments and EndoViS training system. Subsequently, participants filled out a questionnaire regarding the design, realism, overall functionality, and its capabilities to train hand-eye coordination and depth perception, rated on a 5 point Likert scale. Motion data of the instruments were obtained by means of two webcams built into a laparoscopic physical trainer. To identify the surgical instruments in the images, colored markers were placed in each instrument. Thirteen motion-related metrics were used to assess laparoscopic performance of the participants. Statistical analysis of performance was made between novice, intermediate, and expert groups. Internal consistency of all metrics was analyzed with Cronbach's alpha test. RESULTS: Overall scores about features of the EndoViS system were positives. Participants agreed with the usefulness of tasks and the training capacities of EndoViS system (score >4). Results presented significant differences in the execution of three skill tasks performed by participants. Seven metrics showed construct validity for assessment of performance with high consistency levels. CONCLUSIONS: EndoViS training system has been successfully validated. Results showed that EndoViS was able to differentiate between participants of varying laparoscopic experience. This simulator is a useful and effective tool to objectively assess laparoscopic psychomotor skills of the surgeons. PMID- 25515988 TI - Assembling insight. PMID- 25515986 TI - Concomitant cholecystectomy should be routinely performed with laparoscopic Roux en-Y gastric bypass. AB - INTRODUCTION: As the popularity of a laparoscopic Roux-en-Y Gastric Bypass (RYGB) surpassed that of an open approach, practice of concomitant cholecystectomy declined. Low rates of gallbladder disease following RYGB and high complication rates of concomitant cholecystectomy have been published, but these population based studies have lacked long-term outcomes and survival data. STUDY DESIGN: The California Office of Statewide Health Planning and Development longitudinal database was queried for patients who underwent RYGB with or without cholecystectomy between 1995 and 2009. Additionally, patients who underwent cholecystectomy after RYGB were compared to all cholecystectomy patients. Primary outcome was survival; secondary long-term outcomes included cholangitis, common duct stones, dumping syndrome, metabolic derangements, ventral hernia, any hernia, marginal ulcers, and reoperation. Cox proportional hazard analysis was performed to determine adjusted survival and outcomes. RESULTS: Of 134,584 RYGB patients, 21,022 underwent concomitant cholecystectomy. Concomitant cholecystectomy improved both survival (HR[95 % CI] 0.51[.48-.54]) and long-term outcomes (HR 0.84[.77-.91]). Incidence of gallbladder disease following RYGB was 6.8 and 15.2 % at 1 and 5 years. In subsequent analysis of 829,333 cholecystectomy patients, 7,099 underwent prior RYGB with higher risk of conversion to open (HR 1.58[1.41-1.78]), post-operative complication (HR 1.47[1.36-1.6]) and death (HR 1.32[1.17-1.5]). CONCLUSIONS: Concomitant cholecystectomy is safe for RYGB patients. Given high rates of gallbladder disease and increased risk when cholecystectomy is performed following RYGB, cholecystectomy should be considered at the time of RYGB. PMID- 25515987 TI - Endoscopic management of pancreatic fistula after enucleation of pancreatic tumors. AB - INTRODUCTION: Pancreatic fistula (PF) are frequent after pancreatic surgical resection, and particularly after enucleation. Endoscopic treatment might be proposed for postoperative PF, but has never been evaluated after pancreatic enucleation. PATIENTS AND METHODS: From January 2000 to June 2012, 161 patients underwent pancreatic enucleation in our center. In case of PF in the postoperative period, conservative management (somatostatin analogs combined with enteral or parenteral nutrition and drainage) was proposed. If PF persisted after 20 days (output >50 cc/d), endoscopic treatment (pancreatic sphincterotomy and stent placement if evidence of main duct leakage) was proposed. Primary outcome was the delay of PF closure after endoscopic treatment. RESULTS: Ninety-one patients (56 %) developed postoperative PF. PF closed within 3 weeks with conservative management in 78 (86 %) patients. Endoscopic treatment was required in 7 (8 %) patients. Daily PF output was 240 (50-300) mL. Pancreatic sphincterotomy was performed in all patients. A pancreatic stent was inserted in 4 of 5 patients with main pancreatic duct leakage. One patient presented a stent migration requiring a second procedure. No complication of endoscopic treatment was reported. The closure of PF was obtained in all cases, after 13 (3-24) days. Pancreatic stents were removed after 2, 5, 5, and 8 months, respectively. Median postoperative follow-up was 46 (21-70) months. At study endpoint, two patients had small asymptomatic pancreatic collections, four had mild dilatation of main pancreatic duct upstream pancreatic duct leakage, and none developed exocrine pancreatic insufficiency, diabetes, or recurrence of pancreatic tumor. CONCLUSIONS: PF occurs in half patients after enucleation. Endoscopic treatment combining pancreatic sphincterotomy and stenting is safe and effective if conservative treatment fails, avoiding a complementary pancreatic resection. PMID- 25515990 TI - Order through entropy. PMID- 25515989 TI - Programmable self-assembly. PMID- 25515996 TI - Crystal-crystal transitions: Mediated by a liquid. PMID- 25515997 TI - Material witness: The final cut. PMID- 25515998 TI - Colloidal phase transitions: A switch for phase shifting. PMID- 25515999 TI - Icosahedral quasicrystals: Assembled with one component. PMID- 25516000 TI - Colloidal self-assembly: Reversible actuation. PMID- 25516001 TI - Nanoparticle self-assembly: Enantioselective photoactivation. PMID- 25516003 TI - CORR Insights (r): A dedicated research program increases the quantity and quality of orthopaedic resident publications. PMID- 25516002 TI - There Are No Differences in Short- to Mid-term Survivorship Among Total Hip bearing Surface Options: A Network Meta-analysis. AB - BACKGROUND: Total hip arthroplasty (THA) is increasingly being performed in patients with long life expectancies and active lifestyles. Newer implant bearing surfaces, with superior wear characteristics, often are used in this cohort with the goal of improving longevity of the prosthesis, but comparisons across the numerous available bearing surfaces are limited, so the surgeon and patient may have difficulty deciding which implants to use. QUESTIONS/PURPOSES: The purpose of this study was to answer the following question: Is there a short- to mid-term survivorship difference between common THA bearings used in patients younger than age 65 years? METHODS: We conducted a systematic review to identify randomized clinical trials (RCTs) published after 2000 that reported survivorship of ceramic on-ceramic (CoC), ceramic-on-highly crosslinked polyethylene (CoPxl), or metal-on highly crosslinked polyethylene (MoPxl) bearings. To qualify for our review, RCTs had to have a minimum 2-year followup and study patients were required to have an average age younger than 65 years. Direct-comparison meta-analysis and network meta-analysis were performed to combine direct and indirect evidence. RESULTS: Direct-comparison meta-analysis found no differences among the bearing surfaces in terms of the risk of revision; this approach demonstrated a risk ratio for revision of 0.65 (95% confidence interval [CI], 0.19-2.23; p = 0.50) between CoC and CoPxl and a risk ratio for revision of 0.40 (95% CI, 0.06-2.63; p = 0.34) between CoC and MoPxl. Network meta-analysis (with post hoc modification) likewise found no differences in survivorship across the three implant types, demonstrating the following probabilities of most effective implant with 95% credible intervals (CrI): CoC = 64.6% (0%-100%); CoPxl = 24.9% (0%-100%); and MoPxl = 9.9% (0%-100%). The CrIs ranged from 0% to 100% for all three bearing surfaces. Direct-comparison meta-analysis allowed for pooling of five RCTs, including 779 THAs, whereas network meta-analysis (before post hoc analysis) enabled pooling of 18 RCTs, including 2599 THAs. CONCLUSIONS: Current published evidence does not support survivorship differences among commonly used bearing surfaces in patients younger than age 65 years undergoing THA at short- to mid term followup. Long-term RCT data will be needed to determine if a survivorship benefit is realized in younger, more active patients over time. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 25516004 TI - Case-control study evaluating the sow's risk factors associated with stillbirth piglets in Midwestern in Brazil. AB - Reproductive failure in swine herds is often difficult to diagnose and is important to swine production. The present study aims to identify the potential risk factors (infectious/noninfectious) for stillborn piglets in two commercial swine farms situated in midwestern region of Brazil. The potential risk factors were included in a multivariable logistic model, and the dependent variable was defined as the presence of at least one stillborn piglet in a given litter (yes or no). In the best fit model, two variables from the multivariable analysis, total litter size (p = 0.01), and average birth weight (p = 0.03) were significantly associated with the presence of stillborn piglets at the farms examined in this study. Porcine circovirus type 2 (PCV2) was detected in 29.1 % of the litters. Neither parvovirus (PPV) nor leptospirosis infections were identified in this study, suggesting that they have a minor impact on reproductive disease. PMID- 25516007 TI - Local Control Mechanisms of Implicit and Explicit Conflicts. AB - Congruency sequence effects are observed when the congruency effects following incongruent trials are smaller than those following congruent trials. It is typically assumed that such flexible adjustments are evidence of cognitively controlled dynamic modulations. The present study investigated whether cognitive control acts locally or globally when implicit and explicit conflicts exist simultaneously within a system. The implicit SNARC task and explicit Simon task were combined in a single task. The results showed that congruency effects of one type (e.g., SNARC effect) were only smaller following an incongruent trial of the same type (e.g., SNARC effect), but not when following an incongruent trial of the other type (e.g., Simon effect). These results indicate the operation of local control mechanisms triggered by implicit and explicit conflicts. PMID- 25516006 TI - One-year safety of ibuprofen/famotidine fixed combination versus ibuprofen alone: pooled analyses of two 24-week randomized, double-blind trials and a follow-on extension. AB - OBJECTIVE: To evaluate the safety of the fixed combination of ibuprofen and famotidine compared with ibuprofen alone from two 24-week, multicenter, double blind trials designed to evaluate the comparative incidence of endoscopically documented upper gastrointestinal ulcers and a 28-week double-blind extension study. RESEARCH DESIGN AND METHODS: Safety was analyzed by pooling data from the two double-blind trials and the follow-on study. Safety was assessed by monitoring the incidence, causality, and severity of adverse events (AEs). RESULTS: In the pivotal efficacy and safety trials, discontinuation rates due to any cause and dyspepsia were significantly lower for the ibuprofen/famotidine combination versus ibuprofen alone. Other than dyspepsia, gastrointestinal and cardiovascular AEs of special interest were similar. Events judged to be treatment related were significantly lower with the ibuprofen/famotidine combination (20.6% vs. 25%). In the safety extension population, there were no differences in the discontinuation rates and the reporting of AEs or serious AEs (SAEs) between the two groups. Gastrointestinal-related events were similar between the groups. Incidence of cardiovascular-related AEs of special interest were 11% (ibuprofen/famotidine) and 2% (ibuprofen) (p=0.06), possibly due to a higher number of rheumatoid arthritis patients in the combination group. Of these, 80% were reports of hypertension (8% ibuprofen/famotidine vs. 2% ibuprofen). Three cases of hypertension in the ibuprofen/famotidine group were considered treatment related. The probability of a cardiovascular event decreased during days 112-167 of treatment and remained low with continued treatment. CONCLUSIONS: One-year safety data from two pivotal trials and a long-term extension study indicate that the ibuprofen/famotidine combination demonstrates a favorable gastrointestinal safety profile and more patients continued on therapy compared to ibuprofen alone. No new safety signals have been identified. These data offer additional evidence supporting a new therapeutic option to improve gastrointestinal safety and adherence for patients who require long-term ibuprofen. PMID- 25516005 TI - Green tea polyphenol treatment is chondroprotective, anti-inflammatory and palliative in a mouse post-traumatic osteoarthritis model. AB - INTRODUCTION: Epigallocatechin 3-gallate (EGCG), a polyphenol present in green tea, was shown to exert chondroprotective effects in vitro. In this study, we used a post-traumatic osteoarthritis (OA) mouse model to test whether EGCG could slow the progression of OA and relieve OA-associated pain. METHODS: C57BL/6 mice were subjected to surgical destabilization of the medial meniscus (DMM) or sham surgery. EGCG (25 mg/kg) or vehicle control was administered daily for four or eight weeks by intraperitoneal injection starting on the day of surgery. OA severity was evaluated by Safranin O staining and Osteoarthritis Research Society International (OARSI) score, and by immunohistochemical analysis to detect cleaved aggrecan and type II collagen, and expression of proteolytic enzymes matrix metalloproteinase (MMP)-13 and A Disintegrin And Metalloproteinase with Thrombospondin Motifs (ADAMTS5). Real-time polymerase chain reaction (PCR) was performed to characterize the expression of genes critical for articular cartilage homeostasis. During the course of the experiments, tactile sensitivity testing (von Frey test) and open field assays were used to evaluate pain behaviors associated with OA, and expression of pain expression markers and inflammatory cytokines in the dorsal root ganglion (DRG) were determined by real time PCR. RESULTS: Four and eight weeks after DMM surgery, the cartilage in EGCG treated mice exhibited less Safranin O loss and cartilage erosion, and lower OARSI scores compared to vehicle-treated controls, which was associated with reduced staining for aggrecan and type II collagen cleavage epitopes, and reduced staining for MMP-13 and ADAMTS5 in the articular cartilage. Articular cartilage in the EGCG-treated mice also exhibited reduced levels of MMP-1, -3, -8, -13, ADAMTS5, interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha mRNA and elevated gene expression of the MMP regulator Cbp/p300 Interacting Transactivator 2 (CITED2). Compared to vehicle controls, mice treated with EGCG exhibited reduced OA-associated pain, as indicated by higher locomotor behavior (i.e. distance traveled). Moreover, expression of chemokine receptor (CCR2), and pro inflammatory cytokines IL-1beta and TNF-alpha in the DRG were significantly reduced to levels similar to sham-operated animals. CONCLUSIONS: This study provides the first evidence in an OA animal model that EGCG significantly slows OA disease progression and exerts a palliative effect. PMID- 25516008 TI - Instruction-Based Approach-Avoidance Effects: Changing Stimulus Evaluation via the Mere Instruction to Approach or Avoid Stimuli. AB - Prior research suggests that repeatedly approaching or avoiding a certain stimulus changes the liking of this stimulus. We investigated whether these effects of approach and avoidance training occur also when participants do not perform these actions but are merely instructed about the stimulus-action contingencies. Stimulus evaluations were registered using both implicit (Implicit Association Test and evaluative priming) and explicit measures (valence ratings). Instruction-based approach-avoidance effects were observed for relatively neutral fictitious social groups (i.e., Niffites and Luupites), but not for clearly valenced well-known social groups (i.e., Blacks and Whites). We conclude that instructions to approach or avoid stimuli can provide sufficient bases for establishing both implicit and explicit evaluations of novel stimuli and discuss several possible reasons for why similar instruction-based approach-avoidance effects were not found for valenced well-known stimuli. PMID- 25516009 TI - Controllability of time-delayed Boolean multiplex control networks under asynchronous stochastic update. AB - In this article, the controllability of asynchronous Boolean multiplex control networks (ABMCNs) with time delay is studied. Firstly, dynamical model of Boolean multiplex control networks is constructed, which is assumed to be under Harvey' asynchronous update and time delay is introduced both in states and controls. By using of semi-tensor product (STP) approach, the logical dynamics is converted into an equivalent algebraic form by obtaining the control-depending network transition matrices of delayed system. Secondly, a necessary and sufficient condition is proved that only control-depending fixed points of the studied dynamics can be controlled with probability one. Thirdly, respectively for two types of controls, the controllability of dynamical control system is investigated. When initial states and time delay are given, formulae are obtained to show a) the reachable set at time s under specified controls; b) the reachable set at time s under arbitrary controls; c) the reachable probabilities to different destination states. Furthermore, an approach is discussed to find a precise control sequence which can steer dynamical system into a specified target with the maximum reachable probability. Examples are shown to illustrate the feasibility of the proposed scheme. PMID- 25516010 TI - Genetic diversity of donkey populations from the putative centers of domestication. AB - Donkey domestication drastically changed ancient transport systems in Africa and Asia, enabling overland circulation of people and goods and influencing the organization of early cities and pastoral societies. Genetic studies based on mtDNA have pointed to the African wild ass as the most probable ancestor of the domestic donkey, but questions regarding its center of origin remain unanswered. Endeavoring to pinpoint the geographical origin of domestic donkey, we assessed levels and patterns of genetic diversity at 15 microsatellite loci from eight populations, representing its three hypothesized centers of origin: northeast Africa, the Near East and the Arabian Peninsula. Additionally, we compared the donkey genotypes with those from their wild relative, the African wild ass (Equus africanus somaliensis) to visualize patterns of differentiation among wild and domestic individuals. Obtained results revealed limited variation in levels of unbiased expected heterozygosity across populations in studied geographic regions (ranging from 0.637 in northeast Africa to 0.679 in the Near East). Both allelic richness (Ar) and private allelic richness presented considerably higher values in northeast Africa and in the Arabian Peninsula. By looking at variation at the country level, for each region, we were able to identify Sudan and Yemen as the countries possessing higher allelic richness and, cumulatively, Yemen also presented higher values for private allelic richness. Our results support previously proposed northeast Africa as a putative center of origin, but the high levels of unique diversity in Yemen opens the possibility of considering this region as yet another center of origin for this species. PMID- 25516011 TI - Exploring the aqueous vertical ionization of organic molecules by molecular simulation and liquid microjet photoelectron spectroscopy. AB - To study the influence of aqueous solvent on the electronic energy levels of dissolved organic molecules, we conducted liquid microjet photoelectron spectroscopy (PES) measurements of the aqueous vertical ionization energies (VIEaq) of aniline (7.49 eV), veratrole alcohol (7.68 eV), and imidazole (8.51 eV). We also reanalyzed previously reported experimental PES data for phenol, phenolate, thymidine, and protonated imidazolium cation. We then simulated PE spectra by means of QM/MM molecular dynamics and EOM-IP-CCSD calculations with effective fragment potentials, used to describe the aqueous vertical ionization energies for six molecules, including aniline, phenol, veratrole alcohol, imidazole, methoxybenzene, and dimethylsulfide. Experimental and computational data enable us to decompose the VIEaq into elementary processes. For neutral compounds, the shift in VIE upon solvation, DeltaVIEaq, was found to range from ~ 0.5 to -0.91 eV. The DeltaVIEaq was further explained in terms of the influence of deforming the gas phase solute into its solution phase conformation, the influence of solute hydrogen-bond donor and acceptor interactions with proximate solvent molecules, and the polarization of about 3000 outerlying solvent molecules. Among the neutral compounds, variability in DeltaVIEaq appeared largely controlled by differences in solute-solvent hydrogen-bonding interactions. Detailed computational analysis of the flexible molecule veratrole alcohol reveals that the VIE is strongly dependent on molecular conformation in both gas and aqueous phases. Finally, aqueous reorganization energies of the oxidation half-cell ionization reaction were determined from experimental data or estimated from simulation for the six compounds aniline, phenol, phenolate, veratrole alcohol, dimethylsulfide, and methoxybenzene, revealing a surprising constancy of 2.06 to 2.35 eV. PMID- 25516012 TI - Perioperative fellowship curricula in anesthesiology: a systematic review. AB - PURPOSE: Perioperative medicine is emerging as a unique area of medical practice. Anesthesiology graduates are particularly well suited for this role given their training. The purpose of this systematic review is to summarize the various fellowships being offered in perioperative medicine and the scope of clinical perioperative practice that currently exists. The common areas of competency covered in these perioperative medicine fellowships are also identified. SOURCE: On July 28, 2014, we conducted a search of the literature from January 1, 1946, to July 28, 2014 through MEDLINE(r), EMBASETM and the World Wide Web for definitions of perioperative medicine and for curricula for fellowships in perioperative care throughout the world. PRINCIPAL FINDINGS: Currently, seven institutions offer postgraduate fellowships in perioperative medicine, including two Canadian universities (University of Manitoba and University of Toronto), two American universities (Stanford University and University of California, Irvine), two Australian institutions (University of Western Australia, and the Alfred Hospital), and one New Zealand site (North Shore Hospital). Apart from fellowships, we also identified other postgraduate training routes. Graduate master's programs in perioperative medicine were identified in the United Kingdom and in Australia. A new intensive five-day perioperative medicine course was also identified. The scope of the curricula of the fellowships, the main focus of our review, is not uniform, although common elements emerged, including a research component and exposure to pain medicine. CONCLUSIONS: There is a paucity of published literature on what perioperative care entails as well as what perioperative fellowship curricula should include. While we suggest certain areas of focus to include, the subspecialty of perioperative medicine would benefit from a cohesive and consensus-based curriculum to which academic fellowships could adhere. PMID- 25516014 TI - Editorial: (New drug (LCZ696) for the treatment of heart failure with reduced ejection fraction after 10 years. Can one study change the guidelines?). PMID- 25516013 TI - A retrospective analysis of cerebrospinal fluid drainage volume in subarachnoid hemorrhage and the need for early or late ventriculoperitoneal shunt placement. AB - BACKGROUND: External ventricular drains (EVDs) are used to manage acute hydrocephalus and facilitate brain relaxation after subarachnoid hemorrhage (SAH). We conducted a retrospective study on the relationship between CSF drainage volume and requirement and timing (early vs. late) for ventriculoperitoneal shunt (VPS) placement after EVD removal. We also sought to examine what factors were associated with volume of CSF drainage. METHODS: We performed a retrospective analysis of SAH patients who had an EVD placed between January 2008 and June 2012 at Massachusetts General Hospital. Clinical and laboratory variables were abstracted from the medical record. RESULTS: Of 97 patients, 19 failed an EVD clamp trial and had an early VPS placed and 10 had their EVD removed but subsequently required late VPS placement. Average CSF drainage volume per day was highest in patients who required early VPS (median of 201cc, interquartile range [IQR] 186-236) compared to those who did not require a VPS (median of 162cc, IQR 131-202) and those who required late VPS (median of 151cc, IQR 121-171) (P=0.002). There was a significant relationship between average CSF drainage volume per day and age (P=0.005) and sonographic vasospasm (P=0.006). After multivariate analysis, there was a significant relationship between VPS placement/timing and age (P=0.03) and average CSF output/day (P=<0.0001), and a trend towards significance with sonographic vasospasm (P=0.06). CONCLUSIONS: High CSF output is associated with early VPS placement. Prospective research on targeted CSF drainage volume is warranted. PMID- 25516015 TI - How to evaluate population management? Transforming the Care Continuum Alliance population health guide toward a broadly applicable analytical framework. AB - Many countries face the persistent twin challenge of providing high-quality care while keeping health systems affordable and accessible. As a result, the interest for more efficient strategies to stimulate population health is increasing. A possible successful strategy is population management (PM). PM strives to address health needs for the population at-risk and the chronically ill at all points along the health continuum by integrating services across health care, prevention, social care and welfare. The Care Continuum Alliance (CCA) population health guide, which recently changed their name in Population Health Alliance (PHA) provides a useful instrument for implementing and evaluating such innovative approaches. This framework is developed for PM specifically and describes the core elements of the PM-concept on the basis of six subsequent interrelated steps. The aim of this article is to transform the CCA framework into an analytical framework. Quantitative methods are refined and we operationalized a set of indicators to measure the impact of PM in terms of the Triple Aim (population health, quality of care and cost per capita). Additionally, we added a qualitative part to gain insight into the implementation process of PM. This resulted in a broadly applicable analytical framework based on a mixed-methods approach. In the coming years, the analytical framework will be applied within the Dutch Monitor Population Management to derive transferable 'lessons learned' and to methodologically underpin the concept of PM. PMID- 25516016 TI - Ibuprofen versus mecillinam for uncomplicated cystitis--a randomized controlled trial study protocol. AB - BACKGROUND: Although uncomplicated cystitis is often self-limiting, most such patients will be prescribed antibiotic treatment. We are investigating whether treatment of cystitis with an NSAID is as effective as an antibiotic in achieving symptomatic resolution. METHODS/DESIGN: This is a randomized, controlled, double blind trial following the principles of Good Clinical Practice. Women between the ages of 18 to 60 presenting with symptoms of uncomplicated cystitis are screened for eligibility. 500 women from four sites in Norway, Sweden and Denmark are allocated to treatment with 600 mg ibuprofen three times a day or 200 mg mecillinam three times a day for three days. Allocation is conducted using block randomization. The primary outcome is the number of patients who feel cured by day four as recorded in a diary. Adverse events will be handled and reported in accordance with Good Clinical Practice. DISCUSSION: If treatment of uncomplicated cystitis with ibuprofen is as effective as mecillinam for symptom relief, we can potentially reduce the use of antibiotics on a global scale. TRIAL REGISTRATION: EudraCTnr: 2012-002776-14. ClinicalTrials.gov: NCT01849926. PMID- 25516017 TI - Morphology of the Canine Omentum Part 1: Arterial Landmarks that Define the Omentum. AB - Although the omentum remains an enigmatic organ, research during the last decades has revealed its fascinating functions including fat storage, fluid drainage, immune activity, angiogenesis and adhesion. While clinicians both in human and veterinary medicine are continuously exploring new potential omental applications, detailed anatomical data on the canine omentum are currently lacking, and information is often retrieved from human medicine. In this study, the topographic anatomy of the canine greater and lesser omentum is explored in depth. Current nomenclature is challenged, and a more detailed terminology is proposed. Consistent arteries that are contained within folds of the superficial omental wall are documented, described and named, as they can provide the anatomical landmarks that are necessary for unambiguous scientific communication on the canine omentum. In an included dissection video, the conclusions and in situ findings described in this study are demonstrated. PMID- 25516018 TI - Non-targeted metabolomic profile of Fagus sylvatica L. leaves using liquid chromatography with mass spectrometry and gas chromatography with mass spectrometry. AB - INTRODUCTION: Fagus sylvatica L. is one of the most widely distributed broad leaved tree species in central and western Europe, important to the forest sector and an accurate biomarker of climate change. OBJECTIVE: To profile the beech leaf metabolome for future studies in order to investigate deeper into the characterisation of its metabolic response. METHODS: Leaf extracts were analysed using LC-MS by electrospray ionisation in negative mode from m/z 100-1700 and GC MS by electron ionisation in scan mode from m/z 35-800. RESULTS: The LC-MS profile resulted in 56 compounds, of which 43 were identified and/or structurally characterised, including hydroxycinnamic acid derivatives, flavan-3-ols and proanthocyanidins, and flavonols. From a second analysis based on GC-MS, a total of 111 compounds were identified, including carbohydrates, polyalcohols, amino acids, organic acids, fatty acids, phenolic compounds, terpenoids, sterols and other related compounds. Many of the compounds identified were primary metabolites involved in major plant metabolic pathways, however, some secondary metabolites were also detected. Some of them play roles as tolerance-response osmoregulators and osmoprotectors in abiotic stress, or as anti-oxidants that reduce the effect of reactive oxygen species and promote many protective functions in plants. CONCLUSIONS: This study provides a broad and relevant insight into the metabolic status of F. sylvatica leaves, and serves as a base for future studies on physiological and molecular mechanisms involved in biotic or abiotic stress. PMID- 25516019 TI - Cognitive behavior therapy for anxiety in people with dementia: a clinician guideline for a person-centered approach. AB - This article describes a 10-session cognitive-behavioral therapy (CBT) used in a randomized controlled trial with people with anxiety and mild-to-moderate dementia. The aim of the therapy is to reduce symptoms of anxiety by increasing a sense of safety and self-efficacy. The therapy is characterized by a person centered approach to CBT, using individual tailoring to accommodate for cognitive deficits and other challenges. Three phases of therapy are described: (a) socialization to model (including overcoming barriers to participation), goal setting, and formulation; (b) application of cognitive and behavioral change techniques to address unhelpful autonomic reactions, "strategic" reactions, "rules for living," and interpersonal aspects; and (c) consolidation and ending in the context of chronic, deteriorating illness. The approach prioritizes direct work with the person with dementia, with the involvement of a "supportive other" where available and when necessary. The protocol is designed for use by therapists with prior experience in CBT. PMID- 25516020 TI - Identification of the full-length beta-actin sequence and expression profiles in the tree shrew (Tupaia belangeri). AB - The tree shrew (Tupaia belangeri) diverges from the primate order (Primates) and is classified as a separate taxonomic group of mammals - Scandentia. It has been suggested that the tree shrew can be used as an animal model for studying human diseases; however, the genomic sequence of the tree shrew is largely unidentified. In the present study, we reported the full-length cDNA sequence of the housekeeping gene, beta-actin, in the tree shrew. The amino acid sequence of beta-actin in the tree shrew was compared to that of humans and other species; a simple phylogenetic relationship was discovered. Quantitative polymerase chain reaction (qPCR) and western blot analysis further demonstrated that the expression profiles of beta-actin, as a general conservative housekeeping gene, in the tree shrew were similar to those in humans, although the expression levels varied among different types of tissue in the tree shrew. Our data provide evidence that the tree shrew has a close phylogenetic association with humans. These findings further enhance the potential that the tree shrew, as a species, may be used as an animal model for studying human disorders. PMID- 25516021 TI - Transactivation of EGFR by prostaglandin E2 receptors: a nuclear story? AB - The pharmacological modulation of hypoxia-inducible factor-1alpha (HIF-1alpha) and HIF-1alpha-regulated vascular endothelial growth factor-A (VEGF-A) in the kidney has therapeutic interest. Although it is assumed that prostaglandin E(2) (PGE(2)) exerts its biological effects from the extracellular medium through activation of EP receptors located at the cell membrane, we have shown in human renal proximal tubular HK-2 cells (and other cell lines) that intracellular PGE(2) regulates the expression of HIF-1alpha expression and the production of VEGF-A. Here, we have found--through experiments involving EP receptors agonists, EP receptor gene silencing and inhibition of the prostaglandin uptake transporter -that these biological effects of PGE(2) are mediated by intracellular EP(2) receptors. In sharp contrast with cell membrane EP(2), whose activation results in increased production of cAMP, intracellular EP(2) signaling was independent of cAMP. Instead, it involved c-src-dependent transactivation of epidermal growth factor receptor, which led to p38/ERK1/2-dependent activation of mitogen- and stress-activated kinase-1 (MSK-1) and to MSK-1-dependent-histone H3 phosphorylation and transcriptional up-regulation of retinoic acid receptor-beta. Even more important, this signaling pathway was fully reproduced in nuclei isolated from HK-2 cell, which highlights the relevance of nuclear EP receptors in the up-regulation of HIF-1alpha. These results open the possibility that signal cascades that proceed entirely in the cell nucleus might be responsible for several PGE(2) effects that are assumed to be due to cell membrane EP receptors. PMID- 25516022 TI - Factors associated with family caregiver dissatisfaction with acute hospital care of older cognitively impaired relatives. AB - OBJECTIVES: To identify patient and caregiver characteristics associated with caregiver dissatisfaction with hospital care of cognitively impaired elderly adults. DESIGN: Secondary analysis of data from a randomized controlled trial. SETTING: An 1,800-bed general hospital in England providing the only emergency medical services in its area. PARTICIPANTS: Cognitively impaired individuals aged 65 and older randomly assigned to a specialist unit or standard geriatric or internal medical wards (N = 600) and related caregivers (N = 488). MEASUREMENTS: Patient and caregiver health status was measured at baseline, including delirium, cognitive impairment, behavioral and psychological symptoms, activities of daily living, and caregiver strain. Caregiver satisfaction with quality of care was ascertained after hospital discharge or death. RESULTS: Four hundred sixty-two caregivers completed satisfaction questionnaires. Regardless of assignment, 54% of caregivers were dissatisfied with some aspects of care, but overall 87% were satisfied with care. The main areas of dissatisfaction were communication, discharge planning, and medical management. Dissatisfaction was associated with high levels of patient behavioral and psychological symptoms on admission, caregiver strain and poor psychological well-being at admission, a diagnosis of delirium, and the relationship between the caregiver and the patient. There was less dissatisfaction from caregivers of patients managed on the specialist Medical and Mental Health Unit than those on standard wards, after controlling for multiple factors. CONCLUSION: Dissatisfaction was associated with patient behavioral and psychological symptoms and caregiver strain but was not immutable to efforts to improve care. PMID- 25516023 TI - Health outcomes associated with polypharmacy in community-dwelling older adults: a systematic review. AB - OBJECTIVES: To summarize evidence regarding the health outcomes associated with polypharmacy, defined as number of prescribed medications, in older community dwelling persons. DESIGN: Systematic review of MEDLINE (OvidSP 1946 to May, Week 3, 2014). SETTING: Community. PARTICIPANTS: Observational studies examining health outcomes according to number of prescription medications taken. MEASUREMENTS: Association between number of medications and health outcomes. Because of the importance of comorbidity as a potential confounder of the relationship between polypharmacy and health outcomes, articles were assessed regarding the quality of their adjustment for confounding. RESULTS: Of the 50 studies identified, the majority that were rated good in terms of their adjustment for comorbidity demonstrated relationships between polypharmacy and a range of outcomes, including falls, fall outcomes, fall risk factors, adverse drug events, hospitalization, mortality, and measures of function and cognition. However, a number of these studies failed to demonstrate associations, as did a substantial proportion of studies rated fair or poor. CONCLUSION: Data are mixed regarding the relationship between polypharmacy, considered in terms of number of medications, and adverse outcomes in community-dwelling older persons. Because of the challenge of confounding, randomized controlled trials of medication discontinuation may provide more-definitive evidence regarding this relationship than observational studies can provide. PMID- 25516024 TI - Factors mediating the effects of a depression intervention on functional disability in older African Americans. AB - OBJECTIVES: To determine factors mediating the effects of a depression intervention for older African Americans on functional disability and, secondarily, whether functional improvements mediate intervention effects on depressive symptoms. DESIGN: Structural equation modeling to examine mediators in a secondary analysis of a randomized trial with 4-month follow-up. SETTING: Philadelphia region. PARTICIPANTS: Community-dwelling African Americans (>=55) with depressive symptoms living in an urban area (N = 208). INTERVENTION: Up to 10 one-hour sessions over 4 months conducted by licensed social workers who provided care management, referrals and linkages, stress reduction techniques, depression knowledge and symptom recognition, and behavioral activation techniques. MEASUREMENTS: Main outcome was self-reported functional difficulty level for 18 basic activities. Mediators included depression severity (Patient Health Questionnaire), depression knowledge and symptom recognition, behavioral activation, and anxiety. RESULTS: At 4 months, the intervention had positive effects on functional difficulty and all mediators (P < .001). Separate structural equation models indicated that two factors (reduced depressive symptoms (23.5% mediated) and improved depression knowledge and symptom recognition (52.9% mediated)) significantly mediated the intervention's effect on functional disability. Enhancing behavioral activation and decreasing anxiety were not found to mediate improvements in functional disability. The two significant mediators jointly explained 62.5% of the intervention's total effect on functional disability. Functional improvement was not found to mediate the intervention's effect on depressive symptoms. CONCLUSION: This multicomponent depression intervention for African Americans has an effect on functional disability that is driven primarily by enhancing symptom recognition and decreasing depressive symptoms. Reduction of functional difficulties did not account for improvements in depressive symptoms. Nonpharmacological treatments for depressive symptoms that enhance symptom recognition in older African Americans can also reduce their functional difficulties with daily living activities. PMID- 25516025 TI - Cost-effectiveness of a community-integrated home-based depression intervention in older African Americans. AB - OBJECTIVES: To test the cost-effectiveness of a home-based depression program: Beat the Blues (BTB). DESIGN: A cost-effectiveness analysis as part of a previously reported randomized controlled trial that compared BTB with a wait list control group. SETTING: Community. PARTICIPANTS: English-speaking, cognitively intact (Mini-Mental State Examination score >=24), African Americans aged 55 and older with depressive symptoms (Patient Health Questionnaire score >=5) (N = 129). INTERVENTION: Participants randomly assigned to BTB received up to 10 home visits over 4 months from licensed social workers who provided care management, referral and linkage, stress reduction, depression education, and behavioral activation to help participants achieve self-identified goals. MEASUREMENTS: Incremental cost-effectiveness ratios (ICERs) of BTB versus wait list controls during the 4-month study period. The primary ICER was defined as cost per quality-adjusted life year (QALY) using the Euro Quality of Life 5D (EQ 5D) and secondarily using the Health Utilities Index-3 (HUI-3). Additional ICERs were calculated using clinical measures (cost per depression improvement, cost per depression remission). Costs included BTB intervention, depression-related healthcare visits and medications, caregiver time, and social services. RESULTS: BTB cost per participant per month was $146. Base case ICERs were $64,896 per QALY (EQ-5D) and $36,875 per QALY (HUI-3). Incremental cost was $2,906 per depression improvement and $3,507 per remission. Univariate and probabilistic sensitivity analyses yielded a cost/QALY range of $20,500 to $76,500. CONCLUSION: Based on the range of cost-effectiveness values resulting from this study, BTB is a cost-effective treatment for managing depressive symptoms in older African Americans that compares favorably with the cost-effectiveness of previously tested approaches. PMID- 25516027 TI - Adiposity estimated using dual energy X-ray absorptiometry and body mass index and its association with cognition in elderly adults. AB - OBJECTIVES: To determine whether obesity, estimated according to body mass index (BMI), waist circumference, and body fat and abdominal fat assessed using dual energy X-ray absorptiometry (DEXA), was associated with cognitive performance. DESIGN: Cross-sectional. SETTING: Community based. PARTICIPANTS: Individuals aged 74-94 (N = 406). MEASUREMENTS: BMI, waist circumference, body fat, and abdominal fat were assessed using DEXA. Cognitive performance was assessed using a comprehensive neuropsychological battery. RESULTS: When categorized using BMI, overweight individuals had higher global cognitive function and executive function scores than normal-weight individuals. This relationship did not differ according to sex. When categorized according to DEXA, there were no relationships between body fat and cognitive function in the whole group, but women in the middle and highest tertiles of DEXA body fat had better executive function than those in the lowest tertile. Men in the middle tertile of DEXA body fat had significantly better executive function and memory than those in the lowest tertile. BMI had greater power to predict executive function than DEXA body fat. No significant associations were found between cognition and estimates of abdominal adiposity. CONCLUSION: This study found an association between being overweight and better executive function in elderly adults; this association was stronger for the simpler BMI than the more-elaborate DEXA measures. PMID- 25516026 TI - Associations between inflammation and cognitive function in African Americans and European Americans. AB - OBJECTIVES: To examine associations between specific inflammatory biomarkers and cognitive function in African Americans (AAs) and European Americans (EAs) with prevalent vascular risk factors. DESIGN: Cross-sectional analysis using generalized estimating equations to account for familial clustering; standardized beta-coefficients, adjusted for age, sex, and education are reported. SETTING: Community cohort study in Jackson, Mississippi, and Rochester, Minnesota. PARTICIPANTS: Genetic Epidemiology Network of Arteriopathy (GENOA)-Genetics of Microangiopathic Brain Injury (GMBI) Study participants. MEASUREMENTS: Associations between inflammation (high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, soluble tumor necrosis factor (TNF) receptor 1 and 2 (sTNFR1, sTNFR2)) and cognitive function (global, processing speed, language, memory, and executive function) were examined in AAs and EAs (N = 1,965; aged 26-95, 64% women, 52% AA, 75% with hypertension). RESULTS: In AAs, higher sTNFR2 was associated with poorer cognition in all domains (global: -0.11, P = .009; processing speed: -0.11, P < .001; language: -0.08, P = .002; memory: -0.09, P = .008; executive function: -0.07, P = .03); sTNFR1 was associated with slower processing speed (-0.08, P < .001) and poorer executive function (-0.08, P = .008); higher CRP was associated with slower processing speed (-0.04, P = .024), and higher IL6 was associated with poorer executive function (-0.07, P = .02). In EA, only higher sTNFR1 was associated with slower processing speed (-0.05, P = .007). Associations were not found between cognition and sTNFR2, CRP, or IL6 in EA. CONCLUSION: In a population with high vascular risk, adverse associations between inflammation and cognitive function were especially apparent in AAs, primarily involving markers of TNFalpha activity. PMID- 25516029 TI - Association between self-reported sleep duration and serum vitamin D level in elderly Korean adults. AB - OBJECTIVES: To investigate the association between self-reported sleep duration and serum vitamin D level in elderly Korean adults. DESIGN: Cross-sectional data analysis. SETTING: Korean National Health and Nutrition Examination Survey 2010. PARTICIPANTS: Noninstitutionalized adults aged 60 to 80 (N = 1,614). MEASUREMENTS: The confounding variables were serum 25-hydroxy vitamin D level, age, sex, body mass index, smoking history, alcohol consumption, and self reported daily sun exposure and sleep duration. Self-reported daily sleep duration was divided into four groups: Q1 (<=4 hours), Q2 (5-6 hours), Q3 (7-8 hours), and Q4 (>=9 hours). RESULTS: Mean serum vitamin D levels of subjects in the Q1, Q2, Q3, and Q4 groups were 44.18, 48.08, 48.83, and 51.78 nmol/L, respectively. On multivariate linear regression analysis, subjects in the Q2 (B = 3.80, 95% confidence interval (CI) = 0.42-7.19), Q3 (B = 4.89, 95% CI = 1.54 8.24), and Q4 (B = 5.18, 95% CI = 0.78-9.58) groups had significantly higher serum vitamin D levels than subjects in the Q1 group. CONCLUSION: Serum vitamin D level is positively associated with self-reported daily sleep duration in elderly Korean individuals. These results suggest that inadequate sleep duration may be associated with lower vitamin D levels in elderly adults. PMID- 25516028 TI - Effect of exercise and cognitive activity on self-reported sleep quality in community-dwelling older adults with cognitive complaints: a randomized controlled trial. AB - OBJECTIVES: To compare the effects of different types of physical and mental activity on self-reported sleep quality over 12 weeks in older adults with cognitive and sleep complaints. DESIGN: Randomized controlled trial. SETTING: General community. PARTICIPANTS: Seventy-two inactive community-dwelling older adults with self-reported sleep and cognitive problems (mean age 73.3 +/- 6.1; 60% women). INTERVENTION: Random allocation to four arms using a two-by-two factorial design: aerobic+cognitive training, aerobic+educational DVD, stretching+cognitive training, and stretching+educational DVD arms (60 min/d, 3 d/wk for physical and mental activity for 12 weeks). MEASUREMENTS: Change in sleep quality using seven questions from the Sleep Disorders Questionnaire on the 2005 to 2006 National Health and Nutrition Examination Survey (range 0-28, with higher scores reflecting worse sleep quality). Analyses used intention-to-treat methods. RESULTS: Sleep quality scores did not differ at baseline, but there was a significant difference between the study arms in change in sleep quality over time (P < .005). Mean sleep quality scores improved significantly more in the stretching+educational DVD arm (5.1 points) than in the stretching+cognitive training (1.2 points), aerobic+educational DVD (1.1 points), or aerobic+cognitive training (0.25 points) arms (all P < .05, corrected for multiple comparisons). Differences between arms were strongest for waking at night (P = .02) and taking sleep medications (P = .004). CONCLUSION: Self-reported sleep quality improved significantly more with low-intensity physical and mental activities than with moderate- or high-intensity activities in older adults with self-reported cognitive and sleep difficulties. Future longer-term studies with objective sleep measures are needed to corroborate these results. PMID- 25516030 TI - Practical problems with medication use that older people experience: a qualitative study. AB - OBJECTIVES: To identify the practical problems that older people experience with the daily use of their medicines and their management strategies to address these problems and to determine the potential clinical relevance thereof. DESIGN: Qualitative study with semistructured face-to-face interviews. SETTING: A community pharmacy and a geriatric outpatient ward. PARTICIPANTS: Community dwelling people aged 70 and older (N = 59). MEASUREMENTS: Participants were interviewed at home. Two researchers coded the reported problems and management strategies independently according to a coding scheme. An expert panel classified the potential clinical relevance of every identified practical problem and associated management strategy using a 3-point scale. RESULTS: Two hundred eleven practical problems and 184 management strategies were identified. Ninety-five percent of the participants experienced one or more practical problems with the use of their medicines: problems reading and understanding the instructions for use, handling the outer packaging, handling the immediate packaging, completing preparation before use, and taking the medicine. For 10 participants, at least one of their problems, in combination with the applied management strategy, had potential clinical consequences and 11 cases (5% of the problems) had the potential to cause moderate or severe clinical deterioration. CONCLUSION: Older people experience a number of practical problems using their medicines, and their strategies to manage these problems are sometimes suboptimal. These problems can lead to incorrect medication use with clinically relevant consequences. The findings pose a challenge for healthcare professionals, drug developers, and regulators to diminish these problems. PMID- 25516031 TI - Higher Perceived Stress Scale scores are associated with higher pain intensity and pain interference levels in older adults. AB - OBJECTIVES: To determine the prevalence of bodily pain measures (pain intensity and interference) in elderly people and their relationship with Perceived Stress Scale (PSS) scores. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: A representative community sample of 578 individuals aged 70 and older (mean age 78.8, 63% female). MEASUREMENTS: The prevalence of pain intensity and pain interference and their relationship with PSS scores, demographic factors, past medical history, and neuropsychological testing scores were examined. Pain intensity and pain interference were measured using the Medical Outcomes Study 36 item Short-Form Survey bodily pain questions. RESULTS: Bivariate analysis for pain measures showed that PSS scores, neuropsychological test scores, and medical histories were associated with pain intensity and interference. Logistic regression showed that higher PSS scores were significantly associated with greater odds of having moderate to severe pain intensity and moderate to severe pain interference (with and without the inclusion of pain intensity in the models). CONCLUSION: Higher PSS scores are associated with greater pain intensity and interference. In this cross-sectional analysis, directionality cannot be determined. Because perceived stress and pain are potentially modifiable risk factors for cognitive decline and other poor health outcomes, future research should address temporality and the benefits of treatment. PMID- 25516033 TI - Teaching geriatric fellows how to teach: a needs assessment targeting geriatrics fellowship program directors. AB - The entire healthcare workforce needs to be educated to better care for older adults. The purpose of this study was to determine whether fellows are being trained to teach, to assess the attitudes of fellowship directors toward training fellows to be teachers, and to understand how to facilitate this type of training for fellows. A nine-question survey adapted from a 2001 survey issued to residency program directors inquiring about residents-as-teachers curricula was developed and administered. The survey was issued electronically and sent out three times over a 6-week period. Of 144 ACGME-accredited geriatric fellowship directors from geriatric, internal medicine, and family medicine departments who were e-mailed the survey, 101 (70%) responded; 75% had an academic affiliation, 15% had a community affiliation, and 10% did not report. Academic and community programs required their fellows to teach, but just 55% of academic and 29% of community programs offered teaching skills instruction as part of their fellowship curriculum; 67% of academic programs and 79% of community programs felt that their fellows would benefit from more teaching skill instruction. Program directors listed fellow (39%) and faculty (46%) time constraints as obstacles to creation and implementation of a teaching curriculum. The majority of fellowship directors believe that it is important for geriatric fellows to become competent educators, but only approximately half of programs currently provide formal instruction in teaching skills. A reproducible, accessible curriculum on teaching to teach that includes a rigorous evaluation component should be created for geriatrics fellowship programs. PMID- 25516032 TI - Associations between fibrin D-dimer, markers of inflammation, incident self reported mobility limitation, and all-cause mortality in older men. AB - OBJECTIVES: To examine the independent relationships between fibrin D-dimer, interleukin 6 (IL-6), C-reactive protein (CRP), and fibrinogen and incident mobility limitation and mortality. DESIGN: Prospective. SETTING: General practice in 24 British towns. PARTICIPANTS: Men aged 60 to 79 without prevalent heart failure followed up for an average of 11.5 years (N = 3,925). MEASUREMENTS: All cause mortality (n = 1,286) and self-reported mobility disability obtained at examination in 1998 to 2000 and in a postal questionnaire 3 to 5 years later in 2003. RESULTS: High D-dimer (top vs lowest tertile: adjusted odds ratio (aOR) = 1.46, 95% confidence interval = 1.02-2.05) and IL-6 (aOR = 1.43, 95% CI = 1.01 2.02) levels (but not CRP or fibrinogen) were associated with greater incident mobility limitation after adjustment for confounders and prevalent disease status. IL-6, CRP, fibrinogen, and D-dimer were significantly associated with total mortality after adjustment for confounders. Only D-dimer and IL-6 predicted total mortality independent of each other and the other biomarkers. The adjusted hazard ratio (aHR) was 1.16 (95% CI = 1.10-1.22) for a standard deviation increase in log D-dimer and 1.10 (95% CI = 1.04-1.18) for a standard deviation increase in log IL-6. D-dimer was independently related to vascular and nonvascular mortality, and IL-6 was independently related to vascular mortality. Risks of mobility limitation and mortality were greatest in those with a combination of high D-dimer and IL-6 levels. CONCLUSION: D-dimer and IL-6 are associated with risk of mobility limitation and mortality in older men without heart failure. The findings suggest that coagulation leads to functional decline and mortality s that inflammation does not explain. PMID- 25516034 TI - Risk prediction models for postoperative delirium: a systematic review and meta analysis. AB - Postoperative delirium (POD) is a common neuropsychiatric disorder characterized by inattention, fluctuating levels of consciousness, and disorganized thinking. POD can have serious consequences, including institutionalization and death. Risk stratification may target prevention to individuals at greater risk of POD. The objective of this study was to identify all published POD risk prediction models (RPMs) and to compare them with regard to their clinical practicability and predictive and discriminative performance. PubMed and EMBASE were searched from inception to January 1, 2013, for articles describing POD RPMs. Studies were included if they presented data from a cohort study, examined one or more RPMs, examined POD as an outcome, and assessed the performance of the RPM(s). Thirty of 2,246 articles were included, and 37 RPMs were found. Sixteen and six studies described individuals who had undergone cardiovascular and orthopedic surgery, respectively. The Confusion Assessment Method (CAM) for the intensive care unit checklist was the most often used diagnostic method (65%), followed by the Diagnostic and Statistical Manual of Mental Disorders (DSM), Fourth Edition criteria (16%). Predictors most often used in RPMs were age (20), preoperative Mini-Mental State Examination score (10), and preoperative increased alcohol use (7). Thirty RPMs were not validated, three were validated internally, and four were validated externally. Size of the models was not associated with their discriminatory performance. Instead of creating steadily new RPMs, existing RPMs should be further tested, improved, and meta-analytically integrated. It may be too early to implement a particular PODRPM in clinical practice with confidence. PMID- 25516035 TI - Implementation and assessment of a fall screening program in primary care practices. AB - Fall prevention strategies for older adults are underused in primary care. A study was designed to examine the Centers for Medicare and Medicaid Services Physician Quality Reporting System (PQRS) fall measures and to reduce injuries and costs from falls by 10%. This quality improvement project using a pre/post design was implemented in four primary care practices with 2,021 patients aged 65 and older in Asheville, North Carolina. The project used a patient registry, electronic templates, standardized care protocols, a falls clinic to evaluate individuals who reported falling, and patient resource materials. Data were collected from medical records on processes of care, fall-related injuries, and anticipated payments. Individuals billed for at least one outpatient visit from July 2011 through June 2012 (n = 2,021) constituted the cohort for the intervention and for analysis of injuries from falls requiring hospital visits (before the intervention (T1): July 2010 to March 2011; after the intervention (T2): July 2012 to March 2013). Practice sites properly screened 68.8% of older adults for falls, assessed 87% of those who reported falling, and documented the PQRS required plan of care in 23%. Only 20% self-reported falls. Numbers of falls requiring a visit to the hospital were small overall and did not decrease (T1, 2.4%; T2, 2.9%; P = .32); 61% of individuals seen in the hospital for fall related injuries had not reported previous falls. Incorporating the PQRS fall measures into primary care was challenging, and the program was not robust enough to reduce serious falls and hospital costs. PMID- 25516036 TI - Honoring Choices Minnesota: preliminary data from a community-wide advance care planning model. AB - Advance care planning (ACP) increases the likelihood that individuals who are dying receive the care that they prefer. It also reduces depression and anxiety in family members and increases family satisfaction with the process of care. Honoring Choices Minnesota is an ACP program based on the Respecting Choices model of La Crosse, Wisconsin. The objective of this report is to describe the process, which began in 2008, of implementing Honoring Choices Minnesota in a large, diverse metropolitan area. All eight large healthcare systems in the metropolitan area agreed to participate in the project, and as of April 30, 2013, the proportion of hospitalized individuals 65 and older with advance care directives in the electronic medical record was 12.1% to 65.6%. The proportion of outpatients aged 65 and older was 11.6% to 31.7%. Organizations that had sponsored recruitment initiatives had the highest proportions of records containing healthcare directives. It was concluded that it is possible to reduce redundancy by recruiting all healthcare systems in a metropolitan area to endorse the same ACP model, although significantly increasing the proportion of individuals with a healthcare directive in their medical record requires a campaign with recruitment of organizations and individuals. PMID- 25516037 TI - Remembering Gene Stollerman, MD. PMID- 25516038 TI - Nascher's Geriatrics at 100. AB - Ignatz Nascher's Geriatrics-the first American medical textbook on aging-turns 100 this year. This essay is a reappraisal, on its centennial, of Nascher's landmark work. PMID- 25516039 TI - Twenty-first century home-centered medicine: it's about the touch, not the tech.... PMID- 25516040 TI - When the leaves fall. PMID- 25516041 TI - Low apolipoprotein A-1 plasma level in older adults with spontaneous cerebral lobar hemorrhage: a cross-sectional study. PMID- 25516042 TI - Effect of press needles on swallowing reflex in older adults with cerebrovascular disease: a randomized double-blind controlled trial. PMID- 25516043 TI - Aging and within- and between-day variability assessed using 7-day/24-hour ambulatory blood pressure monitoring. PMID- 25516044 TI - Critical pathways: implementation of the Coleman Care Transitions Program in individuals hospitalized with congestive heart failure. PMID- 25516045 TI - Usefulness and effect of online prognostic calculators. PMID- 25516046 TI - Timing does matter: evaluating the effect of comprehensive geriatric assessments on knowledge and attitudes in Year 1 of residency. PMID- 25516047 TI - Cancer risk associated with calcitonin use. PMID- 25516048 TI - Relationship between Pisa syndrome and cholinesterase inhibitor use for elderly adults with Alzheimer's disease. PMID- 25516049 TI - Determinants of long-term care needs of community-dwelling older people in Singapore. PMID- 25516050 TI - Have we been overestimating the risk of end-stage renal disease in older adults with chronic kidney disease? PMID- 25516051 TI - Unveiling adrenal insufficiency can make a difference in elderly adults. PMID- 25516052 TI - High-grade rectal impaction by feces and oral contrast: case report and images. PMID- 25516053 TI - Progressive supranuclear palsy presenting initially as semantic dementia. PMID- 25516054 TI - Delayed hypoglycemia induced by repaglinide in a frail elderly adult with diabetes mellitus. PMID- 25516055 TI - Severe hyponatremia due to escitalopram treatment in an elderly adult with Alzheimer's disease. PMID- 25516056 TI - Diagnosis of late-onset Takayasu arteritis for elderly adults using fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography. PMID- 25516057 TI - Phenazopyridine-induced hemolytic anemia in advanced kidney disease. PMID- 25516058 TI - American Geriatrics Society response to letter to the editor from Marc S. Berger "Misuse of Beers Criteria" July 2014. PMID- 25516059 TI - Response letter. PMID- 25516060 TI - Dietary factors and incidence of dementia: Cox regression analysis with special emphasis on the number of events. PMID- 25516061 TI - Medical student perceptions of radiology use in anatomy teaching. AB - The use of radiology in the teaching of anatomy to medical students is gaining in popularity; however, there is wide variation in how and when radiology is introduced into the curriculum. The authors sought to investigate students' perceptions regarding methods used to depict and teach anatomy and effects of integrated radiology instruction on students' abilities to correctly identify imaging modalities and anatomical structures on radiological images. First-year medical students completed questionnaires at the beginning and end of the first academic year that incorporated ten hours of radiologic anatomy teaching in the anatomy curriculum. Questions used a combination of Likert scales, rankings, and binary options. Students were tested on their ability to identify radiology modalities and anatomical structures on radiology images. Preresponse and postresponse rates were 93% (157/168) and 85% (136/160), respectively. Postmodule, 96.3% of students wanted the same or more radiology integration. Furthermore, 92.4% premodule and 96.2% postmodule agreed that "Radiology is important in medical undergraduate teaching." Modality and structure identification scores significantly increased from 59.8% to 64.3% (P < 0.001) and from 47.4% to 71.2% (P < 0.001), respectively. The top three preferred teaching formats premodule and postmodule were (1) anatomy laboratory instruction, (2) interactive sessions combining radiology with anatomy, and (3) anatomy lectures. Postmodule, 38.3% of students were comfortable reviewing radiology images. Students were positive about integrating radiology into anatomy teaching and most students wanted at least the same level of assimilation but that it is used as an adjunct rather than primary method of teaching anatomy. PMID- 25516062 TI - MicroRNA profiling analysis throughout tomato fruit development and ripening reveals potential regulatory role of RIN on microRNAs accumulation. AB - The development and ripening of tomato fruit are complex processes involving many gene regulatory pathways at the transcriptional and post-transcriptional level. Ripening inhibitor (RIN) is a vital transcription factor, which targets numerous ripening-related genes at the transcriptional level during tomato fruit ripening. MicroRNAs (miRNAs) are a class of short noncoding RNAs that play important roles in post-transcriptional gene regulation. To elucidate the potential regulatory relationship between rin and miRNAs during fruit development and ripening, we identified known miRNAs and profiled their expression in wild-type tomato and rin mutant using a deep sequencing approach combined with quantitative RT-PCR. A total of 33 known miRNA families were identified, of which 14 miRNA families were differently accumulated. Subsequent promoter analysis showed that possible RIN binding motifs (CArG-box) tended to occur frequently in the promoter regions of partial differently expressed miRNAs. In addition, ethylene may participate in the regulation of miRNAs accumulation during tomato fruit ripening. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay confirmed the direct binding of RIN to the promoter of MIR172a. Collectively, these results showed a close correlation between miRNA expression and RIN as well as ethylene, which further elucidated the regulatory roles of miRNAs during fruit development and ripening and enriched the regulatory network of RIN in tomato fruit. PMID- 25516064 TI - Living arrangements, chronic diseases, and prescription drug expenditures among Korean elderly: vulnerability to potential medication underuse. AB - BACKGROUND: Insufficient social security combined with family structure changes has resulted in a poverty of the elderly. The objective of this study was to examine an association of living arrangements of the elderly with chronic disease prevalence and prescription drug use. METHODS: 2008 Korea Health Panel Survey (KHPS) data were used in this study. Information on living arrangements, socio demographics, health behaviors, chronic disease prevalence and healthcare expenditures including out-of-pocket (OOP) prescription drug expenditures for elderly aged 65 or older were collected from self-reported diaries and receipts. OOP prescription drug expenditure as a total cost that subject paid to a pharmacy for prescription drugs was examined. Logistic regression was used to identify differences in major chronic disease prevalence by living arrangements. The association of living arrangements with prescription drug use was analyzed using generalized linear model with a log link and a gamma variance distribution. RESULTS: Proportions of elderly living alone, elderly living with a spouse only, and elderly living with adults aged 20-64 were 14.5%, 48.3%, and 37.2%, respectively. Elderly living alone showed 2.43 odds ratio (OR) (95% confidence interval (CI) = 1.66-3.56) for having major chronic diseases prevalence compared to elderly living with adults. Despite a higher major chronic disease prevalence, elderly living alone showed lower OOP prescription drug expenditures (Cost Ratio = 0.80, 95% CI = 0.67-0.97) after adjusting for the number of major chronic diseases. Total OOP prescription drug expenditures were significantly lower in patients with a low income level versus high income level. CONCLUSIONS: Even though elderly living alone had a higher risk of chronic disease, they spent less on OOP prescription drug expenditures. Optimal drug use is important for elderly with chronic diseases to achieve good health outcomes and quality of life. Public health policies should be supplemented to optimize medical treatment for vulnerable elderly living alone. PMID- 25516063 TI - A large animal model of spinal muscular atrophy and correction of phenotype. AB - OBJECTIVES: Spinal muscular atrophy (SMA) is caused by reduced levels of survival motor neuron (SMN) protein, which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides, and scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness, and the response of clinically relevant biomarkers. METHODS: Using intrathecal delivery of scAAV9 expressing an shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN), and electrophysiology measurements and pathology were performed. RESULTS: Knockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimation (MUNE), as in human SMA. Neuropathology showed loss of motoneurons and motor axons. Presymptomatic delivery of scAAV9-SMN prevented SMA symptoms, indicating that all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures, and pathology. INTERPRETATION: High SMN levels are critical in postnatal motoneurons, and reduction of SMN results in an SMA phenotype that is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration, and abrogation of phenotype can be achieved even after symptom onset. PMID- 25516065 TI - Laser Capture Microdissection of Feline Streptomyces spp Pyogranulomatous Dermatitis and Cellulitis. AB - Suspected Streptomyces spp infections were identified in 4 cats at UC Davis Veterinary Medical Teaching Hospital between 1982 and 2011. Three had ulcerated, dark red mycetomas involving the dermis, subcutis, and fascia with fistulous tracts and/or regional lymphadenopathy. One cat had pyogranulomatous mesenteric lymphadenitis. Granulomatous inflammation in all cats contained colonies of Gram positive, non-acid-fast organisms. All 4 cats failed to respond to aggressive medical and surgical treatment and were euthanized. Laser capture microdissection (LCM) was used to selectively harvest DNA from the affected formalin-fixed, paraffin-embedded (FFPE) tissues. Cloned amplicons from LCM-derived tissue confirmed the presence of Streptomyces spp in the dermatitis cases. Amplicons from the remaining cat with peritoneal involvement aligned with the 16S ribosomal RNA gene for Actinomycetales. Usually considered a contaminant, Streptomyces spp can be associated with refractory pyogranulomatous dermatitis and cellulitis in cats with outdoor access. LCM is useful in the diagnosis of bacterial diseases where contamination may be an issue. PMID- 25516066 TI - A comparison of biochemical and histopathologic staging in cats with chronic kidney disease. AB - Chronic kidney disease (CKD) is prevalent in elderly cats. Frequently, a diagnosis is made in later stages of disease, by which time many renal lesions are irreversible. As such, little headway has been made in identifying an etiology and preventing this common disease. The aim of this study was to evaluate the presence and severity of both reversible and irreversible histopathologic changes in the kidneys of cats at each stage of CKD and, in addition, to determine if lesion prevalence and character were different between stages. A total of 46 cats with CKD were classified according to the International Renal Interest Society (IRIS) as stage I (3 cats), stage II (16 cats), stage III (14 cats), and stage IV (13 cats). Eleven young, nonazotemic and 10 geriatric, nonazotemic cats were included as controls. The severity of tubular degeneration, interstitial inflammation, fibrosis, and glomerulosclerosis was significantly greater in later stages of CKD compared with early stages of disease. Proteinuria was associated with increased severity of tubular degeneration, inflammation, fibrosis, tubular epithelial single-cell necrosis, and decreased normal parenchyma. Presence of hyperplastic arteriolosclerosis, fibrointimal hyperplasia, or other vascular lesions were not found to be significantly different between hypertensive and normotensive cats. The greater prevalence and severity of irreversible lesions in stage III and IV CKD implies that therapeutic interventions should be targeted at earlier stages of disease. PMID- 25516067 TI - The (111) surface of NaAu2: structure, composition, and stability. AB - The (111) surface of single-crystal NaAu(2) is a model for catalytically active, powdered NaAu(2). We prepare and characterize this surface with a broad suite of techniques. Preparation in ultrahigh vacuum consists of the traditional approach of ion bombardment (to remove impurities) and thermal annealing (to restore surface order). Both of these steps, however, cause loss of sodium (Na), and repeated treatments eventually trigger conversion of the surface and near-surface regions to crystalline gold. The bulk has a limited ability to repopulate the surface Na. Under conditions where Na depletion is minimized, electron diffraction patterns are consistent with the bulk-terminated structure, and scanning tunneling microscopy reveals mesa-like features with lateral dimensions of a few tens of nanometers. The tops of the mesas do not possess fine structure characteristic of a periodic lattice, suggesting that the surface layer is disordered under the conditions of these experiments. PMID- 25516068 TI - Latent trajectory classes for alcohol-related blackouts from age 15 to 19 in ALSPAC. AB - BACKGROUND: Alcohol-related blackouts (ARBs) are reported by ~50% of drinkers. While much is known about the prevalence of ARBs in young adults and their cross sectional correlates, there are few prospective studies regarding their trajectories over time during mid-adolescence. This paper reports latent trajectory classes of ARBs between age 15 and 19, along with predictors of those patterns. METHODS: Latent class growth analysis (LCGA) was used to evaluate the pattern of occurrence of ARBs across 4 time points for 1,402 drinking adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC). Multinomial regression analyses evaluated age-15 demography, substance-related items, externalizing characteristics, and estimated peer substance use as predictors of latent class membership. RESULTS: ARBs were reported at age 15 in 30% and at age 19 in 74% of these subjects. Four latent trajectory classes were identified: Class 1 (5.1%) reported no blackouts; for Class 2 (29.5%), ARBs rapidly increased with age; for Class 3 (44.9%), blackouts slowly increased; and for Class 4 (20.5%), ARBs were consistently reported. Using Class 2 (rapid increasers) as the reference, predictors of class membership included female sex, higher drinking quantities, smoking, externalizing characteristics, and estimated peer substance involvement (pseudo R(2) = 0.22). CONCLUSIONS: ARBs were common and repetitive in these young subjects, and predictors of their trajectories over time involved multiple domains representing diverse characteristics. PMID- 25516069 TI - Risk factors for incidence and persistence of disability in chronic major depression and alcohol use disorders: longitudinal analyses of a population-based study. AB - BACKGROUND: Major depression and alcohol use disorders are risk factors for incidence of disability. However, it is still unclear whether a chronic course of these health conditions is also prospectively associated with incidence of disability. The aim of the present study was, first, to confirm whether chronic major depression (MD) and alcohol use disorders (AUD) are, respectively, risk factors for persistence and incidence of disability in the general population; and then to analyze the role of help-seeking behavior in the course of disability among respondents with chronic MD and chronic AUD. METHOD: Data from two assessments in the National Epidemiologic Survey on Alcohol and Related Conditions were analyzed. Disability was measured by eight domains of the Short Form 12 Health Survey version 2 (SF-12). Generalized estimating equations and logistic regression models were run to estimate risk factors for persistence and incidence of disability, respectively. RESULTS: Analyses conducted on data from the US general population showed that chronic MD was the strongest risk factor for incidence and persistence of disability in the social functioning, emotional role and mental health domains. Chronic AUD were risk factors for incidence and persistence of disability in the vitality, social functioning, and emotional role domains. Within the group of chronic MD, physical comorbidity and help-seeking were associated with persistent disability in most of the SF-12 domains. Help seeking behavior was also associated with incidence of problems in the mental health domain for the depression group. Regarding the AUD group, comorbidity with physical health problems was a strong risk factor for persistence of disability in all SF-12 domains. Help-seeking behavior was not related to either persistence or incidence of disability in the chronic alcohol group. CONCLUSIONS: Chronic MD and chronic AUD are independent risk factors for persistence and incidence of disability in the US general population. People with chronic MD seek help for their problems when they experience persistent disability, whereas people with chronic AUD might not seek any help even if they are suffering from persistent disability. PMID- 25516071 TI - Action needed now to turn the general practice crisis into a renaissance. PMID- 25516070 TI - Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. AB - PURPOSE: Combined immunodeficiency (CID) presents a unique challenge to clinicians. Two patients presented with the prior clinical diagnosis of common variable immunodeficiency (CVID) disorder marked by an early age of presentation, opportunistic infections, and persistent lymphopenia. Due to the presence of atypical clinical features, next generation sequencing was applied documenting RAG deficiency in both patients. METHODS: Two different genetic analysis techniques were applied in these patients including whole exome sequencing in one patient and the use of a gene panel designed to target genes known to cause primary immunodeficiency disorders (PIDD) in a second patient. Sanger dideoxy sequencing was used to confirm RAG1 mutations in both patients. RESULTS: Two young adults with a history of recurrent bacterial sinopulmonary infections, viral infections, and autoimmune disease as well as progressive hypogammaglobulinemia, abnormal antibody responses, lymphopenia and a prior diagnosis of CVID disorder were evaluated. Compound heterozygous mutations in RAG1 (1) c256_257delAA, p86VfsX32 and (2) c1835A>G, pH612R were documented in one patient. Compound heterozygous mutations in RAG1 (1) c.1566G>T, p.W522C and (2) c.2689C>T, p. R897X) were documented in a second patient post-mortem following a fatal opportunistic infection. CONCLUSION: Astute clinical judgment in the evaluation of patients with PIDD is necessary. Atypical clinical findings such as early onset, granulomatous disease, or opportunistic infections should support the consideration of atypical forms of late onset CID secondary to RAG deficiency. Next generation sequencing approaches provide powerful tools in the investigation of these patients and may expedite definitive treatments. PMID- 25516072 TI - Arterial pre-hypertension and hypertension in intracranial versus extracranial cerebrovascular stenosis. AB - BACKGROUND AND PURPOSE: Since it has remained unclear whether arterial pre hypertension is a risk factor for cerebrovascular diseases, potential associations between arterial pre-hypertension and intracranial arterial stenosis (ICAS) and extracranial arterial stenosis (ECAS) were assessed. METHODS: The population-based Asymptomatic Polyvascular Abnormalities in Community Study was a sub-study of employees and retirees of the coal mining industry in China. Our study examined asymptomatic polyvascular abnormalities in a general population and with an age of 40+ years without history of stroke, transient ischaemic attacks and coronary heart disease. ICAS was diagnosed by transcranial Doppler sonography and was defined by peak flow velocity criteria; ECAS was diagnosed by carotid duplex sonography and was defined by the diameter of the common carotid artery or internal carotid artery. RESULTS: Out of 4422 study participants, 711 (16.1%) subjects showed an asymptomatic ICAS and 292 (6.6%) showed an asymptomatic ECAS. After adjusting for relevant risk factors, higher prevalence of ICAS was significantly associated with higher prevalence of pre-hypertension [odds ratio (OR) 1.55; 95% confidence interval (CI) 1.11, 2.16; P = 0.010] and hypertension (OR 1.80; 95% CI 1.53, 2.11; P < 0.001). Stratified by gender, the association was stronger for men than for women. Asymptomatic ECAS was not significantly associated with the prevalence of pre-hypertension (OR 0.78; 95% CI 0.55, 1.10) or of hypertension (OR 1.06; 95% CI 0.91, 1.24). CONCLUSIONS: The results suggest that arterial pre-hypertension in addition to hypertension is associated with a higher prevalence of asymptomatic ICAS, more in men. PMID- 25516075 TI - Sense of meaning in life among the oldest old people living in a rural area in northern Sweden. AB - BACKGROUND: Having meaning in life is important for all people, and according to Erikson's developmental theory, this is especially true for older adults. However, there are few studies about meaning in life focusing on the oldest old. AIM: The aim of our study was to illuminate the sense of meaning in life in the oldest old living in northern Sweden. DESIGN: The study has a qualitative explorative and interpretative design. METHOD: We interviewed three men and seven women between 85 and 95 years old and analysed the interviews using qualitative content analysis. FINDINGS: Our findings revealed the following four themes: 'Creating space for living', 'Living in connection with others and nature', 'Seeing oneself as a link between generations' and 'Having trust in God'. CONCLUSIONS: The sense of meaning in life in the oldest old was linked to regarding oneself as having a mission to carry out and to finding beauty, joy and happiness in life. The sense of meaning involved transferring to coming generations what earlier generations had left and having a deeply rooted faith in being taken care of from birth to the afterlife. IMPLICATIONS FOR PRACTICE: When caring for the oldest old, it is important to take their experiences of sense of meaning in life into consideration and to focus on ways to maintain important sources of meaning in life. PMID- 25516074 TI - Response of growth and photosynthesis of Emiliania huxleyi to visible and UV irradiances under different light regimes. AB - Microalgae are capable of acclimating to changes in light and ultraviolet radiation (UVR, 280-400 nm). However, little is known about how the ecologically important coccolithophore Emiliania huxleyi responds to UVR when acclimated to different light regimes. Here, we grew E. huxleyi under indoor constant light or fluctuating sunlight with or without UVR, and investigated its growth, photosynthetic performance and pigmentation. Under the indoor constant light regime, the specific growth rate (MU) was highest, while fluctuating outdoor solar radiation significantly decreased the growth rate. Addition of UVR further decreased the growth rate. The repair rate of photosystem II (PSII), as reflected in changes in PSII quantum yield, showed an inverse correlation with growth rate. Cells grown under the indoor constant light regime exhibited the lowest repair rate, while cells from the outdoor fluctuating light regimes significantly increased their repair rate. Addition of UVR increased both the repair rate and intracellular UV-absorbing compounds. This increased repair capability, at the cost of decreased growth rate, persisted after the cells were transferred back to the indoor again, suggesting an enhanced allocation of energy and resources for repair of photosynthetic machinery damage by solar UVR which persisted for a period after transfer from solar UVR. PMID- 25516073 TI - Effect of patient navigation on colorectal cancer screening in a community-based randomized controlled trial of urban African American adults. AB - PURPOSE: In recent years, colorectal cancer (CRC) screening rates have increased steadily in the USA, though racial and ethnic disparities persist. In a community based randomized controlled trial, we investigated the effect of patient navigation on increasing CRC screening adherence among older African Americans. METHODS: Participants in the Cancer Prevention and Treatment Demonstration were randomized to either the control group, receiving only printed educational materials (PEM), or the intervention arm where they were assigned a patient navigator in addition to PEM. Navigators assisted participants with identifying and overcoming screening barriers. Logistic regression analyses were used to assess the effect of patient navigation on CRC screening adherence. Up-to-date with screening was defined as self-reported receipt of colonoscopy/sigmoidoscopy in the previous 10 years or fecal occult blood testing (FOBT) in the year prior to the exit interview. RESULTS: Compared with controls, the intervention group was more likely to report being up-to-date with CRC screening at the exit interview (OR 1.55, 95 % CI 1.07-2.23), after adjusting for select demographics. When examining the screening modalities separately, the patient navigator increased screening for colonoscopy/sigmoidoscopy (OR 1.53, 95 % CI 1.07-2.19), but not FOBT screening. Analyses of moderation revealed stronger effects of navigation among participants 65-69 years and those with an adequate health literacy level. CONCLUSIONS: In a population of older African Americans adults, patient navigation was effective in increasing the likelihood of CRC screening. However, more intensive navigation may be necessary for adults over 70 years and individuals with low literacy levels. PMID- 25516076 TI - Post-herpetic eosinophilic papules and plaques. PMID- 25516077 TI - A longitudinal comparison of retention in buprenorphine and methadone treatment for opioid dependence in New South Wales, Australia. AB - BACKGROUND AND AIMS: To examine characteristics of first-time methadone and buprenorphine clients and factors associated with risk of leaving first treatment in New South Wales (NSW), Australia. DESIGN: Retrospective linkage study of opioid substitution therapy (OST) treatment, court, custody and mortality data. SETTING: NSW, Australia. PARTICIPANTS: First-time OST entrants (August 2001 December 2010). MEASUREMENTS: Characteristics of clients were examined. Time dependent Cox models examined factors associated with the risk of leaving first treatment, with demographic, criminographic and treatment variables jointly considered. Interactions between medication and other variables upon risk of leaving treatment were examined. FINDINGS: There were 15 600 treatment entrants: 7183 (46%) commenced buprenorphine, 8417 (54%) commenced methadone; the proportion entering buprenorphine increased over time. Those starting buprenorphine switched medications more frequently and had more subsequent treatment episodes. Buprenorphine retention was also poorer. On average, 44% spent 3+ months in treatment compared with 70% of those commencing methadone; however, buprenorphine retention for first-time entrants improved over time, whereas methadone retention did not. Multivariable Cox models indicated that in addition to sex, age, treatment setting and criminographic variables, the risk of leaving a first treatment episode was greater on any given day for those receiving buprenorphine, and was dependent on the year treatment was initiated. There was no interaction between any demographic variables and medication received, suggesting no clear evidence of any particular groups for whom each medication might be better suited in terms of improving retention. CONCLUSIONS: Although retention rates for buprenorphine treatment have improved in New South Wales, Australia, individuals starting methadone treatment still show higher retention rates. PMID- 25516079 TI - Potential risk of monochorionic dizygotic twin blastocyst formation associated with early laser zona dissection of group cultured embryos. AB - OBJECTIVE: To document the risk of in vitro monochorionic dizygotic twin formation in the implementation of a program of blastocyst biopsy with preimplantation genetic screening (PGS). DESIGN: Case report. SETTING: Private infertility laboratory. PATIENT(S): Prospective PGS patients with intracytoplasmic sperm injection-derived, group-cultured blastocysts over a 3 year period. INTERVENTION(S): Group culture in Global medium (Life Global) to optimize blastocyst formation of zygotes produced for blastocyst biopsy for PGS (n <= 8 embryos/25 MUL droplet), and laser zona dissection (LZD) of all day-3 cleaved embryos to promote pre-expansion trophectodermal extrusion at the blastocyst stage (i.e., premature hatching). MAIN OUTCOME MEASURE(S): Blastocyst formation and quality grading on days 5 and 6 of in vitro culture for the vitrified embryo transfer of single or dual euploid blastocysts. RESULT(S): Over 3,000 blastocysts were produced in vitro. On two separate occasions, complete trophectodermal amalgamation was observed between two hatching blastocysts. Vitrified single-euploid blastocyst transfers efficiently implanted and established clinical pregnancies similar to dual-euploid blastocyst transfers, without the risk of twin formation. CONCLUSION(S): The amazing occurrence of monochorionic dizygotic twin formation has now been documented in vitro, supporting the theory that assisted reproductive technology may facilitate this rare perinatal condition. Furthermore, we have provided clinical evidence that the transfer of a single-euploid blastocyst can optimize a patient's pregnancy success while reducing potentially undesirable conditions associated with monochorionic twin pregnancies. PMID- 25516078 TI - International committee for monitoring assisted reproductive technologies: world report on assisted reproductive technologies, 2007. AB - OBJECTIVE: To analyze information on assisted reproductive technology (ART) performed worldwide, and trends in outcomes over successive years. DESIGN: Cross sectional survey on access, efficiency, and safety of ART procedures performed in 55 countries during 2007. SETTING: Not applicable. PATIENT(S): Infertile women and men undergoing ART globally. INTERVENTION(S): Collection and analysis of international ART data. MAIN OUTCOME MEASURE(S): Number of cycles performed, by country and region, including pregnancies, single and multiple birth rates, and perinatal mortality. RESULT(S): Overall, >1,251,881 procedures with ART were reported, and resulted in 229,442 reported babies born. The availability of ART varied by country, from 12 to 4,140 treatments per million population. Of all aspiration cycles, 65.2% (400,617 of 614,540) were intracytoplasmic sperm injection. The overall delivery rate per fresh aspiration was 20.3%, and for frozen-embryo transfer (FET), 18.4%, with a cumulative delivery rate of 25.8%. With wide regional variations, single-embryo transfer represented 23.4% of fresh transfers, and the proportion of deliveries with twins and triplets from fresh transfers was 22.3% and 1.2%, respectively. The perinatal mortality rate was 19.9 per 1,000 births for fresh in vitro fertilization using intracytoplasmic sperm injection, and 9.6 per 1,000 for FET. The proportion of women aged >=40 years increased to 19.8% from 15.5% in 2006. CONCLUSION(S): The international trend toward <3 transferred embryos continued, as did the wider uptake of FET. This was achieved without compromising delivery rates. The application of ART for women aged >40 years was a major component of ART services in some regions and countries. PMID- 25516080 TI - Endometriosis may be associated with mitochondrial dysfunction in cumulus cells from subjects undergoing in vitro fertilization-intracytoplasmic sperm injection, as reflected by decreased adenosine triphosphate production. AB - OBJECTIVE: To determine whether endometriosis is associated with mitochondrial dysfunction in cumulus (granulosa [GC]) cells of subjects undergoing IVF intracytoplasmic sperm injection (ICSI). DESIGN: Prospective cohort study. SETTING: An IVF clinic in a tertiary academic care center. PATIENT(S): Eleven women with endometriosis and 39 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cumulus cell adenosine triphosphate (ATP) levels, mitochondrial DNA (mtDNA), and genomic DNA (gDNA) number. RESULT(S): Cumulus cell ATP content was 65% lower in subjects with surgically proven endometriosis (median 312.5 attomoles/ng total DNA, interquartile range = 116.0-667.8) compared with controls (median 892.4 attomoles/ng total DNA, interquartile range = 403.0-1,412.2). There was no significant difference in mtDNA:gDNA ratio. There were no significant differences in age, body mass index (BMI), basal serum FSH level, total oocyte number, metaphase II (M2) oocyte number, metaphase I oocyte number, percentage of M2 oocytes, fertilization rate, implantation rate, or pregnancy rate (PR). Multivariate regression analysis showed significant positive correlations between ATP and [1] M2 oocyte number (r = 0.307) and [2] pregnancy (r = 0.332). There were also trends toward positive correlations between ATP and [3] age (r = 0.283), [4] total number of oocytes (r = 0.271), [5] percentage of M2 oocytes (r = 0.249), and [6] implantation rate (r = 0.293). There were no statistically significant correlations between mtDNA:gDNA ratio and any demographic factors or clinical outcomes measured. CONCLUSION(S): Surgically confirmed endometriosis may be associated with cumulus cell mitochondrial dysfunction in subjects undergoing IVF-ICSI for infertility, as reflected by decreased ATP production. PMID- 25516081 TI - Longitudinal assessment of circulating insulin-like peptide 3 levels in healthy peripubertal girls. AB - OBJECTIVE: To elucidate the natural course of circulating insulin-like peptide 3 (INSL3) levels according to puberty as well as its relation to other reproductive hormones. DESIGN: Population-based cohort study. SETTING: Not applicable. PATIENT(S): Healthy peripubertal girls (n = 10) examined every 6 months; total number of examinations was 84; median (range) per girl: 9 (4-10), including staging of pubertal breast development and blood samples. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum levels of INSL3, inhibin B, E2, antimullerian hormone, LH, and FSH (validated immunoassays), and T and androstenedione (liquid chromatography-tandem mass spectrometry). RESULT(S): Serum levels of INSL3 varied considerably between girls (range, 0.01-0.27 ng/mL) and within each girl as puberty progressed; intraindividual variation, median (range) 102% (65%-143%). Insulin-like peptide 3 increased in late puberty (B1 to B4+B5); geometric mean 0.03 ng/mL to 0.15 ng/mL. Insulin-like peptide 3 levels reflected markers of large follicles (T, androstendione, inhibin B, and E2) better than markers of small follicles (antimullerian hormone), and INSL3 staining was localized in theca interna cells of antral follicles. CONCLUSION(S): Insulin-like peptide 3 increased in late puberty, albeit inter- and intraindividual variations were substantial. Immunohistochemistry and intraindividual variation, as well as relations to other ovarian hormones, reveal that INSL3 in girls is a unique and specific marker of theca cells surrounding antral follicles. The potential clinical use of INSL3 for evaluation of ovarian function in girls remains to be elucidated. PMID- 25516082 TI - Benzo(a)pyrene disrupts mouse preimplantation embryo development. AB - OBJECTIVE: To determine the effects of Benzo(a)pyrene (BaP) on the development of early preimplantation embryo by exposure to physiologic concentrations of BaP based on a previous report in human ovarian follicular fluid and serum. DESIGN: Zygotes were cultured in 5 nM or 50 nM BaP and then examined for development efficiency, embryo quality, and DNA damage. In addition, embryonic stem cells (ESCs) were used as a model to test the toxic effects of BaP on inner cell mass (ICM) of blastocysts. SETTING: Laboratory. ANIMAL(S): CD1 mice. INTERVENTION(S): Mouse zygotes and ESCs were cultured in medium with 5 nM or 50 nM BaP. MAIN OUTCOME MEASURE(S): The percentage (rate) of blastocyst development, reactive oxygen species level, and quality of embryos assessed by total cell number, cell apoptosis, Oct4- and Nanog-positive cell ratio, and DNA damage on genomic and telomeric DNA were compared between dimethyl sulfoxide control and BaP treatments. RESULT(S): The BaP-treated zygotes exhibited significantly higher reactive oxygen species activity, which might lead to more cell apoptosis, low ratio of Nanog- or Oct4-positive ICM cells, and increasing DNA damage in both genomic and telomeric DNA in blastocysts. By using mouse ESCs derived from ICM cells as a model, we showed that pluripotent cells might also show serious DNA damage after a brief exposure to BaP. CONCLUSION(S): Our data show that BaP could seriously disrupt cell growth and genomic DNA stability and increase cell apoptosis in mouse preimplantation embryo development. PMID- 25516083 TI - Live birth in a 50-year-old woman following in vitro fertilization-embryo transfer with autologous oocytes: a rare case report. AB - OBJECTIVE: To report a live birth with in vitro fertilization (IVF) from a 50 year-old woman with homologous oocytes. DESIGN: Case report. SETTING: Referral center. PATIENT(S): A 50-year-old woman. INTERVENTION(S): IVF with fresh embryo transfer (ET). MAIN OUTCOME MEASURE(S): Live birth after IVF. RESULT(S): A 50 year-old woman conceived with her own oocytes by means of IVF. Three fresh embryos were transferred, resulting in a pregnancy and delivery by cesarean section at 35 weeks of a healthy male baby weighing 2,300 g. CONCLUSION(S): Extensive literature search suggests that this is the first case report of live birth in a 50-year-old woman after IVF-ET with her own oocytes. This is a very rare and unusual case that deviates from the norm and therefore warrants attention. In selected cases, assisted reproductive technology might be reasonable to try for a limited number of times with a woman's own oocytes. PMID- 25516085 TI - First systematic experience of preimplantation genetic diagnosis for single-gene disorders, and/or preimplantation human leukocyte antigen typing, combined with 24-chromosome aneuploidy testing. AB - OBJECTIVE: To study the feasibility, accuracy, and reproductive outcome of 24 chromosome aneuploidy testing (24-AT), combined with preimplantation genetic diagnosis (PGD) for single-gene disorders (SGDs) or human leukocyte antigen (HLA) typing in the same biopsy sample. DESIGN: Retrospective study. SETTING: Preimplantation genetic diagnosis center. PATIENT(S): A total of 238 PGD patients, average age 36.8 years, for whom 317 combined PGD cycles were performed, involving 105 different conditions, with or without HLA typing. INTERVENTION(S): Whole-genome amplification product, obtained in 24-AT, was used for PGD and/or HLA typing in the same blastomere or blastocyst biopsy samples. MAIN OUTCOME MEASURE(S): Proportion of the embryos suitable for transfer detected in these blastomere or blastocyst samples, and the resulting pregnancy and spontaneous abortion rates. RESULT(S): Embryos suitable for transfer were detected in 42% blastocyst and 25.1% blastomere samples, with a total of 280 unaffected, HLA-matched euploid embryos detected for transfer in 212 cycles (1.3 embryos per transfer), resulting in 145 (68.4%) unaffected pregnancies and birth of 149 healthy, HLA-matched children. This outcome is significantly different from that of our 2,064 PGD cycle series without concomitant 24-AT, including improved pregnancy (68.4% vs. 45.4%) and 3-fold spontaneous abortion reduction (5.5% vs. 15%) rates. CONCLUSION(S): The introduced combined approach is a potential universal PGD test, which in addition to achieving extremely high diagnostic accuracy, significantly improves reproductive outcomes of PGD for SGDs and HLA typing in patients of advanced reproductive age. PMID- 25516084 TI - Induction of proteinases in the human preovulatory follicle of the menstrual cycle by human chorionic gonadotropin. AB - OBJECTIVE: To explore the temporal expression in granulosa and theca cells of key members of the MMP and ADAMTS families across the periovulatory period in women to gain insight into their possible roles during ovulation and early luteinization. DESIGN: Experimental prospective clinical study and laboratory based investigation. SETTING: University medical center and private IVF center. ANIMAL AND PATIENT(S): Thirty-eight premenopausal women undergoing surgery for tubal ligation and six premenopausal women undergoing assisted reproductive techniques. INTERVENTION(S): Administration of hCG and harvesting of follicles by laparoscopy and collection of granulosa-lutein cells at oocyte retrieval. MAIN OUTCOME MEASURE(S): Expression of mRNA for matrix metalloproteinase (MMPs) and the A disintegrin and metalloproteinase with thrombospondin-like motifs (ADAMTS) in human granulosa cells and theca cells collected across the periovulatory period of the menstrual cycle and in cultured granulosa-lutein cells after hCG. Localization of MMPs and ADAMTSs by immunohistochemistry. RESULT(S): Expression of MMP1 and MMP19 mRNA increased in both granulosa and theca cells after hCG administration. ADAMTS1 and ADAMTS9 mRNA increased in granulosa cells after hCG treatment, however, thecal cell expression for ADAMTS1 was unchanged, while ADAMTS9 expression was decreased. Expression of MMP8 and MMP13 mRNA was unchanged. Immunohistochemistry confirmed the localization of MMP1, MMP19, ADAMTS1, and ADAMTS9 to the granulosa and thecal cell layers. CONCLUSION(S): The collection of the dominant follicle throughout the periovulatory period has allowed the identification of proteolytic remodeling enzymes in the granulosa and theca compartments that may be critically involved in human ovulation. These proteinases may work in concert to regulate breakdown of the follicular wall and release of the oocyte. PMID- 25516086 TI - Development of an LC-MS/MS method for determining the pharmacokinetics of clonidine following oral administration of Zhenju antihypertensive compound. AB - Zhenju antihypertensive compound (ZJAHC) is a combined Chinese-Western medicine formula including clonidine (CLO), hydrochlorothiazide (HCT), rutin, Chrysanthemum indicum extract and pearl powder. Compared with CLO preparations, ZJAHC shows improved activities and decreased adverse effects. It is believed that the side effects of CLO are caused by its high peak plasma concentration. Hence, study of the influence of ZJAHC on the pharmacokinetic behaviors of clonidine seems essential. In present study, the plasma concentrations of CLO were determined with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The MS/MS transitions monitored for clonidine and internal standard were 230.2 -> 213.1 and 152.2 -> 110.2, respectively. The analyte was quantified in a single run within 3 min. The pharmacokinetic study showed that the area under the plasma concentration-time curve of CLO in ZJAHC (60 ug/kg CLO) was similar to that of CLO-HCT-high (120 ug/kg CLO) but the peak concentration was much lower than that in CLO-HCT-high. ZJAHC could enhance the bioavailability without greatly increasing peak concentration of clonidine. This comprehensive effect of enhancing the bioavailability and avoiding the high peak plasma concentration for CLO might mainly result from the co-contribution of Western medicine and traditional Chinese medicine (TCM), while the effect of TCM was stronger than that of Western medicine. PMID- 25516088 TI - Ten things you should consider before you believe a clinical practice guideline. PMID- 25516089 TI - Performance and interpretation of spirometry among Swedish hospitals. AB - BACKGROUND AND AIMS: It is unclear to what extent spirometric performance and interpretation is standardized in Sweden. The aim of this study was to find out how spirometry is performed and interpreted in large Swedish hospitals. METHODS: In telephone interviews, technicians and physicians working with lung function measurements at 21 large Swedish hospitals were interviewed about routines for spirometry. RESULTS: Answers were obtained from 37 of the 42 departments contacted revealing differences in the spirometric routines. Some departments lack a written method description, and three different prediction equations were used among the departments. Different ways of calculating the forced expiratory volume in 1 s (FEV1)/vital capacity (VC) ratio (FEV%) were found and also differences in performance and interpretation of the reversibility test. When diagnosing chronic obstructive pulmonary disease, none of the departments reported using an individualized diagnostic limit of FEV1/VC based on age, sex and height. CONCLUSION: There is a need for standardization of performance and interpretation of the spirometry test in Sweden and probably also in other countries. PMID- 25516087 TI - Incidence and impact of skin mottling over the knee and its duration on outcome in critically ill patients. AB - PURPOSE: Skin mottling is frequent and can be associated with an increased mortality rate in ICU patients with septic shock. Its overall incidence in ICU and its impact on outcome is unknown. We aimed to assess the incidence of skin mottling over the knee among all critically ill patients admitted in ICU and its role on their outcome. METHODS: An observational study over a 1-year period in a 15-bed medical ICU of a teaching hospital. Skin mottling over the knee was prospectively and qualitatively assessed by trained nurses. RESULTS: Incidence of skin mottling was 29% (230 of 791 patients) in overall, and 49% (32 of 65 patients) in the subset of patients admitted for septic shock. Skin mottling was present on the day on admission in 65% of patients and persisted more than 6 h in 59% of cases. In-ICU mortality was 8% in patients without mottling, 30% in patients with short skin mottling and 40% in patients with persistent skin mottling (p < 0.01 between all groups). In the overall population, skin mottling over the knee was associated with in-ICU mortality independently from SAPS II (aOR 3.29 [95% CI, 2.08-5.19], p < 0.0001). Among patients with skin mottling over the knee, persistence of skin mottling remained associated with increased in ICU mortality independently of organ dysfunctions at the mottling onset (OR 2.77 [95% CI, 1.34-5.72], p = 0.004). CONCLUSIONS: Skin mottling is frequent in the general population of patients admitted in ICU. Occurrence and persistence of skin mottling are independently associated with in-ICU mortality. PMID- 25516090 TI - YAP immunoreactivity is directly related to pilomatrixoma size and proliferation rate. AB - Organ size regulation is a highly coordinated process involving complex mechanisms. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif, also known as WWTR1 (TAZ) have recently been linked to organ size determination and cell proliferation. Pilomatrixoma (PM) is a benign tumor of the adnexal appendages with a certain degree of differentiation toward the matrix of the hair follicle. PM presents as a dermal nodule that usually ranges from 0.5 to 2 cm, rarely exceeding 3 cm. We recently observed a case of unusual "giant" (6.5 cm) PM. Our hypothesis was that YAP and TAZ could be related to PM growth. We analyzed YAP and TAZ immunohistochemical expression in the giant and in ten usual size PMs in relation with tumor size and proliferation rate. YAP nuclear expression was remarkably higher in the giant PM in comparison with usual size PMs and statistically correlated, in a direct manner, with size and proliferation rate of PMs. Contrariwise, TAZ nuclear expression seemed stochastic. Our findings suggest that YAP could play a role in PM growth. PMID- 25516091 TI - Efficacy of intranasal administration of artesunate in experimental cerebral malaria. AB - BACKGROUND: Improving management of patients suffering from cerebral malaria is needed to reduce the devastating mortality and morbidity of the disease in endemic areas. Intravenous artesunate is currently the first-line treatment, but the lack of material and skills in the field make it difficult to implement in endemic areas. Intranasal route provides a very easy and direct gateway to blood and brain to deliver medications, by-passing the brain blood barrier. Therefore, it could be helpful and suitable to administer artesunate in the context of cerebral malaria, especially in young children. In this study, intranasal administration of artesunate to rescue from cerebral malaria using a murine model was tested. METHODS: CBA/J mice infected with Plasmodium berghei ANKA strain received artesunate (20 mg/kg) or a placebo solution intranasally, either on day 5, 6 or 7 post-infection, during a controlled, blinded, randomized trial. Primary endpoint was mortality on day 12 post-infection. Secondary endpoints were parasitaemia and clinical stage. Pharmacokinetics data following administration were collected in blood and brains of treated mice. Local toxicity was evaluated by histopathologic examination of brain and nasal sections in blinded manner. RESULTS: Intranasal administration of artesunate dramatically reduced the mortality rate (p < 0.001), preventing death in most cases. Parasitaemia loads decreased by 88.7% (61.8-100%) within 24 hours after administration. Symptoms of cerebral malaria were prevented or reversed. Dihydroartemisinin was detected in mice blood and brain within 15 minutes of intranasal administration. No direct nasal or brain toxicity was detected. CONCLUSION: Intranasal delivery is an efficient route to timely and efficiently administer artesunate and therefore may contribute to decreasing malaria-related mortality. PMID- 25516093 TI - Cranial dural arteriovenous shunts. Part 3. Classification based on the leptomeningeal venous drainage. AB - The commonly used Borden and Cognard classification systems for the prediction of clinical behavior of cranial dural arteriovenous shunts focus on the venous drainage, particularly the presence of leptomeningeal venous drainage, and on the direction of flow, particularly the presence of retrograde flow. In addition, the latter includes ectasia and spinal drainage as criteria of two distinct grades. However, none of the above classifications (a) differentiates direct from exclusive leptomeningeal venous drainage, (b) considers cortical venous congestion as a factor potentially associated with an aggressive clinical course, and (c) anticipates ectasia in shunts with a mixed dural-cortical venous drainage (type 2). In this study, we analyzed the angiographic images of 107 consecutive patients having a cranial dural arteriovenous fistula with leptomeningeal venous drainage, based on a newly developed scheme. This scheme, symbolized with the acronym "DES," groups the dural shunts according to three factors: directness and exclusivity of leptomeningeal venous drainage and signs of venous strain. According to the combination of the three factors, eight different groups were distinguished. All analyzed cases could be assigned to one of these groups. Directness of leptomeningeal venous drainage expresses the exact site of the shunt (bridging vein vs sinus wall), whereas exclusivity expresses venous outlet restrictions. All bridging vein shunts had a direct leptomeningeal venous drainage. Almost all bridging vein shunts and all "isolated" sinus shunts had an exclusive leptomeningeal venous drainage. Venous strain, manifested as ectasia and/or congestion, denotes the decompensation of the cerebral venous system due to the shunt reflux. The comparison of the presented concept with the currently used classifications highlighted the advantages of the former and the weaknesses of the latter. PMID- 25516094 TI - da Vinci robot-assisted keyhole neurosurgery: a cadaver study on feasibility and safety. AB - The goal of this cadaver study was to evaluate the feasibility and safety of da Vinci robot-assisted keyhole neurosurgery. Several keyhole craniotomies were fashioned including supraorbital subfrontal, retrosigmoid and supracerebellar infratentorial. In each case, a simple durotomy was performed, and the flap was retracted. The da Vinci surgical system was then used to perform arachnoid dissection towards the deep-seated intracranial cisterns. It was not possible to simultaneously pass the 12-mm endoscope and instruments through the keyhole craniotomy in any of the approaches performed, limiting visualization. The articulated instruments provided greater dexterity than existing tools, but the instrument arms could not be placed in parallel through the keyhole craniotomy and, therefore, could not be advanced to the deep cisterns without significant clashing. The da Vinci console offered considerable ergonomic advantages over the existing operating room arrangement, allowing the operating surgeon to remain non sterile and seated comfortably throughout the procedure. However, the lack of haptic feedback was a notable limitation. In conclusion, while robotic platforms have the potential to greatly enhance the performance of transcranial approaches, there is strong justification for research into next-generation robots, better suited to keyhole neurosurgery. PMID- 25516095 TI - The extracellular N-terminal domain of G-protein coupled receptor 83 regulates signaling properties and is an intramolecular inverse agonist. AB - BACKGROUND: Recently, the orphan G-protein coupled receptor 83 (GPR83) was identified as a new participant in body weight regulation. This receptor is highly expressed in the hypothalamic arcuate nucleus and is regulated in response to nutrient availability. Gpr83 knock-out mice are protected from diet-induced obesity. Moreover, in a previous study, we designed and characterized several artificial constitutively activating mutations (CAMs) in GPR83. A particular CAM was located in the extracellular N-terminal domain (eNDo) that is highly conserved among GPR83 orthologs. This suggests the contribution of this receptor part into regulation of signaling, which needed a more detailed investigation. FINDINGS: In this present study, therefore, we further explored the role of the eNDo in regulating GPR83-signaling and demonstrate a proof-of-principle approach in that deletion mutants are characterized by a strong increase in basal Gq/11 mediated signaling, whilst none of the additionally characterized signaling pathways (Gs, Gi, G12/13) were activated by the N-terminal deletion variants. Of note, we detected basal GPR83 MAPK-activity of the wild type receptor, which was not increased in the deletion variants. CONCLUSIONS: Finally, the extracellular portion of GPR83 has a strong regulatory function on this receptor. A suppressive - inverse agonistic - effect of the eNDo on GPR83 signaling activity is demonstrated here, which also suggests a putative link between extracellular receptor activation and proteolytic cleavage. These new insights highlight important aspects of GPR83-regulation and might open options in the development of tools to modulate GPR83-signaling. PMID- 25516096 TI - Perfluorooctanoic acid binds to peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation in 3T3-L1 adipocytes. AB - We examined the effect of perfluorooctanoic acid (PFOA) on adipose cells using 3T3-L1 adipocytes and found that PFOA increased adipocyte differentiation, triglyceride accumulation, and the mRNA level of factors related to adipocyte differentiation. In addition, PFOA bound to peroxisome proliferator-activated receptor gamma (PPAR gamma). These results suggest that PFOA promotes adipocyte differentiation as a PPAR gamma ligand. PMID- 25516097 TI - Controversies surrounding critical illness-related corticosteroid insufficiency in animals. AB - OBJECTIVES: To describe the controversies surrounding critical illness-related corticosteroid insufficiency (CIRCI) and the use of hydrocortisone in critically ill patients, and to present published diagnostic and therapeutic strategies in companion veterinary species. ETIOLOGY: Critical illness-related corticosteroid insufficiency may be due to hypothalamic-pituitary-adrenal (HPA) axis dysfunction, alterations in cortisol-plasma protein binding, target cell enzymatic changes, changes in glucocorticoid receptor (GR) function, or a combination of these or other factors present during critical illness. DIAGNOSIS: Appropriate tests to diagnose CIRCI are unknown. The diagnosis in people is currently based on response to treatment with hydrocortisone. There is currently no consensus on appropriate diagnostic feature(s) in veterinary species. THERAPY: Low-dose hydrocortisone is the treatment of choice for patients with CIRCI. PROGNOSIS: If the patient survives the critical illness, prognosis for resolution of CIRCI and hydrocortisone dependence is very good. PMID- 25516098 TI - Bovine serum albumin in saliva mediates grazing response in Leymus chinensis revealed by RNA sequencing. AB - BACKGROUND: Sheepgrass (Leymus chinensis) is an important perennial forage grass across the Eurasian Steppe and is adaptable to various environmental conditions, but little is known about its molecular mechanism responding to grazing and BSA deposition. Because it has a large genome, RNA sequencing is expensive and impractical except for the next-generation sequencing (NGS) technology. RESULTS: In this study, NGS technology was employed to characterize de novo the transcriptome of sheepgrass after defoliation and grazing treatments and to identify differentially expressed genes (DEGs) responding to grazing and BSA deposition. We assembled more than 47 M high-quality reads into 120,426 contigs from seven sequenced libraries. Based on the assembled transcriptome, we detected 2,002 DEGs responding to BSA deposition during grazing. Enrichment analysis of Gene ontology (GO), EuKaryotic Orthologous Groups (KOG) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that the effects of grazing and BSA deposition involved more apoptosis and cell oxidative changes compared to defoliation. Analysis of DNA fragments, cell oxidative factors and the lengths of leaf scars after grazing provided physiological and morphological evidence that BSA deposition during grazing alters the oxidative and apoptotic status of cells. CONCLUSIONS: This research greatly enriches sheepgrass transcriptome resources and grazing-stress-related genes, helping us to better understand the molecular mechanism of grazing in sheepgrass. The grazing-stress-related genes and pathways will be a valuable resource for further gene-phenotype studies. PMID- 25516099 TI - Evaluation of (99m)Tc-HYNIC-TMTP1 as a tumor-homing imaging agent targeting metastasis with SPECT. AB - INTRODUCTION: TMTP1 (NVVRQ) is a novel tumor-homing peptide, which specifically targets tumor metastases, even at the early stage of occult metastasis foci. Fusing TMTP1 to therapeutic peptides or proteins can increase its anti-cancer efficacy both in vivo and in vitro. Here, we labeled TMTP1 with (99m)Tc to evaluate its targeting properties in an ovarian cancer xenograft tumor mouse model and a gastric cancer xenograft mouse model. METHODS: The invasion ability of SKOV3 and highly metastatic SKOV3.ip cell lines were performed by the Transwell Invasion Assays, and then Rhodamine-TMTP1 was used to detect its affinity to these two cells. Using the co-ligand ethylenediamine-N, N'-diacetic acid (EDDA) and the bifunctional chelator 6-hydrazinonicotinic acid (HYNIC), the TMTP1 peptide was labeled with (99m)Tc. A cell-binding assay was performed by incubating cancer cells with (99m)Tc-HYNIC-TMTP1 with or without an excess dose of cold HYNIC-TMTP1. To evaluate the probe in vivo, nude mice bearing SKOV3, SKOV3.ip and MNK-45 tumor cells were established and subjected to SPECT imaging after injection with (99m)Tc-HYNIC-TMTP1. Ex vivo gamma-counting of dissected tissues from the mice was used to evaluate its biodistribution. RESULTS: (99m)Tc HYNIC-TMTP1 was successfully synthesized. The radiotracer also exhibited high hydrophilicity and excellent stability in vitro and in vivo. It has strong affinity to highly metastatic cancer cell lines but not to poorly metastatic cell lines. After mice were injected with (99m)Tc-HYNIC-TMTP1, non-invasive SPECT imaging detected SKOV3.ip and MNK-45 xenograft tumors but not SKOV3 xenograft tumors. This result can be inhibited by excess HYNIC-TMTP1. The uptake of (99m)Tc HYNIC-TMTP1 in SKOV3.ip xenograft tumors was 0.182+/-0.017% ID/g at 2h p.i. with high renal uptake (74.32+/-15.05% ID/g at 2h p.i.). CONCLUSION: (99m)Tc-HYNIC TMTP1 biodistribution and SPECT imaging demonstrated its ability to target highly metastatic tumors. Therefore, metastasis can be non-invasively investigated by SPECT imaging using (99m)Tc-HYNIC-TMTP1. Meanwhile, this radiotracer has some shortages in the low % ID/g of tumors and high accumulation in the kidney. PMID- 25516102 TI - In Vitro Assessment of Re-treatment Options for Patients with Hepatitis C Virus Genotype 1b Infection Resistant to Daclatasvir Plus Asunaprevir. AB - INTRODUCTION: Daclatasvir is a non-structural protein 5A (NS5A) inhibitor with activity against hepatitis C virus (HCV) genotypes 1-6 in vitro, and asunaprevir is a non-structural protein 3 (NS3) protease inhibitor with activity against genotypes 1, 4, 5, and 6. This study evaluates potential options for the re treatment of HCV genotype 1b-infected patients who have failed combination therapy with daclatasvir plus asunaprevir. METHODS: The antiviral activity of drug combination regimens in HCV subgenomic replicon cell lines representing genotype 1b (Con1 strain) wild-type or a variant with specific NS5A and NS3 amino acid substitutions conferring resistance to daclatasvir and asunaprevir were compared using replicon elimination assays. Drug concentrations representing multiple 50% effective concentrations (EC50) derived in vitro and trough plasma concentrations observed in a clinical setting were utilized. RESULTS: At multiple EC50 values of each drug (3*, 10*, and 30* EC50), combinations of daclatasvir plus sofosbuvir, sofosbuvir plus ledipasvir, sofosbuvir plus simeprevir, and sofosbuvir plus either a next-generation NS3 or NS5A inhibitor demonstrated comparable activity in wild-type and daclatasvir/asunaprevir-resistant cell lines. At clinically relevant drug trough concentrations, combination regimens of daclatasvir plus asunaprevir plus beclabuvir (+/-ribavirin), and daclatasvir plus asunaprevir plus beclabuvir plus sofosbuvir efficiently cleared daclatasvir + asunaprevir-resistant replicons from cells within 5 days of treatment. CONCLUSION: Our in vitro results highlight a number of potential all-oral treatment options for patients who do not achieve a sustained virologic response following therapy with daclatasvir plus asunaprevir. These results require further evaluation in clinical studies. PMID- 25516101 TI - Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering. AB - Although epilepsy is associated with a variety of abnormalities, exactly why some brain regions produce seizures and others do not is not known. We developed a method to identify cellular changes in human epileptic neocortex using transcriptional clustering. A paired analysis of high and low spiking tissues recorded in vivo from 15 patients predicted 11 cell-specific changes together with their 'cellular interactome'. These predictions were validated histologically revealing millimetre-sized 'microlesions' together with a global increase in vascularity and microglia. Microlesions were easily identified in deeper cortical layers using the neuronal marker NeuN, showed a marked reduction in neuronal processes, and were associated with nearby activation of MAPK/CREB signalling, a marker of epileptic activity, in superficial layers. Microlesions constitute a common, undiscovered layer-specific abnormality of neuronal connectivity in human neocortex that may be responsible for many 'non-lesional' forms of epilepsy. The transcriptional clustering approach used here could be applied more broadly to predict cellular differences in other brain and complex tissue disorders. PMID- 25516103 TI - Multiple sulfatase deficiency with neonatal manifestation. AB - Multiple Sulfatase Deficiency (MSD; OMIM 272200) is a rare autosomal recessive inborn error of metabolism caused by mutations in the sulfatase modifying factor 1 gene, encoding the formylglycine-generating enzyme (FGE), and resulting in tissue accumulation of sulfatides, sulphated glycosaminoglycans, sphingolipids and steroid sulfates. Less than 50 cases have been published so far. We report a new case of MSD presenting in the newborn period with hypotonia, apnoea, cyanosis and rolling eyes, hepato-splenomegaly and deafness. This patient was compound heterozygous for two so far undescribed SUMF1 mutations (c.191C > A; p.S64X and c.818A > G; p.D273G). PMID- 25516092 TI - Characteristics and comprehensiveness of adult HIV care and treatment programmes in Asia-Pacific, sub-Saharan Africa and the Americas: results of a site assessment conducted by the International epidemiologic Databases to Evaluate AIDS (IeDEA) Collaboration. AB - INTRODUCTION: HIV care and treatment programmes worldwide are transforming as they push to deliver universal access to essential prevention, care and treatment services to persons living with HIV and their communities. The characteristics and capacity of these HIV programmes affect patient outcomes and quality of care. Despite the importance of ensuring optimal outcomes, few studies have addressed the capacity of HIV programmes to deliver comprehensive care. We sought to describe such capacity in HIV programmes in seven regions worldwide. METHODS: Staff from 128 sites in 41 countries participating in the International epidemiologic Databases to Evaluate AIDS completed a site survey from 2009 to 2010, including sites in the Asia-Pacific region (n=20), Latin America and the Caribbean (n=7), North America (n=7), Central Africa (n=12), East Africa (n=51), Southern Africa (n=16) and West Africa (n=15). We computed a measure of the comprehensiveness of care based on seven World Health Organization-recommended essential HIV services. RESULTS: Most sites reported serving urban (61%; region range (rr): 33-100%) and both adult and paediatric populations (77%; rr: 29-96%). Only 45% of HIV clinics that reported treating children had paediatricians on staff. As for the seven essential services, survey respondents reported that CD4+ cell count testing was available to all but one site, while tuberculosis (TB) screening and community outreach services were available in 80 and 72%, respectively. The remaining four essential services - nutritional support (82%), combination antiretroviral therapy adherence support (88%), prevention of mother to-child transmission (PMTCT) (94%) and other prevention and clinical management services (97%) - were uniformly available. Approximately half (46%) of sites reported offering all seven services. Newer sites and sites in settings with low rankings on the UN Human Development Index (HDI), especially those in the President's Emergency Plan for AIDS Relief focus countries, tended to offer a more comprehensive array of essential services. HIV care programme characteristics and comprehensiveness varied according to the number of years the site had been in operation and the HDI of the site setting, with more recently established clinics in low-HDI settings reporting a more comprehensive array of available services. Survey respondents frequently identified contact tracing of patients, patient outreach, nutritional counselling, onsite viral load testing, universal TB screening and the provision of isoniazid preventive therapy as unavailable services. CONCLUSIONS: This study serves as a baseline for on-going monitoring of the evolution of care delivery over time and lays the groundwork for evaluating HIV treatment outcomes in relation to site capacity for comprehensive care. PMID- 25516106 TI - Self-reported oral health and associated factors in the North Finland 1966 birth cohort at the age of 31. AB - BACKGROUND: The Northern Finland 1966 birth cohort (NFBC 1966) is an epidemiological study where the participants have been controlled since pregnancy both in field tests and using questionnaires. This study aimed to evaluate cross sectionally the association of self-reported oral symptoms (dental caries and bleeding of gums) with sociodemographic and health behavior factors among the subjects. METHODS: Of the 11,541 original members of the cohort, 8,690 (75%) responded to the questionnaire on oral health (dental decay, gingival bleeding and self-estimated dental treatment need) and sociodemographic factors, general health and health behavior. Cross-tabulation and chi-squared tests as well as multiple logistic regression analysis were used to analyze the association between the outcome and explanatory variables. RESULTS: The study group was equally distributed between the genders. One third of the subjects reported having dental decay, one fourth gingival bleeding and a half a dental treatment need. As compared to women, men reported significantly more frequently symptoms (p < 0.05). Logistic regression analysis revealed low tooth brushing frequency increasing the odds most for all oral symptoms ((OR 1.57 (1.39-1.78) for dental decay, 1.94 (1.68-2.24) for gingival bleeding and 1.42 (1.26-1.61) for dental treatment need). Frequent smoking was associated with dental decay (OR 1.63 (1.44 1.84)) and treatment need OR (1.39 (1.23-1.56)), whereas poor general health (OR 1.71 (1.48-1.96)) and high BMI (OR 1.19 (1.03-1.36)) both were associated with gingival bleeding. CONCLUSIONS: Males with single marital status, BMI over 25, poor general health and poor oral health behaviors are at risk for self-reported poor oral health and dental treatment need. PMID- 25516107 TI - Selective excitation with asymmetric adiabatic pulses for NMR spectroscopy. AB - Existing selective pulses are mainly constructed in the forms of classically shaped pulses, such as the Gaussian pulses, or generated by using numerical optimization methods. However, all of these pulses are highly sensitive to radiofrequency (RF) intensity variation, which means their performance is highly dependent on the accuracy and stability of the RF intensity. Even a slight RF intensity deviation can cause severe degradation in the excitation profile. To solve this problem, we propose a method for narrow selective excitation by sequential application of a pair of phase-opposite asymmetric adiabatic pulses, all within two scans. By retaining the adiabatic character, the new method is highly robust to RF intensity variation. Moreover, it has flexible excitation bandwidth, ranging from line-selective to narrow-band-selective pulses. The method is tested both in numerical simulations and solution-state NMR experiments. PMID- 25516108 TI - Differences in single and aggregated nanoparticle plasmon spectroscopy. AB - Vibrational spectroscopy usually provides structural information averaged over many molecules. We report a larger peak position variation and reproducibly smaller FWHM of TERS spectra compared to SERS spectra indicating that the number of molecules excited in a TERS experiment is extremely low. Thus, orientational averaging effects are suppressed and micro ensembles are investigated. This is shown for a thiophenol molecule adsorbed on Au nanoplates and nanoparticles. PMID- 25516105 TI - Reading abilities in school-aged preterm children: a review and meta-analysis. AB - AIM: Children born preterm (at <=32wks) are at risk of developing deficits in reading ability. This meta-analysis aims to determine whether or not school-aged preterm children perform worse than those born at term in single-word reading (decoding) and reading comprehension. METHOD: Electronic databases were searched for studies published between 2000 and 2013, which assessed decoding or reading comprehension performance in English-speaking preterm and term-born children aged between 6 years and 13 years, and born after 1990. Standardized mean differences in decoding and reading comprehension scores were calculated. RESULTS: Nine studies were suitable for analysis of decoding, and five for analysis of reading comprehension. Random-effects meta-analyses showed that children born preterm had significantly lower scores (reported as Cohen's d values [d] with 95% confidence intervals [CIs]) than those born at term for decoding (d=-0.42, 95% CI -0.57 to 0.27, p<0.001) and reading comprehension (d=-0.57, 95% CI -0.68 to -0.46, p<0.001). Meta-regressions showed that lower gestational age was associated with larger differences in decoding (Q[1]=5.92, p=0.02) and reading comprehension (Q[1]=4.69, p=0.03) between preterm and term groups. Differences between groups increased with age for reading comprehension (Q[1]=5.10, p=0.02) and, although not significant, there was also a trend for increased group differences for decoding (Q[1]=3.44, p=0.06). INTERPRETATION: Preterm children perform worse than peers born at term on decoding and reading comprehension. These findings suggest that preterm children should receive more ongoing monitoring for reading difficulties throughout their education. PMID- 25516109 TI - Positive appraisal of in-home family caregivers of dementia patients as an influence on the continuation of caregiving. AB - BACKGROUND: We attempted to determine the factors that influence the continuation of in-home caregiving for patients with dementia. METHODS: The participants were family caregivers of dementia patients who received home care services. Data were collected via a questionnaire completed by caregivers and then returned in the mail. Of the 705 caregivers who received the questionnaire, 405 completed and returned it (response rate: 57.4%). RESULTS: The average age of the caregivers was 63.9 +/- 11.5 years, and they had been providing care for an average of 5.1 +/- 4.1 years. The average age of the patients was 84.7 +/- 7.4 years. We analyzed the path model. Caregivers' current feelings about continuing caregiving were directly affected by a positive appraisal of caregiving (beta = 0.20, P < 0.001) and by the burden they experienced (beta = -0.39, P < 0.001). The continuation of caregiving of patients with worsening symptoms was directly affected by a positive appraisal of caregiving (beta = 0.15, P < 0.01) and by the burden experienced by the caregivers (beta = -0.46, P < 0.001). The continuation of caregiving was indirectly affected by the patients' cognitive impairment and by the behavioral and psychological symptoms of dementia score. CONCLUSIONS: The continuation of in-home caregiving among caregivers of patients with dementia was affected by both positive appraisal and caregiver burden. In addition, the present study revealed that behavioral and psychological symptoms of dementia score indirectly affects the continuation of caregiving by directly affecting caregiver burden. PMID- 25516110 TI - Voluntary and controlled weight loss can reduce symptoms and proton pump inhibitor use and dosage in patients with gastroesophageal reflux disease: a comparative study. AB - A wide variety of pieces of evidence has suggested that obesity is associated with a significant increase in the risk for gastroesophageal reflux disease (GERD) symptoms and its complications. The aim of this study was to evaluate the effect of weight loss on reflux symptoms in overweight/obese patients with proven GERD. We enrolled overweight/obese patients with typical GERD symptoms and erosive esophagitis. At baseline, patients underwent detailed reflux symptoms evaluation and anthropometric assessment, and were divided into two treatment groups: group A received proton pump inhibitor (PPI) and a personalized hypocaloric diet and aerobic exercise; and group B received PPI and a 'standard of care diet'. The dietetic treatment was considered effective if at least 10% of weight loss was achieved within 6 months. All patients were evaluated in terms of anthropometric data, GERD symptoms, and PPI use. In group A, mean body mass index (BMI) decreased from 30.3 +/- 4.1 to 25.7 +/- 3.1 (P < 0.05), and mean weight decreased from 82.1 +/- 16.9 kg to 69.9 +/- 14.4 kg (P < 0.05). In group B, there was no change in BMI and weight. Symptom perception decreased (P < 0.05) in both groups during PPI therapy, but a higher improvement was recorded in group A. In group A, PPI therapy was completely discontinued in 27/50 of the patients, and halved in 16/50. Only 7/50 continued the same PPI dosage. In group B, 22/51 halved the therapy and 29/51 maintained full dosage of therapy, but none was able to discontinue PPI due to a symptom recurrence. Overall, weight loss of at least 10% is recommended in all patients with GERD in order to boost the effect of PPI on reflux symptom relief and to reduce chronic medication use. PMID- 25516111 TI - Differences in relatives' and patients' illness perceptions in functional neurological symptom disorders compared with neurological diseases. AB - OBJECTIVE: The illness perceptions of the relatives of patients with functional neurological symptom disorders (FNSDs) and their relation to the illness perceptions of the patients have been little studied. We aimed to compare illness perceptions of relatives of patients with FNSDs with those held by patients themselves. We used control pairs with neurological diseases (NDs) to examine the specificity of the findings to FNSDs. MATERIAL AND METHODS: Patients with FNSDs (functional limb weakness and psychogenic nonepileptic seizures) and patients with NDs causing limb weakness and epilepsy, as well as their relatives, completed adapted versions of the Illness Perception Questionnaire - Revised (IPQ R). RESULTS: We included 112 pairs of patients with FNSDs and their relatives and 60 pairs of patients with NDs and their relatives. Relatives of patients with FNSDs were more likely to endorse psychological explanations and, in particular, stress as causal factors than patients with FNSDs (p<.001). Relatives of patients with FNSDs were also more pessimistic about the expected duration of the disorder and perceived a greater emotional impact compared with patients themselves (p<.001). However, the latter two differences between patients and relatives were also found in pairs of patients with NDs and their relatives. CONCLUSION: The main difference in illness perceptions between relatives and patients that appeared specific to FNSDs was a tendency for relatives to see psychological factors as more relevant compared with patients. Some other differences were observed between pairs of patients with FNSDs and their relatives, but the same differences were also seen in pairs of patients with NDs and their relatives. These other differences were, therefore, not specific to FNSDs. Discussion about possibly relevant psychological factors with patients suffering from FNSDs may be helped by including relatives. PMID- 25516112 TI - Dose-dependent collagen cross-linking of rabbit scleral tissue by blue light and riboflavin treatment probed by dynamic shear rheology. AB - PURPOSE: To determine the visco-elastic properties of isolated rabbit scleral tissue and dose-dependent biomechanical and morphological changes after collagen cross-linking by riboflavin/blue light treatment. MATERIAL: Scleral patches from 87 adult albino rabbit eyes were examined by dynamic shear rheology. Scleral patches were treated by riboflavin and different intensities of blue light (450 nm), and the impact on the visco-elastic properties was determined by various rheological test regimes. The relative elastic modulus was calculated from non treated and corresponding treated scleral patches, and treatments with different blue light intensities were compared. RESULTS: Shear rheology enables us to study the material properties of scleral tissue within physiological relevant parameters. Cross-linking treatment increased the viscous as well as the elastic modulus and changed the ratio of the elastic versus viscous proportion in scleral tissue. Constant riboflavin application combined with different blue light intensities from 12 mW/cm(2) up to 100 mW/cm(2) increased the relative elastic modulus of scleral tissue by factors up to 1.8. Further enhancement of the applied light intensity caused a decline of the relative elastic modulus. This might be due to destructive changes of the collagen bundle structure at larger light intensities, as observed by histological examination. CONCLUSION: Collagen cross-linking by riboflavin/blue light application increases the biomechanical stiffness of the sclera in a dose-dependent manner up to certain light intensities. Therefore, this treatment might be a suitable therapeutic approach to stabilize the biomechanical properties of scleral tissue in cases of pathological eye expansion. PMID- 25516115 TI - The icephobic performance of alkyl-grafted aluminum surfaces. AB - This work analyzes the anti-icing performance of flat aluminum surfaces coated with widely used alkyl-group based layers of octadecyltrimethoxysilane, fluorinated alkylsilane and stearic acid as they are subjected to repeated icing/deicing cycles. The wetting properties of the samples upon long-term immersion in water are also evaluated. The results demonstrate that smooth aluminum surfaces grafted with alkyl groups are prone to gradual degradation of their hydrophobic and icephobic properties, which is caused by interactions and reactions with both ice and liquid water. This implies that alkyl-group based monolayers on aluminum surfaces are not likely to be durable icephobic coatings unless their durability in contact with ice and/or water is significantly improved. PMID- 25516114 TI - A case of intracranial solitary fibrous tumor/hemangiopericytoma with dedifferentiated component. AB - We report the case of a 51-year-old Japanese man with an intracranial dedifferentiated solitary fibrous tumor/hemangiopericytoma (SFT/HPC) identified morphologically and immunohistochemically, comprised of a typical SFT/HPC with a high-grade pleomorphic component. NAB2-STAT6 fusion transcripts were detected by reverse transcriptase polymerase chain reaction in both the conventional and high grade components. The tumor cells in both components showed the nuclear expression of STAT6 protein, indicating the diagnostic value of these examinations. Intracranial dedifferentiated SFT/HPC is a very rare but important differential diagnosis in intracranial pleomorphic tumors. PMID- 25516113 TI - One-year follow-up of mud-bath therapy in patients with bilateral knee osteoarthritis: a randomized, single-blind controlled trial. AB - The objective of this prospective parallel randomized single-blind study was to assess that a cycle of mud-bath therapy (MBT) provides any benefits over usual treatment in patients with bilateral knee osteoarthritis (OA). Patients with symptomatic primary bilateral knee OA, according to ACR criteria, were included in the study and randomized to one of two groups: one group received a cycle of MBT at spa center of Chianciano Terme (Italy) in addition to the usual treatment, and one group continued their regular care routine alone. Clinical assessments were performed 7 days before enrollment (screening visit), at the time of enrollment (basal time), after 2 weeks, and after 3, 6, 9, and 12 months after the beginning of the study. All assessments were conducted by two researchers blinded to treatment allocation. The primary efficacy outcomes were the global pain score evaluated by Visual Analog Scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscore for physical function (W-TPFS). Of the 235 patients screened, 103 met the inclusion criteria: 53 patients were included in the MBT group and 50 in the control group. In the group of patients treated with MBT, we observed a statistically significant (p < 0.001) reduction of VAS and W-TPFS score at the end of the treatment; this improvement was significant (p < 0.05) also at 3 months of follow-up. The control group did not show significant differences between baseline time and all other times. The differences between one group were significant for both primary parameters already from the 15th day and persisted up to the 9th month. This beneficial effect was confirmed by the significant reduction of symptomatic drug consumption. Tolerability of MBT seemed to be good, with light and transitory side effects. Our results confirm that a cycle of MBT added to usual treatment provides a beneficial effect on the painful symptoms and functional capacities in patients with knee OA that lasts over time. Mud-bath therapy can represent a useful backup to pharmacologic treatment of knee OA or a valid alternative for patients who do not tolerate pharmacological treatments. PMID- 25516116 TI - Polarization-dependent optical absorption of MoS2 for refractive index sensing. AB - As a noncentrosymmetric crystal with spin-polarized band structure, MoS2 nanomaterials have attracts increasing attention in many areas such as lithium ion batteries, flexible electronic devices, photoluminescence and valleytronics. The investigation of MoS2 is mainly focused on the electronics and spintronics instead of optics, which restrict its applications as key elements of photonics. In this work, we demonstrate the first observation of the polarization-dependent optical absorption of the MoS2 thin film, which is integrated onto an optical waveguide device. With this feature, a novel optical sensor combining MoS2 thin film and a microfluidic structure has been constituted to achieve the sensitive monitoring of refractive index. Our work indicates the MoS2 thin film as a complementary material to graphene for the optical polarizer in the visible light range, and explores a new application direction of MoS2 nanomaterials for the construction of photonic circuits. PMID- 25516117 TI - Cerium and yttrium oxide nanoparticles against lead-induced oxidative stress and apoptosis in rat hippocampus. AB - Due to numerous industrial applications, lead has caused widespread pollution in the environment; it seems that the central nervous system (CNS) is the main target for lead in the human body. Oxidative stress and programmed cell death in the CNS have been assumed as two mechanisms related to neurotoxicity of lead. Cerium oxide (CeO2) and yttrium oxide (Y2O3) nanoparticles have recently shown antioxidant effects, particularly when used together, through scavenging the amount of reactive oxygen species (ROS) required for cell apoptosis. We looked into the neuroprotective effects of the combinations of these nanoparticles against acute lead-induced neurotoxicity in rat hippocampus. We used five groups in this study: control, lead, CeO2 nanoparticles + lead, Y2O3 nanoparticles + lead, and CeO2 and Y2O3 nanoparticles + lead. Nanoparticles of CeO2 (1000 mg/kg) and Y2O3 (230 mg/kg) were administered intraperitoneally during 2 days prior to intraperitoneal injection of the lead (25 mg/kg for 3 days). At the end of the treatments, oxidative stress markers, antioxidant enzymes activity, and apoptosis indexes were investigated. The results demonstrated that pretreatments with CeO2 and/or Y2O3 nanoparticles recovered lead-caused oxidative stress markers (ROS, lipid peroxidation, and total thiol molecules) and apoptosis indexes (Bax/Bcl-2 and caspase-3 protein expression). Besides, these nanoparticles reduced the activities of lead-induced superoxide dismutase and catalase as well as the ADP/ATP ratio. Interestingly, the best recovery resulted from the compound of these nanoparticles. Based on these outcomes, it appears that this combination may potentially be beneficial for protection against lead-caused acute toxicity in the brain through improving the oxidative stress-mediated programmed cell death pathway. PMID- 25516118 TI - Relationship of blood levels of Pb with Cu, Zn, Ca, Mg, Fe, and Hb in children aged 0 ~ 6 years from Wuhan, China. AB - The aim of this study was to investigate the relationship of blood lead (Pb) levels with copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), iron (Fe), and hemoglobin (Hb) in children aged from 0-6 years in Wuhan, China. A total of 1047 children from six communities, which were randomly selected in Wuhan city and three communities, located in the urban area and others in the suburban area, were recruited for this study between November 2012 and July 2013. The levels of elements in the blood were detected using an atomic absorption spectrometer, and Hb level was tested by an automated hematology analyzer. The results showed that the mean blood lead level (BLL) is 33.72 +/- 19.03 MUg/L. The BLL was significantly higher among boys than girls (P < 0.05). Higher BLL was also observed in suburbs compared to that in urban areas (P < 0.05). The BLL and Zn level were gradually increased with age. The elevated rate of BLL in children was 20.9 %, while the Zn deficiency rate was 65.0 %. And, the level of Hb in higher BLL group was significantly lower. Negative correlations of the blood levels of Pb with those of Cu (r = -0.087, P = 0.005), Mg (r = -0.102, P = 0.001), and Fe (r = -0.091, P = 0.003) were observed. These data suggested that the elevated rate of BLL in children from Wuhan is still higher according to the updated reference values in the USA. The deficiency of Cu, Mg, and Fe may indicate the elevation of lead absorption. The dietary supplement of Zn, Ca, and Fe in children requires more attention. PMID- 25516119 TI - Adoptive immunotherapy against sarcomas. AB - INTRODUCTION: Conventional treatments reached an unsatisfactory therapeutic plateau in the treatment of advanced unresectable bone and soft tissue sarcomas that remain an unsolved medical need. Several evidences support the concept that adoptive immunotherapy may effectively integrate within the complex and multidisciplinary treatment of sarcomas. AREAS COVERED: In this work we reviewed adoptive immunotherapy strategies that have been explored in sarcoma settings, with specific focus on issues related to their clinic transferability. We schematically divided approaches based on T lymphocytes specific for MHC restricted tumor-associated antigens or relying on MHC-independent immune effectors such as natural killer (NK), cytokine-induced killer (CIK) or gammadelta T cells. EXPERT OPINION: Preclinical findings and initial clinical reports showed the potentialities and drawbacks of different adoptive immunotherapy strategies. The expansion of tumor infiltrating lymphocytes is difficult to be reproduced outside melanoma. Genetically redirected T cells appear to be a promising option and initial reports are encouraging against patients with sarcomas. Adoptive immunotherapy with MHC-unrestricted effectors such as NK, CIK or gammadelta T cells has recently shown great preclinical potential in sarcoma setting and biologic features that may favor clinical transferability. Combination of different immunotherapy approaches and integration with conventional treatments appear to be key issues for successful designing of next clinical trials. PMID- 25516121 TI - PDGF-BB protects mitochondria from rotenone in T98G cells. AB - Rotenone is one of the most-studied neurotoxic substances as it induces oxidative stress processes both in cellular and animal models. Rotenone affects ATP generation, reactive oxygen species (ROS) production, and mitochondrial membrane potential in neurons and astrocyte-like cells. Previous epidemiologic studies have supported the role of neurotrophic factors such as BDNF and GDNF in neuroprotection mainly in neurons; however, only very few studies have focused on the importance of astrocytic protection in neurodegenerative models. In the present study, we assessed the neuroprotective effects of PDGF-BB against toxicity induced by rotenone in the astrocytic-like model of T98G human glioblastoma cell line. Our results demonstrated that pretreatment with PDGF-BB for 24 h increased cell viability, preserved nuclear morphology and mitochondrial membrane potential following stimulation with rotenone, and reduced ROS production nearly to control conditions. These observations were accompanied by important morphological changes induced by rotenone and that PDGF-BB was able to preserve cellular morphology under this toxic stimuli. These findings indicated that PDGF-BB protects mitochondrial functions, and may serve as a potential therapeutic strategy in rotenone-induced oxidative damage in astrocytes. PMID- 25516123 TI - New approach on analysis of pathologic cardiac murmurs based on WPD energy distribution. AB - In this paper, an approach on analysis of the pathologic cardiac murmurs for congenital heart defects was proposed based on the wavelet packet (WP) technique. Considering the difference of the energy intensity distributions for the innocent and pathologic murmurs in frequency domain, the WP decomposition was introduced and the WP energies at each frequency band were calculated and compared. Based on the analysis of a large amount of clinic heart sound data, the murmurs energy distributions were divided into five frequency bands, and the relative evaluation indexes for cardiac murmurs (ICM) were proposed for analysis of the pathologic murmurs. Finally, the threshold values between the innocent and pathologic cardiac murmurs were determined based on the statistical results of the normal heart sounds. The analysis results validate the proposed evaluation indexes and the corresponding thresholds. PMID- 25516122 TI - Interaction between the endocannabinoid and serotonergic system in the exhibition of head twitch response in four mouse strains. AB - More than 10 % of children during school years suffer from a transient tic disorder, and 1 % has a particular type of tic disorder known as Tourette syndrome. At present, there is no available treatment that can improve tics without considerable side effects. Recent evidence indicates that tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, reduced in mice the head twitch responses, a tic pharmacologically induced by the selective serotonin 5-HT2 receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). THC has some considerable side effects that render its use problematic. In this view, cyclohexyl-carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597), an indirect cannabinoid agonist that enhances endogenous anandamide levels, can constitute a valid alternative to the use of direct CB1 receptor agonists. We investigated whether URB597 may reduce the exhibition of DOI-induced head twitch responses in mice. Moreover, to address whether the effects of URB597 on DOI induced behavioral response constitute a general phenomenon, we evaluated four (ABH, C57BL/6N, SJL/J, CD-1) mouse strains. These strains have been selected in order to represent an ample spectrum of genetic background and phenotypic variation. Predictably, DOI induced consistent tic-like behaviors in all mice. While URB597 exerted slight sedation in C57BN/6L mice, this cannabinoid agonist remarkably mitigated the exhibition of DOI-induced head twitch in all strains. Present data may disclose novel avenues for the pharmacological treatment of tic disorders. PMID- 25516124 TI - Model-independent evaluation of tumor markers and a logistic-tree approach to diagnostic decision support. AB - Sensitivity and specificity of using individual tumor markers hardly meet the clinical requirement. This challenge gave rise to many efforts, e.g., combing multiple tumor markers and employing machine learning algorithms. However, results from different studies are often inconsistent, which are partially attributed to the use of different evaluation criteria. Also, the wide use of model-dependent validation leads to high possibility of data overfitting when complex models are used for diagnosis. We propose two model-independent criteria, namely, area under the curve (AUC) and Relief to evaluate the diagnostic values of individual and multiple tumor markers, respectively. For diagnostic decision support, we propose the use of logistic-tree which combines decision tree and logistic regression. Application on a colorectal cancer dataset shows that the proposed evaluation criteria produce results that are consistent with current knowledge. Furthermore, the simple and highly interpretable logistic-tree has diagnostic performance that is competitive with other complex models. PMID- 25516126 TI - Effects of skin surface temperature on photoplethysmograph. AB - Photoplethysmograph (PPG) has been widely used to investigate various cardiovascular conditions. Previous studies demonstrated effects of temperature of the measurement environment; however, an integrated evaluation has not been established in environments with gradual air temperature variation. The purpose of this study is to investigate variations and relationships of blood pressure (BP), PPG and cardiovascular parameters such as heart rate (HR), stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR), by changing skin surface temperature (SST). Local mild cooling and heating was conducted on 16 healthy subjects. The results showed that local SST changes affected Finometer blood pressures (Finger BP), PPG components and TPR, but not the oscillometric blood pressure (Central BP), HR, SV and CO, and indicated that temperature must be maintained and monitored to reliably evaluate cardiovascular conditions in temperature-varying environments. PMID- 25516125 TI - The influence of using digital diagnostic information on orthodontic treatment planning - a pilot study. AB - The purpose of this pilot study was to assess whether orthodontic treatment planning is reproducible when carried out using digital records compared with clinical examinations or using standard records. The study also assessed patients' opinion of face-to-face consultations and potential use of teleorthodontics. The study was designed as a prospective observational cross sectional pilot study and carried out in a UK dental teaching hospital involving 27 subjects. Four consultant Orthodontists carried out treatment planning, firstly following a clinical examination, then using standard records, and then using digital records. Each subject completed a questionnaire. Cohen's kappa coefficient and Fleiss' kappa coefficient were used to assess intra-observer reproducibility and inter-observer reproducibility of treatment planning decisions, respectively. A change in the diagnostic information format affected treatment planning reproducibility for half of the observers. Inter-observer reproducibility was greater when using hard copy records in comparison to digital records. No subjects were unsatisfied with their face-to-face consultation. PMID- 25516127 TI - An application of multi-attribute value theory to patient-bed assignment in hospital admission management: an empirical study. AB - Hospital beds are considered economically scarce and hospitalists strive to balance between utilizing beds more efficiently and complying with preference of physicians and patients when pairing patients to beds. This research is to develop preference-based decision rules for patient-bed assignment in a dynamic environment. A multi-attribute value theory (MAVT) model with additive value function is proposed to quantitatively deploy hospital policies in bed management. To elicit scaling factors and value functions for attributes, a linear programming model is constructed for all preference conditions. An empirical study was conducted with real data collected from two branches of a medical center. The simulated results using value function showed greater benefits when the patient-bed ratio was high and more flexible ward assignment was allowed. Further, a detailed analysis showed that this MAVT model was better in preference matching for both physicians/nurses and patients. At least 79 percent of patients were given beds in designated wards in accordance with their attending physicians' subspecialty, and more than 48 percent of patients' room preferences were matched in the simulated assignment for one branch. PMID- 25516120 TI - A comprehensive view of the epigenetic landscape. Part II: Histone post translational modification, nucleosome level, and chromatin regulation by ncRNAs. AB - The complexity of the genome is regulated by epigenetic mechanisms, which act on the level of DNA, histones, and nucleosomes. Epigenetic machinery is involved in various biological processes, including embryonic development, cell differentiation, neurogenesis, and adult cell renewal. In the last few years, it has become clear that the number of players identified in the regulation of chromatin structure and function is still increasing. In addition to well-known phenomena, including DNA methylation and histone modification, new, important elements, including nucleosome mobility, histone tail clipping, and regulatory ncRNA molecules, are being discovered. The present paper provides the current state of knowledge about the role of 16 different histone post-translational modifications, nucleosome positioning, and histone tail clipping in the structure and function of chromatin. We also emphasize the significance of cross-talk among chromatin marks and ncRNAs in epigenetic control. PMID- 25516128 TI - Information analytics for healthcare service discovery. AB - The concept of being 'patient-centric' is a challenge to many existing healthcare service provision practices. This paper focuses on the issue of referrals, where multiple stakeholders, such as General Practitioners (GPs) and patients, are encouraged to make a consensual decision based on patients' needs. In this paper, we present an ontology-enabled healthcare service provision, which facilitates both patients and GPs in jointly deciding upon the referral decision. In the healthcare service provision model, we define three types of profiles which represent different stakeholders' requirements. This model also comprises a set of healthcare service discovery processes: articulating a service need, matching the need with the healthcare service offerings, and deciding on a best-fit service for acceptance. As a result, the healthcare service provision can carry out coherent analysis using personalised information and iterative processes that deal with requirements which change over time. PMID- 25516129 TI - Manikin families representing obese airline passengers in the US. AB - Aircraft passenger spaces designed without proper anthropometric analyses can create serious problems for obese passengers, including: possible denial of boarding, excessive body pressures and contact stresses, postural fixity and related health hazards, and increased risks of emergency evacuation failure. In order to help address the obese passenger's accommodation issues, this study developed male and female manikin families that represent obese US airline passengers. Anthropometric data of obese individuals obtained from the CAESAR anthropometric database were analyzed through PCA-based factor analyses. For each gender, a 99% enclosure cuboid was constructed, and a small set of manikins was defined on the basis of each enclosure cuboid. Digital human models (articulated human figures) representing the manikins were created using a human CAD software program. The manikin families were utilized to develop design recommendations for selected aircraft seat dimensions. The manikin families presented in this study would greatly facilitate anthropometrically accommodating large airline passengers. PMID- 25516130 TI - Automatic sleep staging using multi-dimensional feature extraction and multi kernel fuzzy support vector machine. AB - This paper employed the clinical Polysomnographic (PSG) data, mainly including all-night Electroencephalogram (EEG), Electrooculogram (EOG) and Electromyogram (EMG) signals of subjects, and adopted the American Academy of Sleep Medicine (AASM) clinical staging manual as standards to realize automatic sleep staging. Authors extracted eighteen different features of EEG, EOG and EMG in time domains and frequency domains to construct the vectors according to the existing literatures as well as clinical experience. By adopting sleep samples self learning, the linear combination of weights and parameters of multiple kernels of the fuzzy support vector machine (FSVM) were learned and the multi-kernel FSVM (MK-FSVM) was constructed. The overall agreement between the experts' scores and the results presented was 82.53%. Compared with previous results, the accuracy of N1 was improved to some extent while the accuracies of other stages were approximate, which well reflected the sleep structure. The staging algorithm proposed in this paper is transparent, and worth further investigation. PMID- 25516131 TI - Lesbian, Gay, and Bisexual Identity as a Moderator of Relationship Functioning After Sexual Assault. AB - Sexual assault is unfortunately common, especially among lesbian, gay, and bisexual (LGB) individuals. Yet, the associations of such victimization have not yet been extensively established in the areas of sexual identity and romantic relationship functioning. Accordingly, the present study examined the associations between lifetime sexual assault, LGB identity, and romantic relationship functioning in a sample of 336 LGB individuals. A history of sexual assault was associated with attachment anxiety and several sexual identity components (i.e., higher levels of acceptance concerns, identity uncertainty, internalized homonegativity, and identity superiority). Furthermore, an association of sexual assault and attachment avoidance was moderated by internalized homonegativity. Finally, a more secure LGB identity was associated with healthier romantic relationship functioning. Collectively, these findings are applicable to services for LGB sexual assault victims, suggesting the incorporation of treatment that bolsters LGB identity and couple functioning. Limitations and future directions are discussed. PMID- 25516132 TI - Revisiting the Derivation of Batterer Subtypes: Towards Profiling the Abuser. AB - Research directed toward profiling an abuser to develop effective treatment modalities should consider the framework for how batterer subtypes were developed. This article evaluates a seminal work in batterer typology for a review of its method and findings. Findings indicate that the formation of batterer subtypes rely on unstable theory and methods: (a) Variables were not held constant, (b) Theoretical constructs lack clarity, (c) There were unclear boundaries for subtypes. A re-evaluation of this particular line of typology research should address the utility and relevance of these batterer subtypes in an effort to address methodological implications that may help profile and treat abusers. PMID- 25516133 TI - Assaults on Inmates and Staff by Perpetrators of Intimate Partner Homicide: An Examination of Competing Hypotheses. AB - The current study presents the results of an analysis of serious and assaultive prison rule violating behavior among male perpetrators of intimate partner homicide (IPH). Data on prison rule violations were collected from a sample of 189 inmates convicted of IPH in a large, southern prison system. The study focused on the degree of continuity in violent behavior among IPH offenders from the community to the prison setting. The current study tested hypotheses derived from both the feminist perspective (FP) and the general violence perspective (GVP). As a group, IPH offenders were better behaved in prison than other incarcerated homicide offenders, thereby offering some support for the FP. However, the lower level of assaultive behavior among the group was not universal. Characteristics associated with continued violent offending in the prison environment were the same as those found in previous studies of incarcerated homicide offenders, thereby lending greater support to the GVP. PMID- 25516134 TI - Differential expression of CYB5A in Chinese and European pig breeds due to genetic variations in the promoter region. AB - Cytochrome b5 (CYB5A) is an important electron transfer protein with homologues in a number of different organisms. In pigs, CYB5A is related to boar taint because of its role in androstenone biosynthesis. To determine the variety of CYB5A expression in pig breeds, genetic variations in the porcine CYB5A promoter region in both Chinese and European pig breeds were examined. Three single nucleotide polymorphisms (NC_010443.4:g.165901487delG, g.165901767T>C and g.165902078C>T) were identified in the porcine CYB5A promoter region. These SNPs occurred in different frequencies in Chinese and European pigs. Chinese pigs were primarily haplotype B (denoted as delG-C-T: the position of nt 165901487 of the CYB5 gene is a G deletion, nt 165901767 is C and nt 165902078 is T), except for Licha black pigs, which were primarily haplotype A (denoted as G-T-C: nt 165901487 is G, nt 165901767 is T and nt 165902078 is C), similar to European pigs. Quantitative PCR data from liver tissues demonstrated that haplotype B individuals had higher CYB5A expression than did those with haplotype A. This was confirmed by in vitro cell transfection assays, in which haplotype B individuals had higher reporter activity than did those with haplotype A. In silico analysis predicted that Myc-associated zinc-finger protein (MAZ) is a potential transcription factor at position 165901767. Electrophoretic mobility shift assays showed this polymorphism affects the stable binding of transcription factors to the CYB5A promoter, which in turn affects the expression levels of this gene. Therefore, this variation of the porcine CYB5A promoter region may explain the differences in androstenone accumulation between Chinese and European pig breeds and may also prove useful as a genetic marker to distinguish the origin of different pig breeds. PMID- 25516135 TI - Degesting the remodeled cardiovascular wall: role of cysteinyl cathepsins in cardiovascular disease. AB - Cardiovascular disease (CVD) is characterized by extensive remodeling of the extracellular matrix (ECM) architecture of the cardiovascular system. Among the many extracellular proteolytic enzymes present in cardiovascular cells and inflammatory cells and involved in ECM remodeling, members of the matrix metalloproteinase family and serine protease family have received the most attention. However, recent findings from laboratory and clinical studies have indicated that lysosomal cysteinyl cathepsins also participate in pathogenesis of CVD. This review summarizes recent knowledge on discoveries regarding the relationship between cysteinly cathepsins and CVD. PMID- 25516136 TI - The role of the TERC-63G>A and TERT-1327C>T telomerase polymorphisms in the study of men with acute coronary syndrome. AB - AIM: Telomerase is a ribonucleoprotein that maintains telomere length. Telomeres and telomerase are involved in cellular ageing and have been connected to some ageing related diseases, like cardiovascular disease. Telomerase dysfunction could be the main underlying mechanism in this connection but this point is still unclear. The aim of this article is to investigate the possible influence of cellular ageing, measured by two telomerase polymorphisms, TERC-63G>A (rs2293607) and TERT-1327C>T (rs2735940), on the whole spectrum of acute coronary artery disease (CAD). METHODS: We studied 150 middle aged men admitted for an acute coronary syndrome (ACS). Cardiovascular risk factors prevalence was collected at admission. Severity variables analyzed were Killip class and number of vessels affected. Telomerase polymorphisms were studied by real time PCR in DNA samples extracted from peripheral blood leukocytes. Clinical follow-up had been developed for more than 600 days and a prognostic combined event was defined. RESULTS: C allele of TERT polymorphism was more prevalent among hypertensive patients (OR: 3.19; 95% CI: 1.37-7.42; P=0.006). None of polymorphisms showed any prognostic value or relation to CAD severity. CONCLUSION: Telomerase dysfunction could be involved in hypertension prevalence. This finding could support new screening strategies in high risk population. The two telomerase polymorphisms analyzed did not show any prognostic value or connection to CAD severity. However, further studies are required to determine the molecular mechanisms responsible for cellular ageing in ACS. PMID- 25516137 TI - The relationship between culprit artery and the clinical outcomes in patients undergoing primary percutaneous coronary intervention for inferior wall ST segment elevation myocardial infarction. AB - BACKGROUND: We observed the effect of culprit artery in patients undergoing primary percutaneous coronary intervention (PCI) caused by inferior wall ST elevation myocardial infarction (STEMI) during hospital stay and 6-month follow ups. METHODS: After exclusion, 233 consecutive patients with inferior wall STEMI (mean age: 55.6+/-12.4 years) undergoing primary PCI were prospectively enrolled in this study. Patients were divided into two groups according to culprit artery: right coronary artery (RCA=group 1 [N.=187]) and left circumflex artery (LCX=group 2 [N.=46]). Patients were followed up for six months. RESULTS: Patients of both groups had similar risk factors such as age, sex, hypertension and diabetes mellitus. While there were more cases of right ventricular infarction (P=0.001), complete atrioventricular block (P=0.002) and proximal located lesions (P=0.002) in RCA group, there was less collateral circulation incidence in LCX group (P=0.04). Ratios of no-reflow and myocardial blush grade after primary PCI were similiar in both groups. There was no significant difference between groups associated with major adverse cardiac events (MACE), target-vessel revascularization and mortality ratios during hospital stay and 6 month follow-up period. CONCLUSIONS: The impact of RCA and LCX on MACE and cardiovascular mortality during hospital stay and the 6-month follow-up (mid term) period are similar in patients on whom primary PCI was performed due to inferior wall STEMI. PMID- 25516138 TI - Recessive thrombocytopenia likely due to a homozygous pathogenic variant in the FYB gene: case report. AB - BACKGROUND: Inherited thrombocytopenias (IT) are a heterogeneous group of rare diseases characterized by a reduced number of blood platelets. The frequency of IT is probably underestimated because of diagnostic difficulties and because not all the existing forms have as yet been identified, with some patients remaining without a definitive diagnosis. Exome Sequencing has made possible the identification of almost all variants in the coding regions of protein-coding genes, thereby providing the opportunity to identify the disease causing gene in a number of patients with indefinite diagnoses, specifically in consanguineous families. CASE PRESENTATION: Familial thrombocytopenia with small size platelets was present in several members of a highly consanguineous family from Northern Iraq. Genotyping of all affected, their unaffected siblings and parents, followed by exome sequencing revealed a strong candidate loss of function variant in a homozygous state: a frameshift mutation in the FYB gene. The protein encoded by this gene is known to be a cytosolic adaptor molecule expressed by T, natural killer (NK), myeloid cells and platelets, and is involved in platelet activation and controls the expression of interleukin-2. Knock-out mice were reported to show isolated thrombocytopenia. CONCLUSION: Inherited thrombocytopenias differ in their presentation, associated features, and molecular etiologies. An accurate diagnosis is needed to provide appropriate management as well as counseling for the individuals and their family members. Exome sequencing may become a first diagnostic tool to identify the molecular basis of undiagnosed familial IT. In this report, the clinical evaluation combined with the power and efficiency of genomic analysis defined the FYB gene as the possible underlying cause of autosomal recessive thrombocytopenia with small platelet size. This is the first report linking pathogenic variants in FYB and thrombocytopenia in humans. PMID- 25516140 TI - People who feel younger tend to live longer, say researchers. PMID- 25516141 TI - Solvent-dependent enthalpic versus entropic anion binding by biaryl substituted quinoline based anion receptors. AB - Anion receptors based on an 8-thiourea substituted quinoline with pentafluorinated (1a) or nonfluorinated (1b) biarylamide groups in the 2-position show similar binding of halide anions with somewhat higher association constants for the more acidic fluorinated derivative. Surprisingly, binding affinities for the halides in the case of the nonfluorinated 1b are similar in nonpolar chloroform or polar DMSO as solvent. Thorough thermodynamic investigations based on NMR van't Hoff analysis show that anion binding in chloroform is mainly enthalpically driven. In DMSO, entropy is the driving force for the binding of the ions with replacement of attached solvent. PMID- 25516139 TI - Effect of monthly vitamin D3 supplementation in healthy adults on adverse effects of earthquakes: randomised controlled trial. AB - OBJECTIVE: To determine whether supplementation with vitamin D improves resilience to the adverse effects of earthquakes. DESIGN: Opportunistic addition to an established randomised double blind placebo controlled trial. SETTING: Christchurch, New Zealand, where a prolonged series of catastrophic earthquakes beginning on 4 September 2010 occurred, which caused widespread destruction, fatalities, and extensive psychological damage. PARTICIPANTS: 322 healthy adults (241 women; 81 men) aged 18-67 who were already participating in the vitamin D and acute respiratory infections study (VIDARIS) between February 2010 and November 2011. INTERVENTION: Participants were randomised to receive an oral dose of either 200,000 IU vitamin D3 monthly for two months then 100,000 IU monthly (n=161) or placebo (n=161) for a total of 18 months. MAIN OUTCOME MEASURE: This is a post hoc analysis from the previously published VIDARIS trial. The primary endpoint in the current analysis was the self reported effects and overall adverse impact of the Christchurch earthquakes as assessed by questionnaire four months after the most destructive earthquake on 22 February 2011, which was used as the index event. The secondary end point was the number of "psychological" adverse events that participants reported at their usual monthly appointments as part of the original VIDARIS trial. RESULTS: 308 participants completed the earthquake impact questionnaire (n=152 in the vitamin D group and 156 in the placebo group). There was no significant difference in the number of self reported adverse effects between those receiving vitamin D supplementation and those receiving placebo. There was also no difference in the overall adverse impact score between treatment groups (chi(2) P=0.44). The exception was that those in the vitamin D group experienced more adverse effects on family relationships (22% v 13%; chi(2) P=0.03). The number of psychological adverse events-such as fatigue, stress, anxiety, and insomnia-that participants reported at their usual monthly appointments was significantly higher after the earthquake (chi(2) P=0.007) but did not differ between treatment groups. CONCLUSION: In this trial, vitamin D supplementation did not reduce the adverse impact of earthquakes in healthy adults. Trial registration Australian New Zealand Clinical Trials Registry (anzctr.org.au) ACTRN12609000486224. PMID- 25516143 TI - Congenital melanotic macules of the tongue. A case report and brief review of the literature. AB - Congenital melanotic macules of the tongue (CMMT) are a rare and benign condition that is probably underestimated. We report the case of an African infant with multiple congenital hyperpigmented macules of the tongue. To avoid a difficult-to perform procedure such as a tongue biopsy, focused clinical monitoring was performed every 3 months for 30 months to detect significant changes. A clinical diagnosis of CMMT was made in the absence of concomitant systemic diseases using the clinical findings, the location on the tongue, the negative family history for melanoma, and the absence of drugs and toxic exposure. Clinical follow-up may be sufficient to monitor CMMT rather than performing a tongue biopsy. PMID- 25516142 TI - Influence of insertion depth in cochlear implantation on vertigo symptoms and vestibular function. AB - OBJECTIVES: The aim of the present study was to investigate the effect of the electrode insertion depth in vestibular function after cochlear implantation. MATERIAL AND METHODS: In a retrospective observational study design, 41 adult patients who had undergone cochlear implantation between 2006 and 2012 at a tertiary referral university hospital were included. The postoperative performed radiograph images of the petrous bone were acquired according to the Stenvers method. These were analyzed to determine electrode insertion depth. Pre- and postoperative subjective vertigo symptoms were assessed by a questionnaire. The function of the horizontal semi-circular canal was evaluated by caloric irrigation and the function of the sacculus was tested by using cervical vestibular evoked myogenic potentials pre- and postoperatively. RESULTS: The average electrode insertion depth was 464 degrees . A certain variability of insertion depth existed among the different electrodes according to their designs. No statistical difference of the insertion depth was found between patients with or without vertigo. There was also no correlation between electrode insertion depth and alterations of the measurable vestibular function. CONCLUSION: In our study the variability of insertion depth didn't have a significant influence on subjective vertigo, horizontal semi-circular canal function or saccular function. Plain radiography is a rapid, simple and cost effective method to determine electrode insertion depth after implantation. However the scalar position of the electrode cannot be analyzed in plain radiography, so that an interscalar dislocation as a possible influence in vestibular function remains undetected. PMID- 25516144 TI - Monitoring intrahepatic cholestasis of pregnancy using the fetal myocardial performance index: a cohort study. AB - OBJECTIVE: To investigate use of the fetal myocardial performance index (MPI) in assessing intrahepatic cholestasis of pregnancy (ICP). METHODS: This was a cohort study including cross-sectional and longitudinal data from 31 women with ICP recruited from June 2012 to March 2014. Fetal left, right and delta MPI (LMPI, RMPI and DMPI), and routine measures of fetal growth and wellbeing, were obtained at each ultrasound examination. Results were evaluated with respect to gestational age (GA)-adjusted reference intervals, level of maternal serum bile acid (SBA) and fetal outcome. Lower SBA (>= 7.5 and < 40 MUmol/L) and high SBA (>= 40 MUmol/L) subgroups of cases were defined for the analysis. RESULTS: A total of 51 ultrasound examinations were performed in 33 fetuses. The mean LMPI, and means of its isovolumetric relaxation time (IRT) and isovolumetric contraction time (ICT) components were significantly higher in all subgroups of cases of ICP relative to the normal reference mean. Considering only the first examination in each case of ICP, IRT was significantly more prolonged in the high SBA group (n = 10) in comparison to the lower SBA group (n = 23) (52.7 +/- 8.0 ms vs 47.3 +/- 4.8 ms, P = 0.02), and both IRT (r = 0.538, P = 0.001) and LMPI (r = 0.367, P = 0.036) were significantly correlated with SBA concentration. The proportion of high SBA cases with LMPI, RMPI or DMPI > 2 SD above the GA-adjusted reference mean was not significantly greater than for the lower SBA group. On analysis of all data from those cases with more than one examination, no significant correlation was found between SBA concentration and any of the MPI variables. CONCLUSIONS: LMPI values increase above the population GA-adjusted mean in cases of ICP, particularly amongst women with higher SBA. A significant correlation between IRT and LMPI at initial examination and increasing SBA concentration was found. A future multicenter prospective study may clarify the prognostic utility of MPI in ICP. PMID- 25516145 TI - CYP1B1 enhances the resistance of epithelial ovarian cancer cells to paclitaxel in vivo and in vitro. AB - Ovarian cancer (OC) is the most frequent cause of mortality among gynecological malignancies, with a 5-year survival rate of approximately 30%. The standard regimen for OC therapy includes a platinum agent combined with a taxane, to which the patients frequently acquire resistance. Resistance arises from the oxidation of anticancer drugs by CYP1B1, a cytochrome P450 enzyme overexpressed in malignant OC. The aim of the present study was to determine the role of CYP1B1 expression in the drug resistance of OC to the taxane, paclitaxel (PTX). Immunohistochemical staining was used to assess CYP1B1 expression in a panel of ovarian samples (53 primary cancer samples, 14 samples of metastastic cancer, 30 benign tumor samples and 19 normal tissue samples). Semi-quantitative RT-PCR was also performed to determine CYP1B1 expression in several OC cell lines. Finally, we used proliferation and toxicity assays, as well as a mouse xenograft model using nude mice to determine whether alpha-naphthoflavone (ANF), a CYP1B1 specific inhibitor, reduces resistance to PTX. CYP1B1 was overexpressed in the samples from primary and metastatic loci of epithelial ovarian cancers. In some cell lines, PTX induced CYP1B1 expression, which resulted in drug resistance. Exposure to ANF reduced drug resistance and enhanced the sensitivity of OC cells to PTX in vitro and in vivo. The expression profile of CYP1B1 suggests that it has the potential to be a useful diagnostic marker and prognostic factor for malignant OC. The inhibition of CYP1B1 expression by specific agents may provide a novel therapeutic strategy for the treatment of patients resistant to PTX and may improve the prognosis of these patients. PMID- 25516146 TI - Is the Susceptibility Vessel Sign on 3-Tesla Magnetic Resonance T2*-Weighted Imaging a Useful Tool to Predict Recanalization in Intravenous Tissue Plasminogen Activator? AB - The aim of this study was to investigate the independent factors associated with the absence of recanalization approximately 24 h after intravenous administration of tissue-type plasminogen activator (IV TPA). The previous studies have been conducted using 1.5-Tesla (T) magnetic resonance imaging (MRI). We studied whether the characteristics of 3-T MRI findings were useful to predict outcome and recanalization after IV tPA. Patients with internal carotid artery (ICA) or middle cerebral artery (MCA) (horizontal portion, M1; Sylvian portion, M2) occlusion and treated by IV tPA were enrolled. We studied whether the presence of susceptibility vessel sign (SVS) at M1 and low clot burden score on T2*-weighted imaging (T2*-CBS) on 3-T MRI were associated with the absence of recanalization. A total of 49 patients were enrolled (27 men; mean age, 73.9 years). MR angiography obtained approximately 24 h after IV tPA revealed recanalization in 21 (42.9 %) patients. Independent factors associated with the absence of recanalization included ICA or proximal M1 occlusion (odds ratio, 69.6; 95 % confidence interval, 5.05-958.8, p = 0.002). In this study, an independent factor associated with the absence of recanalization may be proximal occlusion of the cerebral arteries rather than SVS in the MCA or low T2*-CBS on 3-T MRI. PMID- 25516147 TI - Unusual Magnetic Resonance Imaging and Catheter Angiographic Signs of Intravascular Lymphoma. PMID- 25516148 TI - Magnetic Resonance Imaging Features of Rhabdoid Glioblastomas. AB - PURPOSE: Rhabdoid glioblastoma (rGB) is a recently described, highly aggressive brain tumor, in which glioblastoma (GB) is associated with a rhabdoid component. So far only 21 cases have been reported and its imaging findings have not been studied in detail. In this paper, we present 11 additional cases and aim to depict detailed magnetic resonance imaging (MRI) features of this tumor in comparison with the previous cases of rGBs and our cohort of typical GBs. METHODS: Retrospective evaluation of the glass slides of 249 GB patients disclosed 14 cases with rhabdoid morphology. Eleven of these cases with available MRI were included in the study. Immunohistochemistry was also performed. MRI and clinicopathologic findings were compared with those of previous rGBs and typical GBs. RESULTS: (1) rGB is usually a large, well-delineated solid tumor with extensive necrosis, heterogeneous contrast enhancement, occasional hemorrhage, and cysts, (2) rGB may present at an older age than previously reported, but still in younger individuals compared with typical GB patients, (3) tumor dissemination in the form of leptomeningeal seeding and more rarely extracranial metastases is a feature of rGBs, although leptomeningeal seeding may not be as high as previously reported, (4) prognosis is poor in rGBs. CONCLUSIONS: rGB is a new entity which has not yet appeared in the WHO classification of central nervous system (CNS) tumors. Understanding its clinical and imaging features may help to distinguish it from other tumors of CNS. PMID- 25516150 TI - The Blooming Anatomy Tool (BAT): A discipline-specific rubric for utilizing Bloom's taxonomy in the design and evaluation of assessments in the anatomical sciences. AB - Bloom's taxonomy is a resource commonly used to assess the cognitive level associated with course assignments and examination questions. Although widely utilized in educational research, Bloom's taxonomy has received limited attention as an analytical tool in the anatomical sciences. Building on previous research, the Blooming Anatomy Tool (BAT) was developed. This rubric provides discipline specific guidelines to Blooming anatomy multiple-choice questions (MCQs). To test the efficacy of the BAT, a group of volunteers were randomly split up and asked to Bloom a series of anatomy MCQs using either the BAT or a traditional Bloom's reference called Bloom's Learning Objectives (BLO). Both groups utilized each rubric for a different series of MCQs. Examination question categorizations made using each rubric were tested for accuracy and interrater reliability. In addition, previous experience in anatomy and Bloom's taxonomy were considered. Results demonstrated that volunteers using the BAT had consistently higher levels of interrater reliability, but accuracy varied and was similar between rubrics. Neither measure was substantially impacted by experience in Bloom's taxonomy or anatomy. A poststudy survey indicated that volunteers strongly preferred the BAT and felt it was more helpful in categorizing anatomy MCQs than the BLO. These results suggest that the BAT can be useful in educational research in the anatomical sciences to aid in aligning observer judgment on Bloom taxonomic levels and improve consistency, especially when used in conjunction with a norming session prior to data collection. PMID- 25516149 TI - Single-Stage Coil Embolization of Multiple Intracranial Aneurysms: Technical Feasibility and Clinical Outcomes. AB - PURPOSE: Not infrequently, intracranial aneurysms may be multifocal. However, strategies conferring open surgical access to opposite sides of the brain are limited. Given the recent advances in protection devices and coiling technique, a study of single-stage coil embolization in patients with multiple intracranial aneurysms was undertaken, assessing procedural safety and efficacy. METHODS: Data prospectively accrued between January 2010 and September 2013 were systematically reviewed, assessing clinical and morphologic outcomes of single-stage coil embolization in 172 patients with multiple aneurysms (>= 2 aneurysms each; total, 371 aneurysms). RESULTS: Internal carotid artery (n = 132) was the most common site, with progressively fewer aneurysms found elsewhere (middle cerebral artery, 103; anterior communicating artery, 41; posterior communicating artery, 38). In 26 patients, one-stage embolization of three or more aneurysms took place (25 patients with three each; 1 patient with four). Stents were applied in 109 aneurysms, and in 33 lesions, balloons were used. Occlusion was achieved in 326 aneurysms (87.9 %) through coil embolization, and attempted coiling rarely failed (3 of 371, 0.8 %). Mean procedural time was 111.5 +/- 37.8 min. Although procedure-related adverse events included three instances of treatment failure, asymptomatic thrombi in four patients, and aneurysmal leakage in one patient, procedural morbidity was low (1 of 172, 0.6 %), and no procedure-related deaths occurred. Postembolization follow-up of 303 aneurysms at > 6 months (mean, 15.4 +/- 9.8 months) showed complete occlusion in the vast majority (275 of 303, 90.8 %), with comparatively fewer instances of minor (19 of 303, 6.3 %) and major (9 of 303, 3.0 %) recanalization. Four patients experienced delayed cerebral infarction, but only one suffered permanent neurologic deficit (Glasgow outcome scale 4). CONCLUSION: Single-stage coil embolization of multiple unruptured intracranial aneurysms is technically feasible. The time required for such procedures and the rate of complications observed seem acceptable. PMID- 25516152 TI - Role of probiotics and functional foods in health: gut immune stimulation by two probiotic strains and a potential probiotic yoghurt. AB - There are numerous reports that show the benefits on the health attributed to the probiotic consumptions. Most of the studies were performed using animal models and only some of them were validated in controlled human trials. The present review is divided in two sections. In the first section we describe how the probiotic microorganisms can interact with the intestinal epithelial cells that are the first line of cell in the mucosal site, focusing in the studies of two probiotic strains: Lactobacillus casei DN-114001 (actually Lactobacillus paracasei CNCMI-1518) and Lactobacillus casei CRL 431. Then we describe same beneficial effects attributed to probiotic administration and the administration of fermented milks containing these microorganisms or potential probiotic yoghurt, principally on the immune system and on the intestinal barrier in different experimental mouse models like enteropathogenic infection, malnutrition, cancer and intestinal inflammation. PMID- 25516151 TI - Quadriceps femoris spasticity in children with cerebral palsy: measurement with the pendulum test and relationship with gait abnormalities. AB - BACKGROUND: Development of a reliable and objective test of spasticity is important for assessment and treatment of children with cerebral palsy. The pendulum test has been reported to yield reliable measurements of spasticity and to be sensitive to variations in spasticity in these children. However, the relationship between the pendulum test scores and other objective measures of spasticity has not been studied. The present study aimed to assess the effectiveness of an accelerometer-based pendulum test as a measurement of spasticity in CP, and to explore the correlation between the measurements of this test and the global index of deviation from normal gait in in children with cerebral palsy. METHODS: We studied thirty-six children with cerebral palsy, including 18 with spastic hemiplegia and 18 with spastic diplegia, and a group of 18 typically-developing children. Knee extensor spasticity was assessed bilaterally using the accelerometer-based pendulum test and three-dimensional gait analysis. The Gillette Gait Index was calculated from the results of the gait analysis. RESULTS: The data from the accelerometer-based pendulum test could be used to distinguish between able-bodied children and children with cerebral palsy. Additionally, two of the measurements, first swing excursion and relaxation index, could be used to differentiate the degree of knee extensor spasticity in the children with cerebral palsy. Only a few moderate correlations were found between the Gillette Gait Index and the pendulum test data. CONCLUSIONS: This study demonstrates that the pendulum test can be used to discriminate between typically developing children and children with CP, as well as between various degrees of spasticity, such as spastic hemiplegia and spastic diplegia, in the knee extensor muscle of children with CP. Deviations from normal gait in children with CP were not correlated with the results of the pendulum test. PMID- 25516153 TI - Sequencing chromosome 5D of Aegilops tauschii and comparison with its allopolyploid descendant bread wheat (Triticum aestivum). AB - Flow cytometric sorting of individual chromosomes and chromosome-based sequencing reduces the complexity of large, repetitive Triticeae genomes. We flow-sorted chromosome 5D of Aegilops tauschii, the D genome donor of bread wheat and sequenced it by Roche 454 GS FLX platform to approximately 2.2x coverage. Repetitive sequences represent 81.09% of the survey sequences of this chromosome, and Class I retroelements are the prominent type, with a particular abundance of LTR/Gypsy superfamily. Nonrepetitive sequences were assembled to cover 17.76% of the total chromosome regions. Up to 6188 nonrepetitive gene loci were predicted to be encoded by the 5D chromosome. The numbers and chromosomal distribution patterns of tRNA genes suggest abundance in tRNA(L) (ys) and tRNA(M) (et) species, while the nonrepetitive assembly reveals tRNA(A) (la) species as the most abundant type. A comparative analysis of the genomic sequences of bread wheat and Aegilops chromosome 5D indicates conservation of gene content. Orthologous unique genes, matching Aegilops 5D sequences, numbered 3730 in barley, 5063 in Brachypodium, 4872 in sorghum and 4209 in rice. In this study, we provide a chromosome-specific view into the structure and organization of the 5D chromosome of Ae. tauschii, the D genome ancestor of bread wheat. This study contributes to our understanding of the chromosome-level evolution of the wheat genome and presents a valuable resource in wheat genomics due to the recent hybridization of Ae. tauschii genome with its tetraploid ancestor. PMID- 25516154 TI - Mechanical recanalization in basilar artery occlusion: the ENDOSTROKE study. AB - OBJECTIVE: A study was undertaken to evaluate clinical and procedural factors associated with outcome and recanalization in endovascular stroke treatment (EVT) of basilar artery (BA) occlusion. METHODS: ENDOSTROKE is an investigator initiated multicenter registry for patients undergoing EVT. This analysis includes 148 consecutive patients with BA occlusion, with 59% having received intravenous thrombolysis prior to EVT. Recanalization (defined as Thrombolysis in Cerebral Infarction [TICI] score 2b-3) and collateral status (using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral grading system) were assessed by a blinded core laboratory. Good (moderate) outcome was defined as a modified Rankin Scale score of 0 to 2 (0-3) assessed after at least 3 months (median time to follow-up = 120 days). RESULTS: Thirty-four percent had good and 42% had moderate clinical outcome; mortality was 35%. TICI 2b-3 recanalization was achieved by 79%. Age, hypertension, National Institutes of Health Stroke Scale scores, collateral status, and the use of magnetic resonance imaging prior to EVT predicted clinical outcome, the latter 3 remaining independent predictors in multivariate analysis. Independent predictors of recanalization were better collateral status and the use of a stent retriever. However, recanalization did not significantly predict clinical outcome. INTERPRETATION: Beside initial stroke severity, the collateral status predicts clinical outcome and recanalization in BA occlusion. Our data suggest that the use of a stent retriever is associated with high recanalization rates, but recanalization on its own does not predict outcome. The role of other modifiable factors, including the choice of pretreatment imaging modality and time issues, warrants further investigation. PMID- 25516155 TI - Reducing complexity: a visualisation of multimorbidity by combining disease clusters and triads. AB - BACKGROUND: Multimorbidity is highly prevalent in the elderly and relates to many adverse outcomes, such as higher mortality, increased disability and functional decline. Many studies tried to reduce the heterogeneity of multimorbidity by identifying multimorbidity clusters or disease combinations, however, the internal structure of multimorbidity clusters and the linking between disease combinations and clusters are still unknown. The aim of this study was to depict which diseases were associated with each other on person-level within the clusters and which ones were responsible for overlapping multimorbidity clusters. METHODS: The study analyses insurance claims data of the Gmunder ErsatzKasse from 2006 with 43,632 female and 54,987 male patients who were 65 years and older. The analyses are based on multimorbidity clusters from a previous study and combinations of three diseases ("triads") identified by observed/expected ratios >= 2 and prevalence rates >= 1%. In order to visualise a "disease network", an edgelist was extracted from these triads, which was analysed by network analysis and graphically linked to multimorbidity clusters. RESULTS: We found 57 relevant triads consisting of 31 chronic conditions with 200 disease associations ("edges") in females and 51 triads of 29 diseases with 174 edges in males. In the disease network, the cluster of cardiovascular and metabolic disorders comprised 12 of these conditions in females and 14 in males. The cluster of anxiety, depression, somatoform disorders, and pain consisted of 15 conditions in females and 12 in males. CONCLUSIONS: We were able to show which diseases were associated with each other in our data set, to which clusters the diseases were assigned, and which diseases were responsible for overlapping clusters. The disease with the highest number of associations, and the most important mediator between diseases, was chronic low back pain. In females, depression was also associated with many other diseases. We found a multitude of associations between disorders of the metabolic syndrome of which hypertension was the most central disease. The most prominent bridges were between the metabolic syndrome and musculoskeletal disorders. Guideline developers might find our approach useful as a basis for discussing which comorbidity should be addressed. PMID- 25516157 TI - sigma-Silane, disilanyl, and [W(MU-H)Si(MU-H)W] bridging silylene complexes via the reactions of W(PMe3)4(eta2-CH2PMe2)H with phenylsilanes. AB - W(PMe3)4(eta(2)-CH2PMe2)H reacts with PhSiH3 to give the first examples of diphenyldisilanyl compounds, W(PMe3)4(SiH2SiHPh2)H3 and W(PMe3)3(SiH2Ph)(SiH2SiHPh2)H4, via a mechanism that is proposed to involve migration of a SiHPh2 group to a silylene ligand. In addition to the formation of the aforementioned mononuclear compounds, the reaction of W(PMe3)4(eta(2) CH2PMe2)H with PhSiH3 also yields a novel dinuclear compound, [W(PMe3)2(SiHPh2)H2](MU-Si,P-SiHPhCH2PMe2)(MU-SiH2)[W(PMe3)3H2], which features a bridging silylene ligand that participates in 3-center-2-electron interactions with both tungsten centers. The bonding within the [W(MU-H)Si(MU-H)W] core can be described by a variety of resonance structures, some of which possess multiple bond character between tungsten and silicon. In this regard, [W(PMe3)2(SiHPh2)H2](MU-Si,P-SiHPhCH2PMe2)(MU-SiH2)[W(PMe3)3H2] possesses the shortest W-Si bond length reported. The corresponding reaction of W(PMe3)4(eta(2) CH2PMe2)H with Ph2SiH2 yields the sigma-silane compound, W(PMe3)3(sigma HSiHPh2)H4. PMID- 25516156 TI - Peroxisome proliferator-activated receptors alpha and gamma are linked with alcohol consumption in mice and withdrawal and dependence in humans. AB - BACKGROUND: Peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary ethanol (EtOH) consumption in rat models and are promising therapeutics in the treatment for drug addictions. We studied the effects of different classes of PPAR agonists on chronic EtOH intake and preference in mice with a genetic predisposition for high alcohol consumption and then examined human genomewide association data for polymorphisms in PPAR genes in alcohol-dependent subjects. METHODS: Two different behavioral tests were used to measure intake of 15% EtOH in C57BL/6J male mice: 24-hour 2-bottle choice and limited access (3-hour) 2 bottle choice, drinking in the dark. We measured the effects of pioglitazone (10 and 30 mg/kg), fenofibrate (50 and 150 mg/kg), GW0742 (10 mg/kg), tesaglitazar (1.5 mg/kg), and bezafibrate (25 and 75 mg/kg) on EtOH intake and preference. Fenofibric acid, the active metabolite of fenofibrate, was quantified in mouse plasma, liver, and brain by liquid chromatography tandem mass spectrometry. Data from a human genome-wide association study (GWAS) completed in the Collaborative Study on the Genetics of Alcoholism (COGA) were then used to analyze the association of single nucleotide polymorphisms (SNPs) in different PPAR genes (PPARA, PPARD, PPARG, and PPARGC1A) with 2 phenotypes: DSM-IV alcohol dependence (AD) and the DSM-IV criterion of withdrawal. RESULTS: Activation of 2 isoforms of PPARs, alpha and gamma, reduced EtOH intake and preference in the 2 different consumption tests in mice. However, a selective PPARdelta agonist or a pan agonist for all 3 PPAR isoforms did not decrease EtOH consumption. Fenofibric acid, the active metabolite of the PPARalpha agonist fenofibrate, was detected in liver, plasma, and brain after 1 or 8 days of oral treatment. The GWAS from COGA supported an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with AD but found no association for PPARD with either phenotype. CONCLUSIONS: We provide convergent evidence using both mouse and human data for specific PPARs in alcohol action. Reduced EtOH intake in mice and the genetic association between AD or withdrawal in humans highlight the potential for repurposing FDA-approved PPARalpha or PPARgamma agonists for the treatment of AD. PMID- 25516159 TI - Reply: To PMID 24415656. PMID- 25516158 TI - Breast cancer risk reduction--is it feasible to initiate a randomised controlled trial of a lifestyle intervention programme (ActWell) within a national breast screening programme? AB - BACKGROUND: Breast cancer is the most commonly diagnosed cancer and the second cause of cancer deaths amongst women in the UK. The incidence of the disease is increasing and is highest in women from least deprived areas. It is estimated that around 42% of the disease in post-menopausal women could be prevented by increased physical activity and reductions in alcohol intake and body fatness. Breast cancer control endeavours focus on national screening programmes but these do not include communications or interventions for risk reduction. This study aimed to assess the feasibility of delivery, indicative effects and acceptability of a lifestyle intervention programme initiated within the NHS Scottish Breast Screening Programme (NHSSBSP). METHODS: A 1:1 randomised controlled trial (RCT) of the 3 month ActWell programme (focussing on body weight, physical activity and alcohol) versus usual care conducted in two NHSSBSP sites between June 2013 and January 2014. Feasibility assessments included recruitment, retention, and fidelity to protocol. Indicative outcomes were measured at baseline and 3 month follow-up (body weight, waist circumference, eating and alcohol habits and physical activity). At study end, a questionnaire assessed participant satisfaction and qualitative interviews elicited women's, coaches, and radiographers' experiences. Statistical analysis used Chi squared tests for comparisons in proportions and paired t tests for comparisons of means. Linear regression analyses were performed, adjusted for baseline values, with group allocation as a fixed effect. RESULTS: A pre-set recruitment target of 80 women was achieved within 12 weeks and 65 (81%) participants (29 intervention, 36 control) completed 3 month assessments. Mean age was 58 +/- 5.6 years, mean BMI was 29.2 +/- 7.0 kg/m(2) and many (44%) reported a family history of breast cancer. The primary analysis (baseline body weight adjusted) showed a significant between group difference favouring the intervention group of 2.04 kg (95% CI 3.24 kg to -0.85 kg). Significant, favourable between group differences were also detected for BMI, waist circumference, physical activity and sitting time. Women rated the programme highly and 70% said they would recommend it to others. CONCLUSIONS: Recruitment, retention, indicative results and participant acceptability support the development of a definitive RCT to measure long term effects. TRIAL REGISTRATION: The trial was registered with Current Controlled Trials (ISRCTN56223933). PMID- 25516160 TI - Utility of near infrared light to determine tissue oxygenation during hepato biliary surgery. AB - Near-infrared spectrophotometry assesses cerebral oxygen saturation (ScO2) based on the absorption spectra of oxygenated and deoxygenated hemoglobin, and the translucency of biological tissue, in the near-infrared band. There is increasing evidence that optimising cerebral oxygenation, guided by ScO2, is associated with improved outcomes in a variety of high risk surgical settings. However, in patients with liver disease, bilirubin can potentially render cerebral oximetry inaccurate. As a result, measurement of cerebral oxygen saturation is rarely undertaken in patients undergoing hepatobiliary surgery. We prospectively measured baseline and intraoperative cerebral oxygen saturation in patients undergoing major pancreatic surgery. Indices including bilirubin, sodium, platelets and maximum amplitude on thromboelastography were associated with low baseline ScO2. However, those patients with low ScO2 (<=51%) maintained a similar trend in cerebral oximetry values both at induction and intraoperatively to those with a normal ScO2. We conclude that the pattern of cerebral oximetry is similar in patients undergoing major pancreatic surgery regardless of their underlying liver dysfunction. Therefore, cerebral oximetry may have a role in monitoring neurological function in this high risk group of patients. PMID- 25516162 TI - Evaluation of filtering methods for acquiring radial intra-artery blood pressure waveforms. AB - The methods for evaluating noninvasive blood pressure (NIBP) monitors using an intra-arterial reference are detailed in the ANSI/AAMI/ISO 81060-2:2009 standard. In a recent study, GE Healthcare obtained invasive radial arterial blood pressure waveforms. The work presented here describes the development of filtering strategies for obtaining high fidelity intra-arterial pressure waveforms for NIBP accuracy testing using the 81060-2 standard. The natural frequency and damping factor of each subject-catheter-transducer system was computed from fast-flush transients. These parameters were used to construct filters for removing or reducing resonance artifacts. Additionally, new optimal damping factors were evaluated for designing compensation filters. Theoretical measurement systems using actual damping factors (< 0.4) and natural frequencies were found capable of generating significant systolic resonance artifacts (>= 8 mmHg). Typical filters that may be standardly available in monitoring equipment were observed to be potentially inadequate in removing resonance artifact. Filters with particular optimal damping factors (0.6-0.7) were effective in removing resonance artifact. Clinicians need to understand that resonance artifacts potentially exist in intra arterial waveforms and that the adjustments of monitoring systems may not be adequate. Optimal filters for obtaining intra-arterial waveforms should take into account the damping factor and natural frequency of the measuring system. In research and device evaluation studies it is necessary that optimal filtering be done to minimize the effects of under-damping. PMID- 25516161 TI - Radial artery cannulation decreases the distal arterial blood flow measured by power Doppler ultrasound. AB - Radial arterial cannulation is a popular technique for continuous hemodynamic monitoring in an area of anesthesia and intensive care. Although the risk for invasive monitoring is considerable, there is scarce information about the change in blood flow of cannulated vessel after the catheterization. In the current investigation, we evaluated the change in the cannulated arterial blood flow. Six volunteers (study 1) and eight post-surgical patients (study 2) were enrolled into the studies. In the study 1, the both side of diameter of radial artery (RA), ulnar artery (UA) and dorsal branch of radial artery (DBRA) of participants were measured using power Doppler ultrasound (PDU) with or without proximal oppression. In the study 2, the diameter of RA, UA and DBRA of the both intact and cannulated side were compared. Study 1: The diameter of RA was 3.4 (0.52) [mean (SD)] mm and the proximal oppression significantly decreased the diameter to 1.8 (0.59) mm. The diameter of DBRA measured by PDU also decreased 2.0 (0.60) 1.3 (0.59) mm. Study 2: There was no difference between the diameters of right and left RA, however, the UA was larger [3.4 (0.60) vs. 2.8 (0.83) mm] and the DBRA was narrower [1.4 (0.43) vs. 2.0 (0.47) mm] in the cannulated side. The diameters of DBRA were different between the intact and cannulated side in the patients. Although there is no information of relationships between cause of severe complication and decreased flow, significant reduction of blood flow should be concerned. PMID- 25516163 TI - Effect of planecta and ROSETM on the frequency characteristics of blood pressure transducer kits. AB - Pressure-transducer kits have frequency characteristics such as natural frequency and damping coefficient, which affect the monitoring accuracy. The aim of the present study was to investigate the effect of planecta ports and a damping device (ROSETM, Argon Medical Devices, TX, USA) on the frequency characteristics of pressure-transducer kits. The FloTrac sensor kit (Edwards Lifesciences, CA, USA) and the DTXplus transducer kit (Argon Medical Devices) were prepared with planecta ports, and their frequency characteristics were tested with or without ROSETM. The natural frequency and damping coefficient of each kit were obtained using frequency characteristics analysis software and evaluated by plotting them on the Gardner's chart. By inserting a planecta port, the natural frequency markedly decreased in both the FloTrac sensor kit (from 40 to 22 Hz) and the DTXplus transducer kit (from 35 to 22 Hz). In both kits with one planecta port, the damping coefficient markedly increased by insertion of ROSETM from 0.2 to 0.5, optimising frequency characteristics. In both kits with two planecta ports, however, the natural frequency decreased from 22 to 12 Hz. The damping coefficient increased from 0.2 to 0.8 by insertion of ROSETM; however, optimisation was not achieved even by ROSETM insertion. Planecta ports decrease the natural frequency of the kit. ROSETM is useful to optimise the frequency characteristics in the kits without or with one planecta port. However, optimisation is difficult with two or more planecta ports, even with the ROSETM device. PMID- 25516164 TI - Report of the clinical donor case workshop of the European Association of Tissue Banks Annual Congress 2013. AB - The European Association of Tissue Banks (EATB) Donor Case Workshop is a forum held within the program of the EATB Annual Congress. The workshop offers an opportunity to discuss and evaluate approaches taken to challenging donor selection and donation ethics, and it strengthens networking between tissue banking professionals. The workshops actively engage participants from a wide array of international expertise, in an informal, secure and enjoyable setting in which learning from peers and finding potential solutions for submitted cases are facilitated. This report reflects some of the discussion at the Donor Case Workshop during the EATB Annual Congress in Brussels in 2013. The presented cases demonstrate that the findings, their interpretation, the resulting actions and preventive measures in the different tissue facilities are not always predictable. The varied responses from participants and lack of consensus corroborate this and clearly indicate that operating procedures do not comprehensively cover or prepare for all eventualities. For many of the issues raised there is no relevant information in the published literature. By publication of a summary of the discussions we hope to reach a wider audience, to provide information gathered at the workshop and to stimulate individuals and institutions to undertake further literature reviews or to undertake research in order to gather evidence concerning the discussed topics. PMID- 25516165 TI - BAHA surgery in England--variation in service provision for adults across Strategic Health Authority regions revealed by the Hospital Episode Statistics database. PMID- 25516166 TI - Quantification of endogenous metabolites by the postcolumn infused-internal standard method combined with matrix normalization factor in liquid chromatography-electrospray ionization tandem mass spectrometry. AB - Quantification of endogenous metabolites has enabled the discovery of biomarkers for diagnosis and provided for an understanding of disease etiology. The standard addition and stable isotope labeled-internal standard (SIL-IS) methods are currently the most widely used approaches to quantifying endogenous metabolites, but both have some limitations for clinical measurement. In this study, we developed a new approach for endogenous metabolite quantification by the postcolumn infused-internal standard (PCI-IS) method combined with the matrix normalization factor (MNF) method. MNF was used to correct the difference in MEs between standard solution and biofluids, and PCI-IS additionally tailored the correction of the MEs for individual samples. Androstenedione and testosterone were selected as test articles to verify this new approach to quantifying metabolites in plasma. The repeatability (n=4 runs) and intermediate precision (n=3 days) in terms of the peak area of androstenedione and testosterone at all tested concentrations were all less than 11% relative standard deviation (RSD). The accuracy test revealed that the recoveries were between 95.72% and 113.46%. The concentrations of androstenedione and testosterone in fifty plasma samples obtained from healthy volunteers were quantified by the PCI-IS combined with the MNF method, and the quantification results were compared with the results of the SIL-IS method. The Pearson correlation test showed that the correlation coefficient was 0.98 for both androstenedione and testosterone. We demonstrated that the PCI-IS combined with the MNF method is an effective and accurate method for quantifying endogenous metabolites. PMID- 25516168 TI - Generalized acquired cutis laxa with papular lesions. PMID- 25516167 TI - Adolescents' exposure to tobacco and alcohol content in YouTube music videos. AB - AIMS: To quantify tobacco and alcohol content, including branding, in popular contemporary YouTube music videos; and measure adolescent exposure to such content. DESIGN: Ten-second interval content analysis of alcohol, tobacco or electronic cigarette imagery in all UK Top 40 YouTube music videos during a 12 week period in 2013/14; on-line national survey of adolescent viewing of the 32 most popular high-content videos. SETTING: Great Britain. PARTICIPANTS: A total of 2068 adolescents aged 11-18 years who completed an on-line survey. MEASUREMENTS: Occurrence of alcohol, tobacco and electronic cigarette use, implied use, paraphernalia or branding in music videos and proportions and estimated numbers of adolescents who had watched sampled videos. FINDINGS: Alcohol imagery appeared in 45% [95% confidence interval (CI) = 33-51%] of all videos, tobacco in 22% (95% CI = 13-27%) and electronic cigarettes in 2% (95% CI = 0-4%). Alcohol branding appeared in 7% (95% CI = 2-11%) of videos, tobacco branding in 4% (95% CI = 0-7%) and electronic cigarettes in 1% (95% CI = 0-3%). The most frequently observed alcohol, tobacco and electronic cigarette brands were, respectively, Absolut Tune, Marlboro and E-Lites. At least one of the 32 most popular music videos containing alcohol or tobacco content had been seen by 81% (95% CI = 79%, 83%) of adolescents surveyed, and of these 87% (95% CI = 85%, 89%) had re-watched at least one video. The average number of videos seen was 7.1 (95% CI = 6.8, 7.4). Girls were more likely to watch and also re-watch the videos than boys, P < 0.001. CONCLUSIONS: Popular YouTube music videos watched by a large number of British adolescents, particularly girls, include significant tobacco and alcohol content, including branding. PMID- 25516169 TI - Comparative pharmacokinetics of three monoester-diterpenoid alkaloids after oral administration of Acontium carmichaeli extract and its compatibility with other herbal medicines in Sini Decoction to rats. AB - Sini decoction (SND) is an important traditional Chinese multiherbal formula, which is widely used to treat cardiovascular disease. Acontium carmichaeli (AC) is a leading herb in SND, whose main components are monoester-diterpenoid alkaloids (MDAs). The aim of this study is to compare the pharmacokinetics of three MDAs in rat plasma after oral administration of AC extract and its compatibility with other herbal medicines in SND. A sensitive, accurate and specific LC-MS/MS method was developed to determine the contents of three MDAs in rat plasma. Male Sprague-Dawley rats were randomly assigned to four groups: AC, AC + ZO, AC + GU and SND groups. There were significant differences in the pharmacokinetic parameters (Cmax, Tmax, t1/2, AUC(0-24), MRT and CL). Compared with the AC group, Cmax, AUC(0-24) and CL of three MDAs increased and t1/2 decreased in AC + ZO, AC + GU and SND groups. Little changed in the AC + GU group in comparison with AC + ZO group, which indicated that other ingredients in ZO may promote the absorption rate and accelerate excretion rate of MDAs. The results could be helpful for revealing the compatibility mechanism of Chinese multiherbal medicine and providing clinical medication guidance on AC and its compatibility with other herbal medicines in SND. PMID- 25516170 TI - Tibial ACL insertion site length: correlation between preoperative MRI and intra operative measurements. AB - PURPOSE: This study was undertaken primarily to identify the tibial insertion site length of ruptured ACL fibres in patients undergoing primary ACL reconstruction. A secondary aim was to evaluate the correlation of pre- and intra operative measurements. METHODS: In 146 patients undergoing primary ACL reconstruction, a preoperative measurement on MRI of the tibial ACL insertion site length was taken by two raters and then compared with single surgeon's intra operative measurements using a specialized ruler. Inclusion criteria were primary ACL reconstruction and MRI performed within 3 months prior to surgery on one specific MRI machine at the study centre. Inter-rater and intra-rater reliability based on intra class correlation (ICC) was calculated. Additionally, correlation between preoperative and postoperative measurements and the anthropometric data was assessed using Pearson correlation. RESULTS: The tibial ACL insertion site had a mean length of 16.6 +/- 1.6 mm (11.9-21.0) as measured by MRI, and 16.4 +/- 1.6 mm (11.0-20.0) as measured intra-operatively. The ICCs for intra- and inter rater reliability of the MRI measurements were 0.99 (95 % CI 0.97; 0.99; p < 0.001) and 0.81 (95 % CI 0.75; 0.86; p < 0.001), respectively. Regression analysis demonstrated, after controlling for subject height and weight, that the MRI measurements significantly predicted intra-operative measurement of tibial insertion site length (beta = 0.796; R (2)-change 0.77; p < 0.001). CONCLUSION: Preoperative measurement of the tibial ACL length is possible using MRI and can be a valuable aid in more efficient preoperative planning given the knowledge of expected dimensions of special knee structures. LEVEL OF EVIDENCE: III. PMID- 25516172 TI - Need for guidelines on body recontouring after bariatric surgery. PMID- 25516171 TI - Bone mineral density of the coracoid process decreases with age. AB - PURPOSE: Surgical options in the treatment of recurrent anterior shoulder instability are numerous. The Latarjet procedure is one of the most common procedures performed. It has been previously demonstrated that bone mineral density decreases with age. This reduction thus increases the risk of osteoporosis and osteoporosis-related iatrogenic, traumatic or pathological fractures. The objective of this study was to quantify the bone mineral density of the coracoid process in different age groups. The hypothesis was that mineral bone density of the coracoid process decreases with age. METHODS: Using the hospital's electronic database, 60 patients who underwent a shoulder CT scan were randomly selected retrospectively. Four groups of 15 were formed with mean ages of 20, 30, 40 and 50 years. Bone density, length, width and thickness of the coracoid process 10 mm from the tip were measured four times by two different evaluators. Bone density was expressed in Hounsfield units (HU). RESULTS: The mean bone mineral density of the coracoid process significantly decreased with age (p < 0.0001). A lower but insignificant difference of bone mineral density was observed in females. A good inter- and intra-observer reliability was found for bone mineral density measurement of the coracoid process (0.67 and 0.7, respectively). CONCLUSIONS: The bone mineral density of the coracoid process diminishes with age, thus confirming our hypothesis. There is a good inter- and intra-observer reliability of our CT scan-based coracoid process bone mineral density measurement rendering it reproducible in daily clinical practice. LEVEL OF EVIDENCE: IV. PMID- 25516173 TI - Feasibility and safety of parietal pleural cryobiopsy during semi-rigid thoracoscopy. AB - BACKGROUND AND AIMS: Performing pleural biopsies during semi-rigid thoracoscopy is sometimes a difficult and time-consuming task because of the lack of mechanical power of dedicated flexible forceps in patients with thickened pleura. The purpose of this first ever pilot study was to test the feasibility of taking biopsy specimens by cryoprobe from the parietal pleura during semi-rigid thoracoscopy. Our aim was also to assess the diagnostic value and quality of specimens obtained, morphological features, feasibility of immunohistochemistry staining and possibility of DNA isolation. The secondary aim was to evaluate safety, tolerability and duration of the procedure. METHODS: Fifteen patients with pleural effusion of unknown origin that underwent semi-rigid thoracoscopy were included. Biopsies were obtained using a flexible autoclavable cryoprobe 20416-032 (Erbokryo CA, ERBE, Tubingen, Germany) 2.4 mm in diameter and a semi rigid autoclavable Olympus LTF-160 (Olympus, Tokyo, Japan) thoracoscope. RESULTS: Tissue samples were obtained from 14 patients (93.3%), three from each. Of the samples, 81% were easily interpretable and 19% were interpretable with some difficulty by the pathologist. The samples were of good quality, with the level of artifacts below 25%. The specimens were adequate for histological diagnosis, immunohistochemical staining and DNA isolation. There were no moderate or major bleeding problems after the biopsies; two patients experienced pain. The median duration of three cryobiopsies (per patient) was 4 min (range 3-6 min). CONCLUSIONS: Cryobiopsy during semi-rigid thoracoscopy appears worth to be evaluated in a larger prospective multicenter trial as our preliminary data were promising for efficacy and safety. PMID- 25516174 TI - Clinical diagnosis and therapy of uterine scar defects after caesarean section in non-pregnant women. AB - PURPOSE: Caesarean delivery (c-section) scar dehiscences may cause bleeding abnormalities, e.g. postmenstrual spotting, dysmenorrhea and abdominal pain, secondary sterility and at worst peripartum uterine rupture. The purpose of this study was firstly to identify the correlation of women's complaints after c section with scar-related clinical symptoms. Secondly, the effects of corrective surgery on preoperatively existing complaints were analysed and assessed in the patient population of our clinic. METHODS: We present data of a retrospective study of 13 premenopausal, non-pregnant women with symptomatic c-section scars. In 9 out of 13 patients, a microsurgical uterus reconstruction was performed by mini-laparotomy. The postoperative changes of scar-associated symptoms were assessed by a questionnaire as earliest as 4 months after surgery (N = 5). RESULTS: The c-section scar was visualised by transvaginal sonography in 12 out of 13 women by a typical U- or V-shaped hypoechoic or anechoic fluid accumulation in the region of former uterotomy and in all 13 patients by hysteroscopy. Bleeding disorders were often accompanied by dysmenorrhea/abdominal pain (38.5%, N = 5) and secondary sterility (46.2%, N = 6). Blood residues in the scar pouch and bleeding disorders/postmenstrual spotting were found in 30.8% of patients (N = 4) and combined with secondary sterility in 38.5% of patients (N = 5). Reconstructive surgeries resulted in discontinuation of bleeding disorders in all women and a pregnancy in three out of five patients (60%) with secondary sterility. CONCLUSION: Clinical symptoms, e.g. "bleeding disorders" like postmenstrual spotting, "pain/dysmenorrhea" and "secondary sterility" could be specific indicators for the diagnosis of uterine dehiscence after c-section. Scar dehiscences can be diagnosed by obtaining the patients medical history and asking for typical symptoms followed by vaginal sonography and diagnostic hysteroscopy. If a c-section scar defect is confirmed, microsurgical uterus reconstruction can stop postmenstrual spotting, reduce abdominal pain/dysmenorrhea and improve fertility. PMID- 25516175 TI - Response to: Impact of luteal phase hysteroscopy and concurrent endometrial biopsy on subsequent IVF cycle outcome. PMID- 25516176 TI - Persistent urinary retention after surgery for deep infiltrating endometriosis: a multi-center series of 16 cases. AB - PURPOSE: Persistent urinary retention (UR) is a complication of 3.5-14.3% of patients having undergone deep pelvic endometriosis (DPE) surgery of posterior compartment, and it is prone to persist. The purpose of this study is to identify surgical procedures and clinical circumstances associated with persistent UR, and consider its treatment. METHODS: We undertook a multi-center retrospective study studying medical records of patients who had surgery for DPE between January 2005 and December 2012. Patients who suffered from UR defined as a post-void residual (PVR) volume >100 mL needing intermittent self-catheterizations more than 30 days after surgery were included. Preoperative data (functional complaints, clinical examination, imaging, medical treatment) were recorded. Types of surgery and detailed postoperative urinary symptoms were noted. RESULTS: 881 patients had surgery for DPE and 16 patients were included (1.8%). In 93.8% of cases, a lesion of posterior compartment was clinically significant. Mean lesion size was 28.8 +/ 7.3 mm. Colorectal resection and colpectomy were necessary in 93.8 and 87.5% of cases, respectively. Loss of bladder sensation and straining during urination were the two most common post-operative symptoms. 11 patients still required self catheterization up to 1 year after the intervention. CONCLUSIONS: Patients with increased risks of UR present with a symptomatic and clinically palpable deep pelvic endometriotic lesion of the posterior compartment. Treatment implies surgery with colorectal resection. Bilateral resection of utero-sacral ligaments and posterior colpectomy tend to increase that risk. Complications due to PVR volume and straining during urination may be prevented by self-catheterization. PMID- 25516177 TI - The feasibility of administering varying high-dose consolidation hyperthermic intraperitoneal chemotherapy with carboplatin in the treatment of ovarian carcinoma. AB - OBJECTIVES: Hyperthermic intraperitoneal chemotherapy (HIPEC) is an intriguing method of delivery wherein the cytotoxic agent is continuously heated and circulated throughout the peritoneum in an attempt to bolster drug efficacy. Despite HIPEC's potential, ascertaining the optimal dose without compromising patient tolerability remains indeterminate. METHODS: We retrospectively evaluated 52 advanced stage ovarian cancer patients who were treated with consolidation HIPEC with carboplatin at varying doses (e.g., AUC 6, 8 or 10) subsequent to optimal debulking surgery and the attainment of a clinical complete response to their primary chemotherapy regimen. The following patient and operative characteristics were abstracted: demographics, surgery and pathology data, chemotherapy regimen, intraoperative results, toxicity, postoperative complications, length of hospital stay and survival data. RESULTS: Twelve patients received HIPEC carboplatin at an AUC 6, 15 subjects were treated with carboplatin at an AUC 8 and 25 underwent carboplatin at an AUC 10. There were no intraoperative complications during the administration of HIPEC; mean estimated blood loss was 50 mL and length of hospital stay was 1.65 days. In the overall study population, 5 patients developed grade 3/4 anemia and 33 subjects exhibited grade <=2 thrombocytopenia and neutropenia. Thirteen patients also developed grade <=2 nausea on postoperative day 1, which was successfully addressed with anti-emetic therapy; there were no hospital readmissions. CONCLUSIONS: The results from the current evaluation suggest that consolidation hyperthermic intraperitoneal chemotherapy with carboplatin is both feasible and reasonably tolerated, even at an AUC of 10. However, additional, randomized study of this procedure incorporating chemotherapy dose escalation with a more extensive patient population is warranted. PMID- 25516178 TI - Personal or first-degree family breast cancer history: which has higher impact on tumor detection and tumor size in breast cancer. AB - PURPOSE: A woman's risk of developing breast cancer (BC) is increased if she has a personal history (PH) or family history (FH) of the disease. We compared the impact of the two risk factors PH and FH on tumor detection and tumor size at diagnosis in a cohort of BC patients. METHODS: The study cohort comprised 1,037 invasive BC patients (<=70 years at diagnosis). From these, 92 patients (8.5%) had a positive PH and 151 patients (13.7%) had a positive first-degree FH. RESULTS: Compared to the tumors of patients without PH or FH, the lesions of patients who had a positive PH or a positive FH were more often found by radiologic breast examinations (RBE) (PH: 49.4%, FH: 43.4%, no PH/FH: 26.2%; both comparisons p < 0.001). In patients with a positive FH, the tumors were slightly less often found by RBE as in patients with a positive PH (p = 0.468). Patients with a positive PH or FH had smaller tumors compared with those without such a history (PH: 19.7 mm, FH: 19.6 mm, no PH/FH: 26.7 mm; p = 0.015/p < 0.001). The tumor sizes of patients with a positive PH were almost identical to those of patients with a positive FH (p = 0.999). CONCLUSIONS: In women with a positive FH or PH of BC, the increased awareness of BC risk led to the detection of smaller tumors compared to women who have not had this experience. However, comparison of the two risk factors showed that they had a similar impact on the RBE detection rate of BC lesions and that the tumor sizes were nearly identical. PMID- 25516180 TI - Dietary acrylamide intake and risk of endometrial cancer in prospective cohort studies. AB - PURPOSE: Acrylamide has been associated with carcinogenicity in experimental animals, but potential health risks of dietary acrylamide intake and endometrial cancer in human are inconclusive. Thus, a meta-analysis of prospective cohort studies was conducted to provide a quantitative assessment of the association between dietary acrylamide intake and endometrial cancer risk. METHODS: PubMed database was used to identify prospective cohort studies on dietary acrylamide intake and endometrial cancer risk published up to June 2014. Since smoking is an important source of acrylamide and is inversely associated with endometrial cancer risk, the association was examined in women who never smoked as well. Multivariable relative risks (RR) adjusting for potential confounders were combined using random effects models. RESULTS: Four large prospective cohort studies were identified, which included 453,355 female participants and 2,019 endometrial cancer cases. There was no association between dietary acrylamide intake and endometrial cancer risk overall [pooled RR for high vs. low intake = 1.10; 95% confidence interval (CI) 0.91-1.34]. High acrylamide intake, however, was significantly associated with increased risk of endometrial cancer among women who never smoked (pooled RR for high vs. low intake = 1.39; 95% CI 1.09 1.77). In dose-response analyses, pooled RRs for an increase of 10 ug/day were 1.04 (95% CI 0.97-1.11) among all women and 1.11 (95% CI 1.04-1.19) among never smoking women. CONCLUSIONS: Endometrial cancer risk was not associated with dietary acrylamide intake overall. Among women who never smoked, however, there was a significantly increased endometrial cancer risk in women who consumed high dietary acrylamide. PMID- 25516179 TI - Early prediction for the requirement of second or third dose methotrexate in women with ectopic pregnancy, treated with single-dose regimen. AB - PURPOSE: To investigate the predictive factors for the requirement of additional doses of methotrexate in women with ectopic pregnancy treated with single-dose methotrexate regimen. METHODS: This retrospective cohort study was conducted on women treated with single-dose methotrexate regimen for ectopic pregnancy at a tertiary referral center. Control group included the patients who were treated only with a single dose of methotrexate (n = 131) and study group included the patients who need a second dose or third dose methotrexate (n = 76). The sonographic variables such as size of the ectopic mass, the endometrial thickness and biochemical variables were analyzed via Chi square and student t test. Logistic regression analysis used to determine independent predictors of the additional dose requirement. RESULTS: The size of the ectopic mass and the endometrial thickness were similar in both groups. However, all human chorionic gonadotropin values on day 1, 4 and 7 were significantly higher in study group than the control group (p = 0.0001). Logistic regression analysis revealed that the human chorionic gonadotropin changes between day 1 and 4 is a predictive factor for requirement of additional doses of methotrexate (area under curve: 0.763, p < 0.001) and the cutoff value for human chorionic gonadotropin change was calculated as 22%. The probability of the requirement for an additional dose of methotrexate is 6.45 times more in patients who had less than 22% reduction in human chorionic gonadotropin levels from day 1 to 4 compared to those who had >22% reduction from day 1 to 4. CONCLUSION: Less than 22% reduction in human chorionic gonadotropin levels from day 1 to 4 can be used as a predictive factor for the requirement of an additional dose of methotrexate in single-dose regimen. This cutoff value can be used for patients to inform about the probable longer resolution time and refer to alternative treatment modalities such as two-dose, multiple-dose regimens or surgery. PMID- 25516181 TI - Weight changes in Portuguese patients with depression: which factors are involved? AB - BACKGROUND & AIMS: Depression may lead to obesity, just as obesity can contribute to the disease; yet, changes in the dietary pattern and food habits in depressive syndromes have been scantily investigated. We aimed to identify possible associations between nutritional factors and depressive disorder. METHODS: This cross sectional study included 127 consecutive ambulatory adult patients with depression (DSM-IV), under psychiatric treatment. All study parameters were classified according to sex & age: BMI, waist circumference, %fat mass, food intake & physical activity. RESULTS: Patients' mean age was 48 +/- 13 (18-81) yrs, 94% were women. Overweight/obesity was found in 72% of the cohort, 72% had excessive fat mass & 69% had a waist circumference above the maximum cut-off value. Longer disease was associated with higher BMI +%fat mass, p < 0.003. Weight gain during illness was registered in 87%; just 12% lost weight, though undernutrition did not occur. Weight gain and greater fat mass were related with higher BMI, p = 0.002. The pattern of food intake was poor, monotonous and inadequate in 59% of patients; there was also a regular consumption of hypercaloric foods by 78% pts. Overall, the usual diet was associated with weight gain, p = 0.002. Antidepressants (75%) and benzodiazepines (72%) were prevalent; these drugs were associated with weight gain, p = 0.01; 80% pts did not practice any physical activity. CONCLUSIONS: There was a positive association with overweight/obesity: a striking & clinically worrying prevalence of high fat mass, abdominal fat, weight gain, poor nutritional intake and sedentarism. This unhealthy pattern points towards the need of a multidisciplinary approach to promote healthy lifestyles that may help depressive disorder management. PMID- 25516182 TI - Editorial commentary: women who have sex with women: a unique population for studying the pathogenesis of bacterial vaginosis. PMID- 25516183 TI - Poorer cognitive performance in perinatally HIV-infected children versus healthy socioeconomically matched controls. AB - BACKGROUND: Despite the declining incidence of severe neurological complications such as HIV encephalopathy, human immunodeficiency virus (HIV) infection in children is still associated with a range of cognitive problems. Although most HIV-infected children in industrialized countries are immigrants with a relatively low socioeconomic status (SES), cognitive studies comparing HIV infected children to SES-matched controls are lacking. METHODS: This cross sectional study included perinatally HIV-infected children and controls matched for age, sex, ethnicity, and SES, who completed a neuropsychological assessment evaluating intelligence, information processing speed, attention, memory, executive function, and visual-motor function. Multivariate normative comparison was used to assess the prevalence of cognitive impairment in the HIV-infected group. Multivariable regression analyses were performed to identify HIV- and combination antiretroviral therapy-related factors associated with cognitive performance. RESULTS: In total, 35 perinatally HIV-infected children (median age, 13.8 years; median CD4 count, 770 * 10(6) cells/L; 83% with undetectable HIV RNA) and 37 healthy children (median age, 12.1 years) were included. HIV-infected children scored lower than the healthy controls on all cognitive domains (eg, intelligence quotient [IQ], 76 [standard deviation {SD}, 15.7] vs 87.5 [SD, 13.6] for HIV-infected vs healthy children; P = .002). Cognitive impairment was found in 6 HIV-infected children (17%). The Centers for Disease Control and Prevention (CDC) clinical category at HIV diagnosis was inversely associated with verbal IQ (CDC clinical category C: coefficient -22.98; P = .010). CONCLUSIONS: Our results show that cognitive performance of HIV-infected children is poor compared with that of SES-matched healthy controls. Gaining insight into these cognitive deficits is essential, as subtle impairments may progress to more pronounced complications that will influence future intellectual performance, job opportunities, and community participation of HIV-infected children. PMID- 25516184 TI - Editorial commentary: immunodeficiency at start of antiretroviral therapy: the persistent problem of late presentation to care. PMID- 25516186 TI - Reply to Dellinger. PMID- 25516185 TI - Epidemiological and viral genomic sequence analysis of the 2014 ebola outbreak reveals clustered transmission. AB - Using Ebolavirus genomic and epidemiological data, we conducted the first joint analysis in which both data types were used to fit dynamic transmission models for an ongoing outbreak. Our results indicate that transmission is clustered, highlighting a potential bias in medical demand forecasts, and provide the first empirical estimate of underreporting. PMID- 25516188 TI - Incident bacterial vaginosis (BV) in women who have sex with women is associated with behaviors that suggest sexual transmission of BV. AB - BACKGROUND: Female same-sex partnerships provide a unique opportunity to study the pathogenesis and transmissibility of bacterial vaginosis (BV) because it can be diagnosed in both members of the partnership. We conducted a nationwide community-enrolled cohort study of women who have sex with women, including women coenrolled with their regular female sexual partner (FSP), to investigate the BV incidence rate and factors associated with incident BV. METHODS: Women who have sex with women, without prevalent BV in a cross-sectional study, were enrolled in a 24-month cohort study involving 3-monthly questionnaires and self-collected vaginal swabs that were scored by the Nugent method. We assessed the BV incidence rate per 100 woman-years (WY) and used univariate and multivariable Cox regression analysis to establish factors associated with BV acquisition. RESULTS: Two hundred ninety-eight participants were enrolled in the cohort; 122 were coenrolled with their regular FSP. There were 51 incident cases of BV (rate, 9.75/100 WY; 95% confidence interval [CI], 7.41-12.83). Incident BV was associated with exposure to a new sexual partner (adjusted hazard ratio [AHR], 2.51; 95% CI, 1.30-4.82), a partner with BV symptoms (AHR, 3.99; 95% CI, 1.39 11.45), receptive oral sex (AHR, 3.52; 95% CI, 1.41-8.79), and onset of BV symptoms (AHR, 2.80; 95% CI, 1.39-5.61). Women coenrolled with their BV-negative partner had a greatly reduced risk of incident BV (AHR, 0.26; 95% CI, .11-.61), and high concordance of Nugent category (74%), which was predominantly normal vaginal flora throughout follow-up. CONCLUSIONS: These data highlight the strong influence of sexual relationships and behaviors on BV acquisition and the vaginal microbiota. They provide epidemiological evidence to support exchange of vaginal bacterial species between women and the concept that BV is sexually transmitted. PMID- 25516190 TI - Surgical site infections and postoperative factors. PMID- 25516189 TI - Trends in CD4 count at presentation to care and treatment initiation in sub Saharan Africa, 2002-2013: a meta-analysis. AB - BACKGROUND: Both population- and individual-level benefits of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) are contingent on early diagnosis and initiation of therapy. We estimated trends in disease status at presentation to care and at ART initiation in sub-Saharan Africa. METHODS: We searched PubMed for studies published January 2002-December 2013 that reported CD4 cell count at presentation or ART initiation among adults in sub-Saharan Africa. We abstracted study sample size, year(s), and mean CD4 count. A random effects meta-regression model was used to obtain pooled estimates during each year of the observation period. RESULTS: We identified 56 articles reporting CD4 count at presentation (N = 295 455) and 71 articles reporting CD4 count at ART initiation (N = 549 702). The mean estimated CD4 count in 2002 was 251 cells/uL at presentation and 152 cells/uL at ART initiation. During 2002-2013, neither CD4 count at presentation (beta = 5.8 cells/year; 95% confidence interval [CI], -10.7 to 22.4 cells/year), nor CD4 count at ART initiation (beta = -1.1 cells/year; 95% CI, -8.4 to 6.2 cells/year) increased significantly. Excluding studies of opportunistic infections or prevention of mother-to-child transmission did not alter our findings. Among studies conducted in South Africa (N = 14), CD4 count at presentation increased by 39.9 cells/year (95% CI, 9.2-70.2 cells/year; P = .02), but CD4 count at ART initiation did not change. CONCLUSIONS: CD4 counts at presentation to care and at ART initiation in sub-Saharan Africa have not increased over the past decade. Barriers to presentation, diagnosis, and linkage to HIV care remain major challenges that require attention to optimize population level benefits of ART. PMID- 25516191 TI - Editorial commentary: fluoroquinolone-resistant intestinal organisms and infections after prostate biopsy: shifting sands of the prevention narrative. PMID- 25516192 TI - Use of telemedicine technologies in the management of infectious diseases: a review. AB - Telemedicine technologies are rapidly being integrated into infectious diseases programs with the aim of increasing access to infectious diseases specialty care for isolated populations and reducing costs. We summarize the utility and effectiveness of telemedicine in the evaluation and treatment of infectious diseases patients. The use of telemedicine in the management of acute infectious diseases, chronic hepatitis C, human immunodeficiency virus, and active pulmonary tuberculosis is considered. We recapitulate and evaluate the advantages of telemedicine described in other studies, present challenges to adopting telemedicine, and identify future opportunities for the use of telemedicine within the realm of clinical infectious diseases. PMID- 25516193 TI - A case of long-term excretion and subclinical infection with Middle East respiratory syndrome coronavirus in a healthcare worker. PMID- 25516195 TI - High-dose simvastatin for aneurysmal subarachnoid hemorrhage: multicenter randomized controlled double-blinded clinical trial. AB - BACKGROUND AND PURPOSE: Experimental evidence has indicated the benefits of simvastatin for the treatment of subarachnoid hemorrhage. Two randomized placebo controlled pilot trials that used the highest clinically approved dose of simvastatin (80 mg daily) gave positive results despite the fact that a lower dose of simvastatin (40 mg daily) did not improve clinical outcomes. We hypothesized that a high dose of 80 mg of simvastatin daily for 3 weeks would reduce the incidence of delayed ischemic deficits after subarachnoid hemorrhage compared with a lower dose (40 mg of simvastatin daily) and lead to improved clinical outcomes. METHODS: The study design was a randomized controlled double blinded clinical trial. Patients with aneurysmal subarachnoid hemorrhage (presenting within 96 hours of the ictus) from 6 neurosurgical centers were recruited for 3 years. The primary outcome measure was the presence of delayed ischemic deficits, and secondary outcome measures included a modified Rankin disability score at 3 months and an analysis of cost-effectiveness. RESULTS: No difference was observed between the groups treated with the higher dose or the lower dose of simvastatin in the incidence of delayed ischemic deficits (27% versus 24%; odds ratio, 1.2; 95% confidence interval, 0.7-2.0; P=0.586) or in the rate of favorable outcomes (modified Rankin Scale score, 0-2) at 3 months (73% versus 72%; odds ratio, 1.1; 95% confidence interval, 0.6-1.9; P=0.770). CONCLUSIONS: High-dose simvastatin treatment should not be prescribed routinely for aneurysmal subarachnoid hemorrhage. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01077206. PMID- 25516194 TI - Clinical and microbiological determinants of infection after transrectal prostate biopsy. AB - BACKGROUND: Increasing numbers of infections following transrectal prostate biopsy (TPB) at our hospital led us to investigate clinical and bacterial risk factors to determine if the colonizing rectal Escherichia coli population is the source. METHODS: We performed an observational cohort study of men undergoing TPB (1 January 2010-6 February 2014) at the San Diego Veterans Affairs Medical Center. The primary outcome was clinically significant post-TPB infection. Rectal swabs were collected immediately before the biopsy and cultured selectively for fluoroquinolone-resistant gram-negative bacilli. Fluoroquinolone-resistant clinical and rectal E. coli isolates were compared using phylotyping, pulsed field gel electrophoresis (PFGE) analysis, sequence typing, and virulence gene profiling. RESULTS: Rectal colonization with fluoroquinolone-resistant organisms (98% E. coli) was detected in 121 of 764 subjects (15.8%). Post-TPB infection was more common among fluoroquinolone-resistant-colonized subjects than noncolonized subjects (13/121 [10.7%] vs 8/649 [1.2%]; P < .001). Presence of fluoroquinolone resistant colonizing E. coli was the most significant host characteristic associated with post-TPB infection (odds ratio, 4.5 [95% confidence interval, 1.2 18.2]; P = .03). Escherichia coli infection isolates (n = 18) did not differ from E. coli rectal culture isolates (n = 68) for any of 49 virulence genes or ST131 status (all P > .05). The rectal and clinical isolates of all 9 men with paired isolates had indistinguishable PFGE patterns and identical antimicrobial susceptibility profiles. CONCLUSIONS: The rectal colonizing E. coli population is the source for most fluoroquinolone-resistant post-TPB infections, regardless of clonal background or virulence traits. Screening cultures can identify nearly all patients at risk for fluoroquinolone-resistant post-TPB infection. PMID- 25516196 TI - Safety and effect of metoclopramide to prevent pneumonia in patients with stroke fed via nasogastric tubes trial. AB - BACKGROUND AND PURPOSE: Pneumonia is a major cause of mortality and morbidity in patients with stroke fed via nasogastric tubes and may be because of vomiting and gastro-oesophageal regurgitation. The aim of the study was to assess whether regular treatment with metoclopramide, a D2-receptor antagonist with antiemetic and gastric prokinetic actions, could reduce the rate of aspiration and pneumonia. METHODS: Patients with no signs of pneumonia within 7 days of stroke onset and 48 hours of insertion of a nasogastric tube were recruited into a double-blind randomized placebo-controlled trial. Participants received metoclopramide 10 mg or placebo 3* daily via the nasogastric tube for 21 days or until nasogastric feeds were discontinued. Clinical signs of pneumonia were recorded daily. Pneumonia was diagnosed if the patient had relevant clinical signs, high inflammatory markers, and new infiltrates on the chest radiograph. RESULTS: Sixty patients (mean age, 78 years; 38 women; mean National Institutes for Health Stroke Scale score, 19.25) were randomized in a 1:1 ratio. There were significantly more episodes of pneumonia in the placebo group than in the metoclopramide group (rate ratio, 5.24; P<0.001). There were also significant differences in favor of metoclopramide in the rate of aspiration, oxygen saturation, highest inflammatory markers, and National Institutes for Health Stroke Scale. There was no significant difference in mortality between the groups. CONCLUSIONS: This study suggests that metoclopramide may reduce the rate of pneumonia and may improve other clinical outcomes in patients with subacute stroke fed via nasogastric tube. These findings need to be confirmed in larger randomized and blinded trials. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrialsregister.eu. EudraCT no: 2006-002570-22, URL: http://www.controlled-trials.com/ISRCTN18034911/18034911. PMID- 25516198 TI - Impact of the plasmonic near- and far-field resonance-energy shift on the enhancement of infrared vibrational signals. AB - We report on the impact of the differing spectral near- and far-field properties of resonantly excited gold nanoantennas on the vibrational signal enhancement in surface-enhanced infrared absorption (SEIRA). The knowledge on both spectral characteristics is of considerable importance for the optimization of plasmonic nanostructures for surface-enhanced spectroscopy techniques. From infrared micro spectroscopic measurements, we simultaneously obtain spectral information on the plasmonic far-field response and, via SEIRA spectroscopy of a test molecule, on the near-field enhancement. The molecular test layer of 4,4'-bis(N-carbazolyl) 1,1'-biphenyl (CBP) was deposited on the surface of gold nanoantennas with different lengths and thus different far-field resonance energies. We carefully studied the Fano-type vibrational lines in a broad spectral window, in particular, how the various vibrational signals are enhanced in relation to the ratio of the far-field plasmonic resonance and the molecular vibrational frequencies. As a detailed experimental proof of former simulation studies, we show the clearly red-shifted maximum SEIRA enhancement compared to the far-field resonance. PMID- 25516197 TI - Community-based case-control study of childhood stroke risk associated with congenital heart disease. AB - BACKGROUND AND PURPOSE: A better understanding of the stroke risk factors in children with congenital heart disease (CHD) could inform stroke prevention strategies. We analyzed pediatric stroke associated with CHD in a large community based case-control study. METHODS: From 2.5 million children (aged <20 years) enrolled in a Northern California integrated healthcare plan, we identified children with ischemic and hemorrhagic strokes and randomly selected age- and facility-matched stroke-free controls (3 per case). We determined exposure to CHD (diagnosed before stroke) and used conditional logistic regression to analyze stroke risk factors. RESULTS: CHD was identified in 15 of 412 cases (4%) versus 7 of 1236 controls (0.6%). Cases of childhood stroke (occurring between ages 29 days to 20 years) with CHD had 19-fold (odds ratio, 19; 95% confidence interval 4.2-83) increased stroke risk compared to controls. History of CHD surgery was associated with >30-fold (odds ratio, 31; confidence interval 4-241) increased risk of stroke in children with CHD when compared with controls. After excluding perioperative strokes, the history of CHD surgery still increased the childhood stroke risk (odds ratio, 13; confidence interval 1.5-114). The majority of children with stroke and CHD were outpatients at the time of stroke, and almost half the cases who underwent cardiac surgery had their stroke >5 years after the most recent procedure. An estimated 7% of ischemic and 2% of hemorrhagic childhood strokes in the population were attributable to CHD. CONCLUSIONS: CHD is an important childhood stroke risk factor. Children who undergo CHD surgery remain at elevated risk outside the perioperative period and would benefit from optimized long-term stroke prevention strategies. PMID- 25516199 TI - An autopsied case of corticobasal degeneration showing severe cerebral atrophy over a protracted disease course of 16 years. AB - The patient was a 72-year-old Japanese woman. At the age of 57, she started having difficulty performing daily work and developed agraphia. She also exhibited restlessness and loss of interest, and began to speak less. Thereafter, stereotypical behavior, gait disturbance and dysphagia were noted. CT scan demonstrated left-dominant frontal and temporal lobe atrophy. She died at the age of 72, about 16 years after the onset of symptoms. Neuropathologically, the brain weighed 867 g, and showed remarkable cerebral atrophy with degeneration of the white matter, predominantly in the left dorsal frontal lobe and anterior temporal lobe. Microscopically, severe neuronal loss and gliosis with rarefaction were found in the cerebral cortex, and severe destruction of myelin and axons was observed in the cerebral white matter. Moderate neuronal loss with gliosis was also found in the pallidum and substantia nigra. Gallyas-Braak staining and tau immunostaining revealed pretangle neurons, NFTs, ballooned neurons and astrocytic plaques in the cerebral cortex, subcortical nuclei and brainstem, and argyrophilic threads and coiled bodies in the subcortical white matter. Tau isoform-specific immunostaining revealed that most tau-immunoreactive structures were positive for 4-repeat (4R) tau, but some of the NFTs were positive for 3 repeat (3R) tau in the cerebral neocortex. Immunoblotting demonstrated an accumulation of 4R tau in the cerebral cortex and subcortical white matter. The patient was pathologically diagnosed as having corticobasal degeneration. Her long survival course likely accounts for the severe white matter degeneration and accumulation of 3R tau in NFTs. PMID- 25516200 TI - The opioid system majorly contributes to preference for fat emulsions but not sucrose solutions in mice. AB - Rodents show a stronger preference for fat than sucrose, even if their diet is isocaloric. This implies that the preference mechanisms for fat and sucrose differ. To compare the contribution of the opioid system to the preference of fat and sucrose, we examined the effects of mu-, delta-, kappa-, and non-selective opioid receptor antagonists on the preference of sucrose and fat, assessed by a two-bottle choice test and a licking test, in mice naive to sucrose and fat ingestion. Administration of non-selective and mu-selective opioid receptor antagonists more strongly inhibited the preference of fat than sucrose. While the preference of fat was reduced to the same level as water by the antagonist administration that of sucrose was still greater than water. Our results suggest that the preference of fat relies strongly on the opioid system, while that of sucrose is regulated by other mechanisms in addition to the opioid system. PMID- 25516201 TI - Perceptual evaluation of dysphonic voices: can a training protocol lead to the development of perceptual categories? AB - The purpose of this study was to develop and test a training protocol for the perceptual evaluation of dysphonia. A group of 38 inexperienced listeners participated in a three-phase experiment: a pretest to evaluate their initial performance on categorization of dysphonic voices, a training phase, and a posttest to detect training-related changes in performance. In parallel, a different group of 14 listeners who were experts in voice assessment took a test that was identical to the posttest taken by the inexperienced subjects. The corpus used for the tests was made up of recordings of 142 voices of women reading aloud, with a sampling of voice qualities ranging from normal to severely degraded. The learners' performance on judgments of moderate and severe dysphonia improved between the pretest and the posttest. No improvement was observed for normal voices, whose initial detection was already good, nor for slight dysphonias, which appear to be the most difficult to learn. The improvements were still present on a delayed posttest taken a week later. Unexpectedly, the inexperienced listeners' initial performance was similar to that of the experts. After the training phase, their scores for severely deteriorated voices were even better than the experts'. In conclusion, our training protocol seems to be effective and could therefore be proposed to voice therapists. However, judging intermediate degrees of dysphonia remains fragile and therefore needs to be reinforced by repeated training. PMID- 25516203 TI - A New Interpretation of the Weighted Kappa Coefficients. AB - Reliability and agreement studies are of paramount importance. They do contribute to the quality of studies by providing information about the amount of error inherent to any diagnosis, score or measurement. Guidelines for reporting reliability and agreement studies were recently provided. While the use of the kappa-like family is advised for categorical and ordinal scales, no further guideline in the choice of a weighting scheme is given. In the present paper, a new simple and practical interpretation of the linear- and quadratic-weighted kappa coefficients is given. This will help researchers in motivating their choice of a weighting scheme. PMID- 25516202 TI - Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield. AB - BACKGROUND: Congenital heart defects (CHD), as the most common congenital anomaly, have been reported to be frequently associated with pathogenic copy number variants (CNVs). Currently, patients with CHD are routinely offered chromosomal microarray (CMA) testing, but the diagnostic yield of CMA on CHD patients has not been extensively evaluated based on a large patient cohort. In this study, we retrospectively assessed the detected CNVs in a total of 514 CHD cases (a 422-case clinical cohort from Boston Children's Hospital (BCH) and a 92 case research cohort from Shanghai Children's Medical Center (SCMC)) and conducted a genotype-phenotype analysis. Furthermore, genes encompassed in pathogenic/likely pathogenic CNVs were prioritized by integrating several tools and public data sources for novel CHD candidate gene identification. RESULTS: Based on the BCH cohort, the overall diagnostic yield of CMA testing for CHD patients was 12.8(pathogenic CNVs)-18.5% (pathogenic and likely pathogenic CNVs). The diagnostic yield of CMA for syndromic CHD was 14.1-20.6% (excluding aneuploidy cases), whereas the diagnostic yield for isolated CHD was 4.3-9.3%. Four recurrent genomic loci (4q terminal region, 15q11.2, 16p12.2 and Yp11.2) were more significantly enriched in cases than in controls. These regions are considered as novel CHD loci. We further identified 20 genes as the most likely novel CHD candidate genes through gene prioritization analysis. CONCLUSION: The high clinical diagnostic yield of CMA in this study provides supportive evidence for CMA as the first-line genetic diagnostic tool for CHD patients. The CNVs detected in our study suggest a number of CHD candidate genes that warrant further investigation. PMID- 25516204 TI - Early mortality after hip fracture: what matters? AB - BACKGROUND: Hip fractures in the elderly are followed by increased mortality, which is highest in the period immediately after the fracture. Predictors for early mortality have neither been well identified nor summarized. Identification of early postoperative mortality predictors enables the stratification of high risk patients and can help in the development of strategies aimed at reducing risk and improving outcome after hip fracture. The primary aim of this study was to investigate the incidence of 30-day mortality. The secondary aim was to investigate factors related to early mortality. METHODS: We examined 384 elderly patients with hip fracture. Multivariate logistic regression analysis was used to explore independent prognostic factors for 30-day mortality. RESULTS: By the end of the 30-day follow-up period, 22 patients (6.4%) had died. Postoperative delirium was the only variable independently related to 30-day mortality after hip fracture. Older, male patients with a lower cognitive status had a higher chance of developing postoperative delirium. DISCUSSION: Postoperative delirium is a strong independent marker of high risk for 30-day mortality. Older, male patients with more severe cognitive impairment are at increased risk of developing postoperative delirium. Identifying patients at risk for developing postoperative delirium upon admission and early detection of delirium enable the development of targeted prevention and intervention strategies in older patients with hip fracture. PMID- 25516205 TI - Sudden cardiac death diagnosed with dilated cardiomyopathy in a Kuwaiti family: a case report. AB - BACKGROUND: Dilated cardiomyopathy is myocardial disease characterized by dilatation and impaired contraction of the left ventricle or both left and right ventricle. The majority of these cases are secondary to coronary artery disease, hypertension and valvular cardiomyopathy. Patients diagnosed with dilated cardiomyopathy are further clinically evaluated for evidence of familial history of the disease. Those families have shown to have genetic predisposition to dilated cardiomyopathy; thus, currently there is no available single genetic test that allows comprehensive testing of all causative genes. We report a Kuwaiti case of dilated cardiomyopathy that was diagnosed at young age. The patient clinical presentation pointed out to the fact that this was a familial disease. This case is the first reported in Kuwait clinically presented with familial dilated cardiomyopathy implying a genetic susceptibility factor to be further investigated within the at-risk family members. CASE PRESENTATION: 23-year-old Arab ethnicity Kuwaiti male with strong family history of dilated cardiomyopathy was admitted witnessed with sudden cardiac death. The patient presented with sudden arrhythmic death and survived with permanent anoxic brain injury. Transthoracic echocardiography revealed dilated cardiomyopathy with severe global left ventricular systolic dysfunction. After thorough investigation, the patient shown to have strong family history of dilated cardiomyopathy. CONCLUSION: Familial dilated cardiomyopathy is poorly documented in Kuwait. We present this case with future plan to study the genetic map of his family. PMID- 25516206 TI - Improvement in reading symptoms following botulinum toxin A injection for convergence insufficiency type intermittent exotropia. PMID- 25516207 TI - New phenolic compounds from Coreopsis tinctoria Nutt. and their antioxidant and angiotensin i-converting enzyme inhibitory activities. AB - Three new phenolic compounds, coretinphenol (1), coretincone (2), and coretinphencone (3), were isolated from the buds of Coreopsis tinctoria Nutt., together with nine known compounds, including butein (4), okanin (5), isoliquiritigenin (6), maritimetin (7), taxifolin (8), isookanin (9), marein (10), sachalinoside B (11), and 2-phenylethyl-beta-d-glucoside (12). The chemical structures of these compounds were elucidated by extensive spectroscopic analysis and on the basis of their chemical reactivity. This work represents the first recorded example of the isolation of compounds 1-3, 6, 7, 9, 11, and 12 from C. tinctoria. Compounds 5-9 showed strong diphenyl(2,4,6-trinitrophenyl)iminoazanium (DPPH) radical-scavenging activity, with IC50 values of 3.35 +/- 0.45, 9.6 +/- 2.32, 4.12 +/- 0.21, 6.2 +/- 0.43, and 7.9 +/- 0.53 MUM, respectively. Compounds 2 and 8 exhibited angiotensin I-converting enzyme inhibitory activity, with IC50 values of 228 +/- 4.47 and 145.67 +/- 3.45 MUM, respectively. The activities of phenolic compounds isolated from C. tinctoria support the medicinal use of this plant in the prevention of cardiovascular diseases. PMID- 25516208 TI - Forkhead box C1 promoter upstream transcript, a novel long non-coding RNA, regulates proliferation and migration in basal-like breast cancer. AB - Recent studies have shown that long non-coding RNAs (lncRNAs) have crucial regulating roles in carcinogenesis. Forkhead box C1 (FOXC1) is an important cancer-associated gene in basal-like breast cancer (BLBC). In the present study, a novel lncRNA, FOXC1 promoter upstream transcript (FOXCUT) was investigated in BLBC patients using polymerase chain reaction analysis. The results showed that the expression of FOXCUT and FOXC1 were positively correlated. When the expression of FOXCUT was downregulated by small interfering RNA, the expression of FOXC1 was similarly reduced. Furthermore, in MDA-MB-231 and MDA-MB-468 breast cancer cells, knockdown of FOXCUT markedly inhibited cell proliferation and migration in vitro. In conclusion, FOXCUT lncRNA may be functionally involved in the tumor progression of BLBCs through the regulation of its paired mRNA, FOXC1, demonstrating that FOXCUT may serve as a novel biomarker and therapeutic target in BLBCs. PMID- 25516209 TI - Language barriers: challenges to quality healthcare. PMID- 25516210 TI - Large multifocal cutaneous hemangioma along lines of Blaschko with cardiac failure treated with propranolol. AB - Hemangiomas are classified as focal or segmental according to the morphology and distribution of lesions. Congestive cardiac failure is frequently encountered in diffuse hepatic hemangiomas due to high-volume shunting and rarely in hemangiomas confined to the skin. We report here the case of a large multifocal hemangioma along the lines of Blaschko with high-output cardiac failure, with improvement in cutaneous and hemodynamic symptoms after propranolol therapy. Presentation along the lines of Blaschko raises the possibility of hemangiomas arising as a result of mosaicism. PMID- 25516211 TI - Development of clinical practice guidelines for supportive care in childhood cancer--prioritization of topics using a Delphi approach. AB - INTRODUCTION: Currently, very few guidelines for supportive care for children with cancer exist. In the Netherlands, nationwide guidelines are over 10 years old and mostly based on expert opinion. Consequently, there is growing support and need for clinical practice guidelines (CPGs), which ought to be developed with a well-defined methodology and include a systematic search of literature, evidence summaries, and a transparent description of the decision process for the final recommendations. Development of CPGs is time consuming; therefore, it is important to prioritize topics for which there is the greatest clinical demand. OBJECTIVES: This study aims to prioritize childhood cancer supportive care topics for development of CPGs. METHODS: A Delphi survey consisting of two rounds was conducted to prioritize relevant childhood cancer supportive care topics for the development of CPGs. A group of experts comprising 15 pediatric oncologists, 15 pediatric oncology nurses, and 15 general pediatricians involved in care for childhood cancer patients were invited to participate. All relevant supportive care topics in childhood cancer were rated. RESULTS: In both rounds, 36 panellists (82%) responded. Agreement between panellists was very good, with an intraclass correlation coefficient of 0.918 (95% confidence interval (CI) = 0.849 0.966, p < 0.001) in round 2. The ten topics with the highest score in the final round were infection, sepsis, febrile neutropenia, pain, nausea/vomiting, restrictions in daily life and activities, palliative care, procedural sedation, terminal care, and oral mucositis. CONCLUSION: We successfully used a Delphi survey to prioritize childhood cancer supportive care topics for the development of CPGs. This is a first step towards uniform and evidence-based Dutch guidelines in supportive care in childhood cancer. Even though performed nationally, we believe that this study can also be regarded as an example starting point for international development of CPGs in the field of supportive care in cancer or any other field for that matter. PMID- 25516213 TI - Scientific rigour is far more than a matter of sample size. PMID- 25516212 TI - The effect of complementary and alternative medicine on quality of life, depression, anxiety, and fatigue levels among cancer patients during active oncology treatment: phase II study. AB - BACKGROUND: During the past decade, there has been growing interest in complementary and alternative medicine (CAM) among cancer patients and it is being integrated more frequently within conventional cancer centers. The long term effect of mind-body therapies on quality of life (QoL), depression, anxiety, and fatigue was tested prospectively in this study. PATIENTS AND METHODS: Cancer patients who received six weekly sessions of CAM during their oncological treatments participated in the study. The Hospital Anxiety and Depression Scale (HADS), Brief Fatigue Inventory (BFI) and QoL-EORTC-C30 were completed during the intervention and follow-up period. RESULTS: Over a two-year period, 163 patients entered the study, 135 of whom completed all six CAM sessions. An improvement was demonstrated in the median of BFI from 4.8 to 3.9 (p < 0.001), HADS-Anxiety from 8 to 7 (p < 0.001) and HADS-Depression from 7 to 6 (p < 0.001) after 12 weeks. In addition, the median of global QoL improved from 50 to 67 (p < 0.001), and a significant improvement was noticed in several parameters on the functioning and symptoms scales of the QoL-EORTC-C30. CONCLUSION: Cancer patients who completed six weekly sessions of CAM improved significantly on measured outcomes, regardless of their demographic characteristics. PMID- 25516214 TI - Retrospective cohort study of portacaval lymphadenopathy identified on multidetector CT and implications for follow-up. AB - PURPOSE: Portacaval lymphadenopathy (PCLA) is common in cirrhosis and chronic viral hepatitis and is frequently an incidental finding on abdominal CT scans. We aimed to detect the incidence of malignancy in organs drained by portacaval nodes in patients with PCLA associated with cirrhosis or chronic viral hepatitis, or incidentally detected PCLA. METHODS: We searched CT reports from 2005 to 2007 for the phrases "periportal node" and "portacaval node." MDCTs of patients with portacaval nodes >=10 mm in maximal short-axis size on contrast-enhanced MDCTs, were included. Records were reviewed for presence of malignancy, liver metastases, chronic viral hepatitis, and cirrhosis. Clinical or imaging follow-up >=6 months was performed to detect if malignancy developed in organs drained by portacaval nodes in patients with incidental PCLA, cirrhosis, or chronic viral hepatitis. RESULTS: 479 patients met inclusion criteria [298 males (62%), mean age 61.4 years]. In 285 (59.5%) patients, PCLA was explained by local pathology or systemic lymphadenopathy. PCLA was incidental in 146 (30.5%) patients. Of these, 112 (76.7%) had >=6 months of follow-up (median 26 months). No patient with incidental PCLA developed malignancy in organs drained by these nodes. Cirrhosis or chronic viral hepatitis was present in 48 (10.0%) patients. Of these, 42 (87.5%) had >=6 months follow-up (median 28 months), and only 1 patient developed cholangiocarcinoma (positive predictive value 2.4%). CONCLUSIONS: Development of malignancy is rare in patients with PCLA, either incidental or secondary to cirrhosis or chronic viral hepatitis. Our study suggests that no follow-up of PCLA is required in these settings. PMID- 25516215 TI - MR manifestations of uterine polypoid adenomyoma. AB - PURPOSE: Polypoid adenomyoma (PA) is an uncommon benign tumor of the uterus appearing as a submucosal polypoid mass, or rarely as a subserosal polypoid mass. PA should be differentiated from atypical polypoid adenomyoma or malignant uterine tumors. The purpose of our case series is to evaluate magnetic resonance (MR) manifestations of PA for the differential diagnosis. METHODS: Seven cases with surgically proven PA, five submucosal, and two subserosal, were evaluated. MR imaging findings including contrast enhancement in six cases (four cases with dynamic contrast-enhanced MR study), diffusion-weighted imaging (DWI) in five cases, and susceptibility weighted imaging (SWI) in two cases were retrospectively reviewed. RESULTS: All seven lesions exhibited isointensity compared with the myometrium and 4 of 7 lesions (57%) contained high signal intensity hemorrhagic areas on T1-weighted images. On T2-weighted images, signal intensity was variable and all seven lesions contained cysts. None of five lesions with DWI exhibited high signal intensity compared with the normal myometrium. All six lesions showed intense contrast enhancement similar to that of the myometrium on post-contrast T1-weighted images. Punctate low intensity areas reflecting blood contents were revealed in all two lesions with SWI. CONCLUSIONS: Submucosal or subserosal polypoid masses containing hemorrhagic areas, and cysts reflecting functional endometrium and dilatation of endometrial glands are suggestive for PA. Intense contrast enhancement similar to that of the myometrium may be another characteristic finding for PA. PMID- 25516217 TI - Differences between novel and conventional surveillance paradigms of ventilator associated pneumonia. AB - OBJECTIVE: To investigate the concordance between novel and conventional surveillance paradigms for ventilator-associated pneumonia (VAP). METHODS: This study was conducted at a regional teaching hospital in southern Taiwan with 5 acute intensive care units. To assess the validity of novel ventilator-associated event (VAE) surveillance, we retrospectively applied the VAE algorithm to analyze all VAP cases that were identified using conventional definitions between April 2010 and February 2014. Patient outcomes, including ventilator days, hospital stay lengths, and in-hospital mortality were recorded. RESULTS: Among 165 episodes of conventional VAP, 55 (33.3%), 40 (24.2%), 20 (12.1%), and 2 (1.2%) episodes were classified as a ventilator-associated condition, an infection related ventilator-associated complication, possible VAP, and probable VAP, respectively, according to the new VAE algorithm. Changes in positive end expiratory pressure and inspired oxygen fraction levels during the development of VAP were significant higher among each VAE category than for conventional VAP (all P < .001). In-hospital mortality was significantly higher among patients with ventilator-associated condition than for patients with conventional VAP (P = .0185). CONCLUSIONS: In our study population, novel VAE surveillance only detected one-third of conventional VAP cases. Thus, more studies are needed to further validate VAE surveillance compared with conventional VAP by using strong microbiologic criteria, particularly bronchoalveolar lavage with a protected specimen brush for diagnosing VAP. PMID- 25516216 TI - Overexpression of ERBB4 JM-a CYT-1 and CYT-2 isoforms in transgenic mice reveals isoform-specific roles in mammary gland development and carcinogenesis. AB - INTRODUCTION: Human Epidermal Growth Factor Receptor (ERBB4/HER4) belongs to the Epidermal Growth Factor receptor/ERBB family of receptor tyrosine kinases. While ERBB1, ERBB2 and ERBB3 are often overexpressed or activated in breast cancer, and are oncogenic, the role of ERBB4 in breast cancer is uncertain. Some studies suggest a tumor suppressor role of ERBB4, while other reports suggest an oncogenic potential. Alternative splicing of ERBB4 yields four major protein products, these spliced isoforms differ in the extracellular juxtamembrane domain (JM-a versus JM-b) and cytoplasmic domain (CYT-1 versus CYT-2). Two of these isoforms, JM-a CYT-1 and JM-a CYT-2, are expressed in the mammary gland. Failure to account for isoform-specific functions in previous studies may account for conflicting reports on the role of ERBB4 in breast cancer. METHODS: We have produced mouse mammary tumour virus (MMTV) -ERBB4 transgenic mice to evaluate potential developmental and carcinogenic changes associated with full length (FL) JM-a ERBB4 CYT-1 versus ERBB4 CYT-2. Mammary tissue was isolated from transgenic mice and sibling controls at various developmental stages for whole mount analysis, RNA extraction, and immunohistochemistry. To maintain maximal ERBB4 expression, transgenic mice were bred continuously for a year after which mammary glands were isolated and analyzed. RESULTS: Overexpressing FL CYT-1 isoform resulted in suppression of mammary ductal morphogenesis which was accompanied by decreased number of mammary terminal end buds (TEBs) and Ki-67 positive cells within TEBs, while FL CYT-2 isoform had no effect on ductal growth in pubescent mice. The suppressive ductal phenotype in CYT-1 mice disappeared after mid pregnancy, and subsequent developmental stages showed no abnormality in mammary gland morphology or function in CYT-1 or CYT-2 transgenic mice. However, sustained expression of FL CYT-1 isoform resulted in formation of neoplastic mammary lesions, suggesting a potential oncogenic function for this isoform. CONCLUSIONS: Together, we present isoform-specific roles of ERBB4 during puberty and early pregnancy, and reveal a novel oncogenic property of CYT-1 ERBB4. The results may be exploited to develop better therapeutic strategies in breast cancer. PMID- 25516218 TI - Barriers to the use of face protection for standard precautions by health care providers. AB - Health care providers sometimes choose not to use face protection even when indicated as part of standard precautions. We performed a survey of pediatric health care providers to determine barriers to the routine use of face protection. Lack of availability at the point of care and a perceived lack of need were the most commonly cited issues. Continuing education is needed regarding situations in which face protection is indicated for standard precautions. PMID- 25516220 TI - Vasculitides with cutaneous expression in children: clinico-pathological correlations. AB - The most recent pediatric vasculitis classifications (EULAR/PRINTO/PRES) have proposed the use of an integration of clinical signs and symptoms, laboratory data, imaging and pathologic data. Pediatric vasculitis represent a peculiar clinical-diagnostic model, compared to the corresponding adult pathology chapter, and in particular, dermatopathologic aspects of these diseases identify more specific issues, made contingent by crucial variables such as duration of vasculitis lesion, site of the biopsy, proper biopsy depth, and possibility to correlate histopathological findings with immunopathological results. Possible additional diagnostic difficulties may arise from the fact that, in children, the same systemic disease, such as lupus erythematosus, may present with different clinical manifestations, with histopathological features of a precise type of vasculitis specific for that type of clinical manifestation. Examples are provided by hypocomplementemic urticarial vasculitis, cryoglobulinemic purpura, lymphocytic vasculitis of livedoid lesions. This paper describes the cutaneous histopathological findings of some vasculitis related pediatric diseases, be they pertaining to a systemic vasculitis with corresponding cutaneous vasculitis, to a systemic vasculitis with sporadic cutaneous vasculitic involvement, and to a systemic vasculitis without cutaneous vasculitic involvement. Type and level of histopathological vasculitic involvement, caliber of the vessel, type of vasculitis associated infiltrate, are likewise reliable integration in the complex diagnostic path of vasculitis in childhood. On the basis of these criteria dermatopathologists should be confident in identifying the type of the vasculitis and relate them to a specific pediatric disease. PMID- 25516219 TI - Characterization of patients exposed to multiple devices but free of hospital acquired infection at intensive care unit discharge. AB - Intensive care unit patients exposed to multiple devices but free of hospital acquired infection (HAI) until discharge were identified through a surveillance network of HAIs in Lyon, France, between 2003 and 2011. Multiexposed patients were defined according to the tenth deciles of length of stay and exposures to invasive devices. Overall, 982 (5.0%) multiexposed patients were identified; 154 (15.7%) remained uninfected. Multiexposed infected patients differed from noninfected patients regarding length of exposures and mortality. PMID- 25516221 TI - Small-angle X-ray scattering insights into the architecture-dependent emulsifying properties of amphiphilic copolymers in supercritical carbon dioxide. AB - The supramolecular assembly of a series of copolymers combining poly(ethylene oxide)-rich hydrophilic and fluorinated CO2-philic sequences is analyzed by synchrotron small-angle X-ray scattering (SAXS) in supercritical CO2, as well as in water/CO2 emulsions. These copolymers were designed to have the same molecular weight and composition and to differ only by their macromolecular architecture. The investigated copolymers have random, block, and palm-tree architectures. Besides, thermoresponsive copolymer is also analyzed, having a hydrophilic sequence becoming water-insoluble around 41 degrees C, i.e., just above the critical point of CO2. At the length scale investigated by SAXS, only the random copolymer appears to self-assemble in pure CO2, in the form of a disordered microgel-like network. The random, block, and thermoresponsive copolymers are all able to stabilize water/CO2 emulsions but not the copolymer with the palm-tree architecture, pointing at the importance of macromolecular architecture for the emulsifying properties. A modeling of the SAXS data shows that the block and the thermoresponsive copolymers form spherical micelle-like structures containing about 70% water and 30% polymer. PMID- 25516222 TI - The prognostic value of cyclin D1 expression in head and neck squamous cell carcinoma. AB - The correlation between cyclin D1 overexpression and the clinical outcome of head and neck cancer is not defined. The aim of this meta-analysis was to evaluate the prognostic value of cyclin D1 in patients with head and neck cancer. A search thorough Ovid MEDLINE was performed to enroll all eligible articles. Twenty-two studies comprising a total of 1,929 patients with different head and neck cancers were included. Cyclin D1 overexpression was significantly associated with lymph node metastasis [OR 2.25; 95 % confidence interval (CI) 1.76-2.87] and worse disease-free survival (OR 3.06; 95 % CI 2.42-3.87]. Subgroup analysis revealed that cyclin D1 overexpression correlated significantly with nodal metastasis for laryngeal cancer (OR 2.26; 95 % CI 1.61-3.16) and was a significant poor predictor for nasopharyngeal cancer (OR 4.44; 95 % CI 1.89-10.42). Our meta analysis suggests that cyclin D1 overexpression could represent an important prognostic indicator for patients with head and neck cancer. PMID- 25516223 TI - Efficacy of sublingual immunotherapy for house dust mite allergic rhinitis. AB - In the present study, we investigated the outcomes of sublingual immunotherapy (SLIT) in house dust mite-induced allergic rhinitis (HDM-AR) patients. In this prospective, multicentric study, 186 patients with AR who had positive skin prick test results for HDMs were included. The patients were administered SLIT using Staloral 300 for 1 year. Evaluation of the patients regarding symptom scores, clinical findings and Rhinitis Quality of Life Questionnaire (RQLQ) scores was performed at baseline, and then at 6 and 12 months of therapy. Our results showed that, for all of the evaluated items (symptom scores, clinical findings and RQLQ scores), 12-month values were significantly lower than those at 6 months and baseline. Similarly, 6-month values were significantly lower than those at baseline. There were no complications in any of our patients. SLIT for HDM-AR is a treatment modality that can be used safely. We obtained better results than expected, and the treatment showed a positive psychological effect; the patients believed that SLIT was the final step of treatment and, which made them feel better. PMID- 25516224 TI - Inhibition of the NLRP3 inflammasome provides neuroprotection in rats following amygdala kindling-induced status epilepticus. AB - BACKGROUND: NLRP3 inflammasome is proposed to regulate inflammation in several neurological diseases, but its role in epilepsy remains largely unknown. This study aimed to investigate the role of the NLRP3 inflammasome in neuroinflammation, spontaneous recurrent seizures (SRS) and hippocampal neuronal loss in rat brain following amygdala kindling-induced status epilepticus (SE). METHODS: We detected the protein levels of IL-1beta and NLRP3 inflammasome components by Western blot in the hippocampus of shams and SE rats at different time points following SE. To further examine whether the activation of the NLRP3 inflammasome contributes to SE-associated neuronal damage, we employed a nonviral strategy to knock down NLRP3 and caspase-1 expression in brain before undergoing SE. Proinflammatory cytokine levels and hippocampal neuronal loss were evaluated at 12 hours and at 6 weeks following SE respectively in these NLRP3 and caspase-1 deficient rats. Meanwhile, SRS occurrence was evaluated through a 4-week video recording started 2 weeks after SE in these NLRP3 and caspase-1 deficient rats. RESULTS: IL-1beta levels and NLRP3 inflammasome components levels dramatically increased at 3 hours after SE, and reached a maximum at 12 hours after SE compared with the control group. Knock down of NLRP3 or caspase-1 decreased the levels of IL-1beta and IL-18 at 12 hours after SE, which was accompanied by a significant suppression in the development and severity of SRS during the chronic epileptic phase. Meanwhile, knock down of NLRP3 or caspase-1 led to a remarkable reduction of hippocampal neuronal loss in the CA1 and CA3 area of the hippocampus at 6 weeks after SE. CONCLUSIONS: Our study provides the first evidence that the NLRP3 inflammasome was significantly up-regulated following SE. More importantly, we show that inhibition of the NLRP3 inflammasome provides neuroprotection in rats following SE. These findings suggest that NLRP3 may represent a potential target for the treatment of epileptogenesis. PMID- 25516225 TI - Population diversity in cuticular hydrocarbons and mtDNA in a mountain social wasp. AB - Nestmate recognition is a common phenomenon in social insects that typically is mediated by cuticular hydrocarbons. Geographical variation in cuticular hydrocarbons has been observed, although the pattern of variation is not consistent across species and is usually related to the biology and ecology of the different species. Polistes biglumis (Hymenoptera: Vespidae) is a social wasp that lives in high mountains where populations are separated by significant geographical barriers. Here we investigated the level of chemical variation among populations of P. biglumis in the Alps, and shed light on the phylogeography of this species. Populations could be discriminated by means of their cuticular hydrocarbon profiles, which showed a pattern consistent with the isolation-by distance hypothesis. Molecular data highlighted two areas with different levels of haplotype diversity, although all wasps belonged to the same species. These results suggest that the populations of P. biglumis in the Alps are geographically isolated from one another, favoring their genetic and chemical differentiation. PMID- 25516226 TI - Incompatibility between plant-derived defensive chemistry and immune response of two sphingid herbivores. AB - Herbivorous insects use several different defenses against predators and parasites, and tradeoffs among defensive traits may occur if these traits are energetically demanding. Chemical defense and immune response potentially can interact, and both can be influenced by host plant chemistry. Two closely related caterpillars in the lepidopteran family Sphingidae are both attacked by the same specialist endoparasitoid species but have mostly non-overlapping host plant ranges that differ in secondary chemistry. Ceratomia catalpae is a specialist on Catalpa and also will feed on Chilopsis, which both produce iridoid glycosides. Ceratomia undulosa consumes members of the Oleaceae, which produce seco-iridoid glycosides. Immune response of the two species on a typical host plant species (Catalpa bignonioides for C. catalpa; Fraxinus americana for C. undulosa) was compared using a melanization assay, and did not differ. In a second experiment, the iridoid glycoside catalpol was added to the diets of both insects, and growth rate, mass, chemical defense, and immune response were evaluated. Increased dietary catalpol weakened the immune response of C. undulosa and altered the development rate of C. catalpae by prolonging the third instar and accelerating the fourth instar. Catalpol sequestration was negatively correlated with immune response of C. catalpae, while C. undulosa was unable to sequester catalpol. These results show that immune response can be negatively influenced by increasing concentrations of sequestered defensive compounds. PMID- 25516227 TI - The effect of dietary fatty acids on the cuticular hydrocarbon phenotype of an herbivorous insect and consequences for mate recognition. AB - The cuticular hydrocarbon (CHC) profile of the mustard leaf beetle Phaedon cochleariae is known to mediate mate recognition and is dependent on food plant species; beetles previously were shown to prefer mates that fed on the same plant species and which have a similar CHC pattern. In order to elucidate whether the pattern of ingested fatty acids affects the CHC pattern of P. cochleariae adults, we fed beetles: (a) with two different host plant species differing in fatty acid profile; and (b) artificial diets differing mainly in their composition of mono-, di-, and triunsaturated fatty acids. Analyses of the beetles' CHCs revealed that ingestion of different fatty acid blends results in quantitative effects on the beetle's straight-chain and methyl-branched CHCs. Interestingly, CHC patterns of males and females were affected differently by ingestion of fatty acids. In contrast to the effect on mating caused by feeding on different host plant species, beetles that were fed with different artificial diets, leading to different beetle CHC profiles, did not exhibit mating preference. We suggest that the occurrence of CHC-dependent assortative mating in P. cochleariae does not depend on the dietary fatty acids offered to the beetles in this study, but on other food constituents that affect CHC biosynthesis. PMID- 25516228 TI - Craniofacial morphology in children with van der Woude syndrome and isolated cleft palate. AB - OBJECTIVE: To compare cephalometrically 6-year-old children with van der Woude syndrome and cleft palate (VWS) to children with isolated cleft palate alone (CP). DESIGN: A retrospective case-control study. PATIENTS AND SETTING: Forty four children with VWS were compared to 73 children with CP using lateral cephalograms. The mean age of the children with VWS was 6.6 years (range = 5.9 8.2) and that of the children with CP, 6.2 years (range = 5.7-6.7). Palatal closure had been done at a mean age of 1.4 years (range = 0.8-2.2), mostly with the Veau-Wardill-Killner or the Cronin pushback surgical techniques. The data was collected over a 30-year period. MAIN OUTCOME MEASURE: Linear and angular measurements were obtained from lateral cephalograms. A Student's t-test was used in the statistical analysis. RESULTS: The craniofacial morphology in children with VWS and CP was similar, but those with VWS had slightly smaller diameters of the lower pharyngeal airway. The maxilla and mandible were well related to each other, although a little retrusive in relation to the cranial base. The soft tissue profile reflected the skeletal relationships, no significant protrusion of the lower lip was noted. CONCLUSIONS: Six-year-old children with VWS and CP have similar craniofacial morphology. PMID- 25516229 TI - Relationships between sexual violence and chronic disease: a cross-sectional study. AB - BACKGROUND: Sexual assault is a traumatic event with potentially devastating lifelong effects on physical and mental health. Research has demonstrated that individuals who experience sexual assault during childhood are more likely to engage in risky behaviors later in life, such as smoking, alcohol and drug use, and disordered eating habits, which may increase the risk of developing a chronic disease. Despite the high prevalence and economic burden of sexual assault, few studies have investigated the associations between sexual violence and chronic health conditions in the US. The purpose of this study is to identify associations between sexual violence and health risk behaviors, chronic health conditions and mental health conditions utilizing population based data in Kansas. METHODS: Secondary analysis was done using data from the 2011 Kansas Behavioral Risk Factor Surveillance System sexual violence module (N = 4,886). Crude and adjusted prevalence rate ratios were computed to examine associations between sexual assault and health risk behaviors, chronic health conditions and mental health conditions, overall and after adjusting for social demographic characteristics. Additional logistic regression models were implemented to examine the association between sexual assault and health risk behaviors with further adjustment for history of anxiety or depression. RESULTS: There was a significantly higher prevalence of health risk behaviors (heavy drinking, binge drinking and current smoking), chronic health conditions (disability, and current asthma) and mental health conditions (depression, anxiety, and suicidal ideation) among women who ever experienced sexual assault compared to women who did not, even after adjustment for potential confounders. CONCLUSIONS: Study findings highlight the need for chronic disease prevention services for victims of sexual violence. There are important implications for policies and practices related to primary, secondary, and tertiary prevention, as well as collaborations between sexual violence, chronic disease, and health risk behavior programs. PMID- 25516230 TI - Associations between variants on ADIPOQ and ADIPOR1 with colorectal cancer risk: a Chinese case-control study and updated meta-analysis. AB - BACKGROUND: Epidemiological studies have suggested that variants on adiponectin (ADIPOQ) and its receptor ADIPOR1 (adiponectin receptor 1) are associated with colorectal cancer (CRC) risk; however, the results were inconclusive. The aim of the study was to evaluate the associations between the variants on ADIPOQ and ADIPOR1 and the CRC risk with a hospital-based case-control study in the Chinese population along with meta-analysis of available epidemiological studies. METHODS: With a hospital-based case-control study of 341 cases and 727 controls, the associations between the common variants on ADIPOQ (rs266729, rs822395, rs2241766 and rs1501299) and ADIPOR1 (rs1342387 and rs12733285) and CRC susceptibility were evaluated. Meta-analysis of the published epidemiological studies was performed to investigate the associations between the variants and CRC risk. RESULTS: For the population study, we found that variant rs1342387 of ADIPOR1 was associated with a reduced risk for CRC [adjusted odds ratio (OR) = 0.74, 95% confidential intervals (95% CI) = 0.57-0.97; CT/TT vs. CC]. The meta analysis also suggested a significant association for rs1342387 and CRC risk; the pooled OR was 0.79 (95% CI = 0.66-0.95) for the CT/TT carriers compared to CC homozygotes under the random-effects model (Q = 8.06, df = 4, P = 0.089; I(2) = 50.4%). The case-control study found no significant association for variants rs266729, rs822395, rs2241766, and rs1501299 on ADIPOQ or variant rs12733285 on ADIPOR1 and CRC susceptibility, which were consistent with results from the meta analysis studies. CONCLUSIONS: These data suggested that variant rs1342387 on ADIPOR1 may be a novel CRC susceptibility factor. PMID- 25516231 TI - Misconceptions and miscommunication among Spanish-speaking and English-speaking women with pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: Limited data exist on women's experience with pelvic organ prolapse (POP) symptoms. We aimed to describe factors that prevent disease understanding among Spanish-speaking and English-speaking women. METHODS: Women with POP were recruited from female urology and urogynecology clinics in Los Angeles, California, and Albuquerque, New Mexico. Eight focus groups were conducted, four in Spanish and four in English. Topics addressed patients' emotional responses when noticing their prolapse, how they sought support, what verbal and written information was given, and their overall feelings of the process. Additionally, patients were asked about their experience with their treating physician. All interview transcripts were analyzed using grounded theory qualitative methods. RESULTS: Qualitative analysis yielded two preliminary themes. First, women had misconceptions about what POP is as well as its causes and treatments. Second, there was a great deal of miscommunication between patient and physician which led to decreased understanding about the diagnosis and treatment options. This included the fact that women were often overwhelmed with information which they did not understand. The concept emerged that there is a strong need for better methods to achieve disease and treatment understanding for women with POP. CONCLUSIONS: Our findings emphasize that women with POP have considerable misconceptions about their disease. In addition, there is miscommunication during the patient-physician interaction that leads to further confusion among Spanish-speaking and English-speaking women. Spending more time explaining the diagnosis of POP, rather than focusing solely on treatment options, may reduce miscommunication and increase patient understanding. PMID- 25516232 TI - Frailty, cognitive impairment, and functional disability in older women with female pelvic floor dysfunction. AB - INTRODUCTION AND HYPOTHESIS: There is a growing body of evidence demonstrating frailty as an important predictor of surgical outcomes in older adults undergoing major surgeries. The age-related onset of many symptoms of female pelvic floor dysfunction (PFD) in women suggests that many women seeking treatment for PFD may also have a high prevalence of frailty, which could potentially impact the risks and benefits of surgical treatment options. Our primary objective was to determine the prevalence of frailty, cognitive impairment, and functional disability in older women seeking treatment for PFD. METHODS: We conducted a cross-sectional study with prospective recruitment between September 2011 and September 2012. Women, age 65 years and older, were recruited at the conclusion of their new patient consultation for PFD at a tertiary center. A comprehensive geriatric screening including frailty measurements (Fried Frailty Index), cognitive screening (Saint Louis University Mental Status score), and functional status evaluation for activities of daily living (Katz ADL score) was conducted. RESULTS: Sixteen percent (n/N = 25/150) of women were categorized as frail according to the Fried Frailty Index score. After adjusting for education level, 21.3 % of women (n/N = 32/150) screened positive for dementia and 46 (30.7 %) reported functional difficulty or dependence in performing at least one Katz ADL. Sixty-nine women (46.0 %) chose surgical options for treatment of their PFD at the conclusion of their new patient visit with their physician. CONCLUSIONS: Frailty, cognitive impairment, and functional disability are common in older women seeking treatment for PFD. PMID- 25516233 TI - Acoustic signal emission monitoring as a novel method to predict steam pops during radiofrequency ablation: preliminary observations. AB - Steam pop is an explosive rupture of cardiac tissue caused by tissue overheating above 100 degrees C, resulting in steam formation, predisposing to serious complications associated with radiofrequency (RF) ablations. However, there are currently no reliable techniques to predict the occurrence of steam pops. We propose the utility of acoustic signals emitted during RF ablation as a novel method to predict steam pop formation and potentially prevent serious complications. METHODS: Radiofrequency generator parameters (power, impedance, and temperature) were temporally recorded during ablations performed in an in vitro bovine myocardial model. The acoustic system consisted of HTI-96-min hydrophone, microphone preamplifier, and sound card connected to a laptop computer. The hydrophone has the frequency range of 2 Hz to 30 kHz and nominal sensitivity in the range -240 to -165 dB. The sound was sampled at 96 kHz with 24 bit resolution. Output signal from the hydrophone was fed into the camera audio input to synchronize the video stream. An automated system was developed for the detection and analysis of acoustic events. RESULTS: Nine steam pops were observed. Three distinct sounds were identified as warning signals, each indicating rapid steam formation and its release from tissue. These sounds had a broad frequency range up to 6 kHz with several spectral peaks around 2-3 kHz. Subjectively, these warning signals were perceived as separate loud clicks, a quick succession of clicks, or continuous squeaking noise. Characteristic acoustic signals were identified preceding 80% of pops occurrence. Six cardiologists were able to identify 65% of acoustic signals accurately preceding the pop. An automated system identified the characteristic warning signals in 85% of cases. The mean time from the first acoustic signal to pop occurrence was 46 +/- 20 seconds. The automated system had 72.7% sensitivity and 88.9% specificity for predicting pops. CONCLUSIONS: Easily identifiable characteristic acoustic emissions predictably occur before imminent steam popping during RF ablations. Such acoustic emissions can be carefully monitored during an ablation and may be useful to prevent serious complications during RF delivery. PMID- 25516234 TI - Identification of risk categories for in pancreaticoduodenectomy based on diagnosis. AB - BACKGROUND: Studies of pancreaticoduodenectomy (PD) frequently overlook diagnosis as a variable when evaluating postoperative outcomes or generically group patients according to whether they have 'benign' or 'malignant' disease. Large multicentre studies comparing postoperative outcomes in PD stratified by diagnosis are lacking. The present study was conducted to verify the hypothesis that postoperative morbidity and length of stay (LoS) following PD vary by diagnosis and that patients may be grouped into low- and high-risk categories. METHODS: The database of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) was reviewed for all PDs performed during 2005-2011. Diagnoses were identified using ICD-9 codes and grouped based on the incidence of major morbidity. Univariate and multivariate analyses were utilized to assess the impact of diagnosis on PD outcomes. RESULTS: Of 5537 patients, those with pancreas cancer (n = 3173) and chronic pancreatitis (n = 485) experienced similar incidences of major morbidity (P = 0.95) and were grouped as having low-risk diagnoses. Patients with bile duct and ampullary (n = 1181), duodenal (n = 558) and neuroendocrine (n = 140) disease experienced similar levels of major morbidity (P = 0.78) and were grouped as having high-risk diagnoses. A high-risk diagnosis was identified as an independent risk factor for a prolonged LoS [odds ratio (OR) 1.67], organ space infection (OR 2.57), sepsis or septic shock (OR 1.83), and major morbidity (OR 1.70). Diagnosis did not predict readmission. CONCLUSIONS: The high-risk diagnosis is independently associated with postoperative morbidity and prolonged LoS. Patients with PD should be stratified by diagnosis to more accurately reflect their risk for postoperative complications and the complexity of care they will require. PMID- 25516235 TI - The State of Lesbian, Gay, and Bisexual Affirmative Training: A Survey of Faculty from Accredited Couple and Family Therapy Programs. AB - This study explored the state of lesbian, gay, and bisexual (LGB) affirmative training in the couple and family therapy field. LGB affirmative refers to holding positive views of LGB identities and relationships. A total of 117 faculty members completed the online survey for this study. Participants were asked to respond to items on the following topics: LGB affirmative stances, LGB affirmative program environment, LGB affirmative course content, self-of-the therapist work, and professional opportunities to work with LGB topics and clients. The findings of this study were encouraging as participants reported holding positive beliefs about LGB individuals, that their training programs had fairly affirmative program environments, and that LGB affirmative course content was included in their program curriculum. PMID- 25516236 TI - Comparative analysis of methods of endoscopic surgery of the submandibular gland: 114 surgeries. PMID- 25516237 TI - Bronchoscopic bullectomy with a one-way endobronchial valve to treat a giant bulla in an emphysematic lung: a case report. AB - The conventional treatment for giant bullae in patients with chronic obstructive pulmonary disease is surgical bullectomy, but it is not possible in some patients with poor lung function. Bronchoscopic bullectomy involving implantation of an endobronchial valve (EBV) has emerged as a potential alternative. Here we describe how EBV implantation in a bullous emphysema with a giant bulla in the right middle lobe led to elimination of the bulla and improvements in pulmonary function, 6-min walking distance during the 1-year follow-up. Our case suggests that bronchoscopic bullectomy with an EBV can be a safe and effective alternative to surgical bullectomy. PMID- 25516238 TI - Determination of three antidepressants in urine using simultaneous derivatization and temperature-assisted dispersive liquid-liquid microextraction followed by gas chromatography-flame ionization detection. AB - This paper presents a fast and simple method for the extraction, preconcentration and determination of fluvoxamine, nortriptyline and maprotiline in urine using simultaneous derivatization and temperature-assisted dispersive liquid-liquid microextraction (TA-DLLME) followed by gas chromatography-flame ionization detection (GC-FID). An appropriate mixture of dimethylformamide (disperser solvent), 1,1,2,2-tetrachloroethane (extraction solvent) and acetic anhydride (derivatization agent) was rapidly injected into the heated sample. Then the solution was cooled to room temperature and cloudy solution formed was centrifuged. Finally a portion of the sedimented phase was injected into the GC FID. The effect of several factors affecting the performance of the method, including the selection of suitable extraction and disperser solvents and their volumes, volume of derivatization agent, temperature, salt addition, pH and centrifugation time and speed were investigated and optimized. Figures of merit of the proposed method, such as linearity (r(2) > 0.993), enrichment factors (820-1070), limits of detection (2-4 ng mL(-1)) and quantification (8-12 ng mL( 1)), and relative standard deviations (3-6%) for both intraday and interday precisions (concentration = 50 ng mL(-1)) were satisfactory for determination of the selected antidepressants. Finally the method was successfully applied to determine the target pharmaceuticals in urine. PMID- 25516239 TI - Rectification inversion in oxygen substituted graphyne-graphene-based heterojunctions. AB - Current rectification is found in oxygen-substituted zigzag graphyne nanoribbon/hydrogen-terminated zigzag graphene nanoribbon heterostructure junctions, from the application of nonequilibrium Green's function formalism combined with density functional theory. This behavior could be tuned by varying the number and location of oxygen atoms in the zigzag graphyne nanoribbon parts, and the rectification direction could be reversed due to the parity limitation tunneling effect. Moreover, an obvious negative differential resistance behavior is found and may be explained by two different mechanisms. PMID- 25516240 TI - Magnetic and electronic evolutions of hydrogenated VTe2 monolayer under tension. AB - Two-dimensional nanostructures with controllable magnetic and electronic properties are desirable for their versatile applications in quantum devices. Here, we present a first-principles design on their magnetic and electronic switching controlled by tension. We find that hydrogenated VTe2 monolayer experiences a transfer from anti-ferromagnetism to ferromagnetism via a turning point of paramagnetism, and switches from semiconductor, to metal, further to half-metal as tension increases. We show that its anti-ferromagnetism with semiconducting or metallic character under low tension is contributed to super exchange or mobile-carrier enhanced super-exchange, while the ferromagnetism with half-metallic character under high tension is induced by carrier-mediated double exchange. We further show that the magnetic and electronic evolutions of hydrogenated VS2 and VSe2 monolayers under tension follow the same trend as those of hydrogenated VTe2 monolayer. We predict that tension is efficient and simple to control the magnetic and electronic properties of hydrogenated vanadium dichalcogenides monolayers. The monolayers with controllable magnetism and conductivity may find applications in multi-functional nanodevices. PMID- 25516241 TI - Enhanced ferromagnetism in a Mn(3)C(12)N(12)H(12) sheet. AB - Based on a recent experimental study on the Ni3 C12 S12 sheet [J. Am. Chem. Soc. 2013, 135, 2462] and a theoretical study on the Mn3 C12 S12 sheet [Nanoscale- 2013, 5, 10404], by using density functional theory combined with a thermodynamic model, it is shown that when sulfur atoms are replaced by ?NH? groups the resulting Mn3 C12 N12 H12 sheet can exhibit strong ferromagnetism with a Curie temperature of 450 K. The enhanced ferromagnetism is due to two main factors: the reduced lattice constant and nitrogen is more effective in mediating magnetic couplings through p-d exchange interactions. Furthermore, it is also confirmed that the Mn3 C12 N12 H12 sheet is kinetically and thermally stable, and displays half metallicity. PMID- 25516242 TI - In vitro and in vivo antimicrobial efficacy of natural plant-derived compounds against Vibrio cholerae of O1 El Tor Inaba serotype. AB - In this study, we investigated antibacterial activities of 20 plant-derived natural compounds against Gram-negative enteric pathogens. We found that both flavonoids and non-flavonoids, including honokiol and magnolol, possess specific antibacterial activities against V. cholerae, but not against other species of Gram-negative bacterium which we tested. Using various antibacterial assays, we determined that there was a dose-dependent bactericidal and biofilm inhibitory activity of honokiol and magnolol against Vibrio cholerae. In addition to antibacterial activities, these molecules also induced an attenuating effect on reactive oxygen species (ROS) production and pro-inflammatory responses generated by macrophages in response to lipopolysaccharides (LPS). Additionally, Caenorhabditis elegans lethality assay revealed that honokiol and magnolol have an ability to extend a lifespan of V. cholerae-infected worms, contributing to prolonged survival of worms after lethal infection. Altogether, our data show for the first time that honokiol and magnolol may be considered as attractive protective or preventive food adjuncts for cholera. PMID- 25516243 TI - Improving women doctors' ability to achieve their full leadership potential. PMID- 25516244 TI - Perioperative administration of high-dose recombinant human erythropoietin for delayed graft function prevention in kidney transplantation: a meta-analysis. AB - Delayed graft function (DGF) due to ischemia-reperfusion injury is a major early complication of kidney transplantation (KT). Recombinant human erythropoietin (rHuEPO) has been shown to exert nephroprotective action in animal models. We conducted a meta-analysis to explore the impact of rHuEPO on DGF in KT. Eligible studies comparing perioperative high-dose rHuEPO with placebo or no therapy for prevention of DGF were identified through MEDLINE, CENTRAL, and Transplant Library. Their design and data were assessed by two independent reviewers. Among 737 examined studies, four randomized controlled trials, involving 356 recipients of kidney allografts from deceased donors, fulfilled inclusion criteria. Statistical heterogeneity across studies was not significant (P = 0.98, I(2) = 0%). In a random effects model, no significant difference was found in the occurrence of DGF (odds ratio: 0,74, 95% CI: 0.47-1.18, P = 0.21). At 4 weeks after KT, the rHuEPO group exhibited higher systolic blood pressure (mean difference: 6.47 mmHg, 95% CI: 1.25-11.68, P = 0.02). Perioperative, high-dose rHuEPO administration does not prevent DGF in deceased donor KT. Furthermore, it is associated with higher systolic blood pressure leading to safety concerns. Nonerythropoietic rHuEPO derivatives, designed for nephroprotective action without increasing cardiovascular risk, might prove an alternative but still are at early stages of development. PMID- 25516245 TI - Research on self-purification capacity of Lake Taihu. AB - An effective measure to cope with eutrophication of lakes is to remove nutrients that can cause algal blooming by taking advantage of natural water purification processes. Here, the term "purification" is defined, in a wide sense, as the potential role of a water body to contribute to the reduction of pollutants and thus controlling eutrophication. Also regarded as a kind of ecological regulating services, biological purification involves various processes concerning seasonal nutrient fixation, such as uptake by aquatic macrophyte, biofouling onto foliage substrates, feeding by organisms in higher trophic level, and eternal loss or removal of substance from the water. In order to evaluate the water purification ability, a numerical lake ecosystem model (EcoTaihu) was developed and applied to Lakes Taihu. The model includes the biological interactions between pelagic compartments (phytoplankton and zooplankton, detritus, dissolved organic matter, fish, and nutrients). Under dynamic forcing of meteorological and hydrological parameters, the model was run over years to evaluate the annual nutrient cycles and purification functions. The reproducibility of the model was validated for water body by comparison with the field data from the water quality monitoring campaign. Numerical results revealed that self-purification capacity of nitrogen of Lake Taihu in years 2006, 2008, and 2010 is 4.00 * 10(4), 4.27 * 10(4), and 4.11 * 10(4) ton, respectively, whereas self-purification capacity of phosphorus of Lake Taihu in years 2006, 2008, and 2010 is 1.56 * 10(3), 1.80 * 10(3), and 1.71 * 10(3) ton, respectively. PMID- 25516246 TI - A 3-year study on occurrence of emerging contaminants in an urban stream of Sao Paulo State of Southeast Brazil. AB - This manuscript reports a 3-year study on occurrence of pharmaceuticals, hormones, and triclosan in surface waters of a central urban region of Sao Paulo State of Southeast Brazil (the Monjolinho River in Sao Carlos). Water samples collected once at every 2 months were pre-concentrated by solid-phase extraction (SPE) and analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The most frequently detected compounds in higher concentrations were caffeine, paracetamol, and atenolol (maximum concentrations 129,585, 30,421, and 8199 ng L(-1), respectively), while hormones estrone and 17-beta-estradiol were the least detected, in levels up to 14.8 ng L(-1). There was an increasing trend in concentrations of most of the compounds along the river course, especially downstream of the river where there is discharge of both wastewater treatment plant effluent and raw sewage from a particular region of Sao Carlos city. Concentrations of contaminants were higher during dry periods as a result of decline in the water levels. Decrease in concentrations near the river mouth occurred to different extents for each compound. It was high for caffeine and atenolol, but was very low for carbamazepine and diclofenac. The present study reports the first data about the occurrence of some major emerging contaminants in the Monjolinho River. Besides its regional significance, this work may assist in composing a dataset for water contamination diagnosis focusing on emerging contaminants, both in the Brazilian as well as in the Global studies related to aquatic ecosystems. Such datasets can be helpful for making future public policies on water quality, since these compounds are not yet legally regulated. PMID- 25516247 TI - Green algal over cyanobacterial dominance promoted with nitrogen and phosphorus additions in a mesocosm study at Lake Taihu, China. AB - Enrichment of waterways with nitrogen (N) and phosphorus (P) has accelerated eutrophication and promoted cyanobacterial blooms worldwide. An understanding of whether cyanobacteria maintain their dominance under accelerated eutrophication will help predict trends and provide rational control measures. A mesocosm experiment was conducted under natural light and temperature conditions in Lake Taihu, China. It revealed that only N added to lake water promoted growth of colonial and filamentous cyanobacteria (Microcystis, Pseudoanabaena and Planktothrix) and single-cell green algae (Cosmarium, Chlorella, and Scenedesmus). Adding P alone promoted neither cyanobacteria nor green algae significantly. N plus P additions promoted cyanobacteria and green algae growth greatly. The higher growth rates of green algae vs. cyanobacteria in N plus P additions resulted in the biomass of green algae exceeding that of cyanobacteria. This indicates that further enrichment with N plus P in eutrophic water will enhance green algae over cyanobacterial dominance. However, it does not mean that eutrophication problems will cease. On the contrary, the risk will increase due to increasing total phytoplankton biomass. PMID- 25516249 TI - Indoor/outdoor relationships of bioaerosol concentrations in a retirement home and a school dormitory. AB - The concentrations of bacterial and fungal bioaerosols were measured in a retirement home and a school dormitory from May 2012 to May 2013. In the present work, two active and passive methods were used for bioaerosol sampling. The results from the present work indicated that Bacillus spp., Micrococcus spp., and Staphylococcus spp. were the dominant bacterial genera, while the major fungal genera were Penicillium spp., Cladosporium spp., and Aspergillus spp. The results also indicated that the indoor-to-outdoor (I/O) ratios for total bacteria were 1.77 and 1.44 in the retirement home and the school dormitory, respectively; the corresponding values for total fungal spores were 1.23 and 1.08. The results suggested that in addition to outdoor sources, indoor sources also played a significant role in emitting bacterial and fungal bioaerosols in the retirement home and the school dormitory indoor. PMID- 25516248 TI - Silicon (Si) alleviates cotton (Gossypium hirsutum L.) from zinc (Zn) toxicity stress by limiting Zn uptake and oxidative damage. AB - Silicon (Si) is as an important fertilizer element, which has been found effective in enhancing plant tolerance to variety of biotic and a-biotic stresses. This study investigates the Si potential to alleviate zinc (Zn) toxicity stress in cotton (Gossypium hirsutum L.). Cotton plants were grown in hydroponics and exposed to different Zn concentration, 0, 25, and 50 MUM, alone and/or in combination with 1 mM Si. Incremental Zn concentration in growth media instigated the cellular oxidative damage that was evident from elevated levels of hydrogen peroxide (H2O2), electrolyte leakage, and malondialdehyde (MDA) and consequently inhibited cotton growth, biomass, chlorophyll pigments, and photosynthetic process. Application of Si significantly suppressed Zn accumulation in various plant parts, i.e., roots, stems, and leaves and thus promoted biomass, photosynthetic, growth parameters, and antioxidant enzymes activity of Zn-stressed as well unstressed plants. In addition, Si reduced the MDA and H2O2 production and electrolyte leakage suggesting its role in protecting cotton plants from Zn toxicity-induced oxidative damage. Thus, the study indicated that exogenous Si application could improve growth and development of cotton crop experiencing Zn toxicity stress by limiting Zn bioavailability and oxidative damage. PMID- 25516250 TI - Dynamics of heavy metals and phosphorus in the pore water of estuarine sediments following agricultural intensification in Chao Lake Valley. AB - Previous research has revealed that agricultural intensification in the Chao Lake Valley since the 1980s has led to significant heavy metal and phosphorus (P) contamination of estuarine sediments in this region. However, the pore water plays a more important role than do sediments in the cycling of nutrients and metals in estuarine ecosystems. Average concentrations of Cd, Cr, Ni, Pb, and P in the pore water of estuarine sediments were 0.634, 3.11, 4.98, 3.98, and 49.9 MUg L(-1), respectively. Average diffusive fluxes of these elements from the pore water to overlying water were -0.015, 0.058, 0.768, -0.238, and 20.0 MUg m(-2) d( 1), respectively. Compared with similar studies, the values of heavy metal fluxes were low, indicating minimal diffusion between sediments and overlying waters; however, P diffusion from the sediment pore water to overlying water was high, indicating that the sediments may be a direct source of P to overlying water. Since P is a major cause of algal blooming in agricultural estuaries of Chao Lake, the obtained results could be useful in developing effective management strategies to control pollution in the Chao Lake Valley. PMID- 25516251 TI - Groundwater arsenic removal using granular TiO2: integrated laboratory and field study. AB - High concentrations of arsenic (As) in groundwater pose a great threat to human health. The motivation of this study was to provide a practical solution for As safe water in As geogenic areas using granular TiO2 (GTiO2). The kinetics results indicated that the As (III/V) adsorption on GTiO2 conformed to the Weber-Morris (WM) intraparticle diffusion model. The Langmuir isotherm results suggested that the adsorption capacities for As (III) and As (V) were 106.4 and 38.3 mg/g, respectively. Ion effect study showed that cationic Ca and Mg substantially enhanced As (V) adsorption, whereas no significant impact was observed on As (III). Silicate substantially decreased As (V) adsorption by 57 % and As (III) by 50 %. HCO3 (-) remarkably inhibited As (V) adsorption by 52 %, whereas it slightly reduced As (III) adsorption by 8 %. Field column results demonstrated that ~700 MUg/L As was removed at an empty bed contact time (EBCT) of 1.08 min for 968 bed volumes before effluent As concentration exceeded 10 MUg/L, corresponding to 0.96 mg As/g GTiO2. Two household filters loaded with 110 g GTiO2 in the on-off operational mode can provide 6-L/day As-safe drinking water up to 288 and 600 days from the groundwater containing ~700 MUg/L As and ~217 MUg/L As, respectively. Integration of batch experiments and column tests with systematic variation of EBCTs was successfully achieved using PHREEQC incorporating a charge distribution multisite complexation (CD-MUSIC) model and one-dimensional reactive transport block. PMID- 25516252 TI - Assessment of DNA damage in floriculturists in southern Brazil. AB - The aim of this study was to assess possible genotoxic effects on floriculturists in a region of the state of Rio Grande do Sul, in the south of Brazil, using the micronucleus test (MN) and comet assay. Thirty-seven floriculturists and 37 individuals not exposed to pesticides participated in the study. The micronucleus test was performed with epithelial cells of the oral mucosa. In the microscopic analysis, 2000 cells were evaluated per subject, verifying the frequency of MN and the frequency of other nuclear abnormalities (nuclear buds, binucleated cells, and karyorrhexis). For the comet assay in the peripheral blood lymphocytes, 100 cells were classified in five classes, according to the migration of DNA fragments, thereby generating the frequency of damaged cells and the damage index. There was no difference between the exposed and control groups in the frequencies of MN and other nuclear abnormalities in the epithelial cells of the oral mucosa. However, the comet assay showed that both the frequency of DNA damaged cells and the damage index were significantly greater in the exposed group. The results therefore indicate that floriculturists are exposed to mixtures of pesticides with genotoxic potential. PMID- 25516253 TI - Simulation of runoff and nutrient export from a typical small watershed in China using the Hydrological Simulation Program-Fortran. AB - The Hydrological Simulation Program-Fortran (HSPF), which is a hydrological and water-quality computer model that was developed by the United States Environmental Protection Agency, was employed to simulate runoff and nutrient export from a typical small watershed in a hilly eastern monsoon region of China. First, a parameter sensitivity analysis was performed to assess how changes in the model parameters affect runoff and nutrient export. Next, the model was calibrated and validated using measured runoff and nutrient concentration data. The Nash-Sutcliffe efficiency (E NS ) values of the yearly runoff were 0.87 and 0.69 for the calibration and validation periods, respectively. For storms runoff events, the E NS values were 0.93 for the calibration period and 0.47 for the validation period. Antecedent precipitation and soil moisture conditions can affect the simulation accuracy of storm event flow. The E NS values for the total nitrogen (TN) export were 0.58 for the calibration period and 0.51 for the validation period. In addition, the correlation coefficients between the observed and simulated TN concentrations were 0.84 for the calibration period and 0.74 for the validation period. For phosphorus export, the E NS values were 0.89 for the calibration period and 0.88 for the validation period. In addition, the correlation coefficients between the observed and simulated orthophosphate concentrations were 0.96 and 0.94 for the calibration and validation periods, respectively. The nutrient simulation results are generally satisfactory even though the parameter-lumped HSPF model cannot represent the effects of the spatial pattern of land cover on nutrient export. The model parameters obtained in this study could serve as reference values for applying the model to similar regions. In addition, HSPF can properly describe the characteristics of water quantity and quality processes in this area. After adjustment, calibration, and validation of the parameters, the HSPF model is suitable for hydrological and water-quality simulations in watershed planning and management and for designing best management practices. PMID- 25516254 TI - Modeling for waste management associated with environmental-impact abatement under uncertainty. AB - Municipal solid waste (MSW) treatment can generate significant amounts of pollutants, and thus pose a risk on human health. Besides, in MSW management, various uncertainties exist in the related costs, impact factors, and objectives, which can affect the optimization processes and the decision schemes generated. In this study, a life cycle assessment-based interval-parameter programming (LCA IPP) method is developed for MSW management associated with environmental-impact abatement under uncertainty. The LCA-IPP can effectively examine the environmental consequences based on a number of environmental impact categories (i.e., greenhouse gas equivalent, acid gas emissions, and respiratory inorganics), through analyzing each life cycle stage and/or major contributing process related to various MSW management activities. It can also tackle uncertainties existed in the related costs, impact factors, and objectives and expressed as interval numbers. Then, the LCA-IPP method is applied to MSW management for the City of Beijing, the capital of China, where energy consumptions and six environmental parameters [i.e., CO2, CO, CH4, NOX, SO2, inhalable particle (PM10)] are used as systematic tool to quantify environmental releases in entire life cycle stage of waste collection, transportation, treatment, and disposal of. Results associated with system cost, environmental impact, and the related policy implication are generated and analyzed. Results can help identify desired alternatives for managing MSW flows, which has advantages in providing compromised schemes under an integrated consideration of economic efficiency and environmental impact under uncertainty. PMID- 25516255 TI - Electrical resistivity characteristics of diesel oil-contaminated kaolin clay and a resistivity-based detection method. AB - As the dielectric constant and conductivity of petroleum products are different from those of the pore water in soil, the electrical resistivity characteristics of oil-contaminated soil will be changed by the corresponding oil type and content. The contaminated soil specimens were manually prepared by static compaction method in the laboratory with commercial kaolin clay and diesel oil. The water content and dry density of the first group of soil specimens were controlled at 10 % and 1.58 g/cm(3). Corresponding electrical resistivities of the contaminated specimens were measured at the curing periods of 7, 14, and 28 and 90, 120, and 210 days on a modified oedometer cell with an LCR meter. Then, the electrical resistivity characteristics of diesel oil-contaminated kaolin clay were discussed. In order to realize a resistivity-based oil detection method, the other group of oil-contaminated kaolin clay specimens was also made and tested, but the initial water content, oil content, and dry density were controlled at 0~18 %, 0~18 %, 1.30~1.95 g/cm(3), respectively. Based on the test data, a resistivity-based artificial neural network (ANN) was developed. It was found that the electrical resistivity of kaolin clay decreased with the increase of oil content. Moreover, there was a good nonlinear relationship between electrical resistivity and corresponding oil content when the water content and dry density were kept constant. The decreasing velocity of the electrical resistivity of oil contaminated kaolin clay was higher before the oil content of 12 % than after 12 %, which indicated a transition of the soil from pore water-controlled into oil controlled electrical resistivity characteristics. Through microstructural analysis, the decrease of electrical resistivity could be explained by the increase of saturation degree together with the collapse of the electrical double layer. Environmental scanning electron microscopy (ESEM) photos indicated that the diesel oil in kaolin clay normally had three kinds of effects including oil filling, coating, and bridging. Finally, a resistivity-based ANN model was established based on the database collected from the experiment data. The performance of the model was proved to be reasonably accepted, which puts forward a possible simple, economic, and effective tool to detect the oil content in contaminated clayey soils just with four basic parameters: wet density, dry density, measured moisture content, and electrical resistivity. PMID- 25516257 TI - Early pregnancy IGF-I and placental GH and risk of epithelial ovarian cancer: A nested case-control study. AB - Insulin-like growth factor-I (IGF-I) signaling may promote ovarian tumor development by exerting mitotic, antiapoptotic and proangiogenic effects. During pregnancy, maternal production of IGF-I is regulated by placental growth hormone (GH). Parity is an established protective factor for ovarian cancer, however, no prior study has evaluated placental GH and IGF-I in pregnancy and epithelial ovarian cancer (EOC). Prior prospective studies on the association between IGF-I and EOC in nonpregnant populations were inconclusive and did not address associations in subtypes of EOC. Among members of the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort, we identified 1,045 EOC cases, diagnosed after recruitment (1975-2008) and before March 2011 and 2,658 individually matched controls. Placental GH and IGF-I were measured in serum from the last pregnancy before EOC diagnosis or selection as control. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for tertiles and a doubling of hormone concentrations. Higher IGF I was associated with a nonsignificant decrease in risk for invasive [ORT3 vs. T1 : 0.79 (0.62-1.02); ptrend = 0.07] and endometrioid tumors [ORT3 vs. T1 : 0.55 (0.28-1.07); ptrend = 0.07]. The protective association between higher IGF-I levels and risk of invasive EOC was stronger in analyses limited to women aged <55 years at diagnosis [ORT3 vs. T1 : 0.74 (0.57-0.96); ptrend = 0.03]. Our study provides the first data on placental GH and IGF-I in pregnancy and EOC risk overall and by subtype. Our data suggest higher IGF-I levels in pregnancy may be associated with lower risk of invasive and endometrioid EOC. PMID- 25516258 TI - Implementing an electronic medication overview in Belgium. AB - BACKGROUND: An accurate medication overview is essential to reduce medication errors. Therefore, it is essential to keep the medication overview up-to-date and to exchange healthcare information between healthcare professionals and patients. Digitally shared information yields possibilities to improve communication. However, implementing a digitally shared medication overview is challenging. This articles describes the development process of a secured, electronic platform designed for exchanging medication information as executed in a pilot study in Belgium, called "Vitalink". FINDINGS: The goal of "Vitalink" is to improve the exchange of medication information between professionals working in healthcare and patients in order to achieve a more efficient cooperation and better quality of care. Healthcare professionals of primary and secondary health care and patients of four Belgian regions participated in the project. In each region project groups coordinated implementation and reported back to the steering committee supervising the pilot study. The electronic medication overview was developed based on consensus in the project groups. The steering committee agreed to establish secured and authorized access through the use of electronic identity documents (eID) and a secured, eHealth-platform conform prior governmental regulations regarding privacy and security of healthcare information. DISCUSSION: A successful implementation of an electronic medication overview strongly depends on the accessibility and usability of the tool for healthcare professionals. Coordinating teams of the project groups concluded, based on their own observations and on problems reported to them, that secured and quick access to medical data needed to be pursued. According to their observations, the identification process using the eHealth platform, crucial to ensure secured data, was very time consuming. Secondly, software packages should meet the needs of their users, thus be adapted to daily activities of healthcare professionals. Moreover, software should be easy to install and run properly. The project would have benefited from a cost analysis executed by the national bodies prior to implementation. PMID- 25516259 TI - Born too small: who survives in the public hospitals in Lilongwe, Malawi? AB - OBJECTIVE: Malawi has the highest estimated preterm birth rate in the world. The survival rate of these babies is not known. The main objective of this study was to demonstrate the short-term survival of infants with birth weight below 2500 g nursed in Bwaila Hospital, a district hospital, and the tertiary level Kamuzu Central Hospital (KCH) in Lilongwe. The specific objectives were to calculate birth weight specific survival rates, compare the two hospitals regarding the chances of survival and review the use of antenatal corticosteroids. DESIGN: 1496 babies were included prospectively in the study between June and November 2012. Survival was defined as discharge from the nursery or postnatal ward. RESULTS: Survival was 7% for extremely low birth weight infants, 52% for very low birth weight and 90% for low birth weight (1500-2499 g). There was a marked increase in survival from 1100 g. Survival was significantly higher in KCH only for babies weighing below 1200 g. The majority of deaths occurred within the first 3 days of life. Only 98 of the babies had a mother who had received antenatal corticosteroids. CONCLUSIONS: With the current resources, we suggest focusing efforts on preventing early neonatal deaths in low birth weight infants above 1100 g in the hospitals in Lilongwe. The coverage of antenatal steroids for mothers at risk of preterm delivery can be improved. Further studies are needed on the quality of the obstetric and neonatal care at the hospitals and how to reduce the high rate of preterm birth in Malawi. PMID- 25516261 TI - Relationship between education and age-related cognitive decline: a review of recent research. AB - The association between level of educational attainment and cognitive performance is well studied. People with higher education perform better across a broad range of cognitive tasks. However, there is uncertainty as to whether education moderates the trajectory of age-related cognitive decline. This review paper addresses the potential link between education and age-related cognitive decline by evaluating relevant research published since 2000. Studies reporting data on education and its association with the rate of cognitive decline across various cognitive domains were reviewed. A total of 10 studies were identified with a mean follow-up period of 7.6 years; each contained a population-based, non demented sample. In the majority of studies, results showed that education did not moderate age-associated cognitive decline. The few studies that did find an association between education and decline in specific cognitive functions should be interpreted with caution because of methodological issues. The literature reveals little consistent evidence that normal age-related cognitive decline is moderated by education attainment. This supports a passive theory of cognitive reserve: people with a higher level of education will continue to perform at a higher level of cognitive functioning than their lower educated peers, which may delay the onset of impairment in the future. PMID- 25516260 TI - A database of circadian and diel rhythmic gene expression in the yellow fever mosquito Aedes aegypti. AB - BACKGROUND: The mosquito species Aedes aegypti is the primary vector of many arboviral diseases, including dengue and yellow fevers, that are responsible for a large worldwide health burden. The biological rhythms of mosquitoes regulate many of the physiological processes and behaviors that influence the transmission of these diseases. For insight into the molecular basis of biological rhythms, diel and circadian gene expression profiling has been carried out for many species. To bring these resources to Aedes aegypti researchers, we used microarray technology to carry out a genome wide assessment of gene expression during the 24 hour light/dark (LD) cycle and during constant darkness (DD). The purpose of this report is to describe the methods, the validation of the results, and the organization of this database resource. DESCRIPTION: The Aedes aegypti Circadian Database is a publicly accessible database that can be searched via a text-based query to visualize 44 hour temporal expression patterns of a given gene in Ae. aegypti heads under diel (observed under a 12 hour/12 hour LD cycle) and circadian (observed under DD) conditions. Profiles of gene expression under these conditions were assayed by Nimblegen 12-plex microarrays and rhythmicity was objectively assessed by the JTK_CYCLE algorithm. The output of the search is a graphical representation of the expression data along with computed period length, the time-of-day of gene expression peaks, and statistical determination for rhythmicity. CONCLUSION: Our results show that at least 7.9% of the gene set present in the Aedes aegypti head are rhythmic under LD conditions and 6.7% can be considered circadian, oscillating under constant dark conditions. We present these results in the Aedes aegypti Circadian Database through Bioclock, a public website hosted by the University of Notre Dame at http://www.nd.edu/~bioclock/. This website allows searchable browsing of this quantitative gene expression information. The visualization allows for gene-by-gene comparison of transcript expression under both diel and circadian conditions, and the results are presented graphically in a plot profile of gene expression. The Ae. aegypti Circadian Database provides a community resource for observing diel and circadian fluctuations in gene expression across the Ae. aegypti genome. PMID- 25516262 TI - Captain Webb's legacy: the perils of swimming the English Channel. PMID- 25516263 TI - Quantifying the Risk of Introduction of West Nile Virus into Great Britain by Migrating Passerine Birds. AB - West Nile virus (WNV) is a mosquito borne arbovirus that circulates within avian reservoirs. WNV can spill over into humans and Equidae that are dead-end hosts for WNV but suffer fever, acute morbidity and sometimes death. Outbreaks of WNV are common across Africa and Eastern Europe, and there have also been sporadic outbreaks in Spain and the Camargue Regional Park in France, but never in Great Britain (GB). These areas all fall along a major bird migration route. In this study, we analyse a scenario in which WNV is circulating in the Camargue or in other wetland areas in France and we estimate the risk of northward migrating passerine birds stopping in a WNV hotspot, becoming infected and carrying active infection to GB. If the disease were circulating in the Camargue during a single migratory season, the probability that one or more migrating birds becomes infected and lands in GB whilst still infected is 0.881 with 0.384 birds arriving in areas of suitable vector habitat. However, if WNV became established in the Grand Briere National Park or La Brenne Regional Park wetland areas further to the north, the model predicts that at least one infected bird will continue to GB. Thus, GB is at risk of WNV introduction from the Camargue, but the risk is considerably greater if WNV were to circulate further north than its previous focus in France, but this is highly sensitive to the force of infection in the infected area. However, the risk of establishment and infection of humans in GB is dependent upon a number of additional factors, in particular the vector and epidemiological situation in GB. PMID- 25516264 TI - Sann-Joong-Kuey-Jian-Tang decreases the protein expression of mammalian target of rapamycin but increases microtubule associated protein II light chain 3 expression to inhibit human BxPC-3 pancreatic carcinoma cells. AB - Sann-Joong-Kuey-Jian-Tang (SJKJT), a Traditional Chinese Medicinal prescription, has been used for the treatment of lymphadenopathy and solid tumors, and has shown therapeutic potential in a number of human malignant tumor cell lines, such as Hep-G2 hepatocellular carcinoma cells. Previous mechanistic studies demonstrated that SJKJT inhibited the proliferation of BxPC-3 pancreatic carcinoma cells through the extrinsic and intrinsic apoptotic pathways in vitro. SJKJT was also shown to be cytotoxic to colo 205 colon cancer cells by inducing autophagy in vitro. The present study therefore investigated molecular mechanisms of autophagy in human BxPC-3 pancreatic cancer cells treated with SJKJT. The cytotoxic effects of SJKJT on BxPC-3 human pancreatic carcinoma cells were evaluated using an MTT assay. Furthermore, the expression of autophagy-associated proteins, including mammalian target of rapamycin (mTOR), beclin-1, autophagocytosis-associated protein (Atg)3, Atg7, Atg5-Atg12 and microtubule associated protein II light chain 3 (LC3-II), was assessed using western blot analysis. The results demonstrated that BxPC-3 cells treated with SJKJT exhibited decreased expression levels of mTOR and increased expression of LC3-II protein. In addition, the expression of the beclin-1, Atg3, Atg7 and Atg5-Atg12 proteins was increased during the first 24 h, but decreased from 48 to 72 h. The results showed that SJKJT inhibited the proliferation of human BxPC-3 pancreatic cancer cells in vitro. A possible underlying molecular mechanism may be the induction of autophagy. Further investigation into the therapeutic potential of SJKJT in human pancreatic cancer is required. PMID- 25516265 TI - Protocol for a systematic review and meta-analysis of hepatitis C virus (HCV) prevalence and incidence in the Horn of Africa sub-region of the Middle East and North Africa. AB - BACKGROUND: In the Middle East and North Africa (MENA), hepatitis C virus (HCV) distribution appears to present a wide range of prevalence. The scale and nature of HCV disease burden is poorly known in the Horn of Africa sub-region of MENA including Djibouti, Somalia, and Sudan in addition to Yemen at the southwest corner of the Arabian Peninsula. The aim of this review is to provide a systematic review and synthesis of all epidemiological data on HCV prevalence and incidence among the different population groups in this sub-region of MENA. A second aim of the study is to estimate the national population-level HCV prevalence for each of these four countries. METHODS/DESIGN: The systematic review will be conducted based on the items outlined in the PRISMA statement. PubMed, Embase, and the World Health organization (WHO) regional databases will be searched for eligible studies without language or date restrictions. Observational and intervention studies reporting data on the prevalence or incidence of HCV in any population group in Djibouti, Somalia, Sudan, or Yemen will be included. Additional sources will be obtained through the database of the MENA HIV/AIDS Epidemiology Synthesis Project, including international organizations' reports and country-level reports, and abstracts of international conferences. Study and population characteristics will be extracted from eligible publications, with previously agreed pro formas; and entered into a computerized database. We will pool prevalence using DerSimonian and Laird random-effects models after a Freeman-Tukey transformation to stabilize variances. We will conduct meta-regression analysis to explore the effect of study-level characteristics as potential sources of heterogeneity. DISCUSSION: This proposed systematic review and meta-analysis aims to better describe HCV infection distribution across countries in the Horn of Africa sub-region of MENA; and between sub-population groups within each country. The study will provide empirical evidence necessary for researchers, policy-makers, and public health stakeholders to set research, policy, and programming priorities for HCV prevention, control, and treatment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014010318. PMID- 25516266 TI - Fabrication of nano-structured calcium silicate coatings with enhanced stability, bioactivity and osteogenic and angiogenic activity. AB - The bioactivity and stability of coatings on alloy implants play critical roles in the fast osseointegration and maintenance of a long-term life span of the implants, respectively. Herein, nano-sheet surface on bioactive calcium silicate (CaSiO3, CS) coatings on metal substrates was fabricated by combining atmosphere plasma spraying (APS) and hydrothermal technology (HT). The glassy phase in CS coatings generated by APS was converted into crystalline sheet-like nano structures after HT treatment. Compared with the original CS coating samples, HT treatment decreased the degradation rate of the CS coatings. Moreover, the fabricated nano-structured topography of CS coatings increased the apatite mineralization ability and significantly enhanced the cell attachment, proliferation, differentiation, alkaline phosphatase (ALP) activity and expression of osteogenic genes and angiogenic factors of rat bone marrow stromal cells (bMSCs). Our results suggest that the nano-structured CS coatings have immense potential in improving the clinical performance of medical implants. PMID- 25516267 TI - Influence of surfaces modified with biomimetic extracellular matrices on adhesion and proliferation of mesenchymal stem cells and osteosarcoma cells. AB - Preparation of surfaces modified with biomimetic extracellular matrices (ECMs) is important for investigation of the interaction between ECMs and cells. In the present study, surfaces modified with ECMs from normal somatic cells, stem cells and tumor cells were prepared by cell culture method. The ECMs derived from bone marrow-derived mesenchymal stem cells (MSCs), dermal fibroblasts (FBs), osteoblasts (OBs) and MG63 osteosarcoma cells were deposited on the surfaces of cell-culture polystyrene plates (TCPS). The ECMs from different cell types had different compositions. The effects of the ECM-deposited surfaces on the adhesion, spreading and proliferation of MSCs and MG63 human osteosarcoma cells were dependent on the type of both ECMs and cells. The surfaces deposited with ECMs from MSCs, FBs and OBs promoted cell adhesion more strongly than surfaces deposited with ECMs from MG63 cells and TCPS. Compared to TCPS, the ECM-deposited surfaces promoted proliferation of MSCs while they inhibited the proliferation of MG63 cells. PMID- 25516268 TI - The more, the better: the use of multiple landmark configurations to solve the phylogenetic relationships in musteloids. AB - Although the use of landmark data to study shape changes along a phylogenetic tree has become a common practice in evolutionary studies, the role of this sort of data for the inference of phylogenetic relationships remains under debate. Theoretical issues aside, the very existence of historical information in landmark data has been challenged, since phylogenetic analyses have often shown little congruence with alternative sources of evidence. However, most analyses conducted in the past were based upon a single landmark configuration, leaving it unsettled whether the incorporation of multiple configurations may improve the rather poor performance of this data source in most previous phylogenetic analyses. In the present study, we present a phylogenetic analysis of landmark data that combines information derived from several skeletal structures to derive a phylogenetic tree for musteloids. The analysis includes nine configurations representing different skeletal structures for 24 species. The resulting tree presents several notable concordances with phylogenetic hypotheses derived from molecular data. In particular, Mephitidae, Procyonidae, and Lutrinae plus the genera Martes, Mustela, Galictis, and Procyon were retrieved as monophyletic. In addition, other groupings were in agreement with molecular phylogenies or presented only minor discordances. Complementary analyses have also indicated that the results improve substantially when an increasing number of landmark configurations are included in the analysis. The results presented here thus highlight the importance of combining information from multiple structures to derive phylogenetic hypotheses from landmark data. PMID- 25516270 TI - Low birthrates and high levels of female reproductive inactivity may characterize the reproductive biology of wild Peruvian red uakaris (Cacajao calvus ucayalii). AB - BACKGROUND: Birthrates are key parameters for population models and hunting sustainability analyses frequently used in conservation, but for many rare species, these data do not exist. We examine the reproductive organs of endangered red uakari monkeys to calculate birthrates in the wild. METHODS: We collected reproductive organs from wild uakari monkeys hunted for subsistence by indigenous hunters and examined them for embryos or fetuses. We extrapolated birth dates to test for breeding seasonality and calculated birthrates. RESULTS: Breeding was seasonal, and birthrates were low relative to other neotropical primates. We recorded unexpectedly high numbers of reproductively inactive females compared to other neotropical monkeys. CONCLUSIONS: Reproductive inactivity could be due to delayed reproduction or long periods of lactation. Resource availability may also play a role. Slow reproduction and low birthrates in uakaris, relative other primates, could explain why uakaris have a patchy distribution and appear vulnerable to disturbance. PMID- 25516269 TI - Colorimetric assay for heterogeneous-catalyzed lipase activity: enzyme-regulated gold nanoparticle aggregation. AB - Lipase is a neglected enzyme in the field of gold nanoparticle-based enzyme assays. This paper reports a novel colorimetric probe to rapidly visualize lipase activities by using Tween 20 functioned GNPs (Tween 20-GNPs) as a reporter. The present strategy hence could overcome the limitations caused by the heterogeneous interface in lipase assay. Catalytic hydrolytic cleavage of the ester bond in Tween 20-GNPs by lipase will trigger the rapid aggregation of GNPs at a high salt solution. The color change from red to purple could be used to sense the activity of lipase. The detection limit (3sigma) is as low as 2.8 * 10-2 mg/mL. A preliminary enzyme activity screening was carried out for seven commercially purchased lipase samples. It also has been successfully applied to detecting lipase in fermentation broth of Bacillus subtilis without any pretreatment. PMID- 25516271 TI - A case of recurrent facial herpes simplex mimicking hydroa vacciniforme. PMID- 25516272 TI - Neurofibromatosis type 1 diagnosed in a child based on multiple juvenile xanthogranulomas and juvenile myelomonocytic leukemia. AB - An association between juvenile xanthogranuloma (JXG), neurofibromatosis type 1 (NF1), and juvenile myelomonocytic leukemia (JMML) has been described in the literature but has only been documented in approximately 20 cases. We diagnosed a patient with NF1 at 25 months of age, before any cutaneous stigmata of this disease had appeared, because we decided to screen for the NF1 gene mutation because of his presentation with multiple JXGs and moderate macrocephaly (2.5 standard deviations) at 9 months of age and JMML diagnosed at 20 months of age. The child is well today after treatment with chemotherapy and allogenic bone marrow transplantation. With increased awareness, patients with JXG and NF1 who develop symptoms possibly related to JMML, such as paleness, skin bleeding, cough, unexplained fever, and hepatosplenomegaly, should be further evaluated. We also emphasize that multiple JXG lesions can be an early marker of NF1. PMID- 25516274 TI - Borderline to Moderate Blepharoptosis Correction Using Retrotarsal Tucking of Muller Muscle: Levator Aponeurosis in Asian Eyelids. AB - BACKGROUND: The purpose of this paper is to report the outcome of retrotarsal tucking of Muller muscle-levator aponeurosis for the correction of borderline to moderate ptosis in conjunction with esthetic blepharoplasty in Asian eyelids and to explore the relationship between the extent of advancement and change in the eyelid position (MRD1). METHODS: The medical records of 290 consecutive patients who underwent retrotarsal tucking of Muller muscle-levator aponeurosis from February 2005 to November 2011 were reviewed. Of those, 26 patients (51 eyelids) were statistically analyzed. The correction was performed through an external upper blepharoplasty approach. Once the orbital septum was opened, the Muller muscle-levator aponeurosis was advanced and tucked under the posterior surface of the tarsus by a single lifting suture. The average follow-up period was 20.6 months, with a range of 3-68 months. RESULTS: In 26 patients (51 eyelids), satisfactory results were recorded for 49 of 51 eyelids (96.1 %). The margin reflex distance-1 (MRD1) increased from 1.56 +/- 0.70 mm preoperatively to 3.86 +/- 0.94 mm postoperatively (p < 0.001, Wilcoxon signed rank test). When 6.1 mm of advancement was implemented, an average MRD1 of 1 mm was achieved. For 7.2 and 8.3 mm of advancement, the average MRD1 achieved was 2 and 3 mm each. A noteworthy complication, although not included in statistical analysis, was one patient who had developed corneal irritation caused by the conjunctival exposure to the non-absorbable suture 3 years after the surgery, which led the subject to have the suture removed. CONCLUSION: The author concludes that this procedure is one of the most effective surgical options in correcting borderline to moderate blepharoptosis in conjunction with esthetic blepharoplasty. The main advantage of such a method is that once the orbital septum is opened, Muller muscle-levator aponeurosis is easily advanced and tucked under the posterior surface of the tarsal plate without extensive dissection or resection, which is less traumatic and gives a more vertical lifting vector, thus producing excellent cosmetic results and quick recovery. PMID- 25516275 TI - Effect of Antiadhesion Barrier Solution and Fibrin on Capsular Formation After Silicone Implant Insertion in a White Rat Model. AB - INTRODUCTION: One of the most serious complications of breast reconstruction and augmentation using silicone implants is capsular contracture. Several preventive treatments, including vitamin E, steroids, antibiotics, and cysteinyl leukotriene inhibitors, have been studied, and their clinical effects have been reported. However, the problem of capsular contracture has not yet been completely resolved. This study was performed to compare anti-adhesion barrier solution (AABS) and fibrin in their ability to prevent fibrotic capsule formation and simultaneously evaluated their effect when used in combination by capsular thickness analysis and quantitative analysis of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and type I collagen within the fibrous capsule. MATERIALS AND METHODS: This study used female six-week-old Sprague-Dawley rats. Eighty rats were equally subdivided into the four following groups: AABS-treated, fibrin-treated, AABS and fibrin combined-treated, and untreated control groups. Each rat received two silicone chips under the panniculus carnosus muscle layer. The test materials were applied around the silicon chips. Four weeks later, the implantation sites including the skin and muscle were excised to avoid the risk of losing the fibrous capsule around the implants. The capsular thickness was analyzed by Masson's trichrome stain. Quantitative analysis of type I collagen, MMPs, and TIMPs was performed by real time PCR, Western blot, and zymography. RESULTS: The mean capsular thickness was 668.10 +/- 275.12 MUm in the control group, 356.97 +/- 112.11 MUm in the AABS treated group, 525.96 +/- 130.97 MUm in the fibrin-treated group, and 389.24 +/- 130.51 MUm in the AABS and fibrin combined-treated group. Capsular thickness was significantly decreased in all experimental groups (p < 0.05). Capsular thickness was greater in the fibrin-treated group than in the AABS-treated group (p < 0.05). There was no statistically significant difference in capsular thickness between the AABS and fibrin combined-treated group and the AABS- or fibrin treated group (p > 0.05). Compared to the control group, the experimental groups had significantly lower expressions of type I collagen and MMP-1 (p < 0.05), but there was no statistically significant difference in expressions of type I collagen and MMP-1 between the AABS-, fibrin-, and AABS and fibrin combined treated groups (p > 0.05). The expressions of MMP-2 and TIMP-2 were not significantly different between the control and the experimental groups (p > 0.05). CONCLUSION: AABS is more effective in reducing capsular thickness compared with fibrin treatment in a white rat model. PMID- 25516276 TI - Effect of combining tramadol and morphine in adult surgical patients: a systematic review and meta-analysis of randomized trials. AB - The role for tramadol in multimodal postsurgical analgesic strategies remains unclear. We undertook a systematic review to evaluate the utility of combining tramadol with morphine after surgery. We searched the MEDLINE, EMBASE, LILAC, Cochrane, and Clinical Trial Register databases for randomized, controlled studies comparing tramadol with placebo or active control in patients undergoing surgery. Fourteen studies (713 patients) were included. There was a limited but significant postoperative morphine-sparing effect, with a weighted mean difference (WMD) of -6.9 (95% confidence interval -11.3 to -2.5) mg. This effect was not associated with a decrease in morphine-related adverse effects. No difference in the incidence of nausea, vomiting, sedation, or shivering was observed. There was no decrease in pain intensity at 24 h; the WMD was -0.9 ( 7.2; 5.2) on a 100 mm visual analogue scale at 24 h. We found no significant clinical benefit from the combination of i.v. tramadol and morphine after surgery. PMID- 25516278 TI - Ogilvie's Syndrome in an obstetric patients. PMID- 25516277 TI - Comparison of pulse contour analysis by Pulsioflex and Vigileo to measure and track changes of cardiac output in critically ill patients. AB - BACKGROUND: We compared the new Pulsioflex and the Vigileo devices to measure cardiac index (CI) in critically ill patients. Both devices measure CI by pulse contour analysis. The Pulsioflex device also allows an auto-calibration (not based on thermodilution). METHODS: Patients were included if we administered fluids (20 patients), reduced (20 patients), or increased (20 patients) the dose of norepinephrine. Before and after interventions, we measured CI provided by the Vigileo (CIVig) and Pulsioflex (CIPfx) devices before and after its auto calibration. CI measured by transpulmonary thermodilution (CIthermo) was used as the reference. RESULTS: Considering absolute values of CI (n=120), the percentage error was 59% for CIVig vs CIthermo and 40% for CIthermo vs CIPfx. Auto calibrating CIPfx after interventions did not improve the percentage error between CIPfx and CIthermo (39%). Considering the fluid-induced changes in CI, the coefficient of correlation with changes in CIthermo was 0.50 for CIVig, and 0.73 for CIPfx (P=0.27). It was not significantly improved if CIPfx was auto calibrated (r=0.64). Considering the norepinephrine-induced changes in CI, the coefficient of correlation with changes in CIthermo was 0.41 for CIVig. It tended to be better for CIPfx (r=0.71, P=0.07). It was not significantly improved by auto-calibration (r=0.53). CONCLUSIONS: The Pulsioflex did not reliably estimate the absolute values of CI. For tracking fluid-induced changes in CI, the Pulsioflex was reliable, and also the Vigileo. For tracking norepinephrine induced changes in CI, it was also reliable and tended to be better than the Vigileo. Auto-calibration allowed by the system did not improve its reliability. PMID- 25516279 TI - Risk of preeclampsia and obstetric outcome in donor oocyte and autologous in vitro fertilization pregnancies. AB - BACKGROUND: The aim of the study was to assess the outcome of pregnancies achieved by OD in vitro fertilization compared with those obtained by autologous IVF. METHODS: This retrospective cohort study includes 136 consecutive patients who were referred to our centre between 2009 and 2011. According to the mode of conception, they were divided into two groups, whose pregnancy outcomes were analyzed by chi2 Test for unpaired data. RESULTS: Pregnancy-induced hypertension, cesarean section, complications after delivery resulted more frequent in pregnancies from donor oocyte IVF. The other outcomes considered were non significantly different between the two groups. CONCLUSIONS: The risk of developing preeclampsia, cesarean section, and postpartum complications is higher in patients who conceived by donor oocyte IVF than in patients who underwent autologous IVF. PMID- 25516280 TI - Biology of male fertility control: an overview of various male contraceptive approaches. AB - The population of our planet continues to grow at an alarming rate. If the growth continues at the present rate, the estimated current world population of about seven billion is expected to double in the next forty years. Accumulated data from surveys by the United Nations Population Control Division suggest that a majority of today's young men in many countries are willing to have fewer children than their parents did. However, the contraceptive options available to them have not changed in several decades. In spite of the general agreement that men, like women, must take full responsibility of their fertility, the availability of safe, reversible and affordable contraceptives for men have lagged behind because of the complexity of the science of the male reproductive system. Thus, the contraceptive needs of millions of men/couples go unmet every single day and results in millions of unwanted pregnancies. In this article, we intend to discuss new hormonal and non-hormonal contraceptive approaches that are at various stages of research and development and may someday provide new contraceptives for men. In addition, we intend to discuss many details of three safe, effective, affordable and reversible vas-based approaches that are inching closer to being approved for use by millions of men in multiple countries. Finally, our intention is to discuss the male contraceptive pill that will soon be available to men only in Indonesia. The availability of these male contraceptives will allow both men and women to take full control of their fertility and participate in slowing down the growth of world population. PMID- 25516282 TI - Heterozygous carriers of classical homocystinuria tend to have higher fasting serum homocysteine concentrations than non-carriers in the presence of folate deficiency. AB - BACKGROUND & AIMS: Many studies have reported that serum total homocysteine (tHcy) levels in cystathionine-beta-synthase (CBS) carriers are usually normal and only elevated after a methionine load. However, the amount of methionine required for a loading test is non-physiological and is never reached with regular feeding. Therefore, CBS carriers do not seem to be at an increased risk of cardiovascular diseases. However, the risk of cardiovascular diseases of CBS carriers with folate deficiency has not been studied. We recently found an extraordinarily high carrier rate (1/7.78) of a novel CBS mutation (p.D47E, c.T141A) in an Austronesian Taiwanese Tao tribe who live in a geographic area with folate deficiency. We evaluated if the CBS carriers tend to have higher fasting serum tHcy concentrations than non-carriers in presence of folate deficiency. METHODS: The serum tHcy and folate levels before and after folate replacement were measured in 48 adult Tao carriers, 40 age-matched Tao non carriers and 40 age-matched Han Taiwanese controls. RESULTS: The serum tHcy level of the Tao CBS carriers (17.9 +/- 3.8 MUmol/l) was significantly higher than in Tao non-carriers (15.7 +/- 3.5 MUmol/l; p < 0.008) and Taiwanese controls (11.8 +/- 2.9 MUmol/l; p < 0.001). Furthermore, a high prevalence of folate deficiency in the Tao compared with the Taiwanese controls (4.9 +/- 1.8 ng/ml vs. 10.6 +/- 5.5 ng/ml; p < 0.001) was also noted. Of note, the difference in tHcy levels between the carriers and non-carriers was eliminated by folate supplementation. (carriers:13.65 +/- 2.13 MUmol/l; non-carriers:12.39 +/- 3.25 MUmol/l, p = 0.321). CONCLUSIONS: CBS carriers tend to have a higher tHcy level in the presence of folate deficiency than non-carriers. Although many reports have indicated that CBS carriers are not associated with cardiovascular disease, the risk for CBS carriers with folate deficiency has not been well studied. Owing to a significantly elevated level of fasting tHcy without methionine loading, it is important to evaluate the risk of cardiovascular disease in CBS carriers with folate deficiency. PMID- 25516281 TI - Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. AB - In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html webcite. PMID- 25516283 TI - Binding interaction and gelation in aqueous mixtures of poly(N isopropylacrylamide) and hectorite clay. AB - The binding interaction between poly(N-isopropylacrylamide) (PNIPAm) chains and hectorite clay platelets was directly detected by quartz crystal microbalance with dissipation (QCM-D) to explore the cross-linking mechanism in the strong nanocomposite hydrogel (NC gel), which is in situ polymerized with NIPAm in the clay suspension. PNIPAm chains were allowed to be adsorbed on the gold surface of the QCM electrode. A large frequency shift Deltaf in the QCM as introducing the clay indicated that a large amount of clay platelets were adsorbed on the deposited PNIPAm layer. The relationship between the dissipation shift DeltaD and Deltaf revealed that the adsorption included two steps of fast initial buildup and following densification of the clay platelets. In dilute aqueous mixtures, the PNIPAm chain and clay formed aggregates as observed from the hydrodynamic diameter. A gelation state diagram was established for concentrated aqueous PNIPAm-clay mixtures. The Raman spectrum pointed out the conformation change of the PNIPAm chains in aqueous solutions when the clay was added, which would be caused by the adsorption of PNIPAm chains to the clay platelets. PMID- 25516284 TI - Obituary: Remembering Michael Piatak, Jr. PMID- 25516285 TI - Assessment of spirometry and impulse oscillometry in relation to asthma control. AB - INTRODUCTION: Guidelines advocate the use of spirometry to assess pulmonary function in asthmatic patients. Commonly used measures include forced expiratory volume in 1 s (FEV1), forced expiratory ratio (FEV1/FVC), and forced mid expiratory flow between 25 and 75 % of forced vital capacity (FEF25-75). Impulse oscillometry (IOS) is an effort-independent test performed during tidal breathing. IOS may be used to assess the total and central airway resistance at 5 Hz (R5) and 20 Hz (R20), respectively, and hence derive the peripheral airway resistance from the difference (R5-R20). We compared spirometry and IOS as tests of global airway function (i.e., FEV1, FEV1/FVC, R5) and putative measures of small airways function (i.e., FEF25-75, R5-R20) and their relationship to oral steroid and short-acting beta-agonist (SABA) use as surrogates for long-term asthma control. METHODS: Spirometry and IOS measurements from physician-diagnosed asthmatics were linked to a health informatics database for oral steroid and SABA use 1 year prior to the index measurements. RESULTS: Four hundred forty-two patients had both spirometry and IOS, mean FEV1 = 86 % predicted, 94 % on ICS, median dose 800 ug/day. IOS and spirometry measures were equally predictive of impaired asthma control for both oral steroid and SABA use. For oral steroid use, the adjusted odds ratio, OR (95 % CI) is as follows: FEV1 < 80 %: 1.56(0.99 2.47), p = 0.056; FEV1/FVC < 0.70: 1.67(1.03-2.69), p = 0.037; FEF25-75 < 60 %: 1.84(1.18-2.86), p = 0.007; R5 > 150 %: 1.91(1.25-2.95), p = 0.003; and R5-R20 > 0.1 kPa L(-1) s 1.73(1.12-2.66), p = 0.013. For SABA use, the adjusted OR (95 % CI) is as follows: FEV1 < 80 %: 2.22(1.43-3.44), p < 0.001; FEV1/FVC < 0.70: 2.26(1.44-3.57), p < 0.001; FEF25-75 < 60 %: 2.51(1.65-3.82), p < 0.001; R5 > 150 %: 1.76(1.18-2.63), p = 0.006; and R5-R20 > 0.1 kPa L(-1) s: 2.94(1.94-4.46), p < 0.001. CONCLUSION: Spirometry or IOS measurements were equally useful as potential markers of asthma control in persistent asthmatic patients. PMID- 25516287 TI - Wiring the preterm brain: contribution of new meta-analytic approaches. PMID- 25516286 TI - The effect of different comorbidities on survival of non-small cells lung cancer patients. AB - PURPOSE: Primary lung cancer is one of the most common types of cancers. Comorbidity has been shown to be a negative prognostic factor in the overall lung cancer population. The significance of the individual comorbidities is less well known. The purpose of this paper is to investigate the effect of each comorbid disease groups on survival. METHODS: The analysis is based on all patients with NSCLC who were registered in 2009-2011, in total 10,378 patients. To estimate the effect of each comorbidity group on the survival, we fitted a Cox regression model for each comorbidity group adjusting for age, sex, resection, and stage. RESULTS: Patients with cardiovascular comorbidity have a 30% higher death rate [HR 1.30 with 95% CI (1.13; 1.49)] than patients without comorbidity. Patients with diabetes and patients with cerebrovascular disorders and COPD have a 20% excess mortality than patients without comorbidity: [HR 1.19 with CI (1.02; 1.39) for diabetes, HR 1.18 with CI (1.05; 1.33) for cerebrovascular disorders, and HR 1.20 with CI (1.10; 1.39 for COPD)]. CONCLUSION: Our study shows the importance of cardiovascular disease in lung cancer. Diabetes, cerebrovascular disorders, and COPD also have a significant impact on survival of NSCLC patients. PMID- 25516288 TI - Unmet education, psychological and peer support needs of people with multiple sclerosis. AB - OBJECTIVE: Multiple sclerosis is a complex neurological disease which can cause impairment in a range of aspects of an individual's life. It often requires a degree of adjustment and peer support. The aim of the present study was to examine satisfaction with educational, psychological and peer support services of people with MS across gender, age and symptom severity. METHOD: Participants completed a needs analysis questionnaire using Likert scales to determine the level of satisfaction with the support services. The questionnaire was sent to participants (n=3502) throughout Australia as paper copy with reply paid envelope, or made available to them online via email links. A total of 2805 responded and completed the questionnaire (80% response rate). Of those, 79% were female and 21% were male. The participants ranged in age from 19 to 92 years, (M=52.10; SD=11.82). RESULTS: In terms of psychological services, females were less satisfied with their access to relationship and family counseling. There was also a clear need for more varieties in peer support groups, times, as well as modes of communication, especially among young people and mildly affected groups. Symptom severity was associated with a greater need for almost all education and psychological support services. CONCLUSION: The findings of this study highlight current areas of unmet needs and may be used to inform the design and development of future education, psychological and social support services to ensure they are relevant and useful, as well as providing direction for future research. PMID- 25516289 TI - Total Hip Arthroplasty: Leg Length Discrepancy Affects Functional Outcomes and Patient's Gait. AB - Our study was targeted to investigate the relationship between postoperative leg length discrepancy (LLD) and the outcomes of total hip arthroplasty (THA) including gait, hip function, and lower back pain (LBP). Ninety-two patients who underwent primary THA during Jan 2009 to Apr 2011 in our medical center were enrolled in this study. We measured postoperative LLD of the patients both directly and from the leg radiographs. Six months after the surgery, we evaluated the hip function with Harris Hip Score (HHS), analyzed the gait, and recorded the degree of LBP. Patients with LLD between 10 and 20 mm were given the block footbeds to correct the difference in the leg length. Then 1 year after the surgery, the above-mentioned parameters were evaluated again. (1) LLD: Patients were divided into three groups according to the magnitude: less than 10 mm were grouped as A, those between 10 and 20 mm as B, and more than 20 mm as C. (2) Gait analysis: patients with larger LLD showed slower gait speed (t = 6.527; p < 0.01), longer single support time (t = -2.665; p = 0.01), and shorter foot-off time (t = -8.502; p < 0.01). After half a year of the surgery, Group B patients showed recovery and their functional performance was not significantly different from that of the patients in Group A (t = -0.686; p = 0.49). (3) HHS: In the first half of the follow-up year, patients with smaller LLD showed an improved function (t = 6.56; p < 0.01). At the end of year one, the HHS of Group B patients was not significantly different from that of Group A (t = 1.4; p = 0.16), suggesting a good recovery, however, Group C patients showed no improvement in HHS scores. (4) LBP: Initially, Group B patients suffered from more severe LBP than Group A patients, however, the examination conducted in the end of year 1 exhibited no difference in the LBP levels of the two groups (t = 0.683; p = 0.01, t = -0.85; p = 0.40). After THA surgery, the outcome was found to be significantly associated with the degree of different length of lower limbs. The use of block such as footbed could partly relieve the symptoms of hip dysfunction and LBP. However, the recovery was less significant in patients with leg length difference more than 20 mm. PMID- 25516290 TI - [The "Health system delay" in tuberculosis patients in Saint-Louis Senegal]. AB - Sixty patients with positive acid fast bacilli sputum smears between were enrolled consecutively between March and August 2012 in the Saint-Louis (Senegal) health district to determine the Health System Delay in response to tuberculosis. The length of time between the first consultation of a TB patient and the start of treatment was, on average, 8.1 days and is among the shortest in the literature. This promptness reduces the risk of infection related to delayed care. This is one of the focuses of the National Programme of Fight against nosocomial infections in Senegal (PRONALIN), as well as the implementation of environmental procedures and the use of masks and respiratory protection equipment. PMID- 25516291 TI - [Prevalence of congenital heart diseases in Koranic schools (daara) in Dakar: a cross-sectional study based on clinical and echocardiographic screening in 2019 school children]. AB - Congenital heart diseases are one of the major cardiovascular diseases in developing countries. Most prevalence studies were based on clinical examination of children with echocardiographic confirmation of suspected cases and underestimate its prevalence. The objective of this study was to investigate the prevalence of congenital heart disease in "daara" (Koranic schools) in the city of Dakar and its suburbs on the basis of clinical examination and Doppler echocardiography in school children. This cross-sectional survey was carried out from 9(th) August to 24(th) December 2011, and included a population of 2019 school children aged 5 to 18 years in 16 selected "daaras" under the Academic Inspectorate of Dakar and its suburbs. Anamnestic, clinical and echocardiographic data were recorded in a validated questionnaire. A p < 0.05 was considered to be statistically significant in bivariate analysis. 2 019 school children were included out of which 60.1% were male (sex-ratio: 0.66). The average age was 9.7 years (+/- 3.3 years). 18 cases of congenital heart diseases were detected being a prevalence of 8.9 per 1 000 (95 % CI: 1.8 to 7.9). This included 6 cases of inter-atrial septal aneurysm, 5 cases of peri-membranous ventricular septal defects, 4 cases of patent ductusarteriosus and 3 cases of tetralogy of Fallot. Factors correlated with the presence of congenital heart disease were ageless than 8 (p <0.001) and residence in the suburbs of Dakar (p <0.001). We also detected 10 cases of rheumatic valvular disease, a prevalence of 4.9 per 1 000 (95% CI: 2.4 to 9.1). Our study shows a high prevalence of congenital heart diseases, which is almost identical to the WHO estimates and that ultrasound screening is more sensitive than clinical screening. Reducing the prevalence of these diseases requires implementation of appropriate policies, focusing on awareness and early detection. PMID- 25516292 TI - Perturbing the developing skull: using laser ablation to investigate the robustness of the infraorbital bones in zebrafish (Danio rerio). AB - BACKGROUND: The development of the craniofacial skeleton from embryonic mesenchyme is a complex process that is not yet completely understood, particularly for intramembranous bones. This study investigates the development of the neural crest derived infraorbital (IO) bones of the zebrafish (Danio rerio) skull. Located under the orbit, the IO bones ossify in a set sequence and are closely associated with the lateral line system. We conducted skeletogenic condensation and neuromast laser ablation experiments followed by shape analyses in order to investigate the relationship between a developing IO bone and the formation of the IO series as well as to investigate the highly debated inductive potential of neuromasts for IO ossification. RESULTS: We demonstrate that when skeletogenic condensations recover from laser ablation, the resulting bone differs in shape compared to controls. Interestingly, neighbouring IO bones in the bone series are unaffected. In addition, we show that the amount of canal wall mineralization is significantly decreased following neuromast laser ablation at juvenile and larval stages. CONCLUSIONS: These results highlight the developmental robustness of the IO bones and provide direct evidence that canal neuromasts play a role in canal wall development in the head. Furthermore, we provide evidence that the IO bones may be two distinct developmental modules. The mechanisms underlying developmental robustness are rarely investigated and are important to increase our understanding of evolutionary developmental biology of the vertebrate skull. PMID- 25516293 TI - Transoral robotic surgery in management of oropharyngeal cancers: a preliminary experience at a tertiary cancer centre in India. AB - BACKGROUND: The aim of this observational prospective study was to determine the technical feasibility, safety and adequacy of surgical margins for transoral robotic surgery (TORS) in oropharyngeal cancers. METHODS: From March 2013 to May 2014, 60 patients with oropharyngeal lesions underwent TORS with or without neck dissection using the 'DaVinci' robot. Patients were observed and data recorded on surgical time, blood loss, complications and functional outcome of patients. RESULTS: All 60 patients underwent TORS, with neck dissection performed in 45 of the patients. A positive margin was seen in two patients (3.3 %). Intent to treatment was radical in 42 patients and salvage in 18 patients. None of the patients required tracheostomy, and one patient (1.66 %) died postoperatively. Postoperative complications in the form of primary haemorrhage required active intervention in three patients. Average estimated blood loss was 26.5 +/- 31.1 ml. Postoperatively, all patients had adequate swallowing and speech function with nasal twang reported in three patients on long-term follow up. Patients started tolerating oral feeds within a week of procedure (mean 3.96 days), with the nasogastric tube removed on the ninth postoperative day (mean 9.19 days). No long-term gastrostomy tube dependency was reported. CONCLUSION: TORS is a safe, feasible, minimally invasive procedure in patients with oropharyngeal cancers. It has the least morbidity and offers benefits in terms of avoidance of tracheostomy tube, prolonged Ryle's tube and gastrostomy dependency. PMID- 25516294 TI - [Mass poisoning events]. AB - BACKGROUND: Mass poisoning events are rare and different in some respects from other mass casualties, especially with regard to diagnosis and triage. OBJECTIVES: Based on the description of important historical events and experiences of poison control centers, an overview is provided for different types of mass poisoning events as well as guidelines for specific medical management. MATERIALS AND METHODS: The review is based on a literature search and case reports notified to the Giftinformationszentrum-Nord Poisons Center. RESULTS: Toxicological risk assessment is based on identification of all relevant agents, evaluation of their toxic hazards (toxicity), and evaluation of the exposure (dose and pathway) for all persons exposed. This risk assessment constitutes the basis of medical diagnosis and management. In cases of suspicion of poisoning or poisonings caused by illegal drugs, risk assessment may be difficult due to the lack of important data needed for risk assessment. Mass poisonings caused by ethanol or contaminated food are well understood, with therapy being mainly symptomatic. However, in rare poisonings by other agents, a specific antidote treatment may be important. Thus, adequate antidote supplies must be available for these events. CONCLUSION: As hardly any medical professional has personal practical knowledge of mass poisoning casualties, such events are unique experiences. Thorough preparation and intensive cooperation with poison control centers and-if applicable-public health authorities may be important for best practice event management. PMID- 25516295 TI - Lower Cancer Rates Among Druze Compared to Arab and Jewish Populations in Israel, 1999-2009. AB - The Druze are a small ethnic minority in Israel amounting to about 130,000 residents (or 1.7 % of the total population of the country). Unlike other population groups, the Druze strive to keep their own traditions and marry mainly inside their own community. During the last decade, cancer morbidity among both Jews and Arabs in Israel has been increasing, while data on the Druze are little known and have not been analyzed and compared to other population groups to date. To compare cancer morbidity rates among Druze, Arabs and Jews in Israel during 1999-2009, gender-specific and age-standardized incidence rates of all site cancers and specific cancers of three population groups (Jews, Arabs and Druze) were received from the Israel National Cancer Registry for the period 1999-2009. Based on these rates, periodical incidence rates were calculated and mutually compared across the groups stratified by gender. As the analysis shows, the Druze had significantly lower cancer rates compared to both Arabs and Jews. Thus, for all site cancers, there were significantly higher cancer rates in Jewish males versus Druze males (RR = 1.39, 95 % CI = 1.16-1.65) and in Jewish females versus Druze females (RR = 1.53, 95 % CI = 1.27-1.85), but not statistically significant for Arab males versus Druze males (RR = 1.12 95 % CI = 0.93-1.35). Lung cancer rates in Arab males were also higher compared to Druze males (RR = 1.84, 95 % CI = 1.13-3.00). Jewish males had statistically significant higher rates of prostate cancer compared to Druze males (RR = 2.47, 95 % CI = 1.55-3.91). For thyroid and colon cancers, risks were not significantly different at the 95 % CI level; however, the risks were significantly different at the 90 % CI level (RR = 3.62, 90 % CI 1.20-11.02 and RR = 1.69, 90 % CI = 1.03-2.77, respectively). Jewish females had significantly higher rates of invasive breast cancer (RR = 2.25, 95 % CI = 1.55-3.25), in situ cervical cancer (RR = 4.01, 95 % CI = 1.27-12.66) and lung cancer (RR = 3.22, 95 % CI = 1.12-9.24) compared to Druze females. We thus observed lower cancer rates among Druze versus Arab and Jewish populations in Israel. A reason for these differences may be due to different nutritional habits. Druze still keep a less processed nutritional lifestyle, than is common in industrial society. There may also be other reasons that have not been identified yet. PMID- 25516296 TI - Physicians in the USA: Attendance, Beliefs and Patient Interactions. AB - While much religion-health research depends on social support explanations, little is known about whether religious support is also a part of clinical interactions. How many physicians include religious/spiritual topics in clinical conversations? What characteristics are related to inclusion or avoidance? Using a national sample (n = 1,144), this study provides an overview of religious beliefs and practices of physicians in the USA and their patient interactions. Physician attendance rates are related to the inclusion of religious/spiritual topics, but the religious/spiritual orientation of physicians more closely relates to religious/spiritual patient interactions. Further, some physician specialties have more religious/spiritual physicians than others, providing additional reason to think religious/spiritual patient conversations are not equally distributed throughout the medical landscape. PMID- 25516298 TI - T cell exhaustion and Interleukin 2 downregulation. AB - T cells reactive to tumor antigens and viral antigens lose their reactivity when exposed to the antigen-rich environment of a larger tumor bed or viral load. Such non-responsive T cells are termed exhausted. T cell exhaustion affects both CD8+ and CD4+ T cells. T cell exhaustion is attributed to the functional impairment of T cells to produce cytokines, of which the most important may be Interleukin 2 (IL2). IL2 performs functions critical for the elimination of cancer cells and virus infected cells. In one such function, IL2 promotes CD8+ T cell and natural killer (NK) cell cytolytic activities. Other functions include regulating naive T cell differentiation into Th1 and Th2 subsets upon exposure to antigens. Thus, the signaling pathways contributing to T cell exhaustion could be linked to the signaling pathways contributing to IL2 loss. This review will discuss the process of T cell exhaustion and the signaling pathways that could be contributing to T cell exhaustion. PMID- 25516299 TI - Normal esophageal high-resolution manometry and impedance values in the supine and sitting positions in the population of Northern China. AB - The aim of this study was to investigate the normal high-resolution manometry and impedance (HRiM) values in the supine and sitting positions in the population of Northern China, and to investigate the influence of different body positions and bolus consistency on esophageal HRiM findings. In this study, healthy volunteers in the supine position underwent esophageal HRiM examination of 10 swallows of 5 mL normal saline solution and 10 swallows of 5 mL synthetic gel of known viscosity, and in the sitting position of an additional five swallows of a synthetic gel of known viscosity. Total bolus transit time (TBTT), complete bolus transit rate (CBTR), distal contractile integral (DCI), distal esophageal amplitude (DEA), and integrated relaxation pressure (IRP) were measured. Sixty two healthy volunteers were examined in the supine position and 45 of these performed additional swallows of the viscous gel in the sitting position. In the supine position, normal values for swallowing the liquid and viscous boli were as follows: TBTT 6.9 +/- 0.9 and 8.0 +/- 1.2 s (P < 0.001), CBTR 90.3 +/- 14.0 and 77.9 +/- 20.3% (P < 0.001), DCI 1891.5 +/- 1131.9 and 1967.8 +/- 1140.1 mmHg.s.cm (P = 0.227), DEA 95.3 +/- 35.4 and 98.7 +/- 37.5 mmHg (P = 0.148), and IRP 10.4 +/- 4.9 and 9.0 +/- 4.2 mmHg (P < 0.001), respectively. For swallows of the viscous boli in the sitting position, TBTT, DCI, DEA, and IRP were significantly decreased, while CBTR was unchanged (P = 0.075). Normal HRiM values of the population of Northern China were established. Esophageal transit times of viscous boli were significantly slower, more often incomplete and produced less normal peristalsis in the supine position than swallows of liquid boli. Independent reference values for different manometric systems, body positions, and population need to be established before clinical application. PMID- 25516305 TI - Reliability and validity of using the Lokomat to assess lower limb joint position sense in people with incomplete spinal cord injury. AB - BACKGROUND: Proprioceptive sense (knowing where the limbs are in space) is critical for motor control during posture and walking, and is often compromised after spinal cord injury (SCI). The purpose of this study was to assess the reliability and validity of using the Lokomat, a robotic exoskeleton used for gait rehabilitation, to quantitatively measure static position sense of the legs in persons with incomplete SCI. METHODS: We used the Lokomat and custom software to assess static position sense in 23 able-bodied (AB) subjects and 23 persons with incomplete SCI (American Spinal Injury Association Impairment Scale level B, C or D). The subject's leg was placed into a target position (joint angle) at either the hip or knee and asked to memorize that position. The Lokomat then moved the test joint to a "distractor" position. The subject then used a joystick controller to bring the joint back into the memorized target position. The final joint angle was compared to the target angle and the absolute difference was recorded as an error. All movements were passive. Known-groups validity was determined by the ability of the measure to discriminate between able-bodied and SCI subjects. To evaluate test-retest reliability, subjects were tested twice and intra-class correlation coefficients comparing errors from the two sessions were calculated. We also performed a traditional clinical test of proprioception in subjects with SCI and compared these scores to the robotic assessment. RESULTS: The robot-based assessment test was reliable at the hip and knee in persons with SCI (P <= 0.001). Hip and knee angle errors in subjects with SCI were significantly greater (P <= 0.001) and more variable (P < 0.0001) than in AB subjects. Error scores were significantly correlated to clinical measure of joint position sense (r >= 0.507, P <= 0.013). CONCLUSIONS: This study shows that the Lokomat may be used as a reliable and valid clinical measurement tool for assessing joint position sense in persons with incomplete SCI. Quantitative assessments of proprioceptive deficits after neurological injury will help in understanding its role in the recovery of skilled walking and in the development of interventions to aid in the return to safe community ambulation. PMID- 25516297 TI - IL12Rbeta1: the cytokine receptor that we used to know. AB - Human IL12RB1 encodes IL12Rbeta1, a type I transmembrane receptor that is an essential component of the IL12- and IL23-signaling complex. IL12RB1 is well established as being a promoter of delayed type hypersensitivity (DTH), the immunological reaction that limits tuberculosis. However, recent data demonstrate that in addition to promoting DTH, IL12RB1 also promotes autoimmunity. The contradictory roles of IL12RB1 in human health raises the question, what are the factors governing IL12RB1 function in a given individual, and how is inter individual variability in IL12RB1 function introduced? Here we review recent data that demonstrate individual variability in IL12RB1 function is introduced at the epigenetic, genomic polymorphism, and mRNA splicing levels. Where and how these differences contribute to disease susceptibility and outcome are also reviewed. Collectively, recent data support a model wherein IL12RB1 sequence variability - whether introduced at the genomic or post-transcriptional level - contributes to disease, and that human IL12RB1 is not as simple a gene as we once believed. PMID- 25516307 TI - Nutrition and earthquakes: experience and recommendations. AB - In order to sustain life during the occurrence of a natural disaster, it is vital to ensure that people's intake of water and food is adequate (prioritizing first energy, then protein and water-soluble vitamins). Infants, pregnant women, patients, and the elderly are particularly vulnerable to insufficiencies in food intake, even if they are provided with the same quantity of food as others, and providing them with dietary and nutritional support becomes a high priority as their insufficient intake of energy and protein becomes long term. It is necessary to have a system in place for identifying those who are vulnerable and in need of support and providing them with the items (food) and nutritional care that they require. Eating is equivalent to living, and if the vulnerable themselves recognize the importance of food and nutrition, this will help improve the nutritional situation of the entire population. It is recommended that measures be taken in non-emergency periods such as stockpiling food for special dietary uses. PMID- 25516308 TI - National nutrition surveys in Asian countries: surveillance and monitoring efforts to improve global health. AB - Asian regions have been suffering from growing double burden of nutritional health problems, such as undernutrition and chronic diseases. National nutrition survey plays an essential role in helping to improve both national and global health and reduce health disparities. The aim of this review was to compile and present the information on current national nutrition surveys conducted in Asian countries and suggest relevant issues in implementation of national nutrition surveys. Fifteen countries in Asia have conducted national nutrition surveys to collect data on nutrition and health status of the population. The information on national nutrition survey of each country was obtained from government documents, international organizations, survey website of governmental agencies, and publications, including journal articles, books, reports, and brochures. The national nutrition survey of each country has different variables and procedures. Variables of the surveys include sociodemographic and lifestyle variables; foods and beverages intake, dietary habits, and food security of individual or household; and health indicators, such as anthropometric and biochemical variables. The surveys have focused on collecting data about nutritional health status in children aged under five years and women of reproductive ages, nutrition intake adequacy and prevalence of obesity and chronic diseases for all individuals. To measure nutrition and health status of Asian populations accurately, improvement of current dietary assessment methods with various diet evaluation tools is necessary. The information organized in this review is important for researchers, policy makers, public health program developers, educators, and consumers in improving national and global health. PMID- 25516309 TI - The economic consequences of malnutrition in Cambodia, more than 400 million US dollar lost annually. AB - BACKGROUND: Cambodia is among the 28 worst countries globally with the highest rates of childhood malnutrition. The aim of the assessment was to apply published evidence associating malnutrition and a variety of functional consequences to project economic implications of this high rate of childhood malnutrition. Such information is vital to advocate for appropriate programs and action plan to reduce malnutrition (from severe stunting to micronutrient deficiencies). METHODS: This exercise used a "consequence model" to apply these "coefficients of loss" established in the global scientific literature to Cambodia health, demographic and economic data to develop a national estimation of the economic losses link to malnutrition. RESULTS: The impact of the indicators of malnutrition analysed represent a burden to the national economy of Cambodia estimated at more than $400 million annually -2.5% of GDP. Micronutrient deficiencies suggest deficits in the quality of the diet - representing a national burden of more than $200 million annually while breastfeeding behaviours account for 6% of the burden. 57% of the losses emerge from indicators measured in children, while 43% of losses are from indicators independent of childhood measurements - indicators of maternal behaviour along with maternal and adult nutrition. CONCLUSIONS: Given the low cost of interventions and the high baseline losses, investment in nutrition programs in Cambodia is likely to offer high returns and attractive benefit cost ratios. Since nearly half the losses are determined prior to the birth of the child, this has implications for targeting and timing of programs. PMID- 25516306 TI - Novel H5 clade 2.3.4.6 viruses with both alpha-2,3 and alpha-2,6 receptor binding properties may pose a pandemic threat. AB - The emerging H5 clade 2.3.4.6 viruses of different NA subtypes have been detected in different domestic poultry in China. We evaluated the receptor binding property and transmissibility of four novel H5 clade 2.3.4.6 subtype highly pathogenic avian influenza viruses. The results show that these viruses bound to both avian-type (alpha-2,3) and human-type (alpha-2,6) receptors. Furthermore, we found that one of these viruses, GS/EC/1112/11, not only replicated but also transmitted efficiently in guinea pigs. Therefore, such novel H5 subtype viruses have the potential of a pandemic threat. PMID- 25516310 TI - Low all-cause mortality despite high cardiovascular risk in elderly Greek-born Australians: attenuating potential of diet? AB - Elderly Greek-born Australians (GA) consistently show lower rates of all-cause and CVD mortality compared with Australian-born. Paradoxically, however, this is in spite of a higher prevalence of CVD risk factors. This paper reviews the findings from the Food Habits in Later Life (FHILL) study, other studies on Greek migrants to Australia and clinical studies investigating dietary mechanisms which may explain the "morbidity mortality paradox". The FHILL study collected data between 1988 and 1991 on diet, health and psycho-social variables on 818 people aged 70 and over from Sweden, Greece, Australia (Greeks and Anglo-Celts), Japan and were followed up for 5-7 years to determine survival status. The FHILL study was the first to develop a score which captured the key features of a traditional plant-based Mediterranean diet pattern (MDPS). A higher score improved overall survival in both Greek and non-Greek elderly reducing the risk of death by 50% after 5-7 years. Of the 5 cohorts studied, elderly GA had the lowest risk of death, even though they had the highest rates of obesity and other CVD risk factors (developed in the early years of migration with the introduction of energy dense foods). GA appeared to be "getting away" with these CVD risk factors because of their continued adherence in old age to a Mediterranean diet, especially legumes. We propose that the Mediterranean diet may, in part, be operating to reduce the risk of death and attenuate established CVD risk factors in GA by beneficially altering the gut microbiome and its metabolites. PMID- 25516311 TI - Australasian Society for Parenteral and Enteral Nutrition guidelines for supplementation of trace elements during parenteral nutrition. AB - BACKGROUND: This work represents the first part of a progressive review of AuSPEN's 1999 Guidelines for Provision of Micronutrient Supplementation in Adult Patients receiving Parenteral Nutrition, in recognition of the developments in the literature on this topic since that time. METHODS: A systematic literature review was undertaken and recommendations were made based on the available evidence and with consideration to specific elements of the Australian and New Zealand practice environment. The strength of evidence underpinning each recommendation was assessed. External reviewers provided feedback on the guidelines using the AGREE II tool. RESULTS: Reduced doses of manganese, copper, chromium and molybdenum, and an increased dose of selenium are recommended when compared with the 1999 guidelines. Currently the composition of available multi trace element formulations is recognised as an obstacle to aligning these guidelines with practice. A paucity of available literature and limitations with currently available methods of monitoring trace element status are acknowledged. The currently unknown clinical impact of changes to trace element contamination of parenteral solutions with contemporary practices highlights need for research and clinical vigilance in this area of nutrition support practice. CONCLUSIONS: Trace elements are essential and should be provided daily to patients receiving parenteral nutrition. Monitoring is generally only required in longer term parenteral nutrition, however should be determined on an individual basis. Industry is encouraged to modify existing multi-trace element solutions available in Australia and New Zealand to reflect changes in the literature outlined in these guidelines. Areas requiring research are highlighted. PMID- 25516312 TI - Energy expenditure measured using indirect calorimeter after minimally invasive esophagectomy in ventilated postoperative patients. AB - Minimally invasive esophagectomy has recently become popular after the laparoscopic technique was developed. However, the postoperative energy expenditure in patients undergoing this procedure has not been evaluated. Therefore, we hypothesized that postoperative resting energy expenditure (REE) following minimally invasive esophagectomy is lower than that estimated using the Harris-Benedict equation. Fifteen patients who underwent esophagectomy by thoracoscopy in the prone position were analyzed. After esophagectomy, an indirect calorimeter measured the energy expenditure during ventilation in the ICU. These values and the estimated basal energy expenditure values were compared using the paired t test. The mean age was 66 +/- 10 years and mean duration of ventilator use in the ICU was 697 +/- 70 mins. The acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA) scores at the time of ICU admission were 13 +/- 4 and 2 +/- 1, respectively. The average temperature, heart rate, and respiratory rate during ventilation were 36.2 +/- 0.6 degrees C, 67 +/- 9 beats/min, and 12 +/- 2/min, respectively. The average REE during ventilation was 985 +/- 167 kcal/day (18.1 +/- 3.4 kcal/kg/day). The estimated REE was 1191 +/- 159 kcal/day. The average REE measured using the indirect calorimeter during ventilation was significantly lower than the estimated REE (83 +/- 10% of the estimated REE, p<0.001). In conclusion, the REE measured by an indirect calorimeter after minimally invasive esophagectomy at early postoperative stage under sedation was significantly lower than the REE estimated using the Harris-Benedict equation. PMID- 25516313 TI - Prognostic validity of 3-Minute Nutrition Screening (3-MinNS) in predicting length of hospital stay, readmission, cost of hospitalisation and mortality: a cohort study. AB - It is important to identify patients who are at risk of malnutrition upon hospital admission as malnutrition results in poor outcomes such as longer length of hospital stay, readmission, hospitalisation cost and mortality. The aim of this study was to determine the prognostic validity of 3-Minute Nutrition Screening (3-MinNS) in predicting hospital outcomes in patients admitted to an acute tertiary hospital through a list of diagnosis-related groups (DRG). In this study, 818 adult patients were screened for risk of malnutrition using 3-MinNS within 24 hours of admission. Mortality data was collected from the National Registry with other hospitalisation outcomes retrieved from electronic hospital records. The results were adjusted for age, gender and ethnicity, and matched for DRG. Patients identified to be at risk of malnutrition (37%) using 3-MinNS had significant positive association with longer length of hospital stay (6.6 +/- 7.1 days vs 4.5 +/- 5.5 days, p<0.001), higher hospitalisation cost (S$4540 +/- 7190 vs S$3630 +/- 4961, p<0.001) and increased mortality rate at 1 year (27.8% vs 3.9%), 2 years (33.8% vs 7.2%) and 3 years (39.1% vs 10.5%); p<0.001 for all. The 3-MinNS is able to predict clinical outcomes and can be used to screen newly admitted patients for nutrition risk so that appropriate nutrition assessment and early nutritional intervention can be initiated. PMID- 25516314 TI - Effect of daily milk supplementation on serum and umbilical cord blood folic acid concentrations in pregnant Han and Mongolian women and birth characteristics in China. AB - Many studies have demonstrated the efficacy of folic acid (FA) supplementation in prevention of neural tube defects (NTDs), although the extent of NTDs varies among individuals of different races and ethnic origin. China is a multi-ethnic country with no standard practice for FA-fortified food. Milk is consumed by women, but little is known about the effects of milk on folate concentration in maternal blood and neonatal umbilical cord blood in Han and Mongolian women after stopping taking the supplement for a month and five month, respectively. The objective of this study was to determine whether only daily consumption of liquid milk can increase the blood folate concentration in pregnant women and whether there are differences in blood folate concentrations between Han and Mongolian women after cessation of FA supplementation. Of the 4052 women enrolled in the parallel group design study. Three thousand five hundred and twenty-six women had confirmed pregnancies and were randomized to receive liquid milk or not until delivery. Women who consumed the liquid milk had significantly increased serum folate concentrations at 16 and 32 weeks of gestation as well as cord blood at birth compared to control groups in both ethnic groups. Infants born to women drinking milk also had better the term birth weight and height, which may be related to the increased concentration of folate. In conclusion, daily consumption of milk can increase the serum folate concentration in pregnant Han and Mongolian women in China (differences in the efficacy of FA and milk supplementation) and may enhance birth outcomes. PMID- 25516315 TI - Efficacy of probiotic therapy in full-term infants with critical illness. AB - BACKGROUND: Probiotics are microbial supplements that have shown efficacy in a wide range of applications. To assess the safety and effects of enteral probiotics in critically ill neonates. METHODS: A double-blind, randomized controlled trial was conducted in 100 full-term infants with critical illness according to scores of neonatal acute physiology. Fifty neonatal intensive care patients were randomly assigned to receive probiotics three times daily after birth for 8 days, and fifty patients were not given probiotics, but who received a placebo. The incidence of sepsis, multiple organ dysfunction syndrome (MODS), nosocomial pneumonia, and necrotizing enterocolitis were recorded. The prognosis of probiotic treatment was determined based on the rate of recovery and hospital days. Serum IgA, IgG, and IgM concentrations were measured on days 4 and 8. RESULTS: Infants in the probiotics group showed a significantly reduced rate of nosocomial pneumonia (18% versus 36%) and multiple organ dysfunction syndrome (6% versus 16%) compared with the placebo group (p<0.05). Significant results were demonstrated in favour of the probiotics for days of hospital stay (13 +/- 3.5 d versus 15.8 +/- 5.3 d) (p<0.05). However, there were no significant differences in the occurrence of sepsis, necrotizing enterocolitis, and recovery rate. Patients given probiotics had significantly greater levels of IgA than those in the placebo group (p<0.05). No serious adverse effects in the study population were noted. CONCLUSIONS: Supplements of probiotics to critically ill neonates could enhance immune activity, decrease occurrence of nosocomial pneumonia and MODS, and reduce days in hospital. PMID- 25516317 TI - Management trajectories in the type 2 diabetes Integrated Delivery System project in Taiwan: accounting for behavioral therapy, nutrition education and therapeutics. AB - BACKGROUND AND AIM: Glycated hemoglobin (HbA1c) assessment is basic to diabetes management. Little is done to describe the whole spectrum of the trajectory, its related temporal patterns of metabolic indices, and comorbidities. METHODS AND RESULTS: This was a longitudinal study. In the Diabetes Management through Integrated Delivery System project in Taiwan, enrollees had diabetes, but no major comorbidities. They were randomized into intensive or conventional education (health, diet and exercise) groups. HbA1c was classified by a groupbased trajectory model on the basis of repeated six-monthly measurements. We analyzed data from 1091 subjects who had at least two measurements on HbA1c. HbA1c exhibited three distinct ranges of low (42-53 mmol/mol), intermediate (64 75 mmol/mol) and high (97 mmol/mol), all of which persisted for 4.5 years regardless of receiving intensive education or not. Temporal changes and a time group interaction were found for triglycerides, total cholesterol, HDL-C and LDL C. The high trajectory was associated with the major co-morbidities of retinopathy, nephropathy, neuropathy, stroke, hypoglycemia, and ketoacidosis. Patients in the intensive education group (62.4%), which were equally distributed in the three trajectories, had significantly lower HbA1cs (-0.14%= -1.5 mmol/mol, p=0.026). The intermediate trajectory patients with intensive education had HbA1cs higher than the low trajectory patients with conventional education (beta=0.189, p=0.033). Though not significant, a similar pattern was found for DM education in the high group (beta=0.223, p=0.154). CONCLUSIONS: Novel strategies beyond current education and pharmacotherapeutic regimens are needed to lower HbA1c at least 11 mmol/mol for the high HbA1c group to minimize comorbidities. PMID- 25516318 TI - Early enteral nutrition after total gastrectomy for gastric cancer. AB - OBJECTIVE: To assess the difference between early enteral nutrition (EEN group) and total parenteral nutrition (TPN group) after total gastrectomy for gastric cancer. METHOD: The nutrition index, liver function, patient generated subjective global assessment (PG-SGA) score, the post-operation complications, the hospital stay and hospitalization expense of the postoperative patient after total gastrectomy, admitted to our Department of Surgery from May 2011 to May 2013 were analyzed retrospectively. RESULTS: A total of 72 patients including 37 cases in the EEN group and 35 cases in the TPN group were recruited. Hypoalbuminemia gradually improved in the EEN group about 3-5 days, but it did not increase until average 21 days in the TPN group. The body weight decreased in the EEN group during the first 2 weeks and recovered gradually in 21 days; body weight in the TPN group was significantly lower than the EEN group at 21 days (p<0.05). There were significant differences in both the groups (p<0.05) in nutrition indicators. The incidence of complications in the EEN group and TPN group were 8.1% and 25.7% respectively, with no significant differences (p>0.05). The days of hospital stays in the EEN and in the TPN group were up to 12.2 +/- 2.5 d vs 14.9 +/- 2.9 d (p<0.05) and the hospitalization expenses were 36472 +/- 4833 CNY vs 40140 +/- 3927 CNY (p<0.05), respectively. CONCLUSION: Compared with TPN, EEN was safe and well tolerated and can shorten the hospital stay as well as reduce costs incurred with total gastrectomy for gastric cancer. PMID- 25516316 TI - Turmeric improves post-prandial working memory in pre-diabetes independent of insulin. AB - BACKGROUND AND OBJECTIVES: Cognitive impairment develops with pre-diabetes and dementia is a complication of diabetes. Natural products like turmeric and cinnamon may ameliorate the underlying pathogenesis. METHODS: People >= 60 years (n=48) with newly-recognised untreated pre-diabetes were randomised to a double blind metabolic study of placebo, turmeric (1 g), cinnamon (2 g) or both (1 g & 2 g respectively), ingested at a white bread (119 g) breakfast. Observations were made over 6 hours for pre- and post-working memory (WM), glycaemic and insulin responses and biomarkers of Alzheimer's disease (AD)(0, 2, 4 and 6 hours): amyloid precursor protein (APP), gamma-secretase subunits presenilin-1 (PS1), presenilin-2 (PS2), and glycogen synthase kinase (GSK-3beta). Differences between natural product users and non-users were determined by Students t and chi square tests; and between pre-test and post-test WM by Wilcoxon signed rank tests. Interaction between turmeric and cinnamon was tested by 2-way ANOVA. Multivariable linear regression (MLR) took account of BMI, glycaemia, insulin and AD biomarkers in the WM responses to turmeric and cinnamon. RESULTS: No interaction between turmeric and cinnamon was detected. WM increased from 2.6 to 2.9 out of 3.0 (p=0.05) with turmeric, but was unchanged with cinnamon. WM improvement was inversely associated with insulin resistance (r=-0.418, p<0.01), but not with AD biomarkers. With MLR, the WM responses to turmeric were best predicted with an R2 of 34.5%; and with significant turmeric, BMI and insulin/glucose AUC beta-coefficients. CONCLUSIONS: Co-ingestion of turmeric with white bread increases working memory independent of body fatness, glycaemia, insulin, or AD biomarkers. PMID- 25516319 TI - Pattern and predictors of dairy consumption during adolescence. AB - We aimed to prospectively assess dairy intake among adolescents, and determine the predictors of adequate dairy consumption during adolescence. 634 Sydney schoolchildren (351 girls and 283 boys) who had dietary data at both age 12 and 17 were included for analyses. Dairy consumption was assessed from validated semi quantitative food frequency questionnaires. At age 12, mean total dairy intake was 1.62 serves/day which decreased to 1.40 by age 17 (p<0.0001). Mean serves/day of milk decreased from 1.11 to 0.92 during adolescence. Moreover, 90% of the decrease in serves/day of total dairy was due to reduced milk consumption. At age 12, 8.5% of children consumed >=3.5 serves/day of total dairy and this decreased to 6.2%, 5 years later at age 17 (p=0.001). A lower proportion of girls compared with boys consumed >=3 serves/day of total dairy at both ages 12 (p=0.005) and 17 (p=0.01). Participants with tertiary qualified parents at baseline were 85% more likely to have intakes of the dairy food group above the median during the 5 years, OR 1.85 (95% CI 1.18-2.91). Frequent flavored milk consumption (>=2 serves/week) at baseline was associated with ~5-fold greater likelihood of maintaining intakes of dairy foods above the median during adolescence. Dairy food consumption decreased significantly during adolescence, driven primarily by a decrease in milk consumption. Most adolescents did not meet national recommended guidelines for the dairy food group intake. These findings highlight the need for further research into intervention strategies aimed at sustaining dairy consumption. PMID- 25516320 TI - Assessment of muscle mass and its association with protein intake in a multi ethnic Asian population: relevance in chronic kidney disease. AB - BACKGROUND: Clinical practice guidelines recommend objective nutritional assessments in managing chronic kidney disease (CKD) patients but were developed while referencing to a North-American population. Specific recommendations for assessing muscle mass were suggested (mid-arm circumference, MAC; corrected mid arm muscle area, cAMA; mid-arm muscle circumference, MAMC). This study aimed to assess correlation and association of these assessments with dietary protein intake in a multi-ethnic Asian population of healthy and CKD patients. METHODS: We analyzed 24-hour urine collections of selected participants to estimate total protein intake (TPI; g/day). Ideal body weight (IDW; kg) was calculated and muscle assessments conducted. Analyses involved correlation and linear regression, taking significance at p<0.05. RESULTS: There were 232 stable CKD patients and 103 healthy participants comprising of 51.0% male, 38.5% Chinese, 29.6% Malay, 23.6% Indian, and 8.4% others. The mean TPI was 58.9 +/- 18.4 g/day in healthy participants and 53.6 +/- 19.4 g/day in CKD patients. When normalized to ideal body weight, TPI-IDW (g/kg/day) was similar in healthy and CKD participants. Overall, TPI was associated with MAC (r=0.372, p<0.001), cAMA (r=0.337, p<0.001), and MAMC (r=0.351, p<0.001). TPI-IDW was also associated with MAC (r=0.304, p<0.001), cAMA (r=0.202, p<0.001), and MAMC (r=0.200, p<0.001) but not for TPI normalized to actual body weight. When examined separately, TPI was associated with MAC, cAMA, and MAMC in both CKD and healthy participants, but was associated with TPI-IDW only in CKD patients. CONCLUSION: Total protein intake was associated with muscle assessments in all participants. TPI normalized to IDW should only be used in CKD patients. PMID- 25516321 TI - Assessment of iodine status and associated factors in vulnerable populations in Henan Province, China, in 2012. AB - BACKGROUND: Iodine content in table salt was adjusted from 30-50 mg/kg to 21-39 mg/kg from March of 2012 in Henan Province, China. The vulnerable population may be at risk of iodine deficiency. OBJECTIVES: To determine whether the iodine intake was sufficient in vulnerable populations and to investigate what factors may be associated with iodine status in these vulnerable populations in Henan Province, China. METHODS: A cross-sectional survey was conducted in 17 cities in Henan Province, China, from April 2012 to December 2012 to assess the iodine status in vulnerable populations, including women of reproductive-age (n=2648), pregnant women (n=39684), lactating women (n=6859), infants <2 years of age (n=16481), and children aged 8-10 years (n=3198). Questionnaires (n=4865) related to demographic and dietary factors were collected from the investigated women to identify factors that were related to iodine intake and iodine status. RESULTS: The median urinary iodine concentrations (mUICs) were 205 MUg/L, 198 MUg/L, 167 MUg/L, 205 MUg/L and 200 MUg/L, respectively, in reproductiveage, pregnant and lactating women, infants <2 years of age and children aged 8-10 years. Higher income, and consuming more poultry and fish in the diet had positive impact on UIC levels. Low salt intake, consuming more rice and vegetables in the diet were negative factors for UIC. CONCLUSIONS: Iodine status of the vulnerable populations was generally adequate in Henan Province, China, according to WHO criteria. But the mUICs were slightly above the adequate level in reproductive age women and children aged 8-10 years. It's important to monitor the iodine status in vulnerable populations after the adjustment on iodine content in table salt. PMID- 25516323 TI - Retrospective tracking of young obese children back to birth in Japan: special attention to the relationship with parental obesity. AB - OBJECTIVE: Childhood obesity is tracked to adulthood at a high rate. However, longitudinal studies of obesity in early childhood remain limited. This study aimed at tracking young obese children back to birth in comparison with normal weight children, and investigating the relationship with parental obesity. METHODS: A total of 2,678 (1,353 boys) young children attending kindergarten or nursery school in Nara Prefecture, Japan, were enrolled. The present heights and weights of children and parents were obtained by a questionnaire, and children's heights and weights at birth, 1.5, and 3.5 years were obtained from mother-child health notebooks. Using body mass index (BMI), child and parental obesity were defined as >=90th percentile based on the reference values for Japanese children and >=25 (kg/m2), respectively. RESULTS: The overall prevalence of obesity at birth was 10.2%, and decreased to 5.6% at 5 years. In the retrospective tracking, obese children at 5 years exhibited significantly higher weight Z-scores and BMI percentiles consistently from birth than in normal-weight children. The increased velocity of weight gain as judged by their Z-score during three periods; birth 1.5, 1.5-3.5, and 3.5-5 years were significantly associated with an increased risk for the obesity at 5 years of age. Only maternal obesity was found to be associated with daughters' obesity in the analysis of association of parents children obesity. CONCLUSIONS: It is important to manage body weight from early infancy for reducing the occurrence of obesity at 5 years. Where there is maternal obesity, greater attention may be required, especially for daughters. PMID- 25516322 TI - Feeding patterns before 6 months of age: the relative validity of recall from interviews of mothers of Guatemalan infants and toddlers. AB - The WHO recommends exclusive breastfeeding during the first 6 mo of life; however, deviations from this recommendation are widespread. The objective of the current study was to evaluate exclusive and predominant breastfeeding rates, as defined by the WHO, in a cross-sectional sample of Guatemalan children using retrospective records on the temporal pattern of introducing foods and beverages before 6 mo. Mothers of 150 infants, aged 6 to 23 mo, attending a public health clinic were interviewed about early life feeding practices with a structured questionnaire. In addition, the plausibility of the reported offering of liquids and foods, other than breast milk, since birth was checked against reported current feeding practices. We observed that estimated exclusive breastfeeding was rare with 14% of infants receiving exclusive breastfeeding for 5 mo, and only 9% for the recommended 6 mo. The proportion of infants with predominant breastfeeding, which allows certain liquids such as water, juices and ritual fluids, was 33% through 5 mo and 23% through 6 mo. One-quarter of mothers (n=38) reported implausible answers concerning age-of-introduction of liquids and foods. Nevertheless, retrospective reports at up to 2 y give credible outcomes for estimations of feeding pattern at 6 mo of age. Our findings match the findings of other studies conducted in Guatemala. Overall adherence to the WHO guidelines for feeding in the first semester of infancy was much less than ideal and in need of strengthening. PMID- 25516324 TI - Body satisfaction, emotional intelligence, and the development of disturbed eating: a survey of Taiwanese students. AB - PURPOSE: This study explored the relationship between adolescents' emotional intelligence and the tendency to develop an eating disorder. METHODS: Senior high school students in Taiwan were recruited for the study. A 3- part anonymous questionnaire measured demographic information, body weight satisfaction, and expectation of body weight. Students also completed the Adolescent Emotional Intelligence Scale and the Eating Disorders Attitude- 26 Test (EAT-26). Height and weight were also measured. RESULTS: The mean of EAT-26 score was 8.66 +/- 7.36, and 8.6% students were at high risk to develop eating disorders. Gender, body weight, body dissatisfaction and the expected body shape were significantly related to disturbed eating attitudes and behaviours. Scores of EAT-26 were positively correlated with emotional perception, emotional expression, and emotional application. CONCLUSIONS: Disturbed eating behaviours exist among adolescents in Taiwan, and these behaviours may be related to emotional intelligence. However further studies with larger samples are needed. PMID- 25516325 TI - Water and nutrient intake in pregnant New Zealand women: association with wheeze in their infants at 18 months. AB - The association between water and nutrient intake in pregnant women, and wheeze in their 18 month old infants, was investigated in a prospective study. Volunteers (n=369) recruited from northern New Zealand were visited in months 4 and 7 of pregnancy. At each visit anthropometric measurements were taken, diet assessed by 24-hour recall and 3-day food records and questionnaires determining personal details administered. Eighteen months after birth, infants were measured, and questions on infant feeding and wheeze asked. Overall, mothers reported 32% of their infants had wheezed in the last 12 months. After adjusting for significant covariates and energy intake, higher maternal intakes of dietary water (p=0.009) and manganese (p=0.024) were associated with decreased wheeze, and glucose (p=0.003) with increased wheeze. Prevalence of infant wheeze decreased 18.5% from the lower to the upper quartile of water intake, and 17.4% from the lower to the upper quartile of manganese intake. Wheeze was more common in Polynesian than European infants (41.8% vs 28.9%). Polynesian mothers consumed significantly less dietary water (median 451 g less) and manganese (median 1374 MUg less) than European mothers per day. Glucose was only significant because of strong association with infant wheeze at extremely high maternal intakes of >40 g/day in ~10% of the subjects. There was no association between maternal dietary supplement intake and wheeze. Mothers estimated at high risk of infant wheeze consumed less tap water, whole grains, tea, fruit; and more fruit juice, soft drink, processed meat and fish products, and refined grain products. This is the first study to report an intergenerational association between maternal water, and glucose intake with infant wheeze. PMID- 25516326 TI - Evaluating the micronutrient status of women of child-bearing age living in the rural disaster areas one year after Wenchuan Earthquake. AB - Populations with special physiological state, such as pregnant, nursing and women of child-bearing age, have been identified as nutritionally vulnerable during natural disaster. The objective of this survey was to evaluate the prevalence of anaemia and micronutrient status of women of reproductive age in April 2009 one year after the Wenchuan Earthquake. The survey recruited 58 pregnant, 66 lactating and 242 women of child-bearing age from 19 to 45 years. The concentrations of haemoglobin in whole blood and ferritin and micronutrients in serum were assayed. Among the three groups (pregnant, nursing and child-bearing women), respectively, the prevalence of anaemia was 29.1%, 25.5% and 28.8%; that of iron deficiency was 45.4%, 49.0% and 52.9%; and that of zinc deficiency was 45.4%, 23.0% and 33.5%. The sum of vitamin D deficiency and insufficiency was more than 90% in each group, and the total vitamin B12 deficiency and marginal deficiency prevalence percentages were 47.3%, 17.7% and 35.7%, respectively. The prevalence of vitamin A deficiency and marginal deficiency was 1.8% and 9.1% in pregnant women, 6.1% and 15.2% in nursing women and 8.6% and 21.3% in women of child-bearing age, respectively. Our findings indicated that the micronutrient status of women of reproductive age was poor in the disaster areas. Therefore, improving the micronutrient status of these women should be an urgent priority in these areas. PMID- 25516327 TI - Development and validity of a 3-day smartphone assisted 24-hour recall to assess beverage consumption in a Chinese population: a randomized cross-over study. AB - This paper addresses the need for diet assessment methods that capture the rapidly changing beverage consumption patterns in China. The objective of this study was to develop a 3-day smartphone-assisted 24-hour recall to improve the quantification of beverage intake amongst young Chinese adults (n=110) and validate, in a small subset (n=34), the extent to which the written record and smartphone-assisted recalls adequately estimated total fluid intake, using 24 hour urine samples. The smartphone-assisted method showed improved validity compared with the written record-assisted method, when comparing reported total fluid intake to total urine volume. However, participants reported consuming fewer beverages on the smartphone-assisted method compared with the written record-assisted method, primarily due to decreased consumption of traditional zero-energy beverages (i.e. water, tea) in the smartphone-assisted method. It is unclear why participants reported fewer beverages in the smartphone-assisted method than the written record -assisted method. One possibility is that participants found the smartphone method too cumbersome, and responded by decreasing beverage intake. These results suggest that smartphone-assisted 24 hour recalls perform comparably but do not appear to substantially improve beverage quantification compared with the current written record-based approach. In addition, we piloted a beverage screener to identify consumers of episodically consumed SSBs. As expected, a substantially higher proportion of consumers reported consuming SSBs on the beverage screener compared with either recall type, suggesting that a beverage screener may be useful in characterizing consumption of episodically consumed beverages in China's dynamic food and beverage landscape. PMID- 25516328 TI - Coffee consumption patterns in Korean adults: the Korean National Health and Nutrition Examination Survey (2001-2011). AB - We examined coffee consumption patterns over the past decade among Korean adults. This study was based on seven different cross-sectional data from the Korean National Health and Nutrition Examination Survey (KNHANES) between 2001 and 2011 (17,367 men and 23,591 women aged 19-103 y, mean 48.1 y). Information on frequency and type of coffee consumption was derived from frequency questionnaires or 24-hour recalls. For the study period, the prevalence of daily coffee consumption increased by 20.3% (from 54.6 to 65.7%; p<0.001). For those who consumed 2 or more cups of coffee daily, it dramatically increased by 48.8% (from 29.1 to 43.3%; p<0.001). The instant coffee mix was consumed the most frequently by Korean adults, and it was on the increasing trend among people who were middle aged or older (>=40 y), while it was on the slowdown in young men or on the declining trend in young women. Brewed coffee consumption had an increasing trend by all age groups in recent years. Especially, there was a rapid increase in brewed coffee consumption among young women (strongly) and young men. The instant coffee mix that contains non-dairy creamer and/or sugar still takes up a significant portion of coffee consumption in Korea, which may result in weight gain and insulin resistance, and potential benefits of coffee may be offset. Given high prevalence of coffee consumption in Korea, nutrition education should be conducted to help people (especially the elderly) to make healthy coffee drinking habits. PMID- 25516329 TI - Geographic factors as determinants of food security: a Western Australian food pricing and quality study. AB - Food affordability and quality can influence food choice. This research explores the impact of geographic factors on food pricing and quality in Western Australia (WA). A Healthy Food Access Basket (HFAB) was cost and a visual and descriptive quality assessment of 13 commonly consumed fresh produce items was conducted in store on a representative sample of 144 food grocery stores. The WA retail environment in 2010 had 447 grocery stores servicing 2.9 million people: 38% of stores the two major chains (Coles(r) Supermarkets Australia and Woolworths (r) Limited) in population dense areas, 50% were smaller independently owned stores (Independent Grocers Association(r)) in regional areas as well, and 12% Indigenous community stores in very remote areas. The HFAB cost 24% (p<0.0001) more in very remote areas than the major city with fruit (32%, p<0.0001), vegetables (26.1%, p<0.0005) and dairy (40%, p<0.0001) higher. Higher price did not correlate with higher quality with only 80% of very remote stores meeting all criteria for fresh produce compared with 93% in Perth. About 30% of very remote stores did not meet quality criteria for bananas, green beans, lettuce, and tomatoes. With increasing geographic isolation, most foods cost more and the quality of fresh produce was lower. Food affordability and quality may deter healthier food choice in geographically isolated communities. Improving affordability and quality of nutritious foods in remote communities may positively impact food choices, improve food security and prevent diet-sensitive chronic disease. Policy makers should consider influencing agriculture, trade, commerce, transport, freight, and modifying local food economies. PMID- 25516330 TI - Home food availability is associated with multiple socio-economic indicators in 50 year olds from Canterbury, New Zealand. AB - Financial restraints and poverty lead to poor diets and poor health outcomes. Limited research shows that socioeconomic status is related to home availability of certain foods. However, studies in this area have used different socio economic indicators, which may not equally influence eating-related behaviors. Using multiple indicators of socio-economic status may provide a more accurate picture of these relationships. The aim of this study was to investigate whether several socio-economic indicators are independently associated with home availability of selected foods known to influence chronic disease risk in 50 year olds from Canterbury, New Zealand, participating in the CHALICE study. Participants were selected randomly from health research extracts from Canterbury. Data from 216 participants (110 females, 106 males) were included. The presence (but not quantity) of foods/beverages in the home was measured by a validated home food inventory. Linear regression analyses were performed for the following home food inventory scores: fruit, vegetables, lower fat dairy, obesogenic foods and sweetened beverages with household income, standard of living and education using multivariate models. Higher household income and standard of living were individually associated with a 2% to 3% higher fruit and vegetables (3 to 5 types/forms) and total food scores (6 to 9 types/forms) (p<0.03). Higher education level was associated with a 2.5% increase in fruit and vegetables score (4 types/forms) and an 8% decrease in sweetened beverages score (0.4 beverages) (p<0.02). These results suggest that using only one measure of socio-economic status cannot accurately capture the effects of social inequalities in food availability. Those experiencing the most social disadvantage had a lesser availability of fruit and vegetables which may be detrimental to good health. PMID- 25516331 TI - The influence of age and gender in knowledge, behaviors and attitudes towards sun protection: a cross-sectional survey of Australian outpatient clinic attendees. AB - OBJECTIVE: The aim of this study was to evaluate the differences in knowledge, attitudes, and behaviors regarding sun protection in different age groups and between men and women. METHOD: A multicenter cross-sectional study using a population-based survey of 416 individuals over the age of 18 years was undertaken during 2014. RESULTS: Of individuals aged 18-30 years, 94% had experienced at least one episode of sunburn in the previous year. The likelihood of self-examining increased as age increased (p < 0.001). Only 15% of participants used the recommended amount (40 ml) of sunscreen. Women were twice as likely to put on sunscreen as men. Women had better knowledge about sun protection and sunscreen use, and were twice as likely to know that sunscreen was denatured by heat and had an expiry date (p = 0.01). Women were more than twice as likely to put on sunscreen every day compared with men (p = 0.002). Reported barriers to sunscreen use included greasiness and forgetfulness and this was more commonly reported as age decreased (p = 0.002; p = 0.004). The younger population was less likely to use more than one modality of sun protection (p = 0.05). CONCLUSION: This study highlights a number of gender- and age-specific findings with regards to sun protection. There are knowledge, attitude, and behavior deficiencies within each demographic group that need to be specifically targeted through educational and public health efforts in order to improve general sun protection measures and decrease the incidence of skin cancers. PMID- 25516333 TI - Graphene oxide single sheets as substrates for high resolution cryoTEM. AB - CryoTEM is an important tool in the analysis of soft matter, where generally defocus conditions are used to enhance the contrast in the images, but this is at the expense of the maximum resolution that can be obtained. Here, we demonstrate the use of graphene oxide single sheets as support for the formation of 10 nm thin films for high resolution cryoTEM imaging, using DNA as an example. With this procedure, the overlap of objects in the vitrified film is avoided. Moreover, in these thin films less background scattering occurs and as a direct result, an increased contrast can be observed in the images. Hence, imaging closer to focus as compared with conventional cryoTEM procedures is achieved, without losing contrast. In addition, we demonstrate an ~1.8 fold increase in resolution, which is crucial for accurate size analysis of nanostructures. PMID- 25516332 TI - Association between knowledge of caries preventive practices, preventive oral health habits of parents and children and caries experience in children resident in sub-urban Nigeria. AB - BACKGROUND: The objectives of this study were to assess the association between children and parents' knowledge of caries preventive practices, the parents' caries preventive oral health behaviours and children's caries preventive oral health behaviour and caries experience. METHOD: Three hundred and twenty four participants aged 8-12 years, 308 fathers and 318 mothers were recruited through a household survey conducted in Suburban Nigeria. A questionnaire was administered to generate information on fathers, mothers and children's knowledge of caries prevention measures and their oral health behaviour. Clinical examination was conducted on the children to determine their dmft/DMFT. Analysis was conducted to determine the predictors of the children's good oral health behaviour. RESULT: The mothers' oral health behaviours were significant predictors of the children's oral health behaviours. Children who had good knowledge of caries prevention measures had significant increased odds of brushing their teeth twice daily or more. The children's caries prevalence was 13.9%, the mean dmft was 0.2 and the mean DMFT was 0.09. None of the dependent variables could predict the presence of caries in children. CONCLUSION: The study highlights the effect of maternal oral health behaviour on the oral health behaviour of children aged 8 years to 12 years in suburban Nigeria. A pilot study is needed to evaluate how enhanced maternal preventive oral health practices can improve the oral health preventive practices of children. PMID- 25516334 TI - Effect of concentrates restriction on feed consumption, diet digestibility, and nitrogen utilization in captive Asian elephants (Elephas maximus). AB - In order to study the effect of concentrates restriction on feed consumption, diet digestibility, and utilization of nitrogen in captive Asian elephants (Elephas maximus), two feeding trials were conducted on three juveniles, four sub adults, and three adults. During trial I, the conventional zoo diets of juveniles, sub-adults, and adult contained 22, 17, and 16% of concentrates on dry matter (DM) basis, respectively. During trial II, the amount of concentrate was reduced by 50%. A digestion trial of five days collection period was conducted during each period. The animals ate more roughages when concentrates were restricted. Intake of DM (g/kg BW(0.75) /day) was highest in sub-adults, followed by juveniles and adults. Apparent digestibility of crude protein (CP), neutral detergent soluble (NDS), and supply of digestible energy (DE) was highest in juveniles, followed by sub-adults and adults. Based upon the estimated metabolic fecal nitrogen (MFN) and calculated endogenous urinary nitrogen (EUN) and dermal losses, minimum dietary CP required to meet maintenance requirement was estimated to be 6.12, 6.05, and 5.97% in juveniles, sub-adults, and adults, respectively. Restriction of concentrates resulted in decreased (P < 0.05) digestibility of DM and GE, but the diet still supplied adequate amounts of DE and CP to fulfill estimated requirements of energy and protein during the period of experimentation. Thus, the concentrates portion of the diets of captive Asian elephants should be fed in a restricted way so as to reduce the intake of excessive calories and the potential risk of obesity. PMID- 25516335 TI - Collective cell migration of the nephric duct requires FGF signaling. AB - BACKGROUND: During the course of development, the vertebrate nephric duct (ND) extends and migrates from the place of its initial formation, adjacent to the anterior somites, until it inserts into the bladder or cloaca in the posterior region of the embryo. The molecular mechanisms that guide ND migration are poorly understood. RESULTS: A novel Gata3-enhancer-Gfp-based chick embryo live imaging system was developed that permits documentation of ND migration at the individual cell level for the first time. FGF Receptors and FGF response genes are expressed in the ND, and FGF ligands are expressed in surrounding tissues. FGF receptor inhibition blocked nephric duct migration. Individual inhibitors of the Erk, p38, or Jnk pathways did not affect duct migration, but inhibition of all three pathways together did inhibit migration of the duct. A localized source of FGF8 placed adjacent to the nephric duct did not affect the duct migration path. CONCLUSIONS: FGF signaling acts as a "motor" that is required for duct migration, but other signals are needed to determine the directionality of the duct migration pathway. Developmental Dynamics 244:157-167, 2015. (c) 2014 Wiley Periodicals, Inc. PMID- 25516336 TI - The Enhancement of Children versus Circumcision: A Case of Double Moral Standards? AB - The application of enhancement technologies to children and non-medical infant male circumcision are both topics that enjoy the continuous attention of bioethical research but are usually discussed in isolation from each other. Yet one can show that three major arguments used by opponents of the enhancement of children are also applicable to circumcision. These arguments are based on the insecurity of these procedures, the child's right to an open future, and human nature as a foundation of human dignity. People who reject the enhancement of children because of these arguments but accept circumcision hold mutually inconsistent moral convictions or apply double moral standards to these cases. This is particularly important when legislative systems treat the enhancement of children and circumcision in a considerably different manner, which is true for many contemporary legislative systems. At least three strategies can be adopted in order to avoid such inconsistencies, two of which, however, fail for various reasons. According to a third, more promising strategy, circumcision should be subsumed under human enhancement and treated like other enhancement technologies. This strategy justifies restrictions on, but not the prohibition of circumcision. Furthermore, proponents of circumcision should be prepared for future technologies that provide similar benefits as circumcision but are not as contentious as this intervention, so that, in the future, circumcision could become more and more unacceptable. PMID- 25516337 TI - Comparison of physical therapy anatomy performance and anxiety scores in timed and untimed practical tests. AB - Students in health care professional programs face many stressful tests that determine successful completion of their program. Test anxiety during these high stakes examinations can affect working memory and lead to poor outcomes. Methods of decreasing test anxiety include lengthening the time available to complete examinations or evaluating students using untimed examinations. There is currently no consensus in the literature regarding whether untimed examinations provide a benefit to test performance in clinical anatomy. This study aimed to determine the impact of timed versus untimed practical tests on Master of Physical Therapy student anatomy performance and test anxiety. Test anxiety was measured using the State-Trait Anxiety Inventory (STAI). Differences in performance, anxiety scores, and time taken were compared using paired sample Student's t-tests. Eighty-one of the 84 students completed the study and provided feedback. Students performed significantly higher on the untimed test (P = 0.005), with a significant reduction in test anxiety (P < 0.001). Students who were unsuccessful on the timed test showed the greatest improvement on the untimed test ( x- = 20.4 +/-10%). Eighty-three percent (n = 69) of students preferred the untimed test, 8.4% (n = 7) the timed test, and 8.4% (n = 7) had no preference. Students took on average eight minutes longer on the untimed test. This study found that physical therapy students perform better on untimed tests, which may be related to a reduction in test anxiety. If the intended goal of evaluating health care professional students is to determine fundamental competencies, these factors should be considered when designing future curricula. PMID- 25516339 TI - Piketty symposium: editors' introduction. PMID- 25516338 TI - Exploratory Subset Analysis of African Americans From the PointBreak Study: Pemetrexed-Carboplatin-Bevacizumab Followed by Maintenance Pemetrexed-Bevacizumab Versus Paclitaxel-Carboplatin-Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB/IV Nonsquamous Non-Small-Cell Lung Cancer. AB - INTRODUCTION: African Americans have a greater incidence of lung cancer than whites and have been underrepresented in clinical trials. In the PointBreak trial (pemetrexed-carboplatin-bevacizumab and maintenance pemetrexed-bevacizumab [PemCBev] vs. paclitaxel-carboplatin-bevacizumab and maintenance bevacizumab [PacCBev]), 10% of the patients were African American. PointBreak had negative findings; PemCBev did not demonstrate superior overall survival (OS). MATERIALS AND METHODS: PointBreak subgroup efficacy and safety data were retrospectively analyzed: African Americans versus whites for PemCBev; PemCBev versus PacCBev in African Americans; and academic versus community settings for African Americans. Hazard ratios (HRs) and P values were derived from a multivariate Cox proportional hazards model after adjusting for covariates. RESULTS: Of 939 intent to-treat (ITT) patients, 94 were African American and 805 were white. African American enrollment was uniform across the study sites (median, 1 African American per site). In the PemCBev arm, OS (HR, 1.125; P = .525), progression free survival (PFS) (HR, 1.229; P = .251), response (P = .607), and toxicity profiles were similar in African Americans versus whites. For African Americans, OS (HR, 1.375; P = .209), PFS (HR, 0.902; P = .670), response (P = 1.000), and toxicity profiles were similar in the PemCBev versus PacCBev arm. For African Americans, no significant differences were seen in OS (HR, 0.661; P = .191) or PFS (HR, 0.969; P = .915) in academic versus community practice settings. CONCLUSION: In the PemCBev arm, this exploratory analysis showed no significant differences between African Americans and whites for the efficacy outcomes or toxicity profiles. Consistent with the ITT population negative trial result, for African Americans, the median OS was not superior for either arm. For African Americans, PFS and OS were similar in the academic and community settings. Additional outcomes data for African Americans should be collected in lung cancer studies. PMID- 25516340 TI - Piketty's challenge for sociology. AB - This paper argues that Piketty's book should not simply be seen as that of an economist, but that it contains significant resources for sociologists to draw upon. These are firstly, this approach to social science and his use of visualizations which chime closely with recent claims about the power of description. Secondly I consider his conceptualization of time and history - which in rebutting epochal arguments about the speed of contemporary change allows for a much better appreciation of the 'long duree'; and finally his conceptualization of social classes and privilege through his elaboration of a sociology of accumulation and inheritance. In all these ways, Piketty's work assists in developing an account of elites and wealth which should be highly productive for future sociology. PMID- 25516341 TI - Beyond capital? The challenge for sociology in Britain. AB - This article offers a 'local', British, reading of Piketty's landmark book, Capital in the Twenty-First Century, suggesting that the challenge it offers to sociological approaches to inequality is more fundamental than hitherto recognized. The variations in 'national trajectories' exposed by Piketty reveal Britain to be anomalous in terms of standard approaches to the path dependencies embedded in different welfare regimes. Using the recent work of Monica Prasad on 'settler capitalism' in the USA and the tax and debt-finance regime associated with it, the article suggests that colonialism and empire and its postwar unravelling has had deep consequences for British social stratification, albeit largely neglected by British sociologists. Finally, it points to the fact that the form of tax and debt-finance regime that has become reinforced in Britain is at the heart of recent radical reforms to higher education. These are the currently unexplicated conditions of our future practice as sociologists and, therefore, an obstacle to building a critical sociology on the foundations laid out by Piketty. PMID- 25516342 TI - After Piketty? AB - In this paper, I take Capital in the Twenty-First Century by Thomas Piketty as the starting point for a set of twelve policy proposals that could bring about a genuine shift in the distribution of income towards less inequality. In designing the set of proposals, I draw on the experience of reducing inequality in postwar Europe and on an analysis as to how the economic circumstances are now different in the twenty-first century, highlighting the role of technical change and the rise in capital emphasized by Piketty. The proposed measures span many fields of policy, and are not confined to fiscal redistribution, encompassing science policy, competition policy, public employment, a guaranteed return on small savings, a capital endowment, as well as more progressive taxation of income and wealth transfers, and a participation income. Inequality is embedded in our social structure, and the search for a significant reduction requires us to examine all aspects of our society. I focus on inequality within countries, and what can be achieved by national governments, with the UK specifically in mind. The primary audience is those concerned with policy-making in national governments, but implementation should not be seen purely in these terms. There are different levels of government, and certain proposals, particularly those concerned with taxation, may only be feasible if pursued by a group of countries in collaboration. The last of the twelve proposals - for a basic income for children - is specifically directed at the European Union. Finally, actions by individuals as consumers, as workers, or as employers, can all contribute to reducing inequality. PMID- 25516343 TI - Capital and time: uncertainty and qualitative measures of inequality. AB - This review compares Piketty and Marx's approaches to capital and time in order to argue for the importance of qualitative measures of inequality. These latter measures emphasize varying experiences across classes and through history of uncertainty and insecurity. They explore how the social rhythms of capital profoundly affect the ability to plan a life-course. Quantitative measures such as those used by Piketty that focus on the amount of capital that accrues through time cannot capture such important phenomenon. This is especially because their calculations rest on absolute amounts of capital recorded in formal state statistics. Their limits are particularly revealed if we consider issues of: informal labour, social reproduction, and changing institutional forms of public debt. If we are to build the inter-disciplinary rapprochement between social science and economics that Piketty calls for it must be through asserting the value of qualitative measures of insecurity and its effects on decision making. These are important to track both at the macro-level of institutions and at the micro-level scale of human lives. It is, therefore, through emphasizing the existing strengths of both anthropology and history that we can meet Piketty's important challenge to make our scholarship relevant to current political and social debates. PMID- 25516344 TI - Capital in the twenty-first century: a critique. AB - I set out and explain Piketty's model of the dynamics of capitalism based on two equations and the r > g inequality (his central contradiction of capitalism). I then take issue with Piketty's analysis of the rebuilding of inequality from the 1970s to the present on three grounds: First, his model is based on the (neo classical) assumption that companies are essentially passive actors who invest the amount savers choose to accumulate at equilibrium output - leading to the counterintuitive result that companies respond to the secular fall in growth (and hence their product markets) from the 1970s on by increasing their investment relative to output; this does indeed imply increased inequality on Piketty's beta measure, the ratio of capital to output. I suggest a more realistic model in which businesses determine investment growth based on their expectations of output growth, with monetary policy bringing savings into line with business determined investment; the implication of this model is that beta does not change at all. And in fact as other recent empirical work which I reference has noted, beta has not changed significantly over these recent decades. Hence Piketty's central analysis of the growth of contemporary inequality requires rethinking. Second, despite many references to the need for political economic analysis, Piketty's analysis of the growth of inequality in the period from the 1970s to the present is almost devoid of it, his explanatory framework being purely mathematical. I sketch what a political economic framework might look like during a period when politics was central to inequality. Third, inequality in fact rose on a variety of dimensions apart from beta (including poverty which Piketty virtually makes no reference to in this period), but it is unclear what might explain why inequality rose in these other dimensions. PMID- 25516345 TI - Gendering inequality: a note on Piketty's Capital in the twenty-first century. AB - Thomas Piketty's Capital in the Twenty-First Century is remarkable for moving inequality from the margins to mainstream debate through detailed analysis of longitudinal statistics and, for an economist, by advocating an interdisciplinary perspective and writing in a witty and accessible style. With reference to the post 1970 period, when wage increases are largely responsible for the increase in inequality, Piketty shows how patrimonial capitalists (elite managers) in the top decile and centile of the distribution appropriate a growing share of social wealth as a consequence of their 'power to set their own remuneration' in the context of tolerant social norms rather than through their productive contributions. Piketty raises but defers the question of where these social norms come from to other disciplines. A Feminist Economics perspective indicates that these questions are central to a more inclusive form of economic analysis and such an approach would enrich Piketty's analysis in two main ways. First, by paying greater attention to the processes and social norms through which inequalities are produced and justified and second by highlighting the ways in which inequality is experienced differently depending not only on class, but also on other aspects of identity including gender. This approach also suggests that it is necessary to supplement the ex-post redistributive policies recommended by Piketty: a global wealth tax and more steeply progressive income tax, with ex ante measures to stop the rise in wage inequality in the first place, especially by bridging the huge gulf that exists between those who care for people and those who manage money. PMID- 25516346 TI - The politics of Piketty: what political science can learn from, and contribute to, the debate on Capital in the twenty-first century. AB - Thomas Piketty's imposing volume has brought serious economics firmly into the mainstream of public debate on inequality, yet political science has been mostly absent from this debate. This article argues that political science has an essential contribution to make to this debate, and that Piketty's important and powerful book lacks a clear political theory. It develops this argument by first assessing and critiquing the changing nature of political science and its account of contemporary capitalism, and then suggesting how Piketty's thesis can be complemented, extended and challenged by focusing on the ways in which politics and collective action shape the economy and the distribution of income and wealth. Although Capital's principal message is that 'capital is back' and that without political interventions active political interventions will continue to grow, a political economy perspective would suggest another rather more fundamental critique: the very economic forces Piketty describes are embedded in institutional arrangements which can only be properly understood as political phenomena. In a sense capital itself - the central concept of the book - is almost meaningless without proper consideration of its political foundations. Even if the fact of capital accumulation may respond to an economic logic, the process is embedded in a very political logic. The examples of housing policy and the regulation, and failure to regulate, financial markets are used to illustrate these points. PMID- 25516347 TI - Piketty's capital and social policy. AB - Piketty's Capital (2014) primarily describes and analyses changes in the distribution of wealth and annual incomes. This paper focuses on his policy proposals that make up Part Four of the book. Piketty defends the 'social state' but he discusses it largely in terms of distribution and redistribution between tax units. This neglects the important role of social policy in promoting recognition and redistribution of income and opportunities that is related to gender, race, disability and sexual orientation. Nor does Piketty consider inequalities in health which effect life-time incomes, nor the impact of housing policies on house prices and the distribution of wealth. It is argued that Piketty's approach to social security is simplistic and plays down the complexity of competing policy goals. On taxation, Piketty defends progressive taxation and proposes a global capital levy. The latter proposal runs into formidable problems in seeking global taxation in a world of nation states. Rather than seeking a policy that is, for the foreseeable future, wholly politically impractical, a case is made for less idealistic but more practical and urgent tax coordination between nations to address the widespread avoidance of taxation that large corporations and the very wealthy are now permitted - taxation on which the future of the social state depends. The importance of human and social capital, which are largely set aside by Piketty, are discussed. Finally,it is argued that his approach to policy is to describe trends and propose amelioration of growing inequality rather than to identify causes of the trends and propose policies that might address the causes. Nevertheless, the importance of his work in bringing issues of inequality to the fore, especially among economists, is recognized and applauded. PMID- 25516348 TI - Piketty in the long run. AB - I examine the idea of 'the long run' in Piketty (2014) and related works. In contrast to simplistic interpretations of long-run models of income- and wealth distribution Piketty (2014) draws on a rich economic analysis that models the intra- and inter-generational processes that underly the development of the wealth distribution. These processes inevitably involve both market and non market mechanisms. To understand this approach, and to isolate the impact of different social and economic factors on inequality in the long run, we use the concept of an equilibrium distribution. However the long-run analysis of policy should not presume that there is an inherent tendency for the wealth distribution to approach equilibrium. PMID- 25516349 TI - Where's the capital? A geographical essay. AB - This paper is inspired by Thomas Piketty's book Capital in the Twenty-First Century. Piketty does a wonderful job of tracing income and wealth over time, and relating changes to trends of economic and population growth, and drawing out the implications for inequality, inheritance and even democracy. But, he says relatively little about where capital is located, how capital accumulation in one place relies on activities elsewhere, how capital is urbanized with advanced capitalism and what life is like in spaces without capital. This paper asks 'where is the geography in Capital' or 'where is the geography of capital in Capital'? Following Piketty's lead, the paper develops its analysis through a number of important novels. It examines, first, the debate that Jane Austen ignored colonialism and slavery in her treatment of nineteenth century Britain, second, how Balzac and then Zola provide insight to the urban political economy of capital later in the century, and third, how Katherine Boo attends to inequality as the everyday suffering of the poor. PMID- 25516350 TI - Capital in the twenty-first century: a multidimensional approach to the history of capital and social classes. PMID- 25516352 TI - Influence of food companies' brand mascots and entertainment companies' cartoon media characters on children's diet and health: a systematic review and research needs. AB - Reducing the extent and persuasive power of marketing unhealthy foods to children worldwide are important obesity prevention goals. Research is limited to understand how brand mascots and cartoon media characters influence children's diet. We conducted a systematic review of five electronic databases (2000-2014) to identify experimental studies that measured how food companies' mascots and entertainment companies' media characters influence up to 12 diet-related cognitive, behavioural and health outcomes for children under 12 years. Eleven studies met the inclusion criteria. Studies used 21 unique popular media characters, but no brand mascots. Results suggest that cartoon media character branding can positively increase children's fruit or vegetable intake compared with no character branding. However, familiar media character branding is a more powerful influence on children's food preferences, choices and intake, especially for energy-dense and nutrient-poor foods (e.g. cookies, candy or chocolate) compared with fruits or vegetables. Future research should use a theoretically grounded conceptual model and larger and more diverse samples across settings to produce stronger findings for mediating and moderating factors. Future research can be used to inform the deliberations of policymakers, practitioners and advocates regarding how media character marketing should be used to support healthy food environments for children. PMID- 25516353 TI - Dendritic polyglycerol sulfate as a novel platform for paclitaxel delivery: pitfalls of ester linkage. AB - In this study, dendritic polyglycerol sulfate (dPGS) is evaluated as a delivery platform for the anticancer, tubulin-binding drug paclitaxel (PTX). The conjugation of PTX to dPGS is conducted via a labile ester linkage. A non sulfated dendritic polyglycerol (dPG) is used as a control, and the labeling with an indocarbocyanine dye (ICC) renders multifunctional conjugates that can be monitored by fluorescence microscopy. The conjugates are characterized by (1)H NMR, UV-vis measurements, and RP-HPLC. In vitro cytotoxicity of PTX and dendritic conjugates is evaluated using A549 and A431 cell lines, showing a reduced cytotoxic efficacy of the conjugates compared to PTX. The study of uptake kinetics reveals a linear, non saturable uptake in tumor cells for dPGS-PTX-ICC, while dPG-PTX-ICC is hardly taken up. Despite the marginal uptake of dPG-PTX-ICC, it prompts tubulin polymerization to a comparable extent as PTX. These observations suggest a fast ester hydrolysis and premature drug release, as confirmed by HPLC measurements in the presence of plasma enzymes. PMID- 25516351 TI - Aberrant methylation of the SPARC gene promoter and its clinical implication in gastric cancer. AB - Secreted protein acidic and rich in cysteine (SPARC) gene has been shown to be epigenetically silenced in several cancers. We investigated the loss of expression and promoter methylation of this tumor suppressor gene in gastric cancers and correlated the data with clinicopathological features. We observed the loss of SPARC mRNA and SPARC protein expression in 7 of 10 (70%) gastric cancer cell lines. Upon treatment of expression-negative cell lines with a demethylating agent, expression of mRNA and protein was restored in all cells. Methylation rate of SPARC gene was 80% in ten gastric cancer cell lines and 74% (163 of 220) in primary tumors, while it was 5% in normal gastric mucosa (n = 40). In intestinal gastric cancer, SPARC methylation correlated with a negative prognosis (P < 0.001; relative risk 2.754, 95% confidence interval 1.780-4.261). Immunostaining revealed that SPARC protein was overexpressed in stromal fibroblasts adjacent to neoplastic epithelium but rarely expressed in the primary gastric cancer cells. These results implicate SPARC promoter methylation as an important factor in the tumorigenesis of gastric carcinomas and provide new insights into the potential use of SPARC as a novel biomarker and the potential clinical importance in human gastric cancers. PMID- 25516355 TI - Evaluating deliberative dialogues focussed on healthy public policy. AB - BACKGROUND: Deliberative dialogues have recently captured attention in the public health policy arena because they have the potential to address several key factors that influence the use of research evidence in policymaking. We conducted an evaluation of three deliberative dialogues convened in Canada by the National Collaborating Centre for Healthy Public Policy in order to learn more about deliberative dialogues focussed on healthy public policy. METHODS: The evaluation included a formative assessment of participants' views about and experiences with ten key design features of the dialogues, and a summative assessment of participants' intention to use research evidence of the type that was discussed at the dialogue. We surveyed participants immediately after each dialogue was completed and again six months later. We analyzed the ratings using descriptive statistics and the written comments by conducting a thematic analysis. RESULTS: A total of 31 individuals participated in the three deliberative dialogues that we evaluated. The response rate was 94% (N = 29; policymakers (n = 9), stakeholders (n = 18), researchers (n = 2)) for the initial survey and 56% (n = 14) for the follow-up. All 10 of the design features that we examined as part of the formative evaluation were rated favourably by all participant groups. The findings of the summative evaluation demonstrated a mean behavioural intention score of 5.8 on a scale from 1 (strongly disagree) to 7 (strongly agree). CONCLUSION: Our findings reinforce the promise of deliberative dialogues as a strategy for supporting evidence-informed public health policies. Additional work is needed to understand more about which design elements work in which situations and for different issues, and whether intention to use research evidence is a suitable substitute for measuring actual behaviour change. PMID- 25516354 TI - Exploring the folding pathway of green fluorescent protein through disulfide engineering. AB - We have introduced two disulfide crosslinks into the loop regions on opposite ends of the beta barrel in superfolder green fluorescent protein (GFP) in order to better understand the nature of its folding pathway. When the disulfide on the side opposite the N/C-termini is formed, folding is 2* faster, unfolding is 2000* slower, and the protein is stabilized by 16 kJ/mol. But when the disulfide bond on the side of the termini is formed we see little change in the kinetics and stability. The stabilization upon combining the two crosslinks is approximately additive. When the kinetic effects are broken down into multiple phases, we observe Hammond behavior in the upward shift of the kinetic m-value of unfolding. We use these results in conjunction with structural analysis to assign folding intermediates to two parallel folding pathways. The data are consistent with a view that the two fastest transition states of folding are "barrel closing" steps. The slower of the two phases passes through an intermediate with the barrel opening occurring between strands 7 and 8, while the faster phase opens between 9 and 4. We conclude that disulfide crosslink-induced perturbations in kinetics are useful for mapping the protein folding pathway. PMID- 25516356 TI - Enhanced photocatalytic H2-production activity of bicomponent NiO/TiO2 composite nanofibers. AB - Hydrogen has been regarded as an ideal candidate for the replacement of conventional fossil fuels due to its environmental friendliness and recycling possibility. In this work, mesoporous NiO/TiO2 bicomponent composite nanofibers were prepared by a electrospinning and calcination method. The H2-production activity of the prepared samples was examined by water splitting using methanol as scavenger under simulated solar Xenon lamp irradiation. The effect of NiO loading on the microstructure and photocatalytic H2-production activity of NiO/TiO2 composite samples was studied and discussed. The results demonstrated that the presence of a small amount of NiO obviously inhibited the growth of TiO2 crystallites. With increasing the NiO content, the average crystallite size further decreased. In contrast, the Brunauer-Emmett-Teller (BET) specific surface areas, pore volumes and average pore size steadily increased. Photocatalytic H2 production experiment confirmed that NiO was an efficient co-catalyst for the photocatalytic H2 production of TiO2. The optimal NiO loading was determined to be 0.25 wt.%, giving a H2-production rate of 337 MUmol h(-1) g(-1) with apparent quantum efficiency (QE) of 1.7%, which exceeded the rate on pure TiO2 by more than 7 times. The enhanced H2-production activity was due to the deposition of NiO clusters on the surface of TiO2, which suppressed the recombination of photogenerated electron-hole pairs, reduced the overpotential of hydrogen production and catalyzed production of hydrogen. This work showed that low-cost and earth-abundant NiO could be used as co-catalyst for photocatalytic hydrogen production. PMID- 25516357 TI - FRAIL-HF, a study to evaluate the clinical complexity of heart failure in nondependent older patients: rationale, methods and baseline characteristics. AB - The clinical scenario of heart failure (HF) in older hospitalized patients is complex and influenced by acute and chronic comorbidities, coexistent geriatric syndromes, the patient's ability for self-care after discharge, and degree of social support. The impact of all these factors on clinical outcomes or disability evolution is not sufficiently known. FRAIL-HF is a prospective observational cohort study designed to evaluate clinical outcomes (mortality and readmission), functional evolution, quality of life, and use of social resources at 1, 3, 6, and 12 months after admission in nondependent elderly patients hospitalized for HF. Clinical features, medical treatment, self-care ability, and health literacy were prospectively evaluated and a comprehensive geriatric assessment with special focus on frailty was systematically performed in hospital to assess interactions and relationships with postdischarge outcomes. Between May 2009 and May 2011, 450 consecutive patients with a mean age of 80 +/- 6 years were enrolled. Comorbidity was high (mean Charlson index, 3.4 +/- 2.9). Despite being nondependent, 118 (26%) had minor disability for basic activities of daily living, only 76 (16.2%) had no difficulty in walking 400 meters, and 340 (75.5%) were living alone or with another elderly person. In addition, 316 patients (70.2%) fulfilled frailty criteria. Even nondependent older patients hospitalized for HF show a high prevalence of clinical and nonclinical factors that may influence prognosis and are usually not considered in routine clinical practice. The results of FRAIL-HF will provide important information about the relationship between these factors and different postdischarge clinical, functional, and quality-of-life outcomes. PMID- 25516358 TI - Immunobiology and signaling pathways of cancer stem cells: implication for cancer therapy. AB - Cancer stem cells (CSCs) need to survive cancer treatments with a specific end goal to provide new, more differentiated, metastatic-prone cancerous cells. This happens through diverse signals delivered within the tumor microenvironment where ample evidence indicates that altered developmental signaling pathways play an essential role in maintaining CSCs and accordingly the survival and the progression of the tumor itself. This review summarizes findings on the immunobiological properties of CSCs as compared with cancerous non-stem cells involving the expression of immunological molecules, cytokines and tumor antigens as well as the roles of the Notch, Wnt and Hedgehog pathways in the brain, breast and colon CSCs. We concluded that if CSCs are the main driving force behind tumor support and growth then understanding the molecular mechanisms and the immunological properties directing these cells for immune tolerance is of great clinical significance. Such knowledge will contribute to designing better targeted therapies that could prevent tumor recurrence and accordingly significantly improve cancer treatments and patient survival. PMID- 25516359 TI - Association between intake of B vitamins and cognitive function in elderly Koreans with cognitive impairment. AB - BACKGROUND: It is possible that blood B vitamins level and cognitive function may be affected by dietary intake of these vitamins, no study however has yet been conducted on relationships between B vitamins intake and cognitive function among elderly population in Korea. This study examined the relationship between B vitamins intake and cognitive function among elderly in South Korea. METHODS: Participants consisted of 100 adults with mild cognitive impairment (MCI), 100 with Alzheimer's disease (AD), and 121 normal subjects. Dietary intake data that included the use of dietary supplements were obtained using a 24-hour recall method by well-trained interviewers. Plasma folate and vitamin B12 concentrations were analyzed by radioimmunoassay, and homocysteine (Hcy) was assessed by a high performance liquid chromatography-fluorescence method. RESULTS: Plasma levels of folate and vitamin B12 were positively correlated with B vitamins intake; and plasma Hcy was negatively correlated with total intake of vitamin B2, vitamin B6, vitamin B12 and folate. In the AD group, a multiple regression analysis after adjusting for covariates revealed positive relationships between vitamin B2 intake and test scores for the MMSE-KC, Boston Naming, Word Fluency, Word List Memory and Constructional Recall Tests; and between vitamin B6 intake and the MMSE-KC, Boston Naming, Word Fluency, Word List Memory, Word List Recognition, Constructional Recall and Constructional Praxis Tests. Positive associations were observed between vitamin B12 intake and the MMSE-KC, Boston Naming, Constructional Recall and Constructional Praxis Tests, and between folate intake and the Constructional Recall Test. In the MCI group, vitamin B2 intake was positively associated with the MMSE-KC and Boston Naming Test, vitamin B6 intake was positively associated with the Boston Naming Test, and folate intake was positively associated with the MMSE-KC and Word List Memory test. No associations were observed in the normal group. CONCLUSION: These results suggested that total B vitamins intake is associated with cognitive function in cognitively impaired AD and MCI elderly, and the association is stronger in AD patients. PMID- 25516360 TI - Donepezil can improve daily activities and promote rehabilitation for severe Alzheimer's patients in long-term care health facilities. AB - BACKGROUND: Cholinesterase inhibitors can delay the progression of Alzheimer's disease (AD). Several clinical trials of the drug in moderate to severe AD have consistently reported clinically positive effects. A combining effect with psychosocial intervention was reported in mild to moderate AD patients. Since a therapeutic approach or rehabilitation combined with cholinesterase inhibitors for severe AD patients remains controversial, we performed a prospective intervention for patients in Long-Term Care Health Facilities (LTCHF). METHODS: Two LTCHFs (N1, N2) were enrolled. N1 is a 126-bed facility that does not treat with donepezil but rather with psychosocial intervention (reality orientation and reminiscence). N2 is a 150-bed facility with a 50-bed special dementia unit, in which the physician can prescribe donepezil. On top of the similar psychosocial intervention, rehabilitation is performed in N2. Thirty-two severe AD patients (MMSE < 6) in N1 and N2 (16 vs. 16) were compared for the effect of donepezil (10 mg/d for 3 months) with or without psychosocial intervention (n = 8 vs. 8 for each facility). The Vitality Index was used to assess daily activities and the introduction of rehabilitation. RESULTS: The response ratio (MMSE 3+) of donepezil was 37.5% in N2. The combination of donepezil with the psychosocial intervention improved the Vitality Index total score, and Communication, Eating, and Rehabilitation subscores (Wilcoxon, p = 0.016, 0.038, 0.023, and 0.011, respectively). Most of them were smoothly introduced to rehabilitation, and the proportion of accidental falls decreased. Psychosocial intervention in N1 without the drug only improved the total score (Wilcoxon, p = 0.046). CONCLUSIONS: A combined therapeutic approach of donepezil and psychosocial intervention can have a positive effect, even for severe patients through the introduction of rehabilitation and decreasing accidental falls. However, these findings require replication in a larger cohort. PMID- 25516361 TI - Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: a meta-analysis of randomized controlled trials. AB - To identify the role of vitamin K2 for the prevention and treatment of osteoporosis in postmenopausal women, we conducted this meta-analysis of 19 randomized controlled trials. Our results showed that vitamin K2 might play a role in maintaining the bone mineral density and in reducing the incidence of fractures for postmenopausal women with osteoporosis. INTRODUCTION: Vitamin K2 has been revealed to be effective in the prevention and treatment of osteoporosis in Japan, which was not confirmed in western countries. Thus, we conduct this meta-analysis to verify the hypothesis that vitamin K2 plays a role in the prevention and treatment of osteoporosis for postmenopausal women. METHODS: We searched the Cochrane Library, Pub Med, EMBASE, and ISI web of knowledge (until December 1, 2013) and reference lists of eligible articles. A meta-analysis of all-including randomized controlled trials was then performed. RESULTS: Nineteen randomized controlled trials encompassing 6759 participants have met the inclusion criteria. Subgroup analysis of postmenopausal women with osteoporosis revealed a significant improvement of vertebral BMD for both medium-term and long term results favoring vitamin K2 group (p < 0.00001 and p = 0.0005). However, no significant difference in BMD changes was revealed for the non-osteoporosis subgroup analysis. As for the incidence of fractures, pooled analysis of the seven related studies demonstrated no significant difference in the incidence of fractures favoring vitamin K2 (RR = 0.63, p = 0.08). However, sensitivity analysis by rejecting the study inducing heterogeneity demonstrated a significant difference in the incidence of fractures favoring vitamin K2 (RR = 0.50, p = 0.0005). Significant differences were found in undercarboxylated osteocalcin reduction and osteocalcin increment. The result of adverse reaction analysis showed that vitamin K2 group seemed to have a higher adverse reaction rate (RR = 1.22, p = 0.06). CONCLUSIONS: This meta-analysis seemed to support the hypothesis that vitamin K2 plays kind of a role in the maintenance and improvement of vertebral BMD and the prevention of fractures in postmenopausal women with osteoporosis. The reduction of undercarboxylated osteocalcin and increment of osteocalcin may have some relation to the process of bone mineralization. However, the effect of vitamin K2 for postmenopausal women without osteoporosis had not been identified. Further high-quality RCTs with large sample size are needed to confirm the role of vitamin K2 in osteoporosis for postmenopausal women. PMID- 25516362 TI - Local renin-angiotensin system is associated with bone mineral density of glucocorticoid-induced osteoporosis patients. AB - The local renin-angiotensin system (RAS) is closely related to bone metabolism. However, it is unknown whether the local RAS is related to bone mineral density (BMD) in glucocorticoid-induced osteoporosis (GIOP). Here, we revealed that the two main characteristics of GIOP might inhibit bone formation and enhance bone resorption. INTRODUCTION: The aim of this study is to assess the expression of the main RAS components in the trabecular bone of lumbar vertebrae in GIOP and analyze the relationship between the major RAS components and BMD. METHODS: We collected 96 inpatient cases of lumbar disc herniation from patients who underwent dual-energy X-ray absorptiometry examinations followed by surgical treatment in our hospital. Patients were divided into the GIOP group (n = 48) and control group (n = 48). The circulating and local expression levels of the main RAS components were examined. The correlation between the main RAS components and BMD was then analyzed. RESULTS: The mRNA expression of local bone angiotensin type 1 and 2 receptors (AT1R and AT2R, respectively) and RANKL was higher in the GIOP group compared with the control group (p < 0.001), but there was no difference in the circulating protein levels between groups (p > 0.05). Multiple logistic regression analysis revealed that AT1R and AT2R expression and the RANKL/OPG ratio in local bone were negatively associated with BMD (p < 0.001, odds ratio (OR) 1.236, 95 % confidence interval (CI) 1.207-1.333; p < 0.001, OR 1.971, 95% CI 1.809-2.233; and p < 0.001, OR 1.676, 95% CI 1.546-1.845, respectively). CONCLUSION: This study provides evidence that the role of local RAS is related to BMD in GIOP patients, and suggests that local RAS might influence RANKL/OPG signaling to modulate bone metabolism. PMID- 25516363 TI - Assessment of the external validity of a predictive score for blood transfusion in liver surgery. AB - BACKGROUND: Perioperative bleeding is a predictor of morbidity following liver resection. The transfusion-related score (TRS), which is derived from five variables (cirrhosis, preoperative haemoglobin level, tumour size, vena cava exposure and associated extraliver surgical procedure), has been proposed to predict the likelihood of transfusion in liver resection. OBJECTIVE: The purpose of this observational study was to evaluate the external validity of the TRS. METHODS: In a retrospective, monocentre, observational cohort study of patients undergoing elective liver resection surgery, data for transfused and non transfused patients were compared by univariate analysis. The TRS was calculated for each patient. The frequency of transfusion was calculated for each score level. The accuracy of the TRS was evaluated using the area under the receiver operator characteristic curve (AUC). RESULTS: A total of 205 patients submitted to liver resection were included. Of these, 48 (23.4%) patients received a blood transfusion. There was no significant difference between transfused and non transfused patients in age, American Society of Anesthesiologists (ASA) score or cirrhosis. The AUC for the TRS was 0.68 (95% confidence interval 0.59-0.77). Among TRS items, only vena cava exposure and associated surgical procedures were significantly associated with risk for transfusion. CONCLUSIONS: In the present population, the TRS appeared to serve as a weak predictor of perioperative transfusion. This study confirms that the external validity of the transfusion predictive score should be subject to further investigation before it can be implemented in clinical use. PMID- 25516364 TI - Pepsin and bile acids in saliva in patients with laryngopharyngeal reflux - a prospective comparative study. AB - OBJECTIVES: Laryngopharyngeal reflux (LPR) and biliary duodenogastric reflux can cause damage to the laryngeal mucosa and voice disorders. The aim of this study was to find out whether levels of pepsin and bile acids in the saliva can serve as diagnostic markers of LPR. SETTING: A prospective comparative study. PARTICIPANTS: Twenty-eight patients with LPR proven via high-resolution manometry and combined multichannel intraluminal impedance and 24-h pH monitoring and 48 healthy controls without symptoms of LPR were included in the study. MAIN OUTCOME MEASURES: In the patients with LPR symptoms, oesophagogastroscopy with oesophageal biopsy was performed. The levels of total pepsin, active pepsin, bile acids and the pH of the saliva were determined in all participants and compared between the groups. Reflux symptom index (RSI) and reflux finding score (RFS) were also obtained and compared. The groups differed significantly in RSI (P = 0.00), RFS (P = 0.00), the levels of bile acids (P = 0.005) and total pepsin in saliva (P = 0.023). The levels of total pepsin and bile acids were about three times higher in the patients with LPR than in the healthy controls. There was a significant correlation between the RSI and RFS score and the level of total pepsin and bile acids in the saliva. Histopathological examination of the oesophageal biopsy taken 5 cm above the lower oesophageal sphincter confirmed reflux in almost 93% of patients with symptoms. CONCLUSIONS: The study results show that the levels of total pepsin and bile acids in saliva are significantly higher in patients with LPR than in the controls, thus suggesting this as a useful tool in the diagnosis of LPR and particularly biliary LPR. PMID- 25516365 TI - Step by step: a microgenetic study of the development of strategy choice in infancy. AB - To examine patterns of strategy choice and discovery during problem-solving of a novel locomotor task, 13.5- and 18-month-old infants were placed at the top of a staircase and encouraged to descend. Spontaneous stair descent strategy choices were documented step by step and trial by trial to provide a microgenetic account of problem-solving in action. Younger infants tended to begin each trial walking, were more likely to choose walking with each successive step, and were more likely to lose their balance and have to be rescued by an experimenter. Conversely, older infants tended to begin each trial scooting, were more likely to choose scooting with each successive step, and were more likely to use a handrail to augment balance on stairs. Documenting problem-solving microgenetically across age groups revealed striking similarities between younger infants' strategy development and older children's behaviour on more traditionally cognitive tasks, including using alternative strategies, mapping prior experiences with strategies to a novel task, and strengthening new strategies. As cognitive resources are taxed during a challenging task, resources available for weighing alternatives or inhibiting a well-used strategy are reduced. With increased motor experience, infants can more easily consider alternative strategies and maintain those solutions over the course of the trial. PMID- 25516366 TI - Electric field induced surface-enhanced Raman spectroscopy for multianalyte detection. AB - This work demonstrates the ability to identify thiophenol from a mixture with structurally similar benzyl mercaptan. We exploit the unique alterations that occur in the surface-enhanced Raman spectroscopy (SERS) characteristics in the presence of an oscillating electric field applied using SERS-active microfabricated electrode pairs. PMID- 25516367 TI - Potentiometric detection in UPLC as an easy alternative to determine cocaine in biological samples. AB - The analytical methods which are often used for the determination of cocaine in complex biological matrices are a prescreening immunoassay and confirmation by chromatography combined with mass spectrometry. We suggest an ultra-high-pressure liquid chromatography combined with a potentiometric detector, as a fast and practical method to detect and quantify cocaine in biological samples. An adsorption/desorption model was used to investigate the usefulness of the potentiometric detector to determine cocaine in complex matrices. Detection limits of 6.3 ng mL(-1) were obtained in plasma and urine, which is below the maximum residue limit (MRL) of 25 ng mL(-1). A set of seven plasma samples and 10 urine samples were classified identically by both methods as exceeding the MRL or being inferior to it. The results obtained with the UPLC/potentiometric detection method were compared with the results obtained with the UPLC/MS method for samples spiked with varying cocaine concentrations. The intraclass correlation coefficient was 0.997 for serum (n =7) and 0.977 for urine (n =8). As liquid chromatography is an established technique, and as potentiometry is very simple and cost-effective in terms of equipment, we believe that this method is potentially easy, inexpensive, fast and reliable. PMID- 25516368 TI - Perceived Changes in Social Relations after Earthquake Trauma among Eastern Anatolian Women: Associated Factors and Mental Health Consequences. AB - In this study, we examined social relations in women exposed to earthquake trauma in Eastern Anatolia, Turkey. We examined women's perceptions regarding the changes in their social relations within their neighbourhood, within their marriage and with their children; analysed the factors that were associated with these relations; and tested the hypothesis that an improvement in social relations will protect women's mental health from the negative impact of earthquake trauma. Participants consisted of a random selection of 1253 women, who were interviewed regarding their psychosocial needs and mental health status 1 year after earthquake. They reported trauma-related changes in their social relations; their mental health was evaluated using the Post Traumatic Stress Diagnostic Scale and Brief Symptom Inventory. Our study demonstrated severe earthquake trauma was associated with deteriorated social relations, especially neighbourhood and marital relations. Deteriorated marital and child relations were associated with increased levels of psychiatric distress; deteriorated neighbourhood relations were associated with intrusive posttraumatic stress symptoms. Improved neighbourhood relations, but not family relations, were able to protect women's mental health from the negative impact of trauma. The results are discussed regarding their relevance to gender effects and the provision of relation-specific and symptom-specific disaster relief. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25516369 TI - Network robustness: detecting topological quantum phases. AB - Can the topology of a network that consists of many particles interacting with each other change in complexity when a phase transition occurs? The answer to this question is particularly interesting to understand the nature of the phase transitions if the distinct phases do not break any symmetry, such as topological phase transitions. Here we present a novel theoretical framework established by complex network analysis for demonstrating that across a transition point of the topological superconductors, the network space experiences a homogeneous heterogeneous transition invisible in real space. This transition is nothing but related to the robustness of a network to random failures. We suggest that the idea of the network robustness can be applied to characterizing various phase transitions whether or not the symmetry is broken. PMID- 25516370 TI - Dissecting negative symptoms in schizophrenia: opportunities for translation into new treatments. AB - Among the constellation of symptoms that characterize schizophrenia, negative symptoms have emerged as a critical feature linked to the functional impairment experienced by affected individuals. Despite advances in our understanding of the role of negative symptoms in the illness, effective treatments for these debilitating symptoms have remained elusive. In this review we explore the contemporary conceptualization of negative symptoms in schizophrenia, including the identification of two key subdomains of diminished expression and amotivation, and clarifications around hedonic capacity. We then explore strategies for clinical assessments of negative symptoms, followed by findings using objective paradigms for evaluating discrete aspects of these negative symptoms in clinical populations and animal models, both for symptoms of diminished expression and within the multifaceted motivation system. We conclude with a consideration of current strategies for drug development for these negative symptoms, the role of heterogeneity in the clinical presentation of symptoms in schizophrenia and opportunities for personalized assessment and treatment approaches, as well as a commentary on current clinical drug trial design and the role of environmental opportunities for novel treatments to effect change and improve outcomes for affected individuals. PMID- 25516371 TI - A translational investigation targeting stress-reactivity and prefrontal cognitive control with guanfacine for smoking cessation. AB - Stress and prefrontal cognitive dysfunction have key roles in driving smoking; however, there are no therapeutics for smoking cessation that attenuate the effects of stress on smoking and enhance cognition. Central noradrenergic pathways are involved in stress-induced reinstatement to nicotine and in the prefrontal executive control of adaptive behaviors. We used a novel translational approach employing a validated laboratory analogue of stress-precipitated smoking, functional magnetic resonance imaging (fMRI), and a proof-of-concept treatment period to evaluate whether the noradrenergic alpha2a agonist guanfacine (3 mg/day) versus placebo (0 mg/day) reduced stress-precipitated smoking in the laboratory, altered cortico-striatal activation during the Stroop cognitive control task, and reduced smoking following a quit attempt. In nicotine-deprived smokers (n=33), stress versus a neutral condition significantly decreased the latency to smoke, and increased tobacco craving, ad-libitum smoking, and systolic blood pressure in placebo-treated subjects, and these effects were absent or reduced in guanfacine-treated subjects. Following stress, placebo-treated subjects demonstrated decreased cortisol levels whereas guanfacine-treated subjects demonstrated increased levels. Guanfacine, compared with placebo, altered prefrontal activity during a cognitive-control task, and reduced cigarette use but did not increase complete abstinence during treatment. These preliminary laboratory, neuroimaging, and clinical outcome data were consistent and complementary and support further development of guanfacine for smoking cessation. PMID- 25516373 TI - "First do no harm." A systematic review of the prevalence and management of antipsychotic adverse effects. AB - AIMS: We aim to identify the prevalence and management strategies of nine clinically important categories of antipsychotic adverse effects, namely: extrapyramidal symptoms; sedation; weight gain; type II diabetes; hyperprolactinaemia; metabolic syndrome, dyslipidaemia; sexual dysfunction; and cardiovascular effects. BACKGROUND: Antipsychotic drugs are widely prescribed for schizophrenia and other mental disorders. The adverse effects of antipsychotics are common, with a potential negative impact on adherence and engagement. Despite this, the scientific study of the prevalence or management of adverse antipsychotic effects is a neglected area. METHOD: A systematic review was undertaken using pre-defined search criteria and three databases, with hand searching of citations and references. Inclusion was agreed on by two independent researchers after review of abstracts or full text. Quality analysis of included studies was conducted using pre-agreed criteria. RESULTS: In total, 53 studies met inclusion criteria, revealing the following: (1) antipsychotic polypharmacy was associated with increased frequency of adverse effects, and (2) a longer duration of treatment is associated with greater severity (e.g. higher BMI); (3) clozapine was more strongly associated with metabolic disturbance than other antipsychotics in three studies and olanzapine was associated with the most weight gain in three studies; (4) hyperprolactinaemia was more common in women than men, but 50% men noted sexual dysfunction versus 25-50% in women; (5) despite clinical guideline recommendations there is a low rate of baseline testing for lipids and glucose; and (6) seven studies described adverse effect management strategies, but only two examined their efficacy - one found a significant reduction in weight with non-pharmacological group therapy and the other found a significant reduction in dyslipidaemia with statins. CONCLUSIONS: Antipsychotic adverse effects are diverse and frequently experienced, but are not often systematically assessed. There is a need for further scientific study concerning the management of these side effects. PMID- 25516374 TI - Inhibitory effect of Moutan Cortex aqueous fraction on mast cell-mediated allergic inflammation. AB - Moutan Cortex and its major compounds have been shown to possess various biological activities, including anti-inflammatory properties. However, the effects of Moutan Cortex aqueous fraction (MCA) and its molecular mechanisms have yet to be elucidated. In this study, we attempted to evaluate the effects of MCA on mast cell-mediated allergy inflammation in vitro and in vivo compared with major Moutan Cortex compounds. Thus, we examined the anti-inflammatory effects of a water extract of Moutan Cortex by comparing the inhibition of beta hexosaminadase and tumor necrosis factor-alpha (TNF-alpha) release in an aqueous fraction with other major compounds of Moutan Cortex. The inhibitory mechanism of MCA was investigated by western blotting in IgE-mediated DNP-BSA-stimulated RBL 2H3 cells. We confirmed the pharmacological effects of MCA on compound 48/80 induced allergic reactions in a mouse model by assessing scratching behavior and passive cutaneous anaphylaxis (PCA)-like reaction. Consequently, MCA inhibited IgE-mediated DNP-BSA-induced beta-hexosaminadase and TNF-alpha release via inactivation of p38, ERK, Akt, and NF-kappaB in RBL-2H3 cells. MCA reduced compound 48/80-induced PCA reaction and scratching behavior in mice. This inhibitory effect of MCA is more potent than major compounds of Moutan Cortex. In conclusion, our results suggest that MCA has more potential in the treatment of allergic inflammatory diseases compared to other major compounds of Moutan Cortex. PMID- 25516375 TI - Functional and structural characteristics of methylmalonyl-CoA mutase from Pyrococcus horikoshii. AB - Methylmalonyl-CoA mutase (MCM) requires 5'-deoxyadenosylcobalamin (AdoCbl) as a cofactor and is widely distributed in organisms from bacteria and animals. Although genes encoding putative MCMs are present in many archaea, they are separately encoded in large and small subunits. The large and small subunits of archaeal MCM are similar to the catalytic and AdoCbl-binding domains of human MCM, respectively. In Pyrococcus horikoshii OT3, putative genes PH1306 and PH0275 encode the large and small subunits, respectively. Because information on archaeal MCM is extremely restricted, we examined the functional and structural characteristics of P. horikoshii MCM. Reconstitution experiments using recombinant PH0275 and PH1306 showed that these proteins assemble in equimolar ratios and form of heterotetrameric complexes in the presence of AdoCbl. Subsequent immunoprecipitation experiments using anti-PH0275 and anti-PH1306 antibodies suggested that PH0275 and PH1306 form a complex in P. horikoshii cells in the presence of AdoCbl. PMID- 25516376 TI - Prostaglandin D synthase is a potential novel therapeutic agent for the treatment of gastric carcinomas expressing PPARgamma. AB - The antitumor activity of prostaglandin (PG) D2 has been demonstrated against some types of cancer, including gastric cancer. However, exogenous PGD2 is not useful from a clinical point of view because it is rapidly metabolized in vivo. The aim of this study was to clarify the antitumor efficacy of an alternative, PGD synthase (PGDS), on gastric cancer cells. The effects of PGD2 and PGDS on the proliferation of gastric cancer cells were examined in vivo and in vitro. The expression levels of PGD2 receptors and peroxisome proliferator-activated receptor gamma (PPARgamma) were evaluated by RT-PCR. The effects of a PPARgamma antagonist or siPPARgamma on the proliferation of cancer cells and the c-myc and cyclin D1 expression were examined in the presence or absence of PGD2 or PGDS. PPARgamma was expressed in gastric cancer cell lines, but PGD2 receptors were not. PGD2 and PGDS significantly decreased the proliferation of gastric cancer cells that highly expressed PPARgamma. PGDS increased the PGD2 production of gastric cancer cells. A PPARgamma antagonist and siPPARgamma transfection significantly suppressed the growth-inhibitory effects of PGD2 and PGDS. Expression of c-myc and cyclin D1 was significantly decreased by PGD2 ; this inhibitory effect was suppressed by PPARgamma antagonist. Both PGD2 and PGDS significantly decreased subcutaneous tumor growth in vivo. Tumor volume after PGDS treatment was significantly less than PGD2 treatment. These findings suggest that PGDS and PGD2 decrease the proliferation of gastric cancer cells through PPARgamma signaling. PGDS is a potentially promising therapeutic agent for gastric cancers that express PPARgamma. PMID- 25516372 TI - Developing treatments for cognitive deficits in schizophrenia: the challenge of translation. AB - Schizophrenia is a life-long debilitating mental disorder affecting tens of millions of people worldwide. The serendipitous discovery of antipsychotics focused pharmaceutical research on developing a better antipsychotic. Our understanding of the disorder has advanced however, with the knowledge that cognitive enhancers are required for patients in order to improve their everyday lives. While antipsychotics treat psychosis, they do not enhance cognition and hence are not antischizophrenics. Developing pro-cognitive therapeutics has been extremely difficult, however, especially when no approved treatment exists. In lieu of stumbling on an efficacious treatment, developing targeted compounds can be facilitated by understanding the neural mechanisms underlying altered cognitive functioning in patients. Equally importantly, these cognitive domains will need to be measured similarly in animals and humans so that novel targets can be tested prior to conducting expensive clinical trials. To date, the limited similarity of testing across species has resulted in a translational bottleneck. In this review, we emphasize that schizophrenia is a disorder characterized by abnormal cognitive behavior. Quantifying these abnormalities using tasks having cross-species validity would enable the quantification of comparable processes in rodents. This approach would increase the likelihood that the neural substrates underlying relevant behaviors will be conserved across species. Hence, we detail cross-species tasks which can be used to test the effects of manipulations relevant to schizophrenia and putative therapeutics. Such tasks offer the hope of providing a bridge between non-clinical and clinical testing that will eventually lead to treatments developed specifically for patients with deficient cognition. PMID- 25516377 TI - Comorbidity of attention deficit hyperactivity disorder with personality disorders in homeless people. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a condition that begins in childhood but can continue into adulthood, and may be the cause of many disadaptive behaviors, as in the case of homeless people, who often display a high incidence of personality disorders. The goal of this study is to analyze the comorbidity of ADHD with axis II disorders in a Spanish homeless population. RESULTS: The outcomes show high comorbidity between these two kinds of disorders, and that the prevalence of axis II disorders is higher among people with ADHD than among the general population. CONCLUSIONS: From these results we can draw the conclusion that in homeless people ADHD in childhood continues into adulthood, when it is very often observed together with personality disorders. Finally, the implications of this study both for clinical practice and for future lines of research are discussed. PMID- 25516379 TI - Mortality of first world war military personnel: comparison of two military cohorts. AB - OBJECTIVE: To identify the impact of the first world war on the lifespan of participating military personnel (including in veterans who survived the war). DESIGN: Comparison of two cohorts of military personnel, followed to death. SETTING: Military personnel leaving New Zealand to participate in the first world war. PARTICIPANTS: From a dataset of the New Zealand Expeditionary Forces, we randomly selected participants who embarked on troopships in 1914 and a comparison non-combat cohort who departed on troopships in late 1918 (350 in each group). MAIN OUTCOME MEASURES: Lifespan based on dates of birth and death from a range of sources (such as individual military files and an official database of birth and death records). RESULTS: A quarter of the 1914 cohort died during the war, with deaths from injury predominating (94%) over deaths from disease (6%). This cohort had a significantly shorter lifespan than the late 1918 "non-combat" cohort, with median ages of death being 65.9 versus 74.2, respectively (a difference of 8.3 years shown also in Kaplan-Meier survival curves, log rank P<0.001). The difference for the lifespan of veterans in the postwar period was more modest, with median ages of death being 72.6 versus 74.3, respectively (a difference of 1.7 years, log rank P=0.043). There was no evidence for differences between the cohorts in terms of occupational class, based on occupation at enlistment. CONCLUSIONS: Military personnel going to the first world war in 1914 from New Zealand lost around eight years of life (relative to a comparable military cohort). In the postwar period they continued to have an increased risk of premature death. PMID- 25516380 TI - Clinical efficacy of lamotrigine and changes in the dosages of concomitantly used psychotropic drugs in Alzheimer's disease with behavioural and psychological symptoms of dementia: a preliminary open-label trial. AB - AIM: We investigated the clinical efficacy and changes in the dosages of concomitantly used psychotropic drugs in lamotrigine therapy in Alzheimer's disease with behavioural and psychological symptoms of dementia (BPSD). METHODS: This study was a 16-week, preliminary open-label trial. The subjects were 40 inpatients. The outcome measures assessed were BPSD and cognitive function. BPSD was assessed with the Neuropsychiatric Inventory (NPI) and cognitive function was assessed with the Mini-Mental State Examination. The changes in the dosages of concomitant psychotropic drugs were also assessed. RESULTS: Although the mean changes from baseline NPI scores and the two NPI subscales (anxiety and irritability) were significantly lower within the lamotrigine therapy group, no significant differences were found when we compared the lamotrigine therapy group to the control group. The mean decrease from baseline on the NPI agitation subscale, however, was significantly greater in the lamotrigine therapy group than in the control group (P < 0.05). Furthermore, the mean decrease from baseline in the diazepam-equivalent dose was significantly greater in the lamotrigine therapy group than in the control group (P < 0.05). CONCLUSIONS: The results of this study suggest that the administration of lamotrigine to patients with severe Alzheimer's disease with BPSD may be effective and may make it possible to avoid increasing the dosage of antipsychotic medications prescribed to elderly patients. PMID- 25516381 TI - A psychophysiological investigation of emotion regulation in chronic severe posttraumatic stress disorder. AB - There have been few direct examinations of the volitional control of emotional responses to provocative stimuli in PTSD. To address this gap, an emotion regulation task was administered to 27 Operation Enduring Freedom/Operation Iraqi Freedom combat veterans and 23 healthy controls. Neutral and aversive photographs were presented to participants who did or did not employ emotion regulation strategies. Objective indices included corrugator electromyogram, the late positive potential, and the electrocardiogram. On uninstructed trials, participants with PTSD exhibited blunted cardiac reactivity rather than the exaggerated cardioacceleratory responses seen in trauma cue reactivity studies. On interleaved regulation trials, no measure evidenced group differences in voluntary emotion regulation. Persons with PTSD may not differ from normals in their capacity to voluntarily regulate normative emotional responses to provocative stimuli in the laboratory, though they may nevertheless respond differentially on uninstructed trials and endorse symptoms of dyscontrol pathognomonic of the disorder outside of the laboratory. PMID- 25516378 TI - Genome-wide analysis of alternative splicing in Volvox carteri. AB - BACKGROUND: Alternative splicing is an essential mechanism for increasing transcriptome and proteome diversity in eukaryotes. Particularly in multicellular eukaryotes, this mechanism is involved in the regulation of developmental and physiological processes like growth, differentiation and signal transduction. RESULTS: Here we report the genome-wide analysis of alternative splicing in the multicellular green alga Volvox carteri. The bioinformatic analysis of 132,038 expressed sequence tags (ESTs) identified 580 alternative splicing events in a total of 426 genes. The predominant type of alternative splicing in Volvox is intron retention (46.5%) followed by alternative 5' (17.9%) and 3' (21.9%) splice sites and exon skipping (9.5%). Our analysis shows that in Volvox at least ~2.9% of the intron-containing genes are subject to alternative splicing. Considering the total number of sequenced ESTs, the Volvox genome seems to provide more favorable conditions (e.g., regarding length and GC content of introns) for the occurrence of alternative splicing than the genome of its close unicellular relative Chlamydomonas. Moreover, many randomly chosen alternatively spliced genes of Volvox do not show alternative splicing in Chlamydomonas. Since the Volvox genome contains about the same number of protein-coding genes as the Chlamydomonas genome (~14,500 protein-coding genes), we assumed that alternative splicing may play a key role in generation of genomic diversity, which is required to evolve from a simple one-cell ancestor to a multicellular organism with differentiated cell types (Mol Biol Evol 31:1402-1413, 2014). To confirm the alternative splicing events identified by bioinformatic analysis, several genes with different types of alternatively splicing have been selected followed by experimental verification of the predicted splice variants by RT-PCR. CONCLUSIONS: The results show that our approach for prediction of alternative splicing events in Volvox was accurate and reliable. Moreover, quantitative real time RT-PCR appears to be useful in Volvox for analyses of relationships between the appearance of specific alternative splicing variants and different kinds of physiological, metabolic and developmental processes as well as responses to environmental changes. PMID- 25516382 TI - Two-dimensional layered MoS2 biosensors enable highly sensitive detection of biomolecules. AB - We present a MoS2 biosensor to electrically detect prostate specific antigen (PSA) in a highly sensitive and label-free manner. Unlike previous MoS2-FET-based biosensors, the device configuration of our biosensors does not require a dielectric layer such as HfO2 due to the hydrophobicity of MoS2. Such an oxide free operation improves sensitivity and simplifies sensor design. For a quantitative and selective detection of PSA antigen, anti-PSA antibody was immobilized on the sensor surface. Then, introduction of PSA antigen, into the anti-PSA immobilized sensor surface resulted in a lable-free immunoassary format. Measured off-state current of the device showed a significant decrease as the applied PSA concentration was increased. The minimum detectable concentration of PSA is 1 pg/mL, which is several orders of magnitude below the clinical cut-off level of ~4 ng/mL. In addition, we also provide a systematic theoretical analysis of the sensor platform - including the charge state of protein at the specific pH level, and self-consistent channel transport. Taken together, the experimental demonstration and the theoretical framework provide a comprehensive description of the performance potential of dielectric-free MoS2-based biosensor technology. PMID- 25516384 TI - Implications of agricultural land use change to ecosystem services in the Ganges delta. AB - Ecosystems provide the basis for human civilization and natural capital for green economy and sustainable development. Ecosystem services may range from crops, fish, freshwater to those that are harder to see such as erosion regulation, carbon sequestration, and pest control. Land use changes have been identified as the main sources of coastal and marine pollution in Bangladesh. This paper explores the temporal variation of agricultural land use change and its implications with ecosystem services in the Ganges delta. With time agricultural lands have been decreased and wetlands have been increased at a very high rate mainly due to the growing popularity of saltwater shrimp farming. In a span of 28 years, the agricultural lands have been reduced by approximately 50%, while the wetlands have been increased by over 500%. A large portion (nearly 40%) of the study area is covered by the Sundarbans which remained almost constant which can be attributed to the strict regulatory intervention to preserve the Sundarbans. The settlement & others land use type has also been increased to nearly 5%. There is a gradual uptrend of shrimp and fish production in the study area. The findings suggest that there are significant linkages between agricultural land use change and ecosystem services in the Ganges delta in Bangladesh. The continuous decline of agricultural land (due to salinization) and an increase of wetland have been attributed to the conversion of agricultural land into shrimp farming in the study area. Such land use change requires significant capital, therefore, only investors and wealthier land owners can get the higher profit from the land conversion while the poor people is left with the environmental consequences that affect their long-term lives and livelihood. An environmental management plan is proposed for sustainable land use in the Ganges delta in Bangladesh. PMID- 25516386 TI - Journal of Gastroenterology in the era of globalization. PMID- 25516385 TI - The association between retinal microvascular changes, metabolic risk factors, and liver histology in pediatric patients with non-alcoholic fatty liver disease (NAFLD). AB - BACKGROUND: The prevalence of childhood obesity is increasing worldwide. Studies in adult populations show that retinal microvascular changes are associated with obesity and components of the metabolic syndrome. In our study we have assessed the effect of body mass index (BMI), metabolic parameters, and adiposity on the retinal microvasculature in children. METHODS: Fifty-four consecutive children with biopsy-proven NAFLD were enrolled in this study. Anthropometric and laboratory parameters were obtained using standardized protocols. Retinal caliber was quantified from digital retinal images using well-known computer-based programs. Twenty-four-hour ambulatory blood pressure monitoring was measured using a standard protocol. RESULTS: In our population, the prevalence of retinopathy was of 53 % (13 males). The 29 patients with retinopathy (mean age 10.91 +/- 3.10) showed significantly higher values of triglycerides (mg/day) (105.57 vs. 90.20, p = 0.04), basal insulin (mUI/ml) (17.20 vs. 12.97, p = 0.02), and HOMA-IR (3.37 vs. 2.76, p = 0.04). The patients with a HOMA-IR >2.5 (OR = 3.34, p = 0.02; 95 % IC, 1.07-10.39), and systolic non-dipping (OR 4.16, p = 0.028, 95 % IC, 1.11-13.67), have an increased risk of retinopathy. Moreover, the study of correlation between all stages of liver biopsy (CRN criteria) and the grade of retinopathy showed a positive correlation with fibrosis (r = 0.31) and an NAS score (r = 0.28). CONCLUSIONS: We found an association between metabolic parameters and nocturnal blood pressure on the retinal microvasculature among the obese children with NAFLD. Furthermore, for the first time, we report the positive relationship between hepatic fibrosis in pediatric NAFLD patients and the degree of retinopathy signs. PMID- 25516387 TI - Trends of cost and mortality of patients on haemodialysis with end stage renal disease. AB - AIM: The prevalence of end-stage renal disease in Taiwan is among the highest in the world. Treatment reimbursement for haemodialysis was capped in 1996 in order to contain costs. This study evaluated temporal changes in the costs and utilization of medical care and mortality in patients receiving haemodialysis following capped reimbursement. METHODS: Using insurance claims data in Taiwan between 1998 to 2009, we established eight annual subcohorts of patients with incident haemodialysis, increasing from 6099 in 1998 to 7745 in 2005. With a 4 year follow-up paradigm for each subcohort, we evaluated resources use and costs of medical services, as well as mortality trends. RESULTS: The annual mean cost for each haemodialysis patient increased from US $431 to $737 for emergency visits, US $9007 to $13,280 for hospitalizations and US $79,141 to $92,416 (16.8% increase) for total costs, from the initial to final subcohorts, respectively. Compared to the 1998 subcohort, the adjusted hazard ratio of deaths declined from 0.97 (95% CI 0.91 to 1.02) for the 1999 subcohort to 0.86 (95% CI 0.82 to 0.91) for the 2005 subcohort (P for trend <0.001). The corresponding cumulative probability of deaths decreased from 45.5% to 35.4%. CONCLUSIONS: The mortality for patients with haemodialysis decreased annually, whereas the overall annual cost increased despite capped reimbursement for haemodialysis. These results encourage further study on reasons of increased uses of emergency service and hospitalization. PMID- 25516393 TI - Attached and planktonic Listeria monocytogenes global proteomic responses and associated influence of strain genetics and temperature. AB - Contamination of industrial and domestic food usage environments by the attachement of bacterial food-borne pathogen Listeria monocytogenes has public health and economic implications. Comprehensive proteomics experiments using label-free liquid chromatography/tandem mass spectrometry were used to compare the proteomes of two different L. monocytogenes strains (Siliken_1/2c and F2365_4b), which show very different capacities to attach to surfaces. Growth temperature and strain type were highly influential on the proteomes in both attached and planktonic cells. On the basis of the proteomic data, it is highly unlikely that specific surface proteins play a direct role in adherence to inanimate surfaces. Instead, strain-dependent responses related to cell envelope polymer biosynthesis and stress response regulation likely contribute to a different ability to attach and also to survive external stressors. Collectively, the divergent proteome-level responses observed define strain- and growth temperature-dependent differences relevant to attachment efficacy, highlight relevant proteins involved in stress protection in attached cells, and suggest that strain differences and growth conditions are important in relation to environmental persistence. PMID- 25516394 TI - Recurrent symptoms after Heller myotomy for achalasia: evaluation and treatment. AB - A laparoscopic Heller myotomy with partial fundoplication is considered today in most centers in the United States and abroad the treatment of choice for patients with esophageal achalasia. Even though the operation has initially a very high success rate, dysphagia eventually recurs in some patients. In these cases, it is important to perform a careful work-up to identify the cause of the failure and to design a tailored treatment plan by either endoscopic means or revisional surgery. The best results are obtained by a team approach, in Centers where radiologists, gastroenterologists, and surgeons have experience in the diagnosis and treatment of this disease. PMID- 25516395 TI - A randomized, single-blinded, prospective study that compares complications between cuffed and uncuffed nasal endotracheal tubes of different sizes and brands in pediatric patients. AB - STUDY OBJECTIVE: To compare any association between the problematic distal placement of cuffed and uncuffed nasal endotracheal tubes (NETTs) of different sizes and brands in pediatric patients. DESIGN: Randomized, single-blinded, prospective study. SETTING: Operating room at The Children's Hospital. PATIENTS: Pediatric patients (aged 2-18 years) scheduled for dental surgery under general anesthesia whose American Society of Anesthesiologists physical status is not greater than 2. INTERVENTION: Patients were randomly assigned to preformed cuffed (1) RAE (Ring-Adair-Elwyn) endotracheal tube by Mallinckrodt or (2) nasal AGT NETT by Rusch. MEASUREMENTS: The distance between the tube's distal end and the carina was measured using a fiber optic bronchoscope. Problematic placements were defined where the tip of the tubes was within 0.5 cm of carina. MAIN RESULTS: The odds of a problematic placement was 7 times higher (95% confidence interval of odds ratio, 2.06, 23.4) in patients managed with cuffed tubes than those with uncuffed tubes (P = .002). The distance between the tip of cuffed NETT tubes and carina was significantly less than with uncuffed tubes. CONCLUSIONS: The chances of possible complications were significantly higher with cuffed NETT. The NETT should be kept at least 0.5 cm above carina to avoid possible complications. PMID- 25516397 TI - Differences in physicochemical properties to consider in the design, evaluation and choice between microparticles and nanoparticles for drug delivery. AB - INTRODUCTION: The increase in the development of novel nanoparticle drug delivery systems makes the choice between micro- and nanoscale drug delivery systems ubiquitous. Changes in physical and chemical properties between micro- to nanosized particles give them different properties that influence their physiological, anatomical and clinical behavior and therefore potential application. AREAS COVERED: This review focuses on the effect changes in the surface-to-volume ratio have on the thermal properties, solubility, dissolution and crystallization of micro- versus nanosized drug delivery systems. With these changes in the physicochemical properties in mind, the review covers computational and biophysical approaches to the design and evaluation of micro- and nanodelivery systems. The emphasis of the review is on the effect these properties have on clinical performance in terms of drug release, tissue retention, biodistribution, efficacy, toxicity and therefore choice of delivery system. EXPERT OPINION: Ultimately, the choice between micro- and nanometer-sized delivery systems is not straightforward. However, if the fundamental differences in physical and chemical properties are considered, it can be much easier to make a rational choice of the appropriate drug delivery system size. PMID- 25516396 TI - Sugammadex and pregnancy, is it safe? PMID- 25516398 TI - Early-onset heart failure, alopecia, and cutaneous abnormalities associated with a novel compound heterozygous mutation in desmoplakin. AB - Mutations in the desmosomal protein desmoplakin have been associated with various conditions affecting the skin and heart. The prototype is Carvajal syndrome, characterized by cardiomyopathy, woolly hair, palmoplantar keratoderma (PPK), and skin fragility. We report the case of a 3-year-old boy presenting with severe left-sided heart failure with a preceding history of cutaneous abnormalities including congenital alopecia, PPK, nail dystrophy, and follicular hyperkeratosis on the extensor surfaces. Genetic testing revealed a novel combination of two heterozygous mutations in the DSP gene encoding desmoplakin: R1400X and R2284X. Both are predicted to be deleterious to protein function. This case adds to our understanding of the spectrum of clinical presentations of syndromes associated with desmoplakin mutations and highlights the need for cardiac examination in patients with characteristic cutaneous findings. PMID- 25516400 TI - Reconstruction of distal hand and foot defects with the free proximal peroneal artery perforator flap. AB - BACKGROUND: The proximal peroneal artery perforator (PPAP) flap is a reliable, thin fasciocutaneous flap. The purpose of this article was to report our experience with the use of free PPAP flaps for reconstruction of defects of the distal hand and foot. PATIENTS AND METHODS: From November 2012 to September 2013, 9 patients received reconstruction with 10 free PPAP flaps. The defect locations included the big toe (2 cases), metatarsophalangeal joint (5 cases), dorsal finger (2 cases) and volar finger (1 case). Flaps were raised based on proximal peroneal perforator vessels without sacrificing the peroneal artery. The first dorsal metatarsal artery (5 cases) and digital artery (5 cases) were dissected as recipient vessels. RESULTS: The flap sizes varied from 2.5 x 2 cm to 9 x 5 cm. All of flaps were survival after surgery. One flap suffered from venous thrombosis and was successfully salvaged by performing a venous thrombectomy and vein graft. The donor sites were all primarily closed with minimal morbidities. Follow-up observations were conducted for 7 to 20 months, and all patients had good functional recovery with satisfying cosmetic results. CONCLUSION: Perforators arising from the peroneal artery in the proximal lateral leg can be used to design small, pliable fasciocutaneous flaps. Although the pedicle is short, the vessel diameter is adequate for microvascular anastomosis to the distal foot and hand recipient vessels. The free PPAP flap may be a good option for reconstructing distal hand and foot defects. PMID- 25516401 TI - Clinical implications of growth pattern and extension of tumor-associated intraductal carcinoma of the breast. AB - Tumor specimens from 410 patients with primary invasive breast cancer were investigated to identify the clinically relevant features of tumor-associated intraductal component (IDC) surrounding invasive breast cancer. A tumor associated IDC associated with invasive tumor was mostly localized between the tumor and nipple. Thus, segmental resection of breast tissue is suggested. INTRODUCTION: The goal of the present study was to identify the clinically relevant features of tumor-associated intraductal component (IDC) surrounding invasive breast cancer. PATIENTS AND METHODS: The tumor specimens from 410 patients with primary invasive breast cancer were investigated. The distance between the surgical margins and tumor edge (invasive and intraductal areas) was measured prospectively. RESULTS: Of the 410 investigated patients, 395 were eligible for analysis. An IDC was observed in 241 specimens (61.0%) and was associated with a younger age at diagnosis, postmenopausal status, and positive estrogen receptor, progesterone receptor, and human epidermal growth factor 2 (HER2) expression status. Most cases with tumor-associated ductal carcinoma in situ (DCIS) were found in the upper-outer quadrants of the breasts. An extended intraductal component (EIC) tended to be present in the outer and lower quadrants of the breasts. In the study cohort of 187 patients with tumor-associated DCIS, 1496 surgical margins were investigated. IDC was associated with invasive tumor growth predominantly in the nipple direction. The nipple-associated growth of DCIS correlated with patient age > 40 years, tumor size <= 2 cm, poor histologic differentiation of the noninvasive and invasive components, and positive estrogen and progesterone receptor status and negative HER2 status. CONCLUSIONS: Our data provide evidence that in patients with primary breast cancer, the EIC areas will be mostly segmentally localized between the invasive tumor and the nipple. Therefore, if EIC is present or assumed, surgery should consist of segmental resection of the breast tissue, at least in patients with breast cancer who are > 40 years old, with a tumor size of < 2 cm, and with hormone receptor-positive and HER2-negative, poorly differentiated tumors. PMID- 25516399 TI - Reduced language connectivity in pediatric epilepsy. AB - OBJECTIVE: Functional connectivity (FC) among language regions is decreased in adults with epilepsy compared to controls, but less is known about FC in children with epilepsy. We sought to determine if language FC is reduced in pediatric epilepsy, and examined clinical factors that associate with language FC in this population. METHODS: We assessed FC during an age-adjusted language task in children with left-hemisphere focal epilepsy (n = 19) compared to controls (n = 19). Time series data were extracted for three left regions of interest (ROIS) and their right homologues: inferior frontal gyrus (IFG), middle frontal gyrus (MFG), and Wernicke's area (WA) using SPM8. Associations between FC and factors such as cognitive performance, language dominance, and epilepsy duration were assessed. RESULTS: Children with epilepsy showed decreased interhemispheric connectivity compared to controls, particularly between core left language regions (IFG, WA) and their right hemisphere homologues, as well as decreased intrahemispheric right frontal FC. Increased intrahemispheric FC between left IFG and left WA was a positive predictor of language skills overall, and naming ability in particular. FC of language areas was not affected by language dominance, as the effects remained only when examining participants with left language dominance. Overall FC did not differ according to duration of epilepsy or age of onset. SIGNIFICANCE: FC during a language task is reduced in children, similar to findings in adults. In specific, children with left focal epilepsy demonstrated decreased interhemispheric FC in temporal and frontal language connections and decreased intrahemispheric right frontal FC. These differences were present near the onset of epilepsy. Greater FC between left language centers is related to better language ability. Our results highlight that connectivity of language areas has a developmental pattern and is related to cognitive ability. PMID- 25516402 TI - Current HER2 Testing Recommendations and Clinical Relevance as a Predictor of Response to Targeted Therapy. AB - Clinical decision-making in the treatment of breast cancer depends on an accurate determination and understanding of human epidermal growth factor receptor 2 (HER2) status. The guidelines for HER2 testing were recently updated in late 2013, but limitations continue to exist in the interpretation and clinical application of results when the tumor specimens do not fall neatly into positive or negative categories with immunohistochemistry and fluorescence in situ hybridization testing. The issues, including discordance between pathologists or laboratories, polysomy, and genetic heterogeneity, present challenging situations that are difficult to translate into clinical significance. The present review discussed the changes in the updated American Society of Clinical Oncology/College of American Pathologists guidelines, the clinical relevance of complex issues in HER2 testing, and the implications of the results on the response to HER2-targeted therapies. Great advances have been made in the treatment of HER2-positive breast cancer; however, the challenge remains to determine the best testing analysis that will identify patients who will benefit the most from these therapies. PMID- 25516404 TI - Application of high-intensity ultrasound to palm oil in a continuous system. AB - High-intensity ultrasound (HIU) was used in a continuous system to change the crystallization behavior of palm oil. Different power levels (75, 110, and 180 W) and pulse durations (continuous application and 5, 10, and 15 s pulses) were used to optimize sonication conditions. Results showed that HIU applied at low power level (75 W) was the most efficient condition in inducing palm oil crystallization at 35 degrees C, generating a crystalline network with higher solid fat content (SFC), higher elasticity, and sharper melting profile after 60 min of crystallization. Changes in elasticity observed as a consequence of sonication were maintained after tempering the samples at 25 degrees C for 24 h, but were lost after tempering at 5 degrees C. No significant differences (alpha = 0.05) were observed in SFC values of the sonicated and nonsonicated samples after tempering, whereas the sharper melting behavior observed in the sonicated sample was maintained after tempering. PMID- 25516403 TI - Design of an allosterically regulated retroaldolase. AB - We employed a minimalist approach for design of an allosterically controlled retroaldolase. Introduction of a single lysine residue into the nonenzymatic protein calmodulin led to a 15,000-fold increase in the second order rate constant for retroaldol reaction with methodol as a substrate. The resulting catalyst AlleyCatR is active enough for subsequent directed evolution in crude cell bacterial lysates. AlleyCatR's activity is allosterically regulated by Ca(2+) ions. No catalysis is observed in the absence of the metal ion. The increase in catalytic activity originates from the hydrophobic interaction of the substrate (~2000-fold) and the change in the apparent pKa of the active lysine residue. PMID- 25516405 TI - The effectiveness of exercise as treatment for vasomotor menopausal symptoms: randomised controlled trial. AB - OBJECTIVE: To investigate the effectiveness of exercise as treatment for vasomotor menopausal symptoms. DESIGN: Three-group randomised controlled trial, two exercise interventions and a control group. SETTING: Primary Care, West Midlands UK. POPULATION: Perimenopausal and postmenopausal women experiencing at least five hot flushes/night sweats per day and not taken MHT in previous 3 months were recruited from 23 general practices. METHODS: Participants in both exercise interventions groups were offered two face-to-face consultations with a physical activity facilitator to support engagement in regular exercise. In addition, one exercise group received a menopause-specific information DVD and written materials to encourage regular exercise and the other exercise group was offered the opportunity to attend exercise social support groups in their communities. Interventions lasted 6 months. MAIN OUTCOME MEASURE: The primary outcome was frequency of hot flushes/night sweats at 6-month up. RESULTS: Two hundred and sixty-one women were randomised (n = 87 per group). Neither of the exercise intervention groups reported significantly less frequent hot flushes/night sweats per week than controls (exercise-DVD versus control: -8.9, 95% CI -20.0 to 2.2; exercise-social support versus control: -5.2, 95% CI -16.7 to 6.3). CONCLUSIONS: This trial indicates that exercise is not an effective treatment for hot flushes/night sweats. Contrary to current clinical guidance, women should not be advised that exercise will relieve their vasomotor menopausal symptoms. PMID- 25516406 TI - Epidermal growth factor receptor-targeted lipid nanoparticles retain self assembled nanostructures and provide high specificity. AB - Next generation drug delivery utilising nanoparticles incorporates active targeting to specific sites. In this work, we combined targeting with the inherent advantages of self-assembled lipid nanoparticles containing internal nano-structures. Epidermal growth factor receptor (EGFR)-targeting, PEGylated lipid nanoparticles using phytantriol and 1,2-distearoyl-sn-glycero-3 phosphoethanolamine-PEG-maleimide amphiphiles were created. The self-assembled lipid nanoparticles presented here have internal lyotropic liquid crystalline nano-structures, verified by synchrotron small angle X-ray scattering and cryo transmission electron microscopy, that offer the potential of high drug loading and enhanced cell penetration. Anti-EGFR Fab' fragments were conjugated to the surface of nanoparticles via a maleimide-thiol reaction at a high conjugation efficiency and retained specificity following conjugation to the nanoparticles. The conjugated nanoparticles were demonstrated to have high affinity for an EGFR target in a ligand binding assay. PMID- 25516407 TI - Improving weight of evidence approaches to chemical evaluations. AB - Federal and other regulatory agencies often use or claim to use a weight of evidence (WoE) approach in chemical evaluation. Their approaches to the use of WoE, however, differ significantly, rely heavily on subjective professional judgment, and merit improvement. We review uses of WoE approaches in key articles in the peer-reviewed scientific literature, and find significant variations. We find that a hypothesis-based WoE approach, developed by Lorenz Rhomberg et al., can provide a stronger scientific basis for chemical assessment while improving transparency and preserving the appropriate scope of professional judgment. Their approach, while still evolving, relies on the explicit specification of the hypothesized basis for using the information at hand to infer the ability of an agent to cause human health impacts or, more broadly, affect other endpoints of concern. We describe and endorse such a hypothesis-based WoE approach to chemical evaluation. PMID- 25516408 TI - MitImpact: an exhaustive collection of pre-computed pathogenicity predictions of human mitochondrial non-synonymous variants. AB - Mitochondrial DNA carries a tiny, but fundamental portion of the eukaryotic genetic code. As its nuclear counterpart, it is susceptible to point mutations. Their level of pathogenicity has been assessed for the newly discovered mutations only, leaving some degree of uncertainty on the potential impact of the unknown mutations. Here we present Mitochondrial mutation Impact (MitImpact), a queryable lightweight web interface to a reasoned collection of structurally and evolutionary annotated pathogenicity predictions, obtained by assembling pre computed with on-the-fly-computed sets of pathogenicity estimations, for all the possible mitochondrial missense variants. It presents itself as a resource for fast and reliable evaluation of gene-specific susceptibility of unknown and verified amino acid changes. MitImpact is freely available at http://bioinformatics.css-mendel.it/ (tools section). (c)2014 Wiley Periodicals, Inc. PMID- 25516409 TI - Banking on iPSC--is it doable and is it worthwhile. AB - The discovery of induced pluripotent stem cells (iPSCs) and concurrent development of protocols for their cell-type specific differentiation have revolutionized studies of diseases and raised the possibility that personalized medicine may be achievable. Realizing the full potential of iPSC will require addressing the challenges inherent in obtaining appropriate cells for millions of individuals while meeting the regulatory requirements of delivering therapy and keeping costs affordable. Critical to making PSC based cell therapy widely accessible is determining which mode of cell collection, storage and distribution, will work. In this manuscript we suggest that moderate sized bank where a diverse set of lines carrying different combinations of commonly present HLA alleles are banked and differentiated cells are made available to matched recipients as need dictates may be a solution. We discuss the issues related to developing such a bank and how it could be constructed and propose a bank of selected HLA phenotypes from carefully screened healthy individuals as a solution to delivering personalized medicine. PMID- 25516410 TI - Finite element analysis of the pressure-induced deformation of Schlemm's canal endothelial cells. AB - The endothelial cells lining the inner wall of Schlemm's canal (SC) in the eye are relatively unique in that they support a basal-to-apical pressure gradient that causes these cells to deform, creating giant vacuoles and transendothelial pores through which the aqueous humor flows. Glaucoma is associated with an increased resistance to this flow. We used finite element modeling and estimates of cell modulus made using atomic force microscopy to characterize the pressure induced deformation of SC cells and to estimate the maximum pressure drop that SC cells can support. We examined the effects of cell geometry, cell stiffness, and the contribution of the cell cortex to support the pressure-generated load. We found that the maximum strain generated by this loading occurs at the points of cell-substrate attachment and that the cortex of the cells bears nearly all of this load. The ability of these cells to support a significant transcellular pressure drop is extremely limited (on the order of 5 mmHg or less) unless these cells either stiffen very considerably with increasing deformation or have substantial attachments to their substratum away from their periphery. This puts limits on the flow resistance that this layer can generate, which has implications regarding the site where the bulk of the flow resistance is generated in healthy and glaucomatous eyes. PMID- 25516411 TI - Value of allohaemagglutinins in the diagnosis of a polysaccharide antibody deficiency. AB - Polysaccharide antibody deficiency is characterized by a poor or absent antibody response after vaccination with an unconjugated pneumococcal polysaccharide vaccine. Allohaemagglutinins (AHA) are antibodies to A or B polysaccharide antigens on the red blood cells, and are often used as an additional or alternative measure to assess the polysaccharide antibody response. However, few studies have been conducted to establish the clinical significance of AHA. To investigate the value of AHA to diagnose a polysaccharide antibody deficiency, pneumococcal polysaccharide antibody titres and AHA were studied retrospectively in 180 subjects in whom both tests had been performed. Receiver operating characteristic curves for AHA versus the pneumococcal vaccine response as a marker for the anti-polysaccharide immune response revealed an area under the curve between 0.5 and 0.573. Sensitivity and specificity of AHA to detect a polysaccharide antibody deficiency, as diagnosed by vaccination response, were low (calculated for cut-off 1/4-1/32). In subjects with only low pneumococcal antibody response, the prevalence of bronchiectasis was significantly higher than in subjects with only low AHA (45.5 and 1.3%, respectively) or normal pneumococcal antibody response and AHA (2.4%). A logistic regression model showed that low pneumococcal antibody response but not AHA was associated with bronchiectasis (odds ratio 46.2). The results of this study do not support the routine use of AHA to assess the polysaccharide antibody response in patients with suspected immunodeficiency, but more studies are warranted to clarify the subject further. PMID- 25516413 TI - Narrative message targets within the decision-making process to undergo screening colonoscopy among Latinos: a qualitative study. AB - Colorectal cancer (CRC) is a preventable yet leading cause of cancer mortality among Latinos in the USA. Cultural targeting and narrative messaging are two strategies to increase the low screening colonoscopy rates among Latinos. This study identifies key messages for educational interventions aiming to increase screening colonoscopy used among Latinos and proposes a model to understand the relationship between factors involved in colonoscopy decision-making. Individual in-depth interviews were conducted with 12 Latino participants primarily of Puerto Rican descent on the topics of CRC knowledge, barriers and facilitators to colonoscopy use, and the use of narrative in colorectal health messaging. Knowledge about colorectal anatomy and the anesthesia component of colonoscopy procedure is low. Fear of procedure-related pain and fear of treatment-related burden following a cancer diagnosis are significant barriers to colonoscopy. Fear of disease-related suffering and death following a cancer diagnosis and fear of regret are strong facilitators and can be augmented by cancer narratives. Storytelling is commonly used in Latino culture and is an acceptable method to educate the Latino community about CRC screening via colonoscopy. Machismo is a unique barrier to colonoscopy for Latino men via homophobia and reluctance to seek healthcare. A preliminary model to understand factors in colonoscopy decision-making among Latinos is presented. Counseling practices and educational interventions that use culturally targeted narrative health messaging to mediate fears and increase colonoscopy knowledge may increase screening colonoscopy use among Latinos. PMID- 25516412 TI - Evaluation of a 49 InDel Marker HID panel in two specific populations of South America and one population of Northern Africa. AB - The majority of STR loci are not ideal for the analysis of forensic samples with degraded and/or low template DNA. One alternative to overcome these limitations is the use of bi-allelic markers, which have low mutation rates and shorter amplicons. Human identification (HID) InDel marker panels have been described in several countries, including Brazil. The commercial kit available is, however, mostly suitable for Europeans, with lower discrimination power for other population groups. Recently, a combination of 49 InDel markers used in four different ethnic groups in the USA has been shown to be more informative than another panel from Portugal, already tested in a Rio de Janeiro sample. However, these 49 InDels have yet to be applied to other admixed or isolated populations. We assessed the efficiency of this panel in two urban admixed populations (Rio de Janeiro, Brazil; Tripoli, Libya) and one isolated Native Brazilian community. All markers are in Hardy-Weinberg equilibrium (HWE) after the Bonferroni correction, and no Linkage disequilibrium was detected. Assuming loci independence and no substructure effect, cumulative RMP was 2.7*10(-18), 1.5*10(-20), and 4.5*10(-20) for Native Brazilian, Rio de Janeiro, and Tripoli populations, respectively. The overall Fst value was 0.05512. Rio de Janeiro and Tripoli showed similar admixture levels, however for Native Brazilians one parental cluster represented over 60 % of the total parental population. We conclude that this panel is suitable for HID on these urban populations, but is less efficient for the isolated group. PMID- 25516414 TI - Pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of monoclonal antibodies in children. AB - Monoclonal antibodies (mAbs) constitute a therapeutically and economically important drug class with increasing use in both adult and paediatric patients. The rather complex pharmacokinetic and pharmacodynamic properties of mAbs have been extensively reviewed in adults. In children, however, limited information is currently available. This paper aims to comprehensively review published pharmacokinetic and pharmacokinetic-pharmacodynamic studies of mAbs in children. The current status of mAbs in the USA and in Europe is outlined, including a critical discussion of the dosing strategies of approved mAbs. The pharmacokinetic properties of mAbs in children are exhaustively summarised along with comparisons to reports in adults: for each pharmacokinetic process, we discuss the general principles and mechanisms of the pharmacokinetic/pharmacodynamic characteristics of mAbs, as well as key growth and maturational processes in children that might impact these characteristics. Throughout this review, considerable knowledge gaps are identified, especially regarding children-specific properties that influence pharmacokinetics, pharmacodynamics and immunogenicity. Furthermore, the large heterogeneity in the presentation of pharmacokinetic/pharmacodynamic data limited clinical inferences in many aspects of paediatric mAb therapy. Overall, further studies are needed to fully understand the impact of body size and maturational changes on drug exposure and response. To maximise future knowledge gain, we propose a 'Guideline for Best Practice' on how to report pharmacokinetic and pharmacokinetic pharmacodynamic results from mAb studies in children which also facilitates comparisons. Finally, we advocate the use of more sophisticated modelling strategies (population analysis, physiology-based approaches) to appropriately characterise pharmacokinetic-pharmacodynamic relationships of mAbs and, thus, allow for a more rational use of mAb in the paediatric population. PMID- 25516415 TI - Assessment of the Influence of Inflammation and FCGR3A Genotype on Infliximab Pharmacokinetics and Time to Relapse in Patients with Crohn's Disease. AB - BACKGROUND AND OBJECTIVES: Infliximab is a monoclonal anti-tumor necrosis factor alpha (anti-TNFalpha) antibody that profoundly modified the treatment of Crohn's disease (CD). The polymorphism of Fc fragment of IgG, low affinity IIIa, receptor (CD16a) [FCGR3A] influences the biological response to infliximab in patients with CD. Our aim was to study its influence on infliximab pharmacokinetics and risk of relapse after infliximab discontinuation. METHODS: In 111 CD patients in remission, infliximab was discontinued and its concentrations were measured for 30 months or until relapse. Infliximab pharmacokinetics were described using monocompartmental population modeling. RESULTS: The elimination rate of infliximab increased with C-reactive protein (CRP) [p = 0.00018] and was 16 % higher in FCGR3A-158V/V patients than in F carriers (p = 0.0028). Risk of relapse was higher in patients with baseline CRP >=5 mg/L than in those with a lower value (p = 0.0000029). In addition, there was a first-order interaction between CRP and the FCGR3A genotype; in patients with high CRP, risk of relapse was higher for V/V patients than for F carriers (hazard ratio 4.80 and 2.84 for V/V and F carriers, respectively; p = 0.013). CONCLUSION: Both increased inflammation and FCGR3A-158V/V genotype are associated with increased infliximab elimination and risk of relapse after infliximab discontinuation in patients with CD. PMID- 25516416 TI - Host genetics and diet, but not immunoglobulin A expression, converge to shape compositional features of the gut microbiome in an advanced intercross population of mice. AB - BACKGROUND: Individuality in the species composition of the vertebrate gut microbiota is driven by a combination of host and environmental factors that have largely been studied independently. We studied the convergence of these factors in a G10 mouse population generated from a cross between two strains to search for quantitative trait loci (QTLs) that affect gut microbiota composition or ileal Immunoglobulin A (IgA) expression in mice fed normal or high-fat diets. RESULTS: We found 42 microbiota-specific QTLs in 27 different genomic regions that affect the relative abundances of 39 taxa, including four QTL that were shared between this G10 population and the population previously studied at G4. Several of the G10 QTLs show apparent pleiotropy. Eight of these QTLs, including four at the same site on chromosome 9, show significant interaction with diet, implying that diet can modify the effects of some host loci on gut microbiome composition. Utilization patterns of IghV variable regions among IgA-specific mRNAs from ileal tissue are affected by 54 significant QTLs, most of which map to a segment of chromosome 12 spanning the Igh locus. Despite the effect of genetic variation on IghV utilization, we are unable to detect overlapping microbiota and IgA QTLs and there is no significant correlation between IgA variable pattern utilization and the abundance of any of the taxa from the fecal microbiota. CONCLUSIONS: We conclude that host genetics and diet can converge to shape the gut microbiota, but host genetic effects are not manifested through differences in IgA production PMID- 25516417 TI - Glutathione peroxidase 4 is reversibly induced by HCV to control lipid peroxidation and to increase virion infectivity. AB - OBJECTIVE: Inflammation and oxidative stress drive disease progression in chronic hepatitis C (CHC) towards hepatocellular carcinoma. HCV is known to increase intracellular levels of reactive oxygen species (ROS), but how it eliminates ROS is less well known. The role of the ROS scavenger glutathione peroxidase 4 (GPx4), induced by HCV, in the viral life cycle was analysed. DESIGN: The study was performed using a replicative in vitro HCV infection model and liver biopsies derived from two different CHC patient cohorts. RESULTS: A screen for HCV-induced peroxide scavengers identified GPx4 as a host factor required for HCV infection. The physiological role of GPx4 is the elimination of lipid peroxides from membranes or lipoproteins. GPx4-silencing reduced the specific infectivity of HCV by up to 10-fold. Loss of infectivity correlated with 70% reduced fusogenic activity of virions in liposome fusion assays. NS5A was identified as the protein that mediates GPx4 induction in a phosphatidylinositol-3-kinase-dependent manner. Levels of GPx4 mRNA were found increased in vitro and in CHC compared with control liver biopsies. Upon successful viral eradication, GPx4 transcript levels returned to baseline in vitro and also in the liver of patients. CONCLUSIONS: HCV induces oxidative stress but controls it tightly by inducing ROS scavengers. Among these, GPx4 plays an essential role in the HCV life cycle. Modulating oxidative stress in CHC by specifically targeting GPx4 may lower specific infectivity of virions and prevent hepatocarcinogenesis, especially in patients who remain difficult to be treated in the new era of interferon-free regimens. PMID- 25516418 TI - Value of endoscopy and MRI for predicting intestinal surgery in patients with Crohn's disease in the era of biologics. AB - OBJECTIVE: Severe endoscopic lesions (SEL) in patients with colonic Crohn's disease (CD) have been linked to higher risk of colectomy. The aims of this study were to reassess the predictive value of colonoscopy compared against MRI for requirement of resection surgery in patients with CD and determine the influence of current therapeutic options. DESIGN: In this single-centre, observational, prospective, longitudinal study, patients with an established diagnosis of CD and suspected activity were included. After baseline assessment, including colonoscopy and MRI, patients were followed until resection surgery or the end of study. RESULTS: 112 patients were eligible for analysis. Ulcers were present in 94/112 (84%) of patients at colonoscopy (SELs in 51/112 (46%)) and stenosis in 38/112 (34%). MRI identified ulcers in 79/112 (71%) of patients, stenosis in 36/112 (32%) and intra-abdominal fistulae in 20/112 (18%). Surgical resection requirements (29/112 (26%)) were not associated with the presence of SELs at colonoscopy. The presence of stenosis (p<0.001) or intra-abdominal fistulae (p<0.001) at MRI correlated with a higher risk of surgery. In the multivariate analysis, perianal disease (OR 9 (2 to 39), p=0.003), stenosis (OR 3.4 (1 to 11), p=0.04) and fistulae at MRI (OR 10.6 (2 to 46), p=0.002) increased the risk of abdominal resection surgery, while months under immunomodulators (OR 0.94 (0.90 to 0.98), p=0.002) and/or antitumor necrosis factor (anti-TNF) therapy (OR 0.97 (0.94 to 1), p=0.04) during follow-up decreased this risk. CONCLUSIONS: Perianal disease, stenosis and/or intra-abdominal fistulae at MRI independently predict an increased risk of resection surgery in patients with CD, whereas immunosuppressants and/or anti-TNF therapy reduce such risk. Under current therapeutic strategies, the presence of SELs is not a predictor of resection surgery in patients with CD. PMID- 25516419 TI - Increased expression of GDF-15 may mediate ICU-acquired weakness by down regulating muscle microRNAs. AB - RATIONALE: The molecular mechanisms underlying the muscle atrophy of intensive care unit-acquired weakness (ICUAW) are poorly understood. We hypothesised that increased circulating and muscle growth and differentiation factor-15 (GDF-15) causes atrophy in ICUAW by changing expression of key microRNAs. OBJECTIVES: To investigate GDF-15 and microRNA expression in patients with ICUAW and to elucidate possible mechanisms by which they cause muscle atrophy in vivo and in vitro. METHODS: In an observational study, 20 patients with ICUAW and seven elective surgical patients (controls) underwent rectus femoris muscle biopsy and blood sampling. mRNA and microRNA expression of target genes were examined in muscle specimens and GDF-15 protein concentration quantified in plasma. The effects of GDF-15 on C2C12 myotubes in vitro were examined. MEASUREMENTS AND MAIN RESULTS: Compared with controls, GDF-15 protein was elevated in plasma (median 7239 vs 2454 pg/mL, p=0.001) and GDF-15 mRNA in the muscle (median twofold increase p=0.006) of patients with ICUAW. The expression of microRNAs involved in muscle homeostasis was significantly lower in the muscle of patients with ICUAW. GDF-15 treatment of C2C12 myotubes significantly elevated expression of muscle atrophy-related genes and down-regulated the expression of muscle microRNAs. miR 181a suppressed transforming growth factor-beta (TGF-beta) responses in C2C12 cells, suggesting increased sensitivity to TGF-beta in ICUAW muscle. Consistent with this suggestion, nuclear phospho-small mothers against decapentaplegic (SMAD) 2/3 was increased in ICUAW muscle. CONCLUSIONS: GDF-15 may increase sensitivity to TGF-beta signalling by suppressing the expression of muscle microRNAs, thereby promoting muscle atrophy in ICUAW. This study identifies both GDF-15 and associated microRNA as potential therapeutic targets. PMID- 25516420 TI - Induction of telomere dysfunction mediated by the telomerase substrate precursor 6-thio-2'-deoxyguanosine. AB - The relationships between telomerase and telomeres represent attractive targets for new anticancer agents. Here, we report that the nucleoside analogue 6-thio-2' deoxyguanosine (6-thio-dG) is recognized by telomerase and is incorporated into de novo-synthesized telomeres. This results in modified telomeres, leading to telomere dysfunction, but only in cells expressing telomerase. 6-Thio-dG, but not 6-thioguanine, induced telomere dysfunction in telomerase-positive human cancer cells and hTERT-expressing human fibroblasts, but not in telomerase-negative cells. Treatment with 6-thio-dG resulted in rapid cell death for the vast majority of the cancer cell lines tested, whereas normal human fibroblasts and human colonic epithelial cells were largely unaffected. In A549 lung cancer cell based mouse xenograft studies, 6-thio-dG caused a decrease in the tumor growth rate superior to that observed with 6-thioguanine treatment. In addition, 6-thio dG increased telomere dysfunction in tumor cells in vivo. These results indicate that 6-thio-dG may provide a new telomere-addressed telomerase-dependent anticancer approach. SIGNIFICANCE: Telomerase is an almost universal oncology target, yet there are few telomerase-directed therapies in human clinical trials. In the present study, we demonstrate a small-molecule telomerase substrate approach that induces telomerase-mediated targeted "telomere uncapping," but only in telomerase-positive cancer cells, with minimal effects in normal telomerase negative cells. PMID- 25516422 TI - Bovine Neonatal Pancytopenia is a heritable trait of the dam rather than the calf and correlates with the magnitude of vaccine induced maternal alloantibodies not the MHC haplotype. AB - Bovine Neonatal Pancytopenia (BNP), a bleeding syndrome of neonatal calves, is caused by alloantibodies absorbed from the colostrum of particular cows. A commercial BVD vaccine is the likely source of alloantigens eliciting BNP associated alloantibodies. We hypothesized that the rare occurrence of BNP in calves born to vaccinated dams could be associated with genetic differences within dams and calves. We found that the development of BNP within calves was a heritable trait for dams, not for calves and had a high heritability of 19%. To elucidate which genes play a role in the development of BNP we sequenced candidate genes and characterized BNP alloantibodies. Alloantigens present in the vaccine have to be presented to the dam's immune system via MHC class II, however sequencing of DRB3 showed no differences in MHC class II haplotype between BNP and non-BNP dams. MHC class I, a highly polymorphic alloantigen, is an important target of BNP alloantibodies. Using a novel sequence based MHC class I typing method, we found no association of BNP with MHC class I haplotype distribution in dams or calves. Alloantibodies were detected in both vaccinated BNP and non-BNP dams and we found no differences in alloantibody characteristics between these groups, but alloantibody levels were significantly higher in BNP dams. We concluded that the development of BNP in calves is a heritable trait of the dam rather than the calf and genetic differences between BNP and non-BNP dams are likely due to genes controlling the quantitative alloantibody response following vaccination. PMID- 25516423 TI - Psychoeducation to facilitate return to work in individuals on sick leave and at risk of having a mental disorder: protocol of a randomised controlled trial. AB - BACKGROUND: Sickness absence due to poor mental health is a common problem in many Western countries. To facilitate return to work, it may be important to identify individuals on sick leave and at risk of having a mental disorder and subsequently to offer appropriate treatment. Psychoeducation alone has not previously been used as a return to work intervention, but may be a promising tool to facilitate return to work. Therefore, the aim of the study is to evaluate the effectiveness of psychoeducation designed specifically to facilitate return to work for individuals on sick leave and at risk of having a mental disorder. The psychoeducation was a supplement to the various standard offers provided by the job centres. METHODS/DESIGN: The study is a randomised controlled trial, in which individuals on sick leave either receive psychoeducation and standard case management or standard case management alone. Participants were individuals with mental health symptoms, who had been on sick leave from part-time or full-time work or unemployment for about 4-8 weeks. The psychoeducational intervention was group-based and the course consisted of 2 hour sessions once a week for 6 weeks. The course was given by psychiatric nurses, a psychologist, a social worker, a physiotherapist and a person who had previously been on sick leave due to mental health problems. The sessions focused on stress and work life, and the purpose was to provide individuals on sick leave the skills to understand and improve their mental functioning.The primary outcome is the duration of sickness absence measured by register data. Secondary outcomes include psychological symptoms, mental health-related quality of life, and locus of control. These outcomes are measured by questionnaires at the start of the intervention and at 3 and 6 months follow-up. DISCUSSION: On the basis of this trial, the effect of psychoeducation for individuals on sick leave and at risk of having a mental disorder will be studied. The results will contribute to the continuing research on sickness absence and mental health. It will primarily show whether psychoeducation can lead to faster and sustainable return to work. TRIAL REGISTRATION: Clinical Trial.gov NCT01637363. Registered 6 July 2012. PMID- 25516425 TI - The development of emotion concepts: a story superiority effect in older children and adolescents. AB - Contrary to traditional assumptions, young children are more likely to correctly label someone's emotion from a story that describes the causes and consequences of the emotion than from the person's facial expression. This story superiority effect was examined in a sample of older children and adolescents (N=90, 8-20 years) for the emotions of fear, disgust, shame, embarrassment, and pride. Participants freely labeled the emotion they inferred from a story describing a cause and consequence of each emotion and, separately, from the corresponding facial expression. In each of five age groups, the expected emotion label was used for the emotion story significantly more than for the corresponding facial expression (except for pride). The story superiority effect is strong from childhood to early adulthood and opens the door to new accounts of how emotion concepts develop. PMID- 25516421 TI - Non-invasive control interfaces for intention detection in active movement assistive devices. AB - Active movement-assistive devices aim to increase the quality of life for patients with neuromusculoskeletal disorders. This technology requires interaction between the user and the device through a control interface that detects the user's movement intention. Researchers have explored a wide variety of invasive and non-invasive control interfaces. To summarize the wide spectrum of strategies, this paper presents a comprehensive review focused on non-invasive control interfaces used to operate active movement-assistive devices. A novel systematic classification method is proposed to categorize the control interfaces based on: (I) the source of the physiological signal, (II) the physiological phenomena responsible for generating the signal, and (III) the sensors used to measure the physiological signal. The proposed classification method can successfully categorize all the existing control interfaces providing a comprehensive overview of the state of the art. Each sensing modality is briefly described in the body of the paper following the same structure used in the classification method. Furthermore, we discuss several design considerations, challenges, and future directions of non-invasive control interfaces for active movement-assistive devices. PMID- 25516424 TI - Hydrogen bond network between amino acid radical intermediates on the proton coupled electron transfer pathway of E. coli alpha2 ribonucleotide reductase. AB - Ribonucleotide reductases (RNRs) catalyze the conversion of ribonucleotides to deoxyribonucleotides in all organisms. In all Class Ia RNRs, initiation of nucleotide diphosphate (NDP) reduction requires a reversible oxidation over 35 A by a tyrosyl radical (Y122*, Escherichia coli) in subunit beta of a cysteine (C439) in the active site of subunit alpha. This radical transfer (RT) occurs by a specific pathway involving redox active tyrosines (Y122 ? Y356 in beta to Y731 ? Y730 ? C439 in alpha); each oxidation necessitates loss of a proton coupled to loss of an electron (PCET). To study these steps, 3-aminotyrosine was site specifically incorporated in place of Y356-beta, Y731- and Y730-alpha, and each protein was incubated with the appropriate second subunit beta(alpha), CDP and effector ATP to trap an amino tyrosyl radical (NH2Y*) in the active alpha2beta2 complex. High-frequency (263 GHz) pulse electron paramagnetic resonance (EPR) of the NH2Y*s reported the gx values with unprecedented resolution and revealed strong electrostatic effects caused by the protein environment. (2)H electron nuclear double resonance (ENDOR) spectroscopy accompanied by quantum chemical calculations provided spectroscopic evidence for hydrogen bond interactions at the radical sites, i.e., two exchangeable H bonds to NH2Y730*, one to NH2Y731* and none to NH2Y356*. Similar experiments with double mutants alpha-NH2Y730/C439A and alpha-NH2Y731/Y730F allowed assignment of the H bonding partner(s) to a pathway residue(s) providing direct evidence for colinear PCET within alpha. The implications of these observations for the PCET process within alpha and at the interface are discussed. PMID- 25516427 TI - Simulation of in vivo dynamics during robot assisted joint movement. AB - BACKGROUND: Robots are very useful tools in orthopedic research. They can provide force/torque controlled specimen motion with high repeatability and precision. A method to analyze dissipative energy outcome in an entire joint was developed in our group. In a previous study, a sheep knee was flexed while axial load remained constant during the measurement of dissipated energy. We intend to apply this method for the investigation of osteoarthritis. Additionally, the method should be improved by simulation of in vivo knee dynamics. Thus, a new biomechanical testing tool will be developed for analyzing in vitro joint properties after different treatments. METHODS: Discretization of passive knee flexion was used to construct a complex flexion movement by a robot and simulate altering axial load similar to in vivo sheep knee dynamics described in a previous experimental study. RESULTS: The robot applied an in vivo like axial force profile with high reproducibility during the corresponding knee flexion (total standard deviation of 0.025 body weight (BW)). A total residual error between the in vivo and simulated axial force was 0.16 BW. Posterior-anterior and medio-lateral forces were detected by the robot as a backlash of joint structures. Their curve forms were similar to curve forms of corresponding in vivo measured forces, but in contrast to the axial force, they showed higher total standard deviation of 0.118 and 0.203 BW and higher total residual error of 0.79 and 0.21 BW for posterior anterior and medio-lateral forces respectively. CONCLUSIONS: We developed and evaluated an algorithm for the robotic simulation of complex in vivo joint dynamics using a joint specimen. This should be a new biomechanical testing tool for analyzing joint properties after different treatments. PMID- 25516428 TI - Color vision and neuroretinal function in diabetes. AB - PURPOSE: We investigate how type 2 diabetes (T2DM) and diabetic retinopathy (DR) affect color vision (CV) and mfERG implicit time (IT), whether CV and IT are correlated, and whether CV and IT abnormality classifications agree. METHODS: Adams desaturated D-15 color test, mfERG, and fundus photographs were examined in 37 controls, 22 T2DM patients without DR (NoRet group), and 25 T2DM patients with DR (Ret group). Color confusion score (CCS) was calculated. ITs were averaged within the central 7 hexagons (central IT; <=4.5 degrees ) and outside this area (peripheral IT; >=4.5 degrees ). DR was within (DRIN) or outside (DROUT) of the central 7 hexagons. Group differences, percentages of abnormalities, correlations, and agreement were determined. RESULTS: CCS was greater in the NoRet (P = 0.002) and Ret (P < 0.0001) groups than in control group. CCS was abnormal in 3, 41, and 48 % of eyes in the control, NoRet, and Ret groups, respectively. Ret group CV abnormalities were more frequent in DRIN than in DROUT subgroups (71 vs. 18 %, respectively; P < 0.0001). CCS and IT were correlated only in the Ret group, in both retinal zones (P <= 0.028). Only in the Ret group did CCS and peripheral IT abnormality classifications agree (72 %; P < 0.05). CONCLUSION: CV is affected in patients with T2DM, even without DR. Central DR increases the likelihood of a CV deficit compared with non-central DR. mfERG IT averaged across central or peripheral retinal locations is less frequently abnormal than CV in the absence of DR, and these two measures are correlated only when DR is present. PMID- 25516430 TI - Role of VcrD1 protein in expression and secretion of flagellar components in Vibrio parahaemolyticus. AB - VcrD1 protein is a component of type III secretion system (T3SS) 1 in Vibrio parahaemolyticus. A comparative analysis of secretomes of wild-type and DeltavcrD1 strains revealed that the mutant was defective in secretion of diverse proteins including several flagellar components. Western blot analyses using specific antibodies confirmed that the secretion of at least four flagellar components, such as FlaA, FlgL, FlgE, and FlgM, was affected by the vcrD1 mutation, which was consistent with decreased motility on soft agar plates and the non-flagellated morphology of the mutant. The DeltaexsA mutant, another T3SS1 mutant, did not showed reduced motility, but became non-motile phenotype with the additional DeltavcrD1 mutation. Complementation of wild-type vcrD1 gene into DeltavcrD1 mutant resulted in restored motility. Fractionation of bacterial cytoplasm from the periplasm and membrane revealed lower levels of FlaA and FlgM in the cytoplasm of the DeltavcrD1 mutant, indicating that VcrD1 might regulate the expression of flagellar genes in addition to the secretion of flagellar components in V. parahaemolyticus. Quantitative RT-PCR assays of seven representative flagellar genes in the wild-type and DeltavcrD1 mutant strains demonstrated that transcript levels of two early flagellar genes, flaK and flaL, were not reduced by the vcrD1 mutation, whereas the middle and late flagellar genes were expressed at a lower level in the vcrD1 mutant. This study raises a possibility that VcrD1 plays a role in flagellar morphogenesis in V. parahaemolyticus by regulating the expression and secretion of flagellar components. PMID- 25516429 TI - Interferon-beta-related tumefactive brain lesion in a Caucasian patient with neuromyelitis optica and clinical stabilization with tocilizumab. AB - BACKGROUND: Neuromyelitis optica (NMO) is a severely disabling inflammatory disorder of the central nervous system and is often misdiagnosed as multiple sclerosis (MS). There is increasing evidence that treatment options shown to be beneficial in MS, including interferon-beta (IFN-beta), are detrimental in NMO. CASE PRESENTATION: We here report the first Caucasian patient with aquaporin 4 (AQP4) antibody (NMO-IgG)-seropositive NMO presenting with a tumefactive brain lesion on treatment with IFN-beta. Disease started with relapsing optic neuritis and an episode of longitudinally extensive transverse myelitis (LETM) in the absence of any brain MRI lesions or cerebrospinal fluid-restricted oligoclonal bands. After initial misdiagnosis of multiple sclerosis (MS) the patient received subcutaneous IFN-beta1b and, subsequently, subcutaneous IFN-beta1a therapy for several years. Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain hemisphere and a smaller T2 lesion on the right side. Despite rituximab therapy two further LETM episodes occurred, resulting in severe neurological deficits. Therapeutic blockade of the interleukin (IL)-6 signalling pathway by tocilizumab was initiated, followed by clinical and radiological stabilization. CONCLUSION: Our case (i) illustrates the relevance of correctly distinguishing NMO and MS since these disorders differ markedly in their responsiveness to immunomodulatory and -suppressive therapies; (ii) confirms and extends a previous report describing the development of tumefactive brain lesions under IFN-beta therapy in two Asian NMO patients; and (iii) suggests tocilizumab as a promising therapeutic alternative in highly active NMO disease courses. PMID- 25516431 TI - Paenibacillus ginsengiterrae sp. nov., a ginsenoside-hydrolyzing bacteria isolated from soil of ginseng field. AB - A novel bacterial strain DCY89(T) was isolated from soil sample of ginseng field and was characterized using a polyphasic approach. Cells were Gram-reaction positive, rod-shaped, spore-forming and motile with flagella. The strain was aerobic, esculin and starch positive, catalase- and oxidase-negative, optimum growth temperature, and pH were 25-30 degrees C and 6.0-7.5, respectively. On the basis of 16S rRNA gene sequence analysis, strain DCY89(T) was shown to belong to the genus Paenibacillus and the closest phylogenetic relatives were Paenibacillus cellulosilyticus KACC 14175(T) (98.2%), Paenibacillus kobensis KACC 15273(T) (98.1%), Paenibacillus xylaniclasticus KCTC 13719(T) (96.9%), and Paenibacillus curdlanolyticus KCTC 3759(T) (96.64%). The DNA G+C content was 52.5 mol%, and the predominant respiratory quinone was MK-7. The major fatty acids were iso-C15:0, iso-C16:0, and anteiso-C15:0. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, and phosphatidylglycerol. The results of the genotypic analysis in combination with chemotaxonomic and physiological data demonstrated that DCY89(T) represented a novel species within the genus Paenibacillus, for which we propose the name Paenibacillus ginsengiterrae. The type strain is DCY89(T) (JCM 19887(T) = KCTC 33430(T)). PMID- 25516432 TI - Bone marrow engraftment and associated dermatologic sequelae in a three-yr-old after liver transplantation. AB - We present a case of a three-yr-old child with a history of multisystem Langerhans cell histiocytosis treated with systemic chemotherapy, who developed progressive liver failure and received an orthotopic split liver transplant while continuing on chemotherapy. One month following transplant, he developed acute graft-vs.-host disease of the skin and gastrointestinal tract. Peripheral blood chimerism studies post-transplant demonstrated an increasing predominance of donor lymphocytes and granulocytes. Shortly after, the patient developed vitiligo, and two yr after transplantation, the patient developed skin manifestations of psoriasis. We discuss and review the current literature, which demonstrates that chimerism following liver transplantation is rare and in our patient may be related to his profound immunosuppression around the time of liver transplant as well the development of acute graft-versus-host disease. While autoimmune disease can occur after solid organ and stem cell transplant, our patient developed skin manifestations of autoimmunity after liver transplantation, which is also rarely described. PMID- 25516433 TI - Revisit the spin-FET: multiple reflection, inelastic scattering, and lateral size effects. AB - We revisit the spin-injected field effect transistor (spin-FET) in a framework of the lattice model by applying the recursive lattice Green's function approach. In the one-dimensional case the results of simulations in coherent regime reveal noticeable differences from the celebrated Datta-Das model, which lead us to an improved treatment with generalized result. The simulations also allow us to address inelastic scattering and lateral confinement effects in the control of spins. These issues are very important in the spin-FET device. PMID- 25516434 TI - Celebrating 20 years of enduring passions and changing contexts: a question of Continuing Professional Development? PMID- 25516435 TI - Anti-inflammatory immune skewing is atheroprotective: Apoe-/-FcgammaRIIb-/- mice develop fibrous carotid plaques. AB - BACKGROUND: Stroke, caused by carotid plaque rupture, is a major cause of death in the United States. Whereas vulnerable human plaques have higher Fc receptor (FcgammaR) expression than their stable counterparts, how FcgammaR expression impacts plaque histology is unknown. We investigated the role of FcgammaRIIb in carotid plaque development and stability in apolipoprotein (Apo)e-/- and Apoe-/ FcgammaRIIb-/- double knockout (DKO) animals. METHODS AND RESULTS: Plaques were induced by implantation of a shear stress-modifying cast around the carotid artery. Plaque length and stenosis were followed longitudinally using ultrasound biomicroscopy. Immune status was determined by flow cytometry, cytokine release, immunoglobulin G concentration and analysis of macrophage polarization both in plaques and in vitro. Surprisingly, DKO animals had lower plaque burden in both carotid artery and descending aorta. Plaques from Apoe-/- mice were foam-cell rich and resembled vulnerable human specimens, whereas those from DKO mice were fibrous and histologically stable. Plaques from DKO animals expressed higher arginase 1 (Arg-1) and lower inducible nitric oxide synthase (iNOS), indicating the presence of M2 macrophages. Analysis of blood and cervical lymph nodes revealed higher interleukin (IL)-10, immune complexes, and regulatory T cells (Tregs) and lower IL-12, IL-1beta, and tumor necrosis factor alpha (TNF-alpha) in DKO mice. Similarly, in vitro stimulation produced higher IL-10 and Arg-1 and lower iNOS, IL-1beta, and TNF-alpha in DKO versus Apoe-/- macrophages. These results define a systemic anti-inflammatory phenotype. CONCLUSIONS: We hypothesized that removal of FcgammaRIIb would exacerbate atherosclerosis and generate unstable plaques. However, we found that deletion of FcgammaRIIb on a congenic C57BL/6 background induces an anti-inflammatory Treg/M2 polarization that is atheroprotective. PMID- 25516436 TI - Exercise has a disproportionate role in the pathogenesis of arrhythmogenic right ventricular dysplasia/cardiomyopathy in patients without desmosomal mutations. AB - BACKGROUND: Exercise is associated with age-related penetrance and arrhythmic risk in carriers of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated desmosomal mutations; however, its role in patients without desmosomal mutations (gene-elusive) is uncertain. This study investigates whether exercise is (1) associated with onset of gene-elusive ARVD/C and (2) has a differential impact in desmosomal and gene-elusive patients. METHODS AND RESULTS: Eighty-two ARVD/C patients (39 desmosomal, all probands) were interviewed about regular physical activity from age 10. Participation in endurance athletics, duration (hours/year), and intensity (MET-Hours/year) of exercise prior to clinical presentation were compared between patients with desmosomal and gene elusive ARVD/C. All gene-elusive patients were endurance athletes. Gene-elusive patients were more likely to be endurance athletes (P<0.001) and had done significantly more intense (MET-Hrs/year) exercise prior to presentation (P<0.001), particularly among cases presenting < age 25 (P=0.027). Family history was less prevalent among gene-elusive patients (9% versus 40% desmosomal, P<0.001), suggesting a greater environmental influence. Gene-elusive patients without family history did considerably more intense exercise than other ARVD/C patients (P=0.004). Gene-elusive patients who had done the most intense (top quartile MET-Hrs/year) exercise prior to presentation had a younger age of presentation (P=0.025), greater likelihood of meeting ARVD/C structural Task Force Criteria (100% versus 43%, P=0.02), and shorter survival free from a ventricular arrhythmia in follow-up (P=0.002). CONCLUSIONS: Gene-elusive, non familial ARVD/C is associated with very high intensity exercise suggesting exercise has a disproportionate role in the pathogenesis of these cases. As exercise negatively modifies cardiac structure and promotes arrhythmias, exercise restriction is warranted. PMID- 25516437 TI - Regulated inositol-requiring protein 1-dependent decay as a mechanism of corin RNA and protein deficiency in advanced human systolic heart failure. AB - BACKGROUND: The compensatory actions of the endogenous natriuretic peptide system require adequate processing of natriuretic peptide pro-hormones into biologically active, carboxyl-terminal fragments. Natriuretic peptide pro-peptide processing is accomplished by corin, a transmembrane serine protease expressed by cardiomyocytes. Brain natriuretic peptide (BNP) processing is inadequate in advanced heart failure and is independently associated with adverse outcomes; however, the molecular mechanisms causing impaired BNP processing are not understood. We hypothesized that the development of endoplasmic reticulum stress in cardiomyocytes in advanced heart failure triggers inositol-requiring protein 1 (IRE1)-dependent corin mRNA decay, which would favor a molecular substrate favoring impaired natriuretic peptide pro-peptide processing. METHODS AND RESULTS: Two independent samples of hearts obtained from patients with advanced heart failure at transplant demonstrated that corin RNA was reduced as Atrial natriuretic peptide (ANP)/BNP RNA increased. Increases in spliced X-box protein 1, a marker for IRE1-endoribonuclease activity, were associated with decreased corin RNA. Moreover, ~50% of the hearts demonstrated significant reductions in corin RNA and protein as compared to the nonfailing control sample. In vitro experiments demonstrated that induction of endoplasmic reticulum stress in cultured cardiomyocytes with thapsigargin activated IRE1's endoribonuclease activity and time-dependent reductions in corin mRNA. In HL-1 cells, overexpression of IRE1 activated IRE1 endoribonuclease activity and caused corin mRNA decay, whereas IRE1-RNA interference with shRNA attenuated corin mRNA decay after induction of endoplasmic reticulum stress with thapsigargin. Pre-treatment of cells with Actinomycin D to inhibit transcription did not alter the magnitude or time course of thapsigargin-induced corin mRNA decline, supporting the hypothesis that this was the result of IRE1-mediated corin mRNA degradation. CONCLUSIONS: These data support the hypothesis that endoplasmic reticulum stress mediated, IRE1-dependent targeted corin mRNA decay is a mechanism leading to corin mRNA resulting in corresponding corin protein deficiency may contribute to the pathophysiology of impaired natriuretic peptide pro-hormone processing in humans processing in humans with advanced systolic heart failure. PMID- 25516438 TI - Potential reduction of interstitial myocardial fibrosis with renal denervation. AB - BACKGROUND: Hypertensive cardiomyopathy is characterized by myocyte hypertrophy and interstitial fibrosis. The effects of renal denervation (RD) on the heart are poorly understood. New magnetic resonance imaging techniques (extracellular volume fraction) permit the quantitative assessment of myocardial fibrosis. Our aim was to study the effects of RD on myocardial fibrosis. METHODS AND RESULTS: Twenty-three patients with resistant hypertension undergoing RD and 5 resistant hypertensive controls were prospectively included. Cardiac magnetic resonance imaging at 1.5 T was performed before RD and at 6-month follow-up. Indexed left ventricular mass, septal extracellular volume fraction, and indexed absolute extracellular volume (a quantitative measure of extracellular matrix) were quantified. All data are reported as mean+/-SD deviation (median). Decreases in systolic (161.96+/-19.09 [160] versus 144.78+/-16.48 [143] mm Hg, P<0.0001) and diastolic (85.61+/-12.88 [83] versus 80.39+/-11.93 [81] mm Hg, P=0.018) blood pressures and in indexed left ventricular mass (41.83+/-10.20 [41.59] versus 37.72+/-7.44 [38.49] g/m1.7, P=0.001) were observed at follow-up only in RD patients. No significant differences in extracellular volume were found (26.24+/ 3.92% [26.06%] versus 25.74+/-4.53% [25.63%], P=0.605). A significant decrease in absolute extracellular volume was observed after 6 months in RD patients exclusively (10.36+/-2.25 [10.79] versus 9.25+/-2.38 [9.79] mL/m1.7, P=0.031). This effect was observed independently of blood pressure reduction. CONCLUSIONS: RD significantly decreases left ventricular mass, while extracellular volume remains stable. Our results suggest that the observed left ventricular mass decrease was due not exclusively to a reversion of myocyte hypertrophy but also to an additional reduction in collagen content, indicating interstitial myocardial fibrosis. PMID- 25516440 TI - Renal denervation to treat cardiac fibrosis? PMID- 25516441 TI - Young children's beliefs about self-disclosure of performance failure and success. AB - Self-disclosure of performance information involves the balancing of instrumental, learning benefits (e.g., obtaining help) against social costs (e.g., diminished reputation). Little is known about young children's beliefs about performance self-disclosure. The present research investigates preschool- and early school-age children's expectations of self-disclosure in different contexts. In two experiments, 3- to 7-year-old children (total N = 252) heard vignettes about characters who succeeded or failed at solving a puzzle. Both experiments showed that children across all ages reasoned that people are more likely to self-disclose positive than negative performances, and Experiment 2 showed that children across all ages reasoned that people are more likely to self disclose both positive and negative performances in a supportive than an unsupportive peer environment. Additionally, both experiments revealed changes with age - Younger children were less likely to expect people to withhold their performance information (of both failures and successes) than older children. These findings point to the preschool ages as a crucial beginning to children's developing recognition of people's reluctance to share performance information. PMID- 25516439 TI - Validated contemporary risk model of acute kidney injury in patients undergoing percutaneous coronary interventions: insights from the National Cardiovascular Data Registry Cath-PCI Registry. AB - BACKGROUND: We developed risk models for predicting acute kidney injury (AKI) and AKI requiring dialysis (AKI-D) after percutaneous coronary intervention (PCI) to support quality assessment and the use of preventative strategies. METHODS AND RESULTS: AKI was defined as an absolute increase of >=0.3 mg/dL or a relative increase of 50% in serum creatinine (AKIN Stage 1 or greater) and AKI-D was a new requirement for dialysis following PCI. Data from 947 012 consecutive PCI patients and 1253 sites participating in the NCDR Cath/PCI registry between 6/09 and 7/11 were used to develop the model, with 70% randomly assigned to a derivation cohort and 30% for validation. AKI occurred in 7.33% of the derivation and validation cohorts. Eleven variables were associated with AKI: older age, baseline renal impairment (categorized as mild, moderate, and severe), prior cerebrovascular disease, prior heart failure, prior PCI, presentation (non-ACS versus NSTEMI versus STEMI), diabetes, chronic lung disease, hypertension, cardiac arrest, anemia, heart failure on presentation, balloon pump use, and cardiogenic shock. STEMI presentation, cardiogenic shock, and severe baseline CKD were the strongest predictors for AKI. The full model showed good discrimination in the derivation and validation cohorts (c-statistic of 0.72 and 0.71, respectively) and identical calibration (slope of calibration line=1.01). The AKI D model had even better discrimination (c-statistic=0.89) and good calibration (slope of calibration line=0.99). CONCLUSION: The NCDR AKI prediction models can successfully risk-stratify patients undergoing PCI. The potential for this tool to aid clinicians in counseling patients regarding the risk of PCI, identify patients for preventative strategies, and support local quality improvement efforts should be prospectively tested. PMID- 25516443 TI - Pilot intervention study of a low-salt diet with monomagnesium di-L-glutamate as an umami seasoning in psychiatric inpatients. AB - BACKGROUND: Schizophrenia patients have an elevated prevalence of stroke and cardiovascular risk factors, such as elevated body mass index, hypertension, and hyperlipidaemia. This pilot study investigated the influence of a low-sodium diet using umami seasoning on food intake and clinical parameters in schizophrenia patients. METHODS: A single-blind crossover intervention study was conducted in 15 clinical schizophrenia patients given a low-sodium diet with or without umami seasoning, monomagnesium di-L-glutamate, for 2 weeks. After the initial 2-week intervention, there was a 2-week washout period, and then the interventions were switched. Daily body weight, body mass index, abdominal circumference, blood pressure, and nutrient intake for each subject were determined. RESULTS: The results showed that subjects given monomagnesium di-L-glutamate had an approximately 25.9% reduction in dietary sodium. Furthermore, daily energy intake did not decrease, and no significant changes in body weight, body mass index, abdominal circumference, blood pressure, and nutrient intake were observed. CONCLUSIONS: The use of umami seasonings, such as monomagnesium di-L-glutamate, might be an effective long-term strategy for psychiatric patients requiring restricted sodium intake. PMID- 25516445 TI - Overexpression of PGC1alpha and accumulation of p62 in apocrine carcinoma of the breast. AB - Apocrine carcinoma is categorized as a special type of breast carcinoma because of its specific morphological features. To clarify the characteristics of apocrine carcinoma from the point of view of the mitochondrial profile, we conducted a comparative study between apocrine and non-apocrine carcinomas. The expressions of mitochondrial related factors (PGC1alpha, Nrf1, Nrf2, mtTFA and COX4) were examined in a testing set of breast cancer tissue. Apocrine carcinomas showed a clear tendency towards higher mRNA expression levels of PGC1alpha than non-apocrine carcinomas. The expression of the selected factor, PGC1alpha, as well as that of p62 was further examined. The results revealed that apocrine carcinomas showed a higher immunohistochemical positivity rate for PGC1alpha (21.3% vs. 3.2%; P = 0.008), and that the mRNA expression level of PGC1alpha was significantly higher in apocrine carcinoma than in non-apocrine carcinoma (P = 0.007). The immunohistochemical positivity rate for p62 protein was also higher in apocrine carcinomas (44.7% vs. 21.0%; P = 0.015), although no significant difference in the p62 mRNA expression level was detected between the two types of carcinoma (P = 0.633). In conclusion, this study revealed that apocrine carcinoma overexpressed PGC1alpha contributing to mitochondrial biogenesis, and also p62 protein accumulation. PMID- 25516446 TI - Electrophysiological changes correlated with temperature increases induced by high-intensity focused ultrasound ablation. AB - To gain better understanding of the detailed mechanisms of high-intensity focused ultrasound (HIFU) ablation for cardiac arrhythmias, we investigated how the cellular electrophysiological (EP) changes were correlated with temperature increases and thermal dose (cumulative equivalent minutes [CEM43]) during HIFU application using Langendorff-perfused rabbit hearts. Employing voltage-sensitive dye di-4-ANEPPS, we measured the EP and temperature during HIFU using simultaneous optical mapping and infrared imaging. Both action potential amplitude (APA) and action potential duration at 50% repolarization (APD50) decreased with temperature increases, and APD50 was more thermally sensitive than APA. EP and tissue changes were irreversible when HIFU-induced temperature increased above 52.3 +/- 1.4 degrees C and log10(CEM43) above 2.16 +/- 0.51 (n = 5), but were reversible when temperature was below 50.1 +/- 0.8 degrees C and log10(CEM43) below -0.9 +/- 0.3 (n = 9). EP and temperature/thermal dose changes were spatially correlated with HIFU-induced tissue necrosis surrounded by a transition zone. PMID- 25516448 TI - Author's reply to "how to use the load-sharing classification of spine fractures?" Letter to the Editor of J. Jiang et al. regarding "progressive kyphotic deformity in comminuted burst fractures treated non-operatively: the Achilles tendon of the Thoracolumbar Injury Classification and Severity Score (TLICS)" by Tobias A. Mattei, Joseph Hanovnikian, Dzung H. Dinh. Eur Spine J. 2014; doi 10.1007/s00586-014-3312-0 : Avoiding misleading randomization of apples, oranges and other citruses: the necessity of proper evaluation of comminution in classification systems of thoracolumbar fractures. PMID- 25516447 TI - Insufficient restoration of lumbar lordosis and FBI index following pedicle subtraction osteotomy is an indicator of likely mechanical complication. AB - PURPOSE: Pedicle subtraction osteotomies (PSO) enable correction of spinal deformities but remain difficult and are associated with high complication rates. This study aimed to prospectively review different post-operative complications and mechanical problems in patients who underwent PSO as treatment for sagittal imbalance as sequelae of degenerative disc disease or previous spinal fusion. METHOD: This was a descriptive prospective single center study of 63 patients who underwent sagittal imbalance correction by PSO. Radiographic analysis of pre- and post-operative pelvic and spinal parameters was completed based on EOS images following 3D modeling. Global and sub-group analyses were completed based on the Roussouly classification. A systematic analysis of post-operative complications was conducted during hospital stay and at follow-up visits. RESULTS: Complications included 15 cases (20.2%) of bilateral leg pain, with transient neurological deficit in 6 cases (9.5%), and 9 cases (12.5%) of early surgical site infections. Intra-operative complications included five tears of the dura mater and two cases of excessive blood loss (>5,000 mL). Two mortalities occurred from major intracerebral bleeds in the early post-operative period. Mechanical complications were principally non-union (9 cases) and junctional kyphosis (3 cases). All 19 post-operative complications (28.1%) were revised at an average of 2 years following surgery. All mechanical complications were found in the patients who had insufficient imbalance correction and this was mainly associated with high PI (>60 degrees ) or a moderate PI (45-60o) combined with excess FBI pre-operatively that remained >10 degrees post-operatively. CONCLUSION: Infection and neurologic complications following PSO are relatively common, and frequently reported in the literature. The principal cause of mechanical complications, such as non-union or junctional kyphosis, was insufficient sagittal correction, characterized by post-operative FBI >10 degrees . The risks of insufficient correction are greater in patients with higher pelvic incidence and those patients who required very high correction. PMID- 25516449 TI - The 32nd Manfred Donike workshop on doping analysis. PMID- 25516450 TI - Detection of formestane abuse by mass spectrometric techniques. AB - Formestane (4-hydroxy-androstenedione) is an aromatase inhibitor prohibited in sports and included, since 2004, in the list of prohibited substances updated yearly by the World Anti-Doping Agency (WADA). Since the endogenous production of formestane has been described, it is mandatory for the anti-doping laboratories to use isotope ratio mass spectrometry (IRMS) to establish the exogenous origin before issuing an adverse analytical finding. The described IRMS methods for formestane detection are time-consuming, requiring usually two consecutive liquid chromatographic sample purifications in order to have final extracts of adequate purity before the mass spectrometric analysis. After establishing a procedure for the determination of the origin of formestane by IRMS without the need of derivatization, and integrated in the overall analytical strategy of the laboratory for pseudo-endogenous steroids, a mass spectrometric analysis by gas chromatography-mass spectrometry (GC-MS) and gas chromatography-tandem mass spectrometry (GC-MS/MS) of formestane metabolites was carried out in order to investigate whether other biomarkers of formestane abuse could be integrated in order to avoid time-consuming and expensive IRMS confirmations for formestane. From the metabolic studies performed, the inclusion of 3beta,4alpha-dihydroxy 5alpha-androstan-17-one (4alpha-hydroxy-epiandosterone) in the routine GC-MS procedures has demonstrated to be diagnostic in order to reduce the number of unnecessary confirmations of the endogenous origin of formestane. PMID- 25516451 TI - Degradation of methyltestosterone in urine samples. PMID- 25516442 TI - Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never-smoking women in Asia: a report from the female lung cancer consortium in Asia. AB - Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 * 10(-14) ) even after removing rs2736100 (p value = 4.81 * 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk. PMID- 25516453 TI - Cystic fibrosis (CF) care through the patients' eyes - a nationwide survey on experience and satisfaction with services using a disease-specific questionnaire. AB - The patients' perspective is an important aspect of quality management. A newly developed disease-specific questionnaire was used to assess the patients' experiences with care provided in specialised cystic fibrosis (CF) care centres. METHODS: 90 CF centres in Germany were invited to participate. Centre staff collected patient consent forms and sent the patients' addresses to the study centre. The questionnaires for adults and parents had 100 and 104 items respectively, with 3-6 response categories each. Items were dichotomised into "problem scores" (PS), indicating the presence or absence (PS 0%) of a reported problem. RESULTS: 56 CF centres took part in the survey and recruited 1642 adults with CF and 1205 parents. The response rates were 74% in each group, with 1221 completed questionnaires from adults and 891 from parents. Participants reported good experiences with care. Factor analysis revealed 10 factors covering 70 items. Participants reported the best results for the factors "Physiotherapists" (PS 6%) and "Physician-Patient Relationship" (PS 9%). Factors with the highest problem scores were inpatient and outpatient "Facilities, Hygiene and Services". CF centres received reports of their own results and mean problem scores of all participating institutions. The problem scores differed considerably between CF centres. CONCLUSIONS: The nation-wide CF-specific patient experience survey identified specific shortcomings which were mainly related to communication, centre organisation, and facilities. Centre staff can use the results to improve the quality of care. We suggest that patients' views should become an integral component of efforts to promote patient-centred care. PMID- 25516454 TI - Association between early peak temperature and mortality in neutropenic sepsis. AB - Fever is often the first sign of neutropenic infection, but its prognostic impact has not been established. We aimed to determine whether early peak temperature is associated with mortality in patients with neutropenic sepsis admitted to intensive care units (ICUs). We used a database of admissions to 157 ICUs in Australia and New Zealand between 2005 and 2013 to seek an association between peak temperature within the first 24 h in ICU and in-hospital mortality in neutropenic and non-neutropenic sepsis. Odds ratios for in-hospital death were calculated for four temperature bands, adjusting for illness severity. Two patient cohorts were identified: neutropenic sepsis (N = 4027) and non neutropenic sepsis (N = 114,040). In-hospital mortality was higher in neutropenic sepsis than non-neutropenic sepsis. In both cohorts, early peak temperature below 36.5 degrees C was associated with significantly increased mortality compared to normothermia. Among non-neutropenic patients, an early peak temperature of 37.5 degrees C or higher was associated with reduced mortality compared to normothermia. In contrast, in patients with neutropenic sepsis, fever was not associated with reduced mortality compared to normothermia. Similar findings were seen in a subgroup of the neutropenic sepsis cohort with a documented haematological malignancy. In neutropenic sepsis patients admitted to ICU, a temperature below 36.5 degrees C is associated with increased mortality compared with normothermia. In contrast to non-neutropenic sepsis, fever was not associated with a significant reduction in mortality in neutropenic patients. Interventional studies are needed to determine whether physical or pharmacological measures to reduce fever influence outcomes during neutropenic infections. PMID- 25516457 TI - Comment on: "Two-stage face transplantation: A new concept in vascularized composite allotransplantation". PMID- 25516456 TI - Paraneoplastic pyoderma gangrenosum with posttransplant lymphoproliferative disorder. PMID- 25516455 TI - Evolution of iron overload in patients with low-risk myelodysplastic syndrome: iron chelation therapy and organ complications. AB - This study aimed to evaluate the evolution of iron overload, assessed by serum ferritin (SF), in transfusion-dependent lower risk patients with myelodysplastic syndrome (MDS), as well as to describe the occurrence of organ complications, and to analyze its relationship with iron chelation therapy. This observational retrospective study was conducted from March 2010 to March 2011 in 47 Spanish hospitals. A total of 263 patients with lower risk MDS (International Prognostic Scoring System [IPSS] low/intermediate-1 risk or Spanish Prognostic Index [SPI] 0 1 risk), transfusion-dependent, and who had received >=10 packed red blood cells (PRBC) were included. At MDS diagnosis, patients received a mean of 2.8 +/- 3.9 PRBC/month, and 8.7% of patients showed SF >=1000 MUg/L. Over the course of the disease, patients received a mean of 83.4 +/- 83.3 PRBC, and 36.1% of patients presented SF >=2500 MUg/L. Cardiac, hepatic, endocrine, or arthropathy complications appeared/worsened in 20.2, 11.4, 9.9, and 3.8% of patients, respectively. According to investigator, iron overload was a main cause of hepatic (70.0%) and endocrine (26.9%) complications. A total of 96 (36.5%) patients received iron chelation therapy for >=6 months, being deferasirox the most frequent first chelation treatment (71.9%). Chelation-treated patients showed longer overall survival (p < 0.001), leukemia-free survival (p = 0.007), and cardiac event-free survival (p = 0.017) than non-chelated patients. In multivariable analyses, age (p = 0.011), IPSS (p < 0.001), and chelation treatment (p = 0.015) were predictors for overall survival; IPSS (p = 0.014) and transfusion frequency (p = 0.001) for leukemia-free survival; and chelation treatment (p = 0.040) and Sorror comorbidity index (p = 0.039) for cardiac event free survival. In conclusion, these results confirm the potential survival benefit of iron chelation therapy and provide additional evidence on the deleterious effect of iron overload in lower risk MDS patients. PMID- 25516459 TI - Dapagliflozin therapy in type-2 diabetes: current knowledge and future perspectives. AB - Dapagliflozin is a new antidiabetic agent that belongs to the class of sodium glucose transporter 2 (SGLT-2) inhibitors. By decreasing renal glucose absorption, these agents target hyperglycemia independent of insulin secretion or insulin sensitivity. This unique mechanism of action differentiates them from existing antidiabetic agents currently on the market. It has been hypothesized that SGLT-2 inhibitors can be effectively and safely combined with other agents, including insulin, and incretin-based therapies. They can be used either as monotherapy, or in dual- or triple-agent combinations. Dapagliflozin has been shown to be effective and safe in patients with type-2 diabetes, with modest but significant reductions in HbA1c and a number of potentially beneficial and sustained non-glycemic effects, including those on body weight, plasma lipids and systolic blood pressure. In addition, dapagliflozin has been shown to have a generally favorable safety profile and is well tolerated. Ongoing studies may provide definitive answers on the cardiovascular safety and efficacy of SGLT-2 inhibitors in patients with type-2 diabetes. PMID- 25516458 TI - Kinetics and thermodynamics of metal-binding to histone deacetylase 8. AB - Histone deacetylase 8 (HDAC8) was originally classified as a Zn(II)-dependent deacetylase on the basis of Zn(II)-dependent HDAC8 activity in vitro and illumination of a Zn(II) bound to the active site. However, in vitro measurements demonstrated that HDAC8 has higher activity with a bound Fe(II) than Zn(II), although Fe(II)-HDAC8 rapidly loses activity under aerobic conditions. These data suggest that in the cell HDAC8 could be activated by either Zn(II) or Fe(II). Here we detail the kinetics, thermodynamics, and selectivity of Zn(II) and Fe(II) binding to HDAC8. To this end, we have developed a fluorescence anisotropy assay using fluorescein-labeled suberoylanilide hydroxamic acid (fl-SAHA). fl-SAHA binds specifically to metal-bound HDAC8 with affinities comparable to SAHA. To measure the metal affinity of HDAC, metal binding was coupled to fl-SAHA and assayed from the observed change in anisotropy. The metal KD values for HDAC8 are significantly different, ranging from picomolar to micromolar for Zn(II) and Fe(II), respectively. Unexpectedly, the Fe(II) and Zn(II) dissociation rate constants from HDAC8 are comparable, koff ~0.0006 s(-1), suggesting that the apparent association rate constant for Fe(II) is slow (~3 * 10(3) M(-1) s(-1)). Furthermore, monovalent cations (K(+) or Na(+)) that bind to HDAC8 decrease the dissociation rate constant of Zn(II) by >=100-fold for K(+) and >=10-fold for Na(+), suggesting a possible mechanism for regulating metal exchange in vivo. The HDAC8 metal affinities are comparable to the readily exchangeable Zn(II) and Fe(II) concentrations in cells, consistent with either or both metal cofactors activating HDAC8. PMID- 25516460 TI - Gelastic seizures: incidence, clinical and EEG features in adult patients undergoing video-EEG telemetry. AB - This study aimed to determine clinical features of adult patients with gelastic seizures recorded on video -electroencephalography (EEG) over a 5-year period. We screened video-EEG telemetry reports for the occurrence of the term "gelastic" seizures, and assessed the semiology, EEG features, and duration of those seizures. Gelastic seizures were identified in 19 (0.8%) of 2,446 admissions. The presumed epileptogenic zone was in the hypothalamus in one third of the cases, temporal lobe epilepsy was diagnosed in another third, and the remainder of the cases presenting with gelastic seizures were classified as frontal, parietal lobe epilepsy or remained undetermined or were multifocal. Gelastic seizures were embedded in a semiology, with part of the seizure showing features of automotor seizures. A small proportion of patients underwent epilepsy surgery. Outcome of epilepsy surgery was related to the underlying pathology; two patients with hippocampal sclerosis had good outcomes following temporal lobe resection and one of four patients with hypothalamic hamartomas undergoing gamma knife surgery had a good outcome. PMID- 25516461 TI - Modeling retrospective attribution of responsibility to hazard-managing institutions: an example involving a food contamination incident. AB - Perceptions of institutions that manage hazards are important because they can affect how the public responds to hazard events. Antecedents of trust judgments have received far more attention than antecedents of attributions of responsibility for hazard events. We build upon a model of retrospective attribution of responsibility to individuals to examine these relationships regarding five classes of institutions that bear responsibility for food safety: producers (e.g., farmers), processors (e.g., packaging firms), watchdogs (e.g., government agencies), sellers (e.g., supermarkets), and preparers (e.g., restaurants). A nationally representative sample of 1,200 American adults completed an Internet-based survey in which a hypothetical scenario involving contamination of diverse foods with Salmonella served as the stimulus event. Perceived competence and good intentions of the institution moderately decreased attributions of responsibility. A stronger factor was whether an institution was deemed (potentially) aware of the contamination and free to act to prevent or mitigate it. Responsibility was rated higher the more aware and free the institution. This initial model for attributions of responsibility to impersonal institutions (as opposed to individual responsibility) merits further development. PMID- 25516462 TI - Large loop versus straight-wire excision of the transformation zone for treatment of cervical intraepithelial neoplasia: a randomised controlled trial of electrosurgical techniques. AB - OBJECTIVE: To compare two electrosurgical techniques, straight-wire excision of transformation zone (SWETZ) with large loop excision of transformation zone, as a cone procedure (LLETZ-cone), for the treatment of cervical intraepithelial neoplasia (CIN), when disease is present at the cervical canal. DESIGN: Randomised controlled trial. SETTING: Two public hospitals, one in Rio de Janeiro, Brazil and one in Dublin, Ireland. POPULATION: One hundred and three women with indication to treat CIN located at cervical canal. METHODS: Women were randomised to receive LLETZ-cone or SWETZ. OUTCOMES: Main outcome was the incidence of complete excision of disease at endocervical margin of the surgical specimen. Secondary outcomes were complete excision at ectocervical and stromal margins, time to complete the procedure, specimen fragmentation, blood loss and death after 1 year. RESULTS: Fifty-two women were allocated to LLETZ-cone and 51 to SWETZ. Ten women were lost for main outcome because of damaged specimens. Forty-two women in the LLETZ-cone group had free endocervical margin versus 43 women in the SWETZ group (relative risk 1.04, 95% confidence interval [95% CI] 0.87-1.25; P = 0.64). For secondary outcomes related to margins, we observed a relative risk of 1.15 (95% CI 0.95-1.39; P = 0.15) for ectocervical free margin. For free stromal margin, the relative risk was 1.07 (95% CI 0.89-1.29; P = 0.47). No death was observed. CONCLUSIONS: This study was inconclusive; SWETZ and LLETZ cone were equally effective to treat endocervical disease, with no difference in protecting against margin involvement. Higher, but not severe, blood loss and longer surgical time were observed in the SWETZ group. PMID- 25516463 TI - Autoshortloop feedback regulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion by its metabolite, GnRH-(1-5). AB - Given the central role of the decapeptide gonadotropin-releasing hormone (GnRH) in reproductive function, our long-term objective is to delineate the underlying mechanism regulating these reproductive processes. The outcome of GnRH secretion is in part dependent on the proteolytic metabolism of this decapeptide. In contrast to the belief that the metabolism of GnRH serves only as a degradative process that removes excess GnRH, we have shown that a metabolite of the decapeptide, GnRH-(1-5), can directly regulate GnRH gene expression and reproductive behavior. To further characterize the effect of GnRH-(1-5) on GnRH neuronal function, we determined whether GnRH-(1-5) can directly regulate GnRH secretion and pulsatility using an in vitro perifusion system. We compared the effect of GnRH-(1-5) on GnRH secretion in the immortalized GnRH neuron (GT1-7 cell line), whole rat hypothalamic explant, and enzymatically dispersed rat hypothalamic cells. Tissue preparations were perifused continuously for 9 h during which a 3-h challenge with GnRH-(1-5) was administered (4-6 h). The results show that treatment with GnRH-(1-5) increased (p < 0.05) the mean GnRH secretion and the amplitude of the pulses but not the pulse frequency. The present study supports the notion that GnRH-(1-5) is functionally capable of regulating the reproductive neuroendocrine system. PMID- 25516465 TI - Highly fluorescent C-dots obtained by pyrolysis of quaternary ammonium ions trapped in all-silica ITQ-29 zeolite. AB - C-dots obtained in the homogeneous phase may exhibit a broad particle size distribution. The formation of C-dots within nanometric reaction cavities could be a methodology to gain control on their size distribution. Among the various possibilities, in the present work, the cavities of small pore size zeolites have been used to confine C-dots generated by the pyrolysis of the organic structure directing agent present in the synthesis of these crystalline aluminosilicates. To explore this methodology, ITQ-29 zeolite having a Linde type A (LTA) structure was prepared as pure silica with 4-methyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3.2.1 ij]quinolinium as the organic structure directing agent. Pyrolysis under an inert atmosphere at 550 degrees C of a pure-silica ITQ-29 sample (cubic particles of 4 MUm edge) renders a highly fluorescent zeolite containing about 15 wt% of the carbonised residue. While another small pore zeolite, ITQ-12 (ITW), also renders photoluminescent C-dots under similar conditions, medium or large pore zeolites, such as silicalite (MFI) or pure silica Beta (BEA), failed to produce fluorescent powders under analogous thermal treatment and only decomposition and complete removal of the corresponding quaternary ammonium ion templates was observed for these zeolites. The dissolution of the pyrolysed ITQ-29 zeolite framework and the extraction of the carbon residue with ethyl acetate have allowed the characterisation of C-dots with particle sizes between 5 and 12 nm and a photoluminescence quantum yield of 0.4 upon excitation at 350 nm that is among the highest reported for non-surface functionalized C-dots. Photoluminescence varies with the excitation wavelength and is quenched by oxygen. Pyrolysed ITQ-29 powders can act as fluorescent oxygen sensors. PMID- 25516464 TI - Does microbiota composition affect thyroid homeostasis? AB - The intestinal microbiota is essential for the host to ensure digestive and immunologic homeostasis. When microbiota homeostasis is impaired and dysbiosis occurs, the malfunction of epithelial barrier leads to intestinal and systemic disorders, chiefly immunologic and metabolic. The role of the intestinal tract is crucial in the metabolism of nutrients, drugs, and hormones, including exogenous and endogenous iodothyronines as well as micronutrients involved in thyroid homeostasis. However, the link between thyroid homeostasis and microbiota composition is not yet completely ascertained. A pathogenetic link with dysbiosis has been described in different autoimmune disorders but not yet fully elucidated in autoimmune thyroid disease which represents the most frequent of them. Anyway, it has been suggested that intestinal dysbiosis may trigger autoimmune thyroiditis. Furthermore, hypo- and hyper-thyroidism, often of autoimmune origin, were respectively associated to small intestinal bacterial overgrowth and to changes in microbiota composition. Whether some steps of this thyroid network may be affected by intestinal microbiota composition is briefly discussed below. PMID- 25516466 TI - Genetic association between p73 G4C14-A4T14 polymorphism and risk of squamous cell carcinoma. AB - This study is to evaluate the association between p73 G4C14-A4T14 polymorphism and squamous cell carcinoma (SCC) risk in diverse populations. We searched the PubMed, Embase, China National Knowledge Infrastructure, and Chinese Biomedicine databases for all articles on the association between p73 G4C14-A4T14 polymorphism and SCC risk through March 2014. We performed a comprehensive meta analysis of six case-control studies that included 1,758 SCC cases and 2,970 case free controls. All analyses were performed using STATA 11.0, using two-sided P values. Overall, this meta-analysis showed that the p73 G4C14-A4T14 polymorphism was associated with a significantly increased risk of SCC in three genetic models. However, after excluding one study deviating from Hardy-Weinberg equilibrium, the results then demonstrated that the p73 G4C14-A4T14 polymorphism was only associated with elevated risk of cervical squamous cell carcinoma (for AT/GC vs GC/GC: OR 1.51, 95 % CI 1.14-2.00, P heterogeneity = 0.996; for AT/AT+AT/GC vs GC/GC: OR 1.42, 95 % CI 1.08-1.87, P heterogeneity = 0.994) in subgroup analysis by tumor sites. No publication bias was found in the present study. This meta-analysis suggests that the p73 G4C14-A4T14 polymorphism is associated with an increased risk of cervical squamous cell carcinoma. Further large and well-designed studies are needed to confirm this association. PMID- 25516467 TI - Serum microRNA-21 as a potential diagnostic biomarker for breast cancer: a systematic review and meta-analysis. AB - Serum microRNA-21 (miR-21) expression has been shown to be significantly up regulated in breast cancer, which implies that it could be a biomarker to discriminate breast cancer patients from healthy controls. We therefore performed this meta-analysis to assess the diagnostic value of miR-21 for breast cancer. Relevant articles were collected from PubMed, Scopus, Embase, the Cochrane Library, BioMed Central, ISI Web of Knowledge, China National Knowledge Infrastructure, Wan Fang Data and Technology of Chongqing databases, from inception to June 10, 2014 by two independent researchers. Diagnostic capacity of miR-21 for breast cancer was assessed using pooled sensitivity and specificity, diagnostic odds ratio (DOR), area under the summary receiver operating characteristic (AUC) and Fagan's nomogram. Meta-Disc software and Stata SE 12.0 were used to investigate the source of heterogeneity and to perform the meta analysis. We used six studies with a total of 438 patients and 228 healthy controls in this meta-analysis. The pooled sensitivity, specificity and DOR were 0.79 [95 % confidence interval (CI) 0.66-0.87], 0.85 (95 % CI 0.75-0.91) and 19.46 (95 % CI 8.74-43.30), respectively; positive and negative likelihood ratios were 5 and 0.25, and AUC was 0.89 (95 % CI 0.86-0.91). In addition, heterogeneity was clearly apparent but was not caused by the threshold effect. This meta analysis suggests that miR-21 is a potential biomarker for early diagnosis of breast cancer with high sensitivity and specificity, and its clinical application warrants further investigation. PMID- 25516468 TI - Characterization of the autoimmune response against the nerve tissue S100beta in patients with type 1 diabetes. AB - Type 1 diabetes results from destruction of insulin-producing beta cells in pancreatic islets and is characterized by islet cell autoimmunity. Autoreactivity against non-beta cell-specific antigens has also been reported, including targeting of the calcium-binding protein S100beta. In preclinical models, reactivity of this type is a key component of the early development of insulitis. To examine the nature of this response in type 1 diabetes, we identified naturally processed and presented peptide epitopes derived from S100beta, determined their affinity for the human leucocyte antigen (HLA)-DRB1*04:01 molecule and studied T cell responses in patients, together with healthy donors. We found that S100beta reactivity, characterized by interferon (IFN)-gamma secretion, is a characteristic of type 1 diabetes of varying duration. Our results confirm S100beta as a target of the cellular autoimmune response in type 1 diabetes with the identification of new peptide epitopes targeted during the development of the disease, and support the preclinical findings that autoreactivity against non-beta cell-specific autoantigens may have a role in type 1 diabetes pathogenesis. PMID- 25516469 TI - The impact of medication on health-related quality of life in patients with generalized anxiety disorder. AB - BACKGROUND AND OBJECTIVE: Generalized anxiety disorder (GAD) is a psychiatric disorder characterized by excess worry and anxiety. GAD impacts overall health related quality of life (HRQL), level of functioning, and disability. This literature review was conducted to understand the impact of pharmacological treatments on HRQL and functional outcomes. METHODS: A literature review was conducted to identify randomized controlled trials (RCTs) comparing GAD pharmacological treatments with one or more patient-reported outcome (PRO) measure assessing HRQL, disability, functioning, or work productivity. Four databases were searched (PubMed, EMBASE, Cochrane Reviews, PsycInfo). Limits included English-language publications from 2004-2014. Abstracts and articles were reviewed to select articles reporting results of RCTs of pharmacological treatments for GAD that included one or more PRO measure. Article abstraction and summarization focused on key elements of the study design and PRO results. RESULTS: One hundred sixty-three abstracts were reviewed; 44 articles were requested; 12 articles, representing 19 studies, were deemed relevant. The Sheehan Disability Scale (SDS) and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) were the most frequently utilized PRO measures. In clinical trials with significant anxiety symptom reductions, the SDS and Q-LES-Q also improved with treatment and differentiated from placebo. Two trials included a measure of work productivity; both demonstrated significant improvements with short-term treatment. CONCLUSION: Treatments that reduce anxiety symptoms are also associated with improvements in patient-reported HRQL, function, and disability. In addition to evaluation of treatment impacts on anxiety symptoms, clinical trials should include PRO measures of HRQL, disability, and functioning. PMID- 25516470 TI - Role of interventional radiology in the management of complications after pancreatic surgery: a pictorial review. AB - Pancreatic resections are surgical procedures associated with high incidence of complications, with relevant morbidity and mortality even at high volume centres. A multidisciplinary approach is essential in the management of these events and interventional radiology plays a crucial role in the treatment of patients developing post-surgical complications. This paper offers an overview on the interventional radiological procedures that can be performed to treat different type of complications after pancreatic resection. Procedures such as percutaneous drainage of fluid collections, percutaneous transhepatic biliary procedures, arterial embolisation, venous interventions and fistula embolisation are viable treatment options, with fewer complications compared with re-look surgery, shorter hospital stay and faster recovery. A selection of cases of complications following pancreatic surgery managed with interventional radiological procedure are presented and discussed. Teaching Points * Interventional radiology is crucial to treat complications after pancreatic surgery * Percutaneous drainage of collections can be performed under ultrasound or computed tomography guidance * Percutaneous biliary procedures can be used to treat biliary complications * Venous procedures can be performed effectively through transhepatic or transjugular access * Fistulas can be treated effectively by percutaneous embolisation. PMID- 25516471 TI - HPV vaccination does not lead to risky sexual behaviour in adolescent girls, study finds. PMID- 25516474 TI - Similarities and differences between pediatric and adult patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with highest prevalence among women of childbearing age. However, children younger than 16 years also can develop SLE (childhood-onset lupus/juvenile-type SLE). The aim of our study was to compare the clinical course of adult and pediatric-onset SLE. Data from 342 adult patients followed at the University of Debrecen, Hungary, and 79 children documented in the Hungarian National Pediatric SLE registry were analyzed using hospital medical records. Organ manifestations, laboratory parameters, and immunoserological characteristics were reviewed and the results were evaluated using SPSS for Windows software.Gender distribution was not significantly different between groups with disease starting in childhood vs adulthood. The prevalence of the following manifestations was significantly higher for pediatric than for adult-onset disease including: lupus nephritis (43% pediatric vs 26.4% for adult-onset), hematological disorders (57% vs 36.4%), photosensitivity (20% vs 9%), butterfly rash (61% vs 35.5%) and mucosal ulceration (11.4% vs 4%). For adult-onset SLE, neurological symptoms (30% vs 6%) and polyarthritis (86% vs 68%) occurred significantly more frequently than in children. Anti-SSA, anti-SSB and antiphospholipid antibodies were detected at significantly higher levels in adult-onset patients compared to those in pediatrics. Children were more commonly given high-dose intravenous immunoglobulin treatment (6.3% vs 0.6%) and mycophenolate mofetil (15.2% vs 5.3%) than adults.These results suggest that pediatric and adult-onset SLE differ in multiple aspects, and it is important to recognize these differences for optimal treatment and prognosis of these patients. PMID- 25516475 TI - Au nanorod helical superstructures with designed chirality. AB - A great challenge for nanotechnology is to controllably organize anisotropic nanomaterials into well-defined three-dimensional superstructures with customized properties. Here we successfully constructed anisotropic Au nanorod (AuNR) helical superstructures (helices) with tailored chirality in a programmable manner. By designing the 'X' pattern of the arrangement of DNA capturing strands (15nt) on both sides of a two-dimensional DNA origami template, AuNRs functionalized with the complementary DNA sequences were positioned on the origami and were assembled into AuNR helices with the origami intercalated between neighboring AuNRs. Left-handed (LH) and right-handed (RH) AuNR helices were conveniently accomplished by solely tuning the mirrored-symmetric 'X' patterns of capturing strands on the origami. The inter-rod distance was precisely defined as 14 nm and inter-rod angle as 45 degrees , thus a full helix contains 9 AuNRs with its length up to about 220 nm. By changing the AuNR/origami molar ratio in the assembly system, the average number of AuNR in the helices was tuned from 2 to 4 and 9. Intense chiroptical activities arose from the longest AuNR helices with a maximum anisotropy factor of ~0.02, which is highly comparable to the reported macroscopic AuNR assemblies. We expect that our strategy of origami templated assembly of anisotropic chiral superstructures would inspire the bottom-up fabrication of optically active nanostructures and shed light on a variety of applications, such as chiral fluids, chiral signal amplification, and fluorescence combined chiral spectroscopy. PMID- 25516477 TI - The role of fibroblast growth factor 21 in the pathogenesis of non-alcoholic fatty liver disease and implications for therapy. AB - Non-alcoholic fatty liver disease (NAFLD) includes a cluster of liver disorders ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH) and cirrhosis. Due to its liver and vascular complications, NAFLD has become a public health problem with high morbidity and mortality. The pathogenesis of NAFLD is considered a "multi-hit hypothesis" that involves lipotoxicity, oxidative stress, endoplasmic reticulum stress, a chronic inflammatory state and mitochondrial dysfunction. Fibroblast growth factor 21 (FGF21) is a member of the fibroblast growth factor family with multiple metabolic functions. FGF21 directly regulates lipid metabolism and reduces hepatic lipid accumulation in an insulin-independent manner. Several studies have shown that FGF21 can ameliorate the "multi-hits" in the pathogenesis of NAFLD. The administration of FGF21 reverses hepatic steatosis, counteracts obesity and alleviates insulin resistance in rodents and nonhuman primates. Using several strategies, we show that the reversal of simple fatty liver and NASH is mediated by activation of the FGF21 signaling pathway. In this review, we describe the molecular mechanisms involved in the onset and/or progression of NAFLD, and review the current literature to highlight the therapeutic procedures associated with the FGF21 signaling pathway for simple fatty liver and NASH, which are the two most important types of NAFLD. PMID- 25516476 TI - Glucosamine enhances body weight gain and reduces insulin response in mice fed chow diet but mitigates obesity, insulin resistance and impaired glucose tolerance in mice high-fat diet. AB - OBJECTIVE: This study investigated the potential of glucosamine (GlcN) to affect body weight gain and insulin sensitivity in mice normal and at risk for developing diabetes. METHODS: Male C57BL/6J mice were fed either chow diet (CD) or a high fat diet (HFD) and the half of mice from CD and HFD provided with a solution of 10% (w/v) GlcN. Total cholesterol and nonesterified free fatty acid levels were determined. Glucose tolerance test and insulin tolerance test were performed. HepG2 human hepatoma cells or differentiated 3T3-L1 adipocytes were stimulated with insulin under normal (5 mM) or high glucose (25 mM) conditions. Effect of GlcN on 2-deoxyglucose (2-DG) uptake was determined. JNK and Akt phosphorylation and nucleocytoplasmic protein O-GlcNAcylation were assayed by Western blotting. RESULTS: GlcN administration stimulated body weight gain (6.58+/-0.82 g vs. 11.1+/-0.42 g), increased white adipose tissue fat mass (percentage of bodyweight, 3.7+/-0.32 g vs. 5.61+/-0.34 g), and impaired the insulin response in livers of mice fed CD. However, GlcN treatment in mice fed HFD led to reduction of body weight gain (18.02+/-0.66 g vs. 16.22+/-0.96 g) and liver weight (2.27+/-0.1 vs. 1.85+/-0.12 g). Furthermore, obesity-induced insulin resistance and impaired Akt insulin signaling in the liver were alleviated by GlcN administration. GlcN inhibited the insulin response under low (5 mM) glucose conditions, whereas it restored the insulin response for Akt phosphorylation under high (25 mM) glucose conditions in HepG2 and 3T3-L1 cells. Uptake of 2-DG increased upon GlcN treatment under 5 mM glucose compared to control, whereas insulin-stimulated 2-DG uptake decreased under 5 mM and increased under 25 mM glucose in differentiated 3T3-L1 cells. CONCLUSION: Our results show that GlcN increased body weight gain and reduced the insulin response for glucose maintenance when fed to normal CD mice, whereas it alleviated body weight gain and insulin resistance in HFD mice. Therefore, the current data support the integrative function of the HBP reflecting the nutrient status of lipids or glucose and further implicate the importance of the pathway in insulin signaling for the regulation of metabolism. PMID- 25516473 TI - Analysis of disease activity and response to treatment in a large Spanish cohort of patients with systemic lupus erythematosus. AB - OBJECTIVES: The objectives of this paper are to study the impact of disease activity in a large cohort of patients with systemic lupus erythematosus (SLE) and estimate the rate of response to therapies. METHODS: We conducted a nationwide, retrospective, multicenter, cross-sectional cohort study of 3658 SLE patients. Data on demographics, disease characteristics: activity (SELENA SLEDAI), damage, severity, hospitalizations and therapies were collected. Factors associated with refractory disease were identified by logistic regression. RESULTS: A total of 3658 patients (90% female; median SLE duration (interquartile range): 10.4 years (5.3-17.1)) were included. At the time of their last evaluation, 14.7% of the patients had moderate-severe SLE (SELENA-SLEDAI score >=6). There were 1954 (53.4%) patients who were hospitalized for activity at least once over the course of the disease. At some stage, 84.6% and 78.8% of the patients received glucocorticoids and antimalarials, respectively, and 51.3% of the patients received at least one immunosuppressant. Owing to either toxicity or ineffectiveness, cyclophosphamide was withdrawn in 21.5% of the cases, mycophenolate mofetil in 24.9%, azathioprine in 40.2% and methotrexate in 46.8%. At some stage, 7.3% of the patients received at least one biologic. A total of 898 (24.5%) patients had refractory SLE at some stage. Renal, neuropsychiatric, vasculitic, hematological and musculoskeletal involvement, a younger age at diagnosis and male gender were associated with refractory disease. CONCLUSIONS: A significant percentage of patients have moderately-to-severely active SLE at some stage. Disease activity has a big impact in terms of need for treatment and cause of hospitalization. The effectiveness of the standard therapies for reducing disease activity is clearly insufficient. Some clinical features are associated with refractory SLE. PMID- 25516478 TI - Checkpoint blockade immunotherapy relies on T-bet but not Eomes to induce effector function in tumor-infiltrating CD8+ T cells. AB - Coinhibitory receptor blockade is a promising strategy to boost T-cell immunity against a variety of human cancers. However, many patients still do not benefit from this treatment, and responders often experience immune-related toxicities. These issues highlight the need for advanced mechanistic understanding to improve patient outcomes and uncover clinically relevant biomarkers of treatment efficacy. However, the T-cell-intrinsic signaling pathways engaged during checkpoint blockade treatment are not well defined, particularly for combination approaches. Using a murine model to study how effector CD8(+) T-cell responses to tumors may be enhanced in a tolerizing environment, we identified a critical role for the T-box transcription factor T-bet. Combination blockade of CTLA-4, PD-1, and LAG-3 induced T-bet expression in responding tumor/self-reactive CD8(+) T cells. Eradication of established leukemia using this immunotherapy regimen depended on T-bet induction, which was required for IFNgamma production and cytotoxicity by tumor-infiltrating T cells, and for efficient trafficking to disseminated tumor sites. These data provide new insight into the success of checkpoint blockade for cancer immunotherapy, revealing T-bet as a key transcriptional regulator of tumor-reactive CD8(+) T-cell effector differentiation under otherwise tolerizing conditions. PMID- 25516479 TI - Adoption of obesity prevention policies and practices by Australian primary schools: 2006 to 2013. AB - Despite significant investment in many countries, the extent of schools' adoption of obesity prevention policies and practices has not been widely reported. The aims of this article are to describe Australian schools' adoption of healthy eating and physical activity policies and practices over an 8-year period and to determine if their adoption varies according to schools' size, geographic or socio-economic location. Between 2006 and 2013, a representative randomly selected cohort of primary schools (n = 476) in New South Wales, Australia, participated in four telephone interviews. Repeated measures logistic regression analyses using a Generalised Estimating Equation (GEE) framework were undertaken to assess change over time. The prevalence of all four of the healthy eating practices and one physical activity practice significantly increased, while the prevalence of one physical activity practice significantly decreased. The adoption of practices did not differ by school characteristics. Government investment can equitably enhance school adoption of some obesity prevention policies and practices on a jurisdiction-wide basis. Additional and/or different implementation strategies may be required to facilitate greater adoption of physical activity practices. Ongoing monitoring of school adoption of school policies and practices is needed to ensure the intended benefits of government investment are achieved. PMID- 25516480 TI - Safety and immunogenicity of a delta inulin-adjuvanted inactivated Japanese encephalitis virus vaccine in pregnant mares and foals. AB - In 2011, following severe flooding in Eastern Australia, an unprecedented epidemic of equine encephalitis occurred in South-Eastern Australia, caused by Murray Valley encephalitis virus (MVEV) and a new variant strain of Kunjin virus, a subtype of West Nile virus (WNVKUN). This prompted us to assess whether a delta inulin-adjuvanted, inactivated cell culture-derived Japanese encephalitis virus (JEV) vaccine (JE-ADVAXTM) could be used in horses, including pregnant mares and foals, to not only induce immunity to JEV, but also elicit cross-protective antibodies against MVEV and WNVKUN. Foals, 74-152 days old, received two injections of JE-ADVAXTM. The vaccine was safe and well-tolerated and induced a strong JEV-neutralizing antibody response in all foals. MVEV and WNVKUN antibody cross-reactivity was seen in 33% and 42% of the immunized foals, respectively. JE ADVAXTM was also safe and well-tolerated in pregnant mares and induced high JEV neutralizing titers. The neutralizing activity was passively transferred to their foals via colostrum. Foals that acquired passive immunity to JEV via maternal antibodies then were immunized with JE-ADVAXTM at 36-83 days of age, showed evidence of maternal antibody interference with low peak antibody titers post immunization when compared to immunized foals of JEV-naive dams. Nevertheless, when given a single JE-ADVAXTM booster immunization as yearlings, these animals developed a rapid and robust JEV-neutralizing antibody response, indicating that they were successfully primed to JEV when immunized as foals, despite the presence of maternal antibodies. Overall, JE-ADVAXTM appears safe and well tolerated in pregnant mares and young foals and induces protective levels of JEV neutralizing antibodies with partial cross-neutralization of MVEV and WNVKUN. PMID- 25516482 TI - New insights into the meaning and usefulness of principal component analysis of concatenated trajectories. AB - A comparison between different conformations of a given protein, relating both structure and dynamics, can be performed in terms of combined principal component analysis (combined-PCA). To that end, a trajectory is obtained by concatenating molecular dynamics trajectories of the individual conformations under comparison. Then, the principal components are calculated by diagonalizing the correlation matrix of the concatenated trajectory. Since the introduction of this approach in 1995 it has had a large number of applications. However, the interpretation of the eigenvectors and eigenvalues so obtained is based on intuitive foundations, because analytical expressions relating the concatenated correlation matrix with those of the individual trajectories under consideration have not been provided yet. In this article, we present such expressions for the cases of two, three, and an arbitrary number of concatenated trajectories. The formulas are simple and show what is to be expected and what is not to be expected from a combined-PCA. Their correctness and usefulness is demonstrated by discussing some representative examples. The results can be summarized in a simple sentence: the correlation matrix of a concatenated trajectory is given by the average of the individual correlation matrices plus the correlation matrix of the individual averages. From this it follows that the combined-PCA of trajectories belonging to different free energy basins provides information that could also be obtained by alternative and more straightforward means. PMID- 25516481 TI - Brain regions involved in moxibustion-induced analgesia in irritable bowel syndrome with diarrhea: a functional magnetic resonance imaging study. AB - BACKGROUND: Moxibustion is one of the most commonly used therapies in acupuncture practice, and is demonstrated to be beneficial for patients with diarrhea from irritable bowel syndrome (D-IBS). But its mechanism remains unclear. Because visceral hypersensitivity in IBS patients has been documented by evaluation of perceived stimulations through functional magnetic resonance imaging (fMRI) studies, we focused on observing brain imaging changes in D-IBS patients during rectal balloon distention before and after moxibustion in order to reveal its possible central mechanism and further evaluate its effect. METHODS: This clinical trial is registered under the number: ChiCTR-TRC-10000887. Eighty D-IBS patients were randomly divided into a moxibustion and sham moxibustion group (control group) for a 4-week treatment. Fifteen patients in moxibustion group and thirteen patients in control group completed two fMRI scans during a 50 and 100 ml rectal balloon distention before and after treatment. Rectal pain were obtained with a scan test. Birmingham IBS Symptom Scale and IBS Quality of Life (QOL) Scale were used to evaluate therapeutic effect. RESULTS: After treatment, the decrease in Birmingham IBS Symptom Scale and IBS QOL Scale scores in moxibustion group was significantly greater than that of control group (P < 0.01). The defecation urge threshold and the pain perception threshold of moxibustion group was also significantly higher after treatment than that of control group (P < 0.01). The decrease in pain score during the 100 ml rectal balloon distention in moxibustion group was significantly greater than that of control group (P < 0.05). There was no definite activated center during the 50 ml rectal distention in either group before treatment. After treatment, the prefrontal cortex (PFC) was affected in moxibustion group, while the PFC and the anterior cingulated cortex (ACC) were affected in control group. During the 100 ml distention before treatment in both groups, the PFC and ACC were activated. After treatment, they disappeared in moxibustion group but remained in control group. CONCLUSIONS: Moxibustion can improve symptoms and quality of life in D-IBS patients. It can also decrease rectal sensitivity. The activation of PFC and ACC during a 100 ml rectal distention disappeared after moxibustion treatment. PMID- 25516484 TI - A resolution on folic acid fortification. PMID- 25516486 TI - The effect of solvent choice on the gelation and final hydrogel properties of Fmoc-diphenylalanine. AB - Gels can be formed by dissolving Fmoc-diphenylalanine (Fmoc-PhePhe or FmocFF) in an organic solvent and adding water. We show here that the choice and amount of organic solvent allows the rheological properties of the gel to be tuned. The differences in properties arise from the microstructure of the fibre network formed. The organic solvent can then be removed post-gelation, without significant changes in the rheological properties. Gels formed using acetone are meta-stable and crystals of FmocFF suitable for X-ray diffraction can be collected from this gel. PMID- 25516483 TI - Analytical approaches to support current understanding of exposure, uptake and distributions of engineered nanoparticles by aquatic and terrestrial organisms. AB - Initiatives to support the sustainable development of the nanotechnology sector have led to rapid growth in research on the environmental fate, hazards and risk of engineered nanoparticles (ENP). As the field has matured over the last 10 years, a detailed picture of the best methods to track potential forms of exposure, their uptake routes and best methods to identify and track internal fate and distributions following assimilation into organisms has begun to emerge. Here we summarise the current state of the field, focussing particularly on metal and metal oxide ENPs. Studies to date have shown that ENPs undergo a range of physical and chemical transformations in the environment to the extent that exposures to pristine well dispersed materials will occur only rarely in nature. Methods to track assimilation and internal distributions must, therefore, be capable of detecting these modified forms. The uptake mechanisms involved in ENP assimilation may include a range of trans-cellular trafficking and distribution pathways, which can be followed by passage to intracellular compartments. To trace toxicokinetics and distributions, analytical and imaging approaches are available to determine rates, states and forms. When used hierarchically, these tools can map ENP distributions to specific target organs, cell types and organelles, such as endosomes, caveolae and lysosomes and assess speciation states. The first decade of ENP ecotoxicology research, thus, points to an emerging paradigm where exposure is to transformed materials transported into tissues and cells via passive and active pathways within which they can be assimilated and therein identified using a tiered analytical and imaging approach. PMID- 25516485 TI - A pharmacodynamic comparison of 5 anti-platelet protocols in patients with ST elevation myocardial infarction undergoing primary PCI. AB - BACKGROUND: Despite advances in anti-platelet treatments, there still exists an early increase in both ischemic as well as bleeding events following primary PCI in patients with ST-elevation myocardial infarction (STEMI). Platelet inhibition data of different anti-platelet treatments in the acute phase of a myocardial infarction might offer some insight into these problems. The aim of this study was to evaluate the pharmacodynamic profile of 5 different anti-platelet treatments in the acute phase of STEMI in patients undergoing primary PCI. METHODS: A total of 223 STEMI patients undergoing primary PCI were prospectively included. Patients received either pre-hospital clopidogrel only, pre-hospital clopidogrel followed by prasugrel switch in the cath lab, prasugrel treatment only, pre-hospital clopidogrel followed by ticagrelor switch in the cath lab or pre-hospital ticagrelor only. Platelet reactivity was measured serially using vasodilator-stimulated phosphoprotein (VASP). RESULTS: Patients receiving pre hospital clopidogrel followed by prasugrel switch showed similar platelet inhibition data as patients receiving prasugrel only, with more than 90% being good responders the day after PCI. Average time from prasugrel administration to a VASP value of <50% was 1.5 hours. In patients receiving pre-hospital ticagrelor, 50% were good responders at completion of PCI and average time to a VASP-value of <50% was 2.3 hours. Only 32% of patients receiving clopidogrel only were responders the day after PCI. CONCLUSIONS: Switching from an upstream bolus dose of clopidogrel to prasugrel at the time of PCI, appeared as a safe and feasible option with no tendency for overshoot or attenuation of platelet inhibition. Pre-hospital administration of ticagrelor was associated with a 50% good responder rate at completion of PCI. PMID- 25516488 TI - Basal ganglia cerebral microbleeds and global cognitive function: the Kashima Scan Study. AB - BACKGROUND: We previously showed that global cognitive function was associated with deep or infratentorial (D/I) cerebral microbleeds (CMBs) in a Japanese healthy cohort. We continually recruited participates and performed further investigation to focus on the impact of different distributions of D/I CMBs on gradient-echo magnetic resonance imaging on global cognitive function. METHODS: A total of 1392 subjects including subjects without CMBs (n = 1335), with D/I CMBs limited to the basal ganglia (BG; BG group, n = 33), thalamus (thalamus group, n = 14), and infratentorial area (infratentorial group, n = 10) were included in analyses. Subjects with strictly lobar CMBs (n = 43) were excluded, but subjects in the BG, thalamus, and infratentorial groups could also have lobar CMBs. The mini-mental state examination (MMSE) was administered to determine global cognitive function; scores less than 27 or more than 1.5 standard deviations (SDs) below the age-education-related mean were regarded as impaired. RESULTS: In the multivariable logistic regression analyses, hypertension and severe white matter hyperintensities were associated with the BG group and the thalamus group. In multivariable logistic regression analysis of the association between D/I CMBs classification and impaired MMSE score, only the BG group consistently displayed associations with both MMSE score less than 27 (odds ratio [OR], 5.96; 95% confidence interval [CI], 2.08-17.09) and MMSE score more than 1.5 SDs below the age-education-related mean (OR, 3.34; 95% CI, 1.24-8.99). In the BG group, adjusted mean scores of total MMSE and "attention and calculation" were lower compared with subjects without CMBs. CONCLUSIONS: In our study of D/I CMBs, only BG CMBs have strong association with global cognitive function. This association was independent of CMBs in other location. PMID- 25516489 TI - Fiber-type-specific sensitivities and phenotypic adaptations to dietary fat overload differentially impact fast- versus slow-twitch muscle contractile function in C57BL/6J mice. AB - High-fat diets (HFDs) have been shown to interfere with skeletal muscle energy metabolism and cause peripheral insulin resistance. However, understanding of HFD impact on skeletal muscle primary function, i.e., contractile performance, is limited. Male C57BL/6J mice were fed HFD containing lard (HFL) or palm oil (HFP), or low-fat diet (LFD) for 5weeks. Fast-twitch (FT) extensor digitorum longus (EDL) and slow-twitch (ST) soleus muscles were characterized with respect to contractile function and selected biochemical features. In FT EDL muscle, a 30% 50% increase in fatty acid (FA) content and doubling of long-chain acylcarnitine (C14-C18) content in response to HFL and HFP feeding were accompanied by increase in protein levels of peroxisome proliferator-activated receptor-gamma coactivator 1alpha, mitochondrial oxidative phosphorylation complexes and acyl-CoA dehydrogenases involved in mitochondrial FA beta-oxidation. Peak force of FT EDL twitch and tetanic contractions was unaltered, but the relaxation time (RT) of twitch contractions was 30% slower compared to LFD controls. The latter was caused by accumulation of lipid intermediates rather than changes in the expression levels of proteins involved in calcium handling. In ST soleus muscle, no evidence for lipid overload was found in any HFD group. However, particularly in HFP group, the peak force of twitch and tetanic contractions was reduced, but RT was faster than LFD controls. The latter was associated with a fast-to-slow shift in troponin T isoform expression. Taken together, these data highlight fiber-type-specific sensitivities and phenotypic adaptations to dietary lipid overload that differentially impact fast- versus slow-twitch skeletal muscle contractile function. PMID- 25516492 TI - Late rectal toxicity after low-dose-rate brachytherapy: incidence, predictors, and management of side effects. AB - As clinical outcomes for patients with clinically localized prostate cancer continue to improve, patients and physicians are increasing making treatment decisions based on concerns regarding long-term morbidity. A primary concern is late radiation proctitis, a clinical entity embodied by various signs and symptoms, ranging from diarrhea to rectal fistulas. Here, we present a comprehensive literature review examining the clinical manifestations and pathophysiology of late radiation proctitis after low-dose-rate brachytherapy (BT), as well as its incidence and predictors. The long-term risks of rectal bleeding after BT are on the order of 5-7%, whereas the risks of severe ulceration or fistula are on the order of 0.6%. The most robust predictor appears to be the volume of rectum receiving the prescription dose. In certain situations (e.g., salvage setting, for patients with increased radiosensitivity, and following aggressive biopsy after BT), the risk of these severe toxicities may be increased by up to 10-fold. A variety of excellent management options exist for rectal bleeding, with endoscopic methods being the most commonly used. PMID- 25516493 TI - Clinical implementation and failure mode and effects analysis of HDR skin brachytherapy using Valencia and Leipzig surface applicators. AB - PURPOSE: The planning procedure for Valencia and Leipzig surface applicators (VLSAs) (Nucletron, Veenendaal, The Netherlands) differs substantially from CT based planning; the unfamiliarity could lead to significant errors. This study applies failure modes and effects analysis (FMEA) to high-dose-rate (HDR) skin brachytherapy using VLSAs to ensure safety and quality. METHOD: A multidisciplinary team created a protocol for HDR VLSA skin treatments and applied FMEA. Failure modes were identified and scored by severity, occurrence, and detectability. The clinical procedure was then revised to address high scoring process nodes. RESULTS: Several key components were added to the protocol to minimize risk probability numbers. (1) Diagnosis, prescription, applicator selection, and setup are reviewed at weekly quality assurance rounds. Peer review reduces the likelihood of an inappropriate treatment regime. (2) A template for HDR skin treatments was established in the clinic's electronic medical record system to standardize treatment instructions. This reduces the chances of miscommunication between the physician and planner as well as increases the detectability of an error. (3) A screen check was implemented during the second check to increase detectability of an error. (4) To reduce error probability, the treatment plan worksheet was designed to display plan parameters in a format visually similar to the treatment console display, facilitating data entry and verification. (5) VLSAs are color coded and labeled to match the electronic medical record prescriptions, simplifying in-room selection and verification. CONCLUSIONS: Multidisciplinary planning and FMEA increased detectability and reduced error probability during VLSA HDR brachytherapy. This clinical model may be useful to institutions implementing similar procedures. PMID- 25516491 TI - Emerging applications of small angle solution scattering in structural biology. AB - Small angle solution X-ray and neutron scattering recently resurfaced as powerful tools to address an array of biological problems including folding, intrinsic disorder, conformational transitions, macromolecular crowding, and self or hetero assembling of biomacromolecules. In addition, small angle solution scattering complements crystallography, nuclear magnetic resonance spectroscopy, and other structural methods to aid in the structure determinations of multidomain or multicomponent proteins or nucleoprotein assemblies. Neutron scattering with hydrogen/deuterium contrast variation, or X-ray scattering with sucrose contrast variation to a certain extent, is a convenient tool for characterizing the organizations of two-component systems such as a nucleoprotein or a lipid-protein assembly. Time-resolved small and wide-angle solution scattering to study biological processes in real time, and the use of localized heavy-atom labeling and anomalous solution scattering for applications as FRET-like molecular rulers, are amongst promising newer developments. Despite the challenges in data analysis and interpretation, these X-ray/neutron solution scattering based approaches hold great promise for understanding a wide variety of complex processes prevalent in the biological milieu. PMID- 25516490 TI - Multi-echo length and offset VARied saturation (MeLOVARS) method for improved CEST imaging. AB - PURPOSE: The aim of this study was to develop a technique for rapid collection of chemical exchange saturation transfer images with the saturation varied to modulate signal loss transfer and enhance contrast. METHODS: Multi-echo Length and Offset VARied Saturation (MeLOVARS) divides the saturation pulse of length Tsat into N = 3-8 submodules, each consisting of a saturation pulse with length of Tsat /N (~0.3-1 s), one or more low flip-angle gradient-echo readout(s) and a flip back pulse. This results in N readouts with increasing saturation time from Tsat /N to Tsat without extra scan time. RESULTS: For phantoms, eight images with Tsat incremented every 0.5 s from 0.5-4 s were collected simultaneously using MeLOVARS, which allows rapid determination of exchange rates for agent protons. For live mice bearing glioblastomas, the Z-spectra for five different Tsat values from 0.5 to 2.5 s were acquired in a time normally used for one Tsat . With the additional Tsat -dependence information, LOVARS phase maps were produced with a more clearly defined tumor boundary and an estimated 4.3-fold enhanced contrast to-noise ratio (CNR). We also show that enhancing CNR is achievable by simply averaging the collected images or transforming them using the principal component analysis. CONCLUSIONS: MeLOVARS enables collection of multiple saturation-time weighted images without extra time, producing a LOVARS phase map with increased CNR. PMID- 25516494 TI - Antioxidant effects of hydrogen sulfide on left ventricular remodeling in smoking rats are mediated via PI3K/Akt-dependent activation of Nrf2. AB - There is growing evidence that oxidative stress plays critical roles in the pathogenesis of cardiac remodeling. In the present study, we established a rat model of passive smoking and investigated the antioxidant effects of hydrogen sulfide (H2S) on smoking-induced left ventricular remodeling. Cardiac structure and function were evaluated using 2-dimensional echocardiography. Myocardial fibrosis was detected by Masson's trichrome staining and immunohistochemistry. Oxidative stress was assessed by measuring malondialdehyde levels, superoxide dismutase and glutathione peroxidase activities, and reactive oxygen species generation in the myocardium. Neonatal rat cardiomyocytes transfected with specific siRNA and exposed to cigarette smoke condensate and H2S donor sodium hydrosulfide were used to confirm the involvement of Nrf2 and PI3K/Akt signaling in the antioxidant effects of H2S. Our results indicated that H2S could protect against left ventricular remodeling in smoking rats via attenuation of oxidative stress. Moreover, H2S was also found to increase the phosphorylation of Akt and GSK3beta and decrease the nuclear expression of Fyn, which consequently leads to nuclear translocation of Nrf2 and elevated expression of HO-1 and NQO1. In conclusion, H2S may exert antioxidant effects on left ventricular remodeling in smoking rats via PI3K/Akt-dependent activation of Nrf2 signaling. PMID- 25516496 TI - mESC-based in vitro differentiation models to study vascular response and functionality following genotoxic insults. AB - Because of high exposure to systemic noxae, vascular endothelial cells (EC) have to ensure distinct damage defense and regenerative mechanisms to guarantee vascular health. For meaningful toxicological drug assessments employing embryonic stem cell (ESC)-based in vitro models, functional competence of differentiated progeny and detailed knowledge regarding damage defense mechanisms are essential. Here, mouse ESCs (mESC) were differentiated into functionally competent vascular cells (EC and smooth muscle cells [SMC]). mESC, EC, and SMC were comparatively analyzed regarding DNA repair and DNA damage response (DDR). Differentiation was accompanied by both congruent and unique alterations in repair and DDR characteristics. EC and SMC shared the downregulation of genes involved cell cycle regulation and repair of DNA double-strand breaks (DSBs) and mismatches, whereas genes associated with nucleotide excision repair (NER), apoptosis, and autophagy were upregulated when compared with mESC. Expression of genes involved in base excision repair (BER) was particularly low in SMC. IR induced formation of DSBs, as detected by nuclear gammaH2AX foci formation, was most efficient in SMC, the repair of DSBs was fastest in EC. Together with substantial differences in IR-induced phosphorylation of p53, Chk1, and Kap1, the data demonstrate complex alterations in DDR capacity going along with the loss of pluripotency and gain of EC- and SMC-specific functions. Notably, IR exposure of early vascular progenitors did not impair differentiation into functionally competent EC and SMC. Summarizing, mESC-based vascular differentiation models are informative to study the impact of environmental stressors on differentiation and function of vascular cells. PMID- 25516495 TI - The miR-322-TRAF3 circuit mediates the pro-apoptotic effect of high glucose on neural stem cells. AB - Maternal diabetes increases the risk of neural tube defects (NTDs), and caspase dependent apoptosis and gene dysregulation are implicated in this disease process. This study investigates the role of miR-322 and its putative target gene, TNF receptor-associated factor 3 (TRAF3), in high glucose-induced apoptosis. miR-322 and TRAF3 expression were assessed in embryos of nondiabetic and diabetic dams, and in neural stem cells under high glucose conditions. Maternal diabetes in vivo and high glucose in vitro significantly down-regulated miR-322 and up-regulated TRAF3 protein expression. Overexpression of the antioxidant enzyme, superoxide dismutase 1 (SOD1), or treatment with the SOD1 mimetic Tempol, abolished the effect of maternal diabetes or high glucose on miR 322 and TRAF3 expression, respectively. A miRNA target prediction algorithm reveals 2 miR-322 binding sites the 3'-untranslated region (UTR) of TRAF3 mRNA. A RNA pull-down assay using biotin-labeled miR-322 revealed that miR-322 interacted with the 3'-UTR of TRAF3 mRNA at one specific binding site. The miR-322 mimic or TRAF3 knockdown blocked high glucose-increased TRAF3 protein expression and apoptosis, whereas the miR-322 inhibitor mimicked the effect of high glucose leading to TRAF3 up-regulation and apoptosis. This study demonstrates that both maternal diabetes and high glucose negatively regulate miR-322 through oxidative stress. miR-322 interacts with the 3'-UTR of TRAF3 and represses its translation. The miR-322-TRAF3 pathway is implicated in high glucose-induced caspase activation and apoptosis. PMID- 25516498 TI - Identification of phloem-mobile mRNA. AB - Signaling between cells, tissues and organs is essential for multicellular organisms to coordinate and adapt their development and growth to internal and environmental changes. Plants have evolved a plant-specific symplasmic pathway, called plasmodesmata, for efficient intercellular communication, in addition to the receptor-ligand-based apoplasmic pathway. Long-distance signaling between distant organs is enabled via the phloem tube system, where plasmodesmata contribute to phloem loading and unloading for photosynthate allocation. In addition to signaling by small molecules such as metabolites and phytohormones, the transport of proteins, small RNAs and mRNAs is also considered an important mechanism to achieve long-distance signaling in plants. Recent studies on phloem mobile proteins and small RNAs have revealed their role in crucial physiological processes including flowering, systemic silencing and nutrient allocation. However, the biological role of mRNAs found in the phloem tube is not yet clear, though their mobility over long-distances has been well evidenced. To gain this knowledge, it is important to collect further information on mRNA profiles in the phloem translocation stream. In this review, I summarize the current approaches to identifying the mRNA population in the phloem translocation system, and discuss the possible role of short- and long-distance mRNA transport. PMID- 25516499 TI - Diffusion or bulk flow: how plasmodesmata facilitate pre-phloem transport of assimilates. AB - Assimilates synthesized in the mesophyll of mature leaves move along the pre phloem transport pathway to the bundle sheath of the minor veins from which they are loaded into the phloem. The present review discusses the most probable driving force(s) for the pre-phloem pathway, diffusion down the concentration gradient or bulk flow along a pressure gradient. The driving force seems to depend on the mode of phloem loading. In a majority of plant species phloem loading is a thermodynamically active process, involving the activity of membrane transporters in the sieve-element companion cell complex. Since assimilate movement includes an apoplasmic step, this mode is called apoplasmic loading. Well established is also the polymer-trap loading mode, where the phloem transport sugars are raffinose-family oligomers in herbaceous plants. Also this mode depends on the investment of energy, here for sugar oligomerization, and leads to a high sugar accumulation in the phloem, even though the phloem is not symplasmically isolated, but well coupled by plasmodesmata (PD). Hence the mode polymer-trap mode is also designated active symplasmic loading. For woody angiosperms and gymnosperms an alternate loading mode is currently matter of discussion, called passive symplasmic loading. Based on the limited material available, this review compares the different loading modes and suggests that diffusion is the driving force in apoplasmic loaders, while bulk flow plays an increasing role in plants having a continuous symplasmic pathway from mesophyll to sieve elements. Crucial for the driving force is the question where water enters the pre-phloem pathway. Surprisingly, the role of PD in water movement has not been addressed so far appropriately. Modeling of assimilate and water fluxes indicates that in symplasmic loaders a considerable part of water flux happens through the PD between bundle sheath and phloem. PMID- 25516500 TI - Plasmodesmata of brown algae. AB - Plasmodesmata (PD) are intercellular connections in plants which play roles in various developmental processes. They are also found in brown algae, a group of eukaryotes possessing complex multicellularity, as well as green plants. Recently, we conducted an ultrastructural study of PD in several species of brown algae. PD in brown algae are commonly straight plasma membrane-lined channels with a diameter of 10-20 nm and they lack desmotubule in contrast to green plants. Moreover, branched PD could not be observed in brown algae. In the brown alga, Dictyota dichotoma, PD are produced during cytokinesis through the formation of their precursor structures (pre-plasmodesmata, PPD). Clustering of PD in a structure termed "pit field" was recognized in several species having a complex multicellular thallus structure but not in those having uniseriate filamentous or multiseriate one. The pit fields might control cell-to-cell communication and contribute to the establishment of the complex multicellular thallus. In this review, we discuss fundamental morphological aspects of brown algal PD and present questions that remain open. PMID- 25516497 TI - Prenatal vitamin C and E supplementation in smokers is associated with reduced placental abruption and preterm birth: a secondary analysis. AB - OBJECTIVE: Smoking and pre-eclampsia (PE) are associated with increases in preterm birth, placental abruption and low birthweight. We evaluated the relationship between prenatal vitamin C and E (C/E) supplementation and perinatal outcomes by maternal self-reported smoking status focusing on outcomes known to be impacted by maternal smoking. DESIGN/SETTING/POPULATION: A secondary analysis of a multi-centre trial of vitamin C/E supplementation starting at 9-16 weeks in low-risk nulliparous women with singleton gestations. METHODS: We examined the effect of vitamin C/E by smoking status at randomisation using the Breslow-Day test for interaction. MAIN OUTCOME MEASURES: The trial's primary outcomes were PE and a composite outcome of pregnancy-associated hypertension (PAH) with serious adverse outcomes. Perinatal outcomes included preterm birth and abruption. RESULTS: There were no differences in baseline characteristics within subgroups (smokers versus nonsmokers) by vitamin supplementation status. The effect of prenatal vitamin C/E on the risk of PE (P = 0.66) or PAH composite outcome (P = 0.86) did not differ by smoking status. Vitamin C/E was protective for placental abruption in smokers (relative risk [RR] 0.09; 95% CI 0.00-0.87], but not in nonsmokers (RR 0.92; 95% CI 0.52-1.62) (P = 0.01), and for preterm birth in smokers (RR 0.76; 95% CI 0.58-0.99) but not in nonsmokers (RR 1.03; 95% CI 0.90 1.17) (P = 0.046). CONCLUSION: In this cohort of women, smoking was not associated with a reduction in PE or the composite outcome of PAH. Vitamin C/E supplementation appears to be associated with a reduction in placental abruption and preterm birth among smokers. PMID- 25516501 TI - Taxonomic study of a new eustigmatophycean alga, Vacuoliviride crystalliferum gen. et sp. nov. AB - This study investigated the taxonomic affiliation of the algal strain nak-9, which has been reported to absorb radioactive cesium with high efficiency, using light and electron microscopy, and molecular phylogenetic analysis based on 18S ribosomal RNA gene (rDNA) sequences. This alga is spherical and coccoid, with a smooth cell wall, large vacuole, crystalline structure, reddish globule, and refractile granules (lamellate vesicles). The cells possess one to several greenish parietal chloroplasts with a bulging pyrenoid surrounded by lamellate vesicles. The chloroplasts include orderly thylakoid lamellae but no girdle lamella. Molecular phylogenetic analysis suggests that strain nak-9 is a member of the eustigmatophycean clade, which includes Goniochloris, Pseudostaurastrum, and Trachydiscus. On the basis of these results, we propose that strain nak-9 (NIES-2860) comprises a new species and new genus of the Eustigmatophyceae, Vacuoliviride crystalliferum gen. et sp. nov. PMID- 25516502 TI - A model system for analyzing intercellular communication through plasmodesmata using moss protonemata and leaves. AB - Plant growth, development, and environmental responses require the proper regulation of intercellular movement of signals and nutrients. For this, plants have specialized cytoplasmic channels, the plasmodesmata (PD), which allow the symplasmic movement of micro- and macromolecules between neighboring cells. Internal and external signals spatio-temporally regulate the movement of molecules through the PD to control plant development and environmental responses. Although some aspects of targeted movement of molecules have been revealed, the mechanisms of non-targeted, diffusible flow of molecules through PD, and its regulation and function, remain poorly understood, particularly at the cellular level. Previously, we developed a system to quantitatively analyze non-targeted movement of a photoconvertible fluorescent protein, Dendra2, at the single-cell level in the filamentous protonemata tissue of the moss Physcomitrella patens. In protonemata, one-dimensional intercellular communication can be easily observed and quantitatively analyzed at the cellular level. In this review, we describe how protonemata and leaves of P. patens can be used to study symplasmic movement through PD, and discuss how this system can help improve our understanding of PD regulation and function in development and environmental responses in plants. PMID- 25516505 TI - Clinicopathological features, vitamin D serological levels and prognosis in cutaneous melanoma of shield-sites: an update. AB - Intermittent sun exposure and sunburns are strongly related to the development of melanoma (MM); however, MM can also arise in non-sun exposed areas, where other biological pathways may cause the disease, with different outcomes. At the same time, evidences of serum levels of vitamin D in melanoma patients according to sun-exposed or not-sun-exposed areas are still lacking, especially if compared with the percentage of BRAF mutation. We performed a retrospective analysis with patients registered in our electronic database and an observational study in patients with a recent diagnosis of MM. Performing Kaplan-Meier product and log rank test, median disease-free survival was 78 months in non-shield-sites (NST MM) patients and 20.5 months in shield-sites (ST-MM) patients (p < 0.0001); also in the long term, a better behavior was observed for NST-MM (80 vs. 42 months; p < 0.0001). Among 87 melanoma patients with a recent history of MM (<=30 days), we found that ST-MM patients showed lower values of vitamin D compared with NST-MM patients. Regarding BRAF status, a BRAF mutation was present in 13 % of ST-MM and in 41 % of NST-MM. Performing Mc-Nemar test, we found a statistical significant correlation between low serum levels of vitamin D in ST-MM and low percentage of BRAF mutation (p = 0.03), as well as between serum levels of vitamin D and high percentage of BRAF mutation in NST-MM (p < 0.001). All these aspects confirm that in ST-MM, other pathways play pivotal points, if compared with NST-MM. PMID- 25516504 TI - Role of osteopontin in osteosarcoma. AB - The primary bone malignancy osteosarcoma (OS) is a painful health burden, of which treatment remains a challenging problem. Identification of specific tumor biomarkers may help to investigate and develop the novel effective therapeutic approaches that have specific molecular target for the treatment of patients with OS. Osteopontin (OPN), a phosphorylated glycoprotein, is involved in many biological processes, such as biomineralization, bone remodeling and immune responses and has recently been reported to be associated with OS pathogenesis. Interestingly, both of the up- and down-regulation of OPN are involved in OS. During OS development, genetic or epigenetic disruption causes reduced expression of RUNX2 and OPN through the up-regulation of notch signaling pathway, leading to the development of OS. On the other hand, during hypoxic condition, upregulation of OPN induces the glucose uptake into hypoxic OS cells which is responsible for the OS cell proliferation and drug resistance. Recent evidences show that targeting OPN might be an important tool in OS therapeutics. This review has focused on the association of abnormal OPN expression with the pathogenesis of OS, the efficiency of OPN as a diagnostic tool for OS and the therapeutic aspects of OS by targeting OPN. PMID- 25516503 TI - Mobility of signaling molecules: the key to deciphering plant organogenesis. AB - Signaling molecules move between cells to form a characteristic distribution pattern within a developing organ; thereafter, they spatiotemporally regulate organ development. A key question in this process is how the signaling molecules robustly form the precise distribution on a tissue scale in a reproducible manner. Despite of an increasing number of quantitative studies regarding the mobility of signaling molecules, the detail mechanism of organogenesis via intercellular signaling is still unclear. We here review the potential advantages of plant development to address this question, focusing on the cytoplasmic continuity of plant cells through the plasmodesmata. The plant system would provide a unique opportunity to define the simple transportation mode of diffusion process, and, hence, the mechanism of organogenesis via intercellular signaling. Based on the advances in the understanding of intercellular signaling at the molecular level and in the quantitative imaging techniques, we discuss our current challenges in measuring the mobility of signaling molecules for deciphering plant organogenesis. PMID- 25516506 TI - Involving patients in reducing decision uncertainties around orphan and ultra orphan drugs: a rare opportunity? AB - INTRODUCTION: Uncertainty influences the amount of risk in decision making, and is typically related to clinical benefit, value for money, affordability, and/or adoption/diffusion of the technology (e.g., drug, device, procedure, etc.). Although evidence-based review processes within each stage of the technology lifecycle have been implemented to minimize uncertainty, high-quality information addressing that related to orphan and ultra-orphan drugs is often unavailable. The role that patients, as experts in their disease, may play in providing such information has yet to be fully explored. OBJECTIVE: The objective of this systematic review was to identify existing and proposed opportunities for patients with rare diseases and their families to provide input aimed at reducing decision uncertainties throughout the lifecycle of an orphan or ultra-orphan drug. METHODS: A comprehensive review of published and gray literature describing roles for patients and families in activities related to orphan and ultra-orphan drugs was conducted. In addition, the websites of regulatory and centralized reimbursement decision-making bodies in the top 22 OECD (Organisation for Economic Cooperation and Development) countries by gross domestic product (GDP) were scanned to identify current opportunities for patients with rare diseases in both stages. The websites of umbrella patient organizations for rare diseases in these countries were also scanned. These roles were then mapped onto a matrix to determine the stage in the technology lifecycle and types of uncertainties they directly or indirectly addressed. RESULTS: Across the 22 countries, nine roles for patients within regulatory related processes were identified, with at least one in each country. These roles were not specific to patients with rare diseases. Similarly, six different opportunities for patient input in centralized drug review processes were identified, all of which applied to patients, in general, rather than just those with rare diseases. 'Real-world' examples of patient involvement explicitly related to rare diseases centered around 11 different themes. Seven fell within the research and development or clinical trial stages of a drug's lifecycle. Of the remaining four, three were associated with education and advocacy. All of the proposed roles identified focused on greater involvement in (1) the design and conduct of clinical trials, or (2) the 'valuation' of evidence during reimbursement decision making. When mapped onto the matrix of decision uncertainties, almost all of the existing and proposed roles addressed 'clinical benefit'. Roles for patients in reducing 'value for money', affordability, or adoption/diffusion uncertainties were mainly indirect, and a result of patient involvement in activities aimed at generating information on clinical benefit, which is then used to inform discussions around these uncertainties. CONCLUSIONS: While patient involvement in activities that directly address uncertainties in clinical benefit may not be 'rare', opportunities for reducing those related to 'value for money', affordability, and adoption/diffusion remain scarce. PMID- 25516508 TI - A multidirectional epicrania fugax. PMID- 25516507 TI - Comparative potency of sensory-induced brainstem activation to trigger spreading depression and seizures in the cortex of awake rats: Implications for the pathophysiology of migraine aura. AB - BACKGROUND: Migraine and epilepsy are highly co-morbid neurological disorders associated with episodic dysfunction of both cortical and subcortical networks. The study examined the interrelation between cortical spreading depression, the electrophysiological correlate of migraine aura and seizures triggered at cortical and brainstem levels by repeated sound stimulation in rats with acoustic hypersensitivity (reflex audiogenic epilepsy). METHOD: In awake, freely moving rats with innate audiogenic epilepsy, 25 episodes of running seizure (brainstem seizures) were induced by repeated sound stimulation. Spreading depression and seizures were recorded using implanted cortical electrodes. RESULTS: The first sound-induced brainstem seizures evoked neither spreading depression nor seizures in the cortex. With repetition, brainstem seizures began to be followed by a single cortical spreading depression wave and an epileptiform discharge. Spreading depression was more frequent an early cortical event than seizures: spreading depression appeared after 8.4 +/- 1.0 repeated stimulations in 100% rats (n = 24) while cortical seizures were recorded after 12.9 +/- 1.2 tests in 46% rats. Brainstem seizure triggered unilateral long-latency spreading depression. Bilateral short-latency cortical spreading depression was recorded only after intense cortical seizures. CONCLUSION: These data show that episodic brainstem activation is a potent trigger of unilateral cortical spreading depression. Development of intense seizures in the cortex leads to initiation of spreading depression in multiple cortical sites of both hemispheres. PMID- 25516509 TI - A modified regression method to test publication bias in meta-analyses with binary outcomes. AB - BACKGROUND: The tendency towards publication bias is greater for observational studies than for randomized clinical trials. Several statistical methods have been developed to test the publication bias. However, almost all existing methods exhibit rather low power or have inappropriate type I error rates. METHODS: We propose a modified regression method, which used a smoothed variance to estimate the precision of a study, to test for publication bias in meta-analyses of observational studies. A comprehensive simulation study is carried out, and a real-world example is considered. RESULTS: The simulation results indicate that the performance of tests varies with the number of included studies, level of heterogeneity, event rates, and sample size ratio between two groups. Neither the existing tests nor the newly developed method is particularly powerful in all simulation scenarios. However, our proposed method has a more robust performance across different settings. In the presence of heterogeneity, the arcsine-Thompson test is a suitable alternative, and Peters' test can be considered as a complementary method when mild or no heterogeneity is present. CONCLUSIONS: Several factors should be taken into consideration when employing asymmetry tests for publication bias. Based on our simulation results, we provide a concise table to show the appropriate use of regression methods to test for publication bias based on our simulation results. PMID- 25516511 TI - The role of Toll-like receptor 4 on inflammation and Abeta formation in cortex astrocytes. AB - To investigate the role and possible molecular mechanism of astrocytes in inflammation and amyloid beta-protein (Abeta) formation, in this research, by using LPS to stimulate cultured rat astrocytes in vitro with or without anti-Toll like receptor 4 (TLR4) antibody pretreatment, we first detected the TLR4, TNF alpha, IL-1beta, beta-amyloid precursor protein (beta-APP) and beta-site APP clearing enzyme 1 (BACE1) mRNA with real-time PCR, and TLR4, NF-kappaB/P65 protein in cultured astrocytes by Western blot, and then further probed the translocation of NF-kappaB/P65 using immunofluorescence and the contents of TNF alpha, IL-1beta and Abeta in culture supernatant through ELISA. We found that all of these indexes increased at different degrees after LPS-stimulation. However, if pretreatment with anti- TLR4 antibody, such stimulating effects of LPS on the nuclear translocation of NF-kappaB/P65 and TNF-alpha, IL-1beta, Abeta contents in astrocytic culture supernatant were reduced significantly or disappeared in comparison with the group with only LPS-administration. Our results suggest that TLR4 in astrocytes might play an important role in the inflammation and Abeta formation through the TLR4/NF-kappaB signaling pathway, thus providing new knowledge and understanding of the inflammatory hypothesis of AD pathogenesis. PMID- 25516512 TI - Expression of hepcidin at the choroid plexus in normal aging rats is associated with IL-6/Stat3 signaling pathway. AB - Accumulating evidence has revealed that brain iron concentrations increase with aging, and the choroid plexus (CP) may be at the basis of iron-mediated toxicity and the increase in inflammation and oxidative stress that occurs with aging. The mechanism involves not only hepcidin, the key hormone in iron metabolism, but also iron-related proteins and signaling-transduction molecules, such as IL-6 and signal transducer and activator of transcription 3 (Stat3). The aim of the present study was to investigate the correlation between the IL-6/Stat3 signaling pathway and hepcidin at the CP in normal aging. Quantitative real time PCR and Western blot were used to determine the alterations in specific mRNA and corresponding protein changes at the CP at ages of 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33 and 36 months in Brown-Norway/Fischer (B-N/F) rats. The results demonstrated that hepcidin mRNA level at the CP kept stable in young rats (from 3 to 18 months), and increased with aging (from 21 to 36 months). The alterations of IL-6/p-Stat3 mRNA and protein expressions in normal aging were in accordance with that of hepcidin mRNA. Our data suggest that IL-6 may regulate hepcidin expression at the CP, upon interaction with the cognate cellular receptor, and through the Stat3 signaling transduction pathway. PMID- 25516513 TI - Enhancement of GABA-activated currents by arginine vasopressin in rat dorsal root ganglion neurons. AB - A growing number of studies have shown that arginine vasopressin (AVP) plays an analgesia role in the modulation of nociception. Previous studies have focused on the central mechanisms of AVP analgesia. The aim of the present study was to find out whether peripheral mechanisms are also involved. The effect of AVP on GABA activated currents (IGABA) and GABAA receptor function in freshly isolated dorsal root ganglion (DRG) neurons of rats were studied using whole cell patch clamp technique. The result showed that, IGABA were potentiated by pre-treatment with AVP (1 * 10-10-1 * 10-5 mol/L) in a concentration-dependent manner. Meanwhile, the GABA concentration-response curve was shifted upwards, with an increase of (49.1 +/- 4.0)% in the maximal current response but with no significant change in the EC50 values. These results indicate that the enhancing effect is non competitive. In addition, the effects of AVP on IGABA might be voltage independent. This potentiation of IGABA induced by AVP was almost completely blocked by the V1a receptor antagonist SR49059 (3 * 10-6 mol/L). Also it could be removed by intracellular dialysis of either GDP-beta-S (5 * 10-4mol/L), a non hydrolyzable GDP analog, or GF109203X (2 * 10-6 mol/L), a selective protein kinase C (PKC) inhibitor, with the re-patch clamp. These results suggest that AVP up-regulates the function of the GABAA receptor via G protein-coupled receptors and PKC-dependent signal pathways in rat DRG neurons, and this potentiation may underlie the analgesia induced by AVP. PMID- 25516515 TI - [Intraventricular injection of 5,7-dihydroxytryptamine alters neuronal activity of neurons in the medial prefrontal cortex of rat]. AB - The present study is aimed to investigated the firing activity of pyramidal neurons and interneurons in the medial prefrontal cortex (mPFC) in rats with bilateral intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) by using in vivo extracellular recording. The results showed that the injection of 5,7-DHT reduced the 5-hydroxytryptamine (5-HT) levels in the mPFC and dorsal raphe nucleus in the rats. The firing rate of mPFC pyramidal neurons in rats with 5,7-DHT injection was significantly higher than that of normal rats, and the firing pattern of these neurons also changed significantly towards a more burst firing, while the injection decreased the firing rate of mPFC interneurons and changed the firing pattern of the interneurons towards a more irregular. These results indicate that the lesions of the serotonergic neurons lead to the changes in the firing activity of mPFC pyramidal neurons and interneurons, suggesting that serotonergic system plays an important role in the regulation of the neuronal activity in the mPFC. PMID- 25516514 TI - Neuroprotection by scorpion venom heat resistant peptide in 6-hydroxydopamine rat model of early-stage Parkinson's disease. AB - Neuroprotective effect of scorpion venom on Parkinson's disease (PD) has already been reported. The present study was aimed to investigate whether scorpion venom heat resistant peptide (SVHRP) could attenuate ultrastructural abnormalities in mitochondria and oxidative stress in midbrain neurons of early-stage PD model. The early-stage PD model was established by injecting 6-hydroxydopamine (6-OHDA) (20 MUg/3 MUL normal saline with 0.1% ascorbic acid) into the striatum of Sprague Dawley (SD) rats unilaterally. The rats were intraperitoneally administered with SVHRP (0.05 mg/kg per day) or vehicle (saline) for 1 week. Two weeks after 6-OHDA treatment, the rats received behavior tests for validation of model. Three weeks after 6-OHDA injection, the immunoreactivity of dopaminergic neurons were detected by immunohistochemistry staining, and the ultrastructure of neuronal mitochondria in midbrain was observed by electron microscope. In the meantime, the activities of monoamine oxidase-B (MAO-B), superoxide dismutase (SOD) and content of malondialdehyde (MDA) in the mitochondria of the midbrain neurons, as well as the inhibitory ability of hydroxyl free radical and the antioxidant ability in the serum, were measured by corresponding kits. The results showed that 6-OHDA reduced the optical density of dopaminergic neurons, induced damage of mitochondrial ultrastructure of midbrain neurons, decreased SOD activity, increased MAO-B activity and MDA content, and reduced the antioxidant ability of the serum. SVHRP significantly reversed the previous harmful effects of 6-OHDA in early-stage PD model. These findings indicate that SVHRP may contribute to neuroprotection by preventing biochemical and ultrastructure damage changes which occur during early-stage PD. PMID- 25516516 TI - [Wavelet packet extraction and entropy analysis of telemetry EEG from the prelimbic cortex of medial prefrontal cortex in morphine-induced CPP rats]. AB - The purpose of the present study is to analyze the relationship between the telemetry electroencephalogram (EEG) changes of the prelimbic (PL) cortex and the drug-seeking behavior of morphine-induced conditioned place preference (CPP) rats by using the wavelet packet extraction and entropy measurement. The recording electrode was stereotactically implanted into the PL cortex of rats. The animals were then divided randomly into operation-only control and morphine-induced CPP groups, respectively. A CPP video system in combination with an EEG wireless telemetry device was used for recording EEG of PL cortex when the rats shuttled between black-white or white-black chambers. The telemetry recorded EEGs were analyzed by wavelet packet extraction, Welch power spectrum estimate, normalized amplitude and Shannon entropy algorithm. The results showed that, compared with operation-only control group, the left PL cortex's EEG of morphine-induced CPP group during black-white chamber shuttling exhibited the following changes: (1) the amplitude of average EEG for each frequency bands extracted by wavelet packet was reduced; (2) the Welch power intensity was increased significantly in 10-50 Hz EEG band (P < 0.01 or P < 0.05); (3) Shannon entropy was increased in beta, gamma1, and gamma2waves of the EEG (P < 0.01 or P < 0.05); and (4) the average information entropy was reduced (P < 0.01). The results suggest that above mentioned EEG changes in morphine-induced CPP group rat may be related to animals' drug-seeking motivation and behavior launching. PMID- 25516517 TI - [Short-term memory characteristics of vibration intensity tactile perception on human wrist]. AB - In this study, a recall experiment and a recognition experiment were designed to assess the human wrist's short-term memory characteristics of tactile perception on vibration intensity, by using a novel homemade vibrotactile display device based on the spatiotemporal combination vibration of multiple micro vibration motors as a test device. Based on the obtained experimental data, the short-term memory span, recognition accuracy and reaction time of vibration intensity were analyzed. From the experimental results, some important conclusions can be made: (1) The average short-term memory span of tactile perception on vibration intensity is 3 +/- 1 items; (2) The greater difference between two adjacent discrete intensities of vibrotactile stimulation is defined, the better average short-term memory span human wrist gets; (3) There is an obvious difference of the average short-term memory span on vibration intensity between the male and female; (4) The mechanism of information extraction in short-term memory of vibrotactile display is to traverse the scanning process by comparison; (5) The recognition accuracy and reaction time performance of vibrotactile display compares unfavourably with that of visual and auditory. The results from this study are important for designing vibrotactile display coding scheme. PMID- 25516518 TI - [Transplantation of human embryonic neural stem cells protects rats against cerebral ischemic injury]. AB - The purpose of this study is to explore the fate and effect of human embryonic neural stem cells (hNSCs) after transplantation into ipsilateral lateral ventricle of stroke rats. Adult rats were exposed to one-hour transient middle cerebral artery occlusion (MCAO), and then hNSCs were transplanted into ipsilateral lateral ventricle 7 days after reperfusion. Infarct volume was calculated by cresyl violet staining. The improvements of neural functions were assessed by behavioral tests. Immunofluorescence staining was performed to observe the migration and differentiation of transplanted hNSCs. The results showed that transplanted hNSCs significantly reduced ischemia-induced infarction in MCAO rats, and improved neural functional restoration when assessed by rotarod, footfault and corner-turn tests. The grafted cells migrated predominantly to several specific brain regions, such as corpus callosum and peri infarct area. Furthermore, these cells differentiated into oligodendrocytes and astrocytes in corpus callosum, and neurons in peri-infarct parenchyma. These results suggest that transplanted hNSCs through lateral ventricle of the ischemic side may exert effective therapeutic effects on stroke rats via migration and differentiation in specific brain regions. PMID- 25516519 TI - [Expression profile of microRNAs in the cardiomyocytes derived from mouse embryonic stem cells]. AB - Embryonic stem cells (ESCs), derived from the inner cell mass of blastocysts, are self-renewing and pluripotent cells with the ability to differentiate into all derivatives of three primary germ layers, including cardiomyocytes. Recent studies have revealed that posttranscriptional regulations of lineage specific genes by microRNAs (miRNAs) emerge as a new class of cell fate and lineage determinants of ESCs. However, the miRNAs that control ESC differentiation are still largely unexplored. In the present study, we aimed to identify miRNAs that might be involved in cardiac differentiation of ESCs. Using a hanging drop technique, mouse ESCs (mESCs) were differentiated into cardiomyocytes. We then used the Aligent miRNAs chip (miRbase V16.0) to evaluate miRNA expression levels between the ESC-derived beating area enriched with cardiomyocytes and non-beating area. The expression levels of 19 miRNAs changed over 5-fold between two areas (n = 3, P < 0.05). Among them, 5 miRNAs were upregulated and 14 miRNAs were downregulated in the beating area compared with the non-beating area (P < 0.05). Then quantitative real-time-PCR was used to analyze the miRNAs with the differentiated expression level over 10-fold seen in the Aligent miRNAs chip. miR 196a, miR-196b and miR-467e were confirmed to be significantly lower in the beating area than those in the non-beating area (n = 3, P < 0.05). TargetScan analysis further suggested that miR-196a and miR-196b might be negatively related to the cardiomyocytes differentiation. Our findings provide a new clue for exploring roles of miRNAs in cardiac lineage commitment of mESCs. PMID- 25516520 TI - [Acquirement and evaluation of murine ventricular extracellular matrix]. AB - Cardiac extracellular matrix (ECM), generated from the process of decellularization, has been widely considered as an ideal source of biological scaffolds. However, current ECM preparations are generally difficult to be applied to generate cardiac tissue. Our research was aimed to improve decellularization protocols to prepare cardiac ECM slices. Adult murine ventricular tissues were embedded in low melting agarose and cut into 300 MUm slices, and then were divided randomly into three groups: normal cardiac tissue, SDS treated group (0.1% SDS) and SDS+Triton X-100 treated group (0.1% SDS+0.5% Triton X-100). Total RNA content and protein content quantification, HE staining and immunostaining were used to evaluate the removal of cell components and preservation of vital ECM components. Furthermore, murine embryonic stem cell derived cardiomyocytes (mES-CMs) and mouse embryonic fibroblasts (MEFs) were co cultured with ECM slices to evaluate biocompatibility. The relative residual RNA and protein contents of ECM slices significantly decreased after decellularization. HE staining showed that SDS+Triton X-100 treatment better destroyed cellular structure and removed nuclei of ECM slices, compared with SDS treatment. Immunostaining showed that collagen IV and laminin were better preserved and presented better similarity to original cardiac tissue in ECM slices acquired by SDS+Triton X-100 treatment. However, collagen IV and laminin were significantly decreased and arranged disorderly in SDS treated group. We observed effective survival (>= 12 days) of MEFs and mES-CMs on ECM slices acquired by SDS+Triton X-100 treatment, and signs of integration, whereas those signs were not found in SDS treated group. We concluded that, compared with traditional SDS method, new combined protocol (SDS+Triton X-100) generated ECM slices with better component and structural preservation, as well as better biocompatibility. PMID- 25516521 TI - [High intracellular Mg2+ affects the activities of L-type calcium channel in guinea- pig ventricular myocytes]. AB - This study is aimed to investigate the effects of high intracellular Mg2+ on L type calcium channel in guinea-pig ventricular myocytes. The cardiomyocytes were acutely isolated with enzyme digestion method. By adopting inside-out configuration of patch clamp technique, single channel currents of the L-type calcium channel were recorded under different intracellular Mg2+ concentrations ([Mg2+]i). In control group, which was treated with 0.9 mmol/L Mg2+, the relative activity of calcium channel was (176.5 +/- 34.1)% (n = 7). When [Mg2+]i was increased from 0.9 to 8.1 mmol/L (high Mg2+ group), the relative activities of calcium channel decreased to (64.8 +/- 18.1)% (n = 6, P < 0.05). Moreover, under 8.1 mmol/L Mg2+, the mean open time of calcium channel was shortened to about 25% of that under control condition (P < 0.05), but the mean close time of calcium channel was not altered. These results suggest that high intracellular Mg2+ may inhibit the activities of L-type calcium channel, which is mainly due to the shortening of the mean open time of single L-type calcium channel. PMID- 25516522 TI - [Anti-gastric cancer effect of melatonin and Bcl-2, Bax, p21 and p53 expression changes]. AB - In order to investigate the role of melatonin in inhibiting the proliferation of murine gastric cancer and the underlying molecular mechanism, we performed an in vivo study by inoculating murine foregastric carcinoma (MFC) cells in mice, and then tumor-bearing mice were treated with different concentrations of melatonin (i.p.). The changes of Bcl-2, Bax, p21 and p53 expressions in tumor tissue were detected by using real-time fluorescence quantitative RT-PCR and Western blot. We found that: (1) melatonin resulted in reductions of tumor's volume and weight in the gastric cancer-bearing mice and thus showed anti-cancer effect; (2) melatonin reduced Bcl-2 expression, but increased the expression of Bax, p53 and p21 in tumor tissue. Our results suggest that melatonin could inhibit the growth of tumors in gastric cancer-bearing mice through accelerating the apoptosis of tumor cells. PMID- 25516523 TI - [The progress and prospect of prepulse inhibition in autism]. AB - Prepulse inhibition (PPI) is suppression of the startle reflex when an intense startling stimulus is preceded by a weaker sensory stimulus (the prepulse). It is an operational measurement of sensorimotor gating mechanism to help human adapt to complex environment. This weak prepulse protect central cognitive processing by damping the effect of intense stimuli. Autistics cannot select out behaviorally important information from a lot of irrelevant resources and reflect abnormal gating mechanism and attentional abnormalities. Previous studies have not made agreement on whether autistic patients demonstrated deficits in PPI, because the results depend on age, sex, severity of the disease as well as the experimental parameters used. Moreover, these studies have not covered whether autistics have suffered deficits in higher-order processing. In this review, the "top-down" modulation of selective attention and subjective emotion are introduced into the PPI experiment. We also introduce fear conditioning and perceived spatial separation paradigm to further explore the interaction between autistic cognitive process and gating mechanism. PMID- 25516524 TI - [Research progress on autophagy regulating excessive inflammation]. AB - Autophagy is a highly conserved cellular self-digestion pathway, by which intracellular damaged proteins or organelles are delivered to lysosomes for degradation, so as to protect from various dangerous stimuli and maintain cellular homeostasis. Inflammation is a defensive response to injury or pathogens, through which various inflammatory mediators coordinate host defense and repair. However, uncontrolled inflammatory responses can lead to secondary damage and pathogenesis of inflammatory disease. Recent studies indicate that autophagy pathway and related proteins may play important roles in regulating immune response and controlling excessive inflammation. This review introduced research progress in the role of autophagy in regulating excessive inflammation and possible mechanisms. PMID- 25516525 TI - [Multi-channel in vivo recording techniques: analysis of phase coupling between spikes and rhythmic oscillations of local field potentials]. AB - The purpose of this article is to introduce the measurements of phase coupling between spikes and rhythmic oscillations of local field potentials (LFPs). Multi channel in vivo recording techniques allow us to record ensemble neuronal activity and LFPs simultaneously from the same sites in the brain. Neuronal activity is generally characterized by temporal spike sequences, while LFPs contain oscillatory rhythms in different frequency ranges. Phase coupling analysis can reveal the temporal relationships between neuronal firing and LFP rhythms. As the first step, the instantaneous phase of LFP rhythms can be calculated using Hilbert transform, and then for each time-stamped spike occurred during an oscillatory epoch, we marked instantaneous phase of the LFP at that time stamp. Finally, the phase relationships between the neuronal firing and LFP rhythms were determined by examining the distribution of the firing phase. Phase locked spikes are revealed by the non-random distribution of spike phase. Theta phase precession is a unique phase relationship between neuronal firing and LFPs, which is one of the basic features of hippocampal place cells. Place cells show rhythmic burst firing following theta oscillation within a place field. And phase precession refers to that rhythmic burst firing shifted in a systematic way during traversal of the field, moving progressively forward on each theta cycle. This relation between phase and position can be described by a linear model, and phase precession is commonly quantified with a circular-linear coefficient. Phase coupling analysis helps us to better understand the temporal information coding between neuronal firing and LFPs. PMID- 25516526 TI - Navigating care transitions: a process model of how doctors overcome organizational barriers and create awareness. AB - As reforms push for improved integration across the care continuum, managers and policy makers are increasingly concerned about care transitions, such as during shift changes or when moving patients between units or institutions. The authors examined transitions from an emergency department to inpatient units through a 2 year ethnographic study of an academic medical center. Data include 48 semistructured interviews with doctors and administrators and 349 hr of observations of doctors. The authors show that organizational design poses challenges to doctors attempting between-unit care transitions, including heavy reliance on technology, separation of responsibility and control, and misalignment of routines and temporal rhythms. Each challenge threatened doctors' awareness of the current state of other units and processes. To recover awareness, doctors engaged in time-consuming workarounds. Improved awareness will likely require a mix of interventions, including standardized protocols, work redesign, advanced information technologies specifically designed to enhance awareness, and high-reliability practices, such as safety organizing. PMID- 25516528 TI - Functional repression of PtSND2 represses growth and development by disturbing auxin biosynthesis, transport and signaling in transgenic poplar. AB - Using chimeric repressor silencing technology, we previously reported that functional repression of PtSND2 severely arrested wood formation in transgenic poplar (Populus). Here, we provide further evidence that auxin biosynthesis, transport and signaling were disturbed in these transgenic plants, leading to pleiotropic defects in their growth patterns, including inhibited leaf enlargement and vascular tissue development in the leaf central vein, suppressed cambial growth and fiber elongation in the stem, and arrested growth in the root system. Two transgenic lines, which displayed the most remarkable phenotypic deviation from the wild-type, were selected for detailed studies. In both transgenic lines, expression of genes for auxin biosynthesis, transport and signaling was down-regulated, and indole-3-acetic acid distribution was severely disturbed in the apical buds, leaves, stems and roots of field-grown transgenic plants. Transient transcription dual-luciferase assays of ProPtTYDC2::LUC, ProPttLAX2::LUC and ProPoptrIAA20.2::LUC in poplar protoplasts revealed that expression of auxin-related genes might be regulated by PtSND2 at the transcriptional level. All these results indicate that functional repression of PtSND2 altered auxin biosynthesis, transport and signaling, and thereby disturbed the normal growth and development of transgenic plants. PMID- 25516527 TI - High-speed AFM images of thermal motion provide stiffness map of interfacial membrane protein moieties. AB - The flexibilities of extracellular loops determine ligand binding and activation of membrane receptors. Arising from fluctuations in inter- and intraproteinaceous interactions, flexibility manifests in thermal motion. Here we demonstrate that quantitative flexibility values can be extracted from directly imaging the thermal motion of membrane protein moieties using high-speed atomic force microscopy (HS-AFM). Stiffness maps of the main periplasmic loops of single reconstituted water channels (AqpZ, GlpF) revealed the spatial and temporal organization of loop-stabilizing intraproteinaceous H-bonds and salt bridges. PMID- 25516530 TI - Hide and seek: does the toe-brachial index allow for earlier recognition of peripheral arterial disease in diabetic patients? AB - OBJECTIVE/BACKGROUND: Arterial calcification may render the ankle-brachial index (ABI) unreliable in diabetic patients. Although guidelines recommend the toe brachial index (TBI) for patients with falsely elevated ABI arbitrarily defined as an ABI > 1.4, arterial calcification is also common among diabetic patients with an ABI <= 1.4. This could result in a "falsely normalized" ABI and under diagnosis of peripheral arterial disease (PAD). We investigated whether diabetes invalidates the ABI as opposed to the TBI, and if the TBI may therefore be more suitable for detecting PAD in diabetic patients. METHODS: The difference between ABI and TBI was compared between diabetic and non-diabetic patients with an ABI <= 1.4 referred to the vascular laboratory. A Bland-Altman plot was constructed to assess whether ABI-TBI differences were dependent on the magnitude of the measurements. Subgroup analyses were performed for patients with a normal ABI, and for patients with critical ischemia. RESULTS: The population comprised 161 diabetic (252 limbs) and 160 non-diabetic (253 limbs) patients (mean age 67). Median ABIs (0.79 vs. 0.80) were similar, while median TBI was 0.07 higher in diabetics (p = 0.024). The ABI-TBI difference in diabetics and non-diabetics was similar (0.32 vs. 0.35; p = .084), and was also similar for patients with a normal ABI. Moreover, ABI-TBI differences in diabetic- and non-diabetic patients overlapped, irrespective of the magnitude of the measurements. Diabetes was not associated with larger differences between ankle and toe pressures (mean difference -0.9 mmHg, 95% confidence interval -15 to 13 mmHg) among patients with critical ischemia. CONCLUSION: No evidence was found that the TBI may overcome the potentially invalidated ABI in diabetic patients with an ABI <= 1.4. ABI and TBI are strongly associated, and this relationship is not influenced by diabetes. Therefore, the TBI does not allow for earlier detection of ischemia in diabetes. PMID- 25516531 TI - Poole and Bournemouth hospitals should have another chance to put the case for a merger, charity says. PMID- 25516529 TI - Preaching to the choir: comparing health professionals who enroll in mind-body skills versus herbs and dietary supplements training? AB - BACKGROUND: Observational studies evaluating elective training programs may be biased if learners who enroll differ from nonenrollees. To assess self-selection bias, we compared participants who enrolled in 2 different online courses in complementary and alternative medical therapies. METHODS: Participants were recruited from entering classes in medicine, nursing, social work, and dietetics, and residencies in family medicine and pediatrics. The 2 electives were (a) herbs and dietary supplements and (b) mind-body skills training. Participants completed standardized questionnaires before training. RESULTS: The 218 participants had an average age of 28 years; 76% were trainees. There were no significant differences between enrollees in mind-body skills and herbs and dietary supplements with regard to age, gender, stress levels, mind-body training or practice, mindfulness, empathy, compassion, or resilience. CONCLUSIONS: Those who enroll in mind-body skills are not measurably different than those who enroll in herbs and dietary supplements. There is no evidence of self-selection bias or "preaching to the choir." PMID- 25516532 TI - Minimizing bleeding complications in spinal tumor surgery with preoperative Onyx embolization via dual-lumen balloon catheter. AB - BACKGROUND: Intraoperative bleeding is a significant risk in surgery for highly vascular spinal tumors, but preoperative embolization can safely decrease intraoperative blood loss in extrinsic spine tumors. Onyx, widely used for cerebrovascular embolization, has been increasingly used as an embolic agent for preoperative spinal tumor embolization. The Scepter catheter, a dual-lumen balloon catheter, may improve tumor parenchymal penetration without the danger and limitations of significant embolic reflux. This may reduce bleeding risk during spinal surgery. METHODS: Eleven consecutive cases of preoperative Onyx embolization of extrinsic spinal tumors were identified, all of whom had subsequent spinal surgery. Demographic data and clinical variables were collected. Patients were divided into Scepter (n=6) and non-Scepter (n=5) groups. The Mann-Whitney U test was used to compare continuous outcome variables and the Fisher exact test was used to compare categorical variables. RESULTS: Estimated blood loss in the Scepter group was significantly lower than in the non-Scepter group (584+/-124 vs 2400+/-738 mL, p=0.004). The volume of intraoperative transfusion was also significantly lower (1.2+/-0.4 vs 5.8+/-1.7 units, p=0.004). There was no significant difference in the number of vessels embolized, vials of Onyx used, use of coiling adjunct, contrast load, radiation dose, or fluoroscopy time per pedicle (p>0.05). CONCLUSIONS: The addition of the Scepter catheter to preoperative Onyx embolization is safe and feasible. In this small series, the Scepter catheter was associated with a reduction of intraoperative bleeding by 76% and a 79% lower transfusion volume. This was not accompanied by any unwanted increase in vials of Onyx used, contrast load, radiation dose, or fluoroscopy time. PMID- 25516533 TI - Short term outcomes following clipping and coiling of ruptured intracranial aneurysms: does some of the benefit of coiling stem from less procedural impact on deranged physiology at presentation? AB - BACKGROUND: Endovascular coiling (EVC) has been shown to yield superior clinical outcomes to surgical clipping (SC) in the treatment of ruptured cerebral aneurysms. The reasons for these differences remain obscure. We aimed to assess outcomes of EVC and SC relative to baseline physiological derangement. METHODS: This was an exploratory analysis of prospectively collected trial data. Physiological derangement was assessed using the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring system. Other contributory variables such as age, World Federation of Neurosurgical Societies (WFNS) grade, and development of complications, including hydrocephalus and vasospasm, were included in the analysis. Clinical outcome was independently assessed at 90 days using the modified Rankin Scale (mRS). Hospital stay, ventilated days, and total norepinephrine dose were also used as secondary outcomes. Multivariate analysis was performed using binary logistic regression. RESULTS: EVC was performed in 69 patients and SC in 66 patients. More profound physiological derangement (APACHE II score >15) was the strongest predictor of poor outcome in the overall cohort (OR 17.80, 95% CI 4.78 to 66.21, p<0.0001). For those with more deranged physiology (APACHE II score>15; 59 patients), WFNS grade >=4 (OR 6.74, 1.43 to 31.75) and SC (OR 6.33, 1.27 to 31.38) were significant predictors of poor outcome (p<0.05). Favorable outcome (mRS 0-2) was seen in 11% of SC patients compared with 38% of EVC patients in this subgroup. SC patients had significantly increased total norepinephrine dose, ventilated days, and hospital stay (p<0.05). CONCLUSIONS: More profound physiological derangement at baseline is a strong predictor of eventual poor outcome, and outcomes for patients with more profound baseline physiological derangement may be improved if undergoing a coiling procedure. PMID- 25516534 TI - Flow diverter stent treatment for ruptured basilar trunk perforator aneurysms. AB - OBJECTIVE: Basilar trunk perforator (BTP) aneurysms are rare. Treatment options traditionally considered for these uncommon lesions have included direct surgery, endovascular therapy, or conservative management. Flow diverters represent a newer therapeutic option for BTP aneurysms but pitfalls and complications are unknown. We describe three patients with BTP aneurysms treated with flow diverter stents. METHODS: All three patients had ruptured BTP aneurysms and, after loading doses of dual antiplatelet agents, underwent treatment with a flow diverter alone (two patients) or in combination with an intracranial stent (one patient). RESULTS: Complications directly (two thromboembolic events) or indirectly (one hemorrhage at the external ventricular drain site, probably facilitated by the dual antiplatelet therapy) occurred in all three patients and resulted in permanent morbidity in one case. Imaging follow-up confirmed obliteration in all three patients, and no episodes of rebleeding from the aneurysms were observed at follow-up. CONCLUSIONS: Flow diverters are effective in obliterating BTP aneurysms. However, given the challenges and complications encountered, especially in patients with ruptured lesions, their use must be carefully weighed against other available therapeutic modalities, including observation. PMID- 25516535 TI - Readiness for smoking cessation in coronary heart disease patients across Europe: Results from the EUROASPIRE III survey. AB - BACKGROUND: Readiness for smoking cessation is an important predictor of quit attempts and cessation success. We aimed to investigate the prevalence and correlates of readiness for smoking cessation in coronary heart disease (CHD) patients. DESIGN: The EUROpean Action on Secondary and Primary Prevention by Intervention to Reduce Events III (EUROASPIRE III) survey is a cross-sectional study conducted in 2006-2007 among CHD patients <80 years of age from 22 European regions. METHODS: Patients were interviewed on average 15 months after hospital admission for an acute coronary event or procedure. Readiness for smoking cessation was assessed using the smoking stages of change (SSC) short form questionnaire. Breath carbon monoxide was measured to validate self-reported non smoking. RESULTS: Among 2585 patients who were smoking prior to hospital admission, 25.6%, 16.8%, 8.1%, 5.6% and 44.0% were in the precontemplation (no intention to quit), contemplation (thinking of quitting), preparation (planning to quit), action (having quit within six months) and maintenance (having quit more than six months ago) stages, respectively. Significant multivariable correlates of advancement in SSC showed positive associations of older age and attended cardiac rehabilitation and negative associations of severe depressive symptoms, longer smoking duration and environmental tobacco smoke (ETS) exposure. CONCLUSIONS: One-quarter of CHD patients across Europe who were smoking prior to hospitalisation have no intention to quit, and an additional quarter is thinking of quitting or planning to quit. Patients who are younger, do not attend cardiac rehabilitation, have severe depressive symptoms, have been smoking for longer periods of time and are exposed to ETS may need to be specifically targeted in cessation interventions. PMID- 25516536 TI - Rapid reversal of severe lactic acidosis after thiamine administration in critically ill adults: a report of 3 cases. AB - BACKGROUND: Thiamine plays a critical role in energy metabolism. Critically ill patients may have thiamine deficiency and increased mortality due to potentially irreversible consequences. The aim of this study was to show the impact of thiamine deficiency in a series of patients and the rapid response to thiamine replacement, showing the changes in clinical and metabolic conditions over time. METHODS: We described 3 cases of hospitalized patients who had received parenteral nutrition (PN) without vitamin supplementation. All the patients were admitted to the ICU between 2010 and 2011 with a severe form of lactic acidosis, an unstable circulatory state, and a different neurological disorder (a lethargic state, a severe form of impaired near-coma consciousness, and Wernicke encephalopathy). RESULTS: Intravenous (IV) administration of thiamine was associated with a rapid and marked restoration of acid-base balance, hemodynamic stability and the disappearance of neurological disturbances, and normalization of the clinical and biochemical conditions of all the patients within the following hours. CONCLUSIONS: The 3 cases demonstrated the rapidity of the reversal of severe thiamine deficiency, achieved by appropriate replacement in different hospitalized patients. The regression of clinical and biochemical disorders requires a prompt diagnosis and treatment based on the IV administration of thiamine and magnesium sulfate. In hospitalized patients at risk, thiamine deficiency is prevented by the integration of thiamine supplementation into PN and other forms of nutrition support. PMID- 25516537 TI - Enteral nutrition formula selection: current evidence and implications for practice. AB - Many new enteral nutrition (EN) formulas have been created over the past several decades with a variety of intended uses. Although each is intended to promote improved outcomes, research is often unclear and, in many cases, conflicting. It is important to note that EN products are considered medical foods by the U.S. Food and Drug Administration and therefore do not have to complete premarket review or approval and are not regulated to the same extent as pharmaceuticals. While standard EN formulas are designed to meet the basic macro- and micronutrient requirements of individuals who cannot meet nutrition needs orally, specialty EN products have been developed to exhibit pharmacologic properties, such as immune-enhancing formulas containing arginine, glutamine, nucleotides, and omega-3 fatty acids. With the vast number of products available, rising costs of healthcare, and the drive toward evidence-based practice, it is imperative that clinicians carefully consider research regarding use of specialty formulas, paying close attention to the quality, patient population, clinical end points, and cost to patient and/or facility. PMID- 25516538 TI - Addressing the Social Determinants of Health to Reduce Tobacco-Related Disparities. AB - INTRODUCTION: Comprehensive tobacco prevention and control efforts that include implementing smoke-free air laws, increasing tobacco prices, conducting hard hitting mass media campaigns, and making evidence-based cessation treatments available are effective in reducing tobacco use in the general population. However, if these interventions are not implemented in an equitable manner, certain population groups may be left out causing or exacerbating disparities in tobacco use. Disparities in tobacco use have, in part, stemmed from inequities in the way tobacco control policies and programs have been adopted and implemented to reach and impact the most vulnerable segments of the population that have the highest rates of smokings (e.g., those with lower education and incomes). METHODS: Education and income are the 2 main social determinants of health that negatively impact health. However, there are other social determinants of health that must be considered for tobacco control policies to be effective in reducing tobacco-related disparities. This article will provide an overview of how tobacco control policies and programs can address key social determinants of health in order to achieve equity and eliminate disparities in tobacco prevention and control. RESULTS: Tobacco control policy interventions can be effective in addressing the social determinants of health in tobacco prevention and control to achieve equity and eliminate tobacco-related disparities when they are implemented consistently and equitably across all population groups. CONCLUSIONS: Taking a social determinants of health approach in tobacco prevention and control will be necessary to achieve equity and eliminate tobacco-related disparities. PMID- 25516540 TI - When somebody loses weight, where does the fat go? AB - Ruben Meerman and Andrew Brown explain why the answer might not be what you expect. PMID- 25516539 TI - SearCh for humourIstic and Extravagant acroNyms and Thoroughly Inappropriate names For Important Clinical trials (SCIENTIFIC): qualitative and quantitative systematic study. AB - OBJECTIVES: To describe the development of acronym use across five major medical specialties and to evaluate the technical and aesthetic quality of the acronyms. DESIGN: Acronyms obtained through a literature search of Pubmed.gov followed by a standardised assessment of acronym quality (BEAUTY and CHEATING criteria). PARTICIPANTS: Randomised controlled trials within psychiatry, rheumatology, pulmonary medicine, endocrinology, and cardiology published between 2000 and 2012. MAIN OUTCOME MEASURES: Prevalence proportion of acronyms and composite quality score for acronyms over time. RESULTS: 14,965 publications were identified, of which 18.3% (n=2737) contained an acronym in the title. Acronym use was more common among cardiological studies than among the other four medical specialties (40% v 8-15% in 2012, P<0.001). Except for within cardiology, the prevalence of acronyms increased over time, with the average prevalence proportion among the remaining four specialties increasing from 4.0% to 12.4% from 2000 to 2012 (P<0.001). The median combined acronym quality score decreased significantly over the study period (P<0.001), from a median 9.25 in 2000 to 5.50 in 2012. CONCLUSION: From 2000 to 2012 the prevalence of acronyms in trial reports increased, coinciding with a substantial decrease in the technical and aesthetic quality of the acronyms. Strict enforcement of current guidelines on acronym construction by journal editors is necessary to ensure the proper use of acronyms in the future. PMID- 25516541 TI - Genetic characterization of a novel picornavirus detected in Miniopterus schreibersii bats. AB - Bats are important reservoirs of many viruses with zoonotic potential worldwide, including Europe. Among bat viruses, members of the Picornaviridae family remain a neglected group. We performed viral metagenomic analyses on Miniopterus schreibersii bat faecal samples, collected in Hungary in 2013. In the present study we report the first molecular data and genomic characterization of a novel picornavirus from the bat species M. schreibersii in Europe. Based on phylogenetic analyses, the novel bat picornaviruses unambiguously belong to the Mischivirus genus and were highly divergent from other bat-derived picornaviruses of the Sapelovirus genus. Although the Hungarian viruses were most closely related to Mischivirus A, they formed a separate monophyletic branch within the genus. PMID- 25516542 TI - Vif determines the requirement for CBF-beta in APOBEC3 degradation. AB - APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3) proteins are cellular DNA deaminases that restrict a broad spectrum of lentiviruses. This process is counteracted by Vif (viral infectivity factor) of lentiviruses, which binds APOBEC3s and promotes their degradation. CBF-beta (core binding factor subunit beta) is an essential co-factor for the function of human immunodeficiency virus type 1 Vif to degrade human APOBEC3s. However, the requirement for CBF-beta in Vif-mediated degradation of other mammalian APOBEC3 proteins is less clear. Here, we determined the sequence of feline CBFB and performed phylogenetic analyses. These analyses revealed that mammalian CBFB is under purifying selection. Moreover, we demonstrated that CBF-beta is dispensable for feline immunodeficiency virus Vif-mediated degradation of APOBEC3s of its host. These findings suggested that primate lentiviruses have adapted to use CBF beta, an evolutionary stable protein, to counteract APOBEC3 proteins of their hosts after diverging from other lentiviruses. PMID- 25516544 TI - Bortezomib-induced acute pancreatitis: Case report and review of the literature. AB - Acute pancreatitis is a rare complication of chemotherapy agents. We describe the case of a patient with multiple myeloma who developed acute pancreatitis after treatment with bortezomib, a proteasome inhibitor commonly used in the treatment of this disease. We reviewed the available medical literature on this topic, and found other seven similar cases, all after intravenous bortezomib. Our case is the first one occurring with the subcutaneous route of administration. PMID- 25516543 TI - Molecular and immunological characterization of a DNA-launched yellow fever virus 17D infectious clone. AB - Yellow fever virus (YFV)-17D is an empirically developed, highly effective live attenuated vaccine that has been administered to human beings for almost a century. YFV-17D has stood as a paradigm for a successful viral vaccine, and has been exploited as a potential virus vector for the development of recombinant vaccines against other diseases. In this study, a DNA-launched YFV-17D construct (pBeloBAC-FLYF) was explored as a new modality to the standard vaccine to combine the commendable features of both DNA vaccine and live-attenuated viral vaccine. The DNA-launched YFV-17D construct was characterized extensively both in cell culture and in mice. High titres of YFV-17D were generated upon transfection of the DNA into cells, whereas a mutant with deletion in the capsid-coding region (pBeloBAC-YF/DeltaC) was restricted to a single round of infection, with no release of progeny virus. Homologous prime-boost immunization of AAD mice with both pBeloBAC-FLYF and pBeloBAC-YF/DeltaC elicited specific dose-dependent cellular immune response against YFV-17D. Vaccination of A129 mice with pBeloBAC FLYF resulted in the induction of YFV-specific neutralizing antibodies in all vaccinated subjects. These promising results underlined the potential of the DNA launched YFV both as an alternative to standard YFV-17D vaccination and as a vaccine platform for the development of DNA-based recombinant YFV vaccines. PMID- 25516545 TI - Pre-B cell colony enhancing factor induces Nampt-dependent translocation of the insulin receptor out of lipid microdomains in A549 lung epithelial cells. AB - Pre-B cell colony-enhancing factor (PBEF) is a highly conserved pleiotropic protein reported to be an alternate ligand for the insulin receptor (IR). We sought to clarify the relationship between PBEF and insulin signaling by evaluating the effects of PBEF on the localization of the IRbeta chain to lipid rafts in A549 epithelial cells. We isolated lipid rafts from A549 cells and detected the IR by immunoprecipitation from raft fractions or whole cell lysates. Cells were treated with rPBEF, its enzymatic product nicotinamide adenine dinucleotide (NAD), or the Nampt inhibitor daporinad to study the effect of PBEF on IRbeta movement. We used coimmunoprecipitation studies in cells transfected with PBEF and IRbeta constructs to detect interactions between PBEF, the IRbeta, and caveolin-1 (Cav-1). PBEF was present in both lipid raft and nonraft fractions, whereas the IR was found only in lipid raft fractions of resting A549 cells. The IR-, PBEF-, and Cav-1-coimmunoprecipitated rPBEF treatment resulted in the movement of IRbeta- and tyrosine-phosphorylated Cav-1 from lipid rafts to nonrafts, an effect that could be blocked by daporinad, suggesting that this effect was facilitated by the Nampt activity of PBEF. The addition of PBEF to insulin-treated cells resulted in reduced Akt phosphorylation of both Ser473 and Thr308. We conclude that PBEF can inhibit insulin signaling through the IR by Nampt-dependent promotion of IR translocation into the nonraft domains of A549 epithelial cells. PBEF-induced alterations in the spatial geometry of the IR provide a mechanistic explanation for insulin resistance in inflammatory states associated with upregulation of PBEF. PMID- 25516546 TI - Estriol blunts postprandial blood glucose rise in male rats through regulating intestinal glucose transporters. AB - Despite increased total food intake in healthy, late-stage pregnant women, their peak postprandial blood sugar levels are normally much lower than the levels seen in healthy nonpregnant women. In this study, we sought to determine whether estriol (E3), an endogenous estrogen predominantly produced during human pregnancy, contributes to the regulation of the postprandial blood glucose level in healthy normal rats. In vivo studies using rats showed that E3 blunted the speed and magnitude of the blood glucose rise following oral glucose administration, but it did not appear to affect the total amount of glucose absorbed. E3 also did not affect insulin secretion, but it significantly reduced the rate of intestinal glucose transport compared with vehicle-treated animals. Consistent with this finding, expression of the sodium-dependent glucose transporter 1 and 2 was significantly downregulated by E3 treatment in the brush border membrane and basolateral membrane, respectively, of enterocytes. Most of the observed in vivo effects were noticeably stronger with E3 than with 17beta estradiol. Using differentiated human Caco-2 enterocyte monolayer culture as an in vitro model, we confirmed that E3 at physiologically relevant concentrations could directly inhibit glucose uptake via suppression of glucose transporter 2 expression, whereas 17beta-estradiol did not have a similar effect. Collectively, these data showed that E3 can blunt the postprandial glycemic surge in rats through modulating the level of intestinal glucose transporters. PMID- 25516548 TI - Transcriptome profiling of brown adipose tissue during cold exposure reveals extensive regulation of glucose metabolism. AB - We applied digital gene expression profiling to determine the transcriptome of brown and white adipose tissues (BAT and WAT, respectively) during cold exposure. Male C57BL/6J mice were exposed to cold for 2 or 4 days. A notable induction of genes related to glucose uptake, glycolysis, glycogen metabolism, and the pentose phosphate pathway was observed in BAT from cold-exposed animals. In addition, glycerol-3-phosphate dehydrogenase 1 expression was induced in BAT from cold challenged mice, suggesting increased synthesis of glycerol from glucose. Similarly, expression of lactate dehydrogenases was induced by cold in BAT. Pyruvate dehydrogenase kinase 2 (Pdk2) and Pdk4 were expressed at significantly higher levels in BAT than in WAT, and Pdk2 was induced in BAT by cold. Of notice, only a subset of the changes detected in BAT was observed in WAT. Based on changes in gene expression during cold exposure, we propose a model for the intermediary glucose metabolism in activated BAT: 1) fluxes through glycolysis and the pentose phosphate pathway are induced, the latter providing reducing equivalents for de novo fatty acid synthesis; 2) glycerol synthesis from glucose is increased, facilitating triacylglycerol synthesis/fatty acid re esterification; 3) glycogen turnover and lactate production are increased; and 4) entry of glucose carbon into the tricarboxylic acid cycle is restricted by PDK2 and PDK4. In summary, our results demonstrate extensive and diverse gene expression changes related to glucose handling in activated BAT. PMID- 25516549 TI - Leptin in pregnancy and development: a contributor to adulthood disease? AB - Emerging research has highlighted the importance of leptin in fetal growth and development independent of its essential role in the maintenance of hunger and satiety through the modulation of neuropeptide Y and proopiomelanocortin neurons. Alterations in maternal-placental-fetal leptin exchange may modify the development of the fetus and contribute to the increased risk of developing disease in adulthood. In addition, leptin also plays an important role in reproductive functions, with plasma leptin concentrations rising in pregnant women, peaking during the third trimester. Elevated plasma leptin concentrations occur at the completion of organogenesis, and research in animal models has demonstrated that leptin is involved in the development and maturation of a number of organs, including the heart, brain, kidneys, and pancreas. Elevated maternal plasma leptin is associated with maternal obesity, and reduced fetal plasma leptin is correlated with intrauterine growth restriction. Alterations in plasma leptin during development may be associated with an increased risk of developing a number of adulthood diseases, including cardiovascular, metabolic, and renal diseases via altered fetal development and organogenesis. Importantly, research has shown that leptin antagonism after birth significantly reduces maturation of numerous organs. Conversely, restoration of the leptin deficiency after birth in growth-restricted animals restores the offspring's body weight and improves organogenesis. Therefore, leptin appears to play a major role in organogenesis, which may adversely affect the risk of developing a number of diseases in adulthood. Therefore, greater understanding of the role of leptin during development may assist in the prevention and treatment of a number of disease states that occur in adulthood. PMID- 25516547 TI - Impaired cardiac energy metabolism in embryos lacking adrenergic stimulation. AB - As development proceeds from the embryonic to fetal stages, cardiac energy demands increase substantially, and oxidative phosphorylation of ADP to ATP in mitochondria becomes vital. Relatively little, however, is known about the signaling mechanisms regulating the transition from anaerobic to aerobic metabolism that occurs during the embryonic period. The main objective of this study was to test the hypothesis that adrenergic hormones provide critical stimulation of energy metabolism during embryonic/fetal development. We examined ATP and ADP concentrations in mouse embryos lacking adrenergic hormones due to targeted disruption of the essential dopamine beta-hydroxylase (Dbh) gene. Embryonic ATP concentrations decreased dramatically, whereas ADP concentrations rose such that the ATP/ADP ratio in the adrenergic-deficient group was nearly 50 fold less than that found in littermate controls by embryonic day 11.5. We also found that cardiac extracellular acidification and oxygen consumption rates were significantly decreased, and mitochondria were significantly larger and more branched in adrenergic-deficient hearts. Notably, however, the mitochondria were intact with well-formed cristae, and there was no significant difference observed in mitochondrial membrane potential. Maternal administration of the adrenergic receptor agonists isoproterenol or l-phenylephrine significantly ameliorated the decreases in ATP observed in Dbh-/- embryos, suggesting that alpha- and beta adrenergic receptors were effective modulators of ATP concentrations in mouse embryos in vivo. These data demonstrate that adrenergic hormones stimulate cardiac energy metabolism during a critical period of embryonic development. PMID- 25516550 TI - A combination of exercise and capsinoid supplementation additively suppresses diet-induced obesity by increasing energy expenditure in mice. AB - Exercise effectively prevents the development of obesity and obesity-related diseases such as type 2 diabetes. Capsinoids (CSNs) are capsaicin analogs found in a nonpungent pepper that increase whole body energy expenditure. Although both exercise and CSNs have antiobesity functions, the effectiveness of exercise with CSN supplementation has not yet been investigated. Here, we examined whether the beneficial effects of exercise could be further enhanced by CSN supplementation in mice. Mice were randomly assigned to four groups: 1) high-fat diet (HFD, Control), 2) HFD containing 0.3% CSNs, 3) HFD with voluntary running wheel exercise (Exercise), and 4) HFD containing 0.3% CSNs with voluntary running wheel exercise (Exercise + CSN). After 8 wk of ingestion, blood and tissues were collected and analyzed. Although CSNs significantly suppressed body weight gain under the HFD, CSN supplementation with exercise additively decreased body weight gain and fat accumulation and increased whole body energy expenditure compared with exercise alone. Exercise together with CSN supplementation robustly improved metabolic profiles, including the plasma cholesterol level. Furthermore, this combination significantly prevented diet-induced liver steatosis and decreased the size of adipocyte cells in white adipose tissue. Exercise and CSNs significantly increased cAMP levels and PKA activity in brown adipose tissue (BAT), indicating an increase of lipolysis. Moreover, they significantly activated both the oxidative phosphorylation gene program and fatty acid oxidation in skeletal muscle. These results indicate that CSNs efficiently promote the antiobesity effect of exercise, in part by increasing energy expenditure via the activation of fat oxidation in skeletal muscle and lipolysis in BAT. PMID- 25516554 TI - Crisis of leadership. PMID- 25516551 TI - Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia. AB - Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 (P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 +/- 1.5 MUmol/min) to output by d4 (2.8 +/- 1.4 MUmol/min; P < 0.05 vs. basal). The [U-13C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 +/- 0.01, vs. d4: 0.89 +/- 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 (P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia (P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia. PMID- 25516555 TI - Tuning your practice: strategies to consider in a changing health care environment. PMID- 25516553 TI - Antiretroviral neuropenetration scores better correlate with cognitive performance of HIV-infected patients after accounting for drug susceptibility. AB - BACKGROUND: The aim of the study was to explore how viral resistance and antiretroviral central nervous system (CNS) penetration could impact on cognitive performance of HIV-infected patients. METHODS: We performed a multicentre cross sectional study enrolling HIV-infected patients undergoing neuropsychological testing, with a previous genotypic resistance test on plasma samples. CNS penetration-effectiveness (CPE) scores and genotypic susceptibility scores (GSS) were calculated for each regimen. A composite score (CPE-GSS) was then constructed. Factors associated with cognitive impairment were investigated by logistic regression analysis. RESULTS: A total of 215 patients were included. Mean CPE was 7.1 (95% CI 6.9, 7.3) with 206 (95.8%) patients showing a CPE>=6. GSS correction decreased the CPE value in 21.4% (mean 6.5, 95% CI 6.3, 6.7), 26.5% (mean 6.4, 95% CI 6.1, 6.6) and 24.2% (mean 6.4, 95% CI 6.2, 6.6) of subjects using ANRS, HIVDB and REGA rules, respectively. Overall, 66 (30.7%) patients were considered cognitively impaired. No significant association could be demonstrated between CPE and cognitive impairment. However, higher GSS-CPE was associated with a lower risk of cognitive impairment (CPE-GSSANRS odds ratio 0.75, P=0.022; CPE-GSSHIVDB odds ratio 0.77, P=0.038; CPE-GSSREGA odds ratio 0.78, P=0.038). Overall, a cutoff of CPE-GSS>=5 seemed the most discriminatory according to each different interpretation system. CONCLUSIONS: GSS-corrected CPE score showed a better correlation with neurocognitive performance than the standard CPE score. These results suggest that antiretroviral drug susceptibility, besides drug CNS penetration, can play a role in the control of HIV-associated neurocognitive disorders. PMID- 25516552 TI - Comparison of the physiological relevance of systemic vs. portal insulin delivery to evaluate whole body glucose flux during an insulin clamp. AB - To understand the underlying pathology of metabolic diseases, such as diabetes, an accurate determination of whole body glucose flux needs to be made by a method that maintains key physiological features. One such feature is a positive differential in insulin concentration between the portal venous and systemic arterial circulation (P/S-IG). P/S-IG during the determination of the relative contribution of liver and extra-liver tissues/organs to whole body glucose flux during an insulin clamp with either systemic (SID) or portal (PID) insulin delivery was examined with insulin infusion rates of 1, 2, and 5 mU.kg(-1).min( 1) under either euglycemic or hyperglycemic conditions in 6-h-fasted conscious normal rats. A P/S-IG was initially determined with endogenous insulin secretion to exist with a value of 2.07. During an insulin clamp, while inhibiting endogenous insulin secretion by somatostatin, P/S-IG remained at 2.2 with PID, whereas, P/S-IG disappeared completely with SID, which exhibited higher arterial and lower portal insulin levels compared with PID. Consequently, glucose disappearance rates and muscle glycogen synthetic rates were higher, but suppression of endogenous glucose production and liver glycogen synthetic rates were lower with SID compared with PID. When the insulin clamp was performed with SID at 2 and 5 mU.kg(-1).min(-1) without managing endogenous insulin secretion under euglycemic but not hyperglycemic conditions, endogenous insulin secretion was completely suppressed with SID, and the P/S-IG disappeared. Thus, compared with PID, an insulin clamp with SID underestimates the contribution of liver in response to insulin to whole body glucose flux. PMID- 25516557 TI - Younger women's experiences of deciding against delayed breast reconstruction post-mastectomy following breast cancer: An interpretative phenomenological analysis. AB - Most women do not reconstruct their breast(s) post-mastectomy. The experiences of younger women who maintain this decision, although important to understand, are largely absent in the research literature. This interview-based study uses interpretative phenomenological analysis to explore the experiences of six women, diagnosed with primary breast cancer in their 30s/40s, who decided against delayed reconstruction. Findings reported here focus on one superordinate theme (decision-making) from a larger analysis, illustrating that the women's drive to survive clearly influenced their initial decision-making process. Their tenacity in maintaining their decision is highlighted, despite non-reconstruction sometimes being presented negatively by medical teams. Patient-centred support recommendations are made. PMID- 25516556 TI - Anisotropic poly (glycerol sebacate)-poly (epsilon-caprolactone) electrospun fibers promote endothelial cell guidance. AB - Topographical cell guidance is utilized to engineer highly organized and aligned cellular constructs for numerous tissue engineering applications. Recently, electrospun scaffolds fabricated using poly(glycerol sebacate) (PGS) and poly(epsilon-caprolactone) (PCL) have shown a great promise to support valvular interstitial cell functions for the development of tissue engineered heart valves. However, one of the major drawbacks of PGS-PCL scaffolds is the lack of control over cellular alignment. In this work, we investigate the role of scaffold architecture on the endothelial cell alignment, proliferation and formation of organized cellular structures. In particular, PGS-PCL scaffolds with randomly oriented and highly aligned fibers with tunable mechanical properties were fabricated using electrospinning technique. After one week of culture, endothelial cells on the aligned scaffolds exhibited higher proliferation compared to those cultures on randomly oriented fibrous scaffolds. Furthermore, the endothelial cells reorganized in response to the topographical features of aligned scaffolds forming highly organized cellular constructs. Thus, topographical contact guidance, provided by aligned PGS-PCL scaffolds, is envisioned to be useful in developing cellular structures for vascular tissue engineering. PMID- 25516559 TI - The relationship between male BMI and waist circumference on semen quality: data from the LIFE study. PMID- 25516558 TI - Enhanced miR-210 expression promotes the pathogenesis of endometriosis through activation of signal transducer and activator of transcription 3. AB - STUDY QUESTION: What are the roles of the microRNA miR-210-an miRNA that is up regulated in endometriotic cyst stromal cells (ECSCs)-in the pathogenesis of endometriosis? SUMMARY ANSWER: Up-regulated miR-210 expression in ECSCs is involved in their proliferation, resistance to apoptosis and angiogenesis through signal transducer and activator of transcription (STAT) 3. WHAT IS KNOWN ALREADY: In the pathogenesis of endometriosis, a number of roles for microRNAs (miRNAs) are becoming apparent. STUDY DESIGN, SIZE, DURATION: ECSCs and normal endometrial stromal cells (NESCs) were isolated from ovarian endometriotic tissues (patients aged 24-40 years undergoing salpingo-oophorectomy or evisceration for the treatment of ovarian endometriotic cysts, n = 10) and the eutopic endometrial tissues without endometriosis (premenopausal patients aged 35-45 years undergoing hysterectomies for subserousal leiomyoma, n = 13), respectively. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used a global gene expression microarray technique to identify downstream targets of miR-210, and we assessed the functions of miR-210 in the pathogenesis of endometriosis by using the miR 210-transfected NESCs. MAIN RESULTS AND THE ROLE OF CHANCE: Gene expression microarray analysis revealed that one of the key target molecules of miR-210 is STAT3. In the NESCs, in comparison to the control, miR-210 transfection resulted in the induction of cell proliferation (P < 0.0005), the production of vascular endothelial cell growth factor (VEGF) (P < 0.0005) and the inhibition of apoptosis (P < 0.05) through STAT3 activation [increased levels of mRNA (P < 0.0005), and protein (P < 0.005)]. In the ECSCs, inhibitors of STAT3 inhibited the cell proliferation and VEGF production (P < 0.05), and induced the apoptosis of these cells (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The roles of aberrant miR-210 expression were investigated only in the stromal component of ectopic and eutopic endometrium. Control endometrial tissues were obtained from premenopausal patients who had subserosal leiomyoma and NESC gene expression patterns may be altered in these women. Furthermore, the effects of STAT3 inhibitors were evaluated only in ECSCs and not in NESCs. WIDER IMPLICATIONS OF THE FINDINGS: The present findings indicate that miR-210 induces NESCs to differentiate into the endometriotic phenotype and we speculate that up-regulated miR-210 expression in ECSCs is involved in the creation of the endometriosis specific cellular dysfunctions through epigenetic mechanisms. The data indicate that STAT3 inhibitors may be promising candidates for the treatment of endometriosis. STUDY FUNDING/COMPETING INTERESTS: This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 13237327 to K.N., no. 25861500 to Y.K. and no. 23592407 to H.N.). There are no conflicts of interest to declare. PMID- 25516560 TI - Sperm DNA damage and ART: sins of the fathers and the doctors? PMID- 25516561 TI - Reply: sperm DNA damage and ART: sins of the fathers and the doctors? PMID- 25516562 TI - Editorial: A new Editor-in-Chief and the 40th anniversary of the Journal of Antimicrobial Chemotherapy. PMID- 25516563 TI - A new look for OEM in 2015. PMID- 25516565 TI - Commentary on Raquel A. G. Reyes, "Environmentalist thinking and the question of disease causation in late Spanish Philippines". PMID- 25516570 TI - Phosphatidylinositol 3-kinase and 4-kinase have distinct roles in intracellular trafficking of cellulose synthase complexes in Arabidopsis thaliana. AB - The oriented deposition of cellulose microfibrils in the plant cell wall plays a crucial role in various plant functions such as cell growth, organ formation and defense responses. Cellulose is synthesized by cellulose synthase complexes (CSCs) embedded in the plasma membrane (PM), which comprise the cellulose synthases (CESAs). The abundance and localization of CSCs at the PM should be strictly controlled for precise regulation of cellulose deposition, which strongly depends on the membrane trafficking system. However, the mechanism of the intracellular transport of CSCs is still poorly understood. In this study, we explored requirements for phosphoinositides (PIs) in CESA trafficking by analyzing the effects of inhibitors of PI synthesis in Arabidopsis thaliana expressing green fluorescent protein-tagged CESA3 (GFP-CESA3). We found that a shift to a sucrose-free condition accelerated re-localization of PM-localized GFP CESA3 into the periphery of the Golgi apparatus via the clathrin-enriched trans Golgi network (TGN). Treatment with wortmannin (Wm), an inhibitor of phosphatidylinositol 3- (PI3K) and 4- (PI4K) kinases, and phenylarsine oxide (PAO), a more specific inhibitor for PI4K, inhibited internalization of GFP-CESA3 from the PM. In contrast, treatment with LY294002, which impairs the PI3K activity, did not exert such an inhibitory effect on the sequestration of GFP CESA3, but caused a predominant accumulation of GFP-CESA3 at the ring-shaped periphery of the Golgi apparatus, resulting in the removal of GFP-CESA3 from the PM. These results indicate that PIs are essential elements for localization and intracellular transport of CESA3 and that PI4K and PI3K are required for distinct steps in secretory and/or endocytic trafficking of CESA3. PMID- 25516571 TI - Characterization of the histidine-rich loop of Arabidopsis vacuolar membrane zinc transporter AtMTP1 as a sensor of zinc level in the cytosol. AB - The vacuolar Zn(2+)/H(+) antiporter of Arabidopsis thaliana, AtMTP1, has a long cytosolic histidine-rich loop. A mutated AtMTP1 in which the first half of the loop (His-half) was deleted exhibited a 11-fold higher transport velocity in yeast cells. Transgenic lines overexpressing the His-half-deleted AtMTP1 in the loss-of-function mutant were evaluated for growth and metal content in the presence of various zinc concentrations. These overexpressing lines (35S-AtMTP1 and 35S-His-half lines) showed high tolerance to excess concentrations of zinc at 150 uM, as did the wild type, compared with the loss-of-function line. The His half AtMTP1 transported cobalt in a heterologous expression assay in yeast, but the cumulative amount of cobalt in 35S-His-half plants was not increased. Moreover, the accumulation of calcium and iron was not changed in plants. Under zinc-deficient conditions, growth of 35S-His-half lines was markedly suppressed. Under the same conditions, the 35S-His-half lines accumulated larger amounts of zinc in roots and smaller amounts of zinc in shoots compared with the other lines, suggesting an abnormal accumulation of zinc in the roots of 35S-His-half lines. As a result, the shoots may exhibit zinc deficiency. Taken together, these results suggest that the His-loop acts as a sensor of cytosolic zinc to maintain an essential level in the cytosol and that the dysfunction of the loop results in an uncontrolled accumulation of zinc in the vacuoles of root cells. PMID- 25516572 TI - A mathematical model of phloem sucrose transport as a new tool for designing rice panicle structure for high grain yield. AB - Rice (Oryza sativa) is one of the most important food crops in the world. Numerous quantitative trait loci or genes controlling panicle architecture have been identified to increase grain yield. Yet grain yield, defined as the product of the number of well-ripened grains and their weight, is a complex trait that is determined by multiple factors such as source, sink and translocation capacity. Mechanistic modelling capturing capacities of source, sink and transport will help in the theoretical design of crop ideotypes that guarantee high grain yield. Here we present a mathematical model simulating sucrose transport and grain growth within a complex phloem network. The model predicts that the optimal panicle structure for high yield shows a simple grain arrangement with few higher order branches. In addition, numerical analyses revealed that inefficient delivery of carbon to panicles with higher order branches prevails regardless of source capacity, indicating the importance of designing grain arrangement and phloem structure. Our model highlights the previously unexplored effect of grain arrangement on the yield, and provides numerical solutions for optimal panicle structure under various source and sink capacities. PMID- 25516569 TI - Plant flavoprotein photoreceptors. AB - Plants depend on the surrounding light environment to direct their growth. Blue light (300-500 nm) in particular acts to promote a wide variety of photomorphogenic responses including seedling establishment, phototropism and circadian clock regulation. Several different classes of flavin-based photoreceptors have been identified that mediate the effects of blue light in the dicotyledonous genetic model Arabidopsis thaliana. These include the cryptochromes, the phototropins and members of the Zeitlupe family. In this review, we discuss recent advances, which contribute to our understanding of how these photosensory systems are activated by blue light and how they initiate signaling to regulate diverse aspects of plant development. PMID- 25516573 TI - Mitragynine 'Kratom' related fatality: a case report with postmortem concentrations. AB - A 24-year-old man whose medical history was significant for alcohol abuse and depression was found unresponsive in bed. He had several prior suicide attempts with 'pills' and had also been hospitalized for an accidental overdose on a previous occasion. Autopsy findings were unremarkable apart from pulmonary edema and congestion, and urinary retention. Postmortem peripheral blood initially screened positive for mitragynine 'Kratom' (by routine alkaline drug screen by gas chromatography-mass spectrometry, GC-MS), which was subsequently confirmed by a specific GC-MS selective ion mode analysis following solid-phase extraction. Concentrations were determined in the peripheral blood (0.23 mg/L), central blood (0.19 mg/L), liver (0.43 mg/kg), vitreous (<0.05 mg/L), urine (0.37 mg/L) and was not detected in the gastric. Therapeutic concentrations of venlafaxine, diphenhydramine and mirtazapine were also detected together with a negligible ethanol of 0.02% (w/v). The results are discussed in relation to previous cases of toxicity, and the lack of potential for mitragynine postmortem redistribution. PMID- 25516574 TI - The REPLACE Death after replacement evaluation score for predicting mortality after device replacement or upgrade: should all implantable devices be replaced? PMID- 25516575 TI - Cardiac resynchronization therapy-induced proarrhythmia: understanding preferential conduction within myocardial scars. PMID- 25516576 TI - Modern approach to the sudden unexpected death investigation. PMID- 25516577 TI - Sudden cardiac death risk stratification in dilated cardiomyopathy: climbing the pyramid of knowledge. PMID- 25516578 TI - Contact force during VT ablation: vector orientation is key. PMID- 25516579 TI - Acute atrial stretch results in conduction slowing and complex signals at the pulmonary vein to left atrial junction: insights into the mechanism of pulmonary vein arrhythmogenesis. AB - BACKGROUND: The pulmonary vein-left atrial (PV-LA) junction is key in pathogenesis of AF, and acute stretch is an important stimulus to AF. We aimed to characterize the response of the junction to acute stretch, hypothesizing that stretch would result in electrophysiological changes predisposing to re-entry. METHODS AND RESULTS: Fifteen participants undergoing cardiac surgery underwent evaluation of the right superior PV-LA junction using an epicardial mapping plaque. In 10, this was performed before and after atrial stretch imposed by rapid volume expansion, and in 5, it was performed with an intervening observation period. Activation was characterized by conduction slowing and electrogram fractionation transversely across the PV-LA junction, with lines of block also demonstrated perpendicular to the junction. Conduction was decremental (plaque activation time 135.8 +/- 46.8 ms with programmed extra stimuli at 10 ms above effective refractory period versus 66.1 +/- 22.9 ms with pacing at 400 ms; P<0.001) and percentage fractionation was greater with programmed extra stimuli at 10 ms above (33.5%+/- 15.3% versus 20.7%+/- 14.0%, P=0.001). Right atrial pressure increased by 2.5 +/- 1.8 mm Hg (P=0.002) with volume expansion. Stretch resulted in conduction slowing across the PV-LA junction (increase in activation time 10.9 +/- 14.6 ms in acute stretch group versus -0.1 +/- 4.5 ms in control group; P=0.002). Conduction slowing was more marked with programmed extra stimuli at 10 ms above effective refractory period than with stable pacing (13.4 +/- 16.5 ms versus 1.7 +/- 5.4 ms; P=0.003). Stretch resulted in a significant increase in fractionated electrograms (7.9%+/- 7.0% versus -0.4 +/- 3.3; P=0.004). CONCLUSIONS: Acute stretch results in conduction slowing across the PV-LA junction, with a greater degree of signal complexity. This substrate may be important in AF initiation and maintenance by promoting re-entry. PMID- 25516580 TI - Role of atrial fibrillation burden in assessing thromboembolic risk. PMID- 25516581 TI - The rotor revolution: conduction at the eye of the storm in atrial fibrillation. PMID- 25516582 TI - Troubleshooting implanted cardioverter defibrillator sensing problems I. PMID- 25516583 TI - Electroanatomic mapping of the intercaval bundle in atrial fibrillation. PMID- 25516584 TI - Bypass tracts revisited. PMID- 25516586 TI - Near-fatal coronary artery spasm during cryoballoon pulmonary vein isolation: an unreported complication. PMID- 25516585 TI - Paradoxical septic emboli secondary to pacemaker endocarditis: transvenous lead extraction with distal embolization protection. PMID- 25516587 TI - Isolation of an automatic purkinje focus for ablation of an incessant ventricular tachycardia. PMID- 25516588 TI - Letter by Shiyovich et al regarding article, "resumption of chest compressions after successful defibrillation and risk for recurrence of ventricular fibrillation in out-of-hospital cardiac arrest". PMID- 25516589 TI - Response to letter regarding, "resumption of chest compressions after successful defibrillation and risk for recurrence of ventricular fibrillation in out-of hospital cardiac arrest". PMID- 25516590 TI - Letter by Jackson et al Regarding, "PR Interval Identifies Clinical Response in Patients With Non-Left Bundle Branch Block: A Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy Substudy" by Kutyifa et al. PMID- 25516591 TI - Response to letter regarding, "PR interval identifies clinical response in patients with non-left bundle branch block: a multicenter automatic defibrillator implantation trial-cardiac resynchronization therapy sub-study" by Kutyifa et al. PMID- 25516592 TI - Letter by Gamble et al regarding article, "inappropriate shocks due to subcutaneous air in a patient with a subcutaneous cardiac defibrillator". PMID- 25516594 TI - Single molecule analysis of functionally asymmetric G protein-coupled receptor (GPCR) oligomers reveals diverse spatial and structural assemblies. AB - Formation of G protein-coupled receptors (GPCRs) into dimers and higher order oligomers represents a key mechanism in pleiotropic signaling, yet how individual protomers function within oligomers remains poorly understood. We present a super resolution imaging approach, resolving single GPCR molecules to ~ 8 nm resolution in functional asymmetric dimers and oligomers using dual-color photoactivatable dyes and localization microscopy (PD-PALM). PD-PALM of two functionally defined mutant luteinizing hormone receptors (LHRs), a ligand-binding deficient receptor (LHR(B-)) and a signaling-deficient (LHR(S-)) receptor, which only function via intermolecular cooperation, favored oligomeric over dimeric formation. PD-PALM imaging of trimers and tetramers revealed specific spatial organizations of individual protomers in complexes where the ratiometric composition of LHR(B-) to LHR(S-) modulated ligand-induced signal sensitivity. Structural modeling of asymmetric LHR oligomers strongly aligned with PD-PALM-imaged spatial arrangements, identifying multiple possible helix interfaces mediating inter protomer associations. Our findings reveal that diverse spatial and structural assemblies mediating GPCR oligomerization may acutely fine-tune the cellular signaling profile. PMID- 25516595 TI - Histone deacetylase 6 is a FoxO transcription factor-dependent effector in skeletal muscle atrophy. AB - Skeletal muscle atrophy is a severe condition of muscle mass loss. Muscle atrophy is caused by a down-regulation of protein synthesis and by an increase of protein breakdown due to the ubiquitin-proteasome system and autophagy activation. Up regulation of specific genes, such as the muscle-specific E3 ubiquitin ligase MAFbx, by FoxO transcription factors is essential to initiate muscle protein ubiquitination and degradation during atrophy. HDAC6 is a particular HDAC, which is functionally related to the ubiquitin proteasome system via its ubiquitin binding domain. We show that HDAC6 is up-regulated during muscle atrophy. HDAC6 activation is dependent on the transcription factor FoxO3a, and the inactivation of HDAC6 in mice protects against muscle wasting. HDAC6 is able to interact with MAFbx, a key ubiquitin ligase involved in muscle atrophy. Our findings demonstrate the implication of HDAC6 in skeletal muscle wasting and identify HDAC6 as a new downstream target of FoxO3a in stress response. This work provides new insights in skeletal muscle atrophy development and opens interesting perspectives on HDAC6 as a valuable marker of muscle atrophy and a potential target for pharmacological treatments. PMID- 25516596 TI - 14-3-3tau promotes surface expression of Cav2.2 (alpha1B) Ca2+ channels. AB - Surface expression of voltage-gated Ca(2+) (Cav) channels is important for their function in calcium homeostasis in the physiology of excitable cells, but whether or not and how the alpha1 pore-forming subunits of Cav channels are trafficked to plasma membrane in the absence of the known Cav auxiliary subunits, beta and alpha2delta, remains mysterious. Here we showed that 14-3-3 proteins promoted functional surface expression of the Cav2.2 alpha1B channel in transfected tsA 201 cells in the absence of any known Cav auxiliary subunit. Both the surface to total ratio of the expressed alpha1B protein and the current density of voltage step-evoked Ba(2+) current were markedly suppressed by the coexpression of a 14-3 3 antagonist construct, pSCM138, but not its inactive control, pSCM174, as determined by immunofluorescence assay and whole cell voltage clamp recording, respectively. By contrast, coexpression with 14-3-3tau significantly enhanced the surface expression and current density of the Cav2.2 alpha1B channel. Importantly, we found that between the two previously identified 14-3-3 binding regions at the alpha1B C terminus, only the proximal region (amino acids 1706 1940), closer to the end of the last transmembrane domain, was retained by the endoplasmic reticulum and facilitated by 14-3-3 to traffic to plasma membrane. Additionally, we showed that the 14-3-3/Cav beta subunit coregulated the surface expression of Cav2.2 channels in transfected tsA-201 cells and neurons. Altogether, our findings reveal a previously unidentified regulatory function of 14-3-3 proteins in promoting the surface expression of Cav2.2 alpha1B channels. PMID- 25516597 TI - Structurally similar allosteric modulators of alpha7 nicotinic acetylcholine receptors exhibit five distinct pharmacological effects. AB - Activation of nicotinic acetylcholine receptors (nAChRs) is associated with the binding of agonists such as acetylcholine to an extracellular site that is located at the interface between two adjacent receptor subunits. More recently, there has been considerable interest in compounds, such as positive and negative allosteric modulators (PAMs and NAMs), that are able to modulate nAChR function by binding to distinct allosteric sites. Here we examined a series of compounds differing only in methyl substitution of a single aromatic ring. This series of compounds includes a previously described alpha7-selective allosteric agonist, cis-cis-4-p-tolyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonamide (4MP-TQS), together with all other possible combinations of methyl substitution at a phenyl ring (18 additional compounds). Studies conducted with this series of compounds have revealed five distinct pharmacological effects on alpha7 nAChRs. These five effects can be summarized as: 1) nondesensitizing activation (allosteric agonists), 2) potentiation associated with minimal effects on receptor desensitization (type I PAMs), 3) potentiation associated with reduced desensitization (type II PAMs), 4) noncompetitive antagonism (NAMs), and 5) compounds that have no effect on orthosteric agonist responses but block allosteric modulation (silent allosteric modulators (SAMs)). Several lines of experimental evidence are consistent with all of these compounds acting at a common, transmembrane allosteric site. Notably, all of these chemically similar compounds that have been classified as nondesensitizing allosteric agonists or as nondesensitizing (type II) PAMs are cis-cis-diastereoisomers, whereas all of the NAMs, SAMs, and type I PAMs are cis-trans-diastereoisomers. Our data illustrate the remarkable pharmacological diversity of allosteric modulators acting on nAChRs. PMID- 25516598 TI - The Arabidopsis thaliana homolog of the helicase RTEL1 plays multiple roles in preserving genome stability. AB - In humans, mutations in the DNA helicase Regulator of Telomere Elongation Helicase1 (RTEL1) lead to Hoyeraal-Hreidarsson syndrome, a severe, multisystem disorder. Here, we demonstrate that the RTEL1 homolog in Arabidopsis thaliana plays multiple roles in preserving genome stability. RTEL1 suppresses homologous recombination in a pathway parallel to that of the DNA translocase FANCM. Cytological analyses of root meristems indicate that RTEL1 is involved in processing DNA replication intermediates independently from FANCM and the nuclease MUS81. Moreover, RTEL1 is involved in interstrand and intrastrand DNA cross-link repair independently from FANCM and (in intrastrand cross-link repair) parallel to MUS81. RTEL1 contributes to telomere homeostasis; the concurrent loss of RTEL1 and the telomerase TERT leads to rapid, severe telomere shortening, which occurs much more rapidly than it does in the single-mutant line tert, resulting in developmental arrest after four generations. The double mutant rtel1 1 recq4A-4 exhibits massive growth defects, indicating that this RecQ family helicase, which is also involved in the suppression of homologous recombination and the repair of DNA lesions, can partially replace RTEL1 in the processing of DNA intermediates. The requirement for RTEL1 in multiple pathways to preserve genome stability in plants can be explained by its putative role in the destabilization of DNA loop structures, such as D-loops and T-loops. PMID- 25516599 TI - MicroRNA408 is critical for the HY5-SPL7 gene network that mediates the coordinated response to light and copper. AB - Light and copper are important environmental determinants of plant growth and development. Despite the wealth of knowledge on both light and copper signaling, the molecular mechanisms that integrate the two pathways remain poorly understood. Here, we use Arabidopsis thaliana to demonstrate an interaction between SQUAMOSA PROMOTER BINDING PROTEIN-LIKE7 (SPL7) and ELONGATED HYPOCOTYL5 (HY5), which mediate copper and light signaling, respectively. Through whole genome chromatin immunoprecipitation and RNA sequencing analyses, we elucidated the SPL7 regulon and compared it with that of HY5. We found that the two transcription factors coregulate many genes, including those involved in anthocyanin accumulation and photosynthesis. Moreover, SPL7 and HY5 act coordinately to transcriptionally regulate MIR408, which results in differential expression of microRNA408 (miR408) and its target genes in response to changing light and copper conditions. We demonstrate that this regulation is tied to copper allocation to the chloroplast and plastocyanin levels. Finally, we found that constitutively activated miR408 rescues the distinct developmental defects of the hy5, spl7, and hy5 spl7 mutants. These findings revealed the existence of crosstalk between light and copper, mediated by a HY5-SPL7 network. Furthermore, integration of transcriptional and posttranscriptional regulation is critical for governing proper metabolism and development in response to combined copper and light signaling. PMID- 25516600 TI - Regulation of the KNOX-GA gene module induces heterophyllic alteration in North American lake cress. AB - Plants show leaf form alteration in response to changes in the surrounding environment, and this phenomenon is called heterophylly. Although heterophylly is seen across plant species, the regulatory mechanisms involved are largely unknown. Here, we investigated the mechanism underlying heterophylly in Rorippa aquatica (Brassicaceae), also known as North American lake cress. R. aquatica develops pinnately dissected leaves in submerged conditions, whereas it forms simple leaves with serrated margins in terrestrial conditions. We found that the expression levels of KNOTTED1-LIKE HOMEOBOX (KNOX1) orthologs changed in response to changes in the surrounding environment (e.g., change of ambient temperature; below or above water) and that the accumulation of gibberellin (GA), which is thought to be regulated by KNOX1 genes, also changed in the leaf primordia. We further demonstrated that exogenous GA affects the complexity of leaf form in this species. Moreover, RNA-seq revealed a relationship between light intensity and leaf form. These results suggest that regulation of GA level via KNOX1 genes is involved in regulating heterophylly in R. aquatica. The mechanism responsible for morphological diversification of leaf form among species may also govern the variation of leaf form within a species in response to environmental changes. PMID- 25516601 TI - Transcriptomic analyses indicate that maize ligule development recapitulates gene expression patterns that occur during lateral organ initiation. AB - Development of multicellular organisms proceeds via the correct interpretation of positional information to establish boundaries that separate developmental fields with distinct identities. The maize (Zea mays) leaf is an ideal system to study plant morphogenesis as it is subdivided into a proximal sheath and a distal blade, each with distinct developmental patterning. Specialized ligule and auricle structures form at the blade-sheath boundary. The auricles act as a hinge, allowing the leaf blade to project at an angle from the stem, while the ligule comprises an epidermally derived fringe. Recessive liguleless1 mutants lack ligules and auricles and have upright leaves. We used laser microdissection and RNA sequencing to identify genes that are differentially expressed in discrete cell/tissue-specific domains along the proximal-distal axis of wild-type leaf primordia undergoing ligule initiation and compared transcript accumulation in wild-type and liguleless1-R mutant leaf primordia. We identified transcripts that are specifically upregulated at the blade-sheath boundary. A surprising number of these "ligule genes" have also been shown to function during leaf initiation or lateral branching and intersect multiple hormonal signaling pathways. We propose that genetic modules utilized in leaf and/or branch initiation are redeployed to regulate ligule outgrowth from leaf primordia. PMID- 25516603 TI - Thermoperiodic control of hypocotyl elongation depends on auxin-induced ethylene signaling that controls downstream PHYTOCHROME INTERACTING FACTOR3 activity. AB - We show that antiphase light-temperature cycles (negative day-night temperature difference [-DIF]) inhibit hypocotyl growth in Arabidopsis (Arabidopsis thaliana). This is caused by reduced cell elongation during the cold photoperiod. Cell elongation in the basal part of the hypocotyl under -DIF was restored by both 1-aminocyclopropane-1-carboxylic acid (ACC; ethylene precursor) and auxin, indicating limited auxin and ethylene signaling under -DIF. Both auxin biosynthesis and auxin signaling were reduced during -DIF. In addition, expression of several ACC Synthase was reduced under -DIF but could be restored by auxin application. In contrast, the reduced hypocotyl elongation of ethylene biosynthesis and signaling mutants could not be complemented by auxin, indicating that auxin functions upstream of ethylene. The PHYTOCHROME INTERACTING FACTORS (PIFs) PIF3, PIF4, and PIF5 were previously shown to be important regulators of hypocotyl elongation. We now show that, in contrast to pif4 and pif5 mutants, the reduced hypocotyl length in pif3 cannot be rescued by either ACC or auxin. In line with this, treatment with ethylene or auxin inhibitors reduced hypocotyl elongation in PIF4 overexpressor (PIF4ox) and PIF5ox but not PIF3ox plants. PIF3 promoter activity was strongly reduced under -DIF but could be restored by auxin application in an ACC Synthase-dependent manner. Combined, these results show that PIF3 regulates hypocotyl length downstream, whereas PIF4 and PIF5 regulate hypocotyl length upstream of an auxin and ethylene cascade. We show that, under DIF, lower auxin biosynthesis activity limits the signaling in this pathway, resulting in low activity of PIF3 and short hypocotyls. PMID- 25516602 TI - A NAP-AAO3 regulatory module promotes chlorophyll degradation via ABA biosynthesis in Arabidopsis leaves. AB - Chlorophyll degradation is an important part of leaf senescence, but the underlying regulatory mechanisms are largely unknown. Excised leaves of an Arabidopsis thaliana NAC-LIKE, ACTIVATED BY AP3/PI (NAP) transcription factor mutant (nap) exhibited lower transcript levels of known chlorophyll degradation genes, STAY-GREEN1 (SGR1), NON-YELLOW COLORING1 (NYC1), PHEOPHYTINASE (PPH), and PHEIDE a OXYGENASE (PaO), and higher chlorophyll retention than the wild type during dark-induced senescence. Transcriptome coexpression analysis revealed that abscisic acid (ABA) metabolism/signaling genes were disproportionately represented among those positively correlated with NAP expression. ABA levels were abnormally low in nap leaves during extended darkness. The ABA biosynthetic genes 9-CIS-EPOXYCAROTENOID DIOXYGENASE2, ABA DEFICIENT3, and ABSCISIC ALDEHYDE OXIDASE3 (AAO3) exhibited abnormally low transcript levels in dark-treated nap leaves. NAP transactivated the promoter of AAO3 in mesophyll cell protoplasts, and electrophoretic mobility shift assays showed that NAP can bind directly to a segment (-196 to -162 relative to the ATG start codon) of the AAO3 promoter. Exogenous application of ABA increased the transcript levels of SGR1, NYC1, PPH, and PaO and suppressed the stay-green phenotype of nap leaves during extended darkness. Overexpression of AAO3 in nap leaves also suppressed the stay-green phenotype under extended darkness. Collectively, the results show that NAP promotes chlorophyll degradation by enhancing transcription of AAO3, which leads to increased levels of the senescence-inducing hormone ABA. PMID- 25516604 TI - The benefits of photorespiratory bypasses: how can they work? AB - Bypassing the photorespiratory pathway is regarded as a way to increase carbon assimilation and, correspondingly, biomass production in C3 crops. Here, the benefits of three published photorespiratory bypass strategies are systemically explored using a systems-modeling approach. Our analysis shows that full decarboxylation of glycolate during photorespiration would decrease photosynthesis, because a large amount of the released CO2 escapes back to the atmosphere. Furthermore, we show that photosynthesis can be enhanced by lowering the energy demands of photorespiration and by relocating photorespiratory CO2 release into the chloroplasts. The conductance of the chloroplast membranes to CO2 is a key feature determining the benefit of the relocation of photorespiratory CO2 release. Although our results indicate that the benefit of photorespiratory bypasses can be improved by increasing sedoheptulose bisphosphatase activity and/or increasing the flux through the bypass, the effectiveness of such approaches depends on the complex regulation between photorespiration and other metabolic pathways. PMID- 25516610 TI - Suicide among first-generation and second-generation immigrants in Sweden: association with labour market marginalisation and morbidity. AB - BACKGROUND: Previous research suggests that first-generation immigrants have a lower suicide risk than those both born in Sweden and with both parents born in Sweden (natives), while the suicide risk in the second generation seems higher. The aim of this study was to investigate to what extent suicide risk in first generation and second-generation (both parents born abroad) and intermediate generation (only one parent born abroad) immigrants compared with natives is associated with sociodemographic factors, labour market marginalisation and morbidity. METHODS: A prospective population-based cohort study of 4 034 728 individuals aged 16-50 years was followed from 2005 to 2010. HRs for suicide were calculated for first-generation, intermediate-generation and second-generation immigrants compared with natives. Analyses were controlled for sociodemographic factors, morbidity and labour market marginalisation. RESULTS: The HR of suicide was significantly lower in first-generation immigrants (HR 0.83 CI 0.76 to 0.91), and higher in second-generation (HR 1.32, CI 1.15 to 1.52) and intermediate generation immigrants (HR 1.20, CI 1.08 to 1.33) in comparison to natives. The excess risk was explained by differences in sociodemographics, morbidity and labour market marginalisation. In the fully adjusted models, a higher HR remained only for the Nordic second generation (HR 1.29, CI 1.09 to 1.52). There were no sex differences in HRs. CONCLUSIONS: The risk of suicide was shown to be lower in the first generation and higher in the second generation compared with natives. The higher HR in the Nordic second generation was not explained by differences in sociodemographics, labour market marginalisation and morbidity. Further research is warranted to investigate factors underlying this excess risk. PMID- 25516611 TI - Socioprofessional trajectories and mortality in France, 1976-2002: a longitudinal follow-up of administrative data. AB - BACKGROUND: Occupying a low socioeconomic position is associated with increased mortality risk. To disentangle this association, previous studies considered various dimensions of socioeconomic trajectories across the life course. However, they used a limited number of stages. We simultaneously examined various dimensions of the whole professional trajectory and its association with mortality. METHODS: We used a large sample (337,706 men and 275,378 women) of the data obtained by linking individuals' annual occupation (collected in 1976-2002 from a representative panel of the French salaried population in the semipublic and private sectors) with causes of death obtained from registries. All-cause and cause-specific HRs were estimated using Cox's regression models adjusted for the occupational class at the beginning of the follow-up, the current occupational class, the transition rates between occupational categories and the duration of time spent in occupational categories. RESULTS: An increase in the time spent in the clerk class increased men and women's cardiovascular mortality risk compared with that in the upper class (HRs=1.59 (1.14 to 2.20) and 2.65 (1.14 to 6.13) for 10 years increase, respectively, for men and women). Men with a high rate of transitions had about a 1.2-fold increased risk of all-cause and external-cause mortality compared with those without transitions during their professional life. This association was also observed for women's all-cause mortality. CONCLUSIONS: Strong associations between professional trajectories and mortality from different causes of death were found. Long exposure to lower socioeconomic conditions was associated with increased mortality risk from various causes of death. The results also suggest gradual associations between transition rates and mortality. PMID- 25516612 TI - Phylogeography of the arid shrub Atraphaxis frutescens (Polygonaceae) in northwestern China: evidence from cpDNA sequences. AB - Climatic fluctuations during the Pleistocene are usually considered as a significant factor in shaping intraspecific genetic variation and influencing demographic histories. To well-understand these processes in desert northwest China, we selected arid adapted Atraphaxis frutescens as the study species. Two cpDNA regions (psbK-psbI, psbB-psbH) were sequenced in 272 individuals from 33 natural populations across the range of this shrub, and 10 haplotypes were identified. It was found to contain high levels of total gene diversity (H T = 0.858), and low levels of within-population diversity (H S = 0.092). Analysis of molecular variance (AMOVA) indicates that genetic differentiation primarily occurs among groups of populations. Based on BEAST (Bayesian Evolutionary Analysis Sampling Trees) analysis, we suggest that intraspecific differentiation of the species, resulting from isolated populations, accompanied enhanced desertification during the middle and late Pleistocene. The expansion of the Gurbantunggut and Kumtag deserts in this area appears to have triggered divergence among populations of the western, central, and eastern portions of the region and shaped genetic differentiation among them. Two possible independent glacial refugia were predicted, the Ili Valley and the northern Junggar Basin. Extensive development of arid habitats (desert margin and arid piedmont grassland) coupled with a more equable climate because the early Holocene are factors likely to have generated recent expansion of A. frutescens. PMID- 25516613 TI - Spatial and temporal features of the growth of a bacterial species colonizing the zebrafish gut. AB - The vertebrate intestine is home to microbial ecosystems that play key roles in host development and health. Little is known about the spatial and temporal dynamics of these microbial communities, limiting our understanding of fundamental properties, such as their mechanisms of growth, propagation, and persistence. To address this, we inoculated initially germ-free zebrafish larvae with fluorescently labeled strains of an Aeromonas species, representing an abundant genus in the zebrafish gut. Using light sheet fluorescence microscopy to obtain three-dimensional images spanning the gut, we quantified the entire bacterial load, as founding populations grew from tens to tens of thousands of cells over several hours. The data yield the first ever measurements of the growth kinetics of a microbial species inside a live vertebrate intestine and show dynamics that robustly fit a logistic growth model. Intriguingly, bacteria were nonuniformly distributed throughout the gut, and bacterial aggregates showed considerably higher growth rates than did discrete individuals. The form of aggregate growth indicates intrinsically higher division rates for clustered bacteria, rather than surface-mediated agglomeration onto clusters. Thus, the spatial organization of gut bacteria both relative to the host and to each other impacts overall growth kinetics, suggesting that spatial characterizations will be an important input to predictive models of host-associated microbial community assembly. IMPORTANCE: Our intestines are home to vast numbers of microbes that influence many aspects of health and disease. Though we now know a great deal about the constituents of the gut microbiota, we understand very little about their spatial structure and temporal dynamics in humans or in any animal: how microbial populations establish themselves, grow, fluctuate, and persist. To address this, we made use of a model organism, the zebrafish, and a new optical imaging technique, light sheet fluorescence microscopy, to visualize for the first time the colonization of a live, vertebrate gut by specific bacteria with sufficient resolution to quantify the population over a range from a few individuals to tens of thousands of bacterial cells. Our results provide unprecedented measures of bacterial growth kinetics and also show the influence of spatial structure on bacterial populations, which can be revealed only by direct imaging. PMID- 25516614 TI - Leptin receptor mutation results in defective neutrophil recruitment to the colon during Entamoeba histolytica infection. AB - Amebiasis is an enteric infection caused by Entamoeba histolytica, with symptoms ranging in severity from asymptomatic colonization to dysentery. Humans with the Q223R leptin receptor mutation have increased susceptibility to amebiasis, but the mechanism has been unclear. Using a mouse model expressing the mutation, we tested the impact of the Q223R mutation on the innate immune response to E. histolytica infection. The 223R mutation resulted in delayed clearance of amebae from the cecum, as had been previously observed. We found that neutrophil influx to the site of the infection was reduced 12 h after infection in 223R mice. Depletion of neutrophils with anti-Ly6G monoclonal antibody increased susceptibility of wild-type mice to infection, supporting the importance of neutrophils in innate defense. Leptin expression was increased in the cecum by E. histolytica infection, suggesting that leptin could serve as a homing signal for neutrophils to the gut. Interestingly, neutrophils from mice with the 223R mutation had diminished chemotaxis toward leptin. This impaired chemotaxis likely explained the reduced gut infiltration of neutrophils. The newly recognized effect of the leptin receptor Q223R mutation on neutrophil chemotaxis and the impact of this mutation on multiple infectious diseases suggest a broader impact of this mutation on susceptibility to disease. IMPORTANCE: The Q223R leptin receptor mutation results in increased susceptibility of children and adults to E. histolytica, one of the leading causes of diarrhea morbidity and mortality in children of the developing world. Here we show that the mutation results in reduced neutrophil infiltration to the site of infection. This decreased infiltration is likely due to the mutation's impact on neutrophil chemotaxis toward leptin, an inflammatory agent upregulated in the cecum after infection. The significance of this work thus extends beyond understanding E. histolytica susceptibility by also providing insight into the potential impact of leptin on neutrophil function in other states of altered leptin signaling, which include both malnutrition and obesity. PMID- 25516615 TI - Gut microbiota as an epigenetic regulator: pilot study based on whole-genome methylation analysis. AB - The core human gut microbiota contributes to the developmental origin of diseases by modifying metabolic pathways. To evaluate the predominant microbiota as an epigenetic modifier, we classified 8 pregnant women into two groups based on their dominant microbiota, i.e., Bacteroidetes, Firmicutes, and Proteobacteria. Deep sequencing of DNA methylomes revealed a clear association between bacterial predominance and epigenetic profiles. The genes with differentially methylated promoters in the group in which Firmicutes was dominant were linked to risk of disease, predominantly to cardiovascular disease and specifically to lipid metabolism, obesity, and the inflammatory response. This is one of the first studies that highlights the association of the predominant bacterial phyla in the gut with methylation patterns. Further longitudinal and in-depth studies targeting individual microbial species or metabolites are recommended to give us a deeper insight into the molecular mechanism of such epigenetic modifications. IMPORTANCE: Epigenetics encompasses genomic modifications that are due to environmental factors and do not affect the nucleotide sequence. The gut microbiota has an important role in human metabolism and could be a significant environmental factor affecting our epigenome. To investigate the association of gut microbiota with epigenetic changes, we assessed pregnant women and selected the participants based on their predominant gut microbiota for a study on their postpartum methylation profile. Intriguingly, we found that blood DNA methylation patterns were associated with gut microbiota profiles. The gut microbiota profiles, with either Firmicutes or Bacteroidetes as a dominant group, correlated with differential methylation status of gene promoters functionally associated with cardiovascular diseases. Furthermore, differential methylation of gene promoters linked to lipid metabolism and obesity was observed. For the first time, we report here a position of the predominant gut microbiota in epigenetic profiling, suggesting one potential mechanism in obesity with comorbidities, if proven in further in-depth studies. PMID- 25516616 TI - Sirtuins are evolutionarily conserved viral restriction factors. AB - The seven human sirtuins are a family of ubiquitously expressed and evolutionarily conserved NAD(+)-dependent deacylases/mono-ADP ribosyltransferases that regulate numerous cellular and organismal functions, including metabolism, cell cycle, and longevity. Here, we report the discovery that all seven sirtuins have broad-range antiviral properties. We demonstrate that small interfering RNA (siRNA)-mediated knockdown of individual sirtuins and drug-mediated inhibition of sirtuin enzymatic activity increase the production of virus progeny in infected human cells. This impact on virus growth is observed for both DNA and RNA viruses. Importantly, sirtuin-activating drugs inhibit the replication of diverse viruses, as we demonstrate for human cytomegalovirus, a slowly replicating DNA virus, and influenza A (H1N1) virus, an RNA virus that multiplies rapidly. Furthermore, sirtuin defense functions are evolutionarily conserved, since CobB, the sirtuin homologue in Escherichia coli, protects against bacteriophages. Altogether, our findings establish sirtuins as broad-spectrum and evolutionarily conserved components of the immune defense system, providing a framework for elucidating a new set of host cell defense mechanisms and developing sirtuin modulators with antiviral activity. IMPORTANCE: We live in a sea of viruses, some of which are human pathogens. These pathogenic viruses exhibit numerous differences: DNA or RNA genomes, enveloped or naked virions, nuclear or cytoplasmic replication, diverse disease symptoms, etc. Most antiviral drugs target specific viral proteins. Consequently, they often work for only one virus, and their efficacy can be compromised by the rapid evolution of resistant variants. There is a need for the identification of host proteins with broad spectrum antiviral functions, which provide effective targets for therapeutic treatments that limit the evolution of viral resistance. Here, we report that sirtuins present such an opportunity for the development of broad-spectrum antiviral treatments, since our findings highlight these enzymes as ancient defense factors that protect against a variety of viral pathogens. PMID- 25516617 TI - Kaposi's sarcoma-associated herpesvirus genome programming during the early stages of primary infection of peripheral blood mononuclear cells. AB - The early period of Kaposi's sarcoma-associated herpesvirus (KSHV) infection involves the dynamic expression of viral genes, which are temporally and epigenetically regulated. KSHV can effectively infect and persist in endothelial as well as human B cells with different gene expression patterns. To understand the temporal epigenetic changes which occur when KSHV infects the lymphocytic compartment, we infected human peripheral blood mononuclear cells (PBMCs) and comprehensively analyzed the changes which occurred at the binding sites of virally encoded lytic as well as latent proteins along with epigenetic modifications across the KSHV genome during early primary infection. Using chromatin immunoprecipitation (ChIP) assays, we showed that the KSHV genome acquires a uniquely distinct histone modification pattern of methylation (H3K4me3, H3K9me3, and H3K27me3) and acetylation (H3Ac) during de novo infection of human PBMCs. This pattern showed that the epigenetic changes were temporally controlled. The binding profiles of KSHV latent protein LANA and the immediate early proteins RTA and K8 showed specific patterns at different times postinfection, which reflects the gene expression program. Further analysis demonstrated that KSHV can concurrently express lytic and latent genes which were associated with histone modifications at these specific regions on the viral genome. We identified three KSHV genes, K3, ORF49, and ORF64, which exhibited different profiles of histone modifications during the early stages of PBMC infection. These studies established a distinct pattern of epigenetic modification which correlates with viral gene expression temporally regulated during the first 7 days of PBMC infection and provides clues to the regulatory program required for successful infection by KSHV of human PBMCs. IMPORTANCE: Kaposi's sarcoma-associated herpesvirus (KSHV) has been documented as one of the major contributors to morbidity and mortality in AIDS patients during the AIDS pandemic. During its life cycle, KSHV undergoes latent and lytic replication. Typically, KSHV maintains a stringent preference for latent infection in the infected B cells. However, 1 to 5% of infected cells undergo spontaneous lytic reactivation. KSHV lytic replication and infection of new cells are likely to be critical for maintaining the population of infected cells which drive virus associated pathogenesis. Here, we explored the temporal changes of crucial histone marks on the KSHV genome during early infection of human primary peripheral blood mononuclear cells (PBMCs), which are a physiologically relevant system for monitoring primary infection. These results showed that KSHV possessed a distinct pattern of epigenetic marks during early infection of PBMCs. Further, KSHV concurrently expressed lytic and latent genes during this early period. These results now provide new evidence which contributes to understanding the molecular mechanism that regulates viral gene expression during early infection. PMID- 25516618 TI - Host demise as a beneficial function of indigenous microbiota in human hosts. AB - The age structure of human populations is exceptional among animal species. Unlike with most species, human juvenility is extremely extended, and death is not coincident with the end of the reproductive period. We examine the age structure of early humans with models that reveal an extraordinary balance of human fertility and mortality. We hypothesize that the age structure of early humans was maintained by mechanisms incorporating the programmed death of senescent individuals, including by means of interactions with their indigenous microorganisms. First, before and during reproductive life, there was selection for microbes that preserve host function through regulation of energy homeostasis, promotion of fecundity, and defense against competing high-grade pathogens. Second, we hypothesize that after reproductive life, there was selection for organisms that contribute to host demise. While deleterious to the individual, the presence of such interplay may be salutary for the overall host population in terms of resource utilization, resistance to periodic diminutions in the food supply, and epidemics due to high-grade pathogens. We provide deterministic mathematical models based on age-structured populations that illustrate the dynamics of such relationships and explore the relevant parameter values within which population viability is maintained. We argue that the age structure of early humans was robust in its balance of the juvenile, reproductive age, and senescent classes. These concepts are relevant to issues in modern human longevity, including inflammation-induced neoplasia and degenerative diseases of the elderly, which are a legacy of human evolution. IMPORTANCE: The extended longevity of modern humans is a very recent societal artifact, although it is inherent in human evolution. The age structure of early humans was balanced by fertility and mortality, with an exceptionally prolonged juvenility. We examined the role of indigenous microbes in early humans as fundamental contributors to this age structure. We hypothesize that the human microbiome evolved mechanisms specific to the mortality of senescent individuals among early humans because their mortality contributed to the stability of the general population. The hypothesis that we present provides new bases for modern medical problems, such as inflammation-induced neoplasia and degenerative diseases of the elderly. We postulate that these mechanisms evolved because they contributed to the stability of early human populations, but their legacy is now a burden on human longevity in the changed modern world. PMID- 25516619 TI - Dynamics of Lewis b binding and sequence variation of the babA adhesin gene during chronic Helicobacter pylori infection in humans. AB - Helicobacter pylori undergoes rapid microevolution during chronic infection, but very little is known about how this affects host interaction factors. The best studied adhesin of H. pylori is BabA, which mediates binding to the blood group antigen Lewis b [Le(b)]. To study the dynamics of Le(b) adherence during human infection, we analyzed paired H. pylori isolates obtained sequentially from chronically infected individuals. A complete loss or significant reduction of Le(b) binding was observed in strains from 5 out of 23 individuals, indicating that the Le(b) binding phenotype is quite stable during chronic human infection. Sequence comparisons of babA identified differences due to mutation and/or recombination in 12 out of 16 strain pairs analyzed. Most amino acid changes were found in the putative N-terminal extracellular adhesion domain. One strain pair that had changed from a Le(b) binding to a nonbinding phenotype was used to study the role of distinct sequence changes in Le(b) binding. By transformations of the nonbinding strain with a babA gene amplified from the binding strain, H. pylori strains with mosaic babA genes were generated. Recombinants were enriched for a gain of Le(b) binding by biopanning or for BabA expression on the bacterial surface by pulldown assay. With this approach, we identified several amino acid residues affecting the strength of Le(b) binding. Additionally, the data showed that the C terminus of BabA, which is predicted to encode an outer membrane beta barrel domain, plays an essential role in the biogenesis of this protein. IMPORTANCE: Helicobacter pylori causes a chronic infection of the human stomach that can lead to ulcers and cancer. The bacterium can bind to gastric epithelial cells with specialized outer membrane proteins. The best-studied protein is the BabA adhesin which binds to the Lewis b blood group antigen. Since H. pylori is a bacterium with very high genetic variability, we asked whether babA evolves during chronic infection and how mutations or recombination in babA affect binding. We found that BabA-mediated adherence was stable in most individuals but observed a complete loss of binding or reduced binding in 22% of individuals. One strain pair in which binding was lost was used to generate babA sequences that were mosaics of a functional allele and a nonfunctional allele, and the mosaic sequences were used to identify amino acids critically involved in binding of BabA to Lewis b. PMID- 25516621 TI - Human scavenger receptor class B type I variants, lipid traits, and cardiovascular disease. PMID- 25516622 TI - Compiling the complement of genes implicated in coronary artery disease. PMID- 25516623 TI - Intercalated discs and arrhythmogenic cardiomyopathy. PMID- 25516624 TI - Lipidomics: quest for molecular lipid biomarkers in cardiovascular disease. AB - Lipidomics is the comprehensive analysis of molecular lipid species, including their quantitation and metabolic pathways. The huge diversity of native lipids and their modifications make lipidomic analyses challenging. The method of choice for sensitive detection and quantitation of molecular lipid species is mass spectrometry, either by direct infusion (shotgun lipidomics) or coupled with liquid chromatography. Although shotgun lipidomics allows for high-throughput analysis, low-abundant lipid species are not detected. Previous separation of lipid species by liquid chromatography increases ionization efficiency and is better suited for quantifying low abundant and isomeric lipid species. In this review, we will discuss the potential of lipidomics for cardiovascular research. To date, cardiovascular research predominantly focuses on the role of lipid classes rather than molecular entities. An in-depth knowledge about the molecular lipid species that contribute to the pathophysiology of cardiovascular diseases may provide better biomarkers and novel therapeutic targets for cardiovascular disease. PMID- 25516626 TI - Good fats: lipidomics approach identify novel regulators of glucose homeostasis. PMID- 25516620 TI - Multicenter outbreak of infections by Saprochaete clavata, an unrecognized opportunistic fungal pathogen. AB - Rapidly fatal cases of invasive fungal infections due to a fungus later identified as Saprochaete clavata were reported in France in May 2012. The objectives of this study were to determine the clonal relatedness of the isolates and to investigate possible sources of contamination. A nationwide alert was launched to collect cases. Molecular identification methods, whole-genome sequencing (WGS), and clone-specific genotyping were used to analyze recent and historical isolates, and a case-case study was performed. Isolates from thirty cases (26 fungemias, 22 associated deaths at day 30) were collected between September 2011 and October 2012. Eighteen cases occurred within 8 weeks (outbreak) in 10 health care facilities, suggesting a common source of contamination, with potential secondary cases. Phylogenetic analysis identified one clade (clade A), which accounted for 16/18 outbreak cases. Results of microbiological investigations of environmental, drug, or food sources were negative. Analysis of exposures pointed to a medical device used for storage and infusion of blood products, but no fungal contamination was detected in the unused devices. Molecular identification of isolates from previous studies demonstrated that S. clavata can be found in dairy products and has already been involved in monocentric outbreaks in hematology wards. The possibility that S. clavata may transmit through contaminated medical devices or can be associated with dairy products as seen in previous European outbreaks is highly relevant for the management of future outbreaks due to this newly recognized pathogen. This report also underlines further the potential of WGS for investigation of outbreaks due to uncommon fungal pathogens. IMPORTANCE: Several cases of rapidly fatal infections due to the fungus Saprochaete clavata were reported in France within a short period of time in three health care facilities, suggesting a common source of contamination. A nationwide alert collected 30 cases over 1 year, including an outbreak of 18 cases over 8 weeks. Whole-genome sequencing (WGS) was used to analyze recent and historical isolates and to design a clade specific genotyping method that uncovered a clone associated with the outbreak, thus allowing a case-case study to analyze the risk factors associated with infection by the clone. The possibility that S. clavata may transmit through contaminated medical devices or can be associated with dairy products as seen in previous European outbreaks is highly relevant for the management of future outbreaks due to this newly recognized pathogen. PMID- 25516627 TI - One-shot, one cure with genome editing for dyslipidemia. PMID- 25516625 TI - High-dose simvastatin exhibits enhanced lipid-lowering effects relative to simvastatin/ezetimibe combination therapy. AB - Statins are the frontline in cholesterol reduction therapies; however, their use in combination with agents that possess complimentary mechanisms of action may achieve further reductions in low-density lipoprotein cholesterol. Thirty-nine patients were treated with either 80 mg simvastatin (n=20) or 10 mg simvastatin plus 10 mg ezetimibe (n=19) for 6 weeks. Dosing was designed to produce comparable low-density lipoprotein cholesterol reductions, while enabling assessment of potential simvastatin-associated pleiotropic effects. Baseline and post-treatment plasma were analyzed for lipid mediators (eg, eicosanoids and endocannabinoids) and structural lipids by liquid chromatography tandem mass spectrometry. After statistical analysis and orthogonal projections to latent structures multivariate modeling, no changes were observed in lipid mediator levels, whereas global structural lipids were reduced in response to both monotherapy (R(2)Y=0.74; Q(2)=0.66; cross-validated ANOVA P=7.0*10(-8)) and combination therapy (R(2)Y=0.67; Q(2)=0.54; cross-validated ANOVA P=2.6*10(-5)). Orthogonal projections to latent structures modeling identified a subset of 12 lipids that classified the 2 treatment groups after 6 weeks (R(2)Y=0.65; Q(2)=0.61; cross-validated ANOVA P=5.4*10(-8)). Decreases in the lipid species phosphatidylcholine (15:0/18:2) and hexosyl-ceramide (d18:1/24:0) were the strongest discriminators of low-density lipoprotein cholesterol reductions for both treatment groups (q<0.00005), whereas phosphatidylethanolamine (36:3e) contributed most to distinguishing treatment groups (q=0.017). Shifts in lipid composition were similar for high-dose simvastatin and simvastatin/ezetimibe combination therapy, but the magnitude of the reduction was linked to simvastatin dosage. Simvastatin therapy did not affect circulating levels of lipid mediators, suggesting that pleiotropic effects are not associated with eicosanoid production. Only high-dose simvastatin reduced the relative proportion of sphingomyelin and ceramide to phosphatidylcholine (q=0.008), suggesting a pleiotropic effect previously associated with a reduced risk of cardiovascular disease. PMID- 25516628 TI - In vivo assessment of protease dynamics in cutaneous wound healing by degradomics analysis of porcine wound exudates. AB - Proteases control complex tissue responses by modulating inflammation, cell proliferation and migration, and matrix remodeling. All these processes are orchestrated in cutaneous wound healing to restore the skin's barrier function upon injury. Altered protease activity has been implicated in the pathogenesis of healing impairments, and proteases are important targets in diagnosis and therapy of this pathology. Global assessment of proteolysis at critical turning points after injury will define crucial events in acute healing that might be disturbed in healing disorders. As optimal biospecimens, wound exudates contain an ideal proteome to detect extracellular proteolytic events, are noninvasively accessible, and can be collected at multiple time points along the healing process from the same wound in the clinics. In this study, we applied multiplexed Terminal Amine Isotopic Labeling of Substrates (TAILS) to globally assess proteolysis in early phases of cutaneous wound healing. By quantitative analysis of proteins and protein N termini in wound fluids from a clinically relevant pig wound model, we identified more than 650 proteins and discerned major healing phases through distinctive abundance clustering of markers of inflammation, granulation tissue formation, and re-epithelialization. TAILS revealed a high degree of proteolysis at all time points after injury by detecting almost 1300 N terminal peptides in ~450 proteins. Quantitative positional proteomics mapped pivotal interdependent processing events in the blood coagulation and complement cascades, temporally discerned clotting and fibrinolysis during the healing process, and detected processing of complement C3 at distinct time points after wounding and by different proteases. Exploiting data on primary cleavage specificities, we related candidate proteases to cleavage events and revealed processing of the integrin adapter protein kindlin-3 by caspase-3, generating new hypotheses for protease-substrate relations in the healing skin wound in vivo. The data have been deposited to the ProteomeXchange Consortium with identifier PXD001198. PMID- 25516633 TI - Extending the Transport Theorem to Rough Domains of Integration. AB - Transport theorems, such as that named after Reynolds, are an important tool in the field of continuum physics. Recently, Seguin and Fried used Harrison's theory of differential chains to establish a transport theorem valid for evolving domains that may become irregular. Evolving irregular domains occur in many different physical settings, such as phase transitions or fracture. Here, emphasizing concepts over technicalities, we present Harrison's theory of differential chains and the results of Seguin and Fried in a way meant to be accessible to researchers in continuum physics. We also show how the transport theorem applies to three concrete examples and approximate the resulting terms numerically. Furthermore, we discuss how the transport theorem might be used to weaken certain basic assumptions underlying the description of continua and the challenges associated with doing so. PMID- 25516631 TI - Thermal Pain in Teeth: Electrophysiology Governed by Thermomechanics. AB - Thermal pain arising from the teeth is unlike that arising from anywhere else in the body. The source of this peculiarity is a long-standing mystery that has begun to unravel with recent experimental measurements and, somewhat surprisingly, new thermomechanical models. Pain from excessive heating and cooling is typically sensed throughout the body through the action of specific, heat sensitive ion channels that reside on sensory neurons known as nociceptors. These ion channels are found on tooth nociceptors, but only in teeth does the pain of heating differ starkly from the pain of cooling, with cold stimuli producing more rapid and sharper pain. Here, we review the range of hypotheses and models for these phenomena, and focus on what is emerging as the most promising hypothesis: pain transduced by fluid flowing through the hierarchical structure of teeth. We summarize experimental evidence, and critically review the range of heat transfer, solid mechanics, fluid dynamics, and electrophysiological models that have been combined to support this hypothesis. While the results reviewed here are specific to teeth, this class of coupled thermomechanical and neurophysiological models has potential for informing design of a broad range of thermal therapies and understanding of a range of biophysical phenomena. PMID- 25516634 TI - Thermophysical properties of sulfonium- and ammonium-based ionic liquids. AB - Experimental data for the density, viscosity, refractive index and surface tension of four sulfonium- and ammonium-based Ionic Liquids (ILs) with the common bis(trifluoromethylsulfonyl)imide anion were measured in the temperature range between 288.15 and 353.15 K and at atmospheric pressure. The ILs considered include butyltrimethylammonium bis(trifluoromethylsulfonyl)imide, [N4111][NTf2], tributylmethylammonium bis(trifluoromethylsulfonyl)imide, [N4441][NTf2], diethylmethylsulfonium bis(trifluoromethylsulfonyl)imide, [S221][NTf2], and triethylsulfonium bis(trifluoromethylsulfonyl)imide, [S222][NTf2]. Based on the gathered results and on data taken from literature, the impact of the cation isomerism and of the size of the aliphatic tails, as well as the effect resulting from the substitution of a nitrogen by a sulfur atom as the cation central atom, on the thermophysical properties of sulfonium- and ammonium-based ILs is here discussed. Remarkably, more symmetric cations present a lower viscosity for the same, and sometimes even for higher, alkyl chain lengths at the cation. Additional derivative properties, such as the isobaric thermal expansion coefficient, the surface thermodynamic properties and the critical temperature for the investigated ILs were also estimated and are presented and discussed. PMID- 25516632 TI - On the Mechanics of Fatigue and Fracture in Teeth. AB - Tooth fracture is a major concern in the field of restorative dentistry. However, knowledge of the causes for tooth fracture has developed from contributions that are largely based within the field of mechanics. The present manuscript presents a technical review of advances in understanding the fracture of teeth and the fatigue and fracture behavior of their hard tissues (i.e., dentin and enamel). The importance of evaluating the fracture resistance of these materials, and the role of applied mechanics in developing this knowledge will be reviewed. In addition, the complex microstructures of tooth tissues, their roles in resisting tooth fracture, and the importance of hydration and aging on the fracture resistance of tooth tissues will be discussed. Studies in this area are essential for increasing the success of current treatments in dentistry, as well as in facilitating the development of novel bio-inspired restorative materials for the future. PMID- 25516635 TI - A randomized Phase III trial of weekly or 3-weekly doses of nab-paclitaxel versus weekly doses of Cremophor-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE Trial). AB - Paclitaxel is an agent widely used in second-line chemotherapy for advanced gastric cancer. The aim of this trial is to evaluate the efficacy and safety of 3 weekly or weekly doses of nanoparticle albumin-bound-paclitaxel compared with weekly doses of Cremophor-based paclitaxel in patients with unresectable or recurrent gastric cancer refractory to first-line chemotherapy comprising fluoropyrimidines. A total of 730 patients will be enrolled from 72 institutions. The primary endpoint is the overall survival, and the secondary endpoints are progression-free survival, time to treatment failure, overall response rate, disease control rate, quality of life (by using the EQ-5D system) and safety. PMID- 25516637 TI - Health care-associated hepatitis C virus infection. AB - Hepatitis C virus (HCV) is a blood-borne pathogen that has a worldwide distribution and infects millions of people. Care-associated HCV infections represented a huge part of hepatitis C burden in the past via contaminated blood and unsafe injections and continue to be a serious problem of public health. The present review proposes a panorama of health care-associated HCV infections via the three mode of contamination that have been identified: (1) infected patient to non-infected patient; (2) infected patient to non-infected health care worker (HCW); and (3) infected HCW to non infected patient. For each condition, the circumstances of contamination are described together with the means to prevent them. As a whole, the more important risk is represented by unsafe practices regarding injections, notably with the improper use of multidose vials used for multiple patients. The questions of occupational exposures and infected HCWs are also discussed. In terms of prevention and surveillance, the main arm for combating care-associated HCV infections is the implementation of standard precautions in all the fields of cares, with training programs and audits to verify their good application. HCWs must be sensitized to the risk of blood-borne pathogens, notably by the use of safety devices for injections and good hygiene practices in the operating theatre and in all the invasive procedures. The providers performing exposed-prone procedures must monitor their HCV serology regularly in order to detect early any primary infection and to treat it without delay. With the need to stay vigilant because HCV infection is often a hidden risk, it can be hoped that the number of people infected by HCV via health care will decrease very significantly in the next years. PMID- 25516638 TI - Locally advanced rectal cancer: the importance of a multidisciplinary approach. AB - Rectal cancer accounts for a relevant part of colorectal cancer cases, with a mortality of 4-10/100000 per year. The development of locoregional recurrences and the occurrence of distant metastases both influences the prognosis of these patients. In the last two decades, new multimodality strategies have improved the prognosis of locally advanced rectal cancer with a significant reduction of local relapse and an increase in terms of overall survival. Radical surgery still remains the principal curative treatment and the introduction of total mesorectal excision has significantly achieved a reduction in terms of local recurrence rates. The employment of neoadjuvant treatment, delivered before surgery, also achieved an improved local control and an increased sphincter preservation rate in low-lying tumors, with an acceptable acute and late toxicity. This review describes the multidisciplinary management of rectal cancer, focusing on the effectiveness of neoadjuvant chemoradiotherapy and of post-operative adjuvant chemotherapy both in the standard combined modality treatment programs and in the ongoing research to improve these regimens. PMID- 25516636 TI - Nonproliferative and proliferative lesions of the rat and mouse female reproductive system. AB - The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicological Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in the female reproductive tract of laboratory rats and mice, with color photomicrographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. There is also a section on normal cyclical changes observed in the ovary, uterus, cervix and vagina to compare normal physiological changes with pathological lesions. A widely accepted and utilized international harmonization of nomenclature for female reproductive tract lesions in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. PMID- 25516640 TI - Current status of function-preserving surgery for gastric cancer. AB - Recent advances in diagnostic techniques have allowed the diagnosis of gastric cancer (GC) at an early stage. Due to the low incidence of lymph node metastasis and favorable prognosis in early GC, function-preserving surgery which improves postoperative quality of life may be possible. Pylorus-preserving gastrectomy (PPG) is one such function-preserving procedure, which is expected to offer advantages with regards to dumping syndrome, bile reflux gastritis, and the frequency of flatus, although PPG may induce delayed gastric emptying. Proximal gastrectomy (PG) is another function-preserving procedure, which is thought to be advantageous in terms of decreased duodenogastric reflux and good food reservoir function in the remnant stomach, although the incidence of heartburn or gastric fullness associated with this procedure is high. However, these disadvantages may be overcome by the reconstruction method used. The other important problem after PG is remnant GC, which was reported to occur in approximately 5% of patients. Therefore, the reconstruction technique used with PG should facilitate postoperative endoscopic examinations for early detection and treatment of remnant gastric carcinoma. Oncologic safety seems to be assured in both procedures, if the preoperative diagnosis is accurate. Patient selection should be carefully considered. Although many retrospective studies have demonstrated the utility of function-preserving surgery, no consensus on whether to adopt function-preserving surgery as the standard of care has been reached. Further prospective randomized controlled trials are necessary to evaluate survival and postoperative quality of life associated with function-preserving surgery. PMID- 25516639 TI - Early-onset colorectal cancer: a separate subset of colorectal cancer. AB - Colorectal cancer (CRC) has a great impact on the world population. With increasing frequency, CRC is described according to the presenting phenotype, based on its molecular characteristics. Classification of CRC tumors according to their genetic and/or epigenetic alterations is not only important for establishing the molecular bases of the disease, but also for predicting patient outcomes and developing more individualized treatments. Early-onset CRC is a heterogeneous disease, with a strong familial component, although the disease is sporadic in an important proportion of cases. Different molecular alterations appear to contribute to the apparent heterogeneity of the early-onset population and subgroups can be distinguished with distinct histopathologic and familial characteristics. Moreover, compared with late-onset CRC, there are characteristics that suggest that early-onset CRC may have a different molecular basis. The purpose of this review was to analyze the current state of knowledge about early-onset CRC with respect to clinicopathologic, familial and molecular features. Together, these features make it increasingly clear that this subset of CRC may be a separate disease, although it has much in common with late-onset CRC. PMID- 25516641 TI - Alternative splicing of DNA damage response genes and gastrointestinal cancers. AB - Alternative splicing, which is a common phenomenon in mammalian genomes, is a fundamental process of gene regulation and contributes to great protein diversity. Alternative splicing events not only occur in the normal gene regulation process but are also closely related to certain diseases including cancer. In this review, we briefly demonstrate the concept of alternative splicing and DNA damage and describe the association of alternative splicing and cancer pathogenesis, focusing on the potential relationship of alternative splicing, DNA damage, and gastrointestinal cancers. We will also discuss whether alternative splicing leads to genetic instability, which is considered to be a driving force for tumorigenesis. Better understanding of the role and mechanism of alternative splicing in tumorigenesis may provide new directions for future cancer studies. PMID- 25516642 TI - Genetic and phenotypic heterogeneity in tropical calcific pancreatitis. AB - Tropical calcific pancreatitis (TCP) is a form of chronic non-alcoholic pancreatitis initially reported in the developing parts of the tropical world. The clinical phenotype of TCP has undergone marked changes since its first description in 1968. The disease is now seen in relatively older people with less severe symptoms. In addition, there are varying reports on the proportion of cases presenting with imaging abnormalities like calcification, ductal dilation, and glandular atrophy. Significant progress has also been made in understanding the etiopathology of TCP. The role of malnutrition and cassava toxicity in its pathogenesis is disproven and few studies have focused on the role of micronutrient deficiency and oxidative stress in the etiopathogenesis of TCP. Emerging evidence support an important role for genetic risk factors in TCP. Several studies have shown that, rather than mutations in trypsinogens, variants in serine protease inhibitor kazal type 1, cathepsin B, chymotrypsin C, cystic fibrosis transmembrane regulator, and carboxypeptidase A1, predict risk of TCP. These studies also provided evidence of mutational heterogeneity between TCP and chronic pancreatitis in Western populations. The current review summarizes recent advances that have implications in the understanding of the pathophysiology and thus, heterogeneity in genotype-phenotype correlations in TCP. PMID- 25516643 TI - Oxidative stress and inflammatory signaling in cerulein pancreatitis. AB - Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF kappaB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined. PMID- 25516644 TI - Video capsule endoscopy: perspectives of a revolutionary technique. AB - Video capsule endoscopy (VCE) was launched in 2000 and has revolutionized direct endoscopic imaging of the gut. VCE is now a first-line procedure for exploring the small bowel in cases of obscure digestive bleeding and is also indicated in some patients with Crohn's disease, celiac disease, and polyposis syndrome. A video capsule has also been designed for visualizing the esophagus in order to detect Barrett's esophagus or esophageal varices. Different capsules are now available and differ with regard to dimensions, image acquisition rate, battery life, field of view, and possible optical enhancements. More recently, the use of VCE has been extended to exploring the colon. Within the last 5 years, tremendous developments have been made toward increasing the capabilities of the colon capsule. Although colon capsule cannot be proposed as a first-line colorectal cancer screening procedure, colon capsule may be used in patients with incomplete colonoscopy or in patients who are unwilling to undergo colonoscopy. In the near future, new technological developments will improve the diagnostic yield of VCE and broaden its therapeutic capabilities. PMID- 25516645 TI - Computed tomography perfusion imaging as a potential imaging biomarker of colorectal cancer. AB - Neovascularization was reported to arise early in the adenoma-carcinoma sequence in colorectal cancer (CRC), and the importance of angiogenesis in cancer progression has been established. Computed tomography (CT) perfusion (CTP) based on high temporal resolution CT images enables evaluation of hemodynamics of tissue in vivo by modeling tracer kinetics. CTP has been reported to characterize tumor angiogenesis, and to be a sensitive marker for predicting recurrence or survival in CRC. In this review, we will discuss the biomarker value of CTP in the management of CRC patients. PMID- 25516646 TI - Anti-tumour necrosis factor agent and liver injury: literature review, recommendations for management. AB - Abnormalities in liver function tests, including transient and self-limiting hypertransaminasemia, cholestatic disease and hepatitis, can develop during treatment with anti-tumour-necrosis-factor (TNF) therapy. The optimal management of liver injury related to anti-TNF therapy is still a matter of debate. Although some authors recommend discontinuing treatment in case of both a rise of alanine aminotransferase more than 5 times the upper limit of normal, or the occurrence of jaundice, there are no standard guidelines for the management of anti-TNF related liver injury. Bibliographical searches were performed in PubMed, using the following key words: inflammatory bowel disease (IBD); TNF inhibitors; hypertransaminasemia; drug-related liver injury; infliximab. According to published data, elevation of transaminases in patients with IBD treated with anti TNF is a common finding, but resolution appears to be the usual outcome. Anti-TNF agents seem to be safe with a low risk of causing severe drug-related liver injury. According to our centre experience, we found that hypertransaminasemia was a common, mainly self-limiting finding in our IBD cohort and was not correlated to infliximab treatment on both univariate and multivariate analyses. An algorithm for the management of liver impairment occurring during anti-TNF treatment is also proposed and this highlights the need of a multidisciplinary approach and suggests liver biopsy as a key-point in the management decision in case of severe rise of transaminases. However, hepatic injury is generally self limiting and drug withdrawal seems to be an exception. PMID- 25516647 TI - Hepatitis B and human immunodeficiency virus co-infection. AB - Hepatitis B and human immunodeficiency virus (HBV and HIV) infection share transmission patterns and risk factors, which explains high prevalence of chronic HBV infection in HIV infected patients. The natural course of HBV disease is altered by the HIV infection with less chance to clear acute HBV infection, faster progression to cirrhosis and higher risk of liver-related death in HIV-HBV co-infected patients than in HBV mono-infected ones. HIV infected patients with chronic hepatitis B should be counseled for liver damage and surveillance of chronic hepatitis B should be performed to screen early hepatocellular carcinoma. Noninvasive tools are now available to evaluate liver fibrosis. Isolated hepatitis B core antibodies (anti-HBc) are a good predictive marker of occult HBV infection. Still the prevalence and significance of occult HBV infection is controversial, but its screening may be important in the management of antiretroviral therapy. Vaccination against HBV infection is recommended in non immune HIV patients. The optimal treatment for almost all HIV-HBV co-infected patients should contain tenofovir plus lamivudine or emtricitabine and treatment should not be stopped to avoid HBV reactivation. Long term tenofovir therapy may lead to significant decline in hepatitis B surface Antigen. The emergence of resistant HBV strains may compromise the HBV therapy and vaccine therapy. PMID- 25516648 TI - Hematopoietic stem cell transplantation for non-malignant gastrointestinal diseases. AB - Both, autologous and allogeneic hematopoietic stem cell transplantation (HSCT) can be used to cure or ameliorate a variety of malignant and non-malignant diseases. The rationale behind this strategy is based on the concept of immunoablation using high-dose chemotherapy, with subsequent regeneration of naive T-lymphocytes derived from reinfused hematopoietic progenitor cells. In addition, the use of HSCT allows for the administration of high-dose chemotherapy (whether or not combined with immunomodulating agents such as antithymocyte globulin) resulting in a prompt remission in therapy-refractory patients. This review gives an update of the major areas of successful uses of HSCT in non malignant gastrointestinal disorders. A Medline search has been conducted and all relevant published data were analyzed. HSCT has been proved successful in treating refractory Crohn's disease (CD). Patients with refractory celiac disease type II and a high risk of developing enteropathy associated T-cell lymphoma have shown promising improvement. Data concerning HSCT and mesenchymal SCT in end stage chronic liver diseases are encouraging. In refractory autoimmune gastrointestinal diseases high-dose chemotherapy followed by HSCT seems feasible and safe and might result in long-term improvement of disease activity. Mesenchymal SCT for a selected group of CD is promising and may represent a significant therapeutic alternative in treating fistulas in CD. PMID- 25516649 TI - Pea3 expression promotes the invasive and metastatic potential of colorectal carcinoma. AB - AIM: To investigate the function of Pea3 in colorectal carcinoma (CRC) invasion and metastatic potential. METHODS: The expression of Pea3 during clinical progression of human CRC was investigated using Oncomine Research Edition. To assay Pea3 expression in established CRC cell lines, we performed western blotting of cell lysates. We employed shRNA-mediated knockdown of Pea3 in HCT116 (HCT) and LS174T CRC cells which was confirmed by real-time quantitative PCR (qPCR) and western blotting. Transwell invasion assays, MTS proliferation assays, anoikis assays, and fluorometric matrix metalloprotease (MMP) assays were performed to determine the effects of Pea3 knockdown on invasion, proliferation, anoikis and MMP activity in CRC cells in vitro. Alterations in epithelial mesenchymal transition (EMT) and matrix metalloprotease (MMP) mRNA levels were determined by qPCR. CRC cells were injected into the flanks of nude mice to generate xenografts and tumor growth monitored with serial calliper measurements. To assay metastatic potential, CRC cells were injected into the spleen of nude mice, and histological analysis performed on the livers 21 d later. RESULTS: We demonstrated that reduction of Pea3 expression in CRC cells significantly impaired their invasive capacity (HCT.shPea3, 0.28 +/- 0.04 fold, P < 0.01; LS.shPea3, 0.15 +/- 0.04 fold; SW.shPea3, 0.23 +/- 0.03, P < 0.01), reduced anoikis resistance (HCT.shPea3 75.4% +/- 1.9% viable cells vs HCT.shCtrl 88.6% +/ 0.6% viable cells, P < 0.01; LS.shPea3 71.7% +/- 0.5% viable cells vs LS.Ctrl 89.6% +/- 0.3% viable cells, P < 0.005, but had no effect on proliferation (HCT.shCtrl AUC 5098 +/- 123 vs HCT.shPea3 5689 +/- 151, P < 0.05; LS.shCtrl AUC 5600 +/- 324.1 vs LS.shPea3 6423 +/- 400, P < 0.05). In vivo, HCT.shPea3 and HCT.shCtrl tumour xenografts grew at a similar rate (HCT.shPea3 2.64 +/- 0.82 fold vs HCT.shCtrl 2.88 +/- 0.80 fold, P > 0.05). In keeping with a pro metastatic function for Pea3 in CRC, several EMT markers and MMPs were downregulated in shPea3-expressing cells, suggesting that Pea3 may exert its effects through these processes. A reduction in overall MMP activity was observed in HCT.shPea3 cells compared to their control counterparts (HCT.shPea3 0.61 +/- 0.04 fold, P < 0.005). This translated in vivo to the complete absence of metastases in the livers of mice that were grafted with CRC cells lacking Pea3. Conversely, CRC cells expressing Pea3 formed liver metastases in all mice. CONCLUSION: Our study implicates Pea3 as a mediator of metastases, and provides a biological rationale for the adverse prognosis associated with elevated Pea3 expression in human CRC. PMID- 25516650 TI - Epidemiology of upper gastrointestinal symptoms in Brazil (EpiGastro): a population-based study according to sex and age group. AB - AIM: To determine the prevalences of symptoms consistent with gastroesophageal reflux disease (GERD) and dyspepsia in South America. METHODS: A telephone survey was conducted among adult owners of land-based telephones in Sao Paulo, Brazil, using previously validated computer-assisted sampling and survey protocols. The Portuguese-language survey included (1) sociodemographic characteristics (e.g., weight, height, smoking) and comorbidities; (2) dietary habits; (3) presence of symptoms consistent with GERD or dyspepsia within the prior 3 mo; and (4) use of medications and other therapies to manage symptoms. Data were stratified post-hoc into three homogeneous geographical regions of Sao Paulo according to the Social Exclusion Indices of the districts and postal codes. Survey response data from each respondent were weighted by the numbers of adults and landline telephones in each household. The analyses were weighted to account for sampling design and to be representative of the Sao Paulo population according to city census data. RESULTS: Among 4570 households contacted, an adult from 3050 (66.7%) agreed to participate. The nonresponse rate was 33.3%. The mean (SE) respondent age was 42.6 (16.0) years. More than half of all respondents were women (53.1%), aged 18 through 49 years (66.7%), married or cohabitating (52.5%), and/or above normal weight standards (i.e., 35.3% overweight and 16.3% obese). A total of 26.5% of women were perimenopausal. More than 20% of respondents reported highly frequent symptoms consistent with GERD (e.g., gastric burning sensation = 20.8%) or dyspepsia (e.g., abdominal swelling/distension = 20.9%) at least once per month. Prevalences of these symptoms were significantly (approximately 1.5- to 2.0-fold) higher among women than men but did not vary significantly as a function of advancing age. For instance, 14.1% of women reported that they experienced stomach burning (symptom of GERD) at least twice per week, compared to 8.4% of men (P = 0.012 by chi(2) test). A total of 15.7% of women reported that they experienced abdominal swelling (symptom of dyspepsia) at least twice per week, compared to 6.4% of men (P < 0.001 by chi(2) test). Despite frequent manifestations of GERD or dyspepsia, most (>= 90%) respondents reported that they neither received prescription medications from physicians, nor took behavioral measures (e.g., dietary modifications), to manage symptoms. CONCLUSION: Symptoms consistent with dyspepsia and GERD are prevalent in Brazil and represent major public-health and clinical challenges. PMID- 25516651 TI - Hybrid bioartificial liver support in cynomolgus monkeys with D-galactosamine induced acute liver failure. AB - AIM: To evaluate a hybrid bioartificial liver support system (HBALSS) in cynomolgus monkeys with acute liver failure. METHODS: To establish a model of acute liver failure, 0.3 g/kg of D-galactosamine was injected intravenously into cynomolgus monkeys. Chinese human liver cells were introduced into a perfusion bioreactor to carry out hybrid bioartificial liver support treatment. Forty-eight hours after the injection, one group of cynomolgus monkeys received HBALSS care, and a second experimental group received no treatment. Clinical manifestations of all animals, survival time, liver and kidney functions and serum biochemistry changes were recorded. Simultaneous detection of the number, viability and function of hepatocytes in the hybrid bioartificial liver were also performed. RESULTS: Forty-eight hours after the injection of D-galactosamine, serum biochemistry levels were significantly increased, whereas albumin levels and the Fischer index were significantly reduced compared to baseline (all Ps < 0.05). Of the ten monkeys in the HBALSS treatment group, five survived, with an average duration of survival of 128 +/- 3 h. All cynomolgus monkeys in the control group died, with a duration of survival of 112 +/- 2 h. Survival time was significantly longer with HBALSS treatment (P < 0.05). Moreover, the number, viability and function of hepatocytes were maintained at a high level with HBALSS. CONCLUSION: The novel hybrid bioartificial liver plays a significant role in liver support by significantly reducing serum biochemistry levels and extending animal survival time. PMID- 25516652 TI - Hepatoprotective effect of nitric oxide in experimental model of acute hepatic failure. AB - AIM: To evaluate the effect of nitric oxide (NO) on the development and degree of liver failure in an animal model of acute hepatic failure (AHF). METHODS: An experimental rat model of galactosamine-induced AHF was used. An inhibitor of NO synthase, nitroarginine methyl ester, or an NO donor, arginine, were administered at various doses prior to or after the induction of AHF. RESULTS: All tested groups developed AHF. Following inhibition of the endogenous NO pathway, most liver parameters improved, regardless of the inhibitor dose before the induction of liver damage, and depending on the inhibitor dose after liver damage. Prophylactic administration of the inhibitor was more effective in improving liver function parameters than administration of the inhibitor after liver damage. An attempt to activate the endogenous NO pathway prior to the induction of liver damage did not change the observed liver function parameters. Stimulation of the endogenous NO pathway after liver damage, regardless of the NO donor dose used, improved most liver function parameters. CONCLUSION: The endogenous NO pathway plays an important role in the development of experimental galactosamine-induced AHF. PMID- 25516653 TI - T3-induced liver AMP-activated protein kinase signaling: redox dependency and upregulation of downstream targets. AB - AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T3)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver. METHODS: Fed male Sprague-Dawley rats were given a single ip dose of 0.1 mg T3/kg or T3 vehicle (NaOH 0.1 N; controls) and studied at 8 or 24 h after treatment. Separate groups of animals received 500 mg N-acetylcysteine (NAC)/kg or saline ip 30 min prior T3. Measurements included plasma and liver 8-isoprostane and serum beta hydroxybutyrate levels (ELISA), hepatic levels of mRNAs (qPCR), proteins (Western blot), and phosphorylated AMPK (ELISA). RESULTS: T3 upregulates AMPK signaling, including the upstream kinases Ca(2+)-calmodulin-dependent protein kinase kinase beta and transforming growth factor-beta-activated kinase-1, with T3-induced reactive oxygen species having a causal role due to its suppression by pretreatment with the antioxidant NAC. Accordingly, AMPK targets acetyl-CoA carboxylase and cyclic AMP response element binding protein are phosphorylated, with the concomitant carnitine palmitoyltransferase-1alpha (CPT-1alpha) activation and higher expression of peroxisome proliferator-activated receptor gamma co-activator-1alpha and that of the fatty acid oxidation (FAO)-related enzymes CPT-1alpha, acyl-CoA oxidase 1, and acyl-CoA thioesterase 2. Under these conditions, T3 induced a significant increase in the serum levels of beta hydroxybutyrate, a surrogate marker for hepatic FAO. CONCLUSION: T3 administration activates liver AMPK signaling in a redox-dependent manner, leading to FAO enhancement as evidenced by the consequent ketogenic response, which may constitute a key molecular mechanism regulating energy dynamics to support T3 preconditioning against ischemia-reperfusion injury. PMID- 25516654 TI - Lobaplatin inhibits growth of gastric cancer cells by inducing apoptosis. AB - AIM: To assess the anti-cancer effect of lobaplatin on human gastric cancer cells, and to explore the underlying molecular mechanisms. METHODS: The human gastric cancer cell lines MKN-28, AGS and MKN-45 were used. The cytotoxicity of lobaplatin was detected using an MTS cell proliferation assay. Flow cytometry was used to detect cell apoptosis using Annexin V-FITC Apoptosis Detection Kit. The expression of apoptosis-regulated genes was examined at the protein level using Western blot. RESULTS: Lobaplatin inhibited the proliferation of human gastric cancer cells and induced apoptosis, which may be associated with the up regulation of Bax expression, poly(ADP-ribose) polymerase (PARP) cleavage, p53 expression and the reduction of Bcl-2 expression. CONCLUSION: The cytotoxicity of lobaplatin may be due to its ability of inducing apoptosis of gastric cancer cells, which would support the potential use of lobaplatin for the therapy of gastric cancer. PMID- 25516655 TI - Oesophageal flap valvuloplasty and wrapping suturing prevent gastrooesophageal reflux disease in dogs after oesophageal anastomosis. AB - AIM: To examine the efficiency of oesophageal flap valvuloplasty and wrapping suturing technique in decreasing the rate of postoperative gastrooesophageal reflux disease in a dog model. METHODS: We operated on 10 dogs in this study. First, we resected a 5-cm portion of the distal oesophagus and then restored the continuity of the oesophageal and gastric walls by end-to-end anastomosis. A group of five dogs was subjected to the oesophageal flap valvuloplasty and wrapping suturing technique, whereas another group (control) of five dogs was subjected to the stapling technique after oesophagectomy. The symptom of gastrooesophageal reflux was recorded by 24-h pH oesophageal monitoring. Endoscopy and barium swallow examination were performed on all dogs. Anastomotic leakage was observed by X-ray imaging, whereas benign anastomotic stricture and mucosal damage were observed by endoscopy. RESULTS: None of the 10 dogs experienced anastomotic leakage after oesophagectomy. Four dogs in the new technology group resumed regular feeding, whereas only two of the dogs in the control group tolerated solid food intake. pH monitoring demonstrated that 25% of the dogs in the experimental group exhibited reflux and that none had mucosal damage consistent with reflux. Conversely, both reflux and mucosal damage were observed in all dogs in the control group. CONCLUSION: The oesophageal flap valvuloplasty and wrapping suturing technique can improve the postoperative quality of life through the long-term elimination of reflux oesophagitis and decreased stricture formation after primary oesophageal anastomosis. PMID- 25516657 TI - Pancreaticoduodenectomy with vascular reconstruction for adenocarcinoma of the pancreas with borderline resectability. AB - AIM: To analyze whether pancreaticoduodenectomy with simultaneous resection of tumor-involved vessels is a safe approach with acceptable patient survival. METHODS: Between January 2001 and March 2012, 136 patients received pancreaticoduodenectomy for adenocarcinoma at our hospital. Seventy-eight patients diagnosed with pancreatic head carcinoma were included in this study. Among them, 46 patients received standard pancreaticoduodenectomy (group 1) and 32 patients received pancreaticoduodenectomy with simultaneous resection of the portal vein or the superior mesenteric vein or artery (group 2) followed by reconstruction. The immediate surgical outcomes and survivals were compared between the groups. Fifty-five patients with unresectable adenocarcinoma of the pancreas without liver metastasis who received only bypass operations (group 3) were selected for additional survival comparison. RESULTS: The median ages of patients were 67 years (range: 37-82 years) in group 1, and 63 years (range: 35 86 years) in group 2. All group 2 patients had resection of the portal vein or the superior mesenteric vein and three patients had resection of the superior mesenteric artery. The pancreatic fistula formation rate was 21.7% (10/46) in group 1 and 15.6% (5/32) in group 2 (P = 0.662). Two hospital deaths (4.3%) occurred in group 1 and one hospital death (3.1%) occurred in group 2 (P = 0.641). The one-year, three-year and five-year overall survival rates in group 1 were 71.1%, 23.6% and 13.5%, respectively. The corresponding rates in group 2 were 70.6%, 33.3% and 22.2% (P = 0.815). The one-year survival rate in group 3 was 13.8%. Pancreaticoduodenectomy with simultaneous vascular resection was safe for pancreatic head adenocarcinoma. CONCLUSION: The short-term and survival outcomes with simultaneous resection were not compromised when compared with that of standard pancreaticoduodenectomy. PMID- 25516656 TI - MiR-374b-5p suppresses RECK expression and promotes gastric cancer cell invasion and metastasis. AB - AIM: To profile expression of microRNAs (miRNAs) in gastric cancer cells and investigate the effect of miR-374b-5p on gastric cancer cell invasion and metastasis. METHODS: An miRNA microarray assay was performed to identify miRNAs differentially expressed in gastric cancer cell lines (MGC-803 and SGC-7901) compared with a normal gastric epithelial cell line. Upregulation of miR-374b-5p was newly identified and confirmed via quantitative real-time reverse transcription-PCR (qRT-PCR). MGC-803 cells were transfected with a synthesized anti-miR-374b-5p sequence or a control vector using Lipofectamine reagent, or treated with transfection reagent alone or phosphate-buffered saline as controls. Rate of transfection was verified after 48 h by qRT-PCR. Cells were then subjected to transwell migration, wound scratch and cell counting kit-8 assays. A bioinformatic analysis to identify miR-374b-5p target genes was performed using miRanda, PicTar and TargetScan software. A dual luciferase reporter assay was performed to evaluate the influence of miR-374b-5p on target gene activation, and qRT-PCR and Western blot were used to evaluate the levels of target mRNA and protein following transfection with miR-374b-5p antisense oligonucleotides. RESULTS: The microarray profiling revealed downregulation of 14 (fold change < 0.667; P < 0.05) and upregulation of 12 (fold change > 1.50; P < 0.05) miRNAs in MGC-803 and SGC-7901 cells compared with GES-1 controls. The upregulation of miR 374b-5p (fold change = 1.75 and 1.64 in MGC-803 and SGC-7901, respectively; P < 0.05) was confirmed by qRT-PCR. Compared with the control groups, the restoration of miR-374b-5p expression with anti-miR-374b-5p significantly suppressed the metastasis, invasion and proliferation of MGC-803 cells. The bioinformatic analysis predicted that the 3' untranslated region (UTR) of reversion-inducing cysteine-rich protein with Kazal motif (RECK) contains three miR-374b-5p target sequences. RECK was verified as a target gene in a dual luciferase reporter assay showing that activation of RECK 3'UTR-pmirGLO was increased by co-transfection with miR-374b-5p. Finally, transfection of miR-374b-5p antisense oligonucleotides increased mRNA and protein levels of RECK in MGC-803 cells (P < 0.05). CONCLUSION: These findings indicate that upregulation of miR-374b-5p contributes to gastric cancer cell metastasis and invasion through inhibition of RECK expression. PMID- 25516658 TI - Case-control study of diabetes-related genetic variants and pancreatic cancer risk in Japan. AB - AIM: To examine whether diabetes-related genetic variants are associated with pancreatic cancer risk. METHODS: We genotyped 7 single-nucleotide polymorphisms (SNPs) in PPARG2 (rs1801282), ADIPOQ (rs1501299), ADRB3 (rs4994), KCNQ1 (rs2237895), KCNJ11 (rs5219), TCF7L2 (rs7903146), and CDKAL1 (rs2206734), and examined their associations with pancreatic cancer risk in a multi-institute case control study including 360 cases and 400 controls in Japan. A self-administered questionnaire was used to collect detailed information on lifestyle factors. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between these diabetes-associated variants and pancreatic cancer risk. RESULTS: With the exception of rs1501299 in the ADIPOQ gene (P = 0.09), no apparent differences in genotype frequencies were observed between cases and controls. Rs1501299 in the ADPIOQ gene was positively associated with pancreatic cancer risk; compared with individuals with the AA genotype, the age- and sex-adjusted OR was 1.79 (95%CI: 0.98-3.25) among those with the AC genotype and 1.86 (95%CI: 1.03-3.38) among those with the CC genotype. The ORs remained similar after additional adjustment for body mass index and cigarette smoking. In contrast, rs2237895 in the KCNQ1 gene was inversely related to pancreatic cancer risk, with a multivariable-adjusted OR of 0.62 (0.37-1.04) among individuals with the CC genotype compared with the AA genotype. No significant associations were noted for other 5 SNPs. CONCLUSION: Our case-control study indicates that rs1501299 in the ADIPOQ gene may be associated with pancreatic cancer risk. These findings should be replicated in additional studies. PMID- 25516659 TI - Extraintestinal manifestations in a large series of Italian inflammatory bowel disease patients. AB - AIM: To investigate prevalence, type and time of onset of extraintestinal manifestations (EIMs) in a series of Italian inflammatory bowel disease (IBD) patients. METHODS: Data of 811 IBD consecutive patients, first referred to our Centre from 2000 to 2011, were retrospectively evaluated. RESULTS: Eight hundred and eleven IBD patients (437 M, 374 F) were studied: 595 ulcerative colitis (UC) (73.4%) and 216 Crohn's disease (CD) (26.6%). Among these, 329 (40.6%) showed EIMs: 210 UC (35.3%) and 119 CD (55.1%) (P < 0.0001). Considering the time of the diagnosis of IBD, 37 EIMs (11.2%) were developed before, 229 (69.6%) after and 63 (19.2%) were simultaneous. The type of EIM were as follows: 240 musculoskeletal (29.6%), in 72 CD patients and in 168 UC (P < 0.0001); 47 mucocutaneous (5.8%), in 26 CD and in 21 UC (P = 0.0049); 26 ocular (3.2%), in 16 CD and in 10 UC (CD 7.4% vs UC 1.7%, P = 0.0093); 6 hepatobiliary (0.8%); 10 endocrinological (1.2%). In particular, with regards to the involvement of the musculoskeletal system, arthritis Type 1 was found in 41 CD (19%) and in 61 UC (10.2%) (P = 0.0012) and Type 2 in 25 CD (11.6%) and in 100 UC (16.8%) (P = 0.0012). CONCLUSION: Mucocutaneous manifestations, arthritis Type 1 and uveitis were significantly more frequent in CD than UC. The complications of the musculoskeletal system were the mostly observed ones, often with symptoms more severe than intestinal ones, confirming the need for close cooperation with rheumatologists. PMID- 25516660 TI - Outcome of endotherapy for pancreas divisum in patients with acute recurrent pancreatitis. AB - AIM: To assess the rate of relapses of acute pancreatitis (AP), recurrent AP (RAP) and the evolution of endosonographic signs of chronic pancreatitis (CP) in patients with pancreas divisum (PDiv) and RAP. METHODS: Over a five-year period, patients with PDiv and RAP prospectively enrolled were divided into two groups: (1) those with relapses of AP in the year before enrollment were assigned to have endoscopic therapy (recent RAP group); and (2) those free of recurrences were conservatively managed, unless they relapsed during follow-up (previous RAP group). All patients in both groups entered a follow-up protocol that included clinical and biochemical evaluation, pancreatic endoscopic ultrasonography (EUS) every year and after every recurrence of AP, at the same time as endoscopic retrograde cholangiopancreatography (ERCP). RESULTS: Twenty-two were treated by ERCP and 14 were conservatively managed during a mean follow-up of 4.5 +/- 1.2 years. In the recent RAP group in whom dorsal duct drainage was achieved, AP still recurred in 11 (57.9%) after the first ERCP, in 6 after the second ERCP (31.6%) and in 5 after the third ERCP (26.3%). Overall, endotherapy was successful 73.7%. There were no cases of recurrences in the previous RAP group. EUS signs of CP developed in 57.9% of treated and 64.3% of untreated patients. EUS signs of CP occurred in 42.8% of patients whose ERCPs were successful and in all those in whom it was unsuccessful (P = 0.04). There were no significant differences in the rate of AP recurrences after endotherapy and in the prevalence of EUS signs suggesting CP when comparing patients with dilated and non-dilated dorsal pancreatic ducts within each group. CONCLUSION: Patients with PDiv and recent episodes of AP can benefit from endoscopic therapy. Effective endotherapy may reduce the risk of developing EUS signs of CP at a rate similar to that seen in patients of previous RAP group, managed conservatively. However, in a subset of patients, endotherapy, although successful, did not prevent the evolution of endosonographic signs of CP. PMID- 25516661 TI - Verification of gene expression profiles for colorectal cancer using 12 internet public microarray datasets. AB - AIM: To verify gene expression profiles for colorectal cancer using 12 internet public microarray datasets. METHODS: Logistic regression analysis was performed, and odds ratios for each gene were determined between colorectal cancer (CRC) and controls. Twelve public microarray datasets of GSE 4107, 4183, 8671, 9348, 10961, 13067, 13294, 13471, 14333, 15960, 17538, and 18105, which included 519 cases of adenocarcinoma and 88 normal mucosa controls, were pooled and used to verify 17 selective genes from 3 published studies and estimate the external generality. RESULTS: We validated the 17 CRC-associated genes from studies by Chang et al (Model 1: 5 genes), Marshall et al (Model 2: 7 genes) and Han et al (Model 3: 5 genes) and performed the multivariate logistic regression analysis using the pooled 12 public microarray datasets as well as the external validation. The goodness-of-fit test of Hosmer-Lemeshow (H-L) showed statistical significance (P = 0.044) for Model 2 of Marshall et al in which observed event rates did not match expected event rates in subgroups of the model population. Expected and observed event rates in subgroups were similar, which are called well calibrated, in Models 1, 3 and 4 with non-significant P values of 0.460, 0.194 and 1.000 for H-L tests, respectively. A 7-gene model of CPEB4, EIF2S3, MGC20553, MS4A1, ANXA3, TNFAIP6 and IL2RB was pairwise selected, which showed the best results in logistic regression analysis (H-L P = 1.000, R (2) = 0.951, areas under the curve = 0.999, accuracy = 0.968, specificity = 0.966 and sensitivity = 0.994). CONCLUSION: A novel gene expression profile was associated with CRC and can potentially be applied to blood-based detection assays. PMID- 25516662 TI - Prognostic factors for survival after transarterial chemoembolization combined with microwave ablation for hepatocellular carcinoma. AB - AIM: To analyze prognostic factors for survival after transarterial chemoembolization (TACE) combined with microwave ablation (MWA) for hepatocellular carcinoma (HCC). METHODS: Clinical data of 86 patients who underwent TACE combined with MWA between January 2006 and December 2013 were retrospectively analyzed in this study. Survival curves were detected using log rank test. Univariate analysis was performed using log-rank test with respect to 13 prognostic factors affecting survival. All statistically significant prognostic factors identified by univariate analysis were entered into a Cox proportion hazards regression model to identify independent predictors of survival. P values were two-sided and P < 0.05 was considered statistically significant. RESULTS: Median follow-up time was 47.6 mo, and median survival time of enrolled patients was 21.5 mo. The 1-, 2-, 3- and 5-year overall survival rates were 72.1%, 44.1%, 31.4% and 13.9%, respectively. Tumor size(chi(2) = 14.999, P = 0.000), Barcelona Clinic Liver Cancer (BCLC) stage (chi(2) = 29.765, P = 0.000), Child-Pugh class (chi(2) = 51.820, P = 0.000), portal vein tumor thrombus (PVTT) (chi(2) = 43.086, P = 0.000), arterio-venous fistula (chi(2) = 29.791, P = 0.000), MWA therapy times (chi(2) = 12.920, P = 0.002), Eastern Cooperative Oncology Group (ECOG) score (chi(2) = 28.660, P = 0.000) and targeted drug usage (chi(2) = 10.901, P = 0.001) were found to be significantly associated with overall survival by univariate analysis. Multivariate analysis identified that tumor size (95%CI: 1.608-4.962, P = 0.000), BCLC stage (95%CI: 1.016-2.208, P = 0.020), PVTT (95%CI: 2.062-9.068, P = 0.000), MWA therapy times (95%CI: 0.402 0.745, P = 0.000), ECOG score (95%CI: 1.012-3.053, P = 0.045) and targeted drug usage (95%CI: 1.335-3.143, P = 0.001) were independent prognostic factors associated with overall survival. CONCLUSION: Superior performance status, MWA treatment and targeted drug were favorable factors, and large HCC, PVTT and advanced BCLC stage were risk factors for survival after TACE-MWA for HCC. PMID- 25516663 TI - Analysis of risk factors for postoperative pancreatic fistula following pancreaticoduodenectomy. AB - AIM: To explore the morbidity and risk factors of postoperative pancreatic fistula (POPF) following pancreaticoduodenectomy. METHODS: The data from 196 consecutive patients who underwent pancreaticoduodenectomy, performed by different surgeons, in the General Hospital of the People's Liberation Army between January 1(st), 2013 and December 31(st), 2013 were retrospectively collected for analysis. The diagnoses of POPF and clinically relevant (CR)-POPF following pancreaticoduodenectomy were judged strictly by the International Study Group on Pancreatic Fistula Definition. Univariate analysis was performed to analyze the following factors: patient age, sex, body mass index (BMI), hypertension, diabetes mellitus, serum CA19-9 level, history of jaundice, serum albumin level, blood loss volume, pancreatic duct diameter, pylorus preserving pancreaticoduodenectomy, pancreatic drainage and pancreaticojejunostomy. Multivariate logistic regression analysis was used to determine the main independent risk factors for POPF. RESULTS: POPF occurred in 126 (64.3%) of the patients, and the incidence of CR-POPF was 32.7% (64/196). Patient characteristics of age, sex, BMI, hypertension, diabetes mellitus, serum CA19-9 level, history of jaundice, serum albumin level, blood loss volume, pylorus preserving pancreaticoduodenectomy and pancreaticojejunostomy showed no statistical difference related to the morbidity of POPF or CR-POPF. Pancreatic duct diameter was found to be significantly correlated with POPF rates by univariate analysis and multivariate regression analysis, with a pancreatic duct diameter <= 3 mm being an independent risk factor for POPF (OR = 0.291; P = 0.000) and CR-POPF (OR = 0.399; P = 0.004). The CR-POPF rate was higher in patients without external pancreatic stenting, which was found to be an independent risk factor for CR-POPF (OR = 0.394; P = 0.012). Among the entire patient series, there were three postoperative deaths, giving a total mortality rate of 1.5% (3/196), and the mortality associated with pancreatic fistula was 2.4% (3/126). CONCLUSION: A pancreatic duct diameter <= 3 mm is an independent risk factor for POPF. External stent drainage of pancreatic secretion may reduce CR-POPF mortality and POPF severity. PMID- 25516665 TI - Endoscopic non-technical skills team training: the next step in quality assurance of endoscopy training. AB - AIM: To investigate whether novel, non-technical skills training for Bowel Cancer Screening (BCS) endoscopy teams enhanced patient safety knowledge and attitudes. METHODS: A novel endoscopy team training intervention for BCS teams was developed and evaluated as a pre-post intervention study. Four multi-disciplinary BCS teams constituting BCS endoscopist(s), specialist screening practitioners, endoscopy nurses and administrative staff (A) from English BCS training centres participated. No patients were involved in this study. Expert multidisciplinary faculty delivered a single day's training utilising real clinical examples. Pre and post-course evaluation comprised participants' patient safety awareness, attitudes, and knowledge. Global course evaluations were also collected. RESULTS: Twenty-three participants attended and their patient safety knowledge improved significantly from 43%-55% (P <= 0.001) following the training intervention. 12/41 (29%) of the safety attitudes items significantly improved in the areas of perceived patient safety knowledge and awareness. The remaining safety attitude items: perceived influence on patient safety, attitudes towards error management, error management actions and personal views following an error were unchanged following training. Both qualitative and quantitative global course evaluations were positive: 21/23 (91%) participants strongly agreed/agreed that they were satisfied with the course. Qualitative evaluation included mandating such training for endoscopy teams outside BCS and incorporating team training within wider endoscopy training. Limitations of the study include no measure of increased patient safety in clinical practice following training. CONCLUSION: A novel comprehensive training package addressing patient safety, non-technical skills and adverse event analysis was successful in improving multi-disciplinary teams' knowledge and safety attitudes. PMID- 25516664 TI - Genomic landscape of pancreatic neuroendocrine tumors. AB - AIM: To investigate the prognostic role of genomic stability and copy number alterations (CNAs) pancreatic neuroendocrine tumors (PanNETs). METHODS: A high resolution array-based comparative genomic hybridization approach was utilized in order to investigate and quantify chromosomal aberrations in a panel of 37 primary PanNET and 11 metastatic samples. DNA samples were extracted from formalin-fixed and paraffin-embedded tumor specimen. Genomic findings were correlated with histopathological and immunohistochemical data. Moreover, the dataset was subjected to employing an unsupervised hierarchical clustering analysis approach utilizing Euclidean distance and average linkage and associations between genomically defined tumor groups and recurrent CNAs or clinicopathological features of the study group were assessed. RESULTS: Numerous chromosomal aberrations were recurrently detected in both, primary tumor samples and metastases. Copy number gains were most frequently observed at 06p22.2-p22.1 (27.1%), 17p13.1 (20.8%), 07p21.3-p21.2 (18.8%), 09q34.11 (18.8%). Genomic losses were significantly less frequent and the only recurrent aberration affected 08q24.3 (6.3%). Moreover, we detected a high degree of genomic heterogeneity between primary tumors and metastatic lesions. Unsupervised hierarchical clustering of loci affected by CNAs in more than 3 primary tumor samples revealed two genetically distinct tumor groups as well as two chromosomal clusters of genomic imbalances indicating a small subset of tumors with common molecular features (13.5%). Aberrations affecting 6p22.2-22.1, 8q24.3, 9q34.11 and 17p13.1 (P = 0.011; 0.003; 0.003; 0.001), were significantly associated with a poorer survival prognosis. CONCLUSION: This study suggests that several frequent CNAs in numerous candidate regions are involved in the pathogenesis and metastatic progression of PanNET. PMID- 25516668 TI - Plasma cathepsin L: a prognostic marker for pancreatic cancer. AB - AIM: To assess the prognostic significance of cathepsin L, a cysteine protease that degrades the peri-tumoral tissue, in patients with pancreatic cancer. METHODS: Plasma samples from 127 pancreatic cancer patients were analyzed for cathepsin L levels by ELISA. Out of these patients, 25 underwent surgery and their paraffin-embedded tissue was analyzed for cathepsin L expression by immunohistochemistry. Survival of patients and clinicopathological parameters was correlated with cathepsin L expression in plasma and tissue using appropriate statistical analysis. RESULTS: The mean (+/- SD) cathepsin L in plasma samples of pancreatic cancer patients was 5.98 +/- 2.5 ng/mL that was significantly higher compared to the levels in healthy controls (3.83 +/- 0.45) or chronic pancreatitis patients (3.97 +/- 1.06). Using ROC curve, a cut-off level of 5.0 ng/mL was decided for survival analysis. Elevated plasma levels of cathepsin L were found to be associated with poor prognosis (P = 0.01) in multivariate analysis. The plasma levels of the protease decreased after surgery. Though no significant correlation was seen between plasma and tissue expression of this protease, a trend did emerge that high cathepsin L expression in tissue correlated with its high levels in plasma. CONCLUSION: Cathepsin L levels in plasma of pancreatic cancer patients may be used as a potential prognostic marker for the disease. PMID- 25516669 TI - Significance of downregulation of liver fatty acid-binding protein in hepatocellular carcinoma. AB - AIM: To investigate the significance of downregulation of liver fatty acid binding protein (L-FABP) expression in hepatocellular carcinoma (HCC). METHODS: Tissue microarrays of 146 cases of HCC were used to perform immunohistochemical staining for L-FABP. For each L-FABP-negative HCC, further immunohistochemical staining was performed using a representative whole-tissue section to confirm the downregulation of L-FABP expression and to assess the intratumoral heterogeneity of the staining pattern. Clinical data were retrieved from the clinical files, and histological slides were reviewed. Immunohistochemical staining for cytokeratin (CK) 7, CK 19, beta-catenin, glutamine synthetase (GS), and serum amyloid A were also performed on the tissue microarrays. Clinicopathological features of the L-FABP-negative and L-FABP-positive HCC cases were compared. Furthermore, L-FABP and GS gene expression in HCC and cholangiocarcinoma cell lines were analyzed using real-time reverse transcription polymerase chain reaction. Mutation analysis of HNF1A [encoding hepatocyte nuclear factor 1 (HNF1)alpha] was performed for L-FABP-negative HCC cases. RESULTS: Sixteen (10.9%) of the 146 cases of HCC stained negative for L-FABP. When we examined the correlation between the downregulation pattern of L-FABP and tumor size, most cases of smaller HCC (<= 2 cm in diameter) exhibited focal downregulation, while most cases of larger HCC (> 2 cm in diameter) exhibited diffuse downregulation. The correlation was statistically significant (P = 0.036). When the HCC was smaller, the L-FABP-negative area often corresponded to a "nodule-in-nodule" appearance. Among the small HCC cases, tumor differentiation was significantly lower, and the frequency of intratumoral inflammation was significantly lower in L-FABP-negative cases than in L-FABP-positive cases (P = 0.032 and P = 0.009, respectively). The frequency of positivity for beta-catenin and GS staining was significantly higher in L-FABP-negative cases of small HCC than in L-FABP positive cases of small HCC (P = 0.009 and P = 0.000, respectively). Among six HCC cell lines examined, four showed higher expression of L-FABP, and the remaining two cell lines showed lower or no expression of L-FABP. Two of the 16 L FABP-negative HCC cases possessed a mutation in exon 4 of HNF1A. CONCLUSION: In smaller HCC, L-FABP downregulation probably occurs because of phenotypic changes during tumor progression. Moreover, this downregulation correlated with tumor differentiation and intratumoral inflammation. PMID- 25516667 TI - Clinical epidemiology of ulcerative colitis in Arabs based on the Montreal classification. AB - AIM: To determine the clinical, epidemiological and phenotypic characteristics of ulcerative colitis (UC) in Saudi Arabia by studying the largest cohort of Arab UC patients. METHODS: Data from UC patients attending gastroenterology clinics in four tertiary care centers in three cities between September 2009 and September 2013 were entered into a validated web-based registry, inflammatory bowel disease information system (IBDIS). The IBDIS database covers numerous aspects of inflammatory bowel disease. Patient characteristics, disease phenotype and behavior, age at diagnosis, course of the disease, and extraintestinal manifestations were recorded. RESULTS: Among 394 UC patients, males comprised 51.0% and females 49.0%. According to the Montreal classification of age, the major chunk of our patients belonged to the A2 category for age of diagnosis at 17-40 years (68.4%), while 24.2% belonged to the A3 category for age of diagnosis at > 40 years. According to the same classification, a majority of patients had extensive UC (42.7%), 35.3% had left-sided colitis and 29.2% had only proctitis. Moreover, 51.3% were in remission, 16.6% had mild UC, 23.4% had moderate UC and 8.6% had severe UC. Frequent relapse occurred in 17.4% patients, infrequent relapse in 77% and 4.8% had chronic disease. A majority (85.2%) of patients was steroid responsive. With regard to extraintestinal manifestations, arthritis was present in 16.4%, osteopenia in 31.4%, osteoporosis in 17.1% and cutaneous involvement in 7.0%. CONCLUSION: The majority of UC cases were young people (17 40 years), with a male preponderance. While the disease course was found to be similar to that reported in Western countries, more similarities were found with Asian countries with regards to the extent of the disease and response to steroid therapy. PMID- 25516670 TI - Laterally spreading tumors: limitations of computed tomography colonography. AB - AIM: To prospectively investigate the detection rate of laterally spreading tumors (LSTs) of the colorectum by computed tomography (CT) colonography (CTC). METHODS: Patients with LSTs measuring >= 20 mm detected during colonoscopy were prospectively enrolled in the study. All patients underwent colonoscopy and subsequent CTC on the same day. CTC was performed using multi-detector CT without contrast in the prone and supine positions. Two radiologists blinded to the existence of LSTs read the virtual endoscopic images as well as 2-D images. LSTs were classified into granular and non-granular types based on colonoscopic appearance. RESULTS: Forty-seven pathologically proven LSTs were evaluated prospectively. Histology included adenomas in 19, mucosal cancers in 19 and T1 cancers in 9. The mean diameter of the LSTs was 35.1 mm. Twenty-eight (60%) LSTs were correctly identified by CTC, and the configuration was similar to the colonoscopic appearance in most cases. Detection rate for the granular type was significantly higher than that for the non-granular type (71% vs 31%, P = 0.013). Detection rate of adenomas was significantly lower than mucosal cancers (32% vs 79%, P = 0.008) and T1 cancers (32% vs 78%, P = 0.042). CONCLUSION: The detection rate of LSTs by CTC, particularly the non-granular type was not acceptable. Practitioners should be aware of the relatively low detection rate when using CTC. PMID- 25516666 TI - Cytokine production in patients with cirrhosis and TLR4 polymorphisms. AB - AIM: To analyze the cytokine production by peripheral blood cells from cirrhotic patients with and without TLR4 D299G and/or T399I polymorphisms. METHODS: The study included nine patients with cirrhosis and TLR4 D299G and/or T399I polymorphisms, and 10 wild-type patients matched for age, sex and degree of liver failure. TLR4 polymorphisms were determined by sequence-based genotyping. Cytokine production by peripheral blood cells was assessed spontaneously and also after lipopolysaccharide (LPS) and lipoteichoic acid (LTA) stimulation. RESULTS: Patients with TLR4 polymorphisms had a higher incidence of previous hepatic encephalopathy than wild-type patients (78% vs 20%, P = 0.02). Spontaneous production of interleukin (IL)-6 and IL-10 was lower in patients with TLR4 polymorphisms than in wild-type patients [IL-6: 888.7 (172.0-2119.3) pg/mL vs 5540.4 (1159.2-26053.9) pg/mL, P < 0.001; IL-10: 28.7 (6.5-177.1) pg/mL vs 117.8 (6.5-318.1) pg/mL, P = 0.02]. However, the production of tumor necrosis factor alpha, IL-6 and IL-10 after LPS and LTA stimulation was similar in the two groups. CONCLUSION: TLR4 polymorphisms were associated with a distinctive pattern of cytokine production in cirrhotic patients, suggesting that they play a role in the development of cirrhosis complications. PMID- 25516671 TI - Three-Tesla magnetic resonance elastography for hepatic fibrosis: comparison with diffusion-weighted imaging and gadoxetic acid-enhanced magnetic resonance imaging. AB - AIM: To evaluate the feasibility of 3-Tesla magnetic resonance elastography (MRE) for hepatic fibrosis and to compare that with diffusion-weighted imaging (DWI) and gadoxetic acid-enhanced magnetic resonance (MR) imaging. METHODS: Forty-two patients were included in the study. On MRE, mean stiffness values were measured on the elastograms in kilopascals. The apparent diffusion coefficient (ADC) of the liver was measured using DWI. On gadoxetic acid enhanced MR, the contrast enhancement index (CEI) was calculated as signal intensity (SI)post/SIpre, where SIpost is liver-to-muscle SI ratio on hepatobiliary phase images and SIpre is that on nonenhanced images. Correlation between aspartate aminotransferase to the platelet ratio index (APRI) and three MR parameters was assessed. Each MR parameter was compared between a hepatic fibrosis (HF) group and non-hepatic fibrosis (nHF) group. RESULTS: Liver stiffness showed strong positive correlation with APRI [Spearman correlation coeffiecient (r) = 0.773, P < 0.0001], while ADC and CEI showed weak or prominent negative correlation (r = -0.28 and -0.321, respectively). In the HF group, only liver stiffness showed strong correlation with APRI (r = 0.731, P < 0.0001). Liver stiffness, ADC, and APRI were significantly different between the HF group and nHF group. CONCLUSION: MRE at 3 Tesla could be a feasible method for the assessment of hepatic fibrosis. PMID- 25516673 TI - Introducing an enhanced recovery after surgery program in colorectal surgery: a single center experience. AB - AIM: To study the implementation of an enhanced recovery after surgery (ERAS) program at a large University Hospital from "pilot study" to "standard of care". METHODS: The study was designed as a prospective single centre cohort study. A prospective evaluation of compliance to a protocol based on full application of all ERAS principles, through the progressive steps of its implementation, was performed. Results achieved in the initial pilot study conducted by a dedicated team (n = 47) were compared to those achieved in the shared protocol phase (n = 143) three years later. Outcomes were length of postoperative hospital stay, readmission rate, compliance to the protocol and morbidity. Primary endpoint was the description of the results and the identification of critical issues of large scale implementation of an ERAS program in colorectal surgery emerged in the experience of a single center. Secondary endpoint was the identification of interventions that have been proven to be effective for facilitating the transition from traditional care pathways to a multimodal management protocol according to ERAS principles in colorectal surgery at a single center. RESULTS: During the initial pilot study (March 2009 to December 2010; 47 patients) conducted by a dedicated multidisciplinary team, compliance to the items of ERAS protocol was 93%, with a median length of hospital stay (LOS) of 3 d. Early anastomotic fistulas were observed in 2 cases (4.2%), which required reoperation (Clavien-Dindo grade IIIb). None of the patients had been discharged before the onset of the complication, which could therefore receive prompt treatment. There were also four (8.5%) minor complications (Clavien-Dindo grade II). Thirty days readmission rate was 4%. Perioperative mortality was nil. After implementation of the protocol throughout the Hospital in unselected patients (May 2012 to December 2012; 147 patients) compliance was 74%, with a median LOS of 6 d. Early anastomotic fistulas were observed in 11 cases (7.7%), 5 (3.5%) of which required reoperation (Clavien-Dindo grade IIIb). Two early anastomotic fistulas were treated by radiologic/endoscopic manoeuvres and 4 were treated conservatively. There were also 36 (25.2%) minor complications, 21 (14.7%) of which were Clavien Dindo grade II and 15 (10.5%) of which were Clavien-Dindo grade I. Only two patients whose course was adversely affected by the development of an anastomotic leak had been discharged before the onset of the complication itself, requiring readmission. Readmission rate within 30 d was 4%. Perioperative mortality was 1%. CONCLUSION: Our results confirm that introduction of an ERAS protocol for colorectal surgery allows quicker postoperative recovery and shortens the length of stay compared to historical series. PMID- 25516672 TI - Upper-gastrointestinal bleeding secondary to peptic ulcer disease: incidence and outcomes. AB - AIM: To evaluate the incidence, surgery, mortality, and readmission of upper gastrointestinal bleeding (UGIB) secondary to peptic ulcer disease (PUD). METHODS: Administrative databases identified all hospitalizations for UGIB secondary to PUD in Alberta, Canada from 2004 to 2010 (n = 7079) using the International Classification of Diseases Codes (ICD-10). A subset of the data was validated using endoscopy reports. Positive predictive value and sensitivity with 95% confidence intervals (CI) were calculated. Incidence of UGIB secondary to PUD was calculated. Logistic regression was used to evaluate surgery, in-hospital mortality, and 30-d readmission to hospital with recurrent UGIB secondary to PUD. Co-variants accounted for in our logistic regression model included: age, sex, area of residence (i.e., urban vs rural), number of Charlson comorbidities, presence of perforated PUD, undergoing upper endoscopy, year of admission, and interventional radiological attempt at controlling bleeding. A subgroup analysis (n = 6356) compared outcomes of patients with gastric ulcers to those with duodenal ulcers. Adjusted estimates are presented as odds ratios (OR) with 95%CI. RESULTS: The positive predictive value and sensitivity of ICD-10 coding for UGIB secondary to PUD were 85.2% (95%CI: 80.2%-90.2%) and 77.1% (95%CI: 69.1%-85.2%), respectively. The annual incidence between 2004 and 2010 ranged from 35.4 to 41.2 per 100000. Overall risk of surgery, in-hospital mortality, and 30-d readmission to hospital for UGIB secondary to PUD were 4.3%, 8.5%, and 4.7%, respectively. Interventional radiology to control bleeding was performed in 0.6% of patients and 76% of these patients avoided surgical intervention. Thirty-day readmission significantly increased from 3.1% in 2004 to 5.2% in 2010 (OR = 1.07; 95%CI: 1.01 1.14). Rural residents (OR rural vs urban: 2.35; 95%CI: 1.83-3.01) and older individuals (OR >= 65 vs < 65: 1.57; 95%CI: 1.21-2.04) were at higher odds of being readmitted to hospital. Patients with duodenal ulcers had higher odds of dying (OR = 1.27; 95%CI: 1.05-1.53), requiring surgery (OR = 1.73; 95%CI: 1.34 2.23), and being readmitted to hospital (OR = 1.54; 95%CI: 1.19-1.99) when compared to gastric ulcers. CONCLUSION: UGIB secondary to PUD, particularly duodenal ulcers, was associated with significant morbidity and mortality. Early readmissions increased over time and occurred more commonly in rural areas. PMID- 25516675 TI - Costs of laparoscopic and open liver and pancreatic resection: a systematic review. AB - AIM: To study costs of laparoscopic and open liver and pancreatic resections, all the compiled data from available observational studies were systematically reviewed. METHODS: A systematic review of the literature was performed using the Medline, Embase, PubMed, and Cochrane databases to identify all studies published up to 2013 that compared laparoscopic and open liver [laparoscopic hepatic resection (LLR) vs open liver resection (OLR)] and pancreatic [laparoscopic pancreatic resection (LPR) vs open pancreatic resection] resection. The last search was conducted on October 30, 2013. RESULTS: Four studies reported that LLR was associated with lower ward stay cost than OLR (2972 USD vs 5291 USD). The costs related to equipment (3345 USD vs 2207 USD) and theatre (14538 vs 11406) were reported higher for LLR. The total cost was lower in patients managed by LLR (19269 USD) compared to OLR (23419 USD). Four studies reported that LPR was associated with lower ward stay cost than OLR (6755 vs 9826 USD). The costs related to equipment (2496 USD vs 1630 USD) and theatre (5563 vs 4444) were reported higher for LPR. The total cost was lower in the LPR (8825 USD) compared to OLR (13380 USD). CONCLUSION: This systematic review support the economic advantage of laparoscopic over open approach to liver and pancreatic resection. PMID- 25516674 TI - Prevalence, histologic and clinical characteristics of heterotopic gastric mucosa in Chinese patients. AB - AIM: To determine the prevalence, demographic, clinical and histopathologic features of heterotopic gastric mucosa (HGM) in Chinese patients. METHODS: Patients referred to three endoscopy units were enrolled in this study. The macroscopic characteristics of HGM were documented. Biopsies were obtained and observed using hematoxylin and eosin staining. Helicobacter pylori colonization was examined by Whartin-Starry staining. RESULTS: HGM was observed in 420 Chinese patients, yielding a prevalence of 0.4%. The majority of patients had a single patch (300/420; 71.4%), while the remainder had two (84/420; 20%) or multiple patches (36/420; 8.6%). The size of the patches and the distance from the patch to the frontal incisor teeth varied significantly. The large majority of HGM patches were flat (393/420; 93.6%), whereas the remaining patches were slightly elevated. The primary histological characteristic was fundic-type (216/420; 51.4%) within the HGM patch, and antral- (43/420; 10.2%) and transitional-type (65/420; 15.5%) mucosa were also observed. The prevalence of intestinal metaplasia was 3.1% (13/420) and the prevalence of dysplasia was 1.4% (6/420), indicating the necessity for endoscopic follow-up in patients with HGM. Esophageal and extraesophageal complaints were also observed in patients with HGM. Dysphagia and epigastric discomfort (odds ratios: 6.836 and 115.826, respectively; Ps < 0.05) were independent risk factors for HGM. CONCLUSION: Clinical complaints should be considered to improve the detection rate of HMG. The prevalence of intestinal metaplasia and dysplasia also indicates a need for endoscopic follow-up. PMID- 25516677 TI - Epidemiology of Helicobacter pylori infection among the healthy population in Iran and countries of the Eastern Mediterranean Region: a systematic review of prevalence and risk factors. AB - AIM: To investigate the epidemiology of Helicobacter pylori (H. pylori) infection among the healthy asymptomatic population in Iran and countries of the Eastern Mediterranean Region. METHODS: A computerized English language literature search of PubMed, ISI Web of Science, Scopus, and Google Scholar was performed in September 2013. The terms, "Eastern Mediterranean Regional Office (EMRO)" and "Helicobacter pylori", "H. pylori" and "prevalence" were used as key words in titles and/or abstracts. A complementary literature search was also performed in the following countries: Afghanistan, Bahrain, Djibouti, Egypt, Iran, Iraq, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Pakistan, Palestine, Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia, The United Arab Emirates, and Yemen. RESULTS: In the electronic search, a total of 308 articles were initially identified. Of these articles, 26 relevant articles were identified and included in the study. There were 10 studies from Iran, 5 studies from the Kingdom of Saudi Arabia, 4 studies from Egypt, 2 from the United Arab Emirates, and one study from Libya, Oman, Tunisia, and Lebanon, respectively. The overall prevalence of H. pylori infection in Iran, irrespective of time and age group, ranged from 30.6% to 82%. The overall prevalence of H. pylori infection, irrespective of time and age group, in other EMRO countries ranged from 22% to 87.6%. CONCLUSION: The prevalence of H. pylori in EMRO countries is still high in the healthy asymptomatic population. Strategies to improve sanitary facilities, educational status, and socioeconomic status should be implemented to minimize H. pylori infection. PMID- 25516678 TI - Meta-analysis of laparoscopic vs open cholecystectomy in elderly patients. AB - AIM: To investigate the comparative effect of laparoscopic and open cholecystectomy in elderly patients. METHODS: Laparoscopic cholecystectomy has induced a revolution in the treatment of gallbladder disease. Nevertheless, surgeons have been reluctant to implement the concepts of minimally invasive surgery in older patients. A systematic review of Medline was embarked on, up to June 2013. Studies which provided outcome data on patients aged 65 years or older, subjected to laparoscopic or open cholecystectomy were considered. Mortality, morbidity, cardiac and pulmonary complications were the outcome measures of treatment effect. The methodological quality of selected studies was appraised using valid assessment tools. Tauhe random-effects model was applied to synthesize outcome data. RESULTS: Out of a total of 337 records, thirteen articles (2 randomized and 11 observational studies) reporting on the outcome of 101559 patients (48195 in the laparoscopic and 53364 in the open treatment group, respectively) were identified. Odds ratios (OR) were constantly in favor of laparoscopic surgery, in terms of mortality (1.0% vs 4.4%, OR = 0.24, 95%CI: 0.17 0.35, P < 0.00001), morbidity (11.5% vs 21.3%, OR = 0.44, 95%CI: 0.33-0.59, P < 0.00001), cardiac (0.6% vs 1.2%, OR = 0.55, 95%CI: 0.38-0.80, P = 0.002) and respiratory complications (2.8% vs 5.0%, OR = 0.55, 95%CI: 0.51-0.60, P < 0.00001). Critical analysis of solid study data, demonstrated a trend towards improved outcomes for the laparoscopic concept, when adjusted for age and co morbid diseases. CONCLUSION: Further high-quality evidence is necessary to draw definite conclusions, although best-available evidence supports the selective use of laparoscopy in this patient population. PMID- 25516676 TI - Effects of laparoscopic cholecystectomy on lung function: a systematic review. AB - AIM: To present and integrate findings of studies investigating the effects of laparoscopic cholecystectomy on various aspects of lung function. METHODS: We extensively reviewed literature of the past 24 years concerning the effects of laparoscopic cholecystectomy in comparison to the open procedure on many aspects of lung function including spirometric values, arterial blood gases, respiratory muscle performance and aspects of breathing control, by critically analyzing physiopathologic interpretations and clinically important conclusions. A total of thirty-four articles were used to extract information for the meta-analysis concerning the impact of the laparoscopic procedure on lung function and respiratory physiopathology. The quality of the literature reviewed was evaluated by the number of their citations and the total impact factor of the corresponding journals. A fixed and random effect meta-analysis was used to estimate the pooled standardized mean difference of studied parameters for laparoscopic (LC) and open (OC) procedures. A crude comparison of the two methods using all available information was performed testing the postoperative values expressed as percentages of the preoperative ones using the Mann-Whitney two-sample test. RESULTS: Most of the relevant studies have investigated and compared changes in spirometric parameters.The median percentage and interquartile range (IQR) of preoperative values in forced vital capacity (FVC), forced expiratory volume in 1 s and forced expiratory flow (FEF) at 25%-75% of FVC (FEF25%-75%) expressed as percentage of their preoperative values 24 h after LC and OC were respectively as follows: [77.6 (73.0, 80.0) L vs 55.4 (50.0, 64.0) L, P < 0.001; 76.0 (72.3, 81.0) L vs 52.5 (50.0, 56.7) L, P < 0.001; and 78.8 (68.8, 80.9) L/s vs 60.0 (36.1, 66.1) L/s, P = 0.005]. Concerning arterial blood gases, partial pressure of oxygen [PaO2 (kPa)] at 24 or 48 h after surgical treatment showed reductions that were significantly greater in OC compared with LC [LC median 1.0, IQR (0.6, 1.3); OC median 2.4, IQR (1.2, 2.6), P = 0.019]. Fewer studies have investigated the effect of LC on respiratory muscle performance showing less impact of this surgical method on maximal respiratory pressures (P < 0.01); and changes in the control of breathing after LC evidenced by increase in mean inspiratory impedance (P < 0.001) and minimal reduction of duty cycle (P = 0.01) compared with preoperative data. CONCLUSION: Laparoscopic cholecystectomy seems to be associated with less postoperative derangement of lung function compared to the open procedure. PMID- 25516679 TI - Helicobacter pylori infection and atopic diseases: is there a relationship? A systematic review and meta-analysis. AB - AIM: To review and conduct a meta-analysis of the existing literature on the relationship between Helicobacter pylori (H. pylori), atopy and allergic diseases. METHODS: Studies published in English assessing the prevalence of atopy and/or allergic diseases in patients with H. pylori infection and the prevalence of H. pylori infection in patients with atopy and/or allergic diseases were identified through a MEDLINE search (1950-2014). Random-effect model was used for the meta-analysis. RESULTS: Pooled results of case-control studies showed a significant inverse association of H. pylori infection with atopy/allergic disease or with exclusively atopy, but not with allergic disease, whereas pooled results of cross-sectional studies showed only a significant association between allergic disease and H. pylori infection. CONCLUSION: There is some evidence of an inverse association between atopy/allergic diseases and H. pylori infection, although further studied are needed. PMID- 25516680 TI - Is concomitant radiotherapy necessary with gemcitabine-based chemotherapy in pancreatic cancer? AB - AIM: To evaluate the efficacy and safety of gemcitabine (GEM) plus radiotherapy compared with GEM alone for pancreatic cancer (PC). METHODS: A systematic search for eligible studies comparing gemcitabine plus radiotherapy with gemcitabine alone for PC was performed using MEDLINE, EMBASE, and the Cochrane Library. A quality assessment was performed in each study. Meta-analyses were performed to study the pooled effects of relative risk with 95% confidence interval (CI). RESULTS: A total of 336 participants from four original studies were included. Gemcitabine plus radiotherapy resulted in comparable overall survival (HR = 0.84, 95%CI: 0.53-1.34, P = 0.48) and progress free survival (HR = 0.99, 95%CI: 0.97 1.01, P = 0.36) to gemcitabine alone. Moreover, concomitant radiotherapy was associated with a significantly higher incidence of severe (grade 3 or greater) toxicities, mainly anemia, leukocytopenia, thrombocytopenia, anorexia, nausea/vomiting, and asthenia/fatigue. CONCLUSION: Radiotherapy is not beneficial with gemcitabine-based chemotherapy for PC. Further exploration for better radiotherapy approaches and therapeutic regimens for the treatment of PC is warranted. PMID- 25516681 TI - Late onset fulminant Wilson's disease: a case report and review of the literature. AB - Wilson's disease (WD) is an autosomal recessive inherited disorder of hepatic copper metabolism. WD can be present in different clinical conditions, with the most common ones being liver disease and neuropsychiatric disturbances. Most cases present symptoms at < 40 years of age. However, few reports exist in the literature on patients in whom the disease presented beyond this age. In this report, we present a case of late onset fulminant WD in a 58-year-old patient in whom the diagnosis was established clinically, by genetic analysis of the ATP7B gene disclosing rare mutations (G1099S and c.1707+3insT) as well as by high hepatic copper content. We also reviewed the relevant literature. The diagnosis of WD with late onset presentation is easily overlooked. The diagnostic features and the genetic background in patients with late onset WD are not different from those in patients with early onset WD, except for the age. Effective treatments for this disorder that can be fatal are available and will prevent or reverse many manifestations if the disease is discovered early. PMID- 25516682 TI - Rare combination of familial adenomatous polyposis and gallbladder polyps. AB - Familial adenomatous polyposis is associated with a high incidence of malignancies in the upper gastrointestinal tract (particularly ampullary adenocarcinomas). However, few reports have described a correlation between familial adenomatous polyposis and gallbladder neoplasms. We present a case of a 60-year-old woman with familial adenomatous polyposis who presented with an elevated mass in the neck of the gallbladder (measuring 16 mm * 8 mm in diameter) and multiple small cholecystic polyps. She had undergone a total colectomy for ascending colon cancer associated with familial adenomatous polyposis 22 years previously. The patient underwent laparoscopic cholecystectomy under a preoperative diagnosis of multifocal gallbladder polyps. Pathologic examination of the resected gallbladder revealed more than 70 adenomatous lesions, a feature consistent with adenoma of the gallbladder. This case suggests a requirement for long-term surveillance of the biliary system in addition to the gastrointestinal tract in patients with familial adenomatous polyposis. PMID- 25516683 TI - Hirschsprung's disease in twin to twin transfusion syndrome: a case report. AB - Twin to twin transfusion syndrome (TTTS) is caused by aberrant vascular connections between infant twins and results in high morbidity and mortality in the perinatal period. In donor infants with TTTS and symptoms of intestinal obstruction, small-bowel lesions have been reported in most cases. We report on a 33(+6) gestational wk donor infant with TTTS who had intermittent obstructive episodes, including delayed meconium passage and colonic dilatation on abdominal X-ray. The diagnosis of Hirschsprung's disease was based on a lateral pelvic film with a reversed rectosigmoid ratio. A subsequent barium colon study and rectal suction biopsy indicated a short segment aganglionosis of the colon. PMID- 25516684 TI - Emergency laparoscopic partial splenectomy for ruptured spleen: a case report. AB - Splenic rupture is a common consequence of blunt abdominal trauma. Emergency splenectomy is indicated when conservative management is not effective. With better understanding of the immunologic function of the spleen, surgeons have begun to perform the splenic-preserving surgery. However, it is technical challenge to perform emergency laparoscopic partial splenectomy for patient with spleen rupture. A 15-year-old male patient suffered from grade III spleen injury basing on the American association for the surgery of trauma splenic injury scale. Conservative treatment failed to success basing on the dramatically decreased hemoglobin level. During the laparoscopic exploration, we found that two individual ruptures were associated with the upper pole of spleen. An emergency laparoscopic partial splenectomy was successfully carried out. The operative time was approximate 150 min and the estimated blood loss was 200 mL. The post-operative course was uneventful and the patient was discharged on the 7(th) post-operative day. PMID- 25516685 TI - Focal autoimmune pancreatitis and chronic sclerosing sialadenitis mimicking pancreatic cancer and neck metastasis. AB - Type 1 autoimmune pancreatitis (AIP) or chronic sclerosing sialadenitis (Kuttner's tumour) is an uncommon disorder that has recently been confirmed as an IgG4-related disease. Here, we describe a rare case of a 53-year-old male patient who primarily presented with pancreatic body mass, left neck mass and several lumps in his lower lip mimicking pancreatic cancer (PC) and neck metastasis. The patient underwent pancreatic body mass and labial gland lumps resection as well as an ultrasound-guided biopsy of the left neck mass. He was diagnosed with IgG4 related focal type of AIP (f-AIP) and Kuttner's tumour by immunohistochemistry. The patient responded well to corticosteroid therapy and remains healthy with no signs of recurrence at one year follow-up. The differentiation of f-AIP from PC is very important to avoid unnecessary pancreatic resection. PMID- 25516686 TI - Sclerosing cholangitis secondary to bleomycin-iodinated embolization for liver hemangioma. AB - Sclerosing cholangitis (SC) is a rarely reported morbidity secondary to transcatheter arterial chemoembolization (TACE) with bleomycin-iodinated oil (BIO) for liver cavernous hemangioma (LCH). This report retrospectively evaluated the diagnostic and therapeutic course of a patient with LDH who presented obstructive jaundice 6 years after TACE with BIO. Preoperative imaging identified a suspected malignant biliary stricture located at the convergence of the left and right hepatic ducts. Operative exploration demonstrated a full-thickness sclerosis of the hilar bile duct with right hepatic duct stricture and right lobe atrophy. Radical hepatic hilar resection with right-side hemihepatectomy and Roux en-Y hepaticojejunostomy was performed because hilar cancer could not be excluded on frozen biopsy. Pathological results showed chronic pyogenic inflammation of the common and right hepatic ducts with SC in the portal area. Secondary SC is a long-term complication that may occur in LCH patients after TACE with BIO and must be differentiated from hilar malignancy. Hepatic duct plasty is a definitive but technically challenging treatment modality for secondary SC. PMID- 25516689 TI - Another tragic parenteral nutrition compounding error. AB - Another tragic parenteral nutrition compounding error. PMID- 25516687 TI - Reversal of IgM deficiency following a gluten-free diet in seronegative celiac disease. AB - Selective IgM deficiency (sIGMD) is very rare; it may be associated with celiac disease (CD). We present the case of an 18-year-old man with sIGMD masking seronegative CD. Symptoms included abdominal pain, diarrhea and weight loss. Laboratory tests showed reduced IgM, DQ2-HLA and negative anti-transglutaminase. Villous atrophy and diffuse immature lymphocytes were observed at histology. Tissue transglutaminase mRNA mucosal levels showed a 6-fold increase. The patient was treated with a gluten-free diet (GFD) and six months later the symptoms had disappeared, the villous architecture was restored and mucosal tissue transglutaminase mRNA was comparable to that of healthy subjects. After 1 year of GFD, a complete restoration of normal IgM values was observed and duodenal biopsy showed a reduction of immature lymphocytes and normal appearance of mature immune cells. PMID- 25516691 TI - Pharmaceutical approval update. AB - Ledipasvir/sofosbuvir (Harvoni) for hepatitis C virus genotype 1 infection; dulaglutide (Trulicity) for glycemic control in type-2 diabetes; netupitant/palonosetron (Akynzeo) for prevention of nausea and vomiting related to chemotherapy; and naloxegol (Movantik) for opioid-induced constipation in patients with chronic noncancer pain. PMID- 25516688 TI - Diagnostically untypable hepatitis C virus variants: it is time to resolve the problem. AB - Pakistan is a low income country with more than 10 million hepatitis C virus (HCV) infections and the burden is on continuous raise. Accurate viral genotyping is very critical for proper treatment of the infected individuals as the sustained virological response of the standard antiviral interferon therapy is genotype dependent. We observed at our diagnostic center that 15.6% of HCV patient's samples were not genotype-able by using Ohno et al method. The genotyped samples showed that 3a (68.3%) is the major prevalent genotype in Pakistan followed by 2a (10.3%), 3b (2.6%), 1b (1.5%), 2b (1.2%) and 1a (0.5%). Presence of large number of untypable HCV variants in the current study highlights an important issue of health care setup in Pakistan. Untypable HCV cases create difficulties in treatment of these patients. The problem of routine diagnostics setup of Pakistan should be addressed on priority basis to facilitate the medical professionals in patient's treatment and to help in achieving the maximum sustained virological response. PMID- 25516692 TI - Ceftolozane/Tazobactam: a new option in the treatment of complicated gram negative infections. AB - Ceftolozane/tazobactam: a new option in the treatment of complicated gram negative infections. PMID- 25516693 TI - Generic prices take flight: the FDA is struggling to ground them. AB - The prices of some generic pharmaceuticals have lifted off into the stratosphere. A variety of reasons account for the increases, including loss of competition, dropping of product lines, and delays at the Food and Drug Administration. PMID- 25516694 TI - Stem cell therapy: a look at current research, regulations, and remaining hurdles. AB - Stem cell therapies offer great promise for a wide range of diseases and conditions. However, stem cell research-particularly human embryonic stem cell research-has also been a source of ongoing ethical, religious, and political controversy. PMID- 25516697 TI - European society of medical oncology. AB - Sessions covered metastatic breast cancer, cachexia in non-small-cell lung cancer, recurrent and/or metastatic head and neck squamous-cell carcinoma, and melanoma. PMID- 25516695 TI - Interrupting anticoagulation in patients with nonvalvular atrial fibrillation. AB - Three target-specific oral anticoagulants (TSOACs)-dabigatran, rivaroxaban, and apixaban-have been approved by the FDA to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; however, no agents are currently approved to reverse the anticoagulant effects of these TSOACs in cases of active bleeding. This review discusses the benefits and risks of these TSOACs from a clinician's perspective, with a focus on the interruption of treatment for either elective or emergent surgery, monitoring, and reversal of anticoagulation. Available coagulation assays are not ideal for monitoring the effects of TSOACs and do not provide reliable quantitative measurement of their anticoagulant effects. When necessary, activated partial thromboplastin time (aPTT) may provide qualitative information on dabigatran, and prothrombin time (PT) may provide qualitative assessment of the presence of the factor Xa inhibitors, rivaroxaban and apixaban. Current recommendations for reversal of TSOACs are based largely on limited and sometimes conflicting data from in vitro or in vivo animal models, and clinical experience with these recommendations is also limited. Methods that have been investigated for effectiveness for reversal of the pharmacodynamic effects of the TSOACs include dialysis, activated charcoal, prothrombin complex concentrate (PCC), and recombinant activated factor VII. It is important to note that even within a class of anticoagulant drugs, compounds respond differently to reversal agents; therefore, recommendations for one agent should not be extrapolated to another, even if they are from the same therapeutic class. New antidotes are being explored, including a mouse monoclonal antibody to dabigatran; andexanet alfa, a potential universal factor Xa inhibitor reversal agent; and a synthetic small molecule (PER977) that may be effective for the reversal of factor Xa inhibitors and direct thrombin inhibitors. Given the short half-lives of TSOACs, watchful waiting, rather than reversal, may be the best approach in some circumstances. PMID- 25516696 TI - Overview of insulin and non-insulin delivery devices in the treatment of diabetes. AB - Antidiabetic agents can be delivered orally or with a syringe, but other options are also available, such as insulin and non-insulin pen devices and insulin pumps. This article reviews the available delivery devices and their current place in therapy. PMID- 25516698 TI - Diabetes market grows ever more crowded. AB - Global prevalence of type-2 diabetes is expected to reach 330 million cases by 2022, with medication sales of $67.7 billion. The market is crowded with generic medications, and most products now in the development pipeline are "me-too" drugs. PMID- 25516700 TI - Robot-assisted versus open liver resection in the right posterior section. AB - BACKGROUND: Open liver resection is the current standard of care for lesions in the right posterior liver section. The objective of this study was to determine the safety of robot-assisted liver resection for lesions located in segments 6 and 7 in comparison with open surgery. METHODS: Demographics, comorbidities, clinicopathologic characteristics, surgical treatments, and outcomes from patients who underwent open and robot-assisted liver resection at 2 centers for lesions in the right posterior section between January 2007 and June 2012 were reviewed. A 1:3 matched analysis was performed by individually matching patients in the robotic cohort to patients in the open cohort on the basis of demographics, comorbidities, performance status, tumor stage, and location. RESULTS: Matched patients undergoing robotic and open liver resections displayed no significant differences in postoperative outcomes as measured by blood loss, transfusion rate, hospital stay, overall complication rate (15.8% vs 13%), R0 negative margin rate, and mortality. Patients undergoing robotic liver surgery had significantly longer operative time (mean, 303 vs 233 minutes) and inflow occlusion time (mean, 75 vs 29 minutes) compared with their open counterparts. CONCLUSIONS: Robotic and open liver resections in the right posterior section display similar safety and feasibility. PMID- 25516701 TI - Comparison of outcomes after single-port laparoscopic cholecystectomy in relation to patient body mass index. AB - BACKGROUND AND OBJECTIVES: Single-port laparoscopic cholecystectomy may contribute to a paradigm shift in the field of laparoscopic cholecystectomy surgery by providing patients with benefits beyond those observed after other surgical procedures. This study was designed to evaluate clinically meaningful differences in operative outcomes between obese and nonobese patients after single-port laparoscopic cholecystectomy. METHODS: Data were collected retrospectively from 172 patients who had undergone single-port laparoscopic cholecystectomy performed by the same surgeon at a single medical center between January and December 2011. For the outcome analysis, patients were divided into nonobese and obese patient groups according to their body mass index (<25 kg/m2 vs >=25 kg/m2). RESULTS: Demographic and clinical data did not differ significantly between obese patients (n=65) and nonobese patients (n=107). In addition, statistically significant differences pertaining to most measured surgical outcomes including postoperative hospital stay, bile spillage, additional port use, and open conversion were not detected between the groups. However, the two groups differed significantly regarding operative time such that nonobese patients had shorter operative times than obese patients (P<.05). CONCLUSION: The results of this study showed that operative time for single-port laparoscopic cholecystectomy was the only difference between obese and nonobese patients. Given this result, body mass index may not be as relevant a factor in patient selection for single-port laparoscopic cholecystectomy as previously thought. PMID- 25516702 TI - Transcystic approach to laparoscopic common bile duct exploration. AB - BACKGROUND AND OBJECTIVES: One-stage laparoscopic management for common bile duct stones in patients with gallbladder stones has gained wide acceptance. We developed a novel technique using a transcystic approach for common bile duct exploration as an alternative to the existing procedures. METHODS: From April 2010 to June 2012, 9 consecutive patients diagnosed with cholelithiasis and common bile duct stones were enrolled in this study. The main inclusion criteria included no upper abdominal surgical history and the presence of a stone measuring <5 mm. After the gallbladder was dissected free from the liver connections in a retrograde fashion, the fundus of the gallbladder was extracted via the port incision in the right epigastrium. The choledochoscope was inserted into the gallbladder through the small opening in the fundus of the gallbladder extracorporeally and was advanced toward the common bile duct via the cystic duct under the guidance of both laparoscopic imaging and endoscopic imaging. After stones were retrieved under direct choledochoscopic vision, a drainage tube was placed in the subhepatic space. RESULTS: Of 9 patients, 7 had successful transcystic common bile duct stone clearance. A narrow cystic duct and the unfavorable anatomy of the junction of the cystic duct and common bile duct resulted in losing access to the common bile duct. No bile leakage, hemobilia, or pancreatitis occurred. Wound infection occurred in 2 patients. Transient epigastric colic pain occurred in 2 patients and was relieved by use of anisodamine. A transient increase in the amylase level was observed in 3 patients. Short-term follow-up did not show any recurrence of common bile duct stones. CONCLUSION: Our novel transcystic approach to laparoscopic common bile duct exploration is feasible and efficient. PMID- 25516703 TI - Impact of cosmetic result on selection of surgical treatment in patients with localized prostate cancer. AB - OBJECTIVES: To analyze the effect of cosmetic outcome as an isolated variable in patients undergoing surgical treatment based on the incision used in the 3 variants of radical prostatectomy: open (infraumbilical incision and Pfannestiel incision) and laparoscopic, or robotic (6 ports) surgery. PATIENTS AND METHODS: 612 male patients 40 to 70 years of age with a negative history of prostate disease were invited to participate. Each patient was evaluated by questionnaire accompanied by a set of 6 photographs showing the cosmetic appearance of the 3 approaches, with and without undergarments. Participants ranked the approaches according to preference, on the basis of cosmesis. We also recorded demographic variables: age, body mass index, marital status, education level, and physical activity. RESULTS: Of the 577 patients who completed the questionnaries, the 6 port minimally invasive approach represents the option preferred by 52% of the participants, followed by the Pfannestiel incision (46%), and the infraumbilical incision (11%), respectively. The univariate and multivariate analyses did not show statistically significant differences when comparing the approach preferred by the patients and the sub-analyses for demographic variables, except for patients who exercised who preferred the Pfannestiel incision (58%) instead of minimally invasive approach (42%) with statistically significant differences. CONCLUSION: The minimally invasive approach was the approach of choice for the majority of patients in the treatment of prostate cancer. The Pfannestiel incision represents an acceptable alternative. More research and investment may be necesary to improve cosmetic outcomes. PMID- 25516704 TI - Assessment of gel-coated delayed self-gripping mesh. AB - BACKGROUND: Mesh hernia repair is one of the most frequently performed procedures in general surgery. Recently, use of the self-gripping mesh demonstrated a beneficial effect on postoperative pain in inguinal hernia repairs. However, in intra-abdominal placement, the use of this novel mesh requires greater laparoscopic skill and dexterity because of the mesh's tendency to fold and adhere to itself and to any surrounding tissues. We hypothesized that gel-like coverage of a self-gripping mesh with a water-soluble film would allow delaying the immediate surface adhesion of the mesh to the tissue, which may allow greater freedom and ease in mesh placement for laparoscopic surgeons. METHODS: In this ex vivo animal study, gel-coated self-gripping mesh (ProGrip) was compared with a control uncoated mesh in bovine and porcine tissue specimens and assessed for dislodgement shear forces before and after dissolving of the gel. RESULTS: Gel coating of the mesh reduced preperitoneal dislodgement forces in a porcine abdominal wall specimen by 81% (8.05 +/- 0.66 vs 1.53 +/- 0.82 N, P < .01). Dissolving the gel markedly increased the anchoring forces (10.62 +/- 3.70 vs 1.53 +/- 0.82 N, P < .0001), and after dissolving the gel, the mesh shear dislodgement forces were similar and noninferior to the control mesh (8.05 +/- 0.66 vs 10.62 +/- 3.70 N, P = NS). CONCLUSIONS: We believe that water-soluble gel coating does not impair the adhesive features of the self-gripping mesh and may simplify its use in open and laparoscopic procedures by allowing controlled activation of the self-gripping mechanism. PMID- 25516705 TI - Unilateral versus bilateral wrap crural fixation in laparoscopic Nissen fundoplication for children. AB - INTRODUCTION: Gastroesophageal reflux (GERD) is common in neurologically impaired (NI) children. Fundoplication and gastrostomy have previously been indicated in NI children with GERD who have not responded to medical treatment. The most common reason for fundoplication failure is intrathoracic migration of the wrap. OBJECTIVE: The aim of the study is to measure the effect of wrap fixation on the final outcome of laparoscopic Nissen fundoplication in NI children. PATIENTS AND METHODS: A retrospective file review was conducted for all NI children who underwent laparoscopic Nissen fundoplication in 2 tertiary pediatric surgery centers in the United Arab Emirates from February 15, 2006 to February 15, 2013. Redo fundoplication patients were excluded from the study. Patients were divided into 2 groups: group 1 in which the fundoplication wrap was fixed to the right crus only, and group 2 in which the wrap was fixed to the right and left crus simultaneously. RESULTS: The study population included 68 patients; there were 47 male and 21 female children. Mean age at time of surgery was 8.2 years. Recurrent GERD at 1 year postoperatively was 26% versus 7% in group 1 and group 2, respectively, by upper contrast study. Redo surgery was required in 21% versus 3% in group 1 and group 2, respectively. CONCLUSIONS: Bilateral fixation of the wrap to diaphragmatic crura significantly reduced recurrent GERD, in laparoscopic Nissen fundoplication for neurologically impaired children, with no increased risk of morbidities. Future prospective studies should be conducted with larger patient populations and longer follow-up periods. PMID- 25516706 TI - Persistent bleeding after laparoscopic supracervical hysterectomy. AB - BACKGROUND AND OBJECTIVES: In our clinical experience, there seemed to be a correlation between cervical stump bleeding and adenomyosis. Therefore, we wanted to conduct a study to determine whether there was an actual correlation and to identify other risk factors for persistent bleeding after a laparoscopic supracervical hysterectomy. METHODS: The study included women who underwent laparoscopic supracervical hysterectomy from January 1, 2003, through December 31, 2012. Data were collected on age, postmenopausal status, body mass index (BMI), uterine weight, indication for hysterectomy, concomitant bilateral salpingo-oophorectomy (BSO), presence of endometriosis, surgical ablation of the endocervix, adenomyosis, presence of endocervix in the specimen, and postoperative bleeding. RESULTS: The study included 256 patients, of whom 187 had no postoperative bleeding after the operation, 40 had bleeding within 12 weeks, and 29 had bleeding after 12 weeks. The 3 groups were comparable in BMI, postmenopausal status, uterine weight, indication for hysterectomy, BSO, surgical ablation of the endocervix, adenomyosis, and the presence of endocervix. However, patients who had postoperative bleeding at more than 12 weeks were significantly younger (P = .002) and had a higher rate of endometriosis (P < .001). CONCLUSIONS: Risks factors for postoperative bleeding from the cervical stump include a younger age at the time of hysterectomy and the presence of endometriosis. Therefore, younger patients and those with endometriosis who desire to have no further vaginal bleeding may benefit from total hysterectomy over supracervical hysterectomy. All patients who are undergoing supracervical hysterectomy should be counseled about the possible alternatives, benefits, and risks, including continued vaginal bleeding from the cervical stump and the possibility of requiring future treatment and procedures. PMID- 25516707 TI - Analysis of reoperations after laparoscopic adjustable gastric banding. AB - BACKGROUND AND OBJECTIVES: Laparoscopic adjustable gastric banding is considered the least invasive surgical option for the treatment of morbid obesity. Its initial popularity has been marred by recent long-term studies showing high complication rates. We sought to examine our experience with gastric banding and factors leading to reoperation. METHODS: We reviewed retrospective data of 305 patients who underwent laparoscopic adjustable gastric banding between 2004 and 2011 at a single institution, 42 patients of whom required a reoperation, constituting 13.8%. Patients undergoing elective reoperations for port protrusion from weight loss as a purely cosmetic issue were excluded (n = 10). Patients' demographic data, weight loss, time to reoperation, and complications were analyzed. RESULTS: Of 305 patients, 42 (13.8%) required reoperations: 26 underwent band removal (8.5%) and 16 underwent port revision (5.2%). The mean weight and body mass index for all patients who underwent reoperations were 122.6 kg and 45.0 kg/m(2), respectively. The most common complication leading to band removal was gastric prolapse (n = 14, 4.6%). The most common indication for port revision was a nonfunctioning port (n = 10, 3.3%). CONCLUSION: Laparoscopic adjustable gastric banding was initially popularized as a minimally invasive gastric-restrictive procedure with low morbidity. Our study showed a 13.8% reoperation rate at 3 years' follow-up. Most early reoperations (<2 years) were performed for port revision, whereas later reoperations (>2 years) were likely to be performed for band removal. Laparoscopic adjustable gastric banding is associated with high reoperation rates; therefore bariatric surgeons should carefully consider other surgical weight-loss options tailored to the needs of the individual patient that may have lower complication and reoperation rates. PMID- 25516708 TI - Meta-analysis of drainage versus no drainage after laparoscopic cholecystectomy. AB - BACKGROUND AND OBJECTIVES: Routine drainage after laparoscopic cholecystectomy is still controversial. This meta-analysis was performed to assess the role of drains in reducing complications in laparoscopic cholecystectomy. METHODS: An electronic search of Medline, Science Citation Index Expanded, Scopus, and the Cochrane Library database from January 1990 to June 2013 was performed to identify randomized clinical trials that compare prophylactic drainage with no drainage in laparoscopic cholecystectomy. The odds ratio for qualitative variables and standardized mean difference for continuous variables were calculated. RESULTS: Twelve randomized controlled trials were included in the meta-analysis, involving 1939 patients randomized to a drain (960) versus no drain (979). The morbidity rate was lower in the no drain group (odds ratio, 1.97; 95% confidence interval, 1.26 to 3.10; P = .003). The wound infection rate was lower in the no drain group (odds ratio, 2.35; 95% confidence interval, 1.22 to 4.51; P = .01). Abdominal pain 24 hours after surgery was less severe in the no drain group (standardized mean difference, 2.30; 95% confidence interval, 1.27 to 3.34; P < .0001). No significant difference was present with respect to the presence and quantity of subhepatic fluid collection, shoulder tip pain, parenteral ketorolac consumption, nausea, vomiting, and hospital stay. CONCLUSION: This study was unable to prove that drains were useful in reducing complications in laparoscopic cholecystectomy. PMID- 25516709 TI - Ultrasound-targeted stromal cell-derived factor-1-loaded microbubble destruction promotes mesenchymal stem cell homing to kidneys in diabetic nephropathy rats. AB - Mesenchymal stem cell (MSC) therapy has been considered a promising strategy to cure diabetic nephropathy (DN). However, insufficient MSCs can settle in injured kidneys, which constitute one of the major barriers to the effective implementation of MSC therapy. Stromal cell-derived factor-1 (SDF-1) plays a vital role in MSC migration and involves activation, mobilization, homing, and retention, which are presumably related to the poor homing in DN therapy. Ultrasound-targeted microbubble destruction has become one of the most promising strategies for the targeted delivery of drugs and genes. To improve MSC homing to DN kidneys, we present a strategy to increase SDF-1 via ultrasound-targeted microbubble destruction. In this study, we developed SDF-1-loaded microbubbles (MB(SDF-1)) via covalent conjugation. The characterization and bioactivity of MB(SDF-1) were assessed in vitro. Target release in the targeted kidneys was triggered with diagnostic ultrasound in combination with MB(SDF-1). The related bioeffects were also elucidated. Early DN was induced in rats with streptozotocin. Green fluorescent protein-labeled MSCs were transplanted intravenously following the target release of SDF-1 in the kidneys of normal and DN rats. The homing efficacy was assessed by detecting the implanted exogenous MSCs at 24 hours. The in vitro results showed an impressive SDF-1 loading efficacy of 79% and a loading content of 15.8 MUg/mL. MB(SDF-1) remained bioactive as a chemoattractant. In the in vivo study, SDF-1 was successfully released in the targeted kidneys. The homing efficacy of MSCs to DN kidneys after the target release of SDF-1 was remarkably ameliorated at 24 hours compared with control treatments in normal rats and DN rats. In conclusion, ultrasound-targeted MB(SDF-1) destruction could promote the homing of MSCs to early DN kidneys and provide a novel potential therapeutic approach for DN kidney repair. PMID- 25516711 TI - Cerebrolysin effects on neurological outcomes and cerebral blood flow in acute ischemic stroke. AB - BACKGROUND: Cerebrolysin, a brain-derived neuropeptide, has been shown to improve the neurological outcomes of stroke, but no study has demonstrated its effect on cerebral blood flow. This study aimed to determine the cerebrolysin impact on the neurological outcomes and cerebral blood flow. METHODS: In a randomized, double blinded, placebo-controlled trial, 46 patients who had acute focal ischemic stroke were randomly assigned into two groups to receive intravenously either 30 mL of cerebrolysin diluted in normal saline daily for 10 days (n=23) or normal saline alone (n=23) adjunct to 100 mg of aspirin daily. All patients were examined using the National Institutes of Health Stroke Scale and transcranial Doppler to measure the mean flow velocity and pulsatility index (PI) of their cerebral arteries at baseline as well as on days 30, 60, and 90. RESULTS: The patients' mean age was 60+/-9.7 years, and 51.2% of patients were male. The National Institutes of Health Stroke Scale was significantly lower in the cerebrolysin group compared with the placebo group on day 60 (median 10, interquartile range 9-11, P=0.008) and day 90 (median 11, interquartile range 10 13.5, P=0.001). The median of PI in the right middle cerebral artery was significantly lower in the cerebrolysin group compared with the placebo group on days 30, 60, and 90 (P<0.05). One patient in the cerebrolysin group and two patients in the placebo group died before day 30 (4.3% versus 8.7%). CONCLUSION: Cerebrolysin can be useful to improve the neurological outcomes and the PI of middle cerebral artery in patients with acute focal ischemic stroke. PMID- 25516710 TI - Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer. AB - The K-ras mutation in pancreatic cancer can inhibit drug delivery and increase drug resistance. This is exemplified by the therapeutic effect of PH-427, a small molecule inhibitor of AKT/PDK1, which has shown a good therapeutic effect against a BxPC3 pancreatic cancer model that has K-ras, but has a poor therapeutic effect against a MiaPaCa-2 pancreatic cancer model with mutant K-ras. To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP. PH-427 showed a biphasic release from PH-427-PNP over 30 days during studies in sodium phosphate buffer, and in vitro studies revealed that the PNP was rapidly internalized into MiaPaCa 2 tumor cells, suggesting that PNP can improve PH-427 delivery into cells harboring mutant K-ras. In vivo studies of an orthotopic MiaPaCa-2 pancreatic cancer model showed reduced tumor load with PH-427-PNP as compared with treatment using PH-427 alone or with no treatment. Ex vivo studies confirmed the in vivo results, suggesting that PNP can improve drug delivery to pancreatic cancer harboring mutant K-ras. PMID- 25516712 TI - Remediation of context-processing deficits in schizophrenia: preliminary data with ambiguous sentences. AB - BACKGROUND: Processing of contextual information is essential for the establishment of good interpersonal relations and communicational interactions. Nevertheless, it is known that schizophrenic patients present impairments in the processing of contextual information. The aim of this study is to explore the influence of the remediation of context processing in schizophrenic patients. METHODS: Thirty-one schizophrenic patients and 28 matched healthy participants were included in this study. All participants were assessed on verbal knowledge (Mill-Hill test) and depression intensity (Beck Depression Scale 21 items). Schizophrenic patients were also assessed on thought, language, and communication disorders (Thought, Language and Communication scale). All participants completed a disambiguation task with two different levels of contextualization (high or low context) and a context-processing remediation task containing social scenarios that included ambiguous words and were presented with two different types of instruction: with or without context explanation. RESULTS: For the disambiguation task, results showed no effect of group, but a main effect of context, with better performances in the high-context than the low-context condition. For the context-processing remediation task, results showed a main effect of group: The performance of schizophrenic patients who had received explanations differed from that both of healthy participants and of schizophrenic patients who had not received explanations. CONCLUSION: This study revealed that for all participants, the structuring of context had a positive effect on the contextual integration of ambiguous words. Concerning the remediation task, explanations about the strategies that could be used to take context into account improved the schizophrenic patients' performances. This allows us to consider new methods of remediation that could improve social interaction in schizophrenia. PMID- 25516713 TI - Enhancing the adsorption of ionic liquids onto activated carbon by the addition of inorganic salts. AB - Most ionic liquids (ILs) are either water soluble or present a non-negligible miscibility with water that may cause some harmful effects upon their release into the environment. Among other methods, adsorption of ILs onto activated carbon (AC) has shown to be an effective technique to remove these compounds from aqueous solutions. However, this method has proved to be viable only for hydrophobic ILs rather than for the hydrophilic that, being water soluble, have a larger tendency for contamination. In this context, an alternative approach using the salting-out ability of inorganic salts is here proposed to enhance the adsorption of hydrophilic ILs onto activated carbon. The effect of the concentrations of Na2SO4 on the adsorption of five ILs onto AC was investigated. A wide range of ILs that allow the inspection of the IL cation family (imidazolium- and pyridinium-based) and the anion nature (accounting for its hydrophilicity and fluorination) through the adsorption onto AC was studied. In general, it is shown that the use of Na2SO4 enhances the adsorption of ILs onto AC. In particular, this effect is highly relevant when dealing with hydrophilic ILs that are those that are actually poorly removed by AC. In addition, the COnductor like Screening MOdel for Real Solvents (COSMO-RS) was used aiming at complementing the experimental data obtained. This work contributes with the development of novel methods to remove ILs from water streams aiming at creating "greener" processes. PMID- 25516714 TI - Flavonoids and Melanins: a common strategy across two kingdoms. AB - Ultraviolet (UV) radiations alter a number of metabolic functions in vivant. They produce damages to lipids, nucleic acids and proteins, generating reactive oxygen species such as singlet oxygen (O2), hydroxyl radical (HO) and superoxide anion (O2 (-)). Plants and animals, after their water emersion, have developed biochemical mechanisms to protect themselves from that environmental threat through a common strategy. Melanins in animals and flavonoids in plants are antioxidant pigments acting as free radical scavenging mechanisms. Both are phenol compounds constitutively synthesized and enhanced after exposure to UV rays, often conferring a red-brown-dark tissue pigmentation. Noteworthy, beside anti-oxidant scavenging activity, melanins and flavonoids have acquired secondary functions that, both in plants and animals, concern reproductions and fitness. Plants highly pigmented are more resistant to biotic and abiotic stresses. Darker wild vertebrates are generally more aggressive, sexually active and resistant to stress than lighter individuals. Flavonoids have been associated with signal attraction between flowers and insects and with plant-plant interaction. Melanin pigmentation has been proposed as trait in bird communication, acting as honest signals of quality. This review shows how the molecular mechanisms leading to tissue pigmentation have many functional analogies between plants and animals and how their origin lies in simpler organisms such as Cyanobacteria. Comparative studies between plant and animal kingdoms can reveal new insight of the antioxidant strategies in vivant. PMID- 25516715 TI - The insect ecdysone receptor is a good potential target for RNAi-based pest control. AB - RNA interference (RNAi) has great potential for use in insect pest control. However, some significant challenges must be overcome before RNAi-based pest control can become a reality. One challenge is the proper selection of a good target gene for RNAi. Here, we report that the insect ecdysone receptor (EcR) is a good potential target for RNAi-based pest control in the brown planthopper Nilaparvata lugens, a serious insect pest of rice plants. We demonstrated that the use of a 360 bp fragment (NlEcR-c) that is common between NlEcR-A and NlEcR-B for feeding RNAi experiments significantly decreased the relative mRNA expression levels of NlEcR compared with those in the dsGFP control. Feeding RNAi also resulted in a significant reduction in the number of offspring per pair of N. lugens. Consequently, a transgenic rice line expressing NlEcR dsRNA was constructed by Agrobacterium- mediated transformation. The results of qRT-PCR showed that the total copy number of the target gene in all transgenic rice lines was 2. Northern blot analysis showed that the small RNA of the hairpin dsNlEcR-c was successfully expressed in the transgenic rice lines. After newly hatched nymphs of N. lugens fed on the transgenic rice lines, effective RNAi was observed. The NlEcR expression levels in all lines examined were decreased significantly compared with the control. In all lines, the survival rate of the nymphs was nearly 90%, and the average number of offspring per pair in the treated groups was significantly less than that observed in the control, with a decrease of 44.18-66.27%. These findings support an RNAi-based pest control strategy and are also important for the management of rice insect pests. PMID- 25516716 TI - The viral oncoprotein HBx of Hepatitis B virus promotes the growth of hepatocellular carcinoma through cooperating with the cellular oncoprotein RMP. AB - The smallest gene HBx of Hepatitis B virus (HBV) is recognized as an important viral oncogene (V-oncogene) in the hepatocarcinogenesis. Our previous work demonstrated that RMP is a cellular oncogene (C-oncogene) required for the proliferation of hepatocellular carcinoma (HCC) cells. Here we presented the collaboration between V-oncogene HBx and C-oncogene RMP in the development of HCC. The coexpression of HBx and RMP resulted in the cooperative effect of antiapoptosis and proliferation of HCC cells. In vivo, overexpression of RMP accelerated the growth of HBx-induced xenograft tumors in nude mice and vice versa HBx promoted the growth of RMP-driven xenograft tumors. Although HBx didn't regulate the expression of RMP, HBx and RMP interact with each other and collocalized in the cytoplasm of HCC cells. HBx and RMP collaboratively inhibited the expression of apoptotic factors and promoted the expression of antiapoptotic factors. This finding suggests that HBV may induce, or at least partially contributes to the carcinogenesis of HCC, through its V-oncoprotein HBx interacting with the C-oncoprotein RMP. PMID- 25516717 TI - SIRT1 deacetylates TopBP1 and modulates intra-S-phase checkpoint and DNA replication origin firing. AB - SIRT1, the mammalian homolog of yeast Sir2, is a founding member of a family of 7 protein and histone deacetylases that are involved in numerous biological functions. Previous studies revealed that SIRT1 deficiency results in genome instability, which eventually leads to cancer formation, yet the underlying mechanism is unclear. To investigate this, we conducted a proteomics study and found that SIRT1 interacted with many proteins involved in replication fork protection and origin firing. We demonstrated that loss of SIRT1 resulted in increased replication origin firing, asymmetric fork progression, defective intra S-phase checkpoint, and chromosome damage. Mechanistically, SIRT1 deacetylates and affects the activity of TopBP1, which plays an essential role in DNA replication fork protection and replication origin firing. Our study demonstrated that ectopic over-expression of the deacetylated form of TopBP1 in SIRT1 mutant cells repressed replication origin firing, while the acetylated form of TopBP1 lost this function. Thus, SIRT1 acts upstream of TopBP1 and plays an essential role in maintaining genome stability by modulating DNA replication fork initiation and the intra-S-phase cell cycle checkpoint. PMID- 25516719 TI - Is there a relationship between personality and choice of nursing specialty: an integrative literature review. AB - BACKGROUND: Personality is deemed to play a part in an individual's choice of work, with individuals' preferencing a profession or field of work that will satisfy their personal needs. There is limited research exploring the personality characteristics of nurses within clearly defined nursing specialty areas. Retaining nurses within specialty areas has workforce implications when vacancies are unable to be filled by appropriately experienced staff. The aim of the review was to determine the current state of knowledge regarding the personality profiles of nurses in specialty areas of nursing practice. METHODS: An integrative literature review was undertaken. Five electronic databases were searched using personality and nursing based keywords. No date limit or research design restriction was applied. Rigorous screening and quality appraisal was undertaken considering the research design, methods and limitations of each manuscript. RESULTS: A review of the 13 included articles demonstrated some variability in the personality characteristics of the nursing specialty groups studied. A relationship was identified between personality characteristics and levels of nursing stress and burnout. CONCLUSION: There is some evidence to suggest a relationship between personality characteristics and nursing specialty choice, burnout and job satisfaction. The published literature is limited and the effect of personality on retention is not well established. PMID- 25516718 TI - Ionic liquid solutions as extractive solvents for value-added compounds from biomass. AB - In the past few years, the number of studies regarding the application of ionic liquids (ILs) as alternative solvents to extract value-added compounds from biomass has been growing. Based on an extended compilation and analysis of the data hitherto reported, the main objective of this review is to provide an overview on the use of ILs and their mixtures with molecular solvents for the extraction of value-added compounds present in natural sources. The ILs (or IL solutions) investigated as solvents for the extraction of natural compounds, such as alkaloids, flavonoids, terpenoids, lipids, among others, are outlined. The extraction techniques employed, namely solid-liquid extraction, and microwave assisted and ultrasound-assisted extractions, are emphasized and discussed in terms of extraction yields and purification factors. Furthermore, the evaluation of the IL chemical structure and the optimization of the process conditions (IL concentration, temperature, biomass-solvent ratio, etc.) are critically addressed. Major conclusions on the role of the ILs towards the extraction mechanisms and improved extraction yields are additionally provided. The isolation and recovery procedures of the value-added compounds are ascertained as well as some scattered strategies already reported for the IL solvent recovery and reusability. Finally, a critical analysis on the economic impact versus the extraction performance of IL-based methodologies was also carried out and is here presented and discussed. PMID- 25516720 TI - The role of patients in pressure injury prevention: a survey of acute care patients. AB - BACKGROUND: Pressure injury prevention (PIP) is an important area of patient safety. Encouraging patient participation in care is a growing trend in healthcare as it can increase adherence to treatment plans and improve outcomes. Patients in acute care settings may be able to take on an active role in PIP. However, there is limited information on patients' views of their perceived role in PIP. The aims of our study were to survey hospitalised patients' views on a) their perceived roles in PIP and, b) factors that enable or inhibit patient participation in PIP strategies. METHODS: Eligible participants were 18 years of age or older, from a neurology or orthopaedic ward and had been admitted to hospital at least 24 hours prior to enrolment in the study. A questionnaire comprising of fixed and open-ended responses was administered by researchers to participants. Numerical data was analysed descriptively and free-text comments were content-analysed and grouped into themes. RESULTS: The mean age of participants (n = 51) was 65 years (sd = 16.6); over half were female and three quarters were orthopaedic surgical patients. Eighty-six per cent of participants understood the concept of pressure injury and 80% agreed that patients have a role in PIP. Participants nominated the following PIP strategies that could be undertaken by patients: Keep skin healthy; Listen to your body and Looking after the inside. Strategies required for patient participation in PIP were represented by three themes: Manage pain and discomfort; Work together; Ongoing PI education. CONCLUSION: To ensure successful participation in PIP, patients require education throughout admission, management of pain and discomfort and a supportive and collaborative relationship with health care staff. Health professionals should identify patient ability and motivation to prevent pressure injury (PI), work in partnership with patients to adhere to PIP, and ensure that PIP actions are facilitated with appropriate pain relief. PMID- 25516721 TI - Australian graduating nurses' knowledge, intentions and beliefs on infection prevention and control: a cross-sectional study. AB - BACKGROUND: In recent year, national bodies have been actively addressing the increasing concern on the spread of healthcare-associated infections (HAIs). The current study measures the knowledge, intentions and beliefs of third-year Australian nursing students on key infection prevention and control (IPC) concepts. METHODS: A cross-sectional study of final-year undergraduate nursing students from Schools of Nursing at six Australian universities was undertaken. Students were asked to participate in an anonymous survey. The survey explored knowledge of standard precautions and transmission based precautions. In addition intentions and beliefs towards IPC were explored. RESULTS: 349 students from six universities completed the study. 59.8% (95% CI 58.8-60.8%) of questions were answered correctly. Significantly more standard precaution questions were correctly answered than transmission-based precaution questions (p < 0.001). No association was found between self-reported compliance with IPC activities and gender or age. Certain infection control issues were correlated with the percentage of correctly answered transmission-based precaution questions. The participants were most likely to seek infection control information from an infection control professional. CONCLUSION: Knowledge on transmission-based precautions was substandard. As transmission-based precautions are the foundation of IPC for serious organisms and infections, education institutions should reflect on the content and style of educational delivery on this topic. PMID- 25516722 TI - miR-22 is down-regulated in esophageal squamous cell carcinoma and inhibits cell migration and invasion. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly forms of cancer. Despite advances in the diagnosis and treatment of this cancer, the survival rate at five years is poor. Lately, miR-22 is identified as a tumor-suppressing microRNA in many human cancers. However, the specific function of miR-22 in ESCC is unclear at this point. METHODS: We first measured miR-22 expression level in 30 paired of ESCC and matched normal tissues, ESCC cell lines by real-time quantitative RT-PCR. Invasion assay, MTT proliferation assay and wound-healing assay were performed to test the invasion and proliferation of ESCC cell after overexpression of miR-22. RESULTS: We found that the expression of miR-22 in ESCC tissues and cell lines were much lower than that in normal control, respectively. The expression of miR-22 was inversely correlated with ESCC metastatic ability. Furthermore, transfection of miR-22 expression plasmid could significantly inhibit the cell proliferation, migration and invasion in Eca109 and Kyse410 ESCC cell lines. CONCLUSIONS: Our findings suggest that miR-22 act as tumor suppressor and inhibiting ESCC cell migration and invasion. The findings of this study contribute to the current understanding of the functions of miR-22 in ESCC. PMID- 25516723 TI - Severe hyperhomocysteinemia due to cystathionine beta-synthase deficiency, and Factor V Leiden mutation in a patient with recurrent venous thrombosis. AB - Homocysteine is an amino acid that is toxic to vascular endothelial cells, and plasma elevations have been associated with venous thromboembolism. Severe hyperhomocysteinemia (>100 MUmol/L) may result from mutations in the genes coding for enzymes in the trans-sulfuration or the folate/vitamin B12-dependent re methylation pathways. Here, we report the case of a young woman with severe, recurrent thrombo-embolic events associated with severe hyperhomocysteinemia (111 MUmol/L). We identified a homozygous mutation in the cystathionine beta -synthase gene (p.I278T) and the presence of the Factor V Leiden mutation. Family study shows segregation of elevated homocysteine in heterozygous relatives for the mutation in the cystathionine beta -synthase gene. Management consisted of anticoagulation with warfarin and supplementation with folate, vitamin B6 (pyridoxine) and vitamin B12. After twelve years of follow-up, plasma homocysteine levels remain in the moderate range (~20 MUmol/L, reference range 8 12 MUmol/L) and no further thromboembolic events were identified. PMID- 25516724 TI - The presence of high mobility group box-1 and soluble receptor for advanced glycation end-products in juvenile idiopathic arthritis and juvenile systemic lupus erythematosus. AB - BACKGROUND: The involvement of high mobility group box-1 (HMGB1) in various inflammatory and autoimmune diseases has been documented but clinical trials on the contribution of this pro-inflammatory alarmin in children with juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) are basically absent. To address the presence of HMGB1 and a soluble receptor for advanced glycation end products (sRAGE) in different subtypes of JIA and additionally in children with SLE, we enrolled a consecutive sample of children harvested peripheral blood as well as synovial fluids (SF) at diagnosis and correlated it with ordinary acute-phase reactants and clinical markers. METHODS: Serum and synovial fluids levels of HMGB1 and sRAGE in total of 144 children (97 with JIA, 19 with SLE and 27 healthy controls) were determined by ELISA. RESULTS: The children with JIA and those with SLE were characterised by significantly higher serum levels of HMGB1 and significantly lower sRAGE levels compared to the healthy controls. A positive correlation between serum HMGB1 and ESR, CRP, alpha2 globulin was found while serum sRAGE levels were inversely correlated with the same inflammatory markers in children with JIA. Additionally, high level of serum HMGB1 was related to hepatosplenomegaly or serositis in systemic onset JIA. CONCLUSION: The inverse relationship of the HMGB1 and its soluble receptor RAGE in the blood and SF indicates that inflammation triggered by alarmins may play a role in pathogenesis of JIA as well as SLE. HMGB1 may serve as an inflammatory marker and a potential target of biological therapy in these patients. Further studies need to show whether the determination of HMGB1 levels in patients with JIA can be a useful guideline for detecting disease activity. PMID- 25516725 TI - Automatic Selection of Order Parameters in the Analysis of Large Scale Molecular Dynamics Simulations. AB - Given the large number of crystal structures and NMR ensembles that have been solved to date, classical molecular dynamics (MD) simulations have become powerful tools in the atomistic study of the kinetics and thermodynamics of biomolecular systems on ever increasing time scales. By virtue of the high dimensional conformational state space that is explored, the interpretation of large-scale simulations faces difficulties not unlike those in the big data community. We address this challenge by introducing a method called clustering based feature selection (CB-FS) that employs a posterior analysis approach. It combines supervised machine learning (SML) and feature selection with Markov state models to automatically identify the relevant degrees of freedom that separate conformational states. We highlight the utility of the method in the evaluation of large-scale simulations and show that it can be used for the rapid and automated identification of relevant order parameters involved in the functional transitions of two exemplary cell-signaling proteins central to human disease states. PMID- 25516726 TI - Finding Chemical Reaction Paths with a Multilevel Preconditioning Protocol. AB - Finding transition paths for chemical reactions can be computationally costly owing to the level of quantum-chemical theory needed for accuracy. Here, we show that a multilevel preconditioning scheme that was recently introduced (Tempkin et al. J. Chem. Phys.2014, 140, 184114) can be used to accelerate quantum-chemical string calculations. We demonstrate the method by finding minimum-energy paths for two well-characterized reactions: tautomerization of malonaldehyde and Claissen rearrangement of chorismate to prephanate. For these reactions, we show that preconditioning density functional theory (DFT) with a semiempirical method reduces the computational cost for reaching a converged path that is an optimum under DFT by several fold. The approach also shows promise for free energy calculations when thermal noise can be controlled. PMID- 25516727 TI - Role of Desolvation in Thermodynamics and Kinetics of Ligand Binding to a Kinase. AB - Computer simulations are used to determine the free energy landscape for the binding of the anticancer drug Dasatinib to its src kinase receptor and show that before settling into a free energy basin the ligand must surmount a free energy barrier. An analysis based on using both the ligand-pocket separation and the pocket-water occupancy as reaction coordinates shows that the free energy barrier is a result of the free energy cost for almost complete desolvation of the binding pocket. The simulations further show that the barrier is not a result of the reorganization free energy of the binding pocket. Although a continuum solvent model gives the location of free energy minima, it is not able to reproduce the intermediate free energy barrier. Finally, it is shown that a kinetic model for the on rate constant in which the ligand diffuses up to a doorway state and then surmounts the desolvation free energy barrier is consistent with published microsecond time-scale simulations of the ligand binding kinetics for this system [Shaw, D. E. et al. J. Am. Chem. Soc.2011, 133, 9181-9183]. PMID- 25516728 TI - A retrospective study of the clinical benefit from acetylsalicylic acid desensitization in patients with nasal polyposis and asthma. AB - BACKGROUND: Aspirin-exacerbated respiratory disease (AERD), also known as Samter's triad, is a clinical syndrome which consists of aspirin (ASA) intolerance, chronic rhinosinusitis with nasal polyposis, and intrinsic bronchial asthma (Press Med 119:48-51, 1922). ASA challenge is the gold standard for diagnosing AERD (Curr Allergy Asthma 9:155-163, 2009). The practice of ASA challenge and desensitization in Canada is infrequently utilized, which may explain its omission as a viable therapeutic option in the latest Canadian clinical practice guidelines for acute and chronic rhinosinusitis (AACI 7:1-38, 2011). METHODS: This retrospective study assessed 111 patients who underwent ASA desensitization in the Allergy and Immunology clinic at St. Joseph's Healthcare (SJHC) in London, Ontario. The mean age was 50.7 years, and 52.5% (n = 58) were male. Sixty-one percent (n = 68) claimed prior, significant reactions to ASA, and all patients had features of AERD. RESULTS: Seventy-three percent (n = 81) claimed symptom improvement after achieving maintenance dosing on the desensitization protocol. Of this population, 21.6% (n = 24) improved in all 3 areas of interest (sense of taste or smell, upper respiratory symptoms and lower respiratory symptoms). Twenty-six percent (n = 29) had adverse effects, mostly in the way of gastrointestinal upset, but no severe adverse events were seen. CONCLUSIONS: ASA desensitization helps improve symptoms in patients with AERD. Further, it allows patients to tolerate additional ASA and other non-steroidal anti-inflammatories (NSAIDs) when needed for supplemental analgesia or for cardio protection. This is of particular benefit in those who require these medications for improved quality of life, and for reduced morbidity and mortality, such as those with cardiovascular disease or chronic pain. There should be further studies conducted in Canada as well as consideration for ASA desensitization to be included in the next clinical practice guidelines. PMID- 25516729 TI - Myocardial Dysfunction: A Primary Cause of Death Due To Severe Malaria in A Plasmodium falciparum-Infected Humanized Mouse Model. AB - BACKGROUND: Our study aimed at substantiating the recent claim of myocardial complications in severe malaria by experimentally inducing severe Plasmodium falciparum infection in a humanized mouse model employed as human surrogate. METHODS: Twenty five humanized mice were inoculated with standard in vitro cultured P. falciparum and blood extracts collected from the inner cardiac muscles of infected mice that died were examined for the presence of the infectious cause of death. The therapeutic effect of quinine on 7 mice severely infected with P. falciparum was also evaluated. RESULTS: All the 25 humanized mice inoculated with the in vitro cultured P. falciparum revealed peripheral parasitemia with a total of 10 deaths recorded. Postmortem examination of the inner cardiac muscles of the dead mice also revealed massive sequestration of mature P. falciparum as well as significant infiltration of inflammatory cells such as lymphocytes and monocytes. Postmortem evaluation of the inner cardiac muscles of the P. falciparum-infected mice after quinine therapy showed significant decline in parasite density with no death of mice recorded. CONCLUSIONS: Data obtained from our study significantly corroborated the findings of myocardial dysfunction as the primary cause of death in recent case reports of humans infected with P. falciparum. PMID- 25516730 TI - Differential genomics output and susceptibility of Iranian patients with unilocular hydatidose. AB - BACKGROUND: The objective of this study was to investigate HLA-DRB1*and DQB1* allelic polymorphisms in Iranian patients with hydatidose. This is the first survey dealing with the correlation between HLA-DRB1* and DQB1* alleles and cystic echinococcosis in Iranian patients. METHODS: The study was carried out on 56 patients with confirmed cystic echinococcosis and 30 apparently healthy individuals living in Arak- Markazi Province by HLA-DRB1 and DQB1 typing through PCR-SSP method. The first step was to identify the patients and blood sampling. DNA was prepared from whole blood and PCR-SSP with 31 primer mixes for per sample was used. PCR reaction mixtures were loaded in agarose gels and bands were observed under UV illumination and gel document after electrophoresis. Analysis of results was carried out with specific softwares and frequency and interpretation tables for calculation of P-value in chi(2) test were provided via Fisher's exact test. Significant samples were analyzed by logistic regression and odds-ratios were calculated. RESULTS: A statistically significant positive association was found between HLA-DQB1*03 and the resistance to cystic echinococcosis (P < 0.02) (odds-ratio = 2.87). CONCLUSION: Immunogenetic susceptibility to unilocular hydatidose varies according to the HLA antigens in Arak, Markazi Province, and DQB1*03 molecules are associated with the level of immune response to parasite antigens. PMID- 25516731 TI - Seroprevalence of human fascioliasis in meshkin-shahr district, ardabil province, northwestern iran in 2012. AB - BACKGROUND: The aim of this study was to conduct a seroprevalence survey in Meshkin-Shahr, Ardabil Province, north western Iran to detect the rate of human fascioliasis in the city and nearby villages. Literature shows that no such study has been conducted so far. METHODS: Overall, 458 serum samples were collected by randomized cluster sampling method from 153 males and 305 females referred to different health centers of the region after recalling by staff in those centers in 2012. All cases filled out a questionnaire and an informed consent. Sera were analyzed using indirect-ELISA test. Ten MUg /ml antigens (Liver Fluke Homogenate), serum dilutions of 1:500 and conjugate anti-human coombs with 1:10000 dilutions were utilized to perform the test. Data analysis was conducted using SPSS software ver. 18. RESULTS: Nine cases (1.96%) were positive for fascioliasis by ELISA test. The seroprevalence of fascioliasis among females was 1.63% and 2.6% in males. There was no significant difference as regards age groups, sex, job, residency, literacy and consuming row vegetable. According to job, unemployment subjects had the highest rate of infection as 5.9%. The seroprevalence of infection was 1.52% in illiterate people. As for residency, urban life showed no significant difference with rural life (2.4% vs 1.42). Age group of 40-49 yr old, with 3.3% seropositivity had the highest rate. CONCLUSION: Obtained seroprevalence of fascioliasis shows immediate attention of health authorities to the diseases in the area. The adjacent of Ardabil Province to endemic areas of fasciolosis accentuates this attention. PMID- 25516732 TI - Sequence Diversity of pfmdr1 and Sequence Conserve of pldh in Plasmodium falciparum from Indonesia: Its implications on Designing a Novel Antimalarial Drug with Less Prone to Resistance. AB - BACKGROUND: pfmdr1 and its variants are molecular marker which are responsible for antibiotics resistance in Plasmodium falciparum, a parasitic carrier for malaria disease. A novel strategy to treat malaria disease is by disrupting parasite lactate dehydrogenase (pLDH), a crucial enzyme for Plasmodium survival during their erythrocytic stages. This research was aimed to investigate and characterize the pfmdr1 and pldh genes of P. falciparum isolated from Nusa Tenggara Indonesia. METHODS: Genomic DNA of P.falciparum was isolated from malaria patients in Nusa Tenggara Indonesia. pfmdr1 was amplified using nested PCR and genotyped using Restriction Fragment Length Polymorphism (RFLP). pldh was amplified, sequenced, and analyzed using NCBI public domain databases and alignment using Clustal W ver. 1.83. RESULTS: Genotyping of the pfmdr1 revealed that sequence diversity was extremely high among isolates. However, a sequence analysis of pldh indicated that open reading frame of 316 amino acids of the gene showing 100% homology to the P. falciparum 3D7 reference pldh (GeneBank: XM_001349953.1). CONCLUSION: This is the first report which confirms the heterologous of pfmdr1 and the homologous sequences of P.falciparum pldh isolated from Nusa Tenggara Islands of Indonesia, indicating that the chloroquine could not be used effectively as antimalarial target in the region and the pLDH targeted antimalarial compound would have higher chance to be successful than using chloroquine for curbing malaria worldwide. PMID- 25516733 TI - Pathogenic assays of acanthamoeba belonging to the t4 genotype. AB - BACKGROUND: Acanthamoeba genus is introduced as opportunistic and cosmopolitan parasite. Monkey and wistar rat are appropriate models for experimental study on Acanthamoeba infection. In this study Acanthamoeba spp. were isolated from hot spring (HS), windows dust (WD) and a corneal sample of keratitis patient (KP) and their pathogenicity surveyed by in vitro and in vivo tests. METHODS: Isolates of Acanthamoeba were cultivated axenically for 12 months in PYG medium. Overall, 30 wistar rats, in 6 equal groups were used for developing experimental Acanthamoeba keratitis (AK) and Granulomatous Amoebic Encephalitis (GAE). The Keratitis and Granulomatous Encephalitis experiments were performed by intrastromal and intranasal inoculation of Acanthamoeba cysts, respectively. Pathogenicity of the three isolates was also evaluated by in vitro test using osmotolerance and temperature tolerance assays. Identification of genotypes were performed by PCR technique and sequencing. RESULT: None of the isolates could perform AK and GAE in wistar rats, although all isolates were described as T4 genotype. Isolates obtained from KP and WD could grow only in 30 degrees C, but not in 37 degrees C and 40 degrees C. On the other hand, HS isolate grew in 30 degrees C and 37 degrees C but not in 40 degrees C. Moreover, all of isolate grew in 0.5 M mannitol but not in 1 M and 1.5 M. CONCLUSION: T4 isolates with a long-term axenic culture and different factors related to host and parasite may play role in pathogenicity of these free-living amoebae. PMID- 25516734 TI - Genetic Variation and Selection of Domain I of the Plasmodium vivax Apical Membrane Antigen-1(AMA-1) Gene in Clinical Isolates from Iran. AB - BACKGROUND: Apical Membrane antigen 1 (AMA-1) is positioned on the surface of merozoite and it may play a role in attack to red blood cells. The main aim of present study was to determine the genetic variation, as well as, to detect of selection at domain I of AMA-1 gene Plasmodium vivax isolates in Iran. METHODS: Blood samples were collected from 58 patients positive for P. vivax, mono infection and the domain I of AMA-1 gene was amplified by nested PCR and then sequenced. RESULTS: A total 33 different haplotypes were identified among 58 Iranian sequences. The 23 new haplotypes were determined in this study that was not reported previously in other regions of the world. There were totally observed 36 point mutations at the nucleotide level in the analyzed sequences. Sequences analyses indicated 25 amino acid changes at 20 positions in which 5 sites demonstrated thrimorphic polymorphism and the others were dimorphic in the domain I of the Iranian PvAMA-1 isolates. CONCLUSION: Our findings indicated relatively high level of allelic diversity at the domain I of PvAMA-1 among P.vivax isolates of Iran. Since, PvAMA-1 is considering as vaccine candidate antigen, these data provide valuable information for the development of a PvAMA-1 based malaria vaccine. PMID- 25516735 TI - Genetic Variability of Antigen B2 of Human, Sheep, Goats, Camel and Cattle Isolates of Echinococcus granulosus in Iran. AB - BACKGROUND: Antigen B (AgB) is frequently used for immuno-diagnosis of human cystic echinococcosis (CE). Echinococcus granulosus AgBs show a high degree of genetic variability in different hosts or in different CE endemic areas. The present study aimed to evaluate the genetic polymorphisms of encoding antigen B2 gene (AgB2) among different Iranian isolates of E. granulosus. METHODS: A total of 50 CE isolates were collected from human, sheep, cattle, goat and camels, 10 isolates from each intermediate host of E. granulosus. Total genomic DNA from either protoscolices or germinal layer was extracted from each cyst and PCR-RFLP followed by DNA sequencing was used to evaluate sequence variation and polymorphism of AgB2 in the isolates. RESULTS: After the PCR amplification, using AgB2 primers, an almost 400 bp band was amplified in all of the isolates. The PCR products were digested with Alu1 restriction endonuclease. After restriction enzyme digestion with Alu1' sheep and human isolates gave a similar pattern of RFLP with the gene size of approximately 140 and 240bp and camel and goat isolates gave a similar pattern, but different from sheep and human, with the gene size of approximately 150 and 250bp. Sequence analysis showed the most genetic similarity of AgB2 between human and sheep isolates. CONCLUSION: Findings of this study revealed the differences in the sequences of AgB2 within and between the Iranian isolates of E. granulosus. These differences may affect the performance of any diagnostic test which uses AgB. PMID- 25516736 TI - Bioaccumulation of Some Heavy Metals in the Liver Flukes Fasciola hepatica and F. gigantica. AB - BACKGROUND: Heavy metals tend to bioaccumulate in living organisms, and their accumulation has been a major concern. As mammals are known to excrete heavy metals via their bile, it seems to be very promising to analyse metal burdens of parasites that infect the biliary tree such as liver flukes of the genus Fasciola. The present study was carried out to evaluate F. hepatica and F. gigantica as bioaccumulators of heavy metals, and to estimate their use as sensitive markers of environmental pollution with heavy metals. METHODS: A total of 36 slaughtered buffaloes (26 infected and 10 controls) collected from the slaughter-house of Tanta City, Egypt were used. Samples of muscle and liver tissues were taken from each buffalo. A total of 44 adult Fasciola flukes were collected from the 26 infected buffaloes. Quantification of some heavy metals (Cd, Cr, Cu, Pb and Zn) in samples was carried out using electrothermal atomic absorption spectrometry. RESULTS: Results revealed different concentrations of heavy metals in different host tissues. The adult flukes were classified into F. hepatica (n = 25) and F. gigantica (n = 19). The bio-concentration factor (BCF) of Cr was significantly higher in F. hepatica (P = 0.0465) while BCF of Zn was significantly higher in F. gigantica (P = 0.0189). A comparative study between the two species as regards the BCF was never done before. CONCLUSION: The obtained results indicate the possibility of use of Fasciola flukes as markers of environmental pollution with some heavy metals. PMID- 25516737 TI - Attenuation Effect of UV on Haemonchus contortus Larvae in Experimentally Infected Goats. AB - BACKGROUND: Haemonchus contortus causes severe economic losses in small ruminants, so this study was conducted to study the UV effect on H. contortus larvae and its protective effect. METHODS: Sixteen male goats were divided into 5 groups, control infected, control uninfected and UV 30 minutes exposure; UV 60 minutes exposure and UV booster 60 minutes exposure. The UV groups were exposed to UV irradiation at wave length 254 nm for 30 and 60 minutes. The UV booster 60 min was administrated 2 doses of exposed larvae with an interval of one month. All groups except the control negative one were challenged for 42 days from the beginning. RESULTS: In UV booster 60 min had reduction in egg count per gram feces and worm burden (93% & 34 % respectively). The establishment rate and relative fertility declined in comparison with other groups. These parameters were similar in control infected, UV 30 min and UV 60 min groups. PCV value of UV booster 60 min group was similar to uninfected group. After two weeks from the booster dose of irradiated larvae, increased levels of antibody were found in goats of UV booster 60 min group. CONCLUSION: Two doses of UV 60 min exposure, with an interval of one month, gave reduction not only in egg per gram feces but in worm burden as well. PMID- 25516738 TI - Prevalence and Molecular Diagnosis of Babesia ovis and Theileria ovis in Lohi Sheep at Livestock Experiment Station (LES), Bahadurnagar, Okara, Pakistan. AB - BACKGROUND: Babesia ovis and Theileria ovis are among the important and main etiological agents causing ovine babesiosis and ovine theileriosis, causing severe economic losses among sheep and goats. The aim of the present study was to determine the prevalence and molecular diagnosis of B. ovis and T. ovis in Lohi sheep at Livestock Experiment Station Bahadurnagar, Okara, Pakistan. METHODS: The prevalence of B. ovis and T. ovis was investigated in 200 Lohi sheep of mixed age and sex by PCR during 2011. The assay was employed using primers Bbo-F & Bbo-R, specific for a 549-bp fragment in B. ovis genomic DNA and primers TSsr 170F & TSsr 670R, specific for a 520-bp fragment in T. ovis genomic DNA. The animals were also screened for both haemoparasites through stained thin blood smears. RESULTS: Thirty two (16%), 48 (24%) and 26 (13%) were the number of animals found positive for B. ovis, T. ovis and for mixed infection with both parasites, respectively, through microscopy. Sixty eight (34%), 73 (37%) and 42 (21%) were the number of animals found positive for B. ovis, T. ovis and for mixed infection with both parasites, respectively, through PCR test. CONCLUSION: The results indicate the high sensitivity of PCR for surveying babesiosis and theileriosis and there is noteworthy prevalence of these diseases in sheep at an experimental station where environmental conditions are relatively controlled as compared to field conditions. PMID- 25516739 TI - Morphometric Analysis of Larval Rostellar Hooks in Taenia multiceps of Sheep in Iran and Its Association with Mitochondrial Gene Variability. AB - BACKGROUND: The purposes of the present study were morphometric characterization of rostellar hooks of Taenia multiceps and to investigate the association of hook length variation and the variability within two mitochondrial genes of sheep isolates of the parasite. METHODS: Up to 4500 sheep brains were examined for the presence of C. cerebralis. Biometric characters based on the larval rostellar hook size were measured for each individual isolate. Representative mitochondrial CO1 and 12S rRNA gene sequences for each of the isolates were obtained from NCBI GenBank. Morphometric and genetic data were analyzed using cluster analysis, Interclass Correlation Coefficient (ICC) and random effects model. RESULTS: One hundred and fourteen sheep (2.5%) were found infected with the coenuri. The minimum and maximum number of scoleces per cyst was 40 and 550 respectively. Each scolex contained 22-27 hooks arranged in two rows of large and small hooks. The average total length of the large and small hooks was 158.9 and 112.1 MUm, respectively. Using ICC, statistically significant clusters of different hook sizes were identified within the isolates. The length of the large and small hooks was significantly associated with the variability in mitochondrial 12S rRNA gene. CONCLUSION: Taenia multiceps, is a relatively important zoonotic infection in Iranian sheep with the prevalence rate of 2.5%. Hook length analysis revealed statistically significant difference among individual isolates. Associations between the rostellar hook length and variability in the mitochondrial 12S rRNA was documented. PMID- 25516740 TI - Detection of Asymptomatic Carriers of Plasmodium vivax among Treated Patients by Nested PCR Method in Minab, Rudan and Bashagard, Iran. AB - BACKGROUND: Plasmodium vivax is the most widespread species of Plasmodium in humans and causing about 80 million clinical cases annually. This study was undertaken to detect P. vivax in asymptomatic treated vivax malaria patients to trace latent/sub-patent malaria infection. METHOD: The venous blood of all detected cases with P. vivax in Bashagard, Minab and Roodan Districts in Hormozgan Province from 2009 to 2010 was examined by microscopic and nested PCR methods for presence of the parasite. RESULTS: In microscopic examination of peripheral blood smears, all samples were negative for the presence of the parasites. But, we detected two P. vivax related bands in the electrophoresis of the nested PCR products (120 bp). CONCLUSION: Following up the malaria cases after treatment by a combination of methods, or new diagnostics such as RDTs can be included in the priorities of malaria elimination program in Iran. PMID- 25516742 TI - Prevalence and molecular identification of cryptosporidium spp. In pre-weaned dairy calves in mashhad area, khorasan razavi province, iran. AB - BACKGROUND: Cryptosporidium parvum is a zoonotic pathogen transmissible from a variety of animals to humans and is a considerable public health concern. Dairy cattle have been identified in numerous reports as a major source of environmental contamination with this pathogen. The aim of study was to detect and isolate the Cryptosporidium spp. from fecal samples of naturally infected pre wean calves in the Mashhad area. METHODS: Overall, 300 fecal specimens from 1 to 30 days pre-weaned calves were collected from 10 farms in the Mashhad area the capital center of the Khorasan Razavi Province, Iran and microscopically examined for Cryptosporidium spp. All infected samples were also analyzed using nested PCR. A polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis of the small-subunit (SSU) rRNA gene was also used to detect and identify Cryptosporidium spp. in PCR- positive samples. RESULTS: Eighty five (28.3%) of the specimens were positive for Cryptosporidium spp. The prevalence of Cryptosporidium spp. in 8-14 days old and diarrheic calves were significantly higher than other groups. Restriction digestion of the PCR products by SspI, VspI restriction enzymes and sequence analysis revealed the presence of C. parvum bovine genotype in all isolates. CONCLUSIONS: Our results suggest that pre-weaned calves are likely to be an important reservoir of zoonotic C. parvum. PMID- 25516741 TI - Toxocara nematodes in stray cats from shiraz, southern iran: intensity of infection and molecular identification of the isolates. AB - BACKGROUND: Toxocara is a common nematode of cats in different parts of Iran. Despite the close association of cats with human, no attempt has been done so far for molecular identification of this nematode in the country. Therefore, current study was performed on identification of some isolates of Toxocara from stray cats in Shiraz, Fars Province, Southern Iran, based on morphological and molecular approaches, and also determination of intensity of infection. METHODS: This cross-sectional study was carried out on 30 stray cats trapped from different geographical areas of Shiraz in 2011. Adult male and female worms were recovered from digestive tract after dissection of cats. Morphological features using existing keys and PCR-sequencing of ITS-rDNA region and pcox1 mitochondrial l gene were applied for the delineating the species of the parasites. RESULTS: Eight out of 30 cats (26.7%) were found infected with Toxocara nematodes. All the isolates were confirmed as Toxocara cati based on morphological features and the sequence of ribosomal and mitochondrial targets. Intensity of infection ranged from one to a maximum of 39 worms per cat, with a mean of 10.25+/-12.36, and higher abundance of female nematodes. CONCLUSION: The most prevalent ascaridoid nematode of stray cats in the study area was T. cati and female nematodes were more abundant than that of males. This issue has important role in spreading of eggs in the environment and impact on human toxocariasis. PMID- 25516743 TI - The necessity of confirmatory testing in serodiagnosis of toxoplasmosis in iran. AB - BACKGROUND: Toxoplasma specific IgM antibodies; the common serologic marker in diagnosis of acute toxoplasmosis has its own limitations. Confirmatory testing with other markers, introduced as a complementary tool in distinguish acute and chronic infections is unusual in Iran. In the present study, we investigated the correlation between the results of IgM ELISA, IgA ELISA, and IgG avidity tests in the diagnosis of toxoplasmosis to demonstrate the necessity of confirmatory testing in serodiagnosis of infection in the country. METHODS: A total of 107 positive Toxoplasma IgG and IgM sera were obtained from patients referred to private laboratories and stored at -20 degrees C for futures use. Serologic tests were set up in duplicate to analyze the serum levels of IgG, IgM, IgA, and IgG avidity antibodies using commercial ELISA kits. The results were presented as semi quantitative for IgG, IgM and IgA ELISA, and Relative Avidity Index in percentage for IgG avidity test. Pearson's correlation coefficient (rp) was applied to analyze the data. RESULTS: Of 107 serum samples, T. gondii specific IgM and IgA antibodies were positive in 67.3% and 53.3%, respectively. Besides, 29.9% of the sera displayed low avidity for IgG antibodies. The rp was - 0.572 (P<0.01) between the IgG avidity and IgM ELISA, - 0.364 between the IgG avidity and IgA ELISA (P<0.01), and 0.564 between the IgM and IgA ELISA (P<0.01). CONCLUSION: The study strongly highlights the necessity of confirmatory testing in differential diagnosis of acute and chronic toxoplasmosis in Iran. PMID- 25516744 TI - Effects of frequent announced parasitology quizzes on the academic achievement. AB - BACKGROUND: The effect of frequent examinations on the students' learning has had inconsistent results. This study aimed to assess the effectiveness of frequent announced quizzes on the learning of a representative sample of Iranian medical students. METHODS: This experimental study was conducted among 37 fifth semester medical students who had taken the course in Protozoology and Helminthology, in which the same basic information were provided about different types of protozoa and worms. Initially, in the teaching of helminthology, ten routine sessions were handled with lectures and interactive questions and answers. Then at the beginning of the protozoology topic in the beginning of all of the next 9 sessions, the students were informed that they will have a quiz at the end of each session. At the end of the semester, the total scores of quizzes were compared with the mean final scores of protozoology and helminthology using paired t and repeated measure tests. RESULTS: The mean final scores of the protozoology lesson were not significantly different from that of the helminthology (10.45 +/- 2.75 vs.11.25 +/- 2.56 on the scale of 20, respectively, P=0.13). There was no significant difference in the mean score of the five quizzes compared with the mean final term score of protozoology. The overall mean scores in the helminthology lesson (11.25+/-2.56), protozoology lesson (10.45+/ 2.75), and the quizzes (9.16 +/- 3.55) were significantly different (P <0.0001). CONCLUSION: Frequent announced quizzes were not effective on increasing the medical students' motivation and learning. PMID- 25516745 TI - Effects of Toxoplasma gondii Infection in Level of Serum Testosterone in Males with Chronic Toxoplasmosis. AB - BACKGROUND: Toxoplasma gondii is an intracellular protozoan parasite that infects human and animals. Toxoplasma parasites are isolated from different parts of animals even from semen but there are little information about the effect of toxoplasmosis on fertility in animals and humans. In present study, the effect of chronic toxoplasmosis on serum levels of testosterone in men was studied. METHODS: In this case-control study, 1026 men referred to Arak Post Marriage Center were selected. Three ml of blood samples were collected and sera separated by centrifugation at room temperature. These sera were analyzed for detection of anti-T. gondii IgG antibody. Next 365 positive sera were selected as cases and also the same number of negative sera (365) as controls. Finally the level of testosterone was analyzed for the cases and controls samples. RESULT: Serological tests on the sera of 1,026 men in Arak City showed that 365 of them had anti Toxoplasma antibody. Comparison of testosterone concentration in case and control groups showed that testosterone concentration in case group was less than control group and this difference was statistically significant (P<0.05). CONCLUSION: The chronic toxoplasmosis could affect reproductive parameters in men. PMID- 25516746 TI - Detection of Infection with Larval Stages of Ornithobilharzia turkestanicum using PCR in Field-Collected Snails of Lymnaea gedrosiana from Northwestern Iran. AB - BACKGROUND: Infection with Ornithobilharzia turkestanicum has been reported in a wide range of animals worldwide. This study was undertaken to assess the utility of polymerase chain reaction (PCR), for detecting the infection with O. turkestanicum larvae stages in Lymnaea gedrosiana. METHODS: A total of 6,759 Lymnaeidae snails were collected from six aquatic habitats in West Azarbaijan, northwest Iran. Of these, the snails of L. gedrosiana were identified. To detect infected L. gedrosiana with the larval stages of O. turkestanicum, they were subjected for cercarial shedding and molecular examinations. The genomic DNA was extracted and PCR was performed to specifically amplify a fragment of the nuclear 28SrRNA gene of O. turkestanicum. RESULTS: Of all collected snails, 5.4% (365/6,759) were the snails of L. gedrosiana. The cercarial shedding method revealed that 23.56% (86/365) of the snails were infected. The PCR patterns confirmed that 28.77% (105/365) snails of L. gedrosiana were infected with larval stages of O. turkestanicum. The infected snails were observed in five studied sites. The highest infection rate (66.66%, 20/30) was recorded in the snails of Ghargologh in the northern part. Only 35.24% (37/105) of the infected snails were from the plain areas, whereas the remaining existed in high altitudes. CONCLUSION: It was concluded PCR method could be an efficient and fast method for uncovering the actual rate of infection with larval stages of O. turkestanicum in the snails of L. gedrosiana. This method can be also useful for the domestic animals and public health management programs in the country. PMID- 25516747 TI - Development and Standardization of Dot - ELISA for Detection of Neospora caninum Antibodies in Cattle and Comparison with Standard Indirect ELISA and Direct Agglutination Test (DAT). AB - BACKGROUND: Neospora caninum is a protozoan parasite from phylum apicomplexa and an important agent causing abortion in cattle which produce notable economic loss all around the world. METHODS: Dot-Elisa was set up performing checker board procedure and then 178 sera of cattle examined with commercial indirect ELISA and direct agglutination test (DAT) were also evaluated by dot-ELISA afterwards. RESULTS: Kappa statistical analysis revealed that Dot-ELISA has good agreements with ELISA as well as the DAT and also, Mc Nemar's analyzing showed that this procedure has acceptable ability to discriminate positive results. Relative sensitivity and specificity of Dot-ELISA were respectively 92.63% and 89.16% and 93.4% and 90.8% in comparison with ELISA and DAT. CONCLUSION: Since the dot-ELISA is easy, inexpensive and not needed high experience to interpret the results, it is superior to ELISA and DAT when we aim to screen the cattle on the farm and slaughterhouses or when the laboratory equipment is not available. PMID- 25516748 TI - Prevalence and Rate of Parasitemia of Haemoproteus columbae in Columba Iiviadomesticain Southwest of Iran. AB - BACKGROUND: Parasites affect the health and productivity of birds. Haemoproteus columbae occurs in pigeons widely in tropical and subtropical regions. The present investigation was concentrated on the prevalence of H. columbae and rate of parasitemia in domestic pigeons in southwest of Iran. METHODS: Pigeons regimented in three groups, less than six months old, between six and twenty four months old and more than twenty four months old.Then stained blood smears were studied for presence of H. columbae and finally rate of parasitemia in every group calculated. RESULTS: Mature and immature stages of H. columbae gametocytes were found in 24% of blood smears prepared from 100 healthy domestic pigeons. Mean of parasitemia in infected pigeons was 9.58%. Mean size of macrogametocytes was 4MUm*15MUm and mean size of microgametocytes was 3MUm*12MUm. Mean of parasitemia in infected females was more than males and pipers. Mean of parasitemia in infected old pigeons (pigeons with more than twenty four months old) was more than pigeons with less than six months old and pigeons between six and twenty four months old. CONCLUSION: This study show the prevalence and rate of parasitemia in domestic pigeons in southwest of Iran. We should be care about this parasite in pigeons by knowing the prevalence and high risk groups. PMID- 25516749 TI - Helminth Parasites of Eastern European Hedgehog (Erinaceus concolor) in Northern Iran. AB - BACKGROUND: Recently there is a high tendency among exotic pet owners for keeping hedgehogs. This mammal can transfer some significant zoonotic pathogens to human. Hence, the present study was conducted for the first time to prepare a list of helminth parasites of hedgehogs (Erinaceus concolor) in North of Iran. METHODS: Ten (four males and six females) road killed hedgehogs were collected during April to January 2011 in rural areas of Babol city, Mazandaran province, Iran. All of internal organs were scrutinized for helminth burden. The extracted specimens were fixed and preserved in 70% ethanol and then cleared in Lacto phenol solution. Helminth identification was carried out according to available systematic keys. RESULTS: All the examined hedgehogs (100%) were infected with parasitic helminth as following: two hedgehogs (20%) were infected with Crenosoma striatum, four hedgehogs (40%) harbored Physaloptera clausa, one (10%) host had Hymenolepis erinacei and three (30%) of them were infected with Nephridiacanthus major. CONCLUSION: This is noteworthy that the current survey is the first report of helminth parasites fauna of Eastern European Hedgehog in Iran. Since, this is the first such investigation in our country, more researches are required to perform on unexplored areas of Iran in order to increase our knowledge regarding hedgehog parasitic diseases. PMID- 25516750 TI - An incidental diagnosis of neurocysticercosis in a dental patient. AB - Tenia solium, a parasite causes cysticercous cellulose when affecting the central nervous system, the manifestation is called neurocysticercosis. The most common symptom in neurocysticercosis is seizure. Generally, oral diagnosticians come across cases of oral cysticercosis and it is rare to find a case of neurocysticercosis in the dental office, as it goes undetected. Sometimes, when patients experience seizure in the dental office and subsequent evaluation is performed, rarity such as this can be detected. One case of neurocysticercosis in a 27 year old unmarried female patient detected due to its presentation in the dental office is being reported here. PMID- 25516751 TI - Langerin-expressing dendritic cells in human tissues are related to CD1c+ dendritic cells and distinct from Langerhans cells and CD141high XCR1+ dendritic cells. AB - Langerin is a C-type lectin expressed at high level by LCs of the epidermis. Langerin is also expressed by CD8(+)/CD103(+) XCR1(+) cross-presenting DCs of mice but is not found on the homologous human CD141(high) XCR1(+) myeloid DC. Here, we show that langerin is expressed at a low level on DCs isolated from dermis, lung, liver, and lymphoid tissue and that langerin(+) DCs are closely related to CD1c(+) myeloid DCs. They are distinguishable from LCs by the level of expression of CD1a, EpCAM, CD11b, CD11c, CD13, and CD33 and are found in tissues and tissue-draining LNs devoid of LCs. They are unrelated to CD141(high) XCR1(+) myeloid DCs, lacking the characteristic expression profile of cross-presenting DCs, conserved between mammalian species. Stem cell transplantation and DC deficiency models confirm that dermal langerin(+) DCs have an independent homeostasis to LCs. Langerin is not expressed by freshly isolated CD1c(+) blood DCs but is rapidly induced on CD1c(+) DCs by serum or TGF-beta via an ALK-3 dependent pathway. These results show that langerin is expressed outside of the LC compartment of humans and highlight a species difference: langerin is expressed by the XCR1(+) "DC1" population of mice but is restricted to the CD1c(+) "DC2" population of humans (homologous to CD11b(+) DCs in the mouse). PMID- 25516752 TI - A pathogenic role for ER stress-induced autophagy and ER chaperone GRP78/BiP in T lymphocyte systemic lupus erythematosus. AB - Abnormal regulation of ER stress and apoptosis has been implicated in autoimmune disorders. Particularly, ER stress-induced autophagy and the role of GRP78, or BiP in T lymphocyte survival and death in SLE are poorly understood. This study investigated the pathogenic roles of ER stress-induced autophagy and GRP78/BiP in apoptosis of T lymphocytes. We compared spontaneous and induced autophagy and apoptosis of T lymphocytes in healthy donors and patients with SLE. The molecular mechanism of altered autophagy and apoptosis was investigated in T lymphocytes transfected with siRNA for beclin 1 and CHOP and T lymphocytes overexpressing GRP78. Decreased autophagy and increased apoptosis in response to TG-induced ER stress were observed in lupus T lymphocytes. GRP78 and ER stress-signaling molecules, such as PERK, p-eIF2alpha, IRE1, and ATF6 decreased, whereas CHOP levels increased in lupus T cells in response to TG. The levels antiapoptotic molecules, Bcl-2 and Bcl-XL decreased, whereas the proapoptotic molecules, Bax and caspase 6, increased in lupus T cells. The TG-induced ER stress altered autophagy and apoptosis, which in turn, led to abnormal T cell homeostasis with increased apoptotic T cell death. We hypothesize that aberrant autophagy of T lymphocytes as a result of ER stress and decreased GRP78 expression is involved in the pathogenesis of SLE and might serve as important therapeutic targets. PMID- 25516753 TI - Visualization of bone marrow monocyte mobilization using Cx3cr1gfp/+Flt3L-/- reporter mouse by multiphoton intravital microscopy. AB - Monocytes are innate immune cells that play critical roles in inflammation and immune defense. A better comprehension of how monocytes are mobilized and recruited is fundamental to understand their biologic role in disease and steady state. The BM represents a major "checkpoint" for monocyte homeostasis, as it is the primary site for their production and release. Our study determined that the Cx3cr1(gfp/+) mouse strain is currently the most ideal model for the visualization of monocyte behavior in the BM by multiphoton intravital microscopy. However, we observed that DCs are also labeled with high levels of GFP and thus, interfere with the accuracy of monocyte tracking in vivo. Hence, we generated a Cx3cr1(gfp/+)Flt3L(-/-) reporter mouse and showed that whereas monocyte numbers were not affected, DC numbers were reduced significantly, as DCs but not monocytes depend on Flt3 signaling for their development. We thus verified that mobilization of monocytes from the BM in Cx3cr1(gfp/+)Flt3L(-/-) mice is intact in response to LPS. Collectively, our study demonstrates that the Cx3cr1(gfp/+)Flt3L(-/-) reporter mouse model represents a powerful tool to visualize monocyte activities in BM and illustrates the potential of a Cx3cr1(gfp/+)-based, multifunctionality fluorescence reporter approach to dissect monocyte function in vivo. PMID- 25516756 TI - Interventional Cardiology US Workforce: current challenges. PMID- 25516755 TI - At the bedside: the emergence of group 2 innate lymphoid cells in human disease. AB - ILC2s have been primarily identified at environmental-mucosal interfaces and can be activated quickly by environmental antigens and pathogens to produce large quantities of IL-5 and IL-13. As a result of the production of these cytokines, ILC2s have been implicated in the host response to allergens, viruses, and parasites. However, the exact role of ILC2s in any human disease state is presently unknown, as specifically eliminating these cells is not possible, given that potentially targetable cell-surface markers are shared with other immune cells. Likewise, selectively and completely inhibiting ILC2 activation is also not currently possible, as several activating cytokines, IL-25, IL-33, and TSLP, act in redundancy or are not specific for ILC2 stimulation. Therefore, at this point, we can only identify the relative abundance of ILC2s in organs and tissue identified as being involved in specific diseases, and the contribution of ILC2s in human disease can only be inferred from mouse studies. Given these limitations, in this article, we will review the studies that have examined the presence of ILC2s in human disease states and speculate on their possible role in disease pathogenesis. The intent of the review is to identify priority areas for basic research based on clinical research insights. PMID- 25516754 TI - Critical role for thymic CD19+CD5+CD1dhiIL-10+ regulatory B cells in immune homeostasis. AB - This study tested the hypothesis that besides the spleen, LNs, peripheral blood, and thymus contain a regulatory IL-10-producing CD19(+)CD5(+)CD1d(high) B cell subset that may play a critical role in the maintenance of immune homeostasis. Indeed, this population was identified in the murine thymus, and furthermore, when cocultured with CD4(+) T cells, this population of B cells supported the maintenance of CD4(+)Foxp3(+) Tregs in vitro, in part, via the CD5-CD72 interaction. Mice homozygous for Cd19(Cre) (CD19(-/-)) express B cells with impaired signaling and humoral responses. Strikingly, CD19(-/-) mice produce fewer CD4(+)Foxp3(+) Tregs and a greater percentage of CD4(+)CD8(-) and CD4( )CD8(+) T cells. Consistent with these results, transfer of thymic CD19(+)CD5(+)CD1d(hi) B cells into CD19(-/-) mice resulted in significantly up regulated numbers of CD4(+)Foxp3(+) Tregs with a concomitant reduction in CD4(+)CD8(-) and CD4(-)CD8(+) T cell populations in the thymus, spleen, and LNs but not in the BM of recipient mice. In addition, thymic CD19(+)CD5(+)CD1d(hi) B cells significantly suppressed autoimmune responses in lupus-like mice via up regulation of CD4(+)Foxp3(+) Tregs and IL-10-producing Bregs. This study suggests that thymic CD19(+)CD5(+)CD1d(hi)IL-10(+) Bregs play a critical role in the maintenance of immune homeostasis. PMID- 25516757 TI - Do you see what I see? Time for a standardized approach to angiography-based decision making. PMID- 25516758 TI - Distance, delay, and discontent. PMID- 25516759 TI - Transcatheter aortic valve replacement: does it work and can we afford it? PMID- 25516760 TI - Cardiac paraganglioma. PMID- 25516761 TI - Histological changes of pulmonary arteries treated by balloon pulmonary angioplasty in a patient with chronic thromboembolic pulmonary hypertension. PMID- 25516762 TI - First-in-man MitraClip implantation to treat late postoperative systolic anterior motion: rare cause of tardive mitral repair failure. PMID- 25516764 TI - Age-related limitations of interleukin-6 in predicting early mortality in acute ST-elevation myocardial infarction. AB - Interleukin-6 (IL-6) is an inflammatory cytokine whose levels increase significantly during myocardial infarction (MI). It has been hypothesised that the concentrations of IL-6 at admission may be useful in prognosticating long term outcomes. It is unclear, however, whether IL-6 could improve the prognosis of early mortality in MI. We have compared serum IL-6 levels and analysed the disease course in 158 patients with ST-elevation MI (STEMI) who either survived (n = 148) or died (n = 10) within 30 days following the admission. Patients were treated in a single university centre with primary percutaneous coronary intervention (PCI). The non-survivors (6.3%) displayed most of typical risk factors for poor outcome. In addition they had significantly higher concentrations of IL-6 at hospital admission (median values 8.5 vs. 2.0 pg/ml; p = 0.038). However, they were also significantly older than the survivors (median values 72 vs. 57 years; p = 0.0001). IL-6 levels are known to increase with age and we could confirm a significant correlation between patients' calendar age and circulating IL-6 (p = 0.009). Regression analysis revealed that IL-6 concentrations were significantly affected by patients' age but they did not independently relate to patients' outcome. Such results indicate that circulating IL-6 at admission may be of limited value in predicting early mortality in STEMI. It is important to recognize that, because of the small group of patients who died (N = 10), the results must be interpreted with caution. Therefore, we stress that these results should be viewed as preliminary and further validated in a larger set of patients. PMID- 25516763 TI - The 21st century epidemic: infections as inductors of neuro-degeneration associated with Alzheimer's Disease. AB - Alzheimer's disease (AD) is a complex disease resulting in neurodegeneration and cognitive impairment. Investigations on environmental factors implicated in AD are scarce and the etiology of the disease remains up to now obscure. The disease's pathogenesis may be multi-factorial and different etiological factors may converge during aging and induce an activation of brain microglia and macrophages. This microglia priming will result in chronic neuro-inflammation under chronic antigen activation. Infective agents may prime and drive iper activation of microglia and be partially responsible of the induction of brain inflammation and decline of cognitive performances. Age-associated immune dis functions induced by chronic sub-clinical infections appear to substantially contribute to the appearance of neuro-inflammation in the elderly. Individual predisposition to less efficient immune responses is another relevant factor contributing to impaired regulation of inflammatory responses and accelerated cognitive decline. Life-long virus infection may play a pivotal role in activating peripheral and central inflammatory responses and in turn contributing to increased cognitive impairment in preclinical and clinical AD. PMID- 25516765 TI - Predictive values and other quality criteria of the German version of the Nurse Work Instability Scale (Nurse-WIS) - follow-up survey findings of a prospective study of a cohort of geriatric care workers. AB - BACKGROUND: Until now there has been a lack of effective screening instruments for health care workers at risk. To counteract the forecast shortage for health care workers, the offer of early interventions to maintain their work ability will become a central concern. The Nurse-Work Instability Scale (Nurse-WIS) seems to be suitable as a screening instrument and therefore a prospective study of a cohort of nursing staff from nursing homes was undertaken to validate the Nurse Work Instability Scale (Nurse-WIS). METHODS: The follow-up data was used to test the sensitivity, specificity and the predictive values of the Nurse-WIS. The participants answered a questionnaire in the baseline investigation (T1) and in a follow-up 12 month after baseline. The hypothesis was that geriatric care workers with an increased risk according to the Nurse-WIS in T1 would be more likely to have taken long-term sick leave or drawn a pension for reduced work capacity in T2. RESULTS: 396 persons took part in T1 (21.3% response), 225 in T2 (42.3% loss to-follow-up). In T1, 28.4% indicated an increased risk according to the Nurse WIS. In T2, 10.2% had taken long-term sick leave or had drawn a pension for reduced work capacity. The sensitivity is 73.9% (95%-CI 55.7%-92.3%), the specificity is 76.7% (95%-CI 71.2%-82.8%). The ROC AUC indicated a moderate precision for the scale, at 0.74 (95%-CI 0.64-0.84). The PPV of the Nurse-WIS is 26.6%, and the NPV is 96.3%. For those with an increased risk according to the Nurse-WIS, the probability in T2 of long-term sick leave or a pension for reduced work capacity is around eight times higher (OR 8.3, 95%-CI 2.90-23.07). Persons who had indicated a long-term sick leave or made an application for a pension for reduced work capacity in T1 had a 17 times higher risk (OR 17.4, 95%-CI 3.34 90.55). CONCLUSION: The German version of the Nurse-WIS appears to be a valid instrument with satisfactory predictive capabilities for recording an impending long-term sick leave. Whether the Nurse-WIS can be used as a screening tool which helps to design risk adjusted prevention programs for the afflicted nurse should be studied. PMID- 25516766 TI - Emotional indicators in young patients with Idiopathic Scoliosis: a study through the drawing of Human Figure. AB - BACKGROUND: Investigating Health Related Quality of Life (HRQL) is considered determinant in patients with Adolescent Idiopathic Scoliosis (AIS) in clinical as in research field. The aim of the present study is to explore the most relevant aspects of personality of the patients with AIS and its relationship with HRQL. METHOD: 50 patients (mean age = 16 years) were given a socio-demographic data questionnaire, the Human Figure Drawing (HFD) and SRS (Scoliosis Research Society) -22. RESULTS: In Subtotal SRS-22, patients presented a mean value of 3.9. In HFD, half of these patients presented physical and/or emotional tensions with reference to the shoulders and almost all of them did not show any expression of aggressiveness. No relationship between personality and HRQL was confirmed. The older the patients were, the more body tension was discovered as well as the more concerns about their bodies they showed to have. There was also a correlation between growing old and a decreasing in Mental Health. Previous conservative treatment did not show any impact on personality or on HRQL. CONCLUSIONS: Patients with AIS suffer stress and general concern more frequently with the increase of age. We suggest an appropriate supportive treatment for this type of patients. PMID- 25516768 TI - Functional outcome and satisfaction with a "self-care" protocol for the management of mallet finger injuries: a case-series. AB - BACKGROUND: Mallet finger injuries are usually successfully treated non operatively with a splint. Most patients are reviewed at least twice in a clinic after the initial presentation in A&E. A new protocol promoting "self-care" was introduced at our institution. Patients were provided with structured verbal and written information, and given access to a telephone helpline. METHODS: A prospective electronic patient record was used to identify all patients who presented to the emergency department with a mallet finger with a minimum six month follow-up. A satisfaction and patient reported outcome measure was administered via a postal questionnaire. The response rate was 36/47 (77%). RESULTS: The median QuickDASH score was 2.3 (IQR 0 to 4.6). All patients were satisfied with the treatment plan provided. Nine used the helpline and all were satisfied with information given. Although 13 patients reported some extensor lag, or bump, they had no functional limitation. Seven patients were reviewed by the general practitioner or other clinicians during their treatment period for issues such a skin care, splint size changes or sickness certification. Five were subsequently reviewed at the end of their treatment period in a clinic at their request, or their general practitioner, but did not require further surgical intervention. CONCLUSIONS: Self-care for mallet finger injuries, with adequate patient information and telephone back-up, leads to acceptable functional results and satisfaction. LEVEL OF EVIDENCE: III. PMID- 25516767 TI - A mechanophysical phase transition provides a dramatic example of colour polymorphism: the tribochromism of a substituted tri(methylene)tetrahydrofuran-2 one. AB - BACKGROUND: Derivatives of fulgides have been shown to have interesting photochromic properties. We have synthesised a number of such derivatives and have found, in some cases, that crystals can be made to change colour on crushing, a phenomenon we have termed "tribochromism". We have studied a number of derivatives by X-ray crystallography, to see if the colour is linked to molecular structure or crystal packing, or both, and our structural results have been supported by calculation of molecular and lattice energies. RESULTS: A number of 5-dicyanomethylene-4-diphenylmethylene-3-disubstitutedmethylene tetrahydrofuran-2-one compounds have been prepared and structurally characterised. The compounds are obtained as yellow or dark red crystals, or, in one case, both. In two cases where yellow crystals were obtained, we found that crushing the crystals gave a deep red powder. Structure determinations, including those of the one compound which gave both coloured forms, depending on crystallisation conditions, showed that the yellow crystals contained molecules in which the structure comprised a folded conformation at the diphenylmethylene site, whilst the red crystals contained molecules in a twisted conformation at this site. Lattice energy and molecular conformation energies were calculated for all molecules, and showed that the conformational energy of the molecule in structure IIIa (yellow) is marginally higher, and the conformation thus less stable, than that of the molecule in structure IIIb (red). However, the van der Waals energy for crystal structure IIIa, is slightly stronger than that of structure IIIb - which may be viewed as a hint of a metastable packing preference for IIIa, overcome by the contribution of a more stabilising Coulomb energy to the overall more favourable lattice energy of structure IIIb. CONCLUSIONS: Our studies have shown that the crystal colour is correlated with one of two molecular conformations which are different in energy, but that the less stable conformation can be stabilised by its host crystal lattice. Graphical abstractGraphical representation of the structural and colour change in the tribochromic compound (III). PMID- 25516769 TI - Effects of lignin modification on wheat straw cell wall deconstruction by Phanerochaete chrysosporium. AB - BACKGROUND: A key focus in sustainable biofuel research is to develop cost effective and energy-saving approaches to increase saccharification of lignocellulosic biomass. Numerous efforts have been made to identify critical issues in cellulose hydrolysis. Aerobic fungal species are an integral part of the carbon cycle, equip the hydrolytic enzyme consortium, and provide a gateway for understanding the systematic degradation of lignin, hemicelluloses, and cellulose. This study attempts to reveal the complex biological degradation process of lignocellulosic biomass by Phanerochaete chrysosporium in order to provide new knowledge for the development of energy-efficient biorefineries. RESULTS: In this study, we evaluated the performance of a fungal biodegradation model, Phanerochaete chrysosporium, in wheat straw through comprehensive analysis. We isolated milled straw lignin and cellulase enzyme-treated lignin from fungal-spent wheat straw to determine structural integrity and cellulase absorption isotherms. The results indicated that P. chrysosporium increased the total lignin content in residual biomass and also increased the cellulase adsorption kinetics in the resulting lignin. The binding strength increased from 117.4 mL/g to 208.7 mL/g in milled wood lignin and from 65.3 mL/g to 102.4 mL/g in cellulase enzyme lignin. A detailed structural dissection showed a reduction in the syringyl lignin/guaiacyl lignin ratio and the hydroxycinnamate/lignin ratio as predominant changes in fungi-spent lignin by heteronuclear single quantum coherence spectroscopy. CONCLUSION: P. chrysosporium shows a preference for degradation of phenolic terminals without significantly destroying other lignin components to unzip carbohydrate polymers. This is an important step in fungal growth on wheat straw. The phenolics presumably locate at the terminal region of the lignin moiety and/or link with hemicellulose to form the lignin carbohydrate complex. Findings may inform the development of a biomass hydrolytic enzyme combination to enhance lignocellulosic biomass hydrolysis and modify the targets in plant cell walls. PMID- 25516770 TI - Simultaneous saccharification and fermentation of steam-exploded corn stover at high glucan loading and high temperature. AB - BACKGROUND: Simultaneous saccharification and fermentation (SSF) is a promising process for bioconversion of lignocellulosic biomass. High glucan loading for hydrolysis and fermentation is an efficient approach to reduce the capital costs for bio-based products production. The SSF of steam-exploded corn stover (SECS) for ethanol production at high glucan loading and high temperature was investigated in this study. RESULTS: Glucan conversion of corn stover biomass pretreated by steam explosion was maintained at approximately 71 to 79% at an enzyme loading of 30 filter paper units (FPU)/g glucan, and 74 to 82% at an enzyme loading of 60 FPU/g glucan, with glucan loading varying from 3 to 12%. Glucan conversion decreased obviously with glucan loading beyond 15%. The results indicated that the mixture was most efficient in enzymatic hydrolysis of SECS at 3 to 12% glucan loading. The optimal SSF conditions of SECS using a novel Saccharomyces cerevisiae were inoculation optical density (OD)600 = 4.0, initial pH 4.8, 50% nutrients added, 36 hours pre-hydrolysis time, 39 degrees C, and 12% glucan loading (20% solid loading). With the addition of 2% Tween 20, glucan conversion, ethanol yield, final ethanol concentration reached 78.6%, 77.2%, and 59.8 g/L, respectively, under the optimal conditions. The results suggested that the solid and degradation products' inhibitory effect on the hydrolysis and fermentation of SECS were also not obvious at high glucan loading. Additionally, glucan conversion and final ethanol concentration in SSF of SECS increased by 13.6% and 18.7%, respectively, compared with separate hydrolysis and fermentation (SHF). CONCLUSIONS: Our research suggested that high glucan loading (6 to 12% glucan loading) and high temperature (39 degrees C) significantly improved the SSF performance of SECS using a thermal- and ethanol-tolerant strain of S. cerevisiae due to the removal of degradation products, sugar feedback, and solid's inhibitory effects. Furthermore, the surfactant addition obviously increased ethanol yield in SSF process of SECS. PMID- 25516771 TI - 19q13.11 microdeletion concomitant with ins(2;19)(p25.3;q13.1q13.4)dn in a boy: potential role of UBA2 in the associated phenotype. AB - The 19q13.11 microdeletion syndrome (MIM613026) is a clinically recognisable condition in which a 324-kb minimal overlapping critical region has been recently described. However, genes not included within this region, such as WTIP and UBA2, have been proposed to contribute to the clinical characteristics observed in patients. Using cytogenetic techniques, single nucleotide polymorphism arrays, and the quantitative polymerase chain reaction, we identified a novel case with a 2.49-Mb deletion derived from a de novo chromosomal rearrangement. Based on a review of the literature, we support the notion that UBA2 haploinsufficiency could contribute to the phenotype of this rare genomic disorder. UBA2 belongs to a protein complex with sumoylation activity, and several transcription factors, hormone receptors, and signalling proteins related to brain and sexual development are regulated by this post-translational modification. Additional clinical reports and further research on UBA2 molecular function are warranted. PMID- 25516772 TI - Role of adiponectin and proinflammatory gene expression in adipose tissue chronic inflammation in women with metabolic syndrome. AB - BACKGROUND: The purpose of this research was to study the gene expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), nuclear factor kappa B (NF-kappaB), vascular endothelial growth factor A (VEGF-A) and adiponectin (AdipoQ) genes in the visceral (omental, mesenteric) and subcutaneous adipose tissue depots in metabolic syndrome (MS). We studied 23 women with MS, with a mean age of 50.7 +/- 4.5 years and mean body mass index (BMI) of 45.6 +/- 9.8 kg/m(2). The control group included 10 women, with a mean age of 40.6 +/- 8.7 years and normal BMI (22.3 +/- 3.7 kg/m(2)). The gene expression levels in the omental (OAT), mesenteric (MAT) and subcutaneous (SAT) adipose tissues were assessed by quantitative real-time PCR. FINDINGS: Increased gene expression levels of IL-6 and TNF-alpha were detected in MAT in patients with MS, compared with the control group (p < 0.05 and p < 0.005, respectively). Significant positive correlations were observed between IL-6 mRNA expression levels in OAT and the content of CD14 + cells in the peripheral blood (r = 0.55, p < 0.05), as well as between NF-kappaB and VEGF-A mRNA levels in OAT (r = 0.43, p < 0.05) in patients with MS. The AdipoQ gene expression levels in OAT were significantly decreased in women with MS compared with the control group (p < 0.05). In addition, there were inverse correlations between AdipoQ gene levels in MAT and serum CRP levels (r = -0.63, p < 0.05), as well as between AdipoQ gene levels in MAT and serum IL-6 levels (r = -0.46, p < 0.05). CONCLUSION: These data demonstrate that proinflammatory gene expression of MAT in women with MS was increased compared with the control group. The AdipoQ gene expression levels in OAT were significantly decreased in women with MS compared with the control group. PMID- 25516773 TI - Controlled-release oxycodone versus naproxen at home after ambulatory surgery: a randomized controlled trial. AB - BACKGROUND: Strong opioids in the home setting after ambulatory surgery have rarely been studied for fear of hazardous adverse effects such as respiratory depression. OBJECTIVES: We compared the efficacy of paracetamol/controlled release (CR) oxycodone and paracetamol/naproxen for treatment of acute postoperative pain at home after ambulatory surgery. Secondary outcomes were adverse effects of study medication, treatment satisfaction, and postoperative analgesic compliance. METHODS: Patients undergoing ambulatory knee arthroscopy or inguinal hernia repair surgery (n = 105) were randomized into 3 groups: Group1 paracetamol/naproxen (n = 35), Group 2 paracetamol/CR oxycodone for 24 hours (n = 35), and Group 3 paracetamol/CR oxycodone for 48 hours (n = 35). Pain intensity at movement and at rest using a visual analog scale as well as satisfaction with postoperative analgesia and side effects were recorded for up to 48 hours postoperatively. Compliance with study medication was also assessed. RESULTS: For pain at movement and at rest, no significant differences were found between the paracetamol/naproxen group and either the paracetamol/CR oxycodone for 24 hours group (beta = 2.6 [4.9]; P = 0.597) or the paracetamol/CR oxycodone for 48 hours (beta = -1.7 [5.1]; P = 0.736). No major adverse effects of study medication were registered and satisfaction with postoperative pain treatment was high in all groups. Compliance was comparable across the groups. Despite clear instructions, 8 patients with the lowest pain scores did not use any of the prescribed pain medication. CONCLUSIONS: Paracetamol/CR oxycodone and paracetamol/naproxen are equally effective in treatment of acute postoperative pain at home after ambulatory surgery with comparable patient satisfaction level. We suggest paracetamol/CR oxycodone to be a valuable alternative for the current paracetamol/naproxen gold standard, particularly in patients with a contraindication for nonsteroidal anti-inflammatory drugs. ClinicalTrials.gov identifier: NCT02152592. PMID- 25516774 TI - Efficacy and safety of celecoxib in chinese patients with ankylosing spondylitis: a 6-week randomized, double-blinded study with 6-week open-label extension treatment. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs are the first-line option for treating ankylosing spondylitis (AS) in China. However, no large-scale controlled trials have been conducted in this ethnic population. OBJECTIVE: To evaluate the efficacy and safety of 6 weeks' treatment with celecoxib in patients with AS in China. METHODS: This Phase 3, double-blind, parallel-group study randomized patients with AS aged >=18 to 65 years 1:1 to receive celecoxib 200 mg once daily or diclofenac sustained release 75 mg once daily. After 6 weeks, patients could use celecoxib 400 mg once daily or maintain blinded therapy. The primary efficacy end point was mean change from baseline at Week 6 for Patient's Global Assessment of Pain Intensity score (100-mm visual analog scale). Noninferiority was established if the upper bound of the CI was <10 mm. Secondary objectives included patients' and physicians' assessments of disease activity, change from baseline in C-reactive protein level, and safety. RESULTS: In the per-protocol analysis set the least squares mean change from baseline in the Patient's Global Assessment of Pain Intensity score at Week 6 was -23.8 mm and -27.1 mm in patients receiving celecoxib (n = 111) and diclofenac (n = 108), respectively. The 2-sided 95% CI for the treatment difference (celecoxib - diclofenac) was -2.2 to 8.8. Overall, 4.2% and 6.7% of patients in the celecoxib and diclofenac groups, respectively, reported treatment-related adverse events. All were mild to moderate in severity. CONCLUSIONS: Celecoxib 200 mg once daily is noninferior to diclofenac sustained release 75 mg once daily for pain treatment in Chinese patients with AS. ClinicalTrials.gov identifier: NCT00762463. PMID- 25516776 TI - Neoadjuvant chemoradiotherapy for locally advanced rectal cancer: The debate continues. AB - Rectal carcinoma represents the 30% of all colorectal cancers, with about 40000 new cases/years. In the past two decades, the management of rectal cancer has made important progress, highlighting the main role of a multimodality strategy approach, combining surgery, radiation therapy and chemotherapy. Nowadays, surgery remains the primary treatment and neo-adjuvant chemoradiotherapy, based on fluoropyrimidine (5-FU) continuous infusion, is considered the standard in locally advanced rectal carcinoma. The aim is to reduce the incidence of local recurrence and to perform a conservative surgery. To improve these purposes different drugs combination have been tested in the neo-adjuvant setting. At American Society of Clinical Oncology 2014 an important abstract was presented focusing on the role of adding oxaliplatin to concomitant treatment, in patients with locally advanced rectal carcinoma. Rodel et al reported on the CAO/ARO/AIO 04 randomized phase III trial that compared standard treatment with 5-FU and radiation therapy, to oxaliplatin plus 5-FU in association with radiation therapy. The addition of oxaliplatin to the neo-adjuvant treatment has been shown to improve disease-free survival from 71.2% to 75.9% (P = 0.03). This editorial was planned to clarify the optimal treatment in patients with locally advanced rectal cancer, considering the results from CAO/ARO/AIO-04 study. PMID- 25516775 TI - Release kinetics of inflammatory biomarkers in a clinical model of acute myocardial infarction. AB - RATIONALE: Inflammation in the setting of acute myocardial infarction (MI) has been linked to risk stratification; however, the release kinetics of inflammatory biomarkers in patients with acute MI has been difficult to establish. OBJECTIVE: The aim of this study was to determine the kinetics of changes in the levels of several biomarkers specifically linked to inflammation after transcoronary ablation of septal hypertrophy, a procedure that mimics acute MI. METHODS AND RESULTS: We analyzed release kinetics of C-reactive protein, high-sensitivity C reactive protein, interleukin-6, soluble CD40 ligand, and peripheral blood leukocyte subsets in patients (n=21) undergoing transcoronary ablation of septal hypertrophy. Blood samples were collected before transcoronary ablation of septal hypertrophy and at various times after transcoronary ablation of septal hypertrophy. Serum levels of C-reactive protein were increased at 24 hours (1.0 mg/dL [interquartile range [IQR], 0.7-1.75] versus 0.2 mg/dL [IQR, 0.1-1.05] at baseline [BL]; P<0.001), whereas high-sensitivity C-reactive protein increased as early as 8 hours (2.68 mg/L [IQR, 1.23-11.80] versus 2.17 mg/L [IQR, 1.15-5.06] at BL; P=0.002). Interleukin-6 was significantly increased at 45 minutes (2.59 pg/mL [IQR, 1.69-5.0] versus 1.5 pg/mL [IQR, 1.5-2.21] at BL; P=0.002), and soluble CD40 ligand was significantly decreased at 60 minutes (801.6 pg/mL [IQR, 675.0-1653.5] versus 1750.0 pg/mL [IQR, 1151.0-2783.0] at BL; P=0.016). Elevated counts of polymorphonuclear neutrophils were detectable at 15 minutes, with a significant increase at 2 hours (6415 cells/MUL [IQR, 5288-7827] versus 4697 cells/MUL [IQR, 2892-5620] at BL; P=0.004). Significant monocytosis was observed at 24 hours (729 cells/MUL [IQR, 584-1344] versus 523 cells/MUL [IQR, 369-701] at BL; P=0.015). CONCLUSIONS: Interleukin-6 and neutrophil granulocytes showed a continuous rise at all prespecified time points after induction of MI. Our results provide valuable additional evidence of the diagnostic value of inflammatory biomarkers in the setting of early acute MI. PMID- 25516777 TI - Incidental gall bladder cancers: Are they truly incidental? AB - AIM: To seek and analyze features suggestive of gallbladder cancer (GBC) on preoperative imaging and intraoperative findings in patients diagnosed as having incidental GBC (IGBC). METHODS: The study was conducted on 79 patients of IGBC managed in our department over a 10-year period (2003-2012). Review of preoperative imaging and operative notes was done to ascertain any suspicion of malignancy-in-retrospect. RESULTS: Of the 79 patients, Ultrasound abdomen showed diffuse thickening, not suspicious of malignancy in 5 patients, and diffuse suspicious thickening was seen in 4 patients. Focal thickening suspicious of malignancy was present in 24 patients. Preoperative computed tomography/magnetic resonance imaging was done in 9 patients for suspicion of malignancy. In 5 patients, difficult Cholecystectomy was encountered due to dense/inflammatory adhesions. Intraoperative findings showed focal thickening of the gallbladder and a gallbladder mass in 9 and 17 patients respectively. On overall analysis, 37 patients had preoperative imaging or intraoperative findings suggestive of malignancy, which was either a missed GBC or an unsuspected/unexpected GBC. In 42 (53.2%) patients, there was no evidence suggestive of malignancy and was an unanticipated diagnosis. CONCLUSION: Our study highlights a potential and not-so rare pitfall of Laparoscopic Cholecystectomy. A greater awareness of this clinical entity along with a high index of suspicion and a low threshold for conversion to open procedure, especially in endemic areas may avert avoidable patient morbidity and mortality. PMID- 25516778 TI - TT genotype of GNAS1 T393C polymorphism predicts better outcome of advanced non small cell lung cancer patients. AB - AIM: To evaluate the potential prognostic value of GNAS1 T393C polymorphism in advanced non-small cell lung cancer. METHODS: We extracted genomic DNA from the peripheral blood leucocytes of 94 patients with advanced non-small cell lung cancer. Quantitative real-time polymerase chain reaction was used to determine the allelic discrimination. The correlation between genotype and overall survival was evaluated using the multivariate analysis and Kaplan-Meier approach. RESULTS: Thirty-eight out of 94 (40%) patients displayed a TT genotype, 29 out of 94 (31%) a CT genotype and 27 out of 94 (29%) a CC genotype. The median survival of TT (25 mo) genotype carriers was longer than CT (12 mo) or CC (8 mo) genotype carriers. The favorable TT genotype predicted better overall survival (OS) (2-year OS: 48%; P =0.01) compared with CT (2-year OS: 18%) or CC (2-year OS: 15%) genotype. However, dichotomization between C-genotypes (CC + CT) and T-genotypes (TT) revealed significantly lower survival rates (2-year OS: 16%; P = 0.01) for C allele carriers. CONCLUSION: Our data provided strong evidence that the GNAS1 T393C genetic polymorphism influenced the prognosis in advanced non-small lung cancer with a worse outcome for C allele carriers. PMID- 25516779 TI - Carcinomatous meningitis due to gastric adenocarcinoma: A rare presentation of relapse. AB - While solid tumors are less commonly associated with meningeal involvement; lung, breast and melanoma are the ones most often reported. A few case reports have included gastric carcinoma but these are rare and most often associated with systemic disease at the time of diagnosis. Here we report a unique presentation of gastric carcinoma relapse with leptomeningeal carcinomatosis. An 81-year-old female was diagnosed with gastric cancer approximately one year before presentation. Following neoadjuvant chemotherapy, she had gastrectomy. Her periodic surveillance was stable. Thereafter she presented with a one week history of progressive fatigue lightheadedness, syncope. During hospitalization her mental status deteriorated. A repeat computed axial tomography scan of the head showed no changes to suggest an etiology. A lumbar puncture was performed and cerebral spinal fluid (CSF) cytopathology confirmed gastric signet cell adenocarcinoma. Encephalopathy was likely caused by increased intracranial pressure from communicating hydrocephalus. Leptomeningeal carcinomatosis is associated with short life expectancy. Therapeutic lumbar punctures and best supportive care or systemic therapy can be applied with guarded prognosis. Survival, however, may improve with cytologic negative conversion of the CSF if patient performance status allows treatment. PMID- 25516780 TI - Maturing from embryonic to adult policy on stem cell therapeutics. AB - The National Institutes of Health (NIH) closure of the agency's Center for Regenerative Medicine (CRM), which focused on therapeutic development of induced pluripotent stem cells (iPS), was caused by the lack of progress in practical development of the iPSs for use in human therapies. As the NIH evaluates priorities in future stem cell therapeutic development, adult stem cell processes in the human body need to be prioritized for a number of key reasons, including (1) adult stem cells release many types of molecules that provide much of the therapeutic benefit of stem cells and (2) adult stem cells and somatic cells exist in a state of dynamic transition between different potency levels and can be naturally driven by the microenvironment to a state of pluripotency. Thus, the study and development of adult stems for therapeutic use can include naturally induced pluripotent stem cells (NiPSs) that lack the problematic genetic and epigenetic reprogramming errors found in iPSs. PMID- 25516781 TI - Electronic notebooks in the post-america invents act world. AB - The enactment of the America Invents Acts (AIA) lit a fire under the feet of the patent community in 2013 when the United States instituted a "first-to-file" system. At first glance, many believed that these new laws greatly reduced the need to be diligent in keeping laboratory notebooks. However, it is still imperative to maintain laboratory notebooks, especially in view of some of the potential pitfalls associated with electronic notebooks and their use in a court of law in this post-AIA world. PMID- 25516782 TI - GnRH antagonists: the promise of treating sex-hormone-related diseases. PMID- 25516783 TI - Inhibition of O-GlcNAcase (OGA): A Potential Therapeutic Target to Treat Alzheimer's Disease. PMID- 25516784 TI - Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues. AB - The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide. PMID- 25516785 TI - C5-Alkyl-2-methylurea-Substituted Pyridines as a New Class of Glucokinase Activators. AB - Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model. PMID- 25516786 TI - Direct arginine modification in native peptides and application to chemical probe development. AB - An efficient method for the direct labeling of the Arg guanidinium group in native peptides is reported. This straightforward procedure allows modifying the arginine moiety in peptides with various reporter groups, such as fluorophores, biotin, etc., under mild conditions in an operationally simple procedure. The scope of this method tolerates various functionalized amino acids such as His, Ser, Trp, Tyr, Glu, etc., while the only limitations uncovered so far are restricted to cysteine and free amine residues. The utility of this late-stage diversification method was demonstrated in direct labeling of leuprolide, a clinically used drug, for distribution monitoring in Daphnia, and in labeling of microcystin, a cyanobacterial toxin. PMID- 25516787 TI - Biological and Structural Characterization of Rotamers of C-C Chemokine Receptor Type 5 (CCR5) Inhibitor GSK214096. AB - We recently reported the discovery of preclinical CCR5 inhibitor GSK214096, 1 (J. Med. Chem. 2011, 54, 756). Detailed characterization of 1 revealed that it exists as a mixture of four separable atropisomers A-D. The two slow-interconverting pairs of rotamers A + B and C + D were separated and further characterized. HIV and CCR5-mediated chemotaxis data strongly suggest that the antiviral potency of 1 is due to rotamers A + B and not C + D. Furthermore, integrated UV, vibrational circular dichroism VCD and computational approach allowed to determine the M chirality in C + D (and P chirality in A + B). These findings imply additional avenues to be pursued toward new CCR5 antagonists. PMID- 25516788 TI - beta- and gamma-Amino Acids at alpha-Helical Interfaces: Toward the Formation of Highly Stable Foldameric Coiled Coils. AB - Since peptides are vital for cellular and pathogenic processes, much effort has been put into the design of unnatural oligomers that mimic natural peptide structures, also referred to as foldamers. However, to enable the specific application of foldamers, a thorough characterization of their interaction profiles in native protein environments is required. We report here the application of phage display for the identification of suitable helical environments for a sequence comprising an alternating set of beta- and gamma amino acids. In vitro selected sequences show that an increase in the hydrophobic surface area at the helical interface as well as the incorporation of a polar H bond donor functionality can significantly improve interhelical interactions involving backbone-extended amino acids. Thus, our data provide insight into the principles of the rational design of foldameric inhibitors for protein-protein interactions. PMID- 25516789 TI - Single Diastereomer of a Macrolactam Core Binds Specifically to Myeloid Cell Leukemia 1 (MCL1). AB - A direct binding screen of 100 000 sp(3)-rich molecules identified a single diastereomer of a macrolactam core that binds specifically to myeloid cell leukemia 1 (MCL1). A comprehensive toolbox of biophysical methods was applied to validate the original hit and subsequent analogues and also established a binding mode competitive with NOXA BH3 peptide. X-ray crystallography of ligand bound to MCL1 reveals a remarkable ligand/protein shape complementarity that diverges from previously disclosed MCL1 inhibitor costructures. PMID- 25516791 TI - Optimization of drug-like properties of nonsteroidal glucocorticoid mimetics and identification of a clinical candidate. AB - A series of nonsteroidal "dissociated" glucocorticoid receptor agonists was optimized for drug-like properties such as cytochrome P450 inhibition, metabolic stability, aqueous solubility, and hERG ion channel inhibition. This effort culminated in the identification of the clinical candidate compound ( R )-39. PMID- 25516790 TI - Discovery of APD334: Design of a Clinical Stage Functional Antagonist of the Sphingosine-1-phosphate-1 Receptor. AB - APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/PD profile, producing robust lymphocyte lowering at relatively low plasma concentrations in several preclinical species. This new agent was efficacious in a mouse experimental autoimmune encephalomyelitis (EAE) model of MS and a rat collagen induced arthritis (CIA) model and was found to have appreciable central exposure. PMID- 25516792 TI - Synthesis and Characterization of a "Turn-On" photoCORM for Trackable CO Delivery to Biological Targets. AB - A designed photoactive CO releasing molecule (photoCORM), namely, fac [MnBr(CO)3(pbt)] (1, pbt = 2-(2-pyridyl)benzothiazole), promotes CO-induced death of MDA-MB-231 human breast cancer cells upon illumination with broadband visible light. The CO release from this photoCORM can be tracked by rise in fluorescence within the cellular matrix due to deligation of the pbt ligand. The results of this study suggest the potential of 1 in eradication of cancer cells through CO delivery. PMID- 25516793 TI - Crystal Structure of Sphingosine Kinase 1 with PF-543. AB - The most potent inhibitor of Sphingosine Kinase 1 (SPHK1) so far identified is PF 543. The crystal structure of SPHK1 in complex with inhibitor PF-543 to 1.8 A resolution reveals the inhibitor bound in a bent conformation analogous to that expected of a bound sphingosine substrate but with a rotated head group. The structural data presented will aid in the design of SPHK1 and SPHK2 inhibitors with improved properties. PMID- 25516794 TI - (7-Benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic Acids as S1P1 Functional Antagonists. AB - S1P1 is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acids as potent, centrally available, direct acting S1P1 functional antagonists, with favorable pharmacokinetic and safety properties. PMID- 25516795 TI - Metagenomic analyses of bacteria on human hairs: a qualitative assessment for applications in forensic science. AB - BACKGROUND: Mammalian hairs are one of the most ubiquitous types of trace evidence collected in the course of forensic investigations. However, hairs that are naturally shed or that lack roots are problematic substrates for DNA profiling; these hair types often contain insufficient nuclear DNA to yield short tandem repeat (STR) profiles. Whilst there have been a number of initial investigations evaluating the value of metagenomics analyses for forensic applications (e.g. examination of computer keyboards), there have been no metagenomic evaluations of human hairs-a substrate commonly encountered during forensic practice. This present study attempts to address this forensic capability gap, by conducting a qualitative assessment into the applicability of metagenomic analyses of human scalp and pubic hair. RESULTS: Forty-two DNA extracts obtained from human scalp and pubic hairs generated a total of 79,766 reads, yielding 39,814 reads post control and abundance filtering. The results revealed the presence of unique combinations of microbial taxa that can enable discrimination between individuals and signature taxa indigenous to female pubic hairs. Microbial data from a single co-habiting couple added an extra dimension to the study by suggesting that metagenomic analyses might be of evidentiary value in sexual assault cases when other associative evidence is not present. CONCLUSIONS: Of all the data generated in this study, the next-generation sequencing (NGS) data generated from pubic hair held the most potential for forensic applications. Metagenomic analyses of human hairs may provide independent data to augment other forensic results and possibly provide association between victims of sexual assault and offender when other associative evidence is absent. Based on results garnered in the present study, we believe that with further development, bacterial profiling of hair will become a valuable addition to the forensic toolkit. PMID- 25516797 TI - Enhancing the diagnosis and management of COPD in Primary care. PMID- 25516798 TI - Change in emotion regulation during the course of treatment predicts binge abstinence in guided self-help dialectical behavior therapy for binge eating disorder. AB - BACKGROUND: Dialectical behavior therapy (DBT), which appears to be an effective treatment for binge eating disorder (BED), focuses on teaching emotion regulation skills. However, the role of improved emotion regulation in predicting treatment outcome in BED is uncertain. METHODS: This secondary analysis explored whether change in self-reported emotion regulation (as measured by the Difficulties in Emotion Regulation Scale) during treatment was associated with abstinence from binge eating at post-treatment and 4-, 5-, and 6-month follow-up in individuals who received a guided self-help adaptation of DBT for BED. Participants were 60 community-based men and women with BED who received a self-help manual and six 20 minute support phone calls. RESULTS: Greater improvement in self-reported emotion regulation between pre- and post-treatment predicted abstinence from binge eating at post-treatment, 4-, 5-, and 6-month follow-up. However, some follow-up results were no longer significant when imputed data was excluded, suggesting that the effect of emotion regulation on binge abstinence may be strongest at 4-month follow-up but decline across a longer duration of follow-up. CONCLUSIONS: This study provides preliminary support for the theoretical role played by improved emotion regulation in achieving binge eating abstinence. If this finding is replicated with larger samples, further research should identify specific techniques to help more individuals to effectively regulate their emotions over a longer duration. PMID- 25516796 TI - A straightforward and efficient analytical pipeline for metaproteome characterization. AB - BACKGROUND: The massive characterization of host-associated and environmental microbial communities has represented a real breakthrough in the life sciences in the last years. In this context, metaproteomics specifically enables the transition from assessing the genomic potential to actually measuring the functional expression of a microbiome. However, significant research efforts are still required to develop analysis pipelines optimized for metaproteome characterization. RESULTS: This work presents an efficient analytical pipeline for shotgun metaproteomic analysis, combining bead-beating/freeze-thawing for protein extraction, filter-aided sample preparation for cleanup and digestion, and single-run liquid chromatography-tandem mass spectrometry for peptide separation and identification. The overall procedure is more time-effective and less labor-intensive when compared to state-of-the-art metaproteomic techniques. The pipeline was first evaluated using mock microbial mixtures containing different types of bacteria and yeasts, enabling the identification of up to over 15,000 non-redundant peptide sequences per run with a linear dynamic range from 10(4) to 10(8) colony-forming units. The pipeline was then applied to the mouse fecal metaproteome, leading to the overall identification of over 13,000 non redundant microbial peptides with a false discovery rate of <1%, belonging to over 600 different microbial species and 250 functionally relevant protein families. An extensive mapping of the main microbial metabolic pathways actively functioning in the gut microbiome was also achieved. CONCLUSIONS: The analytical pipeline presented here may be successfully used for the in-depth and time effective characterization of complex microbial communities, such as the gut microbiome, and represents a useful tool for the microbiome research community. PMID- 25516799 TI - The magnetic susceptibility effect of gadolinium-based contrast agents on PRFS based MR thermometry during thermal interventions. AB - BACKGROUND: Proton resonance frequency shift (PRFS) magnetic resonance (MR) thermometry exploits the local magnetic field changes induced by the temperature dependence of the electron screening constant of water protons. Any other local magnetic field changes will therefore translate into incorrect temperature readings and need to be considered accordingly. Here, we investigated the susceptibility changes induced by the inflow and presence of a paramagnetic MR contrast agent and their implications on PRFS thermometry. METHODS: Phantom measurements were performed to demonstrate the effect of sudden gadopentetate dimeglumine (Gd-DTPA) inflow on the phase shift measured using a PRFS thermometry sequence on a clinical 3 T magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) system. By proton nuclear magnetic resonance spectroscopy, the temperature dependence of the Gd-DTPA susceptibility was measured, as well as the effect of liposomal encapsulation and release on the bulk magnetic susceptibility of Gd-DTPA. In vivo studies were carried out to measure the temperature error induced in a rat hind leg muscle upon intravenous Gd-DTPA injection. RESULTS: The phantom study showed a significant phase shift inside the phantom of 0.6 +/- 0.2 radians (mean +/- standard deviation) upon Gd-DTPA injection (1.0 mM, clinically relevant amount). A Gd-DTPA-induced magnetic susceptibility shift of DeltachiGd-DTPA = 0.109 ppm/mM was measured in a cylinder parallel to the main magnetic field at 37 degrees C. The temperature dependence of the susceptibility shift showed dDeltachiGd-DTPA/dT = -0.00038 +/- 0.00008 ppm/mM/ degrees C. No additional susceptibility effect was measured upon Gd release from paramagnetic liposomes. In vivo, intravenous Gd-DTPA injection resulted in a perceived temperature change of 2.0 degrees C +/- 0.1 degrees C at the center of the hind leg muscle. CONCLUSIONS: The use of a paramagnetic MR contrast agent prior to MR-HIFU treatment may influence the accuracy of the PRFS MR thermometry. Depending on the treatment workflow, Gd-induced temperature errors ranging between -4 degrees C and +3 degrees C can be expected. Longer waiting time between contrast agent injection and treatment, as well as shortening the ablation duration by increasing the sonication power, will minimize the Gd influence. Compensation for the phase changes induced by the changing Gd presence is difficult as the magnetic field changes are arising nonlocally in the surroundings of the susceptibility change. PMID- 25516800 TI - Focused ultrasound-mediated drug delivery to pancreatic cancer in a mouse model. AB - BACKGROUND: Many aspects of the mechanisms involved in ultrasound-mediated therapy remain obscure. In particular, the relative roles of drug and ultrasound, the effect of the time of ultrasound application, and the effect of tissue heating are not yet clear. The current study was undertaken with the goal to clarify these aspects of the ultrasound-mediated drug delivery mechanism. METHODS: Focused ultrasound-mediated drug delivery was performed under magnetic resonance imaging guidance (MRgFUS) in a pancreatic ductal adenocarcinoma (PDA) model grown subcutaneously in nu/nu mice. Paclitaxel (PTX) was used as a chemotherapeutic agent because it manifests high potency in the treatment of gemcitabine-resistant PDA. Poly(ethylene oxide)-co-poly(d,l-lactide) block copolymer stabilized perfluoro-15-crown-5-ether nanoemulsions were used as drug carriers. MRgFUS was applied at sub-ablative pressure levels in both continuous wave and pulsed modes, and only a fraction of the tumor was treated. RESULTS: Positive treatment effects and even complete tumor resolution were achieved by treating the tumor with MRgFUS after injection of nanodroplet encapsulated drug. The MRgFUS treatment enhanced the action of the drug presumably through enhanced tumor perfusion and blood vessel and cell membrane permeability that increased the drug supply to tumor cells. The effect of the pulsed MRgFUS treatment with PTX-loaded nanodroplets was clearly smaller than that of continuous wave MRgFUS treatment, supposedly due to significantly lower temperature increase as measured with MR thermometry and decreased extravasation. The time of the MRgFUS application after drug injection also proved to be an important factor with the best results observed when ultrasound was applied at least 6 h after the injection of drug-loaded nanodroplets. Some collateral damage was observed with particular ultrasound protocols supposedly associated with enhanced inflammation. CONCLUSION: This presented data suggest that there exists an optimal range of ultrasound application parameters and drug injection time. Decreased tumor growth, or complete resolution, was achieved with continuous wave ultrasound pressures below or equal to 3.1 MPa and drug injection times of at least 6 h prior to treatment. Increased acoustic pressure or ultrasound application before or shortly after drug injection gave increased tumor growth when compared to other protocols. PMID- 25516801 TI - Biophysical characterization of low-frequency ultrasound interaction with dental pulp stem cells. AB - BACKGROUND: Low-intensity ultrasound is considered an effective non-invasive therapy to stimulate hard tissue repair, in particular to accelerate delayed non union bone fracture healing. More recently, ultrasound has been proposed as a therapeutic tool to repair and regenerate dental tissues. Our recent work suggested that low-frequency kilohertz-range ultrasound is able to interact with dental pulp cells which could have potential to stimulate dentine reparative processes and hence promote the viability and longevity of teeth. METHODS: In this study, the biophysical characteristics of low-frequency ultrasound transmission through teeth towards the dental pulp were explored. We conducted cell culture studies using an odontoblast-like/dental pulp cell line, MDPC-23. Half of the samples underwent ultrasound exposure while the other half underwent 'sham treatment' where the transducer was submerged into the medium but no ultrasound was generated. Ultrasound was applied directly to the cell cultures using a therapeutic ultrasound device at a frequency of 45 kHz with intensity settings of 10, 25 and 75 mW/cm(2) for 5 min. Following ultrasound treatment, the odontoblast-like cells were detached from the culture using a 0.25% Trypsin/EDTA solution, and viable cell numbers were counted. Two-dimensional tooth models based on MU-CT 2D images of the teeth were analyzed using COMSOL as the finite element analysis platform. This was used to confirm experimental results and to demonstrate the potential theory that with the correct combination of frequency and intensity, a tooth can be repaired using small doses of ultrasound. Frequencies in the 30 kHz-1 MHz range were analyzed. For each frequency, pressure/intensity plots provided information on how the intensity changes at each point throughout the propagation path. Spatial peak temporal average (SPTA) intensity was calculated and related to existing optimal spatial average temporal average (SATA) intensity deemed effective for cell proliferation during tooth repair. RESULTS: The results demonstrate that odontoblast MDPC-23 cell numbers were significantly increased following three consecutive ultrasound treatments over a 7-day culture period as compared with sham controls underscoring the anabolic effects of ultrasound on these cells. Data show a distinct increase in cell number compared to the sham data after ultrasound treatment for intensities of 10 and 25 mW/cm(2) (p < 0.05 and p < 0.01, respectively). Using finite element analysis, we demonstrated that ultrasound does indeed propagate through the mineralized layers of the teeth and into the pulp chamber where it forms a 'therapeutic' force field to interact with the living dental pulp cells. This allowed us to observe the pressure/intensity of the wave as it propagates throughout the tooth. A selection of time-dependent snapshots of the pressure/intensity reveal that the lower frequency waves propagate to the pulp and remain within the chamber for a while, which is ideal for cell excitation. Input frequencies and pressures of 30 kHz (70 Pa) and 45 kHz (31 kPa), respectively, with an average SPTA of up to 120 mW/cm(2) in the pulp seem to be optimal and agree with the SATA intensities reported experimentally. CONCLUSIONS: Our data suggest that ultrasound can be harnessed to propagate to the dental pulp region where it can interact with the living cells to promote dentine repair. Further research is required to analyze the precise physical and biological interactions of low-frequency ultrasound with the dental pulp to develop a novel non-invasive tool for dental tissue regeneration. PMID- 25516802 TI - Estimating dynamic changes of tissue attenuation coefficient during high intensity focused ultrasound treatment. AB - BACKGROUND: This study investigated the dynamic changes of tissue attenuation coefficients before, during, and after high-intensity focused ultrasound (HIFU) treatment at different total acoustic powers (TAP) in ex vivo porcine muscle tissue. It further assessed the reliability of employing changes in tissue attenuation coefficient parameters as potential indicators of tissue thermal damage. METHODS: Two-dimensional pulse-echo radio frequency (RF) data were acquired before, during, and after HIFU exposure to estimate changes in least squares attenuation coefficient slope (Deltabeta) and attenuation coefficient intercept (Deltaalpha 0). Using the acquired RF data, Deltabeta and Deltaalpha 0 images, along with conventional B-mode ultrasound images, were constructed. The dynamic changes of Deltabeta and Deltaalpha 0, averaged in the region of interest, were correlated with B-mode images obtained during the HIFU treatment process. RESULTS: At a HIFU exposure duration of 40 s and various HIFU intensities (737-1,068 W/cm(2)), Deltabeta and Deltaalpha 0 increased rapidly to values in the ranges 1.5-2.5 dB/(MHz.cm) and 4-5 dB/cm, respectively. This rapid increase was accompanied with the appearance of bubble clouds in the B-mode images. Bubble activities appeared as strong hyperechoic regions in the B-mode images and caused fluctuations in the estimated Deltabeta and Deltaalpha 0 values. After the treatment, Deltabeta and Deltaalpha 0 values gradually decreased, accompanied by fade-out of hyperechoic spots in the B-mode images. At 10 min after the treatment, they reached values in ranges 0.75-1 dB/(MHz.cm) and 1-1.5 dB/cm, respectively, and remained stable within those ranges. At a long HIFU exposure duration of around 10 min and low HIFU intensity (117 W/cm(2)), Deltabeta and Deltaalpha 0 gradually increased to values of 2.2 dB/(MHz.cm) and 2.2 dB/cm, respectively. This increase was not accompanied with the appearance of bubble clouds in the B-mode images. After HIFU treatment, Deltabeta and Deltaalpha 0 gradually decreased to values of 1.8 dB/(MHz.cm) and 1.5 dB/cm, respectively, and remained stable at those values. CONCLUSIONS: Deltabeta and Deltaalpha 0 estimations were both potentially reliable indicators of tissue thermal damage. In addition, Deltabeta and Deltaalpha 0 images both had significantly higher contrast-to-speckle ratios compared to the conventional B mode images and outperformed the B-mode images in detecting HIFU thermal lesions at all investigated TAPs and exposure durations. PMID- 25516803 TI - Ultrasound stimulation increases proliferation of MC3T3-E1 preosteoblast-like cells. AB - BACKGROUND: Mechanical stimulation of bone increases bone mass and fracture healing, at least in part, through increases in proliferation of osteoblasts and osteoprogenitor cells. Researchers have previously performed in vitro studies of ultrasound-induced osteoblast proliferation but mostly used fixed ultrasound settings and have reported widely varying and inconclusive results. Here we critically investigated the effects of the excitation parameters of low-intensity pulsed ultrasound (LIPUS) stimulation on proliferation of MC3T3-E1 preosteoblastic cells in monolayer cultures. METHODS: We used a custom-designed ultrasound exposure system to vary the key ultrasound parameters-intensity, frequency and excitation duration. MC3T3-E1 cells were seeded in 12-well cell culture plates. Unless otherwise specified, treated cells, in groups of three, were excited twice for 10 min with an interval of 24 h in between after cell seeding. Proliferation rates of these cells were determined using BrdU and MTS assays 24 h after the last LIPUS excitation. All data are presented as the mean +/- standard error. The statistical significance was determined using Student's two-sample two-tailed t tests. RESULTS: Using discrete LIPUS intensities ranging from 1 to 500 mW/cm(2) (SATA, spatial average-temporal average), we found that approximately 75 mW/cm(2) produced the greatest increase in osteoblast proliferation. Ultrasound exposures at higher intensity (approximately 465 mW/cm(2)) significantly reduced proliferation in MC3T3-E1 cells, suggesting that high-intensity pulsed ultrasound may increase apoptosis or loss of adhesion in these cells. Variation in LIPUS frequency from 0.5 MHz to 5 MHz indicated that osteoblast proliferation rate was not frequency dependent. We found no difference in the increase in proliferation rate if LIPUS was applied for 30 min/day or 10 min/day, indicating a habituation response. CONCLUSION: This study concludes that a short-term stimulation with optimum intensity can enhance proliferation of preosteoblast-like bone cells that plays an important role in bone formation and accelerated fracture healing, also suggesting a possible therapeutic treatment for reduced bone mass. PMID- 25516804 TI - Intense focused ultrasound stimulation can safely stimulate inflamed subcutaneous tissue and assess allodynia. AB - BACKGROUND: Potential peripheral sources of deep pain can require invasive evocative tests for their assessment. Here we perform research whose ultimate goal is development of a non-invasive evocative test for deep painful tissue. METHODS: We used a rat model of inflammation to show that intense focused ultrasound (iFU) differentially stimulates inflamed versus control tissue and can identify allodynia. To do so we applied iFU to inflamed and normal tissue below the skin of rats' hind paws and measured the amount of ultrasound necessary to induce paw withdrawal. RESULTS: iFU of sufficient strength (spatial and temporal average intensities ranged from 100-350 W/cm(2)) caused the rat to withdraw its inflamed paw, while the same iFU applied to the contralateral paw failed to induce withdrawal, with sensitivity and specificity generally greater than 90%. iFU stimulation of normal tissue required twice the amount of ultrasound to generate a withdrawal than did inflamed tissue, thereby assessing allodynia. Finally, we verified in a preliminary way the safety of iFU stimulation with acute histological studies coupled with mathematical simulations. CONCLUSIONS: Given that there exist systems to guide iFU deep to the skin, image-guided iFU may one day allow assessment of patient's deep, peripheral pain generators. PMID- 25516805 TI - Retinal vasculitis and ocular vitreous metastasis following complete response to PD-1 inhibition in a patient with metastatic cutaneous melanoma. AB - We report on a 36-year-old woman treated with the anti PD-1 antibody Pembrolizumab for metastatic cutaneous melanoma in the first line setting. She achieved a complete response and then relapsed with metastases to the vitreous cavity with an associated angiographically determined retinal vasculitis. Vitreous metastasis without choroidal involvement is unusual and may be due to individual cell extravasation, vitreous hemorrhage containing malignant cells, or direct spread through the optic nerve. This finding highlights the need for immune sanctuary sites to be monitored in the presence of PD-1 inhibition and we hypothesize that the use of PD-1 inhibitor potentiated the patient's angiographically determined retinal vasculitis. PMID- 25516806 TI - Circulating tumor DNA analysis as a real-time method for monitoring tumor burden in melanoma patients undergoing treatment with immune checkpoint blockade. AB - BACKGROUND: Assessment of therapeutic activity of drugs blocking immune checkpoints such as CTLA-4 and PD-1/PD-L1 can be challenging, as tumors may seem to enlarge or appear anew before regressing, due to intratumoral inflammation. We assessed whether circulating tumor DNA (ctDNA) levels could serve as an early indicator of true changes in tumor burden in patients undergoing treatment with these agents. FINDINGS: Tumors from 12 patients with metastatic melanoma undergoing treatment with checkpoint blocking drugs were analyzed for the presence of hotspot somatic mutations in BRAF, cKIT, NRAS, and TERT. Plasma was collected serially from each patient and levels of ctDNA were compared with radiologic and clinical outcomes. In 5 of 10 patients studied, mutations were detected in BRAF(1), NRAS(2), TERT(1) and ALK(1). Analysis of plasma from 4 of 5 patients identified mutations identical to those found in tumor specimens. Plasma ctDNA levels ranged from undetectable (<0.01%) to 5.5% of total circulating cell free DNA. In 3 patients, increasing ctDNA levels correlated with progressive disease assessed by radiography. In one patient, ctDNA levels increased after undergoing a needle biopsy of a tumor deposit. In another patient, ctDNA levels increased initially as lymphadenopathy progressed by examination, but then became undetectable 3 weeks prior to clinical improvement. CONCLUSIONS: Levels of ctDNA correlated with clinical and radiologic outcomes, and, in one case, preceded eventual tumor regression. Further prospective analysis is required to assess the utility of ctDNA as an early biomarker of clinical outcomes in patients receiving immune checkpoint blocking drugs. PMID- 25516807 TI - Identification of Knowledge Gaps Regarding Healthcare Workers' Exposure to Antineoplastic Drugs: Review of Literature, North America versus Europe. AB - We have been examining the issue of healthcare workers' exposure to antineoplastic drugs for nearly a decade and have observed that there appears to be more publications on the subject matter originating from Europe than from North America. The concern is that findings from Europe may not be generalizable to North America because of differences in handling practices, regulatory requirements, and training. Our objective was to perform a literature review to confirm our observation and, in turn, identify gaps in knowledge that warrants addressing in North America. Using select keywords, we searched for publications in PubMed and Web of Science. All papers were initially classified according to the originating continent and then categorized into one or more subject categories (analytical methods, biological monitoring, occupational exposure, surface contamination, and probability of risk/exposure). Our review identified 16 papers originating from North America and 55 papers from Europe with surface contamination being the subject matter most often studied overall. Based on our results, we are of the opinion that North American researchers need to further conduct dermal and/or urinary drug contamination studies as well as assess the exposure risk faced by healthcare workers who handle antineoplastic drugs. Trends in exposure levels should also be explored. PMID- 25516808 TI - Wet-work Exposure: A Main Risk Factor for Occupational Hand Dermatitis. AB - Wet-work can be defined as activities where workers have to immerse their hands in liquids for >2 hours per shift, or wear waterproof (occlusive) gloves for a corresponding amount of time, or wash their hands >20 times per shift. This review considers the recent literature on wet-work exposure, and examines wet work as a main risk factor for developing irritant contact dermatitis of the hands. The aim of this paper is to provide a detailed description of wet-work exposure among specific occupational groups who extensively deal with water and other liquids in their occupations. Furthermore, it highlights the extent and importance of the subsequent adverse health effects caused by exposure to wet work. PMID- 25516809 TI - Insights into ergonomics among dental professionals of a dental institute and private practitioners in hubli-dharwad twin cities, India. AB - BACKGROUND: To assess the knowledge, attitude, and practice of ergonomics among dental professionals of Hubli-Dharwad twin cities, India. METHODS: Investigator developed, self-administered, closed-ended questionnaire assessing knowledge, attitude, and practices regarding ergonomics during dental practice was filled in by undergraduates, house surgeons, postgraduates, and faculty members of dental institutions and private practitioners from Hubli-Dharwad twin cities. RESULTS: Data were collected from a total of 250 participants, 50 belonging to each academic group. Overall mean knowledge, attitude, and practice scores were 52%, 75%, and 55%, respectively. Significant correlation was found for age with attitude (chi(2) = 10.734, p = 0.030) and behavior (chi(2) = 12.984, p = 0.011). Marital status was significantly associated with all the three domains; knowledge (chi(2) = 29.369, p = 0.000), attitude (chi(2) = 29.023, p = 0.000), and practices (chi(2) = 13.648, p = 0.009). CONCLUSION: Participants had considerable awareness and behavior toward ergonomics in dental practice. The high attitude score indicates stronger acceptance of ergonomics principles and guidelines during routine dental procedures. The current study highlights the situation of ergonomics in dental practice in the form of knowledge, attitude, and practices. PMID- 25516810 TI - Short- and Long-term Effects of a Physical Exercise Intervention on Work Ability and Work Strain in Symptomatic Menopausal Women. AB - BACKGROUND: Physical exercise during leisure time is known to increase physical capacity; however, the long-term effects on work ability and work strain are inconclusive. The aim of this study was to investigate the effects of a 6-month physical exercise program on work ability and work strain after 6 months and 30 months, among women with menopausal symptoms at baseline. METHODS: A questionnaire including questions on work ability and work strain was mailed in the beginning, at 6 months and after 30 months after the intervention to occupationally active women participating in a randomized controlled study on physical exercise and quality of life. The intervention included aerobic exercise training 4 times per week, 50 minutes per session. Work ability was measured with the Work Ability Index (WAI) and with questions about physical and mental work strain. RESULTS: Women aged 47-62 years (N = 89) who were occupationally active at baseline were included in the analyses. The increase in WAI from baseline to the end of the exercise intervention (6 months) was statistically significantly greater among the intervention group than among the control group (regression coefficient 2.08; 95% confidence interval 0.71-3.46). The difference between the groups persisted for 30 months. No significant short- or long-term effects on physical and mental work strain were found. CONCLUSION: A 6-month physical exercise intervention among symptomatic menopausal women had positive short-term as well as long-term effects on work ability. PMID- 25516811 TI - Evaluating Interactive Fatigue Management Workshops for Occupational Health Professionals in the United Kingdom. AB - BACKGROUND: Disabling fatigue is common in the working age population. It is essential that occupational health (OH) professionals are up-to-date with the management of fatigue in order to reduce the impact of fatigue on workplace productivity. Our aim was to evaluate the impact of one-day workshops on OH professionals' knowledge of fatigue and chronic fatigue syndrome (CFS), and their confidence in diagnosing and managing these in a working population. METHODS: Five interactive problem-based workshops were held in the United Kingdom. These workshops were developed and delivered by experts in the field. Questionnaires were self-administered immediately prior to, immediately after, and 4 months following each workshop. Questionnaires included measures of satisfaction, knowledge of fatigue and CFS, and confidence in diagnosing and managing fatigue. Open-ended questions were used to elicit feedback about the workshops. RESULTS: General knowledge of fatigue increased significantly after training (with a 25% increase in the median score). Participants showed significantly higher levels of confidence in diagnosing and managing CFS (with a 62.5% increase in the median score), and high scores were maintained 4 months after the workshops. OH physicians scored higher on knowledge and confidence than nurses. Similarly, thematic analysis revealed that participants had increased knowledge and confidence after attending the workshops. CONCLUSION: Fatigue can lead to severe functional impairment with adverse workplace outcomes. One-day workshops can be effective in training OH professionals in how to diagnose and manage fatigue and CFS. Training may increase general knowledge of fatigue and confidence in fatigue management in an OH setting. PMID- 25516812 TI - The impact of robotics on employment and motivation of employees in the service sector, with special reference to health care. AB - BACKGROUND: The economy is being lifted by the new concept of robotics, but we cannot be sure of all the possible benefits. At this early stage, it therefore becomes important to find out the possible benefits/limitations associated with robotics, so that the positives can be capitalized, established, and developed further for the employment and motivation of employees in the health care sector, for overall economic development. The negatives should also be further studied and mitigated. METHODS: This study is an exploratory research, based on secondary data, such as books on topics related to robotics, websites, public websites of concerned departments for data and statistics, journals, newspapers and magazines, websites of health care providers, and different printed materials (brochures, etc). RESULTS: The impact of robotics has both positive and negative impacts on the employment and motivation of employees in the retail sector. So far, there has been no substantial research done into robotics, especially in the health care sector. CONCLUSION: Replacing employees with robots is an inevitable choice for organizations in the service sector, more so in the health care sector because of the challenging and sometimes unhealthy working environments, but, at the same time, the researchers propose that it should be done in a manner that helps in improving the employment and motivation of employees in this sector. PMID- 25516813 TI - Psychological distress and pain reporting in Australian coal miners. AB - BACKGROUND: Coal mining is of significant economic importance to the Australian economy. Despite this fact, the related workforce is subjected to a number of psychosocial risks and musculoskeletal injury, and various psychological disorders are common among this population group. Because only limited research has been conducted in this population group, we sought to examine the relationship between physical (pain) and psychological (distress) factors, as well as the effects of various demographic, lifestyle, and fatigue indicators on this relationship. METHODS: Coal miners (N = 231) participated in a survey of musculoskeletal pain and distress on-site during their work shifts. Participants also provided demographic information (job type, age, experience in the industry, and body mass index) and responded to questions about exercise and sleep quality (on- and off-shift) as well as physical and mental tiredness after work. RESULTS: A total of 177 workers (80.5%) reported experiencing pain in at least one region of their body. The majority of the sample population (61.9%) was classified as having low-level distress, 28.4% had scores indicating mild to moderate distress, and 9.6% had scores indicating high levels of distress. Both number of pain regions and job type (being an operator) significantly predicted distress. Higher distress score was also associated with greater absenteeism in workers who reported lower back pain. In addition, perceived sleep quality during work periods partially mediated the relationship between pain and distress. CONCLUSION: The study findings support the existence of widespread musculoskeletal pain among the coal-mining workforce, and this pain is associated with increased psychological distress. Operators (truck drivers) and workers reporting poor sleep quality during work periods are most likely to report increased distress, which highlights the importance of supporting the mining workforce for sustained productivity. PMID- 25516815 TI - Improving work functioning and mental health of health care employees using an e mental health approach to workers' health surveillance: pretest-posttest study. AB - BACKGROUND: Mental health complaints are quite common in health care employees and can have adverse effects on work functioning. The aim of this study was to evaluate an e-mental health (EMH) approach to workers' health surveillance (WHS) for nurses and allied health professionals. Using the waiting-list group of a previous randomized controlled trial with high dropout and low compliance to the intervention, we studied the pre- and posteffects of the EMH approach in a larger group of participants. METHODS: We applied a pretest-posttest study design. The WHS consisted of online screening on impaired work functioning and mental health followed by online automatically generated personalized feedback, online tailored advice, and access to self-help EMH interventions. The effects on work functioning, stress, and work-related fatigue after 3 months were analyzed using paired t tests and effect sizes. RESULTS: One hundred and twenty-eight nurses and allied health professionals participated at pretest as well as posttest. Significant improvements were found on work functioning (p = 0.01) and work related fatigue (p < 0.01). Work functioning had relevantly improved in 30% of participants. A small meaningful effect on stress was found (Cohen d = .23) in the participants who had logged onto an EMH intervention (20%, n = 26). CONCLUSION: The EMH approach to WHS improves the work functioning and mental health of nurses and allied health professionals. However, because we found small effects and participation in the offered EMH interventions was low, there is ample room for improvement. PMID- 25516814 TI - Exploring stress levels, job satisfaction, and quality of life in a sample of police officers in Greece. AB - BACKGROUND: The ongoing economic crisis in Greece has affected both stress and quality of life (QoL) at all socioeconomic levels, including professionals in the police force. The aim of this study was to examine perceived stress, job satisfaction, QoL, and their relationships in a sample of police officers in Greece. METHODS: A cross-sectional study was conducted during the first trimester of 2011 in 23 police stations in the greater Athens area. A total of 201 police officers agreed to participate (response rate 44.6%). The General Health Questionnaire-28 (GHQ-28) was used to assess general health, and the World Health Organization Quality of Life-BREF Questionnaire and Perceived Stress Scale-14 (PSS-14) questionnaires were used to assess QoL and perceived stress, respectively. RESULTS: The PSS and GHQ subscales and total scores exhibited strong, positive, and significant correlations coefficients (r): 0.52 for somatic disturbances, 0.56 for stress and insomnia, 0.40 for social dysfunction, and 0.37 for depression, yielding an r equal to 0.57 for the total GHQ score. A higher level of perceived stress was related to a lower likelihood of being satisfied with their job; in this regard, male participants and higher ranked officers reported lower job satisfaction. The PSS and GHQ scores were inversely, consistently, and significantly related to almost all of the QoL aspects, explaining up to 34% of their variability. Parenthood had a positive effect on QoL related to physical health, and women reported lower QoL related to psychological health. CONCLUSION: Higher levels of stress are related to an increased risk of reporting suboptimal job satisfaction and QoL. The magnitude of these associations varied depending on age, gender, and rank, highlighting the need for stress-management training. PMID- 25516816 TI - A 4-Year Follow-up Cohort Study of the Respiratory Functions in Toner-handling Workers. AB - BACKGROUND: Focusing on the respiratory function for health effect indices, we conducted a cross-sectional study on workers who did and did not handle toner to compare the longitudinal changes. METHODS: Among 116 individuals who worked for a Japanese business equipment manufacturer and participated in the study, the analysis included 69 male workers who we were able to follow up for 4 years. We categorized the 40 workers engaged in toner-handling work as the exposed group and the 29 workers not engaged in these tasks as the referent group, and compared their respiratory function test results: peak expiratory flow rate (PEFR), vital capacity (VC), predicted vital capacity (%VC), forced expiratory volume in 1 second (FEV1), and forced expiratory volume in 1 second as a percent of forced vital capacity (FEV1%). RESULTS: The cross-sectional study of the respiratory function test results at the baseline and at the 5(th) year showed no statistically significant differences in PEFR, VC, %VC, FEV1, and FEV1% between the exposed and referent workers. Also, respiratory function time-course for 4 years was calculated and compared between the groups. No statistically significant differences were shown. CONCLUSION: Our study does not suggest any toner exposure effects on respiratory function. However, the number of subjects was small in our study; studies of larger populations will be desired in the future. PMID- 25516817 TI - Hippuric Acid levels in paint workers at steel furniture manufacturers in Thailand. AB - BACKGROUND: The aims of this study were to determine hippuric acid levels in urine samples, airborne toluene levels, acute and chronic neurological symptoms, and to describe any correlation between urinary hippuric acid and airborne toluene. METHODS: The hippuric acid concentration in the urine of 87 paint workers exposed to toluene at work (exposed group), and 87 nonexposed people (control group) was studied. Study participants were selected from similar factories in the same region. Urine samples were collected at the end of a shift and analyzed for hippuric acid by high performance liquid chromatography. Air samples for the estimation of toluene exposure were collected with diffusive personal samplers and the toluene quantified using gas-liquid chromatography. The two groups were also interviewed and observed about their work practices and health. RESULTS: The median of the 87 airborne toluene levels was 55 ppm (range, 12-198 ppm). The median urinary hippuric acid level was 800 mg/g creatinine (range, 90-2547 mg/g creatinine). A statistically significant positive correlation was found between airborne toluene exposure and urine hippuric acid levels (r = 0.548, p < 0.01). Workers with acute symptoms had significantly higher hippuric acid levels than those who did not (p < 0.05). It was concluded that there was a significant correlation between toluene exposure, hippuric acid levels, and health (p < 0.001). CONCLUSION: There appears to be a significant correlation between workers exposure to toluene at work, their urine hippuric acid levels, and resulting symptoms of poor health. Improvements in working conditions and occupational health education are required at these workplaces. There was good correlation between urinary hippuric acid and airborne toluene levels. PMID- 25516818 TI - Lung Function Profiles among Individuals with Nonmalignant Asbestos-related Disorders. AB - BACKGROUND: Inhalation of asbestos fibers can lead to adverse health effects on the lungs. This study describes lung function profiles among individuals with nonmalignant asbestos-related disorders (ARDs). METHODS: The study population was from the Workers' Compensation (Dust Diseases) Board of New South Wales, Sydney, Australia. Lung function measurements were conducted in males with asbestosis (n = 26), diffuse pleural thickening (DPT; n = 129), asbestosis and DPT (n = 14), pleural plaques only (n = 160) and also apparently healthy individuals with a history of asbestos exposure (n = 248). Standardized spirometric and single breath diffusing capacity for carbon monoxide (DLCO) measurements were used. RESULTS: Mean age [standard deviation (SD)] was 66.7 (10.3) years for all participants. Current and ex-smokers among all participants comprised about 9.0% and 54.8%, respectively. Median pack-years (SD) of smoking for ex- and current smokers were 22.7 (19.9). Overall 222 participants (38.6%) and 139 participants (24.2%) had forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) measurements < 80% predicted, and 217 participants (37.7%) had FEV1/FVC results < 70%. A total of 249 individuals (43.8%) had DLco values < 80% predicted and only 75 (13.2%) had DLco/VA results < 80% predicted. A total of 147 participants (25.6%) had peak expiratory flow (PEF) measurements < 80% predicted. The presence of ARDs lowered the lung function measurements compared to those of healthy individuals exposed to asbestos. CONCLUSION: Lung function measurement differs in individuals with different ARDs. Monitoring of lung function among asbestos-exposed populations is a simple means of facilitating earlier interventions. PMID- 25516819 TI - Routine Screening Endoscopy before Bariatric Surgery: Is It Necessary? AB - Background: Routine esophagogastroduodenoscopy (EGD) prior to bariatric surgery has not been consistently shown to change the management of the patient. A study was performed to estimate the proportion of patients undergoing bariatric surgery evaluation who had abnormal findings on preoperative EGD that resulted in alteration of management and, second, to evaluate potential risk factors for occurrence of abnormal findings on the EGD. Methods: An observational, retrospective study in which all 232 patients who were cleared to undergo bariatric surgery and who underwent preoperative EGD between 2006 and 2013 were included at a single tertiary dedicated bariatric center for weight loss management. Abnormal findings on screening EGD and medical or surgical management alteration based on the EGD findings were reviewed. Results: Abnormal findings on screening EGD were found in 143 patients (61.6%). Thirty-five patients had medical management altered (15.1%), while four patients (1.7%) had surgical management altered. Being aged >55 years and the presence of gastroesophageal reflux disease were associated with occurrence of an abnormal finding on screening EGD. Conclusions: While abnormalities on preoperative EGD are often found in patients undergoing bariatric surgery evaluation, rarely do the findings change surgical management. Alternative methods for screening for common GI conditions should be considered in appropriate patients. PMID- 25516820 TI - On translating technology research into industrial applications. PMID- 25516821 TI - Assisted technology for daily living. PMID- 25516822 TI - TVET as an important factor in country's economic development. PMID- 25516823 TI - Molecular dynamics simulations: from structure function relationships to drug discovery. AB - Molecular dynamics (MD) simulation is an emerging in silico technique with potential applications in diverse areas of pharmacology. Over the past three decades MD has evolved as an area of importance for understanding the atomic basis of complex phenomena such as molecular recognition, protein folding, and the transport of ions and small molecules across membranes. The application of MD simulations in isolation and in conjunction with experimental approaches have provided an increased understanding of protein structure-function relationships and demonstrated promise in drug discovery. PMID- 25516824 TI - Resistance to the macrocyclic lactone moxidectin is mediated in part by membrane transporter P-glycoproteins: Implications for control of drug resistant parasitic nematodes. AB - Our objective was to determine if the resistance mechanism to moxidectin (MOX) is similar of that to ivermectin (IVM) and involves P-glycoproteins (PGPs). Several Caenorhabditis elegans strains were used: an IVM and MOX sensitive strain, 13 PGP deletion strains and the IVM-R strain which shows synthetic resistance to IVM (by creation of three point mutations in genes coding for alpha-subunits of glutamate gated chloride channels [GluCls]) and cross-resistance to MOX. These strains were used to compare expression of PGP genes, measure motility and pharyngeal pumping phenotypes and evaluate the ability of compounds that inhibit PGP function to potentiate sensitivity or reverse resistance to MOX. The results suggest that C. elegans may use regulation of PGPs as a response mechanism to MOX. This was indicated by the over-expression of several PGPs in both drug sensitive and IVM-R strains and the significant changes in phenotype in the IVM-R strain in the presence of PGP inhibitors. However, as the inhibitors did not completely disrupt expression of the phenotypic traits in the IVM-R strain, this suggests that there likely are multiple avenues for MOX action that may include receptors other than GluCls. If MOX resistance was mediated solely by GluCls then exposure of the IVM R strain to PGP inhibitors should not have affected sensitivity to MOX. Targeted gene deletions showed that protection of C. elegans against MOX involves complex mechanisms and depends on the PGP gene family, particularly PGP-6. While the results presented are similar to others using IVM, there were some important differences observed with respect to PGPs which may play a role in the disparities seen in the characteristics of resistance to IVM and MOX. The similarities are of concern as parasites resistant to IVM show some degree but not complete cross-resistance to MOX; this could impact nematodes that are resistant to IVM. PMID- 25516825 TI - Temporal trends in prevalence of Plasmodium falciparum drug resistance alleles over two decades of changing antimalarial policy in coastal Kenya. AB - Molecular surveillance of drug resistance markers through time provides crucial information on genomic adaptations, especially in parasite populations exposed to changing drug pressures. To assess temporal trends of established genotypes associated with tolerance to clinically important antimalarials used in Kenya over the last two decades, we sequenced a region of the pfcrt locus encompassing codons 72-76 of the Plasmodium falciparum chloroquine resistance transporter, full-length pfmdr1 - encoding multi-drug resistance protein, P-glycoprotein homolog (Pgh1) and pfdhfr encoding dihydrofolate reductase, in 485 archived Plasmodium falciparum positive blood samples collected in coastal Kenya at four different time points between 1995 and 2013. Microsatellite loci were also analyzed to compare the genetic backgrounds of parasite populations circulating before and after the withdrawal of chloroquine and sulfadoxine/pyrimethamine. Our results reveal a significant increase in the prevalence of the pfcrt K76 wild type allele between 1995 and 2013 from 38% to 81.7% (p < 0.0001). In contrast, we noted a significant decline in wild-type pfdhfr S108 allele (p < 0.0001) culminating in complete absence of this allele in 2013. We also observed a significant increase in the prevalence of the wild-type pfmdr1 N86/Y184/D1246 haplotype from 14.6% in 1995 to 66.0% in 2013 (p < 0.0001) and a corresponding decline of the mutant pfmdr1 86Y/184Y/1246Y allele from 36.4% to 0% in 19 years (p < 0.0001). We also show extensive genetic heterogeneity among the chloroquine sensitive parasites before and after the withdrawal of the drug in contrast to a selective sweep around the triple mutant pfdhfr allele, leading to a mono-allelic population at this locus. These findings highlight the importance of continual surveillance and characterization of parasite genotypes as indicators of the therapeutic efficacy of antimalarials, particularly in the context of changes in malaria treatment policy. PMID- 25516828 TI - A quantitative reverse-transcriptase PCR assay for the assessment of drug activities against intracellular Theileria annulata schizonts. AB - Intracellular schizonts of the apicomplexans Theileria annulata and Theileria parva immortalize bovine leucocytes thereby causing fatal immunoproliferative diseases. Buparvaquone, a hydroxynaphthoquinone related to parvaquone, is the only drug available against Theileria. The drug is only effective at the onset of infection and emerging resistance underlines the need for identifying alternative compounds. Current drug assays employ monitoring of proliferation of infected cells, with apoptosis of the infected host cell as a read-out, but it is often unclear whether active compounds directly impair the viability of the parasite or primarily induce host cell death. We here report on the development of a quantitative reverse transcriptase real time PCR method based on two Theileria genes, tasp and tap104, which are both expressed in schizonts. Upon in vitro treatment of T. annulata infected bovine monocytes with buparvaquone, TaSP and Tap104 mRNA expression levels significantly decreased in relation to host cell actin already within 4 h of drug exposure, while significant differences in host cell proliferation were detectable only after 48-72 h. TEM revealed marked alterations of the schizont ultrastructure already after 2 h of buparvaquone treatment, while the host cell remained unaffected. Expression of TaSP and Tap104 proteins showed a marked decrease only after 24 h. Therefore, the analysis of expression levels of mRNA coding for TaSP and Tap104 allows to directly measuring impairment of parasite viability. We subsequently applied this method using a series of compounds affecting different targets in other apicomplexan parasites, and show that monitoring of TaSP- and Tap104 mRNA levels constitutes a suitable tool for anti-theilerial drug development. PMID- 25516829 TI - Oral effectiveness of PMIC4, a novel hydroxyethylpiperazine analogue, in Leishmania amazonensis. AB - Pentavalent antimonials have saved the lives of thousands of Leishmania-infected patients more than seventy years but, unfortunately, they are highly toxic and require parenteral delivery. Therefore, the search for safer and orally delivered alternative is a need. This paper describes the antileishmanial properties of PMIC4, a novel hydroxyethylpiperazine analogue. PMIC4 showed potent activity against intracellular amastigotes of Leishmania amazonensis, with IC50 of 1.8 MUM and selectivity index higher than 100-fold, calculated in relation to the toxicity on the host cell. Following laboratory animal welfare policies, we analyzed the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties and calculated the Lipinski's rule of five of PMIC4 before proceeding to in vivo tests. PMIC4 satisfied Lipinski's rule of five and presented high probability of human intestinal absorption, suggesting a good chance of druglikeness and oral bioavailability. For in vivo studies, PMIC4 was administered via intralesional injection (3.4 mg/kg/day, three times a week) or orally (34.0 mg/kg/day, five times a week) to L. amazonensis-infected BALB/c mice throughout the 98 day experiments. At the end of the treatment period, serum markers of toxicity were measured. When administered orally, PMIC4 controlled the lesions in L. amazonensis-infected BALB/c mice without altering serological markers of toxicity. These results demonstrate that PMIC4 is a promising molecular scaffold, orally effective against experimental leishmaniasis. PMID- 25516826 TI - Recent advances in candidate-gene and whole-genome approaches to the discovery of anthelmintic resistance markers and the description of drug/receptor interactions. AB - Anthelmintic resistance has a great impact on livestock production systems worldwide, is an emerging concern in companion animal medicine, and represents a threat to our ongoing ability to control human soil-transmitted helminths. The Consortium for Anthelmintic Resistance and Susceptibility (CARS) provides a forum for scientists to meet and discuss the latest developments in the search for molecular markers of anthelmintic resistance. Such markers are important for detecting drug resistant worm populations, and indicating the likely impact of the resistance on drug efficacy. The molecular basis of resistance is also important for understanding how anthelmintics work, and how drug resistant populations arise. Changes to target receptors, drug efflux and other biological processes can be involved. This paper reports on the CARS group meeting held in August 2013 in Perth, Australia. The latest knowledge on the development of molecular markers for resistance to each of the principal classes of anthelmintics is reviewed. The molecular basis of resistance is best understood for the benzimidazole group of compounds, and we examine recent work to translate this knowledge into useful diagnostics for field use. We examine recent candidate gene and whole-genome approaches to understanding anthelmintic resistance and identify markers. We also look at drug transporters in terms of providing both useful markers for resistance, as well as opportunities to overcome resistance through the targeting of the transporters themselves with inhibitors. Finally, we describe the tools available for the application of the newest high-throughput sequencing technologies to the study of anthelmintic resistance. PMID- 25516831 TI - Anthelmintics - from discovery to resistance. AB - The scientific meeting entitled 'Anthelmintics: From Discovery to Resistance' was held in San Francisco in February 2014. The themes of the meeting were drug discovery, modes of action and resistance. Both human and veterinary parasites were covered in the oral and poster presentations. The attendees were from both academic and industrial backgrounds. In the present article we introduce a number of the papers that emerged from the meeting. Several of the papers covered current drug discovery efforts underway worldwide, with some specific examples focusing on ion channels, protein kinases and cysteine proteases. These efforts included the repurposing of known drugs as well as the discovery of novel actives. Two papers described recently-developed whole-organism screening techniques. Finally, we introduce several papers looking at mechanisms and management of drug resistance in human and veterinary parasites. PMID- 25516830 TI - Vaccination of chickens against coccidiosis ameliorates drug resistance in commercial poultry production. AB - Drug resistance is a problem wherever livestock are raised under intensive conditions and drugs are used to combat parasitic infections. This is particularly true for the anticoccidial agents used for the prevention of coccidiosis caused by protozoa of the apicomplexan genus Eimeria in poultry. Resistance has been documented for all the dozen or so drugs approved for use in chickens and varying levels of resistance is present for those currently employed. A possible solution may be the introduction of drug-sensitive parasites into the houses where poultry are raised so that they may replace such drug resistant organisms. This can be achieved by utilizing live vaccines that contain strains of Eimeria that were isolated before most anticoccidial compounds were introduced. Such strains are inherently drug-sensitive. Practical proposals to achieve this objective involve the alternation of vaccination with medication (known as rotation programs) in successive flocks reared in the same poultry house. A proposal for a yearly broiler production cycle involving chemotherapy and vaccination is presented. There are few, if any, examples in veterinary parasitology where it has proved possible to restore sensitivity to drugs used to control a widespread parasite. Further research is necessary to ascertain whether this can result in sustainable and long-term control of Eimeria infections in poultry. PMID- 25516832 TI - WIPO Re:Search: Accelerating anthelmintic development through cross-sector partnerships. AB - Neglected tropical diseases (NTDs), malaria, and tuberculosis have a devastating effect on an estimated 1.6 billion people worldwide. The World Intellectual Property Organization (WIPO) Re:Search consortium accelerates the development of new drugs, vaccines, and diagnostics for these diseases by connecting the assets and resources of pharmaceutical companies, such as compound libraries and expertise, to academic or nonprofit researchers with novel product discovery or development ideas. As the WIPO Re:Search Partnership Hub Administrator, BIO Ventures for Global Health (BVGH) fields requests from researchers, identifies Member organizations able to fulfill these requests, and helps forge mutually beneficial collaborations. Since its inception in October 2011, WIPO Re:Search membership has expanded to more than 90 institutions, including leading pharmaceutical companies, universities, nonprofit research institutions, and product development partnerships from around the world. To date, WIPO Re:Search has facilitated over 70 research agreements between Consortium Members, including 11 collaborations focused on anthelmintic drug discovery. PMID- 25516827 TI - Repurposing drugs for the treatment and control of helminth infections. AB - Helminth infections are responsible for a considerable public health burden, yet the current drug armamentarium is small. Given the high cost of drug discovery and development, the high failure rates and the long duration to develop novel treatments, drug repurposing circumvents these obstacles by finding new uses for compounds other than those they were initially intended to treat. In the present review, we summarize in vivo and clinical trial findings testing clinical candidates and marketed drugs against schistosomes, food-borne trematodes, soil transmitted helminths, Strongyloides stercoralis, the major human filariases lymphatic filariasis and onchocerciasis, taeniasis, neurocysticercosis and echinococcosis. While expanding the applications of broad-spectrum or veterinary anthelmintics continues to fuel alternative treatment options, antimalarials, antibiotics, antiprotozoals and anticancer agents appear to be producing fruitful results as well. The trematodes and nematodes continue to be most investigated, while cestodal drug discovery will need to be accelerated. The most clinically advanced drug candidates include the artemisinins and mefloquine against schistosomiasis, tribendimidine against liver flukes, oxantel pamoate against trichuriasis, and doxycycline against filariasis. Preclinical studies indicate a handful of promising future candidates, and are beginning to elucidate the broad spectrum activity of some currently used anthelmintics. Challenges and opportunities are further discussed. PMID- 25516834 TI - Utilization of computer processed high definition video imaging for measuring motility of microscopic nematode stages on a quantitative scale: "The Worminator". AB - A major hindrance to evaluating nematode populations for anthelmintic resistance, as well as for screening existing drugs, new compounds, or bioactive plant extracts for anthelmintic properties, is the lack of an efficient, objective, and reproducible in vitro assay that is adaptable to multiple life stages and parasite genera. To address this need we have developed the "Worminator" system, which objectively and quantitatively measures the motility of microscopic stages of parasitic nematodes. The system is built around the computer application "WormAssay", developed at the Center for Discovery and Innovation in Parasitic Diseases at the University of California, San Francisco. WormAssay was designed to assess motility of macroscopic parasites for the purpose of high throughput screening of potential anthelmintic compounds, utilizing high definition video as an input to assess motion of adult stage (macroscopic) parasites (e.g. Brugia malayi). We adapted this assay for use with microscopic parasites by modifying the software to support a full frame analysis mode that applies the motion algorithm to the entire video frame. Thus, the motility of all parasites in a given well are recorded and measured simultaneously. Assays performed on third stage larvae (L3) of the bovine intestinal nematode Cooperia spp., as well as microfilariae (mf) of the filarioid nematodes B. malayi and Dirofilaria immitis, yielded reproducible dose responses using the macrocyclic lactones ivermectin, doramectin, and moxidectin, as well as the nicotinic agonists, pyrantel, oxantel, morantel, and tribendimidine. This new computer based-assay is simple to use, requires minimal new investment in equipment, is robust across nematode genera and developmental stage, and does not require subjective scoring of motility by an observer. Thus, the "Worminator" provides a relatively low-cost platform for developing genera- and stage-specific assays with high efficiency and reproducibility, low labor input, and yields objective motility data that is not subject to scorer bias. PMID- 25516833 TI - Automated, high-throughput, motility analysis in Caenorhabditis elegans and parasitic nematodes: Applications in the search for new anthelmintics. AB - The scale of the damage worldwide to human health, animal health and agricultural crops resulting from parasitic nematodes, together with the paucity of treatments and the threat of developing resistance to the limited set of widely-deployed chemical tools, underlines the urgent need to develop novel drugs and chemicals to control nematode parasites. Robust chemical screens which can be automated are a key part of that discovery process. Hitherto, the successful automation of nematode behaviours has been a bottleneck in the chemical discovery process. As the measurement of nematode motility can provide a direct scalar readout of the activity of the neuromuscular system and an indirect measure of the health of the animal, this omission is acute. Motility offers a useful assay for high throughput, phenotypic drug/chemical screening and several recent developments have helped realise, at least in part, the potential of nematode-based drug screening. Here we review the challenges encountered in automating nematode motility and some important developments in the application of machine vision, statistical imaging and tracking approaches which enable the automated characterisation of nematode movement. Such developments facilitate automated screening for new drugs and chemicals aimed at controlling human and animal nematode parasites (anthelmintics) and plant nematode parasites (nematicides). PMID- 25516835 TI - Comparative pharmacology of flatworm and roundworm glutamate-gated chloride channels: Implications for potential anthelmintics. AB - Pharmacological targeting of glutamate-gated chloride channels (GluCls) is a potent anthelmintic strategy, evidenced by macrocyclic lactones that eliminate numerous roundworm infections by activating roundworm GluCls. Given the recent identification of flatworm GluCls and the urgent need for drugs against schistosomiasis, flatworm GluCls should be evaluated as potential anthelmintic targets. This study sought to identify agonists or modulators of one such GluCl, SmGluCl-2 from the parasitic flatworm Schistosoma mansoni. The effects of nine glutamate-like compounds and three monoterpenoid ion channel modulators were measured by electrophysiology at SmGluCl-2 recombinantly expressed in Xenopus laevis oocytes. For comparison with an established anthelmintic target, experiments were also performed on the AVR-14B GluCl from the parasitic roundworm Haemonchus contortus. l-Glutamate was the most potent agonist at both GluCls, but l-2-aminoadipate, d-glutamate and d-2-aminoadipate activated SmGluCl-2 (EC50 1.0 +/- 0.1 mM, 2.4 +/- 0.4 mM, 3.6 +/- 0.7 mM, respectively) more potently than AVR 14B. Quisqualate activated only SmGluCl-2 whereas l-aspartate activated only AVR 14B GluCls. Regarding the monoterpenoids, both GluCls were inhibited by propofol, thymol and menthol, SmGluCl-2 most potently by thymol (IC50 484 +/- 85 MUM) and least potently by menthol (IC50 > 3 mM). Computational docking suggested that agonist and inhibitor potency is attributable to particular interactions with extracellular or membrane-spanning amino acid residues. These results reveal that flatworm GluCls are pharmacologically susceptible to numerous agonists and modulators and indicate that changes to the glutamate gamma-carboxyl or to the propofol 6-isopropyl group can alter the differential pharmacology at flatworm and roundworm GluCls. This should inform the development of more potent compounds and in turn lead to novel anthelmintics. PMID- 25516837 TI - Potential involvement of Brugia malayi cysteine proteases in the maintenance of the endosymbiotic relationship with Wolbachia. AB - Brugia malayi, a parasitic nematode that causes lymphatic filariasis, harbors endosymbiotic intracellular bacteria, Wolbachia, that are required for the development and reproduction of the worm. The essential nature of this endosymbiosis led to the development of anti-Wolbachia chemotherapeutic approaches for the treatment of human filarial infections. Our study is aimed at identifying specific proteins that play a critical role in this endosymbiotic relationship leading to the identification of potential targets in the adult worms. Filarial cysteine proteases are known to be involved in molting and embryogenesis, processes shown to also be Wolbachia dependent. Based on the observation that cysteine protease transcripts are differentially regulated in response to tetracycline treatment, we focused on defining their role in symbiosis. We observe a bimodal regulation pattern of transcripts encoding cysteine proteases when in vitro tetracycline treated worms were examined. Using tetracycline-treated infertile female worms and purified embryos we established that the first peak of the bimodal pattern corresponds to embryonic transcripts while the second takes place within the hypodermis of the adult worms. Localization studies of the native proteins corresponding to Bm-cpl-3 and Bm-cpl 6 indicate that they are present in the area surrounding Wolbachia, and, in some cases, the proteins appear localized within the bacteria. Both proteins were also found in the inner bodies of microfilariae. The possible role of these cysteine proteases during development and endosymbiosis was further characterized using RNAi. Reduction in Bm-cpl-3 and Bm-cpl-6 transcript levels was accompanied by hindered microfilarial development and release, and reduced Wolbachia DNA levels, making these enzymes strong drug target candidates. PMID- 25516836 TI - Compound library screening identified Akt/PKB kinase pathway inhibitors as potential key molecules for the development of new chemotherapeutics against schistosomiasis. AB - Protein kinases (PKs) are one of the largest protein families in most eukaryotic organisms. These enzymes are involved in the control of cell proliferation, differentiation and metabolism and a large number of the anticancer drugs currently used are directed against PKs. The structure and function of PKs are well conserved throughout evolution. In schistosome parasites, PKs were shown to be involved in essential functions at every stage of the parasite life cycle, making these enzymes promising anti-parasite drug targets. In this study, we tested a panel of commercial inhibitors for various PKs and analyzed their effects on pairing and egg production by schistosomes as well as their toxicity towards schistosomula larvae. Results obtained confirmed the deleterious effect of PK targeting on Schistosoma mansoni physiology and the important function of different tyrosine and serine/threonine kinases in the biology and reproduction of this parasite. They also indicated for the first time that the Protein kinase B (also called Akt) which is a major downstream target of many receptor tyrosine kinases and a central player at the crossroads of signal transduction pathways activated in response to growth factors and insulin, can constitute a novel target for anti-schistosome chemotherapy. Structural and functional studies have shown that SmAkt is a conserved kinase and that its activity can be inhibited by commercially available Akt inhibitors. In treated adult worms, Akt/PKB kinase pathway inhibitors induced profound alterations in pairing and egg laying and they also greatly affected the viability of schistosomula larvae. PMID- 25516838 TI - Repurposing of approved drugs from the human pharmacopoeia to target Wolbachia endosymbionts of onchocerciasis and lymphatic filariasis. AB - Lymphatic filariasis and onchocerciasis are debilitating diseases caused by parasitic filarial nematodes infecting around 150 million people throughout the tropics with more than 1.5 billion at risk. As with other neglected tropical diseases, classical drug-discovery and development is lacking and a 50 year programme of macrofilaricidal discovery failed to deliver a drug which can be used as a public health tool. Recently, antibiotic targeting of filarial Wolbachia, an essential bacterial symbiont, has provided a novel drug treatment for filariasis with macrofilaricidal activity, although the current gold standard, doxycycline, is unsuitable for use in mass drug administration (MDA). The anti-Wolbachia (A.WOL) Consortium aims to identify novel anti-Wolbachia drugs, compounds or combinations that are suitable for use in MDA. Development of a Wolbachia cell-based assay has enabled the screening of the approved human drug pharmacopoeia (~2600 drugs) for a potential repurposing. This screening strategy has revealed that approved drugs from various classes show significant bacterial load reduction equal to or superior to the gold-standard doxycycline, with 69 orally available hits from different drug categories being identified. Based on our defined hit criteria, 15 compounds were then selectively screened in a Litomosoides sigmodontis mouse model, 4 of which were active. These came from the tetracycline, fluoroquinolone and rifamycin classes. This strategy of repurposing approved drugs is a promising development in the goal of finding a novel treatment against filariasis and could also be a strategy applicable for other neglected tropical diseases. PMID- 25516839 TI - Serum albumin and alpha-1 acid glycoprotein impede the killing of Schistosoma mansoni by the tyrosine kinase inhibitor Imatinib. AB - In the search for new drugs and drug targets to treat the flatworm disease schistosomiasis, protein kinases (PKs) have come under particular scrutiny because of their essential roles in developmental and physiological processes in schistosome parasites. In this context the application of the anti-cancer Abl tyrosine kinase (TK) inhibitor Imatinib (Gleevec/Glivec; STI-571) to adult Schistosoma mansoni in vitro has indicated negative effects on diverse physiological processes including survival. Motivated by these in vitro findings, we performed in vivo experiments in rodent models of S. mansoni infection. Unexpectedly, Imatinib had no effect on worm burden or egg-production. We found that the blood components serum albumin (SA) and alpha-1 acid glycoprotein (AGP or orosomucoid) negated Imatinib's deleterious effects on adult S. mansoni and schistosomula (post-infective larvae) in vitro. This negative effect was partially reversed by erythromycin. AGP synthesis can increase as a consequence of inflammatory processes or infection; in addition upon infection AGP levels are 6-8 times higher in mice compared to humans. Therefore, mice and probably other rodents are poor infection models for measuring the effects of Imatinib in vivo. Accordingly, we suggest the routine evaluation of the ability of AGP and SA to block in vitro anti-schistosomal effects of small molecules like Imatinib prior to laborious and expensive animal experiments. PMID- 25516840 TI - Praziquantel sensitivity of Kenyan Schistosoma mansoni isolates and the generation of a laboratory strain with reduced susceptibility to the drug. AB - Schistosomiasis is a neglected tropical disease caused by blood-dwelling flukes of the genus Schistosoma. While the disease may affect as many as 249 million people, treatment largely relies on a single drug, praziquantel. The near exclusive use of this drug for such a prevalent disease has led to concerns regarding the potential for drug resistance to arise and the effect this would have on affected populations. In this study, we use an in vitro assay of drug sensitivity to test the effect of praziquantel on miracidia hatched from eggs obtained from fecal samples of Kenyan adult car washers and sand harvesters as well as school children. Whereas in a previous study we found the car washers and sand harvesters to harbor Schistosoma mansoni with reduced praziquantel sensitivity, we found no evidence for the presence of such strains in any of the groups tested here. Using miracidia derived from seven car washers to infect snails, we used the shed cercariae to establish a strain of S. mansoni with significantly reduced praziquantel sensitivity in mice. This was achieved within 5 generations by administering increasing doses of praziquantel to the infected mice until the parasites could withstand a normally lethal dose. This result indicates that while the threat of praziquantel resistance may have diminished in the Kenyan populations tested here, there is a strong likelihood it could return if sufficient praziquantel pressure is applied. PMID- 25516842 TI - Anthelmintic resistance in equine nematodes. AB - Anthelmintics have been applied indiscriminately to control horse nematodes for over 40 years. Three broad-spectrum anthelmintic classes are currently registered for nematode control in horses: benzimidazoles (fenbendazole, oxibendazole), tetrahydropyrimidines (pyrantel) and macrocyclic lactones (ivermectin, moxidectin). Generally, control strategies have focused on nematode egg suppression regimens that involve the frequent application of anthelmintics to all horses at intervals based on strongyle egg reappearance periods after treatment. The widespread use of such programmes has substantially reduced clinical disease, especially that associated with large strongyle species; however, high treatment frequency has led to considerable selection pressure for anthelmintic resistance, particularly in cyathostomin species. Field studies published over the last decade indicate that benzimidazole resistance is widespread globally in cyathostomins and there are also many reports of resistance to pyrantel in these worms. Cyathostomin resistance to macrocyclic lactone compounds is emerging, principally measured as a reduction in strongyle egg reappearance time observed after treatment. Ivermectin resistance is a further concern in the small intestinal nematode, Parascaris equorum, an important pathogen of foals. These issues indicate that horse nematodes must now be controlled using methods less dependent on anthelmintic use and more reliant on management practices designed to reduce the force of infection in the environment. Such strategies include improved grazing management integrated with targeted anthelmintic administration involving faecal egg count (FEC)-directed treatments. The latter require that the supporting diagnostic tests available are robust and practically applicable. Recent research has focused on maximising the value of FEC analysis in horses and on optimizing protocols for anthelmintic efficacy testing. Other studies have sought to develop diagnostics that will help define levels of pre-patent infection. This review describes recent advances in each of these areas of research. PMID- 25516845 TI - Reverse pharmacology for developing an anti-malarial phytomedicine. The example of Argemone mexicana. AB - Classical pharmacology has been the basis for the discovery of new chemical entities with therapeutic effects for decades. In natural product research, compounds are generally tested in vivo only after full in vitro characterization. However drug screening using this methodology is expensive, time-consuming and very often inefficient. Reverse pharmacology, also called bedside-to-bench, is a research approach based on the traditional knowledge and relates to reversing the classical laboratory to clinic pathway to a clinic to laboratory practice. It is a trans-disciplinary approach focused on traditional knowledge, experimental observations and clinical experiences. This paper is an overview of the reverse pharmacology approach applied to the decoction of Argemone mexicana, used as an antimalarial traditional medicine in Mali. A. mexicana appeared as the most effective traditional medicine for the treatment of uncomplicated falciparum malaria in Mali, and the clinical efficacy of the decoction was comparable to artesunate-amodiaquine as previously published. Four stages of the reverse pharmacology process will be described here with a special emphasis on the results for stage 4. Briefly, allocryptopine, protopine and berberine were isolated through bioguided fractionation, and had their identity confirmed by spectroscopic analysis. The three alkaloids showed antiparasitic activity in vitro, of which allocryptopine and protopine were selective towards Plasmodium falciparum. Furthermore, the amount of the three active alkaloids in the decoction was determined by quantitative NMR, and preliminary in vivo assays were conducted. On the basis of these results, the reverse pharmacology approach is discussed and further pharmacokinetic studies appear to be necessary in order to determine whether these alkaloids can be considered as phytochemical markers for quality control and standardization of an improved traditional medicine made with this plant. PMID- 25516843 TI - Identification of beta-hematin inhibitors in a high-throughput screening effort reveals scaffolds with in vitro antimalarial activity. AB - The emergence of drug resistant strains of Plasmodium spp. creates a critical need for the development of novel antimalarials. Formation of hemozoin, a crystalline heme detoxification process vital to parasite survival serves as an important drug target. The quinoline antimalarials including chloroquine and amodiaquine owe their antimalarial activity to inhibition of hemozoin formation. Though in vivo formation of hemozoin occurs within the presence of neutral lipids, the lipophilic detergent NP-40 was previously shown to serve as a surrogate in the beta-hematin (synthetic hemozoin) formation process. Consequently, an NP-40 mediated beta-hematin formation assay was developed for use in high-throughput screening. Here, the assay was utilized to screen 144,330 compounds for the identification of inhibitors of crystallization, resulting in 530 hits. To establish the effectiveness of these target-based beta-hematin inhibitors against Plasmodium falciparum, each hit was further tested in cultures of parasitized red blood cells. This effort revealed that 171 of the beta-hematin inhibitors are also active against the parasite. Dose-response data identified 73 of these beta-hematin inhibitors have IC50 values ?5 MUM, including 25 compounds with nanomolar activity against P. falciparum. A scaffold-based analysis of this data identified 14 primary scaffolds that represent 46% of the 530 total hits. Representative compounds from each of the classes were further assessed for hemozoin inhibitory activity in P. falciparum infected human erythrocytes. Each of the hit compounds tested were found to be positive inhibitors, while a negative control did not perturb this biological pathway in culture. PMID- 25516841 TI - Schistosome ABC multidrug transporters: From pharmacology to physiology. AB - Praziquantel (PZQ) is essentially the only drug currently available for treatment and control of schistosomiasis, a disease affecting hundreds of millions worldwide. Though highly effective overall, PZQ has limitations, most notably its significant lack of activity against immature schistosomes. Furthermore, the availability of only a single drug for a disease of this magnitude makes reports of PZQ-resistant isolates particularly troubling. ATP-binding cassette (ABC) multidrug transporters such as P-glycoprotein (Pgp; ABCB1) are efflux transporters that underlie multidrug resistance (MDR); changes in their expression or structure are also associated with drug resistance in parasites, including helminths. This review will discuss the role these transporters might play in modulating schistosome susceptibility to PZQ, and the implications for developing new or repurposed treatments that enhance the efficacy of PZQ. However, in addition to influencing drug susceptibility, ABC transporters play important roles in several critical physiological functions such as excretion and maintenance of permeability barriers. They also transport signaling molecules with high affinity, and several lines of evidence implicate mammalian transporters in a diverse array of physiological functions, including regulation of immune responses. Like their mammalian counterparts, schistosome ABC transporters appear to be involved in functions critical to the parasite, including excretory activity and reproduction, and we hypothesize that they underlie at least some aspects of parasite-host interactions. Thus, in addition to their potential as targets for enhancers of PZQ susceptibility, these transporters might also serve as candidate targets for agents that disrupt the parasite life cycle and act as antischistosomals on their own. PMID- 25516846 TI - Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate. AB - Leishmania infantum is the etiological agent of zoonotic visceral leishmaniasis in the Mediterranean basin. The disease is fatal without treatment, which has been based on antimonial pentavalents for more than 60 years. Due to resistances, relapses and toxicity to current treatment, the development of new drugs is required. The structure of the L. infantum tyrosine aminotransferase (LiTAT) has been recently solved showing important differences with the mammalian orthologue. The characterization of LiTAT is reported herein. This enzyme is cytoplasmic and is over-expressed in the more infective stages and nitric oxide resistant parasites. Unlike the mammalian TAT, LiTAT is able to use ketomethiobutyrate as co-substrate. The pharmacophore model of LiTAT with this specific co-substrate is described herein. This may allow the identification of new inhibitors present in the databases. All the data obtained support that LiTAT is a good target candidate for the development of new anti-leishmanial drugs. PMID- 25516847 TI - Target-based vs. phenotypic screenings in Leishmania drug discovery: A marriage of convenience or a dialogue of the deaf? AB - Drug discovery programs sponsored by public or private initiatives pursue the same ambitious goal: a crushing defeat of major Neglected Tropical Diseases (NTDs) during this decade. Both target-based and target-free screenings have pros and cons when it comes to finding potential small-molecule leads among chemical libraries consisting of myriads of compounds. Within the target-based strategy, crystals of pathogen recombinant-proteins are being used to obtain three dimensional (3D) structures in silico for the discovery of structure-based inhibitors. On the other hand, genetically modified parasites expressing easily detectable reporters are in the pipeline of target-free (phenotypic) screenings. Furthermore, lead compounds can be scaled up to in vivo preclinical trials using rodent models of infection monitoring parasite loads by means of cutting-edge bioimaging devices. As such, those preferred are fluorescent and bioluminescent readouts due to their reproducibility and rapidity, which reduces the number of animals used in the trials and allows for an earlier stage detection of the infective process as compared with classical methods. In this review, we focus on the current differences between target-based and phenotypic screenings in Leishmania, as an approach that leads to the discovery of new potential drugs against leishmaniasis. PMID- 25516844 TI - Trypanosomatids topoisomerase re-visited. New structural findings and role in drug discovery. AB - The Trypanosomatidae family, composed of unicellular parasites, causes severe vector-borne diseases that afflict human populations worldwide. Chagas disease, sleeping sickness, as well as different sorts of leishmaniases are amongst the most important infectious diseases produced by Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp., respectively. All these infections are closely related to weak health care services in low-income populations of less developed and least economically developed countries. Search for new therapeutic targets in order to hit these pathogens is of paramount priority, as no effective vaccine is currently in use against any of these parasites. Furthermore, present-day chemotherapy comprises old-fashioned drugs full of important side effects. Besides, they are prone to produce tolerance and resistance as a consequence of their continuous use for decades. DNA topoisomerases (Top) are ubiquitous enzymes responsible for solving the torsional tensions caused during replication and transcription processes, as well as in maintaining genomic stability during DNA recombination. As the inhibition of these enzymes produces cell arrest and triggers cell death, Top inhibitors are among the most effective and most widely used drugs in both cancer and antibacterial therapies. Top relaxation and decatenation activities, which are based on a common nicking-closing cycle involving one or both DNA strands, have been pointed as a promising drug target. Specific inhibitors that bind to the interface of DNA-Top complexes can stabilize Top-mediated transient DNA breaks. In addition, important structural differences have been found between Tops from the Trypanosomatidae family members and Tops from the host. Such dissimilarities make these proteins very interesting for drug design and molecular intervention. The present review is a critical update of the last findings regarding trypanosomatid's Tops, their new structural features, their involvement both in the physiology and virulence of these parasites, as well as their use as promising targets for drug discovery. PMID- 25516848 TI - Anti-diabetic activity of different oils through their effect on arylsulfatases. AB - BACKGROUND: Diabetes mellitus (DM) is characterized by the overproduction of the reactive oxygen species which affects the integrity of the lysosomal membrane affecting lysosomal enzymes. The effect of these species is blocked by some natural products as antioxidants. In the current study, groups of normal and streptozotocin (STZ)-induced diabetic rats were treated by Nigella sativa (NS), olive and canola oils and subjected to the study of arylsulfatases as a model of lysosomal enzymes. The aim of the present study is to investigate the effect of STZ-induced diabetes on arylsulfatases in presence and absence of NS, olive and canola oils. METHODS: Different groups of rats were induced by STZ, treated with different oils and compared to their corresponding control group. All groups were subjected for the assays of blood glucose, insulin, catalase and arylsulfatases. A comparative kinetic study of arylsulfatses was performed to detect the alteration of catalytic characterization. RESULTS: The results demonstrated that diabetes causes a significant elevation in the level of hepatic arylsulfatase B and a significant reduction of hepatic catalase as an antioxidant enzyme. NS and olive oils returned catalase and arylsulfatase B activities back near to normal by fixing their catalytic properties. Furthermore, the maximum velocity of arylsulfatases A and B was significantly elevated in the induced diabetes, whereas their Km values were significantly changed. The treatment of diabetic rats by NS and olive oils reduced the degree of significance. CONCLUSION: Diabetes induces significant alterations of the catalytic characters of arylsulfatases and some oils decrease this alteration through an antioxidant mediated effect. PMID- 25516849 TI - Adenoid cystic carcinoma of breast: Recent advances. AB - Adenoid cystic carcinoma (ACC) of the breast is a rare special subtype of breast cancer characterized by the presence of a dual cell population of luminal and basaloid cells arranged in specific growth patterns. Most breast cancers with triple-negative, basal-like breast features (i.e., tumors that are devoid of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, and express basal cell markers) are generally high-grade tumors with an aggressive clinical course. Conversely, while ACCs also display a triple-negative, basal-like phenotype, they are usually low-grade and exhibit an indolent clinical behavior. Many discoveries regarding the molecular and genetic features of the ACC, including a specific chromosomal translocation t(6;9) that results in a MYB-NFIB fusion gene, have been made in recent years. This comprehensive review provides our experience with the ACC of the breast, as well as an overview of clinical, histopathological, and molecular genetic features. PMID- 25516850 TI - Drug-targeting methodologies with applications: A review. AB - Targeted drug delivery to solid tumors is a very active research area, focusing mainly on improved drug formulation and associated best delivery methods/devices. Drug-targeting has the potential to greatly improve drug-delivery efficacy, reduce side effects, and lower the treatment costs. However, the vast majority of drug-targeting studies assume that the drug-particles are already at the target site or at least in its direct vicinity. In this review, drug-delivery methodologies, drug types and drug-delivery devices are discussed with examples in two major application areas: (1) inhaled drug-aerosol delivery into human lung airways; and (2) intravascular drug-delivery for solid tumor targeting. The major problem addressed is how to deliver efficiently the drug-particles from the entry/infusion point to the target site. So far, most experimental results are based on animal studies. Concerning pulmonary drug delivery, the focus is on the pros and cons of three inhaler types, i.e., pressurized metered dose inhaler, dry powder inhaler and nebulizer, in addition to drug-aerosol formulations. Computational fluid-particle dynamics techniques and the underlying methodology for a smart inhaler system are discussed as well. Concerning intravascular drug delivery for solid tumor targeting, passive and active targeting are reviewed as well as direct drug-targeting, using optimal delivery of radioactive microspheres to liver tumors as an example. The review concludes with suggestions for future work, considereing both pulmonary drug targeting and direct drug delivery to solid tumors in the vascular system. PMID- 25516851 TI - Relational coordination and healthcare management in lung cancer. AB - In the current socio-economic scenario characterized by a growing shortage of resources and progressive budget constraints, the need to better coordinate processes in health institutions appears as a relevant aspect to ensure the future sustainability of system. In this sense, Relational Coordination (RC) provides a valuable opportunity for the reconfiguration of clinical guidelines concerning isolated single-level considerations. In this research the RC model has been applied to explain best results in the process of diagnosing and offering clinical treatments for lung cancer. Lung cancer presents the higher rates of tumor's mortality worldwide. Through unstructured and informal interviews with clinicians at both levels (Primary/Specialist Care), a diagnosis of the situation in relation to joint management of lung cancer is provided. Solutions of continuity in terms of coordination are explained due to the observation of lack of effective knowledge transfer between the two levels. It is this disconnection which justifies the introduction of a modified model of RC for the study and implementation of transfer relations between the knowledge holders, in order to structure consolidated and cooperative evidence-based models that lead to a substantial shortening in the response times with a marked outcomes improvement. To our knowledge, the application of this model to a Public Health problem bringing together both levels of care, hasn't been made till now. PMID- 25516854 TI - Follicular contact dermatitis revisited: A review emphasizing neomycin-associated follicular contact dermatitis. AB - Follicular contact dermatitis clinically presents as individual papules that include a central hair follicle. Pathologic features involve the follicle and the surrounding dermis: spongiosis and vesicle formation of the follicular epithelium associated with perifollicular and perivascular lymphocytic inflammation. Using the PubMed database, an extensive literature search was performed on follicular contact dermatitis and neomycin. Relevant papers were reviewed and the clinical and pathologic features, the associated chemicals (including a more detailed description of neomycin), the hypothesized pathogenesis, and the management of follicular contact dermatitis were described. Several agents-either as allergens or irritants-have been reported to elicit follicular contact dermatitis. Several hypotheses have been suggested for the selective involvement of the follicles in follicular contact dermatitis: patient allergenicity, characteristics of the agent, vehicle containing the agent, application of the agent, and external factors. The differential diagnosis of follicular contact dermatitis includes not only recurrent infundibulofolliculitis, but also drug eruption, mite infestation, viral infection, and dermatoses that affect hair follicles. The primary therapeutic intervention for follicular contact dermatitis is withdrawal of the causative agent; treatment with a topical corticosteroid preparation may also promote resolution of the dermatitis. In conclusion, follicular contact dermatitis may be secondary to allergens or irritants; topical antibiotics, including neomycin, may cause this condition. Several factors may account for the selective involvement of the hair follicle in this condition. Treatment of the dermatitis requires withdrawal of the associated topical agent; in addition, topical corticosteroids may be helpful to promote resolution of lesions. PMID- 25516855 TI - Prognostic factors in periodontal therapy and their association with treatment outcomes. AB - During the incipient steps of periodontal treatment, clinicians are usually asked to predict the prognosis of teeth with compromised periodontium. The aim of this literature review was to investigate the association between periodontal Prognosis, Tooth Loss and risk indicators, such as smoking and genetics. Results showed that the definition of good prognosis has much higher predictability than the one for questionable prognosis. Several risk indicators for periodontal prognosis and tooth loss are discussed as well as different definitions of questionable prognosis and their success in predicting tooth loss. In conclusion, the major focus of future studies should be to construct simplified prognostic models with high predictability that will increase the confidence of dentists and periodontists when assigning teeth prognosis. PMID- 25516852 TI - New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers. AB - Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy, including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin, Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed. PMID- 25516856 TI - Sleep disordered breathing in interstitial lung disease: A review. AB - Patients with interstitial lung disease commonly exhibit abnormal sleep architecture and increased sleep fragmentation on polysomnography. Fatigue is a frequent complaint, and it is likely that poor sleep quality is a significant contributor. A number of studies have shown that sleep disordered breathing is prevalent in this population, particularly in the idiopathic pulmonary fibrosis subgroup. The factors that predispose these patients to obstructive sleep apnoea are not well understood, however it is believed that reduced caudal traction on the upper airway can enhance collapsibility. Ventilatory control system instability may also be an important factor, particularly in those with increased chemo-responsiveness, and in hypoxic conditions. Transient, repetitive nocturnal oxygen desaturation is frequently observed in interstitial lung disease, both with and without associated obstructive apnoeas. There is increasing evidence that sleep-desaturation is associated with increased mortality, and may be important in the pathogenesis of pulmonary hypertension in this population. PMID- 25516858 TI - Acute necrotizing pancreatitis: Surgical indications and technical procedures. AB - Necrosis of pancreatic parenchyma or extrapancreatic tissues is present in 10% 20% of patients with acute pancreatitis, defining the necrotizing presentation frequently associated with high morbidity and mortality rates. During the initial phase of acute necrotizing pancreatitis the most important pillars of medical treatment are fluid resuscitation, early enteral nutrition, endoscopic retrograde colangiopancreatography if associated cholangitis and intensive care unit support. When infection of pancreatic or extrapancreatic necrosis occurs, surgical approach constitutes the most accepted therapeutic option. In this context, we have recently assited to changes in time for surgery (delaying the indication if possible to around 4 wk to deal with "walled-off" necrosis) and type of access for necrosectomy: from a classical open approach (with closure over large-bore drains for continued postoperative lavage or semiopen techniques with scheduled relaparotomies), trends have changed to a "step-up" philosophy with initial percutaneous drainage and posterior minimally invasive or endoscopic access to the retroperitoneal cavity for necrosectomy if no improvement has been previously achieved. These approaches are progressively gaining popularity and morbidity and mortality rates have decreased significantly. Therefore, a staged, multidisciplinary, step-up approach with minimally invasive or endoscopic access for necrosectomy is widely accepted nowadays for management of pancreatic necrosis. PMID- 25516857 TI - Role of MGMT as biomarker in colorectal cancer. AB - O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation plays an important role in colorectal carcinogenesis, occurring in about 30%-40% of metastatic colorectal cancer. Its prognostic role has not been defined yet, but loss of expression of MGMT, which is secondary to gene promoter methylation, results in an interesting high response to alkylating agents such as dacarbazine and temozolomide. In a phase 2 study on heavily pre-treated patients with MGMT methylated metastatic colorectal cancer, temozolomide achieved about 30% of disease control rate. Activating mutations of RAS or BRAF genes as well as mismatch repair deficiency may represent mechanisms of resistance to alkylating agents, but a dose-dense schedule of temozolomide may potentially restore sensitivity in RAS-mutant patients. Further development of temozolomide in MGMT methylated colorectal cancer includes investigation of synergic combinations with other agents such as fluoropyrimidines and research for additional biomarkers, in order to better define the role of temozolomide in the treatment of individual patients. PMID- 25516859 TI - Large bowel injuries during gynecological laparoscopy. AB - Laparoscopy is one of the most frequently preferred surgical options in gynecological surgery and has advantages over laparotomy, including smaller surgical scars, faster recovery, less pain and earlier return of bowel functions. Generally, it is also accepted as safe and effective and patients tolerate it well. However, it is still an intra-abdominal procedure and has the similar potential risks of laparotomy, including injury of a vital structure, bleeding and infection. Besides the well-known risks of open surgery, laparoscopy also has its own unique risks related to abdominal access methods, pneumoperitoneum created to provide adequate operative space and the energy modalities used during the procedures. Bowel, bladder or major blood vessel injuries and passage of gas into the intravascular space may result from laparoscopic surgical technique. In addition, the risks of aspiration, respiratory dysfunction and cardiovascular dysfunction increase during laparoscopy. Large bowel injuries during laparoscopy are serious complications because 50% of bowel injuries and 60% of visceral injuries are undiagnosed at the time of primary surgery. A missed or delayed diagnosis increases the risk of bowel perforation and consequently sepsis and even death. In this paper, we aim to focus on large bowel injuries that happen during gynecological laparoscopy and review their diagnostic and management options. PMID- 25516860 TI - Aetiology of idiopathic granulomatous mastitis. AB - Idiopathic granulomatous mastitis is a rare chronic inflammatory lesion of the breast that can clinically and radiographically mimic breast carcinoma. The most common clinical presentation is an unilateral, discrete breast mass, nipple retraction and even a sinus formation often associated with an inflammation of the overlying skin. The etiology of idiopathic granulomatous mastitis is still obscure. Its treatment remains controversial. The cause may be the autoimmune process, infection, a chemical reaction associated with oral contraceptive pills, or even lactation. Various factors, including hormonal imbalance, autoimmunity, unknown microbiological agents, smoking and alpha 1-antitrypsin deficiency have been suggested to play a role in disease aetiology. In this review, causing factors in the aetiology of idiopathic granulomatous mastitis are reviewed in detail. PMID- 25516853 TI - Antimicrobial resistance in Acinetobacter baumannii: From bench to bedside. AB - Acinetobacter baumannii (A. baumannii) is undoubtedly one of the most successful pathogens in the modern healthcare system. With invasive procedures, antibiotic use and immunocompromised hosts increasing in recent years, A. baumannii has become endemic in hospitals due to its versatile genetic machinery, which allows it to quickly evolve resistance factors, and to its remarkable ability to tolerate harsh environments. Infections and outbreaks caused by multidrug resistant A. baumannii (MDRAB) are prevalent and have been reported worldwide over the past twenty or more years. To address this problem effectively, knowledge of species identification, typing methods, clinical manifestations, risk factors, and virulence factors is essential. The global epidemiology of MDRAB is monitored by persistent surveillance programs. Because few effective antibiotics are available, clinicians often face serious challenges when treating patients with MDRAB. Therefore, a deep understanding of the resistance mechanisms used by MDRAB can shed light on two possible strategies to combat the dissemination of antimicrobial resistance: stringent infection control and antibiotic treatments, of which colistin-based combination therapy is the mainstream strategy. However, due to the current unsatisfying therapeutic outcomes, there is a great need to develop and evaluate the efficacy of new antibiotics and to understand the role of other potential alternatives, such as antimicrobial peptides, in the treatment of MDRAB infections. PMID- 25516861 TI - Role of immunotherapy in the treatment of allergic asthma. AB - Allergen-specific immunotherapy (SIT) induces clinical and immunological tolerance as defined by persistence of clinical benefit and associated long-term immunological parameters after cessation of treatment. Although the efficacy of SIT has been shown in terms of reducing symptoms, medication consumption and ameliorating quality of life in both allergic rhinitis and asthma, there has long been some controversies about effectiveness of SIT in the treatment of allergic asthma. The type of allergen, the dose and protocol of immunotherapy, patient selection criteria, the severity and control of asthma, all are significant contributors to the power of efficacy in allergic asthma. The initiation of SIT in allergic asthma should be considered in case of coexisting of other allergic diseases such as allergic rhinitis, unacceptable adverse effects of medications, patient's preference to avoid long-term pharmacotherapy. Steroid sparing effect of SIT in allergic asthma is also an important benefit particularly in patients who have to use these drugs in high doses for a long-time. Symptomatic asthma is a risk factor for systemic reactions and asthma should be controlled at the time of administration of SIT. Both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) have been found to be effective in patients with allergic asthma. Although the safety profile of SLIT seems to be better than SCIT, the results of some studies and meta-analyses suggest that the efficacy of SCIT may appear better and earlier than SLIT in children with allergic asthma. PMID- 25516862 TI - Precancerous lesions of oral mucosa. AB - Precancerous lesions of oral mucosa, known as potentially malignant disorders in recent years, are consists of a group of diseases, which should be diagnosed in the early stage. Oral leukoplakia, oral submucous fibrosis, and oral erythroplakia are the most common oral mucosal diseases that have a very high malignant transformation rate. Oral lichen planus is one of the potentially malignant disorders that may be seen in six different subtypes including papular, reticular, plaque-like, atrophic, erosive, and bullous type, clinically. Atrophic and erosive subtypes have the greater increased malignant transformation risk compared to another subtypes. Although there are various etiological studies, the etiology of almost all these diseases is not fully understood. Geographically, etiologic factors may vary. The most frequently reported possible factors are tobacco use, alcohol drinking, chewing of betel quid containing areca nut, and solar rays. Early diagnosis is very important and can be lifesaving, because in late stages, they may be progressed to severe dysplasia and even carcinoma in situ and/or squamous cell carcinoma. For most diseases, treatment results are not satisfactory in spite of miscellaneous therapies. While at the forefront of surgical intervention, topical and systemic treatment alternatives such as corticosteroids, calcineurin inhibitors, and retinoids are widely used. PMID- 25516863 TI - Eosinophilic chronic rhinosinusitis in East Asians. AB - Chronic rhinosinusitis (CRS) is a common disease worldwide, with a prevalence rate of 5%-15% in the general population. CRS is currently classified into two types: CRS with and without nasal polyps. CRS may also be divided into eosinophilic CRS (ECRS) and non-ECRS subtypes based on the presence of tissue eosinophilic infiltration or not. There are significant geographic and ethnic differences in the tissue eosinophilic infiltration, which is predominant in Western white patients and less common in East Asians, despite an increasing tendency for its prevalence in East Asia countries. ECRS differs significantly from non-ECRS in clinical characteristics, treatment outcomes and strategies, and underlying pathogenic mechanisms. ECRS commonly demonstrates more severe symptoms, polyp diseases with a higher incidence of bilateral polyps and sinonasal diseases on computed tomography, and the increase in blood eosinophils. ECRS is considered a special and recalcitrant subtype of CRS, commonly with poor treatment outcomes compared to non-ECRS. The differentiation of specific subtypes and clinical features of CRS will be important for developing novel treatment strategies and improving treatment outcomes for individual phenotypes of CRS. This review discusses clinical features, diagnosis, treatment and prognosis of ECRS in East Asians. PMID- 25516864 TI - Spectrum of magnetic resonance imaging findings in congenital lumbar spinal stenosis. AB - AIM: To investigate whether congenital lumbar spinal stenosis (CLSS) is associated with a specific degenerative changes of the lumbar spine. METHODS: The lumbar spine magnetic resonance imaging studies of 52 subjects with CLSS and 48 control subjects were retrospectively evaluated. In each examination, the five lumbar levels were assessed for the presence or absence of circumferential or shallow annular bulges, annular tears, anterior or posterior disc herniations, epidural lipomatosis, Schmorl's nodes, spondylolisthesis, pars defects, and stress reactions of the posterior vertebral elements. RESULTS: Compared to control individuals, subjects with CLSS exhibited increased incidence of circumferential and shallow annular bulges, annular tears, disc herniations and spondylolisthesis (P < 0.05). CONCLUSION: CLSS is associated with increased incidence of degenerative changes in specific osseous and soft-tissue elements of the lumbar spine. PMID- 25516865 TI - Appendiceal Crohn's disease clinically presenting as acute appendicitis. AB - AIM: To determine the incidence of appendiceal Crohn's disease (CD) and to summarize the characteristic histologic features of appendiceal CD. METHODS: We reviewed the pathology files of 2179 appendectomy specimens from January 2007 to May 2013. The computer-assisted retrieval search facility was utilized to collect specimens. We selected those cases that were diagnosed as CD or chronic granulomatous inflammation and defined the final diagnosis according to the histologic findings of CD, including transmural lymphocytic inflammation, non caseating epithelioid granulomas, thickening of the appendiceal wall secondary to hypertrophy of muscularis mucosa, mucosal ulceration with crypt abscesses, mucosal fissures, and fistula formation. RESULTS: We found 12 cases (7 male and 5 female patients, with an average age of 29.8 years) of appendiceal CD. The incidence of appendiceal CD was 0.55%. The chief complaints were right lower quadrant pain, abdominal pain, lower abdominal pain, and diarrhea. The duration of symptom varied from 2 d to 5 mo. The histologic review revealed appendiceal wall thickening in 11 cases (92%), transmural inflammation in all cases (100%), lymphoid aggregates in all cases (100%), epithelioid granulomas in all cases (100%), mucosal ulceration in 11 cases (92%), crypt abscesses in 5 cases (42%), perforation in 2 cases (17%), muscular hypertrophy in 1 case (8%), neural hyperplasia in 5 cases (42%), and perpendicular serosal fibrosis in 8 cases (67%). CONCLUSION: A typical and protracted clinical course, unusual gross features of the appendix and the characteristic histologic features are a clue in the diagnosis of appendiceal CD. PMID- 25516866 TI - Tranexamic acid for the management of uterine fibroid tumors: A systematic review of the current evidence. AB - AIM: To conduct a detailed systematic review of the current evidence on the administration and efficacy of tranexamic acid in patients with menorrhagia due to uterine fibroids. METHODS: We conducted an electronic search on the following databases PubMed and Medline (1950-2013); (1980-2013); Cochrane library (1993 2013). RESULTS: A total of 36 articles were retrieved after the initial electronic search. Careful assessment of the retrieved studies led to the final selection of 5 articles for inclusion in the review. CONCLUSION: Tranexamic acid may reduce blood loss perioperatively in myomectomies. It may reduce the menorrhagia in patients with fibroids, however a stratification of fibroids by size and location is required to define the responses. It is safe in general, with mild adverse effects observed in some cases. More studies with a double blind randomized design and larger numbers of participants are necessary to reach more precise and safe conclusions. PMID- 25516867 TI - Reconstruction using a pedicled upper arm fillet flap after excision of a malignant peripheral nerve sheath tumor: A case report. AB - Non-salvageable extremities have been utilized for harvesting fillet flaps as part of the "spare parts" concept in traumatic and oncologic settings. Here we report on the use of a pedicled fillet flap of the upper arm for chest wall reconstruction after excision of a malignant peripheral nerve sheath tumor in a patient with neurofibromatosis. Pedicled flaps as part of the "spare parts" concept provide the advantage of reduced donor-site morbidity, immediate closure, intact vasculature, and adequate soft tissue coverage of large defects. Malignant peripheral nerve sheath tumor is a rare aggressive tumor with a poor prognosis that may result in large defects post resection. Limited data describes the use of pedicled fillet flaps of the upper extremity. We report the use of a pedicled fillet flap of the upper arm as a viable option that can be successfully used for coverage of soft tissue defects of the shoulder and chest wall post complex resections in an oncologic setting. PMID- 25516868 TI - Cecal bascule herniation into the lesser sac. AB - Cecal bascule is a rare cause of bowel obstruction in which a mobile cecum folds anteriorly and superiorly over the ascending colon. Herein, we present the first case of internal herniation of a cecal bascule into the lesser sac through the foramen of winslow, aiming at discussing radiological findings, differential diagnosis, and surgical management of this uncommon condition. A 75-year-old female presented to the emergency room with an 18-h history of sudden onset sharp, progressively worsening abdominal pain associated with vomiting. Physical exam revealed abdominal distention and epigastric tenderness while initial laboratory tests were unremarkable. Computed tomography of her abdomen and pelvis showed a loop of distended colon within lesser sac without signs of bowel ischemia or perforation. On exploratory laparotomy, a cecal bascule was found herniating into lesser sac via foramen of winslow. Upon reduction, the cecum appeared viable therefore a cecopexy was performed without bowel resection. Unlike cecal volvulus, cecal bascule consists of no axial rotation of the bowel with no mesenteric vascular compromise and therefore ischemia would only occur from intraluminal tension or extraluminal compression from the borders of foramen of winslow. The management of internal herniation of a cecal bascule is always surgical including anatomic resection or cecopexy. PMID- 25516869 TI - Tentorial dural arteriovenous fistula presenting as myelopathy: Case series and review of literature. AB - Dural arteriovenous fistula (DAVF) is a rare type of cerebral arteriovenous malformation. Common presenting symptoms are related to hemorrhage. However, rarely these patients may present with myelopathy. We present two cases of DAVF presenting as rapidly progressive myelopathy. Two treatment options are available: microsurgical interruption of the fistula and endovascular embolization. These treatment options of DAVFs have improved significantly in the last decade. The optimal treatment of DAVFs remains controversial, and there is an ongoing debate as to whether primary endovascular or primary microsurgical treatment is the optimal management for these lesions. However, despite treatment a high percentage of patients are still left with severe disability. The potential for functional ambulation in patients with DAVF is related to the time of intervention. This emphasizes the important of early diagnosis and early intervention in DAVF. The eventual outcome may depend on several factors, such as the duration of symptoms, the degree of disability before treatment, and the success of the initial procedure to close the fistula. The usage of magnetic resonance imaging and selective angiography has significantly improved the ability to characterize DAVFs, however, these lesions remain inefficiently diagnosed. If intervention is delayed even prolonged time in rehabilitation does not change the grave prognosis. This review outlines the presentation, classication and management of DAVF as well as discussing patient outcomes. PMID- 25516870 TI - Relapsing polychondritis with p-ANCA associated vasculitis: Which triggers the other? AB - Relapsing polychondritis (RP) is a rare autoimmune disease with chronic inflammatory/destructive lesions of the cartilaginous tissues. In one third of the cases it is associated with other autoimmune disorders, mostly with anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). We report three cases of RP with p-ANCA positive AAV. In the first patient RP developed 1.5 years after the onset of AAV. In the others the signs of RP were present before the onset of severe crescent glomerulonephritis. Patients responded well on steroid and cyclophosphamide. In dialysis dependent cases plasmapheresis was also used successfully. During the 2 and 1.5 years of follow up, they were symptom free, and had stable glomerular filtration rate. The first patient died after four years of follow-up due to the complications of sudden unset pancytopenia, which raises the possibility of associated hemophagocytic syndrome. In the setting of RP or AAV physicians should always be aware of the possibility of sudden or insidious appearance of the other disease. PMID- 25516872 TI - Rare entity: Ectopic liver tissue in the wall of the gallbladder - A case report. AB - Ectopic liver tissue (ELT) is a rare condition, which is usually not diagnosed preoperatively, but coincidentally during abdominal surgery. While the location of ELT can vary, it is usually localized on the gallbladder wall or in close proximity. ELT is associated with various complications, a major complication being extrahepatic hepatocellular carcinoma. A 59-year-old female underwent elective surgery for chronic cholecystitis with stones. During laparoscopic exploration, a 2-cm-diameter ELT was detected in the anterior gallbladder wall and a laparoscopic cholecystectomy was performed. The case is presented due to the rare nature of ELT and as a reminder of ELT-related complications. PMID- 25516871 TI - Gastric trichobezoar associated with perforated peptic ulcer and Candida glabrata infection. AB - Bezoars are accumulations of human or plant fiber located in the gastrointestinal tract of both humans and animals. Patients remain asymptomatic for several years, and the symptoms develop as these accumulations increase in size to the point of obstruction or perforation. We report the case of a 21-year-old patient at 10 d postpartum, who presented with acute abdomen associated with sepsis. Given the urgency of the clinical picture, at no point was the presence of a giant bezoar at gastric level suspected, specifically a trichobezoar. The emergency abdominal and pelvic ultrasound revealed only unspecific signs of perforated hollow viscus. Diagnosis was therefore made intraoperatively. A complete gastric trichobezoar was found with gastric perforation and secondary peritonitis. The peritoneal fluid culture revealed Candida glabrata. PMID- 25516873 TI - Rare multiple fistulas with large saccular aneurysms originating from left anterior descending artery and left main coronary artery. AB - A 49-year-old female patient consulted us for a cardiac evaluation before undergoing colon adenocarcinoma surgery. Three years prior, the patient underwent coronary angiography for dyspnea. The coronary angiography examination revealed a fistula originating from the left anterior descending artery and left main coronary artery, which had soft aneurysmal sacs and most likely drained into the pulmonary artery. Parasternal short axis echocardiography revealed a color flow that could be related to the fistula, but the other echocardiographic findings were normal. The patient did not accept the proposed examination and invasive treatment. PMID- 25516874 TI - Case of cannabinoid hyperemesis syndrome with long-term follow-up. AB - Long-term cannabis use may be associated with attacks of severe nausea and vomiting, and a characteristic learned behavior of compulsive hot bathing, termed cannabinoid hyperemesis syndrome (CHS). Long-term follow-up and prognosis of CHS have not been reported previously. A 44-year-old Caucasian man with a long history of addiction to marijuana presented with chronic abdominal pain complicated by attacks of uncontrollable vomiting for 16 years. He had a compulsion to take scalding hot showers, as many as 15 times a day, to relieve his symptoms. All previous therapies had been ineffective. However, abstinence from marijuana led to rapid and complete resolution of all symptoms and his compulsive hot showering behavior. He has been followed for nine years, and is still doing well without recurrence of symptoms. Physicians should have a high index of suspicion for this under-recognized condition, as excellent long-term prognosis of CHS can be achieved when abstinence is maintained. PMID- 25516875 TI - Scalp block for brain abscess drainage in a patient with uncorrected tetralogy of Fallot. AB - We report a case of an 11-year-old boy with diagnosed but uncorrected tetralogy of Fallot presented to us for brain abscess drainage. The child was managed successfully with scalp block with sedation. PMID- 25516876 TI - Complete oral rehabilitation in a case with severe dental fluorosis. AB - The authors have presented a technique of full occlusal rehabilitation in a case of severe dental fluorosis. In this technique, maxillary and mandibular anterior teeth were simultaneously prepared and restored first. This was followed by simultaneous preparation of maxillary and mandibular posterior teeth that were restored in canine guided occlusion. The technique and sequence followed here is unique and is not available in dental literature. This technique reduces number of appointments while fulfilling all objectives. Periodontal follow-up over 3 years was satisfactory. A restorative treatment protocol has been devised for fluorosis which will act as a guide for the dental practitioners. PMID- 25516878 TI - Selective infiltrated etching to surface treat zirconia using a modified glass agent. AB - PURPOSE: The surface roughness of zirconia specimens and the bond strength of zirconia and resin cements were evaluated after selective infiltrated etching (SIE) surface treatment using a modified glass agent. MATERIALS AND METHODS: One hundred twenty zirconia specimens were divided into four groups according to surface treatment method: untreated control (C), airborne particle abrasion (A), airborne particle abrasion followed by SIE treatment using a modified glass agent (A-SIE), and SIE treatment using a modified glass agent without airborne particle abrasion (SIE). The surface morphology and roughness of the specimens were examined before and after treatment using scanning electron and atomic force microscopy. The specimens were then cemented to resin blocks with a 4-META resin luting system (Superbond C&B). The shear bond strength of the zirconia/ resin interface was measured before and after thermocycling and fatigue testing. RESULTS: The surface roughness and shear bond strength values of the SIE group were higher than those of the other three zirconia groups. The surface roughness (Ra) values were 8.10, 8.34, 9.42, and 12.42 MUm for the C, A, A-SIE, and SIE groups, respectively, with significant differences between SIE and the C and A groups (p<0.05). The shear bond strength values before thermocycling and fatigue testing were 23.37, 23.38, 25.82, and 28.67 MPa for the C, A, A-SIE, and SIE groups, respectively. These values did not decrease after 10,000 cycles of thermocycling for the surface-treated groups, but did decrease for the untreated control group (C). CONCLUSION: SIE treatment using a modified glass agent can increase surface roughness and the bond strength between zirconia and resin cements. The shear bond strength did not decrease after thermocycling and fatigue testing. PMID- 25516877 TI - In vitro acaricidal activity of Atropa belladonna and its components, scopolamine and atropine, against Rhipicephalus (Boophilus) microplus. AB - In vitro efficacy of methanolic extract of Atropa belladonna and its components scopolamine and atropine was assessed against Rhipicephalus (Boophilus) microplus. Five concentrations of the extract (1.25%, 2.5%, 5%, 10%, and 20%) were used whereas scopolamine and atropine were each tested at 0.1%. In adult immersion test, the extract was lethal to ticks at 20% concentration. The LC50 and LC95 values were determined as 6.875% and 17.306%, respectively. The extract caused a significant reduction (P < 0.05) in egg mass production at 10% concentration. In larval packet test, the extract was lethal to larvae in the concentrations of 10% and 20% after 24 h, with LC50 and LC95 values of 1.321% and 4.935%, respectively. Scopolamine and atropine showed 93.3% and 60.0% mortality of adult ticks, respectively, but they caused complete (100%) blocking of hatching as well as 100% larval mortality. Scopolamine and atropine were observed to be more potent than the crude extract at an equivalent concentration in both the bioassays. PMID- 25516879 TI - Two-year clinical performance of dimethacrylatebased composite restorations repaired with a silorane-based composite. AB - PURPOSE: To investigate the clinical performance of a silorane-based composite resin used for repairing dimethacrylate- based composite restorations. MATERIALS AND METHODS: One operator repaired defective dimethacrylate-based resin restorations that were randomly assigned to one of two treatment groups: control (n=50), repaired with Adper SE Plus and Filtek P60 Posterior Restorative (3M ESPE); or test (n=50), repaired with P90 System Adhesive Self-Etch Primer and Bond and Filtek P90 Low Shrink Posterior Restorative (3M ESPE). After 1 week, restorations were finished and polished. Two calibrated examiners (weighted Kappa>=0.78) evaluated the repaired restorations, blindly and independently, at baseline, after 6 months, 1 and 2 years. The parameters examined were marginal adaptation, anatomic form, surface roughness, marginal discoloration, postoperative sensitivity, and secondary caries. The restorations were classified as Alfa, Bravo, or Charlie, according to modified US Public Health Service criteria. Variation in the levels of clinical parameters over time was evaluated by Friedman's ANOVA (alpha=0.05). The Mann-Whitney test assessed the differences between the materials for all clinical criteria at baseline, 6-month, 1- and 2 year recalls (alpha=0.05). The Wilcoxon test compared each composite resin for all clinical criteria at the same recalls (alpha=0.05). RESULTS: After two years, 79 repaired restorations were re-examined. No statistically significant differences were found between the materials at baseline or at the 2-year recall (p>0.05). Comparing baseline and 2-year recall, there was a statistically significant difference for marginal discoloration (p=0.029) in silorane-based composite restorations. CONCLUSION: After two years, the clinical performance of the silorane-based composite was similar to that of the dimethacrylate-based composite when used to make repairs. PMID- 25516881 TI - Bond strength of novel CAD/CAM restorative materials to self-adhesive resin cement: the effect of surface treatments. AB - PURPOSE: To evaluate the effect of different surface treatments on the microtensile bond strength (MUTBS) of novel CAD/CAM restorative materials to self adhesive resin cement. MATERIALS AND METHODS: Two types of CAD/CAM restorative materials (Vita Enamic [VE] and Lava Ultimate [LU]) were used. The specimens were divided into five groups in each test according to the surface treatment performed; Gr 1 (control; no treatment), Gr 2 (sandblasted [SB]), Gr 3 (SB+silane [S]), Gr 4 (hydrofluoric acid [HF]), and Gr 5 (HF+S). A dual-curing self-adhesive resin cement (Bifix SE [BF]) was applied to each group for testing the adhesion after 24 h of storage in distilled water or after 30 days using the MUTBS test. Following fracture testing, specimens were examined with a stereomicroscope and SEM. Surface roughness and morphology of the CAD/CAM restorative materials were characterized after treatment. Data were analyzed using ANOVA and Tukey's test. RESULTS: The surface treatment, type of CAD/CAM restorative material, and water storage periods showed a significant effect on the MUTBS (p<0.001). For the LU/BF system, there was no significant difference in the bond strength values between different surface treatments (p>0.05). On the other hand, for the VE/BF system, surface treatment with HF+S showed higher bond strength values compared with SB and HF surface treatments (p<0.05). Surface roughness and SEM analyses showed that the surface topography of CAD/CAM restorative materials was modified after treatments. CONCLUSION: The effect of surface treatments on the bond strength of novel CAD/CAM restorative materials to resin cement is material dependent. The VE/BF CAD/CAM material provided higher bond strength values compared with the LU/BF CAD/CAM material. PMID- 25516880 TI - Durability of fiber post-to-composite bonds achieved by physical vapor deposition and tribochemical silica coating. AB - PURPOSE: To evaluate post-to-composite bonds in terms of their durability, achieved either by physical vapor deposition (PVD) or tribochemical silica coating (TSC) compared to coupling strategies for fiber posts at chairside. MATERIALS AND METHODS: Thirty uncoated fiber posts (DT Light) each were either left untreated (control) or silanized with a one-bottle (Monobond Plus) or a two bottle (Clearfil SE Bond/Porcelain Bond Activator) silane at the chairside. Thirty coated fiber posts each had already been silica coated and silanized by the manufacturer using PVD (DT Light SL) or TSC (DentinPost Coated) deposition techniques. Surface analysis was carried out by profilometry and x-ray microanalysis. All the posts were surrounded by 2-mm-thick disks of a dual-curing composite resin (MultiCore Flow). After water storage for 24 h at 37 degrees C, the specimens in each group were randomly divided into three subgroups (n=10) and subjected to 0, 1500, and 20,000 thermocycles (5 degrees C to 55 degrees C) prior to push-out testing. Failure modes were evaluated by optical and scanning electron microscopy. The statistical significance was determined with two-way ANOVA, the Student-Newman-Keuls test, and Fisher's exact test. RESULTS: The conditioned posts had significantly higher interfacial bond strengths than the control posts after thermocycling (p<0.05). Extended thermocycling significantly reduced the interfacial strength of chairside silanized posts (p<0.05). This effect was not significant with industrially coated posts (p>0.05). Coatings deposited by TSC reached the highest bond values (p<0.05) and showed predominantly adhesive failures in the form of coating delamination (p<0.0001). In contrast, the other coupling strategies showed significantly lower values and adhesive failures between the post and the composite. CONCLUSION: PVD and TSC techniques enhanced the bond durability of fiber posts. TSC led to a superior post-tocomposite bond, probably based on more effective micromechanical adhesion due to the higher surface roughness. PMID- 25516882 TI - Bond strength and monomer conversion of indirect composite resin restorations, Part 1: Light vs heat polymerization. AB - PURPOSE: To assess the resin microtensile bond strength (MTBS) and the monomer conversion (MC) of indirect composite resin restorations made of three different materials. MATERIALS AND METHODS: Two light-polymerized direct materials (Filtek Z100 and Premise) and one light- and heat-polymerized indirect material (Premise Indirect) were used. For MTBS testing, 42 cylindrical samples were fabricated (7 pairs per material). Surface conditioning included airborne-particle abrasion, cleaning, and application of a silane. Cylinders were bonded to each other using adhesive resin (Optibond FL). Specimens were stored in water for 24 h. Another 15 cylinders (5 per material) were fabricated for MC measurements (FT-IR) immediately and at 24 h. The MTBS data were submitted to one-way ANOVA and the MC to two-way ANOVA (material and storage time) (alpha=0.05), followed by post-hoc comparisons with the Tukey test. RESULTS: The MTBS to Z100 was 72.2 MPa, significantly higher than that to Premise (48.4 MPa) and Premise Indirect (52.7 MPa). The immediate MC was similar for all materials (range 51% to 56%) and significantly increased at 24 h (range 57% to 66%), except for Z100. Premise Indirect showed the highest MC (66% at 24 h). CONCLUSION: Z100 showed better "bondability" than Premise and Premise Indirect. Premise Indirect, with its heat initiator, did not present a higher MC. PMID- 25516883 TI - Effect of a two-step placement procedure on the dislocation resistance of a methacrylate resin-based root canal sealer: a proof of concept. AB - PURPOSE: To investigate whether the placement of a methacrylate root canal sealer or a conventional epoxy root canal sealer in two steps increases their dislocation resistance when compared to a one-step placement procedure. MATERIALS AND METHODS: Eighty single-rooted teeth were randomly allocated to 4 groups (n=20). All canals were instrumented to size 40, 0.06 taper and irrigated according to a standardized protocol. Root canal filling was conducted as follows: group 1: methacrylate sealer placed in two steps; group 2: methacrylate sealer placed in one step; group 3: epoxy sealer placed in two steps; group 4: epoxy sealer placed in one step. After setting, thin slices at different root levels were obtained and submitted to push-out testing. RESULTS were analyzed with non-parametric tests to compare the two-step procedures to their one-step counterparts. Failure modes were determined by stereomicroscopy. Random untested methacrylate sealer specimens were also examined with scanning electron microscopy. RESULTS: At each root level, dislocation resistance was significantly higher for the two-step procedure than for the one-step procedure using the methacrylate sealer (p=0.003, p=0.005, p<0.001) but not the epoxy sealer (p=0.83, p=0.1, p=0.06). Among root levels, there were no significant differences in dislocation resistance in the methacrylate sealer two-step group, while all other groups showed differences. CONCLUSION: A two-step placement procedure resulted in significantly higher dislocation resistance for the methacrylate sealer but not for the epoxy sealer. PMID- 25516884 TI - Self-adhesive resin cements: adhesive performance to indirect restorative ceramics. AB - PURPOSE: To evaluate the bonding performance of self-adhesive resin cements to zirconia and lithium disilicate in self- and dual-curing modes before and after thermocycling. MATERIALS AND METHODS: Rectangular bars (3 mm high, 3 mm wide, 9 mm long) were manufactured from zirconia (Vita In-Ceram YZ for inLab, VITA) and lithium disilicate blocks (IPS e.max Press, Ivoclar Vivadent) (n=240 per material). Zirconia bars were sandblasted (35 MUm Al2O3, 1.5 bar pressure). Lithium disilicate bars were HF etched (20 s, IPS Ceramic Etching Gel, Ivoclar Vivadent) and silanized with ESPE Sil (3M ESPE). Forty bars of zirconia were luted in twos perpendicular to each other as were 40 bars of lithium disilicate using RelyX Unicem Automix 2 (3M ESPE), G-Cem LinkAce (GC Europe) or Maxcem Elite (Kerr) in self- or dual-curing mode. Half of the specimens from each material were submitted to tensile bond strength (TBS) testing after 24-h storage in distilled water at 37 degrees C, and half underwent TBS testing after thermocycling (5000 cycles, 5 degrees C/55 degrees C, 30-s dwell time). Bond strength values for each bonding substrate were analyzed using one-way ANOVA (Student-Newman- Keuls, alpha=0.05). RESULTS: On zirconia, dual-curing resulted in significantly (p<0.05) higher tensile bond strengths compared to self-curing, with the exception of RelyX Unicem 2 after thermocycling. Thermocycling significantly (p<0.05) reduced the tensile bond strength of Maxcem Elite to zirconia in both curing modes. The TBS of self-adhesive cements to lithium disilicate showed no significant (p>0.05) difference between the different curing modes and after thermocycling. CONCLUSION: For most of the investigated self adhesive cements, bond strengths to zirconia were increased by dual curing; this was not true for lithium disilicate. For luting on zirconia with self-adhesive cements, dual curing is strongly recommended in clinical situations. PMID- 25516885 TI - A randomized 10-year prospective follow-up of Class II nanohybrid and conventional hybrid resin composite restorations. AB - PURPOSE: To evaluate the 10-year durability of a nanohybrid resin composite in Class II restorations in a randomized controlled intraindividual comparison with its conventional hybrid resin composite predecessor. MATERIALS AND METHODS: Each of 52 participants received at least two Class II restorations that were as similar as possible. The cavities were chosen at random to be restored with a nanohybrid resin composite (Excite/Tetric EvoCeram (TEC); n=61) and a conventional hybrid (Excite/Tetric Ceram (TC); n=61). The restorations were evaluated with slightly modified USPHS criteria at baseline and then annually for 10 years. The overall performance of the experimental restorations was tested after intra-individual comparison and their ranking was tested using Friedman's two-way ANOVA. The level of significance was set at 5%. RESULTS: Four patient drop-outs with 8 restorations (4TEC, 4TC) were registered during the follow-up. A prediction of the caries risk showed that 16 of the evaluated 52 patients were considered as high risk patients. In total, 22 restorations, 11 TEC (3 premolars, 8 molars) and 11 TC (3 premolars, 8 molars) restorations failed during the 10 years. The main reason for failure was secondary caries (50%). 63% of the recurrent caries lesions were found in high caries risk participants. The overall success rate at 10 years was 80.7%, with an annual failure rate of 1.9%. No statistically significant difference was found in the overall survival rate between the two investigated resin composites. CONCLUSION: The nanohybrid and the conventional hybrid resin composite showed good clinical effectiveness in extensive Class II restorations during the 10-year study. PMID- 25516886 TI - Microtensile bond strength of lithium disilicate ceramics to resin adhesives. AB - PURPOSE: To evaluate the influence of the internal structure of lithium disilicate glass ceramics (LDC) on the microtensile bond strength to a resin adhesive using two surface treatments. MATERIALS AND METHODS: Milling blocks of three types of LDC were sectioned (4 mm thick) using a precision cutting machine: IPS Empress 2 (conventional LDC), IPSe.max CAD (a refined crystal high strength LDC), and Celtra (zirconia reinforced LDC). Cut specimens received crystallization heat treatment as suggested by the manufacturers. Two surface treatments were performed on each group: hydrofluoric acid etching (HF) and airborne particle abrasion using 50-MUm glass beads, while the as-cut surface served as control. Treated surfaces were examined using scanning electron microscopy (SEM). The disks were coated with a silane primer and bonded to pre aged resin composite disks (Tetric EvoCeram) using a resin adhesive (Variolink II) and then stored in water for 3 months. Bonded specimens were sectioned into micro-bars (1x1x6 mm) and microtensile bond strength test (MTBS) was performed. Data were analyzed using two-way ANOVA and Tukey's post-hoc test (alpha=0.05). RESULTS: Statistical analysis revealed significant differences in microtensile bond strength values between different LDCs (F=67, p<0.001), different surface treatments (F=232, p<0.001), and interaction between LDC and surface treatments (F=10.6, p<0.001). Microtensile bond strength of Celtra ceramic (30.4+/-4.6 MPa) was significantly higher than both IPS Empress 2 (21.5+/-5.9 MPa) and IPSe.max ceramics (25.8+/-4.8 MPa), which had almost comparable MTBS values. SEM images demonstrated homogenous glassy matrix and reinforcing zirconia fillers characteristic of Celtra ceramic. Heat treatment resulted in growth and maturation of lithium disilicate crystals. Particle abrasion resulted in abrasion of the glass matrix and exposure of lithium disilicate crystals, while HF etching produced a microrough surface, which resulted in higher MTBS values and reduction in the percentage of adhesive failure for all groups. CONCLUSIONS: Within the limitations of this study, bond strength to lithium disilicate ceramics depends on proper surface treatment and on the chemical composition of the glass ceramic. PMID- 25516887 TI - Effect of chemomechanical caries removal on bonding of self-etching adhesives to caries-affected dentin. AB - PURPOSE: To evaluate the effect of enzyme-based (Papacarie) and sodium hypochlorite-based (Carisolv) chemomechanical caries removal methods on bonding of self-etching adhesives to caries-affected dentin, in comparison to the standard rotary-instrument caries removal method. MATERIALS AND METHODS: Seventy eight carious permanent molars exhibiting frank cavitation into dentin were used. Forty-eight teeth were randomly divided into three groups, according to the caries excavation methods: (i) Papacarie, (ii) Carisolv and (iii) a round steel bur. After caries removal, each group was subdivided into two groups for two-step (Clearfil SE Bond) or one-step (Clearfil S3 Bond) self-etching adhesive application and resin composite buildups. Bonded specimens were sectioned into beams for microtensile bond strength testing. Bond strength data were analyzed using three-way ANOVA and Tukey's test. For interfacial nanoleakage evaluation using a field-emission scanning electron microscope, caries was similarly removed from the remaining thirty carious molars, bonding was performed as for bond strength testing, and the teeth were sectioned. RESULTS: RESULTS of three-way ANOVA revealed that bond strength was significantly affected by "adhesive" (p<0.001) and "dentin" (p<0.001), but not "caries excavation methods" (p>0.05). The bond strength of the two-step self-etching adhesive was significantly higher than that of the one-step self-etching adhesive (p<0.001). Conversely, the bond strength of self-etching adhesives to sound dentin was significantly higher than to residual caries-affected dentin (p<0.001). Greater silver penetration was observed in the bonded interfaces of residual caries-affected dentin and in interfaces bonded with the one-step self-etching adhesive vs those bonded with the two-step self-etching adhesive. CONCLUSION: Chemomechanical caries removal did not affect the bonding of self-etching adhesives to caries-affected dentin as compared to caries excavation with rotary instruments. PMID- 25516888 TI - Epithelial-mesenchymal transitioned circulating tumor cells capture for detecting tumor progression. AB - PURPOSE: This study aimed to detect cell-surface vimentin (CSV) on the surface of epithelial-mesenchymal transitioned (EMT) circulating tumor cells (CTC) from blood of patients with epithelial cancers. EXPERIMENTAL DESIGN: In this study, 101 patients undergoing postsurgery adjuvant chemotherapy for metastatic colon cancer were recruited. EMT CTCs were detected from blood of patients using the 84 1 monoclonal antibody against CSV as a marker. EMT CTCs isolated were characterized further using EMT-specific markers, fluorescent in situ hybridization, and single-cell mutation analysis. RESULTS: Using the 84-1 antibody, we detected CSV exclusively on EMT CTCs from a variety of tumor types but not in the surrounding normal cells in the blood. The antibody exhibited very high specificity and sensitivity toward different epithelial cancer cells. With this antibody, we detected and enumerated EMT CTCs from patients. From our observations, we defined a cutoff of <5 or >=5 EMT CTCs as the optimal threshold with respect to therapeutic response using ROC curves. Using this defined threshold, the presence of >=5 EMT CTCs was associated with progressive disease, whereas patients with <5 EMT CTCs showed therapeutic response. CONCLUSION: Taken together, the number of EMT CTCs detected correlated with the therapeutic outcome of the disease. These results establish CSV as a universal marker for EMT CTCs from a wide variety of tumor types and thus provide the foundation for emerging CTC detection technologies and for studying the molecular regulation of these EMT CTCs. PMID- 25516889 TI - Recurrent PRDM10 gene fusions in undifferentiated pleomorphic sarcoma. AB - PURPOSE: Undifferentiated pleomorphic sarcoma (UPS) is defined as a sarcoma with cellular pleomorphism and no identifiable line of differentiation. It is typically a high-grade lesion with a metastatic rate of about one third. No tumor specific rearrangement has been identified, and genetic markers that could be used for treatment stratification are lacking. We performed transcriptome sequencing (RNA-Seq) to search for novel gene fusions. EXPERIMENTAL DESIGN: RNA Seq, FISH, and/or various PCR methodologies were used to search for gene fusions and rearrangements of the PRDM10 gene in 84 soft tissue sarcomas. RESULTS: Using RNA-Seq, two cases of UPS were found to display novel gene fusions, both involving the transcription factor PRDM10 as the 3' partner and either MED12 or CITED2 as the 5' partner gene. Further screening of 82 soft tissue sarcomas for rearrangements of the PRDM10 locus revealed one more UPS with a MED12/PRDM10 fusion. None of these genes has been implicated in neoplasia-associated gene fusions before. CONCLUSIONS: Our results suggest that PRDM10 fusions are present in around 5% of UPS. Although the fusion-positive cases in our series showed the same nuclear pleomorphism and lack of differentiation as other UPS, it is noteworthy that all three were morphologically low grade and that none of the patients developed metastases. Thus, PRDM10 fusion-positive sarcomas may constitute a clinically important subset of UPS. PMID- 25516891 TI - From the President. PMID- 25516892 TI - Transparency and the pharmaceutical industry. PMID- 25516890 TI - Antitumor activity in RAS-driven tumors by blocking AKT and MEK. AB - PURPOSE: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. EXPERIMENTAL DESIGN: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. RESULTS: Grade 3 rash was the most common dose limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. CONCLUSION: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). PMID- 25516893 TI - Good pharma? Bad pharma? Better pharma. PMID- 25516894 TI - Care of the dying as a paradigm for true healthcare. PMID- 25516895 TI - HIV testing in Lanarkshire. AB - INTRODUCTION: The 2008 UK National Guidelines for HIV testing were designed in order to decrease the proportion of people living with undiagnosed HIV infection. AIMS: Two audits were conducted. The aim of Audit 1 was to determine the proportion of current medical inpatients with an indicator condition that had been tested for HIV. Audit 2 aimed to identify missed opportunities for testing prior to diagnosis among newly diagnosed individuals with HIV. METHODS: Audit 1 involved a case note review looking for indicator conditions and HIV testing of all inpatients. Audit 2 analysed the hospital case notes of all new Lanarkshire HIV patients in 2010 for previous missed diagnostic opportunities. RESULTS: In Audit 1, 36% (63/174) of medical inpatients had a current indicator condition. Of the total population, 1.7% (3/174) had what would be an AIDS-defining condition if they had a positive HIV test. However, only 11% (7/63) of individuals were appropriately HIV tested. For Audit 2, 64% (9/14) of newly diagnosed individuals had previous missed opportunities for diagnosis. CONCLUSION: Increased education of clinical staff around testing guidelines is needed, as we have demonstrated that the 2008 guidelines are not being adhered to. PMID- 25516896 TI - Granulomatosis with polyangiitis and constrictive pericarditis--a case report. AB - Polyangiitis with granulomatosis, previously known as Wegener's granulomatosis, is a systemic necrotising granulomatous vasculitis. It predominantly affects the upper and lower respiratory tracts and the kidneys, but can potentially affect any organ system. It is diagnosed by clinical features, immunology (anti neutrophil cytoplasmic antibodies) and histology. Cardiac involvement occurs in 6 to 44% of cases. We present a case of polyangiitis with granulomatosis and constrictive pericarditis, which occurred despite vigorous immunosuppression and which required surgical pericardectomy. PMID- 25516897 TI - Hypercalcaemia mimicking Huntington's disease: lessons learned from delayed diagnosis. AB - Diagnosis can prove challenging when a patient with a chronic neurological disease presents with acute deterioration. This is especially true in Huntington's disease, where cognitive impairment is prominent. We present a case of hypercalcaemia causing an acute deterioration in physical and cognitive function in a patient with Huntington's disease. Similarity in clinical phenotype between hypercalcaemia and Huntington's disease, as well as failure to appreciate the acute nature of the deterioration resulted in diagnostic delay and prolonged admission. With treatment, the patient improved dramatically. The case highlights key learning points regarding assessment of patients with chronic neurological disease. PMID- 25516898 TI - Accidental awareness under general anaesthesia in the United Kingdom and Ireland. PMID- 25516899 TI - What is the best initial treatment in Parkinson's disease? PMID- 25516900 TI - Changes to clinician attire have done more harm than good. AB - The introduction of 'bare below the elbows' policies to facilitate handwashing led to the disappearance of the white coat from medical and surgical wards. While rates of key healthcare acquired infections in hospitals, e.g. Clostridium difficile and methicillin-resistant Staphylococcus aureus bacteraemia, have fallen, argument continues around the contribution of hand hygiene and dress codes to these changes. Conversely, the number of complaints against clinicians continues to rise, and respect for medical staff is falling. Are these phenomena linked to the disappearance of the white coat? Here, we debate the effects of these changes to clinician attire and ask whether the putative benefits in terms of infection control are outweighed by the possible harms to the doctor-patient relationship alleged to be caused by the loss of the white coat. PMID- 25516901 TI - Informed consent. PMID- 25516902 TI - 'Capacity' and the Adults with Incapacity (Scotland) Act 2000. PMID- 25516903 TI - How should we diagnose and manage photosensitivity? PMID- 25516904 TI - Influencing policy--public health advocacy and health inequalities. PMID- 25516905 TI - Cost and value in medical education--what we can learn from the past. AB - What lessons can be learned from the history of cost and value in medical education? First, the issue of cost and value in medical education has been around for a long time. Rising costs and an economic recession have made us focus on the subject more, but the issue has been just below the surface for over 200 years. A problem like this will not go away by itself - we must tackle it now. Second, the history of cost and value in medical education makes us look critically at who should pay. Should it be students, institutions or governments? We can see from the past that several different models have been tried; that all have their advantages and disadvantages; and that none are perfect. Third, looking at the past should make us realise that the issue of cost in medical education cannot be viewed in isolation. Medical educators throughout history have looked at how cost can affect selection for medical school, how costs can be related to benefits, and the effect of rising costs on career choices. Cost in medical education has always had far reaching consequences and implications. It probably always will. Looking at issues in medical education from the perspective of cost often makes them more stark and explicit - this in turn may help us to start to find solutions. In the future our solutions must be evidence based and must take account of cost. PMID- 25516906 TI - The Scottish Women's Hospital at Royaumont, France 1914-1919. AB - In 1915, under the aegis of the French Red Cross, volunteer medical women from the Scottish Women's Hospital Service for Foreign Service established a hospital at Royaumont Abbey in France, to treat casualties of the First World War. By working as a team comprised of radiologists, bacteriologists and surgeons, they were able to combat gas gangrene and record remarkable results. The circumstances and the way in which the doctors were portrayed in France and Britain prevented them from actively promoting their results to gain wider acceptance. After the War, medical women lost their training and employment opportunities and many left the profession. PMID- 25516907 TI - The Scottish Women's Hospitals for Foreign Service--the Girton and Newnham Unit, 1915-1918. AB - The Scottish Women's Hospitals for Foreign Service were established shortly after the outbreak of the First World War. Opportunities were limited for medical women prior to the war and during it they were unable to obtain a commission in the Royal Army Medical Corps, hence the formation of these voluntary all-women units. The Girton and Newnham Unit, under the leadership of Dr L McIlroy, served with distinction in France, Serbia and Greece, demonstrating clinical competence in the management of the emergency medical and surgical problems associated with warfare, areas usually off-limits to women doctors. They were severely tested but showed endurance and resilience in the running of their hospital in the most difficult of conditions. PMID- 25516908 TI - Celsus: De medicina, Florence 1478. Part 2. PMID- 25516909 TI - Dementia, driving retirement and decision aids. PMID- 25516910 TI - Label-free phenotyping of peripheral blood lymphocytes by infrared imaging. AB - It is now widely accepted that the immune microenvironment of tumors and more precisely Tumor Infiltrating Lymphocytes (TIL) play an important role in cancer development and outcome. TILs are considered to be important prognostic and predictive factors based on a growing body of clinical evidence; however, their presence at the tumor site is not currently assessed routinely. FTIR (Fourier transform infrared) imaging has proven it has value in studying a range of tumors, particularly for characterizing tumor cells. Currently, very little is known about the potential for FTIR imaging to characterize TIL. The present proof of concept study investigates the ability of FTIR imaging to identify the principal lymphocyte subpopulations present in human peripheral blood (PB). A negative cell isolation method was employed to select pure, label-free, helper T cells (CD4(+)), cytotoxic T cells (CD8(+)) and B cells (CD19(+)) from six healthy donors PB by Fluorescence Activated Cell Sorting (FACS). Cells were centrifuged onto Barium Fluoride windows and ten infrared images were recorded for each lymphocyte subpopulation from all six donors. After spectral pre-treatment, statistical analyses were performed. Unsupervised Principal Component Analyses (PCA) revealed that in the absence of donor variability, CD4(+) T cells, CD8(+) T cells and B cells each display distinct IR spectral features. Supervised Partial Least Square Discriminant Analyses (PLS-DA) demonstrated that the differences between the three lymphocyte subpopulations are reflected in their IR spectra, permitting their individual identification even when significant donor variability is present. Our results also show that a distinct spectral signature is associated with antibody binding. To our knowledge this is the first study reporting that FTIR imaging can effectively identify T and B lymphocytes and differentiate helper T cells from cytotoxic T cells. This proof of concept study demonstrates that FTIR imaging is a reliable tool for the identification of lymphocyte subpopulations and has the potential for use in characterizing TIL. PMID- 25516911 TI - Citrate-capped gold nanoparticles for the label-free detection of ubiquitin C terminal hydrolase-1. AB - Ubiquitin C-terminal hydrolase-1 (UCH-L1) is a specific neuronal endoprotease that cleaves the specific peptide bond between ubiquitin molecules. UCH-L1 is released in serum and cerebrospinal fluid after severe brain injury and is considered to be an important biomarker of brain injury. A common polymorphism of UCH-L1 (S18Y) is also linked to a reduced risk of Parkinson's disease. In addition to its function in neuronal tissues, UCH-L1 may also play a part in the progression of certain non-neuronal cancers. UCH-L1 is highly expressed in primary lung tumors and colo-rectal cancers, suggesting a role in tumorigenesis. We report here the development of a sensitive and accurate UCH-L1 assay based on the surface plasmon resonance (SPR) absorbance of gold nanoparticles. We created a unique UCH-L1 substrate containing a ubiquitin molecule with two terminal thiol groups. This UCH-L1 substrate interacted with gold nanoparticles via the terminal thiol groups and induced clustering of the nanoparticles, which was detected by SPR absorbance at 650 nm. UCH-L1 proteolytically cleaved the substrate and the clustered gold nanoparticles were dispersed and could be detected by a shift in the SPR absorbance to 530 nm. This change in absorbance was proportional to the concentration of UCH-L1 and can be used for the quantification of functional UCH L1. The currently available fluorescence-based UCH-L1 assay is affected by a high background signal and a poor detection limit, especially in the presence of serum. The assay reported here can detect concentrations of UCH-L1 as low as 20 ng ml(-1) (0.8 nM) and the presence of serum had no effect on the detection limit. This assay could be adapted for the rapid determination of the severity of brain injury and could also be applied to high-throughput screening of inhibitors of UCH-L1 enzymatic activity in Parkinson's disease and cancer. PMID- 25516912 TI - A sensitive one-step method for quantitative detection of alpha-amylase in serum and urine using a personal glucose meter. AB - Assays of alpha-amylase (AMS) activity in serum and urine constitute the important indicator for the diagnosis of acute pancreatitis, mumps, renal disease and abdominal disorders. Since these diseases confer a heavy financial burden on the health care system, AMS detection in point-of-care is fundamental. Here, a one-step assay for direct determination of the AMS activity was developed using a portable personal glucose meter (PGM). In this assay, maltopentaose was used as a substrate for sensitive detection of AMS with the assistance of alpha glucosidase. In the presence of AMS, maltopentaose can be readily hydrolyzed to form maltotriose and maltose quickly. With the enzymatic hydrolysis of alpha glucosidase, maltotriose and maltose can be turned into glucose rapidly, which can be quantitatively measured using a portable PGM. This assay did not require any cumbersome and time consuming operations, such as surface modification, synthesis of invertase conjugate, washing and centrifugation. Detection of AMS can be achieved using only a one-step mixture, and the limit of detection was 20 U L(-1) which was lower than the clinical cutoff for AMS. More importantly, this sensitive and selective assay was also used for the detection of AMS in human serum/urine samples. The results showed that the recovery of AMS from human serum/urine samples was 91-107%. The rapid and easy-to-operate assay may have potential application in the fields of point-of-care (POC) clinical diagnosis, particularly in rural and remote areas where lab equipment may be limited. PMID- 25516913 TI - Asymmetric core-expanded aza-BODIPY analogues: facile synthesis and optical properties. AB - Significantly large Stokes shifts and enhanced solid state emissions were achieved in a novel series of asymmetric core-expanded aza-BODIPY analogues, 4a 4d, synthesized by a facile and scalable two-step reaction in high yields. PMID- 25516914 TI - Dysphoria induced in dialysis providers by secondary hyperparathyroidism. PMID- 25516915 TI - Clinical outcomes after parathyroidectomy in a nationwide cohort of patients on hemodialysis. AB - BACKGROUND AND OBJECTIVES: Patients receiving dialysis undergo parathyroidectomy to improve laboratory parameters in resistant hyperparathyroidism with the assumption that clinical outcomes will also improve. However, no randomized clinical trial data demonstrate the benefits of parathyroidectomy. This study aimed to evaluate clinical outcomes up to 1 year after parathyroidectomy in a nationwide sample of patients receiving hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using data from the US Renal Data System, this study identified prevalent hemodialysis patients aged >=18 years with Medicare as primary payers who underwent parathyroidectomy from 2007 to 2009. Baseline characteristics and comorbid conditions were assessed in the year preceding parathyroidectomy; clinical events were identified in the year preceding and the year after parathyroidectomy. After parathyroidectomy, patients were censored at death, loss of Medicare coverage, kidney transplant, change in dialysis modality, or 365 days. This study estimated cause-specific event rates for both periods and rate ratios comparing event rates in the postparathyroidectomy versus preparathyroidectomy periods. RESULTS: Of 4435 patients who underwent parathyroidectomy, 2.0% died during the parathyroidectomy hospitalization and the 30 days after discharge. During the 30 days after discharge, 23.8% of patients were rehospitalized; 29.3% of these patients required intensive care. In the year after parathyroidectomy, hospitalizations were higher by 39%, hospital days by 58%, intensive care unit admissions by 69%, and emergency room/observation visits requiring hypocalcemia treatment by 20-fold compared with the preceding year. Cause-specific hospitalizations were higher for acute myocardial infarction (rate ratio, 1.98; 95% confidence interval, 1.60 to 2.46) and dysrhythmia (rate ratio 1.4; 95% confidence interval1.16 to 1.78); fracture rates did not differ (rate ratio 0.82; 95% confidence interval 0.6 to 1.1). CONCLUSIONS: Parathyroidectomy is associated with significant morbidity in the 30 days after hospital discharge and in the year after the procedure. Awareness of clinical events will assist in developing evidence-based risk/benefit determinations for the indication for parathyroidectomy. PMID- 25516916 TI - ANCAs are also antimonocyte cytoplasmic autoantibodies. PMID- 25516919 TI - Degeneracy in cryptophane-xenon complex formation in aqueous solution. AB - The reversible binding of xenon to cryptophane molecules is currently heavily explored for application as a reporter system in NMR. Herein, for aqueous solution, first evidence of degenerate exchange in this host-guest system is presented based on a novel approach using hyperpolarized (129)Xe. PMID- 25516917 TI - Recent changes in therapeutic approaches and association with outcomes among patients with secondary hyperparathyroidism on chronic hemodialysis: the DOPPS study. AB - BACKGROUND AND OBJECTIVES: Elevated parathyroid hormone levels may be associated with adverse clinical outcomes in patients on dialysis. After the introduction of practice guidelines suggesting higher parathyroid hormone targets than those previously recommended, changes in parathyroid hormone levels and treatment regimens over time have not been well documented. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using data from the international Dialysis Outcomes and Practice Patterns Study, trends in parathyroid hormone levels and secondary hyperparathyroidism therapies over the past 15 years and the associations between parathyroid hormone and clinical outcomes are reported; 35,655 participants from the Dialysis Outcomes and Practice Patterns Study phases 1-4 (1996-2011) were included. RESULTS: Median parathyroid hormone increased from phase 1 to phase 4 in all regions except for Japan, where it remained stable. Prescriptions of intravenous vitamin D analogs and cinacalcet increased and parathyroidectomy rates decreased in all regions over time. Compared with 150-300 pg/ml, in adjusted models, all-cause mortality risk was higher for parathyroid hormone=301 450 (hazard ratio, 1.09; 95% confidence interval, 1.01 to 1.18) and >600 pg/ml (hazard ratio, 1.23; 95% confidence interval, 1.12 to 1.34). Parathyroid hormone >600 pg/ml was also associated with higher risk of cardiovascular mortality as well as all-cause and cardiovascular hospitalizations. In a subgroup analysis of 5387 patients not receiving vitamin D analogs or cinacalcet and with no prior parathyroidectomy, very low parathyroid hormone (<50 pg/ml) was associated with mortality (hazard ratio, 1.25; 95% confidence interval, 1.04 to 1.51). CONCLUSIONS: In a large international sample of patients on hemodialysis, parathyroid hormone levels increased in most countries, and secondary hyperparathyroidism treatments changed over time. Very low and very high parathyroid hormone levels were associated with adverse outcomes. In the absence of definitive evidence in support of a specific parathyroid hormone target, there is an urgent need for additional research to inform clinical practice. PMID- 25516920 TI - Mixed diboration of alkenes in a metal-free context. AB - Experimental and theoretical rationalization on regioselective mixed diboration of alkenes, with the unsymmetrical diboron reagent Bpin-Bdan, providing the protecting Bdan moiety in the internal position. PMID- 25516921 TI - An efficient synthesis of pyrido[1,2-a]indoles through aza-Nazarov type cyclization. AB - Transition metal free Bronsted acid mediated synthesis of biologically important pyrido[1,2-a]indole scaffolds through aza-Nazarov type cyclization of readily available diaryl(2-pyridyl)methanol using formic acid has been developed. This methodology has been successfully extended to synthesize atropisomers. PMID- 25516918 TI - M2 macrophage infiltrates in the early stages of ANCA-associated pauci-immune necrotizing GN. AB - BACKGROUND AND OBJECTIVES: This study examined kidney biopsies with focal segmental glomerular fibrinoid necrosis to identify early features of pauci immune necrotizing GN and the primary effector cells mediating initial capillary injury. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Seventeen consecutive kidney biopsies with focal pauci-immune necrotizing GN, obtained over a 6-year period (2007-2012), were studied. Neutrophils and CD68(+), CD163(+), CD3(+), CD56(+), and CD20(+) cells were scored in paraffin sections counterstained with periodic acid-Schiff. Electron microscopy was performed in 15 of 17 biopsies and additional examples of pauci-immune necrotizing GN (n=25). Biopsies with thin basement membrane nephropathy (n=5) served as immunohistologic normal controls. RESULTS: Biopsies with pauci-immune necrotizing GN had a mean of 10 (range=3-25) normal-appearing glomeruli, a mean of 2 (range=1-5) glomeruli with segmental fibrinoid necrosis, and a mean of 2 (range=1-11) glomeruli with cellular crescents. CD68(+) and CD163(+) macrophages predominated at sites of fibrinoid necrosis in pauci-immune necrotizing GN, exceeding the quantity of neutrophils and T cells (mean scores [SD]=2.5 [0.7] and 2.2 [0.75] versus 0.6 [0.5] and 0.1 [0.3], respectively; P<0.001). B and natural killer cells were rare. Normal appearing glomeruli in pauci-immune necrotizing GN had significantly more CD68(+) and CD163(+) macrophages than the controls (CD68(+), 0.9 [0.3] versus 0.4 [0.3]; CD163(+), 1 [0.4] versus 0.4 [0.3]; P<0.001). The quantity of other glomerular infiltrates did not differ from controls. The serum creatinine level at biopsy correlated with the glomerular CD68 and neutrophil scores (r=0.74 and r=0.71, respectively; P=0.001) but did not correlate with the extent of fibrinoid necrosis (r=0.36). Macrophages were localized at minute perforations and attenuations of the capillary basement membrane by electron microscopy. CONCLUSIONS: Early pauci-immune necrotizing GN is characterized by a selective localization of CD163(+) M2 macrophages at sites of glomerular fibrinoid necrosis and in normal-appearing glomeruli. These observations indicate that alternatively activated macrophages are positioned as potential effectors of glomerular injury in the early stages of pauci-immune necrotizing GN and may be potential targets for therapeutic intervention. PMID- 25516922 TI - What is it to do good medical ethics? A kaleidoscope of views. PMID- 25516923 TI - The formative years: medical ethics comes of age. AB - When the Journal of Medical Ethics first appeared in April 1975, the prospects of success seemed uncertain. There were no scholars specialising in the field, the readership could not be guaranteed, and the medical profession itself seemed, at the very least, ambivalent about a subject thought by many to be the province of doctors alone, to be acquired through an apprenticeship model, and certainly not taught or examined in any formal sense. However, change was afoot, fresh scandals created an awareness that outside help was needed to think through the new challenges facing the profession, and the success of the medical groups revealed a clear way forward through multidisciplinary and critically reflective discussion of the host of emerging ethical and legal issues. In this article the formative years of the journal are recaptured, with a claim that the core principles on which it was founded must endure if it is to continue to 'do good medical ethics' over the next 40 years. PMID- 25516924 TI - Reflections on learning and teaching medical ethics in UK medical schools. AB - The development of learning, teaching and assessment of medical ethics and law over the last 40 years is reflected upon with particular reference to the roles of the London Medical Group, the Society for the Study of Medical Ethics, its successor Institute of Medical Ethics; the Journal of Medical Ethics and the General Medical Council. Several current issues are addressed. Although the situation seems incomparably better than it was 40 years ago, the relatively recent events in Mid Staffordshire National Health Service (NHS) Foundation Trust show we cannot be complacent. Whatever role we have in the NHS or medical education, we must all strive to make sure it never happens again. PMID- 25516925 TI - What is it to do good medical ethics? On the concepts of 'good' and 'goodness' in medical ethics. AB - In his book The Varieties of Goodness Georg Henrik von Wright advocates that a useful preliminary to the study of the word 'good' is to compile a list of familiar uses and try to group them under some main headings. The present paper aims at exploring the question, 'What is it to do good medical ethics?', and notably from the vantage point of everyday expressions of the word 'good' and von Wright's grouping of them into six different types of goodness. PMID- 25516926 TI - A bioethics for all seasons. AB - The last four decades have seen the emergence and flourishing of the field of bioethics and its incorporation into wide-ranging aspects of society, from the clinic or laboratory through to public policy and the media. Yet considerable debate still exists over what bioethics is and how it should be done. In this paper I consider the question of what makes good bioethics. Drawing on historical and contemporary examples, I suggest that bioethics encompasses multiple modes of responding to moral disagreement, and that an awareness of which mode is operational in a given context is essential to doing good bioethics. PMID- 25516927 TI - The patient/client/consumer/service user and medical ethics 40 years on. AB - This essay, written from my non-doctor's 'lay' perspective, sketches a gradually improving approach to medical ethics over the 40-year period since this journal was founded. A central feature of this improvement has been the increasing focus of medical ethics on the interests and perspectives of the patients/clients/consumers/service users, whose interests doctors and other healthcare workers serve. Events such as misuse of the end of life 'Liverpool Care Pathway' and the shockingly poor care revealed in National Health Service hospitals in Mid-Staffordshire show that these improvements are by no means universal. Nonetheless, there has been a steady improvement in general terms towards putting patients first and it is not flattery to say that in its consistent support for this concern and in its promotion of non-medical involvement in medical ethics education the Journal of Medical Ethics has itself made a significant contribution to 'doing good medical ethics'. PMID- 25516928 TI - Done good. AB - How did bioethics manage to grow, flourish and ultimately do so well from a very unpromising birth in the 1970s? Many explanations have been advanced. Some ascribe the field's growth to a puzzling, voluntary abnegation of moral authority by medicine to non-physicians. Some think bioethics survived by selling out to the biomedical establishment-public and private. This transaction involved bestowing moral approbation on all manner of biomedicine's doings for a seat at a well-stocked funding table. Some see a sort of clever intellectual bamboozlement at work wherein bioethicists pitched a moral elixir of objective expertise that the morally needy but unsophisticated in medicine and the biological sciences were eager to swallow. While each of these reasons has its defenders, I think the main reason that bioethics did well was that it did good. By using the media to move into the public arena, the field engaged the public imagination, provoked dialogue and debate, and contributed to policy changes that benefitted patients and healthcare providers. PMID- 25516929 TI - Bioethics: why philosophy is essential for progress. AB - It is the JME's 40th anniversary and my 20th anniversary working in the field. I reflect on the nature of bioethics and medical ethics. I argue that both bioethics and medical ethics together have, in many ways, failed as fields. My diagnosis is that better philosophy is needed. I give some examples of the importance of philosophy to bioethics. I focus mostly on the failure of ethics in research and organ transplantation, although I also consider genetic selection, enhancement, cloning, futility, disability and other topics. I do not consider any topic comprehensively or systematically or address the many reasonable objections to my arguments. Rather, I seek to illustrate why philosophical analysis and argument remain as important as ever to progress in bioethics and medical ethics. PMID- 25516930 TI - Good medical ethics. AB - This paper summarises the features of my paper, 'Voluntary Active Euthanasia', and a later jointly authored paper, 'Moral Fictions', which I believe are examples of good medical ethics. PMID- 25516931 TI - What is it to do good medical ethics? AB - This brief paper addresses the question of what it is to do good medical ethics in two parts: First, I consider the problem of how to get started in medical ethics, conceived of as an academic discipline rather than simply to get started being ethical in a medical or biomedical context. The second part gives my own take on the question 'what is bioethics for?' PMID- 25516932 TI - The debate about physician assistance in dying: 40 years of unrivalled progress in medical ethics? AB - Some issues in medical ethics have been present throughout the history of medicine, and thus provide us with an opportunity to ascertain: (1) whether there is progress in medical ethics; and (2) what it means to do good medical ethics. One such perennial issue is physician assistance in dying (PAD). This paper provides an account of the PAD debate in this journal over the last 40 years. It concludes that there is some (but limited) progress in the debate. The distinctions, analogies and hypothetical examples have proliferated, as have empirical studies, but very little has changed in terms of the basic arguments. The paper further argues that many of the contributions to the debate fail to engage fully with the concerns people have about the legal introduction of PAD in the healthcare system, perhaps because many of the contributions sit on the borderline between academic analysis and social activism. PMID- 25516933 TI - The impossibility of informed consent? AB - The problematic nature of informed consent to medical treatment and research, and its relation to autonomy, trust and clinical practice, has been addressed on many occasions and from a variety of ethical perspectives in the pages of the Journal of Medical Ethics. This paper gives an account of how discussion of these issues has developed and changed, by describing a number of significant contributions to these debates which provide examples of 'doing good medical ethics' over the 40 years of the Journal's publication. PMID- 25516934 TI - Good medical ethics, from the inside out--and back again. AB - I argue here that good medical ethics requires an empirically-informed moral psychology of medical virtue along with sound action-guiding prescriptions for virtuous medical practice. After distinguishing between three levels of justification, I indicate how medical virtue ethics can draw constructively on relevant empirical research in developing feasible and realistic aspirational standards for doctors, and in evaluating how policymakers can support doctors in acting on the virtues that doctors agreed to be guided by when they joined the profession. PMID- 25516935 TI - What is good medical ethics? A very personal response to a difficult question. AB - A personal reflection upon a career in medical ethics leads to four conclusions on what makes for 'good medical ethics'. Good medical ethics is practical in approach, philosophically well grounded, cross disciplinary, and while it might not be a necessary feature, the experience of the author suggests that it is the work of 'good people'. PMID- 25516936 TI - Cui bono? Good for whom? Some apologies, confessions, musings, unsubstantiated views, not empirically founded statements, lists, a few commandments, reading suggestions, and rather practical tips for aspiring and experienced bioethicists. AB - Probably almost every day (good working day) in 35 years of 'doing' medical ethics I have asked myself: for whom is good medical ethics good? Who benefits from our critical ethical analysis? In my view the ultimate justification of bioethics lies in contributing to the debate on problems people experience in real life and to changing practices. I discuss some pitfalls and problems present day bioethicists encounter in an interdisciplinary climate, facing scepticism, competition and scarcity of resources, such as disdain from philosophers, take over by other disciplines, dilution of ethical argument, the empirical seduction, and paragraph ethics. PMID- 25516937 TI - What is it to do good medical ethics? Minding the gap(s). AB - This paper discusses the character of medical ethics and suggests that there are significant gaps that warrant greater attention. It describes ways in which the content and form of medical ethics may exclude or marginalise perspectives and contributions, thereby reducing its influence and its potential impact on, and value to, patients, students, carers and society. To consider what it is 'to do good medical ethics' suggests an active approach that seeks out, and learns from, contributions beyond the traditional boundaries of scholarship. PMID- 25516938 TI - Medical humanities and medical alterity in fiction and in life. AB - A widely accepted component of any answer to the question 'What is it to do good medical ethics?' is the commitment to benefit people's health, in principlist terminology, 'beneficence'. This paper addresses deliberate maleficence and the cultural otherness with which it is associated, focusing on the activities of the serial killer Dr Harold Shipman. It finds an uncanny 'fit' between the normal operation of healthcare services and this sort of alterity which has attracted little attention from bioethicists but has been addressed by novelists. To the extent that the medical humanities offers useful insights into hard moral problems, its capacities rest on taking account of both the fictional and the real. PMID- 25516939 TI - What is it to do good ethics? AB - Much of my work in bioethics over the years has been throwing off ethics as pursued in the analytical tradition. I believe the field should steer clear of the rigid style of hyper-rationalist ethics and a reduction of ethics to a search for rules and principles. It should be open to a full range of influence, in style and substance, of literature, history and the social sciences. It should take in the full range of human life, individual and social. PMID- 25516940 TI - Good and not so good medical ethics. AB - In this paper, I provide a brief sketch of the purposes that medical ethics serves and what makes for good medical ethics. Medical ethics can guide clinical practice and biomedical research, contribute to the education of clinicians, advance thinking in the field, and direct healthcare policy. Although these are distinct activities, they are alike in several critical respects. Good medical ethics is coherent, illuminating, accurate, reasonable, consistent, informed, and measured. After this overview, I provide specific examples to illustrate some of the ways in which medical ethics could go wrong as a caution and a reminder that taking on the role of an ethicist involves serious responsibilities that must be exercised with care. PMID- 25516941 TI - Can one do good medical ethics without principles? AB - The criteria for determining what it is to do good medical ethics are the quality of ethical analysis and ethical justifications for decisions and actions. Justifications for decisions and actions rely on ethical principles, be they the 'famous four' or subsidiary ethical principles relevant to specific contexts. Examples from clinical ethics, research ethics and public health ethics reveal that even when not stated explicitly, principles are involved in ethical justifications. Principles may come into conflict, however, and the resolution of an ethical dilemma requires providing good reasons for preferring one principle over another. PMID- 25516942 TI - What is good medical ethics? A clinician's perspective. AB - Speaking from the perspective of a clinician and teacher, good medical ethics needs to make medicine better. Over the past 50 years medical ethics has helped shape the culture in medicine and medical practice for the better. However, recent healthcare scandals in the UK suggest more needs to be done to translate ethical reasoning into ethical practice. Focusing on clinical practice and individual patient care, I will argue that, to be good, medical ethics needs to become integral to the activities of health professionals and healthcare organisations. Ethics is like a language which brings a way of thinking and responding to the world. For ethics to become embedded in clinical practice, health professionals need to progress from classroom learners to fluent social speakers through ethical dialogue, ethical reflection and ethical actions. I will end by discussing three areas that need to be addressed to enable medical ethics to flourish and bring about change in everyday clinical care. PMID- 25516943 TI - What is it to do good medical ethics? From the perspective of a practising doctor who is in Parliament. AB - This article is a personal reflection on work as a physician with work as a member of the UK Parliament's House of Lords. Ethical thinking should underpin everything we do; the 'four principles' of medical ethics provide an applicable and relevant ethical framework. This article explores its application in both domains of work-as a clinician and as a legislator-with some examples of its use 'to do good medical ethics' in both roles. Debates around tobacco and drug control, pandemic control, abortion and assisted suicide are explored. PMID- 25516944 TI - Suffering, compassion and 'doing good medical ethics'. AB - 'Doing good medical ethics' involves attending to both the biomedical and existential aspects of illness. For this, we need to bring in a phenomenological perspective to the clinical encounter, adopt a virtue-based ethic and resolve to re-evaluate the goals of medicine, in particular the alleviation of suffering and the role of compassion in everyday ethics. PMID- 25516945 TI - Food for thought: ethics case discussion as slow nourishment in a fast world. AB - Case discussion offers important opportunities to do good medical ethics, but do we understand what the benefits might be? This paper looks at the 'Case Conference' series in the JME, its origins and methods, examines some cases in outline, and reviews issues that arise that are not usually taken into account. Cases are harder to publish now, not least because of ethical constraints. Ways past this apparently paradoxical outcome are suggested. PMID- 25516946 TI - The relationship between medical law and good medical ethics. AB - In the UK, medical ethics and law are often thought of and taught together, but while 'good medical ethics' is often reflected in law-the need to obtain a patient's adequately informed consent, for example-this is not necessarily the case. Sometimes medical ethics is more demanding than law; at other times, perhaps counterintuitively, the law appears to ask more of doctors than does good medical ethics. PMID- 25516947 TI - Justice and the NICE approach. AB - When thinking about population level healthcare priority setting decisions, such as those made by the National Institute for Health and Care Excellence, good medical ethics requires attention to three main principles of health justice: (1) cost-effectiveness, an aspect of beneficence, (2) non-discrimination, and (3) priority to the worse off in terms of both current severity of illness and lifetime health. Applying these principles requires consideration of the identified patients who benefit from decisions and the unidentified patients who bear the opportunity costs. PMID- 25516948 TI - Good medical ethics, justice and provincial globalism. AB - The summer 2014 Ebola virus outbreak in Western Africa illustrates global health's striking inequalities. Globalisation has also increased pandemics, and disparate health system conditions mean that where one falls ill or is injured in the world can mean the difference between quality care, substandard care or no care at all, between full recovery, permanent ill effects and death. Yet attention to the normative underpinnings of global health justice and distribution remains, despite some important exceptions, inadequate in medical ethics, bioethics and political philosophy. We need a theoretical foundation on which to build a more just world. Provincial globalism (PG), grounded in capability theory, offers a foundation; it provides the components of a global health justice framework that can guide implementation. Under PG, all persons possess certain health entitlements. Global health justice requires progressively securing this health capabilities threshold for every person. PMID- 25516949 TI - Ebola: what it tells us about medical ethics. AB - Good medical ethics needs to look more to the resources of public health ethics and use more societal, population or community values and perspectives, rather than defaulting to the individualistic values that currently dominate discussion. In this paper I argue that we can use the recent response to Ebola as an example of a major failure of the global community in three ways. First, the focus has been on the treatment of individuals rather than seeing that the priority ought to be public health measures. Second, the advisory committee on experimental interventions set up by the WHO has focused on ethical issues related to individuals and their guidance has been unclear. Third, the Ebola issue can be seen as a symptom of a massive failure of the global community to take sufficient notice of global injustice. PMID- 25516950 TI - Defending the four principles approach as a good basis for good medical practice and therefore for good medical ethics. AB - This paper argues that the four prima facie principles-beneficence, non maleficence, respect for autonomy and justice-afford a good and widely acceptable basis for 'doing good medical ethics'. It confronts objections that the approach is simplistic, incompatible with a virtue-based approach to medicine, that it requires respect for autonomy always to have priority when the principles clash at the expense of clinical obligations to benefit patients and global justice. It agrees that the approach does not provide universalisable methods either for resolving such moral dilemmas arising from conflict between the principles or their derivatives, or universalisable methods for resolving disagreements about the scope of these principles-long acknowledged lacunae but arguably to be found, in practice, with all other approaches to medical ethics. The value of the approach, when properly understood, is to provide a universalisable though prima facie set of moral commitments which all doctors can accept, a basic moral language and a basic moral analytic framework. These can underpin an intercultural 'moral mission statement' for the goals and practice of medicine. PMID- 25516951 TI - Doing good medical ethics: a Christian perspective. AB - Despite the rise of the secular state, religion remains a significant force in society. Within Christianity this encompasses a wide variety of beliefs. These range from simple assertions of theism in a cultural context to complex theologies; from liberal emphases on uncertainty and exploration to dogmatic views of divine revelation. How one 'does' good medical ethics depends on these perspectives. Contingently, the Christian contribution to medical ethics has been huge and constructive. Central to that contribution is a core belief in the intrinsic value of human life, respect for which we are accountable to God. Christianity continues to deserve its place 'in the public square' and, specifically, in medical ethical discourse. PMID- 25516952 TI - What is it to practise good medical ethics? A Muslim's perspective. AB - Good medical ethics should aim at ensuring that all human beings enjoy the highest attainable standard of health. With the development of medical technology and health services, it became necessary to expand the four basic principles of medical ethics and link them to human rights. Despite the claim of the universality of those ethical principles, their perception and application in healthcare services are inevitably influenced by the religious background of the societies in which those services are provided. This paper highlights the methodology and principles employed by Muslim jurists in deriving rulings in the field of medical ethics, and it explains how ethical principles are interpreted through the lens of Islamic theory. The author explains how, as a Muslim obstetrician-gynaecologist with a special interest in medical ethics, including international consideration of reproductive ethics issues, he attempts to 'practise good medical ethics' by applying internationally accepted ethical principles in various healthcare contexts, in ways that are consistent with Islamic principles, and he identifies the evidence supporting his approach. He argues that healthcare providers have a right to respect for their conscientious convictions regarding both undertaking and not undertaking the delivery of lawful procedures. However, he also argues that withholding evidence-based medical services based on the conscientious objection of the healthcare provider is unethical as patients have the right to be referred to services providing such treatment. PMID- 25516953 TI - What is it to do good medical ethics? An orthodox Jewish physician and ethicist's perspective. AB - This article, dedicated to the 40th anniversary of the Journal of Medical Ethics, approaches the question 'what does it mean to do good medical ethics?' first from a general perspective and then from the personal perspective of a Jewish Orthodox physician and ethicist who tries, both at a personal clinical level and in national and sometimes international discussions and debates, to reconcile his own religious ethical values-especially the enormous value given by Jewish ethics to the preservation of human life-with the prima facie 'principlist' moral norms of contemporary secular medical ethics, especially that of respect for patients' autonomy. PMID- 25516954 TI - Medical ethics and more: ideal theories, non-ideal theories and conscientious objection. AB - Doing 'good medical ethics' requires acknowledgment that it is often practised in non-ideal circumstances! In this article I present the distinction between ideal theory (IT) and non-ideal theory (NIT). I show how IT may not be the best solution to tackle problems in non-ideal contexts. I sketch a NIT framework as a useful tool for bioethics and medical ethics and explain how NITs can contribute to policy design in non-ideal circumstances. Different NITs can coexist and be evaluated vis-a-vis the IT. Additionally, I address what an individual doctor ought to do in this non-ideal context with the view that knowledge of NITs can facilitate the decision-making process. NITs help conceptualise problems faced in the context of non-compliance and scarcity in a better and more realistic way. Deciding which policy is optimal in such contexts may influence physicians' decisions regarding their patients. Thus, this analysis-usually identified only with policy making-may also be relevant to medical ethics. Finally, I recognise that this is merely a first step in an unexplored but fundamental theoretical area and that more work needs to be done. PMID- 25516955 TI - Scaling ethics up and down: moral craft in clinical genetics and in global health research. AB - This paper engages with the question of what it is to 'do good medical ethics' in two ways. It begins with an exploration of what it might mean to say that health professionals practise good medical ethics as part of practising good ethical medicine. Using the example of the Genethics Club, a well-established national ethics forum for genetics professionals in the UK, the paper develops an account of moral craftsmanship grounded in the concepts of shared moral commitments and practices, moral work, ethics and living morality. In the light of this discussion, the paper goes on to consider what it might mean for a specialist in medical ethics, a bioethicist, to do good medical ethics. Finally, a research agenda focusing on the challenges of thinking about good medical ethics in a global context and a proposal for an innovative approach to bioethics methodology is outlined. PMID- 25516956 TI - Practising what we preach. AB - The question of what makes 'good medical ethics' is explored focusing on the principles and values of the clinical professions, how these are integrated into patient care and shared with the wider public and on the central importance of good communication. The need for an effective learning base at all stages in professional careers is emphasised and the importance of measuring and monitoring outcomes of care and public health issues from an ethical perspective is discussed while acknowledging the difficulties of doing so. The possibility of establishing a wider forum to discuss this topic is mooted. The essay emphasises the importance of practising what we preach. PMID- 25516958 TI - Aligned macroporous monoliths with intrinsic microporosity via a frozen-solvent templating approach. AB - Aligned macroporous monoliths of an organic cage, a polymer of intrinsic microporosity (PIM-1), and a metal-organic framework (HKUST-1) are prepared by a controlled freezing approach. In addition to macropores, all the monoliths contain the intrinsic micropores. PMID- 25516957 TI - Spiroguanidine rhodamines as fluorogenic probes for lysophosphatidic acid. AB - Direct determination of total lysophosphatidic acid (LPA) was accomplished using newly developed spiroguanidines derived from rhodamine B as universal fluorogenic probes. Optimum conditions for the quantitative analysis of total LPA were investigated. The linear range for the determination of total LPA is up to 5 MUM with a limit of detection of 0.512 MUM. PMID- 25516959 TI - Reduction in DNA topoisomerase I level affects growth, phenotype and nucleoid architecture of Mycobacterium smegmatis. AB - The steady-state negative supercoiling of eubacterial genomes is maintained by the action of DNA topoisomerases. Topoisomerase distribution varies in different species of mycobacteria. While Mycobacterium tuberculosis (Mtb) contains a single type I (TopoI) and a single type II (Gyrase) enzyme, Mycobacterium smegmatis (Msm) and other members harbour additional relaxases. TopoI is essential for Mtb survival. However, the necessity of TopoI or other relaxases in Msm has not been investigated. To recognize the importance of TopoI for growth, physiology and gene expression of Msm, we have developed a conditional knock-down strain of TopoI in Msm. The TopoI-depleted strain exhibited extremely slow growth and drastic changes in phenotypic characteristics. The cessation of growth indicates the essential requirement of the enzyme for the organism in spite of having additional DNA relaxation enzymes in the cell. Notably, the imbalance in TopoI level led to the altered expression of topology modulatory proteins, resulting in a diffused nucleoid architecture. Proteomic and transcript analysis of the mutant indicated reduced expression of the genes involved in central metabolic pathways and core DNA transaction processes. RNA polymerase (RNAP) distribution on the transcription units was affected in the TopoI-depleted cells, suggesting global alteration in transcription. The study thus highlights the essential requirement of TopoI in the maintenance of cellular phenotype, growth characteristics and gene expression in mycobacteria. A decrease in TopoI level led to altered RNAP occupancy and impaired transcription elongation, causing severe downstream effects. PMID- 25516961 TI - Looking inwards: opening a window onto human development. PMID- 25516962 TI - Ethical considerations in chimera research. AB - The development of human pluripotent stem cells has opened up the possibility to analyse the function of human cells and tissues in animal hosts, thus generating chimeras. Although such lines of research have great potential for both basic and translational science, they also raise unique ethical issues that must be considered. PMID- 25516963 TI - From naive pluripotency to chimeras: a new ethical challenge? AB - In recent years, there has been much interest in the prospect of generating and using human stem cells that exhibit a state of naive pluripotency. Such a pluripotent state might be functionally confirmed by assessing the chimeric contribution of these cells to non-human blastocysts. Furthermore, the generation of naive human pluripotent stem cells in vitro could lead to the creation of chimeric animal models that can facilitate the study of human development and disease. However, these lines of research raise thorny ethical concerns about the moral status of such chimeric animals. Here, I call attention to these ethical barbs and suggest a way in which to proceed cautiously. PMID- 25516960 TI - RhoC Is an Unexpected Target of RhoGDI2 in Prevention of Lung Colonization of Bladder Cancer. AB - RhoGDI2 (ARHGDIB) suppresses metastasis in a variety of cancers but the mechanism is unclear, thus hampering development of human therapeutics. RhoGDI2 is a guanine nucleotide dissociation inhibitor (GDI) for the Rho family of GTPases thought to primarily bind to Rac1; however, Rac1 activation was not decreased by RhoGDI2 expression in bladder cancer cells. To better understand the GTPase binding partners for RhoGDI2, a mass spectrometry-based proteomic approach was used in bladder cancer cells. As expected, endogenous RhoGDI2 coimmunoprecipitates with Rac1 and unexpectedly also with RhoC. Further analysis demonstrated that RhoGDI2 negatively regulates RhoC, as knockdown of RhoGDI2 increased RhoC activation in response to serum stimulation. Conversely, overexpression of RhoGDI2 decreased RhoC activation. RhoC promoted bladder cancer cell growth and invasion, as knockdown increased cell doubling time, decreased invasion through Matrigel, and decreased colony formation in soft agar. Importantly, RhoC knockdown reduced in vivo lung colonization by bladder cancer cells following tail vein injection in immunocompromised mice. Finally, unbiased transcriptome analysis revealed a set of genes regulated by RhoGDI2 overexpression and RhoC knockdown in bladder cancer cells. IMPLICATIONS: RhoGDI2 suppresses bladder cancer metastatic colonization via negative regulation of RhoC activity, providing a rationale for the development of therapeutics that target RhoC signaling. PMID- 25516964 TI - Mouse and human blastocyst-derived stem cells: vive les differences. AB - Lessons learned from conserved vertebrate developmental pathways have catalyzed rapid advances in pluripotent stem cell differentiation towards therapeutically relevant cell types. The most highly conserved phases of development are associated with the early patterning of the body plan - the so-called phylotypic stage. Both prior to and after this stage there is much more divergence across species. Developmental differences between human and mouse at the blastocyst and early post-implantation stages might help explain the differences among the different stem cell lines derived from these embryos. A better understanding of these early stages of human development will aid our ability to generate and manipulate human stem cells and their derivatives. PMID- 25516965 TI - Modeling human lung development and disease using pluripotent stem cells. AB - Directed differentiation of human pluripotent stem cells (hPSCs) into mature cells, tissues and organs holds major promise for the development of novel approaches in regenerative medicine, and provides a unique tool for disease modeling and drug discovery. Sometimes underappreciated is the fact that directed differentiation of hPSCs also provides a unique model for human development, with a number of important advantages over model organisms. Here, I discuss the importance of using human stem cell models for understanding human lung development and disease. PMID- 25516966 TI - On human development: lessons from stem cell systems. AB - In September 2014, over 100 scientists from around the globe gathered at Wotton House near London for the Company of Biologists' workshop 'From Stem Cells to Human Development'. The workshop covered diverse aspects of human development, from the earliest stages of embryogenesis to differentiation of mature cell types of all three germ layers from pluripotent cells. In this Meeting Review, we summarise some of the exciting data presented at the workshop and draw together the main themes that emerged. PMID- 25516967 TI - Myocardin-related transcription factors control the motility of epicardium derived cells and the maturation of coronary vessels. AB - An important pool of cardiovascular progenitor cells arises from the epicardium, a single layer of mesothelium lining the heart. Epicardium-derived progenitor cell (EPDC) formation requires epithelial-to-mesenchymal transition (EMT) and the subsequent migration of these cells into the sub-epicardial space. Although some of the physiological signals that promote EMT are understood, the functional mediators of EPDC motility and differentiation are not known. Here, we identify a novel regulatory mechanism of EPDC mobilization. Myocardin-related transcription factor (MRTF)-A and MRTF-B (MKL1 and MKL2, respectively) are enriched in the perinuclear space of epicardial cells during development. Transforming growth factor (TGF)-beta signaling and disassembly of cell contacts leads to nuclear accumulation of MRTFs and the activation of the motile gene expression program. Conditional ablation of Mrtfa and Mrtfb specifically in the epicardium disrupts cell migration and leads to sub-epicardial hemorrhage, partially stemming from the depletion of coronary pericytes. Using lineage-tracing analyses, we demonstrate that sub-epicardial pericytes arise from EPDCs in a process that requires the MRTF-dependent motile gene expression program. These findings provide novel mechanisms linking EPDC motility and differentiation, shed light on the transcriptional control of coronary microvascular maturation and suggest novel therapeutic strategies to manipulate epicardium-derived progenitor cells for cardiac repair. PMID- 25516969 TI - Geminin deletion increases the number of fetal hematopoietic stem cells by affecting the expression of key transcription factors. AB - Balancing stem cell self-renewal and initiation of lineage specification programs is essential for the development and homeostasis of the hematopoietic system. We have specifically ablated geminin in the developing murine hematopoietic system and observed profound defects in the generation of mature blood cells, leading to embryonic lethality. Hematopoietic stem cells (HSCs) accumulated in the fetal liver following geminin ablation, while committed progenitors were reduced. Genome-wide transcriptome analysis identified key HSC transcription factors as being upregulated upon geminin deletion, revealing a gene network linked with geminin that controls fetal hematopoiesis. In order to obtain mechanistic insight into the ability of geminin to regulate transcription, we examined Hoxa9 as an example of a key gene in definitive hematopoiesis. We demonstrate that in human K562 cells geminin is associated with HOXA9 regulatory elements and its absence increases HOXA9 transcription similarly to that observed in vivo. Moreover, silencing geminin reduced recruitment of the PRC2 component SUZ12 to the HOXA9 locus and resulted in an increase in RNA polymerase II recruitment and H3K4 trimethylation (H3K4me3), whereas the repressive marks H3K9me3 and H3K27me3 were reduced. The chromatin landscape was also modified at the regulatory regions of HOXA10 and GATA1. K562 cells showed a reduced ability to differentiate to erythrocytes and megakaryocytes upon geminin silencing. Our data suggest that geminin is indispensable for fetal hematopoiesis and regulates the generation of a physiological pool of stem and progenitor cells in the fetal hematopoietic system. PMID- 25516968 TI - Mga is essential for the survival of pluripotent cells during peri-implantation development. AB - The maintenance and control of pluripotency is of great interest in stem cell biology. The dual specificity T-box/basic-helix-loop-helix-zipper transcription factor Mga is expressed in the pluripotent cells of the inner cell mass (ICM) and epiblast of the peri-implantation mouse embryo, but its function has not been investigated previously. Here, we use a loss-of-function allele and RNA knockdown to demonstrate that Mga depletion leads to the death of proliferating pluripotent ICM cells in vivo and in vitro, and the death of embryonic stem cells (ESCs) in vitro. Additionally, quiescent pluripotent cells lacking Mga are lost during embryonic diapause. Expression of Odc1, the rate-limiting enzyme in the conversion of ornithine into putrescine in the synthesis of polyamines, is reduced in Mga mutant cells, and the survival of mutant ICM cells as well as ESCs is rescued in culture by the addition of exogenous putrescine. These results suggest a mechanism whereby Mga influences pluripotent cell survival through regulation of the polyamine pool in pluripotent cells of the embryo, whether they are in a proliferative or quiescent state. PMID- 25516970 TI - A Pak-regulated cell intercalation event leading to a novel radial cell polarity is involved in positioning of the follicle stem cell niche in the Drosophila ovary. AB - In the germarium of the Drosophila ovary, germline cysts are encapsulated one at a time by a follicular epithelium derived from two follicle stem cells (FSCs). Ovaries in flies mutant for the serine/threonine kinase Pak exhibit a novel phenotype, in which two side-by-side cysts are encapsulated at a time, generating paired egg chambers. This striking phenotype originates in the pupal ovary, where the developing germarium is shaped by the basal stalk, a stack of cells formed by cell intercalation. The process of basal stalk formation is not well understood, and we provide evidence that the cell intercalation is driven by actomyosin contractility of DE-Cadherin-adhered cells, leading to a column of disk-shaped cells exhibiting a novel radial cell polarity. Cell intercalation fails in Pak mutant ovaries, leading to abnormally wide basal stalks and consequently wide germaria with side-by-side cysts. We present evidence that Pak mutant germaria have extra FSCs, and we propose that contact of a germline cyst with the basal stalk in the pupal ovary contributes to FSC niche formation. The wide basal stalk in Pak mutants enables the formation of extra FSC niches which are mispositioned and yet functional, indicating that the FSC niche can be established in diverse locations. PMID- 25516971 TI - Rho kinase activity controls directional cell movements during primitive streak formation in the rabbit embryo. AB - During animal gastrulation, the specification of the embryonic axes is accompanied by epithelio-mesenchymal transition (EMT), the first major change in cell shape after fertilization. EMT takes place in disparate topographical arrangements, such as the circular blastopore of amphibians, the straight primitive streak of birds and mammals or in intermediate gastrulation forms of other amniotes such as reptiles. Planar cell movements are prime candidates to arrange specific modes of gastrulation but there is no consensus view on their role in different vertebrate classes. Here, we test the impact of interfering with Rho kinase-mediated cell movements on gastrulation topography in blastocysts of the rabbit, which has a flat embryonic disc typical for most mammals. Time lapse video microscopy, electron microscopy, gene expression and morphometric analyses of the effect of inhibiting ROCK activity showed - besides normal specification of the organizer region - a dose-dependent disruption of primitive streak formation; this disruption resulted in circular, arc-shaped or intermediate forms, reminiscent of those found in amphibians, fishes and reptiles. Our results reveal a crucial role of ROCK-controlled directional cell movements during rabbit primitive streak formation and highlight the possibility that temporal and spatial modulation of cell movements were instrumental for the evolution of gastrulation forms. PMID- 25516973 TI - The Rac1 regulator ELMO controls basal body migration and docking in multiciliated cells through interaction with Ezrin. AB - Cilia are microtubule-based organelles that are present on most cells and are required for normal tissue development and function. Defective cilia cause complex syndromes with multiple organ manifestations termed ciliopathies. A crucial step during ciliogenesis in multiciliated cells (MCCs) is the association of future basal bodies with the apical plasma membrane, followed by their correct spacing and planar orientation. Here, we report a novel role for ELMO-DOCK1, which is a bipartite guanine nucleotide exchange factor complex for the small GTPase Rac1, and for the membrane-cytoskeletal linker Ezrin, in regulating centriole/basal body migration, docking and spacing. Downregulation of each component results in ciliopathy-related phenotypes in zebrafish and disrupted ciliogenesis in Xenopus epidermal MCCs. Subcellular analysis revealed a striking impairment of basal body docking and spacing, which is likely to account for the observed phenotypes. These results are substantiated by showing a genetic interaction between elmo1 and ezrin b. Finally, we provide biochemical evidence that the ELMO-DOCK1-Rac1 complex influences Ezrin phosphorylation and thereby probably serves as an important molecular switch. Collectively, we demonstrate that the ELMO-Ezrin complex orchestrates ciliary basal body migration, docking and positioning in vivo. PMID- 25516972 TI - Ezh2 represses the basal cell lineage during lung endoderm development. AB - The development of the lung epithelium is regulated in a stepwise fashion to generate numerous differentiated and stem cell lineages in the adult lung. How these different lineages are generated in a spatially and temporally restricted fashion remains poorly understood, although epigenetic regulation probably plays an important role. We show that the Polycomb repressive complex 2 component Ezh2 is highly expressed in early lung development but is gradually downregulated by late gestation. Deletion of Ezh2 in early lung endoderm progenitors leads to the ectopic and premature appearance of Trp63+ basal cells that extend the entire length of the airway. Loss of Ezh2 also leads to reduced secretory cell differentiation. In their place, morphologically similar cells develop that express a subset of basal cell genes, including keratin 5, but no longer express high levels of either Trp63 or of standard secretory cell markers. This suggests that Ezh2 regulates the phenotypic switch between basal cells and secretory cells. Together, these findings show that Ezh2 restricts the basal cell lineage during normal lung endoderm development to allow the proper patterning of epithelial lineages during lung formation. PMID- 25516974 TI - Molecular dissection of segment formation in the developing hindbrain. AB - Although many components of the genetic pathways that provide positional information during embryogenesis have been identified, it remains unclear how these signals are integrated to specify discrete tissue territories. Here, we investigate the molecular mechanisms underlying the formation of one of the hindbrain segments, rhombomere (r) 3, specified by the expression of the gene krox20. Dissecting krox20 transcriptional regulation has identified several input pathways: Hox paralogous 1 (PG1) factors, which both directly activate krox20 and indirectly repress it via Nlz factors, and the molecular components of an Fgf dependent effector pathway. These different inputs are channelled through a single initiator enhancer element to shape krox20 initial transcriptional response: Hox PG1 and Nlz factors define the anterior-posterior extent of the enhancer's domain of activity, whereas Fgf signalling modulates the magnitude of activity in a spatially uniform manner. Final positioning of r3 boundaries requires interpretation of this initial pattern by a krox20 positive-feedback loop, orchestrated by another enhancer. Overall, this study shows how positional information provided by different patterning mechanisms is integrated through a gene regulatory network involving two cis-acting elements operating on the same gene, thus offering a comprehensive view of the delimitation of a territory. PMID- 25516975 TI - Enthesis fibrocartilage cells originate from a population of Hedgehog-responsive cells modulated by the loading environment. AB - Tendon attaches to bone across a specialized tissue called the enthesis. This tissue modulates the transfer of muscle forces between two materials, i.e. tendon and bone, with vastly different mechanical properties. The enthesis for many tendons consists of a mineralized graded fibrocartilage that develops postnatally, concurrent with epiphyseal mineralization. Although it is well described that the mineralization and development of functional maturity requires muscle loading, the biological factors that modulate enthesis development are poorly understood. By genetically demarcating cells expressing Gli1 in response to Hedgehog (Hh) signaling, we discovered a unique population of Hh-responsive cells in the developing murine enthesis that were distinct from tendon fibroblasts and epiphyseal chondrocytes. Lineage-tracing experiments revealed that the Gli1 lineage cells that originate in utero eventually populate the entire mature enthesis. Muscle paralysis increased the number of Hh-responsive cells in the enthesis, demonstrating that responsiveness to Hh is modulated in part by muscle loading. Ablation of the Hh-responsive cells during the first week of postnatal development resulted in a loss of mineralized fibrocartilage, with very little tissue remodeling 5 weeks after cell ablation. Conditional deletion of smoothened, a molecule necessary for responsiveness to Ihh, from the developing tendon and enthesis altered the differentiation of enthesis progenitor cells, resulting in significantly reduced fibrocartilage mineralization and decreased biomechanical function. Taken together, these results demonstrate that Hh signaling within developing enthesis fibrocartilage cells is required for enthesis formation. PMID- 25516976 TI - Dose-dependent nuclear beta-catenin response segregates endomesoderm along the sea star primary axis. AB - In many invertebrates, the nuclearization of beta-catenin at one pole of the embryo initiates endomesoderm specification. An intriguing possibility is that a gradient of nuclear beta-catenin (nbeta-catenin), similar to that operating in vertebrate neural tube patterning, functions to distinguish cell fates in invertebrates. To test this hypothesis, we determined the function of nbeta catenin during the early development of the sea star, which undergoes a basal deuterostomal mode of embryogenesis. We show that low levels of nbeta-catenin activity initiate bra, which is expressed in the future posterior endoderm-fated territory; intermediate levels are required for expression of foxa and gata4/5/6, which are later restricted to the endoderm; and activation of ets1 and erg in the mesoderm-fated territory requires the highest nbeta-catenin activity. Transcription factors acting downstream of high nbeta-catenin segregate the endoderm/mesoderm boundary, which is further reinforced by Delta/Notch signaling. Significantly, therefore, in sea stars, endomesoderm segregation arises through transcriptional responses to levels of nbeta-catenin activity. Here, we describe the first empirical evidence of a dose-dependent response to a dynamic spatiotemporal nbeta-catenin activity that patterns cell fates along the primary axis in an invertebrate. PMID- 25516977 TI - Nesprins anchor kinesin-1 motors to the nucleus to drive nuclear distribution in muscle cells. AB - During skeletal muscle development, nuclei move dynamically through myotubes in a microtubule-dependent manner, driven by the microtubule motor protein kinesin-1. Loss of kinesin-1 leads to improperly positioned nuclei in culture and in vivo. Two models have been proposed to explain how kinesin-1 functions to move nuclei in myotubes. In the cargo model, kinesin-1 acts directly from the surface of the nucleus, whereas in an alternative model, kinesin-1 moves nuclei indirectly by sliding anti-parallel microtubules. Here, we test the hypothesis that an ensemble of Kif5B motors acts from the nuclear envelope to distribute nuclei throughout the length of syncytial myotubes. First, using an inducible dimerization system, we show that controlled recruitment of truncated, constitutively active kinesin-1 motors to the nuclear envelope is sufficient to prevent the nuclear aggregation resulting from depletion of endogenous kinesin-1. Second, we identify a conserved kinesin light chain (KLC)-binding motif in the nuclear envelope proteins nesprin 1 and nesprin-2, and show that recruitment of the motor complex to the nucleus via this LEWD motif is essential for nuclear distribution. Together, our findings demonstrate that the nucleus is a kinesin-1 cargo in myotubes and that nesprins function as nuclear cargo adaptors. The importance of achieving and maintaining proper nuclear position is not restricted to muscle fibers, suggesting that the nesprin-dependent recruitment of kinesin-1 to the nuclear envelope through the interaction of a conserved LEWD motif with kinesin light chain might be a general mechanism for cell-type-specific nuclear positioning during development. PMID- 25516978 TI - Gastric bypass has better long-term outcomes than gastric banding. PMID- 25516979 TI - How to use: nutritional assessment in children. PMID- 25516980 TI - Science and culture: Capturing the world's oldest living things. PMID- 25516981 TI - Inner workings: A soft robot that swims like a fish. PMID- 25516983 TI - Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms. AB - Patients with myeloproliferative neoplasms (MPNs) are at significant, cumulative risk of leukemic transformation to acute myeloid leukemia (AML), which is associated with adverse clinical outcome and resistance to standard AML therapies. We performed genomic profiling of post-MPN AML samples; these studies demonstrate somatic tumor protein 53 (TP53) mutations are common in JAK2V617F mutant, post-MPN AML but not in chronic-phase MPN and lead to clonal dominance of JAK2V617F/TP53-mutant leukemic cells. Consistent with these data, expression of JAK2V617F combined with Tp53 loss led to fully penetrant AML in vivo. JAK2V617F mutant, Tp53-deficient AML was characterized by an expanded megakaryocyte erythroid progenitor population that was able to propagate the disease in secondary recipients. In vitro studies revealed that post-MPN AML cells were sensitive to decitabine, the JAK1/2 inhibitor ruxolitinib, or the heat shock protein 90 inhibitor 8-(6-iodobenzo[d][1.3]dioxol-5-ylthio)-9-(3 (isopropylamino)propyl)-9H-purine-6-amine (PU-H71). Treatment with ruxolitinib or PU-H71 improved survival of mice engrafted with JAK2V617F-mutant, Tp53-deficient AML, demonstrating therapeutic efficacy for these targeted therapies and providing a rationale for testing these therapies in post-MPN AML. PMID- 25516984 TI - Kinetic pathway of 40S ribosomal subunit recruitment to hepatitis C virus internal ribosome entry site. AB - Translation initiation can occur by multiple pathways. To delineate these pathways by single-molecule methods, fluorescently labeled ribosomal subunits are required. Here, we labeled human 40S ribosomal subunits with a fluorescent SNAP tag at ribosomal protein eS25 (RPS25). The resulting ribosomal subunits could be specifically labeled in living cells and in vitro. Using single-molecule Forster resonance energy transfer (FRET) between RPS25 and domain II of the hepatitis C virus (HCV) internal ribosome entry site (IRES), we measured the rates of 40S subunit arrival to the HCV IRES. Our data support a single-step model of HCV IRES recruitment to 40S subunits, irreversible on the initiation time scale. We furthermore demonstrated that after binding, the 40S:HCV IRES complex is conformationally dynamic, undergoing slow large-scale rearrangements. Addition of translation extracts suppresses these fluctuations, funneling the complex into a single conformation on the 80S assembly pathway. These findings show that 40S:HCV IRES complex formation is accompanied by dynamic conformational rearrangements that may be modulated by initiation factors. PMID- 25516985 TI - In vivo anticancer activity of rhomboidal Pt(II) metallacycles. AB - The development of novel antitumor agents that have high efficacy in suppressing tumor growth, have low toxicity to nontumor tissues, and exhibit rapid localization in the targeted tumor sites is an ongoing avenue of research at the interface of chemistry, cancer biology, and pharmacology. Supramolecular metal based coordination complexes (SCCs) have well-defined shapes and geometries, and upon their internalization, SCCs could affect multiple oncogenic signaling pathways in cells and tissues. We investigated the uptake, intracellular localization, and antitumor activity of two rhomboidal Pt(II)-based SCCs. Laser scanning confocal microscopy in A549 and HeLa cells was used to determine the uptake and localization of the assemblies within cells and their effect on tumor growth was investigated in mouse s.c. tumor xenograft models. The SCCs are soluble in cell culture media within the entire range of studied concentrations (1 nM-5 uM), are nontoxic, and showed efficacy in reducing the rate of tumor growth in s.c. mouse tumor xenografts. These properties reveal the potential of Pt(II)-based SCCs for future biomedical applications as therapeutic agents. PMID- 25516986 TI - Maternal temperature history activates Flowering Locus T in fruits to control progeny dormancy according to time of year. AB - Seasonal behavior is important for fitness in temperate environments but it is unclear how progeny gain their initial seasonal entrainment. Plants use temperature signals to measure time of year, and changes to life histories are therefore an important consequence of climate change. Here we show that in Arabidopsis the current and prior temperature experience of the mother plant is used to control germination of progeny seeds, via the activation of the florigen Flowering Locus T (FT) in fruit tissues. We demonstrate that maternal past and current temperature experience are transduced to the FT locus in silique phloem. In turn, FT controls seed dormancy through inhibition of proanthocyanidin synthesis in fruits, resulting in altered seed coat tannin content. Our data reveal that maternal temperature history is integrated through FT in the fruit to generate a metabolic signal that entrains the behavior of progeny seeds according to time of year. PMID- 25516988 TI - Moving from Safety I to Safety II, but what about the media? PMID- 25516987 TI - Developing and evaluating the success of a family activated medical emergency team: a quality improvement report. AB - BACKGROUND: Family-activated medical emergency teams (MET) have the potential to improve the timely recognition of clinical deterioration and reduce preventable adverse events. Adoption of family-activated METs is hindered by concerns that the calls may substantially increase MET workload. We aimed to develop a reliable process for family activated METs and to evaluate its effect on MET call rate and subsequent transfer to the intensive care unit (ICU). METHODS: The setting was our free-standing children's hospital. We partnered with families to develop and test an educational intervention for clinicians and families, an informational poster in each patient room and a redesigned process with hospital operators who handle MET calls. We tracked our primary outcome of count of family-activated MET calls on a statistical process control chart. Additionally, we determined the association between family-activated versus clinician-activated MET and transfer to the ICU. Finally, we compared the reason for MET activation between family calls and a 2:1 matched sample of clinician calls. RESULTS: Over our 6-year study period, we had a total of 83 family-activated MET calls. Families made an average of 1.2 calls per month, which represented 2.9% of all MET calls. Children with family-activated METs were transferred to the ICU less commonly than those with clinician MET calls (24% vs 60%, p<0.001). Families, like clinicians, most commonly called MET for concerns of clinical deterioration. Families also identified lack of response from clinicians and a dismissive interaction between team and family as reasons. CONCLUSIONS: Family MET activations were uncommon and not a burden on responders. These calls recognised clinical deterioration and communication failures. Family activated METs should be tested and implemented in hospitals that care for children. PMID- 25516989 TI - Role of androgens in normal and pathological ovarian function. AB - Androgens mediate their actions via the androgen receptor (AR), a member of the nuclear receptor superfamily. AR-mediated androgen action is essential in male reproductive development and function; however, only in the last decade has the suspected but unproven role for AR-mediated actions in female reproduction been firmly established. Deciphering the specific roles and precise pathways by which AR-mediated actions regulate ovarian function has been hindered by confusion on how to interpret results from pharmacological studies using androgens that can be converted into oestrogens, which exert actions via the oestrogen receptors. The generation and analysis of global and cell-specific female Ar knockout mouse models have deduced a role for AR-mediated actions in regulating ovarian function, maintaining female fertility, and have begun to unravel the mechanisms by which AR-mediated androgen actions regulate follicle health, development and ovulation. Furthermore, observational findings from human studies and animal models provide substantial evidence to support a role for AR-mediated effects not only in normal ovarian function but also in the development of the frequent ovarian pathological disorder, polycystic ovarian syndrome (PCOS). This review focuses on combining the findings from observational studies in humans, pharmacological studies and animal models to reveal the roles of AR-mediated actions in normal and pathological ovarian function. Together these findings will enable us to begin understanding the important roles of AR actions in the regulation of female fertility and ovarian ageing, as well as providing insights into the role of AR actions in the androgen-associated reproductive disorder PCOS. PMID- 25516990 TI - Regeneration of Leydig cells in ectopically autografted adult mouse testes. AB - Ectopic autografting of testis tissue is a promising approach for studying testicular development, male germline preservation and restoration of male fertility. In this study, we examined the fate of various testicular cells in adult mouse testes following ectopic autografting at 1, 2, 4 and 8 weeks post grafting. Histological examination showed no evidence of re-establishment of spermatogenesis in autografts, and progressive degeneration of seminiferous tubules was detected. Expression of germ cell-specific proteins such as POU5F1, DAZL, TNP1, TNP2, PRM1 and PRM2 revealed that, although proliferating and differentiating spermatogenic germ cells such as spermatogonia, spermatocytes and spermatids could survive in autografts until 4 weeks, only terminally differentiated germ cells such as sperm persisted in autografts until 8 weeks. The presence of Sertoli and peritubular myoid cells, as indicated by expression of WT1 and ACTA2 proteins, respectively, was evident in the autografts until 8 weeks. Interestingly, seminal vesicle weight and serum testosterone level were restored in autografted mice by 8 weeks post grafting. The expression of Leydig cell-specific proteins such as CYP11A1, HSD3B2 and LHCGR showed revival of Leydig cell (LC) populations in autografts over time since grafting. Elevated expression of PDGFRA, LIF, DHH and NEFH in autografts indicated de novo regeneration of LC populations. Autografted adult testis can be used as a model for investigating Leydig cell regeneration, steroidogenesis and regulation of the intrinsic factors involved in Leydig cell development. The success of this rodent model can have therapeutic applications for adult human males undergoing sterilizing cancer therapy. PMID- 25516991 TI - Randomized controlled trial of cryoanalgesia (ice bag) to reduce pain associated with arterial puncture. AB - BACKGROUND: Arterial puncture can be a painful procedure for many patients. This study investigates whether precooling of a puncture site with ice can reduce the pain associated with arterial puncture. METHODS: This was a stratified randomized controlled trial of a convenience sample of out-patients with a physician order for an arterial blood gas (ABG) test. The intervention group had a plastic bag of ice applied to their wrists for 3 min before drawing an ABG sample from the radial artery. The control group had an ABG sample drawn from the radial artery without the application of ice. Pain from the arterial puncture was measured with a 100-mm visual analog scale. RESULTS: Subjects pretreated with ice reported less pain from arterial puncture compared with subjects in the control group (mean visual analog scale 13.8 +/- 16.9 vs 25 +/- 23 mm, P = .01; median visual analog scale 7 mm, interquartile range (IQR) 1.5-19 vs 20 mm, IQR 4.5-38.5 mm, P = .01). Stratified analysis showed that visual analog scale pain scores were lower in the naive group when ice was applied (naive ice vs naive control: mean visual analog scale 11 +/- 14.3 vs 26.5 +/- 25 mm, P = .02; median visual analog scale 5 mm, IQR 2-14.5 vs 20 mm, IQR 6.5-36 mm, P = .02). Visual analog scale pain scores trended lower in the experienced group when ice was applied (experienced ice vs experienced control: mean visual analog scale 15.9 +/- 18.9 vs 25.1 +/- 22 mm, P = .15; median visual analog scale 8 mm, IQR 0.5-26.5 vs 23 mm, IQR 3.5-40 mm, P = .08). There was no difference in first-attempt success between groups (ice group: 85%, control group: 82.5%, P > .99). Only 3 subjects could not tolerate 3-min ice application. CONCLUSIONS: Ice application before arterial puncture is well tolerated and reduces procedure-related pain. (ClinicalTrials.gov NCT02065115). PMID- 25516992 TI - Can we better estimate resting oxygen consumption by incorporating arterial blood gases and spirometric determinations? AB - BACKGROUND: We hypothesize that oxygen consumption (Vo2) estimation in patients with respiratory symptoms is inaccurate and can be improved by considering arterial blood gases or spirometric variables. METHODS: For this retrospective study, we included consecutive subjects who underwent cardiopulmonary exercise testing. Resting Vo2 was determined using breath-by-breath testing methodology. Using a training cohort (n = 336), we developed 3 models to predict Vo2. In a validation group (n = 114), we compared our models with 7 available formulae. RESULTS: Our first model (Vo2 = -184.99 + 189.64 * body surface area [BSA, m(2)] + 1.49 * heart rate [beats/min] + 51.51 * FIO2 [21% = 0; 30% = 1] + 30.62 * gender [male = 1; female = 0]) showed an R(2) of 0.5. Our second model (Vo2 = 208.06 + 188.67 * BSA + 1.38 * heart rate + 35.6 * gender + 2.06 * breathing frequency [breaths/min]) showed an R(2) of 0.49. The best R(2) (0.68) was obtained with our last model, which included minute ventilation (Vo2 = -142.92 + 0.52 * heart rate + 126.84 * BSA + 14.68 * minute ventilation [L]). In the validation cohort, these 3 models performed better than other available equations, but had wide limits of agreement, particularly in older individuals with shorter stature, higher heart rate, and lower maximum voluntary ventilation. CONCLUSIONS: We developed more accurate formulae to predict resting Vo2 in subjects with respiratory symptoms; however, equations had wide limits of agreement, particularly in certain groups of subjects. Arterial blood gases and spirometric variables did not significantly improve the predictive equations. PMID- 25516993 TI - Effects of Oxygen Supply During Training on Subjects With COPD Who Are Normoxemic at Rest and During Exercise: A Blinded Randomized Controlled Trial. AB - BACKGROUND: It is well established that physical training enhances functionality and quality of life in patients with COPD. However, little data exist concerning the effects of the usefulness of oxygen supply during exercise training for > 3 months in patients with COPD who are normoxemic at rest and during exercise. We hypothesized that oxygen supply during training sessions enables higher training intensity and thus optimizes training results in patients with COPD. METHODS: In this blinded randomized controlled study, we carried out a 24-week training program with progressively increasing loads involving large muscle groups. In addition, we compared the influences of oxygen supplementation. Thirty-six subjects with moderate-to-severe COPD who were not dependent on long-term oxygen therapy trained under supervision for 24 weeks (3 times/week at 30 min/session). Subjects were randomized into 2 groups: oxygen supply via nasal cannula at a flow of 4 L/min and compressed air at the same flow throughout the training program. Lung function tests at rest (inspiratory vital capacity, FEV1, Tiffeneau index), cycle spiroergometry (peak ventilation, peak oxygen uptake, peak respiratory exchange rate, submaximal and peak lactic acid concentrations), 6-min walk tests, and quality-of-life assessments (Medical Outcomes Study 36-Item Short Form questionnaire) were conducted before and after 12 and 24 weeks. RESULTS: Independent of oxygen supplementation, statistically significant improvements occurred in quality of life, maximal tolerated load during cycling, peak oxygen uptake, and 6-min walk test after 12 weeks of training. Notably, there were no further improvements from 12 to 24 weeks despite progressively increased training loads. CONCLUSIONS: Endurance training 3 times/week resulted in significant improvements in quality of life and exercise capacity in subjects with moderate to-severe COPD within the initial 12 weeks, followed by a stable period over the following 12 weeks with no further benefits of supplemental oxygen. PMID- 25516994 TI - Lifestyle Implications of Home Mechanical Insufflation-Exsufflation for Children With Neuromuscular Disease and Their Families. AB - BACKGROUND: Mechanical insufflation-exsufflation (MI-E) is increasingly used in the home management of children with neuromuscular disease. Research to date has focused on the effect of MI-E on physical health. The aim of this study was to qualitatively investigate the impact of home MI-E on the child and family's lifestyle. METHODS: Eight parents and 3 children participated in semistructured interviews. RESULTS: Five themes emerged from parent interviews demonstrating: (1) lifestyle implications, (2) parents becoming experts, (3) parents developing a sense of control over their child's condition, (4) an element of extra care, and (5) impacts on the parent-child relationship. Developing themes from the child interviews showed them adjusting to and then relying on the device. Home MI E medicalized the home, but the overall lifestyle impact was positive. CONCLUSIONS: Although involving a small number of subjects, this study demonstrated a mixture of opposing impacts of home MI-E on lifestyle, both enabling and disabling, which need to be considered when introducing home MI-E. The positive impacts included greater ability to manage the child's health, including avoidance of hospital admissions. Negative impacts were greatest for those parents who were sole operators of the device, including a frequently disrupted lifestyle. PMID- 25516995 TI - Physicochemical aspects and efficiency of albuterol nebulization: comparison of three aerosol types in an in vitro pediatric model. AB - BACKGROUND: Advances in nebulizer design have produced both ultrasonic nebulizers and devices based on a vibrating mesh (vibrating mesh nebulizers), which are expected to enhance the efficiency of aerosol drug therapy. The aim of this study was to compare 4 different nebulizers, of 3 different types, in an in vitro model using albuterol delivery and physical characteristics as benchmarks. METHODS: The following nebulizers were tested: Sidestream Disposable jet nebulizer, Multisonic Infra Control ultrasonic nebulizer, and the Aerogen Pro and Aerogen Solo vibrating mesh nebulizers. Aerosol duration, temperature, and drug solution osmolality were measured during nebulization. Albuterol delivery was measured by a high-performance liquid chromatography system with fluorometric detection. The droplet size distribution was analyzed with a laser granulometer. RESULTS: The ultrasonic nebulizer was the fastest device based on the duration of nebulization; the jet nebulizer was the slowest. Solution temperature decreased during nebulization when the jet nebulizer and vibrating mesh nebulizers were used, but it increased with the ultrasonic nebulizer. Osmolality was stable during nebulization with the vibrating mesh nebulizers, but increased with the jet nebulizer and ultrasonic nebulizer, indicating solvent evaporation. Albuterol delivery was 1.6 and 2.3 times higher with the ultrasonic nebulizer and vibrating mesh nebulizers devices, respectively, than with the jet nebulizer. Particle size was significantly higher with the ultrasonic nebulizer. CONCLUSIONS: The in vitro model was effective for comparing nebulizer types, demonstrating important differences between nebulizer types. The new devices, both the ultrasonic nebulizers and vibrating mesh nebulizers, delivered more aerosolized drug than traditional jet nebulizers. PMID- 25516998 TI - Galileo would have loved sports biomechanics, digitised ECG and his smartphone. PMID- 25516997 TI - [Entrustable professional activities in the internship. Reply]. PMID- 25516999 TI - [The article by Kalinin et al. "Injury to the cavernous segment of the internal artery upon transsphenoidal endoscopic removal of pituitary adenomas" (2013, N degrees 6)]. PMID- 25516996 TI - Role of tautomerism in RNA biochemistry. AB - Heterocyclic nucleic acid bases and their analogs can adopt multiple tautomeric forms due to the presence of multiple solvent-exchangeable protons. In DNA, spontaneous formation of minor tautomers has been speculated to contribute to mutagenic mispairings during DNA replication, whereas in RNA, minor tautomeric forms have been proposed to enhance the structural and functional diversity of RNA enzymes and aptamers. This review summarizes the role of tautomerism in RNA biochemistry, specifically focusing on the role of tautomerism in catalysis of small self-cleaving ribozymes and recognition of ligand analogs by riboswitches. Considering that the presence of multiple tautomers of nucleic acid bases is a rare occurrence, and that tautomers typically interconvert on a fast time scale, methods for studying rapid tautomerism in the context of nucleic acids under biologically relevant aqueous conditions are also discussed. PMID- 25517000 TI - [The long-associative pathway of the white matter: modern view from the perspective of neuroscience]. AB - This review presents basic information about white matter tracts of the human brain, with a special emphasis being placed on long associative fibers (superior and inferior longitudinal fascicles, inferior frontooccipital fascicles, fasciculus arcuatus and fasciclus uncinatus): their structure, history, functions, methods of preoperative and intraoperative identification during neurosurgical operations. Neurological symptoms caused by a damage to each of the above-described long associative fiber are described. There is a detailed analysis of methods of neuropsychological testing and neurophysiological identification in white matter fiber tract mapping in focal brain lesions. PMID- 25517001 TI - [The informed patient: how much participation is healthy?]. PMID- 25517002 TI - How should we describe worsening asthma in Cochrane reviews, and does it matter? PMID- 25517003 TI - Toward a comparative retrospective analysis of rat and rabbit developmental toxicity studies for pharmaceutical compounds. AB - Based on a proposal made at the ICH Workshop in Tallinn, Estonia (2010), the value of the rabbit embryo-fetal development (EFD) versus the rodent EFD was examined by the HESI DART group. A cross-industry data survey provided anonymised EFD and toxicokinetic data from EFD studies on over 400 marketed and unmarketed drugs (over 800 studies) that were entered by experts at RIVM into US EPA's ToxRefDB style database. The nature and severity of findings at the lowest observed adverse effect level (LOAEL) are being reviewed to quantitate the frequency with which lesser signs of embryo-fetal effects (e.g., delays in ossification, minor changes in frequency of variants) are driving the LOAELs. Interpretation was based on exposure rather than administered dose. This paper provides an update of this ongoing project as discussed during a workshop of the European Teratology Society in Ispra, Italy (2013). This was the first presentation of the initial data set, allowing debate on future directions, to provide a better understanding of the implications of either delaying a rabbit EFD or waiving the need in particular circumstances. PMID- 25517004 TI - A decade of researching the social aspects of HIV and AIDS. PMID- 25517005 TI - Peter Orchard Williams. PMID- 25517006 TI - Ocean biology: Marine dreams. PMID- 25517008 TI - NRC submits inter-agency task force report on radiation source protection and security. PMID- 25517007 TI - In memoriam Andre S. Dreiding. AB - In his talk at the 49th Burgenstock Conference on Stereochemistry, the author paid tribute to Andre S. Dreiding, the founder of this event. PMID- 25517009 TI - IAEA scientific forum highlights responsibility for radioactive waste. PMID- 25517010 TI - [Not Available]. PMID- 25517011 TI - ABA mediates PEG-mediated premature differentiation of root apical meristem in plants. AB - Root apical meristem (RAM) is central for indeterminate growth of plant roots and in sensing environmental stimuli, such as water status. Recently, we reported that PEG8000-simulated mild and moderate osmotic stress induces premature differentiation of RAM, which is a conserved adaptive mechanism in higher plants to cope with water stress. Microarray data analysis revealed that the ABA signaling pathway may be involved in water stress-induced RAM premature differentiation. Here we showed that in wheat, ABA contents increased under water stress with the highest level of ABA in the RAM. Exogenous ABA also induces RAM premature differentiation in both wheat and Arabidopsis plants. Further genetic analysis revealed that loss of function mutations in ABA2 and ABA receptors significantly reduced the level of root tip swelling and RAM premature differentiation in response to PEG-simulated water stress. Together, the results suggest that ABA participates in regulation of PEG-mediated premature differentiation of RAM. PMID- 25517012 TI - Thermoresponsive cationic copolymer brushes for mesenchymal stem cell separation. AB - Thermoresponsive, cationic, copolymer brushes poly(N-isopropylacrylamide(IPAAm) co-N,N-dimethylaminopropylacrylamide-co-N-tert-butylacrylamide(tBAAm)) and poly(IPAAm-co-3-acrylamidopropyl trimethylammonium chloride-co-tBAAm) were prepared on glass substrates through surface-initiated atom transfer radical polymerization. Prepared copolymer brushes were investigated as thermally modulated cell separation materials. Densely packed cationic copolymer brushes were formed on the glass substrates, and the positive charge density was modulated by controlling the composition of cationic moieties and species. During observation of cell adhesion and detachment properties on copolymer brushes, human bone marrow mesenchymal stem cells (hbmMSC) exhibited thermally modulated cell adhesion and detachment, while other bone-marrow-derived cells did not adhere. Using these properties, hbmMSC could be purified from mixtures of human bone-marrow-derived cells simply by changing the external temperature. Therefore, the prepared cationic copolymer brush is useful for separation of hbmMSC. PMID- 25517013 TI - Axial hydrogen at C7 position and bumpy tetracyclic core markedly reduce sterol's affinity to amphotericin B in membrane. AB - The interaction of amphotericin B (AmB) with fungal ergosterol (Erg) is stronger than its interaction with mammalian cholesterol (Cho), and this property of AmB as an antifungal drug is thought to be responsible for its selective toxicity toward fungi. However, the mechanism by which AmB recognizes the structural differences between sterols, particularly minor difference in the sterol alicyclic portion, is largely unknown. Thus, to investigate the mode of interaction between AmB and the sterol core, we assessed the affinity of AmB to various sterols with different alicyclic structures. Ion flux assays and UV spectral measurements clearly revealed the importance of the Delta7-double bond of the sterol B-ring for interaction with the drug. AmB showed lower affinity for triene sterols, which have double bonds at the Delta5, Delta7, and Delta9 positions. Intermolecular distance measurements by (13)C{(19)F} rotational echo double resonance (REDOR) revealed that the AmB macrolide ring is in closer contact with the steroid core of Erg than it is with the Cho core in the membrane. Conformational analysis suggested that an axial hydrogen atom at C7 of Delta5-sterol (2, 6) and the protruded A-ring of Delta5,7,9-sterol (4, 8) sterically hampered face-to-face contact between the van der Waals surface of the sterol core and the macrolide of AmB. These results further suggest that the alpha-face of sterol alicycle interacts with the flat macrolide structure of AmB. PMID- 25517014 TI - Asymmetric synthesis of gem-difluoromethylenated linear triquinanes via cascade gem-difluoroalkyl radical cyclization. AB - An asymmetric synthesis of gem-difluoromethylenated linear triquinanes is described exploiting the synthetic utilities of PhSCF2TMS (5) as a "(*)CF2(-)'' building block. The strategy involves fluoride-catalyzed nucleophilic addition of PhSCF2TMS (5) to chiral ketocyclopentenes 6 to provide silylated adducts 9 or alcohol derivatives 10 and 11. Subsequent cascade radical cyclization of the gem difluoroalkyl radical generated from silylated adducts 9 or alcohols 10 and 11 afforded gem-difluoromethylenated linear triquinanes 16 as an approximate 1:1 mixture of two diastereomers (16A and 16B). Alternatively, a convenient asymmetric synthesis of gem-difluoromethylenated linear triquinanes 16A can be accomplished by oxidation of 16a (R = H) to provide ketotriquinane 17 followed by a highly stereoselective nucleophilic addition to 17 employing DIBAL, NaBH4, and various Grignard reagents. PMID- 25517015 TI - Design, synthesis, and evaluation of new thiadiazole-based direct inhibitors of enoyl acyl carrier protein reductase (InhA) for the treatment of tuberculosis. AB - Mycobacterial enoyl acyl carrier protein reductase (InhA) is a clinically validated target for the treatment of tuberculosis infections, a disease that still causes the death of at least a million people annually. A known class of potent, direct, and competitive InhA inhibitors based on a tetracyclic thiadiazole structure has been shown to have in vivo activity in murine models of tuberculosis infection. On the basis of this template, we have here explored the medicinal chemistry of truncated analogues that have only three aromatic rings. In particular, compounds 8b, 8d, 8f, 8l, and 8n show interesting features, including low nanomolar InhA IC50, submicromolar antimycobacterial potency, and improved physicochemical profiles in comparison with the tetracyclic analogues. From this series, 8d is identified as having the best balance of potency and properties, whereby the resolved 8d S-enatiomer shows encouraging in vivo efficacy. PMID- 25517016 TI - The cerebrospinal fluid-stem cell interactions as target for regenerative therapy in neurological diseases. PMID- 25517017 TI - Expectant management of PPROM and major complications before planned delivery: a retrospective cohort study. AB - Women with pre-term pre-labour rupture of membranes (PPROM) 22-33 weeks' gestation were included in a retrospective cohort study with a structured audit to identify risk factors of major complications following PPROM and to assess whether these complications are predictable. Of the 234 women analysed, 106 (45%) delivered within three days. Eighty-four women (36%) had at least one major complication and 45% of these complications occurred within three days. The complication rate was 64% in early PPROM before 28 weeks' gestation and 11% in late PPROM at 28 weeks' gestation or later. Nulliparous women had an increased risk of major complications (adjusted hazards ratio: 3.07 (95% confidence interval: 1.28-7.37)). The complication rates were highest in early PPROM and during the first three days after PPROM. Multiparous women with late PPROM, who do not deliver within the first three days, have the lowest risk of major complications and are suitable for home care. PMID- 25517019 TI - Electrospray droplet exposure to organic vapors: metal ion removal from proteins and protein complexes. AB - The exposure of aqueous nanoelectrospray droplets to various organic vapors can dramatically reduce sodium adduction on protein ions in positive ion mass spectra. Volatile alcohols, such as methanol, ethanol, and isopropanol lead to a significant reduction in sodium ion adduction but are not as effective as acetonitrile, acetone, and ethyl acetate. Organic vapor exposure in the negative ion mode, on the other hand, has essentially no effect on alkali ion adduction. Evidence is presented to suggest that the mechanism by which organic vapor exposure reduces alkali ion adduction in the positive mode involves the depletion of alkali metal ions via ion evaporation of metal ions solvated with organic molecules. The early generation of metal/organic cluster ions during the droplet desolvation process results in fewer metal ions available to condense on the protein ions formed via the charged residue mechanism. These effects are demonstrated with holomyoglobin ions to illustrate that the metal ion reduction takes place without detectable protein denaturation, which might be revealed by heme loss or an increase in charge state distribution. No evidence is observed for denaturation with exposure to any of the organic vapors evaluated in this work. PMID- 25517020 TI - Bombesin-like peptides and their receptors: recent findings in pharmacology and physiology. AB - PURPOSE OF REVIEW: To highlight the research progress of roles of bombesin-like peptides and their receptors in pharmacology and physiology. RECENT FINDINGS: Several new bombesin-derived radioactive or nonradioactive compounds were designed for the diagnosis and therapy of tumors that are overexpressing bombesin receptors. Both gastrin-releasing peptide receptor and neuromedin B receptor activation were shown to induce membrane depolarization and excite neurons in brain. Bombesin receptor subtype-3 was found to be downregulated in the muscle cells and myocytes from obese and type 2 diabetes patients, and its relevant cell signaling events in glucose homeostasis were also investigated. The molecular events triggered by bombesin receptors activation in different types of malignancies is being explored recently and new clues were provided for a better understanding of the biological roles of abnormal expression of bombesin receptors in tumors. Novel cross-talk between gastrin-releasing peptide receptor cell signaling and Sonic hedgehog pathways was identified in small-cell lung carcinoma. SUMMARY: Increasing evidence shows bombesin-like peptides and their receptors play important roles in both physiological state and diseases. More specific and safe tumor targeting Bombesin derivatives are being developed for tumor diagnosis and therapy. PMID- 25517021 TI - Cushing's syndrome in childhood: update on genetics, treatment, and outcomes. AB - PURPOSE OF REVIEW: To provide an update on the genes associated with Cushing's syndrome in children, as well as to familiarize the clinician with recent treatment guidelines and outcome data for children with Cushing's syndrome. RECENT FINDINGS: The list of genes associated with Cushing's syndrome continues to grow. In addition, treatment for childhood Cushing's syndrome is evolving. As long-term follow-up data on children becomes available, clinicians need to be aware of the issues that require attention. SUMMARY: Knowledge of the specific genetic causes of Cushing's syndrome has potential implications for treatment, surveillance, and counseling. Advances in surgical technique, radiation modalities, and medical therapies offer the potential for additional treatment options in Cushing's syndrome. Early identification and management of post treatment morbidities in children treated for Cushing's syndrome is crucial in order to optimize care. PMID- 25517022 TI - Sleep patterns and obesity in childhood. AB - PURPOSE OF REVIEW: To highlight the recent findings on sleep-obesity associations in children. We focus on sleep duration, sleep timing and chronotype, and describe the potential mechanisms underlying sleep-obesity associations. RECENT FINDINGS: Poor sleep is increasingly common in children and associations between short sleep duration in early childhood and obesity are consistently found. Less is known about the infancy period, and the findings in adolescents are inconsistent. Sleep timing patterns may also contribute to obesity risk. Variable and shifted sleep schedules and evening chronotypes have recently been linked to adiposity in adults; less is known about children. Further, there is little understanding regarding the mechanisms of association. The timing of eating, dietary intake, obesogenic eating behaviors, and changes in appetite-regulating hormones have been identified as possible mechanisms for sleep-obesity associations and may be promising avenues for future research. Longitudinal and experimental work with children is needed to determine the nature of associations. SUMMARY: Beyond sleep duration, sleep timing patterns may contribute to obesity risk. Biological and behavioral processes have been proposed as mechanisms that may explain the association. Understanding the pathways through which poor sleep patterns could increase obesity risk in children may provide novel avenues for intervention. PMID- 25517024 TI - Gastrointestinal hormones and gut motility. AB - PURPOSE OF REVIEW: To summarize the recent findings. RECENT FINDINGS: Studies of changes in the plasma levels confirm the earlier concepts, but offer little proof of causal effect. It is increasingly realized that peptides produced in the gut have a paracrine role or an indirect effect via the gut-brain axis. Interest in prokinetic peptide agonists remains high despite the failure of two candidate drugs, but relamorelin and camicinal offer new hope. SUMMARY: We review the original studies published since January 2013 on peptides produced in the gut and with an effect on gastrointestinal motility. PMID- 25517023 TI - An update on childhood bone health: mineral accrual, assessment and treatment. AB - PURPOSE OF REVIEW: To update the reader's knowledge about the factors that influence bone mineral accrual and to review the advances in the assessment of bone health and treatment of bone disorders. RECENT FINDINGS: Maternal vitamin D status influences neonatal calcium levels, bone mineral density (BMD) and bone size. In turn, BMD z-score tends to track in childhood. These factors highlight the importance of bone health as early as fetal life. Dual-energy x-ray absorptiometry is the mainstay of clinical bone health assessment in this population because of the availability of appropriate reference data. Recently, more information has become available about the assessment and treatment of bone disease in chronically ill pediatric patients. SUMMARY: Bone health must become a health focus starting prenatally in order to maximize peak bone mass and to prevent osteoporosis-related bone disease in adulthood. Vitamin D, calcium and weight-bearing activity are the factors of key importance throughout childhood in achieving optimal bone health as BMD z-score tracks through childhood and into adulthood. Recent updates of the International Society for Clinical Densitometry focus on the appropriate use of dual-energy x-ray absorptiometry in children of all ages, including children with chronic disease, and on the treatment of pediatric bone disease. PMID- 25517025 TI - Updates in weight loss surgery and gastrointestinal peptides. AB - PURPOSE OF REVIEW: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy are referred to as 'metabolic surgery' due to hormonal shifts with impacts on diabetes remission and weight loss. The purpose of this review is to summarize recent findings in mechanisms underlying beneficial effects of weight loss surgery. RECENT FINDINGS: Importantly, gut hormone secretion is altered after RYGB and sleeve gastrectomy due to accelerated transit of nutrients to distal parts of the small intestine, leading to excessive release of L-cell peptide hormones [e.g. glucagon-like peptide-1 (GLP-1), peptide YY].Improved glucose metabolism after RYGB and sleeve gastrectomy involves several mechanisms: early increased hepatic insulin sensitivity, resulting from reduced liver fat content in response to the postoperative caloric restriction, improved beta-cell function mediated by exaggerated postprandial GLP-1 secretion; as demonstrated by relapse of impaired glucose tolerance in studies blocking the GLP-1 receptor by exendin 9 39, and later after major weight loss increased peripheral insulin sensitivity. Gut hormone secretion changes towards a more anorectic profile and is likely important for less caloric intake and weight loss. SUMMARY: Changes in gut hormone secretion after RYGB and sleeve gastrectomy surgery induce the beneficial effects on weight and glycemic control through the influence on appetite regulation and insulin secretion. PMID- 25517026 TI - Turner syndrome: update on biology and management across the life span. AB - PURPOSE OF REVIEW: We review recent understanding of the pathophysiology, molecular biology, and management of Turner syndrome. RECENT FINDINGS: Sophisticated genetic techniques are able to detect mosaicism in one-third of individuals previously thought to have monosomy X. Prenatal detection using maternal blood should permit noninvasive detection of most fetuses with an X chromosome abnormality. Disproportionate growth with short limbs has been documented in this condition, and a target gene of short stature homeobox, connective tissue growth factor (Ctgf), has been described. Liver disease is more common in Turner syndrome than previously recognized. Most girls have gonadal failure. Spontaneous puberty and menarche is more commonly seen in girls with XX mosaicism. Low-dose estrogen replacement therapy may be given early to induce a more normal onset and tempo of puberty. Oocyte donation for assisted reproduction carries a substantial risk, particularly if the woman has known cardiac or aortic disease. Neurodevelopmental differences in Turner syndrome are beginning to be correlated with differences in brain anatomy. SUMMARY: An increased understanding of the molecular basis for aspects of this disorder is now developing. In addition, a renewed focus on health maintenance through the life span should provide better general and targeted healthcare for these girls and women. PMID- 25517027 TI - Clinical supervision in the palliative care team setting: a concrete approach to team wellness. AB - Clinical supervision is a structured, case-based approach to learning that is used most often in the mental health field. An established palliative care consultation service at a large, academic medical center implemented a modified clinical supervision model in an effort to improve team members' awareness of their own emotions and the way those emotions impact behavior during, primarily, clinical encounters. This report discusses clinical supervision in detail and, by way of a case, illustrates the power of this intervention as a source of self care and a concrete approach to managing palliative care team well-being. PMID- 25517028 TI - A shape-recovery polymer coating for the corrosion protection of metallic surfaces. AB - Self-healing polymer coatings are a type of smart material aimed for advanced corrosion protection of metals. This paper presents the synthesis and characterization of two new UV-cure self-healing coatings based on acrylated polycaprolactone polyurethanes. On a macroscopic scale, the cured films all show outstanding mechanical properties, combining relatively high Young's modulus of up to 270 MPa with a strain at break above 350%. After thermal activation the strained films recover up to 97% of their original length. Optical and electron microscopy reveals the self-healing properties of these coatings on hot dip galvanized steel with scratches and microindentations. The temperature-induced closing of such defects restores the corrosion protection and barrier properties of the coating as shown by electrochemical impedance spectroscopy and scanning vibrating electrode technique. Therefore, such coatings are a complementary option for encapsulation-based autonomous corrosion protection systems. PMID- 25517029 TI - Associations between variants in IL-33/ST2 signaling pathway genes and coronary heart disease risk. AB - The IL-33/ST2 signaling pathway plays an important role in coronary artery disease (CHD); however, few studies have explored how variants in IL-33/ST2 genes influence CHD risk. Here, we examined the association between genetic variants in IL-33, ST2, and IL-1RAcP of the IL-33/ST2 axis and the risk of CHD. We conducted a case-controlled study with 1146 CHD cases and 1146 age- and sex-frequency matched controls. Twenty-eight single nucleotide polymorphisms (SNPs) in IL-33, ST2, and IL-1RAcP were genotyped by Sequenom MassArray and TaqMan assay. Logistic regression was used to analyze these associations. The SNP rs4624606 in IL-1RAcP was nominally associated with CHD risk. The AA genotype was associated with a 1.85-fold increased risk of CHD (95% confidence interval (CI) = 1.01-3.36; p = 0.045) compared to the TT genotype. Further analysis showed that AA carriers also had a higher risk of CHD than TT + TA carriers (odds ratio (OR) = 1.85; 95% CI = 1.85-3.35; p = 0.043). However, no significant association was observed between variants in IL-33/ST2 genes and CHD risk. Further studies are needed to replicate our results in other ethnic groups with larger sample size. PMID- 25517030 TI - Detection of abnormal extracellular matrix in the interstitium of regenerating renal tubules. AB - Stem/progenitor cells are promising candidates for the regeneration of parenchyma in acute and chronic renal failure. However, recent data exhibit that survival of stem/progenitor cells after implantation in diseased renal parenchyma is restricted. To elaborate basic parameters improving survival, cell seeding was simulated under advanced in vitro conditions. After isolation, renal stem/progenitor cells were mounted in a polyester interstitium for perfusion culture. During generation of tubules, chemically defined CO2 Independent Medium or Leibovitz's L-15 Medium was applied. Specimens were then fixed for transmission electron microscopy to analyze morphological features in generated tubules. Fixation in conventional glutaraldehyde (GA) solution shows development of tubules each exhibiting a polarized epithelium, an intact basal lamina and an inconspicuous interstitium. In contrast, special fixation of specimens in GA solution containing cupromeronic blue, ruthenium red or tannic acid unveils previously not visible extracellular matrix. Control experiments elucidate that a comparable extracellular matrix is not present in the interstitium of the matured kidney. Thus, generation of renal tubules in combination with advanced fixation of specimens for electron microscopy demonstrates that development of abnormal features in the newly developed interstitium has to be considered, when repair of renal parenchyma is performed by implantation of stem/progenitor cells. PMID- 25517031 TI - Long-term effects of maternal citrulline supplementation on renal transcriptome prevention of nitric oxide depletion-related programmed hypertension: the impact of gene-nutrient interactions. AB - Maternal malnutrition can elicit gene expression leading to fetal programming. L citrulline (CIT) can be converted to L-arginine to generate nitric oxide (NO). We examined whether maternal CIT supplementation can prevent N(G)-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor)-induced programmed hypertension and examined their effects on the renal transcriptome in male offspring using next generation RNA sequencing (RNA-Seq) technology. Pregnant Sprague-Dawley rats received L-NAME administration at 60mg/kg/day subcutaneously via osmotic minipump during pregnancy alone or with additional 0.25% L-citrulline solution in drinking water during the whole period of pregnancy and lactation. Male offspring were assigned to three groups: control, L-NAME, and L-NAME + CIT. L-NAME exposure induced hypertension in the 12-week-old offspring, which CIT therapy prevented. Identified differentially expressed genes in L-NAME and CIT-treated offspring kidneys, including Guca2b, Hmox1, Hba2, Hba-a2, Dusp1, and Serpine1 are related to regulation of blood pressure (BP) and oxidative stress. In conclusion, our data suggests that the beneficial effects of CIT supplementation are attributed to alterations in expression levels of genes related to BP control and oxidative stress. Our results suggest that early nutritional intervention by CIT has long term impact on the renal transcriptome to prevent NO depletion-related programmed hypertension. However, our RNA-Seq results might be a secondary phenomenon. The implications of epigenetic regulation at an early stage of programming deserve further clarification. PMID- 25517032 TI - Identification of biomarkers in cerebrospinal fluid and serum of multiple sclerosis patients by immunoproteomics approach. AB - Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the central nervous system. At present, the molecular mechanisms causing the initiation, development and progression of MS are poorly understood, and no reliable proteinaceous disease markers are available. In this study, we used an immunoproteomics approach to identify autoreactive antibodies in the cerebrospinal fluid of MS patients to use as candidate markers with potential diagnostic value. We identified an autoreactive anti-transferrin antibody that may have a potential link with the development and progression of MS. We found this antibody at high levels also in the serum of MS patients and created an immunoenzymatic assay to detect it. Because of the complexity and heterogeneity of multiple sclerosis, it is difficult to find a single marker for all of the processes involved in the origin and progression of the disease, so the development of a panel of biomarkers is desirable, and anti-transferrin antibody could be one of these. PMID- 25517033 TI - Lipidome of atherosclerotic plaques from hypercholesterolemic rabbits. AB - The cellular, macromolecular and neutral lipid composition of the atherosclerotic plaque has been extensively characterized. However, a comprehensive lipidomic analysis of the major lipid classes within atherosclerotic lesions has not been reported. The objective of this study was to produce a detailed framework of the lipids that comprise the atherosclerotic lesion of a widely used pre-clinical model of plaque progression. Male New Zealand White rabbits were administered regular chow supplemented with 0.5% cholesterol (HC) for 12 weeks to induce hypercholesterolemia and atherosclerosis. Our lipidomic analyses of plaques isolated from rabbits fed the HC diet, using ultra-performance liquid chromatography (UPLC) and high-resolution mass spectrometry, detected most of the major lipid classes including: Cholesteryl esters, triacylglycerols, phosphatidylcholines, sphingomyelins, diacylglycerols, fatty acids, phosphatidylserines, lysophosphatidylcholines, ceramides, phosphatidylglycerols, phosphatidylinositols and phosphatidylethanolamines. Given that cholesteryl esters, triacylglycerols and phosphatidylcholines comprise greater than 75% of total plasma lipids, we directed particular attention towards the qualitative and quantitative assessment of the fatty acid composition of these lipids. We additionally found that sphingomyelins were relatively abundant lipid class within lesions, and compared the abundance of sphingomyelins to their precursor phosphatidylcholines. The studies presented here are the first approach to a comprehensive characterization of the atherosclerotic plaque lipidome. PMID- 25517036 TI - Fabrication of 3D core-shell multiwalled carbon nanotube@RuO2 lithium-ion battery electrodes through a RuO2 atomic layer deposition process. AB - Pushing lithium-ion battery (LIB) technology forward to its fundamental scaling limits requires the ability to create designer heterostructured materials and architectures. Atomic layer deposition (ALD) has recently been applied to advanced nanostructured energy storage devices due to the wide range of available materials, angstrom thickness control, and extreme conformality over high aspect ratio nanostructures. A class of materials referred to as conversion electrodes has recently been proposed as high capacity electrodes. RuO2 is considered an ideal conversion material due to its high combined electronic and ionic conductivity and high gravimetric capacity, and as such is an excellent material to explore the behavior of conversion electrodes at nanoscale thicknesses. We report here a fully characterized atomic layer deposition process for RuO2, electrochemical cycling data for ALD RuO2, and the application of the RuO2 to a composite carbon nanotube electrode scaffold with nucleation-controlled RuO2 growth. A growth rate of 0.4 A/cycle is found between ~ 210-240 degrees C. In a planar configuration, the resulting RuO2 films show high first cycle electrochemical capacities of ~ 1400 mAh/g, but the capacity rapidly degrades with charge/discharge cycling. We also fabricated core/shell MWCNT/RuO2 heterostructured 3D electrodes, which show a 50* increase in the areal capacity over their planar counterparts, with an areal lithium capacity of 1.6 mAh/cm(2). PMID- 25517034 TI - Effects of Icariside II on corpus cavernosum and major pelvic ganglion neuropathy in streptozotocin-induced diabetic rats. AB - Diabetic erectile dysfunction is associated with penile dorsal nerve bundle neuropathy in the corpus cavernosum and the mechanism is not well understood. We investigated the neuropathy changes in the corpus cavernosum of rats with streptozotocin-induced diabetes and the effects of Icariside II (ICA II) on improving neuropathy. Thirty-six 8-week-old Sprague-Dawley rats were randomly distributed into normal control group, diabetic group and ICA-II treated group. Diabetes was induced by a one-time intraperitoneal injection of streptozotocin (60 mg/kg). Three days later, the diabetic rats were randomly divided into 2 groups including a saline treated placebo group and an ICA II-treated group (5 mg/kg/day, by intragastric administration daily). Twelve weeks later, erectile function was measured by cavernous nerve electrostimulation with real time intracorporal pressure assessment. The penis was harvested for the histological examination (immunofluorescence and immunohistochemical staining) and transmission electron microscopy detecting. Diabetic animals exhibited a decreased density of dorsal nerve bundle in penis. The neurofilament of the dorsal nerve bundle was fragmented in the diabetic rats. There was a decreased expression of nNOS and NGF in the diabetic group. The ICA II group had higher density of dorsal nerve bundle, higher expression of NGF and nNOS in the penis. The pathological change of major pelvic nerve ganglion (including the microstructure by transmission electron microscope and the neurite outgrowth length of major pelvic nerve ganglion tissue cultured in vitro) was greatly attenuated in the ICA II-treated group (p < 0.01). ICA II treatment attenuates the diabetes-related impairment of corpus cavernosum and major pelvic ganglion neuropathy in rats with Streptozotocin-Induced Diabetes. PMID- 25517035 TI - The study of NADPH-dependent flavoenzyme-catalyzed reduction of benzo[1,2-c]1,2,5 oxadiazole N-oxides (benzofuroxans). AB - The enzymatic reactivity of a series of benzo[1,2-c]1,2,5-oxadiazole N-oxides (benzofuroxans; BFXs) towards mammalian single-electron transferring NADPH:cytochrome P-450 reductase (P-450R) and two-electron (hydride) transferring NAD(P)H: quinone oxidoreductase (NQO1) was examined in this work. Since the =N+ ( >O)O- moiety of furoxan fragments of BFXs bears some similarity to the aromatic nitro-group, the reactivity of BFXs was compared to that of nitro-aromatic compounds (NACs) whose reduction mechanisms by these and other related flavoenzymes have been extensively investigated. The reduction of BFXs by both P 450R and NQO1 was accompanied by O2 uptake, which was much lower than the NADPH oxidation rate; except for annelated BFXs, whose reduction was followed by the production of peroxide. In order to analyze the possible quantitative structure activity relationships (QSARs) of the enzymatic reactivity of the compounds, their electron-accepting potency and other reactivity indices were assessed by quantum mechanical methods. In P-450R-catalyzed reactions, both BFXs and NACs showed the same reactivity dependence on their electron-accepting potency which might be consistent with an "outer sphere" electron transfer mechanism. In NQO1 catalyzed two-electron (hydride) transferring reactions, BFXs acted as more efficient substrates than NACs, and the reduction efficacy of BFXs by NQO1 was in general higher than by single-electron transferring P-450R. In NQO1-catalyzed reactions, QSARs obtained showed that the reduction efficacy of BFXs, as well as that of NACs, was determined by their electron-accepting potency and could be influenced by their binding mode in the active center of NQO1 and by their global softness as their electronic characteristic. The reductive conversion of benzofuroxan by both flavoenzymes yielded the same reduction product of benzofuroxan, 2,3-diaminophenazine, with the formation of o-benzoquinone dioxime as a putative primary reductive intermediate, which undergoes a further reduction process. Overall, the data obtained show that by contrast to NACs, the flavoenzyme-catalyzed reduction of BFXs is unlikely to initiate their redox cycling, which may argue for a minor role of the redox-cycling-type action in the cytotoxicity of BFXs. PMID- 25517038 TI - Self-oriented immobilization of DNA polymerase tagged by titanium-binding peptide motif. AB - We developed a titanium-binding-peptide-1 (TBP-1)-tagged DNA polymerase, for self oriented immobilization onto a titanium oxide (TiO2) substrate. The enzymatic function of a polymerase immobilized on a solid state device is strongly dependent on the orientation of the enzyme. The TBP-tagged DNA polymerase, which was derived from a hyperthermophilic archaeon, was designed to incorporate the RKLPDA peptide at the N-terminus, and synthesized by translation processes in Escherichia coli (E. coli). The specific binding of the TBP-tagged DNA polymerase onto a TiO2 substrate was clearly monitored by surface plasmon resonance spectroscopy (SPR) and by surface potential detection with an extended-gate field effect transistor (FET). In the SPR analyses, constant quantities of the DNA polymerase were stably immobilized on the titanium substrate under flow conditions, regardless of the concentration of the DNA polymerase, and could be completely removed by a 4 M MgCl2 wash after measurement. The FET signal showed the contribution of the molecular charge in the TBP motif to the binding with TiO2. In addition, the TBP-tagged DNA polymerase-tethered TiO2 gate electrode enabled the effective detection of the positive charges of hydrogen ions produced by the DNA extension reaction, according to the FET principle. Therefore, the self-oriented immobilization platform based on the motif-inserted enzyme is suitable for the quick and stable immobilization of functional enzymes on biosensing devices. PMID- 25517037 TI - The importance of study design for detecting differentially abundant features in high-throughput experiments. AB - High-throughput assays, such as RNA-seq, to detect differential abundance are widely used. Variable performance across statistical tests, normalizations, and conditions leads to resource wastage and reduced sensitivity. EDDA represents a first, general design tool for RNA-seq, Nanostring, and metagenomic analysis, that rationally selects tests, predicts performance, and plans experiments to minimize resource wastage. Case studies highlight EDDA's ability to model single cell RNA-seq, suggesting ways to reduce sequencing costs up to five-fold and improving metagenomic biomarker detection through improved test selection. EDDA's novel mode-based normalization for detecting differential abundance improves robustness by 10% to 20% and precision by up to 140%. PMID- 25517039 TI - Degradation of ochratoxin A by Bacillus amyloliquefaciens ASAG1. AB - Ochratoxin A (OTA) is widely found in food and feed products as a mycotoxin contaminant. It is produced by Penicillium species and several Aspergillus species. The identification OTA detoxification microorganisms is believed to be the best approach for decontamination. In this study, we isolated ASAG1, a bacterium with the ability to degrade OTA effectively, from grain depot-stored maize. A 16S rDNA sequencing approach was used to identify this strain as Bacillus amyloliquefaciens ASAG1. The degradation of OTA was detected in both medium and cell-free extracts after incubation with a culture of B. amyloliquefaciens ASAG1 cells. Subsequently, a hydrolysed enzyme (carboxypeptidase) related to the enzymatic conversion of OTA was cloned from the B. amyloliquefaciens ASAG1 genome. Using the Escherichia coli Expression System, we successfully expressed and purified this carboxypeptidase. When this enzyme was incubated with the engineered recombinant E. coli cells, the concentration of OTA was dramatically degraded. Our data therefore indicate that the carboxypeptidase produced by B. amyloliquefaciens ASAG1 is likely responsible for the biodegradation of OTA. PMID- 25517040 TI - Differences in Physicians' and Nurses' Recent Suicide Attempts: An Exploratory Study. AB - The aim of this study was to examine the characteristics of physicians' and nurses' suicide attempts (SA). A retrospective review of 493 medical records of physicians and nurses admitted to an inpatient unit for health professionals; 36 patients had a recent SA. Depression, cluster B and C personality disorders, and a history of previous SA were more prevalent in patients with a recent SA compared to those without it. Both professional groups preferred drug overdose as a suicide method. Physicians made more lethal attempts and had a history of more previous stressors than nurses. Depression, cluster B and C personality disorders, and previous SA should be appropriately screened and treated in order to prevent SA amongst physicians and nurses. PMID- 25517041 TI - Joint Intratracheal Surfactant-Antibacterial Therapy in Experimental Pseudomonas Induced Pneumonia. AB - BACKGROUND: The application of an exogenous pulmonary surfactant as a carrier for intratracheally administered antimicrobials represents a promising therapeutic modality that is still on its way to clinical practice. Owing to its ability to decrease surface tension, exogenous surfactant may enhance delivery of antibiotics into foci of pulmonary infection, thus increasing efficiency and safety of topical antimicrobial therapy in bacterial lung diseases. OBJECTIVES: To assess potential interactions between exogenous surfactant and amikacin in vitro, and to study the effects of their joint intratracheal instillation in rats with acute pneumonia caused by Pseudomonas aeruginosa. METHODS: The antibacterial and surface-active properties of amikacin (Amicil, Kievmedpreparat, Ukraine), porcine pulmonary surfactant (Suzacrin, Docpharm, Ukraine), and their combination were studied in vitro using standard microbiologic procedures and modified Pattle method (estimation of bubble diameter). Similar methods were utilized to study bacterial contamination of lungs and blood, and to assess the surface activity of bronchoalveolar wash (BAW) in 119 Wistar rats, including infected (intratracheal introduction of P. aeruginosa ATCC 27853) and noninfected animals. Histopathologic findings, differential leukocyte counts, and oxygenation parameters were recorded. RESULTS: Antibacterial and surface-active properties of the surfactant and amikacin remained unimpaired in vitro. In rats anti pseudomonal and anti-inflammatory effects of the surfactant-amikacin mixture were more pronounced (p<0.05) than effects of pure amikacin as evidenced by recorded rates of bacterial growth and granulocytic response. The combined therapy considerably restricted tissue damage and mitigated reduction of BAW surface activity. CONCLUSION: The advantages of the joint surfactant-amikacin therapy of Pseudomonas-induced pneumonia may suggest further clinical trials. PMID- 25517042 TI - Interpersonal violence and traumatic brain injuries among Native Americans and women. AB - OBJECTIVES: This study aimed to assess the odds of experiencing a traumatic brain injury (TBI) as a result of interpersonal violence (IPV) among Native Americans compared to other races controlling for gender, age, socioeconomic status, rurality and intoxication at the time of the injury. METHODS: A secondary data analysis of the Arizona Trauma Database consisting of 18 944 cases of TBI between 2008-2010 throughout the state of Arizona was conducted. There were 312 patients who experienced injuries caused by IPV in the sample. Descriptive statistics, cross-tabulations, bivariate analyses and a logistic regression model were used for analyses. RESULTS: The logistic regression model found that Native Americans (OR = 1.15), patients from the other race category (OR = 1.18), females (OR = 1.35) and those who were insured (OR = 1.26) had higher odds of experiencing a TBI as a result of IPV. Rurality and intoxication were mediators of the correlation between Native American race and TBI as a result of IPV. CONCLUSIONS: Native Americans are more likely than Whites and females are more likely than males to experience TBIs as a result of IPV. PMID- 25517043 TI - Controllable coordination-driven self-assembly: from discrete metallocages to infinite cage-based frameworks. AB - CONSPECTUS: Nanosized supramolecular metallocages have a unique self-assembly process that allows chemists to both understand and control it. In addition, well defined cavities of such supramolecular aggregates have various attractive applications including storage, separation, catalysis, recognition, drug delivery, and many others. Coordination-driven self-assembly of nanosized supramolecular metallocages is a powerful methodology to construct supramolecular metallocages with considerable size and desirable shapes. In this Account, we summarize our recent research on controllable coordination-driven assembly of supramolecular metallocages and infinite cage-based frameworks. To this end, we have chosen flexible ligands that can adopt various conformations and metal ions with suitable coordination sites for the rational design and assembly of metal organic supramolecular ensembles. This has resulted in various types of metallocages including M3L2, M6L8, M6L4, and M12L8 with different sizes and shapes. Because the kinds of metal geometries are limited, we have found that we can replace single metal ions with metal clusters to alternatively increase molecular diversity and complexity. There are two clear-cut merits of this strategy. First, metal clusters are much bigger than single metal ions, which helps in the construction and stabilization of large metallocages, especially nanosized cages. Second, metal clusters can generate diverse assembly modes that chemists could not synthesize with single metal ions. This allows us to obtain a series of unprecedented supramolecular metallocages. The large cavities and potential unsaturated coordination sites of these discrete supramolecular cages offer opportunities to construct infinite cage-based frameworks. This in turn can offer us a new avenue to understand self-assembly and realize certain various functionalities. We introduce two types of infinite cage-based frameworks here: cage-based coordination polymers and cage-based polycatenanes, which we can construct through coordination bonds and mechanical bonds, respectively. Through either directly linking the unsaturated coordination sites of metallocages or replacing the labile terminal ligands with bridging ligands, we can produce infinite cage-based frameworks based on coordination bonds. We introduce several interesting cage-based coordination polymers, including a single-crystal-to single-crystal transformation from a M6L8 cage to an infinite cage-based chain. Compared with discrete metallocages, these kinds of materials can give us higher structural stability and complexity, favoring the applications of metallocages. In addition, we discuss how we can use mechanical bonds, such as interlocking and interpenetrating, to construct extended cage-based frameworks. So far, study in this field has focused on polycatenanes constructed from M6L4 and M12L8 cages, as well as a controllable and dynamic self-assembly based on M6L4 metallocages. We also discuss cage-based polycatenanes, which can give dynamic properties to discrete metallocages. We hope that our investigations will bring new insights to the world of the supramolecular metallocages by enlarging its breadth and encourage us to devote more effort to this blossoming field in the future. PMID- 25517044 TI - Rich structural chemistry in new alkali metal yttrium tellurites: three dimensional frameworks of NaYTe4O10, KY(TeO3)2, RbY(TeO3)2, and a novel variant of hexagonal tungsten bronze, CsYTe3O8. AB - Pure polycrystalline phases and single crystals of four new quaternary alkali metal yttrium tellurites, NaYTe4O10, KY(TeO3)2, RbY(TeO3)2, and CsYTe3O8, have been prepared by solid-state and hydrothermal reactions using A2CO3 (A = Na, K, Rb, and Cs), Y(NO3)3.6H2O, Y2O3, and TeO2 as starting reagents. X-ray diffraction analyses suggest that NaYTe4O10 exhibits a highly symmetric three-dimensional (3D) framework consisting of YO8 square antiprisms and chains of TeO4 polyhedra. Within the framework, six- (6-) and eight-membered ring (8-MR) channels are observed. KY(TeO3)2 and RbY(TeO3)2 are isostructural to each other and reveal another 3D framework with structures containing YO6 octahedra and TeO3 trigonal pyramids with 4-MR and 12-MR channels. CsYTe3O8 shows a hexagonal tungsten bronze (HTB)-like topology composed of hexagonal tungsten oxide-like layers of TeO4 polyhedra and YO6 octahedral linkers with 3-MR and 6-MR channels. Thermal analyses, elemental analyses, and spectroscopic characterizations, such as UV-vis diffuse reflectance and infrared spectra, are presented, as are local dipole moment calculations for the constituent asymmetric polyhedra TeO3 and TeO4. PMID- 25517045 TI - Ectodermal Differentiation of Wharton's Jelly Mesenchymal Stem Cells for Tissue Engineering and Regenerative Medicine Applications. AB - Mesenchymal stem cells (MSCs) from Wharton's jelly (WJ) of the human umbilical cord are perinatal stem cells that have self-renewal ability, extended proliferation potential, immunosuppressive properties, and are accordingly excellent candidates for tissue engineering. These MSCs are unique, easily accessible, and a noncontroversial cell source of regeneration in medicine. Wharton's jelly mesenchymal stem cells (WJMSCs) are multipotent and capable of multilineage differentiation into cells like adipocytes, bone, cartilage, and skeletal muscle upon exposure to appropriate conditions. The ectoderm is one of the three primary germ layers found in the very early embryo that differentiates into the epidermis, nervous system (spine, peripheral nerves, brain), and exocrine glands (mammary, sweat, salivary, and lacrimal glands). Accumulating evidence shows that MSCs obtained from WJ have an ectodermal differentiation potential. The current review examines this differentiation potential of WJMSC into the hair follicle, skin, neurons, and sweat glands along with discussing the potential utilization of such differentiation in regenerative medicine. PMID- 25517046 TI - Uncertainty in regional-average petroleum GHG intensities: countering information gaps with targeted data gathering. AB - Recent efforts to model crude oil production GHG emissions are challenged by a lack of data. Missing data can affect the accuracy of oil field carbon intensity (CI) estimates as well as the production-weighted CI of groups ("baskets") of crude oils. Here we use the OPGEE model to study the effect of incomplete information on the CI of crude baskets. We create two different 20 oil field baskets, one of which has typical emissions and one of which has elevated emissions. Dispersion of CI estimates is greatly reduced in baskets compared to single crudes (coefficient of variation = 0.2 for a typical basket when 50% of data is learned at random), and field-level inaccuracy (bias) is removed through compensating errors (bias of ~ 5% in above case). If a basket has underlying characteristics significantly different than OPGEE defaults, systematic bias is introduced through use of defaults in place of missing data. Optimal data gathering strategies were found to focus on the largest 50% of fields, and on certain important parameters for each field. Users can avoid bias (reduced to <1 gCO2/MJ in our elevated emissions basket) through strategies that only require gathering ~ 10-20% of input data. PMID- 25517047 TI - [Twenty years of mitral valve repair. An experience in 322 patients]. AB - BACKGROUND: Mitral valve repair is the preferred procedure for the surgical treatment of mitral valve insufficiency (MI), procedure that we initiated 20 years ago. AIM: To assess our experience and long-term results of mitral valve repair. PATIENTS AND METHODS: The database of the cardiology department was reviewed for the period between December 1991 and December 2012. A total of 322 patients aged 18 to 89 years (62% males) undergoing mitral valve repair were identified. Long-term survival information was obtained consulting death certificate records of the Chilean Identification Service. The latest echocardiogram available was analyzed. RESULTS: MI was degenerative in 144 patients (45%) and ischemic in 104 (32%). A prosthetic ring was used in all ischemic and in 92% of non-ischemic MI. Operative mortality was 7.5%, 13% in ischemic and 4.4% in non-ischemic MI (p < 0.01). Overall long-term survival was 14.1 years; 9.3 and 16 years for ischemic and non-ischemic MI, respectively (p < 0.001). Survival at 5, 10, 15 and 20 years was 79, 63, 54 and 42%, respectively. For degenerative MI survival at 5 and 10 years was 90 and 76% and for ischemic MI, it was 64 and 44%, respectively (p < 0.001). On a multivariate analysis the main predictors of late mortality were age, associated valvular disease and ischemic etiology. Echocardiographic follow-up was available for 223 patients; MI was absent in 53% and was mild in 29%. CONCLUSIONS: In a 20 years follow-up, mitral valve repair for MI had excellent long-term survival and echocardiographic results. The most common etiologies of MI were degenerative and ischemic diseases. The latter had a worst prognosis. The main predictors of long term mortality were age, associated valvular disease and ischemic etiology. PMID- 25517048 TI - [Estimation of thyroid cancer incidence in Chile based on pathological reports]. AB - BACKGROUND: Thyroid cancer (TC) detection is increasing steadily. AIM: To determine the incidence of TC based on pathological reports of thyroidectomies. MATERIAL AND METHODS: Fifty pathology laboratories performing thyroid gland pathological studies were identified. Those that accepted to participate were required to send trimestral reports of all thyroid pathological studies, from March 2011 to February 2012. RESULTS: In the study period, 1309 case of TC were confirmed in 2614 thyroidectomy surgical samples. Considering the susceptible population according to 2012 census, the estimated incidence of TC during 2011 should be higher than 7.86 cases per 100,000 persons/year. Papillary cancer was the most common pathological type in 92% of samples (95% confidence intervals 90 93%). The proportion of microtumors was significantly higher in women than in men and among papillary than in follicular or medullary tumors. Only one fourth of tumors came from thyroidectomies performed in the Ministry of Health network. CONCLUSIONS: The incidence and features of TC in Chile are similar to the figures reported abroad. PMID- 25517049 TI - [Evaluation of serum insulin levels after an oral glucose load for the diagnosis of insulin resistance]. AB - BACKGROUND: In our country, the assessment of insulin resistance (IR) measuring serum insulin levels at 60 and 120 minutes after a 75 g oral glucose tolerance test (OGTT), is usual. However, there is no information about the distribution of serum insulin levels in the Chilean population. AIM: To assess the distribution of serum insulin levels at 60 and 120 minutes during OGTTs and suggest a statistical cut-off point to estimate the degree of IR. MATERIAL AND METHODS: Retrospective analysis of 1815 OGTTs performed in non-diabetic subjects aged between 18 and 75 years, at a university medical center. HOMA-IR (Homeostasis Model Assessment), insulin sensitivity index of Matsuda (ISI-Composite), and their correlation with serum insulin levels at 60 and 120 minutes were calculated. RESULTS: The 75th percentiles for serum insulin levels at 60 and 120 minutes were 127 and 81 uU/mL, respectively. There was a high correlation between HOMA-IR and ISI-Composite (r = -089, p < 0.001). There was a weaker although significant correlation between HOMA-IR and ISI-Composite and insulin levels at 60 (r = 0.56 and -0.79 respectively, p < 0,001) and 120 minutes (r = 0.54 and 0.75 respectively, p < 0,001). CONCLUSIONS: We propose 60 and 120 min serum insulin levels of 130 and 80 uU/mL respectively, as cut-off values for normality during OGTT in Chilean normoglycemic individuals. PMID- 25517050 TI - [Selective use of glucocorticoids during the perioperative period of transsphenoidal surgery for pituitary tumors]. AB - BACKGROUND: There is consensus in promoting the selective use of glucocorticoids (GC) in the peri-operative period of transsphenoidal surgery (TE) for pituitary adenomas (PA). AIM: To evaluate the safety of a selective glucocorticoid administration protocol and the usefulness of immediate postoperative cortisol levels as a predictor of final eucortisolism. PATIENTS AND METHODS: Clinical and biochemical data from 40 patients aged 27 to 78 years (65% males) were prospectively collected. Exclusion criteria were previous use of GC, apoplexy and Cushing disease. Patients with pre-operative short synthetic ACTH test (SST) > 18 ug/dl or basal cortisol > 15 ug/dl did not receive GC. A morning serum cortisol (SC) threshold of 10 ug/dl in postoperative days one to three was used to decide a discharge without GC. Hypotension, dizziness or nausea, requirement of increased dose of corticosteroids, hospitalizations and emergency service visits were investigated, as well as surgical and endocrinological complications. Corticotropic status was evaluated three months after surgery. RESULTS: Macroadenomas were present in 87% of patients. Median hospital stay was 4 days and follow up lasted 9 months. No differences were found in gender, age or tumor size between patients who received or not GC (35 and 65% respectively). Eighty five percent of patients were discharged without GC and all of them had normal corticotropic function three months after surgery. A SC >= 15 ug/dl had 100% specificity to predict eucortisolism. CONCLUSIONS: Selective glucocorticoid administration is safe. A normal corticotropic function before surgery and in the immediate postoperative period are useful to identify patients who do not need GC. PMID- 25517051 TI - [Response of primary care teams to manage mental health problems after the 2010 earthquake]. AB - BACKGROUND: Thirty to 50% of people exposed to a natural disaster suffer psychological problems in the ensuing months. AIM: To characterize the activities in mental health developed by Primary Health Care centers after the earthquake that affected Chile on february 27th, 2010. MATERIAL AND METHODS: A cross sectional study analyzing 16 urban centers of Maule Region, was carried out. A questionnaire was developed to know the preparatory and supportive activities directed to the community and the training and self-care activities directed to Health Care personnel that were made during the 12 months following the catastrophe. In addition, a questionnaire evaluating structural aspects was designed. RESULTS: Only 1/3 of the centers made some preparatory activity and none of them made a diagnosis of population vulnerability. The average of protective Mental Health interventions coverage reached 35% of the population estimated to be most affected. The activities lasted 31 to 62% of the optimal duration standards set by experts (according to the type of action). Important differences between centers in economic and geographical accessibility, construction and professional resources were found. CONCLUSIONS: This study shows the difficulties faced by urban centers of Maule Region to deal with mental health problems caused by the earthquake, which were attributable to the absence of local planning and drills, and to the lack of intra and inter sectorial coordination. PMID- 25517052 TI - [Validation of a brief screening test to assess functional capacity in Chilean older people]. AB - BACKGROUND: The Pfeffer Functional Activities Questionnaire (PFAQ) is a validated instrument used in Chile to diagnose dependency in older people. AIM: To suggest a shorter and easier version of the PFAQ, with appropriate levels of sensitivity and specificity, which may be applied to the general older population. MATERIAL AND METHODS: Three Chilean surveys applied to older people were used, namely the Survey of Life Events of the Elderly, (n = 1,371) and the 2010 and 2013 National Surveys of Quality of Life of Older People (n = 1,954 and 2,644 respectively). To evaluate the instrument, we performed correlation analysis between items and principal components analysis. We calculated internal consistency using Cronbach alpha, we computed sensitivity and specificity indicators, and analyzed convergent and predictive validity. RESULTS: After constructing different scales, the one that gave more information and had the best balance between sensitivity and specificity was chosen. Items with less weight factor and greater gender bias were eliminated, keeping seven questions from the original PFAQ. Reliability was verified using Cronbach alpha's coefficient and from correlations between the new instrument and key variables. CONCLUSIONS: According to our goals, the proposed scale is solely conformed by items that do not have gender bias. It discriminates in the general population adequately, allowing the design of a shorter test, of easier implementation. PMID- 25517053 TI - [Prostate cancer screening is associated with educational level and knowledge about the disease]. AB - BACKGROUND: The screening of prostate cancer allows an earlier diagnosis, allowing more therapeutic options. This screening depends in part on spontaneous patients'? consultation, which is largely related to their educational level. AIM: To evaluate the association between educational level, knowledge of the disease, and prostatic screening. MATERIAL AND METHODS: A questionnaire was applied to 377 men aged between 50 and 90 years to determine their educational level, knowledge of the disease, if they had any prostate screening and age at first screening. Data was analyzed with R Commander. RESULTS: Eighty one percent of respondents had some knowledge of the disease and of these, 68% had prostate screenings compared with 34% of those without knowledge of the disease. Information about prostate cancer was reported by 71% and 96% of respondents with primary and university education, respectively. Fifty nine and 90% of respondents with primary and university education had prostate screenings performed, respectively. CONCLUSIONS: Those respondents with a prostate cancer screening had a better knowledge of the disease and a higher educational level. PMID- 25517054 TI - [Assessment of a distant collaborative program for the treatment of depression in primary care]. AB - BACKGROUND: In the treatment of depression, primary care teams play an important role, whose effectiveness improves when inserted into a collaborative model of disease management. AIM: To report the results of a clinical trial carried out to test the effectiveness of a collaborative program between primary health teams and specialists supported by an electronic platform. MATERIAL AND METHODS: Physicians from four community hospitals belonging to the Reloncavi Health Service network, recruited 81 patients with depression aged 37 to 43 years, 84% of whom were female. Participants were divided in an active group, which participated in the collaborative program and a control group, which received the usual care, according to the Ministry of Health'?s Guidelines for Depression. The main outcome was the Beck Depression Inventory (BDI-I) score at three months of intervention. RESULTS: Participants had an average of 29.6 points (95% CI: 27.6 31.6) in the BDI-I and 38% of them had a high suicide risk. There were no statistically significant baseline differences between active and control group. In the intervention group, the BDI-I score changed from 30.0 (95% CI 27.0 to 32.8) to 15.3 (95% CI 11.8 to 18.8). In the control group the score changed from 29.2 (95% CI: 26.4-31.9) points to 20.8 (95% CI 16.8 to 24.7). The decrease was significantly higher in the intervention groups. CONCLUSIONS: A program of this kind may be useful to assist primary care teams in remote areas of the country to improve treatment outcomes for depression. PMID- 25517055 TI - [Prevalence of congenital malformations at birth in Chilean maternity hospitals]. AB - BACKGROUND: The Latin American Collaborative Study of Congenital Malformations (ECLAMC) is an epidemiological surveillance system operating in 11 South American countries since 1969. AIM: To analyze the Congenital Malformation prevalence rate at birth from 2001 to 2010 in Chilean Hospitals participating in ECLAMC. To compare these rates with those of the period 1982-1994. MATERIAL AND METHODS: Review of the ECLAMC database, which contains information about 282.568 newborns, 2.110 of them stillbirths (0.75%) from 13 Maternity hospitals. RESULTS: In the study period, 10.925 newborns had congenital malformations (3.9 %). Their frequency was lower in live newborns than stillbirths (3.8 and 15.3%, respectively). Compared with the 1982-1994 period, congenital malformation prevalence rates at birth were higher. They stabilized in approximately 4 %, from 1985 to 2010. The prevalence of some anomalies such as Down syndrome increased significantly. On the other hand, there was a reduction in the prevalence of spina bifida and anencephaly. CONCLUSIONS: Prevalence rates of congenital malformations at birth remained stable in the last 18 years in Chilean Hospitals participating in ECLAMC. However the prevalence of some malformations such as Down syndrome, Polydactyly, anotia-microtia, syndactyly and cleft palate have increased. The prevalence rates of spina bifida and anencephaly have decreased. PMID- 25517056 TI - [Magnitude, impact and recommended management strategies for depression, with reference to Chile]. AB - Depression is a global public health priority. Intervention strategies at different levels of care must be implemented. Research is needed in the areas of depression prevention, treatment and rehabilitation. This paper reports a literature review, focused in Chile, on the magnitude, impact, recommended management strategies and new research on depression. PMID- 25517057 TI - [Genetics of ankylosing spondylitis]. AB - Ankylosing spondylitis (AS) is a prototypical inflammatory disease of the locomotor system affecting axial skeleton. It is part of the general group of spondyloarthopathies (SpA). Its strong association with histocompatibility antigen HLA-B27 is known since 1973. However, HLA-B27 contribution to AS genetic risk is approximately 16%. Therefore, other genes are necessarily involved in the pathogenesis of the disease. Genomic development and the possibility of making genome wide screening have contributed enormously to the study of the disease. In this paper, we describe the actual knowledge about AS genetic risk, which has contributed to understand the influence of HLA-B27 on the etiology and pathogenesis of the disease. We also intend to foresee how these findings will result in an improvement of patients'? quality of life. PMID- 25517058 TI - [Mercury in fish and its importance in health]. AB - The contamination of fish with methylmercury (MeHg) could hamper the health promoting properties of fish. Currently, there is strong evidence about the health benefits of seafood consumption. When consumed by the mother before and during pregnancy it improves neurodevelopment of infants and toddlers. Thereafter it reduces the risk of cardiovascular and other chronic diseases. The benefits of fish are mainly due to its content of omega-3 long chain polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Other constituents, such as high biological value proteins, fat-soluble vitamins, minerals and trace elements contribute to the benefits. On the other hand, there is also convincing evidence about the adverse effects of MeHg on neurodevelopment both during gestation and in early childhood. We herein review the effects of mercury on health. Based on international evidence and new data on the mercury content in Chilean fish, we also propose a recommendation for fish consumption for our population. PMID- 25517059 TI - [Recommendations of the Chilean Association for Digestive Endoscopy for the management of gastric pre-malignant lesions]. AB - An expert panel analyzed the available evidence and reached a consensus to release 24 recommendations for primary and secondary prevention of gastric cancer (CG) in symptomatic patients, with indication for upper GI endoscopy. The main recommendations include (1) Search for and eradicate H. pylori infection in all cases. (2) Systematic gastric biopsies (Sydney protocol) in all patients over 40 years of age or first grade relatives of patient with CG, to detect gastric atrophy, intestinal metaplasia or dysplasia. (3) Incorporate the OLGA system (Operative Link on Gastritis Assessment) to the pathological report, to categorize the individual risk of CG. (4) Schedule endoscopic follow-up according to the estimated risk of CG, namely annual for OLGA III- IV, every 3 years for OLGA I- II or persistent H. pylori infection, every 5 years for CG relatives without other risk factors and no follow-up for OLGA 0, H. pylori (-). (4) Establish basic human and material resources for endoscopic follow-up programs, including some essential administrative processes, and (5) Suggest the early CG/total CG diagnosis ratio of each institution and the proportion of systematic recording of endoscopic images, as quality indicators. These measures are applicable using currently available resources, they can complement any future screening programs for asymptomatic population and may contribute to improve the prognosis of CG in high-risk populations. PMID- 25517060 TI - [Perception of medical students about formative assessments during clinical courses]. AB - BACKGROUND: Formative evaluation is a range of formal assessment employed by professors during the teaching process in order to modify curriculum activities, to improve student attainment. For students, it is helpful to evaluate their learning process. Although recommended, it is seldom used. AIM: To evaluate the perception and performance of medical students subjected to formative assessments during an integrative clinical course. MATERIAL AND METHODS: Fourth year medical students that participated in a multiple choice formative assessment, similar to the final exam during 2007 and 2008, responded a survey about the usefulness and quality of such assessment. Student achievement was expressed as the percentage of correct answers of the tests. RESULTS: The formative assessment was answered by 99% of students. In 2007 97% of students considered the experience as excellent or very good and 92% evaluated it as useful or very useful. During 2008 the figures were 89% and 79%. The students outlined that this assessment oriented their study, allowed them to discover their weaknesses and have a perception of the degree of difficulty of the final exam. Over 90% of students that took the formative evaluation, improved their academic achievement. CONCLUSIONS: Formative assessments are well evaluated by medical students and improve their academic achievement. PMID- 25517061 TI - [Management of ischemic strokes derived from intraventricular thrombi: report of two cases]. AB - The origin of 20% of ischemic strokes is a left ventricular thrombus. We report two patients with strokes originating from cardiac thrombi, treated in two different ways. A 42-year-old diabetic man admitted with a left parietal and occipital stroke. An echocardiogram showed a left ventricular thrombus. The patient was subjected to a surgical cardiac revascularization procedure and left ventricular thrombectomy. The postoperative evolution was uneventful and the patient was discharged on oral anticoagulation. On ambulatory follow up, no neurological deterioration was evidenced. A 38-year-old male admitted with an acute ischemic stroke, was subjected to thrombolysis with human plasminogen activator. An echocardiogram showed a left ventricular thrombus, considered the cause of the stroke. The patient was anticoagulated with heparin and discharged ten days after admission with oral anticoagulation. A new echocardiogram performed one month later, did not show the left ventricular thrombus. PMID- 25517062 TI - [Electrocardiographic manifestations of severe accidental hypothermia: report of one case]. AB - We report a 77-year-old female patient who was admitted to the Emergency Department with impairment of consciousness, hypotension, bradycardia and hypothermia. She required endotracheal intubation and transfer to Intensive Care Unit (ICU). Computed tomography of the brain showed no lesions. Electrocardiogram showed abnormalities suggestive of severe hypothermia (bradycardia, marked elevation of J point associated with ST depression, a negative T wave in V2 to V6 and prolongation of QTc), which was confirmed with a pulmonary artery catheter. Myxedema coma, infections and neurological diseases were discarded. The cause of severe hypothermia was unclear, and the probable source was suspected to be accidental. After intensive treatment the patient improved, achieving normalization of electrocardiographic changes, recovery of organic functions and she was discharged home after 22 days. PMID- 25517063 TI - [History of the renin-angiotensin system: great men, a great finding]. AB - The discovery of the renin-angiotensin-aldosterone system (RAS) was one of the important findings in physiology. Two research groups, in both North and South America, independently discovered that renin released a novel vasopressor agent. The Argentine group named it hypertensin, and called hypertensinogen to its plasma protein substrate. The group from the United States named it angiotonin. In 1958, Braun Menendez and Irvine Page suggested that the peptide's name should be angiotensin. Development of angiotensin converting enzyme (ACE) inhibitors proved that the RAS is effective in controlling hypertension and heart failure, and in preventing vascular injury in chronic diseases. Both teams, showing that beyond being great investigators they were remarkable persons, shared the merit of the discovery. PMID- 25517064 TI - [Facial mimicry in borderline personality disorder: on empathy and beyond]. PMID- 25517065 TI - [Empathy and borderline personality disorder: controversies towards a social neuroscience based psychopathology. Reply]. PMID- 25517066 TI - [Facebook and Twitter: new references for Chilean medical journals]. PMID- 25517068 TI - Synthesis and evaluation of a boronate-tagged 1,8-naphthalimide probe for fluoride recognition. AB - A biocompatible fluoride receptor has been developed where the interaction between the boronic acid ester and amine (NH) results in fluoride ion selectivity and enhanced fluorescence quenching. PMID- 25517067 TI - A geometric clustering algorithm with applications to structural data. AB - An important feature of structural data, especially those from structural determination and protein-ligand docking programs, is that their distribution could be mostly uniform. Traditional clustering algorithms developed specifically for nonuniformly distributed data may not be adequate for their classification. Here we present a geometric partitional algorithm that could be applied to both uniformly and nonuniformly distributed data. The algorithm is a top-down approach that recursively selects the outliers as the seeds to form new clusters until all the structures within a cluster satisfy a classification criterion. The algorithm has been evaluated on a diverse set of real structural data and six sets of test data. The results show that it is superior to the previous algorithms for the clustering of structural data and is similar to or better than them for the classification of the test data. The algorithm should be especially useful for the identification of the best but minor clusters and for speeding up an iterative process widely used in NMR structure determination. PMID- 25517069 TI - Do medical homes increase medication adherence for persons with multiple chronic conditions? AB - BACKGROUND: Medications are an integral component of management for many chronic conditions, and suboptimal adherence limits medication effectiveness among persons with multiple chronic conditions (MCC). Medical homes may provide a mechanism for increasing adherence among persons with MCC, thereby enhancing management of chronic conditions. OBJECTIVE: To examine the association between medical home enrollment and adherence to newly initiated medications among Medicaid enrollees with MCC. RESEARCH DESIGN: Retrospective cohort study comparing Community Care of North Carolina medical home enrollees to nonenrollees using merged North Carolina Medicaid claims data (fiscal years 2008-2010). SUBJECTS: Among North Carolina Medicaid-enrolled adults with MCC, we created separate longitudinal cohorts of new users of antidepressants (N=9303), antihypertensive agents (N=12,595), oral diabetic agents (N=6409), and statins (N=9263). MEASURES: Outcomes were the proportion of days covered (PDC) on treatment medication each month for 12 months and a dichotomous measure of adherence (PDC>0.80). Our primary analysis utilized person-level fixed effects models. Sensitivity analyses included propensity score and person-level random effect models. RESULTS: Compared with nonenrollees, medical home enrollees exhibited higher PDC by 4.7, 6.0, 4.8, and 5.1 percentage points for depression, hypertension, diabetes, and hyperlipidemia, respectively (P's<0.001). The dichotomous adherence measure showed similar increases, with absolute differences of 4.1, 4.5, 3.5, and 4.6 percentage points, respectively (P's<0.001). CONCLUSIONS: Among Medicaid enrollees with MCC, adherence to new medications is greater for those enrolled in medical homes. PMID- 25517070 TI - Construct validity and factor structure of survey-based assessment of cost related medication burden. AB - BACKGROUND: Millions of Americans are burdened by out-of-pocket prescription costs. Although many survey measures have been developed to assess this burden, the construct validity and the factor structure of these instruments have not been rigorously assessed. OBJECTIVES: To characterize the factor structure and the construct validity of items assessing cost-related medication burden. METHODS: We applied exploratory factor and confirmatory factor analyses to the 2009 Medicare Current Beneficiary Survey, focusing on 10 items assessing cost related mediation burden among a nationally representative sample of community dwelling Medicare beneficiaries. The fit of competing models was compared using several indices. RESULTS: The study population (N=8777) was predominantly aged over 65 years (83.3%), female (54.4%), and white (84.3%). Two distinct factors were present for the medication cost-reduction strategies: (1) cost-related medication nonadherence and (2) drug-shopping behaviors, not directly impacting medication compliance. The two factors were moderately correlated (r=0.55), highlighting the presence of a 2 distinct but related constructs for cost-related medication burden. An item assessing the use of mail or internet pharmacies did not load well on either factor and may not necessarily measure medication-related cost burden. An item assessing reduced spending on basic needs loaded strongly on the same factor with the cost-related medication nonadherence items, suggesting they together may represent extreme compensatory behaviors that may adversely affect health outcomes. CONCLUSIONS: Two distinct constructs were derived from these items examining cost-related medication burden. Although cost-related medication burden is often associated with nonadherence, drug-shopping behaviors that do not directly impact adherence are also important measure of this burden. PMID- 25517071 TI - Differences between physician social networks for cardiac surgery serving communities with high versus low proportions of black residents. AB - BACKGROUND: Compared with white patients, black patients are more likely to undergo cardiac surgery at low-quality hospitals, even when they live closer to high-quality ones. Opportunities for organizational interventions to alleviate this problem remain elusive. OBJECTIVES: To explore physician isolation in communities with high proportions of black residents as a factor contributing to racial disparities in access to high-quality hospitals for cardiac surgery. RESEARCH DESIGN: Using national Medicare data (2008-2011), we mapped physician social networks at hospitals where coronary artery bypass grafting procedures were performed, measuring their degree of connectedness. We then fitted a series of multivariate regression models to examine for associations between physician connectedness and the proportion of black residents in the hospital service area (HSA) served by each network. MEASURES: Measures of physician connectedness (ie, repeat-tie fraction, clustering, and number of external ties). RESULTS: After accounting for regional differences in healthcare capacity, the social networks of physicians practicing in areas with more black residents varied in many important respects from those of HSAs with fewer black residents. Physicians serving HSAs with many black residents had a smaller number of repeated interactions with each other than those in other HSAs (P<0.001). When these physicians did interact, they tended to assemble in smaller groups of highly interconnected colleagues (P<0.001). They also had fewer interactions with physicians outside their immediate geographic area (P=0.048). CONCLUSIONS: Physicians in HSAs with many black residents are more isolated than those in HSAs with fewer black residents. This isolation may negatively impact on care coordination and information sharing. As such, planned delivery system reforms that encourage minorities to seek care within their established local networks may further exacerbate existing surgical disparities. PMID- 25517072 TI - Using Procedure Codes to Define Radiation Toxicity in Administrative Data: The Devil is in the Details. AB - BACKGROUND: Systematic coding systems are used to define clinically meaningful outcomes when leveraging administrative claims data for research. How and when these codes are applied within a research study can have implications for the study validity and their specificity can vary significantly depending on treatment received. SUBJECTS: Data are from the Surveillance, Epidemiology, and End Results-Medicare linked dataset. STUDY DESIGN: We use propensity score methods in a retrospective cohort of prostate cancer patients first examined in a recently published radiation oncology comparative effectiveness study. RESULTS: With the narrowly defined outcome definition, the toxicity event outcome rate ratio was 0.88 per 100 person-years (95% confidence interval, 0.71-1.08). With the broadly defined outcome, the rate ratio was comparable, with 0.89 per 100 person-years (95% confidence interval, 0.76-1.04), although individual event rates were doubled. Some evidence of surveillance bias was suggested by a higher rate of endoscopic procedures the first year of follow-up in patients who received proton therapy compared with those receiving intensity-modulated radiation treatment (11.15 vs. 8.90, respectively). CONCLUSIONS: This study demonstrates the risk of introducing bias through subjective application of procedure codes. Careful consideration is required when using procedure codes to define outcomes in administrative data. PMID- 25517073 TI - Modeling receipt of influenza A(H1N1)pdm09 vaccinations among US children during the 2009-2010 flu season: findings from the 2010 National Health Interview Survey. AB - OBJECTIVE: Using 32 weeks of data from the 2010 National Health Interview Survey, factors associated with receipt of influenza A(H1N1)pdm09 vaccinations among US children during October 2009 through February 2010 are examined. METHODS: Logistic models estimated receipt of first dose by January 1, 2010 for all children aged 4.5 months through 17 years and receipt of second dose by February 1, 2010 for children aged 6 months through 9 years who received a first dose, using demographic characteristics and measures of family structure, parental education, family income, access to health care, and chronic condition status. All analyses were weighted to yield nationally representative results for the US child population. RESULTS: Receipt of a seasonal influenza vaccination in the 12 months before October 2009 as well as race/ethnicity, family structure, and various measures representing family socioeconomic status were statistically significant correlates of receipt of the first pH1N1 dose, whereas children's asthma and chronic condition status were not. CONCLUSIONS: In the event of future pandemics, public health officials may utilize these findings to target particular segments of the US child population that may have been underserved during the 2009 influenza pandemic. PMID- 25517074 TI - Implications of workforce and financing changes for primary care practice utilization, revenue, and cost: a generalizable mathematical model for practice management. AB - BACKGROUND: Primary care practice transformations require tools for policymakers and practice managers to understand the financial implications of workforce and reimbursement changes. OBJECTIVE: To create a simulation model to understand how practice utilization, revenues, and expenses may change in the context of workforce and financing changes. RESEARCH DESIGN: We created a simulation model estimating clinic-level utilization, revenues, and expenses using user-specified or public input data detailing practice staffing levels, salaries and overhead expenditures, patient characteristics, clinic workload, and reimbursements. We assessed whether the model could accurately estimate clinic utilization, revenues, and expenses across the nation using labor compensation, medical expenditure, and reimbursements databases, as well as cost and revenue data from independent practices of varying size. We demonstrated the model's utility in a simulation of how utilization, revenue, and expenses would change after hiring a nurse practitioner (NP) compared with hiring a part-time physician. RESULTS: Modeled practice utilization and revenue closely matched independent national utilization and reimbursement data, disaggregated by patient age, sex, race/ethnicity, insurance status, and ICD diagnostic group; the model was able to estimate independent revenue and cost estimates, with highest accuracy among larger practices. A demonstration analysis revealed that hiring an NP to work independently with a subset of patients diagnosed with diabetes or hypertension could increase net revenues, if NP visits involve limited MD consultation or if NP reimbursement rates increase. CONCLUSIONS: A model of utilization, revenue, and expenses in primary care practices may help policymakers and managers understand the implications of workforce and financing changes. PMID- 25517075 TI - Trend and factors associated with healthcare use and costs in type 2 diabetes mellitus: a decade experience of a universal health insurance program. AB - BACKGROUND: Little is known about how a universal National Health Insurance program with cost-containment strategies affect costs and quality of diabetes care. OBJECTIVES: To examine the trends of healthcare use and costs for patients with type 2 diabetes mellitus (T2DM) in Taiwan over the last decade, and to identify factors associated with high healthcare cost and poor diabetes care. RESEARCH DESIGN: We delineated the pattern of healthcare use and costs for T2DM in 2000-2010. Generalized linear and logistic regression models were used to identify factors associated with medical costs and diabetes care. SUBJECTS: Representative adult T2DM patients and age-matched and sex-matched nondiabetes individuals were selected from the 2000, 2005, and 2010 National Health Insurance Research Databases. MEASURES: Healthcare use included physician visits, hospital admissions, and antidiabetic drug prescriptions. Indicators of diabetes management included completeness of recommended diabetes tests and medication adherence, assessed using medication possession ratio. RESULTS: The total healthcare cost per diabetes patient was approximately 2.8-fold higher than that for nondiabetes individual. The growth of healthcare cost per diabetes patient was significantly contained by about 3694 New Taiwan dollars (3.6%) between 2005 and 2010, but diabetes care improved over the decade. Diabetes duration, income, place of residence, continuity of care, and enrollment to a pay-for-performance program were associated with healthcare costs and diabetes management. Some public health measures implemented to support diabetes care were also discussed. CONCLUSIONS: Healthcare costs could be controlled without sacrificing the quality of diabetes care by implementing pay-for-performance programs and effective health policies favorable for diabetes care. PMID- 25517076 TI - Metagenomic chromosome conformation capture (meta3C) unveils the diversity of chromosome organization in microorganisms. AB - Genomic analyses of microbial populations in their natural environment remain limited by the difficulty to assemble full genomes of individual species. Consequently, the chromosome organization of microorganisms has been investigated in a few model species, but the extent to which the features described can be generalized to other taxa remains unknown. Using controlled mixes of bacterial and yeast species, we developed meta3C, a metagenomic chromosome conformation capture approach that allows characterizing individual genomes and their average organization within a mix of organisms. Not only can meta3C be applied to species already sequenced, but a single meta3C library can be used for assembling, scaffolding and characterizing the tridimensional organization of unknown genomes. By applying meta3C to a semi-complex environmental sample, we confirmed its promising potential. Overall, this first meta3C study highlights the remarkable diversity of microorganisms chromosome organization, while providing an elegant and integrated approach to metagenomic analysis. PMID- 25517078 TI - Affiliative and "self-as-doer" identities: Relationships between social identity, social support, and emotional status amongst survivors of acquired brain injury (ABI). AB - Social support is an important factor in rehabilitation following acquired brain injury (ABI). Research indicates that social identity makes social support possible and that social identity is made possible by social support. In order to further investigate the reciprocity between social identity and social support, the present research applied the concepts of affiliative and "self-as-doer" identities to an analysis of relationships between social identity, social support, and emotional status amongst a cohort of 53 adult survivors of ABI engaged in post-acute community neurorehabilitation. Path analysis was used to test a hypothesised mediated model whereby affiliative identities have a significant indirect relationship with emotional status via social support and self-as-doer identification. Results support the hypothesised model. Evidence supports an "upward spiral" between social identity and social support such that affiliative identity makes social support possible and social support drives self as-doer identity. Our discussion emphasises the importance of identity characteristics to social support, and to emotional status, for those living with ABI. PMID- 25517079 TI - Applications of PET imaging of neurological tumors with radiolabeled amino acids. AB - Routine diagnostics and treatment monitoring of brain tumors is usually based on contrast-enhanced magnetic resonance imaging (MRI). However, the capacity of structural MRI to differentiate neoplastic tissue from non-specific treatment changes may be limited especially after therapeutic interventions such as neurosurgical resection, radio- and chemotherapy. Metabolic imaging using PET may provide relevant additional information on tumor metabolism, which allows for more accurate diagnostics especially in clinically equivocal situations. In contrast to the widely used 18F-2-fluoro-2-deoxy-D-glucose, which exhibits a poor tumor-to-background contrast within the brain, amino acid tracers provide high sensitivity to detect primary tumors, recurrent or residual gliomas, including most low-grade gliomas. The method improves targeting of biopsy and provides additional information of tumor extent, which is helpful for planning neurosurgery and radiotherapy. In the further course of the disease, amino acid positron-emission tomography (PET) allows a sensitive monitoring of treatment response, the early detection of tumor recurrence, and an improved differentiation of tumor recurrence from treatment-related changes. In the past, the method had only limited availability due to the use of radiopharmaceuticals with a short half-life. In recent years, however, novel amino acid tracers labeled with positron emitters with a longer half-life have been developed and clinically validated which allow a more efficient and cost-effective application. These developments and the well-documented diagnostic performance of PET using radiolabeled amino acids suggest that its application continues to spread and that the method may be available as a routine diagnostic technique for certain indications in the near future. PMID- 25517077 TI - Active torque generation by the actomyosin cell cortex drives left-right symmetry breaking. AB - Many developmental processes break left-right (LR) symmetry with a consistent handedness. LR asymmetry emerges early in development, and in many species the primary determinant of this asymmetry has been linked to the cytoskeleton. However, the nature of the underlying chirally asymmetric cytoskeletal processes has remained elusive. In this study, we combine thin-film active chiral fluid theory with experimental analysis of the C. elegans embryo to show that the actomyosin cortex generates active chiral torques to facilitate chiral symmetry breaking. Active torques drive chiral counter-rotating cortical flow in the zygote, depend on myosin activity, and can be altered through mild changes in Rho signaling. Notably, they also execute the chiral skew event at the 4-cell stage to establish the C. elegans LR body axis. Taken together, our results uncover a novel, large-scale physical activity of the actomyosin cytoskeleton that provides a fundamental mechanism for chiral morphogenesis in development. PMID- 25517080 TI - Current preclinical and clinical applications of hypoxia PET imaging using 2 nitroimidazoles. AB - Hypoxia is a common characteristic of solid tumors and is associated with poor prognosis. Positron emission tomography (PET) can visualize tumor hypoxia in a non-invasive, 3-dimensional manner and can be used to acquire information longitudinally. Multiple 2-nitroimidazole based PET tracers are developed, validated and quantified in the search for the ideal hypoxia tracer and several tracers have shown to reliably represent tumor hypoxia. Furthermore, multiple studies describe the prognostic value of hypoxia PET imaging and the ability to monitor hypoxia during treatment. These applications can be of great potential and their role in treatment planning and modification needs to be further assessed with respect to personalized chemoradiation therapy. In this review we focus on the tracers that were positively validated in preclinical and clinical studies and report accurate quantification and visualization of hypoxia. The characteristics of these tracers are summarized for both preclinical and clinical studies. Furthermore, the clinical applications of hypoxia PET imaging are addressed with a focus on the ability to reliably monitor tumor hypoxia during treatment and the prognostic potential. Also the feasibility studies for hypoxia guided intensity modulated radiation therapy and the patient stratification for hypoxia targeted drugs are assessed. PMID- 25517081 TI - 89Zr-immuno-PET for imaging of long circulating drugs and disease targets: why, how and when to be applied? AB - Positron emission tomography (PET) with 89Zr-labeled monoclonal antibodies (mAbs) or other targeted vehicles (e.g., peptides, nanoparticles and cells), collectively called "89Zr-immuno-PET", can be used for better understanding of disease targets and the in vivo behavior of targeted drugs. This will become increasingly important in the development of next generation mAbs, which are characterized by high potency and/or multiple binding domains. This review provides practical information for researchers who want to implement 89Zr-immuno PET for answering their own biological and pathological questions or for steering their own drug development program. An overview is given of the reagents, labeling protocols, quality tests and critical steps to come to high quality 89Zr conjugates, while possibilities for further improvement are discussed. Since PET has the advantage of allowing quantitative imaging, information is provided about standardization of 89Zr quantification. Issues are summarized for consideration when starting preclinical or clinical 89Zr-immuno-PET studies, to enable at the end unequivocal interpretation of results. Finally, many appealing examples are provided of what can be learned from 89Zr-immuno-PET studies, while future directions are outlined. Most of the current examples are still on the characterization of mAbs in oncology, but the review will show that 89Zr-immuno PET harbors potential for many kinds of targeted drugs and diseases, as well as for elucidating biological processes. PMID- 25517087 TI - Designing new lithium-excess cathode materials from percolation theory: nanohighways in Li(x)Ni(2-4x/3)Sb(x/3)O2. AB - Increasing lithium content is shown to be a successful strategy for designing new cathode materials. In layered Li(x)Ni(2-4x/3)Sb(x/3)O2 (x = 1.00-1.15), lithium excess improves both discharge capacity and capacity retention at 1C. Structural studies reveal a complex nanostructure pattern of Li-Sb and Ni-Sb ordering where the interface between these domains forms the correct local configuration for good lithium mobility. The <1 nm Li-Sb stripe domains and their interfaces thereby effectively act as nanohighways for lithium diffusion. PMID- 25517085 TI - Small cell carcinoma of the bladder. AB - Small cell carcinoma of the urinary bladder is an extremely aggressive and rare tumor. Even though small cell carcinoma most commonly arises from the lungs there are several reports of small cell carcinoma in extrapulmonary sites. Due to its low frequency there is no well-established management for this disease. We report the case of a 61 year-old man with small cell carcinoma of the bladder who underwent radical cystectomy following neoadjuvant chemotherapy. We also reviewed the literature for the optimal treatment strategy. PMID- 25517088 TI - Humanistic psychotherapy research 1990-2015: from methodological innovation to evidence-supported treatment outcomes and beyond. AB - OBJECTIVE: Over the past 25 years, humanistic psychotherapy (HP) researchers have actively contributed to the development and implementation of innovative practice informed research measures and coding systems. METHOD: Qualitative and quantitative research findings, including meta-analyses, support the identification of HP approaches as evidence-based treatments for a variety of psychological conditions. RESULTS: Implications for future psychotherapy research, training, and practice are discussed in terms of addressing the persistent disjunction between significant HP research productivity and relatively low support for HP approaches in university-based clinical training programs, funding agencies, and government-supported clinical guidelines. CONCLUSION: Finally, specific recommendations are provided to further enhance and expand the impact of HP research for clinical training programs and the development of treatment guidelines. PMID- 25517089 TI - Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice. AB - Ticks are notorious vectors of disease for humans, and many species of ticks transmit multiple pathogens, sometimes in the same tick bite. Accordingly, a broad-spectrum vaccine that targets vector ticks and pathogen transmission at the tick/host interface, rather than multiple vaccines against every possible tickborne pathogen, could become an important tool for resolving an emerging public health crisis. The concept for such a tick protective vaccine comes from observations of an acquired tick resistance (ATR) that can develop in non-natural hosts of ticks following sensitization to tick salivary components. Mice are commonly used as models to study immune responses to human pathogens but normal mice are natural hosts for many species of ticks and fail to develop ATR. We evaluated HLA DR3 transgenic (tg) "humanized" mice as a potential model of ATR and assessed the possibility of using this animal model for tick protective vaccine discovery studies. Serial tick infestations with pathogen-free Ixodes scapularis ticks were used to tick-bite sensitize HLA DR3 tg mice. Sensitization resulted in a cytokine skew favoring a Th2 bias as well as partial (57%) protection to infection with Lyme disease spirochetes (Borrelia burgdorferi) following infected tick challenge when compared to tick naive counterparts. I. scapularis salivary gland homogenate (SGH) and a group of immunoinformatic predicted T cell epitopes identified from the I. scapularis salivary transcriptome were used separately to vaccinate HLA DR3 tg mice, and these mice also were assessed for both pathogen protection and epitope recognition. Reduced pathogen transmission along with a Th2 skew resulted from SGH vaccination, while no significant protection and a possible T regulatory bias was seen in epitope vaccinated mice. This study provides the first proof-of-concept for using HLA DR tg "humanized" mice for studying the potential tick protective effects of immunoinformatic- or otherwise-derived tick salivary components as tickborne disease vaccines. PMID- 25517090 TI - Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. AB - Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects. PMID- 25517092 TI - Earth science: Ocean circulation and rapid climate change. PMID- 25517091 TI - Enhancer-core-promoter specificity separates developmental and housekeeping gene regulation. AB - Gene transcription in animals involves the assembly of RNA polymerase II at core promoters and its cell-type-specific activation by enhancers that can be located more distally. However, how ubiquitous expression of housekeeping genes is achieved has been less clear. In particular, it is unknown whether ubiquitously active enhancers exist and how developmental and housekeeping gene regulation is separated. An attractive hypothesis is that different core promoters might exhibit an intrinsic specificity to certain enhancers. This is conceivable, as various core promoter sequence elements are differentially distributed between genes of different functions, including elements that are predominantly found at either developmentally regulated or at housekeeping genes. Here we show that thousands of enhancers in Drosophila melanogaster S2 and ovarian somatic cells (OSCs) exhibit a marked specificity to one of two core promoters--one derived from a ubiquitously expressed ribosomal protein gene and another from a developmentally regulated transcription factor--and confirm the existence of these two classes for five additional core promoters from genes with diverse functions. Housekeeping enhancers are active across the two cell types, while developmental enhancers exhibit strong cell-type specificity. Both enhancer classes differ in their genomic distribution, the functions of neighbouring genes, and the core promoter elements of these neighbouring genes. In addition, we identify two transcription factors--Dref and Trl--that bind and activate housekeeping versus developmental enhancers, respectively. Our results provide evidence for a sequence-encoded enhancer-core-promoter specificity that separates developmental and housekeeping gene regulatory programs for thousands of enhancers and their target genes across the entire genome. PMID- 25517093 TI - Strong and deep Atlantic meridional overturning circulation during the last glacial cycle. AB - Extreme, abrupt Northern Hemisphere climate oscillations during the last glacial cycle (140,000 years ago to present) were modulated by changes in ocean circulation and atmospheric forcing. However, the variability of the Atlantic meridional overturning circulation (AMOC), which has a role in controlling heat transport from low to high latitudes and in ocean CO2 storage, is still poorly constrained beyond the Last Glacial Maximum. Here we show that a deep and vigorous overturning circulation mode has persisted for most of the last glacial cycle, dominating ocean circulation in the Atlantic, whereas a shallower glacial mode with southern-sourced waters filling the deep western North Atlantic prevailed during glacial maxima. Our results are based on a reconstruction of both the strength and the direction of the AMOC during the last glacial cycle from a highly resolved marine sedimentary record in the deep western North Atlantic. Parallel measurements of two independent chemical water tracers (the isotope ratios of (231)Pa/(230)Th and (143)Nd/(144)Nd), which are not directly affected by changes in the global cycle, reveal consistent responses of the AMOC during the last two glacial terminations. Any significant deviations from this configuration, resulting in slowdowns of the AMOC, were restricted to centennial scale excursions during catastrophic iceberg discharges of the Heinrich stadials. Severe and multicentennial weakening of North Atlantic Deep Water formation occurred only during Heinrich stadials close to glacial maxima with increased ice coverage, probably as a result of increased fresh-water input. In contrast, the AMOC was relatively insensitive to submillennial meltwater pulses during warmer climate states, and an active AMOC prevailed during Dansgaard-Oeschger interstadials (Greenland warm periods). PMID- 25517094 TI - Endophilin marks and controls a clathrin-independent endocytic pathway. AB - Endocytosis is required for internalization of micronutrients and turnover of membrane components. Endophilin has been assigned as a component of clathrin mediated endocytosis. Here we show in mammalian cells that endophilin marks and controls a fast-acting tubulovesicular endocytic pathway that is independent of AP2 and clathrin, activated upon ligand binding to cargo receptors, inhibited by inhibitors of dynamin, Rac, phosphatidylinositol-3-OH kinase, PAK1 and actin polymerization, and activated upon Cdc42 inhibition. This pathway is prominent at the leading edges of cells where phosphatidylinositol-3,4-bisphosphate-produced by the dephosphorylation of phosphatidylinositol-3,4,5-triphosphate by SHIP1 and SHIP2-recruits lamellipodin, which in turn engages endophilin. This pathway mediates the ligand-triggered uptake of several G-protein-coupled receptors such as alpha2a- and beta1-adrenergic, dopaminergic D3 and D4 receptors and muscarinic acetylcholine receptor 4, the receptor tyrosine kinases EGFR, HGFR, VEGFR, PDGFR, NGFR and IGF1R, as well as interleukin-2 receptor. We call this new endocytic route fast endophilin-mediated endocytosis (FEME). PMID- 25517095 TI - Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution. AB - The ryanodine receptors (RyRs) are high-conductance intracellular Ca(2+) channels that play a pivotal role in the excitation-contraction coupling of skeletal and cardiac muscles. RyRs are the largest known ion channels, with a homotetrameric organization and approximately 5,000 residues in each protomer. Here we report the structure of the rabbit RyR1 in complex with its modulator FKBP12 at an overall resolution of 3.8 A, determined by single-particle electron cryomicroscopy. Three previously uncharacterized domains, named central, handle and helical domains, display the armadillo repeat fold. These domains, together with the amino-terminal domain, constitute a network of superhelical scaffold for binding and propagation of conformational changes. The channel domain exhibits the voltage-gated ion channel superfamily fold with distinct features. A negative charge-enriched hairpin loop connecting S5 and the pore helix is positioned above the entrance to the selectivity-filter vestibule. The four elongated S6 segments form a right-handed helical bundle that closes the pore at the cytoplasmic border of the membrane. Allosteric regulation of the pore by the cytoplasmic domains is mediated through extensive interactions between the central domains and the channel domain. These structural features explain high ion conductance by RyRs and the long-range allosteric regulation of channel activities. PMID- 25517097 TI - Cell biology: On the endocytosis rollercoaster. PMID- 25517096 TI - Endophilin-A2 functions in membrane scission in clathrin-independent endocytosis. AB - During endocytosis, energy is invested to narrow the necks of cargo-containing plasma membrane invaginations to radii at which the opposing segments spontaneously coalesce, thereby leading to the detachment by scission of endocytic uptake carriers. In the clathrin pathway, dynamin uses mechanical energy from GTP hydrolysis to this effect, assisted by the BIN/amphiphysin/Rvs (BAR) domain-containing protein endophilin. Clathrin-independent endocytic events are often less reliant on dynamin, and whether in these cases BAR domain proteins such as endophilin contribute to scission has remained unexplored. Here we show, in human and other mammalian cell lines, that endophilin-A2 (endoA2) specifically and functionally associates with very early uptake structures that are induced by the bacterial Shiga and cholera toxins, which are both clathrin-independent endocytic cargoes. In controlled in vitro systems, endoA2 reshapes membranes before scission. Furthermore, we demonstrate that endoA2, dynamin and actin contribute in parallel to the scission of Shiga-toxin-induced tubules. Our results establish a novel function of endoA2 in clathrin-independent endocytosis. They document that distinct scission factors operate in an additive manner, and predict that specificity within a given uptake process arises from defined combinations of universal modules. Our findings highlight a previously unnoticed link between membrane scaffolding by endoA2 and pulling-force-driven dynamic scission. PMID- 25517098 TI - Segmented lateral dyke growth in a rifting event at Bardarbunga volcanic system, Iceland. AB - Crust at many divergent plate boundaries forms primarily by the injection of vertical sheet-like dykes, some tens of kilometres long. Previous models of rifting events indicate either lateral dyke growth away from a feeding source, with propagation rates decreasing as the dyke lengthens, or magma flowing vertically into dykes from an underlying source, with the role of topography on the evolution of lateral dykes not clear. Here we show how a recent segmented dyke intrusion in the Bardarbunga volcanic system grew laterally for more than 45 kilometres at a variable rate, with topography influencing the direction of propagation. Barriers at the ends of each segment were overcome by the build-up of pressure in the dyke end; then a new segment formed and dyke lengthening temporarily peaked. The dyke evolution, which occurred primarily over 14 days, was revealed by propagating seismicity, ground deformation mapped by Global Positioning System (GPS), interferometric analysis of satellite radar images (InSAR), and graben formation. The strike of the dyke segments varies from an initially radial direction away from the Bardarbunga caldera, towards alignment with that expected from regional stress at the distal end. A model minimizing the combined strain and gravitational potential energy explains the propagation path. Dyke opening and seismicity focused at the most distal segment at any given time, and were simultaneous with magma source deflation and slow collapse at the Bardarbunga caldera, accompanied by a series of magnitude M > 5 earthquakes. Dyke growth was slowed down by an effusive fissure eruption near the end of the dyke. Lateral dyke growth with segment barrier breaking by pressure build-up in the dyke distal end explains how focused upwelling of magma under central volcanoes is effectively redistributed over long distances to create new upper crust at divergent plate boundaries. PMID- 25517102 TI - Extracting information from qubit-environment correlations. AB - Most works on open quantum systems generally focus on the reduced physical system by tracing out the environment degrees of freedom. Here we show that the qubit distributions with the environment are essential for a thorough analysis, and demonstrate that the way that quantum correlations are distributed in a quantum register is constrained by the way in which each subsystem gets correlated with the environment. For a two-qubit system coupled to a common dissipative environment E, we show how to optimise interqubit correlations and entanglement via a quantification of the qubit-environment information flow, in a process that, perhaps surprisingly, does not rely on the knowledge of the state of the environment. To illustrate our findings, we consider an optically-driven bipartite interacting qubit AB system under the action of E. By tailoring the light-matter interaction, a relationship between the qubits early stage disentanglement and the qubit-environment entanglement distribution is found. We also show that, under suitable initial conditions, the qubits energy asymmetry allows the identification of physical scenarios whereby qubit-qubit entanglement minima coincide with the extrema of the AE and BE entanglement oscillations. PMID- 25517101 TI - Dopaminergic denervation switches dopamine D3 receptor signaling and disrupts its Ca(2+) dependent modulation by CaMKII and calmodulin in striatonigral projections of the rat. AB - In striatonigral projections activation of dopamine D3 receptors (D3Rs) potentiates the stimulation of GABA release and cAMP production caused by activation of dopamine D1 receptors (D1Rs). Cytoplasmic [Ca(2+)] in the terminals controls this response by modulating CaMKII, an enzyme that depresses D3R action. To examine the effects of dopamine deprivation on D3R signaling we investigated their function in striatonigral terminals of hemiparkinsonian rats. Denervation switched the signaling cascade initiated by D3R activation. In the non-lesioned side activation of D3R potentiated the stimulatory effects of D1R activation on cAMP production and K(+)-depolarization induced [(3)H] GABA release. In contrast, in the denervated side the stimulatory effects of both D1R activation and forskolin administration were blocked by D3R activation. In non-lesioned slices, D3R responses were inhibited by the activation of CaMKII produced by K(+) depolarization (via increased Ca(2+) entry). The CaMKII-induced inhibition was blocked by the selective inhibitor KN-62. In denervated tissues the response to D3R stimulation was not modified either by K(+) depolarization or by blocking CaMKII with KN-62. Immunoblotting studies showed that depolarization-induced CaMKII binding to the D3 receptor and CaMKII phosphorylation were suppressed in denervated tissues. We also determined calmodulin expression with PCR and immunoblot techniques. Both techniques showed that calmodulin expression was depressed in the lesioned side. In sum, our studies show that dopaminergic denervation switches the D3R signaling cascade and depresses CaMKII signaling through a process that appears to involve reduced calmodulin levels. Since calmodulin is a major cytoplasmic Ca(2+) buffer our findings suggest that abnormal Ca(2+) buffering may be an important component of the abnormalities observed during dopaminergic denervation. PMID- 25517099 TI - Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity. AB - Interventions that delay ageing mobilize mechanisms that protect and repair cellular components, but it is unknown how these interventions might slow the functional decline of extracellular matrices, which are also damaged during ageing. Reduced insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile Caenorhabditis elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions. It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits. Here we show that rIIS can promote C. elegans longevity through a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity, but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit. PMID- 25517100 TI - Orientation columns in the mouse superior colliculus. AB - More than twenty types of retinal ganglion cells conduct visual information from the eye to the rest of the brain. Each retinal ganglion cell type tessellates the retina in a regular mosaic, so that every point in visual space is processed for visual primitives such as contrast and motion. This information flows to two principal brain centres: the visual cortex and the superior colliculus. The superior colliculus plays an evolutionarily conserved role in visual behaviours, but its functional architecture is poorly understood. Here we report on population recordings of visual responses from neurons in the mouse superior colliculus. Many neurons respond preferentially to lines of a certain orientation or movement axis. We show that cells with similar orientation preferences form large patches that span the vertical thickness of the retinorecipient layers. This organization is strikingly different from the randomly interspersed orientation preferences in the mouse's visual cortex; instead, it resembles the orientation columns observed in the visual cortices of large mammals. Notably, adjacent superior colliculus orientation columns have only limited receptive field overlap. This is in contrast to the organization of visual cortex, where each point in the visual field activates neurons with all preferred orientations. Instead, the superior colliculus favours specific contour orientations within ~30 degrees regions of the visual field, a finding with implications for behavioural responses mediated by this brain centre. PMID- 25517103 TI - Development and use of retinal pigmented epithelial cell line from zebrafish (Danio rerio) for evaluating the toxicity of ultraviolet-B. AB - Danio rerio retinal pigmented epithelial (DrRPE) cell line, derived from the RPE tissue, was established and characterized. The cells were able to grow at a wide range of temperatures from 25 degrees C to 32 degrees C in Leibovitz's L-15 medium. The DrRPE cell line consists of epithelial cells with a diameter of 15-19 MUm. The cell line was characterized by mitochondrial 12S rRNA gene, immunocytochemical analysis, and karyotyping. DrRPE cells treated with 10 MUM of all-trans-retinol for 24 h readily formed lipid droplets. DrRPE cells were irradiated with narrowband ultraviolet-B (UV-B) radiation at different time periods of 0, 10, 20, and 40 min. The cells were subsequently examined for changes in morphology, cell viability, phagocytotic activity, mitochondrial distribution, nuclei morphology, generation of reactive oxygen species, and expression of apoptotic-related genes p53 and Cas3 by quantitative polymerase chain reaction. The results demonstrate that UV-B radiation can cause a considerable decrease in DrRPE cell viability as well as in phagocytotic activity. In addition, the results demonstrate that UV-B radiation can induce the degradation of mitochondria and DNA in cultured DrRPE cells. PMID- 25517104 TI - Effects of a pulmonary rehabilitation program with balance training on patients with COPD. AB - PURPOSE: Patients with chronic obstructive pulmonary disease (COPD) have balance impairments. However, pulmonary rehabilitation (PR) is associated with only minor improvements in functional balance. Therefore, there is a need to explore the role of balance training within PR. This study aimed at assessing the effects of a PR program, with a specific component of balance training, on functional balance of patients with COPD. METHODS: Outpatients with COPD (N = 22, age = 68.0 +/- 11.8 years; forced expiratory volume in 1 second = 72.2 +/- 22.3% predicted) participated in a 12-week PR program including exercise training and psychosocial support and education. Exercise training sessions comprised endurance, strength, and a specific component of balance training. The Timed Up and Go (TUG) test was used to assess functional balance before and after the PR. Health-related quality of life (St George's Respiratory Questionnaire), quadriceps muscle strength (10 repetition maximum), and exercise tolerance (6-minute walk test) were also assessed. RESULTS: Patients demonstrated significant improvements in TUG scores after PR (mean change -1.7 +/- 1.4 seconds; P = .001; effect size = 1.249). Before PR, 9 (41%) participants and after PR only 1 (4.5%) participant had a TUG performance worse than the average performance of age-matched healthy peers (P = .008). The St George's Respiratory Questionnaire symptoms score (P = .012), quadriceps muscle strength (P = .001), and exercise tolerance (P = .001) were also improved. CONCLUSIONS: Pulmonary rehabilitation with a specific component of balance training had a large effect on functional balance in patients with COPD. Findings highlight the value of including balance training in PR programs. Further research is needed to determine the optimal intervention to improve balance and its specific components among patients with COPD. PMID- 25517105 TI - Two-dimensional flexible nanoelectronics. AB - 2014/2015 represents the tenth anniversary of modern graphene research. Over this decade, graphene has proven to be attractive for thin-film transistors owing to its remarkable electronic, optical, mechanical and thermal properties. Even its major drawback--zero bandgap--has resulted in something positive: a resurgence of interest in two-dimensional semiconductors, such as dichalcogenides and buckled nanomaterials with sizeable bandgaps. With the discovery of hexagonal boron nitride as an ideal dielectric, the materials are now in place to advance integrated flexible nanoelectronics, which uniquely take advantage of the unmatched portfolio of properties of two-dimensional crystals, beyond the capability of conventional thin films for ubiquitous flexible systems. PMID- 25517106 TI - The effect of l-citrulline and watermelon juice supplementation on anaerobic and aerobic exercise performance. AB - Citrulline has been proposed as an ergogenic aid, leading to an interest in watermelon given its high citrulline concentration. The aim of this study was to determine the effects of a single, pre-exercise dose of l-citrulline, watermelon juice, or a placebo on the total maximum number of repetitions completed over 5 sets, time to exhaustion, maximal oxygen consumption (VO2max), anaerobic threshold, and flow-mediated vasodilation. A randomised double-blind within participants study design was used to examine these effects among 22 participants (n = 11 males). Supplementation included either a 7.5% sucrose drink containing 6 g of l-citrulline, 710 mL of watermelon juice (~1.0 g citrulline), or a 7.5% sucrose placebo drink. Supplementation was administered 1 or 2 h before exercise testing to investigate a timing effect. There was no significant effect between the three supplements for the total number of repetitions, time to exhaustion, VO2max, anaerobic threshold, or flow-mediated vasodilation. There was also no interaction observed relative to gender or supplement timing (P > 0.05). A single dose of l-citrulline or watermelon juice as a pre-exercise supplement appears to be ineffective in improving exercise performance; however, greater doses of l citrulline have been shown to be safe and are currently left unexamined. PMID- 25517107 TI - Alveolar NF-kappaB signaling regulates endotoxin-induced lung inflammation. AB - PURPOSE/AIM: The alveolar epithelium participates in host defense through inflammatory pathways that activate NF-kappaB. Lung infections involving endotoxins trigger acute respiratory distress syndrome (ARDS) in adult and pediatric patients. The purpose of this study was to test the hypothesis that overexpression of NF-kappaB would worsen and conditional deletion of NF-kappaB signaling would improve endotoxin-induced lung inflammation using transgenic mouse models. MATERIALS AND METHODS: Two previously described transgenic mouse models were used in which overexpression of the RelA/p65 subunit of NF-kappaB was targeted to the lung epithelium using an SPC promoter (SPC-RelA) and conditional deletion of the IKKbeta molecule involved in NF-kappaB signaling was targeted to the lung epithelium using Nkx2.1(Cre) (Nkx2.1(Cre);IKKbeta(F/F)). Adult transgenic and control mice were injected with intratracheal lipopolysaccharide (LPS) or saline followed by lung harvest at 48 h. Collected tissue included whole lungs from transgenic and control mice which was processed for analysis of BAL, lung histology, chemokine expression, and markers of cell apoptosis as well as collection of freshly isolated AECII cells from wild type mice for additional chemokine and apoptotic marker analysis. RESULTS: SPC-RelA mice showed significant increases in lung inflammation and injury following LPS injection with increased neutrophil recruitment as compared to wild type and saline treated controls. In contrast, Nkx2.1(Cre); IKKbeta(F/F) mice showed markedly decreased lung inflammation and injury with decreased neutrophil recruitment as compared to controls. In both models, lung inflammation was associated with increased cell apoptosis and these findings were confirmed in freshly isolated AECII cells in wild type mice following LPS injection. CONCLUSIONS: Overexpression of NF-kappaB targeted to the lung epithelium worsened lung inflammation and injury in response to LPS exposure while conditional deletion of NF-kappaB signaling reduced lung inflammation. Lung inflammation and injury were associated with increased cell apoptosis. PMID- 25517108 TI - A vascular patch prepared from Thai silk fibroin and gelatin hydrogel incorporating simvastatin-micelles to recruit endothelial progenitor cells. AB - Delayed re-endothelialization is one of the major disadvantages in synthetic vascular grafts, especially in small-diameter grafts (inner diameter <6 mm), leading to thrombosis and stenosis of the grafts. Simvastatin, a serum cholesterol-lowering drug, has promotional effects on endothelial progenitor cell (EPC) mobilization from bone marrow and recruitment to sites of vascular injury exhibiting acceleration of re-endothelialization. In this study, we prepared double-layer vascular patches from Thai silk fibroin/gelatin with gelatin hydrogel incorporating simvastatin-micelles (SM) for sustained release of simvastatin to recruit circulation EPCs. To enhance simvastatin solubility, simvastatin was entrapped in micelles of l-lactic acid oligomer-grafted gelatin. The drug loading efficiency was at 4.1 +/- 0.5 MUg/mg micelles. SM had a chemoattractive effect on EPCs comparable to nonmodified simvastatin. Gelatin hydrogel incorporating SM at 100 MUM of simvastatin (GSM100) could enhance in vitro EPC activities of adhesion and proliferation. In vitro results showed the initial cell adhesion of 86%, specific growth rate of 15.33*10(-3) h(-1), and population doubling time of 46.21 h. In vivo implantation of the patches incorporating SM significantly increased the recruitment of circulating EPCs. From the results of immunofluorescence staining, they demonstrated the complete re-endothelialization on the implanted patches containing SM at 2 weeks after implantation in rat carotid arteries. The gelatin hydrogel incorporating SM could be an effective inner layer of multifunctional vascular grafts to accelerate re endothelialization in vascular tissue engineering. PMID- 25517111 TI - Fluctuations due to association and dissociation processes at nanowire-biosensor surfaces and their optimal design. AB - In this work, we calculate the effect of the binding and unbinding of molecules at the surface of a nanowire biosensor on the signal-to-noise ratio of the sensor. We model the fluctuations induced by association and dissociation of target molecules by a stochastic differential equation and extend this approach to a coupled diffusion-reaction system. Where possible, analytic solutions for the signal-to-noise ratio are given. Stochastic simulations are performed wherever closed forms of the solutions cannot be derived. Starting from parameters obtained from experimental data, we simulate DNA hybridization at the sensor surface for different target molecule concentrations in order to optimize the sensor design. PMID- 25517110 TI - Comparison of whole blood and peripheral blood mononuclear cell gene expression for evaluation of the perioperative inflammatory response in patients with advanced heart failure. AB - BACKGROUND: Heart failure (HF) prevalence is increasing in the United States. Mechanical Circulatory Support (MCS) therapy is an option for Advanced HF (AdHF) patients. Perioperatively, multiorgan dysfunction (MOD) is linked to the effects of device implantation, augmented by preexisting HF. Early recognition of MOD allows for better diagnosis, treatment, and risk prediction. Gene expression profiling (GEP) was used to evaluate clinical phenotypes of peripheral blood mononuclear cells (PBMC) transcriptomes obtained from patients' blood samples. Whole blood (WB) samples are clinically more feasible, but their performance in comparison to PBMC samples has not been determined. METHODS: We collected blood samples from 31 HF patients (57+/-15 years old) undergoing cardiothoracic surgery and 7 healthy age-matched controls, between 2010 and 2011, at a single institution. WB and PBMC samples were collected at a single timepoint postoperatively (median day 8 postoperatively) (25-75% IQR 7-14 days) and subjected to Illumina single color Human BeadChip HT12 v4 whole genome expression array analysis. The Sequential Organ Failure Assessment (SOFA) score was used to characterize the severity of MOD into low (<= 4 points), intermediate (5-11), and high (>= 12) risk categories correlating with GEP. RESULTS: Results indicate that the direction of change in GEP of individuals with MOD as compared to controls is similar when determined from PBMC versus WB. The main enriched terms by Gene Ontology (GO) analysis included those involved in the inflammatory response, apoptosis, and other stress response related pathways. The data revealed 35 significant GO categories and 26 pathways overlapping between PBMC and WB. Additionally, class prediction using machine learning tools demonstrated that the subset of significant genes shared by PBMC and WB are sufficient to train as a predictor separating the SOFA groups. CONCLUSION: GEP analysis of WB has the potential to become a clinical tool for immune-monitoring in patients with MOD. PMID- 25517113 TI - A small short-necked hupehsuchian from the lower Triassic of Hubei Province, China. AB - Hupehsuchia is a group of enigmatic Triassic marine reptiles that is known exclusively from two counties in Hubei Province, China. One of the common features of the group was a modestly long neck with nine to ten cervical vertebrae. We report a new species of Hupehsuchia, Eohupehsuchus brevicollis gen. et sp. nov., which for the first time shows a short neck in this group, with six cervicals. The configuration of the skull roof in Eohupehsuchus is also unique among Hupehsuchia, with narrow frontals and posteriorly shifted parietals, warranting recognition of a new species. The taxon superficially resembles Nanchangosaurus in retaining hupehsuchian plesiomorphies, such as low neural spines and small body size. However, its limbs are well-developed, unlike in Nanchangosaurus, although the latter genus is marginally larger in body length. Thus, the individual is unlikely to be immature. Also, Eohupehsuchus shares a suite of synapomorphies with Hupehsuchus, including the second and third layers of dermal ossicles above the dorsal neural spines. A phylogenetic analysis suggests that the new species is not the most basal hupehsuchian despite its short neck, and instead forms the sister taxon of Hupehsuchidae. Until recently, Hupehsuchia contained only two monotypic genera. Now there are at least four genera among Hupehsuchia, and the undescribed diversity is even higher. The left forelimb of the only specimen is incomplete, ending with broken phalanges distally. The breakage could only have occurred pre-burial. The individual may have been attacked by a predator and escaped, given that scavenging is unlikely. PMID- 25517114 TI - Incubation temperature effects on hatchling performance in the loggerhead sea turtle (Caretta caretta). AB - Incubation temperature has significant developmental effects on oviparous animals, including affecting sexual differentiation for several species. Incubation temperature also affects traits that can influence survival, a theory that is verified in this study for the Northwest Atlantic loggerhead sea turtle (Caretta caretta). We conducted controlled laboratory incubations and experiments to test for an effect of incubation temperature on performance of loggerhead hatchlings. Sixty-eight hatchlings were tested in 2011, and 31 in 2012, produced from eggs incubated at 11 different constant temperatures ranging from 27 degrees C to 33 degrees C. Following their emergence from the eggs, we tested righting response, crawling speed, and conducted a 24-hour long swim test. The results support previous studies on sea turtle hatchlings, with an effect of incubation temperature seen on survivorship, righting response time, crawling speed, change in crawl speed, and overall swim activity, and with hatchlings incubated at 27 degrees C showing decreased locomotor abilities. No hatchlings survived to be tested in both years when incubated at 32 degrees C and above. Differences in survivorship of hatchlings incubated at high temperatures are important in light of projected higher sand temperatures due to climate change, and could indicate increased mortality from incubation temperature effects. PMID- 25517115 TI - Bacterial bile metabolising gene abundance in Crohn's, ulcerative colitis and type 2 diabetes metagenomes. AB - We performed an analysis to determine the importance of bile acid modification genes in the gut microbiome of inflammatory bowel disease and type 2 diabetic patients. We used publicly available metagenomic datasets from the Human Microbiome Project and the MetaHIT consortium, and determined the abundance of bile salt hydrolase gene (bsh), 7 alpha-dehydroxylase gene (adh) and 7-alpha hydroxysteroid dehydrogenase gene (hsdh) in fecal bacteria in diseased populations of Crohn's disease (CD), Ulcerative Colitis (UC) and Type 2 diabetes mellitus (T2DM). Phylum level abundance analysis showed a significant reduction in Firmicute-derived bsh in UC and T2DM patients but not in CD patients, relative to healthy controls. Reduction of adh and hsdh genes was also seen in UC and T2DM patients, while an increase was observed in the CD population as compared to healthy controls. A further analysis of the bsh genes showed significant differences in the correlations of certain Firmicutes families with disease or healthy populations. From this observation we proceeded to analyse BSH protein sequences and identified BSH proteins clusters representing the most abundant strains in our analysis of Firmicute bsh genes. The abundance of the bsh genes corresponding to one of these protein clusters was significantly reduced in all disease states relative to healthy controls. This cluster includes bsh genes derived from Lachospiraceae, Clostridiaceae, Erysipelotrichaceae and Ruminococcaceae families. This metagenomic analysis provides evidence of the importance of bile acid modifying enzymes in health and disease. It further highlights the importance of identifying gene and protein clusters, as the same gene may be associated with health or disease, depending on the strains expressing the enzyme, and differences in the enzymes themselves. PMID- 25517116 TI - The switching role of beta-adrenergic receptor signalling in cell survival or death decision of cardiomyocytes. AB - How cell fate (survival or death) is determined and whether such determination depends on the strength of stimulation has remained unclear. In this study, we discover that the cell fate of cardiomyocytes switches from survival to death with the increase of beta-adrenergic receptor (beta-AR) stimulation. Mathematical simulations combined with biochemical experimentation of beta-AR signalling pathways show that the gradual increment of isoproterenol (a non-selective beta1/beta2-AR agonist) induces the switching response of Bcl-2 expression from the initial increase followed by a decrease below its basal level. The ERK1/2 and ICER-mediated feed-forward loop is the hidden design principle underlying such cell fate switching characteristics. Moreover, we find that beta1-blocker treatment increases the survival effect of beta-AR stimuli through the regulation of Bcl-2 expression leading to the resistance to cell death, providing new insight into the mechanism of therapeutic effects. Our systems analysis further suggests a novel potential therapeutic strategy for heart disease. PMID- 25517117 TI - Impact of visceral fat on skeletal muscle mass and vice versa in a prospective cohort study: the Korean Sarcopenic Obesity Study (KSOS). AB - OBJECTIVES: Sarcopenia and visceral obesity have been suggested to aggravate each other, resulting in a vicious cycle. However, evidence based on prospective study is very limited. Our purpose was to investigate whether visceral fat promotes a decrease in skeletal muscle mass and vice versa. METHODS: We observed changes in anthropometric and body composition data during a follow-up period of 27.6 +/- 2.8 months in 379 Korean men and women (mean age 51.9 +/- 14.6 years) from the Korean Sarcopenic Obesity Study (KSOS). Appendicular lean soft tissue (ALST) mass was calculated using dual-energy X-ray absorptiometry, and visceral fat area (VFA) was measured using computed tomography at baseline and follow-up examination. RESULTS: ALST mass significantly decreased, whereas trunk and total fat mass increased in both men and women despite no significant change in weight and body mass index. In particular, women with visceral obesity at baseline had a greater decrease in ALST mass than those without visceral obesity (P = 0.001). In multiple linear regression analysis, baseline VFA was an independent negative predictor of the changes in ALST after adjusting for confounding factors including age, gender, life style and body composition parameters, insulin resistance, high sensitivity C-reactive protein and vitamin D levels (P = 0.001), whereas the association between baseline ALST mass and changes in VFA was not statistically significant (P = 0.555). CONCLUSIONS: This longitudinal study showed that visceral obesity was associated with future loss of skeletal muscle mass in Korean adults. These results may provide novel insight into sarcopenic obesity in an aging society. PMID- 25517118 TI - Unexpected effects of low doses of a neonicotinoid insecticide on behavioral responses to sex pheromone in a pest insect. AB - In moths, which include many agricultural pest species, males are attracted by female-emitted sex pheromones. Although integrated pest management strategies are increasingly developed, most insect pest treatments rely on widespread use of neurotoxic chemicals, including neonicotinoid insecticides. Residual accumulation of low concentrations of these insecticides in the environment is known to be harmful to beneficial insects such as honey bees. This environmental stress probably acts as an "info-disruptor" by modifying the chemical communication system, and therefore decreases chances of reproduction in target insects that largely rely on olfactory communication. However, low doses of pollutants could on the contrary induce adaptive processes in the olfactory pathway, thus enhancing reproduction. Here we tested the effects of acute oral treatments with different low doses of the neonicotinoid clothianidin on the behavioral responses to sex pheromone in the moth Agrotis ipsilon using wind tunnel experiments. We show that low doses of clothianidin induce a biphasic effect on pheromone-guided behavior. Surprisingly, we found a hormetic-like effect, improving orientation behavior at the LD20 dose corresponding to 10 ng clothianidin. On the contrary, a negative effect, disturbing orientation behavior, was elicited by a treatment with a dose below the LD0 dose corresponding to 0.25 ng clothianidin. No clothianidin effect was observed on behavioral responses to plant odor. Our results indicate that risk assessment has to include unexpected effects of residues on the life history traits of pest insects, which could then lead to their adaptation to environmental stress. PMID- 25517121 TI - Reviewers invited: mentoring provided. Please RSVP! PMID- 25517122 TI - Women's experiences of participation in a feminist group for women with complex mental health issues. AB - A sample of women (n = 5) participated in a qualitative service evaluation concerning an open-ended, therapeutic group for women only. Data analysis followed suggestions by Halcomb and Davidson (2006). Main themes derived from the evaluation included: 'Groups are different from individual work', 'Belonging/ not being alone', 'Performance in the group', 'The group as a safety net', 'Life improvements and hope for the future' and 'The extent of emotional despair felt'. In this paper, several sub-themes within the main themes and relevant theories and implications for theory and service provision are discussed. PMID- 25517123 TI - Clinical use of sensory gardens and outdoor environments in norwegian nursing homes: a cross-sectional e-mail survey. AB - Gardens and outdoor environments offer multiple therapeutic possibilities for the residents in nursing homes. Web-based questionnaires were sent to 488 nursing home leaders and 121 leaders responded. The clinical impressions of the leaders and staff regarding the benefits of sensory gardens (SGs) to the residents were consistent with previous research. SGs facilitated taking residents outdoors, offered convenient topics for communication and facilitated social privacy for relatives. For improved clinical use of SGs and outdoor environments, systematic assessment of residents' interests, performance and experiences when outdoors, implementation of seasonal clinical programmes and educational programmes for leaders and staff are recommended. PMID- 25517124 TI - A qualitative analysis of stress and coping in Korean immigrant women in middle age and older-adulthood. AB - This qualitative grounded theory study explored stress-coping mechanisms in 14 Korean immigrant women (age >=40) in the USA, by analyzing existing focus group data about relevant concepts that had been collected in a parent study. Using content analysis, stressors related primarily to socioenvironmental changes following immigration: language barriers, lack of trusting human relationships, and role changes were identified. Both healthy (activities, church, staying busy) and unhealthy (being alone and keeping negative feelings inside) coping strategies were reported by participants. The findings reveal unique aspects of stress-coping among Korean women who had immigrated after being culturally engrained with Confucian influences. PMID- 25517119 TI - Formyl peptide receptor as a novel therapeutic target for anxiety-related disorders. AB - Formyl peptide receptors (FPR) belong to a family of sensors of the immune system that detect microbe-associated molecules and inform various cellular and sensorial mechanisms to the presence of pathogens in the host. Here we demonstrate that Fpr2/3-deficient mice show a distinct profile of behaviour characterised by reduced anxiety in the marble burying and light-dark box paradigms, increased exploratory behaviour in an open-field, together with superior performance on a novel object recognition test. Pharmacological blockade with a formyl peptide receptor antagonist, Boc2, in wild type mice reproduced most of the behavioural changes observed in the Fpr2/3(-/-) mice, including a significant improvement in novel object discrimination and reduced anxiety in a light/dark shuttle test. These effects were associated with reduced FPR signalling in the gut as shown by the significant reduction in the levels of p p38. Collectively, these findings suggest that homeostatic FPR signalling exerts a modulatory effect on anxiety-like behaviours. These findings thus suggest that therapies targeting FPRs may be a novel approach to ameliorate behavioural abnormalities present in neuropsychiatric disorders at the cognitive-emotional interface. PMID- 25517120 TI - Identification of Listeria monocytogenes determinants required for biofilm formation. AB - Listeria monocytogenes is a Gram-positive, food-borne pathogen of humans and animals. L. monocytogenes is considered to be a potential public health risk by the U.S. Food and Drug Administration (FDA), as this bacterium can easily contaminate ready-to-eat (RTE) foods and cause an invasive, life-threatening disease (listeriosis). Bacteria can adhere and grow on multiple surfaces and persist within biofilms in food processing plants, providing resistance to sanitizers and other antimicrobial agents. While whole genome sequencing has led to the identification of biofilm synthesis gene clusters in many bacterial species, bioinformatics has not identified the biofilm synthesis genes within the L. monocytogenes genome. To identify genes necessary for L. monocytogenes biofilm formation, we performed a transposon mutagenesis library screen using a recently constructed Himar1 mariner transposon. Approximately 10,000 transposon mutants within L. monocytogenes strain 10403S were screened for biofilm formation in 96 well polyvinyl chloride (PVC) microtiter plates with 70 Himar1 insertion mutants identified that produced significantly less biofilms. DNA sequencing of the transposon insertion sites within the isolated mutants revealed transposon insertions within 38 distinct genetic loci. The identification of mutants bearing insertions within several flagellar motility genes previously known to be required for the initial stages of biofilm formation validated the ability of the mutagenesis screen to identify L. monocytogenes biofilm-defective mutants. Two newly identified genetic loci, dltABCD and phoPR, were selected for deletion analysis and both DeltadltABCD and DeltaphoPR bacterial strains displayed biofilm formation defects in the PVC microtiter plate assay, confirming these loci contribute to biofilm formation by L. monocytogenes. PMID- 25517125 TI - Development of an assessment of functioning scale for prison environments. AB - This paper reports the development of a global assessment of functioning (GAF), modified from the DSM Axis V GAF for the prison environment. Focus groups, which were conducted with 36 correctional officers and clinicians in two prisons, provided descriptions of behavior in prison settings to re-align the GAF scale. Face validity was established. It was found that Habitation/Behavior, Social, and Symptoms emerged as important domains of functioning in prison. Gender differences were noted with regard to cleanliness, relationships and coping strategies. The cut-off score was identified at a score where offenders were unable to participate in a disciplinary process due to their mental illness. The structure of prison alters human functioning, requiring different assessment language and ratings to measure perceived behavioral norms and/or expectations. Front-line staff need the ability to observe and communicate behavioral changes quickly and accurately in a prison environment without undue burden upon their workload. This assessment was modified by front-line staff specifically for the prison environment to document quick and frequent assessments of observed changes over time in the offender population. PMID- 25517126 TI - A pilot test of the CM-GAF among offenders with mental disorders. AB - A pilot test of clinician-rated validity of scores on a Correction Modified Global Assessment of Functioning (CM-GAF) scale was performed by assessing a random sample of 60 adult male and female offenders at two correctional facilities. Pairs of trained clinicians assessed the offenders with the CM-GAF and GAF instruments. Regression analyses were conducted. Variables included in the analysis were demographic characteristics (age, gender, and race), criminal history (number of incarcerations, violent/non-violent offense, year of current incarceration), number of disciplinary reports (tickets), and Connecticut Department of Corrections (CDOC) risk scores. The model for the CM-GAF yielded one significant predictor variable, Presence of Pending Charges Risk Score (B = 7.25, p = .003), predicting 44.4% of the variance. This finding suggests that higher functioning offenders tend not to have pending charges, which may be a proxy for length of incarceration. Newly admitted offenders are more likely to have pending charges and more likely to exhibit disruptive and disorganized behaviors. Management of mentally ill persons who are incarcerated is facilitated when inter-professional frontline staff can communicate using a common language. Frequent assessment with an instrument that is understandable across disciplines has the potential to improve care, and as few standardized mental health instruments are modified and tested for use in the prison environment. Additional studies, refining scoring across subsamples by age, race, gender, diagnosis, and levels of security, are still needed. PMID- 25517127 TI - Teamwork and teambuilding: considering retreats. PMID- 25517128 TI - Consecutively reconstructing absorption and scattering distributions in turbid media with multiple-illumination photoacoustic tomography. AB - We propose a theoretical framework for consecutively reconstructing absorption and scattering distributions in turbid soft tissue in an iterative manner. This approach takes advantage of the stability of a recently reported least-squares fixed-point iterative method for reconstructing an optical absorption coefficient map to iteratively update estimates of absorption and scattering for each iteration. Simulations demonstrate that this method converges to an accurate estimate of the optical properties within only a small number of iterations and is robust to noise at realistic signal-to-noise levels. PMID- 25517129 TI - Competition between heavy fermion and Kondo interaction in isoelectronic A-site ordered perovskites. AB - With current research efforts shifting towards the 4d and 5d transition metal oxides, understanding the evolution of the electronic and magnetic structure as one moves away from 3d materials is of critical importance. Here we perform X-ray spectroscopy and electronic structure calculations on A-site-ordered perovskites with Cu in the A-site and the B-sites descending along the ninth group of the periodic table to elucidate the emerging properties as d-orbitals change from partially filled 3d to 4d to 5d. The results show that when descending from Co to Ir, the charge transfers from the cuprate-like Zhang-Rice state on Cu to the t(2g) orbital of the B site. As the Cu d-orbital occupation approaches the Cu(2+) limit, a mixed valence state in CaCu(3)Rh(4)O(12) and heavy fermion state in CaCu(3)Ir(4)O(12) are obtained. The investigated d-electron compounds are mapped onto the Doniach phase diagram of the competing RKKY and Kondo interactions developed for the f-electron systems. PMID- 25517130 TI - Combining biologic therapies with other systemic treatments in psoriasis: evidence-based, best-practice recommendations from the Medical Board of the National Psoriasis Foundation. AB - IMPORTANCE: While monotherapy with biologic agents is effective for many patients with psoriasis, some patients require combination therapy. Evidence-based recommendations on combination therapy provide guidance for treating appropriately selected patients with psoriasis. OBJECTIVE: To make evidence based, best-practice recommendations regarding combining biologics with other systemic treatments, including phototherapy, oral medications, or other biologics, for psoriasis treatment. EVIDENCE REVIEW: We searched the MEDLINE database for studies from January 1, 1946, to June 18, 2013, that evaluated therapies combining biologics with phototherapy, oral medications, or other biologic agents. The Medical Board of the National Psoriasis Foundation arrived at best-practice recommendations through group discussion and voting. FINDINGS: Few trials evaluated the efficacy and safety of combination therapies in moderate to severe psoriasis. Combining biologics, such as etanercept or adalimumab, with phototherapy likely results in greater reduction in disease severity than either alone. Etanercept and methotrexate combination is more effective than monotherapy with either medication. A combination of infliximab with methotrexate results in greater efficacy than infliximab alone. With concomitant use of acitretin, the dosing of etanercept can be reduced to maintain similar levels of efficacy. Short term cyclosporine use has been combined with etanercept or adalimumab to control psoriasis flares. Based on the expert opinion of the Medical Board of the National Psoriasis Foundation, the preferred order for combining a second modality with biologics is biologic and methotrexate combination, biologic and acitretin combination, and then biologic and phototherapy combination. In the psoriasis literature, there are overall insufficient data on combining biologics with acitretin, cyclosporine, or a second biologic. CONCLUSIONS AND RELEVANCE: Among appropriately selected patients with psoriasis, carefully chosen combinations may result in greater efficacy, while minimizing toxicity. PMID- 25517132 TI - Bladder neck needle suspension for urinary incontinence in women. AB - BACKGROUND: Bladder neck needle suspension is an operation traditionally used for moderate or severe stress urinary incontinence in women. About a third of adult women experience some urinary incontinence, and about a third of these have moderate or severe symptoms. OBJECTIVES: To determine the effects of needle suspension on stress or mixed urinary incontinence in comparison with other management options. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 12 November 2014), and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised trials that included needle suspension for the treatment of urinary incontinence. DATA COLLECTION AND ANALYSIS: At least two authors assessed trials and extracted data independently. Two trial investigators provided additional information. MAIN RESULTS: We identified 10 trials, which included 375 women having six different types of needle suspension procedures and 489 who received comparison interventions. Needle suspensions were more likely to fail than open abdominal retropubic suspension. There was a higher subjective failure rate after the first year (91/313 (29%) failed versus 47/297 (16%) failed after open abdominal retropubic suspension). The risk ratio (RR) was 2.00 (95% confidence interval (CI) 1.47 to 2.72), although the difference in peri-operative complications was not significant (17/75 (23%) versus 12/77 (16%); RR 1.44, 95% CI 0.73 to 2.83). There were no significant differences for the other outcome measures. This effect was seen in both women with primary incontinence and women with recurrent incontinence after failed primary operations. Needle suspensions may be as effective as anterior vaginal repair (50/156 (32%) failed after needle suspension versus 64/181 (35%) after anterior repair; RR 0.86, 95% CI 0.64 to 1.16), but there was little information about morbidity. Data for comparison with suburethral slings were inconclusive because they came from a small and atypical population.No trials compared needle suspensions with conservative management, peri-urethral injections, or sham or laparoscopic surgery. AUTHORS' CONCLUSIONS: Bladder neck needle suspension surgery is probably not as good as open abdominal retropubic suspension for the treatment of primary and secondary urodynamic stress incontinence because the cure rates were lower in the trials reviewed. However, the reliability of the evidence was limited by poor quality and small trials. There was not enough information to comment on comparisons with suburethral sling operations. Although cure rates were similar after needle suspension compared with after anterior vaginal repair, the data were insufficient to be reliable and inadequate to compare morbidity. PMID- 25517131 TI - Novel genes for airway wall thickness identified with combined genome-wide association and expression analyses. AB - RATIONALE: Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. OBJECTIVES: To investigate the genetic component of AWT. METHODS: AWT was measured on low-dose computed tomography scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome-wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by metaanalysis. An independent cohort was used for validation of the most strongly associated single nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated. MEASUREMENTS AND MAIN RESULTS: Three significant loci on chromosomes 2q (rs734556; P = 6.2 * 10(-7)) and 10q (rs10794108, P = 8.6 * 10(-8); rs7078439, P = 2.3 * 10(-7)) were associated with AWT and confirmed in the metaanalysis in cohorts with comparable lung function: P values = 4.6 * 10(-8), 7.4 * 10(-8), and 7.5 * 10(-8), respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (P = 5.8 * 10(-7)) and rs4796712 in NT5C3B (P = 3.1 * 10( 6)). Higher MAGI2 expression in bronchial biopsies of patients with chronic obstructive pulmonary disease was significantly associated with fewer inflammatory cells. The presence of the NT5C3B risk allele was associated with higher lung tissue expression (P = 1.09 * 10(-41)). CONCLUSIONS: Genetic variants contribute to AWT. Among others, the identified genes are also involved in emphysema, airway obstruction, and bronchial inflammation. PMID- 25517133 TI - Ecology and Physiology of the Pathogenic Cyanobacterium Roseofilum reptotaenium. AB - Roseofilum reptotaenium is a gliding, filamentous, phycoerythrin-rich cyanobacterium that has been found only in the horizontally migrating, pathogenic microbial mat, black band disease (BBD) on Caribbean corals. R. reptotaenium dominates the BBD mat in terms of biomass and motility, and the filaments form the mat fabric. This cyanobacterium produces the cyanotoxin microcystin, predominately MC-LR, and can tolerate high levels of sulfide produced by sulfate reducing bacteria (SRB) that are also associated with BBD. Laboratory cultures of R. reptotaenium infect coral fragments, suggesting that the cyanobacterium is the primary pathogen of BBD, but since this species cannot grow axenically and Koch's Postulates cannot be fulfilled, it cannot be proposed as a primary pathogen. However, R. reptotaenium does play several major pathogenic roles in this polymicrobial disease. Here, we provide an overview of the ecology of this coral pathogen and present new information on R. reptotaenium ecophysiology, including roles in the infection process, chemotactic and other motility responses, and the effect of pH on growth and motility. Additionally, we show, using metabolomics, that exposure of the BBD microbial community to the cyanotoxin MC-LR affects community metabolite profiles, in particular those associated with nucleic acid biosynthesis. PMID- 25517134 TI - Mitigating harmful cyanobacterial blooms in a human- and climatically-impacted world. AB - Bloom-forming harmful cyanobacteria (CyanoHABs) are harmful from environmental, ecological and human health perspectives by outcompeting beneficial phytoplankton, creating low oxygen conditions (hypoxia, anoxia), and by producing cyanotoxins. Cyanobacterial genera exhibit optimal growth rates and bloom potentials at relatively high water temperatures; hence, global warming plays a key role in their expansion and persistence. CyanoHABs are regulated by synergistic effects of nutrient (nitrogen:N and phosphorus:P) supplies, light, temperature, vertical stratification, water residence times, and biotic interactions. In most instances, nutrient control strategies should focus on reducing both N and P inputs. Strategies based on physical, chemical (nutrient) and biological manipulations can be effective in reducing CyanoHABs; however, these strategies are largely confined to relatively small systems, and some are prone to ecological and environmental drawbacks, including enhancing release of cyanotoxins, disruption of planktonic and benthic communities and fisheries habitat. All strategies should consider and be adaptive to climatic variability and change in order to be effective for long-term control of CyanoHABs. Rising temperatures and greater hydrologic variability will increase growth rates and alter critical nutrient thresholds for CyanoHAB development; thus, nutrient reductions for bloom control may need to be more aggressively pursued in response to climatic changes globally. PMID- 25517135 TI - Why are benzodiazepines not yet controlled substances? PMID- 25517137 TI - Ozone trends across the United States over a period of decreasing NOx and VOC emissions. AB - In this work, we evaluate ambient ozone trends at urban, suburban, and rural monitoring sites across the United States over a period of decreasing NOx and VOC emissions (1998-2013). We find that decreasing ozone trends generally occur in the summer, in less urbanized areas, and at the upper end of the ozone distribution. Conversely, increasing ozone trends generally occur in the winter, in more urbanized areas, and at the lower end of the ozone distribution. The 95(th) percentile ozone concentrations decreased at urban, suburban, and rural monitors by 1-2 ppb/yr in the summer and 0.5-1 ppb/yr in the winter. In the summer, there are both increasing and decreasing trends in fifth percentile ozone concentrations of less than 0.5 ppb/yr at urban and suburban monitors, while fifth percentile ozone concentrations at rural monitors decreased by up to 1 ppb/yr. In the winter, fifth percentile ozone concentrations generally increased by 0.1-1 ppb/yr. These results demonstrate the large scale success of U.S. control strategies targeted at decreasing peak ozone concentrations. In addition, they indicate that as anthropogenic NOx emissions have decreased, the ozone distribution has been compressed, leading to less spatial and temporal variability. PMID- 25517138 TI - Informal caregivers of patients with disorders of consciousness: experience of ambiguous loss. AB - PRIMARY OBJECTIVE: This study aimed at better understanding of the complex psychological process underlying the demanding situation of taking care of a relative with disorder of consciousness (DOCs). RESEARCH DESIGN: This is a qualitative study based on the grounded theory constant comparative method. METHODS AND PROCEDURES: Narratives of informal caregivers were collected through in-depth interviews with a psychologist. A three-step coding scheme was applied: coding of narratives to label the specific contents; organization of codes into sub-categories and categories; and theoretical coding to describe the relation between categories. MAIN OUTCOMES AND RESULTS: Twenty informal caregivers participated in one in-depth interview between December 2011 and May 2012. Four major themes emerged: Another person with past in common; Losing and finding myself; Old and new ways of being in relationship; and Dealing with concerns. These themes represent caregivers' efforts to deal with the situation in which their relative is at the same time present and absent. The core salient feature emerging from all these themes is the experience of ambiguous loss. CONCLUSIONS: Features of ambiguous loss that emerged in this study could guide clinicians' interventions to support adjustment of caregivers of patients with DOCs. PMID- 25517136 TI - Conducting research interviews with bereaved family carers: when do we ask? AB - BACKGROUND: Interviews with bereaved family carers to examine the end-of-life experience of the deceased are important tools for palliative care researchers, but the ethics of approaching the bereaved when they are grieving and vulnerable is often debated. OBJECTIVE: The aim of this study was to explore the insights of bereaved family carers about the most appropriate time to be involved in a research interview about the end of life and death of their family member. METHODS: This qualitative study used a social constructionist framework. Twenty two bereaved family carers of people with motor neurone disease (MND) and cancer were interviewed in Western Australia. RESULTS: Most family carers (86%) feel comfortable being interviewed about the death of their family member within the first 5 months of bereavement, with 43% reporting they could be interviewed within weeks after death. Family carers reported that recall would be better earlier in bereavement and felt it may be helpful to them to talk about their experiences earlier. They said bereaved people should be allowed to decide for themselves when to be involved in an interview. CONCLUSIONS: These findings indicate that interviews with the bereaved may be most fruitful for researchers and beneficial to family carers when they are allowed to make the choice about timing for themselves, beginning weeks after the death of their family member. PMID- 25517139 TI - Further closing the resolution gap: integrating cryo-soft x-ray and light microscopies. PMID- 25517140 TI - Lateral exchange smooths the way for vimentin filaments. PMID- 25517141 TI - The ryanodine receptor patchwork: knitting calcium spark dynamics. PMID- 25517142 TI - Time-resolved fluorescence in lipid bilayers: selected applications and advantages over steady state. AB - Fluorescence methods are versatile tools for obtaining dynamic and topological information about biomembranes because the molecular interactions taking place in lipid membranes frequently occur on the same timescale as fluorescence emission. The fluorescence intensity decay, in particular, is a powerful reporter of the molecular environment of a fluorophore. The fluorescence lifetime can be sensitive to the local polarity, hydration, viscosity, and/or presence of fluorescence quenchers/energy acceptors within several nanometers of the vicinity of a fluorophore. Illustrative examples of how time-resolved fluorescence measurements can provide more valuable and detailed information about a system than the time-integrated (steady-state) approach will be presented in this review: 1), determination of membrane polarity and mobility using time-dependent spectral shifts; 2), identification of submicroscopic domains by fluorescence lifetime imaging microscopy; 3), elucidation of membrane leakage mechanisms from dye self-quenching assays; and 4), evaluation of nanodomain sizes by time resolved Forster resonance energy transfer measurements. PMID- 25517144 TI - The microtubule-based cytoskeleton is a component of a mechanical signaling pathway in fly campaniform receptors. AB - In mechanoreceptors, mechanical stimulation by external forces leads to the rapid opening of transduction channels followed by an electrical response. Despite intensive studies in various model systems, the molecular pathway by which forces are transmitted to the transduction channels remains elusive. In fly campaniform mechanoreceptors, the mechanotransduction channels are gated by compressive forces conveyed via two rows of microtubules that are hypothesized to be mechanically reinforced by an intervening electron-dense material (EDM). In this study, we tested this hypothesis by studying a mutant fly in which the EDM was nearly absent, whereas the other ultrastructural elements in the mechanosensitive organelle were still present at 50% (or greater) of normal levels. We found that the mechanosensory response in this mutant was reduced by 90% and the sensitivity by at least 80%. To test whether loss of the EDM could lead to such a reduction in response, we performed a mechanical analysis and estimated that the loss of the EDM is expected to greatly decrease the overall rigidity, leading to a marked reduction in the gating force conveyed to the channel. We argue that this reduction in force, rather than the reduction in the number of transduction channels, is primarily responsible for the nearly complete loss of mechanosensory response observed in the mutant fly. Based on these experiments and analysis, we conclude that the microtubule-based cytoskeleton (i.e., microtubules and EDM) is an essential component of the mechanical signaling pathway in fly campaniform mechanoreceptor. PMID- 25517143 TI - Connecting the dots: the effects of macromolecular crowding on cell physiology. AB - The physicochemical properties of cellular environments with a high macromolecular content have been systematically characterized to explain differences observed in the diffusion coefficients, kinetics parameters, and thermodynamic properties of proteins inside and outside of cells. However, much less attention has been given to the effects of macromolecular crowding on cell physiology. Here, we review recent findings that shed some light on the role of crowding in various cellular processes, such as reduction of biochemical activities, structural reorganization of the cytoplasm, cytoplasm fluidity, and cellular dormancy. We conclude by presenting some unresolved problems that require the attention of biophysicists, biochemists, and cell physiologists. Although it is still underappreciated, macromolecular crowding plays a critical role in life as we know it. PMID- 25517145 TI - Mapping diffusion in a living cell via the phasor approach. AB - Diffusion of a fluorescent protein within a cell has been measured using either fluctuation-based techniques (fluorescence correlation spectroscopy (FCS) or raster-scan image correlation spectroscopy) or particle tracking. However, none of these methods enables us to measure the diffusion of the fluorescent particle at each pixel of the image. Measurement using conventional single-point FCS at every individual pixel results in continuous long exposure of the cell to the laser and eventual bleaching of the sample. To overcome this limitation, we have developed what we believe to be a new method of scanning with simultaneous construction of a fluorescent image of the cell. In this believed new method of modified raster scanning, as it acquires the image, the laser scans each individual line multiple times before moving to the next line. This continues until the entire area is scanned. This is different from the original raster-scan image correlation spectroscopy approach, where data are acquired by scanning each frame once and then scanning the image multiple times. The total time of data acquisition needed for this method is much shorter than the time required for traditional FCS analysis at each pixel. However, at a single pixel, the acquired intensity time sequence is short; requiring nonconventional analysis of the correlation function to extract information about the diffusion. These correlation data have been analyzed using the phasor approach, a fit-free method that was originally developed for analysis of FLIM images. Analysis using this method results in an estimation of the average diffusion coefficient of the fluorescent species at each pixel of an image, and thus, a detailed diffusion map of the cell can be created. PMID- 25517146 TI - Identification of a cholesterol-binding pocket in inward rectifier K(+) (Kir) channels. AB - Cholesterol is the major sterol component of all mammalian plasma membranes. Recent studies have shown that cholesterol inhibits both bacterial (KirBac1.1 and KirBac3.1) and eukaryotic (Kir2.1) inward rectifier K(+) (Kir) channels. Lipid sterol interactions are not enantioselective, and the enantiomer of cholesterol (ent-cholesterol) does not inhibit Kir channel activity, suggesting that inhibition results from direct enantiospecific binding to the channel, and not indirect effects of changes to the bilayer. Furthermore, conservation of the effect of cholesterol among prokaryotic and eukaryotic Kir channels suggests an evolutionary conserved cholesterol-binding pocket, which we aimed to identify. Computational experiments were performed by docking cholesterol to the atomic structures of Kir2.2 (PDB: 3SPI) and KirBac1.1 (PDB: 2WLL) using Autodock 4.2. Poses were assessed to ensure biologically relevant orientation and then clustered according to location and orientation. The stability of cholesterol in each of these poses was then confirmed by molecular dynamics simulations. Finally, mutation of key residues (S95H and I171L) in this putative binding pocket found within the transmembrane domain of Kir2.1 channels were shown to lead to a loss of inhibition by cholesterol. Together, these data provide support for this location as a biologically relevant pocket. PMID- 25517147 TI - Modeling a Ca(2+) channel/BKCa channel complex at the single-complex level. AB - BKCa-channel activity often affects the firing properties of neurons, the shapes of neuronal action potentials (APs), and in some cases the extent of neurotransmitter release. It has become clear that BKCa channels often form complexes with voltage-gated Ca(2+) channels (CaV channels) such that when a CaV channel is activated, the ensuing influx of Ca(2+) activates its closely associated BKCa channel. Thus, in modeling the electrical properties of neurons, it would be useful to have quantitative models of CaV/BKCa complexes. Furthermore, in a population of CaV/BKCa complexes, all BKCa channels are not exposed to the same Ca(2+) concentration at the same time. Thus, stochastic rather than deterministic models are required. To date, however, no such models have been described. Here, however, I present a stochastic model of a CaV2.1/BKCa(alpha-only) complex, as might be found in a central nerve terminal. The CaV2.1/BKCa model is based on kinetic modeling of its two component channels at physiological temperature. Surprisingly, The CaV2.1/BKCa model predicts that although the CaV channel will open nearly every time during a typical cortical AP, its associated BKCa channel is expected to open in only 30% of trials, and this percentage is very sensitive to the duration of the AP, the distance between the two channels in the complex, and the presence of fast internal Ca(2+) buffers. Also, the model predicts that the kinetics of the BKCa currents of a population of CaV2.1/BKCa complexes will not be limited by the kinetics of the CaV2.1 channel, and during a train of APs, the current response of the complex is expected to faithfully follow even very rapid trains. Aside from providing insight into how these complexes are likely to behave in vivo, the models presented here could also be of use more generally as components of higher-level models of neural function. PMID- 25517148 TI - Oxidative stress and ca(2+) release events in mouse cardiomyocytes. AB - Cellular oxidative stress, associated with a variety of common cardiac diseases, is well recognized to affect the function of several key proteins involved in Ca(2+) signaling and excitation-contraction coupling, which are known to be exquisitely sensitive to reactive oxygen species. These include the Ca(2+) release channels of the sarcoplasmic reticulum (ryanodine receptors or RyR2s) and the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Oxidation of RyR2s was found to increase the open probability of the channel, whereas CaMKII can be activated independent of Ca(2+) through oxidation. Here, we investigated how oxidative stress affects RyR2 function and SR Ca(2+) signaling in situ, by analyzing Ca(2+) sparks in permeabilized mouse cardiomyocytes under a broad range of oxidative conditions. The results show that with increasing oxidative stress Ca(2+) spark duration is prolonged. In addition, long and very long-lasting (up to hundreds of milliseconds) localized Ca(2+) release events started to appear, eventually leading to sarcoplasmic reticulum (SR) Ca(2+) depletion. These changes of release duration could be prevented by the CaMKII inhibitor KN93 and did not occur in mice lacking the CaMKII-specific S2814 phosphorylation site on RyR2. The appearance of long-lasting Ca(2+) release events was paralleled by an increase of RyR2 oxidation, but also by RyR-S2814 phosphorylation, and by CaMKII oxidation. Our results suggest that in a strongly oxidative environment oxidation-dependent activation of CaMKII leads to RyR2 phosphorylation and thereby contributes to the massive prolongation of SR Ca(2+) release events. PMID- 25517149 TI - High-melting lipid mixtures and the origin of detergent-resistant membranes studied with temperature-solubilization diagrams. AB - The origin of resistance to detergent solubilization in certain membranes, or membrane components, is not clearly understood. We have studied the solubilization by Triton X-100 of binary mixtures composed of egg sphingomyelin (SM) and either ceramide, diacylglycerol, or cholesterol. Solubilization has been assayed in the 4-50 degrees C range, and the results are summarized in a novel, to our knowledge, form of plots, that we have called temperature-solubilization diagrams. Despite using a large detergent excess (lipid/detergent 1:20 mol ratio) and extended solubilization times (24-48 h) certain mixtures were not amenable to Triton X-100 solubilization at one or more temperatures. DSC of all the lipid mixtures, and of all the lipid + detergent mixtures revealed that detergent resistance was associated with the presence of gel domains at the assay temperature. Once the system melted down, solubilization could occur. In general adding high-melting lipids limited the solubilization, whereas the addition of low-melting lipids promoted it. Lipidomic analysis of Madin-Darby canine kidney cell membranes and of the corresponding detergent-resistant fraction indicated a large enrichment of the nonsolubilized components in saturated diacylglycerol and ceramide. SM-cholesterol mixtures were special in that detergent solubilization was accompanied, for certain temperatures and compositions, by an independent phenomenon of reassembly of the partially solubilized lipid bilayers. The temperature at which lysis and reassembly prevailed was ~25 degrees C, thus for some SM-cholesterol mixtures solubilization occurred both above and below 25 degrees C, but not at that temperature. These observations can be at the origin of the detergent resistance effects observed with cell membranes, and they also mean that cholesterol-containing detergent-resistant membrane remnants cannot correspond to structures existing in the native membrane before detergent addition. PMID- 25517150 TI - PC12 cells that lack synaptotagmin I exhibit loss of a subpool of small dense core vesicles. AB - Neurons communicate by releasing neurotransmitters that are stored in intracellular vesicular compartments. PC12 cells are frequently used as a model secretory cell line that is described to have two subpools of vesicles: small clear vesicles and dense core vesicles. We measured transmitter molecules released from vesicles in NGF-differentiated PC12 cells using carbon-fiber amperometry, and relative diameters of individual vesicles using electron microscopy. Both amperometry and electron micrograph data were analyzed by statistical and machine learning methods for Gaussian mixture models. An electron microscopy size correction algorithm was used to predict and correct for observation bias of vesicle size due to tangential slices through some vesicles. Expectation maximization algorithms were used to perform maximum likelihood estimation for the Gaussian parameters of different populations of vesicles, and were shown to be better than histogram and cumulative distribution function methods for analyzing mixed populations. The Bayesian information criterion was used to determine the most likely number of vesicle subpools observed in the amperometric and electron microscopy data. From this analysis, we show that there are three major subpools, not two, of vesicles stored and released from PC12 cells. The three subpools of vesicles include small clear vesicles and two subpools of dense core vesicles, a small and a large dense core vesicle subpool. Using PC12 cells stably transfected with short-hairpin RNA targeted to synaptotagmin I, an exocytotic Ca(2+) sensor, we show that the presence and release of the small dense core vesicle subpool is dependent on synaptotagmin I. Furthermore, synaptotagmin I also plays a role in the formation and/or maintenance of the small dense core vesicle subpool in PC12 cells. PMID- 25517151 TI - Biophysical properties of novel 1-deoxy-(dihydro)ceramides occurring in mammalian cells. AB - Ceramides and dihydroceramides are N-acyl derivatives of sphingosine and sphinganine, respectively, which are the major sphingoid-base backbones of mammals. Recent studies have found that mammals, like certain other organisms, also produce 1-deoxy-(dihydro)ceramides (1-deoxyDHCers) that contain sphingoid bases lacking the 1-hydroxyl- or 1-hydroxymethyl- groups. The amounts of these compounds can be substantial-indeed, we have found comparable levels of 1 deoxyDHCers and ceramides in RAW 264.7 cells maintained in culture. The biophysical properties of 1-deoxyDHCers have not yet been reported, although these lipids might play important roles in normal cell regulation and in the pathology of diseases in which they are elevated, such as hereditary sensory autonomic neuropathies or diabetes. This study uses several approaches, including surface-pressure measurements, differential scanning calorimetry, and confocal microscopy, to study the behavior of 1-deoxyDHCers of different N-acyl-chain lengths and their interaction with sphingomyelin (SM). The thermotropic behaviors of 1-deoxyDHCers alone and in mixtures with SM are described, together with their interactions in monolayers and giant unilamellar vesicles. The gel-fluid transition temperatures of the pure compounds increase in the order 1 deoxyceramide < ceramide ~ 1-deoxyDHCer < 1-(deoxymethyl)DHCer. In general, canonical ceramides are more miscible with SM in bilayers than are 1 deoxyceramides, and 1-(deoxymethyl)DHCers are the most hydrophobic among them, not even capable of forming monolayers at the air-water interface. Thus, these properties suggest that 1-deoxyDHCer can influence the properties of cellular membranes in ways that might affect biological function/malfunction. PMID- 25517152 TI - Feedback mechanism for microtubule length regulation by stathmin gradients. AB - We formulate and analyze a theoretical model for the regulation of microtubule (MT) polymerization dynamics by the signaling proteins Rac1 and stathmin. In cells, the MT growth rate is inhibited by cytosolic stathmin, which, in turn, is inactivated by Rac1. Growing MTs activate Rac1 at the cell edge, which closes a positive feedback loop. We investigate both tubulin sequestering and catastrophe promotion as mechanisms for MT growth inhibition by stathmin. For a homogeneous stathmin concentration in the absence of Rac1, we find a switchlike regulation of the MT mean length by stathmin. For constitutively active Rac1 at the cell edge, stathmin is deactivated locally, which establishes a spatial gradient of active stathmin. In this gradient, we find a stationary bimodal MT-length distribution for both mechanisms of MT growth inhibition by stathmin. One subpopulation of the bimodal length distribution can be identified with fast-growing and long pioneering MTs in the region near the cell edge, which have been observed experimentally. The feedback loop is closed through Rac1 activation by MTs. For tubulin sequestering by stathmin, this establishes a bistable switch with two stable states: one stable state corresponds to upregulated MT mean length and bimodal MT length distributions, i.e., pioneering MTs; the other stable state corresponds to an interrupted feedback with short MTs. Stochastic effects as well as external perturbations can trigger switching events. For catastrophe-promoting stathmin, we do not find bistability. PMID- 25517153 TI - Capturing transition paths and transition states for conformational rearrangements in the ribosome. AB - To reveal the molecular determinants of biological function, one seeks to characterize the interactions that are formed in conformational and chemical transition states. In other words, what interactions govern the molecule's energy landscape? To accomplish this, it is necessary to determine which degrees of freedom can unambiguously identify each transition state. Here, we perform simulations of large-scale aminoacyl-transfer RNA (aa-tRNA) rearrangements during accommodation on the ribosome and project the dynamics along experimentally accessible atomic distances. From this analysis, we obtain evidence for which coordinates capture the correct number of barrier-crossing events and accurately indicate when the aa-tRNA is on a transition path. Although a commonly used coordinate in single-molecule experiments performs poorly, this study implicates alternative coordinates along which rearrangements are accurately described as diffusive movements across a one-dimensional free-energy profile. From this, we provide the theoretical foundation required for single-molecule techniques to uncover the energy landscape governing aa-tRNA selection by the ribosome. PMID- 25517154 TI - Role of denatured-state properties in chaperonin action probed by single-molecule spectroscopy. AB - The bacterial chaperonin GroEL/GroES assists folding of a broad spectrum of denatured and misfolded proteins. Here, we explore the limits of this remarkable promiscuity by mapping two denatured proteins with very different conformational properties, rhodanese and cyclophilin A, during binding and encapsulation by GroEL/GroES with single-molecule spectroscopy, microfluidic mixing, and ensemble kinetics. We find that both proteins bind to GroEL with high affinity in a reaction involving substantial conformational adaptation. However, whereas the compact denatured state of rhodanese is encapsulated efficiently upon addition of GroES and ATP, the more expanded and unstructured denatured cyclophilin A is not encapsulated but is expelled into solution. The origin of this surprising disparity is the weaker interactions of cyclophilin A with a transiently formed GroEL-GroES complex, which may serve as a crucial checkpoint for substrate discrimination. PMID- 25517155 TI - The structure of misfolded amyloidogenic dimers: computational analysis of force spectroscopy data. AB - Progress in understanding the molecular mechanism of self-assembly of amyloidogenic proteins and peptides requires knowledge about their structure in misfolded states. Structural studies of amyloid aggregates formed during the early aggregation stage are very limited. Atomic force microscopy (AFM) spectroscopy is widely used to analyze misfolded proteins and peptides, but the structural characterization of transiently formed misfolded dimers is limited by the lack of computational approaches that allow direct comparison with AFM experiments. Steered molecular dynamics (SMD) simulation is capable of modeling force spectroscopy experiments, but the modeling requires pulling rates 10(7) times higher than those used in AFM experiments. In this study, we describe a computational all-atom Monte Carlo pulling (MCP) approach that enables us to model results at pulling rates comparable to those used in AFM pulling experiments. We tested the approach by modeling pulling experimental data for I91 from titin I-band (PDB ID: 1TIT) and ubiquitin (PDB ID: 1UBQ). We then used MCP to analyze AFM spectroscopy experiments that probed the interaction of the peptides [Q6C] Sup35 (6-13) and [H13C] Abeta (13-23). A comparison of experimental results with the computational data for the Sup35 dimer with out-of register and in-register arrangements of beta-sheets suggests that Sup35 monomers adopt an out-of-register arrangement in the dimer. A similar analysis performed for Abeta peptide demonstrates that the out-of-register antiparallel beta-sheet arrangement of monomers also occurs in this peptide. Although the rupture of hydrogen bonds is the major contributor to dimer dissociation, the aromatic aromatic interaction also contributes to the dimer rupture process. PMID- 25517157 TI - Direct observation of subunit exchange along mature vimentin intermediate filaments. AB - Actin filaments, microtubules, and intermediate filaments (IFs) are central elements of the metazoan cytoskeleton. At the molecular level, the assembly mechanism for actin filaments and microtubules is fundamentally different from that of IFs. The former two types of filaments assemble from globular proteins. By contrast, IFs assemble from tetrameric complexes of extended, half-staggered, and antiparallel oriented coiled-coils. These tetramers laterally associate into unit-length filaments; subsequent longitudinal annealing of unit-length filaments yields mature IFs. In vitro, IFs form open structures without a fixed number of tetramers per cross-section along the filament. Therefore, a central question for the structural biology of IFs is whether individual subunits can dissociate from assembled filaments and rebind at other sites. Using the fluorescently labeled IF protein vimentin for assembly, we directly observe and quantitatively determine subunit exchange events between filaments as well as with soluble vimentin pools. Thereby we demonstrate that the cross-sectional polymorphism of donor and acceptor filaments plays an important role. We propose that in segments of donor filaments with more than the standard 32 molecules per cross-section, subunits are not as tightly bound and are predisposed to be released from the filament. PMID- 25517156 TI - The role of histone tails in the nucleosome: a computational study. AB - Histone tails play an important role in gene transcription and expression. We present here a systematic computational study of the role of histone tails in the nucleosome, using replica exchange molecular dynamics simulations with an implicit solvent model and different well-established force fields. We performed simulations for all four histone tails, H4, H3, H2A, and H2B, isolated and with inclusion of the nucleosome. The results confirm predictions of previous theoretical studies for the secondary structure of the isolated tails but show a strong dependence on the force field used. In the presence of the entire nucleosome for all force fields, the secondary structure of the histone tails is destabilized. Specific contacts are found between charged lysine and arginine residues and DNA phosphate groups and other binding sites in the minor and major DNA grooves. Using cluster analysis, we found a single dominant configuration of binding to DNA for the H4 and H2A histone tails, whereas H3 and H2B show multiple binding configurations with an equal probability. The leading stabilizing contribution for those binding configurations is the attractive interaction between the positively charged lysine and arginine residues and the negatively charged phosphate groups, and thus the resulting charge neutralization. Finally, we present results of molecular dynamics simulations in explicit solvent to confirm our conclusions. Results from both implicit and explicit solvent models show that large portions of the histone tails are not bound to DNA, supporting the complex role of these tails in gene transcription and expression and making them possible candidates for binding sites of transcription factors, enzymes, and other proteins. PMID- 25517159 TI - The kinetic stability of cytochrome C oxidase: effect of bound phospholipid and dimerization. AB - Thermally induced transitions of the 13-subunit integral membrane protein bovine cytochrome c oxidase (CcO) have been studied by differential scanning calorimetry (DSC) and circular dichroism (CD). Thermal denaturation of dodecyl maltoside solubilized CcO proceeds in two consecutive, irreversible, kinetically driven steps with the apparent transition temperatures at ~ 51 degrees C and ~ 61 degrees C (5MUM CcO at scan rate of 1.5 K/min). The thermal denaturation data were analyzed according to the Lyubarev and Kurganov model of two consecutive irreversible steps. However, because of the limitation of the model to describe the complex mechanism of the thermal denaturation of CcO, the obtained results were utilized only for comparison purposes of kinetic stabilities of CcO under specific protein concentration (5MUM) and scan rate (1.5 K/min). This enabled us to show that both the amphiphilic environment and the self-association state of CcO affect its kinetic stability. Kinetic stabilities of both steps are significantly decreased when all of the phospholipids are removed from CcO by phospholipase A2 (the half-life decreases at 37 degrees C). Conversely, dimerization of CcO induced by sodium cholate significantly increases its kinetic stability of only the first step (the half-life increases at 37 degrees C). Protein concentration-dependent nonspecific oligomerization also indicate mild stabilization of CcO. Both, reversed-phase high-performance liquid chromatography (HPLC) and SDS-PAGE subunit analysis reveal that the first step of thermal denaturation involves dissociation of subunits III, VIa, VIb, and VIIa, whereas the second step is less well defined and most likely involves global unfold and aggregation of the remaining subunits. Electron transport activity of CcO decreases in a sigmoidal manner during the first transition and this dependence is very well described by kinetic parameters for the first step of the thermal transition. Therefore, dissociation of subunit III and/or VIIa is responsible for temperature-induced inactivation of CcO because VIa and VIb can be removed from CcO without affecting the enzyme activity. These results demonstrate an important role of tightly bound phospholipids and oligomeric state (particularly the dimeric form) of CcO for kinetic stability of the protein. PMID- 25517158 TI - Characterization of the conformational fluctuations in the Josephin domain of ataxin-3. AB - As for a variety of other molecular recognition processes, conformational fluctuations play an important role in the cleavage of polyubiquitin chains by the Josephin domain of ataxin-3. The interaction between Josephin and ubiquitin appears to be mediated by the motions of alpha-helical hairpin that is unusual among deubiquitinating enzymes. Here, we characterized the conformational fluctuations of the helical hairpin by incorporating NMR measurements as replica averaged restraints in molecular dynamics simulations, and by validating the results by small-angle x-ray scattering measurements. This approach allowed us to define the extent of the helical hairpin motions and suggest a role of such motions in the recognition of ubiquitin. PMID- 25517160 TI - Connecting thermal and mechanical protein (un)folding landscapes. AB - Molecular dynamics simulations supplement single-molecule pulling experiments by providing the possibility of examining the full free energy landscape using many coordinates. Here, we use an all-atom structure-based model to study the force and temperature dependence of the unfolding of the protein filamin by applying force at both termini. The unfolding time-force relation tau(F) indicates that the force-induced unfolding behavior of filamin can be characterized into three regimes: barrier-limited low- and intermediate-force regimes, and a barrierless high-force regime. Slope changes of tau(F) separate the three regimes. We show that the behavior of tau(F) can be understood from a two-dimensional free energy landscape projected onto the extension X and the fraction of native contacts Q. In the low-force regime, the unfolding rate is roughly force-independent due to the small (even negative) separation in X between the native ensemble and transition state ensemble (TSE). In the intermediate-force regime, force sufficiently separates the TSE from the native ensemble such that tau(F) roughly follows an exponential relation. This regime is typically explored by pulling experiments. While X may fail to resolve the TSE due to overlap with the unfolded ensemble just below the folding temperature, the overlap is minimal at lower temperatures where experiments are likely to be conducted. The TSE becomes increasingly structured with force, whereas the average order of structural events during unfolding remains roughly unchanged. The high-force regime is characterized by barrierless unfolding, and the unfolding time approaches a limit of ~10 MUs for the highest forces we studied. Finally, a combination of X and Q is shown to be a good reaction coordinate for almost the entire force range. PMID- 25517161 TI - Tetracycline determines the conformation of its aptamer at physiological magnesium concentrations. AB - Synthetic riboswitches are versatile tools for the study and manipulation of biological systems. Yet, the underlying mechanisms governing its structural properties and regulation under physiological conditions are poorly studied. We performed spectroscopic and calorimetric experiments to explore the folding kinetics and thermodynamics of the tetracycline-binding aptamer, which can be employed as synthetic riboswitch, in the range of physiological magnesium concentrations. The dissociation constant of the ligand-aptamer complex was found to strongly depend on the magnesium concentration. At physiological magnesium concentrations, tetracycline induces a significant conformational shift from a compact, but heterogeneous intermediate state toward the completely formed set of tertiary interactions defining the regulation-competent structure. Thus, the switching functionality of the tetracycline-binding aptamer appears to include both a conformational rearrangement toward the regulation-competent structure and its thermodynamic stabilization. PMID- 25517162 TI - Ligand binding modulates the structural dynamics and compactness of the major birch pollen allergen. AB - Pathogenesis-related plant proteins of class-10 (PR-10) are essential for storage and transport of small molecules. A prominent member of the PR-10 family, the major birch pollen allergen Bet v 1, is the main cause of spring pollinosis in the temperate climate zone of the northern hemisphere. Bet v 1 binds various ligand molecules to its internal cavity, and immunologic effects of the presence of ligand have been discussed. However, the mechanism of binding has remained elusive. In this study, we show that in solution Bet v 1.0101 is conformationally heterogeneous and cannot be represented by a single structure. NMR relaxation data suggest that structural dynamics are fundamental for ligand access to the protein interior. Complex formation then leads to significant rigidification of the protein along with a compaction of its 3D structure. The data presented herein provide a structural basis for understanding the immunogenic and allergenic potential of ligand binding to Bet v 1 allergens. PMID- 25517163 TI - Exploring the stability limits of actin and its suprastructures. AB - Actin is the main component of the microfilament system in eukaryotic cells and can be found in distinct morphological states. Global (G)-actin is able to assemble into highly organized, supramolecular cellular structures known as filamentous (F)-actin and bundled (B)-actin. To evaluate the structure and stability of G-, F-, and B-actin over a wide range of temperatures and pressures, we used Fourier transform infrared spectroscopy in combination with differential scanning and pressure perturbation calorimetry, small-angle x-ray scattering, laser confocal scanning microscopy, and transmission electron microscopy. Our analysis was designed to provide new (to our knowledge) insights into the stabilizing forces of actin self-assembly and to reveal the stability of the actin polymorphs, including in conditions encountered in extreme environments. In addition, we sought to explain the limited pressure stability of actin self assembly observed in vivo. G-actin is not only the least temperature-stable but also the least pressure-stable actin species. Under abyssal conditions, where temperatures as low as 1-4 degrees C and pressures up to 1 kbar are reached, G actin is hardly stable. However, the supramolecular assemblies of actin are stable enough to withstand the extreme conditions usually encountered on Earth. Beyond ~3-4 kbar, filamentous structures disassemble, and beyond ~4 kbar, complete dissociation of F-actin structures is observed. Between ~1 and 2 kbar, some disordering of actin assemblies commences, in agreement with in vivo observations. The limited pressure stability of the monomeric building block seems to be responsible for the suppression of actin assembly in the kbar pressure range. PMID- 25517164 TI - A pH-dependent kinetic model of dihydrolipoamide dehydrogenase from multiple organisms. AB - Dihydrolipoamide dehydrogenase is a flavoenzyme that reversibly catalyzes the oxidation of reduced lipoyl substrates with the reduction of NAD(+) to NADH. In vivo, the dihydrolipoamide dehydrogenase component (E3) is associated with the pyruvate, alpha-ketoglutarate, and glycine dehydrogenase complexes. The pyruvate dehydrogenase (PDH) complex connects the glycolytic flux to the tricarboxylic acid cycle and is central to the regulation of primary metabolism. Regulation of PDH via regulation of the E3 component by the NAD(+)/NADH ratio represents one of the important physiological control mechanisms of PDH activity. Furthermore, previous experiments with the isolated E3 component have demonstrated the importance of pH in dictating NAD(+)/NADH ratio effects on enzymatic activity. Here, we show that a three-state mechanism that represents the major redox states of the enzyme and includes a detailed representation of the active-site chemistry constrained by both equilibrium and thermodynamic loop constraints can be used to model regulatory NAD(+)/NADH ratio and pH effects demonstrated in progress-curve and initial-velocity data sets from rat, human, Escherichia coli, and spinach enzymes. Global fitting of the model provides stable predictions to the steady state distributions of enzyme redox states as a function of lipoamide/dihydrolipoamide, NAD(+)/NADH, and pH. These distributions were calculated using physiological NAD(+)/NADH ratios representative of the diverse organismal sources of E3 analyzed in this study. This mechanistically detailed, thermodynamically constrained, pH-dependent model of E3 provides a stable platform on which to accurately model multicomponent enzyme complexes that implement E3 from a variety of organisms. PMID- 25517165 TI - Residence times of receptors in dendritic spines analyzed by stochastic simulations in empirical domains. AB - Analysis of high-density superresolution imaging of receptors reveals the organization of dendrites at nanoscale resolution. We present here an apparently novel method that uses local statistics extracted from short-range trajectories for the simulations of long-range trajectories in empirical live cell images. Based on these empirical simulations, we compute the residence time of a receptor in dendritic spines that accounts for receptors' local interactions and geometrical membrane organization. We report here that depending on the type of the spine, the residence time varies from 1 to 5 min. Moreover, we show that there exists transient organized structures, previously described as potential wells that can regulate the trafficking of receptors to dendritic spine: the simulation results suggest that receptor trafficking is regulated by transient structures. PMID- 25517167 TI - Nonlinear compliance modulates dynamic bronchoconstriction in a multiscale airway model. AB - The role of breathing and deep inspirations (DI) in modulating airway hyperresponsiveness remains poorly understood. In particular, DIs are potent bronchodilators of constricted airways in nonasthmatic subjects but not in asthmatic subjects. Additionally, length fluctuations (mimicking DIs) have been shown to reduce mean contractile force when applied to airway smooth muscle (ASM) cells and tissue strips. However, these observations are not recapitulated on application of transmural pressure (PTM) oscillations (that mimic tidal breathing and DIs) in isolated intact airways. To shed light on this paradox, we have developed a biomechanical model of the intact airway, accounting for strain stiffening due to collagen recruitment (a large component of the extracellular matrix (ECM)), and dynamic actomyosin-driven force generation by ASM cells. In agreement with intact airway studies, our model shows that PTM fluctuations at particular mean transmural pressures can lead to only limited bronchodilation. However, our model predicts that moving the airway to a more compliant point on the static pressure-radius relationship (which may involve reducing mean PTM), before applying pressure fluctuations, can generate greater bronchodilation. This difference arises from competition between passive strain-stiffening of ECM and force generation by ASM yielding a highly nonlinear relationship between effective airway stiffness and PTM, which is modified by the presence of contractile agonist. Effectively, the airway at its most compliant may allow for greater strain to be transmitted to subcellular contractile machinery. The model predictions lead us to hypothesize that the maximum possible bronchodilation of an airway depends on its static compliance at the PTM about which the fluctuations are applied. We suggest the design of additional experimental protocols to test this hypothesis. PMID- 25517168 TI - Dynamics of cell area and force during spreading. AB - Experiments on human pulmonary artery endothelial cells are presented to show that cell area and the force exerted on a substrate increase simultaneously, but with different rates during spreading; rapid-force increase systematically occurred several minutes past initial spreading. We examine this theoretically and present three complementary mechanisms that may accompany the development of lamellar stress during spreading and underlie the observed behavior. These include: 1), the dynamics of cytoskeleton assembly at the cell basis; 2), the strengthening of acto-myosin forces in response to the generated lamellar stresses; and 3), the passive strain-stiffening of the cytoskeleton. PMID- 25517166 TI - Superresolution modeling of calcium release in the heart. AB - Stable calcium-induced calcium release (CICR) is critical for maintaining normal cellular contraction during cardiac excitation-contraction coupling. The fundamental element of CICR in the heart is the calcium (Ca(2+)) spark, which arises from a cluster of ryanodine receptors (RyR). Opening of these RyR clusters is triggered to produce a local, regenerative release of Ca(2+) from the sarcoplasmic reticulum (SR). The Ca(2+) leak out of the SR is an important process for cellular Ca(2+) management, and it is critically influenced by spark fidelity, i.e., the probability that a spontaneous RyR opening triggers a Ca(2+) spark. Here, we present a detailed, three-dimensional model of a cardiac Ca(2+) release unit that incorporates diffusion, intracellular buffering systems, and stochastically gated ion channels. The model exhibits realistic Ca(2+) sparks and robust Ca(2+) spark termination across a wide range of geometries and conditions. Furthermore, the model captures the details of Ca(2+) spark and nonspark-based SR Ca(2+) leak, and it produces normal excitation-contraction coupling gain. We show that SR luminal Ca(2+)-dependent regulation of the RyR is not critical for spark termination, but it can explain the exponential rise in the SR Ca(2+) leak-load relationship demonstrated in previous experimental work. Perturbations to subspace dimensions, which have been observed in experimental models of disease, strongly alter Ca(2+) spark dynamics. In addition, we find that the structure of RyR clusters also influences Ca(2+) release properties due to variations in inter RyR coupling via local subspace Ca(2+) concentration ([Ca(2+)]ss). These results are illustrated for RyR clusters based on super-resolution stimulated emission depletion microscopy. Finally, we present a believed-novel approach by which the spark fidelity of a RyR cluster can be predicted from structural information of the cluster using the maximum eigenvalue of its adjacency matrix. These results provide critical insights into CICR dynamics in heart, under normal and pathological conditions. PMID- 25517169 TI - Inherent force-dependent properties of beta-cardiac myosin contribute to the force-velocity relationship of cardiac muscle. AB - The heart adjusts its power output to meet specific physiological needs through the coordination of several mechanisms, including force-induced changes in contractility of the molecular motor, the beta-cardiac myosin (betaCM). Despite its importance in driving and regulating cardiac power output, the effect of force on the contractility of a single betaCM has not been measured. Using single molecule optical-trapping techniques, we found that betaCM has a two-step working stroke. Forces that resist the power stroke slow the myosin-driven contraction by slowing the rate of ADP release, which is the kinetic step that limits fiber shortening. The kinetic properties of betaCM are affected by load, suggesting that the properties of myosin contribute to the force-velocity relationship in intact muscle and play an important role in the regulation of cardiac power output. PMID- 25517170 TI - A GTPase chimera illustrates an uncoupled nucleotide affinity and release rate, providing insight into the activation mechanism. AB - The release of GDP from GTPases signals the initiation of a GTPase cycle, where the association of GTP triggers conformational changes promoting binding of downstream effector molecules. Studies have implicated the nucleotide-binding G5 loop to be involved in the GDP release mechanism. For example, biophysical studies on both the eukaryotic Galpha proteins and the GTPase domain (NFeoB) of prokaryotic FeoB proteins have revealed conformational changes in the G5 loop that accompany nucleotide binding and release. However, it is unclear whether this conformational change in the G5 loop is a prerequisite for GDP release, or, alternatively, the movement is a consequence of release. To gain additional insight into the sequence of events leading to GDP release, we have created a chimeric protein comprised of Escherichia coli NFeoB and the G5 loop from the human Gialpha1 protein. The protein chimera retains GTPase activity at a similar level to wild-type NFeoB, and structural analyses of the nucleotide-free and GDP bound proteins show that the G5 loop adopts conformations analogous to that of the human nucleotide-bound Gialpha1 protein in both states. Interestingly, isothermal titration calorimetry and stopped-flow kinetic analyses reveal uncoupled nucleotide affinity and release rates, supporting a model where G5 loop movement promotes nucleotide release. PMID- 25517171 TI - Blood glucose amplitude variability in critically ill patients. AB - While the discussion on the optimal blood glucose (BG) level target in critically ill patients is on-going, attention shifts towards other aspects of the BG signal, such as hypoglycemia and blood glucose amplitude variability (BGAV). A large number of observational and mostly retrospective studies have demonstrated an association between increased BGAV and worse outcomes. This observed association could partially be explained by endogenous factors such as changes in the status of the patient that cannot be externally influenced. On the other hand, exogenous factors such as insulin and caloric infusions could play a role in increasing or decreasing BGAV. In this review article, intuitive concept of "variability" will be clarified, and possible metrics to quantify BGAV are discussed. Whether it is feasible to actively minimize BGAV in order to improve the outcome of critically ill patients, is questionable. PMID- 25517172 TI - Association between steroid particle sizes and serious complications during epidural injections. PMID- 25517173 TI - Are emotionally attached companion animal caregivers conscientious and neurotic? Factors that affect the human-companion animal relationship. AB - Few studies have examined how personality traits may be related to the amounts and types of attachments humans have toward companion animals (pets). In this study, 1,098 companion animal guardians (owners) completed a survey that included the Big Five Inventory, the Lexington Attachment to Pets Scale, and the Pet Attachment Questionnaire. Each participant chose whether he or she identified as a Cat Person, Dog Person, Both, or Neither. Results indicated that neuroticism, conscientiousness, choosing a dog as a favorite pet, and identifying as a Cat Person, Dog Person, or Both predicted affection for a pet. Conscientiousness, extraversion, and openness decreased avoidant attachment to pets, and neuroticism increased anxious attachment to pets. Both dogs and cats could benefit from pet owners who are conscientious, and there may be some benefits of neuroticism in pet owners. The findings of this study will advance understanding of the human animal bond. As this understanding increases, measurements of human attachment and personality may be useful for the development of tools that could assist shelter employees and veterinarians in counseling people about pet ownership. PMID- 25517174 TI - Pyrazolopyrimidines in 'all-natural' products for erectile dysfunction treatment: the unreliable quality of dietary supplements. AB - A herbal food supplement advertised as a potency pill was screened for the presence of PDE5 inhibitors. The resulting signals were characterised by UV, LC MS in ESI-negative mode, and NMR spectroscopy using 1D and 2D experiments. Several substances were identified, bearing the basic chemical structure of sildenafil, but were not supposed to exhibit PDE5 inhibition. These compounds may be process-related impurities or by-products of different reaction steps in the synthesis of PDE5 analogues. As they were found to be present in different capsules at different concentrations, this is an example of the unreliable quality of dietary supplements. PMID- 25517175 TI - Comparing the water, energy, pesticide and fertilizer usage for the production of foods consumed by different dietary types in California. AB - OBJECTIVE: To compare the use of water, energy, pesticides and fertilizer to produce commodities for two dietary patterns that vary in the content of plant and animal products. DESIGN: A unique analysis using 'real-world' data was performed, in contrast to previous analyses which applied simulated data. Consumption data from the Adventist Health Study were used to identify two dietary patterns with a markedly different consumption of several plant and animal products. State agricultural data were collected and applied to commodity production statistics. Indices were created to allow a comparison of the resource requirements for each dietary pattern. SETTING: California, USA. SUBJECTS: None. RESULTS: The diet containing more animal products required an additional 10 252 litres of water, 9910 kJ of energy, 186 g of fertilizer and 6 g of pesticides per week in comparison to the diet containing less animal products. The greatest contribution to the difference came from the consumption of animal products, particularly beef. CONCLUSIONS: Consuming a more plant-based diet could to an extent alleviate the negative environmental impacts related to food production. As a method to feed ourselves more sustainably, behavioural adjustments appear to be a very important tool. PMID- 25517176 TI - Protonated water dimer on benzene: standing Eigen or crouching Zundel? AB - Protonated water clusters that are hydrogen-bonded to a neutral benzene molecule are a reductionist model for protons at hydrophobic surfaces, which are of fundamental importance in biological energy transduction processes. Of particular interest is the protonated water dimer ("Zundel ion") on benzene, whose gas-phase messenger IR spectrum has been previously interpreted in terms of an asymmetric binding of the protonated water dimer to the benzene ring through a single water molecule. This "standing Eigen" isomer has a hydronium core. We have found an alternative "crouching Zundel" isomer, which attaches to the benzene ring symmetrically via both of its water molecules. When Ar-tagged, it has an IR spectrum in much better agreement with experiment than the standing Eigen isomer, particularly at the lower frequencies. These conclusions are based on static harmonic (and anharmonic) normal-mode analysis using density functional theory with various (dispersion corrected) functionals and particularly on dynamic anharmonic spectra obtained from the dipole autocorrelation functions from classical ab initio molecular dynamics with the BLYP, PBE, and B3LYP functionals. Possible implications to protons on water/organic-phase interfaces are discussed. PMID- 25517177 TI - Microscopic dynamics research on the "mature" process of dye-sensitized solar cells after injection of highly concentrated electrolyte. AB - After injection of electrolyte, the internal three-dimensional solid-liquid penetration system of dye-sensitized solar cells (DSCs) can take a period of time to reach "mature" state. This paper studies the changes of microscopic processes of DSCs including TiO2 energy-level movement, localized state distribution, charge accumulation, electron transport, and recombination dynamics, from the beginning of electrolyte injection to the time of reached mature state. The results show that the microscopic dynamics process of DSCs exhibited a time dependent behavior and achieved maturity ~12 h after injecting the electrolyte into DSCs. Within 0-12 h, several results were observed: (1) the conduction band edge of TiO2 moved slightly toward negative potential direction; (2) the localized states in the band gap of TiO2 was reduced according to the same distribution law; (3) the transport resistance in TiO2 film increased, and electron transport time was prolonged as the time of maturity went on, which indicated that the electron transport process is impeded gradually; (4) the recombination resistance at the TiO2/electrolyte (EL) interface increases, and electron lifetime gradually extends, therefore, the recombination process is continuously suppressed. Furthermore, results suggest that the parameters of EL/Pt-transparent conductive oxide (TCO) interface including the interfacial capacitance, electron-transfer resistance, and transfer time constant would change with time of maturity, indicating that the EL/Pt-TCO interface is a potential factor affecting the mature process of DSCs. PMID- 25517178 TI - Stereoselective synthesis of the C1-C29 part of amphidinol 3. AB - Stereoselective synthesis of the C1-C29 part of amphidinol 3 (AM3) was achieved. The C1-C20 part was assembled from three building blocks via regioselective cross metathesis to form the C4-C5 double bond and addition of an alkenyllithium and a lithium acetylide to two Weinreb amides followed by asymmetric reduction to form the C9-C10 and C14-C15 bonds, respectively. The C21-C29 part was synthesized via successive cross metathesis and oxa-Michael addition sequence to construct the 1,3-diol system at C25 and C27 and Brown asymmetric crotylation to introduce the stereogenic centers at C23 and C24. Coupling of the C1-C20 and C21-C29 parts was achieved by Julia-Kocienski olefination and regio- and stereoselective dihydroxylation of the C20-C21 double bond in the presence of the C4-C5 and C8-C9 double bonds to afford the C1-C29 part of AM3. PMID- 25517179 TI - Basic residue at position 14 is not required for fast assembly and disassembly kinetics in neural cadherin. AB - In spite of their structural similarities, epithelial (E-) and neural (N-) cadherin are expressed at different types of synapses and differ significantly in their dimerization kinetics. Recent studies proposed a transient intermediate in E-cadherin as the key requirement for rapid disassembly kinetics of the adhesive dimer. This E-cadherin intermediate comprises four intermolecular ionic and H bonding interactions between adhesive partners. These interactions are not preserved in N-cadherin except for a basic residue at the 14th position, which could stabilize the intermediate through either H-bonding or ionic interactions with the partner protomer. To investigate the origin of the rapid dimerization kinetics of N-cadherin in the presence of calcium, studies reported here systematically test the role of ionic and H-bonding interactions in dimerization kinetics using R14S, R14A, and R14E mutants of N-cadherin. Analytical size exclusion chromatographic and bead aggregation studies showed two primary results. First, N-cadherin/R14S and N-cadherin/R14A mutants showed fast assembly and disassembly kinetics in the calcium-saturated state similar to that of wild type N-cadherin. These results indicate that the fast disassembly of the calcium saturated dimer of N-cadherin does not require a basic residue at the 14th position. Second, the dimerization kinetics of N-cadherin/R14E were slow in the calcium-saturated state, indicating that negative charge destabilizes the intermediate state. Taken together, these results indicate that the basic residue at the 14th position does not promote rapid dimerization kinetics but that an acidic amino acid in that position significantly impairs dimerization kinetics. PMID- 25517180 TI - [Alcoholism and the aesthetics of existence: Jack London and the white logic of John Barleycorn]. AB - Employing this theme as a guideline, this article examines how his prose amounts to self-practice in the construction of subjectivity and the organization of existence. It investigates how this work is related to the theme of self-care, analyzed by Michel Foucault in volumes 2 and 3 of the History of sexuality, as regards the aesthetics of existence and the art of living which existed in the Greco-Roman and Hellenistic worlds. PMID- 25517185 TI - High-resolution tissue Doppler imaging of the zebrafish heart during its regeneration. AB - The human heart cannot regenerate after injury, whereas the adult zebrafish can fully regenerate its heart even after 20% of the ventricle is amputated. Many studies have begun to reveal the cellular and molecular mechanisms underlying this regenerative process, which have exciting implications for human cardiac diseases. However, the dynamic functions of the zebrafish heart during regeneration are not yet understood. This study established a high-resolution echocardiography for tissue Doppler imaging (TDI) of the zebrafish heart to explore the cardiac functions during different regeneration phases. Experiments were performed on AB-line adult zebrafish (n=40) in which 15% of the ventricle was surgically removed. An 80-MHz ultrasound TDI based on color M-mode imaging technology was employed. The cardiac flow velocities and patterns from both the ventricular chamber and myocardium were measured at different regeneration phases relative to the day of amputation. The peak velocities of early diastolic inflow, early diastolic myocardial motion, late diastolic myocardial motion, early diastolic deceleration slope, and heart rate were increased at 3 days after the myocardium amputation, but these parameters gradually returned to close to their baseline values for the normal heart at 7 days after amputation. The peak velocities of late diastolic inflow, ventricular systolic outflow, and systolic myocardial motion did not significantly differ during the heart regeneration. PMID- 25517186 TI - Detection of gaseous compounds by needle trap sampling and direct thermal desorption photoionization mass spectrometry: concept and demonstrative application to breath gas analysis. AB - A fast detection method to analyze gaseous organic compounds in complex gas mixtures was developed, using a needle trap device (NTD) in conjunction with thermal-desorption photoionization time-of-flight mass spectrometry (TD-PI TOFMS). The mass spectrometer was coupled via a deactivated fused silica capillary to an injector of a gas chromatograph. In the hot injector, the analytes collected on the NTD were thermally desorbed and directly transferred to the PI-TOFMS ion source. The molecules are softly ionized either by single photon ionization (SPI, 118 nm) or by resonance enhanced multiphoton ionization (REMPI, 266 nm), and the molecular ion signals are detected in the TOF mass analyzer. Analyte desorption and the subsequent PI-TOFMS detection step only lasts ten seconds. The specific selectivity of REMPI (i.e., aromatic compounds) and universal ionization characteristics render PI-MS as a promising detection system. As a first demonstrative application, the alveolar phase breath gas of healthy, nonsmoking subjects was sampled on NTDs. While smaller organic compounds such as acetone, acetaldehyde, isoprene, or cysteamine can be detected in the breath gas with SPI, REMPI depicts the aromatic substances phenol and indole at 266 nm. In the breath gas of a healthy, smoking male subject, several xenobiotic substances such as benzene, toluene, styrene, and ethylbenzene can be found as well. Furthermore, the NTD-REMPI-TOFMS setup was tested for breath gas taken from a mechanically ventilated pig under continuous intravenous propofol (2,6 diisopropylphenol, narcotic drug) infusion. PMID- 25517188 TI - New Year's resolutions: NPs and weight loss. PMID- 25517187 TI - Preparation and Evaluation of Surface Modified Lactose Particles for Improved Performance of Fluticasone Propionate Dry Powder Inhaler. AB - BACKGROUND: Dry powder inhalers (DPI) are generally formulated by mixing micronized drug particles with coarse lactose carrier particles to assist powder handling during the manufacturing and powder aerosol delivery during patient use. METHODS: In the present study, surface modified lactose (SML) particles were produced using force control agents, and their in vitro performance on dry powder inhaler (DPI) formulation of Fluticasone propionate was studied. With a view to reduce surface passivation of high surface free energy sites on the most commonly used DPI carrier, alpha- lactose monohydrate, effects of various force control agents such as Pluronic F-68, Cremophor RH 40, glyceryl monostearate, polyethylene glycol 6000, magnesium stearate, and soya lecithin were studied. RESULTS: DPI formulations prepared with SML showed improved flow properties, and atomic force microscopy (AFM) studies revealed decrease in surface roughness. The DSC and X-ray diffraction patterns of SML showed no change in the crystal structure and thermal behavior under the experimental conditions. The fine particle fraction (FPF) values of lactose modified with Pluronic F-68, Cremophor RH 40, glyceryl monostearate were improved, with increase in concentration up to 0.5%. Soya lecithin and PEG 6000 modified lactose showed decrease in FPF value with increase in concentration. Increase in FPF value was observed with increasing concentration of magnesium stearate. Two different DPI devices, Rotahaler((r)) and Diskhaler((r)), were compared to evaluate the performance of SML formulations. FPF value of all SML formulations were higher using both devices as compared to the same formulations prepared using untreated lactose. One month stability of SML formulations at 40 degrees C/75% RH, in permeable polystyrene tubes did not reveal any significant changes in FPF values. CONCLUSION: SML particles can help in reducing product development hindrances and improve inhalational properties of DPI. PMID- 25517189 TI - 27th Annual APRN legislative update: advancements continue for APRN practice. AB - As the tides of healthcare in the United States continue to change, advanced practice registered nurses (APRNs) are at the forefront of legislative history. This overview provides a snapshot of legislative and regulatory activity in 2014 as reported by state Boards of Nursing and nursing organizations representing APRNs. PMID- 25517190 TI - Acute chest pain and pulmonary embolism. PMID- 25517193 TI - Spatio-temporal dynamics of kind versus hostile intentions in the human brain: An electrical neuroimaging study. AB - Neuroscience research suggests that inferring neutral intentions of other people recruits a specific brain network within the inferior fronto-parietal action observation network as well as a putative social network including brain areas subserving theory of mind, such as the posterior superior temporal sulcus (pSTS), the temporo-parietal junction (TPJ), and also the anterior cingulate cortex (ACC). Recent studies on harmful intentions have refined this network by showing the specific involvement of the ACC, amygdala, and ventromedial prefrontal cortex (vmPFC) in early stages (within 200 ms) of information processing. However, the functional dynamics for kind intentions within and among these networks remains unclear. To address this question, we measured electrical brain activity from 18 healthy adult participants while they were performing an intention inference task with three different types of intentions: kind, hostile and non-interactive. Electrophysiological results revealed that kind intentions were characterized by significantly larger peak amplitudes of N2 over the frontal sites than those for hostile and non-interactive intentions. On the other hand, there were no significant differences between hostile and non-interactive intentions at N2. The source analysis suggested that the vicinity of the left cingulate gyrus contributed to the N2 effect by subtracting the kindness condition from the non interactive condition within 250-350 ms. At a later stage (i.e., during the 270 500 ms epoch), the peak amplitude of the P3 over the parietal sites and the right hemisphere was significantly larger for hostile intentions compared to the kind and non-interactive intentions. No significant differences were observed at P3 between kind and non-interactive intentions. The source analysis showed that the vicinity of the left anterior cingulate cortex contributed to the P3 effect by subtracting the hostility condition from the non-interactive condition within 450 550 ms. The present study provides preliminary evidence of the spatio-temporal dynamics sustaining the dissociation between the understandings of different types of social intentions. PMID- 25517194 TI - Excess costs and length of hospital stay attributable to perioperative respiratory events in children. AB - BACKGROUND: Knowledge of the excess hospital costs and prolonged length of stay attributable to perioperative respiratory event (PRE) in pediatric anesthesia is useful for hospital planning. In this study, we compared costs (excess hospital costs and indirect costs) and length of hospital stay between children who had PRE and did not have PRE for noncardiac surgery at a tertiary care hospital in southern Thailand. METHODS: A prospective matched cohort study was conducted in children aged <15 years who underwent general anesthesia between November 2012 and December 2013 at Songklanagarind Hospital. PRE children were matched with no PRE children (1:1) using a random selection procedure on outpatients/inpatients, type of surgery, surgical charge (baht), ASA physical status, age difference <9 years, and difference in time of surgery <6 months. Primary end points were excess hospital costs and number of days hospitalized after surgery. Number of days hospitalized after surgery, excess hospital costs and indirect costs regarding transportation, and income loss of parents between groups were compared using Wilcoxon signed rank test. Any hospital stay after surgery between groups was compared using McNemar chi test. A hurdle model was used to predict any hospital stay and number of days hospitalized after surgery. Multiple mixed effects linear regression was used to identify predictors of adjusted excess hospital costs and indirect costs. RESULTS: A total 430 children were included (215 matched pairs). More PRE children required hospital stay after surgery (81% vs 72%, P = 0.004), and PRE children had a longer number of days hospitalized after surgery (median [interquartile ranges]: 1 [1-3.5] vs 1 [0-2]; P < 0.001) and incurred higher excess costs (P < 0.001) but not indirect costs (P = 0.23). In multivariate analysis, PRE was a significant predictor for hospital stay after surgery (odds ratio, 2.56; 95% confidence interval, 1.23-5.31), longer hospitalization (count ratio, 2.10 [1.31-3.35]), higher excess costs (cost ratio, 1.30 [1.12-1.53]), and indirect cost (cost ratio, 1.58 [1.20-2.08]) after adjusting for patient and anesthesia characteristics. Universal coverage (74%) was associated with 35% and 64% higher excess cost compared with the Comptroller General's Department (17%) and self-pay (7%), respectively (P = 0.003). CONCLUSIONS: The effects of PRE in pediatric anesthesia were hospital stay after surgery, 2 times longer hospitalization, 30% higher excess hospital costs, and 58% higher indirect cost among outpatients. Hospital policy to efficiently manage hospital beds and compensatory budget should be developed. PMID- 25517195 TI - Alphaxalone Reformulated: A Water-Soluble Intravenous Anesthetic Preparation in Sulfobutyl-Ether-beta-Cyclodextrin. AB - BACKGROUND: Alphaxalone is a neuroactive steroid anesthetic that is poorly water soluble. It was formulated in 1972 as Althesin(r) using Cremophor(r) EL, a nonionic surfactant additive. The product was a versatile short-acting IV anesthetic used in clinical practice in many countries from 1972 to 1984. It was withdrawn from clinical practice because of hypersensitivity to Cremophor EL. In the investigations reported here, we compared the properties of 3 anesthetics: a new aqueous solution of alphaxalone dissolved in 7-sulfobutyl-ether-beta cyclodextrin (SBECD, a water-soluble molecule with a lipophilic cavity that enables drug solubilization in water); a Cremophor EL preparation of alphaxalone; and propofol. METHODS: Two solutions of alphaxalone (10 mg/mL) were prepared: one using 13% w/v solution of SBECD in 0.9% saline (PHAX) and the other a solution of alphaxalone prepared as described in the literature using 20% Cremophor EL (ALTH). A solution of propofol (10 mg/mL; PROP) in 10% v/v soya bean oil emulsion was used as a comparator anesthetic. Jugular IV catheters were implanted in male Wistar rats (180-220 g) under halothane anesthesia. Separate groups of 10 implanted rats each were given IV injections of PHAX, ALTH, or PROP from 1.2 mg/kg to lethal doses. Doses of each drug that caused anesthesia (loss of righting reflex and response to tail pinch) and lethality in 50% of rats were calculated by probit analysis. The drugs were also compared for effects on arterial blood pressure and heart rate. RESULTS: IV PHAX, ALTH, and PROP caused dose-related sedation and anesthesia, with 50% effective dose (ED50) values for loss of righting reflex being 2.8, 3.0, and 4.6 mg/kg, respectively. PROP led to death in 10 of 10 rats at doses >30 mg/kg (50% lethal dose (LD50) = 27.7 mg/kg). A dose of alphaxalone 53 mg/kg as ALTH caused 10 of 10 rats to die (LD50 = 43.6 mg/kg), whereas none died when given the same doses of alphaxalone formulated in SBECD. PHAX caused 20% lethality at the maximal dose tested of 84 mg/kg. PHAX caused less cardiovascular depression than PROP. Control experiments with the 3 drug-free vehicles showed no effects. CONCLUSIONS: Alphaxalone caused fast-onset anesthesia at the same dose for both formulations (PHAX and ALTH). The use of SBECD as a drug-solubilizing excipient did not alter the anesthetic effect of alphaxalone, but it did increase the therapeutic index of alphaxalone in PHAX compared with ALTH. PHAX has a higher safety margin than the propofol lipid formulation and also the alphaxalone formulation in Cremophor EL (ALTH). PMID- 25517196 TI - Irritant volatile anesthetics induce neurogenic inflammation through TRPA1 and TRPV1 channels in the isolated mouse trachea. AB - BACKGROUND: Irritating effects of volatile general anesthetics on tracheal nerve endings and resulting spastic reflexes in the airways are not completely understood with respect to molecular mechanisms. Neuropeptide release and neurogenic inflammation play an established role. METHODS: The basal and stimulated calcitonin gene-related peptide (CGRP) release from the isolated superfused mouse trachea was analyzed as an index of sensory neuron activation, applying irritant (desflurane and isoflurane) and nonirritant (sevoflurane) volatile anesthetics as stimuli. Various gas concentrations (0.5-, 1-, or 2-fold minimum alveolar concentration [MAC]) and different O2 atmospheres were used for tracheal stimulation at 38 degrees C. Null mutants of the capsaicin receptor TRPV1 and of the chemoreceptor TRPA1, as well as double knockout mice, were used as tissue donors. RESULTS: Desflurane and, less so, isoflurane caused a concentration-dependent tracheal CGRP release, both saturating at 1 MAC (human), that is, 6% and 1.25%, respectively. With desflurane, the O2 concentration (25% or 94%) did not make a difference. Sevoflurane 1 MAC did not activate tracheal CGRP release. TRPV1 mice showed 75% reduced desflurane responses, and TRPA1 and double-null mutants showed no responses at all. CONCLUSIONS: Our results confirm the clinical experience that desflurane is more irritating than isoflurane at equal anesthetic gas concentration, whereas sevoflurane does not activate tracheobronchial sensory nerves to release neuropeptides and induce neurogenic inflammation. Both irritant receptor channels, TRPA1 more than TRPV1, are involved in mediating the adverse effects that may even extend to systemic proinflammatory sequelae. PMID- 25517197 TI - Anesthesia for cesarean delivery in the Czech Republic: a 2011 national survey. AB - BACKGROUND: The purpose of this national survey was to determine current anesthesia practices for cesarean delivery in the Czech Republic. METHODS: In November 2011, we invited all departments of obstetric anesthesia in the Czech Republic to participate in a prospective study to monitor consecutive peripartum obstetric anesthesia procedures. Data were recorded online in the TrialDB database (Yale University, New Haven, CT). RESULTS: The response rate was 51% (49 of 97 departments); participating centers represented 60% of all births in the country during the study period. There were 1943 cases of peripartum anesthesia care, of which 1166 cases (60%) were anesthesia for cesarean delivery. Estimates were weighted based on population distribution of cesarean delivery among types of participating centers. Neuraxial anesthesia was used in 55.6% (95% confidence interval [CI], 52.8%-58.5%); the distribution of anesthesia techniques differed among type of participating center. The rate of neuraxial anesthesia in university hospitals was 55.6% (95% CI, 51.5%-59.6%), 32.4% (95% CI, 26.4%-39.0%) in regional hospitals, and 60.7% (95% CI, 55.2%-66.0%) in local hospitals. The reasons for cesarean delivery under general anesthesia were emergency procedure (67%), refusal of neuraxial blockade by parturient (30%), failure of neuraxial anesthesia (6%), and preoperative administration of low-molecular-weight heparin (3%). Postcesarean analgesia was primarily provided by systemic opioid (66%) and nonopioid analgesics (61%), solely or in combination. Epidural postoperative analgesia was used in 14% of cases. Compared with national neuraxial anesthesia rate data published in the 1990s (6.7% in 1993), there has been an upward trend in the use of neuraxial anesthesia for cesarean delivery during the 21st century (40.5% in 2000) in the Czech Republic. CONCLUSIONS: The rate of neuraxial anesthesia use for cesarean delivery has increased in the Czech Republic in the last 2 decades. However, the current rate of general anesthesia is high compared with other Western countries. PMID- 25517198 TI - Electrochemical nutrient recovery enables ammonia toxicity control and biogas desulfurization in anaerobic digestion. AB - Organic waste streams can be valorized and reduced in volume with anaerobic digestion (AD). An often-encountered key issue however is the high ammonium (NH4(+)) content of certain waste streams. Ammonia (NH3), in equilibrium with NH4(+), is a toxic compound to the methanogenic community, which limits the organic loading rate and endangers process stability. An electrochemical system (ES) linked to a digester could, besides recovering this nutrient, decrease NH3 toxicity through electrochemical extraction. Therefore, two digesters with and without ES attached in the recirculation loop were operated to test whether the ES could control NH3 toxicity. During periods of high ammonium loading rates, the methane (CH4) production of the ES-coupled reactor was up to 4.5 times higher compared to the control, which could be explained through simultaneous NH4(+) extraction and electrochemical pH control. A nitrogen flux of 47 g N m(-2) membrane d(-1) could be obtained in the ES-coupled reactor, resulting in a current and removal efficiency of 38 +/- 5% and 28 +/- 2%, respectively, at an electrochemical power input of 17 +/- 2 kWh kg(-1) N. The anode also oxidized sulfide, resulting in a significantly lower H2S emission via the biogas. Lastly, limited methanogenic community dynamics pointed to a nonselective influence of the different operational conditions. PMID- 25517200 TI - Silver-catalyzed C-H trifluoromethylation of arenes using trifluoroacetic acid as the trifluoromethylating reagent. AB - Direct trifluoromethylation of arenes using TFA as the trifluoromethylating reagent was achieved with Ag as the catalyst. This reaction not only provides a new protocol for aryl C-H trifluoromethylation, but the generation of CF3. from TFA may prove useful in other contexts and could potentially be extended to other trifluoromethylation reactions. PMID- 25517199 TI - Signaling role of phospholipid hydroperoxide glutathione peroxidase (PHGPX) accompanying sensing of NaCl stress in etiolated sunflower seedling cotyledons. AB - Sunflower seedlings subjected to 120 mM NaCl stress exhibit high total peroxidase activity, differential expression of its isoforms and accumulation of lipid hydroperoxides. This coincides with high specific activity of phospholipid hydroperoxide glutathione peroxidase (PHGPX) in the 10,000g supernatant from the homogenates of 2-6 d old seedling cotyledons. An upregulation of PHGPX activity by NaCl is evident from Western blot analysis. Confocal laser scanning microscopic (CLSM) analysis of sections of cotyledons incubated with anti-GPX4 (PHGPX) antibody highlights an enhanced cytosolic accumulation of PHGPX, particularly around the secretory canals. Present work, thus, highlights sensing of NaCl stress in sunflower seedlings in relation with lipid hydroperoxide accumulation and its scavenging through an upregulation of PHGPX activity in the cotyledons. PMID- 25517201 TI - Aerosol-assisted controlled packing of silica nanocolloids: templateless synthesis of mesoporous silicates with structural tunability and complexity. AB - A template-free synthesis method for mesoporous and macro-/mesoporous hierarchically porous silicates with remarkable structural tunability and complexity is presented. SiO2 nanocolloids having diameters of 3.0-29 nm were prepared as a primary building block by using extended Stober synthesis, and they were subsequently assembled by an aerosol-assisted drying. The silica pore structure can be rationally controlled depending on the initial diameter of SiO2 colloids and the aerosol-assembly temperature that determines the packing density of SiO2 colloids (i.e., amounts of packing defects) in the resultant materials. The present method could produce mesoporous silica spheres with remarkable pore structural tunability (291 < BET surface area <807 m(2) g(-1), 0.42 < pore volume <0.92 cm(3) g(-1), 3.1 < pore size <26 nm). Hierarchically porous materials can also be synthesized by the evaporation-induced phase separation of solvent medium during the aerosol-assisted assembly of SiO2 colloids. By adding aluminum and Pt precursors into the SiO2 colloid suspensions before the aerosol-assisted assembly, mesoporous aluminosilicates supporting uniform Pt nanoclusters (~2 nm) can also be synthesized. This indicates that the synthesis strategy can be used for the direct synthesis of functional silicate materials. PMID- 25517202 TI - Effects of caffeine chewing gum on race performance and physiology in male and female cyclists. AB - This investigation reports the effects of chewing caffeinated gum on race performance with trained cyclists. Twenty competitive cyclists completed two 30 km time trials that included a maximal effort 0.2-km sprint each 10-km. Caffeine (~3-4 mg . kg(-1)) or placebo was administered double-blind via chewing gum at the 10-km point following completion of the first sprint. Measures of power output, oxygen uptake, heart rate, lactate and perceived exertion were taken at set intervals during the time trial. Results indicated no substantial differences in any measured variables between caffeine and placebo conditions during the first 20-km of the time trial. Caffeine gum did however lead to substantial enhancements (mean +/- 90% confidence limits (CLs)) in mean power during the final 10-km (3.8% +/- 2.3%), and sprint power at 30-km (4.0% +/- 3.6%). The increases in performance over the final 10-km were associated with small increases in heart rate and blood lactate (effect size of 0.24 and 0.28, respectively). There were large inter-individual variations in the response to caffeine, and apparent gender related differences in sprint performance. Chewing caffeine gum improves mean and sprint performance power in the final 10-km of a 30-km time trial in male and female cyclists most likely through an increase in nervous system activation. PMID- 25517203 TI - Why is age a major determinant of reproductive outcomes after myomectomy in subfertile women? PMID- 25517204 TI - The effects of mirtazapine versus placebo on alcohol consumption in male high consumers of alcohol: a randomized, controlled trial. AB - BACKGROUND: The number of therapeutic drugs available for the treatment of alcohol use disorders (AUDs) is limited, and a well-tolerated, self-administrable drug is much needed. Subgroups of alcohol-dependent individuals, for example, individuals with heredity for AUD, may respond differently to pharmacological treatments, particularly to drugs affecting the serotonergic system in the brain. RATIONALE: Clinical observations and case reports indicate that mirtazapine, a widely used and well-tolerated antidepressant drug, which increases both noradrenaline and serotonin release but simultaneously blocks serotonergic (5 hydroxytryptamine)3 receptors, reduces alcohol consumption. Moreover, drugs affecting serotonergic (5-hydroxytryptamine)3 receptors have been shown to work differently in individuals with heredity for AUD. METHODS: This double-blind, randomized, placebo-controlled, 2-armed clinical trial aimed to establish whether mirtazapine lowers alcohol consumption in male high consumers. The study population was also subgrouped in accordance with heredity for AUD. After 2 lead in weeks of single-blind placebo, 59 males were randomly assigned to receive 8 weeks of treatment with 30-mg mirtazapine daily (n = 29) or placebo (n = 30). The main outcome was self-reported alcohol consumption (drinks per day) measured by an alcohol diary. The alcohol consumption was calculated as weekly mean during the study period compared with baseline. The data were analyzed in accordance with intention to treat and per protocol. RESULTS: The results suggest that high consumers of alcohol with a heredity for AUD benefit from treatment with mirtazapine. CONCLUSIONS: The results of this study did not support an advantage of mirtazapine over placebo on alcohol consumption in the intention-to-treat analysis. However, mirtazapine could be an alternative to available treatments for alcohol dependence in patients with heredity for AUD. PMID- 25517205 TI - "Spinning one's wheels": Nonimproved patients view their psychotherapy. AB - OBJECTIVE: To explore psychotherapy experiences among nonimproved young adults in psychoanalytic psychotherapy. METHOD: A two-stage, mixed-method design was used. Twenty patients in the clinical range at pretreatment were identified as either with reliable deterioration or with no reliable change at termination. Interviews at termination and 3-year follow-up were analyzed with grounded theory methodology. RESULTS: "Spinning One's Wheels" emerged as a core category. The patients described the therapeutic relationship as distanced and artificial. While they saw active components in therapy and their own activities in life as beneficial, therapy itself was experienced as overly focused on problem insight and past history. CONCLUSIONS: When the therapist does not contribute to the achievement of the patient's treatment goals--even when the patient gains some benefit--the patient does not fully profit from the therapy. PMID- 25517207 TI - Suicidal Ideation among Florida National Guard Members: Combat Deployment and Non Deployment Risk and Protective Factors. AB - This study examined relationships among risk/protective factors and suicidal ideation (SI) in deployed and non-deployed National Guard members, particularly examining for possible differential effects of deployment on SI. A total of 3,098 Florida National Guard members completed an anonymous online survey that assessed variables associated with SI including demographics, current psychiatric diagnoses, and pre-, during, and post-deployment experiences. Those deployed had significantly higher rates of SI (5.5%) than those not deployed (3.0%; p < .001). In multivariate analyses, among those not deployed, SI was significantly associated with major depressive disorder (p < .001), posttraumatic stress disorder (PTSD) (p < .001), prior psychological trauma (p < .01), and heavy/hazardous alcohol consumption (p < .05). In contrast, in the deployed, only PTSD (p < .001) and deployment-related mild traumatic brain injury (p < .05) were independently associated with SI. Risk and protective factors differed by deployment status in National Guard members suggesting the possible need for cohort-specific treatment targets to minimize SI. PMID- 25517208 TI - An Exact Algorithm to Compute the Double-Cut-and-Join Distance for Genomes with Duplicate Genes. AB - Computing the edit distance between two genomes is a basic problem in the study of genome evolution. The double-cut-and-join (DCJ) model has formed the basis for most algorithmic research on rearrangements over the last few years. The edit distance under the DCJ model can be computed in linear time for genomes without duplicate genes, while the problem becomes NP-hard in the presence of duplicate genes. In this article, we propose an integer linear programming (ILP) formulation to compute the DCJ distance between two genomes with duplicate genes. We also provide an efficient preprocessing approach to simplify the ILP formulation while preserving optimality. Comparison on simulated genomes demonstrates that our method outperforms MSOAR in computing the edit distance, especially when the genomes contain long duplicated segments. We also apply our method to assign orthologous gene pairs among human, mouse, and rat genomes, where once again our method outperforms MSOAR. PMID- 25517209 TI - Structure and antimicrobial activity of phloroglucinol derivatives from Achyrocline satureioides. AB - The new prenylated phloroglucinol alpha-pyrones 1-3 and the new dibenzofuran 4, together with the known 23-methyl-6-O-demethylauricepyrone (5), achyrofuran (6), and 5,7-dihydroxy-3,8-dimethoxyflavone (gnaphaliin A), were isolated from the aerial parts of Achyrocline satureioides. Their structures were determined by 1D and 2D NMR spectroscopic studies, while the absolute configuration of the sole stereogenic center of 1 was established by vibrational circular dichroism measurements in comparison to density functional theory calculated data. The same (S) absolute configuration of the alpha-methylbutyryl chain attached to the phloroglucinol nucleus was assumed for compounds 2-6 based on biogenetic considerations. Derivatives 7-16 were prepared from 1 and 5, and the antimicrobial activities of the isolated metabolites and some of the semisynthetic derivatives against a selected panel of Gram-positive and Gram negative bacteria, as well as a set of yeast molds, were determined. PMID- 25517210 TI - Efficient Approach To Discover Novel Agrochemical Candidates: Intermediate Derivatization Method. AB - Intensive competition of intellectual property, easy development of agrochemical resistance, and stricter regulations of environmental concerns make the successful rate for agrochemical discovery extremely lower using traditional agrochemical discovery methods. Therefore, there is an urgent need to find a novel approach to guide agrochemical discovery with high efficiency to quickly keep pace with the changing market. On the basis of these situations, here we summarize the intermediate derivatization method (IDM) between conventional methods in agrochemicals and novel ones in pharmaceuticals. This method is relatively efficient with short time in discovery phase, reduced cost, especially good innovated structure, and better performance. In this paper, we summarize and illustrate "what is the IDM" and "why to use" and "how to use" it to accelerate the discovery of new biologically active molecules, focusing on agrochemicals. Furthermore, we display several research projects in our novel agrochemical discovery programs with improved success rate under guidance of this strategy in recent years. PMID- 25517211 TI - Chemical composition of an aqueous oxalato-/citrato-VO(2+) solution as determinant for vanadium oxide phase formation. AB - Aqueous solutions of oxalato- and citrato-VO(2+) complexes are prepared, and their ligand exchange reaction is investigated as a function of the amount of citrate present in the aqueous solution via continuous-wave electron paramagnetic resonance (CW EPR) and hyperfine sublevel correlation (HYSCORE) spectroscopy. With a low amount of citrate, monomeric cis-oxalato-VO(2+) complexes occur with a distorted square-pyramidal geometry. As the amount of citrate increases, oxalate is gradually exchanged for citrate. This leads to (i) an intermediate situation of monomeric VO(2+) complexes with a mix of oxalate/citrate ligands and (ii) a final situation of both monomeric and dimeric complexes with exclusively citrato ligands. The monomeric citrato-VO(2+) complexes dominate (abundance > 80%) and are characterized by a 6-fold chelation of the vanadium(IV) ion by 4 RCO2(-) ligands at the equatorial positions and a H2O/R-OH ligand at the axial position. The different redox stabilities of these complexes, relative to that of dissolved O2 in the aqueous solution, is analyzed via (51)V NMR. It is shown that the oxidation rate is the highest for the oxalato-VO(2+) complexes. In addition, the stability of the VO(2+) complexes can be drastically improved by evacuation of the dissolved O2 from the solution and subsequent storage in a N2 ambient atmosphere. The vanadium oxide phase formation process, starting with the chemical solution deposition of the aqueous solutions and continuing with subsequent processing in an ambient 0.1% O2 atmosphere, differs for the two complexes. The oxalato-VO(2+) complexes turn into the oxygen-deficient crystalline VO2 B at 400 degrees C, which then turns into crystalline V6O13 at 500 degrees C. In contrast, the citrato-VO(2+) complexes form an amorphous film at 400 degrees C that crystallizes into VO2 M1 and V6O13 at 500 degrees C. PMID- 25517212 TI - A dual delivery of substance P and bone morphogenetic protein-2 for mesenchymal stem cell recruitment and bone regeneration. AB - Implantation of ex vivo expanded and osteogenically differentiated mesenchymal stem cells (MSCs) for bone regeneration has drawbacks for clinical applications, such as poor survival of implanted cells and increased treatment expenses. As a new approach for bone regeneration that can circumvent these limitations, we propose dual delivery of substance P (SP) and bone morphogenetic protein-2 (BMP 2) to facilitate endogenous stem cell recruitment to bone defects by SP and subsequent in situ osteogenic differentiation of those cells by BMP-2. A heparin conjugated fibrin (HCF) gel enabled dual delivery with fast release of SP and slow release of BMP-2, which would be ideal for prompt recruitment of endogenous stem cells in the first stage and time-consuming osteogenic differentiation of the recruited stem cells in the second stage. The HCF gels with SP and/or BMP-2 were implanted into mouse calvarial defects for 8 weeks. Local delivery of SP to the calvarial defects using HCF gel was more effective in recruiting MSCs to the calvarial defects than intraperitoneal or intravenous administration of SP. Many of the cells recruited by SP underwent osteogenic differentiation through local delivery of BMP-2. The efficacy of in vivo bone regeneration was significantly higher in the SP/BMP-2 dual delivery group. The dual delivery of SP and BMP-2 using the HCF gel therefore has potential as an effective bone regeneration strategy. PMID- 25517213 TI - Increased resource use in lung transplant admissions in the lung allocation score era. AB - RATIONALE: In 2005, the lung allocation score (LAS) was implemented to prioritize organ allocation to minimize waiting-list mortality and maximize 1-year survival. It resulted in transplantation of older and sicker patients without changing 1 year survival. Its effect on resource use is unknown. OBJECTIVES: To determine changes in resource use over time in lung transplant admissions. METHODS: Solid organ transplant recipients were identified within the Nationwide Inpatient Sample (NIS) data from 2000 to 2011. Joinpoint regression methodology was performed to identify a time point of change in mean total hospital charges among lung transplant and other solid-organ transplant recipients. Two temporal lung transplant recipient cohorts identified by joinpoint regression were compared for baseline characteristics and resource use, including total charges for index hospitalization, charges per day, length of stay, discharge disposition, tracheostomy, and need for extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: A significant point of increased total hospital charges occurred for lung transplant recipients in 2005, corresponding to LAS implementation, which was not seen in other solid-organ transplant recipients. Total transplant hospital charges increased by 40% in the post-LAS cohort ($569,942 [$53,229] vs. $407,489 [$28,360]) along with an increased median length of stay, daily charges, and discharge disposition other than to home. Post-LAS recipients also had higher post-transplant use of extracorporeal membrane oxygenation (odds ratio, 2.35; 95% confidence interval, 1.56-3.55) and higher incidence of tracheostomy (odds ratio, 1.52; 95% confidence interval, 1.22-1.89). CONCLUSIONS: LAS implementation is associated with a significant increase in resource use during index hospitalization for lung transplant. PMID- 25517214 TI - Mechanism of in situ surface polymerization of gallic acid in an environmental inspired preparation of carboxylated core-shell magnetite nanoparticles. AB - Magnetite nanoparticles (MNPs) with biocompatible coatings are good candidates for MRI (magnetic resonance imaging) contrasting, magnetic hyperthermia treatments, and drug delivery systems. The spontaneous surface induced polymerization of dissolved organic matter on environmental mineral particles inspired us to prepare carboxylated core-shell MNPs by using a ubiquitous polyphenolic precursor. Through the adsorption and in situ surface polymerization of gallic acid (GA), a polygallate (PGA) coating is formed on the nanoparticles (PGA@MNP) with possible antioxidant capacity. The present work explores the mechanism of polymerization with the help of potentiometric acid-base titration, dynamic light scattering (for particle size and zeta potential determination), UV vis (UV-visible light spectroscopy), FTIR-ATR (Fourier-transformed infrared spectroscopy by attenuated total reflection), and XPS (X-ray photoelectron spectroscopy) techniques. We observed the formation of ester and ether linkages between gallate monomers both in solution and in the adsorbed state. Higher polymers were formed in the course of several weeks both on the surface of nanoparticles and in the dispersion medium. The ratio of the absorbances of PGA supernatants at 400 and 600 nm (i.e., the E4/E6 ratio commonly used to characterize the degree of polymerization of humic materials) was determined to be 4.3, similar to that of humic acids. Combined XPS, dynamic light scattering, and FTIR-ATR results revealed that, prior to polymerization, the GA monomers became oxidized to poly(carboxylic acid)s due to ring opening while Fe(3+) ions reduced to Fe(2+). Our published results on the colloidal and chemical stability of PGA@MNPs are referenced thoroughly in the present work. Detailed studies on biocompatibility, antioxidant property, and biomedical applicability of the particles will be published. PMID- 25517215 TI - Osteoprogenitor cells from bone marrow and cortical bone: understanding how the environment affects their fate. AB - Bone is a dynamic organ where skeletal progenitors and hematopoietic cells share and compete for space. Presumptive mesenchymal stem cells (MSC) have been identified and harvested from the bone marrow (BM-MSC) and cortical bone fragments (CBF-MSC). In this study, we demonstrate that despite the cells sharing a common ancestor, the differences in the structural properties of the resident tissues affect cell behavior and prime them to react differently to stimuli. Similarly to the bone marrow, the cortical portion of the bone contains a unique subset of cells that stains positively for the common MSC-associated markers. These cells display different multipotent differentiation capability, clonogenic expansion, and immunosuppressive potential. In particular, when compared with BM MSC, CBF-MSC are bigger in size, show a lower proliferation rate at early passages, have a greater commitment toward the osteogenic lineage, constitutively produce nitric oxide as a mediator for bone remodeling, and more readily respond to proinflammatory cytokines. Our data suggest that the effect of the tissue's microenvironment makes the CBF-MSC a superior candidate in the development of new strategies for bone repair. PMID- 25517216 TI - Customizing properties of beta-chitin in squid pen (gladius) by chemical treatments. AB - The squid pen (gladius) from the Loligo vulgaris was used for preparation of beta chitin materials characterized by different chemical, micro- and nano-structural properties that preserved, almost completely the macrostructural and the mechanical ones. The beta-chitin materials obtained by alkaline treatment showed porosity, wettability and swelling that are a function of the duration of the treatment. Microscopic, spectroscopic and synchrotron X-ray diffraction techniques showed that the chemical environment of the N-acetyl groups of the beta-chitin chains changes after the thermal alkaline treatment. As a consequence, the crystalline packing of the beta-chitin is modified, due to the intercalation of water molecules between beta-chitin sheets. Potential applications of these beta-chitin materials range from the nanotechnology to the regenerative medicine. The use of gladii, which are waste products of the fishing industry, has also important environmental implications. PMID- 25517217 TI - Three new asperentin derivatives from the algicolous fungus Aspergillus sp. F00785. AB - Three new asperentin-type compounds, 6-O-alpha-d-ribosylasperentin (1) and 6-O alpha-d-ribosyl-8-O-methylasperentin (2) and 5-hydroxyl-6-O-methylasperentin (3), along with asperentin (4) and its known analogues (5-9), were isolated from a halotolerant Aspergillus sp. strain F00785, an endotrophic fungus from marine alga. Their structures were determined using extensive NMR and HRESIMS spectroscopic analysis, including the X-ray crystallographic data for the assignment of the absolute configurations of compound 9. Compound 4 exhibited highly potent inhibitory activity against crop pathogens, Colletotrichum gleosporioides Penz. and Colletotrichum gleosporioides (Penz.) Sacc. PMID- 25517218 TI - Optimisation of occupational radiological protection in image-guided interventions: potential impact of dose rate measurements. AB - The optimisation of occupational radiological protection is challenging and a variety of factors have to be considered. Physicians performing image-guided interventions are working in an environment with one of the highest radiation risk levels in healthcare. Appropriate knowledge about the radiation environment is a prerequisite for conducting the optimisation process. Information about the dose rate variation during the interventions could provide valuable input to this process. The overall purpose of this study was to explore the prerequisite and feasibility to measure dose rate in scattered radiation and to assess the usefulness of such data in the optimisation process.Using an active dosimeter system, the dose rate in the unshielded scattered radiation field was measured in a fixed point close to the patient undergoing an image-guided intervention. The measurements were performed with a time resolution of one second and the dose rate data was continuously timed in a data log. In two treatment rooms, data was collected during a 6 month time period, resulting in data from 380 image-guided interventions and vascular treatments in the abdomen, arms and legs. These procedures were categorised into eight types according to the purpose of the treatment and the anatomical region involved.The dose rate varied substantially between treatment types, both regarding the levels and the distribution during the procedure. The maximum dose rate for different types of interventions varied typically between 5 and 100 mSv h(-1), but substantially higher and lower dose rates were also registered. The average dose rate during a complete procedure was however substantially lower and varied typically between 0.05 and 1 mSv h(-1). An analysis of the distribution disclosed that for a large part of the treatment types, the major amount of the total accumulated dose for a procedure was delivered in less than 10% of the exposure time and in less than 1% of the total procedure time.The present study shows that systematic dose rate measurements are feasible. Such measurements can be used to give a general indication of the exposure level to the staff and could serve as a first risk assessment tool when introducing new treatment types or x-ray equipment in the clinic. For example, it could provide an indication for when detailed eye dose measurements are needed. It also gives input to risk management considerations and the development of efficient routines for other radiological protection measures. PMID- 25517219 TI - Care management by oncology nurses to address palliative care needs: a pilot trial to assess feasibility, acceptability, and perceived effectiveness of the CONNECT intervention. AB - BACKGROUND: Specialty palliative care is not accessible for many patients with advanced cancer. There is a need to find alternative palliative care strategies in oncology clinics. OBJECTIVE: The objective of the study was to assess the feasibility, acceptability, and perceived effectiveness of an oncology nurse-led care management approach to improve primary palliative care. METHODS: The study design was a single-arm pilot trial of the Care Management by Oncology Nurses (CONNECT) intervention, in which registered oncology nurses receive specialized training and work closely with oncologists to (1) address symptom needs; (2) engage patients and caregivers in advance care planning; (3) provide emotional support; and (4) coordinate care. The subjects were 23 patients with advanced cancer, 19 caregivers, and 5 oncologists from a community oncology clinic in western Pennsylvania. Feasibility was assessed through enrollment rates, outcome assessment rates, and visit checklists. Patients, caregivers, and oncologists completed three-month assessments of acceptability and perceived effectiveness. RESULTS: The consent-to-approach rate was 86% and enrolled-to-consent rate, 77%. CONNECT was implemented according to protocol for all participants. No participants withdrew after enrollment. Four patients died during the study; three-month outcome assessments were completed with all remaining participants (83%). Patients and caregivers reported high satisfaction with CONNECT and perceived the intervention as helpful in addressing symptoms (85%), coping (91%), and planning for the future (82%). Oncologists unanimously agreed that CONNECT improved the quality of care provided for patients with advanced cancer. CONCLUSION: An oncology nurse-led care management intervention is feasible, acceptable, and was perceived to be effective for improving provision of primary palliative care. A randomized trial of CONNECT is warranted. PMID- 25517220 TI - Enzymatic synthesis of modified oligonucleotides by PEAR using Phusion and KOD DNA polymerases. AB - Antisense synthetic oligonucleotides have been developed as potential gene targeted therapeutics. We previously reported polymerase-endonuclease amplification reaction (PEAR) for amplification of natural and 5'-O-(1 thiotriphosphate) (S)-modified oligonucleotides. Here, we extended the PEAR technique for enzymatic preparation of 2'-deoxy-2'-fluoro-(2'-F) and 2'-F/S double-modified oligonucleotides. The result showed that KOD and Phusion DNA polymerase could synthesize oligonucleotides with one or two modified nucleotides, and KOD DNA polymerase is more suitable than Phusion DNA polymerase for PEAR amplification of 2'-F and 2'-F/S double modified oligonucleotides. The composition of PEAR products were analyzed by electrospray ionization liquid chromatography mass spectrometry (ESI/LC/MS) detection and showed that the sequence of the PEAR products are maintained at an extremely high accuracy (>99.9%), and after digestion the area percent of full-length modified oligonucleotides reaches 89.24%. PEAR is suitable for synthesis of modified oligonucleotides efficiently and with high purity. PMID- 25517221 TI - Quantifying transient interactions between Bacillus phosphatidylinositol-specific phospholipase-C and phosphatidylcholine-rich vesicles. AB - Bacillus thuringiensis secretes the virulence factor phosphatidylinositol specific phospholipase C (BtPI-PLC), which specifically binds to phosphatidylcholine (PC) and cleaves GPI-anchored proteins off eukaryotic plasma membranes. To elucidate how BtPI-PLC searches for GPI-anchored proteins on the membrane surface, we measured residence times of single fluorescently labeled proteins on PC-rich small unilamellar vesicles (SUVs). BtPI-PLC interactions with the SUV surface are transient with a lifetime of 379 +/- 49 ms. These data also suggest that BtPI-PLC does not directly sense curvature, but rather prefers to bind to the numerous lipid packing defects in SUVs. Despite this preference for defects, all-atom molecular dynamics simulations of BtPI-PLC interacting with PC rich bilayers show that the protein is shallowly anchored with the deepest insertions ~18 A above the bilayer center. Membrane partitioning is mediated, on average, by 41 hydrophobic, 8 hydrogen-bonding, and 2 cation-pi (between PC choline headgroups and Tyr residues) transient interactions with phospholipids. These results lead to a quantitative model for BtPI-PLC interactions with cell membranes where protein binding is mediated by lipid packing defects, possibly near GPI-anchored proteins, and the protein diffuses on the membrane for ~100-380 ms, during which time it may cleave ~10 GPI-anchored proteins before dissociating. This combination of short two-dimensional scoots followed by three dimensional hops may be an efficient search strategy on two-dimensional surfaces with obstacles. PMID- 25517222 TI - Are you experienced? Understanding bladder innate immunity in the context of recurrent urinary tract infection. AB - PURPOSE OF REVIEW: Recurrent urinary tract infection (rUTI) is a serious clinical problem, yet effective therapeutic options are limited, especially against multidrug-resistant uropathogens. In this review, we explore the development of a clinically relevant model of rUTI in previously infected mice and review recent developments in bladder innate immunity that may affect susceptibility to rUTI. RECENT FINDINGS: Chronic bladder inflammation during prolonged bacterial cystitis in mice causes bladder mucosal remodelling that sensitizes the host to rUTI. Although constitutive defenses help prevent bacterial colonization of the urinary bladder, once infection occurs, induced cytokine and myeloid cell responses predominate and the balance of immune cell defense and bladder immunopathology is critical for determining disease outcome, in both naive and experienced mice. In particular, the maintenance of the epithelial barrier appears to be essential for preventing severe infection. SUMMARY: The innate immune response plays a key role in determining susceptibility to rUTI. Future studies should be directed towards understanding how the innate immune response changes as a result of bladder mucosal remodelling in previously infected mice, and validating these findings in human clinical specimens. New therapeutics targeting the immune response should selectively target the induced innate responses that cause bladder immunopathology, while leaving protective defenses intact. PMID- 25517223 TI - High-quality genome (re)assembly using chromosomal contact data. AB - Closing gaps in draft genome assemblies can be costly and time-consuming, and published genomes are therefore often left 'unfinished.' Here we show that genome wide chromosome conformation capture (3C) data can be used to overcome these limitations, and present a computational approach rooted in polymer physics that determines the most likely genome structure using chromosomal contact data. This algorithm--named GRAAL--generates high-quality assemblies of genomes in which repeated and duplicated regions are accurately represented and offers a direct probabilistic interpretation of the computed structures. We first validated GRAAL on the reference genome of Saccharomyces cerevisiae, as well as other yeast isolates, where GRAAL recovered both known and unknown complex chromosomal structural variations. We then applied GRAAL to the finishing of the assembly of Trichoderma reesei and obtained a number of contigs congruent with the know karyotype of this species. Finally, we showed that GRAAL can accurately reconstruct human chromosomes from either fragments generated in silico or contigs obtained from de novo assembly. In all these applications, GRAAL compared favourably to recently published programmes implementing related approaches. PMID- 25517224 TI - Benzodiazepine use in the United States. AB - IMPORTANCE: Although concern exists regarding the rate of benzodiazepine use, especially long-term use by older adults, little information is available concerning patterns of benzodiazepine use in the United States. OBJECTIVE: To describe benzodiazepine prescription patterns in the United States focusing on patient age and duration of use. DESIGN, SETTING, AND PARTICIPANTS: A retrospective descriptive analysis of benzodiazepine prescriptions was performed with the 2008 LifeLink LRx Longitudinal Prescription database (IMS Health Inc), which includes approximately 60% of all retail pharmacies in the United States. Denominators were adjusted to generalize estimates to the US population. MAIN OUTCOMES AND MEASURES: The percentage of adults filling 1 or more benzodiazepine prescriptions during the study year by sex and age group (18-35 years, 36-50 years, 51-64 years, and 65-80 years) and among individuals receiving benzodiazepines, the corresponding percentages with long-term (>=120 days) benzodiazepine use, prescription of a long-acting benzodiazepine, and benzodiazepine prescriptions from a psychiatrist. RESULTS: In 2008, approximately 5.2% of US adults aged 18 to 80 years used benzodiazepines. The percentage who used benzodiazepines increased with age from 2.6% (18-35 years) to 5.4% (36-50 years) to 7.4% (51-64 years) to 8.7% (65-80 years). Benzodiazepine use was nearly twice as prevalent in women as men. The proportion of benzodiazepine use that was long term increased with age from 14.7% (18-35 years) to 31.4% (65-80 years), while the proportion that received a benzodiazepine prescription from a psychiatrist decreased with age from 15.0% (18-35 years) to 5.7% (65-80 years). In all age groups, roughly one-quarter of individuals receiving benzodiazepine involved long-acting benzodiazepine use. CONCLUSIONS AND RELEVANCE: Despite cautions concerning risks associated with long-term benzodiazepine use, especially in older patients, long-term benzodiazepine use remains common in this age group. More vigorous clinical interventions supporting judicious benzodiazepine use may be needed to decrease rates of long-term benzodiazepine use in older adults. PMID- 25517226 TI - Styryl ether formation from benzyl alcohols under transition-metal-free basic DMSO conditions. AB - A phenol-catalyzed aerobic oxidative styryl ether formation method was developed with benzyl alcohol under basic DMSO. Styryl ether was obtained after 12 hours of heating at 60-80 degrees C where DMSO was involved in the reaction as the extra carbon source. Control experiments indicated that both phenol and DMSO are crucial for the success of the reaction. A variety of styryl ethers were prepared smoothly from benzyl alcohols in good to excellent yields in an environmentally friendly way. PMID- 25517225 TI - Temporal variability is a personalized feature of the human microbiome. AB - BACKGROUND: It is now apparent that the complex microbial communities found on and in the human body vary across individuals. What has largely been missing from previous studies is an understanding of how these communities vary over time within individuals. To the extent to which it has been considered, it is often assumed that temporal variability is negligible for healthy adults. Here we address this gap in understanding by profiling the forehead, gut (fecal), palm, and tongue microbial communities in 85 adults, weekly over 3 months. RESULTS: We found that skin (forehead and palm) varied most in the number of taxa present, whereas gut and tongue communities varied more in the relative abundances of taxa. Within each body habitat, there was a wide range of temporal variability across the study population, with some individuals harboring more variable communities than others. The best predictor of these differences in variability across individuals was microbial diversity; individuals with more diverse gut or tongue communities were more stable in composition than individuals with less diverse communities. CONCLUSIONS: Longitudinal sampling of a relatively large number of individuals allowed us to observe high levels of temporal variability in both diversity and community structure in all body habitats studied. These findings suggest that temporal dynamics may need to be considered when attempting to link changes in microbiome structure to changes in health status. Furthermore, our findings show that, not only is the composition of an individual's microbiome highly personalized, but their degree of temporal variability is also a personalized feature. PMID- 25517227 TI - Gene expression study in positron emission tomography-positive abdominal aortic aneurysms identifies CCL18 as a potential biomarker for rupture risk. AB - Rupture of abdominal aortic aneurysm (AAA) is a cause of significant mortality and morbidity in aging populations. Uptake of 18-fluorodeoxyglucose (FDG) detected by positron emission tomography (PET) is observed in the wall of 12% of AAA (A+), with most of them being symptomatic. We previously showed that the metabolically active areas displayed adventitial inflammation, medial degeneration and molecular alterations prefacing wall rupture. The aim of this study was to identify new factors predictive of rupture. Transcriptomic analyses were performed in the media and adventitia layers from three types of samples: AAA with-out FDG uptake (A0) and with FDG uptake (A+), both at the positive spot (A+(Pos)) and at a paired distant negative site (A+(Neg)) of the same aneurysm. Follow-up studies included reverse-transcriptase-polymerase chain reaction (RT PCR), immunohistochemical staining and enzyme-linked immunosorbent assay (ELISA). A large number of genes, including matrix metalloproteinases, collagens and cytokines as well as genes involved in osteochondral development, were differentially expressed in the A+(Pos) compared with A+(Neg). Moreover, a series of genes (notably CCL18) was differentially expressed both in the A+(Neg) and A+(Pos) compared with the A0. A significant increase of CCL18 was also found at the protein level in the aortic wall and in peripheral blood of A+ patients compared with A0. In conclusion, new factors, including CCL18, involved in the progression of AAA and, potentially, in their rupture were identified by a genome wide analysis of PET-positive and -negative human aortic tissue samples. Further work is needed to study their role in AAA destabilization and weakening. PMID- 25517229 TI - Experimental realization of photonic topological insulator in a uniaxial metacrystal waveguide. AB - Photonic analogue of topological insulator was recently predicted by arranging epsilon/MU (permittivity/permeability)-matched bianisotropic metamaterials into two-dimensional superlattices. However, the experimental observation of such photonic topological insulator is challenging as bianisotropic metamaterial is usually highly dispersive, so that the epsilon/MU-matching condition can only be satisfied in a narrow frequency range. Here we experimentally realize a photonic topological insulator by embedding non-bianisotropic and non-resonant metacrystal into a waveguide. The cross coupling between transverse electric and transverse magnetic modes exists in metacrystal waveguide. Using this approach, the epsilon/MU-matching condition is satisfied in a broad frequency range which facilitates experimental observation. The topologically non-trivial bandgap is confirmed by experimentally measured transmission spectra and calculated non-zero spin Chern numbers. Gapless spin-filtered edge states are demonstrated experimentally by measuring the magnitude and phase of the fields. The transport robustness of the edge states is also observed when an obstacle was introduced near the edge. PMID- 25517228 TI - Poly(ADP-ribose) polymerase 1-sirtuin 1 functional interplay regulates LPS mediated high mobility group box 1 secretion. AB - Pathophysiological conditions that lead to the release of the prototypic damage associated molecular pattern molecule high mobility group box 1 (HMGB1) also result in activation of poly(ADP-ribose) polymerase 1 (PARP1; now known as ADP ribosyl transferase 1 [ARTD1]). Persistent activation of PARP1 promotes energy failure and cell death. The role of poly(ADP-ribosyl)ation in HMGB1 release has been explored previously; however, PARP1 is a versatile enzyme and performs several other functions including cross-talk with another nicotinamide adenine dinucleotide- (NAD(+)) dependent member of the Class III histone deacetylases (HDACs), sirtuin-1 (SIRT1). Previously, it has been shown that the hyperacetylation of HMGB1 is a seminal event prior to its secretion, a process that also is dependent on HDACs. Therefore, in this study, we seek to determine if PARP1 inhibition alters LPS-mediated HMGB1 hyperacetylation and subsequent secretion due to its effect on SIRT1. We demonstrate in an in vitro model that LPS treatment leads to hyperacetylated HMGB1 with concomitant reduction in nuclear HDAC activity. Treatment with PARP1 inhibitors mitigates the LPS-mediated reduction in nuclear HDAC activity and decreases HMGB1 acetylation. By utilizing an NAD(+)-based mechanism, PARP1 inhibition increases the activity of SIRT1. Consequently, there is an increased nuclear retention and decreased extracellular secretion of HMGB1. We also demonstrate that PARP1 physically interacts with SIRT1. Further confirmation of this data was obtained in a murine model of sepsis, that is, administration of PJ-34, a specific PARP1 inhibitor, led to decreased serum HMGB1 concentrations in mice subjected to cecal ligation and puncture (CLP) as compared with untreated mice. In conclusion, our study provides new insights in understanding the molecular mechanisms of HMGB1 secretion in sepsis. PMID- 25517231 TI - Effect of physical therapy on wound healing and quality of life in patients with venous leg ulcers: a systematic review. AB - IMPORTANCE: Patients with venous leg ulcers (VLUs) have calf muscle pump dysfunction, which is associated with reduced ankle range of motion (ROM). Physical therapy or exercise that targets ankle joint mobility may lead to improvement in calf muscle pump function and subsequent healing. However, little is known regarding the effect of physical therapy or exercise on healing and quality of life (QOL), which is impaired in patients with VLUs. OBJECTIVES: To systematically review the current literature on the effect of physical therapy on healing and QOL outcomes in patients with VLUs and to identify research gaps that warrant further investigation. EVIDENCE REVIEW: PubMed (MEDLINE), CINAHL, and Cochrane databases were searched in April 2014. FINDINGS: We found 10 articles, consisting of randomized clinical trials and single-arm cohort studies with small sample sizes, that used physical therapy or exercise for patients with open or healed VLUs. Although there is evidence that exercise strengthens the calf muscle pump and improves ankle ROM, few studies have investigated the effect of these interventions on QOL and healing, and few involved the supervision of a physical therapist. CONCLUSIONS AND RELEVANCE: The lack of evidence and randomized clinical trials suggests the need for further investigation on physical therapy oriented exercise on wound healing and QOL. In addition, more studies are needed to investigate sustainability of the increased ankle ROM after physical therapy has ended or if VLU reoccurrences are prevented. PMID- 25517233 TI - Nature Index 2014 china. PMID- 25517230 TI - Biogeochemical signals from deep microbial life in terrestrial crust. AB - In contrast to the deep subseafloor biosphere, a volumetrically vast and stable habitat for microbial life in the terrestrial crust remains poorly explored. For the long-term sustainability of a crustal biome, high-energy fluxes derived from hydrothermal circulation and water radiolysis in uranium-enriched rocks are seemingly essential. However, the crustal habitability depending on a low supply of energy is unknown. We present multi-isotopic evidence of microbially mediated sulfate reduction in a granitic aquifer, a representative of the terrestrial crust habitat. Deep meteoric groundwater was collected from underground boreholes drilled into Cretaceous Toki granite (central Japan). A large sulfur isotopic fractionation of 20-600/00 diagnostic to microbial sulfate reduction is associated with the investigated groundwater containing sulfate below 0.2 mM. In contrast, a small carbon isotopic fractionation (<300/00) is not indicative of methanogenesis. Except for 2011, the concentrations of H2 ranged mostly from 1 to 5 nM, which is also consistent with an aquifer where a terminal electron accepting process is dominantly controlled by ongoing sulfate reduction. High isotopic ratios of mantle-derived 3He relative to radiogenic 4He in groundwater and the flux of H2 along adjacent faults suggest that, in addition to low concentrations of organic matter (<70 uM), H2 from deeper sources might partly fuel metabolic activities. Our results demonstrate that the deep biosphere in the terrestrial crust is metabolically active and playing a crucial role in the formation of reducing groundwater even under low-energy fluxes. PMID- 25517232 TI - Propargylic sulfides: synthesis, properties, and application. PMID- 25517234 TI - China in numbers. PMID- 25517235 TI - Chinese Academy of Sciences. PMID- 25517236 TI - Beijing. PMID- 25517237 TI - Shanghai. PMID- 25517238 TI - Hong Kong. PMID- 25517239 TI - Nanjing. PMID- 25517240 TI - Wuhan. PMID- 25517241 TI - Hefei. PMID- 25517242 TI - Hangzhou. PMID- 25517243 TI - Changchun. PMID- 25517244 TI - Guangzhou. PMID- 25517245 TI - Tianjin. PMID- 25517246 TI - Shenzhen. PMID- 25517247 TI - A guide to the Nature Index. PMID- 25517249 TI - Evisceration of the fallopian tube at the site of a pezzer drain after caesarean section: Is conservative management possible? PMID- 25517250 TI - G-CSF induces up-regulation of CXCR4 expression in human hematopoietic stem cells by beta-adrenergic agonist. AB - Introduction C-X-C chemokine receptor type 4/stromal-derived factor-1 (CXCR4/SDF 1) axis dynamically mediates hematopoietic stem cell trafficking in the bone marrow (BM). Granulocyte colony-stimulating factor (G-CSF) as the most effective mobilizing agent induces SDF-1 secretion from BM stromal cells into circulation that recruit CXCR4+ cells such as hematopoietic stem cells (HSCs) into circulation. However, the direct effect of G-CSF on CXCR4 expression of HSC remains unknown. The nervous system regulates HSC migration with effecting on adrenergic receptors. On the other hand, interaction of G-CSF and catecholamines has been demonstrated; hence, we examined the direct effect of G-CSF and catecholamine on CXCR4 expression. Material and methods After enrichment of CD34+ HSCs from the cord blood with magnetic-activated cell sorting (MACS), these cells were exposed to G-CSF (100 ng/ml), epinephrine (10 uM), isoproterenol (10 uM), and propranolol (1 uM) separately and together. Results Our results showed that G CSF have no direct effect on CXCR4 expression on human CD34+ cells in vitro and treating HSCs with epinephrine leads to significantly increased CXCR4 in 1, 3, and 5 hours. Epinephrine and G-CSF-induced up-regulation of CXCR4 mRNA is dependent on beta receptors, so incubation of HSCs with propranolol led to inhibition of such increased expression. In addition, isoproterenol and agonist of beta receptors would significantly increase the expression of CXCR4 approximately 4- and 12-fold after 1-hour incubation, respectively. Discussion Co stimulation of enriched HSCs with G-CSF and isoproterenol resulted to a further enhanced CXCR4 levels. In general, G-CSF-induced CXCR4 expression is the indirect mechanism and is specifically regulated through beta-adrenergic receptors. PMID- 25517251 TI - Solvothermal synthesis of gallium-indium-zinc-oxide nanoparticles for electrolyte gated transistors. AB - Solution-processed field-effect transistors are strategic building blocks when considering low-cost sustainable flexible electronics. Nevertheless, some challenges (e.g., processing temperature, reliability, reproducibility in large areas, and cost effectiveness) are requirements that must be surpassed in order to achieve high-performance transistors. The present work reports electrolyte gated transistors using as channel layer gallium-indium-zinc-oxide nanoparticles produced by solvothermal synthesis combined with a solid-state electrolyte based on aqueous dispersions of vinyl acetate stabilized with cellulose derivatives, acrylic acid ester in styrene and lithium perchlorate. The devices fabricated using this approach display a ION/IOFF up to 1 * 10(6), threshold voltage (VTh) of 0.3-1.9 V, and mobility up to 1 cm(2)/(V s), as a function of gallium-indium zinc-oxide ink formulation and two different annealing temperatures. These results validates the usage of electrolyte-gated transistors as a viable and promising alternative for nanoparticle based semiconductor devices as the electrolyte improves the interface and promotes a more efficient step coverage of the channel layer, reducing the operating voltage when compared with conventional dielectrics gating. Moreover, it is shown that by controlling the applied gate potential, the operation mechanism of the electrolyte-gated transistors can be modified from electric double layer to electrochemical doping. PMID- 25517252 TI - Ab initio study of guanine damage by hydroxyl radical. AB - Multiconfigurational ab initio methods are used in this study to examine two initial reactions that take place during the OH radical attack of the DNA base guanine: a ring opening reaction and a hydrogen transfer reaction. The same reactions are also studied in the presence of a single water molecule. The ring opening reaction has a moderate barrier height of ~20-25 kcal/mol that is relatively insensitive to the presence of water. The barrier of the H-transfer reaction, on the other hand, is lowered from ~50 to ~22 kcal/mol when one water molecule is added, thus becoming comparable to the barrier height of the ring opening reaction. PMID- 25517253 TI - Bromelain has paradoxical effects on blood coagulability: a study using thromboelastography. AB - Bromelain is a crude extract from pineapple that is known for a wide array of pharmacological effects including protein digestion, fibrinolytic and anti-immune inflammatory effects and has been popularly used as a phytotherapeutic drug. However, its clinical values and applications remain understudied. The aim of this study was to investigate the effect of bromelain on the coagulability of blood using thromboelastography (TEG). We identified 0.4 U/ml as the minimum concentration of bromelain that results in modification of a normal TEG tracing. We studied the effects of this dose on whole blood samples obtained from normal and hypercoagulable individuals using TEG and evaluated their plasma using conventional tests including prothrombin time (PT) and activated partial thromboplastin time (APTT). We extended this analysis to investigate the effect of bromelain on platelet aggregation in normal blood and on the coagulability of mice blood in vivo in response to a clinically relevant dose injected intraperitoenally. The addition of bromelain ex vivo reduced coagulability of both normal and hypercoagulable blood significantly and resulted in 47 and 22% prolongation of PT and 20 and 10% prolongation of APTT in normal and hypercoagulable samples, respectively and inhibited adenosine di-phosphate (ADP) induced platelet aggregation by 19%. In vivo, there was a considerable variation in TEG parameters in blood obtained from mice and unexpectedly a paradoxical effect toward hypercoagulability was shown in response to 1.5 mg/kg bromelain injected intraperitoneally into seven different animals. However, these results were not statistically significant when compared with the saline-injected animals. Although the in-vitro findings in this small study indicate a potential anticoagulant effect for bromelain, this needs to be interpreted with caution as neither an oral nor intravenous routes were evaluated. The paradoxical in-vivo data following intraperitoneal administration show the complexity of the effects of bromelain beyond platelets and indicate possible effects on other cells or proteins that require further investigations. PMID- 25517254 TI - Test-retest variability of retinal nerve fiber layer thickness and macular ganglion cell-inner plexiform layer thickness measurements using spectral-domain optical coherence tomography. AB - PURPOSE: To evaluate the test-retest variability of spectral-domain optical coherence tomography (OCT) in measurement of retinal nerve fiber layer (RNFL) thickness and macular ganglion cell-inner plexiform layer (GCIPL) thickness. METHODS: A total of 65 eyes of healthy subjects were enrolled in this observational cross-sectional study. RNFL thickness and GCIPL thickness were measured using the repeat scan optic cube and macular cube protocol using Cirrus HD-OCT (software version 6.0). A single operator obtained 3 measurements during 1 session to determine test-retest variability. Intrasession repeatability was defined by intraclass correlation, limits of agreement, and coefficient of variation. RESULTS: The mean age of patients was 37.89+/-15.11 years (range, 10 to 70 y). The mean RNFL thickness readings as measured during 3 sessions were 93.89+/-9.73, 93.63+/-10.00, and 93.55+/-9.64 MUm and average GCIPL thickness measurements were 82.90+/-4.61, 82.98+/-4.24, and 83.06+/-4.36 MUm, respectively. Coefficient of variation was 1.2 for average RNFL thickness and 0.82 for average GCIPL thickness. The intraclass correlation coefficient showed a good correlation between repeat measurements for both average RNFL and GCC thicknesses (0.994 and 0.990, respectively). The limits of agreement (95% confidence interval) for the 3 sessions ranged from -3.61 to 4.13 MUm for the average RNFL thickness and -2.55 to 2.40 MUm for GCIPL thickness measurements. CONCLUSIONS: In healthy eyes, Cirrus HD-OCT shows excellent intrasession repeatability for RNFL and GCIPL thickness measurements. PMID- 25517255 TI - In vivo imaging of human vasculature in the chorioretinal complex using phase variance contrast method with phase-stabilized 1-MUm swept-source optical coherence tomography. AB - We present a noninvasive phase-variance (pv)-based motion contrast method for depth-resolved imaging of the human chorioretinal complex microcirculation with a newly developed phase-stabilized high speed (100-kHz A-scans/s) 1-MUm swept- ource optical coherence tomography (SSOCT) system. Compared to our previous spectral-domain (spectrometer based) pv-spectral domain OCT (SDOCT) system, this system has the advantages of higher sensitivity, reduced fringe wash-out for high blood flow speeds and deeper penetration in choroid. High phase stability SSOCT imaging was achieved by using a computationally efficient phase stabilization approach. This process does not require additional calibration hardware and complex numerical procedures. Our phase stabilization method is simple and can be employed in a variety of SSOCT systems. Examples of vasculature in the chorioretinal complex imaged by pv-SSOCT from normal as well as diseased eyes are presented and compared to retinal images of the same subjects acquired with fluorescein angiography and indocyanine green angiography. Observations of morphology of vascular perfusion in chorioretinal complex visualized by our method are listed. PMID- 25517256 TI - Dynamic light scattering arising from flowing Brownian particles: analytical model in optical coherence tomography conditions. AB - The statistical model of scattered by flowing Brownian particles coherent radiation is suggested. The model includes the random Doppler shifts caused by particle Brownian motion and the speckle fluctuations caused primarily by the flow motion of particles. Analytical expressions are obtained for the correlation function, power spectrum, and spectral width of scattered radiation in the imaging geometry typically used in optical coherence tomography (OCT). It is shown that the spectral density has the Voigt shape, a well-known spectral profile from atomic and molecular spectroscopy. The approach enables the choice of the experimental regimes for the measurement of Brownian particle motion parameters even in the presence of flow. These regimes are characterized by the dominant contribution of Brownian motion in the spectral width of the flow-caused Doppler shift component. Further, the new formalism suggests that prior attempts to extract transverse flow velocity are only valid at near-perpendicular geometry. The impact of the small scattering volume contributing to the OCT signal is also discussed. PMID- 25517257 TI - Single-beam, dual-view digital holographic interferometry for biomechanical strain measurements of biological objects. AB - We describe a method for dual-view biomechanical strain measurements of highly asymmetrical biological objects, like teeth or bones. By using a spherical mirror, we were able to simultaneously record a digital hologram of the object itself and the mirror image of its (otherwise invisible) rear side. A single laser beam was sufficient to illuminate both sides of the object, and to provide a reference beam. As a result, the system was mechanically very stable, enabling long exposure times (up to 2 min) without the need for vibration isolation. The setup is simple to construct and adjust, and can be used to interferometrically observe any object that is smaller than the mirror diameter. Parallel data processing on a CUDA-enabled (compute unified device architecture) graphics card was used to reconstruct digital holograms and to further correct image distortion. We used the setup to measure the deformation of a tooth due to mastication forces. The finite-element method was used to compare experimental results and theoretical predictions. PMID- 25517258 TI - Analysis of laser transmission and thermal effects on the inner root surface during periodontal treatment with a 940-nm diode laser in an in vitro pocket model. AB - The purpose of this study was to analyze thermal effects during laser-assisted periodontal treatment. An in vitro model for temperature measurements was developed to investigate different laser settings regarding pulp safety. Additionally, the influence of transmission on pulp temperature elevation was evaluated. Longitudinal root sections were irradiated with a 940-nm diode laser with 1.0 and 1.5 W in continuous wave mode. According to wall thicknesses, irradiation times were adjusted to 20 s for upper and 10 s for lower incisors, respectively. Transmission was relatively low in both upper (4.8% to 8.3% of incident power) and lower incisors (10.2% to 15.0%). Samples were embedded in a polyurethane model and six thermocouples were affixed. Regardless of dentine thickness, the middle third of the root was identified to be the area with the most heat load, where a temperature rise of 7.5 degrees C (1.0 W) and 10.5 degrees C (1.5 W) was registered in upper incisors. A difference of 1.5 degrees C to 3 degrees C was detected in lower incisors compared with uppers. All settings were safe except for 1.5 W, 20 s. Transmission affected heat generation remarkably. The proposed model provides advantages regarding heat transfer and enables for spatially resolved temperature measurements. PMID- 25517259 TI - Determination of charge on asphaltene nanoaggregates in air using electrostatic force microscopy. AB - In this paper, we provide measurement of charge of asphaltene nanoaggregates in air using electrostatic force microscopy. We obtain the average surface charge density of the nanoaggregates as 43.7 nC/cm(2). Among the different aspects of asphaltene, one of the least known is its charge and the effect of solvent and compositional variability (of asphaltene) in dictating this charge. For aqueous systems, asphaltene charge demonstrates a strong dependence on the pH and the salt concentration, indicating that a possible ionization of the surface groups leads to this charging. On the contrary, for asphaltene in nonpolar media (e.g., toluene and heptane), it is believed that asphaltene native charge is central in dictating this charging. This native charge is the solvent-independent charge or the asphaltene charge in air. Our measurements, therefore, provide the first direct quantification (i.e., a quantification of charge not from the measurement of the asphaltene mobilities, which in turn requires specification of the nonuniform asphaltene size distribution) of this asphaltene native charge by conducting the measurements in air. Similar measurements in a solvent may introduce a solvent-dependent value, thereby forbidding not only the exact quantification of this native charge but also the understanding of the specific role of the solvent. This measurement, therefore, will provide a useful starting point to quantify the mechanism of asphaltene charging in nonpolar solvents with important ramifications in deciphering the role of asphaltene in transport and handling of crude and heavy oils. PMID- 25517260 TI - Application of catheter and guidewire transmission technology in the reconstruction of gastroduodenal malignant stricture. AB - BACKGROUND: Gastroduodenal obstruction is a preterminal event in patients with advanced and recurrent malignancies of the stomach, pancreas, and duodenum. It severely limits the quality of life in affected patients due to constant vomiting and associated malnutrition. Gastroduodenal stent placement is a very safe and effective method in patients with unresectable malignant tumors. METHODS: Thirty six patients with malignant gastroduodenal stenosis accompanied by gastrointestinal obstruction which was not traversable with a gastroscope were included in the study. Under X-ray monitoring, the catheter was inserted through the stenosis advancing with loach guidewire, which was later replaced by a stiff guidewire. A tri-lumen gastrojejunal catheter was then introduced using the stiff guidewire through the stenosis to perform gastrointestinal decompression and provide intestinal nutrition. In some patients, an intestinal stent was placed at the site of the stenosis. RESULTS: Intubation was successful in 35 patients out of 36. A total of 12 intestinal stents were successfully placed, including two at the pylorus, six at the site of gastrointestinal anastomosis, and four at the descending horizontal part of the duodenum. CONCLUSIONS: Establishing enteral nutrition via intubation using guidewire and catheter delivery technology is a simple, effective and safe strategy for patients with gastroscopic inaccessible malignant gastroduodenal stenosis, and it is recommended in hospital practice. PMID- 25517262 TI - Efficacy of intestinal decompression with long nasointestinal tube and selective contrast radiography in the treatment of small bowel obstruction in elderly patients. AB - BACKGROUND: This study's aim was to assess the efficacy of intestinal decompression with long tube and selective intestinal radiography in the diagnosis and treatment of small bowel obstruction (SBO) in elderly patients. METHODS: Thirty-two elderly patients with SBO received intestinal decompression with a 300-cm long nasointestinal tube inserted into upper jejunum under radiographic control. The long tube was passed into the proximal part of obstruction or the proximal end of ileum driven by intestinal peristalsis. Selective contrast radiography was done using direct injection of double-contrast medium consisting of 20-100 mL of 76% gastrografin and 50-200 mL of air. The dynamic and multi-position radiographic observation was conducted. RESULTS: Intubation was successful in all 32 patients. SBO resolution was successful in 29/32 (90.6%) patients. The 3 remaining patients proceeded to undergo surgery. Radiographic findings showed no obvious abnormalities in 25/32 (78.1%) patients, adhesive SBO in 6/32 (18.6%), and metastatic intestinal tumor in 1/32 (3.1%) patient. CONCLUSIONS: Decompression using long tube can quickly and effectively relieve obstructive symptoms in elderly patients, and help to avoid emergency surgery and to resolve obstruction. Concurrent contrast radiography is helpful to verify the location and degree of obstruction, and to reveal the cause of the obstruction. PMID- 25517261 TI - Fentanyl transdermal patch (Durogesic(r) D-TRANS) for post abdominal laparotomy analgesia: a double blind randomized study. AB - AIM: The fentanyl transdermal patch (Duro-gesic(r) D-TRANS) is a strong pain medication for moderate to severe chronic pain that can provide long-lasting relief for persistent pain. This study was conducted to determine the analgesia and adverse effects of the fentanyl transdermal patch (Durogesic(r) D-TRANS) postelective laparotomy. METHODS: One-hundred twenty patients undergoing elective laparotomy were randomized into two groups of fentanyl and placebo. In the first group, patients received two fentanyl patches with 25 and 50 ug in 10 hours preoperatively. Patient's postoperative assessments included pain score, adverse effects, mean amount and interval of supplementary morphine, respiratory rate and oxygen saturation, which were recorded during 36 hours. RESULTS: The mean pain intensity scores over 36 hours in fentanyl transdermal patch durogesic (FTD) group were significantly less than placebo group (FTD, 35.28; placebo, 46.61 and P=0.01). However, the pain score at the 3rd timepoint in the placebo group was slightly less than the FTD group (39.4+/-2.23 vs. 39.47+/-4.97, respectively). The mean interval and amount of supplementary morphine were significantly better in the FTD group than the placebo group (FTD 367.7+/-349.7 min vs. placebo 59+/ 13.88 min; P=0.04 and FTD 2.10+/-3.46 mg vs. 29.15+/-3.71 mg; P<0.001, respectively). The incidence of adverse effects including vomiting (FTD 16 vs. placebo 9; P=0.45), nausea (FTD 22 vs. placebo 18; P=0.33), itching (FTD 16 vs. placebo 18; P=1.00) and respiratory depression (FTD 1 vs. placebo 0; P=1.00) were not significant between the groups, except the dizziness that had a higher incidence in the FTD group (FTD 23 vs. placebo 1; P=0.02). CONCLUSION: It seems that the fentanyl transdermal patch system is a safe and effective procedure to use in post laparotomy analgesia and its related adverse effects are not serious. PMID- 25517263 TI - The motivational foundations of different therapeutic orientations as indicated by therapists' value preferences. AB - OBJECTIVE: The present study investigates the relationships between therapists' value preferences and their beliefs in the efficacy of the four main therapeutic orientations (cognitive behavior, psychodynamic, client-centered, and eco systemic). METHOD: The study was conducted in Israel. Social workers practicing individual therapy in different psychosocial services participated in the study (n = 528). RESULTS: Personal value preferences explained a significant proportion of the variance in the social workers' beliefs in the efficacy of different therapeutic orientations. Each therapeutic orientation was associated with a specific pattern of value preferences, thus indicating that different therapeutic orientations promote or impede the attainment of the therapists' specific motivational goals. CONCLUSIONS: The study results' implications for understanding the motivational foundations of different therapeutic orientations are discussed, as well as their possible application for therapist training and practice. PMID- 25517264 TI - High-throughput quantitative and qualitative analysis of microsomal incubations by cocktail analysis with an ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometer system. AB - BACKGROUND: Metabolite identification studies are very resource intensive and also are rarely performed in early discovery. Here, we report the validation of an ultraperformance liquid chromatography-high-resolution mass spectrometry (UPLC HRMS) platform for generating high-throughput stability data with structure elucidation in a single injection. MATERIALS & METHODS: Tandem mass spectrometry spectra were obtained for quantitative analysis using a generic information dependent acquisition method from pooled microsomal samples incubated at low compound concentrations. RESULTS: A good correlation was observed between clearance determined using UPLC-HRMS and UPLC-triple-quadrupole analysis. Structural elucidation performed with MassMetaSiteTM (Molecular Discovery, Perugia, Italy) software identified 85% of the major metabolites of eight marketed drugs and over 100 internal compounds under these conditions. CONCLUSION: For the first time, a high-throughput quantitative-qualitative workflow was established using a cocktail approach for sample analysis with UPLC HRMS in order to enable metabolite identification in early discovery projects. PMID- 25517266 TI - Intrinsic and dynamical reaction pathways of an excited state proton transfer. AB - The detailed knowledge of excited state proton transfer mechanisms in complex environments is of paramount importance in chemistry. However, the definition of an effective reaction coordinate and the understanding of the driving force of the reaction can be difficult from both the experimental and the theoretical points of view. Here we analyzed by theoretical approaches the mechanism and the driving forces of the excited state proton transfer reaction occurring between the 7-hydroxy-4-(trifluoromethyl)coumarin photoacid and the 1-methylimidazole base molecules in toluene solution. In particular, we compared the intrinsic and the dynamical reaction pathways, obtained by integrating the reaction coordinate, and by performing ab initio simulations of molecular dynamics, respectively. Time dependent density functional theory and polarizable solvation continuum models were adopted to define the excited state potential energy surface. Results were analyzed by means of the D(CT) electronic density based index. Our findings suggest that the reaction coordinate is mainly composed of several intra- and intermolecular modes of the reactants. An analysis of both the intrinsic coordinate and the dynamical results shows that the charge transfer induced by electronic excitation of the coumarin molecule is the main proton transfer driving force. With regards to the methodological validation, the combination of ab initio molecular dynamics with time-dependent density functional theory appears to be feasible and reliable to study excited state proton transfer reactions in the condensed phase. PMID- 25517265 TI - Polymerase and exonuclease activities in herpes simplex virus type 1 DNA polymerase are not highly coordinated. AB - The herpes polymerase-processivity factor complex consists of the catalytic UL30 subunit containing both polymerase and proofreading exonuclease activities and the UL42 subunit that acts as a processivity factor. Curiously, the highly active exonuclease has minimal impact on the accumulation of mismatches generated by the polymerase activity. We utilized a series of oligonucleotides of defined sequence to define the interactions between the polymerase and exonuclease active sites. Exonuclease activity requires unwinding of two nucleotides of the duplex primer template. Surprisingly, even though the exonuclease rate is much higher than the rate of DNA dissociation, the exonuclease degrades both single- and double stranded DNA in a nonprocessive manner. Efficient proofreading of incorrect nucleotides incorporated by the polymerase would seem to require efficient translocation of DNA between the exonuclease and polymerase active sites. However, we found that translocation of DNA from the exonuclease to polymerase active site is remarkably inefficient. Consistent with inefficient translocation, the DNA binding sites for the exonuclease and polymerase active sites appear to be largely independent, such that the two activities appear noncoordinated. Finally, the presence or absence of UL42 did not impact the coordination of the polymerase and exonuclease activities. In addition to providing fundamental insights into how the polymerase and exonuclease function together, these activities provide a rationale for understanding why the exonuclease minimally impacts accumulation of mismatches by the purified polymerase and raise the question of how these two activities function together in vivo. PMID- 25517267 TI - Accuracy of the Modified Somatic Perception Questionnaire and Pain Disability Index in the detection of malingered pain-related disability in chronic pain. AB - The Modified Somatic Perception Questionnaire (MSPQ) and the Pain Disability Index (PDI) are both popular clinical screening instruments in general orthopedic, rheumatologic, and neurosurgical clinics and are useful for identifying pain patients whose physical symptom presentations and disability may be non-organic. Previous studies found both to accurately detect malingered pain presentations; however, the generalizability of these results is not clear. This study used a criterion groups validation design (retrospective cohort of patients with chronic pain, n = 328) with a simulator group (college students, n = 98) to determine the accuracy of the MSPQ and PDI in detecting Malingered Pain Related Disability. Patients were grouped based on independent psychometric evidence of MPRD. Results showed that MSPQ and PDI scores were not associated with objective medical pathology. However, they accurately differentiated Not-MPRD from MPRD cases. Diagnostic statistics associated with a range of scores are presented for application to individual cases. Data from this study can inform the clinical management of chronic pain patients by screening for psychological overlay and malingering, thus alerting clinicians to the possible presence of psychosocial obstacles to effective treatment and triggering further psychological assessment and/or treatment. PMID- 25517268 TI - Tuberculosis in renal transplant recipients: challenges in developing countries. PMID- 25517269 TI - Dietary counseling and nephrolithiasis. PMID- 25517270 TI - Association of hypovitaminosis D with Systemic Lupus Erythematosus and inflammation. AB - INTRODUCTION: Nowadays it is described a high prevalence of hypovitaminosis D in Systemic Lupus Erythematosus (SLE), which is associated with some clinical manifestations and increased inflammatory activity. OBJECTIVE: To evaluate the association between vitamin D insufficiency with SLE and inflammatory markers. METHODS: Cross-sectional study, in which have been evaluated 45 SLE patients and 24 controls without the disease. Levels of 25-hydroxyvitamin D [25(OH) D] less than 30 ng/mL were considered inadequate. Disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). High sensitivity C reactive protein (hsCRP) and interleukin-6 (IL-6) were evaluated for verification of the inflammatory status. For assessment of renal involvement, analysis of abnormal elements and urinay sediment (AES), quantitative hematuria and pyuria, proteinuria and creatinine clearance in 24-hour urine and serum anti-double stranded DNA were performed. RESULTS: The prevalence of 25(OH)D insufficiency was 55% in SLE patients and 8% in the controls participants (p = 0.001). The median of 25(OH)D was lower in patients than in controls. Patients with insufficient 25(OH)D had higher levels of IL-6 and higher prevalence of hematuria in the AES. There was no correlation between vitamin D and SLEDAI or lupus nephritis. CONCLUSION: In our study, vitamin D deficiency was more prevalent in patients with SLE and was associated with higher levels of IL-6 and hematuria. PMID- 25517271 TI - Evaluation of food intake and excretion of metabolites in nephrolithiasis. AB - INTRODUCTION: Nephrolithiasis is a common condition with high prevalence and recurrence, occurring by a complex and multifactorial process. OBJECTIVE: To analyze the main dietary and metabolic characteristics of patients with nephrolithiasis and compare them with a control group. METHODS: A cross sectional study with 31 patients with nephrolithiasis (NE) and 18 healthy. By the dietary intake it were observed sodium, calcium, protein, potassium, vitamin C, oxalate and water intake in both groups. Metabolic assessment were analyzed in urinary excretion of oxalate and citrate. The presence of hypertension and body mass index (BMI) was also evaluated. RESULTS: In the NE group, it was found that 45.2% had a high intake of sodium and 100% a high intake of oxalate. It was also observed a low calcium, potassium and vitamin C intake by 93.5%, 100% and 94.9% respectively. Regarding protein, only 12.5% had normal protein intake. Concerning water intake, 12.9% had an ingestion less than 1 liter, 54.8% between 1 and 2 liters and 32.3% higher than 2 liters. Hypertension was observed in 64.5% of patients and adequate excretion of oxalate and citrate in 90.5% of them. There was no statistically difference in food intake, BMI and oxalate excretion between groups. However, the NE group showed higher urinary citrate. CONCLUSION: It was found in both groups a high prevalence of overweight patients, a high intake of oxalate and sodium, in addition to inadequate intakes of calcium, potassium and vitamin C. The NE group showed high protein intake and increased excretion of citrate. PMID- 25517272 TI - Computerized tomography contrast induced nephropathy (CIN) among adult inpatients. AB - INTRODUCTION: Contrast induced nephropathy (CIN) is one of the complications of the use of intravascular contrast agents, being defined as a reduction of the glomerular filtration rate caused by the iodinated contrast. Most CIN data derive from the cardiovascular literature, which identified as the most consistent risk factors pre-existing chronic renal insufficiency and diabetes mellitus. However, these studies limit their conclusions to a more specific patient population. Computerized tomography as a cause of CIN has been studied less often. OBJECTIVE: To report on the incidence of computerized tomography contrast induced nephropathy (CIN) in an inpatient population of a tertiary general hospital, identifying potentially avoidable risk factors. METHODS: We performed a prospective cohort study with inpatients admitted at a tertiary hospital requiring contrast-induced CT. The primary outcome was the development of CIN, measure by the alteration of serum creatinine or glomerular filtration rate in 48 or 72 hours. Through clinical interview, we verified possible risk factors and preventive measures instituted by the medical team and their association with development of CIN. RESULTS: Of a total of 410 patients, 35 (8.5%) developed CIN. There was a positive correlation between CIN and the presence of diabetes mellitus (OR = 2.15; 95%CI 1.35-4.06; p = 0.02), heart failure (OR = 2.23; 95%CI 1.18-8.8; p = 0.022), and renal failure (OR = 3.36; 95%CI 1.57- 7.17; p = 0.002) CONCLUSION: Incidence of CIN varies according to the population. Diabetes mellitus, heart failure and renal failure were independent risk factors for the development of CT-associated CIN. Further studies are needed to better understand and treat CT-associated CIN. PMID- 25517273 TI - Impact of an interdisciplinary approach in children and adolescents with lower urinary tract dysfunction (LUTD). AB - INTRODUCTION: The lower urinary tract dysfunction (LUTD) corresponds to changes in the filling or emptying of urine caused by neurogenic, anatomical and functional alterations. OBJECTIVE: To evaluate the impact of treatment in children and adolescents with LUTD. METHODS: Historical cohort of 15 year follow up with the participation of 192 patients (123F, 69M), aged 0.1 to 16.8 years, analyzed at admission (T0) and at final follow-up (T1). Most patients belong to a neurologic bladder dysfunction group (60.4%). The treatment was uroterapy with behavioral and cognitive intervention, timed voiding, oral hydration, laxative diet, biofeedback, sacral nerve stimulation, clean intermittent catheterization (CIC), anticholinergic therapy, rectal enema, treatment of urinary tract infection (UTI) and, in refractory cases, surgical procedures such as continent and incontinent urinary diversion (vesicostomy), bladder augmentation and conduit for performing antegrade colonic enema. RESULTS: The main symptoms were daytime urinary incontinence (82.3%), the non-monosymptomatic nocturnal enuresis (78.6%), fecal incontinence (54.2%) and constipation (47.9%). There was a significant reduction of urinary tract infection (p = 0.0027), daytime urinary incontinence (p < 0.001), nocturnal enuresis (p < 0.001), fecal incontinence (p = 0.010) and of vesicoureteral reflux (p = 0.01). There was significant increase in the use of CIC (p = 0.021), of anticholinergic therapy (p < 0.001) and decrease of chemoprophylaxis (p < 0.001). CONCLUSION: This study showed that treatment of LUTD in children must be individualized, and requires constant monitoring of clinical, laboratory and imaging to minimize the risk of kidney damage. PMID- 25517274 TI - The mothers' experiences in the pediatrics hemodialysis unit. AB - INTRODUCTION: The need for hemodialysis exerts a deep impact on the lives of children and adolescents with end-stage kidney chronic failure and their mothers, who predominantly assume the care related to treatment. The hemodialysis requires that the mother accompanies the child during sessions at least three times a week and, since it is not a healing practice, they also experience the waiting for a kidney transplant, attributing different meanings to this experience. OBJECTIVE: To understand what it means for the mothers to accompany the child in a Pediatric Hemodialysis Unit and to construct a theoretical model representing this experience. METHODS: The Symbolic Interactionism was adopted as a theoretical model and the Grounded Theory as a methodological framework. Data were collected through interviews with 11 mothers. RESULTS: The comparative analysis of the data enabled the identification of two phenomena that compose the experience: "Seeing the child's life being sucked by the hemodialysis machine" expresses the experiences of the mothers that generates new demands to comprehend the new health conditions of their children and "Giving new meaning to the dependence of the hemodialysis machine" that represents the strategies employed to endure the experience. The relationship of these phenomena allowed the identification of the main category: "Having the mother's life imprisoned by the hemodialysis machine", from which we propose a new theoretical model. CONCLUSION: The results of the study allow us to provide a theoretical ground for planning an assistance that meets the real needs of the mothers, identifying aspects that require intervention. PMID- 25517275 TI - Inverse association between serum creatinine and mortality in acute kidney injury. AB - INTRODUCTION: Sepsis is a leading precipitant of Acute Kidney Injury (AKI) in intensive care unit (ICU) patients, and is associated with a high mortality rate. OBJECTIVE: We aimed to evaluate the risk factors for dialysis and mortality in a cohort of AKI patients of predominantly septic etiology. METHODS: Adult patients from an ICU for whom nephrology consultation was requested were included. End stage chronic renal failure and kidney transplant patients were excluded. RESULTS: 114 patients were followed. Most had sepsis (84%), AKIN stage 3 (69%) and oliguria (62%) at first consultation. Dialysis was performed in 66% and overall mortality was 70%. Median serum creatinine in survivors and non-survivors was 3.95 mg/dl (2.63 - 5.28) and 2.75 mg/dl (1.81 - 3.69), respectively. In the multivariable models, oliguria and serum urea were positively associated with dialysis; otherwise, a lower serum creatinine at first consultation was independently associated with higher mortality. CONCLUSION: In a cohort of septic AKI, oliguria and serum urea were the main indications for dialysis. We also described an inverse association between serum creatinine and mortality. Potential explanations for this finding include: delay in diagnosis, fluid overload with hemodilution of serum creatinine or poor nutritional status. This finding may also help to explain the low discriminative power of general severity scores - that assign higher risks to higher creatinine levels - in septic AKI patients. PMID- 25517277 TI - Total body water reduction in subjects with chronic kidney disease on peritoneal dialysis is associated with a better hypertension control. AB - INTRODUCTION: Hypertension is highly prevalent in patients with chronic kidney disease and hypervolemia is one of the principal causes. OBJECTIVE: To evaluate the influence of the reduction of volemia on blood pressure as well as on echocardiographic parameters in patients on continuous ambulatory peritoneal dialysis. METHODS: Twelve patients with no clinical evidence of hypervolemia were submitted to an increase in the rate of the dialysis with the purpose of reducing body weight by 5%. The volemia was evaluated by electrical bioimpedance and by ultrasound of the inferior cava vena (ICV). Blood pressure was measured by ambulatory blood pressure monitoring and cardiac function was evaluated by echocardiography both at baseline and 5 weeks after the intervention period. RESULTS: After the increase in the ultrafiltration, body weight, extracellular water and the inspiratory diameter of the ICV decreased significantly in parallel with a non-significant increase in the collapsing ICV index. Despite the reduction of anti-hypertensive drugs, systolic blood pressure during the sleep period decreased from 138.4 +/- 18.6 to 126.7 +/- 18.0 mmHg, the nocturnal blood pressure drop increased and the final systolic left ventricular diameter decreased significantly. CONCLUSION: Reduction of the volemia of patients on peritoneal dialysis, with no signs of hypervolemia, was associated with a better blood pressure control and with a decrease of the final systolic left ventricular diameter. PMID- 25517276 TI - Brazilian Chronic Dialysis Survey 2013 - trend analysis between 2011 and 2013. AB - INTRODUCTION: National chronic dialysis data have had impact in the treatment planning. OBJECTIVE: To report data of the annual survey of the Brazilian Society of Nephrology about chronic kidney disease patients on dialysis in July 2013 and compare with 2011-12. METHODS: A survey based on data of dialysis units from the whole country. The data collection was performed by using a questionnaire filled out on-line by the dialysis units. RESULTS: Three hundred thirty four (51%) of the dialysis units in the country answered the questionnaire. In July 2013, the total estimated number of patients on dialysis was 100,397. The estimated prevalence and incidence rates of chronic maintenance dialysis were 449 (range: 284 in the North region and 622 in the South) and 170 patients per million population, respectively. The estimated number of new patients starting dialysis in 2013 was 34,161. The annual gross mortality rate was 17.9%. For prevalent patients, 31.4% were aged 65 years or older, 90.8% were on hemodialysis and 9.2% on peritoneal dialysis, 31,351 (31.2%) were on a waiting list of renal transplant, 30% were diabetics, 17% had PTH levels > 600 pg/ml and 23% hemoglobin < 10 g/ dl. A venous catheter was the vascular access for 15.4% of the hemodialysis patients. CONCLUSION: The absolute number of patients on dialysis has increased 3% per year. The prevalence and incidence rates of patients on dialysis leveled off, while the mortality rate tended to decrease compared with 2012. There was a trend towards a better control of the anemia and PTH levels. PMID- 25517278 TI - Selenium plasma levels in hemodialysis patients: comparison between North and Southeast of Brazil. AB - INTRODUCTION: Patients with chronic kidney disease present selenium (Se) plasma deficiency which is an essential trace element with important biological functions and, the best known biological role is attributed to its presence in the antioxidant enzyme, glutathione peroxidase (GPx). The Se content of foods depends on soil and some authors have suggested that Amazon soil (North Brazilian region) has high Se concentrations when compared to other regions of Brazil. OBJECTIVE: The objective of this work was to compare the Se status in hemodialysis (HD) patients from North and Southeast of Brazil. METHODS: Thirty eight patients from Southeast region (22 men and 16 women, 15% diabetic, 53.5 +/- 26.4 yrs) were compared to 40 patients from North region (28 men and 12 women, 22.5% diabetic, 63.5 +/- 11.9 yrs). Se in plasma was determined through atomic absorption spectrophotometry with hydride generation. RESULTS: The plasma Se levels in patients from Southeast region were significantly lower (17.5 +/- 11.9 MUg/L) when compared to patients from the North (37.1 +/- 15.8 MUg/L) (p < 0.001). However, both patient groups presented low Se plasma levels when compared to recommended values (60- 120 MUg/L). There was no correlation between plasma Se levels and analyzed parameters. CONCLUSION: We concluded that patients from North (Amazon) region present higher plasma Se levels when compared to the patients from Southeast of Brazil. However, independently of the region, HD patients presented Se deficiency. PMID- 25517279 TI - Effects of grape powder supplementation on inflammatory and antioxidant markers in hemodialysis patients: a randomized double-blind study. AB - INTRODUCTION: Polyphenols contained in natural sources such as grapes, have been considered pharmacological agents to combat oxidative stress and inflammation, common features in Chronic Kidney Disease patients. OBJECTIVE: To evaluate the effects of grape powder supplementation on inflammatory and antioxidant biomarkers in hemodialysis (HD) patients. METHODS: The double-blind placebo controlled randomized clinical trial evaluated non-diabetic HD patients that received grape powder (500 mg of polyphenols/day) (n = 16, 9 men, 53.0 +/- 9.8 years of age, 111.6 +/- 58.2 HD months) or placebo (n = 16, 9 men, 52.7 +/- 13.7 years of age, 110.4 +/- 93.1 HD months) for five weeks. The glutathione peroxidase (GSH-Px) activity and C-reactive protein (CRP) levels were evaluated by ELISA method. RESULTS: After the intervention period, the patients receiving grape powder showed an increase in the GSH-Px activity (16.5 (41.0) to 42.0 (43.3) nmol/min/ml) (p < 0.05) and they did not have the CRP levels increased as seen in placebo group (2.6 (0.28) to 2.8 (0.23 mg/L) (p < 0.05). CONCLUSION: The use of grape powder as phenolic source could play an important role as an antioxidant and anti-inflammatory agent in non-diabetic HD patients. PMID- 25517280 TI - The cost of alkaline solutions in ambulatory hemodialysis: an analysis about wasteful from the processes control. AB - INTRODUCTION: There are few studies about costs of inputs used in hemodialysis and among these expenditures, the compounds that make up the dialysate are one of the values considered as representative of this therapy. However, there aren't costs studies that guiding solutions. OBJECTIVE: The objective of this article is discuss whether there is wasteful of alkaline solutions in ambulatory hemodialysis and hence the possibility of reduction in cost from the standardization process simulation of establishment of dialysate flow in periods between shifts in hemodialysis outpatients. METHODS: Starting from an observational analytic, a simulation was performed twenty case scenarios, which ten cases established by standardizing processes control on the dialysate flow in recession. The combination of data was performed using as a basis the prices of three suppliers of alkali liquid or powder. RESULTS: It was observed among the scenarios with standardized processes, ranging between 7.7% and 33.3% savings in the alkaline solution cost (powder or liquid), by reducing waste. CONCLUSION: It is possible to restrain the wasteful use of alkaline solutions, both powder and liquid. Consequently, its cost from the patterning on reducing the flow of dialysate during the intervals between shifts observed in the outpatient hemodialysis. However, these results are conditional upon the commitment of health professionals, mainly to supervision exercise and control of activities in quality function deployment. PMID- 25517281 TI - Tuberculosis in renal transplant patients: the experience of a single center in Medellin-Colombia, 2005-2013. AB - INTRODUCTION: Tuberculosis is a common opportunistic infection in renal transplant patients. OBJECTIVE: To obtain a clinical and laboratory description of transplant patients diagnosed with tuberculosis and their response to treatment during a period ranging from 2005 to 2013 at the Pablo Tobon Uribe Hospital. METHODS: Retrospective and descriptive study. RESULTS: In 641 renal transplants, tuberculosis was confirmed in 12 cases. Of these, 25% had a history of acute rejection, and 50% had creatinine levels greater than 1.5 mg/dl prior to infection. The disease typically presented as pulmonary (50%) and disseminated (33.3%). The first phase of treatment consisted of 3 months of HZRE (isoniazid, pyrazinamide, rifampicin and ethambutol) in 75% of the cases and HZME (isoniazid, pyrazinamide, moxifloxacin and ethambutol) in 25% of the cases. During the second phase of the treatment, 75% of the cases received isoniazid and rifampicin, and 25% of the cases received isoniazid and ethambutol. The length of treatment varied between 6 and 18 months. In 41.7% of patients, hepatotoxicity was associated with the beginning of anti-tuberculosis therapy. During a year-long follow-up, renal function remained stable, and the mortality rate was 16.7%. CONCLUSION: Tuberculosis in the renal transplant population studied caused diverse nonspecific symptoms. Pulmonary and disseminated tuberculosis were the most frequent forms and required prolonged treatment. Antituberculosis medications had a high toxicity and mortality. This infection must be considered when patients present with a febrile syndrome of unknown origin, especially during the first year after renal transplant. PMID- 25517282 TI - Smoking as risk factor for chronic kidney disease: systematic review. AB - INTRODUCTION: Chronic kidney disease (CKD) and smoking are public health problems. OBJECTIVE: To assess smoking as a risk factor for progression of CKD. METHODS: We conducted a systematic review in Medline, LILACS, SciELO, Google Scholar, Embase and Trials.gov with articles published until February/2013. Were included: cohort, clinical trials and case-control. Performed in humans, aged >= 18 years with smoking as a risk factor for progression of CKD. We excluded studies that reported no smoking and CKD in the title or had proposed to reduce smoking. RESULTS: Among 94 citations, 12 articles were selected. Of these, six were multicenter conducted in developed countries, four were randomized. Males predominated 51-76%. There was associated with smoking progression in 11 studies. It was found that the consumption >= 15 packs/ year increases the risk of progression of CKD. CONCLUSION: Smoking is a risk factor for progression of CKD. PMID- 25517283 TI - BK polyomavirus in kidney transplant recipients: screening, monitoring and clinical management. AB - BK polyomavirus (BKPyV) is a causal agent of nephropathy, ureteral stenosis and hemorrhagic cystitis in kidney transplant recipients, and is considered an important emerging disease in transplantation. Regular screening for BKPyV reactivation mainly during the first 2 years posttransplant, with subsequent pre emptive reduction of immunosuppression is considered the best option to avoid disease progression, since successful clearance or reduction of viremia is achieved in the vast majority of patients within 6 months. The use of drugs with antiviral properties for patients with persistent viremia has been attempted despite unclear benefits. Clinical manifestations of BKPyV nephropathy, current strategies for diagnosis and monitoring of BKPyV infection, management of immunosuppressive regimen after detection of BKPyV reactivation and the use of antiviral drugs are discussed in this review. PMID- 25517284 TI - Effect of renal revascularization on the development of renal dysfunction in atherosclerotic ischemic nephropathy. AB - Chronic kidney disease (CKD) is characterized by a progressive loss of renal function and its main causes are hypertension and diabetes mellitus. Among the causes of hypertension is atherosclerotic renal disease (ARD). The development of CKD in patients with ARD appears to be due not only to the involvement of the main renal arteries, but also of the renal microcirculation, which may explain the fact that the success of the procedure does not guarantee an improvement in the progression of CKD. To date there is no evidence of benefit of angioplasty compared to medical treatment alone in patients with ARD. The present paper analyzes the most significant studies on renal outcomes in patients with ARD undergoing revascularization or medical treatment alone. PMID- 25517285 TI - Purple urine bag syndrome in end-stage chronic kidney disease. AB - INTRODUCTION: When faced with violet, purple or purplish-blue urine, clinicians should consider urinary tract infection in their differential diagnosis. CASE REPORT: A 60-year-old woman with end-stage kidney disease and non-adherence to renal replacement therapy was admitted to our hospital for placement of hemodialysis catheter. During her hospitalization she had purple urine, and purple urine bag syndrome (PUBS) was diagnosed. She was effectively treated with antibiotics and her urine returned to a dark yellow color. DISCUSSION: Although this condition is often easily treated, diagnosing PUBS in chronic renal patients probably means an increased serum concentration of indoxyl sulfate, metabolite that is involved in the progression of both CKD and cardiovascular disease. CONCLUSION: Hence, in the context of our renal patients, perhaps PUBS is not as benign as supposed. PMID- 25517286 TI - [Acute kidney injury as a complication of biribiri (Averrhoa bilimbi)fruit juice excessive ingestion]. PMID- 25517288 TI - Systemic study on the biogenic pathways of yezo'otogirins: total synthesis and antitumor activities of (+/-)-yezo'otogirin C and its structural analogues. AB - A systematic study of the biomimetic pathways to yezo'otogirin C under aerobic and anaerobic conditions has been investigated, and both are found to be feasible pathways to the natural product depending on the physiological conditions. Because of the lower activation energy, the aerobic process would be more favorable when the in vivo oxygen level is high. In the course of this study, a highly efficient synthetic route to (+/-)-yezo'otogirin C has been established in four steps (31% overall yield) from a readily available compound without using any protecting groups. The natural product and its structural analogues exhibited antitumor activities against several human cancer cell lines and appeared to arrest cell cycles in different phases. PMID- 25517289 TI - Oral vitamin D supplementation has a lower bioavailability and reduces hypersecretion of parathyroid hormone and insulin resistance in obese Chinese males. AB - OBJECTIVE: To examine the vitamin D status, SNP of the vitamin D receptor gene (VDR) and the effects of vitamin D supplementation on parathyroid hormone and insulin secretion in adult males with obesity or normal weight in a subtropical Chinese city. DESIGN: An intervention trial. SETTING: Shenzhen City, Guangdong Province, China. SUBJECTS: From a cross-sectional survey conducted from June to July, eighty-two normal-weight and ninety-nine obese males (18-69 years) were screened to analyse their vitamin D status and for five SNP of VDR. From these individuals, in the same season of a different year, obese and normal-weight male volunteers (twenty-one per group) were included for an intervention trial with oral vitamin D supplementation at 1250 ug/week for 8 weeks. RESULTS: For the survey, there was no significant difference (P>0.05) in baseline circulating 25 hydroxyvitamin D concentrations or in the percentages of participants in different categories of vitamin D status between the two groups. The VDR SNP, rs3782905, was significantly associated with obesity (P=0.043), but none of the examined SNP were correlated with serum 25-hydroxyvitamin D when adjusted for age, BMI and study group. After vitamin D supplementation, serum 25 hydroxyvitamin D concentration, hypersecretions of parathyroid hormone and insulin, and insulin resistance in the obese were changed beneficially (P<0.05); however, the increase in serum 25-hydroxyvitamin D was less than that of the normal-weight men. CONCLUSIONS: For obese and normal-weight men of subtropical China, the summer baseline vitamin D status was similar. However, oral vitamin D supplementation revealed a decreased bioavailability of vitamin D in obese men and ameliorated their hypersecretion of parathyroid hormone and insulin resistance. PMID- 25517290 TI - Suicide in Children: A Systematic Review. AB - The objective of this study was to provide a review of studies on suicide in children aged 14 years and younger. Articles were identified through a systematic search of Scopus, MEDLINE, and PsychINFO. Key words were "children, suicide, psychological autopsy, and case-study." Additional articles were identified through manual search of reference lists and discussion with colleagues. Fifteen published articles were identified, 8 psychological autopsy studies (PA), and 7 retrospective case-study series. Suicide incidence and gender asymmetry increases with age. Hanging is the most frequent method. Lower rates of psychopathology are evident among child suicides compared to adolescents. Previous suicide attempts were an important risk factor. Children were less likely to consume alcohol prior to suicide. Parent-child conflicts were the most common precipitant. PMID- 25517291 TI - Determination of sub-nanomolar levels of low molecular mass thiols in natural waters by liquid chromatography tandem mass spectrometry after derivatization with p-(hydroxymercuri) benzoate and online preconcentration. AB - Low molecular mass (LMM) thiols is a diverse group of compounds, which play several important roles in aquatic ecosystems, even though they typically occur at low concentrations. Comprehensive studies of LMM thiols in natural waters have so far been hampered by selectivity and limit of detection constraints of previous analytical methods. Here, we describe a selective and robust method for the quantification of 16 LMM thiols in natural waters. Thiols were derivatized with 4-(hydroxymercuri)benzoate (PHMB) and preconcentrated online by solid-phase extraction (SPE) before separation by liquid chromatography and determination by electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Their quantification was performed by selective reaction monitoring (SRM), while the presence of a product ion at m/z 355, specific for thiols and common for the investigated compounds, also allows to screen samples for unknown thiols by a precursor ion scan approach. The robustness of the method was validated for aqueous matrices with different pH, sulfide, and dissolved organic carbon (DOC) concentrations. The limits of detection for the thiols were in the sub-nanomolar range (0.06-0.5 nM) and the methodology allowed determination of both reduced and total thiol concentrations (using tris(2-carboxyethyl)phosphine (TCEP) as reducing agent). Six thiols (mercaptoacetic acid, cysteine, homocysteine, N acetyl-cysteine, mercaptoethane-sulfonate, and glutathione) were detected with total concentrations of 7-153 nM in boreal lake or wetland pore waters while four thiols (mercaptoacetic acid, cysteine, homocysteine, and N-acetyl-cysteine) were detected in their reduced form at concentrations of 5-80 nM. PMID- 25517292 TI - Critical review and rethinking of USEPA secondary standards for maintaining organoleptic quality of drinking water. AB - Consumers assess their tap water primarily by its taste, odor, and appearance. Starting in 1979, USEPA promulgated Secondary Maximum Contaminant Levels (SMCLs) as guidance for contaminants with organoleptic effects and also to maintain consumers' confidence in tap water. This review assesses the basis for the 15 SMCLs (aluminum, chloride, color, copper, corrosivity, fluoride, foaming agents, iron, manganese, odor, pH, silver, sulfate, total dissolved solids, zinc) and summarizes advances in scientific knowledge since their promulgation. SMCLs for aluminum, color, pH, silver, sulfate, total dissolved solids, and zinc are appropriate at current values and remain consistent with sensory science literature. Recent advances in sensory and health sciences indicate that SMCLs for chloride, copper, fluoride, iron, and manganese are too high to minimize organoleptic effects. The SMCLs for corrosivity and foaming agents may be outdated. The SMCL for odor requires rethinking as the test does not correlate with consumer complaints. Since current stresses on source and treated waters include chemical spills, algal blooms, and increased salinization, organoleptic episodes that negatively impact consumer confidence and perception of tap water still occur and may increase. Thus, adherence to SMCLs can help maintain production of palatable water along with consumers' confidence in their water providers. PMID- 25517293 TI - Enantioselective construction of functionalized thiopyrano-indole annulated heterocycles via a formal thio [3 + 3]-cyclization. AB - A formal thio [3 + 3]-cyclization catalyzed by a DPEN-derived chiral thiourea has been reported for the construction of optically active thiopyrano-indole annulated heterocyclic compounds in high yields with excellent enantioselectivities. The high reactivity between indoline-2-thione (keto-S) and 2-benzylidenemalononitrile has also been supported by density functional theory (DFT) calculations. PMID- 25517294 TI - Improved hematopoietic differentiation efficiency of gene-corrected beta thalassemia induced pluripotent stem cells by CRISPR/Cas9 system. AB - The generation of beta-thalassemia (beta-Thal) patient-specific induced pluripotent stem cells (iPSCs), subsequent homologous recombination-based gene correction of disease-causing mutations/deletions in the beta-globin gene (HBB), and their derived hematopoietic stem cell (HSC) transplantation offers an ideal therapeutic solution for treating this disease. However, the hematopoietic differentiation efficiency of gene-corrected beta-Thal iPSCs has not been well evaluated in the previous studies. In this study, we used the latest gene-editing tool, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated 9 (Cas9), to correct beta-Thal iPSCs; gene-corrected cells exhibit normal karyotypes and full pluripotency as human embryonic stem cells (hESCs) showed no off-targeting effects. Then, we evaluated the differentiation efficiency of the gene-corrected beta-Thal iPSCs. We found that during hematopoietic differentiation, gene-corrected beta-Thal iPSCs showed an increased embryoid body ratio and various hematopoietic progenitor cell percentages. More importantly, the gene-corrected beta-Thal iPSC lines restored HBB expression and reduced reactive oxygen species production compared with the uncorrected group. Our study suggested that hematopoietic differentiation efficiency of beta-Thal iPSCs was greatly improved once corrected by the CRISPR/Cas9 system, and the information gained from our study would greatly promote the clinical application of beta-Thal iPSC-derived HSCs in transplantation. PMID- 25517295 TI - DEAD-box RNA helicases and epigenetic control of abiotic stress-responsive gene expression. AB - Plant responses to abiotic stresses are controlled by a complex tier of epigenetic, transcriptional and post-transcriptional regulation. We have provided evidence that the DEAD-box RNA helicases, STRESS RESPONSE SUPPRESSOR (STRS) 1 and STRS2 are negative regulators of Arabidopsis thaliana stress-responsive transcription factors. Using GFP-STRS fusion proteins, we have demonstrated that the STRSs are localized to the nucleolus and chromocenters, and are rapidly removed to the nucleoplasm upon application of various abiotic stresses. The STRSs appear to act via RNA-directed DNA methylation to suppress Arabidopsis stress responses; this repressive epigenetic mechanism is abrogated by abiotic stress eventually leading to an open chromatin structure allowing expression of stress-responsive genes. PMID- 25517297 TI - Antibody engineering and therapeutics conference. The annual meeting of the antibody society, Huntington Beach, CA, December 7-11, 2014. AB - The 25th anniversary of the Antibody Engineering & Therapeutics Conference, the Annual Meeting of The Antibody Society, will be held in Huntington Beach, CA, December 7-11, 2014. Organized by IBC Life Sciences, the event will celebrate past successes, educate participants on current activities and offer a vision of future progress in the field. Keynote addresses will be given by academic and industry experts Douglas Lauffenburger (Massachusetts Institute of Technology), Ira Pastan (National Cancer Institute), James Wells (University of California, San Francisco), Ian Tomlinson (GlaxoSmithKline) and Anthony Rees (Rees Consulting AB and Emeritus Professor, University of Bath). These speakers will provide updates of their work, placed in the context of the substantial growth of the industry over the past 25 years. PMID- 25517296 TI - Enhanced differentiation and delivery of mouse retinal progenitor cells using a micropatterned biodegradable thin-film polycaprolactone scaffold. AB - The deterioration of retinal tissue in advanced stages of retinitis pigmentosa and age-related macular degeneration and the lack of signaling cues for laminar regeneration are significant challenges highlighting the need for a tissue engineering approach to retinal repair. In this study, we fabricated a biodegradable thin-film polycaprolactone (PCL) scaffold with varying surface topographies using microfabrication techniques. Mouse retinal progenitor cells (mRPCs) cultured on PCL scaffolds exhibited enhanced potential to differentiate toward a photoreceptor fate in comparison to mRPCs cultured on control substrates, suggesting that PCL scaffolds are promising as substrates to guide differentiation of mRPCs toward a photoreceptor fate in vitro before transplantation. When cocultured with the retinal explants of rhodopsin null mice, mRPC/PCL constructs showed increased mRPC integration rates compared to directly applied dissociated mRPCs. Moreover, these mRPC/PCL constructs could be delivered into the subretinal space of rhodopsin null mice with minimal disturbance of the host retina. Whether cocultured with retinal explants or transplanted into the subretinal space, newly integrated mRPCs localized to the outer nuclear layer and expressed appropriate markers of photoreceptor fate. Thus, the PCL scaffold provides a platform to guide differentiation and organized delivery of mRPCs as a practical strategy to repair damaged retina. PMID- 25517298 TI - Blocking monoclonal antibodies of TIM proteins as orchestrators of anti-tumor immune response. AB - Monoclonal antibody (mAb)-based treatment of cancer has a significant effect on current practice in medical oncology, and is considered now as one of the most successful therapeutic strategies for cancer treatment. MAbs are designed to initiate or enhance anti-tumor immune responses, which can be achieved by either blocking inhibitory immune checkpoint molecules or triggering activating receptors. TIM gene family members are type-I surface molecules expressed in immune cells, and play important roles in the regulation of both innate and adaptive arms of the immune system. Therapeutic strategies based on anti-TIMs mAbs have shown promising results in experimental tumor models, and synergistic combinations of anti-TIMs mAbs with cancer vaccines, adoptive T-cell therapy, radiotherapy and chemotherapy will have great impact on cancer treatment in future clinical development. PMID- 25517299 TI - Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer. AB - The complement system is a powerful tool of the innate immune system to eradicate pathogens. Both in vitro and in vivo evidence indicates that therapeutic anti tumor monoclonal antibodies (mAbs) can activate the complement system by the classical pathway. However, the contribution of complement to the efficacy of mAbs is still debated, mainly due to the lack of convincing data in patients. A beneficial role for complement during mAb therapy is supported by the fact that cancer cells often upregulate complement-regulatory proteins (CRPs). Polymorphisms in various CRPs were previously associated with complement-mediated disorders. In this review the role of complement in anti-tumor mAb therapy will be discussed with special emphasis on strategies aiming at modifying complement activity. In the future, clinical efficacy of mAbs with enhanced effector functions together with comprehensive analysis of polymorphisms in CRPs in mAb treated patients will further clarify the role of complement in mAb therapy. PMID- 25517301 TI - Biosimilars entering the clinic without animal studies. A paradigm shift in the European Union. AB - The concept of biosimilars has spread from Europe to other regions throughout the world, and many regions have drafted regulatory guidelines for their development. Recently, a paradigm shift in regulatory thinking on the non-clinical development of biosimilars has emerged in Europe: In vivo testing should follow a step-wise approach rather than being performed by default. To not require animal testing at all in some instances can well be seen as a revolutionary, but science-based, step. Here, we describe the internal discussions that led to this paradigm shift. The mainstay for the establishment of biosimilarity is the pharmaceutical comparability based on extensive physicochemical and biological characterization. Pharmacodynamic comparability can be evaluated in in vitro assays, whereas pharmacokinetic comparability is best evaluated in clinical studies. It is considered highly unlikely that new safety issues would arise when comparability has been demonstrated based on physicochemical and in vitro comparative studies. PMID- 25517302 TI - Physicochemical characterization of Remsima. AB - Remsima (infliximab) was recently approved as the world's first biosimilar monoclonal antibody (mAb) in both the European Union and Korea. To achieve this, extensive physicochemical characterization of Remsima in relation to Remicade was conducted in order to demonstrate the highly similar properties between the two molecules. A multitude of state-of-the-art analyses revealed that Remsima has identical primary as well as indistinguishable higher order structures compared with the original product. Monomer and aggregate contents of Remsima were also found to be comparable with those of Remicade. In terms of charge isoforms, although Remsima was observed to contain slightly less basic variants than the original antibody, the difference was shown to be largely due to the presence of C-terminal lysine. On the other hand, this lysine was found to be rapidly clipped inside serum in vitro and in vivo, suggesting it has no effect on the biological potency or safety of the drug. Analysis of the glycan contents of the antibodies showed comparable glycan types and distributions. Recent results of clinical studies have further confirmed that the two antibody products are highly similar to each other. Based on this research as well as previous clinical and non clinical comparability studies, Remsima can be considered as a highly similar molecule to Remicade in terms of physicochemical properties, efficacy, and safety for its final approval as a biosimilar product to Remicade. PMID- 25517300 TI - In vitro and in vivo modifications of recombinant and human IgG antibodies. AB - Tremendous knowledge has been gained in the understanding of various modifications of IgG antibodies, driven mainly by the fact that antibodies are one of the most important groups of therapeutic molecules and because of the development of advanced analytical techniques. Recombinant monoclonal antibody (mAb) therapeutics expressed in mammalian cell lines and endogenous IgG molecules secreted by B cells in the human body share some modifications, but each have some unique modifications. Modifications that are common to recombinant mAb and endogenous IgG molecules are considered to pose a lower risk of immunogenicity. On the other hand, modifications that are unique to recombinant mAbs could potentially pose higher risk. The focus of this review is the comparison of frequently observed modifications of recombinant monoclonal antibodies to those of endogenous IgG molecules. PMID- 25517303 TI - Bioanalytical strategy used in development of pharmacokinetic (PK) methods that support biosimilar programs. AB - The development of biosimilar products is expected to grow rapidly over the next five years as a large number of approved biologics reach patent expiry. The pathway to regulatory approval requires that similarity of the biosimilar to the reference product be demonstrated through physiochemical and structural characterization, as well as within in vivo studies that compare the safety and efficacy profiles of the products. To support nonclinical and clinical studies pharmacokinetic (PK) assays are required to measure the biosimilar and reference products with comparable precision and accuracy. The most optimal approach is to develop a single PK assay, using a single analytical standard, for quantitative measurement of the biosimilar and reference products in serum matrix. Use of a single PK assay for quantification of multiple products requires a scientifically sound testing strategy to evaluate bioanalytical comparability of the test products within the method, and provide a solid data package to support the conclusions. To meet these objectives, a comprehensive approach with scientific rigor was applied to the development and characterization of PK assays that are used in support of biosimilar programs. Herein we describe the bioanalytical strategy and testing paradigm that has been used across several programs to determine bioanalytical comparability of the biosimilar and reference products. Data from one program is presented, with statistical results demonstrating the biosimilar and reference products were bioanalytically equivalent within the method. The cumulative work has established a framework for future biosimilar PK assay development. PMID- 25517304 TI - Site-specific antibody-drug conjugation through an engineered glycotransferase and a chemically reactive sugar. AB - Conjugation of small molecule drugs to specific sites on the antibody molecule has been increasingly used for the generation of relatively homogenous preparations of antibody-drug conjugates (ADCs) with physicochemical properties similar or identical to those of the naked antibody. Previously a method for conjugation of small molecules to glycoproteins through existing glycans by using an engineered glycotransferase and a chemically reactive sugar as a handle was developed. Here, for the first time, we report the use of this method with some modifications to generate an ADC from a monoclonal antibody, m860, which we identified from a human naive phage display Fab library by panning against the extracellular domain of human HER2. M860 bound to cell surface-associated HER2 with affinity comparable to that of Trastuzumab (Herceptin), but to a different epitope. The m860ADC was generated by enzymatically adding a reactive keto galactose to m860 using an engineered glycotransferase and conjugating the reactive m860 to aminooxy auristatin F. It exhibited potent and specific cell killing activity against HER2 positive cancer cells, including trastuzumab resistant breast cancer cells. This unique ADC may have utility as a potential therapeutic for HER2 positive cancers alone or in combination with other drugs. Our results also validate the keto-galactose/engineered glycotransferase method for generation of functional ADCs, which could potentially also be used for preparation of ADCs targeting other disease markers. PMID- 25517306 TI - The level of HER2 expression is a predictor of antibody-HER2 trafficking behavior in cancer cells. AB - The receptor tyrosine kinase HER2 is known to play a central role in mitogenic signaling, motivating the development of targeted, HER2-specific therapies. However, despite the longstanding use of antibodies to target HER2, controversies remain concerning antibody/HER2 trafficking behavior in cancer cells. Understanding this behavior has direct relevance to the mechanism of action and effective design of such antibodies. In the current study, we analyzed the intracellular dynamics of trastuzumab, a marketed HER2-targeting antibody, in a panel of breast and prostate cancer cell lines that have a wide range of HER2 expression levels. Our results reveal distinct post-endocytic trafficking behavior of antibody-HER2 complexes in cells with different HER2 expression levels. In particular, HER2-overexpressing cells exhibit efficient HER2 recycling and limited reductions in HER2 levels upon antibody treatment, and consequently display a high level of antibody persistence on their plasma membrane. By contrast, in cells with low HER2 expression, trastuzumab treatment results in rapid antibody clearance from the plasma membrane combined with substantial decreases in HER2 levels and undetectable levels of recycling. A cell line with intermediate levels of HER2 expression exhibits both antibody recycling and clearance from the cell surface. Significantly, these analyses demonstrate that HER2 expression levels, rather than cell origin (breast or prostate), is a determinant of subcellular trafficking properties. Such studies have relevance to optimizing the design of antibodies to target HER2. PMID- 25517305 TI - Monomeric IgG1 Fc molecules displaying unique Fc receptor interactions that are exploitable to treat inflammation-mediated diseases. AB - The IgG1 Fc is a dimeric protein that mediates important antibody effector functions by interacting with Fcgamma receptors (FcgammaRs) and the neonatal Fc receptor (FcRn). Here, we report the discovery of a monomeric IgG1 Fc (mFc) that bound to FcgammaRI with very high affinity, but not to FcgammaRIIIa, in contrast to wild-type (dimeric) Fc. The binding of mFc to FcRn was the same as that of dimeric Fc. To test whether the high-affinity binding to FcgammaRI can be used for targeting of toxins, a fusion protein of mFc with a 38 kDa Pseudomonas exotoxin A fragment (PE38), was generated. This fusion protein killed FcgammaRI positive macrophage-like U937 cells but not FcgammaRI-negative cells, and mFc or PE38 alone had no killing activity. The lack of binding to FcgammaRIIIa resulted in the absence of Fc-mediated cytotoxicity of a scFv-mFc fusion protein targeting mesothelin. The pharmacokinetics of mFc in mice was very similar to that of dimeric Fc. The mFc's unique FcgammaRs binding pattern and related functionality, combined with its small size, monovalency and the preservation of FcRn binding which results in relatively long half-life in vivo, suggests that mFc has great potential as a component of therapeutics targeting inflammation mediated by activated macrophages overexpressing FcgammaRI and related diseases, including cancer. PMID- 25517307 TI - Effect of antigen-dependent clearance on pharmacokinetics of anti-heparin-binding EGF-like growth factor (HB-EGF) monoclonal antibody. AB - Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family and is an important therapeutic target in some types of human cancers. KM3566 is a mouse anti-HB-EGF monoclonal antibody that neutralizes HB-EGF activity by inhibiting the binding of HB-EGF to its receptors. Based on the results of our pharmacokinetics study, a humanized derivative antibody, KHK2866, is rapidly cleared from serum and shows nonlinear pharmacokinetics in cynomolgus monkeys. In this study, we examined the antigen-dependent clearance of an anti-HB-EGF monoclonal antibody in vivo and in vitro in order to pharmacokinetically explain the rapid elimination of KHK2866. We revealed tumor size-dependent clearance of KM3566 in in vivo studies and obtained good fits between the observed and simulated concentrations of KM3566 based on the two-compartment with a saturable route of clearance model. Furthermore, in vivo imaging analyses demonstrated tumor-specific distribution of KM3566. We then confirmed rapid internalization and distribution to lysosome of KM3566 at a cellular level. Moreover, we revealed that the amounts of HB-EGF on cell surface membrane were maintained even while HB EGF was internalized with KM3566. Recycled or newly synthesized HB-EGF, therefore, may contribute to a consecutive clearance of KM3566, which could explain a rapid clearance from serum. These data suggested that the rapid elimination in pharmacokinetics of KM3566 is due to antigen-dependent clearance. Given that its antigen is expressed in a wide range of normal tissue, it is estimated that the rapid elimination of KHK2866 from cynomolgus monkey serum is caused by antigen-dependent clearance. PMID- 25517308 TI - A novel approach to investigate the effect of methionine oxidation on pharmacokinetic properties of therapeutic antibodies. AB - Preserving the chemical and structural integrity of therapeutic antibodies during manufacturing and storage is a major challenge during pharmaceutical development. Oxidation of Fc methionines Met252 and Met428 is frequently observed, which leads to reduced affinity to FcRn and faster plasma clearance if present at high levels. Because oxidation occurs in both positions simultaneously, their individual contribution to the concomitant changes in pharmacokinetic properties has not been clearly established. A novel pH-gradient FcRn affinity chromatography method was applied to isolate three antibody oxidation variants from an oxidized IgG1 preparation based on their FcRn binding properties. Physico chemical characterization revealed that the three oxidation variants differed predominantly in the number of oxMet252 per IgG (0, 1, or 2), but not significantly in the content of oxMet428. Corresponding to the increase in oxMet252 content, stepwise reduction of FcRn affinity in vitro, as well as faster clearance and shorter terminal half-life, in huFcRn-transgenic mice were observed. A single Met252 oxidation per antibody had no significant effect on pharmacokinetics (PK) compared with unmodified IgG. Importantly, only molecules with both heavy chains oxidized at Met252 exhibited significantly faster clearance. In contrast, Met428 oxidation had no apparent negative effect on PK and even led to somewhat improved FcRn binding and slower clearance. This minor effect, however, seemed to be abrogated by the dominant effect of Met252 oxidation. The novel approach of functional chromatographic separation of IgG oxidation variants followed by physico-chemical and biological characterization has yielded the first experimentally-backed explanation for the unaltered PK properties of antibody preparations containing relatively high Met252 and Met428 oxidation levels. PMID- 25517309 TI - Rearranging the domain order of a diabody-based IgG-like bispecific antibody enhances its antitumor activity and improves its degradation resistance and pharmacokinetics. AB - One approach to creating more beneficial therapeutic antibodies is to develop bispecific antibodies (bsAbs), particularly IgG-like formats with tetravalency, which may provide several advantages such as multivalent binding to each target antigen. Although the effects of configuration and antibody-fragment type on the function of IgG-like bsAbs have been studied, there have been only a few detailed studies of the influence of the variable fragment domain order. Here, we prepared four types of hEx3-scDb-Fc, IgG-like bsAbs, built from a single-chain hEx3-Db (humanized bispecific diabody [bsDb] that targets epidermal growth factor receptor and CD3), to investigate the influence of domain order and fusion manner on the function of a bsDb with an Fc fusion format. Higher cytotoxicities were observed with hEx3-scDb-Fcs with a variable light domain (VL)-variable heavy domain (VH) order (hEx3-scDb-Fc-LHs) compared with a VH-VL order, indicating that differences in the Fc fusion manner do not affect bsDb activity. In addition, flow cytometry suggested that the higher cytotoxicities of hEx3-scDb-Fc-LH may be attributable to structural superiority in cross-linking. Interestingly, enhanced degradation resistance and prolonged in vivo half-life were also observed with hEx3-scDb-Fc-LH. hEx3-scDb-Fc-LH and its IgG2 variant exhibited intense in vivo antitumor effects, suggesting that Fc-mediated effector functions are dispensable for effective anti-tumor activities, which may cause fewer side effects. Our results show that merely rearranging the domain order of IgG-like bsAbs can enhance not only their antitumor activity, but also their degradation resistance and in vivo half-life, and that hEx3-scDb-Fc-LHs are potent candidates for next generation therapeutic antibodies. PMID- 25517310 TI - Framework selection can influence pharmacokinetics of a humanized therapeutic antibody through differences in molecule charge. AB - Pharmacokinetic (PK) testing of a humanized (kappaI, VH3 framework) and affinity matured anti-hepatitis C virus E2-glycoprotein (HCV-E2) antibody (hu5B3.kappa1VH3.v3) in rats revealed unexpected fast clearance (34.9 mL/day/kg). This antibody binds to the rat recycling receptor FcRn as expected for a human IgG1 antibody and does not display non-specific binding to baculovirus particles in an assay that is correlated with fast clearance in cynomolgus monkey. The antigen is not expressed in rat so target-dependent clearance does not contribute to PK. Removal of the affinity maturation changes (hu5B3.kappa1VH3.v1) did not restore normal clearance. The antibody was re-humanized on a kappa4, VH1 framework and the non-affinity matured version (hu5B3.kappa4VH1.v1) was shown to have normal clearance (8.5 mL/day/kg). Since the change in framework results in a lower pI, primarily due to more negative charge on the kappa4 template, the effect of additional charge variation on antibody PK was tested by incorporating substitutions obtained through phage display affinity maturation of hu5B3.kappa1VH3.v1. A variant having a pI of 8.61 gave very fast clearance (140 mL/day/kg) whereas a molecule with pI of 6.10 gave slow clearance (5.8 mL/kg/day). Both antibodies exhibited comparable binding to rat FcRn, but biodistribution experiments showed that the high pI variant was catabolized in liver and spleen. These results suggest antibody charge can have an effect on PK through alterations in antibody catabolism independent of FcRn-mediated recycling. Furthermore, introduction of affinity maturation changes into the lower pI framework yielded a candidate with PK and virus neutralization properties suitable for clinical development. PMID- 25517311 TI - A monoclonal antibody against hinge-cleaved IgG restores effector function to proteolytically-inactivated IgGs in vitro and in vivo. AB - We report a chimeric monoclonal antibody (mAb) directed to a neo-epitope that is exposed in the IgG lower hinge following proteolytic cleavage. The mAb, designated 2095-2, displays specificity for IdeS-generated F(ab')2 fragments, but not for full-length IgG or for closely-related F(ab')2 fragments generated with other proteases. A critical component of the specificity is provided by the C terminal amino acid of the epitope corresponding to gly-236 in the IgG1 (also IgG4) hinge. By its ability to bind to IdeS-cleaved anti-CD20 mAb, mAb 2095-2 fully restored antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against WIL2-S cells to the otherwise inactive anti-CD20 IgG1 F(ab')2 fragment. Similarly, 2095-2 reinstated ADCC against MDA-MB-231 cells to an anti-CD142 IgG1 F(ab')2 fragment. mAb 2095-2 was also capable of eliciting both CDC and ADCC to IgG4 F(ab')2 fragments, an IgG subclass that has weaker ADCC and CDC when intact relative to intact IgG1. The in vitro cell-based efficacy of 2095-2 was extended to the in vivo setting using platelets as a cell clearance surrogate. In a canine model, the co-administration of 2095-2 together with IdeS-generated, platelet-targeting anti-CD41/61 F(ab')2 fragment not only restored platelet clearance, but did so at a rate and extent of clearance that exceeded that of intact anti-CD41/61 IgG at comparable concentrations. To further explore this unexpected amplification effect, we conducted a rat study in which 2095-2 was administered at a series of doses in combination with a fixed dose of anti-CD41/61 F(ab')2 fragments. Again, the combination, at ratios as low as 1:10 (w/w) 2095-2 to F(ab')2, proved more effective than the anti-CD41/61 IgG1 alone. These findings suggest a novel mechanism for enhancing antibody-mediated cell-killing effector functions with potential applications in pathologic settings such as tumors and acute infections where protease activity is abundant. PMID- 25517312 TI - A general approach to antibody thermostabilization. AB - Antibody engineering to enhance thermostability may enable further application and ease of use of antibodies across a number of different areas. A modified human IgG framework has been developed through a combination of engineering approaches, which can be used to stabilize antibodies of diverse specificity. This is achieved through a combination of complementarity-determining region (CDR)-grafting onto the stable framework, mammalian cell display and in vitro somatic hypermutation (SHM). This approach allows both stabilization and maturation to affinities beyond those of the original antibody, as shown by the stabilization of an anti-HA33 antibody by approximately 10 degrees C and affinity maturation of approximately 300-fold over the original antibody. Specificities of 10 antibodies of diverse origin were successfully transferred to the stable framework through CDR-grafting, with 8 of these successfully stabilized, including the therapeutic antibodies adalimumab, stabilized by 9.9 degrees C, denosumab, stabilized by 7 degrees C, cetuximab stabilized by 6.9 degrees C and to a lesser extent trastuzumab stabilized by 0.8 degrees C. This data suggests that this approach may be broadly useful for improving the biophysical characteristics of antibodies across a number of applications. PMID- 25517313 TI - Recombinant H22(scFv) blocks CD64 and prevents the capture of anti-TNF monoclonal antibody. A potential strategy to enhance anti-TNF therapy. AB - Tumor necrosis factor (TNF) is a pro-inflammatory cytokine that plays a critical role in many inflammatory diseases. Soluble TNF can be neutralized by monoclonal antibodies (mAbs), and this is a widely-used therapeutic approach. However, some patients do not respond to anti-TNF therapy due to the increased expression of CD64 on monocytes and macrophages. A recent study has shown that CD64 captures anti-TNF mAbs via their Fcgamma domain, which induces the transcription of pro inflammatory genes. Specific blocking of CD64 could therefore be a promising strategy to improve the response to anti-TNF therapy. We used the CD64-specific antibody fragment H22(scFv) and tested its activity against the human CD64(+) cell line HL-60. When stimulated with interferon gamma (IFN-gamma), these cells represent a pro-inflammatory phenotype of the monocyte/macrophage lineage. We found that H22(scFv) binds selectively to and blocks CD64, preventing the capture of anti-TNF mAb. Importantly, H22(scFv) itself does not induce CD64 activation. We also found that transmembrane TNF on HL-60 cells stimulated with IFN-gamma also contributes to the capture of anti-TNF mAb, although via their Fab domain. In conclusion, the specific blocking of CD64 by H22(scFv) could be used a possible anti-inflammatory mechanism for potentiating the effect of anti-TNF antibodies. PMID- 25517314 TI - Failure to upregulate cell surface PD-1 is associated with dysregulated stimulation of T cells by TGN1412-like CD28 superagonist. AB - The CD28 superagonist (CD28SA) TGN1412 was administered to humans as an agent that can selectively activate and expand regulatory T cells but resulted in uncontrolled T cell activation accompanied by cytokine storm. The molecular mechanisms that underlie this uncontrolled T cell activation are unclear. Physiological activation of T cells leads to upregulation of not only activation molecules but also inhibitory receptors such as PD-1. We hypothesized that the uncontrolled activation of CD28SA-stimulated T cells is due to both the enhanced expression of activation molecules and the lack of or reduced inhibitory signals. In this study, we show that anti-CD3 antibody-stimulated human T cells undergo time-limited controlled DNA synthesis, proliferation and interleukin-2 secretion, accompanied by PD-1 expression. In contrast, CD28SA-activated T cells demonstrate uncontrolled activation parameters including enhanced expression of LFA-1 and CCR5 but fail to express PD-1 on the cell surface. We demonstrate the functional relevance of the lack of PD-1 mediated regulatory mechanism in CD28SA-stimulated T cells. Our findings provide a molecular explanation for the dysregulated activation of CD28SA-stimulated T cells and also highlight the potential for the use of differential expression of PD-1 as a biomarker of safety for T cell immunostimulatory biologics. PMID- 25517315 TI - Inhibitors of SRC kinases impair antitumor activity of anti-CD20 monoclonal antibodies. AB - Clinical trials with SRC family kinases (SFKs) inhibitors used alone or in a combination with anti-CD20 monoclonal antibodies (mAbs) are currently underway in the treatment of B-cell tumors. However, molecular interactions between these therapeutics have not been studied so far. A transcriptional profiling of tumor cells incubated with SFKs inhibitors revealed strong downregulation of MS4A1 gene encoding CD20 antigen. In a panel of primary and established B-cell tumors we observed that SFKs inhibitors strongly affect CD20 expression at the transcriptional level, leading to inhibition of anti-CD20 mAbs binding and increased resistance of tumor cells to complement-dependent cytotoxicity. Activation of the AKT signaling pathway significantly protected cells from dasatinib-triggered CD20 downregulation. Additionally, SFKs inhibitors suppressed antibody-dependent cell-mediated cytotoxicity by direct inhibition of natural killer cells. Abrogation of antitumor activity of rituximab was also observed in vivo in a mouse model. Noteworthy, the effects of SFKs inhibitors on NK cell function are largely reversible. The results of our studies indicate that development of optimal combinations of novel treatment modalities with anti-CD20 mAbs should be preceded by detailed preclinical evaluation of their effects on target cells. PMID- 25517316 TI - The human Mullerian inhibiting substance type II receptor as immunotherapy target for ovarian cancer. Validation using the mAb 12G4. AB - Ovarian cancer has the highest mortality rate among gynecologic malignancies. The monoclonal antibody 12G4 specifically recognizes the human Mullerian inhibiting substance type II receptor (MISRII) that is strongly expressed in human granulosa cell tumors (GCT) and in the majority of human epithelial ovarian cancers (EOC). To determine whether MISRII represents an attractive target for antibody-based tumor therapy, we first confirmed by immunohistochemistry with 12G4 its expression in all tested GCT samples (4/4) and all, but one, EOC human tissue specimens (13/14). We then demonstrated in vitro the internalization of 12G4 in MISRII(high)COV434 cells after binding to MISRII and its ability to increase the apoptosis rate (FACS, DNA fragmentation) in MISRII(high)COV434 (GCT) and MISRII(medium)NIH-OVCAR-3 (EOC) cells that express different levels of MISRII. A standard (51)Cr release assay showed that 12G4 mediates antibody-dependent cell meditated cytotoxicity. Finally, in vivo assessment of 12G4 anti-tumor effects showed a significant reduction of tumor growth and an increase of the median survival time in mice xenografted with MISRII(high)COV434 or MISRII(medium)NIH OVCAR-3 cells and treated with 12G4 in comparison to controls treated with an irrelevant antibody. Altogether, our data indicate that MISRII is a new promising target for the control of ovarian GCTs and EOCs. A humanized version of the 12G4 antibody, named 3C23K, is in development for the targeted therapy of MISRII positive gynecologic cancers. PMID- 25517317 TI - Interference of HCV replication by cell penetrable human monoclonal scFv specific to NS5B polymerase. AB - A new class of hepatitis C virus (HCV)-targeted therapeutics that is safe, broadly effective and can cope with virus mutations is needed. The HCV's NS5B is highly conserved and different from human protein, and thus it is an attractive target for anti-HCV therapeutics development. In this study, NS5B bound-phage clones selected from a human single chain variable antibody fragment (scFv) phage display library were used to transform appropriate E. coli bacteria. Two scFv inhibiting HCV polymerase activity were selected. The scFvs were linked to a cell penetrating peptide to make cell penetrable scFvs. The transbodies reduced the HCV RNA and infectious virus particles released into the culture medium and inside hepatic cells transfected with a heterologous HCV replicon. They also rescued the innate immune response of the transfected cells. Phage mimotope search and homology modeling/molecular docking revealed the NS5B subdomains and residues bound by the scFvs. The scFv mimotopes matched residues of the NS5B, which are important for nucleolin binding during HCV replication, as well as residues that interconnect the fingers and thumb domains for forming a polymerase active groove. Both scFvs docked on several residues at the thumb armadillo-like fold that could be the polymerase interactive sites of other viral/host proteins for the formation of the replication complex and replication initiation. In conclusion, human transbodies that inhibited HCV RdRp activity and HCV replication and restored the host innate immune response were produced. They are potentially future interferon-free anti-HCV candidates, particularly in combination with other cognates that are specific to NS5B epitopes and other HCV enzymes. PMID- 25517321 TI - Humane endings: AVMA symposium informs "living document" on animal death. PMID- 25517322 TI - Questions ethics of crating. PMID- 25517318 TI - Targeting arterial wall sulfated glycosaminoglycans in rabbit atherosclerosis with a mouse/human chimeric antibody. AB - The progression of atherosclerosis is favored by increasing amounts of chondroitin sulfate proteoglycans in the artery wall. We previously reported the reactivity of chP3R99 monoclonal antibody (mAb) with sulfated glycosaminoglycans and its association with the anti-atherogenic properties displayed. Now, we evaluated the accumulation of this mAb in atherosclerotic lesions and its potential use as a probe for specific in vivo detection of the disease. Atherosclerosis was induced in NZW rabbits (n = 14) by the administration of Lipofundin 20% using PBS-receiving animals as control (n = 8). Accumulation of chP3R99 mAb in atherosclerotic lesions was assessed either by immunofluorescence detection of human IgG in fresh-frozen sections of aorta, or by immunoscintigraphy followed by biodistribution of the radiotracer upon administration of (99m)Tc-chP3R99 mAb. Immunofluorescence studies revealed the presence of chP3R99 mAb in atherosclerotic lesions 24 h after intravenous administration, whereas planar images showed an evident accumulation of (99m)Tc chP3R99 mAb in atherosclerotic rabbit carotids. Accordingly, (99m)Tc-chP3R99 mAb uptake by lesioned aortic arch and thoracic segment was increased 5.6-fold over controls and it was 3.9-folds higher in carotids, in agreement with immunoscintigrams. Moreover, the deposition of (99m)Tc-chP3R99 mAb in the artery wall was associated both with the presence and size of the lesions in the different portions of evaluated arteries and was greater than in non-targeted organs. In conclusion, chP3R99 mAb preferentially accumulates in arterial atherosclerotic lesions supporting the potential use of this anti glycosaminoglycans antibody for diagnosis and treatment of atherosclerosis. PMID- 25517323 TI - What is your diagnosis? Leiomyosarcoma. PMID- 25517319 TI - Effect of formulation on the stability and aerosol performance of a nebulized antibody. AB - Most monoclonal antibodies (mAbs) are administered to patients intravenously to ensure high bioavailability as rapidly as possible. The airways, however, are an attractive delivery route for mAbs for the treatment of lung diseases, making it possible to increase their concentration in the target organ while limiting their systemic passage. Several challenges must be overcome for translation into clinical practice. For example, the drug and device must be paired for the efficient and reliable deposition of a pharmacologically active and safe mAb in the lung region of interest. Mesh nebulizers appear to be the most effective aerosol-producing devices for delivering large amounts of biopharmaceutical while limiting protein instability during nebulization. We used metrological and analytic methods to analyze the effect of both antibody concentration and surfactant addition on aerosol performance and antibody integrity. These two factors had a limited effect on aerosol performance, but affected antibody aggregation. The addition of surfactants to antibody formulations at concentrations appropriate for lung administration markedly reduced the formation of medium or large aggregates, as shown by dynamic light scattering and fluorescence microscopy. Aggregation was also dependent on the type of mesh nebulizer, highlighting the need to optimize drug and device together. PMID- 25517324 TI - What is your diagnosis? Tension pneumothorax secondary to pulmonary neoplasia. PMID- 25517325 TI - Correction: Ultrasonographic visualization of the liver in sites recommended for blind percutaneous liver biopsy in horses. PMID- 25517326 TI - What is your neurologic diagnosis? Partial rupture of the calcaneal tendon. PMID- 25517327 TI - Pathology in practice. A coyote with sarcoptic mange. PMID- 25517328 TI - Common physical and functional changes associated with aging in dogs. PMID- 25517329 TI - Defining healthy aging in older dogs and differentiating healthy aging from disease. PMID- 25517330 TI - Evaluation of serum biochemical marker concentrations and survival time in dogs with protein-losing enteropathy. AB - OBJECTIVE: To evaluate serum concentrations of biochemical markers and survival time in dogs with protein-losing enteropathy (PLE). DESIGN: Prospective study. ANIMALS: 29 dogs with PLE and 18 dogs with food-responsive diarrhea (FRD). PROCEDURES: Data regarding serum concentrations of various biochemical markers at the initial evaluation were available for 18 of the 29 dogs with PLE and compared with findings for dogs with FRD. Correlations between biochemical marker concentrations and survival time (interval between time of initial evaluation and death or euthanasia) for dogs with PLE were evaluated. RESULTS: Serum C-reactive protein concentration was high in 13 of 18 dogs with PLE and in 2 of 18 dogs with FRD. Serum concentration of canine pancreatic lipase immunoreactivity was high in 3 dogs with PLE but within the reference interval in all dogs with FRD. Serum alpha1-proteinase inhibitor concentration was less than the lower reference limit in 9 dogs with PLE and 1 dog with FRD. Compared with findings in dogs with FRD, values of those 3 variables in dogs with PLE were significantly different. Serum calprotectin (measured by radioimmunoassay and ELISA) and S100A12 concentrations were high but did not differ significantly between groups. Seventeen of the 29 dogs with PLE were euthanized owing to this disease; median survival time was 67 days (range, 2 to 2,551 days). CONCLUSIONS AND CLINICAL RELEVANCE: Serum C reactive protein, canine pancreatic lipase immunoreactivity, and alpha1 proteinase inhibitor concentrations differed significantly between dogs with PLE and FRD. Most initial biomarker concentrations were not predictive of survival time in dogs with PLE. PMID- 25517331 TI - Survival analysis of critically ill dogs with hypotension with or without hyperlactatemia: 67 cases (2006-2011). AB - OBJECTIVE: To determine whether critically ill hypotensive dogs without hyperlactatemia have the same prognosis as critically ill hypotensive dogs with hyperlactatemia. DESIGN: Retrospective case series. ANIMALS: 67 critically ill dogs with hypotension. PROCEDURES: Medical records were searched from January 2006 through December 2011 for dogs that were hospitalized in the intensive care unit and that had hypotension and measurement of blood lactate concentration. Blood lactate concentration, systolic blood pressure, and survival rate were compared between hypotensive dogs with and without hyperlactatemia. RESULTS: 19 of 67 (28%) dogs survived and were discharged from the hospital. Hypotensive dogs without hyperlactatemia had a significantly higher systolic blood pressure and were 3.23 (95% confidence interval, 1.04 to 9.43) times as likely to survive, compared with hypotensive dogs with hyperlactatemia. Age, weight, severity of clinical illness, and duration of hospitalization did not differ significantly between hypotensive dogs with and without hyperlactatemia. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that hypotensive dogs without hyperlactatemia had a better prognosis and chance of surviving to hospital discharge than did hypotensive dogs with hyperlactatemia. Because blood lactate concentration was negatively associated with systolic blood pressure and survival probability, it may be a useful metric for determining the prognosis of hypotensive dogs. PMID- 25517332 TI - Exogenous thyrotoxicosis in dogs attributable to consumption of all-meat commercial dog food or treats containing excessive thyroid hormone: 14 cases (2008-2013). AB - OBJECTIVE: To describe findings in dogs with exogenous thyrotoxicosis attributable to consumption of commercially available dog foods or treats containing high concentrations of thyroid hormone. DESIGN: Retrospective and prospective case series. ANIMALS: 14 dogs. PROCEDURES: Medical records were retrospectively searched to identify dogs with exogenous thyrotoxicosis attributable to dietary intake. One case was found, and subsequent cases were identified prospectively. Serum thyroid hormone concentrations were evaluated before and after feeding meat-based products suspected to contain excessive thyroid hormone was discontinued. Scintigraphy was performed to evaluate thyroid tissue in 13 of 14 dogs before and 1 of 13 dogs after discontinuation of suspect foods or treats. Seven samples of 5 commercially available products fed to 6 affected dogs were analyzed for thyroxine concentration; results were subjectively compared with findings for 10 other commercial foods and 6 beef muscle or liver samples. RESULTS: Total serum thyroxine concentrations were high (median, 8.8 MUg/dL; range, 4.65 to 17.4 MUg/dL) in all dogs at initial evaluation; scintigraphy revealed subjectively decreased thyroid gland radionuclide in 13 of 13 dogs examined. At >= 4 weeks after feeding of suspect food or treats was discontinued, total thyroxine concentrations were within the reference range for all dogs and signs associated with thyrotoxicosis, if present, had resolved. Analysis of tested food or treat samples revealed a median thyroxine concentration for suspect products of 1.52 MUg of thyroxine/g, whereas that of unrelated commercial foods was 0.38 MUg of thyroxine/g. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that thyrotoxicosis can occur secondary to consumption of meat-based products presumably contaminated by thyroid tissue, and can be reversed by identification and elimination of suspect products from the diet. PMID- 25517333 TI - Use of laterally placed vacuum drains for management of aural hematomas in five dogs. AB - CASE DESCRIPTION: 5 dogs (a Newfoundland, Golden Retriever, Shiba Inu, Staffordshire Terrier, and Vizsla) were referred for evaluation and treatment of unilateral aural hematomas within a week after their formation. CLINICAL FINDINGS: Aural hematomas involved the left (3) or right (2) ears. TREATMENT AND OUTCOME: With patients under anesthesia, the aural hematomas were approached surgically from the convex, or lateral, pinnal surface. Two small incisions were used to position a vacuum drain into the incised hematoma cavity. The drain exited at the base of the pinna and adjacent cervical skin. The free end of the drain was attached to a vacuum reservoir for 18 to 21 days. Drains and skin sutures were removed at this time along with the protective Elizabethan collar. All hematomas resolved and surgical sites healed during the minimum 6-month follow-up period. Cosmetic results were considered excellent in 4 of 5 patients. Slight wrinkling of the pinna in 1 patient resulted from asymmetric enlargement of the cartilaginous walls of the hematoma, where vacuum application resulted in a slight folding of the redundant lateral cartilage wall. CLINICAL RELEVANCE: The described treatment was efficient, economical, and minimally invasive and required no bandaging or wound care. Placement of the drain tubing on the convex (lateral) aspect sheltered the system from displacement by patients with an Elizabethan collar in place. Overall cosmetic results were excellent; asymmetric enlargement of the cartilaginous walls of the hematoma with slight folding of the pinna was seen in 1 patient. PMID- 25517334 TI - Comparison of pharmacokinetics and milk elimination of flunixin in healthy cows and cows with mastitis. AB - OBJECTIVE: To determine whether pharmacokinetics and milk elimination of flunixin and 5-hydroxy flunixin differed between healthy and mastitic cows. DESIGN: Prospective controlled clinical trial. ANIMALS: 20 lactating Holstein cows. PROCEDURES: Cows with mastitis and matched control cows received flunixin IV, ceftiofur IM, and cephapirin or ceftiofur, intramammary. Blood samples were collected before (time 0) and 0.25, 0.5, 1, 2, 4, 8, 12, 24, and 36 hours after flunixin administration. Composite milk samples were collected at 0, 2, 12, 24, 36, 48, 60, 72, 84, and 96 hours. Plasma and milk samples were analyzed by use of ultra-high-performance liquid chromatography with mass spectrometric detection. RESULTS: For flunixin in plasma samples, differences in area under the concentration-time curve and clearance were detected between groups. Differences in flunixin and 5-hydroxy flunixin concentrations in milk were detected at various time points. At 36 hours after flunixin administration (milk withdrawal time), 8 cows with mastitis had 5-hydroxy flunixin concentrations higher than the tolerance limit (ie, residues). Flunixin residues persisted in milk up to 60 hours after administration in 3 of 10 mastitic cows. CONCLUSIONS AND CLINICAL RELEVANCE: Pharmacokinetics and elimination of flunixin and 5-hydroxy flunixin in milk differed between mastitic and healthy cows, resulting in violative residues. This may partially explain the high number of flunixin residues reported in beef and dairy cattle. This study also raised questions as to whether healthy animals should be used when determining withdrawal times for meat and milk. PMID- 25517335 TI - Systematic review and meta-analysis of the effectiveness of commercially available vaccines against bovine herpesvirus, bovine viral diarrhea virus, bovine respiratory syncytial virus, and parainfluenza type 3 virus for mitigation of bovine respiratory disease complex in cattle. AB - OBJECTIVE: To evaluate and analyze data from controlled studies on the effectiveness of vaccinating cattle with commercially available viral antigen vaccines for mitigation of the effects of bovine respiratory disease complex (BRDC). DESIGN: Systematic review and meta-analysis. SAMPLE: 31 studies comprising 88 trials. PROCEDURES: Studies that reported the effectiveness of commercially available bovine herpesvirus-1 (BHV-1), bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), and parainfluenza type 3 virus (PI3) vaccines for protection of cattle against BRDC or its components were included in the analysis. Studies or trials were categorized as natural exposure or experimental challenge and were further divided by the viral antigen evaluated and vaccine type (modified-live virus [MLV] or inactivated vaccine). Meta analysis was performed; summary Mantel-Haenszel risk ratios were determined, and Forest plots were generated. RESULTS: In natural exposure trials, beef calves vaccinated with various antigen combinations had a significantly lower BRDC morbidity risk than did nonvaccinated control calves. In trials evaluating BHV-1 and MLV BVDV vaccines in experimental challenge models, vaccinated calves had a lower BRDC morbidity risk than did control calves; however, in experimental challenge trials evaluating MLV BRSV and PI3 vaccines, no significant difference in morbidity or mortality risk was found between vaccinated and control calves. CONCLUSIONS AND CLINICAL RELEVANCE: Estimating clinical efficacy from results of experimental challenge studies requires caution because these models differ substantially from those involving natural exposure. The literature provides data but does not provide sufficiently strong evidence to guide definitive recommendations for determining which virus components are necessary to include in a vaccination program for prevention or mitigation of BRDC in cattle. PMID- 25517337 TI - Evaluation of the efficiency of different disruption methods on yeast cell wall preparation for beta-glucan isolation. AB - Selected methods for yeast cell disruption were evaluated to establish their suitability for cell wall preparation in the process of beta-glucan isolation. The effect of different disruption methods on contents of total saccharides, beta glucans and proteins in the produced cell walls preparations was analyzed. The degree of cell wall purification from intracellular components was established on the basis of the ratio of solubilised material. The investigated methods included: cell exposure to hot water (autoclaving), thermally-induced autolysis, homogenization in a bead mill, sonication and their combinations. Experimental systems were prepared in water (pH 5.0 and pH 7.0) and Tris-HCl buffer (pH 8.0). The Saccharomyces cerevisiae yeast cell wall preparations with the highest degree of cytosol component release and purification of beta-glucans were produced by 30 min of cell homogenization with zirconium-glass beads (0.5 mm in diameter). This was confirmed by the highest ratio of solubilised material (approx. 64%-67%). The thus-produced preparations contained ca. 60% of total saccharides, 13%-14% of beta(1,3)/(1,6)-glucans, and approx. 35% of crude proteins. Similar results were obtained after autolysis coupled with bead milling as well as with sonication, but the time required for these processes was more than 24 h. Homogenization in a bead mill could be valuable for general isolation procedures because allows one to eliminate the different autolytic activity of various yeast strains. PMID- 25517338 TI - Aortic relaxant activity of Crataegus gracilior Phipps and identification of some of its chemical constituents. AB - This study focused on the assessment of the vasorelaxant activity of the organic and aqueous extracts obtained from leaves and fruits of a Mexican hawthorn (Crataegus gracilior) on isolated rat aorta, and on the purification and identification of some of their secondary metabolites by the use of chromatographic and spectroscopic techniques. The results obtained showed that the methanol extract has a significantly more potent and effective vasorelaxant effect than the other tested extracts, with an EC50 = 8.69 +/- 4.34 ug/mL and an Emax = 94.6% +/- 11.30%, values that are close to that of acetylcholine, the positive control. From the same extract, two major triterpenes were isolated and identified as ursolic and corosolic acids by comparison of their experimental NMR spectroscopic data with those reported in the literature. Chlorogenic acid, rutin, quercetin, kaempferol and (+)-catechin were also identified using HPLC coupled with PDAD. All these compounds have already been proven to possess on their own antihypertensive effect and other benefits on cardiovascular diseases and they can support, at least in part, the traditional use of this plant species. PMID- 25517339 TI - Four new furostanol saponins from the rhizomes and roots of Smilax scobinicaulis and their cytotoxicity. AB - Four new furostanol saponins 1-4, along with two known furostanol saponins 5 and 6 and one known spirostanol saponin 7 were isolated from the rhizomes and roots of Smilax scobinicaulis. The structures of the new saponins were elucidated as 26 O-beta-D-glucopyranoside-3beta,26-dihydroxy-(25R)-5alpha-furostan-22-methoxyl-6 one-3-O-alpha-L-arabinopyranosyl-(1->6)-beta-D-glucopyranoside (1), 26-O-beta-D glucopyranoside-3beta,26-dihydroxy-(25R)-5alpha-furostan-22-methoxyl-6-one (2), 26-O-beta-D-glucopyranoside-3beta,26-dihydroxy-(25R)-5alpha-furostan-20(22)-en-6 one (3), 26-O-beta-D-glucopyranoside-3beta,23,26-trihydroxy-(23R, 25R)-5alpha furostan-20(22)-en-6-one (4) on the basis of spectroscopic analysis. The isolated saponins were evaluated for cytotoxic activity against two human cancer cell lines including Hela (cervical carcinoma) and SMMC-7221 (hepatocellular carcinoma). Compounds 1 and 7 demonstrated cytotoxicity against the tested cell lines. PMID- 25517340 TI - Comparative study of the structural and vibroelectronic properties of porphyrin and its derivatives. AB - Density functional theory (DFT and time-dependent-DFT (TD-DFT) were employed to investigate the vibroelectronic structural properties of porphyrin and some derivatives: unsubstituted porphyrin (TPyr), meso-tetraphenylporphyrin (TPP), meso-tetrakis(p-sulfonatophenyl)porphyrin (TSPP), protonated-TPyr (H2TPyr), deuterated-H2TPyr (D4TPyr), protonated-TPP (H2TPP) and deuterated-H2TPP (D4TPP), protonated TSPP (H2TSPP), deuterated-H2TSPP (D4TSPP), dicationic TSPP (H6TSPP) and deuterated-H6TSPP (D8TSPP). The possible internal conversion (IC) and intersystem crossing (ISC) processes of these compounds were investigated. Finally, the relaxed ground state potential energy surface (PES) (S0), and singlet (Sn, n = 1-24) and triplet (Tn) excited state PESs of the TSPP molecule were calculated as function of the dihedral angle (Calpha-Cm-Cphi-C(ph)) rotation. The results of the calculations indicated that while the meso substitutions caused a significant shift in frequencies when the meso-carbons within the parent-porphine (or TPyr) are involved in the vibrational motion of molecules; the protonation of the N atoms at the porphine/porphyrin core causes a significant blue shift when the H on the N atoms within the pyrroline are dominantly involved in the vibrational motions. The deuteration of N atoms not only caused a red-shift in the frequencies of the corresponding peaks below 1600 cm(-1), but also produced new vibrational modes of frequencies in the 2565-2595 cm(-1) range caused by the N-D bond stretching. Similarly, the deuteration of O atoms within the sulfonato groups (-SO3(-)) exhibited a new peak at around 2642 cm(-1) due to O-D bond stretching. The measured Raman spectrum of the H2TSPP is assigned based on the predicted Raman spectra of the compounds studied here and measured Raman spectrum of the TPP (from our previous work). The IR spectrum is assigned based on our calculations and measured IR spectra obtained from the literature. The results of the TD-DFT calculations did not only indicate that the meso-substitution and protonation of the porphyrin bring about a significant read shift in the electronic transitions; but also provided a strong evidence for the IC from the Soret band to Q-bands beside possibility of the ISC process; its existence depend on the other excited state process such as much faster vibrational relaxation; the IC and etc. The ground state PES curve (S0) of the ionic TSPP exhibited two minima at the dihedral angle (Calpha-Cm-Cphi-C) of about 66 degrees (corresponds to the lowest ground state) and 110 degrees (corresponds to next energetically stable state or the local minima). The energy deference between these two minima is 0.0132 eV (or 106 cm(-1)) and the highest potential energy barrier when undergoing from the lowest ground state to this local state is only 0.0219 eV (177 cm(-1); which is compatible with the thermal energy (kT) at 298 K is 207.2 cm(-1). PMID- 25517341 TI - Efficient synthesis and reaction kinetics of readily water soluble esters containing sulfonic groups. AB - A series of various readily water soluble esters were synthesized by a very efficient procedure. These compounds can be useful as thermosensitive tracers for studying the cooling progress in a low enthalpy georeservoir exploitable by double flash geothermal power plant systems. The kinetics of their hydrolysis was investigated. Acylation of primary alcohols or phenols was carried out by a method based on a single-phase solvent system consisting of ethyl acetate acting as an organic solvent and triethylamine acting as a catalyst. Products were characterized by 1H-NMR, and 13C-NMR. PMID- 25517342 TI - Stability of anthocyanins from red grape skins under pressurized liquid extraction and ultrasound-assisted extraction conditions. AB - The stability of anthocyanins from grape skins after applying different extraction techniques has been determined. The following compounds, previously extracted from real samples, were assessed: delphinidin 3-glucoside, cyanidin 3 glucoside, petunidin 3-glucoside, peonidin 3-glucoside, malvidin 3-glucoside, peonidin 3-acetylglucoside, malvidin 3-acetylglucoside, malvidin 3 caffeoylglucoside, petunidin 3-p-coumaroylglucoside and malvidin 3-p coumaroylglucoside (trans). The techniques used were ultrasound-assisted extraction and pressurized liquid extraction. In ultrasound-assisted extraction, temperatures up to 75 degrees C can be applied without degradation of the aforementioned compounds. In pressurized liquid extraction the anthocyanins were found to be stable up to 100 degrees C. The relative stabilities of both the glycosidic and acylated forms were evaluated. Acylated derivatives were more stable than non-acylated forms. The differences between the two groups of compounds became more marked on working at higher temperatures and on using extraction techniques with higher levels of oxygen in the extraction media. PMID- 25517343 TI - Antiprotozoal activity against Entamoeba histolytica of plants used in northeast Mexican traditional medicine. Bioactive compounds from Lippia graveolens and Ruta chalepensis. AB - Amoebiasis caused by Entamoeba histolytica is associated with high morbidity and mortality is becoming a major public health problem worldwide, especially in developing countries. Because of the side-effects and the resistance that pathogenic protozoa build against the standard antiparasitic drugs, e.g., metronidazole, much recent attention has been paid to plants used in traditional medicine around the world in order to find new antiprotozoal agents. We collected 32 plants used in Northeast Mexican traditional medicine and the methanolic extracts of these species were screened for antiprotozoal activity against E. histolytica trophozoites using in vitro tests. Only 18 extracts showed a significant inhibiting activity and among them six plant extracts showed more than 80% growth inhibition against E. histolytica at a concentration of 150 ug/mL and the IC50 values of these extracts were determined. Lippia graveolens Kunth and Ruta chalepensis Pers. showed the more significant antiprotozoal activity (91.54% and 90.50% growth inhibition at a concentration of 150 ug/mL with IC50 values of 59.14 and 60.07 ug/mL, respectively). Bioassay-guided fractionation of the methanolic extracts from these two plants afforded carvacrol (1) and chalepensin (2), respectively, as bioactive compounds with antiprotozoal activity. PMID- 25517345 TI - HIV-1 and its resistance to peptidic carbohydrate-binding agents (CBAs): an overview. AB - The glycoproteins on the surfaces of enveloped viruses, such as HIV, can be considered as a unique target for antiviral therapy. Different carbohydrate binding agents (CBAs) target specific glycans present on viral glycoproteins of enveloped viruses. It has been shown that long-term CBA pressure in vitro can result in mutant HIV-1 isolates with several N-linked glycan deletions on gp120. These studies demonstrated that mainly high-mannose type glycans are deleted. However, interestingly, N241, N262 and N356 on gp120 have never been found to be affected after prolonged CBA exposure. Here, we review the mutation and (cross) resistance profiles of eleven specific generated CBA-resistant HIV-1 strains. We observed that the broad-neutralizing anti-carbohydrate binding mAb 2G12 became completely inactive against all the generated CBA-resistant HIV-1 clade B isolates. In addition, all of the CBAs discussed in this review, with the exception of NICTABA, interfered with the binding of 2G12 mAb to gp120 expressed on HIV-1-infected T cells. The cross-resistance profiles of mutant HIV-1 strains are varying from increased susceptibility to very high resistance levels, even among different classes of CBAs with dissimilar sugar specificities or binding moieties [e.g., alpha(1,3), alpha(1,2), alpha(1,6)]. Recent studies demonstrated promising results in non-topical formulations (e.g., intranasally or subcutaneously), highlighting their potential for prevention (microbicides) and antiviral therapy. PMID- 25517344 TI - Obtaining ready-to-eat blue corn expanded snacks with anthocyanins using an extrusion process and response surface methodology. AB - Extrusion is an alternative technology for the production of nixtamalized products. The aim of this study was to obtain an expanded nixtamalized snack with whole blue corn and using the extrusion process, to preserve the highest possible total anthocyanin content, intense blue/purple coloration (color b) and the highest expansion index. A central composite experimental design was used. The extrusion process factors were: feed moisture (FM, 15%-23%), calcium hydroxide concentration (CHC, 0%-0.25%) and final extruder temperature (T, 110-150 degrees C). The chemical and physical properties evaluated in the extrudates were moisture content (MC, %), total anthocyanins (TA, mg.kg(-1)), pH, color (L, a, b) and expansion index (EI). ANOVA and surface response methodology were applied to evaluate the effects of the extrusion factors. FM and T significantly affected the response variables. An optimization step was performed by overlaying three contour plots to predict the best combination region. The extrudates were obtained under the following optimum factors: FM (%) = 16.94, CHC (%) = 0.095 and T ( degrees C) = 141.89. The predicted extrusion processing factors were highly accurate, yielding an expanded nixtamalized snack with 158.87 mg.kg(-1) TA (estimated: 160 mg.kg(-1)), an EI of 3.19 (estimated: 2.66), and color parameter b of -0.44 (estimated: 0.10). PMID- 25517346 TI - Crystallographic studies evidencing the high energy tolerance to disrupting the interface disulfide bond of thioredoxin 1 from white leg shrimp Litopenaeus vannamei. AB - Thioredoxin (Trx) is a small 12-kDa redox protein that catalyzes the reduction of disulfide bonds in proteins from different biological systems. A recent study of the crystal structure of white leg shrimp thioredoxin 1 from Litopenaeus vannamei (LvTrx) revealed a dimeric form of the protein mediated by a covalent link through a disulfide bond between Cys73 from each monomer. In the present study, X ray-induced damage in the catalytic and the interface disulfide bond of LvTrx was studied at atomic resolution at different transmission energies of 8% and 27%, 12.8 keV at 100 K in the beamline I-24 at Diamond Light Source. We found that at an absorbed dose of 32 MGy, the X-ray induces the cleavage of the disulfide bond of each catalytic site; however, the interface disulfide bond was cleaved at an X ray adsorbed dose of 85 MGy; despite being the most solvent-exposed disulfide bond in LvTrx (~50 A2). This result clearly established that the interface disulfide bond is very stable and, therefore, less susceptible to being reduced by X-rays. In fact, these studies open the possibility of the existence in solution of a dimeric LvTrx. PMID- 25517347 TI - Uncertainty induced by chest wall thickness assessment methods on lung activity estimation for plutonium and americium: a large population-based study. AB - In vivo lung counting aims at assessing the retained activity in the lungs. The calibration factor relating the measured counts to the worker's specific retained lung activity can be obtained by several means and strongly depends on the chest wall thickness. Here we compare, for 374 male nuclear workers, the activity assessed with a reference protocol, where the material equivalent chest wall thickness is known from ultrasound measurements, with two other protocols. The counting system is an array of four germanium detectors.It is found that non site specific equations for the assessment of the chest wall thickness induce large biases in the assessment of activity. For plutonium isotopes or (241)Am the proportion of workers for whom the retained activity is within +/- 10% of the reference one is smaller than 10%.The use of site-specific equations raises this proportion to 20% and 58% for plutonium and (241)Am, respectively.Finally, for the studied population, when site-specific equations are used for the chest wall thickness, the standard uncertainties for the lung activity are 42% and 12.5%, for plutonium and (241)Am, respectively. Due to the relatively large size of the studied population, these values are a relatively robust estimate of the uncertainties due to the assessment of the chest wall thickness for the current practice at this site. PMID- 25517349 TI - Interventional thrombectomy for major stroke--a step in the right direction. PMID- 25517350 TI - An artificial PPR scaffold for programmable RNA recognition. AB - Pentatricopeptide repeat (PPR) proteins control diverse aspects of RNA metabolism in eukaryotic cells. Although recent computational and structural studies have provided insights into RNA recognition by PPR proteins, their highly insoluble nature and inconsistencies between predicted and observed modes of RNA binding have restricted our understanding of their biological functions and their use as tools. Here we use a consensus design strategy to create artificial PPR domains that are structurally robust and can be programmed for sequence-specific RNA binding. The atomic structures of these artificial PPR domains elucidate the structural basis for their stability and modelling of RNA-protein interactions provides mechanistic insights into the importance of RNA-binding residues and suggests modes of PPR-RNA association. The modular mode of RNA binding by PPR proteins holds great promise for the engineering of new tools to target RNA and to understand the mechanisms of gene regulation by natural PPR proteins. PMID- 25517352 TI - Cell-permeable cyclic peptides from synthetic libraries inspired by natural products. AB - Drug design efforts are turning to a new generation of therapeutic targets, such as protein-protein interactions (PPIs), that had previously been considered "undruggable" by typical small molecules. There is an emerging view that accessing these targets will require molecules that are larger and more complex than typical small molecule drugs. Here, we present a methodology for the discovery of geometrically diverse, membrane permeable cyclic peptide scaffolds based on the synthesis and permeability screening of a combinatorial library, followed by deconvolution of membrane-permeable scaffolds to identify cyclic peptides with good to excellent passive cell permeabilities. We use a combination of experimental and computational approaches to investigate structure permeability relationships in one of these scaffolds, and uncover structural and conformational factors that govern passive membrane diffusion in a related set of cyclic peptide diastereomers. Further, we investigate the dependency of permeability on side-chain identity of one of these scaffolds through single point diversifications to show the adaptability of these scaffolds toward development of permeability-biased libraries suitable for bioactivity screens. Overall, our results demonstrate that many novel, cell permeable scaffolds exist beyond those found in extant natural products, and that such scaffolds can be rapidly identified using a combination of synthesis and deconvolution which can, in principle, be applied to any type of macrocyclic template. PMID- 25517351 TI - Outcomes of cardiovascular disease risk factor screening and referrals in a family planning clinic. AB - BACKGROUND: Cardiovascular disease (CVD) screening in Title X settings can identify low-income women at risk of future chronic disease. This study examines follow-up related to newly identified CVD risk factors in a Title X setting. METHODS: Female patients at a North Carolina Title X clinic were screened for CVD risk factors (n=462) and 167/462 (36.1%) were rescreened one year later. Clinical staff made protocol-driven referrals for women identified with newly diagnosed CVD risk factors. We used paired t-tests and chi square tests to compare screening and rescreening results (two-tailed, p<0.05). RESULTS: Among 11 women in need of referrals for newly diagnosed hypertension or diabetes, 9 out of 11 (81.8%) were referred, and 2 of 11 (18.2%) completed referrals. Among hypertensive women who were rescreened (n=21), systolic blood pressure decreased (139 to 132 mmHg, p=0.001) and diastolic blood pressure decreased (90 to 83 mmHg, p=0.006). Hemoglobin A1c did not improve among rescreened diabetic women (n=5, p=0.640). Among women who reported smoking at enrollment, 129 of 148 (87.2%) received cessation counseling and 8 of 148 (5.4%) accepted tobacco quitline referrals. Among smokers, 53 out of 148 (35.8%) were rescreened and 11 of 53 (20.8%) reported nonsmoking at that time. Among 188 women identified as obese at enrollment, 22 (11.7%) scheduled nutrition appointments, but only one attended. Mean weight increased from 221 to 225 pounds (p 0<.05) among 70 out of 188 (37.2%) obese women who were rescreened. CONCLUSIONS: The majority of women in need of referrals for CVD risk factors received them. Few women completed referrals. Future research should examine barriers and facilitators of referral care among low-income women. PMID- 25517353 TI - Cumulative query method for influenza surveillance using search engine data. AB - BACKGROUND: Internet search queries have become an important data source in syndromic surveillance system. However, there is currently no syndromic surveillance system using Internet search query data in South Korea. OBJECTIVES: The objective of this study was to examine correlations between our cumulative query method and national influenza surveillance data. METHODS: Our study was based on the local search engine, Daum (approximately 25% market share), and influenza-like illness (ILI) data from the Korea Centers for Disease Control and Prevention. A quota sampling survey was conducted with 200 participants to obtain popular queries. We divided the study period into two sets: Set 1 (the 2009/10 epidemiological year for development set 1 and 2010/11 for validation set 1) and Set 2 (2010/11 for development Set 2 and 2011/12 for validation Set 2). Pearson's correlation coefficients were calculated between the Daum data and the ILI data for the development set. We selected the combined queries for which the correlation coefficients were .7 or higher and listed them in descending order. Then, we created a cumulative query method n representing the number of cumulative combined queries in descending order of the correlation coefficient. RESULTS: In validation set 1, 13 cumulative query methods were applied, and 8 had higher correlation coefficients (min=.916, max=.943) than that of the highest single combined query. Further, 11 of 13 cumulative query methods had an r value of >=.7, but 4 of 13 combined queries had an r value of >=.7. In validation set 2, 8 of 15 cumulative query methods showed higher correlation coefficients (min=.975, max=.987) than that of the highest single combined query. All 15 cumulative query methods had an r value of >=.7, but 6 of 15 combined queries had an r value of >=.7. CONCLUSIONS: Cumulative query method showed relatively higher correlation with national influenza surveillance data than combined queries in the development and validation set. PMID- 25517348 TI - A randomized trial of intraarterial treatment for acute ischemic stroke. AB - BACKGROUND: In patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion, intraarterial treatment is highly effective for emergency revascularization. However, proof of a beneficial effect on functional outcome is lacking. METHODS: We randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary outcome was the modified Rankin scale score at 90 days; this categorical scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower modified Rankin scores, as compared with usual care alone (shift analysis). RESULTS: We enrolled 500 patients at 16 medical centers in The Netherlands (233 assigned to intraarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before randomization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of symptomatic intracerebral hemorrhage. CONCLUSIONS: In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.). PMID- 25517355 TI - Ultrasonography-guided identification with methylene blue tattooing of the ilioinguinal nerve for neurectomy for chronic pain: a case series. PMID- 25517354 TI - Pax6- and Six3-mediated induction of lens cell fate in mouse and human ES cells. AB - Embryonic stem (ES) cells provide a potentially useful in vitro model for the study of in vivo tissue differentiation. We used mouse and human ES cells to investigate whether the lens regulatory genes Pax6 and Six3 could induce lens cell fate in vitro. To help assess the onset of lens differentiation, we derived a new mES cell line (Pax6-GFP mES) that expresses a GFP reporter under the control of the Pax6 P0 promoter and lens ectoderm enhancer. Pax6 or Six3 expression vectors were introduced into mES or hES cells by transfection or lentiviral infection and the differentiating ES cells analyzed for lens marker expression. Transfection of mES cells with Pax6 or Six3 but not with other genes induced the expression of lens cell markers and up-regulated GFP reporter expression in Pax6-GFP mES cells by 3 days post-transfection. By 7 days post transfection, mES cell cultures exhibited a>10-fold increase over controls in the number of colonies expressing gammaA-crystallin, a lens fiber cell differentiation marker. RT-PCR and immunostaining revealed induction of additional lens epithelial or fiber cell differentiation markers including Foxe3, Prox1, alpha- and beta-crystallins, and Tdrd7. Moreover, gammaA-crystallin- or Prox1-expressing lentoid bodies formed by 30 days in culture. In hES cells, Pax6 or Six3 lentiviral vectors also induced lens marker expression. mES cells that express lens markers reside close to but are distinct from the Pax6 or Six3 transduced cells, suggesting that the latter induce nearby undifferentiated ES cells to adopt a lens fate by non-cell autonomous mechanisms. In sum, we describe a novel mES cell GFP reporter line that is useful for monitoring induction of lens fate, and demonstrate that Pax6 or Six3 is sufficient to induce ES cells to adopt a lens fate, potentially via non-cell autonomous mechanisms. These findings should facilitate investigations of lens development. PMID- 25517356 TI - Hydrophobic handoff for direct delivery of peroxisome tail-anchored proteins. AB - Tail-anchored (TA) proteins are inserted into membranes post-translationally through a C-terminal transmembrane domain (TMD). The PEX19 protein binds peroxisome TA proteins in the cytoplasm and delivers them to the membrane through the PEX3 receptor protein. An amphipathic segment in PEX19 promotes docking on PEX3. However, how this leads to substrate insertion is unknown. Here we reconstitute peroxisome TA protein biogenesis into two sequential steps of substrate TMD engagement and membrane insertion. We identify a series of previously uncharacterized amphipathic segments in PEX19 and identify one whose hydrophobicity is required for membrane insertion, but not TMD chaperone activity or PEX3 binding. A membrane-proximal hydrophobic surface of PEX3 promotes an unconventional form of membrane intercalation, and is also required for TMD insertion. Together, these data support a mechanism in which hydrophobic moieties in the TMD chaperone and its membrane-associated receptor act in a concerted manner to prompt TMD release and membrane insertion. PMID- 25517357 TI - Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3' repair exonuclease 1 (TREX1). AB - IMPORTANCE: Familial chilblain lupus is a rare, autosomal dominant form of lupus erythematosus characterized by cold-induced inflammatory lesions at acral locations presenting in early childhood. Familial chilblain lupus is usually caused by a mutation in TREX1 (3' repair exonuclease 1). OBSERVATIONS: We report on a family with dominant chilblain lupus segregating a novel TREX1 mutation (c.585C>G; H195Q) within the highly conserved exonuclease (Exo) III domain. Affected family members experienced cold-induced chilblain lesions of varying degrees, ranging from bluish-red infiltrations to mutilating necrotic ulcerations. In addition, all patients showed signs of systemic disease, such as arthritis, lymphopenia, or antinuclear antibodies. An increased expression of myxovirus resistance protein A in the skin and induction of interferon-stimulated genes in peripheral blood cells demonstrated activation of type I interferon. CONCLUSIONS AND RELEVANCE: This case further implicates type I interferon dependent innate immune activation in the pathogenesis of TREX1-associated familial chilblain lupus. Unlike previously reported TREX1 mutations, which affect the Exo I or Exo II domains, the mutation presented here alters the Exo III domain, suggesting a particular role of mutations within the catalytic Exo domains in the pathogenesis of familial chilblain lupus. The high prevalence of extracutaneous manifestations, along with activation of type I interferon, underlines the systemic nature of familial chilblain lupus. PMID- 25517358 TI - Update on breast cancer risk prediction and prevention. AB - PURPOSE OF REVIEW: Breast cancer is the most common cancer in women worldwide. This review will focus on current prevention strategies for women at high risk. RECENT FINDINGS: The identification of women who are at high risk of developing breast cancer is key to breast cancer prevention. Recent findings have shown that the inclusion of breast density and a panel of low-penetrance genetic polymorphisms can improve risk estimation compared with previous models. Preventive therapy with aromatase inhibitors has produced large reductions in breast cancer incidence in postmenopausal women. Tamoxifen confers long-term protection and is the only proven preventive treatment for premenopausal women. Several other agents, including metformin, bisphosphonates, aspirin and statins, have been found to be effective in nonrandomized settings. SUMMARY: There are many options for the prevention of oestrogen-positive breast cancer, in postmenopausal women who can be given a selective oestrogen receptor modulator or an aromatase inhibitor. It still remains unclear how to prevent oestrogen negative breast cancer, which occurs more often in premenopausal women. Identification of women at high risk of the disease is crucial, and the inclusion of breast density and a panel of genetic polymorphisms, which individually have low penetrance, can improve risk assessment. PMID- 25517359 TI - The path to personalized medicine in women's cancers: challenges and recent advances. PMID- 25517362 TI - Nobel Prize centenary: Robert Barany and the vestibular system. AB - The hundredth anniversary of Robert Barany's Nobel Prize in Medicine offers the opportunity to highlight the importance of his discoveries on the physiology and pathophysiology of the vestibular organs. Barany developed the method of caloric vestibular stimulation that revolutionized the investigation of the semicircular canals and that is still widely used today. Caloric vestibular stimulation launched experimental vestibular research that was relevant to comprehend the evolution of human locomotion, and Barany's tests continue to be used in neuroscience to understand the influence of vestibular signals on bodily perceptions, cognition and emotions. Only during the last 20 years has caloric vestibular stimulation been merged with brain imaging to localize the human vestibular cortex. PMID- 25517363 TI - Thanatosis. AB - In this quick guide, Rogers and Simpson provide an overview of thanatosis, the fascinating behaviour of feigning death, seen in animals ranging from insects to mammals. PMID- 25517360 TI - Integrated analyses of DNA methylation and hydroxymethylation reveal tumor suppressive roles of ECM1, ATF5, and EOMES in human hepatocellular carcinoma. AB - BACKGROUND: Differences in 5-hydroxymethylcytosine, 5hmC, distributions may complicate previous observations of abnormal cytosine methylation statuses that are used for the identification of new tumor suppressor gene candidates that are relevant to human hepatocarcinogenesis. The simultaneous detection of 5 methylcytosine and 5-hydroxymethylcytosine is likely to stimulate the discovery of aberrantly methylated genes with increased accuracy in human hepatocellular carcinoma. RESULTS: Here, we performed ultra-performance liquid chromatography/tandem mass spectrometry and single-base high-throughput sequencing, Hydroxymethylation and Methylation Sensitive Tag sequencing, HMST seq, to synchronously measure these two modifications in human hepatocellular carcinoma samples. After identification of differentially methylated and hydroxymethylated genes in human hepatocellular carcinoma, we integrate DNA copy number alterations, as determined using array-based comparative genomic hybridization data, with gene expression to identify genes that are potentially silenced by promoter hypermethylation. CONCLUSIONS: We report a high enrichment of genes with epigenetic aberrations in cancer signaling pathways. Six genes were selected as tumor suppressor gene candidates, among which, ECM1, ATF5 and EOMES are confirmed via siRNA experiments to have potential anti-cancer functions. PMID- 25517365 TI - Human genetics: pre-Columbian Pacific contact. AB - Large-scale genetic analysis of the native inhabitants of Rapa Nui (Easter Island) reveals the expected combination of Polynesian ancestry with later European admixture, but also a contribution from Native Americans dating to 1280 1495 AD, demonstrating early trans-Pacific contact. PMID- 25517364 TI - Recognizing the unconscious. AB - Recognition memory enables us to discriminate whether an event has occurred in the past, and is widely interpreted to reflect the conscious retrieval of episodic traces or familiarity. Non-conscious mnemonic influences, such as repetition priming, are thought to have a negligible effect on standard tests of recognition memory. A major difficulty with this conclusion is that it is exclusively based on the results from experimental protocols that use stimulus materials available to conscious perception. In eight experiments (N = 144), we tested the necessity of mechanisms related to conscious perception for accurate recognition memory by manipulating observers' awareness of either the encoded event and/or the retrieval cues. Remarkably, observers made accurate objective and subjective recognition memory-guided judgments without visual awareness of the encoded events, retrieval cues or, most strikingly, both. These results demonstrate that non-conscious processes can drive accurate recognition memory, and are a significant challenge to neurobiological accounts centered on the conscious retrieval of episodic traces or familiarity. PMID- 25517366 TI - Fertility: the role of mTOR signaling and KIT ligand. AB - Activation of a limited pool of diminishing ovarian follicles determines women's reproductive lifespan. A recent rodent study describes the role of mTOR signaling and KIT ligand in granulosa cells of primordial follicles for follicle activation and for reproductive lifespan regulation. PMID- 25517367 TI - Neurobiology: jumping spiders getting on board. AB - A new technique has overcome decades of failure to allow, for the first time, electrophysiological access to the brains of jumping spiders, a group of animals renowned for generating highly complex, seemingly vertebrate-like behavior from their tiny arthropod brains. PMID- 25517368 TI - Neuronal plasticity: how do neurons know what to do? AB - A recent study confirms activity-dependent co-regulation of membrane conductances as a mechanism underlying homeostatic regulation of neuronal properties. How multiple cellular and synaptic homeostatic mechanisms interact in a neuronal circuit is best studied with a combination of experimentation and modeling. PMID- 25517369 TI - Centriole duplication: when PLK4 meets Ana2/STIL. AB - Polo-like kinase 4 is known to drive centriole duplication, but the relevant substrate remains elusive. A new study shows that PLK4 phosphorylates a key centriolar component, Ana2/STIL, to initiate centriole assembly. PMID- 25517370 TI - Fish vision: size selectivity in the zebrafish retinotectal pathway. AB - A recent study has shown that the zebrafish tectum processes inputs from the retina tuned to ethologically relevant size classes, suggesting a role for the tectum in selecting approach or avoidance behaviours based on size-based categorization of visual targets. PMID- 25517372 TI - Evolution: a rapid flight towards birds. AB - Remarkable feathered dinosaur fossils have blurred the lines between early birds and their non-avian dinosaur relatives. Rapid skeletal evolution and decreasing body size along one particular lineage of theropod dinosaurs paved the way for the spectacular radiation of birds. PMID- 25517371 TI - Cell polarity: netrin calms an excitable system. AB - In a tractable model for cell invasion, the Caenorhabditis elegans anchor cell migrates through basement membranes towards a polarity cue provided by netrin. A new study reveals that the anchor cell polarity network can break symmetry and oscillate in the absence of netrin, suggesting the presence of interlinked positive and negative feedback loops, which are common in polarity pathways. PMID- 25517373 TI - Vision: melanopsin as a novel irradiance detector at the heart of vision. AB - A recent study defines a novel role of melanopsin-expressing ipRGCs, showing that these inner retinal photoreceptors function as retinal irradiance detectors and provide a local measure of luminance to regulate functional adaptation in the mammalian retina. PMID- 25517374 TI - Behavioral plasticity: a nose for every season. AB - A recent study in Caenorhabditis elegans identifies the dynamic expression of a single odorant receptor as a molecular mechanism for context-dependent modulation of olfactory preferences and food prioritization. PMID- 25517375 TI - Re-evaluation of the immunological Big Bang. AB - Classically the immunological 'Big Bang' of adaptive immunity was believed to have resulted from the insertion of a transposon into an immunoglobulin superfamily gene member, initiating antigen receptor gene rearrangement via the RAG recombinase in an ancestor of jawed vertebrates. However, the discovery of a second, convergent adaptive immune system in jawless fish, focused on the so called variable lymphocyte receptors (VLRs), was arguably the most exciting finding of the past decade in immunology and has drastically changed the view of immune origins. The recent report of a new lymphocyte lineage in lampreys, defined by the antigen receptor VLRC, suggests that there were three lymphocyte lineages in the common ancestor of jawless and jawed vertebrates that co-opted different antigen receptor supertypes. The transcriptional control of these lineages during development is predicted to be remarkably similar in both the jawless (agnathan) and jawed (gnathostome) vertebrates, suggesting that an early 'division of labor' among lymphocytes was a driving force in the emergence of adaptive immunity. The recent cartilaginous fish genome project suggests that most effector cytokines and chemokines were also present in these fish, and further studies of the lamprey and hagfish genomes will determine just how explosive the Big Bang actually was. PMID- 25517376 TI - Food for thought. PMID- 25517385 TI - Protein disorder: wagging a tail at ubiquitin. PMID- 25517383 TI - Targeting mitochondria metabolism for cancer therapy. AB - Mitochondria have a well-recognized role in the production of ATP and the intermediates needed for macromolecule biosynthesis, such as nucleotides. Mitochondria also participate in the activation of signaling pathways. Overall, accumulating evidence now suggests that mitochondrial bioenergetics, biosynthesis and signaling are required for tumorigenesis. Thus, emerging studies have begun to demonstrate that mitochondrial metabolism is potentially a fruitful arena for cancer therapy. In this Perspective, we highlight recent developments in targeting mitochondrial metabolism for the treatment of cancer. PMID- 25517384 TI - Redox biology: signaling via a peroxiredoxin sensor. PMID- 25517388 TI - Prevalence of Burnout Syndrome in patients admitted with acute coronary syndrome. AB - BACKGROUND: Burnout Syndrome is the extreme emotional response to chronic occupational stress, manifesting as physical and mental exhaustion. Although associated with higher prevalence of cardiovascular risk factors, no study so far has evaluated whether the Burnout Syndrome could be a prevalent factor in non elderly individuals active in the labor market, admitted for acute coronary syndrome (ACS). OBJECTIVE: To evaluate the prevalence of the Burnout Syndrome in non-elderly, economically active patients, hospitalized with ACS. METHODS: Cross sectional study conducted in a tertiary and private cardiology center, with economically active patients aged <65 years, hospitalized with diagnosis of ACS. The Burnout Syndrome was evaluated with the Burnout Syndrome Inventory (BSI), which assesses workplace conditions and four dimensions that characterize the syndrome: emotional exhaustion (EE), emotional distancing (EmD), dehumanization (De) and professional fulfillment (PF). The Lipp's Stress Symptoms Inventory for Adults (LSSI) was applied to evaluate global stress. RESULTS: Of 830 patients evaluated with suspected ACS, 170 met the study criteria, 90% of which were men, overall average age was 52 years, and 40.5% had an average income above 11 minimum wages. The prevalence of the Burnout Syndrome was 4.1%. When we evaluated each dimension individually, we found high EE in 34.7%, high De in 52.4%, high EDi in 30.6%, and low PF in 5.9%. The overall prevalence of stress was 87.5%. CONCLUSION: We found a low prevalence of Burnout Syndrome in an economically active, non-elderly population among patients admitted for ACS in a tertiary and private hospital. PMID- 25517389 TI - Hypotensive response magnitude and duration in hypertensives: continuous and interval exercise. AB - BACKGROUND: Although exercise training is known to promote post-exercise hypotension, there is currently no consistent argument about the effects of manipulating its various components (intensity, duration, rest periods, types of exercise, training methods) on the magnitude and duration of hypotensive response. OBJECTIVE: To compare the effect of continuous and interval exercises on hypotensive response magnitude and duration in hypertensive patients by using ambulatory blood pressure monitoring (ABPM). METHODS: The sample consisted of 20 elderly hypertensives. Each participant underwent three ABPM sessions: one control ABPM, without exercise; one ABPM after continuous exercise; and one ABPM after interval exercise. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR) and double product (DP) were monitored to check post-exercise hypotension and for comparison between each ABPM. RESULTS: ABPM after continuous exercise and after interval exercise showed post-exercise hypotension and a significant reduction (p < 0.05) in SBP, DBP, MAP and DP for 20 hours as compared with control ABPM. Comparing ABPM after continuous and ABPM after interval exercise, a significant reduction (p < 0.05) in SBP, DBP, MAP and DP was observed in the latter. CONCLUSION: Continuous and interval exercise trainings promote post-exercise hypotension with reduction in SBP, DBP, MAP and DP in the 20 hours following exercise. Interval exercise training causes greater post-exercise hypotension and lower cardiovascular overload as compared with continuous exercise. PMID- 25517390 TI - Role of microRNAs 221/222 on statin induced nitric oxide release in human endothelial cells. AB - BACKGROUND: Nitric oxide (NO) has been largely associated with cardiovascular protection through improvement of endothelial function. Recently, new evidence about modulation of NO release by microRNAs (miRs) has been reported, which could be involved with statin-dependent pleiotropic effects, including anti inflammatory properties related to vascular endothelium function. OBJECTIVE: To evaluate the effects of cholesterol-lowering drugs including the inhibitors of cholesterol synthesis, atorvastatin and simvastatin, and the inhibitor of cholesterol absorption ezetimibe on NO release, NOS3 mRNA expression and miRs potentially involved in NO bioavailability. METHODS: Human umbilical vein endothelial cells (HUVEC) were exposed to atorvastatin, simvastatin or ezetimibe (0 to 5.0 MUM). Cells were submitted to total RNA extraction and relative quantification of NOS3 mRNA and miRs -221, -222 and -1303 by qPCR. NO release was measured in supernatants by ozone-chemiluminescence. RESULTS: Both statins increased NO levels and NOS3 mRNA expression but no influence was observed for ezetimibe treatment. Atorvastatin, simvastatin and ezetimibe down-regulated the expression of miR-221, whereas miR-222 was reduced only after the atorvastatin treatment. The magnitude of the reduction of miR-221 and miR-222 after treatment with statins correlated with the increment in NOS3 mRNA levels. No influence was observed on the miR-1303 expression after treatments. CONCLUSION: NO release in endothelial cells is increased by statins but not by the inhibitor of cholesterol absorption, ezetimibe. Our results provide new evidence about the participation of regulatory miRs 221/222 on NO release induction mediated by statins. Although ezetimibe did not modulate NO levels, the down-regulation of miR-221 could involve potential effects on endothelial function. PMID- 25517391 TI - Right ventricular Doppler echocardiographic study of indeterminate form of chagas disease. AB - BACKGROUND: Patients with indeterminate form of Chagas disease/cardiac normality (ICD/CN) exhibited normal electrocardiograms and chest X-rays; however, more sophisticated tests detected some degree of morphological and functional changes in the heart. OBJECTIVE: To assess the prevalence of systolic and diastolic dysfunction of the right ventricle (RV) in patients with ICD/CN. METHODS: This was a case-control and prevalence study. Using Doppler two-dimensional echocardiography (2D), 92 patients were assessed and divided into two groups: group I (normal, n = 31) and group II (ICD/CN, n = 61). RESULTS: The prevalence of RV systolic dysfunction in patients in groups I and II was as follows: fractional area change (0.0% versus 0.6%), mobility of the tricuspid annulus (0.0% versus 0.0%), and S-wave tissue Doppler (6.4% versus 26.0%, p = 0.016). The prevalence of global disorders such as the right myocardial performance index using tissue Doppler (16.1% versus 27.8%, p = 0.099) and pulsed Doppler (61.3% versus 68%, p = 0.141) and diastolic disorders such as abnormal relaxation (0.0% versus 6.0%), pseudonormal pattern (0.0% versus 0.0%), and restrictive pattern (0.0% versus 0.0%) was not statistically different between groups. CONCLUSION: The prevalence of RV systolic dysfunction was estimated to be 26% (S wave velocity compared with other variables), suggesting incipient changes in RV systolic function in the ICD/CN group. PMID- 25517393 TI - Endometriosis: a possible cause of uterine rupture in labour? PMID- 25517392 TI - Monitoring cooperative binding using electrochemical DNA-based sensors. AB - Electrochemical DNA-based (E-DNA) sensors are utilized to detect a variety of targets including complementary DNA, small molecules, and proteins. These sensors typically employ surface-bound single-stranded oligonucleotides that are modified with a redox-active molecule on the distal 3' terminus. Target-induced flexibility changes of the DNA probe alter the efficiency of electron transfer between the redox active methylene blue and the electrode surface, allowing for quantitative detection of target concentration. While numerous studies have utilized the specific and sensitive abilities of E-DNA sensors to quantify target concentration, no studies to date have demonstrated the ability of this class of collision-based sensors to elucidate biochemical-binding mechanisms such as cooperativity. In this study, we demonstrate that E-DNA sensors fabricated with various lengths of surface-bound oligodeoxythymidylate [(dT)n] sensing probes are able to quantitatively distinguish between cooperative and noncooperative binding of a single-stranded DNA-binding protein. Specifically, we demonstrate that oligo(dT) E-DNA sensors are able to quantitatively detect nM levels (50 nM-4 MUM) of gene 32 protein (g32p). Furthermore, the sensors exhibit signal that is able to distinguish between the cooperative binding of the full-length g32p and the noncooperative binding of the core domain (*III) fragment to single-stranded DNA. Finally, we demonstrate that this binding is both probe-length- and ionic strength-dependent. This study illustrates a new quantitative property of this powerful class of biosensor and represents a rapid and simple methodology for understanding protein-DNA binding mechanisms. PMID- 25517395 TI - Effects of adding remifentanil to propofol anesthesia on systemic hemodynamics, cardiac output, and middle cerebral artery flow velocity during electroconvulsive therapy: a pilot study. AB - PURPOSE: The purpose of this study was to examine the effects of adding remifentanil to propofol anesthesia on systemic hemodynamics, cardiac output, and middle cerebral artery (MCA) blood flow velocity during electroconvulsive therapy (ECT). METHODS: Twelve patients undergoing ECT were enrolled in this study. The patients received anesthesia by one of the following 2 methods: either propofol alone at a dose of 1.0 mg/kg, or propofol 0.75 mg/kg with remifentanil 1.0 MUg/kg in turn during successive ECT sessions, immediately before the administration of succinylcholine. All patients were monitored for blood pressure, heart rate, cardiac output, and MCA flow velocity by transcranial Doppler sonography. RESULTS: Middle cerebral artery flow velocity increased after ECT in both anesthesia method groups and lasted for 2 minutes after ECT. No difference in MCA flow velocity was observed between the 2 methods at any time point. Seizure duration was longer under propofol with remifentanil than under propofol alone [propofol with remifentanil, 32 (3) seconds; propofol alone, 24 (4) seconds; P < 0.01]. In contrast, no difference in time to awakening (time from the ECT stimulus to the patient's ability to open eyes) was observed between the 2 groups [propofol with remifentanil, 183 (19) seconds; propofol alone, 185 (21) seconds]. CONCLUSIONS: The addition of remifentanil (1 MUg/kg) is suitable for reduction of the propofol dose during ECT, without any adverse hemodynamic effects, including on cerebral blood flow. PMID- 25517396 TI - Concurrent validation of the Actigraph gt3x+, Polar Active accelerometer, Omron HJ-720 and Yamax Digiwalker SW-701 pedometer step counts in lab-based and free living settings. AB - Activity monitors are frequently used to assess activity in many settings. But as technology advances, so do the mechanisms used to estimate activity causing a continuous need to validate newly developed monitors. The purpose of this study was to examine the step count validity of the Yamax Digiwalker SW-701 pedometer (YX), Omron HJ-720 T pedometer (OP), Polar Active accelerometer (PAC) and Actigraph gt3x+ accelerometer (AG) under controlled and free-living conditions. Participants completed five stages of treadmill walking (n = 43) and a subset of these completed a 3-day free-living wear period (n = 37). Manually counted (MC) steps provided a criterion measure for treadmill walking, whereas the comparative measure during free-living was the YX. During treadmill walking, the OP was the most accurate monitor across all speeds (+/-1.1% of MC steps), while the PAC underestimated steps by 6.7-16.0% per stage. During free-living, the OP and AG counted 97.5% and 98.5% of YX steps, respectively. The PAC overestimated steps by 44.0%, or 5,265 steps per day. The Omron pedometer seems to provide the most reliable and valid estimate of steps taken, as it was the best performer under lab-based conditions and provided comparable results to the YX in free-living. Future studies should consider these monitors in additional populations and settings. PMID- 25517397 TI - Mechanical devices for urinary incontinence in women. AB - BACKGROUND: Incontinence can have a devastating effect on the lives of sufferers with significant economic implications. Non-surgical treatments such as pelvic floor muscle training and the use of mechanical devices are usually the first line of management, particularly when a woman does not want surgery or when she is considered unfit for surgery. Mechanical devices are inexpensive and do not compromise future surgical treatment. OBJECTIVES: To determine whether mechanical devices are useful in the management of adult female urinary incontinence. SEARCH METHODS: For this second update we searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, ClinicalTrials.gov, WHO ICTRP and handsearching of journals and conference proceedings (searched 21 August 2014), EMBASE (January 1947 to 2014 Week 34), CINAHL (January 1982 to 25 August 2014), and the reference lists of relevant articles. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials of mechanical devices in the management of adult female urinary incontinence determined by symptom, sign or urodynamic diagnosis. DATA COLLECTION AND ANALYSIS: The reviewers assessed the identified studies for eligibility and risk of bias and independently extracted data from the included studies. Data analysis was performed using RevMan software (version 5.3). MAIN RESULTS: One new trial was identified and included in this update bringing the total to eight trials involving 787 women. Three small trials compared a mechanical device with no treatment and although they suggested that use of a mechanical device might be better than no treatment, the evidence for this was inconclusive. Four trials compared one mechanical device with another. Quantitative synthesis of data from these trials was not possible because different mechanical devices were compared in each trial using different outcome measures. Data from the individual trials showed no clear difference between devices, but with wide confidence intervals. One trial compared three groups: a mechanical device alone, behavioural therapy (pelvic floor muscle training) alone and behavioural therapy combined with a mechanical device. While at three months there were more withdrawals from the device-only group, at 12 months differences between the groups were not sustained on any measure. AUTHORS' CONCLUSIONS: The place of mechanical devices in the management of urinary incontinence remains in question. Currently there is little evidence from controlled trials on which to judge whether their use is better than no treatment and large well-conducted trials are required for clarification. There was also insufficient evidence in favour of one device over another and little evidence to compare mechanical devices with other forms of treatment. PMID- 25517398 TI - Early life stress inhibits expression of ribosomal RNA in the developing hippocampus. AB - Children that are exposed to abuse or neglect show abnormal hippocampal function. However, the developmental mechanisms by which early life stress (ELS) impairs normal hippocampal development have not been elucidated. Here we propose that exposure to ELS blunts normal hippocampal growth by inhibiting the availability of ribosomal RNA (rRNA). In support of this hypothesis, we show that the normal mouse hippocampus undergoes a growth-spurt during the second week of life, followed by a gradual decrease in DNA and RNA content that persists into adulthood. This developmental pattern is associated with accelerated ribosomal RNA (rRNA) synthesis during the second week of life, followed by a gradual decline in rRNA levels that continue into adulthood. Levels of DNA methylation at the ribosomal DNA (rDNA) promoter are lower during the second week of life compared to earlier development or adulthood. Exposure to brief daily separation (BDS), a mouse model of early life stress, increased DNA methylation at the ribosomal DNA promoter, decreased rRNA levels, and blunted hippocampal growth during the second week of life. Exposure to acute (3 hrs) maternal separation decreased rRNA and increased DNA methylation at the rDNA proximal promoter, suggesting that exposure to stress early in life can rapidly regulate the availability of rRNA levels in the developing hippocampus. Given the critical role that rRNA plays in supporting normal growth and development, these findings suggest a novel molecular mechanism to explain how stress early in life impairs hippocampus development in the mouse. PMID- 25517399 TI - Strategies against burnout and anxiety in medical education--implementation and evaluation of a new course on relaxation techniques (Relacs) for medical students. AB - Burnout and stress-related mental disorders (depression, anxiety) occur in medical students and physicians with a significantly higher prevalence than in the general population. At the same time, the learning of coping mechanisms against stress is still not an integral part of medical education. In this pilot study we developed an elective course for learning relaxation techniques and examined the condition of the students before and after the course. 42 students participated in the semester courses in 2012 and 2013 as well as in a survey at the start and end of each course. The students were instructed in autogenic training (AT) and progressive muscle relaxation according to Jacobsen (PMR) with the goal of independent and regular exercising. At the beginning and the end of the semester/course the students were interviewed using standardized, validated questionnaires on burnout (BOSS-II) and anxiety (STAI-G), depression (BDI), quality of life (SF-12) and sense of coherence (SOC-L9). We compared the results of our students participating in Relacs with results from eight semester medical students (n = 88), assessed with the same questionnaires at similar points of time within their semester. Participating students showed a significant decline in cognitive and emotional burnout stress and in trait anxiety. Furthermore, they showed a reduction in state anxiety and a conspicuous decrease in mean depression. The sense of coherence increased at the same time. A comparative cohort of medical students of 8th semester students, showed lower values for the specified measurement parameters at the beginning, but showed no progressive changes. Our course introducing AT and PMR led to a significant reduction of burnout and anxiety within the participating group of medical students. Even the course attendance for just one semester resulted in significant improvements in the evaluated parameters in contrast to those students who did not attend the course. PMID- 25517401 TI - Multispot multiphoton Ca2+ imaging in acute myocardial slices. AB - Multiphoton microscopy has become essential for dynamic imaging in thick living tissues. High-rate, full-field image acquisition in multiphoton microscopy is achievable by parallelization of the excitation and detection pathways. We developed our approach via a diffractive optical element which splits a pulsed laser into 16 beamlets and exploits a descanned detection system consisting of an array of beamlet-associated photomultiplier tubes. The optical performance of the multiphoton multispot system (MCube) has been characterized in cardiac tissue sections and subsequently used for the first time for fluorescence imaging of cardiomyocyte Ca2+ dynamics in viable acute cardiac slices. Multispot multiphoton microscopy (MMM) has never been used before to monitor Ca2+ dynamics in thick, viable tissue samples. Acute heart slices are a powerful close-to-in vivo model of Ca2+ imaging allowing the simultaneous observation of several cells in their own tissue environment, exploiting the multiphoton excitation ability to penetrate scattering tissues. Moreover, we show that the concurrent high spatial and temporal resolutions afforded by the parallel scanning in MMM can be exploited to simultaneously assess subcellular Ca2+ dynamics in different cells in the tissue. We recorded local Ca2+ release events including macrosparks, travelling waves, and rotors. PMID- 25517402 TI - Lifestyle changes in the management of adulthood and childhood obesity. AB - Adulthood and childhood obesity is rapidly becoming an epidemic problem and it has a short and long term impact on health. Short term consequences are mostly represented by psychological effects, in fact obese children have more chances to develop psychological or psychiatric problems than non--obese children. The main long term effect is represented by the fact that childhood obesity continues into adulthood obesity and this results in negative effects in young adult life, since obesity increases the risk to develop morbidity and premature mortality. The obesity--related diseases are mostly represented by hypertension, type 2 diabetes, dyslipidaemia, cardiovascular diseases. Medical treatment should be discouraged in childhood because of the side effects and it should be only reserved for obese children with related medical complications. Lifestyle changes should be encouraged in both adulthood and childhood obesity. This review focuses on the management of obesity both in adulthood and in childhood, paying particular attention to lifestyle changes that should be recommended. PMID- 25517403 TI - Strong-field ionization of flash pyrolysis reaction products. AB - We report the coupling of a flash pyrolysis molecular beam source with nonresonant strong-field ionization in a time-of-flight mass spectrometer. The saturation laser intensities at which ionization occurs for the various product species are generally found to correlate closely with the ionization energies, as has been seen for closed-shell molecules. It is then possible to use this correlation to identify the product and quantify isomers from among several candidate species whose ionization energies are known. The approach is analogous to using tunable vacuum ultraviolet ionization to identify reaction products. PMID- 25517404 TI - Suicide-bereaved siblings' perception of health services. AB - The authors investigated suicide-bereaved siblings' reported reasons for seeking or not seeking professional support, their reported satisfaction when receiving it, and their recommendations to health services when meeting suicide-bereaved siblings. Using qualitative content analysis of 18 interviews with suicide bereaved siblings, the authors found that the perception of health services as being helpful was influenced by both the participants' and by the deceased siblings' experiences with health services. They conclude that the bereaved sibling's and the deceased sibling's unmet needs may generate negative attitudes toward health services, which reduces the likelihood of seeking professional help as well as medication acceptance in some cases. PMID- 25517407 TI - New frontiers in kinases. PMID- 25517405 TI - Visual search strategies of soccer players executing a power vs. placement penalty kick. AB - INTRODUCTION: When taking a soccer penalty kick, there are two distinct kicking techniques that can be adopted; a 'power' penalty or a 'placement' penalty. The current study investigated how the type of penalty kick being taken affected the kicker's visual search strategy and where the ball hit the goal (end ball location). METHOD: Wearing a portable eye tracker, 12 university footballers executed 2 power and placement penalty kicks, indoors, both with and without the presence of a goalkeeper. Video cameras were used to determine initial ball velocity and end ball location. RESULTS: When taking the power penalty, the football was kicked significantly harder and more centrally in the goal compared to the placement penalty. During the power penalty, players fixated on the football for longer and more often at the goalkeeper (and by implication the middle of the goal), whereas in the placement penalty, fixated longer at the goal, specifically the edges. Findings remained consistent irrespective of goalkeeper presence. DISCUSSION/CONCLUSION: Findings indicate differences in visual search strategy and end ball location as a function of type of penalty kick. When taking the placement penalty, players fixated and kicked the football to the edges of the goal in an attempt to direct the ball to an area that the goalkeeper would have difficulty reaching and saving. Fixating significantly longer on the football when taking the power compared to placement penalty indicates a greater importance of obtaining visual information from the football. This can be attributed to ensuring accurate foot-to-ball contact and subsequent generation of ball velocity. Aligning gaze and kicking the football centrally in the goal when executing the power compared to placement penalty may have been a strategy to reduce the risk of kicking wide of the goal altogether. PMID- 25517406 TI - Internal coordinate molecular dynamics: a foundation for multiscale dynamics. AB - Internal coordinates such as bond lengths, bond angles, and torsion angles (BAT) are natural coordinates for describing a bonded molecular system. However, the molecular dynamics (MD) simulation methods that are widely used for proteins, DNA, and polymers are based on Cartesian coordinates owing to the mathematical simplicity of the equations of motion. However, constraints are often needed with Cartesian MD simulations to enhance the conformational sampling. This makes the equations of motion in the Cartesian coordinates differential-algebraic, which adversely impacts the complexity and the robustness of the simulations. On the other hand, constraints can be easily placed in BAT coordinates by removing the degrees of freedom that need to be constrained. Thus, the internal coordinate MD (ICMD) offers an attractive alternative to Cartesian coordinate MD for developing multiscale MD method. The torsional MD method is a special adaptation of the ICMD method, where all the bond lengths and bond angles are kept rigid. The advantages of ICMD simulation methods are the longer time step size afforded by freezing high frequency degrees of freedom and performing a conformational search in the more important low frequency torsional degrees of freedom. However, the advancements in the ICMD simulations have been slow and stifled by long-standing mathematical bottlenecks. In this review, we summarize the recent mathematical advancements we have made based on spatial operator algebra, in developing a robust long time scale ICMD simulation toolkit useful for various applications. We also present the applications of ICMD simulations to study conformational changes in proteins and protein structure refinement. We review the advantages of the ICMD simulations over the Cartesian simulations when used with enhanced sampling methods and project the future use of ICMD simulations in protein dynamics. PMID- 25517408 TI - Evaluating the clinical and physiological effects of long term ultraviolet B radiation on guinea pigs (Cavia porcellus). AB - Vitamin D is an important hormone in vertebrates. Most animals acquire this hormone through their diet, secondary to exposure to ultraviolet B (UVB) radiation, or a combination thereof. The objectives for this research were to evaluate the clinical and physiologic effects of artificial UVB light supplementation on guinea pigs (Cavia porcellus) and to evaluate the long-term safety of artificial UVB light supplementation over the course of six months. Twelve juvenile acromelanic Hartley guinea pigs were randomly assigned to one of two treatment groups: Group A was exposed to 12 hours of artificial UVB radiation daily and Group B received only ambient fluorescent light for 12 hours daily. Animals in both groups were offered the same diet and housed under the same conditions. Blood samples were collected every three weeks to measure blood chemistry values, parathyroid hormone, ionized calcium, and serum 25 hydroxyvitamin D3 (25-OHD3) levels. Serial ophthalmologic examinations, computed tomography scans, and dual energy x-ray absorptiometry scans were performed during the course of the study. At the end of the study the animals were euthanized and necropsied. Mean +/- SD serum 25-OHD3 concentrations differed significantly in the guinea pigs (p<0.0001) between the UVB supplementation group (101.49+/-21.81 nmol/L) and the control group (36.33+/-24.42 nmol/L). An increased corneal thickness in both eyes was also found in the UVB supplementation compared to the control group (right eye [OD]: p<0.0001; left eye [OS]: p<0.0001). There were no apparent negative clinical or pathologic side effects noted between the groups. This study found that exposing guinea pigs to UVB radiation long term significantly increased their circulating serum 25-OHD3 levels, and that this increase was sustainable over time. Providing guinea pigs exposure to UVB may be an important husbandry consideration that is not currently recommended. PMID- 25517409 TI - Effects of timber harvests and silvicultural edges on terrestrial salamanders. AB - Balancing timber production and conservation in forest management requires an understanding of how timber harvests affect wildlife species. Terrestrial salamanders are useful indicators of mature forest ecosystem health due to their importance to ecosystem processes and sensitivity to environmental change. However, the effects of timber harvests on salamanders, though often researched, are still not well understood. To further this understanding, we used artificial cover objects to monitor the relative abundance of terrestrial salamanders for two seasons (fall and spring) pre-harvest and five seasons post-harvest in six forest management treatments, and for three seasons post-harvest across the edge gradients of six recent clearcuts. In total, we recorded 19,048 encounters representing nine species of salamanders. We observed declines in mean encounters of eastern red-backed salamanders (Plethodon cinereus) and northern slimy salamanders (P. glutinosus) from pre- to post-harvest in group selection cuts and in clearcuts. However, we found no evidence of salamander declines at shelterwoods and forested sites adjacent to harvests. Edge effects induced by recent clearcuts influenced salamanders for approximately 20 m into the forest, but edge influence varied by slope orientation. Temperature, soil moisture, and canopy cover were all correlated with salamander counts. Our results suggest silvicultural techniques that remove the forest canopy negatively affect salamander relative abundance on the local scale during the years immediately following harvest, and that the depth of edge influence of clearcuts on terrestrial salamanders is relatively shallow (<20 m). Small harvests (<4 ha) and techniques that leave the forest canopy intact may be compatible with maintaining terrestrial salamander populations across a forested landscape. Our results demonstrate the importance of examining species-specific responses and monitoring salamanders across multiple seasons and years. Long-term monitoring will be necessary to understand the full impacts of forest management on terrestrial salamanders. PMID- 25517410 TI - A cost-utility analysis of the use of preoperative computed tomographic angiography in abdomen-based perforator flap breast reconstruction. AB - BACKGROUND: Computed tomographic angiography is a diagnostic tool increasingly used for preoperative vascular mapping in abdomen-based perforator flap breast reconstruction. This study compared the use of computed tomographic angiography and the conventional practice of Doppler ultrasonography only in postmastectomy reconstruction using a cost-utility model. METHODS: Following a comprehensive literature review, a decision analytic model was created using the three most clinically relevant health outcomes in free autologous breast reconstruction with computed tomographic angiography versus Doppler ultrasonography only. Cost and utility estimates for each health outcome were used to derive the quality adjusted life-years and incremental cost-utility ratio. One-way sensitivity analysis was performed to scrutinize the robustness of the authors' results. RESULTS: Six studies and 782 patients were identified. Cost-utility analysis revealed a baseline cost savings of $3179, a gain in quality-adjusted life-years of 0.25. This yielded an incremental cost-utility ratio of -$12,716, implying a dominant choice favoring preoperative computed tomographic angiography. Sensitivity analysis revealed that computed tomographic angiography was costlier when the operative time difference between the two techniques was less than 21.3 minutes. However, the clinical advantage of computed tomographic angiography over Doppler ultrasonography only showed that computed tomographic angiography would still remain the cost-effective option even if it offered no additional operating time advantage. CONCLUSIONS: The authors' results show that computed tomographic angiography is a cost-effective technology for identifying lower abdominal perforators for autologous breast reconstruction. Although the perfect study would be a randomized controlled trial of the two approaches with true cost accrual, the authors' results represent the best available evidence. PMID- 25517411 TI - Cost-effectiveness analysis of implants versus autologous perforator flaps using the BREAST-Q. AB - BACKGROUND: Reimbursement has been recognized as a physician barrier to autologous reconstruction. Autologous reconstructions are more expensive than prosthetic reconstructions, but provide greater health-related quality of life. The authors' hypothesis is that autologous tissue reconstructions are cost effective compared with prosthetic techniques when considering health-related quality of life and patient satisfaction. METHODS: A cost-effectiveness analysis from the payer perspective, including patient input, was performed for unilateral and bilateral reconstructions with deep inferior epigastric perforator (DIEP) flaps and implants. The effectiveness measure was derived using the BREAST-Q and interpreted as the cost for obtaining 1 year of perfect breast health-related quality-adjusted life-year. Costs were obtained from the 2010 Nationwide Inpatient Sample. The incremental cost-effectiveness ratio was generated. A sensitivity analysis for age and stage at diagnosis was performed. RESULTS: BREAST-Q scores from 309 patients with implants and 217 DIEP flap reconstructions were included. The additional cost for obtaining 1 year of perfect breast-related health for a unilateral DIEP flap compared with implant reconstruction was $11,941. For bilateral DIEP flaps compared with implant reconstructions, the cost for an additional breast health-related quality-adjusted life-year was $28,017. The sensitivity analysis demonstrated that the cost for an additional breast health-related quality-adjusted life-year for DIEP flaps compared with implants was less for younger patients and earlier stage breast cancer. CONCLUSIONS: DIEP flaps are cost-effective compared with implants, especially for unilateral reconstructions. Cost-effectiveness of autologous techniques is maximized in women with longer life expectancy. Patient-reported outcomes findings can be incorporated into cost-effectiveness analyses to demonstrate the relative value of reconstructive procedures. PMID- 25517412 TI - Estimating implementation and operational costs of an integrated tiered CD4 service including laboratory and point of care testing in a remote health district in South Africa. AB - BACKGROUND: An integrated tiered service delivery model (ITSDM) has been proposed to provide 'full-coverage' of CD4 services throughout South Africa. Five tiers are described, defined by testing volumes and number of referring health facilities. These include: (1) Tier-1/decentralized point-of-care service (POC) in a single site; Tier-2/POC-hub servicing processing < 30-40 samples from 8-10 health-clinics; Tier-3/Community laboratories servicing ~ 50 health-clinics, processing < 150 samples/day; high-volume centralized laboratories (Tier-4 and Tier-5) processing < 300 or > 600 samples/day and serving > 100 or > 200 health clinics, respectively. The objective of this study was to establish costs of existing and ITSDM-tiers 1, 2 and 3 in a remote, under-serviced district in South Africa. METHODS: Historical health-facility workload volumes from the Pixley-ka Seme district, and the total volumes of CD4 tests performed by the adjacent district referral CD4 laboratories, linked to locations of all referring clinics and related laboratory-to-result turn-around time (LTR-TAT) data, were extracted from the NHLS Corporate-Data-Warehouse for the period April-2012 to March-2013. Tiers were costed separately (as a cost-per-result) including equipment, staffing, reagents and test consumable costs. A one-way sensitivity analyses provided for changes in reagent price, test volumes and personnel time. RESULTS: The lowest cost-per-result was noted for the existing laboratory-based Tiers- 4 and 5 ($6.24 and $5.37 respectively), but with related increased LTR-TAT of > 24 48 hours. Full service coverage with TAT < 6-hours could be achieved with placement of twenty-seven Tier-1/POC or eight Tier-2/POC-hubs, at a cost-per result of $32.32 and $15.88 respectively. A single district Tier-3 laboratory also ensured 'full service coverage' and < 24 hour LTR-TAT for the district at $7.42 per-test. CONCLUSION: Implementing a single Tier-3/community laboratory to extend and improve delivery of services in Pixley-ka-Seme, with an estimated local ~ 12-24-hour LTR-TAT, is ~ $2 more than existing referred services per test, but 2-4 fold cheaper than implementing eight Tier-2/POC-hubs or providing twenty-seven Tier-1/POCT CD4 services. PMID- 25517413 TI - Total synthesis of clavatadine A. AB - The first total synthesis of the potent and selective human blood coagulation factor XIa inhibitor clavatadine A (1) is described. Direct, early-stage guanidinylation enabled rapid, convergent access to an immediate clavatadine A precursor. Concomitant lactone hydrolysis and guanidine deprotection with aqueous acid cleanly provided clavatadine A (1) in only four steps (longest linear sequence, 41-43% overall yield). PMID- 25517414 TI - Protective effects of cannabidiol on lesion-induced intervertebral disc degeneration. AB - Disc degeneration is a multifactorial process that involves hypoxia, inflammation, neoinnervation, accelerated catabolism, and reduction in water and glycosaminoglycan content. Cannabidiol is the main non-psychotropic component of the Cannabis sativa with protective and anti-inflammatory properties. However, possible therapeutic effects of cannabidiol on intervertebral disc degeneration have not been investigated yet. The present study investigated the effects of cannabidiol intradiscal injection in the coccygeal intervertebral disc degeneration induced by the needle puncture model using magnetic resonance imaging (MRI) and histological analyses. Disc injury was induced in the tail of male Wistar rats via a single needle puncture. The discs selected for injury were punctured percutaneously using a 21-gauge needle. MRI and histological evaluation were employed to assess the results. The effects of intradiscal injection of cannabidiol (30, 60 or 120 nmol) injected immediately after lesion were analyzed acutely (2 days) by MRI. The experimental group that received cannabidiol 120 nmol was resubmitted to MRI examination and then to histological analyses 15 days after lesion/cannabidiol injection. The needle puncture produced a significant disc injury detected both by MRI and histological analyses. Cannabidiol significantly attenuated the effects of disc injury induced by the needle puncture. Considering that cannabidiol presents an extremely safe profile and is currently being used clinically, these results suggest that this compound could be useful in the treatment of intervertebral disc degeneration. PMID- 25517417 TI - Authors' response: Regarding the paper 'The impact of a supermarket nutrition rating system on purchases of nutritious and less nutritious foods' by Cawley et al. PMID- 25517415 TI - Formation of hydrogen sulfide from cysteine in Saccharomyces cerevisiae BY4742: genome wide screen reveals a central role of the vacuole. AB - Discoveries on the toxic effects of cysteine accumulation and, particularly, recent findings on the many physiological roles of one of the products of cysteine catabolism, hydrogen sulfide (H2S), are highlighting the importance of this amino acid and sulfur metabolism in a range of cellular activities. It is also highlighting how little we know about this critical part of cellular metabolism. In the work described here, a genome-wide screen using a deletion collection of Saccharomyces cerevisiae revealed a surprising set of genes associated with this process. In addition, the yeast vacuole, not previously associated with cysteine catabolism, emerged as an important compartment for cysteine degradation. Most prominent among the vacuole-related mutants were those involved in vacuole acidification; we identified each of the eight subunits of a vacuole acidification sub-complex (V1 of the yeast V-ATPase) as essential for cysteine degradation. Other functions identified included translation, RNA processing, folate-derived one-carbon metabolism, and mitochondrial iron-sulfur homeostasis. This work identified for the first time cellular factors affecting the fundamental process of cysteine catabolism. Results obtained significantly contribute to the understanding of this process and may provide insight into the underlying cause of cysteine accumulation and H2S generation in eukaryotes. PMID- 25517416 TI - Hormone and Drug-Mediated Modulation of Glucose Metabolism in a Microscale Model of the Human Liver. AB - Due to its central role in glucose homeostasis, the liver is an important target for drug development efforts for type 2 diabetes mellitus (T2DM). Significant differences across species in liver metabolism necessitate supplementation of animal data with assays designed to assess human-relevant responses. However, isolated primary human hepatocytes (PHHs) display a rapid decline in phenotypic functions in conventional monolayer formats. Cocultivation of PHHs with specific stromal cells, especially in micropatterned configurations, can stabilize some liver functions for ~4 weeks in vitro. However, it remains unclear whether coculture approaches can stabilize glucose metabolism that can be modulated with hormones in PHHs. Thus, in this study, we compared commonly employed conventional culture formats and previously developed micropatterned cocultures (MPCCs) of cryopreserved PHHs and stromal fibroblasts for mRNA expression of key glucose metabolism genes (i.e., phosphoenolpyruvate carboxykinase-1 [PCK1]) and sensitivity of gluconeogenesis to prototypical hormones, insulin and glucagon. We found that only MPCCs displayed high expression of all transcripts tested for at least 2 weeks and robust gluconeogenesis with responsiveness to hormones for at least 3 weeks in vitro. Furthermore, MPCCs displayed glycogen storage and lysis, which could be modulated with hormones under the appropriate feeding and fasting states, respectively. Finally, we utilized MPCCs in proof-of-concept experiments where we tested gluconeogenesis inhibitors and evaluated the effects of stimulation with high levels of glucose as in T2DM. Gluconeogenesis in MPCCs was decreased after stimulation with drugs (i.e., metformin) and the PHHs accumulated significant amount of lipids following incubation with excess glucose (i.e., 340% in 50 mM glucose relative to physiologic 5 mM glucose controls). In conclusion, MPCCs provide a platform to study glucose metabolism and hormonal responsiveness in cryopreserved PHHs from multiple donors for several weeks in vitro. This model is also useful to study the effects of drugs and overnutrition for applications in T2DM. PMID- 25517418 TI - Lack of association between the 5-HTTLPR and positive screening for mental disorders among children exposed to urban violence and maltreatment. AB - OBJECTIVE: To ascertain whether genetic variations in the serotonin transporter gene (5-HTTLPR 44-bp insertion/deletion polymorphism) influence an increase in depressive and anxiety symptoms in children and adolescents exposed to high levels of violence. METHODS: Saliva samples were collected from a group of children who were working on the streets and from their siblings who did not work on the streets. DNA was extracted from the saliva samples and analyzed for 5 HTTLPR polymorphism genotypes. RESULTS: One hundred and seventy-seven children between the ages of 7 and 14 years were analyzed (114 child workers and 63 siblings). Data on socioeconomic conditions, mental symptoms, and presence and severity of maltreatment and urban violence were collected using a sociodemographic inventory and clinical instruments. There was no positive correlation between the 5-HTTLPR polymorphism and presence of mental symptoms in our sample, although the children were exposed to high levels of abuse, neglect, and urban violence. CONCLUSIONS: Despite previous studies that associated adult psychiatric disorders with the 5-HTTLPR polymorphism and a history of childhood maltreatment, no such association was found in this sample of children at risk. PMID- 25517419 TI - A fatal case of ischemic colitis during clozapine administration. PMID- 25517420 TI - Developmental risks associated with use of psychoactive drugs during pregnancy are largely unknown. PMID- 25517421 TI - Developmental risks associated with use of psychoactive drugs during pregnancy are largely unknown. Authors' reply. PMID- 25517422 TI - A comparison between end-of-life home care clients with cancer and heart failure in Ontario. AB - Individuals with heart failure experience complex symptoms and have a poor prognosis, comparable to those with cancer. However, people with heart failure are less likely to be recognized as needing palliative care. We compared seriously ill home care clients with cancer versus those with heart failure to explore differences between them using existing data from the Resident Assessment Instrument for Home Care (RAI-HC). The sample included 1,475 older adults (65+) in Ontario who had a prognosis of less than 6 months or severe health instability. Clients with heart failure were significantly older (p < .0001) and experienced significantly higher rates of impairment in activities of daily living (p = .005), cognitive impairment (p < .0001), and severe health instability (p < .0001), but were significantly less likely to have a prognosis of less than 6 months (p < .0001). Home care clients with heart failure have needs similar to those with cancer yet are typically not identified as having a terminal prognosis. PMID- 25517424 TI - Metal-promoted intermolecular electron transfer in tetrathiafulvalene thiacalix[4]arene conjugates and tetrachlorobenzoquinone. AB - In this work, two series of tetrathiafulvalene (TTF) and thiacalix[4]arene (TCA) conjugates (TTF-TCA) were designed by CuAAC click reactions. The results obtained from NMR and (1)H NMR NOE indicated that their conformations of thiacalix[4]arene framework may prefer to 1,3-alternate. The cyclic voltammograms of four TTF-TCA compounds containing electroactive TTF units were provided. Meanwhile, their intermolecular electron-transfer (ET) behaviors with tetrachlorobenzoquinone (Q) mediated by different metal ions, Sc(3+), Pb(2+), Ag(+), Cd(2+), and Zn(2+), in CH3CN-CH2Cl2 (V/V = 1:1) solution were studied and analyzed via UV-vis spectroscopy. It was determined that intermolecular ET between each TTF-TCA and Q ensemble was not observed without introduction of the metal ions mentioned above. The added specified metal ions most likely induced the intermolecular ET between TTF-TCA and Q ensemble, and the effects of Sc(3+) functions were the most imperative. The intermolecular ET also proved to be reliant on the structure of TTF-TCA, where TTF-TCA 7a and 7b were more effective than TTF-TCA 6a and 6b. The difference may be credited to TTF-TCA 7a or 7b possessing two independent TTF pendants and providing a more synergic coordination among the TTF radical cation and Q radical anion with a metal ion. PMID- 25517423 TI - Sensitive targeted quantification of ERK phosphorylation dynamics and stoichiometry in human cells without affinity enrichment. AB - Targeted mass spectrometry is a promising technology for site-specific quantification of posttranslational modifications. However, a major constraint is the limited sensitivity for quantifying low-abundance PTMs, requiring the use of affinity reagents for enrichment. Herein, we demonstrate the direct site-specific quantification of ERK phosphorylation isoforms (pT, pY, pTpY) and their relative stoichiometry using a sensitive targeted MS approach termed high-pressure, high resolution separations with intelligent selection, and multiplexing (PRISM). PRISM provides effective enrichment of target peptides into a given fraction from complex mixture, followed by selected reaction monitoring quantification. Direct quantification of ERK phosphorylation in human mammary epithelial cells (HMEC) was demonstrated from as little as 25 MUg tryptic peptides from whole cell lysates. Compared to immobilized metal-ion affinity chromatography, PRISM provided ~10-fold higher signal intensities, presumably due to the better peptide recovery of PRISM. This approach was applied to quantify ERK phosphorylation dynamics in HMEC treated by different doses of epidermal growth factor at both the peak activation (10 min) and steady state (2 h). The maximal ERK activation was observed with 0.3 and 3 ng/mL doses for 10 min and 2 h time points, respectively. The dose-response profiles of individual phosphorylated isoforms showed that singly phosphorylated pT-ERK never increases significantly, while the increase of pY-ERK paralleled that of pTpY-ERK. This data supports for a processive, rather than distributed model of ERK phosphorylation. The PRISM-SRM quantification of protein phosphorylation illustrates the potential for simultaneous quantification of multiple PTMs. PMID- 25517425 TI - Silver nanoclusters-based fluorescence assay of protein kinase activity and inhibition. AB - A simple and sensitive fluorescence method for monitoring the activity and inhibition of protein kinase (PKA) has been developed using polycytosine oligonucleotide (dC12)-templated silver nanoclusters (Ag NCs). Adenosine-5' triphosphate (ATP) was found to enhance the fluorescence of Ag NCs, while the hydrolysis of ATP to adenosine diphosphate (ADP) by PKA decreased the fluorescence of Ag NCs. Compared to the existing methods for kinase activity assay, the developed method does not involve phosphorylation of the substrate peptides, which significantly simplifies the detection procedures. The method exhibits high sensitivity, good selectivity, and wide linear range toward PKA detection. The inhibition effect of kinase inhibitor H-89 on the activity of PKA was also studied. The sensing protocol was also applied to the assay of drug stimulated activation of PKA in HeLa cell lysates. PMID- 25517426 TI - Capillary-like network formation by human amniotic fluid-derived stem cells within fibrin/poly(ethylene glycol) hydrogels. AB - A major limitation in tissue engineering strategies for congenital birth defects is the inability to provide a significant source of oxygen, nutrient, and waste transport in an avascular scaffold. Successful vascularization requires a reliable method to generate vascular cells and a scaffold capable of supporting vessel formation. The broad potential for differentiation, high proliferation rates, and autologous availability for neonatal surgeries make amniotic fluid derived stem cells (AFSC) well suited for regenerative medicine strategies. AFSC derived endothelial cells (AFSC-EC) express key proteins and functional phenotypes associated with endothelial cells. Fibrin-based hydrogels were shown to stimulate AFSC-derived network formation in vitro but were limited by rapid degradation. Incorporation of poly(ethylene glycol) (PEG) provided mechanical stability (65%+/-9% weight retention vs. 0% for fibrin-only at day 14) while retaining key benefits of fibrin-based scaffolds-quick formation (10+/-3 s), biocompatibility (88%+/-5% viability), and vasculogenic stimulation. To determine the feasibility of AFSC-derived microvasculature, we compared AFSC-EC as a vascular cell source and AFSC as a perivascular cell source to established sources of these cell types-human umbilical vein endothelial cells (HUVEC) and mesenchymal stem cells (MSC), respectively. Cocultures were seeded at a 4:1 endothelial-to-perivascular cell ratio, and gels were incubated at 37 degrees C for 2 weeks. Mechanical testing was performed using a stress-controlled rheometer (G'=95+/-10 Pa), and cell-seeded hydrogels were assessed based on morphology. Network formation was analyzed based on key parameters such as vessel thickness, length, and area, as well as the degree of branching. There was no statistical difference between individual cultures of AFSC-EC and HUVEC in regard to these parameters, suggesting the vasculogenic potential of AFSC-EC; however, the development of robust vessels required the presence of both an endothelial and a perivascular cell source and was seen in AFSC cocultures (70%+/-20% vessel length, 90%+/-10% vessel area, and 105%+/-10% vessel thickness compared to HUVEC/MSC). At a fixed seeding density, the coculture of AFSC with AFSC-EC resulted in a synergistic effect on network parameters similar to MSC (150% vessel length, 147% vessel area, 150% vessel thickness, and 155% branching). These results suggest that AFSC-EC and AFSC have significant vasculogenic and perivasculogenic potential, respectively, and are suited for in vivo evaluation. PMID- 25517430 TI - Ultrafast cooling reveals microsecond-scale biomolecular dynamics. AB - The temperature-jump technique, in which the sample is rapidly heated by a powerful laser pulse, has been widely used to probe the fast dynamics of folding of proteins and nucleic acids. However, the existing temperature-jump setups tend to involve sophisticated and expensive instrumentation, while providing only modest temperature changes of ~10-15 degrees C, and the temperature changes are only rapid for heating, but not cooling. Here we present a setup comprising a thermally conductive sapphire substrate with light-absorptive nano-coating, a microfluidic device and a rapidly switched moderate-power infrared laser with the laser beam focused on the nano-coating, enabling heating and cooling of aqueous solutions by ~50 degrees C on a 1-MUs time scale. The setup is used to probe folding and unfolding dynamics of DNA hairpins after direct and inverse temperature jumps, revealing low-pass filter behaviour during periodic temperature variations. PMID- 25517429 TI - Alternatives to antibiotics in semen extenders: a review. AB - Antibiotics are added to semen extenders to be used for artificial insemination (AI) in livestock breeding to control bacterial contamination in semen arising during collection and processing. The antibiotics to be added and their concentrations for semen for international trade are specified by government directives. Since the animal production industry uses large quantities of semen for artificial insemination, large amounts of antibiotics are currently used in semen extenders. Possible alternatives to antibiotics are discussed, including physical removal of the bacteria during semen processing, as well as the development of novel antimicrobials. Colloid centrifugation, particularly Single Layer Centrifugation, when carried out with a strict aseptic technique, offers a feasible method for reducing bacterial contamination in semen and is a practical method for semen processing laboratories to adopt. However, none of these alternatives to antibiotics should replace strict attention to hygiene during semen collection and handling. PMID- 25517428 TI - Smoking-Associated Site-Specific Differential Methylation in Buccal Mucosa in the COPDGene Study. AB - DNA methylation is a complex, tissue-specific phenomenon that can reflect both endogenous factors and exogenous exposures. Buccal brushings represent an easily accessible source of DNA, which may be an appropriate surrogate tissue in the study of environmental exposures and chronic respiratory diseases. Buccal brushings were obtained from a subset of current and former smokers from the COPDGene study. Genome-wide DNA methylation data were obtained in the discovery cohort (n = 82) using the Illumina HumanMethylation450K array. Empirical Bayes methods were used to test for differential methylation by current smoking status at 468,219 autosomal CpG sites using linear models adjusted for age, sex, and race. Pyrosequencing was performed in a nonoverlapping replication cohort (n = 130). Current smokers were significantly younger than former smokers in both the discovery and replication cohorts. Seven CpG sites were associated with current smoking at a false discovery rate less than 0.05 in the discovery cohort. Six of the seven significant sites were pyrosequenced in the replication cohort; five CpG sites, including sites annotated to CYP1B1 and PARVA, were replicated. Correlations between cumulative smoke exposure and time since smoking cessation were observed in a subset of the significantly associated CpG sites. A significant correlation between reduced lung function and increased radiographic emphysema with methylation at cg02162897 (CYP1B1) was observed among female subjects. Site-specific methylation of DNA isolated from buccal mucosa is associated with exposure to cigarette smoke, and may provide insights into the mechanisms underlying differential susceptibility toward the development of smoking-related chronic respiratory diseases. PMID- 25517431 TI - Behavioral abnormalities in prion protein knockout mice and the potential relevance of PrP(C) for the cytoskeleton. AB - The cellular prion protein (PrP(C)) is a highly conserved protein, which is anchored to the outer surface of the plasma membrane. Even though its physiological function has already been investigated in different cell or mouse models where PrP(C) expression is either upregulated or depleted, its exact physiological role in a mammalian organism remains elusive. Recent studies indicate that PrP(C) has multiple functions and is involved in cognition, learning, anxiety, locomotion, depression, offensive aggression and nest building behavior. While young animals (3 months of age) show only marginal abnormalities, most of the deficits become apparent as the animals age, which might indicate its role in neurodegeneration or neuroprotection. However, the exact biochemical mechanism and signal transduction pathways involving PrP(C) are only gradually becoming clearer. We report the observations made in different studies using different Prnp0/0 mouse models and propose that PrP(C) plays an important role in the regulation of the cytoskeleton and associated proteins. In particular, we showed a nocodazole treatment influenced colocalization of PrP(C) and alpha tubulin 1. In addition, we confirmed the observed deficits in nest building using a different backcrossed Prnp0/0 mouse line. PMID- 25517432 TI - A biomimetic strategy to access the silybins: total synthesis of (-)-isosilybin A. AB - We report the first asymmetric, total synthesis of (-)-isosilybin A. A late-stage catalytic biomimetic cyclization of a highly functionalized chalcone is employed to form the characteristic benzopyranone ring. A robust and flexible approach to this chalcone provides an entry to the preparation of the entire isomeric family of silybin natural products. PMID- 25517434 TI - Primary laryngeal cancer-derived miR-193b induces interleukin-10-expression monocytes. AB - The pathogenesis of laryngeal cancer (LC) is unclear. Published data indicate that micro RNAs (miRNA) play an important role in the pathogenesis of cancer. This study aims to elucidate the role of miR-193b in the tumor tolerance of LC. High levels of miR-193b were detected in LC cells as well as in the culture supernatant. Interleukin (IL)-10-expressing Mos were detected in the LC tissue derived single cells. Treating naive Mos with a miR-193b induced expression of IL 10 in the Mos. Culturing the IL-10(+) Mos with effector CD8(+) T cells resulted in the suppression of CD8(+) T-cell activities. PMID- 25517436 TI - Enhancing the role of physical therapy in venous leg ulcer management. PMID- 25517435 TI - The Rho family GEF Asef2 regulates cell migration in three dimensional (3D) collagen matrices through myosin II. AB - Cell migration is fundamental to a variety of physiological processes, including tissue development, homeostasis, and regeneration. Migration has been extensively studied with cells on 2-dimensional (2D) substrates, but much less is known about cell migration in 3D environments. Tissues and organs are 3D, which is the native environment of cells in vivo, pointing to a need to understand migration and the mechanisms that regulate it in 3D environments. To investigate cell migration in 3D environments, we developed microfluidic devices that afford a controlled, reproducible platform for generating 3D matrices. Using these devices, we show that the Rho family guanine nucleotide exchange factor (GEF) Asef2 inhibits cell migration in 3D type I collagen (collagen I) matrices. Treatment of cells with the myosin II (MyoII) inhibitor blebbistatin abolished the decrease in migration by Asef2. Moreover, Asef2 enhanced MyoII activity as shown by increased phosphorylation of serine 19 (S19). Furthermore, Asef2 increased activation of Rac, which is a Rho family small GTPase, in 3D collagen I matrices. Inhibition of Rac activity by treatment with the Rac-specific inhibitor NSC23766 abrogated the Asef2-promoted increase in S19 MyoII phosphorylation. Thus, our results indicate that Asef2 regulates cell migration in 3D collagen I matrices through a Rac-MyoII dependent mechanism. PMID- 25517438 TI - Thromboxane-dependent platelet activation after gastric banding for obesity. PMID- 25517439 TI - Dragging scientific publishing into the 21st century. AB - Scientific publishers must shake off three centuries of publishing on paper and embrace 21st century technology to make scientific communication more intelligible, reproducible, engaging and rapidly available. PMID- 25517437 TI - Prediction of antibiotic resistance by gene expression profiles. AB - Although many mutations contributing to antibiotic resistance have been identified, the relationship between the mutations and the related phenotypic changes responsible for the resistance has yet to be fully elucidated. To better characterize phenotype-genotype mapping for drug resistance, here we analyse phenotypic and genotypic changes of antibiotic-resistant Escherichia coli strains obtained by laboratory evolution. We demonstrate that the resistances can be quantitatively predicted by the expression changes of a small number of genes. Several candidate mutations contributing to the resistances are identified, while phenotype-genotype mapping is suggested to be complex and includes various mutations that cause similar phenotypic changes. The integration of transcriptome and genome data enables us to extract essential phenotypic changes for drug resistances. PMID- 25517440 TI - [New challenges and perspectives in nuclear medicine imaging]. AB - Hybrid positron emission tomography/computer tomography (PET/CT) and single photon emission computer tomography/computer tomography (SPECT/CT) have resulted in significant advances both in medical research and routine clinical use. The most recent multimodality system that combines PET and magnetic resonance imaging (MRI) offers new potentials unthinkable before. The hybrid techniques allow obtaining simultaneous morphologic, functional, and molecular information of a living system. The proper use of multimodality imaging is of high importance as they facilitate both basic medical research and clinical practice. PMID- 25517441 TI - [SPECT radiopharmaceuticals -- novelties and new possibilities]. AB - Actual state of affairs and future perspectives of SPECT radiopharmaceuticals regarding local and international data were summarized. Beyond conventional gamma emitting radioisotopes, localization studies with beta emitting therapeutic radiopharmaceuticals hold increasing importance. Extension of hybrid (SPECT/CT) equipments has modified conventional scintigraphic and SPECT methods as well but more important changes come into the world through novel ligands for specific diagnoses and therapy. PMID- 25517442 TI - [PET radiopharmaceuticals: novelties and new possibilities]. AB - 18F-fluoro-deoxyglucose (FDG) can be considered as the "work-horse" of PET/CT and PET/MR imaging modalities. FDG provides insight in the pathophysiology of tumors and metastases from the point of view of sugar consumption. On the other hand, amino acid metabolism, expression of various receptors in the cells or on the surface of the cells, angiogenesis, appearance of hypoxic cells/tissues and apoptosis also participate in the pathophysiological processes and may have importance in determining the treatment strategy for patients or in monitoring the chosen therapy. Many molecules involved can be labeled by (18)F radionuclide but certain metabolisms require (11)C-labelled agents. Molecular imaging is of key importance in cancer research and various metal complexes containing (44)Sc, (64)Cu, (68)Ga, (86)Y, (89)Zr positron emitters can be very useful in this activity. PMID- 25517443 TI - [New trends in functional medical imaging: quantitative methods]. AB - Deriving quantitative measures from the medical imaging methods is a key issue for the optimal oncologic therapy, when the anatomical abnormalities and changes of the metabolic state of the tissues need to be characterized. In order to improve the effectiveness of the therapy, the results of medical imaging procedures should be comparable after two or more consecutive scans. There are several tomographic imaging applications (CT, MRI, SPECT and PET), but in this work we will focus on the quantitative capability of PET, because this method provides the most versatile possibilities for quantifying the resulting images. PMID- 25517444 TI - [Novelties and new possibilities in radiological diagnostics of brain tumors]. AB - Modern MR imaging with advanced techniques such as diffusion, perfusion and functional imaging as well as spectroscopy have improved the characterization of brain tumors. Unlike conventional imaging providing mainly anatomical or structural information, these advanced applications give insight into the microstructure and physiology of brain tumors. Several biomarkers are available which correlate with tumor cellularity, microstructure, vascularity and metabolism. These techniques not only aid in the imaging diagnosis and treatment planning of brain tumors, but they also play a role in clinical management and monitoring treatment effect. PMID- 25517445 TI - [New opportunities, MRI biomarkers in the evaluation of head and neck cancer]. AB - Magnetic resonance imaging (MRI) has developed rapidly during the past few years and, according to the needs of therapy, has opened new perspectives in oncologic imaging with better and better realization of the latest technological advances. After the introduction of "organ preservation" protocols the role of imaging has become more important. New therapeutic methods (improvement in radiation therapy and chemotherapy) need better tumor characterization and prognostic information along with the most accurate anatomical information. Multiparametric anatomical and functional MR imaging (MM-MRI) using high magnetic field strength (3 Tesla) are useful in determining tumor-specific MRI biomarkers and in evaluating the changes in these parameters during therapy to provide early assessment of the therapeutic response. Diffusion-weighted MRI (DW-MRI) provides information at the cellular level about cell density and the integrity of the plasma membrane. DW MRI shows potential in improving the detection of cancer due to its high specificity and high negative predictive value. Quantification is performed using an apparent diffusion coefficient (ADC), the values are independent of the magnetic field strength. In the latest publications the accuracy of DW-MRI has been reported around 90% for the differentiation between malignant versus benign tumor using an ADC cut-off mean value of 0.700-1.200 10(-3) mm(2)/s units, but no common threshold ADC value exists in clinical routine for the differentiation of malignant and benign tissues. Dynamic contrast-enhanced MRI (DCE-MRI), as a marker of angiogenesis, provides information about vascularization at the tissue level. Angiogenetic alterations cause changes in the parameters of vascular physiology (perfusion, blood volume, capillary permeability) and thus alter the contrast enhancement observed on contrast MRI. High-grade and/or advanced stage tumors are associated with increased blood volume, increased permeability and increased perfusion; the data can be evaluated using semiquantitative or quantitative methods. Magnetic resonance spectroscopic imaging (MRSI) provides biochemical analysis at the molecular level. The results are promising, although further studies are required to determine whether MRSI can be used to identify or exclude cancer within regions where the cancer is not evident on conventional MRI or with the other functional imaging methods. Some of the studies demonstrated the usefulness of these functional MRI methods also in the head and neck region to differentiate benign from malignant tumors, to quantify the response to radiation therapy and chemotherapy, to identify residual or recurrent tumor and to correlate the perfusion or diffusion data with prognosis. There are still some overlaps between benign and malignant changes, and the use of these functional MR measurements in routine diagnostics are still not fully validated today. Functional MR measurements are useful parts of the high quality multiparametric MRI, they offer important supportive biological and molecular information with the aid of high resolution morphological imaging. PMID- 25517446 TI - [Novelties and new possibilities in the radiological diagnostics of kidney and ureter tumors]. AB - The author analyses the opportunities granted by diagnostic imaging for the early perception of kidney and urethral tumors and exact tumor staging. The wide-scale application of non-invasive ultrasound scans has lead to an increase in incidentalomas. Volumetric (multidetector or dual source) CT scans, the various MR techniques and, more recently, PET/CT scans have largely contributed to the exact preoperative staging of tumorous diseases, and help characterize the tumors found. In the case of small kidney tumors, attempts are made to decide which masses require operation and which do not, based on the tumor's absorption of the contrast agent and its wash-out intensity as observed by dynamic contrast enhanced scans. The author points out that despite the achieved development, especially in terms of small tumors, image-guided biopsies still play a significant role. Medical imaging techniques are also indispensable for post therapy follow-up of patients (PET/CT, CT and MR perfusion imaging). PMID- 25517447 TI - [Novelties and new possibilities in radiological diagnostics of tumors of the prostate, seminal vesicle, testicle and penis]. AB - This review analyses the opportunities granted by diagnostic imaging of cancers of the urinary bladder, prostate gland, seminal vesicle, testicle and penis. The author discusses in details the value and role of the various procedures in early detection, characterization of tumors and in determination of the exact tumor staging. All these support the selection of the optimal patient-specific treatment, then the assessment of the efficacy of therapy. PMID- 25517448 TI - [New challenges and earlier approved methods in the laboratory diagnosis of prostate cancer]. AB - Prostate cancer is usually a disease of elderly men, however, over 40 years of age the tumor can appear at any times. PSA is a protein molecule synthesized by prostate cells. Measurement of serum PSA has revolutionized the diagnosis and treatment of prostate cancer. However, PSA is not sufficiently specific for the detection of prostate cancer, since serum PSA might also be elevated in benign prostate diseases, as well as following physical stimulation of the gland (digital rectal examination, biopsy, catheterization, or even ejaculation). To increase the specificity of PSA, different derivative parameters have been developed i.e. PSA density (ratio of PSA to prostate volume), PSA velocity (change of PSA over a time period) or age-specific reference ranges. 65-95% of circulating PSA is bound to different proteins, while the rest of PSA circulates in a non-bound form (free PSA, fPSA). In addition to fPSA, the prostate health index [phi; (-2)proPSA/fPSA*?PSA] is increasingly used to differentiate between carcinoma-induced and non-carcinoma-induced increase in PSA. PCA3 is a non-coding messenger RNA, which is 60-70-fold overexpressed by cancer cells in the prostate. Measurement of urine PCA3 appears to be more sensitive than %tPSA, and is independent of prostate volume, age or tPSA. The author reviews laboratory biomarkers related to prostate cancer, used either in the routine clinical practice, or in research. Laboratory biomarkers seem to be useful tools to reduce the incidence of advanced stage, or metastatic prostate cancer, and the cancer related death rate. A promising perspective for the future is the detection of circulating prostate cancer cells and the profiling of microRNAs, especially on the field of tumor prognosis. PMID- 25517449 TI - [The role of aspiration cytology in tumor diagnostics]. AB - Fine needle aspiration biopsy (FNAB) of focal lesions is a quick, relatively simple and cost-effective diagnostic method. However, performing aspirations and interpreting smears require skill and experience. Before initiating an aspiration the doctor needs to be aware of the limits of cytology as it is vital to know what kind of diagnostic issues can be answered upon a smear and what kind of questions cannot. Traditionally FNAB was performed without radiologic guidance, and therefore almost only palpable lesions were aspirated. Since ultrasound (US) has become widely used in medicine, it is axiomatical that FNAB is ideally performed with US guidance not only for the protection of the patients but also for targeting the lesion more safely. Several cytologists find US guidance unnecessary as a routinely used examination, which may lead to unsatisfactory smears and false negative results. This means not only a loss for the patient, but leads to a negative judgement of this diagnostic method. Our interventional cytology diagnostic team developed a working method resulting in excellent statistical results. In the followings we would like to share our experience refined the past two decades to restore the reputation of this diagnostic method. PMID- 25517450 TI - [Efficacy of first-line afatinib versus chemotherapy in EGFR mutation positive pulmonary adenocarcinoma]. AB - Therapy of patients with advanced NSCLC has lately changed due to the algorithm based on the presence or absence of oncogenic mutations. There is an agreement nowadays that in the presence of activating EGFR mutations, the administration of EGFR TKI (gefitinib, erlotinib, afatinib) is the most efficacious initial treatment. Unlike the first-generation TKIs, afatinib is a new, irreversible ErbB blocker, selectively and effectively blocking signals from the ErbB family receptors. Afatinib's marketing authorization is based on a large, randomized, phase III clinical trial, LUX-Lung 3, where patients in the control arm were treated with the best available chemotherapy (pemetrexed/cisplatin combination). Primary endpoint was progression-free survival (PFS). Patients with common EGFR mutations showed a PFS of 13.6 months when treated with afatinib, while treatment in the control arm resulted in a PFS of 6.9 months. Overall survival (OS) was 31.6 and 28.2 months, respectively. LUX-Lung 3 has been followed by the LUX-Lung 6 trial, comparing afatinib treatment to traditional chemotherapy (gemcitabine/cisplatin) in Asian patients with NSCLC harboring EGFR mutations. This clinical trial has also proved benefit of afatinib: PFS was 11.0 months in the afatinib arm and 5.6 months in the control arm by independent reviewer, while OS was 23.6 months and 23.5 months, respectively. Similarity of the OS values in both trials is explained by the cross-over treatment. When further analyzing OS data, a statistically significant difference between the afatinib and the control arm was seen in the EGFR exon 19 del subgroup (LUX-Lung 3: 33.3 vs. 21.1 months, LUX-Lung 6: 31.4 vs. 18.4 months, respectively). PMID- 25517452 TI - Advancing safer alternatives through functional substitution. AB - To achieve the ultimate goal of sustainable chemicals management policy-the transition to safer chemicals, materials, products, and processes-current chemicals management approaches could benefit from a broader perspective. Starting with considerations of function, rather than characterizing and managing risks associated with a particular chemical, may provide a different, solutions oriented lens to reduce risk associated with the uses of chemicals. It may also offer an efficient means, complementing existing tools, to reorient chemicals management approaches from time-intensive risk assessment and risk management based on single chemicals to comparative evaluation of the best options to fulfill a specific function. This article describes a functional approach to chemicals management we call "functional substitution" that encourages decision makers to look beyond chemical by chemical substitution to find a range of alternatives to meet product performance. We define functional substitution, outline a rationale for greater use of this concept when considering risks posed by uses of chemicals, and provide examples of how functional approaches have been applied toward the identification of alternatives. We also discuss next steps for implementing functional substitution in chemical assessment and policy development. PMID- 25517451 TI - Role of 2-[18F] fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography in the post-therapy surveillance of breast cancer. AB - PURPOSE: To evaluate the usefulness of 2-[18F] fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in the early detection of breast cancer tumor recurrences and its role in post-therapy surveillance. METHODS: FDG-PET/CT was performed on patients with increased serum CA 15-3 levels and/or clinical/radiologic suspicion of recurrence. A group of asymptomatic patients who underwent FDG-PET/CT in the post-therapy surveillance of breast cancer served as the controls. The results were analyzed based on the patients' histological data, other imaging modalities and/or clinical follow-up. Recurrence was defined as evidence of recurrent lesions within 12 months of the FDG-PET/CT scan. RESULTS: Based on elevated serum CA15-3 levels (n = 31) and clinical/radiologic suspicion (n = 40), 71 scans were performed due to suspected recurrence, whereas 69 scans were performed for asymptomatic follow-up. The sensitivity and specificity of FDG-PET/CT were 87.5% and 87.1% in the patients with suspected recurrence and 77.8% and 91.7% in the asymptomatic patients. The positive predictive value in the patients with suspected recurrence (mainly due to elevated serum CA 15-3 levels) was higher than that in asymptomatic patients (P = 0.013). Recurrences were proven in 56.3% (40/71) of the patients with suspected recurrence and in 13% (9/69) of the asymptomatic patients (P < 0.001). FDG-PET/CT resulted in changes in the planned management in 49.3% (35/71) of the patients with suspected recurrence and 10.1% (7/69) of the asymptomatic patients (P < 0.001). After follow-up, 77.5% (55/71) of the patients with suspicious recurrences and 97.1% (67/69) of the asymptomatic patients were surviving at the end of the study (P < 0.001). CONCLUSIONS: FDG-PET/CT was able to detect recurrence, and the results altered the intended patient management in the post therapy surveillance of breast cancer. FDG-PET/CT should be used as a priority in patients with increased serum CA 15-3 levels, or with clinical/radiologic suspicion of recurrence, and might be useful for asymptomatic patients. PMID- 25517453 TI - The aesthetic surgeon's "new normal". PMID- 25517455 TI - Seasonal variation in air particulate matter (PM10) exposure-induced ischemia like injuries in the rat brain. AB - Epidemiological studies imply a significantly positive association between particulate matter (PM) level and ischemic stroke hospitalization. However, considering that PM10 is highly heterogeneous and varies with season within the same location, existing experimental evidence remained low. In the present study, we first treated Wistar rats with PM10 samples collected from different seasons in Taiyuan, a typically coal-burning city of China, and determined ischemia related markers in the cortex. The results indicated that PM10 exposure caused endothelial dysfunction, inflammatory response, and neuro-functional impairment similar to that of cerebral ischemia with season-dependent properties, and the winter sample presented the most obvious injuries. Then, we detected the chemical composition of PM10 samples followed by analysis of their correlation with the above biomarkers and found that winter PM10, characterized by higher polycyclic aromatic hydrocarbons (PAHs) and carbon load, played the major role in causing brain ischemia-like injuries among different season samples. Furthermore, by setting up an ischemic neuron model in vitro, we confirmed that winter PM10 presented the most serious aggravation on ischemia-produced injury outcome. This study provides experimental evidence for clarifying the association between season-dependent PM10 pollution in the atmospheric environment and an increased risk of ischemia-like injuries. PMID- 25517456 TI - Seizing the opportunity: stem cells take on epilepsy. AB - Stem cells represent a promising source of neurons for the potential treatment of a host of neurological conditions, including epilepsy. In this issue of Cell Stem Cell, Cunningham et al. (2014) use cortical GABAergic interneuron progenitors derived from human embryonic stem cells to treat chronic temporal lobe epilepsy in a mouse model. PMID- 25517457 TI - Gene-ectomy: gene ablation with CRISPR/Cas9 in human hematopoietic cells. AB - CRISPR/Cas9 has recently been introduced as a gene editing tool and shows considerable promise. In this issue of Cell Stem Cell, Mandal et al. (2014) show efficient CRISPR/Cas9-mediated ablation of the CCR5 and B2M genes in primary human hematopoietic cells, two editing strategies that are potentially translatable into clinical application. PMID- 25517458 TI - Human somatic cell reprogramming: does the egg know best? AB - Somatic cell nuclear transfer offers an alternative approach to the use of exogenous transcription factors for the reprogramming of somatic cells. But is it a better way? Two groups have performed detailed molecular comparisons between human cell lines made by the two methods and report different conclusions. PMID- 25517459 TI - Pluripotent-stem-cell-derived epicardial cells: a step toward artificial cardiac tissue. AB - Epicardial cells are crucial for heart development, function, and regeneration, but methods to study them have been lacking. Using WNT and BMP signaling pathways, Witty et al. (2014) have now developed an elaborate method to generate fully functional epicardial cells from human pluripotent stem cells, allowing their in vitro investigation. PMID- 25517460 TI - Stem cells to insulin secreting cells: two steps forward and now a time to pause? AB - Two groups recently reported the in vitro differentiation of human embryonic stem cells into insulin-secreting cells, achieving an elusive goal for regenerative medicine. Herein we provide a perspective regarding these developments, compare phenotypes of the insulin-containing cells to human beta cells, and discuss implications for type 1 diabetes research and clinical care. PMID- 25517461 TI - ESC-derived retinal pigmented epithelial cell transplants in patients: so far, so good. AB - Many untreatable blinding diseases involve degeneration of retinal pigmented epithelial (RPE) cells, which has prompted exploration of the therapeutic potential of human-pluripotent-stem-cell-derived RPE. The first safety trials reported in The Lancet of embryonic-stem-cell-derived RPE cell transplants indicate no serious adverse outcomes and encourage further investigation. PMID- 25517462 TI - Developing stem cell therapies for Parkinson's disease: waiting until the time is right. AB - The ability to successfully replace lost nigral dopaminergic neurons in Parkinson's disease (PD) has been clearly shown with fetal ventral mesencephalic transplants, albeit inconsistently. The need to trial this approach with stem cell-derived neurons is approaching, but it should only commence when all the key issues have been adequately resolved. PMID- 25517463 TI - In search of naivety. AB - Devising a cell culture method that maintains human pluripotent stem cells (PSCs) in a state similar to naive mouse embryonic stem cells (ESCs) has been a much sought after goal in recent years. Here I consider the historical background to this quest and ask why it is considered consequential. PMID- 25517464 TI - Quantitative single-cell approaches to stem cell research. AB - Understanding the molecular control of cell fates is central to stem cell research. Such insight requires quantification of molecular and cellular behavior at the single-cell level. Recent advances now permit high-throughput molecular readouts from single cells as well as continuous, noninvasive observation of cell behavior over time. Here, we review current state-of-the-art approaches used to query stem cell fate at the single-cell level, including advances in lineage tracing, time-lapse imaging, and molecular profiling. We also offer our perspective on the advantages and drawbacks of available approaches, key technical limitations, considerations for data interpretation, and future innovation. PMID- 25517465 TI - hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice. AB - Seizure disorders debilitate more than 65,000,000 people worldwide, with temporal lobe epilepsy (TLE) being the most common form. Previous studies have shown that transplantation of GABA-releasing cells results in suppression of seizures in epileptic mice. Derivation of interneurons from human pluripotent stem cells (hPSCs) has been reported, pointing to clinical translation of quality-controlled human cell sources that can enhance inhibitory drive and restore host circuitry. In this study, we demonstrate that hPSC-derived maturing GABAergic interneurons (mGINs) migrate extensively and integrate into dysfunctional circuitry of the epileptic mouse brain. Using optogenetic approaches, we find that grafted mGINs generate inhibitory postsynaptic responses in host hippocampal neurons. Importantly, even before acquiring full electrophysiological maturation, grafted neurons were capable of suppressing seizures and ameliorating behavioral abnormalities such as cognitive deficits, aggressiveness, and hyperactivity. These results provide support for the potential of hPSC-derived mGIN for restorative cell therapy for epilepsy. PMID- 25517466 TI - In vivo activation of a conserved microRNA program induces mammalian heart regeneration. AB - Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart. PMID- 25517467 TI - Comparable frequencies of coding mutations and loss of imprinting in human pluripotent cells derived by nuclear transfer and defined factors. AB - The recent finding that reprogrammed human pluripotent stem cells can be derived by nuclear transfer into human oocytes as well as by induced expression of defined factors has revitalized the debate on whether one approach might be advantageous over the other. Here we compare the genetic and epigenetic integrity of human nuclear-transfer embryonic stem cell (NT-ESC) lines and isogenic induced pluripotent stem cell (iPSC) lines, derived from the same somatic cell cultures of fetal, neonatal, and adult origin. The two cell types showed similar genome wide gene expression and DNA methylation profiles. Importantly, NT-ESCs and iPSCs had comparable numbers of de novo coding mutations, but significantly more than parthenogenetic ESCs. As iPSCs, NT-ESCs displayed clone- and gene-specific aberrations in DNA methylation and allele-specific expression of imprinted genes. The occurrence of these genetic and epigenetic defects in both NT-ESCs and iPSCs suggests that they are inherent to reprogramming, regardless of derivation approach. PMID- 25517470 TI - Facile synthesis and enhanced ultraviolet emission of ZnO nanorods prepared by vapor-confined face-to-face annealing. AB - In this study, we report a novel regrowth method of sol-gel-prepared ZnO films using a vapor-confined face-to-face annealing (VC-FTFA) technique in which mica was inserted between two films, followed by annealing with the FTFA method. The ZnO nanorods are regrown when zinc acetate dihydrate and zinc chloride (ZnCl2) are used as the solvent, because these generate ZnCl2 vapor. The near-band-edge emission intensity of the ZnO nanorods was enhanced through the VC-FTFA method, increasing significantly by a factor of 56 compared to that of ZnO films annealed in open air at 700 degrees C. Our method may provide a route toward the facile fabrication of ZnO nanorods. PMID- 25517468 TI - Efficient ablation of genes in human hematopoietic stem and effector cells using CRISPR/Cas9. AB - Genome editing via CRISPR/Cas9 has rapidly become the tool of choice by virtue of its efficacy and ease of use. However, CRISPR/Cas9-mediated genome editing in clinically relevant human somatic cells remains untested. Here, we report CRISPR/Cas9 targeting of two clinically relevant genes, B2M and CCR5, in primary human CD4+ T cells and CD34+ hematopoietic stem and progenitor cells (HSPCs). Use of single RNA guides led to highly efficient mutagenesis in HSPCs but not in T cells. A dual guide approach improved gene deletion efficacy in both cell types. HSPCs that had undergone genome editing with CRISPR/Cas9 retained multilineage potential. We examined predicted on- and off-target mutations via target capture sequencing in HSPCs and observed low levels of off-target mutagenesis at only one site. These results demonstrate that CRISPR/Cas9 can efficiently ablate genes in HSPCs with minimal off-target mutagenesis, which could have broad applicability for hematopoietic cell-based therapy. PMID- 25517469 TI - Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease. AB - Considerable progress has been made in generating fully functional and transplantable dopamine neurons from human embryonic stem cells (hESCs). Before these cells can be used for cell replacement therapy in Parkinson's disease (PD), it is important to verify their functional properties and efficacy in animal models. Here we provide a comprehensive preclinical assessment of hESC-derived midbrain dopamine neurons in a rat model of PD. We show long-term survival and functionality using clinically relevant MRI and PET imaging techniques and demonstrate efficacy in restoration of motor function with a potency comparable to that seen with human fetal dopamine neurons. Furthermore, we show that hESC derived dopamine neurons can project sufficiently long distances for use in humans, fully regenerate midbrain-to-forebrain projections, and innervate correct target structures. This provides strong preclinical support for clinical translation of hESC-derived dopamine neurons using approaches similar to those established with fetal cells for the treatment of Parkinson's disease. PMID- 25517472 TI - Nevirapine-related adverse events among children switched from efavirenz to nevirapine as compared to children who were started on nevirapine-based antiretroviral therapy directly. AB - In this retrospective study, incidence of nevirapine (NVP) toxicity in children who were switched from efavirenz (EFV) to NVP (treatment experienced [TE] group) was compared with that of children who had started NVP-based antiretroviral therapy directly (treatment naive [TN] group). This study also identified risk factors associated with development of NVP toxicity in children. The incidence and risk of developing NVP toxicities were significantly higher in TE when compared to TN group. Median duration of onset of NVP toxicity from the initiation was 2.14 and 3.84 weeks in TE and TN children, respectively. Mean CD4 count was found to be significantly higher in children who developed toxicity (577 +/- 81 cells/uL) as compared to the children who did not develop toxicity (403 +/- 29 cells/uL). Similarly, children in TE group who developed NVP toxicity had higher mean CD4 cell count than children in TN with NVP toxicity. The risk factors for the development of NVP toxicity include female gender with CD4 count >250 cells/MUL and TE children especially girls with CD4% >15% and boys with CD4 count >400 cells/MUL. To conclude, the higher incidence of NVP toxicity among TE group warrants a cautious approach while switching the NVP- from EFV-based therapy. PMID- 25517473 TI - Graduated compression stockings for prevention of deep vein thrombosis. AB - BACKGROUND: One of the settings where deep vein thrombosis (DVT) in the lower limb and pelvic veins occurs is in hospital with prolonged immobilisation of patients for various surgical and medical illnesses. Using graduated compression stockings (GCS) in these patients has been proposed to decrease the risk of DVT. This is an update of a Cochrane review first published in 2000 and updated in 2010. OBJECTIVES: To evaluate the effectiveness and safety of graduated compression stockings in preventing DVT in various groups of hospitalised patients. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched March 2014) and CENTRAL (2014, Issue 2). SELECTION CRITERIA: Randomised controlled trials (RCTs) involving GCS alone; or GCS used on a background of any other DVT prophylactic method. Results from both these groups of trials were combined in this update. DATA COLLECTION AND ANALYSIS: For this update one review author (AS) extracted the data. These were cross-checked and authenticated by a second author (MJD). Two review authors (AS and MJD) assessed the quality of trials. Disagreements were resolved by discussion. MAIN RESULTS: Nineteen RCTs were identified involving 1681 individual patients and 1064 individual legs (2745 analytic units). Of these 19 trials, nine included patients undergoing general surgery, six included patients undergoing orthopaedic surgery, and only one trial included medical patients. Graduated compression stockings were applied on the day before surgery or on the day of surgery and were worn up until discharge or until the patients were fully mobile. In the majority of the included studies DVT was identified by the radioactive I(125) uptake test. Overall, included studies were of good quality.In the treatment group (GCS) of 1391 units 126 developed DVT (9%) in comparison to the control group (without GCS) of 1354 units where 282 (21%) developed DVT. The Peto odds ratio (OR) was 0.33 (95% confidence interval (CI) 0.26 to 0.41) with an overall effect favouring treatment with GCS (P < 0.00001).Based on results from eight included studies, the incidence of proximal DVT was 7 of 517 (1%) units in the treatment group and 28 of 518 (5%) units in the control group. The Peto OR was 0.26 (95% CI 0.13 to 0.53) with an overall effect favouring treatment with GCS (P = 0.0002). Based on results from five included studies, the incidence of PE was 5 of 283 (2%) participants in the treatment group and 14 of 286 (5%) in the control group. The Peto OR was 0.38 (95% CI 0.15 to 0.96) with an overall effect favouring treatment with GCS (P = 0.04). Limited data were available to accurately assess the incidence of adverse effects and complications with the use of GCS. AUTHORS' CONCLUSIONS: GCS are effective in diminishing the risk of DVT in hospitalised patients, with strong evidence favouring their use in general and orthopaedic surgery. However, evidence for their effectiveness in medical patients is limited to one trial. PMID- 25517475 TI - Active compression-decompression resuscitation and impedance threshold device for out-of-hospital cardiac arrest: a systematic review and metaanalysis of randomized controlled trials. AB - OBJECTIVE: Active compression-decompression resuscitation and impedance threshold device are proposed to improve survival of patients of cardiac arrest by lowering intrathoracic pressure and increasing cardiac output. The results of clinical studies of active compression-decompression resuscitation or impedance threshold device were controversial. This metaanalysis pooled results of randomized controlled trials to examine whether active compression-decompression resuscitation or impedance threshold device would improve outcomes of out-of hospital cardiac arrest in comparison with standard cardiopulmonary resuscitation and to explore factors modifying these effects. DATA SOURCES: Medline and Embase were searched from inception to September 2013. STUDY SELECTION: Randomized controlled trials comparing active compression-decompression resuscitation or impedance threshold device with standard cardiopulmonary resuscitation in out-of hospital cardiac arrest patients were selected. There were no restrictions for language, population, or publication year. DATA EXTRACTION: Data on study characteristics, including patients, intervention details, and outcome measures, were independently extracted. DATA SYNTHESIS: Fifteen trials, including 16,088 patients, were identified from 331 potentially relevant references. Return of spontaneous circulation was designated as the primary outcome. The pooled result showed no significant improvement in return of spontaneous circulation by active compression-decompression resuscitation or impedance threshold device in comparison with standard cardiopulmonary resuscitation (risk ratio, 1.04; 95% CI, 0.93-1.16; I, 46%). There was also no significant difference in survival or neurologic outcome at hospital discharge between active compression-decompression resuscitation or impedance threshold device and standard cardiopulmonary resuscitation. The meta-regression indicated that this minimal effect might be modified by two important prognostic factors, that is, witnessed status and response time. After adjustment of these two factors, impedance threshold device appeared to improve return of spontaneous circulation, which could be further augmented by advanced airway use. CONCLUSIONS: Active compression-decompression resuscitation or impedance threshold device seemed not to improve return of spontaneous circulation in out-of-hospital cardiac arrest patients. The meta regression indicated two probable prognostic factors causing this minimal effect. Nonetheless, these findings referred to differences between trials and could not necessarily be extrapolated to individual patients. The individual patient-level extrapolation may need to be solved by a future randomized controlled trial. PMID- 25517476 TI - Clinical and psychological effects of early mobilization in patients treated in a neurologic ICU: a comparative study. AB - OBJECTIVE: To determine if an early mobilization protocol increased mobility and improved clinical and psychological outcomes. Currently, there is minimal research on the effects of early mobilization in patients with primary neurologic injury. DESIGN: Prospective, two-group pre/post comparative design with data collection 4 months pre- and postintervention with a 4-month run-in period. SETTING: Twenty-two-bed neurologic ICU in a 1,200-bed urban, quaternary-care, academic hospital in Northeast Ohio. SUBJECTS: Critically ill patients with primary neurologic injury admitted to the neurologic ICU. INTERVENTION: An early mobility program included a progressive mobility protocol, written orders, and staff (clinical nurse specialist clinical technician) who advocated for and assisted with mobility. Highest mobility achieved was assessed daily for 13 days, clinical outcomes were retrieved from electronic databases, and psychological profile was collected by valid, reliable questionnaire at/after neurologic ICU discharge. Analyses included comparative statistics and multivariable modeling. MEASUREMENTS AND MAIN RESULTS: Of 637 patients, 260 were preintervention and 377 were postintervention. Patient characteristics were similar between groups, except postintervention group patients had less history of using walking aids and more gait abnormalities, and were less likely to require mechanical ventilation in the neurologic ICU (all p<=0.006). Compared with preintervention, postintervention patients had higher mobility levels and decreased hospital and neurologic ICU length of stay; were more likely to be discharged home (all p<=0.002); had decreased bloodstream infection, hospital-acquired pressure ulcer, and anxiety rates (all p<0.03); and had no change in mortality, ventilator associated pneumonia, deep vein thrombosis, depression, and hostility. In multivariable analyses, postintervention patients had higher mobility levels (p<0.001), had shorter mean hospital and neurologic ICU length of stay (both p<0.001), and were more likely to be discharged home (p=0.033) compared with preintervention patients. CONCLUSIONS: A neurologic ICU early mobility protocol increased highest neurologic ICU mobility and discharge home and decreased length of stay, but did not improve quality metrics or psychological profile. PMID- 25517477 TI - Is long-axis view superior to short-axis view in ultrasound-guided central venous catheterization? AB - OBJECTIVE: To evaluate whether using long-axis or short-axis view during ultrasound-guided internal jugular and subclavian central venous catheterization results in fewer skin breaks, decreased time to cannulation, and fewer posterior wall penetrations. DESIGN: Prospective, randomized crossover study. SETTING: Urban emergency department with approximate annual census of 60,000. SUBJECTS: Emergency medicine resident physicians at the Denver Health Residency in Emergency Medicine, a postgraduate year 1-4 training program. INTERVENTIONS: Resident physicians blinded to the study hypothesis used ultrasound guidance to cannulate the internal jugular and subclavian of a human torso mannequin using the long-axis and short-axis views at each site. MEASUREMENTS AND MAIN RESULTS: An ultrasound fellow recorded skin breaks, redirections, and time to cannulation. An experienced ultrasound fellow or attending used a convex 8-4 MHz transducer during cannulation to monitor the needle path and determine posterior wall penetration. Generalized linear mixed models with a random subject effect were used to compare time to cannulation, number of skin breaks and redirections, and posterior wall penetration of the long axis and short axis at each cannulation site. Twenty-eight resident physicians participated: eight postgraduate year 1, eight postgraduate year 2, five postgraduate year 3, and seven postgraduate year 4. The median (interquartile range) number of total internal jugular central venous catheters placed was 27 (interquartile range, 9-42) and subclavian was six catheters (interquartile range, 2-20). The median number of previous ultrasound guided internal jugular catheters was 25 (interquartile range, 9-40), and ultrasound-guided subclavian catheters were three (interquartile range, 0-5). The long-axis view was associated with a significant decrease in the number of redirections at the internal jugular and subclavian sites, relative risk 0.4 (95% CI, 0.2-0.9) and relative risk 0.5 (95% CI, 0.3-0.7), respectively. There was no significant difference in the number of skin breaks between the long axis and short axis at the subclavian and internal jugular sites. The long-axis view for subclavian was associated with decreased time to cannulation; there was no significant difference in time between the short-axis and long-axis views at the internal jugular site. The prevalence of posterior wall penetration was internal jugular short axis 25%, internal jugular long axis 21%, subclavian short axis 64%, and subclavian long axis 39%. The odds of posterior wall penetration were significantly less in the subclavian long axis (odds ratio, 0.3; 95% CI, 0.1 0.9). CONCLUSIONS: The long-axis view for the internal jugular was more efficient than the short-axis view with fewer redirections. The long-axis view for subclavian central venous catheterization was also more efficient with decreased time to cannulation and fewer redirections. The long-axis approach to subclavian central venous catheterization is also associated with fewer posterior wall penetrations. Using the long-axis view for subclavian central venous catheterization and avoiding posterior wall penetrations may result in fewer central venous catheter-related complications. PMID- 25517480 TI - Study of chromatographic retention of natural terpenoids by chemoinformatic tools. AB - The study of chromatographic retention of natural products can be used to increase their identification speed in complex biological matrices. In this work, six variables were used to study the retention behavior in reversed phase liquid chromatography of 39 sesquiterpene lactones (SL) from an in-house database using chemoinformatics tools. To evaluate the retention of the SL, retention parameters on an ODS C-18 column in two different solvent systems were experimentally obtained, namely, MeOH-H2O 55:45 and MeCN-H2O 35:75. The chemoinformatics approach involved three descriptor type sets (one 2D and two 3D) comprising three groups of each (four, five, and six descriptors), two different training and test sets, four algorithms for variable selection (best first, linear forward, greedy stepwise, and genetic algorithm), and two modeling methods (partial least-squares regression and back-propagation artificial neural network). The influence of the six variables used in this study was assessed in a holistic context, and influences on the best model for each solvent system were analyzed. The best set for MeOH-H2O showed acceptable correlation statistics with training R(2) = 0.91, cross-validation Q(2) = 0.88, and external validation P(2) = 0.80, and the best MeCN-H2O model showed much higher correlation statistics with training R(2) = 0.96, cross-validation Q(2) = 0.92, and external validation P(2) = 0.91. Consensus models were built for each chromatographic system, and although all of them showed an improved statistical performance, only one for the MeCN-H2O system was able to separate isomers as well as to improve the performance. The approach described herein can therefore be used to generate reproducible and robust models for QSRR studies of natural products as well as an aid for dereplication of complex biological matrices using plant metabolomics-based techniques. PMID- 25517479 TI - Integrating Three-Dimensional Vision in Laparoscopy: The Learning Curve of an Expert. AB - BACKGROUND AND PURPOSE: Three-dimensional (3D) laparoscopy has been developed in an attempt to address one of the main limitations of laparoscopic surgery, which is two-dimensional (2D) vision. Still, data on the learning curve during adaptation of such technology in clinical practice are scarce. In this study, perioperative data from the initial operations performed by an experienced laparoscopic surgeon in a 3D laparoscopic setup are presented, aiming to document any difficulties faced during the integration of 3D vision to laparoscopy. PATIENTS AND METHODS: In total, 15 consecutive, unselected cases were operated using 3D laparoscopy within a 30-day period. The cases included five laparoscopic extraperitoneal radical prostatectomies, three nephrectomies, three partial nephrectomies, one nephrouretectomy, one adrenalectomy, one ureterolithotomy, and one radical cystectomy with ureterocutaneostomies. Perioperative data were prospectively collected and analyzed. RESULTS: The transition from 2D to 3D laparoscopy for the expert surgeon seemed to be very rapid without compromising the efficacy of the operation or patient safety. Perioperative outcomes and complications resembled the outcomes of our 2D experience. CONCLUSIONS: Our preliminary experience with 3D laparoscopy was favorable, and we definitely opt for 3D vision in future operations. Nevertheless, current systems are related to several technical limitations that should be addressed to make even more appealing the further development of this technology. Whether the visual comfort offered by 3D vision during laparoscopy can be translated into an improvement in clinical outcomes offered to patients remains to be addressed in the future. PMID- 25517481 TI - Lifesource XL-18 pedometer for measuring steps under controlled and free-living conditions. AB - The primary aim was to examine the criterion and construct validity and test retest reliability of the Lifesource XL-18 pedometer (A&D Medical, Toronto, ON, Canada) for measuring steps under controlled and free-living activities. The influence of body mass index, waist size and walking speed on the criterion validity of XL-18 was also explored. Forty adults (35-74 years) performed a 6-min walk test in the controlled condition, and the criterion validity of XL-18 was assessed by comparing it to steps counted manually. Thirty-five adults participated in the free-living condition and the construct validity of XL-18 was assessed by comparing it to Yamax SW-200 (YAMAX Health & Sports, Inc., San Antonio, TX, USA). During the controlled condition, XL-18 did not significantly differ from criterion (P > 0.05) and no systematic error was found using Bland Altman analysis. The accuracy of XL-18 decreased with slower walking speed (P = 0.001). During the free-living condition, Bland-Altman analysis revealed that XL 18 overestimated daily steps by 327 +/- 118 than Yamax (P = 0.004). However, the absolute percent error (APE) (6.5 +/- 0.58%) was still within an acceptable range. XL-18 did not differ statistically between pant pockets. XL-18 is suitable for measuring steps in controlled and free-living conditions. However, caution may be required when interpreting the steps recorded under slower speeds and free living conditions. PMID- 25517482 TI - Layer-by-layer rose petal mimic surface with oleophilicity and underwater oleophobicity. AB - Surfaces designed with specific wetting properties are still a key challenge in materials science. We present here a facile preparation of a surface assembled by the layer-by-layer technique, using a colloidal dispersion of ionomer particles and linear polyethylene imine. The colloidal ethylene-co-methacrylic acid (EMAA) particles are on the order of half a micron in size with surface features from 40 to 100 nm in width. The resultant surface has roughness on two length scales, one on the micron scale due to the packing of particles and one on the nanoscale due to these surface features on the EMAA particles. This hierarchical structure results in a hydrophobic surface with good water pinning properties (~550 MUN). We show that there is a balance between maximizing contact angle and water pinning force. Furthermore, this surface is oleophilic with regard to many organic solvents, also demonstrating underwater oleophobicity, and given the difference in wetting between aqueous and organic phases, this material may be a candidate material for oil/water separations. PMID- 25517478 TI - Dynamic pituitary-adrenal interactions in response to cardiac surgery. AB - OBJECTIVES: To characterize the dynamics of the pituitary-adrenal interaction during the course of coronary artery bypass grafting both on and off pump. Since our data pointed to a major change in adrenal responsiveness to adrenocorticotropic hormone, we used a reverse translation approach to investigate the molecular mechanisms underlying this change in a rat model of critical illness. DESIGN: CLINICAL STUDIES: Prospective observational study. ANIMAL STUDIES: Controlled experimental study. SETTING: CLINICAL STUDIES: Cardiac surgery operating rooms and critical care units. ANIMAL STUDIES: University research laboratory. SUBJECTS: CLINICAL STUDIES: Twenty, male patients. ANIMAL STUDIES: Adult, male Sprague-Dawley rats. INTERVENTIONS: CLINICAL STUDIES: Coronary artery bypass graft-both on and off pump. ANIMAL STUDIES: Injection of either lipopolysaccharide or saline (controls) via a jugular vein cannula. MEASUREMENTS AND MAIN RESULTS: CLINICAL STUDIES: Blood samples were taken for 24 hours from placement of the first venous access. Cortisol and adrenocorticotropic hormone were measured every 10 and 60 minutes, respectively, and corticosteroid-binding globulin was measured at the beginning and end of the 24-hour period and at the end of operation. There was an initial rise in both levels of adrenocorticotropic hormone and cortisol to supranormal values at around the end of surgery. Adrenocorticotropic hormone levels then returned toward preoperative values. Ultradian pulsatility of both adrenocorticotropic hormone and cortisol was maintained throughout the perioperative period in all individuals. The sensitivity of the adrenal gland to adrenocorticotropic hormone increased markedly at around 8 hours after surgery maintaining very high levels of cortisol in the face of "basal" levels of adrenocorticotropic hormone. This sensitivity began to return toward preoperative values at the end of the 24-hour sampling period. ANIMAL STUDIES: Adult, male Sprague-Dawley rats were given either lipopolysaccharide or sterile saline via a jugular vein cannula. Hourly blood samples were subsequently collected for adrenocorticotropic hormone and corticosterone measurement. Rats were killed 6 hours after the injection, and the adrenal glands were collected for measurement of steroidogenic acute regulatory protein, steroidogenic factor 1, and dosage sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 messenger RNAs and protein using real-time quantitative polymerase chain reaction and Western immunoblotting, respectively. Adrenal levels of the adrenocorticotropic hormone receptor (melanocortin type 2 receptor) messenger RNA and its accessory protein (melanocortin type 2 receptor accessory protein) were also measured by real-time quantitative polymerase chain reaction. In response to lipopolysaccharide, rats showed a pattern of adrenocorticotropic hormone and corticosterone that was similar to patients undergoing coronary artery bypass grafting. We were also able to demonstrate increased intra-adrenal corticosterone levels and an increase in steroidogenic acute regulatory protein, steroidogenic factor 1, and melanocortin type 2 receptor accessory protein messenger RNAs and steroidogenic acute regulatory protein, and a reduction in dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 and melanocortin type 2 receptor messenger RNAs, 6 hours after lipopolysaccharide injection. CONCLUSIONS: Severe inflammatory stimuli activate the hypothalamic pituitary-adrenal axis resulting in increased steroidogenic activity in the adrenal cortex and an elevation of cortisol levels in the blood. Following coronary artery bypass grafting, there is a massive increase in both adrenocorticotropic hormone and cortisol secretion. Despite a subsequent fall of adrenocorticotropic hormone to basal levels, cortisol remains elevated and coordinated adrenocorticotropic hormone-cortisol pulsatility is maintained. This suggested that there is an increase in adrenal sensitivity to adrenocorticotropic hormone, which we confirmed in our animal model of immune activation of the hypothalamic-pituitary-adrenal axis. Using this model, we were able to show that this increased adrenal sensitivity results from changes in the regulation of both stimulatory and inhibitory intra-adrenal signaling pathways. Increased understanding of the dynamics of normal hypothalamic-pituitary-adrenal responses to major surgery will provide us with a more rational approach to glucocorticoid therapy in critically ill patients. PMID- 25517483 TI - Ectopic breast cancer in the anterior chest wall: a case report. PMID- 25517484 TI - Bone marrow fibrosis may be an effective independent predictor of the 'TKI drug response level' in chronic myeloid leukemia. AB - OBJECTIVES: The aim of this study was to assess bone marrow (BM) fibrosis and dysplasia in chronic myeloid leukemia (CML) patients receiving the first generation tyrosine kinase inhibitor (TKI), imatinib, or second-generation TKIs, dasatinib, and nilotinib. We further investigated whether CML under TKI is associated with dysplastic BM changes during the clinicopathological course of the disease. METHODS: In total, pre-treatment BM paraffin blocks of biopsy specimens were available for 41 adult patients diagnosed with chronic phase CML. Post-treatment BM aspirate clot and core biopsy samples were reviewed for fibrosis and dyshematopoiesis. RESULTS: Overall, 13 (31.7%) patients achieved a complete cytogenetic response with imatinib treatment, with no events. In 25 patients, imatinib was discontinued owing to primary or secondary resistance. In patients with initial dysmyelopoiesis, the rate of BM fibrosis was 82.4 versus 47.6% for other patient groups (P = 0.02). Overall, 24 patients with newly diagnosed CML showed marrow fibrosis, among which 19 (79.1%) had imatinib resistance. However, only 5 out of 15 patients (33.5%) without marrow fibrosis had imatinib resistance (P = 0.08). Discussion Our findings indicate that BM fibrosis is an independent predictor of the 'TKI drug response level' in CML and support its inclusion as a critical pathobiological parameter for decision-making with regard to TKI drug selection de novo, calculation of prognosis at the onset of disease, and monitoring response to TKI in the long-term disease course of CML. PMID- 25517487 TI - Photoinduced spectral changes of photoluminescent gold nanoclusters. AB - Ultrasmall photoluminescent gold nanoclusters (Au NCs), composed of several atoms with sizes up to a few nanometers, have recently stimulated extensive interest. Unique molecule-like behaviors, low toxicity, and facile synthesis make photoluminescent Au NCs a very promising alternative to organic fluorophores and semiconductor quantum dots (QDs) in broad ranges of biomedical applications. However, using gold nanoparticles (Au NPs) for bioimaging might cause their degradation under continuous excitation with UV light, which might result in toxicity. We report spectral changes of photoluminescent 2-(N-morpholino) ethanesulfonic acid (MES)-coated (Au-MES) NCs under irradiation with UV/blue light. Photoluminescent water soluble Au- MES NCs with a photoluminescence (PL) band maximum at 476 nm (lambdaex = 420 nm) were synthesized. Under irradiation with 402 nm wavelength light the size of photoluminescent Au-MES NCs decreased (lambdaem = 430 nm). Irradiating the sample solution with 330 nm wavelength light, nonluminescent Au NPs were disrupted, and photoluminescent Au NCs (lambdaem = 476 nm) were formed. Irradiation with 330 nm wavelength light did not directly affect photoluminescent Au-MES NCs, however, increase in PL intensity indicated the formation of photoluminescent Au NCs from the disrupted nonluminescent Au NPs. This study gives a good insight into the photostability of MES-coated Au NPs under continuous excitation with UV/blue light. PMID- 25517488 TI - Effects of oxygen in lungs of rats. AB - PURPOSE: To analyze microscopically the effects of different concentrations of oxygen in the lungs of rats. METHODS: There were 20 rats distributed in three experimental groups (concentration of oxygen to 40%, 70% and 100%) and a control group. The animals were exposed to the oxygen in a chamber of acrylic during three days and after exposition, the animals were submitted to median thoracotomia to remove the lungs. The lung tissue of all of the animals was analyzed as regards presence of acute and chronic inflammation, capillary congestion, alveolar walls thick, interstitial and alveolar edema, alveolar hemorrhage, denudation capillary and alveolar endothelium areas and atelectasis. RESULTS: The analysis histopathologic revealed significant statistics difference for acute and chronic inflammation, capillary congestion, alveolar walls thick, interstitial and alveolar edema, alveolar hemorrhage, denudation capillary and alveolar epithelium areas. CONCLUSIONS: Exposition to the oxygen during 72 hours in the concentration of 40% does not produce significant histopathologic alterations in the lung tissue; in the concentration of 70%, can promotes the alveolar walls thick and capillary congestion and in the concentration of 100% can cause death and originate diffuse pulmonary lesion. PMID- 25517485 TI - Genome-wide screening and functional analysis identify a large number of long noncoding RNAs involved in the sexual reproduction of rice. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) play important roles in a wide range of biological processes in mammals and plants. However, the systematic examination of lncRNAs in plants lags behind that in mammals. Recently, lncRNAs have been identified in Arabidopsis and wheat; however, no systematic screening of potential lncRNAs has been reported for the rice genome. RESULTS: In this study, we perform whole transcriptome strand-specific RNA sequencing (ssRNA-seq) of samples from rice anthers, pistils, and seeds 5 days after pollination and from shoots 14 days after germination. Using these data, together with 40 available rice RNA-seq datasets, we systematically analyze rice lncRNAs and definitively identify lncRNAs that are involved in the reproductive process. The results show that rice lncRNAs have some different characteristics compared to those of Arabidopsis and mammals and are expressed in a highly tissue-specific or stage specific manner. We further verify the functions of a set of lncRNAs that are preferentially expressed in reproductive stages and identify several lncRNAs as competing endogenous RNAs (ceRNAs), which sequester miR160 or miR164 in a type of target mimicry. More importantly, one lncRNA, XLOC_057324, is demonstrated to play a role in panicle development and fertility. We also develop a source of rice lncRNA-associated insertional mutants. CONCLUSIONS: Genome-wide screening and functional analysis enabled the identification of a set of lncRNAs that are involved in the sexual reproduction of rice. The results also provide a source of lncRNAs and associated insertional mutants in rice. PMID- 25517489 TI - Attenuation of copaiba oil in hepatic damage in rats. AB - PURPOSE: To investigate the copaiba oil on the hepatic damage induced by acetaminophen, comparing against corn oil. METHODS: Fifty four rats were distributed into nine study groups (N=6): control group, that didn't receive the acetaminophen; Acetaminophen Group, that only received the acetaminophen; Prophylactic Copaiba Group 1, that received copaiba oil two hours before the acetaminophen; Prophylactic Copaiba Group 7, that received copaiba oil seven days, once by day, before the acetaminophen; Therapy Copaiba Group, that received the copaiba oil two hours after the acetaminophen, the corn's groups were similar than copaiba oil groups; and N-Acetyl-Cysteine Group, that received the N-Acetyl Cysteine two hours after the acetaminophen. Euthanasia was performed after 24 hours. The serum levels transaminases, bilirubin and canalicular enzymes were analyzed. RESULTS: The prophylactic copaiba group 7, therapy copaiba group and N Acetyl-Cysteine Group showed amounts of AST and ALT similar to the control group; and the prophylactic copaiba group 1 and corn's groups showed similar levels to the acetaminophen group. There was no significant difference between the groups regarding the amount of alkaline phosphatase and ? GT (p>0.05). The therapy copaiba group showed the highest levels of total bilirubin and was statistically different from the other groups (p<0.01). CONCLUSIONS: Copaiba oil administered prophylactically for seven days and therapeutically 2 hours after the acetaminophen acute intoxication offered a potential hepato protection against paracetamol-induced hepatic damage, normalizing the biochemical parameters similarly to N-Acetyl-Cysteine, and the treatment with corn oil shows no effect on the liver damage. PMID- 25517490 TI - Phagocytic function of lower spleen pole and autogenous splenic implants in rats. AB - PURPOSE: To investigate whether there are differences between the phagocytic function of the remaining lower spleen pole after subtotal splenectomy and autogenous splenic implants. METHODS: Thirty-six male Wistar rats, weighting 364 +/- 60g were used. They were subjected to subtotal splenectomy preserving the lower spleen pole and to autogenous splenic implant in the greater omentum. Its viability was assessed microscopically. Phagocytic function was assessed by splenic uptake of the radioisotope-labeled colloid and by macrophages counting. RESULTS: The viability of the autogenous splenic implant and of the lower spleen pole was found in 33 animals, with no difference between them. The weight of the implants was higher than the lower pole of animals from groups G1, G7, G30, G60 and G120. The implants phagocytic function by radioisotope uptake was higher than the lower pole in G7 and G120 groups and it did not differ from the other groups. The number of macrophages was higher in G1, G60, G90 and G120 and did not differ from the other groups. CONCLUSION: Until the 16th week, the phagocytic function was more pronounced in autogenous splenic implants when compared with the lower spleen pole, but it became similar thereafter. PMID- 25517492 TI - Tomographic imaging of fragmented cortical bone heteroimplant and methylmethacrylate in segmental bone defect of rabbit tibia. AB - PURPOSE: To evaluate the performance of composites consisting of fragmented cortical bone heteroimplant in association with methylmethacrylate preserved in 98% glycerin, in segmental bone defect of rabbit tibia medial metaphysis. METHODS: In this study were used twelve adult New Zealand rabbits, divided into three groups of four animals each: G30 (30 days), G60 (60 days) and G90 (90 days). The bone defects previously created in the tibia were filled with composites and both were evaluated by cone-beam computed tomography, immediately after surgery and after 30, 60, and 90 days. RESULTS: The composites fulfilled and remained in the sites of bone defects in all cases and were not registered signals of infection, migration or rejection. CONCLUSIONS: The implanted composites promoted the bone defects repair without signals of infection and/or rejection. The composites are one more option for bone defects repair. PMID- 25517491 TI - Electroacupuncture ameliorates experimental colitis induced by TNBS through activation of interleukin-10 and inhibition of iNOS in mice. AB - PURPOSE: To study the anti-inflammatory actions of electroacupuncture (EAc) on an experimental colitis model in mice. METHODS: Thirty-eight male Swiss mice, divided in five groups, were subjected to induction of colitis by TNBS in 50% ethanol. Saline (SAL) and ethanol (ETNL) groups served as controls. TNBS+EAc and TNBS+ dexamethasone subgroups were treated with EAc 100Hz and dexamethasone (DEXA) 1 mg/Kg/day, respectively. After three days, a colon segment was obtained for quantification of myeloperoxidase (MPO) activity, immunohistochemistry for iNOS, malondialdehyde (MDA) and cytokines (IL-1beta and IL-10). RESULTS: Neutrophilic activity, assayed as MPO activity, was significantly higher in the TNBS colitis group than that in the saline control group. TNBS+EAc group showed suppression of IL-10 in the colon. EAc treatment significantly reduced the concentration of MDA and the expression of iNOS, as compared to the other groups. CONCLUSION: Electroacupuncture 100Hz applied to acupoint ST-36 promotes an anti inflammatory action on the TNBS-induced colitis, mediated by increase of IL-10 and decrease of iNOS expression. PMID- 25517493 TI - Effects of a continuous rate infusion of butorphanol in isoflurane-anesthetized horses on cardiorespiratory parameters, recovery quality, gastrointestinal motility and serum cortisol concentrations. AB - PURPOSE: To assess the cardiorespiratory parametes, recovery, gastrointestinal motility and serum cortisol concentrations in horses anesthetized with isoflurane with or without a continuous rate infusion (CRI) of butorphanol for orchiectomy. METHODS: Twelve adult, intact, male horses weighing 332 +/- 55 kg were included in the study. Xilazine was administered as premedication. Anesthesia was induced with ketamine and midazolam and maintained with isoflurane. Butorphanol (0.025 mg kg-1 bolus) or an equivalent volume of saline (0.9%) was given intravenously followed by a CRI of butorphanol (BG) (13 ug kg-1 hour-1) or saline (CG). Cardiorespiratory variables were recorded before (T0) and every 15 minutes for 75 minutes after the start of infusion. Serum cortisol concentration was measured at T0 and 60 minutes, and 30 minutes and 19 hours after the horse stood up. Recovery from anesthesia was evaluated using a scoring system. Gastrointestinal motility was evaluated before anesthesia and during 24 hours after recovery. RESULTS: There were no significant differences between groups in cardiopulmonary variables, or recovery scores or serum cortisol concentrations. A reduction in gastrointestinal motility was recorded for 60 minutes in BG. CONCLUSIONS: Continuous rate infusion of butorphanol in horses anesthetized with isoflurane did not adversely affect the cardiopulmonary variables monitored, or recovery scores. A small but statistically significant reduction in gastrointestinal motility occurred in the butorphanol group. PMID- 25517494 TI - Comparison of effects of sugammadex and neostigmine on QTc prolongation in rabbits under general anesthesia. AB - PURPOSE: To compare the effects of sugammadex and neostigmine, used to antagonize the effects of rocuronium, on the QTc interval. METHODS: This study used 10 adult New Zealand white rabbits of 2.5-3.5 kg randomly divided into two groups: sugammadex group (Group S, n:5) and neostigmine group (Group N, n:5). For general anesthesia administering 2 mg/kg iv propofol and 1 mcg/kg iv fentanyl, 0.6 mg/kg iv rocuronium was given. Later to provide reliable airway for all experimental animals V-Gel Rabbit was inserted. The rabbits were manually ventilated by the same anesthetist. After the V-Gel Rabbit was inserted at 2, 5, 10, 20, 25, 27, 30 and 40 minutes measurements were repeated and recorded. At 25 minutes after induction Group N rabbits were given 0.05 mg/kg iv neostigmine + 0.01 mg/kg iv atropine. Group S were administered 2 mg/kg iv sugammadex. RESULTS: Comparing the QTc interval in the rabbits in Group S and Group N, in the 25th, 27th and 30th minute after muscle relaxant antagonist was administered the QTc interval in the neostigmine group rabbits was significantly increased (p<0.05). CONCLUSION: While sugammadex, administered to antagonize the effect of rocuronium, did not significantly affect the QTc interval, neostigmine+atropine proloned the QTc interval. PMID- 25517495 TI - Acute hyperglycemia prevents dexmedetomidine-induced preconditioning against renal ischemia-reperfusion injury. AB - PURPOSE: To investigate the effects of acute hyperglycemia on dexmedetomidine induced preconditioning against renal ischemia-reperfusion injury. METHODS: Sprague-Dawley rats were randomly arranged to the normoglycemic (NG) or hyperglycemic group (HG), with each group further divided into sham (no I/R injury), I/R (ischemia-reperfusion) and dex (given by dexmedetomidine) groups. Acute hyperglycemia was induced by intraperitoneal injection (i.p.) of 25% glucose (3 g/kg) 45 min before ischemia. Dexmedetomidine (50 MUg/kg, i.p.) was administrated 30 min before induction of ischemia. Renal function, histology, apoptosis, expression of Bax, Bcl-2 and phosphorylated AKT (p-AKT) were detected. RESULTS: I/R insult significantly increased the serum levels of blood urea nitrogen and creatinine, apoptotic tubular epithelial cells, expression of Bax and p-AKT, but decreased Bcl-2 expression. All these changes were further enhanced by hyperglycemia (p<0.05). In hyperglycemic condition, there was no statistically difference between the I/R group and Dex group in all the aforementioned detection indexes (p>0.05). CONCLUSION: Acute hyperglycemia attenuates dexmedetomidine-induced preconditioning against renal ischemia reperfusion injury in non-diabetic rats. PMID- 25517496 TI - Preemptive analgesia effects of ketamine in patients undergoing surgery. A meta analysis. AB - PURPOSE: To evaluate the preemptive analgesia effects of ketamine for postoperative pain. METHODS: PubMed, EMBASE and Cochrane Library were searched to identify randomized controlled trials (RCTs) involved in ketamine for preemptive analgesic up to March 2013. The relative risk (RR) or mean difference (MD) as well as the confounding 95% confidence interval (CI) were calculated by the Revman 5.0 software. RESULTS: A total of five studies including 266 patients were included in this meta-analysis. Overall, ketamine could reduce the postoperative morphine consumption and significantly prolong the time to first analgesic (p < 0.00001, MD = 0.91, 95% CI: 0.56 to 1.26). However, there was no significant difference in indicators of nausea and vomiting (p = 0.87, RR = 1.04, 95% CI: 0.67 to 1.60), surgical time (p = 0.41, MD = -2.13, 95% CI: -7.21 to 2.95) and anesthetic time (p = 0.53, MD = -1.54, 95% CI: -6.34 to -3.26) between ketamine and control group. CONCLUSIONS: Ketamine was able to accomplish some preemptive analgesic effects of reducing postoperative morphine consumption and prolonging the time to first analgesic. Meanwhile, ketamine was as safe as physiological saline in side effects of nausea and vomiting. PMID- 25517497 TI - Single-incision laparoscopic appendectomy versus conventional laparoscopy in adults. A systematic review. AB - PURPOSE: To determine the best treatment option for not complicated acute appendicitis (AA) in adult patients, between single incision laparoscopy (SIL) and conventional laparoscopy (CL), measured by morbidity associated with disease. METHODS: Systematic review. Articles of adults diagnosed with AA treated by SIL or CL were analyzed. Databases included: MEDLINE, LILACS, IBECS, Web of Science, Scopus and Cochrane, using MeSH terms and free words. The studies were analyzed using the MINCIR methodology. Variables included: conversion rate, morbidity, hospital stay, surgery duration, and methodological quality (MQ) of primary studies. Averages, medians and weighted averages were calculated. RESULTS: Thirteen articles were analyzed. For SIL and CL the conversion rate were 3.4% and 0.7 %, the morbidity were 8% and 6.5%, the hospital stay were 2.5 and 2.8 days, the surgery duration were 53.4 and 53.8 minutes, and the MQ were 14.3+/-6.6 and 16.0+/-6.9 points, respectively. CONCLUSION: With the exception of the conversion rate, there are no differences between single incision laparoscopy and conventional laparoscopy for the treatment of acute appendicitis in adults. PMID- 25517498 TI - Evaluated kinetics of terminal and non-terminal addition of hydrogen atoms to 1 alkenes: a shock tube study of H + 1-butene. AB - Single-pulse shock tube methods have been used to thermally generate hydrogen atoms and investigate the kinetics of their addition reactions with 1-butene at temperatures of 880 to 1120 K and pressures of 145 to 245 kPa. Rate parameters for the unimolecular decomposition of 1-butene are also reported. Addition of H atoms to the pi bond of 1-butene results in displacement of either methyl or ethyl depending on whether addition occurs at the terminal or nonterminal position. Postshock monitoring of the initial alkene products has been used to determine the relative and absolute reaction rates. Absolute rate constants have been derived relative to the reference reaction of displacement of methyl from 1,3,5-trimethylbenzene (135TMB). With k(H + 135TMB -> m-xylene + CH3) = 6.7 * 10(13) exp(-3255/T) cm(3) mol(-1) s(-1), we find the following: k(H + 1-butene -> propene + CH3) = k10 = 3.93 * 10(13) exp(-1152 K/T) cm(3) mol(-1) s(-1), [880 1120 K; 145-245 kPa]; k(H + 1-butene -> ethene + C2H5) = k11 = 3.44 * 10(13) exp( 1971 K/T) cm(3) mol(-1) s(-1), [971-1120 K; 145-245 kPa]; k10/k11 = 10((0.058+/ 0.059)) exp [(818 +/- 141) K/T), 971-1120 K. Uncertainties (2sigma) in the absolute rate constants are about a factor of 1.5, while the relative rate constants should be accurate to within +/-15%. The displacement rate constants are shown to be very close to the high pressure limiting rate constants for addition of H, and the present measurements are the first direct determination of the branching ratio for 1-olefins at high temperatures. At 1000 K, addition to the terminal site is favored over the nonterminal position by a factor of 2.59 +/ 0.39, where the uncertainty is 2sigma and includes possible systematic errors. Combining the present results with evaluated data from the literature pertaining to temperatures of <440 K leads us to recommend the following: kinfinity(H + 1 butene -> 2-butyl) = 1.05 * 10(9)T(1.40) exp(-366/T) cm(3) mol(-1) s(-1), [220 2000 K]; kinfinity(H + 1-butene -> 1-butyl) = 9.02 * 10(8)T(1.40) exp(-1162/T) cm(3) mol(-1) s(-1) [220-2000 K]. Analogous rate constants for other unbranched 1 olefins should be very similar. Despite this, a factor of three discrepancy in the branching ratio for terminal and nonterminal addition is noted when comparing the present values with recommendations from a recent model of the important H + propene reaction. This difference is suggested to be well outside of the possible experimental errors of the present study or the expected differences with 1 butene. There thus appear to be inconsistencies in the current model for propene. In particular the addition branching ratio from that model should not be used as a reference value in extrapolations to other systems via rate rules or automated mechanism generation techniques. PMID- 25517499 TI - Somatic mutations in arachidonic acid metabolism pathway genes enhance oral cancer post-treatment disease-free survival. AB - The arachidonic acid metabolism (AAM) pathway promotes tumour progression. Chemical inhibitors of AAM pathway prolong post-treatment survival of cancer patients. Here we test whether non-synonymous somatic mutations in genes of this pathway, acting as natural inhibitors, increase post-treatment survival. We identify loss-of-function somatic mutations in 15 (18%) of 84 treatment-naive oral cancer patients by whole-exome sequencing, which we map to genes of AAM pathway. Patients (n = 53) who survived >= 12 months after surgery without recurrence have significantly (P = 0.007) higher proportion (26% versus 3%) of mutations than those who did not (n = 31). Patients with mutations have a significantly (P = 0.003) longer median disease-free survival (24 months) than those without (13 months). Compared with the presence of a mutation, absence of any mutation increases the hazard ratio for death (11.3) significantly (P = 0.018). The inferences are strengthened when we pool our data with The Cancer Genome Atlas (TCGA) data. In patients with AAM pathway mutations, some downstream pathways, such as the PI3K-Akt pathway, are downregulated. PMID- 25517500 TI - Tissue-specific somatic stem-cell isolation and characterization from human endometriosis. Key roles in the initiation of endometrial proliferative disorders. AB - AIM: The endometrial-proliferation related diseases leads to endometrial hyperplasia, i.e., endometriosis. Endometrial progenitor and stem cells play key roles in the beginning of endometrial proliferative disorders. The purpose of this study was the isolation of stem cells in the endometriosis lesion as well as the evaluation and comparison of the stemness-related target genes in endometriosis endometrial stem cells (EESCs), normal endometrial stem cell (ESCs), endometrial lesions stem cell (ELSCs) and bone marrow mesenchymal stem cells (MSCs). METHODS: EESCs, ESCs, ELSCs and MSCs were isolated. Flowcytometry and real-time PCR were utilized to detect the cell surface marker and expression pattern of 16 stemness genes. The proliferation of all stem cells was observed by MTT assay. The differentiation potential was evaluated by alizarin red, oil red O and RT-PCR method. The karyotyping was performed on EESCs and ELSCs at passage 20. RESULTS: The unique patterns of gene expression were detected although EESCs, ESCs, ELSCs and MSCs have a background expression of stemness-related genes. Spindle-like morphology, normal karyotype, adipogenic and osteogenic potential, significantly expression of Oct4, SALL4, DPPA2, Sox2, Sox17 and also specific surface markers such as CD44, CD105, CD90, CD73 and CD146 in EESCs and ELSCs was observed. CONCLUSION: According to our data, stem cells in endometriosis endometrial and endometriosis are such a informative tools to study of pathogenesis of gynecological diseases. Furthermore, endometrial stem/progenitor cells which easily obtain from tissue may be valuable targets for early diagnosis of endometrial disorders in the future. PMID- 25517501 TI - Efficacy of early bundle therapy on moderate to severe aspiration pneumonia after cervical esophagogastrostomy for esophageal cancer. AB - AIM: The aim of this paper was to investigate the methodology and clinical efficacy of early bundle therapy for complicated moderate to severe aspiration pneumonia after cervical esophagogastrostomy for esophageal cancer. METHODS: A prospective study was conducted to analyze the clinical data from 49 patients who developed complicated moderate to severe aspiration pneumonia after cervical esophagogastrostomy for esophageal cancer. Among them, 27 patients underwent a bundle therapy-tracheostomy followed by ventilator-assisted breathing with reverse trendelenburg position, early goal-directed hemodynamic support, enteral nutrition by nasointestinal tube, effective antibiotic usage and large doses of expectorants in addition to the conventional treatments. The remaining 22 patients underwent conventional treatment (controls). The hospital fatality rates, incidence of serious complications, mechanical ventilation time and ICU length of stay of the two groups were compared. RESULTS: Patients in the bundle therapy group had higher cure rate of pneumonia than the control group (P=0.041), significantly lower fatality rate than the controls (P=0.005), lower incidence of complications than the controls (P<0.05), shorter ICU length of stay than the control group (P=0.017), significantly shorter mechanical ventilation time (P=0.032), lower Acute Physiology and Chronic Health Evaluation II Score (P=0.036) and lower Clinical Pulmonary Infection Score (P=0.047). CONCLUSION: Early bundle therapy can effectively improve the treatment efficacy for moderate to severe aspiration pneumonia after cervical esophagogastrostomy for esophageal cancer. PMID- 25517502 TI - Optoelectronic memory using two-dimensional materials. AB - An atomically thin optoelectronic memory array for image sensing is demonstrated with layered CuIn7Se11 and extended to InSe and MoS2 atomic layers. Photogenerated charge carriers are trapped and subsequently retrieved from the potential well formed by gating a 2D material with Schottky barriers. The atomically thin layered optoelectronic memory can accumulate photon-generated charges during light exposure, and the charges can be read out later for data processing and permanent storage. An array of atomically thin image memory pixels was built to illustrate the potential of fabricating large-scale 2D material based image sensors for image capture and storage. PMID- 25517504 TI - Unusual C,O-Fused Glycosylapigenins from Serjania marginata Leaves. AB - A phytochemical study of a Serjania marginata leaf extract with antiulcer activity afforded 15 compounds, including the new 3-O-alpha-l-arabinopyranosyl(1 >3)-alpha-l-rhamnopyranosyl(1->2)[beta-d-glucopyranosyl(1->4)]-alpha-l arabinopyranosyloleanolic acid (1) and 7,5"-anhydroapigenin 8-C-alpha-(2,6 dideoxy-5-hydroxy-ribo-hexopyranosyl)-4'-O-beta-d-glucopyranoside (4). The structures of the new compounds were determined by spectroscopic analysis, including 1D and 2D NMR techniques, mass spectrometry, and chemical methods. Compound 4 is a C-hexopyranosylapigenin with an unusual cyclic ether linkage between C-5" and C-7 of apigenin. The isolated proanthocyanidins have high antioxidant activities, and these compounds are probably responsible for the gastroprotective effect of the extract. PMID- 25517503 TI - Comparison of inter subject variability and reproducibility of whole brain proton spectroscopy. AB - The aim of these studies was to provide reference data on intersubject variability and reproducibility of metabolite ratios for Choline/Creatine (Cho/Cr), N-acetyl aspartate/Choline (NAA/Cho) and N-acetyl aspartate/Creatine (NAA/Cr), and individual signal-intensity normalised metabolite concentrations of NAA, Cho and Cr. Healthy volunteers underwent imaging on two occasions using the same 3T Siemens Verio magnetic resonance scanner. At each session two identical Metabolic Imaging and Data Acquisition Software (MIDAS) sequences were obtained along with standard structural imaging. Metabolite maps were created and regions of interest applied in normalised space. The baseline data from all 32 volunteers were used to calculate the intersubject variability, while within session and between session reproducibility were calculated from all the available data. The reproducibility of measurements were used to calculate the overall and within session 95% prediction interval for zero change. The within and between session reproducibility data were lower than the values for intersubject variability, and were variable across the different brain regions. The within and between session reproducibility measurements were similar for Cho/Cr, NAA/Choline, Cho and Cr (11.8%, 11.4%, 14.3 and 10.6% vs. 11.9%, 11.4%, 13.5% and 10.5% respectively), but for NAA/Creatine and NAA between session reproducibility was lower (9.3% and 9.1% vs. 10.1% and 9.9%; p <0.05). This study provides additional reference data that can be utilised in interventional studies to quantify change within a single imaging session, or to assess the significance of change in longitudinal studies of brain injury and disease. PMID- 25517505 TI - Effects of whaling on the structure of the Southern Ocean food web: insights on the "krill surplus" from ecosystem modelling. AB - The aim of this study was to examine the ecological plausibility of the "krill surplus" hypothesis and the effects of whaling on the Southern Ocean food web using mass-balance ecosystem modelling. The depletion trajectory and unexploited biomass of each rorqual population in the Antarctic was reconstructed using yearly catch records and a set of species-specific surplus production models. The resulting estimates of the unexploited biomass of Antarctic rorquals were used to construct an Ecopath model of the Southern Ocean food web existing in 1900. The rorqual depletion trajectory was then used in an Ecosim scenario to drive rorqual biomasses and examine the "krill surplus" phenomenon and whaling effects on the food web in the years 1900-2008. An additional suite of Ecosim scenarios reflecting several hypothetical trends in Southern Ocean primary productivity were employed to examine the effect of bottom-up forcing on the documented krill biomass trend. The output of the Ecosim scenarios indicated that while the "krill surplus" hypothesis is a plausible explanation of the biomass trends observed in some penguin and pinniped species in the mid-20th century, the excess krill biomass was most likely eliminated by a rapid decline in primary productivity in the years 1975-1995. Our findings suggest that changes in physical conditions in the Southern Ocean during this time period could have eliminated the ecological effects of rorqual depletion, although the mechanism responsible is currently unknown. Furthermore, a decline in iron bioavailability due to rorqual depletion may have contributed to the rapid decline in overall Southern Ocean productivity during the last quarter of the 20th century. The results of this study underscore the need for further research on historical changes in the roles of top-down and bottom-up forcing in structuring the Southern Ocean food web. PMID- 25517506 TI - Ischemic burden and clinical outcome: is one 'culprit' ischemic segment by dobutamine stress magnetic resonance predictive? AB - AIMS: We sought to evaluate the impact of ischemic burden for the prediction of hard cardiac events (cardiac death or nonfatal myocardial infarction) in patients with known or suspected CAD who undergo dobutamine stress cardiac magnetic resonance imaging (DCMR). METHODS: We included 3166 patients (pts.), mean age 63 +/- 12 years, 27% female, who underwent DCMR in 3 tertiary cardiac centres (University Hospital Heildelberg, German Heart Institute and Kings College London). Pts. were separated in groups based on the number of ischemic segments by wall motion abnormalities (WMA) as follows: 1. no ischemic segment, 2. one ischemic segment, 3. two ischemic segments and 4. >= three ischemic segments. Cardiac death and nonfatal myocardial infarction were registered as hard cardiac events. Pts. with an "early" revascularization procedure (in the first three months after DCMR) were not included in the final survival analysis. RESULTS: Pts. were followed for a median of 3.1 years (iqr 2-4.5 years). 187 (5.9%) pts. experienced hard cardiac events. 2349 (74.2%) had no inducible ischemia, 189 (6%) had ischemia in 1 segment, 292 (9.2%) in 2 segments and 336 (10.6%) >= 3 segments. Patients with only 1 ischemic segment showed a high rate of hard cardiac events of ~ 6% annually, which was 10-fold higher compared to those without ischemia (0.6% annually, p < 0.001) but similar to those with 2 and >= 3 ischemic segments (~ 5.5% and ~ 7%, p = NS). CONCLUSIONS: The presence of inducible ischemia even in a single 'culprit' myocardial segment during DCMR is enough to predict hard cardiac events in patients with known or suspected CAD. PMID- 25517508 TI - Effective use of the built environment to manage behavioural and psychological symptoms of dementia: a systematic review. AB - OBJECTIVE: To determine the effectiveness of built environment interventions in managing behavioural and psychological symptoms of dementia (BPSD) among residents in long-term care settings. METHODS: Systematic review of literature published from 1995-2013. Studies were included if they: were randomized controlled trials, quasi-experimental trials, or comparative cohort studies; were in long-term or specialized dementia care; included residents with dementia and BPSD; and examined effectiveness of a built environment intervention on frequency and/or severity of BPSD. Quality of included studies was assessed using the Downs and Black Checklist. Study design, patient population, intervention, and outcomes were extracted and narratively synthesized. RESULTS: Five low to moderate quality studies were included. Three categories of interventions were identified: change/redesign of existing physical space, addition of physical objects to environment, and type of living environment. One of the two studies that examined change/redesign of physical spaces reported improvements in BPSD. The addition of physical objects to an existing environment (n = 1) resulted in no difference in BPSD between treatment and control groups. The two studies that examined relocation to a novel living environment reported decreased or no difference in the severity and/or frequency of BPSD post-intervention. No studies reported worsening of BPSD following a built environment intervention. CONCLUSIONS: The range of built environment interventions is broad, as is the complex and multi dimensional nature of BPSD. There is inconclusive evidence to suggest a built environment intervention which is clinically superior in long-term care settings. Further high-quality methodological and experimental studies are required to demonstrate the feasibility and effectiveness of such interventions. PMID- 25517509 TI - The nature of expertise in fingerprint matching: experts can do a lot with a little. AB - Expert decision making often seems impressive, even miraculous. People with genuine expertise in a particular domain can perform quickly and accurately, and with little information. In the series of experiments presented here, we manipulate the amount of "information" available to a group of experts whose job it is to identify the source of crime scene fingerprints. In Experiment 1, we reduced the amount of information available to experts by inverting fingerprint pairs and adding visual noise. There was no evidence for an inversion effect experts were just as accurate for inverted prints as they were for upright prints but expert performance with artificially noisy prints was impressive. In Experiment 2, we separated matching and nonmatching print pairs in time. Experts were conservative, but they were still able to discriminate pairs of fingerprints that were separated by five-seconds, even though the task was quite different from their everyday experience. In Experiment 3, we separated the print pairs further in time to test the long-term memory of experts compared to novices. Long term recognition memory for experts and novices was the same, with both performing around chance. In Experiment 4, we presented pairs of fingerprints quickly to experts and novices in a matching task. Experts were more accurate than novices, particularly for similar nonmatching pairs, and experts were generally more accurate when they had more time. It is clear that experts can match prints accurately when there is reduced visual information, reduced opportunity for direct comparison, and reduced time to engage in deliberate reasoning. These findings suggest that non-analytic processing accounts for a substantial portion of the variance in expert fingerprint matching accuracy. Our conclusion is at odds with general wisdom in fingerprint identification practice and formal training, and at odds with the claims and explanations that are offered in court during expert testimony. PMID- 25517507 TI - Comparison of "Live High-Train Low" in normobaric versus hypobaric hypoxia. AB - We investigated the changes in both performance and selected physiological parameters following a Live High-Train Low (LHTL) altitude camp in either normobaric hypoxia (NH) or hypobaric hypoxia (HH) replicating current "real" practices of endurance athletes. Well-trained triathletes were split into two groups (NH, n = 14 and HH, n = 13) and completed an 18-d LHTL camp during which they trained at 1100-1200 m and resided at an altitude of 2250 m (PiO2 = 121.7+/ 1.2 vs. 121.4+/-0.9 mmHg) under either NH (hypoxic chamber; FiO2 15.8+/-0.8%) or HH (real altitude; barometric pressure 580+/-23 mmHg) conditions. Oxygen saturations (SpO2) were recorded continuously daily overnight. PiO2 and training loads were matched daily. Before (Pre-) and 1 day after (Post-) LHTL, blood samples, VO2max, and total haemoglobin mass (Hb(mass)) were measured. A 3-km running test was performed near sea level twice before, and 1, 7, and 21 days following LHTL. During LHTL, hypoxic exposure was lower for the NH group than for the HH group (220 vs. 300 h; P<0.001). Night SpO2 was higher (92.1+/-0.3 vs. 90.9+/-0.3%, P<0.001), and breathing frequency was lower in the NH group compared with the HH group (13.9+/-2.1 vs. 15.5+/-1.5 breath.min(-1), P<0.05). Immediately following LHTL, similar increases in VO2max (6.1+/-6.8 vs. 5.2+/-4.8%) and Hb(mass) (2.6+/-1.9 vs. 3.4+/-2.1%) were observed in NH and HH groups, respectively, while 3-km performance was not improved. However, 21 days following the LHTL intervention, 3-km run time was significantly faster in the HH (3.3+/ 3.6%; P<0.05) versus the NH (1.2+/-2.9%; ns) group. In conclusion, the greater degree of race performance enhancement by day 21 after an 18-d LHTL camp in the HH group was likely induced by a larger hypoxic dose. However, one cannot rule out other factors including differences in sleeping desaturations and breathing patterns, thus suggesting higher hypoxic stimuli in the HH group. PMID- 25517511 TI - Is this car looking at you? How anthropomorphism predicts fusiform face area activation when seeing cars. AB - Anthropomorphism encompasses the attribution of human characteristics to non living objects. In particular the human tendency to see faces in cars has long been noticed, yet its neural correlates are unknown. We set out to investigate whether the fusiform face area (FFA) is associated with seeing human features in car fronts, or whether, the higher-level theory of mind network (ToM), namely temporoparietal junction (TPJ) and medial prefrontal cortex (MPFC) show a link to anthropomorphism. Twenty participants underwent fMRI scanning during a passive car-front viewing task. We extracted brain activity from FFA, TPJ and MPFC. After the fMRI session participants were asked to spontaneously list adjectives that characterize each car front. Five raters judged the degree to which each adjective can be applied as a characteristic of human beings. By means of linear mixed models we found that the implicit tendency to anthropomorphize individual car fronts predicts FFA, but not TPJ or MPFC activity. The results point to an important role of FFA in the phenomenon of ascribing human attributes to non living objects. Interestingly, brain regions that have been associated with thinking about beliefs and mental states of others (TPJ, MPFC) do not seem to be related to anthropomorphism of car fronts. PMID- 25517510 TI - What guidance are researchers given on how to present network meta-analyses to end-users such as policymakers and clinicians? A systematic review. AB - INTRODUCTION: Network meta-analyses (NMAs) are complex methodological approaches that may be challenging for non-technical end-users, such as policymakers and clinicians, to understand. Consideration should be given to identifying optimal approaches to presenting NMAs that help clarify analyses. It is unclear what guidance researchers currently have on how to present and tailor NMAs to different end-users. METHODS: A systematic review of NMA guidelines was conducted to identify guidance on how to present NMAs. Electronic databases and supplementary sources were searched for NMA guidelines. Presentation format details related to sample formats, target audiences, data sources, analysis methods and results were extracted and frequencies tabulated. Guideline quality was assessed following criteria developed for clinical practice guidelines. RESULTS: Seven guidelines were included. Current guidelines focus on how to conduct NMAs but provide limited guidance to researchers on how to best present analyses to different end-users. None of the guidelines provided reporting templates. Few guidelines provided advice on tailoring presentations to different end-users, such as policymakers. Available guidance on presentation formats focused on evidence networks, characteristics of individual trials, comparisons between direct and indirect estimates and assumptions of heterogeneity and/or inconsistency. Some guidelines also provided examples of figures and tables that could be used to present information. CONCLUSIONS: Limited guidance exists for researchers on how best to present NMAs in an accessible format, especially for non-technical end-users such as policymakers and clinicians. NMA guidelines may require further integration with end-users' needs, when NMAs are used to support healthcare policy and practice decisions. Developing presentation formats that enhance understanding and accessibility of NMAs could also enhance the transparency and legitimacy of decisions informed by NMAs. PMID- 25517512 TI - Noninvasive Quantitative Imaging of Collagen Microstructure in Three-Dimensional Hydrogels Using High-Frequency Ultrasound. AB - Collagen I is widely used as a natural component of biomaterials for both tissue engineering and regenerative medicine applications. The physical and biological properties of fibrillar collagens are strongly tied to variations in collagen fiber microstructure. The goal of this study was to develop the use of high frequency quantitative ultrasound to assess collagen microstructure within three dimensional (3D) hydrogels noninvasively and nondestructively. The integrated backscatter coefficient (IBC) was employed as a quantitative ultrasound parameter to detect, image, and quantify spatial variations in collagen fiber density and diameter. Collagen fiber microstructure was varied by fabricating hydrogels with different collagen concentrations or polymerization temperatures. IBC values were computed from measurements of the backscattered radio-frequency ultrasound signals collected using a single-element transducer (38-MHz center frequency, 13 47 MHz bandwidth). The IBC increased linearly with increasing collagen concentration and decreasing polymerization temperature. Parametric 3D images of the IBC were generated to visualize and quantify regional variations in collagen microstructure throughout the volume of hydrogels fabricated in standard tissue culture plates. IBC parametric images of corresponding cell-embedded collagen gels showed cell accumulation within regions having elevated collagen IBC values. The capability of this ultrasound technique to noninvasively detect and quantify spatial differences in collagen microstructure offers a valuable tool to monitor the structural properties of collagen scaffolds during fabrication, to detect functional differences in collagen microstructure, and to guide fundamental research on the interactions of cells and collagen matrices. PMID- 25517514 TI - Establishment of relative and absolute configurations of phaeosphaeride A: total synthesis of ent-phaeosphaeride A. AB - The relative and absolute configurations of phaeosphaeride A have been established via the first total synthesis of ent-phaeosphaeride A. The three contiguous stereogenic centers were installed by Sharpless asymmetric dihydroxylation and a stereoselective intramolecular vinyl anion aldol reaction. This synthesis has altered the originally proposed structure of natural phaeosphaeride A. PMID- 25517515 TI - Imaging samples in silica aerogel using an experimental point spread function. AB - Light microscopy is a powerful tool that allows for many types of samples to be examined in a rapid, easy, and nondestructive manner. Subsequent image analysis, however, is compromised by distortion of signal by instrument optics. Deconvolution of images prior to analysis allows for the recovery of lost information by procedures that utilize either a theoretically or experimentally calculated point spread function (PSF). Using a laser scanning confocal microscope (LSCM), we have imaged whole impact tracks of comet particles captured in silica aerogel, a low density, porous SiO2 solid, by the NASA Stardust mission. In order to understand the dynamical interactions between the particles and the aerogel, precise grain location and track volume measurement are required. We report a method for measuring an experimental PSF suitable for three dimensional deconvolution of imaged particles in aerogel. Using fluorescent beads manufactured into Stardust flight-grade aerogel, we have applied a deconvolution technique standard in the biological sciences to confocal images of whole Stardust tracks. The incorporation of an experimentally measured PSF allows for better quantitative measurements of the size and location of single grains in aerogel and more accurate measurements of track morphology. PMID- 25517513 TI - CD105 is a surface marker for receptor-targeted gene transfer into human long term repopulating hematopoietic stem cells. AB - Hematopoietic stem cells (HSCs) are an important target cell population for gene therapy since they can reconstitute the entire hematopoietic system. HSC-enriched cell populations can be recognized based on cell surface marker expression, such as CD34, which is broadly expressed on immature and partially differentiated cells. In mice, co-expression of CD34 and CD105 was previously shown to be relatively more specific for the most immature, long-term repopulating HSCs. Here, we evaluated whether CD105, which is expressed on 30%-80% of CD34(+) cells, is a marker also for human long-term repopulating HSCs. Therefore, we tracked the mature progeny of CD34(+) cells transduced with the CD105-targeted lentiviral vector CD105-LV in xenotolerant mice. Transduction was blocked with soluble CD105 protein confirming specificity. Importantly, CD105-LV transduced human CD34(+) cells engrafted in NOD-scid IL2Rgamma(-/-) mice with up to 20% reporter gene positive cells detected long term in all human hematopoietic lineages in bone marrow (BM), spleen, and blood. In addition, competitive repopulation experiments in mice showed a superior engraftment of CD105-LV transduced CD34(+) cells in BM and spleen compared with cells transduced with a conventional nontargeted lentiviral vector. Thus, human CD34(+)/CD105(+) cells are enriched for early HSCs with high repopulating capacity. Targeting this cell population with CD105-LV offers a novel gene transfer strategy to reach high engraftment rates of transduced cells and highlights the applicability of receptor-targeted vectors to trace cell subsets offering an alternative to prospective isolation by surface markers. PMID- 25517516 TI - The risk of melanoma in pilots and cabin crew: UV measurements in flying airplanes. PMID- 25517518 TI - Effect of a spray formulation on the reproductive parameters of a susceptible population of Rhipicephalus (Boophilus) microplus. AB - The number of studies emphasizing the possible damage that acaricidal spray formulations can cause on engorged female ticks' reproductive parameters is small. The present study evaluated the deleterious effects of a spray formulation (dichlorvos 60% + chlorpyrifos 20%) on the reproductive parameters of a susceptible population of Rhipicephalus (B.) microplus females, using the Stall Test. The ticks were allocated randomly to treatments according to the mean numbers of females detached from each cow on days -3, -2 and -1 and the cattle pen location. The numbers of engorged female ticks that naturally detached from the cattle were counted daily from day 1 to day 30. For each group, 20 detached engorged female ticks or the available number collected daily were evaluated regarding reproductive parameters. Associations of organophosphates demonstrated elevated acaricidal efficacy, as well as deleterious effects on the reproductive parameters of R. (B.) microplus females. The engorged female weight (days 1 to 7), weight of egg masses (days 5 to 10) and larval hatching percentage (days 5 to 19) were decreased (P <= 0.05). It is possible that a formulation can lead to deleterious effects on R. (B.) microplus females when the tick population analyzed shows elevated sensitivity towards a particular formulation. However, further studies need to be conducted. PMID- 25517519 TI - Hemoplasma prevalence and hematological abnormalities associated with infection in three different cat populations from Southern Brazil. AB - Three hemoplasma species are recognized in domestic cats: Mycoplasma haemofelis, 'Candidatus Mycoplasma haemominutum' and 'Candidatus Mycoplasma turicensis'. We report the prevalence and hematological abnormalities of hemoplasma infection in 369 domestic cats from three different populations (blood donors, hospitalized cats and shelter cats) from Southern Brazil. Complete blood counts were performed at the time of blood collection, and DNA was extracted and tested by conventional PCR for each hemoplasma species. A total of 79 samples (21.40%) were positive for at least one species. The most prevalent hemoplasma was 'Candidatus Mycoplasma haemominutum', with 50/369 (13.55%) positive cats, followed by 'Candidatus Mycoplasma turicensis', 10/369 (2.71%), and Mycoplasma haemofelis, 8/369 (2.16%). Mycoplasma haemofelis and 'Candidatus Mycoplasma haemominutum' coinfection was observed in 4/369 (1.08%), whereas 'Candidatus Mycoplasma haemominutum' and 'Candidatus Mycoplasma turicensis' in 5/369 (1.35%). Three cats (0.81%) were infected with all three hemoplasmas. There was no association between infection and the different populations. Anemia was associated with Mycoplasma haemofelis and 'Candidatus Mycoplasma haemominutum', but not with 'Candidatus Mycoplasma turicensis'. Male cats and cats with outdoor access were more likely to be infected. Although 'Candidatus Mycoplasma haemominutum' is believed to cause minimal or no hematological alterations, the infected cats studied herein were more likely to be anemic. PMID- 25517520 TI - Studies on some fish parasites of public health importance in the southern area of Saudi Arabia. AB - The present study was the first attempt to survey the diversity of fish zoonotic parasites in the southern region of Saudi Arabia, particularly the Najran area, from October 2012 to October 2013. Approximately 163 fish representing seven species (two of freshwater fish and five of marine fish) were examined for fish borne trematode metacercariae using the compression technique, and for zoonotic nematode larvae. Adult flukes were obtained from cats experimentally infected with the metacercariae on day 25 post-infection The prevalence of each parasite species was recorded. The parasites found belonged to two taxa: Digenea (Heterophyes heterophyes and Haplorchis pumilio) in muscle tissue; and nematodes (larvae of Capillaria sp.) in the digestive tract. The morphological characteristics of the fish-borne trematode metacercariae and their experimentally obtained adults were described. This is the first report of these parasites in fish in Saudi Arabia. Moreover, Myripristis murdjan presented higher prevalence of Capillaria sp. infection (22.7%), while Haplorchis pumilio was the dominant metacercarial species (7.9%). Although the number of documented cases continues to increase, the overall risk of human infection is slight. The increasing exploitation of the marine environment by humans and the tendency to reduce cooking times when preparing seafood products both increase the chances of becoming infected with these parasites. Furthermore, our results indicate that certain fish production systems are at risk of presenting fish zoonotic parasites, and that control approaches will benefit from understanding these risk factors. PMID- 25517521 TI - Genetic characterization of Toxoplasma gondii isolates from eared doves (Zenaida auriculata) in Brazil. AB - Eared doves (Zenaida auriculata), which are common in urban, rural and wild areas in many regions of Brazil, are frequently prey for domestic cats. Therefore Toxoplasma gondii isolates obtained from doves may reflect greater environmental diversity than those from other hosts. The aim of the present study was to evaluate T. gondii seroprevalence, isolate and genotype strains from Z. auriculata. Serum and tissue samples were collected from 206 doves for use in the modified agglutination test (MAT) and mouse bioassay. The prevalence of T. gondii antibodies in the doves was 22.3% (46/206), with titers ranging from 16 to 4096, and T. gondii strains were isolated from 12 of these doves. Five genotypes were detected by means of PCR-RFLP, including ToxoDB genotypes #1, #6, #17 and #65, and one genotype that had not previously been described (ToxoDB#182). This was the first report on isolation of T. gondii from Z. auriculata. This study confirmed the genetic diversity of T. gondii isolates and the existence of clonal type II (ToxoDB genotype #1) in Brazil. PMID- 25517522 TI - Serological detection of Toxoplasma gondii, Leishmania infantum and Neospora caninum in cats from an area endemic for leishmaniasis in Brazil. AB - An investigation was made into the occurrence of antibodies to Toxoplasma gondii, Leishmania infantum and Neospora caninum in 151 domestic cats, based on the indirect fluorescent antibody test (IFAT). Serum samples were collected from 151 domestic cats (65 free-roaming and 86 domiciled cats; 55 males and 96 females) in Campo Grande, Mato Grosso do Sul, Brazil between January and April 2013. IgG antibodies to T. gondii, L. infantum and N. caninum were found, respectively, in 49 (32.5%), 34 (22.5%) and 10 (6.6%) sampled cats. A positive correlation was found between T. gondii and N. caninum, T. gondii and L. infantum, and N. caninum and L. infantum (p <0.05) infections. Also, a significant interaction was identified between gender and area of activity on the probability of T. gondii (p = 0.0324) infection. However, no significant interaction was observed between gender and area of activity on infections by either N. caninum or L. infantum. This study showed that cats from an area endemic for visceral leishmaniasis in Brazil are exposed to three different protozoans, two of which are causal agents of important zoonosis. PMID- 25517523 TI - Occurrence of Lutzomyia longipalpis (Phlebotominae) and canine visceral leishmaniasis in a rural area of Ilha Solteira, SP, Brazil. AB - This study aimed to investigate the occurrence of Lutzomyia longipalpis and also the canine visceral leishmaniasis (CVL) in a rural area of Ilha Solteira, state of Sao Paulo. Blood samples were collected from 32 dogs from different rural properties (small farms) and were analyzed by ELISA and the indirect immunofluorescence antibody test (IFAT) in order to diagnose CVL. From these serological tests, 31.25% of the dogs were positive for CVL and these were distributed in 66.7% (8/12) of the rural properties, which were positive for L. longipalpis. CDC (Center for Disease Control and Prevention) light traps were installed in 12 properties (one per property) and insects were caught on three consecutive days per month for one year. L. longipalpis was present on 100% of the rural properties visited, at least once during the twelve-month interval, totaling 64 males and 25 females. The insects were more numerous after the peak of the rain, but the association between prevalence of peridomestic vectors and the climatic data (precipitation, relative air humidity and temperature) and the occurrences of CVL among dogs on each rural property were not statistical significant (p <0.05). However, the occurrence of CVL cases in dogs and the presence of L. longipalpis indicate that more attention is necessairy for the control of this disease in the rural area studied. PMID- 25517524 TI - Retrieval of Trichostrongylus colubriformis infective larvae from grass contaminated in winter and in spring. AB - The survival of infective larvae (L3) of Trichostrongylus colubriformis was evaluated on Brachiaria, Coast-cross and Aruana forage grasses. Feces of sheep parasitized exclusively by T. colubriformis were deposited in winter and spring on experimental plots whose grasses were cut at two heights: 5 cm and 30 cm. One, two, four, eight, 12 and 16 weeks after depositing the feces, fecal and forage samples were collected for the retrieval and quantification of L3. Retrieval of L3 from feces and forage was negligible in winter due to the dry weather, although a few larvae were retrieved in the last larval collections. However, L3 retrieval from fecal samples was greater in spring, especially two weeks after feces were deposited on 30 cm high grasses. At this time, the L3 retrieval rate from the three forage grasses differed significantly (P <0.05), with Aruana grass showing the highest average L3 retrieval rate, followed by Coast-cross and Brachiaria. In conclusion, the winter drought proved very unfavorable for the presence of L3 in the environment, and the microclimate of Aruana pastureland was generally the most favorable for the retrieval of infective larvae. PMID- 25517525 TI - Survey of canine tick-borne diseases in Labrea, Brazilian Amazon: 'accidental' findings of Dirofilaria immitis infection. AB - Blood samples were collected from 99 domestic dogs from the urban and rural areas of the Labrea municipality, state of Amazonas, Brazil. Canine serum samples were tested by immunofluorescence assay against Rickettsia spp., which revealed that only 3.0% (1/33) and 7.6% (5/66) of the dogs from urban and rural areas, respectively, reacted positively to at least one Rickettsia species. DNA was extracted from canine blood and tested by a battery of PCR assays targeting protozoa of the genera Babesia and Hepatozoon, and bacteria of the genera Rickettsia and Ehrlichia and family Anaplasmataceae. All samples were negative in the PCR assays targeting the genera Babesia, Hepatozoon, Ehrlichia and Rickettsia. For Anaplasmataceae, 3% (1/33) and 39.4% (26/66) of the urban and rural dogs, respectively, yielded amplicons that generated DNA sequences 100% identical to the corresponding sequence of Wolbachia endosymbiont of Dirofilaria immitis. Because of these results, all canine DNA samples were further tested in a PCR assay targeting filarial nematodes, which was positive for 18.2% (6/33) and 57.6% (38/66) urban and rural dogs, respectively. Filarial-PCR products generated DNA sequences 100% identical to D. immitis. While tick-borne infections were rare in Labrea, D. immitis infection rates were among the highest reported in South America. PMID- 25517526 TI - Occurrence of anti-Toxoplasma gondii antibodies in meat and dairy goat herds in Rio Grande do Norte, Brazil. AB - Toxoplasmosis is caused by Toxoplasma gondii, which is the main causative agent of abortion in small ruminants. Goats are among the animals that are most susceptible to this protozoon, and the disease that it causes leads to significant economic losses and has implications for public health, since presence of the parasite in products of goat origin is one of the main sources of human infection. Because of the significant economic impact, there is an urgent need to study the prevalence of T. gondii infection among goats in Sertao do Cabugi, which is the largest goat-producing region in Rio Grande do Norte. In the present study, the ELISA assay was used to test 244 serum samples from nine farms, located in four different municipalities in the Sertao do Cabugi region, which is an important goat-rearing region. The results showed that the prevalence of anti-T. gondii antibodies was 47.1% and that there was a significant association between positivity and the variables of age (>= 34 months), location (Lajes, Angicos and Afonso Bezerra) and farm (all the farms). The avidity test was applied to all the 115 ELISA-positive samples to distinguish between acute and chronic infection. One hundred and three samples (89.6%) displayed high avidity antibodies, thus indicating that most of the animals presented chronic infection, with a consequent great impact on the development of the goat production system and a risk to human health. PMID- 25517527 TI - Sheep gastrointestinal helminthiasis in the Sertao region of Paraiba State, Northeastern Brazil: prevalence and risk factors. AB - In this study, we aimed to establish the prevalence and risk factors relating to gastrointestinal helminthiasis, and to characterize the sanitary management practiced among sheep herds in the Sertao region of the state of Paraiba, northeastern Brazil, based on factors that condition the ways of controlling these parasites in these herds. The research was carried out between April and July 2012. We visited 54 farms, where fecal and blood samples were individually collected from 465 animals. On each farm, a questionnaire was applied to gather information on variables relating to potential risk factors. The prevalence of sheep gastrointestinal helminthiasis in the region was 75.9%. At least one animal tested positive for this helminthiasis on 53 (98.1%) of the 54 farms evaluated. The eggs per gram of feces (EPG) analysis showed the following infection burdens: 51.8% with mild infection, 27.1% moderate infection, 9.9% heavy infection and 11.2% fatal infection. Among the sheep farms visited, anthelmintics were used on 81.5% (p <0.05). The most relevant risk factor in this study was the farm area, because it defines the area available for grazing animals. Properties with many animals and little pasture area, which are the most abundant type in the Sertao region of Paraiba, tend to have high prevalence of gastrointestinal helminthiasis, because the animals are more prone to reinfection. The Sertao region of Paraiba presents high prevalence of gastrointestinal helminthiasis among sheep, and the farm area is the most relevant risk factor for the development of these parasites. PMID- 25517528 TI - Differentiation of Haemonchus placei from Haemonchus contortus by PCR and by morphometrics of adult parasites and third stage larvae. AB - Molecular and morphological methods were evaluated to distinguish between Haemonchus contortus and Haemonchus placei species. A total of 141 H. contortus and 89 H. placei male adult specimens collected from artificially infected lambs were identified individually by PCR analysis, using a species-specific primer pair. These PCR results were used as gold standard for Haemonchus spp. identification. Haemonchus placei presented higher mean spicule and barb lengths than H. contortus (P<0.05). However, some measurements overlapped. For this reason, a discriminate function did not allow the correct identification of 13 H. contortus and one H. placei specimen. The sheath tail length of the third stage larvae (L3), which comprises the distance between the tip of the larval tail and the end of the sheath tail, were measured. Only three of the 485 H. placei larvae (0.619%) had a sheath tail shorter than 85 um, while only four of the 500 H. contortus larvae (0.8%) presented a sheath tail longer than 85 um. The results indicated that 6.09% of the male adult specimens would be misclassified based on the discriminate function, while only 0.71% of infective larvae would be misclassified. Therefore, identification of L3 can be used as the first method to indicate the presence of H. placei and/or H. contortus in a population of domestic ruminants. PMID- 25517529 TI - Toxoplasma gondii in domestic and wild animals from forest fragments of the municipality of Natal, northeastern Brazil. AB - Toxoplasmosis stands out as a global disease that has felines as definitive hosts. In the municipality of Natal, Rio Grande do Norte State, Brazil, two parks are notable for their ecological and social importance. This study aimed to investigate the presence of Toxoplasma gondii in short hair cats, bats and small non-volant mammals in these two ecological reserves. Altogether, biological samples were obtained from 154 mammals, 92 wild animals from both areas and 62 domestic cats of the Parque da Cidade. In total, 22 (53.7%) non-volant wild mammals, 11 (21.5%) bats and 28 (52.8%) cats were positive for IgG anti-T. gondii antibodies using the Modified Agglutination Test (>= 25). It was possible to detect the presence of T. gondii DNA, by means of a molecular amplification of a B1 gene fragment (155bp), in 92 tissue samples from wild animals, including Didelphis albiventris, Monodelphis domestica, Artibeus lituratus, Carollia perspicillata and Glossophaga soricina. Of the 62 cats examined by the same molecular method, T. gondii DNA could be detected in 4 cats. In this study, it was observed the circulation of T. gondii in wild species and domestic cats, demonstrating the involvement of wild and domestic animals in the cycle of T. gondii. PMID- 25517530 TI - Pathology of dogs in Campo Grande, MS, Brazil naturally co-infected with Leishmania infantum and Ehrlichia canis. AB - Different parasites that commonly occur concomitantly can influence one another, sometimes with unpredictable effects. We evaluated pathological aspects of dogs naturally co-infected with Leishmania infantum and Ehrlichia canis. The health status of the dogs was investigated based on histopathological, hematological and biochemical analyses of 21 animals infected solely with L. infantum and 22 dogs co- infected with L. infantum and E. canis. The skin of both groups showed chronic, predominantly lymphohistioplasmacytic inflammatory reaction. The plasmacytosis in the lymphoid tissues was likely related with the hypergammaglobulinemia detected in all the dogs. The disorganization of extracellular matrix found in the reticular dermis of the inguinal region and ear, characterized by the substitution of thick collagen fibers for thin fibers, was attributed to the degree of inflammatory reaction, irrespective of the presence of parasites. In addition, the histopathological analysis revealed that twice as many dogs in the co-infected group presented Leishmania amastigotes in the ear skin than those infected solely with Leishmania, increasing the possibility of becoming infected through sand fly vectors. Our findings highlight the fact that the health of dogs infected concomitantly with L. infantum and E. canis is severely compromised due to their high levels of total plasma protein, globulins, alkaline phosphatase and creatine kinase, and severe anemia. PMID- 25517531 TI - Complementary data on four methods for sampling free-living ticks in the Brazilian Pantanal. AB - In this study, four methods for sampling free-living ticks that are used in ecological and human tick-bite risk studies were evaluated. Cloth dragging, carbon dioxide traps and visual searches and inspection of plant litter on the ground were used in field and forest areas within the Brazilian Pantanal. Among the three tick species collected, Amblyomma sculptum predominated, followed by Amblyomma parvum and Amblyomma ovale. Dragging, a cheap and simple technique, yielded the highest numbers of ticks, particularly nymphs. The visual search detected a high number of adult ticks and provided information on tick questing height. Even though laborious, plant litter examination showed that large numbers of ticks may use this stratum. Carbon dioxide (CO2) traps are expensive and difficult to handle, but they are highly efficient for adult ticks, especially A. parvum. These data indicate that one method alone is incapable of providing a representative sample of the tick fauna in a particular area and that multiple techniques should be used for tick population studies. PMID- 25517533 TI - Toxocara cati (Nematoda: Ascarididae) in Didelphis albiventris (Marsupialia: Didelphidae) from Brazil: a case of pseudoparasitism. AB - Eggs of Toxocara cati were found in the feces of Didelphis albiventris from a peridomestic urban environment in Brazil. Negative fecal tests following short term captivity of the opossums, as well as the absence of ascaridids during necropsy, suggest the occurrence of pseudoparasitism. Implications of the findings for the epidemiology of toxocariasis are discussed. PMID- 25517534 TI - Frequency of antibodies against Sarcocystis neurona and Neospora caninum in domestic cats in the state of Bahia, Brazil. AB - Sarcocystis neurona is the major agent of equine protozoal myeloencephalitis. It infects several mammalian species in the Americas, where the definitive hosts, marsupials of the genus Didelphis (D. virginiana and D. albiventris) are found. Domestic cats are one of the confirmed intermediate hosts of the parasite; however, antibodies against S. neurona had never before been demonstrated in Brazilian cats. The aim of this study was to determine whether cats in Bahia, Brazil, are exposed to the parasite. A total of 272 feline serum samples (134 from feral and 138 from house cats) were subjected to an indirect fluorescent antibody test using cultured merozoites of S. neurona as antigen. Positivity was detected in 4.0% (11/272) of the tested samples, with titers ranging from 25 to 800. The feline sera were also tested for antibodies against the protozoan Neospora caninum, with an observed antibody frequency of 2.9%. To the author's knowledge, this is the first study to report antibodies against S. neurona in Brazilian cats. We conclude that cats are exposed to the parasite in the region of this study. Further investigations are needed to confirm the role of cats in the transmission cycle of S. neurona in Brazil. PMID- 25517535 TI - Re-emergence of Chorioptes bovis (Acari: Psoroptidae) in cattle in the state of Rio Grande do Sul, Brazil. AB - Here we describe an outbreak of chorioptic mange in cattle, 56 years after its first identification in Brazil. Between the months of June and July 2011, dermatitis characterized by alopecia and crusted and thickened skin at the insertion of the tail and in the ischiorectal fossa was recognized in 40 (35.7%) out of 112 Holstein cows on a farm in the northeastern mesoregion of the state of Rio Grande do Sul, Brazil. After diagnosing mange caused by Chorioptes bovis, the cows were weighed and treated with 0.5% ivermectin, as a pour-on single dose, and were separated into two groups: cows in early lactation and those in late lactation. The survival rate of C. bovis and the healing rate in the two groups of infested cows were monitored every seven days through skin scrapings. After 28 days of evaluation, the cure rate through treatment was greater among cows in early lactation (p <0.0001). The survival rate of C. bovis was higher in cows in late lactation. PMID- 25517536 TI - Endoparasites of horses from the Formiga city, located in center-west region of the state of Minas Gerais, Brazil. AB - With the aim of studying the endoparasite fauna of horses from the Formiga city, located in center-west region of the state of Minas Gerais, 25 animals that were naturally infected with helminths were evaluated. By means of parasitological necropsies, different endoparasites were found. The subfamily Cyathostominae presented the highest incidence, followed by Trichostrongylus axei, Oxyuris equi, Triodontophorus serratus, Strongyloides westeri, Strongylus edentatus, Habronema muscae, Parascaris equorum, Probstmayria vivipara, Strongylus vulgaris, Gasterophilus nasalis, Anoplocephala magna and Anoplocephala perfoliata. In the present study, if the species Probstmayria vivipara was not considered in the prevalence, the frequency of Cyathostominae was equivalent to 94.85%. The results obtained in this study allowed us to detect and identify different species of helminths in horses, and confirmed the high incidence of nematodes belonging to the subfamily Cyathostominae in the center-west region of Minas Gerais. PMID- 25517537 TI - Morphological and molecular identification of ticks infesting Boa constrictor (Squamata, Boidae) in Manaus (Central Brazilian Amazon). AB - The Boa constrictor is one of the world's largest vertebrate carnivores and is often found in urban areas in the city of Manaus, Brazil. The morphological identification of ticks collected from 27 snakes indicated the occurrence of Amblyomma dissimile Koch 1844 on all individuals sampled. In contrast, Amblyomma rotundatum Koch was found on only two snakes. An analysis of the 16S rRNA molecular marker confirmed the morphological identification of these ectoparasites. PMID- 25517538 TI - Infection of the heart of Pimelodus ornatus (Teleostei, Pimelodidae), by Myxobolus sp. (Myxozoa, Myxobolidae). AB - The phylum Myxozoa Grasse, 1970, consists of a heterogenous group of around 50 genera that are worldwide disseminated in a wide variety of aquatic media. In the present study, 43 specimens of Pimelodus ornatus were collected from an adjacent area to the Cachoeira do Arari municipality on Marajo Island, in the Brazilian state of Para, in 2013. Macroscopic analysis showed the presence of whitened plasmodia located in the cardiac muscle and also in the region between the bulbus arteriosus and atrium cordis. Microscopic analysis on the parasitized tissues revealed spores that were typically piriform, with the anterior portion slightly narrower than the posterior end. The spore valves were symmetrical. The present species is placed in the genus Myxobolus Butschli, 1882, because of the presence of a pair of equal polar capsules in each spore. The prevalence of parasitism observed was 13.9% (6/43). This research note reports the first occurrence of Myxobolus as a parasite of the heart in the teleostean fish P. ornatus in the Amazon region and confirms the occurrence of secondary myocarditis in this fish, caused by parasitism by Myxobolus sp. The rarity of this parasitic species of Myxobolus at this tissue site, associated with other spore morphology characteristics in the fish, suggests that it is an undescribed species. PMID- 25517539 TI - Exposure of free-living jaguars to Toxoplasma gondii, Neospora caninum and Sarcocystis neurona in the Brazilian Pantanal. AB - Toxoplasma gondii, Neospora caninum and Sarcocystis neurona are related apicomplexan parasites that cause reproductive and neurological disorders in a wide range of domestic and wild animals. In the present study, the immunofluorescence antibody test (IFAT) was used to investigate the presence of antibodies against T. gondii, N. caninum and S. neurona in the sera of 11 free living jaguars (Panthera onca) in two protected areas in the Pantanal region of Mato Grosso state, Brazil. Ten jaguars (90.9%) showed seropositivity for T. gondii, eight (72.7%) for S. neurona, and seven (63.6%) for N. caninum antigens. Our findings reveal exposure of jaguars to these related coccidian parasites and circulation of these pathogens in this wild ecosystem. To the best of our knowledge, this is the first serological detection of N. caninum and S. neurona in free-living jaguars. PMID- 25517540 TI - Hospital utilization after a telemonitoring program: a pilot study. AB - The long-term effects of remote monitoring on hospital utilization and health care costs are understudied in home health care. The researchers performed a retrospective study, in a hospital-based home health care agency, to consider the effects of remote monitoring in 326 patients with heart failure 90 days after discharge from services. While statistical significance was not noted, clinical significance suggests that there was a decreased hospital utilization rate and decreased average cost per hospitalization in the remote monitoring group. PMID- 25517541 TI - Multiscale modeling of tissue-engineered fat: is there a deformation-driven positive feedback loop in adipogenesis? AB - Mechanotransduction plays a role in adipose tissues by transducing the environmental mechanical signals. It is recognized that dynamic or cyclic mechanical strains suppress adipogenesis, but static strains activate the adipogenic signaling pathways. This phenomenon needs to be investigated further, given its potential use in tissue engineering of fat. We used in vitro cultures as model systems for studying differentiation and function of adipocytes. Additionally, using the finite element method, we developed here sets of multiscale models (MSM), which represent single or multiple adipocytes embedded in scaffolds, stimulated mechanically in a static regime. Based on in vitro adipocyte culture work, these models were employed to study the hypothesis that the loading state of the plasma membrane (PM) in adipocytes is influenced by neighboring cells, which could reflect positive feedback loops of en mass adipose cell differentiation. We demonstrate that under static loading, tensile strains at the PM increase with the stage of cell maturation. Furthermore, when the cell density was sufficient (above 19 cells per 100 MUm(3)), progressive differentiation in some of the cells caused higher magnitudes of tensile strains in the PMs of other nearby cells. MSM are currently the only feasible means to correlate continuum (macrolevel) construct deformations to subcellular-level PM stretches in distorted cells. These macro-to-micro mechanobiology relationships, revealed through MSM, point to stimulations that promote the formation of lipid droplet accumulations and the increase of adipogenesis. Such models are a cost effective useful platform for achieving better understanding of these deformation driven cell processes toward optimized design of tissue-engineered fat constructs. PMID- 25517542 TI - Fluence-to-effective dose conversion coefficients from a Saudi population based phantom for monoenergetic photon beams from 10 keV to 20 MeV. AB - Fluence-to-dose conversion coefficients are important quantities for radiation protection, derived from Monte Carlo simulations of the radiation particles through a stylised phantom or voxel based phantoms. The voxel phantoms have been developed for many ethnic groups for their accurate reflection of the anatomy. In this study, we used the Monte Carlo code MCNPX to calculate the photon fluence-to effective dose conversion coefficients with a voxel phantom based on the Saudi Arabian male population. Six irradiation geometries, anterior-posterior (AP), posterior-anterior (PA), left lateral (LLAT), right lateral (RLAT), rotational (ROT) and isotropic (ISO) were simulated for monoenergetic photon beams from 10 keV to 20 MeV. We compared the coefficients with the reference values in ICRP Publication 116. The coefficients in the AP and PA geometries match the reference values to 9% and 12% on average as measured by root mean square while those in the LLAT, RLAT ROT and ISO geometries differ, mostly below, from the reference by 23, 22, 15 and 16%, respectively. The torso of the Saudi phantom is wider than the ICRP reference male phantom and likely to cause more attenuation to the lateral beam. The ICRP reference coefficients serve well for the Saudi male population as conservative estimations for the purpose of radiation protection. PMID- 25517543 TI - Rapid Uptake and Inhibition of Viral Propagation by Extracellular OAS1. AB - The oligoadenylate synthetase (OAS) proteins are traditionally considered intracellular antiviral proteins that mediate antiviral activity through the synthesis of 2'-5'-linked oligoadenylates and subsequent activation of the endoribonuclease RNase L. However, we have recently demonstrated that exogenous recombinant OAS1 is taken up by cells and reduces viral replication both in cell culture and in vivo, independent of RNase L. These results demonstrate a novel paracrine antiviral activity of OAS working in parallel with the classical RNase L pathway. In this study, we investigate the uptake kinetics of recombinant porcine OAS1 and show that it is rapidly and efficiently internalized in a manner that can be blocked by heparin. Heparin, furthermore, abolishes the antiviral activity of OAS1, demonstrating the requirement of the intracellular localization of OAS1 to inhibit the virus. In addition, we demonstrate that exogenous OAS1 affects an early step of the viral replication cycle. PMID- 25517544 TI - Structural reorganization of cylindrical nanoparticles triggered by polylactide stereocomplexation. AB - Co-crystallization of polymers with different configurations/tacticities provides access to materials with enhanced performance. The stereocomplexation of isotactic poly(L-lactide) and poly(D-lactide) has led to improved properties compared with each homochiral material. Herein, we report the preparation of stereocomplex micelles from a mixture of poly(L-lactide)-b-poly(acrylic acid) and poly(D-lactide)-b-poly(acrylic acid) diblock copolymers in water via crystallization-driven self-assembly. During the formation of these stereocomplex micelles, an unexpected morphological transition results in the formation of dense crystalline spherical micelles rather than cylinders. Furthermore, mixture of cylinders with opposite homochirality in either THF/H2O mixtures or in pure water at 65 degrees C leads to disassembly into stereocomplexed spherical micelles. Similarly, a transition is also observed in a related PEO-b-PLLA/PEO-b PDLA system, demonstrating wider applicability. This new mechanism for morphological reorganization, through competitive crystallization and stereocomplexation and without the requirement for an external stimulus, allows for new opportunities in controlled release and delivery applications. PMID- 25517545 TI - Adoptive immunotherapy for hematological malignancies using T cells gene-modified to express tumor antigen-specific receptors. AB - Accumulating clinical evidence suggests that adoptive T-cell immunotherapy could be a promising option for control of cancer; evident examples include the graft vs-leukemia effect mediated by donor lymphocyte infusion (DLI) and therapeutic infusion of ex vivo-expanded tumor-infiltrating lymphocytes (TIL) for melanoma. Currently, along with advances in synthetic immunology, gene-modified T cells retargeted to defined tumor antigens have been introduced as "cellular drugs". As the functional properties of the adoptive immune response mediated by T lymphocytes are decisively regulated by their T-cell receptors (TCRs), transfer of genes encoding target antigen-specific receptors should enable polyclonal T cells to be uniformly redirected toward cancer cells. Clinically, anticancer adoptive immunotherapy using genetically engineered T cells has an impressive track record. Notable examples include the dramatic benefit of chimeric antigen receptor (CAR) gene-modified T cells redirected towards CD19 in patients with B cell malignancy, and the encouraging results obtained with TCR gene-modified T cells redirected towards NY-ESO-1, a cancer-testis antigen, in patients with advanced melanoma and synovial cell sarcoma. This article overviews the current status of this treatment option, and discusses challenging issues that still restrain the full effectiveness of this strategy, especially in the context of hematological malignancy. PMID- 25517547 TI - The importance of Anesthesia Progress to dental anesthesiology. PMID- 25517546 TI - Replication of influenza A virus in swine umbilical cord epithelial stem-like cells. AB - In this study, we describe the isolation and characterization of epithelial stem like cells from the swine umbilical cord and their susceptibility to influenza virus infection. Swine umbilical cord epithelial stem cells (SUCECs) expressed stem cell and pluripotency associated markers such as SSEA-1, SSEA-4, TRA 1-60 and TRA 1-81 and Oct4. Morphologically, cells displayed polygonal morphology and were found to express epithelial markers; pancytokeratin, cytokeratin-18 and occludin; mesenchymal cell markers CD44, CD90 and haematopoietic cell marker CD45 were not detected on these cells. The cells had extensive proliferation and self- renewal properties. The cells also possessed immunomodulatory activity and inhibited the proliferation of T cells. Also, higher levels of anti-inflammatory cytokine IL-10 were detected in SUCEC-T cell co-cultures. The cells were multipotent and differentiated into lung epithelial cells when cultured in epithelial differentiation media. We also examined if SUCECs are susceptible to infection with influenza virus. SUCECs expressed sialic acid receptors, used by influenza virus for binding to cells. The 2009 pandemic influenza virus and swine influenza virus replicated in these cells. SUCECs due to their differentiation and immunoregulatory properties will be useful as cellular therapy in a pig model for human diseases. Additionally, our data indicate that influenza virus can infect SUCECs and may transmit influenza virus from mother to fetus through umbilical cord and transplantation of influenza virus-infected stem cells may transmit infection to recipients. Therefore, we propose that umbilical cord cells, in addition to other agents, should also be tested for influenza virus before cryopreservation for future use as a cell therapy for disease conditions. PMID- 25517548 TI - A new protocol to evaluate the effect of topical anesthesia. AB - This double-blind, placebo-controlled, randomized cross-over clinical experimental study tested the reliability, validity, and sensitivity to change of punctuate pain thresholds and self-reported pain on needle penetration. Female subjects without orofacial pain were tested in 2 sessions at 1- to 2-week intervals. The test site was the mucobuccal fold adjacent to the first upper right premolar. Active lidocaine hydrochloride 2% (Dynexan) or placebo gel was applied for 5 minutes, and sensory testing was performed before and after application. The standardized quantitative sensory test protocol included mechanical pain threshold (MPT), pressure pain threshold (PPT), mechanical pain sensitivity (MPS), and needle penetration sensitivity (NPS) assessments. Twenty nine subjects, mean (SD) age 29.0 (10.2) years, completed the study. Test-retest reliability intraclass correlation coefficient at 10-minute intervals between examinations was MPT 0.69, PPT 0.79, MPS 0.72, and NPS 0.86. A high correlation was found between NPS and MPS (r = 0.84; P < .001), whereas NPS and PPT were not significantly correlated. The study found good to excellent test-retest reliability for all measures. None of the sensory measures detected changes in sensitivity following lidocaine 2% or placebo gel. Electronic von Frey assessments of MPT/MPS on oral mucosa have good validity. PMID- 25517549 TI - Comparison of insertion of the modified i-gel airway for oral surgery with the LMA Flexible: a manikin study. AB - We previously modified the i-gel airway to enable its use in the field of oral and maxillofacial surgery and reported its fabrication methods. In general, the standard i-gel airway is quick to insert and has a high success rate, but the modified i-gel airway has yet to be assessed for these attributes. We, therefore, set out to compare the ease of insertion of the modified i-gel airway with the LMA Flexible to investigate the usefulness of the modified i-gel airway. The study participants, who included 20 new interns with no experience using either the LMA Flexible or the modified i-gel airway, inserted each device 3 times into an intubation practice manikin. The variables measured in this study were insertion time and rate of successful insertions. Mean insertion time over 3 attempts was significantly shorter for the modified i-gelTM airway (18.9 +/- 4.7 seconds) than the LMA Flexible (24.9 +/- 5.1 seconds, P < .001). The rate of successful insertions as a total of all 3 attempts was significantly higher for the modified i-gel airway (56/60 times, 93.3%) than the LMA Flexible (45/60 times, 75%; P = .012). When used by an inexperienced operator, the modified i gelTM airway is faster and has a higher success rate than the LMA Flexible, suggesting that it can be easily manipulated during insertion. PMID- 25517551 TI - The effect of intraoral suction on oxygen-enriched surgical environments: a mechanism for reducing the risk of surgical fires. AB - In this study, a mechanical model was applied in order to replicate potential surgical fire conditions in an oxygen-enriched environment with and without high volume suction typical for dental surgical applications. During 41 trials, 3 combustion events were measured: an audible pop, a visible flash of light, and full ignition. In at least 11 of 21 trials without suction, all 3 conditions were observed, sometimes with an extent of fire that required early termination of the experimental trial. By contrast, in 18 of 20 with-suction trials, ignition did not occur at all, and in the 2 cases where ignition did occur, the fire was qualitatively a much smaller, candle-like flame. Statistically comparing these 3 combustion events in the no-suction versus with-suction trials, ignition (P = .0005), audible pop (P = .0211), and flash (P = .0092) were all significantly more likely in the no-suction condition. These results suggest a possible significant and new element to be added to existing surgical fire safety protocols toward making surgical fires the "never-events" they should be. PMID- 25517550 TI - Hemodynamic changes by drug interaction of adrenaline with chlorpromazine. AB - Adrenaline (epinephrine) is included in dental local anesthesia for the purpose of vasoconstriction. In Japan, adrenaline is contraindicated for use in patients receiving antipsychotic therapy, because the combination of adrenaline and an antipsychotic is considered to cause severe hypotension; however, there is insufficient evidence supporting this claim. The purpose of the present study was to clarify the changes in hemodynamics caused by drug interaction between adrenaline and an antipsychotic and to evaluate the safety of the combined use of adrenaline and an antipsychotic in an animal study. Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. A catheter was inserted into the femoral artery to measure blood pressure and pulse rate. Rats were pretreated by intraperitoneal injection of chlorpromazine or chlorpromazine and propranolol, and after 20 minutes, saline or 1 of 3 different doses of adrenaline was administered by intraperitoneal injection. Changes in the ratio of mean arterial blood pressure and pulse rate were measured after the injection of adrenaline. Significant hypotension and tachycardia were observed after the injection of adrenaline in the chlorpromazine-pretreated rats. These effects were in a dose dependent manner, and 100 MUg/kg adrenaline induced significant hemodynamic changes. Furthermore, in the chlorpromazine and propranolol-pretreated rats, modest hypertension was induced by adrenaline, but hypotension and tachycardia were not significantly shown. Hypotension was caused by a drug interaction between adrenaline and chlorpromazine through the activation of the beta adrenergic receptor and showed a dose-dependent effect. Low-dose adrenaline similar to what might be used in human dental treatment did not result in a significant homodynamic change. PMID- 25517552 TI - Acute angle-closure glaucoma after general anesthesia for bone grafting. AB - Acute angle-closure glaucoma (AACG) is a rare complication of general anesthesia. The coexistence of individual risk factors for postoperative AACG and factors associated with intraocular hypertension are considered to be required for postoperative AACG to develop. We present a case of AACG after general anesthesia for oral bone grafting in a patient with no preoperative eye symptoms. In this case, several factors such as postoperative care in a darkened room, psychological stress, and postoperative hypertension may have precipitated the event in this patient, who may have had preexisting undiagnosed elevated intraocular pressure. The interval between the earliest appearance of symptoms at 9 hours and the ultimate diagnosis was 36 hours. In the postoperative period following general anesthesia, any patient is at risk for AACG. It is important that a postoperative diagnosis of AACG should be considered and a timely consultation with an ophthalmologist be considered if a postoperative patient complains of red eyes, visual disorder, eye pain, headache, and nausea. PMID- 25517553 TI - Anesthetic and dental management of a child with IMAGe syndrome. AB - IMAGe syndrome (OMIM 300290) is a rare multisystem disorder that has a broad phenotypic presentation. Though variable, this disorder mainly consists of Intrauterine growth retardation, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital abnormalities. Patients with IMAGe syndrome present as an uncommon yet important challenge for dentists and anesthesiologists due to their wide range of dysmorphic facial features, adrenal insufficiency, electrolyte imbalances, and need for steroid replacement. The purpose of this case report is to describe the successful anesthetic management of a pediatric patient diagnosed with IMAGe syndrome who presented for full mouth dental rehabilitation. PMID- 25517554 TI - Upside-down mask ventilation technique for a patient with a long and narrow mandible. AB - Mask ventilation, along with tracheal intubation, is one of the most basic skills for managing an airway during anesthesia. Facial anomalies are a common cause of difficult mask ventilation, although numerous other factors have been reported. The long and narrow mandible is a commonly encountered mandibular anomaly. In patients with a long and narrow mandible, the gaps between the corners of the mouth and the lower corners of the mask are likely to prevent an adequate seal and a gas leak may occur. When we administer general anesthesia for these patients, we sometimes try to seal the airway using several sizes and shapes of commercially available face masks. We have found that the management of the airway for patients with certain facial anomalies may be accomplished by attaching a mask upside down. PMID- 25517555 TI - Emergency drug kits: pharmacological and technical considerations. AB - The risk for complications while providing dental procedures is greatest when caring for patients having significant medical compromise. It is comforting that significant adverse events can generally be prevented by careful preoperative assessment, along with attentive intraoperative monitoring and support. Nevertheless, the office team must be prepared to manage untoward events should they arise. This continuing education article will address basic emergency drugs that should be available in all dental practices and additional agents that become essential for those practices providing various levels of procedural sedation or general anesthesia. PMID- 25517557 TI - Differential diagnosis of acute hypotension under anesthesia. PMID- 25517561 TI - An insight into the complex prion-prion interaction network in the budding yeast Saccharomyces cerevisiae. AB - The budding yeast Saccharomyces cerevisiae is a valuable model system for studying prion-prion interactions as it contains multiple prion proteins. A recent study from our laboratory showed that the existence of Swi1 prion ([SWI(+)]) and overproduction of Swi1 can have strong impacts on the formation of 2 other extensively studied yeast prions, [PSI(+)] and [PIN(+)] ([RNQ(+)]) (Genetics, Vol. 197, 685-700). We showed that a single yeast cell is capable of harboring at least 3 heterologous prion elements and these prions can influence each other's appearance positively and/or negatively. We also showed that during the de novo [PSI(+)] formation process upon Sup35 overproduction, the aggregation patterns of a preexisting inducer ([RNQ(+)] or [SWI(+)]) can undergo significant remodeling from stably transmitted dot-shaped aggregates to aggregates that co localize with the newly formed Sup35 aggregates that are ring/ribbon/rod- shaped. Such co-localization disappears once the newly formed [PSI(+)] prion stabilizes. Our finding provides strong evidence supporting the "cross-seeding" model for prion-prion interactions and confirms earlier reports that the interactions among different prions and their prion proteins mostly occur at the initiation stages of prionogenesis. Our results also highlight a complex prion interaction network in yeast. We believe that elucidating the mechanism underlying the yeast prion prion interaction network will not only provide insight into the process of prion de novo generation and propagation in yeast but also shed light on the mechanisms that govern protein misfolding, aggregation, and amyloidogenesis in higher eukaryotes. PMID- 25517562 TI - New approaches with surrogate decision makers. AB - A first principle in ethics consultation is that reasoning is essential. A second principle is that the religious and cultural views of patients and their surrogates are usually respected. What can be done when these principles collide when patients or surrogates have religious or cultural views and beliefs that clinicians find unreasonable or even offensive? Mediation may provide some approaches to assist us in providing the most ethically appropriate assistance. PMID- 25517563 TI - Who's at the table? Moral obligations to equal-priority surrogates in clinical ethics consultations. AB - Existing state surrogate decision-maker laws are fragmented and inconsistent and fail to ensure that all eligible decision makers of the same surrogate priority class are included in the healthcare decisions made for an incapacitated loved one. In this article, we explore three categories of harm that result from failing to include all surrogates of equal priority in a patient's healthcare decision, namely harms to the patient, harms to the excluded surrogate, and harms to the family. Given these harms, we argue that clinical ethicists have a moral obligation to take reasonable steps to include all surrogate decision makers of equal priority in the healthcare decision-making process for patients without a designated healthcare proxy. PMID- 25517565 TI - Surrogate decision making and intellectual virtue. AB - Patients can be harmed by a religiously motivated surrogate decision maker whose decisions are contrary to the standard of care; therefore, surrogate decision making should be held to a high standard. Stewart Eskew and Christopher Meyers proposed a two-part rule for deciding which religiously based decisions to honor: (1) a secular reason condition and (2) a rationality condition. The second condition is based on a coherence theory of rationality, which they claim is accessible, generous, and culturally sensitive. In this article, I will propose strengthening the rationality condition by grounding it in a theory of intellectual virtue, which is both rigorous and culturally sensitive. PMID- 25517564 TI - Developing and testing a checklist to enhance quality in clinical ethics consultation. AB - Checklists have been used to improve quality in many industries, including healthcare. The use of checklists, however, has not been extensively evaluated in clinical ethics consultation. This article seeks to fill this gap by exploring the efficacy of using a checklist in ethics consultation, as tested by an empirical investigation of the use of the checklist at a large academic medical system (Cleveland Clinic). The specific aims of this project are as follows: (1) to improve the quality of ethics consultations by providing reminders to ethics consultants about process steps that are important for most patient-centered ethics consultations, (2) to create consistency in the ethics consultation process across the medical system, and (3) to establish an effective educational tool for trainers and trainees in clinical ethics consultation. The checklist was developed after a thorough literature review and an iterative process of revising and testing by a group of experienced ethics consultants. To pilot test the checklist, it was distributed to 46 ethics consultants. After a six-month pilot period in which ethics professionals used the checklist during their clinical activities, a survey was distributed to all of those who used the checklist. The 10-item survey examined consultants' perceptions regarding the three aims listed above. Of the 25 survey respondents, 11 self-reported as experts in ethics consultation, nine perceived themselves to have mid-level expertise, and five self-reported as novices. The majority (68 percent) of all respondents, regardless of expertise, believed that the checklist could be a "helpful" or "very helpful" tool in the consultation process generally. Novices were more likely than experts to believe that the checklist would be useful in conducting consultations. The limitations of this study include: reduced generalizability given that this project was conducted at one medical system, utilized a small sample size, and used self-reported quality outcome measures. Despite these limitations, to the authors' knowledge this is the first investigation of the use of a checklist systematically to improve quality in ethics consultation. Importantly, our findings shed light on ways this checklist can be used to improve ethics consultation, including its use as an educational tool. The authors hope to test the checklist with consultants in other healthcare systems to explore its usefulness in different healthcare environments. PMID- 25517566 TI - Identifying challenges to communicating with patients about their imminent death. AB - The research literature suggests that physicians' attitudes regarding disclosing a diagnosis of cancer have changed, from nondisclosure to full disclosure. Physicians' attitudes towards disclosing a patient's prognosis are likewise said to have changed, although not to the same degree. The aim of this study was to identify inherent challenges in communicating information about imminent death. It included one set of interviews with patients and another set with doctors, and subsequent discussions of ways to overcome obstacles to patients' understanding their situation. Patients were diagnosed with leukemia, myeloma, or lung cancer; the doctors were hematologists and lung oncologists. The two sets of interviews were analyzed separately using a content analysis model developed by Graneheim and Lundman. For each set of interviews, eight content areas were defined as belonging to an area of interest and scrutinized for the information they included regarding communicating prognoses to patients. The main finding was a discrepancy between patients' desire to be fully informed regarding their prognosis and physicians' reluctance to offer a prognosis until a patient had overt signs of approaching death. We conclude that existing guidelines for disclosure of bad news should be modified to encourage disclosure and discussion of uncertain prognostic information, unless a patient is clearly opposed to receiving such information or otherwise not a suitable partner for dialogue. PMID- 25517567 TI - Medical missions to Ghana: The ethics of choosing children for cardiac surgery. AB - The Hearts and Minds of Ghana project travels from Boston Children's Hospital for two weeks each year to provide cardiac surgery to children in Ghana. Of the hundreds of children in need, how to choose who will receive lifesaving surgery? PMID- 25517568 TI - Great need, scarce resources, and choice: reflections on ethical issues following a medical mission. AB - Medical missions to provide cardiac surgical procedures in developing and technologically less advanced countries is a great challenge. It is also immensely gratifying, personally and professionally. Such missions typically present significant ethical dilemmas, especially making difficult choices, given limited time and resources, and the inability to help all children in need of cardiac surgery. We describe some of these issues from our perspective as visiting cardiologists. PMID- 25517569 TI - Ethical aspects of arranging local medical collaboration and care. AB - Yearly pediatric cardiac surgery missions to Ghana are of tremendous benefit to local children, but may create thorny ethical dilemmas for local clinicians who refer and screen children for the mission and who provide care to the children after the mission concludes for the year. This article presents the experiences and concerns of a pediatrician who is a local member of the Hearts and Minds of Ghana project. PMID- 25517570 TI - Pediatric heart surgery in Ghana: three ethical questions. AB - When a group of doctors and nurses from Boston, Massachusetts, provided evaluation and heart surgery to children in Ghana, they encountered three rationing dilemmas: (1) What portion of surgery slots should they reserve for the simplest, most cost-effective surgeries? (2) How much time should be reserved for especially simple, nonsurgical interventions? (3) How much time should be reserved to training local staff to perform such surgeries? This article investigates these three dilemmas. PMID- 25517571 TI - Epilogue: ethical goals for the future. AB - Based on the experiences of the Hearts and Minds of Ghana authors, I present possible approaches to the ethical questions that clinicians who participate in health missions and disaster relief programs often face. PMID- 25517572 TI - The Functional Copy Number Variation-67048 in WWOX Contributes to Increased Risk of COPD in Southern and Eastern Chinese. AB - Recent studies have recognized the genetic variants in the WW domain-containing oxidoreductase (WWOX) gene as genetic determinants of lung function, reflecting that the WWOX gene may be a susceptible factor of chronic obstructive pulmonary disease (COPD), which characters as poor lung function. We have previously showed that the copy number variation-67048 (CNV-67048) of WWOX was associated with lung cancer risk. Here, we hypothesized that the CNV-67048 affects COPD susceptibility. Based on a two-stage case-control study with a total of 1791 COPD patients and 1940 controls of southern and eastern Chinese, we found that the loss genotypes (0-copy and 1-copy) of CNV-67048 harbored a significantly increased risk of COPD, with an odds ratio (OR) as 1.29 (1.11-1.49) when compared with the common 2-copy genotype. The pre-forced expiratory volume in one second (pre-FEV1) to pre-forced vital capacity (pre-FVC) of carriers with loss genotypes (0.729 +/- 0.130) was significantly lower than carriers with 2-copy genotype (0.747 +/- 0.124; p = 7.93 * 10(-5)). However, no significant difference was observed on pre-FEV1, pre-FVC and the annual decline of pre-FEV1 between the loss genotypes and 2-copy genotype carriers. Our data suggest that the loss genotypes of CNV-67048 in WWOX predispose their carriers to COPD, which might be a genetic biomarker to predict risk of COPD in Chinese. PMID- 25517574 TI - Foreseeable risks? Informed consent for studies within the standard of care. PMID- 25517573 TI - Selective surgical localization of axillary lymph nodes containing metastases in patients with breast cancer: a prospective feasibility trial. AB - IMPORTANCE: Nodal ultrasonography with needle biopsy of abnormal lymph nodes helps to define the extent of breast cancer before neoadjuvant chemotherapy. A clip can be placed to designate lymph nodes with documented metastases. Targeted axillary dissection or selective removal of lymph nodes known to contain metastases (clip-containing nodes) as well as sentinel lymph nodes (SLNs) may provide more accurate assessment of the pathologic response after neoadjuvant chemotherapy. OBJECTIVE: To determine the feasibility of image-guided localization and resection of lymph nodes containing known metastases. DESIGN, SETTING, AND PARTICIPANTS: This prospective feasibility trial performed at MD Anderson Cancer Center, Houston, Texas, included 12 patients with axillary nodal metastases confirmed by results of fine-needle aspiration biopsy who had a clip placed in the lymph node targeted for biopsy from December 1, 2012, through November 30, 2013. INTERVENTIONS: Preoperative targeting of the clip-containing lymph node under ultrasonographic guidance consisting of wire localization in 2 patients and placement of radioactive iodine I 125 (125I)-labeled seeds in 10 patients. Surgeons removed the localized lymph node before completion axillary lymph node dissection and used radiography of the specimen to confirm removal of the clip-containing lymph node and seed. MAIN OUTCOMES AND MEASURES: Confirmation of the removal of the clip-containing lymph node. RESULTS: Image-guided localization and selective removal were successful in all 12 patients. Five patients underwent SLN dissection in addition to removal of the clip-containing lymph node. Placement of 125I seeds did not interfere with lymphoscintigraphy or intraoperative identification of SLNs. In 4 of the 5 patients (80%), the clip containing lymph node was one of the SLNs. Ten patients completed neoadjuvant chemotherapy before surgery. Of the 9 patients who underwent lymph node dissection, 4 (44%) had residual nodal disease after chemotherapy; all had disease identified in the clip-containing lymph node. CONCLUSIONS AND RELEVANCE: Axillary lymph nodes marked with a clip can be localized and selectively removed to accomplish targeted axillary dissection, which is technically possible after chemotherapy and is easily performed with other axillary surgery, such as SLN dissection. The ability to add selective removal of the clip-containing lymph nodes to SLN dissection may identify patients for limited nodal surgery after chemotherapy with increased accuracy for determining residual disease compared with SLN identification alone. PMID- 25517575 TI - License to serve--U.S. trainees and the Ebola epidemic. PMID- 25517578 TI - Temporomandibular disorders in young people with an intellectual disability: prevalence of signs and symptoms. AB - AIM: To assess the prevalence of signs and symptoms related to TMJ disorders in a group of young people with intelectual disability (ID) and a matched group of healthy adolescents. MATERIALS AND METHODS: A group of 105 young Special Olympics (SO) athletes (ID group) aged from 14 to 25 years and a control group were examined for the presence or absence of signs and symptoms of TMD through interview and clinical examination. RESULTS: A total of 64 young people with ID (61%) had at least one sign of TMD compared to 41 (39%) of the individuals screened that was free of any TMD symptoms. A significantly higher prevalence of TMJ sounds (palpation and stethoscope), TMJ tenderness, maximum vertical opening, headaches were observed among SO athletes compared to the healthy control group (p<0.05). A significant difference was recorded only for the Temporalis tenderness between the girls and boys (p<0.05). CONCLUSION: TMJ disorders are noticeable problem for intellectually disabled patients and a possible cause of pain that should be examined more in detail. We suggest that oral screening in people with a mental disability should be modified by including basic TMJ examination parameters in order to allow better understanding of the pathological aspects so as to address effective preventive and therapeutic measures. PMID- 25517577 TI - Dental caries and childhood obesity: analysis of food intakes, lifestyle. AB - AIM: The aims of this cross-sectional statistical study were to evaluate the association between obesity and dental caries and to assess the impact of food intake, oral hygiene and lifestyle on the incidence of dental caries in obese paediatric patients, analysed by Dual X-ray Absorptiometry (DXA). MATERIALS AND METHODS: A sample of 96 healthy patients, aged between 6 and 11 years (mean age 8.58+/-1.43) was classified in relation to body composition assessment and McCarthy growth charts and cut- offs. Body composition analysis, to obtain body fat mass (FM) and body fat free mass (FFM) measurements, was determined by means of a DXA fan beam scanner. The subjects underwent dental examination to assess the dmft/DMFT, and completed a questionnaire on food intake, oral hygiene habits and lifestyle. The sample was subsequently subdivided into four groups: Group A (normal weight - caries-free), Group B (normal weight with caries), Group C (pre obese/obese - caries-free), Group D (pre-obese/obese with caries). STATISTICS: The statistical analysis was performed using SPSS software (version 16; SPSS Inc., Chicago IL, USA). Spearman's correlation was performed to evaluate the correlation between dmft/DMFT and FM%. The chi-square test was performed to assess the categorical variables, while the non-parametric Kruskal Wallis test and the Mann Whitney test were employed for the quantitive variables. Statististical significance was set at a P-value of 0.05. RESULTS: The preobese obese children had higher indexes of dental caries than normal weight subjects, both for deciduous teeth (dmft 2.5 +/- 0.54 vs 1.4 +/- 0.38; p=0.030) and permanent teeth (DMFT 2.8 +/- 0.24 vs 1.93 +/- 1.79; p=0.039). The correlations between dmft/DMFT indexes and body composition parameters were analysed and a significant correlation between dmft/DMFT indexes and FM% was observed (p=0.031 for dmft, p=0.022 for DMFT). According to the data recorded, there was no statistically significant difference between Groups A, B, C and D in terms of food intake between meals (p=0.436), frequency of starch intake limited to the main meals (p=0.867), home oral hygiene (p=0.905), dental hygiene performed at school (p=0.389), habit of eating after brushing teeth (p=0.196), participation in extracurricular sport activities (p=0.442) and educational level of parents: father (p=0.454), mother (p=0.978). In contrast, there was a statistically significant difference between Groups A, B, C and D in terms of intake of sugar sweetened drinks (p=0.005), frequency of sugar intake limited to the main meals (p<0.001), frequency of food intake between meals (p=0.038) and sedentary lifestyle (p=0.012). Successive analysis revealed a statistically significant difference between Group A and D in terms of intake of sugar-sweetened drinks (p=0.001), frequency of sugar intake limited to the main meals (p=0.008), and frequency of food intake between meals (p=0.018), and between Group C and D in terms of frequency of sugar intake limited to the main meals (p<0.001), and frequency of food intake between meals (p=0.040). CONCLUSION: This study shows a direct association between dental caries and obesity evident from a correlation between prevalence of dental caries and FM%. The analysis of food intake, dmft/DMFT, FM%, measured by DXA, demonstrates that specific dietary habits (intake of sugar-sweetened drinks, frequency of sugar intake limited to main meals, frequency of food intake between meals) may be considered risk factors that are common to both dental caries and childhood obesity. PMID- 25517579 TI - Relationship between mandibular second molar calcification stages and cervical vertebrae maturity in Italian children and young adults. AB - AIM: The aim of this study was to investigate the relationship between the stages of calcification of the mandibular second molar and the stages of skeletal maturity among Italian children and young adults. MATERIALS AND METHODS: Cross sectional descriptive study. The samples were derived from panoramic radiographs and lateral cephalograms of 500 Italian subjects aged from 10 to 20 years. Dental maturity index (DM) was assessed by calcification stages of the mandibular second molars according to the Demirjian method; skeletal maturity was evaluated with cervical vertebrae maturation index (CVM) according to Hassel and Farman. The Pearson r coefficient and Spearman rank correlation coefficient were estimated to determine the relationship between DM and CVM. RESULTS: Skeletal maturation stages occurred earlier in females (about 6 months). A highly significant correlation between CVM and DM (0.78-0.86 cor according to Pearson test and 0.81 0.85 rho according to Spearman test) was found. DM stage E corresponds to phase CVM 1 and 2 (the phase prior to the growth spurt), DM stage F corresponds to the phase of pubertal growth spurt, stages CVM 2 and CVM 3; DM stage G is indicator of the growth spurt underway (CVM 3-4), but it can still be found during CVM 5 in females. CONCLUSION: The second mandibular molars can be considered reliable indicators for the evaluation of the growth phases. In case of females the end of the growth spurt it is not clearly associated with a dental maturity stage and needs to be stated with further parameters such as CVM. PMID- 25517576 TI - Cell transcriptional state alters genomic patterns of DNA double-strand break repair in human astrocytes. AB - The misrepair of DNA double-strand breaks in close spatial proximity within the nucleus can result in chromosomal rearrangements that are important in the pathogenesis of haematopoietic and solid malignancies. It is unknown why certain epigenetic states, such as those found in stem or progenitor cells, appear to facilitate neoplastic transformation. Here we show that altering the transcriptional state of human astrocytes alters patterns of DNA damage repair from ionizing radiation at a gene locus-specific and genome-wide level. Astrocytes induced into a reactive state exhibit increased DNA repair, compared with non-reactive cells, in actively transcribed chromatin after irradiation. In mapping these repair sites, we identify misrepair events and repair hotspots that are unique to each state. The precise characterization of genomic regions susceptible to mutation in specific transcriptional states provides new opportunities for addressing clonal evolution in solid cancers, in particular those where double-strand break induction is a cornerstone of clinical intervention. PMID- 25517580 TI - Application of three-dimensional digital models for the morphometric analysis of predentition plasters: accuracy and precision. AB - AIM: This study aimed to test the accuracy and precision of measurements of three dimensional (3D) digital models from the pre-dentition period using a noncontact 3D measurement system (3D scanner) versus the gold standard method of direct measurements using a digital caliper on plaster models. MATERIALS AND METHODS: Ten pairs of plaster models were obtained from children during the predentition period. Linear measurements were performed using both methods. Three operators were trained in the use of both methods for this study. Measurements were performed with a minimum 2-week interval between measurements in a randomly chosen order. RESULTS: The mean difference between the measured values using the two methods was <0.2 mm for each measurement. There was no linearity in the measurements using pre-dentition digital models. An ANOVA Gage R&R analysis revealed that there was no significant operator difference (P < 0.307). The rate of variation of the 3D scanner over the total variation was 2.8%. The ICC was 0.982 (P< 0.001), suggesting excellent interoperator agreement. CONCLUSION: The results suggest that measurements of digital 3D pre-dentition models are highly accurate and precise, and also comparable to measurements using the gold standard method. PMID- 25517582 TI - An in vivo comparison of radiographic and clinical examination with separation for assessment of approximal caries in primary teeth. AB - AIM: To compare in vivo, clinical examination (CE) and bitewing radiographs (BW) for the detection of cavitations and initial approximal lesions in deciduous molars with validation after temporary separation (TS) and direct visual examination (DE) of the approximal surfaces. MATERIALS AND METHODS: Thirty children aged 4 to 8 years without visual cavitations or restorations and with at least one approximal contact. Two calibrated examiners evaluated 355 surfaces of primary molars, which were then validated through TS and DE. RESULTS: Of the 280 surfaces considered sound by CE, 24.6% were cavitated after separation. Comparing BW and DE, it was observed that, when the radiolucency involved the inner half of dentin, 68.4% of lesions were cavitated. The sensitivity and specificity of CE and BW were 0.14 and 0.43, and 0.80 and 0.75, respectively. CONCLUSION: DE identified a greater number of pre-cavitated lesions and cavities. BW were useful for detection of decayed surfaces, but with low specificity for diagnosis of sound surfaces, while detection of sound or decayed approximal areas by means of CE alone was not possible. The combination of methods was effective in obtaining an accurate diagnosis of caries in the primary dentition. PMID- 25517581 TI - Clinical evaluation of salivary indices and levels of Streptococcus mutans and Lactobacillus in patients treated with Occlus-o-Guide. AB - AIM: The aim of this study was to assess the changes over time associated with salivary indices and the presence of Streptococcus mutans and Lactobacillus in patients treated with Occlus-o-Guide. MATERIALS AND METHODS: Two groups of patients were evaluated: a test group of 20 patients treated with Occlus-o-Guide and a control group of 20 patients not subjected to orthodontic treatment. Both groups were homogeneous for age and sex. We examined the levels of S. Mutans and Lactobacillus, the salivary flow, the buffer capacity of saliva and the Sillness and Loe plaque index (PI). The samples were taken at baseline (T0), after 3 months (T1) and after 6 months of treatment (T2). All data were compared using Student's t test. RESULTS: The percentage of patients with a level of Streptococcus mutans able to cause caries was decreased in the test group (T0 = 10%, T1 = %, T2 = 0%) compared to the control group (T0 = 0%, T1 = 5%, T2 = 35%), whereas the amount of Lactobacilli was different (test group T0 = 15%, T1 = 0%, T2 = 10%; control group T0 = 0%, T1 = 5%, T2 = 35%). The total salivary flow was increased in the test group (T0 = 47, T1 = 61, T2 = 61) compared to the control group, in which it had remained almost constant (T0 = 44, T1 = 45, T2 = 45). The buffer capacity of saliva was unchanged in both groups over time; the sum of PI plaque indices was reduced in the test group (T0 = 3, T1 = 0, T2 = 2) compared to the control group (T0 = 0, T1 = 14, T2 = 27). CONCLUSION: Despite the presence of the Occlus-o-Guide device, patients are able to maintain a good level of oral hygiene, showing improvements of the examinated parameters at follow-ups. PMID- 25517584 TI - Accuracy of three different apex locators and visual exam in primary teeth with and without root resorption in vitro. AB - AIM: The aim of this study was to evaluate the accuracy and reliability of three apex locators (EndoMaster, Raypex, DentaPort ZX) and visual assessment in primary molar teeth in vitro. MATERIALS AND METHODS: Twenty-four extracted human primary molar teeth with and without root resorption were used in this study. After endodontic access preparation, root canal length was visually measured by means of a K file; then the teeth were embedded into alginate and the roots were measured again by mans of the three apex locators. The results were collected in SPSS 15.0 and statistical evaluations were completed by one-way ANOVA and Kruksal Wallis test. RESULTS: The measurements closest to the visually determined length were obtained with EndoMaster. No statistically significant differences were found between visual and apex locators lengths (p>0.05). CONCLUSION: Within the limitations of this study, the use of apex locators would be useful in the endodontic treatment of primary teeth. PMID- 25517583 TI - Upper and lower arch changes after Mixed Palatal Expansion protocol. AB - AIM: The aim of this study was to evaluate upper and lower dental changes after Mixed Palatal Expansion (MPE) treatment in growing patients with posterior single or bilateral crossbite and mild-to-moderate crowding, as compared to untreated growing subjects by dental cast analysis. MATERIALS AND METHODS: A group of 24 patients (18 girls, 6 boys) was treated with Hyrax-type device and compared with an untreated matched control group at T0 (8.6 yrs. +/- 2) and at T1 (10 yrs. +/- 2) using dental casts. The dental cast analysis was performed on four dental bilateral landmarks, on upper and lower casts; also upper and lower arch depths were measured. The groups were compared using independent sample t-test to estimate dental changes in upper and lower arches. RESULTS: The MPE group showed significant upper and lower arch changes when compared with the control group. Upper intermolar, interpremolar-2nd, interpremolar-1st (P<0.001) and intercanine widths (P<0.05) showed considerable changes in the treated group, while mandibular intermolar (P<0.001), interpremolar-1st (P<0.05) and intercanine widths (P<0.01) were slightly greater in the MPE group when compared with the control group. CONCLUSION: The changes in transverse upper and lower arch dimensions were significant, when compared with those seen in the control group. PMID- 25517585 TI - Meta-analysis of the prevalence of tooth wear in primary dentition. AB - AIM: To conduct a meta-analysis of all the studies published in literature over the past three decades on the prevalence of dental erosion in preschool children. MATERIALS AND METHODS: The Pubmed data base revealed only one systematic review on the prevalence of tooth wear in children up to 5 years old. The search included works published from January 1982 to September 2012, using the following combinations of keywords: 1) "dental erosion" AND "children"; 2) "dental erosion in primary dentition"; 3) "dental" AND "attrition" AND "prevalence". The inclusion criteria for papers on tooth wear were the deciduous dentition observed only on the palatal and buccal sides with the distinction of erosion, attrition and abrasion. We took into consideration only randomized control trials. We excluded articles not written in English, case reports, historical and forensic studies, in vitro and in vivo studies. In case of doubt and/or when an abstract was not available, the full text copy of the article was examined. The first search on Pubmed revealed 29 articles, the same found in the study of Kreulen [2010], however we selected only multicentric studies focused on children of age below 5 years old, in which only the primary dentition (D) and only anterior teeth (incisors) were considered. RESULTS: Both forest plot and scatter plot showed the prevalence of dental erosion in primary dentition, and that older children had a more severe dental erosion. CONCLUSION: Dental erosion should be considered a paediatric dentistry pathological entity as well as dental caries, and it can be related to more severe systemic diseases such as Gastroesophageal reflux disease. In addition, taking care of these little patients is important because they might suffer persentiveness, and also pulpal pathology caused by the typical structure of deciduous teeth, where the pulp cavity is wide and close to the dentine and the enamel. PMID- 25517586 TI - Dental arch relationships assessed by GOSLON Yardstick in children with clefts in Northern Finland. AB - AIM: Our purpose was to evaluate the dental arch relationships using the GOSLON Yardstick in children with cleft lip and or cleft palate in Northern Finland. MATERIALS AND METHODS: The subjects consisted of 62 Finnish patients (36 girls and 26 boys) with clefts born between 1995-2005 in the Northern Ostrobothnia Hospital District of Finland. There were 36 patients with cleft palate, 9 with unilateral cleft lip and palate, 6 with cleft in soft palate, 5 with bilateral cleft lip and palate, 2 with cleft lip and 4 with submucous clefts. The study casts were obtained at the mean age of 6.3 years (5.8-7.8 years) and the cases were selected randomly. The dental arch relationships were assessed by the GOSLON Yardstick method by one calibrated researcher. RESULTS: After the assessment, 77.1% of cases were allocated to categories 1 and 2 (excellent and good), 10.4% category 3 (fair), and 12.5% categories 4 and 5 (poor and very poor). Patients with cleft palate had good prognosis in 84.6% of the cases. Of the patients with soft palate clefts and unilateral cleft lip and palate, 66.7% were allocated to categories 1 and 2. Bilateral cleft lip and palate patients had the poorest prognosis. Patients with submucous cleft and cleft lip had all good prognosis. CONCLUSION: The GOSLON Yardstick is a useful method for assessing dental arch relationships and treatment prognosis not only in cleft lip and palate patients, but also in cleft palate patients. PMID- 25517587 TI - Use of mouth guard in basketball: observational study of a group of teenagers with and without motivational reinforcement. AB - AIM: This study aims at ascertaining the capacity of 2 groups of young athletes to be faithful to the initial oral prevention project, with the difference that the study group received motivational reminders by either researchers and technical staff members of the team during the observation period, while the control group did not receive any motivational reminders. MATERIALS AND METHODS: This observational study was based on two groups selected from a wide group of 150 adolescent basketball players who accepted to use a custom-made mouth guard during their sport sessions. None of the selected athletes (60 adolescents aged between 12 and 15 years) had ever worn a mouth guard during their sports activity. A customised mouth guard was supplied, and subjetcs were requested to wear it for 12 months during training sessions and competitions. The study group was composed of 30 athletes, 15 males and 15 females, who received a constant motivational reinforcement to the use of the mouth guard by their coach and during checkups. Similarly, the control group was composed of 30 athletes (15 males and 15 females) who did not receive any motivational reinforcement. RESULTS: Twelve months after the beginning of the study, 24 subjects belonging to the control group were not using the mouth guard, while only 7 subjects of the study group were not using it. It was also noticed, six months after the beginning of the observation period, a rapid decline in the participants' interest in the use of the mouth guard. CONCLUSION: No traumatic event was registered among those adolescents who had used the mouth guard for the whole period of the study. Female athletes showed greater compliance to this prevention project. It is important that all technical staff members, and particularly the leading coach, encourage the regular use of oral protection devices for prevention among teenagers practicing sports. PMID- 25517588 TI - Microhardness evaluation of enamel adjacent to an improved GIC sealant after different enamel pre-treatment procedures. AB - AIM: This in vitro study was carried out to evaluate the microhardness of enamel adjacent to a glass ionomer cement (GIC) with high fluoride content used as a sealant (Fuji Triage, GC Corp., Japan) after laser, bur or air abrasion treatment procedures. MATERIALS AND METHODS: STUDY DESIGN: 200 freshly extracted non carious human molars were divided into 10 experimental groups according to the enamel pre-treatment method: A air abrasion (Mach 4.1 Kreativ Inc., USA); AP, Air abrasion + conditioning with 20% polyacrylic acid (GC cavity conditioner); L, Er,Cr:YSGG laser application (Waterlase, Biolase Technology, Inc., San Clemente, USA); LP, Er,Cr:YSGG laser application and fissure conditioning; B, ameloplasty carried out with a diamond bur especially designed for preparing fissures (Komet #8833); BP, ameloplasty + fissure conditioning; P, application of 20% polyacrylic acid and all fissures sealed with GIC; C, no fissure treatment, the material was applied directly to the fissures (control); R, application of 37% orthophosphoric acid and fissures sealed with a resin-based sealant (Fissurit; Voco, Germany) (control); N, no treatment (control). Half of each group of teeth were left in artificial saliva for one month and the rest for three months. The teeth were then sectioned and microhardness was measured using a Vickers test apparatus. Kruskal-Wallis, Mann-Whitney U and Dunn's multiple comparison tests were carried out (5% significance). RESULTS: After one month results regarding hardness at the base and lateral walls of fissures were significantly higher in groups A, AP, L, LP, B, BP, P and C than in groups R and N (p<0.01), but no difference was seen between the treatment procedures. The results after three months produced similar findings with evenly increased values for all groups. CONCLUSION: The results of this study showed that the tested GIC with a higher fluoride content seemed to improve the enamel hardness of the fissure enamel and could be regarded as an alternative material in cases where resin sealant applications are questionable. PMID- 25517589 TI - Early orthodontic treatment: a new index to assess the risk of malocclusion in primary dentition. AB - AIM: A new index targeted on the risk of malocclusions in primary dentition, called Baby-ROMA (Risk Of Malocclusion Assessment) index, was set up to assess risks/benefits in early orthodontic therapies. The Baby-ROMA index was designed from the observation that some of the malocclusion signs, observed in primary dentition, can worsen with growth, others remain the same over time and others can even improve. Therefore it would be important to classify the malocclusions observed at an early stage on a risk- based scale. MATERIALS AND METHODS: The reliability of the index was tested on 200 children, referred by their paediatricians to two different Orthodontic Departments, aged 4-6 years and in full primary dentition. The children were evaluated by two operators, both trained and calibrated on the use of the Baby-ROMA index. RESULTS: The K test showed a high reproducibility of the index. It is shown that 50% of patients presented malocclusion and crossbite had the highest prevalence, followed by tooth decay and early loss of deciduous teeth and negative overjet. CONCLUSION: The Baby-ROMA index was helpful to assess the severity of malocclusion and the timing for orthodontic treatment in very young patients (primary teeth). PMID- 25517590 TI - Souakine mouth rinse solution protects deciduous enamel from simulated erosion in vitro. AB - AIM: To determine whether a souakine mouth rinse solution can provide protection of deciduous teeth against simulated erosion in vitro. MATERIALS AND METHODS: Thirty deciduous anterior teeth were used. Half of each tooth was covered with a varnish and teeth were randomly divided into a treated (S) and a control group (C). Each group was immersed in cola drink for 5 minutes and treated with an aqueous solution of Souakine (S) or water (C) for 2 minutes. The treatment was renewed 5 times a day for 8 days. Teeth were then embedded, sectioned and observed under polarised light microscope. Observed data were quantitatively analysed by SPSS software. RESULTS: In group (C), the unvarnished part of the enamel showed a deep green layer of erosion, compared to the varnished part. The difference in depth of this layer was significant (p<0.05). In group (S), the green layer of erosion was highly located in the unvarnished part as compared to the unvarnished part of the control group (C) (p<0.05). This layer of erosion was comparable to that in the varnished part, either in control or treated groups. CONCLUSION: The beneficial results of Souakine against erosion are validated either by a protective or a remineralisation effect. PMID- 25517591 TI - In vivo evaluation of periodontal microcirculatory changes associated with endodontic treatment. AB - AIM: The purpose of this study was to investigate in vivo the gingival microcirculatory changes associated with endodontic treatment using the continuous wave of condensation technique. MATERIALS AND METHODS: Twenty necrotic one canal roots of 20 cooperative patients of both sexes, aged between 20 and 43 years, were selected. All patients were examined by capillaroscopy before, immediately after endodontic treatment, and after 7 days. The last examination was carried out by the same operator, and repeated twice for each examined area: masticatory, buccal and labial mucosa corresponding to the endodontically treated root. All canals were prepared using a simultaneous technique with Ni-Ti files (MTwo files). RESULTS: The images of the masticatory mucosa after root canal obturation showed evident micro-areas of extravasation, with significant bleeding and angio-morphological alterations due to heat. One hour after the endodontic treatment evident extravasation was observed, but a decrease of all altered parameters, was present. After seven days from treatment, in the periodontal tissues, a complete healing was observed. The in vivo evaluation of the vascular pattern during root canal obturation with System B showed that the high temperature in the canal determines visible effects on the vasculature of adjacent sites. It was found that microangiotectonic alterations decrease up to a complete healing after 7 days from treatment. CONCLUSION: All the changes in microcirculation, due to thermal shock of periodontal tissues, are reversible. PMID- 25517592 TI - Rapid and slow maxillary expansion: a posteroanterior cephalometric study. AB - AIM: The purpose of this study was to evaluate and compare the dental and orthopaedic effects of rapid and slow maxillary expansion in a sample of young patients with transversal maxillary deficiency by using a postero-anterior cephalometric analysis. MATERIALS AND METHODS: Two groups of patients were considered: 10 patients (3 males, 7 females) with an average age of 8.9 years were treated with a rapid maxillary expansor (RME); 10 patients (7 males, 3 females) with an average age of 12.2 years were treated with a new slow maxillary expansion appliance (ELA). Postero-anterior cephalometric analyses were made at the beginning of the therapy (T0) and at the end of expansion (T1) using a computerised cephalometric programme. Four parameters were measured: Nasal width, maxillary width, mandibular width, upper molars width. RESULTS: Transversal average width increased 5.435 mm (SD 3.31 mm) between the upper molars in the RME group and 5.547 mm (SD 3.49 mm) in the SME group. Maxillary average width increased 4.254 mm in the first group and 2.845 mm in SME group. Discussion An orthopaedic result was reached with both treatments. These results are in agreement with the orthodontic literature. CONCLUSION: This work confirms the effectiveness, efficiency and usefulness of this new ELA appliance in the correction of transversal deficiency with orthopaedic results, if used in growing patients. PMID- 25517593 TI - Increasing small intestinal permeability worsens colitis in the IL-10-/- mouse and prevents the induction of oral tolerance to ovalbumin. AB - BACKGROUND: Increased intestinal permeability is found in noninflamed portions of the gut of inflammatory bowel disease patients and in their first-degree relatives, suggesting that it is not a consequence of inflammation. Additionally, increased small intestinal permeability precedes colonic disease in animal models of inflammatory bowel disease. However, it is not known how small intestinal permeability modulates disease in the colon. The aim of this study was to determine if increasing small intestinal permeability modulates colonic inflammation in interleukin (IL)-10 mice and if an increase in permeability is sufficient to prevent oral tolerance to a dietary antigen. METHODS: IL-10 mice were treated with the zonula occludens toxin pathway agonist AT-1002 for 8 weeks, and colitis severity was measured at 12 weeks of age. Wild-type mice were also treated with AT-1002 and fed ovalbumin (OVA) to determine the local and systemic immune response to this antigen under increased small intestinal permeability conditions. RESULTS: IL-10 mice treated with AT-1002 showed exacerbated colitis at 12 weeks of age. AT-1002 also induced a significant OVA-specific humoral response compared with mice that received OVA alone. In addition, the intestinal production of IL-10 and TGF-beta in response to oral OVA was prevented when OVA was given with AT-1002. CONCLUSIONS: Increasing small intestinal permeability worsens colitis in IL-10 mice, and it prevents the development of oral tolerance to OVA in wild-type mice. This study suggests that small intestinal permeability is not merely a consequence of inflammation but a condition that leads to two of the main pathological features of inflammatory bowel disease. PMID- 25517594 TI - Factors associated with durable response to infliximab in Crohn's disease 5 years and beyond: a multicenter international cohort. AB - BACKGROUND: Infliximab (IFX) has been used for over a decade worldwide. Less is known about the natural history of IFX use beyond a few years and which patients are more likely to sustain benefits. METHODS: Patients with Crohn's disease (CD) exposed to IFX from Massachusetts General Hospital, Boston, Saint-Antoine Hospital, Paris, and the Swiss IBD Cohort Study were identified through retrospective and prospective data collection, complemented by chart abstraction of electronic medical records. We compared long-term users of IFX (>5 yr of treatment, long-term users of infliximab [LTUI]), with non-LTUI patients to identify prognostic factors. RESULTS: We pooled data on 1014 patients with CD from 3 different databases, of whom 250 were defined as LTUI. The comparison group comprised 290 patients with CD who discontinued IFX: 48 primary nonresponses, 95 loss of responses, and 147 adverse events. Factors associated with LTUI were colonic involvements and an earlier age at the start of IFX. The prevalence of active smokers and obese patients differed markedly, but inversely, between American and European centers but did not impact outcome. The discontinuation rate was stable around 3% to 6%, each year from years 3 to 10. CONCLUSIONS: Young age at start of IFX and colonic CD are factors associated with a beneficial long-term use of IFX. After 5 years of IFX, there is still a 3% to 5% discontinuation rate annually. Several factors associated with a good initial response such as nonsmoker and shorter disease duration at IFX initiation do not seem associated with a longer term response. PMID- 25517595 TI - Aeromonas species: an opportunistic enteropathogen in patients with inflammatory bowel diseases? A single center cohort study. AB - BACKGROUND: The role of Aeromonas species as an enteropathogen in patients with and without inflammatory bowel disease (IBD) is still debated. The aim was to explore the significance of positive Aeromonas stool cultures in IBD and patients without IBD. METHODS: Observational retrospective study including all patients with a stool culture positive for Aeromonas between January 2011 and October 2013 at the Leuven University Hospitals. Demographics, clinical, and endoscopic outcomes and laboratory results were analyzed. RESULTS: A total of 77 patients (11 IBD) were identified. In 37 cases, Aeromonas caused a mild self-limited gastrointestinal infection. Among the 40 patients needing antibiotics, 22 presented a mild-to-moderate gastrointestinal infection; 4 suffered from extraintestinal complications; and 4 were coinfected by Campylobacter spp. A. veronii caused more frequently severe infection than the other species (25% versus 5%; P = 0.046). In 2 patients with ulcerative colitis, Aeromonas triggered a moderate-to-severe flare and 2 cases appeared in the context of de novo Crohn's disease. In contrast, in 1 patient with ulcerative colitis and 2 patients with Crohn's disease, Aeromonas caused a mild gastrointestinal infection not worsening the disease activity and in 4 patients with Crohn's disease, it presented in the context of active disease with no clear pathogenic role. Patients with IBD were treated more often with antibiotics (82 versus 41%, P = 0.012) and had more complications (46 versus 14%, P = 0.024). CONCLUSIONS: Aeromonas caused mostly mild infections but also moderate and severe infections. A. veronii was more prevalent in patients with IBD and was associated with worse clinical outcomes. Aeromonas caused milder infections in patients without IBD. Other risk factors for severe infection were not found. PMID- 25517596 TI - Effect of preoperative biologic drugs on complications and function after restorative proctocolectomy with primary ileal pouch formation: systematic review and meta-analysis. AB - BACKGROUND: Debate exists concerning the presumed risk of postoperative complications in patients with ulcerative colitis (UC) receiving preoperative infliximab (IFX). Meta-analyses are contrasting because of many confounders included into analysis. Our aim was to determine the impact of IFX on pouch related postoperative complications in patients with UC undergoing surgery with primary ileal pouch-anal anastomosis. METHODS: We performed a systematic review to identify studies comparing the outcomes of patients undergoing surgery for UC with or without previous IFX exposure. The primary end points were (1) early ileal pouch-anal anastomosis-related complications after surgery with primary pouch formation and (2) those occurring after ileostomy closure. Secondary end points were the effects of IFX on total, infectious, and noninfectious complications in patients with UC undergoing any type of surgery. Results are reported as pooled odds ratio (OR) with 95% confidence intervals (CIs). RESULTS: Seven papers, including 162 patients receiving biologics and 468 controls all undergoing primary pouch formation, were included for the primary aim. Patients receiving IFX were more likely developing early (OR = 4.12; 95% CI, 2.37-7.15; P < 0.001) and post-ileostomy closure (OR = 2.27; 95% CI, 1.27-4.05; P = 0.005) ileal pouch-anal anastomosis-related complications. Number needed to harm was calculated to be 5 and 4, respectively. Having received at least 3 IFX effusions increased the risk of early complications (OR = 9.59; 95% CI, 2.92-31.44; P = 0.0002), whereas an interval of <12 weeks since last effusion did not (OR = 2.35; 95% CI, 0.98-5.64; P = 0.06). Meta-analyses of 14 studies reporting on any type of surgery found that IFX showed a trend toward higher total and infectious complications, but no significant differences were observed. Biologics were associated with lower surgical site infection (OR = 0.67; 95% CI, 0.45-0.99; P = 0.04). CONCLUSIONS: IFX exposure increases early pouch-specific complications and complications after ileostomy closure in UC. Avoiding primary pouch formation could be a prudent approach. PMID- 25517597 TI - Small bowel capsule endoscopy in the management of established Crohn's disease: clinical impact, safety, and correlation with inflammatory biomarkers. AB - BACKGROUND: Multiple studies have established the superior diagnostic accuracy of video capsule endoscopy (VCE) for the diagnosis of small bowel (SB) Crohn's disease (CD). However, data on the clinical impact of VCE in patients with established CD are scarce. The aim of this study was to examine the impact and safety of VCE on the clinical management of patients with established CD. METHODS: A retrospective, multicenter, cross-sectional study. The study cohort included consecutive patients with established SB CD who underwent VCE in 4 tertiary referral centers (1 Canada, 1 Sweden, and 2 United Kingdom) from January 2008 to October 2013. Patients were excluded if VCE was performed as a part of the initial diagnostic workup. The presence of SB mucosal inflammation was quantified using the Lewis score. Inflammatory biomarkers (C-reactive protein and fecal calprotectin) were measured and correlated with the Lewis score. RESULTS: The study included 187 patients. No SB inflammation was observed in 28.4%, mild to-moderate inflammation in 26.6%, and moderate-to-severe inflammation in 45% of the patients (median Lewis score, 662; range, 0-6400). A change in management was recommended in 52.3% of the patients based on VCE findings. Elevated C-reactive protein, fecal calprotectin, or the combination of both were poorly correlated with significant SB inflammation. SB capsule retention occurred in 4 patients (2.1%). CONCLUSIONS: VCE in patients with established CD is safe, and the results often have a significant clinical impact. VCE should not be limited to CD patients with positive inflammatory markers because their predictive value for significant SB inflammation is poor. PMID- 25517598 TI - Role of inflammasomes in intestinal inflammation and Crohn's disease. AB - : Inflammasomes are multiprotein complexes that process procytokines into mature forms of interleukin 1beta and interleukin 18 and induce pyroptotic cell death. Evidence linking NLRP3, NLRC4, and NLRP6 inflammasomes to intestinal inflammation is reviewed to provide a basis to understand how the innate immune system discriminates pathogenic bacteria from commensal bacteria and shapes microbial ecology. Inflammasomes have a direct and important role limiting colitis by directing effective immune responses against pathogenic bacterial infections in the intestine. Chronic granulomatous disease is presented to reveal a contrasting proinflammatory effect of inflammasomes. This pathogenic effect is unmasked in a state of immunodeficiency where bacterial growth is poorly controlled increasing inflammasome activity. The role of inflammasomes in inflammation associated with Crohn's disease and ulcerative colitis is discussed. Finally, mechanistic studies linking genetic polymorphisms in ATG16L and NOD2 to inflammasome activation provide a basis for new hypotheses to explain how genetic polymorphism associated with Crohn's disease modulate intestinal inflammation. A deeper understanding of the role of inflammasomes in intestinal inflammation is expected to identify new ways of treating inflammatory bowel disease. PMID- 25517599 TI - IBD and extent of coronary atherosclerosis. PMID- 25517600 TI - Clinical remission as defined by the Mayo Score: do we deceive ourselves? PMID- 25517601 TI - Curcumin induces cell death of the main molecular myeloma subtypes, particularly the poor prognosis subgroups. AB - Multiple myeloma (MM), a plasma cell malignancy, remains incurable despite the development of new therapies. Curcumin anti-tumor effects were previously characterized in multiple myeloma, however only few MM cell lines were included in these studies. Since myeloma is a heterogeneous disease it is important to address the impact of myeloma molecular heterogeneity in curcumin cell death induction. In the present study, a large panel of human myeloma cell lines (HMCLs) (n = 29), representing the main molecular MM subgroups, was screened for curcumin sensitivity. We observed that curcumin cell death induction was heterogeneous, of note 16 HMCLs were highly sensitive to curcumin (LD50 < 20.5 MUM), 6 HMCLs exhibited intermediate LD50 values (20.5 MUM <= LD50 < 32.2 MUM) and only 7 HMCLs were weakly sensitive (35 < LD50 < 56 MUM). Cell lines harboring the t(11;14) translocation were less sensitive (median LD50 32.9 MUM) than non t(11;14) (median LD50 17.9 MUM), which included poor prognosis t(4;14) and t(14;16) cells. Interestingly, curcumin sensitivity was not dependent on TP53 status. For the first time we showed that primary myeloma cells were also sensitive, even those displaying del(17p), another poor prognosis factor. We also unravel the contribution of anti-apoptotic Bcl-2 family molecules in curcumin response. We found that down-regulation of Mcl-1, an essential MM survival factor, was associated with curcumin-induced cell death and its knockdown sensitized myeloma cells to curcumin, highlighting Mcl-1 as an important target for curcumin-induced apoptosis. Altogether, these results support clinical trials including curcumin in association with standard therapy. PMID- 25517602 TI - Environmental impacts of surgical procedures: life cycle assessment of hysterectomy in the United States. AB - The healthcare sector is a driver of economic growth in the U.S., with spending on healthcare in 2012 reaching $2.8 trillion, or 17% of the U.S. gross domestic product, but it is also a significant source of emissions that adversely impact environmental and public health. The current state of the healthcare industry offers significant opportunities for environmental efficiency improvements, potentially leading to reductions in costs, resource use, and waste without compromising patient care. However, limited research exists that can provide quantitative, sustainable solutions. The operating room is the most resource intensive area of a hospital, and surgery is therefore an important focal point to understand healthcare-related emissions. Hybrid life cycle assessment (LCA) was used to quantify environmental emissions from four different surgical approaches (abdominal, vaginal, laparoscopic, and robotic) used in the second most common major procedure for women in the U.S., the hysterectomy. Data were collected from 62 cases of hysterectomy. Life cycle assessment results show that major sources of environmental emissions include the production of disposable materials and single-use surgical devices, energy used for heating, ventilation, and air conditioning, and anesthetic gases. By scientifically evaluating emissions, the healthcare industry can strategically optimize its transition to a more sustainable system. PMID- 25517603 TI - Cost-utility analysis of screening for diabetic retinopathy in Japan: a probabilistic Markov modeling study. AB - PURPOSE: To evaluate the cost-effectiveness for a screening interval longer than 1 year detecting diabetic retinopathy (DR) through the estimation of incremental costs per quality-adjusted life year (QALY) based on the best available clinical data in Japan. METHODS: A Markov model with a probabilistic cohort analysis was framed to calculate incremental costs per QALY gained by implementing a screening program detecting DR in Japan. A 1-year cycle length and population size of 50,000 with a 50-year time horizon (age 40-90 years) was used. Best available clinical data from publications and national surveillance data was used, and a model was designed including current diagnosis and management of DR with corresponding visual outcomes. One-way and probabilistic sensitivity analyses were performed considering uncertainties in the parameters. RESULTS: In the base case analysis, the strategy with a screening program resulted in an incremental cost of 5,147 Japanese yen (Y; US$64.6) and incremental effectiveness of 0.0054 QALYs per person screened. The incremental cost-effectiveness ratio was Y944,981 (US$11,857) per QALY. The simulation suggested that screening would result in a significant reduction in blindness in people aged 40 years or over (-16%). Sensitivity analyses suggested that in order to achieve both reductions in blindness and cost-effectiveness in Japan, the screening program should screen those aged 53-84 years, at intervals of 3 years or less. CONCLUSIONS: An eye screening program in Japan would be cost-effective in detecting DR and preventing blindness from DR, even allowing for the uncertainties in estimates of costs, utility, and current management of DR. PMID- 25517605 TI - Revealing the Achilles heel of bacterial toxins. AB - In addition to having antimicrobial properties, defensins inactivate various structurally unrelated bacterial toxins by a yet unknown manner. In this issue of Immunity, Kudryashova et al. (2014b) provide insights into mechanisms by which human ?-defensins destabilize and inactivate bacterial toxins. PMID- 25517604 TI - A genetic variant in 12q13, a possible risk factor for bipolar disorder, is associated with depressive state, accounting for stressful life events. AB - Genome-wide association studies (GWASs) have identified a number of susceptibility genes for schizophrenia (SCZ) and bipolar disorder (BD). However, the identification of risk genes for major depressive disorder (MDD) has been unsuccessful because the etiology of MDD is more influenced by environmental factors; thus, gene-environment (G * E) interactions are important, such as interplay with stressful life events (SLEs). We assessed the G*E interactions and main effects of genes targeting depressive symptoms. Using a case-control design, 922 hospital staff members were evaluated for depressive symptoms according to Beck Depressive Inventory (BDI; "depression" and "control" groups were classified by scores of 10 in the BDI test), SLEs, and personality. A total of sixty-three genetic variants were selected on the basis of previous GWASs of MDD, SCZ, and BD as well as candidate-gene (SLC6A4, BDNF, DBH, and FKBP5) studies. Logistic regression analysis revealed a marginally significant interaction (genetic variant * SLE) at rs4523957 (P uncorrected = 0.0034) with depression and a significant association of single nucleotide polymorphism identified from evidence of BD GWAS (rs7296288, downstream of DHH at 12q13.1) with depression as the main effect (P uncorrected = 9.4 * 10(-4), P corrected = 0.0424). We also found that SLEs had a larger impact on depression (odds ratio ~ 3), as reported previously. These results suggest that DHH plays a possible role in depression etiology; however, variants from MDD or SCZ GWAS evidence or candidate genes showed no significant associations or minimal effects of interactions with SLEs on depression. PMID- 25517606 TI - Hypertension: an immune disorder? AB - T cell depletion can prevent hypertension in experimental animals. What is the nature of T cell activation in hypertension? In this issue of Immunity, Carnevale et al. (2014) implicate PlGF signaling in a reservoir of splenic T cells. PMID- 25517607 TI - Dedicated mTEC progenitors stay true, even into adulthood. AB - Knowledge about the cells giving rise to and maintaining the thymic structure remains limited. In this issue of Immunity, Sekai et al. (2014) identify a postnatal self-renewing unipotential progenitor population capable of generating thymic medullary cells and lay the foundation for research into thymic regeneration. PMID- 25517608 TI - "Toll"-erance in the skin. AB - Interactions between potentially pathogenic commensal bacteria and cutaneous immunity are poorly understood. In this issue of Immunity, Skabytska et al. (2014) show that S. aureus-derived TLR2/6 heterodimer ligands can recruit myeloid derived suppressor cells into the skin, countering rather than promoting inflammation. PMID- 25517609 TI - Tumors STING adaptive antitumor immunity. AB - Immunotherapy is revolutionizing the treatment of cancer patients, but the molecular basis for tumor immunogenicity is unclear. In this issue of Immunity, Deng et al. (2014) and Woo et al. (2014) provide evidence suggesting that dendritic cells detect DNA from tumor cells via the STING-mediated, cytosolic DNA sensing pathway. PMID- 25517610 TI - Balance and imbalance in the immune system: life on the edge. AB - CTLA-4 is a key immune checkpoint in maintaining self-tolerance, which can be co opted by cancer to evade immune attack. In Science, Kuehn et al. (2014) describe clinical manifestations from inherited heterozygous CTLA4 mutations, and some are reminiscent of immune-related consequences from anti-CTLA-4 cancer therapy. PMID- 25517611 TI - The macrophage paradox. AB - Macrophages are a diverse population of phagocytic cells that reside in tissues throughout the body. At sites of infection, macrophages encounter and engulf invading microbes. Accordingly, macrophages possess specialized effector functions to kill or coordinate the elimination of their prey. Nevertheless, many intracellular bacterial pathogens preferentially replicate inside macrophages. Here we consider explanations for what we call "the macrophage paradox:" why do so many pathogenic bacteria replicate in the very cells equipped to destroy them? We ask whether replication in macrophages is an unavoidable fate that essentially defines a key requirement to be a pathogen. Conversely, we consider whether fundamental aspects of macrophage biology provide unique cellular or metabolic environments that pathogens can exploit. We conclude that resolution of the macrophage paradox requires acknowledgment of the richness and complexity of macrophages as a replicative niche. PMID- 25517612 TI - Leukocyte migration into inflamed tissues. AB - Leukocyte migration through activated venular walls is a fundamental immune response that is prerequisite to the entry of effector cells such as neutrophils, monocytes, and effector T cells to sites of infection, injury, and stress within the interstitium. Stimulation of leukocytes is instrumental in this process with enhanced temporally controlled leukocyte adhesiveness and shape-changes promoting leukocyte attachment to the inner wall of blood vessels under hydrodynamic forces. This initiates polarized motility of leukocytes within and through venular walls and transient barrier disruption facilitated sequentially by stimulated vascular cells, i.e., endothelial cells and their associated pericytes. Perivascular cells such as macrophages and mast cells that act as tissue inflammatory sentinels can also directly and indirectly regulate the exit of leukocytes from the vascular lumen. In this review, we discuss current knowledge and open questions regarding the mechanisms involved in the interactions of different effector leukocytes with peripheral vessels in extralymphoid organs. PMID- 25517613 TI - Human defensins facilitate local unfolding of thermodynamically unstable regions of bacterial protein toxins. AB - Defensins are short cationic, amphiphilic, cysteine-rich peptides that constitute the front-line immune defense against various pathogens. In addition to exerting direct antibacterial activities, defensins inactivate several classes of unrelated bacterial exotoxins. To date, no coherent mechanism has been proposed to explain defensins' enigmatic efficiency toward various toxins. In this study, we showed that binding of neutrophil ?-defensin HNP1 to affected bacterial toxins caused their local unfolding, potentiated their thermal melting and precipitation, exposed new regions for proteolysis, and increased susceptibility to collisional quenchers without causing similar effects on tested mammalian structural and enzymatic proteins. Enteric ?-defensin HD5 and ?-defensin hBD2 shared similar toxin-unfolding effects with HNP1, albeit to different degrees. We propose that protein susceptibility to inactivation by defensins is contingent to their thermolability and conformational plasticity and that defensin-induced unfolding is a key element in the general mechanism of toxin inactivation by human defensins. PMID- 25517614 TI - The angiogenic factor PlGF mediates a neuroimmune interaction in the spleen to allow the onset of hypertension. AB - Hypertension is a health problem affecting over 1 billion people worldwide. How the immune system gets activated under hypertensive stimuli to contribute to blood pressure elevation is a fascinating enigma. Here we showed a splenic role for placental growth factor (PlGF), which accounts for the onset of hypertension, through immune system modulation. PlGF repressed the expression of the protein Timp3 (tissue inhibitor of metalloproteinases 3), through the transcriptional Sirt1-p53 axis. Timp3 repression allowed costimulation of T cells and their deployment toward classical organs involved in hypertension. We showed that the spleen is an essential organ for the development of hypertension through a noradrenergic drive mediated by the celiac ganglion efferent. Overall, we demonstrate that PlGF mediates the neuroimmune interaction in the spleen, organizing a unique and nonredundant response that allows the onset of hypertension. PMID- 25517615 TI - STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. AB - Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy. PMID- 25517618 TI - SnapShot: nucleic acid immune sensors, part 1. AB - The innate immune system has evolved sensors that can detect specific molecular fingerprints of non-self RNA or DNA. At the same time, some receptors respond to nucleic acids of both exogenous and endogenous origin, yet they are spatially segregated from endogenous nucleic acids. This SnapShot schematizes families and individual members of nucleic acid sensors with a focus on their ligands and the signaling pathways they employ. PMID- 25517616 TI - STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. AB - Ionizing radiation-mediated tumor regression depends on type I interferon (IFN) and the adaptive immune response, but several pathways control I IFN induction. Here, we demonstrate that adaptor protein STING, but not MyD88, is required for type I IFN-dependent antitumor effects of radiation. In dendritic cells (DCs), STING was required for IFN-? induction in response to irradiated-tumor cells. The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS) mediated sensing of irradiated-tumor cells in DCs. Moreover, STING was essential for radiation induced adaptive immune responses, which relied on type I IFN signaling on DCs. Exogenous IFN-? treatment rescued the cross-priming by cGAS or STING-deficient DCs. Accordingly, activation of STING by a second messenger cGAMP administration enhanced antitumor immunity induced by radiation. Thus radiation-mediated antitumor immunity in immunogenic tumors requires a functional cytosolic DNA sensing pathway and suggests that cGAMP treatment might provide a new strategy to improve radiotherapy. PMID- 25517619 TI - Partial melting of deeply subducted eclogite from the Sulu orogen in China. AB - We report partial melting of an ultrahigh pressure eclogite in the Mesozoic Sulu orogen, China. Eclogitic migmatite shows successive stages of initial intragranular and grain boundary melt droplets, which grow into a three dimensional interconnected intergranular network, then segregate and accumulate in pressure shadow areas and then merge to form melt channels and dikes that transport magma to higher in the lithosphere. Here we show, using zircon U-Pb dating and petrological analyses, that partial melting occurred at 228-219 Myr ago, shortly after peak metamorphism at 230 Myr ago. The melts and residues are complimentarily enriched and depleted in light rare earth element (LREE) compared with the original rock. Partial melting of deeply subducted eclogite is an important process in determining the rheological structure and mechanical behaviour of subducted lithosphere and its rapid exhumation, controlling the flow of deep lithospheric material, and for generation of melts from the upper mantle, potentially contributing to arc magmatism and growth of continental crust. PMID- 25517622 TI - Dead space during one-lung ventilation. AB - PURPOSE OF REVIEW: Describe the importance of monitoring dead space during thoracic surgery, specifically during one-lung ventilation. RECENT FINDINGS: The concept of dead space has gained renewed interest among anesthesiologists ever since breath-by-breath measurement by volumetric capnography became available. Monitoring dead space during thoracic surgery assesses the ventilatory deficiencies related to increases in instrumental, airway and/or alveolar dead space, when ventilating patients with positive pressure and double-lumen tubes. Another interesting use of such monitoring is to detect ventilator-induced lung injury due to tidal overdistension. This type of injury threatens the fragile lungs especially during one-lung ventilation and can clinically be recognized as an increase in airway and alveolar dead space above normal values. To date, lung protective ventilation is based on the use of low tidal volumes and airway pressures to decrease overdistension. It has been shown to reduce the incidence of postoperative pulmonary complications after thoracic surgeries. However, such a ventilatory strategy impairs ventilation and induces hypercapnia due to increases in dead space. Therefore, continuous assessment of dead space is helpful in guiding ventilation and avoiding overdistension while maintaining the elimination of CO(2) during thoracic surgery sufficiently high. SUMMARY: Monitoring dead space helps anesthesiologists monitor the status of the lung and find appropriate ventilatory settings during thoracic surgeries. PMID- 25517617 TI - Distinct epigenetic signatures delineate transcriptional programs during virus specific CD8(+) T cell differentiation. AB - The molecular mechanisms that regulate the rapid transcriptional changes that occur during cytotoxic T lymphocyte (CTL) proliferation and differentiation in response to infection are poorly understood. We have utilized ChIP-seq to assess histone H3 methylation dynamics within naive, effector, and memory virus-specific T cells isolated directly ex vivo after influenza A virus infection. Our results show that within naive T cells, codeposition of the permissive H3K4me3 and repressive H3K27me3 modifications is a signature of gene loci associated with gene transcription, replication, and cellular differentiation. Upon differentiation into effector and/or memory CTLs, the majority of these gene loci lose repressive H3K27me3 while retaining the permissive H3K4me3 modification. In contrast, immune-related effector gene promoters within naive T cells lacked the permissive H3K4me3 modification, with acquisition of this modification occurring upon differentiation into effector/memory CTLs. Thus, coordinate transcriptional regulation of CTL genes with related functions is achieved via distinct epigenetic mechanisms. PMID- 25517620 TI - Inactivated Sendai virus strain Tianjin induces apoptosis in breast cancer MCF-7 cells by promoting caspase activation and Fas/FasL expression. AB - Virotherapy represents a promising new approach for treating cancer. Here the authors have analyzed the effect of ultraviolet-inactivated Sendai virus strain Tianjin (UV-Tianjin) on human breast cancer MCF-7 cells in vitro and in vivo. In vitro, UV-Tianjin inhibited the proliferation of MCF-7, MDA-MB-231, and T47D breast cancer cell lines, although MCF-7 cells were most susceptible to UV Tianjin treatment. Hoechst staining and flow cytometric analysis of UV-Tianjin treated MCF-7 cells revealed that UV-Tianjin induced apoptosis in a dose dependent manner. Moreover, UV-Tianjin treatment resulted in reductions in the mitochondria membrane potential of MCF-7 cells and regulated the levels and activities of Bcl-2, Bax, cyt c, caspases, Fas, and Fas ligand (FasL). In vivo, UV-Tianjin inhibited the growth of MCF-7 tumors in nude mice and increased tumor cell apoptosis compared with saline-treated controls. In addition, the percentage of tumor cells positive for cleaved versions of caspase-7, caspase-8, and caspase 9 was higher in UV-Tianjin-treated tumors than in saline-treated controls. In summary, UV-Tianjin exhibited the antitumor activity in human breast cancer MCF-7 cells both in vitro and in vivo. The UV-Tianjin treatment seemed to induce apoptosis by activating both the mitochondrial and death receptor apoptotic pathways. PMID- 25517623 TI - Thoracic anesthesia in the elderly. AB - PURPOSE OF REVIEW: The mean age of patients presenting for thoracic surgery is rising steadily, associated with an increased demand for thoracic surgical treatments by geriatric patients. With increasing age, physiologic changes and comorbidities have to be considered. Thoracic anesthesia for elderly patients requires greater specific knowledge. RECENT FINDINGS: Respiratory mechanics change progressively during aging, and the pharmacology of different drugs is also altered with increasing age. This has implications for the preoperative, intraoperative and postoperative management of elderly patients scheduled for thoracic surgery. Special focus has to be placed on preoperative evaluation, the ventilation regime and general intraoperative management. Effective postoperative pain treatment after geriatric thoracic surgery requires careful pain assessment and drug titration. SUMMARY: Considering key points of physiology and pharmacology can help to provide best possible care for the increasing number of elderly patients in thoracic surgery. Management of geriatric patients in thoracic surgery offer opportunities for anaesthetic interventions including protective ventilation, use of different anesthetics, anaesthesia monitoring, fluid management and pain therapy. PMID- 25517625 TI - Anthelmintic drugs and nematicides: studies in Caenorhabditis elegans. AB - Parasitic nematodes infect many species of animals throughout the phyla, including humans. Moreover, nematodes that parasitise plants are a global problem for agriculture. As such, these nematodes place a major burden on human health, on livestock production, on the welfare of companion animals and on crop production. In the 21st century there are two major challenges posed by the wide spread prevalence of parasitic nematodes. First, many anthelmintic drugs are losing their effectiveness because nematode strains with resistance are emerging. Second, serious concerns regarding the environmental impact of the nematicides used for crop protection have prompted legislation to remove them from use, leaving agriculture at increased risk from nematode pests. There is clearly a need for a concerted effort to address these challenges. Over the last few decades the free-living nematode Caenorhabditis elegans has provided the opportunity to use molecular genetic techniques for mode of action studies for anthelmintics and nematicides. These approaches continue to be of considerable value. Less fruitful so far, but nonetheless potentially very useful, has been the direct use of C. elegans for anthelmintic and nematicide discovery programmes. Here we provide an introduction to the use of C. elegans as a 'model' parasitic nematode, briefly review the study of nematode control using C. elegans and highlight approaches that have been of particular value with a view to facilitating wider-use of C. elegans as a platform for anthelmintic and nematicide discovery and development. PMID- 25517626 TI - Experimental study of strontium adsorption on anatase nanoparticles as a function of size with a density functional theory and CD model interpretation. AB - The effect of particle size on the adsorption of Sr(2+) onto monodisperse nanometer diameter (4, 20, and 40 nm) anatase samples has been evaluated quantitatively with macroscopic experimental studies. The adsorption of Sr(2+) onto the anatase particles was evaluated by potentiometric titrations in NaCl media, at two ionic strengths (0.03 and 0.3 m), and over a wide range of pH (3 11) and surface loadings, at a temperature of 25 degrees C. Adsorption of Sr(2+) to the surface of the 20 and 40 nm diameter samples was similar, whereas the Sr(2+) adsorption titration curves were shallower for the 4 nm diameter samples. At high pH, the smallest particles adsorbed slightly less Sr(2+) than was adsorbed by the larger particles. At the molecular scale, density functional theory (DFT) calculations were used to evaluate the most stable Sr(2+) surface species on the (101) anatase surface (the predominant crystal face). An inner sphere Sr-tridentate surface species was found to be the most stable. The experimental data were described with a charge distribution (CD) and multisite complexation (MUSIC) model, with a Basic Stern layer description of the electric double layer. The resulting surface complexation model explicitly incorporated the molecular-scale information from the DFT simulation results. For 20 and 40 nm diameter anatase, the CD value for the Sr-tridentate species was calculated using a bond valence interpretation of the DFT-optimized geometry. The CD value for the 4 nm sample was smaller than that for the 20 and 40 nm samples, reflecting the shallower Sr(2+) adsorption titration curves. The adsorption differences between the smallest and larger anatase particles can be rationalized by water being more highly structured near the 4 nm anatase sample and/or the Sr-tridentate surface species may require more well-developed surface terraces than are present on the 4 nm particles. PMID- 25517627 TI - A kinematic comparison of the overhand throw and tennis serve in tennis players: how similar are they really? AB - Tennis coaches often use the fundamental throwing skill as a training tool to develop the service action. However, recent skill acquisition literature questions the efficacy of non-specific training drills for developing complex sporting movements. Thus, this study examined the mechanical analogy of the throw and the tennis serve at three different levels of development. A 500 Hz, 22 camera VICON MX motion capture system recorded 28 elite female tennis players (prepubescent (n = 10), pubescent (n = 10), adult (n = 8)) as they performed flat serves and overhand throws. Two-way ANOVAs with repeated measures and partial correlations (controlling for group) assessed the strength and nature of the mechanical associations between the tasks. Preparatory mechanics were similar between the two tasks, while during propulsion, peak trunk twist and elbow extension velocities were significantly higher in the throw, yet the peak shoulder internal rotation and wrist flexion angular velocities were significantly greater in the serve. Furthermore, all of these peak angular velocities occurred significantly earlier in the serve. Ultimately, although the throw may help to prime transverse trunk kinematics in the serve, mechanics in the two skills appear less similar than many coaches seem to believe. Practitioners should, therefore, be aware that the throw appears less useful for priming the specific arm kinematics and temporal phasing that typifies the tennis serve. PMID- 25517628 TI - Selective angiographic embolisation of an infralevator vulvovaginal haematoma after birth: case report. PMID- 25517629 TI - New perspectives on counselling in audiological habilitation/rehabilitation. AB - OBJECTIVE: To develop and apply a pedagogical method focusing on Empowerment, Empathy, Competence, and Counselling: the EC programme, and to present an initial evaluation. DESIGN: The EC programme was gradually developed within a study circle framework and in dialogue with study circle leaders and participants (clients) with hearing impairment (HI). An evaluation was carried out with the study circle leaders. STUDY SAMPLE: Seventeen upper secondary school students with HI took part in the development of the programme. Eighteen study circle leaders responded to a questionnaire. RESULTS: The EC programme developed consisted of films, CD, and DVD productions to increase insight into one's own hearing ability, to demonstrate for others what HI means, strategies to evaluate situations, and help to act constructively in social situations. The study circle leaders found most of the course material appropriate and easy to use, as a whole or in parts. The leaders' evaluations indicated that the clients had increased their knowledge about how the HI affected themselves and others. The clients had improved their self-confidence and their empathic view of others. CONCLUSION: The EC programme can be used in its entirety or in part. Participation may lead to increased empowerment, empathy, competence and counselling ability. PMID- 25517630 TI - Adaptive tests of temporal resolution: comparison with the gaps-in-noise test in normal-hearing young adults. AB - OBJECTIVE: Auditory processing disorder patients may have deficits in auditory temporal resolution. This study explored: (1) the ear specific norms for young adults using the adaptive tests of temporal resolution (ATTR); (2) the reliability of ATTR using two different modes of stimuli presentation; and (3) the concurrent validity of ATTR with reference to the gaps-in-noise (GIN) test. DESIGN: GIN and ATTR were administered through a standard audiometer and headphones. As ATTR can also be completed using a computer with commercially available headphones, thresholds from these two variants were compared. STUDY SAMPLE: Thirty normal-hearing young adults were recruited. RESULTS: The mean ATTR gap detection thresholds (GDTs) derived under audiometer administration were 4.60 ms (SD 1.49) and 4.97 ms (SD 1.98) for the left and right ear, respectively. The approximated threshold (A. th.), an equivalent measure to the GDT in the GIN, mean values were 5.37 ms (SD 0.98) and 5.33 ms (SD 1.07) for left and right ears, respectively. No significant threshold difference was found between the ATTR variants. A positive, moderate correlation was found, and Bland-Altman plot analysis revealed good agreement, between GDT and A.th. CONCLUSIONS: ATTR and GIN results were moderately associated. Moreover, the ATTR was found to have high test-retest reliability and high specificity for the current participants. PMID- 25517632 TI - The outdated pregnancy: rethinking traditional markers in reproduction. PMID- 25517633 TI - To treat or not to treat: end-of-life care, patient autonomy, and the responsible practice of medicine. PMID- 25517634 TI - Banning sexual orientation therapy: constitutionally supported and socially necessary. PMID- 25517631 TI - Translocation between PI(4,5)P2-poor and PI(4,5)P2-rich microdomains during store depletion determines STIM1 conformation and Orai1 gating. AB - The Orai1-STIM1 current undergoes slow Ca(2+)-dependent inactivation (SCDI) mediated by the binding of SARAF to STIM1. Here we report the use of SCDI by SARAF as a probe of the conformation and microdomain localization of the Orai1 STIM1 complex. We find that the interaction of STIM1 with Orai1 carboxyl terminus (C terminus) and the STIM1 K-domain are required for the interaction of SARAF with STIM1 and SCDI. STIM1-Orai1 must be in a PM/ER microdomain tethered by E Syt1, stabilized by septin4 and enriched in PI(4,5)P2 for STIM1-SARAF interaction. Targeting STIM1 to PI(4,5)P2-rich and -poor microdomains reveals that SARAF-dependent SCDI is observed only when STIM1-Orai1 are within the PI(4,5)P2-rich microdomain. Notably, store depletion results in transient localization of STIM1-Orai1 in the PI(4,5)P2-poor microdomain, which then translocates to the PI(4,5)P2-rich domain. These findings reveal the role of PM/ER tethers in the regulation of Orai1 function and a mode of regulation by PI(4,5)P2 involving translocation between PI(4,5)P2 microdomains. PMID- 25517635 TI - Medical device immunity: should promotion of off-label uses leave medical device manufacturers vulnerable to unlimited liability? PMID- 25517636 TI - Don't let them eat cake: implementing a government-sponsored wellness program that utilizes tax credits to promote healthy behaviors. PMID- 25517639 TI - Stroke awareness in Brazil: what information about stroke is essential? PMID- 25517638 TI - TET1 regulates hypoxia-induced epithelial-mesenchymal transition by acting as a co-activator. AB - BACKGROUND: Hypoxia induces the epithelial-mesenchymal transition, EMT, to promote cancer metastasis. In addition to transcriptional regulation mediated by hypoxia-inducible factors, HIFs, other epigenetic mechanisms of gene regulation, such as histone modifications and DNA methylation, are utilized under hypoxia. However, whether DNA demethylation mediated by TET1, a DNA dioxygenase converting 5-methylcytosine, 5mC, into 5-hydroxymethylcytosine, 5hmC, plays a role in hypoxia-induced EMT is largely unknown. RESULTS: We show that TET1 regulates hypoxia-responsive gene expression. Hypoxia/HIF-2alpha regulates the expression of TET1. Knockdown of TET1 mitigates hypoxia-induced EMT. RNA sequencing and 5hmC sequencing identified the set of TET1-regulated genes. Cholesterol metabolic process genes are among the genes that showed high prevalence and statistical significance. We characterize one of the genes, INSIG1 (insulin induced gene 1), to confirm its expression and the 5hmC levels in its promoter. Knockdown of INSIG1 also mitigates hypoxia-induced EMT. Finally, TET1 is shown to be a transcriptional co-activator that interacts with HIF-1alpha and HIF-2alpha to enhance their transactivation activity independent of its enzymatic activity. TET1 acts as a co-activator to further enhance the expression of INSIG1 together with HIF-2alpha. We define the domain in HIF-1alpha that interacts with TET1 and map the domain in TET1 that confers transactivation to a 200 amino acid region that contains a CXXC domain. The TET1 catalytically inactive mutant is capable of rescuing hypoxia-induced EMT in TET1 knockdown cells. CONCLUSIONS: These findings demonstrate that TET1 serves as a transcription co-activator to regulate hypoxia responsive gene expression and EMT, in addition to its role in demethylating 5mC. PMID- 25517640 TI - Natalizumab treatment for multiple sclerosis. PMID- 25517641 TI - Evaluation of patients with Alzheimer's disease before and after dental treatment. AB - Oral infections may play a role in Alzheimer's disease (AD). Objective To describe the orofacial pain, dental characteristics and associated factors in patients with Alzheimer's Disease that underwent dental treatment. Method 29 patients with mild AD diagnosed by a neurologist were included. They fulfilled the Mini Mental State Exam and Pfeffer's questionnaire. A dentist performed a complete evaluation: clinical questionnaire; research diagnostic criteria for temporomandibular disorders; McGill pain questionnaire; oral health impact profile; decayed, missing and filled teeth index; and complete periodontal investigation. The protocol was applied before and after the dental treatment. Periodontal treatments (scaling), extractions and topic nystatin were the most frequent. Results There was a reduction in pain frequency (p=0.014), mandibular functional limitations (p=0.011) and periodontal indexes (p<0.05), and an improvement in quality of life (p=0.009) and functional impairment due to cognitive compromise (p<0.001) after the dental treatment. Orofacial complaints and intensity of pain also diminished. Conclusion The dental treatment contributed to reduce co-morbidities associated with AD and should be routinely included in the assessment of these patients. PMID- 25517642 TI - Caregivers' quality of life in mild and moderate dementia. AB - OBJECTIVE: To investigate quality of life (QoL) of caregivers of mild and moderate dementia and the aspects related to QoL. METHOD: Cross-sectional assessment of dyads of people with dementia (PwD) and family caregivers (n=88). RESULTS: Burden (p<0.05) and depressive symptoms (p<0.001) were related to caregivers' QoL in both stages of dementia. In mild dementia, caregivers' depressive symptoms (p<0.001) and PwD neuropsychiatric symptoms (p<0.001) were related to burden. PwD aberrant motor activity (p<0.001) and anxiety (p<0.001), and caregiver-reported QoL domains of friends (p<0.001) and mood (p<0.05) were related to depressive symptoms. In moderate dementia, self-reported QoL (p<0.01) and anxiety (p<0.01), and PwD anxiety (p<0.01) were related to burden. Caregivers' anxiety (p<0.001) and self-reported QoL (p<0.001) were related to depressive symptoms. CONCLUSION: Burden and depressive symptoms were related to QoL of caregivers of mild and moderate dementia. However, they are driven by different factors according to dementia severity. PMID- 25517643 TI - Aura-like features and photophobia in sightless migraine patients. AB - Migraine is a central nervous system disorder frequently expressed with paroxysmal visual dysfunctions. OBJECTIVE: To test the hypothesis that normal visual input is vital for the migrainous aura and photophobia. METHOD: We studied the migraine-related visual disturbances in 8 sightless migraineurs identified among 200 visually impaired subjects. RESULTS: The main findings were the visual aura and photophobia disappearance along with blindness development, the oddness of aura - too short, colourful (e.g. blue or fire-like), auditory in nature or different in shape (round forms) - and the lack of photophobia. CONCLUSION: We propose that the aura duration should be accepted as shorter in visually impaired subjects. The changes in aura phenotype observed in our patients may be the result of both cerebral plasticity induced by the visual impairment and/or the lack of visual input per se. Integrity of visual pathways plays a key role in migraine visual aura and photophobia. PMID- 25517644 TI - Clinical and neuropsychological assessment of executive function in a sample of children and adolescents with idiopathic epilepsy. AB - OBJECTIVE: To compare the executive functions of children and adolescents with idiopathic epilepsy with a control group and to correlate with clinical data, intelligence and academic performance. METHOD: Cross-sectional, descriptive and analytical study. Thirty-one cases and thirty-five controls were evaluated by the WCST (Wisconsin Card Sorting Test).The results were compared with clinical data (seizure type and frequency, disease duration and number of antiepileptic drugs used), IQ (WISC-III) and academic performance (APT). RESULTS: Patients with epilepsy had poorer executive function scores. There was no positive linear correlation between test scores and epilepsy variables. There was a positive association between academic performance and some executive function results. CONCLUSION: Children with well controlled idiopathic epilepsy may show deficits in executive functions in spite of clinical variables. Those deficits may influence academic performance. PMID- 25517645 TI - A neurological bias in the history of hysteria: from the womb to the nervous system and Charcot. AB - Hysteria conceptions, from ancient Egypt until the 19th century Parisian hospital based studies, are presented from gynaecological and demonological theories to neurological ones. The hysteria protean behavioral disorders based on nervous origin was proposed at the beginning, mainly in Great Britain, by the "enlightenment nerve doctors". The following personages are highlighted: Galen, William, Sydenham, Cullen, Briquet, and Charcot with his School. Charcot who had hysteria and hypnotism probably as his most important long term work, developed his conceptions, initially, based on the same methodology he applied to studies of other neurological disorder. Some of his associates followed him in his hysteria theories, mainly Paul Richer and Gilles de La Tourette who produced, with the master's support, expressive books on Salpetriere School view on hysteria. PMID- 25517646 TI - Carotid artery dissection plus subdural hematoma after a roller-coaster ride. PMID- 25517647 TI - Neurological complications after H1N1 influenza vaccination. PMID- 25517648 TI - Embryonic stem cells in neurology - current clinical transplantation trials in Parkinson's (PD) and Huntington's (HD) disease. PMID- 25517649 TI - Attributable length of stay and mortality of major bleeding as a complication of therapeutic anticoagulation in the intensive care unit. AB - OBJECTIVE: The aim of this study was to determine the attributable length of stay and mortality due to bleeding as a complication of therapeutic anticoagulation in intensive care unit (ICU) patients. METHODS: Charts of patients from 7 ICUs in British Columbia were screened daily for the occurrence of major bleeding while receiving therapeutic heparin. To determine attributable length of stay and mortality, a matched and unmatched cohort design as well as multivariate analysis were used. We included only patients who were started on anticoagulation on or after day 2 in the ICU. RESULTS: Between 2006 and 2009, a total of 868 patients were started on therapeutic anticoagulation and 139 bled. One hundred five patients who bled were matched to 261 controls. In the matched analysis after adjustment for potential confounders, each bleeding event was associated with an increase in ICU length of stay (hazard ratio for ICU discharge, 0.47; 95% confidence interval, 0.38-0.57; attributable ICU length of stay of 13.8 days). Hospital length of stay was also significantly increased. In the entire cohort analysis, bleeding was also associated with increased ICU length of stay (hazard ratio, 0.59; confidence interval, 0.48-0.72; attributable stay of 6.1 days) and increased hospital length of stay. In both analyses, bleeding was not associated with hospital mortality. CONCLUSIONS: Major bleeding while receiving anticoagulation is associated with a substantial increase in ICU and hospital length of stay. PMID- 25517651 TI - Surgical treatment of pediatric retroperitoneal tumors with invasion of major blood vessels: a single-center experience. AB - BACKGROUND: This study assessed operative experiences with common pediatric retroperitoneal tumors invading major blood vessels. METHODS: Forty-seven pediatric patients with retroperitoneal tumors were enrolled. They included 22 neuroblastomas, 6 gangliocytomas and 19 Wilms' tumors, and underwent primary surgical resection after vascular skeletonization and manipulations of involved vessels. RESULTS: In the above tumors, the one-stage gross total resection rates of, respectively, 95.45%, 100% and 100% were obtained. There was only one complication, namely post-operational early acute renal failure that recovered with dialysis. There were no deaths. CONCLUSIONS: Vascular skeletonization and other vessel manipulations prior to surgery improve the gross total resection rates of pediatric retroperitoneal tumors. PMID- 25517652 TI - Critical role of adsorption equilibria on the determination of surface-enhanced Raman enhancement. AB - Surface-enhanced Raman spectroscopy (SERS) is a useful technique for probing analyte-noble metal interactions and determining thermodynamic properties such as their surface reaction equilibrium constants and binding energies. In this study, we measure the binding equilibrium constants and Gibbs free energy of binding for a series of nitrogen-containing aromatic molecules adsorbed on Klarite substrates. A dual Langmuir dependence of the SERS intensity on concentration was observed for the six species studied, indicating the presence of at least two different binding energies. We relate the measured binding energies to the previously described SERS enhancement value (SEV) and show that the SEV is proportional to the traditional SERS enhancement factor G, with a constant of proportionality that is critically dependent on the adsorption equilibrium constant determined from the dual Langmuir isotherm. We believe the approach described is generally applicable to many SERS substrates, both as a prescriptive approach to determining their relative performance and as a probe of the substrate's affinity for a target adsorbate. PMID- 25517653 TI - Comparison of injury epidemiology between the Wenchuan and Lushan earthquakes in Sichuan, China. AB - OBJECTIVE: We aimed to compare injury characteristics and the timing of admissions and surgeries in the Wenchuan earthquake in 2008 and the Lushan earthquake in 2013. METHODS: We retrospectively compared the admission and operating times and injury profiles of patients admitted to our medical center during both earthquakes. We also explored the relationship between seismic intensity and injury type. RESULTS: The time from earthquake onset to the peak in patient admissions and surgeries differed between the 2 earthquakes. In the Wenchuan earthquake, injuries due to being struck by objects or being buried were more frequent than other types of injuries, and more patients suffered injuries of the extremities than thoracic injuries or brain trauma. In the Lushan earthquake, falls were the most common injury, and more patients suffered thoracic trauma or brain injuries. The types of injury seemed to vary with seismic intensity, whereas the anatomical location of the injury did not. CONCLUSIONS: Greater seismic intensity of an earthquake is associated with longer delay between the event and the peak in patient admissions and surgeries, higher frequencies of injuries due to being struck or buried, and lower frequencies of injuries due to falls and injuries to the chest and brain. These insights may prove useful for planning rescue interventions in trauma centers near the epicenter. PMID- 25517654 TI - Solution-processable singlet fission photovoltaic devices. AB - We demonstrate the successful incorporation of a solution-processable singlet fission material, 6,13-bis(triisopropylsilylethynyl)pentacene (TIPS-pentacene), into photovoltaic devices. TIPS-pentacene rapidly converts high-energy singlet excitons into pairs of triplet excitons via singlet fission, potentially doubling the photocurrent from high-energy photons. Low-energy photons are captured by small-bandgap electron-accepting lead chalcogenide nanocrystals. This is the first solution-processable singlet fission system that performs with substantial efficiency with maximum power conversion efficiencies exceeding 4.8%, and external quantum efficiencies of up to 60% in the TIPS-pentacene absorption range. With PbSe nanocrystal of suitable bandgap, its internal quantum efficiency reaches 170 +/- 30%. PMID- 25517655 TI - Clinical Utility of Ultra-Widefield Imaging with the Optos Optomap Compared with Indirect Ophthalmoscopy in the Setting of Non-Traumatic Rhegmatogenous Retinal Detachment. AB - PURPOSE: To evaluate the clinical utility of ultra-widefield imaging as an adjunctive tool in the diagnosis, management, and follow-up of eyes with non traumatic rhegmatogenous retinal detachment. METHODS: Retrospective chart review of patients with a rhegmatogenous retinal detachment who received ultra-widefield imaging with the Optos(r) Optomap(r) P200Tx. Comparisons were made between UWF imaging and indirect ophthalmoscopy for features of detachments, including extent of detachment, holes, retinopexy, and related pathology. RESULTS: Thirty-six eyes of 34 patients were included. Preoperatively, ultra-widefield imaging more precisely documented the extent of retinal detachments in the superior, inferior, and nasal quadrants in 13.9% of cases. Ultra-widefield imaging failed to detect retinal holes in the superior and inferior quadrants in 11.1% and 19.4% of cases, respectively. In postoperative imaging, UWF photos did not detect retinopexy which was ophthalmoscopy-visible both superiorly and inferiorly in 19.4% of cases. The mean differences in clock hours of the detachments as documented on the clinical exam compared to ultra-widefield imaging in the superior, inferior, temporal, and nasal quadrants were -0.18 +/- 0.84, 0.41 +/- 1.16, 0.08 +/- 1.08, and -0.13 +/- 2.25 hours, respectively. CONCLUSION: Ultra-widefield imaging is a useful adjunct for documentation of rhegmatogenous retinal detachments and their postoperative repair. However, detection of retinal holes, tears, and postoperative scarring is poor, especially in the inferior and superior periphery. PMID- 25517656 TI - Moon jellyfish stings. PMID- 25517658 TI - Promoting the advanced nursing practice role in Latin America. PMID- 25517657 TI - Differential effects of culture senescence and mechanical stimulation on the proliferation and leiomyogenic differentiation of MSC from different sources: implications for engineering vascular grafts. AB - We examined the effects of senescence on the proliferation and leiomyogenic differentiation potential of mesenchymal stem cells (MSCs) isolated from bone marrow (BM-MSCs) or hair follicles (HF-MSCs). To this end, we compared ovine HF MSCs and BM-MSCs in terms of their proliferation and differentiation potential to the smooth muscle cell lineage. We discovered that HF-MSCs are less susceptible to culture senescence compared with BM-MSCs. We hypothesized that application of mechanical forces may enhance the contractility and mechanical properties of vascular constructs prepared from senescent MSCs. Interestingly, HF-MSCs and BM MSCs responded differently to changes in the mechanical microenvironment, suggesting that despite phenotypic similarities, MSCs from different anatomic locations may activate different pathways in response to the same microenvironmental factors. In turn, this may also suggest that cell-based tissue regeneration approaches may need to be tailored to the stem cell origin, donor age, and culture time for optimal results. PMID- 25517659 TI - [News of the inquiry about nursing needs and resources in the Brazilian Journal of Nursing (1955-1958)]. AB - Social historical study that has as object news related to the Assessment of the Resources and Needs of Nursing in Brazil published in the Revista Brasileira de Enfermagem between 1955 and 1958. The primary source is constituted of copies of Revista Brasileira de Enfermagem published within the selected period of the study. The secondary sources are constituted of books, papers, dissertations and thesis related to the Nursing history. The data analysis was supported by the secondary sources and the thought of the sociologist Pierre Bourdieu. The results evidenced that Revista Brasileira de Enfermagem, in addition to making possible the dissemination of news about the Assessment provided visibility to it and, at last, had the symbolic effect of giving power and prestige to the Brazilian Nursing. PMID- 25517660 TI - [Health problems reported by nursing workers in a public hospital of Bahia]. AB - Although the work is essential to human life, the context in which it is done can induct tension, imbalance and consequent illness. Studies indicate nursing as an occupation with high risk for disease, particularly in the hospital environment. The aim of this study was to estimate the occurrence of health problems reported by nursing staff in a hospital in Bahia, Brazil. This is a cross-sectional study, involving 309 nursing professionals. The most frequent health complaints were related to musculoskeletal symptoms such as leg pain 66.4% (192) and back pain 61.8% (178); and to mental health with a predominance of mental fatigue 47% (131) 33 and nervousness 7% (93). The results show that nurses had a higher frequency of postural problems and mental health complaints while respiratory diseases complaints were more prevalent among technicians and assistants. These results highlight the need for greater awareness of the work process and implementation of preventive activities. PMID- 25517661 TI - [Nursing workload and occurrence of incidents and adverse events in ICU patients]. AB - This prospective cohort study aimed to identify the influence of nursing work overload on the occurrence of incidents without injury and adverse events in 399 patients hospitalized in Intensive Care Units (ICU). For data collection, a structured questionnaire was administered and an analysis of medical records was performed. In these admissions, approximately 78% of incidents without injury and adverse events in patients were related to the sphere of Nursing. These occurrences were attributed to overwork, increased the number of days of hospitalization and the risk of death of patients. It is essential that nursing managers work on the staff hospital management avoiding work overload to contribute for patient safety. PMID- 25517662 TI - [Instrument for assessing the quality of the Rapid Response Team at a university public hospital]. AB - The paper describes the construction of a questionnaire to assess the quality of care of a Rapid Response Team at the University Hospital of Londrina, based on the conceptual model of Donabedian (structure-process-outcome). Data collection occurred in March 2012 and the process of adjusting the questionnaire was developed with the application of the Delphi technique involving 15 experts. At the end of the study the questionnaire contained 37 statements, achieving final compliance level higher than 80% in all concepts. It is hoped that the contributions of the expert group produce a more reliable questionnaire to be applied in other similar services. Future applications of this instrument may provide information to better assess the quality of teams of Rapid Response services. PMID- 25517663 TI - [Intervention in situations of psychic crisis: challenges and suggestions of a prehospital care staff]. AB - A qualitative and descriptive research, aimed at knowing how the pre-hospital care professionals perceive the interventions towards people in mental crisis. The study was developed in Santa Catarina with four teams of basic life support units of the Department of Mobile Emergency Care, during April to June 2011. The Collective Subject Discourse was used as the method of analysis. Two themes emerged: Awareness of the difficulties in meeting a person in mental crisis and Suggestions in the search for a closer attention to the person in mental crisis. The difficulties mentioned were related to the lack of training and a local to forward the patients, suggesting a better training and systematization of care. We conclude that it is necessary to invest in the educational process, based on new care strategies guided by the principles of SUS and of the psychosocial paradigm, and revisit the strategy of protocols as guidelines and not as standardizing systems. PMID- 25517664 TI - [Validation of the general guidelines of communication between the nurse and the blind]. AB - This quantitative study, conducted between 2008 April and 2009 March in Fortaleza CE, Brazil, aimed to validate the general guidelines of the communication of the nurse with the blind. Thirty nurses and 30 blinds, divided into control and experimental groups, participated in the study. Thirty nursing consultations were videotaped and analyzed by experts. In contrast to the control group, the experimental group showed good and excellent performance in all guidelines for verbal and non-verbal communication with the blinds. The study results point to the urgency of adopting the teaching of these general guidelines for communicating with the blind in nursing courses, in addition to training nurses in caring for the blind people. PMID- 25517665 TI - [Environmental factors associated with the decision time for seeking care in myocardial infarction]. AB - The purpose was to estimate the decision time (DT) for searching for attendance for men and women suffering from acute myocardial infarction (AMI); and to analyze the influence of surrounding variables in the DT. Transversal study, involving one hundred patients interviewed in hospitals of Salvador-BA, Brazil. For data analysis, it was used the chi-squared or Fisher's exact test, and the Robust Linear Regression Model. AMI at the home predominated, with family members and patients receiving mistaken actions. A high DT was observed both, for women (0.9h) and men (1.4h). Those at home during the initial symptoms had higher DT, compared to those at work; and lower in relation to those in public spaces (p=0.047). Statistically significant interaction occurred among gender and the fact of living with company; and among gender and having a companion and children, for the outcome of the DT. Nursing care focused on the specificity of surrounding factors and gender can optimize early attendance. PMID- 25517666 TI - [Evaluation of coronary risk and its relationship to health actions in hypertensive patients]. AB - The risk of developing acute coronary events was evaluated according to Framingham criteria and health actions performed to hypertensive patients at a Health Unit Family of Vitoria-ES. This is a observational, cross-sectional study, involving 330 hypertensive. The sample considered a 50% prevalence of the disease. Data were collected from medical records and the variables were the coronary risk, blood pressure, the number of visits, educational activities and prescribed drugs. ANOVA was used to compare variables and paired t-test for comparison of pressure during the study period, with significance level of 5%. Respectively, 115 (34.8%) subjects had low risk for myocardial infarction or death from coronary heart disease in the next 10 years; 67 (20.4%) had average risk; and 148 (44.8%) had high-risk. Only the amount of prescribed medications showed significant relationship with high coronary risk. PMID- 25517667 TI - [Defining characteristics of the dysfunctional ventilatory weaning response as indicators of accuracy of ventilatory weaning]. AB - The study aimed to analyze the defining characteristics of the Dysfunctional Ventilatory Weaning Response as an indicator of the accuracy of ventilatory weaning. Observational study of 38 events of ventilatory weaning in adult patients admitted to intensive care. For the defining characteristics, it was calculated: sensitivity, specificity, positive and negative predictive values, accuracy or efficiency, likelihood ratio positive and negative, and diagnostic odds ratio. It was also considered the median number of defining characteristics in the event of success and failure. It was considered accurate: agitation, deterioration in arterial blood gases from baseline parameters, moderate use of accessory muscles of respiration, increased respiratory rate from baseline parameters and respiratory rate increases significantly with respect to baseline parameters. There was statistical difference in the median number of defining characteristics observed. It was concluded that the defining characteristic and the number of them would influence the success of the weaning decision. PMID- 25517668 TI - [Distress of cancer patients: prevalence and associated factors in the opinion of family]. AB - The study aimed to verify the opinion of family members about distress on cancer patients and the factors associated with it. Interviews with 140 family members of cancer patients were conducted. The Distress Thermometer was adapted to be used with family members. Approximately 72.9% of patients were considered in distress, related to concern (80.4%), nervousness (78.4%), sadness (74.5%), pain (67.6%), fatigue (67.6%) and problems with eating (57.8%). The hierarchical logistic regression models showed that while male (OR=0.025) and older ages (OR=0.006 to 0.059) had lower risk of perceiving the distress, individuals Protestants, compared to Catholics, were 12.77 times more likely to perceive it. About the associated factors, nervousness (OR=10.8) contributed significantly more to the perception of distress for family members when compared to fatigue (OR=3.38) or have private health insurance (OR=2.55). Family can be great allies in the evaluation and monitoring of distress in patients with cancer. PMID- 25517669 TI - [Ressignification of life of caregivers of elderly patients with cancer]. AB - The study aimed to analyze the process of becoming a caregiver of elderly patients with cancer, in chemotherapy, in the home context. This is an exploratory study with theoretical and methodological orientation of interpretative anthropology and ethnographic case study. Data were collected from January to September 2009, with four caregivers through semi-structured interviews, observation and consultation records. With data analysis were built four units of meaning. In this paper 'we are focusing the thematic unity "The ressignification of caregiver's life", composed by positive aspects of caregiving activities and of helping to overcome difficulties, such as union, solidarity, opportunity for reapproximation. The difficulties were more evident, especially being unprepared to care at home, which led to changes in the caregiver's familiar and social relationships, resulting in impairment of physical, emotional and social aspects. The nurse, as an agent of care, must provide adequate qualification to the caregivers, helping them in coping with the disease and improving the patient-caregiver-service relationship. PMID- 25517670 TI - [Elderly victims of trauma: preexisting conditions, medications taken at home and indexes of trauma]. AB - The objective was to identify the sociodemographic profile of the elderly victims of trauma, to characterize preexisting conditions and medications taken at home, and to calculate indices of trauma and clinical outcomes. This is a retrospective and exploratory analysis from a database of a general hospital between 2008 and 2010. There were studied 131 elderly, mean age 69.9 years, 73.3% male, 55.1% married, 54.7% retired, 65.6% had preexisting conditions and 48.9% used drugs at home. There was a representative number of falls (31.3%), followed by running over (28.2%), with the head/neck region being the most affected (59.5%). Moderate trauma prevailed (44.3%), with conditions of survival after the event (80.2%). There was an association between mechanism of trauma and preexisting disease (p=0.01) and between mechanism of trauma and sex (p=0.03). The knowledge of the variables involved with the elderly victims of trauma enables healthcare professionals to plan preventive measures aimed at improving the assistance. PMID- 25517671 TI - [Elderlies in street situation or social vulnerability: facilities and difficulties in the use of computational tools]. AB - This study aimed to identify the advantages and difficulties encountered by older people living on the streets or social vulnerability, to use the computer or internet. It is an exploratory qualitative research, in which five elderlies, attended on a non-governmental organization located in the city of Sao Paulo, have participated. The discourses were analyzed by content analysis technique and showed, as facilities, among others, to clarify doubts with the monitors, the stimulus for new discoveries coupled with proactivity and curiosity, and develop new skills. The mentioned difficulties were related to physical or cognitive issues, lack of instructor, and lack of knowledge to interact with the machine. The studies focusing on the elderly population living on the streets or in social vulnerability may contribute with evidence to guide the formulation of public policies to this population. PMID- 25517672 TI - [Long-stay institutions for the elderly: a place of care for those who have no choice?]. AB - This is a descriptive, qualitative research, with comprehensive approach, which aimed to understand the meaning that the longterm institution has to institutionalized elderly. Data were collected with 13 institutionalized elderly in the period from April 5 to May 25, 2013, through narrative interview, and subjected to content analysis, in the form of thematic analysis. The results indicated that being elderly institutionalized means having their care needs met, with respect to their basic needs; access to health services and resources, and to have a place where they can grow old and die. The study concluded that the institution appears as an ambiguous place for the elderly because, even embracing and housing them and meeting their needs, is an environment that prevents the independent and autonomous life. PMID- 25517673 TI - [Experiences and health needs of men in the period post-birth of a child]. AB - This research addresses men's perceptions about their experiences and health needs in the post-birth period. The goal is to distinguish analytically and from a gender perspective the health needs related to the event, experienced, expressed and/or denied by men. This is an exploratory, descriptive and qualitative study carried out in two municipal health areas of Cuiaba, state of Mato Grosso, using a semi structured interview and thematic analysis of the data. The participants were eight men who were experiencing the post-birth period of a child. Above all, they expressed the need to provide financial security to the family, emphasizing also the need of their children's well-being, with the affective return that this experience brings. They did not perceive themselves with health needs during the post-birth period. The support provided by local health services is important so that men can understand the experience of parenthood and its relationship with social and cultural aspects in order to distinguish their own needs, appreciate self-care, and adopt a gender equity perspective. PMID- 25517674 TI - [Maternal perception regarding hospitalized newborns]. AB - Cross-sectional descriptive study conducted in the neonatal unit of a public teaching hospital in the state of Sao Paulo, Brazil, which aimed to determine the perceptions of mothers about their newborns hospitalized children. The sample consisted of 100 women questioned, through the Neonatal Perception Inventory Broussard, about how much trouble was expected to be presented by babies of the general unit, on behaviors such as crying; feeding; regurgitate or vomit; evacuate; sleep and have a routine. Then, the same questions were repeated about their own babies. Ninety mothers considered their children with fewer difficulties than other babies at the unit. Younger women and mothers of infants with higher weights tended to consider their children with more difficulty. The Inventory is easy to apply and may be useful in the evaluation of mother-child interaction, although its result cannot be considered in isolation. PMID- 25517675 TI - [Access to child's health care in primary care services]. AB - It was conducted a qualitative study based on the methodological framework of dialectical hermeneutics, aiming to identify the attribute access from primary care to solve the health problems of children under one year old from the reports of parents and caregivers. Sixteen caregivers of children were involved, all of them seen in the emergency units of Cascavel-PR, in 2010. Four thematic categories were recognized: Family counselling in seeking health care for the child; Absence of reception on the first contact; Presence of risk classification to the child's health attention; Barriers that block the access to health care. It was conclude that, families showed difficulties to reach the solution for their children's health, because of the lack of access to primary care services. PMID- 25517676 TI - [Quality of life of postmenopausal women attended at Primary Health Care]. AB - The experience of menopause is increasingly present, and demand strategies to improve the quality of life of women during this period. This research aimed to evaluate the quality of life for women in the climacteric phase, with or without the use of hormone replacement therapy (HRT). This is a longitudinal epidemiological study of a sample of 99 women per group. It was evaluated the sociodemographic, clinical and behavioral characteristics. It was used the Menopause Rating Scale (MRS) and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). For data analysis, it was used the Student t test, chi square and Tukey. HRT users had an average age of 50.76 +/- 3.63 years, and nonusers of 48.95 +/- 6,27anos (p = 0.01). It was identified a higher frequency of moderate climacteric symptoms of mild intensity. The social aspects evidenced scores below 50 for the two groups. There were differences between groups with respect to the components of the SF-36 and MRS to general health, functional capacity, lower capacity, depression, insomnia and vasomotor phenomena. PMID- 25517677 TI - [Social representations of health education in a time of AIDS]. AB - This is a qualitative and descriptive study, which aimed at identifying and analyzing social representations of health education to HIV patients among health professionals. The setting included three healthcare DST/HIV/AIDS services in Belem-PA, Brazil, and 37 health professionals participated in the study. Data collection was conducted in 2012-2013 on the basis of in-depth interviews and analysis was made on Alceste 4.0 software. Final results indicated that health education can be comprehended in light of categories: educational action; sine qua non: education and training at work, and unit structure; teaching-learning process. Conclusions show that social representations are set as guidance information for precaution-prevention and that they come forth along continuous and emerging action flow, bringing about permanent health education to ensure healthcare services in full. PMID- 25517678 TI - [Autonomy of nursing undergraduate student in the (re)construction of knowledge mediated by problem-based learning]. AB - This is a qualitative study, using the 'Do it yourself' method, which aimed to analyze how Problem-Based Learning (PBL) promotes the development of learner's autonomy in the process of learning to learn. The subjects were 16 students and two tutors involved in the discipline. Data collection techniques combined semi structured interviews, participant observation, log in portfolios, evaluation forms, and audio recording of the tutorials. Data analysis followed interpretation strategies defined by the authors: initial and in depth readings; construction and assembly of meanings' maps; development, description and analysis of empirical categories, in the light of the theoretical framework. The PBL favors the (re)construction of knowledge by the use of prior knowledge and experiences that are shared in small group; through the process of theorization; and by means of relevant knowledge - one that can be applied to practice. We conclude that PBL encourages continuous learning, developing in the student the autonomy in the process of learning to learn. PMID- 25517679 TI - [Effects of nasogastric catheterization in patients with stroke and dysphagia]. AB - This study aimed to analyze the effects of gastric intubation in patients with stroke and dysphagia. A systematic literature review was performed in six databases, using the keywords stroke and intubation, gastrointestinal. One hundred and twenty studies were found, from which three clinical trials were selected. The results showed different outcomes, including: increased serum albumin level (gastrostomy), poor prognosis and risk of death (gastrostomy), increased treatment failures because of blocking, displacement and reinsertion need of the nasogastric tube, and increased incidence of gastrointestinal bleeding (nasogastric tube). From the results obtained in this systematic review, we emphasize the following evidences: a nasogastric catheter should be adopted as a method of early enteral feeding; treatment failures are more common in those who use nasogastric tube-feeding; outcomes related to improved functional status of patients were similar, regardless of the method of nutritional therapy used. PMID- 25517680 TI - [Nutritional damages and disturbances in the sleep pattern of nursing workers]. AB - This article presents an integrative review of national and international scientific publications that investigate the sleep habits, the feed intake and nutritional status of nursing professionals. It was analyzed articles published in national and international journals in the period 2002 to 2014 and made available in the database PubMed / MEDLINE (USA National Library of Medicine), Lilacs / SciELO (Scientific Eletronic Library Online) and Google Scholar. Thirty one articles met the criteria. In the analysis of these studies it has been found a high prevalence of overweight and obesity, a negative change in the eating habits, as well as losses in the sleep patterns of nursing professionals. PMID- 25517682 TI - Twenty natural amino acids identification by a photochromic sensor chip. AB - All 20 natural amino acids identification shows crucial importance in biochemistry and clinical application while it is still a challenge due to highly similarity in molecular configuration of the amino acids. Low efficiency, complicated sensing molecules and environment hindered the successful identification. Here, we developed a facile sensor chip composed of one photochromic molecule with metal ions spotted to form spirooxazine-metallic complexes, and successfully recognized all the 20 natural amino acids as well as their mixtures. The sensor chip gives distinct fluorescent fingerprint pattern of each amino acid, based on multistate of spirooxazine under different light stimulations and discriminated interaction between various metal ions and amino acids. The sensor chip demonstrates powerful capability of amino acids identification, which promotes sensing of biomolecules. PMID- 25517681 TI - Limited in vivo production of type I or type III interferon after infection of macaques with vaccine or wild-type strains of measles virus. AB - The innate immune response to viral infections often includes induction of types I and III interferons (IFNs) and production of antiviral proteins. Measles is a severe virus-induced rash disease, but in vitro studies suggest that in the absence of defective interfering RNAs, neither wild-type (WT) nor vaccine strains of measles virus (MeV) induce IFN. To determine whether IFN is produced in vivo, we studied tissues from macaques infected with vaccine or WT strains of MeV using quantitative reverse transcriptase-polymerase chain reaction to assess levels of IFN and IFN-stimulated gene (ISG) mRNAs and a flow cytometry-based bioassay to assess levels of biologically active IFN. There was little to no induction of type I IFN, type III IFN, Mx, or ISG56 mRNAs in monkeys infected with vaccine or WT MeV and no IFN detection by bioassay. Therefore, the innate responses to infection with vaccine or WT strains of MeV are not dependent on IFN production. PMID- 25517683 TI - Database and registry research in thyroid cancer: striving for a new and improved national thyroid cancer database. AB - BACKGROUND: Health registries have become extremely powerful tools for cancer research. Unfortunately, certain details and the ability to adapt to new information are necessarily limited in current registries, and they cannot address many controversial issues in cancer management. This is of particular concern in differentiated thyroid cancer, which is rapidly increasing in incidence and has many unknowns related to optimal treatment and surveillance recommendations. SUMMARY: In this study, we review different types of health registries used in cancer research in the United States, with a focus on their advantages and disadvantages as related to the study of thyroid cancer. This analysis includes population-based cancer registries, health systems-based cancer registries, and patient-based disease registries. It is important that clinicians understand the way data are collected in, as well as the composition of, these different registries in order to more critically interpret the clinical research that is conducted using that data. In an attempt to address shortcoming of current databases for thyroid cancer, we present the potential of an innovative web-based disease management tool for thyroid cancer called the Thyroid Cancer Care Collaborative (TCCC) to become a patient-based registry that can be used to evaluate and improve the quality of care delivered to patients with thyroid cancer as well as to answer questions that we have not been able to address with current databases and registries. CONCLUSION: A cancer registry that follows a specific patient, is integrated into physician workflow, and collects data across different treatment sites and different payers does not exist in the current fragmented system of healthcare in the United States. The TCCC offers physicians who treat thyroid cancer numerous time-saving and quality improvement services, and could significantly improve patient care. With rapid adoption across the nation, the TCCC could become a new paradigm for database research in thyroid cancer to improve our understanding of thyroid cancer management. PMID- 25517684 TI - The role of the media in agenda setting: the case of long-term care rebalancing. AB - This study investigates the role of print media in state policy agendas in four states-Connecticut, Minnesota, Oregon, and Utah-in rebalancing long-term care away from institutions toward home- and community-based (HCBS) services. Ordinary least squares regression is used to model states' policy agendas, as measured by the proportion of Medicaid long-term care spending on HCBS expenditures and number of rebalancing bills proposed, from 1999 to 2008. Results reveal a relationship between states' rebalancing agendas and the extent of media coverage, and state economic, political, and programmatic characteristics. Findings suggest that media coverage reflects broader shifts in state-level attitudes toward rebalancing. PMID- 25517686 TI - Theoretical studies on the electronic states and liquid structures of ferrocenium based ionic liquids. AB - The solvation effects on the electronic structures and magnetic properties were computed for a series of ferrocenium cations in the ferrocenium-based ionic liquids using RISM-SCF-SEDD calculations coupled with CASSCF. The spin-orbit coupling was calculated to get insight into the spin anisotropy. The values were on the order of 100 cm(-1), exhibiting strong spin anisotropy parallel to the angular momentum. The computed results show that the magnetic properties of the ferrocenium cations are similar both in the isolated state and in ionic liquids. We also carried out molecular dynamics and RISM calculations to investigate the liquid structures. The radial and spatial distribution functions around the cations indicate that the cations are surrounded by about seven TFSA anions above and below the cyclopentadienyl rings and from the side of the ferrocenium cations. The nearest-neighbor cations exist in the oblique directions. The introduction of a butyl group to the ring disturbs the solvation structures, and butyl groups in different cations tend to attract each other like those observed in alkylimidazolium ionic liquids. PMID- 25517687 TI - Entrapment of the superficial peroneal nerve: an anatomical insight. AB - Entrapment of the superficial peroneal nerve is an uncommon neuropathy that may occur because of mechanical compression of the nerve, usually at its exit from the crural fascia. The 2 symptoms include sensory alterations over the distribution area of the superficial peroneal nerve. Clinical examination, electrophysiologic findings, and imaging techniques can establish the diagnosis. Variations in the superficial peroneal sensory innervation over the dorsum of the foot may lead to variable results during neurologic examination and variable symptomatology in patients with nerve entrapment or lesions. Knowledge of the nerve's anatomy at the lower leg, foot, and ankle is of essential significance for the neurologist and surgeon intervening in the area. PMID- 25517685 TI - Determination of essentiality and regulatory function of staphylococcal YeaZ in branched-chain amino acid biosynthesis. AB - The staphylococcal YeaZ is highly conserved in prokaryotic cells and critical for growth of many bacterial pathogens. However, the essentiality for Staphylococcus aureus growth and the biological function of YeaZ behind its essentiality remain undefined. In this study, we created and characterized a defined Pspac-regulated yeaZ expression mutant in S. aureus and demonstrated the indispensability of YeaZ for S. aureus growth. Moreover, we conducted complementation studies, not only confirmed the requirement of YeaZ for S. aureus growth, but also revealed a similarity of essential function between staphylococcal YeaZ and its E. coli homolog. On the other hand, we explored the biological functions of YeaZ and found that YeaZ is involved in the regulation of the transcription of ilv-leu operon that encodes key enzymes responsible for the biosynthesis of the branched chain amino acids, including isoleucine, leucine, and valine (ILV). qPCR analysis showed that the 6-fold downregulation of YeaZ dramatically elevated approximately 17- to 289-fold RNA levels of ilvD, leuA and ilvA. We further confirmed the transcriptional regulation of the ilv-leu operon by YeaZ using an ilv-promoter lux reporter system and gel-shift assays and revealed that YeaZ is able to bind the promoter region of ilv. Furthermore, we established that the regulation of ILV biosynthesis isn't associated with YeaZ's essentiality, as the deletion of the ilv-leu operon did not affect the requirement of YeaZ for growth in culture. Our results demonstrate the essentiality of YeaZ for S. aureus growth and suggest that the staphylococcal YeaZ possesses regulatory function. PMID- 25517688 TI - Enhancement of single particle rare earth doped NaYF4: Yb, Er emission with a gold shell. AB - Upconversion of infrared light to visible light has important implications for bioimaging. However, the small absorption cross-section of rare earth dopants has limited the efficiency of these anti-Stokes nanomaterials. We present enhanced excitation absorption and single particle fluorescent emission of sodium yttrium fluoride, NaYF4: Yb, Er based upconverting nanoparticles coated with a gold nanoshell through surface plasmon resonance. The single gold-shell coated nanoparticles show enhanced absorption in the near infrared, enhanced total emission intensity, and increased green relative to red emission. We also show differences in enhancement between single and aggregated gold shell nanoparticles. The surface plasmon resonance of the gold-shell coated nanoparticle is shown to be dependent on the shell thickness. In contrast to other reported results, our single particle experimental observations are corroborated by finite element calculations that show where the green/red emission enhancement occurs, and what portion of the enhancement is due to electromagnetic effects. We find that the excitation enhancement and green/red emission ratio enhancement occurs at the corners and edges of the doped emissive core. PMID- 25517689 TI - Gamete attachment process revealed in flowering plant fertilization. AB - Sex-possessing organisms perform sexual reproduction, in which gametes from different sexes fuse to produce offspring. In most eukaryotes, one or both sex gametes are motile, and gametes actively approach each other to fuse. However, in flowering plants, the gametes of both sexes lack motility. Two sperm cells (male gametes) that are contained in a pollen grain are recessively delivered via pollen tube elongation. After the pollen tube bursts, sperm cells are released toward the egg and central cells (female gametes) within an ovule ( Fig. 1 ). The precise mechanism of sperm cell movement after the pollen tube bursts remains unknown. Ultimately, one sperm cell fuses with the egg cell and the other one fuses with the central cell, producing an embryo and an endosperm, respectively. Fertilization in which 2 sets of gamete fusion events occur, called double fertilization, has been known for over 100 y. The fact that each morphologically identical sperm cell precisely recognizes its fusion partner strongly suggests that an accurate gamete interaction system(s) exists in flowering plants. PMID- 25517691 TI - Evaluation of multi-resolution satellite sensors for assessing water quality and bottom depth of Lake Garda. AB - In this study we evaluate the capabilities of three satellite sensors for assessing water composition and bottom depth in Lake Garda, Italy. A consistent physics-based processing chain was applied to Moderate Resolution Imaging Spectroradiometer (MODIS), Landsat-8 Operational Land Imager (OLI) and RapidEye. Images gathered on 10 June 2014 were corrected for the atmospheric effects with the 6SV code. The computed remote sensing reflectance (Rrs) from MODIS and OLI were converted into water quality parameters by adopting a spectral inversion procedure based on a bio-optical model calibrated with optical properties of the lake. The same spectral inversion procedure was applied to RapidEye and to OLI data to map bottom depth. In situ measurements of Rrs and of concentrations of water quality parameters collected in five locations were used to evaluate the models. The bottom depth maps from OLI and RapidEye showed similar gradients up to 7 m (r = 0.72). The results indicate that: (1) the spatial and radiometric resolutions of OLI enabled mapping water constituents and bottom properties; (2) MODIS was appropriate for assessing water quality in the pelagic areas at a coarser spatial resolution; and (3) RapidEye had the capability to retrieve bottom depth at high spatial resolution. Future work should evaluate the performance of the three sensors in different bio-optical conditions. PMID- 25517690 TI - Evolution of silver nanoparticles in the rat lung investigated by X-ray absorption spectroscopy. AB - Following a 6-h inhalation exposure to aerosolized 20 and 110 nm diameter silver nanoparticles, lung tissues from rats were investigated with X-ray absorption spectroscopy, which can identify the chemical state of silver species. Lung tissues were processed immediately after sacrifice of the animals at 0, 1, 3, and 7 days post exposure and the samples were stored in an inert and low-temperature environment until measured. We found that it is critical to follow a proper processing, storage and measurement protocol; otherwise only silver oxides are detected after inhalation even for the larger nanoparticles. The results of X-ray absorption spectroscopy measurements taken in air at 85 K suggest that the dominating silver species in all the postexposure lung tissues were metallic silver, not silver oxide, or solvated silver cations. The results further indicate that the silver nanoparticles in the tissues were transformed from the original nanoparticles to other forms of metallic silver nanomaterials and the rate of this transformation depended on the size of the original nanoparticles. We found that 20 nm diameter silver nanoparticles were significantly modified after aerosolization and 6-h inhalation/deposition, whereas larger, 110 nm diameter nanoparticles were largely unchanged. Over the seven-day postexposure period the smaller 20 nm silver nanoparticles underwent less change in the lung tissue than the larger 110 nm silver nanoparticles. In contrast, silica-coated gold nanoparticles did not undergo any modification processes and remained as the initial nanoparticles throughout the 7-day study period. PMID- 25517692 TI - An analog gamma correction scheme for high dynamic range CMOS logarithmic image sensors. AB - In this paper, a novel analog gamma correction scheme with a logarithmic image sensor dedicated to minimize the quantization noise of the high dynamic applications is presented. The proposed implementation exploits a non-linear voltage-controlled-oscillator (VCO) based analog-to-digital converter (ADC) to perform the gamma correction during the analog-to-digital conversion. As a result, the quantization noise does not increase while the same high dynamic range of logarithmic image sensor is preserved. Moreover, by combining the gamma correction with the analog-to-digital conversion, the silicon area and overall power consumption can be greatly reduced. The proposed gamma correction scheme is validated by the reported simulation results and the experimental results measured for our designed test structure, which is fabricated with 0.35 MUm standard complementary-metal-oxide-semiconductor (CMOS) process. PMID- 25517693 TI - A pyridine-containing Cu2+-selective probe based on naphthalimide derivative. AB - A new fluorescent probe P derived from naphthalimide bearing a pyridine group has been synthesized and characterized. The proposed probe P shows high selectivity and sensitivity to Cu2+ in aqueous media. Under optimized conditions, the linear response of P (2 MUM) toward Cu2+ was 0.05-0.9 MUM in ethanol-water solution (3:2, v:v, 50 mM HEPES, pH 7.4), and the detection limit was 0.03 MUM. PMID- 25517694 TI - Recognizing objects in 3D point clouds with multi-scale local features. AB - Recognizing 3D objects from point clouds in the presence of significant clutter and occlusion is a highly challenging task. In this paper, we present a coarse-to fine 3D object recognition algorithm. During the phase of offline training, each model is represented with a set of multi-scale local surface features. During the phase of online recognition, a set of keypoints are first detected from each scene. The local surfaces around these keypoints are further encoded with multi scale feature descriptors. These scene features are then matched against all model features to generate recognition hypotheses, which include model hypotheses and pose hypotheses. Finally, these hypotheses are verified to produce recognition results. The proposed algorithm was tested on two standard datasets, with rigorous comparisons to the state-of-the-art algorithms. Experimental results show that our algorithm was fully automatic and highly effective. It was also very robust to occlusion and clutter. It achieved the best recognition performance on all of these datasets, showing its superiority compared to existing algorithms. PMID- 25517695 TI - Assessment of a newly developed, active pneumatic-driven, sensorimotor test and training device. AB - The sensorimotor system (SMS) plays an important role in sports and in every day movement. Several tools for assessment and training have been designed. Many of them are directed to specific populations, and have major shortcomings due to the training effect or safety. The aim of the present study was to design and assess a dynamic sensorimotor test and training device that can be adjusted for all levels of performance. The novel pneumatic-driven mechatronic device can guide the trainee, allow independent movements or disrupt the individual with unpredicted perturbations while standing on a platform. The test-reliability was evaluated using intraclass correlation coefficient (ICC). Subjects were required to balance their center of pressure (COP) in a target circle (TITC). The time in TITC and the COP error (COPe) were recorded for analysis. The results of 22 males and 14 females (23.7 +/- 2.6 years) showed good to excellent test-retest reliability. The newly designed Active Balance System (ABS) was then compared with the Biodex Balance System SD(r) (BBS). The results of 15 females, 14 males (23.4 +/- 1.6 years) showed modest correlation in static and acceptable correlation in dynamic conditions, suggesting that ABS could be a reliable and comparable tool for dynamic balance assessments. PMID- 25517698 TI - Quality improvement, patient safety, and continuing education: a qualitative study of the current boundaries and opportunities for collaboration between these domains. AB - PURPOSE: Quality improvement/patient safety (QI/PS) and continuing education (CE) efforts have a common aim to improve health care outcomes. Yet, minimal collaboration occurs between them. This lack of integration can be problematic given the finite resources available and the potential value of approaching health care challenges from different perspectives. The authors conducted an exploratory study to understand Canadian leaders' perceptions and experiences with both their own and the other domain, with the aim of increasing their understanding of the boundaries and opportunities for collaborative approaches to improving health care. METHOD: The authors conducted this study in 2011-2012 using a qualitative interpretivist framework to guide the collection and analysis of data from semistructured interviews. They used criterion-based, maximum variation, and snowball sampling to select 15 leaders from the domains of QI/PS and CE to interview. They transcribed verbatim the interviews and coded the transcripts using a directed content analysis approach. RESULTS: Participants described the relationship between QI/PS and CE in four ways: (1) the separation of QI/PS and CE as distinct interventions, (2) (re)positioning CE in QI/PS activities, (3) (re)positioning QI/PS in CE activities, and (4) further integrating QI/PS and CE. CONCLUSIONS: These findings have important implications for how leaders in QI/PS and CE should mindfully and strategically negotiate their relationship to ensure the relevance and effectiveness of their domain's activities. PMID- 25517697 TI - Individual differences in cyber security behaviors: an examination of who is sharing passwords. AB - In spite of the number of public advice campaigns, researchers have found that individuals still engage in risky password practices. There is a dearth of research available on individual differences in cyber security behaviors. This study focused on the risky practice of sharing passwords. As predicted, we found that individuals who scored high on a lack of perseverance were more likely to share passwords. Contrary to our hypotheses, we found younger [corrected] people and individuals who score high on self-monitoring were more likely to share passwords. We speculate on the reasons behind these findings, and examine how they might be considered in future cyber security educational campaigns. PMID- 25517699 TI - Creating a high-reliability health care system: improving performance on core processes of care at Johns Hopkins Medicine. AB - In this article, the authors describe an initiative that established an infrastructure to manage quality and safety efforts throughout a complex health care system and that improved performance on core measures for acute myocardial infarction, heart failure, pneumonia, surgical care, and children's asthma. The Johns Hopkins Medicine Board of Trustees created a governance structure to establish health care system-wide oversight and hospital accountability for quality and safety efforts throughout Johns Hopkins Medicine. The Armstrong Institute for Patient Safety and Quality was formed; institute leaders used a conceptual model nested in a fractal infrastructure to implement this initiative to improve performance at two academic medical centers and three community hospitals, starting in March 2012. The initiative aimed to achieve >= 96% compliance on seven inpatient process-of-care core measures and meet the requirements for the Delmarva Foundation and Joint Commission awards. The primary outcome measure was the percentage of patients at each hospital who received the recommended process of care. The authors compared health system and hospital performance before (2011) and after (2012, 2013) the initiative. The health system achieved >= 96% compliance on six of the seven targeted measures by 2013. Of the five hospitals, four received the Delmarva Foundation award and two received The Joint Commission award in 2013. The authors argue that, to improve quality and safety, health care systems should establish a system-wide governance structure and accountability process. They also should define and communicate goals and measures and build an infrastructure to support peer learning. PMID- 25517696 TI - Ferrets exclusively synthesize Neu5Ac and express naturally humanized influenza A virus receptors. AB - Mammals express the sialic acids N-acetylneuraminic acid (Neu5Ac) and N glycolylneuraminic acid (Neu5Gc) on cell surfaces, where they act as receptors for pathogens, including influenza A virus (IAV). Neu5Gc is synthesized from Neu5Ac by the enzyme cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH). In humans, this enzyme is inactive and only Neu5Ac is produced. Ferrets are susceptible to human-adapted IAV strains and have been the dominant animal model for IAV studies. Here we show that ferrets, like humans, do not synthesize Neu5Gc. Genomic analysis reveals an ancient, nine-exon deletion in the ferret CMAH gene that is shared by the Pinnipedia and Musteloidia members of the Carnivora. Interactions between two human strains of IAV with the sialyllactose receptor (sialic acid--alpha2,6Gal) confirm that the type of terminal sialic acid contributes significantly to IAV receptor specificity. Our results indicate that exclusive expression of Neu5Ac contributes to the susceptibility of ferrets to human-adapted IAV strains. PMID- 25517700 TI - Differences between attendings' and fellows' perceptions of futile treatment in the intensive care unit at one academic health center: implications for training. AB - PURPOSE: Knowing when patients are too ill to benefit from intensive care is essential for clinicians to recommend aggressive or palliative care as appropriate. To explore prognostic ability among critical care fellows, the authors compared fellows' and attendings' assessments of futile critical care and evaluated factors associated with assessments. METHOD: Thirty-six attendings and 14 fellows in intensive care units at the University of California, Los Angeles, were surveyed daily for three months (December 2011-March 2012) to identify patients perceived as receiving futile treatment. Frequency of futile treatment assessments and reasons listed by attendings versus fellows were compared. Predictors of futile treatment assessments by provider type were assessed using multivariate probit models. RESULTS: Attendings made 6,897 assessments on 1,125 patients; fellows made 4,407 assessments on 773 patients. Fellows assessed 161 (20.8%) patients as receiving futile treatment, compared with attendings (123 [10.9%] patients, P<.001), and listed fewer reasons that treatment was futile (P<.001). Fellows were more likely to assess a patient as receiving futile treatment by the second day, whereas attendings took four days. Patients assessed as receiving futile treatment by fellows were less likely than patients so assessed by attendings to die in the hospital (51% versus 68%, P=.003) and within six months (62% versus 85%, P<.001). CONCLUSIONS: Fellows made earlier assessments and judged more patients to be receiving futile treatment than attendings, and their assessments were less predictive of mortality, suggesting that assessment of treatment appropriateness develops with experience. PMID- 25517701 TI - Residents' views of the role of classroom-based learning in graduate medical education through the lens of academic half days. AB - PURPOSE: To examine the role of classroom-based learning in graduate medical education through the lens of academic half days (AHDs) by exploring residents' perceptions of AHDs' purpose and relevance and the effectiveness of teaching and learning in AHDs. METHOD: The authors invited a total of 186 residents in three programs (internal medicine, orthopedic surgery, and hematology) at the University of British Columbia Faculty of Medicine to participate in semistructured focus groups from October 2010 to February 2011. Verbatim transcripts of the interviews underwent inductive analysis. RESULTS: Twenty-seven residents across the three programs volunteered to participate. Two major findings emerged. Purpose and relevance of AHDs: Residents believed that AHDs are primarily for knowledge acquisition and should complement clinical learning. Classroom learning facilitated consolidation of clinical experiences with expert clinical reasoning. Social aspects of AHDs were highly valued as an important secondary purpose. Perceived effectiveness of teaching and learning: Case-based teaching engaged residents in critical thinking; active learning was valued. Knowledge retention was considered suboptimal. Perspectives on the concept of AHDs as "protected time" varied in the three programs. CONCLUSIONS: Findings suggest that (1) engagement in classroom learning occurs through participation in clinically oriented discussions that highlight expert reasoning processes; (2) formal classroom teaching, which focuses on knowledge acquisition, can enhance informal learning occurring during clinical activity; and (3) social aspects of AHDs, including their role in creating communities of practice in residency programs and in professional identity formation, are an important, underappreciated asset for residency programs. PMID- 25517702 TI - Disruptive innovation in academic medical centers: balancing accountable and academic care. AB - Numerous academic medicine leaders have argued that academic referral centers must prepare for the growing importance of accountability-driven payment models by adopting population health initiatives. Although this shift has merit, execution of this strategy will prove significantly more problematic than most observers have appreciated. The authors describe how successful implementation of an accountable care health strategy within a referral academic medical center (AMC) requires navigating a critical tension: The academic referral business model, driven by tertiary-level care, is fundamentally in conflict with population health. Referral AMCs that create successful value-driven population health systems within their organizations will in effect disrupt their own existing tertiary care businesses. The theory of disruptive innovation suggests that balancing the push and pull of academic and accountable care within a single organization is achievable. However, it will require significant shifts in resource allocation and changes in management structure to enable AMCs to make the inherent difficult choices and trade-offs that will ensue. On the basis of the theories of disruptive innovation, the authors present recommendations for how academic health systems can successfully navigate these issues as they transition toward accountability-driven care. PMID- 25517703 TI - Septris: a novel, mobile, online, simulation game that improves sepsis recognition and management. AB - PROBLEM: Annually affecting over 18 million people worldwide, sepsis is common, deadly, and costly. Despite significant effort by the Surviving Sepsis Campaign and other initiatives, sepsis remains underrecognized and undertreated. APPROACH: Research indicates that educating providers may improve sepsis diagnosis and treatment; thus, the Stanford School of Medicine has developed a mobile accessible, case-based, online game entitled Septris (http://med.stanford.edu/septris/). Septris, launched online worldwide in December 2011, takes an innovative approach to teaching early sepsis identification and evidence-based management. The free gaming platform leverages the massive expansion over the past decade of smartphones and the popularity of noneducational gaming.The authors sought to assess the game's dissemination and its impact on learners' sepsis-related knowledge, skills, and attitudes. In 2012, the authors trained Stanford pregraduate (clerkship) and postgraduate (resident) medical learners (n = 156) in sepsis diagnosis and evidence-based practices via 20 minutes of self-directed game play with Septris. The authors administered pre- and posttests. OUTCOMES: By October 2014, Septris garnered over 61,000 visits worldwide. After playing Septris, both pre- and postgraduate groups improved their knowledge on written testing in recognizing and managing sepsis (P < .001). Retrospective self-reporting on their ability to identify and manage sepsis also improved (P < .001). Over 85% of learners reported that they would or would maybe recommend Septris. NEXT STEPS: Future evaluation of Septris should assess its effectiveness among different providers, resource settings, and cultures; generate information about how different learners make clinical decisions; and evaluate the correlation of game scores with sepsis knowledge. PMID- 25517704 TI - Hydrogen bond rotations as a uniform structural tool for analyzing protein architecture. AB - Proteins fold into three-dimensional structures, which determine their diverse functions. The conformation of the backbone of each structure is locally at each C(alpha) effectively described by conformational angles resulting in Ramachandran plots. These, however, do not describe the conformations around hydrogen bonds, which can be non-local along the backbone and are of major importance for protein structure. Here, we introduce the spatial rotation between hydrogen bonded peptide planes as a new descriptor for protein structure locally around a hydrogen bond. Strikingly, this rotational descriptor sampled over high-quality structures from the protein data base (PDB) concentrates into 30 localized clusters, some of which correlate to the common secondary structures and others to more special motifs, yet generally providing a unifying systematic classification of local structure around protein hydrogen bonds. It further provides a uniform vocabulary for comparison of protein structure near hydrogen bonds even between bonds in different proteins without alignment. PMID- 25517705 TI - Medicaid payments and access to care. PMID- 25517707 TI - Clinical practice. Acute pericarditis. PMID- 25517706 TI - Cytisine versus nicotine for smoking cessation. AB - BACKGROUND: Placebo-controlled trials indicate that cytisine, a partial agonist that binds the nicotinic acetylcholine receptor and is used for smoking cessation, almost doubles the chances of quitting at 6 months. We investigated whether cytisine was at least as effective as nicotine-replacement therapy in helping smokers to quit. METHODS: We conducted a pragmatic, open-label, noninferiority trial in New Zealand in which 1310 adult daily smokers who were motivated to quit and called the national quitline were randomly assigned in a 1:1 ratio to receive cytisine for 25 days or nicotine-replacement therapy for 8 weeks. Cytisine was provided by mail, free of charge, and nicotine-replacement therapy was provided through vouchers for low-cost patches along with gum or lozenges. Low-intensity, telephone-delivered behavioral support was provided to both groups through the quitline. The primary outcome was self-reported continuous abstinence at 1 month. RESULTS: At 1 month, continuous abstinence from smoking was reported for 40% of participants receiving cytisine (264 of 655) and 31% of participants receiving nicotine-replacement therapy (203 of 655), for a difference of 9.3 percentage points (95% confidence interval, 4.2 to 14.5). The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months. In a prespecified subgroup analysis of the primary outcome, cytisine was superior to nicotine replacement therapy among women and noninferior among men. Self-reported adverse events over 6 months occurred more frequently in the cytisine group (288 events among 204 participants) than in the group receiving nicotine-replacement therapy (174 events among 134 participants); adverse events were primarily nausea and vomiting and sleep disorders. CONCLUSIONS: When combined with brief behavioral support, cytisine was found to be superior to nicotine-replacement therapy in helping smokers quit smoking, but it was associated with a higher frequency of self-reported adverse events. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12610000590066.). PMID- 25517708 TI - Images in clinical medicine. Saber tibia in Paget's disease of bone. PMID- 25517709 TI - Case records of the Massachusetts General Hospital. Case 39-2014. A 9-year-old girl with Crohn's disease and pulmonary nodules. PMID- 25517710 TI - Cytisine--a tobacco treatment hiding in plain sight. PMID- 25517711 TI - Glucocorticoids and mepolizumab in eosinophilic asthma. PMID- 25517712 TI - Glucocorticoids and mepolizumab in eosinophilic asthma. PMID- 25517713 TI - Glucocorticoids and mepolizumab in eosinophilic asthma. PMID- 25517714 TI - Multidrug-resistant tuberculosis and bedaquiline. PMID- 25517715 TI - Multidrug-resistant tuberculosis and bedaquiline. PMID- 25517716 TI - Ivabradine in stable coronary artery disease. PMID- 25517717 TI - Ivabradine in stable coronary artery disease. PMID- 25517718 TI - Ethical challenges in treating friends and family. PMID- 25517719 TI - Ethical challenges in treating friends and family. PMID- 25517720 TI - More on shift of HIV tropism in stem-cell transplantation with CCR5 delta32/delta32 mutation. PMID- 25517721 TI - More on shift of HIV tropism in stem-cell transplantation with CCR5 delta32/delta32 mutation. PMID- 25517722 TI - Images in clinical medicine. Patulous eustachian tube causing hypermobile eardrums. PMID- 25517723 TI - Optimal time for early laparoscopic cholecystectomy for acute cholecystitis. AB - IMPORTANCE: There is growing evidence in support of performing early laparoscopic cholecystectomy (LC) for acute cholecystitis. However, the definition of early LC varies from 0 through 10 days depending on the research protocol. The optimum time to perform early LC is still unclear. OBJECTIVES: To determine whether outcomes after early LC for acute cholecystitis vary depending on time from presentation to surgery and to determine the optimum time to perform LC for acute cholecystitis. DESIGN, SETTING, AND PARTICIPANTS: We performed a retrospective review of prospectively collected data from the Nationwide Inpatient Sample (NIS) for 2005 through 2009. The population-based sample included 95,523 adults (18 years and older) who underwent LC within 10 days of presentation for acute cholecystitis. INTERVENTIONS: Patients were categorized and analyzed in 2 ways based on length of time from presentation to surgery. First, patients were categorized into 3 groups: 0 through 1 day, 2 through 5 days, and 6 through 10 days. Second, we compared outcomes for each incremental preoperative day (days 0 5). MAIN OUTCOMES AND MEASURES: Outcomes of interest were mortality, length of stay, complications, and cost. Propensity score matching and generalized linear modeling were used. The hypothesis being tested was formulated after data collection was complete. RESULTS: A total of 95,523 patients were selected. After matching the 3 groups based on propensity scores, patients who underwent surgery during days 2 through 5 and days 6 through 10 had increasingly worse outcomes when compared with those undergoing surgery on days 0 through 1. The odds of mortality were 1.26 (95% CI, 1.00-1.58) and 1.93 (95% CI, 1.38-2.68), and the odds of postoperative infections were 0.88 (95% CI, 0.69-1.12) and 1.53 (95% CI, 1.05-2.23) for days 2 through 5 and days 6 through 10, respectively. Adjusted mean hospital cost increased from $8974 (days 0-1) to $17,745 (days 6-10). Analysis by each incremental day revealed the optimal time of surgery to be within the first 48 hours of presentation. CONCLUSIONS AND RELEVANCE: Laparoscopic cholecystectomy performed within 2 days of presentation of acute cholecystitis yielded the best outcomes and lowest costs. Although causality could not be established, delaying LC was associated with more complications, higher mortality, and higher costs. PMID- 25517724 TI - A long isoform of the epithelial sodium channel alpha subunit forms a highly active channel. AB - A long isoform of the human Epithelial Sodium Channel (ENaC) alpha subunit has been identified, but little data exist regarding the properties or regulation of channels formed by alpha728. The baseline whole cell conductance of oocytes expressing trimeric alpha728betagamma channels was 898.1+/-277.2 and 49.59+/-13.2 uS in low and high sodium solutions, respectively, and was 11 and 2 fold higher than the conductances of alpha669betagamma in same solutions. alpha728betagamma channels were also 2 to 5 fold less sensitive to activation by the serine proteases subtilisin and trypsin than alpha669betagamma in low and high Na+ conditions. The long isoform exhibited lower levels of full length and cleaved protein at the plasma membrane and a rightward shifted sensitivity to inhibition by increases of [Na+]i. Both channels displayed similar single channel conductances of 4 pS, and both were activated to a similar extent by reducing temperature, altogether indicating that activation of baseline conductance of alpha728betagamma was likely mediated by enhanced channel activity or open probability. Expression of alpha728 in native kidneys was validated in human urinary exosomes. These data demonstrate that the long isoform of alphaENaC forms the structural basis of a channel with different activity and regulation, which may not be easily distinguishable in native tissue, but may underlie sodium hyperabsorption and salt sensitive differences in humans. PMID- 25517726 TI - Range of movement in ray I of manus and pes and the prehensility of the autopodia in the Early Permian to Late Cretaceous non-anomodont Synapsida. AB - The mobility of ray I was analysed in seventy-eight Early Permian to Late Cretaceous specimens of non-mammalian Synapsida and one extant mammal. In all non mammaliamorph Synapsida investigated, ray I formed a digital arcade. The first phalanx was maximally extendable to the zero position in the metapodiophalangeal joint I. Metapodiale I was the functional equivalent to a basal phalanx of digits II-V. In contrast, there was no digital arcade in ray I in Mesozoic Mammaliamorpha. Phalanx 1 I was dorsally extendable and metapodiale I was functionally part of the metapodium. During the propulsion phase, autopodial rotation occurred in the majority of Synapsida with abducted limb posture. Regarding ray I, the reduction of autopodial rotation can be estimated, e.g., from the decrease of lateral rotation and medial abduction of the first phalanx in the metapodiophalangeal joint I. Autopodial rotation was high in Titanophoneus and reduced in derived Cynodontia. In Mammaliamorpha the mobility of the first ray suggests autopodial rolling in an approximately anterior direction. Most non mammaliamorph Therapsida and probably some Mesozoic Mammaliamorpha had prehensile autopodia with an opposable ray I. In forms with a pronounced relief of the respective joints, ray I could be opposed to 90 degrees against ray III. A strong transverse arch in the row of distalia supported the opposition movement of ray I and resulted in a convergence of the claws of digits II-V just by flexing those digits. A tight articular coherence in the digital joints of digits II-V during strong flexion supported a firm grip capacity. Usually the grip capacity was more pronounced in the manus than in the pes. Prehensile autopodia of carnivorous Therapsida may have been utilized to hold prey while biting, thus helping to avoid fractures of the laterally compressed fangs. PMID- 25517725 TI - Susceptibility of human embryonic stem cell-derived neural cells to Japanese encephalitis virus infection. AB - Pluripotent human embryonic stem cells (hESCs) can be efficiently directed to become immature neuroepithelial precursor cells (NPCs) and functional mature neural cells, including neurotransmitter-secreting neurons and glial cells. Investigating the susceptibility of these hESCs-derived neural cells to neurotrophic viruses, such as Japanese encephalitis virus (JEV), provides insight into the viral cell tropism in the infected human brain. We demonstrate that hESC derived NPCs are highly vulnerable to JEV infection at a low multiplicity of infection (MOI). In addition, glial fibrillary acid protein (GFAP)-expressing glial cells are also susceptible to JEV infection. In contrast, only a few mature neurons were infected at MOI 10 or higher on the third day post-infection. In addition, functional neurotransmitter-secreting neurons are also resistant to JEV infection at high MOI. Moreover, we discover that vimentin intermediate filament, reported as a putative neurovirulent JEV receptor, is highly expressed in NPCs and glial cells, but not mature neurons. These results indicate that the expression of vimentin in neural cells correlates to the cell tropism of JEV. Finally, we further demonstrate that membranous vimentin is necessary for the susceptibility of hESC-derived NPCs to JEV infection. PMID- 25517727 TI - Whole-body insulin sensitivity rather than body-mass-index determines fasting and post-glucose-load growth hormone concentrations. AB - BACKGROUND: Obese, non-acromegalic persons show lower growth hormone (GH) concentrations at fasting and reduced GH nadir during an oral glucose tolerance test (OGTT). However, this finding has never been studied with regard to whole body insulin-sensitivity as a possible regulator. METHODS: In this retrospective analysis, non-acromegalic (NonACRO, n = 161) and acromegalic (ACRO, n = 35), non diabetic subjects were subdivided into insulin-sensitive (IS) and -resistant (IR) groups according to the Clamp-like Index (CLIX)-threshold of 5 mg . kg(-1) . min( 1) from the OGTT. RESULTS: Non-acromegalic IS (CLIX: 8.8 +/- 0.4 mg . kg(-1) . min(-1)) persons with similar age and sex distribution, but lower (p < 0.001) body-mass-index (BMI = 25 +/- 0 kg/m2, 84% females, 56 +/- 1 years) had 59% and 70%, respectively, higher (p < 0.03) fasting GH and OGTT GH area under the curve concentrations than IR (CLIX: 3.5 +/- 0.1 mg . kg(-1) . min(-1), p < 0.001) subjects (BMI = 29 +/- 1 kg/m2, 73% females, 58 +/- 1 years). When comparing on average overweight non-acromegalic IS and IR with similar anthropometry (IS: BMI: 27 +/- 0 kg/m2, 82% females, 58 +/- 2 years; IR: BMI: 27 +/- 0 kg/m2, 71% females, 60 +/- 1 years), but different CLIX (IS: 8.7 +/- 0.9 vs. IR: 3.8 +/- 0.1 mg . kg(-1) . min(-1), p < 0.001), the results remained almost the same. In addition, when adjusted for OGTT-mediated glucose rise, GH fall was less pronounced in IR. In contrast, in acromegalic subjects, no difference was found between IS and IR patients with regard to fasting and post-glucose-load GH concentrations. CONCLUSIONS: Circulating GH concentrations at fasting and during the OGTT are lower in non-acromegalic insulin-resistant subjects. This study seems the first to demonstrate that insulin sensitivity rather than body-mass modulates fasting and post-glucose-load GH concentrations in non-diabetic non acromegalic subjects. PMID- 25517728 TI - Identification and genetic characterization of unique HIV-1 A1/C recombinant strain in South Africa. AB - HIV isolates from South Africa are predominantly subtype C. Sporadic isolation of non-C strains has been reported mainly in cosmopolitan cities. HIV isolate j51 was recovered from a rural South African heterosexual female aged 51 years. Near full length amplification of the genome was attempted using PCR with primers targeting overlapping segments of the HIV genome. Analysis of 5593 bp (gag to vpu) at a bootstrap value greater than 70% found that all but the vpu gene was HIV-1 subtype A1. The vpu gene was assigned HIV-1 subtype C. The recombination breaking point was estimated at position 6035+/- 15 bp with reference to the beginning of the HXB2 reference strain. Isolate j51 revealed a unique genome constellation to previously reported recombinant strains with parental A/C backbones from South Africa though a common recombination with subtype C within the vpu gene. Identification of recombinant strains supports continued surveillance of HIV genetic diversity. PMID- 25517729 TI - Does the current fungicide risk assessment provide sufficient protection for key drivers in aquatic ecosystem functioning? AB - The level of protection provided by the present environmental risk assessment (ERA) of fungicides in the European Union for fungi is unknown. Therefore, we assessed the structural and functional implications of five fungicides with different modes of action (azoxystrobin, carbendazim, cyprodinil, quinoxyfen, and tebuconazole) individually and in mixture on communities of aquatic hyphomycetes. This is a polyphyletic group of fungi containing key drivers in the breakdown of leaf litter, governing both microbial leaf decomposition and the palatability of leaves for leaf-shredding macroinvertebrates. All fungicides impaired leaf palatability to the leaf-shredder Gammarus fossarum and caused structural changes in fungal communities. In addition, all compounds except for quinoxyfen altered microbial leaf decomposition. Our results suggest that the European Union's first tier ERA provides sufficient protection for the tested fungicides, with the exception of tebuconazole and the mixture, while higher-tier ERA does not provide an adequate level of protection for fungicides in general. Therefore, our results show the need to incorporate aquatic fungi as well as their functions into ERA testing schemes to safeguard the integrity of aquatic ecosystems. PMID- 25517730 TI - Intestinal NADPH oxidase 2 activity increases in a neonatal rat model of necrotizing enterocolitis. AB - Necrotizing enterocolitis (NEC) is a complication of prematurity. The etiology is unknown, but is related to enteral feeding, ischemia, infection, and inflammation. Reactive oxygen species production, most notably superoxide, increases in NEC. NADPH oxidase (NOX) generates superoxide, but its activity in NEC remains unknown. We hypothesize that NOX-derived superoxide production increases in NEC. Newborn Sprague-Dawley rats were divided into control, formula fed, formula/LPS, formula/hypoxia, and NEC (formula, hypoxia, and LPS). Intestinal homogenates were analyzed for NADPH-dependent superoxide production. Changes in superoxide levels on days 0-4 were measured. Inhibitors for nitric oxide synthase (L-NAME) and NOX2 (GP91-ds-tat) were utilized. RT-PCR for eNOS, NOX1, GP91phox expression was performed. Immunofluorescence studies estimated the co-localization of p47phox and GP91phox in control and NEC animals on D1, D2, and D4. NEC pups generated more superoxide than controls on D4, while all other groups were unchanged. NADPH-dependent superoxide production was greater in NEC on days 0, 3, and 4. GP91-ds-tat decreased superoxide production in both groups, with greater inhibition in NEC. L-NAME did not alter superoxide production. Temporally, superoxide production varied minimally in controls. In NEC, superoxide generation was decreased on day 1, but increased on days 3-4. GP91phox expression was higher in NEC on days 2 and 4. NOX1 and eNOS expression were unchanged from controls. GP91phox and p47phox had minimal co-localization in all control samples and NEC samples on D1 and D2, but had increased co-localization on D4. In conclusion, this study proves that experimentally-induced NEC increases small intestinal NOX activity. All components of NEC model are necessary for increased NOX activity. NOX2 is the major source, especially as the disease progresses. PMID- 25517732 TI - Molecular epidemiology of carbapenem non-susceptible Acinetobacter baumannii in France. AB - Carbapenem-resistant Acinetobacter baumannii have emerged globally. The objective of this study was to investigate the epidemiology, clonal diversity and resistance mechanisms of imipenem non-susceptible A. baumannii isolates in France. Between December 2010 and August 2011, 132 notifications were collected, including 37 outbreaks corresponding to 242 cases (2 to 55 per cluster). Multilocus sequence typing, pulsed-field gel electrophoresis (PFGE) and characterisation of carbapenemase-encoding genes were performed on 110 non repetitive isolates. Gene blaOXA-23 was the most frequently detected (82%), followed by blaOXA-24 (11%) and blaOXA-58 (7%). Eleven sequence types (ST) were distinguished, among which sequence types ST1, ST2 (64%), ST20, ST25, ST85 and ST107. Isolates from epidemiological clusters had the same ST and resistance genes, indicating probable transmission within centres. In contrast, PFGE types of isolates differed among centres, arguing against transmission among centers. This study provides the first epidemiological snapshot of the population of A. baumannii with reduced susceptibility to carbapenems from France, and further underlines the predominance of international clones. PMID- 25517731 TI - Interleukin-15 modulates adipose tissue by altering mitochondrial mass and activity. AB - Interleukin-15 (IL-15) is an immunomodulatory cytokine that affects body mass regulation independent of lymphocytes; however, the underlying mechanism(s) involved remains unknown. In an effort to investigate these mechanisms, we performed metabolic cage studies, assessed intestinal bacterial diversity and macronutrient absorption, and examined adipose mitochondrial activity in cultured adipocytes and in lean IL-15 transgenic (IL-15tg), overweight IL-15 deficient (IL 15-/-), and control C57Bl/6 (B6) mice. Here we show that differences in body weight are not the result of differential activity level, food intake, or respiratory exchange ratio. Although intestinal microbiota differences between obese and lean individuals are known to impact macronutrient absorption, differing gut bacteria profiles in these murine strains does not translate to differences in body weight in colonized germ free animals and macronutrient absorption. Due to its contribution to body weight variation, we examined mitochondrial factors and found that IL-15 treatment in cultured adipocytes resulted in increased mitochondrial membrane potential and decreased lipid deposition. Lastly, IL-15tg mice have significantly elevated mitochondrial activity and mass in adipose tissue compared to B6 and IL-15-/- mice. Altogether, these results suggest that IL-15 is involved in adipose tissue regulation and linked to altered mitochondrial function. PMID- 25517734 TI - Examining risk and resilience factors for depression: The role of self-criticism and self-compassion. AB - Whereas self-criticism has been proposed as an important risk factor for major depressive disorder (MDD), self-compassion has been suggested as a resilience factor that protects against the development and maintenance of depressive episodes. This study aimed to test the hypothesis that frequent self-criticism and low habitual self-compassion are related to concurrent depression and to vulnerability to depression by comparing groups of currently, remitted and never depressed individuals. As expected, both currently and remitted depressed individuals reported higher levels of self-criticism and lower self-compassion than never depressed controls. Individual differences in self-criticism and self compassion were related to depression status above and beyond additional potential correlates of MDD (i.e., perfectionistic beliefs and cognitions, rumination and overall adaptive emotion regulation). The findings provide support for the idea that increased self-criticism and decreased self-compassion place certain individuals at increased risk for experiencing depression repeatedly or chronically over the course of their lives. PMID- 25517733 TI - Therapeutic vaccination with TNF-Kinoid in TNF antagonist-resistant rheumatoid arthritis: a phase II randomized, controlled clinical trial. AB - OBJECTIVES: Active immunization, or vaccination, with tumor necrosis factor (TNF) Kinoid (TNF-K) is a novel approach to induce polyclonal anti-TNF antibodies in immune-mediated inflammatory diseases. This study was performed to transfer the proof of concept obtained in mice model of rheumatoid arthritis (RA) into human. We designed a pilot study to demonstrate the feasibility of therapeutic vaccination in RA. METHODS: This was a phase IIa, placebo-controlled, multicenter study in adults with RA who previously experienced secondary failure of TNF antagonists. Patients were immunized intramuscularly with 2 or 3 doses of placebo (n = 10) or 90 (n = 6), 180 (n = 12), or 360 ug TNF-K (n = 12). The primary objective was to identify the best dose and schedule based on anti-TNF antibody titers. Clinical symptoms and safety were assessed during 12 months and solicited reactions for 7 days after each injection. RESULTS: The highest anti-TNF antibody response was detected in patients immunized with 360 ug TNF-K and with 3 injections, although this difference was not significant with all other groups. Similar proportions of patients receiving TNF-K and placebo reported adverse events up to month 12. Serious adverse events were reported by 4 patients treated with TNF-K (13.3%) and 3 treated with placebo (30.0%), all unrelated to treatment. At month 12, DAS28-CRP, tender and swollen joint counts, and HAQ scores decreased significantly more in patients who exhibited anti-TNF antibody response than in patients who did not. CONCLUSIONS: TNF-K therapeutic vaccination induced dose- and schedule-dependent anti-TNF antibodies in RA patients and was well tolerated. Patients who developed anti-TNF antibodies showed a trend toward clinical improvement. Although the most aggressive dose and schedule, i.e. 360 mg dose administered 3 times, did show a strong trend of higher antibody response, further studies are warranted to examine even higher and more frequent doses in order to establish the best conditions for clinical improvement. TRIAL REGISTRATION: ClinicalTrials.gov NCT01040715. PMID- 25517736 TI - Development and psychometric evaluation of an information literacy self-efficacy survey and an information literacy knowledge test. AB - OBJECTIVE: To develop and psychometrically evaluate an information literacy (IL) self-efficacy survey and an IL knowledge test. METHODS: In this test-retest reliability study, a 25-item IL self-efficacy survey and a 50-item IL knowledge test were developed and administered to a convenience sample of 53 chiropractic students. Item analyses were performed on all questions. RESULTS: The IL self efficacy survey demonstrated good reliability (test-retest correlation = 0.81) and good/very good internal consistency (mean kappa = .56 and Cronbach's alpha = .92). A total of 25 questions with the best item analysis characteristics were chosen from the 50-item IL knowledge test, resulting in a 25-item IL knowledge test that demonstrated good reliability (test-retest correlation = 0.87), very good internal consistency (mean kappa = .69, KR20 = 0.85), and good item discrimination (mean point-biserial = 0.48). CONCLUSIONS: This study resulted in the development of three instruments: a 25-item IL self-efficacy survey, a 50 item IL knowledge test, and a 25-item IL knowledge test. The information literacy self-efficacy survey and the 25-item version of the information literacy knowledge test have shown preliminary evidence of adequate reliability and validity to justify continuing study with these instruments. PMID- 25517735 TI - Obesity and its relationship with hypertension among adults 50 years and older in Jinan, China. AB - BACKGROUND: The relationship between obesity and hypertension varies with geographical area, race and definitions of obesity. Our study aimed to investigate the prevalence of obesity using standard Chinese criteria based on the body mass index (BMI) and the waist circumference (WC) and to examine the association between obesity and hypertension among middle-aged and elderly people in Jinan city. METHODS: This cross-sectional study examined 1,870 subjects from the blocks randomly selected from among the 6 communities of Jinan, China in 2011 2012. The Student's t-test was used to compare numerical data, and the chi2 test was used to compare categorical data. Multivariate logistic regression analyses were performed to assess the effects of general and central obesity on hypertension after adjusting for age or for education level, smoking, alcohol consumption, and continuous age. RESULTS: The prevalence of general obesity among people age 50 years and older was 21.1% (17.0% for males and 23.1% for females), and the prevalence of central obesity was 77.8% for men and 78.7% for women. For men, compared with a normal BMI, the ORs and 95% CIs for overweight and general obesity were 1.853 (1.252, 2.744) and 3.422 (1.894, 6.182), respectively, after adjusting for age, smoking, alcohol consumption and educational level. Compared with a normal WC, the ORs and 95% CIs for central obesity were 2.334 (1.573, 3.465) and 2.318 (1.544, 3.479), respectively, for men. For women, compared with a normal BMI, the ORs and 95% CIs were 1.942 (1.473, 2.599) and 4.011 (2.817, 5.712), respectively, after adjusting for age, smoking, alcohol consumption and educational level. Compared with a normal WC, the ORs and 95% CIs for central obesity were 2.488 (1.865, 3.319) and 2.379 (1.773, 3.192), respectively, for women. CONCLUSIONS: The relationship between hypertension and general obesity was stronger than the relationship between hypertension and either overweight or central obesity in both genders. PMID- 25517737 TI - Can formative quizzes predict or improve summative exam performance? AB - OBJECTIVE: Despite wide use, the value of formative exams remains unclear. We evaluated the possible benefits of formative assessments in a physical examination course at our chiropractic college. METHODS: Three hypotheses were examined: (1) Receiving formative quizzes (FQs) will increase summative exam (SX) scores, (2) writing FQ questions will further increase SE scores, and (3) FQs can predict SX scores. Hypotheses were tested across three separate iterations of the class. RESULTS: The SX scores for the control group (Class 3) were significantly less than those of Classes 1 and 2, but writing quiz questions and taking FQs (Class 1) did not produce significantly higher SX scores than only taking FQs (Class 2). The FQ scores were significant predictors of SX scores, accounting for 52% of the SX score. Sex, age, academic degrees, and ethnicity were not significant copredictors. CONCLUSION: Our results support the assertion that FQs can improve written SX performance, but students producing quiz questions didn't further increase SX scores. We concluded that nonthreatening FQs may be used to enhance student learning and suggest that they also may serve to identify students who, without additional remediation, will perform poorly on subsequent summative written exams. PMID- 25517738 TI - Emphasis on various subtopics in the anatomy curriculum for chiropractic training: An international survey of chiropractors and anatomists. AB - OBJECTIVE: The aim of this study was to conduct an international survey of the perceived optimal level of anatomy teaching from anatomy academics and practicing chiropractors. We hypothesized that the optimum level of anatomical understanding for chiropractic students does not differ between the anatomists teaching the students and practicing chiropractors. METHODS: The opinion of anatomists teaching in a chiropractic course (n = 16) was compared to practicing chiropractors (n = 589). The students' level of understanding was based on the revised Bloom's taxonomy for 16 different curriculum areas. Anatomists were recruited by contacting the accredited chiropractic courses worldwide. Snowball sampling was used for the practicing chiropractors. Independent-samples Mann Whitney U tests were used to compare the results of anatomists and chiropractors. RESULTS: Opinions differed between anatomists and chiropractors on 9 out of the 16 questions. Where opinions differed, chiropractors recommended a higher standard of anatomical knowledge. The level suggested by chiropractors for these curriculum areas is equal to the "evaluating" level where chiropractic students can remember, understand, apply, and analyze anatomical knowledge to be able to justify a clinical decision. CONCLUSION: Compared to anatomists working in chiropractic programs, chiropractors suggest a higher standard of anatomy be taught to undergraduates. Collaboration between chiropractors and anatomists would likely be beneficial in creating or modifying anatomy curricula for chiropractic students. PMID- 25517739 TI - Stochastic formation of magnetic vortex structures in asymmetric disks triggered by chaotic dynamics. AB - The non-trivial spin configuration in a magnetic vortex is a prototype for fundamental studies of nanoscale spin behaviour with potential applications in magnetic information technologies. Arrays of magnetic vortices interfacing with perpendicular thin films have recently been proposed as enabler for skyrmionic structures at room temperature, which has opened exciting perspectives on practical applications of skyrmions. An important milestone for achieving not only such skyrmion materials but also general applications of magnetic vortices is a reliable control of vortex structures. However, controlling magnetic processes is hampered by stochastic behaviour, which is associated with thermal fluctuations in general. Here we show that the dynamics in the initial stages of vortex formation on an ultrafast timescale plays a dominating role for the stochastic behaviour observed at steady state. Our results show that the intrinsic stochastic nature of vortex creation can be controlled by adjusting the interdisk distance in asymmetric disk arrays. PMID- 25517740 TI - CD103+ dendritic cells producing interleukin-12 in anticancer immunosurveillance. AB - The mechanisms through which tumor antigen-specific T cells are elicited in natural or chemotherapy-induced immunosurveillance have been elusive. In this issue of Cancer Cell, two papers by Broz and colleagues and Ruffell and colleagues delineate an important role for a specific dendritic cell subset characterized by CD103 expression, dependence on transcription factors Batf3 and Irf8, and interleukin-12 production. PMID- 25517741 TI - Building through breaking: the development of cancer neochromosomes. AB - In this issue of Cancer Cell, Garsed and colleagues combine chromosome flow sorting and deep sequencing to characterize the structure of oncogene-containing neochromosomes in liposarcoma and provide evidence that they are generated by a combination of multiple dynamic and destructive processes. PMID- 25517742 TI - ChIP-ping away at EWS/ETS transcription networks. AB - In this issue of Cancer Cell, Riggi and colleagues use a genomic approach to define two distinct molecular mechanisms through which the chimeric EWS/FLI1 oncoprotein regulates target genes in Ewing sarcoma, expanding a framework upon which to model the target gene network and test strategies for antagonizing growth of this tumor. PMID- 25517743 TI - NF GEMMs already! The power and promise of mouse tumor models. AB - Plexiform neurofibromas are one of the most common tumors encountered in individuals with the neurofibromatosis type I (NF1) cancer predisposition syndrome. In this issue of Cancer Cell, Chen and colleagues define the cell of origin for murine Nf1 plexiform neurofibroma and leverage this finding to develop a platform for preclinical drug evaluation. PMID- 25517744 TI - Targeting ions-induced autophagy in cancer. AB - Autophagy is an important cellular homeostasis pathway, but its role in cancer remains to be fully elucidated. In this issue of Cancer Cell, Hall and colleagues describe a TRPM3-dependent autophagy pathway that is selectively important for clear cell renal cell carcinoma and can be effectively inhibited. PMID- 25517745 TI - mTORC1 gRABs the Golgi. AB - A lysosome-based mechanism of amino acid sensing by mTORC1 regulated by Rag GTPases has emerged. In this issue of Cancer Cell, Thomas and colleagues propose a Golgi-based and Rag-independent mechanism mediated by the Rab1A GTPase. Furthermore, Rab1A overexpression in colorectal cancers correlates with mTORC1 activity and sensitivity to mTOR inhibitors. PMID- 25517746 TI - Combination of RAF and MEK inhibition for the treatment of BRAF-mutated melanoma: feedback is not encouraged. AB - In BRAF V600E melanoma patients, RAF inhibitor treatment causes a MEK-inhibitor sensitive, RAF-inhibitor-resistant adaptive reactivation of ERK signaling. In clinical trials combining MEK and RAF inhibitors, therapeutic efficacy was modestly enhanced, suggesting the utility of inhibiting feedback-reactivated pathways. Strategies for optimally inhibiting ERK signaling should be explored. PMID- 25517748 TI - The architecture and evolution of cancer neochromosomes. AB - We isolated and analyzed, at single-nucleotide resolution, cancer-associated neochromosomes from well- and/or dedifferentiated liposarcomas. Neochromosomes, which can exceed 600 Mb in size, initially arise as circular structures following chromothripsis involving chromosome 12. The core of the neochromosome is amplified, rearranged, and corroded through hundreds of breakage-fusion-bridge cycles. Under selective pressure, amplified oncogenes are overexpressed, while coamplified passenger genes may be silenced epigenetically. New material may be captured during punctuated chromothriptic events. Centromeric corrosion leads to crisis, which is resolved through neocentromere formation or native centromere capture. Finally, amplification terminates, and the neochromosome core is stabilized in linear form by telomere capture. This study investigates the dynamic mutational processes underlying the life history of a special form of cancer mutation. PMID- 25517747 TI - Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. AB - Ten antiangiogenic drugs targeting VEGF or its receptors are approved for cancer treatment. However, these agents, intended to block tumors' blood supply, may cause hypoxia, which may fuel tumor progression and treatment resistance. Emerging clinical data suggest that patients whose tumor perfusion or oxygenation increases in response to these agents may actually survive longer. Hence, strategies aimed at alleviating tumor hypoxia while improving perfusion may enhance the outcome of radiotherapy, chemotherapy, and immunotherapy. Here I summarize lessons learned from preclinical and clinical studies over the past decade and propose strategies for improving antiangiogenic therapy outcomes for malignant and nonmalignant diseases. PMID- 25517749 TI - ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. AB - Genetic studies have established anaplastic lymphoma kinase (ALK), a cell surface receptor tyrosine kinase, as a tractable molecular target in neuroblastoma. We describe comprehensive genomic, biochemical, and computational analyses of ALK mutations across 1,596 diagnostic neuroblastoma samples. ALK tyrosine kinase domain mutations occurred in 8% of samples--at three hot spots and 13 minor sites -and correlated significantly with poorer survival in high- and intermediate-risk neuroblastoma. Biochemical and computational studies distinguished oncogenic (constitutively activating) from nononcogenic mutations and allowed robust computational prediction of their effects. The mutated variants also showed differential in vitro crizotinib sensitivities. Our studies identify ALK genomic status as a clinically important therapeutic stratification tool in neuroblastoma and will allow tailoring of ALK-targeted therapy to specific mutations. PMID- 25517750 TI - The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation. AB - Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors. PMID- 25517752 TI - SnapShot: chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in western countries. This SnapShot depicts the origins and evolution of this B cell malignancy, describes prognostic factors and CLL animal models, and illustrates therapies in preclinical and clinical development against CLL. PMID- 25517751 TI - TRPM3 and miR-204 establish a regulatory circuit that controls oncogenic autophagy in clear cell renal cell carcinoma. AB - Autophagy promotes tumor growth by generating nutrients from the degradation of intracellular structures. Here we establish, using shRNAs, a dominant-negative mutant, and a pharmacologic inhibitor, mefenamic acid (MFA), that the Transient Receptor Potential Melastatin 3 (TRPM3) channel promotes the growth of clear cell renal cell carcinoma (ccRCC) and stimulates MAP1LC3A (LC3A) and MAP1LC3B (LC3B) autophagy. Increased expression of TRPM3 in RCC leads to Ca(2+) influx, activation of CAMKK2, AMPK, and ULK1, and phagophore formation. In addition, TRPM3 Ca(2+) and Zn(2+) fluxes inhibit miR-214, which directly targets LC3A and LC3B. The von Hippel-Lindau tumor suppressor (VHL) represses TRPM3 directly through miR-204 and indirectly through another miR-204 target, Caveolin 1 (CAV1). PMID- 25517755 TI - Physiological skin changes during pregnancy. AB - Physicians may often mistake normal physiological skin changes in pregnancy for pathologic changes, so being able to recognize the skin manifestations unique to pregnancy is of the utmost importance to avoid unnecessary testing and stress for the obstetric patient. Most physiological skin changes will resolve postpartum, so reassurance and expectant management is indicated in almost all cases. PMID- 25517754 TI - Dermatologic therapy in pregnancy. AB - Patients present during pregnancy with a variety of dermatologic conditions, most of which can be treated conservatively with topical medication by a primary obstetrician if he or she is familiar with common treatment options. Patients with moderate to severe forms of dermatologic disease or those requiring systemic therapy should be treated in consultation with a dermatologist. Dermatologic surgery can be performed safely in the second trimester using local anesthesia if needed. PMID- 25517756 TI - Dermatoses of pregnancy. AB - The dermatoses of pregnancy represent a distinct heterogenous group of cutaneous disorders that can impact the health of the pregnant woman and potentially the fetus. The current classification of pregnancy-specific cutaneous disorders is reviewed, along with important clinical features. Advances in management of these disorders, along with fetal implications, are discussed. The diagnosis of these disorders is challenging, but important clinical features can aid in diagnosis. There have been important advances in the management of these disorders and better understanding of potential fetal risks. Early recognition is critical for appropriate care. PMID- 25517757 TI - Hair loss in women. AB - Hair loss is a common cause of morbidity for many women. As a key member of the woman's health care team, the obstetrician/gynecologist may be the first person to evaluate the complaint of hair loss. Common types of nonscarring hair loss, including female pattern hair loss and telogen effluvium, may be diagnosed and managed by the obstetrician/gynecologist. A systematic approach to diagnosis and management of these common forms of hair loss is presented. PMID- 25517758 TI - Cutaneous malignancies of the perineum. AB - This review discusses multiple cutaneous malignancies that can present on the perineum. Although all of these neoplasms are uncommon, a focus will be on the more common neoplasms including extramammary Paget disease, basal cell carcinoma, squamous cell carcinoma, and melanoma. Other more rare entities discussed are superficial leiomyosarcoma, giant solitary trichoepithelioma, and cutaneous endometriosis. PMID- 25517759 TI - Metaproteomic analysis of biocake proteins to understand membrane fouling in a submerged membrane bioreactor. AB - Metaproteomic analyses, including two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) separation and matrix-assisted laser desorption/ionization (MALDI)-time-of-flight (TOF)/TOF mass spectrometer (MS) detection, were used to trace and identify biocake proteins on membranes in a bench-scale submerged membrane bioreactor (MBR). 2D-PAGE images showed that proteins in the biocake (S3) at a low transmembrane pressure (TMP) level (i.e., before the TMP jump) had larger gray intensities in the pH 5.5-7.0 region regardless of the membrane flux, similar to soluble microbial product (SMP) proteins. However, the biocake (S2 and S4) at a high TMP level (i.e., after the TMP jump) had many more proteins in the pH range of 4.0-5.5, similar to extracellular polymeric substance (EPS) proteins. Such similarities between biocake proteins and SMP or EPS proteins can be useful for tracing the sources of proteins resulting in membrane fouling. In total, 183 differentially abundant protein spots were marked in the three biocakes (S2, S3, and S4). However, only 32 protein spots co-occurred in the 2D gels of the three biocakes, indicating that membrane fluxes and TMP evolution levels had significant effects on the abundance of biocake proteins. On the basis of the MS and MS/MS data, 23 of 71 protein spots were successfully identified. Of the 23 proteins, outer membrane proteins (Omp) were a major contributor (60.87%). These Omps were mainly from potential surface colonizers such as Aeromonas, Enterobacter, Pseudomonas, and Thauera. Generally, the metaproteomic analysis is a useful alternative to trace the sources and compositions of biocake proteins on the levels of molecules and bacteria species that can provide new insight into membrane fouling. PMID- 25517760 TI - Prediction and management of cardiovascular outcomes in systemic lupus erythematosus. AB - Atherosclerosis is the major cause of cardiovascular disease (CVD), which represents the major cause of death. During recent years, it has become clear that atherosclerosis is a chronic inflammatory condition where immunity could play an important role. Usually, it is when atherosclerotic plaques rupture that CVD follows, but some cases of CVD can occur without apparent atherosclerosis. In systemic lupus erythematosus, the risk of CVD is very high and the prevalence of atherosclerotic plaques, including vulnerable ones, is increased. A combination of traditional and non-traditional risk factors is implicated for the prediction of CVD in systemic lupus erythematosus. Traditional risk factors include hypertension, dyslipidemia, smoking and diabetes, though the exact importance of each of these in systemic lupus erythematosus is not clear. Anti-phospholipid antibodies, systemic inflammation and low levels of natural antibodies such as those against phosphorylcholine (anti-PC) are examples of non-traditional risk factors. Control of disease activity and disease manifestations and of established risk factors is important. PMID- 25517761 TI - Effect of ischemic preconditioning on repeated sprint ability in team sport athletes. AB - This study investigated whether ischemic preconditioning (IPC) in a trained population affected repeated sprint performance. A secondary aim was to assess responses according to gender. Sixteen (nine females and seven males) well trained team sport athletes took part in a randomised crossover study design. Participants underwent an IPC and placebo treatment involving three periods of 5 min occlusion applied unilaterally (3 * 5 min occlusion to each leg) at either 220 mmHg or 50 mmHg. Each period of occlusion was followed by 5 min reperfusion. Following treatment 5 * 6 s maximal effort sprints were undertaken on a cycle ergometer against 7.5% body mass, each interspersed by 24 s recovery. Measured parameters included peak power, total power, percentage decrement, post-exercise blood lactate and ratings of perceived exertion. Nor within subject main effect for IPC was observed, neither was there an interaction effect with gender. Effect sizes were trivial (ES < 0.2) with the exception of a moderate (ES < 1.2) change in post-exercise blood lactate in the female cohort (1.6 +/- 0.4 mmol-1 lower following IPC). Results suggest no benefit to team sport players in utilising IPC as a means of enhancing repeated sprint performance. A lower blood lactate response in female participants following IPC may suggest improved blood flow through vasodilation. PMID- 25517762 TI - Uterine artery ligation at the beginning of total laparoscopic hysterectomy reduces total blood loss and operation duration. AB - The purpose of this study was to compare the feasibility, blood loss, duration of surgery and complications between patients in whom both uterine arteries were ligated by surgical clips and cut using a 5-mm ligature at the beginning of total laparoscopic hysterectomy (TLH) and patients in whom uterine arteries were not ligated at the beginning of TLH. In our prospective study, a total of 60 women underwent TLH. Uterine artery ligation (UAL) was done at the beginning of the procedure. Women were divided into TLH + UAL (n = 30) and TLH (n = 30) groups. In TLH group, TLH was done without ligating the uterine arteries at the beginning of the procedure. In TLH + UAL group, TLH was done with ligation of both uterine arteries at the beginning of the procedure. The mean operating time was longer for the TLH group (99.16 +/- 7.01) than TLH + UAL group (63.27 +/- 7.16). The median total blood loss was higher in TLH group (109.38 +/- 33.03 mL) than TLH + UAL group (47.50 +/- 8.12 mL). UAL at the beginning of TLH is a technically feasible procedure. It reduces the total blood loss and decreases the time taken for the procedure and length of hospital stay. PMID- 25517763 TI - Ion transport controlled by nanoparticle-functionalized membranes. AB - From proton exchange membranes in fuel cells to ion channels in biological membranes, the well-specified control of ionic interactions in confined geometries profoundly influences the transport and selectivity of porous materials. Here we outline a versatile new approach to control a membrane's electrostatic interactions with ions by depositing ligand-coated nanoparticles around the pore entrances. Leveraging the flexibility and control by which ligated nanoparticles can be synthesized, we demonstrate how ligand terminal groups such as methyl, carboxyl and amine can be used to tune the membrane charge density and control ion transport. Further functionality, exploiting the ligands as binding sites, is demonstrated for sulfonate groups resulting in an enhancement of the membrane charge density. We then extend these results to smaller dimensions by systematically varying the underlying pore diameter. As a whole, these results outline a previously unexplored method for the nanoparticle functionalization of membranes using ligated nanoparticles to control ion transport. PMID- 25517764 TI - Systemic treatment of acute liver failure with adipose derived stem cells. AB - PURPOSE OF THE STUDY: The definitive treatment for liver failure is, currently, liver transplantation. Research into other possible treatments, focused on achieving regeneration of the liver parenchyma, have led to the development of methods to generate hepatocytes from stem cells. In our study, we transplant allogenic adipose-derived stem cells (ASCs), not previously differentiated to hepatocytes, to treat acute liver failure induced by intraperitoneal administration of carbon tetrachloride (CCl4) in a Sprague-Dawley rat model. MATERIAL AND METHODS: The ASCs were delivered via the tail vein, having previously been labeled with PKH26, a fluorescent membrane marker. Two control groups were established, Group 1(n = 15) consisting of olive oil (5 mL/kg) and Group 2(n = 15): 1 * 10(6) PKH26-labeled ASCs. Further, two study groups, Group 3(n = 30): CCl4 dissolved in olive oil and Group 4(n = 30): CCl4 dissolved in olive oil and 1 * 10(6) PKH26-labeled ASCs completed the experimental design. RESULTS: Blood samples were analyzed, finding AST and ALT levels significantly higher in treatment over control groups at 24 and 48 hours. The mortality rates were statistically different between control groups and Group 3 (Group 1-3 p = .04, Group 2-3 p = .04) and between Groups 3 and 4 (p = .02). Examining the liver parenchyma, a significantly higher number of ASCs were observed in Group 4 than in Group 2 at all time points (p = .00). CONCLUSIONS: The intravenous injection of allogenic ASCs in this model of CCl4-induced liver failure reduced the mortality in treated animals. ASCs injected in the rat tail vein were found in the liver in animals with induced acute liver failure. PMID- 25517765 TI - Brooding, Reflection, and Distraction: Relation to Non-Suicidal Self-Injury versus Suicide Attempts. AB - The present study examined the relation between cognitive response styles (i.e., brooding, reflection, distraction) and cognitive inflexibility in differentially predicting history of non-suicidal self-injury (NSSI) only, suicide attempt (SA) only, or both (NSSI + SA). College students (N = 352) completed self-report measures of rumination, distraction, and self-harm history, a diagnostic interview, and a computerized task measuring cognitive flexibility. Brooding uniquely predicted SA-only history, while reflection uniquely predicted history of NSSI-only and NSSI + SA. Distraction was associated with lower odds of NSSI only and NSSI + SA. Cognitive inflexibility was not significantly associated with self-harm history. Cognitive vulnerabilities may help identify individuals who are at risk for self-harm and may differentiate between NSSI and SA. PMID- 25517767 TI - First occurrence of Platycladus from the upper Miocene of Southwest China and its phytogeographic implications. AB - Platycladus Spach is native to Central China, but its natural occurrences are very difficult to establish. According to molecular phylogenetic data, this genus might have originated since the Oligocene, but no fossil record has been reported. Here, we describe eight foliage branches from the upper Miocene in western Yunnan, Southwest China as a new species, P. yunnanensis sp. nov., which is characterized by foliage branches spread in flattened sprays, and leaves decussate, imbricate, scale-like and dimorphic. The leaves are amphistomatic, and the stomata are elliptical or oblong, haplocheilic, and monocyclic type. Based on a detailed comparison with the extant genera of Cupressaceae sensu lato, our fossils are classified into the genus Platycladus. The occurrence of P. yunnanensis sp. nov. indicates that this genus had a more southernly natural distribution in the late Miocene than at present. Molecular phylogeny and fossil records support a pre-Oligocene common ancestor for the genera Platycladus, Microbiota and Calocedrus. The separation of the three taxa was most likely caused by the arid belt across Central China during the Oligocene. In addition, the cooling down of the global temperature and the strengthening of Asian monsoon since the Miocene will further promote the migration of these genera. PMID- 25517769 TI - Dose-response and time-course of alpha-tocoferol mediating the cytoprotection of dental pulp cells against hydrogen peroxide. AB - This in vitro study evaluated the potential protective effect of vitamin E alpha tocopherol (alpha-T) isomer against the toxicity of hydrogen peroxide (HP) applied on dental pulp cells. Odontoblast-like MDPC-23 cells were seeded on 96 well plates for 72 h, treated with different concentrations of alpha-T (1, 3, 5, and 10 mM) for different times (1, 4, 8, and 24 h) and then exposed or not to a 0.018% HP solution for 30 min. In positive and negative control groups, cells were exposed to HP or culture medium (DMEM containing 5% DMSO), respectively. Cell viability was assessed by the MTT assay and the absorbance numeric data, expressed as percentage values, were subjected to the statistical analysis by Kruskal-Wallis and Mann-Whitney tests (alpha=5%). Considering the cells in the negative control as having 100% of cell viability, all combinations of alpha-T concentrations and pretreatment times showed a protective effect against HP cytotoxicity. Significant reduction of cell viability (59%) was observed in the positive control compared with the negative control. The highest values of pulp cell viability were obtained after pretreatment with 1 and 3 mM alpha-T concentrations for 24 h followed by exposure to HP (126% and 97% of cell viability, respectively). Under the tested conditions, the most effective cell protection against the cytotoxic effects of HP was provided by the lowest concentrations of alpha-T (1 and 3 mM) applied for 24 h. PMID- 25517766 TI - Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets. AB - BACKGROUND: Epigenetic factors regulate tissue-specific expression and X chromosome inactivation. Previous studies have identified epigenetic differences between sexes in some human tissues. However, it is unclear whether epigenetic modifications contribute to sex-specific differences in insulin secretion and metabolism. Here, we investigate the impact of sex on the genome-wide DNA methylation pattern in human pancreatic islets from 53 males and 34 females, and relate the methylome to changes in expression and insulin secretion. RESULTS: Glucose-stimulated insulin secretion is higher in female versus male islets. Genome-wide DNA methylation data in human islets clusters based on sex. While the chromosome-wide DNA methylation level on the X-chromosome is higher in female versus male islets, the autosomes do not display a global methylation difference between sexes. Methylation of 8,140 individual X-chromosome sites and 470 autosomal sites shows sex-specific differences in human islets. These include sites in/near AR, DUSP9, HNF4A, BCL11A and CDKN2B. 61 X-chromosome genes and 18 autosomal genes display sex-specific differences in both DNA methylation and expression. These include NKAP, SPESP1 and APLN, which exhibited lower expression in females. Functional analyses demonstrate that methylation of NKAP and SPESP1 promoters in vitro suppresses their transcriptional activity. Silencing of Nkap or Apln in clonal beta-cells results in increased insulin secretion. Differential methylation between sexes is associated with altered levels of microRNAs miR-660 and miR-532 and related target genes. CONCLUSIONS: Chromosome-wide and gene specific sex differences in DNA methylation associate with altered expression and insulin secretion in human islets. Our data demonstrate that epigenetics contribute to sex-specific metabolic phenotypes. PMID- 25517770 TI - Expression of glucose transporters 1 and 3 in metastatic and non-metastatic lower lip squamous cell carcinoma. AB - This study aimed to evaluate the immunoexpression of glucose transporters 1 (GLUT 1) and 3 (GLUT-3) in metastatic and non-metastatic lower lip squamous cell carcinoma (LLSCC). Twenty LLSCCs with regional nodal metastasis and 20 LLSCCs without metastasis were selected. The distribution of staining and the percentage of GLUT-1 and GLUT-3 staining in each tumor core and at the deep invasive front were assessed. Most tumors (70%) exhibited peripheral staining for GLUT-1 in nests, sheets and islands of neoplastic cells, whereas predominantly central staining was observed for GLUT-3 (72.5%). A high percentage of GLUT-1-positive cells was observed at the deep invasive front and in the tumor core of metastatic and non-metastatic tumors (p>0.05). The percentage of GLUT-1-positive cells was much higher than that of GLUT-3-positive cells both in the deep invasive front (p<0.001) and in the tumor core (p<0.001) of LLSCCs. No significant differences in the percentage of GLUT-1- and GLUT-3-positive cells were observed according to nodal metastasis, clinical stage or histological grade of malignancy (p>0.05). In conclusion, the results of the present study suggest an important role of GLUT-1 in glucose uptake in LLSCCs, although this protein does not seem to be involved in the progression of these tumors. On the other hand, GLUT-3 expression may represent a secondary glucose uptake mechanism in LLSCCs. PMID- 25517771 TI - Assessment of bone healing in rabbit calvaria grafted with three different biomaterials. AB - This study evaluated the bone regeneration process in rabbit calvaria induced by three types of biomaterials: two xenogenous, consisting of deproteinized bovine bone, while the other was alloplastic, based on biphasic calcium phosphate. Five New Zealand white rabbits weighing between 2,900 and 3,500 g were submitted to four standard 8 mm-diameter perforations at the parietal bone. Three perforations were filled with three grafts and biomaterials, two of them received bovine Bio Oss(r) and Endobon(r) Xenograft Granules, and the other consisted of fully alloplastic Straumann(r) Bone Ceramic. The fourth remaining cavity was used as control with coagulum. After eight weeks, the animals were sacrificed, and the samples were prepared for morphometric and qualitative analysis. The cavities filled with alloplastic biomaterials showed higher percentages of newly formed bone (p<0.05), while the cavities with xenogenous biomaterials showed higher amount of residual graft (p<0.05). Although the results showed greater bone formation with Straumann(r) Bone Ceramic, further studies are required to prove which is the more effective biomaterial for bone induction process. PMID- 25517772 TI - Measurement of elastic modulus and Vickers hardness of surround bone implant using dynamic microindentation--parameters definition. AB - The clinical performance of dental implants is strongly defined by biomechanical principles. The aim of this study was to quantify the Vicker's hardness (VHN) and elastic modulus (E) surround bone to dental implant in different regions, and to discuss the parameters of dynamic microindantion test. Ten cylindrical implants with morse taper interface (Titamax CM, Neodent; 3.5 mm diameter and 7 mm a height) were inserted in rabbit tibia. The mechanical properties were analyzed using microhardness dynamic indenter with 200 mN load and 15 s penetration time. Seven continuous indentations were made distancing 0.08 mm between each other perpendicularly to the implant-bone interface towards the external surface, at the limit of low (Lp) and high implant profile (Hp). Data were analyzed by Student's t-test (?a=0.05) to compare the E and VHN values obtained on both regions. Mean and standard deviation of E (GPa) were: Lp. 16.6 +/- 1.7, Hp. 17.0 +/- 2.5 and VHN (N/mm2): Lp. 12.6 +/- 40.8, Hp. 120.1 +/- 43.7. No statistical difference was found between bone mechanical properties of high and low profile of the surround bone to implant, demonstrating that the bone characterization homogeneously is pertinent. Dynamic microindantion method proved to be highly useful in the characterization of the individual peri-implant bone tissue. PMID- 25517773 TI - Effect of a denture adhesive on the satisfaction and kinesiographic parameters of complete denture wearers: a cross-over randomized clinical trial. AB - The aim of the present study was to assess the effect of a denture adhesive (DA) on patient satisfaction and kinesiographic parameters of complete denture wearers by a cross-over study. Fifty edentulous patients received a set of new complete dentures. After an adaptation period, the participants were enrolled in the trial and randomized to receive a sequence of treatment protocols: Protocol 1- DA use during the first 15 days, followed by no DA for the next 15 days; Protocol 2- no DA during the first 15 days, followed by use of DA for the next 15 days. Outcomes were assessed after 15 days of each sequence of treatment. A questionnaire was used to assess the patients' satisfaction. A kinesiograph was used to record mandible movements and patterns of maxillary complete denture movement during chewing. The Wilcoxon test (alpha=0.05) and a paired sample t-test (alpha=0.05) were used to compare satisfaction levels and kinesiographic data, respectively. Use of DA improved the overall level of patient satisfaction (p<0.001). The kinesiographic recordings revealed a significant increase (1.7 mm) in vertical mandible movements (p<0.001) during chewing and a lower (0.3 mm) vertical intrusion of the maxillary complete dentures (p=0.002) during chewing after using the DA. Use of DA in complete denture wearers improved the patients' satisfaction and altered mandible movements, with increases in vertical movements during chewing and less intrusion of maxillary complete dentures. PMID- 25517775 TI - Detection of apical inflammatory root resorption associated with periapical lesion using different methods. AB - The aim of this study was to detect apical inflammatory root resorption (AIRR) associated with periapical lesion using cone beam computed tomography (CBCT) and scanning electronic microscopy (SEM). This clinical study evaluated AIRR in 88 root apexes, from 52 permanent teeth of 14 patients, extracted for different reasons. The patients were submitted to a clinical interview, review of dental/medical histories and clinical/imaging examinations for treatment planning. All selected teeth showed unrestorable condition because of the extensive coronal breakdown due to carious lesions, and root canal infection associated with periapical lesions. CBCT images were obtained from the patients with the aim of diagnosing the periapical diseases which showed complex or doubtful conditions. Two examiners assessed the presence or absence of AIRR. Apices were also analyzed under SEM. Chi-square test was used to compare the imaging methods for detection of AIRR. The level of statistical significance was set at 5%. AIRR associated with root canal infection and apical periodontitis was found in 61.4% of the cases studied by using SEM, and at least half of the cases by CBCT. The microscopic analysis remains as a reference standard against the imaging method to identify AIRR. PMID- 25517774 TI - Effects of green tea application time on bond strength after enamel bleaching. AB - This study evaluated the effect of green tea application time on the bond strength of enamel after enamel bleaching. Enamel samples were obtained from 80 third molars and randomly divided into 7 experimental groups (G1-G7) and 1 group without treatment (G8): G1, bleached with 10% carbamide peroxide (CP); G2, CP + 10% sodium ascorbate gel (SA) for 15 min; G3, CP + SA for 30 min; G4, CP + SA for 60 min; G5, CP + 10% green tea gel (GT) for 15 min; G6, CP + GT for 30 min; G7, CP + GT for 60 min. The CP was applied onto the enamel surface for 8 h for 14 days. The SA was applied in groups 2, 3 and 4, and the GT was applied in groups 5 8 according to the above described application times. Immediately after treatment, the specimens were bonded with Adper Single Bond 2 and Filtek Z350XT. The specimens were prepared to microtensile bond strength analysis. Fracture mode analysis was performed using a stereoscopic loupe. The data were statistically analyzed by two-way analysis of variance, the Tukey's and Dunnett's tests (?=5%). The means (standard deviation) were: G1, 23.3 (3.2); G2, 25.2 (3.9); G3, 26.4 (5.4); G4, 30.2 (4.5); G5, 26.6 (3.4); G6, 22.0 (5.4); G7, 31.4 (3.3); G8, 31.4 (3.2). All groups had a high percentage of adhesive failures. In conclusion, the bond strength values were higher than the value in the bleached group only when the antioxidants were applied for 60 min. PMID- 25517776 TI - Quantitative assessment of root canal roughness with calcium-based hypochlorite irrigants by 3D CLSM. AB - Chemical solutions play important roles in endodontic treatment and promote ultrastructural changes in dentin surface. The aim of this study was to quantify root canal roughness at different concentrations of calcium hypochlorite (Ca(OCl)2) and sodium hypochlorite (NaOCl) by confocal laser scanning microscopy (CLSM). Fifty-two human mandibular premolars were sectioned and randomly organized into thirteen groups (n=8): saline (control); 1%, 2.5% and 5% NaOCl; 1%, 2.5% and 5% Ca(OCl)2; the hypochlorite groups were further divided into with or without EDTA. The chlorine concentrations of the different solutions were measured by iodine titration (%). The superficial roughness (Sa) was quantified by CLSM. Ca(OCl)2 presented substantial decrease in chlorine concentration that differed from the package indication, but without compromising the dentin ultrastructure changes. There were no significant differences in dentin roughness between Ca(OCl)2 or NaOCl at all studied concentrations. The combination with EDTA provided similar roughness values among the solutions (p>0.05). The 5% Ca(OCl)2 and NaOCl solutions significantly increased dentin roughness and did not differ from the EDTA association (p>0.05). Ca(OCl)2 promoted similar dentin roughness as the NaOCl at the same concentrations and combined with EDTA. It may be concluded that Ca(OCl)2 modified the root canal dentin roughness similarly to NaOCl, at the same concentrations and EDTA combinations used in this study. Ca(OCl)2 and NaOCl, both at 5%, significantly altered dentin roughness, overcoming EDTA association, thus Ca(OCl)2 concentrations ranging from 1% to 2.5% may be suitable solutions for root canal irrigation protocols. PMID- 25517778 TI - Effect of super-oxidized water, sodium hypochlorite and EDTA on dentin microhardness. AB - The present study aimed to evaluate the influence of the following irrigating solutions on the microhardness of root canal dentin: 2% sodium hypochlorite (2NaOCl), 5% sodium hypochlorite (5NaOCl), super-oxidized water (400 ppm Sterilox - Sx) and 17% EDTA (E). Eighty roots from bovine incisors were randomly divided into 8 groups (n=10): 2NaOCl, 5NaOCl, Sx, and 2NaOCl + E, 5NaOCl + E, Sx + E (associated with E as final irrigant for 5 min), E solely and distilled water (dH2O) as the negative control. Root canal preparation was performed by hand instruments, using one of the irrigation protocols for 30 min. Then, 5 mm of the cervical root third were cut out from each sample and subjected to the Vickers microhardness test, at two points, one at approximately 500-1000 um from the root canal lumen (distance 1), and the other at approximately 500-1000 um from the external root surface (distance 2). Data were analyzed by Wilcoxon and Kruskal Wallis tests at 5% significance level. Microhardness values at distance 1 were significantly lower than those at distance 2 for all groups, except 5NaOCl and 5NaOCl + E groups (p>0.05). EDTA showed the lowest microhardness values. However, no statistically significant difference was detected among groups at distance 1 and EDTA was significantly different only from Sx at distance 2. In conclusion, all tested solutions showed lower microhardness at the most superficial root canal dentin layer compared to the one found near the external root surface, except 5NaOCl and 5NaOCl + E; EDTA promoted lower microhardness values in comparison to Sterilox at this site. PMID- 25517777 TI - Effect of a surfactant on the antimicrobial activity of sodium hypochlorite solutions. AB - The objective of the present study was to evaluate the antimicrobial activity of sodium hypochlorite (NaOCl) associated with a surfactant. Seventy single-rooted extracted human teeth were inoculated with Enterococcus faecalis, and incubated for 21 days (37 degrees C). The groups were distributed according to the irrigation solution used during root canal preparation: 5%, 2.5% and 1% NaOCl; 5%, 2.5% and 1% Hypoclean(r), a solution containing a surfactant (cetrimide) associated with NaOCl. Three microbiological samples were collected from each tooth: S1 - before instrumentation; S2 - immediately after instrumentation; and S3 - after a seven-day period. Data were submitted to ANOVA and Tukey test with 5% significance level. The results showed that immediately after root canal preparation (S2), E. faecalis was eliminated in all the experimental groups. However, after 7 days (S3), only the groups in which Hypoclean was used, remained contamination-free, including Hypoclean associated with 1% NaOCl, while the root canals irrigated with 1% NaOCl only, presented the highest percentage of bacterial growth. In conclusion, the addition of surfactant increased the antimicrobial activity of 1% NaOCl to levels similar to 5% NaOCl. PMID- 25517779 TI - Antimicrobial effect and transdentinal diffusion of new intracanal formulations containing nitrofurantoin or doxycycline. AB - The aim of this study was to investigate in vitro the antimicrobial effect and diffusion against E. faecalis of new intracanal medications on the external root surface. The medications tested were a placebo gel (PC); the new formulations with either 3% nitrofurantoin (NIT) or 3% doxycycline hydrochloride (DX) and 2% chlorhexidine (CHX) gel as positive control. The new formulations were tested using the traditional agar diffusion test (ADT) and an adapted agar diffusion method (AADM), where the teeth were filled with the medications and left to diffuse on agar surface seeded with E. faecalis. In the ADT, the larger zones of microbial growth inhibition were seen in DX, followed by CHX and NIT. In the AADM test only DX and CHX showed antimicrobial effect. Statistically significant differences between groups were observed by the Kruskal-Wallis test (?2=47.126; p<0.001). The new intracanal formulations with DX and NIT have demonstrated antimicrobial effect against E. faecalis, but only DX was able to diffuse through the dentinal tubules and exert antimicrobial effect outside the roots. PMID- 25517780 TI - Influence of apical enlargement in cleaning of curved canals using negative pressure system. AB - This study aimed to evaluate, by scanning electron microscopy (SEM), the cleaning of canal walls with moderate curvature subjected to biomechanical preparation with different final diameters using apical negative pressure irrigation. Thirty two mesiobuccal roots of molars were divided into 4 groups (n=8) according to the instrument's final diameter: GI: 30.02, GII: 35.02, GIII: 40.02 and GIV: 45.02. Irrigating procedure was performed at each change of instrument with 1% NaOCl using the Endovac system. Final irrigation was conducted with 17% EDTA for 5 min. The SEM photomicrographs were evaluated under 35* and 1000* magnification, by three calibrated examiners, in a double-blind design. Data were submitted to Kruskal-Wallis and Dunn's post hoc tests (alpha=0.05). Canals instrumented with 30.02 and 35.02 final diameters showed more debris, statistically different from the other groups (p<0.05). Comparing each root canal third, for the cervical and apical portions no statistically significant difference (p>0.05) was found among the four groups. Regarding the presence of smear layer, canals with 30.02 final diameter showed the highest scores, statistically different from the 45.02 group (p<0.05) and similar to the 35.02 and the 40.02 groups (p>0.05). Although none of the studied diameters completely removed debris and smear layer, it may be concluded that instrumentation with higher final diameters was more effective in cleaning the root canals with moderate curvature. PMID- 25517782 TI - Temporomandibular disorders in a sample population of the Brazilian northeast. AB - Temporomandibular disorder (TMD) is a common condition. This study is part of a research group and it investigated the prevalence of TMD and myofascial pain and its association with gender, age and socioeconomic class. The sample comprised 100 subjects, aged 15 to 70, users of the Family Health Units' services, in the city of Recife, PE, Brazil. The TMD degree was evaluated using the Research Diagnostic Criteria for TMD and socioeconomic class by the Economic Classification Criteria Brazil. Categorical variables were analyzed by chi-square test for proportions and Fisher's exact test for 2x2 tables, and binary logistic analysis to track the relationship between the independent and dependent variables. According to the results, 42% of the subjects had TMD and 14% myofascial pain. No statistically significant association could be found between TMD and gender or socioeconomic class, but it was found to have statistically significant association with age, and myofascial pain was associated with socioeconomic class. Considering that the results of the present study should be confirmed by further studies and the fact that this was a pilot study, the prevalence must be analyzed with caution. PMID- 25517781 TI - Physicochemical properties and interfacial adaptation of root canal sealers. AB - This study compared the physicochemical properties and interfacial adaptation to canal walls of Endo-CPM-Sealer, Sealapex and Activ GP with the well-established AH Plus sealer. The following analyses were performed: radiopacity, pH variation and solubility using samples of each material and scanning electron microscopy of root-filled bovine incisors to evaluate the interfacial adaptation. Data were analyzed by the parametric and no-parametric tests (alpha=0.05). All materials were in accordance with the ANSI/ADA requirements for radiopacity. Endo-CPM Sealer presented the lowest radiopacity values and AH Plus was the most radiopaque sealer (p=0.0001). Except for ActiV GP, which was acidic, all other sealers had basic chemical nature and released hydroxyl ions. Regarding solubility, all materials met the ANSI/ADA recommendations, with no statistically significant difference between the sealers (p=0.0834). AH Plus presented the best adaptation to canal walls in the middle (p=0.0023) and apical (p=0.0012) thirds, while the sealers Activ GP and Endo-CPM-Sealer had poor adaptation to the canal walls. All sealers, except for ActiV GP, were alkaline and all of them fulfilled the ANSI/ADA requirements for radiopacity and solubility. Regarding the interfacial adaptation, AH Plus was superior to the others considering the adaptation to the bovine root canal walls. PMID- 25517783 TI - Mixed periapical lesion: an atypical radicular cyst with extensive calcifications. AB - The radicular cyst is an inflammatory odontogenic cyst of endodontic origin. Radiographically, the lesion appears as a periapical radiolucent image. This report describes a very rare case of a mixed periapical radiographic image diagnosed as a radicular cyst. A 37-year-old female patient presented a mixed, well-circumscribed image located in the periapical region of the left maxillary central incisor, which presented unsatisfactory endodontic treatment. Microscopic examination revealed a cavity lined by non-keratinized squamous epithelium and extensive calcifications in the cystic lumen and lining epithelium. Diagnosis of radicular cyst with extensive calcifications was established. Endodontic retreatment was performed and no radiographic signs of recurrence were observed 18 months after treatment. Although very rare, a radicular cyst should be considered in the differential diagnosis of a mixed periapical image associated to teeth with pulp necrosis. PMID- 25517784 TI - Aggressive multilocular osteoblastoma in the mandible: a rare and difficult case to diagnose. AB - Osteoblastoma is a benign neoplasia and is uncommon in the jaws. In some cases, this lesion presents extremely aggressive local characteristics and is termed aggressive osteoblastoma. Because the clinical, radiographic and histopathologic characteristics are similar to those of a variety of benign and malignant tumors, it poses a diagnostic dilemma. This report presents a case of an aggressive osteoblastoma in the mandible and discusses the differential diagnosis of this lesion. A 13-year-old white male sought the Stomatology Clinic at the State University of Paraiba, Campina Grande, PB, Brazil, complaining of asymptomatic swelling on the left side of his face. Cone-beam computerized tomography showed a multilocular, hypodense bone lesion, located in the body of the left mandible and lower third of the ascending ramus. The initial diagnostic hypothesis was juvenile ossifying fibroma or osteosarcoma. After histopathologic examination, the final diagnosis was aggressive osteoblastoma. Surgical resection with a safety margin was performed. There was no evidence of recurrence after a follow up period of 4 years. PMID- 25517785 TI - Expression of Momordica charantia MAP30 and its antitumor effect on bladder cancer cells. AB - BACKGROUND: Momordica charantia (MC) is an edible medicinal plant that is known for its diversified biological functions. Momordica Antiviral Protein 30kD (MAP30) is a type I single chain ribosome-inactivating protein (RIP) isolated from the mature fruit and seeds of MC. Since MAP30 content in MC is limited, the study aim was to generate the recombinant MAP30 protein using prokaryotic expression system and determine its apoptotic/growth inhibitory effects on bladder cancer 5637 cells. METHODS: MAP30 gene was amplified by PCR from MC genomic DNA and identified by sequencing. The target gene was inserted into pET 28a (+) vector and transformed into E. coli BL21 (DE3) cells. Positive clones were selected by PCR. Recombinant protein was efficiently expressed under induction with 1.0 mM Isopropylthio-beta-D-galactoside (IPTG) at 30 degrees C for 4 hours. Cytotoxicity studies were performed using MTT assay by treating 5637 bladder cancer cells with 100 ug/mL, 200 ug/mL, and 400 ug/mL concentrations of MAP30 for 24 hours and 48 hours, respectively. Flow cytometry was used to measure the apoptosis of MAP30-treatedcells in time course experiments. RESULTS: Full length MAP30 gene was successfully expressed in Escherichia coli (E. coli) BL21 strain and MAP30 recombinant protein inhibited the growth of bladder cancer 5637 cells at 200 ug/mL and 400 ug/mL concentrations by inducing apoptosis of target cells in a dose- and time-dependent manner. CONCLUSION: It was, therefore, concluded that the MAP30 recombinant protein displayed potent antitumor activity in vitro. PMID- 25517786 TI - Risk factors and prognosis of acute kidney injury in adult hospitalized patients: a two-year outcome. AB - AIM: Acute kidney injury (AKI) is becoming increasingly common in hospitalized patients. A few studies have defined epidemiological data concerning hospital acquired AKI. The aim of this study was to determine the incidence and the risk factors of hospital-acquired AKI and its treatment and prevention. METHODS: A dataset of 123,105 adults who were treated in the hospital from January 2010 to December 2011, excluding patients with chronic kidney disease (CKD) and community acquired AKI patients, was evaluated. Clinical data of blood urea nitrogen (BUN) and serum creatinine (SCr) were collected and analyzed. AKI was defined and classified according to the Acute Kidney Injury Network (AKIN). Data were compared among patients with hospital-acquired and non-hospital-acquired AKI. RESULTS: Among a cohort of 123,105 hospitalized adult patients, 174 patients were identified with hospital-acquired AKI. The number of cases aged 18-39, 40-59, 60 79 and >=80 years was, respectively, 15 (8.6%), 39 (22.4%), 82 (47.1%), and 38 (21.8%); the 60-79 years age group had the highest number. Univariate analysis showed that the unfavorable prognosis was correlated with >60 years of age, coronary heart disease, diabetes, hypotension, unconsciousness, mechanical ventilation, injuries and multiple organ dysfunction syndrome (MODS). Multivariate logistic regression analysis demonstrated that the coronary heart disease, diabetes, hypotension, mechanical ventilation and MODS were independent unfavorable prognostic factors for hospital-acquired AKI. CONCLUSION: Prerenal and renal factors are the major causes of the development of hospital-acquired AKI. Thus, focusing on the potential risk factors of hospital-acquired AKI may prove to be beneficial to the prognosis of patients. PMID- 25517789 TI - After 10 years: mission accomplished. PMID- 25517793 TI - Low resistance metal contacts to MoS2 devices with nickel-etched-graphene electrodes. AB - We report an approach to achieve low-resistance contacts to MoS2 transistors with the intrinsic performance of the MoS2 channel preserved. Through a dry transfer technique and a metal-catalyzed graphene treatment process, nickel-etched graphene electrodes were fabricated on MoS2 that yield contact resistance as low as 200 Omega . MUm. The substantial contact enhancement (~ 2 orders of magnitude), as compared to pure nickel electrodes, is attributed to the much smaller work function of nickel-graphene electrodes, together with the fact that presence of zigzag edges in the treated graphene surface enhances tunneling between nickel and graphene. To this end, the successful fabrication of a clean graphene-MoS2 interface and a low resistance nickel-graphene interface is critical for the experimentally measured low contact resistance. The potential of using graphene as an electrode interlayer demonstrated in this work paves the way toward achieving high performance next-generation transistors. PMID- 25517795 TI - Twin boundary-assisted lithium ion transport. AB - With the increased need for high-rate Li-ion batteries, it has become apparent that new electrode materials with enhanced Li-ion transport should be designed. Interfaces, such as twin boundaries (TBs), offer new opportunities to navigate the ionic transport within nanoscale materials. Here, we demonstrate the effects of TBs on the Li-ion transport properties in single crystalline SnO2 nanowires. It is shown that the TB-assisted lithiation pathways are remarkably different from the previously reported lithiation behavior in SnO2 nanowires without TBs. Our in situ transmission electron microscopy study combined with direct atomic scale imaging of the initial lithiation stage of the TB-SnO2 nanowires prove that the lithium ions prefer to intercalate in the vicinity of the (101) TB, which acts as conduit for lithium-ion diffusion inside the nanowires. The density functional theory modeling shows that it is energetically preferred for lithium ions to accumulate near the TB compared to perfect neighboring lattice area. These findings may lead to the design of new electrode materials that incorporate TBs as efficient lithium pathways, and eventually, the development of next generation rechargeable batteries that surpass the rate performance of the current commercial Li-ion batteries. PMID- 25517794 TI - Advanced nanocarriers based on heparin and its derivatives for cancer management. AB - To obtain a satisfying anticancer effect, rationally designed nanocarriers are intensively studied. In this field, heparin and its derivatives have been widely attempted recently as potential component of nanocarriers due to their unique biological and physiochemical features, especially the anticancer activity. This review focuses on state-of-the-art nanocarriers with heparin/heparin derivatives as backbone or coating material. At the beginning, the unique advantages of heparin used in cancer nanotechnology are discussed. After that, different strategies of heparin chemical modification are reviewed, laying the foundation of developing various nanocarriers. Then a systematic summary of diverse nanoparticles with heparin as component is exhibited, involving heparin-drug conjugate, polymeric nanoparticles, nanogels, polyelectrolyte complex nanoparticles, and heparin-coated organic and inorganic nanoparticles. The application of these nanoparticles in various novel cancer therapy (containing targeted therapy, magnetic therapy, photodynamic therapy, and gene therapy) will be highlighted. Finally, future challenges and opportunities of heparin-based biomaterials in cancer nanotechnology are discussed. PMID- 25517796 TI - Mutations in exons 3 and 7 resulting in truncated expression of human ATP6V1B1 gene showing structural variations contributing to poor substrate binding causative reason for distal renal tubular acidosis with sensorineural deafness. AB - Distal renal tubular acidosis (dRTA) is an autosomal recessive syndrome results defect in either proximal tubule bicarbonate reabsorption or in distal tubule H(+) secretion and is characterized by severe hyperchloraemic metabolic acidosis in childhood. dRTA is associated with functional variations in the ATP6V1B1 gene encoding beta1 subunit of H(+)-ATPase, key membrane transporters for net acid excretion of alpha-intercalated cells of medullary collecting ducts. In the present study, a 13-year-old male patient suffering with nephropathy and sensorineural deafness was reported in the Department of Nephrology. We predicted improper functioning of ATP6V1B1 gene could be the reason for diseased condition. Therefore, exons 3, 4, and 7 contributing active site of ATP6V1B1 gene was amplified and sequenced (Accession numbers: KF571726, KM222653). The obtained sequences were BLAST searched against the wild type ATP6V1B1 gene which showed novel mutations c.307 A > G, c.308 C > A, c.310 C > G, c.704 T > C, c.705 G > T, c.709 A > G, c.710 A > G, c.714 G > A, c.716 C > A, c.717delC, c.722 C > G, c.728insG, c.741insT, c.753G > C. These mutations resulted in the expression of truncated protein terminating at Lys 209. The mutated ATP6V1B1structure superimposed with wild type showed extensive variations with RMSD 1.336 A and could not bind to substrate ADP leading to non-functional ATPase. These results conclusively explain these mutations in ATP6V1B1 gene resulted in structural changes causing accumulation of H(+) ions contributing to dRTA with sensorineural deafness. PMID- 25517797 TI - Eroded and pedunculated buttock nodule. PMID- 25517799 TI - COPD exacerbations: reducing the burden by predicting the future? PMID- 25517800 TI - Isoniazid preventive therapy in medium-incidence settings: the price is right. PMID- 25517798 TI - Knockdown of the cell cycle inhibitor p21 enhances cartilage formation by induced pluripotent stem cells. AB - The limited regenerative capacity of articular cartilage contributes to progressive joint dysfunction associated with cartilage injury or osteoarthritis. Cartilage tissue engineering seeks to provide a biological substitute for repairing damaged or diseased cartilage, but requires a cell source with the capacity for extensive expansion without loss of chondrogenic potential. In this study, we hypothesized that decreased expression of the cell cycle inhibitor p21 would enhance the proliferative and chondrogenic potential of differentiated induced pluripotent stem cells (iPSCs). Murine iPSCs were directed to differentiate toward the chondrogenic lineage with an established protocol and then engineered to express a short hairpin RNA (shRNA) to reduce the expression of p21. Cells expressing the p21 shRNA demonstrated higher proliferative potential during monolayer expansion and increased synthesis of glycosaminoglycans (GAGs) in pellet cultures. Furthermore, these cells could be expanded ~150-fold over three additional passages without a reduction in the subsequent production of GAGs, while control cells showed reduced potential for GAG synthesis with three additional passages. In pellets from extensively passaged cells, knockdown of p21 attenuated the sharp decrease in cell number that occurred in control cells, and immunohistochemical analysis showed that p21 knockdown limited the production of type I and type X collagen while maintaining synthesis of cartilage-specific type II collagen. These findings suggest that manipulating the cell cycle can augment the monolayer expansion and preserve the chondrogenic capacity of differentiated iPSCs, providing a strategy for enhancing iPSC-based cartilage tissue engineering. PMID- 25517801 TI - Extra-pulmonary tuberculosis: the comorbidity of the near future? PMID- 25517802 TI - Ambulatory tuberculosis treatment in post-Semashko health care systems needs supportive financing mechanisms. AB - The tuberculosis (TB) control strategy in the Republic of Karakalpakstan, Uzbekistan, is being changed to decentralised out-patient care for most TB patients by the Government of Uzbekistan, in collaboration with the international medical humanitarian organisation Medecins Sans Frontieres. Ambulatory treatment of both drug-susceptible and drug-resistant TB from the first day of treatment has been recommended since 2011. Out-patient treatment of TB from the beginning of treatment was previously prohibited. However, the current Uzbek health financing system, which evolved from the Soviet Semashko model, offers incentives that work against the adoption of ambulatory TB treatment. Based on the 'Comprehensive TB Care for All' programme implemented in Karakalpakstan, we describe how existing policies for the allocation of health funds complicate the scale-up of ambulatory-based management of TB. PMID- 25517803 TI - Self-management support and other alternatives to reduce the burden of asthma and chronic obstructive pulmonary disease. AB - While pharmacotherapy is important in the management of asthma and chronic obstructive pulmonary disease, it is also important to consider additional interventions that can further reduce the burden of ill health for patients, their families and the health care system. In this review, the evidence in favour of self-management support that leads to successful self-care by the patient is reviewed, and the key components of successful strategies are outlined; areas where more research is needed are identified. In addition to self-management support, other methods of delivering care, such as telemonitoring, admission avoidance, assisted discharge schemes and use of lay educators, are reviewed. PMID- 25517804 TI - Emphysematous phenotype is an independent predictor for frequent exacerbation of COPD. AB - SETTING: Frequent exacerbation is an important phenotype in chronic obstructive pulmonary disease (COPD), while emphysema is associated with many comorbidities and lung function decline. OBJECTIVE: To investigate unique features of frequent exacerbators and test the hypothesis that emphysematous phenotype is associated with frequent exacerbations of COPD. METHODS: A total of 380 COPD patients were recruited from 16 hospitals in Korea from June 2005 to April 2012 for analysis. We searched for independent predictors of frequent exacerbators in comparison with non-exacerbators. RESULTS: As the severity of emphysema increased, forced expiratory volume in 1 s (FEV1), and FEV1/FVC (forced volume capacity) worsened; hyperinflationary features characterised by higher total lung capacity (TLC) were observed (P < 0.05). Frequent exacerbators had lower body mass index (BMI), higher St George's Respiratory Questionnaire (SGRQ) scores, higher residual volume (RV)/TLC, more severe airflow limitation (lower FEV1 and FEV1/FVC), lower carbon monoxide diffusion capacity, lower serum protein levels and a higher emphysema index than non-exacerbators (P < 0.05). In multivariate analysis, frequent exacerbators were independently associated with a higher emphysema index, lower serum protein levels and higher RV/TLC (P < 0.05). CONCLUSION: Our data show that the severity of emphysema, severe static hyperinflation and serum lower protein levels are independent predictors of frequent exacerbations in COPD patients. PMID- 25517805 TI - Prognostic severity scores for patients with COPD exacerbations attending emergency departments. AB - SETTING: Reported predictors of the adverse evolution of patients with chronic obstructive pulmonary disease exacerbations (eCOPD) are various and inconsistent in the bibliography. OBJECTIVE: To develop clinical prediction rules for short term outcomes in eCOPD patients attending an emergency department (ED). DESIGN: Prospective cohort study of patients with an eCOPD. Short-term outcomes were admission to an intensive care unit (ICU), admission to an intermediate respiratory care unit (IRCU) and death in these groups. Multivariate logistic regression models were developed for each of the outcomes. RESULTS: Predictors of ICU or IRCU admission were use of long-term home oxygen therapy (LT-HOT) or non invasive mechanical ventilation (NIMV), elevated PCO2 and decreased pH upon ED arrival (area under the curve [AUC] 0.87 in the derivation sample; 0.89 in the validation sample). Among those admitted to an ICU or IRCU, predictors of death were increased age, use at home of LT-HOT or NIMV, use of inspiratory accessory muscles upon ED arrival and altered Glasgow Coma Scale (<15 points) (AUC 0.78). CONCLUSIONS: Three clinical predictors available in the ED can be used to create a simple score to predict the need for intensive treatment among eCOPD patients. Such a score can be a tool for clinical practice. PMID- 25517806 TI - Long-acting anticholinergic agents in patients with uncontrolled asthma: a systematic review and meta-analysis. AB - SETTING: A novel effective treatment is necessary for severe asthma. OBJECTIVE: To review clinical trials examining the role of tiotropium in patients with poorly controlled asthma despite inhaled corticosteroid use with or without long acting beta2-agonists. DESIGN: A computerised search of electronic databases (Medline, EMBASE and Cochrane Central Register) was performed. Randomised controlled trials of at least a 4-week treatment duration with findings published in English were included. RESULTS: Five studies involving 1635 patients were analysed. Compared with a placebo or a double dose of inhaled corticosteroids, the addition of tiotropium increased mean trough and peak forced expiratory volume in 1 second by 97 ml (95%CI 71-122) and 103 ml (95%CI 42-163), respectively. The mean differences in morning peak expiratory flow were 19.2 l/min (95%CI 11.8-26.6). Tiotropium also reduced the risk of severe acute exacerbation (OR 0.73, 95%CI 0.56-0.96) and improved Asthma Quality-of-Life Questionnaire score significantly by 0.10 (95%CI 0.04-0.16). There were no differences in serious adverse events. CONCLUSION: The addition of tiotropium may be beneficial for patients with poorly controlled asthma, although exacerbation or safety issues should be clarified in long-term trials before its wide use in asthma. PMID- 25517808 TI - Brief advice to tuberculosis patients in Nepal to stop smoking: a pilot study by the Britain Nepal Medical Trust. AB - SETTING: Tuberculosis (TB) treatment centres in Eastern Nepal. OBJECTIVE: To determine smoking cessation rates among TB patients advised to quit. DESIGN: One intervention and one control centre were studied. At the intervention centre, brief advice about smoking and cessation was given at the start of anti tuberculosis treatment, and repeated 2 and 5 months later. After 6 months of standard treatment, patients were asked about quitting. Expired air carbon monoxide (CO) was measured in those claiming 6 months of abstinence. RESULTS: None of the 51 controls achieved 6 months of abstinence, whereas 77 (39%) of the 195 in the intervention group claimed at least 6 months of abstinence. All claims were verified by CO measurement in expired air (95%CI 31.4-47.6, P < 0.0001 for the difference in smoking cessation). CONCLUSION: Brief advice on smoking cessation to patients starting anti-tuberculosis treatment in the National Tuberculosis Programme (NTP) setting in Eastern Nepal led to 39% quitting for least 6 months. Our results should encourage randomised trials in smokers with TB in Nepal: if substantiated, smoking cessation advice should become a mandatory component of the NTP. PMID- 25517807 TI - Validation of the Mandarin Chinese version of the Leicester Cough Questionnaire in bronchiectasis. AB - BACKGROUND: The Leicester Cough Questionnaire (LCQ) has been validated for assessing cough-specific health status in bronchiectasis. We translated the LCQ into Mandarin Chinese and investigated its validity, reliability and responsiveness. METHODS: The LCQ was translated into Mandarin Chinese using the forward-backward translation procedure. A total of 144 out-patients completed the Mandarin Chinese version of the LCQ (LCQ-MC), the Hospital Anxiety and Depression Scale (HADS) and the St George's Respiratory Questionnaire. Reassessments were performed during exacerbations and at 6 months. Concurrent validation, internal consistency, repeatability and responsiveness were determined. RESULTS: Minor cultural adaptations were made to the wording of LCQ-MC. No other difficulties were found during the translation process, with all items easily adapted to acceptable Mandarin Chinese. The questionnaire was not changed in terms of content layout and the order of the questions. In cognitive debriefing interviews, participants reported that the questionnaire was acceptable, relevant, comprehensive and easy to complete. The LCQ-MC showed good concurrent validity, internal consistency and test-retest reliability. Responsiveness was shown by significant changes in LCQ-MC scores between steady state, the first exacerbation and following 2-week antibiotic treatment (both interval changes, P < 0.01) CONCLUSION: The LCQ-MC is a valid, reliable and responsive instrument for determining cough-specific health status in Chinese bronchiectasis patients. PMID- 25517810 TI - Evaluating the role of primary care physicians in the treatment of latent tuberculosis: a population study. AB - SETTING: Latent tuberculous infection (LTBI) remains a significant source of new active tuberculosis cases. Recent guidelines encourage primary care physicians to prescribe LTBI treatment; however, there have been no investigations into the impact on treatment completion. OBJECTIVE: To estimate LTBI treatment initiation and completion rates by primary care physicians. DESIGN: A historical cohort study was conducted with Quebec residents dispensed isoniazid (INH) between 1 January 1998 and 31 December 2005. Information was obtained from administrative health insurance data. Regression modeling was used to estimate the association of completion rates with prescribing physician specialty, after adjustment for initial health status and other patient characteristics. RESULTS: A total of 14,753 people were dispensed INH for LTBI treatment. Primary care physicians initiated 3863 (26%) treatments. This proportion decreased from 28.7% in 1998 to 21.1% in 2005. Patients initiated on treatment by primary care physicians were less likely to complete treatment (OR 0.79, 95%CI 0.72-0.86). Only 5977 (40.5%) patients completed treatment; the average treatment duration of the primary care physician group was 11 days less (P < 0.0001). CONCLUSION: Primary care physicians initiated a substantial number of LTBI treatments, but less than half of patients completed treatment regardless of the physician specialty. Primary care physicians should be supported to enhance treatment completion. PMID- 25517809 TI - Cost-effectiveness of tuberculosis screening and isoniazid treatment in the TB/HIV in Rio (THRio) Study. AB - OBJECTIVE: To estimate the incremental cost-effectiveness of tuberculosis (TB) screening and isoniazid preventive therapy (IPT) among human immunodeficiency virus (HIV) infected adults in Rio de Janeiro, Brazil. DESIGN: We used decision analysis, populated by data from a cluster-randomized trial, to project the costs (in 2010 USD) and effectiveness (in disability-adjusted life years [DALYs] averted) of training health care workers to implement the tuberculin skin test (TST), followed by IPT for TST-positive patients with no evidence of active TB. This intervention was compared to a baseline of usual care. We used time horizons of 1 year for the intervention and 20 years for disease outcomes, with all future DALYs and medical costs discounted at 3% per year. RESULTS: Providing this intervention to 100 people would avert 1.14 discounted DALYs (1.57 undiscounted DALYs). The median estimated incremental cost-effectiveness ratio was $2273 (IQR $1779-$3135) per DALY averted, less than Brazil's 2010 per capita gross domestic product (GDP) of $11,700. Results were most sensitive to the cost of providing the training. CONCLUSION: Training health care workers to screen HIV-infected adults with TST and provide IPT to those with latent tuberculous infection can be considered cost-effective relative to the Brazilian GDP per capita. PMID- 25517811 TI - A descriptive study of tuberculosis case finding in private health care facilities in a South Indian district. AB - SETTING: A South Indian district providing anti-tuberculosis services through the Revised National TB Control Programme (RNTCP) and private health care facilities. OBJECTIVE: To ascertain the profile of tuberculosis (TB) patients diagnosed and/or treated in private health care facilities. METHODS: Data on TB cases diagnosed and/or treated in all clinical departments of the medical college, 83 nursing homes and RNTCP health care facilities were collected prospectively. RESULTS: About 83% of new TB cases recorded in the private medical college, 47% in nursing homes and 24.5% in RNTCP TB registers were extra-pulmonary. The proportion of retreatment cases was respectively 5.5%, 9.6% and 19.8%. The proportion of males and those in the economically productive age group were similar in the three data sources. About 94% of cases diagnosed in the medical college and 55% in nursing homes were registered for treatment under the RNTCP. About 11% of the smear-positive patients diagnosed in RNTCP were initial defaulters. CONCLUSION: The proportion of extra-pulmonary cases was higher in the medical college and nursing homes and that of retreatment cases was lower than in the RNTCP. PMID- 25517812 TI - Screening for active tuberculosis in high-risk groups. AB - OBJECTIVE: To evaluate an active case-finding strategy among drug users (DUs), economically disadvantaged individuals and recent immigrants from hyperendemic countries, a population at high risk of developing tuberculosis (TB). METHODS: Retrospective, observational study carried out by the Tuberculosis Unit of the City of Barcelona from September 2009 to December 2012. All participants underwent chest X-ray and were screened for symptoms. RESULTS: Of 5982 participants screened, 30 TB cases were detected (total prevalence 0.5%): 26 were pulmonary, 8 were smear-positive and 2 were resistant to multiple drugs. Directly observed treatment was advised for 19 patients (63%). TB prevalence in the recent immigrants group was significantly greater (1.77%) than in all other groups studied: economically disadvantaged individuals 0.30% (RR 5.9, 95%CI 2.30-15.14); DUs 0.62% (RR 2.05, 95%CI 0.91-4.64), non-recent immigrants 0.41% (RR 4.31, 95%CI 1.68-11.4); and all native-born individuals 0.41% (RR 4.33, 95%CI 1.71-10.92). The rate was much greater than the estimated prevalence for the general population of the city (~20 cases/100,000 population). CONCLUSIONS: In high-risk groups, active case finding can be used as a public health intervention to detect a large number of TB cases. PMID- 25517813 TI - Integrating active tuberculosis case finding in antenatal services in Zambia. AB - SETTING: Three out-patient antenatal care (ANC) clinics in Lusaka, Zambia. OBJECTIVE: To estimate tuberculosis (TB) prevalence in human immunodeficiency virus (HIV) infected and symptomatic, non-HIV-infected pregnant women and explore the feasibility of routine TB screening in ANC settings. DESIGN: Peer educators administered TB symptom questionnaires to pregnant women attending their first ANC clinic visit. Presumptive TB patients were defined as all HIV-infected women and symptomatic non-HIV-infected women. Sputum samples were tested using smear microscopy and culture to estimate TB prevalence. RESULTS: All 5033 (100%) women invited to participate in the study agreed, and 17% reported one or more TB symptoms. Among 1152 presumed TB patients, 17 (1.5%) had previously undiagnosed culture-confirmed TB; 2 (12%) were smear-positive. Stratified by HIV status, TB prevalence was 10/664 (1.5%, 95%CI 0. 7-2.8) among HIV-infected women and 7/488 (1.4%, 95%CI 0.6-2.9) among symptomatic non-HIV-infected women. In HIV-infected women, the only symptom significantly associated with TB was productive cough; symptom screening was only 50% sensitive. CONCLUSION: There is a sizable burden of TB in pregnant women in Zambia, which may lead to adverse maternal and infant outcomes. TB screening in ANC settings in Zambia is acceptable and feasible. More sensitive diagnostics are needed. PMID- 25517814 TI - Tuberculosis is associated with non-tuberculosis-related deaths among HIV/AIDS patients in Rio de Janeiro. AB - SETTING: Human immunodeficiency virus (HIV) infected patients followed in a large cohort in Rio de Janeiro, Brazil. OBJECTIVE: To evaluate the association of tuberculosis (TB) and other covariables with non-TB-related (NTR) causes of death (CODs). DESIGN: Patients aged >18 years were followed from 1997 to 2009, until death or 31 December 2009, whichever was earlier. CODs were ascertained using a standardised algorithm. TB diagnosis and prophylaxis followed Brazilian guidelines. Poisson models were used to calculate adjusted rate ratios (aRRs). RESULTS: Of 2887 patients included in the study, 761 had TB (26.4%). NTR death rates were twice as high among patients with TB (4/100 vs. 2.09/100 patient years). TB was associated with NTR deaths (aRR 1.4, 95%CI 1.05-1.86, P = 0.01). Highly active antiretroviral treatment (HAART) was protective against NTR (aRR 0.46, 95%CI 0.34-0.61, P < 0.001). Among patients who had never had active TB, prophylaxis was also protective against NTR (aRR 0.45, P = 0.04). The CD4 cell count increase was very modest for both TB and NTR CODs compared to those who did not die (0 vs. 249 cells, P < 0.001). CONCLUSIONS: TB was significantly associated with increased NTR CODs, indicating rapid progression of disease and increased long-term risk of mortality, probably related to persistent immunodeficiency or incomplete immune recovery. Our results confirm the benefits of HAART and TB prophylaxis. PMID- 25517815 TI - 'I'm fed up': experiences of prior anti-tuberculosis treatment in patients with drug-resistant tuberculosis and HIV. AB - OBJECTIVES: To understand the impact of past experiences of anti-tuberculosis treatment among patients co-infected with the human immunodeficiency virus and multidrug-resistant tuberculosis (MDR-TB) on perceptions and attitudes towards treatment. METHODS: Qualitative study using in-depth interviews with 12 HIV-MDR TB co-infected patients in Mumbai, India. RESULTS: Patients reported unnecessarily long pathways to care and fatigue with diagnostic and treatment procedures. In particular, they expressed concerns over the lack of efficacy of their current treatment regimen based on their experiences with anti-tuberculosis treatment regimens in the past. CONCLUSION: Patients reported negative experiences with previous HIV and anti-tuberculosis treatment. Access to early diagnosis and rapid initiation of integrated care for HIV-MDR-TB co-infected patients, with a strong, patient-centered support system, could help to combat the low morale and lack of faith in treatment described in this group of patients. PMID- 25517816 TI - Factors correlated with tuberculosis reported after death. AB - SETTING: Taiwan. OBJECTIVE: To determine factors associated with tuberculosis (TB) reported after death. DESIGN: A retrospective cohort study was conducted of TB patients newly registered between 2006 and 2008. The national TB database was linked with the Vital Registry System and National Health Insurance database for analysis. RESULTS: A total of 1409 (4.0%) TB cases were reported after death. Age ?75 years (OR 1.70), chest X-ray (CXR) unknown or not performed (OR 2.41), positive sputum bacteriology (OR 1.74), and comorbidities such as cancer (OR 1.21), chronic liver disease (OR 1.21) and chronic kidney disease (OR 2.58) were associated with the reporting of TB cases after death. More than 30% of TB deaths in elderly persons with chronic kidney disease were TB cases that were reported after death. Abnormal CXR and comorbidities such as chronic obstructive pulmonary disease, stroke and diabetes mellitus were less likely to be associated with the reporting of TB cases after death. CONCLUSIONS: Elderly patients with cancer, chronic liver disease or chronic kidney disease require more attention to prevent delayed diagnosis and early mortality from TB. Elderly patients with chronic kidney disease are at highest risk. PMID- 25517817 TI - Are registered sputum smear-negative tuberculosis patients in Karnataka, India, diagnosed by national algorithm? AB - SETTING: Four districts of Karnataka State, India, that have implemented the National Tuberculosis Control Programme (RNTCP). OBJECTIVE: To assess the proportion of patients diagnosed according to the nationally recommended algorithm among new smear-negative (NSN) PTB cases registered under the RNTCP. METHODS: Information on 201 registered NSN-PTB patients as regards date of initial sputum examination, repeat sputum examination and chest X-ray (CXR) if undertaken, treatment initiation and number of days of antibiotic treatment after initial sputum examination, were collected through record review and patient interviews. In patients with negative or unknown human immunodeficiency virus (HIV) status, the algorithm was considered completed if the patient underwent initial sputum examination, antibiotic trial for ?10 days, repeat sputum examination ?10 days after initial sputum examination, CXR after repeat sputum examination and anti-tuberculosis treatment ?10 days after initial sputum examination. In HIV-positive patients, the algorithm was considered completed if CXR was performed after or at the same time as initial sputum examination. RESULTS: Complete information was available for 170 patients. Of these, the algorithm was completed in 14 (8.2%, 95%CI 0.9-15.5): 1/140 patients with negative or unknown HIV status and 13/30 HIV-positive patients. CONCLUSION: The algorithm was not completed in most patients registered for treatment. Measures are needed to improve the diagnostic process for smear-negative PTB. PMID- 25517818 TI - Inadequate values from an interferon-gamma release assay for smear-negative tuberculosis in a high-burden setting. AB - OBJECTIVE: To examine the usefulness of an interferon-gamma release assay (IGRA) for the diagnosis of smear-negative tuberculosis (TB) in China. DESIGN: A total of 624 patients with presumed pulmonary TB were enrolled prospectively and categorised as smear-negative TB, smear-positive TB or no TB. All patients were tested using T-SPOT.TB. RESULTS: Both the smear-negative and smear-positive TB groups had significantly more spot-forming cells (SFCs) than the no TB group (all P < 0.001), while the smear-negative group had fewer SFCs than the smear-positive TB group (P < 0.001). The specificity of T-SPOT.TB was 60.4% (95%CI 53.4-67.1). The sensitivities of T-SPOT.TB in the smear-negative and smear-positive TB groups were respectively 81.4% (95%CI 75.7-86.0) and 93.2% (95%CI 87.6-96.4). The sensitivity in the smear-negative TB group was much lower than that in the smear positive TB (P < 0.05). CONCLUSIONS: The sensitivity of T-SPOT.TB was lower due the paucibacillary nature of the samples, and the specificity was lower due to the high prevalence of latent tuberculous infection in the smear-negative TB patients. The T-SPOT.TB test should only be used as a supplementary test and not as a single test to rule in or rule out smear-negative TB. PMID- 25517819 TI - Tuberculosis Beijing strain outbreak in an Israeli Arab rural community linked to an incarcerated immigrant. AB - A tuberculosis (TB) outbreak with six definite and four probable cases, caused by a Beijing strain isolate, occurred in an Arab rural community in north Israel. Using epidemiological investigation and strain genotyping, we identified the source case as an incarcerated immigrant. This outbreak illustrates how a systematic breakdown in TB prevention and control measures at multiple levels, within prisons and upon exiting prison, can result in rapid, cross-ethnic transmission of TB to a low-risk population. The close social bonds in this rural community and downsizing of the regional TB clinic staff may also have contributed to the magnitude of this outbreak. PMID- 25517820 TI - Comparative bioavailability of rifampicin and isoniazid in fixed-dose combinations and single-drug formulations. AB - SETTING: The bioavailability of rifampicin (RMP) decreases by ~30% on interaction with isoniazid (INH) in stomach acid conditions, which can result in the development of drug resistance and treatment failure. OBJECTIVE: To compare the bioavailability in healthy volunteers of five anti-tuberculosis fixed-drug combinations (FDCs) used in China (formulations A-E) containing RMP and INH against single-drug formulations taken as reference. DESIGN: Two- or three period, two- or three-sequence crossover study of drugs. RESULT: Only RMP formulation E passed the bioequivalence criteria, with 90% confidence intervals for the log-transformed ratios of AUC0-24, AUC0-infinity, and Cmax of respectively 89.9-103.7, 89.6-102.2 and 87.7-107.9. For INH, formulations A, B, C and D passed the bioequivalence test, but not product E, where the 90%CIs of the log-transformed ratios of AUC0-24, AUC0-infinity, and Cmax were respectively 85.2 100.7, 85.2-100.7 and 73.8-100.9. CONCLUSION: According to the results of the bioequivalence analysis carried out in this study, RMP formulations A, B, C and D were not within the acceptable range and only formulation E passed the bioequivalence criteria of 80-125%. In comparison, four-test INH formulations (A, B, C and D) were bioequivalent to the corresponding single-drug formulation, while product E failed in the bioequivalence criteria. PMID- 25517821 TI - In vitro interaction of eupomatenoid-5 from Piper solmsianum C. DC. var. solmsianum and anti-tuberculosis drugs. AB - SETTING: Department of Clinical Analysis and Biomedicine, State University of Maringa, Maringa, Parana, Brazil. OBJECTIVE: To evaluate the in vitro interaction between eupomatenoid-5 (EUP-5), extracted from Piper solmsianum C. DC. var. solmsianum, and first-line anti-tuberculosis drugs against Mycobacterium tuberculosis H37Rv and 20 clinical isolates. DESIGN: Resazurin drugs combination microtiter assay (REDCA) was performed to determine the interaction between EUP-5 and isoniazid, rifampicin (RMP) and ethambutol (EMB). RESULTS: Synergism was observed in M. tuberculosis H37Rv and eight clinical isolates with EUP-5+RMP, and in M. tuberculosis H37Rv and 17 clinical isolates with EUP-5+EMB combinations. CONCLUSION: EUP-5 is a promising compound for further studies on the development of anti-tuberculosis drugs. PMID- 25517823 TI - Compassionate use of bedaquiline in the treatment of pulmonary XDR-TB. PMID- 25517822 TI - Epidemiology of extra-pulmonary tuberculosis in the United States: high rates persist in the post-HIV era. AB - BACKGROUND: The incidence of tuberculosis (TB) in the United States has declined following a logarithmic pattern, with few exceptions. One exception was during the acquired immunodeficiency syndrome (AIDS) epidemic, which was thought to have caused the deviation. However, since then, alternative explanations have been proposed, including the increased burden of chronic diseases, immigration, and the increase in the use of immune suppressant medications. METHODS: Epidemiological data of the Center for Disease Control and Prevention (CDC) and the Bureau of the Census were analyzed regarding TB incidence, human immunodeficiency virus (HIV) infection, immigration status, and age for the period 1953-2011. RESULTS: Data analysis identified a deviation from the logarithmic decline in TB cases that started in the mid-2000s. This divergence did not appear to be related to HIV status. The overall decline in TB cases since 1953 has been almost exclusively due to a reduction in pulmonary TB (PTB) and not to extra-pulmonary TB (EPTB). CONCLUSIONS: The HIV/AIDS epidemic likely played a significant role in the 1979-1985 deviation, but not subsequently. Furthermore, EPTB as a proportion of total TB cases has remained high. Further studies to delineate the etiologies of these findings are needed. PMID- 25517824 TI - Private players in tuberculosis control: will negotiation help to maintain the symbiosis in the ecosystem? PMID- 25517825 TI - Failure of the MGIT 960 culture system in the detection of Mycobacterium tuberculosis. PMID- 25517827 TI - Toward culture-free Raman spectroscopic identification of pathogens in ascitic fluid. AB - The identification of pathogens in ascitic fluid is standardly performed by ascitic fluid culture, but this standard procedure often needs several days. Additionally, more than half of the ascitic fluid cultures are negative in case of suspected spontaneous bacterial peritonitis (SBP). It is therefore important to identify and characterize the causing pathogens since not all of them are covered by the empirical antimicrobial therapy. The aim of this study is to show that pathogen identification in ascitic fluid is possible by means of Raman microspectroscopy and chemometrical evaluation with the advantage of strongly increased speed. Therefore, a Raman database containing more than 10000 single cell Raman spectra of 34 bacterial strains out of 13 different species was built up. The performance of the used statistical model was validated with independent bacterial strains, which were grown in ascitic fluid. PMID- 25517826 TI - Interferon-alpha induces neurotoxicity through activation of the type I receptor and the GluN2A subunit of the NMDA receptor. AB - Elevated levels of interferon-alpha (IFNalpha) in the central nervous system (CNS) are linked to cognitive dysfunction in patients with inflammatory CNS diseases such as HIV-associated neurocognitive disorders (HAND). Increased CNS IFNalpha has also been found to be associated with cognitive dysfunction in a HAND mouse model. Here, we corroborate previous studies showing a dose-dependent decrease in dendritic branching and length caused by IFNalpha treatment and extend those studies. Because both direct and indirect mechanisms of IFNalpha induced neurotoxicity are likely involved, the cell signaling pathway involving the IFNalpha receptor (IFNAR) was initially evaluated. Rat neuronal cultures exposed to IFNalpha demonstrate increased phosphorylation of STAT1 and increased interferon stimulating gene 15 (ISG15) expression, indicators of IFNAR engagement. However, specific blocking antibodies to the IFNAR were found to only partially protect neurons from IFNalpha-induced neurotoxicity. Additionally, inhibiting the GluN2A subunit of N-methyl-D-asparate receptor (NMDAR) was also found to be partially protective against IFNalpha-induced neurotoxicity compared with the GluN2B subunit. Neurotoxicity is evident in neurons extracted from IFNAR KO mice treated with IFNalpha as well, further indicating that IFNAR signaling is not required for IFNalpha neurotoxicity. The neurotoxic actions of IFNalpha are mediated through both the IFNAR as well as the GluN2A subunit of the NMDAR to reduce dendritic arborization in neurons. Complete protection from IFNalpha induced neurotoxicity was demonstrated when both pathways were blocked. Blocking these pathways could lead to potential therapies for cognitive dysfunction during neuroinflammation and specifically lead to better treatments for HAND. PMID- 25517828 TI - The nursing graduate program at 40 years: what can we commemorate? PMID- 25517829 TI - Women survivors of intimate partner violence: the difficult transition to independence. AB - Objective To understand the trajectories that women go through from entering into to leaving relationships involving intimate partner violence (IPV), and identify the stages of the transition process. Method We utilized a constructivist paradigm based on grounded theory. We ensured that the ethical guidelines of the World Health Organization for research on domestic violence were followed. The analysis focused on narratives of 28 women survivors of IPV, obtained from in depth interviews. Results The results showed that the trajectories experienced by women were marked by gender issues, (self) silencing, hope and suffering, which continued after the end of the IPV. Conclusion The transition process consists of four stages: entry - falls in love and becomes trapped; maintenance - silences own self, consents and remains in the relationship; decides to leave - faces the problems and struggles to be rescued; (re) balance - (re) finds herself with a new life. This (long) process was developed by wanting (and being able to have) self-determination. PMID- 25517830 TI - Determinants of emergency contraception non-use among women in unplanned or ambivalent pregnancies. AB - Objective To analyze the determinants of emergency contraception non-use among women in unplanned and ambivalent pregnancies. Method Cross-sectional study with a probabilistic sample of 366 pregnant women from 12 primary health care units in the city of Sao Paulo, Brazil. A multinomial logistic regression was performed, comparing three groups: women who used emergency contraception to prevent ongoing pregnancies (reference); women who made no use of emergency contraception, but used other contraceptive methods; and women who made no use of any contraceptive methods at all. Results Cohabitation with a partner was the common determinant of emergency contraception non-use. No pregnancy risk awareness, ambivalent pregnancies and no previous use of emergency contraception also contributed to emergency contraception non-use. Conclusion Apart from what is pointed out in the literature, knowledge of emergency contraception and the fertile period were not associated to its use. PMID- 25517831 TI - Evaluation of prenatal care in unit with family health strategy. AB - We analyzed prenatal care (PN) provided at a unit of the Family Health Strategy Service in Sao Paulo, according to the indicators of the Program for the Humanization of Prenatal and Birth (PHPB). We compared adequacy of PN in terms of sociodemographic variables, procedures, examinations and maternal and perinatal outcomes. Cross-sectional study with data from records of 308 pregnant women enrolled in 2011. We observed early initiation of PN (82.1%), conducting of a minimum of six consultations (84.1%), puerperal consultation (89.0%); to the extent that there is a sum of the actions, there is a significant drop in the proportion of adequacy. Prenatal care was adequate for 67.9%, with a significant difference between adequacy groups in relation to gestational age and birth weight. Prenatal care deficiencies exist, especially in regards to registration of procedures, exams and immunization. The difference between adequacy groups with respect to perinatal outcomes reinforces the importance of prenatal care that adheres to the parameters of the PHPB. PMID- 25517832 TI - Urinary incontinence related to perineal muscle strength in the first trimester of pregnancy: cross-sectional study. AB - Objective To analyze pelvic floor muscle strength (PFMS), urinary continence and quality of life related to urinary incontinence (UI) of women in the first trimester of pregnancy. Method Cross-sectional study with a sample of 500 women who started prenatal care in a complementary healthcare facility in Guarulhos, state of Sao Paulo, from 2012 and 2013. Pelvic floor muscle strength was evaluated through perineometry. The pregnant women who presented UI answered the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). Results It was found that maternal age (OR=1.06; CI95% 1.02-1.11) and prior UI (OR=15.12; 95%CI 8.19-27.92) are the variables that, in tandem, best explain the occurrence of UI at the beginning of pregnancy. The mean score on the ICIQ-SF was 8.2 (SD=3.9), considered a moderate impact on quality of life. Conclusion Older pregnant women with prior UI are more likely to have UI in the first trimester of pregnancy. PMID- 25517833 TI - Association between perineal trauma and pain in primiparous women. AB - Objective To identify the association between perineal trauma and pain in 473 primiparous women. Method Cross-sectional study in which pain was measured by the numerical pain scale (0 to 10 - 0 being no pain and 10 maximal pain). Results The prevalence and mean intensity of pain were 33.0% and 4.7 points (standard deviation = 2.0) in the numeric scale, respectively. Episiotomy represented the most frequent trauma (46.7%). The occurrence and intensity of the pain were associated with perineal trauma and postpartum time. Having perineal trauma tripled the chance of pain. Each hour elapsed following the birth reduced the chance of pain by 4.8%. Conclusion Primiparous women are subject to a high frequency of perineal trauma, with episiotomy being the most prominent. Perineal pain affects approximately one-third of primiparous women and is associated with the postpartum time and perineal traumas. PMID- 25517834 TI - Use of medicinal plants by black women: ethnography study in a low-income community. AB - Objective To explore beliefs, values and practices related to the use of medicinal plants among low-income black families. Method The research method was ethnography and the participant observation process was done in a low-income community in the peripheral area of the City of Sao Paulo. Twenty black women were interviewed. Results Two cultural sub-themes, I do use medicines that I learned to make with my mother and with religious practitioners to care for diseases and Home medicines are to treat problems that are not serious, and the cultural theme I do use home medicines to treat simple diseases because I always have them at my disposal, they are free and I don't need a medical prescription represent beliefs, values, and practices related to the use of medicinal plants among low-income black families. Conclusion The development of such practices, which can hide ethnic and social vulnerability, reveals the resilience of low income black women in the process of confronting problems during the health illness process. PMID- 25517835 TI - Limits and possibilities experienced by nurses in the treatment of women with chronic venous ulcers. AB - Objective To understand the experiences and expectations of nurses in the treatment of women with chronic venous ulcers. Method Phenomenological research was based on Alfred Schutz, whose statements were obtained in January, 2012, through semi-structured interviews with seven nurses. Results The nurse reveals the difficulties presented by the woman in performing self-care, the perceived limitations in the treatment anchored in motivation, and the values and beliefs of women. It showed professional frustration because venous leg ulcer recurrence, lack of inputs, interdisciplinary work and training of nursing staff. There was an expected adherence to the treatment of women, and it emphasized the need for ongoing care, supported self-care and standard practices in treatment. Conclusion That treatment of chronic venous leg ulcers constitutes a challenge that requires collective investment, involving women, professionals, managers and health institutions. PMID- 25517836 TI - Use and records of child health handbook focused on growth and development. AB - Objective To evaluate the use and records of the Child Health Handbook (CHH), especially growth and development. Method Cross-sectional study with 358 mother child pairs registered in 12 Primary Health Centers (PHCs) of a small municipality. Mothers were interviewed at the PHC from February to April 2013 using a questionnaire. Data analysis was done using WHO Anthro software, Epi InfoTM and Stata. Results Fifty-three percent of the mothers were carrying the CHH at the time of the interview, similar to the proportion of mothers who were instructed to bring the CHH to health appointments. Annotations in the CHH during the visits were reported by 49%. The vaccination schedule was completed in 97% of the CHH, but only 9% and 8% of the CHH, respectively, contained growth charts and properly completed developmental milestones. Conclusion Low rates of use and unsatisfactory record-keeping in the CHH reinforce the need for investment in professional training and community awareness for the CHH to become an effective instrument of promotion of child health. PMID- 25517837 TI - Living with pain: the experience of children and adolescents in palliative care. AB - A qualitative study was conducted with semi-structured interviews with the aim of understanding the experience of children and adolescents under palliative care when managing pain daily and how they describe the intensity, quality and location of pain. We used Piaget's theory of cognitive development as a theoretical framework and oral history as a methodological framework. We found four themes: describing pain; seeking a life closer to normality, despite pain and disease; using a variety of alternatives for pain control; and living with damaged physical appearance. Although pain is a limiting factor in the lives of children and adolescents, we found that they faced their daily pain and still had a life beyond pain and illness. In addition, we highlight the relevance of nurses' understanding that effective management of pain in children is essential for a normal life and less suffering. PMID- 25517838 TI - Nurses' attitudes regarding the importance of families in pediatric nursing care. AB - Affective, cognitive and behavioral components affect nurses' attitudes to include families in the care processes. The purpose of this study was to investigate the attitudes of nurses about the importance of including families in nursing care. Data collection was performed in pediatric and maternal-child unit of a Brazilian university hospital. A sample of 50 nurses completed the Portuguese version of the instrument Families'Importance in Nursing Care-Nurses' Attitudes (FINC-NA). The results indicated that nurses have supportive attitudes regarding families participation in nursing care. Attitudes of lower support for involving families in nursing care were found among nurses with older age, more time in the profession and who had no previous contact with contents related to Family Nursing. The application of the instrument in other contexts of assistance may help to illuminate important aspects of the challenges to implementing a family-centered approach in clinical practice. PMID- 25517839 TI - The practice of nurses caring for families of pediatric inpatients in light of Jean Watson. AB - Objective To know the facilities and the difficulties of nurses in caring practice of hospitalized children's families in the light of Jean Watson's Theory of Human Caring. Method It was used the descriptive qualitative approach. The data collection was conducted in three stages: presentation of theoretical content; engagement with families in the light of Watson's theory; and semi structured interview with 12 pediatric nurses. The interviews were analysed using inductive thematic analysis, being possible to form three themes: Recognizing a framework for care; Considering the institutional context; and Challenges in family's relationship. Results The theory favored reflections about self, about the institutions and about nurses' relationship with the family of the child, normalized by a consciousness toward caring attitudes. Conclusion In this process, it is imperative that nurses recognize the philosophical-theoretical foundations of care to attend the child's family in hospital. PMID- 25517840 TI - Caring for family caregivers: An analysis of a family-centered intervention. AB - Objective To assess the effectiveness of Problem-Solving Therapy (PST) on family caregivers through the use of scales to measure anxiety, depression and emotional distress; and to explore facilitating factors and obstacles for its use based on the narrative of nurses. Method A clinical trial and an exploratory focus group with the use of mixed analysis methodology. The study was conducted in a primary health care center in Tarragona, Spain, and the sample consisted of 122 family caregivers who were included in the home care service, and 10 nurses who participated in the intervention group. Family caregivers with evident symptoms of anxiety, depression and emotional distress received PST in the intervention group. The intervention group also consisted of a discussion with eight nurses, which was transcribed and submitted to content analysis. Conclusion Problem Solving Therapy proved to be effective in reducing perceived anxiety, depression and emotional distress. We identified its strong points and obstacles as described by nurses. PMID- 25517841 TI - Social network of family caregivers of disabled and dependent patients. AB - Cross-sectional study that used the Social Network Index and the genogram to assess the social network of 110 family caregivers of dependent patients attended by a Home Care Service in Sao Paulo, Brazil. Data were analyzed using the test U of Mann-Whitney, Kruskal-Wallis and Spearman correlation. Results were considered statistically significant when p<0,05. Few caregivers participated in activities outside the home and the average number of people they had a bond was 4,4 relatives and 3,6 friends. Caregivers who reported pain and those who had a partner had higher average number of relatives who to trust. The average number of friends was higher in the group that reported use of medication for depression. Total and per capita incomes correlated with the social network. It was found that family members are the primary caregiver's social network. PMID- 25517842 TI - Violence against adolescents: an analysis based on the categories gender and generation. AB - Exploratory and descriptive study based on quantitative and qualitative methods that analyze the phenomenon of violence against adolescents based on gender and generational categories. The data source was reports of violence from the Curitiba Protection Network from 2010 to 2012 and semi-structured interviews with 16 sheltered adolescents. Quantitative data were analyzed using SPSS software version 20.0 and the qualitative data were subjected to content analysis. The adolescents were victims of violence in the household and outside of the family environment, as victims or viewers of violence. The violence was experienced at home, mostly toward girls, with marked overtones of gender violence. More than indicating the magnitude of the issue, this study can give information to help qualify the assistance given to victimized people and address how to face this issue. PMID- 25517843 TI - Practices in primary health care oriented toward the harmful consumption of drugs. AB - Objective To analyze the practices of primary care focused on the harmful consumption of drugs. Method This is a qualitative study, developed with a dialectical-critical approach. Data collection was carried out through semi structured interviews with 10 employees of a basic health unit (UBS). Results The demands are not accepted, and if they go beyond the barriers shaped by the historical absence of health care practices for drug users and moralistic and preconceived ideologies, they are not reinterpreted as health needs; practices that meet these demands and go beyond the barriers are poor; the functionalist approach, which explains drug use as a disease and considers drug users as deviants, supports the few existing practices. Conclusion primary health care is mistakenly focused on addiction; it lacks structural elements of the production process in health and internal dynamics of the working processes that would foster the development of collective practices. PMID- 25517844 TI - Emancipatory practices of nurses in primary health care: the home visit as an instrument of health needs assessment. AB - Objective Identify nurses' emancipatory practices in primary care, to contribute to the improvement of health care. Method A case study type social research of qualitative nature, in which nurses of a primary health care service unit in Sao Paulo were interviewed. Results The home visit was identified as a nursing practice possible to be expanded in order to identify social determinants of health, triggering emancipatory practices in the service. This expansion occurred because the design of health care labour intended by the service team changed its focus from the traditional object of health services, the disease. Conclusion First, it is advocated that social policies lead projects with the purpose of improving health needs. On the other hand, the daily labour needs to provide opportunities for reflection and discussion of healthcare projects, leading workers to propose labour-processes targeted to both the social determinants of health and people's illness. PMID- 25517845 TI - Assessment of primary health care: health professionals' perspective. AB - Objective To assess primary health care attributes of access to a first contact, comprehensiveness, coordination, continuity, family guidance and community orientation. Method An evaluative, quantitative and cross-sectional study with 35 professional teams in the Family Health Program of the Alfenas region, Minas Gerais, Brazil. Data collection was done with the Primary Care Assessment Tool - Brazil, professional version. Results Results revealed a low percentage of medical experts among the participants who evaluated the attributes with high scores, with the exception of access to a first contact. Data analysis revealed needs for improvement: hours of service; forms of communication between clients and healthcare services and between clients and professionals; the mechanism of counter-referral. Conclusion It was concluded that there is a mismatch between the provision of services and the needs of the population, which compromises the quality of primary health care. PMID- 25517846 TI - Social determinants of hospitalizations for ambulatory care sensitive conditions in Guarulhos, Sao Paulo. AB - The study goals present an overview of Hospitalizations for Ambulatory Care Sensitive Conditions (ACSC) in Guarulhos, SP, from 2008 to 2012. This is an ecological study based on secondary data obtained from the Brazilian Hospital Information System, and supported by the Praxical Theory of Intervention of Collective Health Nursing. Applied descriptive statistics for analysis. It was observed that Guarulhos shows an upward trend in hospitalizations by ACSC (20% increase), the most frequent causes of heart failure (11.8%), cerebrovascular disease (10.6%) and angina (9.7%), most frequently in the age group >= 65years old, for both sexes. The results are similar to other Brazilian studies, but their analysis should extrapolate the biological limits and the supply of healthcare resources, focusing on the social determinants of the health-disease process. PMID- 25517847 TI - Overview of hospitalizations by ambulatory care sensitive conditions in the municipality of Cotia, Brazil. AB - Objective To describe the profile of Hospitalizations by Amulatory Care Sensitive Conditions (HACSC), in the Municipality of Cotia, from 2008 to 2012. Method ecological, exploratory, longitudinal study with a quantitative approach. Data on HACSC, by age group and sex, were obtained from the Department of the Unified Health System. For data analysis descriptive statistics were used. Results During the period, there were 46,676 admissions, excluding deliveries, 7,753 (16.61%) by HACSC. The main causes were cerebrovascular diseases, 16.96%, heart failure, 15.50%, hypertension, 10.80% and infection of the kidney and urinary tract, 10.51%. Regarding gender, HACSC occurred predominantly in males. There was a greater number of HACSC at extreme age ranges, especially in the elderly. Conclusion Chronic diseases predominate among the leading causes of HACSC and there was no significant difference between sex. PMID- 25517848 TI - Comprehensiveness and programmatic vulnerability to stds/hiv/aids in primary care. AB - This study aimed to identify programmatic vulnerability to STDs/HIV/AIDS in primary health centers (PHCs). This is a descrip - tive and quantitative study carried out in the city of Sao Paulo. An online survey was applied (FormSUS platform), involving administrators from 442 PHCs in the city, with responses received from 328 of them (74.2%), of which 53.6% were nurses. At - tention was raised in relation to program - matic vulnerability in the PHCs regarding certain items of infrastructure, prevention, treatment, prenatal care and integration among services on STDs/HIV/AIDS care. It was concluded that in order to reach comprehensiveness of actions for HIV/ AIDS in primary health care, it is necessary to consider programmatic vulnerability, in addition to more investment and reor - ganization of services in a dialogue with the stakeholders (users, multidisciplinary teams, and managers, among others). PMID- 25517849 TI - Assessing the vulnerability of women to sexually transmitted diseases STDS/ HIV: construction and validation of markers. AB - Objective To construct and validate markers of vulnerability of women to STDs/HIV, taking into consideration the importance of STDs/HIV. Method Methodological study carried out in three stages: 1) systematic review and identification of elements of vulnerability in the scientific production; 2) selection of elements of vulnerability, and development of markers; 3) establishment of the expert group and validation of the markers (content validity). Results Five markers were validated: no openness in the relationship to discuss aspects related to prevention of STDs/HIV; no perception of vulnerability to STDs/HIV; disregard of vulnerability to STDs/ HIV; not recognizing herself as the subject of sexual and reproductive rights; actions of health professionals that limit women's access to prevention of STDs/HIV. Each marker contains three to eleven components. Conclusion The construction of such markers constituted an instrument, presented in another publication, which can contribute to support the identification of vulnerabilities of women in relation to STDs/HIV in the context of primary health care services. The markers constitute an important tool for the operationalization of the concept of vulnerability in primary health care and to promote inter/multidisciplinary and inter/multi-sectoral work processes. PMID- 25517850 TI - Analysis of the process of translation of knowledge regarding early childhood at the undergraduate level. AB - Objective To analyze innovative contents on Early Child Development Promotion. Method This action-research involves nine faculties from four Higher Education Institutions at inner-state of Sao Paulo, Brazil.Data were collected by syllabi analyses (2009-2011), interviews and focus group. We have adopted an ECDP underpinning from international consensus, thus evaluating KT Results We have found relevant incorporation between teaching and extension in Nursing (87,5%) and Psychology (75%) undergraduate courses, while Pedagogy was restricted to teaching. Conclusion This KT evaluation has evinced innovative potential of extension, regardless teaching and research, for a better Early Childhood. PMID- 25517851 TI - Technologies of birth and models of midwifery care. AB - This article is based on a study of a reform in the organisation of maternity services in the United Kingdom, which aimed towards developing a more woman centred model of care. After decades of fragmentation and depersonalisation of care, associated with the shift of birth to a hospital setting, pressure by midwives and mothers prompted government review and a relatively radical turnaround in policy. However, the emergent model of care has been profoundly influenced by concepts and technologies of monitoring. The use of such technologies as ultrasound scans, electronic foetal monitoring and oxytocic augmentation of labour, generally supported by epidural anaesthesia for pain relief, have accompanied the development of a particular ecological model of birth - often called active management -, which is oriented towards the idea of an obstetric norm. Drawing on analysis of women's narrative accounts of labour and birth, this article discusses the impact on women's embodiment in birth, and the sources of information they use about the status of their own bodies, their labour and that of the child. It also illustrates how the impact on women's experiences of birth may be mediated by a relational model of support, through the provision of caseload midwifery care. PMID- 25517852 TI - Changes in physiological and behavioral parameters of preterm infants undergoing body hygiene: a systematic review. AB - Objective To verify the effect of bathing on the body temperature of preterm infants (PTI). Method Systematic review conducted in the following bibliographic electronic sources: Biblioteca Virtual em Saude/Lilacs (BVS), Cumulated Index of Nursing and Allied Health Literature (CINAHL), Cochrane Library, Google Scholar, PubMed, SCOPUS and Web of Science, using a combination of search terms, keywords and free terms. The review question was adjusted to the PICO acronym (Patient/population, Intervention, Control/comparative intervention, Outcome). The selected publications were evaluated according to levels of evidence and grades of recommendation for efficacy/effectiveness studies, as established by the Joanna Briggs Institute. Results Eight hundred and twenty four (824) publications were identified and four studies met the inclusion criteria, of which three analyzed the effect of sponge baths and the effect of immersion baths. Conclusion Sponge baths showed a statistically significant drop in body temperature, while in immersion baths the body temperature remained stable, although they studied late preterm infants. PMID- 25517853 TI - Role of complementary therapies in the understanding of primary healthcare professionals: a systematic review. AB - Objective To identify the understanding of the healthcare professionals in relation to the role of complementary therapies in primary health care. Method Systematic review by way of the following information sources: PubMed, CINAHL, PeriEnf, AMED, EMBASE, Web of Science, Psicoinfo and Psicodoc, using the keyword Primary Health Care alone, and associated with the following keywords: Medicinal Plants, Herbal Medicine, Homeopathy, Traditional Chinese Medicine, Acupuncture, Anthroposophical Medicine. Results Twenty-two studies from 1986 to 2011 were included. We identified three styles of practice: conventional medicine, complementary therapies and integrative medicine. Positioning professional practices within these three styles may facilitate discussion of concepts of health care, enhancing the health care provided as a result. Conclusion The work process in primary care presents difficulties for conducting integrative and holistic health care, but this practice has been introduced over time by professionals who integrate conventional medicine and complementary therapies, concerned with the care and well-being of patients. PMID- 25517854 TI - Difficulties of familes in caring for children and adolescents with mental disorders: an integrative review. AB - Objective To identify the difficulties of families with children and/or adolescents with mental disorder. Method This is an integrative review. In December 2013, an electronic search was performed on Latin American Caribbean Literature on Health Sciences databases (LILACS) and on Electronic Medicus Index of the National Library of Medicine (MEDLINE) indexed in the Health Virtual Library (BVS) using a combination of descriptors and boolean operators as follows: mental disorders and child or adolescent and caregivers and/not health staff. Results 557 studies were identified, of which 15 were selected for this study. The findings indicated difficulties related to the care for or to interaction with children/adolescents with mental disorder. Conclusion The studies revealed difficulties related to everyday practices of care and feelings expressed during care practices, as well as in relationships with children or adolescents with mental disorder. PMID- 25517856 TI - Beyond gender: proximity to interpersonal trauma in examining differences in believing child abuse disclosures. AB - Survivors of child sexual abuse (CSA) often delay disclosing or do not disclose the abuse for fear of not being believed. Studies document that women believe CSA disclosures more often than do men. Little research has examined theoretical underpinnings for gender differences in believing. However, 1 theory suggests that women may be more empathetic to disclosures because interpersonal trauma (IPT) is proximal to their lives. The present study aimed to extend understanding of how proximity to IPT may shape views of others' experiences of IPT. This study examined whether proximity to IPT (i.e., knowing a close other who had experienced IPT) rather than personal experience would better account for the robust gender differences typically found in believing disclosures. College students (N = 279) completed self-report measures about their personal trauma history and responded to questions regarding knowledge of close others' trauma histories. Participants read a vignette of an adult female disclosing CSA and rated the disclosure for believability. Results indicate that exposure to IPT increased believing, whereas gender did not. These results suggest that one's proximity to IPT may be an alternative explanation for influence on believing CSA rather than gender alone. PMID- 25517855 TI - Deletion of exon 1 of the SLC16A2 gene: a common occurrence in patients with Allan-Herndon-Dudley syndrome. AB - BACKGROUND: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked type of mental retardation resulting from hindered thyroid hormone access to neurons. Clustered nonrecurrent deletions of SLC16A2 exon 1 have been described in three patients with AHDS. We report a fourth patient with such a deletion and discuss possible mechanisms leading to these rearrangements. CASE PRESENTATION: A three-and-a-half year-old male with clinical and biochemical AHDS phenotype and a history of normal neonatal screening for hypothyroidism underwent SLC16A2 molecular analysis. Unexpectedly, he showed skeletal signs of hypothyroidism. METHODS AND RESULTS: The exons of the SLC16A2 (MCT8) gene and the sequences surrounding exon 1 were amplified using PCR. The patient had a 36-kb deletion affecting exon 1 of SLC16A2. The deletion junction was subjected to bioinformatic analyses, along with two other reported exon 1 deletion junctions, identifying possible sequence features and mechanisms responsible for such genomic rearrangements. DISCUSSION/CONCLUSION: This patient had a classic AHDS phenotype with an unexpectedly large anterior fontanel and delayed bone age and dentition. Bioinformatic analyses suggested that exon 1 deletions in patients with AHDS are caused by microhomology-mediated replicative-based and nonhomologous end-joining mechanisms. Rearrangement susceptibility may be due to the size of intron 1 and the percentage of repeat sequences. PMID- 25517857 TI - Lactoylglutathione lyase, a critical enzyme in methylglyoxal detoxification, contributes to survival of Salmonella in the nutrient rich environment. AB - Glyoxalase I which is synonymously known as lactoylglutathione lyase is a critical enzyme in methylglyoxal (MG) detoxification. We assessed the STM3117 encoded lactoylglutathione lyase (Lgl) of Salmonella Typhimurium, which is known to function as a virulence factor, due in part to its ability to detoxify methylglyoxal. We found that STM3117 encoded Lgl isomerises the hemithioacetal adduct of MG and glutathione (GSH) into S-lactoylglutathione. Lgl was observed to be an outer membrane bound protein with maximum expression at the exponential growth phase. The deletion mutant of S. Typhimurium (Deltalgl) exhibited a notable growth inhibition coupled with oxidative DNA damage and membrane disruptions, in accordance with the growth arrest phenomenon associated with typical glyoxalase I deletion. However, growth in glucose minimal medium did not result in any inhibition. Endogenous expression of recombinant Lgl in serovar Typhi led to an increased resistance and growth in presence of external MG. Being a metalloprotein, Lgl was found to get activated maximally by Co(2+) ion followed by Ni(2+), while Zn(2+) did not activate the enzyme and this could be attributed to the geometry of the particular protein-metal complex attained in the catalytically active state. Our results offer an insight on the pivotal role of the virulence associated and horizontally acquired STM3117 gene in non-typhoidal serovars with direct correlation of its activity in lending survival advantage to Salmonella spp. PMID- 25517858 TI - Physicochemical characterization of sewage sludge and green waste for agricultural utilization. AB - In order to valorize the organic wastes, a mixture composed of 60 kg of thick sewage sludge from a wastewater treatment plant, 30 kg of green wastes (made of 10 kg straw of wheat, 10 kg manure farm wastes, and 10 kg of dead leaves), and 10 kg of wood chips was prepared. The organic wastes were mixed and put into a wooden cubic composter having a volume of 1.5 m3. Physicochemical analyses were made every 30 days for five months. The results of the analyses showed that the obtained compost had good physicochemical quality and can be used as an organic fertilizer. The main characteristics of this compost were distinguished by its pH from 7.4 to 7.8, with a ratio of organic matter of 40-42%. During composting, the humification process led to an increase in humic acids from 29.5 to 39.1 mg g( 1), a decrease in fulvic acids from 32.1 to 10.9 mg g(-1), and a global decomposition of hemicellulose, cellulose, and lignin. The obtained results show that a period of 150 days of composting gave a C/N ratio of 15.4. The total metal content in the final compost was much lower than the standard toxic levels for composts to be used as good soil fertilizers. The germination index for the two plants Cicer arietinum and Hordeum vulgare was 93% after the same period of composting, showing that the final compost was not phytotoxic. The study showed the possibility of valorization of the compost and its possible use in the domain of agriculture. PMID- 25517859 TI - Multifunctional PEG modified DOX loaded mesoporous silica nanoparticle@CuS nanohybrids as photo-thermal agent and thermal-triggered drug release vehicle for hepatocellular carcinoma treatment. AB - The combination of a multi-therapeutic mode with a controlled fashion is a key improvement in nanomedicine. Here, we synthesized polyethylene glycol (PEG) modified doxorubicin (DOX)-loaded mesoporous silica nanoparticle (MSN) @CuS nanohybrids as efficient drug delivery carriers, combined with photothermal therapy and chemotherapy to enhance the therapeutic efficacy on hepatocellular carcinoma (HCC). The physical properties of the nanohybrids were characterized by transmission electron microscopy (TEM), N2 adsorption and desorption experiments and by the Vis-NIR absorption spectra. The results showed that the doxorubicin could be stored in the inner pores of mesoporous silica nanoparticles; the CuS nanoparticles, which are coated on the surface of a mesoporous silica nanoparticle, could serve as efficient photothermal therapy (PTT) agents; the loaded drug release could be easily triggered by NIR irradiation. The combination of the PTT treatment with controlled chemotherapy could further enhance the cancer ablation ability compared to any of the single approaches alone. Hence, the reported PEG-modified DOX-loaded mesoporous silica nanoparticle@CuS nanohybrids might be very promising therapeutic agents for HCC treatment. PMID- 25517861 TI - Phosphorylation-independent binding of 14-3-3 to NtCDPK1 by a new mode. AB - 14-3-3 pproteins play essential roles in diverse cellular processes through the direct binding to target proteins. REPRESSION OF SHOOT GROWTH (RSG) is a tobacco (Nicotiana tabacum) transcription factor that is involved in gibberellin (GA) feedback regulation. The 14-3-3 proteins bind to RSG depending on the RSG phosphorylation of Ser-114 and negatively regulate RSG by sequestering it in the cytoplasm in response to GAs. The Ca(2+)-dependent protein kinase NtCDPK1 was identified as an RSG kinase that promotes 14-3-3 binding of RSG by phosphorylation of RSG. 14-3-3 weakly binds to NtCDPK1 by a new mode. The autophosphorylation of NtCDPK1 was necessary for the formation of the binding between NtCDPK1 and 14-3-3 but not for its maintenance. In this study, we showed that 14-3-3 binding to NtCDPK1 does not require the autophosphorylation when RSG was bound to NtCDPK1. These data suggest that 14-3-3 binds to an unphosphorylated motif in NtCDPK1 exposed by a conformational change in NtCDPK1 but not to a phosphate group generated by autophosphorylation of NtCDPK1. PMID- 25517862 TI - Experimental and theoretical studies on halide binding with a p-xylyl-based azamacrocycle. AB - A p-xylyl-based macrocycle L has been synthesized and its binding properties with halides have been investigated by (1)H NMR titrations, single crystal X-ray diffraction analysis, and density functional theory (DFT) calculations. As investigated by (1)H NMR titrations, the ligand preferentially binds a halide in a 1:2 binding mode, with the association constants (in log K2) of 2.82, 2.70, 2.28, and 2.20 for fluoride, chloride, bromide, and iodide, respectively. The overall binding trend was found to be in the order of fluoride > chloride > bromide > iodide, reflecting that the binding strength correlates with the relative basicity and size of the respective halide. Crystallographic studies indicate that the ligand forms 1:2 complexes with chloride, bromide and iodide. In the chloride complex, the ligand is hexaprotonated and each chloride is held via three NH...Cl(-) bonds. The ligand is tetraprotonated for the other complexes, where each halide is H-bonded to two secondary ammonium NH(+) groups via NH...X(-) bonds. The results of DFT calculations performed on [H6L](6+) at M062x/6-311G (d,p) level in both gas and solvent phases, suggest that the ligand binds halides with the binding energy in the order of F(-) > Cl(-) > Br(-) > I( ), supporting the experimental data obtained from (1)H NMR studies. Results from DFT calculations further indicate that a 1:2 binding is energetically more favorable than a 1:1 binding of the ligand. PMID- 25517864 TI - A unifying model for Neoproterozoic-Palaeozoic exceptional fossil preservation through pyritization and carbonaceous compression. AB - Soft-tissue fossils capture exquisite biological detail and provide our clearest views onto the rise of animals across the Ediacaran-Cambrian transition. The processes contributing to fossilization of soft tissues, however, have long been a subject of debate. The Ediacaran Gaojiashan biota displays soft-tissue preservational styles ranging from pervasive pyritization to carbonaceous compression, and thus provides an excellent opportunity to dissect the relationships between these taphonomic pathways. Here geochemical analyses of the Gaojiashan fossil Conotubus hemiannulatus show that pyrite precipitation was fuelled by the degradation of labile tissues through bacterial sulfate reduction (BSR). Pyritization initiated with nucleation on recalcitrant tube walls, proceeded centripetally, decelerated with exhaustion of labile tissues and possibly continued beneath the BSR zone. We propose that pyritization and kerogenization are regulated principally by placement and duration of the decaying organism in different microbial zones of the sediment column, which hinge on post-burial sedimentation rate and/or microbial zone thickness. PMID- 25517863 TI - Omics meets biology: application to the design and preclinical assessment of antivenoms. AB - Snakebite envenoming represents a neglected tropical disease that has a heavy public health impact worldwide, mostly affecting poor people involved in agricultural activities in Africa, Asia, Latin America and Oceania. A key issue that complicates the treatment of snakebite envenomings is the poor availability of the only validated treatment for this disease, antivenoms. Antivenoms can be an efficacious treatment for snakebite envenoming, provided they are safe, effective, affordable, accessible and administered appropriately. The shortage of antivenoms in various regions, particularly in Sub-Saharan Africa and some parts of Asia, can be significantly alleviated by optimizing the use of current antivenoms and by the generation of novel polyspecific antivenoms having a wide spectrum of efficacy. Complementing preclinical testing of antivenom efficacy using in vivo and in vitro functional neutralization assays, developments in venomics and antivenomics are likely to revolutionize the design and preclinical assessment of antivenoms by being able to test new antivenom preparations and to predict their paraspecific neutralization to the level of species-specific toxins. PMID- 25517865 TI - ERG Expression in Prostate Needle Biopsy: Potential Diagnostic and Prognostic Implications. AB - To investigate the prognostic and diagnostic value of ERG immunohistochemistry (IHC) in prostate needle biopsy when combined with AMACR-CK5/6. ERG IHC was assessed in 119 consecutive prostate needle biopsies where the dual-stain AMACR CK5/6 IHC was ordered and in 16 cases with a Gleason score (GS) >=7. IHC results were evaluated in prostate carcinoma (PCA), high-grade prostatic intraepithelial neoplasia (HGPIN), HGPIN with adjacent atypical glands (PINATYP), atypical/suspicious (ASAP) foci, and benign PCA mimickers. GS, HGPIN, extraprostatic extension, perineural invasion, bilateralism of PCA, largest percent of core, and the overall percent of tissue involved by PCA were recorded. ERG was detected in 36% of PCA, 27% of HGPIN, 13% of ATYP/PINATYP, and none of benign mimickers. ERG-positive HGPIN was strongly associated with ERG-positive PCA in the same core compared with ERG-negative HGPIN (P<0.0001). Positive ERG expression in PCA was inversely related to GS and showed trends toward association with higher volume and bilateral disease. ERG was more specific for PCA than AMACR (0.87 vs. 0.23), but less sensitive (0.36 vs. 0.95). In conclusion, ERG IHC is of limited additional diagnostic value when added to AMACR and CK5/6. ERG expression is inversely related to GS and is associated with bilateral involvement and higher PCA tumor volume. ERG-positive HGPIN is strongly associated with the presence of PCA in the same core. Studies investigating the prognostic value of ERG in HGPIN should be implemented to address whether patients with ERG-positive HGPIN are at increased risk for subsequent PCA development. PMID- 25517866 TI - One Size Fits All: Evaluation of the Transferability of a New "Learning" Histologic Image Analysis Application. AB - Quantitative analysis of histologic slides is of importance for pathology and also to address surgical questions. Recently, a novel application was developed for the automated quantification of whole-slide images. The aim of this study was to test and validate the underlying image analysis algorithm with respect to user friendliness, accuracy, and transferability to different histologic scenarios. The algorithm splits the images into tiles of a predetermined size and identifies the tissue class of each tile. In the training procedure, the user specifies example tiles of the different tissue classes. In the subsequent analysis procedure, the algorithm classifies each tile into the previously specified classes. User friendliness was evaluated by recording training time and testing reproducibility of the training procedure of users with different background. Accuracy was determined with respect to single and batch analysis. Transferability was demonstrated by analyzing tissue of different organs (rat liver, kidney, small bowel, and spleen) and with different stainings (glutamine synthetase and hematoxylin-eosin). Users of different educational background could apply the program efficiently after a short introduction. When analyzing images with similar properties, accuracy of >90% was reached in single images as well as in batch mode. We demonstrated that the novel application is user friendly and very accurate. With the "training" procedure the application can be adapted to novel image characteristics simply by giving examples of relevant tissue structures. Therefore, it is suitable for the fast and efficient analysis of high numbers of fully digitalized histologic sections, potentially allowing "high-throughput" quantitative "histomic" analysis. PMID- 25517867 TI - Diagnostic Utility of STAT6 Immunohistochemistry in the Diagnosis of Fat-forming Solitary Fibrous Tumors. PMID- 25517868 TI - Analysis of the distribution and expression of claudin-1 tight junction protein in the oral cavity. AB - BACKGROUND: Claudins are the main sealing proteins of the intercellular tight junctions and play an important role in cancer cell progression and dissemination. The authors have previously shown that overexpression of claudin-1 is associated with angiolymphatic and perineural invasion, consistent with aggressive tumor behavior and with advanced stage disease in oral squamous cell carcinomas (OSCCs). Our goal in this study was to examine claudin-1 expression in a tissue microarray of OSCCs taken from multiple sites within the oral cavity. MATERIALS AND METHODS: This study examined and compared the expression of claudin 1 by immunohistochemistry in 60 tissue samples (49 OSCCs and 10 cases of non neoplastic tissue, single core per case) were analyzed for claudin-1 expression by immunohistochemistry. The tumors included SCCs from the tongue (n=28), the cheek (n=9), gingival (n=4), lip (n=3), and oral cavity (n=5). Nonmalignant normal oral mucosa from the tongue (unmatched cases, n=2). Cancer adjacent tissue samples were taken from the tongue (n=6), gingival (n=2), and palate (n=1). RESULTS: This study demonstrates the expression of claudin-1 protein across a sample of OSCCs originating from multiple locations in the oral cavity. The highest expression of claudin-1 was observed in well-differentiated OSCCs, whereas poorly differentiated OSCCs exhibited mostly negative staining for claudin-1. In addition, we hereby report differential pattern of expression among tumors of different sites within the oral cavity, and between benign and cancerous samples. Our understanding of the exact function and role of claudin-1 in tumorigenesis is expanding exponentially. PMID- 25517869 TI - Human kallikrein 10 expression in surgically removed human pituitary corticotroph adenomas: an immunohistochemical study. AB - Human kallikrein 10 (hk10), a secreted serine protease, was reported to function as a tumor suppressor. hK10 immunoexpression has been demonstrated in lactrotrophs and corticotrophs of the nontumorous human adenohypophysis. In the present study, for the first time we report hK10 immunoexpression in various surgically removed corticotroph adenoma subtypes. Specimens were fixed in formalin and embedded in paraffin. Immunostaining was performed using the streptavidin-biotin-peroxidase complex method with an hK10-specific rabbit polyclonal antibody. Results showed that the endocrinologically active adrenocorticotropic hormone (ACTH)-producing pituitary tumors and the silent subtypes were immunopositve for hK10. Intensity of staining varied between the different subtypes. Intensity was lowest in the silent subtypes (silent corticotroph subtypes 1 and 2) compared with nontumorous human adenohypophysial corticotrophs, whereas the endocrinologically active subtypes (ACTH-secreting adenomas, corticotroph carcinomas, Crooke cell adenomas, Crooke cell carcinomas), showed the highest hK10 immunoexpression. Immunopositivity in the nuclei of the ACTH-secreting adenomas and carcinomas, as well as dual cytoplasmic and nuclear localization of hK10 in some of the secreting tumor types was an intriguing finding. Immunoexpression of hK10 in the ACTH-secreting tumors as well as in the Crooke cell tumors was significantly increased when compared with the nonfunctioning tumors and in the corticotrophs of nontumorous pituitaries. PMID- 25517870 TI - Myoepithelial carcinoma of the lung: a review. AB - Primary myoepithelial carcinoma of the lung is a rare neoplasm with only 8 cases reported in the English literature to date. Myoepithelial carcinomas of the lung are thought to arise from submucosal bronchial glands and have morphologic features similar to their salivary gland counterparts. The pathologic features and immunohistochemical profile of this tumor have not yet been summarized in the literature. Our objective is to review the clinicopathologic features and immunohistochemistry of these tumors. PMID- 25517871 TI - Rapid Identification of FGFR2 Gene Mutations in Taiwanese Patients With Endometrial Cancer Using High-resolution Melting Analysis. AB - OBJECTIVES: Mutations in fibroblast growth factor receptor 2 (FGFR2) gene have been reported in endometrial cancer and mutant FGFR2 has been pointed out as a potential therapeutic target. The aim of the current study was to use a high resolution melting (HRM) analysis to identify FGFR2 hotspot mutations and to investigate the occurrence of these mutations in the Taiwanese population with endometrial cancer. DESIGN AND METHODS: HRM analysis was designed to characterize the FGFR2 hotspot mutations. DNAs were extracted from 72 cases of fresh-frozen endometrial cancer tissues for FGFR2 mutational analysis by HRM analysis. The 6 exons of FGFR2 were screened by HRM analysis. All results were confirmed by direct sequencing. RESULTS: We have identified the 6 reported mutations in the FGFR2 gene. The mutation c.879C>T (p.Q289P) was first reported in endometrial cancer. Each mutation could be readily and accurately identified in the difference plot curves. The frequency of FGFR2 hotspot mutations is 9.7% (7/72) in patients with endometrial cancer in the Taiwanese population. CONCLUSIONS: HRM analysis is rapid, feasible, and a reliable diagnostic method for the detection of FGFR2 mutations in a clinical setting. Our results indicated the prevalence of FGFR2 mutational status in the Taiwanese population with endometrial cancer. PMID- 25517872 TI - Immunohistochemical detection of the BRAF V600E mutant protein in colorectal neoplasms. AB - Reliable assessment of the BRAF mutation status is becoming increasingly important in the clinical management of colorectal carcinomas (CRC). The aim of this study was to investigate the use of a recently developed mutation-specific antibody (VE1; SpringBio, Pleasanton, CA) to detect the BRAF V600E protein in paraffin tissue. We analyzed by immunohistochemistry (IHC) 117 cases that had been evaluated for BRAF mutation using a MALDI-TOF mass spectrometry-based assay. Immunohistochemical staining was evaluated without the knowledge of the genetic data and was considered positive when there was distinct homogenous cytoplasmic staining in the tumor cells. The analyzed cases included 4 polyps, 63 primary CRC, and 50 metastatic CRC. Forty-five of the 46 (97.8%) cases that were positive by IHC had a BRAF V600E mutation by genetic analysis; the 1 discordant case was notably of signet ring cell type. Similarly, 66 of the 67 (98.5%) cases that were negative by IHC were also negative by genetic analysis. Four cases that showed weak cytoplasmic staining and/or nuclear staining in the tumor cells were considered to be IHC equivocal; by genetic analysis, 2 of the 4 were positive and 2 were negative. The overall sensitivity and specificity of IHC for the detection of a BRAF V600E mutant tumor was 93.7% and 95.6%, respectively. Our results support the use of VE1 IHC for identification of colorectal neoplasms harboring the BRAF V600E mutation. Difficulties in immunohistochemical interpretation may arise in a small number of cases and in those cases molecular testing is required. PMID- 25517875 TI - Surgical mentorship from mentee to mentor: lessons from the life of Alfred Blalock, MD. PMID- 25517873 TI - Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation. AB - Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features. PMID- 25517874 TI - Activation of RidA chaperone function by N-chlorination. AB - Escherichia coli RidA is a member of a structurally conserved, yet functionally highly diverse protein family involved in translation inhibition (human), Hsp90 like chaperone activity (fruit fly) and enamine/imine deamination (Salmonella enterica). Here, we show that E. coli RidA modified with HOCl acts as a highly effective chaperone. Although activation of RidA is reversed by treatment with DTT, ascorbic acid, the thioredoxin system and glutathione, it is independent of cysteine modification. Instead, treatment with HOCl or chloramines decreases the amino group content of RidA by reversibly N-chlorinating positively charged residues. N-chlorination increases hydrophobicity of RidA and promotes binding to a wide spectrum of unfolded cytosolic proteins. Deletion of ridA results in an HOCl-sensitive phenotype. HOCl-mediated N-chlorination thus is a cysteine independent post-translational modification that reversibly turns RidA into an effective chaperone holdase, which plays a crucial role in the protection of cytosolic proteins during oxidative stress. PMID- 25517876 TI - The impact of coronary artery disease on outcomes after liver transplantation. AB - AIMS: The aim of this study is to assess the impact of obstructive coronary artery disease (CAD) on outcomes after liver transplantation. BACKGROUND: Patients considered for liver transplantation are at an increased risk for CAD. Obstructive CAD is a contraindication for liver transplantation at most centres. However, the association between severity of CAD and liver transplantation outcomes remains poorly characterized. METHODS: We retrospectively reviewed 386 consecutive liver transplantations performed between January 2001 and December 2005 at Northwestern Memorial Hospital (NMH). A comparative analysis was conducted for a national cohort (n = 23 820) from the United Network for Organ Sharing database. Outcome measures included patient and graft survival, rates of acute myocardial infarction and heart failure. RESULTS: Patient survival remained similar irrespective of CAD severity or cardiovascular risk index (CRI) in the NMH cohort. The CRI closely correlated with the presence of CAD in the NMH cohort [CRI 0, odds ratio (OR) 0.125, 95% confidence interval (95% CI) 0.02-0.61, P = 0.01; CRI 1, OR 1 reference; CRI >=2, OR 2.28, 95% CI 1.09-4.75, P = 0.02]. In the national cohort using Cox regression, high (>=2) CRI (reference 0, hazard ratio 1.376, 95% CI 1.271-1.488, P < 0.0001) predicted patient mortality and exceeded established risk factors, including Hepatitis C virus (HCV) (hazard ratio 1.321, 95% CI 1.242-1.403, P < 0.0001), hepatocellular carcinoma (HCC) (hazard ratio 1.27, 95% CI 1.181-1.370, P < 0.0001) and diabetes (hazard ratio 1.241, 95% CI 1.160-1.326, P < 0.0001). CONCLUSION: Liver transplantation in patients with CAD is not associated with prohibitive risk for cardiac events and patient mortality. Appropriately treated CAD should therefore not represent a contraindication to liver transplantation. PMID- 25517877 TI - Prosthesis embolization into the left ventricle during transcatheter aortic valve implantation. AB - : Images and movie clips documenting the rare occurrence of a percutaneous prosthesis embolization into the left ventricle are presented. The case outcome and the circumstances leading to the event are discussed. PMID- 25517880 TI - In vivo bioavailability and in vitro bioaccessibility of perfluorooctanoic acid (PFOA) in food matrices: correlation analysis and method development. AB - Food is a major source of human exposure to perfluorooctanoic acid (PFOA), however, PFOA bioavailability in food has not been studied. An in vivo mouse model and three in vitro methods (unified BARGE method, UBM; physiologically based extraction test, PBET; and in vitro digestion method, IVD) were used to determine the relative bioavailability and bioaccessibility of PFOA in the presence of 17 foods. PFOA was mixed with foods of different nutritional compositions and fed to mice over a 7-d period. PFOA relative bioavailability was determined by comparing PFOA accumulation in the liver following PFOA exposure via food to that in water. PFOA bioavailability relative to water ranged from 4.30 +/- 0.80 to 69.0 +/- 11.9% and was negatively correlated with lipid content (r = 0.76). This was possibly due to competitive sorption of free fatty acids with PFOA onto transporters on intestine epithelial cells. Besides, cations in the gastrointestinal tract, such as Ca(2+) and Mg(2+), are capable of complexing PFOA and partitioning to the lipid phase. On the other hand, when assessed using in vitro assays, PFOA bioaccessibility varied with methods, being 8.7-73% (UBM), 9.8-99% (PBET), and 21-114% (IVD). PFOA bioaccessibility was negatively correlated with lipid content when assessed using UBM (r = 0.82); however, a poor correlation with food composition was observed for PBET and IVD (r = 0.01-0.50). When in vivo and in vitro data were compared, a strong correlation was observed for UBM (r = 0.79), but poor relationships were observed for PBET and IVD (r = 0.11-0.22). This was probably because the higher lipolysis ability and presence of Ca(2+) and Mg(2+) in the gastrointestinal fluid of UBM resulted in a lower potential to form stable micelles compared to PBET and IVD. These results indicated that PFOA relative bioavailability was mainly affected by lipid content in foods, and UBM has the potential to determine PFOA bioaccessibility in food samples. PMID- 25517879 TI - Lactobacillus rhamnosus CNCM I-3690 and the commensal bacterium Faecalibacterium prausnitzii A2-165 exhibit similar protective effects to induced barrier hyper permeability in mice. AB - Impaired gut barrier function has been reported in a wide range of diseases and syndromes and in some functional gastrointestinal disorders. In addition, there is increasing evidence that suggests the gut microbiota tightly regulates gut barrier function and recent studies demonstrate that probiotic bacteria can enhance barrier integrity. Here, we aimed to investigate the effects of Lactobacillus rhamnosus CNCM I-3690 on intestinal barrier function. In vitro results using a Caco-2 monolayer cells stimulated with TNF-alpha confirmed the anti-inflammatory nature of the strain CNCM I-3690 and pointed out a putative role for the protection of the epithelial function. Next, we tested the protective effects of L. rhamnosus CNCM I-3690 in a mouse model of increased colonic permeability. Most importantly, we compared its performance to that of the well-known beneficial human commensal bacterium Faecalibacterium prauznitzii A2-165. Increased colonic permeability was normalized by both strains to a similar degree. Modulation of apical tight junction proteins expression was then analyzed to decipher the mechanism underlying this effect. We showed that CNCM I 3690 partially restored the function of the intestinal barrier and increased the levels of tight junction proteins Occludin and E-cadherin. The results indicate L. rhamnosus CNCM I-3690 is as effective as the commensal anti-inflammatory bacterium F. prausnitzii to treat functional barrier abnormalities. PMID- 25517882 TI - Human immunodeficiency virus coinfection with hepatitis B virus leads to a decrease in extracellular and intracellular hepatitis B antigen. AB - Chronic hepatitis B virus (HBV) infection could cause severe liver disease including cirrhosis, hepatocellular carcinoma, and end-stage liver failure in HIV positive individuals. The available data from clinical studies suggest that HIV infection modulates the HBV-specific T cell response. However, the virological and molecular aspects of HIV-HBV coinfection are currently poorly understood due to the lack of appropriate model systems. In this study, the effect of HIV infection on the life cycle of HBV was explored using an in vitro model system. The present data show that the extracellular and intracellular hepatitis B surface antigen (HBsAg) and e antigen (HBeAg) decrease significantly in HepG2 cells cotransfected with HIV NL4-3 and pHBV1.3 as compared to those cells transfected only with pHBV1.3. Moreover, a significant decrease in HBV DNA and mRNA expression was also observed in the cotransfected cells. HIV Rev protein, an RNA-bound regulatory protein, could significantly decrease the expression levels of extracellular and intracellular HBsAg and HBeAg by mediating the expression of HBV mRNA in cells cotransfected with plasmids containing HIV-1 Rev and pHBV1.3. Further experiments demonstrate that HIV Rev manipulated neither the promoters of HBV nor the nuclear export of HBV mRNA. These results from the in vitro model system might provide clues to further understand the rapid progression of liver disease in HIV-HBV-coinfected patients. PMID- 25517883 TI - A three-dimensional microporous metal-metalloporphyrin framework. AB - A new porphyrin-based microporous MOF, {Mn(II)0.5[Mn(II)4Cl(Mn(III)Cl ttzpp)2(H2O)4]}.(DEF)20.(CH3OH)18.(H2O)12 (UTSA-57), has been constructed from {5,10,15,20-tetrakis[4-(2,3,4,5-tetrazolyl)phenyl]porphyrinato} manganese(III) chloride as the metalloligand. The MOF adopts the rare scu topology with one dimensional square nanotube-like channels of about 20 A. UTSA-57a exhibits permanent porosity and displays moderately high performance for C2H2/CH4 separation at room temperature. PMID- 25517884 TI - Primary endocardial fibroelastosis and nonimmune hydrops fetalis: case report with autopsy. AB - Endocardial fibroelastosis is an important cause of congestive heart failure and death in infancy and early childhood. When present, it is commonly associated with non immune hydrops fetalis. The aim of this study is to draw attention for possible cardiac abnormalities in cases of fetal hydrops, and report a case of premature death by primary endocardial fibroelastosis with autopsy. PMID- 25517885 TI - Quantification of sickle cells in the peripheral smear as a marker of disease severity. AB - Blinded readers examined peripheral smears of 108 children with steady sickle cell (SC) disease and controls by counting ten 100 * microscope fields and calculating percent of irreversible and reversible SC from total red cell population SC index (SCI). SCI was correlated to disease severity, and transfusion, hydroxyurea, or neither. Controls had a mean of 0.28% SC (range 0 0.64). Children with hemoglobin SS had a mean SCI of 5.12% +/- 5.37 (range 0-30). SCI increased 0.33% with each increasing year (p < 0.0001). Patients with SCI >0.64 were 3.32 times as likely to experience clinical complications (p = 0.0124). Although blood transfusions and hydroxyurea decreased percent of SC, 72% treated patients had SCI >0.64, correlating with persistent sickling. This standardized method quantifies SC in peripheral smears. Percent of SC increased with age and correlated with disease severity, especially hemolytic complications, providing readily available information with minimal or no extra cost. PMID- 25517886 TI - Cerebral processing of proper and common nouns: Perception and production following left hemisphere damage. AB - The goal of this study was to further investigate hemispheric specialization for proper and common nouns by examining the ability of individuals with left hemisphere damage (LHD) to perceive and verbally reproduce famous names and matched common names compared with the performance of matched healthy controls (HC). Ten individuals with LHD due to stroke and 16 age- and education-matched HC completed recognition and production tasks of famous proper and common nouns. All tasks were designed as split-visual field experiments, modelled after the study done by Ohnesorge and Van Lancker. Results contribute to a better understanding of hemispheric roles in perception and production of famous proper nouns, suggesting that (1) both hemispheres can recognize famous proper nouns, possibly due to a right hemisphere role in personal relevance and (2) production of proper nouns as well as common nouns is associated with left hemisphere. PMID- 25517881 TI - Hepatitis C virus life cycle and lipid metabolism. AB - Hepatitis C Virus (HCV) infects over 150 million people worldwide. In most cases HCV infection becomes chronic, causing liver disease ranging from fibrosis to cirrhosis and hepatocellular carcinoma. HCV affects the cholesterol homeostasis and at the molecular level, every step of the virus life cycle is intimately connected to lipid metabolism. In this review, we present an update on the lipids and apolipoproteins that are involved in the HCV infectious cycle steps: entry, replication and assembly. Moreover, the result of the assembly process is a lipoviroparticle, which represents a peculiarity of hepatitis C virion. This review illustrates an example of an intricate virus-host interaction governed by lipid metabolism. PMID- 25517889 TI - Balancing neuromuscular blockade versus preserved muscle activity. AB - PURPOSE OF REVIEW: Acute respiratory distress syndrome (ARDS) is still associated with a high mortality. The best way to ensure mechanical ventilation in ARDS patients is still debated, recent data arguing for a muscle paralysis and a controlled ventilation whereas other elements being in favor of a preserved spontaneous breathing. The purpose of this review is to discuss the benefits and the disadvantages of both strategies. RECENT FINDINGS: Randomized controlled trials have brought the evidence that at the acute phase of ARDS, a 48-h administration of cisatracurium is associated with a decrease in mortality for the most severe hypoxemic patients. Other studies suggest that spontaneous breathing could be deleterious at this period. In the less severe patients (mild ARDS), however, a few studies have demonstrated the benefits of preserving spontaneous breathing with an improvement in oxygenation and a decrease in the length of mechanical ventilation. SUMMARY: In ARDS patients, the ventilator strategy should be a balance between muscle paralysis in the most hypoxemic patients and preserved spontaneous breathing after improvement or from the acute phase in less severe forms. However, monitoring plateau pressure, tidal volume and perhaps also transpulmonary pressure seems crucial to limit the occurrence of ventilator-induced lung injury. PMID- 25517887 TI - Independent recruitment of Igh alleles in V(D)J recombination. AB - How the vast majority of B cells express only one of the two alleles at their immunoglobulin loci remains a biological puzzle. Here, in mice reconstituted with a single haematopoietic stem cell, we demonstrate that each of the two immunoglobulin heavy chain (Igh) alleles has a similar probability to be the first to undergo V(H) to DJ(H) rearrangement. We also observe this similar probability in clones from multipotent and common lymphoid precursors. The extreme biases in the expression of the alleles that we find in more differentiated subsets are mostly due to constraints imposed by early rearrangements. Our data demonstrate that each of the two Igh alleles in a B cell behaves independently of the other, up to the moment when a successful rearrangement in one allele triggers a feedback mechanism that prevents further recombination. PMID- 25517890 TI - Extracorporeal life support for severe acute respiratory distress syndrome. AB - PURPOSE OF REVIEW: To provide a summary of the recent literature on extracorporeal membrane oxygenation (ECMO) in adults with severe acute respiratory distress syndrome (ARDS), focusing on advances in equipment, current conventional and unconventional indications, complications, and future applications. RECENT FINDINGS: ECMO use has increased during the past 5 years. Advances in cannulation, circuit design, and patient selection have made it a safer therapeutic option in severe ARDS, and its use has become more widespread for nonconventional indications. SUMMARY: High-quality evidence for the routine use of ECMO for management of adult patients with severe ARDS is still lacking. An ongoing randomized controlled trial (ECMO to rescue lung injury in severe ARDS) will contribute valuable data to guide clinical decisions to opt for this supportive therapy. PMID- 25517891 TI - Bioaccumulation of perfluoroalkyl acids by earthworms (Eisenia fetida) exposed to contaminated soils. AB - The presence of perfluoroalkyl acids (PFAAs) in biosolids-amended and aqueous film-forming foam (AFFF)-impacted soils results in two potential pathways for movement of these environmental contaminants into terrestrial foodwebs. Uptake of PFAAs by earthworms (Eisenia fetida) exposed to unspiked soils with varying levels of PFAAs (a control soil, an industrially impacted biosolids-amended soil, a municipal biosolids-amended soil, and two AFFF-impacted soils) was measured. Standard 28 day exposure experiments were conducted in each soil, and measurements taken at additional time points in the municipal soil were used to model the kinetics of uptake. Uptake and elimination rates and modeling suggested that steady state bioaccumulation was reached within 28 days of exposure for all PFAAs. The highest concentrations in the earthworms were for perfluorooctane sulfonate (PFOS) in the AFFF-impacted Soil A (2160 ng/g) and perfluorododecanoate (PFDoA) in the industrially impacted soil (737 ng/g). Wet-weight (ww) and organic carbon (OC)-based biota soil accumulation factors (BSAFs) for the earthworms were calculated after 28 days of exposure for all five soils. The highest BSAF in the industrially impacted soil was for PFDoA (0.42 goc/gww,worm). Bioaccumulation factors (BAFs, dry-weight-basis, dw) were also calculated at 28 days for each of the soils. With the exception of the control soil and perfluorodecanoate (PFDA) in the industrially impacted soil, all BAF values were above unity, with the highest being for perfluorohexanesulfonate (PFHxS) in the AFFF-impacted Soil A (139 gdw,soil/gdw,worm). BSAFs and BAFs increased with increasing chain length for the perfluorocarboxylates (PFCAs) and decreased with increasing chain length for the perfluoroalkyl sulfonates (PFSAs). The results indicate that PFAA bioaccumulation into earthworms depends on soil concentrations, soil characteristics, analyte, and duration of exposure, and that accumulation into earthworms may be a potential route of entry of PFAAs into terrestrial foodwebs. PMID- 25517892 TI - Fatigue affects peak joint torque angle in hamstrings but not in quadriceps. AB - Primary aim of this study was to investigate peak joint torque angle (i.e. the angle of peak torque) changes recorded during an isokinetic test before and after a fatiguing soccer match simulation. Secondarily we want to investigate functional Hecc:Qconc and conventional Hconc:Qconc ratio changes due to fatigue. Before and after a standardised soccer match simulation, twenty-two healthy male amateur soccer players performed maximal isokinetic strength tests both for hamstrings and for quadriceps muscles at 1.05 rad . s(-1), 3.14 rad . s(-1) and 5.24 rad . s(-1). Peak joint torque angle, peak torque and both functional Hecc:Qconc and conventional Hconc:Qconc ratios were examined. Both dominant and non-dominant limbs were tested. Peak joint torque angle significantly increased only in knee flexors. Both eccentric and concentric contractions resulted in such increment, which occurred in both limbs. No changes were found in quadriceps peak joint torque angle. Participants experienced a significant decrease in torque both in hamstrings and in quadriceps. Functional Hecc:Qconc ratio was lower only in dominant limb at higher velocities, while Hconc:Qconc did not change. This study showed after specific fatiguing task changes in hamstrings only torque/angle relationship. Hamstrings injury risk could depend on altered torque when knee is close to extension, coupled with a greater peak torque decrement compared to quadriceps. These results suggest the use eccentric based training to prevent hamstrings shift towards shorter length. PMID- 25517893 TI - Comparative analysis of duckweed cultivation with sewage water and SH media for production of fuel ethanol. AB - Energy crises and environmental pollution have caused considerable concerns; duckweed is considered to be a promising new energy plant that may relieve such problems. Lemna aequinoctialis strain 6000, which has a fast growth rate and the ability to accumulate high levels of starch was grown in both Schenk & Hildebrandt medium (SH) and in sewage water (SW). The maximum growth rates reached 10.0 g DW m(-2) day(-1) and 4.3 g DW m(-2) day(-1), respectively, for the SH and SW cultures, while the starch content reached 39% (w/w) and 34% (w/w). The nitrogen and phosphorus removal rate reached 80% (SH) and 90% (SW) during cultivation, and heavy metal ions assimilation was observed. About 95% (w/w) of glucose was released from duckweed biomass hydrolysates, and then fermented by Angel yeast with ethanol yield of 0.19 g g(-1) (SH) and 0.17 g g(-1) (SW). The amylose/amylopectin ratios of the cultures changed as starch content increased, from 0.252 to 0.155 (SH) and from 0.252 to 0.174 (SW). Lemna aequinoctialis strain 6000 could be considered as valuable feedstock for bioethanol production and water resources purification. PMID- 25517894 TI - Owl monkeys (Aotus nigriceps and A. infulatus) follow routes instead of food related cues during foraging in captivity. AB - Foraging at night imposes different challenges from those faced during daylight, including the reliability of sensory cues. Owl monkeys (Aotus spp.) are ideal models among anthropoids to study the information used during foraging at low light levels because they are unique by having a nocturnal lifestyle. Six Aotus nigriceps and four A. infulatus individuals distributed into five enclosures were studied for testing their ability to rely on olfactory, visual, auditory, or spatial and quantitative information for locating food rewards and for evaluating the use of routes to navigate among five visually similar artificial feeding boxes mounted in each enclosure. During most experiments only a single box was baited with a food reward in each session. The baited box changed randomly throughout the experiment. In the spatial and quantitative information experiment there were two baited boxes varying in the amount of food provided. These baited boxes remained the same throughout the experiment. A total of 45 sessions (three sessions per night during 15 consecutive nights) per enclosure was conducted in each experiment. Only one female showed a performance suggestive of learning of the usefulness of sight to locate the food reward in the visual information experiment. Subjects showed a chance performance in the remaining experiments. All owl monkeys showed a preference for one box or a subset of boxes to inspect upon the beginning of each experimental session and consistently followed individual routes among feeding boxes. PMID- 25517895 TI - Candida albicans and Streptococcus mutans: a potential synergistic alliance to cause virulent tooth decay in children. PMID- 25517896 TI - Conference report from International Congress on Infectious Diseases 2014: part 2. AB - This second and final instalment of the conference report from International Congress on Infectious Diseases 2014 follows on from part one, published in Future Microbiology (volume 9/issue 11). The 16th International Congress on Infectious Diseases was held in Cape Town this year, marking the return of the conference to Africa for the first time in 22 years. While infectious diseases such as malaria, tuberculosis and HIV--all still prevalent in the African healthcare landscape--dominated the program, the conference featured several important sessions on fungal infection and a significant number of posters devoted to this critical medical area. Within the context of the rise of antimicrobial resistance, now identified by WHO as one of the three greatest threats to human health, came the message that resistance is not limited to antimicrobials, but that antifungal resistance is also a significant and emerging threat worldwide. PMID- 25517897 TI - Exposure to extremely low-frequency magnetic field affects biofilm formation by cystic fibrosis pathogens. AB - AIMS: To evaluate the in vitro effects of extremely low-frequency magnetic field (ELF-MF) on growth and biofilm formation by Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia and Stenotrophomonas maltophilia strains from cystic fibrosis patients. MATERIALS & METHODS: The motion of selected ions (Fe, Ca, Cu, Zn, Mg, K, Na) was stimulated by the ion resonance effect, then influence on growth and biofilm formation/viability was assessed by spectrophotometry or viability count. RESULTS: Generally, exposure to ELF-MF significantly increased bacterial growth and affected both biofilm formation and viability, although with differences with regard to ions and species considered. CONCLUSION: Exposure to ELF-MF represents a possible new approach for treatment of biofilm-associated cystic fibrosis lung infections. PMID- 25517899 TI - Filamentous hemagglutinin of Bordetella pertussis: a key adhesin with immunomodulatory properties? AB - The filamentous hemagglutinin of pathogenic Bordetellae is a prototype of a large two-partner-system-secreted and beta-structure-rich bacterial adhesin. It exhibits several binding activities that may facilitate bacterial adherence to airway mucosa and host phagocytes in the initial phases of infection. Despite three decades of research on filamentous hemagglutinin, there remain many questions on its structure-function relationships, integrin interactions and possible immunomodulatory signaling capacity. Here we review the state of knowledge on this important virulence factor and acellular pertussis vaccine component. Specific emphasis is placed on outstanding questions that are yet to be answered. PMID- 25517900 TI - Hepatitis E in developed countries: current status and future perspectives. AB - Hepatitis E virus (HEV) was for many years thought to be found almost exclusively in developing countries, where it is a major health issue. Recent studies have shown that HEV causes acute and chronic infection in developed countries. In these geographical settings, HEV is primarily a porcine zoonosis caused by genotypes 3 (HEV3) and 4 (HEV4). The clinical phenotype of hepatitis E continues to emerge, and recent data show that HEV is associated with a range of neurological syndromes including Guillain-Barre syndrome and neuralgic amytrophy. PMID- 25517898 TI - Structure and function of bacteriophage T4. AB - Bacteriophage T4 is the most well-studied member of Myoviridae, the most complex family of tailed phages. T4 assembly is divided into three independent pathways: the head, the tail and the long tail fibers. The prolate head encapsidates a 172 kbp concatemeric dsDNA genome. The 925 A-long tail is surrounded by the contractile sheath and ends with a hexagonal baseplate. Six long tail fibers are attached to the baseplate's periphery and are the host cell's recognition sensors. The sheath and the baseplate undergo large conformational changes during infection. X-ray crystallography and cryo-electron microscopy have provided structural information on protein-protein and protein-nucleic acid interactions that regulate conformational changes during assembly and infection of Escherichia coli cells. PMID- 25517901 TI - Human brucellosis in Maghreb: existence of a lineage related to socio-historical connections with Europe. AB - Despite control/eradication programs, brucellosis, major worldwide zoonosis due to the Brucella genus, is endemic in Northern Africa and remains a major public health problem in the Maghreb region (Algeria/Morocco/Tunisia). Brucella melitensis biovar 3 is mostly involved in human infections and infects mainly small ruminants. Human and animal brucellosis occurrence in the Maghreb seems still underestimated and its epidemiological situation remains hazy. This study summarizes official data, regarding Brucella melitensis infections in Algeria, from 1989 to 2012, with the purpose to provide appropriate insights concerning the epidemiological situation of human and small ruminant brucellosis in Maghreb. Algeria and Europe are closely linked for historical and economical reasons. These historical connections raise the question of their possible impact on the genetic variability of Brucella strains circulating in the Maghreb. Other purpose of this study was to assess the genetic diversity among Maghreb B. melitensis biovar 3 strains, and to investigate their possible epidemiological relationship with European strains, especially with French strains. A total of 90 B. melitensis biovar 3 Maghreb strains isolated over a 25 year-period (1989-2014), mainly from humans, were analysed by MLVA-16. The obtained results were compared with genotypes of European B. melitensis biovar 3 strains. Molecular assays showed that Algerian strains were mainly distributed into two distinct clusters, one Algerian cluster related to European sub-cluster. These results led to suggest the existence of a lineage resulting from socio-historical connections between Algeria and Europe that might have evolved distinctly from the Maghreb autochthonous group. This study provides insights regarding the epidemiological situation of human brucellosis in the Maghreb and is the first molecular investigation regarding B. melitensis biovar 3 strains circulating in the Maghreb. PMID- 25517902 TI - Activity patterns of Eurasian lynx are modulated by light regime and individual traits over a wide latitudinal range. AB - The activity patterns of most terrestrial animals are regarded as being primarily influenced by light, although other factors, such as sexual cycle and climatic conditions, can modify the underlying patterns. However, most activity studies have been limited to a single study area, which in turn limit the variability of light conditions and other factors. Here we considered a range of variables that might potentially influence the activity of a large carnivore, the Eurasian lynx, in a network of studies conducted with identical methodology in different areas spanning latitudes from 49 degrees 7'N in central Europe to 70 degrees 00'N in northern Scandinavia. The variables considered both light conditions, ranging from a day with a complete day-night cycle to polar night and polar day, as well as individual traits of the animals. We analysed activity data of 38 individual free-ranging lynx equipped with GPS-collars with acceleration sensors, covering more than 11,000 lynx days. Mixed linear additive models revealed that the lynx activity level was not influenced by the daily daylight duration and the activity pattern was bimodal, even during polar night and polar day. The duration of the active phase of the activity cycle varied with the widening and narrowing of the photoperiod. Activity varied significantly with moonlight. Among adults, males were more active than females, and subadult lynx were more active than adults. In polar regions, the amplitude of the lynx daily activity pattern was low, likely as a result of the polycyclic activity pattern of their main prey, reindeer. At lower latitudes, the basic lynx activity pattern peaked during twilight, corresponding to the crepuscular activity pattern of the main prey, roe deer. Our results indicated that the basic activity of lynx is independent of light conditions, but is modified by both individual traits and the activity pattern of the locally most important prey. PMID- 25517903 TI - Gender stereotype susceptibility. AB - Gender affects performance on a variety of cognitive tasks, and this impact may stem from socio-cultural factors such as gender stereotyping. Here we systematically manipulated gender stereotype messages on a social cognition task on which no initial gender gap has been documented. The outcome reveals: (i) Stereotyping affects both females and males, with a more pronounced impact on females. Yet an explicit negative message for males elicits a striking paradoxical deterioration in performance of females. (ii) Irrespective of gender and directness of message, valence of stereotype message affects performance: negative messages have stronger influence than positive ones. (iii) Directness of stereotype message differentially impacts performance of females and males: females tend to be stronger affected by implicit than explicit negative messages, whereas in males this relationship is opposite. The data are discussed in the light of neural networks underlying gender stereotyping. The findings provide novel insights into the sources of gender related fluctuations in cognition and behavior. PMID- 25517904 TI - One platform comparison of estrone and folic acid anchored surface engineered MWCNTs for doxorubicin delivery. AB - Our main aim in the present investigation was to assess and compare the in vitro and in vivo cancer targeting propensity of doxorubicin (DOX) loaded folic acid (FA) and estrone (ES) anchored PEGylated multiwalled carbon nanotubes (MWCNTs) employing tumor bearing Balb/c mice. The DOX was loaded into the developed functionalized MWCNTs after proper characterization using dialysis diffusion method. The in vitro, ex vivo, and in vivo studies were performed on the MCF-7 cell line for assessment of the cancer targeting propensity. Both qualitative and quantitative cell uptake studies indicated the preferential higher uptake of estrone anchored nanotube formulation compared to other formulations and free DOX owing to the overexpression of estrogen receptors (ERs) on human breast MCF-7 cells. Similarly, the pharmacokinetic and increased antitumor activities also confirmed the elevated cancer targeting propensity of the estrone and folic acid anchored MWCNT formulations. The DOX/ES-PEG-MWCNTs has also shown significantly longer survival span (43 days) than free DOX (18 days) and control group (12 days). Present outcomes from the ex vivo and in vivo studies are deemed to be of great scientific value and shall assist targeted drug delivery formulation scientists for selection of the targeting moieties in the treatment of human breast cancer. PMID- 25517905 TI - IMOS National Reference Stations: a continental-wide physical, chemical and biological coastal observing system. AB - Sustained observations allow for the tracking of change in oceanography and ecosystems, however, these are rare, particularly for the Southern Hemisphere. To address this in part, the Australian Integrated Marine Observing System (IMOS) implemented a network of nine National Reference Stations (NRS). The network builds on one long-term location, where monthly water sampling has been sustained since the 1940s and two others that commenced in the 1950s. In-situ continuously moored sensors and an enhanced monthly water sampling regime now collect more than 50 data streams. Building on sampling for temperature, salinity and nutrients, the network now observes dissolved oxygen, carbon, turbidity, currents, chlorophyll a and both phytoplankton and zooplankton. Additional parameters for studies of ocean acidification and bio-optics are collected at a sub-set of sites and all data is made freely and publically available. Our preliminary results demonstrate increased utility to observe extreme events, such as marine heat waves and coastal flooding; rare events, such as plankton blooms; and have, for the first time, allowed for consistent continental scale sampling and analysis of coastal zooplankton and phytoplankton communities. Independent water sampling allows for cross validation of the deployed sensors for quality control of data that now continuously tracks daily, seasonal and annual variation. The NRS will provide multi-decadal time series, against which more spatially replicated short-term studies can be referenced, models and remote sensing products validated, and improvements made to our understanding of how large-scale, long-term change and variability in the global ocean are affecting Australia's coastal seas and ecosystems. The NRS network provides an example of how a continental scaled observing systems can be developed to collect observations that integrate across physics, chemistry and biology. PMID- 25517906 TI - A computational model of afterimage rotation in the peripheral drift illusion based on retinal ON/OFF responses. AB - Human observers perceive illusory rotations after the disappearance of circularly repeating patches containing dark-to-light luminance. This afterimage rotation is a very powerful phenomenon, but little is known about the mechanisms underlying it. Here, we use a computational model to show that the afterimage rotation can be explained by a combination of fast light adaptation and the physiological architecture of the early visual system, consisting of ON- and OFF-type visual pathways. In this retinal ON/OFF model, the afterimage rotation appeared as a rotation of focus lines of retinal ON/OFF responses. Focus lines rotated clockwise on a light background, but counterclockwise on a dark background. These findings were consistent with the results of psychophysical experiments, which were also performed by us. Additionally, the velocity of the afterimage rotation was comparable with that observed in our psychophysical experiments. These results suggest that the early visual system (including the retina) is responsible for the generation of the afterimage rotation, and that this illusory rotation may be systematically misinterpreted by our high-level visual system. PMID- 25517908 TI - Activity of coagulation factor XI in patients with spontaneous miscarriage: the presence of risk alleles. AB - The aim of this study was to compare the activity of coagulation factor XI (FXI) between patients with spontaneous miscarriage versus control group with no history of miscarriage and thrombosis, and then we evaluated the occurrence of risk alleles in the relation to miscarriage. FXI activity was determined using a coagulometer (Sysmex, CA 1500, Japan). Single nucleotide polymorphisms (SNPs) of F11 and CYP4V2 genes were evaluated. We examined 55 patients versus 31 control subjects. We found significantly higher activity of FXI (p = 0.04) in patients versus control subjects. The occurrence of two SNPs (rs2289252 and rs2036914) of the F11 gene and SNP (rs13146272) of CYP4V2 gene was not significantly different between both groups. Increased activity of FXI may be a potential risk factor for miscarriage. High activity of FXI diagnosed in women with history of miscarriage is not probably caused by the presence of studied SNPs. PMID- 25517909 TI - Process redesign to improve first case surgical starts in an academic institution. AB - PURPOSE: On time start of the first surgical case improves operating room (OR) utilization, physician, and patient satisfaction and decreases delays in subsequent cases. The goal of our study was to evaluate the effect of a multidisciplinary initiative to improve first patient in the room (FPIR) and first case on time start (FCOTS) metrics in a tertiary care setting. MATERIALS AND METHODS: A multidisciplinary committee focused on first case start data collection. Reasons for both anesthesia and surgical delays were analyzed. Improvement efforts focused on the timely completion of surgical consent, a requirement of a surgical, anesthesia, and nurse team member presence at the patient's bedside by specific time, and parallel processing in the OR. RESULTS: Over 65,100 OR cases were analyzed between 2007 and 2014. There was a statistically significant improvement in FPIR (82.80% versus 69.60%, p < .0001) and FCOTS (66.60% versus 55.90%, p < .0001). Surgical consent completion rate increased from 35% baseline to 68%-100%, depending on the surgical subspecialty. Improvements appeared sustainable several years following process implementation for both FPIR (84.60% versus 69.60%, p < .0001) and FCOTS (67.60% versus 55.90%, p < .0001). CONCLUSIONS: Our study demonstrates a successful targeted, multidisciplinary initiative to improve first case surgical starts in an academic setting. Our approach was organizational rather than punitive or rewarding on an individual basis. Strategies included establishing concrete, time-specific goals and posting them visibly, empowering individuals to fulfill them, and ensuring no compromise in patient safety. In the complex environment of academic medicine including research protocols and teaching in the ORs, our organizational approach proved sustainable over several years. PMID- 25517910 TI - The Effect of Sleep Problems on Suicidal Risk among Young Adults in the Presence of Depressive Symptoms and Cognitive Processes. AB - We aimed to investigate the effect of sleep problems, depression, and cognitive processes on suicidal risk among 460 young adults. They completed self-report questionnaires assessing suicidal behavior, sleep quality, depressive symptoms, emotion regulation, rumination, and impulsivity. Suicidal participants exhibited higher rates of depressive symptoms, sleep problems, expressive suppression, rumination, and impulsivity. A confirmatory factor analysis model revealed pathways to suicidal risk that showed no direct pathways between sleep problems and suicidal risk. Instead, sleep was related to suicidal risk via depression and rumination, which in turn increased suicidal risk. These results suggest that addressing sleep problems will be useful in either the treatment or prevention of depressive and rumination symptoms and reduction in suicidal risk. PMID- 25517907 TI - p-Cresol affects reactive oxygen species generation, cell cycle arrest, cytotoxicity and inflammation/atherosclerosis-related modulators production in endothelial cells and mononuclear cells. AB - AIMS: Cresols are present in antiseptics, coal tar, some resins, pesticides, and industrial solvents. Cresol intoxication leads to hepatic injury due to coagulopathy as well as disturbance of hepatic circulation in fatal cases. Patients with uremia suffer from cardiovascular complications, such as atherosclerosis, thrombosis, hemolysis, and bleeding, which may be partly due to p-cresol toxicity and its effects on vascular endothelial and mononuclear cells. Given the role of reactive oxygen species (ROS) and inflammation in vascular thrombosis, the objective of this study was to evaluate the effect of p-cresol on endothelial and mononuclear cells. METHODS: EA.hy926 (EAHY) endothelial cells and U937 cells were exposed to different concentrations of p-cresol. Cytotoxicity was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5 -diphenyltetrazolium bromide (MTT) assay and trypan blue dye exclusion technique, respectively. Cell cycle distribution was analyzed by propidium iodide flow cytometry. Endothelial cell migration was studied by wound closure assay. ROS level was measured by 2',7' dichlorofluorescein diacetate (DCF) fluorescence flow cytometry. Prostaglandin F2alpha (PGF2alpha), plasminogen activator inhibitor-1 (PAI-1), soluble urokinase plasminogen activator receptor (suPAR), and uPA production were determined by Enzyme-linked immunosorbant assay (ELISA). RESULTS: Exposure to 100-500 uM p cresol decreased EAHY cell number by 30-61%. P-cresol also decreased the viability of U937 mononuclear cells. The inhibition of EAHY and U937 cell growth by p-cresol was related to induction of S-phase cell cycle arrest. Closure of endothelial wounds was inhibited by p-cresol (>100 uM). P-cresol (>50 uM) also stimulated ROS production in U937 cells and EAHY cells but to a lesser extent. Moreover, p-cresol markedly stimulated PAI-1 and suPAR, but not PGF2alpha, and uPA production in EAHY cells. CONCLUSIONS: p-Cresol may contribute to atherosclerosis and thrombosis in patients with uremia and cresol intoxication possibly due to induction of ROS, endothelial/mononuclear cell damage and production of inflammation/atherosclerosis-related molecules. PMID- 25517911 TI - Characterizing heterogeneity in leukemic cells using single-cell gene expression analysis. AB - BACKGROUND: A fundamental challenge for cancer therapy is that each tumor contains a highly heterogeneous cell population whose structure and mechanistic underpinnings remain incompletely understood. Recent advances in single-cell gene expression profiling have created new possibilities to characterize this heterogeneity and to dissect the potential intra-cancer cellular hierarchy. RESULTS: Here, we apply single-cell analysis to systematically characterize the heterogeneity within leukemic cells using the MLL-AF9 driven mouse model of acute myeloid leukemia. We start with fluorescence-activated cell sorting analysis with seven surface markers, and extend by using a multiplexing quantitative polymerase chain reaction approach to assay the transcriptional profile of a panel of 175 carefully selected genes in leukemic cells at the single-cell level. By employing a set of computational tools we find striking heterogeneity within leukemic cells. Mapping to the normal hematopoietic cellular hierarchy identifies two distinct subtypes of leukemic cells; one similar to granulocyte/monocyte progenitors and the other to macrophage and dendritic cells. Further functional experiments suggest that these subtypes differ in proliferation rates and clonal phenotypes. Finally, co-expression network analysis reveals similarities as well as organizational differences between leukemia and normal granulocyte/monocyte progenitor networks. CONCLUSIONS: Overall, our single-cell analysis pinpoints previously uncharacterized heterogeneity within leukemic cells and provides new insights into the molecular signatures of acute myeloid leukemia. PMID- 25517912 TI - Obesity, metabolic health, and the risk of end-stage renal disease. AB - Obesity is associated with chronic kidney disease progression. Whether metabolic risk factors modify this association is unclear. Here we examined associations of body mass index (BMI) and metabolic health with risk of end-stage renal disease (ESRD) in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Among 21,840 participants eligible for analysis, 247 developed ESRD (mean follow-up of 6.3 years). Metabolic health significantly modified the association of BMI with ESRD. In models stratified by the presence or absence of the metabolic syndrome and adjusted for demographic, lifestyle, and clinical factors, higher BMI was associated with lower risk of ESRD in those without (hazard ratio per 5 kg/m2 increase in BMI 0.70, 95% CI 0.52, 0.95) but not those with (hazard ratio, 1.06) the metabolic syndrome. In models stratified by weight and metabolic health, compared with normal weight (BMI 18.5-24.9 kg/m2) participants without the metabolic syndrome the overweight individuals (BMI 25-29.9) and obese individuals (BMI of 30 or more) with the metabolic syndrome had greater risk of ESRD (hazard ratios of 2.03 and 2.29, respectively), whereas obesity without the metabolic syndrome was associated with lower risk of ESRD (hazard ratio 0.47). Thus, higher BMI is associated with lower ESRD risk in those without but not those with the metabolic syndrome. PMID- 25517914 TI - Tumor volumetric measurements in surgically inaccessible pediatric low-grade glioma. AB - Tumor measurement is important in unresectable pediatric low-grade gliomas (pLGGs) to determine either the need for treatment or assess response. Standard methods measure the product of the largest 2 lengths from transverse, anterior posterior, and cranio-caudal dimensions (SM, cm). This single-institution study evaluated tumor volume measurements (VM, cm) in such pLGGs. Of 50 patients treated with chemotherapy for surgically inaccessible pLGG, 8 met the inclusion criteria of having 2 or more sequential MRI studies of T1-weighted Fast-Spoiled Gradient Recalled acquisition. SM and VM were performed by 2 independent neuroradiologists. Associations of measurement methods with defined therapeutic response criteria and patient clinical status were assessed. The mean tumor size at the first MRI scan was 20 cm and 398 cm according to SM and VM, respectively. VM results did not differ significantly from SM-derived spherical volume calculations (Pearson correlation, P<0.0001) with a high interrater reliability. Both methods were concordant in defining the tumor response according to the current criteria, although radiologic progressive disease was not associated with clinical status (SM: P=0.491, VM: P=0.208). In this limited experience, volumetric analysis of unresectable pLGGs did not seem superior to the standard linear measurements for defining tumor response. PMID- 25517915 TI - Experimental and theoretical evidence of an axially chiral borospherene. AB - Chirality plays an important role in chemistry, biology, and materials science. The recent discovery of the B40(-/0) borospherenes marks the onset of a class of boron-based nanostructures. Here we report the observation of axially chiral borospherene in the B(39)(-) nanocluster on the bases of photoelectron spectroscopy, global minimum searches, and electronic structure calculations. Extensive structural searches in combination with density functional and CCSD(T) calculations show that B(39)(-) has a C3 cage global minimum with a close-lying C2 cage isomer. Both the C3 and C2 B(39)(-) cages are chiral with degenerate enantiomers. The C3 global minimum consists of three hexagons and three heptagons around the vertical C3 axis. The C2 isomer is built on two hexagons on the top and at the bottom of the cage with four heptagons around the waist. Both the C3 and C2 axially chiral isomers of B(39)(-) are present in the experiment and contribute to the observed photoelectron spectrum. The chiral borospherenes also exhibit three-dimensional aromaticity, featuring sigma and pi double delocalization for all valence electrons. Molecular dynamics simulations reveal that these chiral B(39)(-) cages are structurally fluxional above room temperature, compared to the highly robust D(2d)B40 borospherene. The current findings add chiral members to the borospherene family and indicate the structural diversity of boron-based nanomaterials. PMID- 25517913 TI - Necroptosis and parthanatos are involved in remote lung injury after receiving ischemic renal allografts in rats. AB - Early renal graft injury could result in remote pulmonary injury due to kidney lung cross talk. Here we studied the possible role of regulated necrosis in remote lung injury in a rat allogeneic transplantation model. In vitro, human lung epithelial cell A549 was challenged with TNF-alpha and conditioned medium from human kidney proximal tubular cells (HK-2) after hypothermia-hypoxia insults. In vivo, the Brown-Norway rat renal grafts were extracted and stored in 4 degrees C Soltran preserving solution for up to 24 h and transplanted into Lewis rat recipients, and the lungs were harvested on day 1 and day 4 after grafting for further analysis. Ischemia-reperfusion injury in the renal allograft caused pulmonary injury following engraftment. PARP-1 (marker for parthanatos) and receptor interacting protein kinase 1 (Rip1) and Rip3 (markers for necroptosis) expression was significantly enhanced in the lung. TUNEL assays showed increased cell death of lung cells. This was significantly reduced after treatment with necrostatin-1 (nec-1) or/and 3-aminobenzamide (3-AB). Acute immune rejection exacerbated the remote lung injury and 3-AB or/and Nec-1 combined with cyclosporine A conferred optimal lung protection. Thus, renal graft injury triggered remote lung injury, likely through regulated necrosis. This study could provide the molecular basis for combination therapy targeting both pathways of regulated necrosis to treat such complications after renal transplantation. PMID- 25517916 TI - Central release of nitric oxide mediates antinociception induced by aerobic exercise. AB - Nitric oxide (NO) is a soluble gas that participates in important functions of the central nervous system, such as cognitive function, maintenance of synaptic plasticity for the control of sleep, appetite, body temperature, neurosecretion, and antinociception. Furthermore, during exercise large amounts of NO are released that contribute to maintaining body homeostasis. Besides NO production, physical exercise has been shown to induce antinociception. Thus, the present study aimed to investigate the central involvement of NO in exercise-induced antinociception. In both mechanical and thermal nociceptive tests, central [intrathecal (it) and intracerebroventricular (icv)] pretreatment with inhibitors of the NO/cGMP/KATP pathway (L-NOArg, ODQ, and glybenclamide) prevented the antinociceptive effect induced by aerobic exercise (AE). Furthermore, pretreatment (it, icv) with specific NO synthase inhibitors (L-NIO, aminoguanidine, and L-NPA) also prevented this effect. Supporting the hypothesis of the central involvement of NO in exercise-induced antinociception, nitrite levels in the cerebrospinal fluid increased immediately after AE. Therefore, the present study suggests that, during exercise, the NO released centrally induced antinociception. PMID- 25517917 TI - Improved biological performance of magnesium by micro-arc oxidation. AB - Magnesium and its alloys have recently been used in the development of lightweight, biodegradable implant materials. However, the corrosion properties of magnesium limit its clinical application. The purpose of this study was to comprehensively evaluate the degradation behavior and biomechanical properties of magnesium materials treated with micro-arc oxidation (MAO), which is a new promising surface treatment for developing corrosion resistance in magnesium, and to provide a theoretical basis for its further optimization and clinical application. The degradation behavior of MAO-treated magnesium was studied systematically by immersion and electrochemical tests, and its biomechanical performance when exposed to simulated body fluids was evaluated by tensile tests. In addition, the cell toxicity of MAO-treated magnesium samples during the corrosion process was evaluated, and its biocompatibility was investigated under in vivo conditions. The results of this study showed that the oxide coating layers could elevate the corrosion potential of magnesium and reduce its degradation rate. In addition, the MAO-coated sample showed no cytotoxicity and more new bone was formed around it during in vivo degradation. MAO treatment could effectively enhance the corrosion resistance of the magnesium specimen and help to keep its original mechanical properties. The MAO-coated magnesium material had good cytocompatibility and biocompatibility. This technique has an advantage for developing novel implant materials and may potentially be used for future clinical applications. PMID- 25517918 TI - Esculetin, a coumarin derivative, exerts in vitro and in vivo antiproliferative activity against hepatocellular carcinoma by initiating a mitochondrial-dependent apoptosis pathway. AB - This study investigated the in vitro and in vivo antiproliferative activity of esculetin against hepatocellular carcinoma, and clarified its potential molecular mechanisms. Cell viability was determined by the MTT (tetrazolium) colorimetric assay. In vivo antitumor activity of esculetin was evaluated in a hepatocellular carcinoma mouse model. Seventy-five C57BL/6J mice were implanted with Hepa1-6 cells and randomized into five groups (n=15 each) given daily intraperitoneal injections of vehicle (physiological saline), esculetin (200, 400, or 700 mg.kg 1.day-1), or 5-Fu (200 mg.kg-1.day-1) for 15 days. Esculetin significantly decreased tumor growth in mice bearing Hepa1-6 cells. Tumor weight was decreased by 20.33, 40.37, and 55.42% with increasing doses of esculetin. Esculetin significantly inhibited proliferation of HCC cells in a concentration- and time dependent manner and with an IC50 value of 2.24 mM. It blocked the cell cycle at S phase and induced apoptosis in SMMC-7721 cells with significant elevation of caspase-3 and caspase-9 activity, but did not affect caspase-8 activity. Moreover, esculetin treatment resulted in the collapse of mitochondrial membrane potential in vitro and in vivo accompanied by increased Bax expression and decreased Bcl-2 expression at both transcriptional and translational levels. Thus, esculetin exerted in vitro and in vivo antiproliferative activity in hepatocellular carcinoma, and its mechanisms involved initiation of a mitochondrial-mediated, caspase-dependent apoptosis pathway. PMID- 25517919 TI - Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines. AB - Pancreatic cancer is the fourth leading cause of cancer death. Gemcitabine is widely used as a chemotherapeutic agent for the treatment of pancreatic cancer, but the prognosis is still poor. Berberine, an isoquinoline alkaloid extracted from a variety of natural herbs, possesses a variety of pharmacological properties including anticancer effects. In this study, we investigated the anticancer effects of berberine and compared its use with that of gemcitabine in the pancreatic cancer cell lines PANC-1 and MIA-PaCa2. Berberine inhibited cell growth in a dose-dependent manner by inducing cell cycle arrest and apoptosis. After berberine treatment, the G1 phase of PANC-1 cells increased by 10% compared to control cells, and the G1 phase of MIA-PaCa2 cells was increased by 2%. Whereas gemcitabine exerts antiproliferation effects through S-phase arrest, our results showed that berberine inhibited proliferation by inducing G1-phase arrest. Berberine-induced apoptosis of PANC-1 and MIA-PaCa2 cells increased by 7 and 2% compared to control cells, respectively. Notably, berberine had a greater apoptotic effect in PANC-1 cells than gemcitabine. Upon treatment of PANC-1 and MIA-PaCa2 with berberine at a half-maximal inhibitory concentration (IC50), apoptosis was induced by a mechanism that involved the production of reactive oxygen species (ROS) rather than caspase 3/7 activation. Our findings showed that berberine had anti-cancer effects and may be an effective drug for pancreatic cancer chemotherapy. PMID- 25517920 TI - Effects of 5-aza-2'deoxycytidine on RECK gene expression and tumor invasion in salivary adenoid cystic carcinoma. AB - Reversion-inducing cysteine-rich protein with kazal motifs (RECK), a novel tumor suppressor gene that negatively regulates matrix metalloproteinases (MMPs), is expressed in various normal human tissues but downregulated in several types of human tumors. The molecular mechanism for this downregulation and its biological significance in salivary adenoid cystic carcinoma (SACC) are unclear. In the present study, we investigated the effects of a DNA methyltransferase (DNMT) inhibitor, 5-aza-2'deoxycytidine (5-aza-dC), on the methylation status of the RECK gene and tumor invasion in SACC cell lines. Methylation-specific PCR (MSP), Western blot analysis, and quantitative real-time PCR were used to investigate the methylation status of the RECK gene and expression of RECK mRNA and protein in SACC cell lines. The invasive ability of SACC cells was examined by the Transwell migration assay. Promoter methylation was only found in the ACC-M cell line. Treatment of ACC-M cells with 5-aza-dC partially reversed the hypermethylation status of the RECK gene and significantly enhanced the expression of mRNA and protein, and 5-aza-dC significantly suppressed ACC-M cell invasive ability. Our findings showed that 5-aza-dC inhibited cancer cell invasion through the reversal of RECK gene hypermethylation, which might be a promising chemotherapy approach in SACC treatment. PMID- 25517921 TI - Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia. AB - In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (>=1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (>=27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival. PMID- 25517922 TI - Low-voltage organic electronics based on a gate-tunable injection barrier in vertical graphene-organic semiconductor heterostructures. AB - The vertical integration of graphene with inorganic semiconductors, oxide semiconductors, and newly emerging layered materials has recently been demonstrated as a promising route toward novel electronic and optoelectronic devices. Here, we report organic thin film transistors based on vertical heterojunctions of graphene and organic semiconductors. In these thin heterostructure devices, current modulation is accomplished by tuning of the injection barriers at the semiconductor/graphene interface with the application of a gate voltage. N-channel devices fabricated with a thin layer of C60 show a room temperature on/off ratio >10(4) and current density of up to 44 mAcm(-2). Because of the ultrashort channel intrinsic to the vertical structure, the device is fully operational at a driving voltage of 200 mV. A complementary p-channel device is also investigated, and a logic inverter based on two complementary transistors is demonstrated. The vertical integration of graphene with organic semiconductors via simple, scalable, and low-temperature fabrication processes opens up new opportunities to realize flexible, transparent organic electronic, and optoelectronic devices. PMID- 25517924 TI - Poly(2-methyl-2-oxazoline)-b-poly(tetrahydrofuran)-b-poly(2-methyl-2-oxazoline) amphiphilic triblock copolymers: synthesis, physicochemical characterizations, and hydrosolubilizing properties. AB - Block copolymers assembled into micelles have gained a lot of attention to improve drug delivery. The recent drawbacks of the poly(ethylene oxide) blocks (PEO) contained in amphiphilic pluronics derivatives made of a central poly(propylene oxide) block surrounded by two PEO blocks were recently revealed, opening the way to the design of new amphiphilic block copolymers able to self assemble in water and to entrap molecules of interest. Here, a family of p(methyloxazoline)-b-p(tetrahydrofuran)-b-p(methyloxazoline) triblock copolymers (called TBCP) is synthesized using cationic ring opening polymerization. Studies of micelle formation using dynamic light scattering, isothermal titration calorimetry (ITC), NMR diffusion-ordered spectroscopy (DOSY), and fluorescence experiments lead us to draw a relationship between copolymer structure and the physicochemical properties of the block copolymers (critical micellar concentration (CMC), Nagg, core diameter, shell thickness, etc.). The packing parameter of the block copolymers indicates the formation of a core-corona structure. Hydrosolubilizing properties of TBCPs were exemplified with curcumin selected as a highly insoluble drug model. Curcumin, a natural polyphenolic compound, has shown a large spectrum of biological and pharmacological activity, including anti-inflammatory, antimicrobial, antioxidant, and anticarcinogenic activities. An optimized formulation process reveals that the aggregation number is the parameter affecting drug encapsulation. Patch clamp experiments carried out to study the interaction of TBCP with the cell membrane demonstrate their permeation property suitable to promote the cellular internalization of curcumin. PMID- 25517925 TI - Catalytic C-H allylation and benzylation of pyrazoles. AB - We describe a general approach for the synthesis of allylated and benzylated pyrazoles. An electron-withdrawing substituent, such as nitro, chloro, and ester groups, at C4 renders the Lewis basic nitrogen atom to be less basic and the C-H bond more acidic than the ones of the parent ring, enabling Pd-catalyzed C-H allylation and benzylation reactions of pyrazoles. The new method expanding the scope of the C-H functionalization of pyrazoles beyond arylation reactions provides a rapid access to complex pyrazole compounds. PMID- 25517926 TI - The growing spectrum of anti-inflammatory interleukins and their potential roles in the development of sepsis. AB - Sepsis, recognized as a deadly immunological disorder, is one of the major causes of death in intensive care units globally. Traditionally, sepsis was characterized by an excessive systemic proinflammatory response to invasive microbial pathogens. However, failures of highly sophisticated trials directed toward the uncontrolled inflammatory reaction have led to an appeal by experts for reevaluation of the present approach toward sepsis. With accumulated evidence, a principal role for immunosuppression in severe sepsis has been evaluated. Different pathways of negative regulation in the pathophysiological process of sepsis have been investigated. Significant among these regulatory elements are the anti-inflammatory cytokines. In the past few years, several interleukins (ILs) have been identified and characterized, among which IL-35 and IL-37 represent newly identified ones in the spectrum of anti-inflammatory cytokines. In this study, we focus on regulatory cytokines of the IL family (including the old members: IL-4, IL-10, and IL-13, and newly discovered ones: IL 35 and IL-37) to address current knowledge regarding their structural and functional characteristics as well as their roles in the development of sepsis. Although the exact roles for these cytokines are pending further elucidation, the current advances in our understanding of mechanisms that regulate the immune responses during severe sepsis may lead to the identification of new diagnostic or treatment targets. PMID- 25517927 TI - Plasma ionization source for atmospheric pressure mass spectrometry imaging using near-field optical laser ablation. AB - Mass spectrometry imaging (MSI) at ambient pressures with submicrometer resolution is challenging, due to the very low amount of material available for mass spectrometric analysis. In this work, we present the development and characterization of a method for MSI based on pulsed laser ablation via a scanning near-field optical microscopy (SNOM) aperture tip. SNOM allows laser ablation of material from surfaces with submicrometer spatial resolution, which can be ionized for further chemical analysis with MS. Efficient ionization is realized here with a custom-built capillary plasma ionization source. We show the applicability of this setup for mass spectrometric analysis of three common MALDI matrices, alpha-4-hydroxycyanocinnamic acid, 3-aminobenzoic acid, and 2,5 dihydroxybenzoic acid. Although the ultimate goal has been to optimize sensitivity for detecting material ablated from submicrometer diameter craters, the effective lateral resolution is currently limited by the sensitivity of the MS detection system. In our case, the sensitivity of the MS was about 1 fmol, which allowed us to achieve a spatial resolution of 2 MUm. We also characterize the analytical figures of merit of our method. In particular, we demonstrate good reproducibility, a repetition rate in the range of only a few seconds, and we determined the amount of substance required to achieve optimal resolution and sensitivity. Moreover, the sample topography is available from SNOM scans, a parameter that is missing in common MSI methods. PMID- 25517928 TI - The environment of professional practice and Burnout in nurses in primary healthcare. AB - OBJECTIVES: to assess how nurses perceive autonomy, control over the environment, the professional relationship between nurses and physicians and the organizational support and correlate them with burnout, satisfaction at work, quality of work and the intention to quit work in primary healthcare. METHOD: cross-sectional and correlation study, using a sample of 198 nurses. The tools used were the Nursing Work Index Revised, Maslach Burnout Inventory and a form to characterize the nurses. To analyze the data, descriptive statistics were applied and Spearman's correlation coefficient was used. RESULTS: the nurses assessed that the environment is partially favorable for: autonomy, professional relationship and organizational support and that the control over this environment is limited. Significant correlations were evidenced between the Nursing Work Index Revised, Maslach Burnout Inventory and the variables: satisfaction at work, quality of care and the intent to quit the job. CONCLUSION: the nurses' perceptions regarding the environment of practice are correlated with burnout, satisfaction at work, quality of care and the intent to quit the job. This study provides support for the restructuring of work processes in the primary health care environment and for communication among the health service management, human resources and occupational health areas. PMID- 25517923 TI - To cross-link or not to cross-link? Cross-linking associated foreign body response of collagen-based devices. AB - Collagen-based devices, in various physical conformations, are extensively used for tissue engineering and regenerative medicine applications. Given that the natural cross-linking pathway of collagen does not occur in vitro, chemical, physical, and biological cross-linking methods have been assessed over the years to control mechanical stability, degradation rate, and immunogenicity of the device upon implantation. Although in vitro data demonstrate that mechanical properties and degradation rate can be accurately controlled as a function of the cross-linking method utilized, preclinical and clinical data indicate that cross linking methods employed may have adverse effects on host response, especially when potent cross-linking methods are employed. Experimental data suggest that more suitable cross-linking methods should be developed to achieve a balance between stability and functional remodeling. PMID- 25517935 TI - Professional and informal mental health support reported by Canadians aged 15 to 24. AB - BACKGROUND: The prevalence of mental health problems in Canada is highest among youth and young adults. Relatively little is known about where they seek support and the factors related to help-seeking. DATA AND METHODS: Based on the 2012 Canadian Community Health Survey-Mental Health, this study describes professional and informal mental health support reported by Canadians aged 15 to 24. RESULTS: In 2012, 12% of 15- to 24-year-olds reported that, in the previous 12 months, they had consulted health professionals about emotional, mental or substance use problems; 27% reported consulting informal sources such as family and friends. Young Canadians with mood, anxiety or substance disorders, one or more chronic physical conditions, higher levels of distress, or who had a traumatic childhood experience were more likely than their contemporaries who did not have these risk factors to report contact with professional and informal sources of support. Those with multiple needs-related factors had significantly higher odds of reporting contact with professional and informal sources. INTERPRETATION: More than one in ten young Canadians consulted professionals and about a quarter sought informal support for mental health problems in the past year. The percentages were higher among those with multiple risk factors. PMID- 25517933 TI - Astrocytes refine cortical connectivity at dendritic spines. AB - During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines. PMID- 25517936 TI - Gender gaps--Life expectancy and proportion of life in poor health. AB - BACKGROUND: The literature suggests that women report worse health but live longer than men--a phenomenon known as the gender paradox in health and mortality. Although studies examining the paradox abound, relatively little is known about mechanisms underlying the gap. DATA AND METHODS: With data on healthy life expectancy from the Global Burden of Disease Study 2010, this article analyses the relationship between length of life and health among men and women in 45 more-developed countries. The proportion of life spent in poor health is used as an indicator of health. This approach accounts for gender differences in longevity and illustrates the female health disadvantage pattern more clearly. RESULTS: Life expectancy at birth and the proportion of life in poor health are closely related for both genders. Furthermore, the larger the female excess in longevity, the larger the female excess in the proportion of life in poor health. INTERPRETATION: By focusing on the proportion of life in poor health, this analysis suggests that women's longevity advantage translates into a health disadvantages relative to men. The results indicate that women suffer from poor health not in spite of living longer, but because they live longer. PMID- 25517934 TI - Quantitative microscopy of functional HIV post-entry complexes reveals association of replication with the viral capsid. AB - The steps from HIV-1 cytoplasmic entry until integration of the reverse transcribed genome are currently enigmatic. They occur in ill-defined reverse transcription- and pre-integration-complexes (RTC, PIC) with various host and viral proteins implicated. In this study, we report quantitative detection of functional RTC/PIC by labeling nascent DNA combined with detection of viral integrase. We show that the viral CA (capsid) protein remains associated with cytoplasmic RTC/PIC but is lost on nuclear PIC in a HeLa-derived cell line. In contrast, nuclear PIC were almost always CA-positive in primary human macrophages, indicating nuclear import of capsids or capsid-like structures. We further show that the CA-targeted inhibitor PF74 exhibits a bimodal mechanism, blocking RTC/PIC association with the host factor CPSF6 and nuclear entry at low, and abrogating reverse transcription at high concentrations. The newly developed system is ideally suited for studying retroviral post-entry events and the roles of host factors including DNA sensors and signaling molecules. PMID- 25517938 TI - Increased drop formation frequency via reduction of surfactant interactions in flow-focusing microfluidic devices. AB - Glass capillary based microfluidic devices are able to create extremely uniform droplets, when formed under the dripping regime, at low setup costs due to their ease of manufacture. However, as they are rarely parallelized, simple methods to increase droplet production from a single device are sought. Surfactants used to stabilize drops in such systems often limit the maximum flow rate that highly uniform drops can be produced due to the lowering interfacial tension causing jetting. In this paper we show that by simple design changes we can limit the interactions of surfactants and maximize uniform droplet production. Three flow focused configurations are explored: a standard glass capillary device (consisting of a single round capillary inserted into a square capillary), a nozzle fed device, and a surfactant shielding device (both consisting of two round capillaries inserted into either end of a square capillary). In principle, the maximum productivity of uniform droplets is achieved if surfactants are not present. It was found that surfactants in the standard device greatly inhibit droplet production by means of interfacial tension lowering and tip-streaming phenomena. In the nozzle fed configuration, surfactant interactions were greatly limited, yielding flow rates comparable to, but lower than, a surfactant-free system. In the surfactant shielding configuration, flow rates were equal to that of a surfactant-free system and could make uniform droplets at rates an order of magnitude above the standard surfactant system. PMID- 25517939 TI - Genkwadaphnin induces IFN-gamma via PKD1/NF-kappaB/STAT1 dependent pathway in NK 92 cells. AB - The flower buds of Daphne genkwa Sieb. et Zucc. have been used as a traditional Chinese medicine although their functional mechanisms have not been discovered yet. We have studied the potential effects of the plant extracts on natural killer (NK) cell activation, and isolated an active fraction. Genkwadaphnin (GD 1) displayed a potent efficacy to induce IFN-gamma transcription in NK cells with concentration- and time-dependent manners. GD-1 treatment triggered the phosphorylation of PKD1, a member of PKC family, MEK and ERK, resulting in IKK activation to induce IkappaB degradation, and the nuclear localization of p65, an NF-kappaB subunit, which regulates IFN-gamma transcription. GD-1 effect on IFN gamma production was blocked by the addition of Rottlerin, a PKC inhibitor, CID 755673, a PKD inhibitor, or Bay11-7082, an IKKalpha inhibitor. The nuclear localization of p65 was also inhibited by the kinase inhibitors. Secreted IFN gamma activates STAT1 phosphorylation as autocrine-loops to sustain its secretion. GD-1 induced the phosphorylation of STAT1 probably through the increase of IFN-gamma. STAT1 inhibitor also abrogated the sustained IFN-gamma secretion. These results suggest that GD-1 is involved in the activation of PKD1 and/or ERK pathway, which activate NK-kappaB triggering IFN-gamma production. As positive feedback loops, secreted IFN-gamma activates STAT1 and elongates its production in NK-92 cells. PMID- 25517941 TI - Ex vivo expanded mesenchymal stromal cell minimal quality requirements for clinical application. AB - Mesenchymal stromal cells (MSCs), as advanced therapy products, must satisfy all the requirements for human use of medicinal products, aiming to maintain the quality and safety of the cells. The MSC manufacturing process for clinical use should comply with the principles of Good Manufacturing Practice (GMP). This ensures that cell preparations are produced and controlled, from the collection and manipulation of raw materials, through the processing of intermediate products, to the quality controls, storage, labeling and packaging, and release. The objective of this document is to provide the minimal quality requirements for the MSC production and its delivery for clinical use, so that the safety of the final cell therapy product will not be compromised. For this purpose, the document evaluates the most important steps of GMP-compliant MSC production: the isolation and expansion process; the validation phase of the process, including all quality controls for the characterization, functionality, potency, and safety of MSCs; and the quality control at the batch release to guarantee the safety of patient infusion. PMID- 25517940 TI - Todralazine protects zebrafish from lethal effects of ionizing radiation: role of hematopoietic cell expansion. AB - The Johns Hopkins Clinical Compound Library (JHCCL), a collection of Food and Drug Administration (FDA)-approved small molecules (1400), was screened in silico for identification of novel beta2AR blockers and tested for hematopoietic stem cell (HSC) expansion and radioprotection in zebrafish embryos. Docking studies, followed by the capacity to hasten erythropoiesis, identified todralazine (Binding energy, -8.4 kcal/mol) as a potential HSC-modulating agent. Todralazine (5 MUM) significantly increased erythropoiesis in caudal hematopoietic tissue (CHT) in wild-type and anemic zebrafish embryos (2.33- and 1.44-folds, respectively) when compared with untreated and anemic control groups. Todralazine (5 MUM) treatment also led to an increased number of erythroid progenitors, as revealed from the increased expression of erythroid progenitor-specific genes in the CHT region. Consistent with these effects, zebrafish embryos, Tg(cmyb:gfp), treated with 5 MUM todralazine from 24 to 36 hours post fertilization (hpf) showed increased (approximately two-folds) number of HSCs at the aorta-gonad mesonephros region (AGM). Similarly, expression of HSC marker genes, runx1 (3.3 folds), and cMyb (1.41-folds) also increased in case of todralazine-treated embryos, further supporting its HSC expansion potential. Metoprolol, a known beta blocker, also induced HSC expansion (1.36- and 1.48-fold increase in runx1 and cMyb, respectively). Todralazine (5 MUM) when added 30 min before 20 Gy gamma radiation, protected zebrafish from radiation-induced organ toxicity, apoptosis, and improved survival (80% survival advantage over 6 days). The 2-deoxyribose degradation test further suggested hydroxyl (OH) radical scavenging potential of todralazine, and the same is recapitulated in vivo. These results suggest that todralazine is a potential HSC expanding agent, which might be acting along with important functions, such as antioxidant and free radical scavenging, in manifesting radioprotection. PMID- 25517943 TI - Gateless patterning of epitaxial graphene by local intercalation. AB - We present a technique to pattern the charge density of a large-area epitaxial graphene sheet locally without using metallic gates. Instead, local intercalation of the graphene-substrate interface can selectively be established in the vicinity of graphene edges or predefined voids. It provides changes of the work function of several hundred meV, corresponding to a conversion from n-type to p type charge carriers. This assignment is supported by photoelectron spectroscopy, scanning tunneling microscopy, scanning electron microscopy and Hall effect measurements. The technique introduces materials contrast to a graphene sheet in a variety of geometries and thus allows for novel experiments and novel functionalities. PMID- 25517942 TI - Spaceflight induces specific alterations in the proteomes of Arabidopsis. AB - Life in spaceflight demonstrates remarkable acclimation processes within the specialized habitats of vehicles subjected to the myriad of unique environmental issues associated with orbital trajectories. To examine the response processes that occur in plants in space, leaves and roots from Arabidopsis (Arabidopsis thaliana) seedlings from three GFP reporter lines that were grown from seed for 12 days on the International Space Station and preserved on orbit in RNAlater were returned to Earth and analyzed by using iTRAQ broad-scale proteomics procedures. Using stringent criteria, we identified over 1500 proteins, which included 1167 leaf proteins and 1150 root proteins we were able to accurately quantify. Quantification revealed 256 leaf proteins and 358 root proteins that showed statistically significant differential abundance in the spaceflight samples compared to ground controls, with few proteins differentially regulated in common between leaves and roots. This indicates that there are measurable proteomics responses to spaceflight and that the responses are organ-specific. These proteomics data were compared with transcriptome data from similar spaceflight samples, showing that there is a positive but limited relationship between transcriptome and proteome regulation of the overall spaceflight responses of plants. These results are discussed in terms of emergence understanding of plant responses to spaceflight particularly with regard to cell wall remodeling, as well as in the context of deriving multiple omics data sets from a single on-orbit preservation and operations approach. PMID- 25517945 TI - Abscisic acid promotes pre-emergence stages of lateral root development in Medicago truncatula. AB - The plant root system is important for plant anchorage and nutrition. Among the different characteristics of the root system, root branching is a major factor of plasticity and adaptation to changing environments. Indeed, many biotic and abiotic stresses, such as drought or symbiotic interactions, influence root branching. Many studies concerning root development and root branching were performed on the model plant Arabidopsis thaliana, but this model plant has a very simplified root structure and is not able to establish any symbiotic interactions. We have recently described 7 stages for lateral root development in the model legume Medicago truncatula and found significant differences in the tissular contribution of root cell layers to the formation of new lateral roots (LR). We have also described 2 transgenic lines expressing the DR5:GUS and DR5:VENUS-N7 reporter genes that are useful to follow LR formation at early developmental stages. Here, we describe the use of these transgenic lines to monitor LR developmental responses of M. truncatula to the phytohormone abscisic acid (ABA) which is a major actor of stress and symbiotic interactions. We show that ABA promotes the formation of new lateral root primordia and their development, mostly at the late, pre-emergence stage. PMID- 25517946 TI - Characterization of a subtropical hawksbill sea turtle (Eretmocheyles imbricata) assemblage utilizing shallow water natural and artificial habitats in the Florida Keys. AB - In order to provide information to better inform management decisions and direct further research, vessel-based visual transects, snorkel transects, and in-water capture techniques were used to characterize hawksbill sea turtles in the shallow marine habitats of a Marine Protected Area (MPA), the Key West National Wildlife Refuge in the Florida Keys. Hawksbills were found in hardbottom and seagrass dominated habitats throughout the Refuge, and on man-made rubble structures in the Northwest Channel near Cottrell Key. Hawksbills captured (N = 82) were exclusively juveniles and subadults with a straight standard carapace length (SSCL) ranging from 21.4 to 69.0cm with a mean of 44.1 cm (SD = 10.8). Somatic growth rates were calculated from 15 recaptured turtles with periods at large ranging from 51 to 1188 days. Mean SSCL growth rate was 7.7 cm/year (SD = 4.6). Juvenile hawksbills (<50 cm SSCL) showed a significantly higher growth rate (9.2 cm/year, SD = 4.5, N = 11) than subadult hawksbills (50-70 cm SSCL, 3.6 cm/year, SD = 0.9, N = 4). Analysis of 740 base pair mitochondrial control region sequences from 50 sampled turtles yielded 12 haplotypes. Haplotype frequencies were significantly different compared to four other Caribbean juvenile foraging aggregations, including one off the Atlantic coast of Florida. Many-to-one mixed stock analysis indicated Mexico as the primary source of juveniles in the region and also suggested that the Refuge may serve as important developmental habitat for the Cuban nesting aggregation. Serum testosterone radioimmunoassay results from 33 individuals indicated a female biased sex ratio of 3.3 females: 1 male for hawksbills in the Refuge. This assemblage of hawksbills is near the northern limit of the species range, and is one of only two such assemblages described in the waters of the continental United States. Since this assemblage resides in an MPA with intensive human use, basic information on the assemblage is vital to resource managers charged with conservation and species protection in the MPA. PMID- 25517944 TI - A molecular toggle after exocytosis sequesters the presynaptic syntaxin1a molecules involved in prior vesicle fusion. AB - Neuronal synapses are among the most scrutinized of cellular systems, serving as a model for all membrane trafficking studies. Despite this, synaptic biology has proven difficult to interrogate directly in situ due to the small size and dynamic nature of central synapses and the molecules within them. Here we determine the spatial and temporal interaction status of presynaptic proteins, imaging large cohorts of single molecules inside active synapses. Measuring rapid interaction dynamics during synaptic depolarization identified the small number of syntaxin1a and munc18-1 protein molecules required to support synaptic vesicle exocytosis. After vesicle fusion and subsequent SNARE complex disassembly, a prompt switch in syntaxin1a and munc18-1-binding mode, regulated by charge alteration on the syntaxin1a N-terminal, sequesters monomeric syntaxin1a from other disassembled fusion complex components, preventing ectopic SNARE complex formation, readying the synapse for subsequent rounds of neurotransmission. PMID- 25517947 TI - Tracking post-hibernation behavior and early migration does not reveal the expected sex-differences in a "female-migrating" bat. AB - Long-distance migration is a rare phenomenon in European bats. Genetic analyses and banding studies show that females can cover distances of up to 1,600 km, whereas males are sedentary or migrate only short distances. The onset of this sex-biased migration is supposed to occur shortly after rousing from hibernation and when the females are already pregnant. We therefore predicted that the sexes are exposed to different energetic pressures in early spring, and this should be reflected in their behavior and physiology. We investigated this in one of the three Central European long-distance migrants, the common noctule (Nyctalus noctula) in Southern Germany recording the first individual partial migration tracks of this species. In contrast to our predictions, we found no difference between male and female home range size, activity, habitat use or diet. Males and females emerged from hibernation in similar body condition and mass increase rate was the same in males and females. We followed the first migration steps, up to 475 km, of radio-tagged individuals from an airplane. All females, as well as some of the males, migrated away from the wintering area in the same northeasterly direction. Sex differences in long-distance migratory behavior were confirmed through stable isotope analysis of hair, which showed greater variation in females than in males. We hypothesize that both sexes faced similarly good conditions after hibernation and fattened at maximum rates, thus showing no differences in their local behavior. Interesting results that warrant further investigation are the better initial condition of the females and the highly consistent direction of the first migratory step in this population as summering habitats of the common noctule occur at a broad range in Northern Europe. Only research focused on individual strategies will allow us to fully understand the migratory behavior of European bats. PMID- 25517948 TI - Fibrosing cholestatic hepatitis C after hematopoietic cell transplantation: report of 3 fatal cases. AB - Development of liver disease after hematopoietic cell transplantation is common and the causes diverse. Infection by hepatitis C virus (HCV) can be seen in patients who are chronically infected before transplant or from passage of virus from an infected donor; the normal 10-year course of hepatitis C after transplant is one of waxing and waning of serum aminotransferase enzymes, with little morbidity. In the series of 3 patients reported here, the course of hepatitis C was rapidly fatal, with the onset of jaundice at day 60 to 80 after transplant and liver histology typical of fibrosing cholestatic hepatitis (marked bile ductular proliferation, ballooned hepatocytes, and associated collagenous fibrosis centered around ductules). The bile ductular reaction pattern varied from elongated structures without a recognizable lumen to a pattern of cuboidal cells with a clear lumen. There was significant cholestasis with bile within hepatocytes and canalicular bile plugs. In situ HCV RNA hybridization studies from 1 patient showed a robust infection with high levels of HCV-infected hepatocytes and active viral replication. All 3 patients were on immunosuppressive drugs after transplant, including mycophenolate mofetil (MMF), which irreversibly inhibits inosine monophosphate dehydrogenase, on which T and B lymphocytes are dependent. We speculate that fatal fibrosing cholestatic hepatitis C in these cases was related to the immunosuppressive effects of MMF, as we had not recognized this presentation of HCV infection before the introduction of MMF. PMID- 25517950 TI - Microcystic meningioma of the calvarium: a series of 9 cases and review of the literature. AB - Meningiomas are one of the most common tumors that arise within the central nervous system; they represent up to 30% of all primary intracranial tumors. Extradural meningiomas are rare (<2% of all meningiomas), and most arise within the calvarium. Intraosseous calvarial meningiomas are usually easy to diagnose histologically if they are of the meningothelial type; however, they may cause diagnostic challenges when they manifest as unusual morphologic variants, such as the microcystic type. To address this issue we present a series of 9 cases of calvarial microcystic meningiomas arising in 7 female and 2 male patients; all patients were adults. The tumors had heterogenous findings on imaging studies and ranged in size from 1.1 to 4.3 cm in greatest dimension. The neoplasms were composed predominantly of stellate and spindle cells with long, thin interconnecting cytoplasmic processes arranged in a complex network. The resulting cellular architecture was "sieve-like" in appearance because of the formation of numerous small "cyst-like" spaces interposed between the cytoplasmic processes of the tumor cells. All of the neoplasms expressed the characteristic immunophenotype of meningiomas (EMA, PR positive). Most tumors were resected, and none of these have recurred during a follow-up period of 1 to 83 months (average 17 mo). The morphology of the tumors and their anatomic location generated problems in diagnosis, especially in 6 patients with a history of malignancy and for whom metastatic disease was suspected clinically. Intraosseous microcystic meningioma is uncommon, and this series, the largest reported to date, describes their clinicopathologic findings, biological behavior, and features that facilitate their accurate diagnosis. PMID- 25517949 TI - Utility of PTEN and ERG immunostaining for distinguishing high-grade PIN from intraductal carcinoma of the prostate on needle biopsy. AB - Intraductal carcinoma of the prostate and high-grade prostatic intraepithelial neoplasia (PIN) have markedly different implications for patient care but can be difficult to distinguish in needle biopsies. In radical prostatectomies, we demonstrated that PTEN and ERG immunostaining may be helpful to resolve this differential diagnosis. Here, we tested whether these markers are diagnostically useful in the needle biopsy setting. Separate or combined immunostains were applied to biopsies containing morphologically identified intraductal carcinoma, PIN, or borderline intraductal proliferations more concerning than PIN but falling short of morphologic criteria for intraductal carcinoma. Intraductal carcinoma occurring with concurrent invasive tumor showed the highest rate of PTEN loss, with 76% (38/50) lacking PTEN and 58% (29/50) expressing ERG. Of biopsies containing isolated intraductal carcinoma, 61% (20/33) showed PTEN loss and 30% (10/33) expressed ERG. Of the borderline intraductal proliferations, 52% (11/21) showed PTEN loss and 27% (4/15) expressed ERG. Of the borderline cases with PTEN loss, 64% (7/11) had carcinoma in a subsequent needle biopsy specimen, compared with 50% (5/10) of PTEN-intact cases. In contrast, none of the PIN cases showed PTEN loss or ERG expression (0/19). On needle biopsy, PTEN loss is common in morphologically identified intraductal carcinoma yet is very rare in high grade PIN. Borderline intraductal proliferations, especially those with PTEN loss, have a high rate of carcinoma on resampling. If confirmed in larger prospective studies, these results suggest that PTEN and ERG immunostaining may provide a useful ancillary assay to distinguish intraductal carcinoma from high grade PIN in this setting. PMID- 25517951 TI - TFE3 translocation-associated perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: morphology, immunophenotype, differential diagnosis. AB - TFE3 translocation-associated PEComa is a distinct form of perivascular epithelioid cell neoplasm, the features of which are poorly defined owing to their general infrequency and limited prior reports with confirmed rearrangement or fusion. Recent investigation has found a lack of TSC gene mutation in these tumors compared with their nonrearranged counterparts, which underscores the importance of recognizing the translocated variant because of hypothetical ineffectiveness of targeted mTOR inhibitor therapy. Six cases were identified, and TFE3 rearrangement was confirmed by fluorescence in situ hybridization. Patient age ranged from 46 to 66 years (median 50 y), and none had a history of a tuberous sclerosis complex. Three cases arose in the uterine corpus, 1 in the vagina, 1 pelvic tumor, and 1 pulmonary tumor that was likely a recurrence/metastasis from a probable uterine primary. Five cases had clear cell epithelioid morphology that showed a spectrum of atypia, while 1 case had a mixture of clear cell epithelioid and spindle cells. A mostly consistent immunophenotype was observed in the clear cell epithelioid cases: each demonstrated diffuse TFE3, HMB45, cathepsinK labeling, either focal or no melanA staining, and variably weak reactivity to smooth muscle markers. The mixed clear cell epithelioid and spindle cell case had a similar expression pattern in its epithelioid component but strong muscle marker positivity in its spindle cell component. Follow-up ranged from 1 to 57 months. Three cases demonstrated aggressive behavior, and 3 cases had no evidence of recurrence. Both GYN-specific and traditional sets of criteria for malignancy were evaluated. The GYN model showed improved inclusion and specificity in comparison to the traditional model. PMID- 25517952 TI - Is carcinoma in columnar-lined esophagus always located adjacent to intestinal metaplasia?: a histopathologic assessment. AB - Diagnostic criteria for Barrett esophagus in the United States and elsewhere, except the United Kingdom and Japan, include the presence of intestinal metaplasia with goblet cells. We analyzed high-grade dysplasia and adenocarcinoma in a complete series of sections of all interfaces between carcinoma in columnar lined esophagus (CLE) and the adjacent mucosa, assessed them for the mucosal types present, and calculated the proportion of each mucosal type in each case. The materials were a consecutive series of 100 endoscopic resection cases, comprising a total of 1251 microscopic sections. After excluding cases in which intestinal-type or cardiac-type mucosa was not adjacent to CLE carcinoma, 70 cases remained, for which 885 sections were available. Whether the adjacent mucosa was primarily cardiac or intestinal in type was assessed, as were the patterns of immunostaining for HGM, MUC-2, and MUC-6. Twenty-four (34.3%) of the 70 CLE carcinomas were completely surrounded by cardiac-type mucosa, and 10 (14.3%) were completely surrounded by intestinal-type mucosa. In 13 (18.6%), the entire non-neoplastic mucosa of the endoscopic resection specimen comprised the cardiac type alone without any intestinal type, and only 3 (4.3%) comprised the intestinal type only, without any cardiac type. From these findings, we consider it unproven histogenetically that the background mucosa of CLE carcinoma is predominantly of the intestinal type. CLE carcinoma was not demonstrated to have a close relationship with CLE mucosa with intestinal metaplasia. PMID- 25517953 TI - A comparative study of proliferative nodules and lethal melanomas in congenital nevi from children. AB - Differentiating proliferative nodules (PNs) from melanomas arising in congenital nevi (CN) is a considerable challenge for dermatopathologists. Most of the specimens dermatopathologists assess that deal with this differential diagnosis involve proliferations of melanocytes arising in the dermis. In this study, we compare the clinical, histologic, and molecular findings of these 2 conditions. In our database, we found 22 examples of PNs arising in the dermis of CN and 2 cases of lethal melanomas arising from the dermis/epidermis of CN of children. Importantly, we found that among dermal melanocytic proliferations arising from CN in children, PNs are far more common than lethal melanomas. Clinically, multiplicity of lesions favored a diagnosis of PNs, whereas ulceration was infrequent in PNs compared with lethal melanomas. Histologically, PNs showed several distinct patterns including expansile nodules of epithelioid melanocytes with mitotic counts lower than that seen in the melanomas (1.67 vs. 12.5 mitoses/mm), a small round blue cell pattern often highly mitotically active, neurocristic-like, blue nevus-like, a nevoid melanoma-like pattern, or an undifferentiated spindle cell pattern. The lethal melanomas both featured expansile nodules of epithelioid melanocytes with high mitotic counts (range, 5 to 20 mitoses/mm) and an ulcerated overlying epidermis. At the molecular level, the PNs showed mostly whole chromosomal copy number aberrations, which in some cases were accompanied by rare partial chromosomal aberrations, whereas both lethal melanomas showed highly elevated copy number aberrations involving 6p25 without gains of the long arm of chromosome 6. PMID- 25517954 TI - Incidental nonuterine high-grade serous carcinomas arise in the fallopian tube in most cases: further evidence for the tubal origin of high-grade serous carcinomas. AB - Most nonuterine high-grade serous carcinomas (HGSCs) in women with hereditary breast and ovarian cancer syndrome, due to germline BRCA1/2 mutation, arise in the fimbria of the fallopian tube. However, the site of origin of sporadic HGSC, which is usually widely disseminated at presentation, is not well established. We sought to characterize cases of HGSC discovered incidentally in patients not known to be at high risk, in order to determine the site distribution and possible origin of sporadic HGSC. Incidental microscopic, non-mass-forming cases of serous tubal intraepithelial carcinoma or HGSC in salpingo-oophorectomy specimens in which the tubes and ovaries had been extensively examined were identified. No patients were known or suspected BRCA1/2 mutation carriers. Twenty one cases were identified (mean age: 57 y). Surgery was for benign disease (n=15), uterine endometrioid adenocarcinoma or atypical hyperplasia (n=3), bladder carcinoma (n=1), or ovarian serous borderline tumor (n=2). In 16 of 21 cases, the lesion was confined to the fallopian tube (unilateral in 14 cases, bilateral in 2). There was serous tubal intraepithelial carcinoma in all cases and invasive HGSC into the underlying lamina propria in 8 of these 16 cases; the invasive focus measured 1.3 cm or less in every case. In the remaining 5 cases, there was fallopian tube mucosal and ovarian involvement; in 2 of these cases, there was also microscopic peritoneal involvement. Sporadic cases of nonuterine HGSC arise in the fallopian tube fimbria in a large majority of cases, providing further evidence for the tubal origin of these neoplasms. PMID- 25517955 TI - Incidental serous tubal intraepithelial carcinoma and early invasive serous carcinoma in the nonprophylactic setting: analysis of a case series. AB - A precursor for invasive ovarian/pelvic high-grade serous carcinoma, termed serous tubal intraepithelial carcinoma (STIC), has been identified and characterized through careful analysis of the fallopian tubes in both prophylactic salpingo-oophorectomy specimens obtained from women with either a family history of breast and/or ovarian cancer or germline mutations of BRCA1 and BRCA2 and in cases of pelvic high-grade serous carcinoma. Data on incidental STICs and clinically occult microscopic invasive high-grade serous carcinomas are limited. We analyzed the clinicopathologic features of 22 cases, including 15 pure STICs and 7 STICs associated with microscopic invasive high-grade serous carcinomas, identified incidentally in fallopian tubes removed for nonprophylactic indications. Patient age ranged from 39 to 79 years (mean: 62.7; median: 61), with only 1 patient under the age of 50. No patients were known to carry BRCA1 or BRCA2 mutations. Of the 12 pure STICs for which the location in the fallopian tube could be established, 9 were in the fimbriated portion, 1 was at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. Of the 7 STICs with associated invasive high-grade serous carcinoma, 3 were located in the fimbriated portion, 2 were at the junction of the fimbria and infundibulum, and 2 were in the nonfimbriated tube. The invasive components were in the fallopian tube in 6 cases, 4 in subepithelial stroma of tubal mucosa, and 2 as an intramucosal (exophytic) luminal lesion without invasion of underlying subepithelial stroma (size range: 1 to 4 mm). The remaining case had a microscopic focus of high-grade serous carcinoma within the ipsilateral ovary (1.3 mm cortical focus) identified only on deeper sections, without an associated invasive component in the fallopian tube. The preferential finding of atypical epithelium with the cytologic features of high-grade serous carcinoma, namely STIC, in the fallopian tubes rather than the ovaries as an incidental (clinically occult) microscopic lesion in the absence of widespread pelvic carcinoma provides further evidence that STIC is the earliest form of pelvic high-grade serous carcinoma and that the fallopian tube is the site of origin. This study demonstrates the potential for complete examination of the fallopian tubes and ovaries to identify STICs and early invasive serous carcinomas that might be more amenable to the earliest intervention and potential cure. PMID- 25517956 TI - Renal leiomyoma: a contemporary multi-institution study of an infrequent and frequently misclassified neoplasm. AB - Renal leiomyoma is an exceptionally rare benign mesenchymal tumor of the kidney predominantly arising in proximity of the renal capsule or pelvis. Its rarity and nonspecific clinical and imaging features may lead to radical or partial nephrectomy on the basis of preoperative suspicion of renal cell carcinoma. The diagnosis of renal leiomyoma is challenging because of the histologic overlap with lipid-poor angiomyolipoma (AML). We conducted a multi-institution study to characterize renal leiomyoma in greater detail. We collected and reviewed 24 cases diagnosed initially as renal leiomyoma in 10 institutions from North America, Canada, and Europe. Immunohistochemical expression of desmin, HMB-45, estrogen receptor (ER), progesterone receptor (PR), and cathepsin K was evaluated. Upon central review, 9 tumors were classified as renal leiomyoma, whereas the remaining were reclassified as AML (n=13), myolipoma (n=1), and medullary fibroma (n=1). All renal leiomyomas were solitary and occurred in female patients (mean age 63 y; range, 44 to 74 y). Tumor size ranged from 0.6 to 7.0 cm (mean 2.9 cm); 7 originated from the renal capsule or the subcapsular area and 1 from a large vessel in the renal sinus. All leiomyomas were diffusely positive for desmin and negative for HMB-45 and cathepsin K; 6/9 (67%) showed diffuse ER and PR expression, and 1 case showed focal ER positivity only. Renal leiomyoma should be included in the histologic differential diagnosis of solid renal masses, particularly in perimenopausal women. The main differential diagnosis is with lipid-poor AML, and cathepsin K plays a key role in distinguishing these 2 lesions. PMID- 25517957 TI - Villin immunohistochemistry is a reliable method for diagnosing microvillus inclusion disease. AB - Microvillus inclusion disease (MVID) is a rare congenital disorder that manifests early in infancy as intractable watery diarrhea. The entity is characterized morphologically by a deficient brush border and apical cytoplasmic inclusions within absorptive cells (enterocytes) due to misplaced assembly of brush border proteins. The diagnosis is based upon histopathology, special stains, immunohistochemistry (IHC), and ultimately upon electron microscopy. Currently, the periodic acid-Schiff stain (PAS) and CD10 IHC are commonly used as adjuncts, but in addition to brush border structures, they stain a variety of apical cytoplasmic inclusions and organelles, thereby interfering with recognition of microvillus inclusions. Villin is a protein that specifically binds to the actin core bundle of microvilli. We utilized villin IHC in formalin-fixed paraffin embedded gastrointestinal biopsies from 6 patients with MVID, 5 with celiac disease, and 17 children with normal intestinal biopsies and compared the results with those obtained with CD10 IHC and PAS staining. All MVID cases had confirmatory electron microscopy at the time of diagnosis. Villin immunoreactivity was restricted to the brush border in the control groups. In MVID, villin IHC showed attenuation or loss of the surface brush border and also highlighted the cytoplasmic microvillus inclusions with clarity. In MVID, CD10 IHC and the PAS stain also showed attenuation or loss of the surface brush border, but staining of a variety of cytoplasmic structures largely obscured the microvillus inclusions. In sum, villin IHC is a reliable and superior adjunct in the diagnosis of MVID. Study of additional cases will determine whether villin IHC would obviate the need for electron microscopic confirmation. PMID- 25517959 TI - NOTCH1 intracellular domain immunohistochemistry as a diagnostic tool to distinguish T-lymphoblastic lymphoma from thymoma. AB - Distinction between lymphocyte-rich thymoma and T-lymphoblastic lymphoma/leukemia (T-LBL) can be problematic because of a predominance of precursor T cells in both, particularly if the epithelial component in a thymoma is undersampled. Because of very different clinical implications, accurate diagnosis is critical. The NOTCH1 signaling pathway is frequently activated in T-LBL and plays a central role in the pathogenesis of this disease. Antibodies to NOTCH1 intracellular domain (N1ICD), recognizing the active form of NOTCH1, have been developed. We hypothesized that detection of N1ICD would be useful in distinguishing T-LBL from thymoma and investigated a series of formalin-fixed, paraffin-embedded tissues for immunoreactivity with an N1ICD antibody using automated immunohistochemistry. Slides were scored using a 25% nuclear reactivity threshold for positivity. Hyperplastic tonsil showed positivity in few scattered interfollicular lymphoid cells, suprabasilar epithelial cells, and endothelial cells. Thymocytes from non neoplastic thymus were largely negative for N1ICD. All thymomas tested (n=23) were negative for N1ICD, although epithelial cells and a small minority of thymocytes may be positive, requiring careful interpretation. All T-LBL cases (n=16) were scored positive for N1ICD: 8 (50%) of these showed diffuse and mostly strong immunoreactivity, whereas the remaining 8 (50%) had less extensive positivity, but with consistently >25% nuclear staining. In conclusion, normal thymocytes do not express significant levels of N1ICD. In keeping with this pattern, thymomas are negative for N1ICD, whereas a high percentage of T-LBL expresses N1ICD. Thus, N1ICD immunohistochemistry appears to be a useful method in distinguishing T-LBL from thymoma. PMID- 25517958 TI - Clinicopathologic characteristics of 29 invasive carcinomas arising in 178 pancreatic mucinous cystic neoplasms with ovarian-type stroma: implications for management and prognosis. AB - Information on the clinicopathologic characteristics of invasive carcinomas arising from mucinous cystic neoplasms (MCNs) is limited, because in many early studies they were lumped and analyzed together with noninvasive MCNs. Even more importantly, many of the largest prior studies did not require ovarian-type stroma (OTS) for diagnosis. We analyzed 178 MCNs, all strictly defined by the presence of OTS, 98% of which occurred in perimenopausal women (mean age, 47 y) and arose in the distal pancreas. Twenty-nine (16%) patients had associated invasive carcinoma, and all were female with a mean age of 53. Invasion was far more common in tumors with grossly visible intracystic papillary nodule formation >=1.0 cm (79.3% vs. 8.7%, P=0.000) as well as in larger tumors (mean cyst size: 9.4 vs. 5.4 cm, P=0.006); only 4/29 (14%) invasive carcinomas occurred in tumors that were <5 cm; however, none were <3 cm. Increased serum CA19-9 level (>37 U/L) was also more common in the invasive tumors (64% vs. 23%, P=0.011). Most invasive carcinomas (79%) were of tubular type, and the remainder (5 cases) were mostly undifferentiated carcinoma (2, with osteoclast-like giant cells), except for 1 with papillary features. Interestingly, there were no colloid carcinomas; 2 patients had nodal metastasis at the time of diagnosis, and both died of disease at 10 and 35 months, respectively. While noninvasive MCNs had an excellent prognosis (100% at 5 y), tumors with invasion often had an aggressive clinical course with 3- and 5-year survival rates of 44% and 26%, respectively (P=0.000). The pT2 (>2 cm) invasive tumors had a worse prognosis than pT1 (<=2 cm) tumors (P=0.000), albeit 3 patients with T1a (<0.5 cm) disease also died of disease. In conclusion, invasive carcinomas are seen in 16% of MCNs and are mostly of tubular (pancreatobiliary) type; colloid carcinoma is not seen in MCNs. Serum CA19-9 is often higher in invasive carcinomas, and invasion is typically seen in OTS depleted areas with lower progesterone receptor expression. Invasion is not seen in small tumors (<3 cm) and those lacking intracystic papillary (mural) nodules of >=1 cm, thus making the current branch-duct intraductal papillary mucinous neoplasm management protocols also applicable to MCNs. PMID- 25517960 TI - Adenocarcinoma of the thymus, enteric type: report of 2 cases, and proposal for a novel subtype of thymic carcinoma. AB - We report 2 cases of primary thymic adenocarcinoma with enteric differentiation. One carcinoma occurred in a 41-year-old man as a 7-cm-diameter cystic tumor and the other one in a 39-year-old woman as a 6-cm-diameter solid mass. Both tumors were located in the anterior mediastinum. Clinical staging did not reveal any extrathymic tumor. Histologically, the tumors were classified as adenocarcinoma, not otherwise specified, and a mucinous (colloid) carcinoma, respectively. Immunohistochemically, both tumors were positive for cytokeratin 20 (CK20), CDX2, and carcinoembryonic antigen, reflecting enteric differentiation. A review of the literature on 43 other cases of primary thymic adenocarcinomas suggested 11 further cases with enteric differentiation, as assessed by CK20 and/or CDX2 expression. We propose that thymic adenocarcinoma with enteric differentiation represents a novel subtype of thymic carcinoma. It is mostly of mucinous morphology and frequently associated with thymic cysts. The clinical outcome is variable. Recognition of primary thymic adenocarcinoma with enteric differentiation is helpful for the differentiation from metastatic disease, mainly from the gastrointestinal tract. PMID- 25517962 TI - Vanishing endometrial cancer in hysterectomy specimens: a myth or a fact. AB - The incidence of endometrial cancers diagnosed on biopsy that have no residual cancer identified at hysterectomy is not well studied. The aim of our study was to determine the incidence and long-term follow-up of this "vanishing cancer" phenomenon. All slides from the initial biopsy/curettage and hysterectomy specimens were reviewed and the diagnosis confirmed by a gynecologic pathologist. The entire endometrium was serially sectioned and submitted for histologic examination. Clinical and pathologic variables were analyzed, including patient demographics, tumor histologic type and grade, stage, biopsy method, adjuvant therapy, surgical procedure, recurrence, and disease-specific survival. We identified 23 biopsy-proven cases of endometrial cancer with no residual disease on hysterectomy specimen. Of the 23 patients, 15 (65.2%) were diagnosed as endometrioid, 6 (26%) serous, 1 clear cell (4.3%), and 1 (4.3%) serous intraepithelial carcinoma. Seventeen underwent dilatation and curettage, and 6 had endometrial biopsy as the primary procedure. The median follow-up was 8.8 years (range, 1.2 to 17 y). Only 2 cases with serous carcinoma underwent adjuvant chemotherapy, and none received radiation therapy. Only 1 patient died of disease after 27 months and was diagnosed as FIGO grade II endometrioid carcinoma on dilatation and curettage. The inability to identify cancer in a hysterectomy specimen for biopsy-confirmed carcinoma does not indicate technical failure. Although there is no specific standard treatment for patients with "vanishing endometrial cancer," the prognosis is excellent; however, close follow-up is suggested. PMID- 25517961 TI - Locus/chromosome aberrations in intraductal papillary mucinous neoplasms analyzed by fluorescence in situ hybridization. AB - Locus and chromosome abnormalities have not been well clarified in intraductal papillary mucinous neoplasms (IPMNs). The aim of this study was to retrospectively examine these abnormalities using fluorescence in situ hybridization. IPMNs (n=28) were histopathologically classified into noninvasive IPMN (n=17) and IPMN with an associated invasive carcinoma (invasive IPMN, n=11) groups. Noninvasive IPMNs possessed non-neoplastic and noninvasive spots in their tissues, and invasive IPMN cases possessed non-neoplastic, noninvasive, and invasive spots. Non-neoplastic (n=28), noninvasive (n=28), and invasive (n=11) spots were then analyzed for aneuploidy of chromosomes 3, 6, 7, 8, 17, and 18 and deletions of p16 and p53 loci. Polysomy 6 and p16 deletion were significantly more frequent in noninvasive than in non-neoplastic spots. Polysomy 7, polysomy 18, p16 deletion, and p53 deletion were significantly more frequent in invasive than in noninvasive spots. Detection of polysomy 7 and p53 deletion gave a high diagnostic accuracy for invasive IPMN (sensitivity, 90.9%; specificity, 94.1%; and accuracy, 92.5%). Our study suggests that: (1) polysomy 6 and p16 deletion may contribute to adenomatous change of IPMN; (2) polysomy 7, polysomy 18, p16 deletion, and p53 deletion play roles in malignant transformation of noninvasive IPMN; and (3) polysomy 7 and p53 deletion may be excellent diagnostic markers for invasive IPMN. PMID- 25517963 TI - Targeting beta-catenin signaling for therapeutic intervention in MEN1-deficient pancreatic neuroendocrine tumours. AB - Inactivating MEN1 mutations are the most common genetic defects present in sporadic and inherited pancreatic neuroendocrine tumours (PNETs). The lack of interventional therapies prompts us to explore the therapeutic approach of targeting beta-catenin signalling in MEN1-mutant PNETs. Here we show the MEN1 encoded scaffold protein menin regulates phosphorylation of beta-catenin. beta catenin signalling is activated in MEN1-mutant human and mouse PNETs. Conditional knockout of beta-catenin suppresses the tumorigenesis and growth of Men1 deficient PNETs, and significantly prolongs the survival time in mice. Suppression of beta-catenin signalling by genetic ablation or a molecular antagonist inhibits the expression of proproliferative genes in menin-null PNETs and potently improves hyperinsulinemia and hypoglycemia in mice. Blockade of beta catenin has no adverse effect on physiological function of pancreatic beta-cells. Our data demonstrate that beta-catenin signalling is an effective therapeutic target for MEN1-mutant PNETs. Our findings may contribute to individualized and combined medication treatment for PNETs. PMID- 25517964 TI - Vertical and horizontal genetic connectivity in Chromis verater, an endemic damselfish found on shallow and mesophotic reefs in the Hawaiian Archipelago and adjacent Johnston Atoll. AB - Understanding vertical and horizontal connectivity is a major priority in research on mesophotic coral ecosystems (30-150 m). However, horizontal connectivity has been the focus of few studies, and data on vertical connectivity are limited to sessile benthic mesophotic organisms. Here we present patterns of vertical and horizontal connectivity in the Hawaiian Islands-Johnston Atoll endemic threespot damselfish, Chromis verater, based on 319 shallow specimens and 153 deep specimens. The mtDNA markers cytochrome b and control region were sequenced to analyze genetic structure: 1) between shallow (< 30 m) and mesophotic (30-150 m) populations and 2) across the species' geographic range. Additionally, the nuclear markers rhodopsin and internal transcribed spacer 2 of ribosomal DNA were sequenced to assess connectivity between shallow and mesophotic populations. There was no significant genetic differentiation by depth, indicating high levels of vertical connectivity between shallow and deep aggregates of C. verater. Consequently, shallow and deep samples were combined by location for analyses of horizontal connectivity. We detected low but significant population structure across the Hawaiian Archipelago (overall cytochrome b: PhiST = 0.009, P = 0.020; control region: PhiST = 0.012, P = 0.009) and a larger break between the archipelago and Johnston Atoll (cytochrome b: PhiST = 0.068, P < 0.001; control region: PhiST = 0.116, P < 0.001). The population structure within the archipelago was driven by samples from the island of Hawaii at the southeast end of the chain and Lisianski in the middle of the archipelago. The lack of vertical genetic structure supports the refugia hypothesis that deep reefs may constitute a population reservoir for species depleted in shallow reef habitats. These findings represent the first connectivity study on a mobile organism that spans shallow and mesophotic depths and provide a reference point for future connectivity studies on mesophotic fishes. PMID- 25517967 TI - Elevation-related variation in leaf stomatal traits as a function of plant functional type: evidence from Changbai Mountain, China. AB - Understanding the variation in stomatal characteristics in relation to climatic gradients can reveal the adaptation strategies of plants, and help us to predict their responses to future climate changes. In this study, we investigated stomatal density (SD) and stomatal length (SL) in 150 plant species along an elevation gradient (540-2357 m) in Changbai Mountain, China, and explored the patterns and drivers of stomatal characteristics across species and plant functional types (PFTs: trees, shrubs, and herbs). The average values of SD and SL for all species combined were 156 mm(-2) and 35 um, respectively. SD was higher in trees (224 mm(-2)) than in shrubs (156 mm(-2)) or herbs (124 mm(-2)), and SL was largest in herbs (37 um). SD was negatively correlated with SL in all species and PFTs (P < 0.01). The relationship between stomatal characteristics and elevation differed among PFTs. In trees, SD decreased and SL increased with elevation; in shrubs and herbs, SD initially increased and then decreased. Elevation-related differences in SL were not significant. PFT explained 7.20 17.6% of the total variation in SD and SL; the contributions of CO2 partial pressure (P CO2), precipitation, and soil water content (SWC) were weak (0.02 2.28%). Our findings suggest that elevation-related patterns of stomatal characteristics in leaves are primarily a function of PFT, and highlight the importance of differences among PFTs in modeling gas exchange in terrestrial ecosystems under global climate change. PMID- 25517968 TI - Cultural diffusion was the main driving mechanism of the Neolithic transition in southern Africa. AB - It is well known that the Neolithic transition spread across Europe at a speed of about 1 km/yr. This result has been previously interpreted as a range expansion of the Neolithic driven mainly by demic diffusion (whereas cultural diffusion played a secondary role). However, a long-standing problem is whether this value (1 km/yr) and its interpretation (mainly demic diffusion) are characteristic only of Europe or universal (i.e. intrinsic features of Neolithic transitions all over the world). So far Neolithic spread rates outside Europe have been barely measured, and Neolithic spread rates substantially faster than 1 km/yr have not been previously reported. Here we show that the transition from hunting and gathering into herding in southern Africa spread at a rate of about 2.4 km/yr, i.e. about twice faster than the European Neolithic transition. Thus the value 1 km/yr is not a universal feature of Neolithic transitions in the world. Resorting to a recent demic-cultural wave-of-advance model, we also find that the main mechanism at work in the southern African Neolithic spread was cultural diffusion (whereas demic diffusion played a secondary role). This is in sharp contrast to the European Neolithic. Our results further suggest that Neolithic spread rates could be mainly driven by cultural diffusion in cases where the final state of this transition is herding/pastoralism (such as in southern Africa) rather than farming and stockbreeding (as in Europe). PMID- 25517965 TI - Genetic variants in nitric oxide synthase genes and the risk of male infertility in a Chinese population: a case-control study. AB - BACKGROUND: In recent years, oxidative stress has been studied extensively as a main contributing factor to male infertility. Nitric Oxide, a highly reactive free radical gas, is potentially detrimental to sperm function and sperm DNA integrity at high levels. Thus, the aim of this study was to investigate the associations between five polymorphisms in nitric oxide synthase genes (NOSs) and the risk of male infertility and sperm DNA damage as well. METHODS: Genotypes were determined by the OpenArray platform. Sperm DNA fragmentation was detected using the Tdt-mediated dUTP nick-end labeling assay, and the level of 8 hydroxydeoxyguanosine (8-OHdG) in sperm DNA was measured using immunofluorescence. The adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated using unconditional logistic regression. RESULTS: Our results revealed a statistically significant difference between the cases and controls in both genotypic distribution (P<0.001) and allelic frequency (P = 0.021) only for the NOS3 rs1799983 SNP. Multivariate logistic regression analyses revealed that rs1799983 was associated with a borderline significantly increased risk of male infertility (GT vs. GG: adjusted OR = 1.30, 95% CI: 1.00-1.70; GT+TT vs. GG: adjusted OR = 1.34, 95% CI: 1.03-1.74; P trend = 0.020). Moreover, NOS3 rs1799983 was positively associated with higher levels of sperm DNA fragmentation (beta = 0.223, P = 0.044). However, the other 4 polymorphisms (NOS1 rs2682826, NOS1 rs1047735, NOS2 rs2297518, and NOS2 rs10459953) were not found to have any apparent relationships with male infertility risk. CONCLUSIONS: Of five NOS gene polymorphisms investigated in the present study, we found NOS3 rs1799983 might cause oxidative sperm DNA damage, thereby contributing to male infertility. PMID- 25517966 TI - The role of biological agents in the management of large vessel vasculitis (LVV): a systematic review and meta-analysis. AB - BACKGROUND: Giant cell arteritis (GCA) and Takayasu's arteritis (TAA) are large vessel vasculitides (LVV) for which corticosteroids (CS) are the mainstay for treatment. In patients with LVV unable to tolerate CS, biological agents have been used with variable effectiveness. OBJECTIVE: To systematically review the effectiveness and safety of biological agents in patients with LVV. METHODS: We searched 5 electronic databases (inception to October 2012) and conference abstracts with no language restrictions. Two reviewers independently selected studies, extracted data and assessed methodological quality. Our protocol was registered in PROSPERO. RESULTS: We included 25 studies (3 RCTs and 22 case series with >=2 cases). 95 GCA and 98 TAA patients received biological agents. The RCTs using anti-TNF agents (infliximab, etanercept and adalimumab) did not suggest a benefit in GCA. GCA patients receiving tocilizumab, in case series, achieved remission (19 patients) and reduction of corticosteroid dose (mean difference, -16.55 mg/day (95% CI: -26.24, -6.86)). In case series, 75 patients with refractory TAA treated with infliximab discontinued CS 32% of the time. Remission was variably defined and the studies were clinically heterogeneous which precluded further analysis. CONCLUSION: This systematic review demonstrated a weak evidence base on which to assess the effectiveness of biological treatment in LVV. Evidence from RCTs suggests that anti-TNF agents are not effective for remission or reduction of CS use. Tocilizumab and infliximab may be effective in the management of LVV and refractory TAA, respectively, although the evidence comes from case series. Future analytical studies are needed to confirm these findings. PMID- 25517969 TI - Impact of the iron-sulfur cluster proximal to the active site on the catalytic function of an O2-tolerant NAD(+)-reducing [NiFe]-hydrogenase. AB - The soluble NAD(+)-reducing hydrogenase (SH) from Ralstonia eutropha H16 belongs to the O2-tolerant subtype of pyridine nucleotide-dependent [NiFe]-hydrogenases. To identify molecular determinants for the O2 tolerance of this enzyme, we introduced single amino acids exchanges in the SH small hydrogenase subunit. The resulting mutant strains and proteins were investigated with respect to their physiological, biochemical, and spectroscopic properties. Replacement of the four invariant conserved cysteine residues, Cys41, Cys44, Cys113, and Cys179, led to unstable protein, strongly supporting their involvement in the coordination of the iron-sulfur cluster proximal to the catalytic [NiFe] center. The Cys41Ser exchange, however, resulted in an SH variant that displayed up to 10% of wild type activity, suggesting that the coordinating role of Cys41 might be partly substituted by the nearby Cys39 residue, which is present only in O2-tolerant pyridine nucleotide-dependent [NiFe]-hydrogenases. Indeed, SH variants carrying glycine, alanine, or serine in place of Cys39 showed increased O2 sensitivity compared to that of the wild-type enzyme. Substitution of further amino acids typical for O2-tolerant SH representatives did not greatly affect the H2 oxidizing activity in the presence of O2. Remarkably, all mutant enzymes investigated by electron paramagnetic resonance spectroscopy did not reveal significant spectral changes in relation to wild-type SH, showing that the proximal iron-sulfur cluster does not contribute to the wild-type spectrum. Interestingly, exchange of Trp42 by serine resulted in a completely redox inactive [NiFe] site, as revealed by infrared spectroscopy and H2/D(+) exchange experiments. The possible role of this residue in electron and/or proton transfer is discussed. PMID- 25517971 TI - Quantitative genetics model as the unifying model for defining genomic relationship and inbreeding coefficient. AB - The traditional quantitative genetics model was used as the unifying approach to derive six existing and new definitions of genomic additive and dominance relationships. The theoretical differences of these definitions were in the assumptions of equal SNP effects (equivalent to across-SNP standardization), equal SNP variances (equivalent to within-SNP standardization), and expected or sample SNP additive and dominance variances. The six definitions of genomic additive and dominance relationships on average were consistent with the pedigree relationships, but had individual genomic specificity and large variations not observed from pedigree relationships. These large variations may allow finding least related genomes even within the same family for minimizing genomic relatedness among breeding individuals. The six definitions of genomic relationships generally had similar numerical results in genomic best linear unbiased predictions of additive effects (GBLUP) and similar genomic REML (GREML) estimates of additive heritability. Predicted SNP dominance effects and GREML estimates of dominance heritability were similar within definitions assuming equal SNP effects or within definitions assuming equal SNP variance, but had differences between these two groups of definitions. We proposed a new measure of genomic inbreeding coefficient based on parental genomic co-ancestry coefficient and genomic additive correlation as a genomic approach for predicting offspring inbreeding level. This genomic inbreeding coefficient had the highest correlation with pedigree inbreeding coefficient among the four methods evaluated for calculating genomic inbreeding coefficient in a Holstein sample and a swine sample. PMID- 25517970 TI - Alterations in Hippocampal Network Activity after In Vitro Traumatic Brain Injury. AB - Traumatic brain injury (TBI) alters function and behavior, which can be characterized by changes in electrophysiological function in vitro. A common cognitive deficit after mild-to-moderate TBI is disruption of persistent working memory, of which the in vitro correlate is long-lasting, neuronal network synchronization that can be induced pharmacologically by the gamma-aminobutyric acid A antagonist, bicuculline. We utilized a novel in vitro platform for TBI research, the stretchable microelectrode array (SMEA), to investigate the effects of TBI on bicuculline-induced, long-lasting network synchronization in the hippocampus. Mechanical stimulation significantly disrupted bicuculline-induced, long-lasting network synchronization 24 h after injury, despite the continued ability of the injured neurons to fire, as revealed by a significant increase in the normalized spontaneous event rate in the dentate gyrus (DG) and CA1. A second challenge with bicuculline 24 h after the first challenge significantly decreased the normalized spontaneous event rate in the DG. In addition, we illustrate the utility of the SMEA for TBI research by combining multiple experimental paradigms in one platform, which has the potential to enable novel investigations into the mechanisms responsible for functional consequences of TBI and speed the rate of drug discovery. PMID- 25517973 TI - Transcriptional alterations of ET-1 axis and DNA damage in lung tissue of a rat obesity model. AB - Obesity has been implicated in the development of many cancers. This can lead to genome damage, especially in the form of double-strand break, the presence of which is now easily detected through nuclear phosphorylation of histone H2AX (gamma-H2AX) focus assay. Recently, the endothelin (ET) axis has also been shown to have a role in the growth and progression of several tumors, including lung cancer. The aim of this study was to evaluate the ET-1 system transcriptional alterations and gamma-H2AX in lung tissue of Zucker rats subdivided into obese (O, n=22) and controls (CO, n=18) rats: under either fasting conditions (CO(fc) O(fc)) or acute hyperglycemia (CO(AH)-O(AH)). Significantly higher prepro-ET-1 (p=0.05) and ET-converting enzyme (ECE)-2 mRNA expression was observed in O with respect to CO. A significant positive association was observed between prepro-ET 1 and ET-A in the whole rat population (p=0.009) or in the obese group alone (p=0.007). The levels of gamma-H2AX in O and in O(AH) rats were significantly higher (p=0.019) than in the corresponding CO and CO(AH) rats (p=0.038). The study shows an inappropriate secretion of ET-1 in O animals with a parallel DNA damage in their lungs, providing novel mechanisms by which ET receptor antagonist may exert organ protection. PMID- 25517974 TI - Lewis Carroll's Doublets net of English words: network heterogeneity in a complex system. AB - Lewis Carroll's English word game Doublets is represented as a system of networks with each node being an English word and each connectivity edge confirming that its two ending words are equal in letter length, but different by exactly one letter. We show that this system, which we call the Doublets net, constitutes a complex body of linguistic knowledge concerning English word structure that has computable multiscale features. Distributed morphological, phonological and orthographic constraints and the language's local redundancy are seen at the node level. Phonological communities are seen at the network level. And a balancing act between the language's global efficiency and redundancy is seen at the system level. We develop a new measure of intrinsic node-to-node distance and a computational algorithm, called community geometry, which reveal the implicit multiscale structure within binary networks. Because the Doublets net is a modular complex cognitive system, the community geometry and computable multi scale structural information may provide a foundation for understanding computational learning in many systems whose network structure has yet to be fully analyzed. PMID- 25517976 TI - Clinical research: a globalized network. AB - Clinical research has become increasingly globalized, but the extent of globalization has not been assessed. To describe the globalization of clinical research, we used all (n = 13,208) multinational trials registered at ClinicalTrials.gov to analyzed geographic connections among individual countries. Our findings indicate that 95% (n = 185) of all countries worldwide have participated in multinational clinical research. Growth in the globalization of clinical research peaked in 2009, suggesting that the global infrastructure that supports clinical research might have reached its maximum capacity. Growth in the globalization of clinical research is attributable to increased involvement of non-traditional markets, particularly in South America and Asia. Nevertheless, Europe is the most highly interconnected geographic region (60.64% of global connections), and collectively, Europe, North America, and Asia comprise more than 85% of all global connections. Therefore, while the expansion of clinical trials into non-traditional markets has increased over the last 20 years and connects countries across the globe, traditional markets still dominate multinational clinical research, which appears to have reached a maximum global capacity. PMID- 25517975 TI - Non-cellulosic polysaccharides from cotton fibre are differently impacted by textile processing. AB - Cotton fibre is mainly composed of cellulose, although non-cellulosic polysaccharides play key roles during fibre development and are still present in the harvested fibre. This study aimed at determining the fate of non-cellulosic polysaccharides during cotton textile processing. We analyzed non-cellulosic cotton fibre polysaccharides during different steps of cotton textile processing using GC-MS, HPLC and comprehensive microarray polymer profiling to obtain monosaccharide and polysaccharide amounts and linkage compositions. Additionally, in situ detection was used to obtain information on polysaccharide localization and accessibility. We show that pectic and hemicellulosic polysaccharide levels decrease during cotton textile processing and that some processing steps have more impact than others. Pectins and arabinose-containing polysaccharides are strongly impacted by the chemical treatments, with most being removed during bleaching and scouring. However, some forms of pectin are more resistant than others. Xylan and xyloglucan are affected in later processing steps and to a lesser extent, whereas callose showed a strong resistance to the chemical processing steps. This study shows that non-cellulosic polysaccharides are differently impacted by the treatments used in cotton textile processing with some hemicelluloses and callose being resistant to these harsh treatments. PMID- 25517977 TI - Ranking competitors using degree-neutralized random walks. AB - Competition is ubiquitous in many complex biological, social, and technological systems, playing an integral role in the evolutionary dynamics of the systems. It is often useful to determine the dominance hierarchy or the rankings of the components of the system that compete for survival and success based on the outcomes of the competitions between them. Here we propose a ranking method based on the random walk on the network representing the competitors as nodes and competitions as directed edges with asymmetric weights. We use the edge weights and node degrees to define the gradient on each edge that guides the random walker towards the weaker (or the stronger) node, which enables us to interpret the steady-state occupancy as the measure of the node's weakness (or strength) that is free of unwarranted degree-induced bias. We apply our method to two real world competition networks and explore the issues of ranking stabilization and prediction accuracy, finding that our method outperforms other methods including the baseline win-loss differential method in sparse networks. PMID- 25517978 TI - The development of a bilingual interactive video to improve physical activity and healthful eating in a head start population. AB - The prevalence of obesity in the Hispanic preschool population remains elevated, particularly among children in low income families below the poverty level. Obesity leads to the early onset of metabolic syndrome and Type 2 diabetes. The Head Start population of Texas is largely comprised of this high risk group. Their physical activity level is suboptimal in part due to lack of available outside play areas and time spent watching television and playing sedentary video games. Dietary intake is frequently high in sugar sweetened beverages and low in vegetables. The group is frequently bilingual with limited vocabulary and has not learned to read. Preserving their Mexican American culture is a concern. This article describes the development and assessment of a group of bilingual interactive video interventions to improve age appropriate physical activity while providing basic nutrition education focusing on increasing vegetable and water intake and decreasing sugar sweetened beverages. Suggestions for development and assessment of content were provided by focus groups of Head Start teachers, managers and dietitians in the Texas counties of Bastrop, Hidalgo and McLennon. A demonstration of the videos was conducted in Bastrop County. Teachers, students and managers felt that the videos provided excellent information, improved exercise participation and engaged the children. PMID- 25517980 TI - Dysexecutive Questionnaire (DEX): Unrestricted structural analysis in large clinical and non-clinical samples. AB - The factorial structure of the Dysexecutive Questionnaire (DEX) is an unresolved issue in scientific literature. One-to-five-factor solutions have been found in several studies by applying different research methods. Only a few of these studies used appropriate analysis procedures to suit a Likert scale-type of answer or investigated large enough samples to ensure the stability of factorial solutions. The present study examines a sample of 2151 subjects, 1482 from the general population and 669 from a clinical population. An unrestricted factorial analysis was carried out on both samples. The results unequivocally point to a single-factor solution in both samples. This means that only one latent variable is displayed in the DEX, which accounts for symptoms of oversight malfunction in activities of daily living. It is concluded that the diversity of results previously obtained in other studies may be due to using research methods that depict Likert-type scales on a continuum when they are actually ordinal categorical measures. In conclusion, the DEX should be considered a screening test that reports symptoms of prefrontal malfunction, although it is unable to specify what areas or functions have been affected, as previous studies have claimed. PMID- 25517982 TI - Baseline immune activity is associated with date rather than with moult stage in the Arctic-breeding barnacle goose (Branta leucopsis). AB - Variation in immune defence in birds is often explained either by external factors such as food availability and disease pressure or by internal factors such as moult and reproductive effort. We explored these factors together in one sampling design by measuring immune activity over the time frame of the moulting period of Arctic-breeding barnacle geese (Branta leucopsis). We assessed baseline innate immunity by measuring levels of complement-mediated lysis and natural antibody-mediated agglutination together with total and differential leukocyte counts. Variation in immune activity during moult was strongly associated with calendar date and to a smaller degree with the growth stage of wing feathers. We suggest that the association with calendar date reflected temporal changes in the external environment. This environmental factor was further explored by comparing the immune activity of geese in the Arctic population with conspecifics in the temperate climate zone at comparable moult stages. In the Arctic environment, which has a lower expected disease load, geese exhibited significantly lower values of complement-mediated lysis, their blood contained fewer leukocytes, and levels of phagocytic cells and reactive leukocytes were relatively low. This suggests that lower baseline immune activity could be associated with lower disease pressure. We conclude that in our study species, external factors such as food availability and disease pressure have a greater effect on temporal variation of baseline immune activity than internal factors such as moult stage. PMID- 25517981 TI - Increased expression of MERTK is associated with a unique form of canine retinopathy. AB - Progressive retinal degenerations are among the most common causes of blindness both in human and in dogs. Canine progressive retinal atrophy (PRA) resembles human retinitis pigmentosa (RP) and is typically characterized by a progressive loss of rod photoreceptors followed by a loss of cone function. The disease gradually progress from the loss of night and day vision to a complete blindness. We have recently described a unique form of retinopathy characterized by the multifocal gray/brown discoloration and thinning of the retina in the Swedish Vallhund (SV) breed. We aimed to identify the genetic cause by performing a genome wide association analysis in a cohort of 18 affected and 10 healthy control dogs using Illumina's canine 22k SNP array. We mapped the disease to canine chromosome 17 (p = 7.7*10(-5)) and found a 6.1 Mb shared homozygous region in the affected dogs. A combined analysis of the GWAS and replication data with additional 60 dogs confirmed the association (p = 4.3*10(-8), OR = 11.2 for homozygosity). A targeted resequencing of the entire associated region in four cases and four controls with opposite risk haplotypes identified several variants in the coding region of functional candidate genes, such as a known retinopathy gene, MERTK. However, none of the identified coding variants followed a compelling case- or breed-specific segregation pattern. The expression analyses of four candidate genes in the region, MERTK, NPHP1, ANAPC1 and KRCC1, revealed specific upregulation of MERTK in the retina of the affected dogs. Collectively, these results indicate that the retinopathy is associated with overexpression of MERTK, however further investigation is needed to discover the regulatory mutation for the better understanding of the disease pathogenesis. Our study establishes a novel gain-of-function model for the MERTK biology and provides a therapy model for retinopathy MERTK inhibitors. Meanwhile, a marker-based genetic counseling can be developed to revise breeding programs. PMID- 25517984 TI - Relating specific emotions to intrinsic motivation: on the moderating role of positive and negative emotion differentiation. AB - Despite the fact that studies on self-determination theory have traditionally disregarded the explicit role of emotions in the motivation eliciting process, research attention for the affective antecedents of motivation is growing. We add to this emerging research field by testing the moderating role of emotion differentiation -individual differences in the extent to which people can differentiate between specific emotions- on the relationship between twelve specific emotions and intrinsic motivation. To this end, we conducted a daily diary study (N = 72) and an experience sampling study (N = 34). Results showed that the relationship between enthusiasm, cheerfulness, optimism, contentedness, gloominess, miserableness, uneasiness (in both studies 1 and 2), calmness, relaxation, tenseness, depression, worry (only in Study 1) on one hand and intrinsic motivation on the other hand was moderated by positive emotion differentiation for the positive emotions and by negative emotion differentiation for the negative emotions. Altogether, these findings suggest that for people who are unable to distinguish between different specific positive emotions the relationship between those specific positive emotions and intrinsic motivation is stronger, whereas the relationship between specific negative emotions and intrinsic motivation is weaker for people who are able to distinguish between the different specific negative emotions. Theoretical and practical implications are discussed. PMID- 25517983 TI - Activated astrocytes enhance the dopaminergic differentiation of stem cells and promote brain repair through bFGF. AB - Astrocytes provide neuroprotective effects against degeneration of dopaminergic (DA) neurons and play a fundamental role in DA differentiation of neural stem cells. Here we show that light illumination of astrocytes expressing engineered channelrhodopsin variant (ChETA) can remarkably enhance the release of basic fibroblast growth factor (bFGF) and significantly promote the DA differentiation of human embryonic stem cells (hESCs) in vitro. Light activation of transplanted astrocytes in the substantia nigra (SN) also upregulates bFGF levels in vivo and promotes the regenerative effects of co-transplanted stem cells. Importantly, upregulation of bFGF levels, by specific light activation of endogenous astrocytes in the SN, enhances the DA differentiation of transplanted stem cells and promotes brain repair in a mouse model of Parkinson's disease (PD). Our study indicates that astrocyte-derived bFGF is required for regulation of DA differentiation of the stem cells and may provide a strategy targeting astrocytes for treatment of PD. PMID- 25517985 TI - Involvement of potassium channels in the progression of cancer to a more malignant phenotype. AB - Potassium channels are a diverse group of pore-forming transmembrane proteins that selectively facilitate potassium flow through an electrochemical gradient. They participate in the control of the membrane potential and cell excitability in addition to different cell functions such as cell volume regulation, proliferation, cell migration, angiogenesis as well as apoptosis. Because these physiological processes are essential for the correct cell function, K+ channels have been associated with a growing number of diseases including cancer. In fact, different K+ channel families such as the voltage-gated K+ channels, the ether a go-go K+ channels, the two pore domain K+ channels and the Ca2+-activated K+ channels have been associated to tumor biology. Potassium channels have a role in neoplastic cell-cycle progression and their expression has been found abnormal in many types of tumors and cancer cells. In addition, the expression and activity of specific K+ channels have shown a significant correlation with the tumor malignancy grade. The aim of this overview is to summarize published data on K+ channels that exhibit oncogenic properties and have been linked to a more malignant cancer phenotype. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. PMID- 25517986 TI - Plastic responses of a sessile prey to multiple predators: a field and experimental study. AB - BACKGROUND: Theory predicts that prey facing a combination of predators with different feeding modes have two options: to express a response against the feeding mode of the most dangerous predator, or to express an intermediate response. Intermediate phenotypes protect equally well against several feeding modes, rather than providing specific protection against a single predator. Anti predator traits that protect against a common feeding mode displayed by all predators should be expressed regardless of predator combination, as there is no need for trade-offs. PRINCIPAL FINDINGS: We studied phenotypic anti-predator responses of zebra mussels to predation threat from a handling-time-limited (crayfish) and a gape-size-limited (roach) predator. Both predators dislodge mussels from the substrate but diverge in their further feeding modes. Mussels increased expression of a non-specific defense trait (attachment strength) against all combinations of predators relative to a control. In response to roach alone, mussels showed a tendency to develop a weaker and more elongated shell. In response to crayfish, mussels developed a harder and rounder shell. When exposed to either a combination of predators or no predator, mussels developed an intermediate phenotype. Mussel growth rate was positively correlated with an elongated weaker shell and negatively correlated with a round strong shell, indicating a trade-off between anti-predator responses. Field observations of prey phenotypes revealed the presence of both anti-predator phenotypes and the trade-off with growth, but intra-specific population density and bottom substrate had a greater influence than predator density. CONCLUSIONS: Our results show that two different predators can exert both functionally equivalent and inverse selection pressures on a single prey. Our field study suggests that abiotic factors and prey population density should be considered when attempting to explain phenotypic diversity in the wild. PMID- 25517987 TI - Comparison of texture features derived from static and respiratory-gated PET images in non-small cell lung cancer. AB - BACKGROUND: PET-based texture features have been used to quantify tumor heterogeneity due to their predictive power in treatment outcome. We investigated the sensitivity of texture features to tumor motion by comparing static (3D) and respiratory-gated (4D) PET imaging. METHODS: Twenty-six patients (34 lesions) received 3D and 4D [18F]FDG-PET scans before the chemo-radiotherapy. The acquired 4D data were retrospectively binned into five breathing phases to create the 4D image sequence. Texture features, including Maximal correlation coefficient (MCC), Long run low gray (LRLG), Coarseness, Contrast, and Busyness, were computed within the physician-defined tumor volume. The relative difference (delta3D-4D) in each texture between the 3D- and 4D-PET imaging was calculated. Coefficient of variation (CV) was used to determine the variability in the textures between all 4D-PET phases. Correlations between tumor volume, motion amplitude, and delta3D-4D were also assessed. RESULTS: 4D-PET increased LRLG ( = 1%-2%, p < 0.02), Busyness ( = 7%-19%, p < 0.01), and decreased MCC ( = 1%-2%, p < 7.5 * 10(-3)), Coarseness ( = 5%-10%, p < 0.05) and Contrast ( = 4%-6%, p > 0.08) compared to 3D-PET. Nearly negligible variability was found between the 4D phase bins with CV < 5% for MCC, LRLG, and Coarseness. For Contrast and Busyness, moderate variability was found with CV = 9% and 10%, respectively. No strong correlation was found between the tumor volume and delta3D-4D for the texture features. Motion amplitude had moderate impact on delta for MCC and Busyness and no impact for LRLG, Coarseness, and Contrast. CONCLUSIONS: Significant differences were found in MCC, LRLG, Coarseness, and Busyness between 3D and 4D PET imaging. The variability between phase bins for MCC, LRLG, and Coarseness was negligible, suggesting that similar quantification can be obtained from all phases. Texture features, blurred out by respiratory motion during 3D-PET acquisition, can be better resolved by 4D-PET imaging. 4D-PET textures may have better prognostic value as they are less susceptible to tumor motion. PMID- 25517988 TI - In Vitro-In Vivo Correlations Observed With Indacaterol-Based Formulations Delivered with the Breezhaler(r). AB - BACKGROUND: Establishing robust in vitro-in vivo correlations (IVIVC) between aerosol performance, pharmacokinetics, and clinical efficacy is critical in developing bioequivalent drug-device combination products. Recent studies have demonstrated that realistic throat models tested under realistic test conditions may provide good IVIVC with respect to total lung deposition. METHODS: The Alberta idealized throat (AIT) model was utilized with mean peak inspiratory flow rates determined from patient breathing studies. Various formulations of indacaterol (e.g., lactose blends, fixed dose combinations, engineered PulmoSphereTM particles) were tested in the AIT model and in clinical pharmacokinetic studies. RESULTS: Good IVIVC were observed with respect to total lung deposition, systemic delivery, and the contribution of oral absorption to systemic delivery, with percentage differences from the mean in vivo measurements <15%, with most comparisons <5%. CONCLUSIONS: Anatomical throat models represent an exciting tool to aid in formulation development of pharmaceutical aerosols. PMID- 25517990 TI - Ideotype population exploration: growth, photosynthesis, and yield components at different planting densities in winter oilseed rape (Brassica napus L.). AB - Rapeseed is one of the most important edible oil crops in the world and the seed yield has lagged behind the increasing demand driven by population growth. Winter oilseed rape (Brassica napus L.) is widely cultivated with relatively low yield in China, so it is necessary to find the strategies to improve the expression of yield potential. Planting density has great effects on seed yield of crops. Hence, field experiments were conducted in Wuhan in the Yangtze River basin with one conventional variety (Zhongshuang 11, ZS11) and one hybrid variety (Huayouza 9, HYZ9) at five planting densities (27.0*10(4), 37.5*10(4), 48.0*10(4), 58.5*10(4), 69.0*10(4) plants ha(-1)) during 2010-2012 to investigate the yield components. The physiological traits for high-yield and normal-yield populations were measured during 2011-2013. Our results indicated that planting densities of 58.5*10(4) plants ha(-1) in ZS11 and 48.0*10(4) plants ha(-1) in HYZ9 have significantly higher yield compared with the density of 27.0*10(4) plants ha(-1) for both varieties. The ideal silique numbers for ZS11 and HYZ9 were ~0.9*10(4) (n m(-2)) and ~1*10(4) (n m(-2)), respectively, and ideal primary branches for ZS11 and HYZ9 were ~250 (n m(-2)) and ~300 (n m(-2)), respectively. The highest leaf area index (LAI) and silique wall area index (SAI) was ~5.0 and 7.0, respectively. Moreover, higher leaf net photosynthetic rate (Pn) and water use efficiency (WUE) were observed in the high-yield populations. A significantly higher level of silique wall photosynthesis and rapid dry matter accumulation were supposed to result in the maximum seed yield. Our results suggest that increasing the planting density within certain range is a feasible approach for higher seed yield in winter rapeseed in China. PMID- 25517991 TI - PiggyBac mediated multiplex gene transfer in mouse embryonic stem cell. AB - PiggyBac system has been shown to have a high efficiency to mediate gene transfer. However, there are no reports on its efficiency to mediate multiplex transgenes in mouse embryonic stem cells. Here we first established an immortalized feeder cell line by introducing four antibiotic resistance genes simultaneously into the original SNL 76/7 feeder cell line utilizing the PiggyBac system. This is the feeder cell line with the most diverse types of antibiotic resistance genes reported so far, which will enable researchers to perform simultaneous multiplex gene transfer or gene targeting experiments in ES cells. With such feeder cell line, we were able to quantitatively characterize the transposition efficiency of PiggyBac system in mouse ES cells using five transposons carrying different inducible fluorescence proteins and antibiotic resistance genes, and the efficiency ranged from about 2% for one transposon to 0.5% for five transposons. The highly efficient multiplex gene transfer mediated by PiggyBac will no doubt provide researchers with more choices in biomedical research and development. PMID- 25517992 TI - Replication attempt: "Effect of BMAP-28 antimicrobial peptides on Leishmania major promastigote and amastigote growth: role of leishmanolysin in parasite survival". AB - This study describes an attempt to replicate experiments from the paper "Effect of BMAP-28 Antimicrobial Peptides on Leishmania major Promastigote and Amastigote Growth: Role of Leishmanolysin in Parasite Survival," which was submitted to the Reproducibility Initiative for independent validation. The cathelicidin bovine myeloid antimicrobial peptide 28 (BMAP-28) and its isomers were previously shown to have potent antiparasitic activity against Leishmania major. We tested the effectiveness of L-BMAP-28 and two of its isomers, the D-amino acid form (D-BMAP 28) and the retro-inverso form (RI-BMAP-28), in both unamidated and amidated forms, as anti-leishmanial agents against Leishmania major promastigotes in vitro. We observed that L-BMAP-28, as well as its D and RI isomers, demonstrate anti-leishmanial activity against L. major promastigotes in vitro. The inhibitory effect was lower than what was seen in the original study. At 2 uM of amidated peptides, the viability was 94%, 36%, and 66% with L-, D- and RI-peptides, versus 57%, 6%, and 18% in the original study. PMID- 25517993 TI - An alternate pathway of arsenate resistance in E. coli mediated by the glutathione S-transferase GstB. AB - Microbial arsenate resistance is known to be conferred by specialized oxidoreductase enzymes termed arsenate reductases. We carried out a genetic selection on media supplemented with sodium arsenate for multicopy genes that can confer growth to E. coli mutant cells lacking the gene for arsenate reductase (E. coli DeltaarsC). We found that overexpression of glutathione S-transferase B (GstB) complemented the DeltaarsC allele and conferred growth on media containing up to 5 mM sodium arsenate. Interestingly, unlike wild type E. coli arsenate reductase, arsenate resistance via GstB was not dependent on reducing equivalents provided by glutaredoxins or a catalytic cysteine residue. Instead, two arginine residues, which presumably coordinate the arsenate substrate within the electrophilic binding site of GstB, were found to be critical for transferase activity. We provide biochemical evidence that GstB acts to directly reduce arsenate to arsenite with reduced glutathione (GSH) as the electron donor. Our results reveal a pathway for the detoxification of arsenate in bacteria that hinges on a previously undescribed function of a bacterial glutathione S transferase. PMID- 25517995 TI - Dizinc cation [Zn2](2+) trapped in a homoleptic metalloid coordination environment stabilized by dispersion forces: [Zn2(GaCp*)6][BAr4(F)]2. AB - The synthesis and characterization of the cationic mixed metal Ga/Zn cluster [Zn2(GaCp*)6](2+) (1) is presented. The reaction of [Zn2Cp*2] with [Ga2Cp*][BAr4(F)] leads to the formation of the novel complex being the first example of a [Zn2](2+) core exclusively ligated by metalloid group-13 organyl ligands. Compound 1 exhibits two different coordination modes: In the solid state, two of the six GaCp* ligands occupy bridging positions, whereas VT (1)H NMR indicates the coexistence of a second isomer in solution featuring six terminal GaCp* ligands. Quantum chemical calculations have been carried out to assign the gallium and zinc positions; the bonding situation in 1 is characterized and the importance of dispersion forces is discussed. PMID- 25517994 TI - Antiphotoaging effect of conditioned medium of dedifferentiated adipocytes on skin in vivo and in vitro: a mechanistic study. AB - Photoaging of skin occurs partially due to decreased synthesis and increased degradation of dermal collagen. Antiphotoaging therapy aims to counteract these effects. This study aimed to investigate whether secretory factors from dedifferentiated adipocytes (DAs) could alleviate photoaging in human dermal fibroblasts (HDFs) and in mice and to clarify the underlying mechanism. DAs were acquired and verified based on cellular biomarkers and multilineage differentiation potential. The concentrations of several cytokines in conditioned medium from DAs (DA-CM) were determined. In vivo pathological changes, collagen types I and III, and matrix metalloproteinase (MMP)-1 and -3 were evaluated following the injection of 10-fold concentrated DA-CM into photoaged mice. In vitro, the effect of DA-CM on stress-induced premature senescence in HDFs was investigated by 5-ethynyl-2'-deoxyuridine (EdU) staining and beta-galactosidase staining. The influence of DA-CM and transforming growth factor-beta1 (TGF-beta1) on the secretion of collagen types I and III, MMP-1, and MMP-3 in HDFs was evaluated by ELISA. In vivo, we found that subcutaneously injected 10-fold concentrated DA-CM increased the expression of collagen types I and III. In vitro, DA-CM clearly mitigated the decreased cell proliferation and delayed the senescence status in HDFs induced by ultraviolet B (UVB). HDFs treated with DA-CM exhibited higher collagen types I and III secretion and significantly lower MMP-1 and MMP-3 secretion. The TGF-beta1-neutralizing antibody could partially reduce the recovery effect. Our results suggest that DAs may be useful for aging skin and their effects are mainly due to secreted factors, especially TGF-beta1, which stimulate collagen synthesis and alleviate collagen degradation in HDFs. PMID- 25517996 TI - Stubborn contaminants: influence of detergents on the purity of the multidrug ABC transporter BmrA. AB - Despite the growing interest in membrane proteins, their crystallization remains a major challenge. In the course of a crystallographic study on the multidrug ATP binding cassette transporter BmrA, mass spectral analyses on samples purified with six selected detergents revealed unexpected protein contamination visible for the most part on overloaded SDS-PAGE. A major contamination from the outer membrane protein OmpF was detected in purifications with Foscholine 12 (FC12) but not with Lauryldimethylamine-N-oxide (LDAO) or any of the maltose-based detergents. Consequently, in the FC12 purified BmrA, OmpF easily crystallized over BmrA in a new space group, and whose structure is reported here. We therefore devised an optimized protocol to eliminate OmpF during the FC12 purification of BmrA. On the other hand, an additional band visible at ~110 kDa was detected in all samples purified with the maltose-based detergents. It contained AcrB that crystallized over BmrA despite its trace amounts. Highly pure BmrA preparations could be obtained using either a DeltaacrAB E. coli strain and n-dodecyl-beta-D-maltopyranoside, or a classical E. coli strain and lauryl maltose neopentyl glycol for the overexpression and purification, respectively. Overall our results urge to incorporate a proteomics-based purity analysis into quality control checks prior to commencing crystallization assays of membrane proteins that are notoriously arduous to crystallize. Moreover, the strategies developed here to selectively eliminate obstinate contaminants should be applicable to the purification of other membrane proteins overexpressed in E. coli. PMID- 25517997 TI - Responses to vocalizations and auditory controls in the human newborn brain. AB - In the adult brain, speech can recruit a brain network that is overlapping with, but not identical to, that involved in perceiving non-linguistic vocalizations. Using the same stimuli that had been presented to human 4-month-olds and adults, as well as adult macaques, we sought to shed light on the cortical networks engaged when human newborns process diverse vocalization types. Near infrared spectroscopy was used to register the response of 40 newborns' perisylvian regions when stimulated with speech, human and macaque emotional vocalizations, as well as auditory controls where the formant structure was destroyed but the long-term spectrum was retained. Left fronto-temporal and parietal regions were significantly activated in the comparison of stimulation versus rest, with unclear selectivity in cortical activation. These results for the newborn brain are qualitatively and quantitatively compared with previous work on newborns, older human infants, adult humans, and adult macaques reported in previous work. PMID- 25517998 TI - A novel GJA8 mutation (p.V44A) causing autosomal dominant congenital cataract. AB - PURPOSE: To examine the mechanism by which a novel connexin 50 (Cx50) mutation, Cx50 V44A, in a Chinese family causes suture-sparing autosomal dominant congenital nuclear cataracts. METHODS: Family history and clinical data were recorded and direct gene sequencing was used to identify the disease-causing mutation. The Cx50 gene was cloned from a human lens cDNA library. Connexin protein distributions were assessed by fluorescence microscopy. Hemichannel functions were analyzed by dye uptake assay. Formation of functional channels was assessed by dye transfer experiments. RESULTS: Direct sequencing of the candidate GJA8 gene revealed a novel c.131T>C transition in exon 2, which cosegregated with the disease in the family and resulted in the substitution of a valine residue with alanine at codon 44 (p. V44A) in the extracellular loop 1 of the Cx50 protein. Both Cx50 and Cx50V44A formed functional gap junctions, as shown by the neurobiotin transfer assay. However, unlike wild-type Cx50, Cx50V44A was unable to form open hemichannels in dye uptake experiments. CONCLUSION: This work identified a unique congenital cataract in the Chinese population, caused by the novel mutation Cx50V44A, and it showed that the V44A mutation specifically impairs the gating of the hemichannels but not the gap junction channels. The dysfunctional hemichannels resulted in the development of human congenital cataracts. PMID- 25518001 TI - Thulium fiber laser lithotripsy in an in vitro ureter model. AB - Using a validated in vitro ureter model for laser lithotripsy, the performance of an experimental thulium fiber laser (TFL) was studied and compared to the clinical gold standard holmium:YAG laser. The holmium laser (lambda = 2120 nm) was operated with standard parameters of 600 mJ, 350 MUs, 6 Hz, and 270-MUm-core optical fiber. The TFL (lambda=1908 nm) was operated with 35 mJ, 500 MUs, 150 to 500 Hz, and a 100-MUm-core fiber. Urinary stones (60% calcium oxalate monohydrate/40% calcium phosphate) of uniform mass and diameter (4 to 5 mm) were laser ablated with fibers through a flexible video-ureteroscope under saline irrigation with flow rates of 22.7 and 13.7 ml/ min for the TFL and holmium laser, respectively. The temperature 3 mm from the tube's center and 1 mm above the mesh sieve was measured by a thermocouple and recorded throughout each experiment for both lasers. Total laser and operation times were recorded once all stone fragments passed through a 1.5-mm sieve. The holmium laser time measured 167+/-41 s (n=12). TFL times measured 111+/-49, 39+/-11, and 23+/-4 s, for pulse rates of 150, 300, and 500 Hz, respectively (n=12 each). Mean peak saline irrigation temperatures reached 24+/-1 degrees C for holmium, and 33+/-3 degrees C, 33+/-7 degrees C, and 39+/-6 degrees C, for TFL at pulse rates of 150, 300, and 500 Hz, respectively. To avoid thermal buildup and provide a sufficient safety margin, TFL lithotripsy should be performed with pulse rates below 500 Hz and/or increased saline irrigation rates. The TFL rapidly fragmented kidney stones due in part to its high pulse rate, high power density, high average power, and observation of reduced stone retropulsion and may provide a clinical alternative to the conventional holmium laser for lithotripsy. PMID- 25518000 TI - The effect of 17beta-estradiol on cutaneous wound healing in protein-malnourished ovariectomized female mouse model. AB - Cutaneous wound healing is delayed by protein malnutrition (PM). On the other hand, estrogen promotes cutaneous wound healing by its anti-inflammatory and cell proliferation effects. Therefore, we hypothesized that estrogen administration in protein-malnourished ovariectomized (OVX) female mice might improve the inflammatory response and promote cutaneous wound healing as well as normal nutrition. To test this hypothesis, we used full-thickness excisional wounds in Control SHAM, PM SHAM, PM OVX and PM OVX+17beta-estradiol mice. The Control diet included 200 g/kg protein and the PM diet included 30 g/kg protein. The ratio of wound area in the Control SHAM group was significantly smaller than those in the three PM groups. In addition, microscopic findings also showed that the ratio of collagen fibers, the ratio of myofibroblasts and the number of new blood vessels in the Control SHAM group were significantly greater than those in the three PM groups. However, the number of Ym1-positive cells as an anti-inflammatory M2-like macrophage marker in the PM OVX+17beta-estradiol group was significantly higher than those in the other three groups. These results indicate that the appearance of anti-inflammatory M2-like macrophages was promoted by estrogen administration; however, it could not promote cutaneous wound healing upon a low-protein diet. Therefore, it may be confirmed that nutrition is more important for promoting cutaneous wound healing than estrogen administration. PMID- 25517999 TI - Endogenous molecules induced by a pathogen-associated molecular pattern (PAMP) elicit innate immunity in shrimp. AB - Invertebrates rely on an innate immune system to combat invading pathogens. The system is initiated in the presence of cell wall components from microbes like lipopolysaccharide (LPS), beta-1,3-glucan (betaG) and peptidoglycan (PG), altogether known as pathogen-associated molecular patterns (PAMPs), via a recognition of pattern recognition protein (PRP) or receptor (PRR) through complicated reactions. We show herein that shrimp hemocytes incubated with LPS, betaG, and PG caused necrosis and released endogenous molecules (EMs), namely EM L, EM-beta, and EM-P, and found that shrimp hemocytes incubated with EM-L, EM beta, and EM-P caused changes in cell viability, degranulation and necrosis of hemocytes, and increased phenoloxidase (PO) activity and respiratory burst (RB) indicating activation of immunity in vitro. We found that shrimp receiving EM-L, EM-beta, and EM-P had increases in hemocyte count and other immune parameters as well as higher phagocytic activity toward a Vibrio pathogen, and found that shrimp receiving EM-L had increases in proliferation cell ratio and mitotic index of hematopoietic tissues (HPTs). We identified proteins of EMs deduced from SDS PAGE and LC-ESI-MS/MS analyses. EM-L and EM-P contained damage-associated molecular patterns (DAMPs) including HMGBa, HMGBb, histone 2A (H2A), H2B, and H4, and other proteins including proPO, Rab 7 GPTase, and Rab 11 GPTase, which were not observed in controls (EM-C, hemocytes incubated in shrimp salt solution). We concluded that EMs induced by PAMPs contain DAMPs and other immune molecules, and they could elicit innate immunity in shrimp. Further research is needed to identify which individual molecule or combined molecules of EMs cause the results, and determine the mechanism of action in innate immunity. PMID- 25518003 TI - Growth mechanism deconvolution of self-limiting supraparticles based on microfluidic system. AB - The synthesis of colloidal supraparticles (SPs) based on self-assembly of nanoscopic objects has attracted much attention in recent years. Here, we demonstrate the formation of self-limiting monodisperse gold SPs with core-shell morphology based on the building blocks of flexible nanoarms in one step. A flow based microfluidic chip is utilized to slow down the assembly process of the intermediates, which surprisingly allows for observation of ultrathin gold nanoplates as first intermediates. Notably, these intermediate cannot be observed in traditional synthesis due to their rapid rolling-up to form the second-order nanostructure of flexible hollow nanoarms. The growth mechanism of SPs can then be deconvoluted into two seed-mediated steps. Monte Carlo simulations confirm that the self-limiting growth of binary SPs is governed by a balance between electrostatic repulsion and van der Waals attraction. PMID- 25518004 TI - Drainage-related Complications in Percutaneous Transhepatic Biliary Drainage: An Analysis Over 10 Years. AB - BACKGROUND: Procedure-related complications of percutaneous transhepatic biliary drainage (PTBD) have been well documented in the literature. However, relatively restricted data are available concerning drainage-related complication rates in long-term PTBD therapy. The present retrospective study evaluated the extent and the nature of drainage complications during PTBD therapy and associated risk factors for these complications. PATIENTS AND METHODS: Between June 1997 and May 2007, a total of 385 patients with PTBD were identified by analyzing the PTBD database and hospital charts, with a total of 2468 percutaneous biliary drainages being identified. RESULTS: Among the identified patients, 243 (63%) had malignant and 142 (37%) had benign bile duct strictures. At least 1 drainage-related complication was observed in 40% of the patients. With respect to the total number of drains, prosthesis complications occurred in 23%. Occlusion, dislocation, and cholangitis were the most common complications observed during PTBD therapy. Risk factors for cholangitis and occlusion were malignant disease, prior occurrence of complications, and bilateral drainage. Proximal stenosis of the biliary system was close to significant. CONCLUSIONS: Drainage-related complications are a major problem in PTBD therapy. The risk factors for occlusion and cholangitis discovered in this study can help to refine individual strategies to reduce the rate of these drainage complications. PMID- 25518002 TI - Caging metal ions with visible light-responsive nanopolymersomes. AB - Polymersomes are bilayer vesicles that self-assemble from amphiphilic diblock copolymers, and provide an attractive system for the delivery of biological and nonbiological molecules due to their environmental compatibility, mechanical stability, synthetic tunability, large aqueous core, and hyperthick hydrophobic membrane. Herein, we report a nanoscale photoresponsive polymersome system featuring a meso-to-meso ethyne-bridged bis[(porphinato)zinc] (PZn2) fluorophore hydrophobic membrane solute and dextran in the aqueous core. Upon 488 nm irradiation in solution or in microinjected zebrafish embryos, the polymersomes underwent deformation, as monitored by a characteristic red-shifted PZn2 emission spectrum and confirmed by cryo-TEM. The versatility of this system was demonstrated through the encapsulation and photorelease of a fluorophore (FITC), as well as two different metal ions, Zn(2+) and Ca(2+). PMID- 25518005 TI - Is Endoscopic Therapy Effective for Angioectasia in Obscure Gastrointestinal Bleeding?: A Systematic Review of the Literature. AB - GOAL: We aimed to summarize pooled rebleeding rates of angioectasia after therapeutic endoscopy, and compare these to historical control (no intervention) rates. BACKGROUND: Obscure gastrointestinal bleeding continues to be challenging to diagnose and treat; in America, small bowel angioectasias are the most common cause. Technology advances led to higher diagnostic yield for these lesions; however, therapeutic impact of endoscopy remains unclear. STUDY: A PubMed search (June 1, 2006 to September 19, 2013) with 2 independent reviews sought articles reporting rebleeding rates of symptomatic angioectasia without therapy (natural history) and after endoscopic treatment. This study list was added to studies in the 2007 American Gastroenterological Association systematic review. Data on number of patients who underwent endoscopic therapy, type of therapy used, number of patients who experienced rebleeding, and follow-up time were extracted. Rebleeding data were pooled and weighted averages were reported with 95% confidence intervals (CI). RESULTS: Twenty-four articles (n=490 patients) with data on endoscopic therapy for angioectasia and 6 natural history cohorts (n=130) receiving no therapy for angioectasia were eligible. Of the endoscopic therapy patients, 121 at push enteroscopy and 427 at balloon-assisted enteroscopy; 209/490 (42.7%; 95% CI, 38%-47%) rebled. Of the control (no therapy) patients, 64/130 (49.2%; 95% CI, 40%-58%) rebled. Number needed to treat is estimated at 15 to 16. CONCLUSIONS: Rebleeding rate after endoscopic therapy for symptomatic small bowel angioectasia may be comparable to that expected without therapy. Endoscopic therapy may be ineffective; if effective, the needed to treat is estimated to be high. Controlled studies, with intervention-stratified and etiology-stratified outcomes are needed. PMID- 25518006 TI - Carcinoid-associated encephalopathy. PMID- 25518007 TI - Cardiovascular dysfunction in adult mice following postnatal intermittent hypoxia. AB - BACKGROUND: Ex-premature infants are at higher risk for hypertension and cardiovascular disease as adults, although the mechanisms underlying such increased risks are unknown. We hypothesize that postnatal exposure to intermittent hypoxia (IH) leads to cardiovascular dysfunction in adulthood with alterations of the renin-angiotensin pathway. METHODS: Neonatal mice were exposed to IH for 4 wk. At the age of 3 mo, various cardiovascular measurements were obtained. RESULTS: IH-exposed mice exhibited higher systolic blood pressure, impaired baroreflex responses, and decreased heart rate variability. Furthermore, IH-exposed mice manifested evidence of endothelial dysfunction, as shown by reduced reperfusion indices after tail vessel occlusion and impaired vasodilatory responses to acetylcholine. CD31(+) endothelial cells isolated from mesenteric arteries of IH-exposed mice expressed higher levels of angiotensin-converting enzyme and reactive oxygen species; plasma angiotensin-II levels were also significantly higher in these animals. In addition, DNA methylation patterns of the Ace1 and the Agt genes in these cells were congruent with their expression patterns. CONCLUSION: Our results suggest that exposures to postnatal IH alter the normal development of the renin-angiotensin system and promote the occurrence of cardiovascular dysfunction during adulthood in mice. PMID- 25518008 TI - Antioxidant response genes sequence variants and BPD susceptibility in VLBW infants. AB - BACKGROUND: Lung injury resulting from oxidative stress contributes to bronchopulmonary dysplasia (BPD) pathogenesis. Nuclear factor erythroid-2 related factor-2 (NFE2L2) regulates cytoprotective responses to oxidative stress by inducing enzymes containing antioxidant response elements (ARE). We hypothesized that ARE genetic variants will modulate susceptibility or severity of BPD in very low-birth-weight (VLBW) infants. METHODS: Blood samples obtained from VLBW infants were used for genotyping variants in the SOD2, NFE2L2, GCLC, GSTP1, HMOX1, and NQO1 genes. SNPs were genotyped utilizing TaqMan probes (Applied Biosystems (ABI), Grand Island, NY), and data were analyzed using the ABI HT7900. Genetic dominance and recessive models were tested to determine associations between SNPs and BPD. RESULTS: In our cohort (n = 659), 284 infants had BPD; 135 of whom developed severe BPD. Presence of the hypomorphic NQO1 SNP (rs1800566) in a homozygous state was associated with increased BPD, while presence of the NFE2L2 SNP (rs6721961) was associated with decreased severe BPD in the entire cohort and in Caucasian infants. In regression models that adjusted for epidemiological confounders, the NQO1 and the NFE2L2 SNPs were associated with BPD and severe BPD, respectively. CONCLUSION: Genetic variants in NFE2L2-ARE axis may contribute to the variance in liability to BPD observed in preterm infants. These results require confirmation in independent cohorts. PMID- 25518009 TI - Hyperactivity in the Gunn rat model of neonatal jaundice: age-related attenuation and emergence of gait deficits. AB - BACKGROUND: Neonatal jaundice resulting from elevated unconjugated bilirubin occurs in 60-80% of newborn infants. Although mild jaundice is generally considered harmless, little is known about its long-term consequences. Recent studies have linked mild bilirubin-induced neurological dysfunction (BIND) with a range of neurological syndromes, including attention-deficit hyperactivity disorder. The goal of this study was to measure BIND across the lifespan in the Gunn rat model of BIND. METHODS: Using a sensitive force plate actometer, we measured locomotor activity and gait in jaundiced (jj) Gunn rats versus their nonjaundiced (Nj) littermates. Data were analyzed for young adult (3-4 mo), early middle-aged (9-10 mo), and late middle-aged (17-20 mo) male rats. RESULTS: jj rats exhibited lower body weights at all ages and a hyperactivity that resolved at 17-20 mo of age. Increased propulsive force and gait velocity accompanied hyperactivity during locomotor bouts at 9-10 mo in jj rats. Stride length did not differ between the two groups at this age. Hyperactivity normalized, and gait deficits, including decreased stride length, propulsive force, and gait velocity, emerged in the 17-20-mo-old jj rats. CONCLUSION: These results demonstrate that, in aging, hyperactivity decreases with the onset of gait deficits in the Gunn rat model of BIND. PMID- 25518010 TI - Changes in lung volume and ventilation following transition from invasive to noninvasive respiratory support and prone positioning in preterm infants. AB - BACKGROUND: To minimize secondary lung injury, ventilated preterm infants are extubated as soon as possible. To maximize extubation success, they are often placed in prone position. The effect of extubation and subsequent prone positioning on lung volumes is currently unknown. METHODS: Changes in end expiratory lung volume (DeltaEELV), tidal volume (VT), and ventilation distribution were monitored during transition from endotracheal to nasal continuous positive airway pressure and following prone positioning using electrical impedance tomography. In addition, the continuous distending pressure (CDP) and oxygen need (FiO2) were recorded. RESULTS: Twenty preterm infants (GA 28.7 +/- 1.7 wk) were included. Following extubation, the CDP decreased from 7.9 +/- 0.5 to 6.0 +/- 0.2 cmH2O, while the FiO2 remained stable. Both DeltaEELV and VT increased significantly (P < 0.05) after extubation, without changing ventilation distribution. Prone positioning resulted in a further increase in DeltaEELV (P < 0.01) and a decrease in respiratory rate. VT remained stable but its distribution clearly shifted toward the ventral lung regions. CONCLUSION: Infants who are transitioned from invasive to noninvasive respiratory support are able to maintain their EELV and increase their VT. Prone positioning increases EELV and shifts tidal ventilation to the ventral lung regions. The latter suggests that infants should preferably be placed in prone position after extubation. PMID- 25518011 TI - Adipocyte-derived exosomal miRNAs: a novel mechanism for obesity-related disease. AB - BACKGROUND: Obesity is frequently complicated by comorbid conditions, yet how excess adipose contributes is poorly understood. Although adipocytes in obese individuals induce systemic inflammation via secreted cytokines, another potential mediator has recently been identified (i.e., adipocyte-derived exosomes). We hypothesized that adipocyte-derived exosomes contain mediators capable of activating end-organ inflammatory and fibrotic signaling pathways. METHODS: We developed techniques to quantify and characterize exosomes shed by adipocytes from seven obese (age: 12-17.5 y, BMI: 33-50 kg/m(2)) and five lean (age: 11-19 y, BMI: 22-25 kg/m(2)) subjects. RESULTS: Abundant exosomal miRNAs, but no mRNAs, were detected. Comparison of obese vs. lean visceral adipose donors detected 55 differentially expressed miRNAs (P < 0.05; fold change >=|1.2|). qRT PCR confirmed downregulation of miR-148b (ratio = 0.2 (95% confidence interval = 0.1, 0.6)) and miR-4269 (0.3 (0.1, 0.8)), and upregulation of miR-23b (6.2 (2.2, 17.8)) and miR-4429 (3.8 (1.1-13.4)). Pathways analysis identified TGF-beta signaling and Wnt/beta-catenin signaling among the top canonical pathways expected to be altered with visceral adiposity based on projected mRNA targets for the 55 differentially expressed miRNAs. A select mRNA target was validated in vitro. CONCLUSION: These data show that visceral adipocytes shed exosomal mediators predicted to regulate key end-organ inflammatory and fibrotic signaling pathways. PMID- 25518012 TI - Development of a pediatric-specific clinical probability tool for diagnosis of venous thromboembolism: a feasibility study. AB - BACKGROUND: Pediatric venous thromboembolism (VTE) is an increasingly common, difficult to diagnose problem. Clinical probability tools (CPT) for adults estimate VTE likelihood, but are not available for children. We hypothesized that a pediatric-specific CPT is feasible. METHODS: Radiology reports were utilized to identify children imaged for suspected VTE. Relevant signs, symptoms, and comorbidity variables, identified from published literature, were extracted from corresponding medical records. Variables associated with pediatric VTE were incorporated into a multivariate logistic regression to create a pilot CPT which was confirmed on a separate cohort. RESULTS: A total of 389 subjects meeting inclusion criteria were identified: 91 with VTE and 298 without. Univariate analysis revealed male gender (odds ratio (OR) = 2.96; P < 0.001), asymmetric extremity (OR = 1.76; P = 0.033), central venous catheter utilization and/or dysfunction (OR = 2.51; P < 0.001), and cancer (OR = 2.35; P = 0.014) as VTE predictive variables. Documentation of an alternate diagnosis was inversely related to VTE (OR = 0.42; P = 0.004). Receiver operating characteristic analysis of the derived CPT demonstrated reasonable ability to discriminate VTE probability in the training cohort (area under the curve (AUC) = 0.73; P < 0.001) and moderate discrimination in a separate validation cohort of 149 children (AUC = 0.64; P = 0.011). CONCLUSION: A pediatric-specific VTE CPT is feasible, would facilitate early diagnosis, and could lead to improved outcomes. PMID- 25518014 TI - Highly efficient hydrogen generation from methanolysis of ammonia borane on CuPd alloy nanoparticles. AB - A low-cost and facile route has been developed for the synthesis of monodisperse CuPd nanoparticles with tunable composition. (Scanning transmission electron microscopy-energy-dispersive x-ray spectroscopy) STEM-EDX results verified the structure of the alloy for the obtained nanoparticles. These CuPd nanoparticles supported on carbon were active catalysts for hydrogen generation from the methanolysis of ammonia borane (AB) at room temperature, and their activities were closely related with the compositions. Cu48Pd52 NPs exhibited the highest activity among the tested catalysts. Moreover, their activity can be further improved by thermal annealing at 300 degrees C under nitrogen flow, with a very high total turnover frequency value of 53.2 min(-1). The reusability test indicated that the Cu48Pd52/C catalyst retains 86% of its initial activity and 100% conversion after 8 cycles. The catalyst, which features lost cost and high efficiency, may help move forward the practical application of AB as a sustainable hydrogen storage material. PMID- 25518013 TI - NF-kappaB decoy oligodeoxynucleotide enhanced osteogenesis in mesenchymal stem cells exposed to polyethylene particle. AB - Excessive generation of wear particles after total joint replacement may lead to local inflammation and periprosthetic osteolysis. Modulation of the key transcription factor NF-kappaB in immune cells could potentially mitigate the osteolytic process. We previously showed that local delivery of ultrahigh molecular-weight polyethylene (UHMWPE) particles recruited osteoprogenitor cells and reduced osteolysis. However, the biological effects of modulating the NF kappaB signaling pathway on osteoprogenitor/mesenchymal stem cells (MSCs) remain unclear. Here we showed that decoy oligodeoxynucleotide (ODN) increased cell viability when primary murine MSCs were exposed to UHMWPE particles, but had no effects on cellular apoptosis. Decoy ODN increased transforming growth factor beta 1 (TGF-beta1) and osteoprotegerin (OPG) in MSCs exposed to UHMWPE particles. Mechanistic studies showed that decoy ODN upregulated OPG expression through a TGF-beta1-dependent pathway. By measuring the alkaline phosphatase activity, osteocalcin levels, Runx2 and osteopontin expression, and performing a bone mineralization assay, we found that decoy ODN increased MSC osteogenic ability when the cells were exposed to UHMWPE particles. Furthermore, the cellular response to decoy ODN and UHMWPE particles with regard to cell phenotype, cell viability, and osteogenic ability was confirmed using primary human MSCs. Our results suggest that modulation of wear particle-induced inflammation by NF kappaB decoy ODN had no adverse effects on MSCs and may potentially further mitigate periprosthetic osteolysis by protecting MSC viability and osteogenic ability. PMID- 25518015 TI - General anesthesia type does not influence serum levels of neutrophil gelatinase associated lipocalin during the perioperative period in video laparoscopic bariatric surgery. AB - OBJECTIVES: Video laparoscopic bariatric surgery is the preferred surgical technique for treating morbid obesity. However, pneumoperitoneum can pose risks to the kidneys by causing a decrease in renal blood flow. Furthermore, as in other surgical procedures, laparoscopic bariatric surgery triggers an acute inflammatory response. Neutrophil gelatinase-associated lipocalin is an early and accurate biomarker of renal injury, as well as of the inflammatory response. Anesthetic drugs could offer some protection for the kidneys and could attenuate the acute inflammatory response from surgical trauma. The objective of this study was to compare the effects of two types of anesthetics, propofol and sevoflurane, on the serum levels of neutrophil gelatinase-associated lipocalin during the perioperative period in laparoscopic bariatric surgery. METHODS: Sixty-four patients scheduled for laparoscopic bariatric surgery were randomized into two anesthesia groups and were administered either total intravenous anesthesia (propofol) or inhalation anesthesia (sevoflurane). In the perioperative period, blood samples were collected at three time points (before anesthesia, 6 hours after pneumoperitoneum and 24 hours after pneumoperitoneum) and urine output was measured for 24 hours. Acute kidney injuries were evaluated by examining both the clinical and laboratory parameters during the postoperative period. The differences between the groups were compared using non-parametric tests. ReBEC (http://www.ensaiosclinicos.gov.br/rg/recruiting/): RBR-8wt2fy RESULTS: None of the patients developed an acute kidney injury during the study and no significant differences were found between the serum neutrophil gelatinase-associated lipocalin levels of the groups during the perioperative period. CONCLUSION: The choice of anesthetic drug, either propofol or sevoflurane, did not affect the serum levels of neutrophil gelatinase-associated lipocalin during the perioperative period in laparoscopic bariatric surgery. PMID- 25518016 TI - The role of intratumoral lymphovascular density in distinguishing primary from secondary mucinous ovarian tumors. AB - OBJECTIVE: Ovarian mucinous metastases commonly present as the first sign of the disease and are capable of simulating primary tumors. Our aim was to investigate the role of intratumoral lymphatic vascular density together with other surgical pathological features in distinguishing primary from secondary mucinous ovarian tumors. METHODS: A total of 124 cases of mucinous tumors in the ovary (63 primary and 61 metastatic) were compared according to their clinicopathological features and immunohistochemical profiles. The intratumoral lymphatic vascular density was quantified by counting the number of vessels stained by the D2-40 antibody. RESULTS: Metastases occurred in older patients and were associated with a higher proportion of tumors smaller than 10.0 cm; bilaterality; extensive necrosis; extraovarian extension; increased expression of cytokeratin 20, CDX2, CA19.9 and MUC2; and decreased expression of cytokeratin 7, CA125 and MUC5AC. The lymphatic vascular density was increased among primary tumors. However, after multivariate analysis, the best predictors of a secondary tumor were a size of 10.0 cm or less, bilaterality and cytokeratin 7 negativity. Lack of MUC2 expression was an important factor excluding metastasis. CONCLUSIONS: The higher intratumoral lymphatic vascular density in primary tumors when compared with secondary lesions suggests differences in the microenvironment. However, considering the differential diagnosis, the best discriminator of a secondary tumor is the combination of tumor size, laterality and the pattern of expression of cytokeratin 7 and MUC2. PMID- 25518017 TI - Impact of cardiology referral: clinical outcomes and factors associated with physicians' adherence to recommendations. AB - OBJECTIVES: Cardiology referral is common for patients admitted for non-cardiac diseases. Recommendations from cardiologists may involve complex and aggressive treatments that could be ignored or denied by other physicians. The purpose of this study was to compare the outcomes of patients who were given recommendations during cardiology referrals and to examine the clinical outcomes of patients who did not follow the recommendations. METHODS: We enrolled 589 consecutive patients who received in-hospital cardiology consultations. Data on recommendations, implementation of suggestions and outcomes were collected. RESULTS: Regarding adherence of the referring service to the recommendations, 77% of patients were classified in the adherence group and 23% were classified in the non-adherence group. Membership in the non-adherence group (p<0.001; odds ratio: 10.25; 95% CI: 4.45-23.62) and advanced age (p = 0.017; OR: 1.04; 95% CI: 1.01-1.07) were associated with unfavorable outcomes. Multivariate analysis identified four independent predictors of adherence to recommendations: follow-up notes in the medical chart (p<0.001; OR: 2.43; 95% CI: 1.48-4.01); verbal reinforcement (p = 0.001; OR: 1.86; 95% CI: 1.23-2.81); a small number of recommendation (p = 0.001; OR: 0.87; 95% CI: 0.80-0.94); and a younger patient age (p = 0.002; OR: 0.98; 95% CI: 0.96-0.99). CONCLUSIONS: Poor adherence to cardiology referral recommendations was associated with unfavorable clinical outcomes. Follow-up notes in the medical chart, verbal reinforcement, a limited number of recommendations and a patient age were associated with greater adherence to recommendations. PMID- 25518018 TI - Predictive factors for perioperative blood transfusion in surgeries for correction of idiopathic, neuromuscular or congenital scoliosis. AB - OBJECTIVE: To evaluate the association of clinical and demographic variables in patients requiring blood transfusion during elective surgery to treat scoliosis with the aim of identifying markers predictive of the need for blood transfusion. METHODS: Based on the review of medical charts at a public university hospital, this retrospective study evaluated whether the following variables were associated with the need for red blood cell transfusion (measured by the number of packs used) during scoliosis surgery: scoliotic angle, extent of arthrodesis (number of fused levels), sex of the patient, surgery duration and type of scoliosis (neuromuscular, congenital or idiopathic). RESULTS: Of the 94 patients evaluated in a 55-month period, none required a massive blood transfusion (most patients needed less than two red blood cell packs). The number of packs was not significantly associated with sex or type of scoliosis. The extent of arthrodesis (r = 0.103), surgery duration (r = 0.144) and scoliotic angle (r = 0.004) were weakly correlated with the need for blood transfusion. Linear regression analysis showed an association between the number of spine levels submitted to arthrodesis and the volume of blood used in transfusions (p = 0.001). CONCLUSION: This study did not reveal any evidence of a significant association between the need for red blood cell transfusion and scoliotic angle, sex or surgery duration in scoliosis correction surgery. Submission of more spinal levels to arthrodesis was associated with the use of a greater number of blood packs. PMID- 25518019 TI - Correlation between the serum and tissue levels of oxidative stress markers and the extent of inflammation in acute appendicitis. AB - OBJECTIVES: To determine the serum and tissue levels of markers of impaired oxidative metabolism and correlate these levels with the histopathology and Alvarado score of acute appendicitis patients. METHOD: Sixty-five acute appendicitis patients (mean age, 31.4+/-12.06 years; male/female, 30/35) and 30 healthy control subjects were studied. The Alvarado score was recorded. Serum samples were obtained before surgery and 12 hours postoperatively to examine the total antioxidant status, total oxidant status, paraoxonase, stimulated paraoxonase, arylesterase, catalase, myeloperoxidase, ceruloplasmin, oxidative stress markers (advanced oxidized protein products and total thiol level) and ischemia-modified albumin. Surgical specimens were also evaluated. RESULTS: The diagnoses were acute appendicitis (n = 37), perforated appendicitis (n = 8), phlegmonous appendicitis (n = 12), perforated+phlegmonous appendicitis (n = 4), or no appendicitis (n = 4). The Alvarado score of the acute appendicitis group was significantly lower than that of the perforated+phlegmonous appendicitis group (p = 0.004). The serum total antioxidant status, total thiol level, advanced oxidized protein products, total oxidant status, catalase, arylesterase, and ischemia-modified albumin levels were significantly different between the acute appendicitis and control groups. There was no correlation between the pathological extent of acute appendicitis and the tissue levels of the markers; additionally, there was no correlation between the tissue and serum levels of any of the parameters. CONCLUSIONS: The imbalance of oxidant/antioxidant systems plays a role in the pathogenesis acute appendicitis. The Alvarado score can successfully predict the presence and extent of acute appendicitis. PMID- 25518020 TI - Differences between postmortem computed tomography and conventional autopsy in a stabbing murder case. AB - OBJECTIVE: The aim of the present work is to analyze the differences and similarities between the elements of a conventional autopsy and images obtained from postmortem computed tomography in a case of a homicide stab wound. METHOD: Comparison between the findings of different methods: autopsy and postmortem computed tomography. RESULTS: In some aspects, autopsy is still superior to imaging, especially in relation to external examination and the description of lesion vitality. However, the findings of gas embolism, pneumothorax and pulmonary emphysema and the relationship between the internal path of the instrument of aggression and the entry wound are better demonstrated by postmortem computed tomography. CONCLUSIONS: Although multislice computed tomography has greater accuracy than autopsy, we believe that the conventional autopsy method is fundamental for providing evidence in criminal investigations. PMID- 25518022 TI - Treatment of osteochondral injuries with platelet gel. AB - OBJECTIVES: Treatments for injured articular cartilage have not advanced to the point that efficient regeneration is possible. However, there has been an increase in the use of platelet-rich plasma for the treatment of several orthopedic disorders, including chondral injuries. Our hypothesis is that the treatment of chondral injuries with platelet gel results in higher-quality repair tissue after 180 days compared with chondral injuries not treated with gel. METHODS: A controlled experimental laboratory study was performed on 30 male rabbits to evaluate osteochondral injury repair after treatment with or without platelet gel. Osteochondral injuries were surgically induced in both knees of each rabbit at the medial femoral condyle. The left knee injury was filled with the platelet gel, and the right knee was not treated. Microscopic analysis of both knee samples was performed after 180 days using a histological grading scale. RESULTS: The only histological evaluation criterion that was not significantly different between treatments was metachromasia. The group that was treated with platelet gel exhibited superior results in all other criteria (cell morphology, surface regularity, chondral thickness and repair tissue integration) and in the total score. CONCLUSION: The repair tissue was histologically superior after 180 days in the study group treated with platelet gel compared with the group of untreated injuries. PMID- 25518021 TI - Fetuin-A is related to syndesmophytes in patients with ankylosing spondylitis: a case control study. AB - OBJECTIVES: New bone formation is one of the hallmark characteristics of ankylosing spondylitis, which is thereby associated with syndesmophytes. Fetuin-A is a molecule that is abundantly found in calcified tissues and it shows high affinity for calcium phosphate minerals and related compounds. Considering the role of fetuin-A in the regulation of calcified matrix metabolism, we compared the fetuin-A levels in ankylosing spondylitis patients with syndesmophytes with those in patients without syndesmophytes and in healthy controls. We also studied other biomarkers that are thought to be related to syndesmophytes. METHODS: Ninety-four patients (49 patients without syndesmophytes, 67.3% male, 40.7+/-8.7 years; 45 patients with syndesmophytes, 71.1% M, 43.9+/-9.9 years) and 68 healthy controls (44.2+/-10.6 years and 70.6% male) were included in this study. Syndesmophytes were assessed on the lateral radiographs of the cervical and lumbar spine. The serum levels of fetuin-A, dickkopf-1, sclerostin, IL-6, high sensitivity C-reactive protein and bone morphogenetic protein-7 were measured with an enzyme-linked immunosorbent assay. RESULTS: Patients with syndesmophytes had significantly higher levels of fetuin-A compared with patients without syndesmophytes and controls (1.16+/-0.13, 1.05+/-0.09 and 1.08+/-0.13 mg/ml, respectively). However, fetuin-A was not different between the patients without syndesmophytes and controls. Bone morphogenetic protein-7 was significantly lower; dickkopf-1 was significantly higher in patients with ankylosing spondylitis compared with controls. The sclerostin concentrations were not different between the groups. In regression analysis, fetuin-A was an independent, significant predictor of syndesmophytes. CONCLUSION: Our results suggest that fetuin-A may a role in the pathogenesis of bony proliferation in ankylosing spondylitis. PMID- 25518024 TI - Oral health after breast cancer treatment in postmenopausal women. AB - OBJECTIVE: Oral health can affect a patient's general health and quality of life. Given the increase in breast cancer survival rates, investigations of factors influencing the quality of life of survivors have gained importance. Therefore, the objective of our study was to characterize oral health in postmenopausal breast cancer survivors. METHODS: We conducted a matched case-control study. Forty-eight women who survived breast cancer (age 62.1+/-9.1 years) and 48 healthy controls (age 61.8+/-8.6 years) were included. For each case and control, a complete oral evaluation chart was completed. RESULTS: The prevalence of chronic periodontal disease was 98% in breast cancer survivors and 87% in controls. The breast cancer survivors had a median of 16 remaining teeth, whereas controls had a median of 22 remaining teeth (p = 0.03). The percentage of sites with gingival bleeding was 16.05% (0-100%) in breast cancer survivors and 0% (0 72%) in controls (p = 0.04). CONCLUSION: Chronic periodontal disease and tooth loss were highly prevalent in postmenopausal breast cancer survivors. To improve survivors' quality of life, a preventive oral health evaluation should be available prior to cancer treatment. PMID- 25518023 TI - Neurobiochemical mechanisms of a ketogenic diet in refractory epilepsy. AB - A ketogenic diet is an important therapy used in the control of drug-refractory seizures. Many studies have shown that children and adolescents following ketogenic diets exhibit an over 50% reduction in seizure frequency, which is considered to be clinically relevant. These benefits are based on a diet containing high fat (approximately 90% fat) for 24 months. This dietary model was proposed in the 1920s and has produced variable clinical responses. Previous studies have shown that the mechanisms underlying seizure control involve ketone bodies, which are produced by fatty acid oxidation. Although the pathways involved in the ketogenic diet are not entirely clear, the main effects of the production of ketone bodies appear to be neurotransmitter modulation and antioxidant effects on the brain. This review highlights the impacts of the ketogenic diet on the modulation of neurotransmitters, levels of biogenic monoamines and protective antioxidant mechanisms of neurons. In addition, future perspectives are proposed. PMID- 25518025 TI - Prediction of Metabolic Interactions With Oxycodone via CYP2D6 and CYP3A Inhibition Using a Physiologically Based Pharmacokinetic Model. AB - Evaluation of a potential risk of metabolic drug-drug interactions (DDI) is of high importance in the clinical setting. In this study, a physiologically based pharmacokinetic (PBPK) model was developed for oxycodone and its two primary metabolites, oxymorphone and noroxycodone, in order to assess different DDI scenarios using published in vitro and in vivo data. Once developed and refined, the model was able to simulate pharmacokinetics of the three compounds and the DDI extent in case of coadministration with an inhibitor, as well as the oxymorphone concentration variation between CYP2D6 extensive metabolizers (EM) and poor metabolizers (PM). The reliability of the model was tested against published clinical studies monitoring different inhibitors and dose regimens, and all predicted area under the concentration-time curve (AUC) ratios were within the twofold acceptance range. This approach represents a strategy to evaluate the impact of coadministration of different CYP inhibitors using mechanistic incorporation of drug-dependent and system-dependent available in vitro and in vivo data. PMID- 25518026 TI - Genetic polymorphism in the serotonin transporter gene-linked polymorphic region and response to serotonin reuptake inhibitors in patients with premature ejaculation. AB - OBJECTIVES: Serotonin plays a central role in ejaculation and selective serotonin reuptake inhibitors have been successfully used to treat premature ejaculation. Here, we evaluated the relationship between a polymorphism in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) and the response of patients with premature ejaculation to SSRI medication. METHODS: Sixty-nine premature ejaculation patients were treated with 20 mg/d paroxetine for three months. The Intravaginal Ejaculatory Latency Time and International Index of Erectile Function scores were compared with baseline values. The patients were scored as having responded to therapy when a 2-fold or greater increase was observed in Intravaginal Ejaculatory Latency Time compared with baseline values after three months. Three genotypes of 5-HTTLPR were studied: LL, LS and SS. The appropriateness of the allele frequencies in 5-HTTLPR were analyzed according to Hardy-Weinberg equilibrium using the chi2-test. RESULTS: The short (S) allele of 5-HTTLPR was significantly more frequent in responders than in nonresponders (p<0.05). Out of the 69 total PE patients, 41 patients (59%) responded to therapy. There was no significant difference in the International Index of Erectile Function score at the end of therapy between the responder and nonresponder groups. The frequencies of the L allele and S allele were 20% and 39%, respectively, in the responder group (p<0.05). CONCLUSION: We conclude that premature ejaculation patients with the SS genotype respond well to selective serotonin reuptake inhibitor therapy. Further studies with large patient groups are necessary to confirm this conclusion. PMID- 25518027 TI - Comparison of Virtual Nutri Plus(r) and Dietpro 5i(r) software systems for the assessment of nutrient intake before and after Roux-en-Y gastric bypass. AB - OBJECTIVES: The assessment of nutritional intake before and after bariatric surgery assists in identifying eating disorders, nutritional deficiencies and weight loss/maintenance. The 7-day record is the gold standard for such an assessment and is interpreted using specialized software. This study sought to compare the Virtual Nutri Plus(r) and Dietpro 5i(r) software systems in assessing nutrient intake in obese patients with type 2 diabetes mellitus who underwent a Roux-en-Y gastric bypass. METHODS: Nutritional intake was assessed in 10 obese women with type 2 diabetes mellitus before and 3 months after Roux-en-Y gastric bypass. The 7-day record was used to assess food intake and then, the Virtual Nutri Plus(r) and Dietpro 5i(r) software systems were used to calculate calorie, macronutrient and micronutrient intake based on validated food chemical composition databases. Clinicaltrials.gov: NCT01251016. RESULTS: During the preoperative period, deficits in the ingestion of total fiber and 15 out of 22 estimated micronutrients were observed when using the Virtual Nutri Plus(r), compared to deficiencies in total fiber and 4 micronutrients when using the Dietpro 5i(r). During the postoperative period, both the Virtual Nutri Plus(r) and Dietpro 5i(r) systems detected deficits in the ingestion of total fiber, carbohydrates and 19 micronutrients, but only the Virtual Nutri Plus(r) detected deficits in complex B vitamins (except B12) and minerals. CONCLUSION: Virtual Nutri Plus(r) was more sensitive than Dietpro 5i(r) for the identification of deficits in nutrient intake in obese, type 2 diabetes mellitus patients undergoing Roux-en-Y gastric bypass. PMID- 25518028 TI - Using computed tomography colonography in patients at high risk of colorectal cancer - a prospective study in a university hospital in South America. AB - OBJECTIVES: The purpose of our study was to report the results of the implementation of computed tomography colonography in a university hospital setting serving a Brazilian population at high risk of colorectal cancer. METHODS: After creating a computed tomography colonography service in our institution, 85 patients at high risk of colorectal cancer underwent computed tomography colonography followed by a same-day optical colonoscopy from September 2010 to May 2012. The overall accuracy of computed tomography colonography in the detection of lesions >=6 mm was compared to that of optical colonoscopy (direct comparison). All colonic segments were evaluated using quality imaging (amount of liquid and solid residual feces and luminal distension). To assess patient acceptance and preference, a questionnaire was completed before and after the computed tomography colonography and optical colonoscopy. Fisher's exact test was used to measure the correlations between colonic distension, discomfort during the exam, exam preference and interpretation confidence. RESULTS: Thirteen carcinomas and twenty-two lesions >=6 mm were characterized. The sensitivity, specificity and accuracy of computed tomography colonography were 100%, 98.2% and 98.6%, respectively. Computed tomography colonography was the preferred method of investigation for 85% of patients. The preparation was reported to cause only mild discomfort for 97.6% of patients. According to the questionnaires, there was no significant relationship between colonic distension and discomfort (p>0.05). Most patients (89%) achieved excellent bowel preparation. There was a statistically significant correlation between the confidence perceived in reading the computed tomography colonography and the quality of the preparation in each colonic segment (p<=0.001). The average effective radiation dose per exam was 7.8 mSv. CONCLUSION: It was possible to institute an efficient computed tomography colonography service at a university hospital that primarily assists patients from the public health system, with high accuracy, good acceptance and effective radiation doses. Our results seem to be comparable to other centers of excellence and fall within acceptable published guidelines, showing that a successful computed tomography colonography program can be reproduced in a South American population screened in a university hospital. PMID- 25518029 TI - An overlooked cause of resistant hypertension: upper airway resistance syndrome - preliminary results. AB - OBJECTIVE: Upper airway resistance syndrome is a sleep-disordered breathing syndrome that is characterized by repetitive arousals resulting in sympathetic overactivity. We aimed to determine whether upper airway resistance syndrome was associated with poorly controlled hypertension. METHODS: A total of 40 patients with resistant hypertension were enrolled in the study. All of the patients underwent polysomnographic examinations and 24-hour ambulatory blood pressure monitoring to exclude white coat syndrome and to monitor treatment efficiency. Among 14 upper airway resistance syndrome patients, 2 patients had surgically correctable upper airway pathologies, while 12 patients were given positive airway pressure therapy. RESULTS: All patients underwent polysomnographic examinations; 22 patients (55%) were diagnosed with obstructive sleep apnea and 14 patients (35%) were diagnosed with upper airway resistance syndrome, according to American Sleep Disorders Association criteria. The patients with upper airway resistance syndrome were younger and had a lower body mass index compared with other patients, while there were no difference between the blood pressure levels and the number of antihypertensive drugs. The arousal index was positively correlated with systolic blood pressure level (p=0.034; rs=0.746), while the Epworth score and AHI were independent of disease severity (p=0.435, rs=0.323 and p=0.819, rs=-0.097, respectively). Eight patients were treated with positive airway pressure treatment and blood pressure control was achieved in all of them, whereas no pressure reduction was observed in four untreated patients. CONCLUSIONS: We conclude that upper airway resistance syndrome is a possible secondary cause of resistant hypertension and that its proper treatment could result in dramatic blood pressure control. PMID- 25518030 TI - Effect of postoperative use of nasal oxygen catheter supplementation in wound healing following total knee arthroplasty. AB - OBJECTIVES: Healing is an event that is fundamental to the success of total knee arthroplasty. The aims of the present study were to compare the rates of complications related to wound healing between two groups of volunteers submitted to total knee arthroplasty and to evaluate the effects of postoperative oxygen supplementation by means of a nasal catheter. METHOD: A total of 109 patients who underwent total knee arthroplasty were randomized into two groups, namely, groups that did and did not receive postoperative oxygen supplementation via a nasal catheter. The surgical wound was monitored every day during the hospital stay and on the 7th, 14th, 21st, 30th and 42nd postoperative days. Characteristics related to healing were observed, including hyperemia, dehiscence, necrosis, phlyctenules and deep and superficial infection. RESULTS: There were no cases of deep infection. Hyperemia was statistically correlated with the total number of complications in the groups, with oxygen demonstrated to be a protective factor against hyperemia. Approximately 30% of the patients who exhibited hyperemia had other complications, independent of oxygen supplementation. CONCLUSION: Oxygen supplementation following total knee arthroplasty was shown to be effective in diminishing hyperemia around the operative wound. The development of hyperemia was a precursor to other complications, irrespective of whether oxygen supplementation was used. PMID- 25518031 TI - Total IgE plasma levels vary according to gender and age in Brazilian patients with allergic rhinitis. AB - OBJECTIVE: Allergic rhinitis is a disease that affects the upper airways and causes inflammation of the nasal mucosa and it is mediated by IgE antibodies produced after sensitization to environmental allergens. Previous reports have indicated that this disease affects males more often than females. The objective of this study was to verify whether total IgE plasma levels vary between genders in patients suffering from allergic rhinitis. METHODS: A total of 171 adult patients suffering from allergic rhinitis (55 males and 116 females) were enrolled. Total IgE plasma levels were determined using commercial kits, with 140 IU/mL considered as a reference value. The mean total IgE plasma levels were compared according to gender and age. RESULTS: The mean age of the overall patient group with allergic rhinitis was 38.4 +/- 19.0 years and a significant difference in age was observed between genders (males: 32.2 +/- 17.8 years; females: 41.4 +/- 18.9 years; p=0.0027). Additionally, the mean total IgE plasma levels were higher in males (413.0 +/- 143.0 IU/mL) than in females (147.9 +/- 98.0 IU/mL) (p<0.0001). These differences persisted even when males and females were stratified by age (up to or older than 20 years of age). CONCLUSIONS: In conclusion, total IgE plasma levels are higher in young adult males than in females suffering from allergic rhinitis. Evaluating total IgE plasma levels can be useful to identify patients at risk of allergic rhinitis in areas with low industrial pollution. PMID- 25518032 TI - An analysis of tacrolimus-related complications in the first 30 days after liver transplantation. AB - OBJECTIVES: Orthotopic liver transplantation has improved survival in patients with end-stage liver disease; however, therapeutic strategies that achieve ideal immunosuppression and avoid early complications are lacking. To correlate the dose and level of Tacrolimus with early complications, e.g., rejection, infection and renal impairment, after liver transplantation. From November 2011 to May 2013, 44 adult liver transplant recipients were studied in this retrospective comparative study. RESULTS: The most frequent indication for liver transplantation was hepatitis C cirrhosis (47.7%), with a higher prevalence observed in male patients (68.18%). The ages of the subjects ranged from 19-71 and the median age was 55.5 years. The mean length of the hospital stay was 16.1+/-9.32 days and the mean Model for End-stage Liver Disease score was 26.18+/ 4.28. There were five cases of acute cellular rejection (11.37%) and 16 cases of infection (36.37%). The blood samples that were collected and analyzed over time showed a significant correlation between the Tacrolimus blood level and the deterioration of glomerular filtration rate and serum creatinine (p<0.05). Patients with infections had a higher serum level of Tacrolimus (p = 0.012). The dose and presence of rejection were significantly different (p = 0.048) and the mean glomerular filtration rate was impaired in patients who underwent rejection compared with patients who did not undergo rejection (p = 0.0084). CONCLUSION: Blood Tacrolimus levels greater than 10 ng/ml were correlated with impaired renal function. Doses greater than 0.15 mg/kg/day were associated with the prevention of acute cellular rejection but predisposed patients to infectious disease. PMID- 25518033 TI - The development and evaluation of individualized templates to assist transoral C2 articular mass or transpedicular screw placement in TARP-IV procedures: adult cadaver specimen study. AB - OBJECTIVES: The transoral atlantoaxial reduction plate system treats irreducible atlantoaxial dislocation from transoral atlantoaxial reduction plate-I to transoral atlantoaxial reduction plate-III. However, this system has demonstrated problems associated with screw loosening, atlantoaxial fixation and concealed or manifest neurovascular injuries. This study sought to design a set of individualized templates to improve the accuracy of anterior C2 screw placement in the transoral atlantoaxial reduction plate-IV procedure. METHODS: A set of individualized templates was designed according to thin-slice computed tomography data obtained from 10 human cadavers. The templates contained cubic modules and drill guides to facilitate transoral atlantoaxial reduction plate positioning and anterior C2 screw placement. We performed 2 stages of cadaveric experiments with 2 cadavers in stage one and 8 in stage two. Finally, guided C2 screw placement was evaluated by reading postoperative computed tomography images and comparing the planned and inserted screw trajectories. RESULTS: There were two cortical breaching screws in stage one and three in stage two, but only the cortical breaching screws in stage one were ranked critical. In stage two, the planned entry points and the transverse angles of the anterior C2 screws could be simulated, whereas the declination angles could not be simulated due to intraoperative blockage of the drill bit and screwdriver by the upper teeth. CONCLUSIONS: It was feasible to use individualized templates to guide transoral C2 screw placement. Thus, these drill templates combined with transoral atlantoaxial reduction plate-IV, may improve the accuracy of transoral C2 screw placement and reduce related neurovascular complications. PMID- 25518034 TI - Preoperative imatinib for patients with primary unresectable or metastatic/recurrent gastrointestinal stromal tumor. AB - OBJECTIVES: Despite its rising popularity, reports on the use of preoperative imatinib mesylate (IM) in patients with advanced gastrointestinal stromal tumor (GIST) are limited. This study aims to explore the clinical efficacy of preoperative IM in patients with primarily unresectable or metastatic/recurrent GIST. METHODS: Between September 2009 and February 2014, patients with primarily unresectable or metastatic/recurrent GIST treated by a single medical team were recruited and considered for preoperative IM therapy. Re-examination was conducted regularly and abdominal enhanced CT data, blood biochemistry and responses to IM were recorded. RESULTS: A total of 18 patients were enrolled, including 13 with a primary tumor (7 stomach, 3 small bowel, 2 rectal and 1 pelvic tumor) and 5 with recurrent or metastatic GIST (2 with liver metastasis, 2 with anastomotic recurrence and 1 with pelvic GIST). The median follow-up time was 9.5 months (range of 3-63). The median tumor sizes before and after initiation of IM treatment were 9.1 cm and 6.0 cm (p=0.003) based on the CT findings, respectively. All patients showed a decrease in tumor burden and the median tumor size reduction was 35%. Sixteen of the 18 patients showed a partial response to IM and two possessed stable disease. Nine of the 18 patients (50%) underwent surgical resection of primary or metastatic/recurrent tumors, with a median of 7 months of IM therapy. One case each of multivisceral resection and tumor recurrence were noted. CONCLUSIONS: IM as a preoperative therapy is feasible and safe for unresectable or metastatic/recurrent GIST that can effectively decrease tumor size, facilitating resection. PMID- 25518035 TI - The effects of vardenafil and pentoxifylline administration in an animal model of ischemic colitis. AB - OBJECTIVES: Vardenafil enhances dilatation of vascular smooth muscle and inhibits platelet aggregation. The purpose of this study was to evaluate the clinical effects of vardenafil and pentoxifylline administration in an experimental model of ischemic colitis. METHODS: Forty female Wistar albino rats weighing 250-300 g were randomized into five experimental groups (each with n = 8) as follows:1) a sham group subjected to a sham surgical procedure and administered only tap water; 2) a control group subjected to a standardized surgical procedure to induce ischemic colitis and administered only tap water; 3) and 4) treatment groups subjected to surgical induction of ischemic colitis followed by the postoperative administration of 5 mg/kg or 10 mg/kg vardenafil, respectively; and 5) a treatment group subjected to surgical induction of ischemic colitis followed by postoperative administration of pentoxifylline at 50 mg/kg/day per day as a single dose for a 3-day period. All animals were sacrificed at 72 h post-surgery and subjected to relaparotomy. We scored the macroscopically visible damage, measured the ischemic area and scored histopathology to determine the severity of ischemia. Tissue malondialdehyde levels were also quantified. RESULTS: The mean Gomella ischemic areas were 63.3 mm2 in the control group; 3.4 and 9.6 mm2 in the vardenafil 5 and vardenafil 10 groups, respectively; and 3.4 mm2 in the pentoxifylline group (p = 0.0001). The mean malondialdehyde values were 63.7 nmol/g in the control group; 25.3 and 25.6 nmol/g in the vardenafil 5 and vardenafil 10 groups, respectively; and 22.8 nmol/g in the pentoxifylline group (p = 0.0001). CONCLUSION: Our findings indicate that vardenafil and pentoxifylline are effective treatment options in an animal model of ischemic colitis. The positive clinical effects produced by these drugs are likely due to their influence on the hemodynamics associated with vascular smooth muscle and platelet functions. PMID- 25518036 TI - Methicillin-resistant Staphylococcus aureus in HIV patients: risk factors associated with colonization and/or infection and methods for characterization of isolates - a systematic review. AB - Staphylococcus aureus is an important cause of infections and HIV-infected individuals are frequently susceptible to this pathogen. The aim of this study was to perform a systematic review to identify both the risk factors associated with colonization/infection by methicillin-resistant S. aureus in HIV patients and the methods used for characterization of isolates. An electronic search of articles published between January 2001 and December 2013 was first conducted. Among 116 studies categorized as being at a quality level of A, B or C, only 9 studies were considered to have high methodological quality (level A). The majority of these studies were retrospective (4/9 studies). The risk factors associated with colonization/infection by S. aureus were use of antimicrobials (4/9 studies), previous hospitalization (4/9 studies) and low CD4+ T lymphocyte counts (<200 cells/MUl) (3/9 studies). Culture in mannitol salt agar (3/9 studies) and the latex agglutination test (5/9 studies) were the main methods used for bacterial phenotypic identification. Genotypic profiles were accessed by pulsed-field gel electrophoresis (6/9 studies) and USA300 was the most prevalent lineage (5/9 studies). Most isolates were resistant to erythromycin (3/9 studies) and susceptible to vancomycin (4/9 studies). Ultimately, use of antimicrobials and previous hospitalization were the main risk factors for colonization/infection by methicillin-resistant S. aureus in HIV-infected individuals. However, the numbers of evaluated patients, the exclusion and inclusion criteria and the characterization of the S. aureus isolates were not uniform, which made it difficult to establish the characteristics associated with HIV patients who are colonized/infected by S. aureus. PMID- 25518039 TI - Morphology-controlled ZnO nanowire arrays for tailored hybrid composites with high damping. AB - Hybrid fiber reinforced composites using a nanoscale reinforcement of the interface have not reached their optimal performance in practical applications due to their complex design and the challenging assembly of their multiscale components. One promising approach to the fabrication of hybrid composites is the growth of zinc oxide (ZnO) nanowire arrays on the surface of carbon fibers to provide improved interfacial strength and out of plane reinforcement. However, this approach has been demonstrated mainly on fibers and thus still requires complex processing conditions. Here we demonstrate a simple approach to the fabrication of such composites through the growth of the nanowires on the fabric. The fabricated composites with nanostructured graded interphase not only exhibit remarkable damping enhancement but also stiffness improvement. It is demonstrated that these two extremely important properties of the composite can be controlled by tuning the morphology of the ZnO nanowires at the interface. Higher damping and flexural rigidity of these composites over traditional ones offer practical high-performance composites. PMID- 25518037 TI - Premedication with dexmedetomidine in pediatric patients: a systematic review and meta-analysis. AB - Premedication is important in pediatric anesthesia. This meta-analysis aimed to investigate the role of dexmedetomidine as a premedicant for pediatric patients. A systematic literature search was conducted to identify randomized controlled trials comparing dexmedetomidine premedication with midazolam or ketamine premedication or placebo in children. Two reviewers independently performed the study selection, quality assessment and data extraction. The original data were pooled for the meta-analysis with Review Manager 5. The main parameters investigated included satisfactory separation from parents, satisfactory mask induction, postoperative rescue analgesia, emergence agitation and postoperative nausea and vomiting. Thirteen randomized controlled trials involving 1190 patients were included. When compared with midazolam, premedication with dexmedetomidine resulted in an increase in satisfactory separation from parents (RD = 0.18, 95% CI: 0.06 to 0.30, p = 0.003) and a decrease in the use of postoperative rescue analgesia (RD = -0.19, 95% CI: -0.29 to -0.09, p = 0.0003). Children treated with dexmedetomidine had a lower heart rate before induction. The incidence of satisfactory mask induction, emergence agitation and PONV did not differ between the groups. Dexmedetomidine was superior in providing satisfactory intravenous cannulation compared to placebo. This meta-analysis suggests that dexmedetomidine is superior to midazolam premedication because it resulted in enhanced preoperative sedation and decreased postoperative pain. Additional studies are needed to evaluate the dosing schemes and long-term outcomes of dexmedetomidine premedication in pediatric anesthesia. PMID- 25518040 TI - Ultralightweight silver nanowires hybrid polyimide composite foams for high performance electromagnetic interference shielding. AB - Ultralightweight silver nanowires (AgNWs) hybrid polyimide (PI) composite foams with microcellular structure and low density of 0.014-0.022 g/cm(3) have been fabricated by a facile and effective one-pot liquid foaming process. The tension flow generated during the cell growth induced the uniform dispersion of AgNWs throughout the cell walls. The interconnected AgNWs network in the cell walls combined with the large 3D AgNWs network caused by 3D structure of foams provided fast electron transport channels inside foams. The electromagnetic interference (EMI) shielding effectiveness (SE) of these foams increased with increasing AgNWs loading as well as the nanowire aspect ratio due to the increasing connections of the conduction AgNWs network. Appropriate surface treatment like etching or spraying facilitated the construction of the seamlessly interconnected 2D AgNWs network on the surface, which could effectively reflect electromagnetic waves. Maximum specific EMI SE of values of 1210 dB.g(-1).cm(3) at 200 MHz, 957 dB.g( 1).cm(3) at 600 MHz, and 772 dB.g(-1).cm(3) at 800-1500 MHz were achieved in sprayed composite foams containing <0.044 vol % AgNWs loading, which far surpasses the best values of other composite materials. The reflections of interconnected AgNWs networks on the surface and inside foams combined with the multiple reflections at interfaces contributed to the shielding effect. PMID- 25518038 TI - Improving CT-guided transthoracic biopsy of mediastinal lesions by diffusion weighted magnetic resonance imaging. AB - OBJECTIVES: To evaluate the preliminary results obtained using diffusion-weighted magnetic resonance imaging and the apparent diffusion coefficient for planning computed tomography-guided biopsies of selected mediastinal lesions. METHODS: Eight patients with mediastinal lesions suspicious for malignancy were referred for computed tomography-guided biopsy. Diffusion-weighted magnetic resonance imaging and apparent diffusion coefficient measurement were performed to assist in biopsy planning with diffusion/computed tomography fused images. We selected mediastinal lesions that could provide discordant diagnoses depending on the biopsy site, including large heterogeneous masses, lesions associated with lung atelectasis or consolidation, lesions involving large mediastinal vessels and lesions for which the results of biopsy using other methods and histopathological examination were divergent from the clinical and radiological suspicion. RESULTS: In all cases, the biopsy needle was successfully directed to areas of higher signal intensity on diffusion-weighted sequences and the lowest apparent diffusion coefficient within the lesion (mean, 0.8 [range, 0.6-1.1]*10-3 mm2/s), suggesting high cellularity. All biopsies provided adequate material for specific histopathological diagnoses of four lymphomas, two sarcomas and two thymomas. CONCLUSION: Functional imaging tools, such as diffusion-weighted imaging and the apparent diffusion coefficient, are promising for implementation in noninvasive and imaging-guided procedures. However, additional studies are needed to confirm that mediastinal biopsy can be improved with these techniques. PMID- 25518041 TI - Persistent integration of reprogramming factors impairs the in vitro cardiogenic potential of induced pluripotent stem cells. PMID- 25518042 TI - Emerging epigenetic maps in atherosclerosis. PMID- 25518044 TI - Citric acid cycle intermediates in cardioprotection. AB - Over the last decade, there has been a concerted clinical effort to deliver on the laboratory promise that a variety of maneuvers can profoundly increase cardiac tolerance to ischemia and/or reduce additional damage consequent upon reperfusion. Here we will review the proximity of the metabolic approach to clinical practice. Specifically, we will focus on how the citric acid cycle is involved in cardioprotection. Inspired by cross-fertilization between fundamental cancer biology and cardiovascular medicine, a set of metabolic observations have identified novel metabolic pathways, easily manipulable in man, which can harness metabolism to robustly combat ischemia-reperfusion injury. PMID- 25518045 TI - Cardiac energetic impairment in heart disease and the potential role of metabolic modulators: a review for clinicians. AB - Cardiac energetic impairment is a frequent finding in patients with both inherited and acquired diseases of heart muscle. In this review the mechanisms of energy generation in the healthy heart and their disturbances in heart muscle diseases are described. Therapeutic agents targeted at correcting cardiac energetic impairment are discussed. PMID- 25518043 TI - Cardiovascular transcriptomics and epigenomics using next-generation sequencing: challenges, progress, and opportunities. PMID- 25518046 TI - Surgical management of patients with ulcerative colitis during pregnancy: maternal and fetal outcomes. AB - BACKGROUND AND AIMS: Ulcerative colitis can develop during the reproductive years, and there are limited data about perinatal care for patients with ulcerative colitis. In this study, we analyzed perinatal follow-up, complications, and maternal and fetal outcomes in pregnant patients undergoing surgery for ulcerative colitis. METHODS: Between January 1998 and July 2013, female patients who underwent surgery during pregnancy for abdominal complications of ulcerative colitis and followed up during their pregnancy in our institution were included in our study. Patient characteristics, complications, operations performed, maternal and fetal morbidity and mortality during the perinatal period, and type of delivery were analyzed. RESULTS: There were nine female patients with a median (range) age of 30 (21-33) years. Indications for surgery were fulminant/refractory colitis (n = 6) and bowel obstruction (n = 3). Operations performed were subtotal colectomy with an end ileostomy (n = 3), Turnbull blowhole procedure (n = 3), adhesiolysis with small bowel resection (n = 1), detorsion and decompression of bowel (n = 1) and adhesolysis (n = 1). Median (range) postoperative length of stay was 11 (5-28) days and median (range) duration of pregnancy was 36 (32-40) weeks. There were only two patients who had a transvaginal delivery, while a cesarean section was performed in seven patients. Indications for cesarean section were as follows: physician's preference (n = 4), planned small bowel surgery with cesarean section (n = 2), and metabolic disorders (n = 1). There were no perinatal maternal or fetal deaths. CONCLUSIONS: Surgery for ulcerative colitis complications can be performed safely if indicated during pregnancy under the care of a multidisciplinary team that includes gastroenterologists, obstetricians, and colorectal surgeons. PMID- 25518047 TI - Increased ultraviolet light exposure is associated with reduced risk of inpatient surgery among patients with Crohn's disease. AB - BACKGROUND AND AIMS: Due to the formation of strictures and fistulas, patients with Crohn's disease (CD) frequently need surgery. Vitamin D has been found to play a role in the degree of inflammation. We aimed to study the effect of UV exposure on the need for inpatient surgery in patients with CD. METHODS: The national inpatient sample, the largest database of hospitalizations from the USA, was used to conduct a retrospective study of patients hospitalized from 2004-2011 with CD by ICD-9CM code 555. Surgery was characterized as any intestinal surgery or fistula repair. An average state UV exposure was calculated for each hospitalization. Multivariate logistic regression was used to calculate the effect of UV exposure on surgery accounting for important covariates. RESULTS: There were 481712 hospitalizations with a primary diagnosis of CD. Of these hospitalizations, 67751 included a relevant surgical procedure code. Mean UV exposure was statistically lower in the group undergoing surgery (4.3 units versus 4.4 units, p = 0.001). The ratio of hospitalizations per UV exposure tertile for CD was statistically different compared with all hospitalizations (p < 0.001). In univariate analysis, increased UV exposure was associated with a lower risk of inpatient surgery with an OR of 0.90 per unit (95% CI 0.84-0.96, p = 0.001). Accounting for age, gender, race/ethnicity, season, income, hospital setting, and Charlson-Deyo comorbidities, the effect of UV exposure remained protective for inpatient surgery (OR 0.91, 95% CI: 0.84-0.98, p = 0.01). CONCLUSIONS: Increased UV exposure is associated with a reduced risk of inpatient surgery among patients with CD. Further studies of vitamin D's role in CD are necessary. PMID- 25518048 TI - Low fecal calprotectin predicts sustained clinical remission in inflammatory bowel disease patients: a plea for deep remission. AB - BACKGROUND AND AIMS: Mucosal healing has become the treatment goal in patients with ulcerative colitis (UC) and Crohn's disease (CD). Whether low fecal calprotectin levels and histological healing combined with mucosal healing is associated with a further reduced risk of relapses is unknown. METHODS: Patients with CD, UC or inflammatory bowel disease-unclassified (IBD-U) scheduled for surveillance colonoscopy collected a stool sample prior to bowel cleansing. Only patients with mucosal healing (MAYO endoscopic score of 0) were included. Fecal calprotectin was measured using a quantitative enzyme-linked immunosorbent assay (R-Biopharm, Germany). Biopsies were obtained from four colonic segments, and histological disease severity was assessed using the Geboes scoring system. Patients were followed until the last outpatient clinic visit or the development of a relapse, which was defined as IBD-related hospitalization, surgery or step up in IBD medication. RESULTS: Of the 164 patients undergoing surveillance colonoscopy, 92 patients were excluded due to active inflammation or missing biopsies. Of the remaining 72 patients (20 CD, 52 UC or IBD-U), six patients (8%) relapsed after a median follow-up of 11 months (range 5-15 months). Median fecal calprotectin levels at baseline were significantly higher for patients who relapsed compared with patients who maintained remission (284 mg/kg vs. 37 mg/kg. p < 0.01). Fecal calprotectin below 56 mg/kg was found to optimally predict absence of relapse during follow-up with 64% sensitivity, 100% specificity, 100% negative predictive value and 20% positive predictive value. The presence or absence of active inflammation determined by Geboes cut-off score of 3.1 was less strongly associated with the risk of relapse (64% sensitivity, 33% specificity, 9% negative predictive value and 92% positive predictive value. CONCLUSION: Low calprotectin levels identify IBD patients who remain in stable remission during follow-up. PMID- 25518049 TI - Development of a short questionnaire to assess the quality of life in Crohn's disease and ulcerative colitis. AB - BACKGROUND AND AIMS: Most of the disease-specific quality of life (QoL) measures for inflammatory bowel disease (IBD) are lengthy and time consuming. None have been established for routine use in clinical practice. We designed this study to develop a short QoL measure in IBD. METHODS: A 32-item questionnaire, the Crohn's and ulcerative colitis questionnaire (CUCQ)-32 was developed by reviewing the literature of the previously validated questionnaires and by consultation with patients and experts. Construct validity was carried out using the Short Form 12 and the EuroQol 5 dimensions questionnaires and two disease severity measures (the Simple Clinical Colitis Activity Index and the Harvey-Bradshaw Index). Test retest analysis was done by asking patients to complete the CUCQ questionnaire twice within a period of two weeks. RESULTS: Data were obtained from 205 patients with IBD who completed the CUCQ-32. Psychometric analysis showed that Cronbach's alpha was 0.88, item-total correlations were good, and there were no ceiling or flooring effects. Stepwise regression identified eight items that accounted for >95% of the variance in the CUCQ-32. The resulting CUCQ-8 demonstrated good internal consistency (Cronbach's alpha = 0.84), had good reproducibility (intraclass correlation coefficient = 0.94), was well correlated with the EuroQol 5 dimensions questionnaire (r = 0.58) and the Short Form-12 (r = 0.65 for physical component and r = 0.63 for mental component), and was responsive to change (responsiveness ratio was 0.64, p-value < 0.05). CONCLUSIONS: CUCQ-8 is a short questionnaire that has the potential to be an efficient tool for assessing the QoL of all patients with IBD in clinical practice. PMID- 25518050 TI - Systematic review of complementary and alternative medicine treatments in inflammatory bowel diseases. AB - OBJECTIVE: We performed a systematic review for Complementary and Alternative Medicine [CAM] as defined by the National Institute of Health in Inflammatory Bowel Disease [IBD], ie Crohn's disease [CD] and ulcerative colitis [UC], with the exception of dietary and nutritional supplements, and manipulative therapies. METHODS: A computerized search of databases [Cochrane Library, Pubmed/Medline, PsychINFO, and Scopus] through March 2014 was performed. We screened the reference sections of original studies and systematic reviews in English language for CAM in IBD, CD and UC. Randomized controlled trials [RCT] and controlled trials [CT] were referred and assessed using the Cochrane risk of bias tool. RESULTS: A total of: 26 RCT and 3 CT for herbal medicine, eg aloe-vera gel, andrographis paniculata, artemisia absinthium, barley foodstuff, boswellia serrata, cannabis, curcumin, evening primrose oil, Myrrhinil intest(r), plantago ovata, silymarin, sophora, tormentil, wheatgrass-juice and wormwood; 1 RCT for trichuris suis ovata; 7 RCT for mind/body interventions such as lifestyle modification, hypnotherapy, relaxation training and mindfulness; and 2 RCT in acupuncture; were found. Risk of bias was quite heterogeneous. Best evidence was found for herbal therapy, ie plantago ovata and curcumin in UC maintenance therapy, wormwood in CD, mind/body therapy and self-intervention in UC, and acupuncture in UC and CD. CONCLUSIONS: Complementary and alternative therapies might be effective for the treatment of inflammatory bowel diseases; however, given the low number of trials and the heterogeneous methodological quality of trials, further in-depth research is necessary. PMID- 25518051 TI - Response to infliximab therapy in ulcerative colitis is associated with decreased monocyte activation, reduced CCL2 expression and downregulation of Tenascin C. AB - BACKGROUND AND AIMS: The cellular mechanisms leading to infliximab therapy response in patients with ulcerative colitis (UC) are incompletely known. We therefore investigated early effects of infliximab therapy on monocytes and associated chemokines linked to clinical therapy response in UC patients. METHODS: Blood and biopsies were obtained from anti-TNF therapy-naive UC patients (n = 43) before (baseline) and during induction therapy with infliximab. Therapy response was evaluated at Week 14. Expression of monocyte activation markers and levels of chemokines in serum and biopsies were determined. Quantitative proteomic analysis was performed in cultured mucosal biopsies, and obtained data was validated in serum. RESULTS: In therapy responders, but not in non responders, infliximab reduced blood monocyte expression of CD14 and CD86, 2 weeks after therapy commenced, relative to baseline. Serum CCL2 levels were decreased only among therapy responders at Week 2 and Week 14, relative to baseline. These data corresponded with lower levels of CD14, CD86 and CCL2 in intestinal tissue in responders as compared with non-responders at Week 14. Proteomic analysis of cultured biopsies showed that infliximab induced a reduction in Tenascin C that predicted downregulation of CCL2. Therapy responders, but not non-responders, had decreased serum Tenascin C levels at Week 2 and Week 14, relative to baseline. CONCLUSIONS: Infliximab therapy response in UC patients is associated with reduced monocyte activation and serum levels of CCL2 2 weeks after therapy commencement. In therapy responders, infliximab influenced Tenascin C, which might be a regulator of CCL2 expression and important for induction of the clinical therapy response. PMID- 25518053 TI - Long-term efficacy and safety of azathioprine in ulcerative colitis. AB - BACKGROUND AND AIMS: Azathioprine (AZA) is an established treatment for ulcerative colitis (UC).However, controversy exists regarding its efficacy in inducing and maintaining clinical remission, and long-term data are lacking. We studied the effectiveness of AZA in a large cohort of UC patients treated in a single center. METHODS: All UC patients treated with AZA were identified from a prospective electronic database. We assessed response to therapy at 4 months and sustained clinical benefit at the last point of follow-up. We also examined predictors of response and sustained clinical benefit, as well as outcomes in those treated with AZA for >5 years. RESULTS: The study included 255 patients. At 4 months, 207 (81.2%) of 255 patients were still on AZA and 163 (63.9%) had responded to therapy. At the last point of follow-up 164 (64.3%) patients were still receiving AZA, of whom 154 (60.4%) achieved sustained clinical benefit. This effect was durable among 71 patients who received AZA for >5 years, with 61 (85.9%) considered to have achieved sustained clinical benefit. Twenty-six patients required admission to hospital for an exacerbation during AZA treatment, 20 patients ultimately required biologic therapy, and 21 underwent colectomy. Only two (2.8%) of 71 patients receiving AZA for >5 years needed to escalate to a biologic therapy, and only one (1.4%) required a colectomy. CONCLUSIONS: AZA is a safe and effective therapy in UC patients who fail 5-aminosalisylates in both the short and long term. Escalation to a biologic therapy or colectomy was unlikely among patients who were able to continue AZA therapy beyond 5 years. PMID- 25518052 TI - European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases. PMID- 25518054 TI - Bariatric surgery in patients with inflammatory bowel disease: an accessible path? Report of a case series and review of the literature. AB - BACKGROUND AND AIMS: Morbid obesity is an emerging problem in the inflammatory bowel disease [IBD] population. Bariatric and IBD surgeries share technical difficulties and elevated morbidity. However, nothing is known about the possibility of performing bariatric surgery in patients with a definite diagnosis of IBD. The aim of this study was to evaluate safety and efficacy of restrictive bariatric surgical procedures in IBD patients. METHODS: Six patients with morbid obesity and IBD were operated on with restrictive bariatric surgery and concomitant or deferred IBD surgery. We compared BMI, excess weight loss, and perioperative complications of restrictive bariatric surgery in IBD with a control group of 95 bariatric patients. We also evaluated clinical, biochemical, pharmacological, and endoscopic characteristics before and after surgery in IBD patients. RESULTS: Perioperative results, in terms of BMI, excess weight loss, and complications after restrictive bariatric surgery, were comparable between obese IBD and control patients. IBD patients experienced a significant postoperative reduction in BMI, CRP levels, WCC, and systolic blood pressure and a significant increment in hemoglobin levels. None of the patients reported signs of malabsorption. All the patients except one were able to discontinue steroids, were in endoscopic remission at 1 year, and were in clinical remission at the latest follow-up visit. Two patients halved azathioprine dosage. One patient had a postoperative clinical recurrence treated with adalimumab. CONCLUSIONS: Bariatric surgery seems to be safe and effective in IBD patients. Concomitant ileocolic resection does not increase perioperative complications. Relationship between IBD and obesity remains unclear, but weight loss could be useful in the pharmacological control of IBD. PMID- 25518055 TI - Prognosis of primary sclerosing cholangitis in israel is independent of coexisting inflammatory bowel Disease. AB - BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a rare chronic progressive cholestatic disorder. We assessed its characteristics and natural history in Israel and compared its outcome with respect to coexisting inflammatory bowel disease (IBD). METHODS: Data on characteristics, course and outcome were retrospectively retrieved on patients diagnosed with PSC from five large Israeli medical centers between 1988 and 2012. Patients with isolated PSC were compared with those with coexisting IBD to identify predictors of outcome. RESULTS: Of 141 patients (56% males) with confirmed PSC, 98 (69.5%) had coexisting IBD. The average age at presentation was 38.8 +/- 15.4 years and duration of follow-up was 7.93 +/- 6.26 years. The crude estimated point prevalence was 4 cases per 105 persons. Demographics and clinical characteristics were similar among all patients except for symptoms at diagnosis (which were more prevalent among PSC-IBD patients) and utilization of multiple diagnostic modalities (which was more prevalent among isolated-PSC patients). More than one third of the entire cohort had cirrhosis. A total of 15 patients (10.6%) died and 19 patients (13.5%) developed malignancy during follow-up. Nine patients (6.3%) underwent liver transplantation. Mean survival for the entire cohort was 26.3 +/- 1.4 years and mean transplant-free survival was 23.5 +/- 1.6 years. Cox proportional hazard regression for transplantation or death revealed two independent risk factors: cirrhosis and malignancy [hazard ratio 4.25 (p = 0.004) and 2.58 (p = 0.046), respectively]. CONCLUSIONS: Survival rate of PSC patients in Israel is longer than reported rates worldwide and is independent of coexisting IBD. PMID- 25518056 TI - Risk factors for Crohn's disease of the neo-small intestine in ulcerative colitis patients with total proctocolectomy and primary or secondary ileostomies. AB - BACKGROUND: De novo Crohn's disease (CD) of the neo-small intestine in ulcerative colitis (UC) patients after total proctocolectomy (TPC) is a new disease entity, which may persist even after a secondary diverting permanent ileostomy for pouch failure. We sought to compare outcomes of primary ileostomy (PI, i.e., stoma created after colectomy without trying of ileal pouch) and secondary ileostomy (SI, i.e., stoma created after pouch failure) and to evaluate factors associated with the development of CD of the neo-small intestine proximal to ileostomy. METHODS: A total of 123 eligible patients were identified from our Pouch Center Registry (PI group, n = 57 and SI group, n = 66). Demographics, clinical features and outcomes (CD of theneo-small intestine, non-CD related strictures, requirement of CD-related medications use, ileostomy-associated hospitalization, ileostomy failure with stoma revision/relocation, and shortgut syndrome) were compared. Step-wise logistic regression models were performed. RESULTS: The median follow-up for the whole cohort was 5.0 (2.0-12.0) years. Younger age at diagnosis and surgery, family history of IBD, toxic megacolon/fulminant colitis, pre-diversion severe diarrhea, prediversion anti-TNF biological therapy, arthralgia/arthropathy and staged surgery were more common in the SI group (p < 0.05). In multivariate analysis, the presence of SI [odds ratio (OR), 8.23; 95% confidence interval (CI), 2.43-27.85], family history of IBD (OR, 9.14; 95% CI, 3.13-26.69), and pre-diversion of weight loss (OR, 3.72; 95% CI, 1.23-11.21) were contributing factors for developing CD of the neo-small intestine. CONCLUSIONS: CD of the neo-small intestine in stoma patients was associated with the presence of SI, family history of IBD, and pre-diversion poor nutrition status. Patients with secondary ileostomy due to pouch failure should be carefully monitored. Aggressive medical, endoscopic or surgical therapy may be needed in patients at risk, before permanent diversion. PMID- 25518057 TI - Prediction of endoscopic disease activity in ulcerative colitis by two different assays for fecal calprotectin. AB - BACKGROUND AND AIMS: As mucosal healing is the goal of treatment in inflammatory bowel disease, defining a fecal [f-] calprotectin cut-off level for mucosal healing is crucial. Previous studies have presented different cut-off levels. The aim of this study was to investigate the ability of two f-calprotectin assays to differentiate mucosal healing from inflammation in ulcerative colitis. METHODS: Sixty-two patients with ulcerative colitis underwent colonoscopy for classification of mucosal inflammation [Mayo endoscopic subscore]. The patients also submitted a fecal sample for f-calprotectin analysis using two different assays, Calpro ELISA and Buhlmann ELISA. RESULTS: The two assays correlated significantly, with a Spearman rank correlation coefficient of 0.86. Both assays showed significantly different f-calprotectin levels in patients with a Mayo endoscopic subscore of 0 [mucosal healing] and 1-3 [inflamed mucosa] [p <0.001]. Using ROC curve analyses, we selected the best cut-off levels for both assays with responding sensitivity and specificity [presented with 95% confidence intervals]; Calpro ELISA cut-off 61 MUg/g, sensitivity 84.1% [75.0-93.2%], specificity 83.3 % [74.0-92.6%], and Buhlmann ELISA cut-off 96 MUg/g, sensitivity 90.9 % [83.7-98.1%], specificity 83.3 % [74.0-92.6%]. Defining mucosal healing as a Mayo endoscopic subscore <=1, cut-off levels increased: Calpro ELISA cut-off 110 MUg/g, sensitivity 80.0%[70-90%], specificity 66.6 % [54.9-78.3%]; and Buhlmann ELISA cut-off 259 MUg/g, sensitivity 83.3 %[74-92.6%], specificity 71.9 % [60.7-83.1%]. CONCLUSIONS: The study demonstrates the need for assay specific cut-off levels in clinical practice,as the f-calprotectin cut-off level for endoscopic disease activity differed in these two assays. PMID- 25518058 TI - Clinical predictors of colectomy in patients with ulcerative colitis: systematic review and meta-analysis of cohort studies. AB - INTRODUCTION: Colectomy is a major event that may significantly affect the outcome of ulcerative colitis (UC) in terms of both quality of life and mortality. This paper aims to identify clinical prognostic factors that may be significantly associated with this event. METHODS: PubMed, ISI Web of Knowledge and Scopus were searched to identify studies investigating the association between clinical factors in adult patients with UC and studied events.The clinical factors evaluated in this meta-analysis were gender, smoking habits, disease extent,use of corticosteroids, and episodes of hospitalization. RESULTS: Of the 3753 initially selected papers, 20 were included. The analysis showed a significantly lower risk of colectomy for female patients (odds ratio [OR] 0.78 [95% CI 0.68, 0.90]) and for smoking patients (OR 0.55 [0.33, 0.91]), and a higher risk for patients with extensive disease (OR 3.68 [2.39,5.69]), for patients who took corticosteroids at least once (OR 2.10 [1.05, 4.22]), and for patients who were hospitalized (OR 4.13 [3.23, 5.27]). CONCLUSION: Gender, smoking habits, disease extent, need for corticosteroids, and hospitalization were all significantly associated with UC prognosis. These results may clarify the relative influences of these and other prognostic factors in the natural course of the disease and therefore help improve the management approach, thus improving the follow-up of patients. PMID- 25518059 TI - Long-term prognosis of ulcerative colitis and its temporal change between 1977 and 2013: a hospital-based cohort study from Korea. AB - BACKGROUND AND AIMS: No previous large-scale studies have evaluated the prognosis of ulcerative colitis (UC) over a period of three decades in a non-Caucasian population. The aims of this study were to update the current information on the natural course of UC in a sizable cohort of Korean patients and to evaluate changes in the treatment paradigms and prognosis of UC over time. METHODS: We retrospectively analyzed 2802 Korean UC patients who visited Asan Medical Center. We divided the study subjects into three groups based on the year of diagnosis (cohort 1: 1977-1999; cohort 2: 2000-2006; and cohort 3: 2007-2013). RESULTS: Five-year cumulative probabilities of prescription of thiopurines (azathioprine or 6-mercaptopurine) and anti-tumor necrosis factor (anti-TNF) agents were 4.1% and 0.0%, respectively, in cohort 1 and 27.9% and 12.7%, respectively, in cohort 3 (P < 0.001). A total of 209 patients (7.5%) underwent colectomy, producing cumulative probabilities of colectomy at 10, 20 and 30 years after diagnosis of 7.8%, 14.2% and 21.3%, respectively. The cumulative probability of colectomy was especially low in patients first diagnosed at our center: 3.1% at 10 years and 4.5% at 20 years. Moreover, the cumulative probability of colectomy decreased significantly over the last 30 years (P = 0.039). CONCLUSION: Thiopurines and anti-TNF agents are used increasingly more frequently and earlier, while the colectomy rate has decreased over the last 30 years in Korean patients with UC. Korean UC patients may have a better clinical course than Western cases, as indicated by a lower colectomy rate. PMID- 25518060 TI - Smoking and early infliximab response in Crohn's disease: a meta-analysis. AB - BACKGROUND: Infliximab is used to treat moderate to severe Crohn's disease (CD), but its efficacy varies. Although cigarette smoking worsens CD, its impact on the infliximab response is unknown. We conducted a systematic review and meta analysis of clinical trials to determine the effect of smoking on the induction response to infliximab. METHODS: A systematic search was performed of MEDLINE, EMBASE, CINAHL, the Cochrane central register of controlled trials, the Cochrane IBD Group Specialized Trials Register for publications, and abstracts from major conferences from January 1996 to December 2010. Random effects meta-analysis using the Mantel-Haenszel method was conducted. Heterogeneity across studies was assessed using the Q statistic, the I2 statistic, and tau2. RESULTS: We identified 12 articles; four were excluded due to use of non-validated scoring systems.The remaining eight included a total of 1658 patients, with 649 active smokers. Luminal response was assessed by the Crohn's Disease Activity Index in four studies (three of which included fistula response) and the Harvey-Bradshaw index in two (both including fistula response), and two studies examined only the fistula response. The relative risk for response to infliximab among smokers was 0.99 (95% CI 0.88-1.11) (tau2 = 0.0143). Analyses of the five studies examining both inflammatory and fistulizing CD were similar to the analysis of all eight studies. The pooled relative risk was 0.92 (95% CI 0.80-1.06) (tau2 = 0.0154). CONCLUSION: Though smoking worsens CD, this meta-analysis does not show a negative effect of smoking on initial response to infliximab. This must be viewed in the proper context, as long-term maintenance of response may yet be influenced by smoking status. PMID- 25518061 TI - Cholestyramine treats primary sclerosing cholangitis-associated inflammatory bowel disease. PMID- 25518062 TI - Acceptance of inflammatory bowel disease treatment recommendations based on appropriateness ratings: do practicing gastroenterologists agree with experts? AB - BACKGROUND: Appropriateness criteria for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) have been developed by expert panels. Little is known about the acceptance of such recommendations by care providers. The aim was to explore how treatment decisions of practicing gastroenterologists differ from those of experts, using a vignette case study and a focus group. METHODS: Seventeen clinical vignettes were drawn from clinical indications evaluated by the expert panel. A vignette case questionnaire asking for treatment options in 9 or 10 clinical situations was submitted to 26 practicing gastroenterologists. For each vignette case, practitioners' answers on treatments deemed appropriate were compared with panel decisions. Qualitative analysis was performed on focus group discussion to explore acceptance and divergence reasons. RESULTS: Two hundred thirty-nine clinical vignettes were completed, 98 for CD and 141 for UC.Divergence between proposed treatments and panel recommendations was more frequent for CD (34%) than for UC (27%). Among UC clinical vignettes, the main divergences with the panel were linked to 5-aminosalicylate (5-ASA) failure assessment and to situations in which stopping treatment was the main decision. For CD, the propositions of care providers diverged from the panel in mild to moderate active disease, for which practitioners were more prone to an accelerated step-up than the panel's recommendations. CONCLUSIONS: In about one third of vignette cases, inflammatory bowel disease treatment propositions made by practicing gastroenterologists diverged from expert recommendations. Practicing gastroenterologists may experience difficulty in applying recommendations in daily practice. PMID- 25518063 TI - Diarrhea in Crohn's disease: investigating the role of the ileal hormone fibroblast growth factor 19. AB - BACKGROUND: Bile acids [BA] are usually reabsorbed by the terminal ileum, but this process is frequently abnormal in Crohn's disease [CD]. BA malabsorption occurs, and excess colonic BA cause secretory diarrhea. Furthermore, the hormone fibroblast growth factor 19 [FGF19] is synthesized in the ileum in response to BA absorption and regulates BA synthesis. We hypothesized that reduced serum FGF19 levels will be associated with diarrheal symptoms and disease activity in both ileal resected[IR-CD] and non-resected CD [NR-CD] patients. METHODS: Fasting serum FGF19 levels were measured in 58 patients [23 IR-CD patients and 35NR-CD patients]. Disease activity was assessed using the Harvey Bradshaw Index and C reactive protein [CRP]. Stool frequency, Bristol Stool Form Scale and length of previous ileal resection were recorded. FGF19 levels were also compared with healthy and diarrhea control patients. RESULTS: FGF19 levels were inversely correlated with ileal resection length in IR-CD patients[r = -0.54, p = 0.02]. In NR-CD patients, median FGF19 levels were significantly lower in patients with active disease compared with inactive disease [103 vs. 158 pg/ml, p = 0.04] and in those with symptoms of diarrhea compared with those without [86 vs. 145 pg/ml, p = 0.035]. FGF19 levels were inversely correlated with stool frequency, Bristol stool form and CRP in NR-CD patients with ileal disease. CONCLUSIONS: Reduced FGF19 levels are associated with ileal resection, diarrhea and disease activity. FGF19 may have utility as a biomarker for functioning ileum in CD. This study supports a potential role of FGF19 in guiding treatments for diarrhea in Crohn's disease. PMID- 25518066 TI - Announcement: Interim U.S. guidance for monitoring and movement of persons with potential Ebola virus exposure. PMID- 25518065 TI - Sirolimus therapy in a patient with severe hyperinsulinaemic hypoglycaemia due to a compound heterozygous ABCC8 gene mutation. AB - INTRODUCTION: Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of severe and persistent hypoglycaemia in neonates. The treatment of severe diazoxide unresponsive HH involves near total pancreatectomy. Mammalian target of rapamycin (mTOR) is a protein kinase that regulates cellular proliferation. mTOR inhibitors are used in cancer patients and recently found to be effective in the treatment of insulinoma and HH patients. CASE: A 36 weeks large for gestational age neonate presented with severe hypoglycaemia on day 1 of life. The hypoglycaemia screen confirmed HH and genetic testing revealed compound heterozygous ABCC8 mutation, confirming diffuse disease. He was unresponsive to the maximal dose of diazoxide (15 mg/kg/day), hence needed treatment with higher concentration of intravenous glucose (25 mg/kg/min), intravenous glucagon and subcutaneous octreotide (30 MUg/kg/day) infusions to maintain normoglycaemia. Sirolimus, a mTOR inhibitor, was commenced at 9 weeks of age following which he showed a marked improvement in his glycaemic control. After 4 weeks of sirolimus therapy, he was discharged home on subcutaneous octreotide injection (20 MUg/kg/day) and oral sirolimus, thereby avoiding the need for a near total pancreatectomy. CONCLUSION: We report the first case of compound heterozygous ABCC8 mutation causing severe diffuse HH that responded to therapy with a mTOR inhibitor. PMID- 25518067 TI - What's the difference between a colonoscopy and a sigmoidoscopy? PMID- 25518069 TI - Torn meniscus: surgery may not be the first option. Weight loss, medications, and physical therapy may be equally effective, safer, and less expensive than surgery. PMID- 25518064 TI - Protein acetylation affects acetate metabolism, motility and acid stress response in Escherichia coli. AB - Although protein acetylation is widely observed, it has been associated with few specific regulatory functions making it poorly understood. To interrogate its functionality, we analyzed the acetylome in Escherichia coli knockout mutants of cobB, the only known sirtuin-like deacetylase, and patZ, the best-known protein acetyltransferase. For four growth conditions, more than 2,000 unique acetylated peptides, belonging to 809 proteins, were identified and differentially quantified. Nearly 65% of these proteins are related to metabolism. The global activity of CobB contributes to the deacetylation of a large number of substrates and has a major impact on physiology. Apart from the regulation of acetyl-CoA synthetase, we found that CobB-controlled acetylation of isocitrate lyase contributes to the fine-tuning of the glyoxylate shunt. Acetylation of the transcription factor RcsB prevents DNA binding, activating flagella biosynthesis and motility, and increases acid stress susceptibility. Surprisingly, deletion of patZ increased acetylation in acetate cultures, which suggests that it regulates the levels of acetylating agents. The results presented offer new insights into functional roles of protein acetylation in metabolic fitness and global cell regulation. PMID- 25518068 TI - I've been taking methotrexate for my rheumatoid arthritis (RA) for several years, but it doesn't seem to be helping my symptoms. My doctor suggested adding a biologic response modifier (BRM) drug, such as etanercept (Enbrel) or adalimumab (Humira) to my treatment plan, but I've heard that BRMs can increase cancer risk. PMID- 25518070 TI - Disrupting cancer's energy source. New knowledge of cancer cells' needs for metastasizing could lead to new treatments, therapies. PMID- 25518071 TI - [Spread of Chikungunya virus in the Americas 2013-2014]. PMID- 25518072 TI - [Plasma DNA measurement as a biomarker of cancer]. AB - BACKGROUND: Carcinoembryonic antigen (CEA) and CA 15-3 serve as biomarkers in the two prevalent cancers of the colon and breast, respectively. However, their sensitivity for screening is tow. Circulating DNA has been suggested as a potential marker. We developed a fluorometric method which enables an easy, fast and reliable DNA measurement. This manuscript presents the results of our experiments to evaluate the significance of DNA measurements in breast and colon patients. METHODS: Patients who had been diagnosed with early stages of colon or breast cancer were recruited into a prospective study. Blood samples were withdrawn for the determination of CEA, CA 15-3 (according to the type of cancer) and circulating DNA concentrations prior to any therapeutic intervention. Control DNA Levels were determined in blood samples of healthy volunteers. RESULTS: Mean circulating DNA in patients with colon cancer was higher than in control subjects [798+409 ng/ml vs. 308 +/- 256 ng/ml, p<0.0001. High DNA concentrations were identified in 40% of colon patients compared with 28% with increased CEA levels. Mean DNA levels among breast cancer patients was higher than the control group [1060 +/- 670.9 ng/mt vs. 376.2 +/- 244.1 ng/ml, p=0.0001]. High DNA concentrations were identified in 53% of breast cancer patients compared with 9% with increased CA 15-3 levels. CONCLUSION: A novel simple, rapid, cheap and reliable fluoroscopic method was used to determine circulating DNA levels in the blood of breast and colon cancer patients. Increased DNA concentrations were found in the blood of early cancer patients. This method demonstrates a better sensitivity compared with the traditional markers. PMID- 25518073 TI - [Nutritional assessment of inpatients with schizophrenia]. AB - BACKGROUND: No thorough examination of the actual nutritiornal composition of the diet of schizophrenia patients in Israel has been carried out. We performed a cross-sectional study evaluating the nutritional assessment and dietary intake of inpatients with schizophrenia treated with antipsychotic drugs, based on the first National Health and Nutrition Examination Survey [MABAT]. METHODS: Sixty inpatients completed a face-to-face interview. The questionnaire included details on health status, alcohol intake, exercise, smoking habits, eating and dieting habits and food supplementation use, knowledge and attitudes regarding nutrition, sources of nutrition knowledge and a 24-hour food recall to gather information on total caloric intake and total fat, protein, carbohydrate, cholesterol, and fiber content. The hospital's menu is according to the requirements of the Ministry of Health (MoH), based on Dietary Reference Intakes. Weight, height, waist and hip measurements were recorded and body mass index and waist/hip ratio were calculated. Data were subsequently compared to data for the general population collected in the MABAT survey. RESULTS: Schizophrenia patients as a group did not eat more food when compared to MABAT subjects, but the relative percentages of calories derived from protein was higher and fiber intake was lower. The schizophrenia patients exercised less, but were not significantly more obese, thodgh there was more abdominal obesity. CONCLUSION: The schizophrenic patients make poor dietary choices, which likely contribute to the adverse metabolic side effects of antipsychotic treatment, thereby promoting the risk of morbidity and mortality. Proactive programmes to improve dietary habits and related nutritional status are necessary. PMID- 25518074 TI - [Ventricular fibrillation following hyperventilation and apneic underwater swimming]. AB - This is a case study of an 18 years old boy who lost consciousness during apneic underwater swimming. When cardiopulmonary resuscitation was initiated ventricular fibrillation was seen on cardiac monitoring. Bradycardia, atrial and ventricular premature beats are a known response to hyperventilation and apneic underwater diving. This case is the first documentation of ventricular fibritllation as a cause of sudden cardiac death during apneic underwater swimming. PMID- 25518075 TI - [Micro-invasive glaucoma surgery]. AB - Intraocular pressure (IOP) reduction is the current treatment in glaucoma. In recent years, minimally invasive glaucoma surgery (MIGS) has been added to the arsenal of surgical options. MIGS can reduce trabecular meshwork resistance to outflow and decrease the IOP with mild side effects. In this article, we review the clinical experience gathered with iSTENT, Bypass, Gold Micro Shunt and the Trabectome. PMID- 25518076 TI - [Evolutionary perspective in precocious puberty]. AB - Pubertal development is subject to substantial heritability, but much variation remains to be explained, including fast changes over the last 150 years, that cannot be explained by changes of gene frequency in the population. This article discusses the influence of environmental factors to adjust maturational tempo in the service of fitness goals. Utilizing evolutionary development thinking (evo devo), the author examines adolescence as an evolutionary life-history stage in its developmental context. The transition from the preceding stage of juvenility entails adaptive plasticity in response to energy resources, social needs of adolescence and maturation toward youth and adulthood. Using Belsky's evolutionary theory of socialization, I show that familial psychosocial environment during the infancy-childhood and childhood-juvenility transitions foster a fast life-history and reproductive strategy rather than early maturation being just a risk factor for aggression and delinquency. The implications of the evo-devo framework for theory building, illuminates new directions in the understanding of precocious puberty other than a diagnosis of a disease. PMID- 25518077 TI - [Pulmonary hyper IgG4 disease]. AB - Hyper IgG4 syndrome (HIDI is a multisystem disease characterized by high levels of immunoglobulin IgG4 with possible involvement of the pancreas, lung and lymph nodes as well as other organs. It was first described in connection to autoimmune pancreatitis but since then, it became clear that it can also affect many other organs. The disease involves the thorax and lesions were described in the mediastinum, airways, lung parenchyma and pleura. it can simultaneously involve multiple organs or be localized in just one. HID can develop in part of the fibro inflammatory diseases of the chest without clear etiology like pseudo tumors, mediastinal and pleural fibrosis or inflammation. HID was also found in connection with various diseases in the airways. The HID lesion is typically rich in plasma cells positive to IgG4, fibrosis and vascutitis. This disease is rare and until now there were almost no cases reported in Israel. High clinical suspicion can make the diagnosis and prescribe the right therapy. The prognosis is favorable if the diagnosis is made on time. New studies are needed to understand the connection and the importance of this pathology to the lungs and also the most suitable treatments available for it. PMID- 25518078 TI - [Hyperhidrosis and social anxiety disorder--the same old thing under a different cloak?]. AB - Hyperhidrosis is a reason for treatment by many specialists in medicine, such as dermatologists, family medicine doctors, surgeons and also psychiatrists. Hyperhidrosis causes considerable distress and disability. Despite the fact that the condition has been known for thousands of years, it is yet unclear whether excessive sweating derives from emotional" activation of the central nervous system, whether the emotional symptoms evolve due to local dysfunction of the sweat glands, or a combination of the two problems. In this article, we will present two conditions: hyperhidrosis and Social Anxiety Disorder, a mental condition with anxiety and avoidanrce in social settings that is frequently accompanied by sweating. We will discuss the similarities and differences between these disorders and the various treatments available for these conditions. Research shows that social anxiety does not explain hyperhidrosis, but that excessive sweating reduces the threshold for social anxiety. Among people with hyperhidrosis, the functional disability and the emotional problems are mediated by the social anxiety. We propose treating the symptoms of hyperhidrosis and social anxiety disorder in combination in order to achieve maximal improvement in these patients. PMID- 25518079 TI - [Seeing the sounds--chest and lung ultrasonography]. AB - Chest ultrasonography was considered hampered and deficient but it is now taking a prominent role as a bedside tool for the diagnosis of lung ailments. Technological development has made it accurate, fast and reliable to the extent that it is gradually replacing the traditional chest X-ray and sometimes also the computed tomography scan. In this article we review and display in a few images the diagnostic possibilities of the thoracic ultrasound examination in a diverse range of maladies such as pneumonia, pulmonary congestion, pleural effusion and other conditions. PMID- 25518081 TI - [Reflections of a "legal alien" the importance of protected time for teaching]. PMID- 25518080 TI - [Allergy to non-steroidal antiinflammatory drugs: recommendations of the Israeli allergy and clinical immunology association]. AB - Drug hypersensitivity is an adverse reaction that was brought-about by a specific immunologic response. Some of these reactions are Linked with significant morbidity and mortality. Nowadays, hypersensitivity reactions to most drugs can be well defined and the risk of re-exposure to the culprit drug and/or related drugs can be properly assessed. Medical history, skin, blood and challenge tests, conducted in an allergy clinic, enable the prediction and prevention of repeated events as well as unnecessary avoidance of needed compounds. Non-steroidal anti inflammatory drugs [NSAID] are the second most prevalent group of drugs that provoke hypersensitivity responses occurring either immediately or later. Immediate type responses to NSAID could be divided into 2 groups, each related to a different mechanism. The most common reaction is not allergic but rather it is mediated by the inhibition of the cyclooxygenase I enzyme pathway. Accordingly, this reaction is not selective to a single chemical compound but rather cross reacts with other members of this "family" of drugs, depending on their biochemical properties. The clinical distinction between those two subtypes of immediate reaction is hard and sometimes utterly impossible. Moreover, the clinical appearance of an immediate reaction may vary from rhinitis, asthma, new appearance or augmentation of chronic urticaria and up to overt anaphylaxis and death. Furthermore, delayed type reactions may also be life-threatening and typically appear 24 hours and up to days following initiation of therapy. In the current review, we present the recommendations of the Israel Association for Allergy and Clinical Immunology for the evaluation and treatment of patients suspected to suffer from hypersensitivity to NSAIDs. PMID- 25518082 TI - [Truth telling to patients--A discussion of Jewish sources (corrected)]. AB - Defining truth and truth-telling to patients are central topics in philosophy, law, and psychology, with many implications in medicine. In the last hundred years, with the transition from paternalistic medicine to a system in which the patient's autonomy is emphasized, the decision on the quantity and quality of medical information to be disclosed to the patient has become more complicated and requires careful consideration and special sensitivity on the part of the doctor. The Israeli Patients' Rights Act (1996] established guidelines for medical staff about telltting the truth to patients with occasional special authority delegated to the doctor to decide for the benefit of the patient at his discretion and with the approval of the institutional ethics committee, but in practice there are difficulties in implementing the Law. This article reviews a selection of sources from Jewish tradition throughout the ages that deal with truthtelling or concealing the truth in medical contexts and other contexts. Sources are drawn from the Bible, Mishna-Talmud, and halachic Literature, from which.conclusions can be drawn regarding this issue. In our opinion, these sources yield messages and values that are also relevant to the modern medical world. This is especially true in a multi-cultural environment such as Israel that requires the physician to consider the patient's background and to communicate information in accordance with his/her will, in an efficient and sensitive manner. PMID- 25518083 TI - [On gods, snakes and staffs--the emblem of the medical profession]. AB - The commonly accepted emblems of the Medical Profession are the staff of the Greek god of medicine--Asklepios (or Asclepius], on which one serpent is entwined. Later, around the 16th century C.E., the wand of the herald of the Greek Gods, e.g., Hermes, on which two snakes are entwined and facing each other, became popular as the emblem of the medical profession. We elaborate on the history of the evolution of these emblems as symbols of medicine, including earlier influences from the times of the ancient Egyptians and Babylonians, which were followed by Judeo-Christian traditions and concepts. The relevance of the use of the wand of Hermes as an emblem of our profession is further discussed. PMID- 25518084 TI - [Preface]. PMID- 25518085 TI - [Address by the rector of the pomeranian Medical University in Szczecin inaugurating the academic year of 2013/2014]. PMID- 25518086 TI - The evaluation of procedure and treatment outcome in patients with tension pneumothorax. AB - INTRODUCTION: Tension pneumothorax is a directly criti- cal illness condition. The aim of this study was to evaluate the outcome of tension pneumothorax treatment in trauma patients. MATERIAL AND METHODS: We assessed the results of treat- ment of 22 patients hospitalized for trauma in 2000-2010, in whom at the time of admission tension pneumothorax symptoms were found. This constituted 18% of trauma patients who at the time of admission to the hospital, during the initial examination, were diagnosed with pneumothorax. In the study group there were 17 men and 5 women. The patients' ages ranged from 21 to 85 years (mean 48.8). In 19 cases tension pneumothorax was associated with polytrauma. Traffic accidents were the cause of most cases. Injury to one or both lungs was observed in 16 patients. Typical paradoxi- cal breathing occurred in 2 patients. The number of frac- tured ribs averaged 6.3 per patient. In each of the patients, immediately on admission, after diagnosis based on clini- cal symptoms, tension pneumothorax decompression was performed by pleural drainage. Lung decompression and improvement of the clinical condition of the patient were obtained in a few minutes after pleural drainage. Then, fur- ther diagnostic and therapeutic procedures were continued. Full time of hospitalization due to polytrauma injury was on average 58.6 days. Two patients died during treatment for polytrauma. Pneumothorax was not the cause of death in either of the patients. CONCLUSION: In summary, the therapeutic standard ordering of tension pneumothorax decompression, directly on admission to the hospital, allows the patient to survive in spite of the grave nature of the injury. PMID- 25518087 TI - [Transverse abdominal plane - anatomical and clinical aspects]. AB - In medicine spectacular progress can be observed at many stages, which sometimes requires the redefinition of already known anatomical structures. One of them is the transverse abdominal plane, which was the focus of anaesthetists. It was observed that anaesthetics introduced locally into this plane have similar power to a traditional epidural procedure or spinal anaesthesia. The concept of the trans- verse abdominal plane is a relatively new anatomical term which was introduced into clinical medicine by anaesthetists. Because of the potential performance of anaesthetic pro- cedures through access to the transverse abdominal plane, there has been a growing interest not only expressed by anaesthetists, but also anatomists who wish to explore new anatomical aspects of this plane. It is generally believed that anatomical studies will provide more information on this plane, which can contribute to a wider spread of this pro- cedure among anaesthetists. PMID- 25518088 TI - [Pregnancy in a rudimentary horn of the uterus]. AB - Pregnancy in a rudimentary horn of the uterus, a rare form of ectopic pregnancy, develops in women affected by developmental abnormalities of the growth and fusion of the Mullerian paramesonephric ducts. In the Polish population, this problem affects 4-8 women per year. The paper analyzes the problems that are associated with pregnancy developing in the rudimentary horn. Due to the continuous progress in medical sciences, maternal mortality has been almost completely eliminated in this form of ectopic pregnancy, while neonatal survival has risen to about 20%. Further devel- opments in medicine allow us to be moderately optimis- tic about further improvement of the treatment's statistics. PMID- 25518089 TI - [Blastocystis hominis- parasites or commensals? ]. AB - Blastocystis hominis (B. hominis) is a cosmopolitan pro- tozoa which parasitizes the human large intestine. This parasite had been considered to be commensal of the large intestine for a long time, because even an intense invasion may be asymptomatic. However, this species is now being regarded as a parasitic organism. In this paper the latest data concerning the epidemiology, diagnostics and treatment of B. hominis invasion have been cited and discussed. PMID- 25518090 TI - [Cellulite - causes, prevention, treatment ]. AB - Cellulite is a multifactorial etiology ailment. It changes the skin topography by the formation of the skin surface's appearance, changes described as "orange peel". This prob- lem concerns 85-98% of women, and for them it is one of the most intolerable aesthetic imperfections. In the past few years the interest of scientists in this problem has clearly increased. Several theories on the pathophysiology of cel- lulite have been produced A number of different thera- peutic regimens have been developed using modern tech- nology. However, despite the many treatment options for cellulite, it is extremely important that patients should be aware that only multidirectional treatment can bring sat- isfactory results. The aim of this review was to describe the causes of cellulite, and its prevention and treatment. PMID- 25518091 TI - [Pleiotropic activity of 3-hydroxy-3-methyl-glutharyl-coenzyme a inhibitors (statins). therapeutic potential in connective tissue diseases ]. AB - 3-Hydroxy-3-Methyl-Glutharyl-Coenzyme A reduct- ase inhibitors, known as statins, form a group of chemical compounds that are characterized by the ability to inhibit cholesterol synthesis. Statins have proved their efficacy as potent drugs in the primary and secondary prevention of cardiovascular events. It has also been shown that the thera- peutic effects of statins go beyond reduction of cholesterol level. These properties, which are separate from the influ- ence on cholesterol synthesis, are sometimes called the pleio- tropic effect. This effect comprises immunomodulation, an anti-inflammatory effect, and endothelial function recovery. PMID- 25518092 TI - [Assessment of sexual dimorphism of finger length ratio (2D:4D) ]. AB - INTRODUCTION: Studies on many populations have shown that the length of the second finger (2D) compared to the fourth (4D), expressed as the finger length ratio (2D:4D), might be characteristic for sexual dimorphism. It was also found that the values of 2D:4D differ significantly between examined populations. It is thought that the value of 2D:4D is determined in early foetal life under the influence of genetic factors and the strong influence of sex hormones. It has been proven that the values of 2D:4D are related to, for instance, sexual orientation, and artistic and sporting ability. Recently, increasing interest in the clinical signifi- cance of finger length ratio in the diagnosis of somatic and mental disorders has been observed. For example, it was found that values of 2D:4D in individuals suffering from congenital adrenal hyperplasia or autism were significantly lower compared to healthy subjects. The aim of the study was to determine sexual dimor- phism in finger length ratio among representatives of the Polish population. MATERIALS AND METHODS: The study group comprised 115 people (57 females and 58 males). Anthropometric meas- urements were taken from the second and fourth finger of the right and left hands - from the point of dactylion (da) to pseudophalangion (pph) using analogue callipers. We calculated the significance of differences in 2D:4D between males and females separately for the right and left hands. RESULTS: In both hands mean 2D:4D values were lower in males than in females. The difference in the right hand reached the statistical significance level with p < 0.05. CONCLUSIONS: Among the subjects from the examined population the 2D:4D ratio shows trends characteristic for sexual dimorphism. PMID- 25518093 TI - [Women's expectations towards gynaecological examination ]. AB - INTRODUCTION: It is commonly known that gynaecologi- cal examinations cause a lot of negative emotions in the majority of women. The aim of my work was: 1. Getting to know women's views on the nature of a pelvic examination and their expectations regarding gynaecologists. 2. To determine the correlation between the examined views and independent variables such as the age of the respondents, residence, and place of examination. MATERIAL AND METHODS: The research material consisted of 1200 women living in the region of Western Pomerania and in Lodz. The measurement tool was a survey of my own authorship. CONCLUSIONS: 1. In the opinion of most women, gynaecological examination is embarrassing and stressful. It has not been proven that this opinion was related to age, residence or place of examination. 2. According to women, the most embarrassing moment of a visit to the gynaecologist is lying down on the gynaecological chair, and the gynecological examination. The most unpleasant aspect is palpation through the vagina and rectum. These feelings differ depending on age, residence and place of taking the examination. 3. The choice of the gynaecologist's gender is dependent on women's age. 4. The frequency of reporting for the gynaecological examination decreases with women's age, and is dependent on their place of residence. 5. A sense of safety and mental comfort during the gynaecological examination is provided by the lack of third parties, except for the presence of a midwife. It is also dependent on the patient's age, her place of residence, as well as the examination site. 6. Women's expectations of a gynaecologist are focused mainly on maintaining a sense of intimacy and safety, getting information about the procedures, as well as a pleasant and individual approach. PMID- 25518094 TI - The risk of abuse of vitamin supplements. AB - The article presents the results of studies on potential risks associated with the abuse of vitamin supplements which until recently had been considered not only highly effica- cious, but also completely safe. Particular consideration is given to vitamins A, E, D and C. The necessity to control the intake of vitamin supplements and even to strictly super- vise the supply to high risk patients is highlighted. PMID- 25518095 TI - An analysis of the feelings of pregnant women at risk of preterm labour. AB - INTRODUCTION: The aim of the study was an analysis of the feelings of pregnant women at risk ofpreterm labour. MATERIAL AND METHOD: 313 expectant mothers aged between 18 to 44 years (ranges: 18-25, 26-30 and 31-44 years) with no psychological disorders, hospitalized and treated due to the risk of preterm labour were surveyed. All the examined pregnant women expressed voluntary and informed consent for the participation in the survey. Each of the questionnaires given to the examined pregnant women contained: a questionnaire form devised by the authors, to establish the characteristics of the surveyed expectant mothers, and the following research standardized tool - Negative and Positive Feelings Scale by P. Brzozowski. RESULTS: The value of the mean level of positive feel- ings state in the group of patients aged 31-44 years with higher education was significantly higher (p < 0.05) than the mean value in the group of patients aged 26-30 years with secondary or primary/vocational education. Marital status and place of residence had no effect on the level of positive feelings as a condition of pregnant women in the study group (p > 0.05). There were no significant statistical differences (p > 0.05) between the level of negative feel- ings trait and age. It was found, however, that the level of negative feelings trait was significantly lower (p = 0.0009) in pregnant women with higher education than in pregnant women who had completed secondary education. CONCLUSION: 1. Among pregnant women at risk of pre- term labour, higher levels of positive feelings were found in pregnant women aged 31-44 years with higher education, being married and residents of a provincial city. 2. In order to reduce negative feelings in pregnant women at risk of preterm labour it seems important to implement appropriate psychological and prophylactic management, provide adequate care in the pregnancy pathology department, as well as support from the medical staff and the family. These activities should be targeted particularly at younger women with primary education or vocational training, not being married and living in rural areas. PMID- 25518096 TI - [Factors influencing body image in individuals with selected dermatological diseases]. AB - INTRODUCTION: The aim of this work was to examine the relationship between body concept and personality, and sociodemographic, physical and medical factors in der- matological patients with skin lesions localized in socially visible body areas. MATERIAL AND METHODS: The study was carried out in 160 dermatological patients (80 females and 80 males) aged 30-60 years (mean = 48.26; SD = 9.15) whose skin lesions were localized in the area of the face/head and/or hands. Body image was measured with the Body Image Questionnaire based on the Body Cathexis Scale of P.F. Secord and S.J. Jourard. The self concept was measured with the Adjective Check List of H.G. Gough and A.B. Heilbrun, and The Wheel Questionnaire of Ben Shalit. CONCLUSIONS: Body self image of dermatological patients was influenced mostly by personality traits. PMID- 25518097 TI - [A comparison of opinions about disabled sports between students of University in Szczecin and disabled athletes ]. AB - INTRODUCTION: Sport among disabled people is becoming more and more popular. It is happening mostly due to the growing number of sports centres for the disabled, and the widespread popularization of this form of activity by organi- zations working for the benefit of disabled people. Also, the mass media play an important role in the process. The aim of the study a comparison of the knowledge and opinions about disabled sports of physical education students and disabled athletes. METHODS: The research was conducted using two dif- ferent questionnaires. One of them was given to students of Physical Education, the other to members of a disabled sports club, "Start". The questionnaires consisted of two sections: a personal profile, and 17 questions about disabled sports. 45 full-time students of Physical Education at the University of Szczecin: 30 (66.7%) women and 15 (33.3%) men. The average age of the group was 23.6 years. The second group, from the disabled sports club, consisted of 33 people, 18 (54.5%) women and 15 (45.5%) men; the aver- age age of the participants was 28.6 years. RESULTS: Among the disabled people, 10 (30.3%) people were unable to name any disabled athlete; among the. group of able-bodied students, there were 33 (73.3%) people who were not able to do the same thing. According to students, disabled people do sports mainly for rehabilitation purposes (51.1%). According to the disabled students' group, however, sport for disabled people means satisfaction and higher self-esteem (36.36%). When it comes to the best source of information on the subject, television proved to be the best one among the media. The able-bodied students rated their knowledge of disabled sports as satisfactory (66.7%), while only 6% of disabled students considered the knowledge of able bodied people about disabled sports to be satisfactory. CONCLUSIONS: 1. The knowledge about disabled sports among students of physical education is superficial. The disabled also do not possess an extensive knowledge about disabled sports. 2. Opinion on the importance of sport in the lives of disabled people differ between the research groups. Able-bodied people see the role of sport mainly as a rehabilitation tool; disabled people, however, see it as an activity giving satisfaction and raising their self-esteem. PMID- 25518098 TI - [Different living environments as a factor differentiating cognitive function and activities of daily living in patients over 50 years of age ]. AB - INTRODUCTION: The aim of the dissertation was to com- pare the psychophysical state of people over 50 years of age from different societies. MATERIAL AND METHODS: The first group consisted of 30 care home residents, the second group consisted of 30 participants of Active Senior Fair. In the research, two scales were applied: Mini-Mental State Examination, measuring the mental state, and Instrumental Activity of Daily Living, measuring agility in the field of complex everyday tasks. CONCLUSIONA: The study indicates the difference in the psychophysical state of both researched groups. The results may be connected with both age difference between groups and different living environment. PMID- 25518099 TI - [Physical activity of fitness world club members in Szczecin ]. AB - INTRODUCTION: This article presents the results of research based on the feelings and responses of members of a sports club, in relation to a fitness programme offered by Fitness World. MATERIAL AND METHODS: The study consisted of a group of 58 participants chosen at random. Statistically, the analysed results of the research show that the biggest group attending Fitness World consists of men between 31 and 50 years of age with higher education, and women between 18 and 30 with, mostly, higher education. In general, men prefer to participate in aerobics group sessions and gym sessions, and women choose to take part in any activities. CONCLUSION: The most preferred time was between 5 p.m. and 10 p.m., usually after work, and with a frequency of twice a week. It was not possible to determine the main reasons for motivation, although 93% prefer to practise regularly. PMID- 25518100 TI - The normal range and the decision interval. AB - The concept of the decision interval which replaces the normal range in medical decision-making in the contemporary setting of evidence- and procedure-based medicine is presented. The definition and some properties of the decision interval are discussed. PMID- 25518101 TI - [Attitudes towards physical disability in the Middle Ages]. AB - The article describes attitudes to disability and physically disabled people, taking into account the aspect of ethical and social location, what physically disabled meant in societies, and ways to solve the problems of disability. The article is based on studies of disability and historical sources. Christ's attitude shown in the Gospels changed the traditional cultures of the ancient treatment of disability in terms of it being seen as a penalty of the divine. The development of Christianity caused a gradual expansion of the ideas of charity, at the same time stepping up care and material support to all those physically disabled in need. Care of the disabled is based mostly on charity. Church activities supported, by the structure of the State and private individuals, was of paramount importance. Medieval society felt responsible for disabled people. PMID- 25518102 TI - Antoni Christian Bryk (1820-1881) - professor of forensic medicine at Jagiellonian University (1852-1860), and director of the surgical clinic of Jagiellonian University in Cracow (1860-1881). AB - scientific discipline. In the 19th century two milestones revolutionised surgery: the development of narcosis, which enabled painless surgery, and the introduction of antisepsis and asepsis. The author presents the beginnings of academic surgery in Cracow. Its pioneer surgeons are presented. Extensive research was undertaken to collect the literature and documents in Polish, Austrian and German archives and libraries in order to prepare this study. Biographical details of the director of the Surgical Clinic, Prof. Antoni Bryk, are provided. He was the first person in Poland to introduce antisepsis and galvanocautery as routine procedures in the Cracow Clinic. The introduction of antisepsis contributed to a reduction in infection during surgery, and a reduction in postoperative mortality in Cracow Surgical Clinic. In this way Professor Bryk became the first Polish surgeon to apply Lister's antiseptic method in the treatment of wounds. Thus enlarged, the scope of surgery for intracranial, bone and other procedures became routine. Surgery is the oldest discipline in medicine. Poland's first university chair of surgery was established in the 18th century. Surgery, which until then had been the domain of barbers and bath house attendants, became a clinical, PMID- 25518103 TI - History of education in medicine and surgery, first hospitals development of urology in danzig/Gdansk. AB - The aim of the study is to present the development of hospital services and the teaching of medicine, and the development of urology in Danzig (Gdanisk). Well known Danzig surgeons who were interested in surgery of the genitourinary system are also presented. The beginning of urological surgery and its development within the framework of the department of surgery and as an independent facility at the Medical Academy of Gdafisk in the post-war period is also described. Extensive research was undertaken for the collection of literature and documents in German and Polish archives and libraries in order to prepare this study. The history of hospitals in Danzig goes back to the arrival of the Teutonic Knights in 1308. The earliest institution, according to historical sources, was the Hospital of the Holy Spirit, built in the years 1310-1311. It was run by the Hospitalet Order until 1382, and was intended for the sick, elderly and disabled people, orphans and needy pilgrim, and the poor. Later centuries saw the further development of hospital services in Danzig. In the 19th century, the city's increas ing population, the development of the sciences, and rapid advances in medicine subsequently led to the establishment of three more hospitals in Gdafisk: The Hospital for Obstetrics and Gynaecological Disease (1819), the Holy Virgin Hospital (1852), and the Evangelical Hospital of Deaconess Sisters (1857), in addition to the old Municipal Hospital. In 1911, new modern buildings of Municipal Hospital in Danzig were finished. On the basis of the Municipal Hospi- tal, the Academy of Practical Medicine was established in 1935. It was known under the name Staatliche Akademie fiir Praktische Medizin in the Free City of Danzig. Five years later (in 1940) the Academy was developed and changed to the Medical Academy of Danzig (Medizinische Akad- emie Danzig - MAD). The beginning of medical teaching at the middle level in Danzig (Gdafsk) dates back to the 16th century. It had its origins in the Chair of Anatomy and Medicine at Danzig Academic Gymnasium (GA; Sive Illustre), an establishment which lasted for 239 years, from 1584 to 1812. The history of surgery in Danzig has its roots in the centuries-old tradition of the medical practice of surgeons who were associated in the Surgeons Guild, teaching, as well medical and scientific research. The Surgeons Guild existed in Danzig from 1454 to 1820. Over the centuries manual intervention was also in the hands of academically uneducated persons such as bath house attendants, barbers, and wandering surgeons. Until the end of 1946 there was no separate urology department in Danzig. Urological surgery was in the hands of surgeons. Interventions and operations on genitourinary organs were carried out, more or less, in all surgical departments. The end of World War II created a new political situation in Europe. Danzig (now Gdafisk) and Pomerania became part of Poland. In 1945, on the basis of the former MAD, the Polish Government established the Polish Academy of Physicians, later renamed the Medical Academy in Gdafisk (Gdafiska Akademia Medyczna - GAM). In 2009, GAM was again renamed, as the Medical University of Gdafisk (Gdaiski Uniwersytet Medyczny). The political changes after World War II accelerated the process of the separation of urology from surgery. In May 1947, a 30-bed Urological Ward was opened in Gdanisk, in Debinki Street, forming part of the First Surgical Clinic of the Academy of Physicians (headed by Prof. Kornel Michejda, 1887-1960, later by Prof. Stanislaw Nowicki, 1893-1972, and lastly by Prof. Zdzislaw Kieturakis, 1904-1971). The first head doctor of the new urological ward was Dr. Tadeusz L$renz (1906-1986), a urologist from Lvov (Lemberg). After the departure of Professor Lorenz to Wrodclaw (Breslau) in 1958, Dr. Jan Renkielski was acting as Head of the Urological Ward until 1971. In 1971 the ward was transformed to the separate Department of Urology. Docent ("lecturer"), and later Professor, Kazimierz Adamkiewicz from Zabrze (Hindenburg) became its Head. Professor Adamkiewicz organized and equipped the Department, leading it quickly to the level of modern departments in the areas of research, teaching, and therapy. During Professor Adamkiewicz's ill- ness, and after his retirement in 1988, Docent Kazimierz Krajka, Later Professor) headed the urological department until his retirement in 2012. Since 1 October 2012, Associate Professor (Docent) Marcin Matuszewski (*1965) has been the head of the Department of Urology in Gdanisk. PMID- 25518104 TI - [Corruption risks in relations between doctor and patient ]. AB - The article describes the problem of corruption occurring in the relationship between doctor and patient. The doctor-patient relationship, including the provision of health services, is one of several potential areas of corruption in the health care system. Among the reasons for the existence of corruption in these relationships are the need to obtain better healthcare for the patient, and higher earnings in the case of a doctor. Indications of corruption are utilitarian (action for personal advantage without ethical aspects), but may also be (actually or in the patient's opinion) the only way to obtain services and save health and even life. Corruption between the doctor and the patient can be limited by better organization of the health care system, including the financing of benefits and education of medical personnel and patients, as well as traditional legal measures, such as prevention or the application of criminal sanctions. PMID- 25518105 TI - [Effect of electroacupuncture intervention on neurological function, cerebral blood flow and cerebral cytochrome P 450 2 C 11 mRNA expression in rats with focal cerebral ischemia]. AB - OBJECTIVE: To observe the effect of electroacupuncture(EA) intervention on changes of neurological function and expression of cerebral cytochrome P 450 2 C 11 (CYP 2 0 11) mRNA in focal cerebral ischemia (FCI) rats, so as to explore its mechanism underlying improvement of ischemic cerebral vascular disease. METHODS: Wistar rats were randomly divided into normal, model, EA and EA+ 17-ODYA (17 Octadecynoic acid, an inhibitor for the metabolism of arachidonic acid by cytochrome P 450) groups. Focal cerebral ischemia rats were induced by middle cerebral artery occlusion (MCAO) with thread embolus. EA was applied to bilateral "Neiguan"(PC 6 ) and "Quchi" (LI 11) after MCAO. Zea Longa's score and beam walking test (BWT) score of rats were used to evaluate the neurological impairment. Local cerebral blood flow (LCBF) of the pial tissue was moni- tored using Laser-Doppler Flowmetry. The expression of cerebral CYP 2 C 11 mRNA was examined by Real-time Quantitative PCR (qPCR). RESULTS: In comparison with the normal group, BWT score and LCBF of the model group were significantly decreased (P<0.05), and Zea Longa's score and cerebral CYP 2 C 11 mRNA expression level of the model group were significantly increased (P<0.05). While in comparison with the model group, BWT score, LCBF and cerebral CYP2 C 11 mRNA levels were considerably up-regulated and Zea Longa's score was down-regulated in the EA group (P<0.05) rather than in the EA + 17- ODYA group (P<0.05). H.E. stainshowed that the nerve impairment of the ischemic cerebral tissue including the neuronal degeneration, necrosis, apoptosis, etc. was relatively milder in the EA group. CONCLUSION: EA intervention can improve cerebral blood flow and up-regulate cerebral CYP 2 C 11 mRNA expression in FCI rats, which may contribute to its action in improving neu- rological impairment. PMID- 25518106 TI - [Effect of moxibustion intervention on expression of gastric epidermal growth factor receptor and extracellular signal regulated kinase 1/2 expression in rats with gastric ulcer]. AB - OBJECTIVE: To observe the effect of moxibustion on epidermal growth factor receptor (EGFR) and phosphorylated extracellular signal regulated kinase 1/2(p ERK1/2) protein expression in gastric ulcer (GU) rats so as to reveal its mechanisms underlying improving GU. METHODS: Fifty SD rats were randomly allocated to control,model, medication ("Sijunzi" Decoction), non-acupoint moxibustion (non-acup-moxi), and acup-moxi groups (n=10 in each group). The GU model was established by intragastric perfusion of absolute alcohol. Rats of the control group were treated by gavage of distilled water. Rats of the medication group were treated by administration of "Sijunzi" Decoction (8 mL x kg(-1) d( 1)),twice a day for 8 days. Moxibustion intervention was applied to bilateral "Zusanli" (ST 36),"Zhongwan" (CV 12),and "Pishu" (BL 20), "Weishu" (BL 21) alternatively for 30 min, once daily for 8 days. The animals' ulcer index (UI) was assessed by Guth's method, and gastric mucosal pathological changes were observed under light microscope following H. E. staining. The expression of gastric EGFR was detected by immunohistochemistry and that of phosphorylated ERK1/2 (p-ERK1/2) protein determined by Western blot. RESULTS: Compared with the control group, the UI, gastric EGFR and p-ERK1/2 protein expression levels were significantly increased in the model group(P<0.01, P<0.05); whereas in comparison with the model group, the UI was notably decreased in the medication, non-acup moxi and acup-moxi groups (P<0.05, P<0.01), and EGFR and p-ERK1/2 protein expression levels were further up-regulated in the three treatment groups (P<0.01). The effects of both medication and acup-moxi groups were obviously superior to those of the non-acup-moxi group (P<0.01, P<0.05). No significant differences were found between the medication and acup-moxi groups in the expression levels of EGFR and p-ERK1/2 proteins (P>0.05). Results of H.E. staining showed that alcohol-induced gastric mucosal injury as breakage, exfoliation, inflammatory cell infiltration, etc. was milder in both medication and acup-moxi groups following the treatment. CONCLUSION: Acupoint-moxibustion has a role in relieving alcohol induced gastric mucosal injury in the rat, which may be closely associated with its effects in up-regulating activities of the EGFR/ERK signal transduction pathway. PMID- 25518107 TI - [Effect of acupoint-catgut-embedding intervention on type II diabetic rats]. AB - OBJECTIVE: To observe the effect of acupoint-catgut-embedding therapy on blood lipid and insulin levels in type I diabetes mellitus rats;s as to reveal its mechanism underlying improvement of pancreatic functions. METHODS: Thirty SD rats were divided into normal, model and treatment group. The type I diabetes model was established by feeding the rats with high-fat diet and intraperitodneal injection of streptozotocin (STZ). Catgut-embedment was performed in acupoint "Zhongwan" (CV 12)-"Xiawan" (CV 10), "Yishu"-"Ganshu" (BL 18), etc., once every 20 days, twice altogether. Fasting blood glucose (FBG) content was assayed by glucose oxidase method; glycosylated hemoglobin A 1 c (HbA 1 c) assayed by ELISA, and serum fasting C-peptide(FC-p) deterriined by chemiluminescence method; and the triglyceride (TG), total cholesterol (TC), and serum insulin (INS) levels were detected by enzymatic method, separately. The rat's pancreas tissues were fixed with 4% paraformaldehyde and cut into sections (4 Im in thickness) and stained with H. E. method. RESULTS: After modeling, the levels of FBG, HbA 1 c, INS and FC-p, TG, TC were significantly increased in the model group in comparison with those of the normal group (P<0.05), while INS sensitive. index was apparently decreased in the model group (P<0.05). Following catgut-embedding treatment, changes of the above-mentioned indexes were all remarkably reversed (P<0.05), and H.E. staining showed an improvement of the injured pancreatic tissue and islet cells. CONCLUSION: Catgut-embedding therapy can reduce fasting blood glucose and insulin resistance, and improve lipid metabolism in type I diabetic rats, which may contribute to its effect in protecting pancreatic islet cells. PMID- 25518108 TI - [Effect of manual acupuncture stimulation of "Baihui" (GV 20) and "Dazhui" (GV 14) on contents of 5-HT, dopamine and ACh and expression of 5-HT mRNA, DA mRNA and AChE mRNA in the hippocampus in methamphetamine addiction rats]. AB - OBJECTIVE: To observe the effect of manual acupuncture stimulation on changes of hippocampal monoamine neurotransmitter levels and expression of 5 hydorxytryptamine (5-HT) mRNA, dopamine (DA) mRNA and acetylcholine esterase (AChE) mRNA in methamphetamine addiction rats, so as to explore its mechanism underlying improvement of drug addiction. METHODS: SD rats were randomly divided into normal control, model and manual acupuncture groups (n=10 in each group). Drug addiction model was established by i.p. of methamphetamine (5 mg/kg), once a day for 15 days. Manual acupuncture stimu- lation was applied to "Baihui" (GV 20) and "Dazhui" (GV 14) once daily for 10 days. The contents of hippocampal 5-HT, DA, acetylcholine (ACh), AChE were measured by ELISA. The expressive Ilieels of hippocampal 5-HT mRNA, DA mRNA and AChE mRNA were determined by fluorescence quantitative RT-POR. RESULTS: In comparison with the normal control group, the con- tents of 5-HT, DA, ACh and AChE and the expression levels of 5-HT mRNA, DA mRNA and AChE mRNA were significantly increased in the model group (P<0.01, P<0.05). After acupuncture intervention, the levels of the above-mentioned 7 indexes were uniformly and significantly down-regulated in the manual acupuncture group (P<0.01, P<0.05). CONCLUSION: Manual acupuncture stimulation of GV 20 and GV 14 can adjust methamphetamine addiction-induced changes of some hippocampal monoa- mine neurotransmitters and expression levels of 5-HT, DA and AChE genes. PMID- 25518109 TI - [Effects of electroacupuncture intervention on expression of pulmonary metalloproteinase-9 and tissue inhibitor-1 proteins in rats with chronic obstructive pulmonary disease]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation on the expression of metalloprotei- nase-9 (MMP-9) and tissue inhibitor-1 (TIMP-1) in the lung tissue in rats with chronic obstructive pulmonary disease (COPD), so as to reveal its mechanisms in protecting the lung tissue. METHODS: Forty male SD rats were equally randomized into control, model, medication and EA groups. The COPD model was established by smoke-fumigation method (passive smoking in a closed box) and endotracheal injection of lipopolysaccharide (200 microg/100 microL) for 30 days. Rats of the medication group were treated by i.p. of dexamethasone acetate injection (2.0 mg/kg), once daily for 22 days. EA was applied to LU 9, ST 36, ST 40 and KI 3 for 20 min, once daily for 22 days. Pathological changes of the pulmonary tissue were observed under optical microscope after hematoxylin and eosin (H.E.) staining. The expression of pulmonary MMP-9 and TIMP-1 was assayed by immunohistochemistry. RESULTS: H.E. staining showed pulmonary diffuse edema, severe inflammatory cell infiltration, and increase of the numbers of goblet cells, proliferation of fibroblasts, etc. in the model group which were relatively milder in the medication and EA groups. The expression levels of pulmonary MMP-9 and TIMP-1 proteins were significantly higher in the model group than in the control group (P<0.05), and were considerably down-regulated in both EA and medication groups in comparison with the model group (P<0.05). There were no significant differences between the EA and medication groups in MMP-9 and TIMP-1 expression levels (P>0.05). CONCLUSION: EA can effectively suppress the increased expression of pulmonary MMP-9 and TIMP 1 in COPD rats, which may contribute to its effect in improving COPD-induced pathological changes. PMID- 25518110 TI - [Effect of electroacupuncture and moxibustion preconditioning on blood endothelin and creatine kinase contents and myocardial HSP 70 expression in rabbits with myocardial ischemia-reperfusion injury]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) and moxibustion (Moxi) preconditioning of bi- lateral "Neiguan" (PC 6) on plasma endothelin (ET) and serum creatine kinase (CK) contents and myocardial hot shock protein 70 (HSP 70) expression in myocardial ischemia-reperfusion injury (MIRI) rabbits, so as to revel their mechanisms underlying prevention of myocardial ischemia. METHODS: A total of 72 New Zealand rabbits were randomly divided into sham operation, MIRI model, EA preconditioning and Moxi preconditioning groups (n = 18/group). Each group was further divided into 0 h, 24 h and 48 h (time-point) subgroups (n=6 in each subgroup). The MIRI model was established by occlusion of the anterior descending branch of the left coronary artery for 40 min and reperfusion for 60 min. The contents of plasma ET and serum CK were detected by ELISA, and myocardial HSP 70 expression was detected by immunohistochemistry. EA and Moxi preconditioning were respectively applied to bilateral PC 6 for 20 min, once daily for 5 days. RESULTS: Following MIRI, contents of plasma ET and serum CK contents were significantly increased at 0 h, 24 h and 48 h in comparison with the sham group (P<0.01, P<0.05), while myo- cardial HSP 70 expression at the 3 time-points was moderately increased (P>0.05). Compared with the model groups, plasma ET contents at both 24 h and 48 h in the EA preconditioning group and at 48 h in the Moxi preconditioning group, CK contents at both 24 h and 48 h only in the EA preconditioning group were significantly down-regulated (P<0.01, P<0.05). Myocardial HSP 70 expression levels in the EA and Moxi preconditioning groups were considerably up-regulated at the three time-points in comparison with the model group(P<0.05, P<0.01). CONCLUSION: Acupuncture and moxibustion pretreatment may suppress MIRI-induced increase of plasma ET and serum CK and up-regulate myocardial HSP 70 protein expression in MIRI rabbits, suggesting a preventive protection action on ischemic myocardium. PMID- 25518111 TI - [Distribution of calcitonin gene related peptide positive neurofibers in local skin tissues of "Neiting"(ST 44), "Zusanli" (ST 36) and "Futu" (ST 32) regions in the rat]. AB - OBJECTIVE: To observe the distribution of calcitonin gene related peptide (CGRP) positive neurofibers in local tissues of "Neiting"(ST 44), "Zusanli" (ST 36) and "Futu" (ST 32) regions in the hind limbs of rats. METHODS: Five adult male SD rats were used in the present study. The local skin tissues of acupoint "Neiting" (ST 44), "Zusanli" (ST 36) and "Futu" (ST 32) regions were dissected from the rat that underwent transcardiac perfusion with 4% paraformaldehyde, and cut into sections (20 microm in thickness), followed by staining with CGRP fluorescent immunohistochemical method and with phalloidin and DAPI, respectively. After that, CGRP-positive neurofibers of the samples were observed and recorded using a laser confocal microscope. RESULTS: CGRP-positive nerve fibers were found to distribute in the dermis and subcutaneous layers of local tissues of acupoint ST 44, ST 36 and ST 32, mainly concentrating around the vessel-like structure. The number and length of CGRP-positive nerve fibers were most in the ST 44 region, more in the ST 36 region and fewer in the ST 32 region, in turn (P<0.01). The distribution of the vessel-like structure also presented a decreasing trend in the above-mentioned three acupoint regions in turn. CONCLUSION: CGRP-positive neurofibers are an important element in the local tissues of acupoint ST 44, ST 36 and ST 32 regions, and present a decreasing tendency in the number from the distal to the proximal part of the hind-limb, showing a similar PMID- 25518112 TI - [Effect of electroacupuncture intervention on spinal AMPA-receptor expression in rats with neuropathic pain]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) intervention on changes of spinal a-amino-3- ydroxy-5-methylisoxazole-4-propionate acid (AMPA) receptor (GluR 1) expression in rats with chronic constrictive injury (CCI) pain, so as to explore its mechanisms underlying improvement of neuropathic pain. METHODS: Sixty male SD rats were randomly divided into sham-operation, CCI model and EA groups (n=20). Neuropathic pain model was established by ligature of the right sciatic nerve. EA stimulation (2 Hz, 1-3 mA) was applied to "Weizhong" (BL 40) and "Huantiao" (GB 30) on the injured limb for 30 min, once a day for 7 days beginning from the 11th day on after CCI. The mechanical and thermal pain thresholds were measured before and after the CCI procedure (baseline) and after EA intervention. The AMPA receptor subunit GluR 1 protein and gene expression in L5-L 6 segments of the spinal cord was detected using Western blot (WB), immunohistochemistry and re- verse transcription (RT)-polymerase chain reaction (PCR), separately. RESULTS: As the results of mechanical and thermal pain thresholds in our past study, EA intervention could markedly raise CCl-reduced decreased pain threshold. Compared with the sham-operation group, the expression levels of spinal GluR 1 protein and mRNA in the model group were significantly increased (P<0.05, P<0.01). Following EA intervention, the expression levels of GluR 1 protein and mRNA were remarkably down-regulated in the EA group in comparison with those of the model group (all P<005). CONCLUSION: EA intervention can down-regulate CCI-induced increase of AMPA receptor GIuR 1 expression in the lumbar spinal cord in CCI rats, which may contribute to its effect in alleviating neuropathic pain. PMID- 25518113 TI - [Effect of manual acupuncture stimulation of "Baihui" (GV 20), etc. on serum IFN gamma and IL-4 contents in rats with chronic fatigue syndrome]. AB - OBJECTIVE: To observe the effect of manual acupuncture stimulation of "Baihui" (GV 20), etc. on serum IFN- gamma and IL-4 contents in rats with chronic fatigue syndrome (CFS). METHODS: A total of 24 male SD rats were equally randomized into control group, model group and acupuncture group. CFS model was established by bounding and forced swimming in cold water once daily for 14 days. Rats in the acupuncture group were treated by manual acupuncture stimulation of bilateral "Zusanli" (ST 36), "Baihui" (GV 20), and "Guanyuan" (CV 4), once daily for 14 days. Serum IFN-gamma and IL-4 contents were detected by ELISA. RESULTS: Compared with the control group, the contention of serum IFN-gamma and ratio of IFN gamma/IL-4 were significant decreased in the model group (P<0.01). While in comparison with the model group, the contention of IFN-gamma and ratio of IFN gamma/IL-4 were obviously increased in the acupuncture group (P<0.05). No significant differences were found among the three groups in serum IL-4 levels (P>0.05). CONCLUSION: Manual acupuncture can inhibit CFS induced reduction of serum IFN-gamma level and the ratio of IFN-gamma/IL-4 in CFS rats, suggesting a favorable adjustment of acupuncture intervention for CFS by balancing the ratio of IFN-gamma/IL-4. PMID- 25518114 TI - [Colorectal nociceptive signal input facilitates impact of acupoint stimulation of "Zusanli" (ST 36) on electrical activities of wide dynamic range neurons in lumbar spinal cord in rats]. AB - OBJECTIVE: To observe changes of electrical activities of wide dynamic neurons (WDR) in the lumbar spinal cord after electroacupuncture (EA) stimulation of "Zusanli" (ST 36) during colorectal distension in rats, so as to analyze alternations of acupoint's functions under pathological conditions. METHODS: Experiments were performed in male Sprague-Dawley rats. Visceral nociceptive information input was generated by colorectal distension (CRD). Extracellular discharges of WDR neu- rons in the dorsal horns of L(1-3) spinal cord were recorded using glass micropipettes and a microelectrode amplifier. EA stimulation (15 Hz, 1, 4, 7, 10 mA) was applied to ipsilateral "Zusanli" (ST 36) area. RESULTS: A total of 40 neurons were recorded in the present study. Under no CRD conditions, the firing rates of WDR neurons were significantly increased by (18.12 +/- 13.56)% (1 mA), (152.38 +/- 36.19)% (4 mA), (231.21 +/- 49.74)% (7 mA) and (331.54 +/- 61.89)% (10 mA) respectively after EA sti- mulation of ST 36. Under CRD conditions, the firing rates of these WDR neurons were increased by (226.78 +/- 39.59)% (1 mA), (282.80 +/- 47.54)% (4 mA), (343.06 +/- 58.35)% (7 mA), and (338.62 +/- 80.04)% (10 mA) respectively after EA stimulation. It showed a considerablely increased sensitivity of electrical activities of WDR neurons to EA stimulation during CRD nociceptive stimulation. CONCLUSION: colorectal distension (visceral nociceptive stimulation) can strengthen the sensitivity of acupoint-EA stimulation-induced increase of firing rates of WDR neurons in the dorsal horns of the lumbar spinal cord in rats, suggesting a potentiation of the acupoint action under visceral nociceptive signal inputs. PMID- 25518115 TI - [Effect of electroacupuncture intervention on renal function and expression of renal beta-catenin in rats with chronic renal failure]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) intervention on renal function and expression of renal beta-catenin in rats with chronic renal failure (CRF), so as to reveal its mechanism underlying improvement of CRF. METHODS: Male SD rats were randomly divided into normal, model and EA groups, with 10 rats in each group. CRF model was induced by feeding the rats with 0.5% Adenine(100 mg/d, in forage) for 21 days. EA (1-3 mA, 1.5-2 Hz) was applied to bilateral "San yinjiao" (SP 6), "Taixi" (KI 3) and "Shenshu" (BL 23) for 20 min, once daily for 30 days. Serum creatinine (Scr) and blood urine nitrogen (BUN) contents were assayed by enzymatic method and deoxy enzymatic method, respectively, and the expression of p-catenin protein in the renal tissue was determined by Western blot. RESULTS: Following modeling, serum Scr and BUN contents and renal p-catenin protein expression level were significantly increased in the model group in comparison with those of the normal group (P<0.05). After EA intervention, serum Scr and BUN contents and the expression of beta-catenin in the renal tissue were all significantly decreased in the EA group compared to the model group (P<0.05). In addition, the animals' body weight values of both model and EA groups were apparently lower than those of the normal group before EA treatment (P<0.05). After EA intervention, the body weight values of the EA group were markedly higher than those of the model group in spite of being still lower than normal rats (P<0.05). CONCLUSION: EA can effectively suppress CRF-induced increase of serum Scr and BUN contents and renal beta-catenin protein expression in CRF rats, suggesting an improvement of the renal function after EA intervention by reducing the expression of beta-catenin in the renal tissue. PMID- 25518116 TI - [Reflection of dysmenorrhea in acupoint sanyinjiao (SP 6) region]. AB - OBJECTIVE: To observe the reflection of dysmenorrhea in acupoint Sanyinjiao (SP 6) region (body surface) so as to verify the relationship between the acupoint and uterus. METHODS: A total of 60 women (15-35 years in age) including 30 primary dysmenorrhea patients (test group) and 30 healthy subjects (control group) were enrolled in the present study. The visual analog scale (VAS) score and mechanical pain threshold of bilateral Sanyinjiao (SP 6) regions were detected to assess changes of skin sensitivity in subjects undergoing menstrual pain and in the non-menstrual period. RESULTS: The VAS value in the menstrual period of test group was significantly higher than that in the non-menstrual period of the same one group and that in the menstrual period of the control group (P<0.01), and the pain threshold in the menstrual period of test group was significantly lower than that in the non-menstrual period of same one group and that in the menstrual period of the control group (P<0.01). No significant differences of both VAS value and pain threshold were found between the two groups in the non-menstrual period (P>0.05). CONCLUSION: An obvious tenderness at Sanyinjiao (SP 6) exists in women undergoing primary dysmenorrhea, sug- gesting a close correlation between Sanyinjiao (SP 6) and uterus. PMID- 25518117 TI - [Observation on therapeutic effects of acupoint injection of metoclopramide for postsurgical gastroparesis syndrome]. AB - OBJECTIVE: To observe the clinical effects of acupoint injection of metoclopramide for postsurgical gastroparesis syndrome (PGS). METHODS: A total of 46 patients with PGS(from abdominal surgery) were randomly divided into control and acupoint injection groups (n=23 in each group). Patients of the acupoint injection group were treated by injection of Metoclopramide (5 mg+ normal saline) into bilateral Zusanli (ST 36) and Weishu (BL 21) alternatively, while patients of the control group treated by injection of 10 mg of Metoclopramide into the deltoid muscle and gluteus maximus muscle alternatively. The treatment of both groups was conducted once daily for 14 days. A 3-point scale of clinical symptoms (abdominal distension, belching, nausea-vomiting, upper-abdominal distending pain, sour regurgitation and gastric burning sensation) was used to evaluate the therapeutic effect. RESULTS: There were no statistical differences between two groups in clinical symptom scores before the treatment (P>0.05). Following treatment, the clinical symptom scores of both groups were significantly decreased in comparison with pre-treatment (P<0.05) and the scores of the acupoint injection group were significantly lower than those of the control group (P<0.05). Of the 23 PGS patients in the control group and acupoint injection group, 0 and 2 were cured, 5 and 10 were significantly improved, 10 and 9 were improved, 8 and 2 failed, with the effective rates being 65.22% and 91.30%, respectively. CONCLUSION: Acupoint injection of Metoclopramide is effective for improving clinical symptoms of PGS patients. PMID- 25518118 TI - [Analysis on Cheng Dan-an's educational thought in his book Chinese acupuncturology]. AB - Mr. CHENG Dan-an, a famous acupuncture master, is the beginner of "Chengjiang Acupuncturological School" in China. This school of thought has a far-reaching impact on current acupunturological education,and its educational thought and teaching features chiefly reflect in CHENG's works. In the present paper, the authors analyze the influence of contemporary historical factors and sum up Mr. CHENG's educational thought on the basis of the written foundation, style and contents of his book Chinese Acupuncturology from four aspects (1) the role of education, (2) the process of education, (3) the teacher's and students' relationship in educational activities,and (4) the compilation of teaching materials about acupuncture and moxibustion. PMID- 25518119 TI - [Our considerations about basic research and clinical translation based on experimental studies on acupuncture-induced blood-pressure reduction]. AB - Basic research is an important component of acupuncture medicine, and is also the driving force for improving clinical practice. Acupuncture therapy has been used to treat hypertension for many years in China, and its underlying mechanism has also been progressively and partially explored, but its therapeutic effect remains controversial. Authors of the present paper summarize the current state of experimental researches on acupuncture treatment of hypertension from the establishment of hypertension model, acupoint selection, stimulation parameters, and related action mechanisms, and simultaneously found a disassocia- tion between the basic research and clinical practice, particularly in the selection of acupoints and stimulation parameters. Therefore, to establish a bridge for better translation from many achievements of experimental studies to clinical application is of great practical significance. The authors hold that the existing problems of clinical practice should be the foothold of basic research, while successful transformation from basic research achievements to clinical practice is our ultimate target. Only in this way, can we incessantly achieve the goal of improving clinical therapeutic effect of acupuncture therapy from the phase of effectiveness verification, and promote the healthy development of acupuncturology. PMID- 25518120 TI - [Development of researches on acupuncture stimulation-induced regulatory effect under pathological state based on resting-state functional magnetic resonance technology]. AB - Using keywords of "acupuncture, fMRI and resting state", authors of the present paper retrieved papers in both Chinese and English from CNKI and PubMed databases without time limitation. A total of 13 articles (11 for acupuncture and 2 for moxibustion) met the standards were subjected to analysis. Of the 13 papers, 6 involve acupuncture analgesia, 2 moxibustion analgesia, 3 mild cognitive impairment, one involves stroke, and the rest one is for depression. Research results of acupuncture analgesia revealed that the analgesic effect is closely related to its regulation on "pain matrix" brain regions and pain-related default mode network. In the studies, a single acupoint is often used, without acupoints combined recipes. Therefore, it is highly recommended that researchers pay more attention to (OD studies on the underlying mechanism of moxibustion, and (improvement of design protocols targeting requirements of acupuncture clinical practice. PMID- 25518121 TI - [Evaluation on quality of large sample clinical trials of acupuncture in foreign countries]. AB - Following retrieving articles about foreign large sample clinical trials of acupuncture (more than 500 cases) from MEDLINE and EMBASE databases (1996-2012) by using keywords of "acupuncture" and "clinical trial", a quality analysis was carried out independently by two researchers. A total of 1373 papers were collected and 37 were considered to meet our preformulated standards in accordance with the principles and methods of evidence-based medicine. Majority of these 37 articles were from some advanced countries including Germany, USA, Japan, Demark, Australia, et al. Their paper quality and research quality are varied including the methodology, standards for diagnosis, inclusive and exclusive criteria, follow-up survey, economic effectiveness, adverse effects, acupoint application and syndrome differentiation of traditional Chinese medicine. Of the 37 papers, 17 are multiple center clinical trials, 18 are one center clinical trials, and 2 are not clear. Our Chinese researchers should pay more attention to foreign well-designed, large example, randomized controlled clinical trials and draw their matured experience and strong points to compensate our weak points and to improve our levels in clinical study on acupuncture treatment of clinical disorders. PMID- 25518123 TI - [Should we tell the truth to patients?]. PMID- 25518122 TI - [On the interrelationship between standardization and intellectual property rights of acu-moxibustion therapy]. AB - Under the condition of knowledge economy, the acu-moxibustion standardization definitely involves intellectual property rights. Then, what is the relationship between the standardization and the intellectual property rights of acu moxibustion? The authors of the present paper hold that it is not only exclusive, but also syncretic. If their relationship cannot be handled properly, their own respective development will be affected adversely. Therefore, a proper handling of the relationship between the two is of great practical significance. The present paper makes a comprehensive analysis about their interaction (mutual promotion and mutual inhibition), similarities (systemic composition, dynamic implementation course, standardization-rated order and ultimate targets) and differences (in properties, working components, secret requirement, effectiveness time limitation, usage cost, etc). PMID- 25518124 TI - [The nurse who is mentioned in the framework of the Cancer Plan will be an advanced practice nurse]. PMID- 25518125 TI - [Quality of life for people living with HIV]. PMID- 25518126 TI - [Precautions with suspected Ebola cases]. PMID- 25518127 TI - [Iatrogenic events associated with primary health care]. PMID- 25518128 TI - [Medications crushed in food, an increased risk of malnutrition]. PMID- 25518129 TI - [New medications for patients with type 2 diabetes]. AB - Type 2 diabetes is characterised by insulin resistance and deficiencywhich explains the multitude of molecules developed for its treatment.The beneficial effects of metformin and sulfamides have been demonstrated. Over the last 10 years, new molecules have appeared: acarbose, repaglinide and incretins. PMID- 25518130 TI - [The nurse's role in the disclosure of a brain tumor]. AB - The announcement of a brain tumour, in particular glioblastoma, is a psychological shock for the patient and their family. A review has been carried out into this subject by a team of nurses sharing their work time between the neurosurgical department and the disclosure process unit. PMID- 25518131 TI - [The diagnosis of functional disability and the nursing relationship]. AB - The announcement of a disability is a huge emotional shock, for the patient as well as for the caregiver. What is the experience of the nurses who witness on a daily basis the patient's suffering? Taking into consideration the psychological impact of an announcement of a disability helps to improve understanding of its consequences on the nursing relationship. PMID- 25518132 TI - [Nurse clinicians, an expertise to value]. PMID- 25518133 TI - [Clinical nursing practice, some elements of clarification in the French context]. AB - In France, certified nurse clinicians have been working in various fields of activity for a number of years. Recent political decisions aim to create the role of nurse clinician specialised in oncology as well as advanced nursing practice. In this context, an explanation of the terminology and the history of this domain is necessary in order to shed light on the ongoing discussion process. PMID- 25518134 TI - [The clinical sector, an experience for more than 30 years]. PMID- 25518135 TI - [Clinical education in nursing]. AB - There are two types of training programmes open to nurses to enable them to become a nurse clinician: certification-based programmes and masters degree. Based on the clinical nursing raisonning, these training courses enable professionals to develop their knowledge in nursing sciences and their expertise, notably in the framework of complex care pathways. PMID- 25518136 TI - [The contribution of nurse clinicians to home nursing practice]. AB - Home nursing care enables the wishes of patients to be met and financial constraints to be taken into consideration. Through a global and transversal approach, the nurse clinician working in freelance practice offers her vision and her expertise in the field of nursing care. She draws on experiential knowledge and best practice recommendations and contributes to the improvement of patients' quality of life, within a multi-disciplinary team. PMID- 25518137 TI - [Nurse clinicians as part of a mobile pain and palliative care team]. AB - A nurse clinician within a mobile pain and palliative care team carries out multiple activities. A philosophical approach and technical and relational skills are required, notably for the carrying out of second line consultations. This specific contribution means the nurse clinician plays an important role within the multidisciplinary team. PMID- 25518138 TI - [The nurse coordinator of home nursing for elderly patients]. AB - Ageing well at home requires the involvement of numerous professionals from the healthcare and social sectors. Optimisingthe coordination of care is essential. In this context, the creation of new functions carried out by nurses offers added value to the support available for elderly people. PMID- 25518139 TI - [A nurse consultation in victimology for minors]. AB - The nurse consultation is an integral part of the treatment of children and adolescents experiencing psychological distress following traumatic events. Specific support is therefore offered to young patients, in particular through the intervention of a clinical nurse specialist. PMID- 25518140 TI - [Health maintenance, relaxation and hypnosis for chronic pain patients]. AB - The treatment of chronic pain patients integrates more and more complementary therapies such as relaxation and hypnosis, implemented by specially trained nurses. These techniques are offered on the basis of nurses' diagnoses carried out in the framework of a clinical approach. PMID- 25518141 TI - [Institutional policy for developing nurses' clinical skills]. AB - The development of clinical skills in nursing can be integrated into the institutional policy of any hospital. Such a project combines training, the optimal use of the skills developed and recognition from the institution. PMID- 25518142 TI - [Bibliography. Nurse clinicians]. PMID- 25518143 TI - [Home telemonitoring, nursing practices to develop]. PMID- 25518144 TI - A message from the Guest Editor. PMID- 25518145 TI - Taking a value network from concept to reality: Canadian Health Leadership Network (a case study). AB - This article describes, in a step-by-step way, how the value network concept has been put to work to increase leadership capacity through the Canadian Health Leadership Network (CHLNet). The three phases in evolving the network are described: startup, value creation, and consolidation phases. This is a case study that underscores the fact that networks are best facilitated rather than administered; that trust and reciprocity are the twin pillars for sustaining any network; and that leadership without ownership can be a driving force behind the success of a value network. PMID- 25518146 TI - Improving the performance of interorganizational networks for preventing chronic disease: identifying and acting on research needs. AB - This article describes the role of interorganizational networks in chronic disease prevention and an action research agenda for promoting understanding and improvement. Through a model of engaged scholarship, leaders with expertise and experience in chronic disease prevention networks helped shape research directions focused on network value, governance, and evolution. The guiding principles for facilitating this research include applying existing knowledge, developing network-appropriate methods and measures, creating structural change, promoting an impact orientation, and fostering cultural change. PMID- 25518147 TI - Implementing comprehensive population-accountable health networks in Quebec. AB - Local health networks were established in 2003 across the province of Quebec as a strategy to make the health system more responsive. This article examines the challenges encountered in the context of this reform and outlines key issues facing network management and governance to achieve the Triple Aim. PMID- 25518148 TI - A network to improve emergency patient care by facilitating practitioners to effectively support practitioners. AB - Networks that integrate academic and clinical activities are developing across Canada. The University of British Columbia, Department of Emergency Medicine, is leading the planning and implementation of a network that integrates clinician researchers and clinical experts with all practitioners in emergency medicine across the province. The intention is to facilitate emergency practitioners supporting emergency practitioners in remote to tertiary care settings to deliver best practices to patients in all BC emergency departments. The structure and objectives of the network demonstrate how focusing directly on patient-centred care across a large dispersed group of caregivers with common needs can effectively improve care delivery. PMID- 25518149 TI - What healthcare leaders can learn from research on dark networks. AB - For 12 years, a research program has been conducted on "dark networks," which are both illegal and covert. One of the major findings is that the structure of the network is conditioned by an existential dilemma-the need to act or exist. The more you do of one, the less you can do of the other. This article examines the findings of that research and applies it to the dilemmas of organizing healthcare networks. PMID- 25518150 TI - Interorganizational networks: fundamental to the Accreditation Canada program. AB - Within the Canadian healthcare system, the term population-accountable health network defines the use of collective resources to optimize the health of a population through integrated interventions. The leadership of these networks has also been identified as a critical factor, highlighting the need for creative management of resources in determining effective, balanced sets of interventions. In this article, using specific principles embedded in the Accreditation Canada program, the benefits of a network approach are highlighted, including knowledge sharing, improving the consistency of practice through standards, and a broader systems-and-population view of healthcare delivery across the continuum of care. The implications for Canadian health leaders to leverage the benefits of interorganizational networks are discussed. PMID- 25518151 TI - How is the "public interest" defined in learning networks? PMID- 25518152 TI - [Human interaction, social cognition, and the superior temporal sulcus]. AB - Human beings are social animals. This ability to live together is ensured by cognitive functions, the neuroanatomical bases of which are starting to be unraveled by MRI-based studies. The regions and network engaged in this process are known as the "social brain ". The core of this network is the superior temporal sulcus (STS), which integrates sensory and emotional inputs. Modeling studies of healthy volunteers have shown the role of the STS.in recognizing others as biological beings, as well as facial and eye-gaze recognition, intentionality and emotions. This cognitive capacity has been described as the "theory of mind ". Pathological models such as autism, in which the main clinical abnormality is altered social abilities and communication, have confirmed the role of the STS in the social brain. Conceptualisation of this empathic capacity has been described as "meta cognition ", which forms the basis of human social organizationand culture. PMID- 25518153 TI - [Functional imaging of pain: from the somatic response to emotions]. AB - Functional brain imaging in subjects experiencing pain (real, observed or imagined) has led to considerable progress in our understanding of the role of the brain andpsyche in pain integration and control, as well as some forms of somatoform pain with no anatomical basis. This research is challenging not only the dichotomy between the soma and psyche, but also the concept of psychosomatic pain. PMID- 25518154 TI - [MRI in patients with dystonias and Tourette syndrome]. AB - Recent developments in magnetic resonance imaging have provided further insights into the pathophysiology of movement disorders including dystonias and Tourette syndrome. Both structural and functional abnormalities have been described in dystonic patients, with a number of genotype-phenotype correlations. Interactions between the cerebello-thalamo-cortical and basal ganglia-cortex networks play a role in the penetrance and expression of dystonia. In Tourette syndrome, motor symptoms and behavioral disorders correlate with structural changes in limbic, motor and associative fronto-striato-parietal circuits of the brain. Both disorders may be related to subtle developmental abnormalities. Compensatory mechanisms may have either a positive or a negative effect (adaptive reactions or faulty activity). PMID- 25518155 TI - [Gonadal toxicity of cancer therapies in children]. AB - Numerous cytotoxic drugs used to treat childhood cancers, as well as pelvic or hypothalamo- pituitary irradiation and gonadal surgery, can affect subsequent hormonal function and fertility. Prevention of these adverse consequences is based primarily on therapeutic de-escalation when possible, and now also on gonad or gamete preservation. These patients and their parents must receive thorough information, taking into account the child's age, the proposed treatments, and the length of follow-up. Teams treating childhood cancers must receive appropriate training, and access to innovative fertility-preserving techniques must be guaranteed at the national level. PMID- 25518156 TI - [Cryopreservation of testicular tissue in children]. AB - The toxicity of cancer therapies can affect all organs and tissues. Some treatments damage spermatogonial stem cells (SSCs), with a risk of infertility. Storage and reimplantation of frozen testicular tissue is a recent approach tofertilitypreservationfor young boys. However, thawed frozen prepubertal testicular tissue must undergo a maturation process to restore sperm production. This process, currently being studied in animal models, can be achieved by in vivo transplantation of SSCs into seminiferous tubules or by testicular grafting, possibly following in vitro maturation. PMID- 25518157 TI - [Ovarian tissue cryopreservation in girls]. AB - Girls who undergo treatment for cancer are at risk of ovarian hormonal dysfunction and subfertility due to the detrimental effects of some chemotherapeutic agents and/or radiotherapy on the gonads. Consequently, fertility-preserving techniques shouldbe discussed before starting gonadotoxic therapy. Ovarian tissue cryopreservation is currently the only option to preserve fertility in prepubertal girls and should be considered if the risk of premature ovarian failure is high. This promising approach involves the storage of a large number of follicles, which may subsequently be transplanted or cultured to obtain mature ovocytes. The results of ovarian tissue cryopreservation in adults are encouraging: at least twenty children have been born after orthotopic autografting of frozen-thawed ovarian cortex. It has been shown twice that transplantedprepubertal ovarian tissue can induce puberty, confirming the functional capacity of frozen-thawed prepubertal ovarian tissue. PMID- 25518158 TI - [Restoring fertility with frozen ovarian tissue; experimental results]. AB - In recent decades, reproductive surgery and medicine have entered a new era of prevention. Oocyte freezing is at the heart of this new era, along with the preservation offemale fertility. Several options are being evaluated, and time will tell which one will prove most suitable for routine use. Currently, only the freezing and transplantation of ovarian tissue seems to have entered clinical practice. Animal studies demonstrated its effectiveness, with pregnancies and births in several species. These studies showed that both slow and rapid freezing (vitrification) allows the survival of more than 80 % of primordial follicles after thawing. Similar results have since been obtained in humans. Freezing allows satisfactory follicular survival Reimplantation of frozen ovarian tissue has helped to restore menstrual cycling and, more importantly, to obtain pregnancies and births, either spontaneously or by IVF This restoration of fertility offers great hopefor female patients having to confront not only their disease but also the prospect of permanent infertility. Related research has led to major advances in biology and reproductive medicine. PMID- 25518159 TI - [Opposition to organ donation in France: marker of a growing social divide?]. AB - Over the past 20 years in France, whereas medical treatments have been advancing, information campaigns on organ donation have multiplied and the Agence de la Biomedecine has been effectively supervising transplant procedures, the donor waiting list has continued to grow. Is this trend linked to a social issue or is it because the law is now unsuitable? The present article examines this question, based on the experience of the President of the Greffe de vie (Graft for Life) Foundation who, for last 7 years, has been trying to increase awareness of organ donation in France. PMID- 25518161 TI - [Conclusion: Learning to live together again]. AB - In the face of increasing individualism, the social links which hold our society together could eventually disintegrate. Specific case studies of the summer 2003 heat wave, as well as mental illnesses, addictions, Alzheimer's disease, prisoners and migrants can offer solutions to help tackle solitude. Voluntary associations can play a key role. PMID- 25518160 TI - [End of life in France]. AB - Two major changes in end-of-life management have occured in recent decades: first, because of the increase in life expectancy and the resulting aging of the population, most deaths now involve old or very old people; second, more than two thirds of deaths occur in a hospital or an institution. Our fellow citizens are afraid of suffering and death. They wish for a peaceful death, as rapid as possible and, in recent surveys, say they favour euthanasia. Yet euthanasia is illegal in France and in most other Western countries (with the exception of the Benelux nations). Palliative care ensures dignity in death, without anxiety of suffering, and is expanding rapidly in France. Leonetti's law of 22 April 2005 ensures the protection of the weakest, who should never be considered unworthy of life, yet is poorly known to the public and even to physicians. It now needs to be applied in practice. PMID- 25518162 TI - [In situ arterial allografting for aortoiliac infection]. AB - From January 2009 to January 2013, we treated 83 patients for aortoiliac infection by resection of all infected material and in situ revascularization with an arterial allograft. Thirteen patients (15.7 %) died during the first month or before discharge. Perioperative mortality was associated with the presence of a visceral fistula: five deaths (27.8%) occurred among the 18 patients with a visceral fistula, and8 (12.3 %) among the 65 without a visceral fistula (p = 0.11). These results confirm those of our previous studies regarding the severity of aortoiliac infection, especially in patients with a visceral fistula, and endorse our in situ allografting strategy. PMID- 25518163 TI - [Abdominal secondary aorto-enteric fistulae complicating aortic graft replacement: postoperative and long-term outcomes in 32 patients]. AB - Management of patients with abdominal secondary aorto-entericfistulae (SAEF) complicating aortic graft replacement is controversial. We retrospectively analyzed the postope- rative and long-term outcomes of all consecutive patients operated on for SAEF betwveen 2002 and2012. All were managed by in situ replacement with a cryopreserved allograft and treatment of the affected digestive tract. Thirty-two patients (median age 65 years) underwent aortic replacement for SAEFa median of 5 years after initial aortic surgery. The fistulae were located in the duodenum (n = 20), small bowel (n = 6), colon (n = 5) or stomach (n = 1). Treatment of the digestive tract included suture (n = 16), resection with anastomosis (n = 12) covered by a defunctioning stoma (n = 1), and Hartmann's procedure (n = 3). Omentoplasty was performed in 18 patients (56 %), and 17 patients (53 %) had afeedingjejunostomy. Eight patients (25 %) died post operatively, 3 with a recurrent aorto-enteric fistula. Fifteen (62.5 %) of the remaining patients developed 27 complications, including 6 patients (19 %) with severe morbidity (Dindo III-IV). The reoperation rate was 21 %. The median hospital stay was 33 days. During follow-up (median 15 months), no further patients had a recurrent aorto-enteric fistula. We conclude that surgery for SAEF is a major procedure associated with high mortality and morbidity. Good long-term results can be obtained by excision of the prosthetic graft with cryopreserved allograft replacement, and by management in a tertialy referral center with expertise in both vascular and digestive surgery. PMID- 25518164 TI - [Aortic reconstruction with graft materials resistant to bacterial infections]. AB - Synthetic graft infection is a rare but extremely serious complication of aortic reconstruction procedures, with morbidity-mortality rates as high as 60 %. Some of the proteins (albumin, gelatin, collagen) used to coat polyester graft materials can establish ionic bonds with antibiotics or can capture antiseptics such as triclosan or ionic silver in their matrices. These active substances are then released from the graft, at varying rates, during the coating degradation that takes place during the weeks following polyester graft implantation in living tissues. Rifampin-bonded prostheses have proved effective against S. aureus and S. epidermidis in several canine models of synthetic aortic graft infection. Rifampin-bonded grafts have also been used successfully in patients with synthetic aortic graft infection by low-virulence bacteria. However, their effectiveness may be limited by the diverse and changing ecology of synthetic aortic graft infections, with an increasing prevalence of multidrug-resistant bacteria and polymicrobial infections. These include species that are naturally, or are likely to become, resistant to rifampin. We evaluated silver-ion-bonded prostheses in this setting but observed a disappointingly high mid-term rate of recurrent infections. Over the past few years we have been involved in the development of polyester vascular prostheses functionalized with a hydroxypropyl beta-cyclodextrin polymeric matrix that can capture and elute several therapeutic agents. The results are promising, as these prostheses enable the sustained release of various antibiotics in amounts several times their minimum inhibitory concentrations. This provides a unique opportunity to functionalize materials for aortic graft reconstruction, based on epidemiological data or individual bacteriological findings. PMID- 25518165 TI - [Role of antivenoms in the treatment of snake envenomation]. AB - The production of antivenoms, which were long deemed ineffective, dangerous and difficult to use, has improved dramatically. These antibodies (immunoglobulin G) are now fragmented, purified and controlled for their quality, leading to significantly better safety and facilitating their emergency use. Envenomation can result in various syndromes depending on the snake species: Viperidae venoms are highly inflammatory, hemorrhagic and necrotising, while Elapidae venoms can cause fatal respiratory paralysis. However, some Viperidae venoms can lead to asphyxiation similar to that observed in Elapidae envenomation while, conversely, Elapidae bites may be complicated by hemorrhage or necrosis, thus complicating etiologic diagnosis. Symptomatic treatment is complex, often insufficient, and frequently associated with adverse events. In contrast, antivenoms neutralize the venom and accelerate its clearance, thus providing an etiological treatment for envenomation, particularly in remote healthcare facilities in developing countries. Current formulations consist of polyvalent antivenoms covering most of the venomous species present in a specific region. The main limitation is their high cost, and the priority should be to develop new treatment strategies, including more affordable antivenoms, especially in developing countries where they are most needed. PMID- 25518167 TI - The 39th anniversary of Phramongkutklao College of Medicine. Foreword. PMID- 25518166 TI - [Prevention of frailty and dependency in older adults]. AB - Aging is associated with the onset of frailty and chronic diseases, leading to physical and cognitive functional decline, reduced autonomy and, eventually, physical dependency. Persons aged 65 years or more should start to be screened in order to detect and prevent frailty, thus allowing the community to anticipate the consequences of aging rather than simply enduring them. According to the Trillard report commissioned by the French President, this could encourage economic growth and save up to 10 billion Euros per year: Fragile and pre-fragile elderly persons are not taken into account by our current healthcare system: it is only once they become truly dependent that they start to receive costly geriatric care Major medical advances could result from early detection of frailty and age-related diseases. In addition, development of specific medical, social and behavioural services could create new jobs and lead to greater economic efficiency. Our healthcare system will have to adapt rapidly to the growth in the elderly population. A pilot study conducted by the Toulouse Gerontopole demonstrates the importance of screening, assessment and intervention for frail and pre-frail populations, who have previously been completely neglected by the French healthcare system. PMID- 25518168 TI - Comparative survival effectiveness between pre-operative and postoperative chemoradiotherapy for locally advanced rectal cancer: a retrospective study in Phramongkutklao Hospital. AB - BACKGROUND: In earlier years, postoperative chemoradiotherapy was a recommended standard treatment for locally advanced rectal cancer Based on several clinical trials, the pre-operative approach was then considered afavorable optimal time to deliver the treatment due to significant improvement in local tumor control. Given that, both pre-operative and postoperative approaches were performed in Phramongkutklao Hospital. OBJECTIVE: This study compared 2-year disease-free survival (DFS) between pre-operative and postoperative chemoradiotherapy in locally advanced rectal cancer. MATERIAL AND METHOD: A retrospective study was conducted in 78patients with clinical stage T3, T4 or node-positive disease who had received either pre-operative or postoperative concurrent chemoradiation that was carried out between 2004 and 2008. The combined multimodality approach consisted of Fluorouracil (5-FU) based chemotherapy and a long course of radiation therapy. After the last session of chemoradiotherapy in the pre operative group, surgery was performed 4-6 weeks later followed by remaining cycles ofchemotherapy whereas the postoperative group began chemoradiotherapy 4-6 weeks after surgery. The primary endpoint was 2-year disease-free survival (DFS). RESULTS: Of the eligible 78 patients, 19 patients (9 pre-operative, 10 postoperative) had recurrence during the first two years after completion ofradiotherapy by which the first event of recurrence was classified as either local recurrence only, distant metastasis only, or both local and distant recurrence. The 2-year DFS between these two groups was not statistically diferent (78.6% pre-operative vs. 72.2% postoperative, p = 0.521), however, the pre-operative, concurrent chemoradiotherapy provided a possible DFS benefit. No statistical difference in overall toxic events between the two treatment groups; however, there is a tendency to develop more toxicity in thepostoperative group. CONCLUSION: No significant statistical difference in 2-year DFS between the pre operative andpostoperative but possible DFS benefit was suggested in pre operative group. PMID- 25518169 TI - Prevalence of injuries in Wushu competition during the 1st Asian Martial Arts Games 2009. AB - OBJECTIVE: To determine the prevalence and characteristic of injuries in Wushu Competition during the IP' Asian MartialArts Games 2009. MATERIAL AND METHOD: Sixty international athletes (38 males) participating in Wushu Competition during the 1st Asian Martial Arts Games 2009. Injuries were recorded on injury report forms to document any injuries seen and treatment provided by tournament physician during competitions. The injury forms described the athlete s causes, type, site, and severity of the injuries. RESULTS: There were 60 international athletes the average age were 22.49 +/- 3.75 years. The prevalence ofinjuries was 228.07/ 1000 athlete exposure (AE). The prevalence in males andfemales was 161.76/1000 AE and 326.09/1000 AE, respectively. The most common injured body parts in males were lower extremities 102.94/1000 AE, followed by head and face injuries 58.82/1000 AE. The most common injured body parts in females were lower extremities 282.61/1000 AE. The most common types of injuries in males were contusions 58.82/1000 AE, concussion 29.41/1000 AE and strain-sprain 29.41/1000 AE. In females the most common type of injury were contusion 195.65/1000 AEfollowed by strain-sprain 130.43/1000 AE. The most common mechanism of injury in males werereceiving a punch 58.82/1000 AE, receiving a kick 44.12/1000 AE and delivering a kick 44.12/1000 AE. Meanwhile, in females common mechanisms were receiving a kick 152.17/1000 AE followed by delivering a kick 130.43/1000 AE. CONCLUSION: High prevalence of injuries in Wushu competition during the 1" Asian MartialArts Games 2009 revealedfemale injuries were higher than male and had a higher prevalence compared with Muay Thai or Taekwondo competitions. PMID- 25518170 TI - Assessment of approximate glenoid size in Thai people. AB - BACKGROUND: The loosening of the glenoid baseplate component is one of the most common complications after reverse total shoulder arthroplasty. The mismatch between size of baseplate and glenoid in Thai People may result in improper baseplate screw fixation and lead to early loosening of the glenoid component. Knowing of the glenoid size will guide the surgeon in placing or choosing the proper size glenoid baseplate to improve screw fixation strength. OBJECTIVE: Study the size ofglenoid in Thai people and compare with previous studies. MATERIAL AND METHOD: The authors measured the glenoid size in anteroposterior and superoinferior directions, the data were recorded in term of mean and standard deviation. The present data were then compared with the previous glenoid studies to identify the differences in size between Thai people and others. RESULTS: Among 160 patients with the mean age of 58.2 +/- 14.2 years, the overall glenoid sizefor the entire study group were 32.3 +/- 3.2 mm and 24.4 +/- 3.2 mm in superoinferior (SI) and anteroposterior (AP) directions, respectively. The male glenoid size were 35.6 +/- 2.6 mm and 26.7 +/- 2.5 mm in SI andAP directions, respectively. The female glenoid SI diameter were 31.0+1.9 mm and in AP diameter were 22.0 +/- 1.7 mm. The glenoid size in Thai people was significantly smaller than the glenoid size from previous studies in Caucasians. CONCLUSION: The overall glenoid size in Thai people was significantly smaller than the previous studies in Caucasians. The female glenoid was also smaller than with the male. These findings alert surgeons to choose the proper glenoid baseplate design to avoid an overhang problem and improve screw fixation, especially in Thaifemale patients. PMID- 25518171 TI - The factors of ketamine that affect sedation in children with oncology procedures: parent satisfaction perspective. AB - BACKGROUND: The pain and its complication during sedation with ketamine remain a significant problem for children with hematologic malignancy. OBJECTIVE: The purpose of the present study was to evaluate further the parental satisfaction for procedural sedation and analgesia during pediatric hematology/oncology procedures perfonned by pediatrician in the Department of Pediatrics, Phramongkutklao Hospital. MATERIAL AND METHOD: The authors prospectively evaluated our experience using intravenous ketamine 1 mg/kg for oncology patients undergoing procedures at Department ofPediatrics, Phramongkutklao Hospital. The procedure was assessed by way ofaphysician-completed form and by evaluation of questionnaires given to parents to estimate levels of pain by using a 0 to 10 mm visual analog scale (VAS) at 2 hours after procedures and results in any adverse events with respect to age, gende, procedures performed, ketamine dosage and recovery time. RESULTS: Total of46 children aged 6 months to 15 years with 46procedures were observed at pediatric unit post-procedure. The indicationsfor procedural sedation and analgesia included lumbar puncture and intrathecal chemotherapy (50%), bone marrow aspiration or biopsy (21.7%), and both plrocedures (28.3%). The median VAS scale during oncology procedures was 3, which were expressed by all the parents/guardians of the children treated. Adverse effects were observed in all children including nausea (30.4%), hypersalivation (26.1%), vomiting (21.7%), hallucinlation (4.2%). No child required admission to hospital and there were no serious complications. CONCLUSION: hntravenous ketamine 1 mg/kg is effective for invasive procedures in children with malignancy. The use of intravenous ketamine may produce psychedelic effects in children. These adverse effects may alter the child's comfort and parental satisfaction especially in the young children. PMID- 25518172 TI - Comparative study of the pullout strength of the 2.4-mm AO locking screw, 2.0-mm AO cortical screw and Herbert screw in sawbones: a biomechanical study. AB - BACKGROUND: Headless screw is a standard implant for an osteochondral fragment fixation. With a threaded design, the screw head can be buried under the articular cartilage to prevent a post-traumatic arthritis. However, the screw is expensive and maybe not available in the emergency situation. The 2.4-mm AO locking screw also has a threaded head which is able to advance underneath the cartilage. This has been usedfor fixation of the osteochondal fracture clinically. We compared the pullout strength of 2.4-mm AO locking screw with those ofHerbert screw and 2.0-mm AO cortical screw. MATERIAL AND METHOD: The studies pemformed by using Instron 4502 to measure the pullout strength in 12 models for each type of the screw. The pullout strength of the 2.4-mm AO locking screw from a corticocancellous bone model was compared with the pullout strength of the Herbert screw from a cancellous bone model and the 2.0-mm AO cortical screw ifom the corticocancellous bone model. The differences in pullout strength between the 2.4-mm AO locking screw and the other two screws were determined by independent t-test. RESULTS: The pullout strength of the 2.4-mm AO locking screw, Herbert screw and 2.0-mm AO cortical screw were 143.49+46.18 N, 72.83 +/- 16.64 N, and 80.38 +/- 1.42 N, respectively. The pullout strength of2.4-mm AO locking screw was signi2ficantly higher than those ofHerbert screw and 2.0-mm AO cortical screw (p<0.001). CONCLUSION: According to the recent biomechanical study, the 2.4 mm AO locking screw in the corticocancellous bone model had pullout strength higher than the Herbert screw in the cancellous bone model and the 2.0-mm AO cortical screw in corticocancellous bone model. The 2.4-mm AO locking screw may use instead of headless screw for intra-articular fixation in a specific situation, such as when the headless screw is unavailable. PMID- 25518173 TI - Comparative study of diagnostic accuracy between office-based closed needle biopsy and open incisional biopsy in patients with musculoskeletal sarcomas. AB - BACKGROUND: The biopsy is a simple but critical step in the diagnosis of the musculoskeletal lesions. Although the open incisional biopsy traditionally has been considered the gold standard with high diagnostic accuracy, an alternative, the closed needle biopsy (CNB), has been developed and widely used as it can be performed at an outpatient clinic under local anesthesia or in combination with the image guidance. In the present study, the authors purpose to study the diagnostic accuracy of CNB without real-time image-guidance at an outpatient clinic by comparing it with open incisional biopsy in musculoskeletal sarcoma patients. MATERIAL AND METHOD: The authors retrospectively reviewed 200 biopsy cases of sarcoma patients since 2002-2011. There were 105 cases of open incisional biopsy 105 cases and 95 cases of CNB. The diagnostic accuracies of both mentioned methods were compared statistically in four aspects of histopathology: nature (benign or malignant), specific diagnosis, histological type and histological grade. The gold standard was afinal pathological diagnosis of the resected specimens receivedfrom definite surgery correlated with clinical findings and imnaging studies. RESULTS: The diagnostic accuracies of open incisional biopsy were 97.14% for nature, 89.52% for specific diagnosis, 89.52% for histological type, 88.57% for histological grade and the diagnostic accuracies of CNB were 96.84%, 89.47%, 88.42%, 86.32%, respectively. There was no significant statistical difference between the two methods in all histological aspects (p-value >0.05). The diagnostic yields of both methods were 98.13% for open incisional biopsy, 97.94% for CNB and there was no significant statistical difference (p-value >0.05). There were 6 cases (3%)for overall major errors, 3 cases (2.86%) firom open incisional biopsy and 3 cases (3.16%) from CNB. There were 18 cases (9%)for minor errors, 9 cases (8.57%) from open incisional biopsy and 9 cases (9.47%) from CNB. There was no biopsy related complication in either method. CONCLUSION: The office-based CNB diagnosis of musculoskeletal sarcoma can achieve an acceptably high diagnostic accuracy rate compared with open incisional biopsy. PMID- 25518174 TI - Effects of curcumin on restoration and improvement of microvasculature characteristic in diabetic rat's choroid of eye. AB - OBJECTIVE: To investigate the effect ofcurcumin on microvasculature changes in STZ-induced diabetic rat' choroid ofeye. MATERIAL AND METHOD: Male rats were divided into three groups: control (C) Diabetic rats were induced by streptozotocin (STZ) (60 mg/kg BW) (DM) diabetic rats treated with curcumin (DMC) (200 mg/kg BW). After 8 weeks of experiments, microvasculature changes of rat's choroid were studied under vascular corrosion cast technique with scanning electron microscope (SEM). RESULTS: There were pathology and destruction of choroid microvasculature of DM group that revealed reduced and shrunken sizes of large and small blood vessels, compared with control group; long posterior ciliary arteries (LPCAs) (C = 113.70 +/- 1.38, DM = 83.53 +/- 2.70, DMC = 109.64 +/- 3.41 microm), choroid arteries (C = 94.97 +/- 2.79, DM = 59.36 +/- 2.61, DMC = 80.31 +/- 3.73 microm), vortex veins (C = 74.11 +/- 3.24, DM = 46.71 +/- 2.56, DMC = 64.66 +/- 3.60 microm), and Choriocapillaris (choroidal capillaries) (C = 13.61 +/- 0.62, DM = 4.46 +/- 0.24, DMC = 9.96 +/- 0.70 microm), respectively. In DM group, LPCAs and Choroid arteries were tortuous and showed shrinkage. Vortex veins became narrow. Choriocapillaris showed the pathological characteristics of vascular lesions including of shrinkage, constriction, microaneurysm and blind ending. Fascinatingly, Choroid microvasculature of the eye in curcumin treated group developed into regenerate and repaired conditions with healthy and normal characteristics. CONCLUSION: Efficiency of curcumin treatment beneficially repaired and regenerated the redevelopment of choroid's microvascular complications of eye in 8-week experiments. Potential treatment with curcumin in diabetes has demonstrated in a meaningful way the therapeutic consequences in the improvement and recovery of choroidal blood vessels in eye pathology ofdiabetic rats. PMID- 25518175 TI - Rotational alignment of femoral component between custom cutting block and conventional technique in total knee arthroplasty. AB - OBJECTIVE: Rotation of femoral components could be optimized to improve function and durability of the knee joint. The purpose of the present study was to assess rotational alignment of femoral component comparing between CT-based, custom cutting blocks and the contemporary total knee arthroplasty, instrument technique. MATERIAL AND METHOD: The prospective control study of 80 patients underwent total knee arthroplasty by using PFC Sigma PS total knee design. Rotation offemoral component was analyzed in all patients using postoperative CT scan. Forty patients were perfonned on by using CT-based, patient-specific cutting blocks with femoral rotational axis relative to transepicondylar axis while forty patients were performed on by using contemporaly instrumentation with alignment at 3 degrees external rotation from posterior condylar line. The rotation of the femoral component with external rotation ofmore than 3 degrees or internal rotation was considered outlier. RESULTS: There was no statistically significant difference among ages, gender; BMI, pre-operative mechanical axis between the two groups. There were eleven outliers in conventional group (range, 5 degrees ofexternal rotation to 3 degrees of internal rotation), three femoral components were in excessive external rotation with the angle of more than 3 degrees and eight femnoral components were in internal rotation. In contrast with custom cutting block group was no outliers offemoral rotation. The average rotational alignment was 1.040 +/- 0.62 external rotation from epicondylar axis in custom cutting group and 1.58 +/- 1.750 in contemporary group. CONCLUSION: Custom cutting, block technique significantly reduced the outlier of the femoral component rotation and aided in positioning of the femoral component in optimal alignment. The improvement of femoral rotation showed no difference in clinical outcome between the two groups. PMID- 25518176 TI - Incidence and risk factors of blastocystis infection in orphans at the Babies' Home, Nonthaburi Province, Thailand. AB - BACKGROUND: Blastocystis infection is one of the most common intestinal protozoan infections reported in Thai population of all age groups for which epidemiological information is important to understand patterns of transmission for developing methods ofprevention and control for each specific group. The authors aimed to study prevalence, incidence and riskfactors associated with Blastocystis infection in orphans and childcare workers. Additionally, subtypes ofBlastocystis were identified MATERIAL AND METHOD: A retrospective cohort study of Blastocystis sp. was conducted in orphans aged less than 5 years and their childcare workers at Babies' Home, Nonthaburi Province, Thailand. A base line survey was conducted in December 2009 and afollow-up survey was conducted in April 2010. A total of 336 and 331 stool samples were collected. Blastocystis infection was examined using short-term in vitro cultivation in Jones's medium supplemented with 10% fetal calf serum. To analyze subtypes ofBlastocystis sp., PCR-RFLP of the small subunit ribosomal RNA gene was performed. RESULTS: Theprevalence ofBlastocystis infection in December 2009 and April 2010 were 8.1% and 13.3%, respectively The inlcidence rate ofBlastocystis infection was 1.6/100 person-months. Subtype analysis ofBlastocystis sp. in December 2009 and in April 2010 showed that subtype 3 was the most predominant (76% and 76%), followed by subtype 1 (16% and 20%), and unidentified subtype (8% and 4%), respectively. Subtype 3 is of human origin, thus person-to-person transmission is considered a major route ofBlastocystis infection in this population. CONCLUSION: Person-to person transmission of Blastocystis infection in orphans living in the same house had been proposed, thus the prevalence and incidence of Blastocystis infection could be used to reflect the hygienic condition in the orphanage. Infection prevention and control practice can be effectively implemented. PMID- 25518177 TI - Oral health survey of the military personnel deployed to the southernmost provinces of Thailand. AB - BACKGROUND: Dental problems are some of the major health problems of deployed miilitaly personnel. There have been no systematically reports of oral health information survey among the deployed military personnel in Thailand. OBJECTIVE: The present study was to determine the oral health problems of the deployed military personnel and effects on personnel fitness. MATERIAL AND METHOD: A cross sectional study and a cluster sampling were conducted during April 2011 and March 2013. The Royal Thai Army (RTA) personnel 12 out of21 task forces in southern most provinces were invited to participate in the study. A standardized questionnaire was used. RESULTS: In total, 2,884 RTA deployed personnel voluntarily participated and completed the questionnaire infonnrmation. Their mean age was 27.8 +/- 9.4 years old. Fifty percent admitted that they had oral problems during the past six months and the most common ones were toothache/hypersensitivity (32.4%), and dental caries (21.5%). The majority of the participants (60.7%) reported that they experienced oral health problems less than 3 times and 2.8% reported sick leave during deployment because of oral conditions. 64.4% reported that their oral problems affected their quality of life and disturbed their duties. CONCLUSION: A relatively high prevalence oforal health problems was reported by the deployed RTA personnel. The problems affected their quality of life and assigned duties. Most ofthe problems were neglected. In order to keep the RTApersonnel fit for deployment, an effective dental health program should be developed. PMID- 25518178 TI - Study of ameliorating effects of ethanolic extract of Centella asiatica on learning and memory deficit in animal models. AB - OBJECTIVE: The present study investigated the effect of Centella asiatica ethanolic extract (CE) on learning and memoly imnpairment induced by either transient bilateral common carotid arteries occlusion (T2 VO) or an intraperitoneal injection of scopolamine in mice. MATERIAL AND METHOD: CE (100, 300, 1000 or 1500 mg/kg, p.o.) were administered to learning and memory impaired mice once daily for 8 consecutive days. Learning and memory performance were evaluated by Morris water maze (MWM) and step-down passive avoidance (PA) test. Changes in malondialdehyde (MDA) levels in the brain were determined by lipid peroxidation assay. RESULTS: T2 VO mice exhibited learning and memory impairment in the MWM and PA tests. Treatment with CE ameliorated the learning and memory impairment of T2VO mice. Furthermore, CE significantly reduced MDA level in the brain of T2VO mice. On the other hand, administration of CE did not attenuate learning and memory impairment induced by scopolamine in mice. CONCLUSION: The present study demonstrated ameliorating effect of CE on learning and memory impairment in T2VO mice. Furthermore, it is likely that the positive effect of CE observed could be, at least partly, accounted by its antioxidative property. Thus, CE might be beneficial for memory impairment in which oxidative stress is an underlying cause. PMID- 25518179 TI - Effects of phenytoin and valproic acid on cognitive functions of Thai epileptic patients: a pilot study. AB - Effects of valproic acid (VPA) and phenytoin (PHT), as monotherapy, on cognitive functions and mood of Thai epileptic patients were investigated. Thai Mental Status Examination (TMSE) and Alcohol Use Disorder Identification Test (AUDIT) were used to screen for eligible subjects. Cognitive performance was assessed by neuropsychological tests including Stroop Color Word Test (SCWT), Wechsler Abbreviated Scale of Intelligence (WASI) test, Profiles of Mood States (POMS) and Adverse Event Profiles (AEP). Thirty epileptic patients, 15 taking PHT and 15 taking VPA, and 15 age and sex matched normal comparators were enrolled. In contrast to the effects of VPA, a statistically significant difference in T-score of WASl similarities and WASI-matrix reasoning subtests was observed between PHT and normal comparator group indicating poorer performance in intellectualfunctioning especially in executive function of the brain in patients taking PHT Vigor is the only mood dimension that demonstrated significant difference between epileptic patients and normal comparators. VPA appears to be more appropriate than PHT when executive brain function is mostly concerned, however, further investigation is needed to gain better insight into the effects of AEDs on cognitive domain of the Thai epileptic patients. PMID- 25518180 TI - Use of a disclosed plaque visualization technique improved the self-performed, tooth brushing ability of primary schoolchildren. AB - BACKGROUND: Disclosing agents have a long history of use as an aid in children's tooth brushing instruction. However, their benefit when used to improve self performed tooth brushing ability without any tooth brushing instruction has not been investigated. OBJECTIVE: To evaluate the effect of disclosed plaque visualization on improving the self-performed, tooth brushing ability of primary school children. MATERIAL AND METHOD: A cluster-randomized, crossover study was conducted in Nakhon Nayok province, Thailand. A total of 122 second-grade schoolchildren, aged 8-10 years old, from 12 schools were randomly divided into 2 groups. The first group was assigned to brush with disclosed plaque visualization, while the other group brushed without disclosed plaque visualization. One month later the groups switched procedures. Tooth brushing ability was evaluated by the subjects' reduction in patient hygiene performance (PHP) scores. The data were analyzed using repeated-measures analysis of variance, with significance set at p<0.05. RESULTS: Disclosed plaque visualization had a significant effect on improving the children's self performed, tooth brushing ability in all areas of the mouth (p<0.001), particularly for anterior teeth, mandibular teeth, buccal surfaces, and areas adjacent to the gingival margin (p<0.001). CONCLUSION: Disclosed plaque visualization is a viable technique to improve children's self-performed tooth brushing ability, and could be used in school-based oral health promotion programs. PMID- 25518181 TI - An outbreak of Paederus dermatitis in Thai military personnel. AB - An outbreak of Paederus dermatitis in Thai military personnel in 2007 was reported. Approximately ninety-one percent ofmilitary personnel who worked in a battalion located in Bangkok experienced Paederus dermatitis in April-May 2007. The most common clinical manifestations were blisters and erythematous rash. The most affected areas were head, neck, back and groin. "Kissing lesions" were seen in 17.3% of cases and 23.5% had multiple lesions. Compared with other reports, we found a high incidence of lesions in unexposed body parts. This disease should be recognized as a differential diagnosis especially in tropical countries. Awareness of the condition and its clinical features will aid early diagnosis and prompt treatment. PMID- 25518182 TI - Size of cervical lymph node and metastasis in squamous cell carcinoma of the oral tongue and floor of mouth. AB - BACKGROUND: Squamous cell carcinoma (SCC) of the oral tongue and floor of mouth are the most common head and neck cancers. Regional metastasis of SCC is most likely found at the cervical lymph node. Size and characteristics of pathologically suspicious lymph nodes are related to the aggressiveness of the primary tumor: The objective of this study is to analyze the conrrelation between sizes of cervical node and metastasis in SCC of oral tongue and floor of mouth. MATERIAL AND METHOD: Retrospective review was conducted firom the patient's charts between January 2008 and December 2012. Clinical, histopathology and surgical records were reviewed. Cervical lymph nodes ofSCC of oral tongue and floor of mouth were reviewed and divided into four groups depending on their size (1-5 mm, 6-9 mm, 10-30 mm and more than 30 am,). A p-value <0.05 was considered statistically significant. RESULTS: 196 patients with SCC of the oral cavity were recorded. Sixteen patients ofSCC of the oral tongue and 15patients of SCC of the floor of mouth underwent neck dissection (641 cervical nodes). Most ofthe patients were diagnosed with stage 3 (41.94%). Extracapsular extension was found in 72.15% of SCC of oral tongue and 73.33 % of SCC ofthe floor of mouth. Size of cervical lymph nodes less than 10 mm was found to be metastasis at 9.27% and 10.82% of SCC of oral tongue and floor of mouth, respectively. CONCLUSION: Cervical node metastasis can be found in SCC of the oral tongue and floor ofmouth with clinlically negative node andsize of cervical node less than 10 mm. Here in, size of cervical node less than 10 mm was still important due to the chance for metastasis especially high grade tumors, advanced stage cancer and lymphovascular invasion. PMID- 25518183 TI - Knowledge of attention deficit hyperactivity disorder and its associated factors among teachers in 3 large primary schools in Phra Nakorn Sri Ayutthaya Province, Thailand. AB - BACKGROUND: Though attention deficit, hyperactivity disorder ADHD is a common problem in childhood. Thai teachers' knowledge regarding the disease has never been assessed. OBJECTIVE: To identify knowledge of Thai teachers regardingADHD and its influencingfactors. MATERIAL AND METHOD: Cross-sectional study was operated in three primary schools in Ayutthaya, Thailand. Standardized questionnaires comprised ofdemographic data, ADHD experiences and the Knowledge of Attention Deficit Disorder Scale, KADDS, were distributed to participating teachers. Results were reported using frequency, percent, mean, and standard deviation. Association between demographic and ADHD experiences and the KADDS score was identified by logistic regression analysis. RESULTS: Lack ofknowledge of ADHD among teachers was apparent. Only 19.4% of them passed the total scale of KADDS. Teachers under 31-years-old were more likely to pass general information and signs, symptoms & diagnosis subscales and total scale. In addition, familiarity with ADHD patients was associated with passing scores of general information subscale and total scale. CONCLUSION: Despite public awareness of ADHD, Thai teachers lacked knowledge concerning the disease. Young teachers were more acquainted with ADHD. Direct experience with ADHD patient might help teachers develop their knowledge on ADHD. PMID- 25518184 TI - 18F-FDG PET/CT findings in endometrial cancer patients: the correlation between SUVmax and clinicopathologic features. AB - OBJECTIVE: To study 18F-FDG PET/CT findings in endometrial cancer patients, to analyze the correlation between the maximum standardized uptake value (SUVmax) and clinicopathologic tumor characteristics. MATERIAL AND METHOD: Retrospective study included 33 endometrial cancer patients who underwent pre-operative 18F-FDG PET/CT and abdominal CT or MRI from June 2005 to October 2009. Pattern of FDG uptake was classified as focal and diffuse uptake. SUVmax was measured at primary tumor in endometrial cavity and correlated with maximum tumor size, menopausal state, histological grade, depth of myometrial invasion and nodal metastasis. The diagnostic performance of 18F-FDG PET/CT was assessed for primary tumor and lymph node metastasis and correlated with those of CT/MRI. RESULTS: Sensitivity of 18F FDG PET/CT in primary tumor detection was slightly higher, without significant difference, than that of either CT or MRI (93.9% vs. 87.9%, p = 0.625). The overall SUVmax mean ofthe primary tumor was 8.24 +/- 5.38. The focal FDG uptake pattern was more common than the diffuse uptake pattern (71.0% and 29.0%, respectively), but the SUVmax was higher in the diffuse uptake pattern (diffuse pattern 12.10 +/- 7.47 vs. focal pattern 6.66 +/- 3.33, p = 0.008). There was significant association between the SUVmax of the primary tumor and maximum tumor size (p = 0.001), but not between the SUVmax of the primary tumor and menopause state, histological grade, depth of myometrial invasion and nodal metastasis (p = 0.522, 0.622, 0.694 and 0.601, respectively). For lymph node detection, the sensitivity of 18F-FDG PET/CT were also higher without statistically significant difference, than those of CT/MRI (on patient basis; 80.0% vs. 40.0%, p = 0.500; on nodal basis 64.7% vs. 47.1%, p = 0.453, respectively). CONCLUSION: 18F-FDG PET/CThad slightly higher diagnostic sensitivity than CT/MRIin both primary tumor and lymph node detection. The finding focal uptake pattern is more common, but the diffuse uptake pattern shows higher FDG uptake. The SUVmax of primary tumors was associated with the maximum tumor size, but not associated with menopause state, histologic grade, depth of myometrial invasion and nodal metastasis. PMID- 25518185 TI - Factors predicting smoking behavior through multilevel interventions in the Royal Thai Army conscripts. AB - OBJECTIVE: To determine factors predicting smoking behavior through multilevel interventions in the Royal Thai Army Conscripts. MATERIAL AND METHOD: The present study was apart ofquasi-experimental research designed to evaluate the effectiveness of smoking cessation program based on ecological model for improving smoking behavior among the conscripts in the three levels ofbehavior change interventions; intrapersonal level, interpersonal level and organizational level. The 89 participants were purposively selected from the first infantry regiment of conscripts who were current smokers from the King's Royal Guards recruited into the Army in the first section of the year 2009 and put into a trial run-through of the three influential factors process throughout the first six months. The instruments used to collect data was a self-dministered questionnaire used between May 2009 and November 2009. In addition, the individual interviews and checklists of observations were employed to collect data related to organizational intervention. Data mining classification was used to predict the influential factors improving smoking behavior after the end of smoking cessation program at six months. RESULTS: The conscripts were able to change their smoking behaviors. 62.9% ofparticipants reduced smoking, and 4.5% could quit smoking. Data mining analysis showed self-efficacy in intrapersonal level was the crucial variable to predict smoking behavior which correctly classified in the model 77.78%, subsequently, behavioralfactors, e.g., duration of smoking and the number of cigarettes smoked per day. Additionally, organizational intervention also had an influence on the change of smoking behavior by strengthening the policy related to tobacco control, settingsmoke free workplace and supportingfrom the commander. For interpersonal intervention, family support alone did not improve their smoking behaviors. CONCLUSION: Self efficacy and organizational intervention can help the conscripts improve their smoking behaviors during service in the army. PMID- 25518186 TI - Comparison between Staheli index on Harris mat footprint and Talar-first metatarsal angle for the diagnosis of flatfeet. AB - BACKGROUND: Flatfoot is practically diagnosed by physical examination, radiographs, or footprint. Talar first-metatarsal angle on a weight-bearing lateral radiograph provides an accurate measurement for the diagnosis offlatfoot and is frequently used by foot and ankle specialists. Staheli Index is also considered as a reliable method. However; there is no information of the sensitivity and specificity of this index compared to the talar-first metatarsal angle for the diagnosis of flatfoot. OBJECTIVE: To evaluate the usefulness of the Staheli Index on Harris matfootprintfor the diagnosis of flatfoot. MATERIAL AND METHOD: The weight-bearing lateral radiographs were obtainedfrom 157patients (314feet). The radiographs were examined for the talar-first metatarsal angle. Harris mat footprint was also obtained from each participant for the measurement of the Staheli Index. The sensitivity and specificity of the Staheli Index was calculated using the talar-first metatarsal angle as a gold standard. ROC curve was also performed to determine the cut-off point of the Staheli Index. Interobserver and intra-observer reliability was also tested. RESULTS: The cut off point ofthe Staheli Index at 0.77 revealed the sensitivity of 70.2% and specificity of 73%, and the accuracy value was 72%for the detection of flatfoot compare4 to the talar-first metatarsal angle. There was no significant difference of the area under the ROC curves performed by two physicians was found. The area under the ROC curves showed no difference when performed at two different times by the same physician. CONCLUSION: The Staheli Index obtained from the Harris mat footprint could be considered as the screening or diagnostic method for flatfoot. PMID- 25518187 TI - Prevalence and gB genotype distribution of human cytomegalovirus among HIV sero negative and HIV sero-positive orphans in Thailand. AB - BACKGROUND: Human Cytomegalovirus (HCMIV infects humans in all geographic areas. Polymorphisms ofglycoprotein B (gB) have been usedforgenotypic characterization of HCMV However information of gB genotyping of HCMV in Thailand is not clearly known especially in children. MATERIAL AND METHOD: A cross-sectional study was conducted to assess HCMV infection in 236 HIV seronegative and HIV seropositive children who attended an orphanage in Nonthaburi, Thailand by nested-PCR technique using urine specimens. HCMV gB genotypes were determined by restrictionfragment length polymorphism (RFLP), andDNA sequencing technique. RESULTS: Sixty-one percent (144/236) of the samples were HCMV positive, which consisted of 66.1% (37/56) of the HIV seropositive children and 59.4% (107/180) of the HIVsero-negative children. Multivariate analysis showed that children who living in one particular room were independently associated with HCMVinfection. Genotypic analysis revealed that the most prevalent genotype in these children was gB1; 85.4% (111/130) followed by gB3; 4.6% (6/130), gB2 and gB4 each at 2.3% (3/130). Mixed gB genotypes were identified in 5.4% (7/130) of the samples. CONCLUSION: HCMV infection, in particular gB1 genotype was commonly ident fled among these Thai orphans. Living in one particular room was associated with getting the infection. To prevent the transmission of HCMV infection in this setting, improvement in hygienic behavior ofchildcare workers should be focused. PMID- 25518188 TI - First pandemic A (H1N1) pdm09 outbreak in a private school, Bangkok, Thailand, June 2009. AB - OBJECTIVE: On June 9, 2009, the Thailand Ministry of Public Health received their first report of an outbreak of the pandemic A (HIN1) pdm09 that occurred in a school. The authors conducted a study to describe the epidemiological characteristics of the outbreak and its resurgence, estimate the basic reproduction number (R) and review recommendations for prevention and control. MATERIAL AND METHOD: Active case finding in the school and reviewing reports to the national surveillance system identified 184 students infected by the new virus. A survey described the illness in the students and the prevention and control measures taken by the school. The basic reproduction number was estimated from data in the early epidemic phase. The other survey was done to assess factors contributing to the resurgence of the outbreak. RESULTS: Students with the pandemic A (HINI) pdm09 had a mild illness resembling seasonal influenza. Overcrowding in the classroom and activities that mixed students from different classes contributed to transmission in the school. The basic reproduction number for this school-based setting is 3.58. The second outbreak occurred because of poor monitoring of absenteeism and management of ill students. CONCLUSION: This was the first outbreak ofthepandemic A (HIN1) pdm09 in Thailand. The source could not be identified. Effective control measures monitoring, screening, strict personal hygiene and proper management of ill students. PMID- 25518189 TI - Effect of parental presence while children undergo common invasive procedures. AB - BACKGROUND: Substantial studies showed the preferences ofparents to present while their children undergo common invasive procedures. There is no consensus in Thailand regarding this issue so, this study was generated. OBJECTIVE: To determine the effect ofparental presence on children's pain, parental satisfaction of care, anxiety of parent and physician, and performance of procedure. MATERIAL AND METHOD: A prospective study was undertaken in convenience sample of 72 in-patient children age under 4 years old at Phramongkutklao Hospital during 8 months period. 22 parents were present with their children during invasive procedures and given instruction to calm down their children, 22 parents were not allowed to be present and the rest willing not to be present which was recruited as control. The authors assessed parental interaction; pain level, anxiety and the success of procedures. RESULTS: There was no statistical significance in pain response, anxiety levels, and parental satisfaction. There was no statistical difference in proficiency of clinician. PMID- 25518190 TI - Non-motor symptoms in Thai patients with Parkinson's disease studied at Phramongkutklao Hospital. AB - BACKGROUND: Non-motor symptoms (NMS) ofParkinson's disease (PD) have been recently recognized to be as disabling as motor symptoms in PD. However these symptoms are still under recognized causing delay in treatment and inadequate management. This study aimed to identify NMS in Thai PD patients using the NMS screening questionnaire (NMSQuest). MATERIAL AND METHOD: Patients with idiopathic Parkinson's disease visiting the neurology clinic in 2008 were enrolled. NMSQuest Thai version (NMSQ-T) was applied to patients to identify NMS. RESULTS: Collected data from questionnaires completed by 165 probable idiopathic PD was analyzed. The demographic profiles showed mean age of 68.6 years with mean disease duration 5.4 years, and male 56.4%. Patients had Hoehn & Yahrstaging, stage-2: 43%, stage 3: 24.8%, stage-I: 24.2% and stage-4: 7.9%. The average dosage oflevodopa was 456.4 mg/d. Mean total NMSQ-T score was 9.5. Most prevalent of non-motor symptom was nocturia (64.2%). The domains which gained most positive answers were urinary domain (54.55%). Inter-domain correlations were significantly found in all, except the sexual domain. Multivariate analysis revealed the duration ofPD and stages were significantly correlated with the total score ofNMS. Only three percent denied having any non-motor symptoms. CONCLUSION: Almost all Thai PD had NMS. Urinary domain is the most prevalent in our series. Screening using NMSQ-Tto recognize NMS would be a helpful tool to improve the quality of life in Thai Parkinson 's disease. PMID- 25518191 TI - Behavioral and psychological symptoms of dementia. AB - OBJECTIVE: To identify the frequency of behavioral and psychological symptoms of dementia (BPSD) and to explore the different characteristics between subgroup and severity of dementia. MATERIAL AND METHOD: Sixty-seven patients with Alzheimer's disease, vascular dementia, and mixed dementia were recruited to our cross sectional study. Neuropsychiatric batteries including the Mini Mental Status Examination-Thai 2002, Thai Geriatric Depression Scale, 23 items from Alzheimer's Disease co-operative Study activities of daily living inventory, Behavioralpathology in Alzheimer's disease rating scale, and Pittsburg Sleep Quality Index were tested. RESULTS: The most common behavioral and psychological symptoms of dementia (BPSD) were sleep problems (100%), paranoid/delusion (59.7%), diurnal disturbance (49.2%) and aggressiveness (46.3%). Hallucination and affective problems were more severe in AD than in VaD/mixed dementia. Sleep problems were identified more severe in mild dementia than moderate-to-severe dementia. With longer duration of having dementia, exceptfor affective problem, there was no diffemence in behavioral and psychological symptoms observed compared to the shorter dementia group. CONCLUSION: Behavioral and psychological symptoms were very common in Alzheimer disease, vascular dementia, and mixed dementia. Since these symptoms cause cognitive and functional decline, institutionalization, caregiver distress and increase direct costs ofcare, the problem must be identified and addressed. PMID- 25518192 TI - Excessive daytime sleepiness and obstructive sleep apnea in Thai epileptic patients. AB - BACKGROUND: Sleepiness is a common complaint in epilepsy. Also obstructive sleep apnea (OSA) is increasingly detected and would affect the epilepsy prognosis. We aimed to determine the frequency and predictors of sleepiness and OSA in epileptic patients. MATERIAL AND METHOD: This was a cross-sectional descriptive study using Epworth Sleepiness Scale questionnaire (ESS) and Sleep Apnea scale of the Sleep Disorders Questionnaire (SA-SDQ) to identify excessive daytime sleepiness and OSA in our consecutive epileptic patients in Neurology out-patient clinic. RESULTS: Overall 113 patients (male 55%) answered a personal survey and completed ESS and SA-SDQ. Mean age was 47 years (range 15-93). Average body mass index (BMI) was 24. Excessive daytime sleepiness (ESS 10) was demonstrated in 37%, and the prevalence of OSA diagnosed by using SA-SDQ was 20% (male 18%, female 22%). OSA were identified 68% among individuals whose BMI of more than 25, which was significant higherfi-equency than in the nomnnal BMI group (32%). The predictors of having OSA were older age and higher BMI. Epworth Sleepiness Scale score was also higher in the OSA group than in non-OSA group. CONCLUSION: Excessive daytime sleepiness was identified around one third ofour epileptic individutals. Twenty percent had met the questionnaire criteria of having OSA. Overweight was the most important and modifiable risk factor ofOSA. PMID- 25518193 TI - Pediatric acute leukemia: the effect of prognostic factors on clinical outcomes at Phramongkutklao Hospital, Bangkok, Thailand. AB - BACKGROUND: Leukemia is the most common malignancy in children. Multiple prognostic factors have been used in order to assist the clinician to decide appropriate risk-adjusted treatment for each patient; the current clinical outcomes of those patients have been significantly improved over the past decades. OBJECTIVE: The purpose of this study was to examine survival outcome in children who were diagnosed with acute leukemia and treated in the Department of Pediatrics, Phramongkutklao Hospital during January 1, 2000 and July 31, 2013. MATERIAL AND METHOD: The authors retrospectively reviewed the patients who were diagnosed with acute leukemia and treated at Phramongkutklao Hospital. Their clinical data were collected and analyzed based on clinicalfeatures inchluding age, initial WBC count at diagnosis, sex, immnunophenotype and cytogenetic abnormalities. RESULTS: Total 152 patients with acute leukemia, 123 patients were diagnosed with acute lymnphoblastic leukemia (ALL) and 29 patients were diagnosed with acute myeloid leukemia (AML). The 5-year survival rates of ALL and AML patients were 72.63% and 30.30%, respectively. In addition, we found a correlation between the ALL patients' clinical outcomes and several prognostic factors including initial white blood cell count, CNS status at diagnosis and ploidy. However, there was no correlation between those factors and clinical outcomes in AML patients. CONCLUSION: Our treatment outcomes on patients with acute leukemia were similar to the reports from other countries. The several prognostic factors especially initial WBC at diagnosis can assist the clinician to select appropriate treatment option for each patient. PMID- 25518194 TI - Xanthones from mangosteen (Garcinia mangostana): multi-targeting pharmacological properties. AB - OBJECTIVE: This review focuses on mangosteen pericarp extracts, xanthones and derivatives for the future laboratory experiment and development in pharmacological aspects. MATERIAL AND METHOD: All relevant literature databases were searched up to 2 March 2014. The search terms included mangosteen, xanthone, mangostin, and gatanin in all of the human, animal, in vitro and in vivo studies. Anti-intflammation, antioxidant, antibacterial, anticancer and antiulcer properties of each substance were the key parameters. RESULTS: Xanthones are a group of oxygen-containing heterocyclic compounds including alpha-mangostin, gamma-mangostin, mangosteen extract, xanthone derivatives and synthetic xanthones, which provide remarkable and diverse pharmacological effects such as anticancer, antioxidant, anti-inflammatory and antimicrobial activities. CONCLUSION: These xanthone compounds may play a major role in therapeutic treatment ofthe diseases but precise mechanisms ofaction are still unclear and needfurther investigation. PMID- 25518195 TI - Comparison of chromosome analysis using cell culture by coverslip technique with flask technique. AB - OBJECTIVE: To determine accuracy rate ofchromosome study from amniotic cellculture by coverslip technique compared with flask technique and to compared timing ofamniotic cell culture, amount ofamniotic cell culture media and cost ofamniotic cell culture. STUDY DESIGN: Cross sectional study. SETTING: Department of Obstetrics and Gynecology, Phramongkutklao Hospital. Subjects: 70 pregnant women who underwent amniocentesis at Phramongkutklao Hospital during November 1, 2007 to February 29, 2008. INTERVENTION: Amniotic cell culture by flask technique and coverslip technique. MAIN OUTCOME MEASURES: Accuracy of amniotic cell culture for chromosome study by coverslip technique compared with flask technique. RESULTS: Totally 70 pregnant women who underwent to amniocentesis and dividedamniotic fluid to cell culture by flask technique and coverslip technique. 69 samples had similar resultfrom both techniques. The only one sample had cell culture failure inboth methods due to blood contamination. Accuracy in coverslip technique was 100% compared with flask technique. In timing of amniotic cell culture, amount ofamniotic cell culture media and cost of amniotic cell culture between 2 methods that coverslip technique was lesser than flask technique. CONCLUSION: There is statistically significant of accuracy in chromosome result between coverslip technique and flask technique. Coverslip technique was lesser than flask technique in timing, amniotic cell culture media and costs ofamniotic cell culture. PMID- 25518196 TI - Prevalence of HIV testing and associated factors among young men who have sex with men (MSM) in Bangkok, Thailand. AB - BACKGROUND: Without the safety and effective vaccine for HIV the HIVvoluntary counseling testing (VCT) has been documented as a central component ofcomprehensive HIV prevention strategies targeting individual risk reduction by modified high risk behaviors. However, the coverage of HIV testing among men who have sex with men (MSM) is suboptimal. Moreove, the information regarding to factors associated with HIV testing among young Thai MSM are limited and not well understood. OBJECTIVE: This study aimed to evaluate the prevalence and factors associated with HIV testing among young MSM in Bangkok, Thailand. MATERIAL AND METHOD: A cross-sectional study was conducted in Bangkok. Descriptive statistics were presented with crude- and adjusted-odds ratios with 95% confidence interval and the logistic regression models were used to identify factors associated with prior HIV testing. RESULTS: Fifty-six participants were enrolled into study and 51.8% of men previously had an HIV test. After adjusting for potential confounders, logistic regression revealed that older age was positively associated with HIV testing (AOR = 14.4, 95% CI 1.88-111.22) while perceived at low riskfor HIV infection was inversely association with HIV testing (AOR = 0.1, 95% CI 0.02-0.94). CONCLUSION: Young MSM in Thailand are at risk for HIV infection and uptake of HIV testing is suboptimal. Understanding the motivators and barriers to HIV testing are essential to planning and improving the effective HIVprevention interventions-relevance to HIV-serostatus. PMID- 25518197 TI - Cytotoxic effect of artemisinin and its derivatives on human osteosarcoma cell lines. AB - BACKGROUND: Osteosarcoma is the most common, non-hematopoietic, primary bone cancer Current standard treatment is to use neoadjuvant chemotherapy followed by surgical resection. However many complications from chemotherapy have been reported. Some studies have reported artemisinin derivatives showed cytotoxic and anti-angiogenic properties. OBJECTIVE: To investigate cytotoxic properties ofartemisinin and its derivatives on human osteosarcoma cell lines. MATERIAL AND METHOD: Osteosarcoma cell lines (MG63 and 148B) were continuously cultured. MTT assay was used to evaluate cytotoxic properties ofartemisinin derivatives at 48 hours of incubation. These cell lines were also tested against doxorubicin as a control. Each IC50 value represented the mean ofat least 3 experiments. Independent t-test was used to test differences between groups. RESULTS: Artemisinin and its derivatives at micromolar range exhibited anti-cancer growth activities in human osteosarcoma cell lines. Among them, RKA182 the new synthetic tetraoxane is the most effective in inhibiting cell growth. In addition, water soluble properties ofdrugs may be the main factor in cytotoxicity. CONCLUSION: The promising result shows that artemisinin and its derivative inhibits the growth of human osteosarcoma cells. This study indicated that RKA182 may be apotent andpromising agent to combat osteosarcoma. Further studies should be conducted of new synthetic drugs as possible anti-cancer drugs or adjuvant therapy in the clinical treatment of osteosarcoma. PMID- 25518198 TI - Practice effect and normative data of an HIV-specific neuropsychological testing battery among healthy Thais. AB - OBJECTIVE: A longitudinal cohort study was conducted in Bangkok, Thailand between 2008 and 2013 in order to determine the practice effect of serial neuropsychological testing and establish normative data among normal (HIV uninfected) Thai volunteers. MATERIAL AND METHOD: The authors enrolled 511 cognitively healthy individuals (HIV-uninfected, no drug abuse or other previous/current neurological or psychological conditions) to assess baseline performance on a HIV-specific neuropsychological testing battery. Ninety-nine subjects were re-assessed at 6 and 12 months to evaluate practice effects. RESULTS: The mean age of the 99 subjects completing longitudinal visits was 49.2 years and 53 were male. The authors identified improved mean raw scores on most neuropsychological tests with repeated measurements; however only change in WHO Auditory Verbal Learning Test (AVLT) scores (learning, attention, immediate and delayed recall tasks) met statistical significance, with larger differences seen between baseline and 6-month compared to 6 and 12 months follow-up. Older age correlated with poorer baseline raw score, and was a predictor of worse performance at 6 months and 12 months on several tasks. Level of education was associated with practice effects on several tests. No similar effects were observed with gender. CONCLUSION: The authors identified improved performance after repeated measurements revealing a significant practice effect on an HIV specific neuropsychological testing battery employed in Bangkok, Thailand. Main predictors were age and educational attainment. PMID- 25518199 TI - Multiple primary melanoma in a Thai male: a case report. AB - Melanoma is a malignant tumor of melanocytes and the most threatening skin cancer documenting one of the highest in mortality rates in comparison to other non-skin cancers due to its potential to metastasize. Although the global incidence of melanoma has increased, the melanoma-related deaths decreased owing to the fact that melanoma is curable under the condition that early diagnosis is made and treatment is undertaken as soon as possible. Patients with primary melanoma developing a second primary melanoma are less common compared to the generalpopulation developing the first. Not only is melanoma less commonly found in Thaipatients but multiple primary melanomas (MPM) are rarely reported. The present report of a 48-year-old Thai male who presented with asymptomatic black patch on the right big toe nail and an atypical mole on the back, both ofwhich were histologically confirmed melanomas. Treatment included amputation of the right big toe and wide excision of melanoma on the back, which cleared the malignancy without recurrence until present. Although MPM are rare in Thais, the authors should be alert in cases displaying multiple moles for the possibility of melanomas. The total body examination, early diagnosis and regular follow-up are important to decrease the mortality rate in melanoma patient. PMID- 25518200 TI - Papulonodular mucinosis in a suspected systemic lupus erythematosus patient. AB - We present a 45-years-old suspected systemic lupus erythematosus (SLE) woman who had papulonodular mucinosis (PNM), without other cutaneous LE lesion. The lesions of PNM distributed on both legs which were an unusual location. In addition, the renal involvement was found and suspected from lupus nephritis. The patient was treated with prednisolone, mycofenolate mofetil and chloroquine. After 2 months of follow-up, the renal involvement was improved along with the disappearance ofskin lesions. PMID- 25518201 TI - Severe vivax malaria: a case report and a literature review. AB - Most cases of severe malaria are caused by infection of Plasmodiumfalciparum. However severe manifestations in the infection of P. knowlesi and P. vivax have been reported in recentyears. The present study reported a 24-year-old Thai male presenting with acute fever and shock. Both blood smears and PCR were positive for P. vivax. He was treated with intravenous artesunate for 3 days in combination with oral mefloquine for 2 days and oral primaquine for 14 days. He was dischargedfrom hospital without any sequelae. PMID- 25518202 TI - [Obstetrics, maternal and fetal medicine, a training requirement]. PMID- 25518203 TI - [Diagnosing pulmonary embolism during pregnancy: how should we do?]. AB - No diagnostic strategy for pulmonary embo- lism (PE) during pregnancy is based on strong evidence and unanimously accepted. Clinical scores are not validated. The diagnostic yield of the non radiating tests is low: D-dimer is rarely negative in pregnant women and lower limb venous compression ultrasonography is poorly sensitive. Nevertheless, they are still recommended as first line exams. The radia- ting exams (ventilation-perfusion scintigra- phy and thoracic angio-CT) have an equiva- lent diagnostic yield (more than 90%). But both raise the risk of cancer: any childhood cancer for the fetus (scintigraphy), and breast cancer for the mother (angio-CT). However, the diagnosis of PE in the pregnant woman has a major impact and must be established with certainty, even if this requires performing radiation imaging. PMID- 25518204 TI - [New guidelines for cervical cancer screening in young patients: what impact? ]. AB - The publication in 2009 of the new recom- mandations by the American College of Obstetricians and Gynaecologists (ACOG) about the screening of cervical cancer enabled us to optimize the treatment, especially in young patients. The aim of these modifications is to decrease overtreatment of low grade lesions and thereby the risk of obstetrical complica- tions. The objective of our article is to briefly recall these new guidelines together with a study conducted in our Department of Obstetrics and Gynaecology which aim is to confirm that our practice follows these instructions and to check that these procedures are safe for the future of these young patients. PMID- 25518205 TI - [Fertility preservation techniques in women of reproductive age ]. AB - As a result of advances in oncologic treatment, a growing number of women diagnosed with cancer may envisage cure. Young women diagnosed with cancer often have a desire to fall pregnant in the future or may even be diagnosed with cancer in the process of family planning. The potential gonadotoxic effect of certain chemotherapeutic agents is well described. Therefore, it is essential that all women concerned about their fertility receive counselling from a reproductive medicine specialist to discuss the fertility preservation options. Currently, ovarian stimulation with cryopreservation of oocytes or fertilized oocytes is the treatment of choice. However, other options such as in vitro maturation or ovarian tissue cryopreservation should be discussed if ovarian stimulation is contraindicated. PMID- 25518206 TI - [Results of in vitro fertilization in natural cycle or with mild stimulation]. AB - Natural cycle, modified natural cycle and mild stimulation are different protocols which provide some advantages compared to conventional stimulation: lower medication cost, less injections, less invasive, low risk of ovarian hyperstimulation and multiple pregnancy. There main drawback is high cancellation rate due to premature ovulation and lack of egg recovery at the retrieval. When an embryo transfer can be performed, the cumulative pregnancy rate is similar to the results in con- ventional stimulation. Those protocols don't provide any advantage in term of results for woman with normal ovarian reserve, however it might be considered as a therapeutic alternative in poor responders. PMID- 25518207 TI - [Management of endometrioma, recto-vaginal and bladder endometriosis]. AB - Endometriosis is a frequent, benign, chronic disease associated with pain and/or infertility. Classically the lesions are found on the pelvic peritoneum, ovary (endometrioma), rectovaginal septum and bladder. Management of endometrioma has evolved over the last few years to individualised treatment. Indeed endometrioma cystectomy can decrease pain and the risk of recurrence but is also associated with a decrease in ovarian reserve. A multi-disciplinary team should manage recto vaginal or bladder endometriosis. Surgical resection of these lesions must be as complete as possible and can be complex. PMID- 25518208 TI - [Reproductive health among migrant women in Geneva: what are the challenges for Community-based participatory research]. AB - Community-based participatory research (CBPR) focuses on inequalities in health by involving community members and researchers in all parts of the research process. The project COMIRES (COmmunity Migrant RESearch), based in the Department of Obstetrics and Gynecology at the University Hospitals of Geneva, engages academic researchers and migrant communities in Geneva in a co-learning process to understand barriers to reproductive health services and evaluate the role of the community. The article illustrates the methodological approach, but also advantages and challenges of CBPR. PMID- 25518210 TI - [Treatment of critical lower limb ischemia]. AB - Critical limb ischemia is a major public health problem in our western countries due to the epidemia of (diabesity). The outcome of patients suffering from critical limb ischemia reains poor with an amputation free survival rate at one year of about 50%. The treatment should be multidiciplinary and done in emergency in specialized centers to ensure the limb salvage: this management should be centered aroud 3 axis: the screening of the cardiovascular risk factors, the best medical treatment and the invasive approaches. Due to multiple endovascular technical innovations, more frail patients with com plex diseases can be treated with good results. Therefore, the endovascular treatment is essential in the management of such patients by vascular surgeons. PMID- 25518211 TI - [Incidence of major lower limb amputation in Geneva: twenty-one years of observation]. AB - Between 1990 and 2010 the incidence of major lowerlimb amputations (by definition any level of amputation above the foot) in the canton of Geneva was 10.02 per 100,000 inhabitants/ year. The analysis of various population groups revealed that the presence of diabetes increased the relative risk of amputation by a factor of 20, and age 65 years or older by a factor of 9. During this 21 years period we observed a gradual decline in the incidence of amputation and an increased age at the time of amputation, despite the increasing prevalence of diabetes and an aging population. This was a reflection on the efforts of primary and secon- dary prevention, initiated in the 1980s in which Geneva was a pioneer. PMID- 25518212 TI - [Trisomy 21: programmed eradication or progress for the community?]. PMID- 25518213 TI - [The room of patients in the hospital]. PMID- 25518214 TI - [Autumn 2014, new chapter of gene therapy for "bubble baby"]. PMID- 25518215 TI - [Support in heart failure: major paradigm shift or small step?]. PMID- 25518216 TI - [Very premature: erythropoietin reduces cerebral lesions]. PMID- 25518217 TI - [The truth about the death of Descartes is not in The Lancet]. PMID- 25518218 TI - [Medical confidentiality in prison: SVM refuses the draft of Vaudois law]. PMID- 25518219 TI - [Ebola: Berne activates a task force]. PMID- 25518220 TI - [The two modes of attention]. PMID- 25518221 TI - [Being recognized]. PMID- 25518222 TI - [A family physician for children, a controversial idea for pediatricians]. PMID- 25518223 TI - [Health, a major political line of research]. PMID- 25518224 TI - [Health care professionals, difficulties between performing and devotion to their jobs]. PMID- 25518225 TI - [The role of the courts in child protection]. PMID- 25518226 TI - [The Ministry of Health guide to ambulatory surgery]. PMID- 25518227 TI - [A plan for preventive health and assistance]. PMID- 25518228 TI - [Raising public awareness of hepatitis]. PMID- 25518229 TI - [Prevention of risky adolescent behavior]. PMID- 25518230 TI - [Caring for children in the face of parental alienation]. PMID- 25518231 TI - [A live internet chat on rare diseases]. PMID- 25518232 TI - [Should we prohibit the sale of cigarettes to persons born after the year 2000?]. PMID- 25518233 TI - [Energy drinks fuel the urge to drink alcohol]. PMID- 25518234 TI - [Childhood obesity and waist circumference]. PMID- 25518235 TI - [It is imperative to be aware of circumcision and forced marriage ]. PMID- 25518236 TI - [Promoting an early intervention for child dermatologic surgery]. PMID- 25518237 TI - [Using wipes to prevent allergens]. PMID- 25518238 TI - [The aftermath of pneumococcal meningitis]. PMID- 25518239 TI - [Multifactoral causes of cerebral palsy]. PMID- 25518240 TI - [Bottle feeding deters breast feeding]. PMID- 25518241 TI - [A study on the epidemiology of burns in children]. PMID- 25518242 TI - [Which antidepressants to use during pregnancy?]. PMID- 25518243 TI - [Preventing vitamin D deficiency]. PMID- 25518244 TI - [Risk factors and prevention of mother-child hiv transmission]. PMID- 25518245 TI - [Should electronic cigarettes be prohibited?]. PMID- 25518247 TI - [Health professionals, guardians of patient confidentiality]. PMID- 25518246 TI - [Hypothermia for neonatal asphyxial encephalopathy]. PMID- 25518248 TI - [Professional confidentiality: speak out or remain silent? ]. AB - People who work with children, in their daily tasks, must choose whether to disclose information entrusted to them. However, they are subject to the law, which authorises or imposes speaking out or remaining silent. In terms of ethics, they can seek the best possible response while respecting professional secrecy when meeting an individual, in a situation, in a place or at a particular time. They must then take responsibility for that decision. PMID- 25518249 TI - [Trust and shared confidentiality in pediatrics]. AB - Carers are faced regularly with situations that may protect or abuse professional secrecy. In growing organisations where collaborations are increasing, everyone should keep in mind that shared secrets are an essential element in the care of children and the trust relationship that accompanies it. PMID- 25518250 TI - [The health care setting and professional confidentiality]. AB - Professional secrecy must be treated with extra vigilance at a time when the dissemination of information and new communication technologies is developing. Hospitals are not excluded from this trend.This change in work practices is an advantage for child care, but also poses risks. In this context, the health framework plays a key role. PMID- 25518251 TI - [Social workers and the confidentiality in pediatric emergencies]. AB - Social workers are subject to professional secrecy as well as other actors involved in prevention and healthcare. In paediatric emergencies in particular, it is a key partner for the medical and healthcare team. If family support requires information sharing, it is restricted to what is necessary for treatment. PMID- 25518252 TI - [Confidentiality and healthcare law]. PMID- 25518253 TI - [Professional confidentiality and the best interests of the child]. AB - Sharing secret information raises many questions. In child protection in particular, the obligation to remain silent and conditions of information sharing are associated with the concept of the best interests of the child. The latter is based on a set of criteria of which case-by-case evaluation remains the responsibility of professionals and requires a framework for decision-making procedures, which must be collegial. PMID- 25518254 TI - [Bibliography. Confidentiality]. PMID- 25518255 TI - [Embracing cultural diversity in child-care facilities]. AB - In child-care facilities, taking into account the cultural diversity of families in migration is essential. Professionals can then review their references and habits to meet families and build a trust relationship. This exchange forms a respectful accompaniment of the values and habits of each, favouring the development of young children. PMID- 25518256 TI - [Child developmental disorder and art therapy]. AB - Accompanying the art therapy of a young girl suffering from evolutive disharmony shows how this therapeutic mediation can be used in a beneficial way. As part of the workshop proposed by carers, the use of painting and collages of different materials led to a transformation process. The girl became less aggressive, more receptive to her emotions and more open to the outside world. PMID- 25518257 TI - Grey matter atrophy in patients suffering from multiple sclerosis. AB - White matter lesions are defining characteristics of multiple sclerosis (MS), whereas grey matter involvement is a less recognised attribute. Recent investigations using dedicated imaging approaches have made it possible to depict cortical lesions. Additionally, grey matter atrophy may be estimated using various methods. Several studies have suggested that grey matter atrophy closely correlates to clinical disability. In this review we have collected information on grey matter atrophy in MS and the effect of disease modifying therapies upon brain atrophy. PMID- 25518258 TI - The relevance of traumatic life events in schizophrenia spectrum disorders. AB - The central goal of this manuscript was to review literature about the interconnections of traumatic life events and symptoms of schizophrenia spectrum of the last 15 years. First of all, the stress-diathesis model and the traumagenic neurodevelopmental model are shortly presented. Psychological effects of traumas and specific psychotic symptoms in connection with traumatic events are discussed. The course of the disease in patients affected by previous traumas and possible mediating factors are also addressed. Studies of both clinical and community samples are cited. It was also our aim to review literature about the neurobiological and neurocognitive processes in people affected by schizophrenia and/or traumatic life events. The role of prefrontal and medial temporal regions are explored with a special emphasis on contextual memory and hippocampal functioning. Finally, the possible effects of exploring traumatic life events on the treatment of schizophrenia are discussed. PMID- 25518259 TI - Complex approaches to study complex trait genetics in multiple sclerosis. AB - Multiple sclerosis (MS) is a complex trait disorder defined by several genes and their interactions with environmental factors. A comprehensive exploration of the susceptibility variants had not been feasible until recently when new developments in biotechnology and bioinformatics made possible sequencing of the whole human genome, cataloguing of nucleotide variants and alignments of these variants in haplotypes. Earlier observations from epidemiological, candidate gene and linkage studies provided ample evidence to support a complex genetic determination of MS. New biotechnology and bioinformatics resources have been recently applied to further successful explorations of the disease. These efforts were paralleled by more careful and reliable ascertainments of disease phenotypes, collaborations among specialized centers to generate sufficient sample size and involvement of clinician-scientists capable of working both on the clinical and scientific study sides. Data obtained from the whole genome association studies (GWAS) elevated our understanding of MS genetics to a new level by identifying an extensive list of genetic determinants. Pathway analyses of MS-associated variants provided evidence to support the immune etiology of the disease. Future research will likely explore how environmental factors interact with the genome, and contribute to the abnormal immune activation and inflammation. This review summarizes the outcomes of MS genetic explorations including those of recent GWAS, and highlights practical consequences of genetic and genomic studies by pointing out as to how the derived data facilitate further elucidation of MS pathogenesis. A better understanding of disease processes is necessary for future advancements in therapeutics and the development of disease prevention strategies. PMID- 25518260 TI - Mechanism of the "dark" axonal degeneration in the central nervous system. AB - BACKGROUND AND PURPOSE: In the central nervous tissue, two types of transsection resulted axonal degeneration are generally accepted: "watery" and "dark". The present paper deals with the assumption that the mechanism of this kind of "dark" axonal degeneration has a relationship with that of the "dark" neuronal degeneration. METHODS: A minute stab wound is inflicted in the parietal cortex of the rat brain. From 1 h to 3 months postinjury, the resulted ultrastructural events in two distant regions of the corticospinal tract (internal capsule and C3 region of the corticospinal tract) are studied. RESULTS: As a novel finding, the first morphological process of "dark" axonal degeneration was found to consists in a striking reduction of the distances between neighboring neurofilaments, which were readily distinguishable and apparently undamaged. This pattern (compacted ultrastructure) persisted for hours. By day 1 postinjury, the compacted axoplasmic elements aggregated into a homogenous and dense ("dark") mass in which hardly any ultrastructural elements could be distinguished. Surrounded by apparently normal or mildly abnormal myelin sheat, this mass underwent a non-isotropic shrinkage during the next three months. Morphological signs of phagocytosis were insignificant. CONCLUSION: The ultrastructural events during the first day post-injury suggest a non-enzymatic mechanism as an alternative to the prevailing molecular-biological mechanism. PMID- 25518261 TI - P-wave dispersion doesn't increase in patients with epilepsy. AB - AIM: Epileptic seizures have occasionally been associated with cardiac conditions as atrioventricular blocks, long QT syndrome etc. P-wave dispersion (PWD), which is the difference between the longest (P max) and shortest P-wave duration (P min), is considered as a forerunner of atrial fibrillation. In this study, we investigated P-wave dispersion (PWD) in epileptic patients; based on the hypothesis that microthromboembolism may occur in atrial fibrillation. METHODS: Seventy five patients with mixed types of epilepsy and 50 age and sex matched healthy individuals were included into the study. P max, P min and PWD values were calculated for each subject from an ECG. RESULTS: The mean age of subjects in the epilepsy group and control group were similar (p>0.05). P max in patients with epilepsy was 125.1+/-0.7 ms, P min was 67.3+/-10.3 ms, and PWD was 57.6+/ 8.3 ms while these values in the control group were 116.8+/-11.0 ms, 66.5+/-5.5 ms and 46.8+/-7.1 ms, respectively. There were no statistically significant difference between two groups (p>0.05). CONCLUSIONS: PWD does not increase in patients with mixed types of epilepsy. Therefore we believe that microthromboembolism due to atrial fibrillation can't cause epileptic seizures in patients with no structural heart disease. PMID- 25518262 TI - [Retinal ganglion cell layer and visual function in patients with progressive external ophthalmoplegia caused by common mtDNA deletion]. AB - AIM: Mitochondrial (mt) disorders are metabolic conditions with multiorgan involvement, which often cause neuroophtalmological symptoms. The aim of the study was to investigate the relation between progressive external ophthalmoplegia (PEO), visual pathway and mitochondrial DNA (mtDNA) mutations in patients younger than 55 years of age. METHODS: Five female patients (35 to 53 years of age) with mithochondrial disease were investigated. Automated threshold perimetry (Octopus G2 test), scanning laser polarimetry (GDx-VCC and GDx-ECC) and Fourier-domain optical coherence tomography (RTVue-100 OCT) were used in addition to detailed ophthalmological examination and evaluation of visually evoked potentials (VEP). Frequent mutations of the mtDNA were investigated in the patients' blood and muscle samples. RESULTS: PEO of various severity levels was found in all patients, using clinical tests. Genetic testing showed "common deletion" of mtDNA in all cases. For both eyes of 4 patients functional and structural ophthalmic tests had normal results. In one patient decreased visual acuity, reduced retinal nerve fiber layer thickness and prolonged L3 VEP latency time were found without optic disc damage and visual field deterioration. CONCLUSION: In 4 of our 5 patients with PEO due to common deletion of mtDNA retinal ganglion cells and visual function remained normal for a long period of life. PMID- 25518263 TI - Prosthodontic treatment of an edentulous epileptic patient with an implant retained overdenture. A case report. AB - This report describes the treatment of a completely edentulous, mentally retarded patient with epilepsy with an implant-retained overdenture, anchored by a locator system. The intractable epileptic condition of the patient with frequent grand mal seizures and complex partial seizures required a stable, well retained prosthesis, however the maxilla and the mandible were severely atrophied. The bone volume of the maxilla allowed the placement of only two implants it the region of the canines, compared with the generally required four. On long time recall, after one year, patient's chewing ability was satisfactory. PMID- 25518264 TI - [Anti-signal recognition particle autoantibody positive myopathy]. AB - Idiopathic inflammatory myopathies are systemic, autoimmune diseases characterized by proximal symmetrical muscle weakness. We review the myositis associated and myositis-specific autoantibodies, among them the anti-SRP autoantibody. Among those autoimmune myopathy cases, that are associated with autoantibodies, we can detect anti-SRP autoantibody positive myositis cases. We describe the role of signal recognition particle, its structure and role in protein biosynthesis. We review how necrotizing autoimmune myopathy is identified, and the differences from classical polymyositis. The anti-SRP titer correlates with disease activity. We present some cases to show how the disease appears in childhood and also some rare cases from the literature. Finally we present a case to draw attention to the importance of this disease. PMID- 25518265 TI - [Dr. Jozsef Kelemen 1934-2014]. PMID- 25518266 TI - Great insight created by tiny holes; celebrating 40 years of brain micropunch technique. PMID- 25518267 TI - [2014 Scientific Meeting of the Kornyey Society]. PMID- 25518268 TI - The impact of diabetes mellitus on the course and outcome of pregnancy during a 5 year follow-up. AB - BACKGROUND/AIM: Women with diabetes, especially diabetes type 1, have worse pregnancy outcomes, as well as increased incidence of spontaneous abortions, pre eclampsia, fetal macrosomia, preterm delivery, congenital anomalies and perinatal mortality. The aim of this study was to analyze the course and outcome of pregnancy in the patients with diabetes in relation to the group of healthy women regarding preterm delivery, perinatal morbidity and mortality. Also, the aim was to compare pregnancy outcomes in the patients with pre-existing diabetes type 1 and the patients with gestational and diabetes type 2. METHODS: This retrospective study included 156 diabetic women treated at the Clinic of Endocrinology, Diabetes and Metabolic Diseases and Gynecology and Obstetrics Clinic of the Clinical Center of Vojvodina from 2006 to 2010. There were 94 patients with gestational diabetes, 48 with type 1 diabetes, and 14 patients with type 2 diabetes. The control group included 106 healthy women hospitalized at the Gynecology and Obstetrics Clinic. RESULTS: The women with type 1 diabetes presented with a statistically significantly higher incidence of cesarean section than those without diabetes, or with type 2 or gestational diabetes (p < 0.0001); the women with type 1 diabetes delivered at an earlier week of gestation (WG) in regard to women without diabetes, or with type 2 or gestational diabetes (p = 0.0017 and p = 0.02, respectively). The incidence of perinatal morbidity: hypoglycemia (p < 0.001), pathological jaundice (p = 0.0021), and other neonatal pathologies at birth (p = 0.0031), was statistically significantly higher and Apgar scores after 1 minute (p = 0.0142) and after 5 minutes (p = 0.0003) were statistically significantly lower in the patients with diabetes compared to the healthy women. The women with type 2 and gestational diabetes were statistically significantly older than those with type 1 diabetes (p = 0.001). A higher incidence of fetal macrosomia in the women with gestational and type 2 diabetes compared to those with type 1 diabetes was at the borderline of statistical significance (p = 0.07), whereas the incidence of hypoglycemia of newborn was statistically significantly higher in the patients with type 1 diabetes (p < 0.0001). Glycosylated hemoglobin (HbA1c) levels were statistically significantly higher in the diabetic women giving birth during and before the week of gestation 36 (p = 0.0087), but there were no differences in HbA1lc levels in regard to fetal macrosomia (p = 0.45) and congenital abnormalities (p = 0.32). CONCLUSION: The results of our study show a higher incidence of perinatal fetal morbidity (hypoglycemia, jaundice, respiratory distress syndrome) in the patients with type 1, type 2 and gestation diabetes than in the healthy controls. Also, we found a higher incidence of cesarean section in the patients with type 1 diabetes than in those with type 2, gestation diabetes and healthy controls. Although delivery in the patients with type 1, type 2 and gestational diabetes was completed approximately one to two weeks earlier compared to the healthy controls there was no statistically significant difference in the incidence of preterm delivery (<= 36th week of gestation) between the women with diabetes and healthy controls. Preterm delivery associated with poorer glycaemic control reflected through higher values of HbA1c in third trimester. Risks from adverse pregnancy outcomes may be reduced to minimum by adequate preconception counseling of diabetic patients and early diagnosis of diabetes in pregnancy, in order to achieve glycemic control during organogenesis and within pregnancy and through the teamwork of endocrinologists, gynecologists and pediatricians. PMID- 25518269 TI - Condition of periodontium in patients with fixed orthodontic appliances. AB - BACKGROUND/AIM: Orthodontic patients should be familiar with techniques of maintaining oral hygiene as well as with proper methods of checking maintenance of oral hygiene. The aim of this study was to determine a correlation between condition of periodontium and techniques of maintaining oral hygiene in patients treated with fixed orthodontic appliances. METHODS: The research population included 100 patients, aged 15-25, treated by the orthodontist from 2005 to 2010. The maintenance of oral hygiene and the condition of periodontium was assessed using the following indices: plaque index, gingival index, bleeding index and oral hygiene index. The study was carried out using data obtained from the especially designed questionnaire as well as by objective examination of periodontal condition in accordance with the World Health Organization methodology, using adequate indicators and indices. RESULTS: The results of the study show a significant correlation between condition of periodontium and oral hygiene in those with fixed orthodontic appliances. The use ofinterdental brushes and mouthwash liquid, as well as teeth brushing, were among the most significant predictors of healthy teeth and mouth. CONCLUSION: Teeth and mouth hygiene determined by frequency of teeth brushing, using of interdental brushes and mouthwash liquid are the basic preconditions for preservation and promotion of tooth and mouth health in patients with fixed orthodontic appliances. PMID- 25518270 TI - Morphological and functional outcome of scleral buckling surgery compared to primary vitrectomy in patients with retinal detachment. AB - BACKGROUND/AIM: Among the proposed operative techniques for retinal detachment (RD) the most commonly applied are classical method with scleral buckling and pars plana vitrectomy (PPV). The aim of this paper was to determine which surgical intervention of these two leads to better morphological results in terms of the applied retina and better functional outcomes in terms of visual acuity (VA) of the operated eye in patients with RD. METHODS: A retrospective study on the comparative section of the effects of scleral buckling surgery and PPV in uncomplicated rhegmatogenous RD was performed. In a 2-year period 97 patients, i.e. 98 eyes with RD were operated on (68 eyes with scleral buckling surgery vs 30 by PPV). RESULTS: In the group with classically operated detachment, the retina was applied in 52 (76.5%) cases vs 30 (100%) patients in PPV group (p < 0.05). Postoperative VA in logMAR was significantly better in both groups compared to preoperative VA: in the classically operated was 1.89 +/- 1.04 preoperatively vs 0.98 +/- 0.70 postoperatively, while in the PPV group, preoperative value was 2.56 +/- 0.67 vs 1.31 +/- 0.74 postoperatively (p = 0.001). CONCLUSION: PPV in uncomplicated forms of RD gives better anatomical results than scleral buckling surgery. VA was significantly improved in both observed groups, while its mean value was postoperatively better in the group that was operated with the classical method. The reason for this could be due to better VA in baseline in the scleral buckling surgery group. PMID- 25518271 TI - Prognostic value of heart rate variability in post-infarction patients. AB - BACKGROUND/AIM: Depressed heart rate variability (HRV) indicating autonomic disequilibrium and propensity to ventricular ectopy can be useful for risk stratification in patients following acute myocardial infarction (AIM). The aim of the study was to assess heart rate variability as a predictor of all-cause mortality in post-infarction patients. METHODS: We analyzed the 24-hour electrocardiographic (ECG) recordings of 100 patients (80 males) during hospitalization for AIM: The mean age of patients was 56.99 + 11.03 years. Time domain heart rate variability analysis was obtained from 8 to 13 days after index infarction by mean of a 24-hour ECG recording, and the calculated parameters were: standard deviation of all normal to normal RR intervals (SDNN), RRmax-RRmin (difference between the longest RR interval and the shortest RR interval), mean RR interval. We also analyzed ventricular premature complexes from the ECG data. The patients underwent clinical evaluation, laboratory tests and echocardiography. RESULTS: Within a one-year follow-up period 11 patients experienced death, 10 of them because of cardiac reason and one because of stroke. There were significantly lower values of SDNN (60.55 +/- 12.84 ms vs 98.38 +/- 28.21 ms), RRmax-RRmin (454.36 +/- 111.00 ms vs 600.99 +/- 168.72 ms) and mean RR interval (695.82 +/- 65.87 ms vs 840.07 +/- 93.97 ms) in deceased patients than in the survivors, respectively (p < 0.01). The deceased patients were of higher mean age, with lower left ventricular ejection fraction (0.46 +/- 0.05 vs 0.56 +/- 0.06 in survivors), and more frequent clinical signs of heart failure and ventricular ectopic activity (> 10VPCs/h; p < 0.01). Multivariate Cox analysis showed that SDNN was a significant, independent predictor of all-cause mortality in post-infarction patients. The other independent predictors were clinical signs of heart failure--Killip class II and III and ventricular ectopic activity. CONCLUSION: Depressed HRV is an independent predictor of mortality in post-infarction patients and may provide useful additional prognostic information in non-invasive risk stratification of these patients. PMID- 25518272 TI - The influence of bacterial vaginosis on gestational week of the completion of delivery and biochemical markers of inflammation in the serum. AB - BACKGROUND/AIM: Preterm delivery is one of the most common complications in pregnancy, and it is the major cause (75-80%) of all neonatal deaths. Bacterial vaginosis predisposes to an increased risk of preterm delivery, premature rupture of membrane and miscarriage. In this syndrome normal vaginal lactobacilli, which produce protective H2O2, are reduced and replaced with anaerobic, gram-negative bacteria and others. The aim of this study was to evaluate the influence of bacterial vaginosis on the week of delivery and biochemical markers of inflammation in the serum. METHODS: A total of 186 pregnant women were included into this study, between the week 16 and 19 of pregnancy. In the study group there were 76 pregnant women with diagnosed bacterial vaginosis by the criteria based on vaginal Gram-stain Nugent score and Amsel criteria. In the control group there were 110 healthy women with normal vaginal flora. Ultrasound examination was performed in both groups. Vaginal fluid and blood samples were taken to determine biochemical markers with colorimetric methods. RESULTS: The week of delivery was statistically significantly shorter in the study group and the levels of biochemical markers of inflammation (C-reactive protein and fibrinogen in the serum) were statistically significantly higher in women with bacterial vaginosis comparing to the control group. Also the levels of uric acid and white blood cells in the serum were higher in the study group compared to the control one. CONCLUSION: Our study indicates that the pregnancy complicated with bacterial vaginosis ends much earlier than the pregnancy without it. Also, higher levels of biochemical markers of inflammation in the serum in the study group, similarly to results of other studies, suggest that pathophysiological processes responsible for preterm delivery can begin very early in pregnancy. PMID- 25518273 TI - Prediction of mortality with unmeasured anions in critically ill patients on mechanical ventilation. AB - BACKGROUND/AIM: Acid-base disorders are common within critically ill patients. Physicochemical approach described by Stewart and modified by Figge gives precise quantification method of metabolic acidosis and insight into its main mechanisms, as well as influence of unmeasured anion on metabolic acidosis. The aims of this study were to determine whether the conventional acid-base variables are connected with survival rate of critically ill patients at Intensive care unit; whether strong ion difference/strong ion gap (SID/SIG) is a better predictor of mortality rate comparing to conventional acid-base variables; to determine all significant predictable parameters for the 28-day mortality rate at intensive care units. METHODS: This retrospective observational analytic study included 142 adult patients requiring mechanical ventilation, survivors (n = 68) and nonsurvivors (n = 74). Apparent strong ion difference (SIDapp), effective strong ion difference (SIDeff) and SIG values were calculated with the Stewart-Figge's quantitative biophysical method. Descriptive and analytical statistical methods were used in the study [t-test, Mann-Whitney U test, chi2-test, binary logistic regression, Reciever operating characteristic (ROC) curves, calibration]. RESULTS: Age, Na+, acute physiology and chronic health evaluation (APACHE II), Cl , albumin, SIG, SID app, SIDeff, and aninon gap (AG) were statistically significant predictors. AG represented a model with imprecise calibration, i.e. a model with little predictive power. APACHE II had p-value more than 0.05 if it was near it, and therefore it could be considered potentially unreliable for outcome prediction. SIDeff and SIG represented models with well-defined calibration. ROC analysis results showed that APACHE II, Cll-, albumin, SIDeff, SIG i AG had the largest area bellow the curve. By creation of logistic models with calibration methods, we found that outcome depends on SIG and APACHE II score. CONCLUSION: Based on our data, unmeasured anions provide prediction of mortality of critically ill patients on mechanical ventilation, unlike the traditional acid-base variables which are not accurate predictors of the 28-day mortality rate. PMID- 25518274 TI - Perceived parental acceptance/rejection, some family characteristics and conduct disorder in adolescents. AB - BACKGROUND/AIM: Conduct disorder is characterized by repetitive and persistent presence of dissocial, aggressive and defiant behavioral patterns, thus represents important public issue with comprehensive and far-reaching consequences both for the individual and society. The aim of this study was to investigate the differences in sociodemographic family characteristics and the prominence of parental acceptance/rejection dimensions in groups of adolescents with and without conduct disorder, as well as to examine the connection between parental acceptance/rejection dimensions and externalizing symptoms in the group of adolescents with conduct disorder. METHODS: This research was conducted on 134 adolescents, aged 15 to 18, using the Parental Acceptance/Rejection Questionnaire (PARQ child), Youth Self-Report (YSR), and a questionnaire constructed for the purpose of this survey. RESULTS: The results showed that the number of adolescents with conduct disorder coming from divorced families was significandy higher than from complete families (44.8% vs 13.4%, respectively; p < 0.001). Also, in this group of adolescents there was a statistically significantly higher number of parents suffering from psychiatric disorders compared to the controls (31.3% vs 8.9%; respectively; p = 0.001). The perceived rejection dimension and the total index of maternal acceptance/rejection were significantly higher in adolescents with conduct disorder than in those with no such disorder (132.30 +/- 38.05 vs 93.91 +/- 26.29 respectively; p < 0.001). Similar results were found for paternal acceptance/rejection dimension (129.40 +/- 39.58 vs 86.10 +/- 15.95 respectively; p < 0.001). Adolescents with conduct disorder and severe perceived maternal and paternal rejection showed a significantly higher average score on the subscale of externalizing symptoms (14.55 +/- 4.45 and 13.27 + 5.05) compared to adolescents with conduct disorder and lower total index of parental acceptance/rejection (8.32 +/- 5.05 and 8.28 +/- 5.08). CONCLUSION: The results suggest that adolescents with conduct disorder perceive their parents as more rejecting and less warm and supportive compared to adolescents without conduct disorder. The perception of significant and severe parental rejection was associated with a significantly higher averaged score on the subscale of externalizing symptoms in the group of adolescents with conduct disorder compared to those with no such disorder. It was found that adolescents with conduct disorder most often come from large families, have divorced parents or parents with multiple psychiatric disorders. PMID- 25518275 TI - Knowledge, attitudes and behavior of children in relation to oral health. AB - BACKGROUND/AIM: Health education plays a very important role in maintaining health of individuals. Good oral health, as a part of general health, is largely dependent on the level of knowledge, attitudes and habits that children already have. The aim of this study is to examine the level of knowledge and habits in children regarding oral hygiene, diet and bad habits. METHODS: The study included 506 school children aged 12 and 15 years in three towns (Foca, Cajnice, Kalinovik, Bosnia and Herzegovina). The survey was conducted in order to assess knowledge, attitudes and habits that children have in relation to their own oral health. RESULTS: Most respondents stated that they began to brush their teeth at the age of 4, while a smaller number linked beginning of tooth brushing to the start of school. The parents more often help the boys during tooth brushing. A total of 54.9% of children brush their teeth after every meal, while 40.1% of them brush teeth only once during the day. Twelve year olds brush their teeth more often, especially after a meal. A total of 92.5% of children had never used fluoride tablets nor are the tablets recommended to them by anyone. More than half of the children (61.7%) visited the dentist for the first time before starting school that is on the regular examination that is performed upon enrollment to school. A pain as a reason for dental visits was present in 43.9%, while the preventive check in only 31.4% of the children. CONCLUSION; Children included in this study, particularly 15-year-olds, are quite well informed about teeth brushing frequency and proper selection of tools for hygiene maintenance, but this knowledge is not applied. Girls are more responsible for their own health, and come regularly to the preventive dental checkups. PMID- 25518276 TI - Antibiotic-loaded cement spacer for treatment of Klebsiella infected total hip and knee arthroplasty. AB - BACKGROUND/AIM: Infection following total hip arthroplasty (THA) or total knee arthoplasty (TKA) may have devastating consequences. Some bacterial strains are often encountered as agents of these infections, others occur less frequently but are sometimes burdened with more severe complications. Kebsiella spp. are uncommon causes of THA or TKA infection. The aim of this study was to identify an effective treatment algorithm for multidrug resistant Kebsiella spp. caused THA or TKA infections. METHODS: During the 3-year period, from January 1 2009 to December 31 2011, we registered and treated 5 patients with THA or TKA multidrug resistant Klebsiella spp. caused infection. All the patients were primarily operated in other institutions, and were admitted in our clinic after the onset of infection symptoms. In three of the cases Klebsiella infection was complicated by additional infection (Staphyloccocus aureus, Pseudomonas aeruginosa and Serratia marscescens). In 3 of the cases we performed revision arthroplasty after double exchange of antibiotic-loaded articulating cement spacer, and in 2 of the cases the standard two-stage revision approach with one antibiotic cement spacer exchange was applied. RESULTS: The mean length of follow-up after reimplantation surgery was 17.1 months (range 2-31 months). One patient died 2 months after the final reimplantation procedure. The initial Klebsiella infection was eradicated in all the patients. At the end follow-up after definitive reimplantation, the patients had no clinical, laboratory or microbiological parameters positive for active infection. CONCLUSION: According to our experience with multidrug resistant Klebsiella TKA/THA infections, two-stage approach, in some cases with double articulating cement spacer exchange prior to definitive reimplantation, is the most effective treatment option. PMID- 25518277 TI - Endurance and resistance training in rehabilitation of patients with multiple sclerosis. PMID- 25518278 TI - A successful retrieval of stripped outer coating of J-tip diagnostic guidewire from the left popliteal artery during elective coronary angiography. AB - INTRODUCTION: Entrapment and fracture of diagnostic or therapeutic devices within the coronary circulatory system are a rare, but increasing problem. CASE REPORT: A 70-year-old man was admitted in our clinic for coronary angiography before the planned aortic valve replacement. An arterial sheath was inserted in the right common femoral artery. After introducing a J-tip diagnostic coronary guidewire into the aorta and advancing a left Judkins diagnostic catheter over it, suddenly occured peeling off of the wire's hydrophilic coating at the aortic arch level. Very soon, this outer coating of guidewire carried by the blood stream was entered into the left femoral artery, then into the left popliteal artery. This stripped part of guidewire was successfully caught and extracted out by using a goose-neck snare catheter. CONCLUSION: A sudden stripping of outer coating of a J tip diagnostic hydrophilic coronary guidewire during coronary angiography is possible to manage quickly and successfully by the use of a simple cathether. PMID- 25518279 TI - Uretrorenoscopy laser lithotripsy treatment of stones impacted in the left ureter 10 years after right kidney autotransplantation. AB - INTRODUCTION: Urinary tract calculosis is a very common condition in general population. It appears in 5-10% of population, and can be managed conservatively or by minimally invasive, endoscopic and surgical procedures or extra-corporeal shock way lithotripsy. Lesions of the ureter can be resolved by JJ stent insertion, end-to-end anastomosis, ureterocystoneostomy, percutaneous nephrostomy, nephrectomy, intestinal graft interposition or kidney autotransplantation. CASE REPORT: We presented surgical treatment and outcome in a female patient, with a large defect of the right ureter due to impacted stone treatment, following a successful autotransplantation of the right kidney. Ten years later a stone impacted in the left ureter was successfully treated by ureterorenoscopy and laser lithotripsy. Asynchronously combined kidney aoutotransplantation and ureterorenoscopic lithotripsy preserved kidney function. CONCLUSION: Bilateral organs preservation should be considered even in the absence of malignancy, especially in younger population. PMID- 25518280 TI - Unusual metastasis of esophageal cancer. AB - INTRODUCTION: Carcinoma of the esophagus is in the eighth place by the frequency of malignant diseases and the sixth cause of death from cancer worldwide. It usually metastasizes to regional lymph nodes, liver, lungs, central nervous system, and bones, but metastases can appear to unusual locations such as facial skin and lips. CASE REPORT: We presented a 56- year-old man who reported to his physician because of upper lip swelling. A physical checkup of the patients also showed a lesion on the skin of the left temporal region and both lesions were biopsied. Based on the results of histopathological and immunohistochemical analyses of the samples a diagnosis of metastatic adenocarcinoma to the skin was established. Additional diagnostic procedures, including esophagogastroduodenoscopy, detected the infiltration into the distal part of esophagus, which was histopathologically confirmed as adenocarcinoma of esophagus. The results of positron emission tomography/computed tomography (PET/CT) examination showed the invasion of the disease. Because of the disease expansion, a multidisciplinary oncology team suggested chemo- and radiotherapy treatment. The patient has received 4 cycles of platinum-based chemotherapy so far. CONCLUSION: The physicians should always consider unusual skin lesions as the first sign of cancer spreading. PMID- 25518281 TI - The first pharmacy in Vranje with the educated pharmacist and its development. PMID- 25518282 TI - The AOA Congress of 1914. PMID- 25518283 TI - Optometry one hundred years ago. PMID- 25518284 TI - An appreciation of Dr. Henry Hofstetter and his role in the preservation and advancement of optometry history. PMID- 25518285 TI - A look at the origins of dissociated phoria and fusional vergence range testing. PMID- 25518286 TI - The interlaminar and the narrowest distances at the L3/4 and L4/5 interspinous spaces and location of the intercrestal line in Thai cadavers. AB - BACKGROUND: Data on the L3/4 andL4/5 interspinous distances are important in performing a lumbar puncture. This has not been studied in Thais. OBJECTIVE: To study the interlaminar and the narrowest distances at theL3/4 and L4/5 interspinous spaces and location ofthe intercrestal line in Thai cadavers. MATERIAL AND METHOD: The interlaminar and the narrowest distances at the L3/4 and L4/5 interspinous spaces and location of the intercrestal line were measured in 87 cadavers. Mean age of cadavers was 66.7+/-10.6 years (range 40-80 years). Measurements were statistically analyzed using unpaired t-tests. RESULTS: The intercrestal line most often intersected at the lower halfofthe L4spinousprocess (32/87, 36.8%), rangingfrom the lower half ofL3 spinous process to the upper half of Si. Mean interlaminar and the narrowest distances at the L3/4 interspinous space were not significantly different from the L4/5 interspinous space: 7.32+/ 2.7 mm vs. 7.05+/-3.0 mm and 5.27+/-2.1 mm vs. 5.38+/-2.4 mm, respectively (p> 0. 05). These interspinous process distances in 71-80year old cadavers were significantly shorter than 40-60 and 61-70 year age groups (p<0.05). CONCLUSION: The present study confirms that the intercrestal line is most commonly at the lower half of the L4 spinous process. Mean interlaminar and the narrowest distances at the L3/4 and L4/5 interspinous spaces were unrelated to gender or body type. The elderly had more narrow interspinous process distances which may be benefitfrom having lumbar puncture done in the sitting andfeet supported position. PMID- 25518288 TI - CT findings of KUB injury in hemodynamically stable blunt abdominal injury patients with microscopic hematuria. AB - BACKGROUND: According to controversial guideline for management in case of hemodynamically stable blunt abdominal injury with microscopic hematuria. Most ofthe patients could be omittedfor abdominal computed tomography (CT). Despite high sensitivity and specificity ofabdominal CT, in addition to high medical cost, there are risks from radiation exposure and adverse reaction from use of contrast media. OBJECTIVE: To evaluate the prevalence ofKUB injury on abdominal CT in case of hemodynamically stable blunt abdominal injury with microscopic hematuria. MATERIAL AND METHOD: Forty-one studies of abdominal CT performed during 1 January 2010 and 30 June 2012 were retrospectively reviewed for KUB injury (categorized byAAST organ injury scale) by consensus oftwo experienced radiologists. RESULTS: KUB injury was found in 36.6%from all selected CTstudies. Almost all cases could be managed conservatively. The cutoffpoint of microscopic hematuria at 20 cells/hpfhas sensitivity 80% and specificity 46.15%. CONCLUSION: One-third ofthe patients have KUB injury but almost all ofthem could be conservatively managed. We proposed that the cutoffpoint of hematuria be equivalent to or greater than 20 cells/hpf to be one of the indicators for predicting KUB injury that needs radiological evaluation; but it should be carefully considered along with clinical information. PMID- 25518287 TI - A new structured interview for children with autism spectrum disorder based on the DSM-IV. AB - BACKGROUND: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder in children. The clinical spectrum of ASD includes autism, childhood disintegrative disorder Asperger syndrome and pervasive developmental disorder not otherwise specified (PDD-NOS). Although the DSM-IVcriteria are well acceptedforASD diagnosis, there are some known limitations for clinicians. The most important issue is lack'ofspecific age-appropriate items in each domain. Thus, the DSM-IVneeds some modifications in order to be appropriate for clinical use. OBJECTIVE: To develop a structured interview for children based on the DSM IVdiagnostic criteria ofautism and PDD-NOS. MATERIAL ANDMETHOD: From June 2006 to December 2008, 140 Thai children, 121 boys and 19 girls, already diagnosed with ASD, were recruited through the child development clinics of Ramathibodi and Thammasat University Hospitals in Thailand. A 26-item structured interview was developed with scoring according to the DSM-IVdiagnostic criteria for autism andPDD- NOS. To test the accuracy of the structured interview and its reliability, 32 children with ASD were selected and interviewed by four clinicians using the new instrument. One clinician interviewed the parents or caregivers, while three others independently took notes and observed the play behavior of the children. All items from the structured interview as scored by each clinician were compared using inter-rater agreement statistics (Kappa). All of the original 140 patients were then clinically diagnosed again using the structured interview and the results were compared with the initial diagnoses. RESULTS: Ofthe 140patients originally diagnosed with ASD, 110 and 30patients were finally diagnosed with the new interview as having autism and PDD-NOS, respectively. The initial diagnoses from 15 cases (10.7%) were changed according to the structured interview Inter-rater reliability among the four clinicians showed a good level ofagreement (Kappa = 0.897) with statistical significance (p<0.001). The authors only compared the items in the structured interview between the autism and PDD-NOSgroups from 105 cases aged 2-5 years (79 cases with autism and 26 cases with PDD-NOS) because there were only 4 cases with PDD-NOS in the other age groups. Highly significant differences (p<0.001) in clinical items between patients with autism and patients with PDD-NOS from the final diagnoses were noted in 6 of 8 items in the category of restricted, repetitive and stereotyped patterns ofbehavior, interests and activities, which were more common in the autism group than the PDD-NOS group. In addition, the autism group had higher frequencies of using finger-pointing to indicate interest rather than verbalization, and idiosyncratic language, than the PDD-NOS group. CONCLUSION: The newly developed structured interview for Thai children with ASD had a high level ofinterrater reliability between four clinicians. However, most children tested using this structured interview were 2-5years ofage, and the study did not include non-autistic groups. The application ofthis structured interview needs further study with a wider variety ofcases, such as ASD cases from different age groups, children with delayed development and normal children. PMID- 25518289 TI - Normal measurements of size of optic nerve sheath complex using computed tomography. AB - OBJECTIVE: To establish normal value of optic nerve sheath complex on computed tomography. MATERIAL AND METHOD: This prospective study was approved by the institutional ethics committee. Measurement of the optic nerve sheath complex at retrobulbar and waist regions was done on volunteers who came for cranial computed tomography examination at Thammasat University Hospital during May 2013 November 2013. There were 138 volunteers (75 males and 63 females) with average age of 57 years. Volunteers were excluded if they have eye symptoms or known related disease that affected optic nerves such as endocrinopathy, or if they have metallic object or prostheses that might confound the measurement. Size of optic nerve sheath complex was measured at retrobulbar and waist regions on reconstructed orbital CT images in a plane parallel to the optic nerve sheath complex. Two measurements were performed separately at 1-month intervals to evaluate reliability and reproducibility of the measurement. Then normal size and range of the optic nerve sheath complex were evaluated. Correlation between age, gender and size of the optic nerve sheath complex were also evaluated as well as difference in size of the complex between both eyes. RESULTS: Normal value of the optic nerve sheath complex (mean +/- 2SDs) at retrobulbar and waist regions are 5.6+/-1.8 (3.8- 7.4) mm and 3.7+/- 0.8 (2.9-4.5) mm. There is no correlation between age, gender and size of the optic nerve sheath complex. No difference in size of the optic nerve sheath complex between both eyes was found. CONCLUSION: Normal value of optic nerve sheath complex at retrobulbar and waist regions in Thai population was established. This information might be useful in diagnosis of some diseases or excluding some conditions. PMID- 25518290 TI - The correlation between acromion-axillary nerve distance and upper arm length; a cadaveric study. AB - BACKGROUND: Deltoid splitting is one of common and useful approaches in proximal humerus surgery. The disadvantage of this approach is high risk of axillary nerve injury. Nowadays, there is no consensus in the proper mean of the individual's axillary nerve location. OBJECTIVE: The present study aim to determine the correlation between the axillary nerve and the upper arm length that may create equations to calculate the nerve location. MATERIAL AND METHOD: Seventy shoulders were measured the distance from lateral acromial edge to axillary nerve and compared with upper arm length in three positions of the shoulder (adduction 30 degrees , abduction 45 degrees and 90 degrees ). The authors used distance of lateral acromial edge to lateral epicondyle and tip ofgreater tuberosity to lateral epicondyle as the upper arm length. RESULTS: The average distance ofshoulder adduction 30 degrees , abduction 45 degrees and90 degrees were 57.9, 57.1 and 52.9 mm, respectively. All of three positions showed linear correlation to upper arm length from both of reference sites. From acromion edge reference, where "Y" is axillary nerve distance in mm and "x" is upper arm length in cm, the relation were Y= 2.3x-10, Y= 2x-2 and Y= 2x-7with the accuracy rate were 88.57%, 85.71% and 81.43%, respectively. From greater tuberosity reference, the relations were Y = 2.54x-14, Y = 2x and Y = 2.3x-12 with the accuracy rates 87.14%, 80% and 84.29%, respectively. CONCLUSION: There is linear correlation between distance from the lateral acromial edge to axillary nerve and the upper arm length. The authors can predict the danger zone in the location of the anterior upper branch of the axillary nerve. However, further clinical study may helpful to prove the equations. Level ofevidence: Basic science anatomy study. PMID- 25518291 TI - The efficacy of 2% chlorhexidine gluconate in 70% alcohol compared with 10% povidone iodine in reducing blood culture contamination in pediatric patients. AB - BACKGROUND: Blood culture is the gold standard for diagnosis of septicemia. However; false-positive blood cultures are associated with increased health care costs due to unnecessary treatment. OBJECTIVE: To evaluate the efficacy of 2% chlorhexidine gluconate in 70% alcohol compared with 10% povidone iodine in reducing blood culture contamination inpediatricpatients. MATERIAL AND METHOD: This is a prospective study of pediatric patients who were admitted at a tertiary care hospital. Pediatric patients who neededpercutaneous blood cultures were recruitedfrom two general pediatric wards and the pediatric intensive care unit. The authors used 10% povidone iodine as an antiseptic in odd months and 2% chlorhexidine gluconate in 70% alcohol as an antiseptic in even months in obtaining the blood culture samples. RESULTS: There were 1,269 blood culture specimens taken from 821 patients. 654 specimens used 10%povidone iodine as an antiseptic and 619 specimens used 2% chlorhexidine gluconate in 70% alcohol as an antiseptic. The 10% povidone iodine group and the 2% chlorhexidine gluconate in 70% alcohol group had the risk of blood culture contamination of 3.21% (95%CI: 2.00%-4.87%) and 2.28% (95% CI: 1.25%-3.79%) respectively. The risk difference ofblood culture contamination was 0.93% (95% confidence interval: 0. 86-2.72%) with p = 0.31. The most common contamination organism was Coagulase negative staphylococci (68.57%). No adverse skin reactions were observed in both antiseptic solutions groups. CONCLUSION: Use of2% chlorhexidine gluconate in 70% alcohol as an antiseptic seems to reduce the risk of blood culture contamination compared to use of 10% povidone iodine. In addition, neither of the antiseptic solutions resulted in adverse skin reactions. PMID- 25518292 TI - Effectiveness of contextual education for self-management in Thai Muslims with type 2 diabetes mellitus during Ramadan. AB - BACKGROUND: Fasting in Ramadan has adverse effects on health of Muslims with diabetes. Key strategies to prepare the patients are to provide appropriate health education to the patients prior to Ramadan and to adjust anti-diabetic medicines during Ramadan. OBJECTIVE: To study outcomes of the specific health care services that providing health education in parallel with counseling by Islamic leader MATERIAL AND METHOD: The Thai Muslims with type 2 diabetes mellitus were divided into two groups. There were 62patients in experimental group that was provided with specific health care service for Thai Muslims with diabetes in which health education prior to Ramadan and adjustment ofanti diabetic medicine applied. The other was control group with 28patients that was provided only with original health care service. The results were monitored after Ramadan by interviews, weight and waist measurements, blood pressure measurement and blood tests. RESULTS: Both mean systolic and diastolic blood pressure were well controlled in both groups and slightly decreased after Ramnadan. The mean diastolic blood pressure of the experimental group decreased after Ramadan (p value = 0.041). From behavior point of view, it was found that the patients in the experimental group had consumed less sweetenedfood (p-value = 0.002). There was no incidence ofsevere hypoglycemia in either experimental or control group. The number and portion of patients with hypoglycemic symptoms in experimental group were lower than those in controlled group (p-value = 0.013). CONCLUSION: Specific health care service by providing health education prior to Ramadan and adjustment ofanti-diabetic medicine application resulted in a positive effect as the patients tended to consume less sweetenedfood to keep blood sugar level in control. Fasting could affect the patients 'health in apositive way as it helps to control blood pressure, while in parallel, adjustment of anti-diabetic medicine application helps to prevent hypoglycemia. This health care service, which can be achieved in collaboration with a health care team and Islamic leaders, is useful and suitable for Thai Muslims with diabetes mellitus type 2. PMID- 25518293 TI - Neuroprotective effects of Bacopa monnieri (Brahmi) on novel object recognition and NMDAR1 immunodensity in the prefrontal cortex, striatum and hippocampus of sub-chronic phencyclidine rat model of schizophrenia. AB - BACKGROUND: Cognitive impairment is a major problem, which eventually develops in schizophrenia. It contributes to the patients 'functional disability and cannot be attenuated by antipsychotic drugs. Bacopa monnieri (Brahmi), a neuroprotective herbal medicine in the elderly, might be a novel neuroprotective agent for prevention of cognitive deficit in schizophrenia. OBJECTIVE: To study neuroprotective effects ofBrahmi on novel object recognition task and cerebral glutamate/N-methyl-D- aspartate receptor subtype 1 (NMDAR1) immunodensity in sub chronic phencyclidine (PCP) rat model ofschizophrenia. MATERIAL AND METHOD: Rats were assigned to three groups; Group-A: Control, Group-B: PCP administration and Group- C: Brahmi + PCP. Discrimination ratio (DR) representing cognitive ability was obtainedfrom novel object recognition task. NMDAR1 immunodensity was measured in prefrontal cortex, striatum, cornu ammonis fields I (CA 1) and 2/3 (CA2/3) and dentate gyrus (DG) using immunohistochemistry. RESULTS: DR was significantly reduced in PCP group compared with control. This occurred alongside NMDAR1 up regulation in CA2/3 and DG but not in prefrontal cortex, striatum or CA1. Brahmi + PCP group showed an increased DR score up to normal which occurred alongside a significantly decreased NMDARI immunodensity in CA2/3 and DG compared with PCP group. CONCLUSION: Cognitive deficit observed in rats receiving PCP was mediated by NMDAR1 up-regulation in CA2/3 and DG Interestingly, receiving Brahmi before PCP administration can restore this cognitive deficit by decreasingNMDAR1 in these brain areas. Therefore, Brahmi could be a novel neuroprotective agentfor the prevention ofcognitive deficit in schizophrenia. PMID- 25518294 TI - Effects of Cymbopogon citratus Stapf water extract on rat antioxidant defense system. AB - BACKGROUND: Cymbopogon citratus, Stapf(CCS) is commonly known as lemon grass. Previous studies showed that it has a strong antioxidant property and have been traditionally used as analgesic, antipyretic, antiseptic in SoutheastAsia. However, the effect of CCS on antioxidant defense system has not been demonstrated. OBJECTIVE: The present study was conducted to investigate the effects of CCS water extract on rat antioxidant defense system, especially on the expression of y-glutamylcysteine ligase (gamma-GCL) and heme oxygenase-1 (HO-1). MATERIAL AND METHOD: The CCS water extract was screenedfor its phytochemical contents and antioxidant activity in vitro. Moreover, the extract was studied in rats to evaluate its effects in vivo. Male Sprague-Dawley rats aged eight weeks (250+/-20 g) were orally administered with CCS at 250, 500 and 1,000 mg/kg/day for one month. RESULTS: The extract contained flavonoids (496.17 mg gallic acid/g CCS extract) and phenolic compounds (4,020.18 mg catechin/g CCS extract). The scavenging activity (DPPH assay) of the extract was demonstrated by EC50 of 917.76+/-86.89 MUg/ ml whereas the EC50 of the potent antioxidant, vitamin C was 31.22+/-1.84 MUg/ml. In the animals, the protein expression of antioxidant enzymes, gammaGCL and HO-1 was significantly increased in the high dose-treated animals (1,000 mg/kg/day). This was consistent with elevation ofserum total antioxidant capacity. CONCLUSION: Taken together the present study provides evidence that CCS water extract exhibits antioxidant activity and antioxidant enzymes induction in vivo. PMID- 25518295 TI - Cholinesterase inhibitory activities of Apai-sa-le recipe and its ingredients. AB - BACKGROUND: Acetylcholinesterase and butyrylcholoinesterase inhibitors are well known drugs commonly used in the treatment ofAlzheimer's disease (AD) to improve cognitive function. These enzyme inhibitors were reported to be found in manyplants. Apai-sa-le recipe was a Thai tradition used as nootropic recipe and formerly claimed to improve memory. Therefore, it is interesting to investigate cholinesterase inhibitory activity ofthe recipe and its ingredients. OBJECTIVE: To determine the whole recipe ofApai-sa-le and its ingredients for inhibitory effect on acetylcholinesterase (AChE) and human butyrylcholinesterase (BuChE) activities. MATERIAL AND METHOD: Thirty grams of each plant and 181 grams of the whole recipe were separately extracted by 95% ethanol, after filtered the filtrate were evaporated and vacuum-dried at 45 degrees C. By Elman method, the inhibitory activities of both enzymes were assessed. The volatile constituents ofeach extract were determined by GCMS. The constituents in the non- volatile extract were examined by TLC and the antioxidant activity was determined. RESULTS: Four plants exhibited specific BuChE inhibitor were Lepidium sativum Linn. (Ls), Piper nigrum L. (Pn), Angelica dahurica Benth (Ad) andAtractylodes lancea DC. (Al), which shown the lC50 of 5.59, 24.52, 73.23, 96.25 MUg/ml, respectively whereas galantamine and the whole recipe showed IC50 of 0.59 and 236 MUg/ml. Only Pn extract inhibited AChE at lCso of 25.46 MUg/ml. By GCMS and TLC fingerprints revealed the main constituents in LS, Ad, Al andPn as apiol, cumialdehyde, furanodiene and piperine. Moreover nine plant extracts and the whole recipe showed antioxidant activity. CONCLUSION: Lepidium sativum Linn. (Ls) extract showed the most potency on BuChE inhibitory effect. Three ingredients and the whole recipe exhibited mild activity. Only Piper nigrum L demonstrated inhibition effect on both AChE and BuChE. PMID- 25518296 TI - Cytotoxic activity against small cell lung cancer cell line and chromatographic fingerprinting of six isolated compounds from the ethanolic extract of Benjakul. AB - BACKGROUND: Benjakul, a Thai traditional herbal preparation, comnprises five plants: Piper chaba, Piper sarmentosum, Piper interruptum, Plumbago indica, and Zingiber officinale. It has widely been used to treat cancer patients in folk medicine in Thailand. Benjakul extract, and its isolated compounds should be investigated for cytotoxic activity and analysis isolated compounds from chemical fingerprinting. OBJECTIVE: To study cytotoxicity ofBenjakul extract and its isolatedpure compounds against human small cell lung cancer cell line (NCI-HI 688) and in normal human lungfibroblast cell line (MRC-5) and analysis the content ofisolated compounds for quality control of Benjakul extract. MATERIAL AND METHOD: Bioassay-guided fractionation was used for isolated active compounds from ethanolic extract of Benjakul. Cytotoxic activity was carried using the SRB assay. HPLC method was applied to analyze six isolated compound contentfrom Benjakul extract. RESULTS: The ethanolic extract ofBenjakul showed cytotoxicity against NCI-H1688 with IC50 value = 36.15+/-4.35 MUg/ml. Hexane fraction as semi separation by VLC showed the best cytotoxic activity (21.1 7+/-7.42 MUg/ml). Six isolated compounds were identified as myristicin, plumbagin, methyl piperate, 6 shogaol, 6-gingerol and piperine. Plumbagin exhibited the highest cytotoxic activity and 6-shogaol was the second most effective cytotoxic constituent (IC50 values = 1.41+/-0.01 and 6.45+/-0.19 MUg/ml, respectively). Piperine showed the highest content in both ofHPLC analysis and column chromatography separation. CONCLUSION: Benjakul extract exhibited cytotoxicity against NCI-HI 688. Plumbagin and 6-shogaol are bioactive markers for cytotoxicity against this small cell lung cancer cell line. Chromatographic fingerprinting can be used to analyze six cytotoxic compounds isolatedfrom the ethanolic extract ofBenjakul. PMID- 25518297 TI - Development and validation of RP-HPLC method to determine anti-allergic compound in Thai traditional remedy called Benjalokawichien. AB - Benjalokawichien (BLW) or Ya-Ha-Rak (HR) is a traditional remedy in the Nationaldrug list of herbal medicinal products AD 2012 of Thailand. For traditional use, BLW is used as antipyretic agent. It also has anti-allergic effect, particularly treating allergic rash. The ethanolic extract of BLW exhibited anti-allergic activity via inhibitory effect against a release ofbeta hexosaminidase in RBL-2H3 cell line. Pectolinarigenin has been identified as the active compound ofBLW extract. In this study, a reversed-phase high performance liquid chromatography (RP-HPLC) method was developed in order to control quality ofpreparation in three aspects such as chemical fingerprint, quantification and stability of the ethanolic extract. The RP-HPLC was performed with a gradient mobile phase composed of 0.1% ortho phosphoric acid and acetronitrile, and peaks were detected at 331 nm. Based on validation results, this analytical method is precise, accurate and stable for quantitative determination ofpectolinarigenin. The amount ofpectolinarigenin in Benjalokawichien extract determined by this method was 18.50 mg/g ofextract. Therefore, this method could be consideredfor quality control ofBLWextract. PMID- 25518298 TI - In vitro antioxidant, anti-inflammatory, cytotoxic activities against prostate cancer of extracts from Hibiscus sabdariffa leaves. AB - BACKGROUND: Hibiscus sabdariffa (HS) leaves are a vegetable, which is used as a healthy sour soup for protection against chronic diseases in Thai traditional medicine. OBJECTIVES: To investigate antioxidant, anti-inflammatory and cytotoxic activities of Hibiscus sabdariffa leave extracts from diferent extraction methods. MATERIAL AND METHOD: Fresh and dry Hibiscus sabdariffa leaves were extracted by various methods such as maceration with 95% and 50% ethanol, squeeze, and boiling with water or decoction. All extracts were testedfor antioxidant activity by using DPPH radical scavenging assay, anti-inflammatory activity by determination on inhibitory effect of nitric oxide production on RAW264. 7 cell. Cytotoxic activity also tested against human prostate cancer cell line (PC-3) by using sulforhodamine B (SRB) assay. Total phenolic content determined by the Folin-Ciocalteu colorimetric method. RESULTS: The results found that the 95% ethanolic extract of Hibiscus sabdariffa dried leaves (HSDE95) showed the highest antioxidant activity with an EC50 of 34.51+/-2.62 MUg/ml and had the highest phenolic content (57.00+/-3.73 mg GAE/g). HSDE95 also showed potent cytotoxicity against prostate cancer cell line with an IC50 of 8.58+/-0.68 MUg/ml whereas HSDE95 and all of extracts ofHibiscus sabdariffa leaves had no anti-inflammatory activity. CONCLUSION: The obtained results revealed that HSDE95 extract showedpotent cytotoxic activity against prostate cancer cells but low antioxidant and anti-inflammatory activities. This extract should be further isolated as active compounds against prostate cancer. PMID- 25518299 TI - A randomized trial between different suture materials (polydioxanone vs. poliglecaprone 25) and different suturing techniques (running subcuticular suture alone vs. with running horizontal mattress) in prevention of hypertrophic scar development in median sternotomy wound. AB - BACKGROUND: Hypertrophic scar development after median sternotomy wound in cardiac surgery patients is quite common in surgical practice and becomes a major concern nowadays. OBJECTIVE: To compare cosmetic outcome between different suture materials and different suture techniques for skin closure in median sternotomy wound. MATERIAL AND METHOD: A randomized clinical trial was conducted in 80 patients who underwent cardiac surgery in Thammasat University Hospital, Thailand. In respect of the materials and the techniques used to suture the skin, the patients were randomly allocated to four groups. In group 1, the skin was closed with subcuticular running 4-0 Poliglecaprone 25 (Monocryl). In group 2, the skin was closed with subcuticular running 4-0 Polydioxanone (PDS). In group 3, the skin was closed with subcuticular running 4-0 Poliglecaprone 25 (Monocryl) and running horizontal mattress 6-0 Nylon. In group 4, the skin was closed with subcuticular running 4-0 Polydioxanone (PDS) and running horizontal mattress 6-0 Nylon. Postoperative evaluation was performed at 2 and 6 weeks, 3 and 6 months follow-up visits. The scar was analyzed in three parts: upper, middle and lower one third of the sternal wound. The outcome measures for surgical wound were width, height and overall appearance of the scar using the Vancouver scar scale (VSS). A linear visual analogue score (VAS) was preformed to assess pain and itch. RESULTS: At 6 months, there were no significant differences between 4 groups ofpatients in every parameters (width, height, VSS, pain score and itch score) at three different wound sites (upper middle and lower). There was a statistically significant and progressive increase in scar stretching, height and total VSSfrom top to bottom of the sternum with the same pattern in all groups ofpatients (p<0. 05). At 6 months, scar showed a statistically significant difference in width when compares to6 weeks and 3 months (p=500 ml and maintaining MAP>=65 mmHg, were all significantly increased in rate ofcompliance (96.0% vs. 2.5%; p<0.001, 100.0% vs. 92.3%;p = 0.029, 100.0% vs. 88.8%;p = 0.003, respectively). Hospital mortality was reduced significantly after implementation of the 6-hour sepsis protocol (18.7% vs. 40.0%; p = 0.005). CONCLUSION: Septic shock mortality was decreased after implementation of the 6-hour sepsis protocol at the emergency department of Thammasat University Hospital. PMID- 25518313 TI - Locked intramedullary nail: metacarpal geometry study in adults. AB - BACKGROUND: Ideal fixation for metacarpal fracture should provide immediate stability to allow early rehabilitation. Locked intramedullary nail may fulfill the need. Metecarpal geometry has to be studied in order to design the locked intramedullaly nail. OBJECTIVE: To study metacarpal geometry in adult cadaver for locked intramedullary nail design. MATERIAL AND METHOD: Radiographs of metacarpals taken from 50 embalmed adult cadavers were measured for essential parameters for locked intramedullary nail design. Total length, proximal metaphyseal width, distal metaphyseal width, isthmus width and medullary canal width were measured. The parameters were analyzed by descriptive statistic. RESULTS: The average total lengths were rangedfrom 44.53 to 65.42 mm. The average metaphyseal widths ofmetacarpal bone were between 11.42 to 16.42 mm. The average medullary canal widths were between 3.05 to 6.74 mm. The extreme small (less than 3 mm) medullary canals were found in index, middle, ring and small metacarpals. CONCLUSION: The results of our study provide crucial preliminary data for locked metacarpal nail design for adult patient. PMID- 25518314 TI - Correlations between gross motor functions and health-related quality of life in Thai children with spastic diplegia. AB - BACKGROUND: The motor disorders of cerebral palsy (CP) may not only affect children sfunctional capacities, but also their health-related quality of life (HR QOL). OBJECTIVE: The purpose ofthis study is to examine the correlation between gross motor functions andHRQOL of Thai children with spastic diplegia. MATERIAL AND METHOD: Fifty children with spastic diplegia were recruited from an outpatient department of Thammasat University Hospital and Rajanukul Hospital. All participants were measured for gross motor functions by the gross motor function measure (GMFM-66) and their HRQOL by reports of the Pediatric Quality of Life Inventory 4.0 (PedsQL). Spearman's rank correlation coefficients were used to determine the correlations between dimensional scores of GMFM-66 and PedsQL. RESULTS: Forty-five of 50 children with spastic diplegia were completely undertaken for both GMFM-66 and PedsQL mea- sures. The total HRQOL scale score had a fairly significant degree of relationship with the total GMFMscore (r = 0.48, p<0.001). The physical health summary score had a notably moderate to good degree of relationship with the total GMFM score (r = 0. 52, p<0.001). The psychosocial health summary score had afair degree relationship with the total GMFMscore (r = 0.27,p = 0.076). CONCLUSION: The gross motor function tended to correlate with HRQOL in children with spastic diplegia, especially with regard to the physical aspects of the HRQOL. PMID- 25518315 TI - Misidentification of infarct core by computed tomography perfusion (CTP) in a patient with acute ischemic stroke with hypoxia. AB - The authors reported a case with acute right, middle cerebral artery infarct in which the early infarct area was detected by CTP recovery later after the treatment. The patient had hypoxia and tachypnea from pulmonary edema during acute ischemic stroke, which may have accentuated the ischemic change in cerebral hemodynamic. With treatment, the causes of hypoxia were corrected and the patient got better and some parts ofthe brain, previously identified as infarct, turned out to be normal. PMID- 25518316 TI - Spontaneous uterine rupture at non-cesarean section scar site with placenta percreta in the second trimester: a case report. AB - BACKGROUND: Uterine rupture was a common occurrence at previously cesarean sectioned scar Early sign ofuterine rupture was a severe fetal bradycardia. CASE REPORT: A 30-year-old, 3 gravida, 1 para woman was presented with an acute abdominal pain and hypovolemic shock. Her gestational age was estimated at 18 weeks by emergency pelvic ultrasound. She had a lower segment scar from a previous caesarean section. Initially, alive intrauterinepregnancy with massive hemoperitoneum was a provisional diagnosis. During exploratory laparotomy, a ruptured of the right uterine fundus was found with placenta percreta. Hysterectomy was performed. Fetal weight was 450 grams, APGAR score 0, 0 and the fetus could not survive. The patient was discharged on the 4th day after surgery in healthy condition. CONCLUSION: Uterine rupture is a catastrophic kituation. Severefetal bradycardia might be an early sign. This case demonstrates the importance ofclinical judgment based on clinical acumen. PMID- 25518317 TI - Acute closed traumatic sciatic nerve injury: a complication of heterotopic ossification and prominence of the femoral nail: a case report. AB - The report of a 27-years-old man with presence of heterotopic ossification (HO) after femoral nailing 7years ago who developed foot drop afterfalling to the ground on his buttocks. Radiographs revealed a prominence ofthefemoral nail with HO in his right hip. EMG confirmedperoneal nerve injury ofthe hip region. Femoral nail and the HO were removed and external neurolysis was performed. At 9 months after surgery, he had not regain motor power thus posterior tibialis tendon transfer was performed to restore ankle dorsiflexion. Finally, at 2 years follow up, he could ambulate well but did not regained sensation, extensor digitorum communis and peroneal muscle function. PMID- 25518318 TI - Modified desensitization protocols for a pediatric patient with anaphylactic reaction to deferoxamine. AB - Thalassemia major is an inherited form of chronic hemolytic anemia that results in iron overload due to regular blood transfusions. Deferoxamine is used as chelating agentfor treatment ofpatients with chronic iron overload worldwide. Anaphylactic reaction to deferoxamine is rare, and the mechanism ofdeferoxamine induced anaphylaxis is not well understood. Only afewpediatric cases ofsuccessful desensitization for deferoxamine hypersensitivity have been described, and a different protocol has been used in each report. We report a case ofanaphylaxis to deferoxamine in a thirteen-years-old Thai boy with Hemoglobin E/beta thalassemia disease who underwent successful desensitization. He had been receiving blood transfusions since the age often months. At age eleven, the patient began treatment with deferoxamine. Treatment was interrupted after the occurrence ofanaphylaxis, with urticaria, wheezing and gastrointestinal symptoms. A skin prick test was positive, indicating a type 1 hypersensitivity reaction. Deferoxamine desensitization was attempted with various differentprotocols. Finally, the patient could tolerate deferoxamine therapy at the dose previously administered. We proposed this modified subcutaneous desensitization protocolforpediatric cases that develop allergic reactions to deferoxamine. PMID- 25518319 TI - Therapeutic hypothermia with extracorporeal membrane oxygenation (ECMO) and surface cooling in post-cardiac arrest patients: 4 case reports. AB - BACKGROUND: Therapeutic hypothermia has been recently approved to show benefits for neurological outcomes in patients after cardiac arrest. Application of both ECMO and surface coolingfor treatment of therapeutic hypothermia has not yet been reported in the literature. We reported four cases that experienced in-hospital cardiac arrest during ECMO application treated with therapeutic hypothermia under surface cooling at Thammasat University Hospital. CASE REPORTS: Four cases ofin hospital cardiac arrest during ECMO application were treated with therapeutic hypothermia under surface cooling with similar machine. The characteristics ofeach patient were described. The core temperature control during treatment was reported with temperature curves. A Glasgow coma score was used as index for neurological outcome CONCLUSION: Application of surface cooling together with extracorporeal membrane oxygenation (ECMO) is safe and feasible. Both devices facilitate treatment with therapeutic hypothermia in patients with post-cardiac arrest. PMID- 25518321 TI - [Review on the secondary metabolites from Xestospongia sponges and their bioactivities]. AB - The genus Xestospongia is one of the most widespread genera of sponges, containing abundant secondary metatolites with novel structures and potent bioactivities. The main structure types of secondary metatolites found in this genus are alkaloids, quinines, terpens, steroids, lipids, polyketones, etc. These metatolites exhibit a variety of bioactivities, such as cytotoxic, antibacterial and antiviral activities. This paper reviews the progress in the chemistry and pharmacological activities of the second metabolities from sponges of Xestospongia, especially for recent five years, with the aim for further research. PMID- 25518320 TI - [Recent development of non-steroidal anti-inflammatory drugs on the neuro inflammation of Alzheimer's disease]. AB - Neuropathological, clinical epidemiology and animal models studies provide clear evidence for the activation of neuroinflammation in Alzheimer's disease (AD), and long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is linked with reduced risk to develop the disease. But the clinical trials got a negative outcome with traditional NSAIDs treating AD. The therapeutic effects of NSAIDs on Alzheimer's disease are still not clear based on the present research. Profound study for anti-inflammatory mechanisms and standardized clinical trials are needed. As cause and effect relationships between neuroinflammation and AD are being worked out, the challenge is how to realize the effect of traditional NSAIDs on treating AD. PMID- 25518322 TI - [Lead compound optimization strategy (3)--Structure modification strategies for improving water solubility]. AB - Water solubility is an essential physical chemistry property of organic small molecule drug and is also a very important issue in drug discovery. Good water solubility often leads to a good drug potency and pleasant pharmacokinetic profiles. To improve water solubility, structure modification is a straight and effective way based on the theory of water solubility. This review summarized valid structure modification strategies for improving water solubility including salt formation, polar group introduction, liposolubility reduction, conformation optimization and prodrug. PMID- 25518323 TI - [Optimization of experimental parameters for quantitative NMR (qNMR) and its application in quantitative analysis of traditional Chinese medicines]. AB - Quantitative NMR (qNMR) is a technology based on the principle of NMR. This technology does not need the references of the determined components, which supplies a solution for the problem of reference scarcity in the quantitative analysis of traditional Chinese medicines. Moreover, this technology has the advantages of easy operation, non-destructiveness for the determined sample, high accuracy and repeatability, in comparison with HPLC, LC-MS and GC-MS. NMR technology has achieved quantum leap in sensitivity and accuracy with the development of NMR hardware. In addition, the choice of appropriate experimental parameters of the pre-treatment and measurement procedure as well as the post acquisition processing is also important for obtaining high-quality and reproducible NMR spectra. This review summarizes the principle of qHNMR, the various experimental parameters affecting the accuracy and the precision of qHNMR, such as signal to noise ratio, relaxation delay, pulse width, acquisition time, window function, phase correction and baseline correction, and their corresponding optimized methods. Moreover, the application of qHNMR in the fields of quantitation of single or multi-components of traditional Chinese medicines, the purity detection of references, and the quality analysis of foods has been discussed. In addition, the existing questions and the future application prospects of qNMR in natural product areas are also presented. PMID- 25518324 TI - [Fluorescent carbon dots and the application in biomedicine]. AB - As a new type of carbon nanomaterials, fluorescent carbon dots (fluorescent CDs) have many advantages when compared with the traditional fluorescent probes. They are photoluminescence stable and resistance to photo bleaching. Moreover, they are excellent in biocompatibility, low-toxic and easy to modify. All these above make them a promising optical image material as a probe in optical image. This article reviews structure, the common carbon sources, the preparation methods, and the light-emitting principles of the carbon dots. We also introduce the research progress of fluorescent carbon dots in biomedicine, and the problems need to be resolved in the study of fluorescent CDs. PMID- 25518325 TI - [Embryotoxicity of Senecionis Scandentis Hebra on in vitro cultured mouse embryos]. AB - The purpose of this study is to evaluate the embryotoxicity of alkaloids in Senecionis Scandentis Hebra on in vitro cultured mouse embryos. Mouse whole embryo culture (WEC) was applied in this study. Post-implantation (8.5 d) mouse embryos were isolated from their mothers, and cultured in medium of immediately centrifuged serum (ICS) with different concentrations of seneciphylline (target concentrations were 100, 50, 25 and 12.5 MUg x mL(-1)) or senkirkine (target concentrations were 50, 25 and 12.5 MUg x mL(-1)) for 48 h. After culturing completed, the development and organic morphodifferentiation of the cultured embryos were evaluated microscopically. Treatment with seneciphylline and senkirkine had adverse effects on the development and organic morphodifferentiation of embryos. The effect also had clear dose-response. Alkaloidals in Senecionis Scandentis Hebra had embryotoxicity on cultured embryos, which indicated that pregnant people exposed to Senecionis Scandentis Hebra may get potential risk on fetus. PMID- 25518326 TI - [Establishment and application of human CHO/NTR1 system]. AB - Neurotensin receptor-1 (NTR1), which can stimulate the intracellular cascade signal pathway, belongs to the large superfamily of G-protein coupled receptors. NTR1 is related to the occurrence and development of several kinds of diseases. In order to screen the inhibitors for the cancers associated with NTR1 protein, we established a CHO (Chinese hamster ovary) cell line in which human neurotensin receptor-1 was highly expressed. The method is to construct the recombinant plasmid which was lysed with the hNTR1 gene and transfect it into CHO cells. After selected with G418, the cell line was evaluated by Western blotting analysis and calcium flux assays. Through the calcium flux assays on FlexStation 3, we got the EC50 value of neurotensin peptide which is the natural NTR1 agonist, and the IC 50 value of SR48692 which is the known NTR1 antagonist. The established human CHO/NTR1 cell line can be used to study the profile of NTR1 biological activity and further screen of NTR1 antagonists and agonists. PMID- 25518327 TI - [Resistance reversal effect of a novel taxane compound NPB304 and its collaboration with verapamil]. AB - The tumor multidrug resistance reversal effect of NPB304, a novel taxane, was studied. MTT assay was used to determine the IC50 of chemotherapy drugs. Western blotting assay was applied to analyze the expression of P-glycoprotein (P-gp). The effect of compounds on the P-gp function and P-gp ATPase activity was determined by rhodamine 123 (Rh123) accumulation assay and analysis kit, respectively. Molecular docking was employed to predict the binding force between compounds and P-gp. Transmembrane transport of NPB304 was analyzed using MDCK II and MDR1-MDCK II cell model. NPB304 displayed multidrug resistance reversal effect on KBV cells and MCF-7/paclitaxel cells, NPB304 collaborative with P glycoprotein (P-gp) inhibitors verapamil enhanced the reversal activity, specifically, 10 MUmol x L(-1) verapamil in combination with paclitaxel reversed resistance by 56.5-fold, while combined with NPB304 increased the reversal fold; NPB304 synergistically increased Rh123 accumulation in the resistant cells when combined with verapamil, and NPB304 at 0-1 MUmol x L(-1) enhanced the ATPase activity activated by verapamil was observed. NPB304 existed the hydrophobic interactions with the TM regions of P-gp, and the binding force between NPB304 and the A chain of the TM region was stronger. P-gp ATPase activity assay demonstrated NPB304 at lower concentrations (0-1.5 MUmol x L(-1)) could activate the P-gp ATPase, playing a role on inhibition of P-gp function. However, NPB304 did not have an obvious feature of P-gp substrate. NPB304 exerted itself and synergy with verapamil activity on reversing tumor resistance via inhibiting the P-gp function. PMID- 25518328 TI - [Design, synthesis and activity of N-acyl-thiochromenothiazol-2-amine as acetylcholinesterase inhibitors]. AB - A series of novel N-acyl-thiochromenothiazol-2-amine derivatives were designed and synthesized, furthermore, their inhibition effect on acetylcholinesterase was investigated. N-Acyl-thiochromenothiazol-2-amines were prepared from thiophenol by Hantzsch reaction, acylation reaction and substitution reaction. Moreover, their bioactivities as AChE inhibitors in vitro were measured with Ellman spectrophotometry. The results showed that most of them had a certain inhibition activity on AChE, and the compound 10a was the best in them. The IC50 of 10a to AChE is 7.92 MUmol x L(-1), and the value is better than that of rivastigmine. N Acyl-thiochromenothiazol-2-amine derivatives showed a certain bioactivity in vitro, which were worth further investigation. PMID- 25518330 TI - [Comparative analysis of the promoting blood effects of the combination of different proportions of danggui and honghua by the principal component analysis and multi-attribute comprehensive index methods]. AB - The combination of Danggui and Honghua (GH) is a popular herb pair commonly used in clinic for the treatment of blood stasis syndrome in China. To evaluate the activating blood circulation and dissipating blood stasis effects of the combination of different proportions of Danggui and Honghua on acute blood stasis rats, and optimize the proportion of GH to have the best activating blood circulation and dissipating blood stasis effect. Acute blood stasis rat model was induced by subcutaneous injection of adrenaline and ice water bath. The blood stasis rats were administrated intragastrically with GH (1 : 0, 4 : 1, 2 : 1, 3 : 2, 1 : 1, 2 : 3, 1: 2, 1 : 4 and 0 : 1) extracts. The whole blood viscosity (WBV), plasma viscosity (PV), and high shear whole blood relative index (HSWBRI), low shear whole blood relative index (LSWBRI), and erythrocyte aggregation index (EAI) were tested to observe the effects of GH on hemorheology of blood stasis rats. And the maximum aggregation induced by adenosine diphosphate (ADP) was tested to observe the effect of GH on platelet aggregation index of blood stasis rats. In addition, the prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT) and plasma fibrinogen (FIB) were tested to observe the effects of GH on blood coagulation function of blood stasis rats. Then principal component analysis and multi-attribute comprehensive index methods were both used to comprehensively evaluate the total activating blood circulation and dissipating blood stasis effects of GH. The results showed that the hemorheological indexes and coagulation parameters of model group both had significant differences with normal group. Compared with model group, GH (1 : 0, 4 : 1, 2: 1, 3 : 2, 1 : 1, 2 : 3, 1 : 2, 1 : 4 and 0 : 1) could improve all the blood hemorheology indexes and regulate part indexes of blood coagulation function and platelet aggregation in acute blood stasis rats. Based on principal component analysis and multi-attribute comprehensive index methods, GH 1 : 1 and GH 3 : 2 both had the best effect of blood circulation and dissipating blood stasis, and the effect of GH 1 : 1 was slightly better than GH 3 : 2. These results suggest that GH could obviously ameliorate the abnormality of hemorheology and blood coagulation function in acute blood stasis rats. The optimized proportion of GH was consistent with regulations of medicine usage that GH 1 : 1 had the highest frequency used in traditional Chinese formulae. It could provide scientific basis for more effective application of the compatibility between Danggui and Honghua in modern clinic medicine. PMID- 25518329 TI - [Chemical constituents of Kadsura oblongifolia and evaluation of their toxicity]. AB - To study the chemical constituents of K. oblongifolia, silica gel column chromatography, MCI and Sephadex LH-20 were used to separate the 70% acetone extract of the stems of K. oblongifolia. The structures of the isolated compounds have been established on the basis of physicochemical and NMR spectroscopic evidence as well as ESI-MS in some cases. Twenty compounds were obtained and identified as heteroclitalignan A (1), kadsulignan F (2), kadoblongifolin C (3), schizanrin F (4), heteroclitalignan C (5), kadsurarin (6), kadsulignan O (7), eburicol (8), meso-dihydroguaiaretic acid (9), kadsufolin A (10), tiegusanin M (11), heteroclitin B (12), (7'S)-parabenzlactone (13), angeloylbinankadsurin B (14), propinquain H (15), quercetin (16), kadsulignan P (17), schizanrin G (18), micrandilactone C (19) and (-)-shikimic acid (20). Compouds 1, 5, 8, 11-15, 18 and 20 were isolated from this plant for the first time. Toxicity of compounds 1 10 were evaluated with zebrafish model to observe the effect on its embryonic development and heart function. The results showed that compounds 7, 9 and 10 caused edema of zebrafish embryo and decreased the heart rate of zebrafish, which exhibited interference effect on heart development of zebrafish. PMID- 25518331 TI - [Development and application of reference materials containing mixed degradation products of amoxicillin and ampicillin]. AB - Reference materials containing mixed degradation products of amoxicillin and ampicillin were developed after optimization of preparation processes. The target impurities were obtained by controlled stress testing, and each major component was identified with HPLC-MS and compared with single traceable reference standard each. The developed reference materials were applied to system suitability test for verifying HPLC system performed in accordance with set forth in China Pharmacopeia and identification of major impurities in samples based on retention and spectra information, which have advantages over the methods put forth in foreign pharmacopoeias. The development and application of the reference materials offer an effective way for rapid identification of impurities in chromatograms, and provide references for analyzing source of impurities and evaluation of drug quality. PMID- 25518332 TI - [In vivo comparison analysis of scandoside methyl ester metabolites in four kinds of liver microsomes using ultra-performance liquid chromatography combined with electrospray ionization tandem orbitrap mass spectrometry]. AB - In order to clarify the metabolism pathways of scandoside methyl ester, the analysis of metabolites profiling in four kinds of liver microsomes was performed by using an ultra-performance liquid chromatography/ electrospray-tandem mass spectrometry (UPLC-ESI-MS). The data obtained from the 0 h-incubation and the 2 h incubation were compared and analyzed. After incubation, 5 metabolites of scandoside methyl ester were found in rat, Beagles, rhesus monkey and human liver microsome. The results showed that scandoside methyl ester's major metabolic pathway in the liver microsomes is hydrolysis, oxidation and reduction reactions, and there are certain kinds differences between species. The study provides a research base for further research about iridoid compounds in vivo metabolic pathways. PMID- 25518333 TI - [1H NMR based metabolomics study of bu-zhong-yi-qi-tang in the spleen-qi deficiency rat model]. AB - The present study aimed to investigate the effect and the mechanisms of Bu-zhong yi-qi-tang (BZYQ) on Spleen-Qi deficiency rat's model using nuclear magnetic resonance (NMR) metabolomics and multivariate statistical analysis methods. The rat Spleen-Qi deficiency model was established as follows: oral administration of Radix Rhei extract, loaded swimming and starvation for 24 h. The body weight and motor behavior of the rats were measured and recorded once a week. BZYQ could significantly improve body weight and behavioral of Spleen-Qi deficiency model rats compared with the model group (P < 0.05, 0.01). After drug administration, the changes in the levels of endogenous metabolites in the spleen including decreasing lactate, taurine and hypoxanthine, increasing glutamate and scyllo inositol compared with the model group. The metabolomics approach is an effective tool for the investigation of the pharmacologic mechanism of BZYQ and it is helpful to further research. PMID- 25518334 TI - [Novel cationic liposome loading siRNA inhibits the expression of hepatitis B virus HBx gene]. AB - In order to solve the problem of selection and in vivo delivery problem in siRNA treatment, hepatitis B virus (HBV) HBx gene which could be targeted by siRNA was studied. The siRNA expression plasmid which specific inhibits HBx expression was obtained by in vitro selection via a dual-luciferase plasmid including HBx-Fluc fusion protein expression domain. The selected siRNA expression plasmid was then encapsulated in PEG-modified cationic liposome, which was devoted into pharmacodynamic studies at both cellular and animal level. The results illustrated that the cationic liposome which encapsulated siRNA expression plasmid could effectively inhibit HBx gene expression both in vitro and in vivo. PMID- 25518335 TI - Controlled release by novel lysostaphin-loaded hydroxyapatite/chitosan composites. AB - Lysostaphin is highly effective on eliminating methicillin resistant Staphylococcus aureus (MRSA). In order to achieve controlled release of lysostaphin, a biocompatible drug carrier is needed. Hydroxyapatite/chitosan (HA/CS) composites were chosen to carry lysostaphin and sample composites with different weight ratios of HA to CS, including 80/20, 70/30, 60/40, and 40/60, were prepared. Multiple analyses were performed to determine the structural and physicochemical properties of the composites, including scanning electron microscopy, X-ray diffraction and Fourier transform infrared spectroscopy. We immersed HA/CS composites loaded with 1 wt% lysostaphin to test in vitro release activity and cultured MC3T3-E1 cells to carry out biocompatibility test. The result of the release behavior of the composites revealed that the controlled release of lysostaphin from 60/40 HA/CS composites was the highest release rate of (87.4 +/- 2.8)%, which lasted for 120 hours. In biocompatibility testing, MC3T3-E1 cells were able to proliferate on the surface of these composites, and the extract liquid from the composites could increase the growth of the cells. These results demonstrate the controlled release of lysostaphin from HA/CS composites and their biocompatibility, suggesting the potential application of these composites to bone injury and infection applications. PMID- 25518336 TI - [Comparative studies on codon usage bias of Ganoderma lucidum based on analysis of genomic and transcriptomic data]. AB - Codon usage bias is an important characteristic of genetic information transfer in organisms. Analysis of codon usage bias of different species is important for understanding the rules on genetic information transfer. The previous method for analysis of codon usage bias is mainly based on genomic data. However, this method is greatly limited, because the genome sequences of higher organisms are still not available up to now. In this study, we found that we could obtain the same optimal codons of Ganoderma lucidum (Curtis: Fr.) P. Karst based on its whole genomic data or large-scale transcriptomic data from its liquid-cultured hyphae, primordium and fruiting body, separately. This result indicated the feasibility to understand the codon usage bias based on the large-scale transcriptomic data. By calculating the proportion of rare codons of Escherichia coli and Saccharomyces cerevisiae in 26 terpene synthases (TS) of G. lucidum, we found that the rare codons of S. cerevisiae have a higher proportion in TS genes, while the rare codons of E. coli have relatively lower, suggesting that the TS genes of G. lucidum are possibly more difficult to be expressed in S. cerevisiae than in E. coli. Chemical synthesis of TS genes according to the yeast optimal codons will be an effective way to solve the problem on the mismatch of gene codon bias between the foreign genes and the host strain. PMID- 25518337 TI - [Enhancement of artemisinin biosynthesis in transgenic Artemisia annua L. by overexpressed HDR and ADS genes]. AB - Artemisnin is a novel sesquiterpene lactone with an internal peroxide bridge structure, which is extracted from traditional Chinese herb Artemisia annua L. (Qinghao). Recommended by World Health Organization, artemisinin is the first line drug in the treatment of encephalic and chloroquine-resistant malaria. In the present study, transgenic A. annua plants were developed by overexpressing the key enzymes involved in the biosynthetic pathway of artemisinin. Based on Agrobacterium-mediated transformation methods, transgenic plants of A. annua with overexpression of both HDR and ADS were obtained through hygromycin screening. The genomic PCR analysis confirmed six transgenic lines in which both HDR and ADS were integrated into genome. The gene expression analysis given by real-time quantitative PCR showed that all the transgenic lines had higher expression levels of HDR and ADS than the non-transgenic control (except ah3 in which the expression level of ADS showed no significant difference compared with control); and the HPLC analysis of artemisinin demonstrated that transgenic A. annua plants produced artemisinin at significantly higher level than non-transgenic plants. Especially, the highest content of artemisinin was found in transgenic line ah70, in which the artemisinin content was 3.48 times compared with that in non transgenic lines. In summary, overexpression of HDR and ADS facilitated artemisinin biosynthesis and this method could be applied to develop transgenic plants of A. annua with higher yield of artemisinin. PMID- 25518338 TI - [Mechanism of prostate cancer invasion and metastasis]. AB - Prostate cancer cells pass through numerous steps during the process of progression and metastasis. Cancer cells from primary site undertake "epithelial mesenchymal transition (EMT)" and migrate into neighboring site and invade into blood vessels. Migrated cancer cells will detach from extracellular matrix (ECM) and float into distant metastasis site. Those detached cells will go through either "apoptosis" or acquire "anoikis resistance" and, finally, transfer to distant metastasis site. When settle at novel metastasis site, "mesenchymal epithelial transition (MET)" will take place. Receptor activator of nuclear factor kappa-B ligand (RANKL) plays significant role in formation of bone metastasis site. PMID- 25518339 TI - [The concept and mechanisms of castration-resistant prostate cancer]. AB - Castration-resistant prostate cancer (CRPC) is the term which has recently been raised instead of androgen-independent or hormone-refractory prostate cancer. CRPC is defined as the status of disease progression despite the serum testosterone level of castration (< 50 ng/mL), which can be caused by various mechanisms including androgen receptor (AR)-dependent and AR-independent pathways. Recent researches have revealed that aberrant activation of AR signaling due to ectopic androgen synthesis, AR amplification, AR overexpression, AR mutation, AR variant, AR cofactor, and AR post-translational modification is a key mechanism of CRPC. In addition, AR-independent pathway can contribute to the emergence of CRPC. Taken together, it has been thought that these various mechanisms heterogeneously make androgen-dependent to castration resistant in a spatiotemporal-specific manner. PMID- 25518340 TI - [Current status of castration resistant prostate cancer basic research]. AB - Recently, novel anti-androgen and CYP-17 inhibitor have been introduced in clinical practice and significance of androgen mediated pathway is re acknowledged in basic research of castration resistant prostate cancer (CRPC). Generations of AR splicing variant and/or AR mutation, which result in ligand independent activation of AR, are still primary mechanism of acquiring castration resistance in addition to classical AR amplification. Chromosomal rearrangement through FOXA emerged as novel AR regulating mechanism. TMPRSS2-ERG gene fusion is one of the most prevalent signatures in CRPC. Regulation through non-coding miRNA also play critical role in AR mediated oncogenic pathways. Here we describe the classical and recent topics in basic research of CRPC. PMID- 25518341 TI - [Evaluation and diagnosis for castration resistant prostate cancer: CRPC]. AB - When considering the diagnosis of castration resistant prostate cancer (CRPC), one of the possible approaches consists of performing examination and diagnosis to determine the presence of CRPC. The definition of CRPC is simple-disease progression despite a serum testosterone value below 50 ng/dL after androgen deprivation therapy (ADT). It is similar to an earlier definition--"an initial relapse" occurring after primary ADT. Therefore, it is important to determine the histopathological type of CRPC to establish a course of treatment thereafter. Regarding the "examinations" and "diagnosis" for the staging of CRPC, it is likely that the circulating tumor cell assay and quantitative imaging examinations will be needed, instead of bone scintigraphy, in the future. PMID- 25518342 TI - [Current status and future direction of the treatment of CRPC (castration resistant prostate cancer)]. AB - A new era of the treatment of prostate cancer has now come in Japan with the approval of several new agents for castration resistant prostate cancer (CRPC), which were delayed by 2-3 years compared to their introduction in Westerns. In addition to those development of new agents, a good news was presented in ASCO 2014 that is a successful phase III trial of chemo-hormonal therapy for hormone naive (responsive) metastatic prostate cancer (HRPC). We must establish a reasonable treatment strategy for the advanced and high risk prostate cancer. PMID- 25518343 TI - [Lipid metabolism and castration resistant prostate cancer]. AB - Epidemiological studies showed the inverse association between statin use and prostate cancer incidence, especially advanced stages, or mortality. Recent report on association of postdiagnostic use of statin with reduction of prostatic or all-cause mortality strengthened the evidence in this subject. Our basic research findings demonstrated multiple mechanisms of lipid on prostate cancer proliferations. We also showed the mechanism of statin action on prostate cancer cells via IGF1-receptor or LDL receptor cascades. These findings will serve the new strategy for progressive and castration resistant prostate cancer management. PMID- 25518344 TI - [Antisense oligodeoxynucleotide therapy for castration-resistant prostate cancer]. AB - Because of recent advances in the field of nucleic-acid chemistry, antisense oligodeoxynucleotide (AS ODN) technology can offer an attractive strategy to specifically inhibit expression of target genes causing a wide variety of diseases, including cancers. In prostate cancer (PC), several genes, involved in the acquisition of castration-resistant (CR) phenotype, have been identified, some of which, such as clusterin and heat shock protein 27, are intensively investigated as optimal targets for AS ODN therapy. In this review, we attempted to summarize the progress in the novel therapeutic strategy using AS ODN against CRPC, and to discuss the data of the recently completed and currently conducting clinical trials using AS ODNs as well as the future prospects of this therapy for treating CRPC. PMID- 25518345 TI - [ASC-J9 for castration-resistant prostate cancer]. AB - Androgen deprivation therapy has been the standard treatment for the patients with advanced prostate cancer. Androgen deprivation therapy initially suppresses the growth of prostate cancer. However, most patients eventually progress to castration-resistant prostate cancer. Novel drugs, including enzalutamide and abiraterone acetate, are recently able to be used for the patients with castration-resistant prostate cancer. Even so, the therapeutic options for castration-resistant prostate cancer are not enough. Interestingly, androgen receptor degradation enhancer ASC-J9 is reported to degrade the androgen receptor, resulting in the suppression of the growth in castration-resistant prostate cancer cells. In this chapter, ASC-J9 for prostate cancer is reviewed. PMID- 25518346 TI - [The development of therapeutics targeting oxidative stress in prostate cancer]. AB - Oxidative stress is caused by increased reactive-oxygen species (ROS) due to augmented ROS production and impaired anti-oxidative capacity. Recently, oxidative stress has been revealed to promote castration resistance via androgen receptor(AR)-dependent pathway such as AR overexpression, AR cofactor, and AR post-translational modification as well as AR-independent pathway, leading to the emergence of castration-resistant prostate cancer (CRPC). Therefore, antioxidants therapy using natural and chemical ROS scavengers and inhibitors of ROS production seems to be a promising therapy for CRPC as well as preventing castration resistance. However, at present, the application to therapeutics is limited. Therefore, further research on oxidative stress in prostate cancer, as well as on the development for clinical application would be needed. PMID- 25518347 TI - [Elucidating the molecular mechanism of prostate cancer progression under chronic hypoxia and development of the novel therapeutic approach]. AB - Cancer cells encounter a hypoxic microenvironment during tumor growth and progression. In addition, androgen-deprivation therapy against prostate cancer can develop secondary to a hypoxic condition caused by drastic blood supply reduction because androgen drives angiogenic inducers including vascular endothelial growth factor (VEGF) and inhibits angiogenesis inhibitor prostatic pigment epithelium-derived factor (PEDF). Extreme hypoxic conditions are not suitable for cancer survival, however, cancer cells soon adapt to a hypoxic environment and survive. We established a prostate cancer cell line cultured under chronic hypoxia and analyzed a castration-resistant phenotype. Here, the Vav3 was identified as a key oncogenic molecule associated with castration resistance under chronic hypoxia. We analyzed the functions of Vav3 and Vav3 mediated signaling to establish a novel therapeutic target for castration resistant prostate cancer. PMID- 25518348 TI - [Novel treatment for prostate cancer targeting prostaglandins]. AB - PGE2 is highly expressed in the prostate, associating with prostate cancer progression. Targeting downstream signaling pathways of PGE2 may represent an attractive new strategy for the treatment of prostate cancer. We have established a novel prostate cancer xenograft model, KUCaP-2. The expression of EP4, one of PGE2 receptors, was significantly up-regulated during the development of castration resistance. A specific EP4 antagonist, ONO-AE3-208, decelerated castration-resistant growth of KUCaP-2 tumors in vivo. Moreover, ONO-AE3-208 could in vitro inhibit the cell invasion and in vivo suppress the bone metastasis of prostate cancer cells. These results indicated that EP4 is a novel target for the treatment of metastatic castration resistant prostate cancer. PMID- 25518349 TI - [Peptide vaccination for castration-resistant prostate cancer]. AB - Since both tumor cells and host immune cell repertoires are diverse and heterogeneous, immune responses against tumor associated antigens shall be substantially different among individual patients with prostate cancer. Subsequently, selection of suitable peptide vaccines for individual patients based on the pre-existing host immunity before vaccination could induce potent anti-tumor responses capable of providing clinical benefit for prostate cancer patients. We have developed a novel immunotherapeutic approach of personalized peptide vaccination (PPV) in which a maximum of four human leukocyte antigen (HLA)-class IA-matched peptides were selected for vaccination among pooled peptides based on both HLA-class IA type and the pre-existing host immunity before vaccination. We discuss our recent results of clinical studies of peptide vaccination for castration-resistant prostate cancer and the future direction of therapeutic cancer vaccines. PMID- 25518350 TI - [Gene therapy for castration resistant prostate cancer]. AB - Prostate is an ideal target organ for the gene therapy as a translational research (TR). It has advantages as follows: prostate is not a life keeping organ, can be approached easily by ultrasound as a routine clinical technique and PSA is a potent tumor marked for the evaluation of clinical response. Many clinical gene therapy trials for castration resistant prostate cancer (CRPC) have been conducted in many institutes showing clinical safety and efficacy including Japanese trial. A phase I/II study of adenovirus-mediated REIC/Dkk-3 gene therapy for CRPC was initiated in Okayama university hospital and oncolytic Herpes virus therapy was also ongoing in Tokyo university hospital. In spite of limited cases, some clinically positive results are observed. In this paper ongoing development of gene therapy for CRPC is reported and legal issues which are essential for the management of clinical gene therapy are also explained. PMID- 25518351 TI - [New inhibitors of adrenal androgen synthesis enzymes]. AB - The androgen sensitivity of prostate cancer is enhanced during hormonal therapy and prostate cancer develops to CRPC in response to DHT of low concentration synthesized from adrenal androgen and signals (cytokines) that activate androgen receptor (AR). New medicines in consideration of these mechanisms were developed recently. They are already used for a clinic abroad, or clinical studies are conducted, and may be introduced in near future in Japan. Therefore, it is extremely important that we master fundamental knowledge of the new medicines for CRPC. Here, I want to describe adrenal androgen synthesis inhibitors among medicines targeting Androgen-AR axis. PMID- 25518352 TI - [New generation of androgen receptor antagonist in castration resistant prostate cancer]. AB - Androgen ablation therapy is performed for prostate cancer patients especially with advanced stage. Nevertheless, outgrowth of hormone independent cancer cells occurs within several years and leads to a lethal condition, so-called castration resistant prostate cancer (CRPC). Even in CRPC cells under low levels of serum androgens, androgen receptor (AR) signaling still functions and is engaged in the establishment of CRPC. Recently, novel AR antagonists have been developed such as enzalutamide or ARN-509. This review focuses on these AR antagonists that have some features including high affinity to AR compared with bicalutamide, preventing nuclear translocation and DNA binding. These new hormonal agents have changed the landscape of CRPC treatment with a promising outcome. PMID- 25518353 TI - [Chemotherapy for CRPC]. AB - Cabazitaxel, new chemotherapeutic agent for castration resistant prostate cancer (CRPC) treated after docetaxel, was developed. In addition, new hormonal drugs for CRPC, such as enzalutamide and abiraterone were also approved in Japan recently. Treatment strategy for CRPC using these drugs is still controversial, therefore we need much more clinical data of Japanese patients with CRPC. Management of this severe condition and future of prostate cancer were discussed. PMID- 25518354 TI - [Current status and prospects of immunotherapy for castration-resistant prostate cancer]. AB - Surgery, radiation and chemotherapy are three major therapies for cancer. But now, hope is being gathered in immunotherapy as a treatment for fourth. Immunotherapy has been done than before, but they are non-specific immunotherapy. Those that have become hot topics are specific immunotherapies targeting certain molecules or antigens. In this chapter, current status and prospects of immunotherapy for castration-resistant prostate cancer (CRPC) are described. As concrete examples, Sipuleucel-T(Provenge), GVAX, PROSTVAC-VF, Ipilimumab (anti CTLA-4 mAb), anti-PD-1 mAb and anti-PSMA mAb are cited. As a result, it is not obtained results which therapy also satisfactory at present. Because of its uncertainties we are in the developmental stages of this therapy and improved outcomes might be achievable. PMID- 25518355 TI - [Targeted radionuclide therapy for castration-resistant prostate cancer]. AB - Although patients with castration-resistant prostate cancer frequently have metastases to the bone, they have a relatively favorable prognosis. Therefore, it is important to keep or improve the level of patient's quality of life. The use of strontium-89 for the management of the pain from bone metastasis was approved in 2007 in Japan. A new bone-targeting radiopharmaceuticals using radium-223 is also promising, because a randomized trial showed an overall survival advantage of radium-223 in prostate patients with bone metastases. In this review, we summarize the role of targeted radionuclide therapy for castration-resistant prostate cancer, focusing on strontium-89 and radium-223. PMID- 25518356 TI - [Molecular targeting drug of kinase inhibitors for castration resistant prostate cancer]. AB - Prostate cancer (PCa) is the most common cancer type in men. One of the most troublesome aspects of PCa is that androgen-dependent PCa inevitably progresses to highly aggressive and life-threatening castration resistant prostate cancer (CRPC). Kinases are key regulators of critical cancer processes such as cancer cell proliferation, invasion, differentiation or angiogenesis. Recent advances have shed light on molecular targeting inhibitors of kinases in CRPC. Aberrant expression of certain kinases has been implicated in the development and progression of PCa. Among them, some kinase inhibitors have emerged as promising drug targets for CRPC. In this review, we provide an overview of new therapeutic agents which arrived in an advanced stage of clinical testing, especially focusing on the targets of HGF/c-Met and PI3K/AKT/mTOR signaling pathways. PMID- 25518357 TI - [Treatment sequence using newly developed agents for men with castration resistant prostate cancer]. AB - Abiraterone acetate(AA), enzalutamide (EZL) and cabazitaxel (CBZ) are becoming available in Japan. Clinical trials demonstrated the benefit of these agents in men with castration resistant prostate cancer (CRPC). However, data on sequence therapy using these agents are very limited. Based on the mechanisms of agents and clinical data, AA and EZL may be indicated in early stage and CBZ may be indicated in late stage of CRPC. Prostate cancer is significantly heterogeneous between individuals and useful biomarkers for deciding the best treatment are unavailable yet. Therefore, it is hard to establish a standard sequence of the treatments. Until clinical trials demonstrate the best treatment sequence, individualized therapy is required for each patient based on patient and disease characteristics. PMID- 25518358 TI - [Screening for prostate cancer: present status and future perspectives]. AB - In Japan, about three fourth municiparities and 90% human dry dock (a thorough medical checkup) institutions provide a prostate specific antigen (PSA) testing as a screening tool for early detection of prostate cancer. However, the exposure of screening for prostate cancer is very low compared to developed Western countries. The merits of introducing PSA-based screening could be cause-specific mortality reduction and prevention of developing metastatic disease, which was recently confirmed by prospective randomized controlled trials. On the other hand, some men participating in the screening program may be of drawbacks in terms of overdetection and overtreatment. Therefore, providing a fact sheet on screening for prostate cancer and also providing an optimal screening system including more accurate cancer detection, minimally invasive treatment and active surveillance strategy, which can reduce overdetection, overtreatment, and loss of QOL due to treatment, would be very important. The merits of PSA screening will increase and the drawbacks will decrease in the future due to progress in the diagnostic modalities and treatment strategies. At present, a baseline consensus is to conduct PSA-based screening according to well-balanced guidelines published by the Japanese Urological Association. PMID- 25518359 TI - [Active surveillance: current status and future perspectives]. AB - Widespread use of PSA testing has resulted in decrease in prostate cancer mortality but increase in clinically indolent prostate cancer. Active surveillance (AS) is an important strategy to reduce prostate cancer overtreatment. However, the optimal criteria for eligibility and predictors of biopsy reclassification remain to be debated. Due to inadequate reliability of PSA-kinetics including PSA-doubling time during AS, repeated biopsy is indispensable for every AS program. To reduce physical and psychological burden associated with repeated biopsy, studies on the clinical usefulness of mpMRI and new biomarkers in AS program are warranted. PMID- 25518360 TI - [Treatment for high-risk localized prostate cancer]. AB - High-risk localized prostate cancer encompasses a significant heterogeneity and the treatment strategy for this group of prostate cancer patients remains controversial. The definition of high-risk localized prostate cancer is not consistent in that which clinicopathological parameters are included as risk factors. Therefore, we need to be careful in comparing the treatment outcome of each report. Recently, there have been significant improvements in the radiotherapeutic and surgical management. High radiation dose levels, long-term androgen deprivation therapy, and the combination of brachytherapy may contribute to the improvement of radiation-based treatment. Although some patients can be cured by standard surgical approach, extended lymph node dissection and multimodal treatment with radiation and chemohormonal therapy may improve surgical outcome. This review focuses on the recent treatment strategy for high risk localized prostate cancer. PMID- 25518361 TI - [Genetic analysis in prostate cancer]. AB - Following mile stone discoveries of ETS family-associated gene fusion and splicing variant of androgen receptor, next generation sequencing (NGS) has been rapidly introduced to prostate cancer research and already provided several important information on genomic alteration of the disease. Those mutational landscapes demonstrated the generally lower mutation rate through treatment-naive to lethal castration resistant stages compared to other major malignant diseases and implicated distinct pathomechanisms with regard to the presence of ETS family associated gene fusion. Future direction of prostate cancer genomics using NGS will pursue the path up to the elucidation of more specific biological characteristics of the disease such as tumor heterogeneity and preference of bone metastasis, whereas another trend will lead this technology to broader application for a larger, unbiased patient population. PMID- 25518362 TI - [MicroRNA in prostate cancer]. AB - MicroRNAs are small non-coding RNAs that negatively regulate gene expression post transcriptionally. MicroRNA profiles have been studied in various cancers including prostate cancer since 2007. According to these results, microRNA signature in prostate cancer differed from their normal counterparts, suggesting that the differential expression of microRNAs in tumors functionally implicated in their pathogenesis. The up-regulation of oncogenic microRNA and down regulation of tumor suppressor microRNA are demonstrated in various cancers. The target genes of microRNA identified include those of apoptosis avoidance, cell proliferation, epithelial mesenchymal transition, angiogenic signalling, and generation of androgen independence in prostate cancer. Elucidation of micro RNA function may provide further advance in diagnosis and treatment of prostate cancer. PMID- 25518364 TI - [Prostate cancer and metabolic syndrome]. AB - In recent years, more and more attention is being paid to metabolic syndrome (MetS). Meanwhile, relations between prostate cancer (PCa) and MetS, PCa and insulin/IGF-1, testosterone and PCa, are intricately intertwined. Some studies elucidated positive correlation between the number of MetS and predisposition to PCa. Specifically, serum IGF-1 and hyperinsulinemia are thought to have a stimulatory effect on the growth of PCa. In contrast, a decrease in insulin secretion accompanied by disease progression has an inhibitory effect on the growth of PCa. Although not much has been done to clarify the correlation, low testosterone environment caused by obesity and diabetes have been implicated in a development of high risk PCa. Hence, elucidation of the complicated relation between PCa and MetS requires diverse analysis. Hopefully, further studies on this subject help reduce prevalence of PCa and find an effective preventative measure against MetS. PMID- 25518363 TI - [Cancer stem cells in prostate cancer]. AB - The cancer stem cell (CSC) hypothesis shows that tumors contain a reservoir of self-renewing cells that maintain the tumor. Such cancer cells were first identified in leukemia in the 1990s. These cells appear to be resistant to various therapies and can survive to repopulate the tumor. Therefore, this concept has important therapeutic implications for recurrence and metastasis. In this review, we introduce the CSC hypothesis and the origin, method of identification and functions of prostate CSCs. In addition, we review the therapeutic challenges of targeting prostate CSCs. PMID- 25518365 TI - [Novel function of astrocytes revealed by optogenetics]. AB - Astrocytes respond to neuronal activity. However, whether astrocytic activity has any significance in brain function is unknown. Signaling pathway leading from astrocytes to neurons would be required for astrocytes to participate in neuronal functions and, here, we investigated the presence of such pathway. Optogenetics was used to manipulate astrocytic activity. A light-sensitive protein, channelrhodopsin-2 (ChR2), was selectively expressed in astrocytes. Photostimulation of these astrocytes induced glutamate release which modulated neuronal activity and animal behavior. Such glutamate release was triggered by intracellular acidification produced by ChR2 photoactivation. Astrocytic acidification occurs upon brain ischemia, and we found that another optogenetic tool, archaerhodopsin (ArchT), could counter the acidification and suppress astrocytic glutamate release. Controlling of astrocytic pH may become a therapeutic strategy upon ischemia. PMID- 25518366 TI - [Neuropathology of Balo's disease]. PMID- 25518367 TI - [Disease concept, etiology and mechanisms of multiple sclerosis]. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system(CNS). MS is assumed to be caused by a complex interplay between genes and environments. Autoimmune mechanisms targeting CNS myelin has long been proposed, yet it has not been proved. Th17 cells producing interleukin-17 and Th1 cells producing interferon-gamma are postulated to play major roles in initiating inflammation while regulatory T cell functions are dampened. The forth nationwide survey of MS in Japan revealed that MS prevalence showed four-folds increase over 30 years and the increase was especially prominent in female. Thus, westernized life style and improved sanitation are suspected to increase MS susceptibility. Genome-wide association studies in Western MS patients disclosed more than 100 disease-susceptibility genes, most of which are immune-related genes. It therefore supports immune-mediated mechanisms to be operative. Detailed magnetic resonance imaging studies revealed an early atrophy of the cerebral gray matter where T cell infiltration is pathologically scarce. Therefore, neurodegenerative process also takes place in the early course beside neuroinflammation. PMID- 25518368 TI - [Clinical concept, etiology and pathology of neuromyelitis optica]. AB - More than a century has passed since the first description of neuromyelitis optica (NMO) or Devic's disease. The relation between NMO and multiple sclerosis (MS) had long been debated, but the discovery of anti-aquaporin-4(AQP4) antibody, an NMO-specific autoantibody has accelerated clinical and experimental research of NMO, and contributed to estabilishing NMO spectrum disorder(NMOSD), a wider disease spectrum than a prototypic opticospinal phenotype and a new disease concept: autoimmune astrocytopathic disease. Clinical, MRI and laboratory findings and therapeutic response in NMOSD are different from those in MS. On the other hand, anti-AQP4 antibody-seronegative NMOSD has some distinct features from seropositive cases, and anti-myelin oligodendrocyte glycoprotein(MOG) antibody is detected in a fraction of cases of seronegative NMOSD. Unlike anti-AQP4 antibody associated NMOSD, anti-MOG antibody-seropositive NMOSD may be a demyelinating desease. In this review, we provide an overview of how the concept of NMOSD has evolved in association with accumulated scientific evidences. PMID- 25518369 TI - [Epidemiology of multiple sclerosis and neuromyelitis optica]. AB - Multiple sclerosis (MS) is thought to be multifactorial diseases caused some environmental factor acts on the genetic background. The number of patients with MS has been increasing in the world, especially in young female. The prevalence of MS is more about high latitudes, and there is the same tendency in Japan. On the other hand, there is no difference in the prevalence of neuromyelitis optica (NMO) by race and latitude. The national epidemiological survey in 2012 showed that the patient number of NMO/NMO spectrum disorder is estimated to be about 4,400 people in Japan. There was no obvious regional difference in prevalence of patients. PMID- 25518370 TI - [Molecular pathology of multiple sclerosis and neuromyelitis optica]. AB - Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory demyelinating diseases of the central nervous system (CNS). The pathological hallmark of MS is sharply demarcated demyelinating plaques with the relative preservation of axons, suggesting autoimmune responses target CNS myelin. In contrast, NMO shows selective and severe attacks of both axons and myelin of the optic nerves and spinal cord, resulting in necrotic cavitation. Neuropathological studies have demonstrated extensive loss of aquaporin-4 (AQP4) and glial fibrillary acidic protein (GFAP) in NMO lesions, especially in perivascular areas of acute inflammatory lesions where immunoglobulins and activated complements are deposited. We recently demonstrated the extensive loss of connexins(Cxs) in active lesions of Balo's disease, MS and NMO. Early disruption of Cx gap junction among glial cells may be a common denominator in heterogeneous human demyelinating conditions. This review aims to discuss the molecular pathology of MS and NMO that have attracted the most attention in the recent years. PMID- 25518371 TI - [Genetic factors in multiple sclerosis and neuromyelitis optica]. AB - The pathogenesis of multiple sclerosis (MS) and neuromyelitis optica (NMO) results from complex interactions between multiple genetic and environmental factors, both of which can confer susceptibility or resistance to the diseases. To date, genome-wide association studies of European descendants have identified 110 variants associated with MS that are outside of the major histocompatibility complex region. It is noteworthy that most of these variants involve immunologically relevant genes. Nevertheless, the majority of heritability of MS and NMO remain to be discovered (missing heritability). The application of next generation sequencing technology combined with recent advances in genome analysis will provide robust data sets for MS and NMO cohorts to enable a much more detailed understanding of these diseases. PMID- 25518373 TI - [Environmental factors: the contribution of infectious agents]. AB - Multiple sclerosis (MS) is a multifactorial disease resulting from complex interactions between predisposing genetic and environmental factors. Among the many potential environmental risk factors, several common infectious agents such as Epstein-Barr virus (EBV), human herpesvirus-6 and Chlamydia pneumoniae(C. pneumoniae) have been causatively implicated in the onset of MS. However, with the exception of EBV, consistent data are yet to be obtained regarding the involvement of infectious agents. With respect to the Japanese population, we found that EBV infection is a risk factor for the subgroup of Japanese MS patients not harboring the HLA-DRB1*0405 allele, a known genetic risk factor for MS in this ethnic group. By contrast, bacterial infections such as Helicobacter pylori and C. pneumoniae are risk factors for Japanese neuromyelitis optica, especially in patients with anti-aquaporin 4 antibodies. PMID- 25518372 TI - [Vitamin D and latitude as environmental factors in multiple sclerosis]. AB - Multiple sclerosis (MS) shows a multifold increase in prevalence with an increase in latitudes, both north and south of the equator. One of the potential factors related to the difference of the prevalence is vitamin D, because the strength of ambient ultraviolet light, which is essential for vitamin D production, decreases with increasing latitude. It is known that vitamin D has immunomodulatory functions and suppresses an animal model of MS. It is also considered that vitamin D-related genes are critical susceptible genes for MS. An approach from environmental and genetic aspects is needed to investigate the association between vitamin D and MS. PMID- 25518374 TI - [Experimental animal model of multiple sclerosis--transverse investigation of MS pathogenesis for therapeutic intervention]. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) in which autoreactive T cells ignites downstream pathogenic cascades. The orphan nuclear receptor, NR4A2, is identified to be a selectively upregulated gene in peripheral blood T cells from relapsing-remitting MS patients. Furthermore, selective upregulation of NR4A2 is observed in peripheral blood T cells and CNS-infiltrating T cells upon immunization with myelin peptide in experimental autoimmune encephalomyelitis (EAE). Intriguingly, IL-17 -producing helper T cells exclusively express NR4A2, suggesting that NR4A2 expression represents a pathogenic T cells in autoimmunity. In addition, a NR4A2 blockade by RNA interference ameliorated EAE, implying the intrinsic roles of NR4A2 in MS/EAE, and could serve as a novel therapeutic target of the diseases. PMID- 25518375 TI - [In vivo experimental models of neuromyelitis optica]. AB - Neuromyelitis optica (NMO) is autoimmune disease targeting against water channel aquaporin 4 (AQP4), mainly located at astrocyte foot processes in the central nervous system (CNS). The basis of NMO pathology is the astrocytopathy, but it is recently revealed that there is the diversity of NMO lesion possibly links to the mechanism of astrocyte death with and without complement. In vitro and in vivo models of NMO suggested that this autoantibody is pathogenic. There are mainly two types of in vivo experimental rodent models of NMO, one is a model of direct intracranial injection of NMO-IgG and the other is a passive transfer of NMO-IgG in experimental autoimmune encephalomyelitis (EAE). Both is useful to study the pathogenicity of NMO-IgG, and is promising to create the new generation therapy for autoimmune CNS diseases. PMID- 25518376 TI - [Disruption of blood-brain barrier in multiple sclerosis and neuromyelitis optica]. AB - Pathological destruction of the blood-brain barrier(BBB) has been considered to be the initial key step of disease process in multiple sclerosis (MS) and neuromyelitis optica (NMO). The pathological findings using autopsy brain section from patients with secondary progressive (SP) MS or relapsing MS demonstrated a leaky BBB in active lesions and our recent data also showed that the sera from patients with relapsing MS or SPMS can induce the BBB breakdown. Recently, the disease-specific autoantibody "anti-aquaporin 4(AQP4) antibodies" was detected in the sera of NMO patients. Because the circulating anti-AQP4 antibodies need to pass through BBB in order to reach the astrocytic endfeets, where AQP4 localized, our recent studies demonstrated the detailed molecular mechanism of the BBB disruption in NMO. PMID- 25518377 TI - [Multiple sclerosis: diagnosis, clinical course and differential diagnosis]. AB - Disease modifying treatment for multiple sclerosis has improved both relapse rate and prognosis. The diagnostic criteria of McDonald were designed for early diagnosis, with a crucial role for magnetic resonance imaging in the 2010 revision, as dissemination in space and time can be established by a single scan. These criteria are likely applicable in pediatric, Asian, and Latin America populations, and include neuromyelitis optica as a differential diagnosis. With recent modifications for widespread use, diagnostic sensitivity and specificity have been improved. Nevertheless, clinical and imaging red flags for atypical manifestations are needed for exclusion of alternative diagnosis. PMID- 25518378 TI - [Diagnostic criteria and differential diagnosis of neuromyelitis optica]. AB - Neuromyelitis optica (NMO) is an autoimmune central nervous system disease associated with anti-aquaporin 4 (AQP4) antibody. Although the current diagnostic criteria requires both optic neuritis and myelitis, many of the patients with anti-AQP4 antibody do not fulfil the criteria, so that they have a chance to be misdiagnosed as having multiple sclerosis (MS). To avoid the misdiagnosis, a sensitive method to detect anti-AQP4 antibody is required although widely used kits has lower sensitivity. Although MS is one of the most important differential diagnosis of NMO, diseases associated with anti-myelin oligodendrocyte glycoprotein antibody may mimic NMO clinical features and should be considered as differential diagnosis. PMID- 25518379 TI - [Blood and cerebrospinal fluid biomarkers in MS/NMO]. AB - Biomarkers have been developed for the purpose of diagnosis, analysis of the pathogenesis, monitoring disease activity and treatment response, selection of treatment, and prediction of prognosis and risk of disease development. In accordance with the development of MRI technique, the significance of imaging biomarkers has been increasing. Whereas, there are a few established and widely used blood/CSF biomarkers except for oligoclonal IgG bands in MS, and anti-AQP4 antibody in NMO. These biomarkers are helpful especially for the diagnosis of atypical cases. The significance of blood/CSF biomarkers are expected to increase for the prediction of the disease, selection of appropriate therapy, prediction of disease susceptibility. PMID- 25518380 TI - [Characteristic features of radiological findings in multiple sclerosis and neuromyelitis optica]. AB - Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the two main autoimmune and inflammatory diseases of the central nervous system (CNS), and conventional magnetic resonance imaging (MRI) is a currently-established tool in the diagnosis of these two diseases. More recently, the utility of both conventional MRI and advanced MR techniques including structural, metabolic and functional MRI have provided new surrogate markers of clinical activity and prognosis. This review focuses on the current knowledge of the details of radiological examination in two distinct diseases, MS and NMO, and clarifies that each has unique characteristic features of radiological and pathological modalities in the CNS. However, advanced MR techniques still need to be fully evaluated and validated by pathological studies. PMID- 25518381 TI - [Electrophysiological diagnosis of multiple sclerosis]. AB - Evoked potentials (EPs) in a daily practice consist of somatosensory evoked potentials (SEP), visual evoked potentials (VEP), auditory brainstem response (ABR) and motor evoked potentials (MEP). EPs can confirm the presence of lesions in patients with suspected involvement, and document the presence of clinically unsuspected lesions in multiple sclerosis (MS) patients. MEP has the highest sensitivity while VEP is the second sensitive. Furthermore, we are able to obtain an increase in sensitivity by using multimodality evoked potentials (MuEP). By doing so, there is a significant correlation between EP abnormalities and Expanded Disability Status Scale. Thus, EPs are useful for the diagnosis or evaluation of MS and predicting neurological disabilities. PMID- 25518382 TI - [Neuropsychological tests in multiple sclerosis]. AB - The prevalence of cognitive impairment is about 40-65% in patients with multiple sclerosis (MS). Cognitive decline appears in MS in the early stages of the disease including clinically isolated syndrome and radiologically isolated syndrome. Cognitive impairments in patients with MS influence their social functioning and employment. Various domains of cognitive function, including processing speed/working memory, long-term memory, word retrieval, visuospatial processing, and executive function are affected in patients with MS. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) in MS and the Minimal Assessment of Cognitive Function in MS (MACFIMS) are commonly utilized to assess cognitive function in patients with MS. Neuropsychological assessments are important in MS to predict prognosis and cognitive outcome in treatment trials. PMID- 25518383 TI - [Short-term high-dose intravenous methylprednisolone therapy]. AB - Short-term, high-dose intravenous methylprednisolone therapy (IVMP), which is called steroid pulse therapy, is widely used as the standard treatment for acute exacerbations of multiple sclerosis (MS), and has been shown to improve neurological symptoms. IVMP is also applied in the acute phase of neuromyelitis optica (NMO), with considerable benefit, although some patients are refractory to IVMP, and the early use of plasmapheresis should be considered in these patients. IVMP acts by inhibiting the cascade of inflammation through several different mechanisms, including reducing the inflammatory cytokines and suppressing the T cell activation. IVMP is well tolerated and relatively safe, but attention should be paid to the development of adverse events, such as psychosis, hyperglycemia and osteonecrosis. PMID- 25518384 TI - [Plasmapheresis in acute phase of multiple sclerosis and neuromyelitis optica]. AB - In acute phase of multiple sclerosis (MS) and neuromyelitis optica (NMO), plasmapheresis (PP) should be considered as the 2nd choice treatment when corticosteroid pulse therapy results in unsuccessful. It is believed that the beneficial effects of PP occur through the elimination of pathogenic humoral and plasma factors, including autoantibodies, complement components, and cytokines. In MS, several clinical trials have shown the efficacy. However, there have been no randomized controlled trials that demonstrated the efficacy of PP in NMO. There are three methods of PP, plasma exchange, double filtration plasmapheresis and immunoadsorption plasmapheresis, available in Japan. But the difference of efficacy among these 3 methods has not been fully evaluated. PMID- 25518385 TI - [Use of interferon-beta in the treatment of multiple sclerosis]. AB - Interferon-beta (IFNbeta) products are widely used as first-line treatment for multiple sclerosis and have well-established benefit-risk profiles over the short and long-term. Commercially available agents in Japan include subcutaneous IFNbeta-1beta (Betaferon) and intramuscular IFNbeta-1a(Avonex). Although these IFNbeta products differ in dosage, frequency of administration and rout of delivery, both reduce relapse rate by about 30% and new lesion activity by about 65%. In addition, IFNbeta products were shown to reduce the disability progression. However, clinical studies have also demonstrated that a subset of patients respond poorly to IFNbeta treatment. Thus, it is an important strategy to identify the patients who have suboptimal treatment responses early, before disability ensures, as measured by combination of clinical data and MRI measures of disease activity. PMID- 25518386 TI - [Fingolimod treatment in multiple sclerosis]. AB - Multiple sclerosis (MS), an inflammatory disorder of the central nervous system, is characterized by relapsing-remitting (RR) clinical course. Fingolimod was the first oral therapy to prevent relapses in patients with RRMS, approved in Japan in 2011. In lymph node, fingolimod acts as functional antagonist, leading to internalization of sphingosine-1-phosphate 1(S1P1) receptors of lymphocytes. Lymphocytes in lymph nodes bearing S1P1 receptors cannot egress from lymph nodes. As a result, lymphocyte count in the circulation is reduced. Fingolimod showed reduced relapses, and suppressed the number of enhancing lesion and the progression of brain atrophy of brain MRI, however, it also showed some adverse effects such as bradycardia, herpes zoster infection, macular edema, liver dysfunction, and teratogenic properties. We proposed indications of fingolimod therapy, and reduced dosage therapy of fingolimod for patients with a lymphocyte count below 0.2 x 10(9) cells/L. PMID- 25518387 TI - [Disease modifying therapies in multiple sclerosis]. AB - The purpose of this section is to introduce the clinical utility of several disease-modifying agents including natalizumab and immunosuppressive treatments that are currently available in Japan, and glatiramer acetate that will be probably available in Japan within a few years. Immunosuppressive therapy has been used to treat multiple sclerosis(MS) for over 30 years based on the hypothesis that MS is a T cell-mediated autoimmune disease. The most commonly used immunosuppressive agents in MS are azathioprine, cyclophosphamide, methotrexate, and mitoxantrone. Like the interferons and glatiramer acetate, immunosuppressive drugs are most efficacious in stages of MS that have an inflammatory component as evidenced by relapses and/or gadolinium-enhancing lesions on MRI or in patients in earlier stages of disease where inflammation predominates over degenerative processes in the CNS. There is no evidence of efficacy in primary progressive MS or later stages of secondary progressive MS. It is appropriate to consider glatiramer acetate for treatment in any patient who has relapsing remitting MS (RRMS), and glatiramer acetate may be helpful in patients with progressive disease. Because of the possibility that natalizumab therapy may be responsible for the increased risk of primary progressive leukoencephalopathy (PML), it is recommended that natalizumab be reserved for use in selected patients with relapsing remitting disease who have failed other therapies either through continued disease activity or medication intolerance, or who have a particularly aggressive initial disease course. PMID- 25518388 TI - [Prevention of relapse of neuromyelitis optica (NMO)]. AB - Treatment of NMO and NMO spectrum disorders is divided into two objectives: one is to control the inflammatory damage in acute attacks, and other one is a maintenance treatment to avoid relapses. The former is based on high-dose intravenous corticosteroids and plasmapheresis, the latter is based on low-dose corticosteroids and non-specific immunosuppressants; like azathioprine, tacrolimus, cyclosporine, mycophenolate mofetil and mitoxantrone. New therapy strategies using monoclonal antibodies like rituximab: an anti-CD20 monoclonal antibody, and eculizumab: an anti-C5 monoclonal antibody, can also prevent relapse of NMO. On the other hand, interferon-beta, natalizumab, and fingolimod, a modifying drug of multiple sclerosis, is not effective in NMO spectrum disorders. PMID- 25518389 TI - [Emerging disease-modifying therapies for multiple sclerosis]. AB - Multiple sclerosis(MS) is an inflammatory demyelinating disease of the central nervous system with yet undetermined etiology. The incidence of MS is rapidly rising in Japan, and in addition to four already-approved disease-modifying therapies (DMTs), namely interferon beta1b, interferonbeta1a, fingolimod and natalizumab, several new DMTs are currently under clinical trials. In this article, emerging DMTs such as alemtuzumab, dimethyl fumarate and teriflunomide as well as fampridine, a novel symptomatic treatment for gait disturbance, and anti-LINGO-1 monoclonal antibody, a possible candidate for future remyelination therapy, will be reviewed. Future treatment strategies such as induction therapy and combined therapy for MS will also be discussed. PMID- 25518390 TI - [Recent advances in the treatment of neuromyelitis optica]. AB - Neuromyelitis optica is an autoimmune-mediated inflammatory disease affected predominantly optic nerve and spinal cord. The pathogenic mechanism was found to be distinct from multiple sclerosis since the discovery of the disease specific autoantibody against water channel aquaporin-4. The pathogenicity of anti aquporin-4 antibody causes complement-dependent and cell-mediated astrocyte damage in the central nervous system, resulting in the severe inflammatory lesions including loss of aquaporin-4. The recent elucidation of pathological mechanism contributed to the development of treatment with monoclonal antibodies, e.g., rituximab, tocilizumab and eculizumab. It also raises the possibility that neutralization of the pathogenic autoantibodies, attenuation of polymorphonuclear leukocyte accumulation, and regulation of the proinflammatory cytokine and chemokine production can be efficacious for acute exacerbation and prevention of the relapses. PMID- 25518391 TI - [Home hospice care, working support and rehabilitation for MS/NMO]. AB - There are a huge amount of physical, mental and financial handicaps to patients with multiple sclerosis (MS) or neuromyelitis optica (NMO) and their family members, although treatment strategies have remarkably progressed recently. Among many important issues, to support them, here we make issues of home hospice care, working support and rehabilitation. We should consider social immaturity and ignorance to resolve the issues, and the key point to contribute useful support is consistent cooperation among medical teams and appropriate understanding of MS/NMO by all the people in our society as well as medical staffs. PMID- 25518392 TI - [How to manage medical treatment during pregnancy and childbirth]. AB - Generally, development of multiple sclerosis (MS) is during the childbearing age. Therefore, pregnancy and delivery are major issues in patients with MS. The Pregnancy in MS study reported that the annual relapse rate decreases during pregnancy and increases during the first 3 months after delivery. Interferon-beta (IFNbeta) therapy is usually discontinued prior to pregnancy. IFNbeta exposure was related to lower birth weight, however not observed any fetal complications or development abnormalities. Recently the new agents are used before pregnancy for MS. Fingolimod is teratogenic in rats. There is limited information on the safety of fingolimod in pregnancy. Natalizumab should not be used during pregnancy unless the clinical condition of the women requires treatment. Further studies are required to determine the potential risks associated with preconception and in utero disease-modifying-drug exposure in patients with MS. Neuromyelitis optica (NMO), recent larger scale studies consistently showed that relapse rate in NMO was significantly higher during the first 3 months postpartum as compared with before or during pregnancy. PMID- 25518393 TI - [Clinical features of pediatric multiple sclerosis: epidemiology and treatment]. AB - Multiple sclerosis (MS) in children is essentially not different from MS in adults; however, in children, it is sometimes difficult to distinguish MS from other demyelinating diseases. The main reason for this is that acute encephalitis/encephalopathy associated with infectious diseases, especially acute disseminated encephalomyelitis (ADEM), often causes demyelinating events in the central nervous system in childhood, and that the demyelinating episodes of MS in younger children clinically resemble ADEM events. Therefore, a number of studies on pediatric demyelinating diseases have been conducted to elucidate the clinical features of pediatric MS. In this article, the clinical features of pediatric MS in Japan were reviewed on the basis of the results of a nationwide survey as well as those in other countries. PMID- 25518394 TI - [Pathogenesis of autoantibodies in demyelinating disorders of the central nervous system]. AB - Several autoantibodies in relation to central nervous system demyelinating diseases (CDD) have been reported. Among them, anti-aquaporin 4(AQP4) antibody in neuromyelitis optica (NMO) is a reliable marker for the diagnosis of NMO and the antibody is thought to be closely related to its pathogenesis. Another antibody, anti-myelin oligodendrocyte glycoprotein (MOG) antibody is recently recognized in relevance to CDD, especially in seronegative NMO. Anti-MOG antibodies are also paid attention in pediatric acute disseminated encephalomyelitis (ADEM) and optic neuritis, however the roles for the pathogenesis in these disorders are still not clear. Generally, B cells and autoantibodies are thought to have certain roles in CDD. PMID- 25518395 TI - [Current state and prospect of pseudoxanthoma elasticum (PXE)]. AB - Pseudoxanthoma elasticum (PXE; OMIM 264800) is a rare, recessively-inherited disorder, which is characterized by progressive calcification and fragmentation of the elastic fibers in the skin, eyes, and cardiovascular system. We have collected clinical information from more than 200 Japanese PXE patients by sending mail to -1,000 hospitals in Japan. In those data, PXE is found to be accompanied by reduced visual acuity in the -30% patients. The incidences of ischemic disorders of the brain and heart in the PXE have been proved to be significantly higher than those in over 50 Japanese as control. Genetic analysis with 70 PXE cases revealed new mutations of ABCC6 that are different from those of Caucasian cases, which showed no genotype-phenotype relationship. PMID- 25518397 TI - [Present situation and new challenges for medical treatment of Kawasaki disease]. AB - To predict resistance to intravenous immunoglobulin (MIG) treatment in patients with severe Kawasaki disease (KD), Gunma, Kurume, and Osaka risk scores were established. Using these scores, prospective randomised trials were performed, and addition of predni- solone or intravenous methylprednisolone -pulse to the standard regimen of IVIG improves coronary artery outcomes in severe KD. Adding the evidences of new and existing therapies, such as infliximab, cyclosporin A, ulinastatin, and plasma exchange, the clinical guideline for medical treatment of the acute phase of KD was revised in 2012. Additional large cohort studies are needed to clarify the applicability of intensive initial treatment. Challenges for the future are: 1) clarification of etiology and establishment of specific therapy, 2) establishment of personalized therapy using genetic markers related to the severity of KD. PMID- 25518398 TI - [Natural history of Kawasaki disease vasculitis]. AB - Kawasaki disease is an acute vasculits syndrome of unknown etiology, which mainly affects small and medium arteries particularly coronary arteries in infants and young children. The cardiovascular problems include coronary artery lesions that develop the aneurysm formation, thrombotic occlusion, progression to coronary artery disease, and pre- mature atherosclerosis. However, the long-term consequences of these cardiovascular problems are still uncertain. In this article the long-term spectrums of Kawasaki disease vasculitis are described by our long-term follow-up study of 2,450 patients from clinical and pathological aspects. We like to emphasize that the long-term cardiovascular prob- lems are important issues not only in children but also in adulthood. PMID- 25518399 TI - [Epidemiology of Kawasaki disease]. AB - Epidemiologic features of Kawasaki disease, in particular in Japan, were summarized. There were three aspects of the epidemiology: (1) frequency(descriptive epidemiology), (2) risk factors(e.g. case-control studies), and (3) natural history(follow-up studies). The nationwide surveys, which was established in 1970, revealed the epidemiologic features of the disease. The number of patients and incidence rate have elevated since mid-1990s. Descriptive features indicates the association between disease onset and both infection and the hosts' factors. A follow-up study over 20 years has been conducted, but it should be continued till all the participants pass away. PMID- 25518400 TI - [Kawasaki disease and innate immunity]. AB - Kawasaki disease (KD) is an acute self-limited systemic vasculitis, and could develop in association with innate immune disorders. An innate immune system appears to play a key role in the development of KD, because pathogen-associated molecular patterns(PAMPs) and damage-associated molecular patterns(DAMPs) are elevated in the sera at acute phase KD, and oral administration of innate immune Nod1 ligand induces KD-like coronary arteritis in mice. PAMPs can be produced massively from microbes in a certain condition. DAMPs are produced from the host cells by the stimulation of PAMPs. We propose a hypothesis that PAMPs and DAMPs activate innate immune system and vascular cells through innate immune pattern recognition receptors(PRR) to release chemokines and cytokines, and induce KD in genetically predisposed individuals. PMID- 25518396 TI - [Pathology of coronary artery in Kawasaki disease]. PMID- 25518401 TI - [Cytokines in Kawasaki disease]. AB - We analyzed plasma levels of 14 cytokines in patients with Kawasaki disease (KD) before intravenous infusion of immunoglobulin (WIG) therapy using multiplex bead assay system. The results demonstrated that both inflammatory(TNF-alpha, IL-6, IL 8, IL-17, IFN-gamma, G-CSF, MCP-1 and sIL-2Ralpha) and anti-inflammatory(IL-10, sTNFR1 and sTNFR2) cytokine levels were simultaneously elevated in patients refractory to the initial IVIG therapy. System-level understanding of the cytokine networks would be the key to develop a new therapeutic strategy to prevent coronary artery injuries in KD. PMID- 25518402 TI - [Susceptibility genes for Kawasaki disease]. AB - More than 45 years have passed since Kawasaki disease(KD) was firstly described. Although the infectious agent possibly triggering the disease has not been identified, a total of 6 susceptibility genes/loci for KD have been identified through genome-wide studies. Although association of these loci are robust and has been confirmed in multiple populations, these can explain only a part of genetic background of the disease. Further investigation of genetic factors including unidentified common and rare variants as well as personal mutations contributing to individuals' susceptibility to the disease and risk for severer manifestation should be warranted and multicenter collaboration of collecting patients' subjects and information is essential for current and future genetic study of KD. PMID- 25518403 TI - [Clinical course and features in acute stage of Kawasaki disease]. AB - Kawasaki disease is diagnosed as a syndrome by definitive 6 principle signs and suspi cious clinical course. Health professionals are requested to know a common knowledge for those characteristics. In Japanese diagnostic guideline, fever is regarded as one of six prin ciple signs because some cases with five principle signs other than fever also developed coronary artery aneurysm. Japanese diagnostic guideline describes that duration of fever do not need 5 days or longer, if the fever resolved before the 5th day by early treatment such as intravenous immunoglobulin. Guideline warns that some incomplete cases also develop coronary artery complications. PMID- 25518404 TI - [Cardiac and extracardiac complications in Kawasaki disease]. AB - In terms of frequency and prognosis, discussions of the complications of Kawasaki disease have focused on coronary artery aneurysms and stenosis. However, as revealed by autopsy findings, medium and small muscular arteries in various organs could be injured in patients with Kawasaki disease, leading to the development of a variety of complications. Accurate diagnosis of Kawasaki disease can be especially difficult when incomplete Kawasaki disease is accompanied by rare complications involving the central nervous system, digestive system, and other systems in the body, which leads to delay in treatment and subsequent development of coronary artery aneurysms and delayed improvement of the existing complications. Doctors who treat Kawasaki disease should be familiar with the rare but important complications of Kawasaki disease. PMID- 25518405 TI - [Biomarker]. AB - The most serious complication of Kawasaki disease(KD) is coronary artery lesions (CAL), which mainly occur in patients with the incomplete form of KD and intravenous gamma-globulin therapy non-responsiveness (IVIG non-responsiveness). Recently, numerous biomarkers for diagnosis of the incomplete form of KD, endothelial dysfunction, and myocardial disturbance, as well as for the prediction of CAL formation and IVIG non- responsiveness, have been reported. However, a useful single biomarker has yet to be described. Pentraxin 3 (PTX3), endothelin-1(ET-1), brain natriuretic peptide(BNP) and N-terminal pro-brain natriuretic peptide are produced and secreted from vascular and/or myocardial tissue, and are very useful for diagnosis of the incomplete form of KD, and for the prediction of IVIG non-responsiveness and CAL formation in the acute phase. Further- more, some biomarkers are helpful for evaluating chronic coronary arteritis and atheroscle- rosis in the convalescent phase of KD. PMID- 25518406 TI - [ECG. Chest X ray]. AB - The electrocardiogram(ECG) findings in Kawasaki disease, which is minimal, often change over time. We have the impression that ECG findings in Kawasaki disease are rarely noticed too much. As the ECG findings, PR prolongation, QTc prolongation, relative low voltage, ST depression or elevation, increased height of T wave, and relative flattening of T wave are sometimes observed. The ischemic changes are similar to that of adults if complicated with coronary lesions. As for the chest X ray, the interstitial shadow such as reticular pattern or reticulogranular pattern takes 90 %. Among others, there are pleural effusion, atelectasis, emphysema, too. PMID- 25518407 TI - [Ultrasound imaging of coronary artery]. AB - Coronary arterial anatomy and the terminology were reviewed. There is a specific portion of coronary artery aneurysm in Kawasaki disease. To investigate coronary arterial lesion, ultrasound imaging is useful because of non-invasive, high special and time resolu tion method. I explained the patient posture, the approaching method to the coronary arter ies, ultrasound setting, measurement of coronary arterial diameter and diastolic measurement. PMID- 25518408 TI - [Cardiac scintigraphy-Pharmacological stress and appropriate management of pediatric radiopharmaceutical administration in patients after Kawasaki disease]. AB - Cardiac scintigraphy accounted for 2.5 % of all 3,884 patients based on a survey ques- tionnaire of pediatric nuclear medicine examinations performed at 14 Japanese institutes in 2011. Myocardial perfusion imaging, classified as cardiac scintigraphy, is essential to detect myocardial ischemia in patients after Kawasaki disease (KD), although its less frequent performance is reported. Adenosine is widely noticed as a medication for pharma- cological stress testing in coronary arterial lesions after KD. We describe characteristics of adenosine including newly-devised administration protocol and pathway making of intravenous injection for stress testing. We comment on optimal radiopharmaceutical administered doses proposed in Japanese consensus guidelines for pediatric nuclear medi- cine. Their proposal doses approximate that calculated by Pediatric Dosage Card of Euro- pean Association of Nuclear Medicine. We hope myocardial perfusion imaging is performed under appropriate management of pediatric radiopharmaceutical administration. PMID- 25518409 TI - [CT, MRI]. AB - Coronary arterial lesions (CAL) due to Kawasaki disease (KD) should be monitored by conventional coronary angiography(CAG) throughout their lives. However, recently multi detector row computed tomography(MDCT) and magnetic resonance coronary angiography (MRCA) have developed remarkably. We performed MRCA in 1,200 cases of KD (age at 4 month to 41 years: medium 8 years) since 1999. MR myocardial imaging is also performed simultaneously in patients with severe stenotic lesions. Noninvasive MRCA is useful to monitor CAL in young children. MDCT is efficient at screening of CAL and at making a diagnosis of no acute coronary syndromes in adults with chest pain. These examinations are very useful to decrease CAG to the least times as possible. PMID- 25518410 TI - [The algorithms of acute phase treatment for patients with Kawasaki disease]. AB - Approximately one decade has passed when the original version of "Guidelines for Medi cal Treatment of Acute Kawasaki Disease" was published. Since then, many clinical stud ies have investigated and new evidences regarding diagnosis and acute phase treatment have been piled up. Based upon the background, Research Committee of the Japanese Society of Pediatric Cardiology and Cardiac Surgery revised the guideline in December 2012. The revised guideline proposed new therapeutic algorithm for acute Kawasaki disease patients. The present review overviews the revised guideline especially focused on the algorithm, and explains how to treat acute phase Kawasaki disease patients. PMID- 25518411 TI - [Aspirin treatment for patients with Kawasaki disease]. AB - Aspirin was first used for patients with Kawasaki disease(KD) at 1970s. Favorable outcomes of KD patients treated with aspirin were reported in 1970-80s and now it is one of the standard therapeutic agents for KD. Its anti-inflammation effects suppress vascular wall inflammation of KD at acute phase. In addition, its antiplatelet effects heal endothelial dysfunction and prevent clot formation in coronary arteries at sub-acute and convalescent phase. Long-term dosage for patients with coronary artery aneurysms(CAA) is also important, however, there are few evidences of risk-benefit assessment for its long-term use especially for middle-aged and senior adults with KD and CAA. PMID- 25518412 TI - [Immunoglobulin therapy]. AB - Kawasaki disease(KD) is an acute, self-limited vasculitis of unknown etiology that predominantly affects infants and children. Coronary artery(CA) aneurysms, the most severe complication, occur in 25 % of untreated children and may lead to ischemic heart disease, myocardial infarction, or sudden death. While a single high dose of intravenous immunoglobulin (IVIG) terminates the fever and acute inflammation in most subjects and dramatically reduces the incidence of CA aneurysms, 10 to 20 % of KD patients are IVIG- resistant and these subjects are at higher risk of developing CA abnormalities. Several mechanisms have been reported for the anti-inflammatory activity of IVIG in different disease states. In this review, we describe the clinical utility and these mechanisms of IVIG in KD. PMID- 25518413 TI - [Prednisolone therapy for Kawasaki disease]. AB - Prednisolone therapy for acute phase Kawasaki disease had been considered to be controversial for several decades. However, recent clinical studies revealed that prednisolone therapy might improve coronary and clinical outcomes. The present paper reviews the roles of prednisolone therapy for acute phase Kawasaki disease patients. PMID- 25518414 TI - [Steroid pulse therapy]. AB - Intravenous methylprednisolone pulse (IVMP) is usually given because of its powerful and rapid immunosuppressive effect. In a randomized control trial for all patients with Kawasaki disease(KD), IVMP plus initial immune globulin(IVIG), compared with IVIG plus placebo, did not decrease the incidence of coronary artery lesions(CAL). It has been reported that suspected IVIG-resistant patients who received initial IVIG plus IVMP, compared with IVIG alone, had earlier defervescence and a significantly lower rate of CAL. For patients resistant to initial or additional IVIG, some studies showed that IVMP was effective for fast defervescence and prevention of CAL. As it stands, IVMP is indicated for initial therapy combined with IVIG for suspected IVIG-resistant patients or rescue therapy for IVIG-resistant patients. PMID- 25518415 TI - [Cyclosporin A treatment for refractory Kawasaki disease]. AB - The association between functional polymorphism of inositol 1,4,5-trisphosphate 3 kinase-C(ITPKC) and susceptibility to Kawasaki disease(KD) and formation of coronary arterial lesions was reported in 2008. Since ITPKC acts as a negative regulator of T-cell activation, activated T cells may play a pivotal role in the pathogenesis of KD. Cyclosporin A(CsA), which potently suppresses the activity of T cells through negative regulation of the nuclear factor of activated T cells(NFAT) pathway, may be a promising candidate for the treatment of refractory KD. In this review, we summarize the results of our clinical trials of CsA for refractory KD, the changes in the levels of cytokines before and after CsA treatment, and the future direction of CsA treatment for refractory KD. PMID- 25518416 TI - [Anti TNF-alpha (infliximab) treatment for intravenous immunoglobulin (IVIG) resistance patients with acute Kawasaki disease the effects of anticytokine therapy]. AB - Among the patients with acute Kawasaki disease treated with intravenous immunoglobulin (IVIG), 10-20 % demonstrate resistance or incomplete effects. Cardiac complication such as the coronary arterial aneurysm is frequent in these patients. For patients with IVIG-resistance, we have surveyed the efficacy and safety of anti-cytokine therapy with use of infliximab (Remicade), chimera type anti TNF-alpha agent, for children. After May, 2005, Remicade has been used in >500 pediatric patients in whom IVIG and intravenous methylprednisolone pulse therapy did not show significant effects. The efficacy and safety of Remicade on patients with IVIG-resistant Kawasaki disease has been observed but 10~20 % of patients was Remicade-resistant. Re-treatment with IVIG or steroids was also effective. The efficacy of Remicade for reducing the fever duration, CRP, WBC counts was promising, but reduction of the incidence of coronary aneurysm was not confirmed. Randomized clinical trial will be needed. PMID- 25518417 TI - [Use of the urinary trypsin inhibitor ulinastatin for acute Kawasaki disease]. AB - Intravenous immunoglobulin (IVIG) therapy is widely recognized as standard treatment for Kawasaki disease(KD). However, about 20 % of KD patients are resistant to IVIG and are considered to be a high risk group for coronary artery lesions (CAL). Ulinastatin(UTI) is one of the neutrophil elastase inhibitors used for patients with pancreatitis or circulatory shock, and several studies have shown its efficacy for KD. Recently, we demonstrated that initial UTI treatment combined with IVIG decreased the number of patients requiring addi- tional rescue treatment and the occurrence of CAL. In this study, no severe adverse events occurred. Further research and a prospective trial are needed to prove the clinical efficacy and demonstrate the limits of UTI in patients with KD. PMID- 25518418 TI - [Plasma exchange therapy]. AB - By the Kawasaki disease, it is important that treatment is effective before the tenth day of illness when a coronary lesion can occur, and it is a well-known fact that early disappearance of inflammation leads directly to the onset restraint of the coronary lesions. Plasma exchange (PE) removes inflammatory cytokine and chemokines in the blood for Kawasaki disease directly and suppresses the inflammation early. The treatment result of the PE for the IVIG-resistant Kawasaki disease is so good, and if it could be started before particularly coronary lesion develops, we will expect an extremely big effect. In addition, when immunoglobulin therapy, steroid pulse therapy or neutrophilic elastase inhibitor therapy is invalid, we can perform PE therapy with the insurance applica- tion in Japan. PMID- 25518419 TI - [Thromboprophylaxis in patients with coronary aneurysms caused by Kawasaki disease]. AB - Patients with coronary artery aneurysms caused by Kawasaki disease are at increased risk of coronary thrombosis and ischemia. To prevent coronary thrombosis, long term thromboprophylaxis using anti-platelet drugs, such as aspirin, dipyridamole, ticlopidine, clopidogrel, and abciximab, with or without warfarin is recommended by official guidelines. In fact, aspirin or aspirin with warfarin are the most frequently administered regimen in these patients with coronary aneurysms. However, still there has been paucity of data and no randomized controlled study to determine the efficacy of these drugs. This short article describes the currently accepted practice of thromboprophylaxis in patients with coronary aneurysms caused by Kawasaki disease. PMID- 25518420 TI - [The role of coronary intervention to coronary artery stenosis in Kawasaki disease]. AB - One characteristic of coronary artery lesions seen in the acute phase of children with Kawasaki disease is the formation of giant coronary aneurysms, with high grade stenosis lesion causing calcification both proximal and distal to the coronary aneurysm as patients reach school age. In balloon angioplasty the usual treatment for stenosis lesions, the presence of calcification makes expansion difficult, and bypass surgery is less than ideal in terms of long-term patency. As a result, these patients are usually given drug therapy and told to limit physical activity. The use of rotational atherectomy enables safe catheterization in these Kawasaki patients in lesions where balloon expansion cannot be obtained by balloon angioplasty. Efficacy is maintained over the long term, as well as during development as patients reach school age. It is now known that the presence of Kawasaki disease-like coronary aneurysms is a predictor of in hospital outcomes in early-onset(patients under 40 years of age) acute coronary syndrome, which suggests the importance of monitoring children with Kawasaki disease coronary aneurysms into adulthood. PMID- 25518421 TI - [Coronary artery bypass grafting for cardiovascular sequelae in Kawasaki disease]. AB - There are several issues regarding surgical revascularization for Kawasaki coronary disease including (1) the choice of conduits and (2) the optimal timing and correct indication for coronary artery bypass grafting(CABG). The internal thoracic artery(ITA) is the best conduit in terms of growth potential for pediatric CABG and for excellent long-term patency. The use of saphenous vein graft should be avoided unless an ITA is unavailable. The indication of CABG for Kawasaki coronary disease has not been established. In principle, coronary aneurysms should be observed continuously for 1 to 2 years under restrictive anticoagulation therapy, because regression of coronary aneurysm often occurs in 50 % within 1 to 2 years. The presence of severe ischemia in giant coronary aneurysms involving either the left main trunk or left anterior descending coronary artery is an absolute indicator for CABG. In addition, giant aneurysms with recurrent thrombosis under restrictive anticoagulation therapy or with severe delayed flow without significant localized stenosis may be an indication for CABG. PMID- 25518422 TI - [Coronary sequelae long after Kawasaki disease and acute coronary syndrome in the adulthood]. PMID- 25518423 TI - [Management for pregnancy and delivery in patients with a history of Kawasaki disease]. AB - We report the results of pregnancy and delivery in patients with coronary artery lesions caused by Kawasaki disease. The mode of delivery should be primarily determined by obstetrical considerations, rather than the coronary arterial lesions caused by Kawasaki disease. An assisted second stage of labor using epidural anesthesia is recommended in patients with a low left ventricular ejection fraction and significant localized stenosis of a coronary artery. However, if the patients are symptomatic or they have ischemic sign, Caesarean section should be recommended based on their general condition. A holter electrocardiogram at the third trimester is useful for decision of the mode of delivery. Aspirin at low doses is considered to be safe during pregnancy and delivery. PMID- 25518424 TI - [Renal erythropoietin-producing cells and kidney disease]. AB - Erythropoietin(EPO) is an indispensable erythropoietic hormone, produced mainly from kidneys in adult, and the production declines with progression of chronic kidney disease(CKD). Renal EPO-producing cells(REPs) are peri-tubular interstitial fibroblasts. Dysfunction and myofibroblast transformation of REPs have been reported in rodent models of kidney injuries. Despite the crucial importance of EPO in health and diseases, many aspects of REPs remain to be elucidated because of technical difficulties to investi- gate the cells in vivo. This review will summarize our recent progress in characterization of REPs. We also summarize the role REPs play in kidney fibrosis and their unique character "plasticity". Future therapeutic approach targeting REPs to treat both anemia and fibrosis in CKD will also be discussed. PMID- 25518425 TI - An experimental infection model for Escherichia coli egg peritonitis in layer chickens. PMID- 25518426 TI - An experimental infection model for Escherichia coli egg peritonitis in layer chickens. PMID- 25518427 TI - Lack of evidence that avian oncogenic viruses are infectious for humans: a review. AB - Chickens may be infected with three different oncogenic viruses: avian leukosis virus (ALV), reticuloendotheliosis virus (REV), and Marek's disease herpesvirus (MDV). Several epidemiological studies have suggested a link between these viruses and different types of cancer in people working in poultry processing plants and with multiple sclerosis. In this article, we analyze the epidemiological evidence that these viruses are causative agents for human cancer, followed by description of the relevant key characteristics of ALV, REV, and MDV. Finally, we discuss the biological evidence or lack thereof that avian tumor viruses are involved in the etiology of human cancer and multiple sclerosis (MS). The recent primary epidemiologic articles that we reviewed as examples were only hypothesis-generating studies examining massive numbers of risk factors for associations with various imprecise, non-viral-specific outcomes. The studies lacked precise evidence of exposure to the relevant viruses and the statistical methods failed to adjust for the large risks of false-positive claims. ALV subgroups A-D and J have been eradicated in the United States from the pure lines down to the parent stocks by the breeder companies, which have greatly reduced the incidence of infection in layer flocks and broilers. As a consequence, potential exposure of humans to these viruses has greatly diminished. Infection of humans working in processing plants with ALV-A and ALV-B is unlikely, because broilers are generally resistant to infection with these two subgroups. Moreover, these viruses enter cells by specific receptors present on chicken, but not on mammalian, cells. Infection of mammalian cell cultures or animals with ALV-A, ALV B, and ALV-J has not been reported. Moreover, humans vaccinated with exogenous or endogenous ALV-contaminated vaccines against yellow fever, measles, and mumps did not become antibody- or virus-positive for ALV. The risks for human infection with REV are similarly limited. First of all, REV also has been eradicated from pure lines down to parent stock by breeder companies in the United States. Broilers can still become infected with REV through infection with fowl pox virus containing REV. However, there is no indication that REV can infect human cells. Low levels of antibodies to ALV and REV in human sera have been reported by a few groups. Absorption of sera with chicken antigens reduced the antibody titers, and there was no clear association with contacts with poultry. Possible cross reactions with human endogenous or exogenous retroviruses were not considered in these publications. MDV is typically associated with infection of chickens, and almost all experimental data show that MDV cannot infect mammalian cells or animals, including nonhuman primates. One study reports the presence of MDV gD DNA in human sera, but this finding could not be confirmed by another group. A Medline search of the term "gene expression in human cancers" was negative for publications with avian retroviruses or MDV. In conclusion, there is no indication that avian oncogenic viruses are involved in human cancer or MS or even able to infect and replicate in humans. PMID- 25518428 TI - Potency, efficacy, and antigenic mapping of H7 avian influenza virus vaccines against the 2012 H7N3 highly pathogenic avian influenza virus from Mexico. AB - In the spring of 2012 an outbreak of H7N3 highly pathogenic (HP) avian influenza virus (AIV) occurred in poultry in Mexico. Vaccination was implemented as a control measure, along with increased biosecurity and surveillance. At that time there was no commercially available H7 AIV vaccine in North America; therefore, a recent H7N3 wild bird isolate of low pathogenicity from Mexico (A/cinnamon teal/Mexico/2817/2006 H7N3) was selected and utilized as the vaccine seed strain. In these studies, the potency and efficacy of this vaccine strain was evaluated in chickens against challenge with the 2012 Jalisco H7N3 HPAIV. Although vaccine doses of 256 and 102 hemagglutinating units (HAU) per bird decreased morbidity and mortality significantly compared to sham vaccinates, a dose of 512 HAU per bird was required to prevent mortality and morbidity completely. Additionally, the efficacy of 11 other H7 AIV vaccines and an antigenic map of hemagglutination inhibition assay data with all the vaccines and challenge viruses were evaluated, both to identify other potential vaccine strains and to characterize the relationship between genetic and antigenic distance with protection against this HPAIV. Several other isolates provided adequate protection against the 2012 Jalisco H7N3 lineage, but antigenic and genetic differences were not clear indicators of protection because the immunogenicity of the vaccine seed strain was also a critical factor. PMID- 25518429 TI - Biological characteristics of Chinese precocious strain of eimeria acervulina and its immune efficacy against different field strains. AB - In this study, the biologic characteristics of one experimental precocious strain of Eimeria acervulina and seven field isolates from different geographic locations in China were compared, and the immune efficacy of two precocious strains against coccidiosis in chickens was assessed to explore their potential use as coccidiosis vaccines. All the different strains were purified by single oocyst separation and their monospecificity was confirmed using E acervulina specific PCR assays. The average sizes of E. acervulina oocysts were 18.28-20.19 X 14.09-14.79 microm and the shape indexes were from 1.28 to 1.40. The prepatent periods ranged from 93 to 115 hr, except for the Heyuan precocious strain (HYP; 75 hr). Chickens infected with Huadu field strain (GHD) produced the highest oocyst output whereas HYP induced the lowest level. When inoculated with 50,000 sporulated oocysts or more, the average weight gains of infected chickens were reduced, with apparent clinical symptoms. To assess the immunogenicity of precocious strains HYP and Baoding (BDP), birds were orally immunized and challenged with seven different field strains of E. acervulina. Body weight gain, fecal oocyst output, and gut lesion scores were compared to evaluate their vaccine potential. The results showed that the average body weight gains of chickens in all the vaccinated and challenged groups were higher than those of nonvaccinated and challenged groups. In general, oocyst shedding was reduced 34.39%-95.31% and gut lesion scores decreased 31.03%-86.21% compared with unvaccinated and challenged control chickens. In summary, this study indicated that the precocious strains of E. acervulina could induce a protective immune effect with various responses against coccidiosis caused by different field strains. PMID- 25518430 TI - Molecular characterization and phylogenetic study of Newcastle disease viruses isolated in Iran, 2010-2012. AB - Newcastle disease (ND) is a highly contagious viral disease and has been a constant threat to the poultry industry worldwide. In this study, partial sequences of ND virus (NDV) fusion genome collected from some provinces in Iran during 2010-2012 in vaccinated commercial farms were characterized and compared with other NDV sequences. All viruses showed the amino acid sequence 112 RRQKRF117 at the C-terminus of the F2 protein and phenylalanine at the N-terminus of the F1 protein, residue 117. These amino acid sequences were identical to a known virulent motif. The phylogenetic analysis showed that the Iranian ND isolates in this study are closely related to the genotype VIId of class II NDV strains. The emergence and identification of new sublineages provide an insight into the high rate of genetic drift occurring in NDV strains in Iran, and raise many concerns about the efficacy of current ND control measures in the country. PMID- 25518431 TI - Evaluation of capillary and myofiber density in the pectoralis major muscles of rapidly growing, high-yield broiler chickens during increased heat stress. AB - Skeletal muscle development proceeds from early embryogenesis through marketing age in broiler chickens. While myofiber formation is essentially complete at hatching, myofiber hypertrophy can increase after hatch by assimilation of satellite cell nuclei into myofibers. As the diameter of the myofibers increases, capillary density peripheral to the myofiber is marginalized, limiting oxygen supply and subsequent diffusion into the myofiber, inducing microischemia. The superficial and deep pectoralis muscles constitute 25% of the total body weight in a market-age bird; thus compromise of those muscle groups can have profound economic impact on broiler production. We hypothesized that marginal capillary support relative to the hypertrophic myofibers increases the incidence of microischemia, especially in contemporary high-yield broilers under stressing conditions such as high environmental temperatures. We evaluated the following parameters in four different broiler strains at 39 and 53 days of age when reared under thermoneutral (20 to 25 C) versus hot (30 to 35 C) environmental conditions: capillary density, myofiber density and diameter, and degree of myodegeneration. Our data demonstrate that myofiber diameter significantly increased with age (P > or = 0.0001), while the absolute numbers of capillaries, blood vessels, and myofibers visible in five 400 x microscopic fields decreased (P > or = 0.0001). This is concomitant with marginalization of vascular support in rapidly growing myofibers. The myofiber diameter was significantly lower with hot environmental temperatures (P > or = 0.001); therefore, the absolute number of myofibers visible in five 400X microscopic fields was significantly higher. The incidence and subjective degree of myodegeneration characterized by loss of cross-striations, myocyte hyperrefractility, sarcoplasmic vacuolation, and nuclear pyknosis or loss also increased in hot conditions. Differences among strains were not observed. PMID- 25518432 TI - An outbreak of Mycobacterium genavense infection in a flock of captive diamond doves (Geopelia cuneata). AB - Two diamond doves (Geopelia cuneata) in a flock of 23 birds housed in an aviary in a zoo in central Japan were found dead as a result of mycobacteriosis. Fecal samples of the remaining doves were positive for mycobacterial infection, and thus they were euthanatized. Clinical signs and gross pathology, including weight loss and sudden death and slight enlargement of the liver and intestine, were observed in a small number of birds (3/23). Disseminated histiocytic infiltration of either aggregates or sheets of epithelioid cells containing acid-fast bacilli, in the absence of caseous necrosis, were observed in different organs of the infected doves, especially lungs (23/23), intestines (9/23), livers (7/23), and hearts (6/23). Mycobacterium sp. was isolated from the livers of three birds (3/23). DNA extracted from frozen liver and formalin-fixed, paraffin-embedded tissues (5/23) were used for amplification of the gene encoding mycobacterial 65 kDa heat shock protein (hsp65). The causative Mycobacterium species was identified by PCR-restriction fragment length polymorphism analysis. Mycobacterium genavense infection was confirmed in three of the diamond doves. Moreover, partial 16S rDNA gene sequencing revealed 100% identity across the three samples tested, and 99.77% nucleotide homology of the isolate sequence to M. genavense. The main route of M. genavense infection in the diamond doves was most likely airborne, suggesting a potential zoonotic risk of airborne transmission between humans and birds. PMID- 25518433 TI - Evaluation of an experimental irradiated oocyst vaccine to protect broiler chicks against avian coccidiosis. AB - The current study investigates the use of irradiated oocysts to protect broiler chicks, raised on litter, from infection with multiple species of Eimeria. In order to determine the optimum radiation dose for each Eimeria species, 1-day-old chicks were immunized with oocysts of Eimeria maxima, Eimeria acervulina, or Eimeria tenella exposed to gamma radiation ranging from 0-500 Gy. The litter oocyst counts at 7 days postimmunization, and the effect on weight gain following a challenge infection, decreased with an optimum dose between 150-200 Gy. Based on this finding, broiler chicks were immunized with a mixture of E. maxima, E. acervulina, and E tenella that had been exposed to 150 or 200 Gy. This resulted in more than a 100-fold reduction in litter oocyst counts and significant protection from a challenge infection, as measured by improved weight gain and feed conversion ratio (FCR). Immunization of birds with oocysts receiving 200 Gy was less effective in providing protection from a challenge infection. An additional formulation of vaccines containing two different oocyst doses of the three species that had been irradiated with 150 Gy were evaluated in their ability to attenuate oocyst output and convey protection to challenge. Results were similar with both high and low numbers of irradiated oocysts. Immunized chicks shed less oocysts at 7 days postimmunization and were protected from negative effects of challenge infection as measured by FCR, changes in weight gain, lesion scores, and measurement of body composition. However, the level of protection was somewhat less than that achieved by immunization with nonirradiated oocysts. The overall conclusion is that an irradiated oocyst vaccine developed in this study can effectively protect chicks that are raised on litter from challenge infection with multiple species of Eimeria, comparable to vaccines with virulent or precocious strains. PMID- 25518434 TI - Detection of infectious bronchitis virus with the use of real-time quantitative reverse transcriptase-PCR and correlation with virus detection in embryonated eggs. AB - Real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assays have been used to detect the presence of challenge virus when the efficacy of infectious bronchitis virus (IBV) vaccine against field viruses is being experimentally evaluated. However, federal guidelines for licensing IBV vaccines indicate that challenge-virus detection following vaccination is to be conducted in embryonated eggs. In this study, we examined qRT-PCR data with the use of universal and type-specific primers and probe sets for IBV detection and compared those data with challenge-virus detection in embryonated eggs to determine if the two methods of evaluating vaccine efficacy are comparable. In addition, we tested the qRT-PCR assays on thermocyclers from two different manufacturers. We found the universal IBV primers and probe set to be comparable to challenge-virus detection in embryonated eggs. However, for some IBV types (Mass41 and Conn on the SmartCycler II and Ark, Mass41, Conn, and GA98 on the ABI 7500) the qRT-PCR assay was more sensitive than virus detection in embryonated eggs. This may simply be due to the universal IBV qRT-PCR assay being more sensitive than virus detection in eggs or to the assay detecting nucleic acid from nonviable virus. This finding is important and needs to be considered when evaluating challenge virus detection for vaccination and challenge studies, because qRT-PCR could potentially identify positive birds that would otherwise be negative by virus detection in embryonated eggs; thus it could lead to a more stringent measure of vaccine efficacy. We also found that the IBV type-specific primers and probe sets designed in this study were in general less sensitive than the universal IBV primers and probe set. Only the Ark-DPI-spedcific assay on the SmartCycler II and the Ark-DPI-, Mass41-, and DE072/GA98- (for detection of GA98 virus only) specific assays on the ABI 7500 were comparable in sensitivity to virus detection in eggs. We found that a number of variables, including the virus type examined, primers and probe efficiency and stability, and assay conditions, including thermocycler platform, can affect the data obtained from qRT-PCR assays. These results indicate that qRT-PCR assays can be used to detect IBV challenge virus, but each assay, including the assay conditions and thermocycler, should be individually evaluated if those data are expected to be comparable to virus detection in embryonated eggs. PMID- 25518435 TI - One-step real-time reverse transcription-PCR for the detection of turkey reoviruses. AB - During late 2010 and early 2011, an unusual problem of lameness and swollen hock joints in commercial turkeys was reported in the upper Midwest, which continues to this day. The disease caused substantial economic losses to turkey producers. Reovirus was isolated from tendons and joint fluids of lame turkeys submitted to the Minnesota Veterinary Diagnostic Laboratory. This study was undertaken to develop a TaqMan real-time reverse transcription-PCR (rRT-PCR) assay for the early detection of turkey reoviruses (both enteric and lameness strains). A primer probe set was designed from the conserved region of the S4 segment of the turkey reovirus genome. The newly developed rRT-PCR was specific for the detection of turkey reoviruses. The detection limit of this assay was 10 genome copies per reaction. For the TARV-MN4 strain of turkey arthritis reovirus, one 50% tissue culture infectious dose was equivalent to 11.6 +/- 0.2 genome copies. The highest coefficient of variation for intraexperimental and interexperimental variability was 0.08 and 0.06, respectively, indicating the reproducibility of the assay. This new test should be useful for the detection of turkey enteric and arthritis reoviruses. PMID- 25518436 TI - Mucin gene mRNA levels in broilers challenged with eimeria and/or Clostridium perfringens. AB - The effects of Eimeria (EM) and Clostridium perfringens (CP) challenges on the mRNA levels of genes involved in mucin (Muc) synthesis (Muc2, Muc5ac, Muc13, and trefoil family factor-2 [TFF2]), inflammation (tumor necrosis factor alpha [TNF alpha] and interleukin-18 [IL-18]), and metabolic processes (cluster of differentiation [CD]36) in the jejunum of broilers were investigated. Two parallel experiments involving 1) EM challenge and 2) EM and CP challenges were conducted. The first experiment was a 2 X 2 study with 12 birds per treatment (N = 48) involving fishmeal substitution (25%) in the diet (FM) and EM challenge. The treatments were: Control (FM-, EM-), Fishmeal (FM+, EM-), EM challenge (FM-, EM+), and fishmeal substitution and EM challenge (FM+, EM+). The second experiment was a 2 X 2 X 2 experiment with six birds per treatment (N = 48) involving fishmeal (FM-, FM+), Eimeria (EM-, EM+), and C perfringens (CP-, CP+). In both arms of the study, male broilers were given a starter diet for the whole period of 16 days, except those assigned to FM+, where 25% of the starter ration was replaced with fishmeal from days 8 to 14. EM inoculation was performed on day 9 and CP inoculation on days 14 and 15. The EM challenge birds were euthanatized for sampling on day 13; postmortem examination and sampling for the Eimeria plus C perfringens challenge arm of the study were on day 16. In the Eimeria challenge arm of the study, fishmeal supplementation significantly suppressed the mRNA levels of TNF-alpha, TFF2, and IL-18 pre-CP inoculation but simultaneously increased the levels of Muc13 and CD36 mRNAs. Birds challenged with Eimeria exhibited increased mRNA levels of Muc13, Muc5ac, TNF-alpha, and IL-18. In the Eimeria and C. perfringens challenge arm, birds exposed to EM challenge exhibited significantly lower mRNA levels of Muc2 and CD36. The mRNA levels of CD36 were also significantly suppressed by CP challenge. Our results showed that the transcription of mucin synthesis genes in the jejunum of broilers is modulated by fishmeal inclusion in the diet. Furthermore, we show for the first time suppression of CD36 mRNA levels in the intestine of broilers challenged with Eimeria or C. perfringens. PMID- 25518437 TI - Effect of cold stress on expression of AMPKalpha-PPARalpha pathway and inflammation genes. AB - Animals are exposed to various environmental stresses every day, including the stress associated with living in cold temperatures. The aim of this study was to investigate the possible mechanisms of interaction between lipid metabolism and inflammation induced by cold stress in the livers of chickens. Fifteen-day-old male chicks were randomly allocated into 12 groups (10 chickens per group). After exposure of the chickens to the cold stress, cholesterol fractionation was used to examine high-density lipoprotein (HDL) and low-density lipoprotein (LDL) concentrations. Aminotransferase activities were examined with the use of the aspartate transaminase (AST) and alanine transaminase (ALT) assay. The AMP activated protein kinase alpha-proliferator-activated receptor alpha (AMPKalpha PPARalpha) pathway genes (AMPKalpha1, AMPKalpha2, PPARalpha, carnitine palmitoyltransferaseI [CPTI], acetyl-CoA carboxylase [ACC]) and inflammatory cytokines (prostaglandin E synthase [PGEs], inducible nitric oxide synthase [iNOS], heme oxygenase-1 [HO-1], nuclear factor kappa-light-chain-enhancer of activated B cells [NF-kappaB], cyclooxygenase-2 [COX-2], and TNF-alpha-like factor [LITAF]) were also measured. The results showed that during the response to cold stress, serum LDL and HDL cholesterol concentrations increased. Histopathologic analyses provided evidence that liver tissues were seriously injured in the chickens exposed to the cold stress. Serum aminotransferase activities were also increased in the group of animals exposed to the cold stress. Additionally, the expressions of AMPKalpha-PPARalpha pathway genes and inflammatory cytokine genes were significantly increased in the animals exposed to cold temperatures. These results suggested that increased inflammation was a feature associated with a lipid-metabolism disorder in the livers of chickens exposed to cold stress. PMID- 25518438 TI - Pathogenesis of histomonosis in experimentally infected specific-pathogen-free (SPF) layer-type chickens and SPF meat-type chickens. AB - Several studies have shown differences in the course of histomonosis, the infection with the trichomonad parasite Histomonas meleagridis, in different chicken breeds. In the present study, 10 specific-pathogen-free (SPF) layer-type (LT) chickens and twelve SPF meat-type (MT) chickens were infected intracloacally with 200,000 H. meleagridis trophozoites. One and two weeks postinfection (p.i.), three birds of each group were euthanatized. The remaining birds were euthanatized 3 wk p.i. Infected birds showed severe gross lesions typical for histomonosis in ceca at the first and second week p.i., while livers showed necrotic foci at 2 and 3 wk p.i., but only very rarely at 1 wk p.i. Differences between groups in the severity of lesions were statistically insignificant. In histopathology, LT chickens showed a significantly more-severe necrosis and ablation of the cecal epithelium 1 wk p.i. Parasites without inflammation were also found in most investigated spleens and lungs but only in a few kidneys. Investigation of these organs for histomonal DNA by real-time PCR confirmed these results. In addition, the humoral immune response against histomonal actinin 1 and 3 was measured by an ELISA. The humoral immune response against actinin 1 started sooner and was significantly higher in LT chickens than in MT chickens. In conclusion, the results of the present study suggest that the genetic background of the birds influences the reaction to infection with H. meleagridis. PMID- 25518439 TI - Effects of dexamethasone immunosuppression on turkey clostridial dermatitis. AB - Clostridia represents a group of anaerobic spore-forming bacteria ubiquitous in the poultry environment. They are widely distributed in soil and survive for many years as highly resistant, inactive spores. They enter the body through wounds and contaminated feed as active bacteria or spores. Multiplication of clostridial bacteria occurs only in the absence of oxygen or in environments with very low concentrations of oxygen. During active multiplication, the clostridial organisms produce several toxins that are responsible for most of the clinical signs seen in clostridial diseases. Immunosuppression is a problem for the poultry industry. In modern, intensive poultry-rearing conditions, stress due to high population densities pose a considerable challenge for the immune system, and infectious agents can exploit this situation to cause disease. Immunosuppression may predispose turkeys to clostridial infection, resulting in clostridial dermatitis and mortality. The purpose of this study was to determine whether immunosuppression predisposes turkeys to clostridial infection and causes clostridial dermatitis. We immunosuppressed 10-wk-old turkey poults with dexamethasone. The birds immunosuppressed and not immunosuppressed were then challenged with Clostridium perfringens, Clostridium septicum, or both and examined for the development of clostridial dermatitis. The dexamethasone-treated birds were found to be more susceptible to C. peifingens/C. septicum challenge and developed clostridial dermatitis than the no-dexamethasone-treated birds through the subcutaneous route. However, oral inoculation of the same agents did not cause any dermatitis lesions in either of the groups. PMID- 25518440 TI - Development and application of a vaccination planning tool for avian influenza. AB - The vaccination planning tool for avian influenza supports evidence-based planning and preparedness for vaccinating poultry at national and regional levels. This study describes the development, testing, and application of a vaccination planning tool for H5N1 highly pathogenic avian influenza (HPAI) used in two South Asian countries. The tool consists of eight planning clusters, 37 planning elements, and 303 referenced planning criteria. Both countries attained a score of 52% among planning clusters as a measure of preparedness. The highest and lowest planning cluster scores included vaccination strategies and financial readiness, respectively. The comprehensive vaccination program was identified as the most-useful planning cluster for assessing preparedness, and 86% of participants indicated that the objectives of the planning tool were achieved. Based on these results, the planning tool provides a structured approach for decision makers to develop their national vaccination program for HPAI as part of an overall strategy for the progressive reduction and control of endemic influenza viruses in poultry. PMID- 25518441 TI - Survivability of Eurasian H5N1 highly pathogenic avian influenza viruses in water varies between strains. AB - Aquatic habitats play a critical role in the transmission and maintenance of low pathogenic avian influenza (LPAI) viruses in wild waterfowl; however, the importance of these environments in the ecology of H5N1 highly pathogenic avian influenza (HPAI) viruses is unknown. In laboratory-based studies, LPAI viruses can remain infective for extended durations (months) in water, but the persistence is strongly dependent on water conditions (temperature, salinity, pH) and virus strain. Little is known about the stability of H5N1 HPAI viruses in water. With the use of an established laboratory model system, the persistence of 11 strains of H5N1 HPAI virus was measured in buffered distilled water (pH 7.2) at two temperatures (17 and 28 C) and three salinities (0, 15,000, and 30,000 ppm). There was extensive variation between the 11 H5N1 HPAI virus strains in the overall stability in water, with a range similar to that which has been reported for wild-bird-origin LPAI viruses. The H5N1 HPAI virus strains responded similarly to different water temperatures and salinities, with all viruses being most stable at colder temperatures and fresh to brackish salinities. These results indicate that the overall stability and response of H5N1 HPAI viruses in water is similar to LPAI viruses, and suggest there has been no increase or loss of environmental survivability in H5N1 HPAI viruses. PMID- 25518442 TI - Description of rotavirus F in broilers from Brazilian poultry farms. AB - Rotaviruses are segmented double-stranded RNA viruses that cause gastroenteritis in mammals and birds. Here we describe the first partial nucleotide sequences of the structural protein VP6 from the genomes of group F rotaviruses that were detected in 5 out of 53 fecal samples (9.43%) from healthy broilers from Brazilian poultry farms based on reverse-transcriptase-PCR with primers designed for this study. The findings support the development of molecular detection systems, which can be used for the assessment of the distribution of rotavirus F in birds, their potential involvement in diseases, and their impact on poultry health. PMID- 25518443 TI - In vitro inactivation of two Egyptian A/H5N1 viruses by four commercial chemical disinfectants. AB - The highly pathogenic H5N1 avian influenza virus (A/H5N1) devastated the poultry industry and posed a serious health threat. Cleaning and disinfection are essential parts of preventative and postoutbreak management of A/H5N1 infections in poultry. In this preliminary study, we used suspension and carrier tests to evaluate the impact of concentration, time of exposure, surface porosity, and organic matter on the ability of four commercial chemical disinfectants to inactivate two A/H5N1 viruses of clade 2.2.1 isolated in 2006 and 2010 from broiler flocks in Egypt. Viruses were incubated with 0.5%, 1%, and 2% of formalin, glutaraldehyde, TH4, and Virkon S for 15, 30, 60, and 120 min at room temperature (22 +/- 2 C). In suspension tests, in the absence of organic matter, all disinfectants, at each concentration, except Virkon S 0.5%, effectively inactivated virus suspensions after a 15-min exposure time. In the presence of organic matter, the use of low concentrations of formalin (0.5%), glutaraldehyde (0.5%), or Virkon S (0.5%) was not sufficient to inactivate the viruses after 15 min. In gauze carrier tests, only formalin at any concentration for 15 min was sufficient to inactivate the viruses, whereas different concentrations or exposure times were required for glutaraldehyde (0.5% for 60 min), TH4 (0.5% for 30 min), and Virkon S (0.5% for 60 min or 1% for 30 min). In wood carrier tests, total inactivation of the virus was obtained at concentrations of 0.5% for 30 min (formalin and TH4) or 60 min (glutaraldehyde and Virkon S). This study emphasizes the need to use high concentrations of and/or extended time of exposure to disinfectants for efficient inactivation of A/H5N1, particularly in the presence of organic matter or different surfaces, which are common in poultry operations. In addition, it seemed that the virus isolated in 2010 was more resistant to disinfectants than the isolate from 2006 when wood was used as a carrier. PMID- 25518445 TI - Liver pathology associated with increased mortality in turkey breeder and meat turkey flocks. AB - Between 2006 and 2011 a series of disease conditions characterized by raised mortality and liver disorders occurred in turkey breeder flocks and in meat turkey flocks in Germany. The flocks were between 12 and 23 wk of age, and mostly hens were affected. Clinical signs were nonspecific and accompanied by mortality varying between 1% and 7%. Affected birds displayed swollen livers that were marbled with black and red spots and yellowish areas. The pericardium was filled with an amber fluid, and the coronary groove was extensively filled with fat. Spleens were swollen, and a serous fluid that seemed to leak from the liver was present in the body cavity. Histopathological findings in all but one case included fatty degeneration of hepatocytes with parenchymal collapse and associated hemorrhages. Some animals showed cholangitis and hepatitis with intranuclear inclusion bodies. In three cases with breeders, electron microscopy detected virus particles that were between 23 and 30 nm and similar to parvo- or picornavirus. In addition, picornavirus RNA was detected in the livers of one meat turkey flock. Investigations by PCR for circovirus, polyomavirus parvovirus, and aviadenovirus yielded negative results in all cases, but an aviadenovirus was isolated from livers twice and a reovirus from the intestines once. Supplementation with vitamin E and selenium seemed to improve the situation. The most likely diagnosis is lipidosis, a metabolic disorder with complex etiology, which has rarely been described in turkeys. PMID- 25518444 TI - Expression of genes encoding matrilin-3 and cyclin-I during the impairment and recovery of chicken growth plate in tibial dyschondroplasia. AB - Tibial dyschondroplasia (TD) is a skeletal disease characterized by the disruption ofendochondral bone formation in avian species. The aim of this study was to determine the expression of Matrilin-3 and Cyclin-I genes in chicken growth plate during impairment and recovery from TD. Gene expressions were analyzed by polymerase chain reaction, and proteins by immunohistochemistry and in situ hybridizations. Expression of genes encoding Matrilin-3 and Cyclin-I were diminished with parallel decrease in proteins during TD, with fewer signs of cartilage cell differentiation. In contrast, there was an increase in mRNA expressions and protein levels of both genes during the recovery phase. These findings suggest that the Matrilin-3 and Cyclin-I genes also play a role in chondrocyte differentiation during the impairment and recovery of growth plate in TD. PMID- 25518446 TI - Psittacine beak and feather disease-like illness in Gouldian finches (Chloebia gouldiae). AB - Beak and feather disease virus (BFDV) is a member of the genus Circovirus and causes psittacine beak and feather disease (PBFD) in Psittaciformes. PBFD is a severe disease generally characterized by immunodeficiency and beak and feather disorders. Although Circovirus spp. have been detected in several nonpsittacine species, little is known about the symptoms and the disease associated with this infection in birds other than Psittaciformes. In this study, we report the identification of Circovirus infection in a flock of Gouldian finches showing beak and feather disorders. Sequence analyses on the rep gene of the virus highlighted a strong similarity at nucleotide and amino acid levels with the corresponding regions of BFDV from psittacine species. By contrast, it was more distant to circoviruses identified in finch and canary. PMID- 25518447 TI - The first case of a major avian type C botulism outbreak in Poland. AB - Major outbreaks of avian type C botulism have been rarely reported from Central Europe. In this paper, we report the first severe outbreak of avian type C botulism in Poland. In 2011-12, two epizootics caused by Clostridium botulinum took place at Jeziorsko dam reservoir and affected an estimated number of 5500 birds in 2011 and 1600 birds in 2012. In total, 24 species ofwaterbirds were affected, including mainly waterfowl (37.0%), shorebirds (27.0%), rallids (25.7%), and larids (9.1%). Mallards (Anas platyrhynchos) and coots (Fulica atra) were most commonly represented among all affected species (27.5% and 25.0% of all recorded carcasses, respectively). Laboratory analyses confirmed the presence of type C botulinum toxin in the internal organs of paralyzed birds. This case study from the Jeziorsko dam reservoir demonstrates that this type of shallow-water habitat is especially prone to avian botulism outbreaks in the climatic conditions of Central Europe. PMID- 25518448 TI - Fowl typhoid (Salmonella Gallinarum) outbreak in Japanese quail (Coturnix coturnix japonica). AB - A fowl typhoid (FT) outbreak is reported in a flock of 400 Japanese quail (Coturnix coturnix japonica) at 91 days of age. Of these, 222 died suddenly, and necropsy revealed swollen liver and spleen with off-white to yellowish granules and reddish small intestine mucosa. Histopathology showed severe multifocal necrosis of liver and spleen (5/5), pulmonary congestion with macrophage infiltration in air capillaries (5/5), discrete interstitial nephritis (2/2), superficial necrosis of the intestinal mucosa with large numbers of coccobacilli (2/2), moderate peritonitis (2/2), and discrete airsacculitis (1/1). Anti Salmonella immunohistochemistry (IHC) stained the cytoplasm of macrophages or free in the liver (5/5), spleen (5/5), lungs (4/5), kidneys (2/2) small intestine mucosa (2/2), cecum (1/1), bone marrow (1/1), air sacs (1/1), and ovary (1/1). In the heart (5/5), brain (2/2), esophagus (2/2), pancreas (2/2), proventriculus (2/2), gizzard (1/1), bursa of Fabricius (1/1), oviduct (1/1), and skeletal muscle (1/1) staining was observed only in the lumen of blood vessels. Salmonella Gallinarum was isolated in pure cultures of liver, spleen, lung, intestine, and blood samples of two birds. PMID- 25518449 TI - Gastric duplication: proventricular cystic choristoma on the spleen of a broiler chicken. AB - Gastric duplication (choristoma) is a very rare anomaly in both humans and other animal species. We report herein a case of proventricular cystic choristoma in a 62-day-old broiler chicken. The broiler chicken was brought from the slaughterhouse to our laboratory after a pale-brown cystic structure closely attached to a thin, compressed spleen was identified. On necropsy, the cystic structure showed a clear mucinous fluid. Histopathologically, the cystic structure was lined by proventricular mucosa presenting in folds and sulci. Submucosal proventricular glands, consisting of secretory units and collecting tubules, occupied parts of the choristomal wall. The gastric mucosa lining the choristomal wall stained positive with periodic acid-Schiff stain, stained negative with Alcian blue staining, and showed a thin layer of smooth muscle fibers and a thick connective tissue layer with Masson trichrome. Ectopic pancreas was noticed attached to the wall of the choristoma. To the best of our knowledge, this represents the first report of choristoma in an avian species. PMID- 25518450 TI - [The evolution of understanding the concept of biliary tract diseases in childhood]. PMID- 25518451 TI - [Holter monitoring data in children with gastroesophageal reflux disease]. AB - The aim of research is to estimate the functional state of the cardiovascular system in children with gastroesophageal reflux disease (GERD) with the help of Holter monitoring. 117 children of school age were examined: 69 children with GERD and 48 children with chronic gastroduodenitis. All children passed esophagogastroduodenoscopy, 24-hour pH-monitoring, electrocardiography and Holter monitoring. According to Holter monitoring data it was revealed that children with GERD had increased low-frequency components of frequency domain analyses, increased number of nocturnal PVCs and increased time of enhanced dispertion periods. Holter monitoring in patients with GERD can be used to detect preclinical ectopic rhythm, to evaluate autonomic dysfunction by frequency domain analyses, to predict nocturnal symptoms. PMID- 25518452 TI - [Iron deficiency anemia and anemia in chronic celiac disease in children]. AB - Anemia in celiac disease (CD) may be associated with deficiency of iron, vitamins, macro- and micronutrients. It is also possible the development of chronic disease anemia (CDA), associated with activation of proinflammatory cytokines. The aim of this work is to optimize the diagnosis and treatment of celiac disease in children on the basis of study of iron metabolism disorders heterogeneity, including the role of CDA. PATIENTS AND METHODS: We observed 34 children with CD aged 1.5 to 17 years, 27 of them children were observed both in the active stage of the disease and in remission. The control group included 25 children aged 1.2 to 17 years who were previously excluded for any chronic (including autoimmune) disease: these children were observed with chronic functional gastrointestinal motility disorders. Special methods of examination were study of iron metabolism, including the determination of the serum hepcidin level, as well as the determination of the serum proinflammatory cytokines (tumor necrosis factor [TNF] -alpha, interleukin [IL] -2, IL-6, IL-10). RESULTS AND DISCUSSION: In active CD in 14.71% of children anemia of varying severity (mild or moderate) were diagnosed. Among these children we observed mild decrease of serum iron in the range 2.2-8.0 g/ml in 15 of 34 children (44%) and a marked reduction in serum ferritin level in 59% of children. In the active celiac disease in the majority of children there is a decrease in the serum hepcidin, but approximately in 20% of children serum hepcidin level was increased. This indicates the development of CDA in these children. During the active stage the average values of IL-2 was significantly increased (p < 0.05). Thus, the iron metabolism disorders in celiac disease is a result of immunopathological process which results in a reduction in iron absorption in the gut due to the intestinal mucosa villous atrophy and to improve the hepcidin production by liver cells and iron depot blocking with the CDA development in 20% of children. PMID- 25518454 TI - [Dyslipidemia in children with cholelithiasis as a marker of metabolic syndrome development]. AB - In the article based on own research shows changes in lipid and carbohydrate metabolism in children with gallstone disease (GSD), characteristic of the metabolic syndrome (MS). The data obtained suggest that obesity is not always a marker of the metabolic syndrome. A key element in the development of MS are the changes of lipid and carbohydrate metabolism. PMID- 25518453 TI - [Morphological features of oesophagogastric junction mucosa in children with gastroesophageal reflux disease]. AB - In present work we studied the morphological features of the esophageal mucosa in 63 children with gastroesophageal reflux disease (GERD). The biopsies were taken at level of 3 cm above a Z-line and at level of 0.5-1 cm above a Z-line. The results of our study showed that the mucosa of the esophago-gastric junction may contain areas covered with columnar epithelium of 44.4% of children in the biopsies from the level of 0.5-1.0 cm above the Z-line. Inflammatory changes in the mucosa of the esophago-gastric junction identified in 71.4% of cases. The inflammation in the majority of cases (82.1%) was observed in the presence of H. pylori infection (p < 0.001). In addition, H. pylori in our study, we noted the relationship detection carditis in overweight child. When compared with the height-weight parameters, the excess body weight was observed in 17 of 28 patients. We couldn't found increasing detection of the cardia in patients with erosive GERD compared with non-erosive variants. PMID- 25518455 TI - [The clinical significance of evaluation of the inflammatory infiltrate in chronic gastroduodenitis in children]. AB - OBJECTIVE: To establish the diagnostic value of the determination of leukocyte composition of inflammatory infiltrate in chronic gastroduodenite in childhood. PATIENTS AND METHODS: We examined 103 patients aged 8-17 with chronic gastroduodenitis associated with Helicobacter pylori. To detect Hp and Epstein Barr viral infections we used esophagogastroduodenoscopy, quick urease test, bacterioscopy of gastrobiopsies. We performed the analysis of the cellular composition of the inflammatory infiltrate. RESULTS: It was found that the number of lymphocytes and neutrophils located in the lamina and intraepithelial increases, which is associated with the degree of inflammation. Increased to the maximum was the number of intraepithelial lymphocytes, both in the body, and in the antrum. Intensity of leukocyte infiltration is directly correlated with the increased prevalence of inflammation. Persistence of Epstein-Barr virus (35.9% of patients) is followed by more severe intraepithelial lymphocytic infiltration in the stomach. In 4-6 months after treatment 18 patients with severe gastritis were repeatedly studied for the inflammatory infiltrate. A significant decrease in the number of intraepithelial neutrophils was found. CONCLUSION: Cellular composition of the infiltrate is an objective characteristic of chronic inflammation in the gastric mucosa. Persistence of Epstein-Barr virus is accompanied by an increase in the amount of intraepithelial lymphocytes and neutrophils. PMID- 25518456 TI - [The treatment of gallbladder cholesterosis in children]. AB - The article contains the results of studies indicating the benefits of conservative therapy in children with gallbladder cholesterosis (GBC). The high efficiency of ursodeoxycholic acid in the treatment of GBC in childhood is shown in the study. Our research in the field of GBC in children allows the authors to propose management algorithm of such patients. PMID- 25518457 TI - [Problem of the choice of the probiotic dose in the physician practice]. AB - Currently, there is ample evidence of the usefulness of probiotics for human health, but, despite this, progress in the scientific and medical recognition of the legal force (legalization) of probiotic agents remains extremely slow. Probiotic preparations are prescribed with the preventive and medical purpose, must be not only safe, but always effective, because these properties affect the economic component of medical activity. Clinical efficacy of probiotics is determined not only by the specifics of strains, but also the adequacy of daily and course dose that should not be underestimated. Recent studies prove the identity of the impacts on human health probiotic agents and functional food products containing probiotic strains in optimal concentrations. Definition of preventive and curative doses of probiotics in children in different age periods remains a challenge for pediatricians. PMID- 25518458 TI - [Influence of ursodeoxycholic acid on the immune status of patients with cholesterosis of gall-bladder depending on cholesterol index in blood]. AB - Application of ursodeoxycholic acid in a standard dosage for 3 months provided a positive effect in relation to the indexes of the immune system for patients with the cholesterosis of gall-bladder. It is shown that medicine assists renewal of T cell immunity, renders positive influence on B-link and renewal of index of immunoregulation can be seen. Reliable increase of specific receptors to CD25, HLA-DR and high level of CD95 testifies about including of the scray reaction of organism under influence of ursodeoxycholic acid on the remaining high indexes of B-cell of immunity. At the initial indexes of lipid spectrum, corresponding to the norm, the efficiency of normalization of immunological changes is more considerable than at the higher level of general cholesterol of serum of blood. PMID- 25518459 TI - [Endosurgical treatment of the bile duct lesions in children]. AB - Question of feasibility of laparoscopic Kasai procedure and laparoscopic hepaticojejunostomy for biliary atresia (the BA) and choledochal cysts (the CC) in children has been a subject of discussion for a long time and still remains unsolved. AIM: To improve the results of surgery for biliary tract malformations (the BTM) in children using laparoscopic technique. MATERIALS AND METHODS: The are 55 patients with BA and CC, who were performed endosurgical operations, and 37 patients, who were performed traditional open surgical procedures. During this study we worked out and put into laparoscopic practice some new methods. We've made an analysis of technical features of liver transplantation after laparoscopic and traditional Kasai's operation in BA. RESULTS: The duration of laparoscopic Kasai procedure was significantly longer than open surgery (p < 0.05). In CC the duration was the similar (p > 0.05). There was no any urgent surgical complication after laparoscopic Kasai procedure in contrast to open surgery. We observed significantly fewer complications (40%) after laparoscopic hepaticojejunostomy than after traditional hepaticojejunoduodenostomy (84.6%, p < 0.05). The average length of stay in ICU and duration of analgesia after laparoscopy was significantly lower than after open surgery (p < 0.05). Comparing the efficiency of endosurgery and traditional operations using coloration of stool, decreasing of bilirubin level and the presence of indications to liver transplantation criteria we didn't find any significant difference (p > 0.05). CONCLUSION: At the same efficiency of laparoscopic and open reconstructive surgery for BA and CC the first has a number of incontrovertible advantages. Our experience allows us to recommend laparoscopic procedures to perform for the correction of BTM in children. PMID- 25518460 TI - [Gastroesophageal reflux disease in children: the role of endoscopy]. AB - The article deals with the problem of modern diagnosis of gastroesophageal reflux disease in children with the use of modern techniques used in endoscopy. This article provides an analysis of the current literature on the efficacy of diagnosis of various manifestations of gastroesophageal reflux disease in children of different ages. The data on the benefits of the various diagnostic techniques and endoscopic techniques. Article illyustrirovavana endofotografiyami original authors. PMID- 25518461 TI - [The functional disorders of the gastrointestinal tract in newborns (the lecture)]. PMID- 25518462 TI - [Functional digestive disorders in infants. Working protocol of diagnostic and treatment]. AB - Functional digestive disorders in infants comprise a group of disorders characterized by several specific features. They are related to structural and physiological peculiarities of the gastrointestinal tract in children during lactotrophic period of nutrition, limited pharmacotherapeutic options and supremacy of dietary correction in this age group, and psychological discomfort that has a negative impact on the quality of life of the whole family. The working protocol "Functional gastrointestinal disorders in infants' was prepared by the Russian Society for Pediatric Gastroenterology, Hepatology, and Nutrition (RusPGHAN) based on the previously proposed European (ESPGHAN) and American (NASPGHAN) guidelines. The protocol includes detailed description of the current approaches to diagnosis and management of the functional digestive disorders in young children, as well as algorithm tables that can be used by pediatricians and familial physicians in routine clinical practice. PMID- 25518463 TI - [Causes of chronic gastrodudenal and bone disorder development in children living under the effect of human induced ecological factors (literature review)]. AB - The literature review discloses modern ideas about new etiological factors that that cause gastroduodenitis and bones metabolism dysfunctions in children. The authors cite literature data that give evidence to possible common mechanisms of development of these pathological conditions associated with exposure to man-made factors, such as heavy metals. Metals that have damaging effect on the epithelial cells of the gastrointestinal tract may violate calcium absorption processes in organism, influence on the processes of bone remodeling. At the same time, patterns of chronic gastroduodenitis associated with exposure to unhealthy environmental factors may increase the risk of osteopeny. Knowledge of new pathogenic mechanisms of chronic gastroduodenitis and bones metabolism dysfunctions will allow to provide effective treatment and prevention of comorbidities in children living in ecologically unsafe areas. PMID- 25518464 TI - [Ulcerative colitis--difficulties of differential diagnosis in children]. AB - Chronic bowel disease (ulcerative colitis and Crohn's disease) in childhood are much more common than diagnosed. They can manifest after acute intestinal infections, eating disorders, as well as against other immunocomplex diseases. Most often, such as ulcerative colitis (UC) occurs in primary sclerosing cholangitis (PSC). According to the literature, its is up to 80.0% of all cases of primary sclerosing cholangitis. Children with such combinations make up 10.0 15.0% of patients in specialized gastroenterology departments. The article presents a case against the background of the development of UC primary sclerosing holanogita. PMID- 25518465 TI - [Abdominal pain syndrome in children with Crohn's disease (case report)]. PMID- 25518466 TI - [Biological therapy in children with inflammatory bowel syndrome (clinical cases)]. PMID- 25518467 TI - [Budd-Chiari syndrome (case report)]. AB - Budd-Chiari syndrome is a rare disease defined by the obstruction of hepatic venous outflow anywhere from the small hepatic veins to the junction of the inferior vena cava and the right atrium. This syndrome is uncommon in children. The article presents a case report of chronic refractory Budd-Chiari syndrome with a leading ascites in 16 years adolescent, which required surgical intervention--transjugular intrahepatic porta systemic shunt. As this syndrome is uncommon in pediatric practice, complex differential diagnostic search and delays in the diagnosis are frequent. This case report emphasizes the importance of a high index of suspicion in the diagnosis of pediatric Budd-Chiari syndrome and highlights the importance of early referral to a specialized pediatric unit for the further treatment. PMID- 25518468 TI - [Vesicular intracellular transport in the digestive organs. Membrane vesicle--the universal mechanism of the functional transport]. AB - On the basis of long-term research of the morpho-functional characteristics of the cells of the stomach, small intestine and gallbladder the mechanism and function of membrane vesicles in the implementation of the main functions of these organs sets out in this article: the secretion of hydrochloric acid by parietal cells, the absorption of nutrients in the small intestine and the fluid at a concentration of bile epitheliocytes of gallbladder. Proofs of the intracellular formation of hydrochloric acid in tubulovesicles of the parietal cells and turnover of its secretory membranes in the process of secretory cycle, that has ensured the re-use and explained the extraordinary life of these unique cells are presented. The credible mechanism of HCl output oppression by H(+)-K(+) ATPase activity blockers has set out on this basis. The article provides detailed endocytosis mechanism of the ions and nutrients absorption by enterocytes. The mechanism of participation of the apical contractile complex of brush border of epithelial cells in the initiation of endocytosis and cytoplasmic microtubules in transport of membrane vesicles in the cytoplasm was analyzed. Based on our research and numerous of the world scientific proceedings the conclusion was done about the existence of two energy dependent types of transport in the absorptive epithelium of the digestive--transmembrane (ionic and nutritive) homeostatic type which is realized by the ATP-system of the basal plasmalemma, and vesicular (endocytosis) type which is impltmented by apical contractile complex of brush border and cytoplasmic microtubules. Both types of transport are interrelated and are under constant cellular control. This observation is relevant to the majority of cells, including those involved in the secretion of various substances: hydrochloric acid by parietal cells, enzymes by main cells of the gastric glands and exocrinocytes of the pancreas, hormone by endocrine cells of the APUD system and, finally, mediators by nerve cells. To clarify the problem of cell transport two types: homeostatic and functional transport should be distinguished. The first type is carried out mainly in relation to ions on basolateral membrane with the help of its ATPase systems and provides intracellular homeostasis and nutritive co- transportation, the second (functional) type defines the basic specific function by means of membrane vesicles. PMID- 25518469 TI - [Gastroesophageal reflux disease and connective tissue dysplasia in aspect of premorbid and comorbid disorders]. AB - AIM: To investigate the phenotypic and visceral signs of connective tissue dysplasia (CTD) and comorbid diseases of the digestive system in gastroesophageal reflux disease (GERD) patients with different types of esophageal reflux as the predictors of its variants. MATERIAL AND METHODS: In 124 patients with GERD the clinical features, phenotypic and visceral signs of undifferentiated CTD were studied in details. RESULTS: In 82.0% of patients with GERD associated with gastroesophageal type of reflux (GER) phenotypic and especially visceral signs of STD were detected, mainly in the form of cardiochalasia and hiatal hernia. In patients with duodenogastroesophageal reflux symptoms (DGER) the signs of STD were marked in 42.0% of cases, mostly in the form of biliary tract structure abnormalities. The risk of GERD associated with prevalence of GER, was 11.9 times higher in the presence of diagnostically meaningful combination of 6 or more signs of STD than in patients with DGER. Realization of predictor options in GER occurs in the preference of sharp, acidic foods, spices, taking medications that reduce lower esophageal sphincter tone. GERD, associated with DGER, is formed in patients with family history of diseases of the biliary tract and in the preference of food rich of calories. CONCLUSION: Study of STD symptoms as predictors of structural development of GERD and its variants is prospective to predict disease, choice of profession and eating behavior, primarily in young adults. PMID- 25518470 TI - [Features of vegetative dysfunction development in patients with cholelithiasis before and after cholecystectomy]. AB - The aim of the present study was a comprehensive study of the features autonomic nervous system in cholelithiasis before and after cholecystectomy. MATERIALS AND METHODS: 88 patients aged 40 to 60 years. 55 patients with cholelithiasis before and after laparoscopic cholecystectomy (CE). Control group consisted of 33 patients of similar age and gender. To investigate the function of the autonomic nervous system were evaluated themes complaint history, physical examination data, and used less Tod mathematical analysis of cardiac rhythm by Baevsky RM using the author's computer-related programs "Korveg" with the definition of heart rate variability and table--Solovevoj Wayne. RESULTS AND CONCLUSIONS: The study of autonomic provision in rest and during exercise were increased sympathetic activity, exceeding those in the control group. Studies indicate a tendency to sympathicotonia patients with gall stones before and after cholecystectomy, which is enhanced adaptive compensatory mechanisms to maintain homeostasis in the body. Identify logical connections between clinical and autonomic indicators will predict flow pattern cholelithiasis before and after cholecystectomy, as well as pick individual therapy for each patient taking into account the autonomic features that can be widely used in practical medicine- not. PMID- 25518471 TI - [Osteoporosis correction in experiment]. AB - Osteoporosis is simulated in rats by chronic administration of omeprazole or serotonin for 6 months; investigated bone status in the model of liver fibrosis and the administration of serotonin against liver fibrosis. The following experimental groups of rats: with bilateral ovariectomy, with bilateral ovariectomy and administration of omeprazole, with the introduction of serotonin, with serotonin administration and bilateral ovariectomy, with model of liver fibrosis, with liver fibrosis model and administration of serotonin were used. The content of Ca, P, alkaline phosphatase, albumin, serum creatinine, and the content of Ca, P, Mg andFe in the bone was determined. It was found that the administration of mesenchymal stromal cells reduces the severity of osteoporosis. The effects of alfacalcidol on experimental osteoporosis was investigated. Introduction of alfacalcidol in all experimental groups increased the bone formation. PMID- 25518472 TI - [Diffuse esophageal spasm: difficulties of diagnosis and treatment]. AB - The article describes the diffuse esophageal spasm which is not amenable to conservative treatment. PMID- 25518473 TI - [Post release to the Congress of Pediatricians of Russia with international participation ("actual problems of pediatrics" (14-16 February 2014)]. PMID- 25518474 TI - [Report on the participation in the 9th International Congress of the European Crohn's and Colitis Organisation (ECCO) (20-22 February 2014) in Copenhagen (Denmark)]. PMID- 25518475 TI - [The XIVth Annual Congress of the Gastroenterological Scientific Society of Russia (prevention, diagnosis and treatment of the digestive tract diseases in the XXI century") The 18th Northwest Conference "St. Petersburg--Pharmacotherapy 2014" The 8th St. Petersburg Hepatological Congress]. PMID- 25518476 TI - ["Wise up, is there an endpoint at the ends of the earth, and can the horizons be broaden?" Gastrointestinal Endoscopy--2014]. PMID- 25518477 TI - [Confocal laser endomicroscopy principles and performing algorithm in gastric mucosa examination]. AB - Accuracy of endoscopic examination in early gastric cancer and precancerous conditions diagnostics for many years depended only on quality of biopsy. That's why, risk of overlooking gastric focal carcinoma, particularly-- multiple, was relatively high. Last couple of years new endoscopic method--confocal laser endomicroscopy (CLE) was released for commercial use. This approach provides real time information about morphology of gastric mucosa during endoscopic examination. CLE is a variation of confocal microscopy--morphologic technique, providing examination of thick specimens or live tissue. CLE system is a single channel fluorescence microscope, used in endoscopy, where confocal probe incorporated into endoscope or mounted into accessory channel. For proper results of CLE intravenous administration of fluorescence agent is needed. In our study in P.A. Herzen Moscow Cancer Research Institute we have used 10% fluorescein sodium, due to acriflavine use is prohibited in Russian Federation. In 157 patients with suspected early gastric cancer mean time of CLE was 24 +/- 3.5 min. In all cases descriptive images were acquired. Mean amount of endomicrosocpic images in one patient was as high as 162 +/- 8.3. PMID- 25518478 TI - [Early gastric cancer and precancerous conditions diagnostics with confocal laser endomicroscopy]. AB - AIM: To develop endomicroscopic criteria of early gastric cancer and precancerous conditions METHODS: 157 suspected for early gastric cancer patients were included in our study. In all cases complex endoscopic examination (narrow-band imaging NBI-HD endoscopy, endosonography (EUS) and endoscope-based confocal laser endomicroscopy (CLE) with precise biopsy) was performed. CLE images compared to pathology data. RESULTS: Precise criteria of intestinal metaplasia in CLE was presence of oval gray goblet cells in epithelium. Gastric adenoma with moderate dysplasia appeared on CLE images as glandular structures in mucosa surface layers. The signs of high-grade dysplastic changes in adenoma were appearing of different shape and size cells with lost polarity. Well-differentiated carcinoma featured destruction of some glands and forming dark cell clusters. Revealed criteria of poor-differentiated carcinoma was total disintegration of glandular structures. Overall accuracy of CLE in early gastric cancer and precancerous conditions diagnostics reached 95,6% (P < 0.001). Selected accuracy in different condition was: 100% in intestinal metaplasia identifying, 86.1%--in adenoma with moderate dysplasia, 96.2% in high-grade dysplasia and cancer in situ, and 100%- in poor-differentiated gastric carcinoma types). CONCLUSION: As the result of our study we have developed precise endomicroscopic criteria of intestinal metaplasia in stomach, gastric adenoma with moderate and high-grade dysplasia and early gastric cancer--as well-differentiated, as poor-differentiated. PMID- 25518479 TI - [Confocal laser endomicroscopy in the diagnosis of diseases of biliary ducts]. AB - Are clinical observations of various diseases of the bile ducts, including cholangiocarcinoma, developed with chronic diseases pancreato-biliary zone. Reflected the complexity of instrumental diagnostics at an early stage of the disease. For the first time at the given pathology diagnostic purposes was applied the method of probe confocal laser endomicroscopy allowed in all cases to clarify and verify the diagnosis. Describes the technique of the research, its results are compared with other diagnostic methods. The authors suggest that in the diagnosis of pancreatic and biliary zone method probe confocal laser endomicroscopy can be crucial in inefficiency or uninformative other methods. PMID- 25518480 TI - [Optimization endoscopy of esophagus pathology on the basis of computerized system of narrow band image segmentation]. AB - In the article possibility of application and results of practical usage colored segmentation narrow band images of esophagus are presented. Algorithm of narrowband endoscopy of upper gastrointestinal tract using automatized pathology discrimination has been developed. Method of automatized discrimination of pathological focus has been carried out during esophagogastroduodenoscopy on 238 patients. Positive increase of diagnostics effectiveness of narrow band endoscopy has been registered in esophagus pathology diagnostics. Statistic analysis of narrow band images esophagus has been carried out. The usage of mathematic modeling has shown the possibility of discrimination of normal and pathological areas for obtaining objective estimation of mucous esophagus condition. PMID- 25518481 TI - [Possibilities of using the noninvasive methods of investigating the morphofunctional changes in the liver in patients with non alcoholic steatohepatitis and type 2 diabetes mellitus]. AB - PURPOSE OF A STUDY: To estimate the possibility of applying the complex of the noninvasive methods of investigating the state of the liver for finalizing of the ways of the differentiated pathogenetic therapy. MATERIALS AND METHOD: Over the 2008 to 2013 period was carried out the open comparative study, in which were included 75 patients with non alcoholic steatohepatitis (NASH) and type 2 diabetes mellitus (SD). The Menghini Method of Liver biopsy was carried out for histological study. The FibroMaksTest was used for the to diagnose of inflammatory and necrotic changes, steatosis and fibrosis of the liver. The determination of the stage of the fibrosis of the liver was conducted with the aid of transient elastography. Was performed the calculation of sensitivity (SE), of specificity (Sp) the results of noninvasive methods with respect to the results of the histological examination of the liver. RESULTS: According to the data of FibroMaksTest, for steatosis 1 of degree the sensitivity composed 81,0%, specificity--100%; for steatosis 2 and 3 degrees--100 and 100%. For determining the inflammatory--necrotic changes 1 of degree the sensitivity composed 100%, specificity--96.9%; 2 degrees-- 95.2 and 93.3%, correspondingly, of 3 degrees- 81.8 and 100%, respectively. During the estimation of the stage of fibrosis 1 sensitivity was 85.4%, specificity--94.4%, respectively; 2 stages--94.1 and 97.1%, respectively; 3 stages--90 and 100%, respectively. During the estimation of the stage of fibrosis by the method of transient elastography of the liver for the degree of fibrosis F1 the sensitivity composed 83.8%, specificity 93.8%; for F it is 2nd 87.5 and 98.6%, respectively; F3-87.5 and 100%, respectively. CONCLUSION: The results of the noninvasive methods of diagnostics of the state of parenchyma of the liver in patient with NASG (transient elastography and the FibroMaksTest) are compared with the data of histological studies, that they make it possible to enlarge the possibilities of the morphological interpretation of the defeat of the liver in patients with SD of 2 types. PMID- 25518482 TI - [Microflora metabolites of different habitats in bronchopulmonary diseases]. AB - PURPOSE: To investigate the content and profile of metabolites of bronchopulmonary and intestinal microflora, especially such as short chain fatty acids (SCFA) in various biological substrates in patients with lung malignant tumors on the background of COPD. Estimate their diagnostic and tactical implication. MATERIALS AND METHODS: The study involved 98 patients with diseases of the bronchopulmonary system. According to the basic nosology patients were divided into two main groups: COPD (38 patients), and lung cancer in combination with COPD (hereinafter LC) (60 patients). The diagnosis was verified by modern methods of examination. Group of norm included 30 healthy individuals. Groups matched by gender and age. The microbiological examination of sputum and feces was conducted in the studied groups of patients. SCFA in sputum and feces of patients with COPD and LC were identified by GLC method. In healthy individuals the SCFA investigation was performed in bronchial washings, obtained during bronchoscopy in 20 people, the SCFA investigation in feces was performed in 30 people. RESULTS: Study of the content and profile of short-chain fatty acids (SCFA) in patients with COPD and lung cancer (LC) in various biosubstrates indicate on the obvious changes in microbiocenosis ofbioptate (bronchopulmonary and intes- tinal), characterized by the dominance of residual and facultative anaerobic microorganisms in the spectrum. Except that more pronounced changes are ascertained at LC. Also, changes of the SCFA parameters in the sputum may indicate on the alterations in the metabolism of epithelial cells of the lower respiratory tract (LRT). Unidirectional change the SCFA in sputum and feces can indicate on either translocation of microflora in the LRT out of the intestine, and on the possible systemic changes in themetabolism of epithelial tissue in the oncological process. The identification of SCFA by GLC method in various biological substrates can be used in examination of patients with lung cancer for diagnostic purposes (for objectification of microecological violations), as well as to evaluate the prognosis of the disease and its complications. PMID- 25518483 TI - [Diagnostic of oncology diseases by the flexible biomarker]. AB - It is Known that the interest of express diagnostic oncology degasses is growing up every ear. Recently, researchers from different countries proved highly effective studies of exhaled air in the diagnosis of breast cancer, cancer of lung and gastrointestinal tract. The purpose of our study was to identify a biomarker in the air of patients using hrormato-mass-spectrometer. We examined 79 patients. 47 patients with clinically and histologically proven oncology proses (II-IV stage), and 32 patients as a control group--without cancer. Chromatograms were obtaining, which was defining from 50 to 70 individual compounds. The overwhelming majority of cancer patients present organic matter--a biomarker and absent in the healthy group. At this stage of the technical capabilities of the equipment made it possible to carry out only a qualitative determination of this biomarker. PMID- 25518484 TI - [A study of urease activity of mouth cavity microflora]. AB - STUDY OBJECTIVE: Analysis of the prevalence of mouth cavity urealytic microflora and determination of the level of its enzymatic activity depending on concentration and amount of urea solution taken as a substrate. MATERIALS AND METHODS: 62 randomly chosen patients at the age of 5-64 took part in the study. Each of them rinsed the mouth with 50 ml of 1% urea solution. Before and after rinsing the concentration of ammonia in the mouth cavity air was measured. In patients with highest and lowest activity of mouth cavity urealytic microflora a series of tests was carried out including mouth rinsing with urea solution in various concentrations and amounts and measuring ammonia concentration before and after rinsing. Obtained results were analyzed using mathematical statistics methods. RESULTS: It was found that in 91% +/- 1.8% of randomly chosen patients (p < 0.05) mouth cavity microflora showed apparent urease activity. The lowest concentration (0.0625% in 50 ml) and volume (0.5 ml of 1% solution) levels of urea solution were obtained that can exert negative influence on the results of helicobacteriosis diagnosis by means of mouth cavity air analysis. CONCLUSION: Urealytic microflora in the mouth cavity is very common and may constitute a factor that decreases the specificity of helicobacteriosis diagnosis by means of the methods based on detection of indicators of gas metabolites resulting from the enzymatic reaction in air samples taken from the mouth cavity after oral administration of urea. PMID- 25518485 TI - [Endoscopic stenting of malignant stenosis in the cervical esophagus]. AB - OBJECTIVE: to define the optimal approach for self-expanding metal stents (SEMS) installing in the cervical esophagus in cases of malignant stenosis and to select the optimal types of stents for this tumor location. MATERIALS: From 2004 to 2013 in P.A. Herzen Moscow Cancer Research Institute in 24 patients with cervical esophagus tumor stenosis endoscopic stenting was performed. 70% of installed stents were Choo Cervical (M.I. Tech, Korea), 13%--unspecialized Choo and Hanaro stents (M.I. Tech, Korea), and 17%--Gianturco-Z stents (Wilson-Cook, Ireland). Main contraindication for cervical esophagus stenting was location of the tumor margin less than 1 cm from the upper esophageal sphincter. In 21% of cases, endoscopic stenting was performed under combined fluoro- and endoscopic guidance, in 79%-- using only endoscopic approach. RESULTS: Technical success of stent placement was achieved in all patients; SEMS was installed at the previously defined level. The accuracy of stenting was not depended from the type of guidance procedure. The most intensive pain was observed in cases with "not specialized" stents with diameter of 18, 20 or 22 mm. Average pain level in such patients was 4.54 points (VAS). In the subgroup with "cervical" stents average pain intensity was not exceed 3 points. Chronic pain syndrome lasts lifelong in 17% of patients. CONCLUSION: The procedure of SEMS positioning under endoscopic guidance with individual selection of stent type allows restoring oral nutrition in patients with severe tumor stenosis of the cervical esophagus. PMID- 25518486 TI - [Possibilities and limitations of retrograde transpapillary stenting of the main pancreatic duct in the treatment of chronic pancreatitis and its complications]. AB - For the last years the role of endoscopic pancreatic stenting in the treatment of chronic pancreatitis and its complica- tions has significantly increased. MATERIALS AND METHODS: In the clinic of abdominal surgery and endoscopy of Pirogov RNRMU based on the University Hospital 31 for the period from 01.1998 to 01.2014 Wirsung duct occlusion, which developed on the background of CP was the cause of performing of 215 endoscopic procedures in 95 patients: 34 (35.8%) women and 61 (64.2%) men. Mean age 49.8 +/- 11.7 years. Study group consisted of 52 (54.7%) patients with strictures of MPD and 43 (45.3%) with pancreatic fistulas. We tried to perform pancreatic stenting in all the cases, as a method of treatment of pathological changes in the pancreatic ductal system. RESULTS: Endoscopic stenting was successfully performed in 64 cases (67.4%), while in 45 (70.3%) cases, this intervention was the definitive method of treatment. Temporary Wirsung duct stenting was performed in 19 (29.7%) cases in which endoscopic retrograde step interven- tions were training to perform surgery. It is significant that the main causes of the technical impossibility of pancreatic stenting was the complete dissociation of Wirsung duct (8), distal localization of occlusive lesions (13), presence of severe angulation in stenotic changes (20) and the length of the scar stricture of the MPD more than 1 cm (17) and particularly a combination of several factors. Clinically significant complications after endoscopic interventions in our study occurred in 6 (2.8%) cases. Lethal outcome occurred in one patient (0.5%). CONCLUSION: According to the results of our study pancreatic stenting was technically feasible in 67.4% of all cases. At the same time, endoscopic correction, if the possibility of its technical implementation, may be the final method of treatment in 70.3% cases. In this endoscopic pancreatic stenting has a low complication rate (2.8%) and mortality (0.5%). The main reasons for the failures and limitations of endoscopic stage treatment is a combination of factors: complete dissociation of the MPD, distal location of the Wirsung duct strictures with severe angulation in this area and a large length of strictures. PMID- 25518487 TI - [The experience of biliary self-expendable nitinol stents for malignant jaundice]. AB - THE AIM: to analyze the effectiveness and possible complications of endoscopic biliary drainage (BD) using self-expanding metal stent (SEMS) in patients with malignant jaundice (MJ). METHODS: From January 2010 to January 2014 in endoscopy department of Pirogov National medical and surgical Center were operated 64 patients with MJ, 38 of them with SEMS. The average patient's age was 65.4 +/- 14.5 years. The mean duration of jaundice was 13 +/- 5.4 days before drainage. The remaining 6 patients (15.8%) were operated with preliminary PTBD. In all 38 patients were diagnosed unresectable tumors. RESULTS: successful endoscopic BD were achieved in all 38 patients. 35 patients were drained with transpapillary SEMS and 3 patients with EUS-guided choledochoduodenoanastomoses (EUS-CDA). Early postoperative complications were observed in 3 (7.8%) patients with no lethality. CONCLUSION: endoscopic BD with SEMS is an effective method of internal drainage for inoperable pancreatobiliary tumors, providing adequate BD for the entire duration of life expectancy. In case of failed transpapillary drainage EUS-guided biliodigestive anastomoses were performed. The complication rate of endoscopic BD in patients with malignant pancreatobiliary tumors in our study was 7.8% and comparable with complication level due to ERCP/EST for benign pathology. PMID- 25518488 TI - [Endoscopic treatment of advanced left colon cancer by stenting]. AB - The aim of research is studying of technical capability of colorectal stenting, its clinical efficiency in permission of obstruction and an assessment of technique safety. Between October 2007 and January 2014 endoscopic stenting by self-expanding metal endoprostheses was successfully performed in 19 patients aged from 29 till 83 years with malig- nant stenoses of the left colon. Treatment was carried out in the endoscopic department of the Federal State Budgetary Institution "Petrovsky National Research Center of Surgery" under the Russian Academy of Medical Sciences. The colonic stent placement reached two intends: pre operative decompression as the first stage of the treatment, allowing to prepare the patient safely to the surgical procedure without colostomy (6) and palliation in those cases in which the clin- ical condition is not feasible (13). In all patients stent insertion was technically successful. Common complication rate was 15.8% (3/19). Colorectal stenting in patients with bowel obstruction is absolutely justified due to allowing considerable life quality improving in inoperable patients and avoiding two-stage surgical treatment. PMID- 25518489 TI - [Ways of improving adherence on telaprevir-based therapy in patients with chronic HCV infection]. AB - AIM: To present the ways of improving adherence on telaprevir-based therapy in patients with chronic HCV infection. BACKGROUND: Telaprevir is a direct antiviral agent, registered in Russian Federation as a treatment for chronic hepatitis C genotype 1 patients in combination with pegylated interferon and ribavirin (PR). Phase III clinical trials showed a significant improvement in efficacy when adding telaprevir to pegylated interferon and ribavirin compare to the duel PR treatment along. Standard telaprevir regiment 750 mg 3 times per day is associated with difficulties in keeping adherence to the treatment. Here we present the results of administering telaprevir 1125 mg twice daily. CONCLUSION: Telaprevir-based 1125 mg twice daily regimen in combination with PR is comparable with telaprevir 750 mg every 8 hours treatment if looking at rates of SVR, relapse incidence, viralogical insufficiency, pharmacokinetics, safety, also taking in consideration higher treatment adherence even in HCV cirrhotic patients. PMID- 25518490 TI - [Multidisciplinary approach to diagnose the sarcoidosis of small intestine]. AB - In the article the clinical case of sarcoidosis of the GI tract as a rare form. Clinical form and the diagnosis of GI tract sarcoidosis are described. PMID- 25518491 TI - [Predominantly intraductal low-grade differentiated adenocarcinoma in young man with long time mask clinic of chronic pancreatitis]. AB - The authors present the case of diagnosis of low-grade adenocarcinoma of the pancreas, a man 34 years old, a long time to mask clinic chronic pancreatitis. Laboratory and instrumental investigations, including tumor markers CD 19-9, CEA, ultrasound, CT, MRI showed no reliable data for the presence of tumor. On the other hand, a young man of 34 years present credible evidence of chronic pancreatitis, in the form of a typical pain, a significant increase in serum am- ylase and lipase, and the presence of parenchymal and ductal signs of pancreatitis in visual research methods. Diagnosis of tumors, including obtaining morphological material, pre-operative pain relief were obtain by endoscopic methods. Histological examination of surgical specimens was detected a rare type of poorly differentiated adenocarcinoma of the pancreas tubulo-papillary structures, with predominant intraductal growth and a minimum depth of invasion due to pronounced fibrotic outcome variables, which leads to a complex disease diagnostics. After 1.5 years, after adequately performed surgery the patient was revealed metastases to the liver. PMID- 25518492 TI - [THE report on the XIVth CONGRESS of the Gastroenterological Scientific Society of Russia in Saint Petersburg, 11-12 OF March, 2014]. PMID- 25518493 TI - [Paradigm of dysbiosis in the modern gastroenterology. The role of microbiota in the treatment and prevention of diseases in the XXI century]. AB - Endogenic microflora (microbiota) is one of the determinative factors of the human health. In the article new doctrine is proposed and 11 principles of microbiota's structural and functional organization are developed. PMID- 25518494 TI - [Does microflora play role in the development of colitis in the disabled parts of colon? Facts and reflections]. PMID- 25518495 TI - Standard therapeutic regimens in H. pylori infection leads to activation of transitory fungal flora in gastric mucus. AB - BACKGROUND: Administration of broad-spectrum antibiotics with antisecretory agents in treatment of H. pylori-associated diseases results in decreased representation of normal intestinal microflora and growth of transitory microflora, whose representatives are yeast-like fungi (Candida). This mayprimarily be caused by disordered microbial biocenosis in stomach, conditioned by eradication of H. pylori. Studies over recent years have yielded reliable information confirming that H. pylori is a source of peptides possessing a potent fungicidal activity. It still remains unclear whether there takes place an activation of fungal flora pre-existing in intestine, or drug-induced disorders of microbiocenosis in stomach. MATERIALS AND METHODS: We carried out a histological and bacterioscopic study of biopsy materials obtained from gastric antral mucosa in 679 patients with H. pylori-associated erosive or/and ulcerative gastric lesions, chronic gastritis and gastroesophageal reflux disease (GERD), with erosive or/and ulcerative duodenal lesions before and after eradication therapy. RESULTS: Prior to treatment, the yeast-like fungi in stomach were revealed in 112 patients (16.5%). Eradication of H. pylori was achieved in 85% of patients, with large growth of elements resembling yeast-like fungi and pseudomycelium being detected in gastric mucosa in 33% of case. CONCLUSIONS: The findings obtained suggest that an increased influx of yeast-like fungi from stomach into the gut may play role in proliferation of intestinal fungal microflora following antihelicobacter therapy. Under the conditions of decreased acidity of gastric juice on the background of antisecretory therapy and the lack of microbial antagonism on behalf of H. pylori in gastric mucus, Candida-genus fungi receive optimal conditions for development and subsequent passage to the intestine. PMID- 25518496 TI - [The parietal intestinal microflora in patients with chronic pancreatitis]. AB - The article presents the results of the proximal small intestine parietal microbiocenosis research in patients with chronic pancreatitis by polymerase chain reaction in real time. The study includes an assessment of the pharmacological correction's efficiency in this category of patients. PMID- 25518497 TI - [Minimally invasive interventions in the treatment of patients with acute necrotizing pancreatitis]. AB - OBJECTIVES: Improve outcomes in patients with acute necrotizing pancreatitis by the differential application of minimally invasive interventions. METHODS: The results of treatment of 97 patients with acute necrotizing pancreatitis requiring minimally invasive surgical intervention were retrospectively analyzed. Percutaneous catheter drainage were used in 76.2% of cases. All patients were divided into two groups based on the effectiveness of minimally invasive interventions. RESULTS: Minimally invasive interventions were the final method of surgical treatment in the 69 patients (1st group). Patients of 2nd group (28.9%) underwent additional traditional surgical necrosectomy. The overall mortality rate was 9.7%. In 1st group died 5 patients (7.2%), in the 2nd--4 (14.3%). Complications of percutaneous catheter drainage (bleeding, damage to organs, catheter dislodgement) were found in 18.1%. CONCLUSIONS: The use of minimally invasive techniques in combination with conservative therapy can decrease treatment time, the rate of morbidity and mortality in patients with acute necrotizing pancreatitis. PMID- 25518498 TI - [Colon microbiota and constituents of metabolic syndrome]. PMID- 25518499 TI - [Abstracts of the 16th International Slavic-Baltic Scientific Forum Saint Petersburg--Gastro-2014" and the Plenum of the Board of the GSSR, March 19-21, 2014]. PMID- 25518500 TI - [The XIII-th Conference of Gastroenterologists of South Russia "prevention and rehabilitation of digestive diseases". Plenum of the Council of the Russian Society of Endoscopy. Scientific and educational seminar on digestive endoscopy. 24 - April 25, 2014, Kislovodsk ]. PMID- 25518501 TI - [Clinical guidelines for the diagnosis and treatment of pulmonary hypertension]. AB - Pulmonary hypertension (PH) is a group of diseases characterized by progressive increases in pulmonary vascular resistance and pulmonary artery pressure, which results in right ventricular heart failure and sudden death. Based on the current version of the guidelines for PH diagnosis and treatment, adopted by the experts of the European Society of Cardiology and the European Respiratory Society in 2009, and on the data of Russian and foreign clinical trials, the Russian experts elaborated clinical guidelines for PH in 2013. The latter consider the current classifications of PH, the specific features of its pathogenesis, and its diagnostic algorithm. The section dealing with drugs for maintenance therapy discusses data on the use of oral anticoagulants, diuretics, cardiac glycosides, and oxygen therapy. PH-specific therapy includes calcium antagonists, prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Surgical procedures for PH involve atrial septostomy, thromboendartectomy, and lung or heart-lung transplantation. A treatment algorithm is proposed for PH patients. The current medicinal approaches using specific therapy agents and their combinations offer new promises for the effective treatment of patients with PH and improve its prognosis. PMID- 25518502 TI - [Effector and regulatory blood lymphocyte subpopulations in stable coronary artery disease]. AB - AIM: To investigate a balance between circulating regulatory T lymphocytes (Treg) exerting antiatherogenic activity and T helper type 1 (Th1) and T helper type 17 (Th1 7) cells having proatherogenic activity in patients with stable coronary artery disease (CAD) and different degrees of coronary atherosclerosis. SUBJECTS AND METHODS: According to coronary angiography findings, 80 patients were allocated to 4 groups: 1) 18 patients with intact coronary arteries; 2) 21 with no progressive coronary atherosclerosis; 3) 16 with progressive coronary atherosclerosis (more than 50% stenosis) in the native coronary arteries; 4) 25 patients with three-vessel lesions. Groups 2 and 3 patients had undergone coronary stenting 23.8 +/- 8.4 and 22.4 +/- 8.7 months before their enrollment, respectively. Lymphocytes were typed by direct immunocytofluorometry: Treg was defined as CD4+CD25highCD127low and CD4+FoxP3+ lymphocytes. For CD4+IL-17a+ Th17 and CD4+INFgamma Th1 analysis, mononuclear cells were preactivated by culture. The serum levels of high-sensitivity C-reactive protein, IL-10, sCD25, and IL-17a were determined by nephelometry, chemiluminescence (Immulite) and ELISA, respectively. RESULTS: Group 4 was found to have lower Treg levels and higher Th17 levels than Group 1. The ratio of Th17/Treg proved to be higher in Groups 3 and 4 than in Group 1 and that of (Th1+Th17)/Treg was higher in Group 3 than in Group 2. The female patients had higher Tregs levels than the male ones. The Th17/Treg index turned out to be increased in patients with a history of myocardial infarction. CONCLUSION: The imbalance of pro- and anti-atherogenic lymphocyte subpopulations plays a role in the pathogenesis of CAD and is associated with progressive atherosclerosis. PMID- 25518503 TI - [Cystatin C and preclinical lesions in the target organs of hypertensive patients]. AB - AIM: To study the association between cystatin C levels and preclinical lesions in the target organs (heart, kidney, vessels) of patients with hypertensive disease (HD) at moderate and high risks for cardiovascular events (CVE). SUBJECTS AND METHODS: The investigation enrolled 47 patents (30 men and 17 women) with Stages I-II HD at moderate (n = 23) and high (n = 24) risks for CVE. The patients' mean age was 46.0 +/- 1.8 years; the duration of HD was 4.1 +/- 0.2 years. The blood level of cystatin C was estimated by photometry using a biochemical autoanalyzer. Glomerular filtration rate (GFR) was calculated by the MDRD formula. Microalbuminuria (MAU) was determined by turbidimetry employing a biochemical autoanalyzer. RESULTS: No association between cystatin C level and 24 hour blood pressure (BP) monitoring readings was found in the patients except the men in whom it was correlated with 24-hour diastolic BP (DBP) (r = 0.36; p < 0.05). The hypertensive patients showed a positive correlation of cystatin C with their age (r = 0.51; p < 0.001). There were higher cystatin C levels in smoking patients with HD (n = 19) and no statistically significant differences in the level of MAU, urine uric acid, and GFR between them. There was a statistically highly significant negative. correlation between cystatin C concentration and GFR by the MDRD formula (r = -0.59; p < 0.001), at the same time, no correlation was found between creatinine clearance (by the Cockroft-Gault formula). There were no statistically significant differences in cystatin C levels in relation to the presence or absence of carotid atherosclerosis (1.01 +/- 0.03 and 0.93 +/- 0.02 mg/l, respectively; p = 0.08). Overall, there was a positive correlation of cystatin C levels with left ventricular mass index (r = 0.58; p < 0.001) and relative myocardial thickness index (r = 0.40; p < 0.05). CONCLUSION: The findings of the association of cystatin C and 24-hour DBP, preclinical lesions in the heart, vessels, and kidney seem to argue for the concept of cardiorenal syndrome in patients with HD just at its early stages. PMID- 25518504 TI - [24-hour systolic wave increment index monitoring in patients with low-renin arterial hypertension]. AB - AIM: To analyze the circadian rhythm of blood pressure (BP) and daily reflected wave values in patients with low-renin hypertension with normal and elevated aldosterone production. SUBJECTS AND METHODS: The investigation included 66 patients. 24-hour BP monitoring was carried out and arterial wall rigidity and reflected wave values were assessed in all the patients. RESULTS: The patients with hyperaldosteronemia were found to have not only statistically significant severer hypertension, impaired circadian rhythms of BP, but also impaired augmentation index (Aix)--mainly its nocturnal increase. A positive correlation was found between nocturnal Aix and resting plasma aldosterone concentrations (r = -0.31; p = 0.002). CONCLUSION: The findings suggest the expediency of 24-hour systolic wave increment index monitoring in hypertensive patients ofthis category. PMID- 25518505 TI - [Molecular genetic markers of predisposition to thrombosis in adolescents with essential hypertension ]. AB - AIM: To estimate the spread and distribution of genotypes and alleles of thrombosis predisposition gene polymorphisms in adolescents with essential hypertension (EH). SUBJECTS AND METHODS: One hundred and thirty-seven 14- to 17 year-old adolescents were examined. There were 3 examined groups: 1) 37 EH patients with prothrombotic changes (PTC); 2) 60 EH patients without PTC; 3) 40 healthy adolescents. Prothrombin time, activated partial thromboplastin time, and the levels of fibrinogen and soluble fibrin monomer complexes were determined. The adolescents were assigned to a PTC group if they had changes by one or several above indicators. Polymerase chain reaction assay was used to type coagulation factor II (FII) and factor V (FV), plasminogen activator inhibitor type 1 (PAI-7), 5,10-methylenetetrahydrofolate reductase (MTHFR), and methionine syntase reductase (MTRR) gene polymorphisms. Group differences were determined by qualitative signs, by using.the chi2test and Yates' correction for continuity and Fisher's exact test if one of the groups had at least 5 individuals. All differences were considered statistically significant at p < 0.05. RESULTS: FV R506Q, FII G20210A, PAI1-675 4G/5G, MTHFR A1298C, and MTRR A66G polymorphisms have not been found to affect the hemostatic system in adolescents with EH. MTHFR C677T may act as a risk factor of PTC in adolescents with EH, by increasing the risk of thrombotic events at an old age. CONCLUSION: It is recommended that the determination of molecular genetic markers for predisposition to thrombosis be actively used in adolescents with EA to form a risk group for thrombotic events and to implement preventive measures.. PMID- 25518506 TI - [Hemodynamic effects of the synthetic analogue of endogenous nitric oxide (II) donors a dinitrosyl iron complex in hypertensive patients with uncomplicated hypertensive crisis]. AB - AIM: To examine the antihypertensive effect of the synthetic analogue of the endogenous nitric oxide donors in patients with grades 2-3 hypertension and uncomplicated hypertensive crisis (HC). SUBJECTS AND METHODS: The study included 30 male patients aged 35 to 73 years (mean age 55.5 +/- 10.8 years). All the patients had grades 2-3 essential or secondary hypertension. Thirteen (43.3%) patients were observed to have signs of HC; 17 (56.7%) patients had persistent blood pressure (BP) elevation. A dinitrosyl iron complex was injected in a dose of 1.5 or 3 mg per kg of body weight. The purpose of its administration was to lower BP by at least 20% of its baseline level. RESULTS: No significant side effects associated with the administration of the test drug were recorded when the clinical trial protocol was implemented. All the patients reported fever and facial hyperemia during and 10-20 minutes after injection. They all (100%) showed efficient blood pressure reduction of at least 20% of the baseline level. Blood pressure changes were similar when the agent was administered in doses of 1.5 or 3 mg/kg. At 6-8 minutes after the drug was injected, there was a maximal decrease in blood pressure, then its gradual rise and stabilization at a lower level than the baseline one within the following 8 hours. There were no significant differences in the magnitude of a blood pressure reduction after administration of 1.5 and 3 mg/kg. CONCLUSION: The findings suggest that the dinitrosyl iron complex is highly effective in treating uncomplicated HC. The antihypertensive effect of the drug persists for 8 hours after its injection, which is very important during prehospital therapy. The drug is well tolerated by patients and causes an insignificant number of side effects. PMID- 25518507 TI - [Pulmonary hypertension in Russia: the first results of the national register]. AB - AIM: To investigate the demographic and clinical characteristics of patients with pulmonary hypertension (PH) and chronic thromboembolic pulmonary hypertension (CTEPH), regions of their residence, the specific features of diagnosis and drug therapy, and the patients' survival within the framework of a multicenter open label prospective study. SUBJECTS AND METHODS: The study enrolled patients over 18 years of age with PH classified as Group 1 (PH) and Group 4 (CTEPH). The follow-up was made in 9 expert centers of Russia on January 1 to February 28, 2014. The data of patients with PH and CTEPH were electronically entered at the register website: www.pul-hyp.medibase.ru. RESULTS: The study included 242 patients (183 women and 59 men) from 44 regions of the Russian Federation. PH of different etiologies was present in 79.3%, including 43.8% with idiopathic PH, 28.5% with congenital heart disease-associated PH, 6.2% with diffuse connective tissue-associated PH, 0.8% with hereditary PH; 20.7% were diagnosed with CTEPH. The patients' mean age at the inclusion in the register was 43.2 +/- 15.8 years; the median PH duration was 4.4 years (1.4 to 10.6%). The distance covered during a 6-minute walk test was 395.2?111.1 m; the Borg dyspnea index was 3.4 +/- 1.4 scores and the functional class was 2.5 +/- 0.8. After right cardiac catheterization, the mean pulmonary artery pressure was 53.1 +/- 19.5 mm Hg; cardiac output, 3.8 +/- 1.2 l/ min; cardiac index, 2.1 +/- 0.6 l/min/m2; pulmonary vascular resistance, 1105 +/- 677.6 dyn.sec/cm5. A positive acute pharmacological test was seen in 16.3% of the patients. The most common comorbidity was erosive ulcerative lesion of the gastrointestinal tract (23.5%), hypertension (16.9%), and obesity (16.5%). 66% of the patients received PH specific therapy: sildenafil (51.6%), bosentan (20.9%), or iloprost (7%); 7.4% of the patients were observed within the framework of clinical trials, 17.7% received combined therapy for PH: 16.3 and 1.4% had dual- or triple-component therapy, respectively; 55.8% of the patients took calcium antagonists, 61.4% had diuretics, 85.6% had antithrombotic drugs. The survival rates were 98% in the first year of the follow-up and 90.1% by the end of 2013. CONCLUSION: The formation of a national register of patients with PH and CTEPH makes it possible to introduce current approaches to diagnosing and treating the patients of this category and to evaluate the efficiency and quality of rendered medical care and will contribute to the estimation of required health care volumes and the expenditure of public health resources. PMID- 25518508 TI - [Efficacy of the energy-modifier cytoflavin in the treatment of patients with hypertensive encephalopathy]. AB - AIM: To evaluate the efficacy of cytoflavin in the treatment of patients with hypertensive encephalopathy (HE). SUBJECTS AND METHODS: One hundred and forty patients aged 39 to 73 years, diagnosed with HE, were examined and randomized to 2 groups. A study group (n = 74) received cytoflavin in a dose of 2 tablets b.i.d. on days 1 to 25 days inclusive during standard basic therapy. A comparison group (n = 66 persons) had standard basic therapy only. A control group consisted of 30 apparently healthy individuals. The investigators studied the frequency of headache, dizziness, and other complaints and the intensity of cephalalgic syndrome, by using a visual analog scale, the quality of life by the Medical Outcomes Study 36-Item Short-Form Health Survey (MOS SF-36) questionnaire, that of sleep by the subjective sleep characteristics questionnaire elaborated at the Moscow City Somnological Center, the level of asthenia by a subjective asthenia rating scale (Multidimensional Fatigue Inventory (MFI-20), and autonomic status, by applying objective and subjective scales on days 1 and 25 of therapy. RESULTS: The study has shown that cytoflavin used in the above dose for 25 days reduces the frequency and magnitude of complaints of headache, dizziness, "venous" complaints, the degree of autonomic and asthenic disorders, and impairments in the quality of sleep and life in the patients with HE at all disease stages. A stepwise discriminant analysis has indicated that the degree of cephalgic syndrome, and autonomic disorders, and worse sleep quality are the most effective points for using the energy-modifier cytoflavin. CONCLUSION: HE treatment based on the current pathogenetic principles may have a preventive impact on the development of HE or slow down the rate of its progression. PMID- 25518509 TI - [A fixed-dose lisinopril and amlodipine combination in conjunction with rosuvastatin in patients with hypertensive disease and coronary heart disease]. AB - AIM: To evaluate the efficacy and safety of a fixed-dose combination of the angiotensin-converting enzyme inhibitor lisinopril 10 mg and the calcium antagonist amlodipine 5 mg (ekvator) in conjunction with rosuvastatin (mertenil). SUBJECTS AND METHODS: The investigation enrolled 50 patients (mean age 57.9 years) with essential hypertension. All the patients received the fixed-dose antihypertensive combination. Stable Functional Class I or II exertional angina was in 46% of the patients. The remaining 54% were found to have brachiocephalic atherosclerosis. All the patients had dyslipidemia and were given rosuvastatin. RESULTS: The mean systolic blood pressure (SBP) initially reached 164.26 mm Hg. During the whole follow-up, the reduction in mean SBP generally accounted for 22.6% (p = 0.000). At the study inclusion, the mean diastolic blood pressure (DBP) reached 99.38 mm Hg. The total decline in mean DBP was 19.3% (p = 0.000). The mean level of total cholesterol (TC) decreased significantly by 32.1% (p = 0.000); that of triglycerides (TG) also fell significantly by 31.8% (p = 0.04); that of high-density lipoproteins increased insignificantly by 11.1% (p = 0.599); that of low-density lipoproteins (LDL) dropped significantly by 47.5% (p = 0.000). CONCLUSION: Being safe, the fixed-dose lisinopril and amlodipine combination is effective in lowering blood pressure in patients with hypertensive disease (HD) concurrent with coronary heart disease (CHD) or atherosclerotic changes in the carotid artery. The use of rosuvastatin in patients with HD concurrent with CHD during 2 months causes positive changes in the blood lipid composition as a significant reduction in the-levels of (TC), LDL, and TG. PMID- 25518510 TI - [Effect of original and generic clopidogrel on prognosis in relation to different gene polymorphisms]. AB - AIM: To analyze the influence of clinical and pharmacogenetic factors on the risk of resistance to original or generic clopidogrel and that of cardiovascular events (CVE) during 12 months of follow-up. SUBJECTS AND METHODS: Two hundred and fifty patients admitted to Moscow hospitals in October 2011 to September 2012 were examined. All the patients received clopidogrel. During their stay at hospital, venous blood samples were collected twice (before and 7-10 days after continuous clopidogrel intake). Platelet function was determined by optical aggregometry. A less than 10% reduction in platelet aggregation was taken as a resistance criterion. In addition, CYP2C9 and CYP2C19 gene polymorphisms were investigated. RESULTS: Whether original or generic clopidogrel is used, the level of baseline or post-7-day ADP-induced platelet aggregation (ADP aggregation) fails to affect the risk of its resistance. Evaluation of ADP-induced platelet aggregation in patients with different CYP2C9 and CYP2C19 gene polymorphisms during the administration of original or generic clopidogrel also showed no significant differences in its resistance. During the 12-month follow-up, CVE significantly less frequently occurred as a result of the intake of original versus generic clopidogrel. CONCLUSION: The use of original clopidogrel does not affect the risk of resistance to antiplatelet drugs, but it is associated with the lower incidence of CVE during a year. PMID- 25518511 TI - [Factors influencing platelet aggregation in patients with acute coronary syndrome]. AB - AIM: To study factors influencing platelet aggregation in patients with acute coronary syndrome (ACS). SUBJECTS AND METHODS: The investigation enrolled 147 patients with ACS. Their blood was sampled on days 1, 3-5, and 8-12 days after the onset of ACS. All the patients received acetylsalicylic acid (ASA) 300 mg on day 1, then 100 mg/day and clopidogrel 300-600 mg on day 1, then 75-150 mg/day. Platelet aggregation was analyzed in 65 patients on day 1 after ASA intake, but prior to clopidogrel therapy. The aggregation was induced by 5 and 20 pmol of ADP. RESULTS: With the use of clopidogrel 75 mg/day on day 3-5, platelet aggregation was reduced by 2.1 and 1.7 times for 5 and 20 MUmol of ADP, respectively, as compared to day 1 (ASA without clopidogrel) and remained unchanged on days 8-12. Increasing the dose of clopidogrel up to 150 mg/day potentiated its antiaggregatory effect. On day 1 (ASA without clopidogrel), there was a direct correlation between platelet aggregation levels and mean platelet volume (MPV) (correlation coefficients (r), 0.526 (p < 0.001) and 0.368 (p = 0.015) for 5 and 20 MUmol of ADP, and between platelet aggregation levels and glycoprotein (GP) IIb-IIIa (r = 0.387; p = 0.002 and r = 0.411 (p < 0.001) for 5 and 20 MUmol of ADP. No similar correlations were found on days 3-5 and 8-12 of administration of ASA and clopidogrel. The genetic polymorphism of GP lIb-Illa (GP Ila Leu33Pro) was not noted to affect platelet aggregation. Examining the effects of genetic variations in cytochrome P450 isoform CYP2C19 (a clopidogrel metabolizer) revealed the enhanced aggregation stimulated with 20 MUmol of ADP in the carriers of slowly clopidogrel-metabolizing haplotype of CYP2C19 (differences were found on days 3-5 as compared to rapidly and routinely metabolizing haplotypes). CONCLUSION: In the patients with ACS, platelet aggregation is influenced by MPV, GP IIb-IIIa levels, and CYP2C19 polymorphism and is not by GP IIb-IIIa polymorphism. PMID- 25518512 TI - [Role of eosinophil granulocytes in the occurrence of restenosis in patients after coronary stenting with drug-eluting stents]. AB - AIM: To study the role of eosinophil granulocytes in the development of restenosis after drug-eluting stent (DES) implantation. MATERIALS AND METHODS: The blood levels of eosinophils, eosinophil cationic protein (ECP), immunoglobulin E (IgE), and C-reactive protein (CRP) were compared in 170 patients with coronary heart disease (CHD) and stable angina who had undergone recoronarography within the first year after endovascular myocardial revascularization using DES. The blood level of eosinophils was determined by the results obtained employing the FACS Calibur flow cytofluorometer (Becton Dickinson, USA). That of ECP, IgE, and CRP was estimated by enzyme immunoassay by means of an Immulite-100 analyzer (Siemens, Germany). The data were presented as median (25th percentile and 75th percentile). RESULTS: The blood eosinophil level was 272 (234; 292) cells/MUl in patients with restenosis while that was 134 (85; 156) cells/MUl in those without restenosis (p = 0.002). The plasma ECP level proved to be greater in the patients who had developed restenosis after DES implantation than in those who had not [17.7 (11.2; 24) and 9 (6.4; 12.9) ng/ml, respectively (p = 0.017). At 6 months after DES implantation, the level of ECP was significantly higher (8.6 (7.3; 9.7) ng/ml) than the baseline level (p = 0.04). Later on, there was an even greater increase in ECP levels. No significant changes were noted in blood ECP levels after bare stent implantation. CONCLUSION: The findings suggest that there is a relationship between the occurrence of restenosis and the enhanced activity of eosinophil granulocytes in CHD patents after DES implantation. PMID- 25518514 TI - [Type 4a myocardial infarction]. AB - An increase in the level of cardiac troponins and creatine kinase MB is sometimes observed even after angiographically and clinically uncomplicated percutaneous coronary interventions. This review article deals with the clinical and prognostic implications of type 4a myocardial infarction. PMID- 25518513 TI - [Results of using the dosing Valsalva-Weber test to determine autonomic disorders in patients with vasovagal syncope]. AB - AIM: To estimate the value of the dosing Valsalva-Weber test (VWT) in the diagnosis of autonomic disorders in patients with vasovagal syncope (VVS). SUBJECTS AND METHODS: The dosing VWT using a specialized Task Force Monitor unit ("CNSystem", Austria) with synchronous noninvasive ECG and blood pressure (BP) monitoring was carried out in 30 patients (mean age 32 +/- 14 years) with VVS and 12 healthy individuals (31 +/- 7 years). The analysis of the test results encompassed the visual assessment of BP change curves and heart rate in different test phases and the calculation of pressure indices, Valsalva coefficient, arterial baroreflex sensitivity, and other parameters (a total of 26). RESULTS: The abnormally changed form of the mean BP curve, which was characterized by that BP by the end of Phase II test failed to achieve the baseline level, was recorded in 10 (33%) patients with VVS and in none of the healthy individuals (p = 0.04). An individual analysis of the gender- and age-adjusted Valsalva coefficient revealed its reduction in 9 (30%) patients while this indicator was within the normal range in all the healthy individuals (p = 0.04). CONCLUSION: During the dosing VWT, the signs of sympathetic insufficiency (impaired adrenergic regulation of BP) are found in 33% of the patients with VVS and those of parasympathetic insufficiency (impaired vagus regulation of cardiochronotropic function) are in 30%. PMID- 25518515 TI - [Clinical diagnosis and prognosis of pulmonary thromboembolism]. AB - Pulmonary thromboembolism (PTE) is a nosological entity that complicates the course of many diseases. This circumstance determines difficulties in the diagnosis and determination of further patient management tactics. Bolus-enhanced computed tomography of pulmonary arteries, a method having high resolution and high accuracy, is presently accepted to be the gold standard to verify the diagnosis. At the same time this radiocontrast study cannot be used as a screening tool by economic and other reasoning, which determines the importance of the clinical diagnosis of the disease. This review considers different approaches to diagnosing PTE and a base of elaborated clinical algorithms and comparatively assesses empirical and scoring systems for the diagnosis and prediction of a disease course characterized by the rapidness and unpredictability of an outcome even in correctly made diagnosis. PMID- 25518516 TI - [Principles of choice of an angiotensin-converting enzyme inhibitor: specific features of perindopril]. AB - Angiotensin-converting enzyme (ACE) inhibitors, a large and heterogeneous group of drugs whose representatives have significant intergroup differences, occupy a special place among many classes of antihypertensive agents. This review focuses on the properties and effects of perindopril, which set off it from other ACE inhibitors, going beyond the scope of the classic effects of this group of drugs. PMID- 25518517 TI - [The role of treatment compliance in combination therapy for heart failure and possibilities of its correction: generalization of Russian and world experience]. AB - Chronic heart failure (CHF) is a serious health problem today. Despite all advances in modern medicine, the high morbidity and mortality rates of CHF force physicians to search for new more effective methods for its control. At the same time, the fact that the designing of new effective medicaments is complex and expensive and that patients show low compliance with drug therapy increases the value of non-drug treatments for heart failure, such as patient education, higher treatment compliance, which make it possible to significantly enhance the efficiency of current combined drug therapy, to improve quality of life, and, possibly, to reduce future heart failure death rates. PMID- 25518518 TI - [Practical aspects of treatment in patients with chronic cerebral ischemia and hypertension in general somatic practice]. AB - The official statistics of the Ministry of Health of the Russian Federation show that the past 10 years have been marked by an increase in the number of patients with chronic cerebral circulatory disorders (CCCD), accounting for at least 700 per 100,000 population. Hypertension is the most studied etiological factor of CCCD. However, its role is often perceived uniquely as the major mechanism for destabilization of the arterial vascular bed. The detailed study of the pathogenesis of impairments in the cerebral vascular bed and neurons will be able to predict the further course of the disease and to choose adequate therapy. PMID- 25518519 TI - [Chronotropic properties of adaptogenic drugs]. AB - Adaptogenic agents of hormonal (melatonin) and plant origin (ginseng and bilobil) produce optimizing effect on circadian rhythm of locomotion and on the temporal dynamics of forced swimming in intact and false-operated rats. Melatonin exhibits the most expressed impact on behavior of animals. After the removal of the pineal gland, these effects of investigated drugs were significantly decreased. It is suggested that the pineal gland may take part in the chronotropic activity of adaptogenic drugs. PMID- 25518520 TI - [Influence of melatonin and diclofenac on circadian rhythm of locomotor activity in rats with local inflammatory arthritis]. AB - Inflammatory arthritis is accompanied by disorganization of the circadian rhythm of locomotion in rats. Control saline injections increased the rhythm disturbances. Chronic administration of melatonin (5 mg/kg) attenuated these chronopathological shifts. Diclofenac demonstrated much lower positive chronopharmacological activity than did melatonin. PMID- 25518521 TI - [The effect of 3-oxypyridine and succinic acid derivatives on obsessive compulsive activity of mice in marble-burying test]. AB - The effect of domestic derivatives of 3-oxypyridine and succinic acid (emoxipine, reamberin, and mexidol) on obsessive-compulsive behavior of mice was studied in the marble-burying test. Additionally the effect of these drugs on the behavior of animals was assessed in the open field test. Amitriptylin and alpha-lipoic acid were used as reference drugs. It was established that single administration of the investigated drugs in optimal doses, corresponding to therapeutic range in humans, inhibits obsessive-compulsive behavior of mice in the marble-burying test. Amitriptylin and alpha-lipoic acid produced similar effects. It is established that emoxipine stimulates the behavior of mice in the open field after single administration. An increase in the emoxipine dose led to decrease of stimulation and gradual development of sedative effect. Reamberin and mexidol, as well as alpha-lipoic acid and amitriptyline, caused sedation in mice tested in the open field. Inhibiting effect of emoxipine, reamberin, mexidol and alpha lipoic acid on the obsessive-compulsive behavior in mice directly depended on sedative action of these drugs. PMID- 25518522 TI - [Study of some pharmacological properties of a new adenine derivative]. AB - It is established that the new compound, 9-[2-(4-isopropylphenoxy)ethyl]adenine (9-IPE-adenine) in a dose of 10 mg/kg per day produces neuroprotective effect in rats with brain ischemia model. 9-IPE-adenine decreased the neurologic deficiency 1.2 times more effectively (p < 0.05) than the reference drug mexidol in analogous dose, and had equal effect with this drug at 25 mg/kg per day on the neurologic deficiency and survival of animals. Electrophysiological studies in hippocampal slices in rats showed that 9-IPE-adenine depressed orthodromic population spikes in CA1 area by 42 +/- 4%. Non-competitive antagonist of NMDA receptor complex MK-801, in contrast to D-AP5 (competitive NMDA receptor antagonist) and CNQX (competitive AMPA receptor antagonist), enhanced the depressive effect of the new drug more than two times. These ese results are indicative of the ability of 9-IPE-adenine to modulate the ion channel of NMDA receptor complex. PMID- 25518524 TI - [Hepatorotective activity of honeysuckle fruit extract in carbon tetrachloride intoxicated rats]. AB - We have studied the effects of the extract from the dry pomace of honeysuckle fruits Lonicera edulis Turcz. and commercial reference preparation Legalon on weight and biochemical liver indexes in rats upon carbon tetrachloride intoxication. The extract of honeysuckle fruits favored a decrease in the total lipid content, reduced specific liver weight, and facilitated restoration of the activity of serum alanine aminotransferase and liver lysosomal enzymes. It the blood of rats, the extract increased superoxide dismutase activity, decreased glutathione level, enhanced antiradical activity, and reduced the level of malonic dialdehyde. The effect of administration of honeysuckle fruits pomace extract on restoration of the liver function was more pronounced than the effect of Legalon. PMID- 25518523 TI - [Using L-carnitine to improve the adaptation of young athletes to physical load and the correction of stress-induced cardiomyopathy]. AB - The mechanisms of L-carnitine action and ergogenic pleiotropic effects of drugs, which play important role in sports medicine are described. Results of a comparative, parallel-group randomized clinical trial of L-carnitine (Elkar, PikFarma) in young athletes (football players, walkers) are reported. Elkar increases the body adaptation to physical stress and has a pronounced therapeutic effect in athletes with stress-induced cardiomyopathy by reducing the representation of potentially dangerous arrhythmia (sinus bradycardia less than 2 - 5 centile, 2nd degree atrioventricular block type II, T-wave inversion in more than 2 leads, and/or ST segment depression) and severity of benign ECG disturbances and hemodynamic changes, and decreasing the concentration of biochemical markers of myocardial damage (troponin, natriuretic peptide, creatine phosphokinase MB fraction) and cortisol. In general, Elkar contributed to a significant reduction in symptoms of cardiac remodeling in 75% of patients and had a weak effect in 25% of patents. It is concluded that the use of Elkar in playing sports and sports coaching quality of endurance is appropriate, especially in terms of myocardial remodeling. PMID- 25518525 TI - [Antitumor and antiproliferative action of the steroidal cytostatic antiestrogen cytestrol acetate on hormone-dependent tumor models]. AB - Cytestrole acetate (CA), in the structure of which the steroidal antiestrogen component is associated with bis-beta-cloroethylamino group, exhibits a strong cytotoxic activity against hormone-dependent cancer cell lines (CaOV, HeLa, MCF 7). In doxorubicin-resistant MCF-7 cells, CA potentiates the cytotoxic effect of etoposide and doxorubicin, and the IC50 for CA in these cells is 40 times lower than that for tamoxifen (TAM). In transplantable mice breast adenocarcinoma Ca 755, the therapeutic CA dose is 25 mg/kg when administered subcutaneously in oil solution for 5 days. On the DMBA-induced mammary tumors in rats, CA injected subcutaneously led to partial regressions 4 weeks after treatment in 75% of test rats, whereas TAM produced this effect in 43% of rats. Among various drug forms of CA, the most active were oil solution of CA in gelatin capsules for oral use and liposomal emulsion for intravenous administration, since these forms exhibited the highest values of Ca-755 tumor growth inhibition index (TGI = 97 - 98%). PMID- 25518526 TI - [Intravenous injection of coenzyme Q10 increases its level in rat brain]. AB - It is established that intravenous injection of solubilized coenzyme Q10 provides quick and lasting increase in its level in the brain as compared to control intact rats and those with cerebral ischemia. These new data provide a basis for studying the efficacy of coenzyme Q10 as a neuroprotective agent in ischemic stroke. PMID- 25518527 TI - [Antiviral activity in vitro and pharmacokinetics of HCV entry inhibitor AVR560]. AB - Several novel compounds were found to be potent inhibitors of the HCV (JFH-1 isolate) infection in vitro. Human serum did not significantly reduce antiviral activity of the lead compound, AVR560 (< 4-fold). The immunohistochemistry studies with the Huh7 cell line, infectable with the HCV (JFH-1 strain), demonstrated that AVR560 inhibited the early steps of viral infection and blocked the spread of the HCV infection in tissue culture. The cytotoxicity in Huh7 and Vero-76 cell lines was mild. AVR560 proved to be a specific HCV inhibitor and exhibited no activity against other flaviviruses such as yellow fever (strain 17D), West Nile (strain NY99), and dengue (New Guinea type 2) in in vitro infection experiments. AVR560 also did not inhibit any of the tested human CYP450 isozymes (3A4, 1A2, 2C19 and 2D6). In the pharmacokinetic studies in mice, rats and dogs, favorable pharmacokinetic profiles and good oral bioavailability were observed for AV560. Further pre-clinical studies with this novel HCV inhibitor are in progress. PMID- 25518528 TI - Hypotensive effect of selective laser trabeculoplasty in patients with medically uncontrolled primary open-angle glaucoma. AB - INTRODUCTION: Glaucoma is a chronic, progressive disease of the optic nerve which if left untreated can lead to blindness at end stages. A decrease of intraocular pressure (IOP) has proven to slow down the progression of the disease. IOP decrease can be achieved by medical, laser and surgical treatment. OBJECTIVE: The aim of this study was to evaluate the response of patients with medically uncontrolled primary open angle glaucoma to selective laser trabeculoplasty (SLT). METHODS: The study involved baseline characteristics recorded for each of 35 patients (48 eyes) in whom, despite being under full medication we could not achieve a satisfactory IOP. Patients, who had pressure above 25 mmHg under the maximal medication therapy, were not included into the study and were referred for surgical treatment. IOP was measured on admission, 1 hour, 7 days, 1, 3, 6 and 12 months after SLT. We considered satisfactory surgical result if IOP was decreased more than 20% of the initial value. Also, we investigated the influence of baseline IOP on SLT outcome after 12 months. Patient inclusion criteria were inability to reach target IOP with maximal medical therapy. Exclusion criteria were congenital glaucoma, any type of angle closure glaucoma, advanced-stage glaucoma, eyes with previous laser or surgical glaucoma applications and patients with baseline IOP > 25 while fully medicated. Patients who could not be followed for at least 12 months were also excluded. RESULTS: The mean age of our patients was 73 +/- 12 years. The mean baseline IOP was 20.48 mmHg (SD = 1.91), and the mean change in IOP from baseline of the treated eye after one year was 4.47 mmHg (SD = 2.12). In eyes with a higher baseline IOP the reduction of pressure at the end of the study was significantly higher. Satisfactory effect of IOP reduction after one year was achieved in 64.58% of eyes. The IOP reduction did not show to be dependent as regarding age and gender. CONCLUSION: SLT effectively lowers IOP in patients with primary open-angle glaucoma, and the intervention is not followed by significant complications. Our results confirm that the IOP reduction is more significant if the initial value is higher. Our first reliable results of IOP reduction were confirmed one month after the procedure so that the procedure should not be repeated before one month has elapsed.The study is limited by a small number of eyes, which is insufficient to make a complete case analysis. PMID- 25518529 TI - [Influence of diabetes mellitus on corneal thickness]. AB - INTRODUCTION: Ultrastructural changes in corneas of patients with diabetes mellitus have been previously described. OBJECTIVE: The aim of this study was to compare central corneal thickness (CDR) values in diabetic patients without retinopa- thy at the stage of diabetic nonproliferative and proliferative retinopathy and CDR in a control group of healthy subjects. METHODS: The study included 121 diabetic patients and 125 healthy subjects matched according to gender and age. Each patient underwent ophthalmological examination involving a dilated fundus examination and CDR measurement using the ultrasound pachymeter. The eyes of diabetic patients were classified according to Early Treatment Diabetic Retinopathy Study into three groups: without diabetic retinopathy (NDR), with nonproliferative diabetic retinopathy (NPDR) and a group with proliferative diabetic retinopathy (PDR). Only one eye of each subject was chosen for the study. RESULTS: The mean CDR value was significantly higher in the diabetic group (570.52 +/- 31.81 MUm) compared with the control group (541.42 +/- 27.82 MUm). The difference between the two groups was statistically significant (p<0.0001). The highest mean CDR value was recorded in the PDR group (585.97 +/- 28.58 MUm), followed by the NPDR group (570.84 +/- 30.27 MUm), whereas the lowest mean CDR value was recorded in the NDR group (559.80 +/- 31.55 MUm). There was a statistically significant difference in CDR between the NDR and PDR groups, as well as between the NPDR and PDR groups (p < 0.001, p < 0.05 respectively). No significant difference was recorded between the NDR and NPDR groups (p>0.05). CONCLUSION: CDR of diabetic patients was higher compared to healthy subjects. The highest mean value of CDR was registered in the PDR group, followed by the NPDR and the NDR groups. PMID- 25518530 TI - Prevalence of Enterococcus faecalis and Porphyromonas gingivalis in infected root canals and their susceptibility to endodontic treatment procedures: a molecular study. AB - INTRODUCTION: Because apical periodontitis is recognizably an infectious disease, elimination or reduction of intracanal bacteria is of utmost importance for optimum treatment outcome. OBJECTIVE: The prevalence of Enterococcus faecalis and Porphyromonas gingivalis in infected root canals was studied Also, the effect of endodontic therapy by using intracanal medicaments, calcium hydroxide paste (CH) or gutta-percha points containing calcium hydroxide (CH-GP) or chlorhexidine (CHX GP) on these microorganisms was assessed by polymerase chain reaction (PCR) assay. METHODS: Fifty-one patients with chronic apical periodontitis were randomly allocated in one of the fol- lowing groups according to the intracanal medicament used: CH, CH-GP and CHX-GP group. Bacterial samples were taken upon access (S1), after chemomechanical instrumentation (S2) and after 15-day medication (S3). PCR assay was used to detect the presence of selected bacteria. RESULTS: E. faecalis was detected in 49% (25/51) and P. gingivalis in 17.6% (9/51) of the samples. Samples which showed no bacterial presence at S1 were excluded from further analysis. Overall analysis of all 29 samples revealed significant differences between S1 and S2 (p < 0.001), S2 and S3 (p < 0.05), and S1 and S3 (p < 0.001). When distinction was made between the intracanal medications, there was a significant difference in the number of PCR positive samples between S1 and 52, S1 and S3, but not between S2 and S3 samples. CONCLUSION: E. faecalis is more prevalent than P. gingivalis in primary endodontic infection. Intracanal medication in conduction with instrumentation and irrigation efficiently eliminates E. faecalis and P. gingivalis from infected root canals. PMID- 25518531 TI - [Efficacy and safety of balloon valvuloplasty as a treatment of choice for pulmonary stenosis in children and adolescents]. AB - INTRODUCTION: Pulmonary artery stenosis (PS) is a congenital heart defect which occurs in 10% of all congenital heart defects. Pulmonary balloon valvuloplasty (BVP) has been the treatment of choice of PS over the last 30 years. OBJECTIVE: The purpose of this study was to evaluate the effi- cacy of this method based on middle-term hospital follow-up, and safety of BVP based on our experience. METHODS: The study included 88 patients diagnosed with PS.The patients were divided into three groups based on the severity of the disease. Also, they were divided into two age groups in order to analyze the frequency of complications. Hemodynamic measurements and echocardiography results were recorded before, 24-36 hours after BVP and at the end of follow-up. RESULTS: The studied group involved patients of average age 3.75 +/- 4.3 years (20 days to 17 years). Immediately after BVP a significant decrease of pressure gradient across the pulmonary valve (PV) was recorded in all patients; this result was similar in all 3 groups of patients regardless of the severity of stenosis (p < 0.001). Complications of BVP occurred most commonly in children up to 12 months of age (ventricular tachycardia 4.5% and supraventricular tachycardia 6.8%). Pulmonary valve in- sufficiency after dilatation occurred in 6.6% of cases, and was most common in children aged up to 12 months. In 87 (98.9%) patients BVP was a definitive solution, and a significant residual stenosis was not recorded during follow-up. CONCLUSION: BVP is a safe and effective procedure in the treatment of isolated PS in children, regardless of the severity of stenosis but also regardless of patients' age. PMID- 25518532 TI - Alpha-1-antitrypsin deficiency in children: clinical characteristics and diagnosis. AB - INTRODUCTION: Alpha-1-antitrypsin deficiency (AATD) is a relatively rare and clinically very heterogeneous autosomal recessive disorder. OBJECTIVE: Presentation of clinical characteristics of AATD in the first months after birth, as well as the significance of testing brothers and sisters for its presence. METHODS: Objectives of the study were analyzed on a sample of eight children (four male and four female, aged 63 months (mean 14.81 +/- 23.96 months; range 1 63 months) with AATD confirmed based on its low serum value and pathological phenotype. RESULTS Of the total of eight patients, six manifested cholestasis syndrome (three male and three female, mean age 2.25 +/- 1.37 months; range 1-4.5 months), while two patients, a 3.5-year-old girl and a 5.25-year-old boy, were without symptoms and clinical-laboratory signs of the disease, disclosed during family testing. Serum alpha-1-antitrypsin level rated 0.30-0.66 g/L (0.37 +/- 0.12), among which seven were with ZZ phenotype 0.30-0.39 (0.33 +/- 0.04), and in a boy with FZ the phenotype was disclosed on family screening, 0.66 g/L. In the group of patients with cholestasis syndrome (serum GTT 444.80 +/- 203.15 U/L; range 201-676 U/L), three had mild to moderate hepatomegaly, one had longitudinal growth delay (< P3; -10.50%) and two had icterus with conjugated hyperbilirubinemia (92 and 109 MUmol/L) and prolonged prothrombin time (PT 14.8 and 17 sec). All children with cholestasis syndrome also had hypertransaminasemia (ALT 80.83 +/- 33 U/L; range 37-124 U/L and AST 116.67 +/- 62.82 U/L; range 58 230 U/L). CONCLUSION: Cholestasis syndrome represents a basic manifestation of AATD in the first months after birth, while early testing of brothers and sisters enables early disclosure and adequate treatment of the subclinical forms of the disease. PMID- 25518533 TI - [Bacterial infections in patients with liver cirrhosis and ascites]. AB - INTRODUCTION: Bacterial infections are common complications and the cause of death in patients with cirrhosis and ascites. There is no standard method for a rapid and low-cost diagnosis, and its prognosis is poor. OBJECTIVE: The aim of this study was to determine the etiology and frequency of bacterial infections in patients with liver cirrhosis of different etiology, and the influence of bacterial infections on the prognosis in patients with liver cirrhosis and ascites. METHODS: Sixty-four patients with cirrhosis and ascites were included in the study. The diagnosis of spontaneous bacterial peritonitis was established based on the diagnostic abdominal paracentesis and the results of biochemical, cytological and microbiologic analysis of ascitic fluid. The diagnosis of urinary infection and pneumonia were made according to the standard criteria. RESULTS: Spontaneous bacterial peritonitis was diagnosed in 23 (35.9%) patients, urinary infections in 16(25%) and pneumonia in 11 (17.2%). Gram positive and gram negative bacteria in spontaneous bacterial peritonitis were etiologically almost equally represented (52%; 48%).The most frequent causes were Escherichia coli and Staphylococcus aureus. In 81% of patients urinary infections were caused by gram negative bacteria (Escherichia coli in 44%). The most frequent cause of pneumonia was Streptococcus pneumoniae (46%). CONCLUSION: Spontaneous bacterial peritonitis, urinary infections and bronchopneumonia are the most frequent bacterial infections in patients with liver cirrhosis and ascites. A timely recognition of bacterial infections and the initiation of treatment have a positive effect on the prognosis of such patients. PMID- 25518534 TI - [The effect of hydrophobicity of group A beta-hemolytic streptococcus in the process of adherence and biofilm production ]. AB - INTRODUCTION: Bacterial cell hydrophobicity and adherence to a substrate are one of the most important factors in biofilm formation. Group A streptococcus is an unstable and low biofilm productor. Importance of biofilm production in streptococcal pathogenesis is still unknown. OBJECTIVE: The aim of this study was to determine the impact of hydrophobicity and adherence on the biofilm production of group A streptococcal invasive and noninvasive isolates, and also to evaluate the stability of biofilm production in time function. METHODS: Adherence, hydrophobicity and biofilm production were investigated in a total of 172 isolates divided into three groups: noninvasive, low invasive and highly invasive. Adher- ence to uncoated and laminin-coated microtiter plates and biofilm production after 12, 24 and 48 hours of incubation was determined using the method described by Stepanovic et al. Hydrophobicity was measured using the MATH test by Rosenberg and SAT test by Lindhal. RESULTS: Correlation between adherence and biofilm produc- tion was detected in the group of noninvasive isolates. These isolates were stable biofilm productors during all three time periods of biofilm production. In the groups of invasive and noninvasive isolates no statistical correlation was detected among the analysed variables. The invasive isolates were un- stable biofilm productors. CONCLUSION: Noninvasive isolates were stable biofilm producers; as detected, they showed a direct correlation between adherence and biofilm production, and a negative impact of hydrophobicity on the biofilm production. Invasive isolates were unstable biofilm productors; it was observed that there was no correlation between adherence and hydrophobicity with biofilm production. PMID- 25518535 TI - [Characteristics of Acute Hepatitis C]. AB - INTRODUCTION: Acute hepatitis C most frequently develops after parenteral infection of hepatitis C virus. The disease often develops into chronic infection, although it can resolve spontaneously. Interferon alpha (INF-alpha) is used in therapy, but still without precise treatment recommendations. OBJECTIVE: The aim was to present characteristics of patients with acute hepatitis C and to assess effectiveness of using recombinant INF-alpha in therapy. METHODS: Total of 55 patients with acute hepatitis C, hospitalized at the Clinic for Infectious Diseases in Belgrade from January 2005 to December 2012 were enrolled in this study. Forty-one patients were under follow-up over six months for evaluation of the development of the disease into a chronic infection and effectiveness of treatment with INF-alpha. RESULTS: Eighty percent of patients were male of average age 29.6 +/- 8.6 years; in 61.8% patients intravenous drug abuse was determined as risk factor. Thirty patients (54.1%) had no symptoms and 38.2% were icteric. Acute hepatitis C spontaneously resolved in 33.3% patients, while in the treated group 79.6% of patients completely recovered (p = 0.006).Treatment success was 92.9% in the group of patients who started with treatment before the 45th day of disease, while in the patients who started treatment later the success rated 58.3% (p = 0.037). CONCLUSION: Acute hepatitis C is most common in young male adults infected via injection drug abuse. The use of INF-alpha is effective in the treatment of the disease, and success of the treatment is more probable if treatment is started before the 45th day. PMID- 25518536 TI - Improvement of sexual function in men with benign prostatic hyperplasia by pharmacologic therapy. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) causes disorders of voiding and sexual function. Phar- macologic therapy reduces symptoms of voiding thus impacting sexual function. OBJECTIVE: To determine sex life status in men with BPH before and after pharmacologic treatment adapted to achieve satisfactory sexual function. METHODS: We studied 117 sexually active BPH patients, not previously treated for BPH. After clinical examinations, symptoms of voiding, sexual and ejaculatory function were measured using standardized IPSS, IIEF and MSHQ-EjD questionnaires. After obtaining patients' personal opinion about the importance of their sex life, therapy was chosen and possible side effects explained. Three groups of 39 patients each were formed.The first group was treated with alpha-blocker, tamsulosin, the second with 5-alpha reductase inhibitor, finasteride, while the third group was administered a combination therapy. The complete examination procedure was repeated after 3 and 6 months of therapy. RESULTS: The average age of patients was 61.34 +/- 3.04 years. Eighty seven percent reported that their sex life was important to a certain degree. Satisfaction with their sex life was reported by 47% of patients before treatment and by 67% of respondents 6 months after treatment. Questionnaire scores indicated general improvement of sexual function in all groups, which was statistically significant compared to baseline only in the group on tamsulosin alpha-blocker (2.95 +/- 7.81; p = 0.028). The overall satisfaction with sex life as a component of sexual function, improved significantly in the group on the combined therapy (0.78 +/- 1.81; p = 0.012). CONCLUSION: Before BPH treatment sexual function should be assessed and therapy customized to the patient's expectations. Side effects of drugs should be presented especially to patients who emphasize the importance of sex life. In the manifested stages of the disease overall satisfaction with sex life may be improved by combined therapy comprising 5-alpha reductase inhibitors and third generation alpha blockers. In earlier stages, BPH alpha blockers monotherapy may improve overall sexual function. PMID- 25518537 TI - Patient satisfaction in outpatient healthcare services at secondary level vs. tertiary level. AB - INTRODUCTION: Patients satisfaction is a very important part of any clinical practice both for evaluation and improvement of healthcare services. OBJECTIVE: The aim of this study was to determine patient satisfaction with public outpatient healthcare services at secondary and tertiary level and to assess possible differences between the two levels. METHODS: In a quantitative cross sectional study, a convenient sample of 646 patients who experienced public outpatient healthcare services at the secondary and tertiary level during the last two months were interviewed. Patient satisfaction questionnaires, with statements regarding various aspects of satisfac- tion, were completed during face-to-face interviews (response rate 84.6%).The research instrument was tested for internal consistency using the Cronbach's coefficient alpha estimate. RESULTS: The patients were significantly more satisfied in tertiary than in secondary outpatient healthcare facilities in almost all aspects of assessment related to general settings, nurse/administrative staff performance and physician performance (p < 0.001). The patients in the secondary healthcare services (SHCS) were more satisfied than in the tertiary healthcare services (THCS) but only regarding the information on location (83.9% vs. 78.3%) and possibilities to enter and move inside the department (88.8% vs. 83.3%). Analysis of data for SHCS and THCS showed that there was no significant difference between the mean overall satisfaction scores with regard to patients' gender, age, marital status, educational level, employment and number of visits. CONCLUSION: There is a need to improve the current level of patient-provider relationship and communication, as well as that of hospital environment, while special efforts should be made to address the problem of patient waiting time and hospital bureaucracy. PMID- 25518538 TI - Convexity meningioma associated with depression: a case report. AB - INTRODUCTION: Meningiomas are slow growing, extra-axial lesions, and can be neurologically silent for a long time and present only with depression. CASE OUTLINE: A 65-year-old woman developed major depression and was treated with antidepressants for two years. Depression failed to respond to drug treatment and there was no improvement. Two months before admission to hospital, due to the onset of epilepsy attack the patient underwent rein- vestigation, and a large temporal convexity meningioma, which corresponded in position to the original electroencephalography focus, was diagnosed using the computer topography of the brain. The patient underwent osteoplastic craniotomy, and a left fronto-temporal convexity meningioma of 5 cm in diameter was completely removed with its attachment to the dura. Histological examination confirmed a fibroblastic meningioma. CONCLUSION: Total resection of convexity meningioma and decompression of the brain tissue in the region of limbic pathways that are involved, may contribute to a complete remission of depression symptoms. This case also illustrates the need for a prompt neuroimaging of the brain when patients present any atypical psychiatric symptoms, with late onset (> 50 years old) of the first depressive episode or fast changes of the mental state. PMID- 25518539 TI - Cervical epidural hematoma: case report. AB - INTRODUCTION: Cervical epidural hematoma is a rare phenomenon in children. MRI scan of the cervical spine is the method of choice in establishing diagnosis and a quick evacuation of hematoma and de- compression. CASE OUTLINE: We present a case of 11-year-old boy whose lower extremities were paralysed after a trivial injury of the cervical spine which he sustained while playing. Seven days after the injury, severe clinical symptoms appeared, and MRI of the spine showed the presence of cervical epidural hematoma. CONCLUSION: Cervical epidural hematoma in children is very rare. Adequate neurological examination, di- agnostics and urgent surgical intervention are of paramount importance for accomplishing good results. Early and persistent rehabilitation are the condition for achieving maximal recovery. PMID- 25518540 TI - Clinical features and endodontic treatment of two-rooted mandibular canines: report of four cases. AB - INTRODUCTION: Predictable endodontic treatment depends on the dentist's knowledge about root canal morphology and its possible anatomic variations. The majority of mandibular canines have one root and root canal, but 15% may have two canals and a smaller number may have two distinct roots. The following clinical reports describe endodontic treatment of mandibular canines with two roots and two root canals. OUTLINE OF CASES Four clinical case reports are presented to exemplify anatomical variation in the human mandibular canine. Detailed analysis of the preoperative radiographs and careful examination of the pulp chamber floor detected the presence of two root canal orifices in all canines. Working length was determined with an electronic apex locator and biomechanical preparation was carried out by using engine driven BioRaCe Ni-Ti rotary instruments in a crown down manner, followed by copious irrigation with 1% sodium hypochlorite. Definitive obturation was performed using cold lateral condensation with gutta percha cones and Top Seal paste. The treatment outcome was evaluated using postoperative radiographs. CONCLUSION: Endodontists should be aware of anatomical variations of the treated teeth, and should never presume that canal systems are simple. PMID- 25518541 TI - A rare case of isolated adrenal metastasis of invasive ductal breast carcinoma. AB - INTRODUCTION: Isolated adrenal metastases of invasive ductal breast carcinoma are extremely rare. We report a case with isolated left adrenal metastases, verified three years after diagnosed breast carcinoma. CASE OUTLINE: A 58-year-old female patient with a right breast tumor, clinically staged as IIIA (T2N2M0) started neoadjuvant anthracycline chemotherapy after biopsy which revealed invasive ductal breast carcinoma. Immunohistochemical findings of tumor biopsy showed hormonal steroid receptors for estrogen and progesterone negative, and human epidermal growth factor receptor 2 (HER2) positive. After 4 cycles of chemotherapy and partial tumor regression the patient underwent radical mastectomy. Definite histopathological analysis confirmed the diagnosis of invasive ductal carcinoma. The patient continued treatment with adjuvant chemotherapy to cumulative dose of anthracyclines, postoperative radiotherapy and adjuvant trastuzumab for one year. Three years later abdominal computerized tomography showed tumor in the left adrenal gland as the only metastatic site. Left adrenalectomy was performed and histopathological finding confirmed breast cancer metastases. Postoperatively, the patient received 6 cycles of docetaxel with trastuzumab and continued trastuzumab until disease progression. One year after left adrenalectomy control abdominal computerized tomography showed a right adrenal tumor with retroperitoneal lymphadenopathy. Treatment with capecitabine was continued for one year, but eventually she developed brain metastasis causing lethal outcome. CONCLUSION: In order to better understand metastatic pathways of invasive ductal breast carcinoma, publications of individual patient cases diagnosed with rare metastatic sites should be encouraged. This might improve our understanding of metastatic behavior of breast cancer and stimulate further clinical research. PMID- 25518542 TI - Desquamative interstitial pneumonia: a case report. AB - INTRODUCTION: Desquamative interstitial pneumonia is one of the rarest idiopathic interstitial pneumonias and the rarest form of smoking-related interstitial lung diseases. It was first described by Liebow in 1965. Histologically, it is characterized by the presence of eosinophilic macrophages uniformly filling airspaces which often contain a finely granular light-brown pigment that does not stain for hemosiderin. The alveolar walls are usually mildly thickened by fibrous tissue and infiltrated by a moderate number of lymphocytes. CASE OUTLINE: Our patient was a 56-year-old male, heavy smoker, with bilateral lung infiltrations of unknown etiology and several months of discomfort in the form of dry cough and shortness of breath. Lung function tests showed a moderate restrictive ventilation disorder and a severe reduction of diffusing capacity. Since bronchoscopic specimens did not reveal lung lesion etiology, an open lung biopsy of the lower left pulmonary lobe was performed, and based on the obtained surgical material the pathohistologically diagnosis of desquamative interstitial pneumonia was established. The patient was started on corticosteroid and immunosuppressive therapy, and he ceased smoking. At the last control examination, two years after the onset of symptoms, the patient was feeling well, and high-resolution computed tomography (HRCT) scan of the thorax showed regression of pathological changes. CONCLUSION: Although, as in our case, the majority of DIP patients improve on treatment, some patients still develop progressive irreversible fibrosis despite therapy. PMID- 25518543 TI - Giant epidermal cyst of the foot. AB - INTRODUCTION: Epidermoid inclusion cysts are usually composed of epidermal elements implanted into the dermal layers. Patients are seen in the outpatient clinics with a mass. Most of the complaints are mechanical and cosmetic problems. CASE OUTLINE: A 34-year-old female patient was admitted to our clinic because of swelling and pain in her right foot. A palpable mass was detected in the first web. On the x-rays of the foot no osseous lesion was detected.There was a soft tissue mass in the first web according to MRI report. Soft tissue mass was excised and sent to pathology. According to pathology report the mass was an epidermoid cyst 5 x 2 x 1.5 cm in size.There were no problems during follow-up of the patient for 6 months after surgery. The patient had no swelling in the foot and had no additional complaints on checkup. CONCLUSION: In the differential diagnosis, we should take into consideration epidermoid cyst of large soft tissue masses of the foot. Surgical excision should be done within the appropriate limits. PMID- 25518544 TI - [The presence of morphine as heroin metabolites in placental tissue and fetus: case report]. AB - INTRODUCTION: Females who have developed addiction to heroin also abuse it during pregnancy. Heroin can be detected in the fetal blood-flow already an hour after maternal i.v. injection. Heroin metabolites enter the fetal blood-flow through the placental barrier by passive transport. CASE OUTLINE: We present a 27-year old female in the 5th month of pregnancy that had a miscarriage. Chemo toxicological analysis (gas chromatography with mass spectrometry--GC/MS), showed the presence of morphine in the fetal liver (31.92 ng/g), placenta (27.94 ng/g) and meconium (136.33 ng/g). The analysis did not show the presence of 6 monoacetylmorphine. CONCLUSION: In all cases when the autopsy of fetus or newborn is performed, with mother suspected as i.v. heroin abuser, chemo- toxicological placental analysis, placenta and meconium should be also done. PMID- 25518545 TI - [Growth retardation in children with chronic renal disease]. AB - Despite recent advances in the management of children with chronic renal disease (CRD), growth retardation remains its most visible comorbid condition. Growth retardation has adverse impact on morbidity and mortality rates, quality of life and education, and in adult patients on job family life, and independent leaving accomodation. Pathophysiology of impaired growth in CRD is complex and still not fully understood. The following complications are: anorexia, malnutrition, inflammation, decreased residual renal function, dialysis frequency and adequacy, renal anemia, metabolic acidosis, fluid/electrolyte imbalance, renal osteodistrophy, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) resistance. Malnutrition is most frequent and most important factor contributing to the degree of growth retardation in infancy. The degree of renal dysfunction is the major determinant of variability in growth from third year of age until puberty onset, while in puberty hypergonadotropic hypogonadism has negative effect. The main factors that influence growth after renal transplantation are the age of the recipient and glucocorticoid drugs dosage with negative effect and allograft function with positive effect. In order to improve growth in children with CRD it is necessary to include: diet with optimal caloric intake, correction of fluid/ electrolyte imbalance, correction of acidosis, renal osteodistrophy and anemia. If growth velocity is insufficient to normalize growth, it is necessary to start recombinant human GH (rhGH) therapy at 0.05 mg/kg per day (0.35 mg/kg per week or 28 IU/m2 per week) administered by subcutaneous injection. PMID- 25518546 TI - [Challenging behavior: behavioral phenotypes of some genetic syndromes]. AB - Challenging behavior in individuals with mental retardation (MR) is relatively frequent, and represents a significant obstacle to adaptive skills. The frequency of specific forms and manifestations of challenging behavior can depend on a variety of personal and environmental factors. There are several prominent theoretical models regarding the etiology of challenging behavior and psychopathology in persons with MR: behavioral, developmental, socio-cultural and biological.The biological model emphasizes the physiological, biochemical and genetic factors as the potential source of challenging behavior. The progress in the field of genetics and neuroscience has opened the opportunity to study and discover the neurobiological basis of phenotypic characteristics. Genetic syndromes associated with MR can be followed by a specific set of problems and disorders which constitutes their behavioral phenotype. The aim of this paper was to present challenging behaviors that manifest in the most frequently studied syndromes: Down syndrome, Fragile X syndrome, Williams syndrome, Prader-Willi syndrome and Angelman syndrome. The concept of behavioral phenotype implies a higher probability of manifesting specific developmental characteristics and specific behaviors in individuals with a certain genetic syndrome. Although the specific set of (possible) problems and disorders is distinctive for the described genetic syndromes, the connection between genetics and behavior should be viewed through probabilistic dimension. The probabilistic concept takes into consideration the possibility of intra-syndrome variability in the occurrence, intensity and time onset of behavioral characteristics, at which the higher variability the lower is the specificity of the genetic syndrome. Identifying the specific pattern of behavior can be most important for the process of early diagnosis and prognosis. In addition, having knowledge about behavioral phenotype can be a landmark in the creation of targeted treatment strategies for individuals with a specific genetic syndrome. PMID- 25518547 TI - [Beginnings of nursing education and nurses' contribution to nursing professional development in Serbia]. AB - The oldest records of developmental beginnings of patients' healthcare relate to the first hospital founded by St. Sava at the monastery Studenica in 1199. The profile of the Kosovian girl became the hallmark of nursing profession in Serbia. The first school for midwives was founded in 1899 at the Department of Gynecology and Obstetrics of the General State Hospital in Belgrade. However, there were no other schools for nurses in Serbia until the foundation of the School for Midwives of the Red Cross Society in 1021. Until then the healthcare of patients and the injured was carried out by self-taught volunteer nurses with completed short courses of patients' healthcare. The first course for male and female nurses was organized by the Serbian Red Cross at the beginning of the First Serbian-Turkish War in 1876. During wars with Serbian participation in 19th and 20th centuries with Serbian participation, nurses gave a remarkable contribution being exposed to extreme efforts and often sacrificing their own lives. In war times great merit belongs to the members of the humanitarian society the Circle of Serbian Sisters founded in Belgrade in 1903, which was the resource of a great number of nurses who became the pride of nursing profession. Generations of nurses were educated on their example. In 2004 the annual award "Dusica Spasic" was established which is awarded to the best medical nurse is Serbia. Dusica Spasic was a medical nurse that died at her workplace, when aged 23 years, nursing the sick from variola. PMID- 25518548 TI - Multiauthorship and false authorship: why worrying about this? AB - Authorship and authorship abuse are in the focus of interest of all main actors in the publication game--authors, reviewers and editors of scientific journals. Along with the steady rise of the number of publications, the number of coauthors in multiauthored papers raises even more, some of them being undeserved authors. Because publication is the main way for evaluating scientists, authorship is prone to abuse, and thus the false/undeserved/gift authorship emerges. This dilutes the responsibility and damages the publication enterprise, thus initiating a constant struggle of scientific community against this type of scientific dishonesty. In this paper, several prevention and corrective measures with the aim to diminish such a dishonest behavior of authors are described. PMID- 25518549 TI - [Bovine sperm chromatin is not protected from the effects ultrasmall gold nanoparticles]. AB - The response of ejaculated bovine spermatozoa to gold nanoparticles was studied by the standard method of nuclear chromatin decondensation in vitro. After the treatment of semen samples with a hydrosol containing gold nanoparticles with an average diameter of 3.0 nm and a concentration of 1 x 10(15) particles/mL, the ability of sperm nuclei to decondense in the presence of sodium dodecyl sulfate (SDS) and dithiothreitol (DTT) dramatically changed compared to the control. The frequencies of gametes with nondecondensed ("intact"), partially decondensed, and completely decondensed nuclei correlated as 40 : 32 : 28% and 0 : 36 : 64% in the experiment and the control, respectively. Moreover, the appearance of a sufficiently large number of gametes with destructed and almost completely destroyed nuclei was noticed in the spermatozoa treated with gold nanoparticles. This article suggests the putative mechanisms of action of ultrasmall gold nanoparticles on the structural and functional integrity of the deoxyribonucleoprotein (DNP) complex of mature male gametes. PMID- 25518550 TI - [Endogenous biorhythms of the oxygen consumption rate in individual development of Lymnaea stagnalis (Lymnaeidae, Gastropoda)]. AB - Two endogenous biorhythms of the oxygen consumption rate with periods of 10.3 and 7.2 weeks have been revealed in the late postlarval ontogenesis of freshwater gastropods Lymnaea stagnalis by singular spectrum analysis. It has been determined that local maxima of both biorhythms in different individuals occur at the same age; in addition to that, the periods of biorhythms are approximately the same in all studied animals and remain unchanged during the whole individual development. It has been noted that the biorhythm with a period of 10.3 weeks is damped (its amplitude decreases from 8 MUL O2/(h x g) at the age of 20 weeks to 3 MUL O2/(h x g) at the time of death), and the biorhythm with the period of 7.2 weeks is sustained (its average amplitude is 2.4 +/- 0.4 MUL O2(h x g). PMID- 25518551 TI - [Topology and planar polarity of the Xenopus embryonic ciliated epithelium]. AB - The effect of mechanical stress on the topology and planar polarity (PP) of the Xenopus embryonic ciliated epithelium was studied. It was found that the explantation of different sections of the blastocoel roof of the early gastrula disrupted the normal orientation of rows of ciliated cells (CCs) and led to the partition of zones with a single PP into several sections with different polarity or to the occurrence of chaotic patterns. Mechanical stretching of explants increased the order of their PP and oriented it predominantly perpendicular to the stretching axis. Changes in mechanical stress had no significant effect on the ciliated epithelium topology. PMID- 25518552 TI - [The effect of weak low-frequency magnetic fields on the intracellular calcium dependent proteinases of fish]. AB - The in vivo and in vitro effects of weak, low-frequency magnetic fields with resonance parameters for calcium ions upon intracellular calcium-dependent proteinases (calpains) in the crucian carp (Carassius carassius (L.) and roach (Rutilus rutilus (L.) were studied. It has been revealed that the impact of a weak low-frequency magnetic field leads to considerable decrease in the activity of calpains in the fish skeletal muscles and brain. PMID- 25518553 TI - [Igf-1 and its isoform expression in hepatic cell tumors and the surrounding tissue in mice liver carcinogenesis induced by diethylnitrozamine]. AB - The expression of the Igf-1 gene in mice liver at different stages of development of hepatocellular carcinoma induced by diethylnitrozamine--from the initial diffuse tissue dysplasia and nodular hyperplasia to the development of multiple adenomas and carcinoma--has been analyzed. It was marked that the level of Igf-1 expression in all liver neoplasms decreased; it increased only in the liver tissue surrounding the carcinoma. The dependence of Igf-1 expression on inflammatory processes accompanying tumor growth was analyzed on the model of acute liver damage by diethylnitrozamine. It was established that the level of Igf-1 expression in liver tissue under acute damage in sexually mature mice was the same as in the control group. By the means of semiquantitative evaluation of the products of two Igf-1 splice isoforms--locally active (Mgf) and circulating (Igf- 1v4)--it has been shown that the amount of mRNA of both isoforms in hepatocellular carcinoma was lower, and in tissue surrounding the tumor higher, than in the samples of the control group. At the same time, the proportion of transcripts of isoforms was stable. PMID- 25518554 TI - [Monitoring of the chitinolytic microbial complex of the phylloplane]. AB - A comprehensive study of chitinolytic microbial complexes of the phylloplane from cultured and forest plants has been conducted. An increase of the number and biomass of metabolically active cells of the representatives of the domain Bacteria and a decrease in fungal biomass in the experimental microcosms have been shown to occur after the introduction of chitin. The characteristic features of the taxonomic structure of metabolically active chitinolytic complexes of the phylloplane of the plants studied have been elucidated. Representatives of the phyla Proteobacteria, Bacteroidetes, and Verrucomicrobia have been shown to play important roles in the chitinolytic complexes of green leaf samples, while mycelial actinobacteria of the phylum Actinobacyteria played a similar role in needles of coniferous trees. A collection of chitinolytic microorganism cultures isolated from the phylloplane of different plant species has been created. PMID- 25518555 TI - [Level nitric oxide (NO) and growth of roots of etiolated pea seedlings]. AB - Data regarding the interrelation of nitric oxide (NO) content in roots of 3-day old etiolated pea seedlings and their growth under different concentrations of N containing compounds were obtained. The concentration of exogenous compounds (sodium nitroprusside SNP, KNO3, NaNO2, L-arginine) rendering an inhibiting effect on the growth of roots were established, and the NO content in roots was determined at these concentration. It was shown that the inhibition of growth and highest NO content in the roots was determined with SNP (4 mM) and NaNO2 (2 mM) during 24 h exposition of seedlings. This dependence was not established in combinations with KNO3 (20 mM) and L-arginine (4 mM). We established that a NO scavenger, hemoglobin (4 MUM), fully or partially removed the toxic effect of SNP, nitrate, and nitrite on growth. The effect of NO on the growth and the participation of N-containing compounds in generation of NO in roots of pea seedlings is discussed. PMID- 25518556 TI - [Dependence of the structure of the capsule surrounding the acanthocephalan Corynosoma strumosum on the species of its natural paratenic host]. AB - The fine and ultrafine structure of the capsules surrounding the acanthocephalan Corynosoma strumosum in natural paratenic hosts of three species--the whitespotted greenling Hexagrammos stelleri, Steller's sculpin Myoxocephalus stelleri, and the saffron cod Eleginus gracilis--was studied. The results of this study, together with earlier data, support the hypothesis that the structure of the capsule depends on the paratenic host species. Three types of capsules differing in the ratio of fibroblasts and inflammatory cells have been identified: fibroblastic (in Japanese smelt, rainbow smelt, and saffron cod), intermediate (in whitespotted greenling), and leukocytic (in Steller's sculpin and the yellowfin sole). It was assumed that the structure of the capsule is determined by the degree of mutual adaptation of organisms in a given host parasite system. PMID- 25518557 TI - [Morphological provision for the specialization of hares to coprophagy: the architectonics of the mucous surface of the intestine]. AB - The macro- and microstructures of the surface of the mucous membrane of the gastrointestinal tract were studied in detail in two hare species (Lepus europaeus and L. timidus) using scanning electron and digital microscopes. The morphology of the gastrointestinal tract of hares, which is similar in the two species studied, was described in detail. The macrostructure of the inner surface of the ileocecal junction was investigated. The particularities of the architectonics of the mucous membrane of the intestine that are specific for hares were revealed. In the jejunum of both hare species, the mucous membrane is represented by villi with merged bases, which form circular plates. The mucosa of the colon forms large conical villi, the surface of which is scattered with secreting cells. The possible functional significance of the revealed morphological particularities is discussed. PMID- 25518558 TI - [Peculiarities of the biotope distribution of click beetle larvae (Coleoptera, Elateridae) in the Irtysh river valley]. AB - The spatial distribution of Elateridae larvae in the Lower Irtysh valley has been analyzed. The larvae analyzed belonged to 19 Elateridae species inhabiting soils of the floodplain and the river terrace. It has been pointed out that the larvae of Paraphotistus nigricornis, A. lineatus, L. parallelus, and A. incanus are most tolerant to the regular spring flooding. It has been found that the species compositions of floodplains and terrace meadows are significantly different. As a rule, species with a wide tropical spectrum inhabit floodplain soils, including bush and forest habitats. At the same time, the terrace was dominated by species characteristic of open habitats, including the steppe zone. It has been revealed that the values of species diversity vary significantly in the floodplain and terrace plots, but the higher species richness (Menhinick index) was registered in the floodplain. PMID- 25518559 TI - [Energy and mass exchange and the productivity of the main ecosystems of Siberia (from eddy covariance measurements). 1. Heat balance structure in the vegetation season]. AB - Direct measurements of heat balance (turbulent heat transfer and evaporation heat consumption) by the method of turbulent pulsations in 1998-2000 and 2002-2004 were used to obtain information on the daily, seasonal, and annual dynamics of energy fluxes and mass transfer between the atmosphere and the typical ecosystems of Siberia (middle-taiga pine forest and raised bog, true four-grass steppe, with the use of data for typical tundra) along the Yenisei meridian (90 degrees E). PMID- 25518560 TI - [The effect of optimal harvesting on the dynamics of size and genetic composition of a two-age population]. AB - The effect of optimal stationary harvesting at a constant harvest rate on the dynamics of a two-age population is considered. It has been shown analytically that harvesting a fixed rate of the population size of only one age cohort is optimal. As has been observed, the maximum of revenue function is unattainable in the case of concurrent harvesting of both age cohorts. It has been demonstrated that the direction of natural selection does not explicitly change when unselectively harvesting individuals; however, the adaptive genetic diversity of an unharvested population can be lost due to harvesting. PMID- 25518561 TI - [The role of interphase prenucleolar bodies in the recovery of the nucleolar structure after reversible hypotonic treatment]. AB - Interphase prenucleolar bodies are globular structures which accumulate in large numbers in the nucleoplasm of cultivated cells after hypotonic treatment and subsequent return to isotonic conditions; detailed studies of the role of these structures in the recovery of the nucleolus have not yet been performed. The limited mobility of interphase pronucleoli within the nucleus has been demonstrated. Exchange of the major nucleolar protein B23 between prenucleolar bodies and the surrounding nucleoplasm, rather than stable binding of this protein to the prenucleolar bodies, has been demonstrated using fluorescence recovery after photobleaching method. Gradual accumulation of B23 in the recovering nucleolus with concomitant disappearance of prenucleolar bodies has been demonstrated. PMID- 25518562 TI - [New photo-induced effects of reactivation and protection of yeast cells under lethal UVB radiation]. AB - Brief exposure of yeasts to low-intensity monochromatic light (400-730 nm) has revealed the effects of photoreactivation and photoprotection of the cells inactivated by medium wave UVB radiation (290-320 nm). The red spectral region with a maximum at 680 nm has been found to be the most active in the initiation of photoreactivation and photoprotection. It has been noted that, according to the regularities investigated, these processes differ fundamentally from the known processes of enzymatic photoreactivation and photoprotection, which have a spectral response limited by, respectively, blue (< 450 nm) and near (< 380 nm) UV light. The data obtained make possible to consider the observed effects of photoreactivation and photoprotection as the manifestation of functioning of some light-dependent defense system capable of increasing the resistance of cells to UVB radiation. PMID- 25518563 TI - [Change in the content of salicylic acid and activities of phenylalanine ammonia lyase and catalase in wheat seedling roots under the influence of Azospirilium lectins]. AB - The time course of changes in the endogenous content of salicylic acid, the ratio between the acid's free and bound forms, and changes in the activities of phenylalanine ammonia-lyase and catalase in wheat seedling roots under the effect of lectins of two strains of the associative nitrogen-fixing bacterium Azospirillum (A. brasilense Sp7 and its mutant defective in lectin activity, A. brasilense Sp7.2.3) is investigated. Differences in plant response to the action of the lectins from these two strains are established. On the basis of the obtained data, a model is proposed for lectin-assisted induction of resistance, according to which the lectin effect on the roots of seedlings results in the accumulation of free salicylic acid, which inhibits catalase activity, ultimately leading to accumulation of hydrogen peroxide and formation of induced resistance. PMID- 25518564 TI - Escherichia coli ST131 causing invasive infections in Romanian patients--a threat we can no longer ignore. AB - Escherichia coli sequence type ST131 is a major pandemic clonal group of drug resistant extraintestinal pathogenic E. coli (ExPEC) involved in community-onset and healthcare-associated infections. Thus far, its presence in our area has been paid little attention. This is a preliminary study intended to detect ST131 among 87 clinical isolates retrieved from a larger and unpublished E. coli collection. The study isolates originated from various specimens associated with invasive infections (blood, deep surgical wounds/abscesses, tracheal aspirates, pleural fluid, cerebrospinal fluid, and peritoneal fluid) and were collected between 2010 and 2014. Based on the main inclusion criteria, resistance to extended-spectrum cephalosporins (ESCs) and/or fluoroquinolones (FQs), the isolates were distributed in three categories: isolates with resistance to FQs (20 isolates), to ESCs (8 isolates), and to FQs and ESCs (59 isolates), respectively. Polymerase chain reaction (PCR) -based assays were performed to determine the major phylogenetic groups, to predict the MLST ST131 status, and to detect the bla(CTX M) content of the ESC-resistant isolates. Overall, the studied isolates derived from phylogenetic groups B2 (42 isolates), A (30 isolates), B1 (11 isolates), and D (4 isolates). Thirty-five isolates, originating from blood (26 isolates), deep wounds (6 isolates), tracheal aspirates (2 isolates), and cerebrospinal fluid (1 isolate), were identified as members of O25b:H4 ST131. Most of them displayed resistance to both ESCs and FQs and harboured group 1 bla(CRX-M) genes. The emergence of ST131 in our region can no longer be ignored. Focused attention to this lineage could reduce infection-related morbidity and antibiotic resistance. PMID- 25518565 TI - Molecular detection of nine antibiotic resistance genes in methicillin resistant Staphylococcus aureus isolates. AB - This study aimed to evaluate the relation between the phenotypic antibiotic susceptibility patterns and the antibiotic resistance genes and to investigate the prevalence of macrolide, lincosamides, streptogramin, aminoglycoside and tetracycline resistance genes among MRSA isolates. A total of 55 clinical MRSA isolates were included in this study, antibiotic resistance was conducted by Kirby-Bauer disk diffusion method, broth microdilution assay and multiplex PCR technique. Our results showed that there was no discordance between conventional susceptibility testing and gene detection by multiplex PCR assay. The prevalence of erm(A), erm(C), tetK, tetM, aacA-aphD, vat(A), vat(B) and vat(C) gene among MRSA isolates was 30.9%, 74.5%, 76.4%, 16.4%, 74.5%, 1.8%, 0% and 5.5%, respectively. These MRSA strains belonged to SCCmec types II, III, IVa and V. Rapid and reliable method for antibiotic susceptibility is important to determine the appropriate therapy decision. Multiplex PCR can be used for confirmation of the results obtained by disk diffusion method or could be used as an alternative diagnostic method in the routine diagnosis for rapid, sensitive, and specific detection of MRSA associated antibiotic resistance genes. PMID- 25518566 TI - Seroprevalence study of anti diphtheria antibodies in two age-groups of Romanian adults. AB - BACKGROUND: Diphtheria represents a serious infectious disease with high epidemic potential. It is a vaccine preventable disease (a minimum vaccine coverage of 95% for children of 1 year and 90% in adults could prevent the disease). Diphtheria vaccination is included in the National Immunization Program (NIP). Complete vaccination for children consists in DTaP (diphtheria toxoid, tetanus toxoid and acellular pertussis vaccine) vaccine administration from the age of 2 months until 4 years and dT vaccine (tetanus toxoid and a reduced dose of diphtheria toxoid) at 14 years old. The aim of this paper was to highlight the protection against diphtheria of an age segment of the Romanian adult population (20 to 39 years old) using a seroprevalence study. MATERIALS AND METHODS: The Romanian subjects were selected from two age groups: 20-29 years (n = 219) and 30-39 years (n = 229), representative for all counties of Romania. The commercial kit Anti Diphtheria Toxoid ELISA (IgG) (EUROIMMUN) was used to detect the antibodies of IgG class against diphtheria toxoid in the sera obtained from our subjects. RESULTS: We detected a 56.6% rate of positive sera (> 0.1 IU/ml--protection level) for the 20-29 age group and 31.7% positivity for the 30-39 age group. These data show a low protection level against diphtheria of the Romanian adult population, which decreases with age. The serologic data on preventable vaccine diseases are useful in order to evaluate the success of the immunization programs. PMID- 25518568 TI - Hematology references for three laboratory mice strains. AB - The paper contains reference data for the main haematologic indicators from three strains of conventional mice: Balb/c, C57BL/6 and CD1. These data listed include the mean and the standard deviation of the studied values. The animals used were divided by sex (sex ratio 1:1) and age. The study was performed in standard conditions. These strains were chosen as they are widely used for preclinical evaluations. Therefore, our data are expected to be useful for investigators conducting qualitative and quantitative toxicity studies in these mice. PMID- 25518567 TI - Differentiation of influenza B lineages from clinical samples by one-step real time RT-PCR. AB - BACKGROUND: Influenza viruses type A and type B are a leading cause of annual epidemics in human populations. Since the 1970s, influenza B viruses have diverged into two antigenically distinct virus lineages called the Yamagata and Victoria lineages. We describe the validation and implementation of a one-step real-time RT-PCR (rRT-PCR) assay that can differentiate between the two genetic lineages of type B. METHODS: Validation of rRT-PCR method was carried out using quantified positive control and reference influenza viruses with specific minor groove binder (MGB) probes. The assay was applied on 102 clinical specimens detected positive for influenza type B. RESULTS: Detection limit was found to be as low as 7.95 RNA copies per reaction. The interassay variability and intra assay variability were found to be low, and comparable for Yamagata and Victoria lineages. No cross-reactivity with the tested subtypes of influenza type A, known to cause human infections, was noticed. Differentiation of influenza B lineages by rRT-PCR was successfully achieved on all of the known positive type B samples. From the total number of clinical specimens tested, 85 samples belonged to B/Yamagata and 17 samples to B/Victoria lineage. CONCLUSION: Differentiation of genetic lineage B influenza virus circulating in Romania in the next seasons by one-step real-time RT-PCR method will supplement the classical test, haemagglutination inhibition (HI), which requires growing of the virus. This method can be advantageous for a balanced selection of samples, in case of lineages co-circulation, for genetic and antigenic characterization. PMID- 25518569 TI - Antimicrobial and antioxidant activities of alcoholic extracts obtained from vegetative organs of A. retroflexus. AB - In vitro antimicrobial and antioxidant activities of Amaranthus retroflexus leaves and inflorescence alcoholic (ethanol 70%) extracts of various concentrations ranging from 0.78 to 400 MUL/ml were analyzed on different clinical and reference bacterial strains (Staphylococcus aureus, Bacillus subtills, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii) and fungal strains (Candida albicans, C. famata, C. utilis, Saccharomyces cerevisiae) using agar disk diffusion method and broth dilution method (MIC determination) for antimicrobial activity and TEAC (Trolox capacity) assay for the evaluation of the antioxidant activity. The adapted diffusion method was used to test the antimicrobial effect of the extracts separately and in combination with a range of standard antibiotics, in order to evidence any synergic effects of A. retroflexus extracts on the antibiotics activity. The extracts showed the highest inhibitory effect against K. pneumoniae and B. subtilis with no activity against S. aureus among the bacterial strains, while in case of the fungal strains the most intensive effect was exhibited against C. famata by both extracts. The A. retroflexus leaves extract improved the ciprofloxacin and ticarcillin-clavulanic acid activity towards the P. aeruginosa clinical strain. The inflorescences extract significantly increased chloramphenicol activity on B. subtilis strain. The antioxidant activity assay showed that the studied extracts exhibited the ability to neutralize the free radicals leading to the conclusion that the tested extracts bear compounds with a broad spectrum of antimicrobial and antioxidant activity that could represent a potential alternative for treating various infectious diseases. PMID- 25518570 TI - KIR genotyping in the selected population in Andhra Pradesh (India). AB - BACKGROUND: The population is not always homogeneous in relation to the representation and functioning of genes. Therefore, the presence of allogenicity is a universal phenomenon. The profound variability is noticed among the members of the human population with reference to the resistance against infections and late onset of diseases. In this line, a few sets of alleles which come under the domain of immune function namely KIRs (Killer immunoglobulin-like receptor genes) and HLA-I have been chosen to report in the population of Puttaparthi (India). OBJECTIVES: The genotyping of the population is the current ongoing focus of our team wherein the distribution of the following alleles has been taken up in the mixed ethnic groups of Puttaparthi as a prelude to earmark them as genotypic markers in future studies relating to susceptible diseases. METHODS: The PCR protocols for the identified immune related genes viz., KIR- 2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 3DL1, 3DL2, 3DL3, 3DS1, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 2DP1, 3DP1; HLA C1 and HLA-C2 have been standardized. RESULTS & INTERPRETATION: In the present study, except KIR 2DL2, the other non-framework inhibitory KIR genes were represented at higher percentage and ranged from 57% to 80% in the chosen population which would suggest its higher survival adaptation. Interestingly, the majority of activating KIR genes were least represented and varied between 5% to 32.5% which is also in compliance with the survival adaptation of the chosen population. The carrier gene frequencies of KIRs were compared with the other populations' viz., Chinese Mongolian, Chinese Han, Greek and Brazilian data. The expected heterozygosity of KIR alleles and their rank in gene diversity among the population of Puttaparthi were also discussed. PMID- 25518571 TI - Immunological investigations in prostatic pathology--a prospective study. AB - BACKGROUND: BPH with prostatitis represents one of the most common urological pathologies affecting most men. The etiology of both conditions remains at the discretion of the various assumptions. OBJECTIVES: The body's cellular immune response in prostate adenoma is a less studied aspect which we have focused on, in this paper. The correlation with a wide range of information from specific investigations such as prostate-specific antigen (PSA) and total histopathology was the secondary aim of this work. METHODS: The study included 31 patients who underwent surgery for prostate adenoma (TUR-P, simple prostatectomy) between 08.2013 and 03.2014. Patients presenting urinary tract infection were excluded from the study. Preoperative evaluation of the immunological examination consisted of lymphocyte immunophenotyping (T, B, NK cells) from peripheral blood performed by flow cytometry. Total PSA was performed in serum by enzyme immunoassay EIA. RESULTS: In all forms of anatomoclinical BPH we found the presence of two major cellular changes: decrease of suppressor/cytotoxic T-cells and decrease of B cells. These deficits may confer an increased susceptibility to viral infection and tumor transformation. NK cells were grown in BPH associated with inflammation. PSA-prostate specific antigen values were grown at less than 50% of the patients in all clinical forms of BPH. PMID- 25518572 TI - Status of immunity against poliomyelitis in the acute flaccid paralysis (AFP) cases in Romania between 2009-2012. AB - Poliovirus (PV), a member of the Enterovirus genus, is the etiological agent of poliomyelitis, an acute paralytic disease. No poliovirus strain has been isolated in Romania since 2009. A serosurvey study carried out between 2009-2012, that involved 76 serum samples from acute flaccid paralysis (AFP) cases, showed a low protection level in the examined subjects against type 1 (80%), type 2 (79%) and type 3 (71%) poliovirus Sabin strains. Samples with titers >= 1:8 were considered positive. Suboptimal seroprevalence in the AFP cases confirmed that a high level of immunization against polio must be assured in our country, because the risk of importation and subsequent transmission of the poliovirus remains until polio is globally eradicated. PMID- 25518574 TI - [The impact of cardiac rehabilitation on selected hemodynamic parameters and risk in patients with heart failure]. AB - Due to the aging of the population is an increase in the incidence of heart failure. Progress in the treatment of cardiovascular disease determines the development of cardiac rehabilitation, which in addition to drug therapy, dietary and psychotherapy plays an important role promoting physical activity The aim of this study was to evaluate the impact of cardiac rehabilitation on the process of treatment and prognosis in patients with heart failure. MATERIAL AND METHODS: The study included 23 women and 46 men, aged 40-74 years (mean age 58.6 +/- 8.1 years) with a diagnosis of heart failure, Class I-III NYHA. All were qualified forthe second stage of rehabilitation. The period of stay in the hospital was 2-4 weeks. Patients were divided into 3 groups: group I population of 19 patients (59.2 +/- 8.3 years) participated in a 2-week rehabilitation program, group II representing 29 patients (55.3 +/- 7.9 years) in 4-week program. In Group III- reference (21 patients, mean age 65.4 +/- 8.2), due to the high risk of using individual cardiac rehabilitation program adapted to the patients. All patients underwent submaximal exercise test. In groups I and II to assess the level of physical fitness, a standard Bruce protocol, while in group III, its modified form. Blood pressure and resting heart rate were also studied. To assess the risk of patients the Duke's indicator was used. Systolic function of the left ventricle were evaluated in echocardiography. After a period of 6 months from the end of the second phase of cardiac rehabilitation, 24 patients who agreed were repeated the whole range of clinical trials conducted in the course of rehabilitation. RESULTS: In the group that received the cardiac rehabilitation based on interval training, after completion of the program, there was a statistically significant increase in EF, while reducing the level of blood pressure and pulse rate. The risk assessment of patients undergoing rehabilitation showed the greatest changes in group II, which after rehabilitation were classified as low risk. After a period of six months from the end of the second stage of rehabilitation analysis of individual parameters showed a further, significant improvement in groups I and II, with the highest rate of change between the studied parameters throughout the study period was observed in group II--subjected to a longer period of rehabilitation. CONCLUSIONS: The rehabilitation gives the favorable effect on the healing process in patients with heart failure by reducing the risk of patients undergoing systematic training. PMID- 25518573 TI - [Programmed cell death: is it only apoptosis?]. AB - Recent reports prove the necessity to modify the classical definitions of cell death. The canonical distinction between apoptosis (defined as programed cell death--PCD) and necrosis (gene independent) in no longer scientifically valid. Furthermore, more than one process mediated by intracellular genetic program has been documented, for example programmed necrosis. Diversity in definitions leads to confusion, particularly regarding specific terminology. Here we present the new unified criteria for the evaluation of cell death mechanisms as proposed by the Nomenclature Committee on Cell Death in recommendations from 2009 and 2012. PMID- 25518575 TI - [The clinical significance of peritoneal transport in children during first year of peritoneal dialysis]. AB - Peritoneal transport status is one of main prognostic factors in patients with end-stage renal disease (ESRD) treated with chronic peritoneal dialysis (PD). The aim of study was evaluation of influence of peritoneal transport status on selected clinical and biochemical parameters in children with ESRD in first year of PD treatment. MATERIALS AND METHODS: 52 children (mean age 10.3 +/- 4.7 years) with preserved residual renal function (RRF) treated with PD were enrolled into the study. In all patients we evaluated in first 12 months of PD treatment: peritoneal equilibration test (PET): D/P (Crea 4h), D/D0 Glu 4h, age, sex, etiology of ESRD, blood pressure, RRF (daily diuresis [mL/kg/24h], residual GFR [mL/min/1.73 m2]), PD parameters, adequacy, rate of PD-related peritonitis, medications, and biochemical parameters. RESULTS: Mean D/P (Crea 4h) was 0.65 +/- 0.13, mean D/D0 glu 4h-0.38 +/- 0.13. Patients were divided into 2 groups: H/HA (high/high-average) peritoneal permeability--26 (50.0%) and L/LA (low/low average)--26 (50.0%) children. Patients with H/HA were significantly (P < 0.05): younger, had slower growth rate, higher systolic blood pressure, worse control of arterial hypertension, slower rates of rGFR and twCCr (total weekly clearance of creatinine) decline, higher incidence of peritonitis, lower total protein and albumin; tendency to lower hemoglobin (P = 0.07) compared to patients with L/LA. CONCLUSIONS: High peritoneal permeability in children with ESRD treated with chronic peritoneal dialysis may be a risk factor for slower growth rate, systolic hypertension, peritonitis and metabolic disturbances: anemia, hypoproteinemia and hypoalbuminemia. Rate of GFR decline is slower in children with high peritoneal transport status. PMID- 25518576 TI - Serum uric acid concentration is associated with early changes of glomerular filtration rate in patients with diabetes type 1 without increased albumin excretion. AB - The early loss of renal function in patients with type 1 diabetes may begin before proteinuria. Only 30% of patients with diabetes manifest overt proteinuria. According to the previous studies, increased urinary albumin excretion, which is considered a classic marker of progression of diabetic kidney disease, can regress to normal urine albumin excretion. The current studies conducted in patients with type 1 diabetes without increased urine albumin excretion showed that the uric acid concentration was an independent factor for the development of diabetic kidney disease. The aim of study was to assess the impact of uric acid concentration and to identify risk factors of the early glomerular filtration loss in patients with type 1 diabetes and normal urinary albumin excretion. MATERIALS AND METHODS: 147 patients (61 women and 86 men) with type 1 diabetes without increased urine albumin excretion were analysed. GFR (gromerular filtration rate) was estimated based on the serum cystatin C concentration. Centile charts were used to determine the variation of uric acid concentration depending on GFR and gender. RESULTS: The mean value of the filtration rate for the study group was 117 ml/min/m2. The uric acid level above 90th percentile in relation to GFR was diagnosed in 8.2% of women and 0% of men, between 90th and 50th percentile in 44.3 % of women and 5.8% of men and below 50th percentile in 47.5% of women and 94.2% of men. Contrary to men in women higher serum acid concentration was strongly associated with higher glomerular filtration rate. Hyperfiltraion was diagnosed in 15 of women and 19 of men. CONCLUSIONS: The high normal uric acid concentration in women with type 1 diabetes might play a crucial role in development of hyperfiltration. PMID- 25518577 TI - [Diffusion tensor imaging (DTI) in the differential diagnosis of normal pressure hydrocephalus and brain atrophy]. AB - Clinical symptomatology of idiopathic normal pressure hydrocephalus, due to its overlap with dementias and neurodegenerative brain disorders, makes diagnosis challenging. As the neurological deficits are reversible there is a need for prompt and reliable noninvasive testing. The aim was to try to use and introduction into clinical practice of new non-invasive method--diffusion tensor imaging (DTI-Diffusion Tensor Imaging) discriminating patients classified as normal pressure hydrocephalus and patients diagnosed with brain atrophy. MATERIAL AND METHODS: Using magnetic resonance-diffusion tensor imaging, we examined white matter changes within the brains of patients diagnosed with idiopathic normal pressure hydrocephalus, cerebral atrophy and controls. Diffusion tensor brain images were obtained with 3Tesla and 1.5 Tesla MR-scanners. Fractional anisotropy brain maps were generated using a computer-automated method, and tract-based spatial statistics were then applied to compare the fractional anisotropy values in the clinical groups. The fractional anisotropy data were further investigated using region-of- interest analysis set within: fibre commissural the lateral ventricles (Fclv), forceps minor of corpus callosum (Fmin), cingulum (Cg), optic radiation (Orad), superior cerebellarpeduncle (Scp), substantia nigra (nucleus ruber) (Sn). RESULTS: Compared with the cerebral atrophy or control group, the FA values in the hydrocephalus group were significantly different in the posterior cingulate (Cg) and the forceps minor of the corpus callosum (Fmin). CONCLUSION: The pattern of white matter tracts changes in select brain regions distinguishes it from cerebral atrophy and control brains. Our pilot study adds to the body of knowledge advancing the understanding of the white matter pathology of idiopathic normal- pressure hydrocephalus. PMID- 25518578 TI - [Quality of life and depressive symptoms in patients diagnosed with uterus cancer]. AB - In the present study quality of life and depressive symptoms as well as the influence of illness on emotional state in patients with diagnosis of uterus cancer was evaluated. The aim of the study was to evaluate quality of life and depressive symptoms in women diagnosed with uterus cancer who underwent surgical treatment and complementary therapy. MATERIAL AND METHODS: The study has been conducted on randomly chosen group of 100 patients diagnosed with uterus cancer who underwent surgical treatment and adjunctive therapy. Surveys has been conducted 6 months after completed therapy when no recurrence of carcinomatous disease was confirmed. Quality of life was evaluated using quality of life questionnaire EORTC QLQ-C30 and depressive symptoms were measured by means of Beck's depression self-rating scale. RESULTS: In the conducted study in most cases patients with diagnosis of uterus cancer didn't show symptoms of depression and in 40% of patients there were mild symptoms of depressive disorder. The results show that patients without depressive symptoms had better quality of life compared to those with concomitant depressive symptoms and it was statistically significant. CONCLUSIONS: Patients with diagnosed uterus cancer in whom no symptoms of depression were detected presented with better quality of life compared to patients with depressive symptoms. Emotional state of patients with uterus cancer can be an important factor influencing their quality of life. PMID- 25518579 TI - [Quality of life and depressiveness of women patients diagnosed with ovarian cancer treated with surgery and after previous adjuvant therapy]. AB - In the present study undertaken to assess the quality of life and depression of women patients diagnosed with ovarian cancer. The aim of the study was to assess quality of life and severity of depression of women diagnosed with ovarian cancer treated with surgery, and then underwent adjuvant radio or chemotherapy treatment. MATERIAL AND METHODS: The principle of study was to included on random selection 42 women diagnosed with ovarian cancer who were treated surgically, and then subjected to adjuvant therapy. Quality of life was based on patient self assessment using the EORTC QLQ C-30 form. The severity of depression was assessed by the Beck Depression Scale. RESULTS: Our results showed that in the vast majority the quality of life of women with ovarian cancer who develop depression, evaluate their own quality of life at a low level. In contrast patients who did not get depressed in most cases evaluated their own quality of life at the average level. In studies it has been shown that patients manifesting symptoms of depression compared to women not having these symptoms differ in a statistically significant way, in terms of quality of life. CONCLUSIONS: The results indicate that women diagnosed with ovarian cancer who have demonstrated the co-existence of depression presented a lower quality of life. The study indicates that in the majority of cases the severity of depression of patients diagnosed with ovarian cancer were mild. PMID- 25518580 TI - Bleeding gastric metastases from cutaneous melanoma. AB - 7% of gastrointestinal tract (GIT) involvements with metastatic cutaneous melanoma concerns the stomach. The aim of the study was to describe a rare case of the cutaneous melanoma metastazing to the stomach. MATERIAL AND METHODS: . Bearing in mind the rarity of such cases, we present our experiences based on the history of 42-year-old woman, who underwent surgical excision of skin tumour located on the trunk. RESULTS: Histopathological examination of the skin tumor led to the diagnosis of melanoma (Clark IV, Breslow 5mm) with ulceration and a number of mitoses 40/10 HPF. PET-CT demonstrated multiple organ dissemination. Patient was admitted to the hospital due to severe, symptomatic anaemia. RBC and FFP transfusions were necessary. Gastroscopy revealed multiple gastric and duodenal ulcers and histopathology confirmed metastatic melanoma. Attempts to achieve endoscopic hemostasis were ineffective due to the extent of lesions. CONCLUSION: In the presence of any alarming GIT symptoms or unclear anaemia, any physician treating patient with a history of melanoma should exclude metastatic tumour. Endoscopy may be useful both for the diagnosis and local treatment of gastric metastases and should be routinely and cautiously conducted. PMID- 25518581 TI - [Carcinoembryonic antigen as a marker of proliferative diseases of the lymphatic system in patients with chronic renal failure--case report]. AB - In patients with CKD, anaemia mainly develops due to a decreased renal synthesis of erythropoietin. The anaemia, both normochromic and normocytic, becomes more severe as the glomerular filtration rate progressively decreases. Tumor markers are used to detect or monitor proliferative diseases. Carcinoembryonic antigen (CEA) is usually produced in the gastrointestinal tract, but its production is terminated before birth. The main application of this indicator is to monitor the treatment and the presence of metastases of colorectal cancer. We present a case of 86-year-old woman who was diagnosed with renal anaemia in stage 4 of chronic kidney disease (CKD), treated by periodic blood transfusions. This paper presents the difficulties in diagnosis and treatment of anemia with complex and different than renal origin anemia in patients with CKD. Patients require the detailed haematological diagnosis. Pointed out the usefulness of CEA in the diagnosis of lymphoma with co-existing renal failure. The use of erythropoietin in doses of nephrology allowed to avoid further blood transfusion. PMID- 25518582 TI - [The prognostic value of hyperglycemia, leukocytosis and decreased glomerular filtration rate in acute coronary syndromes--pharmacological protection capabilities]. AB - The evaluation of the risk of complications and death from cardiovascular causes is conducted in all patients with acute coronary syndromes (ACS) using a variety of methods. The assessment of the risk of cardiovascular events, including also death, the cause of which are cardiovascular diseases, is a very important and essential part of clinical evaluation. Moreover, all patients with ACS are assessed as regards the risk of complications and in-hospital mortality and the short- and long-term patient outcomes. Recently, in the prognostic assessment of ACS patients attention has been paid to hyperglycemia, leukocytosis, and decreased GFR, which might worsen the prognosis. Hyperglycemia on admission and especially its occurrence and persistence during hospitalization speak for particularly poor prognosis. Furthermore, the annual and long-term mortality rate is observed to increase with the higher HbA1c level, regardless of the glucose concentration on admission to hospital. Increased risk of the occurrence of cardiovascular events is observed with the intensity of the inflammation which is reflected, among others, in elevated number of peripheral blood leukocytes. Attention is drawn to the higher rate of complications in patients with increased baseline leukocytosis. The correlation between the increase in leukocyte count and all-cause mortality is statistically significant. A higher risk of non- fatal myocardial infarction is also observed with the increase of leukocytosis. Neutrophils, which are the main pool of white blood cells, and whose activation is observed during PCI, may play a role in these unfavorable phenomena. This activation results in increased production of oxygen free radicals by these cells, intensification of adhesion and aggregation. A number of studies point to the cardioprotective mechanism of action of statins (anti-inflammatory and anti thrombotic) in patients with ACS. The use of leukocyte reduction filters in patients during CABG may be one of the methods limiting the impact of leukocytosis on cardiovascular events in patients with ACS. Renal failure is a strong and independent predictor of mortality in patients with ACS. Contrast induced nephropathy is a complication following coronarography which is performed in patients with ACS for diagnostic and therapeutic purposes. Hyperglycemia also has an adverse effect on this complication. The prevention of contrast-induced nephropathy includes the use of statins prior to PCI. PMID- 25518583 TI - [Mercury pollution in selected food products in Poland in the context of their health safety]. AB - Mercury is a silvery-white chemically active transition metal without known physiological role. It is also a toxin accumulated in living organisms- especially in the aquatic creatures (fish and shellfish). Mercury compounds are involved in biogeochemical cycles (especially atmospheric and hydrobiologic), and thus they become contaminants of food. Such process is facilitated by the increasing environmental chemization. Toxic effects of mercury compounds result from their high affinity to sulfur (sulfhydryl groups of amino acids), accumulation in parenchymal organs, metallic mercury lipophilicity as well as long biological half-life period. In Poland the major sources of mercury exposure in diet are fish products and mushrooms. The role of mercury in human toxicology was presented in the work, along with a review of the literature concerning mercury content in selected food products in Poland. In general, most of foods do not pose a threat to consumers' health. Some restrictions in the amount of predatory fish and mushrooms consumed by pregnant and breastfeeding women as well as small children should be however recommended. PMID- 25518584 TI - [Potential applications of marijuana and cannabinoids in medicine]. AB - Cannabinoids, psychoactive substances present in cannabis, have been known to mankind for hundreds of years. Apart from 9-tetrahydrocannabinol (THC) substances found in the cannabis herb with the highest toxicological value are cannabidiol (CBD) and cannabinol (CBN). The discovery of CB1 and CB2 receptors, located in various tissues (ranging from the brain to peripheral tissues), has defined the potential objective of these new chemical substances' effects. Many studies on the application of cannabinoids in the treatment of various diseases such as diabetes, neoplasms, inflammatory diseases, neurological conditions, pain and vomitting were conducted. Drugs containing e.g. THC appear on the pharmaceutical market. Substances affecting cannabinoid receptors may show beneficial effects, but they may also cause the risk of side effects related mainly to the inhibition of central nervous system. The purpose of this dissertation is the analysis, whether the substances responsible for the effects of marijuana, can find application in medicine. Original articles and reviews were used to summarize the results of studies connected to the topic. PMID- 25518585 TI - [From recognition to practice: The 140th anniversary of the discovery of Clonorchis sinensis]. AB - It has been the 140th anniversary since the discovery of Clonorchis sinensis, of which adult worms were found by McConnell in an oversea Chinese in Calcutta, India, September of 1874. Then, Japanese scholar Kobayashi proved that freshwater fish served as the second intermediate hosts in 1910, while another Japanese parasitologist Muto found that the first intermediate hosts were freshwater snails in 1918. However, the perniciousness has not been recognized until recently. C. sinensis infection was classified as definite carcinogen (group 1) in cholangiocarcinoma in 2009 by the International Agency for Research on Cancer, WHO, and listed as one of the 17 diseases in WHO's first report on neglected tropical diseases in 2010, while its disease burden was published on line in an international journal in 2011. Nevertheless, our awareness on and practices in the control of clonorchiasis still lag behind the reality. Great efforts on research and control of clonorchiasis are especially required in China, since China takes the biggest share in global disease burden of clonorchiasis. PMID- 25518586 TI - [Construction of Plasmodium falciparum signal peptide peptidase-GFP mutant and its expression analysis in the malaria parasite]. AB - OBJECTIVE: To construct recombinant plasmid pSPPcGT which contains signal peptide peptidase gene of Plasmodium falciparum (PJSPP) and GFP, and transfect into P. falciparum (3D7 strain) to obtain mutant parasites which can express PJSPP-GFP. METHODS: Plasmodium falciparum(3D7 strain) genomic DNA was extracted from cultured malaria parasites. The C-terminal region of PJSPP, an 883 bp gene fragment was amplified by PCR, and then cloned into pPM2GT vector to get recombinant vector pSPPcGT. The recombinant vectors were identified by PCR, double restriction enzyme digestion and DNA sequencing. pSPPcGT vector was transfected into malaria parasites. The positive clones were selected by adding inhibitor of Plasmodium falciparum dihydrofolate reductase WR99210 to the culture medium. The pSPP-GFP-transfected parasites were fixed with methanol, stained with DAPI, and observed under immunofluorescence microscope. The PJSPP-GFP expression in P. falciparum was identified by SDS-PAGE and Western blotting. RESULTS: The C terminal region of PJSPP was amplified from P.falciparum (3D7 strain) genomic DNA by PCR with the length of 883 bp. The constructed recombinant vectors were identified by PCR screening, double restriction enzyme digestion and DNA sequencing. The pSPPcGT vector was transfected into P. falciparum and the positive clones were selected by WR99210. GFP fluorescence was observed in transfected parasites by immunofluorescence microscopy, and mainly located in the cytoplasm. The PJSPP-GFP expression in malaria parasites was confirmed by Western blotting with a relative molecular mass of Mr 64,000. CONCLUSION: Recombinant vector PJSPP-GFP is constructed and transfected into P. falciparum to obtain P. falciparum mutant clone which can express PfSPP-GFP. PMID- 25518587 TI - [Construction of HSP47-shRNA and its impact on HSP47 at cellular level]. AB - OBJECTIVE: To construct a short hairpin RNA (shRNA) against HSP47 gene, assess the expression level of HSP47 gene in NIH/3T3 cells, and observe the influence on cell function. METHODS: The HSP47-shRNA sequence presented at the downstream of the U6 promoter. The shRNA expression constructs were created using PCR- based methods. The PCR product was digested with Nhe I/Hind Ill and ligated into pGCsi/U6/Neo vector to produce HSP47-pGCsi-U6-shRNA (HSP47-1-pGCsi-U6-shRNA, HSP47-2-pGCsi-U6-shRNA and HSP47-3-pGCsi-U6-shRNA). The non-interference vector and non-related interference vector served as control. The vectors were transfected into NIH/3T3 fibroblast cells by liposome mediated gene transfection method. Transfection efficiency and fluorescence intensity were determined by fluorescence microscopy at 12, 24, 48, and 72 hours after transfection, respectively. Cells were collected before transfection, and at 24, and 48 hours post-transfection, respectively, HSP47 mRNA and protein expression levels were assessed by real-time PCR and Western blotting. The mRNA expression of TGF-pl, collagen types I and Ill in NIH/3T3 cells, and TGF-beta1 levels in cell culture supernatant were determined. RESULTS: HSP47-shRNA vector was transfected into NIH/3T3 cells by liposome-mediated transfection. The transfection efficiency in each HSP47-shRNA plasmid interference group was about 60.0%, and there is no statistical difference among the interference groups (P> 0.05). A small amount of green fluorescent cells were found at 12 h post-transfection. The number of green fluorescent cells increased with the transfection time, and reached strongest at 72 h after transfection. shRNA interference significantly inhabited HSP47 expression in NIHI/3T3 cells. At 24 h after transfection with HSP47-1-shRNA, the inhibition effect was the strongest, and the relative silence efficiency of HSP47 mRNA was (25.83?1.79)%, lower than that of control group and non-related group (P<0.05). Collagen synthesis and secretion by NIH/3T3 cells reduced significantly at 24 and 48 hours post-transfection with HSP47-1-shRNA; and there was a significant difference between HSP47-1-shRNA intervention group and non-related controls. After transfection for 24 and 48 h, mRNA expression of collagen types I and IlI decreased to (56.52 +/- 1.64)% and (53.48 +/- 2.54)%, (54.17 +/- 2.63)% and (50.21 +/- 2.34)%, respectively, significantly lower than that of the control group and non-related group (P<0.05); however, no significant difference was found among the interference groups (P>0.05). In each HSP47-shRNA plasmid interference group, TGF-p1 mRNA expression was the lowest at 24 h post transfection. The relative mRNA expression level was (63.23?2.18)%, (64.5+3.17)%, and (75.19 +/- 4.20)% in HSP47-1-shRNA, HSP47-2-shRNA, HSP47-3-shRNA groups (P>0.05), respectively, lower than that of the control group and non-related group (P<0.01). At 24 and 48 h post-transfection, TGF-P131 expression was the lowest at 24 h post-transfection, and the relative expression level in HSP47-1 shRNA, HSP47-2-shRNA, HSP47-3-shRNA groups was (51.79 +/- 3.12)%, (66.67 +/- 2.13)%, and (69.61 +/- 3.65)%, respectively. Compared with control group, the expression of TGF-beta1 in HSP47-1-shRNA and HSP47-2-shRNA2 groups was significant inhibited, but there was no significantly difference between control group and HSP47-3-shRNA group (P>0.05). CONCLUSION: HSP47-shRNA. interference plasmid is constructed. HSP47-shRNA effectively inhibits protein expression of HSP47, and results in changes of cell function. PMID- 25518588 TI - [Construction of beta-hydroxyacyl-acyl carrier protein dehydratase mutant of Toxoplasma gondii by tetracycline inducible expression system]. AB - OBJECTIVE: To construct a beta-hydroxyacyl-acyl carrier protein dehydratase (FABZ) mutant of Toxoplasma gondii with tetracycline inducible expression system. METHODS: The fabz gene was amplified from T. gondii genomic DNA, and then used to construct the tetracycline inducible expression vector pTetO7-Sag1-FABZ-Ty-DHFR. The vector was transfected into TATi strain by electroporation. The FABZ defective mutant was selected by pyrimethamine and limitting dilution assay. The expression of Ty-tagged mutant was detected by Western blotting. 5 x 10(5) tachyzoites of FABZ defective mutant were cultured in HFF in the presence of anhydrotetracycline (ATc, 1 microg/ml) for 24 h and 48 h, respectively. The expression of Ty-tagged FABZ protein in the mutant was detected by Western blotting. RESULTS: The mutant could express the transit peptide (t-FABZ) and mature FABZ (m-FABZ) with the Ty-epitope tag. After ATc added in culture medium for 24 h and 48 h, the expression of t-FABZ in the mutant decreased significantly (P<0.05). CONCLUSION: The FABZ mutant is constructed with a tetracycline inducible expression system. PMID- 25518589 TI - [Experimental study on the Der f 1 mRNA molecules derived from dermatophagoides farinae for specific immunotherapy on murine model of asthma]. AB - OBJECTIVE: To investigate the effect of Der f 1 mRNA molecules for specific immunotherapy on murine model of asthma. METHODS: Fifty BALB/c mice were randomly divided into 5 groups: PBS group, Der f 1 sensitization group, Der f 1 specific immunotherapy (SIT) group, beta-actin mRNA SIT group, and Derf 1 mRNA SIT group. On days 0, 7 and 14, mice in PBS group received PBS injection; mice in the other groups were intraperitoneally injected with 10 microg Derf 1. At day 21, the mice in the 4 experimental groups were challenged with a 30-min inhaled dose of Der f 1 (100 microg/ml) for 7 successive days. Two weeks after the final sensitization, the mice in the above five groups were im- munized by intradermal injection with PBS, 1 microg Der f 1, 10 microg Der f 1, 2 microg beta-actin mRNA, and 2 microg Der f 1 mRNA, respectively for 3 times at one-week intervals. Two weeks after the last intradermal injection, all mice were sacrificed and bronchoalveolar lavage fluid (BALF) was collected. ELISA was performed to detect the levels of IFN-gamma and IL-13 in BALF, the number of eosinophils in the BALF was recorded. Splenocytes were prepared, and cultured with Der f 1 al- lergen (10 Jg/ml) for 72 h. Splenocytes of PBS group was cultured without Derf 1 allergen. The levels of IFN-gamma and IL-13 in splenocyte culture supernatant were measured by ELISA, as well as serum antibody levels of total IgE, allergen- specific IgE (sIgE), sIgG1, and sIgG2a. Lung sections were stained in hematoxylin and eosin, and observed under the microsope. RESULTS: Except for PBS group, mice in the other 4 group showed symptoms of acute asthma attack. Com- pared with Derf 1 sensitization group [(897.56 +/- 105.73) pg/ml] and beta-actin mRNA SIT group [(219.47 +/- 64.72) pg/ml], the level of IFN-gamma in BALF from Der f 1 mRNA SIT group [(897.56 +/- 105.73) pg/ml] and Derfl SIT group [(864.48 +/- 70.62)pg/ml] significantly increased (P<0.01). However, the level of IL-13 in BALF from Derf 1 mRNA SIT group [(241.64 +/- 31.41) pg/ml] and Derf 1 SIT group [(321.94 +/- 41.07)pg/ml] was significantly lower than that of Der f 1 sensitization group [(520.62 +/- 43.77) pg/ml] and beta-actin mRNA SIT group [(507.22 +/- 42.26) pg/ml](P<0.01). The number of eosinophils in Der f 1 mRNA SIT group [(1.33 +/- 0.44) x 10(5)/ml] and Der f 1 SIT group [(1.48 +/- 0.39) x 10(5)/ml] was also lower than that of Der f 1 sensitization group [(3.54 +/- 0.52)x10(5)/ml] and beta-actin mRNA SIT group [(2.98-0.53) x 10(5)/ml] (P<0.01). The levels of IFN GAMMA and IL-13 in splenocyte culture supernatant showed that IFN-gamma level in Der f 1 mRNA SIT group [(420.91+69.92) pg/ml] and Der f 1 SIT group [(334.92 +/- 43.72) pg/ml] was significantly higher than that of Der f 1 sensitization group[(123.75 +/- 5.48) pg/ml] and beta-actin mRNA SIT group[(128.84 +/- 59.00) pg/ml] (P<0.01). However, IL-13 level of Der f 1 mRNA SIT group [(268.51 +/- 40.42) pg/ml] and Der f 1 SIT group [(285.26 +/- 62.21) pg/ml] was significantly lower than that of Derf 1 sensitization group [(613.89 +/- 51.54) pg/ml] and beta actin mRNA SIT group [(524.05 +/- 39.12) pg/ml] (P<0.01). Compared with Der f 1 sensitization group [total IgE: (94.34 +/- 11.66) ng/ml, sIgE: (65.67 +/- 9.47) ng/ml, sIgG1: (75.18 +/- 9.52) ng/ml, sIgG2a: (2.81 +/- 1.17) ng/ml] and beta actin mRNA SIT group[total IgE: (86.48 +/- 10.26) ng/ml, sIgE: (62.36 +/- 8.35) ng/ml, sIgG1: (69.51 +/- 8.98) ng/ml, IgG2a: (1.06 +/- 0.11) ng/ml], the serum antibody levels of total IgE [(33.72 +/- 9.78) ng/ml], sIgE [(22.76 +/- 8.09) ng/ml], sIgG1 [(17.87 +/- 7.59) ng/ml] of Der f 1 mRNA SIT group decreased significantly (P<0.01), whereas the level of IgG% [(7.74 +/- 0.88) ng/ml] increased (P<0.01). Compared with Der f 1 sensitization group, the asthmatic symptoms were relieved after immunization with Der f 1 mRNA for specific immunotherapy, including intact structure of respiratory and alveolar epithelial cells, decreased inflammatory cell infiltration, and similar to those in Der f 1 SIT group. However, the breakage and detachment of bronchial epithelial cells occurred in beta-actin mRNA SIT group. CONCLUSION: Derf 1 mRNA vaccine can correct Th1 and Th2 imbalance. PMID- 25518590 TI - [Construction of suppression subtractive hybridization cDNA library of half-blood males of Dermacentor silvarum and analysis of differentially expressed genes]. AB - OBJECTIVE: To construct a suppression subtractive hybridization (SSH) cDNA library of half-blood males of Dermacentor silvarum, and analyze the differentially expressed genes. METHODS: Total RNA was extracted from the half blood males and unfed males of D. silvarum. cDNA was synthesized following the protocol of SMARTER cDNA synthesis kit. After Rsa I digestion, cDNA was ligated to adaptors. The cDNA from the half-blood males was used as the tester, and unfed males as the driver. The SSH library was constructed using TaKaRa PCR-select cDNA subtraction kit. Differentially expressed cDNAs were amplified by nested PCR, cloned into PMD-18T vector, transformed into E. coli DH5alpha, and the white-blue plaque selection was used to get the positive clones. The titer of SSH library and the recombination efficiency were calculated. Individual colonies were randomly selected from library. Subtractive efficiency of the subtracted cDNA library was examined by reverse Northern blotting and RT-PCR. Positive clones with differentially expressed genes were sequenced. Homology comparison and function prediction were performed by Blastn and Blastx. RESULTS: The bands of double-stranded cDNAs from half-blood males and unfed males of D. silvarum were dispersed and longer than 500 bp. After Rsa I digestion, the ds cDNA-fragments were 100-1000 bp. The ligation reaction efficiency of adaptor was more than 25%. Nested PCR showed that the bands of subtracted ds cDNA were gathered, ranging from 250 to 500 bp. The titer of SSH library was 700,000 pfu/ml, and the recombination efficiency was 88.5% (239/270). Reverse Northern hybridization revealed that the clones showed stronger signals in half-blood males cDNA probes than in unfed males cDNA probes. RT-PCR showed that among the eight random selected positive clones, 5 clones were up-expressed under half-blood condition. A total of 87 differentially expressed sequence tags (ESTs, 200-800 bp) were obtained from 115 positive clones. Among the 87 ESTs, 53 ESTs showed sequence similarities to genes from other tick species, and 34 were homologous with genes from other insects. The main biological function of obtained ESTs were related to blood sucking and digestion, such as energy metabolism, signal transduction, and transcription regulation. CONCLUSION: The SSH cDNA library of half-blood male Dermacentor silvarum is constructed. The differential expressed genes are related to blood sucking and digestion. PMID- 25518591 TI - [Effect of immunotherapy with recombinant allergen group 3 from dermatophagoides farinae in asthma mice]. AB - OBJECTIVE: To explore the effect of specific immunotherapy with major 3 group recombinant allergen rDer f 3 of Dermatophagoides farinae in murine asthma model. METHODS: Forty BALB/c mice were randomly divided into 4 groups, namely PBS group (negative control), ovalbumin(0VA) group (positive control), rDerf3 allergen sensitization group (asthma group), and rDerf3 specific immunotherapy group(SIT group). The mice in asthma group and SIT group were injected intraperitoneally with purified rDer f 3 protein on days 0, 7 and 14, respectively, and rDer f 3 solution was inhalated from day 21 for 7 days. During the 25th-27th day, mice in SIT group were injected subcutaneously with 100 jg rDer f 3 allergen for 30 min before nasal inhalation. Mice in groups of PBS and OVA were treated with PBS and OVA, respectively. Twenty-four hours after the final challenge, all mice were sacrificed, the bronchoalveolar lavage fluid (BALF) was collected and the total number of white blood cells and the number of eosinophils were recorded. The levels of IL-5 and IFN-gamma in BALF and supernatant of cultured splenocytes were detected by ELISA, as well as the serum levels of specific IgE and IgG2, antibodies. Lung tissues were stained with haematoxylin and eosin for histological analysis. RESULTS: Compared with the asthma group, the rDer f 3 induced lung inflammation was significantly alleviated in SIT group. The total number of white blood cells [(7.03 +/- 1.38) x 10(8)/ml] in SIT group was considerably lower than that of OVA group [(22.11 +/- 3.70) x 10(8)/ml] and asthma group [(22.75 +/- 3.24) x 10(8)/ml] (P<0.01). The change trend of eosinophil leukocytes was similar with that of white blood cells. IL-5 levels in BALF [(108.20 +/- 11.02) pg/ml] and splenocyte culture supernatant [(98.34 +/- 13.06) pg/ml] in SIT group were significantly lower than that of OVA group [(182.04 +/- 13.94) pg/ml, (208.26 +/- 10.63) pg/ml] and asthma group [(195.33 +/ 15.33) pg/mL, (179.54 +/- 13.65) pg/ml] (P<0.01). Whereas, the level of IFN gamma in BALF [(107.98 +/- 12.64) pg/ml] and supernatant of cultured splenocytes [(105.51 +/- 1.62) pg/ml] in SIT group was significantly higher than those of OVA group and asthma group (P<0.01). Compared with OVA group [(26.87 +/- 4.30) IU/ml] and asthma group [(35.25 +/- 8.84) IU/ml], a lower level of allergen-specific IgE [(9.12 +/- 3.78) IU/ml] and higher level of allergen-specific IgG2, [(38.52 +/- 6.33) microg/ml] were observed in SIT group (P<0.01). CONCLUSION: rDer f 3 allergen can reverse allergen-induced airway and lung inflammation in murine asthma model. PMID- 25518592 TI - [Experimental infection of Galba pervia, Radix swinhoei and Physa acuta with Fasciola hepatica in Dali, Yunnan]. AB - OBJECTIVE: To determine the intermediate host of Fasciola hepatica in Dali of Yunnan Province, and investigate its development and characteristics. METHODS: F. hepatica eggs from cattle were collected from July 2012 to July 2013, and placed in 28 degrees C water bath for incubation. Galba pervia, Radix swinhoei, and Physa acuta were collected from Dali, and used to be infected with F. hepatica in the laboratory. Trematode infections were excluded from the snails before experiment. All the snails were infected with F. hepatica miracidia, reared in mud pots. Dead snails were dissected for observing the development of F. hepatica. The metacercariae were collected and identified by PCR amplification of partial sequence of mitochondrial cytochrome oxidase subunit I (COX1) gene. RESULTS: A total of 1 146 R. swinhoei, 996 P. acuta, and 3 307 G. pervia snails were infected with F. hepatica, respectively. Mother rediae were found in two R. swinhoei snails, but no child rediae were observed in the snails. No larval forms were found in P. acuta. G. pervia was infected by F. hepatica with an infection rate of 27.2% (900/3307). The miracidium escaped from the egg and penetrated into G. pervia at temperature 22 degrees C, developed into a sporocyst after 7-15 days, which transformed into mother redia at the 11 st-20th day post-infection. The mother redia developed into daughter redia at the 30th-37th day, and produced cercaria with longtail, and became metacercaria at the 42nd-55th day. PCR confirmed that the metacercariae were that of F. hepatica, with an obvious band (approximately 500 bp). CONCLUSION: Among the three potential intermediate hosts in Dali, G. pervia is experimentally infected with F. hepatica. PMID- 25518593 TI - [Immunoreactivity and immunogenicity analysis of the recombinant cathepsin L-like protease of Fasciola hepatica in SD rats]. AB - OBJECTIVE: To analyze the immunoreactivity of recombinant cathepsin L-like proteases (CatL) protein of Fasciola hepatica and its immunogenicity in SD rats. METHODS: The E. coli BL21(DE3) cells harbouring recombinant plasmid pET30a-FhCatL were inoculated in LB medium, and the protein expression was induced with IPTG. The recombinant protein FhCatL was analyzed by SDS-PAGE and the immunoreactivity was identified by Western blotting with sera from Fasciola hepatica-infected goat as the primary antibody. Twenty SD rats were randomly divided into immunized group and adjuvant control group. SD rats in immunized group were injected subcutaneously with 200 microg of purified FhCatL protein. All the rats received three immunizations at 3-week intervals. The adjuvant control group with 10 SD rats received only adjuvants emulsified with the same amount of PBS. Serum samples were collected at the day before the second and final immunization, 3, 6, and 9 weeks after the final immunization. The IgG antibody of rats' sera was examined by indirect ELISA and spleen lymphocyte proliferation (SLP) was tested by methyl thiazolyl tetrazolium (MTT). RESULTS: The molecular weight of purified FhCatL was about Mr 42,000. The recombinant FhCatL was recognized by pool sera of goats naturally infected with F. hepatica. The titer of specific antibody IgG in SD rats induced by the recombinant protein against CatL protein was significantly higher than that of the control, and the antibody titer reached the peak at three weeks after the final immunization (1 : 102,400). The stimulation index of splenocytes in immunized group was 2.176 +/- 0.047, which was significantly higher than that of the control (1.171 +/- 0.032) (P<0.05). CONCLUSION: The recombinant FhCatL protein bears stronger immnoreactivity and immunogenicity. PMID- 25518594 TI - [Prevalence of metacercariae of Clonorchis sinensis in wild freshwater fishes from Nenjiang River around Qiqihaer City]. AB - From May to November 2013, a total of 1175 wild freshwater fishes were collected from the rivers of Chuoer, Yalu, Wuyuer, Alun, and Yin in Nenjiang River basin Qiqihaer City, and examined for metacercariae by direct compression method. The metacercariae were collected by artificial digestion method. Forty Kunming mice were infected with 30-40 metacercariae of Clonorchis sinensis. The mice were sacrificed 36 days after infection, and the adult worms were collected from bile duct, and observed under microscope. The results showed that a total of 1 175 fishes, belonging to nine species were taken from the Nenjiang basin of Qiqihaer region. The infection rate of Clonorchis sinensis metacercariae was 51.2% (602/1 175). All the species were infected besides Silurus asotus, and the highest prevalence (82.7%, 91/149) was found in Longnose gudgeon and the lowest (7.1%, 6/84) in Perccottus glenii. Among the rivers, the highest prevalence of metacercariae was in Wuyuer River. (65.7%, 218/332), and the lowest was in Alun River and Yin River (24.1%, 67/278) (P<0.05). Each part of the body in the Carassius auratus and Pseudorasbora parva were susceptible for metacercariae. The main infection site in Longnose gudgeon was the fish scales, and C. sinensis metacercaria was first discovered in the brain tissue of Phoxinus lagowskii. The experimental results showed that the adult worms of C. sinensis were found in the hepatic bile duct of the mice, with an infection rate of 85.0% (34/40). The suckers, digestive system and reproductive system of C. sinensis were visible clearly. PMID- 25518595 TI - [Morphological characteristics and gene expression of Chrysomya megacephala eggs in different developmental stages]. AB - OBJECTIVE: To research the morphological characteristics and differential gene expression of Chrysomya megacephala eggs in different developmental stages. METHODS: After C. megacephala laid eggs (0 h), the eggs were collected every 2 h until eggs hatched into larvae. The morphological characteristics of C. megacephala eggs in different developmental stages were observed by stereo microscopy and scanning electron microscopy. The total RNA of the fly eggs was extracted. The expression levels of bicoid, slalom and chitin synthase genes was determined by real-time flourescence quantitative PCR. Statistic analyses were performed with SPSS 19.0. RESULTS: Under the stereomicroscope, at 0-4 h after egg laying, the morphological change of C. megacephala eggs was not obvious. At the 6th hour after egg laying, somites were formed. After 8 hours the eggs shriveled. At the 9th hour after egg laying, the eggs hatched into larvae. The scanning electron microscope images showed that the morphological change of eggs was not obvious in the first 4 hours, the end of micropyle slightly outward, the surface around the micropyle was smooth. At the 6th hour after egg laying, the end of micropyle began to sag and irregular protrusions formed around the micropyle. At the 8th hour the end of micropyle was obviously dented. After 9 hours larvae hatched from eggs. Real-time fluorescence quantitative PCR indicated that the expression levels of bicoid, slalom and chitin synthase genes from C. megacephala eggs regularly changed with the developmental stages. There was a significant difference in threshold cycle values among the three genes (P<0.05). CONCLUSION: The morphological characteristics of C. megacephala eggs change with the development stage. The levels of gene expression in different development period of C. megacephala eggs are different. PMID- 25518596 TI - [Effect of the excretory/scretory proteins from Trichinella spiralis on apoptosis of NCI-H446 small-cell lung cancer cells]. AB - OBJECTIVE: To investigate the effect of excretory/secretory proteins from Trichinella spiralis on apoptosis of NCI-H446 small-cell lung cancer cells. METHODS: Trichinella spiralis muscle stage larvae (5 x 10(6)/ml) were cultured in culture media for 24 h, the excretory/secretory proteins were collected from the supernatant of culture media. NCI-H446 small-cell lung cancer cells (No. A05) were randomly divided into three groups: experiment group (A), standard control group (apoptosis group, B), and control group (C). NCI-H446 cells in groups A and B were cultured with 0.3 mg/ml T. spiralis excretory/secretory proteins, and 6.4 microg/ml cisplatin for 24 h, respectively. NCI-H446 cells of group C were cultured for 24 h without any treatment. The expression of Bcl-2, Fas and Fasl mRNA was detected by RT-PCR. C-myc protein expression level was examined by Western blotting and immunofluorescence assay. RESULTS: The level of Bcl-2 mRNA was lowest in group A(0.575 +/- 0.047) , Bcl-2 mRNA level in group C (0.975 +/- 0.069) was higher than that of group B (0.850 +/- 0.073) (P<0.05). Fas mRNA level was highest in group A (0.975 +/- 0.115), followed by group B (0.817 +/- 0.121) and group C(0.769 +/- 0.061) (P<0.05). The level of Fasl mRNA in groups A, B, and C was 0.669 +/- 0.051, 0.787 +/- 0.124, and 0.875 +/- 0.125, respectively (P<0.05). Fas/Fasl mRNA ratio in groups A, B, and C was 1.475, 1.038, and 0.878. Western blotting showed that the expression of C-myc protein in group C (1.172 +/ 0.026) was highest, followed by group B (1.074 +/- 0.069) and A (0.566 +/- 0.054) (P<0.05). Immunofluorescence test indicated that the C-mye protein was found in the cytoplasm and the nucleus 24 h after treated with 0.3 mg/ml T. spiralis excretory/secretory proteins and 6.4 p.g/ml cisplatin. CONCLUSION: Trichinella spiralis excretory/secretory proteins may inhibit apoptosis of NCI H446 small-cell lung cancer cells by reducing the apoptosis protein C-myc and Bcl 2 mRNA levels, and causing the increase of Fas/Fasl mRNA ratio. PMID- 25518597 TI - [Functional change of dendritic cells/regulatory T cells/T-helper 17 cells and the mechanism of its cross-regulation in malaria]. AB - The cross-regulation of dendritic cells (DC)/regulatory T cells (Treg)/T-helper cells (Th17) is a complex process that involves multiple signals. During Plasmodium infection, the interaction of DC, Treg, and Th17 influence the cross modification, and induce activation of DC/Treg/Th17 to regulate Th1/Th2 polarization and control the dynamic balance of Th immune response by cytokines. This article summarizes the change in cell function of DC/Treg/Th17 and the mechanism of its cross-regulation in malaria. PMID- 25518598 TI - [Advances on antitumor effect of parasites]. AB - Immune response induced by parasites could inhibit tumor growth and promote apoptosis of tumor cells. The investigation into this character will provide new insights on the anti-tumor effect of parasites. The mechanism of parasite immune evasion may provide a reference for tumor research. Furthermore, some anti parasitic drugs have shown antitumor effect indicating that the development of antitumor drugs may get inspiration from anti-parasitic drug studies. PMID- 25518599 TI - [Role of macrophages in schistosome infection]. AB - Each stage of schistosome in human body can cause disease. Pathogenic factors released by the parasites induce host immune responses and cause a series of immunopathological changes. As a major cell population in in- nate immunity, macrophages are important in the initiation and development of schistosomiasis. This paper summarizes the activation and polarization of macrophages, and the role of macrophages in schistosome immunopathology and immune evasion. PMID- 25518600 TI - [Diagnosis of an imported falciparum malaria case by fluorescence quantitative PCR]. AB - The whole blood sample from a patient with imported falciparum malaria was tested by microscopic examination and fluorescence quantitative PCR. Microscopic examination results showed that Plasmodium falciparum parasites were found in the thick and thin blood films with a low parasite density of 240 parasite/microl of blood. The specific DNA fragment of P. falciparum was amplified by fluorescence quantitative PCR, and this case was further confirmed as P. falciparum infection. PMID- 25518601 TI - [An analysis on Pf60.1 gene polymorphism of Plasmodium falciparum from imported cases]. AB - One hundred and one imported falciparum malaria cases in Wuhan City were confirmed by microscopy and Nest-PCR, and the blood samples were collected. The Pf60.1 gene was amplified by PCR. Among 101 blood samples, three Pf60.1 fragments [313 bp (56.5%, 52/92), 340 bp (37.0%, 34/92), 313 bp+340 bp (6.5%, 6/92)] were amplified from 92 samples. Among 83 blood samples from patients returning from Africa, 313 bp fragment were found in 46 samples (55.4%, 46/83), 340 bp fragment were found in 31 samples (37.1%, 31/83), and 7.2% (6/83) was mixed-fragment (313 bp+340 bp). Among 9 samples from southeast Asia, 6 samples were with 313 bp fragment and 3 samples with 340 bp fragment. The results indicated that the most common genotype was 313 bp-genotype, and there would be polyclonal P. falciparum infections. PMID- 25518602 TI - [Epidemiological analysis of imported malaria in Xiaogan City from 2008 to 2013]. AB - The epidemiological features of 27 imported malaria cases during 2008-2013 in Xiaogan were analyzed. Among the cases, 21(77.8%) were falciparum malaria,and 6(22.2%) were vivax malaria. Twenty-five (97.3%) cases were among 19-47 year-old males. The reported cases increased from 2010 to 2013, and there was no significant difference among seasons. The cases were reported from all the seven counties. Eleven cases (40.7%) were reported by Xiaonan District. Twenty-three cases were infected in Africa. PMID- 25518603 TI - [Preparation and identification of polyclonal antibody against small peptides of beta-tubulin of Toxoplasma gondii]. AB - The amino acid sequences of beta-tubulin from Toxoplasma gondii stains (GT1 and ME49) and human were aligned by ClustalW2 software. Based on the alignment result, the C-terminal peptides of beta-tubulin of T. gondii were artificially synthesized. Rabbits were immunized with 0.5 mg synthesized peptides for five times at 2-week intervals. Serum samples were collected at the second week after the final immunization, and were analyzed for specific antibodies by ELISA. Finally, the specific-beta-tubulin polyclonal antibody was evaluated by Western blotting with the total protein of RH strain, ME49 strain, and PRU strain of T. gondii, respectively. The results showed that beta-tubulin of T. gondii stains (GT1 and ME49) shared 100% amino-acid sequence identity, and there was 98% amino acid homology between T. gondii and human. The main variable region was the C terminus. After the fifth immunization, the titers of polyclonal antibody reached 1 : 52,800. Western blotting result indicated that the specific-beta-tubulin polyclonal antibody reacted with beta-tubulin in all the three strains (RH, ME49, and PRU), respectively. PMID- 25518604 TI - [Dynamic changes of serum antibody titer in a rabbit model of Acanthamoeba keratitis]. AB - Ten healthy New Zealand white rabbits were randomly divided into two groups named as experiment group (n=8) and normal control group (n=2). Left eyes were for experiment, right eyes served as control. New Zealand rabbits were each injected by subconjunctival route with hydrocortisone for three days, and then Acanthamoeba keratitis was induced by intrastromal injection of live Acanthamoeba healyi trophozoites and cysts. Eyes in control group were injected with equivalent volume of physiological saline. Corneal lesions of rabbits were recorded every day after injection, etiological diagnosis was carried out by corneal scraping. Blood samples were examined for serum antibody titer by ELISA. Corneas were removed for pathological examination. Corneal scraping and corneal histopathologic examination proved that experiment eyes were infected by Acanthamoeba, and appeared typical manifestations and pathological changes of Acanthamoeba keratitis. Serum antibody titer raised continuously with infection time and reached the highest level (A450 value=2.2358) on the 28th days post infection, then began to decline and remained higher level than the control until the rabbits were sacrificed. In control group, no significant change in antibody titer had taken place. PMID- 25518605 TI - [A case of imported visceral leishmaniasis in Tengchong County of Yunnan]. PMID- 25518607 TI - Bring on the robocrats. We need a federal agency to smooth the integration of robotics into society. PMID- 25518606 TI - Caution: cops with cameras. PMID- 25518608 TI - Cities to the rescue. PMID- 25518609 TI - Bend by design. New progress in flexible displays. PMID- 25518610 TI - Deep space or bust. NASA will soon launch its new capsule on a maiden flight. PMID- 25518611 TI - Sustainability. What would John Muir do now? PMID- 25518612 TI - Plantibody: (n.) A human antibody produced by plants. PMID- 25518613 TI - Mushroom man. Collecting fungi is more than a hobby for Rodham Tulloss. PMID- 25518614 TI - Power to the Internet of things. Four novel energy-gathering methods will keep gadgets abuzz. PMID- 25518615 TI - Call of the crybaby. Distress calls of infant mammals are strikingly similar. PMID- 25518616 TI - Of germs and germination. Teens take top science prize for a plan to ease world hunger. PMID- 25518617 TI - Never Too old for chemo. As the number of elderly patients with cancer soars, researchers explore how best to treat them. PMID- 25518618 TI - Unpredictive text. How Apple killed typing but still won the phone wars. PMID- 25518619 TI - World changing ideas. 10 problem-solving, planet-improving, lifesaving advances set to drive progress in the years ahead. PMID- 25518620 TI - The gene genie. PMID- 25518621 TI - Reprogrammable cells. PMID- 25518622 TI - Vision-correcting displays. PMID- 25518623 TI - Atomic-scale Legos. PMID- 25518624 TI - Ultrahard recyclable plastics. PMID- 25518625 TI - Wireless charging with sound waves. PMID- 25518626 TI - Batteries that capture low-grade waste heat. PMID- 25518627 TI - Video cameras for nanoparticles. PMID- 25518628 TI - Fossil hunting in the Milky Way. PMID- 25518629 TI - Pain that won't quit. PMID- 25518631 TI - The jet stream is getting weird. PMID- 25518632 TI - The storm God's tale. PMID- 25518630 TI - Taking the sting out of pain. PMID- 25518634 TI - The spider's charade. PMID- 25518633 TI - Immunity's illusion. PMID- 25518635 TI - Conspiracy central. Who believes in conspiracy theories--and why. PMID- 25518636 TI - Up, up and away. World population will hit nearly 11 billion by 2100. PMID- 25518637 TI - [Comparative analysis methods of haze distinction over Yangtze River Delta Region ]. AB - It is crucial to compare the difference and applicability of different haze discrimination methods and its criteria in haze study. Due to the requirement of methods and limitation of data, 4 common methods in two views of regional and temporal in one site are analyzed and studied. Based on the meteorological data from 38 observatories from 1980-2009, haze-day and haze-hour number are both counted for each station, employing Method 1 and 2 (with daily mean observation) and Method 3 (with 14:00 observation). The characteristics and applicability of these three methods are also compared and summarized. Statistical results via these methods are all capable to represent the long-term trend of haze, but haze day numbers counted via these methods show differences, which become less remarkable with decadal changes. Haze days are the most by using Method 1. Method 3 considering the weather phenomenon is more reasonable than Method 1 and 2. According to the data of visibility, relative humidity and PM2.5 concentration in northern Nanjing from May, 2012 to April, 2013, employing 4 haze discrimination methods including the additional one (QX/T 113-2010, i. e. Method 4) , haze-day and haze-hour numbers are counted and compared. The result shows that: the haze day number obtained employing Method 3 is less than others, while the haze-day number obtained employing Method 4 is between those with Method 1 and 3; using all Methods but Method 3 can distinguish the severity of haze significantly. PMID- 25518638 TI - [Trends of urban haze in Jiangsu Province China over the past 33 years]. AB - Based on the surface meteorological data of Jiangsu Province during 1980-2012, climatic characteristics and trends of the weather phenomenon of haze were analyzed. The result indicates that during 1980-2012, the haze day increased, and the severe and moderate haze days significantly increased. In the northern and coastal cities, haze days had a significant increase. Haze is often appeared in the fall and winter, and is rare in the summer, it also occurs inland, and is less in the coast. The haze happens more frequently in June since the straw burning during.summer harvest time. The haze day was evenly distributed during the 80's, and increased during the 90's over southern and southwestern Jiangsu Province, middle and northern Jiangsu haze days had a growing after 2000, especially after 2010. The continuous, regional, and regional-continuous haze days were in an increasing trend. As the urban built-up area has been expanded each year, industrial emissions, coal consumption, and car ownership increase every year, resulting in regional temperature increase and relative humidity decrease, resulting in urban heat island and dry island effects. Thence the haze formation and maintenance conditions increased, which led to the increasing of haze days, and the continuous, regional and regional- continuous haze days were significantly increased. PMID- 25518639 TI - [Temporal variation of background atmospheric CO2 and CH4 at Mount Waliguan, China]. AB - In this paper, the continuous (2009-2010) measurement of atmospheric CO2 and CH4 from the Mount Waliguan Baseline Observatory of Western China are presented. The results show that about 17% of CO2 observations are classified as polluted due to more frequently influence of regional emission on local measurement in summer time. The mean concentration of CO2 measured at the period of 2009 to 2010 was 390.72 x 10(-6) which was 17.4 x 10(-6) higher than that measured from 1995 to 2008, and the median concentration of CH4 was 1851.11 x 10(-9) which was 16 x 10( 9) higher than that from 2002 to 2006, which implied that the regional emission of CO2 and CH4 was continuously increased. The unavailable data were filled by back propagation neural network (BPNN) and optimized by genetic algorithm (GA) , which were analyzed by the Fourier analysis of time series of air temperature, wind speed, concentration of CO2 and CH4. At the daily time scale, strong spectrum peak occurred and concentration recorded at periods of 12 and 24 hours,due to the daily sun activity changes. At the monthly time scale, the spectrum gap occurred in CO2 concentration at periods of 30 day suggesting that the effect of meteorological and phenological factors on the variation of CO2 concentration was insignificant. PMID- 25518640 TI - [Characteristics and sources of organic carbon and elemental carbon in PM2.5 in Shanghai urban area]. AB - Organic carbon (OC) and elemental carbon (EC) in PM2.5 samples collected in Shanghai urban area during June 2010 to May 2011 were analyzed with IMPROVE-TOR protocol. The results showed that the annual average concentrations of OC and EC in PM2.5 were 8.6 MUg.m-3 +/- 6.2 MUg.m-3 and 2.4 MUg.m-3 +/- 1.3 MUg.m-3 respectively, accounting for 20% of PM2.5 mass concentration. The seasonal average concentrations of OC and EC were highest in winter and lowest in summer. And the percentages of OC and EC in PM2.5 were highest in autumn. The annual average OC/EC ratio was 3. 54 +/- 1. 14. The concentrations of secondary organic carbon (SOC) were evaluated by the minimum OC/EC ratio method and the annual average concentration of SOC was 3.9 MUg.m(-3) +/-4.2 MUg.m(-3), accounting for 38.9% of OC. In summer, the concentrations of SOC were relatively low and were correlated well with the maximum hourly concentrations of ozone, which indicated that the photochemical reaction was an important way of SOC formation. In autumn and winter when the west wind direction was predominant, the concentrations of SOC were higher than that in windless condition, which meant the transportation of SOC. The carbonaceous components were associated with source contributions using the principal component analysis (PCA) with eight thermally-derived carbon fractions, OC1, OC2, OC3, OC4, EC1, EC2, EC3 and OPC. Motor vehicle, coal-fired units, biomass burning and road dust were four main sources of OC and EC in PM2.5 in Shanghai urban area, which contributing 69. 8% - 81. 4% of carbonaceous aerosols. The contribution of motor vehicle was high throughout the year. Biomass burning contributed about 15% -20% of OC and EC. The influence of road dust was relatively obvious in spring and autumn. And the contribution of coal-fired units was higher in winter than those in other seasons. PMID- 25518641 TI - [Size distribution and characterization of OC and EC in atmospheric aerosols during the Asian Youth Games of Nanjing, China]. AB - Aerosol samples were collected by an Andersen cascade impactor (Andersen) in Nanjing during the Asian Youth Games (AYG), and organic carbon (OC) and elemental carbon (EC) in particles were determined by DRI Model 2001A carbon analyzer of USA. Observations indicated that OC (51.55%) and EC (54. 81%) were enriched in the fine aerosol particles with size below 1. 1 MUm, the highest mass concentrations of OC and EC were located at 0-0.43 MUm and 0.43-0.65 MUm, respectively, accounting for 20. 90% +/-5.02% and 22. 68% +/-9.90% of the total concentration. The mass concentrations of OC and EC in PM1.1, PM1.1-2.1 and PM(2.1-10) during AYG period were decreased by 43. 44% -56. 17% and 59. 17% 73.55% as compared to the values before AYG. The spectral distribution of OC was bimodal during the whole observation period, while the spectrum distribution of EC was changed from bimodal to unimodal. OC and EC during the observation period were in good homology. OC and EC were attributed to automobile exhaust fumes before AYG. During AYG, OC and EC in PM1.1 were mostly from automobile exhaust fumes, while OC and EC in PM1.1-2.1 and PM2.1-10 were from automobile exhaust fumes and coal combustion. PMID- 25518642 TI - [Pollution characteristics of carbonaceous aerosols in PM2.5 during typical winter days in Wuxi City ]. AB - The purpose of this study was to investigate the process of haze in winter and the variation of carbonaceous aerosols in haze days. Continuous measurements of PM2.5 and meteorological parameters were conducted from Dec 3rd ,2013 to Jan 3rd, 2014, in Wuxi City. The carbonaceous component was quantified with the thermal/optical transmission (TOT) method. The results showed that: Three times of haze progresses occurred during the sampling period. Cold air, wind and rainfall were the most efficient ways to improve air quality. The mass concentration of PM2.5, OC and EC were (132.38 +/- 87.17) MUg.m-3, (22.80+/-9.77) MUg.m-3 and (2.08 +/- 1. 63) MUg.m-3, respectively. The TC accounted for 23.57% of the PM2.5; at the same time, the TC and PM2.5 were found to be strongly correlated (correlation coefficients = 0. 730). There was a negative correlation between the ratio of carbonaceous aerosol in PM2.5 and the concentration of PM2.5, and the ratio in haze days was lower than that in normal days, which suggested that secondary inorganic particles (SO(2-)(4) , NO(-)(3), NH: ) may have a fast growth in haze days. Average OC/EC ratio was 12. 83, and there was a poor correlation between OC and EC, indicating that secondary pollutants might exist. The secondary organic carbon (SOC) was estimated to be 9.04 MUg.m -3, accounting for 40. 96% of OC. PMID- 25518643 TI - [Emission characteristics of PM2.5 from blast furnace iron making]. AB - Electrical low pressure impactor (ELPI) was used to online analyze the PM2.5 particle size and mass concentration distribution in the trapping field and ore tank of blast furnace iron-making plant. Results showed that the grain number concentration of PM2.5 in trapping field after dust removal was in the range of 10(5)-10(6)cm-3 , and the particle size was mainly below 0. 1 MUm. While the grain number concentration of the PM2.5 in ore tank after dust removal was in the range of 10(4)-10(5) cm-3, the particle size was mainly below 1.0 MUm, and the mass concentration distribution showed a single peak. The micro-morphology of PM2.5 monomer was mainly divided into two categories, spherical particles and irregular aggregates. Chemical composition analysis indicated that the concentrations of water soluble SO(2-)(4) , K+ , Ca2+ were higher than other ions in PM2.5, with the percentage of 10. 32% -28.55% , 10. 36% -12. 15% , 3.97% -15. 4% , respectively. The major elements was Fe, Si, Al, with 16. 8% -31. 62% , 2. 24% -8.76% , 1.24% -5. 89% of total mass, respectively; organic carbon and elementary carbon were 2. 7% -4. 6% and 0. 8% -1. 3% , respectively. The emission factors of PM2.5 in trapping field and in ore tank after dust removal were ranged from 0.045 to 0.085 kg t(-1) and 0.042 to 0.071 kg t-1, respectively. PMID- 25518644 TI - [Composition characteristics of atmospheric volatile organic compounds in the urban area of Beibei District, Chongqing]. AB - In order to study the composition and distribution of VOCs (Volatile Organic Compounds) in the atmosphere in the urban area of Beibei district, Chongqing, atmospheric samples were collected from March 2012 to February 2013 with special stainless steel cylinders, and analyzed with a three-stage preconcentration method coupled with GC-MS. 78 species of VOCs were detected in this study, of which there were 25 species of alkanes, 15 species of olefins, 28 species of aromatic hydrocarbons and 10 species of halogenated hydrocarbons. The results showed that the top seven species of VOCs according to the order of annual average concentration in the atmosphere of Beibei were: Dichloromethane (3. 08 x 10(-9) ) , Benzene (2. 09 x 10-9) , Isopentane (1. 85 x 10 -9) , Toluene (1. 51 x 10(-9)) , Propane (1. 51 x 10(-9)), m/p-xylene (1.43 x 10(-9)) and Styrene (1. 39 x 10-9). The concentration of TVOCs (Total Volatile Organic Compounds) in the atmosphere of Beibei was 33. 89 x 10 -9 during the measuring period, and the seasonal variation was obvious with the order of spring (42. 57 x 10 -9) > autumn (33.89 x 10-9) > winter (31.91 x 10 -9) > summer (27.04 x 10(-9)). In the composition of TVOCs, alkanes and aromatic hydrocarbons provided the largest contribution to TVOCs (31.5% and 30.7% ) , followed by halogenated hydrocarbon, accounting for 27.4% , and the last one was olefins, with only 10.4%. By means of ozone formation potential, the analysis results showed that olefins and aromatic hydrocarbon compounds were the two important materials which made the biggest contribution to the formation of ozone in the atmosphere of Beibei. We further analyzed the sources of VOCs in atmosphere of Beibei by the method of Principal Component Analysis (PCA). Vehicle exhaust was the biggest source and its contribution to VOCs was 50. 41%. The calculated results with T/B value also confirmed that traffic was the biggest source contributing to the VOCs in atmosphere of Beibei. PMID- 25518645 TI - [Catalytic oxidation of two-component VOCs and kinetic analysis ]. AB - Catalytic oxidations of two-component volatile organic compounds (VOCs) toluene and chlorobenzene were investigated under microwave heating and tube furnace heating, respectively, and reaction kinetics were analyzed in this paper. The research indicated that competitive adsorption between toluene and chlorobenzene reduced their removal efficiencies by 3% -12% as compared to single component. 'Hot spot effect' and 'non-thermal effect' under microwave irradiation obviously enhanced conversion efficiencies of VOCs, especially, the chlorobenzene removal was increased by 31% -38%. Moreover, reaction temperature and energy consumption were both reduced under microwave heating. The dynamic calculations showed that microwave heating decreased the activation energies by 2 146 J. mol-1 and 1 450 J mol-1 for toluene and chlorobenzene, respectively, as compared with tube furnace heating. Meanwhile, microwave heating enhanced the reaction rate constants of chlorobenzene and toluene to about 35 times and 6 times of that of tube furnace heating. PMID- 25518646 TI - [Ultrafine particle number concentration and size distribution of vehicle exhaust ultrafine particles]. AB - Ultrafine particle (UFP) number concentrations obtained from three different vehicles were measured using fast mobility particle sizer (FMPS) and automobile exhaust gas analyzer. UFP number concentration and size distribution were studied at different idle driving speeds. The results showed that at a low idle speed of 800 rmin-1 , the emission particle number concentration was the lowest and showed a increasing trend with the increase of idle speed. The majority of exhaust particles were in Nuclear mode and Aitken mode. The peak sizes were dominated by 10 nm and 50 nm. Particle number concentration showed a significantly sharp increase during the vehicle acceleration process, and was then kept stable when the speed was stable. In the range of 0. 4 m axial distance from the end of the exhaust pipe, the particle number concentration decayed rapidly after dilution, but it was not obvious in the range of 0. 4-1 m. The number concentration was larger than the background concentration. Concentration of exhaust emissions such as CO, HC and NO showed a reducing trend with the increase of idle speed,which was in contrast to the emission trend of particle number concentration. PMID- 25518647 TI - [Major ion chemistry of surface water in the upper reach of Shule River Basin and the possible controls ]. AB - To analyze the major ion chemistry of water in the upper reach of the Shule River Basin and possible controls, samples of river water, groundwater, precipitation, melt water were collected and methods including descriptive statistics, Gibbs Figure, Piper Triangular diagrams of anions and cations were comprehensive used. Results showed that the major ion compositions and hydrochemical types were significantly different in different waters such as stream water, groundwater and precipitation. The total dissolved solid (TDS) in the river water ranges between 51.7 to 432. 3 mgL-1 with an average of 177.7 mgL-1. The major cations of river water are Ca2+ and Mg2+, accounting for 45% and 31% of the cations respectively. Meanwhile, HCO(3)- constituted about 75% of the anions. The hydrochemical type of river water is HCO(-)(3)-Ca2+-Mg2+. Owing to the interaction between the river and layer, the concentration of SO(2-)4 is relatively higher. Comparing major ion concentrations of the river water with local groundwater and precipitation, concentrations of the river water ranged between precipitation and groundwater but were much closer to the concentration of groundwater, indicating that the surface water was recharged by a mixture of precipitation and groundwater while groundwater is dominant. The chemical composition of surface water samples located in the middle and a bit upper of Gibbs model, which indicates that the major chemical process of river water is controlled by rock weathering and evaporation-crystallization but rock weathering plays a much more important role. PMID- 25518648 TI - [Sediment-water flux and processes of nutrients and gaseous nitrogen release in a China River Reservoir]. AB - The key processes and fluxes of nutrients (N and P) and gaseous N (N2 and N2O) across the sediment-water interface in a river reservoir (Xipi) of the Jiulong River watershed in southeast China were studied. Intact core sediment incubation of nutrients exchange, in-situ observation and lab incubation of excess dissolved N2 and N2O (products of nitrification, denitrification and Anammox), and determination of physiochemical and microbe parameters were carried out in 2013 for three representative sites along the lacustrine zone of the reservoir. Results showed that ammonium and phosphate were generally released from sediment to overlying water [with averaged fluxes of N (479.8 +/- 675.4) mg. (m2. d)-1 and P (4. 56 +/- 0.54) mg. (m2 d) -1] , while nitrate and nitrite diffused into the sediment. Flood events in the wet season could introduce a large amount of particulate organic matter that would be trapped by the dam reservoir, resulting in the high release fluxes of ammonium and phosphate observed in the following low-flow season. No clear spatial variation of sediment nutrient release was found in the lacustrine zone of the reservoir. Gaseous N release was dominated by excess dissolved N2 (98% of total), and the N2 flux from sediment was (15.8 +/- 12. 5) mg (m2. d) -1. There was a longitudinal and vertical variation of excess dissolved N2, reflecting the combined results of denitrification and Anammox occurring in anoxic sediment and fluvial transport. Nitrification mainly occurred in the lower lacustrine zone, and the enrichment of N2O was likely regulated by the ratio of ammonium to DIN in water. PMID- 25518649 TI - [Spatial distribution and pollution assessment of heavy metals in the tidal reach and its adjacent sea estuary of Daliaohe area, China ]. AB - The aim of this article was to explore the pollution level of heavy metals in the tidal reach and its adjacent sea estuary of Daliaohe area. The contents and spatial distribution of As, Cd, Cr, Cu, Ph and Zn in surface water, suspended solids and surface sediments were analyzed respectively. The integrated pollution index and geoaccumulation index were used to evaluate the contamination degree of heavy metals in surface water and surface sediments respectively. The results indicated that the contents of heavy metals in surface water was in the order of Pb < Cu < Cd < Cr < As < Zn. The heavy metal contents in surface water increased from river to sea. Compared with the contents of heavy metals in surface water of the typical domestic estuary in China, the overall contents of heavy metals in surface water were at a higher level. The contents of heavy metals in suspended solids was in the order of Cd < Cu < As < Cr Co > Ni > Cu > Zn > Pb > Cs > As > Cr. (3) The SQG index of sediments is 0. 804, indicating that studied river sediment has a moderate potential biological toxicity effect. Given most of heavy metals exists in residual fraction, the sediments of this region pose a low ecological risk to the environment. PMID- 25518651 TI - [Analysis of particle size characteristics of road sediments in Beijing Olympic Park]. AB - Particle size analysis of road sediment collected in October and November in Beijing Olympic Park indicates that most of the sediments are 76-830 MUm; the grain size of the sediments in the area of large population flow is mainly coarse but the grain size in the area of large traffic volume is fine relatively while most of the sediments are <300 p.m. Moreover, sediments of size range <300 MUm can be easily accumulated on the road with moderate traffic density. The results demonstrate that the effect of pedestrian flow on the composition of the particles is unobvious and the main influences are the traffic density, extensive construction. With the length of dry period increasing, the content of sediments of size range >300 MUm decreases and the content of sediments of size range < 150 MUm increases, however, the change of the content of sediments of size range 150 300 MUm is not obvious. The results indicate that the effectiveness of the road sediment removal depends on the length of dry period, and the accumulation of different size particles varies differently under the different dry days. Compared with the stone road, surface particles can accumulate on the asphalt road more easily as the accumulation of particles is affected by the road material significantly. Therefore, to reduce the urban surface water pollution, it is necessary to improve the design of park road such as using the stone road, which can decrease the roughness of the road. PMID- 25518652 TI - [Levels and distribution of the dioxin-like polychlorinated biphenyls (PCBs) in the surface sediment of the Yellow River ]. AB - The levels of DL-PCBs in the surface sediments collected in 15 different sampling sites from the Tibetan Plateau to the Yellow River estuary along the Yellow River were measured using the GC-MS. The concentrations of ?DL-PCBs ranged from 2. 3 to 14.8 pg.g-1 and the TEQs of DL-PCBs were between 0. 001 4 and 0. 023 1 pgg-1 , with an average of 0. 007 3 pg.g-1. Compared with other domestic and foreign rivers, the DL-PCBs and TEQ levels of the Yellow River were at low levels. The main DL-PCBs congeners in the Yellow River sediments were tetra and penta chlorinated biphenyls. The DL-PCBs congener composition of rural and underdeveloped areas was similar, and there was similar congeners composition between the industry developed areas and the populous areas. Petrochemical industries and hydropower facilities may affect the distribution of DL-PCBs congener in the sediments. A significant correlation between concentrations of DL PCBs and GDP per capita was found. It indicated that the contamination extent of DL-PCBs in the Yellow River was related with the local economic development, DL PCBs levels in developed areas were higher than those in remote rural areas. PMID- 25518653 TI - [Characteristics of nitrogen and phosphorus retention in two different channel forms in a typical headwater stream in the suburb of Hefei City, China ]. AB - To investigate the characteristics of ammonium and phosphorus retention in two typical channel forms, deep pool and winding ditch in headwater stream, four field tracer experiments were conducted in a first-order stream of Ershibu River in Hefei suburban, in which a solution of biologically active (NH4Cl and KH2PO4) and conservative (NaCl) tracers was released to the head of each reach at a constant rate. According to the data sets of tracer experiments, mechanisms of ammonium and phosphorus retention were interpreted by using OTIS model code, transient storage metrics and nutrient spiraling theory. Study results showed that: (1) The value of As in deep pool was larger than that in winding ditch, whereas its value of hydrological parameter alpha was lower by an order of magnitude than that of winding ditch; (2) The value of NH(4)+ -lambda in main channel was higher by two to three orders of magnitude than that of NH(4)+ lambdas,in transient storage zone in deep pool, but in winding ditch the two parameters were closer in terms of numerical size; (3) In deep pool, the value of NH+(4) -Vf was higher by an order of magnitude than that of SRP-Vf, in winding ditch, however, not only the two values of NH(4)+ -Vf and SRP-Vf were close to each other, but NH(4)+ -Sw was nearly equal to SRP-Sw in numerical size as well; (4) The value of NH(4)+ -U was larger by two to three orders of magnitude than that of SRP-U in deep pool, whereas in winding ditch NH(4)+ -U was just larger by one to two orders of magnitude than SRP-U in size; (5) In general, significant difference existed between deep pool and winding ditch in the effect on ammonium and phosphorus retention, and marked retention efficiency was observed for ammonium rather than SRP in deep pool. PMID- 25518654 TI - [Migration and transformation of nitrogen in urban stream located in plain river net area based on water resources regulation]. AB - To study hydrological features and physical and chemical characteristics of urban stream located in the plain river network area in the process of water resources regulation, and to discuss the forming and composition of nitrogen in urban stream based on water resources regulation. Effects of water regulation on the ammonium release from sediments in urban stream were studied under the condition of experimental simulation. The results showed that diurnal variation of water depth under the action of water resources regulation was significant. The value of DO in the overlying water along the water resources regulation path tended to decrease, while the concentration of permanganate index tended to increase. The concentration of nitrate in overlying water along the water resources regulation path gradually decreased, while the concentration of ammonium significantly increased. DO and permanganate index were the main factors influencing the concentrations of nitrate and ammonium in overlying water. Ammonium released from the sediments was an important source of ammonium in overlying water. Water resources regulation had a significant influence (P < 0. 05) on the concentration of ammonium in overlying water, but had no significant influence on the amount of cumulative ammonium released from sediments (P > 0. 05). PMID- 25518655 TI - [Decomposition and phosphorus dynamics of the litters in standing and litterbag of the Hangzhou Bay coastal wetland ]. AB - Wetlands litter decomposition affects wetlands nutrient cycling. The decomposition progress of standing litter was monitored and the litterbag simulation experiment was carried out in order to analyze dynamics of litter decomposition and phosphorus release in Phragmites australis (PA), Spartina alterniflora (SA) and Scirpus mariqueter (SM) marshes of Hangzhou Bay coastal wetland. Results show that the dry mass of standing litter and P concentration decrease gradually and the litter drops to the sediment surface after 180 d. There are distinctive stages of the plant litter decomposition in litterbag simulation experiments. The loss rate is faster during 0- 15 d than that of later days. The loss rate in root decomposition of three plants are SM > PA > SA, while the trend is opposite for that of aboveground tissues. The time needed for 95% of dry mass decomposition in the plant tissues is between 1. 2- 8. 3 a. The P concentration in litters decreases rapidly in the initial stage and then increases slowly while the net P pools decreases all the time. Pearson's correlation coefficient shows that there is no significant correlation between the litter decomposition rate and C/N ratio. However, the litter C/P ratio affects greatly on plant decomposition rate. Environmental factors in the atmospheric temperature also have an impact on the decomposition rate of leaves. The different decomposition progresses between standing litter and litterbag are caused by environmental factors. PMID- 25518656 TI - [Muti-model collaborative retrieval of chlorophyll a in Taihu lake based on data assimilation ]. AB - Under the efforts of many scholars, large amount of remote retrieval models of water quality parameters have been developed. However, each model could only reflect the "true value" from one level because of the natural limitation of remote sensing. To get the relatively true value by combining various retrieval models, in this work, we developed a multi-model collaborative retrieval algorithm for retrieving the concentration of Chlorophyll a based on data assimilation. We measured water quality parameters and water reflectance spectra in Taihu Lake during 2006 to 2009. There were seven retrieve models established and six models were selected to participate in the multi-model collaborative retrieval algorithm. Then these selected models were combined to establish a multi-model for retrieving the concentration of Chlorophyll a. The results indicated: (1) the accuracy of multi-model retrieval algorithm was better than that of single-model retrieval method, with an optimal MAPE of only 22. 4% ; (2) with more models participating in the multi-model collaborative retrieval algorithm, the accuracy became better, the average MAPE was decreased from 25. 6% to 23. 4% , the average RMSE was decreased from 15. 082 MUg.L-1 to 14. 575 MUg.L 1, and the average correlation coefficient was improved from 0.91 to 0. 92; (3) the accuracy and errors of retrieval products could be effective evaluated through calculating the confidence interval, which makes possible the acquirement of spatial and temporal error distribution of Chlorophyll a concentration retrieval in Taihu Lake. PMID- 25518657 TI - [Photobleaching of dissolved organic matter (DOM) from confluence of two rivers under natural solar radiation: a case study of Fujiang River-Jialingjiang River]. AB - Three-dimensional fluorescence spectroscopy combined with ultraviolet-visible absorption spectra was used to investigate the photobleaching process of dissolved organic matter (DOM) sampled from Fujiang River (FJ), Jialingjiang River (JLJ) and the confluence (FJ-JLJ) under natural solar radiation. The results indicated that obvious photochemical degradation of colored dissolved organic matter (CDOM) concentration [ alpha(280) ] and all fluorescence peaks intensity (A, C, M and T) occurred under natural solar radiation, and the degradation degree was in order of JLJ > FJ-JLJ > FJ. Photobleaching properties of DOM samples from different locations showed significant differences, which could be partially explained by the sampling sites surroundings including various landuse types, and dilution effect of river confluence. Light-induced bleaching activity of JLJ samples, which was mainly terrestrial input from forest system, was the highest as compared to the lowest activity of FJ samples, which was predominated by urban inputs. Samples from confluence were in the middle. Additionally, the spectrum slope(S) and absorbance ratio (A250/A350) were increased, while the humification index(HIX) was decreased with increasing irradiation time, which can be used as important indicators for photobleaching properties changes during the process. More importantly, the predominantly allochthonous (terrigenous) characteristics of DOM almost showed a tendency of transferring to autochthonous (authigenic) characteristics due to photobleaching. Especially, IT/Ic firstly decreased and then increased significantly in the process. Thus the photodegradation process may exaggerate DOM autochthonous contribution, and further interfere with the assessment of anthropogenic impacted water quality by using IT/Ic. In addition, mechanisms of light-induced DOM degradation process consistently showed by absorption and fluorescence spectrum parameters suggested the validation of analyzing DOM geochemical characteristics by the two important spectra tools. PMID- 25518658 TI - [Using ultraviolet-visible ( UV-Vis) absorption spectrum to estimate the dissolved organic matter (DOM) concentration in water, soils and sediments of typical water-level fluctuation zones of the Three Gorges Reservoir areas]. AB - Dissolved organic matter (DOM) is a very important component in terrestrial ecosystem. Chromophoric dissolved organic matter (CDOM) is a significant constituent of DOM, which can be measured by ultraviolet-visible (UV-Vis) absorption spectrum. Thus the relationship between CDOM and DOM was investigated and established by several types of models including single-wavelength model, double-wavelength model, absorption spectrum slope (S value) model and three wavelength model, based on the UV-Vis absorption coefficients of soil and sediment samples (sampled in July of 2012) and water samples (sampled in November of 2012) respectively. The results suggested that the three-wavelength model was the best for fitting, and the determination coefficients of water, soil and sediment data were 0. 788, 0. 933 and 0. 856, respectively. Meanwhile, the nominal best model was validated with the UV-Vis data of 32 soil samples and 36 water samples randomly collected in 2013, showing the RRMSE and MRE were 16. 5% and 16. 9% respectively for soil DOM samples, 10. 32% and 9. 06% respectively for water DOM samples, which further suggested the prediction accuracy was higher in water DOM samples as compared with that in soil DOM samples. PMID- 25518659 TI - [Synthesis of Cu2O-Ag-AgBr/MA visible photocatalyst and its performance in degradation of 2-chlorophenol]. AB - Cu2O-Ag-AgBr/MA plasmon photocatalyst was prepared by the co-deposition of Cu2O and Ag-AgBr nanoparticles on mesoporous alumina (MA). The samples were characterized by means of X-ray diffraction (XRD) ,X-ray photoelectron spectroscopy (XPS) and diffuse reflectance UV-vis spectra (UV-vis DRS). The results showed that both Ag+ and Ag0 existed on the surface. The photocatalytic activity of the samples prepared were evaluated by degradation of 2-chlorophenol (2-CP) under visible light (lambda >420 nm) irradiation. The results showed that the catalyst had high photocatalytic activity for the degradation of 2-CP. Meanwhile, the doping of Cu2O nanoparticles significantly inhibited the release of silver ions during the photocatalytic reaction, which improved the photostability of the catalyst. Analyses on the effects of various scavengers showed that h+ , O2- and OH radicals were the primary active species. PMID- 25518660 TI - [Effects of particle size of zero-valent iron on the reactivity of activating persulfate and kinetics for the degradation of acid orange 7]. AB - This research described the heterogeneous reactions of persulfate with different particle sizes of zero-valent iron (including 1 mm-ZVI,150 MUm-ZVI,50 nm-ZVI) for degradation of acid orange 7(AO7) , and studied the kinetics and intermediate products of AO7 under these systems. The results demonstrated that these three types of ZVI were efficient in promoting the degradation of AO7, the degradation efficiencies of AO7 were 43% , 97% , and 100% within 90 min respectively, in the 1 mm-ZVI,150 MUm-ZVI and 50 nm- ZVI systems, respectively. With the results of kinetic fitting models, the pseudo first-order kinetics exhibited better fitting results in the 1 mm-ZVI,150 MUm-ZVI systems, while the second-order kinetics exhibited better fitting results in the 50 nm-ZVI system. And the different ZVI types exhibited difference on the AO7 degradation rate constant, which ranged as 50 nm-ZVI > 150 MUm-ZVI > 1 mm-ZVI. The iron corrosion products coating on the ZVI after reaction were composed of alpha-Fe2 O3 and some Fe3O4 in the 1 mm-ZVI system while that consisted of Fe3O4 and alpha-Fe2O3, FeOOH respectively, in thel50 MUm-ZVI and 50 nm-ZVI systems,. Which were identified by scanning electron microscope (SEM) with energy dispersive spectrometer (EDS) and Raman spectroscopy. Some intermediate products, including 2-naphthalenol, 2 methylphenol, 4-ethyl- 3-methyl-phenol, isoindole- 1,3-dione and phthalic acid et al. were identified by GC/MS measurement. Both UV-vis absorbance spectra and GC/MS determination indicated that there was difference in degradation paths of AO7 between the three systems. PMID- 25518661 TI - [Degradation of 2, 4-D by combined catalytic dechlorination and biological oxidation]. AB - In this paper, Pd/Fe nanoparticles were used to degrade 2,4-D. Then the resulted solution of 2,4-D dechlorination was biological oxidized by activated sludge. And the effects of initial pH, activated sludge volume, initial contaminant concentration and temperature on the removal of PA were studied. Polymerase Chain Reaction-Denaturing Gradient Gel Electrophoresis (PCR-DGGE) was used to study microbial community structure. And High Performance Liquid Chromatography (HPLC) was employed to determine and analyze the degradation process of target pollutant. The conclusions can be summarized as follows: (1) Pd/Fe can degrade 2,4-D efficiently, 2-CPA was the intermediate product, and the end product was PA. (2) Compared with 2,4-D, the dechlorination product PA has lower biological toxicity, and can be more easily degraded by activated sludges. (3) pH = 7, 50 mL activated sludge/200 mL solution, PA initial concentration of 14. 6 mg L-1 and 30 degrees C favored the PA removal. Under suitable conditions, the removal rate of PA can reach to 84. 3% after 96 hours. PMID- 25518662 TI - [Treatment of marine-aquaculture effluent by the multi-soil-layer (MSL) system and subsurface flow constructed wetland]. AB - To evaluate the feasibility of using multi-soil-layer (MSL) system and subsurface flow constructed wetland to treat the wastewater of marine cultured Penaeus vannamei and to determine the suitable process for the local aquaculture wastewater pollution characteristics. In this study, MSL system and four constructed wetland systems with Spartina anglica, Phragmites australis, Typha latifolia and unplanted system were evaluated for their potentials of pollutants removal capacity. The results showed the average removal rates of chemical oxygen demand (COD), total phosphorus (TP), total nitrogen (TN), ammonia nitrogen (NH(4)+ -N) and nitrate (NO-(3) -N) by MSL system were 80. 38% +/- 2. 14% , 68. 14% +/- 3.51% , 40.79% +/- 3. 10% , 42. 68% +/- 2.90% and 54. 19% +/- 5. 15% , respectively. Additionally, the ability of pollutants removal of other four wetland systems decreased in the order: Spartina anglica, Phragmites australis, Typha latifolia and unplanted system. PMID- 25518663 TI - [Variation of different carbon sources in the sewage treatment process]. AB - The biodegradability and speciation of organics were studied through long-term analysis of A2/O treatment. The majority of the organic matters were particle organics which accounted for 61% of the total organics. The proportions of rapidly degradable, slowly degradable and refractory organics were 15. 8% , 54. 2% and 30% respectively. Rapidly biodegradable organics were mainly dissolved organics while slowly biodegradable organics were particle organics. The variation of these two kinds of carbon sources was analyzed during the treatment process. It was noted that microbial hydrolysis fermentation took place in the anaerobic and anoxic tanks, which led to the transformation of slowly biodegradable organics and the anaerobic tank had the highest transformation rate. The transformation and utilization of rapidly/slowly biodegradable organics were analyzed through calculation. The results showed that the transformation efficiency of slowly biodegradable organics in the anaerobic and anoxic tanks in two hours was 33% and 20%, respectively. Furthermore, the amount and species of aliphatic acid increased in the anaerobic and anoxic tanks comparing with raw water. PMID- 25518664 TI - [Effect of gas-lift device on nitrogen removal efficiency of ANAMMOX reactor ]. AB - The effect of air-lift device on the nitrogen removal efficiency of ANAMMOX reactor was studied by increasing the substrate concentration to improve nitrogen load rate and inoculate ANAMMOX sludge. The results showed that the effluent recirculation was achieved by using nitrogen gas produced from the ANAMMOX process as power in the air-lift room. With the increase of nitrogen removal rate, the rate of effluent recirculation was increased, which diluted influent substrate concentration and alleviated the inhibition of ANAMMOX bacteria,. After 183 d operation, the effluent NH4+ -N and NO2- -N concentrations were increased to 46. 3 mg L-1 and 53.21 mg.L-1, and the nitrogen removal rate was kept stable at 28.3 kg (m3.d)-1, when the influent NH4+ -N and NO2- -N concentrations were increased to 700 mg.L-1 and 840 mgL-1, respectively. The effluent recirculation system formed by gas-lift devices is an economic and effective solution to the inhibition caused by high substrate concentration in traditional reactor, meanwhile, the power consumption of the external reflux pump was reduced. PMID- 25518665 TI - [Enhancement for anaerobic digestion of sewage sludge pretreated by microwave and its combined processes ]. AB - To improve anaerobic digestion and dewatering of sludge, impacts of sludge pretreated by microwave (MW) and its combined processes on sludge anaerobic digestion and dewatering were investigated. The results showed that microwave and its combined processes could effectively enhance anaerobic sludge digestion. Not only the cumulative methane production in the test of the MW-H2O2-alkaline (0. 2) was increased by 13. 34% compared with the control, but also its methane production rate was much higher than that of the control. Compared with the single MW process, the addition of both H2O2 and alkaline enhanced the solubilization of particle COD( >0. 45 micron) , indicating that synergistically generated soluble organics were faster to biodegrade which resulted in the enhancement of anaerobic digestion. The MW-acid process was effective in improving sludge dewaterability, e. g. , Capillary Suction Time (CST) at only 9. 85 s. The improvement of sludge dewatering was significantly correlated with sludge physical properties such as zeta potential, surface charge density and particle size. Under different sludge pretreatment conditions, the sludge dewatering after anaerobic digestion was similar, though the difference of sludge dewatering to some degrees was observed for pretreated sludge. PMID- 25518666 TI - [Pilot study of thermal treatment/thermophilic anaerobic digestion process treating waste activated sludge of high solid content]. AB - A pilot-scale experiment about the process of "thermal pretreatment at 70 degrees C/thermophilic anaerobic digestion" of waste activated sludge of high solid content (8% -9% ) was conducted. The process employed thermal treatment of 3 days to accelerate the hydrolysis and thermophilic digestion to enhance anaerobic reaction. Thus it was good at organic removal and stabilization. When the solid retention time (SRT) was longer than 20 days, the VSS removal rate was greater than 42. 22% and it was linearly correlated to the SRT of the aerobic digestion with the R2 of 0. 915 3. It was suggested that SRT of anaerobic digestion was 25 days in practice. VSS removal rate and biogas production rate of the pilot experiment were similar to those of the run-well traditional full-scale sludge anaerobic digestion plants (solid content 3% -5% ) and the plant of high solid content using German technique. PMID- 25518667 TI - [Effects of temperature on combined process of ABR and MBR for domestic sewage treatment and analysis of microbial community]. AB - Effects of temperature on the combined process of ABR and MBR ( CAMBR) for domestic sewage treatment were investigated and the changes in the bacterial community structure were analyzed by PCR-DGGE technique. The HRT, recycle ratio 1, recycle ratio 2, pH and DO were 7.5 h, 200% , 50%, 6.5~8.5 and 3 mg.L-1, respectively. The temperature were controlled at three gradients: middle (25 degrees C +/-5 degrees C ), low (10 degrees C+/-5 degrees C) and high (35 degrees C+/-5 degrees C ). The results showed that the change of temperature had little influence on COD removal, and the CAMBR in stable state showed good performance in COD removal. In addition, the CAMBR achieved good effluent quality in middle or high temperature environment, and the average TN removal efficiency was 70% with an effluent TN of 9 mg L-1, and the average TP removal efficiency was 73% with the effluent TP below 0. 8 mg L-1. For the process operated in low temperature environment, the average TN removal efficiency was only 57% with an effluent TN of 15 mg L-1, and the average TP removal efficiency was decreased to 67% with an effluent TP of 1 mg.L-1. DGGE analysis indicated that throughout the process, the microbial population within the system maintained its diversity in distribution, while the dominant flora was prominent. During the same period, microbial populations in each compartment were similar. However, the structure of microbial community had significant differences between the ABR and the MBR due to the change of microenvironment in each compartment. Thus, the contributions of the ABR and the MBR were intensified, guaranteeing the efficiency of nitrogen and phosphorus removal in the system. PMID- 25518668 TI - [Microbial community of municipal discharges in a sewage treatment plant]. AB - There are numerous microorganisms, especial pathogens, in the discharges. Those microorganisms are discharged into the river and sea through sewage outfalls, which results in possible health risks to coastal populations. And more attention should be paid to municipal discharges in developing countries. This study investigated the microbial community in the discharges by constructing 16S rDNA clones library and using the PCR-RFLP technology. Phylogenetic analysis of bacteria in municipal discharges showed that there were 59 species, which were divided into 11 classes. Proteobacteria accounted for 85% of all the bacteria, of which beta-Proteobacteria and gamma- Proteobacteria were the dominant classes. Bacteria in the waste water treating process had important influence on microbial community in municipal discharges, therefore, municipal sewage plant should choose the process according to the characteristics and purifying capacity of the receiving water body. Legionella spp. accounted for approximately 10% , the Legionnaires' disease resulted from which might be of top risk for the residents in the surrounding of the municipal discharges outfall and receiving water. Dechloromonas aromatica could make use of chlorite ( CIO - ) , which led to its survival from chlorine disinfection, and it alerted us that several disinfection methods should be used together to ensure the bacterial safety of municipal discharges. Coliform group and other pathogenic bacteria, such as Salmonella spp. , Shigella spp. , Escherichia coli, Vibrio cholerae, Staphylococcus aureus, Arcobacter spp. were not detected in this study, and it indicated that we should do more work and use more methods to investigate the perniciousness of discharges. PMID- 25518669 TI - [Pilot-scale cultivation of Spirulina plantensis with digested piggery wastewater ]. AB - The swine waste pretreated with coagulation sedimentation was used for the outdoor pilot-scale cultivation of Spirulina platensis isolated from digested piggery wastewater (DPW) in a raceway pond. The growth of S. platensis and removal of nitrogen/ phosphorus were studied, moreover, the conversion efficiency of total nitrogen (TN) or total phosphorus (TP) from DPW to S. platensis was calculated. On this basis, the existing problems and countermeasures during outdoor pilot-scale culture were analyzed and summarized combined with the laboratory research. We conducted 6 batches culture experiments, only 3 of which could reach the S. platensis harvest requirements (D560 >0. 8). Meanwhile, the 3 successful batches achieved removal of COD, ammonia nitrogen, TN, TP with corresponding 28. 6% -48. 5% , 0.4% -48. 5% , 41. 8% -48. 6% , 14. 3% -94. 5% , and the conversion efficiency of TN or TP from DPW to S. platensis reached 12. 1% -98. 5% , 21.2% -83.7% , respectively. High concentration of ammonia nitrogen and insect attack of remaining egg hatching in the pretreated swine waste were the main factors to cause the slow-growing of the 3 batches of S. platensis. Therefore, it is highly necessary for the removal of ammonia nitrogen with biological treatment technology and insect eggs with membrane to achieve a stable high productivity. PMID- 25518670 TI - [Spectral characteristics of soluble metabolites during endogenous respiration]. AB - Endogenous respiration phase plays an important role in the sewage treatment process. In order to clearly understand the endogenous respiration process of the activated sludge process, three-dimensional fluorescence spectroscopy, ultraviolet spectroscopy and respirogram were employed for the analysis of endogenous respiration process. Results showed that the three-dimensional fluorescence spectroscopy and UV spectroscopy could identify all stages significantly. The following conclusions could be drawn: (1) Rapid decline phase of endogenous respiration:the excitation wavelength (EX) and emission wavelength (Em) of humic peak showed blue shift of 5 nm and 6 nm, respectively, the fluorescence index f450/500 and HIX (humification index) were reduced by 9. 3% and 0.2%, respectively, UV253/203 and UV254 increased by 37.5% and 200%, respectively. These results indicated the presence of bioavailable organics; (2)Slow decline phase of endogenous respiration: f450/500 was increased by 0. 5% , HIX was reduced by 0. 2% , UV253/203 was reduced by 20% , UV254 was increased by 16. 7%. These results indicated that hydrolysis or autolysis of cells might occur; (3)Stable phase of endogenous respiration: humic acid peak remained unchanged, indicating the adaption of microorganisms to starving environment. The analysis of the endogenous respiration process from the perspective of metabolites provides a new way for control of microbial wastewater treatment process. PMID- 25518671 TI - [Endogenous respiration process analysis of heterotrophic biomass and autotrophic biomass based on respiration map ]. AB - The endogenous process is an important metabolic part of the activated sludge, and the understanding of this process is still unclear. Characteristics of endogenous respiration for heterotrophic bacteria and autotrophic nitrifiers were analyzed using respirogram. Results showed that both heterotrophic and autotrophic bacteria entered the stage of endogenous respiration at almost the same time, but heterotrophic bacteria first entered the stage of dormancy i. e. , they were easier to recover a higher proportion of biomass during the dormancy stage, indicating that heterotrophic bacteria exhibited strong environmental adaptability. Autotrophic bacteria were, however, quite different. This finding confirmed that autotrophic bacteria were more vulnerable from the viewpoint of endogenous respiration. In addition, the study also found that the increase of endogenous respiration rate ratio reflected the decreased sludge activity. And the proportion of endogenous respiration was an important parameter to characterize the activity of activated sludge, which can be used as a quantitative index for the health status of activated sludge. The findings further deepened the understanding of endogenous respiration process and provided a theoretical basis for the operation and management of wastewater treatment plants. PMID- 25518672 TI - [Influence of S-metolachlor and Cd2+ on photosynthesis of Scenedesmus obliquus]. AB - The single and combined effects of Cd2+ and S-metolachlor on the chlorophyll content and chlorophyll fluorescence parameters of Scenedesmus obliquus were studied by using standard toxic testing method. Both Cd2+ and S-metolachlor had effects on the chlorophyll content and fluorescence parameters such as F0, FV/Fm, FV/F0, Y( II), qP, NPQ and rETR after 96 h-exposure, showing that Cd2+ and S metolachlor damaged the PS II in algae, inhibited the primary reaction of photosynthesis, stopped the process of photosynthetic electron transport, and destroyed its ability of heat dissipation. The effects of Cd2 + on the chlorophyll content and fluorescence parameters were greater than those of S metolachlor, and the effects increased with the increasing concentration. The average drop of Y( II ) was 62. 5% in the control group when the light intensity was 231 MUmol (m2.s) -1 , and it was 68. 0% , 82. 5% and 100% respectively in Cd2+ -treated groups, and 66. 1% , 72. 1% and 79.6% respectively in S-metolachlor treated group with the increasing concentration. The combined effects of Cd2+ and S-metolachlor on the chlorophyll fluorescence parameters were mainly due to the impacts of Cd2+. PMID- 25518673 TI - [Effect of environmental factors on fish community structure in the Huntai River Basin at multiple scales]. AB - In June 2012, fishes was investigated at 65 sampling sites in the Huntai River basin in Northeast of China. Forty species were collected, belonging to 9 orders, 14 families,33 genera. Cobitidae and Cyprinidae were the dominant fishes in the community structure in the Huntai River basin, accounting for 13. 21% and 65. 83% of the fish community, respectively. There were two types of spatial distribution of fish community, one was distributed in the head water and tributaries in the upstream, and the other was in the plain rivers. Nemachilus nudus, Cobitis granoei and Phoxinus lagowskii dominated the local community in the upper reaches of the Dahuofang Reservoir and shenwo River, while Carassius ayratus and Hemiculter leucisculdus dominated the local community in the plain rivers. CCA (canonical correspondence analysis) was used to distinguish the primary environmental variables that affected the fish community structure. The results indicated fish community was mainly affected by environment factors at watershed and reach scales. Proportions of woodland and urban land, and altitude were three important environmental factors affecting the fish community at the watershed scale. Dissolved oxygen, total nitrogen, pH and habitat inhomogeneity significantly affected the fish community at the reach scale, whereas substrate didn't show significant influence at the microhabitat scale. Environmental factors at watershed scale explained 7. 66% of the variation of fish community structure, environmental factors at reach scale explained 10. 57% of the variation of fish community structure. Environmental factors at reach scale influenced the fish community more significantly. PMID- 25518674 TI - [Succession of rotifer community and its relationship with environmental factors in a new Estuarial Landscape River, Shanghai]. AB - The community structures of rotifers were surveyed in Lin'gang B Gang River, a new estuarial river in Shanghai, from December 2011 to November 2012. A total of 23 rotifer species were identified, of which 19 species were the indicator of environmental pollution. Rotifer species' number rose monthly from 2 to 13. A conspicuous succession of dominant species was observed from a single dominant species (Keratella cochlearis) to several species. The rotifer community structure of Lin'gang B Gang River differs with that of the outer water body (Lu Chaoyin River). Pearson analysis showed that the rotifers' density had a significant correlation with water temperature and chlorophyll-a (P <0. 05) , but had no significant correlation with salinity; the densities of dominant species (except Keratella cochlearis) presented negatively correlations with concentration of nutrients and salinity (P < 0. 05). The low species similarity index between every month demonstrated that aquatic ecosystem of Lin'gang B Gang River was in the unstable state. However, the increase of Margalef index and Shannon-Wiener index of rotifers and the decline of E/O value monthly showed the water environment of Lin'gang B Gang. River was improved. PMID- 25518675 TI - [Anaerobic reduction of humus/Fe (III) and electron transport mechanism of Fontibacter sp. SgZ-2]. AB - Humus and Fe(III) respiration are important extracellular respiration metabolism. Electron transport pathway is the key issue of extracellular respiration. To understand the electron transport properties and the environmental behavior of a novel Fe(III)- reducing bacterium, Fontibacter sp. SgZ-2, capacities of anaerobic humus/Fe(III) reduction and electron transport mechanisms with four electron acceptors were investigated in this study. The results of anaerobic batch experiments indicated that strain SgZ-2 had the ability to reduce humus analog [ 9,10-anthraquinone-2,6-disulfonic acid (AQDS) and 9,10-anthraquinone-2-sulfonic acid (AQS)], humic acids (HA), soluble Fe(III) (Fe-EDTA and Fe-citrate) and Fe(III) oxides [hydrous ferric oxide (HFO)]. Fermentative sugars (glucose and sucrose) were the most effective electron donors in the humus/Fe(III) reduction by strain SgZ-2. Additionally, differences of electron carrier participating in the process of electron transport with different electron acceptors (i. e. , oxygen, AQS, Fe-EDTA and HFO) were investigated using respiratory inhibitors. The results suggested that similar respiratory chain components were involved in the reducing process of oxygen and Fe-EDTA, including dehydrogenase, quinones and cytochromes b-c. In comparison, only dehydrogenase was found to participate in the reduction of AQS and HFO. In conclusion, different electron transport pathways may be employed by strain SgZ-2 between insoluble and soluble electron acceptors or among soluble electron acceptors. Preliminary models of electron transport pathway with four electron acceptors were proposed for strain SgZ-2, and the study of electron transport mechanism was explored to the genus Fontibacter. All the results from this study are expected to help understand the electron transport properties and the environmental behavior of the genus Fontibacter. PMID- 25518676 TI - [Source apportionment of soil heavy metals in Jiapigou goldmine based on the UNMIX model]. AB - The paper determines 16 kinds of metal elements' concentration in soil samples which collected in Jipigou goldmine upper the Songhua River. The UNMIX Model which was recommended by US EPA to get the source apportionment results was applied in this study, Cd, Hg, Pb and Ag concentration contour maps were generated by using Kriging interpolation method to verify the results. The main conclusions of this study are: (1)the concentrations of Cd, Hg, Pb and Ag exceeded Jilin Province soil background values and enriched obviously in soil samples; (2)using the UNMIX Model resolved four pollution sources: source 1 represents human activities of transportation, ore mining and garbage, and the source 1's contribution is 39. 1% ; Source 2 represents the contribution of the weathering of rocks and biological effects, and the source 2's contribution is 13. 87% ; Source 3 is a comprehensive source of soil parent material and chemical fertilizer, and the source 3's contribution is 23. 93% ; Source 4 represents iron ore mining and transportation sources, and the source 4's contribution is 22. 89%. (3)the UNMIX Model results are in accordance with the survey of local land use types, human activities and Cd, Hg and Pb content distributions. PMID- 25518677 TI - [Environmental magnetic properties and their spatial variability of topsoil in Shihezi City]. AB - The 80 topsoil samples (0-10 cm) are collected from different land use types in built-up areas, northern new town (including chemical concentration area and concentrated residential areas) and suburban agricultural land at Shihezi oasis city in arid zone of Xinxiang, China. The aim of this study is to analysis the magnetic parameters of concentration, composition and particle size of magnetic properties for the urban topsoils, and to describe the spatial distribution under different circumstances of land use. The magnetic grain parameters show that the soils are dominated with coarser multi domain (MD) ferrimagnetic grain. The magnetic mineralogy parameters suggest that samples are dominated by ferrimagnetic minerals corresponding to magnetite-like minerals, but contain a small amount of anti-ferromagnetic material. From the spatial distribution, the concentration of magnetic minerals are ranked in the order of northern new town > built-up areas > suburban agricultural land. Particle size of magnetic minerals are ranked in the order of northern new town > suburban agricultural land > built up areas. The high concentration of magnetic parameters areas is coincident with factories' area. However, the magnetic concentration in heavy chemical industry region (N1-N7) are low, and particle size of the magnetic particles is larger. XLF, SIRM and SOFT are effective magnetic parameter indexes indicating the light industrial zone of the study area. While, the discrimination in the heavy chemical industry area needs to combine with a magnetic particle parameters (XFD%) . PMID- 25518678 TI - [Effects of different amounts of phosphate fertilizers on copper, zinc transfer in red soil under the application of KH2PO4]. AB - In order to study the effects of different phosphate addition amounts on migration and transformation of heavy metals (Cu, Zn) in soil, an indoor leaching experiment using soil columns was carry out to study the leaching behavior of Cu and Zn. The KH2PO4 was chosen as the fertilizer application at the doses of 5 mg.kg-1, 15 mg.kg-1 and 25 mg.kg-1. The results showed that KH2PO4, could reduce the leachate pH, but different phosphate amounts had little effect on leachate pH, pH in leachate kept rising in the whole leaching process. With the application of KH2PO4, Cu migration was mainly in the surface layer while Zn migrated into deeper soil. Concentrations of Cu, Zn in deep soil leachate were low indicating that it was harmless to the shallow groundwater. After leaching, heavy metals mainly existed in the residual form in soil, the proportion of residual form of Cu was around 60% and the proportion of residual form of Zn was around 40%. High concentration of KH2PO4 helps the transformation of Zn from residual organic combination state to exchange state. PMID- 25518679 TI - [Influence of sulfur on the bioavailability of arsenic uptake by rice (Oryza. sativa L. ) and its speciation in soil ]. AB - Pot experiments using exogenous arsenic-polluted paddy soils were carried out to investigate the influence of different forms of sulfur fertilizers (sulfur and gypsum) on As uptake by rice and its chemical speciation. Soil solution pH value ranged 7. 38-7. 45 in different growth period of rice, and the pH value of AsS0 and AsS1 treatments was higher than that of AsS2 treatment. Variation of Eh value in soil solution was about 200 mV and the Eh of AsS0 was higher than those of AsS1 and AsS2 treatments. From dry matter weight of root and stem and grain of rice, S-fertilizer applied by sulfur and gypsum could improve the amounts of dry matter in rice, while the effects of sulfur treatments and gypsum treatments were not significant. Concentrations of Fe and Mn in iron-manganese plaque on rice roots were 10-30 g.kg-1 and 0.1-1.3 g.kg-1, respectively. Contents of Fe-Mn plaque were mainly different in the tiller stage. Elemental S treatment could more greatly promote the formation of Fe-Mn plaque of rice root than gypsum treatment. Concentrations of As adsorbed by rice roots surface plaque were 583 719 mg.kg-' in tiller stage, 466-621 mg.kg-1 in boot stage, and 310-384 mg kg-1 in flower and matur stage. And it was consistent with the thickness of Fe-Mn plaque on rice root surface. Concentrations of As uptake in roots and stem and leaf and grain were significantly reduced by the application of S fertilizer, and it may be related to the amount of As adsorbed by Fe-Mn plaque at boot stage. According to chemical speciation of soil arsenic, As of non-specific and specific adsorption was most active, and their amounts of As adsorbed in AsS, treatment were significantly lower by 2.85 mg kg-~' than that in AsS2 treatment in tiller stage, and was 0.77 mg.kg- higher than that in AsS2 treatment in the flower stage. Perhaps soil arsenic was easily dissolved in the soil solution and the bioavailability of AsS, treatment was better than that of AsS, treatment. PMID- 25518680 TI - [Effects of sulfur on transformation of selenium in soil and uptake of selenium in rape]. AB - The high-quality, high-yield rape (Brassica napus L. cv. Xiangnongyou 571) was chosen as the experimental material to undergo seedling stage soil cultivation and solution cultivation. This study was aimed to investigate the effects of sulfur (S) on the fraction and species of amend selenium (Se) in soil by applying S fertilizer, and to reveal the mechanism through which S controls the Se uptake of rape. The results showed that applications of both Se at 5 mg.kg-1 and S at 150 mg.kg-1 could provide some boost to rape growth, however such boost was unremarkable; S application could significantly reduce Se content in shoots and roots by as much as 64. 0% and 39. 1% , respectively; S application could significantly decrease the pH value and increase the organic matter content by as much as 0. 65 units and 1.76 g.kg-1 , respectively; S application could significantly decrease soluble Se and Fe/Mn oxide-bound Se, and significantly increase organic matter-bound Se, however, there was no remarkable effect on exchangeable and residual Se. S could significantly decrease the content of Se(IV) in the soluble Se and significantly increase the content of Se(IV) in the exchangeable Se, with remarkable decrease in Se(VI) content in both fractions, and no remarkable effect on Se(II). S had a profound effect on the uptake of Se by rape seedlings when Se( IV) and Se( VI) were applied. The Se contents in shoot and root of the Se( VI)-treated rape were 7.3 and 3.2 times respectively as high as that of the Se( IV)-treated rape, while with a S rate of 2 mmolL-1, their Se contents were lower than 32.6% and 8.7% of that of the Se(IV)-treated rape. In conclusion, in addition to improving crop growth, appropriate amount of S fertilizer could also reduce soil pH and increase organic content, causing available Se in soil to be Fe/Mn oxide-bound and organic matter-bound, and retarding its transformation to Se( VI), thus reducing Se uptake by rape. This has significant value for regulation of Se content in crops from Se-rich regions, ensuring food quality and safety, benefiting the long-term use of soil Se resources and regional economic development. PMID- 25518681 TI - [Impact of reclaimed water irrigation on soil chemical properties and culturable microorganisms ]. AB - This research used batch soil column experiment to study the effects of irrigating with reclaimed water and tap water on the soil chemical properties and culturable microorganisms. The results indicated that reclaimed water could markedly increase the soil organic material (OM) and total nitrogen (TN) content, but it had no obvious effect on total phosphorus (TP), available phosphorus (AP) and pH value. Reclaimed water irrigation could significantly enhance the amounts of surface soil bacteria and actinomycetes at a depth of 0-20 cm, but it had little effect on the biomass of 20-40 cm and 40-60 cm soil layers. The dominant bacteria in tap water irrigation area was the genus Bacillus whereas that of reclaimed water irrigation area was the genus Acinetobacter. Tap water irrigation area had four endemic genera and reclaimed water irrigation area had six endemic genera. Reclaimed water had no obvious effect on the microbial community Shannon diversity of 0-20 cm soil layer, while it decreased Pielou evenness index, and improved Margalef richness index. Through SPSS 17. 0 correlation analysis between soil microbes quantity and soil chemical properties, it was shown that the soil microbes quantity was positively correlated with OM, TN, TP and AP, but negatively correlated with soil water content (SWC) and pH value. Based on CANOCO 4.5 detrended correspondence analysis (DCA) and redundancy analysis (RDA) between soil microbes species and soil chemical properties, it was shown that AP had the strongest correlation with the microbial community (P = 0.002). TN and TP had larger impact on Streptococcus, Aeromonas and Neisseria. OM and AP had larger impact on Aerococcus, Planococcus and Halobacterium. PMID- 25518683 TI - [Effects of different soil types on the foliar delta13C values of common local plant species in karst rocky desertification area in central Guizhou Province]. AB - By measuring the foliar delta13C values of common local plant species grown in different soil types in Wangjiazhai catchments, a typical karst desertification area in Qingzhen City, Central Guizhou, we studied the impact of soil type and rocky desertification grade on the foliar delta13C values. The results showed that the foliar delta13C values were more negative in yellow soil area than those in black calcareous area and there was no obvious difference in foliar delta13C values between these two soil types. The distribution interval of foliar delta13C values in yellow soil area was narrower than those in black calcareous area and the variation coefficient of foliar delta13C values in yellow soil area were smaller than those in black calcareous area. With increasing degree of karst rocky desertification, the foliar delta13C values of plant community in black calcareous area increased, whereas those in yellow soil area first increased and then decreased. The result of multiple comparison showed that the difference in foliar delta13C values of plant community among rocky desertification grade was not obvious in yellow soil area, but it was obvious in black calcareous area. Correlation analysis between the foliar delta13C values of plant species and the main environmental factors indicated that slope and soil thickness were the main factors which affected the foliar delta13C values of plants in yellow soil area and soil water contant was the main factor in black calcareous area. The impact of soil on the foliar delta13C values was realized by adjusting the soil moisture in study area. PMID- 25518682 TI - [Influence of different slope position and profile in Disporopsis pernyi forest land on soil microbial biomass and enzyme activity in southwest Karst mountain of China ]. AB - Soil microbial biomass and enzyme activity are important parameters to evaluate the quality of the soil environment. The goal of this study was to determine the influence of different slope position and section in Disporopsis pernyi forest land on the soil microbial biomass and enzyme activity in southwest Karst Mountain. In this study, we chose the Dip forest land at Yunfo village Chengdong town Liangping country Chongqing Province as the study object, to analyze the influence of three different slope positions [Up Slope(US), Middle Slope(MS), Below Slope(BS)] and two different sections-upper layer(0-15 cm) and bottom layer(15-30 cm) on the soil microbial biomass carbon (SMBC), soil microbial biomass nitrogen (SMBN), microbial carbon entropy (qMBC), microbial nitrogen entropy (qMBN) , catalase(CAT), alkaline phosphatase (ALK), urease(URE), and invertase(INV). The results showed that the same trend (BS > MS > US) was found for SMBC, SMBN, qMBC, qMBN, CAT and INV of upper soil layer, while a different trend (BS > US > MS) was observed for ALK. In addition, another trend (MS > US > BS) was observed for URE. The same trend (BS > MS >US) was observed for SMBN, qMBN, CAT, ALK, URE and INV in bottom layer, but a different trend (MS > BS > US) was observed for SMBC and qMBC. The SMBC, SMBN, CAT, ALK, URE and INV manifested as upper > bottom with reduction of the section, while qMBC and qMBN showed the opposite trend. Correlation analysis indicated that there were significant (P <0.05) or highly significant (P < 0.01) positive correlations among SMBC in different slope position and section, soil enzyme activity and moisture. According to the two equations of regression analysis, SMBC tended to increase with the increasing CAT and ALK, while decreased with the increasing pH. Then SMBN tended to increase with the increasing URE and INV. PMID- 25518685 TI - [Ability of typical greenery shrubs of Beijing to adsorb and arrest PM2.5 ]. AB - Four typical types of green shrubs of Beijing (Euonymus japonicus, Buxus microphylla, Berberis thunbergii cv. atropurpurea, Taxus cuspidate cv. nana) were selected to study their capacities in adsorbing and arresting PM2.5 using both field observations and air chamber simulations. Concurrently, in order to analyze the pollution characteristics of Beijing in winter and spring, the PM2.5 concentrations of December 2012 to May 2013 were collected. Experimental results showed that: From the gas chamber experiments, the ability to adsorb and arrest PM2.5 was in the order of Berberis thunbergii cv. atropurpurea > Buxus microphylla > Taxus cuspidate cv. nana > Euonymus japonicus, mainly due to the differences in leaf characteristics; Outside measurement results showed that the ability to adsorb and arrest PM2.5 was ranked as Buxus microphylla > Berberis thunbergii cv. atropurpurea > Taxus cuspidate cv. nana > Euonymus japonicus. Chamber simulation and outdoor observation showed that Buxus microphylla and Berberis thunbergii cv. atropurpurea had strong ability to adsorb and arrest PM2.5; Meanwhile, the slight differences between the chamber simulation and outdoor observation results might be related to plant structure. Compared to tree species, the planting condition of shrub species was loose, and it greened quickly; By analyzing the Beijing PM2.5 concentration values in winter and spring, it was found that the PM2.5 concentration was particularly high in the winter of Beijing, and evergreen shrubs maintained the ability to adsorb and arrest PM2.5. PMID- 25518684 TI - [Effect of carbon substrate concentration on N2, N2O, NO, CO2, and CH4 emissions from a paddy soil in anaerobic condition]. AB - Understanding the effects of carbon and nitrogen substrates concentrations on the emissions of denitrification gases including nitrogen (N2) , nitrous oxide (N2O) and nitric oxide (NO), carbon dioxide (CO2) and methane (CH4) from anaerobic paddy soils is believed to be helpful for development of greenhouse gas mitigation strategies. Moreover, understanding the quantitative dependence of denitrification products compositions on carbon substrate concentration could provide some key parameters or parameterization scheme for developing process oriented model(s) of nitrogen transformation. Using a silt loam soil collected from a paddy field, we investigated the influence of carbon substrate concentration on the emissions of the denitrification gases, CO2 and CH4 from anaerobically incubated soils by setting two treatments: control (CK) with initial soil nitrate and dissolved organic carbon (DOC) concentrations of ~ 50 mg.kg-1 and -28 mg kg-1 , respectively; and DOC added (C + ) with initial soil nitrate and DOC concentrations of ~50 mg.kg-1 and ~300 mg.kg-1 , respectively. The emissions of denitrification gases, CO2 and CH4, as well as concentrations of carbon and nitrogen substrates for each treatment were dynamically measured, using the gas-flow-soil-core technique and a paralleling substrate monitoring system. The results showed that CH4 emission was not observed in CK treatment while observed in C treatment. Aggregate emission of greenhouse gases for C + treatment was significantly higher comparing with the CK treatment (P <0. 01). The mass fractions of NO, N20 and N2 emissions in total nitrogen gases emissions were approximately 9% , 35% and 56% for CK treatment, respectively; and approximately 31% , 50% and 19% for C+ treatment, respectively, with significant differences between these two treatments (P < 0.01). The results indicated that carbon substrate concentrations can significantly change the composition of nitrogen gas emissions. The results also implicated that organic fertilizer should not be applied to nitrate-rich paddy soils prior to or during flooding so as to mitigate greenhouse gases emissions. PMID- 25518686 TI - [Effects of chlorides on Cd transformation in a simulated grate incinerator during sludge incineration process ]. AB - The effects of organic chloride-PVC and inorganic chloride-NaCl on Cd partitioning during sludge incineration with adding Cd(CH3COO)2 . 2H2O to the real sludge were investigated using a simulated tubular incineration furnace. And transformation and distribution of Cd were studied in different sludge incineration operation conditions. The results indicated that the partitioning of Cd tended to be enhanced in the fly ash and fule gas as the chloride content increasing. The migration and transformation of Cd-added sludge affected by different chloride were not obvious with the increasing of chloride content. With increasing temperature, organic chloride (PVC) and inorganic chloride (NaC1) can reduce the Cd distribution in the bottom ash. However, the effect of chlorides, the initial concentration and incineration time on Cd emissions had no significant differences. Using SEM-EDS and XRD technique, different Cd compounds including CdCl2, Na2CdCl4, K2CdCl6, K2CdSiO4 and NaCdO2 were formed in the bottom ash and fly ash after adding NaCl to the sludge. In contrast, after adding PVC to the sludge, the Na2CdCl4 and CdCl2 were the main forms of Cd compounds, at the same time, K4CdCI6 and K6CdO4 were also formed. The two different mechanisms of chlorides effects on Cd partitioning were affected by the products of Cd compound types and forms. PMID- 25518687 TI - [Spatial temporal differentiation of product-based and consumption-based CO2 emissions and balance in the Beijing-Tianjin-Hebei region: an economic input- output analysis]. AB - Distinguishing product-based and consumption-based CO2 emissions in the open economic region is the basis for differentiating the emission responsibility, which is attracting increasing attention of decision-makers'attention. The spatial and temporal characteristics of product-based and consumption-based CO2 emissions, as well as carbon balance, in 1997, 2002 and 2007 of JING- JIN-JI region were analyzed by the Economic Input-Output-Life Cycle Assessment model. The results revealed that both the product- based and consumption-based CO2 emissions in the region have been increased by about 4% annually. The percentage of CO2 emissions embodied in trade was 30% -83% , to which the domestic trading added the most. The territorial and consumption-based CO2 emissions in Hebei province were the predominant emission in JING-JIN-JI region, and the increasing speed and emission intensity were stronger than those of Beijing and Tianjin. JING-JIN-JI region was a net inflow region of CO2 emissions, and parts of the emission responsibility were transferred. Beijing and Tianjin were the net importers of CO2 emissions, and Hebei was a net outflow area of CO2 emissions. The key CO2 emission departments in the region were concentrated, and the similarity was great. The inter-regional mechanisms could be set up for joint prevention and control work. - Production and distribution of electricity, gas and water and smelting and pressing of metals had the highest reliability on CO2 emissions, and took on the responsibility of other departments. The EIO-LCA model could be used to analyze the product-based and consumption-based CO2 emissions, which is helpful for the delicate management of regional CO2 emissions reduction and policies making, and stimulating the reduction cooperation at regional scale. PMID- 25518688 TI - [Study on feasible emission control level of air pollutions for cement industry ]. AB - The revised National Emission Standard of Air Pollutions for Cement Industry has been issued, which will be effective for the new enterprises and the existing enterprises on Mar. 1st, 2014 and July 1st, 2015, respectively. In the process of revision, the key technical issues on determination of standard limits was how to determine the feasible emission control level of air pollutions. Feasible emission control requirements were put forward, according to air pollutants emission, technologies, environmental management requirements and foreign standards, etc. The main contents of the revised standard include expanding the scope of application, increasing the pollutants, improving the particulate and NO emissions control level, and increasing special emission limits applied to key areas of air pollutants. The standard will become the gripper of pollution prevention, total emission reduction, structural adjustment and optimization of the layout, and will promote scientific and technical progression for the cement industry. PMID- 25518689 TI - Military children and families: introducing the issue. PMID- 25518690 TI - The demographics of military children and families. AB - Since the advent of the all-volunteer force in the 1970s, marriage, parenthood, and family life have become commonplace in the U.S. military among enlisted personnel and officers alike, and military spouses and children now outnumber service members by a ratio of 1.4 to 1. Reviewing data from the government and from academic and nonacademic research, Molly Clever and David R. Segal find several trends that distinguish today's military families. Compared with civilians, for example, service members marry younger and start families earlier. Because of the requirements of their jobs, they move much more frequently than civilians do, and they are often separated from their families for months at a time. And despite steady increases since the 1970s in the percentage of women who serve, the armed forces are still overwhelmingly male, meaning that the majority of military parents are fathers. Despite these distinguishing trends, Clever and Segal's chief finding is that military families cannot be neatly pigeonholed. Instead, they are a strikingly diverse population with diverse needs. Within the military, demographic groups differ in important ways, and the service branches differ from one another as well. Military families themselves come in many forms, including not only the categories familiar from civilian life--two-parent, single parent, and so on--but also, unique to the military, dual-service families in which both parents are service members. Moreover, military families' needs change over time as they move through personal and military transitions. Thus the best policies and programs to help military families and children are flexible and adaptable rather than rigidly structured. PMID- 25518691 TI - Economic conditions of military families. AB - For military children and their families, the economic news is mostly good. After a period of steady pay increases, James Hosek and Shelley MacDermid Wadsworth write, service members typically earn more than civilians with a comparable level of education. Moreover, they receive many other benefits that civilians often do not, including housing allowances, subsidized child care, tuition assistance, and top-of-the-line comprehensive health care. Of course, service members tend to work longer hours than civilians do, and they are exposed to hazards that civilians rarely, if ever, face. The extra pay they receive when they are deployed to combat zones helps their families cope financially but cannot alleviate the stress. Though service members are relatively well paid, the military lifestyle takes a toll on the earnings of their spouses. Chiefly because the military requires service members to move frequently, spouses' careers are regularly interrupted, and employers are hesitant to offer them jobs that require a large investment in training or a long learning curve. More military spouses than comparable civilian spouses are either unemployed or work fewer hours than they would like, and military spouses overall tend to earn less than their civilian counterparts. Despite the military's relatively high pay, some service members and their families--particularly among the junior enlisted ranks--report financial distress, and a handful even qualify for food stamps. Moreover, precisely because military pay tends to be higher than civilian pay, families may see a drop in income when a service member leaves the armed forces. Finally, the pay increases of recent years have slowed, and force cutbacks are coming; both of these factors will alter the financial picture for service members, possibly for the worse. PMID- 25518692 TI - Military children from birth to five years. AB - Because most research on military families has focused on children who are old enough to go to school, we know the least about the youngest and perhaps most vulnerable children in these families. Some of what we do know, however, is worrisome--for example, multiple deployments, which many families have experienced during the wars in Iraq and Afghanistan, may increase the risk that young children will be maltreated. Where the research on young military children is thin, Joy Osofsky and Lieutenant Colonel Molinda Chartrand extrapolate from theories and research in other contexts--especially attachment theory and research on families who have experienced disasters. They describe the circumstances that are most likely to put young children in military families at risk, and they point to ways that families, communities, the military, and policy makers can help these children overcome such risks and thrive. They also review a number of promising programs to build resilience in young military children. Deployment, Osofsky and Chartrand write, is particularly stressful for the youngest children, who depend on their parents for nearly everything. Not only does deployment separate young children from one of the central figures in their lives, it can also take a psychological toll on the parent who remains at home, potentially weakening the parenting relationship. Thus one fundamental way to help young military children become resilient is to help their parents cope with the stress of deployment. Parents and caregivers themselves, Osofsky and Chartrand write, can be taught ways to support their young children's resilience during deployment, for example, by keeping routines consistent and predictable and by finding innovative ways to help the child connect with the absent parent. The authors conclude by presenting 10 themes, grounded in research and theory, that can guide policies and programs designed to help young military children. PMID- 25518693 TI - Child care and other support programs. AB - The U.S. military has come to realize that providing reliable, high-quality child care for service members' children is a key component of combat readiness. As a result, the Department of Defense (DoD) has invested heavily in child care. The DoD now runs what is by far the nation's largest employer-sponsored child-care system, a sprawling network with nearly 23,000 workers that directly serves or subsidizes care for 200,000 children every day. Child-care options available to civilians typically pale in comparison, and the military's system, embedded in a broader web of family support services, is widely considered to be a model for the nation. The military's child-care success rests on four pillars, write Major Latosha Floyd and Deborah A. Phillips. The first is certification by the military itself, including unannounced inspections to check on safety, sanitation, and general compliance with DoD rules. The second is accreditation by nationally recognized agencies, such as the National Association for the Education of Young Children. The third is a hiring policy that sets educational and other requirements for child-care workers, and the fourth is a pay scale that not only sets wages high enough to discourage the rapid turnover common in civilian child care but also rewards workers for completing additional training. Floyd and Phillips sound a few cautionary notes. For one, demand for military child care continues to outstrip the supply In particular, as National Guard and Reserve members have been activated during the wars in Iraq and Afghanistan, the DoD has sometimes struggled to provide child care for their children. And force reductions and budget cuts are likely to force the military to make difficult choices as it seeks to streamline its child-care services in the years ahead. PMID- 25518694 TI - Resilience among military youth. AB - Much research on children in military families has taken a deficit approach--that is, it has portrayed these children as a population susceptible to psychological damage from the hardships of military life, such as frequent moves and separation from their parents during deployment. But M. Ann Easterbrooks, Kenneth Ginsburg, and Richard M. Lerner observe that most military children turn out just fine. They argue that, to better serve military children, we must understand the sources of strength that help them cope with adversity and thrive. In other words, we must understand their resilience. The authors stress that resilience is not a personal trait but a product of the relationships between children and the people and resources around them. In this sense, military life, along with its hardships, offers many sources for resilience--for example, a strong sense of belonging to a supportive community with a shared mission and values. Similarly, children whose parents are deployed may build their self-confidence by taking on new responsibilities in the family, and moving offers opportunities for adventure and personal growth. As the wars in Iraq and Afghanistan drew more and more service members into combat, the military and civilian groups alike rolled out dozens of programs aimed at boosting military children's resilience. Although the authors applaud this effort, they also note that few of these programs have been based on scientific evidence of what works, and few have been rigorously evaluated for their effectiveness. They call for a program of sustained research to boost our understanding of military children's resilience. PMID- 25518695 TI - How wartime military service affects children and families. AB - How are children's lives altered when a parent goes off to war? What aspects of combat deployment are most likely to put children at risk for psychological and other problems, and what resources for resilience can they tap to overcome such hardships and thrive? To answer these questions, Patricia Lester and Lieutenant Colonel Eric Flake first examine the deployment cycle, a multistage process that begins with a period of anxious preparation after a family receives notice that a parent will be sent into combat. Perhaps surprisingly, for many families, they write, the most stressful part of the deployment cycle is not the long months of separation that follow but the postdeployment period, when service members, having come home from war, must be reintegrated into families whose internal rhythms have changed and where children have taken on new roles. Lester and Flake then walk us through a range of theoretical perspectives that help us understand the interconnected environments in which military children live their lives, from the dynamics of the family system itself to the external contexts of the communities where they live and the military culture that helps form their identity. The authors conclude that policy makers can help military-connected children and their families cope with deployment by, among other things, strengthening community support services and adopting public health education measures that are designed to reduce the stigma of seeking treatment for psychological distress. They warn, however, that much recent research on military children's response to deployment is flawed in various ways, and they call for better-designed, longer-term studies as well as more rigorous evaluation of existing and future support programs. PMID- 25518696 TI - When a parent is injured or killed in combat. AB - When a service member is injured or dies in a combat zone, the consequences for his or her family can be profound and long-lasting. Visible, physical battlefield injuries often require families to adapt to long and stressful rounds of treatment and rehabilitation, and they can leave the service member with permanent disabilities that mean new roles for everyone in the family. Invisible injuries, both physical and psychological, including traumatic brain injury and combat-related stress disorders, are often not diagnosed until many months after a service member returns from war (if they are diagnosed at all-many sufferers never seek treatment). They can alter a service member's behavior and personality in ways that make parenting difficult and reverberate throughout the family. And a parent's death in combat not only brings immediate grief but can also mean that survivors lose their very identity as a military family when they must move away from their supportive military community. Sifting through the evidence on both military and civilian families, Allison Holmes, Paula Rauch, and Stephen Cozza analyze, in turn, how visible injuries, traumatic brain injuries, stress disorders, and death affect parents' mental health, parenting capacity, and family organization; they also discuss the community resources that can help families in each situation. They note that most current services focus on the needs of injured service members rather than those of their families. Through seven concrete recommendations, they call for a greater emphasis on family focused care that supports resilience and positive adaptation for all members of military families who are struggling with a service member's injury or death. PMID- 25518697 TI - Building communities of care for military children and families. AB - Military children don't exist in a vacuum; rather, they are embedded in and deeply influenced by their families, neighborhoods, schools, the military itself, and many other interacting systems. To minimize the risks that military children face and maximize their resilience, write Harold Kudler and Colonel Rebecca Porter, we must go beyond clinical models that focus on military children as individuals and develop a public health approach that harnesses the strengths of the communities that surround them. In short, we must build communities of care. One obstacle to building communities of care is that at many times and in many places, military children and their families are essentially invisible. Most schools, for example, do not routinely assess the military status of new students' parents. Thus Kudler and Porter's strongest recommendation is that public and private institutions of all sorts--from schools to clinics to religious institutions to law enforcement--should determine which children and families they serve are connected to the military as a first step toward meeting military children's unique needs. Next, they say, we need policies that help teachers, doctors, pastors, and others who work with children learn more about military culture and the hardships, such as a parent's deployment, that military children often face. Kudler and Porter review a broad spectrum of programs that may help build communities of care, developed by the military, by nonprofits, and by academia. Many of these appear promising, but the authors emphasize that almost none are backed by strong scientific evidence of their effectiveness. They also describe new initiatives at the state and federal levels that aim to break down barriers among agencies and promote collaboration in the service of military children and families. PMID- 25518698 TI - Unlocking insights about military children and families. AB - As this issue of the Future of Children makes clear, we have much yet to learn about military children and their families. A big part of the reason, write Anita Chandra and Andrew London, is that we lack sufficiently robust sources of data. Until we collect more and better data about military families, Chandra and London say, we will not be able to study the breadth of their experiences and sources of resilience, distinguish among subgroups within the diverse military community, or compare military children with their civilian counterparts. After surveying the available sources of data and explaining what they are lacking and why, Chandra and London make several recommendations. First, they say, major longitudinal national surveys, as well as administrative data systems (for example, in health care and in schools), should routinely ask about children's connections to the military, so that military families can be flagged in statistical analyses. Second, questions on national surveys and psychological assessments should be formulated and calibrated for military children to be certain that they resonate with military culture. Third, researchers who study military children should consider adopting a life-course perspective, examining children from birth to adulthood as they and their families move through the transitions of military life and into or out of the civilian world. PMID- 25518699 TI - Afterword: what we can learn from military children and families. PMID- 25518700 TI - Introduction: Two-generation mechanisms of child development. PMID- 25518701 TI - Two-generation programs in the twenty-first century. AB - Most of the authors in this issue of Future of Children focus on a single strategy for helping both adults and children that could become a component of two-generation programs. Lindsay Chase-Lansdale and Jeanne Brooks-Gunn, on the other hand, look at actual programs with an explicit two-generation focus that have been tried in the past or are currently under way. These explicitly two generation programs have sought to build human capital across generations by combining education or job training for adults with early childhood education for their children. Chase-Lansdale and Brooks-Gunn explain the theories behind these programs and review the evidence for their efficacy. A first wave of such programs in the 1980s and 1990s produced mostly disappointing results, but the evaluations they left behind pointed to promising new directions. More recently, a second wave of two-generation programs--the authors dub them "Two-Generation 2.0"--has sought to rectify the flaws of earlier efforts, largely by building strong connections between components for children and adults, by ensuring that children and adults receive services of equal duration and intensity, and by incorporating advances in both education and workforce development. These Two Generation 2.0 programs are still in their infancy, and we have yet to see clear evidence that they can achieve their goals or be implemented cost-effectively at scale. Nonetheless, Chase-Lansdale and Brooks-Gunn write, the theoretical justification for these programs is strong, their early results are promising, and the time is ripe for innovation, experimentation, and further study. PMID- 25518702 TI - Stress and child development. AB - Children's early social experiences shape their developing neurological and biological systems for good or for ill, writes Ross Thompson, and the kinds of stressful experiences that are endemic to families living in poverty can alter children's neurobiology in ways that undermine their health, their social competence, and their ability to succeed in school and in life. For example, when children are born into a world where resources are scarce and violence is a constant possibility, neurobiological changes may make them wary and vigilant, and they are likely to have a hard time controlling their emotions, focusing on tasks, and forming healthy relationships. Unfortunately, these adaptive responses to chronic stress serve them poorly in situations, such as school and work, where they must concentrate and cooperate to do well. But thanks to the plasticity of the developing brain and other biological systems, the neurobiological response to chronic stress can be buffered and even reversed, Thompson writes, especially when we intervene early in children's lives. In particular, warm and nurturing relationships between children and adults can serve as a powerful bulwark against the neurobiological changes that accompany stress, and interventions that help build such relationships have shown particular promise. These programs have targeted biological parents, of course, but also foster parents, teachers and other caregivers, and more distant relatives, such as grandparents. For this reason, Thompson suggests that the concept of two-generation programs may need to be expanded, and that we should consider a "multigenerational" approach to helping children living in poverty cope and thrive in the face of chronic stress. PMID- 25518703 TI - Intergenerational payoffs of education. AB - Better-educated parents generally have children who are themselves better educated, healthier, wealthier, and better off in almost every way than the children of the less educated. But this simple correlation does not prove that the relationship is causal. Neeraj Kaushal sifts through the evidence from economics and public policy and reviews large national and international studies to conclude that, indeed, education has large intergenerational payoffs in many areas of children's lives, and that these payoffs persist over time. Kaushal shows that, if anything, traditional measures of returns to education--which focus on income and productivity--almost certainly underestimate the beneficial effects that parents' education has on their children. She reports causal positive effects not only on children's test scores, health, and behavior, but also on mothers' behaviors that can affect their children's wellbeing, such as teenage childbearing and substance use. Her findings suggest that, as a component of two-generation programs, helping parents extend their education could go a long way toward reducing inequality across generations and promoting children's healthy development. Thus the rationale for two-generation programs that boost parents' education is compelling. However, Kaushal cautions, the U.S. education system reinforces socioeconomic inequality across generations by spending more money on educating richer children than on educating poorer children. By themselves, then, two-generation programs will not necessarily ameliorate the structural factors that perpetuate inequality in this country. PMID- 25518704 TI - Two-generation programs and health. AB - Parents' health and children's health are closely intertwined--healthier parents have healthier children, and vice versa. Genetics accounts for some of this relationship, but much of it can be traced to environment and behavior, and the environmental and behavioral risk factors for poor health disproportionately affect families living in poverty. Unhealthy children are likely to become unhealthy adults, and poor health drags down both their educational attainment and their income. Because of the close connection between parents' and children's health, write Sherry Glied and Don Oellerich, we have every reason to believe that programs to improve parents' health will improve their children's health as well. Yet few programs aim to work this way, except for a narrow category of programs that target pregnant women, newborns, and very young children. Glied and Oellerich assess these programs, discuss why there are so few of them, and suggest ways to expand them. Their chief conclusion is that structural barriers in the U.S. healthcare system stand in the way of such programs. Some of these barriers have to do with health insurance, access to care, and benefits, but the biggest one is the fact that physicians typically specialize in treating either children or adults, rather than families as a whole. The Affordable Care Act has begun to break down some of these barriers, the authors write, but much remains to be done. PMID- 25518705 TI - Boosting family income to promote child development. AB - Families who live in poverty face disadvantages that can hinder their children's development in many ways, write Greg Duncan, Katherine Magnuson, and Elizabeth Votruba-Drzal. As they struggle to get by economically, and as they cope with substandard housing, unsafe neighborhoods, and inadequate schools, poor families experience more stress in their daily lives than more affluent families do, with a host of psychological and developmental consequences. Poor families also lack the resources to invest in things like high-quality child care and enriched learning experiences that give more affluent children a leg up. Often, poor parents also lack the time that wealthier parents have to invest in their children, because poor parents are more likely to be raising children alone or to work nonstandard hours and have inflexible work schedules. Can increasing poor parents' incomes, independent of any other sort of assistance, help their children succeed in school and in life? The theoretical case is strong, and Duncan, Magnuson, and Votruba-Drzal find solid evidence that the answer is yes- children from poor families that see a boost in income do better in school and complete more years of schooling, for example. But if boosting poor parents' incomes can help their children, a crucial question remains: Does it matter when in a child's life the additional income appears? Developmental neurobiology strongly suggests that increased income should have the greatest effect during children's early years, when their brains and other systems are developing rapidly, though we need more evidence to prove this conclusively. The authors offer examples of how policy makers could incorporate the findings they present to create more effective programs for families living in poverty. And they conclude with a warning: if a boost in income can help poor children, then a drop in income--for example, through cuts to social safety net programs like food stamps--can surely harm them. PMID- 25518706 TI - Parents' employment and children's wellbeing. AB - Since modern welfare reform began in the 1980s, we have seen low-income parents leave the welfare rolls and join the workforce in large numbers. At the same time, the Earned Income Tax Credit has offered a monetary incentive for low income parents to work. Thus, unlike some of the other two-generation mechanisms discussed in this issue of Future of Children, policies that encourage low-income parents to work are both widespread and well-entrenched in the United States. But parents' (and especially mothers') work, writes Carolyn Heinrich, is not unambiguously beneficial for their children. On the one hand, working parents can be positive role models for their children, and, of course, the income they earn can improve their children's lives in many ways. On the other hand, work can impair the developing bond between parents and young children, especially when the parents work long hours or evening and night shifts. The stress that parents bring home from their jobs can detract from their parenting skills, undermine the atmosphere in the home, and thereby introduce stress into children's lives. Unfortunately, it is low-income parents who are most likely to work in stressful, low-quality jobs that feature low pay, little autonomy, inflexible hours, and few or no benefits. And low-income children whose parents are working are more likely to be placed in inadequate child care or to go unsupervised. Two-generation approaches, Heinrich writes, could maximize the benefits and minimize the detriments of parents' work by expanding workplace flexibility, and especially by mandating enough paid leave so that mothers can breastfeed and form close bonds with their infants; by helping parents place their children in high-quality child care; and by helping low-income parents train for, find, and keep a well-paying job with benefits. PMID- 25518707 TI - Family assets and child outcomes: evidence and directions. AB - For poor families, the possession of assets--savings accounts, homes, and the like--has the potential not only to relieve some of the stress of living in poverty but also to make a better future seem like a real possibility. If children in families that own certain assets fare better than children in families without them, then helping poor families build those assets would be an effective strategy for two-generation programs. Indeed, write Michal Grinstein Weiss, Trina Williams Shanks, and Sondra Beverly, plenty of evidence shows that assets are connected to positive outcomes for poor children. For example, young people who have any college savings at all, even a very small amount, are more likely to go to college; children in households with assets score higher on standardized achievement tests; and children of homeowners experience fewer behavioral problems. But this evidence comes from longitudinal data sets and is therefore correlational. Looking for causal relationships, the authors examine the results of experimental programs that opened various types of savings accounts for poor people and matched their contributions. Several of these trials included a control group that did not receive a savings account, making it possible to attribute any positive outcomes directly to the savings accounts rather than to their owners' personal characteristics. These programs dispelled the myth that poor people can't save; participants were generally able to accumulate savings. It's too early to tell, however, whether assets and asset building programs have long-term effects on children's wellbeing, though one experiment found positive impacts on disadvantaged children's social-emotional development at age four. The most promising programs share several features: they are opened early in life; they are opened automatically, with no action required from the recipients; and they come with an initial deposit. PMID- 25518708 TI - B cells produce less IL-10, IL-6 and TNF-alpha in myasthenia gravis. AB - B cells from myasthenia gravis (MG) patients with autoantibodies (Aab) against acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or with no detectable Aab were investigated as cytokine producing cells in this study. B cells were evaluated for memory phenotypes and expressions of IL-10, IL-6 and IL 12A. Induced productions of IL-10, IL-6, IL-12p40, TNF-alpha and LT from isolated B cells in vitro were measured by immunoassays. MG patients receiving immunosuppressive treatment had higher proportions of memory B cells compared with healthy controls and untreated patients. With CD40 stimulation MG patients produced significantly lower levels of IL-10, IL-6. With CD40 and B cell receptor stimulation of B cells, TNF-alpha production also decreased in addition to these cytokines. The lower levels of these cytokine productions were not related to treatment. Our results confirm a disturbance of B cell subpopulations in MG subgroups on immunosuppressive treatment. B cell derived IL-10, IL-6 and TNF alpha are down-regulated in MG, irrespective of different antibody productions. Ineffective cytokine production by B cells may be a susceptibility factor in dysregulation of autoimmune Aab production. PMID- 25518710 TI - Targeting microRNA-122: walking on cutting edge of hepatitis C virus infection therapy. AB - Hepatitis C virus (HCV) infection, with an estimated 170 million carriers worldwide, remains a major cause of chronic liver disease. Current anti-HCV treatments have significant side effects and have met with only partial success. Therefore, a more effective therapeutic modality for HCV infection is needed. The stability and propagation of HCV is dependent on the interaction between its genome and a highly abundant liver microRNA (miRNA), known as microRNA-122 (miR 122). As a conserved host factor that would not be expected to evolve resistance mutations, miR-122 makes an attractive antiviral target. In this review we will discuss how targeting miR-122, using antisense oligonucleotides (ASOs), can be a new anti-HCV treatment. PMID- 25518709 TI - Enantioselective metabolism of primaquine by human CYP2D6. AB - BACKGROUND: Primaquine, currently the only approved drug for the treatment and radical cure of Plasmodium vivax malaria, is still used as a racemic mixture. Clinical use of primaquine has been limited due to haemolytic toxicity in individuals with genetic deficiency in glucose-6-phosphate dehydrogenase. Earlier studies have linked its therapeutic effects to CYP2D6-generated metabolites. The aim of the current study was to investigate the differential generation of the CYP2D6 metabolites by racemic primaquine and its individual enantiomers. METHODS: Stable isotope 13C-labelled primaquine and its two enantiomers were incubated with recombinant cytochrome-P450 supersomes containing CYP2D6 under optimized conditions. Metabolite identification and time-point quantitative analysis were performed using LC-MS/MS. UHPLC retention time, twin peaks with a mass difference of 6, MS-MS fragmentation pattern, and relative peak area with respect to parent compound were used for phenotyping and quantitative analysis of metabolites. RESULTS: The rate of metabolism of (+)-(S)-primaquine was significantly higher (50% depletion of 20 MUM in 120 min) compared to (-)-(R)-primaquine (30% depletion) when incubated with CYP2D6. The estimated Vmax (MUmol/min/mg) were 0.75, 0.98 and 0.42, with Km (MUM) of 24.2, 33.1 and 21.6 for (+/-)-primaquine, (+)-primaquine and (-)-primaquine, respectively. Three stable mono-hydroxylated metabolites, namely, 2-, 3- and 4-hydroxyprimaquine (2-OH-PQ, 3-OH-PQ, and 4-OH PQ), were identified and quantified. 2-OH-PQ was preferentially formed from (+) primaquine in a ratio of 4:1 compared to (-)-primaquine. The racemic (+/-) primaquine showed a pattern similar to the (-)-primaquine; 2-OH-PQ accounted for about 15-17% of total CYP2D6-mediated conversion of (+)-primaquine. In contrast, 4-OH-PQ was preferentially formed with (-)-primaquine (5:1), accounting for 22% of the total (-)-primaquine conversion. 3-OH-PQ was generated from both enantiomers and racemate. 5-hydroxyprimaquine was unstable. Its orthoquinone degradation product (twice as abundant in (+)-primaquine compared to (-) primaquine) was identified and accounted for 18-20% of the CYP2D6-mediated conversion of (+)-primaquine. Other minor metabolites included dihydroxyprimaquine species, two quinone-imine products of dihydroxylated primaquine, and a primaquine terminal alcohol with variable generation from the individual enantiomers. CONCLUSION: The metabolism of primaquine by human CYP2D6 and the generation of its metabolites display enantio-selectivity regarding formation of hydroxylated product profiles. This may partly explain differential pharmacologic and toxicologic properties of primaquine enantiomers. PMID- 25518711 TI - Phylogenetic analysis and recombination events in full genome sequences of apple stem grooving virus. AB - Apple stem grooving virus (ASGV) is one of the most important viral pathogens infecting pome and stone fruit trees worldwide. In this study, with the complete nucleotide sequence of isolate ASGV-T47, which we generated, molecular variation and recombination in ASGV full genomic sequences worldwide were analyzed. ASGV T47 shared 79.7-97.6% nucleotide identity with the other isolates worldwide and had the highest identity with an isolate from Japan. Phylogenetic analysis based on whole genome clustered all 16 isolates from around the world into two groups with no correlation to host or geographical origin. Four isolates were detected to be recombinants. Selection pressure estimation indicated that the two codons at positions 1756 and 1798 are under positive selection, while purifying selection is the primary evolutionary dynamics for ASGV. PMID- 25518712 TI - Distribution of HIV-1 subtypes circulating in Slovakia (2009-2012). AB - Slovakia is one of the European countries reporting a low prevalence of human immunodeficiency virus 1 (HIV-1) infection. The HIV-1 subtype B was previously the most prevalent in Slovakia and mostly associated with men having sex with men (MSM) (Habekova et al., 2010). The aim of this study was to determine the distribution of individual HIV-1 subtypes among the virus-positive individuals diagnosed in 2009-2012 in Slovakia and to compare these data with those from 2004 2008. The HIV-1 subtype B exhibited the highest prevalence (86.1%) and was mostly associated with MSM as stated before. HIV-1 non-B subtypes were found in 13.9% of patients, led by CRF01_AE (6.3%) and followed by subtype C (2.8%), F1 (1.4%), CRF03_AB (1.4%), G (0.7%), CRF02_AG (0.7%), and CRF12_BF (0.7%). The incidence of non-B subtypes varied in 2009-2012, showing a maximum in 2012. MSM represented the main risk group for total HIV-1 (68.1%) as well as B subtype (63.9%) infections in Slovakia. In contrast, the heterosexual contact represented the main route of HIV-1 acquisition of the non-B subtype virus infection. Together with the increase in the number of patients infected with the viruses of non-B subtype also other changes were observed: infections with the viruses of non-B subtype became more common among MSM and not so strongly associated with heterosexual contact. All these findings may help to design the right strategy for retaining of HIV epidemic in Slovakia at low level. PMID- 25518713 TI - Interferon lambda induces antiviral response to herpes simplex virus 1 infection. AB - Lambda interferons (IFN-lambda) are known to induce potent antiviral response in a wide variety of target cells. They activate the same intracellular signalling pathways and have similar biological activities as IFN-alpha/beta, including antiviral activity, but signal via distinct receptor complex, which is expressed in a cell- and species-specific manner. IFN-lambda was reported to induce in vitro marked antiviral activity against various RNA viruses, but corresponding data on DNA viruses are sparse. Therefore we examined the IFN-lambda1 induced antiviral activity against two strains of herpes simplex virus 1, a highly pathogenic ANGpath and moderately pathogenic KOS. The antiviral response was determined in vitro in Vero cells, known as deficient in production of type I IFNs and in Vero E6 cells, responding to viral infection with abundant IFN-lambda production, although deficient in production of type I IFNs. The results showed that IFN-lambda1 induced in Vero cells higher antiviral activity against ANGpath strain than against KOS strain. In Vero E6 cells endogenous IFN-lambda induced higher antiviral activity against ANGpath strain than against KOS strain, but because of the virus induction of IFN-lambda expression the antiviral activity was detected later. The observed differences between the IFN-lambda1-induced antiviral activities against viral strains of various pathogenicity suggest that virus attributes may play role in the antiviral state of cells induced by IFN lambda. PMID- 25518714 TI - Recombinant VP1 protein of duck hepatitis virus 1 expressed in Pichia pastoris and its immunogenicity in ducks. AB - The VP1 gene of duck hepatitis virus type 1 (DHV-1) strain VJ09 was amplified by reverse transcription PCR from the liver of a duckling with clinical symptoms of viral hepatitis. The resulting VP1 cDNA was 720 bp in length and encoded a 240 amino-acid protein. In VP1 gene-based phylogenetic analysis, the VJ09 strain grouped with DHV-1 genotype C. The VP1 gene was inserted into the expression vector pPICZalphaA and expressed in Pichia pastoris. The expressed VP1 protein was purified and identified by western blot analysis. To evaluate the recombinant VP1's immunogenic potential in ducklings, the antibodies raised in the immunized ducklings were titrated by ELISA, and lymphocyte proliferation and virus neutralization assays were performed. The results show that the recombinant VP1 protein induced a significant immune response in ducklings and this could be a candidate for the development of a subunit vaccine against DHV-1 genotype C. PMID- 25518715 TI - Vectors expressing chimeric Japanese encephalitis dengue 2 viruses. AB - Vectors based on self-replicating RNAs (replicons) of flaviviruses are becoming powerful tool for expression of heterologous genes in mammalian cells and development of novel antiviral and anticancer vaccines. We constructed two vectors expressing chimeric viruses consisting of attenuated SA14-14-2 strain of Japanese encephalitis virus (JEV) in which the PrM/M-E genes were replaced fully or partially with those of dengue 2 virus (DENV-2). These vectors, named pJED2 and pJED2-1770 were transfected to BHK-21 cells and produced chimeric viruses JED2V and JED2-1770V, respectively. The chimeric viruses could be passaged in C6/36 but not BHK-21 cells. The chimeric viruses produced in C6/36 cells CPE 4-5 days after infection and RT-PCR, sequencing, immunofluorescence assay (IFA) and Western blot analysis confirmed the chimeric nature of produced viruses. The immunogenicity of chimeric viruses in mice was proved by detecting DENV-2 E protein-specific serum IgG antibodies with neutralization titer of 10. Successful preparation of infectious clones of chimeric JEV-DENV-2 viruses showed that JEV based expression vectors are fully functional. PMID- 25518716 TI - Sensitivity of drug-resistant mutants of hepatitis B virus to poly-IC. AB - The long-term benefits of antiviral treatment are limited by the resistance of hepatitis B virus (HBV). However, the effect of interferon (IFN)alpha treatment on drug-resistant HBVs is so far unknown. We, therefore, investigated the effects of IFN-alpha inducer poly-IC on the replication of HBV mutants resistant to drugs such as lamivudine (LAM), adefovir dipivoxil (ADV) and entecavir (ETV) in mice. HBV DNA and HBV DNA intermediate (RI) were employed as markers of the virus replication and 2',5'-oligoadenylate synthase (OAS) mRNA as a marker of IFN alpha/beta induction. Poly-IC inhibited wtHBV replication and increased levels of OAS mRNA. Compared to the wt virus, the capacity of virus replication was reduced in most LAMr and ETVr mutants except those with mutations rtM(204V+L180M+V173L), and was similary in the ADVr mutants except rt(A121V+N236T). The virus replication was reduced after poly-IC treatment with LAMr and ADVr mutants similary to the wt virus. In contrast, ETVr mutants were resistant to the poly-IC treatment. In conclusion, the capacity of HBV replication and the sensitivity to IFN therapy are influenced by drug-resistant mutations. The IFN therapy may effectively inhibit HBV replication in particular in patients with LAMr or ADVr mutations but not in patients with ETVr mutations. PMID- 25518717 TI - Interleukin 8 enhances the immune response of ducks to avian influenza vaccine. AB - Interleukins are reported to be valuable immunostimulants in enhancing the immune efficiency of conventional vaccines. In this study, the effect of expression of interleukin 8 (IL-8) on the immune response of ducks to avian influenza vaccine was investigated. The results showed that the serum antibody titer, lymphocyte transformation efficiency and serum interferon gamma (IFN-gamma) level of ducks injected with avian influenza vaccine along with a plasmid expressing duck IL-8 were higher than those of ducks injected with conventional immunostimulant Astragalus polysaccharide (APS) or empty plasmid. Therefore, the duck IL-8 may be used as a good immunostimulant to enhance the immune efficiency of avian influenza vaccine in ducks. PMID- 25518718 TI - Association of host tropism of Middle East syndrome coronavirus with the amino acid structure of host cell receptor dipeptidyl peptidase 4. AB - The Middle East syndrome coronavirus (MERS-CoV) is a recently emerging betacoronavirus with high fatality. Recently, dipeptidyle peptidase (CD26, DPP4) was identified as the host cell receptor for MERS-CoV. Interestingly, despite of common presence of DPP4 receptors the binding and infection of various cells shows imminent variability. In this report, we provide a tool for prediction of the host tropism of the virus based on the host receptor binding interface. We found out that, in the binding of MERS-CoV to cells the amino acid residues in lancets 4 and 5 of DPP4 receptor, namely K267, Q286, T288, R317, R336, Q344 A291, L294, and I295 are involved. Changes in these residues correspond to profound decrease in virus binding to cells. The nine residues at the interface between the virus spikes and the lancets 4 and 5 of host DPP4 can be used as a predictive tool for the host tropism and virus affinity to host cell receptors. PMID- 25518719 TI - Analysis of the complete sequences of two biologically distinct Zucchini yellow mosaic virus isolates further evidences the involvement of a single amino acid in the virus pathogenicity. AB - The complete genome sequences of two Slovak Zucchini yellow mosaic virus isolates (ZYMV-H and ZYMV-SE04T) were determined. These isolates differ significantly in their pathogenicity, producing either severe or very mild symptoms on susceptible cucurbit hosts. The viral genome of both isolates consisted of 9593 nucleotides in size, and contained an open reading frame encoding a single polyprotein of 3080 amino acids. Despite their different biological properties, an extremely high nucleotide identity could be noted (99.8%), resulting in differences of only 5 aa, located in the HC-Pro, P3, and NIb, respectively. In silico analysis including 5 additional fully-sequenced and phylogenetically closely-related isolates known to induce different symptoms in cucurbits was performed. This suggested that the key single mutation responsible for virus pathogenicity is likely located in the N-terminal part of P3, adjacent to the PIPO. PMID- 25518720 TI - The flavonoid from Polygonum perfoliatum L. inhibits herpes simplex virus 1 infection. AB - Herpes simplex virus 1 (HSV-1) is one of the most prevalent human pathogens in both industrialized and developing countries. This study was performed to analyze the antiviral activity of purified flavonoid from Polygonum perfoliatum L. against HSV-1 infection in vitro and in vivo. Flavonoid showed no inhibitory effect, when treated before virus infection, but it strongly inhibited viral replication and cell-to-cell spread which was vital for the virus's propagation. The therapeutic effect of the flavonoid in treating HSV-1 induced encephalitis was also investigated in mice. A dose-dependent increase of survival rate and mean survival time (MST) were observed in the flavonoid-treated mice. These results suggested that the flavonoid may be a viable therapeutic option for recurrent HSV-1 infection. PMID- 25518721 TI - Roles of p38 MAPK in the regulation of the inflammatory response to swine influenza virus-induced acute lung injury in mice. AB - Swine influenza virus (SIV), one of the most important zoonotic agents, is associated with major public health concerns. The current study was conducted to investigate the role of p38 mitogen-activated protein kinase (p38 MAPK) in the regulation of the inflammatory response to acute lung injury (ALI) induced by SIV of H9N2 subtype (H9N2-SIV) in mice. For this purpose, BALB/c mice were intranasally infected with 20 LD(50) of H9N2-SIV (infected group), while non infected mice served as control (control group). To assess the effect of p38 MAPK, its specific inhibitor SB203580 was employed followed by SIV infection (SB group). At various times after infection, mouse lungs were subjected to pathological and histological observations and detection of inflammatory cytokines tumor necrosis factor alpha (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 and phosphorylated p38 MAPK. The obtained results showed obvious inflammatory responses, injury and raised levels of inflammatory cytokines and phosphorylated p38 MAPK in the lungs of virus-infected mice. In the mice inoculated with the virus alone, the level of phosphorylated p38 MAPK increased from day 2 and peaked at day 6 post infection (p.i.). However, SB203580 caused lower increases in inflammatory cytokines and phosphorylated p38 MAPK and a milder lung injury. These findings indicate that the activation of p38 MAPK upregulated the inflammatory responses to H9N2-SIV-induced ALI, increased its severity and promoted the production of inflammatory cytokines. PMID- 25518722 TI - Agroinoculation of Carica papaya with infectious clones of papaya mosaic virus. PMID- 25518723 TI - Acute exacerbation of chronic obstructive pulmonary disease among hospitalized patients caused by influenza virus infection. PMID- 25518724 TI - Prevalence of porcine circovirus 2 and virus-specific antibodies in wild boars (Sus scrofa) in Slovakia. PMID- 25518725 TI - Emergence of Val27Ala mutation in M2 protein associated with amantadine resistance in highly pathogenic avian influenza H5N1 viruses in India. PMID- 25518726 TI - "Throwing a rock at their armored tank": civilian authority and military tobacco control. AB - BACKGROUND: Tobacco use is a major cause of chronic disease, disability and death among military personnel and veterans. However, civilian public health and tobacco control advocates have been relatively silent on the issue. Research on the tobacco industry shows a long history of interference in military tobacco policy through relationships with the United States (US) Congress. The military cannot autonomously implement tobacco control, but is subject to Congressional oversight. Thus, the primary obstacles to effective tobacco control in the military are Congressional political opposition and tobacco industry influence, and by extension, a lack of civilian awareness and support in the policy arena. METHODS: As part of a larger project to explore the topic of civilian support for military tobacco control, we analyzed data from focus groups with public health professionals to better understand their sense of agency and authority in regards to military tobacco control. Researchers conducted 4 focus groups with a total of 36 public health professionals at key conferences for those working in public health and tobacco control. Data were coded and the research team developed an interpretive account that captured patterns and variations in the data. RESULTS: Public health and tobacco control participants shared a sense of futility regarding civilian efforts to engage in military tobacco control. This stemmed from feeling ignorant of military culture and structure, identifying powerful discourses that opposed tobacco control, particularly in a military context, and the very-real presence of the tobacco industry lobby throughout the policy process. CONCLUSIONS: A strong public health voice on military tobacco control might serve to begin problematizing the tobacco industry's influence in the military policy arena. As the military moves to institute stronger tobacco control policy, public health and tobacco control professionals should work to engage with and aid its efforts from the outside. Only with such civilian side support can the goal of a tobacco free military be realized. PMID- 25518727 TI - Diffusion of uncharged solutes through human nail plate. AB - Passive diffusion data for uncharged solutes in hydrated human nail plate are collected and compared to the predictions of two theories for diffusion of uncharged solutes in dense keratin matrices. Quantitative agreement between the experimental data and the theories examined is poor. Concerns with both the experiments and the theories are identified and discussed. It is evident from the analysis that magnitude of the experimental nail permeability data may be questioned, as may the extrapolation procedures used to estimate the properties of dense fiber arrays from more dilute systems. Despite these caveats, it can be inferred that the microstructure of the nail plate is more complex than that assumed in the described models. The influence of residual lipids is implicated. More rigorous experiments and theoretical analysis of mass transport in the nail plate system are warranted. Successful completion of these tasks could lead not only to better predictions of transungual drug delivery, but also to better models of skin permeability, if hydrated nail plate can indeed serve as a model for the corneocyte phase of (partially hydrated) stratum corneum. PMID- 25518729 TI - Scaling in complex systems: a link between the dynamics of networks and growing interfaces. AB - We consider growing interfaces as dynamical networks whose nodes are the discrete points of the interface and the edges the physical interactions among them. We map the points of the interface formed at each time into a graph by means of a visibility algorithm. As the corresponding interfaces grow, their visibility graphs change over time. We show that the visibility graphs are all scale free for each time. We use the variance of the node degrees as a measure of the dynamical properties of these graphs. This magnitude reveals an unexpected scaling behaviour of these graphs in both the number of nodes and time. This enables to define three robust exponents that characterize any type of dynamics with more detail than the classical scaling analysis applied directly to the physical interfaces. To check the feasibility of this approach we study and classify six different dynamical processes and estimate their critical exponents. We conclude that the dynamics of physical systems far from equilibrium can be determined by its corresponding visibility network. Indeed, this methodology is able to discern among dynamical processes that hitherto have been classified in the same universality class according to the scaling analysis of their interfaces. PMID- 25518728 TI - Comparative genomic analysis of clinical and environmental strains provides insight into the pathogenicity and evolution of Vibrio parahaemolyticus. AB - BACKGROUND: Vibrio parahaemolyticus is a Gram-negative halophilic bacterium. Infections with the bacterium could become systemic and can be life-threatening to immunocompromised individuals. Genome sequences of a few clinical isolates of V. parahaemolyticus are currently available, but the genome dynamics across the species and virulence potential of environmental strains on a genome-scale have not been described before. RESULTS: Here we present genome sequences of four V. parahaemolyticus clinical strains from stool samples of patients and five environmental strains in Hong Kong. Phylogenomics analysis based on single nucleotide polymorphisms revealed a clear distinction between the clinical and environmental isolates. A new gene cluster belonging to the biofilm associated proteins of V. parahaemolyticus was found in clincial strains. In addition, a novel small genomic island frequently found among clinical isolates was reported. A few environmental strains were found harboring virulence genes and prophage elements, indicating their virulence potential. A unique biphenyl degradation pathway was also reported. A database for V. parahaemolyticus (http://kwanlab.bio.cuhk.edu.hk/vp) was constructed here as a platform to access and analyze genome sequences and annotations of the bacterium. CONCLUSIONS: We have performed a comparative genomics analysis of clinical and environmental strains of V. parahaemolyticus. Our analyses could facilitate understanding of the phylogenetic diversity and niche adaptation of this bacterium. PMID- 25518730 TI - Economic evaluation of implementation strategies in health care. AB - Economic evaluations can inform decisions about the efficiency and allocation of resources to implementation strategies-strategies explicitly designed to inform care providers and patients about the best available research evidence and to enhance its use in their practices. These strategies are increasingly popular in health care, especially in light of growing concerns about quality of care and limits on resources. But such concerns have hardly motivated health authorities and other decision-makers to spend on some form of economic evaluation in their assessments of implementation strategies. This editorial addresses the importance of economic evaluation in the context of implementation science-particularly, how these analyses can be most efficiently incorporated into decision-making processes about implementation strategies. PMID- 25518731 TI - Mortality following Traumatic Brain Injury among Individuals Unable to Follow Commands at the Time of Rehabilitation Admission: A National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems Study. AB - Severe traumatic brain injury (TBI) has been associated with increased mortality. This study characterizes long-term mortality, life expectancy, causes of death, and risk factors for death among patients admitted within the National Institute on Disability and Rehabilitation Research (NIDRR) TBI Model Systems Programs (TBIMS) who lack command following at the time of admission for inpatient TBI rehabilitation. Of the 8084 persons enrolled from 1988 and 2009, 387 from 20 centers met study criteria. Individuals with moderate to severe TBI who received inpatient rehabilitation were 2.2 times more likely to die than individuals in the U.S. general population of similar age, gender, and race, with an average life expectancy (LE) reduction of 6.6 years. The subset of individuals who were unable to follow commands on admission to rehabilitation was 6.9 times more likely to die, with an average LE reduction of 12.2 years. Relative to the U.S. general population matched for age, gender, and race/ethnicity, these non-command following individuals were more than four times more likely to die of circulatory conditions, 44 times more likely to die of pneumonia, and 38 times more likely to die of aspiration pneumonia. The subset of individuals with TBI who are unable to follow commands upon admission to inpatient rehabilitation are at a significantly increased risk of death when compared with the U.S. general population and compared with all individuals with moderate to severe TBI receiving inpatient rehabilitation. Respiratory causes of death predominate, compared with the general population. PMID- 25518732 TI - The efficacy of tumor debulking surgery is improved by adjuvant immunotherapy using imiquimod and anti-CD40. AB - BACKGROUND: Tumor debulking surgery followed by adjuvant chemotherapy or radiotherapy is a standard treatment for many solid malignancies. Although this approach can be effective, it often has limited success against recurrent or metastatic cancers and new multimodality approaches are needed. Adjuvant immunotherapy is another potentially effective approach. We therefore tested the efficacy of the TLR7 agonist imiquimod (IMQ) combined with agonistic anti-CD40 in an incomplete debulking model of malignant mesothelioma. METHODS: Established subcutaneous murine ABA-HA mesothelioma tumors in BALB/c mice were surgically debulked by 75% and treated with either: i) saline; ii) intratumoral IMQ; iii) systemic anti-CD40 antibody, or using a combination of IMQ and anti-CD40. Tumour growth and survival were monitored, and the role of anti-tumor CD4 and CD8 T cells in therapeutic responses was determined. RESULTS: The combination therapy of partial debulking surgery, IMQ and anti-CD40 significantly delayed tumor growth in a CD8 T cell dependent manner, and promoted tumor regression in 25% of animals with establishment of immunological memory. This response was associated with an increase in ICOS+ CD8 T cells and tumor-specific CTL activity in tumor draining lymph nodes along with an increase in ICOS+ CD8 T cells in responding tumours. CONCLUSIONS: We show that the post-surgical environment can be significantly altered by the co-administration of adjuvant IMQ and anti-CD40, resulting in strong, systemic anti-tumor activity. Both adjuvants are available for clinical use/trial, hence this treatment regimen has clear translational potential. PMID- 25518733 TI - A fruitless upstream region that defines the species specificity in the male specific muscle patterning in Drosophila. AB - The muscle of Lawrence (MOL) is a male-specific muscle present in the abdomen of some adult Drosophila species. Formation of the MOL depends on innervation by motoneurons that express fruitless, a neural male determinant. Drosophila melanogaster males carry a pair of MOLs in the 5th abdominal segment, whereas D. subobscura males carry a pair in both the 5th and 4th segments. We hypothesized that the fru gene of D. subobscura but not that of D. melanogaster contains a cis element that directs the formation of the additional pair of MOLs. Successively extended 5' DNA fragments to the P1 promoter of D. subobscura or the corresponding fragments that are chimeric (i.e., containing both melanogaster and subobscura elements) were introduced into D. melanogaster and tested for their ability to induce the MOL to locate the hypothetical cis element. We found that a 1.5-2-kb genomic fragment located 4-6-kb upstream of the P1 promoter in D. subobscura but not that of D. melanogaster permits MOL formation in females, provided this fragment is grafted to the distal ~4-kb segment from D. melanogaster, demonstrating that this genomic fragment of D. subobscura contains a cis element for the MOL induction. PMID- 25518735 TI - Gut microbiota and energy balance: role in obesity. AB - The microbial community populating the human digestive tract has been linked to the development of obesity, diabetes and liver diseases. Proposed mechanisms on how the gut microbiota could contribute to obesity and metabolic diseases include: (1) improved energy extraction from diet by the conversion of dietary fibre to SCFA; (2) increased intestinal permeability for bacterial lipopolysaccharides (LPS) in response to the consumption of high-fat diets resulting in an elevated systemic LPS level and low-grade inflammation. Animal studies indicate differences in the physiologic effects of fermentable and non fermentable dietary fibres as well as differences in long- and short-term effects of fermentable dietary fibre. The human intestinal microbiome is enriched in genes involved in the degradation of indigestible polysaccharides. The extent to which dietary fibres are fermented and in which molar ratio SCFA are formed depends on their physicochemical properties and on the individual microbiome. Acetate and propionate play an important role in lipid and glucose metabolism. Acetate serves as a substrate for de novo lipogenesis in liver, whereas propionate can be utilised for gluconeogenesis. The conversion of fermentable dietary fibre to SCFA provides additional energy to the host which could promote obesity. However, epidemiologic studies indicate that diets rich in fibre rather prevent than promote obesity development. This may be due to the fact that SCFA are also ligands of free fatty acid receptors (FFAR). Activation of FFAR leads to an increased expression and secretion of enteroendocrine hormones such as glucagon-like-peptide 1 or peptide YY which cause satiety. In conclusion, the role of SCFA in host energy balance needs to be re-evaluated. PMID- 25518734 TI - Mycoplasma pneumoniae as a causative agent of community-acquired pneumonia in children: clinical features and laboratory diagnosis. AB - BACKGROUND: Mycoplasma pneumoniae is a common cause of community-acquired pneumonia (CAP) in children. The aim of this study was to assess the prevalence of Mycoplasma pneumoniae infection in children with CAP and find clinical, radiological and laboratory features helpful to diagnose Mycoplasma pneumoniae pneumonia. Furthermore, we evaluated the value of serology, real-time PCR (RT PCR) and culture for the accurate diagnosis of Mycoplasma pneumoniae pneumonia. METHODS: The study included 166 children aged between 1 and 15 years with radiologically confirmed pneumonia. Throat swab specimens were cultured and assessed by RT-PCR for the presence of Mycoplasma pneumoniae. Mycoplasma pneumoniae-specific IgM and IgG antibodies were determined using ELISA in paired sera. RESULTS: Mycoplasma pneumoniae pneumonia was diagnosed in 14.5% CAP cases. Cough (p=0.029), headache (p=0.001) and wheezing (p=0.036) were more frequent in children with Mycoplasma pneumoniae pneumonia compared to children with pneumonia caused by other pathogens. Logistic regression analysis showed that headache (odds ratio [OR] =36.077, p=0.001) and wheezing (OR=5.681, p=0.003) were significantly associated with MP pneumonia. Neither radiological findings, nor common laboratory parameters distinguished Mycoplasma pneumoniae infection in children with CAP. Using IgG serology in paired sera as the gold standard, we found that sensitivity of IgM serology, RT-PCR and culture was equal (81.82%), while specificity values were 100%, 98.6% and 100% respectively. We observed that combination of IgM detection in acute-phase serum and RT-PCR was positive for 91.7% of cases with Mycoplasma pneumoniae infection. CONCLUSIONS: There are no characteristic radiological findings, or routine laboratory tests that would distinguish CAP caused by Mycoplasma pneumoniae from other CAP. It was found that clinical features such as headache and wheezing are indicative for Mycoplasma pneumoniae infection. Furthermore, it was found that during the acute phase of disease, detection of IgM antibodies in combination with RT-PCR allows for precise and reliable diagnosis of Mycoplasma pneumoniae infections in children. PMID- 25518736 TI - Wiskott-Aldrich syndrome iPS cells produce megakaryocytes with defects in cytoskeletal rearrangement and proplatelet formation. AB - Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterised by microthrombocytopenia, complex immunodeficiency, autoimmunity, and haematologic malignancies. It is caused by mutations in the gene encoding WAS protein (WASP), a regulator of actin cytoskeleton and chromatin structure in various blood cell lineages. The molecular mechanisms underlying microthrombocytopenia caused by WASP mutations remain elusive. Murine models of WASP deficiency exhibited only mild thrombocytopenia with normal-sized platelets. Here we report on the successful generation of induced pluripotent stem cell (iPSC) lines from two patients with different mutations in WASP (c.1507T>A and c.55C>T). When differentiated into early CD34+ haematopoietic and megakaryocyte progenitors, the WAS-iPSC lines were indistinguishable from the wild-type iPSCs. However, all WAS iPSC lines exhibited defects in platelet productionin vitro. WAS-iPSCs produced platelets with more irregular shapes and smaller sizes. Immunofluorescence and electron micrograph showed defects in cytoskeletal rearrangement, F-actin distribution, and proplatelet formation. Proplatelet defects were more pronounced when using culture systems with stromal feeders comparing to feeder-free culture condition. Overexpression of WASP in the WAS-iPSCs using a lentiviral vector improved proplatelet structures and increased the platelet size. Our findings substantiate the use of iPSC technology to elucidate the disease mechanisms of WAS in thrombopoiesis. PMID- 25518737 TI - A new chromo-fluorogenic probe based on BODIPY for NO2 detection in air. AB - A novel colorimetric probe for the selective and sensitive detection of NO2 in solution and in air based on a BODIPY core containing an oxime group has been prepared. PMID- 25518738 TI - The chickpea genomic web resource: visualization and analysis of the desi-type Cicer arietinum nuclear genome for comparative exploration of legumes. AB - BACKGROUND: Availability of the draft nuclear genome sequences of small-seeded desi-type legume crop Cicer arietinum has provided an opportunity for investigating unique chickpea genomic features and evaluation of their biological significance. The increasing number of legume genome sequences also presents a challenge for developing reliable and information-driven bioinformatics applications suitable for comparative exploration of this important class of crop plants. RESULTS: The Chickpea Genomic Web Resource (CGWR) is an implementation of a suite of web-based applications dedicated to chickpea genome visualization and comparative analysis, based on next generation sequencing and assembly of Cicer arietinum desi-type genotype ICC4958. CGWR has been designed and configured for mapping, scanning and browsing the significant chickpea genomic features in view of the important existing and potential roles played by the various legume genome projects in mutant mapping and cloning. It also enables comparative informatics of ICC4958 DNA sequence analysis with other wild and cultivated genotypes of chickpea, various other leguminous species as well as several non-leguminous model plants, to enable investigations into evolutionary processes that shape legume genomes. CONCLUSIONS: CGWR is an online database offering a comprehensive visual and functional genomic analysis of the chickpea genome, along with customized maps and gene-clustering options. It is also the only plant based web resource supporting display and analysis of nucleosome positioning patterns in the genome. The usefulness of CGWR has been demonstrated with discoveries of biological significance made using this server. The CGWR is compatible with all available operating systems and browsers, and is available freely under the open source license at http://www.nipgr.res.in/CGWR/home.php. PMID- 25518739 TI - A powerful association test for qualitative traits incorporating imprinting effects using general pedigree data. AB - For qualitative traits and diallelic marker loci, the pedigree disequilibrium test (PDT) based on general pedigrees and its extension (Monte Carlo PDT (MCPDT)) for dealing with missing genotypes are simple and powerful tests for association. There is an increasing interest of incorporating imprinting into association analysis. However, PDT and MCPDT do not take account of the information on imprinting effects in the analysis, which may reduce their test powers when the effects are present. On the other hand, the transmission disequilibrium test with imprinting (TDTI*) combines imprinting into the mapping of association variants. However, TDTI* only accommodates two-generation nuclear families and thus is not suitable for extended pedigrees. In this article, we first extend PDT to incorporate imprinting and propose PDTI for complete pedigrees (no missing genotypes). To fully utilize pedigrees with missing genotypes, we further develop the Monte Carlo PDTI (MCPDTI) statistic based on Monte Carlo sampling and estimation. Both PDTI and MCPDTI are derived in a two-stage framework. Simulation study shows that PDTI and MCPDTI control the size well under the null hypothesis of no association and are more powerful than PDT and TDTI* (based on a sample of nuclear families randomly selecting from pedigrees) when imprinting effects exist. PMID- 25518740 TI - PlexinA polymorphisms mediate the developmental trajectory of human corpus callosum microstructure. AB - PlexinA is a neuronal receptor protein that facilitates axon guidance during embryogenesis. This gene is associated with several neurological disorders including Alzheimer's disease, Parkinson's disease and autism. However, the effect of variants of PlexinA on brain structure remains unclear. We demonstrate that single-nucleotide polymorphisms within the intron and 3'-untranslated region segments of several human PlexinA genes alter the post-natal developmental trajectory of corpus callosum microstructure. This is the first demonstration that PLXNA mediation of neuroanatomical traits can be detected in humans using in vivo neuroimaging techniques. This result should encourage future research that targets specific disease-related polymorphisms and their relevant neural pathways. PMID- 25518743 TI - On the mechanical and electronic properties of thiolated gold nanocrystals. AB - We present a quantitative exploration, combining experiment and simulation, of the mechanical and electronic properties, as well as the modifications induced by an alkylthiolated coating, at the single nanoparticle (NP) level. We determined the response of the NPs to external pressure in a controlled manner using an atomic force microscope tip. We found a strong reduction in their Young's modulus, as compared to bulk gold, and a significant influence of strain on the electronic properties of the alkylthiolated NPs. Electron transport measurements of tiny molecular junctions (NP/alkylthiol/CAFM tip) show that the effective tunnelling barrier through the adsorbed monolayer strongly decreases by increasing the applied load, which translates in a remarkable and unprecedented increase in the tunnel current. These observations are successfully explained using simulations based on the finite element analysis (FEA) and first-principles calculations that permit one to consider the coupling between the mechanical response of the system and the electric dipole variations at the interface. PMID- 25518741 TI - Downregulation of the microRNA-1/133a cluster enhances cancer cell migration and invasion in lung-squamous cell carcinoma via regulation of Coronin1C. AB - Lung cancer is clearly the primary cause of cancer-related deaths worldwide. Recent molecular-targeted strategy has contributed to improvement of the curative effect of adenocarcinoma of the lung. However, such current treatment has not been developed for squamous cell carcinoma (SCC) of the disease. The new genome wide RNA analysis of lung-SCC may provide new avenues for research and the development of the disease. Our recent microRNA (miRNA) expression signatures of lung-SCC revealed that clustered miRNAs miR-1/133a were significantly reduced in cancer tissues. Here, we found that restoration of both mature miR-1 and miR-133a significantly inhibited cancer cell proliferation, migration and invasion. Coronin-1C (CORO1C) was a common target gene of the miR-1/133a cluster, as shown by the genome-wide gene expression analysis and the luciferase reporter assay. Silencing of CORO1C gene expression inhibited cancer cell proliferation, migration and invasion. Furthermore, CORO1C-regulated molecular pathways were categorized by using si-CORO1C transfectants. Further analysis of novel cancer signaling pathways modulated by the tumor-suppressive cluster miR-1/133a will provide insights into the molecular mechanisms of lung-SCC oncogenesis and metastasis. PMID- 25518742 TI - Mutations in the glucocerebrosidase gene are responsible for Chinese patients with Parkinson's disease. AB - Pathological mutations in the glucocerebrosidase gene (GBA) have been suggested to be associated with Parkinson's disease (PD) in various ethnic populations. Most studies on Chinese PD patients have only screened the N370S and L444P mutations in the GBA gene. To investigate the GBA mutations in Chinese population, we performed complete sequencing of the GBA gene in 184 Chinese PD patients and 130 Chinese control individuals. As a result, we identified three novel and nine reported GBA mutations. The novel mutations include 5-bp deletion (c.334_338delCAGAA), L264I and L314V and the nine reported GBA mutations are R163Q, F213I, E326K, S364S, F347L, V375L, L444P, RecNciI and Q497R. The novel 5 bp deletion (CAGAA) produces a short truncated GBA protein of 142 amino acids, which loses major function domains of the 536 amino acids. Our data also reveals that the frequency of GBA mutations within this Chinese PD cohort was 8.7%, which is significantly higher than 1.54% observed in the Chinese control cohort (chi(2) = 7.22, P = 0.0072; odds ratio (OR) = 6.095, 95% confidence interval of OR = 1.546-24.030). The most common L444P mutation accounts 2.74%, which confer more genetic risk for PD in this Chinese population. In conclusion, novel and known GBA mutations were identified and were found to be associated to PD in this Chinese population. PMID- 25518744 TI - Could international compulsory licensing reconcile tiered pricing of pharmaceuticals with the right to health? AB - BACKGROUND: The heads of the Global Fund and the GAVI Alliance have recently promoted the idea of an international tiered pricing framework for medicines, despite objections from civil society groups who fear that this would reduce the leeway for compulsory licenses and generic competition. This paper explores the extent to which an international tiered pricing framework and the present leeway for compulsory licensing can be reconciled, using the perspective of the right to health as defined in international human rights law. DISCUSSION: We explore the practical feasibility of an international tiered pricing and compulsory licensing framework governed by the World Health Organization. We use two simple benchmarks to compare the relative affordability of medicines for governments - average income and burden of disease - to illustrate how voluntary tiered pricing practice fails to make medicines affordable enough for low and middle income countries (if compared with the financial burden of the same medicines for high income countries), and when and where international compulsory licenses should be issued in order to allow governments to comply with their obligations to realize the right to health. An international tiered pricing and compulsory licensing framework based on average income and burden of disease could ease the tension between governments' human rights obligation to provide medicines and governments' trade obligation to comply with the Agreement on Trade-Related Aspects of Intellectual Property Rights. PMID- 25518745 TI - Emotionally induced galactorrhoea in a non-lactating female--"Pseudo- Lactation"? AB - BACKGROUND: Galactorrhoea is a common clinical problem in endocrinology. Visual and auditory cues from the newborn are known to stimulate prolactin secretion in lactating women. However, hyperprolactinaemia and galactorrhoea in a non lactating female due to visual and auditory stimuli from an unrelated newborn has not been reported in the past. We report the first such case of 'pseudo lactation'. CASE PRESENTATION: An 18-year-old girl with type 1 diabetes mellitus presented with galactorrhoea. Apparently galactorrhoea was preceded by seeing the baby, hearing her cries or when remembering her memories. Her menstrual cycles were normal and did not complain of any headache or visual disturbances. She was only on metformin and insulin. Symptoms have rapidly resolved after the newborn was shifted to another location. Examination revealed scanty nipple discharge with gentle pressure. Investigations revealed an elevated serum prolactin of 62.5 ng/mL (2717.4 pmol/L) and fasting plasma glucose of 142 mg/dL (7.9 mmol/L) and HbA1c of 7.6%. Her thyroid function was normal and MRI at the time of galactorrhoea was not available. At 3 months prolactin was normal and MRI revealed only a slight asymmetry of the pituitary without evidence of microadenoma. CONCLUSION: The strong temporal relationship between her symptoms and emotional attachment to the newborn with exclusion of other causes on clinical, biochemical and radiological evidence, raise the possibility that transient hyperprolactinaemia was due to a transient lactotroph hyperplasia and hyper function which had been triggered by the stimulatory cues from the newborn.Emotionally induced "pseudo lactation" may be a rare but important cause for transient hyperprolactinaemia in a non-lactating female. PMID- 25518746 TI - Genetic and environmental contributions to stability in adult obsessive compulsive behavior. AB - This study investigates the relative contribution of genetic and environmental factors to the stability of obsessive-compulsive (OC) symptoms in an adult population-based sample. We collected data from twin pairs and their siblings, using the Padua Inventory Revised Abbreviated, from the population-based Netherlands Twin Register (NTR) in 2002 (n = 10.134) and 2008 (n = 15.720). Multivariate twin analyses were used to estimate the stability of OC symptoms as a function of genetic and environmental components. OC symptoms were found to be highly stable, with a longitudinal phenotypic correlation of 0.63. Longitudinal broad sense heritability was found to be 56.0%. Longitudinal correlations for genetic (r = 0.58 for additive, r = 1 for non-additive genetic factors) and non shared environment (r = 0.46) reflected stable effects, indicating that both genes and environment are influencing the stability of OC symptoms in adults. For the first time, evidence is reported for non-additive genetic effects on the stability of OC symptoms. In conclusion, this study showed that OC symptoms are highly stable across time in adults, and that genetic effects contribute mostly to this stability, both in an additive and non-additive way, besides non-shared environmental factors. These data are informative with respect to adult sample selection for future genetic studies, and suggest that gene-gene interaction studies are needed to further understand the dominance effect found in this study. PMID- 25518747 TI - Substituent effects on the properties of pnicogen-bonded complexes H2XP:PYH2, for X, Y = F, Cl, OH, NC, CCH, CH3, CN, and H. AB - Ab initio MP2/aug'-cc-pVTZ calculations have been carried out on the pnicogen bonded homodimers (PH2X)2 and the binary complexes H2XP:PYH2, for X, Y = F, Cl, OH, NC, CCH, CH3, CN, and H. The binding energies of these complexes are influenced by the nature of the X,Y pair, the intermolecular distance, the relative orientation of the interacting molecules, and the charge-transfer energies from the lone pair of one P to the sigma-hole of the other. Binary complexes with X,Y = F, Cl, OH, and NC, as well as the homodimers, have a trans arrangement of the P-A and P-A' bonds with respect to the P...P bond, with A and A', the atoms of X and Y, respectively, bonded to the P atoms. The trendlines for the homodimers in plots of the binding energy versus the P-P distance, and the binding energy versus the total charge-transfer energy, exhibit better correlations than the trendlines for the binary complexes. The trendlines for the homodimers mark the boundary of the region in which points for the binary complexes appear. Pnicogen-bond radii for P in PH2X molecules have been determined from the P-P distances in the homodimers. The sum of these radii provides an excellent approximation to the P-P distance in the corresponding binary complex. EOM-CCSD spin-spin coupling constants (1p)J(P-P) have also been computed for all complexes. Coupling constants for the dimers and binary complexes exhibit a similar linear increase as the P-P distance decreases. PMID- 25518752 TI - Combating multidrug resistance in bacterial infection by targeting functional proteome with natural products. AB - Antibiotic resistance has become a major clinical and public health problem within the lifetime of most people living today. Development of new therapeutic approaches to prevent antimicrobial chemotherapy from bacterial multidrug resistance has thus been becoming a primary consideration in the medicinal community. In this study, we describe a protocol that is potential for combating multidrug resistance by rational screening of natural medicines to target the bacterial functional proteome. To achieve this, a pipeline of integrating virtual screening and susceptibility testing has been described to identify antibacterial agents from various natural products with diverse structures and high drug likeness. A number of promising candidates with potent antibacterial activity were identified, from which six available compounds were assayed to determine their susceptibility to four multidrug-resistant strains. Consequently, while most tested candidates showed moderate (20 < MIC < 50 MUg/mL) or low (MIC>50 MUg/mL) antibacterial activities, two natural products, i.e. pseudopterosin A and ciprofloxacin, were measured to possess strong broad-spectrum potency combating different strains (MIC < 20 MUg/mL). PMID- 25518756 TI - Post angioplasty coronary artery bypass grafting in patient with myasthenia gravis. AB - A 62 years old patient developed myasthenia gravis 2 years after his percutaneous coronary intervention. He was advised thymectomy for myasthenia gravis. During his cardiological evaluation, he was incidentally diagnosed to have 3 vessel disease. Hence, a simultaneous surgical intervention was performed consisting of thymectomy and CABG via standard cardiopulmonary bypass through median sternotomy. Previous medical history of diabetes and corticosteroid therapy made the patient immunocompromised. Therefore, a careful overall therapeutic strategy was devised to prevent mediastinitis. After his thymectomy and coronary artery bypass grafting, he was extubated within 6 hours. Plasmapheresis was done one day before the surgery and on first postoperative day. His medications for myasthenia gravis (pyridostigmine and prednisolone) were not stopped before and after the surgery. Patient was discharged on 6th postoperative day without any complications. On his follow-up 6 weeks postoperatively, his condition was unremarkable. PMID- 25518757 TI - Mitral valve replacement with preservation of subvalvular apparatus in a patient with familial dextrocardia and situs solitus. AB - Familial dextrocardia with situs solitus is extremely rare entity. Dextrocardia offers a difficult situation to surgeon. A different strategy for cannulation and approach to the left atrium has to be followed. Surgery in such settings has rarely been reported. We present the case of a patient with dextrocardia and situs solitus wherein a left sided approach was adopted for a better exposure of the valve. The patient had a rheumatic regurgitant mitral valve with ruptured chordae to anterior mitral leaflet. Since the valve was severely thickened, it was replaced rather than repaired. The left sided approach provided good exposure of the valve. PMID- 25518754 TI - Evaluation of opioid modulation in major depressive disorder. AB - Although opioids have known antidepressant activity, their use in major depressive disorder (MDD) has been greatly limited by risk of abuse and addiction. Our aim was to determine whether opioid modulation achieved through a combination of a MU-opioid partial agonist, buprenorphine (BUP), and a potent MU opioid antagonist, samidorphan (SAM), would demonstrate antidepressant activity without addictive potential. A placebo-controlled crossover study assessed the opioid pharmacodynamic profile following escalating doses of SAM co-administered with BUP in opioid-experienced adults. A subsequent 1-week, placebo-controlled, parallel-group study was conducted in subjects with MDD and an inadequate response to standard antidepressant therapy. This second study evaluated safety and efficacy of ratios of BUP/SAM that were associated with partial and with maximal blockade of opioid responses in the initial study. Pupillometry, visual analog scale assessments, and self-reported questionnaires demonstrated that increasing amounts of SAM added to a fixed dose of BUP resulted in dose-dependent reductions in objective and subjective opioid effects, including euphoria and drug liking, in opioid-experienced adults. Following 7 days of treatment in subjects with MDD, a 1 : 1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs placebo in HAM-D17 total score (p=0.032) and nearly significant improvement in Montgomery-Asberg Depression Rating Scale (MADRS) total score (p=0.054). Overall, BUP/SAM therapy was well tolerated. A combination of BUP and SAM showed antidepressant activity in subjects with MDD. Balanced agonist antagonist opioid modulation represents a novel and potentially clinically important approach to the treatment of MDD and other psychiatric disorders. PMID- 25518758 TI - Intraprocedural thrombus formation in the left main tract during primary percutaneous coronary intervention. AB - A 67 years old male presented with acute myocardial infarction. Emergency coronary angiography demonstrated subocclusive stenosis in the proximal Left Anterior Descending artery (LAD). Primary Percutaneous Coronary Intervention (PCI) was complicated with intraprocedural thrombosis in the distal Left Main Tract (LMT) following implantation of a stent in the mid LAD. The thrombus was successfully managed with heparin and quadruple antiplatelet therapy (abciximab, aspirin, clopidogrel, and cilostazol) after several attempts of thrombectomy adequate distal flow was achieved. The lesion in the proximal LAD was successfully treated using a kissing stent technique in the second stage. PMID- 25518759 TI - Right ventricular perforation: a rare complication of pulmonary artery catheterization. AB - A 70 years old male underwent Coronary Artery Bypass and Graft (CABG) surgery. After induction, a Pulmonary Artery Catheter (PAC) was inserted via right IJV with some difficulty in achieving PA tracing. During distal RCA anastomosis, surgeon noticed PAC tip coming out of Right Ventricular (RV) surface. Resistance was felt on trying to pull PAC, so it was left there. Cardiac surgeon then opened the Right Atrium (RA) and pulled out the catheter. Multiple attempts during insertion of PA catheter should always raise the suspicion of PAC tip slipping back into the RV. It should be closely monitored during surgery and communicated to the surgeon. PMID- 25518760 TI - Saphenous vein graft pseudoaneurysm: a case for medical management. AB - Saphenous vein bypass pseudoaneurysm is rare but fatal complication after coronary bypass surgery. Pseudoaneurysm is managed either with a surgical or percutaneous approach. This patient underwent quadruple coronary artery bypass grafting 10 years earlier and was referred for recurrence of angina. Coronary and graft angiography revealed a pseudoaneurysm in the saphenous vein graft supplying the intermediate coronary artery. After discussion with the cardiothoracic surgeons, the patient was managed conservatively. He was continued on Aspirin, beta-blockers, statins, nitrates and angiotensin converting enzyme inhibitors. He was followed-up regularly in outpatient clinic with a planned repeat coronary and graft angiography. The patient's symptoms remain stable and repeat angiography 24 months later did not show any significant deterioration of the graft pseudoaneurysm. He remains stable at 12 months after the repeated angiography. PMID- 25518761 TI - Gorlin-Goltz syndrome. AB - A 12 years old girl was presented with bilateral swellings on angle and body of mandible. On general physical examination, there were polydactyly and papular lesions on arm. Histopathology of mandibular lesions revealed odontogenic keratocysts. Marsupialization of the cysts followed by enucleation was done. The patient was reviewed every six months and there was no recurrence at the end of two years. PMID- 25518762 TI - Orf with unusual features. AB - We describe a case of Orf in an immunocompetent man with no history of direct contact with farm animals. The patient presented with numerous large lesions on hands and feet including a lesion in the subungual area. Later on multiple lesions with more bizarre morphology developed on the trunk. The diagnosis was suspected on clinical appearance of the lesion and confirmed later by histopathology. We consider contact with contaminated soil as the possible source of infection as virus can survive in pastures. Awareness of unusual clinical patterns of known entities is important to avoid unnecessary interventions. PMID- 25518763 TI - Primary cutaneous nocardiosis. AB - Nocardiosis is a rare human infection due to ubiquitous soil born gram-positive, filametous aerobic bacteria. First signs are frequently cutaneous either as part of systemic infection disseminated to the skin, or as primary cutaneous inoculation. An 88 years old man presented with a 3-day history of red papules and pustules with pain on his forehead. The combination of the unusual clinical presentation, laboratory examinations, and a favorable response to co-trimoxazole therapy were consistent with a diagnosis of primary cuteneous nocardiosis. Early recognition and treatment of the disease will improve the cure rate. PMID- 25518764 TI - Large hiatal hernia in infancy with right intrathoracic stomach along with left sided morgagni hernia. AB - Congenital diaphragmatic hernia is a very common intrathoracic fetal anomaly with Morgagni hernia typically seen on right side anteriorly and Bochdalek hernia on left side posteriorly, because of the protective effects of liver and heart on either side respectively. Hiatal hernias range from herniation of a small portion of stomach into thoracic cavity to herniation of entire stomach into the left thoracic cavity. Very rarely the herniated stomach has been reported in the right thoracic cavity. Early diagnosis and treatment of all diaphragmatic hernias is essential to reduce the associated morbidity and mortality. We present a very rare and interesting case of an 18 months old baby girl with reverse scenarios. She had a large hiatal hernia with right intrathoracic stomach along with a left sided Morgagni hernia in combination. PMID- 25518765 TI - MTA monoblock obturation technique in endodontic retreatment. AB - A 48-year-old male patient presented to the Department of Endodontics for evaluation of right first permanent molar, which had received non-surgical root canal treatment two years ago and was restored with core material. The presenting symptoms included swelling in the buccal vestibule and pain overnight. Clinical examination demonstrated that the mandibular right first molar was sensitive to percussion and also showed fluctuant swelling in the vestibule proximal to the molar and mild mobility. Radiographic examination revealed a poor quality obturation of the mesial and distal root, distal root resorption, extensive periapical and furcation radiolucency and bone loss. A diagnosis of acute periapical abscess of the mandibular right first molar was made. Tooth was treated non-surgically by the manual application of MTA in the root canal. Follow up evaluation was performed at one year after the treatment. Clinically, treatment was considered successful due to the absence of clinical signs, symptoms and radiographic appearance with substantial reduction (more than 50%) in the diameter of the periapical radiolucency. Mineral trioxide aggregate monoblock obturation technique appears to be a valid technique to obtain periradicular healing in re-treatment of previously root canal treated teeth with periapical lesion. PMID- 25518766 TI - An unusual presentation of Menetrier's Disease. AB - Menetrier's Disease (MD) is a rare acquired hypertrophic gastropathy characterized by giant hypertrophic rugal folds, hypochlorhydria, and hypoproteinemia. The definitive etiology of MD is controversial, although infection with Helicobacter pylori (H. pylori) has been implicated in adults. It presents as a constellation of symptoms including epigastric pain, fatigue, vomiting, weight loss, anorexia, and edema. None of these signs and symptoms is specific for the disease. The gastrointestinal symptoms and the degree of hypoalbuminemia can be profound, the latter resulting from the leakage of protein from the gastric lining. The disease is more common in males. Herein, we report a case of a young woman presenting with the chief complaint of peripheral edema with minimal gastrointestinal symptoms, which was diagnosed as MD on endoscopic evaluation and histopathological examination of gastric biopsy. A high index of suspicion is needed to correctly diagnose this condition for its optimal management. PMID- 25518767 TI - Herniation of the liver: an extremely rare entity. AB - We hereby present the case of a 75 years old female who was complaining of right upper quadrant abdominal pain. She had a history of cystectomy, cholecystectomy and choledochotomy operations for liver hydatid cyst 5 years ago. In addition, multiple endoscopic retrograde cholangiopancreatography sessions had been performed for recurrent biliary duct stones in the last 4 years. Radiological investigations revealed the presence of cirrhosis and the herniation of the left liver lobe through the abdominal incisional hernia defect. Secondary sclerosing cholangitis as a result of the previous operations was suggested to be the probable etiology for cirrhosis. The cirrhotic patient with an advanced age was found to be high risk for surgery. In addition, her symptoms were minimal. Thus, she was managed conservatively. Herniation of the liver is very rare. It is quite difficult to speculate any predisposing risk factors for liver herniation because of the rarity of this condition. PMID- 25518768 TI - Gossypiboma as a cause of intestinal obstruction. AB - Gossypiboma / textiloma / retained surgical sponge is an avoidable surgical complication which can lead to patient morbidity, mortality and profound medicolegal implications. Retained surgical sponge can present early as abscess formation and septic complications or follow a silent course for many years to present later as intestinal obstruction, fistula formation or simply be extruded through rectum. A lady presented 8 months after laparotomy with symptoms of bowel obstruction due to a retained surgical sponge that had eroded into the rectosigmoid junction. The introduction of WHO Safety Checklist in operation theatres where advance tagging systems are not available, would lead to development of standard protocols and help in avoiding the occurrence of such retained surgical foreign bodies. PMID- 25518769 TI - Acuphagia as a cause of gastric bezoar causing gastric outlet obstruction. AB - Acuphagia, the compulsive ingestion of sharp objects is a rare form of Pica. A 25 years old female presented in Outpatient Department with complaints of persistent pain in epigastrium and melena for one month. Initially treated for gastritis, she failed to respond to the therapy. Her upper Gastrointestinal (GI) endoscopy was planned which showed a mass of needles and blades in the fundus of stomach. An attempt was made for endoscopic removal but this was not possible without damaging the esophagus. On inquiring again she gave a history of ingestion of metallic pins and blades after a fight with her husband. She was admitted with a diagnosis of acuphagia. She underwent a formal laparotomy with anterior gastrostomy. A total of 40 shaving blades and 508 sewing machine needles were recovered. Her postoperative recovery was uneventful. Upon discharged, she was referred to Department of Psychiatry for evaluation and treatment. PMID- 25518770 TI - Endoscopic closure of tracheoesophageal fistulas with the over-the-scope clip system. AB - Management of Tracheoesophageal Fistulas (TEFs) is associated with high morbidity and mortality and remains an interdisciplinary challenge. We describe the first two cases of successful endoscopic closure of TEFs due to tracheostomy tube and thoracic hydatid cysts surgery, using the Over-The-Scope Clip (OTSC) system. The OTSC system is composed of an application cap, which is mounted onto the distal tip of the endoscope and a connected releasing mechanism, installed on the handle of the scope. The rotation of the handle allows the release of the clip by a two tube sliding mechanism. Atraumatic version of OTSCs with medium sized caps, twin graspers and anchor were used in these cases. Both fistulae were successfully sealed with one clip. No complication was observed that could be ascribed to the clip itself or to the technique. One patient died because of pneumonia and septicemia after 1 week, but the symptoms of other patient were immediately improved. A thoracic radiography taken after 1 month showed that the clip is in place. Although prospective comparative clinical studies are needed to work out the drawbacks of the new OTSC device, it might be considered as a valid alternative to operation in TEFs. PMID- 25518771 TI - Incidentally discovered giant mucocele of the appendix. AB - Mucocele of the appendix is a rare but well-recognized entity that can mimic several common clinical conditions or present as an incidental radiological or surgical finding at laparotomy. Mucoceles are characterized by distension of the lumen due to accumulation of mucoid substance. They can result from mucosal hyperplasia, mucinous cystadenoma, or mucinous cystadenocarcinoma. If untreated, they may rupture producing the potentially fatal entity Pseudomyxoma peritonei, which is difficult to treat both surgically or medically. Appendectomy is used for simple mucocele or for cystadenoma. Preoperative diagnosis of a mucocele is helpful at the time of surgical intervention with careful mobilization, particularly of large lesions reducing the possibility of rupture and complications. The authors report a case of a 65-year-old man presenting with peritonitis due to a pre-pyloric gastric perforation also having an incidental giant mucocele of the appendix. PMID- 25518772 TI - Mixed ovarian germ cell tumor composed of immature teratoma, yolk sac tumor and embryonal carcinoma. AB - We report the case of a 19-year-old woman experiencing lower abdominal distension and pain. Laboratory tests indicated elevated serum levels of Alpha-Fetoprotein (AFP) and human Chorionic Gonadotropin (hCG). A large mass was detected in the abdomen by physical examination and by transvaginal ultrasonography. Exploratory laparotomy was performed, and a smooth-surfaced, spherical, solid tumor was found on the left ovary, measuring 11.5 x 9.9 x 6.9 cm. Histological evaluation revealed that the tumor consisted of a combination of immature teratoma, Yolk Sac Tumor, and embryonal carcinoma; this is a very rare combination in mixed germ cell tumors. PMID- 25518773 TI - Epithelioid trophoblastic tumor: an unusual malignancy of ovary. AB - Epithelioid Trophoblastic Tumor (ETT) is a distinct but rare variety of gestational trophoblastic tumors. Misdiagnosis delays effective treatment and affects the survival. The case being reported here involved a 43 years old lady presented with 4 months history of intermenstrual per vaginal bleeding and 6 weeks amenorrhea. Workup has revealed pelvic mass. The patient underwent laparotomy with transabdominal hysterectomy and bilateral salpingo-oophorectomy. Histopathology turned out to be clear cell carcinoma of the ovary. Patient was put on chemotherapy but there was progression of disease. Review of histopathology and immunohistochemistry revealed it as Epithelioid Trophoblastic Tumor; serum b-hCG was also raised. The case was really challenging for histopathologist. By the time final diagnosis was made, patient developed extensive metastases in lungs and liver and expired. Such an uncommon yet distinct trophoblastic tumor should be kept in mind by pathologists and treating physicians. PMID- 25518774 TI - Laparoscopically diagnosed invasive mole presenting as acute hemoperitoneum. AB - A young multipara presented with acute abdominal pain. She had history of dilatation and evacuation for a missed miscarriage 2 months back. The diagnosis of ectopic pregnancy was made on the basis of clinical presentation and laboratory investigations. Laparoscopy was performed which revealed features of invasive mole. The procedure was converted to laparotomy and hysterectomy was performed. Patient recovered well. Histopathology confirmed the diagnosis of invasive mole. Follow-up till 12 weeks reported return to normal betahCG (beta subunit of human Chorionic Gonadotropin) levels. PMID- 25518775 TI - Orogenital ulcers of pyoderma gangrenosum resembling sexually transmitted disease. AB - Pyoderma gangrenosum is a non-infectious neutrophilic dermatosis that may be either idiopathic or associated with some underlying diseases like inflammatory bowel diseases, SLE, sarcoidosis, vasculitis etc. It can occur in any part of the body but pyoderma gangrenosum involving oral cavity and genital regions presenting as orogenital ulcers would be clinically quite difficult to be distinguished from Sexually Transmitted Diseases (STDS). We present such a case that was initially managed on the lines of sexually transmitted diseases, which later on came out to be pyoderma gangrenosum, after excluding all other diseases having almost same clinical presentations, on the basis of laboratory results and histopathology. PMID- 25518776 TI - Acute renal failure following multiple wasp stings. AB - Wasp bite induced ATN from direct venom toxicity is very rare. We report two such cases. The first case was a 14 years old boy admitted with oliguria following multiple wasp stings. He had grossly deranged renal function requiring hemodialysis support. The other patient was a 24 years old man admitted with similar history and also required hemodialysis support. Renal biopsy in both cases was consistent with acute tubular necrosis without any casts or other changes, suggesting direct venom toxicity. Both the patients recovered completely after a period of few weeks, highlighting the importance of early detection and treatment of renal failure from wasp venom. PMID- 25518777 TI - A unique MRI presentation of fungal infection in the brain. AB - Fungal infections of CNS are common in certain geographic locations. MRI with or without contrast is a useful prediagnostic tool. However, the findings may sometimes be misleading. In this case report, the authors present unusual imaging findings in the MRI of fungal infection in an immunocompetent host, whereby hyper intense signals were seen on T2-weighted images and patchy post-contrast enhancement was observed with surrounding edema. These findings were suggestive of a neoplastic lesion but it was identified as aspergillosis on subsequent histopathology. This unusual MRI finding of CNS highlights the need to consider fungal infection as a differential diagnosis of all mass lesions on MRI, irrespective of their signal characteristics. PMID- 25518778 TI - Giant supratentorial neurenteric cyst. AB - Intracranial neurenteric cysts are rare congenital lesions that may be mistaken for other cystic neoplastic and nonneoplastic lesions. A 35 years old right handed man presented with a one year history of progressive left hemiparesis, headache, personality changes and seizures. Clinical examination revealed a confused patient with left hemiparesis (power 4/5 in both left upper and lower limbs), upper motor neuron type signs in left half of the body (up going plantar reflex and exaggerated deep tendon reflexes at 3+), left facial weakness of upper motor neuron type. CT scan head with contrast revealed a non-enhancing spherical cystic lesion in the frontotemporoparietal region with minimal to moderate mass effect. The cyst was removed using a combination of hydrodissection and excision. Recovery was complete with no evidence of recurrence or residual disease at 3 months. PMID- 25518779 TI - Acute disseminated encephalomyelitis and thrombocytopenia following Epstein-Barr virus infection. AB - Epstein-Barr Virus (EBV) causes a broad spectrum of disease in humans with several clinical syndromes and is ubiquitous, infecting more than 95% of the world's population. Central Nervous System (CNS) disease alone associated with Epstein-Barr virus rarely occurs in previously healthy individuals. Systemic viral illness in children and complications are rare, but may occur. In few cases, it is associated with a variety of CNS and hematological complications like acute disseminated encephalomyelitis, transverse myelitis, neuropsychiatric syndrome, GBS, autoimmune thrombocytopenia and hemolytic anemia and they usually respond to immunotherapy. We report previously healthy boy, who presented with left sided weakness, headache and thrombocytopenia following EBV infection. The thrombocytopenia was resistant to intravenous immunoglobulin and methylprednisolone but responded well to Rituximab. PMID- 25518780 TI - Delayed Cauda Equina syndrome due to a migratory bullet. AB - A 35 years old man presented with Cauda Equina syndrome caused by a bullet migrating down the spinal canal. The patient initially showed no neurological deficits after the gunshot injury but after 15 months he presented again with urinary and fecal incontinence. Lumbo-sacral X-ray showed a bullet at the level of L5-S1 so he was operated under fluoroscopic guidance. Patient's neurological deficits improved after the operation. In authors' opinion it is vital to do follow-up after a gunshot injury to detect migrating bullet. Decompression of Cauda Equina should be done as soon as the neurological deficits occur. PMID- 25518781 TI - An unusual presentation of endobronchial Hodgkin's lymphoma. AB - Endobronchial involvement of Hodgkin's lymphoma is a rare presentation of the disease. However, it needs to be considered in patients presenting with non resolving pneumonia in the setting of Hodgkin's disease. In such cases, clinicians need to ensure adequate and multiple biopsies as patients may have co existent pulmonary infection and disease involvement. A 16 years old patient reported with a history of relapsed Hodgkin's disease, with bilateral pulmonary infiltrates, that failed to resolve after empiric antibiotic therapy. Positron Emission Tomography (PET) scan was performed demonstrating equivocal uptake in left upper lobe. Bronchoscopy revealed a necrotic endobronchial mass. Initial biopsy only revealed necrotic inflammatory debris, however, since the patient continued to lose weight, repeat biopsy was performed which demonstrated CD 30 positive Hodgkin's lymphoma cells. PMID- 25518782 TI - Bifocal adult embryonal rhabdomyosarcoma. AB - Embryonal rhabdomyosarcoma is commonly seen in young children, its occurrence in the adult population is rare. Here, we describe a 36-year-old male with the diagnosis of adult embryonal rhabdomyosarcoma who was admitted with two large masses protruding from the left side of the neck and lower trunk. Diagnosis was established through biopsy and immunohistochemical studies of the masses. Treatment included surgical resection along with chemotherapy and radiotherapy with complete resolution of masses. Furthermore, a follow-up was scheduled 12 months post-treatment. PMID- 25518783 TI - Mucinous borderline ovarian tumor with ascites. AB - Borderline mucinous tumors are epithelial ovarian tumors with low rate of growth and low potential to invade or metastasize and associated with significantly better prognosis and excellent disease-free survival after surgical removal than other epithelial ovarian cancers. The accepted initial treatment is surgical removal of the tumor. Fertility-sparing surgery may suffice in young patients with tumors confined to the ovary. Radical surgery is recommended in patients with advanced disease and advanced age. Long-term surveillance is recommended to document and treat late recurrences. We report a case of a 59 years old postmenopausal patient with complex ovarian mucinous tumor and gross ascites; she had received three lines of chemotherapeutic agents pre-operatively, without any favorable outcome. Then, she went for staging laparotomy and histopathology showed borderline ovarian mucinous tumor required no further treatment and is fine till date. PMID- 25518784 TI - Partial expression of the Papillon-Lefevre syndrome. AB - Papillon-Lefevre Syndrome (PLS) is a rare autosomal recessive genodermatosis characterized by palmar-plantar hyperkeratosis, and destructive periodontitis. It is transmitted with an estimated frequency of one to four per million individuals. The two hallmarks of the syndrome, dermatological lesions and destructive periodontitis, are known to occur as an independent diseases. We present a unique case of Papillon-Lefevre syndrome in a 28 years old woman with its pathognomonic dermatological features without oral features. PMID- 25518785 TI - Petroclival meningioma: a rare cause of serous otitis media. AB - A 22 years man presented with aural fullness and hearing impairment in his right ear for one year. Otoscopy showed middle ear effusion in the right ear and nasopharyngoscopy revealed a protruding mass on the right side of the nasopharynx. Computed tomography of the nasopharynx showed a large intracranial tumor extending to the infratemporal region via foramen ovale. The patient received staged surgeries and final pathology was diagnosed as meningioma. Approximately 20% of all intracranial tumors are meningiomas and only about 2% of these occur in the petroclival region. Although most meningiomas are benign and asymptomatic, they can cause head and neck manifestations as extending through a skull foramen, across a cranial suture or through a tumor-induced bone defect. Radiographic evaluation is required to rule out this rare clinical entity. PMID- 25518786 TI - Bilateral haemorrhagic vocal cords with supraglottic bruising following blunt laryngeal trauma. AB - Isolated vocal cord haemorrhage secondary to blunt neck trauma is rare. It can lead to compromised airway in a patient with otherwise minimal clinical findings. The authors report a patient with traumatic haemorrhage in the supraglottis and vocal cords. A 24 years old Caucasian male presented with acute hoarseness, dysphagia, and a tender anterior neck swelling 3 hours after he was punched in his neck. There was no stridor or surgical emphysema. Flexible pharyngolaryngoscopy revealed no endolaryngeal mucosal tear but evidence of bleeding into his true vocal cords. The patient was successfully treated with dexamethasone, analgesia and voice rest. The patient refused to stay in hospital for overnight airway monitoring. The authors believe that all patients presenting with a blunt neck trauma should undergo laryngoscopy for assessment and monitoring of the airway. PMID- 25518787 TI - Intra-parotid dermoid cyst: excision through a face lift incision. AB - Intra-parotid dermoid cysts are extremely rare. Clinically, they present like any other parotid lump and pre-operative diagnosis is rarely possible. A 62 years old Caucasian man presented with a painless lump in his right parotid region. The Magnetic Resonance Imaging (MRI) scan revealed a 3 x 3 cm mass in the parotid tail. Cytological examination was unhelpful. The patient underwent successful excision of the cyst through a small face lift incision. No drain was inserted and the patient was discharged home the same day. The patient made an uneventful recovery and was highly satisfied with the aesthetic outcome. The definite histopathological diagnosis was an intra-parotid dermoid cyst. PMID- 25518788 TI - Acute fulminant invasive fungal sinusitis with cavernous sinus syndrome. AB - Acute fulminant invasive fungal sinusitis is most commonly found in immunocompromised patients with conditions such as diabetes mellitus, malignancies and acquired immune deficiency syndrome. The most common pathogens are Aspergillus and Mucoraceae and the sinus most frequently involved is the maxillary sinus. Fever, rhinorrhea, facial pain, headache, and diplopia are common presenting symptoms. Complications of this infection include intracranial and / or intraorbital spread of the infection; the prognosis is poor. Here, a rare case of acute fulminant invasive fungal sinusitis with cavernous sinus syndrome is reported. PMID- 25518789 TI - Congenital extrusion of testis (scrotoschisis). AB - A one-day, full term newborn, born to a healthy mother presented with exposed right testicle out of right hemiscrotum since birth. Physical examination showed normal looking testicle and spermatic cord, which was stained with meconium. All baseline investigations and ultrasound of abdomen were within normal limits. There was no visible associated anomaly. Scrotum was explored and viable testis was repositioned. Postoperative recovery was uneventful. At three months follow up, testicle was good in size and normal in position. PMID- 25518790 TI - Torsion of a wandering spleen: an unusual abdominal catastrophe. AB - Wandering spleen is a rare clinical entity characterised by splenic hypermobility resulting from laxity or maldevelopment of the suspensory gastrosplenic, splenorenal, and phrenicocolic ligaments. Diagnosis is quite difficult, especially in children because of the lack of symptoms and signs until splenic torsion have occurred. An array of investigations is possible but US with color Doppler, CT with intravenous contrast and MRI are frequently being used to diagnose wandering spleen with or without torsion. We present a case of 5 years old child with torsion of wandering spleen to highlight the importance of prompt diagnosis and management. PMID- 25518791 TI - Touraine-Solente-Gole syndrome in two siblings. AB - Hypertrophic Osteoarthropathy secondary to various causes is not a common entity but primary hypertrophic osteoarthropathy (also called Touraine-Solente-Gole Syndrome) is an extremely rare genetic disorder. It was first described in 1868 by Friedrich and has premier features of clubbing, periostosis and pachydermia. Based on clinical manifestations Touraine Solente and Gole distinguished it into three forms as complete, incomplete and fruste form. Most of the cases described up till now had onset in late adolescence. This report describes two siblings having symptoms consistent with Touraine-Solente-Gole Syndrome which had onset in early childhood. PMID- 25518792 TI - An infant with biliary ascites. AB - Biliary ascites in children due to perforation of bile duct is a rare entity. The exact pathogenesis is not known but there are proposed mechanisms including congenital weakness of ductal wall, pancreaticobiliary malunion, tuberculosis, necrotizing enterocolitis and rupture of choledochal cyst. Presentation may be acute or sub-acute. Progressive insidious course is the common presentation in children with jaundice, clay colored stool, abdominal distension with slightly elevated liver enzymes but well documented cholestasis. Clinical suspicion with ultrasound, CT, MRCP and ascitic tap provides clue to the diagnosis. Both conservative and surgical interventions are in practice for managing these children. We report a 7 months old infant with biliary ascites due to perforation of bile duct. PMID- 25518793 TI - Congenital amegakaryocytic thrombocytopenia with multiple physical anomalies in a female neonate. AB - Congenital Amegakaryocytic Thrombocytopenia (CAMT) is a rare disorder of infancy characterized by isolated thrombocytopenia along with hypoplasia or aplasia of megakaryocytes in the bone marrow. It is caused by c-mpl mutation which disrupts the function of thrombopoietin (TPO) receptor. CAMT in association with physical anomalies is a rare entity with only limited data from single case reports being available. Here we present a case of 35 days neonate who had CAMT together with facial malformations and cardiac defects. PMID- 25518794 TI - Acute disseminated encephalomyelitis: an uncommon presentation of hyper IgE syndrome. AB - The hyper-immunoglobulin E (IgE) syndrome (HIES), also known as Job's syndrome is a rare primary immunodeficiency characterized by the clinical triad of recurrent staphylococcal abscesses of skin, recurrent cyst-forming pneumonia, and an elevated serum IgE level of > 2000 IU/ml. Although, most cases are sporadic, families with autosomal dominant (AD-HIES) and recessive (AR-HIES) traits have been reported. Very few articles were published previously on central nervous system abnormalities with definite neurologic manifestations which may vary from partial facial nerve paralysis to hemiplegia in children but Acute Disseminated Encephalomyelitis (ADEM) in a child with HIES hitherto has not been reported. Here we describe a 5-year-old male child with HIES who presented with neurologic manifestations of ADEM. PMID- 25518795 TI - Disseminated Bacille Calmette-Guerin (BCG) disease in an infant with severe combined immunodeficiency. AB - Bacille Calmette-Guerin (BCG) vaccine is administered to all newborns in countries where tuberculosis is still endemic. It is a live attenuated vaccine and considered quite safe in immunocompetent children. Disseminated BCG disease is the most serious complication seen only in individuals with underlying primary or secondary immunodeficiencies. We report a case of disseminated BCG disease in an infant with Severe Combined Immunodeficiency (SCID) who received BCG administration prior to diagnosis of SCID. PMID- 25518796 TI - Vascular Ehlers-Danlos syndrome: a rare disorder presenting with focal convulsions. AB - Vascular Ehlers-Danlos Syndrome (VEDS), previously called Ehlers-Danlos syndrome type-IV, is a heterogeneous group of heritable connective tissue disorders characterized by thin, translucent skin, easy bruising, arterial, intestinal, and/or uterine fragility. There is large vessel involvement that leads to arterial rupture often preceded by aneurysm, arteriovenous fistulae, or dissection. Noninvasive imaging studies such as CT angiography and MR angiography are preferred as diagnostic studies for this condition. We are reporting a 4 years old girl who was presented with right sided unilateral convulsions and hypertension. CT angiogram showed stenosis with post-stenotic dilatation of coeliac and superior mesenteric arteries. There were extensive calcified plaques with atherosclerotic changes in the segment of right common iliac artery with aneurysmal dilatation of celiac, superior mesenteric and common iliac artery. Radiological findings were consistent with vascular Ehlers-Danlos syndrome. She was successfully managed with anti-hypertensive and anticonvulsants. PMID- 25518797 TI - Hair-cotton threads bezoar in two years child. AB - We report a case of 2 years old male child who presented with acute intestinal obstruction with palpable and mobile mass in the abdomen. He was diagnosed as a case of intestinal obstruction due to phytobezoar containing cotton threads. Surgical intervention is the treatment of choice for such conditions. Small bowel obstruction due to bezoar made of hair cotton threads is extremely rare. These cases are rarely reported in paediatric age group. PMID- 25518798 TI - Phenytoin induced toxic epidermal necrolysis. AB - Toxic Epidermal Necrolysis (TEN) which is characterized by the detachment of the epidermis from the dermis is a rare (1.89/1.000.000 annually) and potentially life-threatening condition. The overall mortality is 20 - 30%. TEN is characterized by sudden apoptosis of keratinocytes leading to mucous membrane erosions and epidermal detachment; detachment of less than 10% of the total body surface area defines Stevens-Johnson Syndrome (SJS); when greater than 30%, it defines TEN, while intermediate cases are called SJS/TEN overlap. Many drugs, including prednisolone, cyclosporin, and intravenous immunoglobulin (IVIG), have been used in an attempt to halt the disease process. The use of phenytoin as a prophylactic anticonvulsant after brain surgery, particularly for brain tumors, is a common practice, regardless of whether the patient has a previous history of convulsions. This report described a case of haemorrhagic stroke where phenytoin use induced TEN. PMID- 25518799 TI - Coexisting pulmonary tuberculosis and unsuspected bronchial foreign body removed by fiberoptic bronchoscopy after 42 years. AB - Aspiration of foreign bodies into the tracheobronchial tree is extremely rare in adults without an underlying predisposing factor. A high index of suspicion is the most important factor leading to a diagnosis of tracheobronchial foreign body aspiration. Unless the patients give a clear history of aspiration, a foreign body may remain occult for years. To our knowledge, the longest bronchial foreign body retention in an adult recorded in English literature is 40 years. We present a case of coexisting pulmonary tuberculosis and unsuspected foreign body which remained in the bronchus of an adult for 42 years before the diagnosis. PMID- 25518801 TI - Multiple pulmonary artery aneurysms: a rare cause of massive hemoptysis as presentation of Behcet's disease. AB - We report a case of an acute episode of massive hemoptysis in a diagnosed patient of Behcet's disease, managed conservatively, using angio-guided vascular plug and coils for occluding the multiple bilateral pulmonary artery aneurysms with thoracic surgery backup. The episode of massive hemoptysis was caused by ruptured Pulmonary Artery Aneurysms (PAA). PMID- 25518800 TI - Pneumonia caused by diesel fuel aspiration. AB - An 18 years old Turkish boy was admitted to hospital due to cough, chest pain and shortness of breath for 4 days. Twentyfour hours before the onset of symptoms, the patient had accidentally aspirated diesel while siphoning from the fuel tank of a car. On admission, he was febrile and tachypnoeic. There were fine crackles on auscultation of the lungs. Chest X-ray revealed bilateral infiltration in the lower lung zones. Arterial blood gas analysis showed pH of 7.42, PaO2 of 45.6 mmHg, PaCO2 of 41.3 mmHg and oxygen saturation of 85.2%. He was treated with course of corticosteroid, antibiotic and oxygen supplementation. Chest X-ray showed near-complete resolution 2 weeks after discharge. PMID- 25518802 TI - Vestibular schwannoma: an unusual post radiotherapy response. AB - Vestibular schwannoma is a relatively uncommon tumor. Although, it is benign but locally expansile and spreads to damage the adjacent structures. Treatment strategy includes surgery, Stereotactic Radiosurgery (SRS) either by standard or hypofractionated protocols. Due to its benign nature, radiation therapy cannot remove the tumor completely, instead radiation therapy halts the growth of vestibular schwannoma and inactivates this benign tumor. Response of radiation in the form of tumor shrinkage is seen 2 - 2.5 years after the radiations. We report a case of vestibular Schwannoma in which residual tumor of 3.1 cm size following subtotal resection was irradiated of the dose of 54 Gy in 30 equal fractions on 3 Dimensional Conformal Radiation Therapy (3-DCRT). A follow-up CT scan brain after 2 months of radiotherapy showed complete disappearance of the disease categorized as complete response. This is an unusual phenomenon and is likely due to the very rarely seen malignant transformation or presence of malignant component in this benign tumor. PMID- 25518803 TI - Cataract in a preterm newborn: a possible side effect of linezolid therapy. AB - Cataract may cause visual loss especially in the newborn period if early and urgent intervention is not managed. Approximately 1/3 of cases are congenital, 1/3 are related with systemic diseases and the remaining 1/3 are idiopathic or sporadic. The prevalence of congenital cataract in developed countries is estimated as 1 - 3 per 10,000 live births. There are a number of medicines besides systemic and infectious diseases which may cause cataract. Linezolid is a member of the oxazolidinone antibiotic family which can be used in serious infections caused by vancomycin resistant E. faecium (VRE), methicillin resistant S. aureus (MRSA), methicillin resistant coagulase negative staphylococci and penicillin resistant S. pneumonia in infants and children. Side effects are reported as diarrhea, vomiting, headache, transaminase elevation, rashes and optic neuropathy. Herein, we report a preterm newborn who developed thrombocytopenia and bilateral cataracts during linezolid therapy and relieved one week after the discontinuation of the therapy. PMID- 25518804 TI - Lead toxicity in battery workers. AB - Lead poisoning is a medical condition caused by increased levels of lead in the body. Routes of exposure include contaminated air, water, soil, food and consumer products. Occupational exposure is the main cause of lead poisoning in the adults. Two cases of occupational lead poisoning in adult battery workers are hereby presented. Both male patients had initial non-specific symptoms of intermittent abdominal pain, fatigue and headache for 6 - 8 years. Later on, they developed psychosis, slurred speech, tremors of hands and initially underwent treatment for Parkinsonism and Wilson's disease because of clinical misdiagnosis. They were diagnosed with lead poisoning later and were treated successfully with lead chelator (CaNa2 EDTA). PMID- 25518805 TI - 2014 ABJS Earl McBride Lecture: Disruptive innovation: orthopaedics in the 21st century. PMID- 25518807 TI - Lipoid Proteinosis Resulting from a Large Homozygous Deletion Affecting Part of the ECM1 Gene and Adjacent Long Non-coding RNA. PMID- 25518806 TI - Does Patient Sex Affect the Rate of Mortality and Complications After Spine Surgery? A Systematic Review. AB - BACKGROUND: Available studies disagree regarding the influence of patient sex on mortality and complications after spine surgery. We sought to conduct a systematic review and pool the results of existing research to better understand this issue. QUESTIONS/PURPOSES: We performed a systematic review to address two questions: (1) Does sex (male versus female) influence mortality after spine surgery? (2) Does sex impact the development of postoperative complications after spine surgery? METHODS: This systematic review was performed through a query of PubMed using a structured search algorithm. Additional queries of Embase, SCOPUS, Web of Science, and the tables of contents of orthopaedic and neurosurgical journals were also conducted using search terms such as "sex factors", "male or female", "risk factors", and "spine surgery". Selected papers were independently abstracted by three of the authors (AJS, ENR, EIW) and pooling was performed. Our literature search returned 720 studies, of which 99 underwent full review. Of these, 50 were selected for final abstraction. The Cochrane Q test was used to assess study heterogeneity; significant study heterogeneity was present and so a random-effects model was used. A Harbord test was used to evaluate for the presence of publication bias; this analysis found no statistically significant evidence of publication bias. RESULTS: Males were at increased odds of mortality after spine surgery (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.35 1.97; p<0.001). No differences between the sexes were identified for the odds of complications (OR, 1.04; 95% CI, 0.95-1.13; p=0.42). CONCLUSIONS: Our results determined that males were at elevated odds of mortality but not of complications after spine surgery. These results should be used to inform preoperative discussion and decision-making at the time of surgical consent. Future work should be directed at determining the underlying factors responsible for increased mortality among males and prospective studies specifically designed to evaluate sex-based differences in outcomes after spine surgery. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25518809 TI - Growth Charts for Individuals with Mucopolysaccharidosis VI (Maroteaux-Lamy Syndrome). AB - BACKGROUND: The skeletal phenotype of mucopolysaccharidosis VI (MPS VI) is characterized by short stature and growth failure. OBJECTIVE: The purpose of this study was to construct reference growth curves for MPS VI patients with rapidly and slowly progressive disease. METHODS: We pooled cross-sectional and longitudinal height for age data from galsulfase (Naglazyme((r)), BioMarin Pharmaceutical Inc.), treatment naive patients (n = 269) who participated in various MPS VI studies, including galsulfase clinical trials and their extension programs, the MPS VI clinical surveillance program (CSP), and the MPS VI survey and resurvey studies, to construct growth charts for the MPS VI population. There were 229 patients included in this study, of which data from 207 patients <=25 years of age with 513 height measurements were used for constructing reference growth curves. RESULTS: Height for age growth curves for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles were constructed for patients with rapidly and slowly progressing disease defined by the pre-enzyme replacement therapy (ERT) uGAG levels of > or <=200 MUg/mg creatinine. The mean (SD) pre-ERT uGAG levels were 481.0 (218.6) and 97.8 (56.3) MUg/mg creatinine for the patients <=25 years of age with rapidly (n = 131) and slowly (n = 76) progressing MPS VI disease, respectively. The median growth curves for patients with <= and >200 MUg/mg creatinine were above and below the median (50th percentile) growth curve for the entire MPS VI population. CONCLUSION: MPS VI growth charts have been developed to assist in the clinical management of MPS VI patients. PMID- 25518810 TI - Practical quantum private query of blocks based on unbalanced-state Bennett Brassard-1984 quantum-key-distribution protocol. AB - Until now, the only kind of practical quantum private query (QPQ), quantum-key distribution (QKD)-based QPQ, focuses on the retrieval of a single bit. In fact, meaningful message is generally composed of multiple adjacent bits (i.e., a multi bit block). To obtain a message a1a2...al from database, the user Alice has to query l times to get each ai. In this condition, the server Bob could gain Alice's privacy once he obtains the address she queried in any of the l queries, since each a(i) contributes to the message Alice retrieves. Apparently, the longer the retrieved message is, the worse the user privacy becomes. To solve this problem, via an unbalanced-state technique and based on a variant of multi level BB84 protocol, we present a protocol for QPQ of blocks, which allows the user to retrieve a multi-bit block from database in one query. Our protocol is somewhat like the high-dimension version of the first QKD-based QPQ protocol proposed by Jacobi et al., but some nontrivial modifications are necessary. PMID- 25518808 TI - The tumour suppressor DLC2 ensures mitotic fidelity by coordinating spindle positioning and cell-cell adhesion. AB - Dividing epithelial cells need to coordinate spindle positioning with shape changes to maintain cell-cell adhesion. Microtubule interactions with the cell cortex regulate mitotic spindle positioning within the plane of division. How the spindle crosstalks with the actin cytoskeleton to ensure faithful mitosis and spindle positioning is unclear. Here we demonstrate that the tumour suppressor DLC2, a negative regulator of Cdc42, and the interacting kinesin Kif1B coordinate cell junction maintenance and planar spindle positioning by regulating microtubule growth and crosstalk with the actin cytoskeleton. Loss of DLC2 induces the mislocalization of Kif1B, increased Cdc42 activity and cortical recruitment of the Cdc42 effector mDia3, a microtubule stabilizer and promoter of actin dynamics. Accordingly, DLC2 or Kif1B depletion promotes microtubule stabilization, defective spindle positioning, chromosome misalignment and aneuploidy. The tumour suppressor DLC2 and Kif1B are thus central components of a signalling network that guides spindle positioning, cell-cell adhesion and mitotic fidelity. PMID- 25518812 TI - Lewandowsky's Rosaceiform Eruption: a Form of Cutaneous Tuberculosis Confirmed by PCR in Two Patients. AB - INTRODUCTION: Cutaneous tuberculosis (TBC) is a chronic disease caused by Mycobacterium tuberculosis, and is present in less than 1-2% of all TBC cases. The current problem with diagnosis is the demonstration of bacillus in the skin, especially paucibacillar forms, where sources like polymerase chain reaction (PCR) have improved diagnostic capacity. CASE PRESENTATION: Two cases of cutaneous TBC are reported. The first patient was 52-year-old woman with facial erythematous papulo-nodular lesions which had been developing for 4 months, and had previously been treated as acne rosacea, with partial response. Histopathological studies showed chronic granulomatous inflammation. TBC was suspected, so PCR was performed, which showed positive for M. tuberculosis. The second case was a 43-year-old woman with a facial rosaceiform plaque which began 6 months previously, and was treated as rosacea without any change for 5 months. Skin biopsy and PCR were positive for TBC. Both cases were treated using primary schedule for TBC, and both presented a favorable response. DISCUSSION: A clinical profile called Lewandowsky's rosacea-like eruption has been previously described. The condition has been questioned for years and was later removed from the spectrum of tuberculids and cutaneous TBC for not being able to isolate microorganisms in skin samples, a situation that might now change. In paucibacillar forms, when culture and staining are negative and TBC is still suspected, it is recommended to use DNA amplification by PCR for an accurate diagnosis. Both cases bring up the concern about once again bringing Lewandowsky's rosaceiform eruption into the spectrum of cutaneous TBC, and the discussion about the current definition of tuberculid. PMID- 25518811 TI - Risk factors for colorectal neoplasms based on colonoscopy and pathological diagnoses of Chinese citizens: a multicenter, case-control study. AB - PURPOSE: Since observational data in the urban residents are required to better assess the risk factors of colorectal neoplasm occurrence and the effectiveness of colonoscopy screening and surveillance, we conducted a case-control study at multicenters in China to identify patient characteristics and neoplasm features of colorectal adenoma (CRA) and colorectal carcinoma (CRC). METHODS: A total of 4089 patients who had undergone a colonoscopy from 19 hospitals were enrolled, of which 1106 had CRA and 466 had CRC. They were compared with controls. The analysis provides features and risk factors of colorectal neoplasm using multivariate logistic regression. RESULTS: Increasing age, a family history of colorectal cancer or previous cases of colorectal adenoma or hypertension disease, gastrointestinal surgery, regular intake of pickled food (adjusted odds ratio [aOR] 1.42, 95 % confidence interval [CI], 1.048-1.924), consumption of alcohol, and a positive result of fecal occult blood testing (FOBT; aOR 2.509, 95 % CI 1.485-4.237) were associated with an increased risk of CRA. In the CRC group, increasing age, regular intake of pickled foods, and a positive FOBT result were risk factors. In addition, a positive abdominal computed tomography (CT) before a colonoscopy and physical signs of emaciation were also significantly associated with an increasing risk of colorectal carcinoma. Regular intake of vegetables decreased the risk of both CRA and CRC. CONCLUSIONS: Age, pickled foods, and a positive FOBT are risk factors for colorectal neoplasm. Vegetable intake was associated with a decreased risk of CRA and CRC. PMID- 25518815 TI - MR imaging findings of mass-forming endosalpingiosis in both ovaries: a case report. AB - A 50-year-old postmenopausal woman, who underwent ultrasonography at a periodic medical checkup, was found to have bilateral ovarian masses. Pelvic magnetic resonance imaging (MRI) showed bilateral multilocular cystic ovarian masses. The cyst walls and septal structure demonstrated contrast enhancement. She underwent bilateral salpingo-oophorectomy. Microscopic examination revealed that the cysts were lined with cuboidal or columnar epithelial cells, and some of the cells were ciliated. The final histopathological diagnosis was endosalpingiosis. Endosalpingiosis is defined as the presence of ectopic ciliated epithelium, resembling the normal endosalpinx, without endometrial stroma. It rarely presents as a tumor-like mass on MRI. PMID- 25518813 TI - Periodontal treatment outcomes during pregnancy and postpartum. AB - OBJECTIVE: This study was conducted to compare periodontal therapy outcomes during pregnancy and after delivery. MATERIALS AND METHODS: One hundred nine pregnant women up to the 20th gestational week (GW) were randomized into two groups: the test group (comprehensive periodontal therapy during pregnancy) and the control group (comprehensive periodontal therapy after delivery). Periodontal examinations comprised plaque index (PI), gingival index (GI), periodontal probing depth (PPD), clinical attachment level (CAL), bleeding on probing (BOP), and gingival crevicular fluid (GCF) volume. After baseline examination, women in the test group received periodontal treatment up to the 24th GW. The final examination was performed at the 26th to the 28th GW. Women in the control group were treated 30 days after delivery and reexamined 30 days after treatment. RESULTS: Periodontal therapy significantly reduced periodontal inflammation in both groups. The mean percentage of sites with BOP was reduced from 49.14 % (+/ 22.49) to 11.10 % (+/-7.84) and from 45.71 % (+/-17.86) to 8.07 % (+/-5.21) in the test and control groups, respectively (p = 0.95). No statistically significant differences were observed between groups concerning PI, GI, PPD, CAL, and GCF. The reduction in mean percentage of sites with BOP stratified for initial PPD >=4 mm was higher in the control group (p < 0.01), but no differences were seen regarding GCF in these sites. CONCLUSIONS: Hormonal changes during pregnancy do not interfere in treatment outcomes in women with widespread gingival inflammation and limited periodontal destruction. The role of these hormonal changes in pregnant women with different disease patterns remains uncertain. CLINICAL RELEVANCE: Periodontal health can be reestablished irrespective of the hormonal challenge that takes place during pregnancy. PMID- 25518814 TI - Effect of bone graft density on in vitro cell behavior with enamel matrix derivative. AB - OBJECTIVES: Bone replacement grafting materials play an important role in regenerative dentistry. Despite a large array of tested bone-grafting materials, little information is available comparing the effects of bone graft density on in vitro cell behavior. Therefore, the aim of the present study is to compare the effects of cells seeded on bone grafts at low and high density in vitro for osteoblast adhesion, proliferation, and differentiation. MATERIALS AND METHODS: The response of osteoblasts to the presence of a growth factor (enamel matrix derivative, (EMD)) in combination with low (8 mg per well) or high (100 mg per well) bone grafts (BG; natural bone mineral, Bio-Oss(r)) density, was studied and compared for osteoblast cell adhesion, proliferation, and differentiation as assessed by real-time PCR. Standard tissue culture plastic was used as a control with and without EMD. RESULTS: The present study demonstrates that in vitro testing of bone-grafting materials is largely influenced by bone graft seeding density. Osteoblast adhesion was up to 50 % lower when cells were seeded on high density BG when compared to low-density BG and control tissue culture plastic. Furthermore, proliferation was affected in a similar manner whereby cell proliferation on high-density BG (100 mg/well) was significantly increased when compared to that on low-density BG (8 mg/well). In contrast, cell differentiation was significantly increased on high-density BG as assessed by real-time PCR for markers collagen 1 (Col 1), alkaline phosphatase (ALP), and osteocalcin (OC) as well as alizarin red staining. The effects of EMD on osteoblast adhesion, proliferation, and differentiation further demonstrated that the bone graft seeding density largely controls in vitro results. EMD significantly increased cell attachment only on high-density BG, whereas EMD was able to further stimulate cell proliferation and differentiation of osteoblasts on control culture plastic and low-density BG when compared to high-density BG. CONCLUSION: The results from the present study demonstrate that the in vitro conditions largely influence cell behavior of osteoblasts seeded on bone grafts and in vitro testing. CLINICAL RELEVANCE: These results also illustrate the necessity for careful selection of bone graft seeding density to optimize in vitro testing and provide the clinician with a more accurate description of the osteopromotive potential of bone grafts. PMID- 25518816 TI - Upset Over Sexual versus Emotional Infidelity Among Gay, Lesbian, Bisexual, and Heterosexual Adults. AB - One hypothesis derived from evolutionary perspectives is that men are more upset than women by sexual infidelity and women are more upset than men by emotional infidelity. The proposed explanation is that men, in contrast to women, face the risk of unwittingly investing in genetically unrelated offspring. Most studies, however, have relied on small college or community samples of heterosexual participants. We examined upset over sexual versus emotional jealousy among 63,894 gay, lesbian, bisexual, and heterosexual participants. Participants imagined which would upset them more: their partners having sex with someone else (but not falling in love with them) or their partners falling in love with someone else (but not having sex with them). Consistent with this evolutionary perspective, heterosexual men were more likely than heterosexual women to be upset by sexual infidelity (54 vs. 35 %) and less likely than heterosexual women to be upset by emotional infidelity (46 vs. 65 %). This gender difference emerged across age groups, income levels, history of being cheated on, history of being unfaithful, relationship type, and length. The gender difference, however, was limited to heterosexual participants. Bisexual men and women did not differ significantly from each other in upset over sexual infidelity (30 vs. 27 %), regardless of whether they were currently dating a man (35 vs. 29 %) or woman (28 vs. 20 %). Gay men and lesbian women also did not differ (32 vs. 34 %). The findings present strong evidence that a gender difference exists in a broad sample of U.S. adults, but only among heterosexuals. PMID- 25518817 TI - Longitudinal Associations Among Relationship Satisfaction, Sexual Satisfaction, and Frequency of Sex in Early Marriage. AB - The current research used two 8-wave longitudinal studies spanning the first 4-5 years of 207 marriages to examine the potential bidirectional associations among marital satisfaction, sexual satisfaction, and frequency of sex. All three variables declined over time, though the rate of decline in each variable became increasingly less steep. Controlling for these changes, own marital and sexual satisfaction were bidirectionally positively associated with one another; higher levels of marital satisfaction at one wave of assessment predicted more positive changes in sexual satisfaction from that assessment to the next and higher levels of sexual satisfaction at one wave of assessment predicted more positive changes in marital satisfaction from that assessment to the next. Likewise, own sexual satisfaction and frequency of sex were bidirectionally positively associated with one another. Additionally, partner sexual satisfaction positively predicted changes in frequency of sex and own sexual satisfaction among husbands, yet partner marital satisfaction negatively predicted changes in both frequency of sex and own sexual satisfaction. Controlling these associations, marital satisfaction did not directly predict changes in frequency of sex or vice versa. Only the association between partner sexual satisfaction and changes in own sexual satisfaction varied across men and women and none of the key effects varied across the studies. These findings suggest that sexual and relationship satisfaction are intricately intertwined and thus that interventions to treat and prevent marital distress may benefit by targeting the sexual relationship and interventions to treat and prevent sexual distress in marriage may benefit by targeting the marital relationship. PMID- 25518818 TI - The hamster (Mesocricetus auratus) as an experimental model of toxocariasis: histopathological, immunohistochemical, and immunoelectron microscopic findings. AB - Toxocariasis is a globally distributed parasitic infection caused by the larval stage of Toxocara spp. The typical natural hosts of the parasite are dogs and cats, but humans can be infected by the larval stage of the parasite after ingesting embryonated eggs in soil or from contaminated hands or fomites. The migrating larvae are not adapted to complete their life cycle within accidental or paratenic hosts like humans and laboratory animals, respectively, but they are capable of invading viscera or other tissues where they may survive and induce disease. In order to characterize hamsters (Mesocricetus auratus) as a model for Toxocara canis infection, histopathological and immunohistochemistry procedures were used to detect pathological lesions and the distribution of toxocaral antigens in the liver, lungs, and kidneys of experimentally infected animals. We also attempted to characterize the immunological parameters of the inflammatory response and correlate them with the histopathological findings. In the kidney, a correlation between glomerular changes and antigen deposits was evaluated using immunoelectron microscopy. The hamster is an adequate model of experimental toxocariasis for short-term investigations and has a good immunological and pathological response to the infection. Lung and liver manifestations of toxocariasis in hamsters approximated those in humans and other experimental animal models. A mixed Th2 immunological response to T. canis infection was predominant. The hamster model displayed a progressive rise of anti-toxocaral antibodies with the formation of immune complexes. Circulating antigens, immunoglobulin, and complement deposits were detected in the kidney without the development of a definite immune complex nephropathy. PMID- 25518819 TI - Cronkhite-Canada syndrome showing elevated levels of antinuclear and anticentromere antibody. AB - A 56-year-old female initially visited an otorhinolaryngologist because of an impaired sense of taste in September, 2010 and was referred to our facility in October, 2010. She was diagnosed with Basedow's disease for which she underwent subtotal thyroidectomy in 1984 and arthritis involving multiple joints, primarily affecting her hands. In addition, the anticentromere antibody (ACA) level was markedly high. On physical examination, alopecia as well as hyperpigmentation of the dorsum of the hands and back was observed. Dystrophic changes of the fingernails and a bilateral thumb abduction deformity were observed. Antinuclear antibodies were elevated. Gastrointestinal endoscopy and colonoscopy revealed the mucosa carpeted with strawberry-like polypoid lesions. Histopathological examination of the biopsied specimen of the stomach revealed a corkscrew-like appearance. Thus, the patient was diagnosed with Cronkhite-Canada syndrome (CCS). She admitted to our hospital in November, 2010. Oral prednisolone was administered with success. In July, 2012, her antimitochondrial M2 antibody level was elevated. To the best of our knowledge, the present case is the first patient with CCS, a history of Basedow's disease, and elevated levels of ACA and antimitochondrial M2 antibody. We consider the present case suggests CCS could be caused by immunological abnormality. PMID- 25518821 TI - Nanoparticle-electrode collisions as a dynamic seeding route for the growth of metallic nanostructures. AB - The collisions between colloidal metal nanoparticles and a carbon electrode were explored as a dynamic method for the electrodeposition of a diverse range of electrocatalytically active Ag and Au nanostructures whose morphology is dominated by the electrostatic interaction between the charge of the nanoparticle and metal salt. PMID- 25518820 TI - [Complex reconstruction with internal locking plate fixation for Charcot arthropathy]. AB - BACKGROUND: Osteosynthesis and reposition of the Charcot foot is challenging with respect to choice of a proper implant. There is currently no international consensus regarding the optimal implant. OBJECTIVES: Locking plates seem to be an innovative and stable method for reconstruction. The aim of this work is to analyze bone fusion, complications, pseudoarthrosis, and patient satisfaction. METHODS: This paper presents a retrospective analysis of 63 consecutive Charcot feet treated between 2004 and 2014. The mean follow-up time was 2.4 years. RESULTS: All Charcot feet treated between 2004 and 2014 were Sanders type II or III. A bony fusion was achieved in 50 % of the cases, 26 % had a functional pseudoarthrosis with intact implants and pain-free mobility, and 22 % showed no healing with broken implants. Conclusion Internal fixation with locking plates is superior to screw fixation only with regard to biomechanics. We prefer internal fixation plates to external fixation because of stability even in the case of pseudoathrosis and because of the learning curve. PMID- 25518822 TI - An unusual liver mass: primary malignant mesothelioma of the liver : CT and MRI findings and literature review. AB - Primary malignant mesothelioma of the liver is extremely rare, and radiologic features have been defined in only one case. We present radiologic findings of two cases which are pathologically proven as primary malignant mesothelioma of the liver. Malignant mesothelioma of the liver may be included in a differential diagnosis list if there is a heterogeneous, hemorrhagic and necrotic lesion in the liver, with peripheral serpiginous vascular structures and increasing septal enhancement in post-contrast images. PMID- 25518823 TI - Strong Bias Towards Analytic Perception in ASD Does not Necessarily Come at the Price of Impaired Integration Skills. AB - We first demonstrated analytic processing in ASD under conditions in which integral processing seems mandatory in TD observers, a pattern that is often taken to indicate a local default processing in ASD. However, this processing bias does not inevitably come at the price of impaired integration skills. Indeed, examining the same group of individuals with ASD on a task with explicit demands for integrated representations, Experiment 2 showed that the same observers with ASD demonstrated intact spatial integration. The results further showed that performance was not only quantitatively, but also qualitatively comparable to that of TD observers, demonstrating the sensitivity of integration in ASD to the same interactive effects of Gestalt cues. PMID- 25518824 TI - The relationship between autistic symptomatology and independent living skills in adolescents and young adults with fragile X syndrome. AB - Few studies have examined the relationship between autistic symptomatology and competence in independent living skills in adolescents and young adults with fragile X syndrome (FXS). In this study, 70 individuals with FXS, aged 15-25 years, and 35 matched controls were administered direct measures of independent living skills and autistic symptomatology. Results showed that higher levels of autistic symptomatology were associated with lower levels of competence in independent living skills in individuals with FXS, but not in controls. These data indicated that the relationship between autistic symptomatology and independent living skills was syndrome-specific. Early intervention strategies that address autistic symptomatology are sorely needed to improve functional outcomes in this population. PMID- 25518825 TI - Lactobacillus rhamnosus LA68 and Lactobacillus plantarum WCFS1 differently influence metabolic and immunological parameters in high fat diet-induced hypercholesterolemia and hepatic steatosis. AB - In this study, two Lactobacillus strains (L. rhamnosus LA68 and L. plantarum WCFS1) were evaluated for their effects on high fat diet induced pathology in mice. The aim was to determine whether the administration of lactic acid bacteria had beneficial effects on ameliorating pathology. C57BL/6 mice fed a high fat diet were orally administered with the Lactobacillus strains. Both the metabolic and immunological parameters were analyzed. The administration of both of the strains had beneficial effects on mouse weight, serum cholesterol, TNF-alpha levels and liver histology. LA68 lowered the total cholesterol and HDL levels more prominently, whereas WCFS1 was more potent in lowering the TG and LDL levels. Leptin and adiponectin levels were increased in all experimental groups to different extents. The administration of L. plantarum WCFS1 led to a marked increase in leptin levels, as well as an increase in CD3+CD4+ and CD3+CD8+ cells, and a decrease of CD25+ cells, and had a lowering effect on IL-6 production and cell metabolic activity. In conclusion, active administration of both Lactobacillus strains had a positive effect on HFD-induced pathology. Although both of the tested strains had beneficial effects, oral administration of WCFS1 increased leptin levels and had a more prominent immunomodulatory effect, which should be taken into consideration in case of humane usage. PMID- 25518826 TI - [New: ZGN now "online first"]. PMID- 25518827 TI - [Non-invasive genetic prenatal testing--an ethical discourse]. AB - The non-invasive genetic prenatal testing (NIPT) provides better diagnostic results for the autosomal aneuploidies and decreases the rate of invasive diagnostic methods. With NIPT the possibility for a real screening method is given while posing a lot of ethical questions which have to be answered by the scientific and public communities. PMID- 25518828 TI - ISUOG consensus statement on the impact of non-invasive prenatal testing (NIPT) on prenatal ultrasound practice. PMID- 25518829 TI - [Peri- and postoperative management for minimally invasive fetoscopic surgery of spina bifida]. AB - Minimally invasive fetoscopic surgery for spina bifida has been developed to improve the postnatal neurological function of affected fetuses and to achieve a reduced maternal trauma compared to open fetal surgery. This article gives an overview on the peri- and postoperative management of such cases at our centre. PMID- 25518830 TI - [Periodontal diseases--a review on the association between maternal periodontitis and adverse pregnancy outcome]. AB - Several prospective clinical trials have indicated an association between maternal periodontal status and adverse pregnancy outcome, e.g., low birth weight, pre-term birth and pre-eclampsia. However, the translation of these findings into clinical care and decision making is still a matter of debate. Gynecologists and obstetricians are usually not very familiar with periodontal diseases and do not always consider this pathology in routine preconception counselling. This article outlines the clinical pictures of the most common periodontal diseases and thus helps the gynecologists to identify patients with periodontal diseases. PMID- 25518831 TI - [New percentile values for the anthropometric dimensions of twin neonates: analysis of perinatal survey data of 2007-2011 from all 16 states of Germany]. AB - AIM: The aim of this study was to develop new national standards for birth weight, length, head circumference, and weight for length for newborn twins based on the German perinatal survey of 2007-2011. We also assessed trends in anthropometric measurements by comparing these new percentile values with the percentile values of 1990-1994. MATERIAL AND METHODS: Perinatal survey data of 110,313 newborn twins from all the states of Germany collected in the years 2007 2011 were kindly provided by the AQUA Institute in Gottingen, Germany. Sex specific percentile values were calculated using cumulative frequencies. Percentile values at birth were computed for the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles for 21-40 completed weeks of gestation. Percentile curves and tabulated values for the years 2007-2011 were compared with the published values of 1990-1994. RESULTS AND DISCUSSION: The new percentile curves (2007-2011) closely resemble the previous ones (1990-1994). Small differences can nonetheless be found. For example, for birth weight the new values for the 10th percentile are a little higher. CONCLUSIONS: We recommend using the new percentile values instead of the old ones. PMID- 25518832 TI - Congenital disseminated HSV-1 infection in preterm twins after primary gingivostomatitis of the mother: case report and review of the literature. AB - Transplacental transmission of HSV infection is rare, typically associated with Herpes Simplex Virus 2 (HSV-2) and often reported in term infants, whereas only a few cases of preterm infants with Herpes Simplex Virus 1 (HSV-1) infection are found in the literature. We report the case of a transplacental HSV-1 infection in preterm twins born at 27 weeks gestation. At 23 weeks gestation the mother had experienced primary gingivostomatitis and "flu-like" symptoms, which healed without specific treatment. At birth both infants presented disseminated ulcerated skin lesions at the head, trunk and extremities. Soon after birth, the infants required mechanical ventilation and showed multiple organ involvement. On the basis of the mother's positive HSV-1 serology, treatment was established before the Tzanck test, serological findings and polymerase chain reaction of the skin and blood had confirmed the neonatal infection. In spite of the early diagnosis within hours after birth and immediate treatment, the extensive skin involvement associated with rapidly progressing multiorgan failure resulted in death of both infants within 3 days. Although a primary HSV-1 infection during pregnancy is extremely rare, gingivostomatitis with general symptoms can lead to transplacental infection and should therefore be taken seriously. Prompt recognition and treatment in the mother are paramount and might be life-saving for the infants. PMID- 25518833 TI - [Letter to the editor. Lower neonatal mortality in the East]. PMID- 25518834 TI - [Letter to the editor . Infant mortality in Germany (2008-2012) -Low the East? ZGN 2014; 218 : 153-163 ]. PMID- 25518835 TI - [Opinion on guest comments, and readers' letters regarding the article about infant mortality in Germany (2008-2012) - low in the east ?, ZGN 2014; 218 : 153 163]. PMID- 25518836 TI - Copper(ii)-catalyzed coupling reaction: an efficient and regioselective approach to N',N'-diaryl acylhydrazines. AB - Using N'-aryl acylhydrazines as aryl donors, a novel copper(ii)-catalyzed homo coupling reaction of N'-aryl acylhydrazines has been developed for the synthesis of N',N'-diaryl acylhydrazines. We also provided a complementary procedure for the preparation of unsymmetrical diaryl acylhydrazines via cross-coupling reaction. These protocols featured mild reaction conditions, wide functional group tolerance and highly regioselective products. Control experiments indicated that this kind of coupling reaction might undergo a transient acyl diazene intermediate. PMID- 25518837 TI - Statins for primary prevention of venous thromboembolism. AB - BACKGROUND: Venous thromboembolism (VTE) is common in clinical practice. The efficacy of statins in the primary prevention of VTE remains unproven. This is an update of the review first published in 2011. OBJECTIVES: To assess the efficacy of statins in the primary prevention of VTE. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases (PVD) Group Trials Search Co-ordinator searched the Specialised Register (last searched February 2014) and CENTRAL (2014, Issue 1). SELECTION CRITERIA: Randomised controlled trials (RCTs) that assessed statins in the primary prevention of VTE were considered. The outcomes we evaluated were the rates of VTE, cardiovascular and cerebrovascular events, death and adverse events. Two authors (L Li, JH Tian) independently selected RCTs against the inclusion criteria. Disagreements were resolved by discussion with a third author (KH Yang). DATA COLLECTION AND ANALYSIS: Data extraction was independently carried out by two authors (L Li, JH Tian). Disagreements were resolved by discussion with a third author (PZ Zhang). Two authors (L Li, JH Tian) independently assessed the risk of bias according to a standard quality checklist provided by the PVD Group. MAIN RESULTS: For this update we included one RCT with 17,802 participants that assessed rosuvastatin compared with placebo for the prevention of VTE. The quality of the evidence was moderate because of imprecision, as the required sample size for the outcomes of this review was not achieved. Analysis showed that when compared with placebo rosuvastatin reduced the incidence of VTE (odds ratio (OR) 0.57, 95% confidence interval (CI) 0.37 to 0.86) and deep vein thrombosis (DVT) (OR 0.45, 95% CI 0.25 to 0.79), the risk of any (fatal and non-fatal) myocardial infarction (MI) (OR 0.45, 95% CI 0.30 to 0.69), and any (fatal and non-fatal) stroke (OR 0.51, 95% CI 0.34 to 0.78). There was no difference in the incidence of pulmonary embolism (PE) (OR 0.77, 95% CI 0.41 to 1.46), fatal MI (OR 1.50, 95% CI 0.53 to 4.22), fatal stroke (OR 0.30, 95% CI 0.08 to 1.09) or death after VTE (OR 0.50, 95% CI 0.20 to 1.24). The incidence of any serious adverse events was no different between the rosuvastatin and placebo groups (OR 1.07, 95% CI 0.95 to 1.20). AUTHORS' CONCLUSIONS: Available evidence showed that rosuvastatin was associated with a reduced incidence of VTE, but the evidence was limited to a single RCT and any firm conclusions and suggestions could be not drawn. Randomised controlled trials of statins (including rosuvastatin) are needed to evaluate their efficacy in the prevention of VTE. PMID- 25518838 TI - Strengthening malaria diagnosis and appropriate treatment in Namibia: a test of case management training interventions in Kavango Region. AB - BACKGROUND: Despite its importance in control and elimination settings, malaria diagnosis rates tend to be low in many African countries. An operational research pilot was conducted in Namibia to identify the key barriers to appropriate diagnosis of malaria in public health facilities and to evaluate the effectiveness of various training approaches in improving the uptake and adherence to rapid diagnostic tests (RDTs). METHODS: After identifying case management weaknesses through focus group discussions, training interventions were designed to address these barriers over a six-month period. The study had three intervention districts and one control within the Kavango region of Namibia where poor case management practices were observed. The interventions included an enhanced training model, clinical mentorship, and SMS reminders. Monthly data on testing and treatment were collected for the period of April to September 2012 and, for comparison, the same months during the prior year from all 52 health facilities in Kavango. The same indicators were also obtained at district level for a follow-up period of 15 months from October 2012 to December 2013 to observe whether any improvements were sustained over time. RESULTS: All intervention arms produced significant improvements in case management practices compared to the control district (all p < 0.02). Overall, districts receiving any training improved testing rates from 25% to 66% at minimum compared to the control. The enhanced training plus mentorship arm resulted in a significantly greater proportion of fevers receiving RDTs compared to the district receiving enhanced training alone, increasing from 27% to over 90% at endline. No ACT was prescribed to untested patients after caregivers received mentorship or SMS reminders. These improvements were all sustained over the 15-month follow-up. CONCLUSIONS: These changes show a reversal of improper case management practices over the six-month study period and demonstrate that implementing simple training interventions can have a significant, sustainable impact on the uptake of and adherence to malaria RDTs. Findings from this work have already informed Namibia's roll out of a more robust case management training programme. The approaches used in Namibia may be applicable to other resource-constrained countries, providing practical guidance on sustainable approaches to febrile illness management. PMID- 25518839 TI - Hormonal therapy (hCG and rhFSH) for infertile men with adult-onset idiopathic hypogonadotropic hypogonadism. AB - Adult-onset idiopathic male hypogonadotropic hypogonadism (IMHH) is a very rare but treatable disease. This study was conducted to examine the efficacy and safety of a combination of human chorionic gonadotropin (hCG) and recombinant human follicle-stimulating hormone (rhFSH) for inducing spermatogenesis in men with adult-onset IMHH. Seven men (34-45 years of age) with azoospermia and/or sexual dysfunction, with a low serum testosterone concentration, and apulsatile secretion of luteinizing hormone, were referred to our hospital for infertility. All had normal secondary sexual characteristics. Thorough endocrinologic examination and magnetic resonance imaging revealed no identifiable cause of hypogonadotropic hypogonadism. Adult-onset IMHH was diagnosed in all cases and treatment was started with 150 IU rhFSH and 5,000 IU hCG, both administered two times per week. Spermatogenesis was restored in five of the seven patients. During treatment one patient achieved spontaneous pregnancy with his wife, and spermatozoa recovered from the other four patients were frozen for future use in intracytoplasmic sperm injection. PMID- 25518840 TI - Potential environmental implications of nanoscale zero-valent iron particles for environmental remediation. AB - OBJECTIVES: Nanoscale zero-valent iron (nZVI) particles are widely used in the field of various environmental contaminant remediation. Although the potential benefits of nZVI are considerable, there is a distinct need to identify any potential risks after environmental exposure. In this respect, we review recent studies on the environmental applications and implications of nZVI, highlighting research gaps and suggesting future research directions. METHODS: Environmental application of nZVI is briefly summarized, focusing on its unique properties. Ecotoxicity of nZVI is reviewed according to type of organism, including bacteria, terrestrial organisms, and aquatic organisms. The environmental fate and transport of nZVI are also summarized with regards to exposure scenarios. Finally, the current limitations of risk determination are thoroughly provided. RESULTS: The ecotoxicity of nZVI depends on the composition, concentration, size and surface properties of the nanoparticles and the experimental method used, including the species investigated. In addition, the environmental fate and transport of nZVI appear to be complex and depend on the exposure duration and the exposure conditions. To date, field-scale data are limited and only short term studies using simple exposure methods have been conducted. CONCLUSIONS: In this regard, the primary focus of future study should be on 1) the development of an appropriate and valid testing method of the environmental fate and ecotoxicity of reactive nanoparticles used in environmental applications and 2) assessing their potential environmental risks using in situ field scale applications. PMID- 25518841 TI - The role of chorion on toxicity of silver nanoparticles in the embryonic zebrafish assay. AB - OBJECTIVES: This study was designed to investigate how the size- and surface coating-dependent toxicity of silver nanoparticles (AgNPs) is influenced by the presence and absence of the chorion in an embryonic zebrafish assay. METHODS: Normal and dechorinated embryos were exposed to four different AgNPs, 20 or 110 nm in size, with polypyrrolidone (PVP) or citrate surface coatings in a standard zebrafish embryo medium (EM). This was then compared to a 62.5 MUM calcium chloride (CaCl2) solution where agglomeration was controlled. RESULTS: Embryonic toxicity in the absence of the chorion was greater than in its presence. The smaller 20 nm AgNPs were more toxic than the larger 110 nm AgNPs, regardless of the chorion and test media. However, surface coating affected toxicity, since PVPcoated AgNPs were more toxic than citrate-coated AgNPs; this was strongly affected by the presence of the chorion in both EM and CaCl2. CONCLUSIONS: Our results demonstrate the permeability function of the chorion on the size- and surface coating-dependent toxicity of AgNPs. Thereafter, careful experiment should be conducted to assess nanoparticle toxicity in zebrafish embryos. PMID- 25518842 TI - Acute toxicity assessment of Osthol content in bio-pesticides using two aquatic organisms. AB - OBJECTIVES: This study focused on the assessment of acute toxicity caused by Osthol, a major component of environment-friendly biological pesticides, by using two aquatic organisms. METHODS: The assessment of acute toxicity caused by Osthol was conducted in Daphnia magna and by examining the morphological abnormalities in Danio rerio embryos. RESULTS: The median effective concentration value of Osthol in D. magna 48 hours after inoculation was 19.3 MUM. The median lethal concentration of D. rerio embryo at 96 hours was 30.6 MUM. No observed effect concentration and predicted no effect concentration values of Osthol in D. magna and D. rerio were calculated as 5.4 and 0.19 MUM, respectively. There was an increase in the morphological abnormalities in D. rerio embryo due to Osthol over time. Coagulation, delayed hatching, yolk sac edema, pericardial edema, and pigmentation were observed in embryos at 24-48 hours. Symptoms of scoliosis and head edema occurred after 72 hours. In addition, bent tails, ocular defects, and symptoms of collapse were observed in fertilized embryo tissue within 96 hours. Ocular defects and pigmentation were the additional symptoms observed in this study. CONCLUSIONS: Because Osthol showed considerable toxicity levels continuous toxicity evaluation in agro-ecosystems is necessary when bio-pesticides containing Osthol are used. PMID- 25518844 TI - Stimulant use disorders in people with psychosis: a meta-analysis of rate and factors affecting variation. AB - OBJECTIVE: Stimulant abuse and dependence often complicate the care of people with psychotic disorders. This study systematically reviews the prevalence estimates reported for stimulant abuse and dependence in people with psychotic disorders, and examines personal, clinical, regional and methodological factors which explain variation in these rates. METHODS: PsychINFO, EMBASE and MEDLINE (1946-2013) were searched systematically for studies reporting on stimulant drug use disorders in representative samples of people with psychotic disorders. Random effects models estimated the pooled rate of a stimulant use disorder, defined to include stimulant abuse and stimulant dependence. Study characteristics associated with heterogeneity in rates of stimulant use disorder were examined by subgroup analyses for categorical variables, by meta-regression for continuous independent variables and by multiple meta-regression. RESULTS: Sixty-four studies provided 68 estimates of lifetime or recent stimulant use disorders in 22,500 people with psychosis. The pooled rate of stimulant use disorder was 8.9% (95% CI 7.4%, 10.5%). Higher rates of stimulant use disorders were reported in studies of affective psychosis, studies from inpatient settings, studies from the USA and Australia, and studies with higher rates of cannabis disorder; in multiple meta-regression analysis these factors explained 68% of between-study variance. Rates of stimulant use disorder were stable over time, and unrelated to age, sex, stage of psychosis, type of stimulant drug or study methodology factors. CONCLUSIONS: Reported rates of stimulant use disorder in people with psychosis are much higher than in the general population but vary widely and are associated with regional, service setting and clinical differences between studies. It is likely that stimulants contribute to the overall burden of psychosis, and that social and environmental factors combine with drug and illness-related factors to influence stimulant use in psychosis. PMID- 25518845 TI - The effects of oscillating positive expiratory pressure therapy in adults with stable non-cystic fibrosis bronchiectasis: A systematic review. AB - Airway clearance techniques (ACTs) are recommended for patients with stable non cystic fibrosis (non-CF) bronchiectasis, but the efficacy of oscillating positive expiratory pressure (PEP) therapy compared to other techniques has not been reviewed. A systematic review of studies was conducted in stable patients comparing the effect of oscillating PEP therapy to other ACTs or a control condition. Data were extracted related to sputum expectoration, lung function, gas exchange, quality of life (QOL), symptoms, and exacerbation rate. Seven studies were included with a total of 146 patients, with a mean (SD) PEDro score of 7(1). Oscillating PEP therapy enhanced sputum expectoration compared to no treatment, but has equivalent benefits as the active cycle of breathing technique with gravity-assisted drainage (mean difference [95% CI] -2.8 g [-8.8 to 3.2 g]). Oscillating PEP has a similar effect as other ACTs on dynamic lung volumes, gas exchange and breathlessness. Use of oscillating PEP improved disease-specific QOL (p < 0.001) and cough-related QOL (p < 0.002) compared to no treatment but did not reduce exacerbation rate. In conclusion, in stable non-CF bronchiectasis, oscillating PEP therapy is associated with improvement in sputum expectoration and QOL compared to no treatment. Compared to other ACTs, the effect upon sputum expectoration, lung function, gas exchange, and symptoms are equivalent. PMID- 25518846 TI - Left atrial appendage occlusion. AB - Left atrial appendage (LAA) occlusion for stroke and thromboembolism prevention in patients with atrial fibrillation (AF) represents a significant advancement in the field of cardiovascular disease. Prevention and avoidance of the devastating consequences of thromboembolic complications from AF continues to be central in the management of these patients. The role of LAA as a nidus for thrombus formation is well documented. Multiple approaches to exclude the LAA from the circulation either percutaneously or surgically have been described and are undergoing testing. Although pharmacological therapy for stroke prevention remains the cornerstone of treatment, device and surgical exclusion of the LAA have proven to be viable alternatives in carefully selected patients. Even though current evidence show that LAA occlusion is safe and effective, approval and adoption of this strategy has been quite difficult due to paucity of randomised clinical trial data on the risk and benefit ratio, cost effectiveness and the issues of procedural risk as well as longer-term outcome. This review aims to provide an update on the current status of LAA occlusion, specifically looking at interpretation of current clinical data, available techniques and devices, issues with current devices and future direction. PMID- 25518847 TI - Abstracts from the Collaboration in Cancer Drug Trials: 2014 Chabner Colloquium. PMID- 25518843 TI - Spicy food consumption is associated with adiposity measures among half a million Chinese people: the China Kadoorie Biobank study. AB - BACKGROUND: Few animal experiments and volunteer-based intervention studies have showed a controversial effect of spicy foods on weight management; however, information is scant on the association between spicy food intake and obesity. This study aims to examine the impact of spicy food on quantitative adiposity measures in the Chinese population; a population with a low prevalence of general obesity, but a high prevalence of central obesity. METHODS: A total of 434,556 adults (255,094 females), aged 30-79 years, were included from the China Kadoorie Biobank (CKB) study. Information on spicy food intake was obtained using a questionnaire survey. Body mass index (BMI), percentage body fat (BF%), waist circumference (WC), and WC/height ratio (WHtR) were analyzed as continuous variables. RESULTS: The prevalence of daily spicy food eating was 30.4% in males and 30.0% in females, with dramatically geographic diversity (ranging from 99.4% in Hunan to 2.7% in Zhejiang). The covariates-adjusted BMI, BF%, WC, and WHtR significantly increased with increasing frequency, strength, and duration of spicy food eating regardless of gender (p < 0.001). Among regular spicy food consumers, strength of spicy food eating showed significant and positive association with all adiposity measures in both genders (except for BF% in males). Compared with non-consumers, daily spicy food eating was significantly associated with an increase of 0.44 and 0.51 of BMI (kg/m2), 0.79 and 1.01 of BF%, 1.4 and 1.0 of WC (cm), and 0.008 and 0.006 of WHtR in males and females, respectively. In stratified analyses of 18 consecutive BMI subgroups, a significantly increasing trend in the effect of daily spicy food eating on WC and WHtR with increasing BMI was noted in males; whereas a decreasing trend was seen in females. CONCLUSIONS: The data indicate that spicy food intake is a risk factor for obesity in Chinese adult population, especially for central obesity in males. Further studies are needed to elucidate the mechanisms underlying this association. PMID- 25518848 TI - Simplified methods for estimating glomerular filtration rate in cats and for detection of cats with low or borderline glomerular filtration rate. AB - OBJECTIVES: Diagnosis of early feline chronic kidney disease (CKD) is challenging. Glomerular filtration rate (GFR) is the best overall indicator of kidney function, but multisample plasma clearance methods to determine GFR are labour intensive, time consuming and stressful for feline patients. This study aimed to develop simplified methods to detect decreased GFR in cats. METHODS: Data from a nine-sample combined plasma exogenous creatinine-iohexol clearance test of 73 cats were used. Limited sampling strategies were developed by comparing all sampling time combinations with the complete nine sampling times set and selecting the best sampling time combinations based on maximum relative error. By regression analysis, the ability of routine blood (serum creatinine, serum urea) and urine (urine specific gravity, urinary protein:creatinine ratio) variables to predict GFR or identify cats with low or borderline GFR was examined. Cut-off clearance marker concentrations to predict low or borderline GFR was determined at three time points after marker injection. All procedures were analysed for three clearance markers (exo-iohexol, creatinine, endo iohexol). RESULTS: For reliable estimation of GFR, at least three blood samples for clinical purposes and five blood samples for research purposes are required. Regression formulae based on routine variables did not reliably predict GFR, but accurately identified cats with low (sensitivity 96.5-98.2%; specificity 60 91.3%) or borderline (sensitivity 91.1-96%; specificity 76.5-81.8%) GFR. Clearance marker concentrations exceeding given marker cut-off concentrations also identified cats with low or borderline GFR with high sensitivities and specificities. CONCLUSIONS AND RELEVANCE: These simplified methods will facilitate the detection of early kidney dysfunction in cats. Early diagnosis allows timely therapeutic intervention, and future studies must reveal whether this improves the long-term outcome of cats with CKD. PMID- 25518849 TI - Swimming-induced exercise promotes hypertrophy and vascularization of fast skeletal muscle fibres and activation of myogenic and angiogenic transcriptional programs in adult zebrafish. AB - BACKGROUND: The adult skeletal muscle is a plastic tissue with a remarkable ability to adapt to different levels of activity by altering its excitability, its contractile and metabolic phenotype and its mass. We previously reported on the potential of adult zebrafish as a tractable experimental model for exercise physiology, established its optimal swimming speed and showed that swimming induced contractile activity potentiated somatic growth. Given that the underlying exercise-induced transcriptional mechanisms regulating muscle mass in vertebrates are not fully understood, here we investigated the cellular and molecular adaptive mechanisms taking place in fast skeletal muscle of adult zebrafish in response to swimming. RESULTS: Fish were trained at low swimming speed (0.1 m/s; non-exercised) or at their optimal swimming speed (0.4 m/s; exercised). A significant increase in fibre cross-sectional area (1.290+/-88 vs. 1.665+/-106 MUm2) and vascularization (298+/-23 vs. 458+/-38 capillaries/mm2) was found in exercised over non-exercised fish. Gene expression profiling by microarray analysis evidenced the activation of a series of complex transcriptional networks of extracellular and intracellular signaling molecules and pathways involved in the regulation of muscle mass (e.g. IGF-1/PI3K/mTOR, BMP, MSTN), myogenesis and satellite cell activation (e.g. PAX3, FGF, Notch, Wnt, MEF2, Hh, EphrinB2) and angiogenesis (e.g. VEGF, HIF, Notch, EphrinB2, KLF2), some of which had not been previously associated with exercise-induced contractile activity. CONCLUSIONS: The results from the present study show that exercise-induced contractile activity in adult zebrafish promotes a coordinated adaptive response in fast muscle that leads to increased muscle mass by hypertrophy and increased vascularization by angiogenesis. We propose that these phenotypic adaptations are the result of extensive transcriptional changes induced by exercise. Analysis of the transcriptional networks that are activated in response to exercise in the adult zebrafish fast muscle resulted in the identification of key signaling pathways and factors for the regulation of skeletal muscle mass, myogenesis and angiogenesis that have been remarkably conserved during evolution from fish to mammals. These results further support the validity of the adult zebrafish as an exercise model to decipher the complex molecular and cellular mechanisms governing skeletal muscle mass and function in vertebrates. PMID- 25518851 TI - PROGgeneV2: enhancements on the existing database. AB - BACKGROUND: We recently published PROGgene, a tool that can be used to study prognostic implications of genes in various cancers. The first version of the tool had several areas for improvement. In this paper we present some major enhancements we have made on the existing tool in the new version, PROGgeneV2. RESULTS: In PROGgeneV2, we have made several modifications to enhance survival analysis capability of the tool. First, we have increased the repository of public studies catalogued in our tool by almost two folds. We have also added additional functionalities to perform survival analysis in a variety of new ways. Survival analysis can now be performed on a) single genes b) multiple genes as a signature, c) ratio of expression of two genes, and d) curated/published gene signatures in new version. Users can now also adjust the survival analysis models for available covariates. Users can study prognostic implications of entire gene signatures in different cancer types, which are searchable by keywords. Also, unique to our tool, in the new version, users will be able to upload and use their own datasets to perform survival analysis on genes of interest. CONCLUSIONS: We believe, like its predecessor, PROGGeneV2 will continue to be useful for the scientific community for formulating research hypotheses and designing mechanistic studies. With added datasets PROGgeneV2 is the most comprehensive survival analysis tool available. PROGgeneV2 is available at http://www.compbio.iupui.edu/proggene. PMID- 25518850 TI - Endothelial perturbations and therapeutic strategies in normal tissue radiation damage. AB - Most cancer patients are treated with radiotherapy, but the treatment can also damage the surrounding normal tissue. Radiotherapy side-effects diminish patients' quality of life, yet effective biological interventions for normal tissue damage are lacking. Protecting microvascular endothelial cells from the effects of irradiation is emerging as a targeted damage-reduction strategy. We illustrate the concept of the microvasculature as a mediator of overall normal tissue radiation toxicity through cell death, vascular inflammation (hemodynamic and molecular changes) and a change in functional capacity. Endothelial cell targeted therapies that protect against such endothelial cell perturbations and the development of acute normal tissue damage are mostly under preclinical development. Since acute radiation toxicity is a common clinical problem in cutaneous, gastrointestinal and mucosal tissues, we also focus on damage in these tissues. PMID- 25518852 TI - Conserved syntenic clusters of protein coding genes are missing in birds. AB - BACKGROUND: Birds are one of the most highly successful and diverse groups of vertebrates, having evolved a number of distinct characteristics, including feathers and wings, a sturdy lightweight skeleton and unique respiratory and urinary/excretion systems. However, the genetic basis of these traits is poorly understood. RESULTS: Using comparative genomics based on extensive searches of 60 avian genomes, we have found that birds lack approximately 274 protein coding genes that are present in the genomes of most vertebrate lineages and are for the most part organized in conserved syntenic clusters in non-avian sauropsids and in humans. These genes are located in regions associated with chromosomal rearrangements, and are largely present in crocodiles, suggesting that their loss occurred subsequent to the split of dinosaurs/birds from crocodilians. Many of these genes are associated with lethality in rodents, human genetic disorders, or biological functions targeting various tissues. Functional enrichment analysis combined with orthogroup analysis and paralog searches revealed enrichments that were shared by non-avian species, present only in birds, or shared between all species. CONCLUSIONS: Together these results provide a clearer definition of the genetic background of extant birds, extend the findings of previous studies on missing avian genes, and provide clues about molecular events that shaped avian evolution. They also have implications for fields that largely benefit from avian studies, including development, immune system, oncogenesis, and brain function and cognition. With regards to the missing genes, birds can be considered 'natural knockouts' that may become invaluable model organisms for several human diseases. PMID- 25518853 TI - Distress criterion influences prevalence rates of functional gastrointestinal disorders. AB - BACKGROUND: Functional gastrointestinal disorders (FGID) are defined by a combination of chronic or recurrent gastrointestinal symptoms. Prevalence rates of FGID are high. Symptoms are associated with distress, and sufferers show high stress levels. However, the current diagnostic criteria do not consider subjective distress elicited by the symptoms, thus potentially leading to overestimated prevalence rates. The aim of this study was to explore the reduction in prevalence rates when distress is considered in the diagnostic criteria. METHODS: In this web-based study, FGID were diagnosed using the Rome II criteria. Prevalence rates with and without subjective distress elicited by the symptoms were computed. Additionally, stress levels and stress reactivity were assessed. RESULTS: Prevalence rates of FGID in our sample were similar to those in other studies. However, when considering the distress criterion, on average, a decrease of 38.51% was found in the prevalence rates of FGID. Sufferers who were subjectively distressed by their symptoms reported significantly higher stress levels than non-distressed subjects (all p < 0.001). CONCLUSIONS: The consideration of a criterion of subjective distress in the diagnosis of FGID has consequences for actual prevalence rates of FGID. Distressed subjects differ markedly from non-distressed subjects in terms of their stress levels. The inclusion of a distress criterion in the ongoing development of diagnostic criteria for FGID is therefore warranted. PMID- 25518854 TI - Long-term quality of VKA treatment and clinical outcome after extreme overanticoagulation in 14,777 AF and VTE patients. AB - Vitamin K antagonists (VKA) are widely used in atrial fibrillation and venous thromboembolism (VTE). Their efficacy and safety depend on individual time in the therapeutic range (iTTR). Due to the variable dose-response relationship within patients, also patients with initially stable VKA treatment may develop extreme overanticoagulation (EO). EO is associated with an immediate bleeding risk, but it is unknown whether VKA treatment will subsequently restabilise. We evaluated long-term quality of VKA treatment and clinical outcome after EO. EO was defined as international normalized ratio (INR) >= 8.0 and/or unscheduled vitamin K supplementation. We included a consecutive cohort of initially stable atrial fibrillation and venous thromboembolism patients. In EO patients, the 90 days pre and post-period were compared. In addition, patients with EO were compared with patients without EO using a matched 1:2 cohort. Of 14,777 initially stable patients, 800 patients developed EO. The pre-period was characterised by frequent overanticoagulation, and half of EO patients had an inadequate iTTR (< 65 %). After EO, underanticoagulation became more prevalent. Although the mean time between INR-measurements decreased from 18.6 to 13.2 days, after EO inadequate iTTR became more frequent (62 %), p-value < 0.001. A 2.3 times (95 % confidence interval [CI] 2.0-2.5) higher risk for iTTR< 65 % after EO, was accompanied by increased risk of bleeding (hazard ratio [HR] 2.1;CI 1.4-3.2), VKA-related death 17.0 (HR 17.0;CI 2.1-138) and thrombosis (HR 5.7;CI 1.5-22.2), compared to the 1600 controls. In conclusion, patients continuing VKA after EO have long-lasting inferior quality of VKA treatment despite intensified INR-monitoring, and an increased risk of bleeding, thrombosis and VKA-related death. PMID- 25518855 TI - Prevalence, distribution, and social determinants of tobacco use in 30 sub Saharan African countries. AB - BACKGROUND: Although the Framework Convention on Tobacco Control prioritizes monitoring of tobacco use by population-based surveys, information about the prevalence and patterns of tobacco use in sub-Saharan Africa is limited. We provide country-level prevalence estimates for smoking and smokeless tobacco (SLT) use and assess their social determinants. METHODS: We analyzed population based data of the most recent Demographic Health Surveys performed between 2006 and 2013 involving men and women in 30 sub-Saharan African countries. Weighted country-level prevalence rates were estimated for 'current smoking' (cigarettes, pipe, cigars, etc.) and 'current SLT use' (chewing, snuff, etc.). From the pooled datasets for men and women, social determinants of smoking and SLT use were assessed through multivariate analyses using a dummy country variable as a control and by including a within-country sample weight for each country. RESULTS: Among men, smoking prevalence rates were high in Sierra Leone (37.7%), Lesotho (34.1%), and Madagascar (28.5%); low (<10%) in Ethiopia, Benin, Ghana, Nigeria, and Sao Tome & Principe; the prevalence of SLT use was <10% in all countries except for Madagascar (24.7%) and Mozambique (10.9%). Among women, smoking and SLT prevalence rates were <5% in most countries except for Burundi (9.9%), Sierra Leone (6%), and Namibia (5.9%) (smoking), and Madagascar (19.6%) and Lesotho (9.1%) (SLT use). The proportion of females who smoked was lower than SLT users in most countries. Older age was strongly associated with both smoking and SLT use among men and women. Smoking among both men and women was weakly associated, but SLT use was strongly associated, with education. Similarly, smoking among men and women was weakly associated, but SLT use was strongly associated, with the wealth index. Smoking and SLT use were also associated with marital status among both men and women, as well as with occupation (agriculturists and unskilled workers). CONCLUSIONS: Prevalence of smoking among women was much lower than in men, although the social patterns of tobacco use were similar to those in men. Tobacco control strategies should target the poor, not/least educated, and agricultural and unskilled workers, who are the most vulnerable social groups in sub-Saharan Africa. PMID- 25518857 TI - Use of micro-HPLC-MS/MS method to assess diurnal effects on steroid hormones. PMID- 25518856 TI - Pyrosequencing of supra- and subgingival biofilms from inflamed peri-implant and periodontal sites. AB - BACKGROUND: To investigate the microbial composition of biofilms at inflamed peri implant and periodontal tissues in the same subject, using 16S rRNA sequencing. METHODS: Supra- and submucosal, and supra- and subgingival plaque samples were collected from 7 subjects suffering from diseased peri-implant and periodontal tissues. Bacterial DNA was isolated and 16S rRNA genes were amplified, sequenced and aligned for the identification of bacterial genera. RESULTS: 43734 chimera depleted, denoised sequences were identified, corresponding to 1 phylum, 8 classes, 10 orders, 44 families and 150 genera. The most abundant families or genera found in supramucosal or supragingival plaque were Streptoccocaceae, Rothia and Porphyromonas. In submucosal plaque, the most abundant family or genera found were Rothia, Streptococcaceae and Porphyromonas on implants. The most abundant subgingival bacteria on teeth were Prevotella, Streptococcaceae, and TG5. The number of sequences found for the genera Tannerella and Aggregatibacter on implants differed significantly between supra- and submucosal locations before multiple testing. The analyses demonstrated no significant differences between microbiomes on implants and teeth in supra- or submucosal and supra- or subgingival biofilms. CONCLUSION: Diseased peri-implant and periodontal tissues in the same subject share similiar bacterial genera and based on the analysis of taxa on a genus level biofilm compositions may not account for the potentially distinct pathologies at implants or teeth. PMID- 25518858 TI - Qualitative point-of-care human chorionic gonadotropin testing: can we defuse this ticking time bomb? PMID- 25518859 TI - VEGAS2: Software for More Flexible Gene-Based Testing. AB - Gene-based tests such as versatile gene-based association study (VEGAS) are commonly used following per-single nucleotide polymorphism (SNP) GWAS (genome wide association studies) analysis. Two limitations of VEGAS were that the HapMap2 reference set was used to model the correlation between SNPs and only autosomal genes were considered. HapMap2 has now been superseded by the 1,000 Genomes reference set, and whereas early GWASs frequently ignored the X chromosome, it is now commonly included. Here we have developed VEGAS2, an extension that uses 1,000 Genomes data to model SNP correlations across the autosomes and chromosome X. VEGAS2 allows greater flexibility when defining gene boundaries. VEGAS2 offers both a user-friendly, web-based front end and a command line Linux version. The online version of VEGAS2 can be accessed through https://vegas2.qimrberghofer.edu.au/. The command line version can be downloaded from https://vegas2.qimrberghofer.edu.au/zVEGAS2offline.tgz. The command line version is developed in Perl, R and shell scripting languages; source code is available for further development. PMID- 25518860 TI - A small-molecule mimic of a peptide docking motif inhibits the protein kinase PDK1. AB - There is great interest in developing selective protein kinase inhibitors by targeting allosteric sites, but these sites often involve protein-protein or protein-peptide interfaces that are very challenging to target with small molecules. Here we present a systematic approach to targeting a functionally conserved allosteric site on the protein kinase PDK1 called the PDK1-interacting fragment (PIF)tide-binding site, or PIF pocket. More than two dozen prosurvival and progrowth kinases dock a conserved peptide tail into this binding site, which recruits them to PDK1 to become activated. Using a site-directed chemical screen, we identified and chemically optimized ligand-efficient, selective, and cell penetrant small molecules (molecular weight ~ 380 Da) that compete with the peptide docking motif for binding to PDK1. We solved the first high-resolution structure of a peptide docking motif (PIFtide) bound to PDK1 and mapped binding energy hot spots using mutational analysis. We then solved structures of PDK1 bound to the allosteric small molecules, which revealed a binding mode that remarkably mimics three of five hot-spot residues in PIFtide. These allosteric small molecules are substrate-selective PDK1 inhibitors when used as single agents, but when combined with an ATP-competitive inhibitor, they completely suppress the activation of the downstream kinases. This work provides a promising new scaffold for the development of high-affinity PIF pocket ligands, which may be used to enhance the anticancer activity of existing PDK1 inhibitors. Moreover, our results provide further impetus for exploring the helix alphaC patches of other protein kinases as potential therapeutic targets even though they involve protein-protein interfaces. PMID- 25518862 TI - Delivering the evidence to improve the health of women and newborns: State of the World's Midwifery, report 2014. AB - The State of the World's Midwifery Report 2014: A universal pathway, a women's right to health (SoWMy2014) was published in June 2014 and joins the ranks of a number of publications which contribute to the growing body of evidence about a global midwifery workforce that can improve maternal and child health.This editorial provides an overview of these publications that have been supported by global movements in the area of sexual, reproductive, maternal, and newborn and child health over the last four years. Background information is given on the methodology and data collection of SoWMy2014, the main findings cover the area of the availability, accessibility, acceptability and quality of midwifery services and a 2 page country brief shows the SRMNH data and workforce projections for each of the 73 "Countdown countries" that participated.SoWMy 2014 report shows that midwives can provide 87% of the needed essential care for women and newborns, when educated and trained to international standards. Midwives however, are most effective when they work within a functional health system and enabling environment.Also, a supportive team of auxiliaries, physicians and specialists is essential in order to ensure coverage of SRMNH services to women and newborns across the whole continuum of care, from pre-pregnancy through to pregnancy, childbirth and the post-natal period and from household to hospital.Based on these findings, the report puts forward a vision of Midwifery2030, a pathway for women's health and for midwifery policy and planning through the end of 2030. It promotes women-centered and midwife-led care to achieve the goal of universal health coverage for all women. PMID- 25518861 TI - Structural basis of HIV-1 capsid recognition by PF74 and CPSF6. AB - Upon infection of susceptible cells by HIV-1, the conical capsid formed by ~250 hexamers and 12 pentamers of the CA protein is delivered to the cytoplasm. The capsid shields the RNA genome and proteins required for reverse transcription. In addition, the surface of the capsid mediates numerous host-virus interactions, which either promote infection or enable viral restriction by innate immune responses. In the intact capsid, there is an intermolecular interface between the N-terminal domain (NTD) of one subunit and the C-terminal domain (CTD) of the adjacent subunit within the same hexameric ring. The NTD-CTD interface is critical for capsid assembly, both as an architectural element of the CA hexamer and pentamer and as a mechanistic element for generating lattice curvature. Here we report biochemical experiments showing that PF-3450074 (PF74), a drug that inhibits HIV-1 infection, as well as host proteins cleavage and polyadenylation specific factor 6 (CPSF6) and nucleoporin 153 kDa (NUP153), bind to the CA hexamer with at least 10-fold higher affinities compared with nonassembled CA or isolated CA domains. The crystal structure of PF74 in complex with the CA hexamer reveals that PF74 binds in a preformed pocket encompassing the NTD-CTD interface, suggesting that the principal inhibitory target of PF74 is the assembled capsid. Likewise, CPSF6 binds in the same pocket. Given that the NTD-CTD interface is a specific molecular signature of assembled hexamers in the capsid, binding of NUP153 at this site suggests that key features of capsid architecture remain intact upon delivery of the preintegration complex to the nucleus. PMID- 25518863 TI - Anxious attachment style and hopelessness as predictors of burden in caregivers of patients with disorders of consciousness: a pilot study. AB - OBJECTIVE: Previous studies on caregivers of patients with disorders of consciousness (DOCs) have highlighted that their overall burden is not related to disease duration or diagnosis, but mainly to their personal characteristics. The aim of this study was to investigate the impact of attachment style and hopelessness on overall burden in caregivers of patients in both vegetative state and minimally conscious state. METHODS AND PROCEDURE: Nineteen caregivers of patients with DOCs, hosted in a long-term care facility, were assessed using the Caregiver Burden Inventory, the Attachment Style Questionnaire, and the Beck Hopelessness Scale. Socio-demographic information was also collected. Data were analysed through descriptive statistics, correlations, one sample t-test and a multiple regression analysis using SPSS. OUTCOMES AND RESULTS: Burden was not associated with duration of caregiving and gender had no effect on overall burden. Multiple regression analysis indicated that preoccupied attachment style and hopelessness together predicted 49% of the total variability of burden (R(2 )= 0.489; adjusted R = 0.43). CONCLUSIONS: These data suggest that caregivers need psychological assessment and support in order to keep under control the level of burden and to help themselves be a better resource for their relatives. PMID- 25518864 TI - Association of ICP, CPP, CT findings and S-100B and NSE in severe traumatic head injury. Prognostic value of the biomarkers. AB - OBJECTIVE: The association was studied of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) on S-100B and neuron-specific enolase (NSE) in severe traumatic brain injury (sTBI). The relationship was explored between biomarkers, ICP, CPP, CT-scan classifications and the clinical outcome. MATERIALS AND METHODS: Data were collected prospectively and consecutively in 48 patients with Glasgow Coma Scale score <= 8, age 15-70 years. NSE and S-100B were analysed during 5 consecutive days. The initial and follow-up CT-scans were classified according to the Marshall, Rotterdam and Morris-Marshall classifications. Outcome was evaluated with extended Glasgow outcome scale at 3 months. RESULTS: Maximal ICP and minimal CPP correlated with S-100B and NSE levels. Complex relations between biomarkers and CT classifications were observed. S-100B bulk release (AUC = 0.8333, p = 0.0009), and NSE at 72 hours (AUC = 0.8476, p = 0.0045) had the highest prediction power of mortality. Combining Morris-Marshall score and S-100B bulk release improved the prediction of clinical outcome (AUC = 0.8929, p = 0.0008). CONCLUSION: Biomarker levels are associated with ICP and CPP and reflect different aspects of brain injury as evaluated by CT-scan. The biomarkers might predict mortality. There are several pitfalls influencing the interpretation of biomarker data in respect to ICP, CPP, CT-findings and clinical outcome. PMID- 25518866 TI - Mycetoma, mycoses and pregnancy. PMID- 25518867 TI - Association of suboptimal health status with psychosocial stress, plasma cortisol and mRNA expression of glucocorticoid receptor alpha/beta in lymphocyte. AB - Suboptimal health status (SHS) has become a new public health challenge in China. This study investigated whether high SHS is associated with psychosocial stress, changes in cortisol level and/or glucocorticoid receptor (GR) isoform expression. Three-hundred eighty-six workers employed in three companies in Beijing were recruited. The SHS score was derived from data collection in the SHS questionnaire (SHSQ-25). The short standard version of the Copenhagen Psychosocial Questionnaire (COPSOQ) was used to assess job-related psychosocial stress. The mean value of the five scales of COPSOQ and distribution of plasma cortisol and mRNA expression of GRalpha/GRbeta between the high level of SHS group and the low level of SHS group were compared using a general linear model procedure. Multiple linear regression analysis was used to analyze the effect of psychosocial stress on SHS. We identified three factors that were predictive of SHS, including "demands at work", "interpersonal relations and leadership" and "insecurity at work". Significantly higher levels of plasma cortisol and GRbeta/GRalpha mRNA ratio were observed among the high SHS group. High level of SHS is associated with decreased mRNA expression of GRalpha. This study confirmed the association between chronic psychosocial stress and SHS, indicating that improving the psychosocial work environment may reduce SHS and then prevent chronic diseases effectively. PMID- 25518865 TI - Longitudinal quantification and visualization of intracerebral haemorrhage using multimodal magnetic resonance and diffusion tensor imaging. AB - OBJECTIVE: To demonstrate a set of approaches using diffusion tensor imaging (DTI) tractography whereby pathology-affected white matter (WM) fibres in patients with intracerebral haemorrhage (ICH) can be selectively visualized. METHODS: Using structural neuroimaging and DTI volumes acquired longitudinally from three representative patients with ICH, the spatial configuration of ICH related trauma is delineated and the WM fibre bundles intersecting each ICH lesion are identified and visualized. Both the extent of ICH lesions as well as the proportion of WM fibres intersecting the ICH pathology are quantified and compared across subjects. RESULTS: This method successfully demonstrates longitudinal volumetric differences in ICH lesion load and differences across time in the percentage of fibres which intersect the primary injury. CONCLUSIONS: Because neurological conditions such as intracerebral haemorrhage (ICH) frequently exhibit pathology-related effects which lead to the exertion of mechanical pressure upon surrounding tissues and, thereby, to the deformation and/or displacement of WM fibres, DTI fibre tractography is highly suitable for assessing longitudinal changes in WM fibre integrity and mechanical displacement. PMID- 25518868 TI - Premenstrual syndrome is associated with blunted cortisol reactivity to the TSST. AB - This study assessed the effects of premenstrual syndrome (PMS) and menstrual phases on the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic nervous system axis and psychological responses to the Trier Social Stress Test (TSST). Thirty-six PMS women (mean age 21.69 +/- 2.16 years) and 36 control women (mean age 22.03 +/- 2.48 years) participated in the TSST task, either in the follicular phase or in the late luteal phase (each group N = 18). Saliva samples, heart rate and subjective stress levels were collected for seven time points throughout the test (10, 20, 30, 40, 55, 70 and 100 min). The results indicated that in comparison with control women, PMS women displayed blunted cortisol stress responses to the TSST irrespective of the menstrual phases, as indexed by the cortisol levels across time, area under the curve with respect to ground (AUCg) and peak change scores of cortisol. The results also demonstrated that the measurements indexed by cortisol levels across time, AUCg and peak change scores of heart rate were smaller in women tested during the late luteal phase than during the follicular phase. Correlation results indicated that AUCg was negatively correlated with PMS scores. These results suggest that measures of cortisol, rather than heart rate or subjective responses to stress, may be most closely associated with PMS. Furthermore, hypo-reactivity of the HPA axis may be pathologically relevant to PMS because it predicts heightened PMS severity. PMID- 25518869 TI - Bioactive DOPA melanin isolated and characterised from a marine actinobacterium Streptomyces sp. MVCS6 from Versova coast. AB - The melanin pigment produced from Streptomyces sp., MVCS6 was isolated and dihydroxyphenyalanine (DOPA) melanin compound was biochemically identified and spectroscopically characterised (ultraviolet and FT-IR). DOPA melanin showed a promising activity as an antibacterial natural product against 12 pathogenic bacteria from hospital isolations, particularly, against Pseudomonas aeruginosa RMMH7 (inhibition zone of 18 +/- 0.02 at 30 MUg/disc, and MIC of 10 +/- 0.02 MUg/mL) and Vibrio parahaemolytics RMMH12 (inhibition zone of 15 mm +/- 0.03 at 30 MUg/disc, and MIC of 14 +/- 0.02 MUg/mL). Moreover, in vitro evaluation of reducing power (Ascorbic Acid Equivalent (160 MUg/mL)), DPPH radical-scavenging (89%), NO-scavenging (72%) and lipid peroxidation activities (89.6%) were determined. Cytotoxicity of DOPA melanin against cervical cancer cell line showed a dose-response activity, and IC50 value was found to be 300 MUg/mL. These results would open the way to propose Streptomyces sp. MVCS6 as a promising source of bioactive eumelanin with therapeutic potential in medicine. PMID- 25518870 TI - Albumin and its application in drug delivery. AB - INTRODUCTION: Rapid clearance of drugs from the body results in short therapeutic half-life and is an integral property of many protein and peptide-based drugs. To maintain the desired therapeutic effect patients are required to administer higher doses more frequently, which is inconvenient and risks undesirable side effects. Drug delivery technologies aim to minimise the number of administrations and dose-related toxicity while maximising therapeutic efficacy. AREAS COVERED: This review describes albumin's inherent biochemical and biophysical properties, which make it an attractive drug delivery platform and the developmental status of drugs that are associated, conjugated or genetically fused with albumin. Albumin interacts with a number of cell surface receptors including gp18, gp30, gp60, FcRn, cubilin and megalin. The importance of albumin's interaction with the FcRn receptor, the basis for albumin's long circulatory half-life, is described, as are engineered albumins with improved pharmacokinetics. Albumin naturally accumulates at tumours and sites of inflammation, a characteristic which can be augmented by the addition of targeting ligands. The development of albumin drug conjugates which reply upon this property is described. EXPERT OPINION: Albumin's inherent biochemical and biophysical properties make it an ideal drug delivery platform. Recent advances in our understanding of albumin physiology and the improvement in albumin-based therapies strongly suggest that albumin-based therapies have a significant advantage over alternative technologies in terms of half-life, stability, versatility, safety and ease of manufacture. Given the importance of the albumin:FcRn interaction, the interpretation of the pharmacokinetic and pharmacodynamic profiles of albumin-based therapeutics with disturbed albumin:FcRn interaction may have to be reassessed. The FcRn receptor has additional functionality, especially in relation to immunology, antigen presentation and delivery of proteins across mucosal membranes, consequently albumin-based fusions and conjugates may have a future role in oral and pulmonary based vaccines and drug delivery. PMID- 25518871 TI - Improving the learning of clinical reasoning through computer-based cognitive representation. AB - OBJECTIVE: Clinical reasoning is usually taught using a problem-solving approach, which is widely adopted in medical education. However, learning through problem solving is difficult as a result of the contextualization and dynamic aspects of actual problems. Moreover, knowledge acquired from problem-solving practice tends to be inert and fragmented. This study proposed a computer-based cognitive representation approach that externalizes and facilitates the complex processes in learning clinical reasoning. The approach is operationalized in a computer based cognitive representation tool that involves argument mapping to externalize the problem-solving process and concept mapping to reveal the knowledge constructed from the problems. METHODS: Twenty-nine Year 3 or higher students from a medical school in east China participated in the study. Participants used the proposed approach implemented in an e-learning system to complete four learning cases in 4 weeks on an individual basis. For each case, students interacted with the problem to capture critical data, generate and justify hypotheses, make a diagnosis, recall relevant knowledge, and update their conceptual understanding of the problem domain. Meanwhile, students used the computer-based cognitive representation tool to articulate and represent the key elements and their interactions in the learning process. RESULTS: A significant improvement was found in students' learning products from the beginning to the end of the study, consistent with students' report of close-to-moderate progress in developing problem-solving and knowledge-construction abilities. No significant differences were found between the pretest and posttest scores with the 4-week period. The cognitive representation approach was found to provide more formative assessment. CONCLUSIONS: The computer-based cognitive representation approach improved the learning of clinical reasoning in both problem solving and knowledge construction. PMID- 25518872 TI - Childhood somatic complaints predict generalized anxiety and depressive disorders during young adulthood in a community sample. AB - BACKGROUND: Children with somatic complaints are at increased risk for emotional disorders during childhood. Whether this elevated risk extends into young adulthood - and to which specific disorders - has rarely been tested with long term prospective-longitudinal community samples. Here we test whether frequent and recurring stomach aches, headaches, and muscle aches during childhood predict emotional disorders in adulthood after accounting for childhood psychiatric and physical health status and psychosocial adversity. METHOD: The Great Smoky Mountains Study is a community representative sample with 1420 participants. Children/adolescents were assessed 4-7 times between ages 9-16 years. They were assessed again up to three times between ages 19-26 years. Childhood somatic complaints were coded when subjects or their parents reported frequent and recurrent headaches, stomach aches, or muscular/joint aches at some point when children were aged 9-16 years. Psychiatric disorders were assessed with the Child and Adolescent Psychiatric Assessment and the Young Adult Psychiatric Assessment. RESULTS: Frequent and recurrent somatic complaints in childhood predicted adulthood emotional disorders. After controlling for potential confounders, predictions from childhood somatic complaints were specific to later depression and generalized anxiety disorder. Long-term predictions did not differ by sex. Somatic complaints that persisted across developmental periods were associated with the highest risk for young adult emotional distress disorders. CONCLUSIONS: Children from the community with frequent and recurrent physical distress are at substantially increased risk for emotional distress disorders during young adulthood. Preventions and interventions for somatic complaints could help alleviate this risk. PMID- 25518873 TI - Body mass index is associated with the maternal lines but height is heritable across family lines in the Lifeways Cross-Generation Cohort Study. AB - OBJECTIVES: Overweight and obesity is a problem in children in particular and determining pathways of transmission is important in prevention. We aimed to examine associations for body mass index (BMI) across three generations of the same families. PARTICIPANTS: Members of 556 families in the Lifeways Cross Generation Cohort Study 2001-2014. SETTING: Community-based study with linkage to health records in the Republic of Ireland. METHODS: Employing a novel mixed method approach which adjusts for age and familial group, BMI correlations were estimated at three ages of the index child, that is, at birth and at ages 5 and 9. Height was also examined for comparative purposes. RESULTS: Correlation of offspring's BMI with that of the mother increased with age (correlation coefficient 0.15 increasing to 0.28, p value <0.001 in all cases) while no consistent pattern was seen with offspring and fathers. There was an association also with each parent and their own mother. Offspring's BMI was correlated to a lesser extent with that of the maternal grandmother while for girls only there was an association with that of the paternal grandmother at ages 0 and 5 (correlation coefficients 0.25, 0.28, p values 0.02, 0.01, respectively). In contrast, height of the child was strongly associated with those of all family members at age 5, but at birth and at age 9 only there was an association with those of the parents and the paternal grandfather. Correlation of offspring's height with those of the mother and father increased with age. CONCLUSIONS: The results suggest that BMI is predominantly associated with the maternal line, possibly either with intrauterine development, or inherited through the X chromosome, or both, while height is a more complex trait with genetic influences of the parents and that of the paternal grandfather predominating. PMID- 25518874 TI - A population-based study of premature mortality in relation to neighbourhood density of alcohol sales and cheque cashing outlets in Toronto, Canada. AB - OBJECTIVE: Alcohol overuse and poverty, each associated with premature death, often exist within disadvantaged neighbourhoods. Cheque cashing places (CCPs) may be opportunistically placed in disadvantaged neighbourhoods, where customers abound. We explored whether neighbourhood density of CCPs and alcohol outlets are each related to premature mortality among adults. DESIGN: Retrospective population-based study. SETTING: 140 neighbourhoods in Toronto, Ontario, 2005 2009. PARTICIPANTS: Adults aged 20-59 years. MEASURES: Our primary outcome was premature all-cause mortality among adults aged 20-59 years. Across neighbourhoods we explored neighbourhood density, in km(2), of CCPs and alcohol outlets, and the relation of each to premature mortality. Poisson regression provided adjusted relative risks (aRRs) and 95% CIs, adjusting for material deprivation quintile (Q), crime Q and number of banks. RESULTS: Intentional self harm, accidental poisoning and liver disease were among the top five causes of premature death among males aged 20-59 years. The overall premature mortality rate was 96.3/10,000 males and 55.9/10,000 females. Comparing the highest versus lowest CCP density Q, the aRR for death was 1.25 (95% CI 1.15 to 1.36) among males and 1.11 (95% CI 0.99 to 1.24) among females. The corresponding aRR comparing the highest Q versus lowest Q alcohol outlet density in relation to premature mortality was 1.36 (95% CI 1.25 to 1.48) for males and 1.11 (95% CI 1.00 to 1.24) for females. The pattern of the relation between either CCPs or alcohol outlet density and premature mortality was typically J shaped. CONCLUSIONS: There is a J-shaped relation between CCP or alcohol outlet density and premature mortality, even on controlling for conventional measures of poverty. Formal banking and alcohol reduction strategies might be added to health promotion policies aimed at reducing premature mortality in highly affected neighbourhoods. PMID- 25518876 TI - The web-based ASSO-food frequency questionnaire for adolescents: relative and absolute reproducibility assessment. AB - BACKGROUND: A new food frequency questionnaire (FFQ) has been recently developed within the Italian Adolescents and Surveillance System for the Obesity prevention (ASSO) Project; it was found to be appropriate for ranking adolescents in food and nutrient levels of intake. The aim of this study was to assess the relative and absolute reproducibility of the ASSO-FFQ for 24 food groups, energy and 52 nutrients. METHODS: A test-retest study was performed on two ASSO-FFQs administered one month apart of each other to 185 adolescents, aged 14-17 and attending secondary schools in Palermo (Italy). Wilcoxon test assessed differences in median daily intakes between the two FFQs. Agreement was evaluated by quintiles comparison and weighted kappa. Intraclass Correlation Coefficients (ICC) and Bland-Altman method assessed the relative and absolute reliability respectively. RESULTS: Significant difference (p < 0.05) in median intakes was found only for bread substitutes, savoury food, water, soft drinks, carbohydrates and sugar. The subjects classified into the same or adjacent quintiles for food groups ranged from 62% (white bread) to 91% (soft drinks); for energy and nutrients from 64% (polyunsaturated fatty acids) to 90% (ethanol). Mean values of weighted kappa were 0.47 and 0.48, respectively for food groups and nutrients. Fair to good ICC values (>0.40) were assessed for thirteen food groups, energy and forty-three nutrients. Limits of Agreement were narrow for almost all food groups and all nutrients. CONCLUSIONS: The ASSO-FFQ is a reliable instrument for estimating food groups, energy and nutrients intake in adolescents. PMID- 25518875 TI - The REFORM study protocol: a cohort randomised controlled trial of a multifaceted podiatry intervention for the prevention of falls in older people. AB - INTRODUCTION: Falls and fall-related injuries are a serious cause of morbidity and cost to society. Foot problems and inappropriate footwear may increase the risk of falls; therefore podiatric interventions may play a role in reducing falls. Two Cochrane systematic reviews identified only one study of a podiatry intervention aimed to reduce falls, which was undertaken in Australia. The REFORM trial aims to evaluate the clinical and cost-effectiveness of a multifaceted podiatry intervention in reducing falls in people aged 65 years and over in a UK and Irish setting. METHODS AND ANALYSIS: This multicentre, cohort randomised controlled trial will recruit 2600 participants from routine podiatry clinics in the UK and Ireland to the REFORM cohort. In order to detect a 10% point reduction in falls from 50% to 40%, with 80% power 890 participants will be randomised to receive routine podiatry care and a falls prevention leaflet or routine podiatry care, a falls prevention leaflet and a multifaceted podiatry intervention. The primary outcome is rate of falls (falls/person/time) over 12 months assessed by patient self-report falls diary. Secondary self-report outcome measures include: the proportion of single and multiple fallers and time to first fall over a 12 month period; Short Falls Efficacy Scale-International; fear of falling in the past 4 weeks; Frenchay Activities Index; fracture rate; Geriatric Depression Scale; EuroQoL-five dimensional scale 3-L; health service utilisation at 6 and 12 months. A qualitative study will examine the acceptability of the package of care to participants and podiatrists. ETHICS AND DISSEMINATION: The trial has received a favourable opinion from the East of England-Cambridge East Research Ethics Committee and Galway Research Ethics Committee. The trial results will be published in peer-reviewed journals and at conference presentations. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN68240461 assigned 01/07/2011. PMID- 25518877 TI - Instability after total knee arthroplasty. AB - Total knee arthroplasty (TKA) has shown to portend good long-term survivorship and excellent patient satisfaction. There are various etiologies of failure of a TKA. Instability is a major cause of the need for revision. Often, increased constraint is needed to supplement or perform the function of incompetent ligament and soft tissue structures. Posterior cruciate retaining (PCR) TKA has the least constraint. Posterior cruciate substituting (PS) TKA increases sagittal constraint. Varus-valgus constraint (VVC) adds a marked increase in coronal stability. The ultimate in constraint in TKA is a linked hinged implant. In revision TKA, it is the surgeon's responsibility to implant the prosthesis with the necessary constraint to impart adequate stability. PMID- 25518878 TI - Proactive outreach for smokers using VHA mental health clinics: protocol for a patient-randomized clinical trial. AB - BACKGROUND: Persons with a mental health diagnosis have high rates of tobacco use and face numerous barriers to cessation including high levels of nicotine dependence, low rates of tobacco treatment referrals from mental health providers, and limited availability of tobacco treatment targeted to their needs. This manuscript describes the rationale and methods of a clinical trial with the following aims: 1) Compare the reach and efficacy of a proactive telephone-based tobacco cessation program for Veterans Health Administration (VHA) mental health clinic patients to VHA usual care and 2) Model longitudinal associations between baseline patient characteristics and long-term abstinence. METHODS/DESIGN: We will use the electronic medical record to identify patients across four VHA healthcare facilities who have a clinical reminder code indicating current tobacco use in the past six months and who have had a mental health clinic visit in the past 12 months. We will send each patient an introductory letter and baseline survey. Survey respondents (N = 3840) will be randomized in a 1:1 fashion to intervention or control. Control participants will receive VHA usual care. Intervention participants will receive proactive motivational telephone outreach to offer tobacco treatment. Intervention participants interested in treatment will receive eight weeks of nicotine replacement therapy plus eight sessions of specialized telephone counseling over two months, followed by monthly maintenance counseling for four months. We will conduct telephone surveys with participants at six and 12 months to assess study outcomes. We will collect a mailed saliva sample from patients reporting 7-day abstinence on the telephone surveys. The primary outcome will be cotinine-validated abstinence at 12-month follow-up. DISCUSSION: Mental health patients are a high-risk smoking population with significant barriers to cessation. This study will evaluate the efficacy of a program that proactively reaches out to smokers with a mental health treatment history to engage them into telephone cessation counseling targeted to the needs of mental health patients. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01737281 (registered November 5, 2012). PMID- 25518880 TI - Suggestions for establishing a sustainable risk communication platform for carcinogenic factors. PMID- 25518879 TI - Stereotactic ablative body radiation therapy for tumors in the lung in octogenarians: a retrospective single institution study. AB - BACKGROUND: Treatment of cancer in the lung in octogenarians is limited by their health and functional status. Stereotactic ablative radiotherapy is an established noninvasive treatment option for medically inoperable patients, with a toxicity profile that may be more tolerable in elderly patients. METHODS: Patients more than 80 years old treated with stereotactic ablative radiotherapy for malignant tumors in the lung between January 2007 and August 2012 at a single institution were identified and retrospectively analyzed for toxicity and survival. RESULTS: Thirty patients were identified with a total of 32 lesions treated. Patients ranged in age from 80.8 to 90.7 years old (median 84.9) at the time of treatment. Twenty patients had ECOG performance status 0-1, and 10 had performance status 2-3. Stage distribution at treatment was: stage I (20 patients), stage III (1), stage IV (1), and 8 recurrent tumors. Patients were treated to a median total dose of 54 Gy in 3 fractions (range 20-60 Gy in 1 to 5 fractions). Median follow up was 13 months (range 2-60 months). Fifteen patients were still living at last review. There was one failure in field and one failure in the same lobe that was treated. One patient died with progressive regional disease, and four died of progressive metastatic disease. Three patients had late grade 3 pulmonary dyspnea with no grade 4 or 5 toxicities. One patient had late grade 2 pneumonitis, and 3 patients had late grade 1 pneumonitis. Three patients had grade 1 chest wall pain. CONCLUSIONS: Octogenarians tolerated ablative treatment with minimal toxicity. Stereotactic ablative body radiotherapy is an option to consider in treatment of elderly patients. PMID- 25518881 TI - Strategies for an effective tobacco harm reduction policy in Indonesia. AB - Tobacco consumption is a major causative agent for various deadly diseases such as coronary artery disease and cancer. It is the largest avoidable health risk in the world, causing more problems than alcohol, drug use, high blood pressure, excess body weight or high cholesterol. As countries like Indonesia prepare to develop national policy guidelines for tobacco harm reduction, the scientific community can help by providing continuous ideas and a forum for sharing and distributing information, drafting guidelines, reviewing best practices, raising funds, and establishing partnerships. We propose several strategies for reducing tobacco consumption, including advertisement interference, cigarette pricing policy, adolescent smoking prevention policy, support for smoking cessation therapy, special informed consent for smokers, smoking prohibition in public spaces, career incentives, economic incentives, and advertisement incentives. We hope that these strategies would assist people to avoid starting smoking or in smoking cessation. PMID- 25518882 TI - The survival outcomes and prognosis of stage IV non-small-cell lung cancer treated with thoracic three-dimensional radiotherapy combined with chemotherapy. AB - BACKGROUND: The impact of thoracic three-dimensional radiotherapy on the prognosis for stage IV non-small-cell lung cancer is unclear. This study is to investigate survival outcomes and prognosis in patients with stage IV non-small cell lung cancer (NSCLC) treated with thoracic three-dimensional radiotherapy and systemic chemotherapy. METHODS: Ninety three patients with stage IV NSCLC had received at least four cycles of chemotherapy and thoracic three-dimensional radiotherapy of >=40 Gy on primary tumors. The data from these patients were retrospectively analyzed. RESULTS: Of the 93 patients, the median survival time (MST) was 14.0 months, and the 1, 2, and 3-year survival rates were 54.8%, 20.4%, and 12.9%, respectively. The MST of patients received radiation dose to primary tumor >=63Gy and <63 Gy for primary tumor were 15.0 and 8.0 months, respectively (P = 0.001). Patients had metastasis to a single site and lower tumor volume (<170 cm(3)) also produced longer overall survival time (P = 0.002, P = 0.020, respectively). For patients with metastasis at a single site, thoracic radiation dose >=63 Gy remained a prognostic factor for better overall survival (P = 0.030); patients with metastases at multiple sites, radiation dose >=63 Gy had a trend to improve overall survival (P = 0.062). A multivariate analysis showed that radiation dose >=63 Gy (P = 0.017) and metastasis to a single site (P = 0.038) are associated with better overall survival, and the volume of primary tumor was marginally correlated with OS (P = 0.054). CONCLUSIONS: In combination with systemic chemotherapy, radiation dose >=63 Gy on primary tumor and metastasis to a single site are significant factors for better OS, aggressive thoracic radiotherapy may have an important role in improving OS. PMID- 25518883 TI - Varestrongylus eleguneniensis sp. n. (Nematoda: Protostrongylidae): a widespread, multi-host lungworm of wild North American ungulates, with an emended diagnosis for the genus and explorations of biogeography. AB - BACKGROUND: A putative new species of Varestrongylus has been recently recognized in wild North American ungulates based on the ITS-2 sequences of larvae isolated from feces during a wide geographic survey. No taxonomic description was provided, as adult specimens were not examined. METHODS: Lungworm specimens were collected in the terminal bronchioles of muskoxen from Quebec, and a woodland caribou from central Alberta, Canada. The L3 stage was recovered from experimentally infected slugs (Deroceras spp.). Description of specimens was based on comparative morphology and integrated approaches. Molecular identity was determined by PCR and sequencing of the ITS-2 region of the nuclear ribosomal DNA, and compared to other protostrongylids. RESULTS: Varestrongylus eleguneniensis sp. n. is established for a recently discovered protostrongylid nematode found in caribou (Rangifer tarandus), muskoxen (Ovibos moschatus) and moose (Alces americanus); hosts that collectively occupy an extensive geographic range across northern North America. Adults of Varestrongylus eleguneniensis are distinguished from congeners by a combination of characters in males (distally bifurcate gubernaculum, relatively short equal spicules not split distally, a strongly elongate and bifurcate dorsal ray, and an undivided copulatory bursa) and females (reduced provagina with hood-like fold extending ventrally across prominent genital protuberance). Third-stage larvae resemble those found among other species in the genus. The genus Varestrongylus is emended to account for the structure of the dorsal ray characteristic of V. eleguneniensis, V. alpenae, V. alces and V. longispiculatus. CONCLUSIONS: Herein we describe and name V. eleguneniensis, a pulmonary protostrongylid with Rangifer tarandus as a primary definitive host, and which secondarily infects muskoxen and moose in areas of sympatry. Biogeographic history for V. eleguneniensis and V. alpenae, the only two endemic species of Varestrongylus known from North America, appears consistent with independent events of geographic expansion with cervid hosts from Eurasia into North America during the late Pliocene and Quaternary. PMID- 25518884 TI - A point-of-care test for facing the burden of undiagnosed celiac disease in the Mediterranean area: a pragmatic design study. AB - BACKGROUND: We aimed at assessing the factors that can influence results of the dissemination of an already validated, new generation commercial Point-of-Care Test (POCT) for detecting celiac disease (CD), in the Mediterranean area, when used in settings where it was designed to be administered, especially in countries with poor resources. METHODS: Pragmatic study design. Family pediatricians at their offices in Italy, nurses and pediatricians in Slovenia and Turkey at pediatricians', schools and university primary care centers looked for CD in 3,559 (1-14 yrs), 1,480 (14-23 yrs) and 771 (1-18 yrs) asymptomatic subjects, respectively. A new generation POCT detecting IgA-tissue antitransglutaminase antibodies and IgA deficiency in a finger-tip blood drop was used. Subjects who tested positive and those suspected of having CD were referred to a Celiac Centre to undergo further investigations in order to confirm CD diagnosis. POCT Positive Predictive Value (PPV) at tertiary care (with Negative Predictive Value) and in primary care settings, and POCT and CD rates per thousand in primary care were estimated. RESULTS: At tertiary care setting, PPV of the POCT and 95% CI were 89.5 (81.3-94.3) and 90 (56-98.5) with Negative Predictive Value 98.5 (94.2-99.6) and 98.7% (92-99.8) in children and adults, respectively. In primary care settings of different countries where POCT was performed by a different number of personnel, PPV ranged from 16 to 33% and the CD and POCT rates per thousand ranged from 4.77 to 1.3 and from 31.18 to 2.59, respectively. CONCLUSIONS: Interpretation of POCT results by different personnel may influence the performance of POC but dissemination of POCT is an urgent priority to be implemented among people of countries with limited resources, such as rural populations and school children. PMID- 25518886 TI - Methy-sens Comet assay and DNMTs transcriptional analysis as a combined approach in epigenotoxicology. AB - Epigenotoxicology needs simple and fast tools to assess xenobiotic epigenetic load. This work proposes a comet assay modification designed to detect global methylation changes (Methy-sens Comet) through enzymatic digestion with two restriction enzymes (HpaII, MspI). In the methylation-sensitive protocol tested for repeatability on A549 cells, nickel chloride induced hypermethylation and decitabine-induced hypomethylation. A concomitant assessment of DNA methyltransferases (DNMTs) genes transcriptional levels has been performed, to implement a multifunctional approach to epigenotoxicology. Methy-sens Comet showed a general good repeatability and sensitivity to methylation changes while DNMTs transcriptional levels granted additional proof of xenobiotic-induced impairment of methylome maintenance. PMID- 25518885 TI - Comparison of different commercial ELISAs for detection of antibodies against porcine respiratory and reproductive syndrome virus in serum. AB - BACKGROUND: In recent years, several new ELISAs for the detection of antibodies against the porcine reproductive and respiratory disease virus (PRRSV) in pig serum have been developed. To interpret the results, specificity and sensitivity data as well as agreement to a reference ELISA must be available. In this study, three commercial ELISAs (INgezim PRRS 2.0 - ELISA II, Priocheck(r) PRRSV Ab porcine - ELISA III and CIVTEST suis PRRS E/S PLUS - ELISA IV, detecting PRRSV type 1 antibodies) were compared to a standard ELISA (IDEXX PRRS X3 Ab Test - ELISA I). The serum of three pigs vaccinated with an attenuated PRRSV live vaccine (genotype 2) was tested prior to and several times after the vaccination. Furthermore, serum samples of 245 pigs of PRRSV positive herds, 309 pigs of monitored PRRSV negative herds, 256 fatteners of assumed PRRSV negative herds with unknown herd history and 92 wild boars were tested with all four ELISAs. RESULTS: ELISAs II and III were able to detect seroconversion of vaccinated pigs with a similar reliability. According to kappa coefficient, the results showed an almost perfect agreement between ELISA I as reference and ELISA II and III (kappa > 0.8), and substantial agreement between ELISA I and ELISA IV (kappa = 0.71). Sensitivity of ELISA II, III and IV was 96.0%, 100% and 91.5%, respectively. The specificity of the ELISAs determined in samples of monitored PRRSV negative herds was 99.0%, 95.1% and 96.4%, respectively. In assumed negative farms that were not continually monitored, more positive samples were found with ELISA II to IV. The reference ELISA I had a specificity of 100% in this study. CONCLUSIONS: All tested ELISAs were able to detect a PRRSV positive herd. The specificity and sensitivity of the tested commercial ELISAs, however, differed. ELISA II had the highest specificity and ELISA III had the highest sensitivity in comparison to the reference ELISA. ELISA IV had a lower sensitivity and specificity than the other ELISAs. PMID- 25518887 TI - Assays of fibrin network properties altered by VKAs in atrial fibrillation - importance of using an appropriate coagulation trigger. AB - Atrial fibrillation (AF) is a prothrombotic condition, involving increased thrombin generation and fibrinogen concentrations. Vitamin K antagonists (VKAs) prevent arterial thromboembolism if optimal anticoagulation is achieved by individualised drug doses, assessed by determining the Prothrombin time-related International Normalized Ratio (Pt-INR). There is evidence that formation of tight-laced fibrin networks is pathogenic in prothrombotic diseases. This study was performed among AF patients, to test whether long-term treatment with VKAs affects the structure of fibrin networks, and whether the effect is altered by employing different coagulation triggers: exogenous thrombin (1 IU/ml), 10 pM tissue factor (TF) or a commercial Pt-INR reagent (containing 400-fold more TF). In the thrombin-based method, fibrin network porosity (scanning electron microscopy) and liquid permeability (flow measurements) correlated inversely to fibrinogen concentrations, while positive correlations to the degree of anticoagulation were shown with the Pt-INR reagent. In the method with 10 pM TF, the two above relationships were detected, though the influence of Pt-INR was more profound than that of fibrinogen concentrations. Moreover, greater shortening of clot lysis time (CLT) arose from more permeable clots. As a coagulation trigger, 10 pM TF vs exogenous thrombin or the Pt-INR reagent is more informative in reflecting the in vivo process from thrombin generation to fibrin formation. Since fibrin network permeability rose in parallel to elevations of INR and shortening of CLT in AF patients, antithrombotic effects on prevention of thrombotic complications may be achieved from impairment of thrombin generation, resulting in formation of permeable clots susceptible to fibrinolysis. PMID- 25518891 TI - Rice bran protein hydrolysates prevented interleukin-6- and high glucose-induced insulin resistance in HepG2 cells. AB - Rice bran, which is a byproduct of rice milling process, contains various nutrients and biologically active compounds. Rice bran protein hydrolysates have various pharmacological activities such as antidiabetic and antidyslipidemic effects. However, there are limited studies about the mechanisms of rice bran protein hydrolysates (RBP) on insulin resistance and lipid metabolism. RBP used in this study were prepared from Thai Jasmine rice. When HepG2 cells were treated with IL-6, the IRS-1 expression and Akt phosphorylation were suppressed. This effect of IL-6 was prevented by RBP in association with inhibition of STAT3 phosphorylation and SOCS3 expression. RBP could increase the phospho-AMPK levels and inhibit IL-6- or high glucose-induced suppression of AMPK and Akt activation. High glucose-induced dysregulation of the expression of lipogenic genes, including SREBP-1c, FASN and CPT-1, was normalized by RBP treatment. Moreover, impaired glucose utilization in insulin resistant HepG2 cells was significantly alleviated by concurrent treatment with RBP. Our results suggested that RBP suppresses inflammatory cytokine signaling and activates AMPK, and thereby these effects may underlie the insulin sensitizing effect. PMID- 25518892 TI - A microwave-assisted multicomponent synthesis of substituted 3,4 dihydroquinazolinones. AB - A microwave-assisted, multicomponent protocol for the synthesis of substituted 3,4-dihydroquinazolinones via a novel cascade imine/cyclization/aza-Henry reaction sequence is reported. Starting from o-formyl carbamates, a series of structurally diverse 3,4-dihydroquinazolinones was synthesized via a cyclic iminium ion intermediate in moderate to excellent yields. Notably, the reaction is fast, flexible, simple to perform and tolerates a variety of functional groups. PMID- 25518893 TI - Adherence to generic v. brand antidepressant treatment and the key role of health system factors. AB - One of the major challenges with antidepressant (AD) use is poor adherence and early treatment discontinuation. In addition to socio-demographic and clinical variables, treatment discontinuation may also be related to the capacity of the health system to assure and maintain continuity and intensity of care. Among health system factors that may interfere with adherence to pharmacological treatment, use of generic drugs may play a key role. It has been argued that, although the lower cost of generics may favour persistence on treatment, a widespread a priori scepticism about their effectiveness and safety by doctors and patients may have an opposite effect. This compelling research question has recently been addressed by an observational cohort study that involved 16 778 Medicare fee-for-service beneficiaries who received a new depression diagnosis and initiated generic v. brand AD therapy. The study found that generic initiation was associated with improved adherence. The benefits resulted from the lower out-of-pocket cost associated with generic ADs. In this commentary, we discuss the main findings of this study in view of its methodological strengths and limitations, and we suggest implications for policy. PMID- 25518894 TI - Live-cell multiplane three-dimensional super-resolution optical fluctuation imaging. AB - Super-resolution optical fluctuation imaging (SOFI) provides an elegant way of overcoming the diffraction limit in all three spatial dimensions by computing higher-order cumulants of image sequences of blinking fluorophores acquired with a classical widefield microscope. Previously, three-dimensional (3D) SOFI has been demonstrated by sequential imaging of multiple depth positions. Here we introduce a multiplexed imaging scheme for the simultaneous acquisition of multiple focal planes. Using 3D cross-cumulants, we show that the depth sampling can be increased. The simultaneous acquisition of multiple focal planes significantly reduces the acquisition time and thus the photobleaching. We demonstrate multiplane 3D SOFI by imaging fluorescently labelled cells over an imaged volume of up to 65 * 65 * 3.5 MUm(3) without depth scanning. In particular, we image the 3D network of mitochondria in fixed C2C12 cells immunostained with Alexa 647 fluorophores and the 3D vimentin structure in living Hela cells expressing the fluorescent protein Dreiklang. PMID- 25518895 TI - Attitudes and preferences for the clinical management of hypertension and hypertension-related cardiac disease in general practice: results of the Italian Hypertension and Heart Survey. AB - The aim of this study was to evaluate attitudes and preferences for the clinical management of hypertensive patients with cardiac organ disease, including left ventricular hypertrophy (LVH) and coronary artery disease (CAD), in Italy. A predefined 15-item questionnaire was anonymously administered to a large community sample of general practitioners (GPs) and specialised physicians between November 2012 and June 2013. Estimated prevalence of hypertension-related clinical conditions was stratified into four groups (10-20%, 20-40%, 40-50%, >50%); preferences were reported as percentage among valid answers to the survey questionnaire. A total of 1319 physicians (672 males, age 55.0 +/- 7.1 years, age of medical activity 27.1 +/- 7.6 years), among whom 1264 GPs and 55 specialised physicians, was included. LVH was reported to be the most frequent marker of organ damage by the majority of physicians (73.5%). LV diastolic dysfunction was reported to be relatively frequent (>40%) by more than half of the specialised physicians (58.2%) and less frequent (10-20%) by GPs (49.8%); LV systolic dysfunction, atrial fibrillation and CAD were considered to be less frequent (10 20%) by the majority of physicians (61.3, 71.6 and 53.3%, respectively). Echocardiography was the preferred diagnostic tool used to estimate LVH (76.6%). Tight blood pressure control (130/80 mm Hg) was considered to be the most appropriate by the majority of physicians, both in hypertensive patients with LVH and in those with CAD. With the well-known limitations of a cross-sectional survey, this study provides information on attitudes and preferences for the clinical management of outpatients with hypertension and high CV risk profile in general practice in Italy. PMID- 25518896 TI - Spectral analyses of systolic blood pressure and heart rate variability and their association with cognitive performance in elderly hypertensive subjects. AB - Systolic hypertension is associated with cognitive decline in the elderly. Altered blood pressure (BP) variability is a possible mechanism of reduced cognitive performance in elderly hypertensives. We hypothesized that altered beat to-beat systolic BP variability is associated with reduced global cognitive performance in elderly hypertensive subjects. In exploratory analyses, we also studied the correlation between diverse discrete cognitive domains and indices of systolic BP and heart rate variability. Disproving our initial hypothesis, we have shown that hypertension and low education, but not indices of systolic BP and heart rate variability, were independent predictors of lower global cognitive performance. However, exploratory analyses showed that the systolic BP variability in semi-upright position was an independent predictor of matrix reasoning (B = 0.08 +/- .03, P-value = 0.005), whereas heart rate variability in semi-upright position was an independent predictor of the executive function score (B = -6.36 +/- 2.55, P-value = 0.02). We conclude that myogenic vascular and sympathetic modulation of systolic BP do not contribute to reduced global cognitive performance in treated hypertensive subjects. Nevertheless, our results suggest that both systolic BP and heart rate variability might be associated with modulation of frontal lobe cognitive domains, such as executive function and matrix reasoning. PMID- 25518897 TI - Predictors of vascular remodelling in hypertensive subjects with well-controlled blood pressure levels. AB - We evaluated the structural/functional characteristics of the arterial wall in a cohort of hypertensives with well-controlled blood pressure (BP) levels. We studied 40 hypertensives with well-controlled BP. We assessed by B-mode ultrasound the mean intima-media thickness (mean-IMT) and maximum-IMT (M-MAX) of carotid artery (common, bulb, internal) bilaterally. Endothelial function was evaluated by post-occlusion flow-mediated dilation (FMD) of the brachial artery. Along with traditional risk factors, we studied the impact of serum high sensitivity C-reactive protein (hs-CRP) and osteoprotegerin (OPG). Forty normotensive subjects served as controls. In the hypertensives, the BP levels were well controlled (office BP: 129/79 mm Hg, ambulatory BP monitoring: 121/75 mm Hg). Compared with controls, higher BP levels and body mass index were present in hypertensives, whereas age and metabolic parameters were similar. In hypertensives, the IMT (mean-IMT 0.68 mm, M-MAX 0.81 mm) was significantly higher than in controls (mean-IMT 0.60 mm, M-MAX 0.71 mm). FMD was impaired in hypertensives (5.9%) compared with controls (9.2%). In multivariate analyses, it turned out that in hypertensives IMT parameters were related to age, hs-CRP and OPG. Low-density lipoprotein (LDL) cholesterol was the only factor related to FMD. IMT and FMD had no relationship with BP levels. In conclusion, in hypertensives with well-controlled BP, the pro-atherogenic remodelling (IMT) is mainly dependent on age and the inflammatory cytokines, OPG in particular. The functional impairment of the arterial wall (FMD) was related to the levels of LDL cholesterol. Under these conditions, when the impact of BP is minimized, the role of inflammatory cytokines and lipids on structural/functional remodelling becomes predominant. PMID- 25518898 TI - Hypothesis: bones toughness arises from the suppression of elastic waves. AB - Bone and other natural material exhibit a combination of strength and toughness that far exceeds that of synthetic structural materials. Bone's toughness is a result of numerous extrinsic and intrinsic toughening mechanisms that operate synergistically at multiple length scales to produce a tough material. At the system level however no theory or organizational principle exists to explain how so many individual toughening mechanisms can work together. In this paper, we utilize the concept of phonon localization to explain, at the system level, the role of hierarchy, material heterogeneity, and the nanoscale dimensions of biological materials in producing tough composites. We show that phonon localization and attenuation, using a simple energy balance, dynamically arrests crack growth, prevents the cooperative growth of cracks, and allows for multiple toughening mechanisms to work simultaneously in heterogeneous materials. In turn, the heterogeneous, hierarchal, and multiscale structure of bone (which is generic to biological materials such as bone and nacre) can be rationalized because of the unique ability of such a structure to localize phonons of all wavelengths. PMID- 25518899 TI - Scalable quantum computing based on stationary spin qubits in coupled quantum dots inside double-sided optical microcavities. AB - Quantum logic gates are the key elements in quantum computing. Here we investigate the possibility of achieving a scalable and compact quantum computing based on stationary electron-spin qubits, by using the giant optical circular birefringence induced by quantum-dot spins in double-sided optical microcavities as a result of cavity quantum electrodynamics. We design the compact quantum circuits for implementing universal and deterministic quantum gates for electron spin systems, including the two-qubit CNOT gate and the three-qubit Toffoli gate. They are compact and economic, and they do not require additional electron-spin qubits. Moreover, our devices have good scalability and are attractive as they both are based on solid-state quantum systems and the qubits are stationary. They are feasible with the current experimental technology, and both high fidelity and high efficiency can be achieved when the ratio of the side leakage to the cavity decay is low. PMID- 25518900 TI - Can community health officer-midwives effectively integrate skilled birth attendance in the community-based health planning and services program in rural Ghana? AB - BACKGROUND: The burden of maternal mortality in sub-Saharan Africa is very high. In Ghana maternal mortality ratio was 380 deaths per 100,000 live births in 2013. Skilled birth attendance has been shown to reduce maternal mortality and morbidity, yet in 2010 only 68 percent of mothers in Ghana gave birth with the assistance of skilled birth attendants. In 2005, the Ghana Health Service piloted a strategy that involved using the integrated Community-based Health Planning and Services (CHPS) program and training Community Health Officers (CHOs) as midwives to address the gap in skilled attendance in rural Upper East Region (UER). The study assesses the feasibility of and extent to which the skilled delivery program has been implemented as an integrated component of the existing CHPS, and documents the benefits and challenges of the integrated program. METHODS: We employed an intrinsic case study design with a qualitative methodology. We conducted 41 in-depth interviews with health professionals and community stakeholders. We used a purposive sampling technique to identify and interview our respondents. RESULTS: The CHO-midwives provide integrated services that include skilled delivery in CHPS zones. The midwives collaborate with District Assemblies, Non-Governmental Organizations (NGOs) and communities to offer skilled delivery services in rural communities. They refer pregnant women with complications to district hospitals and health centers for care, and there has been observed improvement in the referral system. Stakeholders reported community members' access to skilled attendants at birth, health education, antenatal attendance and postnatal care in rural communities. The CHO-midwives are provided with financial and non-financial incentives to motivate them for optimal work performance. The primary challenges that remain include inadequate numbers of CHO midwives, insufficient transportation, and infrastructure weaknesses. CONCLUSIONS: Our study demonstrates that CHOs can successfully be trained as midwives and deployed to provide skilled delivery services at the doorsteps of rural households. The integration of the skilled delivery program with the CHPS program appears to be an effective model for improving access to skilled birth attendance in rural communities of the UER of Ghana. PMID- 25518901 TI - Severity of childhood obstructive sleep apnea and hypertension improved after adenotonsillectomy. AB - OBJECTIVE: To report improvements in childhood obstructive sleep apnea (OSA) and hypertension after adenotonsillectomy. STUDY DESIGN: Case series with planned data collection. SETTING: Tertiary referral center. SUBJECTS AND METHODS: Fifty consecutive patients (36 boys and 14 girls; median age, 7.0 years) who underwent plasma knife-assisted total tonsillectomy and adenoidectomy for OSA between January 2010 and March 2013 were assessed with the body mass index z score, apnea hypopnea index (AHI), systolic blood pressure (BP), and diastolic BP at baseline and at >=6 months postoperatively. Changes in these parameters were statistically analyzed using nonparametric tests with the bootstrap approach. RESULTS: The median follow-up period was 9.6 months. Postoperatively, the median AHI significantly reduced from 9.8 to 1.6 (P<.001). Although the median systolic BP and diastolic BP insignificantly changed in the overall group, both were significantly reduced in children with preoperative hypertension (systolic: from 119.0 to 113.0 [P=.038]; diastolic: from 79.0 to 68.0 [P=.005]). Accordingly, the hypertension rate significantly reduced from 34% to 14% (P=.006). However, the change in OSA severity was not well correlated with the change in hypertension severity. In multiple logistic regression analysis with forward selection, a combination of preoperative hypertension and severe OSA was a significant predictor of postoperative hypertension (relative risk, 15.4; 95% confidence interval, 3.7-64.3; P<.001). CONCLUSION: The decreased hypertension rate indicates that a reduction of the AHI is not all that matters after adenotonsillectomy in childhood OSA. However, patients with preoperative severe OSA and hypertension need careful management of their elevated BP despite surgical treatment. PMID- 25518903 TI - Corrigendum. PMID- 25518902 TI - Extracorporeal membrane oxygenation after tonsillectomy. PMID- 25518904 TI - Comparison of 4D CT, ultrasonography, and 99mTc sestamibi SPECT/CT in localizing single-gland primary hyperparathyroidism. AB - OBJECTIVE: The present study was designed to evaluate 4D computerized tomography (CT) as a means of localizing abnormal parathyroid glands in primary hyperparathyroidism (HPT). STUDY DESIGN: Case series with expertized image review. SETTING: Tertiary care hospital. SUBJECTS AND METHODS: A total of 38 patients were recruited for study, all of whom had undergone focused parathyroidectomy for single-lesion primary HPT between June 2011 and September 2013. In each patient, 3 imaging procedures were performed: cervical ultrasonography (US), 99mTc-sestamibi SPECT/CT (SeS), and 4D CT. Collective imaging data were blindly reviewed and compared. RESULTS: 4D CT outperformed US and SeS in terms of sensitivity (P=.27), specificity (P=.01), positive predictive value (PPV) (P<.01), negative predictive value (NPV) (P=.19), and accuracy (P<.01). In 7.9% (3/38) of patients, 4D CT provided specific anatomic information that was unaffordable by US and SeS. Localization by 4D CT correlated with tissue parathyroid hormone level (P=.02), maximum diameter (P=.01), and volume (P<.01) of abnormal parathyroid glands. CONCLUSION: 4D CT proved helpful in localizing target parathyroid glands of primary HPT that were missed by traditional imaging. PMID- 25518906 TI - Chemistry in one dimension. AB - We report benchmark results for one-dimensional (1D) atomic and molecular systems interacting via the Coulomb operator |x|(-1). Using various wavefunction-type approaches, such as Hartree-Fock theory, second- and third-order Moller-Plesset perturbation theory and explicitly correlated calculations, we study the ground state of atoms with up to ten electrons as well as small diatomic and triatomic molecules containing up to two electrons. A detailed analysis of the 1D helium like ions is given and the expression of the high-density correlation energy is reported. We report the total energies, ionization energies, electron affinities and other physical properties of the many-electron 1D atoms and, using these results, we construct the 1D analog of Mendeleev's periodic table. We find that the 1D periodic table contains only two groups: the alkali metals and the noble gases. We also calculate the dissociation curves of several 1D diatomics and study the chemical bond in H2(+), HeH(2+), He2(3+), H2, HeH(+) and He2(2+). We find that, unlike their 3D counterparts, 1D molecules are primarily bound by one electron bonds. Finally, we study the chemistry of H3(+) and we discuss the stability of the 1D polymer resulting from an infinite chain of hydrogen atoms. PMID- 25518905 TI - Routine computed tomography in the evaluation of vocal fold movement impairment without an apparent cause. AB - OBJECTIVE: Routine computed tomography (CT) for vocal fold movement impairment (VFMI) without an apparent cause is common. However, given increased cancer risk associated with ionizing radiation exposure, our purpose is to evaluate the utility of routine scans for these patients. STUDY DESIGN: Retrospective case series. SETTING: Houston, Texas. SUBJECTS AND METHODS: A 5-year review of patients with VFMI diagnosed at an academic institution was conducted. For patients without an apparent cause (eg, recent head, neck, or cardiothoracic surgery or known malignancy), CT head/neck and chest was performed to evaluate the recurrent laryngeal nerve course. Data included demographics, symptoms, radiography, and interventions. Statistical analyses were performed via chi(2) analysis. RESULTS: Of 406 patients with VFMI, 47 (11%) patients had no apparent cause clinically. Routine CT revealed abnormalities in 10 (21%) patients, of which only 3 (6%) could account for VFMI: benign thyroid adenoma (1), papillary thyroid cancer (1), and an esophageal mass (1). The most common lesion detected involved the thyroid. Demographic data and symptom type were not significantly associated with detection of a VFMI-attributable lesion on CT. Overall, routine CT did not identify a focal etiology in 94% patients with VFMI without an apparent cause. CONCLUSION: Routine pan-CT evaluation failed to reveal an etiology in 94% of patients with VFMI without an apparent cause. Patients may be subjected to health risks associated with radiation exposure without significant diagnostic benefit. Further studies should consider more judicious use of CT in the context of risk factors and safer imaging modalities as the initial diagnostic step. PMID- 25518907 TI - Topological ring-currents and bond-currents in the altan-[r,s]-coronenes. AB - pi-Electron ring-currents for the altans of the four regular [r,s]-coronenes are calculated by the topological HLPM approach. The bond-current pattern of the parent structure is generally preserved in the core of the corresponding altan. Altan-[10,5]-coronene appears to support an anomalous diamagnetic current in its [4n]-periphery. This invites further investigation. PMID- 25518908 TI - Safety issues and concerns of new immunomodulators in rheumatology. AB - INTRODUCTION: The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis. Since the first anti-TNF-alpha therapies, numerous molecules have been identified as targets of immunomodulatory therapies, such as IL-1 (anakinra, canakinumab), IL-6 (tocilizumab), CD20(+) B cells (rituximab), CTLA4 (abatacept) and two additional anti-TNF-alpha therapies (certolizumab pegol, golimumab). AREAS COVERED: In the present review, we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy. The risk of infection should be identified before initiating a biologic treatment and markers checked over time, in particular for tuberculosis and hepatitis B and C viruses. Other infections (bacterial, viral, parasitic; opportunistic; surgery-related) and safety issues may require temporary interruption of the treatment until complete resolution. No significantly increased risk of malignancy, both hematological and solid, has been associated with the use of biologic agents. In all cases, it is difficult to dissect the risks related to biologics from those related to baseline treatments. EXPERT OPINION: Detailed medical history and laboratory screening should be performed before starting biologic therapies. Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects. PMID- 25518910 TI - Widespread detection of antibodies to Leptospira in feral swine in the United States. AB - As feral swine continue to expand their geographical range and distribution across the United States, their involvement in crop damage, livestock predation, and pathogen transmission is likely to increase. Despite the relatively recent discovery of feral swine involvement in the aetiology of a variety of pathogens, their propensity to transmit and carry a wide variety of pathogens is disconcerting. We examined sera from 2055 feral swine for antibody presence to six serovars of Leptospira that can also infect humans, livestock or domestic animals. About 13% of all samples tested positive for at least one serovar, suggesting that Leptospira infection is common in feral swine. Further studies to identify the proportion of actively infected animals are needed to more fully understand the risk they pose. PMID- 25518911 TI - The osteogenetic efficacy of goat bone marrow-enriched self-assembly peptide/demineralized bone matrix in vitro and in vivo. AB - In clinical practice, the prolonged duration, high cost, critical technique requirements, and ethical issues make the classical construction method of tissue engineered bones difficult to apply widely. The major essentials in tissue engineering strategies include seed cells, growth factors, and scaffolds. This study aimed to incorporate these factors in a rapid and cost-effective manner. A self-assembly peptide/demineralized bone matrix (SAP/DBM) composite was artificially established and used for bone marrow enrichment via a selective cell retention approach. Then, goat mesenchymal stem cells (gMSCs) were seeded onto the SAP/DBM or DBM. The proliferation status of gMSCs in different scaffolds was analyzed, and the osteogenetic efficacy was evaluated after osteogenic induction. Bilateral critical-sized femoral defects (20-mm in length) were created in goats, and then the defects were implanted with the postenriched composite or DBM. Then, bone scan imaging, micro-computed tomography (CT) analysis and histological examination were performed to assess the reparative effects of the different implants. Compared with the DBM scaffolds, the growth of gMSCs in the postenriched SAP/DBM composite was faster and the expression levels of the osteo specific genes (i.e., alkaline phosphatase, osteocalcin, osteopontin, and runt related transcription factor 2) were significantly higher after 14 days of osteogenic induction. More importantly, the postenriched SAP/DBM composite significantly enhanced bone metabolic activity in the defect area compared with DBM at 2 and 4 weeks postoperation. Moreover, bone reconstruction was complete in marrow-enriched SAP/DBM composite, but not in the DBM. In addition, all of the osteo-related parameters, including the ratio of bone volume to total bone volume, bone mineral density, new trabecular number, and new trabecular thickness, were significantly higher in the marrow-enriched SAP/DBM than those in the DBM. These results indicated that the SAP/DBM composite held great potential for clinical applications; immediate implantation after marrow enrichment could be a new and effective strategy for treating bone defect. PMID- 25518913 TI - Clinical Neuropathology image 1-2015: Crystal-storing histiocytosis of the central nervous system. PMID- 25518912 TI - Socioeconomic differences in the use of ill-defined causes of death in 16 European countries. AB - BACKGROUND: Cause-of-death data linked to information on socioeconomic position form one of the most important sources of information about health inequalities in many countries. The proportion of deaths from ill-defined conditions is one of the indicators of the quality of cause-of-death data. We investigated educational differences in the use of ill-defined causes of death in official mortality statistics. METHODS: Using age-standardized mortality rates from 16 European countries, we calculated the proportion of all deaths in each educational group that were classified as due to "Symptoms, signs and ill-defined conditions". We tested if this proportion differed across educational groups using Chi-square tests. RESULTS: The proportion of ill-defined causes of death was lower than 6.5% among men and 4.5% among women in all European countries, without any clear geographical pattern. This proportion statistically significantly differed by educational groups in several countries with in most cases a higher proportion among less than secondary educated people compared with tertiary educated people. CONCLUSIONS: We found evidence for educational differences in the distribution of ill-defined causes of death. However, the differences between educational groups were small suggesting that socioeconomic inequalities in cause-specific mortality in Europe are not likely to be biased. PMID- 25518915 TI - Synthesis and characterization of bimetallic metal-organic framework Cu-Ru-BTC with HKUST-1 structure. AB - The bimetallic metal-organic framework Cu-Ru-BTC with the stoichiometric formula Cu2.75Ru0.25(BTC)2.xH2O, which is isoreticular to HKUST-1, was successfully prepared in a direct synthesis using mild reaction conditions. The partial substitution of Cu(2+) by Ru(3+) centers in the paddlewheel structure and the absence of other Ru-containing phases was proven using X-ray absorption spectroscopy. PMID- 25518914 TI - Brain Tumor Epidemiology - A Hub within Multidisciplinary Neuro-oncology. Report on the 15th Brain Tumor Epidemiology Consortium (BTEC) Annual Meeting, Vienna, 2014. AB - The Brain Tumor Epidemiology Consortium (BTEC) is an open scientific forum, which fosters the development of multi-center, international and inter-disciplinary collaborations. BTEC aims to develop a better understanding of the etiology, outcomes, and prevention of brain tumors (http://epi.grants.cancer.gov/btec/). The 15th annual Brain Tumor Epidemiology Consortium Meeting, hosted by the Austrian Societies of Neuropathology and Neuro-oncology, was held on September 9 11, 2014 in Vienna, Austria. The meeting focused on the central role of brain tumor epidemiology within multidisciplinary neuro-oncology. Knowledge of disease incidence, outcomes, as well as risk factors is fundamental to all fields involved in research and treatment of patients with brain tumors; thus, epidemiology constitutes an important link between disciplines, indeed the very hub. This was reflected by the scientific program, which included various sessions linking brain tumor epidemiology with clinical neuro-oncology, tissue based research, and cancer registration. Renowned experts from Europe and the United States contributed their personal perspectives stimulating further group discussions. Several concrete action plans evolved for the group to move forward until next year's meeting, which will be held at the Mayo Clinic at Rochester, MN, USA. PMID- 25518918 TI - Real-time estimation of respiratory rate from a photoplethysmogram using an adaptive lattice notch filter. AB - BACKGROUND: Many researchers have attempted to acquire respiratory rate (RR) information from a photoplethysmogram (PPG) because respiration affects the waveform of the PPG. However, most of these methods were difficult to operate in real-time because of their complexity or computational requirements. From these needs, we attempted to develop a method to estimate RR from a PPG with a light computational burden. METHODS: To obtain RR information, we adopt a sequential filtering structure and frequency estimation technique, which extracts a dominant frequency from a given signal. In particular, we used an adaptive lattice notch filter (ALNF) to estimate RR from a PPG along with an additional heart rate that is utilized as an adaptation parameter of our method. Furthermore, we designed a sequential infinite impulse response (IIR) notch filtering system (i.e., harmonic IIR notch filter) to eliminate the cardiac component and its harmonics from the PPG. We compared the proposed method with Burg's AR modeling method, which is widely used to estimate RR from a PPG, using open-source data and measured data. RESULTS: By using a statistical test, it was determined that our adaptive lattice type respiratory rate estimator (ALRE) was significantly more accurate than Burg's AR model method (p <0.0001). Furthermore, the ALRE's tracking performance was better than that of Burg's method, and the variances of its estimates were smaller than those of Burg's method. CONCLUSIONS: In short, our method showed a better performance than Burg's AR modeling method for real-time applications. PMID- 25518919 TI - E-cadherin as a potential biomarker of malignant transformation in oral leukoplakia: a retrospective cohort study. AB - BACKGROUND: Numerous attempts have been made to establish and develop tumor markers that could determine the susceptibility of normal tissues to transform into cancerous ones. To determine whether altered expression patterns of E cadherin could be an early event in the progression of potentially malignant disorders to oral squamous cell carcinoma, this study aimed to assess the relationship between the immunoexpression of E-cadherin and the different degrees of epithelial dysplasia in oral leukoplakia. METHODS: Surgically excised specimens from patients with oral leukoplakia (n=31), oral cavity squamous cell carcinoma with cervical lymph node metastasis (n=12) and normal oral mucosa (n=9) were immunostained for E-cadherin. Oral leukoplakia samples were distributed into low and high risk group according to a binary system for grading oral epithelial dysplasia. Comparative analyses between E-cadherin expression and microscopic features (WHO histological grading and epithelial dysplasia) were performed by Pearson Chi-square test (P<0.05). RESULTS: Differences in E-cadherin expression were observed between normal oral mucosa and low risk oral leukoplakia (P=0.006), low and high risk oral leukoplakia (P=0.019), and high risk oral leukoplakia and oral cavity squamous cell carcinoma with cervical lymph node metastasis (P=0.0001). In addition, as epithelia undergo dysplastic changes, the risk of malignant transformation increases, and there is a reduction or loss of E cadherin expression by keratinocytes. Reduced E-cadherin expression was an early phenomenon and it was observed in moderate-severe dysplasia, showing that the loss of epithelial cohesion may be an indicator of progression to oral cavity squamous cell carcinoma. CONCLUSIONS: E-cadherin could be used as a novel biomarker to identify lesions with potential risk for malignant transformation, which may provide opportunities for prophylactic interventions in high risk patient groups. PMID- 25518920 TI - Endurance training or beta-blockade can partially block the energy metabolism remodeling taking place in experimental chronic left ventricle volume overload. AB - BACKGROUND: Patients with chronic aortic valve regurgitation (AR) causing left ventricular (LV) volume overload can remain asymptomatic for many years despite having a severely dilated heart. The sudden development of heart failure is not well understood but alterations of myocardial energy metabolism may be contributive. We studied the evolution of LV energy metabolism in experimental AR. METHODS: LV glucose utilization was evaluated in vivo by positron emission tomography (microPET) scanning of 6-month AR rats. Sham-operated or AR rats (n = 10-30 animals/group) were evaluated 3, 6 or 9 months post-surgery. We also tested treatment intervention in order to evaluate their impact on metabolism. AR rats (20 animals) were trained on a treadmill 5 times a week for 9 months and another group of rats received a beta-blockade treatment (carvedilol) for 6 months. RESULTS: MicroPET revealed an abnormal increase in glucose consumption in the LV free wall of AR rats at 6 months. On the other hand, fatty acid beta-oxidation was significantly reduced compared to sham control rats 6 months post AR induction. A significant decrease in citrate synthase and complex 1 activity suggested that mitochondrial oxidative phosphorylation was also affected maybe as soon as 3 months post-AR.Moderate intensity endurance training starting 2 weeks post-AR was able to partially normalize the activity of various myocardial enzymes implicated in energy metabolism. The same was true for the AR rats treated with carvedilol (30 mg/kg/d). Responses to these interventions were different at the level of gene expression. We measured mRNA levels of a number of genes implicated in the transport of energy substrates and we observed that training did not reverse the general down-regulation of these genes in AR rats whereas carvedilol normalized the expression of most of them. CONCLUSION: This study shows that myocardial energy metabolism remodeling taking place in the dilated left ventricle submitted to severe volume overload from AR can be partially avoided by exercise or beta-blockade in rats. PMID- 25518921 TI - Resurrection and redescription of Varestrongylus alces (Nematoda: Protostrongylidae), a lungworm of the Eurasian moose (Alces alces), with report on associated pathology. AB - BACKGROUND: Varestrongylus alces, a lungworm in Eurasian moose from Europe has been considered a junior synonym of Varestrongylus capreoli, in European roe deer, due to a poorly detailed morphological description and the absence of a type-series. METHODS: Specimens used in the redescription were collected from lesions in the lungs of Eurasian moose, from Vestby, Norway. Specimens were described based on comparative morphology and integrated approaches. Molecular identification was based on PCR, cloning and sequencing of the ITS-2 region of the nuclear ribosomal DNA. Phylogenetic analysis compared V. alces ITS-2 sequences to these of other Varestrongylus species and other protostrongylids. RESULTS: Varestrongylus alces is resurrected for protostrongylid nematodes of Eurasian moose from Europe. Varestrongylus alces causes firm nodular lesions that are clearly differentiated from the adjacent lung tissue. Histologically, lesions are restricted to the parenchyma with adult, egg and larval parasites surrounded by multinucleated giant cells, macrophages, eosinophilic granulocytes, lymphocytes. The species is valid and distinct from others referred to Varestrongylus, and should be separated from V. capreoli. Morphologically, V. alces can be distinguished from other species by characters in the males that include a distally bifurcated gubernaculum, arched denticulate crura, spicules that are equal in length and relatively short, and a dorsal ray that is elongate and bifurcated. Females have a well-developed provagina, and are very similar to those of V. capreoli. Morphometrics of first-stage larvae largely overlap with those of other Varestrongylus. Sequences of the ITS-2 region strongly support mutual independence of V. alces, V. cf. capreoli, and the yet undescribed species of Varestrongylus from North American ungulates. These three taxa form a well supported crown-clade as the putative sister of V. alpenae. The association of V. alces and Alces or its ancestors is discussed in light of host and parasite phylogeny and host historical biogeography. CONCLUSIONS: Varestrongylus alces is a valid species, and should be considered distinct from V. capreoli. Phylogenetic relationships among Varestrongylus spp. from Eurasia and North America are complex and consistent with faunal assembly involving recurrent events of geographic expansion, host switching and subsequent speciation. PMID- 25518922 TI - Implications of screening and childcare exclusion policies for children with Shiga-toxin producing Escherichia coli infections: lessons learned from an outbreak in a daycare centre, Norway, 2012. AB - BACKGROUND: In Norway, it is recommended that children with Shiga-Toxin producing Escherichia coli (STEC) infections are excluded from daycare centers until up to five consecutive negative stool cultures are obtained. Children with gastrointestinal illness of unknown etiology are asked to remain home for 48 hours after symptoms subside. On 16 October 2012, two cases of STEC infection were reported from a daycare center, where other children were also symptomatic. Local health authorities temporarily closed the daycare center and all children and staff were screened for pathogenic E. coli. We present the results of the outbreak investigation in order to discuss the implications of screening and the exclusion policies for children attending daycare in Norway. METHODS: Stool specimens for all children (n = 91) and employees at the daycare center (n = 40) were tested for pathogenic E. coli. Information on demographics, symptoms and potential exposures was collected from parents through trawling interviews and a web-based questionnaire. Cases were monitored to determine the duration of shedding and the resulting exclusion period from daycare. RESULTS: We identified five children with stx1- and eae-positive STEC O103:H2 infections, and one staff member and one child with STEC O91:H- infections. Three additional children who tested positive for stx1 and eae genes were considered probable STEC cases. Three cases were asymptomatic. Median length of time of exclusion from daycare for STEC cases was 53 days (range 9 days-108 days). Survey responses for 75 children revealed mild gastrointestinal symptoms among both children with STEC infections and children with negative microbiological results. There was no evidence of common exposures; person-to-person transmission was likely. CONCLUSIONS: The results of screening indicate that E. coli infections can spread in daycare centres, reflected in the proportion of children with STEC and EPEC infections. While screening can identify asymptomatic cases, the implications should be carefully considered as it can produce unanticipated results and have significant socioeconomic consequences. Daycare exclusion policies should be reviewed to address the management of prolonged asymptomatic shedders. PMID- 25518923 TI - Comparative proteomic profiling of pancreatic ductal adenocarcinoma cell lines. AB - Pancreatic cancer is one of the most fatal cancers and is associated with limited diagnostic and therapeutic modalities. Currently, gemcitabine is the only effective drug and represents the preferred first-line treatment for chemotherapy. However, a high level of intrinsic or acquired resistance of pancreatic cancer to gemcitabine can contribute to the failure of gemcitabine treatment. To investigate the underlying molecular mechanisms for gemcitabine resistance in pancreatic cancer, we performed label-free quantification of protein expression in intrinsic gemcitabine-resistant and - sensitive human pancreatic adenocarcinoma cell lines using our improved proteomic strategy, combined with filter-aided sample preparation, single-shot liquid chromatography mass spectrometry, enhanced spectral counting, and a statistical method based on a power law global error model. We identified 1931 proteins and quantified 787 differentially expressed proteins in the BxPC3, PANC-1, and HPDE cell lines. Bioinformatics analysis identified 15 epithelial to mesenchymal transition (EMT) markers and 13 EMT-related proteins that were closely associated with drug resistance were differentially expressed. Interestingly, 8 of these proteins were involved in glutathione and cysteine/methionine metabolism. These results suggest that proteins related to the EMT and glutathione metabolism play important roles in the development of intrinsic gemcitabine resistance by pancreatic cancer cell lines. PMID- 25518924 TI - miRNA-183 suppresses apoptosis and promotes proliferation in esophageal cancer by targeting PDCD4. AB - In our previous study, miRNA-183, a miRNA in the miR-96-182-183 cluster, was significantly over-expressed in esophageal squamous cell carcinoma (ESCC). In the present study, we explored the oncogenic roles of miR-183 in ESCC by gain and loss of function analysis in an esophageal cancer cell line (EC9706). Genome-wide mRNA microarray was applied to determine the genes that were regulated directly or indirectly by miR-183. 3'UTR luciferase reporter assay, RT-PCR, and Western blot were conducted to verify the target gene of miR-183. Cell culture results showed that miR-183 inhibited apoptosis (p < 0.05), enhanced cell proliferation (p < 0.05), and accelerated G1/S transition (p < 0.05). Moreover, the inhibitory effect of miR-183 on apoptosis was rescued when miR-183 was suppressed via miR 183 inhibitor (p < 0.05). Western blot analysis showed that the expression of programmed cell death 4 (PDCD4), which was predicted as the target gene of miR 183 by microarray profiling and bioinformatics predictions, decreased when miR 183 was over-expressed. The 3'UTR luciferase reporter assay confirmed that miR 183 directly regulated PDCD4 by binding to sequences in the 3'UTR of PDCD4. Pearson correlation analysis further confirmed the significant negative correlation between miR-183 and PDCD4 in both cell lines and in ESCC patients. Our data suggest that miR-183 might play an oncogenic role in ESCC by regulating PDCD4 expression. PMID- 25518925 TI - Galangin and kaempferol suppress phorbol-12-myristate-13-acetate-induced matrix metalloproteinase-9 expression in human fibrosarcoma HT-1080 cells. AB - Matrix metalloproteinase (MMP)-9 degrades type IV collagen in the basement membrane and plays crucial roles in several pathological implications, including tumorigenesis and inflammation. In this study, we analyzed the effect of flavonols on MMP-9 expression in phorbol-12-myristate-13-acetate (PMA)-induced human fibrosarcoma HT-1080 cells. Galangin and kaempferol efficiently decreased MMP-9 secretion, whereas fisetin only weakly decreased its secretion. Galangin and kaempferol did not affect cell viability at concentrations up to 30 MUM. Luciferase reporter assays showed that galangin and kaempferol decrease transcription of MMP-9 mRNA. Moreover, galangin and kaempferol strongly reduce IkappaBalpha phosphorylation and significantly decrease JNK phosphorylation. These results indicate that galangin and kaempferol suppress PMA-induced MMP-9 expression by blocking activation of NF-kappaB and AP-1. Therefore, these flavonols could be used as chemopreventive agents to lower the risk of diseases involving MMP-9. PMID- 25518926 TI - Comparative analysis of the conserved functions of Arabidopsis DRL1 and yeast KTI12. AB - Patterning of the polar axis during the early leaf developmental stage is established by cell-to-cell communication between the shoot apical meristem (SAM) and the leaf primordia. In a previous study, we showed that the DRL1 gene, which encodes a homolog of the Elongator-associated protein KTI12 of yeast, acts as a positive regulator of adaxial leaf patterning and shoot meristem activity. To determine the evolutionally conserved functions of DRL1, we performed a comparison of the deduced amino acid sequence of DRL1 and its yeast homolog, KTI12, and found that while overall homology was low, well-conserved domains were presented. DRL1 contained two conserved plant-specific domains. Expression of the DRL1 gene in a yeast KTI12-deficient yeast mutant suppressed the growth retardation phenotype, but did not rescue the caffeine sensitivity, indicating that the role of Arabidopsis Elongator-associated protein is partially conserved with yeast KTI12, but may have changed between yeast and plants in response to caffeine during the course of evolution. In addition, elevated expression of DRL1 gene triggered zymocin sensitivity, while overexpression of KTI12 maintained zymocin resistance, indicating that the function of Arabidopsis DRL1 may not overlap with yeast KTI12 with regards to toxin sensitivity. In this study, expression analysis showed that class-I KNOX genes were downregulated in the shoot apex, and that YAB and KAN were upregulated in leaves of the Arabidopsis drl1-101 mutant. Our results provide insight into the communication network between the SAM and leaf primordia required for the establishment of leaf polarity by mediating histone acetylation or through other mechanisms. PMID- 25518928 TI - MicroRNA-26a regulates RANKL-induced osteoclast formation. AB - Osteoclasts are unique cells responsible for the resorption of bone matrix. MicroRNAs (miRNAs) are involved in the regulation of a wide range of physiological processes. Here, we examined the role of miR-26a in RANKL-induced osteoclastogenesis. The expression of miR-26a was up-regulated by RANKL at the late stage of osteoclastogenesis. Ectopic expression of an miR-26a mimic in osteoclast precursor cells attenuated osteoclast formation, actin-ring formation, and bone resorption by suppressing the expression of connective tissue growth factor/CCN family 2 (CTGF/CCN2), which can promote osteoclast formation via up regulation of dendritic cell-specific transmembrane protein (DC-STAMP). On the other hand, overexpression of miR-26a inhibitor enhanced RANKL-induced osteoclast formation and function as well as CTGF expression. In addition, the inhibitory effect of miR-26a on osteoclast formation and function was prevented by treatment with recombinant CTGF. Collectively, our results suggest that miR-26a modulates osteoclast formation and function through the regulation of CTGF. PMID- 25518929 TI - Comparative N-linked glycan analysis of wild-type and alpha1,3 galactosyltransferase gene knock-out pig fibroblasts using mass spectrometry approaches. AB - Carbohydrate antigens expressed on pig cells are considered to be major barriers in pig-to-human xenotransplantation. Even after alpha1,3-galactosyltransferase gene knock-out (GalT-KO) pigs are generated, potential non-Gal antigens are still existed. However, to the best of our knowledge there is no extensive study analyzing N-glycans expressed on the GalT-KO pig tissues or cells. Here, we identified and quantified totally 47 N-glycans from wild-type (WT) and GalT-KO pig fibroblasts using mass spectrometry. First, our results confirmed the absence of galactose-alpha-1,3-galactose (alpha-Gal) residue in the GalT-KO pig cells. Interestingly, we showed that the level of overall fucosylated N-glycans from GalT-KO pig fibroblasts is much higher than from WT pig fibroblasts. Moreover, the relative quantity of the N-glycolylneuraminic acid (NeuGc) antigen is slightly higher in the GalT-KO pigs. Thus, this study will contribute to a better understanding of cellular glycan alterations on GalT-KO pigs for successful xenotransplantation. PMID- 25518927 TI - Are macrophages in tumors good targets for novel therapeutic approaches? AB - The development of cancer has been an extensively researched topic over the past few decades. Although great strides have been made in cancer prevention, diagnosis, and treatment, there is still much to be learned about cancer's micro environmental mechanisms that contribute to cancer formation and aggressiveness. Macrophages, lymphocytes which originate from monocytes, are involved in the inflammatory response and often dispersed to areas of infection to fight harmful antigens and mutated cells in tissues. Macrophages have a plethora of roles including tissue development and repair, immune system functions, and inflammation. We discuss various pathways by which macrophages get activated, various approaches that can regulate the function of macrophages, and how these approaches can be helpful in developing new cancer therapies. PMID- 25518930 TI - TLR4 mediates pneumolysin-induced ATF3 expression through the JNK/p38 pathway in Streptococcus pneumoniae-infected RAW 264.7 cells. AB - Activating transcription factor-3 (ATF3) acts as a negative regulator of cytokine production during Gram-negative bacterial infection. A recent study reported that ATF3 provides protection from Streptococcus pneumoniae infection by activating cytokines. However, the mechanism by which S. pneumoniae induces ATF3 after infection is still unknown. In this study, we show that ATF3 was upregulated via Toll-like receptor (TLR) pathways in response to S. pneumoniae infection in vitro. Induction was mediated by TLR4 and TLR2, which are in the TLR family. The expression of ATF3 was induced by pneumolysin (PLY), a potent pneumococcal virulence factor, via the TLR4 pathway. Furthermore, ATF3 induction is mediated by p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Thus, this study reveals a potential role of PLY in modulating ATF3 expression, which is required for the regulation of immune responses against pneumococcal infection in macrophages. PMID- 25518931 TI - The early induction of suppressor of cytokine signaling 1 and the downregulation of toll-like receptors 7 and 9 induce tolerance in costimulated macrophages. AB - Toll-like receptors (TLR) 7 and 9 transduce a cellular signal through the MyD88 dependent pathway and induce the production of inflammatory mediators against microbial nucleotide components. The repeated stimulation of TLR4 leads to endotoxin tolerance, but the molecular mechanisms of tolerance induced through the costimulation of individual TLR has not yet been established, although endosomal TLRs share signaling pathways with TLR4. In the present study, mouse macrophages were simultaneously stimulated with the TLR7 agonist, gardiquimod (GDQ), and the TLR9 agonist, CpG ODN 1826, to examine the mechanism and effector functions of macrophage tolerance. Compared with individual stimulation, the costimulation of both TLRs reduced the secretion of TNF-alpha and IL-6 through the delayed activation of the NF-kappaB pathway; notably, IL-10 remained unchanged in costimulated macrophages. This tolerance reflected the early induction of suppressor of cytokine signaling-1 (SOCS-1), according to the detection of elevated TNF-alpha secretion and restored NF-kappaB signaling in response to the siRNA-mediated abrogation of SOCS-1 signaling. In addition, the restimulation of each TLRs using the same ligand significantly reduced the expression of both TLRs in endosomes. These findings revealed that the costimulation of TLR7 and TLR9 induced macrophage tolerance via SOCS-1, and the restimulation of each receptor or both TLR7 and TLR9 downregulated TLR expression through a negative feedback mechanisms that protects the host from excessive inflammatory responses. Moreover, the insufficient and impaired immune response in chronic viral infection might also reflect the repeated and simultaneous stimulation of those endosomal TLRs. PMID- 25518932 TI - Itch E3 ubiquitin ligase positively regulates TGF-beta signaling to EMT via Smad7 ubiquitination. AB - TGF-beta regulates pleiotropic cellular responses including cell growth, differentiation, migration, apoptosis, extracellular matrix production, and many other biological processes. Although non-Smad signaling pathways are being increasingly reported to play many roles in TGF-beta-mediated biological processes, Smads, especially receptor-regulated Smads (R-Smads), still play a central mediatory role in TGF-beta signaling for epithelial-mesenchymal transition. Thus, the biological activities of R-Smads are tightly regulated at multiple points. Inhibitory Smad (I-Smad also called Smad7) acts as a critical endogenous negative feedback regulator of Smad-signaling pathways by inhibiting R Smad phosphorylation and by inducing activated type I TGF-beta receptor degradation. Roles played by Smad7 in health and disease are being increasingly reported, but the molecular mechanisms that regulate Smad7 are not well understood. In this study, we show that E3 ubiquitin ligase Itch acts as a positive regulator of TGF-beta signaling and of subsequent EMT-related gene expression. Interestingly, the Itch-mediated positive regulation of TGF-beta signaling was found to be dependent on Smad7 ubiquitination and its subsequent degradation. Further study revealed Itch acts as an E3 ubiquitin ligase for Smad7 polyubiquitination, and thus, that Itch is an important regulator of Smad7 activity and a positive regulator of TGF-beta signaling and of TGF-beta-mediated biological processes. Accordingly, the study uncovers a novel regulatory mechanism whereby Smad7 is controlled by Itch. PMID- 25518933 TI - Baseline neutrophil-lymphocyte ratio (>=2.8) as a prognostic factor for patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation. AB - BACKGROUND: The neutrophil-lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response and may predict the clinical outcome in some cancers, such as head and neck cancer and gastric cancer. However, the value of this ratio is variable in different cancers. Studies of the relationship between NLR and both survival and response to chemoradiation have been limited with respect to locally advanced rectal cancer. METHODS AND MATERIALS: From 2006 to 2011, 199 consecutive locally advanced rectal cancer patients who were treated with neoadjuvant chemoradiation in the Shanghai Cancer Center were enrolled and analysed retrospectively. Tumor response was evaluated by pathological findings. The baseline total white blood cell count (WBC) and the neutrophil, lymphocyte, platelet counts were recorded. The neutrophil-lymphocyte ratio (NLR) and the relationship with clinical outcomes such as overall survival (OS) and disease free survival (DFS) was analyzed. RESULTS: With ROC analysis, the baseline NLR value was found to significantly predict prognosis in terms of OS well in locally advanced rectal cancer patients. A multivariate analysis identified that a cut off value of NLR >= 2.8 could be used as an independent factor to indicate decreased OS (HR, 2.123; 95% CI, 1.140-3.954; P = 0.018). NLR >= 2.8 was also associated with worse DFS in univariate analysis (HR, 1.662; 95% CI, 1.037-2.664; P = 0.035), though it was not significant in the multivariate analysis (HR, 1.363; 95% CI, 0.840-2.214; P = 0.210). There was no observed significant correlation of mean value of NLR to the response to neoadjuvant chemoradiation. The mean NLR in the ypT0-2 N0 group was 2.68 +/- 1.38, and it was 2.77 +/- 1.38 in the ypT3-4/N+ group, with no statistical significance (P = 0.703). The mean NLR in the TRG 0-1 group was 2.68 +/- 1.42, and it was 2.82 +/- 1.33 in the TRG 2 3 group with no statistical significance (P = 0.873). CONCLUSIONS: An elevated baseline NLR is a valuable and easily available prognostic factor for OS in addition to tumor response after neoadjuvant therapy. Baseline NLR could be a useful candidate factor for stratifying patients and making treatment decisions in locally advanced rectal cancer. PMID- 25518934 TI - Calcineurin regulates the yeast synaptojanin Inp53/Sjl3 during membrane stress. AB - During hyperosmotic shock, Saccharomyces cerevisiae adjusts to physiological challenges, including large plasma membrane invaginations generated by rapid cell shrinkage. Calcineurin, the Ca(2+)/calmodulin-dependent phosphatase, is normally cytosolic but concentrates in puncta and at sites of polarized growth during intense osmotic stress; inhibition of calcineurin-activated gene expression suggests that restricting its access to substrates tunes calcineurin signaling specificity. Hyperosmotic shock promotes calcineurin binding to and dephosphorylation of the PI(4,5)P2 phosphatase synaptojanin/Inp53/Sjl3 and causes dramatic calcineurin-dependent reorganization of PI(4,5)P2-enriched membrane domains. Inp53 normally promotes sorting at the trans-Golgi network but localizes to cortical actin patches in osmotically stressed cells. By activating Inp53, calcineurin repolarizes the actin cytoskeleton and maintains normal plasma membrane morphology in synaptojanin-limited cells. In response to hyperosmotic shock and calcineurin-dependent regulation, Inp53 shifts from associating predominantly with clathrin to interacting with endocytic proteins Sla1, Bzz1, and Bsp1, suggesting that Inp53 mediates stress-specific endocytic events. This response has physiological and molecular similarities to calcineurin-regulated activity-dependent bulk endocytosis in neurons, which retrieves a bolus of plasma membrane deposited by synaptic vesicle fusion. We propose that activation of Ca(2+)/calcineurin and PI(4,5)P2 signaling to regulate endocytosis is a fundamental and conserved response to excess membrane in eukaryotic cells. PMID- 25518935 TI - Identification of protein disulfide isomerase 1 as a key isomerase for disulfide bond formation in apolipoprotein B100. AB - Apolipoprotein (apo) B is an obligatory component of very low density lipoprotein (VLDL), and its cotranslational and posttranslational modifications are important in VLDL synthesis, secretion, and hepatic lipid homeostasis. ApoB100 contains 25 cysteine residues and eight disulfide bonds. Although these disulfide bonds were suggested to be important in maintaining apoB100 function, neither the specific oxidoreductase involved nor the direct role of these disulfide bonds in apoB100 lipidation is known. Here we used RNA knockdown to evaluate both MTP-dependent and -independent roles of PDI1 in apoB100 synthesis and lipidation in McA-RH7777 cells. Pdi1 knockdown did not elicit any discernible detrimental effect under normal, unstressed conditions. However, it decreased apoB100 synthesis with attenuated MTP activity, delayed apoB100 oxidative folding, and reduced apoB100 lipidation, leading to defective VLDL secretion. The oxidative folding-impaired apoB100 was secreted mainly associated with LDL instead of VLDL particles from PDI1-deficient cells, a phenotype that was fully rescued by overexpression of wild-type but not a catalytically inactive PDI1 that fully restored MTP activity. Further, we demonstrate that PDI1 directly interacts with apoB100 via its redox active CXXC motifs and assists in the oxidative folding of apoB100. Taken together, these findings reveal an unsuspected, yet key role for PDI1 in oxidative folding of apoB100 and VLDL assembly. PMID- 25518937 TI - The volumes and transcript counts of single cells reveal concentration homeostasis and capture biological noise. AB - Transcriptional stochasticity can be measured by counting the number of mRNA molecules per cell. Cell-to-cell variability is best captured in terms of concentration rather than molecule counts, because reaction rates depend on concentrations. We combined single-molecule mRNA counting with single-cell volume measurements to quantify the statistics of both transcript numbers and concentrations in human cells. We compared three cell clones that differ only in the genomic integration site of an identical constitutively expressed reporter gene. The transcript number per cell varied proportionally with cell volume in all three clones, indicating concentration homeostasis. We found that the cell-to cell variability in the mRNA concentration is almost exclusively due to cell-to cell variation in gene expression activity, whereas the cell-to-cell variation in mRNA number is larger, due to a significant contribution of cell volume variability. We concluded that the precise relationship between transcript number and cell volume sets the biological stochasticity of living cells. This study highlights the importance of the quantitative measurement of transcript concentrations in studies of cell-to-cell variability in biology. PMID- 25518936 TI - Asef controls vascular endothelial permeability and barrier recovery in the lung. AB - Increased levels of hepatocyte growth factor (HGF) in injured lungs may reflect a compensatory response to diminish acute lung injury (ALI). HGF-induced activation of Rac1 GTPase stimulates endothelial barrier protective mechanisms. This study tested the involvement of Rac-specific guanine nucleotide exchange factor Asef in HGF-induced endothelial cell (EC) cytoskeletal dynamics and barrier protection in vitro and in a two-hit model of ALI. HGF induced membrane translocation of Asef and stimulated Asef Rac1-specific nucleotide exchange activity. Expression of constitutively activated Asef mutant mimicked HGF-induced peripheral actin cytoskeleton enhancement. In contrast, siRNA-induced Asef knockdown or expression of dominant-negative Asef attenuated HGF-induced Rac1 activation evaluated by Rac GTP pull down and FRET assay with Rac1 biosensor. Molecular inhibition of Asef attenuated HGF-induced peripheral accumulation of cortactin, formation of lamellipodia-like structures, and enhancement of VE-cadherin adherens junctions and compromised HGF-protective effect against thrombin-induced RhoA GTPase activation, Rho-dependent cytoskeleton remodeling, and EC permeability. Intravenous HGF injection attenuated lung inflammation and vascular leak in the two-hit model of ALI induced by excessive mechanical ventilation and thrombin signaling peptide TRAP6. This effect was lost in Asef(-/-) mice. This study shows for the first time the role of Asef in HGF-mediated protection against endothelial hyperpermeability and lung injury. PMID- 25518938 TI - Cytoskeletal forces during signaling activation in Jurkat T-cells. AB - T-cells are critical for the adaptive immune response in the body. The binding of the T-cell receptor (TCR) with antigen on the surface of antigen-presenting cells leads to cell spreading and signaling activation. The underlying mechanism of signaling activation is not completely understood. Although cytoskeletal forces have been implicated in this process, the contribution of different cytoskeletal components and their spatial organization are unknown. Here we use traction force microscopy to measure the forces exerted by Jurkat T-cells during TCR activation. Perturbation experiments reveal that these forces are largely due to actin assembly and dynamics, with myosin contractility contributing to the development of force but not its maintenance. We find that Jurkat T-cells are mechanosensitive, with cytoskeletal forces and signaling dynamics both sensitive to the stiffness of the substrate. Our results delineate the cytoskeletal contributions to interfacial forces exerted by T-cells during activation. PMID- 25518939 TI - PAR3 and aPKC regulate Golgi organization through CLASP2 phosphorylation to generate cell polarity. AB - The organization of the Golgi apparatus is essential for cell polarization and its maintenance. The polarity regulator PAR complex (PAR3, PAR6, and aPKC) plays critical roles in several processes of cell polarization. However, how the PAR complex participates in regulating the organization of the Golgi remains largely unknown. Here we demonstrate the functional cross-talk of the PAR complex with CLASP2, which is a microtubule plus-end-tracking protein and is involved in organizing the Golgi ribbon. CLASP2 directly interacted with PAR3 and was phosphorylated by aPKC. In epithelial cells, knockdown of either PAR3 or aPKC induced the aberrant accumulation of CLASP2 at the trans-Golgi network (TGN) concomitantly with disruption of the Golgi ribbon organization. The expression of a CLASP2 mutant that inhibited the PAR3-CLASP2 interaction disrupted the organization of the Golgi ribbon. CLASP2 is known to localize to the TGN through its interaction with the TGN protein GCC185. This interaction was inhibited by the aPKC-mediated phosphorylation of CLASP2. Furthermore, the nonphosphorylatable mutant enhanced the colocalization of CLASP2 with GCC185, thereby perturbing the Golgi organization. On the basis of these observations, we propose that PAR3 and aPKC control the organization of the Golgi through CLASP2 phosphorylation. PMID- 25518942 TI - Conformational modulation of peptides using beta-amino benzenesulfonic acid ((S)Ant). AB - This communication describes the utility of a conformationally restricted aromatic beta-amino acid (2-aminobenzenesulfonic acid, (S)Ant) inducing various folding interactions in short peptides. Sandwiching (S)Ant between diverse amino acid residues was shown to form robust folded architectures featuring a variety of H-bonded networks, suggesting its utility in inducing peptide folding. PMID- 25518941 TI - c-di-GMP induction of Dictyostelium cell death requires the polyketide DIF-1. AB - Cell death in the model organism Dictyostelium, as studied in monolayers in vitro, can be induced by the polyketide DIF-1 or by the cyclical dinucleotide c di-GMP. c-di-GMP, a universal bacterial second messenger, can trigger innate immunity in bacterially infected animal cells and is involved in developmental cell death in Dictyostelium. We show here that c-di-GMP was not sufficient to induce cell death in Dictyostelium cell monolayers. Unexpectedly, it also required the DIF-1 polyketide. The latter could be exogenous, as revealed by a telling synergy between c-di-GMP and DIF-1. The required DIF-1 polyketide could also be endogenous, as shown by the inability of c-di-GMP to induce cell death in Dictyostelium HMX44A cells and DH1 cells upon pharmacological or genetic inhibition of DIF-1 biosynthesis. In these cases, c-di-GMP-induced cell death was rescued by complementation with exogenous DIF-1. Taken together, these results demonstrated that c-di-GMP could trigger cell death in Dictyostelium only in the presence of the DIF-1 polyketide or its metabolites. This identified another element of control to this cell death and perhaps also to c-di-GMP effects in other situations and organisms. PMID- 25518940 TI - The Dictyostelium prestalk inducer differentiation-inducing factor-1 (DIF-1) triggers unexpectedly complex global phosphorylation changes. AB - Differentiation-inducing factor-1 (DIF-1) is a polyketide that induces Dictyostelium amoebae to differentiate as prestalk cells. We performed a global quantitative screen for phosphorylation changes that occur within the first minutes after addition of DIF-1, using a triple-label SILAC approach. This revealed a new world of DIF-1-controlled signaling, with changes in components of the MAPK and protein kinase B signaling pathways, components of the actinomyosin cytoskeletal signaling networks, and a broad range of small GTPases and their regulators. The results also provide evidence that the Ca(2+)/calmodulin dependent phosphatase calcineurin plays a role in DIF-1 signaling to the DimB prestalk transcription factor. At the global level, DIF-1 causes a major shift in the phosphorylation/dephosphorylation equilibrium toward net dephosphorylation. Of interest, many of the sites that are dephosphorylated in response to DIF-1 are phosphorylated in response to extracellular cAMP signaling. This accords with studies that suggest an antagonism between the two inducers and also with the rapid dephosphorylation of the cAMP receptor that we observe in response to DIF-1 and with the known inhibitory effect of DIF-1 on chemotaxis to cAMP. All MS data are available via ProteomeXchange with identifier PXD001555. PMID- 25518943 TI - Distinct metabolic responses of an ovarian cancer stem cell line. AB - BACKGROUND: Cancer metabolism is emerging as an important focus area in cancer research. However, the in vitro cell culture conditions under which much cellular metabolism research is performed differ drastically from in vivo tumor conditions, which are characterized by variations in the levels of oxygen, nutrients like glucose, and other molecules like chemotherapeutics. Moreover, it is important to know how the diverse cell types in a tumor, including cancer stem cells that are believed to be a major cause of cancer recurrence, respond to these variations. Here, in vitro environmental perturbations designed to mimic different aspects of the in vivo environment were used to characterize how an ovarian cancer cell line and its derived, isogenic cancer stem cells metabolically respond to environmental cues. RESULTS: Mass spectrometry was used to profile metabolite levels in response to in vitro environmental perturbations. Docetaxel, the chemotherapeutic used for this experiment, caused significant metabolic changes in amino acid and carbohydrate metabolism in ovarian cancer cells, but had virtually no metabolic effect on isogenic ovarian cancer stem cells. Glucose deprivation, hypoxia, and the combination thereof altered ovarian cancer cell and cancer stem cell metabolism to varying extents for the two cell types. Hypoxia had a much larger effect on ovarian cancer cell metabolism, while glucose deprivation had a greater effect on ovarian cancer stem cell metabolism. Core metabolites and pathways affected by these perturbations were identified, along with pathways that were unique to cell types or perturbations. CONCLUSIONS: The metabolic responses of an ovarian cancer cell line and its derived isogenic cancer stem cells differ greatly under most conditions, suggesting that these two cell types may behave quite differently in an in vivo tumor microenvironment. While cancer metabolism and cancer stem cells are each promising potential therapeutic targets, such varied behaviors in vivo would need to be considered in the design and early testing of such treatments. PMID- 25518944 TI - Trust in health information websites: A systematic literature review on the antecedents of trust. AB - Health websites are important sources of information for consumers. In choosing websites, trust in websites largely determines which website to access and how to best utilize the information. Thus, it is critical to understand why consumers trust certain websites and distrust others. A systematic literature review was conducted with the goal of identifying the antecedents of trust in health information websites. After four rounds of screening process, 20 articles between 2000 and 2013 were harvested. Factors that determine trust are classified into individual difference antecedents, website-related antecedents, and consumer-to website interaction-related antecedents. The most frequently studied antecedents were socio-demographics, information quality, appearance, and perceived reputation of the website. Each antecedent of trust are discussed in detail and future research directions are proposed. PMID- 25518945 TI - Intergenerational transfer of blood pressure knowledge and screening: a school based hypertension awareness program in Singapore. AB - OBJECTIVE: This study aims to examine the efficacy of a hypertension awareness education program in Singapore in reaching out to a wider population of diverse racial and intergenerational cohorts by dispatching grade five children as information intermediaries to their immediate and extended family members. METHOD: After receiving structured instruction and training on blood pressure screening, students were requested to share knowledge gained in school with their family members at home and practice blood pressure measurement on family volunteers. We assessed pre- and post-program blood pressure knowledge change, attitude toward screening, and the diffusion of blood pressure information. One adult family member was also asked to complete a short survey at the program end. RESULTS: A comparison of the students' (final n = 3926) pre- and post-program survey data showed that knowledge and attitudes towards knowledge sharing improved after participating in the program. The post-program survey also revealed that students generally felt confident and displayed positive attitudes in performing blood pressure screening on family members. On average, each student practiced blood pressure measurement on 3.04 people. Female family members were more likely to be targeted for knowledge sharing and screening than male family members. The family members' survey revealed positive attitudes towards screening, but family members were not confident about getting their measurements done regularly. CONCLUSION: The program met its objectives in raising the awareness of grade five children and provision of knowledge. It also met the larger objective of raising hypertension awareness in a wider population, especially those who otherwise might not directly receive health education and blood pressure screening. PMID- 25518948 TI - Enhancing catalytic activity and stability for CO2 methanation on Ni@MOF-5 via control of active species dispersion. AB - A novel, highly active catalyst Ni@MOF-5 showed unexpected activity at low temperature for CO2 methanation. The characterization results indicated that Ni was uniformly and highly dispersed over MOF-5. This catalyst showed high stability and almost no deactivation in long term stability tests up to 100 h. PMID- 25518946 TI - Association of urinary calcium excretion with serum calcium and vitamin D levels. AB - BACKGROUND AND OBJECTIVES: Population-based data on urinary calcium excretion are scarce. The association of serum calcium and circulating levels of vitamin D [25(OH)D2 or D3] with urinary calcium excretion in men and women from a population-based study was explored. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Multivariable linear regression was used to explore factors associated with square root-transformed 24-hour urinary calcium excretion (milligrams per 24 hours) taken as the dependent variable with a focus on month specific vitamin D tertiles and serum calcium in the Swiss Survey on Salt Study. RESULTS: In total, 624 men and 669 women were studied with mean ages of 49.2 and 47.0 years, respectively (age range=15-95 years). Mean urinary calcium excretion was higher in men than in women (183.05 versus 144.60 mg/24 h; P<0.001). In adjusted models, the association (95% confidence interval) of square root urinary calcium excretion with protein-corrected serum calcium was 1.78 (95% confidence interval, 1.21 to 2.34) mg/24 h per milligram per deciliter in women and 0.59 (95% confidence interval, -0.11 to 1.29) mg/24 h per milligram per deciliter in men. Men in the third 25(OH)D3 tertile had higher square root urinary calcium excretion than men in the first tertile (0.99; 95% confidence interval, 0.36 to 1.63 mg/24 h per nanogram per milliliter), and the corresponding association was 0.32 (95% confidence interval, -0.22 to 0.85) mg/24 h per nanogram per milliliter in women. These sex differences were more marked under conditions of high urinary sodium or urea excretions. CONCLUSIONS: There was a positive association of serum calcium with urinary calcium excretion in women but not men. Vitamin 25(OH)D3 was associated with urinary calcium excretion in men but not women. These results suggest important sex differences in the hormonal and dietary control of urinary calcium excretion. PMID- 25518947 TI - Cyclovirus CyCV-VN species distribution is not limited to Vietnam and extends to Africa. AB - Cycloviruses, small ssDNA viruses of the Circoviridae family, have been identified in the cerebrospinal fluid from symptomatic human patients. One of these species, cyclovirus-Vietnam (CyCV-VN), was shown to be restricted to central and southern Vietnam. Here we report the detection of CyCV-VN species in stool samples from pigs and humans from Africa, far beyond their supposed limited geographic distribution. PMID- 25518949 TI - Performances of two different panfungal PCRs to detect mould DNA in formalin fixed paraffin-embedded tissue: what are the limiting factors? AB - BACKGROUND: Detection of fungal DNA from formalin-fixed, paraffin-embedded (FFPE) tissue is challenging due to degradation of DNA and presence of PCR inhibitors in these samples. We analyzed FFPE samples of 26 patients by panfungal PCR and compared the results to the composite diagnosis according to the European Organization for Research and Treatment of Cancer (EORTC) criteria. Additionally we analyzed the quality of human and fungal DNA and their level of age-dependent degradation, as well as the existence of PCR inhibition in these tissue samples. METHODS: We evaluated two 45-cycle panfungal PCR tests that target the internal transcribed spacer 2 (ITS2) as well as the ITS1-5.8S-ITS2 (ITS1-2) region. The PCRs were applied to 27 FFPE specimens from 26 patients with proven invasive fungal disease (IFD), and one patient with culture and histologically negative but PCR-positive fungal infection collected at our institution from 2003 to 2010. Quality of DNA in FFPE tissue samples was evaluated using fragments of the beta globin gene for multiplex PCR, inhibition of PCR amplification was evaluated by spiking of C. krusei DNA to each PCR premix. RESULTS: In 27 FFPE samples the ITS2 PCR targeting the shorter fragment showed a higher detection rate with a sensitivity of 53.8% compared to the ITS1-2 fragment (sensitivity 38%). Significant time-dependent degradation of human DNA in FFPE sample extracts was detected based on partial beta-globin gene amplification which was not in correlation to successful panfungal PCR identification of fungal organisms. The analytical sensitivity of both assays compared with culture was 60 CFU/ml of a Candida krusei reference strain. The performance of the two tests in an Aspergillus proficiency panel of an international external quality assessment programme showed considerable sensitivity. CONCLUSION: Panfungal diagnostic PCR assays applied on FFPE specimens provide accurate identification of molds in highly degraded tissue samples and correct identification in samples stored up to 7 years despite sensitivity limitations, mainly caused by partial PCR inhibition and DNA degradation by formalin. PMID- 25518950 TI - Diagnostic yield and safety of CT scans in ICU. AB - PURPOSE: Critically ill patients often require CT scans. Adverse events (AE) can occur during intra-hospital transport (IHT). The aim of this prospective study was to determine the diagnostic and therapeutic yield and the safety of CT scans in ICU patients. METHODS: All ICU patients having a CT scan for diagnostic purposes were eligible. Diagnostic yield was evaluated by the agreement (full, partial or disagreement) between the physician main diagnostic hypothesis before the CT scan and the diagnosis established after the CT scan. Therapeutic yield was assessed by therapeutic changes after the CT scan. The safety was determined by the AE rate during IHT. RESULTS: A total of 533 CT scans were performed on 359 patients in three teaching hospital ICUs. The diagnostic yield of CT scan showed 40.7 % of full agreement, 5.6 % of partial agreement and 53.7 % of disagreement with the main diagnostic hypothesis formulated before the CT scan. The CT-scan brought new elements to the diagnosis in 22.9 % of the cases. There was 54.4 % of therapeutic change after CT scan, while 22.3 % of AE occurred during IHT, including 6.7 % of life-threatening events. AE occurred more frequently in the first 48 h after ICU admission, in the most severely ill patients (higher SAPS II at admission), and when there was a large amount of equipment required for transport. CONCLUSIONS: The CT scan as a diagnostic procedure invalidated a diagnostic hypothesis and led to a therapeutic change in more than half of the cases. PMID- 25518952 TI - Sepsis: needs for defining severity. PMID- 25518951 TI - Chloride-liberal vs. chloride-restrictive intravenous fluid administration and acute kidney injury: an extended analysis. AB - PURPOSE: In a previous study, restricting intravenous chloride administration in ICU patients decreased the incidence of acute kidney injury (AKI). To test the robustness of this finding, we extended our observation period to 12 months. METHODS: The study extension included a 1-year control period (18 August 2007 to 17 August 2008) and a 1-year intervention period (18 February 2009 to 17 February 2010). During the extended control period, patients received standard intravenous fluids. During the extended intervention period, we continued to restrict all chloride-rich fluids. We used the Kidney Disease: Improving Global Outcomes (KDIGO) staging to define AKI. RESULTS: We studied 1,476 control and 1,518 intervention patients. Stages 2 and 3 of KDIGO defined AKI decreased from 302 (20.5 %; 95 % CI, 18.5-22.6 %) to 238 (15.7 %; 95 % CI, 13.9-17.6 %) (P < 0.001) and the use of RRT from 144 (9.8 %; 95 % CI, 8.3-11.4 %) to 103 (6.8 %; 95 % CI, 5.6-8.2 %) (P = 0.003). After adjustment for relevant covariates, liberal chloride therapy remained associated with a greater risk of KDIGO stages 2 and 3 [hazard ratio 1.32 (95 % CI 1.11-1.58); P = 0.002] and use of RRT [hazard ratio 1.44 (95 % CI 1.10-1.88); P = 0.006]. However, on sensitivity assessment of each 6-month period, KDIGO stages 2 and 3 increased in the new extended intervention period compared with the original intervention period. CONCLUSIONS: On extended assessment, the overall impact of restricting chloride-rich fluids on AKI remained. However, sensitivity analysis suggested that other unidentified confounders may have also contributed to fluctuations in the incidence of AKI. PMID- 25518954 TI - A 'work smarter, not harder' approach to improving healthcare quality. PMID- 25518953 TI - Effects of levosimendan for low cardiac output syndrome in critically ill patients: systematic review with meta-analysis and trial sequential analysis. AB - PURPOSE: To assess the benefits and harms of levosimendan for low cardiac output syndrome in critically ill patients. METHODS: We conducted a systematic review with meta-analyses and trial sequential analyses (TSA) of randomised clinical trials comparing levosimendan with any type of control. Two reviewers independently assessed studies for inclusion. The Cochrane Collaboration methodology was used. Random-effects risk ratios (RR) and 95 % confidence intervals (CI) were derived for the principal primary outcome mortality at maximal follow-up. RESULTS: A total of 88 trials were included in the systematic review and 49 trials (6,688 patients) in the meta-analysis. One trial had low risk of bias and nine trials (2,490 patients) were considered lower risk of bias. Trials compared levosimendan with placebo, control interventions, and other inotropes. Pooling all trials including heterogenous populations was considered inappropriate. Pooled analysis of 30 trials including critically ill patients not having cardiac surgery showed an association between levosimendan and mortality (RR 0.83, TSA-adjusted 95 % CI 0.59-0.97), while trials with lower risk of bias showed no significant difference (RR 0.83, TSA-adjusted 95 % CI 0.48-1.55). Conventional meta-analysis of all 14 trials including cardiac surgery patients showed an association, while lower risk of bias trials showed no association between levosimendan and mortality (RR 0.52, 95 % CI 0.37-0.73 versus RR 1.02, 95 % CI 0.48-2.16). CONCLUSIONS: The available evidence is inconclusive whether or not levosimendan may have a beneficial effect on mortality due to risks of systematic errors and random errors. Further well-designed randomised trials are needed. PMID- 25518955 TI - The dynamically evolving nematocyst content of an anthozoan, a scyphozoan, and a hydrozoan. AB - Nematocytes, the stinging cells of cnidarians, are the most evolutionarily ancient venom apparatus. These nanosyringe-like weaponry systems reach pressures of approximately 150 atmospheres before discharging and punching through the outer layer of the prey or predator at accelerations of more than 5 million g, making them one of the fastest biomechanical events known. To gain better understanding of the function of the complex, phylum-specific nematocyst organelle, and its venom payload, we compared the soluble nematocyst's proteome from the sea anemone Anemonia viridis, the jellyfish Aurelia aurita, and the hydrozoan Hydra magnipapillata, each belonging to one of the three basal cnidarian lineages which diverged over 600 Ma. Although the basic morphological and functional characteristics of the nematocysts of the three organisms are similar, out of hundreds of proteins identified in each organism, only six are shared. These include structural proteins, a chaperone which may help maintain venon activity over extended periods, and dickkopf, an enigmatic Wnt ligand which may also serve as a toxin. Nevertheless, many protein domains are shared between the three organisms' nematocyst content suggesting common proteome functionalities. The venoms of Hydra and Aurelia appear to be functionally similar and composed mainly of cytotoxins and enzymes, whereas the venom of the Anemonia is markedly unique and based on peptide neurotoxins. Cnidarian venoms show evidence for functional recruitment, yet evidence for diversification through positive selection, common to other venoms, is lacking. The final injected nematocyst payload comprises a mixture of dynamically evolving proteins involved in the development, maturation, maintenance, and discharge of the nematocysts, which is unique to each organism and potentially to each nematocyst type. PMID- 25518957 TI - Why do patients with neurodegenerative frontal syndrome fail to answer: 'In what way are an orange and a banana alike?'. AB - Concept formation is the ability to create an abstract link between dissimilar objects or thoughts and is crucial for abstract and creative thinking. This process is related to the integrity of the prefrontal cortex, given the altered performances reported in patients with frontal damage, particularly those suffering from the behavioural variant of frontotemporal dementia. However, the cognitive mechanisms and neural bases of verbal concept formation are not clearly understood. The present study was aimed at addressing the following unresolved issues regarding concept formation in the field of neurology and cognitive neuroscience: (i) Are alterations in concept formation specific to frontotemporal dementia or are they also present in other cortical neurodegenerative disorders such as Alzheimer's disease? (ii) Is impaired performance in concept formation due to cortical lesions specific to frontotemporal dementia or to a cortico subcortical frontal syndrome? and (iii) What are the cognitive mechanisms and neural bases underlying concept formation? To address these questions, we designed the Verbal Concept Formation Task, an experimental paradigm based on the similarities test. Patients presenting with severe frontal dysfunction (frontotemporal dementia, n = 18, and the Richardson form of progressive supranuclear palsy, n = 21) or with medial temporal pathology (amnestic mild cognitive impairment or Alzheimer's disease, n = 14) and healthy participants (n = 18) were given the Verbal Concept Formation Task and a large battery of neuropsychological tests. In addition, all participants underwent 3D T1-weighted MRI to analyse grey matter volume using voxel-based morphometry. Frontal patients were significantly impaired on the Verbal Concept Formation Task as compared to non-frontal participants (P = 0.00001). Global performance score was positively correlated with scores in cognitive tasks assessing executive functions and with grey matter volume in several areas, mostly in the frontal-basal-ganglion network. Two types of errors were observed in frontal patients. The most frequent was discriminating instead of grouping items ('linking deficit'). Patients also linked items on a concrete instead of an abstract basis ('abstraction deficit'). Linking and abstraction deficits were related to partially different areas: the linking deficit to the dorsal anterior cingulate cortex, right middle frontal gyrus and both inferior parietal lobules and the abstraction deficit to the head of the caudate nuclei and the left superior frontal gyrus. These data suggest that verbal concept formation requires the integrity of the prefrontal-basal ganglion functional network. In addition, it can be divided into two distinct cognitive processes, which are underlain by two partially different neural networks. PMID- 25518958 TI - Genetic manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer's disease. AB - In adult mammals, neural progenitors located in the dentate gyrus retain their ability to generate neurons and glia throughout lifetime. In rodents, increased production of new granule neurons is associated with improved memory capacities, while decreased hippocampal neurogenesis results in impaired memory performance in several memory tasks. In mouse models of Alzheimer's disease, neurogenesis is impaired and the granule neurons that are generated fail to integrate existing networks. Thus, enhancing neurogenesis should improve functional plasticity in the hippocampus and restore cognitive deficits in these mice. Here, we performed a screen of transcription factors that could potentially enhance adult hippocampal neurogenesis. We identified Neurod1 as a robust neuronal determinant with the capability to direct hippocampal progenitors towards an exclusive granule neuron fate. Importantly, Neurod1 also accelerated neuronal maturation and functional integration of new neurons during the period of their maturation when they contribute to memory processes. When tested in an APPxPS1 mouse model of Alzheimer's disease, directed expression of Neurod1 in cycling hippocampal progenitors conspicuously reduced dendritic spine density deficits on new hippocampal neurons, to the same level as that observed in healthy age-matched control animals. Remarkably, this population of highly connected new neurons was sufficient to restore spatial memory in these diseased mice. Collectively our findings demonstrate that endogenous neural stem cells of the diseased brain can be manipulated to become new neurons that could allow cognitive improvement. PMID- 25518960 TI - A self-assembled 3D Pt/TiO2 architecture for high-performance photocatalytic hydrogen production. AB - A 3D Pt/TiO2 architecture assembled from 1D nanowires has been designed and successfully prepared by an environmentally-friendly one-pot solvothermal process. The formation mechanism has been investigated and the unique architecture exhibits an excellent photocatalytic hydrogen production rate as high as 13.33 mmol h(-1) g(-1), the corresponding apparent quantum efficiency reaches 34%. PMID- 25518959 TI - Decision making on unsafe abortions in Sri Lanka: a case-control study. AB - BACKGROUND: Following an unintended pregnancy, not every woman would invariably choose to undergo an unsafe abortion. It suggests that in the decision making process, women face both 'push' factors that favour abortion and 'pull' factors that work against it. This study assessed the circumstances that surrounded a woman's decision to undergo an unsafe abortion, compared to a decision to continue, when faced with an unintended pregnancy in Sri Lanka. METHODS: An unmatched case-control study was conducted among 171 women admitted to nine hospitals in eight districts following an unsafe abortion (Cases) and 600 women admitted to the same hospitals for delivery of an unintended term pregnancy (Controls). Interviewer-administered-questionnaires and in-depth interviews assessed women's characteristics, decision making process and underlying reasons for their decision. The risk of abortion related to their decision making was assessed using odds ratio (OR) and 95% confidence interval (CI). RESULTS: Compared to controls, the cases were significantly less-educated, employed, unmarried and primi-gravid (p < 0.05). All knew the 'illegal' status of abortion, mainly through media (65.5% cases versus 80% controls). When making a decision, the risk of undergoing an unsafe abortion was significant among those who sought assistance (44% versus 32%; OR = 1.7 (95% CI = 1.2-2.4)), with more reliance placed on non-medical sources such as spouse/partner, friend, neighbour and family/relation. Speaking to women with past experience of induced abortions (31% versus 21.5%; OR = 1.6 (1.1-2.4) and failure in making the final decision with partners also imparted a significant risk for abortion (64% versus 34%; OR = 3.4; 2.4-4.8). A decision favouring unsafe abortion was predominantly based on their economic instability (29.5%) and poor support by partners (14%), whereas a decision against it was based on ethical considerations (44% religious beliefs: 12% social stigma) over its legal implications (4%). Most abortions were performed by unqualified persons (36.1% self proclaimed abortionists; 26.2% not revealed their qualifications) for a wide range of payment in non-sterile environments (45.9% unknown place) using septic procedures (38.5% trans-vaginal insertions; 24.6% unaware of the procedure). CONCLUSIONS: Women's risk of unsafe abortion was associated with unreliable sources of information during decision making that led to poor knowledge and positive attitudes on its safety; poor access to affordable abortion services; and their economic instability. PMID- 25518956 TI - Reducing lost to follow-up in a large clinical trial of prevention of mother-to child transmission of HIV: the Breastfeeding, Antiretrovirals and Nutrition study experience. AB - BACKGROUND/AIMS: Retaining patients in prevention of mother-to-child transmission of HIV studies can be challenging in resource-limited settings, where high lost to follow-up rates have been reported. In this article, we describe the effectiveness of methods used to encourage retention in the Breastfeeding, Antiretrovirals, and Nutrition study and analyze factors associated with lost to follow-up in the study. METHODS: The Breastfeeding, Antiretrovirals, and Nutrition clinical trial was designed to evaluate the efficacy of three different mother-to-child HIV transmission prevention strategies. Lower than expected participant retention prompted enhanced efforts to reduce lost to follow-up during the conduct of the trial. Following study completion, we employed regression modeling to determine predictors of perfect attendance and variables associated with being lost to follow-up. RESULTS: During the study, intensive tracing efforts were initiated after the first 1686 mother-infant pairs had been enrolled, and 327 pairs were missing. Of these pairs, 60 were located and had complete data obtained. Among the 683 participants enrolling after initiation of intensive tracing efforts, the lost to follow-up rate was 3.4%. At study's end, 290 (12.2%) of the 2369 mother-infant pairs were lost to follow-up. Among successfully traced missing pairs, relocation was common and three were deceased. Log-binomial regression modeling revealed higher maternal hemoglobin and older maternal age to be significant predictors of perfect attendance. These factors and the presence of food insecurity were also significantly associated with lower rates of lost to follow-up. CONCLUSION: In this large HIV prevention trial, intensive tracing efforts centered on reaching study participants at their homes succeeded in finding a substantial proportion of lost to follow-up participants and were very effective in preventing further lost to follow-up during the remainder of the trial. The association between food insecurity and lower rates of lost to follow-up is likely related to the study's provision of nutritional support, including a family maize supplement, which may have contributed to patient retention. PMID- 25518961 TI - The topoisomerase II catalytic inhibitor ICRF-193 preferentially targets telomeres that are capped by TRF2. AB - The increased level of chromosome instability in cancer cells is not only a driving force for oncogenesis but also can be the Achille's heel of the disease since many chemotherapies kill cells by inducing a nontolerable rate of DNA damage. A wealth of published evidence showed that telomere stability can be more affected than the bulk of the genome by several conventional antineoplastic drugs. In the present study, HT1080 cell lines compromised for either telomere repeats binding factor 2 (TRF2) or POT1 were treated with ICRF-193 (3 MUM, 24 h) or bleomycin (1 MUM, 24 h). DNA damage was assayed by combining telomeric DNA staining of a (CCCTAA)n PNA probe with immunofluorescence of 53BP1 to score the rate of telomere colocalization with 53BP1 foci. We found that ICRF-193, but not bleomycin, leads to DNA damage preferentially at telomeres, which can be rescued by TRF2 inhibition. POT1 inhibition exacerbates telomere dysfunction induced by ICRF-193. Thus, ICRF-193 induces damage at telomeres properly capped by TRF2 but not by POT1. These findings are expected to broaden our view on the mechanism by which conventional therapeutic molecules act to eliminate cancer cells and how to use TRF2 and POT1 levels as surrogate markers for anti-topoisomerase II sensitivity. PMID- 25518962 TI - NH2-terminal truncations of cardiac troponin I and cardiac troponin T produce distinct effects on contractility and calcium homeostasis in adult cardiomyocytes. AB - Cardiac troponin I (TnI) has an NH2-terminal extension that is an adult heart specific regulatory structure. Restrictive proteolytic truncation of the NH2 terminal extension of cardiac TnI occurs in normal hearts and is upregulated in cardiac adaptation to hemodynamic stress or beta-adrenergic deficiency. NH2 terminal truncated cardiac TnI (cTnI-ND) alters the conformation of the core structure of cardiac TnI similarly to that produced by PKA phosphorylation of Ser(23/24) in the NH2-terminal extension. At organ level, cTnI-ND enhances ventricular diastolic function. The NH2-terminal region of cardiac troponin T (TnT) is another regulatory structure that can be selectively cleaved via restrictive proteolysis. Structural variations in the NH2-terminal region of TnT also alter the molecular conformation and function. Transgenic mouse hearts expressing NH2-terminal truncated cardiac TnT (cTnT-ND) showed slower contractile velocity to prolong ventricular rapid-ejection time, resulting in higher stroke volume. Our present study compared the effects of cTnI-ND and cTnT-ND in cardiomyocytes isolated from transgenic mice on cellular morphology, contractility, and calcium kinetics. Resting cTnI-ND, but not cTnT-ND, cardiomyocytes had shorter length than wild-type cells with no change in sarcomere length. cTnI-ND, but not cTnT-ND, cardiomyocytes produced higher contractile amplitude and faster shortening and relengthening velocities in the absence of external load than wild-type controls. Although the baseline and peak levels of cytosolic Ca(2+) were not changed, Ca(2+) resequestration was faster in both cTnI-ND and cTnT-ND cardiomyocytes than in wild-type control. The distinct effects of cTnI-ND and cTnT-ND demonstrate their roles in selectively modulating diastolic or systolic functions of the heart. PMID- 25518965 TI - [Use of TNF inhibition therapy in patients with axial spondyloarthritis]. PMID- 25518963 TI - [Ga-68-PSMA PET/CT for prostate cancer]. AB - Prostate-specific membrane antigen (PSMA) is expressed as a cell surface protein physiologically in the prostate and can be found in all stages of prostate cancer. Even in castration-resistant prostate cancers, this overexpression of PSMA occurs. Due to the enzymatic activity of PSMA it was possible develop specific inhibitors from which "small molecule" radiopharmaceuticals were derived. By coupling the specific binding motif glutamate-urea-lysine with the chelator HBED-CC, which complexes Ga-68 very effectively, a new radiopharmaceutical is available for Ga-68-PSMA-PET/CT. According to the first results in patients with prostate carcinoma, this new diagnostic tool exhibited advantages in image quality compared to choline-PET/CT. An initial study demonstrated the higher contrast of the PET signal and an improved diagnostic accuracy. The properties of even further new PSMA PET radiopharmaceuticals can be of increasing importance for the diagnostic work-up of prostate cancer in all stages. In conjunction with therapeutic PSMA radiopharmaceuticals, a new field of theragnostics is opened. PMID- 25518964 TI - [Therapy refractory monoarthritis of the wrist under TNF-alpha inhibition]. PMID- 25518969 TI - Measurement and control of quasiparticle dynamics in a superconducting qubit. AB - Superconducting circuits have attracted growing interest in recent years as a promising candidate for fault-tolerant quantum information processing. Extensive efforts have always been taken to completely shield these circuits from external magnetic fields to protect the integrity of the superconductivity. Here we show vortices can improve the performance of superconducting qubits by reducing the lifetimes of detrimental single-electron-like excitations known as quasiparticles. Using a contactless injection technique with unprecedented dynamic range, we quantitatively distinguish between recombination and trapping mechanisms in controlling the dynamics of residual quasiparticle, and show quantized changes in quasiparticle trapping rate because of individual vortices. These results highlight the prominent role of quasiparticle trapping in future development of superconducting qubits, and provide a powerful characterization tool along the way. PMID- 25518970 TI - Phosphate tethers in natural product synthesis. AB - Recent advances in phosphate tether-mediated natural product synthesis are reviewed. Synthetic approaches toward dolabelide C, (-)-salicylihalimide A, (-) tetrahydrolipstatin, and (+)-strictifolione are included. In addition, current efforts in method development are briefly reviewed, including a detailed study on the effect of stereochemical complexity on the phosphate-mediated, diastereoselective ring-closing metathesis reaction and recent advances in multi reaction, one-pot sequential processes mediated by the phosphate tether. Overall, this review seeks to highlight the utility of phosphate triesters to serve as multifunctional tethers with protecting group and latent leaving group characteristics and the ability to orchestrate multiple, orthogonal reaction pathways to allow for the facile synthesis of complex, bioactive small molecules and their analogs. PMID- 25518971 TI - Modern extensions of native chemical ligation for chemical protein synthesis. AB - Over the past 20 years, native chemical ligation has facilitated the synthesis of numerous complex peptide and protein targets, with and without post-translational modifications, as well as the design and construction of a variety of engineered protein variants. This powerful methodology has also served as a platform for the development of related chemoselective ligation technologies which have greatly expanded the scope and flexibility of ligation chemistry. This chapter details a number of important extensions of the original native chemical ligation manifold, with particular focus on the application of new methods in the total chemical synthesis of proteins. Topics covered include the development of auxiliary-based ligation methods, the post-ligation manipulation of Cys residues, and the synthesis and utility of unnatural amino acid building blocks (bearing reactive thiol or selenol functionalities) in chemoselective ligation chemistry. Contemporary applications of these techniques to the total chemical synthesis of peptides and proteins are described. PMID- 25518972 TI - Aurophilicity in gold(I) catalysis: for better or worse? AB - This book chapter discusses the effects of aurophilicity on gold catalysis. First, a brief historic account of aurophilicity in organogold chemistry is given, focusing on the pioneering results which set the stage for its association with catalytic intermediates (gold vinyl and gold aryl complexes); this is followed by an introduction to cationic gold(I) as an electrophilic catalyst, and the first isolation of organogold intermediates from catalysis. In the main section, the growing number of reports observing aurophilic interactions in catalysis or illustrative model systems is reviewed in a non-comprehensive tutorial way. The effects of aurophilicity are discussed in the following structures: (1) the geminal diauration of C(sp2)-atoms; (2) geminal diauration of other atoms; (3) sigma-pi-diauration of terminal alkynes. It is apparent that in most cases efficient catalysis is hindered by aurophilic effects as less active aggregates tend to be formed from more active species [LAu]+, but there are a growing number of reports using aurophilicity as a driving force to access new reactivity and selectivity. PMID- 25518973 TI - Gold-catalyzed carbene transfer reactions. AB - In homogeneous gold catalysis, generations and reactions of metal carbenes have been one of the most rapidly developing areas because of their diverse reactivity under mild conditions. This review covers recent advances in the gold-catalyzed oxygen atom transfer and carbene transfer reactions to alkynes. Atom transfer to an alkyne enables alkynes to function as metal carbene synthons. Many such reactions fulfill redox neutrality starting from safe and easily handled precursors. PMID- 25518966 TI - [Rheumatology training for medical students. Comparison of learning success and acceptance with virtual vs. real patient demonstrations]. AB - BACKGROUND: Recently, new teaching methods, such as internet-based e-learning, have gained importance at German universities. At the same time, however, students see fewer patients with rheumatic diseases during their medical education. OBJECTIVE: The aim of the study was to compare the gain of knowledge and the acceptance of the teaching methodology between educational films and patient-related teaching. MATERIALS AND METHODS: Both teaching methods communicated identical facts concerning representative rheumatic diseases. Afterwards, participants had to pass a knowledge test and had to evaluate both teaching methods. RESULTS: Patient-related teaching achieved a better increase of knowledge and better results in evaluations than the educational films. The combination of both teaching methods produced better results than any form on its own. CONCLUSIONS: Educational films are suited to improve the practical teaching. However, the results stress the importance of practical lessons with real-life cases and argue against the reduction of the educational capacity at German universities. PMID- 25518974 TI - Gold-catalyzed transformation of unsaturated alcohols. AB - The use of gold-complexes to activate carbon-carbon pi-bonds has become a well known and highly reliable mode of reactivity for applications in organic synthesis. This review covers the use of gold-catalysts for activation of unsaturated alcohols to effect substitution with concomitant loss of water and is mostly focused on reactions where the pi-acidity appears to overcome the inherent Lewis acidity of the complexes for alcohol activation. Select examples from the literature which demonstrate advances made between 2011 and 2014 are presented. PMID- 25518975 TI - Assisted reproduction involving gestational surrogacy: an analysis of the medical, psychosocial and legal issues: experience from a large surrogacy program. AB - STUDY QUESTION: What are the medical, psychosocial and legal aspects of gestational surrogacy (GS), including pregnancy outcomes and complications, in a large series? SUMMARY ANSWER: Meticulous multidisciplinary teamwork, involving medical, legal and psychosocial input for both the intended parent(s) (IP) and the gestational carrier (GC), is critical to achieve a successful GS program. WHAT IS KNOWN ALREADY: Small case series have described pregnancy rates of 17-50% for GS. There are no large case series and the medical, legal and psychological aspects of GS have not been addressed in most of these studies. To our knowledge, this is the largest reported GS case series. STUDY DESIGN, SIZE AND DURATION: A retrospective cohort study was performed. Data were collected from 333 consecutive GC cycles between 1998 and 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 178 pregnancies achieved out of 333 stimulation cycles, including fresh and frozen transfers. The indications for a GC were divided into two groups. Those who have 'failed to carry', included women with recurrent implantation failure (RIF), recurrent pregnancy loss (RPL) and previous poor pregnancy outcome (n = 96; 132 cycles, pregnancy rate 50.0%). The second group consisted of those who 'cannot carry' including those with severe Asherman's syndrome, uterine malformations/uterine agenesis and maternal medical diseases (n = 108, 139 cycles, pregnancy rate 54.0%). A third group, of same-sex male couples and single men, were analyzed separately (n = 52, 62 cycles, pregnancy rate 59.7%). In 49.2% of cycles, autologous oocytes were used and 50.8% of cycles involved donor oocytes. MAIN RESULTS AND THE ROLE OF CHANCE: The 'failed to carry' group consisted of 96 patients who underwent 132 cycles at a mean age of 40.3 years. There were 66 pregnancies (50.0%) with 17 miscarriages (25.8%) and 46 confirmed births (34.8%). The 'cannot carry pregnancy' group consisted of 108 patients who underwent 139 cycles at a mean age of 35.9 years. There were 75 pregnancies (54.0%) with 15 miscarriages (20.0%) and 56 confirmed births (40.3%). The pregnancy, miscarriage and live birth rates between the two groups were not significantly different (P = 0.54; 0.43; 0.38, respectively). Of the 178 pregnancies, 142 pregnancies were ongoing (surpassed 20 weeks) or had ended with a live birth and the other 36 pregnancies resulted in miscarriage (25.4%). Maternal (GS) complication rates were low, occurring in only 9.8% of pregnancies. Fetal anomalies occurred in only 1.8% of the babies born. LIMITATIONS, REASONS FOR CAUTION: Although it is a large series, the data are retrospective and conclusions must be drawn accordingly while considering bias, confounding and power. Due to the retrospective nature of this study, follow-up data on 6.3% of birth outcomes were incomplete. In addition, long-term follow-up data on GCs and IPs were not available to us at the time of publication. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the largest GS series published. We have included many details regarding not only the medical protocol but also the counseling and legal considerations, which are an inseparable part of the process. Data from this study can be included in discussions with future intended parents and gestational carriers regarding success rates and complications of GS. PMID- 25518977 TI - Simultaneous giant mucinous cystadenoma of the appendix and intestinal schistosomiasis: 'case report and brief review'. AB - Both mucinous cystadenoma of the appendix and intestinal schistosomiasis are rare lesions. We report a rare case of simultaneous giant mucinous cystadenoma of the appendix and intestinal schistosomiasis. A 64-year-old man from China presented with a one-year history of pain in the right lower quadrant of the abdomen. There were no other pertinent historical findings, other than schistosomiasis. Imaging showed a large, tubular, mesenteric cystic structure extending downwards from the inferior wall of the cecum. Right hemicolectomy was performed for the appendiceal tumor. The final pathological diagnosis was mucinous cystadenoma with calcified Schistosome eggs within the mucosa and submucosa of the appendix, small intestine, colon, and lymph nodes. We deduced that the pathogenesis of appendiceal mucinous cystadenoma in our case was Schistosome eggs causing luminal obstruction, finally resulting in intraluminal accumulation of mucoid material. Postoperatively, the patient recovered well. PMID- 25518976 TI - Association of assisted reproductive technology (ART) treatment and parental infertility diagnosis with autism in ART-conceived children. AB - STUDY QUESTION: Are assisted reproductive technology (ART) treatment factors or infertility diagnoses associated with autism among ART-conceived children? SUMMARY ANSWER: Our study suggests that the incidence of autism diagnosis in ART conceived children during the first 5 years of life was higher when intracytoplasmic sperm injection (ICSI) was used compared with conventional IVF, and lower when parents had unexplained infertility (among singletons) or tubal factor infertility (among multiples) compared with other types of infertility. WHAT IS KNOWN ALREADY: Some studies found an increased risk of autism among ART conceived infants compared with spontaneously-conceived infants. However, few studies, and none in the USA, have examined the associations between types of ART procedures and parental infertility diagnoses with autism among ART-conceived children. STUDY DESIGN, SIZE, DURATION: Population-based retrospective cohort study using linkages between National ART Surveillance System (NASS) data for 1996-2006, California Birth Certificate data for 1997-2006, and California Department of Developmental Services (DDS) Autism Caseload data for 1997-2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: All live born ART-conceived infants born in California in 1997-2006 (n = 42 383) with 5-year observation period were included in the study. We assessed the annual incidence of autism diagnosis documented in DDS, which includes information on the vast majority of persons with autism in California, and the association of autism diagnosis with ART treatment factors and infertility diagnoses. MAIN RESULTS AND THE ROLE OF CHANCE: Among ART-conceived singletons born in California between 1997 and 2006, the incidence of autism diagnosis remained at ~0.8% (P for trend 0.19) and was lower with parental diagnosis of unexplained infertility (adjusted hazard risk ratio [aHRR]; 95% confidence interval: 0.38; 0.15-0.94) and higher when ICSI was used (aHRR 1.65; 1.08-2.52), when compared with cases without these patient and treatment characteristics. Among ART-conceived multiples, the incidence of autism diagnosis between 1997 and 2006 remained at ~1.2% (P for trend 0.93) and was lower with parental diagnosis of tubal factor infertility (aHRR 0.56; 0.35-0.90) and higher when ICSI was used (aHRR 1.71; 1.10-2.66). LIMITATIONS, REASONS FOR CAUTION: Study limitations include imperfect data linkages, lack of data on embryo quality and possible underestimation of autism diagnosis cases. Limitations of the observational study design could affect the analysis by the possibility of residual confounders. Since information about ICSI use was missing for most frozen/thawed embryo transfer cycles, our findings of association of ICSI use and autism diagnosis can only be generalizable to fresh embryo transfer cycles. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides additional evidence of the association between some types of ART procedures with autism diagnosis. Additional research is required to explain the increased risk of autism diagnosis with ICSI use, as well as studies on the effectiveness and safety of ICSI. PMID- 25518979 TI - Disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural disease: case report. AB - We report the neuroimaging and histopathologic findings of a 12-year-old female patient with a disseminated oligodendroglial-like leptomeningeal tumor with anaplastic progression and presumed extraneural metastatic disease. These tumors may represent distinct pathology primarily seen in pediatric patients. Neuroimaging demonstrates diffuse, progressive enhancement of the leptomeninges often with interval development of intraparenchymal lesions on follow-up. Disease is typically confined to the central nervous system, though diffuse peritoneal disease was seen in our case, possibly through metastatic seeding of the abdomen via ventriculoperitoneal shunt. PMID- 25518978 TI - Unpacking the 'black box' of total pathogen burden: is number or type of pathogens most predictive of all-cause mortality in the United States? AB - A 'black box' paradigm has prevailed in which researchers have focused on the association between the total number of pathogens for which individuals are seropositive (i.e. total pathogen burden) and various chronic diseases, while largely ignoring the role that seropositivity for specific combinations of pathogens may play in the aetiology of such outcomes and consequently mortality. We examined the association between total pathogen burden as well as specific pathogen combinations and all-cause mortality in the United States. Data were from individuals aged ?25 years tested for cytomegalovirus (CMV), herpes simplex virus (HSV)-1, HSV-2 and Helicobacter pylori, with mortality follow-up to 31 December 2006 in the National Health and Nutrition Examination Survey (NHANES) III (N = 6522). We did not observe a statistically significant graded relationship between total pathogen burden level and all-cause mortality. Furthermore, compared to those seronegative for all four pathogens, the greatest statistically significant rate of all-cause mortality was for those CMV+/HSV-2+ (hazard ratio 1.95, 95% confidence interval 1.13-3.35) adjusting for age, gender, race/ethnicity, education level, body mass index (kg/m2) and smoking status. Interventions targeting prevention or treatment of particular pathogens may be more effective for reducing mortality than those focused solely on reducing overall pathogen burden. PMID- 25518982 TI - Inhibitory effect of leonurine on the formation of advanced glycation end products. AB - Long-term hyperglycemia is a typical symptom of diabetes mellitus (DM) which can cause a high level of protein glycation and lead to the formation of advanced glycation end products (AGEs). The accumulation of AGEs in turn deteriorates DM and its complications. Insulin, the only hormone that directly decreases blood sugar in vivo, is vulnerable to glycation which causes the loss of its biological activity. In this study, we used a porcine insulin (PI)-methylglyoxal (MGO) model to investigate the inhibitory effect of leonurine (LN), a natural alkaloid extracted from Herba leonuri, on AGE formation. Assays including AGE-specific fluorescence, and fructosamine level and carbonyl group content determination showed that LN can dose-dependently suppress PI glycation. A significantly decreased cross-linking level on the glycated PI was also proven by SDS-PAGE electrophoresis. A further liquid chromatography-mass spectrometry study suggested that LN may inhibit PI glycation through trapping MGO and keeping it from reacting with PI. Our results thus indicate that LN is a promising anti glycation agent for the prevention of diabetes and its complications via inhibiting AGE formation. PMID- 25518980 TI - The interleukin-1 receptor antagonist anakinra improves endothelial dysfunction in streptozotocin-induced diabetic rats. AB - BACKGROUND: Endothelial dysfunction is a crucial early phenomenon in vascular diseases linked to diabetes mellitus and associated to enhanced oxidative stress. There is increasing evidence about the role for pro-inflammatory cytokines, like interleukin-1beta (IL-1beta), in developing diabetic vasculopathy. We aimed to determine the possible involvement of this cytokine in the development of diabetic endothelial dysfunction, analysing whether anakinra, an antagonist of IL 1 receptors, could reduce this endothelial alteration by interfering with pro oxidant and pro-inflammatory pathways into the vascular wall. RESULTS: In control and two weeks evolution streptozotocin-induced diabetic rats, either untreated or receiving anakinra, vascular reactivity and NADPH oxidase activity were measured, respectively, in isolated rings and homogenates from mesenteric microvessels, while nuclear factor (NF)-kappaB activation was determined in aortas. Plasma levels of IL-1beta and tumor necrosis factor (TNF)-alpha were measured by ELISA. In isolated mesenteric microvessels from control rats, two hours incubation with IL-1beta (1 to 10 ng/mL) produced a concentration-dependent impairment of endothelium-dependent relaxations, which were mediated by enhanced NADPH oxidase activity via IL-1 receptors. In diabetic rats treated with anakinra (100 or 160 mg/Kg/day for 3 or 7 days before sacrifice) a partial improvement of diabetic endothelial dysfunction occurred, together with a reduction of vascular NADPH oxidase and NF-kappaB activation. Endothelial dysfunction in diabetic animals was also associated to higher activities of the pro-inflammatory enzymes cyclooxygenase (COX) and the inducible isoform of nitric oxide synthase (iNOS), which were markedly reduced after anakinra treatment. Circulating IL-1beta and TNF-alpha levels did not change in diabetic rats, but they were lowered by anakinra treatment. CONCLUSIONS: In this short-term model of type 1 diabetes, endothelial dysfunction is associated to an IL-1 receptor-mediated activation of vascular NADPH oxidase and NF-kappaB, as well as to vascular inflammation. Moreover, endothelial dysfunction, vascular oxidative stress and inflammation were reduced after anakinra treatment. Whether this mechanism can be extrapolated to a chronic situation or whether it may apply to diabetic patients remain to be established. However, it may provide new insights to further investigate the therapeutic use of IL-1 receptor antagonists to obtain vascular benefits in patients with diabetes mellitus and/or atherosclerosis. PMID- 25518981 TI - Antinociceptive and anti-inflammatory activities of Geranium bellum and its isolated compounds. AB - BACKGROUND: Geranium bellum Rose, locally known as "Pata de leon", is a perennial plant distributed in the mountains of Hidalgo, Mexico. It is widely used in Mexican traditional medicine to treat fever, pain, and gastrointestinal disorders. To date, there are not published studies regarding the in vivo antinociceptive and anti-inflammatory potential of the acetone-aqueous extract from the aerial parts of G. bellum. METHODS: Antinociceptive effects of the acetone-aqueous G. bellum (AGB) extract and the isolated compounds were assessed using experimental pain models, including thermal nociception like hot plate test, and chemical nociception induced by intraperitoneal acetic acid or subplantar formalin injection in vivo. The anti-inflammatory properties of the extract were studied using systemic administration in carrageenan-induced paw edema. RESULTS: Intra-gastric administration of AGB (75, 150, and 300 mg/kg) showed a dose-dependent antinociceptive effect in intraperitoneal acetic acid (writhing), thermal nociception in CD1 mice, and subplantar formalin models, as well as anti-inflammatory effect in carrageenan- induced paw edema in Wistar rats. Geraniin and quercetin showed the highest antinociceptive activity in writhing test, whereas ellagic acid was the most active compound in the hot plate model. CONCLUSION: These studies provide evidences that G. bellum shows antinociceptive and anti- inflammatory effects, and gives support to its use in treating pain in Mexican traditional medicine. PMID- 25518983 TI - Development and evaluation of a full-scale spray scrubber for ammonia recovery and production of nitrogen fertilizer at poultry facilities. AB - Significant ammonia emissions from animal facilities need to be controlled due to its negative impacts on human health and the environment. The use of acid spray scrubber is promising, as it simultaneously mitigates and recovers ammonia emission for fertilizer. Its low pressure drop contribution on axial fans makes it applicable on US farms. This study develops a full-scale acid spray scrubber to recover ammonia emissions from commercial poultry facilities and produce nitrogen fertilizer. The scrubber performance and economic feasibility were evaluated at a commercial poultry manure composting facility that released ammonia from exhaust fans with concentrations of 66-278 ppmv and total emission rate of 96,143 kg yr(-1). The scrubber consisted of 15 spray scrubber modules, each equipped with three full-cone nozzles that used dilute sulphuric acid as the medium. Each nozzle was operated at 0.59 MPa with a droplet size of 113 MUm and liquid flow rate of 1.8 L min(-1). The scrubber was installed with a 1.3-m exhaust fan and field tested in four seasons. Results showed that the scrubber achieved high NH3 removal efficiencies (71-81%) and low pressure drop (<25 Pa). Estimated water and acid losses are 0.9 and 0.04 ml m(-3) air treated, respectively. Power consumption rate was between 89.48 and 107.48 kWh d(-1). The scrubber effluents containing 22-36% (m/v) ammonium sulphate are comparable to the commercial-grade nitrogen fertilizer. Preliminary economic analysis indicated that the break-even time is one year. This study demonstrates that acid spray scrubbers can economically and effectively recover NH3 from animal facilities for fertilizer. PMID- 25518984 TI - Reducing THMFP by H2O2/UV oxidation for humic acid of small molecular weight. AB - In this study, the merits of using H2O2/UV oxidation for reducing trihalomethane formation potential (THMFP), colour, and dissolved organic carbon (DOC) of smaller molecular humic acid were investigated, especially the energy consumption based on EEO. The results show that THMFP decreases by increasing oxidation time, H2O2 dose and UV intensity. The reaction constant in descending order is kColour>kDOC>kTHMFP. Furthermore, EEO shows three trends. First, it decreases as H2O2 dose increases. That is, by increasing the amount of H2O2 dose, the electrical energy efficiency becomes better. Second, EEO,9 W>EEO,13 W, implying that higher UV power would result in a higher electrical energy efficiency. Third, EEO,THMFP>EEO,DOC>EEO,colour. That is, the electric energy efficiency is the best for colour removal, second for DOC removal, and third for THMFP reduction. The operation costs for 90% removal of colour, DOC, and THMFP are from 0.31 to 0.69, from 0.78 to 1.72, and from 1.11 to 2.29 US$/m3, respectively. However, reducing THMs to Taiwan's drinking water standard of 80 ug/L needs only 0.25-0.60 US$/m3. Therefore, the condition with UV of 9 W, H2O2 of 50 mg/L, and oxidation time of 23 min can be applied for THMs reduction as the cost is the smallest of 0.25 US$/m3, even lower than current Taiwan's drinking water price of 0.3 US$/m3. PMID- 25518985 TI - Enhanced dewaterability of waste-activated sludge by combined cationic polyacrylamide and magnetic field pretreatment. AB - The potential function of combining magnetic field (MF) pretreatment with cationic polyacrylamide (CPAM) additive on enhancing the dewaterability of waste activated sludge was investigated in the present work. Two reactors were involved in a specially designed experimental apparatus, one of which was built with MF accessories. Several parameters were conducted, including CPAM dosages, MF strengths and processing times, respectively. Capillary suction time (CST) and specific resistance to filtration (SRF) were used to evaluate sludge dewaterability. Extracellular polymeric substances (EPS) concentration was also determined in an attempt to identify the observed changes in dewaterability. It was indicated by the results that both CPAM conditioning and MF pretreatment on sludge can lower CST and SRF values. However, subjecting to a combination of MF pretreatment and CPAM conditioning, sludge dewaterability was significantly enhanced beyond the level observed of CPAM addition alone. The lowest CST and SRF values of 36.5 s and 0.75*10(12) m kg(-1), respectively, were obtained when sludge was co-conditioned by CPAM (at a dosage of 40 mg L(-1)) and MF (at an induction of 40 mT) for 30 min, suggesting the optimal condition for enhancing sludge dewaterability. It is also shown from the significant correlations between EPS, protein, polysaccharide and CST/SRF that the increment of EPS concentration in sludge supernatant may be the major reason for the enhancement of dewaterability. PMID- 25518988 TI - A practical guide to using boron doped diamond in electrochemical research. AB - Conducting, boron doped diamond (BDD), in addition to its superior material properties, offers several notable attributes to the electrochemist making it an intriguing material for electrochemical research. These include the widest solvent window of all electrode materials; low background and capacitive currents; reduced fouling compared to other electrodes and; the ability to withstand extreme potentials, corrosive and high temperature/pressure environments. However, BDD is not your typical electrode material, it is a semi conductor doped degenerately with boron to present semi-metallic characteristics. Input from materials scientists, chemists and physicists has been required to aid understanding of how to work with this material from an electrochemical viewpoint and improve electrode quality. Importantly, depending on how the BDD has been grown and then subsequently treated, prior to electrochemical measurement, the resulting material properties can vary quite significantly from one electrode to the next. This likely explains the variability seen by different researchers working on the same experimental systems. The aim of this "protocols" article is not to provide a state-of-the-art review of diamond electrochemistry, suitable references are provided to the interested reader, but instead serves as a reference point for any researcher wishing to commence work with diamond electrodes and interpret electrochemical data. It provides information on how best to characterise the material properties of the electrode before use and outlines the interplay between boron dopant density, non-diamond-carbon content, grain morphology, surface chemistry and redox couple identity. All should ideally be considered when interpretating electrochemical data arising from the diamond electrode. This will aid the reader in making meaningful comparisons between data obtained by different researchers using different diamond electrodes. The guide also aims to help educate the researcher in choosing which form of BDD is best suited to their research application. PMID- 25518987 TI - Disinfection of bore well water with chlorine dioxide/sodium hypochlorite and hydrodynamic cavitation. AB - The effect of hydrodynamic cavitation (HC) on potable water disinfection of chemicals was investigated. The bore well water was introduced into HC set-up to examine the effect of HC alone and combination of HC and chemicals such as chlorine dioxide and sodium hypochlorite. The effect of inlet pressure and geometrical parameters on disinfection was studied using HC alone and the results showed that increasing inlet pressure and using more and bigger holes of orifice plates can result in a higher disinfection rates. When HC was combined with chemicals, HC can reduce the doses of the chemicals and shorten the time of disinfection. It was also found that the decrease in bacteria concentration followed a first-order kinetic model. As for the experiment of combination of HC and sodium hypochlorite for disinfection, HC not only improves the disinfection rate but also degrades natural organic matter and chloroform. Compared with only sodium hypochlorite disinfection, combined processes get higher disinfection rate and lower production of chloroform, particularly the pretreatment with HC enhances the disinfection rate by 32% and there is a simultaneous reduction in production of chloroform by 39%. PMID- 25518986 TI - Characterization of bio-oil and biochar from high-temperature pyrolysis of sewage sludge. AB - The influence of temperature (550-850 degrees C) on the characteristics of bio oil and biochar from the pyrolysis of sewage sludge (SS) in a horizontal tube reactor was investigated. Results showed that when the pyrolysis temperature increased from 550 degrees C to 850 degrees C, the yield of bio-oil decreased from 26.16% (dry ash-free basis) to 20.78% (dry ash-free basis). Main components of bio-oil were phenols, esters, cholests, ketones, amides, indoles, and nitriles. Besides, the elevated heating rate of 25 degrees C/min was demonstrated to favour the complete combustion of bio-oil. Moreover, caused by the increase in temperature, the yield of biochar decreased from 54.9 to 50.6 wt%, Brunauer-Emmet Teller surface area increased from 48.51 to 81.28 m2/g. Furthermore, pH was increased from 5.93 of SS to 7.15-8.96 of biochar. The negative zeta-potential was also strengthened (-13.87 to -11.30 mV) and principal functional groups on the surface of biochar were -OH, C=O, C=C, -NO2, and S=O. PMID- 25518989 TI - Bisphenol A Concentration in Breast Milk following Consumption of a Canned Coffee Drink. AB - BACKGROUND: Bisphenol A (BPA) is generally considered to be an endocrine disruptor. Previous reports indicate that the BPA content in breast milk is higher than that in serum; however, BPA is considered to be excreted in the urine and not to accumulate in the body. OBJECTIVE: The current study aimed at evaluating the migration of BPA from a commercially available canned coffee drink in a container that was coated with vinyl chloride resin into breast milk. METHODS: Ten women who had breastfed for >=12 months, were ready to cease breastfeeding, and drank commercially available canned coffee drinks daily were approached to participate. A canned coffee drink in which the can contained vinyl chloride resin was chosen. Samples (5 mL each) of urine and breast milk were collected prior to and after ingestion (1 h, 2 h, 4 h, and 6 h) of a 190-mL canned coffee drink. BPA measurements were conducted using an ELISA kit. RESULTS: Each 190-mL can of coffee contained 196.9 ng/mL BPA, resulting in 37.4 MUg that was consumed in each drink. In breast milk, peak BPA excretion occurred at 1 hour; in urine, excretion occurred rapidly during the first hour, remaining relatively unchanged at 2 hours. CONCLUSION: The present results indicate that BPA is excreted into the breast milk in addition to the urine and feces. Therefore, it is important to reduce both direct and indirect dietary BPA intake. PMID- 25518990 TI - Novel metabotropic glutamate receptor 4 and glutamate receptor 8 therapeutics for the treatment of anxiety. AB - INTRODUCTION: The fast actions of the excitatory neurotransmitter glutamate are mediated by glutamate-gated ion channels (ionotropic Glu receptors). Metabotropic glutamate receptors (mGlus) are coupled to second messenger pathways via G proteins and modulate glutamatergic and GABAergic neurotransmission. Of the eight different types of mGlus (mGlu1-mGlu8), mGlu4, mGlu6, mGlu7 and mGlu8 are members of group III. Except for mGlu6, group III receptors are generally located presynaptically and regulate neurotransmitter release. Because of their role in modulating excitatory neurotransmission, mGlus are attractive targets for therapies aimed at treating anxiety disorders. AREAS COVERED: In this review, the authors discuss the role of mGlu4 and mGlu8 in anxiety disorders. They also discuss how mGlu4 and mGlu8 have distinct expression patterns in the brain, which might have related functions. Finally, the authors discuss how compounds that target more than one mGlu receptor might be therapeutically more effective. EXPERT OPINION: mGlu4 might compensate for mGlu8 deficiency, and deficiency of both receptors might result in a more pronounced phenotype than deficiency of either receptor alone. The distinct and overlapping anatomical distribution and functions of mGlu4 and mGlu8 suggest that both receptors, either individually or combined, are attractive therapeutic targets in anxiety disorders, post-traumatic stress disorder, Parkinson's disease, and multiple sclerosis. PMID- 25518992 TI - Predictors of smoking among Swedish adolescents. AB - BACKGROUND: Smoking most often starts in adolescence, implying that understanding of predicting factors for smoking initiation during this time period is essential for successful smoking prevention. The aim of this study was to examine predicting factors in early adolescence for smoking in late adolescence. METHODS: Longitudinal cohort study, involving 649 Swedish adolescents from lower secondary school (12-13 years old) to upper secondary school (17-18 years old). Tobacco habits, behavioural, intra- and interpersonal factors and socio-demographic variables were assessed through questionnaires. Descriptive statistics, univariable and multivariable logistic regression were used to identify predicting factors. RESULTS: Smoking prevalence increased from 3.3% among 12-13 year olds to 25.1% among 17-18 year olds. Possible predictors of smoking were: female sex, lower parental education, poorer family mood, poorer self-rated health, poorer self-esteem, less negative attitude towards smoking, binge drinking, snus use and smoking. In a multivariable logistic regression analysis, female sex (OR 1.64, CI 1.08-2.49), medium and low self-esteem (medium: OR 1.57, CI 1.03-2.38, low: 2.79, CI 1.46-5.33), less negative attitude towards smoking (OR 2.81, CI 1.70-4.66) and ever using snus (OR 3.43, CI 1.78-6.62) remained significant independent predicting factors. CONCLUSIONS: The study stresses the importance of strengthening adolescents' self-esteem, promoting anti-smoking attitudes in early adolescence, as well as avoidance of early initiation of snus. Such measures should be joint efforts involving parents, schools, youth associations, and legislating authorities. PMID- 25518993 TI - Roles of oxidative damage and mitochondria-mediated apoptosis in ethylbenzene induced hepatotoxic effects in rat. AB - The mechanisms underlying hepatoxic effects of ethylbenzene still remain unknown. We investigated the toxic effects of ethylbenzene on liver and explored the mechanism of mitochondria-mediated apoptosis pathway. Forty male Sprague-Dawley rats were used as an in vivo model with ethylbenzene inhalation of 0, 433.5 mg/m(3), 4335 mg/m(3) and 6500 mg/m(3) for 13 weeks. Levels of malondialdehyde, glutathione, glutathione peroxidase and superoxide dismutase were assayed. Meanwhile, the ultrastructure of hepatic tissues was observed and cell apoptosis was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Furthermore, we investigated the expression levels of mRNA and protein of bax, bcl-2, cytochrome c, caspase-9 and caspase-3 in rat liver tissues. Compared with control group, the malondialdehyde levels were significantly elevated while glutathione levels and activities of glutathione peroxidase and superoxide dismutase were decreased, respectively. The mitochondria of liver appeared swollen with vacuolar structure and loss of cristae in 6500 mg/m(3) ethylbenzene-treated group, and ethylbenzene induced a significant increase in the percentage of apoptotic cells as compared to the control group. In addition, enhanced mRNA and protein expression levels of all measured genes were observed in ethylbenzene-treated groups except the decreased bcl-2 expression levels. Our results indicated that ethylbenzene may induce oxidative damage and apoptosis in rat liver. Mitochondrial-mediated pathway was involved in the apoptosis process. PMID- 25518995 TI - Cytotoxic T-cell cytokines put cancer under arrest. PMID- 25518994 TI - Systematic review of pleural plaques and lung function. AB - CONTEXT: US EPA proposed a Reference Concentration for Libby amphibole asbestos based on the premise that pleural plaques are adverse and cause lung function deficits. OBJECTIVE: We conducted a systematic review to evaluate whether there is an association between pleural plaques and lung function and ascertain whether results were dependent on the method used to identify plaques. METHODS: Using the PubMed database, we identified studies that evaluated pleural plaques and lung function. We assessed each study for quality, then integrated evidence and assessed associations based on the Bradford Hill guidelines. We also compared the results of HRCT studies to those of X-ray studies. RESULTS: We identified 16 HRCT and 36 X-ray studies. We rated six HRCT and 16 X-ray studies as higher quality based on a risk-of-bias analysis. Half of the higher quality studies reported small but statistically significant mean lung function decrements associated with plaques. None of the differences were clinically significant. Many studies had limitations, such as inappropriate controls and/or insufficient adjustment for confounders. There was little consistency in the direction of effect for the most commonly reported measurements. X-ray results were more variable than HRCT results. Pleural plaques were not associated with changes in lung function over time in longitudinal studies. CONCLUSION: The weight of evidence indicates that pleural plaques do not impact lung function. Observed associations are most likely due to unidentified abnormalities or other factors. PMID- 25518997 TI - Effects of fixed orthodontic treatment using conventional versus metal-injection molding brackets on salivary nickel and chromium levels: a double-blind randomized clinical trial. AB - INTRODUCTION: Despite the importance of nickel and chromium release from orthodontic brackets, there are no in vivo or in vitro studies on this issue in the case of metal-injection molding (MIM) brackets. METHODS: Saliva samples were collected from 30 orthodontic patients divided randomly into two groups of conventional and MIM brackets, before treatment and 2 months later. Approved attendees with odd and even numbers were, respectively, assigned to the control and treatment groups. For blinding, the patients were not informed of their bracket types, and the saliva samples were coded. Nickel and chromium levels were determined using atomic absorption spectrophotometry. Data were analysed using repeated-measures two-way analysis of covariance, independent-samples t-test, chi squared, Spearman and point-biserial correlation coefficients, Mann-Whitney, and Wilcoxon tests (alpha = 0.05). RESULTS: Mean nickel level increased from 7.87+/ 8.14 (pre-treatment) to 12.57+/-9.96 (2nd month) in the control group, and from 8.62+/-9.85 (pre-treatment) to 8.86+/-6.42 ug/l in the MIM group. Both of these increases were significant (Wilcoxon P < 0.03). Average chromium level changed from 0.25+/-0.56 (pre-treatment) to 0.35+/-0.62 and from 0.42+/-0.48 to 0.26+/ 0.57 ug/l in the MIM group. Only the reduction observed in the MIM group was significant (Wilcoxon P = 0.0438). Age and gender had no significant influence on ion levels (P > 0.1). The differences between both ions' levels measured in the 60th day in both bracket groups were not significant (Mann-Whitney P > 0.05). The extents of changes over time were not significantly different between the bracket types (Mann-Whitney P > 0.05). LIMITATIONS: The sample size was not predetermined based on power calculations. The spectrophotometer was limited to detecting chromium concentrations above 0.25 ug/l. Ion discharge from brackets might continuously change. The current in vivo methods are unable to take such fluctuations into account. CONCLUSION: Nickel might increase in patients undergoing treatment with both bracket types, although the rate of increase might be greater in patients under treatment with conventional brackets. Using MIM brackets might reduce salivary chromium for a trivial but generalizable amount. Still, ion levels leached from conventional versus MIM brackets might not show a difference after 2 months. Age and gender might not affect the ion levels in normal people or orthodontic patients. REGISTRATION: The protocol is registered offline at the university library. PROTOCOL: The protocol was not published before the trail commencement. FUNDING: Self-funded (S. H.). CONFLICT OF INTEREST: None to declare. PMID- 25518999 TI - Erratum to: A new F-18 labeled PET tracer for fatty acid imaging. PMID- 25518996 TI - Effect of methotrexate on the mandibular development of arthritic rabbits. AB - INTRODUCTION: Juvenile idiopathic arthritis affecting the temporomandibular joint (TMJ) can cause severe disturbances of the mandibular development. Methotrexate (MTX) is often administered as a common used remission-inducing agent to treat this disease. The aim of this study was to investigate the effect of low dose MTX on the mandibular growth in arthritic rabbits. SUBJECTS AND METHODS: Eighteen 10 week-old female New Zealand white rabbits were randomly assigned to three groups with six animals in each group. After being sensitized to ovalbumin (OA), the first and the second group received intra-articular injections with OA. The first group remained untreated, the second was treated by weekly injections of MTX. Cephalograms were taken from each animal at 10, 13, 16, 19, and 22 weeks of age and six mandibular distances measured. RESULTS: All distances showed an increase between 10 and 20 per cent, whereas growth was more accentuated in the sagittal dimension. Significant differences in the overall growth could be observed between the arthritic and the control animals and less accentuated between the arthritic and the MTX animals. In contrast, existing differences between the groups were not significant during the intervals, but time had the greatest influence on mandibular growth. CONCLUSIONS: MTX seems to have a positive impact on growth in rabbits suffering from experimental arthritis of the TMJ. PMID- 25518998 TI - Platelet adhesion on endothelium early after vein grafting mediates leukocyte recruitment and intimal hyperplasia in a murine model. AB - Intimal hyperplasia (IH) is the substrate for accelerated atherosclerosis and limited patency of vein grafts. However, there is still no specific treatment targeting IH following graft surgery. In this study, we used a mouse model of vein grafting to investigate the potential for early intervention with platelet function for later development of graft IH. We transferred the inferior vena cava (IVC) from donor C57BL/6 mice to the carotid artery in recipients using a cuff technique. We found extensive endothelial injury and platelet adhesion one hour following grafting. Adhesion of leukocytes was distinct in areas of platelet adhesion. Platelet and leukocyte adhesion was strongly reduced in mice receiving a function-blocking antibody against the integrin alphaIIbbeta3. This was followed by a reduction of IH one month following grafting. Depletion of platelets using antiserum also reduced IH at later time points. These findings indicate platelets as pivotal to leukocyte recruitment to the wall of vein grafts. In conclusion, the data also highlight early intervention of platelets and inflammation as potential treatment for later formation of IH and accelerated atherosclerosis following bypass surgery. PMID- 25519000 TI - A novel NTRK1 mutation in a patient with congenital insensitivity to pain with anhidrosis. PMID- 25519001 TI - Reliability of a 3 T MRI protocol for objective grading of supraspinatus tendonosis and partial thickness tears. AB - BACKGROUND: Partial thickness supraspinatus tears and tendonosis can be managed either nonoperatively or by various arthroscopic techniques. New biologic treatment approaches are currently being investigated. MRI is commonly used for objective imaging outcome evaluation but there is a lack of reliability studies. We propose a novel MRI classification of partial supraspinatus tears and tendonosis and evaluate its inter-observer and intra-observer reliability. METHODS: Digital MRI scans (3 Tesla) of 65 patients investigated for assessment of supraspinatus pathology or subacromial impingement were evaluated by three independent and experienced musculoskeletal (MSK) radiologists. Tendonosis (absent, focal, generalized), partial thickness (PT) tears (absent, 0%-25% PT, 25%-50% PT, 50%-100% PT, and full thickness tears), and anteroposterior extent of tears (less than 5 mm, 5-10 mm, greater than 10 mm) were scored by each radiologist on two separate occasions (t1, t2), 2 months apart. The inter observer and intra-observer agreement and weighted kappa values for each parameter were calculated. RESULTS: The range of weighted intra-observer kappa (IAK) was 0.84-0.93 for evaluation of tendonosis; 0.84 (all raters) for depth of partial thickness, 0.74-0.84 for AP tear size, and 0.83-0.85 for the total score. The range of weighted inter-observer kappa (IEK) over two time points (t1, t2) was 0.55-0.74 for tendonosis, 0.69-0.84 for depth for partial thickness tears, 0.57-0.80 for AP tear size, and 0.63-0.80 for the total score. CONCLUSION: A comprehensive MRI grading protocol is proposed and is reliable for the evaluation of supraspinatus tendonosis and partial thickness tears with good to excellent kappa values. This rotator cuff MRI protocol can be applied to evaluate morphological tendon outcomes after different treatment modalities. PMID- 25519002 TI - Higher plasma lipopolysaccharide concentrations are associated with less favorable phenotype in overweight/obese men. AB - PURPOSE: Lipopolysaccharide (LPS) from the outer membrane of gram-negative bacteria might be an inflammation trigger in adipose tissue. It has recently been proposed that there is a link between adipose tissue distribution and blood LPS. However, the number of studies on this topic is scarce, and further investigation in humans is required. In this study, we explored the association between plasma LPS concentrations and body fat distribution, as well as the biochemical parameters that may indicate the presence of metabolic disorders. METHODS: Sixty seven young adult men with body mass index of 26-35 kg/m(2) were evaluated. Anthropometry, body composition and body fat distribution, blood pressure, energy expenditure, physical activity level, dietary intake, and biochemical parameters were assessed. RESULTS: Men with median plasma LPS >= 0.9 EU/mL presented higher sagittal abdominal diameter, trunk fat percentage, and android fat percentage, and mass, insulin and alanine aminotransferase concentrations, homeostasis model assessment of insulin resistance (HOMA-IR), and beta cell dysfunction (HOMA-B) than those with lower plasma LPS. LPS correlated positively with the trunk fat percentage, and android fat percentage, and mass, insulin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase concentrations, as well as HOMA-IR and HOMA-B. CONCLUSION: Our results suggest that a higher plasma LPS concentration is associated with a less favorable phenotype as characterized by higher central adiposity, higher values of HOMA-IR, and beta cell function impairment in overweight/obese men. PMID- 25519003 TI - Dehydration affects cardiovascular nitric oxide synthases and caveolins in growing rats. AB - PURPOSE: During the postnatal stage, cardiovascular nitric oxide (NO) system and caveolins (cav) may be regulated differentially in response to hypovolemic state induced by water restriction. Our aim was to examine the effects of water restriction on NO synthases (NOS) and cav in the atria, ventricle and aorta of growing rats. METHODS: Male Sprague-Dawley rats aged 25 and 50 days were divided into (n = 15): WR: water restriction 3 days; WAL: water ad libitum 3 days. Systolic blood pressure, NOS activity and NOS/cav protein levels were measured. RESULTS: Dehydration induced a larger increase in SBP in WR25 group. Ventricular NOS activity, endothelial NOS (eNOS) and neuronal isoform (nNOS) of WR25 pups were increased, and both cav were decreased. In the WR50 group, NOS activity remained unchanged. In the atria, NOS activity, eNOS and nNOS decreased in WR25 associated with increased cav-1; in the WR50 group, NOS activity was increased without changes in NOS isoforms. In the aorta of WR25, NOS activity and inducible NOS (iNOS) were decreased; NOS activity was unchanged in WR50, despite the decreased levels of eNOS and increased iNOS, cav-1 and cav-3. CONCLUSIONS: NO system adjustments in cardiovascular system under osmotic stress in vivo depend on postnatal age, being eNOS and nNOS, the isoforms that determine NOS activity in cardiac tissue in 25-day-old pups. Changes in cav abundance during hypovolemic state may contribute to age-related NO production. PMID- 25519004 TI - Personalized Medicine Through SNP Testing for Breast Cancer Risk: Clinical Implementation. AB - Single nucleotide polymorphisms (SNPs) have the potential to improve personalized medicine in breast cancer care. As new SNPs are discovered, further enhancing risk classification, SNP testing may serve to complement family history and phenotypic risk factors when assessed in a clinical setting. SNP analysis is particularly relevant to high-risk women who may seek out such information to guide their decision-making around risk-reduction. However, little is known about how high-risk women may respond to SNP testing with regard to clinical decision making. We examined high-risk women's interest in SNP testing for breast cancer risk through an online survey of hypothetical testing scenarios. Women stated their preferences for sharing test results and selected the most likely follow-up action they would pursue in each of the test result scenarios (above average and below average risk for breast cancer). Four hundred seventy-eight women participated. Most women (89 %) did not know what a SNP was prior to the study. Once SNP testing was described, 75 % were interested in SNP testing. Participants stated an interest in lifestyle interventions for risk-reduction and wanted to discuss their testing results with their doctor or a genetic counselor. Women are interested in SNP testing and are prepared to make lifestyle changes based on testing results. Women's preference for discussing testing results with a healthcare provider aligns with the current trend towards SNP testing in a clinical setting. PMID- 25519006 TI - Proteins from the 18 glycosyl hydrolase family are associated with kidney dysfunction in patients with diabetes type 2. AB - OBJECTIVES: To investigate chitotriosidase (CHIT1) activity and chitinase-3-like protein 1 (YKL-40) concentration in plasma of type 2 diabetic patients and evaluate their relationship with kidney dysfunction. MATERIALS AND METHODS: 94 diabetic subjects and 33 controls were enrolled in the study. Plasma CHIT1 activity and YKL-40 concentration were measured along with routine laboratory parameters. RESULTS: Levels of CHIT1 and YKL-40 in plasma of type 2 diabetic patients increased progressively with the degree of albuminuria. CHIT1 discriminated normoalbuminuric subjects from those with abnormal albuminuria better than YKL-40. CONCLUSIONS: CHIT1represent a supportive biomarker connected with development of diabetic vascular complications, especially kidney dysfunction. PMID- 25519005 TI - Environmental surveillance for human astrovirus in Shandong Province, China in 2013. AB - Human astroviruses (HAstVs) are one of the leading viral agents of acute gastroenteritis. However, there is limited information on HAstVs in China. Here, we describe the molecular characterization of HAstVs in Shandong, China via sewage surveillance. A total of 23 sewage samples were collected from sewage treatment plants in the cities of Jinan and Linyi in 2013. After concentration via adsorption-elution method, 9 samples (39.1%) were positive by reverse transcription PCR (RT-PCR) for the presence of the 719-nt HAstV nucleotide sequence. Genetic cloning and sequencing were performed on positive PCR products, and 26 HAstV sequences were obtained. Phylogenetic analysis on these sequences revealed 4 genotypes (HAstV-1, -2, -4 and -5), with HAstV-1 and -5 as the most common genotypes in Jinan and Linyi, respectively. Homologous comparison revealed Shandong sequences had relatively less genetic divergence among themselves than with foreign sequences. This study represents the first effort to investigate the genotypes and molecular epidemiology of HAstVs via sewage surveillance in China. The high detection rate in this study reflects that HAstVs circulated at a relatively high frequency in the local population, and demonstrates that environmental surveillance is an effective method in investigating circulating HAstVs. PMID- 25519007 TI - Phenotypic and genotypic characterization of lactic acid bacteria from traditional cheese in Khorramabad city of Iran with probiotic potential. AB - Lactic acid bacteria (LAB) with proteolitic activity are used as aromatic and antibacterial substances, cholesterol reduces, bile salt hydrolyses, and probiotic. The aims of this project were to isolate and identify natural LAB flora involved in traditional fermentation in cheeses of Khoramabad city and also to survey their probiotic potential. In order to achieve this goal, LAB were isolated and characterized using phenotypic and genotypic methods (PCR sequencing); in the next stage, they were analyzed lowering cholesterol medium, hydrolysis of the bile, resistance to bile-resistant PH acidic stomach. At the end of the study, 88 cocci and 3 bacill were found: 58 Enterococcus faecium, 16 Enterococcus hirae, 5 Lactococcus lactis, 3 Lactobacillus plantarum, and 9 undetermined. The probiotic results of the bacteria had effects on the reduction of cholesterol, resistance to stomach acid, had relative antibacterial effects, and some strains had effects on hydrolyzing the bile. For further identification, the PCR method and the application of 16s-DNA-ITS genes and its sequencing were found useful. This study showed that lactic acid bacteria in the traditional cheese of the Khorramabad city have relative probiotic effect and that these lactic acid bacteria in fermented milk are suitable. PMID- 25519009 TI - A significant enhancement of water vapour uptake at low pressure by amine functionalization of UiO-67. AB - The functionalization of UiO-67 with -NH2 groups enhances CO2 and CH4 adsorption at 1 bar and 298 K and positively influences the framework's interaction with water as evidenced by the significant enhancement of water vapour adsorption at 0.1 < P/P0 < 0.3 and 298 K. PMID- 25519008 TI - Percutaneous treatment of spontaneous left main coronary artery dissection using drug-eluting stent. AB - BACKGROUND: Spontaneous coronary artery dissection is a rare cause of ischemic heart disease and sudden death. Prompt diagnosis is of paramount importance, especially in cases when it manifests with ST elevation myocardial infarction (STEMI). CASE PRESENTATION: We report a case of a 42 year-old woman, who presented with an anterior STEMI in a hospital without on-site percutaneous coronary intervention (PCI) facilities. She was transferred to our hospital and coronary angiography revealed a spontaneous dissection of the left main stem coronary artery (LM). The dissection was successfully managed with PCI. CONCLUSION: PCI appears to be a potential option, for the treatment of selected cases with spontaneous LM dissection, presenting with an acute coronary syndrome. PMID- 25519010 TI - Nrdp1 expression to predict clinical outcome and efficacy of adjuvant anthracyclines-based chemotherapy in breast cancer: A retrospective study. AB - BACKGROUND: Existing reports showed loss of Nrdp1, an E3 ubiquitin ligase, promoted breast cancer malignancy because of failure to deregulate ErbB3. However, the correlation between Nrdp1 expression with clinical data is still unknown. OBJECTIVE: We explored the predictive value of Nrdp1 regarding the clinical outcome of patients and the benefit of adjuvant anthracycline-based chemotherapy. METHODS: 113 primary breast cancer samples were obtained during surgery and the patients received average 10-year follow-up. We obtained Nrdp1 and ErbB3 expressions by immunohistochemistry. RESULTS: Nrdp1 expression correlates with overall survival and disease-free survival of patients, with a hazard ratio of 0.237 (p=0.001) and 0.280 (p< 0.001) respectively. Additionally Nrdp1 correlates inversely with ErbB3 expression in tumor tissue (p=0.009). However the prognosis of Nrdp1 was not solely dependent on its regulation of ErbB3 degradation since there was also a significant correlation between Nrdp1 and overall survival (p=0.005) in ErbB3-negative patients. In patients who received anthracycline-based chemotherapy, low Nrdp1 expression indicated decreased disease-free survival (p=0.006) and high rates of metastasis and/or recurrence (p<0.001). CONCLUSION: Nrdp1 may serve as a useful biomarker for the clinical outcome and efficacy of adjuvant anthracyclines-based chemotherapy in breast cancer.The prognosis of Nrdp1 was not solely dependent on its deregulation of ErbB3. PMID- 25519011 TI - Detection of circulating tumour cells in peripheral blood of patients with malignant pleural mesothelioma. AB - BACKGROUND: The independent prognostic value of Circulating Tumour Cells (CTC) level has been demonstrated in several solid tumours. There is currently few data on Malignant Pleural Mesothelioma (MPM) and CTC. We investigated whether the presence of CTC was correlated with prognosis factors and treatment efficacy. METHODS/OBJECTIVES: MPM patients (pts) were enrolled in a prospective monocentric study. CTC detection was made using the "CellSearch" assay. The correlation between the presence of CTC and worse prognosis factors was assessed using the X(2) test. Comparison of Overall Survival (OS) and Progression Free Survival (PFS) according to CTC detection was performed using the log-rank test. RESULTS: Twenty-seven MPM pts with a median follow-up of 4.2 months were included. CTC were detected in 44% of pts with a median level of 1.5. No significant correlation was observed between the presence of CTC and worse prognosis factors. Moreover, CTC detection was not a significant predictor of OS or PFS (p=0.155 and p=0.32 respectively). CONCLUSIONS: CTC were detected in a small cohort of MPM patients. We couldn't demonstrate a significant prognostic value or a difference in OS/PFS between CTC levels. Further analyses, validation studies and detection techniques are needed to establish their real clinical value in MPM. PMID- 25519012 TI - Evaluation of genetic variants in miRNAs in patients with colorectal cancer. AB - BACKGROUND: Aberrant expression and structural alteration of miRNAs are considered to participate in cancer development. It has been suggested that common single-nucleotide polymorphisms (SNPs) in miRNAs are associated with susceptibility to several human diseases including colorectal cancer (CRC). METHODS: A case-control study at 157 CRC patients and 299 healthy controls of Greek origin was undertaken in order to investigate the association between the genotype and allelic frequencies of three common SNPs (rs2910164, rs11614913 and rs3746444) in pre-miRNAs, miR-146a, miR-196a2 and miR-499. RESULTS: The risk for CRC was significantly higher at the carriers of miR-146a rs2910164 CC genotype and C allele (p=0.02 and p< 0.001, respectively). None of the other performed analysis showed any statistically significant results. CONCLUSIONS: Our findings suggest that the rs2910164 polymorphism in pre-miRNA, miR-146a may be associated with the risk of CRC. PMID- 25519013 TI - Bilateral granulomatous mastitis with a different etiology. AB - Idiopathic granulomatous mastitis (IGM) and Tuberculosis mastitis (TM) are rare inflammatory diseases of the breast that can clinically mimic malignancy causing misdiagnosis as breast cancer. We present a rare case of bilateral granulomatous mastitis with a different etiology. An initial lesion developed in the right breast was diagnosed as IGM, which was treated with antibiotics and surgery. A subsequent lesion developed in the contralateral breast 5 months later and was diagnosed as TM, which also completely responded to antituberculosis medication without surgical excision. Differential diagnosis was made using the results of the polymerase chain reaction for tuberculosis (TBC-PCR) of both of the breast lesions in addition to typical pathologic findings of IGM in the right breast and an antituberculosis medication response in the left breast. To the best of our knowledge, this is the first case of bilateral granulomatous mastitis with a different etiology. PMID- 25519014 TI - Association of TNF-alpha (-238 and -308) promoter polymorphisms with susceptibility of oral squamous cell carcinoma in North Indian population. AB - BACKGROUND: The pro-inflammatory cytokines play an essential role in immune response and are involved in a variety of inflammatory and infectious disease. Tumor necrosis factor alpha (TNF-alpha) gene polymorphism has been a potential determinant of susceptibility to various types of cancer. OBJECTIVE: To evaluate the association of TNF-alpha gene promoter (-238) G/A and (-308) G/A polymorphisms with the susceptibility of OSCC patients in North Indian population. METHODS: A total 272 patients with OSCC and 185 healthy volunteers were genotypes for the TNF-alpha (-238) G/A and (-308) G/A gene polymorphism. Genotypes were identified by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). Genotype frequencies were evaluated by Chi-square test and Odds ratio (OR) relative risk. RESULTS: TNF-alpha (-238) G/A polymorphism was significantly associated with OSCC patients as compared to healthy volunteers (GG vs. GA: OR=0.3500, 95% CI=0.1289-09502; p=0.036; G vs. A: OR=0.3589 1.477, 95% CI=0.1335-0.9652; p=0.0386). No significant association was found in TNF-alpha (-308) G/A gene polymorphism with OSCC patients and controls. CONCLUSIONS: We conclude that the TNF-alpha (-238) G/A polymorphism was significantly associated with OSCC however TNF-alpha (-308) G/A polymorphism was not associated in OSCC patients. PMID- 25519015 TI - Relationship between the expression of phosphorylated heat shock protein beta-1 with lymph node metastases of breast cancer. AB - BACKGROUND: Heat shock protein beta-1 (HspB1) is a chaperone of the sHsp (small heat shock protein). The common functions of sHsps are chaperone activity, inhibition of apoptosis, regulation of cell development, and cell differentiation, take part in signal transduction. OBJECTIVE: To study the intracellular localization of phosphorylated features and non-phosphorylated forms of HspB1 in primary breast cancer cells and to evaluate their relationship with regional lymphatic metastasis. MATERIAL AND METHODS: Tumor biopsies of breast tissue were collected from 100 patients with a confirmed diagnosis of invasive carcinoma, nonspecific type, between the ages of 31-80 years. Immunohistochemistry was used to determine the intracellular localization of phosphorylated and non-phosphorylated forms of HspB1. RESULTS: The result of this study showed that biopsies from patients with lymph node metastasis exhibited significantly higher levels of phosphorylated forms of HspB1 in the nucleus and cytoplasm compared with the group without lymph node metastasis. Analysis showed that the expression of phosphorylated forms of the chaperone HspB1 correlates with the amount and percentage of lymph node metastases affected. CONCLUSION: The nuclear expression of phosphorylated and non-phosphorylated forms of the chaperone HspB1 is a marker of tumor cells associated with lymphatic metastasis of breast cancer. PMID- 25519016 TI - A novel molecular marker of breast cancer stem cells identified by cell-SELEX method. AB - BACKGROUND: Breast cancer stem cells (CSCs) are thought to initiate mammary tumors and render them resistant to anti-cancer therapies. However, there are currently no ideal biomarkers to identify this minority population in breast cancer. OBJECTIVE: To find out the oligonucleotides with high specificity and affinity for mammosphere cells using a high capacity ssDNA library. METHODS: We used the cell-SELEX (systematic evolution of ligands by exponential enrichment process) method. MCF-7 cells were cultured in serum-free media to form mammosphere cells as enriched stem cells, and were used as the positive target cells. The normal breast epithelial MCF-10A and MCF-7sal cells, which are MCF-7 cells treated with Salinomycin, were used as the negative target cells. We collected the ssDNA pools that were bound to positive target cells, and could not bind negative target cells. RESULTS: After 13 rounds of selection, we isolated the MS03 aptamer with high specificity and affinity for mammosphere cells. When compared with CD44(+)/CD24(-/low) cells, MS03(+) cells did not show any significant difference in sphere formation ability in vitro. In addition, 63.3% of MS03 aptamer-selected cells exhibited the CD44(+)/CD24(-/low) phenotype. Because the MS03 aptamer is synthesized easily and non-immunogenic, it is much more flexible than CD44/CD24 as a breast CSC biomarker. CONCLUSIONS: The MS03 aptamer may become a promising molecular probe during diagnostic and therapeutic applications in breast cancer. PMID- 25519017 TI - Effect of zinc and polyphenols supplementation on antioxidative defense mechanisms and the frequency of microsatellite instability in chemically-induced mammary carcinogenesis in the rat. AB - The aim of the present study was to assess the effect of dietary supplementation (with zinc or zinc and polyphenolic compounds - resveratrol or genistein) on antioxidant enzymes (glutathione peroxidase - GPx, catalase - CAT and superoxide dismutase - SOD) and the frequency of microsatellite instability (MSI) in a widely used model of mammary carcinogenesis induced in the rat by treatment with 7,12-dimethyl-1,2-benz[a]anthracene (DMBA). The impact of selected compounds on the intensity of DMBA-induced carcinogenesis was also assessed. Sixty four Sprague-Dawley female rats were divided into study groups which, apart from the standard diet and DMBA, were treated with zinc, zinc and resveratrol or zinc and genistein via gavage for a period ranging from 40 days to 20 weeks of age. On the basis of the obtained results it can be said that synergistic reaction between Zn(II) and genistein causes a delay in cancer development as compared with the animals treated with DMBA but with no food supplementation. Supplementation with Zn(II) and polyphenolic compounds resulted in the occurrence of microsatellite instabilities in tumors. LOH (loss of heterozygosity) was found in tumor samples at microsatellite D1Mgh6 and D3Mgh9. DMBA treatment increased significantly the glutathione peroxidase activity whereas it had no effect on the SOD and CAT activities, as compared with control rats. Diet supplementation has an effect on the activity of selected antioxidant enzymes. Diet supplementation has an effect on the occurrence of microsatellite instabilities as well as on the intensity of the neoplastic process. The intensity of occurrence of microsatellite instabilities does not depend on the activity of selected antioxidant enzymes. PMID- 25519018 TI - The prognostic role of TCF4 expression in locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy. AB - BACKGROUND: At present no useful factors to predict the sensitivity to neoadjuvant chemoradiotherapy (nCRT) have been established in patients with locally advanced rectal cancer (LARC). OBJECTIVE: The objective of this study was to explore the prognostic role of T cell factor 4 (TCF4) expression in predicting tumor response to nCRT and tumor outcomes for patients with LARC. METHODS: The study enrolled 96 patients who underwent nCRT followed by total mesorectal excision (TME). The TCF4 expression of all patients' biopsies before nCRT was evaluated by Immunohistochemical staining method. RESULTS: After completion of nCRT, 5 cases (5.2%) achieved clinical complete response (cCR) thus the remaining 91 patients underwent a standardized total mesorectal excision (TME) procedure. There were 44 patients (45.8%) achieved good tumor response (including TRG 3-4 and 5 cCR patients) while poor response (TRG 0-2) was achieved in 52 patients (54.2%). Our results demonstrated that patients with low expression of TCF4 were more sensitive to nCRT than those with high TCF4 expression (P=0.031). Low TCF4 expression before nCRT and good response were significantly associated with improved 5-year disease-free survival and 5-year overall survival (P<0.05). Multivariate analysis confirmed that the pretreatment TCF4 expression was an independent prognostic factor. CONCLUSIONS: Our data revealed that low TCF4 protein expression was a useful predictive factor of good tumor response to nCRT and good outcomes in patients with LARC. PMID- 25519019 TI - Profiles of differential expression of circulating microRNAs in hepatitis B virus positive small hepatocellular carcinoma. AB - BACKGROUND: Abnormally expressed circulating microRNA (miRNA) may serve as a potential biomarker for the diagnosis of cancer patients. OBJECTIVE: We sought to determine the differentially expressed circulating microRNAs in patients with hepatitis B virus (HBV)-positive small hepatocellular carcinoma (HCC) compared to other HBV-positive benign liver diseases. METHODS: The miScript miRNA PCR Array was used to detect the levels of 84 miRNAs in plasma or serum samples of patients with HBV-related small HCC (23 cases), liver cirrhosis (LC) (20 cases), chronic hepatitis B (CHB) (20 cases) and healthy controls (16 cases). MiRNAs with fold change values ? 2 or ? 0.5 compared to healthy controls were considered to be deregulated miRNAs. RESULTS: The results of duplicate plasma experiments were not reliable. Comprehensive analysis of the two serum experiments showed that the quality controls all met the requirements. We found 18 differentially expressed miRNAs. Relative to healthy controls, nine, three, and 11 miRNAs were up regulated in the CHB group, LC group and small HCC group, respectively. In contrast, one, three, and three miRNAs were down-regulated in the same patient groups, respectively. Interestingly, miR-195, miR-25 and miR-16 were up regulated, and miR-205 was down-regulated, in all three experimental groups. Moreover, only in the HCC group, miR-18a, miR-100, miR-145 and miR-223 were up regulated 3.48-, 2.95-, 2.12- and 3.91-fold, respectively, and miR-200a and miR 222 were down-regulated 2.56- and 2.00-fold, respectively. CONCLUSIONS: Our study demonstrated the presence of six differentially expressed serum microRNAs in HBV positive small HCC compared to other benign liver diseases associated with HBV. PMID- 25519020 TI - Decreased expression of fecal miR-4478 and miR-1295b-3p in early-stage colorectal cancer. AB - BACKGROUND: Colorectal cancer (CRC) is a major cause of cancer-related deaths world-wide. Detection of molecular markers in stool samples is a promising strategy for CRC screening. MicroRNAs (miRNAs) are short, non-coding RNA molecules that are commonly dysregulated in neoplasia. OBJECTIVE: The objective of this study was to evaluate the fecal miRNAs differentiation between early stage CRC patients and healthy subjects. METHODS: Stool samples were collected from 40 patients with early stage (I, II) CRC and 16 healthy controls. RNA was extracted from all samples using miRNAeasy Mini Kits. MiRNA microarray expression profiling was performed with Agilent's miRNA Microarray system on 12 CRC and 8 normal stool samples. The expression levels of miR-4478 and miR-1295b-3p were determined by the SYBR Green miScript PCR system. RESULTS: In profiling study, we found 215 down-regulated miRNAs in CRC group. Furthermore, in validation study we found that the expression levels of fecal miR-4487 and miR-1295b-3p were significantly decreased in CRC patients compared to healthy controls. CONCLUSIONS: The expression of miR-4478 and miR-1295b-3p were significantly diminished in stool samples of CRC patients with early stage (I, II) in comparison with normal group. These miRNAs maybe use as potential non-invasive molecular markers for CRC diagnosis, but further studies are needed. PMID- 25519022 TI - Evaluation of Annexin A2 as a novel diagnostic serum biomarker for lung cancer. AB - Annexin A2 (ANXA2) is a 36 kDa protein which orchestrates multiple biologic processes and clinical associations, especially in cancer progression. It is important to establish a specific and sensitive ANXA2 enzyme-linked immunosorbent assay (ELISA) for the study of ANXA2 functions and its clinical application. Therefore, we prepared a polyclonal antibody (PAb) in rabbits and a monoclonal antibody (MAb) in mices immunized with a recombinant ANXA2 protein. Based on our self-made MAb and PAb, highly specific and sensitive ELISA was developed. The detection limitation of ANXA2 was 10 ng/mL and the linear dynamic range was between 10 and 500 ng/mL. Using the established ELISA, we detected ANXA2 protein in human serum. It was found that soluble ANXA2 concentration in serum samples from 42 lung cancer patients was significantly higher than that from 43 healthy individuals (p< 0.01). Our data provides a new approach for detecting soluble ANXA2, especially in large ongoing and future clinical studies. PMID- 25519021 TI - Expression of glucose regulated protein 78 (GRP78) determines colorectal cancer response to chemotherapy. AB - BACKGROUND: Colorectal cancer (CRC) is an important health problem all over the world. A great improvement in the screening and early detection of CRC has been achieved. However, a new molecular prognostic marker is largely required. Glucose regulated protein 78-kDa (GRP78) is the central regulator of the endoplasmic reticulum (ER) and has an important role in the proliferation, differentiation and resistance to chemotherapy in cancer cells. OBJECTIVE: The aim of the present study was to investigate the impact of elevated level of GRP78 on CRC prognosis and chemosensitivity. METHODS: Sixty eight CRC tissue samples were collected and protein expression of GRP78 was evaluated using immunohistochemistry. The clinicopathological factors of the patients were correlated with GRP78 level. RESULTS: GRP78 expression increased with the progression from early to advanced CRC stages. In addition, GRP78 level was increased with the progression from early T1-2 to late T3-4 tumor localization (p< 0.05). Moreover, a significant association was found between GRP78 expression and response to chemotherapy (p< 0.05). Association between GRP78 expression and patient's clinical characteristics including lymph node involvement and metastasis was not significant. CONCLUSIONS: Results suggest the possibility to use GRP78 as a biomarker for progression of CRC and its chemosensitivity to therapy. PMID- 25519024 TI - Drugs for rheumatoid arthritis. PMID- 25519025 TI - Visualization of astrocytic primary cilia in the mouse brain by immunofluorescent analysis using the cilia marker Arl13b. AB - In vertebrates, almost all somatic cells extend a single immotile cilium, referred to as a primary cilium. Increasing evidence suggests that primary cilia serve as cellular antennae in many types of tissues by sensing chemical or mechanical stimuli in the milieu surrounding the cells. In rodents an antibody to adenylyl cyclase 3 (AC3) has been widely used to label the primary cilia of neurons in vivo by immunostaining, whereas the lack of markers for the primary cilia of astrocytes has made it difficult to observe astrocytic primary cilia in vivo. Here, we obtained a visualization of astrocytic primary cilia in the mouse brain. In the somatosensory cortex, a large portion of neurons and astrocytes at postnatal day 10 (P10), and of neurons at P56 had AC3-positive primary cilia, whereas only approx. one-half of the astrocytes in the P56 mice carried primary cilia weakly positive for AC3. In contrast, the majority of astrocytes had ADP ribosylation factor-like protein 13B (Arl13b)-positive primary cilia in the somatosensory cortex and other brain regions of P56 mice. The lengths of astrocytic primary cilia positive for Arl13b varied among the brain regions. Our data indicate that Arl13b is a noteworthy marker of astrocytic primary cilia in the brain. PMID- 25519026 TI - Mean lung pressure during adult high-frequency oscillatory ventilation: an experimental study using a lung model. AB - In adult high-frequency oscillatory ventilation (HFOV), stroke volume (SV) and mean lung pressure (PLung) are important for lung protection. We measured the airway pressure at the Y-piece and the lung pressure during HFOV using a lung model and HFOV ventilators for adults (R100 and 3100B). The lung model was made of a 20-liter, airtight rigid plastic container (adiabatic compliance: 19.3 ml/cmH2O) with or without a resistor (20 cmH2O/l/sec). The ventilator settings were as follows: mean airway pressure (MAP), 30 cmH2O; frequency, 5-15 Hz (every 1 Hz); airway pressure amplitude (AMP), maximum;and % of inspiratory time (IT), 50% for R100, 33% or 50% for 3100B. The measurements were also performed with an AMP of 2/3 or 1/3 maximum at 5, 10 and 15 Hz. The PLung and the measured MAP were not consistently identical to the setting MAP in either ventilator, and decreasing IT decreased the PLung in 3100B. In conclusion, we must pay attention to the possible discrepancy between the PLung and the setting MAP during adult HFOV. PMID- 25519027 TI - Mental health status among Japanese medical students: a cross-sectional survey of 20 universities. AB - The purposes of this study were to evaluate the mental health status of Japanese medical students and to examine differences based on gender, as well as on university type and location, using the results of a nationwide survey. Between December 2006 and March 2007, we conducted a questionnaire survey among fourth year medical students at 20 randomly selected medical schools in Japan. The data from 1,619 students (response rate: 90.6%; male: 1,074; female: 545) were analyzed. We used the Japanese version of the 12-item General Health Questionnaire (GHQ-12) to measure mental health status. Poor mental health status (GHQ-12 score of 4 points or higher) was observed in 36.6% and 48.8% of the male and female medical students, respectively. The ratio of the age-adjusted prevalence of poor mental health status in female versus male medical students was 1.33 (95% confidence interval: 1.10-1.62). The universities were categorized into two groups based on the university type (national/public: 15 vs. private: 5) or location (in a large city: 7 vs. in a local city: 13 cities). The prevalence of poor mental health status in both men and women differed between these groups, although not significantly. The GHQ-12 scores in men significantly differed between the categorized groups of universities. These results suggest that adequate attention must be paid to the mental health of medical students, especially females, and that a system for providing mental health care for medical students must be established in the context of actual conditions at each university. PMID- 25519023 TI - Establishing a large prospective clinical cohort in people with head and neck cancer as a biomedical resource: head and neck 5000. AB - BACKGROUND: Head and neck cancer is an important cause of ill health. Survival appears to be improving but the reasons for this are unclear. They could include evolving aetiology, modifications in care, improvements in treatment or changes in lifestyle behaviour. Observational studies are required to explore survival trends and identify outcome predictors. METHODS: We are identifying people with a new diagnosis of head and neck cancer. We obtain consent that includes agreement to collect longitudinal data, store samples and record linkage. Prior to treatment we give participants three questionnaires on health and lifestyle, quality of life and sexual history. We collect blood and saliva samples, complete a clinical data capture form and request a formalin fixed tissue sample. At four and twelve months we complete further data capture forms and send participants further quality of life questionnaires. DISCUSSION: This large clinical cohort of people with head and neck cancer brings together clinical data, patient-reported outcomes and biological samples in a single co-ordinated resource for translational and prognostic research. PMID- 25519028 TI - Living will interest and preferred end-of-life care and death locations among Japanese adults 50 and over: a population-based survey. AB - The main purpose of this study was to determine the relationships between Japanese individuals' interest in living wills and their preferred end-of-life care and death locations. Questionnaires were mailed to 1,000 individuals aged >50 to measure these 2 factors. We examined the associations between the respondents' characteristics and their preferred care and death locations by using multinomial logistic regression models. The response rate was 74%. Home was the most frequently preferred place for end-of-life care (64%), and a palliative care unit (PCU) was the most commonly preferred place to die (51%). Living will interest was associated with a preference for care (odds ratio [OR] 4.74, 95% confidence interval [CI] 1.95-12.1) and death (OR 2.75, 95% CI 1.70-4.47) in a PCU rather than a hospital, but it was not associated with the choice between receiving care or dying at home instead of a hospital. We must consider why Japanese people think home death is impracticable. The Japanese palliative care system should be expanded to meet patients' end-of-life needs, and this includes not only facilitating home care but also increasing access to PCU care. PMID- 25519029 TI - Protective effect of eicosapentaenoic acid on insulin resistance in hyperlipidemic patients and on the postoperative course of cardiac surgery patients: the possible involvement of adiponectin. AB - Accumulated studies have shown that omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) have protective roles against inflammatory responses such as hyperlipidemia, diabetes mellitus (DM) and cardiovascular diseases. Here we examined the effects of administering EPA to hyperlipidemic patients and other patients undergoing cardiac surgery to determine whether this treatment would increase plasma EPA levels and to clarify the association between EPA treatment and adiponectin production in hyperlipidemic patients. We also assessed the effect of preoperative EPA administration on postoperative adverse events such as postoperative atrial fibrillation (POAF) and postoperative infection in the cardiac surgery patients. The EPA administration significantly increased the serum EPA concentrations in both patient populations (p<0.001). In the hyperlipidemic patients, the EPA administration significantly increased plasma adiponectin levels (p<0.05), accompanied by a decrease in insulin resistance designated by the HOMA-IR (homeostasis model assessment of insulin resistance) score (p<0.05) and Hs-CRP (high sensitivity C-reactive protein) value (p<0.05). In the cardiac surgery patients, no significant effect of EPA on cardiac adverse events such as POAF was observed. However, our results clearly demonstrated that both the neutrophil-to-lymphocyte ratio and the 2nd-line antibiotic requirement in the EPA group were significantly decreased compared to the untreated control group (p<0.05). We suggest that EPA administration may exert anti-inflammatory effects in patients with hyperlipidemia and in those undergoing cardiac surgery, possibly through an increase in plasma adiponectin levels. PMID- 25519030 TI - Severe case of peripheral leukocytosis initially diagnosed as myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable, but possibly prefibrotic primary myelofibrosis. AB - Leukocytosis is occasionally seen in patients with presumptive but undiagnosed myeloproliferative disorders (MPD). A 74-year-old woman was admitted to our hospital for tarry stools, anemia, and marked peripheral leukocytosis of 1.4*10(5)/MUL. Gastroenteroscopy revealed an acute gastric and duodenal mucosal lesion that was treated successfully via endoscopic hemoclipping. Bone marrow aspiration revealed marked megakaryocyte proliferation with atypia of naked nuclei and marrow hypercellularity (90% cellularity). A fluorescence in situ hybridization test could not detect the BCR-ABL fusion gene. Bone marrow aspiration later revealed further abnormalities of megakaryocytes. The patient died from cerebral bleeding. The present case fulfilled 2 of the 3 major criteria of primary myelofibrosis according to the World Health Organization 2008 classification:namely, megakaryocytic hyperplasia with hypercellular marrow and granulocytic hyperplasia. However, the megakaryocytic abnormality was not strictly compatible with the criteria. Instead, we considered prefibrotic primary myelofibrosis as a possibility, although myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) was technically the correct diagnosis. The present case shows that MPN diagnosis remains difficult and suggests that other cases of peripheral leukocytosis with diagnosed MDS/MPN-U might include similar findings. PMID- 25519032 TI - Management of lacerated and swollen tongue after convulsive seizure with a mouth protector: interprofessional collaboration including dentists in intensive care. AB - We encountered a 74-year-old male patient with tongue laceration after convulsive seizures under intensive care. The tongue showed severe swelling, and the right ventral surface had been lacerated by his isolated and pointed right lower canine. Our university hospital has established a perioperative management center, and is promoting interprofessional collaboration, including dentists, in perioperative management. Dentists collaborating in the perioperative management center took dental impressions, with the support of anesthesiologists who opened the patient's jaw under propofol sedation, to produce a mouth protector. By raising the patient's bite, the completed mouth protector prevented the isolated tooth from contacting the tongue and protected the lacerated wound. Use of the mouth protector prevented the lacerated tongue from coming into contact with the pointed tooth, and the tongue healed gradually. These findings underscore that interprofessional collaboration including dentists can improve the quality of medical care. PMID- 25519031 TI - Ultrastructural analysis of an enterolith composed of deoxycholic acid. AB - A 67-year-old Japanese man underwent enterotomy because of enterolith ileus. Component analysis by infrared spectroscopy revealed that the enterolith was composed of a high concentration of deoxycholic acid. We further analyzed and compared the ultrastructure of the enterolith and a commercially available powdered form of deoxycholic acid by means of scanning electron microscopy and energy dispersive X-ray spectroscopy. Energy dispersive X-ray spectroscopy analysis revealed that the ratios of carbon and oxygen in the enterolith were equal to those in the deoxycholic acid powder. Scanning electron microscopy analysis showed rectangular prism-shaped particles on the surface of the enterolith. This structure was similar to that of the deoxycholic acid powder. The surgically removed enterolith had a twisted and coiled appearance. Possible mechanisms underlying the formation of this unique form are discussed. PMID- 25519033 TI - POEMS syndrome in a 20-year-old patient diagnosed following a complaint of reduced visual acuity. AB - We report a case of POEMS syndrome in a 20-year-old patient diagnosed after visiting an eye clinic with a chief complaint of reduced visual acuity. A male university student aged 20 years was referred to our department complaining of blurred vision in both eyes that had persisted for 1 month. He also noted headache, nausea, and paresthesia in the lower extremities around the same time. The visual acuity of his right and left eye was 20/40 and 20/20, respectively. Optic disc edema and serous retinal detachment were present. Brain magnetic resonance imaging showed no intracranial abnormalities, while elevated cerebrospinal fluid pressure, reduced nerve conduction velocity in both lower extremities, hepatosplenomegaly, M proteinemia, high blood VEGF levels, osteoblastic and osteolytic changes in the spine, and atypical plasma cells in bone lesions were noted. From the above findings, the patient was diagnosed with POEMS syndrome. He received high-dose dexamethasone, thalidomide, and radiotherapy on the sacral mass, followed by high-dose melphalan with autologous stem-cell support, and showed subsequent systemic and ophthalmologic improvement. Here, we report the youngest case ever of POEMS syndrome with ocular manifestation. If patients have optic disc edema in both eyes with no intracranial space-occupying lesion, POEMS syndrome should be considered in differential diagnosis, regardless of age. PMID- 25519035 TI - A Social Evaluation of Perception on Body Contouring Surgery by Turkish Male Aesthetic Surgery Patients. AB - Although aesthetic procedures are known to have a higher impact on women, men are becoming more inclined toward such procedures since the last decade. To determine the reason behind the increase in demand for male aesthetic procedures and to learn about the expectations and inquietude related to body contouring surgery, a prospective questionnaire study was conducted on 200 Turkish males from January 1, 2011-May 31, 2012. Demographic information, previous aesthetic procedures and thoughts on body contouring procedures with given reasons were questioned. The results of the study showed that 53 % of all participants considered undergoing body contouring surgery with the given reason that they believed their current body structure required it. For those who did not consider contouring operations, 92.5 % said they felt that they did not need such a procedure. The results of the statistical analysis showed that BMI was a significant factor in the decision making process for wanting to undergo body contouring procedures. The results of the study showed that men's consideration for aesthetic operations depends mainly on necessity and that the most considered region was the abdominal zone in regard to contouring. We can conclude that men are becoming more interested in body contouring operations and therefore different surgical procedures should be refined and re-defined according to the expectations of this new patient group. PMID- 25519034 TI - Consistently high unprotected anal intercourse (UAI) and factors correlated with UAI among men who have sex with men: implication of a serial cross-sectional study in Guangzhou, China. AB - BACKGROUND: China experiencing an increasing HIV epidemic among men who have sex with men (MSM), and unprotected anal intercourse (UAI) has played a key role in this process. The aims of this study were to examine the trend of UAI and to explore the factors correlated with UAI among MSM in Guangzhou, China. METHODS: Data from 2008 to 2013 were retrieved from the annual serological and behavioral surveys system. We collected information on demographic, HIV related sexual behavior with men and women, access to HIV prevention services, and symptoms of sexually transmitted infections. Chi-square test was used to examine the similarity of the participants during the study period. Univariate and multivariate logistic regression were conducted to test the factors associated with UAI. Trend test was used to check the change of UAI in different characteristic stratums during the study period. RESULTS: In total, 58.4% (range from 54.5% to 62.0%) of the participants reported that they engaged in UAI in the past six months. Participants who aged less than 20 [Adjusted Odds Ratio (AOR): 2.22, 95% Confidential Interval (CI): 1.07-4.61], only attended elementary school (or less) (AOR: 1.41, 95% CI: 1.04-1.90), cohabiting with male partner (AOR: 2.15, 95% CI: 1.66-2.79), divorced or widowed (AOR: 2.80, 95% CI: 1.54-5.07), did not test for HIV in the past year (AOR: 1.36, 95% CI: 1.12-1.65), and had 10 or more partners in the past six months (AOR: 1.85, 95% CI: 1.18-2.91) had higher odds of UAI. However, the proportions of UAI were stable in different stratums during the study period. CONCLUSIONS: The proportion of MSM engaged in UAI was consistently high during the study period. Effective intervention strategies, which include but not limit to risk reduction counseling and testing services, are urgently needed to bring down the risk behaviors of the MSM in Guangzhou, in order to control HIV/STIs epidemic in this specific population. PMID- 25519036 TI - [Osteosynthesis of talonavicular fusion with a claw plate and compression screw]. AB - OBJECTIVE: A new method of osteosynthetic stabilization of talonavicular fusion is presented. INDICATIONS: Idiopathic and posttraumatic talonavicular arthritis, talonavicular destruction in rheumatoid arthritis, adult acquired flatfoot deformity, cavovarus deformity, talonavicular degenerative disease in tarsal coalition. CONTRAINDICATION: Major hindfoot deformity or instability, severe osteopenic conditions of tarsal bones. SURGICAL TECHNIQUE: Talonavicular fusion is stabilized with a medioplantar 6.5-mm lag screw in combination with a dorsolateral 3.5-mm claw plate (Charlotte Claw compression plate; Fa. Wright Medical Technology, Memphis, USA) by a dorsal surgical access. POSTOPERATIVE MANAGEMENT: Nonweight-bearing in a cast or walker for 6 weeks; after radiologic control increasing weight-bearing is allowed. RESULTS: The technique was used in 44 patients, among them 31 cases of isolated talonavicular fusion. Complete bony healing was observed in 42 cases after medium follow-up time of 13.3 months. All 19 cases of isolated talonavicular fusion without posterior tibial tendon dysfunction healed uneventfully; two cases of non-union were observed in 12 patients with posterior tibial tendon dysfunction. PMID- 25519037 TI - Vertebral body replacement by posterior approach for metastatic disease in the thoracic spine--modified technique using an expandable cage. AB - OBJECTIVE: To describe the technique of all-posterior vertebral body replacement using an expandable cage and angled instruments. This method facilitates implant seating with limited posterior decompression useful in the setting of metastatic disease. INDICATIONS: Patients with metastatic disease of the thoracic spine with or without spinal cord compression. CONTRAINDICATIONS: Patients with a limited life expectancy of less than 6 months. Multiple foci of metastatic disease in the spine. SURGICAL TECHNIQUE: A hemilaminectomy was performed followed by nerve root sacrifice. The pleura was mobilized away from the vertebral body, after which decompression and tumor resection was performed from an all-posterior approach. An expandable vertebral body cage was inserted with a rotational manoeuvre and expanded in situ. POSTOPERATIVE MANAGEMENT: The patient was mobilized on postoperative day 1. A chest X-ray is also recommended to exclude incidental pneumothorax. RESULTS: Four patients were operated by an all-posterior vertebral body replacement during a 6-month period. The average length of surgical procedure was 187 min (range 165-220 min). No patient required a transthoracic approach. There were no intra- or postoperative complications and all patients could be discharged to home self-ambulating. PMID- 25519039 TI - Length of sick leave as a risk marker of hip fracture: a nationwide cohort study from Sweden. AB - Sickness absence is a risk marker for future health outcomes, but no previous studies have examined its association with osteoporotic fractures in old age. The results of this prospective population-based cohort study based on Swedish registers suggest that sickness absence is associated with higher risk of hip fracture. INTRODUCTION: Number of sick leave days is a risk marker for future health outcomes, but few studies have examined its association with major public health concerns in old age, such as osteoporotic fractures. The aim of this prospective, nationwide, population-based cohort study based on Swedish registers was to investigate the association between number of sick leave days and future risk of hip fracture. METHODS: Participants included were all 983,244 individuals who were living in Sweden on 31 December 1995, aged 50 to 64 years, employed, and with no previous hip fracture. Those with sick leave days in 1995 were compared to those with no sickness absence. Incidence of hip fracture was followed from 1996 to 2010. RESULTS: According to Cox regression models adjusted for sociodemographic factors and morbidity, being on sick leave more than 3 months, irrespective of cause, was associated with a 2.0-fold (hazard ratio (HR) 1.96, 95% confidence interval (CI) 1.74-2.20) and 1.4-fold (HR 1.40, 95% CI 1.27-1.56) increased risk of hip fracture in men and women, respectively. Analyses repeated among those with previous non-hip fractures replicated the significant associations. CONCLUSION: This nationwide cohort study suggests that sickness absence in working-age women and men is a risk marker of hip fracture at old ages. PMID- 25519040 TI - Uncovering new structural insights for antimalarial activity from cost-effective aculeatin-like derivatives. AB - A series of new aculeatin-like analogues were synthesized in two steps by combining two sets of building blocks. Many compounds showed inhibitory activities in vitro against Plasmodium falciparum and have helped to gain more insight into structure-activity relationships around the spirocyclohexadienone pharmacophoric scaffold. Plasmodium falciparum thioredoxin reductase (PfTrxR) has been investigated as a putative cellular target. Moreover, a new aculeatin-like scaffold without Michael acceptor properties, efficient at 0.86 MUM against P. falciparum 3D7, was identified and raises the prospect of developing a new antimalarial agent. PMID- 25519041 TI - Phase III study on efficacy of taxanes plus bevacizumab with or without capecitabine as first-line chemotherapy in metastatic breast cancer. AB - Taxanes (T) plus bevacizumab (B) and taxanes plus capecitabine (X) showed better progression-free survival (PFS) compared to taxanes alone. Since life-threatening or highly symptomatic situations require polychemotherapy in metastatic breast cancer (MBC), combination of taxanes, capecitabine plus bevacizumab appears reasonable. TABEA (NCT01200212), a prospectively randomized, open-label, phase III trial compares taxanes (paclitaxel 80 mg/m(2) i.v. d1,8,15 q22 or docetaxel 75 mg/m(2) i.v. d1 q22) plus bevacizumab (15 mg/kg i.v. d1 q22) with (TBX) or without capecitabine (TB, 1800 mg/m(2) daily d1-14 q22) as first-line therapy in MBC. Histologically confirmed HER2-negative, locally advanced or MBC patients with a chemotherapy indication and measurable or non-measurable target lesions (RECIST criteria) were included. Primary objective was PFS. Secondary objectives were response rate and duration, clinical benefit rate (complete response, partial response, stable disease >=24 weeks), 3-year overall survival, PFS in patients >=65 years, toxicity, and compliance. We assumed 10 and 13.3 months PFS for TB and TBX, respectively (HR = 0.75), requiring 432 patients and 386 events. Preplanned interim futility and safety analyses after 100 events in 202 patients showed no efficacy benefit and higher toxicity for TBX. Recruitment and therapy were stopped following advice from the IDMC. Final analysis revealed a HR 1.13 [95 %CI 0.806-1.59], P = 0.474, for PFS. Overall grade 3-4 adverse event (77.3 vs. 62.1 %, P = 0.014) and serious adverse event (40.0 vs. 30.2 %, P = 0.127) rates were higher for TBX after 26.1 months median follow-up, with six deaths for TBX versus 1 for TB. Adding capecitabine to TB cannot be recommended as first line therapy in MBC. PMID- 25519042 TI - In vivo anti-metastatic effects of uPAR retargeted measles virus in syngeneic and xenograft models of mammary cancer. AB - The urokinase receptor (uPAR) plays a critical role in breast cancer (BC) progression and metastases and is a validated target for novel therapies. The current study investigates the effects of MV-uPA, an oncolytic measles virus fully retargeted against uPAR in syngeneic and xenograft BC metastases models. In vitro replication and cytotoxicity of MVs retargeted against human (MV-h-uPA) or mouse (MV-m-uPA) uPAR were assessed in human and murine cancer and non-cancer mammary epithelial cells. The in vivo effects of species-specific uPAR retargeted MVs were assessed in syngeneic and xenograft models of experimental metastases, established by intravenous administration of luciferase expressing 4T1 or MDA-MD 231 cells. Metastases progression was assessed by in vivo bioluminescence imaging. Tumor targeting was evaluated by qRT-PCR of MV-N, rescue of viable viral particles, and immunostaining of MV particles in lungs from tumor bearing mice. In vitro, MV-h-uPA and MV-m-uPA selectively infected, replicated, and induced cytotoxicity in cancer compared to non-cancer cells in a species-specific manner. In vivo, MV-m-uPA delayed 4T1 lung metastases progression and prolonged survival. These effects were associated with identification of viable viral particles, viral RNA, and detection of MV-N by immunostaining from lung tissues in treated mice. In the human MDA-MB-231 metastases model, intravenous administration of MV h-uPA markedly inhibited metastases progression and significantly improved survival, compared to controls. No significant treatment-related toxicity was observed in treated mice. The above preclinical findings strongly suggest that uPAR retargeted measles virotherapy is a novel and feasible systemic therapy strategy against metastatic breast cancer. PMID- 25519043 TI - Fulvestrant and male breast cancer: a pooled analysis. AB - Male breast cancer is an uncommon malignancy; little is known regarding hormonal manipulations for tamoxifen-resistant male breast cancer patients. This is the first pooled analysis of the literature to synthesize all available data and to evaluate the efficacy and safety of fulvestrant in male breast cancer. This study was performed in accordance with the PRISMA guidelines. All studies that examined the efficacy of fulvestrant in male breast cancer, regardless of sample size, were considered eligible. The search strategy retrieved 31 articles; of these, five articles were eligible (23 patients) for this pooled analysis. The mean age of the study sample was 63.1 years. Adjuvant hormonal treatment was administered in 87.5 % of cases. Fulvestrant was given as first or second line in 40 % of patients, while as third line or beyond in 60 % of patients. 79.0 % of patients at fulvestrant administration had visceral metastases. Regarding best response, in 26.1 % PR was achieved, in 47.8 % of cases SD was recorded, whereas in 26.1 % of patients PD was noted. The median PFS was equal to 5 months. No grade 3 and 4 adverse events were recorded; of note, hot flashes were reported in 18.2 % of male breast cancer patients. Fulvestrant may potentially play a promising role in the optimal therapeutic strategy for male patients with breast cancer diagnosis. However, further clinical and pharmacokinetic investigations are more than warranted before fulvestrant use becomes a common practice in male breast cancer patients. PMID- 25519044 TI - The intracellular carboxyl tail of the PAR-2 receptor controls intracellular signaling and cell death. AB - The protease-activated receptors are a group of unique G protein-coupled receptors, including PAR-1, PAR-2, PAR-3 and PAR-4. PAR-2 is activated by multiple trypsin-like serine proteases, including trypsin, tryptase and coagulation proteases. The clusters of phosphorylation sites in the PAR-2 carboxyl tail are suggested to be important for the binding of adaptor proteins to initiate intracellular signaling to Ca(2+) and mitogen-activated protein kinases. To explore the functional role of PAR-2 carboxyl tail in controlling intracellular Ca(2+), ERK and AKT signaling, a series of truncated mutants containing different clusters of serines/threonines were generated and expressed in HEK293 cells. Firstly, we observed that lack of the complete C-terminus of PAR 2 in a mutated receptor gave a relatively low level of localization on the cell plasma membrane. Secondly, the shortened carboxyl tail containing 13 amino acids was sufficient for receptor internalization. Thirdly, the cells expressing truncation mutants showed deficits in their capacity to couple to intracellular Ca(2+) and ERK and AKT signaling upon trypsin challenge. In addition, HEK293 cells carrying different PAR-2 truncation mutants displayed decreased levels of cell survival after long-lasting trypsin stimulation. In summary, the PAR-2 carboxyl tail was found to control the receptor localization, internalization, intracellular Ca(2+) responses and signaling to ERK and AKT. The latter can be considered to be important for cell death control. PMID- 25519046 TI - CD200 in growing rat lungs: developmental expression and control by dexamethasone. AB - CD200 belongs to cell adhesion molecules of the immunoglobulin superfamily. It lacks intracellular signaling motifs and exerts immunosuppressive effect in various tissues. We have reported previously that CD200 is predominantly associated with the capillary network in the alveolar septum of adult rats. The alveolar endothelial cells express CD200, which is confined to their luminal cell membrane facing the blood-air barrier. Our present results show that lung CD200 protein increases gradually with advancing age, being maximally expressed in the early postnatal (P) period. CD200 protein expression, however, declines at P5 but increases again after P7, reaching the adult level at P21. In developing lungs in fetal and neonatal stages, double-immunofluorescence staining has confirmed intense CD200 immunoreactivity delineating the vascular profiles in the double layers of the alveolar capillaries; this staining becomes diffuse and patchy with time. Unlike in adult lungs, immunoelectron microscopy has revealed that CD200 expression in fetal and early postnatal lungs is localized over the entire luminal cell membrane and in the cytoplasm of the endothelia. CD200 expression is progressively redistributed to a specific luminal domain of alveolar endothelia during pulmonary microvascular maturation. In neonatal rats treated with dexamethasone, the amount of lung CD200 significantly increases and is also elevated with time. Upregulation of endothelial CD200 has further been confirmed in isolated pulmonary microvascular endothelial cells treated with dexamethasone. Thus, lung CD200 is developmentally regulated, possibly under hormonal influence. PMID- 25519045 TI - Auditory feedback modulates development of kitten vocalizations. AB - Effects of hearing loss on vocal behavior are species-specific. To study the impact of auditory feedback on feline vocal behavior, vocalizations of normal hearing, hearing-impaired (white) and congenitally deaf (white) cats were analyzed at around weaning age. Eleven animals were placed in a soundproof booth for 30 min at different ages, from the first to the beginning of the fourth postnatal month, every 2 weeks of life. In total, 13,874 vocalizations were analyzed using an automated procedure. Firstly, vocalizations were detected and segmented, with voiced and unvoiced vocalizations being differentiated. The voiced isolation calls ('meow') were further analyzed. These vocalizations showed developmental changes affecting several parameters in hearing controls, whereas the developmental sequence was delayed in congenitally deaf cats. In hearing impaired and deaf animals, we observed differences both in vocal behavior (loudness and duration) and in the calls' acoustic structure (fundamental frequency and higher harmonics). The fundamental frequency decreased with age in all groups, most likely due to maturation of the vocal apparatus. In deaf cats, however, other aspects of the acoustic structure of the vocalizations did not fully mature. The harmonic ratio (i.e., frequency of first harmonic divided by fundamental frequency) was higher and more variable in deaf cats than in the other study groups. Auditory feedback thus affects the acoustic structure of vocalizations and their ontogenetic development. The study suggests that both the vocal apparatus and its neuronal motor control are subject to maturational processes, whereas the latter is additionally dependent on auditory feedback in cats. PMID- 25519047 TI - Expression of the heparin-binding growth factor midkine and its receptor, Ptprz1, in adult rat pituitary. AB - Midkine (MK) belongs to a family of secreted heparin-binding growth factors and is highly expressed in various tissues during development. MK has multiple functions, such as regulation of cell proliferation, migration, survival and differentiation. We recently reported that MK mRNA is strongly expressed in the developing rat pituitary gland. In the adult pituitary, however, expression of MK and its receptor and the characteristics of the cells that produce them, have not been determined. Therefore, in this study, we investigate whether MK and its receptor, protein tyrosine phosphatase receptor-type Z (Ptprz1), are present in the adult rat pituitary. In situ hybridization, real-time reverse transcription PCR and immunoblotting were performed to assess MK and Ptprz1 expression. We also characterize MK- and Ptprz1-expressing cells by double-staining with in situ hybridization and immunohistochemical techniques for each pituitary hormone or S100 protein [a marker of folliculostellate (FS) cells]. MK-expressing cells were located in the anterior and posterior lobes but not in the intermediate lobe. Double-staining and immunoblotting revealed that MK mRNA and protein were only expressed in FS cells in the anterior pituitary. Regarding Ptprz1 expression, Ptprz1 mRNA was detected in adrenocorticotropic hormone (ACTH) cells and growth hormone (GH) cells but not in prolactin cells, thyroid-stimulating hormone cells, luteinizing hormone cells, or FS cells. These findings suggest that MK produced in FS cells acts locally on ACTH cells and GH cells via Ptprz1 in the adult rat anterior pituitary. PMID- 25519048 TI - Understanding Gas adsorption selectivity in IRMOF-8 using molecular simulation. AB - Grand canonical Monte Carlo simulations were used to explore the adsorption behavior of methane, ethane, ethylene, and carbon dioxide in isoreticular metal organic frameworks, IRMOF-1, noninterpenetrated IRMOF-8, and interpenetrated IRMOF-8. The simulated isotherms are compared with experimentally measured isotherms, when available, and a good agreement is observed. In the case of IRMOF 8, the agreement is much better for the interpenetrated model than for the noninterpenetrated model, suggesting that the experimental data was obtained on an essentially interpenetrated structure. Simulations show that carbon dioxide is preferentially adsorbed over methane, and a selective adsorption at low pressures of ethane over ethylene, especially in the case of IRMOF-8, confirm recent experimental results. Analysis of simulation results on both the interpenetrated and the noninterpenetrated structures shows that interpenetration is responsible for the higher adsorbed amounts of ethane at low pressures (<100 kPa) and for the interesting selectivity for ethane in ethane/ethylene binary mixtures. Van der Waals interactions seem to be enhanced in the interpenetrated structure, favoring ethane adsorption. This indicates that interpenetrated MOF structures may be of interest for the separation of small gas molecules. PMID- 25519049 TI - Clinical coding of prospectively identified paediatric adverse drug reactions--a retrospective review of patient records. AB - BACKGROUND: National Health Service (NHS) hospitals in the UK use a system of coding for patient episodes. The coding system used is the International Classification of Disease (ICD-10). There are ICD-10 codes which may be associated with adverse drug reactions (ADRs) and there is a possibility of using these codes for ADR surveillance. This study aimed to determine whether ADRs prospectively identified in children admitted to a paediatric hospital were coded appropriately using ICD-10. METHODS: The electronic admission abstract for each patient with at least one ADR was reviewed. A record was made of whether the ADR(s) had been coded using ICD-10. RESULTS: Of 241 ADRs, 76 (31.5%) were coded using at least one ICD-10 ADR code. Of the oncology ADRs, 70/115 (61%) were coded using an ICD-10 ADR code compared with 6/126 (4.8%) non-oncology ADRs (difference in proportions 56%, 95% CI 46.2% to 65.8%; p < 0.001). CONCLUSIONS: The majority of ADRs detected in a prospective study at a paediatric centre would not have been identified if the study had relied on ICD-10 codes as a single means of detection. Data derived from administrative healthcare databases are not reliable for identifying ADRs by themselves, but may complement other methods of detection. PMID- 25519050 TI - Efficient passivated phthalocyanine-quantum dot solar cells. AB - The power conversion efficiency of CdSe and CdS quantum dot sensitized solar cells is enhanced by passivation with asymmetrically substituted phthalocyanines. The introduction of the phthalocyanine dye increases the efficiency up to 45% for CdSe and 104% for CdS. The main mechanism causing this improvement is the quantum dot passivation. This study highlights the possibilities of a new generation of dyes designed to be directly linked to QDs instead of the TiO2 electrodes. PMID- 25519051 TI - [Real-time MRI/US fusion-guided biopsy in biopsy-naive and pre-biopsied patients with suspicion for prostate cancer]. AB - BACKGROUND: Magnetic resonance imaging (MRI)/ultrasound (US) fusion-guided biopsy detects more prostate cancer (PCa) than transrectal US (TRUS)-guided biopsy in patients with an indication for prostate re-biopsy. The aim of this study was a) to compare the detection rates of MRI/US fusion-guided biopsy with conventional TRUS in a double centre cohort and b) to investigate the influence of the number of pre-biopsies on the PCa detection rate. MATERIAL AND METHODS: In the period from January 2012 to July 2014, 310 consecutive patients gave written informed consent and underwent 3 Tesla MRI scans of the prostate. All patients had at least one PCa suspicious lesion in the MRI and were biopsied by MRI/US fusion followed by a conventional 10-core biopsy of the prostate. Detection rates based on technique, Gleason score and number of pre-biopsies were calculated. RESULTS: The overall detection rate of the study was 51% (158 patients). Among these 158 patients a histopathological Gleason score of 6 was detected in 60 patients (38%), a Gleason score of 7 in 54 patients (34%) and a Gleason score>=8 in 44 patients (28%). MRI/US fusion-guided biopsy detected 110 (69.7%) of the overall detected 158 PCa. TRUS-guided biopsy detected a higher rate of Gleason score 6 (54%) and a lower rate of Gleason score>=8 (15%) lesions in comparison to 38% Gleason 6 and 28% Gleason>=8 in the MRI/US fusion-guided biopsy, respectively. Furthermore, a lower Gleason score was observed in patients with more than one pre-biopsy. The detection rate in biopsy-naive patients undergoing MRI/US fusion was 75% (40 patients) among 75% detected Gleason score>=7. CONCLUSION: MRI/US fusion-guided biopsy detected more PCa and also more clinically significant cancer than conventional TRUS. In our cohort patients with more than one pre biopsy showed lower Gleason scores. The included patients with an initial MRI/US fusion-guided biopsy should be further investigated. PMID- 25519052 TI - Dirac Cones in two-dimensional conjugated polymer networks. AB - Linear electronic band dispersion and the associated Dirac physics has to date been limited to special-case materials, notably graphene and the surfaces of three-dimensional (3D) topological insulators. Here we report that it is possible to create two-dimensional fully conjugated polymer networks with corresponding conical valence and conduction bands and linear energy dispersion at the Fermi level. This is possible for a wide range of polymer types and connectors, resulting in a versatile new family of experimentally realisable materials with unique tuneable electronic properties. We demonstrate their stability on substrates and possibilities for doping and Dirac cone distortion. Notably, the cones can be maintained in 3D-layered crystals. Resembling covalent organic frameworks, these materials represent a potentially exciting new field combining the unique Dirac physics of graphene with the structural flexibility and design opportunities of organic-conjugated polymer chemistry. PMID- 25519053 TI - Cross-sector collaborations in Aboriginal and Torres Strait Islander childhood disability: a systematic integrative review and theory-based synthesis. AB - INTRODUCTION: Aboriginal and Torres Strait Islander children in Australia experience a higher prevalence of disability and socio-economic disadvantage than other Australian children. Early intervention is vital for improved health outcomes, but complex and fragmented service provision impedes access. There have been international and national policy shifts towards inter-sector collaborative responses to disability, but more needs to be known about how collaboration works in practice. METHODS: A systematic integrative literature review using a narrative synthesis of peer-reviewed and grey literature was undertaken to describe components of inter- and intra-sector collaborations among services to Aboriginal and Torres Strait Islander children with a disability and their families. The findings were synthesized using the conceptual model of the ecological framework. RESULTS: Thirteen articles published in a peer-reviewed journal and 18 articles from the grey literature met inclusion criteria. Important factors in inter- and intra-sector collaborations identified included: structure of government departments and agencies, and policies at the macro- (government) system level; communication, financial and human resources, and service delivery setting at the exo- (organizational) system level; and relationships and inter- and intra-professional learning at the meso- (provider) system level. CONCLUSIONS: The policy shift towards inter-sector collaborative approaches represents an opportunity for the health, education and social service sectors and their providers to work collaboratively in innovative ways to improve service access for Aboriginal and Torres Strait Islander children with a disability and their families. The findings of this review depict a national snapshot of collaboration, but as each community is unique, further research into collaboration within local contexts is required to ensure collaborative solutions to improve service access are responsive to local needs and sustainable. PMID- 25519056 TI - Biomimicry at the nanoscale: current research and perspectives of two-photon polymerization. AB - Living systems such as cells and tissues are extremely sensitive to their surrounding physico-chemical microenvironment. In the field of regenerative medicine and tissue engineering, the maintenance of culture conditions suitable for the formation of proliferation niches, for the self-renewal maintenance of stem cells, or for the promotion of a particular differentiation fate is an important issue that has been addressed using different strategies. A number of investigations suggests that a particular cell behavior can be in vitro resembled by mimicking the corresponding in vivo conditions. In this context, several biomimetic environments have been designed in order to control cell phenotypes and functions. In this review, we will analyze the most recent examples of the control of the in vitro physical micro/nano-environment by exploiting an innovative technique of high resolution 3D photolithography, the two-photon polymerization (2pp). The biomedical applications of this versatile and disruptive computer assisted design/manufacturing technology are very wide, and range from the fabrication of biomimetic and nanostructured scaffolds for tissue engineering and regenerative medicine, to the microfabrication of biomedical devices, like ossicular replacement prosthesis and microneedles. PMID- 25519055 TI - Colorectal cancer treatment in octogenarians: elective or emergency surgery? AB - BACKGROUND: The purpose of this research was to assess the characteristics of octogenarian patients with colorectal cancer and compare specific outcomes due to different types of surgical procedures used to treat the disease. METHODS: A total of 346 octogenarian patients undergoing surgery for colorectal cancer between April 2000 and April 2010 were retrospectively assessed according to elective (n = 261) or emergent (n = 85) admission group. The two groups were compared for clinical variables, surgical procedures, morbidity and mortality, ICU admission, length of hospital stay and overall survival. RESULTS: The two groups had similar comorbidities. The emergent group had a more advanced Dukes' stage, higher American Society of Anesthesiologists grading, lower anastomosis rate (40.2 vs 80.1%), higher stoma rate (30.6 vs 9.6%), more complications (71.8 vs 43.3%), nine days longer length of hospital stay and higher (82.4% vs 36.4%) ICU admission rate. Overall mortality was 9.5%, with a higher mortality rate in the emergent group (30.6%) than the elective group (3.1%). CONCLUSIONS: Octogenarians who undergo elective colorectal cancer surgery have better results than those requiring emergent surgery, but both are quite acceptable and we recommend surgical intervention should not be delayed. PMID- 25519057 TI - Prevalence of Leptospira antibodies in wild boars (Sus scrofa) from Northern Portugal: risk factor analysis. AB - Leptospirosis is a zoonosis of worldwide distribution, caused by infection with pathogenic spirochaetes of the genus Leptospira. The wild boar (Sus scrofa), an important hunting species in Europe, seems to play a significant role in the epidemiological cycle of leptospirosis. A total of 101 serum samples from wild boar hunted in Northern Portugal were analysed for leptospiral antibodies detection by microscopic agglutination test. Sera were collected during hunting seasons (2011-2013) and tested with 17 different pathogenic serovars of Leptospira. Antibodies against nine serovars were detected in 66 (65.4%) of these sera. Serovars Tarassovi and Altodouro exhibited the highest seroreactivity rates (23.8% and 16.8%, respectively), followed by Autumnalis (7.9%) and Bratislava (6.9%). Age and district of origin were found to be risk factors for the presence of leptospiral antibodies in contrast to gender. From a One Health perspective, this study revealed that wild boar should be considered as a potential source of leptospirosis dissemination for humans and animal species (domestic and wild) in shared environments, particularly in the Tras-os-Montes region. PMID- 25519058 TI - New data on programmed aging - slow phenoptosis. AB - This review summarizes the latest data on biochemistry and physiology of living organisms. These data suggest that aging, i.e. coordinated age-dependent weakening of many vital functions leading to gradual increase in the probability of dying, is not common to all organisms. Some species have been described whose probability of death does not depend on age or even decreases with age, this being accompanied by constant or increasing fertility. In the case of the naked mole rat (a non-aging mammal), a mechanism has been identified that protects this animal from cancer and the most common age-related diseases. The high molecular weight polysaccharide hyaluronan, a linear polymer composed of multiple repeated disaccharide of glucuronic acid and glucosamine, plays the key role in this mechanism. Hyaluronan is accumulated in the intercellular spaces in the organs and tissues of the naked mole rat. This polysaccharide provides early contact inhibition of cell division (anti-cancer effect). In addition, hyaluronan prevents the development of certain types of apoptosis, in particular, those induced by reactive oxygen species (ROS) (geroprotective effect preventing ROS induced decrease in cellularity in the organs and tissues of aging organisms). Extraordinary longevity of the naked mole rat (over 30 years, which is long for a rodent the size of a mouse) is connected to its eusocial lifestyle, when only the "queen" and its few "husbands" breed, while the huge army of non-breeding "subordinates" provide the "royal family" with protection from predators, food, and construction and maintenance of an underground labyrinth size of a football field. This way of life removes the pressure of natural selection from the "family" and makes aging - the program that is counterproductive for the individual but increases "evolvability" of its offspring - unnecessary. The example of the naked mole rat demonstrates the optional character of the aging program for the organism. Many facts indicating that aging can be regulated by an organism provide another argument in favor of optionality of aging. Cases have been described when aging as a program useful for the evolution of offspring but counterproductive for the parental individual slows under conditions that threaten the very existence of the individual. These conditions include food restriction (the threat of death from starvation), heavy muscular work, decrease or increase in the environmental temperature, small amounts of poisons (including ROS; here we speak about the paradoxical geroprotective effect of the low doses of prooxidants that inhibit apoptosis). On the other hand, aging can be inhibited (and maybe even cancelled) artificially. This can be done by turning off the genes encoding the proteins participating in the aging program, such as FAT10, p66shc, and some others. In addition, the gene of the antioxidant enzyme catalase can be addressed into mitochondria, where it will split mitochondrial hydrogen peroxide, the level of which increases with age. However, today the simplest way to slow down the aging program is the use of mitochondria-targeted low molecular weight antioxidant compounds of plastoquinonyl decyltriphenylphosphonium-type (SkQ1), which prolong the life of animals, plants, and fungi and inhibit the development of many age-related diseases and symptoms. PMID- 25519054 TI - MiR-223-3p targeting SEPT6 promotes the biological behavior of prostate cancer. AB - MicroRNAs (miRNAs) present frequently altered expression in urologic cancers including prostate, bladder, and kidney cancer. The altered expression of miR-223 has been reported in cancers and other diseases in recent researches. MiR-223 is up-regulated in systemic lupus erythematosus and rheumatoid arthritis. In neoplastic diseases, miR-223 is proved to be up-expressed in plasma or serum and cancer tissues compared with normal tissues in pancreatic cancer, gastric cancer, et al. However, whether altered expression of miR-223 is associated with prostate cancer (PCa) and what it is potential functions in PCa remained unveiled. In this study, we firstly found miR-223-3p were up-regulated in prostate cancer tissues and then we study functional role of miR-223-3p in PCa using DU145, PC3 and LNCaP cell lines. Our data suggested that miR-223-3p might target gene SEPT6 and promoted the biological behavior of prostate cancer. Notably, we found increasing SEPT6 expression might reverse the biological activity induced by miR-223-3p, which might be a potential therapeutic target for PCa. PMID- 25519059 TI - Receptor regulation of senile phenoptosis. AB - Here we present a concept that considers organism aging as an additional facultative function promoting evolution, but counterproductive for an individual. We hypothesize that aging can be inhibited or even arrested when full mobilization of all resources is needed for the survival of an individual. We believe that the organism makes such a decision based on the analysis of signals of special receptors that monitor a number of parameters of the internal and external environment. The amount of available food is one of these parameters. Food restriction is perceived by the organism as a signal of coming starvation; in response to it, the organism inhibits its counterproductive programs, in particular, aging. We hypothesize that the level of protein obtained with food is estimated based on blood concentration of one of the essential amino acids (methionine), of carbohydrates - via glucose level, and fats - based on the level of one of the free fatty acids. When the amount of available food is sufficient, these receptors transmit the signal allowing aging. In case of lack of food, this signal is cancelled, and as a result aging is inhibited, i.e. age-related weakening of physiological functions is inhibited, and lifespan increases (the well-known geroprotective effect of partial food restriction). In Caenorhabditis elegans, lowering of the ambient temperature has a similar effect. This geroprotective effect is removed by the knockout of one of the cold receptors, and replacement of the C. elegans receptor by a similar human receptor restores the ability of low temperature to increase the lifespan of the nematode. A chain of events linking the receptor with the aging mechanism has been discovered in mice - for one of the pain receptors in neurons, the nerve endings of which entwine pancreas beta-cells. Age-related activation of these receptors inhibits the work of insulin genes in beta-cells. Problems with insulin secretion lead to oxidative stress, chronic inflammation, and type II diabetes, which can be regarded as one of the forms of senile phenoptosis. In conclusion, we consider the role of some psychological factors in the regulation of the aging program. PMID- 25519061 TI - Microbiota and mitobiota. Putting an equal sign between mitochondria and bacteria. AB - The recent revival of old theories and setting them on modern scientific rails to a large extent are also relevant to mitochondrial science. Given the widespread belief that mitochondria are symbionts of ancient bacterial origin, the processes inherent to mitochondrial physiology can be revised based on their comparative analysis with possible involvement of bacteria. Such comparison combined with discussion of the role of microbiota in pathogenesis allows discussion of the role of "mitobiota" (we introduce this term) as the combination of different phenotypic manifestations of mitochondria in the organism reflecting pathological changes in the mitochondrial genome. When putting an equal sign between mitochondria and bacteria, we find similarity between the mitochondrial and bacterial theories of cancer. The presence of the term "bacterial infection" suggests "mitochondrial infection", and mitochondrial (oxidative) theory of aging can in some way be transformed into a "bacterial theory of aging". The possible existence of such processes and the data confirming their presence are discussed in this review. If such a comparison has the right to exist, the homeostasis of "mitobiota" is of not lesser physiological importance than homeostasis of microbiota, which has been so intensively discussed recently. PMID- 25519060 TI - The programmed aging paradigm: how we get old. AB - According to the traditional explanations ("old paradigm"), aging is due to the progressive accumulation of heterogeneous damages that are insufficiently contrasted by natural selection. An opposite interpretation ("new paradigm") sees aging as selectively advantageous in terms of supra-individual natural selection, and this implies the indispensable existence of genetically controlled specific mechanisms that determine it. The aim of this work is to expound synthetically the progressive alterations that mark the aging by showing how these changes are clearly defined and regulated by genes. The possibility of such a description, based on sound evidence, is an essential element for the plausibility of the new paradigm, and a fundamental argument against the tenability of the old paradigm. PMID- 25519062 TI - Phenoptosis in arthropods and immortality of social insects. AB - In general, there are no drastic differences in phenoptosis patterns in plant and animal organisms. However, there are some specific features characteristic for insects and other arthropods: 1) their development includes metamorphosis with different biochemical laws at consecutive developmental stages; 2) arthropods can reduce or stop development and aging when in a state of diapause or temporal cold immobility; 3) their life cycle often correlates with seasonal changes of surroundings; 4) polymorphism is widespread - conspecifics differ by their lifespans and phenoptosis features; 5) lifespan-related sexual dimorphism is common; 6) significant situational plasticity of life cycle organization is an important feature; for example, the German wasp (Paravespula germanica) is obligatorily univoltine in the temperate zone, while in tropical regions its lifespan increases and leads to repeated reproduction; 7) life cycles of closely related species may differ significantly, for example, in contrast to German wasp, some tropical hornets (Vespa) have only one reproduction period. Surprisingly, many insect species have been shown to be subjected to gradual aging and phenoptosis, like the highest mammals. However, queens of social insects and some long-lived arachnids can apparently be considered non-aging organisms. In some species, lifespan is limited to one season, while others live much longer or shorter. Cases of one-time reproduction are rather rare. Aphagia is common in insects (over 10,000 species). Cannibalism is an important mortality factor in insects as well as in spiders. In social insects, which exist only in colonies (families), the lifetime of a colony can be virtually unlimited. However, in case of some species the developmental cycle and death of a colony after its completion are predetermined. Most likely, natural selection in insects does not lengthen individual lifespan, but favors increase in reproduction efficiency based on fast succession of generations leading to increased evolvability. PMID- 25519063 TI - Modern evolutionary mechanics theories and resolving the programmed/non programmed aging controversy. AB - Modern programmed (adaptive) theories of biological aging contend that organisms including mammals have generally evolved mechanisms that purposely limit their lifespans in order to obtain an evolutionary benefit. Modern non-programmed theories contend that mammal aging generally results from natural deteriorative processes, and that lifespan differences between species are explained by differences in the degree to which they resist those processes. Originally proposed in the 19th century, programmed aging in mammals has historically been widely summarily rejected as obviously incompatible with the mechanics of the evolution process. However, relatively recent and continuing developments described here have dramatically changed this situation, and programmed mammal aging now has a better evolutionary basis than non-programmed aging. Resolution of this issue is critically important to medical research because the two theories predict that very different biological mechanisms are ultimately responsible for age-related diseases and conditions. PMID- 25519064 TI - Decrease in ATP biosynthesis and dysfunction of biological membranes. Two possible key mechanisms of phenoptosis. AB - Metabolic syndrome is extremely prevalent in the world and can be considered as one of main factors leading to accelerated aging and premature death. This syndrome may be closely linked with age-related disruptions in hypothalamic pituitary system function, which perhaps represent a trigger mechanism of development of endocrine and cardiovascular pathologies. Age-related elevation of the sensitivity threshold of the hypothalamus to regulatory signals in association with low mobility and excessive diet trigger a cascade of biochemical reactions that might be used for activation of programmed death of the organism - phenoptosis. Accumulation of fatty acids in a cell and resulting lipotoxicity include resistance to insulin and leptin, endoplasmic reticulum stress, uncoupling of oxidation and phosphorylation, and dysfunction of biological membranes. Decrease in ATP synthesis is correlated with accumulation of calcium ions in cells, dysfunction of mitochondria, and increasing apoptotic activity. Age-related activation of mTOR (which is greatly influenced by excess energy substrates) has deleterious impact on one of the main mechanisms of cell defense by which defective mitochondria are replaced: mitophagy and biogenesis of mitochondria will be suppressed, and this will increase in greater degree mitochondrial dysfunction and oxidative stress. Fatty acid-induced inflammation will increase activity of nuclear factor NF-kappaB, the well-known stimulator of age-related pathologies. The final stage of phenoptosis can be represented by endothelium dysfunction related with oxidative stress, insulin resistance, and the most prevalent cardiovascular pathologies. PMID- 25519065 TI - Pineal gland as an endocrine gravitational lunasensor: manifestation of moon phase dependent morphological changes in mice. AB - We found that some morphological properties of the pineal gland and submandibular salivary gland of mice are significantly distinct at the new and full moon. We suppose that the differences are initiated by the displacements of the electron dense concretions in the secretory vesicles of pinealocytes. This presumably occurs under the influence of the gravitational field, which periodically changes during different phases of the moon. It seems that the pinealocyte is both an endocrine and gravisensory cell. A periodic secretion of the pineal gland probably stimulates, in a lunaphasic mode, the neuroendocrine system that, in turn, periodically exerts influence on different organs of the body. The observed effect probably serves, within the lifelong clock of a brain, to control development and aging in time. PMID- 25519066 TI - The problem of determination of cause of laboratory animal's death: a critical review of definitions of "fatal" and "incidental" lesions. AB - The determination of the cause of a laboratory animal's death in gerontological experiments has become extraordinarily urgent in connection with the appearance of ideas on the programmed death of organisms. Unfortunately, the past approach to diagnosis of fatal and incidental changes based only on data of autopsy and histopathology (according to the human pathology model) is not correct for laboratory rodents. Nevertheless, the exact determination of death causes is principally possible in the future under conditions of adequate experimental design (including a large set of clinical, physiological, biochemical, and morphological examinations). However, it seems that even in this case causes of some experimental animal's death will remain unclear. PMID- 25519067 TI - Prevention of peroxidation of cardiolipin liposomes by quinol-based antioxidants. AB - In mammalian mitochondria, cardiolipin molecules are the primary targets of oxidation by reactive oxygen species. The interaction of oxidized cardiolipin molecules with the constituents of the apoptotic cascade may lead to cell death. In the present study, we compared the effects of quinol-containing synthetic and natural amphiphilic antioxidants on cardiolipin peroxidation in a model system (liposomes of bovine cardiolipin). We found that both natural ubiquinol and synthetic antioxidants, even being introduced in micro- and submicromolar concentrations, fully protected the liposomal cardiolipin from peroxidation. The duration of their action, however, varied; it increased with the presence of either methoxy groups of ubiquinol or additional reduced redox groups (in the cases of rhodamine and berberine derivates). The concentration of ubiquinol in the mitochondrial membrane substantially exceeds the concentrations of antioxidants we used and would seem to fully prevent peroxidation of membrane cardiolipin. In fact, this does not happen: cardiolipin in mitochondria is oxidized, and this process can be blocked by amphiphilic cationic antioxidants (Y. N. Antonenko et al. (2008) Biochemistry (Moscow), 73, 1273-1287). We suppose that a fraction of mitochondrial cardiolipin could not be protected by natural ubiquinol; in vivo, peroxidation most likely threatens those cardiolipin molecules that, being bound within complexes of membrane proteins, are inaccessible to the bulky hydrophobic ubiquinol molecules diffusing in the lipid bilayer of the inner mitochondrial membrane. The ability to protect these occluded cardiolipin molecules from peroxidation may explain the beneficial therapeutic action of cationic antioxidants, which accumulate electrophoretically within mitochondria under the action of membrane potential. PMID- 25519068 TI - Preventive and therapeutic effects of SkQ1-containing Visomitin eye drops against light-induced retinal degeneration. AB - The human retina is constantly affected by light of varying intensity, this being especially true for photoreceptor cells and retinal pigment epithelium. Traditionally, photoinduced damages of the retina are induced by visible light of high intensity in albino rats using the LIRD (light-induced retinal degeneration) model. This model allows study of pathological processes in the retina and the search for retinoprotectors preventing retinal photodamage. In addition, the etiology and mechanisms of retina damage in the LIRD model have much in common with the mechanisms of the development of age-related retinal disorders, in particular, with age-related macular degeneration (AMD). We have studied preventive and therapeutic effects of Visomitin eye drops (based on the mitochondria-targeted antioxidant SkQ1) on albino rat retinas damaged by bright light. In the first series of experiments, rats receiving Visomitin for two weeks prior to illumination demonstrated significantly less expressed atrophic and degenerative changes in the retina compared to animals receiving similar drops with no SkQ1. In the second series, the illuminated rats were treated for two weeks with Visomitin or similar drops without SkQ1. The damaged retinas of the experimental animals were repaired much more effectively than those of the control animals. Therefore, we conclude that Visomitin SkQ1-containing eye drops have pronounced preventive and therapeutic effects on the photodamaged retina and might be recommended as a photoprotector and a pharmaceutical preparation for the treatment of AMD in combination with conventional medicines. PMID- 25519069 TI - Mitochondria-targeted antioxidant SkQ1 accelerates maturation in Campbell dwarf hamsters (Phodopus campbelli). AB - We tested two hypotheses. 1) SkQ1 positively affects postnatal development of hamsters in litters born to parents receiving long-term SkQ1 treatment. 2) SkQ1 accelerates maturation of juvenile females receiving the antioxidant treatment from 10 days of age. Parental pairs were kept in an outdoor vivarium under conditions close to natural. At the age of 25 days, juvenile males in litters born to parents treated daily with SkQ1 (50 nmol/kg per os) had higher epididymis mass. Both the size of a litter and SkQ1 affected epididymis mass in young males. Both the litter size and SkQ1 affected uterus mass in 25-day-old females. Juvenile females who received SkQ1 treatment from 10 days of age demonstrated earlier opening of the vagina. This experiment was replicated with the same result. At the age of 2.5 months, virgin females treated with SkQ1 from the early age demonstrated higher ovary mass. PMID- 25519070 TI - Effects of mitochondria-targeted plastoquinone derivative antioxidant (SkQ1) on demography of free-breeding Campbell dwarf hamsters (Phodopus campbelli) kept in outdoor conditions. reproduction and lifespan: explanation in the framework of ultimate loads. AB - We studied demographic effects of the mitochondria-targeted antioxidant SkQ1 on free-breeding Campbell dwarf hamsters (Phodopus campbelli, Thomas, 1905, Rodentia, Cricetidae) in an outdoor vivarium with seasonally varying day length and temperatures. The animals were kept in pairs from their young age. We removed litters from parental cages at their age of 25 days. Experimental hamsters received daily 50 nmol/kg SkQ1 with water by oral dosing, whereas control animals received water. SkQ1 had no effect on the lifespan of either males or females in reproductive pairs. Mortality among females was higher than among males irrespective of SkQ1 treatment, this being related to higher costs of reproduction in females. However, SkQ1 accelerated breeding in pairs in the first half of the reproductive period of a year. Although there were no statistical differences in body mass of males and females between experimental and control animals during most of their life, SkQ1-receiving males had higher body mass at the end of their life. The opposite tendency was characteristic for old females. One-year-old males and females of the experimental and control groups showed no difference in intensity of immune response to sheep red blood cells. The dermal hypersensitivity response to phytohemagglutinin (test for T-cell immunity) was significantly higher in SkQ1-treated 1- and 1.5-year-old males. This was not true for females. There was a tendency toward increased density of the neutrophil population in blood in 1-year-old SkQ1-treated males. However, experimental males showed no difference from control males in the activity of the "peroxidase endogenous hydrogen peroxide system" of neutrophils. The background level of stress estimated by the concentration of cortisol in blood serum was significantly lower in the SkQ1-treated males during autumn adaptive adjustment of the organism. A similar trend was also observed during the January frosts, when the background level of stress was rather high. We observed no differences between cortisol concentration in experimental and control animals during the reproductive period in early spring and mid-summer. We tend to interpret the absence of geroprotective effect of SkQ1 on free-breeding dwarf hamsters by its ability to intensify breeding. We previously demonstrated the ability of SkQ1 to increase the lifespan of non-breeding females. PMID- 25519072 TI - Aging is a simple deprivation syndrome driven by a quasi-programmed preventable and reversible drift of control system set points due to inappropriate organism environment interaction. AB - There are two well-known but opposing concepts of the reason for aging. The first supposes that senescence is programmed similarly to the genetic program of development from a zygote up to a mature organism. Genetically determined senile wasting is thought to be associated with the necessity to renovate the population to ensure its adaptation and survival. According to the concept of the stochastic aging (due to accumulation of occasional error and damage), there is no built-in program of aging. There is only a program of development up to the state of maturity, and then the organism should be able to maintain itself limitlessly. However, although the efficiency of repair systems is assumed to be rather high, it is less than 100%. Just this has to result in aging because of accumulation of various errors. We have continued and developed another approach that considers both programmed and stochastic concepts to be incorrect. Aging is a simple deprivation syndrome driven by preventable and even reversible drifts of control systems set points because of an inappropriate "organism-environment" interaction. PMID- 25519071 TI - Therapeutic doses of SkQ1 do not induce cytochromes P450 in rat liver. AB - The effect of SkQ1 (a mitochondria-targeted antioxidant) on the level of cytochromes P450 in rat liver was studied. It was found that administration of therapeutic dose of SkQ1 with drinking water for 5 days (250 nmol/kg of body weight per day) did not alter the level of cytochromes P450. Under the same conditions, the standard dose of phenobarbital used for the induction of cytochromes P450 caused the 2.7-fold increase in the content of these cytochromes. We conclude that therapeutic doses of SkQ1 do not induce cytochromes P450 in rats. PMID- 25519073 TI - Effect of the mitochondria-targeted antioxidant SkQ1 on development of spontaneous tumors in BALB/c mice. AB - The mitochondria-targeted antioxidant SkQ1 (10-(6' plastoquinonyldecyl)triphenylphosphonium) is a new pharmaceutical substance with a wide spectrum of effects including increase in lifespan of laboratory animals (for example, of BALB/c mice males) and inhibition of development of some experimental tumors and also of tumor cell growth. In this work, the effects of SkQ1 on development of spontaneous tumors in female and male BALB/c mice housed in an SPF-class vivarium were studied. We found that the addition of SkQ1 to drinking water at the dose of 1 and 30 nmol/kg body weight per day throughout the lifespan modified the spectrum of spontaneous tumors in the female mice, decreasing the incidence of follicular lymphomas. SkQ1 at the dose of 1 nmol/kg per day also suppressed the dissemination of these neoplasms, but it did not significantly influence the overall incidence of benign and malignant tumors (including primary multiple tumors) or the lifespan of the tumor-bearing mice (both males and females). Hence, the previously described ability of SkQ1 to increase the lifespan of laboratory BALB/c mice is not related to its anticarcinogenic activity. PMID- 25519074 TI - The potential role of immunotherapy to treat colorectal cancer. AB - INTRODUCTION: Colorectal cancer (CRC) is the fourth most common cancer and the second leading cause of cancer-related death worldwide. Surgery, chemotherapy, radiation therapy and anti-angiogenic therapies form the backbone of treatment for CRC in various stages. Immunotherapy is frequently used either alone or in combination with chemotherapy for the treatment of various cancers such as melanoma, prostate cancer and renal cell cancer. Current CRC research is moving forward to discover ways to incorporate immunotherapies into the treatment of CRC. AREAS COVERED: The aim of this review is to summarize the potential role of immunotherapy in CRC. Herein, the authors provide a brief overview of immune modulatory cells, immune surveillance and escape in CRC. They also review vaccine trials in addition to cytokines and monoclonal antibodies. This coverage includes ongoing trials and checkpoint inhibitors such as cytotoxic T lymphocyte antigen 1, programmed cell death-1, and PDL1. EXPERT OPINION: Checkpoint inhibitors in combination with either chemotherapy or chemo-antiangiogenic-therapy may represent a future therapeutic approach for CRC incorporating immune system targeting. Given the success of immune-based therapy in other tumor types, the authors anticipate that a similar breakthrough in CRC will be forthcoming. PMID- 25519075 TI - Carbonyl trapping and antiglycative activities of olive oil mill wastewater. AB - The use of natural compounds as antiglycative agents to reduce the load of advanced glycation end products from diet is very promising. Olive mill wastewater is a by-product of the olive oil extraction processes with a high content of hydroxytyrosol, hydroxytyrosol derivatives and molecules containing o dihydroxyl functions such as verbascoside. Two powders were obtained after the ultrafiltration and nanofiltration of olive mill wastewater, and successive spray drying with maltodextrin and acacia fiber. The samples were characterized by phenolic composition and antioxidant capacity. Antiglycative capacity was evaluated by in vitro BSA-glucose and BSA-methylglyoxal assays, formation of Amadori products and direct trapping of reactive dicarbonyls (methylglyoxal and glyoxal). Both ultrafiltered and nanofiltered olive mill wastewater powders had an activity comparable to quercetin and hydroxytyrosol against the inhibition of protein glycation (IC50 = 0.3 mg mL(-1)). The antiglycative activity of the powder was further investigated after separation by reverse phase solid extraction. Fractions extracted with the methanol content higher than 40% and rich in hydroxytyrosol and verbascoside exerted the highest reactivity against dicarbonyls. Data confirmed that the direct trapping of dicarbonyl compounds is the main route explaining the antiglycative action rather than of the already known antioxidant capacity. Results support further investigations to evaluate the technological feasibility to use olive mill wastewater powders as antiglycative ingredients in foods or in pharmacological preparations in future. PMID- 25519076 TI - Antibiotic embedded absorbable prosthesis for prevention of surgical mesh infection: experimental study in rats. AB - INTRODUCTION: Ventral hernias are a common problem in a general surgery and hernioplasty is an integral part of a general surgeon's practice. The use of prosthetic material has drastically reduced the risk of recurrence, but has introduced additional potential complications such as surgical wound infections, adhesion formation, graft rejection, etc. The development of a wound infection in a hernia that is repaired with a prosthetic material is a grave complication, often requiring removal of the prosthesis. This experimental study examined efficacy of completely absorbable, hydrophilic, PGA-TMC (polyglycolic acid trimethylene carbonate) prosthesis impregnated with antibiotic for reduction of infectious complications. METHODS: Antibiotic-impregnated PGA-TMC prostheses were placed intraperitoneally in 90 Wistar white rats that were randomized and distributed into four groups. Group 0 (23 rats): there were placed PGA-TMC prosthesis without antibiotic impregnation (control group). Group 1 (25 rats): meshes were placed and infected later with 1 * 10(8) UFC of S. aureus/1 ml/2 cm(2) (Staphylococcus aureus ATCC 6538 American Type Culture Collection, Rockville, MD). Group 2 (21 rats): cefazolin-impregnated prostheses were placed (1 g * 100 ml, at the rate of 1 ml/cm(2) of prosthesis) and were subsequently infected with the same bacterial inoculate. Group 3 (21 rats): cefazolin impregnated prostheses with double quantity of cefazolin and infected. A week later these animals were killed and specimens were extracted for bacterial quantification and histological studies. RESULTS: Evident decrease of bacterial colonization was observed in series 2 and 3 [the ones impregnated with cefazolin, in comparison with the group 1 (infected without previous antibiotic impregnation)] with statistically significant results (p < 0.00). Results were really positive when the antibiotic solution had been applied to the mesh. There have been formed adherences to the prosthesis when placing it in contact with intraabdominal viscera. However, cefazolin impregnation of the mesh has reduced an adhesion formation, mostly when the infection reached a minimum, inhibiting the inflammatory answer to the infection in a prosthetic material. CONCLUSION: Impregnation of the absorbable hydrophilic prosthesis PGA-TMC with cefazolin prevents the infection of the prosthesis placed in infected localization. Therefore, we think this option should be considered as a new and useful alternative in case of contaminated and dirty surgical fields or when a replacement of the prosthesis is required. PMID- 25519077 TI - Reoperation for persistent pain after groin hernia surgery: a population-based study. AB - PURPOSE: The aim of the present study was to assess the outcome results after reoperation for persistent pain after hernia surgery in a population-based setting. METHODS: All patients who had undergone surgery for persistent pain after previous groin hernia surgery 1999-2006 were identified in the Swedish Hernia Register (n = 237). Data on the surgical technique used were abstracted from the medical records. The patients were asked to answer a set of questions including SF-36 to evaluate the prevalence of pain after reoperation. RESULTS: The study group consisted of 95 males and 16 females, mean age 53 years. In 27 % of cases an intervention aimed at suspected ilioinguinal neuralgia was performed. The mesh was removed completely in 28% and partially in 13%. A suture at the pubic tubercle was removed in 13% of cases. Decrease in pain after the most recent reoperation was reported by 69 patients (62%), no change in pain by 21 patients (19%) and increase in pain in 21 patients (19%). There was no significant difference in outcome between mesh removal, removal of sutures at the tubercle or interventions aimed at the ilioinguinal nerve. All subscales of SF-36 were significantly reduced when compared to the age- and gender-matched general population (p < 0.05). CONCLUSIONS: Patients reoperated for persistent pain after hernia surgery often report a reduction in pain, but the natural course of persistent pain, the relatively low response rate and selection of patients make it difficult to draw definite conclusions. PMID- 25519078 TI - Antihypertensive potential of the aqueous extract which combine leaf of Persea americana Mill. (Lauraceae), stems and leaf of Cymbopogon citratus (D.C) Stapf. (Poaceae), fruits of Citrus medical L. (Rutaceae) as well as honey in ethanol and sucrose experimental model. AB - BACKGROUND: The present study was designed to evaluate the effects of the aqueous extract obtained from the mixture of fresh leaf of Persea americana, stems and fresh leaf of Cymbopogon citratus, fruits of Citrus medica and honey on ethanol and sucrose induced hypertension in rats. METHODS: Rats were divided into eight groups of 6 rats each and daily treated for 5 weeks. The control group received distilled water (1 mL/kg) while rats of groups 2, 3 and 4 received ethanol 40 degrees (3 g/kg/day), 10% sucrose as drinking water and the two substances respectively. The remaining groups received in addition to sucrose and ethanol, the aqueous extract (50, 100 and 150 mg/kg) or nifedipine (10 mg/kg) respectively. Many parameters including hemodynamic, biochemical and histopathological were assessed at the end of the study. RESULTS: The concomitant consumption of ethanol and sucrose significantly (p < 0.001) increased the blood pressure and the heart rate compared to distilled water treated-rats. The levels of total cholesterol, LDL-cholesterol, triglycerides, atherogenic index, glucose, proteins, AST, ALT, creatinin, potassium, sodium and albumin increased while the HDL-cholesterol decreased under ethanol and sucrose feeding. Chronic ethanol and sucrose intake significantly decreased the activities of superoxide dismutase (SOD) and catalase (CAT) as well as the contents of reduced glutathione (GSH) and nitrites whereas elevated the malondialdehyde (MDA) levels. Histological analysis revealed among other vascular congestion, inflammation, tubular clarification and thickening of the vessel wall in rats treated with alcohol and sucrose. Administration of the aqueous extract or nifedipine prevented the hemodynamic, biochemical, oxidative and histological impairments induced chronic ethanol and sucrose consumption. CONCLUSION: Current results suggest that the aqueous extract used in this study possess antihypertensive activity against ethanol and sucrose induced hypertension in rats by the improvement of biochemical and oxidative status, and by protecting liver, kidney and vascular endothelium against damages induced by chronic consumption of ethanol and sucrose. PMID- 25519079 TI - Additional procedures performed during elective colon surgery and their adverse impact on postoperative outcomes. AB - BACKGROUND: The need for additional procedures during a segmental elective colectomy is considered to lead to increased postoperative morbidity, but there have been few data that have validated and quantified this risk. PURPOSE: We hypothesized that patients having additional procedures performed during a segmental colectomy have worse outcomes compared to patients undergoing a colectomy alone. PATIENTS AND METHODS: All patients in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database who underwent an elective open or laparoscopic segmental colectomy during 2005-2009 and met the inclusion criteria were analyzed. Using current procedural terminology (CPT) codes, patients were stratified into three groups. Group 1 only had CPT codes for a colectomy. Group 2 had additional CPT codes for procedures that were considered related to the colectomy, such as splenic flexure mobilization and endoscopy or a relatively minor procedure such as an appendectomy. Group 3 included patients that had additional procedures performed along with a segmental colectomy. Serious morbidity, overall morbidity, return to the operating room, and death were calculated and compared for each group. RESULTS: There were 25,996 patients in the open and 20,396 patients in the laparoscopic colectomy group. Thirty-six percent of patients in the open colectomy group vs. 18 % in the laparoscopic colectomy group had additional procedures performed. After adjustment for available differences in the groups, patients undergoing open and laparoscopic segmental colectomy along with an additional procedure had worse postoperative outcomes compared to patients undergoing a colectomy alone. LIMITATIONS: The study is limited by the possibility of coding errors in the ACS NSQIP database leading to a case ascertainment bias and a selection bias given the observational nature of the study. It also could not differentiate between additional procedures that were planned or incidental at the time of surgery. CONCLUSIONS: A proportion of patients undergoing elective open and laparoscopic segmental colon resections undergo additional procedures that adversely impact postoperative outcomes. This is mainly related to the type of additional procedures performed and therefore should be accounted for when counseling patients about the risks of surgery and in comparisons of outcomes. PMID- 25519080 TI - High-protein diet improves postoperative weight gain after massive small-bowel resection. AB - INTRODUCTION: Short bowel syndrome (SBS) is a morbid clinical condition that results from massive small-bowel resection (SBR). After SBR, there is a dramatic weight loss in the acute postoperative period. Our aim was to determine the impact of a high-protein diet (HPD) on weight gain and body composition in mice after SBR. METHODS: C57BL/6 mice underwent 50 % proximal SBR. Postoperatively, mice were randomly selected to receive standard rodent liquid diet (LD) (n = 6) or an isocaloric HPD (n = 9) for 28 days. Mice weights were recorded daily. Body composition analyses were obtained weekly. Student's t test was used for statistical comparisons with p < 0.05 considered significant. RESULTS: Mice that were fed HPD after SBR returned to baseline weight on average at postoperative day (POD) 8 versus mice that were fed LD that returned to baseline weight on average at POD 22. Total fat mass and lean mass were significantly greater by POD 14 within the HPD group. Both groups of mice demonstrated normal structural adaptation. CONCLUSION: HPD results in greater weight gain and improved body composition in mice after SBR. This finding may be clinically important for patients with SBS since improved weight gain may reduce the time needed for parenteral nutrition. PMID- 25519081 TI - Timing of discharge: a key to understanding the reason for readmission after colorectal surgery. AB - PURPOSE: There is a growing interest in surgery regarding the balance between appropriate hospital length of stay (LOS) and prevention of unnecessary readmissions. This study examines the relationship between postoperative LOS and unplanned readmission after colorectal resection, exploring whether patients discharged earlier have different readmission risk profiles. METHODS: Patients undergoing colorectal resection were selected by Common Procedural Terminology (CPT) code from the 2012 ACS National Surgical Quality Improvement Program (NSQIP) database. Patients were stratified by LOS quartile. Kaplan-Meier analysis was used to examine characteristics associated with 30-day unplanned readmission. Factors with a p < 0.1 were included in the Cox proportional hazards model. Subsequently, chi-square analysis compared LOS, patient, and perioperative factors with the primary reason for readmission. Factors with a p < 0.2 were included in a multivariable logistic regression for each readmission reason. RESULTS: For 33,033 patients undergoing colorectal resection, the overall 30-day unplanned readmission rate was 11 %. After adjusting for patient and perioperative factors, a postoperative LOS >=8 days was associated with a 55 % increase in the relative hazard of readmission. Patients with a <=3-day LOS were more likely to be readmitted with ileus/obstruction (odds ratio (OR): 1.8, p = 0.001) and pain (OR: 2.2, p = 0.007). LOS was not significantly associated with readmission for intraabdominal infection or medical complications. CONCLUSIONS: Patients with longer LOS and complicated hospital courses continue to be high risk post-discharge, while straightforward early discharges have a different readmission risk profile. More targeted readmission prevention strategies are critical to focusing resource utilization for colorectal surgery patients. PMID- 25519082 TI - How I do it: Martius flap for rectovaginal fistulas. AB - Rectovaginal fistulas present a difficult problem that is frustrating for patients and surgeons alike. Surgical options range from collagen plugs and endorectal advancement flaps to sphincter repairs or resection with coloanal reconstruction. For recurrent or complex rectovaginal fistulas, especially in the setting of prior radiation, Crohn's disease, or large wounds, bringing in healthy tissue into the space provides an excellent opportunity for improved results. The bulbocavernosus muscle and its surrounding vascularized tissue pedicle, first described by Martius in 1928, is an excellent option for fistula closure. Surgeons caring for these patients should be aware of this technique and have it as one method in their operative armamentarium when faced with these challenging cases. PMID- 25519083 TI - Feasibility and outcomes of early oral feeding after total gastrectomy for cancer. AB - BACKGROUND: Little data are available supporting the feasibility and safety of early oral feeding in patients after total gastrectomy. The aim of this study was to analyze the potential applicability of early provision of oral diet in these settings. METHODS: Medical records of 353 patients who underwent total gastrectomy for gastric cancer between 2006 and 2012 were retrospectively analyzed. Early oral feeding was defined as clear liquid diet on postoperative day (POD) 1 followed by gradual introduction of solid diet on POD 2 to 3. Late oral feeding was defined as initiation of liquid diet from POD 4 to 6 and gradually advancing to solid diets. RESULTS: Early oral feeding was implemented in 185 of 353 (52 %) patients. Prompt provision of food did not increase the risk of anastomotic failure (odds ratio 0.924, 95 % confidence interval 0.609-1.402, P = 0.709). The number of reoperations and in-hospital mortality rates was unaffected by the timing of nutritional intervention. Early feeding tended to be associated with fewer surgical (15 vs 24 %, P = 0.027) and general (8 vs 23 %, P < 0.001) complications. However, subsequent multivariate regression models failed to confirm significant correlations between timing of oral meals and postoperative morbidity. CONCLUSION: Our findings suggested that early oral feeding is feasible and safe after total gastrectomy for gastric cancer. However, benefits of such early nutritional interventions require further studies. PMID- 25519091 TI - Fundamental frequency from classical molecular dynamics. AB - We give a theoretical validation for calculating fundamental frequencies of a molecule from classical molecular dynamics (MD) when its anharmonicity is small enough to be treated by perturbation theory. We specifically give concrete answers to the following questions: (1) What is the appropriate initial condition of classical MD to calculate the fundamental frequency? (2) From that condition, how accurately can we extract fundamental frequencies of a molecule? (3) What is the benefit of using ab initio MD for frequency calculations? Our analytical approaches to those questions are classical and quantum normal form theories. As numerical examples we perform two types of MD to calculate fundamental frequencies of H2O with MP2/aug-cc-pVTZ: one is based on the quartic force field and the other one is direct ab initio MD, where the potential energies and the gradients are calculated on the fly. From those calculations, we show comparisons of the frequencies from MD with the post vibrational self-consistent field calculations, second- and fourth-order perturbation theories, and experiments. We also apply direct ab initio MD to frequency calculations of C-H vibrational modes of tetracene and naphthalene. We conclude that MD can give the same accuracy in fundamental frequency calculation as second-order perturbation theory but the computational cost is lower for large molecules. PMID- 25519085 TI - 2014 SSAT State-of-the-Art Conference: advances in diagnosis and management of gastroesophageal reflux disease. AB - Gastroesophageal reflux disease affects at least 10 % of people in Western societies and produces troublesome symptoms and impairs patients' quality of life. The effective management of GERD is imperative as the diagnosis places a significant cost burden on the United States healthcare system with annual direct cost estimates exceeding 9 billion dollars annually. While effective for many patients, 30-40 % of patients receiving medical therapy with proton pump inhibitors experience troublesome breakthrough symptoms, and recent evidence suggests that this therapy subjects patients to increased risk of complications. Given the high cost of PPI therapy, patients are showing a decrease in willingness to continue with a therapy that provides incomplete relief; however, due to inconsistent outcomes and concern for procedure-related side effects following surgery, only 1 % of the GERD population undergoes anti-reflux surgery annually. The discrepancy between the number of patients who experience suboptimal medical treatment and the number considered for anti-reflux surgery indicates a large therapeutic gap in the management of GERD. The objective of the SSAT State-of-the-Art Conference was to examine technologic advances in the diagnosis and treatment of GERD and to evaluate the ways in which we assess the outcomes of these therapies to provide optimal patient care. PMID- 25519084 TI - Minimally invasive resection of choledochal cyst: a feasible and safe surgical option. AB - BACKGROUND: The use of minimally invasive surgery (MIS) for choledochal cyst (CC) has not been well documented. We sought to define the overall utilization and outcomes associated with the use of the open versus MIS approach for CC. We examined the factors associated with receipt of MIS for CC, as well as characterized perioperative and long-term outcomes following open versus MIS for CC. METHODS: Between 1972 and 2014, a total of 368 patients who underwent resection for CC were identified from an international, multicenter database. A 2:1 propensity score matching was used to create comparable cohorts of patients to assess the effect of MIS on short-term outcomes. RESULTS: Three hundred thirty two patients had an open procedure, whereas 36 patients underwent an MIS approach. Children were more likely to be treated with a MIS approach (children, 24.0 % vs. adults, 2.1 %; P<0.001). Conversely, patients who had any medical comorbidity were less likely to undergo MIS surgery (open, 26.2 % vs. MIS, 2.8 %; P=0.002). In the propensity-matched cohort, MIS resection was associated with decreased length of stay (open, 7 days vs. MIS, 5 days), lower estimated blood loss (open, 50 mL vs. MIS, 17.5 mL), and longer operative time (open, 237 min vs. MIS, 301 min) compared with open surgery (all P<0.05). The overall and degree of complication did not differ between the open (grades I-II, n=13; grades III-IV, n=15) versus MIS (grades I-II, n=5; grades III-IV, n=5) cohorts (P=0.85). Five year overall survival was 98.6 % (open, 98.0 % vs. MIS, 100.0 %; P=0.45); no patient who underwent MIS developed a subsequent cholangiocarcinoma. CONCLUSIONS: MIS resection of CC was demonstrated to be a feasible and safe approach with acceptable short-term outcomes in the pediatric population. MIS for benign CC disease was associated with similar perioperative morbidity but a shorter length of stay and a lower blood loss when compared with open resection. PMID- 25519093 TI - Spin cycle. PMID- 25519094 TI - Keep asking the question. PMID- 25519095 TI - Honest brokers. PMID- 25519096 TI - Challenge the abuse of science in setting policy. PMID- 25519092 TI - Birt-Hogg-Dube syndrome. State-of-the-art review with emphasis on pulmonary involvement. AB - BACKGROUND: Birt-Hogg-Dube syndrome (BHDS) is a rare, inherited autosomal dominant disorder characterized by the development of cutaneous lesions, renal tumors, pulmonary cysts, and spontaneous pneumothorax. The gene responsible for BHDS is located on the short arm of chromosome 17 (17p11.2) and codes for the protein folliculin, which is believed to be an oncogene suppressor protein. METHODS: We reviewed currently published literature on the main characteristics of BHDS. RESULTS: Pulmonary cysts and spontaneous pneumothorax are often the presenting manifestations that lead to a final diagnosis in family members affected by the syndrome. CONCLUSIONS: Certain imaging characteristics of pulmonary cysts, including size and location, can suggest the diagnosis of BHDS based on chest computed tomography alone. The main concern in patients with BHDS is the increased risk of renal carcinoma. The aim of this review is to describe the main pathological, clinical, and imaging aspects of BHDS, ranging from its genetic basis to treatment, with emphasis on pulmonary involvement. PMID- 25519108 TI - Ebola threatens a way of life. PMID- 25519109 TI - Evolution: Bird family tree is in fine feather. PMID- 25519110 TI - Putin's Russia divides and enrages scientists. PMID- 25519112 TI - 365 days: 2014 in science. PMID- 25519114 TI - 365 days: Nature's 10. PMID- 25519115 TI - Scientific method: Defend the integrity of physics. PMID- 25519116 TI - Infectious disease: Mobilizing Ebola survivors to curb the epidemic. PMID- 25519118 TI - Environment: Flood resilience a must for delta cities. PMID- 25519119 TI - Astrobiology: Prescient words on comets and life. PMID- 25519120 TI - Hungary: Research agency will lose autonomy. PMID- 25519121 TI - Refereeing: What football can teach science. PMID- 25519122 TI - Conservation: Pool resources for protected areas. PMID- 25519123 TI - Martin L. Perl (1927-2014). PMID- 25519124 TI - Organic synthesis: Better chemistry through radicals. PMID- 25519125 TI - Synthetic biology: Toehold gene switches make big footprints. PMID- 25519127 TI - Conservation: Mind the gaps. PMID- 25519128 TI - Materials science: Two steps for a magnetoelectric switch. PMID- 25519129 TI - Influenza: An RNA-synthesizing machine. PMID- 25519130 TI - 2014 Editors' choice. PMID- 25519131 TI - Functionalized olefin cross-coupling to construct carbon-carbon bonds. AB - Carbon-carbon (C-C) bonds form the backbone of many important molecules, including polymers, dyes and pharmaceutical agents. The development of new methods to create these essential connections in a rapid and practical fashion has been the focus of numerous organic chemists. This endeavour relies heavily on the ability to form C-C bonds in the presence of sensitive functional groups and congested structural environments. Here we report a chemical transformation that allows the facile construction of highly substituted and uniquely functionalized C-C bonds. Using a simple iron catalyst, an inexpensive silane and a benign solvent under ambient atmosphere, heteroatom-substituted olefins are easily reacted with electron-deficient olefins to create molecular architectures that were previously difficult or impossible to access. More than 60 examples are presented with a wide array of substrates, demonstrating the chemoselectivity and mildness of this simple reaction. PMID- 25519133 TI - The exclusion of a significant range of ages in a massive star cluster. AB - Stars spend most of their lifetimes on the main sequence in the Hertzsprung Russell diagram. The extended main-sequence turn-off regions--containing stars leaving the main sequence after having spent all of the hydrogen in their cores- found in massive (more than a few tens of thousands of solar masses), intermediate-age (about one to three billion years old) star clusters are usually interpreted as evidence of internal age spreads of more than 300 million years, although young clusters are thought to quickly lose any remaining star-forming fuel following a period of rapid gas expulsion on timescales of order 10(7) years. Here we report, on the basis of a combination of high-resolution imaging observations and theoretical modelling, that the stars beyond the main sequence in the two-billion-year-old cluster NGC 1651, characterized by a mass of about 1.7 * 10(5) solar masses, can be explained only by a single-age stellar population, even though the cluster has a clearly extended main-sequence turn-off region. The most plausible explanation for the existence of such extended regions invokes a population of rapidly rotating stars, although the secondary effects of the prolonged stellar lifetimes associated with such a stellar population mixture are as yet poorly understood. From preliminary analysis of previously obtained data, we find that similar morphologies are apparent in the Hertzsprung-Russell diagrams of at least five additional intermediate-age star clusters, suggesting that an extended main-sequence turn-off region does not necessarily imply the presence of a significant internal age dispersion. PMID- 25519132 TI - An AUTS2-Polycomb complex activates gene expression in the CNS. AB - Naturally occurring variations of Polycomb repressive complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, autism susceptibility candidate 2 (AUTS2). Although AUTS2 is often disrupted in patients with neuronal disorders, the mechanism underlying the pathogenesis is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2 mediated recruitment of P300 leads to gene activation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases. PMID- 25519134 TI - Deterministic switching of ferromagnetism at room temperature using an electric field. AB - The technological appeal of multiferroics is the ability to control magnetism with electric field. For devices to be useful, such control must be achieved at room temperature. The only single-phase multiferroic material exhibiting unambiguous magnetoelectric coupling at room temperature is BiFeO3 (refs 4 and 5). Its weak ferromagnetism arises from the canting of the antiferromagnetically aligned spins by the Dzyaloshinskii-Moriya (DM) interaction. Prior theory considered the symmetry of the thermodynamic ground state and concluded that direct 180-degree switching of the DM vector by the ferroelectric polarization was forbidden. Instead, we examined the kinetics of the switching process, something not considered previously in theoretical work. Here we show a deterministic reversal of the DM vector and canted moment using an electric field at room temperature. First-principles calculations reveal that the switching kinetics favours a two-step switching process. In each step the DM vector and polarization are coupled and 180-degree deterministic switching of magnetization hence becomes possible, in agreement with experimental observation. We exploit this switching to demonstrate energy-efficient control of a spin-valve device at room temperature. The energy per unit area required is approximately an order of magnitude less than that needed for spin-transfer torque switching. Given that the DM interaction is fundamental to single-phase multiferroics and magnetoelectrics, our results suggest ways to engineer magnetoelectric switching and tailor technologically pertinent functionality for nanometre-scale, low energy-consumption, non-volatile magnetoelectronics. PMID- 25519135 TI - Reconstruction and control of a time-dependent two-electron wave packet. AB - The concerted motion of two or more bound electrons governs atomic and molecular non-equilibrium processes including chemical reactions, and hence there is much interest in developing a detailed understanding of such electron dynamics in the quantum regime. However, there is no exact solution for the quantum three-body problem, and as a result even the minimal system of two active electrons and a nucleus is analytically intractable. This makes experimental measurements of the dynamics of two bound and correlated electrons, as found in the helium atom, an attractive prospect. However, although the motion of single active electrons and holes has been observed with attosecond time resolution, comparable experiments on two-electron motion have so far remained out of reach. Here we show that a correlated two-electron wave packet can be reconstructed from a 1.2-femtosecond quantum beat among low-lying doubly excited states in helium. The beat appears in attosecond transient-absorption spectra measured with unprecedentedly high spectral resolution and in the presence of an intensity-tunable visible laser field. We tune the coupling between the two low-lying quantum states by adjusting the visible laser intensity, and use the Fano resonance as a phase-sensitive quantum interferometer to achieve coherent control of the two correlated electrons. Given the excellent agreement with large-scale quantum-mechanical calculations for the helium atom, we anticipate that multidimensional spectroscopy experiments of the type we report here will provide benchmark data for testing fundamental few-body quantum dynamics theory in more complex systems. They might also provide a route to the site-specific measurement and control of metastable electronic transition states that are at the heart of fundamental chemical reactions. PMID- 25519140 TI - A novel surgical method of managing a high output pharyngostome. AB - Pharyngocutaneous fistulas following large oncological surgical resection of the upper aerodigestive tract are common and typically heal over a number of weeks. A pharyngostome is a surgically created non-healing opening into the pharynx, which is far less common and often difficult to manage. PMID- 25519136 TI - The contribution of the Precambrian continental lithosphere to global H2 production. AB - Microbial ecosystems can be sustained by hydrogen gas (H2)-producing water-rock interactions in the Earth's subsurface and at deep ocean vents. Current estimates of global H2 production from the marine lithosphere by water-rock reactions (hydration) are in the range of 10(11) moles per year. Recent explorations of saline fracture waters in the Precambrian continental subsurface have identified environments as rich in H2 as hydrothermal vents and seafloor-spreading centres and have suggested a link between dissolved H2 and the radiolytic dissociation of water. However, extrapolation of a regional H2 flux based on the deep gold mines of the Witwatersrand basin in South Africa yields a contribution of the Precambrian lithosphere to global H2 production that was thought to be negligible (0.009 * 10(11) moles per year). Here we present a global compilation of published and new H2 concentration data obtained from Precambrian rocks and find that the H2 production potential of the Precambrian continental lithosphere has been underestimated. We suggest that this can be explained by a lack of consideration of additional H2-producing reactions, such as serpentinization, and the absence of appropriate scaling of H2 measurements from these environments to account for the fact that Precambrian crust represents over 70 per cent of global continental crust surface area. If H2 production via both radiolysis and hydration reactions is taken into account, our estimate of H2 production rates from the Precambrian continental lithosphere of 0.36-2.27 * 10(11) moles per year is comparable to estimates from marine systems. PMID- 25519137 TI - Protein quality control at the inner nuclear membrane. AB - The nuclear envelope is a double membrane that separates the nucleus from the cytoplasm. The inner nuclear membrane (INM) functions in essential nuclear processes including chromatin organization and regulation of gene expression. The outer nuclear membrane is continuous with the endoplasmic reticulum and is the site of membrane protein synthesis. Protein homeostasis in this compartment is ensured by endoplasmic-reticulum-associated protein degradation (ERAD) pathways that in yeast involve the integral membrane E3 ubiquitin ligases Hrd1 and Doa10 operating with the E2 ubiquitin-conjugating enzymes Ubc6 and Ubc7 (refs 2, 3). However, little is known about protein quality control at the INM. Here we describe a protein degradation pathway at the INM in yeast (Saccharomyces cerevisiae) mediated by the Asi complex consisting of the RING domain proteins Asi1 and Asi3 (ref. 4). We report that the Asi complex functions together with the ubiquitin-conjugating enzymes Ubc6 and Ubc7 to degrade soluble and integral membrane proteins. Genetic evidence suggests that the Asi ubiquitin ligase defines a pathway distinct from, but complementary to, ERAD. Using unbiased screening with a novel genome-wide yeast library based on a tandem fluorescent protein timer, we identify more than 50 substrates of the Asi, Hrd1 and Doa10 E3 ubiquitin ligases. We show that the Asi ubiquitin ligase is involved in degradation of mislocalized integral membrane proteins, thus acting to maintain and safeguard the identity of the INM. PMID- 25519144 TI - Drinking pattern is more strongly associated with under-reporting of alcohol consumption than socio-demographic factors: evidence from a mixed-methods study. AB - BACKGROUND: Under-reporting of alcohol consumption is widespread; surveys typically capture 40-60% of alcohol sales. However the population distribution of under-reporting is not well understood. METHODS: Mixed-methods study to identify factors associated with under-reporting, using the nationally-representative Health Survey for England (HSE) 2011 (overall response rate 66%). Comparison of retrospective computer-assisted personal interview and seven-day drinking diary (n = 3,774 adults 18+, 50% women, diary response rate 69%) to identify factors associated with diary responses exceeding those of the interview using multivariable linear regression for three outcomes: drinking days in the week recorded, volume consumed on heaviest drinking day in the week recorded, and weekly alcohol consumption. Qualitative semi-structured interviews (n = 10) explored reasons for under-reporting in further detail. RESULTS: Number of drinking days was slightly greater in the diary than the interview (P < 0.001). Reported consumption was higher in the diary than in the interview for heaviest drinking day in the week recorded (0.7 units greater among men, 1.2 units among women, P < 0.001), and weekly alcohol consumption in women only (1.1 units among women, P = 0.003). Participants who drank more frequently, more heavily, and had a more varied drinking pattern with respect to the types of drink consumed or choice of drinking venues had a larger difference between their diary week and their interview week.The qualitative interviews identified having a non-routine drinking pattern, self-perception as a non-frequent drinker, and usually tracking drinking using experiential approaches as linked to more drinking being reported in the diary than the retrospective interview. CONCLUSIONS: Heavy drinking and non-routine drinking patterns may be associated with greater under-reporting of alcohol consumption. Estimates of drinking above recommended levels are likely to be disproportionately under-estimated. PMID- 25519143 TI - The effect of cryopreservation on the genome of gametes and embryos: principles of cryobiology and critical appraisal of the evidence. AB - BACKGROUND: Cryopreservation has been extensively used in assisted reproductive technology, agriculture and conservation programmes for endangered species. The literature reports largely positive results regarding the survival of frozen thawed cells and clinical outcomes. Nonetheless, it is unclear whether or not cryopreservation of sperm, oocytes and embryos causes any disruption in their genetic integrity. Drawing on the available published evidence, this review paper describes in detail the physical and biochemical factors of cryopreservation that could potentially affect genomic integrity. METHODS: A critical review of the published literature using PubMed with particular emphasis on studies which include assessment of genetic stability after cryopreservation of oocyte, sperm and embryos. The search was performed in 2014 and covered the period from the beginning of electronic records until July 2014. No language restrictions were applied. RESULTS: Cryopreservation is associated with extensive damage to cell membranes, and results in alteration of the functional and metabolic status of the cells and mitochondria. Some evidence suggests an increase in DNA single strand breaks, and degree of DNA condensation or fragmentation in sperm after cryopreservation. The extent of these changes may vary between different individuals and different techniques. The addition of antioxidants to the cryopreservation media and the use of well-controlled cooling regimes could potentially improve such outcomes. Limited numbers of studies on oocytes provide controversial results regarding the effect on DNA fragmentation, sister chromatid exchange (SCE) and aneuploidy. The only study on human embryos suggested that vitrification affects DNA integrity to a much lesser extent than slow freezing. Animal studies show increases in mitochondrial DNA mutations in embryos after cryopreservation. The limited numbers of long-term follow-up studies in humans provide reassurance that derives mostly from retrospective studies with some methodological weaknesses. CONCLUSIONS: This review provides an overview of studies performed to date on the effect of cryopreservation on the oocyte, sperm and embryos. Controversy of the reported data has highlighted the gaps in our knowledge not only for clinical studies, but also for basic research in human embryos. New perspectives for future research are proposed. PMID- 25519145 TI - Electro-acoustic performance of the new bone vibrator Radioear B81: a comparison with the conventional Radioear B71. AB - OBJECTIVE: The objective is to evaluate the electro-acoustic performance of a new audiometric bone vibrator, the B81 from Radioear Corporation, USA. Comparison will be made with the widely used B71 which has well-known limitations at low frequencies. DESIGN: The B81 is based on the balanced electromagnetic separation transducer (BEST) principle where static forces are counterbalanced so that nonlinear distortion forces are reduced and maximum hearing levels can be increased. STUDY SAMPLE: Maximum hearing level, total harmonic distortion (THD), frequency response, and electrical impedance were measured for six devices of each bone vibrator type on an artificial mastoid. RESULTS: It was found that B81 reaches 10.7-22.0 dB higher maximum (@ THD = 6% or Vin = 6 VRMS) hearing levels than B71 for frequencies below 1500 Hz, and had significantly lower THD up to 1000 Hz. There was no statistically significant difference between their frequency response, except a deviation at the mid frequencies (alpha = 0.01) where B81 was more efficient and the electrical impedances were practically the same. CONCLUSIONS: In general, B81 had an improved electro-acoustic performance compared to B71 and is compatible with same audiometers. In particular, B81 allows for sensorineural hearing loss to be measured at considerably higher hearing levels than with B71 below 1500 Hz. PMID- 25519146 TI - Inviting parents to take part in paediatric palliative care research: a mixed methods examination of selection bias. AB - BACKGROUND: Recruitment to paediatric palliative care research is challenging, with high rates of non-invitation of eligible families by clinicians. The impact on sample characteristics is unknown. AIM: To investigate, using mixed methods, non-invitation of eligible families and ensuing selection bias in an interview study about parents' experiences of advance care planning (ACP). DESIGN: We examined differences between eligible families invited and not invited to participate by clinicians using (1) field notes of discussions with clinicians during the invitation phase and (2) anonymised information from the service's clinical database. SETTING: Families were eligible for the ACP study if their child was receiving care from a UK-based tertiary palliative care service (Group A; N = 519) or had died 6-10 months previously having received care from the service (Group B; N = 73). RESULTS: Rates of non-invitation to the ACP study were high. A total of 28 (5.4%) Group A families and 21 (28.8%) Group B families (p < 0.0005) were invited. Family-clinician relationship appeared to be a key factor associated qualitatively with invitation in both groups. In Group A, out-of-hours contact with family was statistically associated with invitation (adjusted odds ratio 5.46 (95% confidence interval 2.13-14.00); p < 0.0005). Qualitative findings also indicated that clinicians' perceptions of families' wellbeing, circumstances, characteristics, engagement with clinicians and anticipated reaction to invitation influenced invitation. CONCLUSION: We found evidence of selective invitation practices that could bias research findings. Non-invitation and selection bias should be considered, assessed and reported in palliative care studies. PMID- 25519147 TI - Doctors' and nurses' views and experience of transferring patients from critical care home to die: a qualitative exploratory study. AB - BACKGROUND: Dying patients would prefer to die at home, and therefore a goal of end-of-life care is to offer choice regarding where patients die. However, whether it is feasible to offer this option to patients within critical care units and whether teams are willing to consider this option has gained limited exploration internationally. AIM: To examine current experiences of, practices in and views towards transferring patients in critical care settings home to die. DESIGN: Exploratory two-stage qualitative study SETTING/PARTICIPANTS: Six focus groups were held with doctors and nurses from four intensive care units across two large hospital sites in England, general practitioners and community nurses from one community service in the south of England and members of a Patient and Public Forum. A further 15 nurses and 6 consultants from critical care units across the United Kingdom participated in follow-on telephone interviews. FINDINGS: The practice of transferring critically ill patients home to die is a rare event in the United Kingdom, despite the positive view of health care professionals. Challenges to service provision include patient care needs, uncertain time to death and the view that transfer to community services is a complex, highly time-dependent undertaking. CONCLUSION: There are evidenced individual and policy drivers promoting high-quality care for all adults approaching the end of life encompassing preferred place of death. While there is evidence of this choice being honoured and delivered for some of the critical care population, it remains debatable whether this will become a conventional practice in end of life in this setting. PMID- 25519148 TI - Preclinical Efficacy for AKT Targeting in Clear Cell Carcinoma of the Ovary. AB - The aim of this study was to determine the role of AKT as a therapeutic target in ovarian clear cell carcinoma (CCC), an aggressive, chemoresistant histologic subtype of ovarian cancer. AKT activation was assessed by immunohistochemistry (IHC) using human tissue microarrays of primary ovarian cancers, composed of both CCC and serous adenocarcinoma (SAC). The growth-inhibitory effect of AKT-specific targeting by the small-molecule inhibitor, perifosine, was examined using ovarian CCC cell lines in vitro and in vivo. Finally, the activity of perifosine was examined using in CCC-derived tumors that had acquired resistance to anti-VEGF or chemotherapeutics such as bevacizumab or cisplatin, respectively. Interestingly, AKT was frequently activated both in early-stage and advanced-stage CCCs. Treatment of CCC cells with perifosine attenuated the activity of AKT-mTORC1 signaling, inhibited proliferation, and induced apoptosis. The effect of perifosine was more profound under conditions of high AKT activity compared with low AKT activity. Increased AKT activation and enhanced sensitivity to perifosine were observed in the context of cisplatin-resistant CCC. Treatment with perifosine concurrently with cisplatin significantly enhanced the antitumor effect of cisplatin. Moreover, perifosine showed significant antitumor activity in CCC-derived tumors that had acquired resistance to bevacizumab or cisplatin. Collectively, these data reveal that AKT is frequently activated in ovarian CCCs and is a promising therapeutic target in aggressive forms of ovarian cancer. IMPLICATIONS: AKT-targeted therapy has value in a first-line setting as well as a second-line treatment for recurrent disease developing after platinum-based chemotherapy or bevacizumab treatment. PMID- 25519149 TI - DNA-Directed Polymerase Subunits Play a Vital Role in Human Telomeric Overhang Processing. AB - Telomeres consist of TTAGGG repeats bound by the shelterin complex and end with a 3' overhang. In humans, telomeres shorten at each cell division, unless telomerase (TERT) is expressed and able to add telomeric repeats. For effective telomere maintenance, the DNA strand complementary to that made by telomerase must be synthesized. Recent studies have discovered a link between different activities necessary to process telomeres in the S phase of the cell cycle to reform a proper overhang. Notably, the human CST complex (CTC1/STN1/TEN1), known to interact functionally with the polymerase complex (POLA/primase), was shown to be important for telomere processing. Here, focus was paid to the catalytic (POLA1/p180) and accessory (POLA2/p68) subunits of the polymerase, and their mechanistic roles at telomeres. We were able to detect p68 and p180 at telomeres in S-phase using chromatin immunoprecipitation. We could also show that the CST, shelterin, and polymerase complexes interact, revealing contacts occurring at telomeres. We found that the polymerase complex could associate with telomerase activity. Finally, depletion of p180 by siRNA led to increased overhang amounts at telomeres. These data support a model in which the polymerase complex is important for proper telomeric overhang processing through fill-in synthesis, during S phase. These results shed light on important events necessary for efficient telomere maintenance and protection. IMPLICATIONS: This study describes the interplay between DNA replication components with proteins that associate with chromosome ends, and telomerase. These interactions are proposed to be important for the processing and protection of chromosome ends. PMID- 25519150 TI - Virtual screening of potential inhibitor against FtsZ protein from Staphylococcus aureus. AB - The gram-positive bacterium Staphylococcus aureus, responsible for a wide variety of diseases in human involve all organ systems ranging from localized skin infections to life-threatening systemic infections. FtsZ, the key protein of bacterial cell division was selected as a potent anti bacterial target. In order to identify the new compounds structure based screening process was carried out. An enrichment study was performed to select a suitable scoring function and to retrieve potential candidates against FtsZ from a large chemical database. The docking score and docking energy values were compared and their atomic interaction was also evaluated. Furthermore molecular dynamics simulation were also been performed to check the stability and the amino acids interacted towards the FtsZ. Finally we selected C ID 16284, 25916, 15894, 13403 as better lead compounds. From these results, we conclude that our insilico results will provide a framework for the detailed in vitro and in vivo studies about the FtsZ protein activity in drug development process. PMID- 25519151 TI - An agent-based model approach to multi-phase life-cycle for contact inhibited, anchorage dependent cells. AB - Cellular agent-based models are a technique that can be easily adapted to describe nuances of a particular cell type. Within we have concentrated on the cellular particularities of the human Endothelial Cell, explicitly the effects both of anchorage dependency and of heightened scaffold binding on the total confluence time of a system. By expansion of a discrete, homogeneous, asynchronous cellular model to account for several states per cell (phases within a cell's life); we accommodate and track dependencies of confluence time and population dynamics on these factors. Increasing the total motility time, analogous to weakening the binding between lattice and cell, affects the system in unique ways from increasing the average cellular velocity; each degree of freedom allows for control over the time length the system achieves logistic growth and confluence. These additional factors may allow for greater control over behaviors of the system. Examinations of system's dependence on both seed state velocity and binding are also enclosed. PMID- 25519152 TI - In-silico structural, virtual screening and docking studies of Human Cytochrome P450 2A7 protein. AB - Among CYPs, CYP2A sub-family is well known for its function to metabolize xenobiotics. CYP2A includes three members: CYP2A6, CYP2A7 and CYP2A13. Of these three proteins, structure and function of CYP2A6 and CYP2A13 are widely studied whereas very little study has been carried out on CYP2A7. In the initial in vitro studies on CYP2A7, full protein in its active form could not be expressed. The exact structure and function of CYP2A7 is still not revealed. However, up regulation of CYP2A7 has been reported in malignant oesophageal cells and colon cancer cells. In the present study, we generated the structure of CYP2A7 protein. The modelled proteins were validated and subjected to molecular docking analyses. The energy and RMSD calculations demonstrated that the protein is highly conserved in nature i.e. the protein is not much flexible. Here the ligand molecules of NCI Diversity Set II from the ZINC database against the active site of the CYP2A7 protein were screened. Five compounds that possess good inhibitory activity against CYP2A7 active site were identified. The top ranking molecule (ZINC01572309) has a minimum energy score of -12.0 Kcal/Mol. This compound is thus a good starting point for further development of strong inhibitors. Our in silico approach could help in better structural and functional analysis of CYP2A7. Apart from structural description of CYP2A7, elaboration of binding sites for inhibitors provides us with an opportunity to utilize binding pockets in targeted inactivation of this protein for further research. PMID- 25519153 TI - Ecogenomics of Geminivirus from India and neighbor countries: An in silico analysis of recombination phenomenon. AB - Recombination is one of the keys factor in evolutionary processes, involved in shaping the architecture of genomes and consequent phenotype. Understanding the recombination phenomenon especially among viruses will help in disease management. The present study aimed for in-silico analysis of recombination phenomenon among Begomoviruses. Particularly emphasizing on viruses strains reported from India and neighboring countries. A total of 956 virus sequences have been used in this study. The Tomato yellow leaf curl China viruses, namely gi|29825986|; gi|283468151|; gi|190559151| and gi|61652782| were identified with the highest number of recombination event (1273). However, the Mung bean yellow mosaic India virus (gi|66351988|) was found to have 1170 recombination event. The phylogenic analysis among the highly recombinant sequences was carried to get an insight of the evolution among viral sequences in this class of plant viruses. The phylogenetic analysis revealed a pattern in diversity among these virus strains and a split tree analysis showed diversity in the range of 0.049128335 to 10.269852. This in silico analysis may pave way for a greater understanding of recombination phenomenon in Ggeminiviruses and it might be helpful for strategic plant viral disease management. PMID- 25519154 TI - Magnetic nanoparticles-loaded Physarum polycephalum: Directed growth and particles distribution. AB - Slime mold Physarum polycephalum is a single cell visible by an unaided eye. The slime mold optimizes its network of protoplasmic tubes to minimize expose to repellents and maximize expose to attractants and to make efficient transportation of nutrients. These properties of P. polycephalum, together with simplicity of its handling and culturing, make it a priceless substrate for designing novel sensing, computing and actuating architectures in living amorphous biological substrate. We demonstrate that, by loading Physarum with magnetic particles and positioning it in a magnetic field, we can, in principle, impose analog control procedures to precisely route active growing zones of slime mold and shape topology of its protoplasmic networks. PMID- 25519155 TI - Design of potential RNAi (miRNA and siRNA) molecules for Middle East respiratory syndrome coronavirus (MERS-CoV) gene silencing by computational method. AB - The Middle East respiratory syndrome coronavirus (MERS-CoV) is a virus that manifests itself in viral infection with fever, cough, shortness of breath, renal failure and severe acute pneumonia, which often result in a fatal outcome. MERS CoV has been shown to spread between people who are in close contact. Transmission from infected patients to healthcare personnel has also been observed and is irredeemable with present technology. Genetic studies on MERS-CoV have shown that ORF 1ab encodes replicase polyproteins and play a foremost role in viral infection. Therefore, ORF 1ab replicase polyprotein may be used as suitable target for disease control. Viral activity can be controlled by RNA interference (RNAi) technology, a leading method for post transcriptional gene silencing in a sequence specific manner. However, there is a genetic inconsistency in different viral isolates; it is a great challenge to design potential RNAi (miRNA and siRNA) molecules which can silence the respective target genes rather than any other viral gene simultaneously. In current study four effective miRNA and five siRNA molecules for silencing of nine different strains of MERS-CoV were rationally designed and corroborated using computational methods, which might lead to knockdown the activity of virus. siRNA and miRNA molecules were predicted against ORF1ab gene of different strains of MERS-CoV as effective candidate using computational methods. Thus, this method may provide an insight for the chemical synthesis of antiviral RNA molecule for the treatment of MERS-CoV, at genomic level. PMID- 25519156 TI - In silico elucidation and inhibition studies of selected phytoligands against Mitogen activated protein kinases of protozoan parasites. AB - Parasitic MAPKs exhibiting significant divergence with humans and playing an imperative role in parasitic metabolic activities have been exploited from several years as important targets for development of novel therapeutics. In addition, the emergence of the drug resistant variants of parasitic diseases in the recent years has aroused a great need for the development of potent inhibitors against them. In the present study we selected the metabolically active MAPKs LmxMPK4, PfMAP2 and TbMAPK5 of the three parasitic protozoans Leishmania mexicana, Plasmodium falciparum and Trypanosoma brucei respectively. The homology modeling technique was used to develop the 3D structures of these proteins and the same was validated by PROCHECK, ERRAT, ProQ and ProSA web servers to check the reliability. Ten phytoligands were employed for molecular docking studies with these proteins to search for potent phytoligand as a broad spectrum inhibitor. In this regard two phytoligands (Aspidocarpine for LmxMPK4 & TbMAPK5 and Cubebin for PfMAP2) were found to be more effective inhibitors, in term of robust binding energy, strong inhibition constant and better interactions between protein-ligand complexes. Furthermore predicted ADME & Toxicity properties suggested that these identified phytoligands exhibited comparable results to control drugs potentiating them as persuasive therapeutic agents for Leishmania, Trypanosoma and Plasmodium sp. PMID- 25519157 TI - Molecular dynamics simulation studies of the wild type and E92Q/N155H mutant of Elvitegravir-resistance HIV-1 integrase. AB - Although Elvitegravir (EVG) is a newly developed antiretrovirals drug to treat the acquired immunodeficiency syndrome (AIDS), drug resistance has already been found in clinic, such as E92Q/N155H and Q148H/G140S. Several structural investigations have already been reported to reveal the molecular mechanism of the drug resistance. As full length crystal structure for HIV-1 integrase is still unsolved, we herein use the crystal structure of the full length prototype foamy virus (PFV) in complex with virus DNA and inhibitor Elvitegravir as a template to construct the wild type and E92Q/N155H mutant system of HIV-1 integrase. Molecular dynamic simulations was used to revel the binding mode and the drug resistance of the EVG ligand in E92Q/N155H. Several important interactions were discovered between the mutated residues and the residues in the active site of the E92Q/N155H double mutant pattern, and cross correlation and clustering methods were used for detailed analysis. The results from the MD simulation studies will be used to guide the experimental efforts of developing novel inhibitors against drug-resistant HIV integrase mutants. PMID- 25519158 TI - Prosaposin: a protein with differential sorting and multiple functions. AB - In eukaryotes the delivery of newly synthesized proteins to their final destination is dependent on a series of functionally distinct compartments, including the endoplasmic reticulum and the Golgi apparatus, which plays a role in post-translational modification, sorting and distribution of proteins. Most cargo is sorted within, and exits from, the trans-Golgi network (TGN). Proteins delivered to lysosomes include hydrolytic enzymes and nonenzymic activator proteins. They are directed away from the cell surface by their binding to mannose-6-phosphate receptors (MPR). However, in I-cell disease, in which the MPR pathway is disrupted, the nonenzymic sphingolipid activator protein, prosaposin, continue to traffic to lysosomes. This observation led to discovery of a new lysosomal sorting receptor, sortilin. The targeting prosaposin to the lysosomes results from the interaction of its C-terminus with sortilin. Deletion of the C terminus did not interfere with its secretion, but abolished its transport to the lysosomes. Mutational analysis revealed that the first half of the prosaposin C terminus contains a motif required for its binding to sortilin and its transport to the lysosomes. Prosaposin can be also secreted to the extracellular space as oligomers. Extracellular prosaposin showed to exert a variety of responses in nervous tissues including the activation of G protein-coupled receptors and ERK phosphorylation. Lastly, prosaposin has been found to be expressed in other fluids of the body such as pancreatic juice, bile, cerebrospinal fluid, milk and seminal fluid, indicating that prosaposin is not only a house keeping lysosomal protein but an essential factor in the development and maintenance of the nervous systems and other systems of the body. PMID- 25519159 TI - Bivalirudin for acute coronary syndromes: premises, promises and doubts. AB - Bivalirudin is a valuable anticoagulant option in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention. Advantages over heparin as a parenteral anticoagulant include more predictable pharmacokinetics and pharmacodynamics, shorter half-life, no need for cofactors, some degree of antiplatelet effect, and the ability to inhibit clot-bound thrombin. Clinical evidence supporting the use of bivalirudin over heparin in current ACS guidelines, however, derives mostly from early randomised trials that may no longer reflect current management patterns, now including the use of oral antiplatelet agents more potent than clopidogrel (i.e. prasugrel or ticagrelor) and a broader implementation of strategies to reduce bleeding (i.e. radial access for percutaneous coronary intervention, and use of glycoprotein IIb/IIIa inhibitors only in bailout situations). Defining the fine balance between bivalirudin efficacy and safety over heparins in the context of other antithrombotic treatments remains a challenge in clinical practice, particularly in a fast-evolving scenario, such as ACS, where numerous new trials have been presented in very recent times. Here we provide an up-to-date overview of the evidence on the use of bivalirudin in ACS, with focus on new data, open issues, and future directions. PMID- 25519160 TI - Plasma microRNA-100 is associated with coronary plaque vulnerability. AB - BACKGROUND: Although numerous studies have reported altered plasma levels of various microRNAs (miRNAs) in patients with cardiovascular disease, there are no data on the relationship between plasma miRNAs and vulnerable coronary plaque. In this study, we investigated whether plasma miRNAs might be a sensitive marker of coronary plaque vulnerability. METHODS AND RESULTS: Integrated backscatter intravascular ultrasound (IB-IVUS) was performed in 32 consecutive patients with angina pectoris who underwent percutaneous coronary intervention. Three dimensional analysis of IB-IVUS was performed to determine the percentage of lipid volume (%LV) and fibrous volume (%FV). Circulating miRNAs were measured in EDTA-plasma simultaneously obtained from the aorta and the coronary sinus (CS). Muscle-enriched (miR-133a, miR-208a, miR-499), vascular-enriched (miR-92a, miR 100, miR-126, miR-127, miR-145), and myeloid cell-enriched miRNAs (miR-155, miR 223) were measured. Plasma miR-100 was higher in the CS than in the aorta, but there were no significant differences in the levels of other miRNAs between the aorta and CS. Plasma miR-100 in the aorta was positively correlated with %LV (r=0.48, P<0.01) and negatively correlated with %FV (r=-0.41, P<0.05). Importantly, transcoronary concentration gradient of circulating miR-100 was more strongly correlated with %LV (r=0.53, P<0.01) and %FV (r=-0.56, P<0.01). CONCLUSIONS: miR-100 might be released into the coronary circulation from vulnerable coronary plaques. This study provides insights into the role of miRNAs in coronary atherosclerotic disease. PMID- 25519161 TI - Recurrent Lower Urinary Tract Infections Have a Detrimental Effect on Patient Quality of Life: a Prospective, Observational Study. AB - INTRODUCTION: This study investigated the effects of recurrent urinary tract infections (rUTI) and the impact of prophylaxis on rUTI and patients' quality of life (QoL). METHODS: Altogether, 575 patients affected by rUTI were included in a 6-month observational study. QoL was assessed using the Hospital Anxiety and Depression (HAD) and the Leicester scales. Statistical analyses were performed using SAS(r) Version 8.2 software (SAS Institute Inc., Cary, NC, USA). The significance level was set at 5%. Spearman correlation was used to assess the degree of correlation between infectious episodes and HAD and Leicester scores. For each parameter, the comparison between Day 0 and Day 180 was performed using Wilcoxon signed-rank test for quantitative data. RESULTS: In total, 61.9% of patients suffering from rUTI exhibited some degree of depression at baseline (Day 0). Alternative oral non-antimicrobial prophylactic treatment for rUTI [Escherichia coli lyophilized bacterial lysate (OM-89)] was administered to 94.4% of patients (1 capsule a day for 90 days), followed by a 3-month treatment-free period. At the end of the study (Day 180), the mean number of UTI decreased by 59.3% (P <= 0.0001), the total HAD score decreased by 32.1% (P <= 0.0001), and the mean Leicester score decreased by 44.0% (P <= 0.0001) from baseline. There was a correlation trend between the reduction in the numbers of UTI at the end of the study compared to the 6 months prior to study entry and the reduction in the anxiety, depression, total HAD scores, activity, feeling, and total Leicester scores registered from Day 0 to Day 180, suggesting a lessening of emotional problems, and social and functional handicaps with decreasing UTI incidence. CONCLUSIONS: This study showed that rUTI had a negative impact on patients' QoL and that effective alternative prophylaxis significantly improved their QoL. PMID- 25519162 TI - Evaluation of High-Dose Daptomycin Versus Vancomycin Alone or Combined with Clarithromycin or Rifampin Against Staphylococcus aureus and S. epidermidis in a Novel In Vitro PK/PD Model of Bacterial Biofilm. AB - INTRODUCTION: Medical device infections are associated with significant morbidity and mortality. These difficult-to-treat infections often result in antibiotic failure and resistance. Combination therapy is often required, however, the most optimal combination is unknown. We evaluated the in vitro activity of daptomycin (DAP) or vancomycin (VAN) alone and in combination with rifampin (RIF) or clarithromycin (CLA) against strains of Staphylococcus aureus and S. epidermidis grown in biofilm on 3 prosthetic device materials. METHODS: One methicillin resistant S. aureus (MRSA R5266), one heteroresistant vancomycin-intermediate S. aureus (hVISA R3640), and one methicillin-resistant S. epidermidis (MRSE R461) strain was evaluated in a CDC biofilm reactor with titanium, Teflon(r), and steel coupons. Regimens simulated included DAP 10 mg/kg/day, and VAN 1 g q12h alone or in combination with RIF 600 mg q24h or CLA 250 mg q12h. Additional regimens including DAP 12 mg/kg/day or VAN +/- RIF 450 mg q12h were evaluated against the hVISA strain. RESULTS: DAP + RIF or VAN + RIF demonstrated enhanced activity against R3640 in embedded biofilm (EB) cells in all materials versus DAP or VAN alone (P <= 0.040). Only DAP + RIF demonstrated sustained bactericidal activity (>=3.80 log10 CFU/cm2 reduction from baseline) against EB and planktonic cells of R5266 and EB cells of R461 in all 3 materials. Of interest, CLA did not appear to enhance DAP or VAN killing activities, and the addition of RIF prevented the emergence of resistance to DAP or VAN in all organisms. CONCLUSION: Using an in vitro bacterial biofilm model containing three common prosthetic device materials, DAP + RIF and VAN + RIF were the most effective regimens. DAP + RIF displayed the greatest activity and represents a promising combination to evaluate for treatment of biofilm-associated staphylococcal infections. PMID- 25519164 TI - Embracing a broad spirituality in end of life discussions and advance care planning. AB - Advance care planning for end of life typically focuses on the mechanics of completing living wills and durable power of attorney documents. Even when spiritual aspects of end of life care are discussed, the dominant assumptions are those of traditional religious systems. A broad view of spirituality is needed, one that may involve traditional religious beliefs but also includes personal understandings of what is holy or sacred. Embracing this broad practice of spirituality will help both familial and professional caregivers honor an essential aspect of end of life discussions and promote greater discernment of the deep meaning in advance care documents. PMID- 25519163 TI - Tandem mass spectrometry and ion mobility mass spectrometry for the analysis of molecular sequence and architecture of hyperbranched glycopolymers. AB - Multidimensional mass spectrometry techniques, combining matrix-assisted laser desorption/ionization (MALDI) or electrospray ionization (ESI) with tandem mass spectrometry (MS(2)), multistage mass spectrometry (MS(n)) or ion mobility mass spectrometry (IM-MS), have been employed to gain precise structural insight on the compositions, sequences and architectures of small oligomers of a hyperbranched glycopolymer, prepared by atom transfer radical copolymerization of an acrylate monomer (A) and an acrylate inimer (B), both carrying mannose ester pendants. The MS data confirmed the incorporation of multiple inimer repeat units, which ultimately lead to the hyperbranched material. The various possible structures of n-mers with the same composition were subsequently elucidated based on MS(2) and MS(n) studies. The characteristic elimination of bromomethane molecule provided definitive information about the comonomer connectivity in the copolymeric AB2 trimer and A2B2 tetramer, identifying as present only one of the three possible trimeric isomers (viz. sequence BBA) and only two of the six possible tetrameric isomers (viz. sequences BBA2 and BABA). Complementary IM-MS studies confirmed that only one of the tetrameric structures is formed. Comparison of the experimentally determined collision cross-section of the detected isomer with those predicted by molecular simulations for the two possible sequences ascertained BBA2 as the predominant tetrameric architecture. The multidimensional MS approaches presented provide connectivity information at the atomic level without requiring high product purity (due to the dispersive nature of MS) and, hence, should be particularly useful for the microstructure characterization of novel glycopolymers and other types of complex copolymers. PMID- 25519165 TI - Prognostic value of the dynamics of M-type phospholipase A2 receptor antibody titers in patients with idiopathic membranous nephropathy treated with two different immunosuppression regimens. AB - CONTEXT: The dynamics of anti-phospholipase A2 antibody titers during treatment could predict clinical responses in patients with membranous nephropathy. OBJECTIVES: We analyzed the predictive value of the dynamics of these antibodies on clinical responses. MATERIALS AND METHODS: The serum antibody levels were measured before and during treatment in 79 patients with anti-phospholipase A2 receptor antibody membranous nephropathy treated with two different immunosuppression regimens RESULTS: In both groups of patients, the relative reduction in antibody titers at 3 and 6 months preceded and predicted the clinical responses. CONCLUSIONS: Antibody titer dynamics was useful for predicting clinical responses. PMID- 25519166 TI - Recurrent posterior circulation infarction caused by anomalous occipital bony process in a young patient. AB - BACKGROUND: Structural anomaly of the cervical spine or craniocervical junction has been reported as one of the rare causes of ischemic stroke. We report a case of a young patient with recurrent posterior circulation infarction that may have been associated with an anomalous occipital bony process compressing the vertebral artery. CASE PRESENTATION: A 23-year-old man experienced recurrent posterior circulation infarction 5 times over a period of 5 years. He had no conventional vascular risk factors. Young age stroke work-up including thorough cardiac, intra- and extracranial vascular evaluation and laboratory tests for the hypercoagulable state or connective tissue disease yielded unremarkable results. An anomalous bony process from the occipital base compressing the left vertebral artery was observed on brain CT. All the recurrent strokes were explainable by the arterial thromboembolism originating from the compressed left vertebral artery. Therefore, the left vertebral artery compressed by the anomalous occipital bony process may have been the culprit behind the recurrent thromboembolic strokes in our patient. Intractable recurrent strokes even under optimal medical treatment led us to make a decision for the intervention. Instead of surgical removal of the anomalous occipital bony process, the left vertebral artery was occluded permanently by endovascular coiling after confirming that this would cause no neurological deficits or flow disturbance in the posterior circulation. There was no recurrence of stroke for 2 years after permanent occlusion of the left vertebral artery. CONCLUSION: Arterial thromboembolism originating from the left vertebral artery compressed by the anomalous occipital bony process is a rare but not to be overlooked cause of posterior circulation infarction. When intractable to medical treatment, endovascular occlusion of the vertebral artery without flow disturbance to the posterior circulation may be a useful treatment option when surgical removal is not feasible. PMID- 25519167 TI - Pregnancy after kidney and liver transplantation: its outcome and effect on the graft, mother, and neonate. AB - BACKGROUND: The influence of pregnancy on graft function in patients after solid organ transplantation is still uncertain. MATERIAL AND METHODS: Our study is based on a group of 78 cases after liver (LTR) and/or renal transplantation (RTR) with 91 deliveries in the past 12 years in the 1st Department of Obstetrics and Gynecology, Warsaw Medical University. We compared duration of pregnancy, mode of delivery, weight of neonates, and graft function. RESULTS: Rate of preterm delivery was very high (74% RTR and 43% LTR). The average duration of pregnancy was shorter in the RTR than in the LTR group (34.7 vs. 36.8 p<0.001) with a high rate of cesarean sections (81.4% in RTR and 68.1% in LTR). Birth weight in LTR (2898 g) was higher than in RTR (2248 g) (p<0.0001). Currently, 29 RTR and 38 LTR have preserved graft function. Thus, graft survival in the study group is longer than in the general RTR or LTR population. CONCLUSIONS: Pregnancy after kidney or liver transplantation does not seem to increase the risk of graft loss, but is associated with a higher risk of maternal and fetal complications. In our data these complications occur more often in the RTR group. PMID- 25519169 TI - C-terminal-truncated hepatitis B virus X protein enhances the development of diethylnitrosamine-induced hepatocellular carcinogenesis. AB - Hepatitis B virus X protein (HBx) is involved in the development of hepatocellular carcinoma (HCC). The HBx sequence is a preferential site of integration into the human genome, leading to the formation of C-terminal truncated HBx proteins (Ct-HBx). We previously reported that Ct-HBx proteins were able to potentiate cell transformation in vitro. Our present goal was to compare the ability of Ct-HBx and full-length HBx (FL-HBx) proteins to develop or enhance HCC in transgenic mice. In the absence of treatment, neither Ct-HBx- nor FL-HBx transgenic mice developed HCC. In young mice treated with diethylnitrosamine (DEN) at 8 months of age, a significantly higher incidence and number of liver lesions were observed in Ct-HBx mice than in FL-HBx and control mice. The earlier development of tumours in Ct-HBx-transgenic mice was associated with increased liver inflammation. At 10 months, macroscopic and microscopic analyses showed that, statistically, FL-HBx mice developed more liver lesions with a larger surface area than control mice. Furthermore, during DEN-induced initiation of HCC, Ct-HBx- and FL-HBx-transgenic mice showed higher expression of IL-6, TNF alpha and IL-1beta transcripts, activation of STAT3, ERK and JNK proteins and an increase in cell apoptosis. In conclusion, in DEN-treated transgenic mice, the expression of Ct-HBx protein causes a more rapid onset of HCC than does FL-HBx protein. HBV genome integration leading to the expression of a truncated form of HBx protein may therefore facilitate HCC development in chronically infected patients. PMID- 25519168 TI - Prognostic impact of urokinase-type plasminogen activator system components in clear cell renal cell carcinoma patients without distant metastasis. AB - BACKGROUND: Members of the urokinase-type plasminogen activator (uPA) system including uPA, its receptor uPAR and the plasminogen activator inhibitor 1 (PAI 1) play an important role in tumour invasion and progression in a variety of tumour types. Since the majority of clear cell renal cell carcinoma (ccRCC) shows distant metastasis at time of diagnosis or later, the interplay of uPA, uPAR and PAI-1 might be of importance in this process determining the patients' outcome. METHODS: Corresponding pairs of malignant and non-malignant renal tissue specimens were obtained from 112 ccRCC patients without distant metastasis who underwent tumour nephrectomy. Tissue extracts prepared from fresh-frozen tissue samples by detergent extraction were used for the determination of antigen levels of uPA, uPAR and PAI-1 by ELISA. Antigen levels were normalised to protein concentrations and expressed as ng per mg of total protein. RESULTS: Antigen levels of uPA, uPAR, and PAI-1 correlated with each other in the malignant tissue specimens (rs=0.51-0.65; all P<0.001). Antigen levels of uPA system components were significantly higher in tissue extracts of non-organ confined tumours (pT3+4) compared to organ-confined tumours (pT1+2; all P<0.05). Significantly elevated levels of uPAR and PAI-1 were also observed in high grade ccRCC. When using median antigen levels as cut-off points, all three uPA system factors were significant predictors for disease-specific survival (DSS) in univariate Cox's regression analyses. High levels of uPA and uPAR remained independent predictors for DSS with HR=2.86 (95% CI 1.07-7.67, P=0.037) and HR=4.70 (95% CI 1.51-14.6, P=0.008), respectively, in multivariate Cox's regression analyses. A combination of high antigen levels of uPA and/or uPAR further improved the prediction of DSS in multivariate analysis (HR=14.5, 95% CI 1.88-111.1, P=0.010). Moreover, high uPA and/or uPAR levels defined a patient subgroup of high risk for tumour-related death in ccRCC patients with organ-confined disease (pT1+2) (HR=9.83, 95% CI 1.21 79.6, P=0.032). CONCLUSIONS: High levels of uPA and uPAR in tumour tissue extracts are associated with a significantly shorter DSS of ccRCC patients without distant metastases. PMID- 25519170 TI - Influenza A virus utilizes a suboptimal Kozak sequence to fine-tune virus replication and host response. AB - The segment-specific non-coding regions (NCRs) of influenza A virus RNA genome play important roles in controlling viral RNA transcription, replication and genome packaging. In this report, we present, for the first time to our knowledge, a full view of the segment-specific NCRs of all influenza A viruses by bioinformatics analysis. Our systematic functional analysis revealed that the eight segment-specific NCRs identified could differentially regulate viral RNA synthesis and protein expression at both transcription and translation levels. Interestingly, a highly conserved suboptimal nucleotide at -3 position of the Kozak sequence, which downregulated protein expression at the translation level, was only present in the segment-specific NCR of PB1. By reverse genetics, we demonstrate that recombinant viruses with an optimized Kozak sequence at the -3 position in PB1 resulted in a significant multiple-cycle replication reduction that was independent of PB1-F2 expression. Our detailed dynamic analysis of virus infection revealed that the mutant virus displays slightly altered dynamics from the wild-type virus on both viral RNA synthesis and protein production. Furthermore, we demonstrated that the level of PB1 expression is involved in regulating type I IFN production. Together, these data reveal a novel strategy exploited by influenza A virus to fine-tune virus replication dynamics and host antiviral response through regulating PB1 protein expression. PMID- 25519172 TI - Kiwi seed test for detection of enterocutaneous fistula. PMID- 25519171 TI - Adjuvant effect of the human metapneumovirus (HMPV) matrix protein in HMPV subunit vaccines. AB - The human metapneumovirus (HMPV) fusion (F) protein is the most immunodominant protein, yet subunit vaccines containing only this protein do not confer complete protection. The HMPV matrix (M) protein induces the maturation of antigen presenting cells in vitro. The inclusion of the M protein into an F protein subunit vaccine might therefore provide an adjuvant effect. We administered the F protein twice intramuscularly, adjuvanted with alum, the M protein or both, to BALB/c mice at 3 week intervals. Three weeks after the boost, mice were infected with HMPV and monitored for 14 days. At day 5 post-challenge, pulmonary viral titres, histopathology and cytokine levels were analysed. Mice immunized with F+alum and F+M+alum generated significantly more neutralizing antibodies than mice immunized with F only [titres of 47 +/- 7 (P<0.01) and 147 +/- 13 (P<0.001) versus 17 +/- 2]. Unlike F only [1.6 +/- 0.5 * 10(3) TCID50 (g lung)(-1)], pulmonary viral titres in mice immunized with F+M and F+M+alum were undetectable. Mice immunized with F+M presented the most important reduction in pulmonary inflammation and the lowest T-helper Th2/Th1 cytokine ratio. In conclusion, addition of the HMPV-M protein to an F protein-based vaccine modulated both humoral and cellular immune responses to subsequent infection, thereby increasing the protection conferred by the vaccine. PMID- 25519174 TI - Proprotein convertase subtilisin/kexin type 9 expression is transiently up regulated in the acute period of myocardial infarction in rat. AB - BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) has been confirmed as a major factor regulating cholesterol homeostasis and has low density lipoprotein receptor (LDLR) independent effects. In addition, the pathogenesis of acute myocardial infarction (AMI) involves lipids alteration and other acute phase responses. It remains unknown whether the PCSK9 expression is influenced by the impact of AMI. The present study aimed to investigate the changes of PCSK9 concentration using AMI rat model. METHODS: AMI (n = 6-8 at each time point) or sham operated (n = 6) adult male rats model were used. Whole blood and liver tissue were collected at 1, 3, 6, 9, 12, 24, 48, and 96 hour (h) post infarction. The plasma PCSK9 concentration was measured by ELISA and lipid profiles were measured by enzymatic assay. The liver mRNA levels of PCSK9, LDLR, sterol response element binding protein-2 (SREBP-2) and hepatocyte nuclear factor 1alpha (HNF1alpha) were measured by quantitative real-time PCR. RESULTS: The plasma PCSK9 concentration was increased from 12 h to 96 h (P < 0.05 vs. control). Paralleled with the enhanced plasma PCSK9 concentration, the hepatic PCSK9 mRNA expression was up-regulated by 2.2-fold at 12 h and 4.1-fold at 24 h. Hepatic mRNA levels of LDLR, SREBP-2 and HNF1alpha were all increased and lipid profiles underwent great changes at this acute period. CONCLUSIONS: We firstly demonstrated that PCSK9 was transiently up-regulated in the acute period of AMI, which is also driven by transcriptional factors, SREBP-2 and HNF1alpha, suggesting that the role of PCSK9 in myocardial injury may be needed further study. PMID- 25519175 TI - Urine as an important source of sodium increases decomposition in an inland but not coastal tropical forest. AB - Nutrient pulses can profoundly impact ecosystem processes and urine is a frequently deposited source of N and K, and Na. Na is unimportant to plants, but its addition can increase decomposition and change invertebrate community structure in Na-poor tropical forests. Here we used synthetic urine to separate the effects of Na from urine's other nutrients and contrasted their roles in promoting decomposition and detritivore recruitment in both a Na-poor inland Ecuadorian and Na-rich coastal Panamanian tropical forest. After 2 days, invertebrate communities did not vary among +Na, H2O, Urine+Na, and Urine-Na treatments. But after 2 weeks, Ecuador wood, but not cellulose, decomposition was twofold higher on Urine+Na and +Na plots compared to H2O and Urine-Na plots accompanied by >20-fold increases in termite abundance on these plots. Panama, in contrast, showed no effect of Na on decomposition. In both forests, plots fertilized with urine had nearly twofold decrease in detritivores after 2 weeks that was likely a shock effect from ammonification. Moreover, the non-Na nutrients in urine did not enhance decomposition at this time scale. On control plots, Panama had higher decomposition rates for both cellulose and wood than Ecuador, but the addition of Na in Ecuador alleviated these differences. These results support the hypothesis that in Na-poor tropical forests, urine can enhance wood decomposition and generate an important source of heterogeneity in the abundance and activity of brown food webs. PMID- 25519173 TI - Spontaneous white matter damage, cognitive decline and neuroinflammation in middle-aged hypertensive rats: an animal model of early-stage cerebral small vessel disease. AB - INTRODUCTION: Cerebral small vessel disease (cSVD) is one of the most prevalent neurological disorders. The progressive remodeling of brain microvessels due to arterial hypertension or other vascular risk factors causes subtle, but constant cognitive decline through to manifest dementia and substantially increases the risk for stroke. Preliminary evidence suggests the contribution of the immune system to disease initiation and progression, but a more detailed understanding is impaired by the unavailability of appropriate animal models. Here, we introduce the spontaneously hypertensive rat (SHR) as a model for early onset cSVD and unveiled substantial immune changes in conjunction with brain abnormalities that resemble clinical findings. RESULTS: In contrast to age matched normotensive Wistar Kyoto (WKY) rats, male SHR exhibited non-spatial memory deficits. Magnetic resonance imaging showed brain atrophy and a reduction of white matter volumes in SHR. Histological analyses confirmed white matter demyelination and unveiled a circumscribed blood brain barrier dysfunction in conjunction with micro- and macrogliosis in deep cortical regions. Flow cytometry and histological analyses further revealed substantial disparities in cerebral CD45high leukocyte counts and distribution patterns between SHR and WKY. SHR showed lower counts of T cells in the choroid plexus and meningeal spaces as well as decreased interleukin-10 levels in the cerebrospinal fluid. On the other hand, both T and NK cells were significantly augmented in the SHR brain microvasculature. CONCLUSIONS: Our results indicate that SHR share behavioral and neuropathological characteristics with human cSVD patients and further undergird the relevance of immune responses for the initiation and progression of cSVD. PMID- 25519177 TI - Mono- and dinuclear metal complexes containing the 1,5,9-triazacyclododecane ([12]aneN3) unit and their interaction with DNA. AB - The ability of mononucleating and dinucleating macrocylic polyamines and their novel nickel, copper and zinc complexes to induce the left-handed form of poly d(GC) was evaluated. The influence of the nuclearity, the presence or absence of metals ions, the linker length in the case of dinucleating ligands and the metal ion was determined. Almost all dinuclear metal complexes efficiently induced Z DNA, the zinc ones being the least and the copper ones the most efficient ones. Additionally, the X-ray structures of three dinuclear metal complexes and one partially protonated ligand could be determined. PMID- 25519176 TI - Altitudinally divergent adult phenotypes in Iberian wall lizards are not driven by egg differences or hatchling growth rates. AB - The interplay between ecological conditions and life histories has been widely acknowledged in vertebrates, particularly in lizards. Environmental conditions may exert different selective pressures and produce divergent phenotypes even in geographically and genetically close populations. The Iberian wall lizard constitutes a perfect model organism as it is considered a species complex with a complicated evolutionary history. Here, we focus on two proximate populations in which we examined adult morphology and reproductive investment of wild-caught lizards along a 500-m altitudinal gradient with contrasting environmental conditions, where adults show marked morphological differences in spite of being closely related. Also, we performed a common garden experiment to examine embryonic and hatchling growth. We focused on reproductive investment per clutch, incubation time, egg size, morphology and growth rate of hatchlings. Results showed clutch size differences between populations that were independent of the larger body size of highland females. However, there were no egg morphological differences between populations, except for egg width, and this difference disappeared after controlling for female body size. Hatchling lizards from both populations did not differ in morphology. Moreover, we did not observe differences between populations or sexes in hatchling growth. Overall, we provide evidence that the differences in adult body size and clutch size are not driven by size at hatching which is not contributed to by egg size, nor are intrinsic hatchling growth rates associated with the environmental conditions experienced in our common garden experiment, suggesting that adult phenotypes are not the result of intrinsic differences between populations. PMID- 25519178 TI - Differences between chemical element contents in hyperplastic and nonhyperplastic prostate glands investigated by neutron activation analysis. AB - In order to clarify the differences between Ag, Br, Ca, Co, Cr, Fe, Hg, K, Mg, Mn, Na, Rb, Sb, Sc, Se, and Zn contents in hyperplastic (patients with benign prostate hyperplasia (BPH), n = 32) and nonhyperplastic (control group of healthy male inhabitants, n = 32) prostates, an instrumental neutron activation analysis was performed. Mean values (M +/- SEpsilonMU) for mass fraction (mg/kg, dry mass basis) of chemical elements in glands of patients with BPH were the following: Ag, 0.0346 +/- 0.0060; Br, 30.4 +/- 3.6; Ca, 2030 +/- 165; Co, 0.0716 +/- 0.0097; Cr, 1.073 +/- 0.119; Fe, 130.0 +/- 7.9; Hg, 0.232 +/- 0.030; K, 14,470 +/- 740; Mg, 1200 +/- 80; Mn, 1.19 +/- 0.09; Na, 11,610 +/- 870; Rb, 14.7 +/- 0.8; Sb, 0.163 +/- 0.025; Sc, 0.0257 +/- 0.0040; Se, 1.243 +/- 0.079; and Zn, 1235 +/- 92. It was observed that in BPH tissue, the mass fraction of Co (p < 0.015), Cr (p < 0.0002), Hg (p < 0.000007), K (p < 0.001), Rb (p < 0.048), Sb (p < 0.0001), and Se (p < 0.000001) were significantly higher than in controls. In the sixth to eighth decades, the mass fractions of almost all chemical elements in hyperplastic prostates did not depend from age. Our finding of correlation between pairs of prostatic chemical element mass fractions indicates that there is a great disturbance of prostatic chemical element relationships with a benign hyperplastic transformation. The results apparently confirm the disturbed homeostasis of Zn and Se and some other chemical elements in the etiology of BPH. PMID- 25519180 TI - Corrigendum: "The role of prefrontal catecholamines in attention and working memory". AB - [This corrects the article on p. 33 in vol. 8, PMID: 24782714.]. PMID- 25519179 TI - Safety and efficacy of biocompatible perfusion strategy in a contemporary series of patients undergoing coronary artery bypass grafting - a two-center study. AB - OBJECTIVE: The profile of patients referred for coronary artery bypass grafting (CABG) is continuously changing to include older patients with multiple comorbidities. We assessed the safety and efficacy of a biocompatible perfusion strategy (BPS) in a contemporary series of patients undergoing isolated CABG. METHODS: BPS consisted of a membrane oxygenator, tip-to-tip closed-system heparin bonded cardiopulmonary bypass circuits without a cardiotomy reservoir, low systemic anticoagulation (target ACT - 250-300 sec) using heparin titration curves, low prime volume, avoidance of systemic cooling, and routine use of cell saver and anti-fibrinolytics. Data were prospectively collected using the American Society of Thoracic Surgeons National Adult Cardiac Surgery Database definitions. RESULTS: 964 consecutive patients (mean age 66 +/- 11 years, 83% male) undergoing CABG between 2008 and 2012 were enrolled. 30-day mortality was 1.4%. Rates of postoperative stroke, myocardial infarction, sternal infection and reoperation for bleeding were 0.9%, 1.3%, 1.9% and 4.2%, respectively. Average 24 hour chest tube drainage was 440 +/- 280 ml. Blood products were used in 34% of patients (total donor exposure of 1.7 +/- 4.7 units/patient). Predictors of hospital mortality in multivariable analysis were left main disease and preoperative treatment with anti-arrhythmic or immunosuppressive medications. Predictors of allogeneic blood transfusions included older age, small body surface area, female gender, increased serum creatinine, lower preoperative LVEF and hematocrit. Priority of surgery, dual antiplatelet therapy and cardiopulmonary bypass time were not predictors of adverse outcomes or blood transfusions. CONCLUSIONS: In a contemporary cohort of patients undergoing CABG, the use of BPS is safe and effective. It is associated with excellent clinical outcomes and reduced allogeneic blood transfusions. PMID- 25519181 TI - Combined approaches for fixation of Schatzker type II tibial plateau fractures involving the posterolateral column: a prospective observational cohort study. AB - INTRODUCTION: This study aimed to investigate the surgical techniques and the clinical efficacy of combined approaches for the treatment of Schatzker type II tibial plateau fractures involving the posterolateral column [lateral and posterolateral columns (LPCs) fractures] in a prospective cohort. MATERIALS AND METHODS: From January 2007 through December 2010, a total of 65 patients with LPCs underwent dual-plate fixation via a combined anterior and posterior approach. The anterior and posterior approaches were the conventional anterolateral approach and a posteromedial inverted L-shaped approach, respectively, with the patients in a floating position. RESULTS: Ultimately, 41 patients were followed up for a mean period of 52.5 months. All fractures healed. The mean time to radiographic bony union was 15.2 weeks and the mean time to full weight-bearing was 18.7 weeks. No parameter associated with knee alignment changed significantly between immediately postoperation and 2 years postoperation. No collapse of the reduced articular surface was detected. Two years postoperation, the mean Hospital for Special Surgery score was 92.3; the mean Short Form-36 score was 90.1, and the mean range of knee motion was 1.7 degrees -123.6 degrees (extension-flexion). Two patients suffered dehiscence of the anterolateral incision and another suffered partial necrosis at the margin of the posteromedial incision postoperatively. All healed in response conservative treatment. Another two patients experienced numbness in the posteromedial inferior region of the calf. No implant loosening, breakage, fixation failure, or other complication was observed during follow-up. CONCLUSIONS: LPCs are not uncommon. Careful preoperative analysis of computed tomography images and impeccable preparation are necessary to avoid neglecting a posterolateral column fracture. It is inappropriate to generalize one scenario for all Schatzker type II fractures: a single approach cannot address all subtypes of these fractures. Dual-plate fixation via a combined approach is an effective treatment for LPCs. PMID- 25519183 TI - Differential gene expression in uterine endometrium during implantation in pigs. AB - Embryonic mortality during the implantation period strongly affects litter size in pigs. To analyze the differentially expressed genes (DEGs) in the endometrium during implantation and further to identify candidate genes for litter size, tissues of endometrial attachment sites and intersites were collected from nine pregnant sows on Days 13, 18, and 24 of pregnancy. Endometrium tissue was also collected from another three nonpregnant sows. Samples were hybridized to the porcine Agilent GeneChip microarray. The analysis of gene expression patterns over the implantation period revealed 858 DEGs at endometrial attachment sites. Comparisons of the gene files of attachment sites and intersites revealed 12, 51, and 89 DEGs on Days 13, 18, and 24 of pregnancy, respectively. Annotated function was used to identify overrepresented genetic processes, and several biological processes were considered as the most enriched. Genes related to vascular development, proteolysis, RNA metabolism and translation, protein modification, immune response, and hormone-related are discussed in detail. Then we combined microarray technology and linkage analysis to select powerful candidate genes for quantitative trait loci affecting pig litter size. Eighty-seven DEGs were located in quantitative trait loci related to litter size, that is, total number born and number born alive. Those candidate genes were thought to affect litter size by influencing embryonic implantation. Furthermore, single nucleotide polymorphism of VEGFA was shown to be associated with litter size in pigs. This study identified candidate genes for litter size that were related to embryonic implantation and could be a resource for target studies of genetic markers for litter size in pigs. PMID- 25519182 TI - How central are clients in sexual networks created by commercial sex? AB - Sex workers are traditionally considered important vectors of transmission of sexually transmitted infections (STI). The role of clients is commonly overlooked, partially due to the lack of evidence on clients' position in the sexual network created by commercial sex. Contrasting the diffusion importance of sex workers and their clients in the map of their sexual encounters in twoWeb mediated communities, we find that from diffusion perspective, clients are as important as sex workers. Their diffusion importance is closely linked to the geography of the sexual encounters: as a result of different movement patterns, travelling clients shorten network distances between distant network neighborhoods and thus facilitate contagion among them more than sex workers, and find themselves more often in the core of the network by which they could contribute to the persistence of STIs in the community. These findings position clients into the set of the key actors and highlight the role of human mobility in the transmission of STIs in commercial sexual networks. PMID- 25519184 TI - DS1, a delta subunit-containing GABA(A) receptor agonist, increases gonadotropin subunit gene expression in mouse pituitary gonadotrophs. AB - 4-Chloro-N-[6,8-dibromo-2-(2-thienyl)imidazo[1,2-alpyridine-3-yl] (DS1) is a GABA(A) receptor agonist that selectively binds to delta subunit-containing GABA(A) alpha4beta3delta receptors. In the present study, we examined the effect of DS1 on pituitary gonadotropin subunit gene expression using the mouse pituitary gonadotroph cell line LbetaT2. DS1 increased the promoter activity of the gonadotropin subunits luteinizing hormone beta (LHbeta), follicle-stimulating hormone beta (FSHbeta), and alpha. Gonadotropin-releasing hormone (GnRH) receptor promoters were also activated by DS1. The effects of DS1 on gonadotropin subunit promoters were obvious, but they were less than those induced by stimulation with GnRH. GnRH-stimulated gonadotropin subunit promoters were enhanced in the presence of DS1. A prototypic specific agonist for GABAA receptors, muscimol, failed to increase LHbeta and FSHbeta subunit promoter activity and had no effect on GnRH-increased LHbeta and FSHbeta promoter activity. In addition, SKF97541, a specific agonist for GABAB receptors, did not modulate basal or GnRH-induced LHbeta and FSHbeta promoter activity. A natural GABA compound failed to increase gonadotropin promoter activity and potentiated the effect of GnRH on the FSHbeta promoter. DS1 increased the activity of serum response element (SRE) and cAMP response element (CRE) promoters, which reflect the activity of the extracellular signal-regulated kinase and cAMP/protein kinase A (PKA) pathways, and GnRH increased SRE and CRE promoter activity was enhanced in the presence of DS1. A specific inhibitor of the ERK signaling pathway, U0126, prevented DS1-induced LHbeta and FSHbeta promoter activity almost completely; however, H89, a PKA inhibitor, did not modulate the effect of DS1. Our current observations demonstrate that the GABAA alpha4beta3delta receptor agonist DS1 can stimulate gonadotropin subunit gene expression in association with the ERK signaling pathway. PMID- 25519185 TI - Peroxisome proliferator activator receptor gamma (PPARG) regulates conceptus elongation in sheep. AB - The ovine blastocyst hatches from the zona pellucida by Day 8 and develops into an ovoid or tubular conceptus (embryo and associated extraembryonic membranes) that grows and elongates into a filamentous form between Days 12 and 16. The trophectoderm of the elongating conceptus synthesizes and secretes interferon tau (IFNT) as well as prostaglandins (PGs) via prostaglandin synthase two (PTGS2). Intrauterine infusion of a PTGS2 inhibitor prevents conceptus elongation in sheep. Although many PGs are secreted, PGI2 and PGJ2 can activate nuclear peroxisome proliferator activator receptors (PPARs) that heterodimerize with retinoic X receptors (RXRs) to regulate gene expression and cellular function. Expression of PPARD, PPARG, RXRA, RXRB, and RXRG is detected in the elongating ovine conceptus, and nuclear PPARD and PPARG are present in the trophectoderm. Consequently, PPARD and PPARG are hypothesized to have essential roles in conceptus elongation in ruminants. In utero loss-of-function studies of PPARD and PPARG in the ovine conceptus trophectoderm were conducted using morpholino antisense oligonucleotides (MAOs) that inhibit mRNA translation. Elongating, filamentous-type conceptuses were recovered from ewes infused with a control morpholino or PPARD MAO. In contrast, PPARG MAO resulted in severely growth retarded conceptuses or conceptus fragments with apoptotic trophectoderm. In order to identify PPARG-regulated genes, PPARG chromatin immunoprecipitation sequencing and RNA sequencing were conducted using Day 14 ovine conceptuses. These analyses revealed candidate PPARG-regulated genes involved in biological pathways, including lipid and glucose uptake, transport, and metabolism. Collectively, results support the hypothesis that PTGS2-derived PGs and PPARG are essential regulators of conceptus elongation, with specific roles in trophectoderm survival and proliferation. PMID- 25519186 TI - Processive pulses of retinoic acid propel asynchronous and continuous murine sperm production. AB - The asynchronous cyclic nature of spermatogenesis is essential for continual sperm production and is one of the hallmarks of mammalian male fertility. While various mRNA and protein localization studies have indirectly implicated changing retinoid levels along testis tubules, no quantitative evidence for these changes across the cycle of the seminiferous epithelium currently exists. This study utilized a unique mouse model of induced synchronous spermatogenesis, localization of the retinoid-signaling marker STRA8, and sensitive quantification of retinoic acid concentrations to determine whether there are fluctuations in retinoid levels at each of the individual stages of germ cell differentiation and maturation to sperm. These data show that processive pulses of retinoic acid are generated during spermatogonial differentiation and are the likely trigger for cyclic spermatogenesis and allow us, for the first time, to understand how the cycle of the seminiferous epithelium is generated and maintained. In addition, this study represents the first direct quantification of a retinoid gradient controlling cellular differentiation in a postnatal tissue. PMID- 25519187 TI - Site-specific increases in utero- and fetoplacental arterial vascular resistance in eNOS-deficient mice due to impaired arterial enlargement. AB - The sites of elevated vascular resistance that impede placental perfusion in pathological pregnancies are unknown. In the current study, we identified these sites in a knockout mouse model (eNOS(-/-)) with reduced uterine (-55%) and umbilical (-29%) artery blood flows caused by endothelial nitric oxide synthase deficiency. Uteroplacental and fetoplacental arterial vascular trees of pregnant mice near term were imaged using x-ray microcomputed tomography (n = 5-10 placentas from 3-5 dams/group). The resulting three-dimensional images were analyzed to assess vessel geometry and vascular resistance. In control and eNOS( /-) trees, ~90% of total uteroplacental vascular resistance was located in the radial arteries. Changes in eNOS(-/-) vessel geometry, including 30% reductions in uterine, radial, and spiral artery diameters, were calculated to increase arterial resistance downstream of the uterine artery by 2.3-fold, predicting a 57% decrease in uterine blood flow. Despite large reductions in eNOS(-/-) spiral arteries (-55% by volume) and maternal canals (-67% by volume), these vessels were relatively minor contributors to resistance. In the eNOS(-/-) fetoplacental tree, the number of arterioles (50-75 MUm diameter) increased by 26%. Nevertheless, calculated resistance rose by 19%, predominantly because arteries near the periphery of the tree selectively exhibited a 7%-9% diameter reduction. We conclude that previously observed decreases in uterine and umbilical blood flows in eNOS(-/-) pregnancies are associated with markedly divergent structural changes in the uteroplacental versus fetoplacental circulations. Results showed the radial arteries were critical determinants of uteroplacental resistance in mice and therefore warrant greater attention in future studies in pathological human pregnancies. PMID- 25519188 TI - gamma-Glutamyl transpeptidase (GgtA) of Aspergillus nidulans is not necessary for bulk degradation of glutathione. AB - Aspergillus nidulans exhibited high gamma-glutamyl transpeptidase (gammaGT) activity in both carbon-starved and carbon-limited cultures. Glucose repressed, but casein peptone increased gammaGT production. Null mutation of creA did not influence gammaGT formation, but the functional meaB was necessary for the gammaGT induction. Deletion of the AN10444 gene (ggtA) completely eliminated the gammaGT activity, and the mRNA levels of ggtA showed strong correlation with the observed gammaGT activities. While ggtA does not contain a canonical signal sequence, the gammaGT activity was detectable both in the fermentation broth and in the hyphae. Deletion of the ggtA gene did not prevent the depletion of glutathione observed in carbon-starved and carbon-limited cultures. Addition of casein peptone to carbon-starved cultures lowered the formation of reactive species (RS). Deletion of ggtA could hinder this decrease and resulted in elevated RS formation. This effect of gammaGT on redox homeostasis may explain the reduced cleistothecia formation of DeltaggtA strains in surface cultures. PMID- 25519190 TI - [Skilled communication as "intervention" : Models for systematic communication in the healthcare system]. AB - Specific communication training is currently not integrated into anesthesiology curricula. At the same time communication is an important key factor when working with colleagues, in the physician-patient relationship, during management of emergencies and in avoiding or reducing the legal consequences of adverse medical events. Therefore, focused attention should be brought to this area. In other high risk industries, specific communication training has been standard for a long time and in medicine there is an approach to teach and train these soft skills by simulation. Systematic communication training, however, is rarely an established component of specialist training. It is impossible not to communicate whereby nonverbal indications, such as gestures, mimic expression, posture and tone play an important part. Miscommunication, however, is common and leads to unproductive behavior. The cause of this is not always obvious. This article provides an overview of the communication models of Shannon, Watzlawick et al. and Schulz von Thun et al. and describes their limitations. The "Process Communication Model(r)" (PCM) is also introduced. An overview is provided with examples of how this tool can be used to look at the communication process from a systematic point of view. People have different psychological needs. Not taking care of these needs will result in individual stress behavior, which can be graded into first, second and third degrees of severity (driver behavior, mask behavior and desperation). These behavior patterns become exposed in predictable sequences. Furthermore, on the basis of this model, successful communication can be established while unproductive behavior that occurs during stress can be dealt with appropriately. Because of the importance of communication in all areas of medical care, opportunities exist to focus research on the influence of targeted communication on patient outcome, complications and management of emergencies. PMID- 25519192 TI - Control of guanine-rich DNA secondary structures depending on the protease activity using a designed PNA peptide. AB - We constructed a regulation system for DNA secondary structure formation of G rich sequences using a designed PNA peptide exhibiting an on-to-off switching functionality, depending on the protease activity. This study introduces the new concept of a simple and powerful system for regulating quadruplex-related important biological events. PMID- 25519191 TI - Pulmonary vascular remodeling before and after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension: a cardiac magnetic resonance study. AB - Phase-contrast magnetic resonance imaging (PC-MRI) offers a range of surrogate markers to quantify the hemodynamic changes associated with chronic thromboembolic pulmonary hypertension (CTEPH). Our aim was to noninvasively monitor effects of pulmonary vascular remodeling before and after endarterectomy (PEA) in patients with CTEPH by using PC-MRI. Fifty-seven consecutive patients (mean age 56.7 +/- 16, 28 female) underwent PC-MRI before and after PEA as part of their peri-operative routine workup. Pulmonary artery (PA) maximum flow velocity (maxV), acceleration time/ejection time (AT/ET), distensibility [(PA maximum area - PA minimum area)/PA minimum area], mid-systolic flow deceleration (notch), and the timing of deceleration (notch ratio) were recorded. Mean PA pressure was obtained from standard right heart catheter procedures. maxV and AT/ET were decreased before PEA and significantly improved afterwards (60.8 +/- 16 vs. 73.8 +/- 19 cm/s, p = 0.007; 0.32 +/- 0.06 vs. 0.36 +/- 0.09, p = 0.0015). Surprisingly, distensibility did not change significantly (30 +/- 19 vs. 26 +/- 12%, p = 0.11). Forty-five patients (78%) had a systolic notch before PEA that persisted in only 10 (18%; p = 0.00001). Among patients with a persisting notch, the notch ratio did not significantly increase (1.3 +/- 0.2 vs. 1.6 +/- 1.5, p = 0.32). Our data show early PA reverse remodeling after PEA. Flow velocities increase while PA flow wave reflections represented by mid-systolic flow deceleration are abolished. In some patients a mid-systolic notch persists, suggesting increased downstream resistance as a consequence of small vessel arteriopathy. PMID- 25519193 TI - Approach for selective separation of thiophenic and sulfidic sulfur compounds from petroleum by methylation/demethylation. AB - Detailed characterization of petroleum derived sulfur compounds has been challenging, due to the complex composition of the hydrocarbon matrix. A novel method was developed for selective separation of thiophenic and sulfidic compounds from petroleum. Sulfur compounds were methylated to sulfonium salts by AgBF4 and CH3I, then the polar salts were separated by precipitation from petroleum matrix. The thiophenic and sulfidic sulfonium salts were sequentially demethylated with 7-azaindole and 4-dimethylaminopyridine, obtaining original thiophenic and sulfidic compounds, respectively. The method was validated by model compounds, and applied to a diesel and a vacuum distillation petroleum fraction. Sulfur fractions were characterized by gas chromatography (GC) coupled with a sulfur chemiluminescence detector (SCD) and quadrupole mass spectrometry (MS), and high resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). The technique was effective to selectively obtain high purity thiophenic and sulfidic compounds and showed rare discrimination among sulfur compounds with ranging molecular weights and degrees of unsaturation. The method would facilitate multifaceted detailed characterization of sulfur compounds in an organic complex matrix. PMID- 25519195 TI - Society for Maternal Fetal Medicine 2015 Annual Pregnancy Meeting supplemental episode: A Guide to San Diego. PMID- 25519196 TI - End-of-life care in the neonatal intensive care unit: experiences of staff and parents. AB - OBJECTIVE: The aim of the study is to determine the perceptions of end-of-life care practices and experience with infants who have died in the NICU among neonatologists, advanced practitioners, nurses, and parents, and also to determine perceived areas for improvement and the perceived value of a palliative care team. STUDY DESIGN: This descriptive, exploratory cross-sectional study using surveys consisting of 7-point Likert scales and free response comments was sent to all neonatologists (n = 14), advanced practitioners (n = 40), and nurses (n = 184) at Connecticut Children's Medical Center's neonatal intensive care units (NICUs) in April 2013 and to all parents whose infants died in these NICUs from July 1, 2011, to December 31, 2012 (n = 28). RESULTS: The response rates were 64.3% for physicians; 50.0% for practitioners; 40.8% for nurses; and 30.4% for parents. Most providers reported they feel comfortable delivering end-of-life care. Bereavement support, debriefing/closure conferences, and education did not occur routinely. Families stressed the importance of memory making and bereavement/follow-up. Consistent themes of free responses include modalities for improving end-of-life care, inconsistency of care delivery among providers, and the importance of memory making and follow-up. CONCLUSION: End-of-life experiences in the NICU were perceived as variable and end-of-life practices were, at times, perceived as inconsistent among providers. There are areas for improvement, and participants reported that a formalized palliative care team could help. Families desire memory making, follow-up, and bereavement support. PMID- 25519194 TI - Cardiac thromboxane A2 receptor activation does not directly induce cardiomyocyte hypertrophy but does cause cell death that is prevented with gentamicin and 2 APB. AB - BACKGROUND: We have previously shown that the thromboxane (TXA2) receptor agonist, U46619, can directly induce ventricular arrhythmias that were associated with increases in intracellular calcium in cardiomyocytes. Since TXA2 is an inflammatory mediator and induces direct calcium changes in cardiomyocytes, we hypothesized that TXA2 released during ischemia or inflammation could also cause cardiac remodeling. METHODS: U46619 (0.1-10 MUM) was applied to isolated adult mouse ventricular primary cardiomyocytes, mouse ventricular cardiac muscle strips, and cultured HL-1 cardiomyocytes and markers of hypertrophy and cell death were measured. RESULTS: We found that TXA2 receptors were expressed in ventricular cardiomyocytes and were functional via calcium imaging. U46619 treatment for 24 h did not increase expression of pathological hypertrophy genes (atrial natriuretic peptide, beta-myosin heavy chain, skeletal muscle alpha actin) and it did not increase protein synthesis. There was also no increase in cardiomyocyte size after 48 h treatment with U46619 as measured by flow cytometry. However, U46619 (0.1-10 MUM) caused a concentration-dependent increase in cardiomyocyte death (trypan blue, MTT assays, visual cell counts and TUNEL stain) after 24 h. Treatment of cells with the TXA2 receptor antagonist SQ29548 and inhibitors of the IP3 pathway, gentamicin and 2-APB, eliminated the increase in cell death induced by U46619. CONCLUSIONS: Our data suggests that TXA2 does not induce cardiac hypertrophy, but does induce cell death that is mediated in part by IP3 signaling pathways. These findings may provide important therapeutic targets for inflammatory-induced cardiac apoptosis that can lead to heart failure. PMID- 25519197 TI - Comparison of stool colonization in premature infants by three dose regimes of a probiotic combination: a randomized controlled trial. AB - OBJECTIVE: To compare stool colonization among premature infants receiving high dose probiotics versus standard dose. STUDY DESIGN: This blinded, randomized, placebo-controlled trial was conducted in a Level III neonatal unit. Eligibility criteria were gestational age 27-33 weeks, age < 96 hours, tolerating milk >= 15 mL/kg/day and availability for follow-up. Gastro-intestinal/life-threatening malformations and necrotizing enterocolitis/sepsis were exclusions. A total of 149 subjects were randomly allocated to groups A through D (received 12-hourly probiotic supplements of 10(10) cells for 21 days, 10(10) cells for 14 days, 10(9) cells for 21 days and placebo, respectively). Key outcome was stool colonization by a probiotic organism at 28 days. RESULTS: Colonization with Lactobacillus and Bifidobacterium was significantly higher in groups A, B, and C versus placebo respectively, but groups A through C did not differ from each other. There were trends toward more colony forming unit (cfu) of Lactobacillus and Bifidobacterium per milliliter of stool in group A versus B and B versus C. Groups A and B and spontaneous preterm labor (SPL) independently predicted high Lactobacillus counts on day 28; groups A, B, and C and SPL predicted high Bifidobacterium counts. CONCLUSION: Proportion of infants colonized with probiotic species was similar with high-dose and standard dose regimes. PMID- 25519198 TI - Capacity planning for maternal-fetal medicine using discrete event simulation. AB - BACKGROUND: Maternal-fetal medicine is a rapidly growing field requiring collaboration from many subspecialties. We provide an evidence-based estimate of capacity needs for our clinic, as well as demonstrate how simulation can aid in capacity planning in similar environments. METHODS: A Discrete Event Simulation of the Center for Fetal Diagnosis and Treatment and Special Delivery Unit at The Children's Hospital of Philadelphia was designed and validated. This model was then used to determine the time until demand overwhelms inpatient bed availability under increasing capacity. FINDINGS: No significant deviation was found between historical inpatient censuses and simulated censuses for the validation phase (p = 0.889). Prospectively increasing capacity was found to delay time to balk (the inability of the center to provide bed space for a patient in need of admission). With current capacity, the model predicts mean time to balk of 276 days. Adding three beds delays mean time to first balk to 762 days; an additional six beds to 1,335 days. CONCLUSION: Providing sufficient access is a patient safety issue, and good planning is crucial for targeting infrastructure investments appropriately. Computer-simulated analysis can provide an evidence base for both medical and administrative decision making in a complex clinical environment. PMID- 25519199 TI - Early-onset severe preeclampsia by first trimester pregnancy-associated plasma protein A and total human chorionic gonadotropin. AB - OBJECTIVE: This study aims to evaluate the relationship between early-onset severe preeclampsia and first trimester serum levels of pregnancy-associated plasma protein A (PAPP-A) and total human chorionic gonadotropin (hCG). STUDY DESIGN: The association between early-onset severe preeclampsia and abnormal levels of first trimester PAPP-A and total hCG in maternal serum were measured in a sample of singleton pregnancies without chromosomal defects that had integrated prenatal serum screening in 2009 and 2010 (n = 129,488). Logistic binomial regression was used to estimate the relative risk (RR) of early-onset severe preeclampsia in pregnancies with abnormal levels of first trimester PAPP-A or total hCG as compared with controls. RESULTS: Regardless of parity, women with low first trimester PAPP-A or high total hCG were at increased risk for early onset severe preeclampsia. Women with low PAPP-A (multiple of the median [MoM] <= the 10th percentile in nulliparous or <= the 5th percentile in multiparous) or high total hCG (MoM >= the 90th percentile in nulliparous or >= the 95th percentile in multiparous) were at more than a threefold increased risk for early onset severe preeclampsia (RR, 4.2; 95% confidence interval [CI], 3.0-5.9 and RR, 3.3; 95% CI, 2.1-5.2, respectively). CONCLUSION: Routinely collected first trimester measurements of PAPP-A and total hCG provide unique risk information for early-onset severe preeclampsia. PMID- 25519200 TI - Amplitude-integrated electroencephalography: a survey of practices in the United States. AB - OBJECTIVE: Amplitude-integrated electroencephalography (aEEG) is a simplified method for continuous monitoring of brain activity in the neonatal intensive care unit (NICU). Our objective was to describe current aEEG use in the United States. STUDY DESIGN: An online survey was distributed to the American Academy of Pediatrics Section on Perinatal Pediatrics' list serve. RESULT: A total of 654 surveys were received; 55% of respondents reported using aEEG. aEEG was utilized more often in academic and levels III and IV NICUs; hypoxic-ischemic encephalopathy and suspected seizures were the most common indications for use. aEEG was primarily interpreted by neonatologists (87%), with approximately half reporting either self-teaching or hospital-based training for interpretation. For those not using aEEG, uncertain clinical benefit (40%) and cost (17%) were reported as barriers to use. CONCLUSION: More than half of neonatologists utilize aEEG, with practice variation by NICU setting. Barriers to wider adoption include education regarding potential benefit, training, and cost. PMID- 25519201 TI - How do maternal views of delivery outcomes vary by demographics and preferred mode of delivery? AB - OBJECTIVE: To investigate how maternal views of delivery outcomes vary by demographic characteristics and preference toward mode of delivery (MOD). STUDY DESIGN: Survey of 719 pregnant women in outpatient clinics at an academic institution during their third trimester. Women ranked outcomes such as vaginal delivery (VD), cesarean delivery (CD), urinary incontinence, perineal lacerations, and induction of labor (IOL) on a visual analog scale (VAS) in order of worst imaginable (0) to best possible (100) outcomes. RESULTS: Women of all ages ranked VD as more desirable than CD. However, women >= 35 years of age had greater valuations of both MOD compared with women <35 years, with mean VAS scores of 88.4 versus 86.4 for VD (p < 0.001) and 61.5 versus 51.9 for CD (p < 0.001). Women with a college education or higher also rated both MOD as more desirable than women with less than a college education. Additionally, women who preferred VD rather than CD had greater valuations of perineal laceration (43.3 vs. 31.5, p = 0.001) and urinary incontinence (40.7 vs. 30.1, p = 0.002). CONCLUSION: Significant differences exist in women's views toward MOD and peripartum outcomes, by demographics and preferred MOD. Understanding delivery preferences better enables clinicians to counsel women about labor and management options. PMID- 25519202 TI - Urinary tract infections in a neonatal intensive care unit. AB - OBJECTIVE: Our aim was to describe laboratory findings and imaging results for neonatal patients diagnosed with urinary tract infection (UTI). STUDY DESIGN: Medical records were reviewed for infants diagnosed with UTI in a single neonatal intensive care unit (NICU) over a 13-year period. RESULTS: Of the 8,241 patients admitted to the NICU during the study period, 137 infants were diagnosed with UTI. Imaging was reviewed for 101 patients. Renal pelvis dilation was found in 34% of patients and vesicoureteral reflux was found in 21%. Renal pelvis dilation was not associated with reflux (OR: 0.53 [95% CI: 0.18-1.5]). The sensitivity of urinalysis to detect a positive culture was 76%, and the specificity was 41%. Tests of cure for bacterial infections were uniformly negative. CONCLUSION: Renal pelvis dilation was common but not associated with reflux among NICU patients diagnosed with UTI. Diagnostic criteria in this population are not well defined, and guidelines are needed for diagnosis and management of UTIs in NICU patients. PMID- 25519203 TI - Functionally reciprocal mutations of the prolactin signalling pathway define hairy and slick cattle. AB - Lactation, hair development and homeothermy are characteristic evolutionary features that define mammals from other vertebrate species. Here we describe the discovery of two autosomal dominant mutations with antagonistic, pleiotropic effects on all three of these biological processes, mediated through the prolactin signalling pathway. Most conspicuously, mutations in prolactin (PRL) and its receptor (PRLR) have an impact on thermoregulation and hair morphology phenotypes, giving prominence to this pathway outside of its classical roles in lactation. PMID- 25519204 TI - Assessing self-management in patients with diabetes mellitus type 2 in Germany: validation of a German version of the Summary of Diabetes Self-Care Activities measure (SDSCA-G). AB - BACKGROUND: One of the most widely used self-reporting tools assessing diabetes self-management in English is the Summary of Diabetes Self-Care Activities (SDSCA) measure. To date there is no psychometric validated instrument in German to assess self-management in patients with diabetes mellitus. Therefore, this study aimed to translate the SDSCA into German and examine its psychometric properties. METHODS: The English version of the SDSCA was translated into German following the guidelines for cultural adaptation. The German version of the SDSCA (SDSCA-G) was administered to a random sample of 315 patients with diabetes mellitus type 2. Reliability was analyzed using Cronbach's alpha coefficient and item characteristics were assessed. Exploratory and confirmatory factor analysis (EFA and CFA) were carried out to explore the construct validity. A multivariable linear regression model was used to identify the influence of predictor variables on the SDSCA-G sum score. RESULTS: The Cronbach's alpha for the SDSCA-G (all items) was alpha = 0.618 and an acceptable correlation between the SDSCA-G and Self-management Diabetes Mellitus-Questionnaire (SDQ) (rho = 0.664) was identified. The EFA suggested a four factor construct as did the postulated model. The CFA showed the goodness of fit of the SDSCA-G. However, item 4 was found to be problematic regarding the analysis of psychometric properties. The omission of item 4 yielded an increase in Cronbach's alpha (alpha = 0.631) and improvements of the factor structure and model fit. No statistically significant influences of predictor variables on the SDSCA-G sum score were observed. CONCLUSION: The revised German version of the SDSCA (SDSCA-G) is a reliable and valid tool assessing self-management in adults with type 2 diabetes in Germany. PMID- 25519205 TI - Chondrosarcoma of the nasal cavity in a patient with Maffucci syndrome: case report and review of the literature. AB - INTRODUCTION: Maffucci syndrome is a rare, congenital, non-hereditary mesodermal dysplasia, manifested by multiple enchondromas and hemangiomas. Malignant transformation of these lesions is seen in up to 40% of the cases. CASE REPORT: We present a case of a patient with Maffucci syndrome and an associated chondrosarcoma of the nose. Treatment consisted of surgical resection. Because of the low grade of the tumor, additional treatment, such as radiotherapy, was not necessary. CONCLUSION: Maffucci syndrome is an exceedingly rare mesodermal dysplasia. Its manifestation in the head and neck region is even less common. Malignant transformation of the associated enchondromas is common, and should be considered whenever a change of the clinical course occurs. Random, periodically performed X-ray examinations give little additional information on malignant transformation and are considered useless. PMID- 25519206 TI - Nano-porous architecture of N-doped carbon nanorods grown on graphene to enable synergetic effects of supercapacitance. AB - A novel nano-porous 3D architecture of N-doped carbon nanorods arrays grown on the surface of graphene has been prepared by carbonizing polyaniline/graphene oxide (PANI-GO) composite with PANI nanorod arrays on both sides of GO nanosheets. The obtained carbon materials are entirely composed of regularly grown carbon nanorods on graphene with height of about 100 nm and width about 30 nm, showing porous property due to the decomposition of PANI chains. The morphology of PANI grown on GO at the different growth stages was investigated to demonstrate the mechanism of the finally hierarchical architecture formation. Due to its large specific surface area and incorporation of the nitrogen groups into the carbon matrix, the obtained 3D carbon material enhances the ionic transport and the super-capacitance by synergetic effect of both double-layer and faradaic capacitances. This study provides a controllable approach to fabricate hierarchical carbon material based on conducting polymers and graphene oxide with promising applications in the high-rate electrode material of supercapacitors. PMID- 25519207 TI - Subclinical and clinical contrast-induced acute kidney injury: data from a novel blood marker for determining the risk of developing contrast-induced nephropathy (ENCINO), a prospective study. AB - OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL) is produced in response to tubular injury. Contrast-induced acute kidney injury (CI-AKI) is associated with adverse outcomes in chronic kidney disease (CKD) patients. We sought to characterize blood NGAL level and the degree of kidney injury in CKD patients who underwent coronary angiography. METHODS: This study was a prospective, blinded assessment of blood samples obtained from patients with estimated glomerular filtration rates (eGFRs) between 15 and 90 mL/min/1.73 m2 undergoing elective coronary angiography with iodinated contrast. Blood NGAL and serum creatinine were measured at baseline, 1, 2, 4, 6, 12, 24 and 48 h after contrast administration. RESULTS: A total of 63 subjects with a mean eGFR of 48.17+/-16.45 mL/min/1.73 m2 were enrolled. There was a graded increase in baseline NGAL levels across worsening stages of CKD (p=0.0001). Post-procedure NGAL increased from baseline in each stage of CKD. Eight (12.7%) patients were diagnosed with CI-AKI by diagnostic criteria of 2012 KDIGO definition of CI-AKI, and seven (11.1%) patients developed subclinical CI-AKI defined by a twofold or greater rise in NGAL. There was no relationship between baseline eGFR and diabetes on the composite outcome of subclinical and clinical CI-AKI. CONCLUSIONS: Baseline and post-procedure NGAL are progressively elevated according to the baseline stage of CKD. Using a twofold rise in NGAL, 46.7% of composite CI-AKI is detected and complements the 53.3% of cases identified using KDIGO criteria. Traditional risk predictors were not independently associated with this composite outcome. PMID- 25519208 TI - Effects of melatonin on the serum levels of pro-inflammatory cytokines and tissue injury after renal ischemia reperfusion in rats. AB - We investigated the changes in the serum levels of tumor necrosis factor (TNF) alpha and interleukin (IL)-6, the pro-inflammatory cytokines, and the possible effect of melatonin on the modulation of these inflammatory molecules after renal ischemia reperfusion (IR). The study was carried out in the laboratory of Department of Pharmacology. Forty-six male Wistar albino rats were divided into five groups as control (n=6), positive control (n=4), sham (n=12), renal IR (n=12), and renal IR melatonin (n=12). After 1 h renal pedicle occlusion, the blood samples were taken for the measurement of cytokine levels at second hour of the reperfusion. The rats were sacrificed after 24 h of reperfusion for histopathological evaluation. Melatonin or vehicle was administrated to IR rats. Lipopolysaccharide (LPS) was administered to the positive control group and the blood was taken at fourth hour. Serum TNF-alpha levels increased significantly in renal IR and LPS groups. Serum IL-6 levels were not different from control except the LPS group. There was no significant correlation between the serum TNF-alpha levels and the histopathological score after renal IR. Melatonin treatment reversed the increase of serum TNF-alpha levels and histopathological injury in renal tissue after renal IR. Melatonin may have a protective effect by reducing the serum level of TNF-alpha in renal IR. PMID- 25519209 TI - Protective effect of baicalein on renal ischemia/reperfusion injury in the rat. AB - OBJECTIVE: To investigate the protective effect and the mechanism of baicalein (Bai) in rats with renal ischemia-reperfusion injury (RIRI). METHODS: Twenty-four male Sprague-Dawley rats were divided into three groups: sham, IR, and IR+Bai. Bai was administered by tail vein injection (30 mg/kg) 30 min before reperfusion in the IR+Bai group. The IR group and sham group received saline vehicle via the intravenous route. RESULTS: Rats that underwent RIRI exhibited renal functional impairment, histological changes, significantly increased advanced oxidation protein product (AOPP) and malondialdehyde (MDA) levels (p<0.01), and ICAM-1 and MCP-1 protein and mRNA expression were significantly upregulated (p<0.01). Administration of Bai reduced AOPP and MDA levels, significantly inhibited expression of inflammatory factors (p<0.05), and markedly improved renal function. CONCLUSION: Bai promotes the recovery of renal function in established acute RIRI, and alleviates kidney injury in a rat model. PMID- 25519210 TI - Evaluation of relationship between sexual functions, depression and quality of life in patients with chronic kidney disease at predialysis stage. AB - AIM: The relation of chronic kidney disease (CKD) with metabolic, psychiatric and endocrinologic disorder is well-known. Depressive mood and sexual dysfunction are frequently observed as renal functions deteriorate. We aimed to analyze the relationship of sexual dysfunction, depressive mood and life quality in patients with CKD at predialysis stage. PATIENTS AND METHODS: Fifty-three patients; 27 female and 26 male with CKD who had estimated glomerular filtration rate (eGFR) between 15 and 90 mL/min and followed up in the Nephrology Department, Bursa Sevket Yilmaz Education and Research Hospital, were enrolled. Age- and sex matched 20 female and 20 male healthy control subjects were assigned to the control group. Detailed medical and sexual history was obtained by using Female Sexual Function Index (FSFI), Erectile Function International Evaluation Form (IEFF), Short form (SF) 36 Form and Beck Depression Questionnaire (BDI). Biochemical and hormonal parameters including urea, creatinine, uric acid, sedimentation rate, c-reactive protein, total testosterone, DHEA-S, FSH, LH, TSH, estradiol and prolactin were analyzed. FINDINGS: Depression was observed in 12 male (46%) and 14 female (51%) patients. The frequency of depression among male patients and control subjects was similar, however, significantly higher in female patients than female controls (p=0.036). Physical function score, physical role score and pain score in SF 36 of entire patients were significantly lower than controls (p=0.0001, 0.0001, 0.001, respectively). The frequency of depression was similar between patients and controls (p>0.05). When SF 36 tests of male and female patients were compared, general health status, vitality and mental health status were significantly better in male patients (p=0.005, 0.016, 0.035, respectively). SF 36 scores of female patients were significantly lower than female controls (p=0.0001). The frequency of erectile dysfunction (ED) was similar between male patients (84%) and controls (75%) (p=0.62). On the other hand, sexual dysfunction was significantly higher in female patients when compared to female controls (92% vs. 30%; p=0.0001). CONCLUSION: We showed that sexual dysfunction and depression are more frequent among female patients with CKD at predialysis stage; however, it does not have significant impact on life quality. When life quality of female and male patients was compared, general health status, vitality and mental health status of female patients were poorer. We failed to demonstrate a relationship between sexual dysfunction and sex hormone level. PMID- 25519211 TI - Snapshotted glass and gel transitions of stable colloidal dispersions after shear driven aggregation in a microchannel. AB - Intense shear can lead to aggregation of colloids that are highly stable at rest. The aggregation process typically has an induction time, and then becomes explosive, leading to rapid phase transitions. We study the phase evolution during shear-driven aggregation in a short microchannel (MC) under intense shear for a colloid with a high interaction energy barrier that ensures high stability of particles and clusters before and after intense shear. The short residence time allows us to snapshot the phase evolution by repeatedly cycling the colloid in the MC. It is found that, depending on the particle concentration, in addition to a fluid of clusters and a solid-like gel, there is another solid-like state between them: Wigner glass of clusters. Their transitions occur over a large range of particle concentrations. We have proposed a phase diagram that describes how the transitions of the three phases evolve in the aggregation steady state in the colloidal interaction vs. particle concentration plane. PMID- 25519212 TI - Previously diagnosed influenza infections and the risk of developing epilepsy. AB - Several epidemiological studies suggest a possible involvement of viral infection in the development of epilepsy. While recent research from in vitro studies increasingly supports the role of herpes simplex virus type 1 (HSV-1) in the pathogenesis of epilepsy, little is known about the role of other viral infections such as influenza. Using data from the Clinical Practice Research Datalink (CPRD), we conducted a matched case-control analysis to assess the association between GP-diagnosed influenza infections and the risk of developing an incident diagnosis of epilepsy. During the study period 11 244 incident epilepsy cases and 44 976 matched control patients were identified. Prior exposure to influenza was reported in 7.5% of epilepsy cases and 6.7% of controls [adjusted odds ratio (aOR) 1.12, 95% confidence interval (CI) 1.03-1.22]. Prior history of 'complicated influenza', i.e. influenza associated with a possible super-infection, was associated with a slightly increased epilepsy risk (aOR 1.64, 95% CI 1.10-2.46), particularly if recorded within the 2 months preceding the epilepsy diagnosis (aOR 6.03, 95% CI 1.10-33.2). Our findings suggest that prior influenza exposure does not appear to materially alter the risk of developing epilepsy. By contrast, influenza episodes accompanied by complications were associated with a slightly increased epilepsy risk. PMID- 25519213 TI - Spinal cord ependymomas and the appearance of other de novo tumors: a systematic review. AB - INTRODUCTION: Ependymomas are rare glial tumors of the brain representing less than 5% of brain tumors. However, spinal cord ependymomas in adults account for over 60% of all ependymomas including those arising from the filum terminale and only 40% are intracranial. Reports of the appearance of another neoplasia at a different location in patients with spinal ependymoma are scarce. METHODS: We searched PubMed for studies related to spinal cord ependymomas published over the last 30 years (from January 1984) and retrieved 1197. RESULTS: We identified only two studies that met our criteria and we found an incidence of 9% of secondary neoplasias after treatment for spinal ependymoma. The neoplasms were diagnosed from 2 months to 20 years after patients underwent surgery for intraspinal ependymoma. These included pancreatic cancer, prostate cancer, Hodgkin lymphoma, intracranial meningioma, mucin-producing pulmonary adenocarcinoma, gastric cancer and astrocytoma. CONCLUSIONS: The genetic abnormalities affecting patients with spinal ependymomas may indicate a predisposition to the development of secondary cancers or a general failure of the repairing mechanism in their DNA. The unaffected survival rates in those individuals permit for a long period the accumulation of different mutations on the genome and thus the appearance of a second cancer. However, more studies are needed, particularly in young patients with high survival rates. PMID- 25519219 TI - Patient self-assessment of flare in rheumatoid arthritis: criterion and concurrent validity of the Flare instrument. AB - The French Flare instrument (FI) aims to identify flares in rheumatoid arthritis between consultation. The objective of the present study was to present both concurrent and criterion validity of the Danish version of FI, as compared to DAS28-CRP. The study was a cross-sectional study comparing FI with DAS28-CRP among patients with rheumatoid arthritis (RA) in connection with the same outpatient visit. The study population consisted of 117 prevalent patients diagnosed with RA according to the ACR 1987/2010 criteria. Consecutive patients were included in the study in relation to their outpatient treatment at the Department of Rheumatology, Aarhus University Hospital, Denmark between 01 October 2012 and 31 December 2012. The sensitivity and specificity were 85.4 (95 % CI, 72.2; 93.9) and 50.7 (95 % CI, 38.4; 63.0), respectively. The positive predictive value was 53.6 (95 %CI, 47.0; 60.1) and the negative predictive value 83.9 (95 % CI, 71.7; 91.5). Positive and negative likelihood ratio were 1.73(95 % CI, 1.33; 2.26) and 0.29 (95 % CI, 0.14; 0.59). Tests with high sensitivity and small LR are most useful for ruling out the disease. Hence, our findings indicate that FI works well in ruling out a flare among patients with RA. PMID- 25519221 TI - Capturing molecules with plasmonic nanotips in microfluidic channels by dielectrophoresis. AB - Over the last decades, different concepts have been established for the use of plasmonic nanostructures in sensing applications. One challenge in this context lies in delivering the analyte of interest to the location of the nanostructures and selectively attaching it to their surfaces. Here we present a method for the collection and concentration of molecules on arrays of metallic nanocones, making use of the high electric field gradients at the nanotips. For this purpose, the nanocones are integrated into a microfluidic channel and used as nanoelectrodes. By applying an AC voltage, dielectrophoresis is used to capture molecules from the channel region near the nanocones. Simulations of the dielectrophoretic forces in the channel are presented as well as experimental proof of the proposed method. After attachment of the molecules, optical read-out techniques can directly be performed on the plasmonic nanostructures. PMID- 25519220 TI - Cytotoxicity effect of degraded and undegraded kappa and iota carrageenan in human intestine and liver cell lines. AB - BACKGROUND: Carrageenan is a linear sulphated polysaccharide extracted from red seaweed of the Rhodophyceae family. It has broad spectrum of applications in biomedical and biopharmaceutical field. In this study, we determined the cytotoxicity of degraded and undegraded carrageenan in human intestine (Caco-2; cancer and FHs 74 Int; normal) and liver (HepG2; cancer and Fa2N-4; normal) cell lines. METHODS: Food grade k-carrageenan (FGKC), dried sheet k-carrageenan (DKC), commercial grade k-carrageenan (CGKC), food grade i-carrageenan (FGIC) and commercial grade i-carrageenan (CGIC) were dissolved in hydrochloric acid and water to prepare degraded and undegraded carrageenan, respectively. Carrageenan at the concentration range of 62.5 - 2000.0 MUg mL(-1) was used in the study. MTT assay was used to determine the cell viability while the mode of cell death was determined by May-Grunwald Giemsa (MGG) staining, acridine orange-ethidium bromide (AO/EtBr) staining, agarose gel electrophoresis and gene expression analysis. RESULTS: Degraded FGKC, DKC and CGKC showed IC50 in 24, 48 and 72 hours treated Caco-2, FHs 74 Int, HepG2 and Fa2N-4 cell lines as tested by MTT assay. Degraded FGIC and CGIC only showed its toxicity in Fa2N-4 cells. The characteristics of apoptosis were demonstrated in degraded k-carrageenan treated Caco-2, FHs 74 Int, HepG2 and Fa2N-4 cells after MGG staining. When Caco-2 and HepG2 cells were undergone AO/EtBr staining, chromatin condensation and nuclear fragmentation were clearly seen under the microscope. However, DNA ladder was only found in HepG2 cells after gel electrophoresis analysis. Degraded k carrageenan also inactivated PCNA, Ki-67 and survivin gene in HepG2. On the other hand, undegraded FGKC, DKC, CGKC, FGIC and CGIC treated cells showed no cytotoxic effect after analyzed by the same analyses as in degraded carrageenan. CONCLUSION: Degraded k-carrageenan inhibited cell proliferation in Caco-2, FHs 74 Int, HepG2 and Fa2N-4 cell lines and the anti-proliferative effect was related to apoptosis together with inactivation of cell proliferating genes as determined by morphological observation and molecular analysis. However, no cytotoxic effect was found in undegraded carrageenan towards normal and cancer intestine and liver cell lines. PMID- 25519222 TI - CMS reimbursement reform and the incidence of hospital-acquired pulmonary embolism or deep vein thrombosis. AB - BACKGROUND: In October 2008, the Centers for Medicare & Medicaid Services (CMS) stopped reimbursing hospitals for the marginal cost of treating certain preventable hospital-acquired conditions. OBJECTIVE: This study evaluates whether CMS's refusal to pay for hospital-acquired pulmonary embolism (PE) or deep vein thrombosis (DVT) resulted in a lower incidence of these conditions. DESIGN: We employ difference-in-differences modeling using 2007-2009 data from the Nationwide Inpatient Sample, an all-payer database of inpatient discharges in the U.S. Discharges between 1 January 2007 and 30 September 2008 were considered "before payment reform;" discharges between 1 October 2008 and 31 December 2009 were considered "after payment reform." Hierarchical regression models were fit to account for clustering of observations within hospitals. PARTICIPANTS: The "before payment reform" and "after payment reform" incidences of PE or DVT among 65-69-year-old Medicare recipients were compared with three different control groups of: a) 60-64-year-old non-Medicare patients; b) 65-69-year-old non Medicare patients; and c) 65-69-year-old privately insured patients. Hospital reimbursements for the control groups were not affected by payment reform. INTERVENTION: CMS payment reform for hospital-based reimbursement of patients with hip and knee replacement surgeries. MAIN MEASURES: The outcome was the incidence proportion of hip and knee replacement surgery admissions that developed pulmonary embolism or deep vein thrombosis. KEY RESULTS: At baseline, pulmonary embolism or deep vein thrombosis were present in 0.81% of all hip or knee replacement surgeries for Medicare patients aged 65-69 years old. CMS payment reform resulted in a 35% lower incidence of hospital-acquired pulmonary embolism or deep vein thrombosis in these patients (p = 0.015). Results were robust to sensitivity analyses. CONCLUSION: CMS's refusal to pay for hospital acquired conditions resulted in a lower incidence of hospital-acquired pulmonary embolism or deep vein thrombosis after hip or knee replacement surgery. Payment reform had the desired direction of effect. PMID- 25519223 TI - A rare manifestation of tuberous xanthomas. PMID- 25519224 TI - Trends in prevalent and incident opioid receipt: an observational study in Veterans Health Administration 2004-2012. AB - BACKGROUND: Improved understanding of temporal and regional trends may support safe and effective prescribing of opioids. OBJECTIVE: We describe national, regional, and facility-level trends and variations in opioid receipt between fiscal years (FY) 2004 and 2012. DESIGN: Observational cohort study using Veterans Health Administration (VHA) administrative databases. PARTICIPANTS: All patients receiving primary care within 137 VHA healthcare systems during a given study year and receiving medications from VHA one year before and during a given study year. MAIN MEASURES: Prevalent and incident opioid receipt during each year of the study period. KEY RESULTS: The overall prevalence of opioid receipt increased from 18.9% of all veteran outpatients in FY2004 to 33.4% in FY2012, a 76.7% relative increase. In FY2012, women had higher rates of prevalent opioid receipt than men (42.4% vs. 32.9%), and the youngest veterans (18-34 years) had higher prevalent opioid receipt compared to the oldest veterans (>= 80 years) (47.6% vs. 17.9%). All regions in the United States saw increased rates of prevalent opioid receipt during this time period. Prevalence rates varied widely by facility: in FY2012, the lowest-prescribing facility had a rate of 13.5%, and the highest of 50.8%. Annual incident opioid receipt increased from 8.8% in FY2004 to 10.2% in FY2011, with a decline to 9.8% in FY2012. Incident prescribing increased at some facilities and decreased at others. Facilities with high prevalent prescribing tended to have flat or decreasing incident prescribing rates during the study time frame. CONCLUSIONS: Rates of opioid receipt increased throughout the study time frame, with wide variation in prevalent and incident rates across geographical region, sex, and age groups. Prevalence and incidence rates reflect distinct prescribing practices. Areas with the highest prevalence tended to have lower increases in incident opioid receipt over the study period. This likely reflects facility-level variations in prescribing practices as well as baseline rates of prevalent use. Future work assessing opioid prescribing should employ methodologies to account for and interpret both prevalent and incident opioid receipt. PMID- 25519227 TI - Molecular dynamics simulation of spin-lattice NMR relaxation in poly-L-lysine dendrimers: manifestation of the semiflexibility effect. AB - NMR relaxation experiments are widely used to investigate the local orientation mobility in dendrimers. In particular, the NMR method allows one to measure the spin-lattice relaxation rate, 1/T1, which is connected with the orientational autocorrelation function (ACF) of NMR active groups. We calculate the temperature (Theta) and frequency (omega) dependences of the spin-lattice NMR relaxation rates for segments and NMR active CH2 groups in poly-L-lysine (PLL) dendrimers in water, on the basis of full-atomic molecular dynamics simulations. It is shown that the position of the maximum of 1/T1(omega) depends on the location of the segments inside the dendrimer. This dependence of the maximum is explained by the restricted flexibility of the dendrimer. Such behavior has been predicted recently by the analytical theory based on the semiflexible viscoelastic model. The simulated temperature dependences of 1/T1 for terminal and inner groups in PLL dendrimers of n = 2 and n = 4 generations dissolved in water are in good agreement with the NMR experimental data, which have been obtained for these systems previously by us. It is shown that in the case of PLL dendrimers, the traditional procedure of the interpretation of NMR experimental data - when smaller values of 1/T1 correspond to higher orientation mobility - is applicable to the whole accessible frequency interval only for the terminal groups. For the inner groups, this procedure is valid only at low frequencies. PMID- 25519232 TI - Hickam's dictum and the rare convergence of antisynthetase syndrome and hemoglobin SC disease. PMID- 25519233 TI - A cross-sectional study of doctors', managers' and public representatives' views regarding acceptable level of risk in discharges from the emergency department. AB - BACKGROUND: Discharging a patient from the emergency department (ED) always involves some risk of a poor outcome. AIM: This study examined the hypothesis that there would be an increasing gradient of risk aversion from physicians through clinicians in management and managers to public representatives regarding an acceptable level of risk when considering discharging a patient from the ED. METHODS: An internet survey was conducted among 180 consultant physicians, 47 clinicians involved in management, 143 senior healthcare managers and 418 public representatives in Ireland. Subjects asked to assess three clinical vignettes for the level of risk for death within the next week that could have been prevented by admission at which discharge from the ED would be acceptable. Choices ranged from 1/100 risk of death to 'no risk of death is acceptable'. The median of each subject's responses was the primary outcome measure. RESULTS: The response rates were 64% for consultant physicians, 57% for clinicians in management, 53% for managers and 29% for public representatives. The median risk choice (interquartile range) was 1/1000 (1/500-1/5000), 1/1000 (1/500-1/10,000), 1/5000 (1/1000-1/10,000) and 1/10,000 (1/1000-0) in the respective groups (Jonckheere Terpstra test P < 0.0001). All pairwise comparisons between doctors and managers or public representatives were significant. Older clinicians were significantly more risk tolerant than younger clinicians. CONCLUSIONS: There are significant differences in risk tolerance when considering discharge from the ED between different groups with doctors being most risk tolerant and politicians most risk averse. PMID- 25519225 TI - Genetic mutation of p53 and suppression of the miR-17~92 cluster are synthetic lethal in non-small cell lung cancer due to upregulation of vitamin D Signaling. AB - Lung cancer is the leading cause of cancer-related fatalities. Recent success developing genotypically targeted therapies, with potency only in well-defined subpopulations of tumors, suggests a path to improving patient survival. We used a library of oligonucleotide inhibitors of microRNAs, a class of posttranscriptional gene regulators, to identify novel synthetic lethal interactions between miRNA inhibition and molecular mechanisms in non-small cell lung cancer (NSCLC). Two inhibitors, those for miR-92a and miR-1226*, produced a toxicity distribution across a panel of 27 cell lines that correlated with loss of p53 protein expression. Notably, depletion of p53 was sufficient to confer sensitivity to otherwise resistant telomerase-immortalized bronchial epithelial cells. We found that both miR inhibitors cause sequence-specific downregulation of the miR-17~92 polycistron, and this downregulation was toxic only in the context of p53 loss. Mechanistic studies indicated that the selective toxicity of miR-17~92 polycistron inactivation was the consequence of derepression of vitamin D signaling via suppression of CYP24A1, a rate-limiting enzyme in the 1alpha,25 dihydroxyvitamin D3 metabolic pathway. Of note, high CYP24A1 expression significantly correlated with poor patient outcome in multiple lung cancer cohorts. Our results indicate that the screening approach used in this study can identify clinically relevant synthetic lethal interactions and that vitamin D receptor agonists may show enhanced efficacy in p53-negative lung cancer patients. PMID- 25519234 TI - Paget-Schroetter syndrome. PMID- 25519235 TI - High alcohol consumption and the risk of renal damage: a systematic review and meta-analysis. AB - BACKGROUND: The risk of renal damage in patients with high alcohol consumption is controversial. The objective of this meta-analysis was to evaluate the associations between high alcohol consumption and progression of kidney damage including chronic kidney disease (CKD), end-stage renal disease (ESRD) and proteinuria. METHODS: A literature search was performed using MEDLINE, EMBASE and Cochrane Databases from inception through August 2014 to identify studies investigating the association between high alcohol consumption and CKD, ESRD or proteinuria. Studies that reported odds ratios, relative risks or hazard ratios comparing the risk of CKD, ESRD or proteinuria in patients consuming high amount of alcohol versus those who did not consume alcohol were included. Pooled risk ratios (RRs) and 95% confidence interval (CI) were calculated using a random effect, generic inverse variance method. RESULTS: Twenty studies with 292 431 patients were included in our analysis to assess the associations between high alcohol consumption and progression of kidney damage. The pooled RRs of CKD, proteinuria and ESRD in patients with high alcohol consumption were 0.83 (95% CI: 0.71-0.98), 0.85 (95% CI: 0.62-1.17) and 1.00 (95% CI: 0.55-1.82), respectively. Post hoc analysis assessing the sex-specific association between high alcohol consumption and CKD demonstrated pooled RRs of 0.72 (95% CI: 0.57-0.90) in males and 0.78 (95% CI: 0.58-1.03) in females. CONCLUSIONS: Our study demonstrates an inverse association between high alcohol consumption and risk for developing CKD in males. There is no significant association between high alcohol consumption and the risk for developing proteinuria or ESRD. PMID- 25519236 TI - Prevalence and Impact of Intimate Partner Violence (IPV) Among an Ethnic Minority Population. AB - The present study examined the prevalence of lifetime experiences of physical and psychological intimate partner violence (IPV) among members of the Turkish ethnic minority population in Flanders. In addition, this study explored how lifetime IPV victimization affects ethnic minority victims' current mental, relational, and sexual well-being. Using a population-based representative sample, data from 392 adult Turkish women and men were investigated. Lifetime experiences of physical violence were reported by 14.3% of the Turkish respondents, while 66.0% reported at least one incidence of psychological abuse. Women were much more likely than men to report physical IPV victimization, but no gender differences were found for psychological IPV. With regard to the impact of IPV, it was found that lifetime IPV experiences do not appear to affect victims' current mental health. However, higher levels of physical and/or psychological IPV victimization were related to increased levels of relationship dissatisfaction, anxious and avoidant attachment orientations, sexual dissatisfaction, sexual dysfunction (with distress), and to decreased levels of sexual communication. These adverse relational and sexual outcomes of IPV victimization were mainly present among women but were also, to a lesser degree, relevant for men. PMID- 25519237 TI - Alcohol Use, Alcohol-Related Outcome Expectancies, and Partner Aggression Among Males Court-Mandated to Batterer Intervention Programs: A Brief Report. AB - Additional work is needed to determine how and/or why the relationship between alcohol use and increased risk of partner aggression (PA) exists. Researchers have begun to examine whether alcohol-related outcome expectancies (i.e., beliefs about the cognitive and behavioral effects of alcohol) are associated with PA irrespective of alcohol use. We examined the relationship between alcohol use, alcohol expectancies, and PA among 360 males arrested for a domestic violence offense and court-mandated to treatment. Results indicate that certain alcohol expectancies do play a role in the relationship between alcohol use and some forms of PA. PMID- 25519238 TI - SPECT findings in autism spectrum disorders and medically refractory seizures. AB - A high rate of seizures and electroencephalogram abnormalities has been noted in individuals with autism spectrum disorders (ASDs). Common underlying neurodevelopmental abnormalities may exist in the brains of individuals with both ASDs and epilepsy. Single-photon emission computed tomography (SPECT) studies of the brain have provided sensitive brain function findings. Such studies often reveal not only localized areas of hyperperfusion, which could be related to the seizure-onset zone, but also localized areas of hypoperfusion that may correlate with the focal reductions in function observed in the prefrontal lobes, cingulate gyrus, superior temporal gyrus, and mesial temporal lobes of many individuals with both ASDs and epilepsy. The focal neuronal dysfunction revealed by SPECT could be caused by aberrant neuronal connectivity. This article is part of a Special Issue entitled "Autism and Epilepsy". PMID- 25519241 TI - Enteric neural crest cells regulate vertebrate stomach patterning and differentiation. AB - In vertebrates, the digestive tract develops from a uniform structure where reciprocal epithelial-mesenchymal interactions pattern this complex organ into regions with specific morphologies and functions. Concomitant with these early patterning events, the primitive GI tract is colonized by the vagal enteric neural crest cells (vENCCs), a population of cells that will give rise to the enteric nervous system (ENS), the intrinsic innervation of the GI tract. The influence of vENCCs on early patterning and differentiation of the GI tract has never been evaluated. In this study, we report that a crucial number of vENCCs is required for proper chick stomach development, patterning and differentiation. We show that reducing the number of vENCCs by performing vENCC ablations induces sustained activation of the BMP and Notch pathways in the stomach mesenchyme and impairs smooth muscle development. A reduction in vENCCs also leads to the transdifferentiation of the stomach into a stomach-intestinal mixed phenotype. In addition, sustained Notch signaling activity in the stomach mesenchyme phenocopies the defects observed in vENCC-ablated stomachs, indicating that inhibition of the Notch signaling pathway is essential for stomach patterning and differentiation. Finally, we report that a crucial number of vENCCs is also required for maintenance of stomach identity and differentiation through inhibition of the Notch signaling pathway. Altogether, our data reveal that, through the regulation of mesenchyme identity, vENCCs act as a new mediator in the mesenchymal-epithelial interactions that control stomach development. PMID- 25519240 TI - Are outcomes after total knee arthroplasty worsening over time? A time-trends study of activity limitation and pain outcomes. AB - BACKGROUND: To examine whether function and pain outcomes of patients undergoing primary total knee arthroplasty (TKA) are changing over time. METHODS: The Mayo Clinic Total Joint Registry provided data for time-trends in preoperative and 2 year post-operative activity limitation and pain in primary TKA patients from 1993-2005. We used chi-square test and analysis for variance, as appropriate. Multivariable-adjusted analyses were done using logistic regression. RESULTS: In a cohort of 7,229 patients who underwent primary TKA during 1993-2005, mean age was 68.4 years (standard deviation (SD), 9.8), mean BMI was 31.1 (SD, 6.0) and 55% were women. Crude estimates showed that preoperative moderate-severe overall limitation were seen in 7.3% fewer patients and preoperative moderate-severe pain in 2.7% more patients in 2002-05, compared to 1992-95 (p < 0.001 for both). At 2 years, crude estimates indicated that compared to 1992-95, moderate-severe post TKA overall limitation was seen in 4.7% more patients and moderate-severe post TKA pain in 3.6% more patients in 2002-05, both statistically significant (p <= 0.018) and clinically meaningful. In multivariable-adjusted analyses that adjusted for age, sex, anxiety, depression, Deyo-Charlson index, body mass index and preoperative pain/limitation, patients had worse outcomes 2-year post-TKA in 2002-2005 compared to 1993-95 with an odds ratio (95% confidence interval (CI); p value) of 1.34 (95% CI: 1.02, 1.76, p = 0.037) for moderate-severe activity limitation and 1.79 (95% CI: 1.17, 2.75, p = 0.007) for moderate-severe pain. CONCLUSION: Patient-reported function and pain outcomes after primary TKA have worsened over the study period 1993-95 to 2002-05. This time-trend is independent of changes in preoperative pain/limitation and certain patient characteristics. PMID- 25519239 TI - Mitochondrial protein sorting as a therapeutic target for ATP synthase disorders. AB - Mitochondrial diseases are systemic, prevalent and often fatal; yet treatments remain scarce. Identifying molecular intervention points that can be therapeutically targeted remains a major challenge, which we confronted via a screening assay we developed. Using yeast models of mitochondrial ATP synthase disorders, we screened a drug repurposing library, and applied genomic and biochemical techniques to identify pathways of interest. Here we demonstrate that modulating the sorting of nuclear-encoded proteins into mitochondria, mediated by the TIM23 complex, proves therapeutic in both yeast and patient-derived cells exhibiting ATP synthase deficiency. Targeting TIM23-dependent protein sorting improves an array of phenotypes associated with ATP synthase disorders, including biogenesis and activity of the oxidative phosphorylation machinery. Our study establishes mitochondrial protein sorting as an intervention point for ATP synthase disorders, and because of the central role of this pathway in mitochondrial biogenesis, it holds broad value for the treatment of mitochondrial diseases. PMID- 25519242 TI - VEGF189 binds NRP1 and is sufficient for VEGF/NRP1-dependent neuronal patterning in the developing brain. AB - The vascular endothelial growth factor (VEGFA, VEGF) regulates neurovascular patterning. Alternative splicing of the Vegfa gene gives rise to three major isoforms termed VEGF121, VEGF165 and VEGF189. VEGF165 binds the transmembrane protein neuropilin 1 (NRP1) and promotes the migration, survival and axon guidance of subsets of neurons, whereas VEGF121 cannot activate NRP1-dependent neuronal responses. By contrast, the role of VEGF189 in NRP1-mediated signalling pathways has not yet been examined. Here, we have combined expression studies and in situ ligand-binding assays with the analysis of genetically altered mice and in vitro models to demonstrate that VEGF189 can bind NRP1 and promote NRP1 dependent neuronal responses. PMID- 25519243 TI - Postnatal subventricular zone progenitors switch their fate to generate neurons with distinct synaptic input patterns. AB - New granule cell neurons (GCs) generated in the neonatal and adult subventricular zone (SVZ) have distinct patterns of input synapses in their dendritic domains. These synaptic input patterns determine the computations that the neurons eventually perform in the olfactory bulb. We observed that GCs generated earlier in postnatal life had acquired an 'adult' synaptic development only in one dendritic domain, and only later-born GCs showed an 'adult' synaptic development in both dendritic domains. It is unknown to what extent the distinct synaptic input patterns are already determined in SVZ progenitors and/or by the brain circuit into which neurons integrate. To distinguish these possibilities, we heterochronically transplanted retrovirally labeled SVZ progenitor cells. Once these transplanted progenitors, which mainly expressed Mash1, had differentiated into GCs, their glutamatergic input synapses were visualized by genetic tags. We observed that GCs derived from neonatal progenitors differentiating in the adult maintained their characteristic neonatal synapse densities. Grafting of adult SVZ progenitors to the neonate had a different outcome. These GCs formed synaptic densities that corresponded to neither adult nor neonatal patterns in two dendritic domains. In summary, progenitors in the neonatal and adult brain generate distinct GC populations and switch their fate to generate neurons with specific synaptic input patterns. Once they switch, adult progenitors require specific properties of the circuit to maintain their characteristic synaptic input patterns. Such determination of synaptic input patterns already at the progenitor-cell level may be exploited for brain repair to engineer neurons with defined wiring patterns. PMID- 25519244 TI - Calm1 signaling pathway is essential for the migration of mouse precerebellar neurons. AB - The calcium ion regulates many aspects of neuronal migration, which is an indispensable process in the development of the nervous system. Calmodulin (CaM) is a multifunctional calcium ion sensor that transduces much of the signal. To better understand the role of Ca(2+)-CaM in neuronal migration, we investigated mouse precerebellar neurons (PCNs), which undergo stereotyped, long-distance migration to reach their final position in the developing hindbrain. In mammals, CaM is encoded by three non-allelic CaM (Calm) genes (Calm1, Calm2 and Calm3), which produce an identical protein with no amino acid substitutions. We found that these CaM genes are expressed in migrating PCNs. When the expression of CaM from this multigene family was inhibited by RNAi-mediated acute knockdown, inhibition of Calm1 but not the other two genes caused defective PCN migration. Many PCNs treated with Calm1 shRNA failed to complete their circumferential tangential migration and thus failed to reach their prospective target position. Those that did reach the target position failed to invade the depth of the hindbrain through the required radial migration. Overall, our results suggest the participation of CaM in both the tangential and radial migration of PCNs. PMID- 25519246 TI - Optimization and characterization of gluten-free spaghetti enriched with chickpea flour. AB - This work was focused on the optimization and characterization of maize-based spaghetti fortified with chickpea flour. To the aim, the study has been organized in two subsequent trials. In the first one, the chickpea flour amount added to the spaghetti was continuously increased until the overall sensory quality of pasta reached its sensory threshold. Spaghetti samples loaded with 15% chickpea flour showed poor elasticity and increased firmness, so this concentration represented the highest chickpea flour concentration to be used. The second experimental step was aimed to improve the overall sensory quality of the enriched spaghetti by means of hydrocolloids as pectin, guar flour and agar. Final pasta was characterized for the nutritional composition, the glycemic response and the main quality attributes. The best results were obtained by the addition of guar flour. PMID- 25519245 TI - Canonical Wnt signalling regulates epithelial patterning by modulating levels of laminins in zebrafish appendages. AB - The patterning and morphogenesis of body appendages - such as limbs and fins - is orchestrated by the activities of several developmental pathways. Wnt signalling is essential for the induction of limbs. However, it is unclear whether a canonical Wnt signalling gradient exists and regulates the patterning of epithelium in vertebrate appendages. Using an evolutionarily old appendage - the median fin in zebrafish - as a model, we show that the fin epithelium exhibits graded changes in cellular morphology along the proximo-distal axis. This epithelial pattern is strictly correlated with the gradient of canonical Wnt signalling activity. By combining genetic analyses with cellular imaging, we show that canonical Wnt signalling regulates epithelial cell morphology by modulating the levels of laminins, which are extracellular matrix components. We have unravelled a hitherto unknown mechanism involved in epithelial patterning, which is also conserved in the pectoral fins - evolutionarily recent appendages that are homologous to tetrapod limbs. PMID- 25519247 TI - Novel strategies for capturing health-protective mango phytochemicals in shelf stable food matrices. AB - Cost-effective methods for concentration and stabilization of otherwise perishable mango fruit phytoactives into shelf stable high protein ingredients were developed to combat stunting (malnutrition) in rural Africa. Mango juices complexed with sunflower oil and protein-rich legume flours yielded carotenoid enriched oils and pelleted polyphenol-enriched flour matrices. Carotenoids from juices were concentrated 9-10 times in the fortified sunflower oil. Protein-rich soy and peanut flours captured 2.2-3.2 mg/g polyphenols from the juices. Alternatively, mango juice was sorbed and co-dried with flours, which stably bound the polyphenols, carotenoids, and natural sugars in soy or peanut protein rich matrices. The concentration of provitamin A carotenoids was almost doubled and total polyphenols were enriched 4-5 times higher in the matrices compared to fresh pureed juice. Both strategies require minimal instrumentation, are compatible with rural village dietary practices; and capture the benefits of otherwise perishable seasonal resources by complexing healthful proteins together with phytoactive compounds. PMID- 25519248 TI - Consumer knowledge and attitudes about genetically modified food products and labelling policy. AB - The purpose of this study was to examine the relationship between consumer knowledge, attitudes and behaviours towards foods containing genetically modified organisms (GMOs) and the prevalence of GMO labelling in northern New Jersey supermarkets. This cross-sectional study surveyed 331 adults, New Jersey supermarket customers (mean age 26 years old, 79.8% women). The results show a strong, positive correlation between consumer attitudes towards foods not containing GMOs and purchasing behaviour (Pearson's r = 0.701, p < 0.001) with lesser correlations between knowledge and behaviour (Pearson's r = 0.593, p < 0.001) and knowledge and attitudes (Pearson's r = 0.413, p < 0.001). GMO labelling would assist consumers in making informed purchase decisions. PMID- 25519249 TI - Pomegranate ellagitannins inhibit alpha-glucosidase activity in vitro and reduce starch digestibility under simulated gastro-intestinal conditions. AB - Pomegranate extract was tested for its ability to inhibit alpha-amylase and alpha glucosidase activity. Pomegranate extract strongly inhibited rat intestinal alpha glucosidase in vitro whereas it was a weak inhibitor of porcine alpha-amylase. The inhibitory activity was recovered in an ellagitannins-enriched fraction and punicalagin, punicalin, and ellagic acid were identified as alpha-glucosidase inhibitors (IC(50) of 140.2, 191.4, and 380.9 MUmol/L, respectively). Kinetic analysis suggested that the pomegranate extract and ellagitannins inhibited alpha glucosidase activity in a mixed mode. The inhibitory activity was demonstrated using an in vitro digestion system, mimicking the physiological gastro-intestinal condition, and potatoes as food rich in starch. Pre-incubation between ellagitannins and alpha-glucosidase increased the inhibitory activity, suggesting that they acted by binding to alpha-glucosidase. During digestion punicalin and punicalagin concentration decreased. Despite this loss, the pomegranate extract retained high inhibitory activity. This study suggests that pomegranate ellagitannins may inhibit alpha-glucosidase activity in vitro possibly affecting in vivo starch digestion. PMID- 25519250 TI - Developing NaviCanPlan: A Mobile Web Resource Locator for Cancer Providers and Survivors. AB - As of January, 2012, an estimated 13.7 million persons are living as cancer survivors. This population is expected to grow to nearly 18 million by 2022. While their treatment may be considered successful, many cancer survivors experience long-term physical, emotional, and psychosocial late effects of treatment. Our focus was on community-based cancer care-both rural and urban-as almost 90% of cancer care occurs in community settings, where a full complement of supportive healthcare professionals may not be available. This study describes the results of stakeholder engagement and the feedback processes used to create NaviCanPlan, a mobile web resource locator designed to educate and inform both providers and survivors in finding health-related services, often in noncancer center settings. Individual interviews with survivors and providers regarding resource needs to address a variety of physical and psychosocial late effects were supplemented with site visits, web-based polling, and webinars discussions. Overall, the results indicated a need for a programmatic approach to providing education about community, medical, and nonmedical resources for providers and survivors. Design and content criteria for a web-based mobile resource locator were defined, articulated, and implemented. PMID- 25519251 TI - Estimation of dabigatran plasma concentrations in the perioperative setting. An ex vivo study using dedicated coagulation assays. AB - The perioperative management of dabigatran is challenging, and recommendations based on activated partial thromboplastin time (aPTT) and thrombin time (TT) are unsatisfactory. Dedicated coagulation tests have limitations at plasma concentrations < 50 ng/ml. Therefore, a more sensitive test, which is available 24/7, is required. It was the aim of this study to investigate the performance of the Hemoclot Thrombin Inhibitors(r) LOW (HTI LOW) kit, a diluted thrombin time, and the STA(r) - ECA II(ECA-II) kit, a chromogenic variant of the ecarin clotting time, that were developed to measure low dabigatran concentrations, compared to reference dabigatran analysis by liquid chromatography tandem mass-spectrometry (LC-MS/MS). This study included 33 plasma samples from patients treated with dabigatran etexilate who had plasma concentrations < 200 ng/ml. HTI LOW and ECA II were performed along with HTI, aPTT (STA(r)-C. K.Prest(r) and SynthasIL(r)) and TT (STA(r) - Thrombin). All procedures were performed according to recommendations by the manufacturers. Linear (or curvilinear) correlations and Bland-Altman analyses were calculated. For free dabigatran concentrations < 50 ng/ml, the R2 of linear correlations were 0.69, 0.84 and 0.61, with HTI, HTI LOW and ECA-II, respectively. The R2 for TT, STA(r)-C. K.Prest(r) and SynthasIL(r) were 0.67, 0.42 and 0.15. For HTI, HTI LOW and ECA-II, Bland-Altman analyses revealed mean differences of -6 ng/ml (95 %CI: -25-14 ng/ml), 1 ng/ml (95 %CI: 18-19 ng/ml) and -1 ng/ml (95 %CI: -25-23 ng/ml), demonstrating that tests dedicated to measuring low concentrations are more accurate than HTI. In conclusion, the use of HTI LOW or ECA-II to assess low plasma dabigatran concentrations is supported by our findings. PMID- 25519252 TI - Cordyceps sinensis (a traditional Chinese medicine) for treating chronic kidney disease. AB - BACKGROUND: Cordyceps sinensis (Cordyceps, Dong Chong Xia Cao), a herbal medicine also known as Chinese caterpillar fungus, is one of the most commonly used ingredients in traditional Chinese medicine for the treatment of people with chronic kidney disease (CKD). OBJECTIVES: This review aimed to evaluate the therapeutic effects and potential adverse effects of Cordyceps sinensis for the treatment of people with CKD. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 14 April 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. We also searched CINAHL, AMED, Current Controlled Trials, OpenSIGLE, and Chinese databases including CBM, CMCC, TCMLARS, Chinese Dissertation Database, CMAC and Index to Chinese Periodical Literature. SELECTION CRITERIA: Randomised and quasi randomised trials comparing Cordyceps or its products with placebo, no treatment, or conventional treatment were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two authors independently assessed data quality and extracted data. Statistical analyses were performed using the random-effects model and the results expressed as risk ratio (RR) for dichotomous outcomes or mean difference (MD) for continuous data with 95% confidence intervals (CI). MAIN RESULTS: We included 22 studies that involved 1746 participants. Among people with CKD who were not receiving dialysis, Cordyceps preparations were found to significantly decrease serum creatinine (14 studies, 987 participants): MD -60.76 MUmol/L, 95% CI -85.82 to -35.71); increase creatinine clearance (6 studies, 362 participants): MD 9.22 mL/min, 95% CI 3.10 to 15.34) and reduce 24 hour proteinuria (4 studies, 211 participants: MD -0.15 g/24 h, 95% CI -0.24 to 0.05). However, suboptimal reporting and flawed methodological approaches meant that risk of bias was assessed as high in four studies and unclear in 18 studies, and hence, these results need to be interpreted with caution. AUTHORS' CONCLUSIONS: We found that Cordyceps preparation, as an adjuvant therapy to conventional medicine, showed potential promise to decrease serum creatinine, increase creatine clearance, reduce proteinuria and alleviate CKD-associated complications, such as increased haemoglobin and serum albumin. However, definitive conclusions could not be made because of the low quality of evidence. PMID- 25519253 TI - Interferon gamma release assay in the diagnosis of tuberculous mastitis. AB - Tuberculous mastitis is rare, especially in Western countries. We describe a case where the interferon gamma release assay blood test led to diagnosis and successful treatment of the disease. PMID- 25519255 TI - New series about medical publishing. PMID- 25519256 TI - A meta-analysis of fast track surgery for patients with gastric cancer undergoing gastrectomy. AB - INTRODUCTION: This meta-analysis evaluated the safety and efficacy of fast track surgery (FTS) for patients with gastric cancer undergoing gastrectomy. METHODS: Randomised controlled trials (RCTs) published between 1 January 1995 and 21 June 2013 comparing FTS with conventional perioperative care for patients with gastric cancer undergoing gastrectomy were identified in the PubMed, EmbaseTM and Cochrane Library databases, and were analysed systematically using RevMan software (Nordic Cochrane Centre, Copenhagen, Denmark). RESULTS: Seven RCTs (524 patients) were analysed. Compared with conventional perioperative care, FTS treatment with/without laparoscopy was associated with shorter postoperative hospitalisation, less hospitalisation expenditure (both p<0.00001), less pain and better quality of life. Short-term morbidity and readmission rates did not differ between treatments. No incidents of death occurred during the short-term follow up period. CONCLUSIONS: In patients with gastric cancer undergoing gastrectomy, the FTS pathway reduces the length and cost of postoperative hospitalisation while maintaining short-term morbidity, readmission and mortality rates comparable with those of conventional care. PMID- 25519257 TI - Successful management of abdominal wound dehiscence using a vacuum assisted closure system combined with mesh-mediated medial traction. AB - Management of the open abdomen has advanced significantly in recent years with the increasing use of vacuum assisted closure (VAC) techniques leading to increased rates of fascial closure. We present the case of a patient who suffered two complete abdominal wall dehiscences after an elective laparotomy, meaning primary closure was no longer possible. She was treated successfully with a VAC system combined with continuous medial traction using a Prolene((r)) mesh. This technique has not been described before in the management of patients following wound dehiscence. PMID- 25519258 TI - Delayed presentation of a large congenital laryngeal cleft in an adult. AB - Laryngeal clefts are rare congenital malformations of the posterior laryngotracheal wall that lead to an abnormal communication between the airway and pharyngo-oesophageal tract. The condition is almost universally identified during infancy with minor laryngeal clefts very rarely diagnosed in adulthood. We present our tertiary centre's experience of a large laryngeal cleft presenting at an advanced age, with the aim of increasing awareness of this correctible cause of respiratory distress and aspiration in adults. PMID- 25519259 TI - A systematic review and meta-analysis of complications following the posterior and lateral surgical approaches to total hip arthroplasty. AB - INTRODUCTION: Total hip arthroplasty is one of the most commonly performed orthopaedic procedures. Despite this, medical evidence to inform the choice of surgical approach is lacking. Currently in the UK, the two most frequently performed approaches to the hip are the posterior and the direct lateral. METHODS: This systematic review was performed according to Cochrane guidelines following an extensive search for prospective controlled trials published in any language before January 2014. Of the 728 records identified from searches, 6 prospective studies (including 3 randomised controlled trials) involving 517 participants provided data towards this review. FINDINGS: Compared with the lateral approach, the posterior approach conferred a significant reduction in the risk of Trendelenburg gait (odds ratio [OR]: 0.31, p=0.0002) and stem malposition (OR: 0.24, p=0.02), and a non-significant reduction in dislocation (OR: 0.37, p=0.16) and heterotopic ossification (OR: 0.41, p=0.13). Neither approach conferred a functional advantage. We draw attention to the paucity of evidence and the need for a further randomised trial. PMID- 25519260 TI - Incisional hernia rate after laparoscopic colorectal resection is reduced with standardisation of specimen extraction. AB - INTRODUCTION: Incisional hernia is a common complication of laparoscopic colorectal surgery. Extraction site may influence the rate of incisional hernias. Major risk factors for the development of incisional hernias include age, diabetes, obesity and smoking status. In this study, we investigated the effect of specimen extraction site on incisional hernia rate. METHODS: Two cohorts of patients who underwent laparoscopic colorectal resections in a single centre in 2005 (n=85) and 2009 (n=139) were studied retrospectively. In 2005 all specimens were extracted through transverse muscle cutting incisions. In 2009 all specimens were extracted through midline incisions. Demographic variables, rate of incisional hernias and risk factors for hernia development were compared between the year groups. All patients had been followed up clinically for two years. RESULTS: A total of 224 patients (mean age: 67.5 years, standard deviation: 16.35 years) were included in this study. Of these, 85 patients were in the 2005 transverse group and 139 were in the 2009 midline group. The total incisional hernia rate for the series was 8.0% at the two-year follow-up visit. For the 2005 group, the incisional hernia rate was 15.3% (n=13) and for the 2009 group, it was 3.6% (n=5) (p<0.01). The body mass index was higher in patients who developed incisional hernias than in those who did not (p=0.02). CONCLUSIONS: The 2005 group had a significantly higher incisional hernia rate than the 2009 group. This is due to the differences in the incision technique and extraction site between the two groups. PMID- 25519261 TI - Laparoscopic incisional and ventral hernia repair in a district general hospital. AB - INTRODUCTION: The laparoscopic approach to repairing ventral and incisional hernias has gained increasing popularity worldwide. We reviewed the experience of laparoscopic ventral hernia repair at a district general hospital in the UK with particular reference to patients with massive defects (diameter >=15cm) and the morbidly obese. METHODS: A total of 144 patients underwent laparoscopic ventral (incisional or umbilical/paraumbilical) hernia repair between April 2007 and September 2012. RESULTS: The prevalence of conversion to open surgery was 2.8%. The prevalence of postoperative complications was 3.5%. Median postoperative follow-up was 30.2 months. A total of 5.6% cases suffered late complications and 2.8% developed recurrence. Thirty-four patients underwent repair of defects >=10cm in diameter with a prevalence of recurrence of 5.6%. Sixteen patients underwent repair of 'massive' incisional hernia (diameter >=15cm) with a prevalence of recurrence of 12.5%. Sixteen patients with a body mass index (BMI) >=40kg/m(2) (range, 40-61kg/m(2)) underwent laparoscopic repair with a prevalence of recurrence of 6.3% (p>0.05 vs BMI <40kg/m(2)). CONCLUSIONS: Laparoscopic ventral hernia repair can be carried out safely with a low prevalence of recurrence. It may have advantages in morbidly obese patients in whom open repair would represent a significant undertaking. Laparoscopic ventral hernia repair may be used in cases of large and massive hernias, in which the risk of recurrence increases but is comparable with open repair and associated with low morbidity. PMID- 25519262 TI - Blood cultures in acute surgical admissions. AB - INTRODUCTION: Obtaining blood cultures prior to the administration of antimicrobial therapy was a key recommendation of the 2012 UK Surviving Sepsis Campaign. Few studies have examined the effect blood cultures have on clinical management and there have been none on acute surgical admissions. This retrospective study sought to evaluate the effect of blood cultures on clinical management in acute surgical admissions. METHODS: Data on acute surgical patients admitted between 1 January and 31 December 2012 were extracted from hospital records. Patients given intravenous antibiotics within 24 hours of admission were identified. Data collected included antibiotics administered, blood culture results, admission observations and white blood cell count. Case notes were reviewed for patients with positive cultures to establish whether the result led to a change in management. RESULTS: Of 5,887 acute surgical admissions, 1,346 received intravenous antibiotics within 24 hours and 978 sets of blood cultures were taken in 690 patients. The recommended two sets of cultures were obtained in 246 patients (18%). Patients who had blood cultures taken had the same in hospital mortality as those who had none taken (3.6% vs 3.5%, p=0.97). Blood cultures were positive in 80 cases (11.6%). The presence of systemic inflammatory response syndrome did not increase positivity rates (12.9% vs 10.3%, p=0.28). Overall, cultures altered management in two patients (0.3%). CONCLUSIONS: Blood cultures rarely affect clinical management. In order to assess the additional value that blood cultures bring to sepsis management in acute surgical admissions, a prospective randomised trial focusing on outcome is needed. PMID- 25519263 TI - Non-centralised service for palliative stenting of malignant gastric outlet obstruction. AB - INTRODUCTION: Malignant gastric outlet obstruction (GOO) is a common, debilitating and frequently pre-terminal symptom of intra-abdominal malignancies. Traditional 'gold standard' treatment has been palliative surgical gastro enterostomy. Over the past two decades, use of self-expanding metallic stents (SEMSs) to relieve malignant GOO has become first-line treatment. We present the results from a single district general hospital in the UK in which malignant GOO was treated with SEMSs over a six-year period. METHODS: All patients who underwent palliative stenting for malignant gastro-duodenal tumours in our centre for six years up to January 2013 were assessed retrospectively. Outcomes were assessed with regard to: technical and clinical success; return to oral nutrition; prevalence of complications and re-intervention; and overall survival. RESULTS: Thirty-two stents were implanted in 29 patients. Technical success was 100%. Clinical success and return to oral nutrition were both 91%. The prevalence of complications was 16%. The prevalence of re-intervention was 13%. Mean survival was 91 (range, 5-392) days. Median wait from decision to implant a stent to stent implantation was 1 (range, 0-14) day. Overall, 25 covered and nine uncovered stents were implanted. CONCLUSION: Stent implantation for GOO in this patient group is an established and preferable alternative to surgical intervention. Much of the treatment for malignancies of the upper gastrointestinal tract has now been centralised. Our data showed comparable results with published data for these procedures, with a high prevalence of success and low prevalence of major complications. It is of considerable benefit to these patients not to have to travel to a regional centre for stent implantation. PMID- 25519264 TI - Management of open lower limb injuries in South West England and Wales. AB - INTRODUCTION: The joint British Association of Plastic, Reconstructive and Aesthetic Surgeons/British Orthopaedic Association standards define best practice management in open diaphyseal fractures of the lower limb. The aim of our study was to review the regional approach and experience in South West England and Wales. A further objective was to evaluate service provision with regard to the standards' key recommendations. METHODS: A prospective audit was undertaken of open diaphyseal fracture patients. Compliance with published standards within all orthoplastic services in South West England and Wales was assessed, and facilities were evaluated. RESULTS: A total of 86 patients were managed between October 2012 and March 2013. This was a 56% increase from 2008. Over half (56%) presented directly to the orthoplastic services with all patients undergoing debridement within 24 hours. Two-thirds (66%) of procedures were in daylight hours excluding those requiring immediate surgical intervention. Adherence to correct antibiotic therapy was 88% at admission, 50% at primary surgery and 62% at definitive surgery. Almost two-thirds (60%) of primary procedures were performed with combined senior orthoplastic teams, with 81% achieving definitive soft tissue coverage and fixation within seven days. Compliance improved in units with larger patient caseloads and where there was an early combined approach during daylight hours. CONCLUSIONS: Increased open lower limb fracture workload was demonstrated across South West England and Wales, probably owing to centralisation of trauma services. An improvement in early transfer of this patient group to orthoplastic facilities has allowed all patients to be assessed and debrided within the recommended timeframe. Standards were most likely to be met in those centres seeing higher numbers of injuries and when there was a daylight hours procedure by combined orthoplastic teams. PMID- 25519265 TI - The epidemiology of reoperations for orthopaedic trauma. AB - INTRODUCTION: The Royal College of Surgeons of England (RCS) has issued guidance regarding the use of reoperation rates in the revalidation of UK-based orthopaedic surgeons. Currently, little has been published concerning acceptable rates of reoperation following primary surgical management of orthopaedic trauma, particularly with reference to revalidation. METHODS: A retrospective review was conducted of patients undergoing clearly defined reoperations following primary surgical management of trauma between 1 January 2010 and 31 December 2011. A full case note review was undertaken to establish the demographics, clinical course and context of reoperation. A review of the imaging was performed to establish whether the procedure performed was in line with accepted trauma practice and whether the technical execution was acceptable. RESULTS: A total of 3,688 patients underwent primary procedures within the time period studied while 70 (1.90%, 99% CI: 1.39-2.55) required an unplanned reoperation. Thirty-nine (56%) of these patients were male. The mean age of patients was 56 years (range: 18-98 years) and there was a median time to reoperation of 50 days (IQR: 13-154 days). Potentially avoidable reoperations occurred in 41 patients (58.6%, 99% CI: 43.2 72.6). This was largely due to technical errors (40 patients, 57.1%, 99% CI: 41.8 71.3), representing 1.11% (99% CI: 0.73-1.64) of the total trauma workload. Within RCS guidelines, 28-day reoperation rates for hip, wrist and ankle fractures were 1.4% (99% CI: 0.5-3.3), 3.5% (99% CI: 0.8%-12.1) and 1.86% (99% CI: 0.4-6.6) respectively. CONCLUSIONS: We present novel work that has established baseline reoperation rates for index procedures required for revalidation of orthopaedic surgeons. PMID- 25519266 TI - Necrotising soft tissue infection in a UK metropolitan population. AB - INTRODUCTION: Necrotising soft tissue infection (NSTI) is a rare but life threatening diagnosis. Geographic, economic and social variances influence presentation and prognosis. As the current literature does not reflect a UK metropolitan population, we conducted a retrospective chart review to establish pertinent features relevant to our practice. METHODS: Patients with histologically confirmed diagnoses of NSTI presenting to two London teaching hospitals between January 2007 and July 2013 were included in the study. Features of presentation, surgical and medical management, microbiological findings and outcome were evaluated. RESULTS: Twenty-four patients with histologically confirmed NSTI were included. Two age clusters were identified, with means of 46 years (standard deviation [SD]: 10 years) and 80 years (SD: 6 years). Pain, erythema and sepsis were common findings. Hypertension, hypercholesterolaemia and type II diabetes mellitus were common co-morbidities. A third of younger patients had human immunodeficiency virus or hepatitis C, with a quarter dependent on drugs and/or alcohol. The mean Laboratory Risk Indicator for Necrotising Fasciitis (LRINEC) score was 5.8 (SD: 3.3). The lower extremities, groin and perineum were common sites of infection. Fourteen patients required inotropic support and seventeen required transfusions. The median number of surgical procedures was 5 (range: 1-17). Group A Streptococcus was the most frequently identified pathogen. Five patients died. Being elderly, female sex and failure to use clindamycin as a first-line antibiotic were associated with significantly higher mortality. CONCLUSIONS: In contrast to other recent series, group A streptococcal monomicrobial NSTI remains the most common presentation in our population. Survival is anticipated in young patients, regardless of premorbid status. Elderly patients have a poor prognosis. The negative predictive value of the LRINEC score is questioned. Use of clindamycin as a first-line antibiotic is supported. PMID- 25519267 TI - Dissections of regional lymph nodes for treatment of skin cancer: predicting annual caseloads that will optimise outcomes. AB - INTRODUCTION: Dissection of regional lymph nodes (RLNs) can lead to significant morbidity and a high prevalence of complications. Published guidance states that these procedures should be carried out by surgeons who are members of a specialist skin multidisciplinary team who carry out a combined minimum of 15 axillary/groin dissections per year. However, there is little evidence to guide this minimum figure of procedures. We report on the burden of service provision and prevalence of complications across the South West of England and Wales. METHODS: A 12-month review of dissections of RLNs for skin cancer was undertaken covering five Plastic Surgery Units with a collective catchment of 8.4 million people. Detailed data were collected on patient demographics, pathology, timing of surgery, and prevalence of complications. RESULTS: A total of 163 dissections were carried out. Forty-three per cent of patients experienced one or more complication. In that 12-month period, an average of 8 axillary/groin dissections was carried out per surgeon. A funnel plot demonstrated that the prevalence of complications for individual surgeons was within the limit of the plot but, in many cases, this was based only on a relatively small number of procedures per consultant. If surgeons carried out 10 procedures per year, the upper and lower limits on the plot were 73% and 11%, respectively. CONCLUSIONS: Funnel plots can provide a useful guide as to whether the prevalence of complications for procedures for individual surgeons lies within acceptable limits. Based on these results, 10 procedures per consultant per year should be sufficient to enable meaningful assessment of the prevalence of complications. PMID- 25519268 TI - Cryptorchidism and the value of ultrasonography. AB - INTRODUCTION: The aim of this study was to evaluate the usefulness and accuracy of ultrasonography in investigating cryptorchidism. METHODS: Case notes were reviewed of all children with cryptorchidism who had undergone ultrasonography for their testes between February and October 2010. Preoperative ultrasonography findings for presence or absence and position of testes were noted and compared with the operative findings. The sensitivity and specificity of ultrasonography were calculated. RESULTS: A total of 50 testes in 42 boys were examined by ultrasonography preoperatively during the study period. The median age was 6 years. All had single B-mode greyscale ultrasonography using greyscale and Doppler imaging. Of the 50 testes, 42 were visualised intracanalicularly or in the superficial inguinal pouch, 2 were intra-abdominal and 6 could not be detected. However, on examination under anaesthesia, 37 out of the 50 testes were palpable in the groin and 13 were impalpable. Two out of the remaining thirteen were found to be atrophic on diagnostic laparoscopy. The sensitivity and specificity of ultrasonography in determining the presence of testes was 85% and 25% respectively. CONCLUSIONS: Ultrasonography has low sensitivity and specificity in determining the presence of testes and localisation of their position. When performing an examination under anaesthesia and using a laparoscopic technique, ultrasonography is not recommended in cases of cryptorchidism. PMID- 25519269 TI - Hospital trends of admissions and procedures for acute leg ischaemia in England, 2000-2011. AB - INTRODUCTION: Acute leg ischaemia (ALI) is a common vascular emergency for which new minimally invasive treatment options were introduced in the 1990s. The aim of this study was to determine recent hospital trends for ALI in England and to assess whether the introduction of the new treatment modalities had affected management. METHODS: Routine hospital data covering ALI were provided by Hospital Episode Statistics for the years 2000 to 2011 and mortality data were obtained from the Office for National Statistics. All data were age standardised, reported per 100,000 of the population, and stratified by age band (60-74 years and >=75 years) and sex. RESULTS: Hospital admissions have risen significantly from 60.3 to 94.3 per 100,000 of the population, with an average annual increase of 6.2% since 2003 (p<0.001). The rise was greater in the older age group (from 79.9 to 134.4 vs 49.3 to 73.0) and yet procedures for ALI have shown a significant decrease since 2000 from 14.3 to 12.4 per 100,000 (p=0.013), independent of age and sex. Open embolectomy of the femoral artery remains the most common procedure and the proportion of endovascular interventions showed only a small increase. Only a few deaths were attributed to ALI (range: 95-150 deaths per year). CONCLUSIONS: Hospital workload for ALI has increased, particularly since 2003, but this trend does not appear to have translated into increased endovascular or surgical activity. PMID- 25519270 TI - Patient reported outcome measures in septorhinoplasty surgery. AB - INTRODUCTION: Surgical procedures incorporating a cosmetic element such as septorhinoplasty and otoplasty are currently under threat in the National Health Service (NHS) as they are deemed to be procedures of 'limited clinical benefit' by many primary care providers. Patient reported outcome measures (PROMs), which assess the quality of care delivered from the patients' perspective, are becoming increasingly important in documenting the effectiveness of such procedures. METHODS: The Rhinoplasty Outcomes Evaluation (ROE) questionnaire, a validated PROM tool, was used to assess patient satisfaction in 141 patients undergoing septorhinoplasty surgery over a 90-month period at the University Hospital Southampton NHS Foundation Trust. RESULTS: Overall, 100 patients with a mean follow-up period of 36 months completed the study. The mean ROE score was 73.3%. In addition, 75% of patients questioned were happy with the final result of their operation and 83% would undergo the procedure again if required. These benefits occurred irrespective of age, sex and primary versus revision surgery, and were maintained for up to 71 months following surgery. CONCLUSIONS: This study has shown that patients are generally satisfied with their functional and cosmetic outcomes following septorhinoplasty surgery. These results help support the case for septorhinoplasty surgery to continue being funded as an NHS procedure. PMID- 25519272 TI - BD NokorTM admix needle for percutaneous needle fasciotomy: a novel use of a universal pharmacy needle. PMID- 25519271 TI - A review of cervical spine injury associated with maxillofacial trauma at a UK tertiary referral centre. AB - INTRODUCTION: The aim of this study was to determine the incidence and patterns of cervical spine injury (CSI) associated with maxillofacial fractures at a UK trauma centre. METHODS: A retrospective analysis was conducted of 714 maxillofacial fracture patients presenting to a single trauma centre between 2006 and 2012. RESULTS: Of the 714 maxillofacial fracture patients, 2.2% had associated CSI including a fracture, cord contusion or disc herniation. In comparison, 1.0% of patients without maxillofacial trauma sustained a CSI (odds ratio: 2.2, p=0.01). The majority (88%) of CSI cases of were caused by a road traffic accident (RTA) with the remainder due to falls. While 8.8% of RTA related maxillofacial trauma patients sustained a CSI, only 2.0% of fall related patients did (p=0.03, not significant). Most (70%) of the CSIs occurred at C1/C2 or C6/C7 levels. Overall, 455, 220 and 39 patients suffered non-mandibular, isolated mandibular and mixed mandibular/non-mandibular fractures respectively. Their respective incidences of CSI were 1.5%, 1.8% and 12.8% (p=0.005, significant). Twelve patients with concomitant CSI had their maxillofacial fractures treated within twenty-four hours and all were treated within four days. CONCLUSIONS: The presence of maxillofacial trauma mandates exclusion and prompt management of cervical spine injury, particularly in RTA and trauma cases involving combined facial fracture patterns. This approach will facilitate management of maxillofacial fractures within an optimum time period. PMID- 25519273 TI - The use of a hypodermic needle to pass intraosseous cerclage wire through bone. PMID- 25519274 TI - Intraoperative ultrasonography localisation of intramuscular abdominal lipomas. PMID- 25519275 TI - Improving exposure in posterior cervical surgery: the elastoplasty. PMID- 25519276 TI - Preventing cement fragments in revision arthroplasty from escaping the sterile field. PMID- 25519277 TI - The Tooting Tube: a bespoke high-arm sling for upper limb rehabilitation. PMID- 25519278 TI - Angiocath used for retrograde cannulation of the transplant ureter. PMID- 25519279 TI - Tip to stitch the superior corner of the quadriceps tendon incision in knee arthrotomy. PMID- 25519280 TI - The novel use of an external fixator connecting rod and synthetic bone substitute to achieve anatomic reduction of depressed tibial plateau fracture fragments. PMID- 25519281 TI - Modification of the parachute technique to simplify vascular anastomosis in kidney transplantation. PMID- 25519282 TI - Penrose drain guided insertion of a laparoscopic Nathanson liver retractor. PMID- 25519283 TI - The use of FRED(r) to reduce intraoperative spectacle fogging. PMID- 25519284 TI - Calibration of the small bowel in stricture-forming small-bowel Crohn's disease. PMID- 25519285 TI - Maximising vacuum drainage prior to wound closure. PMID- 25519286 TI - A simple technique to improve the administration of nerve root blocks. PMID- 25519287 TI - Bedside methylene blue 'nephrostogram'. PMID- 25519288 TI - An opportunity to shape future NICE guidance. PMID- 25519289 TI - Recent NICE guidance of interest to surgeons. PMID- 25519290 TI - Reaction parameters for the synthesis of N,N-dimethyl fatty hydrazides from oil. AB - Hydrazide derivatives have been synthesized from methyl esters, hydrazones and vegetable oils. They are important due to their diverse applications in pharmaceutical products, detergents as well as in oil and gas industries. The chemical synthesis of fatty hydrazides is well-established; however, only a few publications described the synthesis of fatty hydrazide derivatives, particularly, when produced from refined, bleached and deodorized palm olein. Here, the synthesis and characterization of N,N-dimethyl fatty hydrazides are reported. The N,N-dimethyl fatty hydrazides was successfully synthesized from fatty hydrazides and dimethyl sulfate in the presence of potassium hydroxide with the molar ratio of 1:1:1, 6 hours reaction time and 80C reaction temperature in ethanol. The product yield and purity were 22% and 89%, respectively. The fatty hydrazides used were synthesized from refined, bleached and deodorized palm olein with hydrazine monohydrate at pH 12 by enzymatic route. Fourier transform infrared, gas chromatography and nuclear magnetic resonance (NMR) spectroscopy techniques were used to determine the chemical composition of N,N-dimethyl fatty hydrazides. Proton NMR confirmed the product obtained were N,N-dimethyl fatty hydrazides. PMID- 25519291 TI - Comparative anti-inflammatory potential of crystalline and amorphous nano curcumin in topical drug delivery. AB - The problem of poor bioavailability and clinical efficacy of curcumin can be sorted out after converting crystalline Curcumin (CrysCur) into amorphous NanoCurcumin (NanoCur). Amorphous NanoCur was prepared by converting into nanoemulsion (o/w) using water titration method. The formulation were pre-screen by different physical stress tests, followed by in vitro release study, zeta potential, viscosity, transmittance, globule size distribution and ex vivo studies. The morphology of the NanoCur was determined using transmission electron microscopy (TEM) which revealed fairly spherical shape and good correlation with droplet size distribution study. The NanoCur was converted to gel using Cabopol 934. The composition of optimized NanoCur was curcumin (0.154% w/w), Carbopol 934 (0.702% w/w), ethanolic oil phase [ethanol (0.013% w/w): Capryol 90 (0.015%w/w)], Tween 20 (0.076%w/w) as surfactant, PEG 200 (0.038%w/w) as a co-surfactant and distilled water (q.s) as hydration phase. The steady state flux (Jss), permeability coefficient (Kp) and enhancement ratio (Er) of NanoCur gel was determined and compared with CrysCur gel. Anti-inflammatory effects of the formulations were evaluated in carrageenan-induced paw edema method in rats using Diclofenac as a reference. These ant-inflammatory effects of NanoCur was highly significant (p<0.001) compared to CrysCur and significantly (p<0.05) comparable with standard Diclofenac. The histology of the formulation treated skin showed insignificant changes in the integrity except in the group treated with NanoCur. The slight disruption in the integrity of skin may be because of surfactant present in the nano formulations. Short term storage stability showed insignificant changes in the droplet size and zeta potential, proving its high shelf-life. Finally, it was concluded that NanoCur could be a promising tool in the management of topical inflammation. PMID- 25519293 TI - Reviewer: an endangered species?! PMID- 25519292 TI - Tides of change: improving glucometrics in a large multihospital health care system. AB - BACKGROUND: This study explores the relationship between education for inpatient diabetes providers and the utilization of insulin order sets, inpatient glucometrics, and length of stay in a large health care system. METHODS: The study included patients with and without the diagnosis of diabetes. An education campaign included provider-directed diabetes education administered via online learning modules and in-person presentations by trained individuals. Relationships among provider-attended diabetes education, order set usage, and inpatient glucometrics (hypo- and hyperglycemia) were analyzed, as well as length of stay. RESULTS: Insulin use knowledge scores for all providers averaged 52%, and improved significantly to 93% (P < .001) by the end of the education intervention period. Likewise utilization of electronic basal-bolus order sets increased from a baseline of 20% for patients receiving insulin to 86% within 6 weeks (P < .01) of introduction of order sets. During the study, the incidence of hypoglycemia and hyperglycemia declined from 1.47% to 1.27% and from 23.21% to 17.80%, respectively. However, these improvements were not sustained beyond the completion of the education campaign. CONCLUSIONS: Education of diabetes health care providers was provided in a large, multihospital system through the use of online learning modules. Adoption of standardized insulin order sets was associated with an improvement in glucometrics. This educational and quality initiative resulted in overall improvements in insulin knowledge, adherence to recommended order sets, inpatient glucometrics, and patient length of stay. These improvements were not sustained, reinforcing the need for repeated educational interventions for those involved in providing inpatient diabetes care. PMID- 25519294 TI - Carbohydrate-to-Insulin Ratio in a Mediterranean Population of Type 1 Diabetic Patients on Continuous Subcutaneous Insulin Infusion Therapy. AB - BACKGROUND: The carbohydrate-to-insulin ratio (CIR) is initially calculated from the total daily insulin dose (TDID). However, CIR likely presents variations owing to different population characteristics and intraday variations not being taken into account by most formulas. No information is available concerning the Mediterranean population. We investigated the CIR used by patients with type 1 diabetes (T1DM) using continuous subcutaneous insulin infusion (CSII) therapy in a Mediterranean area, to identify possible intraday variations and establish an adequate formula to calculate CIR. METHODS: Data from 170 T1DM patients from Barcelona were obtained retrospectively from the Spanish National Registry of CSII Therapy (SNR-CSII). Theoretical CIR was calculated using the formula: 500 divided by TDID. This theoretical CIR was compared to the real CIR. RESULTS: The real CIR was also compared between main meals. Patients with HbA1c < 7% (n = 44) were considered a reference group for accurate bolus calculation and were analyzed as a subgroup. The real CIR used was 11.5 g/UI for breakfast, 12 g/UI for lunch, and 13.3 g/UI for dinner. CIR obtained by the 500/TDID formula for all meals was 15.5 g/UI. We obtained similar results for the group with HbA1c < 7%. The real CIR differed significantly from the theoretical CIR values and between breakfast and the other main meals (P < .005). CONCLUSIONS: CIR in our population was significantly lower for breakfast than for other meals. CIR using the 500/TDID formula underestimated prandial insulin requirements. A calculation of 350/TDID for breakfast and 400/TDID for lunch and dinner would be more appropriate for this population. PMID- 25519296 TI - Biomolecular characterization of adrenal gland tumors by means of SR-FTIR. AB - The adrenal glands are small endocrine organs located on the bottom pole of each kidney. Anatomically they are composed of cortical and medullar parts. Due to dysfunctional processes they can transform into the pathological lesions (in both cortex and medulla). The incidentally detected adrenal lesions have become an arising clinical problem nowadays. The crucial issue for an accurate treatment strategy is relevant diagnosis. Distinguishing between benign and malignant lesions is often difficult during the standard histological examination. Hence the alternative methods of differentiation are investigated. One of them is Fourier transform infrared spectroscopy which allows the analysis of the biomolecular composition of the studied tissue. In this paper we present the very preliminary FTIR studies for defining the biomolecular pattern of three types of adrenal lesions: adenoma (AA) and adrenal cortical hyperplasia (ACH) - both derived from adrenal cortex as well as pheochromocytoma (PCC) - from the medullar part of the gland. All studied cases were classified as benign lesions. The general observations show that cortically derived tissues are rich in lipids and they are rather protein depleted while for medullar pheochromocytoma there is the opposite relationship. Furthermore, the unequivocal differences were noticed within the "fingerprinting" range. In addition subtle shifts in absorption band positions were observed between studied cases. PMID- 25519295 TI - Comparative performance assessment of point-of-care testing devices for measuring glucose and ketones at the patient bedside. AB - Point-of-care (POC) testing devices for monitoring glucose and ketones can play a key role in the management of dysglycemia in hospitalized diabetes patients. The accuracy of glucose devices can be influenced by biochemical changes that commonly occur in critically ill hospital patients and by the medication prescribed. Little is known about the influence of these factors on ketone POC measurements. The aim of this study was to assess the analytical performance of POC hospital whole-blood glucose and ketone meters and the extent of glucose interference factors on the design and accuracy of ketone results. StatStrip glucose/ketone, Optium FreeStyle glucose/ketone, and Accu-Chek Performa glucose were also assessed and results compared to a central laboratory reference method. The analytical evaluation was performed according to Clinical and Laboratory Standards Institute (CLSI) protocols for precision, linearity, method comparison, and interference. The interferences assessed included acetoacetate, acetaminophen, ascorbic acid, galactose, maltose, uric acid, and sodium. The accuracies of both Optium ketone and glucose measurements were significantly influenced by varying levels of hematocrit and ascorbic acid. StatStrip ketone and glucose measurements were unaffected by the interferences tested with exception of ascorbic acid, which reduced the higher level ketone value. The accuracy of Accu-Chek glucose measurements was affected by hematocrit, by ascorbic acid, and significantly by galactose. The method correlation assessment indicated differences between the meters in compliance to ISO 15197 and CLSI 12 A3 performance criteria. Combined POC glucose/ketone methods are now available. The use of these devices in a hospital setting requires careful consideration with regard to the selection of instruments not sensitive to hematocrit variation and presence of interfering substances. PMID- 25519297 TI - Electromyographic analysis of anterior cruciate deficient knees with and without functional bracing during lunge exercise. AB - BACKGROUND: The use of functional knee braces for returning to sports or during demanding activities following anterior cruciate ligament rupture is common; yet despite being commonly prescribed, its mechanism of action remains unknown. OBJECTIVES: To examine the effect of functional knee braces on mean muscle activity when performing lunge exercises. STUDY DESIGN: Pre-/post-test (within subject research design). METHODS: A total of 10 male participants with unilateral isolated anterior cruciate ligament deficiency participated. Electromyographic activities of six muscles around the knee were recorded during lunge exercises, with and without wearing a custom functional knee brace. The lunge cycle movement was subdivided into three phases: eccentric, isometric, and concentric. RESULTS: The quadriceps and hamstrings were no different in the braced and unbraced conditions. When braced, the mean amplitude of the medial gastrocnemius was significantly lower throughout the whole movement (p = 0.01) and during the concentric (p = 0.006) and eccentric (p = 0.028) phases, but not within the isometric phase. The lateral gastrocnemius was found to have lower mean amplitude in the isometric phase (p = 0.044). CONCLUSION: With its origin on the medial femoral condyle, perhaps reduced medial gastrocnemius activity may better guide knee rotation and assist the joint achieving a healthier kinematic pattern. CLINICAL RELEVANCE: Lower medial gastrocnemius activity may facilitate lower medial compartment contact pressure, for which greater loading is known to increase the risk of osteoarthritis in anterior cruciate ligament-deficient (ACLD) knees. However, further research is needed. PMID- 25519298 TI - Anatomic study on mental canal and incisive nerve canal in interforaminal region in Chinese population. AB - PURPOSE: This study was aimed to detect the positions of mental canal and incisive nerve canal as well as the prolongation of mandibular canal in interforaminal region in Chinese population to supply the reference data of the surgical safe zone in chin for clinicians. MATERIALS AND METHODS: A total of 80 formalin-fixed semi-mandibles of Chinese adult cadavers were dissected, the positions and courses of mental canal and incisive nerve canal as well as the prolongation of mandibular canal in interforaminal region were measured. RESULTS: The mental foramina were present in all cases (100 %), and most of them were located below 2nd premolar (58.75 %). Accessory mental foramina were observed in 5 %. The anterior end of mandibular canal, extending along the course of 7.37 +/- 1.10 mm above the lower border of mandible to interforaminal region about 3.54 +/ 0.70 mm medial to the mental foramen, most often ended below between the two premolars (73.75 %), where it continued as the incisive nerve canal (100 %) and the mental canal (96.25 %). Mental canal, with the wall formed by compact bone, being 2.60 +/- 0.60 mm in diameter and 4.01 +/- 1.20 mm in length, opened into mental foramen. Incisive nerve canal, with the wall formed by thin compact bone and/or partly or completely by spongy bone, being 1.76 +/- 0.27 mm in diameter and 24.87 +/- 2.23 mm in length, extended to the incisor region along the course of 9.53 +/- 1.43 mm above the lower border of mandible, and most often ended below the lateral incisor (70.00 %). CONCLUSION: This research recommended for chin operations in Chinese population: the surgical safe zone could be set in the region about over 4 mm anterior to the mental foramen, and over 12 mm above inferior border of mandible for anterior alveolar surgery, or within 9 mm above inferior border of mandible for genioplasty. PMID- 25519299 TI - Murimonas intestini gen. nov., sp. nov., an acetate-producing bacterium of the family Lachnospiraceae isolated from the mouse gut. AB - Three strains of an anaerobic, Gram-stain-positive coccobacillus were isolated from the intestines of mice. These strains shared 100 % similarity in their 16S rRNA gene sequences, but were distantly related to any described members of the family Lachnospiraceae (<94 %). The most closely related species with names that have standing in nomenclature were Robinsoniella peoriensis, Ruminococcus gnavus, Blautia producta and Clostridium xylanolyticum. Phylogenetic relationships based on 16S rRNA gene sequence analysis were confirmed by partial sequencing of hsp60 genes. The use of an in-house database search pipeline revealed that the new isolates are most prevalent in bovine gut samples when compared with human and mouse samples for Ruminococcus gnavus and B. producta. All three isolated strains shared similar cellular fatty acid patterns dominated by C16 : 0 methyl ester. Differences in the proportions of C12 : 0 methyl ester, C14 : 0 methyl ester and C18 : 1 cis-11 dimethyl acetal were observed when compared with phylogenetically neighbouring species. The major short-chain fatty acid produced by strain SRB-530 5-H(T) was acetic acid. This strain tested positive for utilization of d fructose, d-galacturonic acid, d-malic acid, l-alanyl l-threonine and l-glutamic acid but was negative for utilization of amygdalin, arbutin, alpha-d-glucose, 3 methyl d-glucose and salicin, in contrast to the type strain of the closest related species Robinsoniella peoriensis. The isolates were not able to use mannitol for growth. Based on genotypic, phenotypic and chemotaxonomic characteristics, we propose to create the new genus and species Murimonas intestini gen. nov., sp. nov. to accommodate the three strains SRB-530-5-H(T) ( = DSM 26524(T) = CCUG 63391(T)) (the type strain of Murimonas intestini), SRB-509-4 S-H ( = DSM 27577 = CCUG 64595) and SRB-524-4-S-H ( = DSM 27578 = CCUG 64594). PMID- 25519300 TI - Actinokineospora spheciospongiae sp. nov., isolated from the marine sponge Spheciospongia vagabunda. AB - A Gram-staining-positive, aerobic organism, isolated from the Red Sea sponge Spheciospongia vagabunda was investigated to determine its taxonomic position. On the basis of results of 16S rRNA gene sequence analysis strain EG49(T) was most closely related to Actinokineospora cibodasensis and Actinokineospora baliensis (both 97.3 % similarity) and Actinokineospora diospyrosa and Actinokineospora auranticolor (both 97.0 % similarity). The 16S rRNA gene sequence similarity to all other species of the genus Actinokineospora was <97.0 %. The quinone system of strain EG49(T) contained the menaquinones MK-9(H4) (47 %), MK-9(H6) (27 %) and MK-9(H2) (15 %) in major amounts. Minor amounts of MK-7(H4) (2 %), MK-9(H0) (1 %), MK-9(H8) (3 %) and MK-10(H4) (3 %) were detected as well in addition to MK 8(H4), MK-8(H6), MK-10(H2) and MK-10(H6) (all <1 %). The diagnostic diamino acid of the peptidoglycan was meso-diaminopimelic acid. In the polar lipid profile, diphosphatidylglycerol, phosphatidylethanolamine and hydroxyphosphatidylethanolamine were predominant. Phosphatidylinositol-mannoside, two unidentified phospholipids and two glycoglipids as well as one aminoglycolipid, one aminolipid and one unidentified lipid were found in addition. The fatty acid profile was composed of mainly iso-branched fatty acids: iso-C16 : 0, iso-C14 : 0, iso-C15 : 0 and iso-C16 : 1H. All these findings clearly supported the classification of the strain as representing a member of the genus Actinokineospora. In addition, the results of physiological and biochemical tests also allowed phenotypic differentiation of strain EG49(T) from the most closely related species of the genus Actinokineospora. Strain EG49(T) represents a novel species of the genus Actinokineospora, for which we propose the name Actinokineospora spheciospongiae sp. nov., with strain EG49(T) ( = DSM 45935(T) = CCM 8480(T) = LMG 27700(T)) as the type strain. PMID- 25519301 TI - Periostin: a novel prognostic predictor for meningiomas. AB - The expression and role of periostin in meningiomas remains unknown. Tissue specimens of 175 convexity meningiomas were immunohistochemically examined with antibodies against periostin and Ki67. The expression levels of periostin and Ki67 were compared among different WHO groups. The role of periostin and Ki67 in postoperative prognosis of meningiomas was also analyzed. Negative (-) expression of Ki67 was observed in 101 (57.7 %) cases of all the surgical tissue samples. The Ki67 expressions differed significantly among the WHO groups (P < 0.001) and correlated positively with the WHO grade (r = 0.673, P < 0.001). Low/negative staining of periostin was observed in 116 (66.3 %) cases. The periostin expressions differed significantly among the WHO groups (P < 0.001). Periostin expression correlated positively with the WHO grade (r = 0.742, P < 0.001). There was a positive correlation between Ki67 expression and periostin (r = 0.513, P < 0.001). Both Ki67 expression and periostin expression was found statistically different between brain invasion tumor and non-invasion tumor (p < 0.001). The recurrence rate and PFS rate in both varied Ki67 expression groups and periostin expression groups was statistically different (P < 0.001). The survival time and PFS time in both varied Ki67 expression groups and periostin expression groups was also statistically different (P < 0.001). Periostin was expressed in tumor stroma of meningiomas. Both periostin and Ki67 may behave as a maker in predicting the grade and prognosis in meningiomas. Drugs that targets periostin aims at reducing invasion of meningioma patients should be further researched. PMID- 25519302 TI - LINAC-based stereotactic radiosurgery to the brain with concurrent vemurafenib for melanoma metastases. AB - While selective BRAF inhibitors have demonstrated improved outcomes in patients with metastatic BRAF V600E mutant melanoma, management of brain metastases prior to and during therapy presents challenges. Stereotactic radiosurgery (SRS) is an effective treatment for melanoma brain metastases, but there is limited safety and efficacy data on the use of SRS during BRAF therapy. An analysis was performed of patients with metastatic melanoma and brain metastases treated with SRS while on vemurafenib. MRI scans were reviewed post-SRS to evaluate local control (LC) as well as distant control. We identified 80 metastatic melanoma brain lesions treated in 24 patients. The median planning target volume was 0.28 cm(3) (range 0.05-4.19 cm(3)), and lesions were treated to a median dose of 24 Gy (range 15-24 Gy). The median follow up was 5.1 months (range 2-25.2 months). Eight (10 %) lesions showed progression at a median of 6.1 months (range 2-20.1 months) following SRS. Kaplan-Meier LC estimates at 6 and 12 months were 92 and 75 %, respectively. Fourteen (58 %) patients were noted to have distant brain failure at a median of 3.4 months (range 1.9-16.1 months) following treatment with SRS. Median overall (OS) from the date of SRS was 7.2 months (range 1.5-26.8 months) with a median of 11.9 months (range 1.5-28.5 months) since the date of brain metastases diagnosis. There was no evidence of increased toxicity with the combination of SRS and vemurafenib. SRS to brain metastases appears to be both safe and effective for patients treated concurrently with BRAF inhibitors. PMID- 25519303 TI - The role of IDO in brain tumor immunotherapy. AB - Malignant glioma comprises the majority of primary brain tumors. Coincidently, most of those malignancies express an inducible tryptophan catabolic enzyme, indoleamine 2,3 dioxygenase 1 (IDO1). While IDO1 is not normally expressed at appreciable levels in the adult central nervous system, it's rapidly induced and/or upregulated upon inflammatory stimulus. The primary function of IDO1 is associated with conversion of the essential amino acid, tryptophan, into downstream catabolites known as kynurenines. The depletion of tryptophan and/or accumulation of kynurenine has been shown to induce T cell deactivation, apoptosis and/or the induction of immunosuppressive programming via the expression of FoxP3. This understanding has informed immunotherapeutic design for the strategic development of targeted molecular therapeutics that inhibit IDO1 activity. Here, we review the current knowledge of IDO1 in brain tumors, pre clinical studies targeting this enzymatic pathway, alternative tryptophan catabolic mediators that compensate for IDO1 loss and/or inhibition, as well as proposed clinical strategies and questions that are critical to address for increasing future immunotherapeutic effectiveness in patients with incurable brain cancer. PMID- 25519304 TI - Afferent nerve ending density in the human laryngeal mucosa: potential implications on endoscopic evaluation of laryngeal sensitivity. AB - Laryngeal sensitivity is crucial for maintaining safe swallowing, thus avoiding silent aspiration. The sensitivity test, carried out by fiberoptic endoscopic examination of swallowing, plays an important role in the assessment of dysphagic patients. The ventricular folds appear to be more sensitive than the epiglottis during the sensitivity test. Therefore, this study aimed to investigate the mechanical sensitivity of the supraglottic larynx. In seven healthy adults undergoing microlaryngoscopy to remove vocal cord polyps, we excised mucosal samples from the epiglottis and ventricular folds. We measured afferent nerve fiber density by immunoelectron microscopy. All of the subjects underwent an endoscopic sensitivity test based on lightly touching the laryngeal surface of the epiglottis and ventricular folds. The discomfort level was self-rated by the subjects on the visual analog scale. Samples were fixed and stored in cryoprotectant solution at 4 degrees C. Sections were stained with the protein gene product 9.5, a pan-neuronal selective marker. Nerve fiber density was calculated as the number of fibers per millimeter length of section. The mean nerve fiber density was higher in ventricular samples than in epiglottis samples (2.96 +/- 2.05 vs 0.83 +/- 0.51; two-sided p = 0.018). The mean visual analog scale scores were significantly higher for touching the ventricular folds than for touching the epiglottis (8.28 +/- 1.11 vs 4.14 +/- 1.21; two-sided p = 0.017). The higher sensitivity of the ventricular region should be considered for further refining clinical endoscopic evaluation of laryngeal sensitivity. PMID- 25519305 TI - Time trends and age-period-cohort analyses on incidence rates of thyroid cancer in Shanghai and Hong Kong. AB - BACKGROUND: Increasing incidence rates of thyroid cancer have been noted worldwide, while the underlying reasons remain unclear. METHODS: Using data from population-based cancer registries, we examined the time trends of thyroid cancer incidence in two largest cities in China, Shanghai and Hong Kong, during the periods 1973-2009 and 1983-2011, respectively. We further performed age-period cohort analyses to address the possible underlying reasons for the observed temporal trends. RESULTS: We observed continuous increases in the incidence rates of thyroid cancer in Shanghai and Hong Kong, since the 1980s, in addition to higher incidence rates in the 1970s in both sexes in Shanghai. The age standardized incidence rate of thyroid cancer increased by 3.1% [95% confidence interval (CI): 1.0%, 5.1%] and 3.8% (95% CI: 1.9%, 5.7%) per year on average, respectively, in Shanghai men and women during the period 1973-2009, while it increased by 2.2% (95% CI: 1.5%, 2.8%) and 2.7% (1.6%, 3.8%) per year on average, respectively, in Hong Kong men and women during the period 1983-2011. We observed global changes in trends across all age groups in similar ways, in addition to varied trends across different generations (birth cohorts). CONCLUSIONS: The increased incidence rates of thyroid cancer in these two Chinese populations during recent decades may be contributable to a combination of the introduction of more sensitive diagnostic techniques and the increasing prevalence of environmental exposures in the populations. PMID- 25519307 TI - Glial cells in familial amyloidotic polyneuropathy. AB - INTRODUCTION: Transthyretin V30M mutation is the most common variant leading to Familial Amyloidotic Polyneuropathy. In this genetic disorder, Transthyretin accumulates preferentially in the extracellular matrix of peripheral and autonomic nervous systems leading to cell death and dysfunction. Thus, knowledge regarding important biological systems for Transthyretin clearance might unravel novel insights into Familial Amyloidotic Polyneuropathy pathophysiology. Herein, our aim was to evaluate the ability of glial cells from peripheral and autonomic nervous systems in Transthyretin uptake and degradation. We assessed the role of glial cells in Familial Amyloidotic Polyneuropathy pathogenesis with real-time polymerase chain reaction, immunohistochemistry, interference RNA and confocal microscopy. RESULTS: Histological examination revealed that Schwann cells and satellite cells, from an Familial Amyloidotic Polyneuropathy mouse model, internalize and degrade non-fibrillar Transthyretin. Immunohistochemical studies of human nerve biopsies from V30M patients and disease controls showed intracellular Transthyretin immunoreactivity in Schwann cells, corroborating animal data. Additionally, we found Transthyretin expression in colon of this Familial Amyloidotic Polyneuropathy mouse model, probably being synthesized by satellite cells of the myenteric plexus. CONCLUSIONS: Glial cells from the peripheral and autonomic nervous systems are able to internalize Transthyretin. Overall, these findings bring to light the closest relationship between Transthyretin burden and clearance from the nervous system extracellular milieu. PMID- 25519308 TI - Sevoflurane Used for Color Doppler Ultrasound Examination in Children. AB - The objective of this study is to investigate the feasibility of sevoflurane inhalation in pediatric color doppler ultrasound examination. In this study, 30 cases of children under 1 year were selected. They were all I or II levels according to American Society of Anesthesiology. Children with severe cyanotic congenital heart disease or severe pneumonia were excluded. All the children received anesthesia with sevoflurane. The University of Michigan Sedation Scale was assessed and bispectral index (BIS) was recorded before induction (T0), after induction (T1), when maintaining (T2), and when waking-up (T3). Blood pressure and heart rate were monitored during the color doppler ultrasound examination, the time to receive sedation examination and anesthesia recovery time were also recorded. (1) Score for UMSS was zero at T0 and 3 at T1; (2) BIS value was 93.18 +/- 2.94 at T0 and decreased to 87.6 +/- 3.9 at T1; (3) Blood pressure or heart rate did not decline obviously; (4) The time to receive sedation examination was 46.4 +/- 13.1 s and anesthesia recovery time was 7.8 +/- 5.3 min. In conclusion, sevoflurane can be used in pediatric color doppler ultrasound examination safely and effectively. PMID- 25519309 TI - Association Between a Variant in ADAMTS5 and the Susceptibility to Hepatocellular Carcinoma in a Chinese Han Population. AB - A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is considered to be an important anti-angiogenic protein, in which the first TSR domain is crucial for its anti-angiogenic activity. Previous study showed that ADAMTS5 plays a role in suppression of hepatocellular carcinoma (HCC) progression through its anti-angiogenic activity. The rs2380585 G>A single-nucleotide polymorphism (SNP) is a missense mutation, located in the ADAMTS5 first TSR domain coding sequence (CDS). In this study, we investigated the impacts of ADAMTS5 rs2380585 polymorphism on the risk and progress of hepatocellular carcinoma. A total of 220 HCC patients and 220 controls in a Chinese Han population were enrolled and genotyped. The associations between SNPs and HCC incidence and progression were analyzed with logistic regression model. We found that individuals with the ADAMTS5 rs2380585 A allele was significantly associated with decreased HCC risk (OR = 0.348, 95 % CI 0.236-0.512; p = 0.000). Individuals having the ADAMTS5 rs2380585 polymorphic genotype (GA+AA) had an OR of 0.348 (95 % CI 0.201-0.600; p = 0.000) for developing HCC, compared with individuals having the ADAMTS5 rs2380585 ancestral genotype. However, stratified analyses did not find any evident gene-covariates interaction. The SNP of rs2380585 was irrelevant to the frequencies of clinicopathological characteristics. Our results for the first time indicate that ADAMTS5 rs2380585 polymorphism contributes to HCC susceptibility. PMID- 25519310 TI - Genetic Analysis Workshop 18: Methods and strategies for analyzing human sequence and phenotype data in members of extended pedigrees. AB - Genetic Analysis Workshop 18 provided a platform for developing and evaluating statistical methods to analyze whole-genome sequence data from a pedigree-based sample. In this article we present an overview of the data sets and the contributions that analyzed these data. The family data, donated by the Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Ethnic Samples Consortium, included sequence-level genotypes based on sequencing and imputation, genome-wide association genotypes from prior genotyping arrays, and phenotypes from longitudinal assessments. The contributions from individual research groups were extensively discussed before, during, and after the workshop in theme-based discussion groups before being submitted for publication. PMID- 25519311 TI - Multiphase analysis by linkage, quantitative transmission disequilibrium, and measured genotype: systolic blood pressure in complex Mexican American pedigrees. AB - We apply a multiphase strategy for pedigree-based genetic analysis of systolic blood pressure data collected in a longitudinal study of large Mexican American pedigrees. In the first phase, we conduct variance-components linkage analysis to identify regions that may harbor quantitative trait loci. In the second phase, we carry out pedigree-based association analysis in a selected region with common and low-frequency variants from genome-wide association studies and whole genome sequencing data. Using sequencing data, we compare approaches to pedigree analysis in a 10 megabase candidate region on chromosome 3 harboring a gene previously identified by a consortium for blood pressure genome-wide association studies. We observe that, as expected, the measured genotype analysis tends to provide larger signals than the quantitative transmission disequilibrium test. We also observe that while linkage signals are contributed by common variants, strong associations are found mainly at rare variants. Multiphase analysis can improve computational efficiency and reduce the multiple testing burden. PMID- 25519312 TI - Identification of rare variants for hypertension with incorporation of linkage information. AB - We conducted linkage analysis using the genome-wide association study data on chromosome 3, and then assessed association between hypertension and rare variants of genes located in the regions showing evidence of linkage. The rare variants were collapsed if their minor allele frequencies were less than or equal to the thresholds: 0.01, 0.03, or 0.05. In the collapsing process, they were either unweighted or weighted by the nonparametric linkage log of odds scores in 2 different schemes: exponential weighting and cumulative weighting. Logistic regression models using the generalized estimating equations approach were used to assess association between the collapsed rare variants and hypertension adjusting for age and gender. Evidence of association from the weighted and unweighted collapsing schemes with minor allele frequencies <=0.01, after accounting for multiple testing, was found for genes DOCK3 (p = 0.0090), ARMC8 (p = 1.29E-5), KCNAB1 (p = 5.8E-4), and MYRIP (p = 5.79E-6). DOCK3 and MYRIP are newly discovered. Incorporating linkage scores as weights was found to help identify rare causal variants with a large effect size. PMID- 25519313 TI - Family-based association test using normal approximation to gene dropping null distribution. AB - We derive the analytical mean and variance of the score test statistic in gene dropping simulations and approximate the null distribution of the test statistic by a normal distribution. We provide insights into the gene-dropping test by decomposing the test statistic into two components: the first component provides information about linkage, and the second component provides information about fine mapping under the linkage peak. We demonstrate our theoretical findings by applying the gene-dropping test to the simulated data set from Genetic Analysis Workshop 18 and comparing its performance with existing population and family based association tests. PMID- 25519314 TI - Data for Genetic Analysis Workshop 18: human whole genome sequence, blood pressure, and simulated phenotypes in extended pedigrees. AB - Genetic Analysis Workshop 18 (GAW18) focused on identification of genes and functional variants that influence complex phenotypes in human sequence data. Data for the workshop were donated by the T2D-GENES Consortium and included whole genome sequences for odd-numbered autosomes in 464 key individuals selected from 20 Mexican American families, a dense set of single-nucleotide polymorphisms in 959 individuals in these families, and longitudinal data on systolic and diastolic blood pressure measured at 1-4 examinations over a period of 20 years. Simulated phenotypes were generated based on the real sequence data and pedigree structures. In the design of the simulation model, gene expression measures from the San Antonio Family Heart Study (not distributed as part of the GAW18 data) were used to identify genes whose mRNA levels were correlated with blood pressure. Observed variants within these genes were designated as functional in the GAW18 simulation if they were nonsynonymous and predicted to have deleterious effects on protein function or if they were noncoding and associated with mRNA levels. Two simulated longitudinal phenotypes were modeled to have the same trait distributions as the real systolic and diastolic blood pressure data, with effects of age, sex, and medication use, including a genotype-medication interaction. For each phenotype, more than 1000 sequence variants in more than 200 genes present on the odd-numbered autosomes individually explained less than 0.01-2.78% of phenotypic variance. Cumulatively, variants in the most influential gene explained 7.79% of trait variance. An additional simulated phenotype, Q1, was designed to be correlated among family members but to not be associated with any sequence variants. Two hundred replicates of the phenotypes were simulated, with each including data for 849 individuals. PMID- 25519315 TI - A 2-step penalized regression method for family-based next-generation sequencing association studies. AB - Large-scale genetic studies are often composed of related participants, and utilizing familial relationships can be cumbersome and computationally challenging. We present an approach to efficiently handle sequencing data from complex pedigrees that incorporates information from rare variants as well as common variants. Our method employs a 2-step procedure that sequentially regresses out correlation from familial relatedness and then uses the resulting phenotypic residuals in a penalized regression framework to test for associations with variants within genetic units. The operating characteristics of this approach are detailed using simulation data based on a large, multigenerational cohort. PMID- 25519317 TI - Admixture mapping analysis in the context of GWAS with GAW18 data. AB - Admixture mapping is a disease-mapping strategy to identify disease susceptibility variants in an admixed population that is a result of mating between 2 historically separated populations differing in allele frequencies and disease prevalence. With the increasing availability of high-density genotyping data generated in genome-wide association studies, it is of interest to investigate how to apply admixture mapping in the context of the genome-wide association studies and how to adjust for admixture in association tests. In this study, we first evaluated 3 different local ancestry inference methods, LAMP, LAMP-LD, and MULTIMIX. Then we applied admixture mapping analysis based on estimated local ancestry. Finally, we performed association tests with adjustment for local ancestry. PMID- 25519316 TI - Comparing the power of family-based association tests for sequence data with applications in the GAW18 simulated data. AB - We apply a family-based extension of the sequence kernel association test (SKAT) to 93 trios extracted from the 20 pedigrees in the Genetic Analysis Workshop 18 simulated data. Each extracted trio includes a unique set of parents to ensure conditionally independent trios are sampled. We compare the empirical type I error and power between the family-based SKAT and the burden test under varying percentages of causal single-nucleotide polymorphisms included in the analysis. Our investigation using simulated data suggests that, under the setting used for Genetic Analysis Workshop 18 data, both the family-based SKAT and the burden test have limited power, and that there is no substantial impact of percentage of signal on the power of either test. The low power is partially a result of the small sample size. However, we find that both the family-based SKAT and the burden test are more powerful when we use only rare variants, rather than common variants, to test the association. PMID- 25519318 TI - Family-based tests applied to extended pedigrees identify rare variants related to hypertension. AB - The application of family-based tests to whole-genome sequenced data provides a new window on the role of rare variant alleles in the etiology of disease. By applying family-based tests to these data, we can now identify rare variants associated with disease. Approaches for common variants, by contrast, require large sample sizes for power, and are powerless when faced with rare variants. When we tested Yip et al's 2011 family-based association tests for rare variants on pedigrees from the Genetic Analysis Workshop 18, we found that weighted collapsing methods generally have more power than unweighted methods, but are more prone to type I errors. We then evaluated a sliding window modification of the weighted family-based association tests for rare variants method. Although this modification inflates the rate of false positives, it significantly increases the power of family-based association tests for rare variants to identify causal rare variants. PMID- 25519319 TI - Two-stage family-based designs for sequencing studies. AB - The cost of next-generation sequencing is now approaching that of the first generation of genome-wide single-nucleotide genotyping panels, but this is still out of reach for large-scale epidemiologic studies with tens of thousands of subjects. Furthermore, the anticipated yield of millions of rare variants poses serious challenges for distinguishing causal from noncausal variants for disease. We explore the merits of using family-based designs for sequencing substudies to identify novel variants and prioritize them for their likelihood of causality. While the sharing of variants within families means that family-based designs may be less efficient for discovery than sequencing of a comparable number of unrelated individuals, the ability to exploit cosegregation of variants with disease within families helps distinguish causal from noncausal ones. We introduce a score test criterion for prioritizing discovered variants in terms of their likelihood of being functional. We compare the relative statistical efficiency of 2-stage versus1-stage family-based designs by application to the Genetic Analysis Workshop 18 simulated sequence data. PMID- 25519320 TI - Rare genetic variant analysis on blood pressure in related samples. AB - The genetic variants associated with blood pressure identified so far explain only a small proportion of the total heritability of this trait. With recent advances in sequencing technology and statistical methodology, it becomes feasible to study the association between blood pressure and rare genetic variants. Using real baseline phenotype data and imputed dosage data from Genetic Analysis Workshop 18, we performed a candidate gene association analysis. We focused on 8 genes shown to be associated with either systolic or diastolic blood pressure to identify the association with both common and rare genetic variants, and then did a genome-wide rare-variant analysis on blood pressure. We performed association analysis for rare coding and splicing variants within each gene region and all rare variants in each sliding window, using either burden tests or sequence kernel association tests accounting for familial correlation. With a sample size of only 747, we failed to find any novel associated genetic loci. Consequently, we performed analyses on simulated data, with knowledge of the underlying simulating model, to evaluate the type I error rate and power for the methods used in real data analysis. PMID- 25519321 TI - Evaluation of the power and type I error of recently proposed family-based tests of association for rare variants. AB - Until very recently, few methods existed to analyze rare-variant association with binary phenotypes in complex pedigrees. We consider a set of recently proposed methods applied to the simulated and real hypertension phenotype as part of the Genetic Analysis Workshop 18. Minimal power of the methods is observed for genes containing variants with weak effects on the phenotype. Application of the methods to the real hypertension phenotype yielded no genes meeting a strict Bonferroni cutoff of significance. Some prior literature connects 3 of the 5 most associated genes (p <1 * 10(-4)) to hypertension or related phenotypes. Further methodological development is needed to extend these methods to handle covariates, and to explore more powerful test alternatives. PMID- 25519322 TI - Family-based Bayesian collapsing method for rare-variant association study. AB - In this study, we analyze the Genetic Analysis Workshop 18 data to identify the genes and underlying single-nucleotide polymorphisms on 11 chromosomes that exhibit significant association with systolic blood pressure. We propose a novel family-based method for rare-variant association detection based on the hierarchical Bayesian framework. The method controls spurious associations caused by population stratification, and improves the statistical power to detect not only individual rare variants, but also genes with either continuous or binary outcomes. Our method utilizes nuclear family information, and takes into account the effects of all single-nucleotide polymorphisms in a gene, using a hierarchical model. When we apply this method to the genome-wide Genetic Analysis Workshop 18 data, several genes and single-nucleotide polymorphisms are identified as potentially related to systolic blood pressure. PMID- 25519323 TI - Identifying cryptic population structure in multigenerational pedigrees in a Mexican American sample. AB - Cryptic population structure can increase both type I and type II errors. This is particularly problematic in case-control association studies of unrelated individuals. Some researchers believe that these problems are obviated in families. We argue here that this may not be the case, especially if families are drawn from a known admixed population such as Mexican Americans. We use a principal component approach to evaluate and visualize the results of three different approaches to searching for cryptic structure in the 20 multigenerational families of the Genetic Analysis Workshop 18 (GAW18). Approach 1 uses all family members in the sample to identify what might be considered "outlier" kindreds. Because families are likely to differ in size (in the GAW18 families, there is about a 4-fold difference in the number of typed individuals), approach 2 uses a weighting system that equalizes pedigree size. Approach 3 concentrates on the founders and the "marry-ins" because, in principle, the entire pedigree can be reconstructed with knowledge of the sequence of these unrelated individuals and genome-wide association study (GWAS) data on everyone else (to identify the position of recombinations). We demonstrate that these three approaches can yield very different insights about cryptic structure in a sample of families. PMID- 25519324 TI - Kernel score statistic for dependent data. AB - The kernel score statistic is a global covariance component test over a set of genetic markers. It provides a flexible modeling framework and does not collapse marker information. We generalize the kernel score statistic to allow for familial dependencies and to adjust for random confounder effects. With this extension, we adjust our analysis of real and simulated baseline systolic blood pressure for polygenic familial background. We find that the kernel score test gains appreciably in power through the use of sequencing compared to tag-single nucleotide polymorphisms for very rare single nucleotide polymorphisms with <1% minor allele frequency. PMID- 25519325 TI - Analysis of Genetic Analysis Workshop 18 data with gene-based penalized regression. AB - Under the premise that multiple causal variants exist within a disease gene and that we are underpowered to detect these variants individually, a variety of methods have been developed that attempt to cluster rare variants within a gene so that the variants may gather strength from one another. These methods group variants by gene or proximity, and test one gene or marker window at a time. We propose analyzing all genes simultaneously with a penalized regression method that enables grouping of all (rare and common) variants within a gene while subgrouping rare variants, thus borrowing strength from both rare and common variants within the same gene. We apply this approach using a burden based weighting of the rare variants to the Genetic Analysis Workshop 18 data. PMID- 25519326 TI - Whole genome sequencing data from pedigrees suggests linkage disequilibrium among rare variants created by population admixture. AB - Next-generation sequencing technologies have been designed to discover rare and de novo variants and are an important tool for identifying rare disease variants. Many statistical methods have been developed to test, using next-generation sequencing data, for rare variants that are associated with a trait. However, many of these methods make assumptions that rare variants are in linkage equilibrium in a gene. In this report, we studied whether transmitted or untransmitted haplotypes carry an excess of rare variants using the whole genome sequencing data of 15 large Mexican American pedigrees provided by the Genetic Analysis Workshop 18. We observed that an excess of rare variants are carried on either transmitted or nontransmitted haplotypes from parents to offspring. Further analyses suggest that such nonrandom associations among rare variants can be attributed to population admixture and single-nucleotide variant calling errors. Our results have significant implications for rare variant association studies, especially those conducted in admixed populations. PMID- 25519327 TI - A Bayesian hierarchical gene model on latent genotypes for genome-wide association studies. AB - The primary goal of genome-wide association studies is to determine which genetic markers are associated with genetic traits, most commonly human diseases. As a result of the "large p, small n" nature of genome-wide association study data sets, and especially because of the collinearity due to linkage disequilibrium, multivariate regression results in an ill-posed problem. To overcome these obstacles, we propose preprocessing single-nucleotide polymorphisms to adjust for linkage disequilibrium, and a novel Bayesian statistical model that exploits a hierarchical structure between single-nucleotide polymorphisms and genes. We obtain posterior samples using a hybrid Metropolis-within-Gibbs sampler, and further conduct inference on single-nucleotide polymorphism and gene associations using centroid estimation. Finally, we illustrate the proposed model and estimation procedure and discuss results obtained on the data provided for the Genetic Analysis Workshop 18. PMID- 25519328 TI - A dual-clustering framework for association screening with whole genome sequencing data and longitudinal traits. AB - Current sequencing technology enables generation of whole genome sequencing data sets that contain a high density of rare variants, each of which is carried by, at most, 5% of the sampled subjects. Such variants are involved in the etiology of most common diseases in humans. These diseases can be studied by relevant longitudinal phenotype traits. Tests for association between such genotype information and longitudinal traits allow the study of the function of rare variants in complex human disorders. In this paper, we propose an association screening framework that highlights the genotypic differences observed on rare variants and the longitudinal nature of phenotypes. In particular, both variants within a gene and longitudinal phenotypes are used to create partitions of subjects. Association between the 2 sets of constructed partitions is then evaluated. We apply the proposed strategy to the simulated data from the Genetic Analysis Workshop 18 and compare the obtained results with those from sequence kernel association test using the receiver operating characteristic curves. PMID- 25519329 TI - Comparison of several sequence-based association methods in pedigrees. AB - Genome-wide association studies are very powerful in determining the genetic variants affecting complex diseases. Most of the available methods are very useful in detecting association between common variants and complex diseases. Recently, methods to detect rare variants in association with complex diseases have been developed with the increasingly available sequencing data from next generation sequencing. In this paper, we evaluate and compare several of these recent methods for performing statistical association using whole genome sequencing data in pedigrees. Specifically, functional principal component analysis (FPCA), extended combined multivariate and collapsing (CMC) method for families, a generalized T(2) method, and chi-square minimum approach were compared by analyzing all the genetic variants, common and rare, of both the real data set and the simulated data set provided as part of Genetic Analysis Workshop 18. PMID- 25519330 TI - Estimating and adjusting for ancestry admixture in statistical methods for relatedness inference, heritability estimation, and association testing. AB - It is well known that genetic association studies are not robust to population stratification. Two widely used approaches for the detection and correction of population structure are principal component analysis and model-based estimation of ancestry. These methods have been shown to give reliable inference on population structure in unrelated samples. We evaluated these two approaches in Mexican American pedigrees provided by the Genetic Analysis Workshop 18. We also estimated identity-by-descent sharing probabilities and kinship coefficients, with adjustment for ancestry admixture, to confirm documented pedigree relationships as well as to identify cryptic relatedness in the sample. We also estimated the heritability of the first simulated replicate of diastolic blood pressure (DBP). Finally, we performed an association analysis with simulated DBP, comparing the performance of an association method that corrects for population structure but does not account for relatedness to a method that adjusts for both population and pedigree structure. Analyses with simulated DBP were performed with knowledge of the underlying trait model. PMID- 25519331 TI - Collapsing singletons may boost signal for associating rare variants in sequencing study. AB - Advances in next-generation sequencing technology have made it possible to comprehensively interrogate the entire spectrum of genomic variations including rare variants. They may help capture the remaining genetic heritability which has not been fully explained by previous genome-wide association studies. Here we performed a gene-based genome-wide scan to identify hypertension susceptibility loci in analysis of a whole genome sequencing cohort of 103 unrelated individuals. We found that collapsing singletons may boost signals for associating rare variants and identified SETX statistically significant by a genome-wide gene-based threshold (p value <5.0 * 10(-6)). The function of SETX in hypertension may be worthy of further investigation. PMID- 25519332 TI - Detection of imprinting effects for hypertension based on general pedigrees utilizing all affected and unaffected individuals. AB - Imprinting effects can lead to parent-of-origin patterns in many complex human diseases. For hypertension, previous studies revealed the possible involvement of imprinted genes. Genetic Analysis Workshop 18 real data, with hypertensive phenotype and genotype of more than 1000 individuals from 20 pedigrees, provided us an opportunity to further substantiate such findings. To test for imprinting effects, we developed a pedigree-parental-asymmetry test taking both affected and unaffected offspring into consideration (PPATu). We carried out a simulation study based on the Genetic Analysis Workshop 18 pedigrees to show that PPATu has well-controlled type I error and is indeed more powerful than the pedigree parental-asymmetry test (PPAT), an existing method that does not utilize information from unaffected offspring. We then applied PPATu to Genetic Analysis Workshop 18 genome-wide association study data from 20 pedigrees. We identified a number of single-nucleotide polymorphisms showing significant imprinting effects that are within genomic regions that have been previously implicated to be associated with hypertension. PMID- 25519333 TI - Application of noncollapsing methods to the gene-based association test: a comparison study using Genetic Analysis Workshop 18 data. AB - Rare variants have been proposed to play a significant role in the onset and development of common diseases. However, traditional analysis methods have difficulties in detecting association signals for rare causal variants because of a lack of statistical power. We propose a two-stage, gene-based method for association mapping of rare variants by applying four different noncollapsing algorithms. Using the Genome Analysis Workshop18 whole genome sequencing data set of simulated blood pressure phenotypes, we studied and contrasted the false positive rate of each algorithm using receiver operating characteristic curves. The statistical power of these methods was also evaluated and compared through the analysis of 200 simulated replications in a smaller genotype data set. We showed that the Fisher's method was superior to the other 3 noncollapsing methods, but was no better than the standard method implemented with famSKAT. Further investigation is needed to explore the potential statistical properties of these approaches. PMID- 25519334 TI - Evaluation of logistic Bayesian LASSO for identifying association with rare haplotypes. AB - It has been hypothesized that rare variants may hold the key to unraveling the genetic transmission mechanism of many common complex traits. Currently, there is a dearth of statistical methods that are powerful enough to detect association with rare haplotypes. One of the recently proposed methods is logistic Bayesian LASSO for case-control data. By penalizing the regression coefficients through appropriate priors, logistic Bayesian LASSO weeds out the unassociated haplotypes, making it possible for the associated rare haplotypes to be detected with higher powers. We used the Genetic Analysis Workshop 18 simulated data to evaluate the behavior of logistic Bayesian LASSO in terms of its power and type I error under a complex disease model. We obtained knowledge of the simulation model, including the locations of the functional variants, and we chose to focus on two genomic regions in the MAP4 gene on chromosome 3. The sample size was 142 individuals and there were 200 replicates. Despite the small sample size, logistic Bayesian LASSO showed high power to detect two haplotypes containing functional variants in these regions while maintaining low type I errors. At the same time, a commonly used approach for haplotype association implemented in the software hapassoc failed to converge because of the presence of rare haplotypes. Thus, we conclude that logistic Bayesian LASSO can play an important role in the search for rare haplotypes. PMID- 25519335 TI - Use of admixture and association for detection of quantitative trait loci in the Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Ethnic Samples (T2D-GENES) study. AB - Admixture mapping and association testing have been successfully applied to the detection of genes for complex diseases. Methods have also been developed to combine these approaches. As an initial step to determine the feasibility of combining admixture and association mapping in the context of whole genome sequencing, we have applied several methods to data from the Genetic Analysis Workshop 18. Here, we describe the steps necessary to carry out such a study from selection of reference populations and preprocessing of data through to the testing itself. We detected one significant result with a Bonferroni corrected p value of 0.032 at single nucleotide polymorphism rs12639065. Computing local ancestry for Hispanic populations was challenging because there are relatively few methods by which to handle 3-way admixture, and publicly available Native American reference panels are scarce. However, combining admixture and association is a promising approach for detection of quantitative trait loci because it might be able to elevate the power of detection by combining 2 different sources of genetic signal. PMID- 25519336 TI - A powerful statistical method identifies novel loci associated with diastolic blood pressure triggered by nonlinear gene-environment interaction. AB - The genetic basis of blood pressure often involves multiple genetic factors and their interactions with environmental factors. Gene-environment interaction is assumed to play an important role in determining individual blood pressure variability. Older people are more prone to high blood pressure than younger ones and the risk may not display a linear trend over the life span. However, which gene shows sensitivity to aging in its effect on blood pressure is not clear. In this work, we allowed the genetic effect to vary over time and propose a varying coefficient model to identify potential genetic players that show nonlinear response across different age stages. We detected 2 novel loci, gene MIR1263 (a microRNA coding gene) on chromosome 3 and gene UNC13B on chromosome 9, that are nonlinearly associated with diastolic blood pressure. Further experimental validation is needed to confirm this finding. PMID- 25519337 TI - Single-marker and multi-marker mixed models for polygenic score analysis in family-based data. AB - Genome-wide association studies have proven successful but they remain underpowered for detecting variants of weaker effect. Alternative methods propose to test for association by using an aggregate score that combines the effects of the most associated variants. The set of variants that are to be aggregated may come from either of two modeling approaches: single-marker or multi-marker. The goal of this paper is to evaluate this alternative strategy by using sets of single-nucleotide polymorphisms identified by the two modeling approaches in the simulated pedigree data set provided for the Genetic Analysis Workshop 18. We focused on quantitative traits association analysis of diastolic blood pressure and of Q1, which served to control the statistical significance of our results. We carried out all analyses with knowledge of the underlying simulation model. We found that the probability to replicate association with the aggregate score depends on the single-nucleotide polymorphism set size and, for smaller sets (<=100), on the modeling approach. Nonetheless, assessing the statistical significance of these results in this data set was challenging, likely because of linkage because we are analyzing pedigree data, and also because the genotypes were the same across the replicates. Further methods need to be developed to facilitate the application of this alternative strategy in pedigree data. PMID- 25519338 TI - Practical investigation of the performance of robust logistic regression to predict the genetic risk of hypertension. AB - Logistic regression is usually applied to investigate the association between inherited genetic variants and a binary disease phenotype. A limitation of standard methods used to estimate the parameters of logistic regression models is their strong dependence on a few observations deviating from the majority of the data. We used data from the Genetic Analysis Workshop 18 to explore the possible benefit of robust logistic regression to estimate the genetic risk of hypertension. The comparison between standard and robust methods relied on the influence of departing hypertension profiles (outliers) on the estimated odds ratios, areas under the receiver operating characteristic curves, and clinical net benefit. Our results confirmed that single outliers may substantially affect the estimated genotype relative risks. The ranking of variants by probability values was different in standard and in robust logistic regression. For cutoff probabilities between 0.2 and 0.6, the clinical net benefit estimated by leave one-out cross-validation in the investigated sample was slightly larger under robust regression, but the overall area under the receiver operating characteristic curve was larger for standard logistic regression. The potential advantage of robust statistics in the context of genetic association studies should be investigated in future analyses based on real and simulated data. PMID- 25519339 TI - Prediction of genetic contributions to complex traits using whole genome sequencing data. AB - Although markers identified by genome-wide association studies have individually strong statistical significance, their performance in prediction remains limited. Our goal was to use animal breeding genomic prediction models to predict additive genetic contributions for systolic blood pressure (SBP) using whole genome sequencing data with different validation designs. The additive genetic contributions of SBP were estimated via linear mixed model. Rare variants (MAF<0.05) were collapsed through the k-means method to create a "collapsed single-nucleotide polymorphisms." Prediction of the additive genomic contributions of SBP was conducted using genomic Best Linear Unbiased Predictor (GBLUP) and BayesCpi. Estimates of predictive accuracy were compared using common single-nucleotide polymorphisms (SNPs) versus common and collapsed SNPs, and for prediction within and across families. The additive genetic variance of SBP contributed to 18% of the phenotypic variance (h(2) = 0.18). BayesCpi had slightly better prediction accuracies than GBLUP. In both models, within-family predictions had higher accuracies both in the training and testing set than didacross-family design. Collapsing rare variants via the k-means method and adding to the common SNPs did not improve prediction accuracies. The prediction model, including both pedigree and genomic information, achieved a slightly higher accuracy than using either source of information alone. Prediction of genetic contributions to complex traits is feasible using whole genome sequencing and statistical methods borrowed from animal breeding. The relatedness of individuals between the training and testing set strongly affected the performance of prediction models. Methods for inclusion of rare variants in these models need more development. PMID- 25519340 TI - Modeling of multivariate longitudinal phenotypes in family genetic studies with Bayesian multiplicity adjustment. AB - Genetic studies often collect data on multiple traits. Most genetic association analyses, however, consider traits separately and ignore potential correlation among traits, partially because of difficulties in statistical modeling of multivariate outcomes. When multiple traits are measured in a pedigree longitudinally, additional challenges arise because in addition to correlation between traits, a trait is often correlated with its own measures over time and with measurements of other family members. We developed a Bayesian model for analysis of bivariate quantitative traits measured longitudinally in family genetic studies. For a given trait, family-specific and subject-specific random effects account for correlation among family members and repeated measures, respectively. Correlation between traits is introduced by incorporating multivariate random effects and allowing time-specific trait residuals to correlate as in seemingly unrelated regressions. The proposed model can examine multiple single-nucleotide variations simultaneously, as well as incorporate familyspecific, subject-specific, or time-varying covariates. Bayesian multiplicity technique is used to effectively control false positives. Genetic Analysis Workshop 18 simulated data illustrate the proposed approach's applicability in modeling longitudinal multivariate outcomes in family genetic association studies. PMID- 25519341 TI - A novel transmission-based test of association for multivariate phenotypes: an application to systolic and diastolic blood pressure levels. AB - Unlike case-control studies, family-based tests for association are protected against population stratification. Complex genetic traits are often governed by quantitative precursors and it has been argued that it may be a more powerful strategy to analyze these quantitative precursors instead of the clinical end point trait. Although methods have been developed for family-based association tests for single quantitative traits, it is of interest to develop such methods for multivariate phenotypes. We propose a novel transmission-based approach based on a trio design using a simple logistic regression to test for association with a multivariate phenotype. We use our proposed method to analyze data on systolic and diastolic blood pressure levels provided in Genetic Analysis Workshop 18. However, we find that the bivariate analysis of the two phenotypes did not provide more promising results compared to univariate analyses, suggesting a possibility of a different set of major genetic variants modulating the two phenotypes. PMID- 25519342 TI - Bivariate genetic association analysis of systolic and diastolic blood pressure by copula models. AB - We conduct genetic association analysis in the subset of unrelated individuals from the San Antonio Family Studies pedigrees, applying a two-stage approach to take account of the dependence between systolic and diastolic blood pressure (SBP and DBP). In the first stage, we adjust blood pressure for the effects of age, sex, smoking, and use of antihypertensive medication based on a novel modification of censored regression. In the second stage, we model the bivariate distribution of the adjusted SBP and DBP phenotypes by a copula function with interpretable SBP-DBP correlation parameters. This allows us to identify genetic variants associated with each of the adjusted blood pressures, as well as variants that explain the association between the two phenotypes. Within this framework, we define a pleiotropic variant as one that reduces the SBP-DBP correlation. Our results for whole genome sequence variants in the gene ULK4 on chromosome 3 suggest that inference obtained from a copula model can be more informative than findings from the SBP-specific and DBP-specific univariate models alone. PMID- 25519343 TI - Penalized multivariate linear mixed model for longitudinal genome-wide association studies. AB - We consider analysis of Genetic Analysis Workshop 18 data, which involves multiple longitudinal traits and dense genome-wide single-nucleotide polymorphism (SNP) markers. We use a multivariate linear mixed model to account for the covariance of random effects and multivariate residuals. We divide the SNPs into groups according to the genes they belong to and score them using weighted sum statistics. We propose a penalized approach for genetic variant selection at the gene level. The overall modeling and penalized selection method is referred to as the penalized multivariate linear mixed model. Cross-validation is used for tuning parameter selection. A resampling approach is adopted to evaluate the relative stability of the identified genes. Application to the Genetic Analysis Workshop 18 data shows that the proposed approach can effectively select markers associated with phenotypes at gene level. PMID- 25519344 TI - Analysis of the progression of systolic blood pressure using imputation of missing phenotype values. AB - We present a genome-wide association study of a quantitative trait, "progression of systolic blood pressure in time," in which 142 unrelated individuals of the Genetic Analysis Workshop 18 real genotype data were analyzed. Information on systolic blood pressure and other phenotypic covariates was missing at certain time points for a considerable part of the sample. We observed that the dropout process causing missingness is not independent of the initial systolic blood pressure; that is, the data is not missing completely at random. However, after the adjustment for age, the impact of systolic blood pressure on dropouts was no longer significant. Therefore, we decided to impute missing phenotype values by using information from individuals with complete phenotypic data. Progression of systolic blood pressure (?SBP/?t) was defined based on the imputed phenotypes and analyzed in a genome-wide fashion. We also conducted an exhaustive genome-wide search for interaction between single-nucleotide polymorphisms (7.14 * 10(10) tests) under an allelic model. The suggested data imputation and the association analysis strategy proved to be valid in the sense that there was no evidence of genome-wide inflation or increased type I error in general. Furthermore, we detected 2 single-nucleotide polymorphisms (SNPs) that met the criterion for genome-wide significance (p<=5 * 10(-8)), which was also confirmed via Monte Carlo simulation. In view of the rather small sample size, however, the results have to be followed-up in larger studies. PMID- 25519345 TI - Mixed-effects models for GAW18 longitudinal blood pressure data. AB - In this paper, we propose two mixed-effects models for Genetic Analysis Workshop 18 (GAW18) longitudinal blood pressure data. The first method extends EMMA, an efficient mixed-model association-mapping algorithm. EMMA corrects for population structure and genetic relatedness using a kinship similarity matrix. We replace the kinship similarity matrix in EMMA with an estimated correlation matrix for modeling the dependence structure of repeated measurements. Our second approach is a Bayesian multiple association-mapping algorithm based on a mixed-effects model with a built-in variable selection feature. It models multiple single nucleotide polymorphisms (SNPs) simultaneously and allows for SNP-SNP interactions and SNP-environment interactions. We applied these two methods to the longitudinal systolic blood pressure (SBP) and diastolic blood pressure (DBP) data from GAW18. The extended EMMA method identified a single SNP on Chr5:75506197 (p-value = 4.67 * 10(-7)) for SBP and three SNPs on Chr3:23715851 (p-value = 9.00 * 10(-8)), Chr 17:54834217 (p-value = 1.98 * 10(-7)), and Chr21:18744081 (p-value = 4.95 * 10(-7)) for DBP. The Bayesian method identified several additional SNPs on Chr1:17876090 (Bayes factor [BF] = 102), Chr3:197469358 (BF = 69), Chr15:87675666 (BF = 43), and Chr19:41642807 (BF = 33) for SBP. Furthermore, for SBP, we found a single SNP on Chr3:197469358 (BF = 69) that has a strong interaction with age. We further evaluated the performances of the proposed methods by simulations. PMID- 25519346 TI - Bivariate association analysis of longitudinal phenotypes in families. AB - Statistical genetic methods incorporating temporal variation allow for greater understanding of genetic architecture and consistency of biological variation influencing development of complex diseases. This study proposes a bivariate association method jointly testing association of two quantitative phenotypic measures from different time points. Measured genotype association was analyzed for single-nucleotide polymorphisms (SNPs) for systolic blood pressure (SBP) from the first and third visits using 200 simulated Genetic Analysis Workshop 18 (GAW18) replicates. Bivariate association, in which the effect of an SNP on the mean trait values of the two phenotypes is constrained to be equal for both measures and is included as a covariate in the analysis, was compared with a bivariate analysis in which the effect of an SNP was estimated separately for the two measures and univariate association analyses in 9 SNPs that explained greater than 0.001% SBP variance over all 200 GAW18 replicates.The SNP 3_48040283 was significantly associated with SBP in all 200 replicates with the constrained bivariate method providing increased signal over the unconstrained bivariate method. This method improved signal in all 9 SNPs with simulated effects on SBP for nominal significance (p-value <0.05). However, this appears to be determined by the effect size of the SNP on the phenotype. This bivariate association method applied to longitudinal data improves genetic signal for quantitative traits when the effect size of the variant is moderate to large. PMID- 25519347 TI - Mixed-effects models for joint modeling of sequence data in longitudinal studies. AB - In this paper, we propose a novel mixed-effects model for longitudinal changes of systolic blood pressure (SBP) over time that can estimate the joint effect of multiple sequence variants on SBP after accounting for familial correlation and the time dependencies within individuals. First we carried out agenome-wide association study (GWAS) using chromosome 3 single-nucleotide polymorphisms(SNPs) to identify regions associated with SBP levels. In a second step, we examined the sequence data to fine-map additional variants in these regions. Four SNPs from two intergenic regions (PLXNA1-TPRA1, BPESC1-PISTR1) and one gene (NLGN1) were detected to be significantly associated with SBP after adjusting for multiple testing. These SNPs were used to capture the multilocus genotype diversity in the regions. The multilocus genotypes derived from these four variants were then treated as random effects in the mixed-effects model, and the corresponding confidence intervals (Cis) were built to assess the significance of the joint effect of the sequence variants on SBP. We found that multilocus genotypes (GG,TT,AG,GG), (GG,TT,GG,GG), and (GG,TT,AA,AG) are associated with higher SBPand (GG,CT,AA,AA), (AA,TT,AA,AA), and (AG,CT,AA,AG) are associated with lower SBP. The linear mixed-effects models provide a powerful tool for GWAS and the analysis of joint modeling of multilocus genotypes. PMID- 25519348 TI - Fast genome-wide pedigree quantitative trait loci analysis using MENDEL. AB - The linkage era left a rich legacy of pedigree samples that can be used for modern genome-wide association sequencing (GWAS) or next-generation sequencing (NGS) studies. Family designs are naturally equipped to detect rare variants, control for population stratification, and facilitate the study of parent-of origin effects. Unfortunately, pedigree likelihoods are notoriously hard to compute, and current software for association mapping in pedigrees is prohibitively slow in processing dense marker maps. In a recent release of the comprehensive genetic analysis software MENDEL, we implemented an ultra-fast score test for association mapping with pedigree-based GWAS or NGS study data. Our implementation (a) works for random sample data, pedigree data, or a mix of both;(b) allows for covariate adjustment, including correction for population stratification;(c) accommodates both univariate and multivariate quantitative traits; and (d) allows missing values in multivariate traits. In this paper, we assess the capabilities of MENDEL on the Genetic Analysis Workshop 18 sequencing data. For instance, when jointly testing the 4 longitudinally measured diastolic blood pressure traits, it takes MENDEL less than 51 minutes on a standard laptop computer to read, quality check, and analyze a data set with 959 individuals and 8.3 million single-nucleotide polymorphisms (SNPs). Our analysis reveals association of one SNP in the q32.2 region of chromosome 1. MENDEL is freely available on http://www.genetics.ucla.edu/software. PMID- 25519350 TI - Testing for associations between systolic blood pressure and single-nucleotide polymorphism profiles obtained from sparse principal component analysis. AB - BACKGROUND: Hypertension is a prevalent condition linked to major cardiovascular conditions and multiple other comorbidities. Genetic information can offer a deeper understanding about susceptibility and the underlying disease mechanisms. The Genetic Analysis Workshop 18 (GAW18) provides abundant genotype data to determine genetic associations for being hypertensive and for the underlying trait of systolic blood pressure (SBP). The high-dimensional nature of this data promotes dimension reduction techniques to remove excess noise and also synthesize genetic information for complex, polygenic traits. METHODS: For both measured and simulated phenotype data from GAW18, we use sparse principal component analysis to obtain sparse genetic profiles that represent the underlying data structures. We then detect associations between the obtained sparse principal components (PCs) and SBP, a major indicator of hypertension, following up by investigating the sparse PCs for genetic structure to gain insight into new patterns. RESULTS: After adjusting for multiple testing, 27 of 122 PCs were significantly associated with measured SBP, offering a large number of components to investigate. Considering the top 3 PCs, linked genetic regions have been identified; these may act in unison while associated with SBP. Simulated data offered similar results. CONCLUSIONS: Sparse PCs can offer a new data-driven approach to structuring genotype data and understanding the genetic mechanics behind complex, polygenic traits such as hypertension. PMID- 25519349 TI - Does the inclusion of rare variants improve risk prediction? AB - Every known link between a genetic variant and blood pressure improves the understanding and potentially the risk assessment of related diseases such as hypertension. Genetic data have become increasingly comprehensive and available for an increasing number of samples. The availability of whole-genome sequencing data means that statistical genetic models must evolve to meet the challenge of using both rare variants (RVs) and common variants (CVs) to link previously unidentified genome loci to disease-related traits. Penalized regression has two features, variable selection and proportional coefficient shrinkage, that allow researchers to build models tailored to hypothesized characteristics of the genotype-phenotype map. The following work uses the Genetic Analysis Workshop 18 data to investigate the performance of a spectrum of penalized regressions using at first only CVs or only RVs to predict systolic blood pressure (SBP). Next, combinations of CVs and RVs are used to model SBP, and the impact on prediction is quantified. The study demonstrates that penalized regression improves blood pressure prediction for any combination of CVs and RVs compared with maximum likelihood estimation. More significantly, models using both types of variants provide better predictions of SBP than those using only CVs or only RVs. The predictive mean squared error was reduced by up to 11.5% when RVs were added to CV-only penalized regression models. Elastic net regression with equally weighted LASSO and ridge components, in particular, can use large numbers of single nucleotide polymorphisms to improve prediction. PMID- 25519351 TI - Comparing logistic regression, support vector machines, and permanental classification methods in predicting hypertension. AB - In this paper, we compare logistic regression and 2 other classification methods in predicting hypertension given the genotype information. We use logistic regression analysis in the first step to detect significant single-nucleotide polymorphisms (SNPs). In the second step, we use the significant SNPs with logistic regression, support vector machines (SVMs), and a newly developed permanental classification method for prediction purposes. We also detect rare variants and investigate their impact on prediction. Our results show that SVMs and permanental classification both outperform logistic regression, and they are comparable in predicting hypertension status. PMID- 25519352 TI - Correction: A dual clustering framework for association screening with whole genome sequencing data and longitudinal traits. PMID- 25519353 TI - Rare variant analysis of blood pressure phenotypes in the Genetic Analysis Workshop 18 whole genome sequencing data using sequence kernel association test. AB - Sequence kernel association test (SKAT) has become one of the most commonly used nonburden tests for analyzing rare variants. Performance of burden tests depends on the weighting of rare and common variants when collapsing them in a genomic region. Using the systolic and diastolic blood pressure phenotypes of 142 unrelated individuals in the Genetic Analysis Workshop 18 data, we investigated whether performance of SKAT also depends on the weighting scheme. We analyzed the entire sequencing data for all 200 replications using 3 weighting schemes: equal weighting, Madsen-Browning weighting, and SKAT default linear weighting. We considered two options: all single-nucleotide polymorphisms (SNPs) and only low frequency SNPs. A SKAT default weighting scheme (which heavily downweights common variants) performed better for the genes in which causal SNPs are mostly rare. This SKAT default weighting scheme behaved similarly to other weighting schemes after eliminating all common SNPs. In contrast, the equal weighting scheme performed the best for MAP4 and FLT3, both of which included a common variant with a large effect. However, SKAT with all 3 weighting schemes performed poorly. Overall power across all causal genes was about 0.05, which was almost identical to the type I error rate. This poor performance is partly due to a small sample size because of the need to analyze only unrelated individuals. Because a half of causal SNPs were not found in the annotation file based on the 1000 Genomes Project, we suspect that performance was also affected by our use of incomplete annotation information. PMID- 25519354 TI - Pedigree-based random effect tests to screen gene pathways. AB - The new generation of sequencing platforms opens new horizons in the genetics field. It is possible to exhaustively assay all genetic variants in an individual and search for phenotypic associations. The whole genome sequencing approach, when applied to a large human sample like the San Antonio Family Study, detects a very large number (>25 million) of single nucleotide variants along with other more complex variants. The analytical challenges imposed by this number of variants are formidable, suggesting that methods are needed to reduce the overall number of statistical tests. In this study, we develop a single degree-of-freedom test of variants in a gene pathway employing a random effect model that uses an empirical pathway-specific genetic relationship matrix as the focal covariance kernel. The empirical pathway-specific genetic relationship uses all variants (or a chosen subset) from gene members of a given biological pathway. Using SOLAR's pedigree-based variance components modeling, which also allows for arbitrary fixed effects, such as principal components, to deal with latent population structure, we employ a likelihood ratio test of the pathway-specific genetic relationship matrix model. We examine all gene pathways in KEGG database gene pathways using our method in the first replicate of the Genetic Analysis Workshop 18 simulation of systolic blood pressure. Our random effect approach was able to detect true association signals in causal gene pathways. Those pathways could be easily be further dissected by the independent analysis of all markers. PMID- 25519355 TI - Pathway-based analysis of rare and common variants to test for association with blood pressure. AB - Our goal is to test the effect of both rare and common variants in a blood pressure study. We use a pathway-based approach, gene-set enrichment analysis, to search for related genes affecting 4 phenotypes: systolic blood pressure, diastolic blood pressure, the difference between each of them and mean arterial pressure, which is a weighted linear combination of systolic and diastolic blood pressure. Using the real Genetic Analysis Workshop 18 data, we consider both rare and common variants in our analysis and incorporate other covariates by using a recently proposed test statistic. Our study identified a commonly enriched gene set/pathway for the two derived phenotypes we analyzed: the difference between systolic and diastolic blood pressure and mean arterial pressure, but none is identified with the individual blood pressure phenotypes. The gene CD47, in the enriched gene pathway/set, was reported in previous studies to be related to blood pressure. The findings are not surprising because the sample size we use in our analysis is small, and hence power to detect small but important effects is likely inadequate. PMID- 25519356 TI - Estimating proportions of explained variance: a comparison of whole genome subsets. AB - Following the publication of the ENCODE project results, there has been increasing interest in investigating different areas of the chromosome and evaluating the relative contribution of each area to expressed phenotypes. This study aims to evaluate the contribution of variants, classified by minor allele frequency and gene annotation, to the observed interindividual differences. In this study, we fitted Bayesian linear regression models to data from Genetic Analysis Workshop 18 (n = 395) to estimate the variance of standardized and log transformed systolic blood pressure that can be explained by subsets of genetic markers. Rare and very rare variants explained an overall higher proportion of the variance, as did markers located within a gene rather than flanking regions. The proportion of variance explained by rare and very rare variants decreased when we controlled for the number of markers, suggesting that the number of contributing rare alleles plays an important role in the genetic architecture of chronic disease traits. Our findings lend support to the "common disease, rare variant" hypothesis for systolic blood pressure and highlight allele frequency and functional annotation of a polymorphism as potentially crucial considerations in whole genome study designs. PMID- 25519357 TI - Pathway analysis for genetic association studies: to do, or not to do? That is the question. AB - In Genetic Analysis Workshop 18 data, we used a 3-stage approach to explore the benefits of pathway analysis in improving a model to predict 2 diastolic blood pressure phenotypes as a function of genetic variation. At stage 1, gene-based tests of association in family data of approximately 800 individuals found over 600 genes associated at p<0.05 for each phenotype. At stage 2, networks and enriched pathways were estimated with Cytoscape for genes from stage 1, separately for the 2 phenotypes, then examining network overlap. This overlap identified 4 enriched pathways, and 3 of these pathways appear to interact, and are likely candidates for playing a role in hypertension. At stage 3, using 157 maximally unrelated individuals, partial least squares regression was used to find associations between diastolic blood pressure and single-nucleotide polymorphisms in genes highlighted by the pathway analyses. However, we saw no improvement in the adjusted cross-validated R (2). Although our pathway-motivated regressions did not improve prediction of diastolic blood pressure, merging gene networks did identify several plausible pathways for hypertension. PMID- 25519358 TI - Integrated statistical and pathway approach to next-generation sequencing analysis: a family-based study of hypertension. AB - Genome wide association studies (GWAS) have been used to search for associations between genetic variants and a phenotypic trait of interest. New technologies, such as next-generation sequencing, hold the potential to revolutionize GWAS. However, millions of polymorphisms are identified with next-generation sequencing technology. Consequently, researchers must be careful when performing such a large number of statistical tests, and corrections are typically made to account for multiple testing. Additionally, for typical GWAS, the p value cutoff is set quite low (approximately <10(-8)). As a result of this p value stringency, it is likely that there are many true associations that do not meet this threshold. To account for this we have incorporated a priori biological knowledge to help identify true associations that may not have reached statistical significance. We propose the application of a pipelined series of statistical and bioinformatic methods, to enable the assessment of the association of genetic polymorphisms with a disease phenotype--here, hypertension--as well as the identification of statistically significant pathways of genes that may play a role in the disease process. PMID- 25519359 TI - Application of family-based tests of association for rare variants to pathways. AB - Pathway analysis approaches for sequence data typically either operate in a single stage (all variants within all genes in the pathway are combined into a single, very large set of variants that can then be analyzed using standard "gene based" test statistics) or in 2-stages (gene-based p values are computed for all genes in the pathway, and then the gene-based p values are combined into a single pathway p value). To date, little consideration has been given to the performance of gene-based tests (typically designed for a smaller number of single-nucleotide variants [SNVs]) when the number of SNVs in the gene or in the pathway is very large and the genotypes come from sequence data organized in large pedigrees. We consider recently proposed gene-based tests for rare variants from complex pedigrees that test for association between a large set of SNVs and a qualitative phenotype of interest (1-stage analyses) as well as 2-stage approaches. We find that many of these methods show inflated type I errors when the number of SNVs in the gene or the pathway is large (>200 SNVs) and when using standard approaches to estimate the genotype covariance matrix. Alternative methods are needed when testing very large sets of SNVs in 1-stage approaches. PMID- 25519360 TI - Dynamic pathway analysis of genes associated with blood pressure using whole genome sequence data. AB - Groups of genes assigned to a pathway, also called a module, have similar functions. Finding such modules, and the topology of the changes of the modules over time, is a fundamental problem in understanding the mechanisms of complex diseases. Here we investigated an approach that categorized variants into rare or common and used a hierarchical model to jointly estimate the group effects of the variants in a pathway for identifying enriched pathways over time using whole genome sequencing data and blood pressure data. Our results suggest that the method can identify potentially biologically meaningful genes in modules associated with blood pressure over time. PMID- 25519361 TI - An exploration of heterogeneity in genetic analysis of complex pedigrees: linkage and association using whole genome sequencing data in the MAP4 region. AB - We conduct pedigree-based linkage and association analyses of simulated systolic blood pressure data in the nonascertained large Mexican American pedigrees provided by Genetic Analysis Workshop 18, focusing on observed sequence variants in MAP4 on chromosome 3. Because pedigrees are large and sequence data have been completed by imputation, it is feasible to conduct analysis for each pedigree separately as well as for all pedigrees combined. We are interested in quantifying and explaining between-pedigree heterogeneity in linkage and association signals. To this end, we first examine minor allele frequency differences between pedigrees. In some of the pedigrees, rare and low-frequency variants occur at a higher prevalence than in all pedigrees combined. In simulation replicate 1, we conduct variance-components linkage and association analysis of all 894 MAP4 variants to compare analytic approaches in single pedigree and combined analysis. In all 200 replicates, we similarly examine the 15 causal variants in MAP4 known under the generating model. We illustrate how random allele frequency variation among pedigrees leads to heterogeneity in pedigree-specific linkage and association signals. PMID- 25519363 TI - False-positive rates in two-point parametric linkage analysis. AB - Two-point linkage analyses of whole genome sequence data are a promising approach to identify rare variants that segregate with complex diseases in large pedigrees because, in theory, the causal variants have been genotyped. We used whole genome sequence data and simulated traits provided by Genetic Analysis Workshop 18 to evaluate the proportion of false-positive findings in a binary trait using classic two-point parametric linkage analysis. False-positive genome-wide significant log of odds (LOD) scores were identified in more than 80% of 50 replicates for a binary phenotype generated by dichotomizing a quantitative trait that was simulated with a polygenic component (that was not based on any of the provided whole genome sequence genotypes). In contrast, when the trait was truly nongenetic (created by randomly assigning affected-unaffected status), the number of false-positive results was well controlled. These results suggest that when using two-point linkage analyses on whole genome sequence data, one should carefully examine regions yielding significant two-point LOD scores with multipoint analysis and that a more stringent significance threshold may be needed. PMID- 25519362 TI - Genetic Analysis Workshop 18 single-nucleotide variant prioritization based on protein impact, sequence conservation, and gene annotation. AB - Grouping variants based on gene mapping can augment the power of rare variant association tests. Weighting or sorting variants based on their expected functional impact can provide additional benefit. We defined groups of prioritized variants based on systematic annotation of Genetic Analysis Workshop 18 (GAW18) single-nucleotide variants; we focused on variants detected by whole genome sequencing, specifically on the high-quality subset presented in the genotype files. First, we divided variants between coding and noncoding. Coding variants are fewer than 1% of the total and are more likely to have a biological effect than noncoding variants. Coding variants were further stratified into protein changing and protein damaging groups based on the effect on protein amino acid sequence. In particular, missense variants predicted to be damaging, splice site alterations, and stop gains were assigned to the protein damaging category. Impact of noncoding variants is more difficult to predict. We decided to rely uniquely on conservation: we combined (a) the mammalian phastCons Conserved Element and (b) the PhyloP score, which identify conserved intervals and the single-nucleotide position, respectively. This reduced the noncoding variants to a number comparable to coding variants. Finally, using gene structure definition from the widely used RefSeq database, we mapped variants to genes to support association tests that require collapsing rare variants to genes. Companion GAW18 papers used these variant priority groups and gene mapping; one of these paper specifically found evidence of stronger association signal for protein damaging variants. PMID- 25519364 TI - Next-generation linkage and association methods applied to hypertension: a multifaceted approach to the analysis of sequence data. AB - To realize the full potential of next-generation sequencing, it is important to consider multiple sources of genetic information, including inheritance, association, and bioinformatics. To illustrate the promise of such an approach, we applied our next-generation linkage and association (NGLA) methods to the sequence data of a large 57-member Mexican American family with hypertension. Our results show that OSBPL10--a disease susceptibility gene for dyslipidemia--may also influence systolic blood pressure (SBP). In particular, our NGLA dense single-nucleotide polymorphism (SNP) analysis identified a 2.5-megabase (Mb) region that strongly cosegregates with low SBP (maximum posterior probability of linkage [PPL] = 68%). Furthermore, using the posterior probability of linkage disequilibrium (PPLD), we fine-mapped this region and identified 12 SBP associated variants (PPLD ranging between 4% and 14%) that comprise a rare, 4 site haplotype. This haplotype extends into the candidate gene, OSBPL10 (oxysterol-binding protein-like 10). In contrast to our NGLA methods, a commonly used filter-based approach identified 23 variants with little evidence for spatial clustering around any particular gene or region of interest. PMID- 25519365 TI - Whole genome sequence analysis of the simulated systolic blood pressure in Genetic Analysis Workshop 18 family data: long-term average and collapsing methods. AB - Analysis of longitudinal family data is challenging because of 2 sources of correlations: correlations across longitudinal measurements and correlations among related individuals. We investigated whether analysis using long-term average (average of all 3 visits) can enhance gene discovery compared with a single-visit analysis. We analyzed all 200 replicates of simulated systolic blood pressure (SBP) in Genetic Analysis Workshop 18 (GAW18) family data using both single-marker and collapsing methods. We considered 2 collapsing approaches: collapsing all variants and collapsing low-frequency variants. Analysis using long-term average performed slightly better than SBP measured at a single visit. Collapsing all variants performed much better than collapsing low-frequency variants at MAP4 and FLNB, which included a common variant with a relatively large effect. For several variants in gene MAP4, single-marker analysis also provided high power. In contrast, collapsing only low-frequency variants performed much better for SCAP, DNASE1L3, and LOC152217, where rare variants in these genes had larger effect than common variants. However, for other causal variants, all approaches provided disappointingly poor performance. This poor performance appeared to occur because most of these causal variants explained a very small fraction of phenotypic variance. We also found that collapsing multiple variants did worse than single-marker analysis for several genes when they contained causal single-nucleotide polymorphisms (SNPs) with both positive and negative effects. Because half of causal SNPs were not found in the annotation file based on the 1000 Genomes Project, we found that power was also affected by our use of incomplete annotation information. PMID- 25519366 TI - Small sample properties of rare variant analysis methods. AB - We are now well into the sequencing era of genetic analysis, and methods to investigate rare variants associated with disease remain in high demand. Currently, the more common rare variant analysis methods are burden tests and variance component tests. This report introduces a burden test known as the modified replication based sum statistic and evaluates its performance, and the performance of other common burden and variance component tests under the setting of a small sample size (103 total cases and controls) using the Genetic Analysis Workshop 18 simulated data with complete knowledge of the simulation model. Specifically we look at the variable threshold sum statistic, replication-based sum statistics, the C-alpha, and sequence kernel association test. Using minor allele frequency thresholds of less than 0.05, we find that the modified replication based sum statistic is competitive with all methods and that using 103 individuals leads to all methods being vastly underpowered. Much larger sample sizes are needed to confidently find truly associated genes. PMID- 25519367 TI - Higher criticism approach to detect rare variants using whole genome sequencing data. AB - Because of low statistical power of single-variant tests for whole genome sequencing (WGS) data, the association test for variant groups is a key approach for genetic mapping. To address the features of sparse and weak genetic effects to be detected, the higher criticism (HC) approach has been proposed and theoretically has proven optimal for detecting sparse and weak genetic effects. Here we develop a strategy to apply the HC approach to WGS data that contains rare variants as the majority. By using Genetic Analysis Workshop 18 "dose" genetic data with simulated phenotypes, we assess the performance of HC under a variety of strategies for grouping variants and collapsing rare variants. The HC approach is compared with the minimal p-value method and the sequence kernel association test. The results show that the HC approach is preferred for detecting weak genetic effects. PMID- 25519368 TI - Analysis of homozygosity disequilibrium using whole-genome sequencing data. AB - Homozygosity disequilibrium (HD), a nonrandom sizable run of homozygosity in the genome, may be related to the evolution of populations and may also confer susceptibility to disease. No studies have investigated HD using whole genome sequencing (WGS) analysis. In this study, we used an enhanced version of Loss-Of Heterozygosity Analysis Suite (LOHAS) software to investigate HD through analysis of real and simulated WGS data sets provided by Genetic Analysis Workshop 18. Using a local polynomial model, we derived whole-genome profiles of homozygosity intensities for 959 individuals and characterized the patterns of HD. Generalized estimating equation analysis for 855 related samples was performed to examine the association between patterns of HD and 3 phenotypes of interest, namely diastolic blood pressure, systolic blood pressure, and hypertension status, with covariate adjustments for age and gender. We found that 4.48% of individuals in this study carried sizable runs of homozygosity (ROHs). Distributions of the length of ROHs were derived and revealed a familial aggregation of HD. Genome-wide homozygosity association analysis identified 5 and 3 ROHs associated with diastolic blood pressure and hypertension, respectively. These regions contain genes associated with calcium channels (CACNA1S), renin catalysis (REN), blood groups (ABO), apolipoprotein (APOA5), and cardiovascular diseases (RASGRP1). Simulation studies showed that our homozygosity association tests controlled type 1 error well and had a promising power. This study provides a useful analysis tool for studying HD and allows us to gain a deeper understanding of HD in the human genome. PMID- 25519369 TI - Imputation in families using a heuristic phasing approach. AB - Whole genome sequencing (WGS) remains prohibitively expensive, which has encouraged the development of methods to impute WGS data into nonsequenced individuals using a framework of single nucleotide polymorphisms genotyped for genome-wide association studies (GWAS). Although successful methods have been developed for cohorts of unrelated individuals, current imputation methods in related individuals are limited by pedigree size, by the distance of relationships, or by computation time. In this article, we describe a method for imputation in arbitrarily shaped multigenerational pedigrees that can impute genotypes across distantly related individuals based on identity by descent. We evaluate this approach using GWAS data and apply this approach to WGS data distributed for Genetic Analysis Workshop 18. PMID- 25519370 TI - Genotypic discrepancies arising from imputation. AB - The ideal genetic analysis of family data would include whole genome sequence on all family members. A strategy of combining sequence data from a subset of key individuals with inexpensive, genome-wide association study (GWAS) chip genotypes on all individuals to infer sequence level genotypes throughout the families has been suggested as a highly accurate alternative. This strategy was followed by the Genetic Analysis Workshop 18 data providers. We examined the quality of the imputation to identify potential consequences of this strategy by comparing discrepancies between GWAS genotype calls and imputed calls for the same variants. Overall, the inference and imputation process worked very well. However, we find that discrepancies occurred at an increased rate when imputation was used to infer missing data in sequenced individuals. Although this may be an artifact of this particular instantiation of these analytic methods, there may be general genetic or algorithmic reasons to avoid trying to fill in missing sequence data. This is especially true given the risk of false positives and reduction in power for family-based transmission tests when founders are incorrectly imputed as heterozygotes. Finally, we note a higher rate of discrepancies when unsequenced individuals are inferred using sequenced individuals from other pedigrees drawn from the same admixed population. PMID- 25519371 TI - Identity-by-descent graphs offer a flexible framework for imputation and both linkage and association analyses. AB - We demonstrate the flexibility of identity-by-descent (IBD) graphs for genotype imputation and testing relationships between genotype and phenotype. We analyzed chromosome 3 and the first replicate of simulated diastolic blood pressure. IBD graphs were obtained from complete pedigrees and full multipoint marker analysis, facilitating subsequent linkage and other analyses. For rare alleles, pedigree based imputation using these IBD graphs had a higher call rate than did population-based imputation. Combining the two approaches improved call rates for common alleles. We found it advantageous to incorporate known, rather than estimated, pedigree relationships when testing for association. Replacing missing data with imputed alleles improved association signals as well. Analyses were performed with knowledge of the underlying model. PMID- 25519372 TI - Joint analysis of sequence data and single-nucleotide polymorphism data using pedigree information for imputation and recombination inference. AB - We developed a general framework for family-based imputation using single nucleotide polymorphism data and sequence data distributed by Genetic Analysis Workshop 18. By using PedIBD, we first inferred haplotypes and inheritance patterns of each family from SNP data. Then new variants in unsequenced family members can be obtained from sequenced relatives through their shared haplotypes. We then compared the results of our method against the imputation results provided by Genetic Analysis Workshop organizers. The results showed that our strategy uncovered more variants for more unsequenced relatives. We also showed that recombination breakpoints inferred by PedIBD have much higher resolution than those inferred from previous studies. PMID- 25519373 TI - Using Mendelian inheritance errors as quality control criteria in whole genome sequencing data set. AB - Although the technical and analytic complexity of whole genome sequencing is generally appreciated, best practices for data cleaning and quality control have not been defined. Family based data can be used to guide the standardization of specific quality control metrics in nonfamily based data. Given the low mutation rate, Mendelian inheritance errors are likely as a result of erroneous genotype calls. Thus, our goal was to identify the characteristics that determine Mendelian inheritance errors. To accomplish this, we used chromosome 3 whole genome sequencing family based data from the Genetic Analysis Workshop 18. Mendelian inheritance errors were provided as part of the GAW18 data set. Additionally, for binary variants we calculated Mendelian inheritance errors using PLINK. Based on our analysis, nonbinary single-nucleotide variants have an inherently high number of Mendelian inheritance errors. Furthermore, in binary variants, Mendelian inheritance errors are not randomly distributed. Indeed, we identified 3 Mendelian inheritance error peaks that were enriched with repetitive elements. However, these peaks can be lessened with the inclusion of a single filter from the sequencing file. In summary, we demonstrated that erroneous sequencing calls are nonrandomly distributed across the genome and quality control metrics can dramatically reduce the number of mendelian inheritance errors. Appropriate quality control will allow optimal use of genetic data to realize the full potential of whole genome sequencing. PMID- 25519374 TI - Evaluating the concordance between sequencing, imputation and microarray genotype calls in the GAW18 data. AB - Genotype errors are well known to increase type I errors and/or decrease power in related tests of genotype-phenotype association, depending on whether the genotype error mechanism is associated with the phenotype. These relationships hold for both single and multimarker tests of genotype-phenotype association. To assess the potential for genotype errors in Genetic Analysis Workshop 18 (GAW18) data, where no gold standard genotype calls are available, we explored concordance rates between sequencing, imputation, and microarray genotype calls. Our analysis shows that missing data rates for sequenced individuals are high and that there is a modest amount of called genotype discordance between the 2 platforms, with discordance most common for lower minor allele frequency (MAF) single-nucleotide polymorphisms (SNPs). Some evidence for discordance rates that were different between phenotypes was observed, and we identified a number of cases where different technologies identified different bases at the variant site. Type I errors and power loss is possible as a result of missing genotypes and errors in called genotypes in downstream analysis of GAW18 data. PMID- 25519375 TI - PREST-plus identifies pedigree errors and cryptic relatedness in the GAW18 sample using genome-wide SNP data. AB - Pedigree errors and cryptic relatedness often appear in families or population samples collected for genetic studies. If not identified, these issues can lead to either increased false negatives or false positives in both linkage and association analyses. To identify pedigree errors and cryptic relatedness among individuals from the 20 San Antonio Family Studies (SAFS) families and cryptic relatedness among the 157 putatively unrelated individuals, we apply PREST-plus to the genome-wide single-nucleotide polymorphism (SNP) data and analyze estimated identity-by-descent (IBD) distributions for all pairs of genotyped individuals. Based on the given pedigrees alone, PREST-plus identifies the following putative pairs: 1091 full-sib, 162 half-sib, 360 grandparent grandchild, 2269 avuncular, 2717 first cousin, 402 half-avuncular, 559 half-first cousin, 2 half-sib+first cousin, 957 parent-offspring and 440,546 unrelated. Using the genotype data, PREST-plus detects 7 mis-specified relative pairs, with their IBD estimates clearly deviating from the null expectations, and it identifies 4 cryptic related pairs involving 7 individuals from 6 families. PMID- 25519376 TI - De novo mutations discovered in 8 Mexican American families through whole genome sequencing. AB - De novo mutations enrich the sequence diversity and carry the clue of evolutional selection. Recent studies suggest the de novo mutations could be one of the risk factors for complex diseases. We conducted a survey of de novo mutations using the whole genome sequence data but only available on the odd autosomes of Mexican American families provided by Genetic Analysis Workshop 18. We extracted 8 three generation families who have sequencing data available from 20 large pedigrees. By comparing the known single nucleotide variants (SNVs) in dbSNP129 and the de novo variants transmitted in the Mexican American families, we were able to estimate a de novo mutation rate of 1.64(+/-0.42) * 10(-8) per position per haploid genome. This result is consistent with the estimates in literature that required many extensive validation efforts, such as genotyping and further resequencing. Our analysis suggests the importance of using family samples for studying rare variants. PMID- 25519377 TI - On family-based genome-wide association studies with large pedigrees: observations and recommendations. AB - Family based association studies are employed less often than case-control designs in the search for disease-predisposing genes. The optimal statistical genetic approach for complex pedigrees is unclear when evaluating both common and rare variants. We examined the empirical power and type I error rates of 2 common approaches, the measured genotype approach and family-based association testing, through simulations from a set of multigenerational pedigrees. Overall, these results suggest that much larger sample sizes will be required for family-based studies and that power was better using MGA compared to FBAT. Taking into account computational time and potential bias, a 2-step strategy is recommended with FBAT followed by MGA. PMID- 25519378 TI - A generalized least-squares framework for rare-variant analysis in family data. AB - Rare variants may, in part, explain some of the hereditability missing in current genome-wide association studies. Many gene-based rare-variant analysis approaches proposed in recent years are aimed at population-based samples, although analysis strategies for family-based samples are clearly warranted since the family-based design has the potential to enhance our ability to enrich for rare causal variants. We have recently developed the generalized least squares, sequence kernel association test, or GLS-SKAT, approach for the rare-variant analyses in family samples, in which the kinship matrix that was computed from the high dimension genetic data was used to decorrelate the family structure. We then applied the SKAT-O approach for gene-/region-based inference in the decorrelated data. In this study, we applied this GLS-SKAT method to the systolic blood pressure data in the simulated family sample distributed by the Genetic Analysis Workshop 18. We compared the GLS-SKAT approach to the rare-variant analysis approach implemented in family-based association test-v1 and demonstrated that the GLS-SKAT approach provides superior power and good control of type I error rate. PMID- 25519379 TI - Combined linkage and family-based association analysis improves candidate gene detection in Genetic Analysis Workshop 18 simulation data. AB - Because the genotype-phenotype correlation information is investigated differently by linkage and association analyses, various efforts have been made to model linkage and association jointly. However, joint modeling methods are usually computationally intensive; hence they cannot currently accommodate large pedigrees with dense markers. This article proposes a simple method to combine the linkage and association evidence with the aim of improving the detection power of disease susceptibility genes. Our detection power comparisons show that the combined linkage-association p values can improve remarkably the causal gene detection power in Genetic Analysis Workshop 18 simulation data. PMID- 25519380 TI - Comparison of multilevel modeling and the family-based association test for identifying genetic variants associated with systolic and diastolic blood pressure using Genetic Analysis Workshop 18 simulated data. AB - Identifying genetic variants associated with complex diseases is an important task in genetic research. Although association studies based on unrelated individuals (ie, case-control genome-wide association studies) have successfully identified common single-nucleotide polymorphisms for many complex diseases, these studies are not so likely to identify rare genetic variants. In contrast, family-based association studies are particularly useful for identifying rare variant associations. Recently, there has been some interest in employing multilevel models in family-based genetic association studies. However, the performance of such models in these studies, especially for longitudinal family based sequence data, has not been fully investigated. Therefore, in this study, we investigated the performance of the multilevel model in the family-based genetic association analysis and compared it with the conventional family-based association test, by examining the powers and type I error rates of the 2 approaches using 3 data sets from the Genetic Analysis Workshop 18 simulated data: genome-wide association single-nucleotide polymorphism data, sequence data, and rare-variants-only data. Compared with the univariate family-based association test, the multilevel model had slightly higher power to identify most of the causal genetic variants using the genome-wide association single nucleotide polymorphism data and sequence data. However, both approaches had low power to identify most of the causal single-nucleotide polymorphisms, especially those among the relatively rare genetic variants. Therefore, we suggest a unified method that combines both approaches and incorporates collapsing strategy, which may be more powerful than either approach alone for studying genetic associations using family-based data. PMID- 25519381 TI - A comparative analysis of family-based and population-based association tests using whole genome sequence data. AB - The revolution in next-generation sequencing has made obtaining both common and rare high-quality sequence variants across the entire genome feasible. Because researchers are now faced with the analytical challenges of handling a massive amount of genetic variant information from sequencing studies, numerous methods have been developed to assess the impact of both common and rare variants on disease traits. In this report, whole genome sequencing data from Genetic Analysis Workshop 18 was used to compare the power of several methods, considering both family-based and population-based designs, to detect association with variants in the MAP4 gene region and on chromosome 3 with blood pressure. To prioritize variants across the genome for testing, variants were first functionally assessed using prediction algorithms and expression quantitative trait loci (eQTLs) data. Four set-based tests in the family-based association tests (FBAT) framework--FBAT-v, FBAT-lmm, FBAT-m, and FBAT-l--were used to analyze 20 pedigrees, and 2 variance component tests, sequence kernel association test (SKAT) and genome-wide complex trait analysis (GCTA), were used with 142 unrelated individuals in the sample. Both set-based and variance-component-based tests had high power and an adequate type I error rate. Of the various FBATs, FBAT-l demonstrated superior performance, indicating the potential for it to be used in rare-variant analysis. The updated FBAT package is available at: http://www.hsph.harvard.edu/fbat/. PMID- 25519382 TI - Combining information from linkage and association mapping for next-generation sequencing longitudinal family data. AB - In this analysis, we investigate the contributions that linkage-based methods, such as identical-by-descent mapping, can make to association mapping to identify rare variants in next-generation sequencing data. First, we identify regions in which cases share more segments identical-by-descent around a putative causal variant than do controls. Second, we use a two-stage mixed-effect model approach to summarize the single-nucleotide polymorphism data within each region and include them as covariates in the model for the phenotype. We assess the impact of linkage disequilibrium in determining identical-by-descent states between individuals by using markers with and without linkage disequilibrium for the first part and the impact of imputation in testing for association by using imputed genome-wide association studies or raw sequence markers for the second part. We apply the method to next-generation sequencing longitudinal family data from Genetic Association Workshop 18 and identify a significant region at chromosome 3: 40249244-41025167 (p-value = 2.3 * 10(-3)). PMID- 25519383 TI - A comparison of whole genome sequencing with exome sequencing for family-based association studies. AB - As the cost of DNA sequencing decreases, association studies based on whole genome sequencing are now becoming feasible. It is still unclear, however, how much more we could gain from whole genome sequencing compared to exome sequencing, which has been widely used to study a variety of diseases. In this project, we performed a comparison between whole genome sequencing and exome sequencing for family-based association analysis using data from Genetic Analysis Workshop 18. Whole genome sequencing was able to identify several significant hits within intergenic regions. However, the increased cost of multiple testing counteracted the benefits and resulted in a higher false discovery rate. Our results suggest that exome sequencing is a cost-effective way to identify disease related variants. With the decreasing sequencing cost and accumulating knowledge of the human genome, whole genome sequencing has the potential to identify important variants in regulatory regions typically inaccessible for exome sequencing. PMID- 25519384 TI - Adjustment of familial relatedness in association test for rare variants. AB - High-throughput sequencing technology allows researchers to test associations between phenotypes and all the variants identified throughout the genome, and is especially useful for analyzing rare variants. However, the statistical power to identify phenotype-associated rare variants is very low with typical genome-wide association studies because of their low allele frequencies among unrelated individuals. In contrast, a family-based design may have more power because rare variants are more likely to be enriched in families than among unrelated individuals. Regardless, an analysis of family-based association studies needs to account appropriately for relatedness between family members. We analyzed the observed quantitative trait systolic blood pressure as well as the simulated Q1 data in the Genetic Analysis Workshop 18 data set using 4 tests: (a) a single variant test, (b) a collapsing test, (c) a single-variant test where familial relatedness was accounted for, and (d) a collapsing test where familial relatedness was accounted for. We then compared the results of the 4 methods and observed that adjusting for familial relatedness could appropriately control the false-positive rate while maintaining reasonable power to detect several strongly associated variants/genes. PMID- 25519385 TI - Extended T(2) tests for longitudinal family data in whole genome sequencing studies. AB - Family data and rare variants are two key features of whole genome sequencing analysis for hunting the missing heritability of common human diseases. Recently, Zhu and Xiong proposed the generalized T(2) tests that combine rare variant analysis and family data analysis. In similar fashion, we developed the extended T(2) tests for longitudinal whole genome sequencing data for family-based association studies. The new methods simultaneously incorporate three correlation sources: from linkage disequilibrium, from pedigree structure, and from the repeated measures of covariates. We assess and compare these methods using the simulated data from Genetic Analysis Workshop 18. We show that, in general, the extended T(2) tests incorporating longitudinal repeated measures have higher power than the single-time-point T(2) tests in detecting hypertension-associated genome segments. PMID- 25519386 TI - Adjusting for population stratification and relatedness with sequencing data. AB - To avoid inflated type I error and reduced power in genetic association studies, it is necessary to adjust properly for population stratification and known/unknown subject relatedness. It would be interesting to compare the performance of a principal component-based approach with a linear mixed model. Furthermore, with the availability of genome-wide sequencing data, the question of whether it is preferable to use common variants or rare variants for such an adjustment remains largely unknown. In this paper, we use the Genetic Analysis Workshop 18 data to empirically investigate these issues. We consider both a quantitative trait and a binary trait. PMID- 25519387 TI - Gene-based analysis of rare and common variants to determine association with blood pressure. AB - Systolic blood pressure and diastolic blood pressure are known risk factors for cardiovascular diseases and understanding their genetic basis will have important public health implications. For rare variants, it is extremely challenging to make statistical inference for single-maker tests. Therefore, joint analysis of a set of variants has been proposed. In this paper, we applied recently proposed methods "test for testing the effect of an optimally weighted combination of variants" and "variable weight-TOW" to determine genetic regions that are associated with blood pressure. Then least absolute shrinkage and selection operator, as well as sparse partial least square methods, were used to identify significant markers within a gene or in intergenic regions. We investigated the effect of rare variants and common variants, and their combined effect. PMID- 25519388 TI - A variance component-based gene burden test. AB - We propose a novel variance component approach for the analysis of next generation sequencing data. Our method is based on the detection of the proportion of the trait phenotypic variance that can be explained by the introduction of a new variance component that accounts for the local gene specific departure of the empirical kinship relationship matrix, estimated from single-nucleotide polymorphism (SNP) genotypes, from their theoretical expectation based on the genealogical information in the pedigree. We tested our method with simulated phenotypes and imputed SNP genotypes from the Genetic Analysis Workshop 18 data set. We observed considerable variation in the differences between theoretical and gene-specific kinship estimates that proved to be informative for our test and allowed us to detect the MAP4 causal gene at a genome-wide significance level. The distribution of our test statistic show no inflation under the null hypothesis and results from a random set of genes suggest that the detection of MAP4 is both sensitive and specific. The use of 2 different strategies for the selection of the SNPs used to derive the gene specific empirical kinship relationship matrices provides us with suggestive evidence that our method is performing as an empirical test of linkage. PMID- 25519389 TI - A goodness-of-fit association test for whole genome sequencing data. AB - Although many genetic factors have been successfully identified for human diseases in genome-wide association studies, genes discovered to date only account for a small proportion of overall genetic contributions to many complex traits. Association studies have difficulty in detecting the remaining true genetic variants that are either common variants with weak allelic effects, or rare variants that have strong allelic effects but are weakly associated at the population level. In this work, we applied a goodness-of-fit test for detecting sets of common and rare variants associated with quantitative or binary traits by using whole genome sequencing data. This test has been proved optimal for detecting weak and sparse signals in the literature, which fits the requirements for targeting the genetic components of missing heritability. Furthermore, this p value-combining method allows one to incorporate different data and/or research results for meta-analysis. The method was used to simultaneously analyse the whole genome sequencing and genome-wide association studies data of Genetic Analysis Workshop 18 for detecting true genetic variants. The results show that goodness-of-fit test is comparable or better than the influential sequence kernel association test in many cases. PMID- 25519390 TI - Population structure at different minor allele frequency levels. AB - Inferring population genetic structure from large-scale genotyping of single nucleotide polymorphisms or variants is an important technique for studying the history and distribution of extant human populations, but it is also a very important tool for adjusting tests of association. However, the structures inferred depend on the minor allele frequency of the variants; this is very important when considering the phenotypic association of rare variants. Using the Genetic Analysis Workshop 18 data set for 142 unrelated individuals, which includes genotypes for many rare variants, we study the following hypothesis: the difference in detected structure is the result of a "scale" effect; that is, rare variants are likely to be shared only locally (smaller scale), while common variants can be spread over longer distances. The result is similar to that of using kernel principal component analysis, as the bandwidth of the kernel is changed. We show how different structures become evident as we consider rare or common variants. PMID- 25519391 TI - Identifying rare variants associated with hypertension using the C-alpha test. AB - Important rare variants may be near significantly associated common variants based on genetic distance. For this reason, we conducted an analysis of rare variants informed by tests of single-marker association at loci with common variants. We identified highly significant common variants within chromosome 3, as well as rare variants around these locations. Based on a predetermined window size, we then analyzed these rare variants with the C-alpha test to determine significant associations with hypertension. We found significant rare variants around common variants; however, the C-alpha test was sensitive to the specified window size. When comparing markers in genes to markers not in genes, we found that markers not in genes had more significant C-alpha test p values than markers in genes. PMID- 25519392 TI - Haplotype approach for association analysis on hypertension. AB - We applied a gene-based haplotype approach for the genome-wide association analysis on hypertension using Genetic Analysis Workshop 18 data for unrelated individuals. Association of single-nucleotide polymorphisms and clinical outcome were first assessed and haplotypes were then constructed based on the gene information and the linkage disequilibrium plot. Extensive haplotype analysis was also conducted for the whole chromosome 3. We found 1 block from the ULK4 gene and 2 blocks from the LOC64690 gene that were significantly associated with hypertension. PMID- 25519393 TI - Identifying rare variant associations in population-based and family-based designs. AB - For almost all complex traits studied in humans, the identified genetic variants discovered to date have accounted for only a small portion of the estimated trait heritability. Consequently, several methods have been developed to identify rare single-nucleotide variants associated with complex traits for population-based designs. Because rare disease variants tend to be enriched in families containing multiple affected individuals, family-based designs can play an important role in the identification of rare causal variants. In this study, we utilize Genetic Analysis Workshop 18 simulated data to examine the performance of some existing rare variant identification methods for unrelated individuals, including our recent method (rPLS). The simulated data is used to investigate whether there is an advantage to using family data compared to case-control data. The results indicate that population-based methods suffer from power loss, especially when the sample size is small. The family-based method employed in this paper results in higher power but fails to control type I error. Our study also highlights the importance of the phenotype choice, which can affect the power of detecting causal genes substantially. PMID- 25519394 TI - Testing optimally weighted combination of variants for hypertension. AB - Testing rare variants directly is possible with next-generation sequencing technology. In this article, we propose a sliding-window-based optimal-weighted approach to test for the effects of both rare and common variants across the whole genome. We measured the genetic association between a disease and a combination of variants of a single-nucleotide polymorphism window using the newly developed tests TOW and VW-TOW and performed a sliding-window technique to detect disease-susceptible windows. By applying the new approach to unrelated individuals of Genetic Analysis Workshop 18 on replicate 1 chromosome 3, we detected 3 highly susceptible windows across chromosome 3 for diastolic blood pressure and identified 10 of 48,176 windows as the most promising for both diastolic and systolic blood pressure. Seven of 9 top variants influencing diastolic blood pressure and 8 of 9 top variants influencing systolic blood pressure were found in or close to our top 10 windows. PMID- 25519395 TI - A partition-based approach to identify gene-environment interactions in genome wide association studies. AB - It is believed that almost all common diseases are the consequence of complex interactions between genetic markers and environmental factors. However, few such interactions have been documented to date. Conventional statistical methods for detecting gene and environmental interactions are often based on the linear regression model, which assumes a linear interaction effect. In this study, we propose a nonparametric partition-based approach that is able to capture complex interaction patterns. We apply this method to the real data set of hypertension provided by Genetic Analysis Workshop 18. Compared with the linear regression model, the proposed approach is able to identify many additional variants with significant gene-environmental interaction effects. We further investigate one single-nucleotide polymorphism identified by our method and show that its gene environmental interaction effect is, indeed, nonlinear. To adjust for the family dependence of phenotypes, we apply different permutation strategies and investigate their effects on the outcomes. PMID- 25519396 TI - Discovering pure gene-environment interactions in blood pressure genome-wide association studies data: a two-step approach incorporating new statistics. AB - Environment has long been known to play an important part in disease etiology. However, not many genome-wide association studies take environmental factors into consideration. There is also a need for new methods to identify the gene environment interactions. In this study, we propose a 2-step approach incorporating an influence measure that capturespure gene-environment effect. We found that pure gene-age interaction has a stronger association than considering the genetic effect alone for systolic blood pressure, measured by counting the number of single-nucleotide polymorphisms (SNPs)reaching a certain significance level. We analyzed the subjects by dividing them into two age groups and found no overlap in the top identified SNPs between them. This suggested that age might have a nonlinear effect on genetic association. Furthermore, the scores of the top SNPs for the two age subgroups were about 3times those obtained when using all subjects for systolic blood pressure. In addition, the scores of the older age subgroup were much higher than those for the younger group. The results suggest that genetic effects are stronger in older age and that genetic association studies should take environmental effects into consideration, especially age. PMID- 25519397 TI - Genotype imputation accuracy with different reference panels in admixed populations. AB - Genome-wide association studies have successfully identified common variants that are associated with complex diseases. However, the majority of genetic variants contributing to disease susceptibility are yet to be discovered. It is now widely believed that multiple rare variants are likely to be associated with complex diseases. Using custom-made chips or next-generation sequencing to uncover the effects of rare variants on the disease can be very expensive in current technology. Consequently, many researchers use the genotype imputation approach to predict the genotypes at these rare variants that are not directly genotyped in the study sample. One important question in genotype imputation is how to choose a reference panel that will produce high imputation accuracy in a population of interest. Using whole genome sequence data from the Genetic Analysis Workshop 18 data set, this report compares genotype imputation accuracy among reference panels representing different degrees of genetic similarity to a study sample of admixed Mexican Americans. Results show that a reference panel that closely matches the ancestry of the study population can increase imputation accuracy, but it can also result in more missing genotype calls. Having a larger size reference panel can reduce imputation error and missing genotype, but the improvement may be limited. We also find that, for the admixed study sample, the simple selection of a single best-reference panel among HapMap African, European, or Asian population is not appropriate. The composite reference panel combining all available reference data should be used. PMID- 25519398 TI - Evaluation of estimated genetic values and their application to genome-wide investigation of systolic blood pressure. AB - The concept of breeding values, an individual's phenotypic deviation from the population mean as a result of the sum of the average effects of the genes they carry, is of great importance in livestock, aquaculture, and cash crop industries where emphasis is placed on an individual's potential to pass desirable phenotypes on to the next generation. As breeding or genetic values (as referred to here) cannot be measured directly, estimated genetic values (EGVs) are based on an individual's own phenotype, phenotype information from relatives, and, increasingly, genetic data. Because EGVs represent additive genetic variation, calculating EGVs in an extended human pedigree is expected to provide a more refined phenotype for genetic analyses. To test the utility of EGVs in genome wide association, EGVs were calculated for 847 members of 20 extended Mexican American families based on 100 replicates of simulated systolic blood pressure. Calculations were performed in GAUSS to solve a variation on the standard Best Linear Unbiased Predictor (BLUP) mixed model equation with age, sex, and the first 3 principal components of sample-wide genetic variability as fixed effects and the EGV as a random effect distributed around the relationship matrix. Three methods of calculating kinship were considered: expected kinship from pedigree relationships, empirical kinship from common variants, and empirical kinship from both rare and common variants. Genome-wide association analysis was conducted on simulated phenotypes and EGVs using the additive measured genotype approach in the SOLAR software package. The EGV-based approach showed only minimal improvement in power to detect causative loci. PMID- 25519399 TI - A penalized linear mixed model for genomic prediction using pedigree structures. AB - Genetic Analysis Workshop 18 provided a platform for evaluating genomic prediction power based on single-nucleotide polymorphisms from single-nucleotide polymorphism array data and sequencing data. Also, Genetic Analysis Workshop 18 provided a diverse pedigree structure to be explored in prediction. In this study, we attempted to combine pedigree information with single-nucleotide polymorphism data to predict systolic blood pressure. Our results suggested that the prediction power based on pedigree information only could be unsatisfactory. Using additional information such as single-nucleotide polymorphism genotypes would improve prediction accuracy. In particular, the improvement can be significant when there exist a few single-nucleotide polymorphisms with relatively larger effect sizes. We also compared the prediction performance based on genome-wide association study data (ie, common variants) and sequencing data (ie, common variants plus low-frequency variants). The experimental result showed that inclusion of low frequency variants could not lead to improvement of prediction accuracy. PMID- 25519400 TI - Considering interactive effects in the identification of influential regions with extremely rare variants via fixed bin approach. AB - In this study, we analyze the Genetic Analysis Workshop 18 (GAW18) data to identify regions of single-nucleotide polymorphisms (SNPs), which significantly influence hypertension status among individuals. We have studied the marginal impact of these regions on disease status in the past, but we extend the method to deal with environmental factors present in data collected over several exam periods. We consider the respective interactions between such traits as smoking status and age with the genetic information and hope to augment those genetic regions deemed influential marginally with those that contribute via an interactive effect. In particular, we focus only on rare variants and apply a procedure to combine signal among rare variants in a number of "fixed bins" along the chromosome. We extend the procedure in Agne et al [1] to incorporate environmental factors by dichotomizing subjects via traits such as smoking status and age, running the marginal procedure among each respective category (i.e., smokers or nonsmokers), and then combining their scores into a score for interaction. To avoid overlap of subjects, we examine each exam period individually. Out of a possible 629 fixed-bin regions in chromosome 3, we observe that 11 show up in multiple exam periods for gene-smoking score. Fifteen regions exhibit significance for multiple exam periods for gene-age score, with 4 regions deemed significant for all 3 exam periods. The procedure pinpoints SNPs in 8 "answer" genes, with 5 of these showing up as significant in multiple testing schemes (Gene-Smoking, Gene-Age for Exams 1, 2, and 3). PMID- 25519401 TI - Genetic association analysis for common variants in the Genetic Analysis Workshop 18 data: a Dirichlet regression approach. AB - We propose a genetic association analysis using Dirichlet regression to analyze the Genetic Analysis Workshop 18 data. Clinical variables, arranged in a longitudinal data structure, are employed to fit a multistate transition model in which the transition probabilities are served as a response in the proposed analysis. Furthermore, a gene-based association analysis via penalized regression is implemented using the markers at a single-nucleotide polymorphism level that we previously identified via nonpenalized Dirichlet regression. PMID- 25519402 TI - Association mapping of blood pressure levels in a longitudinal framework using binomial regression. AB - Heritable quantitative characters underline complex genetic traits. However, a single quantitative phenotype may not be a suitably good surrogate for a clinical end point trait. It may be more optimal to use a multivariate phenotype vector correlated with the end point trait to carry out an association analysis. Existing methods, such as variance components and principal components, suffer from inherent limitations, such as lack of robustness or difficulty in biological interpretation of association findings. In an effort to circumvent these limitations, we propose a novel regression approach based on a conditional binomial model to detect association between a single-nucleotide polymorphism and a multivariate phenotype vector. We use our proposed method to analyze data on systolic and diastolic blood pressure levels provided in Genetic Analysis Workshop 18. We find that the bivariate analysis of the two phenotypes yields more promising results in terms of lower p-values compared to univariate analyses. PMID- 25519403 TI - Bivariate linear mixed model analysis to test joint associations of genetic variants on systolic and diastolic blood pressure. AB - Genetic variants that predispose adults and the elderly to high blood pressure are largely unknown. We used a bivariate linear mixed model approach to jointly test the associations of common single-nucleotide polymorphisms with systolic and diastolic blood pressure using data from a genome-wide association study consisting of genetic variants from chromosomes 3 and 9 and longitudinal measured phenotypes and environment variables from unrelated individuals of Mexican American ethnicity provided by the Genetic Analysis Workshop 18. Despite the small sample size of a maximum of 131 unrelated subjects, a few single-nucleotide polymorphisms appeared significant at the genome-wide level. Simulated data, which was also provided by Genetic Analysis Workshop 18 organizers, showed higher power of the bivariate approach over univariate analysis to detect the association of a selected single-nucleotide polymorphism with modest effect. This suggests that the bivariate approach to longitudinal data of jointly measured and correlated phenotypes can be a useful strategy to identify candidate single nucleotide polymorphisms that deserve further investigation. PMID- 25519404 TI - Genetic association analysis using weighted false discovery rate approach on Genetic Analysis Workshop 18 data. AB - In a genome-wide association study, association between disease trait and hundreds of thousands of genetic markers are tested. Several methods have been proposed to control the false discovery rate in such high-throughput data to adjust for multiple hypotheses testing. For Genetic Analysis Workshop 18, we applied the method of false discovery rate control with p value weighting on family-based association tests on quantitative trait to detect association between single-nucleotide polymorphisms (SNPs) and mean arterial pressure. This method can improve statistical power by incorporating independent but relevant information about the research objective. Using the real genetic and phenotype data of chromosome 3 from Genetic Analysis Workshop 18, 1 SNP from gene CACNA2D3 was found to have significant association with mean arterial pressure. PMID- 25519405 TI - Using a Bayesian latent variable approach to detect pleiotropy in the Genetic Analysis Workshop 18 data. AB - Pleiotropy, which occurs when a single genetic factor influences multiple phenotypes, is present in many genetic studies of complex human traits. Longitudinal family data, such as the Genetic Analysis Workshop 18 data, combine the features of longitudinal studies in individuals and cross-sectional studies in families, thus providing richer information about the genetic and environmental factors associated with the trait of interest. We recently proposed a Bayesian latent variable methodology for the study of pleiotropy, in the presence of longitudinal and family correlation. The purpose of this work is to evaluate the Bayesian latent variable method in a real data setting using the Genetic Analysis Workshop 18 blood pressure phenotypes and sequenced genotype data. To detect single-nucleotide polymorphisms with pleiotropic effect on both diastolic and systolic blood pressure, we focused on a set of 6 single-nucleotide polymorphisms from chromosome 3 that was reported in the literature to be significantly associated with either diastolic blood pressure or the binary hypertension trait. Our analysis suggests that both diastolic blood pressure and systolic blood pressure are associated with the latent hypertension severity variable, but the analysis did not find any of the 6 single-nucleotide polymorphisms to have statistically significant pleiotropic effect on both diastolic blood pressure and systolic blood pressure. PMID- 25519406 TI - Prediction of hypertension based on the genetic analysis of longitudinal phenotypes: a comparison of different modeling approaches for the binary trait of hypertension. AB - For the analysis of the longitudinal hypertension family data, we focused on modeling binary traits of hypertension measured repeatedly over time. Our primary objective is to examine predictive abilities of longitudinal models for genetic associations. We first identified single-nucleotide polymorphisms (SNPs) associated with any occurrence of hypertension over the study period to set up covariates for the longitudinal analysis. Then, we proceeded to the longitudinal analysis of the repeated measures of binary hypertension with covariates including SNPs by accounting for correlations arising from repeated outcomes and among family members. We examined two popular models for longitudinal binary outcomes: (a) a marginal model based on the generalized estimating equations, and (b) a conditional model based on the logistic random effect model. The effects of risk factors associated with repeated hypertensions were compared for these two models and their prediction abilities were assessed with and without genetic information. Based on both approaches, we found a significant interaction effect between age and gender where males were at higher risk of hypertension before age 35 years, but after age 35 years, women were at higher risk. Moreover, the SNPs were significantly associated with hypertension after adjusting for age, gender, and smoking status. The SNPs contributed more to predict hypertension in the marginal model than in the conditional model. There was substantial correlation among repeated measures of hypertension, implying that hypertension was considerably correlated with previous experience of hypertension. The conditional model performed better for predicting the future hypertension status of individuals. PMID- 25519407 TI - Accounting for relatedness in family-based association studies: application to Genetic Analysis Workshop 18 data. AB - In the last few years, a bewildering variety of methods/software packages that use linear mixed models to account for sample relatedness on the basis of genome wide genomic information have been proposed. We compared these approaches as implemented in the programs EMMAX, FaST-LMM, Gemma, and GenABEL (FASTA/GRAMMAR Gamma) on the Genetic Analysis Workshop 18 data. All methods performed quite similarly and were successful in reducing the genomic control inflation factor to reasonable levels, particularly when the mean values of the observations were used, although more variation was observed when data from each time point were used individually. From a practical point of view, we conclude that it makes little difference to the results which method/software package is used, and the user can make the choice of package on the basis of personal taste or computational speed/convenience. PMID- 25519408 TI - A comparison of two collapsing methods in different approaches. AB - Sequencing technologies have enabled the investigation of whole genomes of many individuals in parallel. Studies have shown that the joint consideration of multiple rare variants may explain a relevant proportion of the genetic basis for disease so that grouping of rare variants, termed collapsing, can enrich the association signal. Following this assumption, we investigate the type I error and the power of two proposed collapsing methods (combined multivariate and collapsing method and the functional principal component analysis [FPCA]-based statistic) using the case-control data provided for the Genetic Analysis Workshop 18 with knowledge of the true model. Variants with a minor allele frequency (MAF) of 0.05 or less were collapsed per gene for combined multivariate and collapsing. Neither of the methods detected any of the truly associated genes reliably. Although combined multivariate and collapsing identified one gene with a power of 0.66, it had an unacceptably high false-positive rate of 75%. In contrast, FPCA covered the type I error level well but at the cost of low power. A strict filtering of variants by small MAF might lead to a better performance of the collapsing methods. Furthermore, the inclusion of information on functionality of the variants could be helpful. PMID- 25519409 TI - Analysis of baseline, average, and longitudinally measured blood pressure data using linear mixed models. AB - This article compares baseline, average, and longitudinal data analysis methods for identifying genetic variants in genome-wide association study using the Genetic Analysis Workshop 18 data. We apply methods that include (a) linear mixed models with baseline measures, (b) random intercept linear mixed models with mean measures outcome, and (c) random intercept linear mixed models with longitudinal measurements. In the linear mixed models, covariates are included as fixed effects, whereas relatedness among individuals is incorporated as the variance covariance structure of the random effect for the individuals. The overall strategy of applying linear mixed models decorrelate the data is based on Aulchenko et al.'s GRAMMAR. By analyzing systolic and diastolic blood pressure, which are used separately as outcomes, we compare the 3 methods in identifying a known genetic variant that is associated with blood pressure from chromosome 3 and simulated phenotype data. We also analyze the real phenotype data to illustrate the methods. We conclude that the linear mixed model with longitudinal measurements of diastolic blood pressure is the most accurate at identifying the known single-nucleotide polymorphism among the methods, but linear mixed models with baseline measures perform best with systolic blood pressure as the outcome. PMID- 25519410 TI - Mapping genes with longitudinal phenotypes via Bayesian posterior probabilities. AB - Most association studies focus on disease risk, with less attention paid to disease progression or severity. These phenotypes require longitudinal data. This paper presents a new method for analyzing longitudinal data to map genes in both population-based and family-based studies. Using simulated systolic blood pressure measurements obtained from Genetic Analysis Workshop 18, we cluster the phenotype data into trajectory subgroups. We then use the Bayesian posterior probability of being in the high subgroup as a quantitative trait in an association analysis with genotype data. This method maintains high power (>80%) in locating genes known to affect the simulated phenotype for most specified significance levels (alpha). We believe that this method can be useful to aid in the discovery of genes that affect severity or progression of disease. PMID- 25519411 TI - Hierarchical linear modeling of longitudinal pedigree data for genetic association analysis. AB - Genetic association analysis on complex phenotypes under a longitudinal design involving pedigrees encounters the problem of correlation within pedigrees, which could affect statistical assessment of the genetic effects. Approaches have been proposed to integrate kinship correlation into the mixed-effect models to explicitly model the genetic relationship. These have proved to be an efficient way of dealing with sample clustering in pedigree data. Although current algorithms implemented in popular statistical packages are useful for adjusting relatedness in the mixed modeling of genetic effects on the mean level of a phenotype, they are not sufficiently straightforward to handle the kinship correlation on the time-dependent trajectories of a phenotype. We introduce a 2 level hierarchical linear model to separately assess the genetic associations with the mean level and the rate of change of a phenotype, integrating kinship correlation in the analysis. We apply our method to the Genetic Analysis Workshop 18 genome-wide association studies data on chromosome 3 to estimate the genetic effects on systolic blood pressure measured over time in large pedigrees. Our method identifies genetic variants associated with blood pressure with estimated inflation factors of 0.99, suggesting that our modeling of random effects efficiently handles the genetic relatedness in pedigrees. Application to simulated data captures important variants specified in the simulation. Our results show that the method is useful for genetic association studies in related samples using longitudinal design. PMID- 25519412 TI - Comparing baseline and longitudinal measures in association studies. AB - In recent years, longitudinal family-based studies have had success in identifying genetic variants that influence complex traits in genome-wide association studies. In this paper, we suggest that longitudinal analyses may contain valuable information that can enable identification of additional associations compared to baseline analyses. Using Genetic Analysis Workshop 18 data, consisting of whole genome sequence data in a pedigree-based sample, we compared 3 methods for the genetic analysis of longitudinal data to an analysis that used baseline data only. These longitudinal methods were (a) longitudinal mixed-effects model; (b) analysis of the mean trait over time; and (c) a 2-stage analysis, with estimation of a random intercept in the first stage and regression of the random intercept on a single-nucleotide polymorphism at the second stage. All methods accounted for the familial correlation among subjects within a pedigree. The analyses considered common variants with minor allele frequency above 5% on chromosome 3. Analyses were performed without knowledge of the simulation model. The 3 longitudinal methods showed consistent results, which were generally different from those found by using only the baseline observation. The gene CACNA2D3, identified by both longitudinal and baseline approaches, had a stronger signal in the longitudinal analysis (p = 2.65 * 10(-7)) compared to that in the baseline analysis (p = 2.48 * 10(-5)). The effect size of the longitudinal mixed-effects model and mean trait were higher compared to the 2-stage approach. The longitudinal results provided stable results different from that using 1 observation at baseline and generally had lower p values. PMID- 25519413 TI - Detecting longitudinal effects of haplotypes and smoking on hypertension using B splines and Bayesian LASSO. AB - The behavior of a gene can be dynamic; thus, if longitudinal data are available, it is important that we study the dynamic effects of genes on a trait over time. The effect of a haplotype can be expressed by time-varying coefficients. In this paper, we use the natural cubic B-spline to express these coefficients that capture the trends of the effects of haplotypes, some of which may be rare, over time; that is, at different ages. More specifically, to capture disease associated common and rare haplotypes and environmental factors for data from unrelated individuals, we developed a method of time-varying coefficients that uses the logistic Bayesian LASSO methodology and B-spline by setting proper prior distributions. Haplotype and environmental effect coefficients are obtained by using Markov chain Monte Carlo methods. We applied the method to analyze the MAP4 gene on chromosome 3 and have identified several haplotypes that are associated with hypertension with varying effect sizes in the range of 55 to 85 years of age. PMID- 25519414 TI - A multi-level model for analyzing whole genome sequencing family data with longitudinal traits. AB - Compared with microarray-based genotyping, next-generation whole genome sequencing (WGS) studies have the strength to provide greater information for the identification of rare variants, which likely account for a significant portion of missing heritability of common human diseases. In WGS, family-based studies are important because they are likely enriched for rare disease variants that segregate with the disease in relatives. We propose a multilevel model to detect disease variants using family-based WGS data with longitudinal measures. This model incorporates the correlation structure from family pedigrees and that from repeated measures. The iterative generalized least squares algorithm was applied to estimation of parameters and test of associations. The model was applied to the data of Genetic Analysis Workshop 18 and compared with existing linear mixed effect models. The multilevel model shows higher power at practical p-value levels and a better type I error control than linear mixed-effect model. Both multilevel and linear mixed-effect models, which use the longitudinal repeated information, have higher power than the methods that only use data collected at one time point. PMID- 25519415 TI - Gene analysis for longitudinal family data using random-effects models. AB - We have extended our recently developed 2-step approach for gene-based analysis to the family design and to the analysis of rare variants. The goal of this approach is to study the joint effect of multiple single-nucleotide polymorphisms that belong to a gene. First, the information in a gene is summarized by 2 variables, namely the empirical Bayes estimate capturing common variation and the number of rare variants. By using random effects for the common variants, our approach acknowledges the within-gene correlations. In the second step, the 2 summaries were included as covariates in linear mixed models. To test the null hypothesis of no association, a multivariate Wald test was applied. We analyzed the simulated data sets to assess the performance of the method. Then we applied the method to the real data set and identified a significant association between FRMD4B and diastolic blood pressure (p-value = 8.3 * 10(-12)). PMID- 25519416 TI - Association analysis of whole genome sequencing data accounting for longitudinal and family designs. AB - Using the whole genome sequencing data and the simulated longitudinal phenotypes for 849 pedigree-based individuals from Genetic Analysis Workshop 18, we investigated various approaches to detecting the association of rare and common variants with blood pressure traits. We compared three strategies for longitudinal data: (a) using the baseline measurement only, (b) using the average from multiple visits, and (c) using all individual measurements. We also compared the power of using all of the pedigree-based data and the unrelated subset. The analyses were performed without knowledge of the underlying simulating model. PMID- 25519417 TI - Evaluation of gene-based association tests for analyzing rare variants using Genetic Analysis Workshop 18 data. AB - The focus of our work is to evaluate several recently developed pooled association tests for rare variants and assess the impact of different gene annotation methods and binning strategies on the analyses of rare variants under Genetic Analysis Workshop 18 real and simulated data settings. We considered the sample of 103 unrelated individuals with sequence data, genotypes of rare variants from chromosome 3, real phenotype of hypertension status and simulated phenotypes of systolic blood pressure (SBP) and diastolic blood pressure (DBP), and covariates of age, sex, and the interaction between age and sex. In the analysis of real phenotype data, we did not obtain significant results for any binning strategy; however, we observed a slight deviation of the p-values from the uniform distribution based on the protein-damaging variant grouping strategy. Evaluation of methods using simulated data showed lack of power even at the conservative level of 0.05 for most of the causal genes on chromosome 3. Nevertheless, analysis of MAP4 produced good power for all tests at various levels of the tests for both DBP and SBP. Our results also confirmed that Fisher's method is not only robust but can also improve power over individual pooled linear and quadratic tests and is often better than other robust tests such as SKAT-O. PMID- 25519418 TI - Detecting association of rare and common variants by testing an optimally weighted combination of variants with longitudinal data. AB - Increasing evidence shows that complex diseases are caused by both common and rare variants. Recently, several statistical methods for detecting associations of rare variants have been developed, including the test for testing the effect of an optimally weighted combination of variants (TOW) developed by our group in 2012. These methodologies consider phenotype measurement at only one time point. Because many sequence data have been developed on population cohorts that contain phenotype measurements at multiple time points, such as the data set provided in the Genetic Analysis Workshop 18 (GAW18), we extend TOW from phenotype measurement at one time point to phenotype measurements at multiple time points. We then apply the newly proposed method to the GAW18 data set and compare the power of the new method with TOW using only one phenotype measurement. The application results show that the newly proposed method jointly modeling phenotype measurements at all time points has increased power over TOW. PMID- 25519419 TI - Entropy-based method for assessing the influence of genetic markers and covariates on hypertension: application to Genetic Analysis Workshop 18 data. AB - Many complex diseases are related to genetics, and it is of great interest to evaluate the association between single-nucleotide polymorphisms (SNPs) and disease outcome. The association of genetics with outcome can be modified by covariates such as age, sex, smoking status, and membership to the same pedigree. In this paper, we propose a block entropy method to separate two classes of SNPs, for which the association with hypertension is either sensitive or insensitive to the covariates. We also propose a consistency entropy method to further reduce the number of SNPs that might be associated with the outcome. Based on the data provided by the organizers of Genetic Analysis Workshop 18, we calculated the block entropies for six different blocking strategies. Using block entropy and consistency entropy, we identified 230 SNPs on chromosome 9 that are most likely to be associated with the outcome and whose associations with hypertension are sensitive to the covariates. PMID- 25519420 TI - Identifying rare-variant associations in parent-child trios using a Gaussian support vector machine. AB - As the availability of cost-effective high-throughput sequencing technology increases, genetic research is beginning to focus on identifying the contributions of rare variants (RVs) to complex traits. Using RVs to detect associated genes requires statistical approaches that mitigate the lack of power with the analysis of single RVs. Here we report the development and application of an approach that aggregates and evaluates the transmissions of RVs in parent child trios. An initial score that incorporates the distortion in transmission of the observed RVs from the parents to their offspring is calculated for each variant. The scores are analyzed using a support vector machine that handles these data by mapping the transmission distortion of the multiple RVs into a one dimensional score in a nonlinear fashion when parent-child trios with affected and nonaffected children are contrasted. We refer to this approach as Trio-SVM. A total of 275 trios were available in the Genetic Analysis Workshop 18 data for analysis. Because of their nonindependence and the extended linkage disequilibrium (LD) within pedigrees, Trio-SVM was vulnerable to type I errors in detecting association. Using the GAW18 data with simulated trait values, Trio-SVM has an appropriate type I error, but it lacks power with a sample of 267 trios. Larger samples of 500 to 1000 trios, derived from combining the simulated data, provided sufficient power. Two chromosome 3 candidate genes were tested in the real GAW18 data with Trio-SVM, and they showed marginal associations with hypertension. PMID- 25519421 TI - Gaussian graphical models for phenotypes using pedigree data and exploratory analysis using networks with genetic and nongenetic factors based on Genetic Analysis Workshop 18 data. AB - Graphical models are increasingly used in genetic analyses to take into account the complex relationships between genetic and nongenetic factors influencing the phenotypes. We propose a model for determining the network structure of quantitative traits while accounting for the correlated nature of the family based samples using the kinship coefficient. The Gaussian graphical model of age, systolic blood pressure, diastolic blood pressure, hypertension, blood pressure medication use, and smoking status was derived for three time points using real data. We also explored binary sparse graphical models of single-nucleotide polymorphisms (SNPs), covariates, and quantitative traits for exploratory analysis of the data. We validated the applicability of this method by producing a network graph using 20 causal variants, 21 noncausal variants, and 6 binary and quantitative phenotypes using the simulated data. To improve the model's ability to identify associations between the causal variants and the phenotypes, we intend to conduct follow-up studies investigating how to use the relationships between SNPs and between SNPs and phenotypes when analyzing genome wide association data with multiple phenotypes. PMID- 25519422 TI - Cohort Profile Update: The Mater-University of Queensland Study of Pregnancy (MUSP). AB - The Mater-University of Queensland Study of Pregnancy (MUSP) and its outcomes began in 1981 with data collected on 7223 pregnant woman-child pairs (6753 mothers, of whom 520 had 2 study children, less 50 who had multiple births). These women, and their children, were initially followed for up to 21 years. Since then there have been additional follow-ups of the mothers (27 years) and their children (30 years). There has also been a substantial increase in the breadth of topics addressed, with the collection of biological samples, the administration of structured clinical assessments of mental health and cognitive capacity, and markers of physical health such as lung function and blood pressure. MUSP was originally developed as a birth cohort study. It has become a longitudinal study of growth, development and ageing with an emphasis on the generational transmission of a wide range of factors impacting on adult health outcomes. We welcome interest in our study; for study background and publications visit [www.socialscience.uq.edu.au/musp] or contact [j.najman@uq.edu.au]. PMID- 25519423 TI - Comparison of psychiatric disability on the health of nation outcome scales (HoNOS) in resettled traumatized refugee outpatients and Danish inpatients. AB - BACKGROUND: Currently, the mental health issues of traumatized refugees are mainly documented in terms of posttraumatic stress disorder, depression, and anxiety. Importantly, there are no reports of the level of psychiatric disability in treatment seeking traumatized refugees resettled in the West. Insufficient acknowledgment of the collective load of bio-psycho-social problems in this patient group hinders effective psychiatric and social service utilization outside the specialized clinics for traumatized refugees. METHODS: The level of psychiatric disability in traumatized refugees from Danish specialized clinics (N = 448) is documented using routine monitoring data from pre- and post-treatment on the Health of Nation Outcome Scales (HoNOS). Furthermore, the HoNOS ratings are compared with routine monitoring data from Danish inpatients with different diagnoses (N = 10.911). RESULTS: The routinely collected data indicated that despite their outpatient status, traumatized refugees had higher levels of psychiatric disability at pre-treatment compared to most inpatients. Moreover, the traumatized refugees had a HoNOS profile characterized by an overall high problem level in various psychiatric and social domains. The rate of pre- to post treatment improvement on the HoNOS was smaller for the traumatized refugees than it was for the psychiatric inpatients. CONCLUSIONS: The level, and the versatile profile, of psychiatric disability on the HoNOS point to complex bio-psycho social problems in resettled treatment seeking traumatized refugees. Thus, a broader assessment of symptoms and better cooperation between psychiatric, health care, and social systems is necessary in order to meet the treatment needs of this group. PMID- 25519424 TI - Four tetrazolate-based 3D frameworks with diverse subunits directed by inorganic anions and azido coligand: hydro/solvothermal syntheses, crystal structures, and magnetic properties. AB - Four tetrazolate (tz(-))-based magnetic metal-organic frameworks, [Cu5(MU3 OH)2(SO4)2(tz)4]n (), {[Cu3(tz)4Cl2].1.4CH3OH}n (), [Cu(N3)(tz)]n () and {[Cu5(tz)9]Cl.4H2O}n (), were hydro/solvothermally synthesized, and structurally and magnetically characterized. Structural analyses reveal that the former two samples exhibit the same eight-connected topological framework assembled from different subunits. Hourglass-shaped {Cu5(MU3-OH)2}(8+) cores in are periodically extended by mixed MU3-/MU4-tz(-) and MU4-SO4(2-) heterolinkers, while the linear {Cu3(MU-Cl)2}(4+) blocks in are repeatedly intersected by ditopic MU3-tz(-) connectors. In contrast, the square grid-shaped network of is constructed from linear {Cu(MU1,1-N3)}(+) chains and MU3-tz(-) linkers. Complex consists of trigonal-prismatic {Cu8(MU3-tz)6}(10+) subunits, which are interlinked into hexagonal microporous architecture by mirror-symmetry MU4-tz(-) ligands. Thus, the various subunits of are significantly tuned by the co-coordination of the inorganic anions and/or the azido co-ligand, and the backbone extensions are directed by the polytopic tetrazolate ligand. Magnetically, different ordering arrangements of the non-zero magnetizations produced in the local Cu(II)5 and Cu(II)3 subunits eventually lead to unusual ferrimagnetic and canted antiferromagnetic properties in and . Strong antiferromagnetic couplings mediated by the mixed tz(-) and/or azido bridges result in overall S = 0 spin ground states of and . PMID- 25519425 TI - The use of self-gripping (ProgripTM) mesh during laparoscopic total extraperitoneal (TEP) inguinal hernia repair: a prospective feasibility and long term outcomes study. AB - BACKGROUND: The use of self-gripping mesh during laparoscopic TEP inguinal hernia repairs may eliminate the need for any additional fixation, and thus reduce post operative pain without the added concern for mesh migration. Long-term outcomes are not yet prospectively studied in a controlled fashion. METHODS: Under IRB approval, from January 2011-April 2013, 91 hernias were repaired laparoscopically with self-gripping mesh without additional fixation. Patients were followed for at least 1 year. Demographics and intraoperative data (defect location, size, and mesh deployment time) are recorded. VAS is used in the recovery room (RR) to score pain, and the Carolinas Comfort Scale TM (CCS), a validated 0-5 pain/quality of life (QoL) score where a mean score of >1.0 means symptomatic pain, is employed at 2 weeks and at 1 year. Morbidities, narcotic usage, days to full activity and return to work, and CCS scores are reported. RESULTS: Sixty two patients, with 91 hernias repaired with self-gripping mesh, completed follow-up at a mean time period of 14.8 months. Seventeen hernias were direct defects (average size 3.0 cm). Mesh deployment time was 193.7 s. RR pain was 1.1/10 using a VAS. Total average oxycodone/acetaminophen (5 mg/325 mg) usage = 5.0 tablets, days to full activity was 1.6, and return to work was 4.2 days. Thirteen small asymptomatic seromas were palpated without any recurrences or groin tenderness, and all seromas resolved by the 6 month visit. Transient testis discomfort was reported in five patients. Urinary retention was 3.2%. Mean CCSTM scores at the first visit for groin pain laying, bending, sitting, walking, and step-climbing were 0.2, 0.5, 0.4, 0.3, and 0.3, respectively. At the first post op visit, 4.8% had symptomatic pain (CCS > 1). At 14.8 months, no patients reported symptomatic pain with CCS scores for all 62 patients averaging 0.02, (range 0-0.43). There are no recurrences thus far. CONCLUSIONS: Self-gripping mesh can be safely used during laparoscopic TEP inguinal hernia repairs; our cohort had a rapid recovery, and at the 1-year follow-up visit, there were no recurrences and no patients reported any chronic pain as defined by a CCSTM > 1. PMID- 25519427 TI - William Orange CB, MD, FRCP, LSA: A Broadmoor pioneer. AB - William Orange was the second Medical Superintendent of Broadmoor and in the 23 years he spent there created a management style that was greatly admired. Among his patients were the painter Richard Dadd, the Surgeon of Crowthorne and the Brighton poisoner. As advisor to the Home Office he also made a significant contribution to the interface between medicine and the law. PMID- 25519426 TI - Intra-operative double-stapled colorectal or coloanal anastomotic complications of laparoscopic low anterior resection for rectal cancer: double-stapled anastomotic complication could result in persistent anastomotic leakage. AB - BACKGROUND: Laparoscopic surgery for rectal cancer is technically demanding and can be hindered by unexpected intra-operative complications. Among the various intra-operative complications, double-stapled anastomotic complications are more serious and complicated to manage. The purpose of this study is to analyze the impact of intra-operative double-stapled colorectal or coloanal anastomotic complications on short-term surgical outcomes and persistent leak, and risk factors of intra-operative double-stapled anastomotic complication. METHODS: Consecutive 363 cases of laparoscopic low anterior resection from August 2004 to November 2012 were analyzed in this study. We retrospectively reviewed intra operative double-stapled anastomotic complications and compared patient characteristics, surgical data, post-operative clinical data, and pathological data between groups with and without intra-operative double-stapled anastomotic complications. And we analyzed risk factors for double-stapled anastomotic complication. RESULTS: There were 20 intra-operative double-stapled anastomotic complications among the patients (5.5 %). Operation time was longer (304.8 +/- 122.0 vs. 197.1 +/- 87.5 min, p = 0.001) and more diversion ileostomy were made (75 vs. 34.7 %, p < 0.001) in the group with double-stapled anastomotic complications. There were no differences in terms of surgical morbidity, conversion rate, anastomotic leakage, and hospital stay. However, there was more persistent anastomotic leakage (15 vs. 0.9 %, p = 0.003) in the group with double stapled anastomotic complications. In univariate analysis, risk factors for double-stapled anastomotic complications were male, T4 stage lesion, and three or more stapler firings. CONCLUSIONS: The double-stapled anastomotic complications during laparoscopic low anterior resection increased operation time and rate of diversion ileostomy. Although these factors did not adversely affect short-term surgical outcome including post-operative morbidity and anastomotic leakage, double-stapled anastomotic complications could increase persistent anastomotic leakage rate. PMID- 25519428 TI - Tobacco control policy development in the European Union: do political factors matter? AB - BACKGROUND: There has been much variation between European countries in the development of tobacco control policy. Not much is known about the factors that shape this variation. This study aimed to assess the role of political factors in tobacco control policy development. METHODS: We used data from 11 European countries from 1996 to 2010. Multilevel regression modelling was used to investigate associations between the Tobacco Control Scale (TCS) and indicators of left-wing government and government effectiveness (policy formulation, implementation and enforcement), with control for confounders. RESULTS: An association was found between left-wing government and TCS over the period 1996 2003, but not over the whole period. The association between government effectiveness and TCS was significant and negative over the whole period, but positive between 2001 and 2005. Residual analysis showed that TCS scores from 2002 onwards were higher than expected based on the political factors. Associations varied among the five subscales of the TCS. CONCLUSIONS: The results suggest that, on the whole, national political factors have had only a minor influence on the large variations in tobacco control policy development in Europe over the last 15 years. However, there are indications that left-wing governments were important for early adoption of tobacco control policy, and high government effectiveness was important in the phase of adopting innovative policies. However, since 2002, with the advent of international treaties, the influence of national politics has diminished. PMID- 25519429 TI - Rapid isolation of gluten-digesting bacteria from human stool and saliva by using gliadin-containing plates. AB - The number of individuals with gluten intolerance has increased dramatically over the last years. To date, the only therapy for gluten intolerance is the complete avoidance of dietary gluten. To sustain a strictly gluten-free diet, however, is very challenging. Therefore, there is need for a non-dietary therapy. Any such treatment must appreciate that the immunogenic part of gluten are gliadin peptides which are poorly degraded by the enzymes of the gastrointestinal tract. Probiotic therapy and oral enzyme therapy containing gluten-degrading bacteria (GDB) and their gliadin-digesting enzymes are possible new approaches for the treatment of gluten intolerance, however effectively isolating GDB for these treatments is problematic. The goal of this study was to develop an easy technique to isolate GDB rapidly and efficiently with the hope it might lead to newer ways of developing either probiotics or traditional medicines to treat gluten intolerance. Several researchers have already isolated successfully GDB by using gluten minimal or limited agar plates. Although these plates can be used to isolate bacteria which can tolerate gluten, further assays are needed to investigate if the same bacteria can also digest gluten. The agar plates we developed can detect bacteria which cannot only tolerate gluten but are able to digest it as well. Therefore, we were able to combine two steps into one step. Using such technologies, we were able to isolate five GDB from saliva and stool, and identified three bacterial reference strains with gluten-degrading activity. The technique we developed to isolate bacteria with gluten-degrading activity is fast, effective, and easy to use. The GDB isolated by our technology could have potential as part of a probiotic or enzymatic therapy for people with gluten intolerance. PMID- 25519431 TI - Detecting differential patterns of interaction in molecular pathways. AB - We consider statistical inference for potentially heterogeneous patterns of association characterizing the expression of bio-molecular pathways across different biologic conditions. We discuss a modeling approach based on Gaussian directed acyclic graphs and provide computational and methodological details needed for posterior inference. Our application finds motivation in reverse phase protein array data from a study on acute myeloid leukemia, where interest centers on contrasting refractory versus relapsed patients. We illustrate the proposed method through both synthetic and case study data. PMID- 25519430 TI - Nitric oxide suppresses LPS-induced inflammation in a mouse asthma model by attenuating the interaction of IKK and Hsp90. AB - A feature of allergic airway disease is the observed increase of nitric oxide (NO) in exhaled breath. Gram-negative bacterial infections have also been linked with asthma exacerbations. However, the role of NO in asthma exacerbations with gram-negative bacterial infections is still unclear. In this study, we examined the role of NO in lipopolysaccharide (LPS)-induced inflammation in an ovalbumin (OVA)-challenged mouse asthma model. To determine whether NO affected the LPS induced response, a NO donor (S-nitroso-N-acetylpenicillamine, SNAP) or a selective inhibitor of NO synthase (1400W) was injected intraperitoneally into the mice before the LPS stimulation. Decreased levels of proinflammatory cytokines were demonstrated in the bronchoalveolar lavage fluid from mice treated with SNAP, whereas increased levels of cytokines were found in the 1400W-treated mice. To further explore the molecular mechanism of NO-mediated inhibition of proinflammatory responses in macrophages, RAW 264.7 cells were treated with 1400W or SNAP before LPS stimulation. LPS-induced inflammation in the cells was attenuated by the presence of NO. The LPS-induced IkappaB kinase (IKK) activation and the expression of IKK were reduced by NO through attenuation of the interaction between Hsp90 and IKK in the cells. The IKK decrease in the lung immunohistopathology was verified in SNAP-treated asthma mice, whereas IKK increased in the 1400W-treated group. We report for the first time that NO attenuates the interaction between Hsp90 and IKK, decreasing the stability of IKK and causing the down-regulation of the proinflammatory response. Furthermore, the results suggest that NO may repress LPS-stimulated innate immunity to promote pulmonary bacterial infection in asthma patients. PMID- 25519432 TI - Real-time monitoring of progression towards renal failure in primary care patients. AB - Chronic renal failure is a progressive condition that, typically, is asymptomatic for many years. Early detection of incipient kidney failure enables ameliorative treatment that can slow the rate of progression to end-stage renal failure, at which point expensive and invasive renal replacement therapy (dialysis or transplantation) is required. We use routinely collected clinical data from a large sample of primary care patients to develop a system for real-time monitoring of the progression of undiagnosed incipient renal failure. Progression is characterized as the rate of change in a person's kidney function as measured by the estimated glomerular filtration rate, an adjusted version of serum creatinine level in a blood sample. Clinical guidelines in the UK suggest that a person who is losing kidney function at a relative rate of at least 5% per year should be referred to specialist secondary care. We model the time-course of a person's underlying kidney function through a combination of explanatory variables, a random intercept and a continuous-time, non-stationary stochastic process. We then use the model to calculate for each person the predictive probability that they meet the clinical guideline for referral to secondary care. We suggest that probabilistic predictive inference linked to clinical criteria can be a useful component of a real-time surveillance system to guide, but not dictate, clinical decision-making. PMID- 25519433 TI - Unanswered clinical questions in the management of cardiometabolic risk in the elderly: a statement of the Spanish Society of Internal Medicine. AB - BACKGROUND: Despite the progressive increase in life expectancy and the relationship between aging with multi-morbidities and the increased use of healthcare resources, current clinical practice guidelines (CPG) on cardiometabolic risk cannot be adequately applied to elderly subjects with multiple chronic conditions. Its management frequently becomes complicated by both, an excessive use of medications that may lead to overtreatment, drug interactions and increased toxicity, and errors in dosage and non-compliance. Concerned by this gap, the Spanish Society of Internal Medicine created a group of independent experts on cardiometabolic risk who discussed what they considered to be unanswered questions in the management of elderly patients. DISCUSSION: Current guidelines do not specifically address the problem of elderly with multiple chronic conditions. For this reason, the combined use of the limited available evidence, clinical experience and common sense, could all help us to address this unmet need. In very old people, life expectancy and functionality are the most important factors for guiding potential treatments. Their higher propensity to develop serious adverse events and their shorter lifespan could prevent them from obtaining the potential benefits of the interventions administered. SUMMARY: In this document, experts on cardiometabolic risk factors have established a number of consensual recommendations that have taken into account international guidelines and clinical experience, and have also considered the more effective use of healthcare resources. This document is intended to provide general recommendations for clinicians and to promote the effective use of procedures and medications. PMID- 25519435 TI - Expert opinion on emerging drugs: chronic low back pain. AB - INTRODUCTION: It is difficult to overestimate the personal and socioeconomic impact of chronic low back pain (CLBP). It is the leading cause of years lost to disability and poses the highest economic toll among chronic illnesses. Despite the strong need for extensive research efforts, few drugs have consistently demonstrated effectiveness for this condition. AREAS COVERED: In this review, the epidemiology, rationale for mechanism-based treatment, competitive environment and market trends, and the preclinical and clinical evidence supporting over 15 different classes of analgesic medications studied for CLBP or related pain conditions are discussed. Treatments are divided by drug category, type of CLBP they are likely to treat (e.g., neuropathic or mechanical), and whether they are new formulations of existing treatments, new indications for existing treatments or represent novel mechanisms of action. Databases searched included MEDLINE, Embase, Pharmaprojects and various clinical trial registries. EXPERT OPINION: Many barriers exist for the development of medications for CLBP including difficulties in identifying pathophysiological mechanisms, biologic resiliency secondary to multiple concurrent pain pathways and off-target and sometimes serious side effects. Nevertheless, the volume and diversity of novel molecular entities has continued to surge and includes possible disease-modifying therapies such as gene and stem cell therapy. PMID- 25519434 TI - Increasing obesity and comorbidity in patients undergoing primary total hip arthroplasty in the U.S.: a 13-year study of time trends. AB - BACKGROUND: Few, if any data are available are available regarding the time trends in characteristics of patients who have undergone primary THA. Our objective was to examine the time-trends in key demographic and clinical characteristics of patients undergoing primary total hip arthroplasty (THA). METHODS: We used the data from the Mayo Clinic Total Joint Registry from 1993 2005 to examine the time-trends in demographics (age, body mass index (BMI)), medical (Deyo-Charlson index) and psychological comorbidity (anxiety, depression) and underlying diagnosis of patients undergoing primary THA. Chi-square test and analysis for variance were used. Multivariable-adjusted logistic regression (age, sex, comorbidity-adjusted) compared 1993-95 to other study periods. Odds ratio (OR) and 95% confidence interval (CI) are presented. RESULTS: The primary THA cohort consisted of 6,168 patients with 52% women. In unadjusted analyses, compared to 1993-95, significantly more patients (by >2-times for most) in 2002 05 had: BMI >= 40, 2.3% vs. 6.3%; depression, 4.1% vs. 9.8%; and anxiety, 3.4% vs. 5.7%; and significantly fewer had an underlying diagnosis of rheumatoid/inflammatory arthritis, 3.7% vs. 1.5% (p <= 0.01 for all). In multivariable-adjusted models, compared to 1993-95, significantly more patients in 2003-05 had (all p-values <= 0.01): BMI >= 40, OR, 2.79 (95% CI: 1.85, 4.22); Deyo-Charlson Index >= 3, 1.32 (1.07, 1.63); depression, 2.25 (1.66, 3.05); and anxiety, 1.71 (1.19, 2.15). Respectively, fewer patients had a diagnosis of RA/inflammatory arthritis: 0.28 (0.17, 0.46; p < 0.01). Over the 13-year study period, Deyo-Charlson index increased by 22% (0.9 to 1.1) and the mean age decreased by 0.7 years (65.0 to 64.3) (p < 0.01 for both). CONCLUSIONS: Obesity, medical and psychological comorbidity increased and the underlying diagnosis of RA/inflammatory arthritis decreased rapidly in primary THA patients over 13 years. Our cohort characteristics are similar to previously described characteristics of national U.S. cohort, suggesting that these trends may be national rather than local trends. This is important information for policy makers to take into account for resource allocation. Studies of THA outcomes and utilization should take these rapidly changing patient characteristics into account. PMID- 25519436 TI - Social preferences influence the short-term exchange of social grooming among male bonobos. AB - The emotional mediation hypothesis proposes a mediating role of social bonds in the exchange of services. This model predicts that the form of short-term exchange of services depends on the relationship between the individuals involved. Here, we test this prediction in the exchange of grooming among males in a wild bonobo community for which close relatedness could be excluded. As bonobo males hardly engage in food sharing or agonistic support, grooming is mainly exchanged for grooming. While overall grooming, both given and received, correlates across dyads and within sessions, the form of grooming exchange within a given session differs according to dyadic association preferences. Individuals with a higher tendency to associate, ergo more familiar individuals, exhibit larger time differences and reduced reciprocation in consecutive grooming bouts than less familiar individuals. These results support the idea that emotional components are involved in the exchange of services between unrelated individuals. PMID- 25519437 TI - Accuracy of influenza vaccination rate estimates in United States nursing home residents. AB - The US Center for Medicare and Medicaid Services (CMS) requires nursing homes and long-term-care facilities to document residents' vaccination status on the Resident Assessment Instrument (RAI). Vaccinating residents can prevent costly hospital admissions and deaths. CMS and public health officials use RAI data to measure vaccination rates in long-term-care residents and assess the quality of care in nursing homes. We assessed the accuracy of RAI data against medical records in 39 nursing homes in Florida, Georgia, and Wisconsin. We randomly sampled residents in each home during the 2010-2011 and 2011-2012 influenza seasons. We collected data on receipt of influenza vaccination from charts and RAI data. Our final sample included 840 medical charts with matched RAI records. The agreement rate was 0.86. Using the chart as a gold standard, the sensitivity of the RAI with respect to influenza vaccination was 85% and the specificity was 77%. Agreement rates varied within facilities from 55% to 100%. Monitoring vaccination rates in the population is important for gauging the impact of programmes and policies to promote adherence to vaccination recommendations. Use of data from RAIs is a reasonable approach for gauging influenza vaccination rates in nursing-home residents. PMID- 25519438 TI - Neonatal vancomycin trough level audit using British National Formulary for Children dosing. PMID- 25519439 TI - Parallel RNA extraction using magnetic beads and a droplet array. AB - Nucleic acid extraction is a necessary step for most genomic/transcriptomic analyses, but it often requires complicated mechanisms to be integrated into a lab-on-a-chip device. Here, we present a simple, effective configuration for rapidly obtaining purified RNA from low concentration cell medium. This Total RNA Extraction Droplet Array (TREDA) utilizes an array of surface-adhering droplets to facilitate the transportation of magnetic purification beads seamlessly through individual buffer solutions without solid structures. The fabrication of TREDA chips is rapid and does not require a microfabrication facility or expertise. The process takes less than 5 minutes. When purifying mRNA from bulk marine diatom samples, its repeatability and extraction efficiency are comparable to conventional tube-based operations. We demonstrate that TREDA can extract the total mRNA of about 10 marine diatom cells, indicating that the sensitivity of TREDA approaches single-digit cell numbers. PMID- 25519440 TI - Study on the methodology of developing evidence-based clinical practice guidelines of Chinese medicine. AB - At present, evidence-based clinical practice guideline (EBCPG) is the main mode of developing clinical practice guidelines (CPGs) in the world, but in China, most of CPGs of Chinese medicine (CM) are still guidelines based on expert consensus. The objective of this study is to construct initially the methodology of developing EBCPGs of CM and to promote the development of standardization of CM. Based on the development of "Guideline for Diagnosis and Treatment of Common Pediatric Diseases in CM", the methodology of developing EBCPG of CM was explored by analyzing the pertinent literature and considering the characteristics of CM. In this study, the key problem was to put forward the suggestion and strategies. However, due to the methodology study of developing EBCPG of CM is still in the initial stage, there are still some problems which need further study. PMID- 25519441 TI - Study on diagnosis criteria of fire-heat syndrome based on receiver operating characteristic curve and principal component analysis. AB - OBJECTIVE: To establish the diagnostic quantitative criteria for fire-heat syndrome (FHS) of Chinese medicine (CM) based on the receiver operating characteristic (ROC) curve and principal component analysis (PCA). METHODS: The symptoms and signs of FHS cases and healthy subjects from Guangzhou, Henan and Hunan of China were collected through questionnaire, and the diagnostic quantitative score tables were established for the three regions, respectively, with the method of maximum likelihood analysis. The homogeneity test was then performed on the diagnostic score tables for the three regions with ROC curve, and the diagnostic efficiency of diagnostic score tables for the three regions was compared with the prospective test and retrospective test. The method of PCA was adopted to obtain the analysis matrix for classifying the tapes of FHS. RESULTS: Twenty-seven elements of FHS were confirmed through Chi-square test, and the diagnostic score tables for the three regions were established with the method of maximum likelihood analysis on the basis of the collected case data. According to the ROC curve test, the areas under ROC curve of Guangzhou diagnostic score table assessment with candidates in Guangzhou, Henan and Hunan were 0.998, 0.961 and 0.956, respectively. It showed that the diagnostic efficiency of Guangzhou diagnostic score tables was the highest one. With the prospective test, the area under ROC of Guangzhou diagnostic score table was 0.949, and more than any other diagnostic score table. By PCA, FHS was classified into excess fire and deficiency fire, and then classified into syndrome of flaring up of Heart (Xin) fire, syndrome of Lung (Fei)-Stomach (Wei) excess fire, syndrome of deficiency of Liver (Gan)-yin and Kidney (Shen)-yin, and syndrome of deficiency of Lung-yin from the view of viscera. In the retrospective test, the consistency with clinicians' diagnosis was 69.4%, and in the prospective test, it was 70.1%. CONCLUSIONS: The Guangzhou diagnostic score table could be used as the recommended criteria for the diagnosis of FHS. The classification of FHS was basically in conformity with the clinical situation. PMID- 25519443 TI - Research on constitution of Chinese medicine and implementation of translational medicine. AB - Translational medicine is a new concept presented in recent decades, the core of which is to build a bridge between basic medical research and clinical application. From the beginning of constitution of Chinese medicine, clinical application has been given priority. Therefore, the idea of translational medicine is fully demonstrated in the research into the three key scientific problems of "classification of constitution of Chinese medicine", "relationship between constitution and disease" and "adjustment of constitution". Under its guidance, not only was the systematic theory of constitution of Chinese medicine established, but also the Constitution of Chinese Medicine Scale and the Standards of Classification and determination of Constitution of Chinese Medicine were developed, which translates methods of classifying the nine constitutional types into guidance for prevention of disease, management of health and clinical application. The research findings of constitution of Chinese medicine have been applied in clinical practice and public health, establishing the diagnosis and treatment model of constitution-disease-syndrome differentiation. The nationwide application of constitution differentiation has shown good effect. In the future, constitution of Chinese medicine should strengthen the evidence-based research and multi-disciplinary cooperation, and establish a research team on comprehensive constitution of Chinese medicine and translational medicine, to translate the findings into clinical practice and public health more accurately and quickly. PMID- 25519442 TI - Protective effect of emodin against airway inflammation in the ovalbumin-induced mouse model. AB - OBJECTIVE: To investigate whether emodin exerts protective effects on mouse with allergic asthma. METHODS: A mouse model of allergic airway inflflammation was employed. The C57BL/6 mice sensitized and challenged with ovalbumin (OVA) were intraperitoneally administered 10 or 20 mg/kg emodin for 3 days during OVA challenge. Animals were sacrificed 48 h after the last challenge. Inflammatory cell count in the bronchoalveolar lavage fluid (BALF) was measured. The levels of interleukin (IL)-4, IL-5, IL-13 and eotaxin in BALF and level of immunoglobulin E (IgE) in serum were measured with enzyme-linked immuno sorbent assay kits. The mRNA expressions of IL-4, IL-5, heme oxygenase (HO)-1 and matrix metalloproteinase-9 (MMP-9) were determined by real-time quantitative polymerase chain reaction. RESULTS: Emodin induced significant suppression of the number of OVA-induced total inflammatory cells in BALF. Treatment with emodin led to significant decreases in the levels of IL-4, IL-5, IL-13 and eotaxin in BALF and total IgE level in serum. Histological examination of lung tissue revealed marked attenuation of allergen-induced lung eosinophilic inflammation. Additionally, emodin suppressed IL-4, IL-5 and MMP-9 mRNA expressions and induced HO-1 mRNA expression. CONCLUSION: Emodin exhibits anti-inflammatory activity in the airway inflammation mouse model, supporting its therapeutic potential for the treatment of allergic bronchial asthma. PMID- 25519445 TI - Developing, delivering and documenting rehabilitation in a multi-centre randomised controlled surgical trial: experiences from the ProFHER trial. AB - OBJECTIVES: A rigorous approach to developing, delivering and documenting rehabilitation within randomised controlled trials of surgical interventions is required to underpin the generation of reliable and usable evidence. This article describes the key processes used to ensure provision of good quality and comparable rehabilitation to all participants of a multi-centre randomised controlled trial comparing surgery with conservative treatment of proximal humeral fractures in adults. METHODS: These processes included the development of a patient information leaflet on self-care during sling immobilisation, the development of a basic treatment physiotherapy protocol that received input and endorsement by specialist physiotherapists providing patient care, and establishing an expectation for the provision of home exercises. Specially designed forms were also developed to facilitate reliable reporting of the physiotherapy care that patients received. RESULTS: All three initiatives were successfully implemented, alongside the measures to optimise the documentation of physiotherapy. Thus, all participating sites that recruited patients provided the sling immobilisation leaflet, all adhered to the physiotherapy protocol and all provided home exercises. There was exemplary completion of the physiotherapy forms that often reflected a complex patient care pathway. These data demonstrated equal and high access to and implementation of physiotherapy between groups, including the performance of home exercises. CONCLUSION: In order to increase the validity and relevance of the evidence from trials of surgical interventions and meet international reporting standards, careful attention to study design, conduct and reporting of the intrinsic rehabilitation components is required. The involvement of rehabilitation specialists is crucial to achieving this. Cite this article: Bone Joint Res 2014;3:335-40. PMID- 25519444 TI - Qiangzhi decoction protects mice from influenza A pneumonia through inhibition of inflammatory cytokine storm. AB - OBJECTIVE: To investigate the preventive effects of Qiangzhi Decoction (, QZD) on influenza A pneumonia through inhibition of inflammatory cytokine storm in vivo and in vitro. METHODS: One hundred ICR mice were randomly divided into the virus control, the Tamiflu control and the QZD high-, medium-, and low-dose groups. Mice were infected intranasally with influenza virus (H1N1) at 10 median lethal dose (LD50). QZD and Tamiflu were administered intragastrically twice daily from day 0 to day 7 after infection. The virus control group was treated with distilled water alone under the same condition. The number of surviving mice was recorded daily for 14 days after viral infection. The histological damage and viral replication and the expression of inflammatory cytokines were monitored. Additionally, the suppression capacity on the secretion of regulated on activation normal T cells expressed and secreted (RANTES) and tumor necrosis factor-alpha (TNF-alpha) in epithelial and macrophage cell-lines were evaluated. RESULTS: Compared with the virus control group, the survival rate of the QZD groups significantly improved in a dose-dependent manner (P<0.05), the viral titers in lung tissue was inhibited (P<0.05), and the production of inflammatory cytokines interferon-gamma (IFN-gamma), interleukin-6 (IL-6), TNF-alpha, and intercellular adhesion molecule-1 (ICAM-1) were suppressed (P<0.05). Meanwhile, the secretion of RANTETS and TNF-alpha by epithelial and macrophage cell-lines was inhibited with the treatment of QZD respectively in vitro (p<0.05) CONCLUSIONS: The preventive effects of QZD on influenza virus infection might be due to its unique cytokine inhibition mechanism. QZD may have significant therapeutic potential in combination with antiviral drugs. PMID- 25519446 TI - Integrative Frequency Power of EEG Correlates with Progression of Mild Cognitive Impairment to Dementia in Parkinson's Disease. AB - Clinically, predicting the progression of mild cognitive impairment (MCI) and diagnosing dementia in Parkinson's disease (PD) are difficult. This study aims to explore an integrative electroencephalography (EEG) frequency power that could be used to predict the progression of MCI in PD patients. Twenty-six PD patients, in this study, were divided into the mild cognitive impairment group (PDMCI, 17 patients) and dementia group (PDD, 9 patients) according to cognitive performance. Beta peak frequency, alpha relative power, and alpha/theta power were recorded and analyzed for the prediction. Mini Mental State Examination (MMSE) scores at initiation, in the first year, and in the second year were examined. The sensitivity, specificity, positive predictive value, Matthew correlation coefficient, and positive likelihood ratio were calculated in both the integrative EEG biomarkers and single best biomarker. Of the 17 patients with MCI for 2 years, 6 progressed to dementia. Integrative EEG biomarkers, mainly associated with beta peak frequency, can predict conversion from MCI to dementia. These biomarkers had sensitivity of 82% and specificity of 78%, compared with sensitivity of 61% and specificity of 58% of the beta peak frequency. In conclusion, the integrative EEG frequency powers were more sensitive and specific to MCI progression in PD patients. PMID- 25519447 TI - Controlled direct growth of Al2O3-doped HfO2 films on graphene by H2O-based atomic layer deposition. AB - Graphene has been drawing worldwide attention since its discovery in 2004. In order to realize graphene-based devices, thin, uniform-coverage and pinhole-free dielectric films with high permittivity on top of graphene are required. Here we report the direct growth of Al2O3-doped HfO2 films onto graphene by H2O-based atom layer deposition (ALD). Al2O3-onto-HfO2 stacks benefited the doping of Al2O3 into HfO2 matrices more than HfO2-onto-Al2O3 stacks did due to the micro molecular property of Al2O3 and the high chemical activity of trimethylaluminum (TMA). Al2O3 acted as a network modifier, maintained the amorphous structure of the film even to 800 degrees C, and made the film smooth with a root mean square (RMS) roughness of 0.8 nm, comparable to the surface of pristine graphene. The capacitance and the relative permittivity of Al2O3-onto-HfO2 stacks were up to 1.18 MUF cm(-2) and 12, respectively, indicating the high quality of Al2O3-doped HfO2 films on graphene. Moreover, the growth process of Al2O3-doped HfO2 films introduced no detective defects into graphene confirmed by Raman measurements. PMID- 25519448 TI - Prevalence of detectable C-Peptide according to age at diagnosis and duration of type 1 diabetes. AB - OBJECTIVE: It is generally accepted that complete beta-cell destruction eventually occurs in individuals with type 1 diabetes, which has implications for treatment approaches and insurance coverage. The frequency of residual insulin secretion in a large cohort of individuals at varying ages of diagnosis and type 1 diabetes duration is unknown. RESEARCH DESIGN AND METHODS: The frequency of residual insulin secretion was determined by measurement of nonfasting serum C peptide concentration in 919 individuals with type 1 diabetes according to prespecified groups based on age at diagnosis and duration of disease (from 3 to 81 years' duration). Stimulated C-peptide was measured in those with detectable nonfasting values and a group of those with undetectable values as control. RESULTS: The overall frequency of detectable nonfasting C-peptide was 29%, decreasing with time from diagnosis regardless of age at diagnosis. In all duration groups, the frequency of C-peptide was higher with diagnosis age >18 years compared with <=18 years. Nineteen percent of those with undetectable nonfasting C-peptide were C-peptide positive upon stimulation testing. CONCLUSIONS: The American Diabetes Association's definition of type 1 diabetes as "usually leading to absolute insulin deficiency" results in clinicians often considering the presence of residual insulin secretion as unexpected in this population. However, our data suggest that residual secretion is present in almost one out of three individuals 3 or more years from type 1 diabetes diagnosis. The frequency of residual C-peptide decreases with time from diagnosis regardless of age at diagnosis, yet at all durations of disease, diagnosis during adulthood is associated with greater frequency and higher values of C-peptide. PMID- 25519449 TI - Most people with long-duration type 1 diabetes in a large population-based study are insulin microsecretors. AB - OBJECTIVE: Small studies using ultrasensitive C-peptide assays suggest endogenous insulin secretion is frequently detectable in patients with long-standing type 1 diabetes (T1D), but these studies do not use representative samples. We aimed to use the stimulated urine C-peptide-to-creatinine ratio (UCPCR) to assess C peptide levels in a large cross-sectional, population-based study of patients with T1D. RESEARCH DESIGN AND METHODS: We recruited 924 patients from primary and secondary care in two U.K. centers who had a clinical diagnosis of T1D, were under 30 years of age when they received a diagnosis, and had a diabetes duration of >5 years. The median age at diagnosis was 11 years (interquartile range 6-17 years), and the duration of diabetes was 19 years (11-27 years). All provided a home postmeal UCPCR, which was measured using a Roche electrochemiluminescence assay. RESULTS: Eighty percent of patients (740 of 924 patients) had detectable endogenous C-peptide levels (UCPCR >0.001 nmol/mmol). Most patients (52%, 483 of 924 patients) had historically very low undetectable levels (UCPCR 0.0013-0.03 nmol/mmol); 8% of patients (70 of 924 patients) had a UCPCR >=0.2 nmol/mmol, equivalent to serum levels associated with reduced complications and hypoglycemia. Absolute UCPCR levels fell with duration of disease. Age at diagnosis and duration of disease were independent predictors of C-peptide level in multivariate modeling. CONCLUSIONS: This population-based study shows that the majority of long-duration T1D patients have detectable urine C-peptide levels. While the majority of patients are insulin microsecretors, some maintain clinically relevant endogenous insulin secretion for many years after the diagnosis of diabetes. Understanding this may lead to a better understanding of pathogenesis in T1D and open new possibilities for treatment. PMID- 25519452 TI - Videofluoroscopy-guided balloon dilatation for treatment of severe pharyngeal dysphagia. AB - Balloon dilatation is a widely accepted technique in the management of esophageal and other types of gastrointestinal strictures, but it is rarely used for the treatment of pharyngeal dysphagia. Therefore, the aim of our prospective study was to evaluate the use of videofluoroscopy-guided balloon dilatation (VGBD) for the treatment of severe pharyngeal dysphagia. The study included 32 stroke patients who had been diagnosed with oral and/or pharyngeal dysphagia. All patients underwent dilatation of the esophageal inlet using a balloon catheter under videofluoroscopic guidance during one or more sessions. Following esophageal dilatation, manual feeding was provided twice weekly. VGBD was effective in 10 out of 32 patients; however, the remaining 22 patients were unable to attempt oral food consumption because aspiration was not completely resolved on videofluoroscopy. According to this case series, VGBD may provide treatment for patients with severe pharyngeal dysphagia, who have not consumed food orally for a long period of time. PMID- 25519453 TI - Variations in apparent diffusion coefficient values following chemotherapy in pediatric neuroblastoma. AB - PURPOSE: In children the assessment of solid tumors' response to chemotherapy is based primarily on size reduction, which can be unreliable and a late marker, in the presence of necrosis. We aimed to establish whether apparent diffusion coefficient (ADC) values of childhood neuroblastomas show proportional changes in relation to chemotherapy response. METHODS: We evaluated 15 pediatric patients with abdominopelvic neuroblastomas, who had undergone MRI before and after chemotherapy. Two radiologists retrospectively analyzed all images by drawing a round uniform region-of-interest in the solid/contrast-enhancing portion of the lesions in consensus. The ADC values from pre- and postchemotherapy images were compared. RESULTS: Postchemotherapy ADC values were significantly higher than those obtained before treatment (P < 0.05, for minimum, maximum, and median ADC values). CONCLUSION: Our results support diffusion-weighted MRI as a promising noninvasive biomarker of therapeutic responses. To the best of our knowledge, this is the first report to compare diffusion- weighted imaging findings before and after chemotherapy in childhood neuroblastic tumors. PMID- 25519454 TI - Functional MRI compliance in children with attention deficit hyperactivity disorder. AB - PURPOSE: We aimed to test the effect of prescan training and orientation in functional magnetic resonance imaging (fMRI) in children with attention deficit hyperactivity disorder (ADHD) and to investigate whether fMRI compliance was modified by state anxiety. METHODS: Subjects included 77 males aged 6-12 years; there were 53 patients in the ADHD group and 24 participants in the healthy control group. Exclusion criteria included neurological and/or psychiatric comorbidities (other than ADHD), the use of psychoactive drugs, and an intelligence quotient outside the normal range. Children were individually subjected to prescan orientation and training. Data were acquired using a 1.5 Tesla scanner and an 8-channel head coil. Functional scans were performed using a standard neurocognitive task. RESULTS: The neurocognitive task led to reliable fMRI maps. Compliance was not significantly different between ADHD and control groups based on success, failure, and repetition rates of fMRI. Compliance of ADHD patients with extreme levels of anxiety was also not significantly different. CONCLUSION: The fMRI compliance of ADHD children is typically lower than that of healthy children. However, compliance can be increased to the level of age-matched healthy control children by addressing concerns about the technical and procedural aspects of fMRI, providing orientation programs, and performing on-task training. In patients thus trained, compliance does not change with the level of state anxiety suggesting that the anxiety hypothesis of fMRI compliance is not supported. PMID- 25519455 TI - A comparative analysis on the binding characteristics of various mammalian albumins towards a multitherapeutic agent, pinostrobin. AB - The interaction of pinostrobin (PS), a multitherapeutic agent with serum albumins of various mammalian species namely, goat, bovine, human, porcine, rabbit, sheep and dog was investigated using fluorescence quench titration and competitive drug displacement experiments. Analysis of the intrinsic fluorescence quenching data revealed values of the association constant, K(a) in the range of 1.49 - 6.12 * 10(4) M(-1), with 1:1 binding stoichiometry. Based on the PS-albumin binding characteristics, these albumins were grouped into two classes. Ligand displacement studies using warfarin as the site I marker ligand correlated well with the binding data. Albumins from goat and bovine were found to be closely similar to human albumin on the basis of PS binding characteristics. PMID- 25519456 TI - Recurrent spontaneous coronary dissections in a patient with a de novo fibrillin 1 mutation without Marfan syndrome. PMID- 25519457 TI - Fragmentation pathways and structural characterization of 14 nerve agent compounds by electrospray ionization tandem mass spectrometry. AB - Organophosphate nerve agents (OPNAs) are some of the most widely used and proliferated chemical warfare agents. As evidenced by recent events in Syria, these compounds remain a serious military and terrorist threat to human health because of their toxicity and the ease with which they can be used, produced and stored. There are over 2,000 known, scheduled compounds derived from common parent structures with many more possible. To address medical, forensic, attribution, remediation and other requirements, laboratory systems have been established to provide the capability to analyze 'unknown' samples for the presence of these compounds. Liquid chromatography/mass spectrometric methods have been validated and are routinely used in the analysis of samples for a very limited number of these compounds, but limited data exist characterizing the electrospray ionization (ESI) and mass spectrometric fragmentation pathways of the compound families. This report describes results from direct infusion ESI/MS, ESI/MS(2) and ESI/MS(3) analysis of 14 G and V agents, the major OPNA families, using an AB Sciex 4000 QTrap. Using a range of conditions, spectra were acquired and characteristic fragments identified. The results demonstrated that the reproducible and predictable fragmentation of these compounds by ESI/MS, ESI/MS(2) and ESI/MS(3) can be used to describe systematic fragmentation pathways specific to compound structural class. These fragmentation pathways, in turn, may be useful as a predictive tool in the analysis of samples by screening and confirmatory laboratories to identify related compounds for which authentic standards are not readily available. PMID- 25519450 TI - Early childhood gut microbiomes show strong geographic differences among subjects at high risk for type 1 diabetes. AB - OBJECTIVE: Gut microbiome dysbiosis is associated with numerous diseases, including type 1 diabetes. This pilot study determines how geographical location affects the microbiome of infants at high risk for type 1 diabetes in a population of homogenous HLA class II genotypes. RESEARCH DESIGN AND METHODS: High-throughput 16S rRNA sequencing was performed on stool samples collected from 90 high-risk, nonautoimmune infants participating in The Environmental Determinants of Diabetes in the Young (TEDDY) study in the U.S., Germany, Sweden, and Finland. RESULTS: Study site-specific patterns of gut colonization share characteristics across continents. Finland and Colorado have a significantly lower bacterial diversity, while Sweden and Washington state are dominated by Bifidobacterium in early life. Bacterial community diversity over time is significantly different by geographical location. CONCLUSIONS: The microbiome of high-risk infants is associated with geographical location. Future studies aiming to identify the microbiome disease phenotype need to carefully consider the geographical origin of subjects. PMID- 25519459 TI - [Primary care, investigating in a healthier future[editorial]]. PMID- 25519458 TI - Renal cell tumour characteristics in patients with the Birt-Hogg-Dube cancer susceptibility syndrome: a retrospective, multicentre study. AB - BACKGROUND: The Birt-Hogg-Dube syndrome is a rare cancer susceptibility syndrome characterised by renal tumours, lung cysts and pneumothoraces, and fibrofolliculomas. It is caused by dominantly inherited mutations in FLCN. Our objective was to report renal tumour characteristics in a large series of patients with the Birt-Hogg-Dube syndrome. METHODS: We studied French Birt-Hogg Dube patients with a history of renal tumour. RESULTS: We included 33 patients with 21 distinct germline FLCN mutations. Median age at diagnosis of first renal tumour was 46, and age varied from 20 to 83. Twenty cases had one renal tumour, the remainder had two or more tumours. Most cases (23/33, 70%) had oncocytoma or renal cell carcinoma of the chromophobe or hybrid chromophobe-oncocytoma type, three had clear cell carcinoma (9%), and the other seven had carcinoma of papillary, undifferentiated or undetermined histology. Four cases had metastatic disease, although none died of it. CONCLUSIONS: Age at renal tumour diagnosis was highly variable, highlighting the need for regular surveillance from young adulthood to old age. Most cases had tumour types classically associated with Birt-Hogg-Dube, i.e. oncocytoma or renal cell carcinoma of the chromophobe or hybrid type. Nevertheless, 9% had clear cell renal cell carcinoma. Geneticists, urologists and oncologists should therefore be alert to the possibility of Birt Hogg-Dube in patients with renal cell carcinoma of clear cell histology, especially if there are associated manifestations. Finally, the behaviour of metastatic carcinoma seemed more indolent than in sporadic renal cancers. PMID- 25519460 TI - [Coronary heart disease in the front [editorial]]. PMID- 25519461 TI - [Outcome of myocardial revascularisation in patients fifty years old and younger]. AB - INTRODUCTION: Most patients that undergo coronary artery bypass grafting (CABG) are around 70 years of age when operated on. We investigated the outcome of CABG in patients 50 years and younger, focusing on early complications, operative mortality and long-term survival. MATERIAL AND METHOD: A retrospective study on 1626 patients that underwent CABG in Iceland 2001-2012. One hundred patients aged 50 years or younger were compared to 1526 older patients. RESULTS: The male:female ratio, risk factors and extension of coronary artery disease were comparable in both groups, as was the proportion of patients with left main disease. Left ventricular ejection fraction was significantly lower in the younger patients (52 vs. 55%, p=0.004) and more of them had a recent myocardial infarction (41 vs. 27%, p=0.003). Minor complications were less common in the younger group (30 vs. 50%, p<0.001), especially new onset atrial fibrillation (14 vs. 35%, p<0,001). Chest tube bleeding for the first 24 hours postoperatively was also less in the younger group (853 vs. 999 ml, p=0.015) and they received fewer units of packed red cells (1.3 vs. 2.8 units, p<0.001). However, the incidence of major complications was comparable (6 vs. 11%, p=0.13) and the same was true for 30 day mortality (1 vs. 3%, p=0.5). Mean hospital stay was 2 days shorter for younger patients (p<0.001). There was a non-significant trend for improved disease-specific survival for the younger patients, or 99% vs. 95% 5-year survival (p=0.07). CONCLUSION: In younger patients undergoing CABG minor complications are less common than in older patients, their hospital stay is shorter and transfusions less common. There was also a trend for improved disease specific survival for the younger patients. PMID- 25519462 TI - [National nutrition surveys and dietary changes in Iceland. Economic differences in healthy eating]. AB - INTRODUCTION: Here we compare results on food and nutrient intake from the two most recent Icelandic national nutrition surveys from 2010/11 and 2002 and compare intake of energy giving nutrients from 1990. Finally we assess associations beween a healthy diet and difficulties people have in making ends meet. MATERIALS AND METHODS: Participants were selected by a random sample from the national register. Final sample was 1912 individuals in 2010/11 and 1934 in 2002, response rate 68.6% and 70.6% respectively. Diet was assessed by 24-hour recall. Results from the surveys were calculated using t-test and sssociations between a healthy diet and difficulties making ends meet by linear regression. RESULTS: Consumption of bread, bisquits, cakes and cookies, margarine, highly processed meat products, chips, sugared soft drinks and whole milk was lower in 2010/11 than in 2002 while consumption of whole grain bread, oat meal, fruits, vegetables, meat and cod liver oil was higher. Fish intake was unchanged. Fat intake decreased from 1990 to 2010/11, from 41E% to 35E%, saturated fatty acids from 20.0E% to 14.5E% and trans-fatty acids from 2.0E% to 0.8E%. Most of the changes occurred between 1990 and 2002. People having difficulties making ends meet consumed less fruits, vegetables and whole grain bread but more soft drinks in 2010/11 than those not having difficulties. CONCLUSION: Dietary changes in Iceland from 2002 have mostly been toward recommended intake. Between 1990 and 2002 fat consumption decreased considerably, while less significant changes occurred from 2002 til 2010/11. Economic status is associated with healthy diet in Iceland. PMID- 25519451 TI - A new approach for diagnosing type 1 diabetes in autoantibody-positive individuals based on prediction and natural history. AB - OBJECTIVE: We assessed whether type 1 diabetes (T1D) can be diagnosed earlier using a new approach based on prediction and natural history in autoantibody positive individuals. RESEARCH DESIGN AND METHODS: Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Natural History Study (TNNHS) participants were studied. A metabolic index, the T1D Diagnostic Index60 (Index60), was developed from 2-h oral glucose tolerance tests (OGTTs) using the log fasting C-peptide, 60-min C peptide, and 60-min glucose. OGTTs with Index60 >=2.00 and 2-h glucose <200 mg/dL (Ind60+Only) were compared with Index60 <2.00 and 2-h glucose >=200 mg/dL (2hglu+Only) OGTTs as criteria for T1D. Individuals were assessed for C-peptide loss from the first Ind60+Only OGTT to diagnosis. RESULTS: Areas under receiver operating characteristic curves were significantly higher for Index60 than for the 2-h glucose (P < 0.001 for both DPT-1 and the TNNHS). As a diagnostic criterion, sensitivity was higher for Ind60+Only than for 2hglu+Only (0.44 vs. 0.15 in DPT-1; 0.26 vs. 0.17 in the TNNHS) OGTTs. Specificity was somewhat higher for 2hglu+Only OGTTs in DPT-1 (0.97 vs. 0.91) but equivalent in the TNNHS (0.98 for both). Positive and negative predictive values were higher for Ind60+Only OGTTs in both studies. Postchallenge C-peptide levels declined significantly at each OGTT time point from the first Ind60+Only OGTT to the time of standard diagnosis (range -22 to -34% in DPT-1 and -14 to -27% in the TNNHS). C-peptide and glucose patterns differed markedly between Ind60+Only and 2hglu+Only OGTTs. CONCLUSIONS: An approach based on prediction and natural history appears to have utility for diagnosing T1D. PMID- 25519463 TI - [Review on coronary artery disease - part I: epidemiology, pathophysiology, clinical presentation and work-up]. AB - Coronary artery disease affects thousands of Icelanders and is the most common cause of death in Iceland. In recent years great strides have been taken towards deeper understanding and improved treatment of this common disease, resulting in markedly improved outcomes. This evidence based review article is the first of two on coronary artery diseases. It will discuss the epidemiology and pathogenesis of coronary artery disease but also clinical presentation and diagnostic work-up. The review is aimed at a wide readership of physicians, other health care providers and students of health sciences. Current literature will be reviewed with special focus on recent Icelandic studies. PMID- 25519464 TI - Serotonin, glutamate and glycerol are released after the injection of hypertonic saline into human masseter muscles - a microdialysis study. AB - BACKGROUND: Chronic myalgia is associated with higher muscle levels of certain algesic biomarkers. The aim of this study was to investigate if hypertonic saline induced jaw myalgia also leads to release of such biomarkers and if there were any sex differences in this respect. METHODS: Healthy participants, 15 men and 15 aged-matched women (25.7 +/- 4.3 years) participated. Intramuscular microdialysis into masseter muscles was performed to sample serotonin (5-HT), glutamate, lactate, pyruvate, glucose and glycerol. After 2 hours 0.2 mL hypertonic saline (58.5 mg/mL) was injected into the masseter on one side and 0.2 mL isotonic saline (9 mg/mL) into the contralateral masseter close to the microdialysis catheter. Microdialysis continued for 1 hour after the injections. Pressure pain thresholds (PPT) and pain were assessed before and after injections. RESULTS: The median (IQR) peak pain intensity (0-100 visual analogue scale) after hypertonic saline was 52.5 (38.0) and after isotonic saline 7.5 (24.0) (p < 0.05). 5-HT, glutamate and glycerol increased after hypertonic saline injection (p < 0.05). Lactate, pyruvate and glucose showed no change. PPT after microdialysis was reduced on both sides (p < 0.05) but without side differences. Pain after hypertonic saline injection correlated positively to 5-HT (p < 0.05) and negatively to glycerol (p < 0.05). CONCLUSIONS: 5-HT, glutamate and glycerol increased after a painful hypertonic saline injection into the masseter muscle, but without sex differences. Since increased levels of 5-HT and glutamate have been reported in chronic myalgia, this strengthens the validity of the pain model. Glycerol warrants further investigations. PMID- 25519465 TI - Comparative proteomics analysis of global cellular stress responses to hydroxyurea-induced DNA damage in HeLa cells. AB - Both environmental agents and spontaneous cellular events cause serious DNA damage, threatening the integrity of the genome. In response to replication stress or genotoxic agents triggered DNA damage, degradation of p12 subunit of DNA polymerase delta (Pol delta) results in an inter-conversion between heterotetramer (Pol delta4) and heterotrimer (Pol delta3) forms and plays a significant role in DNA damage response in eukaryotic cells. In this work, we used mass spectrometry-based proteomic approach to identify those cellular stress response protein changes corresponding to the degradation of p12 in DNA-damaged HeLa cells by the treatment with hydroxyurea (HU). A total of 736 +/- 13 proteins in non-treated control group and 741 +/- 19 protein spots in HU-treated cells were detected, of which 34 proteins (17 up-regulated and 17 down-regulated) exhibited significantly altered protein expression levels. Their physiological roles are mainly associated with cellular components, molecular functions, and biological processes by gene ontology analysis, among which 21 proteins were mapped to KEGG pathways. They are involved in 5 primary pathways with the subsets involving 16 secondary pathways by further KEGG analysis. More interestingly, the up-regulation of translationally controlled tumor protein was further identified to be associated with p12 degradation by Western blot analysis. Our works may enlarge and broaden our view for deeply understanding how global cellular stress responds to DNA damage, which could contribute to the etiology of human cancer or other diseases that can result from loss of genomic stability. PMID- 25519466 TI - Inflammatory myofibroblastic tumours: a pictorial review. AB - OBJECTIVES: To present the most important characteristics of inflammatory myofibroblastic tumours (IMTs) arising in different locations of the body with histological correlation. METHODS: To review the symptoms and main radiological findings of IMTs. On ultrasonography (US), these tumours can appear as hypoechoic or hyperechoic masses and a variable Doppler appearance with increased vascularity. Computed tomography (CT) and magnetic resonance (MR) are the most used imaging tools in their evaluation. On contrast-enhanced CT, IMTs can appear as homogeneous or heterogeneous lesions, with variable enhancement on delayed acquisitions due to fibrosis. These findings are also present on gadolinium contrast-enhanced MR. On T1-weighted and T2-weighted sequences, IMTs usually show low signal intensity reflecting also the presence of fibrotic tissue. RESULTS: To show the main clinical symptoms and radiological features of IMTs in different locations: head and neck, lung, genitourinary, hepatic, splenic, gastrointestinal tract, mesenteric, muskuloskeletal. CONCLUSIONS: Although IMTs in some organs are not uncommon, they are not usually included in the differential diagnosis of masses. Their radiological features suggest malignant neoplasms, whereas they are not. Consequently, this is an underdiagnosed entity and only after an histological exam could a definitive diagnosis be achieved. TEACHING POINTS: * Their radiological features suggest malignant neoplasms, whereas they are not * CT and MR imaging are the most used tools in their evaluation * IMT is an underdiagnosed entity * The definitive diagnosis is only after histological exam. PMID- 25519468 TI - Role of the extracellular signal-regulated kinase 1/2 signaling pathway in the process of thrombin-promoting airway remodeling in ovalbumin-allergic rats. AB - CONTEXT: Although it is recognized that thrombin plays a key role in airway remodeling during chronic asthma. In a previous study, we have proved that thrombin promotes airway remodeling via PAR-1 in OVA-allergic rats, but little is known about intracellular signaling pathway involved in the event. OBJECTIVE: In this study, we intend to explore the impact of pERK1/2 signaling pathway on the process of thrombin-induced airway remodeling in OVA-allergic rats. MATERIALS AND METHODS: A rat model of chronic asthma was set up by systemic sensitization and repeated challenge to OVA. The doses of thrombin, recombinant hirudin, PAR-1 inhibitor ER-112780-06, and pERK1/2 inhibitor PD98059 varied for different groups. The expression of pERK1/2 was analyzed by western blot and RT-PCR. Secretion of TGF-beta1 and IL-6 was detected by ELISA. RESULTS: The expression of pERK1/2 was higher in the airway of asthmatic rats than those of normal rats, and was significantly increased by thrombin treatment but decreased by thrombin inhibitor treatment. Airway remodeling was enhanced by thrombin but weakened by pERK1/2 inhibitor. Expression of growth factors and IL-6 in asthmatic rats was significantly increased by thrombin treatment and decreased by thrombin-inhibitor treatment and pERK1/2 inhibitor treatment. CONCLUSION: These results suggest that ERK1/2 signaling pathway may play an important role in the process of thrombin promoting airway remodeling in OVA-allergic rats, and pERK1/2 inhibitor effectively inhibits the process. PMID- 25519469 TI - Thiram modulates pro-inflammatory mediators in RAW 264.7 murine macrophage cells. AB - Thiram (TMTD) is a widely used dithiocarbamate pesticide and fungicide and is one of potent contact allergens. In the light of known properties, thiram is also considered to be used as an inhibitor of inflammation. To investigate whether known pro-oxidative properties of thiram might be involved in immunogenic mechanisms, we carried out an in vitro study aimed at analysis of reactive oxygen species (ROS) generation, activation of NF-kappaB, expression of iNOS and COX-2, production of NO, PGE2 and IL-1beta in murine macrophage cells (RAW 264.7). The cells were treated by thiram alone (0.5 ug/mL; 2 MUM and 2 ug/mL; 8 MUM) or concomitantly with bacterial endotoxin (LPS; 1 MUg/mL). LPS was used as an endotoxin that triggers changes characteristic for inflammatory state of the cell. TMTD increased ROS production, level of oxidized glutathione (GSSG) and activated NF-kappaB. The consequence of NF-kappaB activation was the increase of IL-1beta and NO production characteristic for inflammation. However, we did not observe changes in PGE2 concentration. We observed expression of iNOS, COX-2 proteins and NO and PGE2 production in macrophages treated with thiram concomitantly with LPS lower than those in cells stimulated with LPS alone. Thiram (2 ug/mL) decreased NF-kappaB activation and production of LPS-induced IL 1beta. In conclusion, we demonstrated changes induced by TMTD characteristic for inflammation. Hence, it can be supposed that they may participate in the elicitation phase of allergic contact dermatitis induced by thiram. However, when TMTD acts concomitantly with LPS, it decreases the intensity of inflammation state in RAW 264.7. PMID- 25519470 TI - Differential effects of ponesimod, a selective S1P1 receptor modulator, on blood circulating human T cell subpopulations. AB - Ponesimod, a novel selective sphingosine-1-phosphate 1 receptor modulator in the development for the treatment of autoimmune diseases, dose-dependently reduced lymphocyte counts in peripheral blood of healthy subjects. It rapidly and transiently reduced the number of circulating T and B cells, but not natural killer cells. T lymphocyte subsets exhibited differential sensitivities with a maximum decrease from baseline ranging from 67% to 89% following high doses. Naive T cells were more sensitive than memory T cells. CD4(+) T cells were more sensitive than CD8(+) T cells or CD4(+)CD25(+) T regulatory cells. The differential effects on specialized T cell subsets may contribute to the immunomodulatory activity of ponesimod. The therapeutic potential of ponesimod has been recently shown in phase II studies of chronic plaque psoriasis and relapsing-remitting multiple sclerosis. Our data suggest that lymphocyte sequestration underlies the therapeutic potential of ponesimod in multiple autoimmune and chronic inflammatory diseases. PMID- 25519471 TI - Interventions for fatigue in peripheral neuropathy. AB - BACKGROUND: Persistent feelings of fatigue (or subjective fatigue), which may be experienced in the absence of physiological factors, affect many people with peripheral neuropathy. A variety of interventions for subjective fatigue are available, but little is known about their efficacy or the likelihood of any adverse effects for people with peripheral neuropathy. OBJECTIVES: To assess the effects of drugs and physical, psychological or behavioural interventions for fatigue in adults or children with peripheral neuropathy. SEARCH METHODS: On 5 November 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, CINAHL Plus, LILACS and AMED. We also searched reference lists of all studies identified for inclusion and relevant reviews, and contacted the authors of included studies and known experts in the field to identify additional published or unpublished data. We also searched trials registries for ongoing studies. SELECTION CRITERIA: We considered for inclusion randomised controlled trials (RCTs) and quasi-RCTs comparing any form of intervention for fatigue management in adults with peripheral neuropathy with placebo, no intervention or an alternative form of intervention for fatigue. Interventions considered included drugs, pacing and grading of physical activity, general or specific exercise, compensatory strategies such as orthotics, relaxation, counselling, cognitive and educational strategies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted study data. We contacted study authors for additional information. We collected information on adverse events from the included trials. MAIN RESULTS: The review includes three trials, which were all at low risk of bias, involving 530 people with peripheral neuropathy. The effects of amantadine from one randomised, double-blind, placebo-controlled, cross-over trial comparing amantadine with placebo for the treatment of fatigue in 80 people with Guillain Barre syndrome (GBS) were uncertain for the proportion of people achieving a favourable outcome six weeks post-intervention (odds ratio (OR) 0.56 (95% confidence interval (CI) 0.22 to 1.35, N = 74, P = 0.16). We assessed the quality of this evidence as low. Two parallel-group randomised double-blind, placebo controlled trials comparing the effects of two doses of ascorbic acid with placebo for reducing fatigue in adults with Charcot-Marie-Tooth disease type 1A (CMT1A) showed that the effects of ascorbic acid at either dose are probably small (standardised mean difference (SMD) -0.12 (95% CI -0.32 to 0.08, n = 404, P = 0.25)) for change in fatigue after 12 to 24 months (moderate quality evidence). Neither ascorbic acid study measured fatigue at four to 12 weeks, which was our primary outcome measure. No serious adverse events were reported with amantadine. Serious adverse events were reported in the trials of ascorbic acid. However,risk of serious adverse events was similar with ascorbic acid and placebo. AUTHORS' CONCLUSIONS: One small imprecise study in people with GBS showed uncertain effects of amantadine on fatigue. In two studies in people with CMT1A there is moderate-quality evidence that ascorbic acid has little meaningful benefit on fatigue. Information about adverse effects was limited, although both treatments appear to be well tolerated and safe in these conditions.There was no evidence available from RCTs to evaluate the effect of other drugs or other interventions for fatigue in either GBS, CMT1A or other causes of peripheral neuropathy. The cost effectiveness of different interventions should also be considered in future randomised clinical trials. PMID- 25519467 TI - Distinct aspects of frontal lobe structure mediate age-related differences in fluid intelligence and multitasking. AB - Ageing is characterized by declines on a variety of cognitive measures. These declines are often attributed to a general, unitary underlying cause, such as a reduction in executive function owing to atrophy of the prefrontal cortex. However, age-related changes are likely multifactorial, and the relationship between neural changes and cognitive measures is not well-understood. Here we address this in a large (N=567), population-based sample drawn from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) data. We relate fluid intelligence and multitasking to multiple brain measures, including grey matter in various prefrontal regions and white matter integrity connecting those regions. We show that multitasking and fluid intelligence are separable cognitive abilities, with differential sensitivities to age, which are mediated by distinct neural subsystems that show different prediction in older versus younger individuals. These results suggest that prefrontal ageing is a manifold process demanding multifaceted models of neurocognitive ageing. PMID- 25519472 TI - Theoretical study on the relationship between Rp-phosphorothioation and base-step in S-DNA: based on energetic and structural analysis. AB - Phosphorothioation (PT), previously used in synthetic antisense drugs to arrest the transcription or translation process, is also a novel physiological modification in bacteria DNAs. In the previous study, we reported that Rp phosphorothioation (Rp-PT) destabilizes B-type helix significantly, using a quantum-mechanics-based energy scoring function developed with a dinucleotide model ( Zhang et al. J. Phys. Chem. B , 2012 , 116 , 10639 - 10648 ). A consequent question surfaces in the field of the phosphorothioated DNA (S-DNA) research: does the endogenous chemical modification interact with the base sequence in the bacterial genomes, e.g., in terms of the most common structure of the B-type helix? In this work, we carried out further energetic analysis on the backbone relative energies calculated with the scoring function according to 16 groups of base-step classifications. Moreover, we conducted molecular dynamics simulations of the B-helical structure with the different base-pair steps, to investigate the detailed structural changes upon the O-/S-substitution. As a result, the Rp-PT modification definitively enhances the stiffness of the backbone and differentiates backbone stability as an interaction with base-steps. Furthermore, certain exceptional sequences such as GT and CC were highlighted in the structural analysis of the sulfur local contacts and relative orientation of double strands, indicating that Rp-PT can cross-talk with particular base-steps. The special effects between the phosphorothioation and base-step may be related to the conservative consensus observed highly frequently in bacterial genomes. PMID- 25519474 TI - Patients with long-lasting dizziness: a follow-up after neurotological and psychotherapeutic inpatient treatment after a period of at least 1 year. AB - Patients who experience chronic dizziness are considered to be difficult to treat. Persisting symptoms of vertigo can be caused by recurrent organic as well as a variety of psychogenic factors, the latter usually being part of anxiety and depression disorders. Psychotherapeutic interventions can achieve improvements, the effects, however, in general do not persist over a longer time. The purpose of this study is to investigate the long-term effects of a symptom-related indoor treatment including neurotological and psychotherapeutic approaches as well as vestibular and balance rehabilitation. 23 indoor patients 16 male patients and 7 female., mean age 56.6 years (SD 12) with chronic vestibular symptoms (longer than six months), who were treated with neurotological counseling, psychotherapy, vestibular and balance rehabilitation and-if necessary-antidepressant drugs during a lengthy hospital stay [average 40 days (SD 14)], were re-examined. After a time period of at least one year (average 32 months; SD 15) they were asked to answer a questionnaire concerning post-therapeutic status of dizziness, symptoms and coping strategies as well as the Hospital Anxiety and Depression Score (HADS D). 18 of 23 patients (78%) reported a sustained reduction in their vertiginous symptoms. Four patients did not report a persistent improvement and one even got worse. Patients with a chronic form of dizziness can improve through a coordinated neurotologic and psychotherapeutic approach including vestibular and balance rehabilitation. PMID- 25519473 TI - Consideration of vocal fold position in unilateral vocal fold paralyses. AB - The objective of this study was to improve the evaluation of unilateral vocal fold paralyses (uVFP) by means of an area measurement of the glottic plane, which describes the position of the paralysed vocal fold. The area measurements were related to electromyographic findings and clinical outcome (recovery, voice quality). In 56 patients (33 women and 23 men), uVFP were confirmed by endolaryngeal electromyography (EMG) of the paralysed vocal fold and cricothyroid muscles (CT). The EMG response was classified on a 4-point scale (from 0 to 3). Vocal fold position was divided into 'paramedian' and 'intermediate' and additionally quantified by measurement of the glottic area. An 'area quotient' (AQ) was calculated and related to the EMG findings and clinical outcome. Voice qualities were objectified regarding their additive noise (breathiness) and irregularity (roughness) using the 'Gottingen Hoarseness Diagram'. The majority of uVFP was due to iatrogenic lesions. The AQ of classically graduated 'paramedian' and 'intermediate' vocal fold positions was significantly different but did not correlate with objective voice quality values. There were no significant correlations regarding EMG findings, duration or recovery from paralyses. Laryngeal EMG remains the gold standard for verifying uVFP. But EMG did not correlate significantly with AQ or functional outcome of uVFP. The measurement of an AQ is suitable for obtaining continuous data describing the position of paralysed vocal folds beyond the terms 'paramedian' or 'intermediate' and provides the basis for clinical evaluations of diagnostic tools and therapeutic interventions. PMID- 25519475 TI - WPSS is a strong prognostic indicator for clinical outcome of allogeneic transplant for myelodysplastic syndrome in Southeast Asian patients. AB - To better understand the predictive factors and improve clinical outcome of allogeneic transplant for patients with myelodysplastic syndrome (MDS), we retrospectively analyzed the post-transplant outcome of 60 Southeast Asian patients with MDS. Multivariate analysis showed that WHO classification-based Prognostic Scoring System (WPSS) significantly affect overall survival (OS), progression-free survival (PFS), cumulative incidence of relapse (CIR), and cumulative incidence of non-relapse mortality (CINRM). Stratified by WPSS into very low/low, intermediate, high, and very high-risk categories, 3-year OS was 100, 61, 37, and 18% (p = 0.02); PFS was 100, 55, 32, and 18% (p = 0.014); CIR was 12, 24, 38, and 59% (p = 0.024); CINRM was 0, 6, 12, and 26% (p = 0.037), respectively. WHO classification, Revised International Prognostic Scoring System (IPSS-R), IPSS-R-defined cytogenetic risk groups, donor gender, and acute and chronic graft vs host disease (GVHD) also influenced different aspects of transplant outcome. We found that WPSS is a powerful predictor of post-transplant outcome. WPSS provides an important model not only for prognostication but also for exploration of further post-transplant measures such as immunological maneuvers or novel therapy to improve the poor outcome of high-risk patients. PMID- 25519476 TI - FLT3 internal tandem duplication in acute promyelocytic leukemia: central nervous system relapse. PMID- 25519477 TI - Relationship between circulating tumor cells and tumor response in colorectal cancer patients treated with chemotherapy: a meta-analysis. AB - BACKGROUND: The prognostic value of circulating tumor cells (CTCs) in colorectal cancer (CRC) patients and their value in predicting tumor response to chemotherapy are controversial. The aim of this meta-analysis was to assess the prognostic and predictive value of CTCs in CRC patients treated with chemotherapy. METHODS: A comprehensive literature search for relevant studies was conducted in PubMed, Embase, the Cochrane Database, the Science Citation Index and the Ovid Database, and the reference lists of relevant studies were also perused for other relevant studies (up to April, 2014). Using the random-effects model in Stata software, version 12.0, the meta-analysis was performed using odds ratios (ORs), risk ratios (RRs), hazard ratios (HRs) and 95% confidence intervals (CIs) as effect measures. Subgroup and sensitivity analyses were also performed. RESULTS: Thirteen eligible studies were included. Our meta-analysis indicated that the disease control rate was significantly higher in CRC patients with CTC low compared with CTC-high (RR = 1.354, 95% CI [1.002-1.830], p = 0.048). CRC patients in the CTC-high group were significantly associated with poor progression-free survival (PFS; HR = 2.500, 95% CI [1.746-3.580], p < 0.001) and poor overall survival (OS; HR = 2.856, 95% CI [1.959-4.164], p < 0.001). Patients who converted from CTC-low to CTC-high or who were persistently CTC-high had a worse disease progression (OR = 27.088, 95% CI [4.960-147.919], p < 0.001), PFS (HR = 2.095, 95% CI [1.105-3.969], p = 0.023) and OS (HR = 3.604, 95% CI [2.096 6.197], p < 0.001) than patients who converted from CTC-high to CTC-low. CONCLUSIONS: Our meta-analysis indicates that CTCs are associated with prognosis in CRC patients treated with chemotherapy. Moreover, CTCs could provide additional prognostic information to tumor radiographic imaging and might be used as a surrogate and novel predictive marker for the response to chemotherapy. PMID- 25519478 TI - Normative data and clinically significant effect sizes for single-item numerical linear analogue self-assessment (LASA) scales. AB - BACKGROUND: Single-item assessments have been the most often-used measures in National Cancer Institute (NCI) cancer control clinical trials, but normative data are not available. Our objective was to examine the normative data and clinically significant effect sizes for single-item numerical linear analogue self-assessment (LASA) scale for overall quality of life (QOL). METHODS: We analyzed baseline data from 36 clinical trials and 6 observational studies with various populations, including healthy volunteers, cancer trial patients (patients with advanced incurable cancer or patients receiving treatment with curative intent) and hospice patients as well as their caregivers. The overall QOL LASA was rated 0 (as bad as it can be) to 10 (as good as it can be). We calculated the summary statistics and the proportion of patients reporting a clinically meaningful deficit (CMD) of a score equal to 5 or less on the 0-10 scale. RESULTS: In total, for the collective sample of 9,295 individuals, the average overall QOL reported was 7.39 (SD = 2.11) with a markedly skewed distribution with roughly 17% reporting a score of 5 or below indicating a clinically significant deficit in overall QOL. Hospice patients report a much worse average score of 5.7 upon entry to hospice; hospice caregivers average 7.4. Cancer patients vary within these two extremes with most patients averaging in the 7's on the 0-10 scale (range, 0 to 10 p-value < 0.0001). Men and women's QOL distributions were virtually identical (with average of 7.6 vs. 7.5, p-value = 0.046). Overall QOL was weakly related to performance status with a Spearman correlation coefficient of -0.29 (p-value < 0.0001). Overall QOL was related to tumor response (p-value = 0.0094), i.e. patients with a full or partial response reported a CMD in 11.4% of cases compared to 14.4% among those with stable disease and 18.5% among those with disease progression. Data missingness was high for performance status and tumor response associations. CONCLUSIONS: This study provides the normative data for cancer patients and healthy volunteers for overall QOL using the LASA. These can serve as benchmarks for future studies and inform clinical practice decision-making. PMID- 25519481 TI - Extension of the primary care research object model (PCROM) as clinical research information model (CRIM) for the "learning healthcare system". AB - BACKGROUND: Patient data from general practices is already used for many types of epidemiological research and increasingly, primary care systems to facilitate randomized clinical trials. The EU funded project TRANSFoRm aims to create a "Learning Healthcare System" at a European level that is able to support all types of research using primary care data, to recruit patients and follow patients in clinical studies and to improve diagnosis and therapy. The implementation of such a Learning Healthcare System needs an information model for clinical research (CRIM), as an informational backbone to integrate aspects of primary care with clinical trials and database searches. METHODS: Workflow descriptions and corresponding data objects of two clinical use cases (Gastro Oesophageal Reflux Disease and Type 2 Diabetes) were described in UML activity diagrams. The components of activity diagrams were mapped to information objects of PCROM (Primary Care Research Object Model) and BRIDG (Biomedical Research Integrated Domain Group) and evaluated. The class diagram of PCROM was adapted to comply with workflow descriptions. RESULTS: The suitability of PCROM, a primary care information model already used for clinical trials, to act as an information model for TRANSFoRm was evaluated and resulted in its extension with 14 new information object types, two extensions of existing objects and the introduction of two new high-ranking concepts (CARE area and ENTRY area). No PCROM component was redundant. Our result illustrates that in primary care based research an important but underestimated portion of research activity takes place in the area of care (e.g. patient consultation, screening, recruitment and response to adverse events). The newly introduced CARE area for care-related research activities accounts for this shift and includes Episode of Care and Encounter as two new basic elements. In the ENTRY area different aspects of data collection were combined, including data semantics for observations, assessment activities, intervention activities and patient reporting to enable case report form (CRF) based data collection combined with decision support. CONCLUSIONS: Research with primary care data needs an extended information model that covers research activities at the care site which are characteristic for primary care based research and the requirements of the complicated data collection processes. PMID- 25519483 TI - Correlation of histological components with tumor invasion in pulmonary adenocarcinoma. AB - BACKGROUND: Pulmonary adenocarcinoma (PA) is the most common histologic type of primary lung cancer. Generally, adenocarcinoma was composed by five major components. The present study aimed to evaluate changes in the composition of adenocarcinoma components as the tumor grows; in addition, to analyze the correlation between the occupancy rates of histologic components of the tumor in regard to prognosis. METHODS: Pathologic data were retrospectively evaluated for 206 patients who underwent curative resection of PA. We investigated how histologic component occupancy rates changed as tumor size and N stage increased. To evaluate local invasiveness, the major components of the present group and absent group of pleural invasion, lymphatic invasion, and vascular invasion were compared. RESULTS: The mean percentages of acinar and solid components significantly increased with an increase in size (P = 0.006, P < 0.001) ; however, the percentage of lepidic components decreased (P < 0.001). In cases with a solid component and a micropapillary component, a gradual increase was found with an increase N stage (P = 0.001, P < 0.001); however the percentage of lepidic components decreased (P < 0.001). Average differences of histologic components dependent upon whether pleural, lympathic and vascular invasion were present, the difference of micropapillary and lepidic components were statistically significant. With logistic regression analysis, as the occupancy rate of the lepidic component increased, the probability of pleural invasion, lymphatic invasion, and vascular invasion decreased; in cases with a micropapillary component, as the occupancy rate of increased, the probability of lymphatic invasion and vascular invasion increased. In multivariate analysis using the Cox propotional hazards model, the occupancy rates of acinar(p = 0.043; odds ratio = 1.023), micropapillary(p = 0.002; odds ratio = 1.051) and lepidic (p = 0.005; odds ratio = 0.966) components were significantly associated with recurrence. CONCLUSIONS: The lower the occupancy rate of a lepidic component and the higher the occupancy rates of acinar, solid, and micropapillary components, the likelihood of tumor progression increased. In addition, as the occupancy rate of a lepidic component decreased and a micropapillary component increased, local invasiveness and recurrence rate increased; thus, increasing the probability of a poor prognosis. PMID- 25519485 TI - Impact of transjugular intrahepatic portosystemic shunt on post-colectomy complications in patients with ulcerative colitis and primary sclerosing cholangitis. AB - OBJECTIVE: Primary sclerosing cholangitis (PSC) occurs in approximately 5% of patients with ulcerative colitis (UC). The risk of colon cancer is higher in patients undergoing colectomy, who have simultaneous PSC & UC. Our aim was to study the impact, in terms of post-colectomy survival and complications, of transjugular intrahepatic portosystemic shunt (TIPS) before colectomy in these patients. METHODS: In this retrospective, case-control study, information was obtained on demographics, disease characteristics, TIPS characteristics, and post colectomy complications. Nine patients with PSC and UC who underwent TIPS prior to colectomy (the Study group) and 37 patients with PSC and UC who underwent only colectomy without TIPS (the Control group) were included. Either an analysis of variance or the non-parametric Kruskal-Wallis test were used for continuous variables and Fisher's Exact test or Pearson's chi-squared test was used for categorical factors. RESULTS: There was no difference in the mean age between the two groups; however patients in the Study group had lower platelet count (P = 0.005) as well as higher Model for End- Stage Liver disease (MELD) scores (P < 0.001). Also, patients in the Study group had increased PSC severity as determined by Mayo PSC Risk Scores (1.50 vs. 0.20) (P = 0.001). Total bilirubin levels were higher in the Study group (2.3 vs. 0.8 mg/dL) (P = 0.011). Comparing the post-operative complication rates without adjusting for disease severity, the Study group had more wound infections (P = 0.034), more wound dehiscence (P = 0.022), and a higher re-admission rate within 30 days (P = 0.032); however, the post-operative mortality was not significantly different. CONCLUSION: Patients with PSC and UC who underwent TIPS prior to colectomy had higher rates of complications; however, this was probably due to the greater severity of cirrhosis and PSC in this population. PMID- 25519484 TI - Potential protective effect of Tualang honey on BPA-induced ovarian toxicity in prepubertal rat. AB - BACKGROUND: To investigate the potential protective effects of Tualang honey against the toxicity effects induced by Bisphenol A (BPA) on pubertal development of ovaries. METHODS: This study was conducted on pre-pubertal female Sprague Dawley rats. Animals were divided into four groups (n = 8 in each group). Group I was administered with vehicle 0.2 ml of corn oil (Sigma-Aldrich, USA) using oral gavage daily for six weeks; these animals served as negative control (CO group), Group II was administered with BPA suspended in corn oil at 10 mg/kg body weight and served as positive control (PC group), Group III was administered with 200 mg/kg body weight of Tualang honey 30 min before the administration of BPA at 10 mg/kg (TH group) while Group IV was administered with 200 mg/kg body weight of Tualang honey 30 min before the administration of corn oil (THC group). Body weight of all animals were monitored weekly. RESULTS: The BPA-exposed animals exhibited disruption of their estrus cycle, while those animals treated with BPA together with Tualang honey, exhibited an improvement in percentage of normal estrous cycle. Their ovaries had lower numbers of atretic follicles compared to the PC group but higher than the CO group. CONCLUSIONS: Tualang honey has a potential role in reducing BPA-induced ovarian toxicity by reducing the morphological abnormalities of the ovarian follicles and improving the normal estrous cycle. PMID- 25519488 TI - Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine. AB - Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infection-induced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine. PMID- 25519487 TI - Assessment of microRNA differential expression and detection in multiplexed small RNA sequencing data. AB - Small RNA sequencing can be used to gain an unprecedented amount of detail into the microRNA transcriptome. The relatively high cost and low throughput of sequencing bases technologies can potentially be offset by the use of multiplexing. However, multiplexing involves a trade-off between increased number of sequenced samples and reduced number of reads per sample (i.e., lower depth of coverage). To assess the effect of different sequencing depths owing to multiplexing on microRNA differential expression and detection, we sequenced the small RNA of lung tissue samples collected in a clinical setting by multiplexing one, three, six, nine, or 12 samples per lane using the Illumina HiSeq 2000. As expected, the numbers of reads obtained per sample decreased as the number of samples in a multiplex increased. Furthermore, after normalization, replicate samples included in distinct multiplexes were highly correlated (R > 0.97). When detecting differential microRNA expression between groups of samples, microRNAs with average expression >1 reads per million (RPM) had reproducible fold change estimates (signal to noise) independent of the degree of multiplexing. The number of microRNAs detected was strongly correlated with the log2 number of reads aligning to microRNA loci (R = 0.96). However, most additional microRNAs detected in samples with greater sequencing depth were in the range of expression which had lower fold change reproducibility. These findings elucidate the trade-off between increasing the number of samples in a multiplex with decreasing sequencing depth and will aid in the design of large-scale clinical studies exploring microRNA expression and its role in disease. PMID- 25519486 TI - Evidence for multiple, distinct ADAR-containing complexes in Xenopus laevis. AB - ADAR (adenosine deaminase acting on RNA) is an RNA-editing enzyme present in most metazoans that converts adenosines in double-stranded RNA targets into inosines. Although the RNA targets of ADAR-mediated editing have been extensively cataloged, our understanding of the cellular function of such editing remains incomplete. We report that long, double-stranded RNA added to Xenopus laevis egg extract is incorporated into an ADAR-containing complex whose protein components resemble those of stress granules. This complex localizes to microtubules, as assayed by accumulation on meiotic spindles. We observe that the length of a double-stranded RNA influences its incorporation into the microtubule-localized complex. ADAR forms a similar complex with endogenous RNA, but the endogenous complex fails to localize to microtubules. In addition, we characterize the endogenous, ADAR-associated RNAs and discover that they are enriched for transcripts encoding transcriptional regulators, zinc-finger proteins, and components of the secretory pathway. Interestingly, association with ADAR correlates with previously reported translational repression in early embryonic development. This work demonstrates that ADAR is a component of two, distinct ribonucleoprotein complexes that contain different types of RNAs and exhibit diverse cellular localization patterns. Our findings offer new insight into the potential cellular functions of ADAR. PMID- 25519489 TI - Molecular speciated isotope dilution mass spectrometric methods for accurate, reproducible and direct quantification of reduced, oxidized and total glutathione in biological samples. AB - Novel protocols were developed to accurately quantify reduced (GSH), oxidized (GSSG) and total (tGSH) glutathione in biological samples using molecular speciated isotope dilution mass spectrometry (SIDMS). For GSH and GSSG measurement, the sample was spiked with isotopically enriched analogues of the analytes ((310)GSH and (616)GSSG), along with N-ethylmaleimide (NEM), and treated with acetonitrile to solubilize the endogenous analytes via protein precipitation and equilibrate them with the spikes. The supernatant was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the analytes were quantified with simultaneous tracking and correction for auto-oxidation of GSH to GSSG. For tGSH assay, a (310)GSH-spiked sample was treated with dithiothreitol (DTT) to convert disulfide-bonded glutathione to GSH. After removing the protein, the supernatant was analyzed by LC-MS/MS and the analyte was quantified by single spiking isotope dilution mass spectrometry (IDMS). The mathematical relationships in IDMS and SIDMS quantifications are based on isotopic ratios and do not involve calibration curves. The protocols were validated using spike recovery tests and by analyzing synthetic standard solutions. Red blood cell (RBC) and saliva samples obtained from healthy subjects, and whole blood samples collected and shipped from a remote location were analyzed. The concentrations of tGSH in the RBC and whole blood samples were 2 orders of magnitude higher than those found in saliva. The fractions of GSSG were 0.2-2.2% (RBC and blood) and 15-47% (saliva) of the free glutathione (GSH + 2xGSSG) in the corresponding samples. Up to 3% GSH was auto-oxidized to GSSG during sample workup; the highest oxidations (>1%) were in the saliva samples. PMID- 25519490 TI - Enzymatically crosslinked dendritic polyglycerol nanogels for encapsulation of catalytically active proteins. AB - The enormous potential of nanogel scaffolds for protein encapsulation has been widely recognized. However, constructing stable polymeric nanoscale networks in a facile, mild, and controllable fashion still remains a technical challenge. Here, we present a novel nanogel formation strategy using horseradish peroxidase (HRP) catalyzed crosslinking on phenolic derivatized dendritic polyglycerol (dPG) in the presence of H2O2 in an inverse miniemulsion. This "enzymatic nanogelation" approach was efficient to produce stable 200 nm dPG nanogel particles, and was performed under physiological conditions, thus making it particularly beneficial for encapsulating biological proteins. Purification of the nanogels was easy to handle and practical because there was no need for a post-quenching step. Interestingly, the use of dPG resulted in higher HRP laden nanogels than for linear polyethylene glycol (PEG) analogs, which illustrates the benefits of dendritic backbones in nanogels for protein encapsulation. In addition, the mild immobilization contributed to the enhanced thermal stability and reusability of HRP. The nanogel preparation could be easily optimized to achieve the best HRP activity. Furthermore, a second enzyme, Candida antarctica lipase B (CalB), was successfully encapsulated and optimized for activity in dPG nanogels by the same enzymatic methodology, which shows the perspective applications of such techniques for encapsulation of diverse proteins. PMID- 25519491 TI - A diarylethene as the SO2 gas generator upon UV irradiation. AB - A closed-ring isomer of a diarylethene having a sulfone group works as the reagent for SO2 gas generation with thermal stability even at 70 degrees C, and it rapidly reverts to the open-ring isomer and generates the SO2 gas to induce cell death upon UV irradiation. PMID- 25519492 TI - Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction. AB - Coronary heart disease is one of the main causes of death in the developed world, and treatment success remains modest, with high mortality rates within 1 year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases, including heart disease. Here we address the potential of telomerase (Tert) activation in prevention of heart failure after MI in adult mice. We use adeno-associated viruses for cardiac-specific Tert expression. We find that upon MI, hearts expressing Tert show attenuated cardiac dilation, improved ventricular function and smaller infarct scars concomitant with increased mouse survival by 17% compared with controls. Furthermore, Tert treatment results in elongated telomeres, increased numbers of Ki67 and pH3-positive cardiomyocytes and a gene expression switch towards a regeneration signature of neonatal mice. Our work suggests telomerase activation could be a therapeutic strategy to prevent heart failure after MI. PMID- 25519494 TI - Bias in the study of prediction of change: a Monte Carlo simulation study of the effects of selective attrition and inappropriate modeling of regression toward the mean. AB - BACKGROUND: Medical researchers often use longitudinal observational studies to examine how risk factors predict change in health over time. Selective attrition and inappropriate modeling of regression toward the mean (RTM) are two potential sources of bias in such studies. METHOD: The current study used Monte Carlo simulations to examine bias related to selective attrition and inappropriate modeling of RTM in the study of prediction of change. This was done for multiple regression (MR) and change score analysis. RESULTS: MR provided biased results when attrition was dependent on follow-up and baseline variables to quite substantial degrees, while results from change score analysis were biased when attrition was more strongly dependent on variables at one time point than the other. A positive association between the predictor and change in the health variable was underestimated in MR and overestimated in change score analysis due to selective attrition. Inappropriate modeling of RTM, on the other hand, lead to overestimation of this association in MR and underestimation in change score analysis. Hence, selective attrition and inappropriate modeling of RTM biased the results in opposite directions. CONCLUSION: MR and change score analysis are both quite robust against selective attrition. The interplay between selective attrition and inappropriate modeling of RTM emphasizes that it is not an easy task to assess the degree to which obtained results from empirical studies are over- versus underestimated due to attrition or RTM. Researchers should therefore use modern techniques for handling missing data and be careful to model RTM appropriately. PMID- 25519493 TI - Selenium: an element for life. AB - This review aims to illustrate the importance of selenium (Se) for maintenance of overall health, especially for the thyroid, immunity, and homeostasis. Furthermore, it outlines the role of Se in reproduction and in virology and discusses the effects of Se supplementation in critical illness. The multifaceted aspects of this essential nutrient have attracted worldwide clinical and research interest in the last few decades. Se exerts its activity in the form of the aminoacid selenocysteine incorporated in selenoproteins. The impact of Se administration should be considered in relation to its apparent U shaped effects, i.e., exhibiting major advantages in Se-deficient individuals but specific health risks in those with Se excess. Addition of selenium to the administration of levothyroxine may be useful in patients with low Se intake and with mild-form or early-stage Hashimoto's thyroiditis (HT). Serum Se concentration (possibly also at tissue level) decreases in inflammatory conditions and may vary with the severity and duration of the inflammatory process. In such cases, the effect of Se supplementation seems to be useful and rational. Meanwhile, Se's ability to improve the activity of T cells and the cytotoxicity of natural killer cells could render it effective in viral disease. However, the evidence, and this should be stressed, is at present conflicting as to whether Se supplementation is of benefit in patients with HT, though there are indications that it is advantageous in cases of mild/moderate Graves' Orbitopathy. The role of Se in type 2 diabetes mellitus (T2DM) is ambiguous, driven by both Se intake and serum levels. The evidence that insulin and glycaemia influence the transport and activity of Se, via regulatory activity on selenoproteins, and that high serum Se may have a diabetogenic effect suggests a 'Janus-effect' of Se in T2DM. Though the evidence is not as yet clear-cut, the organic form (selenomethionine), due to its pharmacokinetics, is likely to be more advantageous in long-term prevention, and supplementation efforts, while the inorganic form (sodium selenite) has proven effective in an acute, e.g., sepsis, clinical setting. Recent data indicate that functional selenoprotein single-nucleotide polymorphisms (SNPs) may interfere with Se utilization and effectiveness. PMID- 25519496 TI - Absence of predispositional attentional sensitivity to angry faces in children with autism spectrum disorders. AB - A rapid allocation of attention towards threatening stimuli in the environment is crucial for survival. Angry facial expressions act as threatening stimuli, and capture humans' attention more rapidly than emotionally positive facial expressions - a phenomenon known as the Anger Superiority Effect (ASE). Despite atypical emotional processing, adults with Autism Spectrum Disorders (ASD) have been reported to show ASE similar to typically developed (TD) individuals. One important question is whether the basic process for ASE is intact in individuals with ASD or whether instead they acquire an alternative process that enables ASE. To address this question, we tested the prevalence of ASE in young children with and without ASD using a face-in-the-crowd task. ASE was clearly observed in TD children, whereas ASD children did not show the effect. In contrast to previous reports of ASE in adults or relatively older children with ASD, our results suggest that in ASD basic predispositional mechanisms to allocate attention quickly towards angry faces are not preserved. PMID- 25519497 TI - Esophageal cancer treated by endoscopic submucosal dissection after neoadjuvant chemoradiotherapy: a case report. AB - INTRODUCTION: The treatment of esophageal cancer remains clinically challenging because of the overall poor prognosis associated with the disease. The mortality rate associated with surgical treatment is high, and the majority of diagnosed patients are old. As such, surgery is not possible in many cases, even when the cancer has progressed to a resectable state. CASE PRESENTATION: We present the case of an 82-year-old Korean man who presented to our institution with intermittent odynophagia. Esophageal cancer with submucosal invasion and metastasis to three regional lymph nodes was diagnosed. After neoadjuvant chemoradiotherapy, his regional lymph nodes disappeared. Because of his poor pulmonary function, surgical treatment could not be performed. Endoscopic submucosal dissection was carried out instead, and endoscopic triamcinolone injections were performed serially. Neither recurrence nor abnormal symptoms such as dysphagia or regurgitation have developed for 36 months. CONCLUSIONS: The literature suggests that endoscopic submucosal dissection after chemoradiotherapy is a viable treatment modality in patients with esophageal cancer with a high surgical treatment risk. PMID- 25519498 TI - A microelectrochemical biosensor for real-time in vivo monitoring of brain extracellular choline. AB - A first generation Pt-based polymer enzyme composite biosensor developed for real time neurochemical monitoring was characterised in vivo for sensitive and selective detection of choline. Confirmation that the sensor responds to changes in extracellular choline was achieved using local perfusion of choline which resulted in an increase in current, and the acetylcholinesterase inhibitor neostigmine which produced a decrease. Interference by electroactive species was tested using systemic administration of sodium ascorbate which produced a rapid increase in extracellular levels before gradually returning towards baseline over several hours. There was no overall change in the response of the biosensor during the same period of monitoring. Oxygen interference was examined using pharmacological agents known to change tissue oxygenation. Chloral hydrate produced an immediate increase in O2 before gradually returning to baseline levels over 3 h. The biosensor signal displayed an initial brief decrease before increasing to a maximum after 1 h and returning to baseline within 2 h. L-NAME caused a decrease in O2 before returning to baseline levels after ca. 1.5 h. In contrast, the biosensor current increased over the same time period before slowly returning to baseline levels over several hours. Such differences in time course and direction suggest that changes in tissue O2 levels do not affect the ability of the sensor to monitor choline reliably. Although it was found to rapidly respond to behavioural activation, examination of baseline in vivo data suggests a stable viable signal for at least 14 days after implantation. Using in vitro calibration data the basal extracellular concentration of choline was estimated to be 6.3 MUM. PMID- 25519499 TI - Fixation for avulsion fracture of the calcaneal tuberosity using a side-locking loop suture technique and anti-slip knot. PMID- 25519495 TI - TRPV4 as a therapeutic target for joint diseases. AB - Biomechanical factors play a critical role in regulating the physiology as well as the pathology of multiple joint tissues and have been implicated in the pathogenesis of osteoarthritis. Therefore, the mechanisms by which cells sense and respond to mechanical signals may provide novel targets for the development of disease-modifying osteoarthritis drugs (DMOADs). Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable cation channel that serves as a sensor of mechanical or osmotic signals in several musculoskeletal tissues, including cartilage, bone, and synovium. The importance of TRPV4 in joint homeostasis is apparent in patients harboring TRPV4 mutations, which result in the development of a spectrum of skeletal dysplasias and arthropathies. In addition, the genetic knockout of Trpv4 results in the development of osteoarthritis and decreased osteoclast function. In engineered cartilage replacements, chemical activation of TRPV4 can reproduce many of the anabolic effects of mechanical loading to accelerate tissue growth and regeneration. Overall, TRPV4 plays a key role in transducing mechanical, pain, and inflammatory signals within joint tissues and thus is an attractive therapeutic target to modulate the effects of joint diseases. In pathological conditions in the joint, when the delicate balance of TRPV4 activity is altered, a variety of different tools could be utilized to directly or indirectly target TRPV4 activity. PMID- 25519500 TI - [Always looking to the future--read KliMo and publish in KliMo]. PMID- 25519501 TI - [Editorial: new technologies]. PMID- 25519502 TI - [Visual analysis for an early detection of diabetic neuropathy]. AB - Diabetic neuropathy is the most common long-term complication of diabetes mellitus. It comes along with significant nerve dysfunction, which is not reversible. Hence, it is essential to detect nerve fibre abnormalities as early as possible. In this paper, we investigate markers describing degradation of corneal nerves. We apply statistical computations and visual analysis to identify those variables of two clinical studies that separate DN patients from a control group. In this way, the diagnosis of DN patients is supported. The visual analysis is based on different representations visualizing both the statistical results and the gathered multi-variate data. The user can interactively manipulate the views, or select data that will be shown by further displays. In this way, the understanding of the data and its classification is supported. Ambiguous categorisations can be identified and grouped into a so-called "fuzzy group". For this group, further investigations are needed to decide about diabetic neuropathy. PMID- 25519503 TI - [Large-scale imaging of corneal nerve fibres by guided eye movements]. AB - BACKGROUND: The high resolution of corneal confocal microscopy (CCM) allows in vivo imaging of the corneal sub-basal nerve plexus (SNP). The field of view of a single CCM image (0.16 mm2) is not sufficient for the reliable morphometric characterisation of the SNP. Therefore we are developing a highly automated mosaicking technique for large-area imaging of the SNP using CCM image sequences. METHODS: In order to acquire an image sequence of a larger area of the SNP, the view direction of the patient is guided by a computer-controlled moving fixation target on a display in front of the non-examined eye. The CCM image sequence is recorded with 30 fps. An online calculated mosaic image allows the medical operator to observe the acquisition process and assess the quality and size of the resulting image during the CCM recording process. Remaining image artefacts are corrected in an automated post-processing step. RESULTS: Using a first prototype system and an appropriate fixation target trajectory, a mean growth of the covered SNP area of 0.18 mm2/s could be achieved. CONCLUSION: Using the presented technology, large-area images of the SNP can be generated. The technology is characterized by a high degree of automation and short examination times. PMID- 25519504 TI - [Current progress of the artificial accommodation system]. AB - In case of presbyopia or cataract the "artificial accommodation system" represents one future possibility to durably restore the ability to accommodate. The work presented describes recent progress in the development of the artificial accommodation system. Major advances were achieved in the fields of the actuator system for the active optics, the pupil near reflex sensor, the communication system, the power supply system as well as in system integration. Beside the technical advances, first trials were performed to implant the artificial accommodation system into animals. These trials showed that the new lens shaped design and the C-shaped haptics are beneficial for implantation and secure fixation of the implant inside the capsular bag. PMID- 25519505 TI - [Optimisation of the visualisation technique for optical paths through intraocular lenses for characterisation of multifocal imaging properties of Fresnel-zone plates]. AB - The utilisation of the diffractive properties of Fresnel zone plates offers the possibility of intraocular lens designs with multiple foci. Such intraocular lenses can be manufactured by two-photon polymerisation (2PP). This paper explains the underlying concept and shows the principles for visualisation of the focus properties of such implants. PMID- 25519506 TI - [Ophthalmological imaging with ultrahigh field magnetic resonance tomography: technical innovations and frontier applications]. AB - This review documents technical progress in ophthalmic magnetic resonance imaging (MRI) at ultrahigh fields (UHF, B(0) >= 7.0 T). The review surveys frontier applications of UHF-MRI tailored for high spatial resolution in vivo imaging of the eye, orbit and optic nerve. Early examples of clinical ophthalmic UHF-MRI including the assessment of melanoma of the choroid membrane and the characterisation of intraocular masses are demonstrated. A concluding section ventures a glance beyond the horizon and explores research promises along with future directions of ophthalmic UHF-MRI. PMID- 25519507 TI - [Effect of pseudophacic mini-monovision as an option for independence of spectacles in everyday life]. AB - BACKGROUND: Modern day patients who undergo bilateral cataract surgery expect to be spectacles-independent after surgery. The options that are available to attain this goal are pseudophakic monovision, implanting multifocal IOLs or alternatively accommodative IOLs. The aim of this study is to establish the suitability in daily life when attaining minor monovision, named hereafter mini monovision. MATERIAL/METHODS: In this clinical retrospective study 30 patients were examined. These subjects where bilaterally pseudophake and received either AcrySof(r)-IOL or Acreos(r) Adapt-IOL with a slight anisometropia of between 0.5 and 1.75 D and with a maximal astigmatism up to 1.5 D. Visual acuity (VA) for distance (ETDRS), intermediate (Jaeger 80 cm) and near (Jaeger 40 cm) as well as defocus curves were assessed. Furthermore were examined: the reading speed using the font size of the Radner reading chart, anisoconia (FA Oculus according to Esser), stereopsis (Titmus), subjective patient satisfaction (adapted VF-14 questionnaire) and the subjective dependence on having to wear spectacles. RESULTS: The median anisometropia was at 0.75 D; the age was between 61 and 80 (median being at 73 years). 12 patients were male and 18 female. When examined with binocular vision 100 % could attain distance VA of at least decimal 1.0 (LogMAR 0) and an intermediate VA of at least decimal 0.8 (LogMAR 0.1), up to 86.57 % a near VA of at least Jaeger 5, (LogMAR 0.4); up to 63.33 % even managed at least Jaeger 3 (LogMAR 0.3). The median average reading speed for binocular uncorrected reading under photopic conditions was 145 words/minute and under mesopic conditions 117 words/minute. The critical font size was LogRAD 0.60 (Jaeger 5-6), the anisoconia at 2 % and stereopsis at 80 arc seconds. The general dependence on glasses was reduced from 100 % preoperatively to 13 %, postoperatively. Simultaneously a high patient satisfaction score of 93.18 in the VF-14 questionnaire was attained. The result is comparable to those quoted in the literature on full monovision and mulitifocal IOLs. CONCLUSION: To attain spectacles independency, pseudophake mini-monovision is a cost efficient alternative to multifocal lenses for well selected patients. A relative reduction in near VA must be taken into account. To establish the refractive target further examinations are required. Establishing the accurate depth of vision will be helpful in attaining this. PMID- 25519508 TI - Pharmacokinetics and in vivo fate of intra-articularly transplanted human bone marrow-derived clonal mesenchymal stem cells. AB - In this study, we report the pharmacokinetics and in vivo fate of intra articularly transplanted human mesenchymal stem cells (MSCs) in comparison with those of intravenously administered cells. Bone marrow-derived human clonal mesenchymal stem cells (hcMSCs) were transplanted to nude mice through intravenous or intra-articular routes. The numbers of hcMSCs in blood and tissue samples were measured by the quantitative real-time-polymerase chain reaction (qPCR) with human Alu (hAlu) as a detection marker. Following intra-articular transplantation, the blood levels of hcMSCs peaked 8 h postdose and gradually diminished, showing a 95-fold higher mean residence time than hcMSCs delivered through the intravenous route. Unlike intravenously administered hcMSCs, intra articularly injected hcMSCs were mainly retained at injection joint sites where their levels 8 h postdose were 116-fold higher than those in muscle tissues. Regardless of injection routes, biodistribution patterns did not significantly differ between normal and osteoarthritis-induced mice. Quantitative analysis using hAlu-specific qPCR revealed that hcMSC levels in joint tissues were significantly higher than those in muscle tissues 120 days postdose. These dramatic differences in kinetic behavior and fate of intra-articularly transplanted hcMSCs compared with intravenously administered hcMSCs may provide insights useful for the development of human MSCs for arthritis therapeutics. PMID- 25519509 TI - Primary hyperoxalurias: diagnosis and treatment. AB - Primary hyperoxalurias (PH) comprise a group of three distinct metabolic diseases caused by derangement of glyoxylate metabolism in the liver. Recent years have seen advances in several aspects of PH research. This paper reviews current knowledge of the genetic and biochemical basis of PH, the specific epidemiology and clinical presentation of each type, and therapeutic approaches in different disease stages. Potential future specific therapies are discussed. PMID- 25519510 TI - Evaluation and validation of a robust single cell RNA-amplification protocol through transcriptional profiling of enriched lung cancer initiating cells. AB - BACKGROUND: Although profiling of RNA in single cells has broadened our understanding of development, cancer biology and mechanisms of disease dissemination, it requires the development of reliable and flexible methods. Here we demonstrate that the EpiStem RNA-AmpTM methodology reproducibly generates microgram amounts of cDNA suitable for RNA-Seq, RT-qPCR arrays and Microarray analysis. RESULTS: Initial experiments compared amplified cDNA generated by three commercial RNA-Amplification protocols (Miltenyi MUMACSTM SuperAmpTM, NuGEN Ovation(r) One-Direct System and EpiStem RNA-AmpTM) applied to single cell equivalent levels of RNA (25-50 pg) using Affymetrix arrays. The EpiStem RNA AmpTM kit exhibited the highest sensitivity and was therefore chosen for further testing. A comparison of Affymetrix array data from RNA-AmpTM cDNA generated from single MCF7 and MCF10A cells to reference controls of unamplified cDNA revealed a high degree of concordance. To assess the flexibility of the amplification system single cell RNA-AmpTM cDNA was also analysed using RNA-Seq and high-density qPCR, and showed strong cross-platform correlations. To exemplify the approach we used the system to analyse RNA profiles of small populations of rare cancer initiating cells (CICs) derived from a NSCLC patient-derived xenograft. RNA-Seq analysis was able to identify transcriptional differences in distinct subsets of CIC, with one group potentially enriched for metastasis formation. Pathway analysis revealed that the distinct transcriptional signatures demonstrated in the CIC subpopulations were significantly correlated with published stem-cell and epithelial-mesenchymal transition signatures. CONCLUSIONS: The combined results confirm the sensitivity and flexibility of the RNA-AmpTM method and demonstrate the suitability of the approach for identifying clinically relevant signatures in rare, biologically important cell populations. PMID- 25519511 TI - The validity of self-reported body mass index in a population-based osteoarthritis study. AB - BACKGROUND: Obesity is a well-known risk factor for osteoarthritis (OA). The majority of obesity research in OA is performed using self-reported BMI-data, however, its validity in persons with OA is unknown. The aim of this study was to compare the validity of self-reported body mass index (BMI) in persons with and without clinical osteoarthritis (OA) in a population-based survey. METHODS: Height and weight were self-reported, and thereafter measured in 600 persons with and without clinical OA according to the American College of Rheumatology criteria (knees, hips and/or hands). We compared the differences between measured and self-reported heights, weights and BMIs (kg/m2) for the two groups and explored whether demographic/clinical factors were associated with inaccurate reporting in the OA patients using multivariate linear regression analyses. RESULTS: Mean (SD) age was 64 (8.7) years and 412 (69%) were women. Participants with clinical OA (n = 449) underreported their BMI to a greater extent than participants without clinical OA (n = 151) [mean (SD) difference 1.34 (1.68) kg/m2 and 0.78 (1.40) kg/m2 (p = 0.000), respectively]. There was a strong dose dependent association between higher measured BMI and greater underreporting of BMI in multivariate analyses (BMI 25-29.99 kg/m2: B = 0.40, 95% CI, 0.06, 0.77), BMI >= 30 kg/m2: B = 1.30, 95% CI, 0.86, 1.75) in the clinical OA patients. A higher age as well as the time interval from self-reported to measured BMI-data were associated with inaccurate reporting. CONCLUSIONS: Researchers using self reported height and weight data should be aware of limited agreement with actual height and weight in overweight and obese individuals with clinical OA. PMID- 25519513 TI - Ethnic sensitivity assessment - pharmacokinetic comparability between Japanese and non-Japanese healthy subjects on selected mAbs. AB - OBJECTIVE: Ethnic sensitivity studies (ESSs), where safety and pharmacokinetics (PK) are assessed in Japanese subjects, are routinely conducted according to Japanese regulatory requirement before the subsequent clinical studies. The necessity of ESSs is questionable in case of mAbs, where inherent IgG characteristics are considered ethnically insensitive. This report investigated PK profiles and immunogenicity (IG) following a single administration of mAbs in Japanese and non-Japanese healthy subjects. RESEARCH DESIGN AND METHODS: PK and IG comparison between Japanese and non-Japanese healthy subjects was made on mAbs data available from public domain and unpublished internal reports. PK comparison was made based on statistical approach as well as assumed typical IgG profile using modeling and simulation. RESULTS: When compared directly, most mAbs showed no difference between ethnic groups. When profiles of various mAbs were fit to an assumed typical IgG PK model, the majority of mAbs follow the expected behavior regardless of ethnicities. Deviations from this behavior did not appear to be due to inherent ethnic differences. When the incidence of IG was assessed, only Adalimumab showed apparent ethnic difference. CONCLUSIONS: The overall lack of observational difference may facilitate discussion of mAbs' early clinical development in Japan, including the utility of dedicated ESSs. PMID- 25519512 TI - Reduction factors for wooden houses due to external gamma-radiation based on in situ measurements after the Fukushima nuclear accident. AB - For estimation of residents' exposure dose after a nuclear accident, the reduction factor, which is the ratio of the indoor dose to the outdoor dose is essential, as most individuals spend a large portion of their time indoors. After the Fukushima nuclear accident, we evaluated the median reduction factor with an interquartile range of 0.43 (0.34-0.53) based on 522 survey results for 69 detached wooden houses in two evacuation zones, Iitate village and Odaka district. The results indicated no statistically significant difference in the median reduction factor to the representative value of 0.4 given in the International Atomic Energy Agency (IAEA)-TECDOC-225 and 1162. However, with regard to the representative range of the reduction factor, we recommend the wider range of 0.2 to 0.7 or at least 0.2 to 0.6, which covered 87.7% and 80.7% of the data, respectively, rather than 0.2 to 0.5 given in the IAEA document, which covered only 66.5% of the data. We found that the location of the room within the house and area topography, and the use of cement roof tiles had the greatest influence on the reduction factor. PMID- 25519514 TI - Endostaples: are they the solution to graft migration and Type I endoleaks? AB - Effective proximal sealing, especially in the long-term, remains a limitation of contemporary endovascular aortic aneurysm repair (EVAR). Endostaples that fixate the proximal stent-graft to the aortic neck wall, aiming for better apposition and proximal sealing have been recently introduced in clinical practice to address this problem. Initial experimental studies have shown that endostaples can increase proximal stent-graft fixation to levels equivalent or superior to that of a hand-sewn anastomosis. Further clinical studies aimed to investigate whether this increased proximal fixation results in reduced migration and better sealing with lower rates of type I endoleak. The present chapter discusses the efficacy of endostaples in reducing migration and type I endoleak after EVAR, based on published clinical data. PMID- 25519515 TI - XVI(th) QTLMAS: simulated dataset and comparative analysis of submitted results for QTL mapping and genomic evaluation. AB - BACKGROUND: A common dataset was simulated and made available to participants of the XVI(th) QTL-MAS workshop. Tasks for the participants were to detect QTLs affecting three traits, to assess their possible pleiotropic effects, and to evaluate the breeding values in a candidate population without phenotypes using genomic information. METHODS: Four generations consisting of 20 males and 1000 females were generated by mating each male with 50 females. The genome consisted of 5 chromosomes, each of 100 Mb size and carrying 2,000 equally distributed SNPs. Three traits were simulated in order to mimic milk yield, fat yield and fat content. Genetic (co)variances were generated from 50 QTLs with pleiotropic effects. Phenotypes for all traits were expressed only in females, and were provided for the first 3 generations. Fourteen methods for detecting single-trait QTL and 3 methods for investigating their pleiotropic nature were proposed. QTL mapping results were compared according to the following criteria: number of true QTL detected; number of false positives; and the proportion of the true genetic variance explained by submitted positions. Eleven methods for estimating direct genomic values of the candidate population were proposed. Accuracies and bias of predictions were assessed by comparing estimated direct genomic values with true breeding values. RESULTS: The number of true detections ranged from 0 to 8 across methods and traits, false positives from 0 to 15, and the proportion of genetic variance captured from 0 to 0.82, respectively. The accuracy and bias of genomic predictions varied from 0.74 to 0.85 and from 0.86 to 1.34 across traits and methods, respectively. CONCLUSIONS: The best results in terms of detection power were obtained by ridge regression that, however, led to a large number of false positives. Good results both in terms of true detections and false positives were obtained by the approaches that fit polygenic effects in the model. The investigation of the pleiotropic nature of the QTL permitted the identification of few additional markers compared to the single-trait analyses. Bayesian and grouped regularized regression methods performed similarly for genomic prediction while GBLUP produced the poorest results. PMID- 25519516 TI - Genome wide association analysis of the QTL MAS 2012 data investigating pleiotropy. AB - BACKGROUND: Different genome wide association methods (GWAS) including multivariate analysis techniques were applied to identify quantitative trait loci (QTL) and pleiotropy in the simulated data set provided by the QTL-MAS workshop 2012 held in Alghero (Italy). METHODS: Genetic correlations and heritabilities for all three quantitative traits were obtained by a multivariate animal model. In a second step the data were corrected for a polygenic component containing the genomic-based kinship matrix. Residuals from this model were later used for QTL detection in a regression analysis, to achieve genome-wide rapid association (GRAMMAR). In order to take pleiotropic effects into account, all three traits were condensed via principle component techniques to two principal components (PC) which reflect the phenotypic variance covariance structure of all traits. The PCs were analyzed by single trait analysis by GRAMMAR. As an alternative to GRAMMAR, the data set was analyzed by Bayesian methods implemented in the package snptest. The program allows the analysis of the data in a univariate and a multivariate way, where all three traits are investigated simultaneously. RESULTS: According to the polygenic model, analyses the three traits revealed high heritability (0.56, 0.55, and 0.66). Traits 1 and 2 were highly correlated (rg = 0.84). All applied GWAS revealed 10 QTL on four different chromosomes. No QTL was detected on chromosome 5. The Bayesian multivariate analysis revealed significant pleiotropic SNPs. CONCLUSIONS: Principal component and multivariate analyses seem to be promising in order to characterize the genetic basis of trait relationships. PMID- 25519517 TI - Regional Heritability Mapping to identify loci underlying genetic variation of complex traits. AB - BACKGROUND: Genome-wide association studies can have limited power to identify QTL, partly due to the stringent correction for multiple testing and low linkage disequilibrium between SNPs and QTL. Regional Heritability Mapping (RHM) has been advanced as an alternative approach to capture underlying genetic effects. In this study, RHM was used to identify loci underlying variation in the 16(th) QTLMAS workshop simulated traits. METHODS: The method was implemented by fitting a mixed model where a genomic region and the overall genetic background were added as random effects. Heritabilities for the genetic regional effects were estimated, and the presence of a QTL in the region was tested using a likelihood ratio test (LRT). Several region sizes were considered (100, 50 and 20 adjacent SNPs). Bonferroni correction was used to calculate the LRT thresholds for genome wide (p < 0.05) and suggestive (i.e., one false positive per genome scan) significance. RESULTS: Genomic heritabilities (0.31, 0.32 and 0.48, respectively) and genetic correlations (0.80, -0.42 and 0.19, between trait-pairs 1&2, 1&3 and 2&3) were similar to the simulated ones. RHM identified 7 QTL (4 at genome-wide and 3 at suggestive level) for Trait1; 4 (2 genome-wide and 2 suggestive) for Trait2; and 7 (6 genome-wide and 1 suggestive) for Trait3. Only one of the identified suggestive QTL was a false-positive. The position of these QTL tended to coincide with the position where the largest QTL (or several of them) were simulated. Several signals were detected for the simulated QTL with smaller effect. A combined analysis including all significant regions showed that they explain more than half of the total genetic variance of the traits. However, this might be overestimated, due to Beavis effect. All QTL affecting traits 1&2 and 2&3 had positive correlations, following the trend of the overall correlation of both trait-pairs. All but one QTL affecting traits 1&3 were negatively correlated, in agreement with the simulated situation. Moreover, RHM identified extra loci that were not found by association and linkage analysis, highlighting the improved power of this approach. CONCLUSIONS: RHM identified the largest QTL among the simulated ones, with some signals for the ones with small effect. Moreover, RHM performed better than association and linkage analysis, in terms of both power and resolution. PMID- 25519518 TI - Genome wide association analysis of the 16th QTL- MAS Workshop dataset using the Random Forest machine learning approach. AB - BACKGROUND: Genome wide association studies are now widely used in the livestock sector to estimate the association among single nucleotide polymorphisms (SNPs) distributed across the whole genome and one or more trait. As computational power increases, the use of machine learning techniques to analyze large genome wide datasets becomes possible. METHODS: The objective of this study was to identify SNPs associated with the three traits simulated in the 16th MAS-QTL workshop dataset using the Random Forest (RF) approach. The approach was applied to single and multiple trait estimated breeding values, and on yield deviations and to compare them with the results of the GRAMMAR-CG method. RESULTS: The two QTL mapping methods used, GRAMMAR-CG and RF, were successful in identifying the main QTLs for trait 1 on chromosomes 1 and 4, for trait 2 on chromosomes 1, 4 and 5 and for trait 3 on chromosomes 1, 2 and 3. CONCLUSIONS: The results of the RF approach were confirmed by the GRAMMAR-CG method and validated by the effective QTL position, even if their approach to unravel cryptic genetic structure is different. Furthermore, both methods showed complementary findings. However, when the variance explained by the QTL is low, they both failed to detect significant associations. PMID- 25519519 TI - A selective genotyping approach identifies QTL in a simulated population. AB - BACKGROUND: Identification of QTLs for important phenotypic traits, through the use of medium-density genome-wide SNP panels, is one of the most challenging areas in animal genetics, for preventing the time-consuming direct sequencing of putative candidate genes, when searching for the mutations that affect the trait. Appropriate statistical analyses allow the identification of genomic regions associated with the investigated trait in the genotyped population. METHODS: The selective genotyping technique was applied to 1000 genotyped animals with known phenotype. Sliding windows composed of five consecutive SNPs were created for each chromosome; we assumed that the QTLs were encoded by the windows showing the highest difference in the frequency of the same alleles between the most divergent productive groups (the two tails of the distribution). RESULTS: Ten windows affected at least one trait. For five of these windows, the highest and significant effect was given by one only SNP, which could therefore be taken as the QTL itself. CONCLUSIONS: In this study we proposed a simple method to identify genomic regions associated to the phenotype under study. The identification of the DNA region is the first step to search for the mutation which is really responsible for the trait variability, through the direct sequencing of the genome regions that encode the QTL. PMID- 25519520 TI - Estimation of genomic breeding values using the Horseshoe prior. AB - BACKGROUND: A method for estimating genomic breeding values (GEBV) based on the Horseshoe prior was introduced and used on the analysis of the 16(th) QTLMAS workshop dataset, which resembles three milk production traits. The method was compared with five commonly used methods: Bayes A, Bayes B, Bayes C, Bayesian Lasso and GLUP. METHODS: The main difference between the methods is the prior distribution assumed during the estimation of the SNP effects. The distribution of the Bayesian Lasso is a Laplace distribution; for Bayes A is a Student-t; for Bayes B and Bayes C is a spike and slab prior combining a proportion of SNP without effect and a proportion with effect distributed as a Student-t or Gaussian for Bayes B and C, respectively; for GBLUP is similar to a ridge regression. The distribution for the Horseshoe prior behaves like log(1+1/beta(2)) (up to a constant). It has an infinite spike at zero and heavy tail that decay by beta(-2) (slower than the Laplace or the Student-t). The implementation of all methods (except GBLUP) was done using a MCMC approach, where the relevant parameters defining the prior distributions were jointly estimated from the data. The GBLUP was done using ASREML. RESULTS: The accuracy for all methods ranged from 0.74 to 0.83, representing an improvement of 44% to 78% over the traditional BLUP evaluation. GEBV with the highest accuracy were obtained with Bayes A, Bayes B and the Horseshoe prior. The Horseshoe tended to select smaller number of SNP and assigning them larger effects, while strongly shrinking the remaining SNP to have an effect closer to zero. CONCLUSIONS: The Horseshoe prior showed a different shrinkage pattern than the other methods. While for this specific dataset, this has little impact on the accuracy of the GEBV, it may prove a good property to discriminate true effect from noise, and thereby, improve overall prediction under different scenarios. PMID- 25519521 TI - Regularized group regression methods for genomic prediction: Bridge, MCP, SCAD, group bridge, group lasso, sparse group lasso, group MCP and group SCAD. AB - BACKGROUND: Genomic prediction is now widely recognized as an efficient, cost effective and theoretically well-founded method for estimating breeding values using molecular markers spread over the whole genome. The prediction problem entails estimating the effects of all genes or chromosomal segments simultaneously and aggregating them to yield the predicted total genomic breeding value. Many potential methods for genomic prediction exist but have widely different relative computational costs, complexity and ease of implementation, with significant repercussions for predictive accuracy. We empirically evaluate the predictive performance of several contending regularization methods, designed to accommodate grouping of markers, using three synthetic traits of known accuracy. METHODS: Each of the competitor methods was used to estimate predictive accuracy for each of the three quantitative traits. The traits and an associated genome comprising five chromosomes with 10000 biallelic Single Nucleotide Polymorphic (SNP)-marker loci were simulated for the QTL-MAS 2012 workshop. The models were trained on 3000 phenotyped and genotyped individuals and used to predict genomic breeding values for 1020 unphenotyped individuals. Accuracy was expressed as the Pearson correlation between the simulated true and the estimated breeding values. RESULTS: All the methods produced accurate estimates of genomic breeding values. Grouping of markers did not clearly improve accuracy contrary to expectation. Selecting the penalty parameter with replicated 10-fold cross validation often gave better accuracy than using information theoretic criteria. CONCLUSIONS: All the regularization methods considered produced satisfactory predictive accuracies for most practical purposes and thus deserve serious consideration in genomic prediction research and practice. Grouping markers did not enhance predictive accuracy for the synthetic data set considered. But other more sophisticated grouping schemes could potentially enhance accuracy. Using cross validation to select the penalty parameters for the methods often yielded more accurate estimates of predictive accuracy than using information theoretic criteria. PMID- 25519522 TI - A case of isolated syncope due to bilateral carotid artery dissection: a lesson from ancient Greece? PMID- 25519523 TI - Synthesis and characterization of MU-nitrido, MU-carbido and MU-oxo dimers of iron octapropylporphyrazine. AB - Three MU-X bridged diiron octapropylporphyrazine complexes having Fe(III)-O Fe(III), Fe(+3.5)-N[double bond, length as m-dash]Fe(+3.5) and Fe(IV)[double bond, length as m-dash]C[double bond, length as m-dash]Fe(IV) structural units have been prepared and characterized by UV-vis, EPR, X-ray absorption spectroscopy and electrochemical methods. Single crystals of all the complexes were obtained from benzene-acetonitrile and their structures were determined by X ray diffraction. In contrast to MU-oxo complex (), MU-nitrido () and MU-carbido () dimers crystallized with one benzene molecule per two binuclear complex molecules arranged cofacially to the porphyrazine planes at Fe-Cbenzene distances of 3.435-3.725 A and 3.352-3.669 A for and , respectively. The short distances suggest an interaction between the iron sites and the benzene pi-system which is stronger in the case of the Fe(IV)[double bond, length as m-dash]C[double bond, length as m-dash]Fe(IV) unit with a higher Lewis acidity. The Fe-X-Fe angle increases in the sequence -- from 158.52 degrees to 168.5 degrees and 175.10 degrees , respectively, in agreement with the Fe-X bond order. However, the lengths of the Fe-X bonds do not follow this trend: Fe-O = 1.75/1.76 A > Fe-C = 1.67/1.67 A > Fe-N = 1.65/1.66 A indicating unexpectedly long Fe-C bonds. This observation can be explained by back pi-donation from the MU-carbido ligand to the Fe-C antibonding orbital thus decreasing the bond order which is confirmed by DFT calculations. PMID- 25519524 TI - Application of the Human Intestinal Tract Chip to the non-human primate gut microbiota. AB - The human intestinal microbiota is responsible for various health-related functions, and its diversity can be readily mapped with the 16S ribosomal RNA targeting Human Intestinal Tract (HIT) Chip. Here we characterise distal gut samples from chimpanzees, gorillas and marmosets, and compare them with human gut samples. Our results indicated applicability of the HITChip platform can be extended to chimpanzee and gorilla faecal samples for analysis of microbiota composition and enterotypes, but not to the evolutionary more distant marmosets. PMID- 25519525 TI - Safety and efficacy of human breast milk Lactobacillus fermentum CECT 5716. A mini-review of studies with infant formulae. AB - Human breast milk has been described as a source of lactic acid bacteria. Lactobacillus fermentum CECT5716 is a human breast milk strain whose probiotic properties, safety and efficacy has been demonstrated in vitro and in vivo, including controlled trials with human adults. Since the origin of this probiotic strain is human breast milk, we aimed to investigate the safety and efficacy of an infant and a follow-on formulas supplemented with this strain of L. fermentum. We carried out two randomised controlled trials: one trial with infants of 6-12 months of age (follow-on formula study) and another one with infants from 1 to 5 months of age (infant formula study). The results from the trials showed that the probiotic formulas were safe, well tolerated and might be useful for the prevention of community-acquired infections. PMID- 25519526 TI - Consumption of partially hydrolysed guar gum stimulates Bifidobacteria and butyrate-producing bacteria in the human large intestine. AB - Partially hydrolysed guar gum (PHGG) is a water-soluble dietary fibre that is non digestible in the upper gastrointestinal tract. It is believed that PHGG benefits the health of hosts by altering the colonic microbiota and stimulating short chain fatty acid (SCFA) production. However, it remains unclear which bacteria ferment PHGG in the human large intestine. In this study, the effect of PHGG on faecal bacteria was analysed to specify the bacteria that contribute to the fermentation of PHGG in the human large intestine. Ten healthy volunteers consumed PHGG (6 g/day) for 2 weeks. Faeces were collected at 2 weeks prior to consumption, at the end of 2 weeks of consumption, and 2 weeks after consumption of PHGG. Bacterial DNA was extracted from these collected faeces and subjected to real-time PCR using bacterial group- or species-specific primers. The copy number of the butyryl-CoA CoA-transferase gene and the 16S rRNA gene copy numbers of Bifidobacterium, the Clostridium coccoides group, the Roseburia/ Eubacterium rectale group, Eubacterium hallii, and butyrate-producing bacterium strain SS2/1 were significantly increased by the intake of PHGG. Other bacteria and bacterial groups were not significantly influenced by the intake of PHGG. It was believed that the Roseburia/E. rectale group bacteria, Bifidobacterium, the lactate utilising, butyrate-producing bacteria, E. hallii and bacterium strain SS2/1, would contribute to the fermentation of PHGG in the human large intestine. PHGG may benefit health by stimulating Bifidobacterium and butyrate-producing bacteria in the human large intestine. PMID- 25519527 TI - Effects of the probiotic Enterococcus faecium NCIMB 10415 on selected lactic acid bacteria and enterobacteria in co-culture. AB - Enterococcus faecium NCIMB 10415 is used as a probiotic for piglets and has been shown to modify the porcine intestinal microbiota. However, the mode of action of this probiotic modification is still unclear. One possible explanation is the direct growth inhibiting or stimulating effect of the probiotic on other indigenous bacteria. Therefore, the aim of the present study was to examine the growth interactions of the probiotic with different indigenous porcine bacteria in vitro. Reference strains were cultivated with the probiotic E. faecium strain NCIMB10415 (SF68) in a checkerboard assay with 102 to 105 cells/ml inoculum per strain. Growth kinetics were recorded for 8 h and used to determine specific growth of the co-cultures. Additionally, total DNA was extracted from the co cultures at the end of the incubation to verify which strain in the co-culture was affected. Co-cultivation with eight Enterococcus spp. tester strains showed strain-specific growth differences. Three of four E. faecium strains were not influenced by the probiotic strain. PCR results showed reduced growth of the probiotic strain in co-culture with E. faecium DSM 6177. Three of four Enterococcus faecalis strains showed reduced specific growth in co-culture with the probiotic strain. However, E. faecalis DSM 20478 impaired growth of the probiotic E. faecium strain. The growth of Lactobacillus johnsonii DSM 10533 and Lactobacillus reuteri DSM 20016 was enhanced in co-culture with the probiotic strain, but co-cultivations with Lactobacillus mucosae DSM13345 or Lactobacillus amylovorus DSM10533 showed no differences. Co-cultures with the probiotic E. faecium showed no impact on the growth rate of four different enterobacterial reference strains (2 strains of Salmonella enterica and 2 strains of Escherichia coli), but PCR results showed reduced cell numbers for a pathogenic E. coli isolate at higher concentration of the probiotic strain. As the in vitro effect of the probiotic E. faecium on enterococci was strain specific and the growth of certain Lactobacillus spp. was enhanced by the probiotic, these results indicate a direct effect of the probiotic on certain members of the porcine gastro intestinal microbiota. PMID- 25519528 TI - High-throughput, deterministic single cell trapping and long-term clonal cell culture in microfluidic devices. AB - We report the design and validation of a two-layered microfluidic device platform for single cell capture, culture and clonal expansion. Under manual injection of a cell suspension, deterministic trapping of hundreds to thousands of single cells (adherent and non-adherent) in a high throughput manner and at high trapping efficiency was achieved simply through the incorporation of a U-shaped hydrodynamic trap into the downstream wall of each micro-well. Post single cell trapping, we confirmed that these modified micro-wells permit the attachment, spreading and proliferation of the trapped single cells for multiple generations over extended periods of time (>7 days) under media perfusion. Due to its a) low cost, b) simplicity in fabrication and operation, c) high trapping efficiency, d) reliable and repeatable trapping mechanism, e) cell size selection and f) capability to provide perfused long-term culture and continuous time-lapse imaging, the microfluidic device developed and validated in this study is seen to have significant potential application in high-throughput single cell quality assessment and clonal analysis. PMID- 25519529 TI - Abstracts from the 2014 International Nitric Oxide Society Conference,June 16-20, 2014, Cleveland, Ohio. PMID- 25519682 TI - Relaxation of a hydrophilic polymer induced by moisture desorption through the glass transition. AB - Regarding the underlying special relaxation feature of a water-plasticized hydrophilic polymer during performance evolution with water content change, we report the water desorption kinetics and periodic creep responses of poly(vinyl alcohol) (PVA) films subsequent to rejuvenation by above-glass transition relative humidity (RH) annealing and following RH-jump at various rates. A Moisture Sorption Analyzer and a Dynamic Mechanical Analyzer are utilized to control RH and to capture data to probe the evolving relaxation towards equilibrium under two temperature-RH conditions. This result reveals an evident jump rate dependence of desorption kinetics and recoverable creep deformation. The different target RH yields the different change patterns of normalized water content and retardation time. PVA manifests a rapid relaxation stage with the special viscoelastic response before experience of usual physical aging. By analysis of the superposition principle and the relevant characteristic parameters, the relaxation of the hydrophilic polymer after water desorption through the glass transition is generalized as three successive phases. PMID- 25519681 TI - The subcellular localization of GABA transporters and its implication for seizure management. AB - The ability to modulate the synaptic GABA levels has been demonstrated by using the clinically effective and selective GAT1 inhibitor tiagabine [(R)-N-[4,4-bis(3 methyl-2-thienyl)-3-butenyl]nipecotic acid]. N-[4,4-bis(3-methyl-2-thienyl)-3 butenyl]-3-hydroxy-4-(methylamino)-4,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol (EF1502) which not only inhibits GAT1 like tiagabine but also BGT1 has been shown to modulate extrasynaptic GABA levels. The simultaneous inhibition of synaptic and extrasynaptic GABA transporters using tiagabine and EF1502, respectively has been demonstrated to exert a synergistic anticonvulsant effect in several seizure models in mice. The pharmacological profile of these and similar compounds has been thoroughly investigated in in vitro systems, comparing the GAT subtype selectivity with the ability to inhibit GABA uptake in primary cultures of neurons and astrocytes. However, an exact explanation has not yet been found. In the present study, the ability of GATs to form homo and/or heterodimers was investigated as well as to which membrane micro environment the GATs reside. To investigate dimerization of GATs, fusion proteins of GATs tagged with either yellow fluorescent protein or cerulean fluorescent protein were made and fluorescence resonance energy transfer (FRET) was measured. It was found that GATs form both homo- and hetero-dimers in N2A and HEK-293 cells. Microdomain localization of GATs as investigated by detergent resistant membrane fractions after treatment of tissue with Brij-98 or Triton X-100 revealed that BGT1 and GAT1 mostly localize to non-membrane rafts independent of the detergent used. However, GAT3 localizes to membrane rafts when using Brij-98. Taken together, these results suggest that the observed hetero dimerization of GATs in the FRET study is unlikely to have functional implications since the GATs are located to very different cellular compartments and cell types. PMID- 25519680 TI - An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. AB - BACKGROUND: Charcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3). METHODS: 80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes. RESULTS: This trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group. CONCLUSIONS: These results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults. TRIAL REGISTRATION: EudraCT Number: 2010-023097-40. ClinicalTrials.gov Identifier: NCT01401257. The Committee for Orphan Medicinal Products issued in February 2014 a positive opinion on the application for orphan designation for PXT3003 (EMA/OD/193/13). PMID- 25519684 TI - USP7 overexpression predicts a poor prognosis in lung squamous cell carcinoma and large cell carcinoma. AB - In non-small cell lung cancer (NSCLC), both USP7 expression and p53 gene status were reported to be an indicator of poor prognosis in adenocarcinoma patients; however, its roles and mechanisms in lung squamous cell carcinoma and large cell carcinoma need to be clarified. The USP7 expression was examined in NSCLC tumors (excluding adenocarcinoma), their corresponding non-tumorous tissues, and NSCLC cells. Then, the prognostic role of USP7 was analyzed in 110 NSCLC samples (excluding the adenocarcinoma). Finally, the roles and mechanisms of USP7 in the proliferation, metastasis, and invasion of a NSCLC cell were assessed using a specific vshRNA. The USP7 expression was higher in NSCLC tissues compared to non tumorous samples, accordingly, the high level of USP7 was detected in NSCLC cell lines compared with HBE cell. After the USP7 downregulation, the H460 cells exhibited decreased metastasis/invasion in vitro and in vivo. The preliminary mechanism study indicated overexpression of USP7 might regulate the p53-MDM2 pathway by inducing the MDM2 de-ubiquitination and subsequent stabilization, which resulted in the upregulation of the Bad phosphorylation. Additionally, we also found that USP7 might induce cell epithelial-mesenchymal transition to enhance the cell invasive ability. Clinically, USP7 overexpression significantly correlated with malignant phenotype. Furthermore, the 5-year overall survival in patients with USP7(low) was higher than that of USP7(high). Multivariate analysis showed USP7 overexpression was an independent prognostic marker for these cancers. USP7 overexpression may regulate the survival and invasive properties of squamous cell carcinoma and large cell carcinoma cells, and may serve as a molecular target. PMID- 25519685 TI - Curcumin ameliorate DENA-induced HCC via modulating TGF-beta, AKT, and caspase-3 expression in experimental rat model. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. In laboratory animal models, diethylnitrosamine (DENA) is a well-known agent that has a potent hepatocarcinogenic effect that is used to induce HCC. As curcumin has a potent anti-inflammatory effect with strong therapeutic potential against a variety of cancers, our present study aims to investigate its curative effects and the possible mechanisms of action against DENA-induced HCC in male rats. Investigation of biochemical and molecular parameters of HCC animal model liver showed an overexpression of TGF-beta and Akt proteins accompanied with a significant reduction of the proapoptotic marker caspase-3. DENA-induced hepatic cellular injury resulted also in a significant increase in liver function marker enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lipid peroxides in this group. Curcumin treatment partially reversed DENA-induced damage as it reduced the overexpression of the angiogenic and anti-apoptotic factors TGF-beta and Akt and improved caspase-3 expression. Also, it could partially normalize the serum values of liver marker enzymes and lipid peroxidation and improve liver architecture. Curcumin shows a unique chemotherapeutic effect in reversing DENA-induced HCC in rat model. This effect is possibly mediated through its proapoptotic, antioxidant, anti-angiogenic, as well as antimitotic effects. It interferes and modulates cell signaling pathways and hence turns death signals and apoptosis on within tumor cells. PMID- 25519686 TI - Inhibition of progression of PanIN through antagonizing EGFR. AB - Pancreatic ductal adenocarcinoma (PDAC) is an extremely malignant tumor with high lethality in humans. Pancreatic intraepithelial neoplasia (PanIN) is the predominant precancerous lesion for PDAC. Although PanIN is frequently detected in the normal and inflamed pancreas, only a few of PanIN eventually progress into PDAC. Thus, inhibition of PanIN-to-PDAC conversion is critical for preventing the occurrence of PDAC. Here, we evaluated the effect of inhibition of epidermal growth factor receptor (EGFR) signaling on the progression of low-grade PanIN into high-grade PDAC in an established mouse PDAC model (Ptf1a-Cre; K-rasG12D). We found that intraductal infusion of EGFR inhibitors at 12 weeks of age, which induced sustained inhibition of EGFR signaling in the pancreas, significantly decreased the incidence of high-grade PanIN in these mice at 24 weeks of age. Thus, our study suggests that inhibition of EGFR signaling may prevent development of PDAC. PMID- 25519687 TI - BDNF serum levels are not related to cognitive functioning in older depressed patients and controls. AB - BACKGROUND: Depression and cognitive decline are highly prevalent in older persons and both are associated with low serum brain derived neurotrophic factor (BDNF). Mutual pathways of depression and cognitive decline in older persons may explain the overlap in symptoms and low serum BDNF. We hypothesized that serum BDNF levels are lower in depressed elderly with poor cognitive performance (global or specifically in working memory, speed of information processing, and episodic memory) compared to depressed elderly without cognitive impairment or non-depressed controls. METHODS: BDNF Serum levels and cognitive functioning were examined in 378 depressed persons and 132 non-depressed controls from a large prospective study on late-life depression. The association between BDNF levels and each cognitive domain among the depressed patients was tested by four separate linear regression models adjusted for relevant covariates. An analysis of covariance (ANCOVA) was performed to compare BDNF serum levels in three groups (depression with cognitive impairment, depression without cognitive impairment, and non-depressed controls), when adjusted for potential confounders. RESULTS: No significant linear association was found between BDNF and any of the four cognitive domains tested. There are no differences in BDNF levels between controls and depressed patients with or without cognitive impairment global or in specific domains after controlling for confounders. CONCLUSIONS: BDNF serum levels in this cohort of older depressed patients and controls are not related to cognitive functioning. As BDNF is essential for the survival and functioning of neurons, its levels may remain normal in stages of disease where remission is achievable. PMID- 25519688 TI - Reduced dietary salt for the prevention of cardiovascular disease. AB - BACKGROUND: This is an update of a Cochrane review that was first published in 2011 of the effects of reducing dietary salt intake, through advice to reduce salt intake or low-sodium salt substitution, on mortality and cardiovascular events. OBJECTIVES: 1. To assess the long-term effects of advice and salt substitution, aimed at reducing dietary salt, on mortality and cardiovascular morbidity.2. To investigate whether a reduction in blood pressure is an explanatory factor in the effect of such dietary interventions on mortality and cardiovascular outcomes. SEARCH METHODS: We updated the searches of CENTRAL (2013, Issue 4), MEDLINE (OVID, 1946 to April week 3 2013), EMBASE (OVID, 1947 to 30 April 2013) and CINAHL (EBSCO, inception to 1 April 2013) and last ran these on 1 May 2013. We also checked the references of included studies and reviews. We applied no language restrictions. SELECTION CRITERIA: Trials fulfilled the following criteria: (1) randomised, with follow-up of at least six months, (2) the intervention was reduced dietary salt (through advice to reduce salt intake or low-sodium salt substitution), (3) participants were adults and (4) mortality or cardiovascular morbidity data were available. Two review authors independently assessed whether studies met these criteria. DATA COLLECTION AND ANALYSIS: A single author extracted data and assessed study validity, and a second author checked this. We contacted trial authors where possible to obtain missing information. We extracted events and calculated risk ratios (RRs) and 95% confidence intervals (CIs). MAIN RESULTS: Eight studies met the inclusion criteria: three in normotensives (n = 3518) and five in hypertensives or mixed populations of normo- and hypertensives (n = 3766). End of trial follow-up ranged from six to 36 months and the longest observational follow-up (after trial end) was 12.7 years.The risk ratios (RR) for all-cause mortality in normotensives were imprecise and showed no evidence of reduction (end of trial RR 0.67, 95% confidence interval (CI) 0.40 to 1.12, 60 deaths; longest follow-up RR 0.90, 95% CI 0.58 to 1.40, 79 deaths n=3518) or in hypertensives (end of trial RR 1.00, 95% CI 0.86 to 1.15, 565 deaths; longest follow-up RR 0.99, 95% CI 0.87 to 1.14, 674 deaths n=3085). There was weak evidence of benefit for cardiovascular mortality (hypertensives: end of trial RR 0.67, 95% CI 0.45 to 1.01, 106 events n=2656) and for cardiovascular events (hypertensives: end of trial RR 0.76, 95% CI 0.57 to 1.01, 194 events, four studies, n = 3397; normotensives: at longest follow-up RR 0.71, 95% CI 0.42 to 1.20, 200 events; hypertensives: RR 0.77, 95% CI 0.57 to 1.02, 192 events; pooled analysis of six trials RR 0.77, 95% CI 0.63 to 0.95, n = 5912). These findings were driven by one trial among retirement home residents that reduced salt intake in the kitchens of the homes, thereby not requiring individual behaviour change.Advice to reduce salt showed small reductions in systolic blood pressure (mean difference (MD) -1.15 mmHg, 95% CI -2.32 to 0.02 n=2079) and diastolic blood pressure (MD -0.80 mmHg, 95% CI -1.37 to -0.23 n=2079) in normotensives and greater reductions in systolic blood pressure in hypertensives (MD -4.14 mmHg, 95% CI -5.84 to -2.43 n=675), but no difference in diastolic blood pressure (MD -3.74 mmHg, 95% CI -8.41 to 0.93 n=675).Overall many of the trials failed to report sufficient detail to assess their potential risk of bias. Health-related quality of life was assessed in one trial in normotensives, which reported significant improvements in well-being but no data were presented. AUTHORS' CONCLUSIONS: Despite collating more event data than previous systematic reviews of randomised controlled trials, there is insufficient power to confirm clinically important effects of dietary advice and salt substitution on cardiovascular mortality in normotensive or hypertensive populations. Our estimates of the clinical benefits from advice to reduce dietary salt are imprecise, but are larger than would be predicted from the small blood pressure reductions achieved. Further well-powered studies would be needed to obtain more precise estimates. Our findings do not support individual dietary advice as a means of restricting salt intake. It is possible that alternative strategies that do not require individual behaviour change may be effective and merit further trials. PMID- 25519689 TI - Highly efficient piezotronic strain sensors with symmetrical Schottky contacts on the monopolar surface of ZnO nanobelts. AB - Piezotronic strain sensors have drawn a lot of attention since the piezotronic theory was established. In this work, we developed a flexible piezotronic strain sensor based on an indium-doped ZnO nanobelt, of which the top surface was the monopolar surface. By connecting two electrodes with the two ends of the top surface of the nanobelt, the strain sensor was constructed. Compared with a nanorod/nanowire based strain sensor, this monopolar surface device avoids the need to identify the polar direction. Under strain, a static potential with the same value and polarity was generated by the coupling effect of the piezoelectric effect and the Poisson effect. This induced piezopotential influenced the Schottky barrier heights at the interfaces of both the source and drain electrodes, resulting in current changes with the same trend at forward and reverse biases. By applying a series of periodical strains, the sensor showed clear, fast and accurate current responses. The gauge factor achieved for compressive strain was 4036. This type of piezotronic strain sensor with a polar surface facing upward presented a high performance and easier fabrication, showing promise for applications in electrical mechanical sensors and MEMS. PMID- 25519691 TI - Erratum to: Accuracies of facial soft tissue depth means for estimating ground truth skin surfaces in forensic craniofacial identification. PMID- 25519690 TI - Balloon-Occluded Retrograde Transvenous Obliteration (BRTO) for Treatment of Gastric Varices: Review and Meta-Analysis. AB - AIM: To perform a systematic review and meta-analysis of the effectiveness and complications of BRTO for gastric varices. MATERIALS AND METHODS: A systematic review was performed to identify relevant articles. Inclusion criteria were applied to select studies with at least ten patients with acute bleeding or at risk gastric varices treated with BRTO. Meta-analysis with random effects model was performed to calculate data for immediate technical success, clinical success, and complications. RESULTS: A total of 1,016 Patients from 24 studies met inclusion criteria. Technical success rate for BRTO was 96.4 % (95 % CI 93.7, 98.3 %; Q = 3,269.26, p < 0.01, I (2) = 99.39 %). Clinical success (defined as no recurrence or rebleed of gastric varices, or complete obliteration of varices on subsequent imaging) rate was 97.3 % (95 % CI 95.2, 98.8 %; Q = 3,105.91, p < 0.01, I (2) = 99.29 %). Major complication rate was 2.6 % (95 % CI 1.1, 4.6 %; Q = 3,348.98, p < 0.01, I (2) = 99.34 %). Esophageal variceal recurrence rate was 33.3 % (95 % CI 24.6, 42.6 %; Q = 7,291.75, p < 0.01, I (2) = 99.74 %). CONCLUSION: BRTO is safe and efficacious for gastric varices, and current best evidence suggests that BRTO could be considered as therapy for patients with gastric varices. PMID- 25519692 TI - Solution-processed multilayer small-molecule light-emitting devices with high efficiency white-light emission. AB - Recent developments in the field of pi-conjugated polymers have led to considerable improvements in the performance of solution-processed organic light emitting devices (OLEDs). However, further improving efficiency is still required to compete with other traditional light sources. Here we demonstrate efficient solution-processed multilayer OLEDs using small molecules. On the basis of estimates from a solvent resistance test of small host molecules, we demonstrate that covalent dimerization or trimerization instead of polymerization can afford conventional small host molecules sufficient resistance to alcohols used for processing upper layers. This allows us to construct multilayer OLEDs through subsequent solution-processing steps, achieving record-high power efficiencies of 36, 52 and 34 lm W(-1) at 100 cd m(-2) for solution-processed blue, green and white OLEDs, respectively, with stable electroluminescence spectra under varying current density. We also show that the composition at the resulting interface of solution-processed layers is a critical factor in determining device performance. PMID- 25519693 TI - Characterization of a novel two-component system in Burkholderia cenocepacia. AB - Two-component systems are important regulatory systems that allow bacteria to adjust to environmental conditions, and in some bacteria are used in pathogenesis. We identified a novel two-component system in Burkholderia cenocepacia, an opportunistic pathogen that causes pneumonia in cystic fibrosis (CF) patients. The putative operon encodes BceS, a sensor kinase, and BceR, a response regulator. Our studies indicated that the bceR mutant showed a statistically significant decrease in protease, swimming motility, and quorum sensing when compared to the wild-type, but there was no significant difference in phospholipase C activity, swarming, and biofilm formation. In addition, the mutant showed a statistically significant reduction in virulence compared to the wild-type using the alfalfa plant model. Examination of the Burkholderia cepacia complex (a group of organisms that are phenotypically similar, but genotypically distinct) revealed that this system is prevalent in B. ambifaria, B. multivorans, B. vietnamiensis and B. dolosa. Interestingly, all these organisms have been associated with CF patients. The collective results indicate that BceSR influences various activities important in Burkholderia physiology and possibly pathogenesis. This information could be important in the design of novel therapeutics for Burkholderia infections. PMID- 25519697 TI - Biotechnological production and application of fructooligosaccharides. AB - Currently, prebiotics are all carbohydrates of relatively short chain length. One important group is the fructooligosaccharides (FOS), a special kind of prebiotic associated to the selective stimulation of the activity of certain groups of colonic bacteria. They have a positive and beneficial effect on intestinal microbiota, reducing the incidence of gastrointestinal infections and also possessing a recognized bifidogenic effect. Traditionally, these prebiotic compounds have been obtained through extraction processes from some plants, as well as through enzymatic hydrolysis of sucrose. However, different fermentative methods have also been proposed for the production of FOS, such as solid-state fermentations utilizing various agro-industrial by-products. By optimizing the culture parameters, FOS yields and productivity can be improved. The use of immobilized enzymes and cells has also been proposed as being an effective and economic method for large-scale production of FOS. This article is an overview of the results considering recent studies on FOS biosynthesis, physicochemical properties, sources, biotechnological production and applications. PMID- 25519694 TI - Nitrite-dependent anaerobic methane-oxidising bacteria: unique microorganisms with special properties. AB - Microbial mediated nitrite-dependent anaerobic methane oxidation (N-DAMO), which couples the oxidation of methane to nitrite reduction, is a recently discovered process. The discovery of N-DAMO process makes great contributions to complete the biogeochemical cycles of carbon and nitrogen, and to develop novel economic biotechnology for simultaneous carbon and nitrogen removal. This process is catalysed by the unique bacterium "Candidatus Methylomirabilis oxyfera" (M. oxyfera), which belongs to the candidate phylum NC10, a phylum having no members in pure culture. In recent years, some microbiological properties of M. oxyfera have been unravelled. The most prominent examples are the discoveries of the special ultrastructure (star-like) of the cell shape and the unique chemical composition (10MeC16:1Delta7) of M. oxyfera that have not been found in other bacteria yet. More importantly, a new intra-aerobic pathway was discovered in M. oxyfera. It seems that M. oxyfera produces oxygen intracellularly by the conversion of two nitric oxide molecules to dinitrogen gas and oxygen, and the produced oxygen is then used for methane oxidation and normal respiration. The current paper is a systematic review in the microbiological properties of M. oxyfera, especially for its special properties. PMID- 25519698 TI - Interactions of multitargeted kinase inhibitors and nucleoside drugs: Achilles heel of combination therapy? AB - Multitargeted tyrosine kinase inhibitors (TKI) axitinib, pazopanib, and sunitinib are used to treat many solid tumors. Combination trials of TKIs with gemcitabine, a nucleoside anticancer drug, in pancreas, renal, lung, ovarian, and other malignancies resulted in little benefit to patients. TKI interactions with human nucleoside transporters (hNT) were studied by assessing inhibition of [(3)H]uridine uptake in yeast producing recombinant hNTs individually and in cultured human cancer cell lines. Axitinib, pazopanib, and sunitinib inhibited hENT1 at low micromolar concentrations. In A549, AsPC-1, and Caki-1 cells, [(3)H]uridine, [(3)H]thymidine, [(3)H]gemcitabine, and [(3)H]fluorothymidine (FLT) accumulation was blocked by all three TKIs. Pazopanib > axitinib >= sunitinib inhibited hENT1 with IC50 values of 2, 7, and 29 MUmol/L, respectively, leading to reduced intracellular gemcitabine and FLT accumulation. Pretreatment or cotreatment of Caki-1 cells with TKIs reduced cellular accumulation of [(3)H]nucleosides, suggesting that TKI scheduling with nucleoside drugs would influence cytotoxicity. In combination cytotoxicity experiments that compared sequential versus simultaneous addition of drugs in Caki-1 cells, cytotoxicity was greatest when gemcitabine was added before TKIs. In clinical settings, TKI inhibitor concentrations in tumor tissues are sufficient to inhibit hENT1 activity, thereby reducing nucleoside chemotherapy drug levels in cancer cells and reducing efficacy in combination schedules. An additional unwanted interaction may be reduced FLT uptake in tumor tissues that could lead to aberrant conclusions regarding tumor response. PMID- 25519699 TI - The use of dipeptide derivatives of 5-aminolaevulinic acid promotes their entry to tumor cells and improves tumor selectivity of photodynamic therapy. AB - The use of endogenous protoporphyrin IX generated after administration of 5 aminolaevulinic acid (ALA) has led to many applications in photodynamic therapy (PDT). However, the bioavailability of ALA is limited by its hydrophilic properties and limited cell uptake. A promising approach to optimize the efficacy of ALA-PDT is to deliver ALA in the form of prodrugs to mask its hydrophilic nature. The aim of this work was to evaluate the potential of two ALA dipeptide derivatives, N-acetyl terminated leucinyl-ALA methyl ester (Ac-Leu-ALA-Me) and phenylalanyl-ALA methyl ester (Ac-Phe-ALA-Me), for their use in PDT of cancer, by investigating the generation of protoporphyrin IX in an oncogenic cell line (PAM212-Ras), and in a subcutaneous tumor model. In our in vitro studies, both derivatives were more effective than ALA in PDT treatment, at inducing the same protoporphyrin IX levels but at 50- to 100-fold lower concentrations, with the phenylalanyl derivative being the most effective. The efficient release of ALA from Ac-Phe-ALA-Me appears to be consistent with the reported substrate and inhibitor preferences of acylpeptide hydrolase. In vivo studies revealed that topical application of the peptide prodrug Ac-Phe-ALA-Me gave greater selectivity than with ALA itself, and induced tumor photodamage, whereas systemic administration improved ALA-induced porphyrin generation in terms of equivalent doses administered, without induction of toxic effects. Our data support the possibility of using particularly Ac-Phe-ALA-Me both for topical treatment of basal cell carcinomas and for systemic administration. Further chemical fine tuning of this prodrug template should yield additional compounds for enhanced ALA-PDT with potential for translation to the clinic. PMID- 25519702 TI - A preclinical evaluation of SKLB261, a multikinase inhibitor of EGFR/Src/VEGFR2, as a therapeutic agent against pancreatic cancer. AB - The clinical prognosis of pancreatic cancer remains rather disappointing despite tremendous efforts in exploring medical treatments in the past two decades. Development of more effective treatment strategies is still desperately needed to improve outcomes in patients with pancreatic cancer. SKLB261 is a multikinase inhibitor obtained recently through a lead optimization. In this investigation, we shall evaluate its anti-pancreatic cancer effects both in vitro and in vivo. SKLB261 is a multikinase inhibitor potently inhibiting EGFR, Src, and VEGFR2 kinases. It could significantly inhibit cell proliferation, migration, and invasion, and induce apoptosis in cellular assays of human pancreatic cancer cells that are sensitive or resistant to dasatinib and/or gemcitabine. Western blot analysis showed that SKLB261 inhibited the activation of EGFR and Src kinases as well as their downstream signaling proteins, including FAK, ERK, and STAT3. SKLB261 also showed potent antiangiogenic effects in transgenic zebrafish models. In vivo, SKLB261 displayed more potent antitumor activities than dasatinib, gemcitabine, or erlotinib in pancreatic cancer xenografts, including BxPC-3, PANC-1, AsPC-1, and HPAC. Furthermore, mice receiving SKLB261 therapy showed significant survival advantage compared with vehicle-treated and gemcitabine-treated groups in an experimental metastasis model of pancreatic cancer. These data, together with the good pharmacokinetic properties and low toxicity of this compound, provide a rationale for the ongoing clinical evaluation of SKLB261 in the treatment of pancreatic cancer. PMID- 25519700 TI - MLN0128, an ATP-competitive mTOR kinase inhibitor with potent in vitro and in vivo antitumor activity, as potential therapy for bone and soft-tissue sarcoma. AB - The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that exists in two complexes (mTORC1 and mTORC2) and integrates extracellular and intracellular signals to act as a master regulator of cell growth, survival, and metabolism. The PI3K/AKT/mTOR prosurvival pathway is often dysregulated in multiple sarcoma subtypes. First-generation allosteric inhibitors of mTORC1 (rapalogues) have been extensively tested with great preclinical promise, but have had limited clinical utility. Here, we report that MLN0128, a second generation, ATP-competitive, pan-mTOR kinase inhibitor, acts on both mTORC1 and mTORC2 and has potent in vitro and in vivo antitumor activity in multiple sarcoma subtypes. In vitro, MLN0128 inhibits mTORC1/2 targets in a concentration dependent fashion and shows striking antiproliferative effect in rhabdomyosarcoma (RMS), Ewing sarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, osteosarcoma, and liposarcoma. Unlike rapamycin, MLN0128 inhibits phosphorylation of 4EBP1 and NDRG1 as well as prevents the reactivation of pAKT that occurs via negative feedback release with mTORC1 inhibition alone. In xenograft models, MLN0128 treatment results in suppression of tumor growth with two dosing schedules (1 mg/kg daily and 3 mg/kg b.i.d. t.i.w.). At the 3 mg/kg dosing schedule, MLN0128 treatment results in significantly better tumor growth suppression than rapamycin in RMS and Ewing sarcoma models. In addition, MLN0128 induces apoptosis in models of RMS both in vitro and in vivo. Results from our study strongly suggest that MLN0128 treatment should be explored further as potential therapy for sarcoma. PMID- 25519703 TI - Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer. AB - BACKGROUND: Although chemotherapy for prostate cancer (PCa) can improve patient survival, some tumours are chemo-resistant. Tumour molecular profiles may help identify the mechanisms of drug action and identify potential prognostic biomarkers. We performed in vivo transcriptome profiling of pre- and post treatment prostatic biopsies from patients with advanced hormone-naive prostate cancer treated with docetaxel chemotherapy and androgen deprivation therapy (ADT) with an aim to identify the mechanisms of drug action and identify prognostic biomarkers. METHODS: RNA sequencing (RNA-Seq) was performed on biopsies from four patients before and ~22 weeks after docetaxel and ADT initiation. Gene fusion products and differentially-regulated genes between treatment pairs were identified using TopHat and pathway enrichment analyses undertaken. Publically available datasets were interrogated to perform survival analyses on the gene signatures identified using cBioportal. RESULTS: A number of genomic rearrangements were identified including the TMPRSS2/ERG fusion and 3 novel gene fusions involving the ETS family of transcription factors in patients, both pre and post chemotherapy. In total, gene expression analyses showed differential expression of at least 2 fold in 575 genes in post-chemotherapy biopsies. Of these, pathway analyses identified a panel of 7 genes (ADAM7, FAM72B, BUB1B, CCNB1, CCNB2, TTK, CDK1), including a cell cycle-related geneset, that were differentially-regulated following treatment with docetaxel and ADT. Using cBioportal to interrogate the MSKCC-Prostate Oncogenome Project dataset we observed a statistically-significant reduction in disease-free survival of patients with tumours exhibiting alterations in gene expression of the above panel of 7 genes (p = 0.015). CONCLUSIONS: Here we report on the first "real time" in vivo RNA-Seq-based transcriptome analysis of clinical PCa from pre- and post-treatment TRUSS-guided biopsies of patients treated with docetaxel chemotherapy plus ADT. We identify a chemotherapy-driven PCa transcriptome profile which includes the down-regulation of important positive regulators of cell cycle progression. A 7 gene signature biomarker panel has also been identified in high-risk prostate cancer patients to be of prognostic value. Future prospective study is warranted to evaluate the clinical value of this panel. PMID- 25519701 TI - Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with epigenetic modifications. AB - Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). Despite sunitinib's clinical efficacy, patients eventually develop drug resistance and disease progression. Herein, we tested the hypothesis whether initial sunitinib resistance may be transient and could be overcome by dose increase. In selected patients initially treated with 50 mg sunitinib and presenting with minimal toxicities, sunitinib dose was escalated to 62.5 mg and/or 75 mg at the time of tumor progression. Mice bearing two different patient-derived ccRCC xenografts (PDX) were treated 5 days per week with a dose-escalation schema (40-60-80 mg/kg sunitinib). Tumor tissues were collected before dose increments for immunohistochemistry analyses and drug levels. Selected intrapatient sunitinib dose escalation was safe and several patients had added progression-free survival. In parallel, our preclinical results showed that PDXs, although initially responsive to sunitinib at 40 mg/kg, eventually developed resistance. When the dose was incrementally increased, again we observed tumor response to sunitinib. A resistant phenotype was associated with transient increase of tumor vasculature despite intratumor sunitinib accumulation at higher dose. In addition, we observed associated changes in the expression of the methyltransferase EZH2 and histone marks at the time of resistance. Furthermore, specific EZH2 inhibition resulted in increased in vitro antitumor effect of sunitinib. Overall, our results suggest that initial sunitinib-induced resistance may be overcome, in part, by increasing the dose, and highlight the potential role of epigenetic changes associated with sunitinib resistance that can represent new targets for therapeutic intervention. PMID- 25519704 TI - Importance of remission and residual somatic symptoms in health-related quality of life among outpatients with major depressive disorder: a cross-sectional study. AB - BACKGROUND: Major depressive disorder (MDD) is strongly associated with an impaired quality of life (QoL), which is itself affected by various factors. Symptom-oriented ratings poorly reflect the impact of disease on the QoL and level of functioning of the mental health of subjects. The purpose of this study was to assess health-related QoL (HRQoL) using preference-based measures in outpatients with MDD with regard to their remission achievement and clinical factors affecting the HRQoL. METHODS: This was a cross-sectional observational study. We recruited 811 patients with MDD from 14 psychiatric outpatient clinics in Korea. They were divided into three groups as follows: a new visit group (n = 287), a remitted group (n = 235), and a non-remitted group (n = 289). The 17-item Hamilton Depression Rating Scale was used to assign patients to the remitted or non-remitted group. The general HRQoL was assessed with the EuroQol 5D (EQ-5D), using both the EQ-5D index score and the EuroQol Visual Analog Scale (EQ-VAS). The disease-specific HRQoL was assessed with the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). RESULTS: The non-remitted group showed a significant impairment of HRQoL in view of the subscales of EQ-5D index scores, EQ-VAS, and Q-LES-Q-SF. The EQ-5D index score in the remitted group was 0.77 +/- 0.10, while it was 0.57 +/- 0.23 in the non-remitted group and 0.58 +/- 0.24 in the new visit group (p < 0.0001). The EQ-VAS scores for the remitted and non-remitted groups were 72.5 +/- 16.6 and 50.9 +/- 20.3, respectively (p < 0.0001). Likewise, patients with remission had the Q-LES-Q-SF total score of 46.5 +/- 8.8, whereas those with non-remission reported 36.7 +/- 7.7 (p < 0.0001). The symptom severity measured by the Depression and Somatic Symptoms Scale was significantly correlated with the HRQoL. Furthermore, patients with severe somatic symptoms showed a significantly lower EQ-5D index score (0.54 +/- 0.24) than those with mild/moderate somatic symptoms (0.75 +/- 0.12; p = 0.002). CONCLUSION: Non-remitted MDD patients, especially those with more severe somatic symptoms, show a distinct impairment of HRQoL and more clinical symptoms, suggesting the importance of achieving remission in the treatment of MDD. PMID- 25519705 TI - Work productivity loss from depression: evidence from an employer survey. AB - BACKGROUND: National working groups identify the need for return on investment research conducted from the purchaser perspective; however, the field has not developed standardized methods for measuring the basic components of return on investment, including costing out the value of work productivity loss due to illness. Recent literature is divided on whether the most commonly used method underestimates or overestimates this loss. The goal of this manuscript is to characterize between and within variation in the cost of work productivity loss from illness estimated by the most commonly used method and its two refinements. METHODS: One senior health benefit specialist from each of 325 companies employing 100+ workers completed a cross-sectional survey describing their company size, industry and policies/practices regarding work loss which allowed the research team to derive the variables needed to estimate work productivity loss from illness using three methods. Compensation estimates were derived by multiplying lost work hours from presenteeism and absenteeism by wage/fringe. Disruption correction adjusted this estimate to account for co-worker disruption, while friction correction accounted for labor substitution. The analysis compared bootstrapped means and medians between and within these three methods. RESULTS: The average company realized an annual $617 (SD = $75) per capita loss from depression by compensation methods and a $649 (SD = $78) loss by disruption correction, compared to a $316 (SD = $58) loss by friction correction (p < .0001). Agreement across estimates was 0.92 (95% CI 0.90, 0.93). CONCLUSION: Although the methods identify similar companies with high costs from lost productivity, friction correction reduces the size of compensation estimates of productivity loss by one half. In analyzing the potential consequences of method selection for the dissemination of interventions to employers, intervention developers are encouraged to include friction methods in their estimate of the economic value of interventions designed to improve absenteeism and presenteeism. Business leaders in industries where labor substitution is common are encouraged to seek friction corrected estimates of return on investment. Health policy analysts are encouraged to target the dissemination of productivity enhancing interventions to employers with high losses rather than all employers. TRIAL REGISTRATION: CLINICAL TRIALS REGISTRATION NUMBER: NCT01013220. PMID- 25519706 TI - Use of diffusion-weighted magnetic resonance imaging (DW-MRI) to investigate the effect of chemoradiotherapy on the salivary glands. PMID- 25519707 TI - The impact of age on survival of diffuse large B-cell lymphoma - a population based study. AB - BACKGROUND: For Diffuse large B-cell lymphoma (DLBCL), the International Prognostic Index is the major tool for prognostication and considers an age above 60 years as a risk factor. However, there are several indications that increasing age is associated with more biological complexity, resulting in differences in DLBCL biology depending on age. METHODS: We conducted a registry-based retrospective cohort study of all Swedish DLBCL patients diagnosed 2000-2013, to evaluate the importance of age at diagnosis for survival of DLBCL patients. RESULTS: In total, 7166 patients were included for further analysis. Survival declined for every 10-year age group and every age group above the age of 39 had a statistically decreased survival compared to the reference group of 20-29 years. In an analysis of relative survival, and in a multifactorial model adjusted for stage, ECOG performance status, serum lactate dehydrogenase and involvement of extranodal sites, each age group above age 39 had a significantly higher risk ratio (p=0.01) compared to the reference group. CONCLUSION: This is one of the largest population-based studies of DLBCL published to date. In this study, age persisted as a significant adverse risk factor for patients as young as 40 years, even after adjustment for other risk factors. PMID- 25519708 TI - Costs of colorectal cancer in different states of the disease. AB - OBJECTIVES: This cross-sectional study estimates the resource use and costs among prevalent colorectal cancer (CRC) patients in different states of the disease. METHODS: Altogether 508 Finnish CRC patients (aged 26-96; colon cancer 56%; female 47%) answered a questionnaire enquiring about informal care, work capacity, and demographic factors. Furthermore, data on direct medical resource use and productivity costs were obtained from registries. Patients were divided into five mutually exclusive groups based on the disease state and the time from diagnosis: primary treatments (the first six months after the diagnosis), rehabilitation, remission, metastatic disease, and palliative care. The costs were calculated for a six-month period. Multivariate modeling was performed to find the cost drivers. RESULTS: The costs were highest during the primary treatment state and the advanced disease states. The total costs for the cross sectional six-month period were ?22 200 in the primary treatment state, ?2106 in the rehabilitation state, ?2812 in the remission state, ?20 540 in the metastatic state, and ?21 146 in the palliative state. Most of the costs were direct medical costs. The informal care cost was highest per patient in the palliative care state, amounting to 33% of the total costs. The productivity costs varied between disease states, constituting 19-40% of the total costs, and were highest in the primary treatment state. CONCLUSIONS: The first six months after the diagnosis of CRC are resource intensive, but compared with the metastatic disease state, which lasts on average for 2-3 years, the costs are rather modest. Informal care constitutes a remarkable share of the total costs, especially in the palliative state. These results form a basis for the evaluation of the cost effectiveness of new treatments when allocating resources in CRC treatment. PMID- 25519711 TI - Practical assay for nitrite and nitrosothiol as an alternative to the Griess assay or the 2,3-diaminonaphthalene assay. AB - Nitrite is a heavily assayed substrate in the fields of food safety, water quality control, disease diagnosis, and forensic investigation and more recently in basic biological studies on nitric oxide physiology and pathology. The colorimetric Griess assay and the fluorimetric 2,3-diaminonaphthalene (DAN) assay are the current gold standards for nitrite quantification. They are not without limitations, yet have amazingly survived 156 and 44 years, respectively, due to the lack of a practical alternative. Both assays exhibit slow detection kinetics due to inactivation of nucleophiles under strongly acidic media, require an extensive incubation time for reaction to go completion, and hence offer a limited detection throughput. By converting an intermolecular reaction of the Griess assay intramolecularly, we designed a novel probe (NT555) for nitrite detection, which displays superior detection kinetics and sensitivity. NT555 was constructed following our "covalent-assembly" probe design principle. Upon detection, it affords a gigantic bathochromic shift of the absorption spectrum and a sensitive turn-on fluorescence signal from a zero background, both of which are typical of an "assembly" type probe. Overall, NT555 has addressed various difficulties associated with the Griess and the DAN assays and represents an attractive alternative for practical applications. PMID- 25519710 TI - Perceptions of malaria and acceptance of rapid diagnostic tests and related treatment practises among community members and health care providers in Greater Garissa, North Eastern Province, Kenya. AB - BACKGROUND: Conventional diagnosis of malaria has relied upon either clinical diagnosis or microscopic examination of peripheral blood smears. These methods, if not carried out exactly, easily result in the over- or under-diagnosis of malaria. The reliability and accuracy of malaria RDTs, even in extremely challenging health care settings, have made them a staple in malaria control programmes. Using the setting of a pilot introduction of malaria RDTs in Greater Garissa, North Eastern Province, Kenya, this study aims to identify and understand perceptions regarding malaria diagnosis, with a particular focus on RDTs, and treatment among community members and health care workers (HCWs). METHODS: The study was conducted in five districts of Garissa County. Focus group discussions (FGD) were performed with community members that were recruited from health facilities (HFs) supported by the MENTOR Initiative. In-depth interviews (IDIs) and FGDs with HCWs were also carried out. Interview transcripts were then coded and analysed for major themes. Two researchers reviewed all codes, first separately and then together, discussed the specific categories, and finally characterized, described, and agreed upon major important themes. RESULTS: Thirty four FGDs were carried out with a range of two to eight participants (median of four). Of 157 community members, 103 (65.6%) were women. The majority of participants were illiterate and the highest level of education was secondary school. Some 76% of participants were of Somali ethnicity. Whilst community members and HCWs demonstrated knowledge of aspects of malaria transmission, prevention, diagnosis, and treatment, gaps and misconceptions were identified. Poor adherence to negative RDT results, unfamiliarity and distrust of RDTs, and an inconsistent RDT supply were the main challenges to become apparent in FGDs and IDIs. CONCLUSION: Gaps in knowledge or incorrect beliefs exist in Greater Garissa and have the potential to act as barriers to complete and correct malaria case management. Addressing these knowledge gaps requires comprehensive education campaigns and a reliable and constant RDT supply. The results of this study highlight education and supply chain as key factors to be addressed in order to make large scale roll out of RDTs as successful and effective as possible. PMID- 25519712 TI - Interlayer structure and self-healing in suspensions of brush-stabilized nanoplatelets with smectic order. AB - We have investigated the rheology of an uncured epoxy fluid containing high aspect ratio (length/thickness ~ 160) alpha-zirconium phosphate (ZrP) nanoplatelets with smectic order. The nanoplatelets were exfoliated into monocrystalline sheets with uniform thickness using a monoamine-terminated oligomer. The oligomers were densely grafted to the plate surfaces and behave as a molecular brush. Suspensions containing ~ 2 vol.% ZrP and above show liquid crystalline order with scattering peaks characteristic of a smectic (layered) mesophase. At much higher loading, ~ 4 vol.% ZrP, there is a sharp transition in visual appearance, steady shear rheology, and linear and non-linear viscoelasticity that is attributed to the reversible interdigitation of oligomer chains between closely spaced layers. The oligomers are proposed to serve as inter-lamellar bridges that store elastic stresses for intermediate rates of deformation, but are able to relax on longer time scales. Under steady shearing conditions, the smectic suspensions with "overlapped" microstructure show a discontinuous flow curve characteristic of shear banding that is attributed to the dynamic pull-out of oligomer chains from the overlap region. At high shear rates, the limiting viscosity of the concentrated suspensions is on the same order of magnitude as the unfilled suspending fluid. When the rate of deformation is reduced below a critical time scale, the original network strength, and corresponding microstructure, is recovered through a passive self-healing process. The unique combination of concentration-dependent yield stress, low post yield viscosity, and self-healing is potentially useful for various applications in the liquid state, and desirable for scalable processing of nanocomposite materials for structural applications. PMID- 25519713 TI - Communicating With School Nurses About Sexual Orientation and Sexual Health: Perspectives of Teen Young Men Who Have Sex With Men. AB - Black and Latino young men who have sex with men (YMSM) are at disproportionate risk for sexually transmitted diseases (STDs), including HIV. This study informs school-centered strategies for connecting YMSM to health services by describing their willingness, perceived safety, and experiences in talking to school staff about sexual health. Cross-sectional data were collected from Black and Latino YMSM aged 13-19 through web-based questionnaires (N = 415) and interviews (N = 32). School nurses were the staff members youth most often reported willingness to talk to about HIV testing (37.8%), STD testing (37.1%), or condoms (37.3%), but least often reported as safe to talk to about attraction to other guys (11.4%). Interviews revealed youth reluctance to talk with school staff including nurses when uncertain of staff members' perceptions of lesbian, gay, bisexual, transgender, and questioning (LGBTQ) people or perceiving staff to lack knowledge of LGBTQ issues, communities, or resources. Nurses may need additional training to effectively reach Black and Latino YMSM. PMID- 25519714 TI - Teachers' perceptions of full- and part-time nurses at school. AB - Teachers and school nurses partner together to help ensure students stay healthy and engaged in school. The purpose of this study is to generate a deeper understanding of teachers' perceptions on the benefits and challenges of working with full- or part-time school nurses. We conducted a qualitative analysis of open-ended survey responses from 129 teachers in nine low-income, ethnically diverse urban schools. These schools were part of a multiyear project that placed full-time nurses in four schools, while five schools with part-time nurses were used as a comparison group. Findings indicate that teachers had strong appreciation for the wide range of responsibilities undertaken by the school nurse. Teachers' level of satisfaction was linked to the number of hours the nurse is on-site, where teachers reported greater satisfaction with nurses who worked on campus full time. Results point to factors that may improve working relations between teachers and nurses. PMID- 25519715 TI - Human Adenomyosis Endometrium Stromal Cells Secreting More Nerve Growth Factor: Impact and Effect. AB - Abnormal expression of nerve growth factor (NGF) was found in adenomyosis (AM). We collected AM foci from patients and eutopic endometrium from non-AM controls. Endometrium stromal cells (ESCs) were cultured. Different levels of 17beta estradiol, tumor necrosis factor (TNF), CoCl2, and H2O2 were added to the culture system separately, then the expression level of NGF in ESCs was detected. After adding different levels of NGF, the proliferation and apoptosis of ESCs and aromatase expression were detected. We found that 17beta-estradiol promoted NGF production in AM ESCs but not in control ESCs; TNF promoted NGF production in both AM and control ESCs; and CoCl2 inhibited NGF production in control ESCs, but had no effect in AM ESCs. Nerve growth factor promoted the proliferation and synthesis of aromatase in AM ESCs. In conclusion, locally increased estrogen levels and inflammation may cause increased NGF production in the uterus of patients with AM. Nerve growth factor stimulated the proliferation and increased aromatase expression of ESCs from AM foci, suggesting NGF might contribute to the pathology and etiology of AM. PMID- 25519716 TI - Vitamin C Induces the Reduction of Oxidative Stress and Paradoxically Stimulates the Apoptotic Gene Expression in Extravillous Trophoblasts Derived From First Trimester Tissue. AB - AIM: To investigate the effects of vitamin C on the expression of the genes related to apoptosis in extravillous trophoblasts (EVTs) in the first trimester. METHODS: Extravillous trophoblasts were cultured under 2% O2 followed by 2% O2 or 8% O2 with or without vitamin C. The level of reactive oxygen species (ROS) in the cultured medium was estimated using electron spin resonance spectroscopy. The expression levels of the genes TP53, BCL2, and BAX were quantified using real time quantitative polymerase chain reaction. RESULTS: Reactive oxygen species were found to be decreased after adding vitamin C under increasing oxygen concentrations. In addition, the ratio of BAX/BCL2 also increased after adding vitamin C under conditions of 2% O2, while the gene expression level of BCL2 increased after adding vitamin C under increasing oxygen concentrations. In contrast, the gene expression level of TP53 and the ratio of BAX/BCL2 both decreased. CONCLUSION: We have revealed that vitamin C reduces ROS and may promote the apoptosis of EVTs under conditions of 2% O2 while paradoxically preventing apoptosis under increasing oxygen concentrations. PMID- 25519717 TI - Serum MicroRNAs as Diagnostic Biomarkers for Macrosomia. AB - BACKGROUND: Macrosomia is defined as an infant's birth weight of more than 4000 g. Although microRNAs (miRNAs) have been implicated in the pathogenesis of various diseases, the associations between serum miRNAs and macrosomia have been rarely reported. METHODOLOGY: We used the Taqman Low Density Array followed by quantitative reverse transcriptase polymerase chain reaction assays to screen for miRNAs associated with macrosomia using serum samples collected 1 week before delivery. RESULTS: Profiling results showed that 1 miRNA was significantly upregulated and 10 miRNAs were significantly downregulated in serum samples of macrosomia (DeltaDeltaCt > 3-fold). The expression levels of miR-21 were significantly decreased in macrosomia as compared to the controls in the third trimester. Receiver operating characteristic (ROC) curve analyses showed that the area under the ROC curve for miR-21 was 67.7% (sensitivity = 66.7% and specificity = 70.0%). CONCLUSIONS: miR-21 in maternal serum is differentially expressed between macrosomia and controls, and miR-21 could be used as a candidate biomarker to predict macrosomia. PMID- 25519719 TI - Recognizing 2014 manuscript reviewers. PMID- 25519718 TI - Paternal heterochromatin formation in human embryos is H3K9/HP1 directed and primed by sperm-derived histone modifications. AB - The different configurations of maternal and paternal chromatin, acquired during oogenesis and spermatogenesis, have to be rearranged after fertilization to form a functional embryonic genome. In the paternal genome, nucleosomal chromatin domains are re-established after the protamine-to-histone exchange. We investigated the formation of constitutive heterochromatin (cHC) in human preimplantation embryos. Our results show that histones carrying canonical cHC modifications are retained in cHC regions of sperm chromatin. These modified histones are transmitted to the oocyte and contribute to the formation of paternal embryonic cHC. Subsequently, the modifications are recognized by the H3K9/HP1 pathway maternal chromatin modifiers and propagated over the embryonic cleavage divisions. These results are in contrast to what has been described for mouse embryos, in which paternal cHC lacks canonical modifications and is initially established by Polycomb group proteins. Our results show intergenerational epigenetic inheritance of the cHC structure in human embryos. PMID- 25519720 TI - Incidence, Timing, and Predictors of Delayed Shunting for Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Although hydrocephalus is often treated with permanent cerebrospinal fluid (CSF) shunting during hospitalization for acute aneurysmal subarachnoid hemorrhage (SAH), little is known about the development of delayed hydrocephalus. METHODS: Using administrative data on all visits to nonfederal emergency departments and acute care hospitals across California from 2005 to 2010, we identified patients with SAH and discharged without placement of a CSF shunt. Patients were followed for up to 7 years to determine whether they subsequently developed delayed hydrocephalus, as indicated by hospitalization for a permanent CSF diversion procedure. RESULTS: In 8,889 patients discharged with SAH, 116 (1.3 %) went on to develop delayed hydrocephalus. Most (>90 %) diagnoses of delayed hydrocephalus occurred within the first year after discharge. Cox proportional hazards analysis identified microsurgical clipping (hazard ratio 2.0; 95 % confidence interval 1.2-3.3), temporary ventriculostomy placement (2.5; 1.6-4.1), mechanical ventilation (1.7; 1.1-2.8), and discharge to a skilled nursing facility (2.9; 1.8-4.6) as being significantly associated with the development of delayed hydrocephalus. At 1 year after discharge, the cumulative rate of delayed hydrocephalus was 0.9 % (95 % CI, 0.7-1.1 %) for those without temporary ventriculostomy placement during the initial hospitalization, versus 5.7 % (95 % CI, 3.9-8.1 %) in those who had received a temporary ventriculostomy. CONCLUSION: Delayed hydrocephalus after SAH occurs rarely overall, but in a substantial proportion of patients who required temporary ventriculostomy during the initial hospitalization. These results support vigilant surveillance of patients after removal of a temporary ventriculostomy, given the potential of delayed hydrocephalus to impair recovery or even result in clinical deterioration following SAH. PMID- 25519721 TI - Causal assessment of pharmaceutical treatments: why standards of evidence should not be the same for benefits and harms? AB - It is increasingly acknowledged both among epidemiologists and regulators that the assessment of pharmaceutical harm requires specific methodological approaches that cannot simply duplicate those developed for testing efficacy. However, this intuition lacks sound epistemic bases and delivers ad hoc advice. This paper explains why the same methods of scientific inference do not fare equally well for efficacy and safety assessment by tracing them back to their epistemic foundations. To illustrate this, Cartwright's distinction into clinching and vouching methods is adopted and a series of reasons is provided for preferring the latter to the former: (1) the need to take into account all available knowledge and integrate it with incoming data; (2) the awareness that a latent unknown risk may always change the safety profile of a given drug (precautionary principle); (3) cumulative learning over time; (4) requirement of probabilistic causal assessment to allow decision under uncertainty; (5) impartiality; and (6) limited and local information provided by randomised controlled trials. Subsequently, the clinchers/vouchers distinction is applied to a case study concerning the debated causal association between paracetamol and asthma. This study illustrates the tension between implicit epistemologies adopted in evaluating evidence and causality; furthermore, it also shows that discounting causal evidence may be a result of unacknowledged low priors or lack of valid alternative options. We conclude with a presentation of the changing landscape in pharmacology and the trend towards an increased use of Bayesian tools for assessment of harms. PMID- 25519722 TI - An enzyme-linked immuno-mass spectrometric assay with the substrate adenosine monophosphate. AB - An enzyme-linked immuno-mass spectrometric assay (ELIMSA) with the specific detection probe streptavidin conjugated to alkaline phosphatase catalyzed the production of adenosine from the substrate adenosine monophosphate (AMP) for sensitive quantification of prostate-specific antigen (PSA) by mass spectrometry. Adenosine ionized efficiently and was measured to the femtomole range by dilution and direct analysis with micro-liquid chromatography, electrospray ionization, and mass spectrometry (LC-ESI-MS). The LC-ESI-MS assay for adenosine production was shown to be linear and accurate using internal (13)C(15)N adenosine isotope dilution, internal (13)C(15)N adenosine one-point calibration, and external adenosine standard curves with close agreement. The detection limits of LC-ESI-MS for alkaline phosphatase-streptavidin (AP-SA, ~190,000 Da) was tested by injecting 0.1 MUl of a 1 pg/ml solution, i.e., 100 attograms or 526 yoctomole (5.26E-22) of the alkaline-phosphatase labeled probe on column (about 315 AP-SA molecules). The ELIMSA for PSA was linear and showed strong signals across the picogram per milliliter range and could robustly detect PSA from all of the prostatectomy patients and all of the female plasma samples that ranged as low as 70 pg/ml with strong signals well separated from the background and well within the limit of quantification of the AP-SA probe. The results of the ELIMSA assay for PSA are normal and homogenous when independently replicated with a fresh standard over multiple days, and intra and inter diem assay variation was less than 10 % of the mean. In a blind comparison, ELIMSA showed excellent agreement with, but was more sensitive than, the present gold standard commercial fluorescent ELISA, or ECL-based detection, of PSA from normal and prostatectomy samples, respectively. PMID- 25519723 TI - Agar films containing silver nanoparticles as new supports for electromembrane extraction. AB - A new support containing silver nanoparticles to assist electromembrane extraction (EME) procedures is proposed. For the first time, synthesized agar films containing silver nanoparticles (AgNPs) have been used as a support for liquid membranes in EME. Agarose films of 20 MUm thickness containing 107.9 mg Ag/g agar were synthesized and characterized by transmission electron microscopy (TEM) and atomic force microscopy (AFM), showing isolated spherical silver nanoparticles of 20-30 nm diameter with homogeneous distribution. Nanometallic films were cut and glued to narrow bore glass tubes and used as supports for a dihexyl ether liquid membrane for use in an EME procedure. EME conditions were optimized and applied to the extraction of selected non-steroidal anti inflammatory drugs (NSAIDs). The results were compared to those using polypropylene membranes (450 MUm and 100 MUm thickness), achieving 10- to 70-fold higher extraction efficiency. This article opens a new line of research into electrically assisted microextraction systems by combining other possible kinds of nanometallic films, including different metals, film functionalization through metallic NPs, and the use of low polarity solvents. Also, very low currents are obtained during the extraction process, which lead to high electromigration of the analytes. PMID- 25519724 TI - A simple method for simultaneous determination of N-arachidonoylethanolamine, N oleoylethanolamine, N-palmitoylethanolamine and 2-arachidonoylglycerol in human cells. AB - The endocannabinoid system has been considered as a target for pharmacological intervention. Accordingly, inhibition of fatty acid amide hydrolase (FAAH), a degrading enzyme of the endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG) as well as of the endocannabinoid-like substances N-oleoylethanolamine (OEA) and N-palmitoylethanolamine (PEA), can cause augmented endogenous cannabinoid tone. Using liquid chromatography coupled with positive electrospray ionisation mass spectrometry, we herein describe a method to simultaneously quantify levels of AEA, OEA, PEA and 2-AG in cultured cells. The procedure was developed according to the FDA guidelines for bioanalytical methods validation. The limits of quantification (LOQs) were 0.05 pmol for AEA, 0.09 pmol for OEA, 0.10 pmol for PEA and 0.80 pmol for 2-AG when molecular ion monitoring was used. In H460 human lung carcinoma cells, basal levels of all four analytes ranged between 2 and 17 pmol mg(-1) protein with PEA showing the lowest and OEA the highest concentrations. Endocannabinoid levels observed in mesenchymal stem cells were of the same order of magnitude when compared to those in H460 human lung carcinoma cells. PMID- 25519725 TI - Gravimetric preparation and characterization of primary reference solutions of molybdenum and rhodium. AB - Gravimetrically prepared mono-elemental reference solutions having a well-known mass fraction of approximately 1 g/kg (or a mass concentration of 1 g/L) define the very basis of virtually all measurements in inorganic analysis. Serving as the starting materials of all standard/calibration solutions, they link virtually all measurements of inorganic analytes (regardless of the method applied) to the purity of the solid materials (high-purity metals or salts) they were prepared from. In case these solid materials are characterized comprehensively with respect to their purity, this link also establishes direct metrological traceability to The International System of Units (SI). This, in turn, ensures the comparability of all results on the highest level achievable. Several national metrology institutes (NMIs) and designated institutes (DIs) have been working for nearly two decades in close cooperation with commercial producers on making an increasing number of traceable reference solutions available. Besides the comprehensive characterization of the solid starting materials, dissolving them both loss-free and completely under strict gravimetric control is a challenging problem in the case of several elements like molybdenum and rhodium. Within the framework of the European Metrology Research Programme (EMRP), in the Joint Research Project (JRP) called SIB09 Primary standards for challenging elements, reference solutions of molybdenum and rhodium were prepared directly from the respective metals with a relative expanded uncertainty associated with the mass fraction of U rel(w) < 0.05 %. To achieve this, a microwave-assisted digestion procedure for Rh and a hotplate digestion procedure for Mo were developed along with highly accurate and precise inductively coupled plasma optical emission spectrometry (ICP OES) and multicollector inductively coupled plasma mass spectrometry (MC-ICP-MS) methods required to assist with the preparation and as dissemination tools. PMID- 25519726 TI - Silicon coupled-resonator optical-waveguide-based biosensors using light scattering pattern recognition with pixelized mode-field-intensity distributions. AB - Chip-scale, optical microcavity-based biosensors typically employ an ultra-high quality microcavity and require a precision wavelength-tunable laser for exciting the cavity resonance. For point-of-care applications, however, such a system based on measurements in the spectral domain is prone to equipment noise and not portable. An alternative microcavity-based biosensor that enables a high sensitivity in an equipment-noise-tolerant and potentially portable system is desirable. Here, we demonstrate the proof-of-concept of such a biosensor using a coupled-resonator optical-waveguide (CROW) on a silicon-on-insulator chip. The sensing scheme is based on measurements in the spatial domain, and only requires exciting the CROW at a fixed wavelength and imaging the out-of-plane elastic light-scattering intensity patterns of the CROW. Based on correlating the light scattering intensity pattern at a probe wavelength with the light-scattering intensity patterns at the CROW eigenstates, we devise a pattern-recognition algorithm that enables the extraction of a refractive index change, Deltan, applied upon the CROW upper-cladding from a calibrated set of correlation coefficients. Our experiments using an 8-microring CROW covered by NaCl solutions of different concentrations reveal a Deltan of ~1.5 * 10(-4) refractive index unit (RIU) and a sensitivity of ~752 RIU(-1), with a noise-equivalent detection limit of ~6 * 10(-6) RIU. PMID- 25519728 TI - Functional importance of T-type voltage-gated calcium channels in the cardiovascular and renal system: news from the world of knockout mice. AB - Over the years, it has been discussed whether T-type calcium channels Cav3 play a role in the cardiovascular and renal system. T-type channels have been reported to play an important role in renal hemodynamics, contractility of resistance vessels, and pacemaker activity in the heart. However, the lack of highly specific blockers cast doubt on the conclusions. As new T-type channel antagonists are being designed, the roles of T-type channels in cardiovascular and renal pathology need to be elucidated before T-type blockers can be clinically useful. Two types of T-type channels, Cav3.1 and Cav3.2, are expressed in blood vessels, the kidney, and the heart. Studies with gene-deficient mice have provided a way to investigate the Cav3.1 and Cav3.2 channels and their role in the cardiovascular system. This review discusses the results from these knockout mice. Evaluation of the literature leads to the conclusion that Cav3.1 and Cav3.2 channels have important, but different, functions in mice. T-type Cav3.1 channels affect heart rate, whereas Cav3.2 channels are involved in cardiac hypertrophy. In the vascular system, Cav3.2 activation leads to dilation of blood vessels, whereas Cav3.1 channels are mainly suggested to affect constriction. The Cav3.1 channel is also involved in neointima formation following vascular damage. In the kidney, Cav3.1 regulates plasma flow and Cav3.2 plays a role setting glomerular filtration rate. In conclusion, Cav3.1 and Cav3.2 are new therapeutic targets in several cardiovascular pathologies, but the use of T-type blockers should be specifically directed to the disease and to the channel subtype. PMID- 25519727 TI - Mesenteric lymphatic vessels adapt to mesenteric venous hypertension by becoming weaker pumps. AB - Lymphangions, the segments of lymphatic vessels between two adjacent lymphatic valves, actively pump lymph. Acute changes in transmural pressure and lymph flow have profound effects on lymphatic pump function in vitro. Chronic changes in pressure and flow in vivo have also been reported to lead to significant changes in lymphangion function. Because changes in pressure and flow are both cause and effect of adaptive processes, characterizing adaptation requires a more fundamental analysis of lymphatic muscle properties. Therefore, the purpose of the present work was to use an intact lymphangion isovolumetric preparation to evaluate changes in mesenteric lymphatic muscle mechanical properties and the intracellular Ca(2+) in response to sustained mesenteric venous hypertension. Bovine mesenteric veins were surgically occluded to create mesenteric venous hypertension. Postnodal mesenteric lymphatic vessels from mesenteric venous hypertension (MVH; n = 6) and sham surgery (Sham; n = 6) animals were isolated and evaluated 3 days after the surgery. Spontaneously contracting MVH vessels generated end-systolic active tension and end-diastolic active tension lower than the Sham vessels. Furthermore, steady-state active tension and intracellular Ca(2+) concentration levels in response to KCl stimulation were also significantly lower in MVH vessels compared with those of the Sham vessels. There was no significant difference in passive tension in lymphatic vessels from the two groups. Taken together, these results suggest that following 3 days of mesenteric venous hypertension, postnodal mesenteric lymphatic vessels adapt to become weaker pumps with decreased cytosolic Ca(2+) concentration. PMID- 25519729 TI - Evolution of the oxygen sensitivity of cytochrome c oxidase subunit 4. AB - Vertebrates possess two paralogs of cytochrome c oxidase (COX) subunit 4: a ubiquitous COX4-1 and a hypoxia-linked COX4-2. Mammalian COX4-2 is thought to have a role in relation to fine-tuning metabolism in low oxygen levels, conferred through both structural differences in the subunit protein structure and regulatory differences in the gene. We sought to elucidate the pervasiveness of this feature across vertebrates. The ratio of COX4-2/4-1 mRNA is generally low in mammals, but this ratio was higher in fish and reptiles, particularly turtles. The COX4-2 gene appeared unresponsive to low oxygen in nonmammalian models (zebrafish, goldfish, tilapia, anoles, and turtles) and fish cell lines. Reporter genes constructed from the amphibian and reptile homologues of the mammalian oxygen-responsive elements and hypoxia-responsive elements did not respond to low oxygen. Unlike the rodent ortholog, the promoter of goldfish COX4-2 did not respond to hypoxia or anoxia. The protein sequences of the COX4-2 peptide showed that the disulfide bridge seen in human and rodent orthologs would be precluded in other mammalian lineages and lower vertebrates, all of which lack the requisite pair of cysteines. The coordinating ligands of the ATP-binding site are largely conserved across mammals and reptiles, but in Xenopus and fish, sequence variations may disrupt the ability of the protein to bind ATP at this site. Collectively, these results suggest that many of the genetic and structural features of COX4-2 that impart responsiveness and benefits in hypoxia may be restricted to the Euarchontoglires lineage that includes primates, lagomorphs, and rodents. PMID- 25519731 TI - Short-chain fatty acids and acidic pH upregulate UT-B, GPR41, and GPR4 in rumen epithelial cells of goats. AB - Currently, the mechanism(s) responsible for the regulation of urea transporter B (UT-B) expression levels in the epithelium of the rumen remain unclear. We hypothesized that rumen fermentation products affect ruminal UT-B expression. Therefore, the effects of short-chain fatty acids (SCFA), pH, ammonia, and urea on mRNA and protein levels of UT-B were assayed in primary rumen epithelial cell cultures and in rumen epithelium obtained from intact goats. In vitro, SCFA and acidic pH were found to synergetically stimulate both mRNA and protein expression of UT-B, whereas NH4Cl decreased mRNA and protein levels of UT-B at pH 6.8. Treatment with urea increased both levels at pH 7.4. When goats received a diet rich in nitrogen (N) and nonfiber carbohydrates (NFC), their rumen epithelium had higher levels of UT-B, and the rumen contained higher concentrations of SCFA and NH3-N with a lower pH. An increase in plasma urea-N concentration was also observed compared with the plasma of the goats that received a diet low in N and NFC. In a second feeding trial, goats that received a NFC-rich, but isonitrogenous, diet had higher mRNA and protein levels of UT-B, and higher levels of G protein-coupled receptor (GPR) 41 and GPR4, in their rumen epithelium. The ruminal concentrations of SCFA and NH3-N also increased, while a lower pH was detected. In contrast, the serum urea-N concentrations remained unchanged. These data indicate that ruminal SCFA and pH are key factors, via GPR4 and GPR41, in the dietary regulation of UT-B expression, and they have priority over changes in plasma urea. PMID- 25519730 TI - Impact of nutrients on circadian rhythmicity. AB - The suprachiasmatic nucleus (SCN) in the mammalian hypothalamus functions as an endogenous pacemaker that generates and maintains circadian rhythms throughout the body. Next to this central clock, peripheral oscillators exist in almost all mammalian tissues. Whereas the SCN is mainly entrained to the environment by light, peripheral clocks are entrained by various factors, of which feeding/fasting is the most important. Desynchronization between the central and peripheral clocks by, for instance, altered timing of food intake can lead to uncoupling of peripheral clocks from the central pacemaker and is, in humans, related to the development of metabolic disorders, including obesity and Type 2 diabetes. Diets high in fat or sugar have been shown to alter circadian clock function. This review discusses the recent findings concerning the influence of nutrients, in particular fatty acids and glucose, on behavioral and molecular circadian rhythms and will summarize critical studies describing putative mechanisms by which these nutrients are able to alter normal circadian rhythmicity, in the SCN, in non-SCN brain areas, as well as in peripheral organs. As the effects of fat and sugar on the clock could be through alterations in energy status, the role of specific nutrient sensors will be outlined, as well as the molecular studies linking these components to metabolism. Understanding the impact of specific macronutrients on the circadian clock will allow for guidance toward the composition and timing of meals optimal for physiological health, as well as putative therapeutic targets to regulate the molecular clock. PMID- 25519735 TI - Erythropoietin's inhibiting impact on hepcidin expression occurs indirectly. AB - Under conditions of accelerated erythropoiesis, elevated erythropoietin (Epo) levels are associated with inhibition of hepcidin synthesis, a response that ultimately increases iron availability to meet the enhanced iron needs of erythropoietic cells. In the search for erythroid regulators of hepcidin, many candidates have been proposed, including Epo itself. We aimed to test whether direct interaction between Epo and the liver is required to regulate hepcidin. We found that prolonged administration of high doses of Epo in mice leads to great inhibition of liver hepcidin mRNA levels, and concomitant induction of the hepcidin inhibitor erythroferrone (ERFE). Epo treatment also resulted in liver iron mobilization, mediated by increased ferroportin activity and accompanied by reduced ferritin levels and increased TfR1 expression. The same inhibitory effect was observed in mice that do not express the homodimeric Epo receptor (EpoR) in liver cells because EpoR expression is restricted to erythroid cells. Similarly, liver signaling pathways involved in hepcidin regulation were not influenced by the presence or absence of hepatic EpoR. Moreover, Epo analogs, possibly interacting with the postulated heterodimeric beta common EpoR, did not affect hepcidin expression. These findings were supported by the lack of inhibition on hepcidin found in hepatoma cells exposed to various concentrations of Epo for different periods of times. Our results demonstrate that hepcidin suppression does not require the direct binding of Epo to its liver receptors and rather suggest that the role of Epo is to stimulate the synthesis of the erythroid regulator ERFE in erythroblasts, which ultimately downregulates hepcidin. PMID- 25519733 TI - Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress. AB - Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress. PMID- 25519734 TI - Acute intermittent optogenetic stimulation of nucleus tractus solitarius neurons induces sympathetic long-term facilitation. AB - Acute intermittent hypoxia (AIH) induces sympathetic and phrenic long-term facilitation (LTF), defined as a sustained increase in nerve discharge. We investigated the effects of AIH and acute intermittent optogenetic (AIO) stimulation of neurons labeled with AAV-CaMKIIa, hChR2(H134R), and mCherry in the nucleus of the solitary tract (NTS) of anesthetized, vagotomized, and mechanically ventilated rats. We measured renal sympathetic nerve activity (RSNA), phrenic nerve activity (PNA), power spectral density, and coherence, and we made cross-correlation measurements to determine how AIO stimulation and AIH affected synchronization between PNA and RSNA. Sixty minutes after AIH produced by ventilation with 10% oxygen in balanced nitrogen, RSNA and PNA amplitude increased by 80% and by 130%, respectively (P < 0.01). Sixty minutes after AIO stimulation, RSNA and PNA amplitude increased by 60% and 100%, respectively, (P < 0.01). These results suggest that acute intermittent stimulation of NTS neurons can induce renal sympathetic and phrenic LTF in the absence of hypoxia or chemoreceptor afferent activation. We also found that while acute intermittent optogenetic and hypoxic stimulations increased respiration-related RSNA modulation (P < 0.01), they did not increase synchronization between central respiratory drive and RSNA. We conclude that mechanisms that induce LTF originate within the caudal NTS and extend to other interconnecting neuronal elements of the central nervous cardiorespiratory network. PMID- 25519732 TI - Chronic and acute effects of stress on energy balance: are there appropriate animal models? AB - Stress activates multiple neural and endocrine systems to allow an animal to respond to and survive in a threatening environment. The corticotropin-releasing factor system is a primary initiator of this integrated response, which includes activation of the sympathetic nervous system and the hypothalamic-pituitary adrenal (HPA) axis. The energetic response to acute stress is determined by the nature and severity of the stressor, but a typical response to an acute stressor is inhibition of food intake, increased heat production, and increased activity with sustained changes in body weight, behavior, and HPA reactivity. The effect of chronic psychological stress is more variable. In humans, chronic stress may cause weight gain in restrained eaters who show increased HPA reactivity to acute stress. This phenotype is difficult to replicate in rodent models where chronic psychological stress is more likely to cause weight loss than weight gain. An exception may be hamsters subjected to repeated bouts of social defeat or foot shock, but the data are limited. Recent reports on the food intake and body composition of subordinate members of group-housed female monkeys indicate that these animals have a similar phenotype to human stress-induced eaters, but there are a limited number of investigators with access to the model. Few stress experiments focus on energy balance, but more information on the phenotype of both humans and animal models during and after exposure to acute or chronic stress may provide novel insight into mechanisms that normally control body weight. PMID- 25519736 TI - Fetal iron deficiency induces chromatin remodeling at the Bdnf locus in adult rat hippocampus. AB - Fetal and subsequent early postnatal iron deficiency causes persistent impairments in cognitive and affective behaviors despite prompt postnatal iron repletion. The long-term cognitive impacts are accompanied by persistent downregulation of brain-derived neurotrophic factor (BDNF), a factor critical for hippocampal plasticity across the life span. This study determined whether early life iron deficiency epigenetically modifies the Bdnf locus and whether dietary choline supplementation during late gestation reverses these modifications. DNA methylation and histone modifications were assessed at the Bdnf-IV promoter in the hippocampus of rats [at postnatal day (PND) 65] that were iron-deficient (ID) during the fetal-neonatal period. Iron deficiency was induced in rat pups by providing pregnant and nursing dams an ID diet (4 mg/kg Fe) from gestational day (G) 2 through PND7, after which iron deficiency was treated with an iron sufficient (IS) diet (200 mg/kg Fe). This paradigm resulted in about 60% hippocampal iron loss on PND15 with complete recovery by PND65. For choline supplementation, pregnant rat dams were given dietary choline (5 g/kg) from G11 through G18. DNA methylation was determined by quantitative sequencing of bisulfite-treated DNA, revealing a small alteration at the Bdnf-IV promoter. Chromatin immunoprecipitation analysis showed increased HDAC1 binding accompanied by reduced binding of RNA polymerase II and USF1 at the Bdnf-IV promoter in formerly ID rats. These changes were correlated with altered histone methylations. Prenatal choline supplementation reverses these epigenetic modifications. Collectively, the findings identify epigenetic modifications as a potential mechanism to explicate the long-term repression of Bdnf following fetal and early postnatal iron deficiency. PMID- 25519737 TI - Activation of the hypothalamic paraventricular nucleus by forebrain hypertonicity selectively increases tonic vasomotor sympathetic nerve activity. AB - We recently reported that mean arterial pressure (MAP) is maintained in water deprived rats by an irregular tonic component of vasomotor sympathetic nerve activity (SNA) that is driven by neuronal activity in the hypothalamic paraventricular nucleus (PVN). To establish whether generation of tonic SNA requires time-dependent (i.e., hours or days of dehydration) neuroadaptive responses or can be abruptly generated by even acute circuit activation, forebrain sympathoexcitatory osmosensory inputs to PVN were stimulated by infusion (0.1 ml/min, 10 min) of hypertonic saline (HTS; 1.5 M NaCl) through an internal carotid artery (ICA). Whereas isotonic saline (ITS; 0.15 M NaCl) had no effect (n = 5), HTS increased (P < 0.001; n = 6) splanchnic SNA (sSNA), phrenic nerve activity (PNA), and MAP. Bilateral PVN injections of muscimol (n = 6) prevented HTS-evoked increases of integrated sSNA and PNA (P < 0.001) and attenuated the accompanying pressor response (P < 0.01). Blockade of PVN NMDA receptors with d-(2R)-amino-5-phosphonovaleric acid (AP5; n = 6) had similar effects. Analysis of respiratory rhythmic bursting of sSNA revealed that ICA HTS increased mean voltage (P < 0.001) without affecting the amplitude of inspiratory or expiratory bursts. Analysis of cardiac rhythmic sSNA likewise revealed that ICA HTS increased mean voltage. Cardiac rhythmic sSNA oscillation amplitude was also increased, which is consistent with activation of arterial baroreceptor during the accompanying pressor response. Increased mean sSNA voltage by HTS was blocked by prior PVN inhibition (muscimol) and blockade of PVN NMDA receptors (AP5). We conclude that even acute glutamatergic activation of PVN (i.e., by hypertonicity) is sufficient to selectively increase a tonic component of vasomotor SNA. PMID- 25519739 TI - Products of lipid peroxidation, but not membrane susceptibility to oxidative damage, are conserved in skeletal muscle following temperature acclimation. AB - Changes in oxidative capacities and phospholipid remodeling accompany temperature acclimation in ectothermic animals. Both responses may alter redox status and membrane susceptibility to lipid peroxidation (LPO). We tested the hypothesis that phospholipid remodeling is sufficient to offset temperature-driven rates of LPO and, thus, membrane susceptibility to LPO is conserved. We also predicted that the content of LPO products is maintained over a range of physiological temperatures. To assess LPO susceptibility, rates of LPO were quantified with the fluorescent probe C11-BODIPY in mitochondria and sarcoplasmic reticulum from oxidative and glycolytic muscle of striped bass (Morone saxatilis) acclimated to 7 degrees C and 25 degrees C. We also measured phospholipid compositions, contents of LPO products [i.e., individual classes of phospholipid hydroperoxides (PLOOH)], and two membrane antioxidants. Despite phospholipid headgroup and acyl chain remodeling, these alterations do not counter the effect of temperature on LPO rates (i.e., LPO rates are generally not different among acclimation groups when normalized to phospholipid content and compared at a common temperature). Although absolute levels of PLOOH are higher in muscles from cold- than warm acclimated fish, this difference is lost when PLOOH levels are normalized to total phospholipid. Contents of vitamin E and two homologs of ubiquinone are more than four times higher in mitochondria prepared from oxidative muscle of warm- than cold-acclimated fish. Collectively, our data demonstrate that although phospholipid remodeling does not provide a means for offsetting thermal effects on rates of LPO, differences in phospholipid quantity ensure a constant proportion of LPO products with temperature variation. PMID- 25519740 TI - Breast ultrasound in the management of gynecomastia in Peutz-Jeghers syndrome in monozygotic twins: two case reports. AB - INTRODUCTION: Peutz-Jeghers syndrome is an autosomal dominant disease with incomplete penetrance and variable expression caused by germline mutation of serine threonine kinase 11/liver kinase B1; it is characterized by hamartomatous polyps in the gastrointestinal tract, mucocutaneous melanin pigmentation, and increased predisposition to neoplasms. In Peutz-Jeghers syndrome, bilateral Sertoli cell testicular tumors cause endocrine manifestations including gynecomastia and feminization. This study aimed to assess the role of breast ultrasound in the evaluation of the effectiveness of an innovative surgical approach. CASE PRESENTATION: This report presents a pair of European 9-year-old identical male twins with Peutz-Jeghers syndrome, bilateral prepubertal gynecomastia, and testicular multifocal calcifications. Both twins were treated with anastrozole for 2 years. After finishing treatment, both underwent subcutaneous mastectomy performed by the "modified" Webster technique. Breast examination and ultrasound were performed before and after the pharmacological and surgical treatment. A breast ultrasound scan before surgery showed bilateral gynecomastia in both patients. No solid nodular or cystic formations were present on either side. After pharmacological therapy and surgical glandular removal, a breast examination showed a significant reduction in breast volume; 1 year after surgery, a breast ultrasound scan of both patients showed a total absence of glandular parenchyma, with muscle planes well represented. CONCLUSIONS: Breast examination and ultrasound have proved to be a valid approach in the assessment of the treatment of prepubertal gynecomastia because they allow the efficacy of the pharmacological and surgical treatment to be evaluated in a multidisciplinary approach to one of the most frequent endocrine manifestations of Peutz-Jeghers syndrome. PMID- 25519738 TI - Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ. AB - It is critical for cells to maintain a homeostatic balance of water and electrolytes because disturbances can disrupt cellular function, which can lead to profound effects on the physiology of an organism. Dehydration can be classified as either intra- or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra- and extracellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT1R) and angiotensin type 2 receptors (AT2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the mitogen-activated protein (MAP) kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the subfornical organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and ANG II. PMID- 25519741 TI - Pain assessment for people with dementia: a systematic review of systematic reviews of pain assessment tools. AB - BACKGROUND: There is evidence of under-detection and poor management of pain in patients with dementia, in both long-term and acute care. Accurate assessment of pain in people with dementia is challenging and pain assessment tools have received considerable attention over the years, with an increasing number of tools made available. Systematic reviews on the evidence of their validity and utility mostly compare different sets of tools. This review of systematic reviews analyses and summarises evidence concerning the psychometric properties and clinical utility of pain assessment tools in adults with dementia or cognitive impairment. METHODS: We searched for systematic reviews of pain assessment tools providing evidence of reliability, validity and clinical utility. Two reviewers independently assessed each review and extracted data from them, with a third reviewer mediating when consensus was not reached. Analysis of the data was carried out collaboratively. The reviews were synthesised using a narrative synthesis approach. RESULTS: We retrieved 441 potentially eligible reviews, 23 met the criteria for inclusion and 8 provided data for extraction. Each review evaluated between 8 and 13 tools, in aggregate providing evidence on a total of 28 tools. The quality of the reviews varied and the reporting often lacked sufficient methodological detail for quality assessment. The 28 tools appear to have been studied in a variety of settings and with varied types of patients. The reviews identified several methodological limitations across the original studies. The lack of a 'gold standard' significantly hinders the evaluation of tools' validity. Most importantly, the samples were small providing limited evidence for use of any of the tools across settings or populations. CONCLUSIONS: There are a considerable number of pain assessment tools available for use with the elderly cognitive impaired population. However there is limited evidence about their reliability, validity and clinical utility. On the basis of this review no one tool can be recommended given the existing evidence. PMID- 25519742 TI - A gas-phase amplified quartz crystal microbalance immunosensor based on catalase modified immunoparticles. AB - A novel signal amplification strategy for quartz crystal microbalance (QCM) based on catalytic gas generation was developed to construct an ultrasensitive immunosensor for the detection of proteins (immunoglobulin G, IgG, used as a model). A catalase modified immunoparticle was prepared to form a sandwich-type immunocomplex with the IgG and anti-IgG antibodies that were immobilized on the QCM sensor. The amount of immunoparticles on the sensor surface was thus controlled by the IgG concentration. Then H2O2 was added and catalyzed by catalase for oxygen generation. The generated oxygen replaced some of the liquid on the sensor surface, leading to the change in the shear modulus of the immunocomplex layer and the apparent viscosity and density of the liquid layer. Due to the ultrasensitive response of QCM to these changes, a significant frequency shift related to the IgG concentration was achieved. Different parameters, including the flow cell structure, operation temperature, immunoparticle concentration, and H2O2 concentration were optimized to achieve steady and efficient frequency shifts. Under the optimal conditions, the proposed gas-phase amplified QCM sensor could achieve up to 72 times improvement of detection sensitivity compared to the label-free sensor as a control, in the concentration range of 0.1-3.0 MUg mL(-1). The detection limit was also reduced from 236 ng mL(-1) to 51.0 ng mL(-1) at the 3Sblank level. PMID- 25519744 TI - [70 Years after the End of World War II and the National Socialist Dictatorship - The Final Names of the 'Memorial File Jewish Ophthalmologists']. PMID- 25519743 TI - Transferrin receptor-targeted theranostic gold nanoparticles for photosensitizer delivery in brain tumors. AB - Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient, but also nonspecific to brain stroma. These are major limitations in the effective treatment of brain cancer. Transferrin peptide (Tfpep) targeted gold nanoparticles (Tfpep-Au NPs) loaded with the photodynamic pro-drug, Pc 4, have been designed and compared with untargeted Au NPs for delivery of the photosensitizer to brain cancer cell lines. In vitro studies of human glioma cancer lines (LN229 and U87) overexpressing the transferrin receptor (TfR) show a significant increase in cellular uptake for targeted conjugates as compared to untargeted particles. Pc 4 delivered from Tfpep-Au NPs clusters within vesicles after targeting with the Tfpep. Pc 4 continues to accumulate over a 4 hour period. Our work suggests that TfR-targeted Au NPs may have important therapeutic implications for delivering brain tumor therapies and/or providing a platform for noninvasive imaging. PMID- 25519745 TI - An optimal polymerization process for low mean molecular weight HBOC with lower dimer. AB - The new research tried to improve the distribution of molecular weight of Hb based oxygen carriers (HBOC), a bottleneck of glutaraldehyde (GDA)-polymerization process. The orthogonal experiments were done on the basis of the early study of human placenta Hemoglobin (Hb)-crosslinked-GDA and three factors were selected including the molar ratio of GDA and Hb, Hb concentration, and the rate of the feeding GDA. The optimal match condition of polymerization process prepared for the purpose of lower mean molecular weight, content of super-weight molecule, and the content of dimer. The results showed that the molar ratio of GDA and Hb was the greatest influencing factor on the molecular weight distribution of polymerized-Hb, followed by the Hb concentration, and the last is the rate of feeding GDA. The optimum matching conditions had reached the objective that the mean molecular weight with 155.54 +/- 5.79, the content of dimer with 17.23 +/- 3.71, and content of super-weight molecule with 0.17 +/- 0.09, and the results can be repeated in the 30 times expansion experiments. PMID- 25519746 TI - Extensive xanthomas with severe coronary artery disease in a young patient with familial hypercholesterolemia. PMID- 25519747 TI - A mimic of hypertrophic cardiomyopathy. PMID- 25519748 TI - Endogenously produced Indian Hedgehog regulates TGFbeta-driven chondrogenesis of human bone marrow stromal/stem cells. AB - Human bone marrow stromal/stem cells (hBMSCs) have an inherent tendency to undergo hypertrophy when induced into the chondrogenic lineage using transforming growth factor-beta 1 (TGFbeta) in vitro, reminiscent of what occurs during endochondral ossification. Surprisingly, Indian Hedgehog (IHH) has received little attention for its role during hBMSC chondrogenesis despite being considered a master regulator of endochondral ossification. In this study, we investigated the role that endogenously produced IHH plays during hBMSC chondrogenesis. We began by analyzing the expression of IHH throughout differentiation using quantitative polymerase chain reaction and found that IHH expression was upregulated dramatically upon chondrogenic induction and peaked from days 9 to 12 of differentiation, which coincided with a concomitant increase in the expression of chondrogenesis- and hypertrophy-related markers, suggesting a potential role for endogenously produced IHH in driving hBMSC chondrogenesis. More importantly, pharmacological inhibition of Hedgehog signaling with cyclopamine or knockdown of IHH almost completely blocked TGFbeta1-induced chondrogenesis in hBMSCs, demonstrating that endogenously produced IHH is necessary for hBMSC chondrogenesis. Furthermore, overexpression of IHH was sufficient to drive chondrogenic differentiation, even when TGFbeta signaling was inhibited. Finally, stimulation with TGFbeta1 induced a significant and sustained upregulation of IHH expression within 3 h that preceded an upregulation in all cartilage-related genes analyzed, and knockdown of IHH blocked the effects of TGFbeta1 entirely, suggesting that the effects of TGFbeta1 are being mediated through endogenously produced IHH. Together, our findings demonstrate that endogenously produced IHH is playing a critical role in regulating hBMSC chondrogenesis. PMID- 25519749 TI - TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. AB - The Therapeutic Intensification in De Novo Leukaemia (TIDEL)-II study enrolled 210 patients with chronic phase chronic myeloid leukemia (CML) in two equal, sequential cohorts. All started treatment with imatinib 600 mg/day. Imatinib plasma trough level was performed at day 22 and if <1000 ng/mL, imatinib 800 mg/day was given. Patients were then assessed against molecular targets: BCR-ABL1 <=10%, <=1%, and <=0.1% at 3, 6, and 12 months, respectively. Cohort 1 patients failing any target escalated to imatinib 800 mg/day, and subsequently switched to nilotinib 400 mg twice daily for failing the same target 3 months later. Cohort 2 patients failing any target switched to nilotinib directly, as did patients with intolerance or loss of response in either cohort. At 2 years, 55% of patients remained on imatinib, and 30% on nilotinib. Only 12% were >10% BCR-ABL1 at 3 months. Confirmed major molecular response was achieved in 64% at 12 months and 73% at 24 months. MR4.5 (BCR-ABL1 <=0.0032%) at 24 months was 34%. Overall survival was 96% and transformation-free survival was 95% at 3 years. This trial supports the feasibility and efficacy of an imatinib-based approach with selective, early switching to nilotinib. This trial was registered at www.anzctr.org.au as #12607000325404. PMID- 25519751 TI - How I use fibrinogen replacement therapy in acquired bleeding. AB - Fibrinogen is a critical protein for hemostasis and clot formation. However, transfusion guidelines have variable recommendations for maintaining fibrinogen levels in bleeding patients. An increasing number of studies support the practice of fibrinogen replacement therapy for acquired coagulopathies, and additional studies are underway. Fibrinogen therapy can be administered with cryoprecipitate or fibrinogen concentrates, and clinical practice varies according to their availability and licensing status. Fibrinogen concentrate therapy has been studied in animal models and clinical trials and supports the critical role of fibrinogen repletion in bleeding patients. Point-of-care testing will have an important role in guiding fibrinogen replacement for hemostatic therapy in clinical settings such as cardiovascular surgery, postpartum hemorrhage, and trauma. Fibrinogen therapy is an important component of a multimodal strategy for the treatment of coagulopathic bleeding. PMID- 25519750 TI - Hepcidin is suppressed by erythropoiesis in hemoglobin E beta-thalassemia and beta-thalassemia trait. AB - Hemoglobin E (HbE) beta-thalassemia is the most common severe thalassemia syndrome across Asia, and millions of people are carriers. Clinical heterogeneity in HbE beta-thalassemia is incompletely explained by genotype, and the interaction of phenotypic variation with hepcidin is unknown. The effect of thalassemia carriage on hepcidin is also unknown, but it could be relevant for iron supplementation programs aimed at combating anemia. In 62 of 69 Sri Lankan patients with HbE beta-thalassemia with moderate or severe phenotype, hepcidin was suppressed, and overall hepcidin inversely correlated with iron accumulation. On segregating by phenotype, there were no differences in hepcidin, erythropoiesis, or hemoglobin between severe or moderate disease, but multiple linear regression showed that erythropoiesis inversely correlated with hepcidin only in severe phenotypes. In moderate disease, no independent predictors of hepcidin were identifiable; nevertheless, the low hepcidin levels indicate a significant risk for iron overload. In a population survey of Sri Lankan schoolchildren, beta-thalassemia (but not HbE) trait was associated with increased erythropoiesis and mildly suppressed hepcidin, suggesting an enhanced propensity to accumulate iron. In summary, the influence of erythropoiesis on hepcidin suppression associates with phenotypic disease variation and pathogenesis in HbE beta-thalassemia and indicates that the epidemiology of beta thalassemia trait requires consideration when planning public health iron interventions. PMID- 25519753 TI - Immunocompetence and high metabolic rates enhance overwinter survival in the root vole, Microtus oeconomus. AB - Despite its presumed significance, the association between immune defence, energy expenditures and overwinter survival is rarely studied. We analysed individual variation in immunocompetence quantified as neutrophil-to-lymphocyte ratio (N/L), total white blood cells (WBC) and natural antibody levels, along with resting (RMR) and peak metabolic rates (PMR) and mortality during three consecutive winter seasons in a natural population of the root vole, Microtus oeconomus. In early winter, WBC count was negatively correlated with RMR, whereas N/L ratio was negatively correlated with swim-elicited PMR. We suggest that while the first correlation reflected the trade-off between energy allocation in immunocompetence and other metabolically demanding processes, the latter correlation stemmed from stress-induced immunosuppression elicited by the necessity to cope with swimming in frequently flooded habitat. In addition, the analysis carried out during the first year of study characterized by a high population density and prevalence of infestation with a blood parasite--Babesia spp., showed that its intensity was inversely correlated with the N/L ratio. In summary, our results suggest that elevated N/L ratio increases the winter survival of free-ranging rodents by increasing their ability to cope with parasitic infections. PMID- 25519752 TI - Biological significance of HLA locus matching in unrelated donor bone marrow transplantation. AB - We hypothesized that the compatibility of each HLA loci between donor and patient induced divergent transplant-related immunologic responses, which attributed to the individualized manifestation of clinical outcomes. Here, we analyzed 7898 Japanese pairs transplanted with T-cell-replete marrow from an unrelated donor with complete HLA allele typing data. Multivariable competing risk regression analyses were conducted to evaluate the relative risk (RR) of clinical outcomes after transplantation. A significant RR of HLA allele mismatch compared with match was seen with HLA-A, -B, -C, and -DPB1 for grade III-IV acute graft-versus host disease (GVHD), and HLA-C for chronic GVHD. Of note, only HLA-C and HLA-DPB1 mismatch reduced leukemia relapse, and this graft-versus-leukemia effect of HLA DPB1 was independent of chronic GVHD. HLA-DRB1 and HLA-DQB1 double (DRB1_DQB1) mismatch was revealed to be a significant RR for acute GVHD and mortality, whereas single mismatch was not. Thus, the number of HLA-A, -B, -C, -DPB1, and DRB1_DQB1 mismatches showed a clear-cut risk difference for acute GVHD, whereas the number of mismatches for HLA-A, -B, -C, and DRB1_DQB1 showed the same for mortality. In conclusion, we determined the biological response to HLA locus mismatch in transplant-related immunologic events, and provide a rationale for use of a personalized algorithm for unrelated donor selection. PMID- 25519754 TI - Developmental stress can uncouple relationships between physiology and behaviour. AB - Phenotypic correlations (rP) have frequently been observed between physiological and behavioural traits, and the nature of these associations has been shown to be modulated by a range of environmental stressors. Studies to date have examined the effects of acute stressors on physiology-behaviour interrelations, but the potential for permanent changes induced by exposure to stress during development remains unexplored. We exposed female zebra finches to dietary restriction during the nestling stage and tested how this affected rP among a variety of physiological traits (haematocrit, stress-induced corticosterone level and basal metabolic rate (BMR)) and behavioural traits (activity and feeding rates in novel and familiar environments). Developmental stress completely uncoupled the relationship between activity in a novel environment and two physiological traits: haematocrit and BMR. This suggests that nutritionally based developmental stress has provoked changes in the energy budget that alleviate the trade-off between maintenance (BMR) and locomotor activities. PMID- 25519755 TI - Changing factors associated with parent activation after pediatric hematopoietic stem cell transplant. AB - PURPOSE: To identify factors associated with parent activation in parents of children undergoing pediatric hematopoietic stem cell transplant (HSCT) in the 6 months following HSCT, and to address if their association with parent activation changes over time. METHODS: Measures for this analysis, including the Parent Patient Activation Measure (Parent-PAM), were completed by parents (N = 198) prior to their child's HSCT preparative regimen and again at 6 months post-HSCT. Clinical data were also collected. A repeated measures model was built to estimate the association between clinical and demographic factors and parent well being on Parent-PAM scores. Interactions with time were considered to test for changing effects over time. RESULTS: Throughout the HSCT course, older parent age was associated with lower Parent-PAM scores (beta = -0.29, p = 0.02) and never being married was associated with higher scores (versus married, beta = 12.27, p = 0.03). While higher parent emotional functioning scores were not associated with activation at baseline, they were important at 6 months (baseline, beta = 0.002, p = 0.96; interaction, beta = 0.14, p = 0.03). At baseline, longer duration of illness was associated with increased activation, but this effect diminished with time (baseline, beta = 3.29, p = 0.0002; interaction, beta = 2.40, p = 0.02). Activation levels dropped for parents of children who went from private to public insurance (baseline, beta = 2.95, p = 0.53; interaction, beta = -13.82, p = 0.004). Clinical events did not affect Parent-PAM scores. CONCLUSIONS: Our findings reveal important changes in the factors associated with parent activation in the first 6 months after pediatric HSCT. These findings may reflect the emotional and financial toll of pediatric HSCT on parent activation. PMID- 25519756 TI - Stopping paclitaxel premedication after two doses in patients not experiencing a previous infusion hypersensitivity reaction. AB - PURPOSE: Paclitaxel-based chemotherapy continues to be an integral component of breast cancer treatment. Prolonged use of paclitaxel may result in repeated doses of premedications that can have unwanted side effects. Infusion hypersensitivity reactions occurring beyond the second dose of paclitaxel are infrequent and not well characterized. We previously published the results of a small, prospective pilot trial demonstrating the safety and feasibility of discontinuing premedications in patients who received the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction. In this study, we aimed to retrospectively characterize the incidence of rescue medication using this abbreviated premedication regimen in our institution following the publication of the pilot study. METHODS: Patients with stages I-IV breast cancer who received paclitaxel from January 2011 through June 2013 were screened for eligibility. Patients who did not experience an infusion hypersensitivity reaction with their first or second dose of paclitaxel and discontinued paclitaxel premedication for subsequent doses were included in this analysis. The primary endpoint was to estimate the incidence of rescue medication use for the treatment of paclitaxel infusion hypersensitivity during doses three to six of paclitaxel in the study population. RESULTS: In total, 449 patients received paclitaxel-based chemotherapy for the treatment of breast cancer during the interval time period. After receiving the first two doses of paclitaxel-based chemotherapy without experiencing an infusion hypersensitivity reaction, 234 breast cancer patients had their premedications discontinued for all remaining paclitaxel doses. These patients tolerated future paclitaxel doses without severe or life-threatening complications related to infusion hypersensitivity. The majority of patients did not have any symptoms of an infusion reaction, with only two of these patients requiring rescue medication to treat an infusion hypersensitivity reaction with subsequent paclitaxel doses (0.85; 95 % confidence interval (CI), 0.10-3.05 %). CONCLUSIONS: Discontinuation of paclitaxel premedications in breast cancer patients who have not experienced an infusion hypersensitivity reaction with the first two doses of paclitaxel is not associated with increased rate of rescue medication use for infusion hypersensitivity. PMID- 25519757 TI - Evaluation of the progression and treatment of experimental periodontitis in rats subjected to chemotherapy with 5-fluorouracil. AB - AIM: This study aimed to evaluate the progression and treatment of experimental periodontitis (EP) in rats treated with 5-fluorouracil (5-FU). MATERIALS AND METHODS: One-hundred fifty rats were divided into groups: C--control, EP--EP induction, EP/scaling and root planing (SRP)--EP induction and SRP, 5-FU- systemic treatment with 5-FU, 5-FU/EP--systemic treatment with 5-FU and EP induction, and 5-FU/EP/SRP--systemic treatment with 5-FU, EP induction and SRP. Systemic treatment consisted of the administration of 80 and 40 mg/kg of 5-FU. The animals were euthanised at 7, 15 and 30 days. Histological and immunohistochemical analyses for the detection of the receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG) and tartrate resistant acid phosphatase (TRAP) were performed at the furcation region. A histometric analysis was performed to evaluate the percentage of bone in the furcation region (PBF). RESULTS: In the 5-FU/EP and 5-FU/EP/SRP groups, there was less PBF, greater breakdown of periodontal tissues and increased immunostaining for RANKL compared with the EP and EP/SRP groups. CONCLUSION: It can be concluded that 5-FU aggravates PE progression, impairs the host response to SRP mechanical therapy and does not seem to cause changes in the healthy periodontium. PMID- 25519758 TI - Targeting those with decreased meaning and peace: a supportive care opportunity. AB - PURPOSE: To evaluate if an individual's level of meaning/peace (M/P) predicts various quality of life (QOL) and mental well-being measures. To identify targets that might enhance the overall spiritual well-being and QOL of ovarian cancer patients. METHODS: Multi-site analysis of women with newly diagnosed stages II-IV ovarian, primary peritoneal, or fallopian tube cancer. Patients completed the following surveys: Functional Assessment of Chronic Illness Therapy-Ovarian (FACT O), Functional Assessment of Chronic Illness Therapy-Spiritual (FACIT-Sp), Edmonton Symptom Assessment System (ESAS), Hospital Anxiety and Depression Scale (HADS), Templer's Death Anxiety Scale (DAS), Herth Hope Index (HHI), and Brief Multidimensional Measure of Religiousness/Spirituality (BMMRS). Linear regression models were created to examine the effect of M/P (FACIT-Sp) upon QOL, symptoms, and other measures of mental well-being. These models adjusted for the effect of site, race, age, stage, anaphylaxis to chemotherapy, and partner status as potential confounders. RESULTS: This study enrolled 104 patients from three separate sites. After adjusting for potential confounders, it was found that higher M/P predicted better QOL (FACT-O) (p < 0.0001). Higher M/P also predicted decreased death anxiety, depression, and anxiety (p <= 0.005). Finally, higher M/P predicted increased hope and coping scores (p <= 0.0005). CONCLUSIONS: Level of M/P is associated with several important mental and physical health states. This information may allow providers to identify patients at increased risk for mental/physical distress and may facilitate early referral to targeted psychotherapy interventions focused on improving patient QOL and decreasing anxiety and depression. PMID- 25519759 TI - New fat-derived products for treating skin-induced lesions of scleroderma in nude mice. AB - INTRODUCTION: Scleroderma is characterized by cutaneous manifestations that mainly affect the hands, arms and face. As of today, there is no treatment for fibrotic skin lesions of scleroderma. Previously we generated and validated a model of scleroderma-like skin sclerosis in nude mice, appropriate to inject human derived products. We showed that the subcutaneous injection of micro-fat (MF), purified and injected using small caliber cannulas, have anti-fibrotic and pro-angiogenic effects and appears more suitable for the treatment of skin lesions of scleroderma compared to the gold standard (Coleman's technique or macro-fat). Here we compared the long-term efficacy of micro-fat "enriched" with other therapeutic products including the stromal vascular fraction (SVF) of fat and platelet-rich plasma (PRP) from blood in our murine model of scleroderma. METHODS: We used 72 nude mice in this study. We formed six experimental groups: Macro-fat, MF, SVF, PRP, MF + SVF, MF + PRP. This project has three phases: i) Induction of skin sclerosis by daily subcutaneous injections of bleomycin (BLM) for 4 weeks in nude mice; ii) Purification and injection of the different cell therapy products; iii) Histological analyses done 8 weeks post-injections. RESULTS: MF + SVF and MF + PRP significantly reversed dermal and epidermal sclerosis (P <0.01). Macro-fat, SVF, PRP only corrected the dermal sclerosis (P <0.05). Epidermal sclerosis was reduced in treatments containing MF (P <0.01). MF was more stable. Products containing the SVF were associated with a significant increase of the local vascularization (P <0.01). CONCLUSIONS: All tested substances were effective in treating skin-induced lesions of scleroderma with different levels of fibrosis and vascular improvement; MF derived products are more stable and SVF demonstrated better pro-angiogenic effects. The observed efficacy of this combination of products in the animal model provides a rationale for potential clinical applications to treat human disease. PMID- 25519760 TI - Identification of chilling stress-responsive tomato microRNAs and their target genes by high-throughput sequencing and degradome analysis. AB - BACKGROUND: MicroRNAs (miRNAs) are a class of noncoding small RNAs (sRNAs) that are 20-24 nucleotides (nt) in length. Extensive studies have indicated that miRNAs play versatile roles in plants, functioning in processes such as growth, development and stress responses. Chilling is a common abiotic stress that seriously affects plants growth and development. Recently, chilling-responsive miRNAs have been detected in several plant species. However, little is known about the miRNAs in the model plant tomato. 'LA1777' (Solanum habrochaites) has been shown to survive chilling stress due to its various characteristics. RESULTS: Here, two small RNA libraries and two degradome libraries were produced from chilling-treated (CT) and non-chilling-treated (NT) leaves of S. habrochaites seedlings. Following high-throughput sequencing and filtering, 161 conserved and 236 novel miRNAs were identified in the two libraries. Of these miRNAs, 192 increased in the response to chilling stress while 205 decreased. Furthermore, the target genes of the miRNAs were predicted using a degradome sequencing approach. It was found that 62 target genes were cleaved by 42 conserved miRNAs, while nine target genes were cleaved by nine novel miRNAs. Additionally, nine miRNAs and six target genes were validated by quantitative real-time PCR (qRT-PCR). Target gene functional analysis showed that most target genes played positive roles in the chilling response, primarily by regulating the expression of anti-stress proteins, antioxidant enzyme and genes involved in cell wall formation. CONCLUSIONS: Tomato is an important model plant for basic biological research. In this study, numerous conserved and novel miRNAs involved in the chilling response were identified using high-throughput sequencing, and the target genes were analyzed by degradome sequencing. The work helps identify chilling-responsive miRNAs in tomato and increases the number of identified miRNAs involved in chilling stress. Furthermore, the work provides a foundation for further study of the regulation of miRNAs in the plant response to chilling stress. PMID- 25519761 TI - Comparison of two-stage open versus percutaneous pedicle screw fixation in treating pyogenic spondylodiscitis. AB - BACKGROUND: Percutaneous pedicle screw instrumentation is a minimally invasive surgical technique; however, the effects of using percutaneous pedicle screw fixation in treating patients with spinal infections have not yet been well demonstrated. The aim of this study, therefore, was to determine whether percutaneous posterior pedicle screw instrumentation is superior to the traditional open approach in treating pyogenic spondylodiscitis. METHODS: We retrospectively reviewed data for 45 patients treated for pyogenic spondylodiscitis with anterior debridement and interbody fusion followed by a second-stage procedure involving either traditional open posterior pedicle screw fixation or percutaneous posterior pedicle screw fixation. Twenty patients underwent percutaneous fixation and 25 patients underwent open fixation. Demographic, operative, and perioperative data were collected and analyzed. RESULTS: The average operative time for the percutaneous procedure was 102.5 minutes, while the average time for the open procedure was 129 minutes. The average blood loss for the percutaneous patients was 89 ml versus a 344.8 ml average for the patients in the open group. Patients who underwent the minimally invasive surgery had lower visual analogue scale scores and required significantly less analgesia afterwards. After two years of follow-up, neither recurrent infection nor intraoperative complications, such as wound infection or screw loosening, were found in the percutaneous group. Moreover, there was no significant difference in outcome between the two groups in terms of Oswestry Disability Index scores. CONCLUSIONS: Anterior debridement and interbody fusion with bone grafting followed by minimally invasive percutaneous posterior instrumentation is an alternative treatment for pyogenic spondylodiscitis which can result in less intraoperative blood loss, shorter operative time, and reduced postoperative pain with no adverse effect on infection control. PMID- 25519762 TI - Long-range magnetic interaction and frustration in double perovskites Sr2NiIrO6 and Sr2ZnIrO6. AB - One often counts the nearest neighbouring (NN) exchange interactions for understanding of a magnetic insulator. Here we present first-principles calculations for the newly synthesized double perovskites Sr2NiIrO6 and Sr2ZnIrO6, and we find that the 2NN Ir-Ir antiferromagnetic coupling is even stronger than the 1NN Ni-Ir ferromagnetic one. Thus, the leading antiferromagnetic interactions in the fcc Ir sublattice give rise to a magnetic frustration. Sr2NiIrO6 and Sr2ZnIrO6 hence appear very similarly as a distorted low-temperature antiferromagnet (probably, of type III). This work highlights the long-range magnetic interactions of the delocalized 5d electrons, and it also addresses why the spin-orbit coupling is ineffective here. PMID- 25519763 TI - Mind-body interventions: applications and potential opportunities for health education practice. AB - Mind-body interventions (MBIs) have become increasingly popular. In the current article, we examine the potential role of MBIs for improving health and promoting wellness. We first describe typologies of MBIs and prevalence of their use. We also examine the efficacy evidence about how MBIs offer many psychological and physiological benefits, including reductions in disease symptoms and improvements in coping, behavior regulations, quality of life, and well-being. We further discuss how the health education discipline has long supported the inherent holism of the human being, the importance of healing potential of the mind on one's health, and values capacity for self-regulation and describe the potential opportunities for health educators as it relates to MBIs. Finally, we discuss implications for the profession of health education and promotion. PMID- 25519764 TI - Human serum paraoxonase-1 (hPON1): in vitro inhibition effects of moxifloxacin hydrochloride, levofloxacin hemihidrate, cefepime hydrochloride, cefotaxime sodium and ceftizoxime sodium. AB - In this study, we investigated the effects of antibacterial drugs (moxifloxacin hydrochloride, levofloxacin hemihidrate, cefepime hydrochloride, cefotaxime sodium and ceftizoxime sodium) on human serum paraoxonase-1 (hPON1) enzyme activity from human serum in vitro conditions. For this purpose, hPON1 enzyme was purified from human serum using simple chromatographic methods. The antibacterial drugs exhibited inhibitory effects on hPON1 at low concentrations. Ki constants were calculated to be 2.641 +/- 0.040 mM, 5.525 +/- 0.817 mM, 35.092 +/- 1.093 mM, 252.762 +/- 5.749 mM and 499.244 +/- 10.149 mM, respectively. The inhibition mechanism of moxifloxacin hydrochloride was competitive, whereas levofloxacin hemihidrate, cefepime hydrochloride, cefotaxime sodium and ceftizoxime sodium were noncompetitive inhibitors. PMID- 25519765 TI - Effects of botulinum neurotoxin on spatio-temporal gait parameters of patients with chronic stroke: a prospective open-label study. AB - BACKGROUND: Nowadays, administration of botulinum neurotoxin type A is considered a safe, well tolerated and effective treatment for muscles tone reduction in focal spasticity care. Lack of evidence regards instead its functional role on gait parameters, as well patterns. AIM: To assess the botulinum neurotoxin treatment efficacy on chronic poststroke subjects, in order to investigate its functional effects on spatio-temporal gait parameters, in addition to the evaluation of spasticity grade based on clinical scales. DESIGN: A prospective open-label study along 16-weeks trials. SETTING: Outpatient neurophysiology rehabilitation structure and laboratory of movement and gait analysis. POPULATION: Twenty chronic poststroke patients, suffering from equinovarus foot deformity, with a stabilized hemiparesis were recruited according to inclusion criteria of the protocol. METHODS: Single neurotoxin-based local intramuscular injections were given according to a specific protocol concerning both the considered muscles and the relative toxin doses, with a maximum total dose ranged between 200 U and 400 U. Patients were observed both at baseline (t0) and for 4 following monthly visits (t1, t2, t3, t4) after injections at baseline. Gait analysis sessions were performed at each visit, by means of a video-cameras based system and body reflective markers attached to the body, based on a protocol. Authors focus on both global and local gait temporospatial parameters, such as walking speed, stride-length, cadence, stride-time, step-width, single limb support, double support and limp index to point out the functional changes due to the treatment. For comparison prior to and after the treatment, clinical scales like Modified Ashworth Scale, Berg Balance Scale and Rivermead Mobility Index have been also considered. RESULTS: Subsequent to the neurotoxin intramuscular injections, patients reported statistical significant gait improvements after 90 days (t3) regarding temporospatial parameters: (P<0.05) for walking speed, single limb support and double support and (P<0.10) for stride-length, stride-time, cadence and step-width. CONCLUSION: The botulinum neurotoxin treatment has demonstrated its efficacy for a functional recovery of gait, as pointed out by a statistically significant improvement of some spatio-temporal parameters. Thus, the analyzed changes reveal an improved balance and self-confidence in gait. Studies involving a wider population data are nevertheless needed to better confirm this efficacy. CLINICAL REHABILITATION IMPACT: The poststroke botulinum neurotoxin-based treatment is a safe and potentially useful neurorehabilitative approach for the analyzed data. PMID- 25519766 TI - Impact of intraoperative magnetic resonance imaging and functional neuronavigation on surgical outcome in patients with gliomas involving language areas. AB - Balancing the benefit of extensive tumor resection with the consequence of potential postoperative language deficits remains a challenge in glioma surgery involving language areas. This study is designed to evaluate the impact of intraoperative magnetic resonance imaging (iMRI) and functional neuronavigation on surgical outcome in patients with gliomas involving language areas. Two hundred seventeen patients were prospectively enrolled, 124 in the study group underwent iMRI and functional neuronavigation-guided microsurgery and 93 in the control group underwent conventional navigation-guided microsurgery. Extent of tumor volume resection (EoR) and rate of gross total resection (rGTR) were calculated perioperatively. Aphasia quotient (AQ) was assessed to evaluate the change of language function perioperatively and at 6-month follow-up. Survival outcome for glioblastoma, including progression-free survival (PFS) and overall survival (OS), were recorded. In 198 glioma patients (112 in the study group and 86 in the control group), EoR (95.50 versus 89.85%, p < 0.001) and rGTR (69.60 versus 47.70%, p = 0.002) were significantly higher in the study group, and language functions were also better at 6-month follow-up in the study group (87.47 versus 78.73, p = 0.001). Furthermore, postoperative new aphasia occurred in 34.8% of the control group, whereas it occurred only in 2.3% of the study group (p < 0.001). In addition, PFS (12.5 versus 6.6 m, p = 0.003) and OS (19.6 versus 13.0 m, p < 0.001) for patients with glioblastomas were dramatically prolonged in the study group than in the control group. These results indicated that iMRI and functional neuronavigation may help maximize tumor resection, minimize language deficits in patients with gliomas involving language areas, and improve survival time for patients with glioblastomas. PMID- 25519768 TI - A sensitive detection of T4 polynucleotide kinase activity based on beta cyclodextrin polymer enhanced fluorescence combined with an exonuclease reaction. AB - A strategy for T4 polynucleotide kinase activity detection was proposed based on a beta-cyclodextrin polymer (polybeta-CD) and an exonuclease reaction. The fluorescence of pyrene enhanced by more than 10 times in the presence of polybeta CD, and a simple detection of T4 PNK was achieved with a detection limit of 0.02 units per mL. PMID- 25519767 TI - Modern Gamma Knife radiosurgery of vestibular schwannomas: treatment concept, volumetric tumor response, and functional results. AB - The objective of the present study was longitudinal evaluation of the volumetric tumor response and functional results after Gamma Knife radiosurgery of vestibular schwannomas, performed according to the modern standards of treatment. From October 2003 to September 2007, 133 consecutive patients with vestibular schwannomas were treated according to the concept of robotic Gamma Knife microradiosurgery, which is based on precise irradiation of the lesion, sparing adjacent structures, and delivery of the high radiation energy to the target. Multiple small-sized isocenters located within the border of the neoplasm were applied. The mean marginal dose was 11.5 Gy (range, 11-12 Gy). In total, 126 cases with a minimum posttreatment follow-up of 2 years (range, 2-7 years; median, 4 years) were analyzed. Temporary enlargement was noted in 25% of tumors at 6 months after radiosurgery. At 3 years of follow-up, tumor shrinkage, stabilization, and increase in volume were marked in 73%, 23%, and 4% of cases, respectively. All progressing lesions spontaneously stabilized later on and did not require additional management. In 3% of patients, transitory impairment of the facial nerve function was marked; however, neither its permanent dysfunction nor trigeminal neuropathy attributed to radiosurgery was noted. Impairment of hearing compared to its pretreatment level was revealed in 4%, 12%, 13%, and 16% of patients at 6 months, 1 year, 2 years, and 3 years after radiosurgery, respectively, and this trend was statistically significant (P = 0.0042). Overall, 77% of patients with serviceable hearing before treatment preserved it 3 years thereafter. In conclusion, modern Gamma Knife radiosurgery provides effective and safe management of vestibular schwannomas. Nevertheless, possible temporary tumor enlargement, delay of its growth arrest, transient dysfunction of the cranial nerves, and gradual deterioration of hearing after irradiation should be always taken into consideration. PMID- 25519770 TI - Research highlights: cell separation at the bench and beyond. AB - We highlight recent progress in applying micro- and nanotechnology enabled cell separations to life sciences and clinical use. Microfluidic systems operate on a scale that matches that of cells (10-100 MUm) and therefore allow interfacing and separations that are sensitive at this scale. Given the corresponding dimensions, it is not surprising that a wide array of microfluidic cell separation technologies have been developed using hydrodynamic, electrical, magnetic and optical forces, and have been applied to a range of biological and clinical problems in sample preparation. Passive separation approaches have distinct advantages for point of care applications or when downstream cell-based therapies are envisioned. We highlight a recent approach that allows for passive hydrodynamic filtering of cells over almost two orders of magnitude in flow conditions, which allowed the researchers to interface with a standard manual pipettor, creating a "microfluidic pipette tip". In a second work, passive separation by size yields distinct populations of mesenchymal stem cells that can be used therapeutically. The researchers report on other biophysical separations that would be expected to refine these cell populations further for the most efficacious cell-based therapies. In an intriguing twist, we highlight a creative idea in which stem cell populations could potentially also be extracted from a patient with less invasive surgeries, performing the separation using magnetic nanoparticles in vivo without bulk tissue disruption. New cell separation technologies will continue to be demonstrated, however, a major research thrust appears to be now developing these technologies to address unique application niches in point-of-care sample preparation for research and diagnostics or cell based therapies. PMID- 25519769 TI - Which frail older patients use online health communities and why? A mixed methods process evaluation of use of the Health and Welfare portal. AB - BACKGROUND: Frail older people often receive fragmented care from multiple providers. According to the literature, there is an urgent need for coordination of care. Online and eHealth tools are increasingly used to improve coordination. However, there are significant barriers to their implementation in frail older people. OBJECTIVE: Our aim was to (1) evaluate differences in use of a personal online health community (POHC) for frail older people in relation to personal characteristics, and (2) explore barriers and facilitators for use as experienced by older people and their informal caregivers, using the case of the Health and Welfare Information Portal (ZWIP). METHODS: This is a mixed methods study. For the quantitative analysis, we used POHC usage information (2 years follow-up) and baseline characteristics of frail older people. For the qualitative analysis, we used semistructured interviews with older people and their informal caregivers. Participants were recruited from 11 family practices in the east of the Netherlands and frail older people over 70 years. The ZWIP intervention is a personal online health community for frail older people, their informal caregivers, and their providers. ZWIP was developed at the Geriatrics Department of Radboud University Medical Center. We collected data on POHC use for 2 years as well as relevant patient characteristics. Interview topics were description of use, reasons for use and non-use, and user profiles. RESULTS: Of 622 frail patients in the intervention group, 290 were connected to ZWIP; 79 used ZWIP regularly (at least monthly). Main predictors for use were having an informal caregiver, having problems with activities of daily living, and having a large number of providers. Family practice level predictors were being located in a village, and whether the family practitioners had previously used electronic consultation and cared for a large percentage of frail older people. From 23 interviews, main reasons for use were perceiving ZWIP to be a good, quick, and easy way of communicating with providers and the presence of active health problems. Important reasons for non-use were lack of computer skills and preferring traditional means of consultation. CONCLUSIONS: Only 27.2% (79/290) of frail older enrolled in the POHC intervention used the POHC frequently. For implementation of personal online health communities, older people with active health problems and a sizable number of health care providers should be targeted, and the informal caregiver, if present, should be involved in the implementation process. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 11165483; http://www.controlled-trials.com/isrctn/pf/11165483 (Archived by WebCite at http://www.webcitation.org/6U3fZovoU). PMID- 25519771 TI - Comparative cost of illness analysis and assessment of health care burden of Duchenne and Becker muscular dystrophies in Germany. AB - BACKGROUND: Our study aimed to determine the burden of illness in dystrophinopathy type Duchenne (DMD) and Becker (BMD), both leading to progressive disability, reduced working capacity and high health care utilization. METHODS: A micro-costing method was used to examine the direct, indirect and informal care costs measuring the economic burden of DMD in comparison to BMD on patients, relatives, payers and society in Germany and to determine the health care burden of these diseases. Standardized questionnaires were developed based on predefined structured interview guidelines to obtain data directly from patients and caregivers using the German dystrophinopathy patient registry. The health-related quality of life (HRQOL) was analyzed using PedsQLTM Measurement Model. RESULTS: In total, 363 patients with genetically confirmed dystrophinopathies were enrolled. Estimated annual disease burden including direct medical/non-medical, indirect and informal care costs of DMD added up to ? 78,913 while total costs in BMD were ? 39,060. Informal care costs, indirect costs caused by loss of productivity and absenteeism of patients and caregivers as well as medical costs of rehabilitation services and medical aids were identified as the most important cost drivers. Total costs notably increased with disease progression and were consistent with the clinical severity; however, patients' HRQOL declined with disease progression. CONCLUSION: In conclusion, early assessments of economic aspects and the disease burden are essential to gain extensive knowledge of a distinct disease and above all play an important role in funding drug development programs for rare diseases. Therefore, our results may help to accelerate payer negotiations such as the pricing and reimbursement of new therapies, and will hopefully contribute to facilitating the efficient translation of innovations from clinical research over marketing authorization to patient access to a causative treatment. PMID- 25519772 TI - Predictors of Lowest Weight and Long-Term Weight Regain Among Roux-en-Y Gastric Bypass Patients. AB - BACKGROUND: Weight loss surgery (WLS) outcomes are poorly understood. This study aimed to evaluate the relationship of well-documented (e.g., health, diet, physical activity) and theoretically relevant variables (e.g., substance use and "food addiction") with both weight nadir and weight regain (WR) following WLS. METHODS: A sample of 97 Roux-en-Y gastric bypass patients (M time since surgery = 8.86 years) were surveyed about pre- and post-WLS weight, health, self-management behaviors, alcohol problems, and clinical symptoms. RESULTS: Patients lost a mean of 42 % (SD = 10.71 %) of total weight at weight nadir, but 26 % (SD = 19.66 %) of the lost weight was regained by the time of the survey. Correlates of lower weight nadir and WR differed considerably, with minor overlap. Weight nadir was associated with pre-WLS drug use and post-WLS medical comorbidities. WR, on the other hand, was associated with post-WLS adherence to dietary and physical activity modification. Post-WLS nocturnal eating, depression, and problematic alcohol use were also associated with WR. With all associated variables in regression models, number of post-WLS medical comorbidities (beta = -.313, p < 0.01) and post-WLS depression (beta = 0.325, p < 0.01) accounted for the most variance and remained as significant predictors of weight nadir and WR, respectively. CONCLUSIONS: While weight nadir was associated with relatively few and largely nonmodifiable variables, WR was significantly associated with adherence-related behaviors, mood symptoms, and pathological patterns of food and alcohol use, all of which are potentially modifiable. These findings underscore the importance of long-term behavioral and psychosocial monitoring after surgery. PMID- 25519773 TI - Long-Term Results of Primary Vertical Banded Gastroplasty. AB - BACKGROUND: The vertical banded gastroplasty (VBG) used to be a common restrictive bariatric procedure but has been abandoned by many due to a high failure rate, a high incidence of long-term complications, and the newer adjustable gastric band (AGB) and sleeve. However, potential favorable long-term results and the upcoming banded gastric bypass, with a similar mechanical outlet restriction and control of the pouch size, renewed our interest in the VBG. Therefore, we investigated the long-term outcome of primary VBG at the Catharina Hospital in the Netherlands. METHODS: Patients that underwent a primary VBG between 1998 and 2008 were included. Patients' characteristics, operative details, evolution on weight and comorbidities, complications, and outcome of revisions were reviewed. RESULTS: A total of 392 patients (80 % female) were reviewed with a mean age of 40 +/- 9 years and body mass index of 44 +/- 5 kg/m(2). Mean follow-up after VBG was 66 +/- 50 months and showed a mean excess weight loss (EWL) of 53 +/- 27 % and comorbidity reduction of 54 %. One hundred fifty-two patients (39 %) out of 227 patients (58 %) with long-term complaints underwent revisional surgery. Main reasons for revision were weight regain and vomiting/food intolerance. Analysis before revision showed an outlet dilatation (17 %), pouch dilatation (16 %), and outlet stenosis (10 %). After revision, an additional EWL of 23 % and 33 % further reduction in comorbidities was seen. CONCLUSIONS: Primary VBG has an acceptable EWL of 53 % and 55 % of comorbidities were improved. However, the high complication rate, often necessitating revision, underlines the limits of this procedure. PMID- 25519774 TI - Cyclosporine treatment in severe gestational pemphigoid. AB - Gestational pemphigoid, a rare autoimmune skin disease typically occurring during pregnancy, is caused by autoantibodies against collagen XVII. Clinically it is characterised by severe itching followed by erythematous and bullous lesions of the skin. Topical or oral glucocorticoids usually relieve symptoms, but in more severe cases systemic immunosuppressive treatments are needed. Data on immunosuppressive medication controlling gestational pemphigoid are sparse. We report 3 intractable cases of gestational pemphigoid treated with cyclosporine. PMID- 25519776 TI - Voronoi dipole moments for the simulation of bulk phase vibrational spectra. AB - We present the Voronoi tessellation of electron density data to obtain molecular dipole moments in bulk phase ab initio molecular dynamics simulations for the calculation of vibrational spectra. Opposed to the established scheme of maximally localized Wannier functions, this approach does not rely on computationally demanding localization procedures. Nevertheless, we show at the examples of methanol, benzene, and phenol that it provides infrared and Raman spectra of similar quality and is even superior in specific cases like the Raman spectra of benzene and phenol. We have also applied the Voronoi method to a mixture of the ionic liquid 1-ethyl-3-methylimidazolium acetate with water, and show that it is advantageous in systems with significant charge transfer. PMID- 25519777 TI - Self-relevant beauty evaluation: Evidence from an event-related potentials study. AB - This study examines the electrophysiological correlates of beauty evaluation when participants performed the self-reference task. About 13 (7 men, 6 women) undergraduates participated in the experiment using event-related potentials. Results showed that the response to self-relevant information was faster compared to other-relevant information and no significant differences for self-relevant relative to mother-relevant information were observed. Both physical and interior beauty words for self-relevant information showed an enhanced late positive component as compared to other-relevant information. Physical beauty for self relevant information yielded a larger late positive component in contrast to mother-relevant information but not for interior beauty. This study indicates that beauty is specific to the person who judges it though an individual and one's mother may hold similar views of interior beauty. PMID- 25519778 TI - Conservative versus interventional management for primary spontaneous pneumothorax in adults. AB - BACKGROUND: Primary spontaneous pneumothorax is widely managed according to size with interventional techniques based on practice guidelines. Interventional management is not without complications and observational data suggest conservative management works. The current guidelines are based on expert consensus rather than evidence, and a systematic review may help in identifying evidence for this practice. OBJECTIVES: The objective of the review is to compare conservative and interventional treatments of adult primary spontaneous pneumothorax for outcomes of clinical efficacy, tolerability and safety. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 6, 2014); MEDLINE via Ovid SP (1920 to 26th June 2014); EMBASE via Ovid SP (1947 to 26th June 2014); CINAHL via EBSCO host (1980 to 26th June 2014); and ISI Web of Science (1945 to 26th June 2014). We searched ongoing trials via the relevant databases and contacted authors. We also searched the 'grey literature'. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and we accepted quasi-RCTs if a systematic method of allocation was used. Participants were limited to adults aged 18 to 50 years, with their first symptomatic primary spontaneous pneumothorax with radiological evidence and no underlying lung disease. DATA COLLECTION AND ANALYSIS: Two of five authors independently reviewed all studies in the search criteria and made inclusions and exclusions according to the selection criteria. No statistical methods were necessary as there were no included trials. MAIN RESULTS: We identified 358 studies with duplicates removed. There were three potentially relevant studies that we excluded as they were not randomized controlled trials. There was one ongoing trial that was relevant and we contacted the authors and confirmed the study is ongoing at June 2014. We will update this review when this ongoing study is completed. AUTHORS' CONCLUSIONS: There are no completed randomized controlled trials comparing conservative and interventional management for primary spontaneous pneumothorax in adults. There is a lack of high-quality evidence for current guidelines in management and a need for randomized controlled trials comparing conservative and interventional management for this condition. PMID- 25519779 TI - Poor functional recovery after delirium is associated with other geriatric syndromes and additional illnesses. AB - BACKGROUND: Delirious individuals are at increased risk for functional decline, institutionalization and death. Delirium is also associated with other geriatric syndromes, behavioral care issues, and new illnesses. The objectives of this study were to determine how often certain geriatric syndromes, care issues, and additional diagnoses occur in delirious individuals, and to see whether they correlate with worse functional recovery. METHODS: Consecutive delirious older medical in-patients (n = 343) were followed for the occurrence of geriatric syndromes (falls, pressure ulcers, poor oral intake, and aspiration), care issues (refusing treatments or care, need for sitters, security services, physical restraints, and new neuroleptic medications) and additional diagnoses occurring after the third day of admission. Poor functional recovery was defined by any one of death, permanent institutionalization or increased dependence for activities of daily living (ADLs) at discharge or three months after discharge from hospital, elicited through chart review or a follow-up telephone interview. RESULTS: Poor functional recovery was seen in 237 (69%) delirious patients. Geriatric syndromes and additional illnesses were common and associated with poor functional recovery (falls in 21%, adjusted OR 2.27; possible aspiration in 26%, adjusted OR 3.06; poor oral intake in 49%, adjusted OR = 2.31; additional illnesses in 38%, adjusted OR 3.54). Care issues were also common (range 9%-54%) but not associated with poor recovery. CONCLUSIONS: Geriatric syndromes, behavioral care issues and additional illnesses are common in delirium. Future studies should assess whether monitoring for and intervening against geriatric syndromes and additional illnesses may improve functional outcomes after delirium. PMID- 25519780 TI - Oxidative stress in songbirds exposed to dietary methylmercury. AB - Long-term, sublethal methylmercury exposure can cause reproductive depression, immune suppression, endocrine disruption and other problems in birds. We used two biomarkers to detect oxidative stress in livers of zebra finches (Taeniopygia guttata) developmentally exposed to sublethal levels of dietary methylmercury (0.0, 0.3, 0.6, 1.2, or 2.4 MUg/g wet weight in diet). Our findings indicate that young adult finches exposed to environmentally relevant concentrations of mercury in ovo and through their diets, exhibited oxidative stress in their livers. We measured the ratio of the antioxidant glutathione in its reduced form (GSH) versus its oxidized form (GSSG) and the activity of the superoxide dismutase (SOD) enzyme suite. Blood total mercury served as a proxy for liver mercury concentration, and was on average 8.4 times the dietary dose (e.g., birds consuming 0.6 MUg/g had blood mercury levels of ~5 MUg/g on a wet weight basis). Consistent with what is known from large, aquatic bird species, there was a significant, negative relationship between GSH/GSSG ratios and tissue mercury concentrations, which is indicative of oxidative stress. This relationship was driven by a significant increase in the oxidized glutathione in the livers of birds with higher blood mercury levels. SOD activity was also found to have a significant, negative relationship with blood mercury. PMID- 25519781 TI - Essential medicines for chronic respiratory diseases: can people breathe easily in low-income countries? PMID- 25519782 TI - Xpert(r) MTB/RIF for extra-pulmonary tuberculosis: time to look beyond accuracy. PMID- 25519783 TI - Preventing HIV-associated tuberculosis with antiretroviral therapy: shut the stable door early! PMID- 25519784 TI - Accelerating progress towards tuberculosis elimination: the need for combination treatment and prevention. AB - Although estimated tuberculosis (TB) incidence is now falling globally, we are unlikely to achieve the Millennium Development Goal (MDG) TB targets without changing the emphasis of the global TB response in high human immunodeficiency virus prevalence settings. Two independent modelling exercises using South African data with different structures and assumptions conclude that, until new drugs, diagnostics and vaccines are available, a fully funded and accessible combination approach to anti-tuberculosis treatment and prevention, based on knowledge of local TB epidemiology and evidence-informed policy, is essential to accelerate progress towards zero new tuberculous infections, zero TB deaths and zero suffering from TB. PMID- 25519785 TI - The global burden of chronic respiratory disease in adults. AB - With an aging global population, chronic respiratory diseases are becoming a more prominent cause of death and disability. Age-standardised death rates from chronic obstructive pulmonary disease (COPD) are highest in low-income regions of the world, particularly South Asia and sub-Saharan Africa, although airflow obstruction is relatively uncommon in these areas. Airflow obstruction is, by contrast, more common in regions with a high prevalence of cigarette smoking. COPD mortality is much more closely related to the prevalence of a low forced vital capacity which is, in turn, associated with poverty. Mortality from asthma is less common than mortality from COPD, but it is also relatively more common in poorer areas, particularly Oceania, South and South-East Asia, the Middle East and Africa. Again this contrasts with the asthma prevalence among adults, which is highest in high-income regions. In high-income areas, mortality due to asthma, which is predominantly an adult problem, has fallen substantially in recent decades with the spread of new guidelines for treatment that emphasise the use of inhaled steroids to control the disease. Although mortality rates have been falling, the prevalence of atopy has been increasing between generations in Western Europe. Changes in the prevalence of wheeze among adults has been more varied and may have been influenced by the reduction in smoking and the increase in the use of inhaled steroids. PMID- 25519788 TI - Annual risk of tuberculous infection measured using serial skin testing, Orel Oblast, Russia, 1991-2005. AB - OBJECTIVE: To compare trends in direct annual risk of tuberculous infection (ARTI) during 1991-2005 in relation to tuberculosis (TB) incidence and to indirect estimates of ARTI derived from the prevalence of tuberculin skin test (TST) positivity in schoolchildren in Orel Oblast, Russia. DESIGN: In 2005, we abstracted annual TST results and vaccination histories from a representative sample of schoolchildren in Orel Oblast, Russia, where bacille Calmette-Guerin (BCG) vaccination and annual TST of children are nearly universal. We calculated direct ARTI based on the percentage of children tested with TST conversions each year, excluding conversions following BCG vaccination. RESULTS: We analysed records from 13 206 children, with a median of 10 recorded TST results per child. The ARTI increased from 0.2% in 1991 to 1.6% in 2000, paralleling trends in TB incidence. Similar results were observed when the ARTI was estimated based on prevalence of infection among children aged 3-5 years using a 12 mm cut-off to define TST positivity. Results differed substantially when 10 or 15 mm cut-offs were used or when prevalence was determined among children aged 6-8 years. CONCLUSION: ARTI measured through TST conversion increased as TB incidence increased in Orel Oblast. ARTI measured through serial TSTs can thus provide an indicator of changing trends in TB incidence. PMID- 25519787 TI - Latent tuberculous infection in the United States and Canada: who completes treatment and why? AB - OBJECTIVES: To assess latent tuberculous infection (LTBI) treatment completion rates in a large prospective US/Canada multisite cohort and identify associated risk factors. METHODS: This prospective cohort study assessed factors associated with LTBI treatment completion through interviews with persons who initiated treatment at 12 sites. Interviews were conducted at treatment initiation and completion/cessation. Participants received usual care according to each clinic's procedure. Multivariable models were constructed based on stepwise assessment of potential predictors and interactions. RESULTS: Of 1515 participants initiating LTBI treatment, 1323 had information available on treatment completion; 617 (46.6%) completed treatment. Baseline predictors of completion included male sex, foreign birth, not thinking it would be a problem to take anti-tuberculosis medication, and having health insurance. Participants in stable housing who received monthly appointment reminders were more likely to complete treatment than those without stable housing or without monthly reminders. End-of-treatment predictors of non-completion included severe symptoms and the inconvenience of clinic/pharmacy schedules, barriers to care and changes of residence. Common reasons for treatment non-completion were patient concerns about tolerability/toxicity, appointment conflicts, low prioritization of TB, and forgetfulness. CONCLUSIONS: Less than half of treatment initiators completed treatment in our multisite study. Addressing tangible issues such as not having health insurance, toxicity concerns, and clinic accessibility could help to improve treatment completion rates. PMID- 25519789 TI - Implementation of tuberculosis infection prevention and control in Mozambican health care facilities. AB - SETTING: District and urban health care facilities in three provinces (Manica, Sofala, Tete) in central Mozambique. OBJECTIVE: To assess the level of implementation of selected tuberculosis infection prevention and control (TB-IPC) measures. DESIGN: In a cross-sectional study of TB-IPC implementation in 29 health care facilities, we assessed TB clinics, laboratories, out-patient departments and medical and TB wards. Assessment included selected managerial, administrative and environmental measures and the availability and use of respiratory protective equipment (N95 respirators). RESULTS: Guidelines for diagnosis and treatment of (presumptive) TB patients were not present in all facilities. Staff instructed patients on sputum collection in 91%, but only 4% observed it. Using a pragmatic '20% rule', 52% of the rooms assessed had adequate ventilation. Potentially, this could be increased to 76%. Three quarters of the health care workers had N95 respirators. Only 36% knew how to use it correctly. CONCLUSION: Implementation of TB-IPC measures showed wide variations within health care facilities. Relatively simple measures to improve TB-IPC include the availability of guidelines, opening doors and windows to improve ventilation, and training and support on correct N95 respirator use. However, even relatively simple measures are challenging to implement, and require careful attention in and evaluation of the implementation process. PMID- 25519790 TI - CD4 deficit and tuberculosis risk persist with delayed antiretroviral therapy: 5 year data from CIPRA HT-001. AB - SETTING: Port-au-Prince, Haiti. OBJECTIVE: To determine long-term effects of early vs. delayed initiation of antiretroviral therapy (ART) on immune recovery and tuberculosis (TB) risk in human immunodeficiency virus (HIV) infected individuals. DESIGN: Open-label randomized controlled trial of immediate ART in HIV-infected adults with CD4 counts between 200 and 350 cells/mm(3) vs. deferring ART until the CD4 count was <200 cells/mm(3). The primary comparisons were CD4 counts over time and risk for incident TB, with 5 years of follow-up. RESULTS: A total of 816 participants were enrolled, with 408 in each treatment arm. The early treatment group started ART within 2 weeks, while the deferred treatment group started ART a median of 1.3 years after enrollment. After 5 years, the mean CD4 count in the early treatment group was significantly higher than in the deferred treatment group (496 cells/mm(3), 95% confidence interval [CI] 477-515 vs. 373 cells/mm(3), 95%CI 357-389; P < 0.0001). TB risk was higher in the deferred treatment group (unadjusted HR 2.41, 95%CI 1.56-3.74; P < 0.0001) and strongly correlated with lower CD4 counts in time-dependent multivariate analysis. CONCLUSION: Delays in ART initiation for HIV-infected adults with CD4 counts of 200-350 cells/mm(3) can result in long-term immune dysfunction and persistent increased risk for TB. PMID- 25519791 TI - Long-term risk of tuberculosis in haematopoietic stem cell transplant recipients: a 10-year nationwide study. AB - BACKGROUND: Tuberculosis (TB) is a serious problem for patients undergoing haematopoietic stem cell transplantation (HSCT) in TB-endemic areas; however, data on these patients are limited. METHODS: We obtained data on 2040 HSCT recipients from the Registry of Catastrophic Illness in Taiwan from 1997 to 2006. We also obtained data on age-, sex- and enrolment date-matched controls from the Longitudinal Health Insurance Database. The cumulative incidence of active TB in HSCT recipients and controls and risk factors for TB were analysed. RESULTS: Among 2040 HSCT recipients identified, 39 (1.9%) had newly diagnosed TB. The incidence rate was 688 per 100 000 person-years. The 10-year cumulative TB incidence was respectively 3.52% and 0.38% in HSCT recipients and controls (P < 0.001). HSCT was an independent risk factor for TB compared with matched controls. Among post-HSCT patients, independent risk factors for TB included age ?18 years and allogeneic recipients with graft-versus-host disease (GVHD). Post HSCT patients with subsequent TB had a higher mortality rate than those without TB (P < 0.001). CONCLUSION: HSCT is associated with an increased risk of TB in endemic regions. Older age and development of chronic GVHD are independent predictors of late onset active TB in HSCT recipients. PMID- 25519786 TI - Gaps in using bronchodilators, inhaled corticosteroids and influenza vaccine among 23 high- and low-income sites. AB - BACKGROUND: Increasing access to essential respiratory medicines and influenza vaccination has been a priority for over three decades. Their use remains low in low- and middle-income countries (LMICs), where little is known about factors influencing use, or about the use of influenza vaccination for preventing respiratory exacerbations. METHODS: We estimated rates of regular use of bronchodilators, inhaled corticosteroids and influenza vaccine, and predictors for use among 19 000 adults in 23 high-income countries (HICs) and LMIC sites. RESULTS: Bronchodilators, inhaled corticosteroids and influenza vaccine were used significantly more in HICs than in LMICs, after adjusting for similar clinical needs. Although they are used more commonly by people with symptomatic or severe respiratory disease, the gap between HICs and LMICs is not explained by the prevalence of chronic obstructive pulmonary disease or doctor-diagnosed asthma. Site-specific factors are likely to influence use differently. The gross national income per capita for the country is a strong predictor for use of these treatments, suggesting that economics influence under-treatment. CONCLUSION: We still need a better understanding of determinants for the low use of essential respiratory medicines and influenza vaccine in low-income settings. Identifying and addressing these more systematically could improve the access and use of effective treatments. PMID- 25519792 TI - Vitamin D status and incidence of tuberculosis among contacts of pulmonary tuberculosis patients. AB - A prospective cohort study was conducted from 2009 to 2012 to assess the relationship between serum baseline 25-hydroxivytamin D (vitamin D) status and the incidence of tuberculosis (TB) among 572 contacts of 89 pulmonary TB patients in Castellon, Spain. Three new cases of pulmonary TB occurred, with an incidence density of 3.6 per 1000 person-years. Mean vitamin D status was 13.7 ng/ml for cases and 25.7 ng/ml for non-cases. Vitamin D status showed a significant inverse association with TB incidence (adjusted HR 0.88, 95%CI 0.80-0.97). This result is in line with the hypothesis that vitamin D deficiency is associated with TB incidence. PMID- 25519793 TI - Ascertaining in vivo virulence of Mycobacterium tuberculosis lineages in patients in Mbeya, Tanzania. AB - We evaluated the relationship between the degree of immunodeficiency indicated by the number of circulating CD4+ T-cells and Mycobacterium tuberculosis lineages identified by spoligotyping and mycobacterial interspersed repetitive units variable number of tandem repeats genotyping in human immunodeficiency virus (HIV) infected individuals with pulmonary tuberculosis from Mbeya, Tanzania. Of M. tuberculosis strains from 129 patients, respectively 55 (42.6%) and 37 (28.7%) belonged to Latin American Mediterranean and Delhi/Central-Asian lineages, while 37 (28.7%) patients were infected with other strains. There was no difference in the distribution of M. tuberculosis lineages among patients with early or advanced stages of HIV infection (P = 0.785), indicating that the virulence of strains from these lineages may not be substantially different in vivo. PMID- 25519794 TI - Improved diagnosis of childhood tuberculous meningitis using more than one nucleic acid amplification test. AB - BACKGROUND: Early treatment is critical to reducing tuberculous meningitis (TBM) related morbidity and mortality. Diagnosis based on cerebrospinal fluid (CSF) culture is impractical due to slow turnaround times, while microscopy has poor sensitivity. Enhanced detection methods are essential to guide early treatment initiation, especially in vulnerable young children. METHODS: We assessed the diagnostic accuracy of the GenoType((r)) MTBDRplus and Xpert((r)) MTB/RIF assays on CSF collected from paediatric meningitis suspects prospectively enrolled at Tygerberg Hospital, Cape Town, South Africa. Fluorescent auramine-O microscopy, liquid culture for Mycobacterium tuberculosis, GenoType and Xpert assays were performed on all CSF samples. RESULTS: Of 101 meningitis suspects, 55 were diagnosed with TBM and 46 served as non-TBM controls. Using a pre-defined TBM case definition as reference standard, sensitivities and specificities were 4% and 100% for fluorescent microscopy, 22% and 100% for culture, 33% and 98% for GenoType, 26% and 100% for Xpert, 22% and 100% for microscopy and culture combined and 49% and 98% for GenoType and Xpert combined. Culture, GenoType and Xpert combined performed best, with 56% sensitivity and 98% specificity. CONCLUSION: Although commercial nucleic-acid amplification tests performed on CSF revealed incrementally improved diagnostic accuracy, providing rapid microbiological confirmation, they cannot serve as a rule-out test. PMID- 25519795 TI - Accuracy of the Xpert(r) MTB/RIF assay for the diagnosis of extra-pulmonary tuberculosis in South Korea. AB - SETTING: The Xpert((r)) MTB/RIF assay has been endorsed by the World Health Organization for the detection of pulmonary and extra-pulmonary tuberculosis (EPTB). OBJECTIVE: To determine the accuracy of the Xpert assay in diagnosing EPTB in South Korea, a country with an intermediate TB burden. DESIGN: We retrospectively reviewed the medical records of 1429 patients in whom the Xpert assay using EPTB specimens was requested between 1 January 2011 and 31 October 2013 in a tertiary referral hospital in South Korea. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of EPTB and detection of rifampicin (RMP) resistance were calculated. RESULTS: Using culture as gold standard, the sensitivity, specificity, PPV and NPV of the assay were respectively 67.7%, 98.1%, 60% and 98.6%. Using a composite reference standard, the sensitivity, specificity, PPV and NPV were respectively 49.3%, 100%, 100% and 95.1%. The sensitivity, specificity, PPV and NPV for the detection of RMP resistance among specimens with positive results for Mycobacterium tuberculosis were respectively 80%, 100%, 100% and 97.7%. CONCLUSION: The Xpert assay showed acceptable sensitivity in certain groups and excellent specificity in diagnosing EPTB and detecting RMP resistance in an intermediate TB burden country. PMID- 25519796 TI - Pooling sputum from multiple individuals for Xpert(r) MTB/RIF testing: a strategy for screening high-risk populations. AB - SETTING: Symptom-based screening for tuberculosis (TB) disease is limited by poor performance of symptom screening in several key populations. We tested the hypothesis that pooling sputum from multiple individuals for Xpert((r)) MTB/RIF testing would reduce the number of tests required while retaining an acceptable sensitivity, thus allowing the use of Xpert for TB screening. METHODS: We compared pooling ratios that would require the least number of assays using Xpert and determined that for a population with a TB prevalence of approximately 3%, a 1:5 pooling ratio is optimal. To evaluate sensitivity, we generated pools of one specimen with known Mycobacterium tuberculosis culture positivity (smear microscopy-positive or -negative) with four culture-negative specimens. RESULTS: All 20 of the pools generated from a smear- and culture-positive sputum sample were positive using Xpert. Of the 22 pools with a smear-negative, culture positive sample, we included 17 in the analysis, of which 13 (76%) were Xpert positive. CONCLUSIONS: Pooling of sputum samples using Xpert achieved reasonable sensitivity and warrants further evaluation of the systematic screening of high TB prevalence populations. PMID- 25519797 TI - Is frontloaded sputum microscopy an option in active tuberculosis case finding? AB - SETTING: Active tuberculosis (TB) case finding (ACF) in Phnom Penh, Cambodia using light-emitting diode fluorescence microscopy (FM). OBJECTIVE: To evaluate the smear-positive yield of frontloaded (same-day) smear microscopy in ACF. DESIGN: All presumptive TB cases screened through ACF were asked to provide three sputum specimens: two spot specimens on Day 1 and a morning specimen on Day 2 (spot-spot-morning, SSM). Laboratory technicians blinded to previous results read the smears using FM. We considered only SSM series with at least one positive smear to calculate the proportion of TB cases missed and to determine the difference between the spot-spot (SS) and spot-morning (SM) approach. RESULTS: Of 4616 presumptive TB patients enrolled, 3306 provided three sputum samples. Of 2957 (89.4%) who followed the SSM approach, 188 (6.4%) were smear-positive: 177 on SM and 160 on SS. The incremental yield of the second sputum sample was 18.1% for SM vs. 9.4% for SS. Relative to any smear-positive case detected by SSM, 28/188 (14.9%, 95%CI 10.1-20.8) TB cases would be missed by SS vs. 11/188 (5.9%, 95%CI 3.0-10.2) by SM. The difference in the proportion of missed TB patients was 9.0% (P = 0.006). CONCLUSION: ACF frontloaded sputum microscopy is inferior in terms of smear-positive yield: the SS approach would have missed a significant proportion of smear-positive TB. PMID- 25519798 TI - Validation of a commercial serodiagnostic kit for diagnosing pulmonary Mycobacterium avium complex disease. AB - SETTING: A commercial serodiagnostic kit for diagnosing pulmonary disease due to Mycobacterium avium complex (MAC-PD) was developed and launched in Japan in 2011. OBJECTIVE: To evaluate the performance of this kit in routine clinical settings. METHODS: In this retrospective single-centre study, data on serum levels of anti glycopeptidolipid (GPL) core IgA antibody (U/ml) measured using the kit were analysed in patients diagnosed with MAC-PD according to American Thoracic Society criteria, in those with pulmonary tuberculosis (PTB) or pulmonary M. kansasii disease and in healthy volunteers. RESULTS: The anti-GPL-core IgA antibody levels of serum were significantly higher (P < 0.0001) in patients with MAC-PD (n = 485) than in those with PTB (n = 133) or pulmonary M. kansasii disease (n = 23) or in healthy subjects (n = 265). When the cut-off level was set at 0.7 U/ml, the sensitivity and specificity were respectively 78.6% and 96.9%. Higher antibody levels were observed in patients with greater extent of disease on chest computed tomography (P < 0.0001). CONCLUSIONS: The serodiagnostic kit revealed good sensitivity and specificity. The antibody levels may reflect disease activity. Additional work is needed to determine whether the diagnostic assay could be used in conjunction with current diagnostic criteria to improve the diagnosis of MAC PD. PMID- 25519799 TI - Gender patterns of tuberculosis testing and disease in South Africa. AB - SETTING: In South Africa, tuberculosis (TB) has been the leading cause of death for over a decade. The TB incidence rate is the second highest in the world, and continues to rise. OBJECTIVE: To examine gender patterns in South Africa's TB epidemic. This is one of the first studies to use National Health Laboratory Service (NHLS) data to evaluate the epidemic at the national level. DESIGN: Observational study using NHLS retrospective data for every TB test performed in public health facilities between 2009 and 2011. RESULTS: Despite an increase in the number of TB tests performed, the number of TB cases remained relatively constant. Although prevalence rates differ between health districts, we find a similar female-to-male ratio (0.70) in each district. The age profile for TB resembles that of human immunodeficiency virus (HIV), with peak TB prevalence in women occurring 7 years earlier than in men. The female-to-male ratio of TB cases and 3+ positive (severe) cases decreases rapidly between ages 25 and 35 years. CONCLUSION: These age and gender patterns are driven by the HIV epidemic and risks associated with pregnancy and childbearing. Increasing the quality and quantity of active TB case finding at existing points of care would be a sustainable and cost-effective intervention for both treatment and prevention. PMID- 25519800 TI - Tuberculosis and excess alcohol use in the United States, 1997-2012. AB - BACKGROUND: Excess alcohol use among tuberculosis (TB) patients complicates TB control strategies. OBJECTIVES: To characterize the role of excess alcohol use in TB control, we describe the epidemiology of excess alcohol use and TB in the United States among those aged ?15 years. DESIGN: Using data reported to the National Tuberculosis Surveillance System, 1997-2012, we examined associations between excess alcohol use and TB treatment outcomes and markers for increased transmission (involvement in a local genotype cluster of cases) using multivariate logistic regression. We used Cox proportional hazards regression analysis to examine the relationship between excess alcohol use and the rate of conversion from positive to negative in sputum culture results. RESULTS: Excess alcohol use was documented for 31 207 (15.1%) of 207 307 patients. Prevalence of excess alcohol use was greater among male patients (20.6%) and US-born patients (24.6%). Excess alcohol use was associated with a positive sputum smear result (aOR 1.23, 95%CI 1.18-1.28) and death during treatment (vs. completion of treatment) (aOR 1.16, 95%CI 1.10-1.22). The rate of culture conversion was higher among patients without excess alcohol use (adjusted hazard ratio 1.20, 95%CI 1.18 1.23). CONCLUSIONS: Excess alcohol use was common among patients with TB, and was associated with TB transmission, lower rates of sputum culture conversion, and greater mortality. PMID- 25519801 TI - Treatment options and outcomes of hospitalised tuberculosis patients: a nationwide study. AB - SETTING: Although standardised multidrug treatments exist, mortality among hospitalised tuberculosis (TB) patients is high. OBJECTIVE: To characterise TB patients requiring acute hospital care and identify factors associated with in hospital mortality. DESIGN: Using a Japanese national database of acute-care hospitals, we identified patients with sputum smear-positive pulmonary TB who were discharged (both deceased and alive) between July 2010 and March 2013. Demographic characteristics, comorbidity, procedures and treatments were examined. We performed a multivariable logistic regression analysis to identify risk factors for in-hospital mortality. RESULTS: Of 877 treated patients (566 males, mean age 74.5 years) identified, 152 (17.3%) died. A standard four-drug regimen of isoniazid (INH), rifampicin (RMP), ethambutol (EMB) and pyrazinamide was given to 279 (31.8%) patients, and INH, RMP and EMB to 335 (38.2%) patients. Multivariable analysis showed that the three-drug regimen was significantly associated with higher rates of in-hospital mortality (OR 1.87, 95%CI 1.07-3.27, P = 0.028). Other factors associated with in-hospital death were age, male sex, smoking habit, emergency admission, dementia and severe respiratory condition. CONCLUSION: The risk factors for in-hospital death identified include the use of the three-drug regimen. Treatment choice could influence the outcome of hospitalised TB patients. PMID- 25519803 TI - Anisotropic softening of magnetic excitations along the nodal direction in superconducting cuprates. AB - The high-Tc cuprate superconductors are close to antiferromagnetic order. Recent measurements of magnetic excitations have reported an intriguing similarity to the spin waves--magnons--of the antiferromagnetic insulating parent compounds, suggesting that magnons may survive in damped, broadened form throughout the phase diagram. Here we show by resonant inelastic X-ray scattering on Bi(2)Sr(2)CaCu(2)O(8+delta) (Bi-2212) that the analogy with spin waves is only partial. The magnon-like features collapse along the nodal direction in momentum space and exhibit a photon energy dependence markedly different from the Mott insulating case. These observations can be naturally described by the continuum of charge and spin excitations of correlated electrons. The persistence of damped magnons could favour scenarios for superconductivity built from quasiparticles coupled to spin fluctuations. However, excitation spectra composed of particle hole excitations suggest that superconductivity emerges from a coherent treatment of electronic spin and charge in the form of quasiparticles with very strong magnetic correlations. PMID- 25519802 TI - Dehydroxymethylepoxyquinomicin, a novel nuclear factor-kappaB inhibitor, reduces chemokines and adhesion molecule expression induced by IL-1beta in human corneal fibroblasts. AB - PURPOSE: Dehydroxymethylepoxyquinomicin (DHMEQ) is derived from the antibiotic, epoxyquinomicin C, and is a novel low molecular weight nuclear factor-kappaB (NF kappaB) inhibitor. We investigated the effects of DHMEQ on the expression of chemokines and the intercellular adhesion molecule (ICAM)-1 induced by proinflammatory cytokines in cultures of the human corneal fibroblasts (HCFs). METHODS: The cytotoxicity of DHMEQ on cultured HCFs was evaluated by cell proliferation assays. Cultures were exposed to interleukin (IL)-1beta, and the production of IL-8 and monocyte chemoattractant protein (MCP)-1 was assessed by enzyme-linked immunosorbent assay. The degree of expression of ICAM-1 was measured by flow cytometry. The translocation of NF-kappaB p65 into the nucleus of HCFs was assessed by immunocytochemistry. RESULTS: DHMEQ was not toxic to cultured HCFs at doses up to 10 MUg/ml. DHMEQ significantly suppressed the production of both IL-8 and MCP-1 in IL-1beta-stimulated HCFs. In addition, DHMEQ down-regulated ICAM-1 expression in IL-1beta-stimulated HCFs in a dose-dependent manner. DHMEQ inhibited the IL-1beta-induced nuclear accumulation of p65, a component of NF-kappaB, in HCFs. CONCLUSIONS: The suppression of inflammatory chemokines IL-8 and MCP-1 and inhibition of the expression of ICAM-1 in cultured HCFs by DHMEQ indicates that DHMEQ may have a therapeutic potential for treating ICAM-1 and chemokine-mediated corneal inflammatory disorders. PMID- 25519805 TI - The association between bronchial anthracofibrosis and pneumoconiosis: A retrospective cross-sectional study. AB - OBJECTIVES: Bronchial anthracofibrosis (BAF) is associated with occupational hazardous dust exposure. The aim of the present study was to determine the prevalence of BAF and BAC without fibrosis in patients with pneumoconiosis, and to evaluate the associations between BAC/BAF and occupational dust exposure and clinical manifestations among patients with pneumoconiosis. METHODS: A retrospective cross-sectional study (n=170) among individuals who were diagnosed with pneumoconiosis or suspicious pneumoconiosis and underwent bronchoscopy between January 2000 and February 2013 was performed. Multiple logistic regression analysis was performed to estimate associations. RESULTS: In total, 153 eligible subjects were included in the study because their records contained all the required information. Of these, 81 (53%) and 63 (41%) had BAC and BAF, respectively. Occupational coal dust exposure increased the risk of BAF and BAC (odds ratio [OR]=2.980, 95% confidence interval [CI]=1.184-8.128; OR=2.840, 95% CI=1.092-7.926, respectively). Profusion category 3 pneumoconiosis also increased the risk of BAC (OR=33.887, 95% CI=5.317-394.729). CONCLUSIONS: BAF and BAC are associated with occupational exposure to coal dust. Therefore, clinicians should consider occupational history when they investigate the association between BAC/BAF and risk factors such as tuberculosis, lung cancer, and biomass fuel exposure. PMID- 25519806 TI - Role of dexamethasone in prevention of high altitude pulmonary edema. PMID- 25519804 TI - Nonsense codon suppression in fission yeast due to mutations of tRNA(Ser.11) and translation release factor Sup35 (eRF3). AB - In the fission yeast Schizosaccharomyces pombe, sup9 mutations can suppress the termination of translation at nonsense (stop) codons. We localized sup9 physically to the spctrnaser.11 locus and confirmed that one allele (sup9-UGA) alters the anticodon of a serine tRNA. We also found that another purported allele is not allelic. Instead, strains with that suppressor (renamed sup35 F592S) have a single base pair substitution (T1775C) that introduces an amino acid substitution in the Sup35 protein (Sup35-F592S). Reduced functionality of Sup35 (eRF3), the ubiquitous guanine nucleotide-responsive translation release factor of eukaryotes, increases read-through of stop codons. Tetrad dissection revealed that suppression is tightly linked to (inseparable from) the sup35-F592S mutation and that there are no additional extragenic modifiers. The Mendelian inheritance indicates that the Sup35-F592S protein does not adopt an infectious amyloid state ([PSI (+)] prion) to affect suppression, consistent with recent evidence that fission yeast Sup35 does not form prions. We also report that sup9 UGA and sup35-F592S exhibit different strengths of suppression for opal stop codons of ade6-M26 and ade6-M375. We discuss possible mechanisms for the variation in suppressibility exhibited by the two alleles. PMID- 25519807 TI - Studies on the diastereoselective oxidation of 1-thio-beta-D-glucopyranosides: synthesis of the usually less favoured R(S) sulfoxide as a single diastereoisomer. AB - A detailed study on the diastereoselective oxidation of 1-thio-beta-D glucopyranosides is reported. It has been shown that the sense and the degree of stereochemical outcome of the oxidation are highly dependent on the substituent of the sulfur and on the protective group of the C2-OH. In the case of thioglycosides with a bulky aglycone, the mesylation of C2-OH has a significant effect on the stereochemical outcome of the oxidation, affording the usually less favoured RS sulfoxide as a single diastereoisomer. The absolute configuration of the final sulfinyl glycosides was ascertained by NMR analysis and corroborated by X-ray crystallography. PMID- 25519808 TI - Quantitative measurements of the articular areas of mandibular condyles with temporomandibular joint disorders using magnetic resonance imaging. AB - OBJECTIVE: The authors sought to clarify the variation in the condylar anterior functional surface (AFS) of patients with temporomandibular joint (TMJ) disorders using quantitative measurements by magnetic resonance imaging (MRI). METHODS: MR images of 68 joints (2 males, 32 females) were used. The subjects were classified into three groups: with/without defects of cortical bone groups and a combination group without defects. The AFS was measured as the length between the protrusive point and the apex of the condyle on MRI (4-mm-thick slices), and the quad value of the length was defined as the area on the slice. The summed quad values of all slices were used as the AFS area. Differences in the areas among the three groups were compared by one-way analysis of variance (ANOVA). RESULTS: The non-defect group had significantly larger AFS areas than the defect group. CONCLUSIONS: Quantitative measurement on MR images clarified the changes in the condylar sagittal appearance. PMID- 25519809 TI - Dynamic observation on the growth behaviors in manganese silicide/silicon nanowire heterostructures. AB - Metal silicide nanowires (NWs) are very interesting materials with diverse physical properties. Among the silicides, manganese silicide nanostructures have attracted wide attention due to their several potential applications, including in microelectronics, optoelectronics, spintronics and thermoelectric devices. In this work, we exhibited the formation of pure manganese silicide and manganese silicide/silicon nanowire heterostructures through solid state reaction with line contacts between manganese pads and silicon NWs. Dynamical process and phase characterization were investigated by in situ transmission electron microscopy (in situ TEM) and spherical aberration corrected scanning transmission electron microscopy (Cs-corrected STEM), respectively. The growth dynamics of the manganese silicide phase under thermal effects were systematically studied. Additionally, Al2O3, serving as the surface oxide, altered the growth behavior of the MnSi nanowire, enhancing the silicide/Si epitaxial growth and effecting the diffusion process in the silicon nanowire as well. In addition to fundamental science, this significant study has great potential in advancing future processing techniques in nanotechnology and related applications. PMID- 25519810 TI - Bimatoprost 0.01% in treatment-naive patients with open-angle glaucoma or ocular hypertension: an observational study in the Korean clinical setting. AB - BACKGROUND: This study evaluates the efficacy and tolerability (ie, occurrence and severity of hyperemia) of bimatoprost 0.01% in treatment-naive patients with open-angle glaucoma (OAG) or ocular hypertension in the Korean clinical setting. METHODS: In this multicenter, open-label, observational study, treatment-naive patients with OAG, including patients with normal-tension glaucoma (NTG, defined as IOP <=21 mm Hg), or ocular hypertension received bimatoprost 0.01% once daily. Hyperemia was assessed at baseline and weeks 6 and 12, graded by a masked evaluator using a photonumeric scale (0, +0.5, +1, +2, +3), and grouped as (0 to +1) and (+2 to +3). Shifts between groupings were reported as no change, improved ([+2 to +3] to [0 to +1]), or worsened ([0 to +1] to [+2 to +3]). Other adverse events were monitored. Mean IOP changes from baseline at weeks 6 and 12 were reported. Supplemental analyses were conducted for IOPs >21 versus <=21 mm Hg. RESULTS: Of 295 treatment-naive patients included in the intent-to-treat/safety population, 73 (24.7%) had baseline IOP >21 mm Hg (mean, 25.7 +/- 5.0 mm Hg) and 222 (75.3%) had baseline IOP <=21 mm Hg (mean, 16.3 +/- 3.0 mm Hg); 96.3% had hyperemia graded none (36.3%) to mild (17.3%). At week 12, hyperemia was graded none to mild in 83.7% (n = 220). Worsening occurred in 12.3% of patients by week 6 and 12.7% by week 12. Small improvements occurred in 0.8% and 0.5% of patients at weeks 6 and 12, respectively. Hyperemia scores were generally low and the majority of patients had no change in severity during the study. Mean IOP at weeks 6 and 12 was reduced to 16.4 +/- 4.0 mm Hg (-34.5%; P < 0.0001) and 16.7 +/ 3.9 mm Hg (-32.0%; P < 0.001) in the baseline-IOP >21 mm Hg group versus 13.3 +/ 2.6 mm Hg (-17.8%; P < 0.001) and 13.7 +/- 2.8 mm Hg (-15.9%; P < 0.001) in the baseline-IOP <=21 mm Hg group, respectively. CONCLUSIONS: In treatment-naive patients, bimatoprost 0.01% induced low shifts in worsening of hyperemia and significant reductions in IOP, regardless of baseline IOP. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION NUMBER: NCT01594970. PMID- 25519812 TI - Patient participation in patients with heart failure receiving structured home care--a prospective longitudinal study. AB - BACKGROUND: Patient participation is important for improving outcomes, respect for self-determination and legal aspects in care. However, how patients with heart failure view participation and which factors may be associated with participation is not known. The aim of this study was therefore to describe the influence of structured home care on patient participation over time in patients diagnosed with heart failure, and to explore factors associated with participation in care. METHODS: The study had a prospective pre-post longitudinal design evaluating the influence of structured home care on participation in patients at four different home care units. Patient participation was measured using 3 scales and 1 single item. Self-care behavior, knowledge, symptoms of depression, socio- demographic and clinical characteristics were measured to explore factors associated with patient participation. Repeated measure ANOVA was used to describe change over time, and stepwise regression analyses were used to explore factors associated with patient participation. RESULTS: One hundred patients receiving structured heart failure home care were included. Mean age was 82 years, 38 were women and 80 were in New York Heart Association functional class III. One aspect of participation, received information, showed a significant change over time and had increased at both six and twelve months. Better self-care behavior was associated with all four scales measuring different aspects of participation. Experiencing lower degree of symptoms of depression, having better knowledge, being of male sex, being of lower age, cohabiting and having home help services were associated with one or two of the four scales measuring different aspects of participation. CONCLUSION: Patients experienced a fairly high level of satisfaction with participation in care at baseline, and there was a significant improvement over time for participation with regard to received information after being admitted to structured home care. Higher level of patient participation was consistently associated with better self-care behavior. This study shows that patient participation may need to be further focused upon, and that the association with self-care may be interesting to target in future interventions. PMID- 25519816 TI - Structural tailoring of hydrogen-bonded poly(acrylic acid)/poly(ethylene oxide) multilayer thin films for reduced gas permeability. AB - Hydrogen bonded poly(acrylic acid) (PAA)/poly(ethylene oxide) (PEO) layer-by layer assemblies are highly elastomeric, but more permeable than ionically bonded thin films. In order to expand the use of hydrogen-bonded assemblies to applications that require a better gas barrier, the effect of assembling pH on the oxygen permeability of PAA/PEO multilayer thin films was investigated. Altering the assembling pH leads to significant changes in phase morphology and bonding. The amount of intermolecular hydrogen bonding between PAA and PEO is found to increase with increasing pH due to reduction of COOH dimers between PAA chains. This improved bonding leads to smaller PEO domains and lower gas permeability. Further increasing the pH beyond 2.75 results in higher oxygen permeability due to partial deprotonation of PAA. By setting the assembling pH at 2.75, the negative impacts of COOH dimer formation and PAA ionization on intermolecular hydrogen bonding can be minimized, leading to a 50% reduction in the oxygen permeability of the PAA/PEO thin film. A 20 bilayer coating reduces the oxygen transmission rate of a 1.58 mm natural rubber substrate by 20 *. These unique nanocoatings provide the opportunity to impart a gas barrier to elastomeric substrates without altering their mechanical behavior. PMID- 25519815 TI - Voice quality in laryngotracheal stenosis: impact of dilation and level of stenosis. AB - OBJECTIVE: To assess the impact of suspension microlaryngoscopy with balloon dilation on voice-related quality of life (V-RQOL) in laryngotracheal stenosis (LTS). METHODS: Retrospective chart review of LTS patients dilated at a tertiary care academic hospital from 2010 to 2013. Data were obtained and then analyzed. LTS was stratified by (1) subglottic or tracheal stenosis and (2) multilevel stenosis (MLS; glottic and subglottic/tracheal). Pre- and postoperative V-RQOL and grade, roughness, breathiness, asthenia, strain (GRBAS) scores were compared. The number and frequency of balloon dilation procedures over the lifetime were secondary outcome variables. RESULTS: Thirty-eight patients were identified: 26 subglottic/tracheal and 12 multilevel. Of these, 71.4% required multiple dilations, with greatest dilations/patient for multilevel stenosis (4.8). V-RQOL improved in the 27 patients with completed pre- and postoperative scores from a mean of 70.4 to 80 (P=.025). Pre/postoperative V-RQOLs for tracheal/subglottic (mean, 82.8/93.8) were significantly higher (P=.0001/.0001) than multilevel stenosis (48/55.3). Voice quality-of-life improvement was significant for the subglottic/tracheal cohort (P=.036) but not for the MLS group. GRBAS was performed pre- and postoperatively in 10 patients with improvement in all domains except breathiness. CONCLUSION: Laryngotracheal stenosis is associated with dysphonia. Patients with glottic involvement have significantly worse voice quality of life than those with tracheal/subglottic stenosis. Endoscopic balloon dilation improves V-RQOL in patients with subglottic/tracheal stenosis. PMID- 25519817 TI - Investigating adsorption/desorption of carbon dioxide in aluminum compressed gas cylinders. AB - Between June 2010 and June 2011, the National Institute of Standards and Technology (NIST) gravimetrically prepared a suite of 20 carbon dioxide (CO2) in air primary standard mixtures (PSMs). Ambient mole fraction levels were obtained through six levels of dilution beginning with pure (99.999%) CO2. The sixth level covered the ambient range from 355 to 404 MUmol/mol. This level will be used to certify cylinder mixtures of compressed dry whole air from both the northern and southern hemispheres as NIST standard reference materials (SRMs). The first five levels of PSMs were verified against existing PSMs in a balance of air or nitrogen with excellent agreement observed (the average percent difference between the calculated and analyzed values was 0.002%). After the preparation of a new suite of PSMs at ambient level, they were compared to an existing suite of PSMs. It was observed that the analyzed concentration of the new PSMs was less than the calculated gravimetric concentration by as much as 0.3% relative. The existing PSMs had been used in a Consultative Committee for Amount of Substance Metrology in Chemistry Key Comparison (K-52) in which there was excellent agreement (the NIST-analyzed value was -0.09% different from the calculated value, while the average of the difference for all 18 participants was -0.10%) with those of other National Metrology Institutes and World Meteorological Organization designated laboratories. In order to determine the magnitude of these losses at the ambient level, a series of "daughter/mother" tests were initiated and conducted in which the gas mixture containing CO2 from a "mother" cylinder was transferred into an evacuated "daughter" cylinder. These cylinder pairs were then compared using cavity ring-down spectroscopy under high reproducibility conditions (the average percent relative standard deviation of sample response was 0.02). A ratio of the daughter instrument response to the mother response was calculated, with the resultant deviation from unity being a measure of the CO2 loss or gain. Cylinders from three specialty gas vendors were tested to find the appropriate cylinder in which to prepare the new PSMs. All cylinders tested showed a loss of CO2, presumably to the walls of the cylinder. The vendor cylinders exhibiting the least loss of CO2 were then purchased to be used to gravimetrically prepare the PSMs, adjusting the calculated mole fraction for the loss bias and an uncertainty calculated from this work. PMID- 25519813 TI - Dendritic cells during Staphylococcus aureus infection: subsets and roles. AB - Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that play a crucial role in both innate and adaptive immune responses. DCs orient the immune responses by modulating the balance between protective immunity to pathogens and tolerance to self-antigens. Staphylococcus aureus (S. aureus) is a common member of human skin microbiota and can cause severe infections with significant morbidity and mortality. Protective immunity to pathogens by DCs is required for clearance of S. aureus. DCs sense the presence of the staphylococcal components using pattern recognition receptors (PRRs) and then orchestrate immune systems to resolve infections. This review summarizes the possible roles of DCs, in particular their Toll-like receptors (TLRs) involved in S. aureus infection and strategies by which the pathogen affects activation and function of DCs. PMID- 25519818 TI - Self-organization of star-shaped columnar liquid crystals with a coaxial nanophase segregation revealed by a combined experimental and simulation approach. AB - Fully consistent X-ray data and molecular dynamics simulations on new star-shaped liquid crystals yield two nanosegregated architectures with a coaxial stacking of two functional discotic units: tris(triazolyl)triazine and triphenylene. Analysis of lattice order along the principal axes reveals preferential staggered arrangement of the stacked molecules in the columnar assembly. PMID- 25519819 TI - Coherent two-dimensional photocurrent spectroscopy in a PbS quantum dot photocell. AB - Recently there has been growing interest in the role of coherence in electronic dynamics. Coherent multidimensional spectroscopy has been used to reveal coherent phenomena in numerous material systems. Here we utilize a recent implementation of coherent multidimensional spectroscopy--two-dimensional photocurrent spectroscopy--in which we detect the photocurrent from a PbS quantum dot photocell resulting from its interactions with a sequence of four ultrafast laser pulses. We observe sub-picosecond evolution of two-dimensional spectra consistent with multiple exciton generation. Moreover, a comparison with two-dimensional fluorescence spectra of the quantum dots demonstrates the potential of two dimensional photocurrent spectroscopy to elucidate detailed origins of photocurrent generating electronic state coherence pathways. Since the measurement is based on detecting the photocell current in situ, the method is well suited to study the fundamental ultrafast processes that affect the function of the device. This opens new avenues to investigate and implement coherent optimization strategies directly within devices. PMID- 25519820 TI - [Therapy of pediatric femoral fractures. Two versus three elastic stable intramedullary nails]. AB - BACKGROUND: The conservative treatment of pediatric femoral fractures can be socially and financially burdensome for patients and families due to the long period of immobilization. New operative techniques have consistently gained significance in the treatment of such fractures due to a shorter period of immobilization. Elastic stable intramedullary nailing (ESIN) in particular has been proven to lead to better outcome in comparison to conservative treatment. This article presents the first study that compares the outcome of three versus two ESINs in the treatment of pediatric femoral shaft fractures. MATERIAL AND METHODS: A retrospective analysis of all patients who underwent operative treatment of femoral fractures with ESINs in our hospital from 2009-2012 was carried out. A follow-up examination was performed in mid-2013 by standardized evaluation of leg length discrepancy and the movement capacity of the hip and knee joint. RESULTS: The follow-up examination revealed a leg length discrepancy of the injured leg when three ESINs were used (p = 0.013) and an impairment of the movement capacity in the hip joint of the injured leg (p = 0.029). In addition the surgery time for metal removal of three ESINs was higher (p = 0.046). All other evaluated parameters did not show any differences. CONCLUSION: In this study population the treatment of pediatric femoral shaft fractures with three ESINs showed no benefit in comparison to two ESINs and therefore should not be used to treat femoral fractures. The leg length discrepancy using three ESINs may be explained by a nonsymmetrical distribution of support points leading to an increased micromovement of the bone with increased callus formation. PMID- 25519821 TI - [Lisfranc dislocation fracture: Dynamic examination under anesthesia and minimally invasive stabilization with mini-TightRope(r)]. AB - As Lisfranc joint injuries are rare and standard radiographic examinations can be difficult to interpret the correct diagnosis is often initially overlooked. Delayed treatment frequently results in painful and disabling arthritis, consequently, primary targeted diagnostics are essential for the functional outcome. We report on a patient with a Lisfranc fracture dislocation, with the injury severity only becoming obvious by dynamic examination with the patient under anesthesia. Due to the massive swelling we performed a minimally invasive primary stabilization using one K-wire and a mini-TightRope(r). PMID- 25519822 TI - [High-pressure injection injury of the hand. Underestimation of injury severity]. AB - A 44-year-old man sustained a high-pressure injection injury of the left index finger with hot hydraulic oil in an occupational accident. On presentation to the occupational physician 4 h later the wound was irrigated and cleaned. At this time X-ray diagnostics, wound revision, administration of antibiotics and immobilization were not performed. The following day the patient presented to a hospital with painful swelling and reddening of the left index finger where an emergency surgical wound revision, administration of antibiotics and immobilization of the finger were performed due to a phlegmon of the flexor tendon. Despite subsequent revision operations, necrosis of the flexor tendon sheath occurred with a skin subcutis defect necessitating a full thickness skin transplantation and ultimately operative fusion of the distal interphalangeal joint of the index finger. After a total period of treatment of 9 months the patient still presented with local soft tissue swelling and paresthesia as well as a limited range of motion of the proximal interphalangeal joint. The patient filed a complaint for wrong treatment of the high-pressure injection injury in terms of an inaccurate examination and lack of administration of antibiotics at the first presentation. The expert opinion of the arbitration board ascertained medical malpractice at the first presentation. An emergency surgical wound revision had already been indicated at the first presentation and the revision procedures would have been less extensive and it was highly probability that surgical fusion of the distal interphalangeal joint could have been avoided. The arbitration furthermore concluded that iatrogenic maltreatment led to a phlegmon of the flexor tendon with the need for subsequent revision operations including surgical fusion of the distal interphalangeal joint which resulted in an affected grip control. The delay in surgical treatment must be considered as the reason for the much worse initial situation that finally led to the functional impairment of the left index finger. PMID- 25519824 TI - Metronomic oral cyclophosphamide plus prednisone in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer. AB - We evaluated the efficacy and safety of metronomic oral cyclophosphamide (CTX) and prednisone in metastatic castration-resistant prostate cancer (mCRPC) patients. We analyzed retrospectively patients with mCRPC previously treated with docetaxel, and who received metronomic CTX (from 50 mg PO daily to 150 mg PO, 14 days/7 days off) and prednisone 10 mg PO daily between September 2009 and April 2014 were analyzed. The primary endpoint was prostate-specific antigen (PSA) decrease >=50 %. Secondary analysis included PSA decrease >=30 %, time-to treatment failure (TTF) and toxicity. Demographics and baseline characteristics were summarized using descriptive statistics. PSA response and adverse events were reported as relative rates. Kaplan-Meier estimates were calculated and plotted for time-to-event endpoints. Forty patients were evaluated. The median age was 69 years old (52-86), 12 (30.0 %) patients presented a Karnofsky performance status (KPS) of <80 %, and 34 (85 %) presented with bone with or without nodal metastases. Median pre-treatment PSA was 192 ng/dL (7-2696 ng/dL). All patients were previously exposed to docetaxel, including 33 (82.5 %) with docetaxel-refractory disease. PSA response rate was achieved in eight (20.0 %) out of 40 patients. Additionally, PSA declines of >=30 % occurred in 14 (35.0 %) patients. The median TTF was 3 months (95 % confidence interval 2.5-3.5). The treatment was well tolerated. Grade 3/4 lymphopenia was reported in 11 (27.5 %) patients and was the only grade 3-4 toxicity reported. Metronomic oral CTX showed activity and safety in docetaxel-pretreated mCRPC patients. This regimen deserves further investigation in this setting. PMID- 25519825 TI - Filming protein fibrillogenesis in real time. AB - Protein fibrillogenesis is a universal tool of nano-to-micro scale construction supporting different forms of biological function. Its exploitable potential in nanoscience and technology is substantial, but the direct observation of homogeneous fibre growth able to underpin a kinetic-based rationale for building customized nanostructures in situ is lacking. Here we introduce a kinetic model of de novo protein fibrillogenesis which we imaged at the nanoscale and in real time, filmed. The model helped to reveal that, in contrast to heterogeneous amyloid assemblies, homogeneous protein recruitment is principally characterized by uniform rates of cooperative growth at both ends of growing fibers, bi directional growth, with lateral growth arrested at a post-seeding stage. The model provides a foundation for in situ engineering of sequence-prescribed fibrous architectures. PMID- 25519823 TI - Chronic kidney disease in lithium-treated older adults: a review of epidemiology, mechanisms, and implications for the treatment of late-life mood disorders. AB - Lithium is an important medication in the treatment of mood disorders. However, clinicians are hesitant to use lithium in older adults for fear of its medical effects, particularly kidney disease. This review describes the current understanding of the epidemiology and mechanisms underlying chronic kidney disease (CKD) in older lithium users, with recommendations for using lithium safely in late life. Prevalence estimates of CKD in older lithium users range from 42-50%, which does not differ greatly from the 37.8% rates seen in community dwelling non-lithium using, non-psychiatric populations. Clinical and pre clinical data suggest a variety of synergistic mechanisms contributing to CKD in older lithium users, including aging, cardiovascular factors, oxidative stress, inflammation, nephrogenic diabetes insipidus, acute kidney injury, and medication interactions. With regards to CKD, lithium can be used safely in many older adults with mood disorders. Compared to patients with pre-existing CKD, those with an estimated glomerular filtration rate >60 mL/min/1.73 m(2) are probably not as susceptible to lithium-associated renal decline. Using lithium concentrations <0.8 mmol/L; monitoring lithium concentrations and renal function every 3-6 months; being vigilant about concurrent medication use (e.g., diuretics, anti-inflammatories); as well as preventing/treating acute kidney injury, nephrogenic diabetes insipidus, diabetes mellitus, hypertension, smoking, and coronary artery disease can all help prevent CKD and further renal decline in older lithium users. PMID- 25519826 TI - An acenocoumarol dosing algorithm exploiting clinical and genetic factors in South Indian (Dravidian) population. AB - OBJECTIVE: The objective of this study was to determine the influence of CYP2C9, VKORC1, CYP4F2, and GGCX genetic polymorphisms on mean daily dose of acenocoumarol in South Indian patients and to develop a new pharmacogenetic algorithm based on clinical and genetic factors. METHODS: Patients receiving acenocoumarol maintenance therapy (n = 230) were included in the study. Single nucleotide polymorphisms (SNP) of CYP2C9, VKORC1, CYP4F2, and GGCX were genotyped by real-time polymerase chain reaction (RT-PCR) method. RESULTS: The mean daily acenocoumarol maintenance dose was found to be 3.7 +/- 2.3 (SD) mg/day. The CYP2C9 *1*2, CYP2C9 *1*3, and CYP2C9 *2*3 variant genotypes significantly reduced the dose by 56.7 % (2.0 mg), 67.6 % (1.6 mg), and 70.3 % (1.5 mg) than wild-type carriers 4.1 mg, p < 0.0001. The genetic variants of CYP2C9 and GGCX (rs11676382) were found to be associated with lower acenocoumarol dose, whereas CYP4F2 (rs2108622) was associated with higher doses. Age, body mass index (BMI), variation of CYP2C9, VKORC1, CYP4F2, and GGCX were the major determinants of acenocoumarol maintenance dose, accounting for 61.8 % of its variability (adjusted r (2) = 0.615, p < 0.0001). Among the VKORC1 variants, rs9923231 alone contributed up to 28.6 % of the acenocoumarol dose variation. CONCLUSION: VKORC1 rs9923231 polymorphism had the highest impact on acenocoumarol daily dose. A new pharmacogenetic algorithm was established to determine the acenocoumarol dose in South Indian population. PMID- 25519827 TI - A case of intramuscular myxoma presenting as a swollen shoulder: a case report. AB - INTRODUCTION: Intramuscular myxoma is a rare benign mesenchymal tumor. Myxomas most commonly occur in the heart. They may occur less frequently in aponeurotic tissues, bone, genitourinary tract, subcutaneous tissue and skin. CASE PRESENTATION: The case described here is a 44-year-old Turkish woman who presented with the complaint of a swelling in her right shoulder. A preoperative magnetic resonance imaging revealed a lobular contoured mass lesion in her deltoid muscle. The mass was marginally excised and pathology revealed intramuscular myxoma. CONCLUSION: Intramuscular myxoma of the deltoid muscle is a very rare benign tumor. In the differential diagnosis, reactive lesions, myxoid nodular fasciitis and low -grade myxoid sarcomas should be kept in mind, upon which the treatment should be planned. PMID- 25519829 TI - Editorial: pharmacological and toxicological evaluation of plant extracts and natural products. PMID- 25519828 TI - Reablement in community-dwelling adults: study protocol for a randomised controlled trial. AB - BACKGROUND: As a result of the ageing population, there is an urgent need for innovation in community health-care in order to achieve sustainability. Reablement is implemented in primary care in some Western countries to help meet these challenges. However, evidence to support the use of such home-based rehabilitation is limited. Reablement focuses on early, time-intensive, multidisciplinary, multi-component and individualised home-based rehabilitation for older adults with functional decline. The aim of this study is to investigate the effectiveness of reablement in home-dwelling adults compared with standard treatment in relation to daily activities, physical functioning, health-related quality of life, use of health-care services, and costs. METHODS/DESIGN: The study will be a 1:1 parallel-group randomised controlled superiority trial conducted in a rural municipality in Norway. The experimental group will be offered reablement and the control group offered standard treatment. A computer generated permuted block randomisation sequence, with randomly selected block sizes, will be used for allocation. Neither participants nor health-care providers will be blinded, however all research assistants and researchers will be blinded. The sample size will consist of 60 participants. People will be eligible if they are home-dwelling, over 18 years of age, understand Norwegian and have functional decline. The exclusion criteria will be people in need of institution-based rehabilitation or nursing home placement, and people who are terminally ill or cognitively reduced. The primary outcome will be self-perceived performance, and satisfaction with performance of daily activities, assessed with the Canadian Occupational Performance Measure. In addition, physical capacity, health-related quality of life, use of health-care services, and cost data will be collected at baseline, and after 3 and 9 months in both groups, and again after 15 months in the intervention group. Data will be analysed on an intention to-treat basis using a linear mixed model for repeated measures. DISCUSSION: The findings will make an important contribution to evaluating cost-effective and evidence-based rehabilitation approaches for community-dwelling adults. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov November 20, 2012, identifier: NCT02043262. PMID- 25519832 TI - Antitumour efficacy of Piper tuberculatum and piplartine based on the hollow fiber assay. AB - Piper tuberculatum, popularly known in Brazil as "jaborandi falso" and "pimenta darta", is widely used in folk medicine for the treatment of several diseases. In this study, the in vivo hollow fiber assay was used to investigate the antitumour efficacy of the crude extract and piplartine obtained from P. tuberculatum roots. Human glioblastoma (SF-295) and colon carcinoma (HCT-8) cell lines were used. In vitro cytotoxicity was assayed by the MTT assay. In the hollow fiber assay, nude mice implanted with tumour cells in hollow fibers were treated for four consecutive days via the intraperitoneal route, and tumour cell populations were assessed by the MTT assay. Both the crude extract and piplartine displayed cytotoxicity. In the hollow fiber assay, tumour growth inhibition rates were 24.6 54.8 % for the crude extract and 33.7-62.2 % for piplartine. No signal of toxicity was noticed. In conclusion, the crude extract and piplartine obtained from P. tuberculatum roots displayed in vitro and in vivo anticancer efficacy. PMID- 25519833 TI - Bornyl cinnamate inhibits inflammation-associated gene expression in macrophage cells through suppression of nuclear factor-kappaB signaling pathway. AB - Formosan sweetgum (Liquidamber formosana) is an endemic tree species. Various parts of this tree are used as a traditional Chinese medicine for treating pain, inflammation, and rheumatic disorders. In this study, we investigated the anti inflammatory potential of bornyl cinnamate, a cinnamic acid derivative from the essential oil of L. formosana. Pretreatment with bornyl cinnamate significantly inhibited lipopolysaccharide-induced proinflammatory molecules, including nitric oxide, prostaglandin-E2, tumor necrosis factor alpha, and interleukin-1beta production, in murine macrophage RAW 264.7 cells. RT-PCR and immunoblotting analysis revealed that the inhibition of the proinflammatory molecules occurred through the downregulation of their corresponding mediator genes. Immunofluorescence and luciferase reporter assays revealed that the inhibition of proinflammatory genes by bornyl cinnamate was caused by the suppression of nuclear translocation and transcriptional activation of the redox-sensitive transcription factor nuclear factor kappaB. In addition, bornyl cinnamate increased the protein stability of the inhibitor of nuclear factor kappaB, an endogenous repressor of nuclear factor kappaB, through inhibition of its phosphorylation and proteasomal degradation. Furthermore, bornyl cinnamate significantly blocked the lipopolysaccharide-induced activation of I-kappaB kinase alpha, an upstream kinase of the inhibitor of nuclear factor kappaB alpha. Taken together, these results suggest that bornyl cinnamate could inhibit proinflammatory molecules through the suppression of the redox-sensitive nuclear factor kappaB signaling pathway. PMID- 25519835 TI - HPLC quantification of all five ginkgolic acid derivatives in Ginkgo biloba extracts using 13 : 0 ginkgolic acid as a single marker compound. AB - An HPLC quantification method for ginkgolic acid derivatives in Ginkgo biloba leaf extracts was developed. Using 13 : 0 ginkgolic acid as a marker compound, the relative correlation factors of the four other ginkgolic acid derivatives - namely, 15 : 0 ginkgolic acid, 15 : 1 ginkgolic acid, 17 : 1 ginkgolic acid, and 17 : 2 ginkgolic acid - to 13 : 0 ginkgolic acid were determined by HPLC and subsequently used for calculating their contents in ten hydro-ethanolic refined extract samples. In other words, the content of 13 : 0 ginkgolic acid in the extracts was determined using the isolated compound as an external standard. Subsequently the now known concentration of this compound functioned as an internal standard for the quantification of the other four ginkgolic acid derivatives via the described correlation factors. This HPLC method was validated by two independent control measurements, one with an external standard for every individual compound and one based on the present method with the single marker compound alone. The results did not differ significantly in any of the 10 tested extract samples. The protocol presented here thus not only uses the same reference substance for G. biloba extracts as the current Chinese Pharmacopoeia method but also incorporates the advantages of the current European Pharmacopoeia approach. It is simple, reproducible, and can be used to determine the total contents of ginkgolic acid derivatives in G. biloba leaf extracts. PMID- 25519834 TI - Isolation and identification of twelve metabolites of isocorynoxeine in rat urine and their neuroprotective activities in HT22 cell assay. AB - Isocorynoxeine, one of the major alkaloids from Uncaria Hook, shows the effects of lowering blood pressure, vasodilatation, and protection against ischemia induced neuronal damage. In this paper, the metabolism of isocorynoxeine was investigated in rats. Twelve metabolites and the parent drug were isolated by using solvent extraction and repeated chromatographic methods, and determined by spectroscopic methods including UV, MS, NMR, and CD experiments. Seven new compounds were identified as 11-hydroxyisocorynoxeine, 5-oxoisocorynoxeinic acid 22-O-beta-D-glucuronide, 10-hydroxyisocorynoxeine, 17-O-demethyl-16,17-dihydro-5 oxoisocorynoxeine, 5-oxoisocorynoxeinic acid, 21-hydroxy-5-oxoisocorynoxeine, and oxireno[18, 19]-5-oxoisocorynoxeine, together with six known compounds identified as isocorynoxeine, 18,19-dehydrocorynoxinic acid, 18,19-dehydrocorynoxinic acid B, corynoxeine, isocorynoxeine-N-oxide, and corynoxeine-N-oxide. Possible metabolic pathways of isocorynoxeine are proposed. Furthermore, the activity assay for the parent drug and some of its metabolites showed that isocorynoxeine exhibited a significant neuroprotective effect against glutamate-induced HT22 cell death at the maximum concentration. However, little or weak neuroprotective activities were observed for M-3, M-6, M-7, and M-10. Our present study is important to further understand their metabolic fate and disposition in humans. PMID- 25519836 TI - Identification of cancer stem cell subpopulations of CD34(+) PLC/PRF/5 that result in three types of human liver carcinomas. AB - CD34(+) stem cells play an important role during liver development and regeneration. Thus, we hypothesized that some human liver carcinomas (HLCs) might be derived from transformed CD34(+) stem cells. Here, we determined that a population of CD34(+) cells isolated from PLC/PRF/5 hepatoma cells (PLC) appears to function as liver cancer stem cells (LCSCs) by forming HLCs in immunodeficient mice with as few as 100 cells. Moreover, the CD34(+) PLC subpopulation cells had an advantage over CD34(-) PLCs at initiating tumors. Three types of HLCs were generated from CD34(+) PLC: hepatocellular carcinomas (HCCs); cholangiocarcinomas (CC); and combined hepatocellular cholangiocarcinomas (CHCs). Tumors formed in mice transplanted with 12 subpopulations and 6 progeny subpopulations of CD34(+) PLC cells. Interestingly, progenies with certain surface antigens (CD133, CD44, CD90, or EPCAM) predominantly yielded HCCs. CD34(+) PLCs that also expressed OV6 and their progeny OV6(+) cells primarily produced CHC and CC. This represents the first experiment to demonstrate that the OV6(+) antigen is associated with human CHC and CC. CD34(+) PLCs that also expressed CD31 and their progeny CD31(+) cells formed CHCs. Gene expression patterns and tumor cell populations from all xenografts exhibited diverse patterns, indicating that tumor-initiating cells (TICs) with distinct antigenic profiles contribute to cancer cell heterogeneity. Therefore, we identified CD34(+) PLC cells functioning as LCSCs generating three types of HLCs. Eighteen subpopulations from one origin had the capacity independently to initiate tumors, thus functioning as TICs. This finding has broad implications for better understanding of the multistep model of tumor initiation and progression. Our finding also indicates that CD34(+) PLCs that also express OV6 or CD31 result in types of HLCs. This is the first report that PLC/PRF/5 subpopulations expressing CD34 in combination with particular antigens defines categories of HLCs, implicating a diversity of origins for HLC. PMID- 25519837 TI - A novel function for UDP glycosyltransferase 8: galactosidation of bile acids. AB - The human UDP glycosyltransferase (UGT) superfamily comprises four families of enzymes that catalyze the addition of sugar residues to small lipophilic chemicals. The UGT1 and UGT2 enzymes use UDP-glucuronic acid, and UGT3 enzymes use UDP-N-acetylglucosamine, UDP-glucose, and UDP-xylose to conjugate xenobiotics, including drugs and endobiotics such as metabolic byproducts, hormones, and signaling molecules. This metabolism renders the substrate more polar and more readily excreted from the body and/or functionally inactive. The fourth UGT family, called UGT8, contains only one member that, unlike other UGTs, is considered biosynthetic. UGT8 uses UDP galactose to galactosidate ceramide, a key step in the synthesis of brain sphingolipids. To date other substrates for this UGT have not been identified and there has been no suggestion that UGT8 is involved in metabolism of endo- or xenobiotics. We re-examined the functions of UGT8 and discovered that it efficiently galactosidates bile acids and drug-like bile acid analogs. UGT8 conjugates bile acids ~60-fold more efficiently than ceramide based on in vitro assays with substrate preference deoxycholic acid > chenodeoxycholic acid > cholic acid > hyodeoxycholic acid > ursodeoxycholic acid. Activities of human and mouse UGT8 are qualitatively similar. UGT8 is expressed at significant levels in kidney and gastrointestinal tract (intestine, colon) where conjugation of bile acids is likely to be metabolically significant. We also investigate the structural determinants of UDP-galactose selectivity. Our novel findings suggest a new role for UGT8 as a modulator of bile acid homeostasis and signaling. PMID- 25519838 TI - Concatenated hERG1 tetramers reveal stoichiometry of altered channel gating by RPR-260243. AB - Activation of human ether-a-go-go-related gene 1 (hERG1) K(+) channels mediates repolarization of action potentials in cardiomyocytes. RPR-260243 [(3R,4R)-4-[3 (6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluorophenyl)-prop-2-ynyl] piperidine-3-carboxylic acid] (RPR) slows deactivation and attenuates inactivation of hERG1 channels. A detailed understanding of the molecular mechanism of hERG1 agonists such as RPR may facilitate the design of more selective and potent compounds for prevention of arrhythmia associated with abnormally prolonged ventricular repolarization. RPR binds to a hydrophobic pocket located between two adjacent hERG1 subunits, and, hence, a homotetrameric channel has four identical RPR binding sites. To investigate the stoichiometry of altered channel gating induced by RPR, we constructed and characterized tetrameric hERG1 concatemers containing a variable number of wild-type subunits and subunits containing a point mutation (L553A) that rendered the channel insensitive to RPR, ostensibly by preventing ligand binding. The slowing of deactivation by RPR was proportional to the number of wild-type subunits incorporated into a concatenated tetrameric channel, and four wild-type subunits were required to achieve maximal slowing of deactivation. In contrast, a single wild-type subunit within a concatenated tetramer was sufficient to achieve half of the maximal RPR-induced shift in the voltage dependence of hERG1 inactivation, and maximal effect was achieved in channels containing three or four wild-type subunits. Together our findings suggest that the allosteric modulation of channel gating involves distinct mechanisms of coupling between drug binding and altered deactivation and inactivation. PMID- 25519839 TI - Effects of oxygen adsorption on the surface state of epitaxial silicene on Ag(111). AB - Epitaxial silicene, which is one single layer of silicon atoms packed in a honeycomb structure, demonstrates a strong interaction with the substrate that dramatically affects its electronic structure. The role of electronic coupling in the chemical reactivity between the silicene and the substrate is still unclear so far, which is of great importance for functionalization of silicene layers. Here, we report the reconstructions and hybridized electronic structures of epitaxial 4 * 4 silicene on Ag(111), which are revealed by scanning tunneling microscopy and angle-resolved photoemission spectroscopy. The hybridization between Si and Ag results in a metallic surface state, which can gradually decay due to oxygen adsorption. X-ray photoemission spectroscopy confirms the decoupling of Si-Ag bonds after oxygen treatment as well as the relatively oxygen resistance of Ag(111) surface, in contrast to 4 * 4 silicene [with respect to Ag(111)]. First-principles calculations have confirmed the evolution of the electronic structure of silicene during oxidation. It has been verified experimentally and theoretically that the high chemical activity of 4 * 4 silicene is attributable to the Si pz state, while the Ag(111) substrate exhibits relatively inert chemical behavior. PMID- 25519840 TI - Relative genomic stability of adipose tissue derived mesenchymal stem cells: analysis of ploidy, H19 long non-coding RNA and p53 activity. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) are multipotent and have been derived from various tissues. Although MSCs share many basic features, they often display subtle tissue specific differences. We previously demonstrated that bone marrow (BM) MSCs frequently become polyploid in culture. This tendency was mediated by a reduction in the expression of H19 long non-coding RNA during the transition from a diploid to a polyploid state. METHODS: MSCs were derived from both BM and adipose tissue of mice and expanded under normoxic and hypoxic culture conditions. Cells were stained by propidium iodide and their ploidy was evaluated by FACS. Gene expression of independent MSC preparations was compared by quantitative real time PCR and protein expression levels by Western blot analysis. p53 silencing in MSCs was performed by a specific small hairpin RNA (shRNA). RESULTS: We set to examine whether genomic instability is common to MSCs originating from different tissues. It is demonstrated that adipose derived MSCs (ASCs) tend to remain diploid during culture while a vast majority of BM MSCs become polyploid. The diploid phenotype of ASCs is correlated with reduced H19 expression compared to BM MSCs. Under hypoxic conditions (3% oxygen) both ASCs and BM MSCs demonstrate increased RNA expression of H19 and Vascular endothelial growth factor A. Importantly, ASC gene expression is significantly less variable than BM MSCs under both oxygen conditions, indicating to their superior homogeneity. Gene expression analysis revealed that p53 target genes, often induced by DNA damage, are up-regulated in ASCs under basal conditions. However, p53 activation following treatment with DNA damaging agents was strongly elevated in BM MSCs compared to ASCs. We found that p53 is involved in maintaining the stable diploid state of ASCs as p53 shRNA induced ploidy changes in ASCs but not in BM MSCs. CONCLUSIONS: The increased genomic stability of murine ASCs together with their lower H19 expression and relative homogeneity suggest a tissue specific higher stability of ASCs compared to BM MSCs, possibly due to higher activity of p53. The tissue specific differences between MSCs from a different tissue source may have important consequences on the use of various MSCs both in vitro and in vivo. PMID- 25519842 TI - Odontoid process and clival regeneration with Chiari malformation worsening after transoral decompression: an unexpected and previously unreported cause of "accordion phenomenon". AB - PURPOSE: Transoral odontoidectomy followed by occipito-cervical fixation is a widely used approach to relieve ventral compressions at the craniovertebral junction (CVJ). Despite the large amount of literature on this approach and its complications, no previous reports of odontoid process and clival regeneration following transoral odontoidectomy are present in the English literature. METHODS: We report the case of odontoid process and clival regeneration following transoral odontoidectomy. RESULTS: A 7-year-old boy presented with symptoms of brainstem and upper cervical spinal cord compression due to a complex malformation at the CVJ including a basilar invagination with Chiari malformation. A successful transoral microsurgical endoscopic-assisted odontoidectomy extended to the clivus was performed along with occipito cervical instrumentation and fusion. Clinical and radiological resolution of the CVJ compression was evident up to 2 years post-op, when the child had a relapse of some of the presenting symptoms and the follow-up CT and MRI scans showed a quite complete regrowth of the odontoid process, clival partial regeneration and recurrence of preoperative Chiari malformation. CONCLUSIONS: Besides the need of an accurate complete resection of the periosteum, which apparently was incompletely performed in our case, our experience suggests the need of resection of the odontoid down to the dentocentral synchondrosis and an accurate lateral removal of the bone surrounding the anterior tubercle of the Clivus is advised when an anterior CVJ decompression is required in children presenting a still evident synchondrosis at neuroradiological investigation. PMID- 25519841 TI - The landscape of transposable elements in the finished genome of the fungal wheat pathogen Mycosphaerella graminicola. AB - BACKGROUND: In addition to gene identification and annotation, repetitive sequence analysis has become an integral part of genome sequencing projects. Identification of repeats is important not only because it improves gene prediction, but also because of the role that repetitive sequences play in determining the structure and evolution of genes and genomes. Several methods using different repeat-finding strategies are available for whole-genome repeat sequence analysis. Four independent approaches were used to identify and characterize the repetitive fraction of the Mycosphaerella graminicola (synonym Zymoseptoria tritici) genome. This ascomycete fungus is a wheat pathogen and its finished genome comprises 21 chromosomes, eight of which can be lost with no obvious effects on fitness so are dispensable. RESULTS: Using a combination of four repeat-finding methods, at least 17% of the M. graminicola genome was estimated to be repetitive. Class I transposable elements, that amplify via an RNA intermediate, account for about 70% of the total repetitive content in the M. graminicola genome. The dispensable chromosomes had a higher percentage of repetitive elements as compared to the core chromosomes. Distribution of repeats across the chromosomes also varied, with at least six chromosomes showing a non random distribution of repetitive elements. Repeat families showed transition mutations and a CpA -> TpA dinucleotide bias, indicating the presence of a repeat induced point mutation (RIP)-like mechanism in M. graminicola. One gene family and two repeat families specific to subtelomeres also were identified in the M. graminicola genome. A total of 78 putative clusters of nested elements was found in the M. graminicola genome. Several genes with putative roles in pathogenicity were found associated with these nested repeat clusters. This analysis of the transposable element content in the finished M. graminicola genome resulted in a thorough and highly curated database of repetitive sequences. CONCLUSIONS: This comprehensive analysis will serve as a scaffold to address additional biological questions regarding the origin and fate of transposable elements in fungi. Future analyses of the distribution of repetitive sequences in M. graminicola also will be able to provide insights into the association of repeats with genes and their potential role in gene and genome evolution. PMID- 25519843 TI - Cu-Catalyzed selective C3-formylation of imidazo[1,2-a]pyridine C-H bonds with DMSO using molecular oxygen. AB - Using the widely available DMSO as the formylation reagent under oxidative conditions, an efficient Cu-catalyzed C3-formylation reaction of imidazo[1,2 a]pyridine C-H bonds to directly generate structurally sophisticated 3-formyl imidazo[1,2-a]pyridine derivatives has been developed. The reaction proceeded to generate products in good yields, and used the environmentally friendly molecular oxygen as the oxidant. PMID- 25519845 TI - Cysteine-mediated redox signalling in the mitochondria. AB - The mitochondria are critical mediators of cellular redox homeostasis due to their role in the generation and dissipation of reactive oxygen/nitrogen species (ROS/RNS). Modulations in ROS/RNS levels in the mitochondria are often reflected through oxidation/nitrosation of highly redox-sensitive cysteine residues within this organelle. Oxidation/nitrosation of functional cysteines on mitochondrial proteins serves to modulate protein activity, localization, and complexation in response to cellular stress, thereby controlling critical processes such as oxidative phosphorylation, apoptosis, and redox signalling. In this review, we describe mitochondrial sources of ROS/RNS, cysteine modifications that are triggered by increased mitochondrial ROS/RNS, and examples of key mitochondrial proteins that are regulated through cysteine-mediated redox signalling. We highlight recent advancements in proteomic methods to study cysteine posttranslational modifications. These tools will further aid in illuminating the important role of cysteine in maintaining and transducing redox signals in the mitochondria. PMID- 25519844 TI - Effect of individually tailored biopsychosocial workplace interventions on chronic musculoskeletal pain, stress and work ability among laboratory technicians: randomized controlled trial protocol. AB - BACKGROUND: Among laboratory technicians, the prevalence of neck and shoulder pain is widespread possibly due to typical daily work tasks such as pipetting, preparing vial samples for analysis, and data processing on a computer including mouse work - all tasks that require precision in motor control and may result in extended periods of time spent in static positions.In populations characterized by intense chronic musculoskeletal pain and diagnosed conditions in conjunction with psycho-physiological symptoms such as stress-related pain and soreness and other disabling conditions, multifactorial approaches applying a combination of individually tailored physical and cognitive strategies targeting the areas most needed, may be an effective solution to the physical and mental health challenges.The aim of this study is therefore to investigate the effect of an individually tailored biopsychosocial intervention strategy on musculoskeletal pain, stress and work disability in lab technicians with a history of musculoskeletal pain at a single worksite in Denmark. METHODS/DESIGN: In this single-blind two-armed parallel-group randomized controlled trial with allocation concealment, participants receive either an individualized multifactorial intervention or "usual care" for 10 weeks at the worksite. INCLUSION CRITERIA: 1) female laboratory technician (18-67 years of age) and 2) Pain intensity >= 3 (0 10 Visual Analogue Scale) lasting >=3 months with a frequency of >= 3 days per week in one or more of the following regions: i) upper back i) low back iii) neck, iv) shoulder, v) elbow and/or vi) hand. EXCLUSION CRITERIA: 1) life threatening disease and 2) pregnancy. Stress, as measured by Cohen's perceived stress questionnaire is not an inclusion criteria, thus participants can participate regardless of their stress level.We will implement an individualized intervention addressing biopsychosocial elements of musculoskeletal pain with the following components; i) increasing physical capacity through strength- and motor control training; ii) lowering or preventing development of stress through mindfulness practice and learning de-catastrophizing pain management strategies through cognitive training.The primary outcome at 10-week follow-up is the between-group difference in intensity of perceived musculoskeletal pain during the last week (average value of back, neck, shoulder, elbow and hand) assessed by questionnaire (modified visual analogue scale 0-10). DISCUSSION: This study will provide experimental evidence to guide workplace initiatives designed towards reducing chronic musculoskeletal pain and stress. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02047669. PMID- 25519846 TI - Pycnogenol(r) and Centella asiatica in the management of asymptomatic atherosclerosis progression. AB - AIM: The aim of the study was to evaluate the effect of the nutritional supplements Pycnogenol(r) and total triterpenic fraction of Centella asiatica (TTFCA) on atherosclerosis progression in low-risk asymptomatic subjects with carotid or femoral stenosing plaques. METHODS: This was an observational pilot, substudy of the San Valentino epidemiological cardiovascular study. The study included 824 subjects aged 45-60 without any conventional risk factors who had a stenosing atherosclerotic plaque (>50-60%) in at least one carotid or common femoral bifurcation, allocated into 6 groups: Group 1 (Controls): management was based on education, exercise, diet and lifestyle changes. This same management plan was used in all other groups; group 2: Pycnogenol(r) 50 mg/day; group 3: Pycnogenol(r) 100 mg/day; group 4: Aspirin(r) 100 mg/day or ticlopidine 250 mg/day if intolerant to aspirin; group 5: Aspirin(r) 100 mg/day and Pycnogenol(r) 100 mg/day; group 6: Pycnogenol(r) 100 mg/day plus TTFCA 100 mg/day. The follow up lasted 42 months. Plaque progression was assessed using the ultrasonic arterial score based on the arterial wall morphology and the number of plaques that progressed and on the number of subjects that had cardiovascular events. A secondary endpoint was to evaluate the changes in oxidative stress at baseline and at 42 months. RESULTS: The ultrasonic score increased significantly in groups 1, 2, and 4 (>1%) but not in groups 3, 5 and 6 (<1%) suggesting a beneficial effect of Pycnogenol(r) 100 mg. Considering the percent of patients that progressed from class V (asymptomatic) to VI (symptomatic) there was a progression of plaques in 48.09% of controls. In the Pycnogenol(r) 100 (group 3, 10.4%) and in the Aspirin(r)+ Pycnogenol(r) (group 5, 10.68%) progression was half of what observed with antiplatelet agent (group 4, 20.93%); in the TTFCA+ Pycnogenol(r)group (group 6) progression was 7.4 times lower than in controls; 3.22 times lower than in the antiplatelet agents group (4). Events (hospital admission, specialized care) were observed in 16.03% of controls; there were 8.83% of subjects with events with Pycnogenol(r) 50 mg and 8% in group 3 (Pycnogenol(r) 100 mg). In group 4 (antiplatelets), 8.52% of subjects had events; in group 5, 6.87% of subjects had events and in group 6 (TTFCA+ Pycnogenol(r)) only 4.41% had events (this was the lowest event rate; P<0.05). All treatment groups had a significantly lower event rate (P<0.05) in comparison with controls. Considering treatments groups 2, 3, 5, 6 had a lower number (P<0.05) of subjects in need of cardiovascular management in comparison with controls. The need for risk factor management was higher in controls and lower in group 6 (P<0.05). In groups 2 to 6 the need for risk factor management was lower than in controls (P<0.05). Including all events (hospital admission, need for treatment or for risk management) 51.9% of controls were involved. In the other groups there was a reduction (from a -9.28% reduction in group 2 to a -26% in group 6) (P<0.002). The most important reduction (higher that in all groups; P<0.05) was in group 6. At 42 months, oxidative stress in all the Pycnogenol(r) groups was less than in the control group. In the combined group of Pycnogenol(r) and TTFCA the oxidative stress was less than with Pycnogenol(r) alone (P<0.001). CONCLUSION: Pycnogenol(r) and the combination of Pycnogenol(r) +TTFCA appear to reduce the progression of subclinical arterial plaques and the progression to clinical stages. The reduction in plaque and clinical progression was associated with a reduction in oxidative stress. The results justify a large, randomized, controlled study to demonstrate the efficacy of the combined Pycnogenol(r) and TTFCA prophylactic therapy in preclinical atherosclerosis. PMID- 25519847 TI - eMental health experiences and expectations: a survey of youths' Web-based resource preferences in Canada. AB - BACKGROUND: Due to the high prevalence of psychological disorders and the lack of access to care among Canadian youth, the development of accessible services is increasingly important. eMental Health is an expanding field that may help to meet this need through the provision of mental health care using technology. OBJECTIVE: The primary goals of the study are to explore youth experiences with traditional and online mental health resources, and to investigate youth expectations for mental health websites. METHODS: A Web-based survey containing quantitative and qualitative questions was delivered to youth aged 17-24 years. Participants were surveyed to evaluate their use of mental health resources as well as their preferences for various components of a potential mental health website. RESULTS: A total of 521 surveys were completed. Most participants (61.6%, 321/521) indicated that they had used the Internet to seek information or help for feelings they were experiencing. If they were going through a difficult time, 82.9% (432/521) of participants were either "somewhat likely" or "very likely" to use an information-based website and 76.8% (400/521) reported that they were either "somewhat unlikely" or "very unlikely" to visit social media websites for information or help-seeking purposes during this time. Most (87.7%, 458/521) participants rated their online privacy as very important. Descriptions of interventions and treatments was the most highly rated feature to have in a mental health-related website, with 91.9% (479/521) of participants regarding it as "important" or "very important". When presented a select list of existing Canadian mental health-related websites, most participants had not accessed any of the sites. Of the few who had, the Canadian Mental Health Association website was the most accessed website (5.8%, 30/521). Other mental health-related websites were accessed by only 10.9% of the participants (57/521). CONCLUSIONS: The findings suggest that despite interest in these tools, current eMental Health resources either do not meet the needs of or are not widely accessed by youth with mental health problems. In order to improve access to these resources for Canadian youth, Web-based platforms should provide information about mental health problems, support for these problems (peer and professional), and information about resources (self-help as well as ability to locate nearby resources), while protecting the privacy of the user. These findings will not only assist in the development of new mental health platforms but may also help improve existing ones. PMID- 25519848 TI - NICE advises extra pregnancy support for women at risk of mental health problems. PMID- 25519849 TI - Grafting {Cp*Rh}(2+) on the surface of Nb and Ta Lindqvist-type POM. AB - New hybrid POM based on Lindqvist-type polyoxometalates [M6O19](8-) (M = Nb, Ta) and organometallic fragment {Cp*Rh}(2+) have been isolated and characterized. X ray quality crystals of K4[(Cp*Rh)2Nb6O19].20H2O () and Cs4[(Cp*Rh)2Ta6O19].18H2O () were obtained from solutions with {Cp*Rh} : [M6O19](8-) stoichiometry 2 : 1. The solution behavior of the hybrid polyoxoanions was studied with ESI-MS and (1)H DOSY NMR. Amongst the poorly investigated chemistry of polyoxotantalates, complex is the first complex bearing a grafted organometallic fragment. The formation of 1 : 1 complexes was detected by ESI-MS techniques. PMID- 25519851 TI - Does Alcohol or Delinquency Help Adolescents Feel Better Over Time? A Study on the Influence of Heavy Drinking and Violent/Property Offending on Negative Emotions. AB - Conceptualizing adolescent drinking and delinquency as adaptations to strain, we explore whether they (a) decrease or increase the probability of feeling depression and anxiety later and (b) ameliorate or aggravate the effect of strain on the negative emotions over time. These relationships are also examined for gender differences by analyzing data separately for males and females as well as both combined. We conducted ordinary least squares regression analysis of panel data from the first two waves of the National Longitudinal Study of Adolescent to Adult Health. Heavy drinking and serious delinquency were found to increase the probability of feeling depression and anxiety later, whereas they tend to ameliorate the emotionally deleterious effect of strain for males and, to a lesser extent, females. PMID- 25519850 TI - Comparison of the preference-based EQ-5D-5L and SF-6D in patients with end-stage renal disease (ESRD). AB - OBJECTIVES: The objective of this study was to compare the performance of the 5 level EuroQol 5-dimension (EQ-5D-5L) and the Short Form 6-dimension (SF-6D) instruments in assessing patients with end-stage renal disease (ESRD) in Singapore. METHODS: In a cross-sectional study, ESRD patients attending a tertiary hospital were interviewed using a battery of questionnaires including the EQ-5D-5L, the kidney disease quality of life instrument (KDQOL-36), and questions assessing dialysis history and socio-demographic characteristics. We reviewed patients' medical records for their clinical information. We assessed the construct validity of the EQ-5D-5L and SF-6D index scores and compared their ability to distinguish between patients differing in health status and the magnitude of between-group difference they quantified. RESULTS: One hundred and fifty ESRD patients on dialysis (mean age, 60.1 years; female, 48.7%) participated in the study. Both EQ-5D-5L and SF-6D demonstrated satisfactory known-groups validity; the EQ-5D-5L was more sensitive to differences in clinical outcomes and the SF-6D was more sensitive to differences in health outcomes measured by KDQOL scales. The intraclass correlation coefficient between the measures was 0.36. The differences in the EQ-5D-5L index score for patients in better and worse health status were greater than those measured by the SF-6D index score. CONCLUSIONS: Both EQ-5D-5L and SF-6D are valid instruments for assessing ESRD patients. However, the two preference-based measures cannot be used interchangeably and it appears that EQ-5D-5L would lead to more favorable cost-effectiveness results than SF-6D if they are used in economic evaluations of interventions for ESRD. PMID- 25519852 TI - The roles of C-terminal residues on the thermal stability and local heme environment of cytochrome c' from the thermophilic purple sulfur bacterium Thermochromatium tepidum. AB - A soluble cytochrome (Cyt) c' from thermophilic purple sulfur photosynthetic bacterium Thermochromatium (Tch.) tepidum exhibits marked thermal tolerance compared with that from the closely related mesophilic counterpart Allochromatium vinosum. Here, we focused on the difference in the C-terminal region of the two Cyts c' and examined the effects of D131 and R129 mutations on the thermal stability and local heme environment of Cyt c' by differential scanning calorimetry (DSC) and resonance Raman (RR) spectroscopy. In the oxidized forms, D131K and D131G mutants exhibited denaturing temperatures significantly lower than that of the recombinant control Cyt c'. In contrast, R129K and R129A mutants denatured at nearly identical temperatures with the control Cyt c', indicating that the C-terminal D131 is an important residue maintaining the enhanced thermal stability of Tch. tepidum Cyt c'. The control Cyt c' and all of the mutants increased their thermal stability upon the reduction. Interestingly, D131K exhibited narrow DSC curves and unusual thermodynamic parameters in both redox states. The RR spectra of the control Cyt c' exhibited characteristic bands at 1,635 and 1,625 cm(-1), ascribed to intermediate spin (IS) and high spin (HS) states, respectively. The IS/HS distribution was differently affected by the D131 and R129 mutations and pH changes. Furthermore, R129 mutants suggested the lowering of their redox potentials. These results strongly indicate that the D131 and R129 residues play significant roles in maintaining the thermal stability and modulating the local heme environment of Tch. tepidum Cyt c'. PMID- 25519854 TI - An improved fast photochemical oxidation of proteins (FPOP) platform for protein therapeutics. AB - Unlike small-molecule drugs, the size and dynamics of protein therapeutics challenge existing methods for assessing their high order structures (HOS). To extend fast photochemical oxidation of proteins (FPOP) to protein therapeutics, we modified its platform by introducing a mixing step prior to laser irradiation to minimize unwanted H(2)O(2)-induced oxidation. This improvement plus standardizing each step yield better reproducibility as determined by a fitting process whereby we used a non-FPOP spectrum as a template to report the unmodified level. We also tested different buffer systems for this modified FPOP platform with cytochrome c. The outcome is a standard oxidation profile that can be compared between different laboratories and regulatory agencies that wish to adopt FPOP for quality control purposes. PMID- 25519855 TI - Adult staphylococcal scalded skin syndrome successfully treated with plasma exchange. PMID- 25519856 TI - Two-dimensional graphene analogues for biomedical applications. AB - The increasing demand of clinical biomedicine and fast development of nanobiotechnology has substantially promoted the generation of a variety of organic/inorganic nanosystems for biomedical applications. Biocompatible two dimensional (2D) graphene analogues (e.g., nanosheets of transition metal dichalcogenides, transition metal oxides, g-C3N4, Bi2Se3, BN, etc.), which are referred to as 2D-GAs, have emerged as a new unique family of nanomaterials that show unprecedented advantages and superior performances in biomedicine due to their unique compositional, structural and physicochemical features. In this review, we summarize the state-of-the-art progress of this dynamically developed material family with a particular focus on biomedical applications. After the introduction, the second section of the article summarizes a range of synthetic methods for new types of 2D-GAs as well as their surface functionalization. The subsequent section provides a snapshot on the use of these biocompatible 2D-GAs for a broad spectrum of biomedical applications, including therapeutic (photothermal/photodynamic therapy, chemotherapy and synergistic therapy), diagnostic (fluorescent/magnetic resonance/computed tomography/photoacoustic imaging) and theranostic (concurrent diagnostic imaging and therapy) applications, especially on oncology. In addition, we briefly present the biosensing applications of these 2D-GAs for the detection of biomacromolecules and their in vitro/in vivo biosafety evaluations. The last section summarizes some critical unresolved issues, possible challenges/obstacles and also proposes future perspectives related to the rational design and construction of 2D-GAs for biomedical engineering, which are believed to promote their clinical translations for benefiting the personalized medicine and human health. PMID- 25519858 TI - Left ventricular function by echocardiogram in children with sickle cell anaemia in Mumbai, Western India. AB - INTRODUCTION: Cardiovascular events and complications are the leading cause of mortality and morbidity in patients with sickle cell disease. Cardiac abnormalities occur frequently and at an early stage in sickle cell anaemia patients, despite being more evident in adulthood. Sickle cell anaemia patients are increasingly able to reach adulthood owing to improved healthcare, and may, therefore, suffer the consequences of chronic cardiac injury. Thus, the study of cardiac abnormalities is essential in children OBJECTIVE: The aim of this study was to determine the echocardiographic changes in left ventricular function in children suffering from sickle cell disease in Mumbai, Western India. METHODS: The study comprised of 48 cases of sickle cell anaemia and 30 non-anaemic controls with normal haemoglobin and electrophoresis pattern. M-mode, two dimensional, and Doppler echocardiographic measurements of patients and controls were performed according to the criteria of the American Echocardiography Society. RESULTS: On Doppler study, the A wave height was increased and the E/A ratio was decreased, whereas the deceleration and isovolumetric relaxation times were prolonged, which is typically seen in slowed or impaired myocardial relaxation (p<0.001). Although chamber dilatations were present, echocardiographic parameters showed no statistically significant correlation with severity of anaemia and age among the sickle cell patients. CONCLUSIONS: We conclude that the increased left ventricular stiffness, compared with controls, might be due to fibrosis related to ischaemia caused by SS disease in addition to wall hypertrophy. PMID- 25519859 TI - Sarcoma botryoides in an infant. AB - A 17-month-old girl with no medical history presented at our emergency room with abnormal vaginal bleeding and vaginal tissue loss with a "grape bunch" appearance. Physical examination showed no abnormalities, but gynaecological examination showed abnormal vaginal tissue protruding through the vagina introitus. Given the typical clinical presentation, the age of the girl and the location and aspect of the lesion, there was a high suspicion of the botryoid variant of embryonal rhabdomyosarcoma of the vagina. Histology of a biopsy of the lesion was consistent with embryonal rhabdomyosarcoma. As no metastases were detected, the girl received chemotherapy. This case report describes the importance of early recognition of the typical clinical symptoms of sarcoma botryoides, since a rapid diagnosis followed by treatment is necessary to prevent death. PMID- 25519860 TI - Pancreaticoatmospheric fistula following severe acute necrotising pancreatitis. AB - Severe acute necrotising pancreatitis is associated with numerous local and systemic complications. Abdominal compartment syndrome requiring urgent decompressive laparotomy is a potential complication of this disease process and is associated with increased morbidity and mortality. We describe the case of a pancreaticoatmospheric fistula following decompressive laparotomy in a patient with severe acute necrotising pancreatitis. While this fistula was managed successfully using the current standard of care for pancreatic fistulas, the wound care for in this patient with drainage of the fistula through an open abdomen, is a significant challenge. PMID- 25519861 TI - A surgically treated pulmonary sclerosing haemangioma that clinically and radiologically mimicked a thrombosed pulmonary artery aneurysm. AB - We report the case of a 70-year-old woman with a surgically treated pulmonary sclerosing haemangioma that clinically and radiologically mimicked a thrombosed pulmonary artery aneurysm. She underwent intravenous thrombolytic therapy because of acute pulmonary embolism in the bilaterally segmental arteries. The pulmonary embolism had almost disappeared except for a nodular lesion in the middle lobe branch of the pulmonary artery, and a thrombosed pulmonary artery aneurysm with thrombus was suspected in the CT image. The patient underwent a video-assisted thoracoscopic middle lobectomy. The final pathological diagnosis was sclerosing haemangioma. She had experienced no recurrence for 1 year after surgery, and we continue to take great care during her follow-up. PMID- 25519853 TI - Erratum to: medication prescription and adherence disparities in non valvular atrial fibrillation patients: an Italian portrait from the ARAPACIS study. PMID- 25519862 TI - Emphysematous cystitis due to recurrent Clostridium difficile infection. AB - A 78-year-old woman with long-standing obstipation presented herself to the hospital with diarrhoea and progressive abdominal cramping since 2 days. Acute abdomen developed and an emergency exploratory laparotomy was indicated, which showed no signs of bowel ischaemia. After admission to the internal ward, stool Clostridium difficile PCR was tested positive. Hence the diagnosis of pseudomembranous colitis became apparent. Abdominal imaging demonstrated multiple gas foci in the wall of the bladder and extensive pseudomembranous colitis. The patient was initially treated with oral vancomycin and secondarily with metronidazole for recurrent C. difficile infection. Resolution of diarrhoea and abdominal cramping was noted on 6-week follow-up visit. PMID- 25519863 TI - Abiotrophia defectiva endocarditis. AB - A previously healthy 27-year-old Jamaican man presented to the University Hospital of the West Indies with recurrent joint pain, remitting and relapsing fever, and shortness of breath. He was subsequently found to have Abiotrophia defectiva endocarditis. This was the first time this organism had been isolated at our institution. Despite culture directed antibiotics, his clinical course was quite severe with mitral regurgitation and congestive cardiac failure requiring mitral valve replacement. He recovered well postoperatively and is currently being followed at our outpatient cardiology clinic. This report highlights the severe presentation and often poor outcome associated with A. defectiva endocarditis and stresses that the outcome may be improved by early and appropriate surgical intervention. PMID- 25519864 TI - Occult foreign body in the lung mimicking bronchogenic carcinoma. AB - Undiagnosed and retained foreign bodies in lungs may result in serious complications such as pneumonia, atelectasis or bronchiectasis. We describe a clinical scenario of chronic and recurrent cough in a 41-year-old woman with no comorbidities. Her chest CT scan was suggestive of a mass lesion in the right main bronchus. Bronchoscopic examination showed no growth; instead, note was made of a plastic foreign body. The foreign body was retracted using a rigid Bronchoscope. The patient admitted unintentionally aspirating this plastic object when she was in her early 20s but denied any serious respiratory complication at that time or later. However, she was admitted 6 years prior to current presentation with pneumonia and discharged home following parenteral antibiotic therapy. On retrieval of the foreign body her clinical condition improved and she has been following up at our clinic for the past 2 years. PMID- 25519866 TI - Tuberous sclerosis complex with autosomal dominant polycystic kidney disease: a rare duo. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant condition characterised by the presence of multiple hamartomas in various organ systems in the body. The kidneys are affected in 80% of patients, usually in the form of renal angiomyolipomas, renal cysts or renal cell carcinoma. Although extremely rare, TSC and autosomal dominant polycystic kidney disease (ADPKD) can co-exist in the same patient as a result of concurrent deletion of both polycystic kidney disease (PKD) 1 and TSC2 genes present on the chromosome 16p13.3. These patients develop end-stage renal disease at an earlier age and have an increased risk of malignancy. We present a case of a 30-year-old man with a history of tuberous sclerosis, presenting with loin pain and subsequently diagnosed to have ADPKD. PMID- 25519865 TI - Failure to identify or effectively manage prescription opioid dependence acted as a gateway to heroin use-buprenorphine/naloxone treatment and recovery in a surgical patient. AB - The prescribing of opioid pain medication has increased markedly in recent years, with strong opioid dispensing increasing 18-fold in Tayside, Scotland since 1995. Despite this, little data is available to quantify the problem of opioid pain medication dependence (OPD) and until recently there was little guidance on best practice treatment. We report the case of a young mother prescribed dihydrocodeine for postoperative pain relief who became opioid dependent. When her prescription was stopped without support, she briefly used heroin to overcome her withdrawal. After re-exposure to dihydrocodeine following surgery 9 years later and treatment with methadone for dependency, she was transferred to buprenorphine/naloxone. In our clinical experience and in agreement with Department of Health and Royal College of General Practitioner guidance, buprenorphine/naloxone is the preferred opioid substitution treatment for OPD. Our patient remains within her treatment programme and has returned to work on buprenorphine 16 mg/naloxone 4 mg in conjunction with social and psychological support. PMID- 25519867 TI - Severe drug-induced interstitial lung disease successfully treated with corticosteroid plus recombinant human soluble thrombomodulin. AB - There is no established therapeutic option for corticosteroid (CS) refractory drug-induced interstitial lung disease (DILD). We report a case of CS refractory severe DILD successfully treated with recombinant human soluble thrombomodulin (rhTM). A 64-year-old Japanese man was admitted with symptoms of fever, dry cough and dyspnoea. A chest radiograph showed bilateral infiltrations. DILD from Nijutsutou, a Chinese medicine, was suspected based on a history of similar interstitial lung disease after its administration 4 years prior and a positive drug-induced lymphocyte stimulation test. Nijutsutou was promptly discontinued and high doses of CS administered, but the patient's bilateral infiltrations remained unimproved. Since coagulation tests also indicated a rapid aggravation of coagulopathy, rhTM was added to the CS therapy. The patient's lung infiltration ameliorated and plasma levels of D-dimer and high morbidity group box 1 (HMGB1) decreased. rhTM may be an alternative agent for CS refractory DILD. Further study is necessary to confirm this. PMID- 25519868 TI - A rare diabetes ketoacidosis in combined severe hypernatremic hyperosmolarity in a new-onset Asian adolescent with type I diabetes. AB - A 13-year-old Asian boy presented with an 8 h history of lethargy and vomiting. He had a 3-week history of polyuria, polydipsia and a 6 kg weight loss over a period of 1 month. Fluid intake prior to admission was over 6 L of sports drinks and cola per day. Initial biochemical findings were as follows: plasma glucose 1351 mg/dL, serum sodium 154 mEq/L, serum osmolarity 425 mOsm/L, arterial blood pH 6.96 and urine ketone of 3+. He was treated with intensive fluid resuscitation and an insulin infusion. He completely recovered without any neurological deficits. Severe hypernatremia is rare in diabetic ketoacidosis (DKA) but was exhibited in this case. Excess intake of carbonated carbohydrate-rich beverages may exacerbate the initial severe presentation of type I diabetes mellitus (T1DM). To the best of our knowledge, this is the first case of an Asian child with DKA combined with severe hypernatremic hyperosmolarity at onset of T1DM. PMID- 25519869 TI - Refractory Wegener's granulomatosis presenting with alveolar haemorrhage, treated with rituximab. PMID- 25519857 TI - Rapid diagnostic tests for diagnosing uncomplicated non-falciparum or Plasmodium vivax malaria in endemic countries. AB - BACKGROUND: In settings where both Plasmodium vivax and Plasmodium falciparum infection cause malaria, rapid diagnostic tests (RDTs) need to distinguish which species is causing the patients' symptoms, as different treatments are required. Older RDTs incorporated two test lines to distinguish malaria due to P. falciparum, from malaria due to any other Plasmodium species (non-falciparum). These RDTs can be classified according to which antibodies they use: Type 2 RDTs use HRP-2 (for P. falciparum) and aldolase (all species); Type 3 RDTs use HRP-2 (for P. falciparum) and pLDH (all species); Type 4 use pLDH (fromP. falciparum) and pLDH (all species).More recently, RDTs have been developed to distinguish P. vivax parasitaemia by utilizing a pLDH antibody specific to P. vivax. OBJECTIVES: To assess the diagnostic accuracy of RDTs for detecting non-falciparum or P. vivax parasitaemia in people living in malaria-endemic areas who present to ambulatory healthcare facilities with symptoms suggestive of malaria, and to identify which types and brands of commercial test best detect non-falciparum and P. vivax malaria. SEARCH METHODS: We undertook a comprehensive search of the following databases up to 31 December 2013: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; MEDION; Science Citation Index; Web of Knowledge; African Index Medicus; LILACS; and IndMED. SELECTION CRITERIA: Studies comparing RDTs with a reference standard (microscopy or polymerase chain reaction) in blood samples from a random or consecutive series of patients attending ambulatory health facilities with symptoms suggestive of malaria in non falciparum endemic areas. DATA COLLECTION AND ANALYSIS: For each study, two review authors independently extracted a standard set of data using a tailored data extraction form. We grouped comparisons by type of RDT (defined by the combinations of antibodies used), and combined in meta-analysis where appropriate. Average sensitivities and specificities are presented alongside 95% confidence intervals (95% CI). MAIN RESULTS: We included 47 studies enrolling 22,862 participants. Patient characteristics, sampling methods and reference standard methods were poorly reported in most studies. RDTs detecting 'non falciparum' parasitaemiaEleven studies evaluated Type 2 tests compared with microscopy, 25 evaluated Type 3 tests, and 11 evaluated Type 4 tests. In meta analyses, average sensitivities and specificities were 78% (95% CI 73% to 82%) and 99% (95% CI 97% to 99%) for Type 2 tests, 78% (95% CI 69% to 84%) and 99% (95% CI 98% to 99%) for Type 3 tests, and 89% (95% CI 79% to 95%) and 98% (95% CI 97% to 99%) for Type 4 tests, respectively. Type 4 tests were more sensitive than both Type 2 (P = 0.01) and Type 3 tests (P = 0.03).Five studies compared Type 3 tests with PCR; in meta-analysis, the average sensitivity and specificity were 81% (95% CI 72% to 88%) and 99% (95% CI 97% to 99%) respectively. RDTs detecting P.vivax parasitaemiaEight studies compared pLDH tests to microscopy; the average sensitivity and specificity were 95% (95% CI 86% to 99%) and 99% (95% CI 99% to 100%), respectively. AUTHORS' CONCLUSIONS: RDTs designed to detect P. vivax specifically, whether alone or as part of a mixed infection, appear to be more accurate than older tests designed to distinguish P. falciparum malaria from non falciparum malaria. Compared to microscopy, these tests fail to detect around 5% ofP. vivax cases. This Cochrane Review, in combination with other published information about in vitro test performance and stability in the field, can assist policy-makers to choose between the available RDTs. PMID- 25519870 TI - Xanthogranulomatous pyelonephritis presenting as palmoplantar keratoderma. PMID- 25519871 TI - Psychosocial work factors and first depressive episode: retrospective results from the French national SIP survey. AB - OBJECTIVES: The objective was to explore the associations between psychosocial work factors and first depressive episode. Additional objectives included the study of the frequency and duration of exposure, and the evaluation of the induction period between exposures and outcome and of the reversibility of the effects. METHODS: The study was based on a sample of 13,648 men and women from the 2006 national representative French SIP survey. Retrospective evaluation was performed for depressive episode for the whole life history, for psychological demands, skill discretion, social support, tension with the public, reward and work-life imbalance for each job, and within each job before and after each major change, and for time-varying covariates. The outcome was the first depressive episode. Statistical analysis was performed using weighted discrete time logistic regression model. RESULTS: High psychological demands and low social support were risk factors for first depressive episode for both genders. The risk increased with the frequency of exposure to these factors. Associations were found with the frequency of exposure to tension with the public among women and to work-life imbalance among men. The risk increased with the duration of exposure to psychological demands and low social support for both genders, however, these associations become non-significant when recent exposure was taken into account. Past exposure older than 2 years was not associated with the outcome. CONCLUSION: Associations between psychosocial work factors and first depressive episode were observed, including dose-response associations. However, after removal of the exposure, the risk may be reduced after 2 years. PMID- 25519872 TI - An assessment of selected hydrochemical parameter trend of the Nakdong River water in South Korea, using time series analyses and PCA. AB - Time series analyses (autocorrelation, spectral density, and cross-correlation) and principal component analysis (PCA) were used to understand the characteristics of the selected hydrochemical parameters pH, turbidity, alkalinity, Cl, hardness, total dissolved solids (TDS), and metals Fe and Mn in the Nakdong River, South Korea. Autocorrelation and spectral density for pH, alkalinity, hardness, and Cl were very similar to TDS, whereas Fe, Mn, and turbidity showed different trends from TDS. Cross-correlograms of pH, alkalinity, hardness, and Cl versus TDS were very similar to each other. Those of Fe and turbidity represented the opposite relations with other components. Cross correlation coefficients had the highest values at zero lag, indicating that pH, alkalinity, hardness, and Cl are controlling factors for TDS. On the other hand, Fe and turbidity showed the highest values at 6-month lag and Mn at a month lag. PCA indicated that TDS had very close relation with hardness, pH, and Cl and very small relation with Mn. Turbidity and Fe had relatively opposite relations with TDS. It was concluded that the geostatistical methods were very useful for evaluating the hydrochemical characteristics of the Nakdong River water in South Korea. PMID- 25519873 TI - Petrophysical examination of CO2-brine-rock interactions-results of the first stage of long-term experiments in the potential Zaosie Anticline reservoir (central Poland) for CO2 storage. AB - The objective of the study was determination of experiment-induced alterations and changes in the properties of reservoir rocks and sealing rocks sampled from potential reservoir for CO2. In the experiment, rocks submerged in brine in specially constructed reactors were subjected to CO2 pressure of 6 MPa for 20 months at room temperature. Samples of Lower Jurassic reservoir rocks and sealing rocks (sandstones, claystones, and mudstones) from the Zaosie Anticline (central Poland) were analysed for their petrophysical properties (specific surface area, porosity, pore size and distribution) before and after the experiment. Comparison of the ionic composition the brines before and after the experiment demonstrated an increase in total dissolved solids as well as the concentration of sulphates and calcium ions. This indicates partial dissolution of the rock matrix and the cements. As a result of the reaction, the properties of reservoir rocks did not changed significantly and should not affect the process of CO2 storage. In the case of the sealing rocks, however, the porosity, the framework density, as well as the average capillary and threshold diameter increased. Also, the pore distribution in the pore space changed in favour of larger pores. The reasons for these changes could not be explained by petrographic characteristics and should be thoroughly investigated. PMID- 25519875 TI - Dielectrophoresis-driven spreading of immersed liquid droplets. AB - In recent years electrowetting-on-dielectric (EWOD) has become an effective tool to control partial wetting. EWOD uses the liquid-solid interface as part of a capacitive structure that allows capacitive and interfacial energies to adjust by changes in wetting when the liquid-solid interface is charged due to an applied voltage. An important aspect of EWOD has been its applications in microfluidics in chemistry and biology and in optical devices and displays in physics and engineering. Many of these rely on the use of a liquid droplet immersed in a second liquid due to the need either for neutral buoyancy to overcome gravity and shield against impact shocks or to encapsulate the droplet for other reasons, such as in microfluidic-based DNA analyses. Recently, it has been shown that nonwetting oleophobic surfaces can be forcibly wetted by nonconducting oils using nonuniform electric fields and an interface-localized form of liquid dielectrophoresis (dielectrowetting). Here we show that this effect can be used to create films of oil immersed in a second immiscible fluid of lower permittivity. We predict that the square of the thickness of the film should obey a simple law dependent on the square of the applied voltage and with strength dependent on the ratio of difference in permittivity to the liquid-fluid interfacial tension, Deltaepsilon/gamma(LF). This relationship is experimentally confirmed for 11 liquid-air and liquid-liquid combinations with Deltaepsilon/gamma(LF) having a span of more than two orders of magnitude. We therefore provide fundamental understanding of dielectrowetting for liquid-in liquid systems and also open up a new method to determine liquid-liquid interfacial tensions. PMID- 25519874 TI - Competition between items in working memory leads to forgetting. AB - Switching attention from one thought to the next propels our mental lives forward. However, it is unclear how this thought-juggling affects our ability to remember these thoughts. Here we show that competition between the neural representations of pictures in working memory can impair subsequent recognition of those pictures. We use pattern classifiers to decode functional magnetic resonance imaging (fMRI) data from a retro-cueing task where participants juggle two pictures in working memory. Trial-by-trial fluctuations in neural dynamics are predictive of performance on a surprise recognition memory test: trials that elicit similar levels of classifier evidence for both pictures (indicating close competition) are associated with worse memory performance than trials where participants switch decisively from thinking about one picture to the other. This result is consistent with the non-monotonic plasticity hypothesis, which predicts that close competition can trigger weakening of memories that lose the competition, leading to subsequent forgetting. PMID- 25519876 TI - High serum 25-hydroxyvitamin D levels are associated with pediatric sepsis. AB - Despite major advances in intensive care, sepsis continues to be a major cause of morbidity and mortality. Vitamin D is involved in various physiologic functions, including cellular responses during infection and inflammation. The aim of this study was to evaluate diagnostic value of 25-hydroxyvitamin D in childhood sepsis because it can be fatal if diagnosis delayed. The study included 40 children with sepsis and 20 children without sepsis (control group). We included only the patients with high probable sepsis, judged by clinical and laboratory findings, including positive blood culture. Blood samples were collected from patients with sepsis before treatment (pre-treatment group) and 48-72 hours later (post treatment group). Treatment varied from ampicillin-sulbactam to cephalosporin. Blood samples were collected from control group once on admission. Serum 25 hydroxyvitamin D levels were significantly higher in sepsis (pre-treatment group) than control group (74 +/- 8 ng/ml vs. 28 +/- 12 ng/ml, p = 0.01) and the serum 25-hydroxyvitamin D levels were decreased to 44 +/- 5 ng/ml (p = 0.01) after treatment. Moreover, we found significant positive correlation between 25 hydroxyvitamin D and each of well-know sepsis markers, C-reactive protein, tumor necrosis factor-alpha and interleukin-6. A cut-off point of 20 ng/mL for serum 25 hydroxyvitamin D showed 84% sensitivity and 76% specificity for sepsis diagnosis. This is the first study evaluating the diagnostic role of vitamin D in pediatric sepsis, thereby suggesting that serum 25-hydroxyvitamin D level can be used as a diagnostic marker for sepsis with high sensitivity and specificity. PMID- 25519878 TI - A coumarin based gold(i)-alkynyl complex: a new class of supramolecular hydrogelators. AB - A phosphine-gold(i)-alkynyl-coumarin complex, [Au{7-(prop-2-ine-1-yloxy)-1 benzopyran-2-one}(DAPTA)] (), was synthesized and the formation of long luminescent fibers in solution was characterized via fluorescence microscopy and dynamic light scattering. The fibers presented strong blue and green luminescence, suggesting that the gold(i) in the complex increased intersystem crossing due to the heavy atom effect, resulting in a significant increase in triplet emission. The X-ray structure of the fibers indicates that both aurophilic, pi-pi interactions and hydrogen bonding contribute to their formation in aqueous solvents. PMID- 25519877 TI - Safety of allopurinol compared with other urate-lowering drugs in patients with gout: a systematic review and meta-analysis. AB - Allopurinol is the most widely used urate-lowering drug (ULD). Together with efficacy and cost, safety is an aspect that helps taking clinical decisions. This systematic review analyzes allopurinol safety. The literature search was performed in MEDLINE, EMBASE, and the Cochrane Library (January 2014). SELECTION CRITERIA: (a) patients >18, (b) gout by the ACR criteria or evidence of urate crystal in synovial fluid, (c) comparator (placebo or other ULD), and (d) RCTs, cohorts, or meta-analysis. PRIMARY OUTCOMES: rate of adverse events and death. The quality was assessed with the Jadad's scale. A meta-analysis with fixed effects was performed. From 544 studies, seven met the eligibility criteria and were included. All RCT presented a low power for safety. All RCTs included a mixed population of patients with gout and hyperuricemia. Allopurinol (300 mg) was compared to febuxostat (40-240 mg) in five RCTs, to benzbromarone and probenecid in two RCTs, and to placebo in one. In the RCTs comparing allopurinol with benzbromarone and probenecid, the highest discontinuation rate was with probenecid (26 %), followed by allopurinol (11 %) and benzbromarone (4 %). The incidence of adverse events was similar between allopurinol (range 38.6-85) and febuxostat (range 41.8-80). Six patients on febuxostat and three on allopurinol died during the studies; no deaths were judged related to drug. The combined risk of adverse events was RR = 1.04 (95 % CI 0.98, 1.11). Allopurinol is a safe option, slightly better than other ULDs. The grade of evidence is high, but further research is needed to evaluate higher doses and long-term safety. PMID- 25519879 TI - Early administration of isosorbide dinitrate improves survival of cyanide poisoned rabbits. AB - CONTEXT: More effective, rapidly delivered, safer antidotes are needed for cyanide poisoning. Previous study has demonstrated a beneficial effect of isosorbide dinitrate on the survival of cyanide-poisoned mice. OBJECTIVE: To evaluate the effectiveness of isosorbide dinitrate compared with that of sodium nitrite in cyanide poisoning. MATERIALS AND METHODS: A comparative animal study was performed using 18 rabbits, randomized into 3 study groups. Animals were poisoned intravenously with potassium cyanide (1 mg/kg). The first group was not given any further treatment. The second and third groups were treated intravenously 1 min after poisoning with sodium nitrite (6 mg/kg) and isosorbide dinitrate (50 MUg/kg), respectively. The primary outcome was short-term survival of up to 30 min. Secondary outcomes included time to death, a clinical score, mean blood pressure, pulse, blood pH, and lactate and methemoglobin levels. RESULTS: Rabbits treated with isosorbide dinitrate or sodium nitrite survived while only one untreated rabbit survived. Median time to death of the 5 poisoned and untreated animals was 10 min. All the animals collapsed soon after poisoning, exhibiting rapidly disturbed vital signs and developed lactic metabolic acidosis; average peak blood lactate levels were 15.5-19.1 mmol/L at 10 min after poisoning. The treated animals improved gradually with practically full recovery of the clinical scores, vital signs, and blood gas levels. Sodium nitrite administration raised methemoglobin to an average peak of 7.9%, while isosorbide dinitrate did not change methemoglobin levels. CONCLUSION: Early administration of isosorbide dinitrate improved the short-term survival of cyanide-poisoned rabbits. Isosorbide dinitrate shows potential as an antidote for cyanide poisoning and may exert its effect using a nitric-oxide-dependent mechanism. PMID- 25519880 TI - Sustaining control of schistosomiasis mansoni in moderate endemicity areas in western Cote d'Ivoire: a SCORE study protocol. AB - BACKGROUND: Schistosomiasis is a parasitic disease that occurs in the tropics and subtropics. The mainstay of control is preventive chemotherapy with praziquantel. In Africa, an estimated 230 million people require preventive chemotherapy. In western Cote d'Ivoire, infections with Schistosoma mansoni are widespread. To provide an evidence-base for programme decisions about preventive chemotherapy to sustain control of schistosomiasis, a 5-year multi-country study with different treatment arms has been designed by the Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) and is currently being implemented in various African settings, including Cote d'Ivoire. METHODS/DESIGN: We report the study protocol, including ethics statement and insight from a large-scale eligibility survey carried out in four provinces in western Cote d'Ivoire. The study protocol has been approved by the ethics committees of Basel and Cote d'Ivoire. A total of 12,110 children, aged 13-14 years, from 264 villages were screened for S. mansoni using duplicate Kato-Katz thick smears from single stool samples. Among the schools with a S. mansoni prevalence of 10-24%, 75 schools were selected and randomly assigned to one of three treatment arms. In each school, three stool samples are being collected from 100 children aged 9-12 years annually and one stool sample from 100 first-year students at baseline and in the final year and subjected to duplicate Kato-Katz thick smears. Cost and coverage data for the different intervention arms, along with environmental, political and other characteristics that might impact on the infection prevalence and intensity will be recorded in each study year, using a pretested village inventory form. DISCUSSION: The study will document changes in S. mansoni infection prevalence and intensity according to different treatment schemes. Moreover, factors that determine the effectiveness of preventive chemotherapy will be identified. These factors will help to develop reasonable measures of force of transmission that can be used to make decisions about the most cost-effective means of lowering prevalence, intensity and transmission in a given setting. The gathered information and results will inform how to effectively sustain control of schistosomiasis at a low level in different social-ecological contexts. TRIAL REGISTRATION: ISRCTN99401114 (date assigned: 12 November 2014). PMID- 25519881 TI - Protein expression, characterization and activity comparisons of wild type and mutant DUSP5 proteins. AB - BACKGROUND: The mitogen-activated protein kinases (MAPKs) pathway is critical for cellular signaling, and proteins such as phosphatases that regulate this pathway are important for normal tissue development. Based on our previous work on dual specificity phosphatase-5 (DUSP5), and its role in embryonic vascular development and disease, we hypothesized that mutations in DUSP5 will affect its function. RESULTS: In this study, we tested this hypothesis by generating full-length glutathione-S-transferase-tagged DUSP5 and serine 147 proline mutant (S147P) proteins from bacteria. Light scattering analysis, circular dichroism, enzymatic assays and molecular modeling approaches have been performed to extensively characterize the protein form and function. We demonstrate that both proteins are active and, interestingly, the S147P protein is hypoactive as compared to the DUSP5 WT protein in two distinct biochemical substrate assays. Furthermore, due to the novel positioning of the S147P mutation, we utilize computational modeling to reconstruct full-length DUSP5 and S147P to predict a possible mechanism for the reduced activity of S147P. CONCLUSION: Taken together, this is the first evidence of the generation and characterization of an active, full-length, mutant DUSP5 protein which will facilitate future structure-function and drug development-based studies. PMID- 25519882 TI - "It is about how the net looks": a qualitative study of perceptions and practices related to mosquito net care and repair in two districts in eastern Uganda. AB - BACKGROUND: Prolonging net durability has important implications for reducing both malaria transmission and the frequency of net replacement. Protective behaviour, such as net care and repair, offers promise for improving net integrity and durability. Given the potential cost-savings and public health benefit associated with extending the useful life of long-lasting insecticidal nets (LLINs), prevention and mitigation of damage will become ever more critical to ensuring adequate net coverage at the population level. METHODS: A qualitative assessment was conducted in two districts in central eastern Uganda in September 2013. Data on household net care and repair behaviour, attitudes and practices were collected from 30 respondents through in-depth interviews (IDIs), observations, photos, and video to gather an in-depth understanding of these behaviours. RESULTS: Net damage was common and the most cited causes were children and rodents. Responses revealed strong social norms about net cleanliness and aesthetics, and strong expectations that others should care for and repair their own nets. Respondents were receptive and able to repair nets, though longer-term repair methods, such as sewing and patching, were not as commonly reported or observed. Self-reported behaviour was not always consistent with observed or demonstrated behaviour, revealing potential misconceptions and the need for clear and consistent net care and repair messaging. CONCLUSIONS: Respondents considered both aesthetics and malaria protection important when deciding whether, when, and how to care for and repair nets. BCC should continue to emphasize the importance of maintaining net integrity for malaria prevention purposes as well as for maintaining aesthetic appeal. Additional research is needed, particularly surrounding washing, drying, daily storage routines, and gender roles in care and repair, in order to understand the complexity of these behaviours, and refine existing or develop new behaviour change communication (BCC) messages for net care and repair. PMID- 25519883 TI - Genoprotective effects of Origanum vulgare ethanolic extract against cyclophosphamide-induced genotoxicity in mouse bone marrow cells. AB - CONTEXT: Cyclophosphamide (CP), an alkylating chemotherapeutic agent, can bind DNA, causing chromosome breaks, micronucleus (Mn) formation, and cell death. Because Origanum vulgare L. (Lamiaceae) has antioxidative properties, it might protect against DNA damage. OBJECTIVE: The genoprotective effect of O. vulgare ethanolic extract against CP-induced genotoxicity in mouse bone marrow cells was evaluated using a Mn assay. MATERIALS AND METHODS: Mice were pre-treated with aerial parts of O. vulgare ethanolic extract at different doses (50, 100, 200, or 400 mg/kg) for 7 d. One hour after the last administration of O. vulgare, animals were injected with CP at 200 mg/kg. After 24 h, the bone marrow cells of both femurs were flushed and the frequency of MnPCEs was evaluated to measure the chromosomal damages. In addition, the number of PCEs per 1000 NCEs in each animal was recorded to evaluate the bone-marrow suppression; mitotic activity was calculated as [PCE/(PCE + NCE)] * 100 to assess the cell division. RESULTS: At 400 mg/kg, O. vulgare displayed its maximum protective effect, reduced the number of MnPCEs from 10.52 +/- 1.07 for CP group to 2.17 +/- 0.26 and completely normalized the mitotic activity (p < 0.001). Origanum vulgare also led to significant proliferation and hypercellularity of immature myeloid elements after the mice were treated with CP, mitigating the bone marrow suppression. DISCUSSION AND CONCLUSION: Origanum vulgare ethanolic extract exerts a potent genoprotective effect against CP-induced genotoxicity in mice bone marrow, which might be possibly due to the scavenging of free radicals during oxidative stress conditions. PMID- 25519884 TI - Nut consumption among U.S. adults, 2009-2010. AB - Data from the National Health and Nutrition Examination Survey, 2009-2010. Almost 40% (38.2%) of adults consumed nuts on a given day. More non-Hispanic white (43.6%) than non-Hispanic black (23.7%) or Hispanic (25.5%) adults consumed nuts. Approximately 80% of nuts consumed (84.0% by men and 79.7% by women) were nuts or seeds as single-item foods or nut butters. PMID- 25519885 TI - Current level and determinants of inappropriate admissions to township hospitals under the new rural cooperative medical system in China: a cross-sectional study. AB - BACKGROUND: The increased funding and reimbursement for the New Rural Cooperative Medical System (NRCMS) have provided residents in rural China with better access to inpatient services. This research aims to examine the level of inappropriate admissions to township hospitals under NRCMS, and the determinants that influence inappropriate admissions. METHODS: A total of 2,044 medical records in 10 township hospitals were collected from five counties in Midwestern China by stratified cluster sampling and evaluated using the Appropriateness Evaluation Protocol (AEP), which was developed by a Delphi expert consultation of 32 experts. A two-level logistic regression model by MLwiN 2.30 was used to examine the determinants of inappropriate admissions. RESULTS: Township hospitals had an average inappropriate admission rate of 26.5%. The highest rate of inappropriate admission was among patients aged more than 59 years old (30.1%). Inappropriate admissions mostly occurred for respiratory and circulatory diseases. Township hospital similarity and clustering were observed. Two-level logistic regression analysis showed that age, treating department, and disease were determinants of inappropriate admission. CONCLUSIONS: Township hospitals have a high rate of inappropriate admissions. Explicit diagnostic criteria and a standardized supervision system should be developed to reduce this. PMID- 25519888 TI - Doubly robust estimation of attributable fractions in survival analysis. AB - The attributable fraction is a commonly used measure that quantifies the public health impact of an exposure on an outcome. It was originally defined for binary outcomes, but an extension has recently been proposed for right-censored survival time outcomes; the so-called attributable fraction function. A maximum likelihood estimator of the attributable fraction function has been developed, which requires a model for the outcome. In this paper, we derive a doubly robust estimator of the attributable fraction function. This estimator requires one model for the outcome, and one joint model for the exposure and censoring. The estimator is consistent if either model is correct, not necessarily both. PMID- 25519886 TI - HTLV-1-infected CD4+ T-cells display alternative exon usages that culminate in adult T-cell leukemia. AB - BACKGROUND: Reprogramming cellular gene transcription sustains HTLV-1 viral persistence that ultimately leads to the development of adult T-cell leukemia/lymphoma (ATLL). We hypothesized that besides these quantitative transcriptional effects, HTLV-1 qualitatively modifies the pattern of cellular gene expression. RESULTS: Exon expression analysis shows that patients' untransformed and malignant HTLV-1(+) CD4(+) T-cells exhibit multiple alternate exon usage (AEU) events. These affect either transcriptionally modified or unmodified genes, culminate in ATLL, and unveil new functional pathways involved in cancer and cell cycle. Unsupervised hierarchical clustering of array data permitted to isolate exon expression patterns of 3977 exons that discriminate uninfected, infected, and transformed CD4(+) T-cells. Furthermore, untransformed infected CD4+ clones and ATLL samples shared 486 exon modifications distributed in 320 genes, thereby indicating a role of AEUs in HTLV-1 leukemogenesis. Exposing cells to splicing modulators revealed that Sudemycin E reduces cell viability of HTLV-1 transformed cells without affecting primary control CD4+ cells and HTLV-1 negative cell lines, suggesting that the huge excess of AEU might provide news targets for treating ATLL. CONCLUSIONS: Taken together, these data reveal that HTLV-1 significantly modifies the structure of cellular transcripts and unmask new putative leukemogenic pathways and possible therapeutic targets. PMID- 25519889 TI - Poisson and negative binomial item count techniques for surveys with sensitive question. AB - Although the item count technique is useful in surveys with sensitive questions, privacy of those respondents who possess the sensitive characteristic of interest may not be well protected due to a defect in its original design. In this article, we propose two new survey designs (namely the Poisson item count technique and negative binomial item count technique) which replace several independent Bernoulli random variables required by the original item count technique with a single Poisson or negative binomial random variable, respectively. The proposed models not only provide closed form variance estimate and confidence interval within [0, 1] for the sensitive proportion, but also simplify the survey design of the original item count technique. Most importantly, the new designs do not leak respondents' privacy. Empirical results show that the proposed techniques perform satisfactorily in the sense that it yields accurate parameter estimate and confidence interval. PMID- 25519890 TI - Sample size calculation for treatment effects in randomized trials with fixed cluster sizes and heterogeneous intraclass correlations and variances. AB - When comparing two different kinds of group therapy or two individual treatments where patients within each arm are nested within care providers, clustering of observations may occur in both arms. The arms may differ in terms of (a) the intraclass correlation, (b) the outcome variance, (c) the cluster size, and (d) the number of clusters, and there may be some ideal group size or ideal caseload in case of care providers, fixing the cluster size. For this case, optimal cluster numbers are derived for a linear mixed model analysis of the treatment effect under cost constraints as well as under power constraints. To account for uncertain prior knowledge on relevant model parameters, also maximin sample sizes are given. Formulas for sample size calculation are derived, based on the standard normal as the asymptotic distribution of the test statistic. For small sample sizes, an extensive numerical evaluation shows that in a two-tailed test employing restricted maximum likelihood estimation, a safe correction for both 80% and 90% power, is to add three clusters to each arm for a 5% type I error rate and four clusters to each arm for a 1% type I error rate. PMID- 25519891 TI - Magnetic microgels, a promising candidate for enhanced magnetic adsorbent particles in bioseparation: synthesis, physicochemical characterization, and separation performance. AB - For specific applications in the field of high gradient magnetic separation of biomaterials, magnetic nanoparticle clusters of controlled size and high magnetic moment in an external magnetic field are of particular interest. We report the synthesis and characterization of magnetic microgels designed for magnetic separation purposes, as well as the separation efficiency of the obtained microgel particles. High magnetization magnetic microgels with superparamagnetic behaviour were obtained in a two-step synthesis procedure by a miniemulsion technique using highly stable ferrofluid on a volatile nonpolar carrier. Spherical clusters of closely packed hydrophobic oleic acid-coated magnetite nanoparticles were coated with cross linked polymer shells of polyacrylic acid, poly-N-isopropylacrylamide, and poly-3-acrylamidopropyl trimethylammonium chloride. The morphology, size distribution, chemical surface composition, and magnetic properties of the magnetic microgels were determined using transmission electron microscopy, X-ray photoelectron spectroscopy, and vibrating sample magnetometry. Magnetically induced phase condensation in aqueous suspensions of magnetic microgels was investigated by optical microscopy and static light scattering. The condensed phase consists of elongated oblong structures oriented in the direction of the external magnetic field and may grow up to several microns in thickness and tens or even hundreds of microns in length. The dependence of phase condensation magnetic supersaturation on the magnetic field intensity was determined. The experiments using high gradient magnetic separation show high values of separation efficiency (99.9-99.97%) for the magnetic microgels. PMID- 25519893 TI - Data size reduction strategy for the classification of breath and air samples using multicapillary column-ion mobility spectrometry. AB - Ion mobility spectrometry combined with multicapillary column separation (MCC IMS) is a well-known technology for detecting volatile organic compounds (VOCs) in gaseous samples. Due to their large data size, processing of MCC-IMS spectra is still the main bottleneck of data analysis, and there is an increasing need for data analysis strategies in which the size of MCC-IMS data is reduced to enable further analysis. In our study, the first untargeted chemometric strategy is developed and employed in the analysis of MCC-IMS spectra from 264 breath and ambient air samples. This strategy does not comprise identification of compounds as a primary step but includes several preprocessing steps and a discriminant analysis. Data size is significantly reduced in three steps. Wavelet transform, mask construction, and sparse-partial least squares-discriminant analysis (s-PLS DA) allow data size reduction with down to 50 variables relevant to the goal of analysis. The influence and compatibility of the data reduction tools are studied by applying different settings of the developed strategy. Loss of information after preprocessing is evaluated, e.g., by comparing the performance of classification models for different classes of samples. Finally, the interpretability of the classification models is evaluated, and regions of spectra that are related to the identification of potential analytical biomarkers are successfully determined. This work will greatly enable the standardization of analytical procedures across different instrumentation types promoting the adoption of MCC-IMS technology in a wide range of diverse application fields. PMID- 25519892 TI - Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models. AB - Close resemblance of murine and human trials is essential to achieve the best predictive value of animal-based translational cancer research. Kras-driven genetically engineered mouse models of non-small-cell lung cancer faithfully predict the response of human lung cancers to systemic chemotherapy. Owing to development of multifocal disease, however, these models have not been usable in studies of outcomes following focal radiotherapy (RT). We report the development of a preclinical platform to deliver state-of-the-art image-guided RT in these models. Presence of a single tumour as usually diagnosed in patients is modelled by confined injection of adenoviral Cre recombinase. Furthermore, three dimensional conformal planning and state-of-the-art image-guided dose delivery are performed as in humans. We evaluate treatment efficacies of two different radiation regimens and find that Kras-driven tumours can temporarily be stabilized upon RT, whereas additional loss of either Lkb1 or p53 renders these lesions less responsive to RT. PMID- 25519894 TI - Too much of a good thing: the unique and repeated paths toward copper adaptation. AB - Copper is a micronutrient essential for growth due to its role as a cofactor in enzymes involved in respiration, defense against oxidative damage, and iron uptake. Yet too much of a good thing can be lethal, and yeast cells typically do not have tolerance to copper levels much beyond the concentration in their ancestral environment. Here, we report a short-term evolutionary study of Saccharomyces cerevisiae exposed to levels of copper sulfate that are inhibitory to the initial strain. We isolated and identified adaptive mutations soon after they arose, reducing the number of neutral mutations, to determine the first genetic steps that yeast take when adapting to copper. We analyzed 34 such strains through whole-genome sequencing and by assaying fitness within different environments; we also isolated a subset of mutations through tetrad analysis of four lines. We identified a multilayered evolutionary response. In total, 57 single base-pair mutations were identified across the 34 lines. In addition, gene amplification of the copper metallothionein protein, CUP1-1, was rampant, as was chromosomal aneuploidy. Four other genes received multiple, independent mutations in different lines (the vacuolar transporter genes VTC1 and VTC4; the plasma membrane H+-ATPase PMA1; and MAM3, a protein required for normal mitochondrial morphology). Analyses indicated that mutations in all four genes, as well as CUP1 1 copy number, contributed significantly to explaining variation in copper tolerance. Our study thus finds that evolution takes both common and less trodden pathways toward evolving tolerance to an essential, but highly toxic, micronutrient. PMID- 25519895 TI - Autophagy competes for a common phosphatidylethanolamine pool with major cellular PE-consuming pathways in Saccharomyces cerevisiae. AB - Autophagy is a highly regulated pathway that selectively degrades cellular constituents such as protein aggregates and excessive or damaged organelles. This transport route is characterized by engulfment of the targeted cargo by autophagosomes. The formation of these double-membrane vesicles requires the covalent conjugation of the ubiquitin-like protein Atg8 to phosphatidylethanolamine (PE). However, the origin of PE and the regulation of lipid flux required for autophagy remain poorly understood. Using a genetic screen, we found that the temperature-sensitive growth and intracellular membrane organization defects of mcd4-174 and mcd4-P301L mutants are suppressed by deletion of essential autophagy genes such as ATG1 or ATG7. MCD4 encodes an ethanolamine phosphate transferase that uses PE as a precursor for an essential step in the synthesis of the glycosylphosphatidylinositol (GPI) anchor used to link a subset of plasma membrane proteins to lipid bilayers. Similar to the deletion of CHO2, a gene encoding the enzyme converting PE to phosphatidylcholine (PC), deletion of ATG7 was able to restore lipidation and plasma membrane localization of the GPI-anchored protein Gas1 and normal organization of intracellular membranes. Conversely, overexpression of Cho2 was lethal in mcd4 174 cells grown at restrictive temperature. Quantitative lipid analysis revealed that PE levels are substantially reduced in the mcd4-174 mutant but can be restored by deletion of ATG7 or CHO2. Taken together, these data suggest that autophagy competes for a common PE pool with major cellular PE-consuming pathways such as the GPI anchor and PC synthesis, highlighting the possible interplay between these pathways and the existence of signals that may coordinate PE flux. PMID- 25519896 TI - Cryptic virulence and avirulence alleles revealed by controlled sexual recombination in pea aphids. AB - Although aphids are worldwide crop pests, little is known about aphid effector genes underlying virulence and avirulence. Here we show that controlling the genetics of both aphid and host can reveal novel recombinant genotypes with previously undetected allelic variation in both virulence and avirulence functions. Clonal F1 progeny populations were derived from reciprocal crosses and self-matings between two parental genotypes of pea aphid (Acyrthosiphon pisum) differing in virulence on a Medicago truncatula host carrying the RAP1 and RAP2 resistance genes. These populations showed Mendelian segregation consistent with aphid performance being controlled largely by a dominant virulence allele derived from only one parent. Altered segregation ratios on near-isogenic host genotypes differing in the region carrying RAP1 were indicative of additional heritable functions likely related to avirulence genes originating from both parents. Unexpectedly, some virulent F1 progeny were recovered from selfing of an avirulent parent, suggesting a reservoir of cryptic alleles. Host chlorosis was associated with virulence, whereas necrotic hypersensitive-like response was not. No maternal inheritance was found for any of these characteristics, ruling out sex-linked, cytoplasmic, and endosymbiotic factors. Our results demonstrate the tractability of dissecting the genetic basis of pest-host resistance mechanisms and indicate that the annual sexual cycle in aphids may lead to frequent novel genotypes with both increased and decreased virulence. Availability of genomes for both pest and host can facilitate definition of cognate gene-for-gene relationships, potentially leading to selection of crop genotypes with multiple resistance traits. PMID- 25519898 TI - [Selective internal radiotherapy (SIRT) of liver tumors]. AB - METHODICAL INNOVATIONS: Selective internal radiotherapy (SIRT) is a safe and efficacious, minimally invasive procedure to treat primary and secondary unresectable liver tumors. For hepatocellular carcinoma (HCC), SIRT has proven to be a well-tolerated therapy option even in advanced stages of disease. STANDARD RADIOLOGICAL METHODS: In cases of portal vein thrombosis SIRT is the alternative to transarterial chemoembolization (TACE). PERFORMANCE: The role of SIRT regarding downstaging and bridging to transplantation is promising and SIRT has also been shown to be highly effective and well-tolerated in metastastic liver disease. ACHIEVEMENTS: The results of prospective randomized trials are awaited to prove the efficiency and safety of SIRT described in numerous retrospective and prospective non-randomized studies. PRACTICAL RECOMMENDATIONS: The indications are established within the framework of a tumor board. PMID- 25519897 TI - A neuroprotective function of NSF1 sustains autophagy and lysosomal trafficking in Drosophila. AB - A common feature of many neurodegenerative diseases is the accumulation of toxic proteins that disrupt vital cellular functions. Degradative pathways such as autophagy play an important protective role in breaking down misfolded and long lived proteins. Neurons are particularly vulnerable to defects in these pathways, but many of the details regarding the link between autophagy and neurodegeneration remain unclear. We previously found that temperature-sensitive paralytic mutants in Drosophila are enriched for those exhibiting age-dependent neurodegeneration. Here we show that one of these mutants, comatose (comt), in addition to locomotor defects, displays shortened lifespan and progressive neurodegeneration, including loss of dopaminerigic (DA) neurons. comt encodes N ethyl-maleimide sensitive fusion protein (NSF1), which has a well-documented role in synaptic transmission. However, the neurodegenerative phenotypes we observe in comt mutants do not appear to depend on defects in synaptic transmission, but rather from their inability to sustain autophagy under stress, due at least in part to a defect in trafficking of lysosomal proteases such as cathepsin-L. Conversely, overexpression of NSF1 rescues alpha-synuclein-induced toxicity of DA neurons in a model of Parkinson's disease. Our results demonstrate a neuroprotective role for NSF1 that involves mediation of fusion events crucial for degradative pathways such as autophagy, providing greater understanding of cellular dysfunctions common to several neurodegenerative diseases. PMID- 25519899 TI - [O tempora, o mores - unlocking a new area in healthcare training]. PMID- 25519900 TI - Hepatocyte growth factor signalizes peritoneal membrane failure in peritoneal dialysis. AB - BACKGROUND: Hepatocyte growth factor (HGF) counteracts peritoneal fibrosis in animal models and in-vitro studies, but no study explored effluent HGF in peritoneal dialysis (PD) patients with ultrafiltration failure (UFF). Our aim was to assess the relationship between effluent HGF with UF profile, free water transport (FWT) and small-solute transport. METHODS: We performed 4-hour, 3.86% PET with additional UF measurement at 60 minutes in 68 PD patients. MTACcreatinine, FWT, small-pore ultrafiltration, and effluent HGF were quantified. RESULTS: Effluent HGF negatively correlated with UF (r=-0.80, p=0.009) and FWT (r=-0.69, p=0.04). Patients with UFF had higher dialysate HGF (103 pg/mL vs 77 pg/mL, p=0.018) and, although not statistically significant, those with FWT compromise had also higher dialysate HGF compared with subgroup of UFF without FWT compromise (104 pg/mL vs 88 pg/mL, p=0.08). FWT<=45% without clinical UFF was documented in some patients who also had increased effluent HGF. CONCLUSIONS: Dialysate HGF concentration is significantly higher among patients with UFF, specially, if FWT is impaired, being a sign of peritoneal membrane deterioration. PMID- 25519901 TI - Expression of rabies glycoprotein and ricin toxin B chain (RGP-RTB) fusion protein in tomato hairy roots: a step towards oral vaccination for rabies. AB - Transgenic hairy roots of Solanum lycopersicum were engineered to express a recombinant protein containing a fusion of rabies glycoprotein and ricin toxin B chain (rgp-rtxB) antigen under the control of constitutive CaMV35S promoter. Asialofetuin-mediated direct ELISA of transgenic hairy root extracts was performed using polyclonal anti-rabies antibodies (Ab1) and epitope-specific peptidal anti-RGP (Ab2) antibodies which confirmed the expression of functionally viable RGP-RTB fusion protein. Direct ELISA based on asialofetuin-binding activity was used to screen crude protein extracts from five transgenic hairy root lines. Expressions of RGP-RTB fusion protein in different tomato hairy root lines varied between 1.4 and 8 ug in per gram of tissue. Immunoblotting assay of RGP-RTB fusion protein from these lines showed a protein band on monomeric size of ~84 kDa after denaturation. Tomato hairy root line H03 showed highest level of RGP-RTB protein expression (1.14 %) and was used further in bench-top bioreactor for the optimization of scale-up process to produce large quantity of recombinant protein. Partially purified RGP-RTB fusion protein was able to induce the immune response in BALB/c mice after intra-mucosal immunization. In the present investigation, we have not only successfully scaled up the hairy root culture but also established the utility of this system to produce vaccine antigen which subsequently will reduce the total production cost for implementing rabies vaccination programs in developing nations. This study in a way aims to provide consolidated base for low-cost preparation of improved oral vaccine against rabies. PMID- 25519903 TI - HTRA1 (high temperature requirement A serine peptidase 1) gene is transcriptionally regulated by insertion/deletion nucleotides located at the 3' end of the ARMS2 (age-related maculopathy susceptibility 2) gene in patients with age-related macular degeneration. AB - Dry age-related macular degeneration (AMD) accounts for over 85% of AMD cases in the United States, whereas Japanese AMD patients predominantly progress to wet AMD or polypoidal choroidal vasculopathy. Recent genome-wide association studies have revealed a strong association between AMD and an insertion/deletion sequence between the ARMS2 (age-related maculopathy susceptibility 2) and HTRA1 (high temperature requirement A serine peptidase 1) genes. Transcription regulator activity was localized in mouse retinas using heterozygous HtrA1 knock-out mice in which HtrA1 exon 1 was replaced with beta-galactosidase cDNA, thereby resulting in dominant expression of the photoreceptors. The insertion/deletion sequence significantly induced HTRA1 transcription regulator activity in photoreceptor cell lines but not in retinal pigmented epithelium or other cell types. A deletion construct of the HTRA1 regulatory region indicated that potential transcriptional suppressors and activators surround the insertion/deletion sequence. Ten double-stranded DNA probes for this region were designed, three of which interacted with nuclear extracts from 661W cells in EMSA. Liquid chromatography-mass spectrometry (LC-MS/MS) of these EMSA bands subsequently identified a protein that bound the insertion/deletion sequence, LYRIC (lysine-rich CEACAM1 co-isolated) protein. In addition, induced pluripotent stem cells from wet AMD patients carrying the insertion/deletion sequence showed significant up-regulation of the HTRA1 transcript compared with controls. These data suggest that the insertion/deletion sequence alters the suppressor and activator cis-elements of HTRA1 and triggers sustained up-regulation of HTRA1. These results are consistent with a transgenic mouse model that ubiquitously overexpresses HtrA1 and exhibits characteristics similar to those of wet AMD patients. PMID- 25519902 TI - The optimal corepressor function of nuclear receptor corepressor (NCoR) for peroxisome proliferator-activated receptor gamma requires G protein pathway suppressor 2. AB - Repression of peroxisome proliferator-activated receptor gamma (PPARgamma) dependent transcription by the nuclear receptor corepressor (NCoR) is important for homeostatic expression of PPARgamma target genes in vivo. The current model states that NCoR-mediated repression requires its direct interaction with PPARgamma in the repressive conformation. Previous studies, however, have shown that DNA-bound PPARgamma is incompatible with a direct, high-affinity association with NCoR because of the inherent ability of PPARgamma to adopt the active conformation. Here we show that NCoR acquires the ability to repress active PPARgamma-mediated transcription via G protein pathway suppressor 2 (GPS2), a component of the NCoR corepressor complex. Unlike NCoR, GPS2 can recognize and bind the active state of PPARgamma. In GPS2-deficient mouse embryonic fibroblast cells, loss of GPS2 markedly reduces the corepressor function of NCoR for PPARgamma, leading to constitutive activation of PPARgamma target genes and spontaneous adipogenesis of the cells. GPS2, however, is dispensable for repression mediated by unliganded thyroid hormone receptor alpha or a PPARgamma mutant unable to adopt the active conformation. This study shows that GPS2, although dispensable for the intrinsic repression function of NCoR, can mediate a novel corepressor repression pathway that allows NCoR to directly repress active PPARgamma-mediated transcription, which is important for the optimal corepressor function of NCoR for PPARgamma. Interestingly, GPS2-dependent repression specifically targets PPARgamma but not PPARalpha or PPARdelta. Therefore, GPS2 may serve as a unique target to manipulate PPARgamma signaling in diseases. PMID- 25519904 TI - Intramembrane aromatic interactions influence the lipid sensitivities of pentameric ligand-gated ion channels. AB - Although the Torpedo nicotinic acetylcholine receptor (nAChR) reconstituted into phosphatidylcholine (PC) membranes lacking cholesterol and anionic lipids adopts a conformation where agonist binding is uncoupled from channel gating, the underlying mechanism remains to be defined. Here, we examine the mechanism behind lipid-dependent uncoupling by comparing the propensities of two prokaryotic homologs, Gloebacter and Erwinia ligand-gated ion channel (GLIC and ELIC, respectively), to adopt a similar uncoupled conformation. Membrane-reconstituted GLIC and ELIC both exhibit folded structures in the minimal PC membranes that stabilize an uncoupled nAChR. GLIC, with a large number of aromatic interactions at the interface between the outermost transmembrane alpha-helix, M4, and the adjacent transmembrane alpha-helices, M1 and M3, retains the ability to flux cations in this uncoupling PC membrane environment. In contrast, ELIC, with a level of aromatic interactions intermediate between that of the nAChR and GLIC, does not undergo agonist-induced channel gating, although it does not exhibit the expected biophysical characteristics of the uncoupled state. Engineering new aromatic interactions at the M4-M1/M3 interface to promote effective M4 interactions with M1/M3, however, increases the stability of the transmembrane domain to restore channel function. Our data provide direct evidence that M4 interactions with M1/M3 are modulated during lipid sensing. Aromatic residues strengthen M4 interactions with M1/M3 to reduce the sensitivities of pentameric ligand-gated ion channels to their surrounding membrane environment. PMID- 25519905 TI - Rom2-dependent phosphorylation of Elo2 controls the abundance of very long-chain fatty acids. AB - Sphingolipids are essential components of eukaryotic membranes, where they serve to maintain membrane integrity. They are important components of membrane trafficking and function in signaling as messenger molecules. Sphingolipids are synthesized de novo from very long-chain fatty acids (VLCFA) and sphingoid long chain bases, which are amide linked to form ceramide and further processed by addition of various headgroups. Little is known concerning the regulation of VLCFA levels and how cells coordinate their synthesis with the availability of long-chain bases for sphingolipid synthesis. Here we show that Elo2, a key enzyme of VLCFA synthesis, is controlled by signaling of the guanine nucleotide exchange factor Rom2, initiating at the plasma membrane. This pathway controls Elo2 phosphorylation state and VLCFA synthesis. Our data identify a regulatory mechanism for coordinating VLCFA synthesis with sphingolipid metabolism and link signal transduction pathways from the plasma membrane to the regulation of lipids for membrane homeostasis. PMID- 25519907 TI - Dual roles of histone H3 lysine 9 acetylation in human embryonic stem cell pluripotency and neural differentiation. AB - Early neurodevelopment requires cell fate commitment from pluripotent stem cells to restricted neural lineages, which involves the epigenetic regulation of chromatin structure and lineage-specific gene transcription. However, it remains unclear how histone H3 lysine 9 acetylation (H3K9Ac), an epigenetic mark representing transcriptionally active chromatin, is involved in the neural commitment from pluripotent embryonic stem cells (ESCs). In this study, we demonstrate that H3K9Ac gradually declines during the first 4 days of in vitro neural differentiation of human ESCs (hESCs) and then increases during days 4-8. Consistent with this finding, the H3K9Ac enrichment at several pluripotency genes was decreased, and H3K9Ac occupancies at the loci of neurodevelopmental genes increased during hESC neural commitment. Inhibiting H3K9 deacetylation on days 0 4 by histone deacetylase inhibitors (HDACis) promoted hESC pluripotency and suppressed its neural differentiation. Conversely, HDACi-elicited up-regulation of H3K9 acetylation on days 4-8 enhanced neural differentiation and activated multiple neurodevelopmental genes. Mechanistically, HDACis promote pluripotency gene transcription to support hESC self-renewal through suppressing HDAC3 activity. During hESC neural commitment, HDACis relieve the inhibitory activities of HDAC1/5/8 and thereby promote early neurodevelopmental gene expression by interfering with gene-specific histone acetylation patterns. Furthermore, p300 is primarily identified as the major histone acetyltransferase involved in both hESC pluripotency and neural differentiation. Our results indicate that epigenetic modification plays pivotal roles during the early neural specification of hESCs. The histone acetylation, which is regulated by distinct HDAC members at different neurodevelopmental stages, plays dual roles in hESC pluripotency maintenance and neural differentiation. PMID- 25519906 TI - Post-transcriptional regulation of programmed cell death 4 (PDCD4) mRNA by the RNA-binding proteins human antigen R (HuR) and T-cell intracellular antigen 1 (TIA1). AB - Post-transcriptional processing of mRNA transcripts plays a critical role in establishing the gene expression profile of a cell. Such processing events are mediated by a host of factors, including RNA-binding proteins and microRNAs. A number of critical cellular pathways are subject to regulation at multiple levels that allow fine-tuning of key biological responses. Programmed cell death 4 (PDCD4) is a tumor suppressor and an important modulator of mRNA translation that is regulated by a number of mechanisms, most notably as a target of the oncomiR, miR-21. Here, we provide evidence for post-transcriptional regulation of PDCD4 by the RNA-binding proteins, HuR and TIA1. Complementary approaches reveal binding of both HuR and TIA1 to the PDCD4 transcript. Consistent with a model where RNA binding proteins modulate the PDCD4 transcript, knockdown of HuR and/or TIA1 results in a significant decrease in steady-state PDCD4 mRNA and protein levels. However, fractionation experiments suggest that the mode of regulation of the PDCD4 transcript likely differs in the cytoplasm and the nucleus as the pool of PDCD4 mRNA present in the cytoplasm is more stable than the nuclear pool of PDCD4 transcript. We observe a competitive mode of binding between HuR and TIA1 on the PDCD4 transcript in the cytoplasm, suggesting that these two factors dynamically interact with one another as well as the PDCD4 transcript to maintain tight control of PDCD4 levels. Overall, this study reveals an additional set of regulatory interactions that modulate the expression of PDCD4, a key pro apoptotic factor, and also reveals new insights into how HuR and TIA1 functions are integrated to achieve such regulation. PMID- 25519908 TI - Proteolytic activation of the protease-activated receptor (PAR)-2 by the glycosylphosphatidylinositol-anchored serine protease testisin. AB - Protease-activated receptors (PARs) are a family of seven-transmembrane, G protein-coupled receptors that are activated by multiple serine proteases through specific N-terminal proteolytic cleavage and the unmasking of a tethered ligand. The majority of PAR-activating proteases described to date are soluble proteases that are active during injury, coagulation, and inflammation. Less investigation, however, has focused on the potential for membrane-anchored serine proteases to regulate PAR activation. Testisin is a unique trypsin-like serine protease that is tethered to the extracellular membrane of cells through a glycophosphatidylinositol (GPI) anchor. Here, we show that the N-terminal domain of PAR-2 is a substrate for testisin and that proteolytic cleavage of PAR-2 by recombinant testisin activates downstream signaling pathways, including intracellular Ca(2+) mobilization and ERK1/2 phosphorylation. When testisin and PAR-2 are co-expressed in HeLa cells, GPI-anchored testisin specifically releases the PAR-2 tethered ligand. Conversely, knockdown of endogenous testisin in NCI/ADR-Res ovarian tumor cells reduces PAR-2 N-terminal proteolytic cleavage. The cleavage of PAR-2 by testisin induces activation of the intracellular serum response element and NFkappaB signaling pathways and the induction of IL-8 and IL 6 cytokine gene expression. Furthermore, the activation of PAR-2 by testisin results in the loss and internalization of PAR-2 from the cell surface. This study reveals a new biological substrate for testisin and is the first demonstration of the activation of a PAR by a serine protease GPI-linked to the cell surface. PMID- 25519910 TI - Coordinated regulation of the orosomucoid-like gene family expression controls de novo ceramide synthesis in mammalian cells. AB - The orosomucoid-like (ORMDL) protein family is involved in the regulation of de novo sphingolipid synthesis, calcium homeostasis, and unfolded protein response. Single nucleotide polymorphisms (SNPs) that increase ORMDL3 expression have been associated with various immune/inflammatory diseases, although the pathophysiological mechanisms underlying this association are poorly understood. ORMDL proteins are claimed to be inhibitors of the serine palmitoyltransferase (SPT). However, it is not clear whether individual ORMDL expression levels have an impact on ceramide synthesis. The present study addressed the interaction with and regulation of SPT activity by ORMDLs to clarify their pathophysiological relevance. We have measured ceramide production in HEK293 cells incubated with palmitate as a direct substrate for SPT reaction. Our results showed that a coordinated overexpression of the three isoforms inhibits the enzyme completely, whereas individual ORMDLs are not as effective. Immunoprecipitation and fluorescence resonance energy transfer (FRET) studies showed that mammalian ORMDLs form oligomeric complexes that change conformation depending on cellular sphingolipid levels. Finally, using macrophages as a model, we demonstrate that mammalian cells modify ORMDL genes expression levels coordinately to regulate the de novo ceramide synthesis pathway. In conclusion, we have shown a physiological modulation of SPT activity by general ORMDL expression level regulation. Moreover, because single ORMDL3 protein alteration produces an incomplete inhibition of SPT activity, this work argues against the idea that ORMDL3 pathophysiology could be explained by a simple on/off mechanism on SPT activity. PMID- 25519909 TI - Smoothened goes molecular: new pieces in the hedgehog signaling puzzle. AB - A general aim of studies of signal transduction is to identify mediators of specific signals, order them into pathways, and understand the nature of interactions between individual components and how these interactions alter pathway behavior. Despite years of intensive study and its central importance to animal development and human health, our understanding of the Hedgehog (Hh) signaling pathway remains riddled with gaps, question marks, assumptions, and poorly understood connections. In particular, understanding how interactions between Hh and Patched (Ptc), a 12-pass integral membrane protein, lead to modulation of the function of Smoothened (Smo), a 7-pass integral membrane protein, has defied standard biochemical characterization. Recent structural and biochemical characterizations of Smoothened domains have begun to unlock this riddle, however, and lay the groundwork for improved cancer therapies. PMID- 25519911 TI - The ether lipid precursor hexadecylglycerol stimulates the release and changes the composition of exosomes derived from PC-3 cells. AB - Exosomes are vesicles released by cells after fusion of multivesicular bodies with the plasma membrane. In this study, we have investigated whether ether lipids affect the release of exosomes in PC-3 cells. To increase the cellular levels of ether lipids, the ether lipid precursor hexadecylglycerol was added to cells. Lipidomic analysis showed that this compound was in fact able to double the cellular levels of ether lipids in these cells. Furthermore, increased levels of ether lipids were also found in exosomes released by cells containing high levels of these lipids. Interestingly, as measured by nanoparticle tracking analysis, cells containing high levels of ether lipids released more exosomes than control cells, and these exosomes were similar in size to control exosomes. Moreover, silver staining and Western blot analyses showed that the protein composition of exosomes released in the presence of hexadecylglycerol was changed; the levels of some proteins were increased, and the levels of others were reduced. In conclusion, this study clearly shows that an increase in cellular ether lipids is associated with changes in the release and composition of exosomes. PMID- 25519912 TI - Determinants of endogenous ligand specificity divergence among metabotropic glutamate receptors. AB - To determine the structural origins of diverse ligand response specificities among metabotropic glutamate receptors (mGluRs), we combined computational approaches with mutagenesis and ligand response assays to identify specificity determining residues in the group I receptor, mGluR1, and the group III receptors, mGluR4 and mGluR7. Among these, mGluR1 responds to L-glutamate effectively, whereas it binds weakly to another endogenous ligand, L-serine-O phosphate (L-SOP), which antagonizes the effects of L-glutamate. In contrast, mGluR4 has in common with other group III mGluR that it is activated with higher potency and efficacy by L-SOP. mGluR7 differs from mGluR4 and other group III mGluR in that L-glutamate and L-SOP activate it with low potency and efficacy. Enhanced versions of the evolutionary trace (ET) algorithm were used to identify residues that when swapped between mGluR1 and mGluR4 increased the potency of L SOP inhibition relative to the potency of L-glutamate activation in mGluR1 mutants and others that diminished the potency/efficacy of L-SOP for mGluR4 mutants. In addition, combining ET identified swaps from mGluR4 with one identified by computational docking produced mGluR7 mutants that respond with dramatically enhanced potency/efficacy to L-SOP. These results reveal that an early functional divergence between group I/II and group III involved variation at positions primarily at allosteric sites located outside of binding pockets, whereas a later divergence within group III occurred through sequence variation both at the ligand-binding pocket and at loops near the dimerization interface and interlobe hinge region. They also demonstrate the power of ET for identifying allosteric determinants of evolutionary importance. PMID- 25519913 TI - Cyclophosphamide-induced posterior reversible encephalopathy syndrome (PRES): a case report. AB - INTRODUCTION: Posterior reversible encephalopathy syndrome is a clinicoradiologic entity characterized by headache, seizures, decreased vision, impaired consciousness and white matter oedema in bilateral occipitoparietal regions. Hypertensive encephalopathy, eclampsia, immunosuppressive/cytotoxic drugs, organ transplantation, renal disease, autoimmune diseases and vasculitides are reported risk factors of posterior reversible encephalopathy syndrome. Reports of cyclophosphamide-induced posterior reversible encephalopathy syndrome are rare and occurred in a background of renal failure, fluid overload or active connective tissue disease. CASE PRESENTATION: We report a case of posterior reversible encephalopathy syndrome developing as a direct consequence of intravenous cyclophosphamide therapy in a 33-year-old normotensive Sri Lankan woman with lupus nephritis but quiescent disease activity and normal renal function. CONCLUSIONS: This case report highlights the need for awareness and early recognition of this rare but serious adverse effect of cyclophosphamide that occurred in the absence of other known risk factors of posterior reversible encephalopathy syndrome and that early appropriate intervention leads to a good outcome. PMID- 25519914 TI - A pilot study of a mindfulness based stress reduction program in adolescents with implantable cardioverter defibrillators or pacemakers. AB - Adolescents with implantable cardioverter defibrillators (ICDs) or pacemakers (PMs) face unique challenges that can cause psychosocial distress. Psychosocial interventions are effective for adults with cardiac devices and could potentially impact adolescents' adjustment to these devices. Mindfulness Based Stress Reduction (MBSR) is a structured psycho-educational program that includes meditation, yoga, and group support and has been studied extensively among adults. This study examined the feasibility of the MBSR program for adolescents with ICDs/PMs, a population previously unexamined in the research literature. The participants completed measures of anxiety and depression (Hospital Anxiety and Depression Scale) and coping (Responses to Stress Questionnaire) at baseline and after the six-session MBSR intervention. Mean age of the cohort (n = 10) was 15 +/- 3 years, 6 were male, 6 had a PM, and 4 had an ICD. Feasibility was demonstrated by successful recruitment of 10 participants, 100 % participation and completion. Anxiety decreased significantly following the intervention, with a large effect size, t[9] = 3.67, p < .01, n (2) = .59. Anxiety frequency decreased from baseline to post-intervention (Fisher's exact test p = .024), and 90 % of participants reported decreased anxiety scores post-intervention. Coping skills related negatively to anxiety (r = -.65, p = .04) and depression (r = .88, p = .001). Post-intervention, the group independently formed their own Facebook group and requested to continue meeting monthly. Although generalizability is limited due to the small sample size, this successful pilot study paves the way for larger studies to examine the efficacy of MBSR interventions in adolescents with high-risk cardiac diagnoses. PMID- 25519915 TI - The impact of pulmonary insufficiency on the right ventricle: a comparison of isolated valvar pulmonary stenosis and tetralogy of fallot. AB - Pulmonary insufficiency (PI) is associated with right ventricular (RV) dilation, dysfunction, and exercise intolerance in patients with tetralogy of fallot (TOF). We sought to compare RV function and exercise performance in patients with valvar pulmonary stenosis (VPS) following pulmonary balloon valvuloplasty to those with repaired TOF with similar degrees of PI. We performed a cross-sectional study of patients with VPS and TOF. Cardiac magnetic resonance (CMR) and exercise stress test were performed. Subjects were matched by time from initial procedure and severity of PI using propensity scores. After matching, there were 16 patients with VPS and 16 with TOF for comparison, with similar demographics. Time from initial procedure was 14 years (12-16), p = 0.92, and pulmonary regurgitant fraction was 19 % (6-31), p = 0.94, Patients with TOF had lower ejection fraction [58 % (53-66) vs. 65 % (60-69), p = 0.04] and more RV hypertrophy [69 g/m(2) (52 86) vs. 44 g/m(2) (32-66), p = 0.04] compared to those with VPS. Aerobic capacity was worse in patients with TOF [68 +/- 19 % mVO2 (56-84) vs. 82 +/- 9.2 % (74-89) in VPS, p = 0.01], with a trend for less habitual physical activity [0.9 (0-12) vs. 8 h/week (4-12), p = 0.056], respectively. With similar degrees of PI, patients with TOF demonstrate worse RV function and aerobic capacity as compared to patients with just VPS. Habitual exercise may in part explain differences in exercise performance and should be further explored. PMID- 25519917 TI - Modulation of Calcium Signaling of Angiotensin AT1, Endothelin ETA, and ETB Receptors by Silibinin, Quercetin, Crocin, Diallyl Sulfides, and Ginsenoside Rb1. AB - Angiotensin II and endothelin-1 are potent vasoconstrictive peptides that play a central role in blood pressure regulation. Both peptides exert their pleiotropic effects via binding to their respective G-protein-coupled receptors, i.e., angiotensin AT1 and endothelin type A and type B receptors. In the present study, we have selected six structurally different plant-derived compounds with known cardioprotective properties to evaluate their ability to modulate calcium signaling of the above-mentioned receptors. For this purpose, we used and validated a cellular luminescence-based read-out system in which we measured intracellular calcium signaling in Chinese hamster ovary cells that express the calcium sensitive apo-aequorin protein. Firstly, silibinin, a flavanolignan that occurs in milk thistle (Silybum marianum), was investigated and found to be an antagonist for the human angiotensin AT1 receptor with an affinity constant of about 9 uM, while it had no effect on endothelin type A or type B receptor activation. Quercetin and crocin partially impeded intracellular calcium signaling resulting in a non-receptor-related reduction of the responses recorded for the three investigated G-protein-coupled receptors. Two organosulfur compounds, diallyl disulfide and diallyl trisulfide, as well as the triterpene saponin ginsenoside Rb1 did not affect the activation of the angiotensin AT1 and endothelin type A and type B receptors. In conclusion, we were able, by using a nonradioactive cellular read-out system, to identify a novel pharmacological property of the flavanolignan silibinin. PMID- 25519918 TI - Meroterpenes with toll-like receptor 3 regulating activity from the endophytic fungus Guignardia mangiferae. AB - The endophytic fungus Guignardia mangiferae isolated from Ilex cornuta leaves was shown to produce a family of meroterpenes with toll-like receptor 3 regulating activity (1-9), of which 1-3 possessed new structures. The absolute stereochemistry of 1-3 was assigned through a combination of nuclear magnetic resonance experiments, chemical derivation, CD spectra, and single-crystal X-ray diffraction analyses (CuK alpha ). The precursor labeled cultivation suggests that these meroterpenes are most likely assembled through terpenoid-shikimate pathways. Moreover, meroterpenes 1-3, 5-7, and 9 selectively upregulate, but 4 and 8 downregulate the toll-like receptor 3 expression in mouse dendritic cells at 10.0 uM. PMID- 25519919 TI - Tuning structural instability toward enhanced magnetocaloric effect around room temperature in MnCo(1-x)Zn(x)Ge. AB - Magnetocaloric effect is the phenomenon that temperature change of a magnetic material is induced by application of a magnetic field. This effect can be applied to environmentally-benign magnetic refrigeration technology. Here we show a key role of magnetic-field-induced structural instability in enhancing the magnetocaloric effect for MnCo(1-x)Zn(x)Ge alloys (x = 0-0.05). The increase in x rapidly reduces the martensitic transition temperature while keeping the ferromagnetic transition around room temperature. Fine tuning of x around x = 0.03 leads to the concomitant structural and ferromagnetic transition in a cooling process, giving rise to enhanced magnetocaloric effect as well as magnetic-field-induced structural transition. Analyses of the structural phase diagrams in the T-H plane in terms of Landau free-energy phenomenology accounts for the characteristic x-dependence of the observed magnetocaloric effect, pointing to the importance of the magnetostructural coupling for the design of high-performance magnetocalorics. PMID- 25519916 TI - The EHEC-host interactome reveals novel targets for the translocated intimin receptor. AB - Enterohemorrhagic E. coli (EHEC) manipulate their human host through at least 39 effector proteins which hijack host processes through direct protein-protein interactions (PPIs). To identify their protein targets in the host cells, we performed yeast two-hybrid screens, allowing us to find 48 high-confidence protein-protein interactions between 15 EHEC effectors and 47 human host proteins. In comparison to other bacteria and viruses we found that EHEC effectors bind more frequently to hub proteins as well as to proteins that participate in a higher number of protein complexes. The data set includes six new interactions that involve the translocated intimin receptor (TIR), namely HPCAL1, HPCAL4, NCALD, ARRB1, PDE6D, and STK16. We compared these TIR interactions in EHEC and enteropathogenic E. coli (EPEC) and found that five interactions were conserved. Notably, the conserved interactions included those of serine/threonine kinase 16 (STK16), hippocalcin-like 1 (HPCAL1) as well as neurocalcin-delta (NCALD). These proteins co-localize with the infection sites of EPEC. Furthermore, our results suggest putative functions of poorly characterized effectors (EspJ, EspY1). In particular, we observed that EspJ is connected to the microtubule system while EspY1 appears to be involved in apoptosis/cell cycle regulation. PMID- 25519920 TI - Human induced pluripotent stem cell-derived B lymphocytes express sIgM and can be generated via a hemogenic endothelium intermediate. AB - The differentiation of human pluripotent stem cells to the B-cell lymphoid lineage has important clinical applications that include in vitro modeling of developmental lymphogenesis in health and disease. Here, we first demonstrate the capacity of human induced pluripotent stem cells (hiPSCs) to differentiate into CD144(+)CD73(-)CD43/CD235a(-) cells, characterized as hemogenic endothelium, and show that this population is capable of differentiating to CD10(+)CD19(+) B lymphocytes. We also demonstrate that B lymphocytes generated from hiPSCs are able to undergo full VDJ rearrangement and express surface IgM (sIgM(+)), thus representing an immature B-cell subset. Efficiency of sIgM expression on the hiPSC-derived B lymphocytes (~ 5% of CD19(+) cells) was comparable with B lymphocytes generated from human umbilical cord blood (UCB) hematopoietic progenitor cells. Importantly, when assessed by global transcriptional profiling, hiPSC-derived B-cells show a very high level of similarity when compared with their UCB-derived counterparts, such that from more than 47,000 different transcripts, only 45 were significantly different (with a criteria adjusted P value P<0.05, log FC >1.5 or 2.8-fold). This represents a unique in vitro model to delineate critical events during lymphogeneisis in development and lymphoid diseases such as acute lymphocytic leukemia. PMID- 25519921 TI - Brain-derived neurotrophic factor as a driving force behind neuroplasticity in neuropathic and central sensitization pain: a new therapeutic target? AB - INTRODUCTION: Central sensitization is a form of maladaptive neuroplasticity underlying many chronic pain disorders, including neuropathic pain, fibromyalgia, whiplash, headache, chronic pelvic pain syndrome and some forms of osteoarthritis, low back pain, epicondylitis, shoulder pain and cancer pain. Brain-derived neurotrophic factor (BDNF) is a driving force behind neuroplasticity, and it is therefore crucial for neural maintenance and repair. However, BDNF also contributes to sensitization of pain pathways, making it an interesting novel therapeutic target. AREAS COVERED: An overview of BDNF's sensitizing capacity at every level of the pain pathways is presented, including the peripheral nociceptors, dorsal root ganglia, spinal dorsal horn neurons, and brain descending inhibitory and facilitatory pathways. This is followed by the presentation of several potential therapeutic options, ranging from indirect influencing of BDNF levels (using exercise therapy, anti-inflammatory drugs, melatonin, repetitive transcranial magnetic stimulation) to more specific targeting of BDNF's receptors and signaling pathways (blocking the proteinase activated receptors 2-NK-kappabeta signaling pathway, administration of phencyclidine for antagonizing NMDA receptors, or blockade of the adenosine A2A receptor). EXPERT OPINION: This section focuses on combining pharmacotherapy with multimodal rehabilitation for balancing the deleterious and therapeutic effects of BNDF treatment in chronic pain patients, as well as accounting for the complex and biopsychosocial nature of chronic pain. PMID- 25519923 TI - Correction: Preparation of hexagonal GeO2 particles with particle size and crystallinity controlled by peptides, silk and silk-peptide chimeras. AB - Correction for 'Preparation of hexagonal GeO2 particles with particle size and crystallinity controlled by peptides, silk and silk-peptide chimeras' by Estefania Boix et al., Dalton Trans., 2014, 43, 16902-16910. PMID- 25519922 TI - Evaluation of national trends in the utilization of partial nephrectomy in relation to the publication of the American Urologic Association guidelines for the management of clinical T1 renal masses. AB - BACKGROUND: Partial nephrectomy has been underutilized in the United States. We investigated national trends in partial nephrectomy (PN) utilization before and after publication of the American Urological Association (AUA) Practice Guideline for management of the clinical T1 renal mass. METHODS: We identified adult patients who underwent radical (RN) or PN from November 2007 to October 2011 in the Nationwide Inpatient Sample (NIS). PN prevalence was calculated prior to (11/2007-10/2009) and after Guidelines publication (11/2009-10/2011) and compared the rate of change by linear regression. We also examined the nephrectomy trends in patients with chronic kidney disease (CKD). Statistical analysis included linear regression to determine point-prevalence of PN rates in CKD patients and logistic regression to identify variables associated with PN. RESULTS: During the study period, 30,944 patients underwent PN and 64,767 RN. The prevalence PN increased from 28.9% in the years prior to guideline release to 35.3% in the years following guideline release with an adjusted odds ratio (OR) of 1.24 (CI 1.01-1.54; p = 0.049). The rate of PN significantly increased throughout the study period (R2 0.15, p = 0.006): however, the rate of change was not increased after the guidelines. (p = 0.46). Overall rate of PN in patients with CKD did not increase over time (R2 0.0007, p = 0.99). CONCLUSION: We noted a 6.4% absolute increase in PN after release of the AUA guidelines on clinical T1 renal mass was published; however, the rate of increase was not likely associated with guideline release. The rate of PN performed is increasing; however, further investigation regarding medical decision-making surrounding PN is needed. PMID- 25519924 TI - Functional imaging in neurodegenerative disorders: past, present and future. PMID- 25519926 TI - The Ability to Diagnose Intrahepatic Cholangiocarcinoma Definitively Using Novel Branched DNA-Enhanced Albumin RNA In Situ Hybridization Technology. AB - BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) often is a diagnosis determined by exclusion. Distinguishing ICC from other metastatic adenocarcinomas based on histopathologic or immunohistochemical analysis often is difficult and requires an extensive workup. This study aimed to determine whether albumin, whose expression is restricted to the liver, has potential as a biomarker for ICC using a novel and highly sensitive RNA in situ hybridization (ISH) platform. METHODS: Modified branched DNA probes were developed for albumin RNA ISH. The study evaluated 467 patient samples of primary and metastatic lesions. RESULTS: Of the 467 samples evaluated, 83 were ICCs, 42 were hepatocellular carcinomas (HCCs), and 332 were nonhepatic carcinomas including tumors arising from the perihilar region and bile duct, pancreas, stomach, esophagus, colon, breast, ovary, endometrium, kidney, and urinary bladder. Albumin RNA ISH was highly sensitive for cancers of liver origin, staining positive in 82 (99 %) of 83 ICCs and in 42 HCCs (100 %). Perihilar and distal bile duct carcinomas as well as carcinomas arising at other sites tested negative for albumin. Notably, 6 (22 %) of 27 intrahepatic tumors previously diagnosed as carcinomas of undetermined origin tested positive for albumin. CONCLUSIONS: Albumin RNA ISH is a sensitive and highly specific diagnostic tool for distinguishing ICC from metastatic adenocarcinoma to the liver or carcinoma of unknown origin. Albumin RNA ISH could replace the extensive diagnostic workup, leading to timely confirmation of the ICC diagnosis. Additionally, the assay could serve as a guide to distinguish ICC from perihilar adenocarcinoma. PMID- 25519928 TI - Expression of the Novel Costimulatory Molecule B7-H5 in Pancreatic Cancer. AB - BACKGROUND: This study investigated how the B7-H5 protein, a new member of the B7 family, is expressed in normal human pancreas tissues and examined its expression changes in pancreatic cancer. METHODS: In this analysis, B7-H5 expression was examined by immunohistochemical staining of frozen specimens from patients undergoing pancreatic resection. RESULTS: Membranous B7-H5 protein was expressed on normal ductal epithelium within the pancreas. Other cell types from the normal pancreas, such as acinar cells and islet cells, did not express B7-H5. In adenocarcinoma, B7-H5 staining was decreased or absent. Interestingly, B7-H5 expression in intraductal papillary mucinous neoplasms varied with grade. No B7 H5 expression was found with other cancer types such as neuroendocrine tumors, but normal ducts adjacent to tumors were highly positive. CONCLUSIONS: The findings showed that B7-H5 expression was restricted to ductal cells in the normal pancreas and the expression was downregulated in pancreatic adenocarcinomas. In addition, the findings showed that B7-H5 expression changes within different stages of dysplasia. The study suggests that loss of the B7-H5 signal may contribute to immune evasion of pancreatic adenocarcinoma. However future studies are needed. PMID- 25519927 TI - Characterization of Anthropometric Changes that Occur During Neoadjuvant Therapy for Potentially Resectable Pancreatic Cancer. AB - BACKGROUND: Little is known about changes in body composition that may occur during neoadjuvant therapy for pancreatic cancer. This study was designed to characterize these changes and their potential relationships with therapeutic outcomes. METHODS: The study population consisted of patients with potentially resectable pancreatic cancer treated on a phase II trial of neoadjuvant chemotherapy and chemoradiation. Skeletal muscle and adipose tissue compartments were measured before and after administration of neoadjuvant therapy using SliceOMatic software (TomoVision, 2012) and protocol-mandated CT scans. Sarcopenia was defined using gender-adjusted norms. RESULTS: Among 89 eligible patients, 46 (52 %) patients met anthropometric criteria for sarcopenia prior to the initiation of neoadjuvant therapy. Further depletion of skeletal muscle, visceral adipose tissue, and subcutaneous adipose tissue occurred during neoadjuvant therapy, but these losses did not preclude the performance of potentially curative surgery. Degree of skeletal muscle loss correlated with disease-free survival while visceral adipose loss was associated with overall and progression-free survival. However, completion of all therapy, including pancreatectomy, was the only independently significant predictor of outcome in a multivariate analysis of overall survival. DISCUSSION: These data suggest that body composition analysis of standard CT images may provide clinically relevant information for patients with potentially resectable pancreatic cancer who receive neoadjuvant therapy. Anthropometric changes must be considered in the design of preoperative therapy regimens, and further efforts should focus on maintenance of muscle and visceral adipose tissue in the preoperative setting. PMID- 25519929 TI - Analysis of Charges Associated with Definitive Nonsurgical Therapy for Early Stage Lateralized Tonsil Cancer. AB - OBJECTIVE: The cost of treatment as it affects comparative effectiveness is becoming increasingly more important. Because cost data are not readily available, we evaluated the charges associated with definitive nonsurgical therapy for early-stage lateralized tonsil cancers. METHODS: Patients treated with unilateral radiation therapy (RT) for T1 or T2 tonsil cancer between 1995 and 2007 were retrospectively reviewed. Total and radiation-specific charges, from 3 months before to 4 months after radiation, were adjusted for inflation. All facets of treatment were evaluated for significant associations with total billing. RESULTS: Eighty-four patients were identified. Three-year overall survival, disease-specific survival, and recurrence-free survival were 97 % [95 % confidence interval (CI) 0.88-0.99], 98 % (95 % CI 0.89-1), and 96 % (95 % CI 0.88-0.99), respectively. The median for radiation-specific charges was $60,412 (range $16,811-$84,792). The median for total charges associated with treatment was $109,917 (range $36,680-$231,895). Total billing for treatment was significantly associated with the year of diagnosis (p = 0.008), intensity modulated radiation therapy versus wedge pair RT (p = 0.005), preradiation direct laryngoscopy (p < 0.0001), chemotherapy (p < 0.0001), gastrostomy tube placement (p = 0.004), and postradiation neck dissection (p = 0.005). CONCLUSIONS: Although cost data for treatment are not readily available, historically, the recovery rate is approximately 30 %. The charges associated with definitive nonsurgical therapy for early-stage lateralized tonsil cancer have a wide range likely due to treatment-related procedures, the use of chemotherapy, and evolving RT technologies. These benchmark data are important given renewed interested in primary surgery for tonsil cancer. Cost of care, disease control, and functional outcomes will be critical for comparisons of effectiveness when selecting treatment modalities. PMID- 25519930 TI - Surgical Strategy for T2 Gallbladder Cancer According to Tumor Location. AB - BACKGROUND: Radical cholecystectomy is recommended for T2 gallbladder cancer. However, it is unclear whether hepatic resection is essential for peritoneal-side gallbladder cancer. METHODS: From January 2000 to December 2011, we identified T2 gallbladder cancer patients who had undergone curative intent surgery. A peritoneal-side tumor was defined when the epicenter of the tumor was located within the free peritoneal-side gallbladder mucosa. Hepatic-side gallbladder cancer was defined when the epicenter of the tumor was located within the gallbladder bed or neck. RESULTS: A total of 157 patients with T2 gallbladder cancer were included; 33 peritoneal-side and 124 hepatic-side tumors. In total, 122 patients underwent hepatic resection, whereas the remaining 35 patients did not. After a median follow-up period of 40 (range 5-170) months, the survival of the peritoneal-side group was better than that of the hepatic-side group (p = 0.002). In a multivariate analysis, tumor location, lymph node metastasis, hepatic resection, lymphatic invasion, and perineural invasion were significant prognostic factors (p = 0.045, p < 0.001, p = 0.003, p = 0.046, and p = 0.027, respectively). For the peritoneal-side group, there was no recurrence or death after cholecystectomy without hepatic resection. However, hepatic resection was an important factor associated with overall survival in patients with hepatic side gallbladder cancer (p = 0.007). CONCLUSIONS: In T2 gallbladder cancer patients, hepatic resection is recommended when there is tumor invasion of the gallbladder bed or neck. However, it is not always necessary in selected patients with peritoneal-side gallbladder cancer. PMID- 25519925 TI - The genetics of colony form and function in Caribbean Acropora corals. AB - BACKGROUND: Colonial reef-building corals have evolved a broad spectrum of colony morphologies based on coordinated asexual reproduction of polyps on a secreted calcium carbonate skeleton. Though cnidarians have been shown to possess and use similar developmental genes to bilaterians during larval development and polyp formation, little is known about genetic regulation of colony morphology in hard corals. We used RNA-seq to evaluate transcriptomic differences between functionally distinct regions of the coral (apical branch tips and branch bases) in two species of Caribbean Acropora, the staghorn coral, A. cervicornis, and the elkhorn coral, A. palmata. RESULTS: Transcriptome-wide gene profiles differed significantly between different parts of the coral colony as well as between species. Genes showing differential expression between branch tips and bases were involved in developmental signaling pathways, such as Wnt, Notch, and BMP, as well as pH regulation, ion transport, extracellular matrix production and other processes. Differences both within colonies and between species identify a relatively small number of genes that may contribute to the distinct "staghorn" versus "elkhorn" morphologies of these two sister species. CONCLUSIONS: The large number of differentially expressed genes supports a strong division of labor between coral branch tips and branch bases. Genes involved in growth of mature Acropora colonies include the classical signaling pathways associated with development of cnidarian larvae and polyps as well as morphological determination in higher metazoans. PMID- 25519931 TI - Long-Term Comparison of Aesthetical Outcomes After Oncoplastic Surgery and Lumpectomy in Breast Cancer Patients. AB - BACKGROUND: Lumpectomy may result in major deformities and asymmetries in approximately one-third of patients. Although oncoplastic surgery (OP) could be a useful alternative to avoid them, lack of strong data is causing some debate. The purpose of this study was to compare aesthetic outcomes in patients undergoing OP versus lumpectomy using three different assessment methods. METHODS: A total of 122 patients were included in this cross-sectional multicentric study; 57 underwent OP (46.7 %), and 65 underwent lumpectomy (53.3 %). Two breast surgeons and two plastic surgeons from different institutions using the Garbay scale independently evaluated aesthetic outcomes. BCCT.core software was applied in both groups, and the patients evaluated their aesthetic outcomes answering a questionnaire about their satisfaction rate. RESULTS: OP group had a higher proportion of excellent aesthetic results according to the BCCT.core software analysis (p = 0.028) and the specialists (p = 0.002). Multifactorial analyses showed that age >=70 years (RP = 6.02; 95 % confidence interval [CI] 1.73-21.0; p = 0.005), tumors in the medial, inferior, and central quadrants (RP = 4.21; 95 % CI 1.88-9.44; p < 0.001), and large breasts (RP = 7.55; 95 % CI 2.48-23.0; p < 0.001) were significant risk factors for poor aesthetic outcomes after lumpectomy. The patients classified their results as better than those by the specialists and by the software, with no statistical difference between the groups. CONCLUSIONS: Excellent aesthetic results were more frequent in the OP group according to BCCT.core software analysis and specialists. In addition, some clinical conditions and tumor locations in the breast can be considered risky factors for poor aesthetic outcomes in lumpectomy. PMID- 25519932 TI - Additional support for neoadjuvant therapy in the management of pancreatic cancer. PMID- 25519933 TI - Fatty acid composition of freshwater wild fish in subalpine lakes: a comparative study. AB - In this study, the proximate and fatty acid compositions of the muscle tissue of 186 samples of fish belonging to fifteen species of freshwater fish harvested in subalpine lakes (bleak, shad, crucian carp, whitefish, common carp, pike, black bullhead, burbot, perch, Italian roach, roach, rudd, wels catfish, chub and tench) were investigated. Most of the fish demonstrated a lipid content in the fillet lower than 2.0 g 100 g(-1) wet weight (range 0.6-9.7). A strong relationship between feeding behavior and fatty acid composition of the muscle lipids was observed. Planktivorous fish showed the lowest amounts of n-3 fatty acids (p < 0.05), but the highest monounsaturated fatty acid (MUFA) contents, in particular 18:1n-9. Conversely, carnivorous fish showed the highest amounts of saturated fatty acids and n-3 fatty acids (p < 0.05), but the lowest MUFA contents. Omnivorous fish showed substantial proportions of n-3 fatty acids and the highest contents of n-6 fatty acids. Principal component analysis showed a distinct separation between fish species according to their feeding habits and demonstrated that the most contributing trophic markers were 18:1n-9, 18:3n-3, 22:6n-3 and 20:4n-6. The quantitative amounts n-3 polyunsaturated fatty acid in muscle tissues varied depending on the fish species, the lipid content and the feeding habits. Some species were very lean, and therefore would be poor choices for human consumption to meet dietary n-3 fatty acid requirements. Nevertheless, the more frequently consumed and appreciated fish, shad and whitefish, had EPA and DHA contents in the range 900-1,000 mg 100 g(-1) fresh fillet. PMID- 25519935 TI - Laparoscopic resectional gastric bypass: initial experience in morbidly obese Korean patients. AB - PURPOSE: Roux-en-Y gastric bypass (RYGB) is thought to be the gold standard treatment for morbid obesity. However, concerns have been raised by investigators in areas where gastric cancer is prevalent regarding the inaccessibility of the excluded stomach to regular surveillance. This study aimed to evaluate the technical feasibility and short-term surgical outcomes of resectional RYGB. METHODS: Sixteen consecutive patients who underwent laparoscopic gastric bypass with distal gastric resection for the primary purpose of weight loss between January 2011 and December 2013 were retrospectively reviewed. The perioperative outcomes and weight loss results of these patients were analyzed. RESULTS: All procedures were successfully performed laparoscopically. The mean length of the operation and the mean hospital stay were 170 min (range 110-225) and 4 days (range 2-7), respectively. The prevalence of early postoperative complications reached 18.7% after resectional RYGB, but a severe complication requiring reoperation occurred in only one patient (6.3%). The percent of excess weight loss was 78.9% over a mean follow-up period of 14 months. Obesity-related comorbidities including diabetes, hypertension and dyslipidemia resolved or improved after surgery in most patients. CONCLUSION: Resectional RYGB is technically feasible and can be a viable option in countries with a high risk of gastric cancer, where surgeons are already well trained in laparoscopic gastrectomy. PMID- 25519936 TI - Hiroki Takahashi et al. "Usefulness of endoscopic breast-conserving surgery for breast cancer" Surgery Today in November (2014) 44: 2037-2044. PMID- 25519938 TI - Acquired Idiopathic Generalized Anhidrosis: An Immunohistopathological Investigation of Peri-glands Infiltrated with Immunoreactive Cells. PMID- 25519937 TI - Valve-related complications after mechanical heart valve implantation. AB - The number of heart valve surgeries is increasing, and 19,164 patients underwent heart valve surgery in Japan in 2011. The early mortality rate has remained stable for more than 10 years. Many patients now survive for many years, with a reported 10-year survival rate of at least 60 %. However, unfavorable complications can occur after valve surgery. Valve-related complications include thromboembolisms, bleeding complications and prosthetic valve endocarditis, followed by structural and nonstructural prosthetic valve dysfunctions. Our review of studies published after 2000 revealed that the rate of all valve related complications was 0.7-3.5 % per patient-year. Thromboembolisms occur at a rate of approximately 1 % per patient-year, and bleeding complications occur at almost 0.5 % per patient-year. Thromboembolic and hemorrhagic events related to anticoagulant therapy should be considered during life-long follow-up. The occurrence rate of endocarditis reaches 0.5 % per patient-year, with a poor postoperative survival. Structural dysfunctions have been largely overcome, and the nonstructural dysfunction rate is 0.4-1.2 % per patient-year. The nonstructural dysfunctions induced by paravalvular leaks and pannus ingrowth are also issues that need to be resolved. PMID- 25519939 TI - Introduction to special section: quantitative methods. PMID- 25519934 TI - Dual effect of oxidative stress on leukemia cancer induction and treatment. AB - Oxidative stress (OS) has been characterized by an imbalance between the production of reactive oxygen species (ROS) and a biological system's ability to repair oxidative damage or to neutralize the reactive intermediates including peroxides and free radicals. High ROS production has been associated with significant decrease in antioxidant defense mechanisms leading to protein, lipid and DNA damage and subsequent disruption of cellular functions. In humans, OS has been reported to play a role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, multiple sclerosis and Parkinson's disease, as well as atherosclerosis, autism, cancer, heart failure, and myocardial infarction. Although OS has been linked to the etiology and development of chronic diseases, many chemotherapeutic drugs have been shown to exert their biologic activity through induction of OS in affected cells. This review highlights the controversial role of OS in the development and progression of leukemia cancer and the therapeutic application of increased OS and antioxidant approaches to the treatment of leukemia patients. PMID- 25519940 TI - Do health preferences contradict ordering of EQ-5D labels? AB - PURPOSE: The aim of this study was to test whether the ordering of item labels in EQ-5D instruments disagrees with the preferences of US adults. METHODS: A preference inversion occurs when "worse" health along a scale or score is preferred. As a sub-study of the 2013 United States Measurement and Valuation of Health Study, we tested for 33 EQ-5D preference inversions using paired comparisons with unique samples of 50 or more US adults, aged 18 or older. Specifically, we tested whether health preferences contradicted ordering of EQ-5D labels. RESULTS: The EQ-5D-3L and EQ-5D-Y item labels had no significant preference inversions. The EQ-5D-5L version had preference inversions between Levels 4 and 5. For example, 30 out of 59 respondents (51 %) preferred being "extremely" over "severely anxious or depressed," contrary to the ordering of labels for that item. CONCLUSIONS: Preference inversions between Levels 4 and 5 on the EQ-5D-5L were tested and confirmed; therefore, valuation studies may find that Levels 4 and 5 have the same value. To mitigate such inversions, labels could be revised or a 4-level version could be considered. PMID- 25519941 TI - Burnout and demographic characteristics of workers experiencing different types of work-home interaction. AB - OBJECTIVES: The purpose of this study was to explore configurations of positive versus negative interactions between work and home (WHI) and their relation to burnout and demographic characteristics. MATERIAL AND METHODS: Sample of 533 Polish workers were interviewed by means of self-administered questionnaires (SWING and MBI-GS). Demographic and work characteristics were also controlled. RESULTS: Cluster analysis distinguished 5 types of WHIs: positive WHI (18%), negative WHI (15.9%), no interaction (29.3%), mutual positive interactions (15.4%) and positive HWI (21.4%). The quality of WHI was associated with number of work hours and tenure at main place of employment. The effect of gender on the quality of work-home interaction was not significant. Configuration of WHIs affected the level of burnout. Again, there was no significant difference between men and women in terms of burnout and its sub-dimensions. The least burned-out were people from positive WHI, positive HWI and mutual positive interaction groups. The most burned-out were people who experienced negative WHI the most often. In this group, predominance of men working more than 10 h per day was observed. The majority of study group (71%) experienced rather integration than segmentation of both spheres. CONCLUSIONS: Our results suggest that segmentation is not an universal and effective strategy of coping with work and home demands - it may prevent the positive home-work spillover, which can be buffer or remedy against stress or burnout. We consider cluster analysis the appropriate method in research on relation to work-family balance issue, which may be useful in unraveling relationships between this phenomenon and attitudes and behaviors. PMID- 25519943 TI - Photobiological safety of the recently introduced energy efficient household lamps. AB - OBJECTIVES: Nowadays more and more newly introduced light sources (tungsten halogen, compact fluorescent (CFL) and light-emitting diode (LED) lamps) are used in households. It is important to know whether their radiation poses any possible risk for human health or not. These light sources emit optical radiation not solely in the visible spectrum. Other bands emitted by these sources, i.e., ultraviolet and infrared, are potentially hazardous for human health. The visible light, especially the blue light, could also damage human retina. The purpose of this study was to determine the ultraviolet (UV) and blue light (BL) emissions from halogen bulbs, CFLs and LED lamps, and to evaluate them from the point of view of possible health risks for general public. MATERIAL AND METHODS: The exposure of UV and BL emissions from 19 types of CFLs, 11 types of halogen lamps and 4 types of LED lamps produced by different manufacturers were measured at 200 mm distance from the source. RESULTS: The exposures to UV and BL were below the International Commission on Non-Ionizing Radiation Protection (ICNIRP) exposure limits in spite of the very conservative assumption of the assessment. CONCLUSIONS: Results of this study indicate that the UV and BL radiation from the newly introduced lamps does not exceed the current exposure limit values and thus, in comparison with the former incandescent bulbs, does not result in a higher risk for general public. PMID- 25519944 TI - Evaluation of exposure to electromagnetic radiofrequency radiation in the indoor workplace accessible to the public by the use of frequency-selective exposimeters. AB - OBJECTIVES: The aim of the study was to identify and assess electromagnetic radiofrequency radiation (EMRR) exposure in a workplace located in a publicly accessible environment, and represented by offices (where exposure is caused by various transmitters of local fixed indoor and outdoor wireless communication systems). MATERIAL AND METHODS: The investigations were performed in 45 buildings (in urban and rural areas in various regions of Poland), using frequency selective electric field strength (E-field) exposimeters sensitive to the EMRR with a frequency range of 88-2500 MHz, split into 12 sub-bands corresponding to the operating frequencies of typical EMRR sources. The variability of the E-field was analyzed for each frequency range and the total level of exposure by statistical parameters of recorded exposimetric profiles: minimum, maximum, median values and 25-75th - percentiles. RESULTS: The main sources of exposure to EMRR are mobile phone base transceiver stations (BTS) and radio-television transmitters (RTV). The frequency composition in a particular office depends on the building's location. The E-field recorded in buildings in urban and rural areas from the outdoor BTS did not exceed respectively: medians - 0.19 and 0.05 V/m, 75th percentiles -0.25 and 0.09 V/m. In buildings equipped with the indoor BTS antennas the E-field did not exceed: medians - 1 V/m, 75th percentiles - 1.8 V/m. Whereas in urban and rural areas, the median and 75th percentile values of the E-field recorded in buildings located near the RTV (within 1 km) did not exceed: 1.5 and 3.8 V/m or 0.4 and 0.8 V/m, for radio FM band or for TV bands, respectively. CONCLUSIONS: Investigations confirmed the practical applicability of the exposimetric measurements technique for evaluating parameters of worker's exposure in both frequency- and time-domain. The presented results show EMRR exposure of workers or general public in locations comparable to offices to be well below international limits. PMID- 25519946 TI - Yoga reduces cardiovascular risk as much as walking or cycling, study shows. PMID- 25519947 TI - Micro-sized porous carbon spheres with ultra-high rate capability for lithium storage. AB - Biomass-derived carbon materials, as one type of promising anode material for lithium ion batteries (LIBs), have demonstrated intrinsic potential and superiority. Here, we report a facile and efficient approach to fabricate micro sized porous carbon spheres (PCSs) by an integrated procedure of enzymolysis, pre oxidation, and carbonization. Benefiting from the uniquely abundant pore accessiblity, the PCSs exhibit an ultra-high rate capability with a value of 150 mA h g(-1) at an ultrafast charge/discharge current density of 20 A g(-1), and they take only ca. 27 s to be fully charged. It is believed that the uniquely porous structure can shorten the transport paths and further enhance the rapid transport of the electrolytes and Li ions on the surface and within the electrode materials. The low cost and easy large-scale preparation of the PCS electrodes, as well as the superior high rate capability would open up an opportunity to develop high rate lithium ion batteries. PMID- 25519948 TI - Dendritic glycopolymers based on dendritic polyamine scaffolds: view on their synthetic approaches, characteristics and potential for biomedical applications. AB - In this review we highlight the potential for biomedical applications of dendritic glycopolymers based on polyamine scaffolds. The complex interplay of the molecular characteristics of the dendritic architectures and their specific interactions with various (bio)molecules are elucidated with various examples. A special role of the individual sugar units attached to the dendritic scaffolds and their density is identified, which govern ionic and H-bond interactions, and biological targeting, but to a large extent are also responsible for the significantly reduced toxicity of the dendritic glycopolymers compared to their polyamine scaffolds. Thus, the application of dendritic glycopolymers in drug delivery systems for gene transfection but also as therapeutics in neurodegenerative diseases has great promise. PMID- 25519949 TI - Isotonic versus hypotonic solutions for maintenance intravenous fluid administration in children. AB - BACKGROUND: Maintenance intravenous fluids are frequently used in hospitalised children who cannot maintain adequate hydration through enteral intake. Traditionally used hypotonic fluids have been associated with hyponatraemia and subsequent morbidity and mortality. Use of isotonic fluid has been proposed to reduce complications. OBJECTIVES: To establish and compare the risk of hyponatraemia by systematically reviewing studies where isotonic is compared with hypotonic intravenous fluid for maintenance purposes in children.Secondly, to compare the risk of hypernatraemia, the effect on mean serum sodium concentration and the rate of attributable adverse effects of both fluid types in children. SEARCH METHODS: We ran the search on 17 June 2013. We searched the Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (OvidSP), Embase (OvidSP), and ISI Web of Science. We also searched clinical trials registers and screened reference lists. We updated this search in October 2014 but these results have not yet been incorporated. SELECTION CRITERIA: We included randomised controlled trials that compared isotonic versus hypotonic intravenous fluids for maintenance hydration in children. DATA COLLECTION AND ANALYSIS: At least two authors assessed and extracted data for each trial. We presented dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean differences with 95% CIs. MAIN RESULTS: Ten studies met the inclusion criteria, with a total of 1106 patients. The majority of the studies were performed in surgical or intensive care populations (or both). There was considerable variation in the composition of intravenous fluid, particularly hypotonic fluid, used in the studies. There was a low risk of bias for most of the included studies. Ten studies provided data for our primary outcome, a total of 449 patients in the analysis received isotonic fluid, while 521 received hypotonic fluid. Those who received isotonic fluid had a substantially lower risk of hyponatraemia (17% versus 34%; RR 0.48; 95% CI 0.38 to 0.60, high quality evidence). It is unclear whether there is an increased risk of hypernatraemia when isotonic fluids are used (4% versus 3%; RR 1.24; 95% CI 0.65 to 2.38, nine studies, 937 participants, low quality evidence), although the absolute number of patients developing hypernatraemia was low. Most studies had safety restrictions included in their methodology, preventing detailed investigation of serious adverse events. AUTHORS' CONCLUSIONS: Isotonic intravenous maintenance fluids with sodium concentrations similar to that of plasma reduce the risk of hyponatraemia when compared with hypotonic intravenous fluids. These results apply for the first 24 hours of administration in a wide group of primarily surgical paediatric patients with varying severities of illness. PMID- 25519951 TI - Xp11 translocation renal cell carcinoma morphologically mimicking clear cell papillary renal cell carcinoma in an adult patient: report of a case expanding the morphologic spectrum of Xp11 translocation renal cell carcinomas. AB - Xp11 translocation renal cell carcinoma (RCC) is a relatively rare tumor mainly affecting children and adolescents. It shows significant morphological overlap with the 2 most common adult renal tumors, which are the clear cell (conventional) RCC and papillary RCC. We describe case of a young adult female who presented with right flank pain and abdominal mass. Radiological investigations showed features suggestive of renal cell carcinoma in the right kidney. Histopathological findings while suggestive of Xp11 carcinoma, showed significant overlap with the recently described entity clear cell papillary RCC. TFE3 immunohistochemistry confirmed the tumor to be Xp11 translocation RCC. The patient had an aggressive course with lymph node metastasis. In this report, we discuss differential diagnosis and the diagnostic challenges of Xp11 translocation RCC in adults. PMID- 25519950 TI - Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation. AB - BACKGROUND: Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non-pharmacological treatment of cognitive deficits in this population is unclear. OBJECTIVES: To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adult patients treated with cranial irradiation. SEARCH METHODS: In August 2014. we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and PsycINFO and checked the reference lists of included studies. We also searched for ongoing trials via ClinicalTrials.gov, the Physicians Data Query and the Meta Register of Controlled Trials. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated pharmacological or non pharmacological interventions in cranial irradiated adults, with objective cognitive functioning as a primary or secondary outcome measure. DATA COLLECTION AND ANALYSIS: Two review authors (JD, KZ) independently extracted data from selected studies and carried out a 'Risk of bias' assessment. Cognitive function, fatigue and mood outcomes were reported. No data were pooled. MAIN RESULTS: Sixteen studies were identified for possible inclusion in the review, six of which were included. Three studies investigated prevention and three studies investigated amelioration. Due to differences between studies in the interventions being evaluated, a meta-analysis was not possible. Two studies investigated a pharmacological intervention for the prevention of cognitive deficits; memantine compared with placebo, and d-threo-methylphenidate HCL compared with placebo. In the first study the primary cognitive outcome of memory at six months did not reach significance, but there was significant improvement in overall cognitive function compared to placebo, with similar adverse events across groups. The second study found no statistically significant difference between arms, with few adverse events. The third study investigated a rehabilitation program for the prevention of cognitive deficits but did not carry out a statistical comparison of cognitive performance between groups.Three studies investigated the use of a pharmacological intervention for the treatment of cognitive deficits; methylphenidate compared with modafinil, two different doses of modafinil, and donepezil compared with placebo. The first study found improvements in cognitive function in both the methylphenidate and modafinil arms; few adverse events were reported. The second study combined treatment arms and found improvements across all cognitive tests, however, a number of adverse events were reported. Both studies were limited by a small sample size. The third study did not find an improvement in the primary cognitive outcome of overall performance, but did find improvement in an individual test of memory, compared to placebo; adverse events were not reported. No non-pharmacological studies for the amelioration of cognitive deficits were eligible. There were a number of limitations across studies but few without high risks of bias. AUTHORS' CONCLUSIONS: There is supportive evidence that memantine may help prevent cognitive deficits for adults with brain metastases receiving cranial irradiation. There is supportive evidence that donepezil may have a role in treating cognitive deficits in adults with primary or metastatic brain tumours who have been treated with cranial irradiation. Patient withdrawal affected the statistical power of both studies. Further research that tries to minimise the withdrawal of consent, and subsequently reduce the requirement for imputation procedures, may offer a higher quality of evidence.There is no strong evidence to support any non-pharmacological interventions (medical or cognitive/behavioural) in the prevention or amelioration of cognitive deficits. Non-randomised studies appear promising but are as yet to be conclusive via translation into high quality evidence. Further research is required. PMID- 25519952 TI - Maximal fat oxidation, but not aerobic capacity, is affected by oral contraceptive use in young healthy women. AB - PURPOSE: Synthetic ovarian hormones contained in oral contraceptives (OC) may alter the aerobic capacity and lipid metabolism in oral contraceptive users (OC+) compared with non-users (OC-). The aim of this study was thus to investigate the differences between OC- and OC+ (1) in cardiorespiratory parameters at the anaerobic threshold (AT) and at the maximal aerobic capacity and (2) in the exercise intensity (Lipoxmax) at which lipid oxidation rate is maximal (MLOR). METHODS: Twenty-one healthy untrained women (22.0 +/- 0.6 years old) who took OC (OC+; low-dose monophasic OC, n = 11) or not (OC-; n = 10) performed two experimental exercise sessions. In the first one, cardiorespiratory parameters at the AT and at the maximal aerobic capacity were assessed during a maximal incremental exercise session. In the second one, Lipoxmax and MLOR were measured during a submaximal incremental exercise session. RESULTS: No significant difference was observed in cardiorespiratory parameters at the AT and at the maximal aerobic capacity between OC+ and OC- women. OC+ women showed higher MLOR (7.6 +/- 1.9 vs 4.6 +/- 1.0 mg min(-1) kg FFM(-1); p < 0.01) that was elicited by higher Lipoxmax (45.2 +/- 5.2 vs 36.2 +/- 4.1 % of VO2max; p < 0.001) compared to OC- women. CONCLUSIONS: OC+ and OC- women did not differ in cardiorespiratory parameters at the AT and at the maximal aerobic capacity. However, OC+ women show higher MLOR and Lipoxmax compared with OC- women. The hormonal status appears to be an important MLOR and Lipoxmax determinant in untrained women. PMID- 25519953 TI - Changes in electrical pain threshold of fascia and muscle after initial and secondary bouts of elbow flexor eccentric exercise. AB - PURPOSE: This study investigated changes in electrical pain threshold (EPT) after repeated eccentric exercise bouts to test the hypothesis that fascia would become more sensitive than muscle when greater delayed onset muscle soreness (DOMS) is induced. METHODS: Ten young men performed two eccentric exercise bouts (ECC1, ECC2) consisting of ten sets of six maximal isokinetic eccentric contractions of the elbow flexors with the same arm separated by 4 weeks. Maximal voluntary isometric contraction torque, range of motion, muscle soreness assessed by a visual analogue scale (VAS) and pressure pain threshold (PPT) were measured before, immediately after and 1-5 days after exercise. EPT was assessed in the biceps brachii fascia (BBF), biceps brachii muscle, and brachialis fascia (BF) 1 day before, immediately after, and 1, 2 and 4 days after exercise. RESULTS: All measures showed smaller changes (P < 0.05) after ECC2 than ECC1. EPT decreased after both bouts and the largest decreases were evident at 2 days post-exercise (P < 0.05). The decreases in EPT after ECC1 were greater (P < 0.05) for both BBF (Baseline: 1.45 +/- 0.23 mA, 2 days post-exercise: 0.13 +/- 0.11 mA) and BF (1.64 +/- 0.29 mA, 0.26 +/- 0.2 mA) than muscle (1.56 +/- 0.29 mA, 0.69 +/- 0.33 mA). Changes in EPT were correlated with the changes in PPT (r = 0.63-0.87, P <= 0.05) but not with VAS (r = -0.01 to 0.50). CONCLUSION: These results show that fascia becomes more sensitive than muscle to electrical stimulation after the initial eccentric exercise, suggesting that damage inflammation to fascia than muscle fibres is more associated with DOMS. PMID- 25519954 TI - Exercise increases sphingoid base-1-phosphate levels in human blood and skeletal muscle in a time- and intensity-dependent manner. AB - PURPOSE: Sphingosine-1-phosphate (S1P) regulates cardiovascular function and plays an important role in muscle biology. We have previously reported that cycling exercise increased plasma S1P. Here, we investigated the effect of exercise duration and intensity on plasma and skeletal muscle S1P levels. METHODS: In the first experiment, 13 male athletes performed a 60-min exercise at 65 % of VO2max and a graded exercise until exhaustion on a rowing ergometer. Samples of the venous blood were taken, and plasma, erythrocytes and platelets were isolated. In the second experiment, ten male moderately active subjects performed three consecutive periods of one-leg knee extension exercise (at 25, 55 and 85 % of the maximal workload). Muscle biopsies and blood samples from the radial artery and femoral veins were taken. RESULTS: Under basal conditions, S1P was released from the leg, as its concentration was lower in the arterial than in the venous plasma (p < 0.01). Exercise until exhaustion increased plasma S1P and sphinganine-1-phosphate (SA1P) concentration (p < 0.05), whereas moderate intensity exercise elevated only SA1P (p < 0.001). Although knee extension increased muscle S1P content (p < 0.05), it was not released but taken up across the leg during exercise. However, sphingosine was released from both working and resting leg at the highest workload (p < 0.05). CONCLUSIONS: Plasma S1P concentration is elevated only by high-intensity exercise which results, at least in part, from increased availability of sphingosine released by skeletal muscle. In addition, exercise markedly affects S1P dynamics across the leg. We speculate that S1P may play an important role in adaptation of skeletal muscle to exercise. PMID- 25519955 TI - The Sm protein methyltransferase PRMT5 is not required for primordial germ cell specification in mice. AB - PRMT5 is a type II protein arginine methyltransferase with roles in stem cell biology, reprograming, cancer and neurogenesis. During embryogenesis in the mouse, it was hypothesized that PRMT5 functions with the master germline determinant BLIMP1 to promote primordial germ cell (PGC) specification. Using a Blimp1-Cre germline conditional knockout, we discovered that Prmt5 has no major role in murine germline specification, or the first global epigenetic reprograming event involving depletion of cytosine methylation from DNA and histone H3 lysine 9 dimethylation from chromatin. Instead, we discovered that PRMT5 functions at the conclusion of PGC reprograming I to promote proliferation, survival and expression of the gonadal germline program as marked by MVH. We show that PRMT5 regulates gene expression by promoting methylation of the Sm spliceosomal proteins and significantly altering the spliced repertoire of RNAs in mammalian embryonic cells and primordial cells. PMID- 25519957 TI - Evaluation of Viewpoints of Health Care Professionals on the Role of Ethics Committees and Hospitals in the Resolution of Clinical Ethical Dilemmas Based on Practice Environment. AB - We sought to evaluate whether health care professionals' viewpoints differed on the role of ethics committees and hospitals in the resolution of clinical ethical dilemmas based on practice location. We conducted a survey study from December 21, 2013 to March 15, 2014 of health care professionals at six hospitals (one tertiary care academic medical center, three large community hospitals and two small community hospitals). The survey consisted of eight clinical ethics cases followed by statements on whether there was a role for the ethics committee or hospital in their resolution, what that role might be and case specific queries. Respondents used a 5-point Likert scale to express their degree of agreement with the premises posed. We used the ANOVA test to evaluate whether respondent views significantly varied based on practice location. 240 health care professionals (108-tertiary care center, 92-large community hospitals, 40-small community hospitals) completed the survey (response rate: 63.6 %). Only three individual queries of 32 showed any significant response variations across practice locations. Overall, viewpoints did not vary across practice locations within question categories on whether the ethics committee or hospital had a role in case resolution, what that role might be and case specific queries. In this multicenter survey study, the viewpoints of health care professionals on the role of ethics committees or hospitals in the resolution of clinical ethics cases varied little based on practice location. PMID- 25519958 TI - [Multiple system atrophy and autophagy]. AB - Macroautophagy is a dynamic process whereby cytoplasmic molecules are sequestered within autophagosomes. There exist two groups of mammalian autophagy-related gene (Atg) 8 homologues (LC3 and GABARAPs), which play essential role in autophagosomal formation. We determined whether Atg8 homologues are affected in Lewy body disease (LBD) and multiple system atrophy (MSA). The level of LC3 was increased in an insoluble fraction from the brain of patients with LBD, whereas the level of GABARAPs was decreased in LBD. The level of matured GABARAPs was significantly decreased in the cerebellum of MSA, and that the higher levels of matured and lipidated LC3 were detected in detergent-insoluble fraction of MSA. Furthermore, immunohistochemical staining revealed that both LC3 and GABARAPs were localized in Lewy bodies and glial cytoplasmic inclusions in MSA were positive for LC3. These findings suggest that autophagic function is impaired through alteration of Atg8 homologues in LBD and MSA. Autophagy-enhancing strategies can therefore have therapeutic efficacy for various neurodegenerative diseases including LBD and MSA. PMID- 25519956 TI - Functional screen reveals essential roles of miR-27a/24 in differentiation of embryonic stem cells. AB - MicroRNAs play important roles in controlling the embryonic stem cell (ESC) state. Although much is known about microRNAs maintaining ESC state, microRNAs that are responsible for promoting ESC differentiation are less reported. Here, by screening 40 microRNAs pre-selected by their expression patterns and predicted targets in Dgcr8-null ESCs, we identify 14 novel differentiation-associated microRNAs. Among them, miR-27a and miR-24, restrained by c-Myc in ESC, exert their roles of silencing self-renewal through directly targeting several important pluripotency-associated factors, such as Oct4, Foxo1 and Smads. CRISPR/Cas9-mediated knockout of all miR-27/24 in ESCs leads to serious deficiency in ESC differentiation in vitro and in vivo. Moreover, depleting of them in mouse embryonic fibroblasts can evidently promote somatic cell reprogramming. Altogether, our findings uncover the essential role of miR-27 and miR-24 in ESC differentiation and also demonstrate novel microRNAs responsible for ESC differentiation. PMID- 25519959 TI - [Sema4A as a biomarker predicting responsiveness to IFN beta treatment]. AB - Approximately one-third of patients with multiple sclerosis (MS) exhibit markedly high-level-expression of Sema4A. The expression of Sema4A is increased on DCs in MS patients and shed from these cells in a metalloproteinase-dependent manner. DC derived Sema4A is critical for Th17 cell differentiation, and MS patients with high Sema4A levels exhibit Th17 skewing. Furthermore, patients with high Sema4A levels have more severe disabilities and are unresponsive to IFN-beta treatment. We investigated whether recombinant Sema4A abrogates the efficacy of IFN-beta in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Administration of Sema4A concurrently with IFN-beta abrogated the efficacy of IFN beta. These effects of Sema4A were attributed to promote Th1 and Th17 differentiation and to increase adhesive activation of T cells to endothelial cells, even in the presence of IFN-beta.Thus unresponsiveness to IFN-beta treatment of MS patients with high Sema4A was also confirmed by model mice EAE. We recommend assaying Sema4A first, and then selecting DMD other than IFN-beta for patients with high Sema4A. PMID- 25519960 TI - [Hereditary spastic paraplegia: up to date]. AB - Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders that are clinically characterized by progressive spasticity and weakness of the lower limbs. HSP genetic loci are designated SPG1-72 in order of their discovery. In 206 Japanese families with autosomal dominant HSP, SPG4 was the most common form, accounting for 38%, followed by SPG3A (5%), SPG31 (5%), SPG10 (2%), and SPG8 (1%). We have identified novel mutations in the C12orf65 gene and the LYST gene in several Japanese families with autosomal recessive HSP. JASPAC will facilitate gene discovery and mechanistic understanding of HSP. The future challenge will be the establishment of treatment of HSP. PMID- 25519961 TI - [Clinical aspects of hereditary spastic paraplegias]. AB - Hereditary spastic paraplegias (HSPs) were characterized by progressive leg spasticity with various additional symptoms as follows: peripheral neuropathy, cerebellar ataxia, extrapyramidal symptoms, mental impairment, optic atrophy, pigmental retinopathy, and so on. Many genetic loci (SPG1-72) and more than 50 genes were identified so far. Recently, we identified the causative gene, C12orf65, that was reported the gene for Leigh syndrome, for autosomal recessive spastic paraplegia with optic atrophy and neuropathy (SPG55). We also identified the mutation of the LYST gene, that is causative gene for Chediak-Higashi syndrome, for the autosomal recessive complicated spastic paraplegia with cerebellar ataxia and neuropathy. In this review, we introduced clinical symptoms about our cases suffered from SPG4, SPG11, SPG55 and complicated spastic paraplegia due to adult Chediak-Higashi syndrome. SPG4, that is usually exhibits pure spastic paraplegia, but our case shows mental impairment and variable age of onset. HSPs are clinically and genetically heterogeneous syndromes, i. e., same gene mutations with different clinical manifestations or same clinical presentations with different gene mutations. We should perform board range differential diagnosis and analysis of numerous causative genes to the patients with spastic paraplegia, especially autosomal recessive trait. PMID- 25519962 TI - [Cognitive impairment in multiple sclerosis]. AB - The various lesions affecting the central nervous system in multiple sclerosis (MS) lead to a wide range of symptoms. Until now, physical disabilities have been the main focus of studies on the symptoms of MS; however, cognitive impairment that prominently affects sustained attention and information processing speed has been found by neuropsychological studies to affect over half of all MS patients. Because this cognitive impairment typically involves domain-specific deficits rather than global cognitive decline, it is usually difficult to detect. Cognitive dysfunction in MS patients could influence social activities, such as employment status. Therefore, we must pay greater attention to cognitive function in the milieu of clinical neurology. PMID- 25519963 TI - [Neuronal dysfunction in multiple sclerosis]. AB - The precise mechanisms of cortical damage in multiple sclerosis (MS) remain unknown. Microglia, the resident immune cells in the central nervous system (CNS), are involved in the chronic neuroinflammation in MS cortical lesions. Microglia produce various inflammatory cytokines such as IFN-gamma and IL-beta, reactive oxygen species, and glutamate. IL-beta secretion is induced by NLRP3. ROS is induced by GM-CSF-producing Th17 cells. Glutamate is released via gap junctions. These molecules exert neurotoxicity. Meanwhile, damaged neurons produce fractalkine and FGF-2, which suppress microglial activation and enhance microglial neuroprotection through anti-inflammatory and anti-oxidant effect. Fractalkine accelerates microglial clearance of neuronal debris via inducing the release of MFG-E8. FGF-2 induces microglial migration through the FGFR3-Wnt-ERK signaling pathway. These molecules suppress microglial neuroinflammation, and enhance neuroprotection, which may give us clues for future therapeutic strategy cortical damage in MS. PMID- 25519964 TI - [Infrastructure for the clinical research of muscular dystrophies: remudy and MDCTN]. AB - Remudy, operated by the NCNP, runs two national registries for Dystrophinopathy and GNE myopathy in Japan under the collaboration with the TREAT-NMD alliance. The aim is to construct the clinical research infrastructure and accelerate the clinical development research for these rare diseases. We successfully provide the data sets for the feasibility studies, send out the appropriate information of the clinical trials for the candidates to speed up the recruitment for trials, collaboration with the Muscular Dystrophy Clinical Trial Network: MDCTN, as well as present the natural history and epidemiological data of the rare diseases with a new 'registry based' research style. Remudy provides a prototype of the clinical research infrastructure to over come the rare and incurable diseases. PMID- 25519965 TI - [Therapeutic development in myotonic dystrophy]. AB - Myotonic dystrophy (DM), the commonest form of muscular dystrophy in adults, is a multisystem disease caused by repeat expansions located in untranslated regions of the affected genes. Its pathogenesis results from expression of RNAs with these expanded repeats, which causes sequestration of splicing factors and thus series of splicing misregulation. An increased understanding of the disease mechanism has accelerated the development of therapeutic strategies, including correction of individual missplicing by antisense oligonucleotides (ASOs), ASO- or small molecule-mediated neutralization of the RNA toxicity by preventing sequestration of splicing factors, degradation of the toxic RNA by ASOs, and stabilization of the expanded repeats. ASOs targeting the toxic RNA have exhibited promising results in animal models, and a clinical trial has recently been launched. With the advent of clinical trials, we are confronting several challenges. As with other rare diseases, we must identify eligible patients. It may be more important in Japan to establish a standardized best practice management of currently available approaches (e.g., pacemaker use) followed by nationwide dissemination. The national DM registry, about to be launched shortly, might be a promising tool to overcome these issues and lead to improved management of DM. PMID- 25519966 TI - [Neurodegenerative disease and TREM2]. AB - The functional loss of triggering receptor expressed on myeloid cells-2 (TREM2) leads to a chronic neurodegenerative disease, named Nasu-Hakola disease. A murine in vitro study revealed that the absence of TREM2 expression on microglia impaired phagocytosis for tissue debris clearance and increased pro-inflammatory cytokine production; these are necessary to maintain the microenvironmental homeostasis of the central nervous system. On the other hand, the function of TREM2 is still unclear, especially in the fields of human pathology and morphology. In 2013, it was reported that non-synonymous variants of TREM2 were associated with Alzheimer's disease in Caucasians; however, supplementary studies in Asian populations, such as the Japanese, could not confirm this result. In this review, I discuss how TREM2 can contribute to neurodegenerative disease. PMID- 25519967 TI - [Biochemical abnormality of mutant TDP-43 protein]. AB - Dominant mutations in the TDP-43 gene are causative for familial ALS, however, the relationship between mutant protein biochemical phenotypes and disease course and their significance to disease pathomechanism are unclarified. We found that longer half-lives of mutant proteins correlated with accelerated disease onset. Increased stability of TDP-43 protein was also observed in ALS/FTLD linked mutations in RNA recognition motif of TDP-43. Based on our findings, we established a cell model in which chronic stabilization of wild-type TDP-43 protein provoked cytotoxicity and recapitulated pathogenic protein cleavage and insolubility to the detergent sarkosyl, TDP-43 properties that have been observed in the lesions of sporadic ALS. Moreover, these cells expressing stabilized TDP 43 showed proteasomal impairment and dysregulation of their own mRNA levels. These results suggest that chronically increased stability of mutant or wild-type TDP-43 proteins results in a gain of toxicity through abnormal proteostasis. PMID- 25519968 TI - [Aberration of the spliceosome in amyotrophic lateral sclerosis]. AB - TDP-43 is a nuclear protein that plays a role in RNA metabolism, and its dysfunction has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a typical adult-onset motor neuron disease. We investigated RNA metabolism in relation to TDP-43 function in neuronal tissues affected by ALS, and found a decrease in the number of nuclear GEM bodies, as well as reduced expression of minor spliceosomes, which are functional RNA-protein complexes. Similar features have been reported in spinal muscular atrophy (SMA), a motor neuron disease affecting infants. These findings, together with those reported in SMA, strongly suggest that reduction of minor spliceosomes has an important role in the pathomechanism underlying the selective degeneration of motor neurons characteristic of both ALS and SMA. PMID- 25519969 TI - [Clinical and neuroimaging characteristics of patients with hereditary diffuse leukoencephalopathy with spheroids (HDLS)]. AB - Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant early-onset dementia that affects the cerebral white matter predominantly. Mutations in colony stimulating factor-1 receptor (CSF-1R) were identified as the genetic cause of HDLS, and this enabled the antemorterm diagnosis of HDLS by genetic testing. This review paper describes clinical and neuroimaging findings in genetically-proven HDLS cases. The mean age at onset was 45 years ranging from 18 to 78 years. The most frequent initial symptom was cognitive decline. A wide range of clinical features including intellectual decline, behavioral and character changes, convulsion, pyramidal signs and motor symptoms have been described. Series of brain MRI study exhibit the white matter changes on FLAIR images, which were occasionally asymmetric in the early phase of the disease. Early MRI features are alteration of corpus callosum and dilatation of lateral ventricles showing central atrophy. Hyperintensity lesions detected by diffusion weighted images were detectable in some cases with HDLS. Brain CT study showed spotty calcification in the affected white matter. HDLS is not rare disease and should be considered as differential diagnosis of early-onset dementia exhibiting the white matter disease. PMID- 25519970 TI - [MRI comparison between hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and primary progressive multiple sclerosis (PPMS)]. AB - Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant inherited leukoencephalopathy characterized by numerous cerebral neuroaxonal spheroids. To date, detection of colony stimulating factor 1 receptor (CSF-1R) gene mutation in HDLS gave us hint to think its pathophysiology as a microglial dysfunction, so called "primary microgliopathy". Clinical features of HDLS are variable. Typically, psychiatric symptoms and cognitive decline are initial features of HDLS. However, in some cases, when motor symptoms precede cognitive decline, HDLS may mimic primary progressive multiple sclerosis (PPMS). Herein we tried to clarify MRI features of HDLS (2 women, age 22-28 years, average 25.0 years, EDSS 7.00) in comparison with PPMS (6 men and 10 women, age 29-64 years, average 33.7 years, EDSS 6.03). In consequence, our MRI findings suggesting HDLS rather than PPMS are as follows: restricted diffusivity, severe corpus callosum atrophy, and preferential involvement of deep white matter lesion compared with periventricular white matter. In contrast, characteristic features suggesting PPMS are as follows: prevailing periventricular white matter lesion, cerebellar lesions, optic neuritis, and cervical spinal cord lesion. Sagittal fluid-attenuated inversion recovery (FLAIR) images of brain and cervical cord are highly useful to discriminate these two diseases. PMID- 25519971 TI - [Emerging concept of the production and absorption of cerebrospinal fluid, and recent progress in the diagnosis and treatment of iNPH]. AB - Recently, there has been emerging a new attractive hypothesis that cerebrospinal fluid (CSF) is not circulating or absorbed from arachnoid villi, but absorbed from capillaries of the brain surface to vasculature or excreting through arterial walls and cribriform plate to cervical lymph nodes. About 90% of patients with iNPH (idiopathic normal pressure hydrocephalus) show DESH (Disproportionately Enlarged Subarachnoid-space Hydrocephalus) sign on brain CT/MRI. Identification of the DESH sign is important for the diagnosis of iNPH, and it is helpful for the judgement whether DESH sign is positive or not to detect apparent hyperperfusion in the high-convexity of the brain in iNPH patients with N-isopropyl-p-[(123)I] iodoamphetamine (IMP) single photon emission computed tomography (SPECT). We have named this characteristic finding in IMP SPECT as the CAPPAH (Convexity APPArent Hyperperfusion) sign, and would like to emphasize its usefulness in the clinical diagnosis of iNPH. PMID- 25519972 TI - [Current and future prospects of endovascular treatment for acute ischemic stroke]. AB - Recently, remarkable progress has been made in the field of endovascular treatment, and endovascular treatment for acute ischemic stroke due to large vessel occlusion has been an effective and therapeutic option. However, there is no randomized control trial as to superiority of endovascular treatment for acute ischemic stroke compared to the standard treatment including intravenous rt-PA. Inclusion criteria for the performance of endovascular treatment for acute ischemic stroke will need to be defined more precisely, and high rates of fast recanalization will be needed in future. We expect the evidence that endovascular treatment for acute ischemic stroke due to large vessel occlusion is superior to standard treatment by the detailed images of the brain, more strict indications and novel endovascular devices such as percutaneous transluminal mechanical thrombectomy devices. PMID- 25519974 TI - Chemoenzymatic flow cascade for the synthesis of protected mandelonitrile derivatives. AB - A chemoenzymatic two-step cascade process, with both steps having incompatible reaction conditions, was successfully performed in continuous flow. The chemoenzymatic aqueous formation of cyanohydrins was integrated with a subsequent organic phase protection step in a single flow process utilising a membrane-based phase separation module. The wider applicability of our setup was demonstrated with the synthesis of nine protected cyanohydrin derivatives, all obtained in good yields and high to excellent enantioselectivity. PMID- 25519975 TI - Systematic aging of degradable nanosuspension ameliorates vibrating-mesh nebulizer performance. AB - CONTEXT: The process of vibrating-mesh nebulization is affected by sample physicochemical properties. Exemplary, electrolyte supplementation of diverse formulations facilitated the delivery of adequate aerosols for deep lung deposition. OBJECTIVE: This study addressed the impact of storage conditions of poly(lactide-co-glycolide) nanosuspension on aerosol properties when nebulized by the eFlow(r)rapid. MATERIALS AND METHODS: First, purified nanosuspensions were supplemented with electrolytes (i.e. sodium chloride, lactic and glycolic acid). Second, the degradable nanoparticles (NP) were incubated at different temperatures (i.e. 4, 22 and 36 degrees C) for up to two weeks. The effect of formulation supplementation and storage on aerosol characteristics was studied by laser diffraction and correlated with the sample conductivity. RESULTS AND DISCUSSION: Nebulization of purified nanosuspensions resulted in droplet diameters of >7.0 um. However, electrolyte supplementation and storage, which led to an increase in sample conductivity (>10-20 uS/cm), were capable of providing smaller droplet diameters during vibrating-mesh nebulization (<=5.0 um). No relevant change of NP properties (i.e. size, morphology, remaining mass and molecular weight of the employed polymer) was observed when incubated at 22 degrees C for two weeks. CONCLUSION: Sample aging is an alternative to electrolyte supplementation in order to ameliorate the aerosol characteristics of degradable NP formulations when nebulized by vibrating-mesh technology. PMID- 25519973 TI - Epigenetic regulation of Atrophin1 by lysine-specific demethylase 1 is required for cortical progenitor maintenance. AB - Lysine-specific demethylase 1 (LSD1) is involved in gene regulation and development; however, its precise function, molecular targets and underlying mechanisms during development are poorly understood. Here we show that LSD1 is required for neuronal progenitor cell (NPC) maintenance during cortical development. A ChIP-seq analysis identified a LSD1-binding site (LBAL) downstream of Atrophin1 (ATN1). Surprisingly, tranylcypromine (LSD1 inhibitor) treatment increased H3K4 methylation at LBAL, leading to ATN1 repression and NPC differentiation. Knockdown of LSD1 and ATN1 phenocopied each other in inducing NPC premature differentiation and depletion, which could be rescued by ATN1 overexpression, suggesting that LSD1 controls NPC differentiation via regulation of ATN1 methylation status and expression. The involvement of LSD1 in ATN1 expression and NPC maintenance were confirmed in knockout mice. These findings hint at the potential application for the clinical drug, tranylcypromine, in the prevention and/or treatment of ATN1-associated degenerative disease, dentatorubral-pallidoluysian atrophy. PMID- 25519976 TI - Diffusion-weighted perinatal postmortem magnetic resonance imaging as a marker of postmortem interval. AB - OBJECTIVE: To evaluate perinatal body organ apparent diffusion coefficient (ADC) values at postmortem magnetic resonance imaging (PMMR) in order to evaluate postmortem changes. METHODS: Postmortem diffusion-weighted imaging (DWI) of the thorax and abdomen were performed with diffusion gradient values b = 0, 500, and 1000 s/mm(2) on 15 foetal and childhood cases (mean 33.3 +/- 7.8 weeks gestation) compared to 44 live infants (mean age 75.5 +/- 53.4 days). Mean ADC values were calculated from regions of interest (ROIs) for the lungs, liver, spleen and renal cortex, compared to normative live infantile body ADC values of similar gestational age. RESULTS: Mean ADC values were significantly lower in postmortem cases than in normal controls for liver (0.88 10(-3) mm(2)/s +/- SD 0.39 vs. 1.13 +/- 0.13; p < 0.05) and renal cortex (0.85 +/- 0.26 vs. 1.19 +/- 0.13; p < 0.05) but not spleen or muscle. Mean lung ADC values were significantly higher than normal controls (1.06 +/- 0.18 vs. 0 +/- 0; p < 0.001), and there was a significant correlation between postmortem interval and lung ADC (R(2) = 0.55). CONCLUSION: Lung PMMR ADC values are related to postmortem interval, making them a potential marker of time since death. Further research is needed to understand the organ-specific changes which occur in the postmortem period. KEY POINTS: * Liver and spleen PM ADC values were lower than controls. * Lung ADC changes correlate with PM interval. * These findings may be useful in medicolegal cases. PMID- 25519977 TI - Preoperative cardiac computed tomography for demonstration of congenital cardiac septal defect in adults. AB - OBJECTIVES: We aimed to evaluate the role of preoperative cardiac computed tomography (CT) for adults with congenital cardiac septal defect (CSD). METHODS: Sixty-five consecutive patients who underwent preoperative CT and surgery for CSD were included. The diagnostic accuracy of CT and the concordance rate of the subtype classification of CSD were evaluated using surgical findings as the reference standard. Sixty-five patients without CSD who underwent cardiac valve surgery were used as a control group. An incremental value of CT over echocardiography was described retrospectively. RESULTS: Sensitivity and specificity of CT for diagnosis of CSD were 95 % and 100 %, respectively. The concordance rate of subtype classification was 91 % in CT and 92 % in echocardiography. The maximum size of the defect measured by CT correlated well with surgical measurement (r = 0.82), and the limit of agreement was -0.9 +/- 7.42 mm. In comparison with echocardiography, CT was able to detect combined abnormalities in three cases, and exclusively provided correct subtype classification or clarified suspected abnormal findings found on echocardiography in seven cases. CONCLUSIONS: Cardiac CT can accurately demonstrates CSD in preoperative adult patients. CT may have an incremental role in preoperative planning, particularly in those with more complex anatomy. KEY POINTS: * Cardiac CT can demonstrate cardiac septal defect accurately in preoperative planning. * Cardiac CT can demonstrate combined abnormalities of cardiac septal defect. * Cardiac CT may have an incremental role over echocardiography in complex anatomy. PMID- 25519978 TI - Retrograde-outflow percutaneous isolated hepatic perfusion using cisplatin: A pilot study on pharmacokinetics and feasibility. AB - OBJECTIVES: This study aimed to evaluate the feasibility and underlying pharmacokinetics of the retrograde-outflow technique for percutaneous isolated hepatic perfusion (PIHP). METHODS: Retrograde-outflow PIHP was performed in 12 male pigs (weight, 37-44 kg) by redirecting hepatic outflow through the portal vein. Blood with cisplatin (2.5 mg/kg) in an extracorporeal circuit was circulated through the liver under isolation using rotary pumps with balloon catheters. Hepatic angiographic examinations were conducted during perfusion, and histopathological examinations of the organs were conducted after perfusion. The maximum platinum concentration (C max), area under the concentration-time curve (AUC), and chronologic laboratory data were measured. RESULTS: Retrograde-outflow isolated hepatic angiography confirmed that contrast media flowed into the portal veins in all 12 pigs. The hepatic veins and inferior vena cava were not opacified. Hepatic C max (86.3 mg/l) was 39-fold greater than systemic C max (2.2 mg/l), and hepatic AUC (1330.8 min . mg/l) was 30-fold greater than systemic AUC (44.6 min . mg/l). Histopathological examinations revealed no ischaemic changes or other abnormalities in the liver, duodenum, small intestine, or colon. Within 1 week of the procedure, chronologic laboratory data (n = 3) normalized or returned to pre-therapy levels. CONCLUSIONS: The retrograde-outflow technique appears to enable safe and feasible PIHP therapy. KEY POINTS: * The portal vein acted as an outflow tract under retrograde-outflow PIHP. * Plasma hepatic-to systemic exposure ratio was 39.2 for the maximum platinum concentration. * Plasma hepatic-to-systemic exposure ratio was 29.8 for the AUC. * The retrograde-outflow technique appears to enable safe and feasible PIHP. PMID- 25519979 TI - Nutritional and behavioral determinants of adolescent obesity: a case-control study in Sri Lanka. AB - BACKGROUND: Global prevalence of adolescent obesity is rising at an alarming rate leading to increase risk of adult obesity. Obesity in adolescence is postulated to have a significant impact on both physical and psychological health of an individual. The study aim was to identify nutritional and behavioral risk factors associated with obesity among adolescent Sri Lankan school girls. METHODS: In this case-control study, age and ethnicity matched 100 cases (BMI-for-age above +2SD) and 100 controls (BMI-for-age between -2SD to +1 SD) adolescent girls between 14 to 18 years of age were recruited. Predicted risk factors of obesity were assessed through an interviewer administrated questionnaire. A three day diet diary and long version of international physical activity questionnaire were used to assess daily energy intake and energy expenditure from physical activity, respectively. The significant differences in mean values were evaluated using paired t-test. Multivariable logistic regression analysis was performed to assess the risk factors associated with obesity. RESULTS: Obese girls had significantly higher BMI (31.3, 20.2 kgm-2 p < 0.0001), waist circumference (90.8, 68.2 cm p < 0.0001), energy intake (2235.4, 1921.7 kcal p < 0.0001) and lower energy expenditure from physical activity (894.6, 1844.3 MET (metabolic equivalent) min/week p < 0.0001). High family income (Odds ratio [OR], 2.99, 95% confidence interval [CI] 1.13-7.88), first born in family (2.73, 1.25-5.97), skipping breakfast (3.99, 1.81-8.80), consumption of fruits < 4 days per week (2.18, 1.02 4.67), screen viewing > 2 hours/ day (2.96, 1.33-6.61), energy intake (3.97, 3.19 16.36), significantly increased the risk of obesity, whereas increased physical activity (4.34, 1.33-14.14) decreased the risk. Irregular menstruation (4.34, 1.33-14.14) was noted among the obese. CONCLUSION: Socioeconomic and behavior factors are major determinants of adolescent obesity in Sri Lanka. There is an urgent need to implement awareness as well as behavior modification programmes targeting adolescents, parents and schools to control childhood and adolescent obesity. PMID- 25519980 TI - Harmonization of malaria rapid diagnostic tests: best practices in labelling including instructions for use. AB - BACKGROUND: Rapid diagnostic tests (RDTs) largely account for the scale-up of malaria diagnosis in endemic settings. However, diversity in labelling including the instructions for use (IFU) limits their interchangeability and user friendliness. Uniform, easy to follow and consistent labelling, aligned with international standards and appropriate for the level of the end user's education and training, is crucial but a consolidated resource of information regarding best practices for IFU and labelling of RDT devices, packaging and accessories is not available. METHODS: The Roll Back Malaria Partnership (RBM) commissioned the compilation of international standards and regulatory documents and published literature containing specifications and/or recommendations for RDT design, packaging and labelling of in vitro diagnostics (IVD) (which includes RDTs), complemented with a questionnaire based survey of RDT manufacturers and implementers. A summary of desirable RDT labelling characteristics was compiled, which was reviewed and discussed during a RBM Stakeholder consultation meeting and subsequently amended and refined by a dedicated task force consisting of country programme implementers, experts in RDT implementation, IVD regulatory experts and manufacturers. RESULTS: This process led to the development of consensus documents with a list of suggested terms and abbreviations as well as specifications for labelling of box, device packaging, cassettes, buffer bottle and accessories (lancets, alcohol swabs, transfer devices, desiccants). Emphasis was placed on durability (permanent printing or water-resistant labels), legibility (font size, letter type), comprehension (use of symbols) and ease of reference (e.g. place of labelling on the box or cassette packaging allowing quick oversight). A generic IFU template was developed, comprising background information, a template for procedure and reading/interpretation, a selection of appropriate references and a symbol key of internationally recognized symbols together with suggestions about appropriate lay-out, style and readability. CONCLUSIONS: The present document together with its additional files compiled proposes best practices in labelling and IFU for malaria RDTs. It is expected that compliance with these best practices will increase harmonization among the different malaria RDT products available on the market and improve their user friendliness. PMID- 25519981 TI - DFBAlab: a fast and reliable MATLAB code for dynamic flux balance analysis. AB - BACKGROUND: Dynamic Flux Balance Analysis (DFBA) is a dynamic simulation framework for biochemical processes. DFBA can be performed using different approaches such as static optimization (SOA), dynamic optimization (DOA), and direct approaches (DA). Few existing simulators address the theoretical and practical challenges of nonunique exchange fluxes or infeasible linear programs (LPs). Both are common sources of failure and inefficiencies for these simulators. RESULTS: DFBAlab, a MATLAB-based simulator that uses the LP feasibility problem to obtain an extended system and lexicographic optimization to yield unique exchange fluxes, is presented. DFBAlab is able to simulate complex dynamic cultures with multiple species rapidly and reliably, including differential-algebraic equation (DAE) systems. In addition, DFBAlab's running time scales linearly with the number of species models. Three examples are presented where the performance of COBRA, DyMMM and DFBAlab are compared. CONCLUSIONS: Lexicographic optimization is used to determine unique exchange fluxes which are necessary for a well-defined dynamic system. DFBAlab does not fail during numerical integration due to infeasible LPs. The extended system obtained through the LP feasibility problem in DFBAlab provides a penalty function that can be used in optimization algorithms. PMID- 25519982 TI - A mechanistic investigation on the utilization of lactose as a protective agent for multi-unit pellet systems. AB - The effect of lactose particle size on the extent of pellet coat damage was investigated. The extent of pellet coat damage increased linearly with lactose median particle size. It was observed that coated pellets compressed with coarser lactose grades had larger and deeper surface indentations. The surfaces of the pellets compressed with coarser lactose grades were also found to be significantly rougher. Micronized lactose was capable of protecting pellet coats from damage brought about by the presence of coarser lactose particles. The findings suggested a protective effect that micronized lactose conferred to pellet coats was not only through dimensional delimitations but also by higher interparticulate friction and longer particle rearrangement phase. As a result, the pellet volume fraction in the system was reduced. The extent of pellet coat damage was found to escalate when the pellet volume fraction in such system increased beyond a critical value of 0.39. PMID- 25519985 TI - Translational and rotational motion control of microgels enabling shoaling and schooling. AB - A technique for adequate flow control is important in the fields of science and engineering. In this study, we hypothesized that the unrestricted flow control inside a chamber containing 'schools of magnetic particles' might be possible through control of an external magnetic field, biomimicking the flow generated by schools of fish. Microgels based on superparamagnetic iron oxide nanoparticles (SPIONs) and poly(acrylic acid) hydrogels were employed. With an increase in the SPION content, the microgels responded more efficiently to the translational movement of the magnetic field. Rotational movement was more efficiently achieved with anisotropic distribution of SPIONs inside microgels, which was induced by applying a magnetic field immediately prior to crosslinking. The systems of the anisotropic microgels successfully provided microflow for effective mixing in a capillary. This biomimetic flow control may be useful for the control of fluid systems of any micro- or nano-size and any shape, regardless of the tortuosity. PMID- 25519986 TI - Patchouli alcohol protects against lipopolysaccharide-induced acute lung injury in mice. AB - BACKGROUND: Patchouli alcohol (PA), a natural compound isolated from Pogostemon cablin, has been reported to possess anti-inflammatory activity. However, the effects of PA on lipopolysaccharide (LPS)-induced acute lung injury (ALI) have not yet been studied. In the present study, we investigated in vivo the effect of PA on ALI induced by LPS. METHODS: Mice were administrated intranasally with LPS to induce lung injury. PA was administrated intraperitoneally 1 h before or after the LPS challenge. RESULTS: The results showed that PA significantly decreased the wet-to-dry weight ratio of lungs and the number of total cells, neutrophils, and macrophages in bronchoalveolar lavage fluid at 7 h after the LPS challenge. In addition, PA also suppressed the production of inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 in bronchoalveolar lavage fluid. Furthermore, Western blot analysis showed that PA inhibited the phosphorylation of IkappaB-alpha and p65 nuclear factor kappaB (NF kappaB) induced by LPS. CONCLUSIONS: Our results suggest that the anti inflammatory effects of PA against LPS-induced ALI may be due to its ability to inhibit NF-kappaB signaling pathways. PMID- 25519983 TI - Clearly different mechanisms of enhancement of short-lived Nef-mediated viral infectivity between SIV and HIV-1. AB - BACKGROUND: One of the major functions of Nef is in the enhancement of the infectivity of the human and simian immunodeficiency viruses (HIV and SIV, respectively). However, the detailed mechanism of the enhancement of viral infectivity by Nef remains unclear. Additionally, studies of mechanisms by which Nef enhances the infectivity of SIV are not as intensive as those of HIV-1. METHODS: We generated short-lived Nef constructed by fusing Nef to a proteasome mediated protein degradation sequence to characterize the Nef role in viral infectivity. RESULTS: The apparent expression level of the short-lived Nef was found to be extremely lower than that of the wild-type Nef. Moreover, the expression level of the short-lived Nef increased with the treatment with a proteasome inhibitor. The infectivity of HIV-1 with the short-lived Nef was significantly lower than that with the wild-type Nef. On the other hand, the short-lived Nef enhanced the infectivity of SIVmac239, an ability observed to be interestingly equivalent to that of the wild-type Nef. The short-lived Nef was not detected in SIVmac239, but the wild-type Nef was, suggesting that the incorporation of Nef into SIVmac239 is not important for the enhancement of SIVmac239 infectivity. CONCLUSIONS: Altogether, the findings suggest that the mechanisms of infectivity enhancement by Nef are different between HIV-1 and SIVmac239. Lastly, we propose the following hypothesis: even when the expression level of a protein is extremely low, the protein may still be sufficiently functional. PMID- 25519987 TI - Malignancy rates after surgical excision of discordant breast biopsies. AB - BACKGROUND: Vacuum-assisted core-needle biopsy (VAB) is increasingly used to perform breast biopsies instead of automated-gun core-needle biopsy (CNB). The significance of discordance between radiologic and pathologic findings has not been well established in the era of VAB predominance. This retrospective study was conducted to determine the rate of malignancy after surgical excisional biopsy (EXB) of these lesions at our two institutions. MATERIALS AND METHODS: We reviewed medical records from January 2008-June 2013 to identify female patients who underwent EXB for a Breast Imaging-Reporting and Data System (BI-RADS) 4 or 5 lesions found to be benign and discordant on CNB. Clinicopathologic data were gathered, and analysis was performed using descriptive statistics. RESULTS: A total of 8081 core biopsies were performed in the study timeframe. Six of 81 (7.4%) patients who had an EXB for a benign discordant breast lesion were found to have malignant pathology (two invasive, four in situ). Four of 63 (6.3%) lesions originally biopsied by VAB were upgraded, compared with 2 of 17 (11.8%) originally biopsied by CNB. There were no statistically significant differences in the rates of upgrade to malignancy when data were stratified by BI-RADS score or method of biopsy. CONCLUSIONS: The overall rate of malignancy after EXB of benign discordant lesions was 7.4%. Despite the widespread adoption of VAB, EXB is still warranted for clarification of discordant radiologic-pathologic findings. PMID- 25519989 TI - Targeting a cryptic allosteric site for selective inhibition of the oncogenic protein tyrosine phosphatase Shp2. AB - Protein tyrosine phosphatases (PTPs) have been the subject of considerable pharmaceutical-design efforts because of the ubiquitous connections between misregulation of PTP activity and human disease. PTP-inhibitor discovery has been hampered, however, by the difficulty in identifying cell-permeable compounds that can selectively target PTP active sites, and no PTP inhibitors have progressed to the clinic. The identification of allosteric sites on target PTPs therefore represents a potentially attractive solution to the druggability problem of PTPs. Here we report that the oncogenic PTP Shp2 contains an allosteric-inhibition site that renders the enzyme sensitive to potent and selective inhibition by cell permeable biarsenical compounds. Because Shp2 contains no canonical tetracysteine biarsenical-binding motif, the enzyme's inhibitor-binding site is not readily predictable from its primary or three-dimensional structure. Intriguingly, however, Shp2's PTP domain does contain a cysteine residue (C333) at a position that is removed from the active site and is occupied by proline in other classical PTPs. We show that Shp2's unusual cysteine residue constitutes part of a Shp2-specific allosteric-inhibition site, and that Shp2's sensitivity to biarsenicals is dependent on the presence of the naturally occurring C333. The determinative role of this residue in conferring inhibitor sensitivity is surprising because C333's side chain is inaccessible to solvent in Shp2 crystal structures. The discovery of this cryptic Shp2 allosteric site may provide a means for targeting Shp2 activity with high specificity and suggests that buried yet-targetable allosteric sites could be similarly uncovered in other protein families. PMID- 25519988 TI - Histone acetylation mediated by Brd1 is crucial for Cd8 gene activation during early thymocyte development. AB - During T-cell development, Cd8 expression is controlled via dynamic regulation of its cis-regulatory enhancer elements. Insufficiency of enhancer activity causes variegated Cd8 expression in CD4(+)CD8(+) double-positive (DP) thymocytes. Brd1 is a subunit of the Hbo1 histone acetyltransferase (HAT) complex responsible for acetylation of histone H3 at lysine 14 (H3K14). Here we show that deletion of Brd1 in haematopoietic progenitors causes variegated expression of Cd8, resulting in the appearance of CD4(+)CD8(-)TCRbeta(-/low) thymocytes indistinguishable from DP thymocytes in their properties. Biochemical analysis confirms that Brd1 forms a HAT complex with Hbo1 in thymocytes. ChIP analysis demonstrates that Brd1 localizes at the known enhancers in the Cd8 genes and is responsible for acetylation at H3K14. These findings indicate that the Brd1-mediated HAT activity is crucial for efficient activation of Cd8 expression via acetylation at H3K14, which serves as an epigenetic mark that promotes the recruitment of transcription machinery to the Cd8 enhancers. PMID- 25519991 TI - Social information use and the evolution of unresponsiveness in collective systems. AB - Animal groups in nature often display an enhanced collective information processing capacity. It has been speculated that natural selection will tune this response to be optimal, ensuring that the group is reactive while also being robust to noise. Here, we show that this is unlikely to be the case. By using a simple model of decision-making in a dynamic environment, we find that when individuals behave rationally and are subject to selection based on their accuracy, optimality of collective decision-making is not attained. Instead, individuals overly rely on social information and evolve to be too readily influenced by their neighbours. This is due to a classic evolutionary conflict between individual and collective interest. The result is a sub-optimal system that is poised on the cusp of total unresponsiveness. Individuals in the evolved group exhibit delayed reactions to changes in the environment, before responding with rapid, socially reinforced transitions, reminiscent of familiar human and animal social systems (markets, stampedes, fashions, etc.). Our results demonstrate that behaviour of this type may not be pathological, but instead could represent an evolutionary attractor for such collective systems. PMID- 25519990 TI - Minimal within-host dengue models highlight the specific roles of the immune response in primary and secondary dengue infections. AB - In recent years, the within-host viral dynamics of dengue infections have been increasingly characterized, and the relationship between aspects of these dynamics and the manifestation of severe disease has been increasingly probed. Despite this progress, there are few mathematical models of within-host dengue dynamics, and the ones that exist focus primarily on the general role of immune cells in the clearance of infected cells, while neglecting other components of the immune response in limiting viraemia. Here, by considering a suite of mathematical within-host dengue models of increasing complexity, we aim to isolate the critical components of the innate and the adaptive immune response that suffice in the reproduction of several well-characterized features of primary and secondary dengue infections. By building up from a simple target cell limited model, we show that only the innate immune response is needed to recover the characteristic features of a primary symptomatic dengue infection, while a higher rate of viral infectivity (indicative of antibody-dependent enhancement) and infected cell clearance by T cells are further needed to recover the characteristic features of a secondary dengue infection. We show that these minimal models can reproduce the increased risk of disease associated with secondary heterologous infections that arises as a result of a cytokine storm, and, further, that they are consistent with virological indicators that predict the onset of severe disease, such as the magnitude of peak viraemia, time to peak viral load, and viral clearance rate. Finally, we show that the effectiveness of these virological indicators to predict the onset of severe disease depends on the contribution of T cells in fuelling the cytokine storm. PMID- 25519992 TI - Apparent power-law distributions in animal movements can arise from intraspecific interactions. AB - Levy flights have gained prominence for analysis of animal movement. In a Levy flight, step-lengths are drawn from a heavy-tailed distribution such as a power law (PL), and a large number of empirical demonstrations have been published. Others, however, have suggested that animal movement is ill fit by PL distributions or contend a state-switching process better explains apparent Levy flight movement patterns. We used a mix of direct behavioural observations and GPS tracking to understand step-length patterns in females of two related butterflies. We initially found movement in one species (Euphydryas editha taylori) was best fit by a bounded PL, evidence of a Levy flight, while the other (Euphydryas phaeton) was best fit by an exponential distribution. Subsequent analyses introduced additional candidate models and used behavioural observations to sort steps based on intraspecific interactions (interactions were rare in E. phaeton but common in E. e. taylori). These analyses showed a mixed-exponential is favoured over the bounded PL for E. e. taylori and that when step-lengths were sorted into states based on the influence of harassing conspecific males, both states were best fit by simple exponential distributions. The direct behavioural observations allowed us to infer the underlying behavioural mechanism is a state switching process driven by intraspecific interactions rather than a Levy flight. PMID- 25519993 TI - Neocartilage integration in temporomandibular joint discs: physical and enzymatic methods. AB - Integration of engineered musculoskeletal tissues with adjacent native tissues presents a significant challenge to the field. Specifically, the avascularity and low cellularity of cartilage elicit the need for additional efforts in improving integration of neocartilage within native cartilage. Self-assembled neocartilage holds significant potential in replacing degenerated cartilage, though its stabilization and integration in native cartilage require further efforts. Physical and enzymatic stabilization methods were investigated in an in vitro model for temporomandibular joint (TMJ) disc degeneration. First, in phase 1, suture, glue and press-fit constructs were compared in TMJ disc intermediate zone defects. In phase 1, suturing enhanced interfacial shear stiffness and strength immediately; after four weeks, a 15-fold increase in stiffness and a ninefold increase in strength persisted over press-fit. Neither suture nor glue significantly altered neocartilage properties. In phase 2, the effects of the enzymatic stabilization regimen composed of lysyl oxidase, CuSO4 and hydroxylysine were investigated. A full factorial design was employed, carrying forward the best physical method from phase 1, suturing. Enzymatic stabilization significantly increased interfacial shear stiffness after eight weeks. Combined enzymatic stabilization and suturing led to a fourfold increase in shear stiffness and threefold increase in strength over press-fit. Histological analysis confirmed the presence of a collagen-rich interface. Enzymatic treatment additionally enhanced neocartilage mechanical properties, yielding a tensile modulus over 6 MPa and compressive instantaneous modulus over 1200 kPa at eight weeks. Suturing enhances stabilization of neocartilage, and enzymatic treatment enhances functional properties and integration of neocartilage in the TMJ disc. Methods developed here are applicable to other orthopaedic soft tissues, including knee meniscus and hyaline articular cartilage. PMID- 25519994 TI - Multi-scale modelling of the dynamics of cell colonies: insights into cell adhesion forces and cancer invasion from in silico simulations. AB - Studying the biophysical interactions between cells is crucial to understanding how normal tissue develops, how it is structured and also when malfunctions occur. Traditional experiments try to infer events at the tissue level after observing the behaviour of and interactions between individual cells. This approach assumes that cells behave in the same biophysical manner in isolated experiments as they do within colonies and tissues. In this paper, we develop a multi-scale multi-compartment mathematical model that accounts for the principal biophysical interactions and adhesion pathways not only at a cell-cell level but also at the level of cell colonies (in contrast to the traditional approach). Our results suggest that adhesion/separation forces between cells may be lower in cell colonies than traditional isolated single-cell experiments infer. As a consequence, isolated single-cell experiments may be insufficient to deduce important biological processes such as single-cell invasion after detachment from a solid tumour. The simulations further show that kinetic rates and cell biophysical characteristics such as pressure-related cell-cycle arrest have a major influence on cell colony patterns and can allow for the development of protrusive cellular structures as seen in invasive cancer cell lines independent of expression levels of pro-invasion molecules. PMID- 25519997 TI - [Overcoming the language barrier: UroEvidence translates Cochrane abstracts]. PMID- 25519996 TI - [Cytoreductive radical prostatectomy for prostate cancer with minimal osseous metastases: results of a first feasibility and case control study]. AB - BACKGROUND: Androgen deprivation therapy (ADT) represents the standard treatment for patients with prostate cancer (PCA) and osseous metastases. We explored the role of cytoreductive radical prostatectomy in PCA with low volume skeletal metastases in terms of a feasibility study. MATERIAL AND METHODS: A total of 23 patients with biopsy proven PCA, minimal osseous metastases (<=3 hot spots on bone scan), absence of visceral or extensive lymph node metastases and a decrease in prostate-specific antigen (PSA) to <1.0 ng/ml after neoadjuvant ADT were included in the feasibility study (group A). The control group (group B) consisted of 38 men with metastatic PCA who were treated by ADT alone. Surgery related complications, time to castration resistance, symptom-free, cancer specific and overall survival were analyzed using descriptive statistical analyses. RESULTS: The mean age was 61 years (range 42-69 years) and 64 years (47 83) in groups A and B, respectively, with similar patient characteristics in terms of initial PSA level, biopsy Gleason score, clinical stage and extent of metastatic disease. The median follow-up was 34.5 months (7-75 months) and 47 months (28-96 months) in groups A and B, respectively. Median time to castration resistance was 40 months (9-65 months) and 29 months (16-59 months) in groups A and B, respectively (p=0.04). Patients in group A experienced significantly better clinical symptom-free (38.6 versus 26.5 months, p=0.032) and cancer specific survival rates (95.6% versus 84.2%, p=0.043) whereas the overall survival was similar. In group A none of the men underwent palliative surgical procedures for locally progressing PCA compared to 29% in group B. CONCLUSIONS: Cytoreductive radical prostatectomy is feasible in well-selected men with metastatic PCA who responded well to neoadjuvant ADT. These men have a long life expectancy and the risk of locally recurrent PCA and local complications are reduced. Cytoreductive radical prostatectomy might be a treatment option in the multimodal management of PCA with minimal osseous metastases. PMID- 25519998 TI - Screening and treatment for Staphylococcus aureus in patients undergoing hemodialysis: a systematic review and meta-analysis. AB - BACKGROUND: This study was performed to evaluate the effectiveness of surveillance for screening and treatment of patients with chronic kidney disease undergoing hemodialysis and colonized by Staphylococcus aureus. METHODS: A systematic review and meta-analysis were performed. The literature search involved the following databases: the Cochrane Controlled Trials Register, Embase, LILACS, CINAHL, SciELO, and PubMed/Medline. The descriptors were "Staphylococcus aureus", "MRSA", "MSSA", "treatment", "decolonization", "nasal carrier", "colonization", "chronic kidney disease", "dialysis", and "haemodialysis" or "hemodialysis". Five randomized controlled trials that exhibited agreement among reviewers as shown by a kappa value of >0.80 were included in the study; methodological quality was evaluated using the STROBE statement. Patients who received various treatments (various treatments group) or topical mupirocin (mupirocin group) were compared with those who received either no treatment or placebo (control group). The outcomes were skin infection at the central venous catheter insertion site and bacteremia. RESULTS: In total, 2374 patients were included in the analysis, 626 (26.4%) of whom were nasal carriers of S. aureus. The probability of S. aureus infection at the catheter site for hemodialysis was 87% lower in the mupirocin group than in the control group (odds ratio [OR], 0.13; 95% confidence interval [CI], 0.05-0.34; p<0.001). The risk of bacteremia was 82% lower in the mupirocin group than in the control group (OR, 0.18; 95% CI, 0.08-0.42; p<0.001). No statistically significant difference in bacteremia was observed between the various treatments group (excluding mupirocin) and the control group (OR, 0.77; 95% CI, 0.51-1.15; p=0.20). CONCLUSIONS: Twenty-six percent of patients undergoing hemodialysis were nasal carriers of S. aureus. Of all treatments evaluated, topical mupirocin was the most effective therapy for the reduction of S. aureus catheter site infection and bacteremia in patients undergoing chronic hemodialysis. PMID- 25519995 TI - Analytical reduction of combinatorial complexity arising from multiple protein modification sites. AB - Combinatorial complexity is a major obstacle to ordinary differential equation (ODE) modelling of biochemical networks. For example, a protein with 10 sites that can each be unphosphorylated, phosphorylated or bound to adaptor protein requires 3(10) ODEs. This problem is often dealt with by making ad hoc assumptions which have unclear validity and disallow modelling of site-specific dynamics. Such site-specific dynamics, however, are important in many biological systems. We show here that for a common biological situation where adaptors bind modified sites, binding is slow relative to modification/demodification, and binding to one modified site hinders binding to other sites, for a protein with n modification sites and m adaptor proteins the number of ODEs needed to simulate the site-specific dynamics of biologically relevant, lumped bound adaptor states is independent of the number of modification sites and equal to m + 1, giving a significant reduction in system size. These considerations can be relaxed considerably while retaining reasonably accurate descriptions of the true system dynamics. We apply the theory to model, using only 11 ODEs, the dynamics of ligand-induced phosphorylation of nine tyrosines on epidermal growth factor receptor (EGFR) and primary recruitment of six signalling proteins (Grb2, PI3K, PLCgamma1, SHP2, RasA1 and Shc1). The model quantitatively accounts for experimentally determined site-specific phosphorylation and dephosphorylation rates, differential affinities of binding proteins for the phosphorylated sites and binding protein expression levels. Analysis suggests that local concentration of site-specific phosphatases such as SHP2 in membrane subdomains by a factor of approximately 10(7) is critical for effective site-specific regulation. We further show how our framework can be extended with minimal effort to consider binding cooperativity between Grb2 and c-Cbl, which is important for receptor trafficking. Our theory has potentially broad application to reduce combinatorial complexity and allow practical simulation of a variety ODE models relevant to systems biology and pharmacology applications to allow exploration of key aspects of complexity that control signal flux. PMID- 25519999 TI - Mural art therapy for young offenders hospitalised with a mental illness. AB - OBJECTIVE: To describe a mural art therapy project completed within an adolescent unit of a secure forensic psychiatric hospital. METHOD: The planning, implementation and consecutive stages of the mural art therapy project are described. Pertinent themes are identified. RESULTS: A cohort of adolescent forensic inpatients was engaged in a group therapeutic process involving collaboration, design and the completion of an art mural. The participants generally approved of the project and identified themes of gaining a sense of achievement, empowerment, teamwork, involvement and ownership. The art mural transformed and improved the visual and spatial environment of the Adolescent unit courtyard. CONCLUSIONS: Mural art therapy was acceptable to young offenders hospitalised with mental illness, which has relevance for adolescent psychiatric units and youth detention centres. PMID- 25520000 TI - A guide to clinical research supervision for psychiatrists: a mentoring approach. AB - OBJECTIVES: To provide a guide for clinically-based psychiatrist supervisors of research projects for early career researchers. METHODS: This paper will describe a mentoring framework for supervision, for psychiatrist clinical research supervisors and early career researchers. RESULTS: The domains discussed include, across various aspects of a study: the role of the supervisor, project management, and where and when to seek advice. CONCLUSIONS: Supervision of clinical research can be a professionally rewarding experience for psychiatrists, as well as early career researcher supervisees. PMID- 25520001 TI - The structure and reliability of the Health of the Nation Outcome Scales. AB - OBJECTIVE: The Health of the Nation Outcome Scales (HoNOS) has been suggested as an outcome measure for the evaluation of mental health services in several countries; however, the scoring, reliability and structure of HoNOS are all ambiguous. METHODS: A total of 80,161 completed HoNOS forms were checked for internal reliability and structural integrity. Parallel analysis was used to investigate the likelihood that HoNOS consists of 12 independent scales. The reliability of the scale was investigated using ordinal reliability analysis. Confirmatory factor analysis was used to investigate the factor structure. RESULTS: Parallel analysis suggested that HoNOS had three underlying factors and could not be considered as 12 independent scales. The 12-item scale had good reliability. Confirmatory factor analysis found that a one factor, four-item scale produced the most acceptable fit. CONCLUSIONS: HoNOS should not be considered as 12 independent scales. Although the four-item scale is acceptable psychometrically, it has practical problems, as it focuses only on the social aspects of outcome measurement. It is possible that there are other factor structures that would encompass more items, but any study of these should test for invariance between groups of service users. PMID- 25520002 TI - Psychosocial short stature with psychosis: a case report. AB - OBJECTIVE: Our objective was to report and describe a case of psychosocial short stature in an adolescent girl with psychotic features. Psychosocial short stature is a rare condition in which emotional stress or deprivation in childhood profoundly reduces growth, leading to persistent short stature. This disorder is variably known as psychosocial dwarfism, hyperphagic short stature or maternal deprivation dwarfism. In the literature, psychosocial short stature has not been associated previously with psychosis. CONCLUSIONS: We formulate that our patient's short stature, developmental regression and psychotic features were culminations of insecure mother-child attachment, personal traumatic experiences, immigrant status, high family expressed emotions and social isolation. Neuropsychiatric influences were critically regarded due to our patient's fluctuations in behaviour and affect, in the setting of cortical volume loss on brain MRI. Diagnostic hypotheses included childhood disintegrative disorder or childhood-onset schizophrenia. The management plan involved inpatient family psychoeducation, a pharmacological trial with an atypical antipsychotic and community mental health service follow-up for family therapy and psychotherapy. PMID- 25520003 TI - Serum Levels of Thioredoxin Are Associated with Stroke Risk, Severity, and Lesion Volumes. AB - Oxidative stress increases serum thioredoxin (TRX), a redox-regulating protein with antioxidant activity recognized as an oxidative stress marker. The aim of this study was to assess the clinical significance of serum TRX levels in Chinese patients with acute ischemic stroke (AIS). From January 1, 2012, to December 31, 2013, all patients with first-ever acute ischemic stroke were recruited to participate in the study. Serum levels of TRX were assayed with solid-phase sandwich enzyme-linked immunosorbent assay (ELISA), and the severity of stroke was evaluated with the National Institutes of Health Stroke Scale (NIHSS) score on admission. The results indicated that the median serum TRX levels were significantly (P < 0.0001) higher in stroke patients as compared to normal cases [15.03 ng/mL (interquartile range (IQR), 10.21-32.42) and 8.95 ng/mL (6.79 11.05), respectively]. We found the serum TRX reflected the disease severity of AIS. There was a significant positive association between serum TRX levels and NIHSS scores (r = 0.476, P < 0.0001). After adjusting for all other possible covariates, TRX remained as an independent marker of AIS with an adjusted OR of 1.245 (95 % confidence interval (CI), 1.164-1.352; P < 0.0001). Based on the receiver operating characteristic (ROC) curve, the optimal cutoff value of serum TRX levels as an indicator for auxiliary diagnosis of AIS was projected to be 11.0 ng/mL, which yielded a sensitivity of 80.3 % and a specificity of 73.7 %, with the area under the curve at 0.807 (95 % CI, 0.766-0.847). Further, in our study, we found that an increased risk of AIS was associated with serum TRX levels >=11.0 ng/mL (adjusted OR 6.99; 95 % CI, 2.87-12.87) after adjusting for possible confounders. Our study demonstrated that serum TRX levels at admission were associated with stroke severity and lesion volumes. Elevated levels could be considered as a novel, independent diagnosis marker of AIS in a Chinese sample. PMID- 25520004 TI - Aldose Reductase Regulates Microglia/Macrophages Polarization Through the cAMP Response Element-Binding Protein After Spinal Cord Injury in Mice. AB - Inflammatory reactions are the most critical pathological processes occurring after spinal cord injury (SCI). Activated microglia/macrophages have either detrimental or beneficial effects on neural regeneration based on their functional polarized M1/M2 subsets. However, the mechanism of microglia/macrophage polarization to M1/M2 at the injured spinal cord environment remains unknown. In this study, wild-type (WT) or aldose reductase (AR)-knockout (KO) mice were subjected to SCI by a spinal crush injury model. The expression pattern of AR, behavior tests for locomotor activity, and lesion size were assessed at between 4 h and 28 days after SCI. We found that the expression of AR is upregulated in microglia/macrophages after SCI in WT mice. In AR KO mice, SCI led to smaller injury lesion areas compared to WT. AR deficiency-induced microglia/macrophages induce the M2 rather than the M1 response and promote locomotion recovery after SCI in mice. In the in vitro experiments, microglia cell lines (N9 or BV2) were treated with the AR inhibitor (ARI) fidarestat. AR inhibition caused 4-hydroxynonenal (HNE) accumulation, which induced the phosphorylation of the cAMP response element-binding protein (CREB) to promote Arg1 expression. KG501, the specific inhibitor of phosphorylated CREB, could cancel the upregulation of Arg1 by ARI or HNE stimulation. Our results suggest that AR works as a switch which can regulate microglia by polarizing cells to either the M1 or the M2 phenotype under M1 stimulation based on its states of activity. We suggest that inhibiting AR may be a promising therapeutic method for SCI in the future. PMID- 25520006 TI - An Asia pacific alliance for rare diseases. PMID- 25520005 TI - Therapeutic Intervention of Learning and Memory Decays by Salidroside Stimulation of Neurogenesis in Aging. AB - Cognition in all mammals including human beings declines during aging. The cellular events responsible for this decay involve a reduction of neurogenesis in the dentate gyrus. Here, we show that treatment with a nature product from a traditional Chinese medicine, namely salidroside restores the capacity of the dentate gyrus to generate new neurons and intercepts learning and memory decays in mice during aging. We uncover that new neurons in aging mice have functional features of an adult granule neuron by forming excitatory synapses with their putative targeting neurons. Genetic inhibition of synaptic transmission from new neurons abolishes the therapeutic effects of salidroside in behavioral tests. We also identify that salidroside targets CREB transcription for the survival of new neurons in the dentate gyrus of old mice. Thus, salidroside is therapeutically effective against learning and memory decays via stimulation of CREB-dependent functional neurogenesis in aging. PMID- 25520007 TI - Tankyrase-mediated beta-catenin activity regulates vasopressin-induced AQP2 expression in kidney collecting duct mpkCCDc14 cells. AB - Aquaporin-2 (AQP2) mediates arginine vasopressin (AVP)-induced water reabsorption in the kidney collecting duct. AVP regulates AQP2 expression primarily via Gsalpha/cAMP/PKA signaling. Tankyrase, a member of the poly(ADP-ribose) polymerase family, is known to mediate Wnt/beta-catenin signaling-induced gene expression. We examined whether tankyrase plays a role in AVP-induced AQP2 regulation via ADP-ribosylation of G protein-alpha (Galpha) and/or beta-catenin mediated transcription of AQP2. RT-PCR and immunoblotting analysis revealed the mRNA and protein expression of tankyrase in mouse kidney and mouse collecting duct mpkCCDc14 cells. dDAVP-induced AQP2 upregulation was attenuated in mpkCCDc14 cells under the tankyrase inhibition by XAV939 treatment or small interfering (si) RNA knockdown. Fluorescence resonance energy transfer image analysis, however, revealed that XAV939 treatment did not affect dDAVP- or forskolin induced PKA activation. Inhibition of tankyrase decreased dDAVP-induced phosphorylation of beta-catenin (S552) and nuclear translocation of phospho-beta catenin. siRNA-mediated knockdown of beta-catenin decreased forskolin-induced AQP2 transcription and dDAVP-induced AQP2 expression. Moreover, inhibition of phosphoinositide 3-kinase/Akt, which was associated with decreased nuclear translocation of beta-catenin, diminished dDAVP-induced AQP2 upregulation, further indicating that beta-catenin mediates AQP2 expression. Taken together, tankyrase plays a role in AVP-induced AQP2 regulation, which is likely via beta catenin-mediated transcription of AQP2, but not ADP-ribosylation of Galpha. The results provide novel insights into vasopressin-mediated urine concentration and homeostasis of body water metabolism. PMID- 25520009 TI - Norepinephrine stimulates the epithelial Na+ channel in cortical collecting duct cells via alpha2-adrenoceptors. AB - There is good evidence for a causal link between excessive sympathetic drive to the kidney and hypertension. We hypothesized that sympathetic regulation of tubular Na(+) absorption may occur in the aldosterone-sensitive distal nephron, where the fine tuning of renal Na(+) excretion takes place. Here, the appropriate regulation of transepithelial Na(+) transport, mediated by the amiloride sensitive epithelial Na(+) channel (ENaC), is critical for blood pressure control. To explore a possible effect of the sympathetic transmitter norepinephrine on ENaC-mediated Na(+) transport, we performed short-circuit current (Isc) measurements on confluent mCCDcl1 murine cortical collecting duct cells. Norepinephrine caused a complex Isc response with a sustained increase of amiloride-sensitive Isc by ~44%. This effect was concentration dependent and mediated via basolateral alpha2-adrenoceptors. In cells pretreated with aldosterone, the stimulatory effect of norepinephrine was reduced. Finally, we demonstrated that noradrenergic nerve fibers are present in close proximity to ENaC-expressing cells in murine kidney slices. We conclude that the sustained stimulatory effect of locally elevated norepinephrine on ENaC-mediated Na(+) absorption may contribute to the hypertensive effect of increased renal sympathetic activity. PMID- 25520008 TI - Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways. AB - Although salt is a major environmental factor in the development of hypertension, the degree of salt sensitivity varies widely among individuals. The mechanisms responsible for this variation remain to be elucidated. Recent studies have revealed the involvement of two important signaling pathways in renal tubules that play key roles in electrolyte balance and the maintenance of normal blood pressure: the beta2-adrenergic stimulant-glucocorticoid receptor (GR)-with-no lysine kinase (WNK)4-Na(+)-Cl(-) cotransporter pathway, which is active in distal convoluted tubule (DCT)1, and the Ras-related C3 botulinum toxin substrate (Rac)1 mineralocorticoid receptor (MR) pathway, which is active in DCT2, connecting tubules, and collecting ducts. beta2-Adrenergic stimulation due to increased renal sympathetic activity in obesity- and salt-induced hypertension suppresses histone deacetylase 8 activity via cAMP/PKA signaling, increasing the accessibility of GRs to the negative GR response element in the WNK4 promoter. This results in the suppression of WNK4 transcription followed by the activation of Na(+)-Cl(-) cotransporters in the DCT and elevated Na(+) retention and blood pressure upon salt loading. Rac1 activates MRs, even in the absence of ligand binding, with this activity increased in the presence of ligand. In salt sensitive animals, Rac1 activation due to salt loading activates MRs in DCT2, connecting tubules, and collecting ducts. Thus, GRs and MRs are independently involved in two pathways responsible for renal Na(+) handling and salt-sensitive hypertension. These findings suggest novel therapeutic targets and may lead to the development of diagnostic tools to determine salt sensitivity in hypertensive patients. PMID- 25520011 TI - Regulation of calcium reabsorption along the rat nephron: a modeling study. AB - We expanded a mathematical model of transepithelial transport along the rat nephron to include the transport of Ca(2+) and probe the impact of calcium sensing mechanisms on Ca(2+) reabsorption. The model nephron extends from the medullary thick ascending limb (mTAL) to the inner medullary collecting duct (IMCD). Our model reproduces several experimental findings, such as measurements of luminal Ca(2+) concentrations in cortical tubules, and the effects of furosemide or deletion of the transient receptor potential channel vanilloid subtype 5 (TRPV5) on urinary Ca(2+) excretion. In vitro microperfusion of rat TAL has demonstrated that activation of the calcium-sensing receptor CaSR lowers the TAL permeability to Ca(2+), PCa (TAL) (Loupy A, Ramakrishnan SK, Wootla B, Chambrey R, de la Faille R, Bourgeois S, Bruneval P, Mandet C, Christensen EI, Faure H, Cheval L, Laghmani K, Collet C, Eladari D, Dodd RH, Ruat M, Houillier P. J Clin Invest 122: 3355, 2012). Our results suggest that this regulatory mechanism significantly impacts renal Ca(2+) handling: when plasma Ca(2+) concentration ([Ca(2+)]) is raised by 10%, the CaSR-mediated reduction in PCa (TAL) per se is predicted to enhance urinary Ca(2+) excretion by ~30%. If high [Ca(2+)] also induces renal outer medullary potassium (ROMK) inhibition, urinary Ca(2+) excretion is further raised. In vitro, increases in luminal [Ca(2+)] have been shown to activate H(+)-ATPase pumps in the outer medullary CD and to lower the water permeability of IMCD. Our model suggests that if these responses exhibit the sigmoidal dependence on luminal [Ca(2+)] that is characteristic of CaSR, then the impact of elevated Ca(2+) levels in the CD on urinary volume and pH remains limited. Finally, our model suggests that CaSR inhibitors could significantly reduce urinary Ca(2+) excretion in hypoparathyroidism, thereby reducing the risk of calcium stone formation. PMID- 25520010 TI - Altered myogenic vasoconstriction and regulation of whole kidney blood flow in the ASIC2 knockout mouse. AB - Previous studies from our laboratory have suggested that degenerin proteins contribute to myogenic constriction, a mechanism of blood flow regulation and protection against pressure-dependent organ injury, in renal vessels. The goal of the present study was to determine the importance of one family member, acid sensing ion channel 2 (ASIC2), in myogenic constriction of renal interlobar arteries, myogenic regulation of whole kidney blood flow, renal injury, and blood pressure using ASIC2(+/+), ASIC2(+/-), and ASIC2(-/-) mice. Myogenic constriction in renal interlobar arteries was impaired in ASIC2(+/-) and ASIC2(-/-) mice, whereas constriction to KCl/phenylephrine was unchanged. Correction of whole kidney renal vascular resistance (RVR) during the first 5 s after a 10- to 20 mmHg step increase in perfusion pressure, a timeframe associated with myogenic mediated correction of RVR, was slowed (4.2 +/- 0.9, 0.3 +/- 0.7, and 2.4 +/- 0.3 resistance units/s in ASIC2(+/+), ASIC2(+/-), and ASIC2(-/-) mice). Although modest reductions in function were observed in ASIC2(-/-) mice, greater reductions were observed in ASIC2(+/-) mice, which may be explained by protein protein interactions of ASIC2 with other degenerins. Isolated glomeruli from ASIC2(+/-) and ASIC2(-/-) mice had modest alterations in the expression of inflammation and injury markers (transforming growth factor-beta, mouse anti target of antiproliferative antibody-1, and nephrin), whereas ASIC2(+/-) mice had an increase in the remodeling marker collagen type III. Consistent with a more severe loss of function, mean arterial pressure was increased in ASIC2(+/-) mice (131 +/- 3 mmHg) but not in ASIC2(-/-) mice (122 +/- 3 vs. 117 +/- 2 mmHg in ASIC2(+/+) mice). These results suggest that ASIC2 contributes to transduction of the renal myogenic response and are consistent with the protective role of myogenic constriction against renal injury and hypertension. PMID- 25520013 TI - Downregulation of transient receptor potential M6 channels as a cause of hypermagnesiuric hypomagnesemia in obese type 2 diabetic rats. AB - We assessed the expression profile of Mg(2+)-transporting molecules in obese diabetic rats as a cause of hypermagnesiuric hypomagnesemia, which is involved in the development of insulin resistance, hypertension, and coronary diseases. Kidneys were obtained from male Otsuka Long-Evans Tokushima fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) obese diabetic rats at the ages of 16, 24, and 34 wk. Expression profiles were studied by real-time PCR and immunohistochemistry together with measurements of urine Mg(2+) excretion. Urine Mg(2+) excretion was increased in 24-wk-old OLETF rats and hypomagnesemia was apparent in 34-wk-old OLETF rats but not in LETO rats (urine Mg(2+) excretion: 0.16 +/- 0.01 MUg.min( 1).g body wt(-1) in 24-wk-old LETO rats and 0.28 +/- 0.01 MUg.min(-1).g body wt( 1) in 24-wk-old OLETF rats). Gene expression of transient receptor potential (TRP)M6 was downregulated (85.5 +/- 5.6% in 34-wk-old LETO rats and 63.0 +/- 3.5% in 34-wk-old OLETF rats) concomitant with Na(+)-Cl(-) cotransporter downregulation, whereas the expression of claudin-16 in tight junctions of the thick ascending limb of Henle was not different. The results of the semiquantitative analysis of immunohistochemistry were consistent with these findings (TRPM6: 0.49 +/- 0.04% in 16-wk-old LETO rats, 0.10 +/- 0.01% in 16-wk old OLETF rats, 0.52 +/- 0.03% in 24-wk-old LETO rats, 0.10 +/- 0.01% in 24-wk old OLETF rats, 0.48 +/- 0.02% in 34-wk-old LETO rats, and 0.12 +/- 0.02% in 34 wk-old OLETF rats). Gene expression of fibrosis-related proinflammatory cytokines as well as histological changes showed that the hypermagnesiuria-related molecular changes and tubulointerstitial nephropathy developed independently. TRPM6, located principally in distal convoluted tubules, appears to be a susceptible molecule that causes hypermagnesiuric hypomagnesemia as a tubulointerstitial nephropathy-independent altered tubular function in diabetic nephropathy. PMID- 25520012 TI - Acute effects of aldosterone on the epithelial Na channel in rat kidney. AB - The acute effects of aldosterone administration on epithelial Na channels (ENaC) in rat kidney were examined using electrophysiology and immunodetection. Animals received a single injection of aldosterone (20 MUg/kg body wt), which reduced Na excretion over the next 3 h. Channel activity was assessed in principal cells of cortical collecting ducts as amiloride-sensitive whole cell clamp current (INa). INa averaged 100 pA/cell, 20-30% of that reported for the same preparation under conditions of chronic stimulation. INa was negligible in control animals that did not receive hormone. The acute physiological response correlated with changes in ENaC processing and trafficking. These effects included increases in the cleaved forms of alpha-ENaC and gamma-ENaC, assessed by Western blot, and increases in the surface expression of beta-ENaC and gamma-ENaC measured after surface protein biotinylation. These changes were qualitatively and quantitatively similar to those of chronic stimulation. This suggests that altered trafficking to or from the apical membrane is an early response to the hormone and that later increases in channel activity require stimulation of channels residing at the surface. PMID- 25520014 TI - Pitfalls in pediatric radiology. AB - This essay depicts some of the diagnostic errors identified in a large academic pediatric imaging department during a 13-year period. Our aim is to illustrate potential situations in which errors are more likely to occur and more likely to cause harm, and to share our difficult cases so other radiologists might learn without having to experience those situations themselves. PMID- 25520015 TI - Tackling the problem of error in diagnostic radiology. PMID- 25520016 TI - Anesthetic diffusion through lipid membranes depends on the protonation rate. AB - Hundreds of substances possess anesthetic action. However, despite decades of research and tests, a golden rule is required to reconcile the diverse hypothesis behind anesthesia. What makes an anesthetic to be local or general in the first place? The specific targets on proteins, the solubility in lipids, the diffusivity, potency, action time? Here we show that there could be a new player equally or even more important to disentangle the riddle: the protonation rate. Indeed, such rate modulates the diffusion speed of anesthetics into lipid membranes; low protonation rates enhance the diffusion for local anesthetics while high ones reduce it. We show also that there is a pH and membrane phase dependence on the local anesthetic diffusion across multiple lipid bilayers. Based on our findings we incorporate a new clue that may advance our understanding of the anesthetic phenomenon. PMID- 25520018 TI - Karunesh Ganguly MD, PhD and Gary M. Abrams MD, FAAN. PMID- 25520017 TI - Transactional sex and prevalence of STIs: a cross-sectional study of MSM and transwomen screened for an HIV prevention trial. AB - Few studies have characterised the degree of engagement in transactional sex among men and transgender women who have sex with men and explored its association with sexually transmitted infections and human immunodeficiency virus in Ecuador. We screened 642 men who have sex with men and transgender women for a pre-exposure prophylaxis clinical trial (iPrEx) in Guayaquil, Ecuador, 2007-2009. We analysed the association of degree of engagement in transactional sex and prevalence of sexually transmitted infections including human immunodeficiency virus using chi-square and analysis of variance tests. Although just 6.2% of those who screened self-identified as sex workers, 52.1% reported having engaged in transactional sex. Compared to those who had never been paid for sex, those who had been paid were more likely to have a sexually transmitted infection (56.6% vs. 45.0%, p = 0.007) and trended towards a higher human immunodeficiency virus prevalence (16.6% vs. 10.4%, p = 0.082) at screening. Transgender women compared to other men who have sex with men were more likely to have sexually transmitted infections diagnosed at screening (75.6% vs. 50.0%, p = 0.001). Transactional sex is practiced widely but occasionally among the men who have sex with men and transgender women in Guayaquil who screened for the iPrEx study; however, engaging in transactional sex may not lead to a sex worker self identification. Both transactional sex and being a transgender woman are associated with sexually transmitted infections prevalence. PMID- 25520019 TI - Neurologic rehabilitation. PMID- 25520020 TI - Poststroke upper limb recovery. AB - Upper limb recovery after a stroke is suboptimal. Only a few individuals achieve full functional use of the hemiparetic arm. Complex primary and secondary impairments may affect recovery of upper limb function in stroke survivors. In addition, multiple personal, social, behavioral, economic, and environmental factors may interact to positively or negatively influence recovery during the different stages of rehabilitation. The current management of upper limb dysfunction poststroke has become more evidence based. In this article, we review the standard of care for upper limb poststroke rehabilitation, the evidence supporting the treatment modalities that currently exist and the exciting new developments in the therapeutic pipeline. PMID- 25520022 TI - Treatment of poststroke aphasia: current practice and new directions. AB - Aphasia is an acquired neurologic disorder that impairs an individual's ability to use and/or understand language. It commonly occurs after stroke or other injury to the brain's language network. The authors present the current methods of diagnosis and treatment of aphasia. They include a review of the evidence for the benefits of speech-language therapy, the most widespread approach to aphasia treatment, and a discussion of newer interventions such as medication and brain stimulation. These methods hold much promise for improving patient outcomes in aphasia; however, additional research regarding the best approaches to aphasia treatment will greatly improve our clinical approach. PMID- 25520023 TI - Hemispatial neglect: clinic, pathogenesis, and treatment. AB - Hemispatial neglect is characterized by a failure of awareness on the side of space and body opposite the site of injury, has been extensively studied for its theoretical interest in revealing brain mechanisms of awareness and attention. More recently, it has become apparent that hemispatial neglect reflects not only damage of specific anatomical regions, but also the large-scale dysfunction of networks of brain regions specialized in attention, motor, and multimodal sensory processing. Finally, although previous studies showed that the symptoms of hemispatial neglect could be effectively, albeit transiently, improved by a variety of behavioral, pharmacological, and physical interventions, only recently have treatment studies begun to show long-lasting therapeutic effects. Future advances will require the integration of advanced brain imaging methods to identify abnormal brain circuitries and-in combination with sensory, cognitive, and neural stimulation-methods to modulate activity in those circuitries. PMID- 25520021 TI - Rehabilitation of poststroke cognition. AB - Given the increasing rates of stroke and our aging population, it is critical that we continue to foster innovation in stroke rehabilitation. Although there is evidence supporting cognitive rehabilitation in stroke, the set of cognitive domains effectively addressed to date represents only a small subset of the problems experienced by stroke survivors. Further, a gap remains between investigational treatments and our evolving theories of brain function. These limitations present opportunities for improving the functional impact of stroke rehabilitation. The authors use a case example to encourage the reader to consider the evidence base for cognitive rehabilitation in stroke, focusing on four domains critical to daily life function: (1) speech and language, (2) functional memory, (3) executive function and skilled learned purposive movements, and (4) spatial-motor systems. Ultimately, they attempt to draw neuroscience and practice closer together by using translational reasoning to suggest possible new avenues for treating these disorders. PMID- 25520024 TI - Spinal cord injury medicine and rehabilitation. AB - The rehabilitation of spinal cord injury (SCI) is a complicated process, but one in which new research is developing novel and increasingly promising methods of restorative neurology. Spinal cord injury medicine addresses not only the neurologic injury, but all the secondary complications in other organ systems whose regulation is disrupted after SCI. To some degree, the rehabilitation of SCI is focused on return to the community and functional goals are paramount, regardless of whether they can be achieved through some mechanism of compensation or due to a growing effort at engendering neurologic plasticity and recovery. The authors present a typical case of cervical incomplete SCI and discuss the medical complications and considerations for care during acute rehabilitation. They also review current methods of planning and executing rehabilitation, along with emerging methods that are leading to, in varying degrees, greater neurologic recovery. Finally, new approaches in SCI rehabilitation, namely neuromodulation, are discussed as efforts are made to further augment neural plasticity and recovery in SCI. PMID- 25520025 TI - Amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting 20,000 to 30,000 people in the United States. The mainstay of care of patients affected by this disease is supportive and given the multifaceted nature of their needs is provided most efficiently through multidisciplinary clinics that have shown to prolong survival and improve quality of life. The authors discuss in detail evidence-based management of individuals affected by this condition. PMID- 25520026 TI - Exercise in neuromuscular disease. AB - In this review, the authors present an overview of the role of exercise in neuromuscular disease (NMD). The authors demonstrate that despite the different pathologies in NMDs, exercise is beneficial, whether aerobic/endurance or strength/resistive training. The authors analyze methodological flaws of existing studies and suggest improvements for future trial protocols. Finally, we discuss specialized exercise training of specific muscles, as well as new technologies adapted from other neurologic disorders, including body-weight-supported treadmill ambulation, robotic-assisted gait training, and neuromuscular electrical stimulation. PMID- 25520027 TI - Mild-moderate TBI: clinical recommendations to optimize neurobehavioral functioning, learning, and adaptation. AB - Traumatic brain injury (TBI) can result in functional deficits that persist long after acute injury. The authors present a case study of an individual who experienced some of the most common debilitating problems that characterize the chronic phase of mild-to-moderate TBI-difficulties with neurobehavioral functions that manifest via complaints of distractibility, poor memory, disorganization, poor frustration tolerance, and feeling easily overwhelmed. They present a rational strategy for management that addresses important domain-general targets likely to have far-ranging benefits. This integrated, longitudinal, and multifaceted approach first addresses approachable targets and provides an important foundation to enhance the success of other, more specific interventions requiring specialty intervention. The overall approach places an emphasis on accomplishing two major categories of clinical objectives: optimizing current functioning and enhancing learning and adaptation to support improvement of functioning in the long-term for individuals living with brain injury. PMID- 25520028 TI - Moderate-to-severe traumatic brain injury. AB - Managing patients with moderate-to-severe traumatic brain injury (TBI), particularly those with combat-related blast injury, is exceptionally challenging. Optimal care requires the coordinated efforts of numerous providers, contributing to an interdisciplinary team. Given the complexities of TBI and the variety of physiologic, physical, cognitive, behavioral, and emotional manifestations of the injury, a holistic approach to patient care is needed throughout the entire continuum of care. In this article, the authors provide an overview of how interdisciplinary care is provided from the acute to the chronic settings, and illustrate the important role that rehabilitation plays throughout the continuum of care in facilitating maximizing recovery, functional independence, and quality of life. Common conditions associated with TBI are illustrated through a case presentation of an individual with blast-related polytrauma and help to frame a more detailed discussion of subtopics including neurointensive care, posttraumatic seizures, venous thromboembolic disease prevention, spasticity management, vestibular disorders, endocrine dysfunction, and psychological trauma. PMID- 25520029 TI - Closed-loop rehabilitation of age-related cognitive disorders. AB - Cognitive deficits are common in older adults, as a result of both the natural aging process and neurodegenerative disease. Although medical advancements have successfully prolonged the human lifespan, the challenge of remediating cognitive aging remains. The authors discuss the current state of cognitive therapeutic interventions and then present the need for development and validation of more powerful neurocognitive therapeutics. They propose that the next generation of interventions be implemented as closed-loop systems that target specific neural processing deficits, incorporate quantitative feedback to the individual and clinician, and are personalized to the individual's neurocognitive capacities using real-time performance-adaptive algorithms. This approach should be multimodal and seamlessly integrate other treatment approaches, including neurofeedback and transcranial electrical stimulation. This novel approach will involve the generation of software that engages the individual in an immersive and enjoyable game-based interface, integrated with advanced biosensing hardware, to maximally harness plasticity and assure adherence. Introducing such next generation closed-loop neurocognitive therapeutics into the mainstream of our mental health care system will require the combined efforts of clinicians, neuroscientists, bioengineers, software game developers, and industry and policy makers working together to meet the challenges and opportunities of translational neuroscience in the 21st century. PMID- 25520031 TI - Stable dispersions of azide functionalized ferromagnetic metal nanoparticles. AB - Ferromagnetic nanoparticles are covalently modified in order to enhance the dispersion stability as well as the antifouling properties. Insertion of an azide moiety allows "click"-reaction of a relevant tag molecule. This and the high saturation magnetization of the presented nanocomposite offer a promising platform for magnetic biosensors. PMID- 25520030 TI - Spasticity and intrathecal baclofen. AB - Severe spastic tone and/or spastic hypertonia can be the most disabling consequences of a neurologic insult, resulting from an excess of muscle tone. Baclofen, a GABA-B agonist, is one of the most widely used drugs in treating abnormal or disabling spastic tone. However, the effectiveness of baclofen taken orally is often limited by its systemic side effects, including sedation, confusion, and lethargy. Intrathecal baclofen (ITB) delivered by an implanted catheter can work directly at the spinal cord level to reduce spastic tone through presynaptic inhibition. Several decades after Penn and Kroin (1984) proved that continuous infusion of intrathecal baclofen reduced spinal cord spasticity, numerous studies have demonstrated the benefits of ITB therapy and proven its effectiveness in modulating and reducing spastic tone. In this article the authors review current methods of management with ITB therapy; summarize the current knowledge, controversies, and available scientific literature; illustrate through different clinical cases treatment strategies and their outcomes; and lastly, provide a synopsis of current clinical practice in ITB therapy with insights into new therapeutic developments. PMID- 25520032 TI - Selective conversion of nitroarenes using a carbon nanotube-ruthenium nanohybrid. AB - Ruthenium nanoparticles were assembled on carbon nanotubes and the resulting nanohybrid was used in the hydrazine-mediated catalytic hydrogenation of various nitroarenes, at room temperature. Depending on the solvent, a selective transformation occurred, giving either access to the corresponding aniline or hydroxylamine derivative. PMID- 25520034 TI - Voice problems in the fitness industry: Factors associated with chronic hoarseness. AB - PURPOSE: To determine factors associated with chronic hoarseness in Australian group fitness instructors (GFIs). METHOD: A total of 361 GFIs (81 males, 280 females), aged between 18-67 years currently active in the Australian fitness industry, completed a 65-item self-completion questionnaire distributed via SurveyMonkey. Demographic, lifestyle and voice use variables thought to influence vocal health and voice production in the GFI population were examined using logistic regression analyses. GFIs' chronic hoarseness with response options "positive" and "negative" was considered as the outcome variable of interest. RESULT: Approximately 39% of the study participants reported having chronic hoarseness. Multivariable logistic regression modelling revealed a set of statistically significant factors associated with chronic hoarseness. These include: younger age, partial voice loss while instructing, partial voice loss after instructing and using vocal volume louder than normal speaking voice whilst instructing. CONCLUSION: This study has identified factors associated with the presentation of chronic hoarseness in the Australian GFI population. Prospective studies are required to validate the findings of this study in order to better understand predictive factors of chronic hoarseness among GFIs. PMID- 25520033 TI - Biological and clinical significance of epigenetic silencing of MARVELD1 gene in lung cancer. AB - Epigenetic silence in cancer frequently altered signal-transduction pathways during the early stages of tumor development. Recent progress in the field of cancer epigenetics has led to new opportunities for diagnosis and treatment of cancer. We previously demonstrated that novel identified nuclear factor MARVELD1 was widely expressed in human tissues, but down-regulated by promoter methylation in multiple cancers. This study was carried out to determine the biological and clinical significance of MARVELD1 gene silencing in lung cancer. Here, we found the reduced MARVELD1 expression significantly correlated with diagnostic histopathology and malignant degree of lung cancers. DNA hypermethylation and histone deacetylation synergistically inactivated MARVELD1 gene in lung cancer cells. Moreover, MARVELD1 modulated the efficiency of nonsense-mediated mRNA decay (NMD) through interaction with NMD core factor SMG1. The decreased MARVELD1 level in lung cancer reduces NMD efficiency through diminishing the association between NMD complex component UPF1/SMG1 and premature termination codons containing mRNA (PTC-mRNA). The results suggested that MARVELD1 silencing is an appealing diagnostic biomarker for lung cancer and epigenetic silencing of MARVELD1 gene links with the regulatory mechanism of NMD pathway in lung cancer, which may be required for tumorigenesis. PMID- 25520035 TI - Robotically assisted treadmill exercise training for improving peak fitness in chronic motor incomplete spinal cord injury: A randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of robotically assisted body weight supported treadmill training (RABWSTT) for improving cardiovascular fitness in chronic motor incomplete spinal cord injury (CMISCI). DESIGN: Pilot prospective randomized, controlled clinical trial. SETTING: Outpatient rehabilitation specialty hospital. PARTICIPANTS: Eighteen individuals with CMISCI with American Spinal Injury Association (ASIA) level between C4 and L2 and at least one-year post injury. Interventions CMISCI participants were randomized to RABWSTT or a home stretching program (HSP) three times per week for three months. Those in the home stretching group were crossed over to three months of RABWSTT following completion of the initial three month phase. OUTCOME MEASURES: Peak oxygen consumption (peak VO(2)) was measured during both robotic treadmill walking and arm cycle ergometry: twice at baseline, once at six weeks (mid-training) and twice at three months (post-training). Peak VO(2) values were normalized for body mass. RESULTS: The RABWSTT group improved peak VO(2) by 12.3% during robotic treadmill walking (20.2 +/- 7.4 to 22.7 +/- 7.5 ml/kg/min, P = 0.018), compared to a non-significant 3.9% within group change observed in HSP controls (P = 0.37). Neither group displayed a significant change in peak VO2 during arm cycle ergometry (RABWSTT, 8.5% (P = 0.25); HSP, 1.76% (P = 0.72)). A repeated measures analysis showed statistically significant differences between treatments for peak VO(2) during both robotic treadmill walking (P = 0.002) and arm cycle ergometry (P = 0.001). CONCLUSION: RABWSTT is an effective intervention model for improving peak fitness levels assessed during robotic treadmill walking in persons with CMISCI. PMID- 25520036 TI - Segregation of a spontaneous Klrd1 (CD94) mutation in DBA/2 mouse substrains. AB - Current model DBA/2J (D2J) mice lack CD94 expression due to a deletion spanning the last coding exon of the Klrd1 gene that occurred in the mid- to late 1980s. In contrast, DBA/2JRj (D2Rj) mice, crosses derived from DBA/2J before 1984, and C57BL/6J (B6) mice lack the deletion and have normal CD94 expression. For example, BXD lines (BXD1-32) generated in the 1970s by crossing B6 and D2J do not segregate for the exonic deletion and have high expression, whereas BXD lines 33 and greater were generated after 1990 are segregating for the deletion and have highly variable Klrd1 expression. We performed quantitative trait locus analysis of Klrd1 expression by using BXD lines with different generation times and found that the expression difference in Klrd1 in the later BXD set is driven by a strong cis-acting expression quantitative trait locus. Although the Klrd1/CD94 locus is essential for mousepox resistance, the genetic variation among D2 substrains and the later set of BXD strains is not associated with susceptibility to the Influenza A virus PR8 strain. Substrains with nearly identical genetic backgrounds that are segregating functional variants such as the Klrd1 deletion are useful genetic tools to investigate biological function. PMID- 25520037 TI - A high-density linkage map for Astyanax mexicanus using genotyping-by-sequencing technology. AB - The Mexican tetra, Astyanax mexicanus, is a unique model system consisting of cave-adapted and surface-dwelling morphotypes that diverged >1 million years (My) ago. This remarkable natural experiment has enabled powerful genetic analyses of cave adaptation. Here, we describe the application of next-generation sequencing technology to the creation of a high-density linkage map. Our map comprises more than 2200 markers populating 25 linkage groups constructed from genotypic data generated from a single genotyping-by-sequencing project. We leveraged emergent genomic and transcriptomic resources to anchor hundreds of anonymous Astyanax markers to the genome of the zebrafish (Danio rerio), the most closely related model organism to our study species. This facilitated the identification of 784 distinct connections between our linkage map and the Danio rerio genome, highlighting several regions of conserved genomic architecture between the two species despite ~150 My of divergence. Using a Mendelian cave-associated trait as a proof-of-principle, we successfully recovered the genomic position of the albinism locus near the gene Oca2. Further, our map successfully informed the positions of unplaced Astyanax genomic scaffolds within particular linkage groups. This ability to identify the relative location, orientation, and linear order of unaligned genomic scaffolds will facilitate ongoing efforts to improve on the current early draft and assemble future versions of the Astyanax physical genome. Moreover, this improved linkage map will enable higher-resolution genetic analyses and catalyze the discovery of the genetic basis for cave-associated phenotypes. PMID- 25520038 TI - Redox-dependent DNA distortion in a SoxR protein-promoter complex studied using fluorescent probes. AB - The [2Fe-2S] transcriptional factor SoxR, a member of the MerR family, is regulated by the reversible oxidation and reduction of [2Fe-2S] clusters and functions as a sensor of oxidative stress in Escherichia coli. In the oxidized state, distortion of the target DNA promoter region initiates transcription by RNA polymerase, thereby activating transcription. The inactive reduced state of the protein has remained uncharacterized. Here, we directly observed redox dependent conformational changes in the promoter DNA by site-specifically replacing selected adenine (A) and cytosine (C) bases in the promoter oligonucleotide with the fluorescent probes 2-aminopurine (2Ap) and pyrrolocytosine (pyrrolo-dC), respectively. Reduction of the [2Fe-2S] cluster in the SoxR-DNA complex dramatically weakened the fluorescence intensity of the 2Ap moieties incorporated into the central part of the DNA. In contrast, the fluorescence of 2Ap moieties incorporated at A in other regions and the fluorescence of pyrrolo-dC moieties in the central region of the DNA (C3 and C3') were only slightly decreased by the reduction. These results strongly suggest that the redox change causes a large conformational change within a region confined to the central A-T base pairs in the promoter region of the DNA. PMID- 25520039 TI - Metastatic melanoma - a review of current and future treatment options. AB - Despite advances in treatment and surveillance, melanoma continues to claim approximately 9,000 lives in the US annually (SEER 2013). The National Comprehensive Cancer Network currently recommends ipilumumab, vemurafenib, dabrafenib, and high-dose IL-2 as first line agents for Stage IV melanoma. Little data exists to guide management of cutaneous and subcutaneous metastases despite the fact that they are relatively common. Existing options include intralesional Bacillus Calmette-Guerin, isolated limb perfusion/infusion, interferon-alpha, topical imiquimod, cryotherapy, radiation therapy, interferon therapy, and intratumoral interleukin-2 injections. Newly emerging treatments include the anti programmed cell death 1 receptor agents (nivolumab and pembrolizumab), anti programmed death-ligand 1 agents, and oncolytic vaccines (talimogene laherparepevec). Available treatments for select sites include adoptive T cell therapies and dendritic cell vaccines. In addition to reviewing the above agents and their mechanisms of action, this review will also focus on combination therapy as these strategies have shown promising results in clinical trials for metastatic melanoma treatment. PMID- 25520041 TI - Total phenolic content, ferric reducing and DPPH scavenging activity of Arum dioscoridis. AB - Arum dioscoridis, locally called 'Gavur pancari', is a wild plant the leaves of which have been used as vegetable and for preparing special soup which has a sour taste. This study was set up to determine in vitro antioxidant activities and total phenolic and flavonoid contents of different extracts of A. dioscoridis. Free radical scavenging activity was evaluated using 2,2-diphenyl-1 picrylhydrazyl (DPPH) and ferric reducing activity with different concentrations of ethanol, methanol, acetone and water extracts of the plant leaves. Total phenolic and flavonoid contents were widely variable depending on solvents. Ethanol and methanol extractions of the plant material showed better performances with respect to both phenolic and flavonoid contents, respectively. The highest phenolic and flavonoid contents of ethanol and methanol extracts were 100.890 mg/g GAE and 72.643 mg/g QE, respectively. The lower DPPH scavenging and ferric reducing activities were determined in comparison with previous reports and standard synthetic chemicals. PMID- 25520040 TI - Discovery of osmotic sensitive transcription factors in fish intestine via a transcriptomic approach. AB - BACKGROUND: Teleost intestine is crucial for seawater acclimation by sensing osmolality of imbibed seawater and regulating drinking and water/ion absorption. Regulatory genes for transforming intestinal function have not been identified. A transcriptomic approach was used to search for such genes in the intestine of euryhaline medaka. RESULTS: Quantitative RNA-seq by Illumina Hi-Seq Sequencing method was performed to analyze intestinal gene expression 0 h, 1 h, 3 h, 1 d, and 7 d after seawater transfer. Gene ontology (GO) enrichment results showed that cell adhesion, signal transduction, and protein phosphorylation gene categories were augmented soon after transfer, indicating a rapid reorganization of cellular components and functions. Among >50 transiently up-regulated transcription factors selected via co-expression correlation and GO selection, five transcription factors, including CEBPB and CEBPD, were confirmed by quantitative PCR to be specific to hyperosmotic stress, while others were also up regulated after freshwater control transfer, including some well-known osmotic stress transcription factors such as SGK1 and TSC22D3/Ostf1. Protein interaction networks suggest a high degree of overlapping among the signaling of transcription factors that respond to osmotic and general stresses, which sheds light on the interpretation of their roles during hyperosmotic stress and emergency. CONCLUSIONS: Since cortisol is an important hormone for seawater acclimation as well as for general stress in teleosts, emergency and osmotic challenges could have been evolved in parallel and resulted in the overlapped signaling networks. Our results revealed important interactions among transcription factors and offer a multifactorial perspective of genes involved in seawater acclimation. PMID- 25520043 TI - Representativeness of shorter measurement sessions in long-term indoor air monitoring. AB - Indoor air quality (IAQ) considerably influences health, comfort and the overall performance of people who spend most of their lives in confined spaces. For this reason, there is a strong need to develop methods for IAQ assessment. The fundamental issue in the quantitative determination of IAQ is the duration of measurements. Its inadequate choice may result in providing incorrect information and this potentially leads to wrong conclusions. The most complete information may be acquired through long-term monitoring. However it is typically perceived as impractical due to time and cost load. The aim of this study was to determine whether long-term monitoring can be adequately represented by a shorter measurement session. There were considered three measurable quantities: temperature, relative humidity and carbon dioxide concentration. They are commonly recognized as indicatives for IAQ and may be readily monitored. Scaled Kullback-Leibler divergence, also called relative entropy, was applied as a measure of data representativeness. We considered long-term monitoring in a range from 1 to 9 months. Based on our work, the representative data on CO2 concentration may be acquired while performing measurements during 20% of time dedicated to long-term monitoring. In the case of temperature and relative humidity the respective time demand was 50% of long-term monitoring. From our results, in indoor air monitoring strategies, there could be considered shorter measurement sessions, while still collecting data which are representative for long-term monitoring. PMID- 25520044 TI - Stimulus-driven attentional capture by subliminal onset cues. AB - In two experiments, we tested whether subliminal abrupt onset cues capture attention in a stimulus-driven way. An onset cue was presented 16 ms prior to the stimulus display that consisted of clearly visible color targets. The onset cue was presented either at the same side as the target (the valid cue condition) or on the opposite side of the target (the invalid cue condition). Because the onset cue was presented 16 ms before other placeholders were presented, the cue was subliminal to the participant. To ensure that this subliminal cue captured attention in a stimulus-driven way, the cue's features did not match the top-down attentional control settings of the participants: (1) The color of the cue was always different than the color of the non-singleton targets ensuring that a top down set for a specific color or for a singleton would not match the cue, and (2) colored targets and distractors had the same objective luminance (measured by the colorimeter) and subjective lightness (measured by flicker photometry), preventing a match between the top-down set for target and cue contrast. Even though a match between the cues and top-down settings was prevented, in both experiments, the cues captured attention, with faster response times in valid than invalid cue conditions (Experiments 1 and 2) and faster response times in valid than the neutral conditions (Experiment 2). The results support the conclusion that subliminal cues capture attention in a stimulus-driven way. PMID- 25520042 TI - Incidence of traumatic cervical spine fractures in the Norwegian population: a national registry study. AB - BACKGROUND: The incidence of cervical spine fractures (CS-fx) in the general population is sparingly assessed. The aim of the current study was to estimate the incidence of traumatic CS-fx and of open surgery of cervical spine injuries in the Norwegian population. METHODS: The Norwegian Patient Register (NPR) is an administrative database that contains activity data from all Norwegian government owned hospitals and outpatient clinics. The diagnoses and procedures are coded according to the International Statistical Classification of Diseases and Related Health Problems (ICD-10) and the NOMESCO Classification of Surgical Procedures (NCSP), respectively. We retrieved information on all severe traumatic cervical spine injuries between 2009 and 2012 from the NPR. Updated information on the date of death is included through routine linkage to the General Register Office. RESULTS: Between 2009 and 2012, a total of 3 248 patients met our criteria for severe traumatic cervical spine injury. A total of 2 963 patients had one or more CS-fx, and 285 had severe non-fracture cervical spine injuries. The median age was 54 years, and 69% of the patients were male. The incidence of CS-fx and severe non-fracture injuries in the total Norwegian population was 16.5/100 000/year, and the incidence of CS-fx was 15.0/100 000/year. A total of 18% of the patients were treated with open surgery, resulting in an estimated incidence of surgery for acute traumatic cervical spine injury of 3.0/100 000/ year in the Norwegian population. The 1- and 3-month mortality rates were 4% and 6%, respectively. PMID- 25520045 TI - Reading first or smelling first? Effects of presentation order on odor identification. AB - Verbal labels are potent manipulators for olfactory perception, and verbal descriptors used in a cued olfactory identification test will influence the testing results. The main aim of the present study was to test whether the order of presentation of the odorants and the corresponding set of labels (verbal descriptors with or without pictures) would influence the results of a psychophysical odor identification test in 100 normosmic subjects (49 women and 51 men) and 100 patients with olfactory dysfunction (61 women and 39 men). Additionally, we investigated whether the scores would be different between subjects identifying odors from a list of verbal descriptors and subjects using both pictures and verbal descriptors. The subjects were examined with the extended, 32-item "Sniffin' Sticks" identification test. We found that the scores of normosmic subjects were significantly higher when the subjects were presented with label options prior to smelling, whereas for patients the scores in the two conditions did not differ. Moreover, in both groups the scores were not significantly different when the subjects were presented either with verbal descriptors only or with verbal descriptors and pictures. Our findings seem to be of importance not only to research involving psychophysical olfactory identification tests or in a clinical context, but also to further experiments investigating human olfaction and cognition. PMID- 25520046 TI - A proposal of postoperative follow-up pathways for lung cancer. AB - OBJECTIVES: Although follow-up surveillance after resection for lung cancer is commonly performed in clinical practice, there is no standard follow-up program. We attempted to establish follow-up examination schedules that we considered would be acceptable to the majority of doctors, and would like to propose them as standard postoperative follow-up pathways. METHODS: We carried out a retrospective analysis of patients' data and reviewed the time of detection of recurrence and the site of recurrence after resection. Published papers were also reviewed. The postoperative follow-up pathways were established based on these data. PROPOSED FOLLOW-UP PATHWAY: The follow-up period was set at as 5 years after resection, and physical examinations, chest radiography, chest CT and blood examination are recommended. Two follow-up pathways were proposed taking the risk of recurrence into consideration: the Risk of recurrence-based pathway and the Comprehensive pathway. In the Risk of recurrence-based pathway, the follow-up examination schedule is modified according to the risk of recurrence. In the Comprehensive pathway, a single universal examination schedule is recommended for all patients. The choice between these two pathways is left to the discretion of the attending doctor. CONCLUSIONS: We proposed two follow-up pathways, based on retrospective analysis of patients' data and a review of published papers, which we considered would be acceptable to the majority of doctors and would be suited to the current medical environment in Japan. A prospective study to evaluate the efficacy of the follow-up pathways is ongoing. PMID- 25520047 TI - Mid-term outcomes of cardiovascular surgery for patients with Marfan syndrome. AB - OBJECTIVES: Cardiovascular manifestations determine the prognosis and survival of patients with Marfan syndrome (MFS). We assessed the early and mid-term outcomes of cardiovascular surgery for this patient population. PATIENTS AND METHODS: We conducted a retrospective evaluation of patients with MFS who underwent surgery in our department. The endpoint was the requirement for a second cardiovascular surgery, and death from any cause. RESULTS: From February 2002 to March 2013, we performed 24 surgeries on 13 patients with MFS. At the time of initial surgery, the patients' aged ranged from 19 to 64 years of age (mean 34.7 +/- 11.3 years) and included 5 men (38.5 %). Five of 13 initial surgeries (38.5 %) were emergencies. Seven patients (53.8 %) presented with aortic dissection at initial surgery, and one of the remaining six patients suffered from new aortic dissection during follow-up. Eight patients (61.5 %) underwent a second surgery, and a second surgery was not required for 100, 75.0, and 53.6 % of patients at 1, 3, and 5 years, respectively. The mean time interval between the first and the second surgeries was 52.8 +/- 28.2 months. No patient died while hospitalized, and three subsequently died from unknown causes. Survival rates were 100, 90.9 and 64.9 % at 3, 5, and 7 years, respectively. CONCLUSION: Although we obtained satisfactory early outcomes for patients with MFS, there were three late deaths from unknown causes. Therefore, we recommend that patients with MFS should remain under close surveillance. PMID- 25520049 TI - Is there a role for JAK inhibitors in BCR-ABL1-negative myeloproliferative neoplasms other than myelofibrosis? AB - Current data suggest that constitutively active JAK-STAT signaling plays a central role in the pathogenesis of BCR-ABL1-negative myeloproliferative neoplasms (MPNs), regardless of the specific underlying molecular abnormality. This observation provides strong rationale for use of JAK inhibitors for MPN treatment, and these drugs were first tested in myelofibrosis (MF) patients. Ruxolitinib, a JAK-1/2 inhibitor, is effective at controlling splenomegaly and constitutional symptoms, but has limited benefit in reversing bone marrow fibrosis or inducing complete or partial remissions. Ruxolitinib is currently in Phase 3 testing for treatment of hydroxyurea resistant/intolerant polycythemia vera (PV). Preliminary data reveals response rates of 60% for hematocrit control and 38% for spleen volume reduction per protocol-defined criteria, in addition to improving disease-related symptoms. These endpoints however have limited value as surrogates for long-term clinically relevant outcomes such as freedom-from cardiovascular/thrombohemorrhagic events or time-to-hematological transformation, and the early crossover design of the aforementioned trial introduces limitations in terms of analysis of these latter endpoints. In contrast, other recent trials in PV have demonstrated the feasibility of using long-term clinically relevant outcomes as a primary endpoint. We also discuss the role of JAK inhibitors for treatment of CSF3RT618I-mutated chronic neutrophilic leukemia and hematologic malignancies with rearranged JAK2 gene. PMID- 25520048 TI - Pleiotropic actions of iron balance in diabetes mellitus. AB - As an essential element, iron plays a central role in many physiological processes, including redox balance, inflammation, energy metabolism, and environment sensing. Perturbations in iron homeostasis are associated with several conditions, including hyperglycemia and diabetes, both of which have been studied in patients and animal models. To clarify the pleiotropic role of iron homeostasis in diabetes development, the early studies on diseases with iron overload, studies on clinical iron depletion therapies, associations between iron related genetic polymorphisms and diabetes, and etiological mechanisms underlying iron perturbations-impaired insulin secretion and insulin sensitivity were carefully reviewed and discussed. Hereditary hemochromatosis, transfusion dependent thalassemia, and excess heme iron intake can increase the risk of developing diabetes. Genetically modified mice and mice fed a high-iron diet present with discrepant phenotypes due to differences in tissue iron distribution. Moreover, several genetic polymorphisms related to iron homeostasis have been associated with the risk of developing diabetes. Tightly controlled iron metabolism is essential for insulin secretion and insulin sensitivity, and iron overload in pancreatic islets alters reactive oxygen species (ROS) generation, as well as hypoxia-inducible factor-1alpha (HIF-1alpha) stability and adenosine triphosphate (ATP) synthesis, thereby impairing the function and viability of beta-cells. Decreased levels of adiponectin, macrophage-mediated inflammation, and ROS-mediated liver kinase B1 (LKB1)/adenosine monophosphate activated protein kinase (AMPK) activation can contribute to iron overload induced insulin resistance, whereas iron deficiency could also participate in obesity-related inflammation, hypoxia, and insulin resistance. Because iron homeostasis is closely correlated with many metabolic processes, future studies are needed in order to elucidate the finely tuned network among iron homeostasis, carbohydrate and lipid metabolism, inflammation, and hypoxia. PMID- 25520050 TI - Effects of External and Internal Hyperthermia on LDL Transport and Accumulation Within an Arterial Wall in the Presence of a Stenosis. AB - Effects of hyperthermia on transport of low-density lipoprotein (LDL) through a stenosed arterial wall are analyzed comprehensively in the present work. The realistic and pertinent aspects of an arterial wall is represented by a multi layer model, with a proper representation of the thickened intima region due to the atherosclerotic plaque formation. Effects of external and internal hyperthermia on LDL concentration levels are established along with the range of influence of these effects. Various modules of the current work are comprehensively compared with pertinent literature and are found to be in excellent agreement. The effects of external and internal hyperthermia as well as the load level and the axial location of the plaque formation on LDL transport and accumulation for a stenosed artery are established in this work. PMID- 25520051 TI - Clinical characteristics and treatment strategies for idiopathic spinal extradural arachnoid cysts: a single-center experience. AB - BACKGROUND: Idiopathic spinal epidural arachnoid cysts (SEACs) are relatively rare lesions with diverse clinical manifestations depending on the affected spinal region and nerve roots. To assess the relationship between clinical presentation and surgical outcome, we conducted a retrospective review of medical records and neuroimages from idiopathic SEAC patients. METHODS: Of 15 consecutive patients with idiopathic SEACs, 14 underwent surgical treatment at the Beijing Tiantan Hospital between January 2008 and July 2013. Case histories, clinical presentations, imaging findings, operative findings, and surgical outcomes were reviewed. RESULTS: Of the 15 patients, 5 were children (median age, 13 years) and 10 were adults (median age, 35 years). The male-to-female ratio was 4:1. The median disease duration was 1 year in children and 4 years in adults. The most common manifestations were progressive paraparesis (73.3 %) and radiculopathy (66.7 %). All pediatric lesions affected thoracic segments, while 80 % of adult lesions affected lumbar segments. Fourteen patients underwent microsurgical treatment, with cyst excision in nine (combined with fistula closure in four) and partial cyst excision in five (with fistula closure in three). No recurrences were observed during follow-up (average of 23 months). Excellent outcome was achieved in six cases, good outcome in four, fair in two, and poor in two. CONCLUSIONS: Idiopathic SEAC mainly affect the thoracic segments in children and the lumbar segments in adults, and often results in progressive paraparesis and radiculopathy. Early surgical intervention is suggested for progressive symptomatic patients to restore neurological function. PMID- 25520052 TI - No 5-ALA fluorescence seen in a recurrent papillary tumour of the pineal region (PTPR). PMID- 25520053 TI - Molecules with a sense of logic: a progress report. AB - In this tutorial review, the most recent developments in the field of molecular logic and information processing are discussed. Special emphasis is given to the report of progress in the concatenation of molecular logic devices and switches, the design of memory systems working according to the principles of sequential logic, the mimicking of transistors, and the research on photochromic platforms with an unprecedented degree of functional integration. Furthermore, a series of achievements that add up to the conceptual diversity of molecular logic is introduced, such as the realization of highly complex and logically reversible Toffoli and Fredkin gates by the action of DNAzymes or the use of a multifluorophoric platform as a viable approach towards keypad lock functions. PMID- 25520055 TI - Medical training: some "forgotten" common competencies. PMID- 25520054 TI - Brain intracellular metabolites are freely diffusing along cell fibers in grey and white matter, as measured by diffusion-weighted MR spectroscopy in the human brain at 7 T. AB - Due to the specific compartmentation of brain metabolites, diffusion-weighted magnetic resonance spectroscopy opens unique insight into neuronal and astrocytic microstructures. The apparent diffusion coefficient (ADC) of brain metabolites depends on various intracellular parameters including cytosol viscosity and molecular crowding. When diffusion time (t d) is long enough, the size and geometry of the compartment in which the metabolites diffuse strongly influence metabolites ADC. In a previous study, performed in the macaque brain, we measured neuronal and astrocytic metabolites ADC at long t d (from 86 to 1,011 ms) in a large voxel enclosing an equal proportion of white and grey matter. We showed that metabolites apparently diffuse freely along the axis of dendrites, axons and astrocytic processes. To assess potential differences between these two tissue types, here we measured for the first time in the Human brain the t d-dependency of metabolites trace/3 ADC at 7 teslas using a localized diffusion-weighted STEAM sequence, in parietal and occipital voxels, respectively, containing mainly white and grey matter. We show that, in both tissues and over the observed timescale (t d varying from 92 to 712 ms) metabolite ADC reaches a non-zero plateau, suggesting that metabolites are not confined inside subcellular regions such as cell bodies, or inside subcellular compartments such as organelles, but are rather free to diffuse in the whole fiber-like structure of neurons and astrocytes. Beyond the fundamental insights into intracellular compartmentation of metabolites, this work also provides a new framework for interpreting results of neuroimaging techniques based on molecular diffusion, such as diffusion weighted magnetic resonance spectroscopy and imaging. PMID- 25520057 TI - 231Pa/230Th evidence for a weakened but persistent Atlantic meridional overturning circulation during Heinrich Stadial 1. AB - The strength of Atlantic meridional overturning circulation is believed to affect the climate over glacial-interglacial and millennial timescales. The marine sedimentary (231)Pa/(230)Th ratio is a promising paleocirculation proxy, but local particle effects may bias individual reconstructions. Here we present new Atlantic sedimentary (231)Pa/(230)Th data from the Holocene, the last glacial maximum and Heinrich Stadial 1, a period of abrupt cooling ca. 17,500 years ago. We combine our results with published data from these intervals to create a spatially distributed sedimentary (231)Pa/(230)Th database. The data reveal a net (231)Pa deficit during each period, consistent with persistent (231)Pa export. In highly resolved cores, Heinrich (231)Pa/(230)Th ratios exceed glacial ratios at nearly all depths, indicating a significant reduction, although not cessation, of overturning during Heinrich Stadial 1. These results support the inference that weakened overturning was a driver of Heinrich cooling, while suggesting that abrupt climate oscillations do not necessarily require a complete shutdown of overturning. PMID- 25520056 TI - Osteogenic differentiation and gene expression profile of human dental follicle cells induced by human dental pulp cells. AB - Dental follicle cells (DFCs) differentiate into cementoblasts or osteoblasts under appropriate triggering. However, the mechanism(s) for osteogenic differentiation of DFCs are still unclear. The purpose of this study was to examine the effects of dental papilla-derived human dental pulp cells (hDPCs) on osteogenic differentiation of human DFCs (hDFCs) in vitro and in vivo and to compare gene expression in hDFCs in the presence or absence of hDPCs. To evaluate the osteogenic differentiation of hDFCs induced by hDPCs, hDFCs were cultured in osteogenic medium with or without hDPCs-conditioned medium (CM) in vitro and the cells transplanted into the subcutaneous tissue of immunodeficient mice in vivo. The hDPCs-CM enhanced alkaline phosphatase promoter activity of hDFCs in osteogenic culture. The expression of several osteoblast marker genes was increased in hDFCs treated with hDPCs-CM compared to hDFCs in normal medium. The hDFCs induced by hDPCs-CM also produced more calcified nodules than hDFCs in normal medium. In transplantation experiments, hDPCs-CM promoted the osteogenic induction and bone formation of hDFCs. Microarray analysis and quantitative real time PCR showed that osteogenesis-related genes including WNT2, VCAN, OSR2, FOSB, and POSTN in hDFCs were significantly upregulated after induction by hDPCs-CM compared to hDFCs in normal medium. These findings indicate that hDPCs could increase the expression of osteogenic genes in hDFCs and stimulate their osteogenesis and could be a cellular resource for bone regeneration therapy when induced by hDPCs-derived factors. PMID- 25520059 TI - Social aspects of multiple sclerosis for Iranian individuals. AB - PURPOSE: This study aimed to determine the social aspects of multiple sclerosis (MS) in the Iranian individuals. METHODS: A qualitative case study approach was used for this study, which is a part of a larger qualitative study about health care delivery system of MS. Participants were selected on the basis of purposive sampling method. Semi-structured interviews regarding the social aspects of MS were conducted with 18 MS patients, 6 family members and 7 health care providers. Besides interviews with the participants, documents related to the aim of the study, including weblogs, MS magazines, special websites of individuals with MS and news agencies. Data analysis was performed using the qualitative content analysis technique. RESULTS: Data obtained has been categorised into five main categories, including confronting stigma symbols, the outcome of stigma, walling in due to stigma, disturbance in normal life and concern about job. CONCLUSION: There are multiple social effects of MS on the afflicted individuals, which affect various dimensions of their life. Policy makers and health care providers must also consider these effects of MS on other dimensions of the individuals' life. Implications for Rehabilitation Multiple sclerosis (MS) is a disease which restricts social life for patients, in addition to physical impacts. Individuals with MS experienced stigma as well as problems with employment and marital life, due to improper information about MS in society. We recommend that health care workers offer proper information about MS to patients and their family members to minimise the social problems faced by them. We recommend that mass media offers proper information about MS to people in society to disseminate the correct picture of MS. We recommend that the rehabilitation team offers psychological support to patients and their families for their empowerment, to facilitate dealing with the impacts of the disease. We recommend that health care providers teach the family members about patient support and communication skills. PMID- 25520058 TI - Near-instant surface-selective fluorogenic protein quantification using sulfonated triarylmethane dyes and fluorogen activating proteins. AB - Agonist-promoted G-protein coupled receptor (GPCR) endocytosis and recycling plays an important role in many signaling events in the cell. However, the approaches that allow fast and quantitative analysis of such processes still remain limited. Here we report an improved labeling approach based on the genetic fusion of a fluorogen activating protein (FAP) to a GPCR and binding of a sulfonated analog of the malachite green (MG) fluorogen to rapidly and selectively label cell surface receptors. Fluorescence microscopy and flow cytometry demonstrate that this dye does not cross the plasma membrane, binds with high affinity to a dL5** FAP-GPCR fusion construct, activating tagged surface receptors within seconds of addition. The ability to rapidly and selectively label cell surface receptors with a fluorogenic genetically encoded tag allows quantitative imaging and analysis of highly dynamic processes like receptor endocytosis and recycling. PMID- 25520060 TI - Success of a cervical cancer screening program: trends in incidence in songkhla, southern Thailand, 1989-2010, and prediction of future incidences to 2030. AB - BACKGROUND: Cervical cancer has been a leading female cancer in Thailand for decades, and has been second to breast cancer after 2007. The Ministry of Public Health (MoPH) has provided opportunistic screening with Pap smears for more than 30 years. In 2002, the MoPH and the National Health Security Office provided countrywide systematic screening of cervical cancer to all Thai women aged 35-60 years under universal health care coverage insurance scheme at 5-year intervals. OBJECTIVES: This study characterized the cervical cancer incidence trends in Songkhla in southern Thailand using joinpoint and age period cohort (APC) analysis to observe the effect of cervical cancer screening activities in the past decades, and to project cervical cancer rates in the province, to 2030. MATERIALS AND METHODS: Invasive and in situ cervical cancer cases were extracted from the Songkhla Cancer Registry from 1990 through 2010. Age standardized incidence rates were estimated. Trends in incidences were evaluated by joinpoint and APC regression models. The Norpred package was modified for R and was used to project the future trends to 2030 using the power of 5 function and cut trend method. RESULTS: Cervical cancer incidence in Songkhla peaked around 1998-2000 and then dropped by -4.7% per year. APC analysis demonstrated that in situ tumors caused an increase in incidence in early ages, younger cohorts, and in later years of diagnosis. CONCLUSIONS: Both joinpoint and APC analysis give the same conclusion in continuation of a declining trend of cervical cancer to 2030 but with different rates and the predicted goal of ASR below 10 or even 5 per 100,000 women by 2030 would be achieved. Thus, maintenance and improvement of the screening program should be continued. Other population based cancer registries in Thailand should analyze their data to confirm the success of cervical cancer screening policy of Thailand. PMID- 25520061 TI - Association of vitamin D receptor gene polymorphisms with prostate cancer risk in the Pakistani population. AB - BACKGROUND: Vitamin D receptor (VDR) gene has been a subject of extensive pharmacogenetic research recently. Association studies between different types of cancers including prostate cancer (PCa) and VDR gene polymorphism have also been conducted. The objective of this study was to find possible associations between PCa and VDR gene polymorphisms in the Pakistani population. MATERIALS AND METHODS: A total of 162 subjects, including prostate cancer patients and controls, were genotyped for Apa I, Taq I and Fok I polymorphisms in the VDR gene using allele specific PCR, PCR-RFLP and direct DNA sequencing. Allelic frequencies were tested for Hardy-Weinberg equilibrium and associations between the genetic markers and PCa were calculated using logistic regression. RESULTS: Apa I CC genotype was found to have strongest association with PCa risk, and "A" genotype was found to have protective effect. Fok I and Taq I did not have appreciable levels of association with PCa, although Taq I "TC" heterozygotes seemed to have some protective effect. Similarly the "C" allele of Fok I also seemed to have protective effect. CONCLUSIONS: To our knowledge, this is the first report showing association between VDR gene polymorphisms and PCa in Pakistan. Our findings may be somewhat skewed because of small sample size and tendency of consanguineous marriages in Pakistani society; nevertheless, it shows the trend of association and protective effects of certain VDR gene polymorphisms against PCa. PMID- 25520062 TI - Fentanyl increases colorectal carcinoma cell apoptosis by inhibition of NF-kappaB in a Sirt1-dependent manner. AB - BACKGROUND: Fentanyl is used as an analgesic to treat pain in a variety of patients with cancer and recently it has become considered to also act as an antitumor agent. The study present was designed to investigate the effects of fentanyl on colorectal cancer cell growth and plausible mechanisms. MATERIALS AND METHODS: The human colorectal carcinoma cell line HCT116 was subcutaneously injected into nude mice. The viability of HCT116 was tested by MTT assay, and apoptosis by flow cytometry and caspase-3 activity. The expression of Sirt1 and NF-kappaB were evaluated by Western blotting and the levels of Sirt1 and NF kappaB by fluorescence method. SiRNA was used to silence and Ad-Sirt1 to overexpress Sirt1. RESULTS: Our data showed that fentanyl could inhibit tumor growth, with increased expression of Sirt1 and down-regulation of Ac-p65 in tumors. Compared with control cells without treatment, HCT116 cells that were incubated with fentanyl had a higher apoptotic rate. Moreover, fentanyl could increase expression and activity of Sirt1 and inhibitor expression and activity of NF-kappaB, which might be mechanisms of fentanyl action. CONCLUSIONS: Fentanyl increased colorectal carcinoma cell apoptosis by inhibition of NF-kappaB activation in a Sirt1-dependent manner. PMID- 25520063 TI - Age of diagnosis of breast cancer in china: almost 10 years earlier than in the United States and the European union. AB - BACKGROUND: The study aimed to describe the age distribution of breast cancer diagnosis among Chinese females for comparison with the United States and the European Union, and provide evidence for the screening target population in China. MATERIALS AND METHODS: Median age was estimated from hospital databases from 7 tertiary hospitals in China. Population-based data in China, United States and European Union was extracted from the National Central Cancer Registry, SEER program and GLOBOCAN 2008, respectively. Age-standardized distribution of breast cancer at diagnosis in the 3 areas was estimated based on the World Standard Population 2000. RESULTS: The median age of breast cancer at diagnosis was around 50 in China, nearly 10 years earlier than United States and European Union. The diagnosis age in China did not vary between subgroups of calendar year, region and pathological characteristics. With adjustment for population structure, median age of breast cancer at diagnosis was 50~54 in China, but 55~59 in United States and European Union. CONCLUSIONS: The median diagnosis age of female breast cancer is much earlier in China than in the United States and the European Union pointing to racial differences in genetics and lifestyle. Screening programs should start at an earlier age for Chinese women and age disparities between Chinese and Western women warrant further studies. PMID- 25520064 TI - Risk of cancer mortality according to the metabolic health status and degree of obesity. AB - BACKGROUND: We investigated the risk of cancer mortality according to obesity status and metabolic health status using sampled cohort data from the National Health Insurance system. MATERIALS AND METHODS: Data on body mass index and fasting blood glucose in the sampled cohort database (n=363,881) were used to estimate risk of cancer mortality. Data were analyzed using a Cox proportional hazard model (Model 1 was adjusted for age, sex, systolic blood pressure, diastolic blood pressure, total cholesterol level and urinary protein; Model 2 was adjusted for Model 1 plus smoking status, alcohol intake and physical activity). RESULTS: According to the obesity status, the mean hazard ratios were 0.82 [95% confidence interval (CI), 0.75-0.89] and 0.79 (95% CI, 0.72-0.85) for the overweight and obese groups, respectively, compared with the normal weight group. According to the metabolic health status, the mean hazard ratio was 1.26 (95% CI, 1.14-1.40) for the metabolically unhealthy group compared with the metabolically healthy group. The interaction between obesity status and metabolic health status on the risk of cancer mortality was not statistically significant (p=0.31). CONCLUSIONS: We found that the risk of cancer mortality decreased according to the obesity status and increased according to the metabolic health status. Given the rise in the rate of metabolic dysfunction, the mortality from cancer is also likely to rise. Treatment strategies targeting metabolic dysfunction may lead to reductions in the risk of death from cancer. PMID- 25520065 TI - Tobacco use, beliefs and risk awareness in university students from 24 low, middle and emerging economy countries. AB - The aim of this study was to determine the prevalence of tobacco use, beliefs and risk awareness and psychosocial correlates of tobacco use among university students in 24 low, middle and emerging economy countries. Using anonymous questionnaires, data were collected from 16953 undergraduate university students (mean age 20.9, SD=2.9) from 25 universities in 24 countries across Asia, Africa and the Americas. Results indicate that overall 13.3% of the university students were current tobacco users, 22.4% for men and 6.6% for women, ranging from 3.8% in Singapore to 32.5% in Cameroon. The risk awareness of the smoking lung cancer link was 83.6%, while the risk awareness of the smoking heart disease link was 46.5%. Multivariate logistic regression found that older age, male gender, having a wealthy family background, living in a low income country, residing off campus on their own, poor beliefs in the importance not to smoke, awareness of the smoking heart disease link, hit by a sexual partner, depressive symptoms, and substance use (binge drinking and illicit drug use) were associated with current tobacco use. PMID- 25520067 TI - MiRNA molecular profiles in human medical conditions: connecting lung cancer and lung development phenomena. AB - MiRNAs are endogenous, single stranded ~22-nucleotide non-coding RNAs (ncRNAs) which are transcribed by RNA polymerase II and mediate negative post transcriptional gene regulation through binding to 3'untranslated regions (UTR), possibly open reading frames (ORFs) or 5'UTRs of target mRNAs. MiRNAs are involved in the normal physiology of eukaryotic cells, so dysregulation may be associated with diseases like cancer, and neurodegenerative, heart and other disorders. Among all cancers, lung cancer, with high incidence and mortality worldwide, is classified into two main groups: non-small cell lung cancer and small cell lung cancer. Recent promising studies suggest that gene expression profiles and miRNA signatures could be a useful step in a noninvasive, low-cost and repeatable screening process of lung cancer. Similarly, every stage of lung development during fetal life is associated with specific miRNAs. Since lung development and lung cancer phenomena share the same physiological, biological and molecular processes like cell proliferation, development and shared mRNA or expression regulation pathways, and according to data adopted from various studies, they may have partially shared miRNA signature. Thus, focusing on lung cancer in relation to lung development in miRNA studies might provide clues for lung cancer diagnosis and prognosis. PMID- 25520066 TI - Diagnostic accuracy of ultrasonography in differentiating benign and malignant thyroid nodules using fine needle aspiration cytology as the reference standard. AB - BACKGROUND: In Pakistan thyroid cancer is responsible for 1.2% cases of all malignant tumors. Ultrasonography (US) is helpful in detecting cancerous thyroid nodules on basis of different features like echogenicity, margins, microcalcifications, size, shape and abnormal neck lymph nodes. We therefore aimed to calculate diagnostic accuracy of ultrasound in detection of carcinoma in thyroid nodules taking fine needle aspiration cytology as the reference standard. MATERIALS AND METHODS: A cross-sectional analytical study was designed to prospectively collect data from December 2010 till December 2012 from the Department of Radiology in Aga Khan University Hospital, Karachi, Pakistan. A total of 100 patients of both genders were enrolled after informed consent via applying non-probability consecutive sampling technique. Patients referred to Radiology department of Aga Khan University to perform thyroid ultrasound followed by fine-needle aspiration cytology of thyroid nodules were included. They were excluded if proven for thyroid malignancy or if their US or FNAC was conducted outside our institution. RESULTS: The subjects comprised 76 (76%) females and 24 males. Mean age was 41.8+/-SD 12.3 years. Sensitivity and specificity with 95%CI of ultrasound in differentiating malignant thyroid nodule from benign thyroid nodule calculated to be 91.7% (95%CI, 0.72-0.98) and 78.94% (0.68-0.87) respectively. Reported positive predictive value and negative PV were 57.9% (0.41-0.73) and 96.8% (0.88-0.99) and overall accuracy was 82%. Likelihood ratio (LR) positive was computed to be 4.3 and LR negative was 0.1. CONCLUSIONS: Ultrasonography has a high diagnostic accuracy in detecting malignancy in thyroid nodules on the basis of features like echogenicity, margins, micro calcifications and shape. PMID- 25520068 TI - Are beta blockers new potential anticancer agents? AB - beta-Blockers have been one of the most widely used and versatile drugs for the past half a century. A new potential for their use as anti-cancer drugs has emerged in the past few years. Various retrospective case control studies have been suggestive that use of beta-blockers before the diagnosis of cancer could have preventive and protective effects against non-small cell lung carcinoma, melanoma, and breast, pancreatic and prostate cancers. Experimental and clinical observations are still inconclusive with some inconsistent findings. However, indications are pointing toward a positive role of some beta-blockers against certain forms of cancers. This mini review is an effort to present the up to date published results of case-control studies and experimental findings. PMID- 25520069 TI - Epidemiology, etiology, diagnosis and treatment of prostate cancer. AB - Prostate cancer is more common in men over the age of 65 years. There are 15% cases with positive family history of prostate cancer Worldwide. Prostate cancer is the second leading cause of death among the U.S. men. Prostate cancer incidence is strongly related to age with the highest rates in older man. Globally millions of people are suffering from this disease. This study aims to provide awareness about prostate cancer as well as an updated knowledge about the epidemiology, etiology, diagnosis and treatment of prostate cancer. PMID- 25520070 TI - Overweight, obesity, oxidative stress and the risk of breast cancer. AB - There is growing scientific evidence linking excess body weight to breast cancer risk. However, there is no common consensus on this relation due partly to methodologies used, populations studied and the cancer subtype. We report here a summary of the present state of knowledge on the role of overweight and obesity in pathogenesis of breast cancer and possible mechanisms through which excess body weight might influence the risk, focusing on the role of oxidative stress in breast cancer etiology. The findings demonstrate duality of excess body weight action in dependence on menopausal status: a statistically significant increased risk in postmenopausal overweight/ obese women and non-significant preventive effect among premenopausal women. Due to several gaps in the literature on this topic, additional studies are needed. Future research should address factors influencing the excess body weight - breast cancer relationship, such as race/ethnicity, tumor subtype, receptor status, the most appropriate measure of adiposity, reproductive characteristics, and lifestyle components. PMID- 25520071 TI - Olanzapine for preventing nausea and vomiting induced by moderately and highly emetogenic chemotherapy. AB - Nausea and vomiting are common adverse events in chemotherapy. In spite of the serious effects on the quality of life and further treatment, they remain overlooked by physicians, and no standard treatment has been developed. Neurokinin-1 (NK-1) receptor antagonists and palonosetron are the major agents in the standard regimen for treating moderately and highly emetogenic chemotherapy induced nausea and vomiting (CINV). However, NK-1 receptor antagonists first became commercially available at the end of 2013 and palonosetron has not been extensively applied in China. Olanzapine was recommended as a therapy for moderate and severe CINV in antiemesis-clinical practice guidelines in oncology in 2014 for the first time. It is an atypical antipsychotic agent, which can block multiple receptors on neurotransmitters. During more than 10 years, olanzapine has demonstrated significant effects in preventing CINV and treating breakthrough and refractor CINV, which was observed in case reports, precise retrospective studies, and phase I, II and III clinical trials, with no grade 3 to 4 adverse events. In particular, it is superior to aprepitant and dexamethasone in delayed nausea and vomiting. Therefore, this compound is worthy of further investigation. PMID- 25520073 TI - Evaluation of treatment outcomes of early-stage endometrial cancer radiotherapy: a single center experience. AB - BACKGROUND: Postoperative adjuvant radiotherapy (RT) in the management of early stage endometrial cancer (EC) is still controversial. Here we report our institutional experience with patients who received postoperative RT for stage I II EC over a period of 35 years and assess potential predictors of local recurrence (LR), distant metastasis (DM), and overall survival (OS). MATERIALS AND METHODS: A total of 188 patients undergoing postoperative RT for stage IA-II EC between 1977 and 2012 were evaluated. Some 96 received median 46 Gy whole pelvic radiotherapy (WPRT) (range: 40-60 Gy), 37 were given WPRT with vaginal cuff therapy (VCT), and 55 received only VCT either with brachytherapy (BT) or stereotactic body radiotherapy (SBRT). Chemotherapy was given to 5 patients with uterine papillary serous carcinoma (UPSC). Logistic regression analysis was used to assess the effect of clinicopathological factors on LR, DM, and OS. RESULTS: Median follow-up time was 11 years (range: 1-35 years). At the time of analysis, 34 patients were not alive. Of the 15 patients with LR, 7 (46.7%) recurred in the vaginal stump, 5 (33.3%) in the pelvic region, and 3 (20%) in the paraaortic nodal region, while 12 had distant metastasis. UPSC histology (p=0.027), sole VCT (p=0.041), high histologic grade (p=0.034), and age>=71 (p=0.04) were poor prognostic factors on univariate analysis. CONCLUSIONS: In our patients receiving radiotherapy for early-stage EC, grade III disease and age>=71 were associated with shorter OS whereas UPSC histology was an independent predictor for both LR and DM. PMID- 25520072 TI - Ursolic acid promotes apoptosis of SGC-7901 gastric cancer cells through ROCK/PTEN mediated mitochondrial translocation of cofilin-1. AB - Ursolic acid, extracted from the traditional Chinese medicine bearberry, can induce apoptosis of gastric cancer cells. However, its pro-apoptotic mechanism still needs further investigation. More and more evidence demonstrates that mitochondrial translocation of cofilin-1 appears necessary for the regulation of apoptosis. Here, we report that ursolic acid (UA) potently induces the apoptosis of gastric cancer SGC-7901 cells. Further mechanistic studies revealed that the ROCK1/PTEN signaling pathway plays a critical role in UA-mediated mitochondrial translocation of cofilin-1 and apoptosis. These findings imply that induction of apoptosis by ursolic acid stems primarily from the activation of ROCK1 and PTEN, resulting in the translocation of cofilin-1 from cytoplasm to mitochondria, release of cytochrome c, activation of caspase-3 and caspase-9, and finally inducing apoptosis of gastric cancer SGC-7901 cells. PMID- 25520074 TI - Polymorphism of p53 gene codon 72 in endometrial cancer: correlation with tumor grade and histological type. AB - BACKGROUND: Endometrial cancer is the fourth most common cancer among women in developed countries. Patients with endometrial cancer may benefit from systemic chemotherapy alone or in combination with targeted therapies if the disease is clinically diagnosed prior to spread and metastasis to other organs. The aim of this study was to evaluate the prognostic role of p53 polymorphism and its correlation with tumor grade in human uterine endometrial carcinomas. MATERIALS AND METHODS: A total of 75 patients with endometrial carcinomas were studied for possible mutations in exon 4 of the p53 gene using polymerase chain reaction and restricting fragment length polymorphism techniques and sequencing. RESULTS: In recent study, The rate of homozygote genotype of pro/pro or Arg/Arg in high grade group was higher than in comparison with low grade one. In addition samples that were undigested in RFLP, showed mutation in exone 4. CONCLUSIONS: Our findings showed that high grade endometrial carcinomas are highly associated with TP53 polymorphisms in comparison with low grades. PMID- 25520075 TI - BRCA1 promoter hypermethylation signature for early detection of breast cancer in the Vietnamese population. AB - Breast cancer, a leading cause of death among women in most countries worldwide, is rapidly increasing in incidence in Vietnam. One of biomarkers is the disruption of the genetic material including epigenetic changes like DNA methylation. With the aim of finding hypermethylation at CpG islands of promoter of BRCA1 gene, belonged to the tumor suppressor gene family, as the biomarker for breast cancer in Vietnamese population, sensitive methyl specific PCR (MSP) was carried out on 115 samples including 95 breast cancer specimens and 20 normal breast tissues with other diseases which were obtained from Ho Chi Minh City Medical Hospital, Vietnam. The result indicated that the frequency of BRCA1 hypermethylation reached 82.1% in the cases (p<0.001). In addition, the DNA hypermethylation of this candidate gene increased the possibility to be breast cancer with high incidence via calculated odd ratios (p<0.05). In conclusion, hypermethylation of this candidate gene could be used as the promising biomarker application with Vietnamese breast cancer patients. PMID- 25520076 TI - Clinical utility of haptoglobin in combination with CEA, NSE and CYFRA21-1 for diagnosis of lung cancer. AB - PURPOSE: To investigate the clinical value in lung cancer of a combination of four serum tumor markers, haptoglobin (Hp), carcinoembryonic antigen (CEA), neuron specific enolase (NSE) as well as the cytokeratin 19 fragment (CYFRA21-1). MATERIALS AND METHODS: Serum Hp (with immune-turbidimetric method), CEA, NSE, CYFRA21-1 (with chemiluminescence method) level were assessed in 193 patients with lung cancer, 87 patients with benign lung disease and 150 healthy controls. Differences of expression were compared among groups, and joint effects of these tumor markers for the diagnosis of lung cancer were analyzed. RESULTS: Serum tumor marker levels in patients with lung cancer were obviously higher than those with benign lung disease and normal controls (p<0.01). The sensitivities of Hp, CEA, NSE and CYFRA21-1 were 43.5%, 40.9%, 23.3% and 41.5%, with specificities of 90.7%, 99.2%, 97.9% and 97.9%. Four tumor markers combined together could produce a positive detection rate of 85.0%, significantly higher than that of any single test. With squamous carcinomas, the positive detection rates with Hp and CYFRA21 1 were higher than that of other markers. In the adenocarcinoma case , the positive detection rate of CEA was higher than that of other markers. For small cell carcinomas, the positive detection rate of NSE was highest. The area under receiver operating characteristic curve (AUCROC) of Hp in squamous carcinoma (0.805) was higher than in adenocarcinoma (0.664) and small cell carcinoma (0.665). CONCLUSIONS: Hp can be used as a new serum tumor marker for lung cancer. Combination detection of Hp, CEA, NSE and CYFRA21-1 could significantly improve the sensitivity and specificity in diagnosis of lung cancer, and could be useful for pathological typing. PMID- 25520077 TI - Lack of prognostic value of human epidermal growth factor-like receptor 2 status in inflammatory breast cancer (IBC): a meta-analysis. AB - Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer which is more likely to be her-2/ neu amplified. While the her-2/neu status has been utilised to predict prognosis, the published data are inconsistent. The present meta-analysis was conducted to determine whether the her-2/neu status predicts outcomes. Papers were selected from the PubMed database based on defined inclusion and exclusion criteria. Parameters such as total patients, follow-up time and outcome statistics (i.e. overall survival (OS), relapse-free survival (RFS) were collected. The analysis included 6 studies with 2,838 IBC patients. The summary hazards ratio (HR) estimating the association of OS with HER-2 positive disease was 0.96 (95% confidence interval (95%CI: 0.85-1.10)), with similar findings for RFS (HR=0.81, 95%CI: 0.61-1.09). No obvious statistical heterogeneity was detected. This meta-analysis suggests that HER-2-positive status is not an independent adverse prognostic factor for survival among IBC patient cases. PMID- 25520078 TI - XRCC3 Thr241Met gene polymorphism and risk of colorectal cancer in Kashmir: a case control study. AB - XRCC (X-ray cross-complementing group) genes contribute to important DNA repair mechanisms that play roles in the repair of single strand breaks (SSBs) induced by a variety of external and internal factors, including ionizing radiation, alkylating agents and reactive oxygen species. These repair genes have a pivotal role in maintaining genomic stability through different pathways of base excision repair (BER). The aim of this study was to investigate the XRCC3 Thr241Met gene polymorphism in colorectal cancer (CRC) in Kashmir. We investigated the genotype distribution of XRCC3 gene in 120 CRC cases in comparison with 150 healthy subjects and found a significant association between XRCC3 genotypes and CRC (p<=0.05). Both heterozygous genotype (Thr/Met) as well as homozygous variant genotype (Met/Met) were moderately associated with elevated risk of CRC [OR=2.53; OR=2.29 respectively]. Also, Thr/Met and Met/Met genotypes demonstrated a significant association with the risk of CRC (p=0.003). This study displayed a significantly elevated risk for CRC in individuals with XRCC3 Thr/Met and Met/Met Genotype of about 2.5 times that with the Thr/Thr wild genotype. PMID- 25520079 TI - Efficacy of aprepitant for nausea in patients with head and neck cancer receiving daily cisplatin therapy. AB - BACKGROUND: Although efficacy of aprepitant for suppressing emesis associated with single-dose cisplatin has been demonstrated, there are limited data on the antiemetic effect of this oral neurokinin-1 receptor antagonist during daily administration of cisplatin. Accordingly, we investigated the efficacy and safety of aprepitant in patients with head and neck cancer (HNC) receiving combination therapy with cisplatin and 5-FU (FP therapy). MATERIALS AND METHODS: Twenty patients with HNC were prospectively studied who received a triple antiemetic regimen comprising granisetron (40 MUg/kg on Days 1-4), dexamethasone (8 mg on Days 1-4), and aprepitant (125 mg on day 1 and 80 mg on days 2-5) with FP therapy (cisplatin 20 mg/m2 on days 1-4; 5-FU 400 mg/m2 on days 1-5) (aprepitant group). We also retrospectively studied another 20 HNC patients who received the same regimen except for aprepitant (control group). RESULTS: For efficacy endpoints based on nausea, the aprepitant group showed significantly better results, including a higher rate of complete response (no vomiting and no salvage therapy) for the acute phase (p=0.0342), although there was no marked difference between the two groups with regard to percentage of patients in whom vomiting was suppressed. There were no clinically relevant adverse reactions to aprepitant. CONCLUSIONS: This study suggested that a triple antiemetic regimen containing aprepitant is safe and effective for HNC patients receiving daily cisplatin therapy. PMID- 25520080 TI - Variables that affect the satisfaction of Brazilian women with external breast prostheses after mastectomy. AB - BACKGROUND: : In 2012, the breast cancer estimate worldwide stood at 1.67 million new cases, these accounting for 25% of all types of cancer diagnosed in women. For 2014, 57,120 new cases are expected, with a risk estimated at 56.1 cases for every 100,000 women. The objective of this study was to analyze the satisfaction regarding the use of external breast prostheses by women undergoing mastectomy. MATERIALS AND METHODS: This cross-sectional study was conducted with 76 women who used an external breast prosthesis (EBP), registered in the services of the Cuiaba Center for Comprehensive Rehabilitation, Mato Grosso, Brazil, from 2009 to 2012. Data were collected from the records of women who had requested the opening of a process of external breast prosthesis concession. RESULTS: Satisfaction with the EBP was identified in 56.6% of the women. Those satisfied with the EBP reported that its weight was not annoying (p<0.01). Although the women felt body sensations of stitches, pains, pulling, dormancy and phantom limb, they are satisfied with the EBP. The variable related to the displacement of the breast prosthesis during activity of everyday life has demonstrated that even though the women have reported the possibility of displacements, they are satisfied with the EBP. The satisfaction with the use of external breast prosthesis did not affect the sexuality of the women with mastectomy. CONCLUSIONS: Learning the specificities of the EBP, taking into consideration the satisfaction of its use, allows the rehabilitation team, by listening to their clientele more attentively, following up this woman throughout her life journey, supporting and guiding the best way of use, with an eye to her personal, emotional and social life, as well as to her self-esteem. PMID- 25520081 TI - Hepatitis B virus DNA negativity acts as a favorable prognostic factor in hepatocellular carcinoma patients. AB - BACKGROUND: This retrospective study was aimed to investigate the efficacy of prophylactic agents in hepatocellular carcinoma (HCC) patients receiving TACE and compare the difference between lamivudine and entecavir. MATERIALS AND METHODS: A consecutive series of 203 HBV-related HCC patients receiving TACE were analyzed including 91 patients given prophylactic agents. Virologic events, defined as an increase in serum HBV DNA level to more than 1 log10 IU/ml higher than the nadir level, hepatitis flares due to HBV reactivation and progression free survival (PFS) were the main endpoints. RESULTS: Some 48 (69.6%) reached virologic response. Prophylaxis significantly reduced virologic events (8.8% vs 58.0%, p=0.000) and hepatitis flares (1.1% vs 13.4%, p=0.001). Patients presenting undetectable HBV DNA levels displayed a significantly improved PFS as compared to those who never achieved undetectable HBV DNA. Prophylaxis and e-antigen positivity were the only significant variables associated with virologic events. In addition, prophylaxis was the only independent protective factor for hepatitis flares. Liver cirrhosis, more cycles of TACE, HBV DNA negativity, a lower Cancer of the Liver Italian Program score, non-metastasis and no hepatitis flares were protective factors for PFS. Prophylactic lamivudine demonstrated similar efficacy as entecavir. CONCLUSIONS: Prophylactic agents are efficacious for prevention of HBV reactivation in HCC patients receiving TACE. Achievement of undetectable HBV DNA levels displayed a significant capability in improving PFS. Moreover, persistent tumor residual lesions, positive HBV DNA and hepatitis B flares might be causes of tumor progression in these patients. PMID- 25520082 TI - Updated meta-analysis on HER2 polymorphisms and risk of breast cancer: evidence from 32 studies. AB - BACKGROUND: Several studies have been performed to investigate the association of the HER2 Ile655Val polymorphism and breast cancer risk. However, the results were inconsistent. To understand the precise relationship, a meta-analysis was here conducted. MATERIALS AND METHODS: A search of PubMed conducted to investigate links between the HER2 Ile655Val polymorphism and breast cancer, identified a total of 32 studies, of which 29, including 14,926 cases and 15,768 controls, with odds ratios (ORs) with 95% confidence intervals were used to assess any association. RESULTS: In the overall analysis, the HER2 Ile655Val polymorphism was associated with breast cancer in an additive genetic model (OR=1.136, 95% CI 1.043-1.239, p=0.004) and in a dominant genetic (OR=1.118, 95% CI 1.020-1.227, p=0.018), while no association was found in a recessive genetic model. On subgroup analysis, an association with breast cancer was noted in the additive genetic model (OR=1.111, 95% CI: 1.004-1.230, p=0.042) for the Caucasian subgroup. No significant associations were observed in Asians and Africans in any of the genetic models. CONCLUSIONS: In summary, our meta-analysis findings suggest that the HER2 Ile655Val polymorphism is marginally associated with breast cancer susceptibility in worldwide populations with additive and dominant models, but not a recessive model. PMID- 25520083 TI - High rate of advanced colorectal polyps in a 10-year-long retrospective study in Qazvin, Iran. AB - BACKGROUND: Polyps are common lesions in the gastrointestinal (GI) tract. Colon cancer is mostly a result of progression from polyps. The present study aimed to evaluate demographic, clinical, and histological characteristics of colorectal polyps in Iran, particularly neoplastic and advanced types. MATERIALS AND METHODS: Over a period of 10 years, specimens of all colorectal polyps obtained from colonoscopy were studied. The variables subjected to statistical analysis were age, sex, and the chief clinical complaint of the patients who underwent colonoscopy, their motivation, and the site, size, and histological types of detected polyps. The level of significance was set at p value<0.05. RESULTS: Data were obtained from a total of 352 patients. No difference was seen between male and female patients regarding histological types. Only in nine patients was screening the reason for colonoscopy. Almost two-thirds (66.2%) of the polyps were neoplastic. Familial polyposis syndrome and inflammatory bowel disease were seen in 4.3% and 3.0% of the patients with neoplastic polyps, respectively. Sites of polyps were the sigmoid, rectum, and descending colon in 40.1%, 34.5%, and 17% of the cases, respectively. The advanced type made up 58.8% of neoplastic polyps. Only 3.6% of the patients undergoing colonoscopy in the study period had biopsied polyps. DISCUSSION: No difference was observed between male and female patients in terms of overall incidence of polyps, histological and anatomical profiles, and mean age distribution. Anatomical and histological profiles agreed with the studies performed in areas with a low risk of colon cancer. The findings show that colonoscopy was not performed when it was necessary. A meaningful increase in the number polyp biopsy cases and a corresponding decrease in polyp size in the last few years of the study can be associated with the presence of more GI specialist clinicians in hospital centers, and this holds out much hope for the further improvement of the situation in the future. PMID- 25520084 TI - Roles of p53 and caspases in induction of apoptosis in MCF- 7 breast cancer cells treated with a methanolic extract of Nigella sativa seeds. AB - BACKGROUND: Nigella Sativa (NS) is an herb from the Ranunculaceae family that exhibits numerous medicinal properties and has been used as important constituent of many complementary and alternative medicines (CAMs). The ability of NS to kill cancer cells such as PC3, HeLa and hepatoma cells is well established. However, our understanding of the mode of death caused by NS remains nebulous. The objective of this study was to gain further insight into the mode and mechanism of death caused by NS in breast cancer MCF-7 cells. MATERIALS AND METHODS: Human breast cancer cells (MCF-7) were treated with a methanolic extract of NS, and a dose- and time-dependent study was performed. The IC50 was calculated using a Cell Titer Blue(r) viability assay assay, and evidence for DNA fragmentation was obtained by fluorescence microscopy TUNEL assay. Gene expression was also profiled for a number of apoptosis-related genes (Caspase-3, -8, -9 and p53 genes) through qPCR. RESULTS: The IC50 of MCF-7 cells was 62.8 MUL/mL. When MCF-7 cells were exposed to 50 MUL/mL and 100 MUL/mL NS for 24 h, 48 h and 72 h, microscopic examination (TUNEL assay) revealed a dose- and time-dependent increase in apoptosis. Similarly, the expression of the Caspase-3, -8, -9 and p53 genes increased significantly according to the dose and time. CONCLUSIONS: NS induced apoptosis in MCF-7 cells through both the p53 and caspase pathways. NS could potentially represent an alternative source of medicine for breast cancer therapy. PMID- 25520085 TI - Prognostic value of PLCE1 expression in upper gastrointestinal cancer: a systematic review and meta-analysis. AB - BACKGROUND: A number of studies have identified a shared susceptibility locus in phospholipase C epsilon 1 (PLCE1) for esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinomas (GCA). However, the results of PLCE1 expression in esophageal and gastric cancer remain inconsistent and controversial. Moreover, the effects on clinicopathological features remain undetermined. This study aimed to provide a precise quantification of the association between PLCE1 expression and the risk of ESCC and GCA through meta analysis. MATERIALS AND METHODS: Eligible studies were identified from PubMed, Wanfang Data, ISI Web of Science, and the Chinese National Knowledge Infrastructure databases. Using RevMan5.2 software, pooled odds ratios (ORs) with 95% confidence intervals (CIs) were employed to assess the association of PLCE1 expression with clinicopathological features relative to ESCC or GCA. RESULTS: Seven articles were identified, including 761 esophageal and gastric cancer cases and 457 controls. Overall, we determined that PLCE1 expression was associated with tumor progression in both esophageal cancers (pooled OR=5.93; 95%CI=3.86 to 9.11) and gastric cancers (pooled OR=9.73; 95%CI=6.46 to 14.7). Moreover, invasion depth (pooled OR=3.62; 95%CI=2.30 to 5.70) and lymph node metastasis (pooled OR=4.21; 95%CI=2.69 to 6.59) were linked with PLCE1 expression in gastric cancer. However, no significant associations were determined between PLCE1 overexpression and the histologic grade, invasion depth, and lymph node metastasis in esophageal cancer. CONCLUSIONS: Our meta- analysis results indicated that upregulated PLCE1 is significantly associated with an increased risk of tumor progression in ESCC and GCA. Therefore, PLCE1 expression can be appropriately regarded as a promising biomarker for ESCC and GCA patients. PMID- 25520086 TI - Combination doxorubicin and interferon-alpha therapy stimulates immunogenicity of murine pancreatic cancer Panc02 cells via up-regulation of NKG2D ligands and MHC class I. AB - BACKGROUND: Pancreatic adenocarcinoma is a malignant gastrointestinal cancer with significant morbidity and mortality. Despite severe side effects of chemotherapy, the use of immunotherapy combined with chemotherapy has emerged as a common clinical treatment. In this study, we investigated the efficacy of the combined doxorubicin and interferon-alpha (IFN-alpha) therapy on murine pancreatic cancer Panc02 cells in vitro and in vivo and underlying mechanisms. MATERIALS AND METHODS: A Panc02-bearing mouse model was established to determine whether doxorubicin and interferon-alpha (IFN-alpha) could effectively inhibit tumor growth in vivo. Cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) was evaluated using a standard LDH release assay. To evaluate the relevance of NK cells and CD8 T cells to the combination therapy-mediated anti-tumor effects, they were depleted in tumor-bearing mice by injecting anti asialo-GM-1 antibodies or anti-CD8 antibodies, respectively. Finally, the influence of doxorubicin+interferon-alpha (IFN-alpha) on the ligands of NK and T cells was assessed by flow cytometry. RESULTS: The combination therapy group demonstrated a significant inhibition of growth of Panc02 in vivo, resulting from activated cytotoxicity of NK cells and CTLs. Depleting CD8 T cells or NK cells reduced the anticancer effects mediated by immunochemotherapy. Furthermore, the doxorubicin+IFN-a treatment increased the expression of major histocompatibility complex class I (MHC I) and NKG2D ligands on Panc02 cells, suggesting that the combined therapy may be a potential strategy for enhancing immunogenicity of tumors. All these data indicate that the combination therapy using doxorubicin and interferon-alpha (IFN-alpha) may be a potential strategy for treating pancreatic adenocarcinoma. PMID- 25520087 TI - Exploring factors related to metastasis free survival in breast cancer patients using Bayesian cure models. AB - BACKGROUND: Breast cancer is a fatal disease and the most frequently diagnosed cancer in women with an increasing pattern worldwide. The burden is mostly attributed to metastatic cancers that occur in one-third of patients and the treatments are palliative. It is of great interest to determine factors affecting time from cancer diagnosis to secondary metastasis. MATERIALS AND METHODS: Cure rate models assume a Poisson distribution for the number of unobservable metastatic-component cells that are completely deleted from the non-metastasis patient body but some may remain and result in metastasis. Time to metastasis is defined as a function of the number of these cells and the time for each cell to develop a detectable sign of metastasis. Covariates are introduced to the model via the rate of metastatic-component cells. We used non-mixture cure rate models with Weibull and log-logistic distributions in a Bayesian setting to assess the relationship between metastasis free survival and covariates. RESULTS: The median of metastasis free survival was 76.9 months. Various models showed that from covariates in the study, lymph node involvement ratio and being progesterone receptor positive were significant, with an adverse and a beneficial effect on metastasis free survival, respectively. The estimated fraction of patients cured from metastasis was almost 48%. The Weibull model had a slightly better performance than log-logistic. CONCLUSIONS: Cure rate models are popular in survival studies and outperform other models under certain conditions. We explored the prognostic factors of metastatic breast cancer from a different viewpoint. In this study, metastasis sites were analyzed all together. Conducting similar studies in a larger sample of cancer patients as well as evaluating the prognostic value of covariates in metastasis to each site separately are recommended. PMID- 25520088 TI - Evaluation of health-related quality of life for hypothesized medical states associated with cervical cancer. AB - BACKGROUND: When evaluating health-economics for cervical cancer prevention policies in Japan, it is important to use Japanese value settings. This study aimed to obtain preference-based measures (preference measures) for hypothesized health states among healthy Japanese women, and to examine differences between the EuroQol-5D (EQ-5D) and standard gamble (SG) instruments. MATERIALS AND METHODS: The investigation was performed among female students at a nursing university. We used written hypothetical scenarios describing three grades of cervical intraepithelial neoplasia (CIN) and eight stages of cervical cancer, both at diagnosis and after medical intervention. Preference measures were evaluated using both EQ-5D and SG. RESULTS: We received responses from 136 women. The mean number of respondents per stage was 24.6 (SD: 2.7). At diagnosis, average EQ-5D scores for CIN1, CIN2, CIN3, IA1, IA2, IB1, IB2, IIA, IIB, III, and IV stages were 0.84 (0.14), 0.78 (0.12), 0.73 (0.10), 0.78 (0.12), 0.72 (0.12), 0.63 (0.13), 0.64 (0.12), 0.68 (0.08), 0.62 (0.13), 0.55 (0.21), and 0.18 (0.24), respectively. Using one-way analysis of variance with the Tukey-Kramer method for multiple comparisons (each stage vs. CIN1), we found significant differences for IB1 and more advanced stages (p<0.05). After medical intervention, corresponding EQ-5D scores were 0.84 (0.12), 0.81 (0.12), 0.84 (0.12), 0.80 (0.15), 0.78 (0.11), 0.64 (0.15), 0.63 (0.15), 0.71 (0.15), 0.50 (0.17), 0.52 (0.17), 0.21 (0.28). The multiple comparisons identified significant differences for IB1 and more advanced stages, excepting IIA (p<0.05). SG evaluations were more variable and relatively higher than EQ-5D evaluations. CONCLUSIONS: We obtained preference measures for three grades of CIN1-3 and eight stages of cervical cancer. In combination with appropriate sensitivity analyses, these preference measures will provide a basis for an economic evaluation of cervical cancer prevention in Japan. We suggest that EQ-5D is appropriate for cost-utility analysis of this topic. PMID- 25520089 TI - Prognostic factors and adjuvant treatments for surgically treated cancers of the biliary tract: a multicentre study of the Anatolian Society of Medical Oncology (ASMO). AB - BACKGROUND: Biliary tract cancers are rare, and surgical resection is the standard treatment at early stages. However, reports on the benefits of adjuvant treatment following surgical resection are conflicting. This study aimed to evaluate the factors affecting survival and adjuvant treatments in patients with surgically treated biliary tract cancers. MATERIALS AND METHODS: Patient clinical features, adjuvant treatments, and efficacy and prognostic factor data were evaluated. Survival analyses were performed using SPSS 15.0. RESULTS: The median overall survival was 30.7 months (95% confidence interval [CI], 18.4-42.9 months). Median survival was 19 months (95% CI, 6-33) for patients treated with fluorouracil based chemotherapy and 53 months (95% CI, 33.2-78.8) with gemcitabine based chemotherapy (p=0.033). On univariate analysis, poor prognostic factors for survival were galbladder localization, perineural invasion, hepatic invasion, a lack of adjuvant chemoradiotherapy treatment, and a lack of lymph node dissection. On multivariate analysis, perineural invasion was a poor prognostic factor (p=0.008). CONCLUSIONS: Biliary tract cancers generally have poor prognoses. The main factors affecting survival are tumour localization, perineural invasion, hepatic invasion, adjuvant chemoradiotherapy, and lymph node dissection. Gemcitabine-based adjuvant chemotherapy is more effective than 5 fluorouracil-based chemotherapy. PMID- 25520090 TI - Lack of association of the cyclooxygenase-2 gene 8473T>C polymorphism with breast cancer risk: a meta-analysis. AB - BACKGROUND: Associations between the 8473T>C polymorphism (rs5275) in the cyclooxygenase-2 (COX-2) gene and breast cancer (BC) risk are still inconclusive and ambiguous. The aim of this meta-analysis was to comprehensively estimate the genetic risk of 8473T>C polymorphism in the COX-2 gene for BC. MATERIALS AND METHODS: We searched PubMed, Web of Science, Medline, Chinese biomedical (CBM), Weipu, China national knowledge infrastructure (CNKI), and Wanfang databases, covering all publications (last search was updated on Aug 17, 2014). Statistical analyses were performed using Revman 5.3 and STATA 10.0 software. RESULTS: A total of 6,720 cases and 9,794 controls in 12 studies were included in this study. The results indicated no significant associations between the 8473T>C polymorphism of the COX-2 gene and BC risk for the CC+TC vs TT model (pooled odds ratio (OR)=0.97, 95% confidence interval (CI)=0.90-1.03, and p=0.29). On subgroup analysis, we also found that subdivision on ethnicity among Caucasians, Asians and others also revealed no relationship with BC susceptibility. With the study design (CC+TC vs TT), no significant associations were found in either population based case-control studies (PCC), or hospital-based case-control studies (HCC). CONCLUSIONS: This present meta-analysis suggests that the 8473T>C polymorphism in the COX-2 gene is not a conspicuous low- penetrant risk factor for developing BC. PMID- 25520091 TI - The XPD Lys751Gln polymorphism has predictive value in colorectal cancer patients receiving oxaliplatin-based chemotherapy: a systemic review and meta-analysis. AB - BACKGROUND: The predictive value of the xeroderma pigmentosum group D (XPD) Lys751Gln polymorphism regarding clinical outcomes of patients with colorectal cancer (CRC) receiving oxaliplatin-based chemotherapy has been evaluated in numerous published studies, but the results remain inconclusive. Therefore, we performed a meta-analysis to determine the precise role of the XPD Lys751Gln polymorphism in this clinical situation and optimize individual chemotherapy. MATERIALS AND METHODS: A multiple search strategy was used to identify eligible studies. Pooled odds ratios (ORs), generalized odds ratio (ORG) and their 95% confidence intervals (CIs) were used to estimate the objective response, while hazard ratios (HRs) with 95%CIs were used for progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 17 studies including 2,286 patients met the inclusion criteria. Overall, the XPD 751Gln allele was associated with a non-significant reduced objective response to oxaliplatin-based chemotherapy in all patients or in the Asian and Caucasian subgroups. However, poor PFS and OS of CRC patients treated with oxaliplatin-based regimens were significantly related to the XPD 751Gln allele in the dominant model (PFS: HR=2.10, 95%CI: 1.65-2.67; OS: HR=3.18, 95%CI: 1.57-6.47). On stratified analysis by ethnicity, these relationships were more pronounced in Asians (PFS: HR=2.49, 95%CI: 1.79-3.47; OS: HR=5.25, 95%CI: 3.46-7.94) than in Caucasians (PFS: HR=1.73, 95%CI: 1.22-2.46; OS: HR=1.78, 95%CI: 1.06-2.99). CONCLUSIONS: The XPD Lys751Gln polymorphism may have prognostic value in patients with CRC undergoing oxaliplatin-based chemotherapy. PMID- 25520092 TI - Lack of association between polymorphisms in genes MTHFR and MDR1 with risk of childhood acute lymphoblastic leukemia. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is a complex disease caused by interactions between hazardous exogenous or/and endogenous agents and many mild effect inherited susceptibility mutations. Some of them are known, but their functional roles still requireinvestigation. Age is a recognized risk factor; children with disease onset after the age of ten have worse prognosis, presumably also triggered by inherited factors. MATERIALS AND METHODS: The MDR1 gene polymorphisms rs1045642, rs2032582 and MTHFR gene polymorphisms rs1801131 and rs1801133 were genotyped in 68 ALL patients in remission and 102 age and gender matched controls; parental DNA samples were also available for 42 probands. RESULTS: No case control association was found between analyzed polymorphisms and a risk of childhood ALL development. Linkage disequilibrium was not observed in a family-based association study either. Only marginal association was observed between genetic marker rs2032582A and later disease onset (p=0.04). CONCLUSIONS: Our data suggest that late age of ALL onset could be triggered by mild effect common alleles. PMID- 25520093 TI - Clinical significance of serum vascular endothelial growth factor and complement 3a levels in patients with colorectal cancer in southern Iran. AB - BACKGROUND: Colon cancer (CRC) is perhaps the second most common cause of cancer mortality. This study determined the clinical significance of serum vascular endothelial growth factor (VEGF) and serum complement 3a (C3a) levels in patients with CRC in Fars province, southern Iran. MATERIALS AND METHODS: Between June 2010 and June 2012, 110 patients with CRC of both genders and different age groups were divided into 3 groups. Group A included patients who had just undergone surgery; Group B had undergone chemotherapy after surgery; and Group C had undergone chemotherapy and radiotherapy after surgery. Twenty one healthy subjects with normal colonoscopy were considered as a control group. ELISA was undertaken to determine VEGF and C3a levels before and after treatment measures. RESULTS: The mean age of patients was 53.9+/-14.1 years. Considering VEGF level, a significant decrease was visible after treatment measures in groups A and B, but not Group C. For VEGF level, the difference was not statistically significant between two genders and various age groups before and after treatment. No significant difference was found for VEGF level between patients and normal group before any treatment. Regarding C3a levels in 101 subjects, they significantly decreased after treatment measures. Before and after treatment, the difference was statistically significant between two genders, but was not statistically significant among various age groups. CONCLUSIONS: As VEGF and C3a levels were significantly lower in patients after treatment, these may be beneficial markers in assessment of CRC therapy especially in early stages. PMID- 25520094 TI - Health disparities between Black Hispanic and Black non-Hispanic cervical cancer cases in the USA. AB - BACKGROUND: Globally, cervical cancer is a major public health concern. Cervical cancer is the second most common cancer among women, resulting in approximately 500,000 cases per year. The purpose of this study is to compare disease characteristics between Black Hispanic (BH) and Black non-Hispanic (BNH) women in the US. MATERIALS AND METHODS: We used stratified random sampling to select cervical cancer patient records from the SEER database (1973-2009). We used Chi square and independent samples t-test to examine differences in proportions and means. RESULTS: The sample included 2,000 cervical cancer cases of Black non Hispanic and 91 Black Hispanic women. There were statistically significant differences between black Hispanic and black non- Hispanics in mean age at diagnosis (p<0.001), mean survival time (p<0.001), marital status (p<0.001), primary site of cancer (p<0.001); lymph node involvement (p<0.001); grading and differentiation (p<0.0001); and tumor behavior (p<0.001). Black women were more likely to develop cervical cancer and to have the highest mortality rates from the disease. CONCLUSIONS: Findings from this study show clear racial and ethnic disparities in cervical cancer incidence and prognosis that should be addressed. PMID- 25520095 TI - Increased sister chromatid exchange in peripheral blood lymphocytes from humans exposed to pesticide: evidence based on a meta-analysis. AB - BACKGROUND: Sister chromatid exchange (SCE) in human peripheral blood lymphocytes is one of the most extensively studied biomarkers employed to evaluate genetic damage subsequent to pesticide exposure. OBJECTIVE: To estimate the pooled levels of SCE in human peripheral blood lymphocytes among population exposed to pesticide. MATERIALS AND METHODS: Meta-analysis on the association between SCE frequency and pesticide exposure was performed with STATA 10.0 software package and Review Manager 5.0.24 in this study. RESULTS: The overall means of SCE were 7.88 [95% confidence intervals (95%CI): 6.71-9.04] for exposure group and 6.05 (95%CI: 5.13-6.95) for controls, respectively. There was statistically significant difference in the SCE frequency in human peripheral blood lymphocytes between pesticide-exposed groups and control groups, and the summary estimate of weighted mean difference was 1.69 (95%CI: 1.01-2.38). We also observed that pesticide-exposed population had significantly higher SCE frequency than control groups among smokers, nonsmokers, pesticide applicator, pesticide producer, other exposure population and Asian population in stratified analyses. CONCLUSIONS: Data indicate that the SCE frequency in human peripheral blood lymphocytes might be an indicator of early genetic effects for pesticide-exposed populations. PMID- 25520096 TI - Modeling age-specific cancer incidences using logistic growth equations: implications for data collection. AB - Large scale secular registry or surveillance systems have been accumulating vast data that allow mathematical modeling of cancer incidence and mortality rates. Most contemporary models in this regard use time series and APC (age-period cohort) methods and focus primarily on predicting or analyzing cancer epidemiology with little attention being paid to implications for designing cancer registry, surveillance or evaluation initiatives. This research models age specific cancer incidence rates using logistic growth equations and explores their performance under different scenarios of data completeness in the hope of deriving clues for reshaping relevant data collection. The study used China Cancer Registry Report 2012 as the data source. It employed 3-parameter logistic growth equations and modeled the age-specific incidence rates of all and the top 10 cancers presented in the registry report. The study performed 3 types of modeling, namely full age-span by fitting, multiple 5-year- segment fitting and single-segment fitting. Measurement of model performance adopted adjusted goodness of fit that combines sum of squred residuals and relative errors. Both model simulation and performance evalation utilized self-developed algorithms programed using C# languade and MS Visual Studio 2008. For models built upon full age-span data, predicted age-specific cancer incidence rates fitted very well with observed values for most (except cervical and breast) cancers with estimated goodness of fit (Rs) being over 0.96. When a given cancer is concerned, the R valuae of the logistic growth model derived using observed data from urban residents was greater than or at least equal to that of the same model built on data from rural people. For models based on multiple-5-year-segment data, the Rs remained fairly high (over 0.89) until 3-fourths of the data segments were excluded. For models using a fixed length single-segment of observed data, the older the age covered by the corresponding data segment, the higher the resulting Rs. Logistic growth models describe age-specific incidence rates perfectly for most cancers and may be used to inform data collection for purposes of monitoring and analyzing cancer epidemic. Helped by appropriate logistic growth equations, the work vomume of contemporary data collection, e.g., cancer registry and surveilance systems, may be reduced substantially. PMID- 25520097 TI - Hormone receptor, HER2/NEU and EGFR expression in ovarian carcinoma--is here a prognostic phenotype? AB - PURPOSE: We aimed to evaluate the effects of hormone receptor, HER2, and epidermal growth factor receptor (EGFR) expression on epithelial ovarian cancer (EOC) prognosis and investigate whether or not phenotypic subtypes might exist. MATERIALS AND METHODS: The medical records of 82 patients who were diagnosed with EOC between 2003 and 2012 and treated by platinum-based chemotherapy were retrospectively evaluated. Expression of EGFR, oestrogen (ER), progesterone (PR), and cerbB2 (HER2) receptors were assessed immunohistochemically on paraffin embedded tissues of these patients. Three phenotypic subtypes were defined according to ER, PR, and HER2 expression and associations of these with EGFR expression, clinicopathologic features, platinum sensitivity, and survival were investigated. RESULTS: When we classified EOC patients into three subtypes, 63.4% had hormone receptor positive (HR(+)) (considering breast cancer subtypes, luminal A), 18.3% had triple negative, and 18.3% had HER2(+) disease. EGFR positivity was observed in 37 patients (45.1%) and was significantly more frequent with advanced disease (p=0.013). However, no significant association with other clinicopathologic features and platinum sensitivity was observed. HER2(+) patients had significantly poorer outcomes than HER2(-) counterparts (triple negative and HR positive patients) (p=0.019). Multivariate analysis demonstrated that the strongest risk factor for death was residual disease after primary surgery. CONCLUSIONS: Triple negative EOC may not be an aggressive phenotype as in breast cancer. The HER2 positive EOC has more aggressive behaviour compared to triple negative and HR(+) phenotypes. EGFR expression is more frequent in advanced tumours, but is not related with poorer outcome. Additional ovarian cancer molecular subtyping using gene expression analysis may provide more reliable data. PMID- 25520098 TI - Epidemiology and prevention of prostate cancer in Vietnam. AB - Prostate cancer is the second most common cancer in men worldwide and a leading cause of mortality. Incidences continues to rise and vary substantially between populations. Although the prevalence of prostate cancer is relatively low in Vietnam, some hospital-based reports have shown an upward trend in recent years. While certain non-modifiable factors such as age, race and genetics are known to be mainly responsible, the literature has also suggested that environmental exposures can delay the onset of this disease. The present study provides a review of the epidemiology of prostate cancer in Vietnam by systematically searching several electronic databases. The results confirm an increasing trend of prostate cancer over the past decade, with age-standardised rate more than doubled from 2.2 per 100,000 men in 2000 to 4.7 per 100,000 men in 2010. However, no study has been found on modifiable risk factors, with the exception of one in vitro experiment that showed the inhibitory effect of garlic on the growth of prostate cancer cells. The lack of epidemiological information poses a difficulty to develop public health interventions to prevent this emerging malignant disease in Vietnam. PMID- 25520099 TI - Quality of life among breast cancer patients undergoing treatment in national cancer centers in Nepal. AB - PURPOSE: To study the quality of life and to identify associated factors among breast cancer patients undergoing treatment in national cancer centers in Nepal. MATERIALS AND METHODS: One hundred breast cancer patients were selected and interviewed using a structured questionnaire. European Organization of Research and Treatment of Cancer EORTC-QLQ-C30 and EORTC-QLQ-BR23 were used to assess quality of life and modified Medical Outcome Study -Social Support survey(mMOS SS) was used to assess social support. Only multi-item scales of EORTC C30 and BR23 were analyzed for relationships. Independent sample T-tests and ANOVA were applied to analyze differences in mean scores. RESULTS: The score of global health status/quality of life (GHS/GQoL) was marginally above average (mean=52.8). The worst performed scales in C-30 were emotional and social function while best performed scales were physical and role function. In BR-23, most of the patients fell into the problematic group regarding sexual function and enjoyment. Almost 90% had financial difficulties. Symptom scales did not demonstrate many problems. Older individuals, patients with stage I breast cancer and thosewith good social support were found to have good GHS/GQoL. Of all the influencing factors, social support was established to have strong statistical associations with most of the functional scales: GHS/GQoL (0.003), emotional function (<0.001), cognitive function (0.020), social function (<0.001) and body image function (0.011). Body image was significantly associated with most of the influencing factors: monthly family income (0.003), type of treatment (<0.001), type of surgery (<0.001), stage of cancer (0.017) and social support (0.011). CONCLUSIONS: Strategies to improve social support of the patients undergoing treatment should be given priority and financial difficulties faced by breast cancer patients should be well addressed from a policy making level by initiating health financing system. PMID- 25520100 TI - Comparison of primary breast cancer size by mammography and sonography. AB - PURPOSE: To compare tumor size by mammography and sonography and align with pathological results in primary breast cancer cases. MATERIALS AND METHODS: We retrospectively reviewed 95 primary breast cancer patients who underwent mammography and sonography from January 2011 to June 2012. The largest tumor diameter was chosen as sizing reference for each imaging modality. The measurements of mammography and sonography were considered concordant if they were within the measurement of pathological results+/-0.5 cm. Pearson's correlation coefficient was calculated for imaging results. RESULTS: The range of the maximum diameter was 0.6 cm-10.5 cm and mean value was 3.81+/-2.04 cm by pathological results, 0.7 cm-12.4 cm and 3.99+/-2.19 cm by mammography, and 0.9 cm-11.0 cm and 3.63+/-2.01 cm by sonography, respectively. Sonography (R: 0.754), underestimated tumor size, but had a better correlation with pathological tumor size compared to mammography (R: 0.676), which overestimated tumor size. CONCLUSIONS: Sonography is superior to mammography in assessment of primary breast cancer. PMID- 25520101 TI - Ifosfamide-containing regimens for treating patients with osteosarcomas. AB - BACKGROUND: This systemic analysis was conducted to evaluate the efficacy and safety of an ifosfamide- containing regimen in treating patients with osteosarcoma. METHODS: Clinical studies evaluating the efficacy and safety of Ifosfamide-containing regimen on response and safety for patients with osteosarcoma were identified by using a predefined search strategy. Pooled response rate (RR) of treatment were calculated. RESULTS: When ifosfamide containing regimens were evaluated, 4 clinical studies which including 134 patients with osteosarcoma were considered eligible for inclusion. Systemic analysis suggested that, in all patients, pooled RR was 44.8% (60/134) in ifosfamide-containing regimens. Major adverse effects were neutropenia, leukopenia, and fatigue inIfosfamide-containing regimens; No treatment related death occurred in cantharidin combined regimens. CONCLUSION: This systemic analysis suggests that ifosfamide-containing regimens are associated with good response rate and acceptable toxicity in treating patients with osteosarcoma, but this result should be confirmed by randomized clinical trials. PMID- 25520102 TI - Social support and its predictors among Iranian cancer survivors. AB - BACKGROUND: Social support is an important factor in psycho-social well-being of cancer survivors. There is little information about level of social support and its predictors among cancer survivors in Iran or other Middle Eastern countries. The aims of present study were to determine the social support and its prediction factors among Iranian cancer survivors. MATERIALS AND METHODS: In this descriptive-correlational study 187 cancer patients in one educational center and one private oncology office in northwest of Iran participated using a convenient sampling method. The data collection tool consisted of a researcher-prepared checklist and the Multidimensional Scale of Perceived Social Support Assessment (MSPSS). Data analysis was performed using SPSS statistical software with descriptive statistics and multiple linear regression analysis. RESULTS: The total score of MSPSS was 68 from a possible score between 7 and 84. Participants believed that they received a high level of support from their family members and significant others. Multiple linear regression analysis showed that single and depressed cancer survivors and participants with lower levels of physical activity believed that they received lower levels of social support. CONCLUSIONS: Iranian cancer survivors receive high levels of social support and family members are the most important source of this support. In planning any supportive care program for Iranian cancer survivors this strength should be considered. Especially, single and depressed and patients with lower levels of physical activity need more attention. PMID- 25520103 TI - Prevalence of colorectal polyps in a group of subjects at average-risk of colorectal cancer undergoing colonoscopic screening in Tehran, Iran between 2008 and 2013. AB - BACKGROUND: Colorectal cancer (CRC) is one of the prime causes of mortality around the globe, with a significantly rising incidence in the Middle East region in recent decades. Since detection of CRC in the early stages is an important issue, and also since to date there are no comprehensive epidemiologic studies depicting the Middle East region with special attention to the average risk group, further investigation is of significant necessity in this regard. AIM: Our aim was to investigate the prevalence of preneoplastic and neoplastic lesions of the colon in an average risk population. MATERIALS AND METHODS: A total of 1,208 eligible asymptomatic, average- risk adults older than 40 years of age, referred to Firuzgar Hospotal in the years 2008-2012, were enrolled. They underwent colonoscopy screening and all polypoid lesions were removed and examined by an expert gastrointestinal pathologist. The lesions were classified by size, location, numbers and pathologic findings. Size of lesions was measured objectively by endoscopists. RESULTS: The mean age of participants was 56.5+/ 9.59 and 51.6% were male. The overall polyp detection rate was 199/1208 (16.5 %), 26 subjects having non-neoplastic polyps, including hyperplastic lesions, and 173/1208 (14.3%) having neoplastic polyps, of which 26 (2.15%) were advanced neoplasms .The prevalence of colorectal neoplasia was more common among the 50-59 age group. Advanced adenoma was more frequent among the 60-69 age group. The majority of adenomas were detected in the distal colon, but a quarter of advanced adenomas were found in the proximal colon; advance age and male gender was associated with the presence of adenoma. CONCLUSIONS: It seems that CRC screening among average-risk population might be recommended in countries such as Iran. However, sigmioidoscopy alone would miss many colorectal adenomas. Furthermore, the 50-59 age group could be considered as an appropriate target population for this purpose in Iran. PMID- 25520104 TI - May the platelet to lymphocyte ratio be a prognostic factor for epithelial ovarian cancer? AB - BACKGROUND: The study aimed to evaluate changes in hematologic parameters, including white blood cell, platelet count, platelet indices, the platelet to lymphocyte and neutrophil to lymphocyte ratios in patients with early and advanced stages of epithelial ovarian cancers. MATERIALS AND METHODS: The study included 100 patients with epithelial ovarian cancer who underwent primary staging exploratory laparotomy. Preoperative hematologic parameters, tumor histopathologic type, grade, stage and serum CA-125 levels were retrospectively analyzed. These parameters were compared between the patients with early (stage I II) and advanced (stage III-IV) ovarian cancer. RESULTS: White blood cell count and platelet indices, including mean platelet volume, platelet distribution width and platelet crit did not show a statistically significant difference between groups with early and advanced ovarian cancer. However, the neutrophil to lymphocyte ratio, platelet count, the platelet to lymphocyte ratio and CA-125 level showed a statistically significant difference between the two groups (p<0.05, p<0.01, p<0.001, p<0.01 respectively). CONCLUSIONS: It was found that the neutrophil to lymphocyte ratio, platelet count and the platelet to lymphocyte ratio increased with the increasing stage of ovarian cancer. Furthermore, it was seen that the platelet to lymphocyte ratio is an independent prognostic factor related to the stage of epithelial ovarian cancer. PMID- 25520105 TI - Association of urinary cesium with breast cancer risk. AB - BACKGROUND: The aim of this study is to examine the association of urinary cesium with breast cancer risk. MATERIALS AND METHODS: We collected survey data and urine specimens from 240 women with incident invasive breast cancer before their treatment and 246 age-matched female controls between October 2009 and July 2010. Urinary concentrations of cesium were determined by inductively coupled plasma mass spectrometry. Interviews were conducted by face-to-face to obtain information on potential breast cancer risk factors. Logistic regression analysis was used to estimate the associations. RESULTS: Creatinine-adjusted levels [median (25th, 75th) ug/g] of cesium in cases and controls were 17.6 (13.1, 24.0) and 19.3 (15.3, 25.7), respectively. After adjustment for potential risk factors, women in the second and highest tertile of cesium showed a decreased risk of breast cancer in a dose-dependent manner as compared with those in the lowest tertile [ORs and 95% CIs: 0.75 (0.46- 1.22) and 0.50 (0.30-0.82), respectively]. This decrease was more evident in women with ER positive or localized clinical stage in an exploratory stratification analysis. CONCLUSIONS: These findings suggest that cesium may have anticancer efficacy and urinary cesium has potential as a biomarker for breast cancer risk assessment. PMID- 25520106 TI - Gene microarray assessment of multiple genes and signal pathways involved in androgen-dependent prostate cancer becoming androgen independent. AB - To study the gene expression change and possible signal pathway during androgen dependent prostate cancer (ADPC) becoming androgen-independent prostate cancer (AIPC), an LNCaP cell model of AIPC was established using flutamide in combination with androgen-free environment inducement, and differential expression genes were screened by microarray. Then the biological process, molecular function and KEGG pathway of differential expression genes are analyzed by Molecule Annotation System (MAS). By comparison of 12,207 expression genes, 347 expression genes were acquired, of which 156 were up-ragulated and 191 down regulated. After analyzing the biological process and molecule function of differential expression genes, these genes are found to play crucial roles in cell proliferation, differntiation, cell cycle control, protein metabolism and modification and other biological process, serve as signal molecules, enzymes, peptide hormones, cytokines, cytoskeletal proteins and adhesion molecules. The analysis of KEGG show that the relevant genes of AIPC transformation participate in glutathione metabolism, cell cycle, P53 signal pathway, cytochrome P450 metabolism, Hedgehog signal pathway, MAPK signal pathway, adipocytokines signal pathway, PPAR signal pathway, TGF-beta signal pathway and JAK-STAT signal pathway. In conclusion, during the process of ADPC becoming AIPC, it is not only one specific gene or pathway, but multiple genes and pathways that change. The findings above lay the foundation for study of AIPC mechanism and development of AIPC targeting drugs. PMID- 25520107 TI - Alu methylation in serum from patients with nasopharyngeal carcinoma. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China and Southeast Asia. Alu elements are among the most prevalent repetitive sequences and constitute 11% of the human genome. Although Alu methylation has been evaluated in many types of cancer, few studies have examined the levels of this modification in serum from NPC patients. OBJECTIVE: To compare the Alu methylation levels and patterns between serum from NPC patients and normal controls. MATERIALS AND METHODS: Sera from 50 NPC patients and 140 controls were examined. Quantitative combined bisulfite restriction analysis-Alu (qCOBRA-Alu) was applied to measure Alu methylation levels and characterize Alu methylation patterns. Amplified products were classified into four patterns according to the methylation status of 2 CpG sites: hypermethylated (methylation at both loci), partially methylated (methylation of either of the two loci), and hypomethylated (unmethylated at both loci). RESULTS: A comparison of normal control sera with NPC sera revealed that the latter presented a significantly lower methylation level (p=0.0002) and a significantly higher percentage of hypomethylated loci (p=0.0002). The sensitivity of the higher percentage of Alu hypomethyted loci for distinguishing NPC patients from normal controls was 96%. CONCLUSIONS: Alu elements in the circulating DNA of NPC patients are hypomethylated. Moreover, Alu hypomethylated loci may represent a potential biomarker for NPC screening. PMID- 25520108 TI - Detection rate of colorectal adenoma or cancer in unselected colonoscopy patients: Indonesian experience in a private hospital. AB - BACKGROUND: Colorectal cancer is currently the third most common cancer in Indonesia, yet colonoscopy--the most accepted mode of screening to date--is not done routinely and national data are still lacking. OBJECTIVE: To determine the detection rate of colorectal cancers and adenomas in unselected patients undergoing colonoscopy for various large bowel symptoms at the Digestive Disease and GI Oncology Centre, Medistra Hospital in Jakarta, Indonesia. MATERIALS AND METHODS: Colonoscopy data from January 2009 to December 2012 were reviewed. New patients referred for colonoscopy were included. Data collected were patient demographic and significant colonoscopy findings such as the presence of hemorrhoids, colonic polyps, colonic diverticula, inflammation, and tumor mass. Histopathological data were obtained for specimens taken by biopsy. Associations between categorical variables were analyzed using chi-square test, while mean differences were tested using the t-test. RESULTS: A total of, 1659 cases were included in this study, 889 (53.6%) of them being men. Polyps or masses were found in 495 (29.8%) patients while malignancy was confirmed in 74 (4.5%). Patients with a polyp or mass were significantly older (60.2 vs 50.8 years; p<0.001; t-test) and their presence was significantly associated with male gender (35.0% vs 23.9%; prevalent ratio [PR] 1.71; 95% confidence interval [CI] 1.38 2.12; p<0.001) and age>50 years (39.6% vs 16.6%; PR 3.29; 95% CI 2.59-4.12; p<0.001). Neoplastic lesions was found in 257 (16.1%), comprising 180 (11.3%) adenomas, 10 (0.6%) in situ carcinomas, and 67 (4.2%) carcinomas. CONCLUSIONS: Polyps or masses were found in 30% of colonoscopy patients and malignancies in 16.1%. These figures do not represent the nation-wide demographic status of colorectal cancer, but may reflect a potentially increasing major health problem with colorectal cancer in Indonesia. PMID- 25520109 TI - Radixin knockdown by RNA interference suppresses human glioblastoma cell growth in vitro and in vivo. AB - Radixin, a member of the ERM (ezrin-radixin-moesin) family, plays important roles in cell motility, invasion and tumor progression. It is expressed in a variety of normal and neoplastic cells, including many types of epithelial and lymphoid examples. However, its function in glioblastomas remains elusive. Thus, in this study, radixin gene expression was first examined in the glioblastoma cells, then suppressed with a lentivirus-mediated short-hairpin RNA (shRNA) method.We found that there were high levels of radixin expression in glioblastoma U251cells. Radixin shRNA caused down-regulation of radixin gene expression and when radixin silenced cells were implanted into nude mice, tumor growth was significantly inhibited as compared to blank control cells or non- sense shRNA cells. In addition, microvessel density in the tumors was significantly reduced. Thrombospondin-1 (TSP-1) and E-cadherin were up-regulated in radixin- suppressed glioblastoma U251 cells. In contrast, MMP9 was down-regulated. Taken together, our findings suggest that radixin is involved in GBM cell migration and invasion, and implicate TSP-1, E-cadherin and MMP9 as metastasis-inducing factors. PMID- 25520110 TI - Evidence based analysis of Cisplatin for treating patients with cutaneous squamous cell carcinoma. AB - BACKGROUND: This analysis was conducted to evaluate the efficacy and safety of cisplatin based chemotherapy for treating patients with cutaneous squamous cell carcinoma. METHODS: Clinical studies evaluating the efficacy and safety of cisplatin based regimens on response and safety for patients with cutaneous squamous cell carcinoma were identified using a predefined search strategy. Pooled response rates (RR) of treatment were calculated. RESULTS: In cisplatin based regimens, 4 clinical studies which including 50 patients with advanced cutaneous squamous cell carcinoma were considered eligible for inclusion. Regimens included cisplatin, doxorubicin, or vindesine. Pooled analysis suggested that, in all patients, the pooled RR was 60% (30/50) in cisplatin based regimens. Nausea and vomiting were the main side effects. No grade III or IV renal or liver toxicity were observed. No treatment related death occurred with the cisplatin based treatments. CONCLUSION: Evidence based analysis suggests that cisplatin based regimens are associated with a good response rate and acceptable toxicity for treating patients with cutaneous squamous cell carcinoma. PMID- 25520111 TI - Health beliefs and breast cancer screening behaviors among Iranian female health workers. AB - BACKGROUND: Breast cancer is a serious health problem. Early detection is crucial for optimal treatment and reducing mortality. OBJECTIVE: The aim of this study was to evaluate health beliefs concerning performance of breast self- examination (BSE) and mammography in a sample of Iranian female health workers. MATERIALS AND METHODS: This cross-sectional study was performed among 441 female health care workers (physicians=88, nurses=163, midwives=38, officers=68, and others=84) in 3 different health centers in Yazd, Iran. Data were collected using a self administered questionnaire which included demographic characteristics and then Persian version of the Champion's Health Belief Model Scale (CHBMS). RESULTS: The mean age of the participants was 34.7+/-13.7. It was found that 41.9% of the workers performed BSE in the past and 14.9% of them regularly, but only 10.6% of them had undergone a mammogram. Perceived barriers to BSE (F=6.351, P=0.021) and mammography (F=5.214, p=0.022) were significantly higher in officers than physicians, nurses or midwives. Perceived barriers were lower among those who had performed BSE and mammography, but not significant (p=0.34 and p=0.56, respectively). Furthermore, perceived susceptibility and perceived benefits of the workers who had BSE and mammography were significantly higher than who did not (p<0.05). Perceived seriousness was not a significant variable in BSE and mammography (p=0.71 and p=0.43, respectively). CONCLUSIONS: The health beliefs of health workers concerning the perceived susceptibility of breast cancer and the perceived benefits BSE and mammography significantly impact their screening practices. PMID- 25520112 TI - Comparative outcome of Thai pediatric osteosarcoma treated with two protocols: the role of high-dose methotrexate (HDMTX) in a single institute experience. AB - BACKGROUND: High-dose methotrexate (HD-MTX) is recognized as an efficient component of therapy against pediatric osteosarcoma in combination with other drugs such as cisplatin (CDP), carboplatin (CBDCA), doxorubicin (ADM), etoposide (VP-16) and ifosfamide (IFO). OBJECTIVES: To demonstrate the feasibility and effectiveness of the HD-MTX/CDP/DOX/VP-16/IFO [MTX(+)] protocol comparable to CDP/ADM/CBDCA/IFO [MTX(-)] for treating childhood osteosarcoma at Ramathibodi Hospital (1999-2014). MATERIALS AND METHODS: A retrospective analysis was conducted of osteosarcoma patients aged less than 18 years treated with two chemotherapeutic regimens between 1999 and 2014. A total of 45 patients received the MTX(-) and 21 the MTX(+) protocol. RESULTS: Overall limb-salvage and amputation rate were 12.9% and 77.7%, respectively. Kaplan- Meier analysis results for 3-year disease free survival (DFS) and overall survival (OS) regardless of treatment regimens were 43.4+/-6.0% and 53.2+/-6.1% respectively. The 3-year DFS and OS were improved significantly with the MTX(+) protocol compared to MTX(-) protocol (p=0.010 and p=0.009, log rank test) [69.8+/-10.5%, 79.8+/-9.1% for MTX(+) and 31.1+/-6.9%, 42.2+/-7.4% for MTX(-) protocol, respectively]. Patients with metastatic osteosarcoma treated with the MTX(+) protocol had statistically significant higher 3-year DFS and OS than those treated with the MTX(-) protocol (66.7+/-13.6% and 15.0+/-8.0% for 3-year DFS, p=0.010, 73.3+/-13.2% and 20+/-8.9% for 3-year OS, p=0.006, respectively). The independent risk factors for having inferior 3-year DFS and OS were poor histological response (tumor necrosis <90%) and treatment with the MTX(-) protocol. The multivariate analysis identified only the treatment with the MTX(-) protocol as an independent predictor of inferior OS with a hazard ratio (HR) of 3.53 (95% confidence interval of 1.2-10.41, p=0.022). CONCLUSIONS: Our study demonstrated the tolerability, feasibility and efficacy of the HDMTX-based regimen improving the survival rate in pediatric osteosarcoma cases, in line with reports from developed countries. PMID- 25520113 TI - Clinical features of patients with esophageal and second primary cancers. AB - BACKGROUND: The prevalence of esophageal cancer (EC) with second primary cancers (SPC) is increasing worldwide. This study was aimed to understand the clinical features of EC patients with SPC in the Taiwanese population. MATERIALS AND METHODS: Clinical and laboratory data for 180 EC patients with or without SPC were collected between January 2009 and December 2013. Information on treatment approaches, location of SPCs and ABO blood type were also collected and stratified. RESULTS: The most common SPC in EC patients was hypopharyngeal cancer, followed by laryngeal cancer and hepatocellular carcinoma in our study. Malignancies of colon, prostate and lung were also found. There was a significant higher portion of blood type A in the EC patients with SPC compared with those without (42.4% vs 19.5%, P=0.006). CONCLUSIONS: The frequency and SPC site distribution and blood type A should be considered in clinical evaluation of EC patients with a high risk of developing SPC in the Taiwanese population. PMID- 25520114 TI - Interference of fisetin with targets of the nuclear factor-kappaB signal transduction pathway activated by Epstein-Barr virus encoded latent membrane protein 1. AB - Fisetin is an effective compound extracted from lacquer which has been used in the treatment of various diseases. Preliminary data indicate that it also exerts specific anti-cancer effects. However, the manner in which fisetin regulates cancer growth remains unknown. In this study, we elucidated interference of fisetin with targets of the nuclear factorkappaB signal transduction pathway activated by Epstein-Barr virus encoding latent membrane protein 1 (LMP1)in nasopharyngeal carcinoma (NPC) cells, Results showed that fisetin inhibited the survival rate of CNE-LMP1 cells and NF-kappaB activation caused by LMP1. Fisetin also suppressed nuclear translocation of NF-kappaB (p65) and IkappaBalpha phosphorylation, while inhibiting CyclinD1, all key targets of the NF-kappaB signal transduction pathway. It was suggested that interference effects of fisetin with signal transduction activated by LMP1 encoded by the Epstein-Barr virus may play an important role in its anticancer potential. PMID- 25520115 TI - Significant association of metabolic indices, lipid profile, and androgen levels with prostate cancer. AB - OBJECTIVES: To compare the metabolic indices, lipid profile, androgens, and prostate specific antigen between prostate cancer and BPH and between grades of prostate cancer in a cross-sectional study. MATERIALS AND METHODS: The study enrolled 95 cases of prostate cancer and 95 cases of benign prostatic hyperplasia (BPH). Prostate gland volume was measured using transrectal ultrasound. We compared insulin, testosterone, dihydrotestosterone, prostate specific antigen levels and lipid profile between prostate cancer of different grades and BPH. Further, prostate cancer patients were classified into low grade and high grade. Unpaired t-test for normally distributed variables and Man-Whitney U test for non normal variables were used to assess differences. RESULTS: We found that prostate cancer patients had significantly higher levels of insulin, testosterone, PSA, cholesterol, triglycerides, low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) in comparison to their BPH counterparts. Higher levels of these parameters also correlated with a higher grade of the disease. CONCLUSIONS: We conclude that higher levels of insulin, testosterone, PSA, and cholesterol correlate with a higher risk of prostate cancer, and also with a higher grade of the disease. PMID- 25520116 TI - Decreased HDL-dependent paraoxonase and arylesterase enzyme activity may indicate a worse prognosis in multiple myeloma. AB - BACKGROUND: Multiple myeloma (MM) is a haematological cancer characterized by clonal proliferation of plasma cells.The aim of this study was to investigate the activity of serum paraoxonase-1 (PON1) and arylesterase (ARE) in multiple myeloma with and without free light chain excretion(FLCe-MM and NFLCe-MM); as well as to investigate possible alterations in oxidative stress parameters. MATERIALS AND METHODS: Total thiol (T.thl), oxidative stress index (OSI), total oxidant status (TOS) and total antioxidant status (TAS) were examined in addition to the PON1 and ARE enzyme activities in twenty one FLCe-MM and nineteen NFLCe-MM subjects. Routine parameters like lipid panel, serum total protein, albumin, creatinine, blood urea nitrogen (BUN), uric acid and hemoglobin levels were compared with the oxidative stress markers. RESULTS: Serum total protein, BUN, creatinin, and uric acid levels were significantly higher (p=0.04, p=0.001, p=0.001 and p=0.0022, respectively), while hemoglobin and albumin levels were significantly lower in FLCe-MM patients (p=0.009 and p=0.04,respectively). PON1 and ARE activities were significantly lower in patients with FLCe-MM compared to those with NFLCe-MM (p=0.001 and p=0.008, respectively). CONCLUSIONS: Depending on our results of prognostic markers of MM such as age, hemoglobin, albumin, and creatinine we feel confident to presume FLCe-MM as a subgroup with a worse prognosis. A decrease in PON1 and ARE activities may contribute to the prognosis and may be used as a prognostic tool in MM. PMID- 25520117 TI - Drug resistance effects of ribosomal protein L24 overexpression in hepatocellular carcinoma HepG2 cells. AB - BACKGROUND: The morbidity and mortality rate of liver cancer continues to rise in China and advanced cases respond poorly to chemotherapy. Ribosomal protein L24 has been reported to be a potential therapeutic target whose depletion or acetylation inhibits polysome assembly and cell growth of cancer. MATERIALS AND METHODS: Total RNA of cultured amycin-resistant and susceptible HepG2 cells was isolated, and real time quantitative RT-PCR were used to indicate differences between amycin-resistant and susceptible strains of HepG2 cells. Viability assays were used to determine amycin resistance in RPL24 transfected and control vector and null- transfected HepG2 cell lines. RESULTS: The ribosomal protein L24 transcription level was 7.7 times higher in the drug-resistant HepG2 cells as compared to susceptible cells on quantitative RT-PCR analysis. This was associated with enhanced drug resistance as determined by methyl tritiated thymidine (3H-TdR) incorporation. CONCLUSIONS: The ribosomal protein L24 gene may have effects on drug resistance mechanisms in hepatocellular carcinoma HepG2 cells. PMID- 25520118 TI - Genetic epidemiological analysis of esophageal cancer in high-incidence areas of China. AB - Genetic epidemiological studies have shown that genetic susceptibility to esophageal cancer (EC) is an important cause of its high incidence within families in some areas of China. The purpose of this study was to obtain evidence of a genetic basis of EC in Xin-an and Xin-xiang counties in China. Familial aggregation and complex segregation analyses were performed of 79 EC families in these counties. The heritability of EC was examined using Falconer's method and complex segregation analysis was conducted with the SEGREG program in Statistical Analysis for Genetic Epidemiology (SAGE version 5.3.1). The results showed that the distribution of EC in families did not fit well into a binomial distribution. The heritability of EC among first-degree and second- degree relatives was 67.0+/ 7.31% and 43.1%+/-9.80%, respectively, and the summing up powered heritability was 53.2+/-6.74%. The segregation ratio was 0.045. Complex segregation analysis showed that the genetic model of EC was additive. The current results provide evidence for an inherited propensity to EC in certain high-risk groups in China, and support efforts to identify the genes that confer susceptibility to this disease. PMID- 25520119 TI - Diagnostic aspects of fine needle aspiration for lung lesions: series of 245 cases. AB - BACKGROUND: Transthoracic fine needle aspiration (FNA) is one of several methods for establishing tissue diagnosis of lung lesions. Other tissue or cell sources for diagnosis include sputum, endobronchial biopsy, washing and brushing, endobronchial FNA, transthoracic core needle biopsy, biopsy from thoracoscopy or thoracotomy. The purpose of this study was to compare the sensitivity and specificity of FNA and other diagnostic tests in diagnosing lung lesions. MATERIALS AND METHODS: The population included all patients undergoing FNA for lung lesions at Meir Medical Center from 2006 through 2010. Information regarding additional tissue tests was derived from the electronic archives of the Department of Pathology, patient records and files from the Department of Oncology. Sensitivity, specificity, diagnostic accuracy, and positive and negative predictive values were calculated for each test. RESULTS: FNA was carried out in 245 patients. Malignant tumors were diagnosed in 190 cases (78%). They included adenocarcinoma (43%), squamous cell carcinoma (15%), non-small cell carcinoma, not otherwise specified (19%), neurondocrine tumors (7%), metastases (9%) and lymphoma (3%). The specificity of FNA for lung neoplasms was 100%; sensitivity and diagnostic accuracy were 87%. CONCLUSIONS: FNA is the most sensitive procedure for establishing tissue diagnoses of lung cancer. Combination with core needle biopsy increases the sensitivity. Factors related to the lesion (nature, degenerative changes, location) and to performance of all stages of test affect the ability to establish a diagnosis. PMID- 25520120 TI - Brief descriptive epidemiology of primary malignant brain tumors from North-East India. AB - Brain tumors are a mixed group of neoplasms that originate from the intracranial tissues and the meninges with degrees of malignancy varying greatly from benign to aggressive. Not much is known about the epidemiology of primary malignant brain tumors (PMBTs) in our population in North-East India. In this analysis, an attempt was made to identify the age groups, gender distribution, topography and different histological types of PMBT with data from a hospital cancer registry. A total of 231 cases of PMBT were identified and included for the present analysis. Our analysis has shown that most of PMBT occur at 20-60 years of age, with a male to female ratio of 2.3:1. Some 70.5% of cases occurred in cerebral lobes except for the occipital lobe, and astrocytic tumors were the most common broad histological type. In our population the prevalence of PMBT is 1% of all cancers, mostly affecting young and middle aged patients. As brain tumors are rare, so case-control analytic epidemiological studies will be required to establish the risk factors prevalent in our population. PMID- 25520121 TI - Clinical safety of chemotherapy for elderly cancer patients complicated with hypertension. AB - OBJECTIVE: To access the safety of chemotherapy for elderly cancer patients complicated with hypertension. METHODS: Elderly cancer patients who were complicated with hypertension and treated by chemotherapy were recruited. All patients were treated by chemotherapy after an intervention on hypertension by psychotherapy, exercise guidance, salt regulation and nutrition support, therapy on hypertension, as well as prevention on hypertension associated complications. RESULTS: In 68 eligible patients, two suspended chemotherapy because of adverse reactions and 4 because of disease progression. The remaining 62 patients completed chemotherapy smoothly based on good hypertension control. CONCLUSION: With effective control of blood pressure, chemotherapy for elderly cancer patients complicated with hypertension is generally safe. PMID- 25520122 TI - A systematic review of MRI, scintigraphy, FDG-PET and PET/CT for diagnosis of multiple myeloma related bone disease--which is best? AB - AIM: The purpose of the current study was to conduct a systematic review of the published literature to evaluate the diagnostic accuracy of FDG-PET, PTE/CT, MRI and scintigraphy for multiple myeloma related bone disease. METHODS: Through a search of PubMed, EMBASE, and the Cochrane Library, two reviewers independently assessed the methodological quality of each study. We estimated pooled sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR), and two sample Z-tests were conducted to evaluate for differences in sensitivity, specificity, area under the curve (AUC), and the Q* index between any two diagnostic modalities. RESULTS: A total of 17 studies were reviewed. The MRI had a pooled sensitivity of 0.88, specificity of 0.68, AUC of 0.897, and Q*index of 0.828, whereas for MIBI, the corresponding values were 0.98, 0.90, 0.991, and 0.962, respectively, and for bone scan, they were 066, 0.83, 0.805, and 0.740, respectively. The corresponding values of MIBI were 0.98, 0.90, 0.991, and 0.962, respectively. For PET and PET/CT, the values were 0.91, 0.69, 0.927 and 0.861, respectively. Statistically significant differences were not found in the sensitivity, specificity, AUC, and Q* index between MRI, scintigraphy, FDG-PET and PET/CT. CONCLUSIONS: On the condition that X ray is taken as a reference in our study, we suggested that FDG-PET, PTE/CT, MRI and scintigraphy are all associated with high detection rate of bone disease in patients with MM. Thus, in clinical practice, it is recommended that we could choose these tests according to the condition of the patient. PMID- 25520123 TI - Effects of TNF secreting HEK cells on B lymphocytes' apoptosis in human chronic lymphocytic leukemias. AB - BACKGROUND: Tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) is an antitumor candidate in cancer therapy. This study focused on effects of TRAIL, as a proapototic ligand that causes apoptosis, in B-CELL chronic lymphocytic leukemia cells (B-CLL) . MATERIALS AND METHODS: A population of HEK 293 cells was transducted by lentivirus that these achieved ability for producing the TRAIL protein and then HEK 293 cells transducted were placed in the vicinity of CLL cells. After 24 hours of co-culture, apoptosis of CLL cells was assessed by annexin V staining. RESULTS: The amount of Apoptosis was examined separately in four groups: 293 HEK TRAIL (16.17+/-1.04%); 293 HEK GFP (2.7+/-0.57%); WT 293 HEK (2+/-2.6%); and CLL cells (0.01+/-0.01%). Among the groups studied, the maximum amount of apoptosis was in the group that the vector encoding TRAIL was transducted. In this group, the mean level of soluble TRAIL in the culture medium was 253 pg/ml; also flow cytometry analyzes showed that proapotosis in this group was 32.8+/-1.6%, which was higher than the other groups. CONCLUSIONS: In this study, we have demonstrated that TNF secreted from HEK 293 cells are effective in death of CLL cells. PMID- 25520124 TI - Developing scales for the assessment of fatigue in Turkish pediatric oncology patients aged 13-18 and their parents. AB - BACKGROUND: This study was planned in an attempt to develop scales for the assessment of fatigue in pediatric oncology patients aged 13-18 and also for their parents. MATERIALS AND METHODS: In collecting the study data, we used the Child and Parent Information Form, Visual Fatigue Scale, Scale for the Assessment of Fatigue in Pediatric Oncology Patients Aged 13-18 and the Scale for the Assessment of Fatigue in Pediatric Oncology Patients Aged 13-18 for Parents. We also used Pearson correlation analysis, Cronbach alpha coefficient, factor analysis and ROC analysis for the study data. RESULTS: In this study, the total Cronbach alpha value of the parent form was 0.99, the total factor load was 0.72 0.94 with 95% the total variance being explained. The cutoff point of the parent form is 73 points. The total Cronbach alpha value of the child form was 0.99, the total factor load was 0.82-0.95, with 89.4% of the total variance being explained. The cutoff point of the child form was 75.5 points. CONCLUSIONS: This study suggests that the Scale for the Assessment of Fatigue in Pediatric Oncology Patients Aged 13-18 and the Scale for the Assessment of Fatigue in Pediatric Oncology Patients Aged 13-18 for Parents are valid and reliable instruments in assessing the fatigue symptoms of children in Turkey. PMID- 25520125 TI - Time trends of nasopharyngeal carcinoma in urban Guangzhou over a 12-year period (2000-2011): declines in both incidence and mortality. AB - Nasopharyngeal carcinoma (NPC) is an uncommon disease in most countries but occurs with much greater frequency in southern China. This study aimed to examine the secular trends of NPC in urban Guangzhou over the time period of 2000-2011 using data from the Guangzhou Cancer Registry. Age-adjusted annual incidence rates of NPC were calculated by the direct method using the WHO World Standard Population (1960) as the reference. The average annual percentage change (AAPC) was used as an estimate of the trend. A total of 7,532 new cases of NPC and 3,449 related deaths were registered. In both genders, the peak incidence occurred in the 50- to 59-year age group, and this age distribution pattern remained similar throughout. The AAPC in NPC incidence rates was -3.26% (95% CI: -5.4%--1.1) for males and -5.74% (95% CI: -8.9%--2.5) for females, resulting in a total decrease of 39.3% (from 22.14 to 13.44 per 100,000 population) for males and 48.6% (from 10.1 to 5.18 per 100,000 population) for females over this 12-year period. The AAPCs in NPC mortality rates were -4.62% (95%CI: -3.5%--5.7) for males and -6.75% (95% CI: -5.2%--8.3) for females, resulting in a total decrease of -46.1% (from 12.1 to 6.54 per 100,000 population) for males and 51.7% (from 4.14 to 2.00 per 100,000 population) for females. The age-adjusted incidence and mortality rates of NPC declined during 2000-2011 in urban Guangzhou but remained high. Future efforts to improve prevention, early detection and treatment strategies are needed. PMID- 25520126 TI - Risk of gastric cancer in children with Helicobacter pylori infection. AB - BACKGROUND: Helicobacter pylori (H. pylori) is the most common chronic infectious agent in the stomach. Most importantly, it may lead to atrophy, metaplasia and cancer. The aim of this study was to investigate the incidence of H. pylori infection and to detect early mucosal changes that may lead to malignant degeneration in children. MATERIALS AND METHODS: Children who underwent upper gastrointestinal endoscopy were included. Familial history of gastric cancer was noted. Endoscopic examinations were performed by a single pediatric gastroenterologist. A minimum of three biopsy samples were collected during endoscopy. The patients were accepted as H. pylori infected if results of biopsies and rapid urease test were both positive. Biopsies were evaluated for the presence and degree of chronic inflammation, the activity and severity of gastritis, glandular atrophy and intestinal metaplasia. RESULTS: A total of 750 children (388 boys, 362 girls) were evaluated in our study, with a mean age of 10.1 years. A total of 390 patients (52%) were found to be infected with H. pylori. Among the H. pylori infected patients, 289 (74%) were diagnosed to have chronic superficial gastritis, 24 (6.2%) had gastric atrophy. Most strikingly, intestinal metaplasia was observed in 11 children, all were in the H. pylori positive group. There was no difference in the mean of age, gender and socioeconomic class between H. pylori infected and non-infected groups. The frequency of gastric cancer in family members (4 in number) was higher in patients with H. pylori infection. No gastric cancer case was reported from the parents of non-infected children. The worst biopsy parameters (atropy and metaplasia) were improved after H. pylori eradication on control endoscopy. CONCLUSIONS: The current study shows a higher prevalence of familial history of gastric cancer in H. pylori infected children. Intestinal metaplasia was also higher in the infected children. Eradication of H. pylori infection for this risk group may prevent subsequent development of gastric cancer. PMID- 25520127 TI - Improved eradication rate of standard triple therapy by adding bismuth and probiotic supplement for Helicobacter pylori treatment in Thailand. AB - BACKGROUND: Helicobacter pylori (H. pylori) remains an important cause of gastric cancer and peptic ulcer disease worldwide. Treatment of H. pylori infection is one of the effective ways to prevent gastric cancer. However, standard triple therapy for H. pylori eradication is no longer effective in many countries, including Thailand. This study was designed to evaluate the efficacy of adding bismuth and probiotic to standard triple therapy for H. pylori eradication. MATERIALS AND METHODS: In this prospective single center study, H. pylori infected gastritis patients were randomized to receive 7- or 14-day standard triple therapy plus bismuth with probiotic or placebo. Treatment regimen consisted of 30 mg lansoprazole twice daily, 1 g amoxicillin twice daily, 1 g clarithromycin MR once daily and 1,048 mg bismuth subsalicylate twice daily. Probiotic bacteria composed of Bifidobacterium lactis, Lactobacillus acidophilus and Lactobacillus paracasei. Placebo was conventional drinking yogurt without probiotic. CYP2C19 genotyping and antibiotic susceptibility tests were also done. H pylori eradication was defined as a negative 13C-urea breath test at least 2 weeks after completion of treatment. RESULTS: One hundred subjects were enrolled (25 each to 7- and 14-day regimens with probiotic or placebo). Antibiotic susceptibility tests showed 36.7% metronidazole and 1.1% clarithromycin resistance. CYP2C19 genotyping revealed 40.8%, 49% and 10.2% were rapid, intermediate and poor metabolizers, respectively. The eradication rates of 7- or 14 regimens with probiotics were 100%. Regarding adverse events, the incidence of bitter taste was significantly lower in the 7- day regimen with the probiotic group compared with 7- day regimen with placebo (40% vs. 64%; p=0.04). CONCLUSIONS: The 7-day standard triple therapy plus bismuth and probiotic can provide an excellent cure rate of H. pylori (100%) in areas with low clarithromycin resistance such as Thailand, regardless of CYP2C19 genotype. Adding a probiotic also reduced treatment-related adverse events. PMID- 25520128 TI - Inhibition effects of lamellarin D on human leukemia K562 cell proliferation and underlying mechanisms. AB - Lamellarin D (LamD) is a marine alkaloid with a pronounced cytotoxicity against a large panel of cancer cells, affecting cell growth and inducing apoptosis. However, the molecular mechanisms of action of this compound are poorly understood. In this study, the anticancer efficacy of LamD was investigated in human leukemia K562 cells. The results showed suppressed cell proliferation and induction of G0/G1-phase arrest,while expression of CDK1, and activity of smad3 and smad5 were reduced, but that of p27, p53 and STGC3 was increased. LamD induced cell apoptosis through activation of caspases-8/-3, inhibition of survivin and Bcl-2, suggesting that this compound may also act through a caspase independent pathway. Moreover, LamD inhibited the secretion of TGF-beta, IL 1beta, IL-6, IL-8 and other inflammatory cytokines and the transcriptional activity of transcription factor NF-kappaB in human leukemia K562 cells. Taken together, our results suggest that LamD-mediated inhibition of leukemia cell proliferation may be related to the induction of apoptosis and the regulation of cell cycle, tumor- related gene expression and cytokine expression, which may provide a new way of thinking for the treatment leukemia. PMID- 25520129 TI - Annexin A2 and CD105 expression in pancreatic ductal adenocarcinoma is associated with tumor recurrence and prognosis. AB - To investigate the value of expression of annexin A2, microvessel density (MVD) and CD105 in pancreatic ductal adenocarcinoma (PDAC) tissues and adjacent normal tissues, immunohistochemical staining was used. The positive expression rate of Annexin A2 and the MVD in pancreatic ductal adenocarcinoma tissues was higher than that in in adjacent normal tissues (p<0.005). Expression of Annexin A2 and MVD correlated with histological grade (p<0.05). MVD of cancers in TNM stage IIb was higher than that in TNM stageI~IIa (p<0.026). Cancerous tissues with Annexin A2 staining grade 3+ had lower MVD than the tissues with the other Annexin A2 staining grade (p<0.05). Patients with high MVD had worse prognosis. However , our study did not confirm Annexin A2 was an independent risk factor for patients with PDAC. We confirmed MVD labeled by CD105 was an independent risk factor for patients with PDAC and had moderate predictive value of prognosis. PMID- 25520130 TI - Serum periplakin as a potential biomarker for urothelial carcinoma of the urinary bladder. AB - The objectives of this study were to examine serum periplakin expression in patients with urothelial carcinoma of the urinary bladder and in normal controls, and to examine relationships with clinicopathological findings. Detection of serum periplakin was performed in 50 patients and 30 normal controls with anti periplakin antibodies using the automatic dot blot system, and a micro-dot blot array with a 256 solid-pin system. Levels in patients with urothelial carcinoma of the urinary bladder were significantly lower than those in normal controls (0.31 and 5.68, respectively; p<0.0001). The area under the receiver-operator curve level for urothelial carcinoma of the urinary bladder was 0.845. The sensitivity and specificity, using a cut-off point of 4.045, were 83.7% and 73.3%, respectively. In addition, serum periplakin levels were significantly higher in patients with muscle-invasive cancer than in those with nonmuscle invasive cancer (P=0.03). In multivariate Cox proportional hazards regression analysis, none of the clinicopathological factors was associated with an increased risk for progression and cancer-specific survival. Examination of the serum periplakin level may play a role as a non- invasive diagnostic modality to aid urine cytology and cystoscopy. PMID- 25520131 TI - Prevalence and characteristics of colorectal polyps in symptomatic and asymptomatic Iranian patients undergoing colonoscopy from 2009-2013. AB - BACKGROUND: Colorectal cancer is the third most common type of cancer in males and the second in females in Iran. Males are more likely to develop CRC than women and age is considered as a main risk factor for colorectal cancer. Prevalence of colorectal cancer has been increasing in Asian countries. AIM: The object of this study was to determine the clinical and pathology characteristics of colorectal polyps in Iranian patients and to investigate the variation between our populations with other populations. MATERIALS AND METHODS: A total of 167 patients with colorectal polyps were included in our study. All underwent colonoscopy during 2009-2013 and specimens were taken through polypectomy and transferred to pathology. All data in patient files including pathology reports were collected and analyzed by SPSS 16 software. A two-tailed test was used and a P-value of <0.05 was considered significant. RESULTS: Mean age of participants was 57+/-15. Some 84 were females (50.3%) and 83 males (49.7%). Total of 225 polyps were detected which 119 (52.9%) were in males and 106 (47.1%) were in females. Solitary polyps were observed in 124 patients (74%), 26 (15.6%) had two polyps and 17 (10.1%) with more than two polyps (three to five). Rectosigmoid was the site of most of the polyps (63.1%), followed by 19.6% in the descending colon, 7.6% in the transverse, 5.8% in the ascending, and 3.1% in the cecum, data being missing in two cases. CONCLUSIONS: Recto sigmoid was site of most of the polyps. The most prevalent type of lesion was adenomatous polyps detected in 78 (34.7%). Mixed hyperplastic adenomatous type observed in 70 (31.1%). This high prevalence of adenomatous polyps in Iranian patients implies the urgent need for screening plans to prevent further healthcare problems with colorectal cancer in the Iranian population. PMID- 25520132 TI - Preclinical activity of lobaplatin as a single agent and in combination with taxanes for ovarian carcinoma cells. AB - Lobaplatin, one of the third-generation platinum compounds, has shown encouraging anticancer activity in a variety of tumor types. However, the efficacy of lobaplatin in ovarian cancer has not been systemically evaluated. In this study, lobaplatin as a single agent and in combination with taxanes was investigated in vitro and in an in vitro model of ovarian carcinoma. Using the sulforhodamine B (SRB) assay, the cytotoxic effects of lobaplatin alone and in combination with taxanes were compared with cisplatin and carboplatin in seven ovarian cancer cell lines. In addition, in-vitro antitumor activities were evaluated with cisplatin sensitive and cisplatin-resistant human ovarian cancer xenografts in nude mice. The cytotoxicity of lobaplatin was similar to or higher than that of cisplatin and carboplatin, with IC50 values from 0.9 to 13.8 MUmol/L in a variety of ovarian cancer cells. The combination of lobaplatin with docetaxel yielded enhanced cytotoxic activity in vitro. In addition, in platinum-sensitive ovarian cancer xenografts, lobaplatin alone showed similar antitumor activity to cisplatin and carboplatin. Furthermore, lobaplatin alone or in combination with docetaxel exhibited significant activity in platinum-resistant ovarian cancer xenografts. These results indicate that the use of lobaplatin alone or in combination with docetaxel might be a rational and novel therapeutic strategy for ovarian cancer. Further clinical development of lobaplatin is clearly warranted. PMID- 25520133 TI - Tim-3 expression by peripheral natural killer cells and natural killer T cells increases in patients with lung cancer--reduction after surgical resection. AB - BACKGROUND: The purpose of this study was to investigate Tim-3 expression on peripheral CD3-CD56+ natural killer (NK) cells and CD3+CD56+ natural killer T (NKT) cells in lung cancer patients. MATERIALS AND METHODS: We analyzed Tim-3+CD3 CD56+ cells, Tim-3+CD3-CD56dim cells, Tim-3+CD3-CD56bright cells, and Tim- 3+CD3+CD56+ cells in fresh peripheral blood from 79 lung cancer cases preoperatively and 53 healthy controls by flow cytometry. Postoperative blood samples were also analyzed from 21 members of the lung cancer patient cohort. RESULTS: It was showed that expression of Tim-3 was significantly increased on CD3-CD56+ cells, CD3- CD56dim cells and CD3+CD56+ cells in lung cancer patients as compared to healthy controls (p=0.03, p=0.03 and p=0.04, respectively). When analyzing Tim-3 expression with cancer progression, results revealed more elevated Tim-3 expression in CD3-CD56+ cells, CD3-CD56dim cells and CD3+CD56+ cells in cases with advanced stages (III/IV) than those with stage I and II (p=0.02, p=0.04 and p=0.01, respectively). In addition, Tim-3 expression was significantly reduced on after surgical resection of the primary tumor (p<0.01). CONCLUSIONS: Tim-3 expression in natural killer cells from fresh peripheral blood may provide a useful indicator of disease progression of lung cancer. Furthermore, it was indicated that Tim-3 might be as a therapeutic target. PMID- 25520134 TI - Long-term treatment results in soft tissue sarcomas of the thoracic wall treated with pre-or-postoperative radiotherapy--a single institution experience. AB - OBJECTIVE: To evaluate the long term results among patients with soft tissue sarcoma of the thoracic wall. MATERIALS AND METHODS: Twenty-six patients who were treated with pre-or postoperative radiotherapy between December 1980-December 2007, with a diagnosis of soft tissue sarcoma of the thoracic wall were retrospectively evaluated. RESULTS: The median age was 44 years (14-85 years) and 15 of them were male. A total of 50% of patients were grade 3. The most common histologic type of tumor was undifferentiated pleomorphic sarcoma (26.9%). Tumor size varied between 2-25 cm (median 6.5 cm). Seventeen of the cases had marginal and 9 had wide local resection. Four cases received preoperative radiotherapy and 22 postoperative radiotherapy. Six of the patients with large and high grade tumors received chemotherapy. Median follow-up time was 82 months (9-309 months). Local recurrence and metastasis was detected in 34.6% and 42.3% of patients, respectively. Five- year local control (LC), disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS) were 62%, 38%, 69%, and 76% respectively. On univariate analysis, the patients with positive surgical margins had a markedly lower 5-year LC rate than patients with negative surgical margin, but the difference was not significant (43% vs 78%, p=0.1). Five-year DFS (66% vs 17%) and DSS (92% vs 60%) rates were significantly worse for the patients who had high grade tumors (p=0.01, p=0.008 respectively). CONCLUSIONS: Tumor grade and surgical margin are essential parameters for determining the prognosis of thoracic wall soft tissue sarcoma both in our series and the literature. PMID- 25520135 TI - Promoter methylation of MGMT gene in serum of patients with esophageal squamous cell carcinoma in North East India. AB - BACKGROUND: Promoter hypermethylation is a common event in human cancer. O6 methylguanine-DNA methyltransferase (MGMT) is a gene involved in DNA repair, which is methylated in a variety of cancers. We aimed to explore the methylation status of MGMT gene among the North Eastern population where esophageal cancer incidence and exposure to carcinogens like nitrosamines is high. MATERIALS AND METHODS: A total of 100 newly diagnosed esophageal cancer cases along with equal number of age, sex and ethnicity matched controls were included in this study. Methylation specific PCR was used to determine the MGMT methylation status in serum samples. RESULTS: Aberrant promoter methylation of the MGMT gene was detected in 70% of esophageal cancer cases. Hypermethylation of MGMT gene was found to be influenced by environmental factors like betel quid and tobacco which contain potent carcinogens like nitrosamines. Tobacco chewing and tobacco smoking habit synergistically with MGMT methylation elevated the risk for esophageal cancer development [adjusted OR=5.02, 95% CI=1.35-18.74; p=0.010 for tobacco chewing and Adjusted OR=3.00, 95% CI=1.22-7.36; p=0.014 for tobacco smoking]. CONCLUSIONS: Results suggest that the DNA hypermethylation of MGMT is an important mechanism for MGMT gene silencing resulting in esophageal cancer development and is influenced by the environmental factors. Thus MGMT hypermethylation can be used as a biomarker for esophageal cancer in high incidence region of North East India. PMID- 25520136 TI - Clinical significance of BCR-ABL fusion gene subtypes in chronic myelogenous and acute lymphoblastic leukemias. AB - BACKGROUND: Some reports have suggested that chronic myeloid leukemia (CML) patients have a higher prevalence of M-bcr than acute lymphoblastic leukemia (ALL) patients, which show a higher prevalence of m-bcr. However, the relationship between BCR-ABL subtypes and progression of CML and ALL remains unclear. MATERIALS AND METHODS: 354 CML chronic phase (CML-CP) patients, 26 CML blastic phase (CML-BP) patients and 72 ALL patients before treatment with BCR-ABL positive were recruited for blood routine examination and bone marrow smear cytology. Some 80 CML-CP and 32 ALL patients after imatinib (IM) treatment were followed-up for BCR-ABL relative concentrations detected after treatment for 3, 6 and 9 months and 1 year. RESULTS: Before treatment, CML-CP patients showed lower BCR-ABL relative concentrations with a higher proportion of M-bcr (42.7%) compared to CML-BP and ALL patients while ALL patients had a higher BCR-ABL relative concentration with high expression of m-bcr (51.4%). Patients with M-bcr demonstrated higher WBC counts than those with m-bcr and the mixed group and higher PLT counts were noted in the CML-CP and ALL groups. After imatinib (IM) treatment, patients with m-bcr showed higher BCR-ABL relative concentrations in both CML-CP and ALL groups. CONCLUSIONS: This study identified the BCR-ABL gene as an important factor in CML and ALL cases. The M-bcr subtype was associated more with CML while the m-bcr subtype was associated more with ALL. Patients with m-bcr seem to have a poorer response to IM in either CML or ALL patients compared to M-bcr patients. PMID- 25520138 TI - No association of hypoxia inducible factor-1alpha gene polymorphisms with breast cancer in North-West Indians. AB - BACKGROUND: Hypoxia inducible factor-1 alpha (HIF-1alpha) is the key regulator of cellular responses to hypoxia and plays a central role in tumour growth. Presence of Single nucleotide polymorphisms (SNPs) in the critical regulatory domains of HIF-1alpha may result in the overexpression of the protein and subsequent changes in the expression of the downstream target genes. The aim of study was to investigate the association of three SNPs (g.C111A, g.C1772T and g.G1790A) of HIF 1alpha with the risk of breast cancer in North Indian sporadic breast cancer patients. MATERIALS AND METHODS: A total of 400 subjects, including 200 healthy controls and 200 patients with breast cancer were recruited in this study. Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The CC and CA genotype frequency of HIF-1alpha g.C111A polymorphism was 100 vs 99% and 0 vs 1% in breast cancer patients and healthy controls respectively. The frequencies of CC, CT and TT genotype of g.C1772T polymorphism were 76 vs 74.5%, 19 vs 21% and 5 vs 4.5% in breast cancer patients and control individuals respectively. There was no significant difference in genotype and allele frequencies of HIF-1alpha g.C1772T polymorphism between cases and control individuals (p>0.05). For g.G1790A genotypes, all patients and controls had only GG genotype. CONCLUSIONS: The three HIF-1alpha polymorphisms (g.C111A, g.C1772T and g.G1790A) are not associated with breast cancer risk in North-West Indian patients. PMID- 25520137 TI - Silencing of COX-2 by RNAi modulates epithelial-mesenchymal transition in breast cancer cells partially dependent on the PGE2 cascade. AB - In order to prove whether downregulation of COX-2 (Cyclooxygenase-2) could modulate the epithelial- mesenchymal transition (EMT) of breast cancer, celecoxib and siRNA were respectively used to inhibit COX-2 function and expression in MDA MB-231 cells. The EMT reversal effect in the RNAi treated group was better than that of the celecoxib group while there were no obvious differences in the medium PGE2 levels between the two groups. The results show that COX-2 pathways may contribute considerably to EMT of breast cancer cells, partially dependent on the PGE2 cascade. Akt2, ZEB2 and Snail were measured to clarify the underlying mechanisms of COX-2 on EMT; COX-2 may modulate EMT of breast cancer by regulating these factors. This finding may be helpful to elucidate the mechanisms of selective COX-2 inhibitor action in EMT modulation in breast cancer. PMID- 25520139 TI - Differences in cancer incidence among predominantly Muslim and Buddhist subpopulations in Songkhla. AB - BACKGROUND: The population of Songkhla, a province in Southern Thailand, can be divided into a predominantly Muslim subpopulation (PMSP, approximately 70% Muslim) and a predominantly Buddhist subpopulation (PBSP, around 14% Muslim). OBJECTIVES: This study was conducted to 1) describe the incidence of various cancers in both PMSP and PBSP, and 2) compare the incidence of various cancers between the two subpopulations. MATERIALS AND METHODS: Cancer cases diagnosed between 1990 and 2010 were drawn from the database of Songkhla Cancer Registry. Population denominators were estimated from the 3 population censuses surveyed by the National Statistical Office of Thailand in 1990, 2000, and 2010. RESULTS: The age-standardized incidence rates (ASR) of the 5 commonest male cancers among both subpopulations were calculated. In females, a lower incidence of cancers of the cervix and breast in PMSP compared to PBSP, with odds ratios of 0.54 (95% CI: 0.45-0.64) and 0.51 (95% CI: 0.43-0.60) respectively, was observed. In males, the incidence of cancers of the lung, liver, colon-rectum, and some other cancers were significantly different between the two populations in the past, but only prostate cancer showed a lower incidence among males in PMSP in recent years. Independent of sex and year of diagnosis, the incidence of lung, liver, NHL, and colorectal cancers was lower in MPSP compared to BPSP, with odds ratios of 0.75 (95% CI: 0.65-0.85), 0.74 (95% CI: 0.62-0.88), 0.74 (95% CI: 0.60-0.91), and 0.67 (95% CI: 0.56-0.78) respectively. CONCLUSIONS: The differences in incidence of some cancers and religion- related culture between the two subpopulations need 2 sets of cancer-control plans and goals to fit the unique population context in deep Southern Thailand. This plan can be used in the 3 southernmost provinces of Thailand where the percentage of Muslims is over 85%. PMID- 25520140 TI - Laparoscopic versus open surgery for rectal cancer: a systematic review and meta analysis of randomized controlled trials. AB - BACKGROUND AND AIM: Laparoscopic and open rectum surgery for rectal cancer remains controversial. This systematic review compared the short-term and long term efficiency and complications associated with laparoscopic and open resection for rectal cancer. MATERIALS AND METHODS: We searched PubMed, Embase, Cochrane Library, ISI Web of Knowledge and the China Biology Medicine Database to identify potential randomized controlled trials from their inception to March 31, 2014 without language restriction. Additional articles were identified from searching bibliographies of retrieved articles. Two reviewers independently assessed the full-text articles according to the pre-specified inclusion and exclusion criteria as well as the methodological quality of included trials. The meta analysis was performed using RevMan 5.2. RESULTS: A total of 16 randomized controlled trials involving 3,045 participants (laparoscopic group, 1,804 cases; open group, 1,241 cases) were reviewed. Laparoscopic surgery was associated with significantly lower intraoperative blood loss, earlier return of bowel movement and reduced length of hospital stay as compared to open surgery, although with increased operative time. It also showed an obvious advantage for minimizing late complications of adhesion-related bowel obstruction. Importantly, there were no significant differences in other postoperative complications, oncological clearance, 3-year and 5-year or 10 year recurrence and survival rates between two procedures. CONCLUSIONS: On the basis of this meta-analysis we conclude that laparoscopic surgery has advantages of earlier postoperative recovery, less blood loss and lower rates of adhesion-related bowel obstruction. In addition, oncological outcome is comparable after laparoscopic and open resection for rectal cancer. PMID- 25520141 TI - Curdione inhibits proliferation of MCF-7 cells by inducing apoptosis. AB - BACKGROUND: Curdione, one of the major components of Curcuma zedoaria, has been reported to possess various biological activities. It thus might be a candidate anti-flammatory and cancer chemopreventive agent. However, the precise molecular mechanisms of action of curdione on cancer cells are still unclear. In this study, we investigated the effect of curdione on breast cancer. MATERIALS AND METHODS: Xenograft nude mice were used to detect the effect of curdione on breast cancer in vivo; we also tested the effect of curdione on breast cancer in vitro by MTT, Flow cytometry, JC-I assay, and western blot. RESULTS: Firstly, we found that curdione significantly suppressed tumor growth in a xenograft nude mouse breast tumor model in a dose-dependent manner. In addition, curdione treatment inhibited cell proliferation and induced cell apoptosis. Moreover, after curdione treatment, increase of impaired mitochondrial membrane potential occurred in a concentration dependent manner. Furthermore, the expression of apoptosis-related proteins including cleaved caspase-3, caspase-9 and Bax was increased in curdione treatment groups, while the expression of the anti-apoptotic Bcl-2 was decreased. Inhibitors of caspase-3 were used to confirm that curdione induced apoptosis. CONCLUSIONS: Overall, our observations first suggested that curdione inhibited the proliferation of breast cancer cells by inducing apoptosis. These results might provide some molecular basis for the anti-cancer activity of curdione. PMID- 25520142 TI - [Effect of transparent yellow and orange colored contact lenses on color discrimination in the yellow color range]. AB - BACKGROUND: Colored transparent filters cause a change in color perception and have an impact on the perceptible amount of different colors and especially on the ability to discriminate between them. Yellow or orange tinted contact lenses worn to enhance contrast vision by reducing or blocking short wavelengths also have an effect on color perception. METHODS: The impact of the yellow and orange tinted contact lenses Wohlk SPORT CONTRAST on color discrimination was investigated with the Erlangen colour measurement system in a study with 14 and 16 subjects, respectively. In relation to a yellow reference color located at u' = 0.2487/v' = 0.5433, measurements of color discrimination thresholds were taken in up to 6 different color coordinate axes. Based on these thresholds, color discrimination ellipses were calculated. These results are given in the Derrington, Krauskopf and Lennie (DKL) color system. RESULTS: Both contact lenses caused a shift of the reference color towards higher saturated colors. Color discrimination ability with the yellow and orange colored lenses was significantly enhanced along the blue-yellow axis in comparison to the reference measurements without a tinted filter. Along the red-green axis only the orange lens caused a significant reduction of color discrimination threshold distance to the reference color. CONCLUSION: Yellow and orange tinted contact lenses enhance the ability of color discrimination. If the transmission spectra and the induced changes are taken into account, these results can also be applied to other filter media, such as blue filter intraocular lenses. PMID- 25520143 TI - [Orbital metastasis of a previously unknown lung carcinoma mimicking posterior ischemic optic neuropathy]. AB - A 65-year-old patient presented with increasing loss of vision in the right eye. A relative afferent pupillary defect as well as visual field perimetry deficits in an otherwise unremarkable eye led to the presumed diagnosis of ischemia of the optic nerve; however, further imaging revealed an extensive necrotic bronchial carcinoma in the left upper lobe metastasizing to the orbit with compression of the optic nerve. The clinical and histological features are discussed with respect to possible primary origins of orbital metastases. PMID- 25520144 TI - [Significance of transcanalicular laser assisted dacryocystorhinostomy in modern lacrimal drainage surgery]. AB - For the treatment of postsaccal lacrimal drainage obstructions transcanalicular laser dacryocystorhinostomy (TCL-DCR) represents a less invasive alternative to external Toti procedures. Herein, a diode laser optical fiber is inserted into the lacrimal sac via the canaliculi. Under visual control with a nasal endoscope laser energy is applied until a patent osteotomy between the sac and nasal mucosa has been created. Published success rates of 70-90% get close to the excellent results of Toti procedures. Besides describing therapy planning and surgical technique, pros and cons of TCL-DCR are discussed. PMID- 25520145 TI - Pregnant women are a reservoir of malaria transmission in Blantyre, Malawi. AB - BACKGROUND: During pregnancy, women living in malaria-endemic regions are at increased risk of malaria infection and can harbour chronic placental infections. Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP-IPTp) is administered to reduce malaria morbidity. It was hypothesized that the presence of placental malaria infection and SP-IPTp use would increase the risk of peripheral blood gametocytes, the parasite stage that is transmissible to mosquitoes. This would suggest that pregnant women may be important reservoirs of malaria transmission. METHODS: Light microscopy was used to assess peripheral gametocytaemia in pregnant women enrolled in a longitudinal, observational study in Blantyre, Malawi to determine the association between placental malaria and maternal gametocytaemia. The relationship between SP-IPTp and gametocytaemia was also examined. RESULTS: 2,719 samples from 448 women were analysed and 32 episodes of microscopic gametocytaemia were detected in 27 women. At the time of enrolment 22 of 446 women (4.9%) had gametocytaemia and of the 341 women for whom there was sufficient sampling to analyse infection over the entire course of pregnancy, 27 (7.9%) were gametocytaemic at least once. Gametocytaemia at enrollment was associated with placental malaria, defined as malaria pigment or parasites detected by histology or qPCR, respectively (OR: 32.4, 95% CI: 4.2 250.2), but was not associated with adverse maternal or foetal outcomes. Administration of SP-IPTp did not affect gametocyte clearance or release into peripheral blood. CONCLUSIONS: Gametocytaemia is present in 5% of pregnant women at their first antenatal visit and associated with placental malaria. SP-IPTp does not alter the risk of gametocytaemia. These data suggest that pregnant women are a significant reservoir of gametocyte transmission and should not be overlooked in elimination efforts. Interventions targeting this population would benefit from reaching women prior to first antenatal visit. PMID- 25520146 TI - Evaluation of a vaccine formulation against Streptococcus pneumoniae based on choline-binding proteins. AB - Streptococcus pneumoniae has proteins that are attached to its surface by binding to phosphorylcholine of teichoic and lipoteichoic acids. These proteins are known as choline-binding proteins (CBPs). CBPs are an interesting alternative for the development of a cost-effective vaccine, and PspA (pneumococcal surface protein A) is believed to be the most important protective component among the different CBPs. We sought to use CBPs eluted from pneumococci as an experimental vaccine. Since PspA shows variability between isolates, we constructed strains producing different PspAs. We used the nonencapsulated Rx1 strain, which produces PspA from clade 2 (PspA2), to generate a pspA-knockout strain (Rx1 DeltapspA) and strains expressing PspA from clade 1 (Rx1 pspA1) and clade 4 (Rx1 pspA4). We grew Rx1, Rx1 DeltapspA, Rx1 pspA1, and Rx1 pspA4 in Todd-Hewitt medium containing 0.5% yeast extract and washed cells in 2% choline chloride (CC). SDS-PAGE analysis of the proteins recovered by a CC wash showed few bands, and the CBPs PspA and PspC (pneumococcal surface protein C) were identified by mass spectrometry analysis. Subcutaneous immunization of mice with these full-length native proteins without adjuvant led to significantly higher rates of survival than immunization with diluent after an intranasal lethal challenge with two pneumococcal strains and also after a colonization challenge with one strain. Importantly, immunization with recombinant PspA4 (rPspA4) without adjuvant did not elicit significant protection. PMID- 25520147 TI - Measurement of phenotype and absolute number of circulating heparin-binding hemagglutinin, ESAT-6 and CFP-10, and purified protein derivative antigen specific CD4 T cells can discriminate active from latent tuberculosis infection. AB - The tuberculin skin test (TST) and interferon gamma (IFN-gamma) release assays (IGRAs) are used as adjunctive tests for the evaluation of suspected cases of active tuberculosis (TB). However, a positive test does not differentiate latent from active TB. We investigated whether flow cytometric measurement of novel combinations of intracellular cytokines and surface makers on CD4 T cells could differentiate between active and latent TB after stimulation with Mycobacterium tuberculosis-specific proteins. Blood samples from 60 patients referred to the Singapore Tuberculosis Control Unit for evaluation for active TB or as TB contacts were stimulated with purified protein derivative (PPD), ESAT-6 and CFP 10, or heparin-binding hemagglutinin (HBHA). The CD4 T cell cytokine response (IFN-gamma, interleukin-2 [IL-2], interleukin-17A [IL-17A], interleukin-22 [IL 22], granulocyte-macrophage colony-stimulating factor [GM-CSF], and tumor necrosis factor alpha [TNF-alpha]) and surface marker expression (CD27, CXCR3, and CD154) were then measured. We found that the proportion of PPD-specific CD4 T cells, defined as CD154(+) TNF-alpha(+) cells that were negative for CD27 and positive for GM-CSF, gave the strongest discrimination between subjects with latent and those with active TB (area under the receiver operator characteristic [ROC] curve of 0.9277; P < 0.0001). Also, the proportions and absolute numbers of HBHA-specific CD4 T cells were significantly higher in those with latent TB infection, particularly CD154(+) TNF-alpha(+) IFN-gamma(+) IL-2(+) and CD154(+) TNF-alpha(+) CXCR3(+). Finally, we found that the ratio of ESAT-6- and CFP-10 responding to HBHA-responding CD4 T cells was significantly different between the two study populations. In conclusion, we found novel markers of M. tuberculosis specific CD4 cells which differentiate between active and latent TB. PMID- 25520148 TI - Schistosoma mansoni soluble egg antigens enhance T cell responses to a newly identified HIV-1 Gag H-2b epitope. AB - Schistosome infection induces significant T helper type 2 (Th2) and anti inflammatory immune responses and has been shown to negatively impact vaccine efficacy. Our goal was to determine if the administration of schistosome soluble egg antigens (SEA) would negatively influence the induction of cytotoxic T lymphocyte (CTL) and Th1-type T cell responses to an HIV candidate vaccine in the Th1-biased C57BL/6 mouse strain. Initial experiments failed, as we were unable to detect any response to the defined class I epitope for HIV-1 IIIB Gag. Therefore, we initiated an epitope mapping study to identify C57BL/6 (H-2(b)) T cell epitopes in HIV-1 IIIB Gag in order to perform the experiments. This analysis defined two previously unreported minimal class I H-2(b) and class II I-A(b) epitopes for HIV-1 IIIB Gag. The newly defined HIV-1 IIIB Gag epitopes were used to evaluate the influence of SEA on the generation of CTL and Th1-type HIV-1 IIIB Gag responses. Surprisingly, in contrast to our hypothesis, we observed that the coadministration of SEA with a Listeria monocytogenes vector expressing HIV-1 IIIB Gag (Lm-Gag) led to a significantly increased frequency of gamma interferon (IFN-gamma)-producing CD8(+) and CD4(+) T cells in C57BL/6 mice compared to mice immunized with Lm-Gag only. These observations suggest that SEA contains, in addition to Th2-type and immune-suppressive molecules, substances that can act with the Lm-Gag vaccine to increase CTL and Th1-type vaccine-specific immune responses. PMID- 25520149 TI - Use and clinical interpretation of pneumococcal antibody measurements in the evaluation of humoral immune function. AB - Pneumococcal vaccination is a commonly used technique for assessing the humoral immune status of a patient suspected of having immunodeficiency. Interpretation of what constitutes an adequate response, however, can be challenging. This is due to the complexity of the data generated from serotype-specific assays, historical variations in the assays used to measure pneumococcal antibodies, and varying recommendations on the relevant cut points that define response. In this review, we summarize the historical evolution of assays used for this purpose and discuss the analytical considerations that have influenced published data. We also examine current clinical recommendations for defining an adequate response to vaccination, with a particular focus on the interpretation of serotype specific data generated by multiplex assays. PMID- 25520150 TI - Seroprevalence of cytomegalovirus among children 1 to 5 years of age in the United States from the National Health and Nutrition Examination Survey of 2011 to 2012. AB - Cytomegalovirus (CMV) seroprevalence among U.S. children 1 to 5 years old was assessed in the National Health and Nutrition Examination Survey of 2011 to 2012. The overall seroprevalence (95% confidence interval) of IgG was 20.7% (14.4 to 28.2%), that of IgM was 1.1% (0.4 to 2.4%), and that of low IgG avidity was 3.6% (1.7 to 6.6%), corresponding to a 17.3% (10.1 to 26.7%) prevalence of recent infection among IgG-positive children. PMID- 25520154 TI - In-plane particle counting at contact lines of evaporating colloidal drops: effect of the particle electric charge. AB - Complete understanding of colloidal assembly is still a goal to be reached. In convective assembly deposition, the concentration gradients developed in evaporating drops or reservoirs are usually significant. However, collective diffusion of charge-stabilized particles has been barely explored. The balance between convective and diffusive flows may dictate the particle dynamics inside evaporating colloidal drops. In this work we performed in situ counting of fluorescent particles in the vicinity of the triple line of evaporating sessile drops by using confocal laser scanning microscopy. We used particles of different sizes, with different charge response over the pH scale and we focused on charged and nearly uncharged particles. Two substrates with different receding contact angles were used. Binary colloidal mixtures were used to illustrate simultaneously the accumulation of particles with two different charge states at the triple line. The deposition rate close to the triple line was different depending on the electric state of the particle, regardless of the substrate used. PMID- 25520153 TI - Synergistic Effect of Sulindac and Simvastatin on Apoptosis in Lung Cancer A549 Cells through AKT-Dependent Downregulation of Survivin. AB - PURPOSE: Non-steroidal anti-inflammatory drugs (NSAIDs) and statins are potential chemopreventive or chemotherapeutic agents. The mechanism underlying the deregulation of survivin by NSAIDs and statins in human non-small cell lung cancer cells has not been elucidated. In this study, we investigated the synergistic interaction of sulindac and simvastatin in lung cancer A549 cells. MATERIALS AND METHODS: Cell viability was measured by an MTT assay, while the expression of apoptotic markers, AKT, and survivin in response to sulindac and simvastatin was examined by Western blotting. DNA fragmentation by apoptosis was analyzed by flow cytometry in A549 cells. Reactive oxygen species (ROS) generation was measured by flow cytometry using H2DCFDA and MitoSOX Red, and the effects of pretreatment with N-acetylcysteine were tested. The effects of AKT on survivin expression in sulindac- and simvastatin-treated cells were assessed. Survivin was knocked down or overexpressed to determine its role in apoptosis induced by sulindac and simvastatin. RESULTS: Sulindac and simvastatin synergistically augmented apoptotic activity and intracellular ROS production in A549 cells. Inhibition of AKT by siRNA or LY294002 inhibited survivin, while AKT overexpression markedly increased survivin expression, even in the presence of sulindac and simvastatin. Moreover, survivin siRNA enhanced sulindac- and simvastatininduced apoptosis. In contrast, survivin upregulation protected against sulindac- and simvastatin-induced apoptosis. CONCLUSION: Combined treatment with sulindac and simvastatin augmented their apoptotic potential in lung cancer cells through AKT signaling-dependent downregulation of survivin. These results indicate that sulindac and simvastatin may be clinically promising therapies for the prevention of lung cancer. PMID- 25520151 TI - Tetravalent recombinant dengue virus-like particles as potential vaccine candidates: immunological properties. AB - BACKGROUND: Currently, a licensed vaccine for Dengue Virus (DENV) is not yet available. Virus-like particles (VLP) have shown considerable promise for use as vaccines and have many advantages compared to many other types of viral vaccines. VLPs have been found to have high immunogenic potencies, providing protection against various pathogens. RESULTS: In the current study, four DENV-VLP serotypes were successfully expressed in Pichia pastoris, based on co-expression of the prM and E proteins. The effects of a tetravalent VLP vaccine were also examined. Immunization with purified, recombinant, tetravalent DENV1-4 VLPs induced specific antibodies against all DENV1-4 antigens in mice. The antibody titers were higher after immunization with the tetravalent VLP vaccine compared to titers after immunization with any of the dengue serotype VLPs alone. Indirect immunofluorescence assay (IFA) results indicated that sera from VLP immunized mice recognized the native viral antigens. TNF-alpha and IL-10 were significantly higher in mice immunized with tetravalent DENV-VLP compared to those mice received PBS. The tetravalent VLP appeared to stimulate neutralizing antibodies against each viral serotype, as shown by PRNT50 analysis (1:32 against DENV1 and 2, and 1:16 against DENV3 and 4). The highest titers with the tetravalent VLP vaccine were still a little lower than the monovalent VLP against the corresponding serotype. The protection rates of tetravalent DENV-VLP immune sera against challenges with DENV1 to 4 serotypes in suckling mice were 77, 92, 100, and 100%, respectively, indicating greater protective efficacy compared with monovalent immune sera. CONCLUSIONS: Our results provide an important basis for the development of the dengue VLP as a promising non-infectious candidate vaccine for dengue infection. PMID- 25520156 TI - Natural occurrence of four Alternaria mycotoxins in tomato- and citrus-based foods in China. AB - A total of 70 tomato-based and 86 citrus-based products collected in China were analyzed for alternariol, alternariol monomethyl ether, tentoxin, and tenuazonic acid by ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry. No toxins were found in any fresh tomato or citrus fruit samples. Tenuazonic acid was the predominant toxin detected in all tomato ketchup (10.2-1787 MUg/kg) and tomato juice samples (7.4-278 MUg/kg). Alternariol was quantitated at higher level than alternariol monomethyl ether with the ratio of alternariol/alternariol monomethyl ether ranging from 0.37 to 104 in 14 alternariol-positive tomato ketchup samples. Tentoxin was detected at much lower levels in all samples analyzed. Some citrus juice samples were positive for tenuazonic acid and alternariol monomethyl ether. It is necessary to conduct a systemic surveillance of Alternaria toxins in raw and processed foods to provide the scientific basis for risk assessment of dietary exposure to these toxins in Chinese populations. PMID- 25520155 TI - Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion. AB - The membrane localization and activation of cytoskeletal protein talin are key steps to initiate the integrin transmembrane receptors' activation, which mediates many cellular adhesive responses such as cell migration, spreading and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to the membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin-binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion. PMID- 25520157 TI - Birthweight and risk markers for type 2 diabetes and cardiovascular disease in childhood: the Child Heart and Health Study in England (CHASE). AB - AIMS/HYPOTHESIS: Lower birthweight (a marker of fetal undernutrition) is associated with higher risks of type 2 diabetes and cardiovascular disease (CVD) and could explain ethnic differences in these diseases. We examined associations between birthweight and risk markers for diabetes and CVD in UK-resident white European, South Asian and black African-Caribbean children. METHODS: In a cross sectional study of risk markers for diabetes and CVD in 9- to 10-year-old children of different ethnic origins, birthweight was obtained from health records and/or parental recall. Associations between birthweight and risk markers were estimated using multilevel linear regression to account for clustering in children from the same school. RESULTS: Key data were available for 3,744 (66%) singleton study participants. In analyses adjusted for age, sex and ethnicity, birthweight was inversely associated with serum urate and positively associated with systolic BP. After additional height adjustment, lower birthweight (per 100 g) was associated with higher serum urate (0.52%; 95% CI 0.38, 0.66), fasting serum insulin (0.41%; 95% CI 0.08, 0.74), HbA1c (0.04%; 95% CI 0.00, 0.08), plasma glucose (0.06%; 95% CI 0.02, 0.10) and serum triacylglycerol (0.30%; 95% CI 0.09, 0.51) but not with BP or blood cholesterol. Birthweight was lower among children of South Asian (231 g lower; 95% CI 183, 280) and black African Caribbean origin (81 g lower; 95% CI 30, 132). However, adjustment for birthweight had no effect on ethnic differences in risk markers. CONCLUSIONS/INTERPRETATION: Birthweight was inversely associated with urate and with insulin and glycaemia after adjustment for current height. Lower birthweight does not appear to explain emerging ethnic difference in risk markers for diabetes. PMID- 25520158 TI - Multidisciplinary cancer care may impact on the postoperative mortality and survival of patients with oesophageal and oesophagogastric junction cancer: a retrospective cohort study. AB - BACKGROUND: Modern management of Oesophageal and oesophagogastric junction (OGJ) cancers requires a multidisciplinary approach, which was implemented at our health centre in 2005. This study aimed to assess the impact of this change on clinical outcomes. METHODS: A retrospective cohort study was conducted, covering all patients treated for oesophageal and OGJ cancer at the cancer centre established by the Bellvitge University Hospital and Catalonian Institute of Oncology, over two time periods, i.e. 2000-2004 and 2005-2008. Descriptive and multivariate analyses were performed using survival at 1 and 3 years as dependent variables. RESULTS: Between 1 January 2000 and 31 December 2008, 586 patients were included. Number of patients with unknown stage at diagnosis was significantly reduced. Preoperative strategies at the oesophageal location clearly increased in the recent period. A multidisciplinary approach resulted in a significant reduction in surgical mortality (11.8 vs. 2 %) in the period 2005 2008. Analysis restricted to patients undergoing surgery with curative intent indicated a significant increase in 1- and 3-year survival in the latter period (68.4 vs. 89.8 and 38.2 vs. 57.1 %, respectively). Multivariate analysis showed that variables associated with improved survival were: age; tumour stage; radical intent of treatment (surgery and radical combined chemoradiotherapy); and therapeutic strategy. CONCLUSION: Better selection of patients for therapy together with improved staging resulted in a significant improvement in 1- and 3 year survival in cases undergoing surgery with curative intent. These changes would support the adoption of a multidisciplinary approach to clinical decision making in cases of oesophageal and OGJ cancer. PMID- 25520159 TI - Severe erytrodermic psoriasis in child twins: from clinical-pathological diagnosis to treatment of choice through genetic analyses: two case reports. AB - BACKGROUND: Pediatric erythroderma is a severe cutaneous disorder, which may pose diagnostic and therapeutic challenges. Psoriasis, ichthyoses, atopy, seborrhoeic dermatitis, pityriasis rubra pilaris, infections, metabolic diseases, drugs reaction, may cause erythroderma. The therapy should be tailored on each aetiology, if possible. The biochemical and metabolic imbalance should be corrected, and particular attention should be paid to the psychosocial behavior often related to this disfiguring disease. CASE PRESENTATION: Two 3 year-old Caucasian twins have been suffering from an unmanageable erythroderma since the age of 8 months. The diagnosis of psoriasis, already remarkably expressed in the father's family in three cases of fraternal twins, could be enforced for several points. Major histocompatibility complex, class I, Cw*06 was detected in both twins; we found no transglutaminase-1, no corneodesmosin, nor any Interleukin-36 receptor antagonist gene mutations. We performed a cutaneous histology, positive immunostaining for Lympho-epithelial Kazal-type-related inhibitor, dermoscopy and reflectance confocal microscopy. The twins had previously received systemic steroids, short cycles of low-dosage ciclosporine, followed by etanercept at the dosage of 0,8 mg/kg, without reliable results. Cyclosporine was then reconsidered at a dosage of 5 mg/kg/day with close blood monitoring. After three months of treatment, consistent clearing and significant improvement of their social and psychological behaviour were achieved. After over one year of continuous therapy with cyclosporine, the twins have still maintained the result obtained. CONCLUSION: Pediatric erythroderma may pose a great challenge as a potentially life-threatening condition causing extreme distress in children, parents and pediatricians. In young patients it is mandatory to establish correct clinical and instrumental procedures, possibly supplemented by genetic analyses such as those we required, in order to determine an effective and safe therapy in terms of cost-benefit and put patients and family in the best condition to perform common daily activities. PMID- 25520160 TI - Correct wilderness medicine definitions and their impact on care. PMID- 25520161 TI - Author's reply to Lipman: 'correct wilderness medicine definitions and their impact on care'. PMID- 25520162 TI - On telomeres long and short. PMID- 25520165 TI - Functional Impairment Variability in Children With ADHD Due to Emotional Impulsivity. AB - OBJECTIVE: The present study utilized ecological momentary assessment (EMA) to examine the effects of emotional impulsivity on overall functional impairment and functional impairment variability (FIV) of children with and without ADHD. METHOD: Parents of 74 children, 8- to 12-year-olds (42 with ADHD, 32 without ADHD), completed EMA assessment protocol ratings of their child's mood (3 times daily) and functional impairment (1 time daily) over the course of 28 days. RESULTS: Hierarchical regression analyses supported the interaction of ADHD diagnostic status and greater EMA-derived emotional impulsivity in the estimation of total functional impairment (Total FI) and FIV. Thus, greater emotional impulsivity was found to be related to greater Total FI and FIV among children with ADHD but not among children without ADHD. CONCLUSION: This study suggests that children with ADHD and greater emotional impulsivity demonstrate greater overall levels of functional impairment, with the severity of their impairment varying significantly over time. PMID- 25520164 TI - Add-on lithium for the treatment of unipolar depression: too often forgotten? PMID- 25520166 TI - Executive Dysfunction and Functional Impairment Associated With Sluggish Cognitive Tempo in Emerging Adulthood. AB - OBJECTIVE: Research has identified a relationship between sluggish cognitive tempo (SCT) symptoms and symptoms of ADHD, anxiety, and depression; however, no study has controlled for symptoms of ADHD, anxiety, and depression when examining impairment related to SCT symptoms. This study aimed to examine (a) the extent to which functional impairment and executive function (EF) problems were accounted for by SCT symptoms when controlling for ADHD, anxiety, and depression symptoms, and (b) which type of symptoms were associated with the greatest amount of impairment. METHOD: College students ( N = 458) completed self-report scales of ADHD, SCT, anxiety, and depression symptoms, as well as functional impairment and EF problems. RESULTS: Thirteen percent of the sample was found to have high levels of SCT symptoms. SCT symptoms showed a moderate to strong correlation with the other symptom sets; however, high levels of SCT symptoms often occurred separate from high levels of ADHD, anxiety, or depression symptoms. SCT symptoms accounted for the most unique variance for both EF problems and functional impairment. Students with high levels of SCT symptoms, with or without high levels of ADHD symptoms, exhibited more impairment and EF problems than the controls. CONCLUSION: SCT is a clinical construct worthy of additional study, particularly among college students. PMID- 25520163 TI - Neurophysiological effects of acute oxytocin administration: systematic review and meta-analysis of placebo-controlled imaging studies. AB - BACKGROUND: Oxytocin (OXT) plays a prominent role in social cognition and may have clinical applications for disorders such as autism, schizophrenia and social anxiety. The neural basis of its mechanism of action remains unclear. METHODS: We conducted a systematic literature review of placebo-controlled imaging studies using OXT as a pharmacological manipulator of brain activity. RESULTS: We identified a total of 21 studies for inclusion in our review, and after applying additional selection criteria, 11 of them were included in our fMRI voxel-based meta-analysis. The results demonstrate consistent alterations in activation of brain regions, including the temporal lobes and insula, during the processing of social stimuli, with some variation dependent on sex and task. The meta-analysis revealed significant left insular hyperactivation after OXT administration, suggesting a potential modulation of neural circuits underlying emotional processing. LIMITATIONS: This quantitative review included only a limited number of studies, thus the conclusions of our analysis should be interpreted cautiously. This limited sample size precluded a more detailed exploration of potential confounding factors, such as sex or other demographic factors, that may have affected our meta-analysis. CONCLUSION: Oxytocin has a wide range of effects over neural activity in response to social and emotional processing, which is further modulated by sex and task specificity. The magnitude of this neural activation is largest in the temporal lobes, and a meta-analysis across all tasks and both sexes showed that the left insula demonstrated the most robust activation to OXT administration. PMID- 25520167 TI - Mmp1 and Mmp2 cooperatively induce Drosophila fat body cell dissociation with distinct roles. AB - During Drosophila metamorphosis, the single-cell layer of fat body tissues gradually dissociates into individual cells. Via a fat body-specific RNAi screen in this study, we found that two matrix metalloproteinases (MMPs), Mmp1 and Mmp2, are both required for fat body cell dissociation. As revealed through a series of cellular, biochemical, molecular, and genetic experiments, Mmp1 preferentially cleaves DE-cadherin-mediated cell-cell junctions, while Mmp2 preferentially degrades basement membrane (BM) components and thus destroy cell-BM junctions, resulting in the complete dissociation of the entire fat body tissues into individual cells. Moreover, several genetic interaction experiments demonstrated that the roles of Mmp1 and Mmp2 in this developmental process are cooperative. In conclusion, Mmp1 and Mmp2 induce fat body cell dissociation during Drosophila metamorphosis in a cooperative yet distinct manner, a finding that sheds light on the general mechanisms by which MMPs regulate tissue remodeling in animals. PMID- 25520169 TI - Engineering increased triacylglycerol accumulation in Saccharomyces cerevisiae using a modified type 1 plant diacylglycerol acyltransferase. AB - Diacylglycerol acyltransferase (DGAT) catalyzes the acyl-CoA-dependent acylation of sn-1,2-diacylglycerol to produce triacylglycerol (TAG). This enzyme, which is critical to numerous facets of oilseed development, has been highlighted as a genetic engineering target to increase storage lipid production in microorganisms designed for biofuel applications. Here, four transcriptionally active DGAT1 genes were identified and characterized from the oil crop Brassica napus. Overexpression of each BnaDGAT1 in Saccharomyces cerevisiae increased TAG biosynthesis. Further studies showed that adding an N-terminal tag could mask the deleterious influence of the DGATs' native N-terminal sequences, resulting in increased in vivo accumulation of the polypeptides and an increase of up to about 150-fold in in vitro enzyme activity. The levels of TAG and total lipid fatty acids in S. cerevisiae producing the N-terminally tagged BnaDGAT1.b at 72 h were 53 and 28 % higher than those in cultures producing untagged BnaA.DGAT1.b, respectively. These modified DGATs catalyzed the synthesis of up to 453 mg fatty acid/L by this time point. The results will be of benefit in the biochemical analysis of recombinant DGAT1 produced through heterologous expression in yeast and offer a new approach to increase storage lipid content in yeast for industrial applications. PMID- 25520168 TI - Mercury bioremoval by Yarrowia strains isolated from sediments of mercury polluted estuarine water. AB - Difference in mercuric ion removal by resting and growing cells of two mercury resistant yeast strains, identified as Yarrowia spp. (strains Idd1 and Idd2), were studied. Resting cells of strain Idd2 exhibited high maximum Hg(2+) removal capacity (59 mg mercury per g dry cell weight [gdw(-1)]) by adsorption than those of resting cells of strain Idd1 (32 mg gdw(-1)). The resting cells of strain Idd2 exhibited a higher Hg(2+) desorption capacity using CaCl2 (68 %) and EDTA (48 %) than strain Idd1, depicting weaker binding of Hg(2+) onto strain Idd2 unlike strain Idd1. The actively growing yeast cells showed opposite Hg removal characteristics to those of the resting cells. Strain Idd1 adsorbed less Hg(2+) from culture medium supplemented with Hg(2+) than strain Idd2. However, the growing strain Idd1 reduced and vaporized 27 % of supplemented Hg(2+) as metallic mercury (Hg(0)), while the growing strains Idd2 vaporized 15 % of the supplemented Hg(2+). These two yeast strains are potential biotechnological tools for the eventual bioremediation of polluted aquatic systems. PMID- 25520170 TI - Granulation, control of bacterial contamination, and enhanced lipid accumulation by driving nutrient starvation in coupled wastewater treatment and Chlorella regularis cultivation. AB - Bacterial contamination and biomass harvesting are still challenges associated with coupling of microalgae and wastewater treatment technology. This study investigated aggregation, bacterial growth, lipid production, and pollutant removal during bacteria contaminated Chlorella regularis cultivation under nutrient starvation stress, by supposing the C/N/P ratios of the medium to 14/1.4/1 (MB2.5) and 44/1.4/1 (MB4.0), respectively. Granules of 500-650 MUm were formed in the bacteria contaminated inoculum; however, purified C. regularis were generally suspended freely in the medium, indicating that bacterial presence was a prerequisite for granulation. Extracellular polymeric substance (EPS) analysis showed that polysaccharides were dominant in granules, while protein mainly distributed in the outer layer. Denaturing gradient gel electrophoresis (DGGE) results revealed Sphingobacteriales bacterium and Sphingobacterium sp. are vital organisms involved in the flocculation of microalgae, and nitrifiers (Stenotrophomonas maltophilia) could co-exist in the granular. Both EPS and DGGE results further supported that bacteria played key roles in granulation. C. regularis was always dominant and determined the total biomass concentration during co-cultivation, but bacterial growth was limited owing to nutrient deficiency. Starvation strategy also contributed to enhancement of lipid accumulation, as lipid content in MB4.0 with a greater C/N/P led to the greatest increase in the starvation period, and the maximum lipid productivity reached 0.057 g/(L.day). Chemical oxygen demand and nitrogen removal in MB4.0 reached 92 and 96%, respectively, after 3 days of cultivation. Thus, cultivation of microalgae in high C/N/P wastewater enabled simultaneous realization of biomass granulation, bacterial overgrowth limitation, enhanced lipid accumulation, and wastewater purification. PMID- 25520171 TI - The two putative comS homologs of the biotechnologically important Bacillus licheniformis do not contribute to competence development. AB - In Bacillus subtilis, natural genetic competence is subject to complex genetic regulation and quorum sensing dependent. Upon extracellular accumulation of the peptide-pheromone ComX, the membrane-bound sensor histidine kinase ComP initiates diverse signaling pathways by activating-among others-DegQ and ComS. While DegQ favors the expression of extracellular enzymes rather than competence development, ComS is crucial for competence development as it prevents proteolytic degradation of ComK, the key transcriptional activator of all genes required for the uptake and integration of DNA. In Bacillus licheniformis, ComX/ComP sensed cell density negatively influences competence development, suggesting differences from the quorum-sensing-dependent control mechanism in Bacillus subtilis. Here, we show that each of six investigated strains possesses both of two different, recently identified putative comS genes. When expressed from an inducible promoter, none of the comS candidate genes displayed an impact on competence development neither in B. subtilis nor in B. licheniformis. Moreover, disruption of the genes did not reduce transformation efficiency. While the putative comS homologs do not contribute to competence development, we provide evidence that the degQ gene as for B. subtilis negatively influences genetic competency in B. licheniformis. PMID- 25520172 TI - Fungal naphtho-gamma-pyrones--secondary metabolites of industrial interest. AB - Naphtho-gamma-pyrones (NGPs) are secondary metabolites mainly produced by filamentous fungi (Fusarium sp., Aspergillus sp.) that should be considered by industrials. Indeed, these natural biomolecules show various biological activities: anti-oxidant, anti-microbial, anti-cancer, anti-HIV, anti hyperuricuric, anti-tubercular, or mammalian triacylglycerol synthesis inhibition which could be useful for pharmaceutical, cosmetic, and/or food industries. In this review, we draw an overview on the interest in studying fungal NGPs by presenting their biological activities and their potential values for industrials, their biochemical properties, and what is currently known on their biosynthetic pathway. Finally, we will present what remains to be discovered about NGPs. PMID- 25520174 TI - Erratum to: A novel thermophilic endo-beta-1,4-mannanase from Aspergillus nidulans XZ3: functional roles of carbohydrate-binding module and Thr/Ser-rich linker region. PMID- 25520175 TI - Levels of serum brain-derived neurotrophic factor in Type 2 diabetes mellitus patients with and without depressive symptoms. PMID- 25520176 TI - Poly-linker primer system for detection of single nucleotide polymorphisms and its application in genotyping hepatitis B virus. PMID- 25520173 TI - Abundance and diversity of polycyclic aromatic hydrocarbon degradation bacteria in urban roadside soils in Shanghai. AB - Understanding the impact of polycyclic aromatic hydrocarbons (PAHs) on soil environments is of increasingly important concern. Therefore, the microbial degradation of PAHs in soils has drawn considerable attention, but little is known about the PAH degradation genes in urban soils. In this study, we examined the diversity and abundance of the PAH degradation bacteria and evaluated whether the specific bacteria can reflect PAH contents in the soils from urban roadsides directly receiving traffic emission. The results of phylogenetic analysis indicated that low PAH degradation bacterial diversity occurred in the urban roadside soils, only including Mycobacterium sp., Terrabacter sp., and one novel cluster. The community composition diversity of PAH degradation bacteria did not show a significant difference across the sampling sites. The abundance of PAH degradation genes ranged from 5.70 * 10(6) to 6.44 * 10(7) gene copies g(-1) dry soil, with an average abundance of 1.43 * 10(7) gene copies g(-1) dry soil, and their spatial variations were related significantly to PAH contents in the soils. The Mycobacterium sp. was the most widely detected and estimated to occupy 65.9 100 % of the total PAH degradation bacteria at most of the soil samples, implying that the Mycobacterium sp. might play a primary role in degrading PAHs in the contaminated urban soil environments. PMID- 25520177 TI - Regulation of histone demethylase KDM6B by hypoxia-inducible factor-2alpha. AB - Lysine (K)-specific demethylase 6B (KDM6B) is a histone H3K27 demethylase, which specifically catalyzes the demethylation of H3 lysine-27 tri/dimethylation (H3K27me3/2). KDM6B can activate gene transcription by promoting transcriptional elongation which is associated with RNA polymerase II and related elongation factors. So KDM6B is important for the regulation of gene expression. Previous studies have indicated that several histone demethylases such as KDM3A, KDM4B, and KDM4C are regulated by hypoxia-inducible factor (HIF). But, the effect of hypoxia on KDM6B is not fully understood. In this study, we found that the expression levels of KDM6B mRNA and protein are modestly up-regulated under hypoxia (1% O2) or mimic hypoxia (desferrioxamine mesylate or CoCl2 treatment) (P<0.05). The result of RNAi shows that the up-regulation of KDM6B is dependent on HIF-2alpha, but not on HIF-1alpha. The result of chromatin immunoprecipitation assay indicates that there is a hypoxia response element in KDM6B promoter (-4041 to -4037). The result of Co-IP assay indicates that KDM6B can form complex with HIF-2alpha or HIF-1alpha. The knockdown experiment implies that KDM6B is a potential regulator for HIF-2alpha target genes. These data demonstrate that KDM6B is a new hypoxia response gene regulated by HIF-2alpha. Our results also show that KDM6B is a potential co-activator of HIF-alpha, which is important for the activation of hypoxia response genes. PMID- 25520179 TI - Switching adhesion and friction by light using photosensitive guest-host interactions. AB - Friction and adhesion between two beta-cyclodextrin functionalized surfaces can be switched reversibly by external light stimuli. The interaction between the cyclodextrin molecules attached to the tip of an atomic force microscope and a silicon wafer surface is mediated by complexation of ditopic azobenzene guest molecules. At the single molecule level, the rupture force of an individual complex is 61 +/- 10 pN. PMID- 25520178 TI - Interleukin-1beta and tumor necrosis factor-alpha increase stiffness and impair contractile function of articular chondrocytes. AB - Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are major proinflammatory cytokines involved in osteoarthritis (OA). These cytokines disturb chondrocyte metabolism by suppressing the synthesis of extracellular matrix proteins and stimulating the release of catabolic proteases, but little is known about their role in chondrocyte mechanics. Thus, the aim of this study was to measure the effects of IL-1beta and TNF-alpha on the mechanical properties of the chondrocytes. Chondrocytes from goat knee joints were cultured in 96-well plates. The cellular stiffness and contractile function were probed using optical magnetic twisting cytometry, the cytoskeleton and the expression of extracellular matrix proteins were visualized using immunofluorescent staining, and chondrocyte phenotypical expression was measured by western blot analysis. Results showed that chondrocyte stiffness was dramatically decreased by disruption of F-actin but was unaffected by disruption of the intermediate filament vimentin. Treatment with 10 ng/ml IL-1beta or 40 ng/ml TNF-alpha for 24 h substantially increased the expression level of F-actin and cellular stiffness, and impaired cell stiffening in response to the contractile agonist histamine, but these effects were blocked by the Rho-associated protein kinase inhibitor Y27632. In conclusion, IL-1beta and TNF-alpha substantially change the mechanical properties of the chondrocytes in vitro. While changes of chondrocyte mechanics in vivo during OA progression remain unclear, this finding reveals a prominent role of these cytokines in cellular mechanics and provides insight for anti-cytokine therapies of OA. PMID- 25520180 TI - Fabrication of Ni-Ti-O nanotube arrays by anodization of NiTi alloy and their potential applications. AB - Nickel-titanium-oxide (Ni-Ti-O) nanotube arrays (NTAs) prepared on nearly equiatomic NiTi alloy shall have broad application potential such as for energy storage and biomedicine, but their precise structure control is a great challenge because of the high content of alloying element of Ni, a non-valve metal that cannot form a compact electronic insulating passive layer when anodized. In the present work, we systemically investigated the influence of various anodization parameters on the formation and structure of Ni-Ti-O NTAs and their potential applications. Our results show that well controlled NTAs can be fabricated during relatively wide ranges of the anodization voltage (5-90 V), electrolyte temperature (10-50 degrees C) and electrolyte NH4F content (0.025-0.8 wt%) but within a narrow window of the electrolyte H2O content (0.0-1.0 vol%). Through modulating these parameters, the Ni-Ti-O NTAs with different diameter (15-70 nm) and length (45-1320 nm) can be produced in a controlled manner. Regarding potential applications, the Ni-Ti-O NTAs may be used as electrodes for electrochemical energy storage and non-enzymic glucose detection, and may constitute nanoscaled biofunctional coating to improve the biological performance of NiTi based biomedical implants. PMID- 25520181 TI - Alcohol consumption, hospitalization and medical expenditure: a large epidemiological study on the medical insurance system in Japan. AB - AIMS: This study investigated the relationship between alcohol drinking habits and the onset of high medical expenditure in a Japanese male population. METHODS: The cohort comprised 94,307 male beneficiaries 40-69 years of age of the Japanese medical insurance system, who had daily alcohol drinking habits. The likelihood of incurring high medical expenditure, defined as the >=90th percentile of the medical expenditure distribution in the study population 1 year after baseline, as well as the likelihood of undergoing hospitalization that year were compared among the participants grouped according to their alcohol consumption amount (<2, 2-3.9, 4-5.9, >=6 drinks/day). RESULTS: Participants who ranked in the top 10% medical expenditure group within the 1 year after baseline each incurred at least 2152 euros/year. The top 10% medical expenditure group accounted for 61.1% of the total medical expenditure in the study population. The odds ratios (95% confidence intervals) for ranking in the top 10% group during the 1-year period, compared with the <2 drinks (23 g of alcohol)/day group, were 1.08 (1.02-1.15) for 2-3.9 drinks/day, 1.11 (1.05-1.19) for 4-5.9 drinks/day, and 1.31 (1.18-1.45) for >=6 drinks/day after adjustment for age, body mass index, and smoking and exercise habits. The adjusted odds ratios for undergoing hospitalization were 1.11 (1.04-1.19), 1.14 (1.06-1.24) and 1.39 (1.24-1.56), respectively. CONCLUSION: The likelihood of incurring high medical expenditure and undergoing hospitalization increased with daily alcohol consumption amount. PMID- 25520182 TI - Developing and proposing the ethno-cultural gerontological nursing model. AB - By 2050, for the first time in U.S. history, almost half of elders will be from ethnic minority groups. To meet the needs of this rapidly diversifying population, nurses need to be able to marry transcultural nursing knowledge with gerontological nursing knowledge. The purpose of this article is to propose a new theoretical model for explaining health outcomes and health responses for older individuals in unique ethno-cultural groups and to discuss implications and applications of the model to transcultural gerontological nursing practice and research. The discussion will include (1) an overview of currently available theoretical knowledge in the area, (2) a description of the theory development process, (3) presentation of the proposed ethno-cultural gerontological nursing theoretical model, and (4) discussion of how this model can enhance nursing's contributions to reducing health disparities. This model is presented not as a finished product but as a basis for future discussion and refinement. PMID- 25520183 TI - Biological relevance of citrullinations: diagnostic, prognostic and therapeutic options. AB - OBJECTIVE: Citrullination has become a hot topic within recent years due to its involvement in diseases such as rheumatoid arthritis (RA), multiple sclerosis and fibrosis. Citrullinations are the conversion of arginine to citrulline by peptidylarginine deiminase (PAD) enzymes, which affect protein properties. The aim of this review is to summarize the advances in citrullination research and further explore the potential of citrullination as a diagnostic tool as well as inhibition of PAD enzymes as a target for treatment. METHOD: We reviewed current literature with emphasis on the role of citrullination in health and disease, the nature of enzymes responsible for citrullination, and the potential of applying citrullinations in diagnostics and pharmaceuticals. CONCLUSION: Current literature suggests that increased levels of citrullinated proteins are found in several if not all inflammatory diseases. In RA measurement of anti-citrullinated protein antibodies (ACPA) against citrullinated protein fragments are widely used as a prognostic biomarker. More recently, it has been indicated that levels of selected citrullinated proteins carries additional potential as biomarkers. This includes citrullinated vimentin which provide prognostic information in diseases as fibrosis and ankylosing spondylitis. In addition, recent studies suggest that inhibition of PAD is a target for treatment of diseases such as RA and cancer where proteins that are citrullinated are believed to influence the disease activity. PMID- 25520184 TI - Neurological and functional recovery after thoracic spinal cord injury. AB - OBJECTIVE: To describe neurological and functional outcomes after traumatic paraplegia. DESIGN: Retrospective analysis of longitudinal database. SETTING: Spinal Cord Injury Model Systems. PARTICIPANTS: Six hundred sixty-one subjects enrolled in the Spinal Cord Injury Model Systems database, injured between 2000 and 2011, with initial neurological level of injury from T2-12. Two hundred sixty five subjects had second neurological exams and 400 subjects had Functional Independence Measure (FIM) scores >=6 months after injury. OUTCOME MEASURES: American Spinal Injury Association Impairment Scale (AIS) grade, sensory level (SL), lower extremity motor scores (LEMS), and FIM. RESULTS: At baseline, 73% of subjects were AIS A, and among them, 15.5% converted to motor incomplete. The mean SL increase for subjects with an AIS A grade was 0.33 +/- 0.21; 86% remained within two levels of baseline. Subjects with low thoracic paraplegia (T10-12) demonstrated greater LEMS gain than high paraplegia (T2-9), and also had higher 1 year FIM scores, which had not been noted in earlier reports. Better FIM scores were also correlated with better AIS grades, younger age and increase in AIS grade. Ability to walk at 1 year was associated with low thoracic injury, higher initial LEMS, incomplete injury and increase in AIS grade. CONCLUSION: Little neurological recovery is seen in persons with complete thoracic SCI, especially with levels above T10. Persons who are older at the time of injury have poorer functional recovery than younger persons. Conversion to a better AIS grade is associated with improvement in self-care and mobility at 1 year. PMID- 25520186 TI - ATPase-dependent auto-phosphorylation of the open condensin hinge diminishes DNA binding. AB - Condensin, which contains two structural maintenance of chromosome (SMC) subunits and three regulatory non-SMC subunits, is essential for many chromosomal functions, including mitotic chromosome condensation and segregation. The ATPase domain of the SMC subunit comprises two termini connected by a long helical domain that is interrupted by a central hinge. The role of the ATPase domain has remained elusive. Here we report that the condensin SMC subunit of the fission yeast Schizosaccharomyces pombe is phosphorylated in a manner that requires the presence of the intact SMC ATPase Walker motif. Principal phosphorylation sites reside in the conserved, glycine-rich stretch at the hinge interface surrounded by the highly basic DNA-binding patch. Phosphorylation reduces affinity for DNA. Consistently, phosphomimetic mutants produce severe mitotic phenotypes. Structural evidence suggests that prior opening (though slight) of the hinge is necessary for phosphorylation, which is implicated in condensin's dissociation from and its progression along DNA. PMID- 25520187 TI - A new alternariol glucoside from fungus Alternaria alternate cib-137. AB - A new secondary metabolite, 2-O-methylalternariol 4-O-beta-[4-methoxyl glucopyranoside] (1), together with four known compounds alternariol methyl ether (2), altenuene (3), isoaltenuene (4) and 2-(2'S-hydroxypropyl)-5-methyl-7 hydroxychromone (5), was isolated from the fungus Alternaria alternate cib-137. Its structure was elucidated on the basis of spectroscopic data. Compounds 3 and 4 demonstrated moderate activity against Staphylococcus aureus. PMID- 25520185 TI - Insights into the molecular basis of the NOD2 signalling pathway. AB - The cytosolic pattern recognition receptor NOD2 is activated by the peptidoglycan fragment muramyl dipeptide to generate a proinflammatory immune response. Downstream effects include the secretion of cytokines such as interleukin 8, the upregulation of pro-interleukin 1beta, the induction of autophagy, the production of antimicrobial peptides and defensins, and contributions to the maintenance of the composition of the intestinal microbiota. Polymorphisms in NOD2 are the cause of the inflammatory disorder Blau syndrome and act as susceptibility factors for the inflammatory bowel condition Crohn's disease. The complexity of NOD2 signalling is highlighted by the observation that over 30 cellular proteins interact with NOD2 directly and influence or regulate its functional activity. Previously, the majority of reviews on NOD2 function have focused upon the role of NOD2 in inflammatory disease or in its interaction with and response to microbes. However, the functionality of NOD2 is underpinned by its biochemical interactions. Consequently, in this review, we have taken the opportunity to address the more 'basic' elements of NOD2 signalling. In particular, we have focused upon the core interactions of NOD2 with protein factors that influence and modulate the signal transduction pathways involved in NOD2 signalling. Further, where information exists, such as in relation to the role of RIP2, we have drawn comparison with the closely related, but functionally discrete, pattern recognition receptor NOD1. Overall, we provide a comprehensive resource targeted at understanding the complexities of NOD2 signalling. PMID- 25520188 TI - Predictors of body appearance cognitive distraction during sexual activity in a sample of men with ED. AB - Our aim is to scrutinize the extent to which aspects of body dissatisfaction and relationship variables predict body appearance cognitive distraction during sexual activity (BACDSA) in a sample of men diagnosed with ED. A total of 65 heterosexual Portuguese participants with ED completed a survey that included questions on socio-demographic data as well as body-related and relationship measures. We used the Global Body Dissatisfaction (GBD) Subscale of the Body Attitudes Test; a version of the Contour Drawing Rating Scale; a single item on partner's opinion perceived about one's body appearance; the Global Measure of Relationship Satisfaction; and the Inclusion of Other in Self Scale. Open questions assessed focus on specific body parts during sexual activity and relationship length. Hierarchical multiple regression indicated that only GBD was a significant predictor of BACDSA, contrary to the relationship measures that showed no significant predictive effect (R(2) =0.47). Our results support the important role of individual factors on explanatory models of sexual dysfunctions, suggesting that interventions addressing individual factors that affect BACDSA may be of preference. PMID- 25520189 TI - Effects of swimming activity on the copulatory behavior of sexually active male rats. AB - Physical activity has long been associated with better sexual function. This study investigated the effects of moderate swimming exercise on the copulatory behavior of sexually potent male rats. Two sets of sexually potent male rats highly active and moderately active- were identified depending on baseline sexual activity. Each of the two sets of rats was further randomly divided into two groups (swimming and sedentary). There were 16 rats in each of the four study groups (highly active swimming, highly active sedentary, moderately active swimming and moderately active sedentary). The copulatory behavior parameters and serum testosterone levels were measured and compared between the rats of the swimming and sedentary groups following a month long training period in which rats were made to swim for 1 h every alternate day. Swimming significantly improved the sexual performance of highly active rats, as indicated by increased intromission frequency and intromission ratio, compared with the sedentary controls. Swimming improved both sexual desire and performance, as indicated by reduced mount latency and increased intromission ratio, respectively, in swimming moderately active rats compared with the sedentary moderately active controls. Therefore, swimming activity improves the copulatory behavior of both highly active and moderately active male rats. PMID- 25520190 TI - Conformation transitions of eukaryotic polyribosomes during multi-round translation. AB - Using sedimentation and cryo electron tomography techniques, the conformations of eukaryotic polyribosomes formed in a long-term cell-free translation system were analyzed over all the active system lifetime (20-30 translation rounds during 6-8 h in wheat germ extract at 25 degrees C). Three distinct types of the conformations were observed: (i) circular polyribosomes, varying from ring-shaped forms to circles collapsed into double rows, (ii) linear polyribosomes, tending to acquire planar zigzag-like forms and (iii) densely packed 3D helices. At the start, during the first two rounds of translation mostly the circular (ring shaped and double-row) polyribosomes and the linear (free-shaped and zigzag-like) polyribosomes were formed ('juvenile phase'). The progressive loading of the polyribosomes with translating ribosomes induced the opening of the circular polyribosomes and the transformation of a major part of the linear polyribosomes into the dense 3D helices ('transitional phase'). After 2 h from the beginning (about 8-10 rounds of translation) this compact form of polyribosomes became predominant, whereas the circular and linear polyribosome fractions together contained less than half of polysomal ribosomes ('steady-state phase'). The latter proportions did not change for several hours. Functional tests showed a reduced translational activity in the fraction of the 3D helical polyribosomes. PMID- 25520191 TI - Rescue of splicing-mediated intron loss maximizes expression in lentiviral vectors containing the human ubiquitin C promoter. AB - Lentiviral vectors almost universally use heterologous internal promoters to express transgenes. One of the most commonly used promoter fragments is a 1.2-kb sequence from the human ubiquitin C (UBC) gene, encompassing the promoter, some enhancers, first exon, first intron and a small part of the second exon of UBC. Because splicing can occur after transcription of the vector genome during vector production, we investigated whether the intron within the UBC promoter fragment is faithfully transmitted to target cells. Genetic analysis revealed that more than 80% of proviral forms lack the intron of the UBC promoter. The human elongation factor 1 alpha (EEF1A1) promoter fragment intron was not lost during lentiviral packaging, and this difference between the UBC and EEF1A1 promoter introns was conferred by promoter exonic sequences. UBC promoter intron loss caused a 4-fold reduction in transgene expression. Movement of the expression cassette to the opposite strand prevented intron loss and restored full expression. This increase in expression was mostly due to non-classical enhancer activity within the intron, and movement of putative intronic enhancer sequences to multiple promoter-proximal sites actually repressed expression. Reversal of the UBC promoter also prevented intron loss and restored full expression in bidirectional lentiviral vectors. PMID- 25520192 TI - Annotating RNA motifs in sequences and alignments. AB - RNA performs a diverse array of important functions across all cellular life. These functions include important roles in translation, building translational machinery and maturing messenger RNA. More recent discoveries include the miRNAs and bacterial sRNAs that regulate gene expression, the thermosensors, riboswitches and other cis-regulatory elements that help prokaryotes sense their environment and eukaryotic piRNAs that suppress transposition. However, there can be a long period between the initial discovery of a RNA and determining its function. We present a bioinformatic approach to characterize RNA motifs, which are critical components of many RNA structure-function relationships. These motifs can, in some instances, provide researchers with functional hypotheses for uncharacterized RNAs. Moreover, we introduce a new profile-based database of RNA motifs--RMfam--and illustrate some applications for investigating the evolution and functional characterization of RNA. All the data and scripts associated with this work are available from: https://github.com/ppgardne/RMfam. PMID- 25520193 TI - Novel RNA chaperone domain of RNA-binding protein La is regulated by AKT phosphorylation. AB - The cellular function of the cancer-associated RNA-binding protein La has been linked to translation of viral and cellular mRNAs. Recently, we have shown that the human La protein stimulates IRES-mediated translation of the cooperative oncogene CCND1 in cervical cancer cells. However, there is little known about the underlying molecular mechanism by which La stimulates CCND1 IRES-mediated translation, and we propose that its RNA chaperone activity is required. Herein, we show that La binds close to the CCND1 start codon and demonstrate that La's RNA chaperone activity can change the folding of its binding site. We map the RNA chaperone domain (RCD) within the C-terminal region of La in close proximity to a novel AKT phosphorylation site (T389). Phosphorylation at T389 by AKT-1 strongly impairs its RNA chaperone activity. Furthermore, we demonstrate that the RCD as well as T389 is required to stimulate CCND1 IRES-mediated translation in cells. In summary, we provide a model whereby a novel interplay between RNA-binding, RNA chaperoning and AKT phosphorylation of La protein regulates CCND1 IRES-mediated translation. PMID- 25520194 TI - RECQL5 and BLM exhibit divergent functions in cells defective for the Fanconi anemia pathway. AB - Fanconi anemia (FA) patients exhibit bone marrow failure, developmental defects and cancer. The FA pathway maintains chromosomal stability in concert with replication fork maintenance and DNA double strand break (DSB) repair pathways including RAD51-mediated homologous recombination (HR). RAD51 is a recombinase that maintains replication forks and repairs DSBs, but also rearranges chromosomes. Two RecQ helicases, RECQL5 and Bloom syndrome mutated (BLM) suppress HR through nonredundant mechanisms. Here we test the impact deletion of RECQL5 and BLM has on mouse embryonic stem (ES) cells deleted for FANCB, a member of the FA core complex. We show that RECQL5, but not BLM, conferred resistance to mitomycin C (MMC, an interstrand crosslinker) and camptothecin (CPT, a type 1 topoisomerase inhibitor) in FANCB-defective cells. RECQL5 suppressed, while BLM caused, breaks and radials in FANCB-deleted cells exposed to CPT or MMC, respectively. RECQL5 protected the nascent replication strand from MRE11-mediated degradation and restarted stressed replication forks in a manner additive to FANCB. By contrast BLM restarted, but did not protect, replication forks in a manner epistatic to FANCB. RECQL5 also lowered RAD51 levels in FANCB-deleted cells at stressed replication sites implicating a rearrangement avoidance mechanism. Thus, RECQL5 and BLM impact FANCB-defective cells differently in response to replication stress with relevance to chemotherapeutic regimes. PMID- 25520195 TI - Active destabilization of base pairs by a DNA glycosylase wedge initiates damage recognition. AB - Formamidopyrimidine-DNA glycosylase (Fpg) excises 8-oxoguanine (oxoG) from DNA but ignores normal guanine. We combined molecular dynamics simulation and stopped flow kinetics with fluorescence detection to track the events in the recognition of oxoG by Fpg and its mutants with a key phenylalanine residue, which intercalates next to the damaged base, changed to either alanine (F110A) or fluorescent reporter tryptophan (F110W). Guanine was sampled by Fpg, as evident from the F110W stopped-flow traces, but less extensively than oxoG. The wedgeless F110A enzyme could bend DNA but failed to proceed further in oxoG recognition. Modeling of the base eversion with energy decomposition suggested that the wedge destabilizes the intrahelical base primarily through buckling both surrounding base pairs. Replacement of oxoG with abasic (AP) site rescued the activity, and calculations suggested that wedge insertion is not required for AP site destabilization and eversion. Our results suggest that Fpg, and possibly other DNA glycosylases, convert part of the binding energy into active destabilization of their substrates, using the energy differences between normal and damaged bases for fast substrate discrimination. PMID- 25520196 TI - Identifying causal regulatory SNPs in ChIP-seq enhancers. AB - Thousands of non-coding SNPs have been linked to human diseases in the past. The identification of causal alleles within this pool of disease-associated non coding SNPs is largely impossible due to the inability to accurately quantify the impact of non-coding variation. To overcome this challenge, we developed a computational model that uses ChIP-seq intensity variation in response to non coding allelic change as a proxy to the quantification of the biological role of non-coding SNPs. We applied this model to HepG2 enhancers and detected 4796 enhancer SNPs capable of disrupting enhancer activity upon allelic change. These SNPs are significantly over-represented in the binding sites of HNF4 and FOXA families of liver transcription factors and liver eQTLs. In addition, these SNPs are strongly associated with liver GWAS traits, including type I diabetes, and are linked to the abnormal levels of HDL and LDL cholesterol. Our model is directly applicable to any enhancer set for mapping causal regulatory SNPs. PMID- 25520197 TI - Identification of a pKa-regulating motif stabilizing imidazole-modified double stranded DNA. AB - The predictable 3D structure of double-stranded DNA renders it ideally suited as a template for the bottom-up design of functionalized nucleic acid-based active sites. We here explore the use of a 14mer DNA duplex as a scaffold for the precise and predictable positioning of catalytic functionalities. Given the ubiquitous participation of the histidine-based imidazole group in protein recognition and catalysis events, single histidine-like modified duplexes were investigated. Tethering histamine to the C5 of the thymine base via an amide bond, allows the flexible positioning of the imidazole function in the major groove. The mutual interactions between the imidazole and the duplex and its influence on the imidazolium pKaH are investigated by placing a single modified thymine at four different positions in the center of the 14mer double helix. Using NMR and unrestrained molecular dynamics, a structural motif involving the formation of a hydrogen bond between the imidazole and the Hoogsteen side of the guanine bases of two neighboring GC base pairs is established. The motif contributes to a stabilization against thermal melting of 6 degrees C and is key in modulating the pKaH of the imidazolium group. The general features, prerequisites and generic character of the new pKaH-regulating motif are described. PMID- 25520199 TI - The effect of low or high molecular weight oat beta-glucans on the inflammatory and oxidative stress status in the colon of rats with LPS-induced enteritis. AB - PURPOSE: The aim of the study was to investigate the protective effect of low and high molecular weight beta-glucans on the chosen immunological parameters, markers of antioxidative potential in rats' colon tissue, the number of lactic acid bacteria (LAB) and the concentration of short-chain fatty acids (SCFA) in rats' faeces. METHODS: The experiment was carried out on 72 8-week old male Sprague-Dawley rats: control (n = 36) and experimental (n = 36). In half of the animals from each group enteritis was induced by LPS (10 mg kg(-1)). Rats from the experimental group were divided into two groups receiving high (GI) or low (GII) molecular weight beta-glucans for 6 consecutive weeks. RESULTS: LPS evoked enteritis in all the treated animals, manifested by changes in the levels of IL 10, IL-12 and TNF-alpha, as well as in the number of intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) in the colon tissue. Dietary supplementation with beta-glucans following LPS treatment partially reversed this effect. The changes in SCFA concentration were noted, indicating an improvement of the fermentation process in the colon. This effect coincided with an increased number of LAB, pointing at the prebiotic properties of beta-glucans. The positive influence of beta-glucans was also manifested by the improved values of antioxidative potential markers (TAS, SOD, GR and GPx activity, TBARS concentration), noted especially in rats with LPS-induced enteritis. This influence was more pronounced in the case of low molecular weight oat beta-glucan (GII). CONCLUSIONS: The present study showed a positive effect of beta-glucans, especially the low molecular weight form, on the colon tissue of healthy rats, as well as animals with LPS-induced enteritis. PMID- 25520200 TI - Can you experience 'top-down' effects on perception?: The case of race categories and perceived lightness. AB - A recent surge of research has revived the notion that higher-level cognitive states such as beliefs, desires, and categorical knowledge can directly change what we see. The force of such claims, however, has been undercut by an absence of visually apparent demonstrations of the form so often appealed to in vision science: such effects may be revealed by statistical analyses of observers' responses, but you cannot literally experience the alleged top-down effects yourself. A singular exception is an influential report that racial categorization alters the perceived lightness of faces, a claim that was bolstered by a striking visual demonstration that Black faces appear darker than White faces, even when matched for mean luminance. Here, we show that this visually compelling difference is explicable in terms of purely low-level factors. Observers who viewed heavily blurred versions of the original Black and White faces still judged the Black face to be darker and the White face to be lighter even when these observers could not perceive the races of the faces, and even when they explicitly judged the faces to be of the same race. We conclude that the best subjectively appreciable evidence for top-down influences on perception does not reflect a genuinely top-down effect after all: instead, such effects arise from more familiar (if subtle) bottom-up factors within visual processing. PMID- 25520198 TI - Subgenomic promoter recognition by the norovirus RNA-dependent RNA polymerases. AB - The replication enzyme of RNA viruses must preferentially recognize their RNAs in an environment that contains an abundance of cellular RNAs. The factors responsible for specific RNA recognition are not well understood, in part because viral RNA synthesis takes place within enzyme complexes associated with modified cellular membrane compartments. Recombinant RNA-dependent RNA polymerases (RdRps) from the human norovirus and the murine norovirus (MNV) were found to preferentially recognize RNA segments that contain the promoter and a short template sequence for subgenomic RNA synthesis. Both the promoter and template sequence contribute to stable RdRp binding, accurate initiation of the subgenomic RNAs and efficient RNA synthesis. Using a method that combines RNA crosslinking and mass spectrometry, residues near the template channel of the MNV RdRp were found to contact the hairpin RNA motif. Mutations in the hairpin contact site in the MNV RdRp reduced MNV replication and virus production in cells. This work demonstrates that the specific recognition of the norovirus subgenomic promoter is through binding by the viral RdRp. PMID- 25520202 TI - Erratum to: Composition of weathering crusts on sandstones from natural outcrops and architectonic elements in an urban environment. PMID- 25520201 TI - Assessment of hospital inpatient discharge summaries, written for general practitioners, from a department of medicine for the elderly service in a large teaching hospital. AB - BACKGROUND: The discharge document summarising an acute inpatient stay in hospital is often the only means of communication between secondary and primary care. This is especially important in the elderly population who have multiple morbidities and are often on many medications. AIMS: This study aimed to assess if information important to general practitioners is being included in inpatient hospital discharge summaries for patients of the medicine for the elderly service in a large teaching hospital. METHODS: After a thorough literature review, a "gold standard" letter was defined as having included a discharge diagnosis, medications on discharge and follow-up plans. Forty computerised discharge summaries were retrospectively assessed for inclusion of these parameters. The study group consisted of the first eight sequentially discharged patients under the care of each of the five consultants during a 1-month period (1 September 2011-30 September 2011). RESULTS: A discharge diagnosis was included in 37 of the 40 summaries (92.5 %), medications on discharge were included in 39 summaries (97.5 %) and follow-up was recorded in 35 summaries (87.5 %). CONCLUSIONS: This study showed that the information assessed was available in the vast majority of discharge summaries for patients admitted acutely under the care of this medicine for the elderly service. Improvements can be made, including documentation of follow-up plans. PMID- 25520203 TI - Can the origin of some metals in the seagrass Posidonia oceanica be determined by the indexes of metals pollutions? AB - To assess metal pollution, Fe, Mn, Cu, Zn, Pb, Ni, Co, As, Cd, and Hg contents in samples of the seagrass Posidonia oceanica and surface sediment, collected at eight locations along the Montenegrin coast, were determined. The metal pollution index (MPI) and metal enrichment factor (EF) were then calculated. MPI and EF were lower in sediment than in P. oceanica at the same locations. This was very evident for EF values of Hg and Cd. Based on the Pearson's correlations and EF values, it was possible to conclude that the last two metals' content in the seagrass did not originate from the crustal sources or natural weathering processes. PMID- 25520204 TI - Effect of plant harvesting on the performance of constructed wetlands during winter: radial oxygen loss and microbial characteristics. AB - The aboveground tissue of plants is important for providing roots with constant photosynthetic resources. However, the aboveground biomass is usually harvested before winter to maintain the permanent removal of nutrients. In this work, the effects of harvest on plants' involvement in oxygen input as well as in microbial abundance and activity were investigated in detail. Three series of constructed wetlands with integrated plants ("unharvested"), harvested plants ("harvested"), and fully cleared plants ("cleared") were set up. Better performance was found in the unharvested units, with the radial oxygen loss (ROL) rates ranging from 0.05 to 0.59 MUmol O2/h/plant, followed by the harvested units that had relatively lower ROL rates (0.01 to 0.52 MUmol O2/h/plant). The cleared units had the lowest removal efficiency, which had no rhizome resources from the plants. The microbial population and activity were highest in the unharvested units, followed by the harvested and cleared units. Results showed that bacterial abundances and enhanced microbial activity were ten times higher on root surfaces compared with sands. These results indicate that late autumn harvesting of the aboveground biomass exhibited negative effects on plant ROL as well as on the microbial population and activity during the following winter. PMID- 25520205 TI - Bioconcentration and bioaccumulation of metal in freshwater Neotropical fish Geophagus brasiliensis. AB - From the concentration in water and sediments, bioconcentration and bioaccumulation of copper (Cu), manganese (Mn), zinc (Zn), iron (Fe), cobalt (Co), cadmium (Cd), chrome (Cr), silver (Ag), lead (Pb), nickel (Ni), aluminum (Al), and arsenic (As) were determined in the gills, liver, and muscles of Geophagus brasiliensis in the Alagados Reservoir, Ponta Grossa, Parana, Brazil. Metals were quantified through AAS, and a study was carried out on the existing relations between metal and body weight, size, and genre of this species. The level of metal in the water of the reservoir was lower than the maximum set forth in the legislation, except for that of Cd and Fe. In sediments, Cu, Cd, Cr, and Ni presented concentrations above the threshold effect level (TEL). Pb and Cr were above the limits for the G. brasiliensis. The tendency of metals present in the muscles of G. brasiliensis was Al > Cu > Zn > Fe > Co > Mn > Cr > Ag > Ni > Pb > Cd > As. In the gills, it was Al > Fe > Zn > Mn > Co > Ag > Cr > Ni > Cu > As > Pb > Cd, and the liver presented Al > Cu > Zn > Co > Fe > Mn > Pb > Ag > Ni > Cr > As > Cd. The bioconcentration and bioaccumulation of metal in the tissues follow the global tendency liver > gills > muscle. The statistical analysis did not point to significant differences in the metal concentration and body weight, size, and gender of the species in the three tissues under analysis. PMID- 25520206 TI - Different influences of field aging on nickel toxicity to Folsomia candida in two types of soil. AB - Metal aging in soils has been considered an important factor influencing its availability and toxicity to organisms. In this study, we report the influence of 5 years field aging on the nickel (Ni) toxicity to collembolan Folsomia candida based on two different types of soil from Dezhou (DZ) and Qiyang (QY) counties in China. Acute and chronic toxicity of Ni to F. candida was assessed in both freshly spiked and field aging contaminated soils. We found that 5 years field aging increased the EC50 and 2d-LC50 values of Ni to F. candida in the DZ soil, while little influence on the Ni toxicity was observed in the QY soil. There was no adverse effect of the long-term field aging on the Ni toxicity to the survival of F. candida in the two tested soils. In addition, field aging of the two soils impacted differently the water-soluble Ni concentrations, which were significantly correlated to the juvenile production of F. candida based on a logistic model. Our study highlights different effects of long-term field aging on the Ni toxicity to F. candida between divergent types of soil, and this should be taken into account in future toxicity testing and risk assessment practices. PMID- 25520207 TI - Analysis of serum levels of 15 trace elements in breast cancer patients in Shandong, China. AB - Experimental and epidemiological studies suggest that serum levels of trace elements may be associated with breast cancer risk. We compared serum levels of 15 trace elements between breast cancer patients and normal controls from Shandong, China, for the first time to assess whether serum levels of trace elements were associated with breast cancer risk. Eighty-eight breast cancer patients and 84 healthy controls were enrolled in the study. A Spectraspan V direct current plasma atomic emission spectrometer was used to determine the serum levels of 15 trace elements including Zn, Mn, Al, Cd, Fe, Mg, Ca, Pb, Cu, Se, Ni, Ti, Co, Li, and Cr. Breast cancer patients had significantly higher serum levels of Cd (p = 0.000), Mg (p = 0.001), Cu (p = 0.000), Co (p = 0.006), and Li (p = 0.003) and borderline higher Cr (p = 0.052), while significantly lower Mn (p = 0.000), Al (p = 0.000), Fe (p = 0.000), and Ti (p = 0.000) compared to their matched controls. However, there were no significant differences in serum levels of Zn (p = 0.824), Ca (p = 0.711), Pb (p = 0.274), Se (p = 0.236), and Ni (p = 0.185) between the two groups. Our study showed a possible association between serum levels of trace elements and breast cancer risk in eastern China, though it warrants further investigations to confirm the association. If confirmed, modulation of trace elements may help reduce breast cancer risk. PMID- 25520208 TI - QSAR as a random event: a case of NOAEL. AB - Quantitative structure-activity relationships (QSAR) for no observed adverse effect levels (NOAEL, mmol/kg/day, in logarithmic units) are suggested. Simplified molecular input line entry systems (SMILES) were used for molecular structure representation. Monte Carlo method was used for one-variable models building up for three different splits into the "visible" training set and "invisible" validation. The statistical quality of the models for three random splits are the following: split 1 n = 180, r (2) = 0.718, q (2) = 0.712, s = 0.403, F = 454 (training set); n = 17, r (2) = 0.544, s = 0.367 (calibration set); n = 21, r (2) = 0.61, s = 0.44, r m (2) = 0.61 (validation set); split 2 n = 169, r (2) = 0.711, q (2) = 0.705, s = 0.409, F = 411 (training set); n = 27, r (2) = 0.512, s = 0.461 (calibration set); n = 22, r (2) = 0.669, s = 0.360, r m (2) = 0.63 (validation set); split 3 n = 172, r (2) = 0.679, q (2) = 0.672, s = 0.420, F = 360 (training set); n = 19, r (2) = 0.617, s = 0.582 (calibration set); n = 21, r (2) = 0.627, s = 0.367, r m (2) = 0.54 (validation set). All models are built according to OCED principles. PMID- 25520209 TI - Community-based theater and adults with psychiatric disabilities: social activism, performance and community engagement. AB - The present study is an in-depth qualitative inquiry with an established theater troupe composed of adults living with psychiatric disabilities known as The Stars of Light. A grounded theory methodology is used to describe dimensions of social activism and characteristics of theater as a medium of engagement at the individual, setting/troupe, and community levels of analysis. Analysis of a broad scope of interview data, performance content, community contacts, and historical data from the troupe's 19-year history led to the identification of eight emergent theoretical concepts formulated from 17 supporting associated themes. The theoretical concepts characterize the impacts of community-based theater in the lives of participants, and theater troupe processes that contribute to community education and positive social change for adults living with psychiatric disabilities. Advantages, limitations, and future directions for research and action in community-based theater settings are discussed within the context of present research findings. PMID- 25520211 TI - Detecting and Explaining Aberrant Responding to the Outcome Questionnaire-45. AB - We applied item response theory based person-fit analysis (PFA) to data of the Outcome Questionnaire-45 (OQ-45) to investigate the prevalence and causes of aberrant responding in a sample of Dutch clinical outpatients. The [Formula: see text] person-fit statistic was used to detect misfitting item-score patterns and the standardized residual statistic for identifying the source of the misfit in the item-score patterns identified as misfitting. Logistic regression analysis was used to predict person misfit from clinical diagnosis, OQ-45 total score, and Global Assessment of Functioning code. The [Formula: see text] statistic classified 12.6% of the item-score patterns as misfitting. Person misfit was positively related to the severity of psychological distress. Furthermore, patients with psychotic disorders, somatoform disorders, or substance-related disorders more likely showed misfit than the baseline group of patients with mood and anxiety disorders. The results suggest that general outcome measures such as the OQ-45 are not equally appropriate for patients with different disorders. Our study emphasizes the importance of person-misfit detection in clinical practice. PMID- 25520210 TI - The relation of SMI and the VSEP in a risk sample for neurodegenerative disorders. AB - Vagus somatosensory evoked potentials (VSEP) have been shown to have higher latencies with aging, which are even more increased in patients with Alzheimer's disease and subjects with mild cognitive impairment compared to age-matched healthy controls. In this study, the association of VSEP with subjective memory impairment (SMI), a potential risk or prodromal marker for Alzheimer's disease, was examined. The association of VSEP latencies and SMI was studied in a healthy risk cohort, including 358 elderly subjects, who are in a longitudinal study of risk factors for neurodegenerative disorders. The results show increased VSEP latencies for peak P2 at Fz-F4 in subjects who report SMI and are worried about it as compared to subjects who report memory impairment, but are not concerned and subjects without complaints. The results support a potential role of VSEP for the detection of very early neurodegenerative processes which may precede Alzheimer's disease. PMID- 25520212 TI - A Review of Child and Adolescent Diagnostic Interviews for Clinical Practitioners. AB - The publication of the DSM-5 poses a challenge for many interview instruments due to the changes for many of the diagnoses. Six of the more widely used and studied interview instruments (structured and semistructured) were reviewed with a focus on usefulness for the practicing clinician and researcher. Use of these types of assessment procedures can facilitate the accuracy of diagnoses given by potentially reducing clinician bias. Each interview instrument varied in its strengths and characteristics related to amount of flexibility associated with administration of items; breadth of coverage of diagnoses based on DSM-IV; time required for administration; presence of screening items or modular format; and psychometric support for its reliability and validity, as well as amount of training required for use, and costs associated with acquiring and learning the format. Recommendations were made regarding the utilization of different instruments for specific diagnostic questions along with future recommendations for enhancing the format and utility of these instruments, especially in relation to the publication of the DSM-5. PMID- 25520213 TI - Perceived Characteristics of Intervention Scale: Development and Psychometric Properties. AB - The Perceived Characteristics of Intervention Scale (PCIS), a 20-item assessment measure, was developed to assess health care providers' views of interventions. Two hundred and fifteen Department of Veterans Affairs' residential treatment providers from 38 programs across the United States completed an online survey that included the PCIS as well as self-reported use of two evidence-based treatments. The PCIS was anchored to ask about two evidence-based psychotherapies for posttraumatic stress disorder, prolonged exposure, and cognitive processing therapy. The PCIS is a reliable measure of perceived characteristics of interventions, with some preliminary support for its validity. Consideration of providers' perceptions of particular evidence-based treatments may serve as an aid to improve their dissemination, implementation, and sustained use. PMID- 25520214 TI - Oral glucose in preterm neonates during oropharyngeal suctioning: a randomized controlled cross-over trial. AB - To investigate whether orally applied glucose reduces pain response during oropharyngeal suctioning in preterm infants with a birth weight >1500 g, we conducted a randomized, double-blind, placebo-controlled cross-over trial on 32 preterm infants undergoing oropharyngeal suctioning while on nasal continuous positive airway pressure (CPAP). The Premature Infant Pain Profile (PIPP) score was assessed and compared in a cross-over design to investigate whether there was a significant difference in the patients' pain response. The mean PIPP score during oropharyngeal suctioning after placebo was 8.6 (KI 7.8-9.4). After glucose administration, the mean PIPP score was 8.0 (KI 7.1-8.9). Comparison of the treatment effects reached no statistic significance (p = 0.23). During the oral study drug administration during nasal CPAP, we observed 47 adverse events, but none necessitated therapeutic intervention and none was classified as serious. CONCLUSION: In our study, late preterm infants in the first days of life did not benefit significantly from analgesia with glucose during oropharyngeal suctioning. The oral administration of glucose under nasal CPAP led to no serious adverse events. PMID- 25520216 TI - Understanding the domino reaction between 3-chloroindoles and methyl coumalate yielding carbazoles. A DFT study. AB - The molecular mechanism of the reaction between N-methyl-3-chloroindole and methyl coumalate yielding carbazole has been studied using DFT methods at the MPWB1K/6-311G(d,p) level in toluene. This reaction is a domino process that comprises three consecutive reactions: (i) a polar Diels-Alder (P-DA) reaction between indole and methyl coumalate yielding two stereoisomeric [2 + 4] cycloadducts (CAs); (ii) the elimination of HCl from these CAs affording two stereoisomeric intermediates; and (iii) the extrusion of CO2 in these intermediates, finally yielding the carbazole. This P-DA reaction proceeds in a completely regioselective and slightly exo selective fashion. In spite of the highly polar character of this P-DA reaction, it presents a high activation enthalpy of 21.8 kcal mol(-1) due to the loss of the aromatic character of the indole during the C-C bond formation. Thermodynamic calculations suggest that the P-DA reaction is the rate-determining step of this domino reaction; in addition, the initial HCl elimination in the formal [2 + 4] CAs is kinetically favoured over the extrusion of CO2. Although the P-DA reaction is kinetically and thermodynamically very unfavourable, the easier HCl and CO2 elimination from the [2 + 4] CAs together with the strong exergonic character of the CO2 extrusion makes the P-DA reaction irreversible. An ELF topological analysis of the bonding changes along the P-DA reaction supports a two-stage one-step mechanism. An analysis of the global DFT reactivity indices at the ground state of the reagents confirms the highly polar character of this P-DA reaction. Finally, the complete regioselectivity of the studied reactions can be explained using the Parr functions. PMID- 25520215 TI - Slow unloading leads to DNA-bound beta2-sliding clamp accumulation in live Escherichia coli cells. AB - The ubiquitous sliding clamp facilitates processivity of the replicative polymerase and acts as a platform to recruit proteins involved in replication, recombination and repair. While the dynamics of the E. coli beta2-sliding clamp have been characterized in vitro, its in vivo stoichiometry and dynamics remain unclear. To probe both beta2-clamp dynamics and stoichiometry in live E. coli cells, we use custom-built microfluidics in combination with single-molecule fluorescence microscopy and photoactivated fluorescence microscopy. We quantify the recruitment, binding and turnover of beta2-sliding clamps on DNA during replication. These quantitative in vivo results demonstrate that numerous beta2 clamps in E. coli remain on the DNA behind the replication fork for a protracted period of time, allowing them to form a docking platform for other enzymes involved in DNA metabolism. PMID- 25520217 TI - Natural Killer Cell Functional Activity After 4-1BB Costimulation. AB - Reports show enhancement of CD8 T cells' activity through CD137 (4-1BB) signal; however, not all data proved similar effect in natural killer (NK) cells. Here, the impact of 4-1BB signal on NK cells' function was assessed during short term cultures. To that end, cytokine-activated NK cells were cocultured with adenovirally transduced MCF-7 stimulator cells expressing 4-1BB ligand. Cellular cytotoxicity, cytokine production, and expression of cytotoxicity related genes were assessed after overnight cultures. Sharp decrease of CD56+ and CD56bright NK cells was demonstrated. 4-1BB neither enhanced cellular degranulation nor improved IFN-gamma production although it promoted granzyme B, perforin, and FasL gene expression. 4-1BB signal stimulated higher proportions of CD56bright population to degranulate and express CD107a; however, it could not recover killing activity against K562 targets. Our data could not show major promotion in activity of all NK subpopulations. Due to great heterogeneity of NK cells, more investigation is needed to draw a comprehensive conclusion. PMID- 25520219 TI - New weapon in fighting atherosclerosis: effective inhibition of circulating low density lipoprotein cholesterol. AB - Last but not least a warning. Cholesterol is not only a pathogenic metabolite, it is an essential biological component. Indiscriminate cholesterol lowering may be inappropriate and harmful. The more effective is a weapon, the higher is the potential for a collateral damage (Fig. 1, Ref. 10). PMID- 25520221 TI - The effect of hyaluronate-carboxymethyl-cellulose on the formation of postoperative adhesion in stomach visceral peritoneum damage. AB - OBJECTIVE: In this study, we aimed at investigating the effect of placing hyaluronate- carboxymethyl-cellulose membrane (HCMC) on the formation of adhesion postoperatively in a damaged area in the peritoneum of the anterior stomach wall. METHODS: The study was conducted on 30 rabbits. A transverse peritoneal damage was inflicted on the stomach anterior walls of all rabbits. In the first treatment group, HCMC was placed on the sutured anterior wall of stomach of 15 rabbits. In the second control group, on the other hand, no treatment was conducted on 15 rabbits. On the 30th day after the operation, relaparatomy was performed on the rabbits and adhesions were evaluated by an independent surgeon according to seriousness and prevalence scores. RESULTS: There were postoperative adhesions (POA) in 12 (80 %) rabbits in the control group. On the other hand, there were POA in 5 rabbits (33.3 %) in the treatment group. In the treatment group, adhesion was totally prevalent in 2 rabbits (13.3 %), whereas this ratio was 7 (46.6 %) in the control group (p < 0.01). CONCLUSIONS: The study suggested that the use of hyaluronate-carboxymethyl-cellulose could be beneficial on damaged peritoneum surfaces following abdominal surgery in order to reduce POA development to a minimum (Tab. 3, Fig. 3, Ref. 22). PMID- 25520220 TI - Morphine and nicotine addiction and withdrawal influence baroreflex sensitivity and blood pressure in two-kidney one clip hypertensive (2K1C) rats. AB - OBJECTIVE: This study aimed to investigate the effects of addiction to morphine and nicotine as well as their withdrawal on both baroreflex sensitivity and blood pressure in hypertensive rats. METHODS: In this experimental study 40 male rats were divided into two main groups as follows: in group I, hypertensive rats received saline for 8 weeks; in group II, hypertensive rats were treated with morphine and nicotine for 8 weeks. At the end of 8 weeks group II rats were divided into four sub-groups including, 3 sub-groups of those were put on drug withdrawal protocol. At the end of experiment, blood pressure, heart rate, plasma renin activity (PRA), serum NO concentration and baroreflex sensitivity (BRS) were measured. RESULTS: RESULTS demonstrated that BP and BRS were significantly lower in addicted to morphine and nicotine hypertensive rats compared to control (p < 0.05). Addiction withdrawal (in morphine and nicotine withdrawal rats) completely reversed BP and BRS to the pre-addiction levels (p < 0.05). Withdrawal in the only nicotine treated group lowered BP and BRS compared to group that had received morphine and nicotine together (p < 0.05). CONCLUSION: RESULTS of current study may propose simultaneous morphine and nicotine withdrawal can prevent cardiovascular complications raised due to withdrawal (Fig. 5, Ref. 58). PMID- 25520218 TI - Non-invasive one-point carotid wave intensity in a large group of healthy subjects: A ventricular-arterial coupling parameter. AB - The analysis of wave intensity (WI) evaluates the working condition of the heart interacting with the arterial system. WI in normal subjects has two peaks, the first (W 1) reflects left ventricle (LV) contractile performance, the second (W 2) is related to the ability of the LV to actively stop aortic blood flow. The aim of the study was to investigate the reference values of W 1 and W 2 in a group of apparently healthy subjects through a radiofrequency-based system. 680 subjects (388 men mean age 43.0 +/- 17.4 years, range 16-92; 292 women mean age 44.8 +/- 17.7 years, range 16-86) were enrolled and underwent physical examination, blood pressure (BP) and heart rate (HR) measurements and comprehensive transthoracic echocardiogram was performed. Measurement of local WI was obtained at the level of the left common carotid artery before the bifurcation, using a high definition echo-tracking system. W 1 was (12.37 +/- 6.89) * 10(3) and (9.76 +/- 4.8) * 10(3) mmHg m/s(3), p < 0.0001; W 2 was (3.21 +/- 1.81) * 10(3) and (2.98 +/- 1.69) * 10(3) mmHg m/s(3), p = ns in men and women, respectively. The cohort was divided into 5 age groups (ages 16-29; 30-39; 40-49; 50-59; >60) and stratified by gender. After adjustment for height, systolic BP and HR, W 1 decreased with age (p < 0.0001 in men and p = 0.026 in women for trend) while no relation was found for W 2. Multivariable regression analysis using age, gender, height, systolic BP, HR, ejection fraction and stroke volume indexed by body surface are predicted W 1 and age, systolic BP, HR and E/A as a measure of diastolic function, predicted W 2. Inter and intra-observer variability and feasibility of WI analysis were satisfactory. We reported the values and their clinical correlations of the two peaks (W 1 and W 2) of WI, a non-invasive hemodynamic index for assessing ventricular-arterial coupling in a large group of apparently healthy subjects. PMID- 25520222 TI - Role of the nitric oxide on rosuvastatin-induced relaxation of the calf cardiac vein during cooling. AB - OBJECTIVE: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors including rosuvastatin do not only lower plasma cholesterol but also have non cholesterol lowering effects on the vessel wall, which decrease cardiovascular complications. The aim of the present study was to evaluate the effect of cooling (to 28 degrees C) on the vasodilatation induced by rosuvastatin (10-9-3x10-4M) on serotonin-pre-contracted calf cardiac vein and the role of nitric oxide in these effects. MATERIAL AND METHODS: Ring preparations of veins obtained from calf hearts were suspended in organ baths containing 25 ml of Krebs-Henseleit solution, maintained at 37 degrees C and continuously gassed with 95% O(2)-5% CO(2). After a resting period, preparations were contracted with serotonin (10-6 M) at 37 degrees C. RESULTS: Rosuvastatin produced concentration-dependent relaxation of calf cardiac vein precontracted with serotonin (10-6 M). During cooling, the pIC(50) value, but not the maximal response, to rosuvastatin was significantly higher than at 37 degrees C. Cooling to 28 degrees C in the presence of NG-nitro-L-arginine methyl ester (L-NAME, 10-4 M) decreased the pIC(50) values to rosuvastatin. CONCLUSION: The results of the present study suggested that nitric oxide played an essential role in the cooling-induced changes of rosuvastatin in calf cardiac vein (Fig. 1, Ref. 23). PMID- 25520223 TI - The comparison of preemptive analgesic effects of curcumin and diclofenac. AB - OBJECTIVE: Preemptive analgesia is an antinociceptive treatment that prevents central sensitization. Antinociceptive effects of diclofenac are well-known. The aim of this study was to investigate preemptive analgesic effects of curcumin and diclofenac, before acute and inflammatory induced pain in rat model. MATERIAL AND METHODS: Fourty eight old female (n = 6 in each group) Wistar Albino rats were included in the study. Paw movements in response to paw flinching in response to formalin injection or thermal stimulation were compared after curcumin (400 mg kg (1), p.o.) and diclofenac (10 mg kg(-1), i.p.) administration. Saline was used as a control. The solvent ethanol was administered in another group of rats. Preemptive analgesic effect was significant in both tests when curcumin and diclofenac was administrated before the pain stimuli. RESULTS: Oral administration of curcumin and intraperitoneal injection of diclofenac increase the response time in hot plate test and decrease the number of flinches in formalin test (p < 0.001 vs p < 0.05). CONCLUSION: These results suggest that curcumin had preemptive analgesic effects on acute thermal, and inflammatory induced pain in rats as diclofenac (Fig. 2, Ref. 35). PMID- 25520224 TI - Inhibitory effects of piperonylic acid on the excessive proliferation of vascular smooth muscle cells and luminal stenosis. AB - PURPOSE: Combining in vivo and in vitro experiments, we explored the function and mechanism of piperonylic acid inhibiteing excessive proliferation of vascular smooth muscle cells, and intimal hyperplasia and luminal stenosis after blood vessel injury. METHODS: A model of rat thoracic aorta restenosis after balloon injury was constructed, intragastrically administered with piperonylic acid. 21 days later, their thoracic aortas were subjected tests of morphology, SM-alpha actin, proliferating cell nuclear antigen (PCNA), and expression levels of P21 and P27 by HE staining, immunohistochemistry, and computer image analysis. RESULTS: The proliferation of vascular smooth muscle cells induced by fetal calf serum was active, and the expressions of P21 and P27 were low. Piperonylic acid obviously promoted the protein expressions of P21 and P27 while inhibiting proliferation and DNA synthesis. After the injury of rat thoracic aorta, the cells moved towards the intima and proliferated excessively, leading to evident neogenesis of intima and luminal stenosis. The SM-alpha-actin immunohistochemistry confirms that the intima contained abundant smooth muscle cells and that the expression of PCNA was high while the expression of P21 and P27 was low. The intervention of piperonylic acid significantly facilitated the gene expressions of P21 and P27, lowered the PCNA expression, and inhibited the formation of intima and the reconstruction of pathological vessels, thus remarkably suppressing luminal stenosis. CONCLUSION: Piperonylic acid can inhibit the excessive proliferation of vascular smooth muscle cells and the lumen narrowing after injury of blood vessels, the mechanism of which is associated with the promoted gene expressions of cell cycle key regulators P21 and P27 (Tab. 4, Fig. 4, Ref. 22). PMID- 25520226 TI - Comparison of history of adolescents with substance-induced psychosis, early onset schizophrenia and substance use disorders. AB - OBJECTIVE: The contribution contains a comparison of the history data of adolescent patients hospitalized at the Department of Child Psychiatry, Children's Faculty Hospital in Bratislava with the diagnoses of Substance-Induced Psychosis (SIP), Early Onset Schizophrenia (EOS) and with Substance Use Disorders (SUD). BACKGROUND: SIP is rarely recorded and little documented by the age of 18. The etiology of this disorder is still relatively unclear. METHODS: The data collection was carried out from patients hospitalized between January 1, 2001 and December 31, 2012. We recorded data from 20 patients hospitalized with SIP, 50 patients hospitalized with EOS, and 50 patients hospitalized with SUD. We collected and compared the data on family history, perinatal complications, early psychomotor development, data on psychical problems before their hospitalization, and presence of unfavorable life situations in their childhood. CONCLUSION: The data of adolescents with SIP are more similar to the data of patients with EOS than patients with SUD in terms of the burden of family history, the frequency of complications during pregnancy and delivery, and the frequency of the subsequent early psychomotor impairment. In terms of unfavorable life situations and psychological problems for which they were monitored in a psychiatric ward before their hospitalization with SIP, their data are more similar to those of patients with SUD than with EOS (Tab. 3, Fig. 1, Ref. 21). PMID- 25520225 TI - The effect of ovariectomy on the skin flap viability and myeloperoxidase levels. AB - OBJECTIVES: Estrogen could affect the rate and quality of wound healing in skin. We aimed to investigate the effects of ovariectomy on skin flap viability and myeloperoxidase (MPO) levels in a rat model. BACKGROUND: Estrogens have many important beneficial and protective roles in skin that they improve collagen content and quality, maintain skin thickness and enhance vascularization. It has been shown that estrogen supplementation accelerates cutaneous wound healing in elderly patients. METHODS: Forty-eight cycling female Wistar albino rats were randomly divided into three groups (n = 16); ovariectomy (Group 1), sham (Group 2), and control (Group 3). Rats were subjected to bilateral ovariectomy in the Group 1, and only laparotomy in the Group 2. Twenty-one days later in the Group 1 and 2, a dorsal caudally based skin flap elevation was done. In the Group 3, the rats had a dorsal skin flap without any surgical intervention. Ten days later, the flaps were harvested for histopathologic examination and biochemical analyses. RESULTS: The rats in the Group 1 had significantly larger necrotic area and lower flap viability than in the Group 2 and 3 (p<0.05). Histopathologic examination showed that necrotic flap regions contained muscle necrosis with an abundant neutrophil infiltration, and severe edema in the Group 1. The MPO activity in the distal of skin flaps was significantly higher in the Group 1 compared to the Group 2 and 3 (p<0.05). CONCLUSION: This study shows that ovariectomy has deleterious effects on skin flap viability in a rat model (Tab. 1, Fig. 6, Ref. 44). PMID- 25520227 TI - Combined surgical treatment of lung cancer and heart diseases. AB - OBJECTIVE: The co-incidence of lung cancer and heart disease is increasing. This can be caused by population ageing, which has more co-morbidities and most likely due to the common etiological causes of both entities, i.e. smoking, hypertension and obesity. The aim of this study was to analyze the outcomes of simultaneously performed heart surgery and pulmonary resection in a selected group of patients. METHODS: From January 2002 to December 2011 we performed in our department 1115 pulmonary resections for lung tumor. Significant heart disease requiring surgical treatment was diagnosed in 21 patients from the whole group. In 12 patients, group A; simultaneous heart surgery and lung resection procedure were performed. RESULTS: Group A consisted of 8 men and 4 women with the median age of 67.8 +/- 5.9 years. In this group, 10 lobectomy procedures and 2 wedge resections for pulmonary metastasis were done. Nine patients underwent coronary artery revascularization, 2 patients underwent mitral valve replacement and one patient underwent tumor removal from the left atrium. In 5 patients, extracorporeal circulation (ECC) was needed, the remaining 7 patients underwent myocardial revascularization using an off-pump technique. Group B consisted of 7 men and 5 women with the age of 68.5 +/- 7.4 years. Ten lobectomy procedures and 2 wedge resections were performed. CONCLUSION: The risk of simultaneously performed lung resection and cardiac surgery is not high. Despite the certain differences in clinical indicators between group A and B, the safety of simultaneous procedure, in group A, was evident. Furthermore, earlier lung resection was enabled and the eventual complications from further surgical procedure were avoided (Tab. 5, Ref. 33). PMID- 25520228 TI - Postoperative rectal anastomotic complications. AB - Colorectal cancer represents the most common tumour of the gastrointestinal tract and the second most common tumour in men as well as women. The trend of increasing incidence of colorectal cancer is alerting. We undertook a retrospective study on 588 patients with rectal cancer and operated by rectal resection with anastomosis between the years 2002-2012. In our sample, we observed 54 (9.2 %) cases of anastomosis insufficiencies requiring reoperation. Out of 54 insufficient anastomoses, 36 (66 %) were in the lower two thirds of the rectum and only 18 (34 %) in the oral one. Although we have observed similar occurrences of anastomosis insufficiency in both groups - classical vs. staple suture (9.5 % and 9.0 %, respectively), the majority of stapler anastomoses (94 %) were made in the aboral part of the rectum. However, we can state that a majority of authors prefer the staple anastomosis as the one with lowest risk, mainly in the distal region of anastomosis. The high ligation of inferior mesenteric artery was performed in 182 (31 %) patients; out of these, we observed anastomosis insufficiency in 12 cases (22 %), which is exactly similar to that in the group of patients without high ligation of the inferior mesenteric artery. We did not observe the use of antibiotics in therapeutical doses as a positive factor for anastomosis insufficiencies, and neither was oncological therapy observed as a risk factor. In our group of patients we agreed that age, level of anastomosis and corticosteroids are high-risk factors. The purpose of these reports, is for the sake of future to share and reference our experiences with cases of rectal and rectosigmoideal resection over the last 11 years. We consider it important to reference our results, especially the risk factors regarding the healing of rectal anastomosis, because anastomotic healing is a surgical problem with potentially deadly consequences for patients (Tab. 4, Ref. 24). PMID- 25520229 TI - Deceased elderly in-patients with pulmonary embolism. AB - Pulmonary embolism (PE) in the elderly is an immediate threat of life. Especially in old age clinical signs of PE are non-specific and could be both underestimated and overestimated. AIM OF THE STUDY: The retrospective long-term study was aimed at conducting an analysis and comparison of pertinent influence of age, gender and immobility on occurrence of PE and sudden death. PATIENTS AND METHOD: Between 1995 and 2012 years we had altogether 12,746 elderly patients of an average age 80.6 +/- 7.0 y (range 65-103 y) hospitalized at the Department of Geriatrics. All in-patients 65+ y were randomly admitted for internal hospitalization from the catchment area of Brno city (100,000 inhabitants). The subject of our interest was to study the documentation of deaths (including autopsy findings), which was caused by PE. Out of this number there were 8,540 women (66.3 %) and 4,206 men (33.7 %). Among all hospitalized patients PE in 700 cases (5.5 % of all admitted patients) was shown in a medical report. Among them there were 424 survivors (60.6 %; 134 men and 290 women). CONCLUSION: The high occurrence of PE (particularly silent form) has crucial importance in the elderly mortality. Our recommendations would like to emphasize the need of no underestimation of this fact and to carry out preventive measures in all age groups (including the "oldest old" and frail persons) (Tab. 3, Ref. 41). PMID- 25520230 TI - Objective determination of skin phototypes in healthy children by diffuse reflectance spectroscopy. AB - INTRODUCTION: The clinical method of evaluating the color of the skin based on visual assessment is subjective and thus inaccurate. The objective determination of skin phototypes and levels of melanin in the skin is important for diagnosing the pigment disorders and also for adequate photoprotection. Diffuse reflectance spectroscopy (DRS) is a non-invasive, precise and objective method for quantifying the melanin levels. OBJECTIVE: The aim of this study is to assess the characteristic DRS spectrum of healthy skin in children and to detect the differences between them based on age, gender and skin phototype. MATERIAL AND METHODS: Skin pigmentation was measured by DRS in 73 children patients with experimental spectrophotometer UM-ES600. The amount of melanin is quantified from the obtained DRS spectra by proposed melanin quantification angle alpha obtained by comparing the reflectance properties of skin sample and universal depigmented sample (albino skin). RESULTS: We evaluated spectroscopic characteristics of children's healthy skin depending on age, gender and phototype. The value of melanin quantification angle alpha grew proportionally from phototype I to phototype IV, without any correlation to age or gender. We confirmed a clear association between clinical determination of Fitzpatrick's skin phototypes and objective data collected by DRS and related angle alpha. CONCLUSIONS: Our proposed index quantifies the difference in melanin levels in healthy children skin and also for different skin phototypes. The proposed method and melanin quantification angle alpha can further be used for the objectification of the progress of pigmentary diseases or for monitoring the effect of their therapy (Tab. 5, Fig. 4, Ref. 29). PMID- 25520231 TI - The effect of Vancomycin degradation products in the topical treatment of osteomyelitis. AB - BACKGROUND: The topical application of Vancomycin is increasingly being used in orthopedics because of the development of methicillin resistant bacteria. Consequently, resistance to Vancomycin has recently been on the rise. One possible explanation for this phenomenon could be the thermal degradation of Vancomycin to antibacterially inactive crystalline degradation products (CDP-1s). The aim of our in vitro experiment was to compare the creation and elution characteristics of CDP-1s and the active form of Vancomycin (factor B) released from bone grafts. METHODS: CDP-1s and the factor B released from bone grafts into the buffer solution were measured using the high-performance liquid chromatography method at progressive intervals. RESULTS: The factor B was released from bone grafts at the highest levels, typically on the first day (618.8 mg/L). CDP-1 levels kept increasing until the end of measurement on day 15, when the concentration of CDP-1s (1280.7 mg/L) was much higher compared to that of factor B (217.5 mg/L). CONCLUSIONS: We confirmed the tendency of Vancomycin to convert to antimicrobially ineffective CDP-1s. Although Vancomycin is decomposed into crystalline degradation products, its active forms are released from bone grafts in sufficient concentration for more than two keks (Tab. 3, Fig. 1, Ref. 15). PMID- 25520232 TI - A rare endoscopic appearance of primary gastrointestinal mantle cell lymphoma resembling ulcerative colitis. PMID- 25520234 TI - Televised medical talk shows--what they recommend and the evidence to support their recommendations: a prospective observational study. AB - OBJECTIVE: To determine the quality of health recommendations and claims made on popular medical talk shows. DESIGN: Prospective observational study. SETTING: Mainstream television media. SOURCES: Internationally syndicated medical television talk shows that air daily (The Dr Oz Show and The Doctors). INTERVENTIONS: Investigators randomly selected 40 episodes of each of The Dr Oz Show and The Doctors from early 2013 and identified and evaluated all recommendations made on each program. A group of experienced evidence reviewers independently searched for, and evaluated as a team, evidence to support 80 randomly selected recommendations from each show. MAIN OUTCOMES MEASURES: Percentage of recommendations that are supported by evidence as determined by a team of experienced evidence reviewers. Secondary outcomes included topics discussed, the number of recommendations made on the shows, and the types and details of recommendations that were made. RESULTS: We could find at least a case study or better evidence to support 54% (95% confidence interval 47% to 62%) of the 160 recommendations (80 from each show). For recommendations in The Dr Oz Show, evidence supported 46%, contradicted 15%, and was not found for 39%. For recommendations in The Doctors, evidence supported 63%, contradicted 14%, and was not found for 24%. Believable or somewhat believable evidence supported 33% of the recommendations on The Dr Oz Show and 53% on The Doctors. On average, The Dr Oz Show had 12 recommendations per episode and The Doctors 11. The most common recommendation category on The Dr Oz Show was dietary advice (39%) and on The Doctors was to consult a healthcare provider (18%). A specific benefit was described for 43% and 41% of the recommendations made on the shows respectively. The magnitude of benefit was described for 17% of the recommendations on The Dr Oz Show and 11% on The Doctors. Disclosure of potential conflicts of interest accompanied 0.4% of recommendations. CONCLUSIONS: Recommendations made on medical talk shows often lack adequate information on specific benefits or the magnitude of the effects of these benefits. Approximately half of the recommendations have either no evidence or are contradicted by the best available evidence. Potential conflicts of interest are rarely addressed. The public should be skeptical about recommendations made on medical talk shows. Additional details of methods used and changes made to study protocol. PMID- 25520236 TI - Atomic and electronic structures of an extremely fragile liquid. AB - The structure of high-temperature liquids is an important topic for understanding the fragility of liquids. Here we report the structure of a high-temperature non glass-forming oxide liquid, ZrO2, at an atomistic and electronic level. The Bhatia-Thornton number-number structure factor of ZrO2 does not show a first sharp diffraction peak. The atomic structure comprises ZrO5, ZrO6 and ZrO7 polyhedra with a significant contribution of edge sharing of oxygen in addition to corner sharing. The variety of large oxygen coordination and polyhedral connections with short Zr-O bond lifetimes, induced by the relatively large ionic radius of zirconium, disturbs the evolution of intermediate-range ordering, which leads to a reduced electronic band gap and increased delocalization in the ionic Zr-O bonding. The details of the chemical bonding explain the extremely low viscosity of the liquid and the absence of a first sharp diffraction peak, and indicate that liquid ZrO2 is an extremely fragile liquid. PMID- 25520237 TI - Isolation and structural characterization of the milled wood lignin, dioxane lignin, and cellulolytic lignin preparations from brewer's spent grain. AB - The structure of the lignin from brewer's spent grain (BSG) has been studied in detail. Three different lignin preparations, the so-called "milled-wood" lignin (MWL), dioxane lignin (DL), and cellulolytic lignin (CEL), were isolated from BSG and then thoroughly characterized by pyrolysis GC/MS, 2D-NMR, and derivatization followed by reductive cleavage (DFRC). The data indicated that BSG lignin presents a predominance of guaiacyl units (syringyl/guaiacyl ratio of 0.4-0.5) with significant amounts of associated p-coumarates and ferulates. The flavone tricin was also present in the lignin from BSG, as also occurred in other grasses. 2D-NMR (HSQC) revealed that the main substructures present are beta-O-4' alkyl-aryl ethers (77-79%) followed by beta-5' phenylcoumarans (11-13%) and lower amounts of beta-beta' resinols (5-6%) and 5-5' dibenzodioxocins (3-5%). The results from 2D-NMR (HMBC) and DFRC indicated that p-coumarates are acylating the gamma-carbon of lignin side chains and are mostly involved in condensed structures. DFRC analyses also indicated a minor degree of gamma-acylation with acetate groups, which takes place preferentially on S lignin (6% of S units are acetylated) over G lignin (only 1% of G units are acetylated). PMID- 25520238 TI - Towards the sustainability of information campaigns: training Promotores to increase the psychosis literacy of Spanish-speaking communities. AB - PURPOSE: To assess the acceptability and efficacy of training community health workers (promotores) in Mexico to both recognize psychosis and to teach others to recognize psychosis. METHODS: Two studies were carried out utilizing a single group design. In Study 1, promotores watched a DVD-based psychosis literacy training. In Study 2, promotores were trained to administer a flip-chart version of the program and they then administered it to community residents. RESULTS: Significant increases in the post-training assessment of psychosis literacy were observed. CONCLUSION: Promotores can be an important resource in identifying psychosis early and enhancing the sustainability of psychosis literacy information campaigns. PMID- 25520240 TI - Carbon nanodots as ligand exchange probes in Au@C-dot nanobeacons for fluorescent turn-on detection of biothiols. AB - Au nanoparticle-carbon dot core-shell (Au@C-dot) nanocomposite was synthesized in aqueous medium at room temperature using the carbon dots as reducing agents themselves. The carbon nanodots also function as an effective stabilizer by forming a thin layer surrounding Au nanoparticles (Au NPs) similar to self assembled monolayers. Ligand exchange with thiol containing biomolecules resulted in the release of carbon dots from the Au NP surface leading to an enhancement of fluorescence. Simultaneously the agglomeration of Au NPs stimulated by the interaction of biothiols led to changes in the surface plasmon properties of Au NPs. A detailed spectroscopic investigation revealed a combination of static and dynamic quenching being involved in the process. Thus, the Au nanoparticle-carbon dot composite could be used as a dual colorimetric and fluorometric sensor for biothiols ranging from amino acids, peptides, proteins, enzymes etc. with a detection limit of 50 nM. PMID- 25520239 TI - Evaluation of the MALDI-TOF MS profiling for identification of newly described Aeromonas spp. AB - The genus Aeromonas comprises primarily aquatic bacteria and also serious human and animal pathogens with the occurrence in clinical material, drinking water, and food. Aeromonads are typical for their complex taxonomy and nomenclature and for limited possibilities of identification to the species level. According to studies describing the use of MALDI-TOF MS in diagnostics of aeromonads, this modern chemotaxonomical approach reveals quite high percentage of correctly identified isolates. We analyzed 64 Aeromonas reference strains from the set of 27 species. After extending the range of analyzed Aeromonas species by newly described ones, we proved that MALDI-TOF MS procedure accompanied by Biotyper tool is not a reliable diagnostic technique for aeromonads. We obtained quite high percentage of false-positive, incorrect, and uncertain results. The identification of newly described species is accompanied with misidentifications that were observed also in the case of pathogenic aeromonads. PMID- 25520241 TI - Fine motor skills of the hands in Polish and Czech female senior citizens from different backgrounds. AB - The aim of the present study was an in-depth analysis of fine motor skills of the hands in elderly women from different socio-cultural backgrounds. The research also included analysis of the associations of age with the variables assessing right- and left-hand motor skills and its effect on hand performance asymmetry. The study examined 486 women over the age of 60. The study measured dominant and non-dominant hand performance using the motor performance series test battery (aiming, line tracking, inserting pins, tapping) from the Vienna test system. The best results in the tests assessing coordinated hand movements were achieved by the group of elderly women attending a University of the Third Age in Poland. This may be the result of a larger variety of physical activity programs offered at this type of institution. However, due to the cross-sectional design of the study, additional research of a longitudinal nature needs to be performed using the same sample of individuals to draw any definitive conclusions. Additionally, a decrease in the differences between dominant and non-dominant hand function with age was observed. PMID- 25520242 TI - Endogenous sex hormones and cognitive function in the elderly. AB - BACKGROUND: Estrogen and testosterone may influence cognitive function in the older adult, but the relationship between sex hormones and cognitive function is complex. AIM: To examine associations of sex hormones and cognitive function among older adults >=65 years old. METHODS: Using a cross-sectional research design, data were collected once from 71 elderly (mean age 86.4 years). Global cognitive function and executive function were measured with standardized instruments, and saliva samples were collected for salivary estradiol and testosterone. RESULTS: Estradiol was significantly and positively correlated with global cognitive function in men only (r = 0.54, p < 0.05). Testosterone was not significantly correlated with global cognitive function or executive function in either gender. DISCUSSION AND CONCLUSION: Associations between sex hormones and cognitive function were mostly non-significant. However, higher estradiol was significantly correlated with better global cognitive function in men, suggesting gender-specific differences. Along with sex hormones, other comorbidity may need to be assessed together in relation to cognitive function in the elderly. Accordingly, clinicians play an important role in educating and promoting beneficial actions to preserve cognitive function. PMID- 25520243 TI - Erratum to: MRI features of the anterolateral ligament of the knee. PMID- 25520244 TI - Emergence of disassortative mixing from pruning nodes in growing scale-free networks. AB - Disassortative mixing is ubiquitously found in technological and biological networks, while the corresponding interpretation of its origin remains almost virgin. We here give evidence that pruning the largest-degree nodes of a growing scale-free network has the effect of decreasing the degree correlation coefficient in a controllable and tunable way, while keeping both the trait of a power-law degree distribution and the main properties of network's resilience and robustness under failures or attacks. The essence of these observations can be attributed to the fact the deletion of large-degree nodes affects the delicate balance of positive and negative contributions to degree correlation in growing scale-free networks, eventually leading to the emergence of disassortativity. Moreover, these theoretical prediction will get further validation in the empirical networks. We support our claims via numerical results and mathematical analysis, and we propose a generative model for disassortative growing scale-free networks. PMID- 25520245 TI - Intrapleural Epinephrine Irrigation for Massive Malignant Hemothorax. AB - Massive malignant hemothorax (MMH) is a rare and serious complication encountered in the field of oncology and can be life threatening. It is often difficult and complex to manage. Herein, we present cases of four patients who had MMH and in whom a hemothorax was successfully stopped via continuous intrapleural irrigation with epinephrine (5-mg epinephrine/1,000-mL normal saline, infused at 100 mL/h) instead of a conventional surgical approach. Although no patient deaths were attributed to intractable bleeding, two deaths were related to multiple organ failure. Despite the limited number of cases, this method was a convenient, effective, and inexpensive alternative to open surgical or thoracoscopic drainage for MMH. PMID- 25520248 TI - Over expression of hRad9 protein correlates with reduced chemosensitivity in breast cancer with administration of neoadjuvant chemotherapy. AB - Human Rad 9 (hRad9), part of the Rad9-Hus1-Rad1 complex plays an important role in DNA damage repair as an up-stream regulator of checkpoint signaling, however little is known about its role in response to chemotherapy of breast cancer and whether hRad9 inhibition can potentiate the cytotoxic effects of chemotherapy on breast cancer cells remains to be elucidated. Fifty cases of breast cancer receiving neoadjuvant therapy were collected. All these cases were revised and classified into chemotherapy sensitive (CS) or chemotherapy resistant (CR) group according to the Miller and Payne (MP) grading system. Immunohistochemically, hRad9 positive tumours showed nuclear and/or cytoplasmic staining. hRad9 over expression was associated with an impaired neoadjuvant chemotherapy response. A significant correlation was found between expression of hRad9 and Cyclin D1. In vitro, hRad9 was knocked down using siRNA in breast cancer cell line MCF-7 and MDA-MB-231. Deregulated expression of Rad9 accompanied by down expression of chk1 enhanced the sensitivity of human breast cancer cells to doxorubicin. Our work suggests that hRad9 might be a potential predictor for the response to chemotherapy in patients with breast cancer and its clinical value as a target for improving chemosensitivity needs further exploration. PMID- 25520249 TI - Changes in body weight and pulse: outcome events in overweight and obese subjects with cardiovascular disease in the SCOUT trial. AB - BACKGROUND/OBJECTIVES: The Sibutramine Cardiovascular OUTcomes (SCOUT) trial showed a significantly increased relative risk of nonfatal cardiovascular events, but not mortality, in overweight and obese subjects receiving long-term sibutramine treatment with diet and exercise. We examined the relationship between early changes (both increases and decreases) in pulse rate, and the impact of these changes on subsequent cardiovascular outcome events in both the placebo and sibutramine groups. SUBJECTS/METHODS: 9804 males and females, aged ?55 years, with a body mass index of 27-45 kg m(-)(2) were included in this current subanalysis of the SCOUT trial. Subjects were required to have a history of cardiovascular disease and/or type 2 diabetes mellitus with at least one cardiovascular risk factor, to assess cardiovascular outcomes. The primary outcome event (POE) was a composite of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death. Time-to-event analyses of the POE were performed using Cox regression models. RESULTS: During the initial 6-week sibutramine treatment period, the induced pulse rate increase was related to weight change (1.9+/-7.7 beats per minute (bpm) with weight increase; 1.4+/-7.3 bpm, 0-5 kg weight loss; 0.6+/-7.4 bpm, ?5 kg weight loss). Throughout the subsequent treatment period, those continuing on sibutramine showed a consistently higher mean pulse rate than the placebo group. There was no difference in POE rates with either an increase or decrease in pulse rate over the lead-in period, or during lead-in baseline to 12 months post randomization. There was also no relationship between pulse rate at lead-in baseline and subsequent cardiovascular events in subjects with or without a cardiac arrhythmia. CONCLUSION: Baseline pulse rate and changes in pulse rate may not be an important modifier nor a clinically useful predictor of outcome in an individual elderly cardiovascular obese subject exposed to weight management. PMID- 25520250 TI - Epigenetic patterns in successful weight loss maintainers: a pilot study. AB - DNA methylation changes occur in animal models of calorie restriction, simulating human dieting, and in human subjects undergoing behavioral weight loss interventions. This suggests that obese (OB) individuals may possess unique epigenetic patterns that may vary with weight loss. Here, we examine whether methylation patterns in leukocytes differ in individuals who lost sufficient weight to go from OB to normal weight (NW; successful weight loss maintainers; SWLMs) vs currently OB or NW individuals. This study examined peripheral blood mononuclear cell (PBMC) methylation patterns in NW (n=16, current/lifetime BMI 18.5-24.9) and OB individuals (n=16, current body mass index (BMI)?30), and SWLM (n=16, current BMI 18.5-24.9, lifetime maximum BMI ?30, average weight loss 57.4 lbs) using an Illumina Infinium HumanMethylation450 BeadArray. No leukocyte population-adjusted epigenome-wide analyses were significant; however, potentially differentially methylated loci across the groups were observed in ryanodine receptor-1 (RYR1; P=1.54E-6), myelin protein zero-like 3 (MPZL3; P=4.70E-6) and alpha 3c tubulin (TUBA3C; P=4.78E-6). In 32 obesity-related candidate genes, differential methylation patterns were found in brain-derived neurotrophic factor (BDNF; gene-wide P=0.00018). In RYR1, TUBA3C and BDNF, SWLM differed from OB but not NW. In this preliminary investigation, leukocyte SWLM DNA methylation patterns more closely resembled NW than OB individuals in three gene regions. These results suggest that PBMC methylation is associated with weight status. PMID- 25520256 TI - New insights into the anti-obesity activity of xanthones from Garcinia mangostana. AB - Obesity has reached epidemic proportions worldwide. This condition, and its related diseases such as diabetes and cardiovascular diseases, have become major public health challenges. Fruits are important dietary components, and bioactive constituents from fruits are considered to be a promising source for developing effective and safe anti-obesity drugs. Garcinia mangostana Linn. (Clusiaceae) is a tropical evergreen tree, and its fruit, mangosteen, is called 'Queen of Fruit'. The pericarp of G. mangostana has been used for centuries in Southeast Asia as a medicinal agent for treatment of various diseases. Products derived from mangosteen are widely consumed to ameliorate metabolic dysfunction and resultant metabolic syndrome. However, the chemical principles and mechanisms underlying these effects are unclear. This review summarizes the recent chemical and pharmacological studies related to G. mangostana, including weight reduction, anti-adipogenesis, anti-inflammation and anti-oxidation activity. The aim of this review is to shed light on the role of G. mangostana and its constituents in preventing and treating obesity, which should encourage more interest in the development of relevant therapeutic methods. PMID- 25520251 TI - Adipose tissue gene expression and metabolic health of obese adults. AB - Obese subjects with a similar body mass index (BMI) exhibit substantial heterogeneity in gluco- and cardiometabolic heath phenotypes. However, defining genes that underlie the heterogeneity of metabolic features among obese individuals and determining metabolically healthy and unhealthy phenotypes remain challenging. We conducted unsupervised hierarchical clustering analysis of subcutaneous adipose tissue transcripts from 30 obese men and women ?40 years old. Despite similar BMIs in all subjects, we found two distinct subgroups, one metabolically healthy (group 1) and one metabolically unhealthy (group 2). Subjects in group 2 showed significantly higher total cholesterol (P=0.005), low density lipoprotein cholesterol (P=0.006), 2-h insulin during oral glucose tolerance test (P=0.015) and lower insulin sensitivity (SI, P=0.029) compared with group 1. We identified significant upregulation of 141 genes (for example, MMP9 and SPP1) and downregulation of 17 genes (for example, NDRG4 and GINS3) in group 2 subjects. Intriguingly, these differentially expressed transcripts were enriched for genes involved in cardiovascular disease-related processes (P=2.81 * 10(-11)-3.74 * 10(-02)) and pathways involved in immune and inflammatory response (P=8.32 * 10(-5)-0.04). Two downregulated genes, NDRG4 and GINS3, have been located in a genomic interval associated with cardiac repolarization in published GWASs and zebra fish knockout models. Our study provides evidence that perturbations in the adipose tissue gene expression network are important in defining metabolic health in obese subjects. PMID- 25520257 TI - Printing Insecurity? The Security Implications of 3D-Printing of Weapons. AB - In 2013, the first gun printed out of plastic by a 3D-printer was successfully fired in the U.S. This event caused a major media hype about the dangers of being able to print a gun. Law enforcement agencies worldwide were concerned about this development and the potentially huge security implications of these functional plastic guns. As a result, politicians called for a ban of these weapons and a control of 3D-printing technology. This paper reviews the security implications of 3D-printing technology and 3D guns. It argues that current arms control and transfer policies are adequate to cover 3D-printed guns as well. However, while this analysis may hold up currently, progress in printing technology needs to be monitored to deal with future dangers pre-emptively. PMID- 25520258 TI - A Troubled Solution: Medical Student Struggles with Evidence and Industry Bias. AB - This empirical work attends to the tensions and contradictions medical students articulate when they discuss their objection to industry's influence in medicine. Findings are based on 50 semi-structured interviews with medical students who are critical of the pharmaceutical industry's influence in medical education in the United States and Canada. These students advocate evidence-based medicine (EBM) as one solution to the problems with industry influence in medicine; namely industry bias in medical research. This investigation is an effort to understand why EBM is posed as a solution to industry bias in light of the literature demonstrating the ways that what is considered 'evidence-based' is influenced by industry. Participants articulate a struggle to find the 'best' evidence in a context where industry interests are integral in the production of medical knowledge. PMID- 25520260 TI - Postnatal demoralisation among women admitted to a hospital mother-baby unit: validation of a psychometric measure. AB - Demoralisation is a psychological state characterised by experiences of distress and sadness, helplessness, subjective incompetence and hopelessness, in the context of a stressful situation. Experiences of demoralisation may be particularly relevant to women who have recently given birth, who can feel incompetent, isolated and helpless. The psychometric properties of the Demoralisation Scale among women in the postnatal period participating in a clinical program were examined. Women admitted with their infants to a hospital mother-baby unit in Australia for five nights were recruited consecutively (N = 209) and assessed at admission and discharge. The Demoralisation Scale was perceived as relevant and exhibited high reliability, acceptable construct validity and good sensitivity to change. The mean demoralisation score was high (M = 30.9, SD = 15.5) and associated with negative experiences of motherhood and functional impairment, independent of depression and anxiety symptoms. Mean demoralisation decreased significantly after program completion (M = 18.4, SD = 12.4). More participants showed a significant improvement in demoralisation (57.5 %) than in depression (34.8 %) and anxiety (9.8 %) symptoms. Demoralisation can provide a useful framework for understanding and measuring the experiences of women participating in postnatal clinical programs and in directing treatment towards helping women to acquire the necessary caregiving skills and increasing parental efficacy. The Demoralisation Scale is a useful clinical tool for assessing intervention effects. PMID- 25520261 TI - Pedobacter bambusae sp. nov., isolated from soil of a bamboo plantation. AB - An ivory white, rod-shaped, non-motile, non-spore forming, Gram-staining negative, and aerobic bacterium designated THG-G118T, was isolated from a soil sample collected in a bamboo plantation in Seoul, Republic of Korea. The 16S rRNA gene sequence analysis revealed a clear affiliation of strain THG-G118T with the genus Pedobacter. Strain THG-G118T was found to show the closest phylogenetic relationship with Pedobacter metabolipauper WB2.3-71T with 16S rRNA gene sequence similarity of 97.3 %. The major cellular fatty acids of strain THG-G118T were identified as C16:0, C18:0, iso-C15:0 and summed feature 3 (C16:1 omega7c and/or C16:1 omega6c), and the predominant menaquinone as menaquinone MK-7. The major polar lipids were found to be phosphatidylethanolamine (PE), unidentified phospholipid and unidentified aminophospholipids. Strain THG-G118T was found to contain ceramide phosphorylethanolamine 2 (CerPE-2) and dihydrosphingosine as the major ceramide. The G+C content of the genomic DNA was found to be 41.7 mol%. DNA DNA hybridization experiments revealed a low level of DNA-DNA relatedness (<42.5 %) between strain THG-G118T and its closest relatives. The phenotypic, chemotaxonomic and phylogenetic data showed that strain THG-G118T could be clearly distinguished from the members of the genus Pedobacter. Based on the results of a polyphasic study, a new species, Pedobacter bambusae sp. nov., is proposed. The type strain is THG-G118T (=KACC 17544T = JCM 19364T). PMID- 25520262 TI - Cancer suppression by compression. AB - Recent experiments indicate that uniformly compressing a cancer mass at its surface tends to transform many of its cells from proliferative to functional forms. Cancer cells suffer from the Warburg effect, resulting from depleted levels of cell membrane potentials. We show that the compression results in added free energy and that some of the added energy contributes distortional pressure to the cells. This excites the piezoelectric effect on the cell membranes, in particular raising the potentials on the membranes of cancer cells from their depleted levels to near-normal levels. In a sample calculation, a gain of 150 mV in is so attained. This allows the Warburg effect to be reversed. The result is at least partially regained function and accompanying increased molecular order. The transformation remains even when the pressure is turned off, suggesting a change of phase; these possibilities are briefly discussed. It is found that if the pressure is, in particular, applied adiabatically the process obeys the second law of thermodynamics, further validating the theoretical model. PMID- 25520263 TI - Fertility decline and child schooling in urban settings of Burkina Faso. AB - As evidenced in Western rich countries, Asia, and Latin America, lower fertility allows couples to invest more in each of their children's schooling. This postulate is the key rationale of family planning policies in sub-Saharan Africa. Yet, most studies on Africa have found no correlation or even a positive relationship between the number of children in a family and their educational attainment. These mixed results are usually explained by African family solidarity and resource transfers that might reduce pressures on household resources occasioned by many births as well as methodological problems that have afflicted much research on the region. Our study aims to assess the impact of family size on children's schooling in Ouagadougou (capital of Burkina Faso), using a better measure of household budget constraints and taking into account the simultaneity of fertility and schooling decisions. In contrast to most prior studies on sub-Saharan Africa, we find a net negative effect of sibship size on the level of schooling achieved by children--one that grows stronger as they progress through the educational system. PMID- 25520264 TI - Clinical analysis of twenty cases of cervical cancer associated with pregnancy. AB - OBJECTIVES: The objectives are to investigate the therapeutic methods and prognosis of cervical cancer associated with pregnancy. METHODS: Combined with a literature review, we analyzed the clinical characteristics, diagnosis and treating process, and prognosis of 20 cases of cervical cancer associated with pregnancy admitted in our hospital from 2000 to 2009. RESULTS: Fifteen cases were treated with surgery, four cases with radiotherapy or synchronous chemoradiation, and one case with palliative systemic chemotherapy. Fourteen cases were disease free survivals, five cases died of distant metastasis, and one case was lost to follow-up. Also, for survival, there were seven in eight cases of early pregnancy, two in four cases of mid-pregnancy, one in two cases of late pregnancy, four in six postpartum cases, and one in three cases of vaginal delivery. CONCLUSIONS: There was a close relationship between clinical stage, diagnosis time, delivery method, and the prognosis of cervical cancer associated with pregnancy. For late pregnancy and postpartum cervical cancer surgery, preoperative and postoperative combination chemotherapy might improve the prognosis. PMID- 25520265 TI - Intracranial pseudoaneurysm after intracranial pressure monitor placement. AB - Traumatic intracranial pseudoaneurysms are a rare but severe complication following arterial injury. Pseudoaneurysm formation can occur secondary to blunt or penetrating trauma or iatrogenic injury. We report a case of traumatic pseudoaneurysm secondary to placement of an intracranial pressure (ICP) monitor. A 27-year-old man was involved in a motorcycle accident resulting in multiple intracranial hemorrhages. The patient underwent craniectomy and placement of an ICP monitor. 17 days later he developed dilation of his left pupil, with imaging demonstrating a new hemorrhage in the vicinity of the previous ICP monitor. A cerebral angiogram confirmed a left-sided distal M4 pseudoaneurysm which was treated by n-butyl cyanoacrylate embolization. Intracranial pseudoaneurysm formation following neurosurgical procedures is uncommon. Delayed intracranial hemorrhage in a region of prior intracranial manipulation, even following a procedure as 'routine' as placement of an ICP monitor, should raise the suspicion for this rare but potentially lethal complication. PMID- 25520266 TI - Monitoring postcolonoscopy colorectal cancers: dangerous crossroads? PMID- 25520268 TI - Traction-assisted dissection with soft tissue coverage is effective for repairing recurrent urethrocutaneous fistula following hypospadias surgery. AB - INTRODUCTION: Urethrocutaneous fistula (UCF) complicating hypospadias surgery is associated with compromised tissue and perfusion at the UCF site, especially if recurrent. We report our technique for UCF repair. METHODS: Between 1997 and 2014, we treated 35 UCF in 26 postoperative hypospadias patients; 12 UCF were recurrent (mean 2.5; range 1-5). Mean age at UCF repair was 9.3 years (range 2 22). Our repair involves making a superficial incision 3-5 mm around the fistula orifice, placing multiple stay sutures in the outer edge of this incision and dissecting only the epidermis under traction for 7-10 mm. This technique does not compromise underlying connective tissue or tissue perfusion. The skin layer of the inner edge of the circumferential incision is trimmed completely and the fistula closed using 7/0 absorbable interrupted sutures. A pedicled external spermatic fascia, or tunica vaginalis flap is then mobilized to cover the repair site through a subcutaneous tunnel and the skin closed. A urethral catheter is placed and removed the next day. Duration of follow-up was calculated as the period from discharge home until the last outpatient clinic attendance. RESULTS: Repair was successful in all cases. Penile cosmesis was acceptable to good without any testicular complications or scrotal deformity. At mean follow-up of 7.4 years (range 0.4-17.3) there have been no recurrences. CONCLUSIONS: Our technique allows UCF to be repaired effectively and is also indicated for recurrences. PMID- 25520267 TI - Angle-recession glaucoma: long-term clinical outcomes over a 10-year period in traumatic microhyphema. AB - This study aims to determine the incidence of angle recession and glaucoma after traumatic microhyphema. Records of all patients treated for traumatic hyphema or microhyphema admitted to a district hospital throughout a 10-year period were retrospectively reviewed. Patients with open-globe injury were excluded. The following clinical features were recorded during patients' initial presentation and follow-up visits: Snellen visual acuity, examination with slit-lamp biomicroscopy, intraocular pressure (IOP), dilated fundoscopic examination, gonioscopic examination and treatment. For patients with IOP > 21 mmHg and requiring glaucoma medications, visual field tests were performed. A total of 97 patients met the study criteria, of which 62 had microhyphema and 35 had gross hyphema. Among the traumatic microhyphema patients, 47 (75.8 %) had angle recession and 4 (6.5 %) had glaucoma with mean follow-up of 49 months (range 6-98 months). A statistically significant association was found between angle recession greater than 180 degrees and the occurrence of glaucoma (p < 0.01). No statistically significant differences were found between groups of patients with microhyphema or gross hyphema regarding the incidence of angle recession and glaucoma. The complications of angle recession and glaucoma in patients after traumatic microhyphema appear similar to those found in patients after gross hyphema. PMID- 25520269 TI - Epitope mapping via selection of anti-FVIII antibody-specific phage-presented peptide ligands that mimic the antibody binding sites. AB - The most serious complication in today's treatment of congenital haemophilia A is the development of neutralising antibodies (inhibitors) against factor VIII (FVIII). Although FVIII inhibitors can be eliminated by immune tolerance induction (ITI) based on repeated administration of high doses of FVIII, 20-30% of patients fail to become tolerant. Persistence of FVIII inhibitors is associated with increased morbidity and mortality. Data from recent studies provide evidence for a potential association between ITI outcome and epitope specificity of FVIII inhibitors. Nevertheless the determination of epitopes and their clinical relevance has not yet been established. In this study a general strategy for the identification of anti-FVIII antibody epitopes in haemophilia A patient plasma was to be demonstrated. Phage-displayed peptide libraries were screened against anti-FVIII antibodies to isolate specific peptides. Peptide specificity was confirmed by FVIII-sensitive ELISA binding. Peptide residues essential for antibody binding were identified by mutational analysis and epitopes were predicted via FVIII homology search. The proposed mapping strategy was validated for the monoclonal murine antibody (mAb) 2-76. Binding studies with FVIII variants confirmed the location of the predicted epitope at the level of individual amino acids. In addition, anti-FVIII antibody-specific peptide ligands were selected for 10 haemophilia A patients with FVIII inhibitors. Detailed epitope mapping for three of them showed binding sites on the A2, A3 and C2 domains. Precise epitope mapping of anti-FVIII antibodies using antibody-specific peptide ligands can be a useful approach to identify antigenic sites on FVIII. PMID- 25520270 TI - Appearance-based trust behaviour is reduced in children with autism spectrum disorder. AB - Typical individuals make rapid and reliable evaluations of trustworthiness from facial appearances, which can powerfully influence behaviour. However, the same may not be true for children with autism spectrum disorder. Using an economic trust game, the current study revealed that like typical children, children with autism spectrum disorder rationally modulate their trust behaviour based on non face cues to partner trustworthiness (e.g. reputation information). Critically, however, they are no more likely to place their trust in partners with faces that look trustworthy to them, than those that look untrustworthy. These results cannot be accounted for by any group differences in children's conceptualization of trustworthiness, ability to read trustworthiness from faces or understanding of the experimental paradigm. Instead, they seem to suggest that there may be a selective failure to spontaneously use facial cues to trustworthiness to guide behaviour in an ecologically valid context. PMID- 25520271 TI - Computer-Aided Diagnosis for Distinguishing Pancreatic Mucinous Cystic Neoplasms From Serous Oligocystic Adenomas in Spectral CT Images. AB - OBJECTIVE: This preliminary study aims to verify the effectiveness of the additional information provided by spectral computed tomography (CT) with the proposed computer-aided diagnosis (CAD) scheme to differentiate pancreatic serous oligocystic adenomas (SOAs) from mucinous cystic neoplasms of pancreas cystic lesions. MATERIALS AND METHODS: This study was conducted from January 2010 to October 2013. Twenty-three patients (5 men and 18 women; mean age, 43.96 years old) with SOA and 19 patients (3 men and 16 women; mean age, 41.74 years old) with MCN were included in this retrospective study. Two types of features were collected by dual-energy spectral CT imaging as follows: conventional and additional quantitative spectral CT features. Classification results of the CAD scheme were compared using the conventional features and full feature data set. Important features were selected using support vector machine classification method combined with feature-selection technique. The optimal cutoff values of selected features were determined through receiver-operating characteristic curve analyses. RESULTS: Combining conventional features with additional spectral CT features improved the overall accuracy from 88.37% to 93.02%. The selected features of the proposed CAD scheme were tumor size, contour, location, and low energy CT values (43 keV). Iodine-water basis material pair densities in both arterial phase (AP) and portal venous phase (PP) were important factors for differential diagnosis of SOA and MCN. The optimal cutoff values of long axis, short axis, 40 keV monochromatic CT value in AP, iodine (water) density in AP, 43 keV monochromatic CT value in PP, and iodine (water) density in PP were 3.4 mm, 3.1 mm, 35.7 Hu, 0.32533 mg/mL, 39.4 Hu, and 0.348 mg/mL, respectively. CONCLUSION: The combination of conventional features and additional information provided by dual-energy spectral CT shows a high accuracy in the CAD scheme. The quantitative information of spectral CT may prove useful in the diagnosis and classification of SOAs and MCNs with machine learning algorithms. PMID- 25520272 TI - Evaluation of Dose Uncertainty to the Target Associated With Real-Time Tracking Intensity-Modulated Radiation Therapy Using the CyberKnife Synchrony System. AB - We investigated the dose uncertainty caused by errors in real-time tracking intensity-modulated radiation therapy (IMRT) using the CyberKnife Synchrony Respiratory Tracking System (SRTS). Twenty lung tumors that had been treated with non-IMRT real-time tracking using CyberKnife SRTS were used for this study. After validating the tracking error in each case, we did 40 IMRT planning using 8 different collimator sizes for the 20 patients. The collimator size was determined for each planning target volume (PTV); smaller ones were one-half, and larger ones three-quarters, of the PTV diameter. The planned dose was 45 Gy in 4 fractions prescribed at 95% volume border of the PTV. Thereafter, the tracking error in each case was substituted into calculation software developed in house and randomly added in the setting of each beam. The IMRT planning incorporating tracking errors was simulated 1000 times, and various dose data on the clinical target volume (CTV) were compared with the original data. The same simulation was carried out by changing the fraction number from 1 to 6 in each IMRT plan. Finally, a total of 240 000 plans were analyzed. With 4 fractions, the change in the CTV maximum and minimum doses was within 3.0% (median) for each collimator. The change in D99 and D95 was within 2.0%. With decreases in the fraction number, the CTV coverage rate and the minimum dose decreased and varied greatly. The accuracy of real-time tracking IMRT delivered in 4 fractions using CyberKnife SRTS was considered to be clinically acceptable. PMID- 25520273 TI - Adverse effects of energy drinks. PMID- 25520274 TI - Anomericity of T-2 toxin-glucoside: masked mycotoxin in cereal crops. AB - T-2 toxin is a trichothecene mycotoxin produced when Fusarium fungi infect grains, especially oats and wheat. Ingestion of T-2 toxin contaminated grain can cause diarrhea, hemorrhaging, and feed refusal in livestock. Cereal crops infected with mycotoxin-producing fungi form toxin glycosides, sometimes called masked mycotoxins, which are a potential food safety concern because they are not detectable by standard approaches and may be converted back to the parent toxin during digestion or food processing. The work reported here addresses four aspects of T-2 toxin-glucosides: phytotoxicity, stability after ingestion, antibody detection, and the anomericity of the naturally occurring T-2 toxin glucoside found in cereal plants. T-2 toxin-beta-glucoside was chemically synthesized and compared to T-2 toxin-alpha-glucoside prepared with Blastobotrys muscicola cultures and the T-2 toxin-glucoside found in naturally contaminated oats and wheat. The anomeric forms were separated chromatographically and differ in both NMR and mass spectrometry. Both anomers were significantly degraded to T 2 toxin and HT-2 toxin under conditions that mimic human digestion, but with different kinetics and metabolic end products. The naturally occurring T-2 toxin glucoside from plants was found to be identical to T-2 toxin-alpha-glucoside prepared with B. muscicola. An antibody test for the detection of T-2 toxin was not effective for the detection of T-2 toxin-alpha-glucoside. This anomer was produced in sufficient quantity to assess its animal toxicity. PMID- 25520275 TI - Cognitive and affective disturbances following focal brainstem lesions: a review and report of three cases. AB - Although insights in cerebellar neurocognition and affect are continuously growing, little is known about the role of the brainstem in cognitive and behavioural processing. In this paper, it is hypothesized that the brainstem is an inherent functional part of the cerebellocerebral network subserving cognition and affect, and that isolated brainstem damage may cause a constellation of symptoms closely resembling the cerebellar cognitive affective syndrome (CCAS) following cerebellar pathology. In order to investigate these premises, the available literature on cognitive and affective disturbances following brainstem lesions was critically reviewed starting from the pioneer descriptions in the 1950s till June 2012. Three personal cases were added to a study group of 75 cases with isolated vascular brainstem damage. In a cohort of 30 patients that allowed construction of anatomoclinical correlations in a reliable way, a range of cognitive and behavioural symptoms, typically associated with impairment of cortical or limbic areas, were identified. Executive dysfunction, attentional deficits and a decline in general intellectual capacity represent the most common cognitive findings, but memory, visuospatial skills, language and praxis may be impaired as well. Almost half of the cases presented with behavioural or affective changes. Analysis of SPECT findings indicates that functional suppression of frontal, parietal and to a lesser extent also the temporal areas are common phenomena after isolated brainstem stroke. As reflected by diaschisis affecting the cerebellocerebral network, a loss of excitatory input from the brainstem to the cerebellum and cerebrum may induce disruption of several cortical regions as well as emotional control centres resulting in and a constellation of symptoms closely resembling the CCAS. The pathophysiological mechanism underlying brainstem-induced cognitive and affective disturbances is discussed. PMID- 25520277 TI - Against the odds in Las Vegas. PMID- 25520278 TI - Impact of bilateral ST36 and PC6 electroacupuncture on the depth of sedation in general anaesthesia. AB - OBJECTIVE: To investigate the impact of electroacupuncture (EA) at bilateral acupuncture points ST36 and PC6 on the level of sedation in general anaesthesia. METHODS: 40 patients undergoing abdominal surgery were randomly divided into two groups: EA combined with general anaesthesia (EA group, n=20) and general anaesthesia control group (n=20). The bilateral acupuncture points ST36 and PC6 were selected in both groups. Target-controlled infusion (TCI) of propofol was used for the induction and maintenance of general anaesthesia to reach an equilibrium state of Narcotrend Index (NT index). In the EA group, EA was performed with a Hans EA device. In the control group, general anaesthesia was performed without EA stimulation. In both groups, heart rate (HR), mean blood pressure (MAP) and NT index were recorded at corresponding time points up to 30 min after the end of acupuncture. RESULTS: The NT indices of the EA group showed a downward trend after EA stimulation (p=0.01). From 15 min after the start of EA stimulation the NT indices of the EA group were significantly lower than those of the control group (p<0.05). HR and MAP of the two groups showed no significant differences at any time points (p>=0.05). CONCLUSIONS: EA stimulation at bilateral ST36 and PC6 significantly deepens the sedation level of general anaesthesia in patients with propofol TCI, has little impact on haemodynamics and provides significant delayed sedation effects. PMID- 25520279 TI - Use of NADA ear acupuncture in an adolescent patient with phantom limb pain after surgery for osteosarcoma. PMID- 25520280 TI - Effect of electroacupuncture on the inflammatory response in patients with acute pancreatitis: an exploratory study. AB - OBJECTIVES: To examine the effects of electroacupuncture (EA) on inflammatory responses in patients with acute pancreatitis (AP). METHODS: Eighty patients with mild or severe AP were randomly allocated to a control group or an EA group. All patients were managed conservatively. In addition, the EA group received acupuncture for 30 min per day for 7 days at bilateral points ST36, LI4, TE6, ST37 and LR3. Interleukin (IL)-6, IL-10 and C-reactive protein (CRP) levels were measured on admission and on day 7. The time to re-feeding and length of stay in hospital were also recorded. RESULTS: A total of 58 patients provided complete data. The characteristics of the patients in the EA and control groups were similar. After 7 days the serum concentrations of IL-10 were higher in the EA group than in the control group (mild AP: 6.2+/-1.2 vs 5.2+/-0.9 pg/mL, p<0.05; severe AP: 14.9+/-7.8 vs 7.9+/-6.3 pg/mL, p<0.05). For patients with severe AP, the CRP level in the EA group was lower than in the control group (p<0.05). CONCLUSIONS: EA may reduce the severity of AP by inducing anti-inflammatory effects and reducing the time to re-feeding; however, it did not reduce the length of hospital stay. TRIAL REGISTRATION NUMBER: ChiCTR-TRC-13003572. PMID- 25520281 TI - Neuropathological Techniques to Investigate Central Nervous System Sections in Multiple Sclerosis. AB - Immunohistochemical techniques (IHC) and in situ hybridization (ISH) are widely used techniques to study the expression of proteins and messenger RNAs in tissues and are extremely important to confirm and interpret biochemical and molecular results from the same tissues. Investigation of human brain by IHC and ISH therefore still plays an important role in the elucidation of pathogenetic mechanisms in diseases such as multiple sclerosis. In this review we describe the processing of human brain tissues as well as basic and advanced immunohistochemical staining and ISH techniques used for neuropathological analysis of such pathological brains. PMID- 25520282 TI - Derivation of Neural Precursor Cells from Human Embryonic Stem Cells for DNA Methylomic Analysis. AB - Embryonic stem cells are self-renewing pluripotent cells with competency to differentiate into all three-germ lineages. Many studies have demonstrated the importance of genetic and epigenetic molecular mechanisms in the maintenance of self-renewal and pluripotency. Stem cells are under unique molecular and cellular regulations different from somatic cells. Proper regulation should be ensured to maintain their unique self-renewal and undifferentiated characteristics. Understanding key mechanisms in stem cell biology will be important for the successful application of stem cells for regenerative therapeutic medicine. More importantly practical use of stem cells will require our knowledge on how to properly direct and differentiate stem cells into the necessary type of cells. Embryonic stem cells and adult stem cells have been used as study models to unveil molecular and cellular mechanisms in various signaling pathways. They are especially beneficial to developmental studies where in vivo molecular/cellular study models are not available. We have derived neural stem cells from human embryonic stem cells as a model to study the effect of teratogen in neural development. We have tested commercial neural differentiation system and successfully derived neural precursor cells exhibiting key molecular features of neural stem cells, which will be useful for experimental application. PMID- 25520276 TI - Cerebellar endocannabinoids: retrograde signaling from purkinje cells. AB - The cerebellar cortex exhibits a strikingly high expression of type 1 cannabinoid receptor (CB1), the cannabinoid binding protein responsible for the psychoactive effects of marijuana. CB1 is primarily found in presynaptic elements in the molecular layer. While the functional importance of cerebellar CB1 is supported by the effect of gene deletion or exogenous cannabinoids on animal behavior, evidence for a role of endocannabinoids in synaptic signaling is provided by in vitro experiments on superfused acute rodent cerebellar slices. These studies have demonstrated that endocannabinoids can be transiently released by Purkinje cells and signal at synapses in a direction opposite to information transfer (retrograde). Here, following a description of the reported expression pattern of the endocannabinoid system in the cerebellum, I review the accumulated in vitro data, which have addressed the mechanism of retrograde endocannabinoid signaling and identified 2-arachidonoylglycerol as the mediator of this signaling. The mechanisms leading to endocannabinoid release, the effects of CB1 activation, and the associated synaptic plasticity mechanisms are discussed and the remaining unknowns are pointed. Notably, it is argued that the spatial specificity of this signaling and the physiological conditions required for its induction need to be determined in order to understand endocannabinoid function in the cerebellar cortex. PMID- 25520283 TI - Genetic Manipulation of Human Embryonic Stem Cells. AB - One of the great advantages of embryonic stem (ES) cells over other cell types is their accessibility to genetic manipulation. They can easily undergo genetic modifications while remaining pluripotent, and can be selectively propagated, allowing the clonal expansion of genetically altered cells in culture. Since the first isolation of ES cells in mice, many effective techniques have been developed for gene delivery and manipulation of ES cells. These include transfection, electroporation, and infection protocols, as well as different approaches for inserting, deleting, or changing the expression of genes. These methods proved to be extremely useful in mouse ES cells, for monitoring and directing differentiation, discovering unknown genes, and studying their function, and are now being extensively implemented in human ES cells (HESCs). This chapter describes the different approaches and methodologies that have been applied for the genetic manipulation of HESCs and their applications. Detailed protocols for generating clones of genetically modified HESCs by transfection, electroporation, and infection will be described, with special emphasis on the important technical details that are required for this purpose. All protocols are equally effective in human-induced pluripotent stem (iPS) cells. PMID- 25520284 TI - Generation and Characterization of Patient-Specific Induced Pluripotent Stem Cell for Disease Modeling. AB - One major hurdle to the development of effective treatments to many diseases is the lack of suitable human model systems. The ability to reprogram human somatic cells to induced pluripotent stem cells (iPSC) offers an excellent opportunity to generate human disease models with primary cells. Currently, several methods to generate iPSC lines exist, and iPSC can be generated from various tissue sources including skin fibroblasts, blood, hair follicles, dental tissue, and urine. In this chapter we describe the generation and characterization of iPSC from blood or fibroblast on a routine base and focus on the integration-free methodologies. PMID- 25520285 TI - Enhancing Human Cardiomyocyte Differentiation from Induced Pluripotent Stem Cells with Trichostatin A. AB - Human induced pluripotent stem (iPS) cells are a promising source of autologous cardiomyocytes to repair and regenerate myocardium for treatment of heart disease. In this study, we describe a method for enhanced cardiomyocyte production from human iPS cells by treating embryoid bodies with a histone deacetylase inhibitor, trichostatin A (TSA), together with activin A and bone morphogenetic protein (BMP)-4. The resulting cardiomyocytes expressed cardiac specific transcription factors and contractile proteins at both gene and protein levels. Functionally, the contractile embryoid bodies (EBs) displayed calcium cycling and were responsive to the chronotropic agents isoprenaline (0.1 MUM) and carbachol (1 MUM). The cardiomyocytes derived from human iPS cells may be used to engineer functional cardiac muscle tissue for studying pathophysiology of cardiac disease, for drug discovery test beds, and potentially for generation of cardiac grafts to surgically replace damaged myocardium. PMID- 25520286 TI - Mesoderm Differentiation from hiPS Cells. AB - Human induced pluripotent stem (hiPS) cells are very attractive tools for modeling diseases and regenerative medicine. However, to achieve them, the efficient differentiation methods of hiPS cells into aimed cell type in vitro are necessary. Because mesoderm cells are useful in particular, we have developed the differentiation of mouse embryonic stem (mES) cells into mesoderm cells previously. In this time, these methods were improved for hiPS cells and now human mesoderm cells are able to be obtained efficiently. It is certain that the new methods are applicable to various studies and therapies. PMID- 25520287 TI - Patient-Specific Induced Pluripotent Stem Cell Models: Characterization of iPS Cell-Derived Cardiomyocytes. AB - Despite significant advances in medical treatment, cardiovascular disease is still a major cause of morbidity and mortality in advanced countries. To improve the outcome, the further promotion of basic cardiovascular science has a pivotal role for the developing novel therapeutic approach. However, due to the inaccessibility of human heart tissue, we couldn't obtain the sufficient amount of patient's heart tissues. The discovery of human-induced pluripotent stem cells (iPSCs) is highly expected to provide the breakthrough to this obstruction. Through the patient-specific iPSCs-derived cardiomyocytes, we could analyze the patient-specific heart diseases directly and repetitively. Herein we introduce the outline of creation for cardiac disease modeling using patient-specific iPSCs. Within several topics, we present the actual representative methodologies throughout the process from the derivation of cardiomyocytes to those of functional analysis. PMID- 25520288 TI - Generation and Neuronal Differentiation of Patient-Specific Induced Pluripotent Stem Cells Derived from Niemann-Pick Type C1 Fibroblasts. AB - Patient-specific induced pluripotent stem cells (iPSCs) are discussed to provide a powerful tool to investigate pathological mechanisms of diseases. Moreover, such cells might be a future platform for individualized personal treatment of diseases with a broad spectrum of mutations and thus resulting in phenotypical specificities.Here, we present a protocol for the induction of induced pluripotent stem cells from patient fibroblasts with Niemann-Pick type C1 disease (NPC1). The induction is based on a retroviral system, using the "classical" transcription factors, which were described by Takahashi and colleagues in 2007. To obtain a neuronal in vitro model system of NPC1, human iPSCs were differentiated to neural progenitor cells (NPCs) and subsequently to cells of the neural lineage, namely, neurons and glial cells. iPSCs, NPCs, and terminal neuronal differentiated cells (NDCs) were characterized by means of immunocytochemistry as well as patch clamp recordings and calcium imaging to prove the functional maturation. PMID- 25520289 TI - Modeling Axonal Phenotypes with Human Pluripotent Stem Cells. AB - Impaired axonal development and degeneration are implicated in many debilitating disorders, such as hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS), and periphery neuropathy. Human pluripotent stem cells (hPSCs) have provided researchers with an excellent resource for modeling human neuropathologic processes including axonal defects in vitro. There are a number of steps that are crucial when developing an hPSC-based model of a human disease, including generating induced pluripotent stem cells (iPSCs), differentiating those cells to affected cell types, and identifying disease-relevant phenotypes. Here, we describe these steps in detail, focusing on the neurodegenerative disorder HSP. PMID- 25520290 TI - In Vitro Modeling of Alcohol-Induced Liver Injury Using Human-Induced Pluripotent Stem Cells. AB - Alcohol consumption has long been associated with a majority of liver diseases and has been found to influence both fetal and adult liver functions. In spite of being one of the major causes of morbidity and mortality in the world, currently, there are no effective strategies that can prevent or treat alcoholic liver disease (ALD), due to a lack of human-relevant research models. Recent success in generation of functionally active mature hepatocyte-like cells from human-induced pluripotent cells (iPSCs) enables us to better understand the effects of alcohol on liver functions. Here, we describe the method and effect of alcohol exposure on multistage hepatic cell types derived from human iPSCs, in an attempt to recapitulate the early stages of liver tissue injury associated with ALD. We exposed different stages of iPSC-induced hepatic cells to ethanol at a pathophysiological concentration. In addition to stage-specific molecular markers, we measured several key cellular parameters of hepatocyte injury, including apoptosis, proliferation, and lipid accumulation. PMID- 25520291 TI - Modeling Genomic Imprinting Disorders Using Induced Pluripotent Stem Cells. AB - Induced pluripotent stem cell (iPSC) technology has allowed for the invaluable modeling of many genetic disorders including disorders associated with genomic imprinting. Genomic imprinting involves differential DNA and histone methylation and results in allele-specific gene expression. Most of the epigenetic marks in somatic cells are erased and reestablished during the process of reprogramming into iPSCs. Therefore, in generating models of disorders associated with genomic imprinting, it is important to verify that the imprinting status and allele specific gene expression patterns of the parental somatic cells are maintained in their derivative iPSCs. Here, we describe three techniques: DNA methylation analysis, allele-specific PCR, and RNA FISH, which we use to analyze genomic imprinting in iPSC models of neurogenetic disorders involving copy number variations of the chromosome 15q11-q13 region. PMID- 25520292 TI - Patient-Specific Induced Pluripotent Stem Cell Models: Generation and Characterization of Cardiac Cells. AB - The generation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes has been of utmost interest for the study of cardiac development, cardiac disease modeling, and evaluation of cardiotoxic effects of novel candidate drugs. Several protocols have been developed to guide human stem cells toward the cardiogenic path. Pioneering work used serum to promote cardiogenesis; however, low cardiogenic throughputs, lack of chemical definition, and batch-to batch variability of serum lots constituted a considerable impediment to the implementation of those protocols to large-scale cell biology. Further work focused on the manipulation of pathways that mouse genetics indicated to be fundamental in cardiac development to promote cardiac differentiation in stem cells. Although extremely elegant, those serum-free protocols involved the use of human recombinant cytokines that tend to be quite costly and which can also be variable between lots. The latest generation of cardiogenic protocols aimed for a more cost-effective and reproducible definition of the conditions driving cardiac differentiation, using small molecules to manipulate cardiogenic pathways overriding the need for cytokines. This chapter details methods based on currently available cardiac differentiation protocols for the generation and characterization of robust numbers of hiPSC-derived cardiomyocytes under chemically defined conditions. PMID- 25520294 TI - Standardized transthoracic echocardiography in patients with primary and secondary mitral valve regurgitation. PMID- 25520295 TI - Spinal Accessory Nerve: Ultrasound Findings and Correlations with Neck Lymph Node Levels. AB - Purpose: To evaluate the ultrasound characteristics of the spinal accessory nerve (SAN) and correlate nerve location with neck lymph node level. Materials and Methods: 50 participants with 100 SANs were enrolled in this study. The SAN was traced from the trapezius muscle to the upper neck and was identified by a hypoechoic linear structure without color Doppler flow. The ultrasound characteristics of the SAN, such as visibility, diameter, relationship with adjacent structures, and its correlation with lymph node levels, were evaluated. Results: The SAN was identified in 96 %-100 % of segments. The mean diameter of the SAN was 0.54 +/- 0.09 mm. The SANs was located between the trapezius and levator scapulae muscles and 90.8 % were traced into the trapezius muscle. In the upper neck, the SAN passed deep into the sternocleidomastoid (SCM) muscle in 38 % of cases and between the two heads of the SCM muscle in 62 % of cases. The SAN was found at neck lymph node levels II, III, IV, and V, but not I or VI. Conclusion: Continuous ultrasound monitoring of the SAN and its correlation with lymph node levels is possible in most patients. Our current findings may assist in the future prevention of SAN injury during ultrasound-guided procedures. PMID- 25520297 TI - Emergency radiology: state of the art. PMID- 25520296 TI - toyLIFE: a computational framework to study the multi-level organisation of the genotype-phenotype map. AB - The genotype-phenotype map is an essential object to understand organismal complexity and adaptability. However, its experimental characterisation is a daunting task. Thus, simple models have been proposed and investigated. They have revealed that genotypes differ in their robustness to mutations; phenotypes are represented by a broadly varying number of genotypes, and simple point mutations suffice to navigate the space of genotypes while maintaining a phenotype. Nonetheless, most current models focus only on one level of the map (folded molecules, gene regulatory networks, or networks of metabolic reactions), so that many relevant questions cannot be addressed. Here we introduce toyLIFE, a multi level model for the genotype-phenotype map based on simple genomes and interaction rules from which a complex behaviour at upper levels emerges remarkably plastic gene regulatory networks and metabolism. toyLIFE is a tool that permits the investigation of how different levels are coupled, in particular how and where mutations affect phenotype or how the presence of certain metabolites determines the dynamics of toyLIFE gene regulatory networks. The model can easily incorporate evolution through more complex mutations, recombination, or gene duplication and deletion, thus opening an avenue to explore extended genotype-phenotype maps. PMID- 25520293 TI - Imaging biomarkers in primary brain tumours. AB - We are getting used to referring to instrumentally detectable biological features in medical language as "imaging biomarkers". These two terms combined reflect the evolution of medical imaging during recent decades, and conceptually comprise the principle of noninvasive detection of internal processes that can become targets for supplementary therapeutic strategies. These targets in oncology include those biological pathways that are associated with several tumour features including independence from growth and growth-inhibitory signals, avoidance of apoptosis and immune system control, unlimited potential for replication, self-sufficiency in vascular supply and neoangiogenesis, acquired tissue invasiveness and metastatic diffusion. Concerning brain tumours, there have been major improvements in neurosurgical techniques and radiotherapy planning, and developments of novel target drugs, thus increasing the need for reproducible, noninvasive, quantitative imaging biomarkers. However, in this context, conventional radiological criteria may be inappropriate to determine the best therapeutic option and subsequently to assess response to therapy. Integration of molecular imaging for the evaluation of brain tumours has for this reason become necessary, and an important role in this setting is played by imaging biomarkers in PET and MRI. In the current review, we describe most relevant techniques and biomarkers used for imaging primary brain tumours in clinical practice, and discuss potential future developments from the experimental context. PMID- 25520298 TI - A Longitudinal Study of Rejecting and Autonomy-Restrictive Parenting, Rejection Sensitivity, and Socioemotional Symptoms in Early Adolescents. AB - Rejection sensitivity (RS) has been defined as the tendency to readily perceive and overreact to interpersonal rejection. The primary aim of this study was to test key propositions of RS theory, namely that rejecting experiences in relationships with parents are antecedents of early adolescents' future RS and symptomatology. We also expanded this to consider autonomy-restrictive parenting, given the importance of autonomy in early adolescence. Participants were 601 early adolescents (age 9 to 13 years old, 51% boys) from three schools in Australia. Students completed questionnaires at school about parent and peer relationships, RS, loneliness, social anxiety, and depression at two times with a 14-month lag between assessments. Parents also reported on adolescents' difficulties at Time 1 (T1). It was anticipated that more experience of parental rejection, coercion, and psychological control would be associated with adolescents' escalating RS and symptoms over time, even after accounting for peer victimisation, and that RS would mediate associations between parenting and symptoms. Structural equation modelling supported these hypotheses. Parent coercion was associated with adolescents' increasing symptoms of social anxiety and RS over time, and parent psychological control was associated with increasing depressive symptoms over time. Indirect effects via RS were also found, with parent rejection and psychological control linked to higher T1 RS, which was then associated with increasing loneliness and RS. Lastly, in a separate model, peer victimisation and RS, but not parenting practices, were positively associated with concurrent parent reports of adolescents' difficulties. PMID- 25520299 TI - State-based Marketplaces using 'clearinghouse' plan management models are associated with lower premiums. AB - The state-based and federally facilitated health insurance Marketplaces, or exchanges, enrolled more than eight million people during the first open enrollment period, which ended March 31, 2014. There is significant variation in how states have designed and implemented their Marketplaces. We examined how premiums varied with states' involvement in the Marketplaces through governance, plan management authority, and strategy during the first year that the exchanges have been open. State-based Marketplaces using "clearinghouse" plan management models had significantly lower adjusted average premiums for all plans within each metal level compared to state-based Marketplaces using "active purchaser" models and the federally facilitated and partnership Marketplaces. Clearinghouse management models are those in which all health plans that meet published criteria are accepted. Active purchaser models are those in which states negotiate premiums, provider networks, number of plans, and benefits. Our baseline estimates provide valuable benchmarks for evaluating future performance of states' involvement in governance, plan management, and regulatory authority of the insurance Marketplaces. PMID- 25520300 TI - E-cigarettes may work as well as nicotine patches in reducing and quitting smoking, but evidence is limited. PMID- 25520301 TI - Sleep disturbance and neurocognitive function during the recovery from a sport related concussion in adolescents. AB - BACKGROUND: Sleep disturbances are a hallmark sign after a sport-related concussion (SRC). Poor sleep has been shown to adversely affect baseline neurocognitive test scores, but it is not comprehensively understood how neurocognitive function is affected by disrupted sleep during recovery from a concussion. PURPOSE: To identify the correlation between adolescent athletes' neurocognitive function and their self-reported sleep quantity and sleep disturbance symptoms during recovery from SRC. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Immediate Post-Concussion Assessment and Cognition Testing (ImPACT) data were retrospectively collected for 545 adolescent athletes treated for SRC at a sports medicine concussion clinic. Patients were stratified into groups based on 2 criteria: self-reported sleep duration and self reported sleep disturbance symptoms during postinjury ImPACT testing. Sleep duration was classified as short (<7 hours), intermediate (7-9 hours), and long (>9 hours). Sleep disturbance symptoms were self-reported as part of the Post Concussion Symptom Scale (PCSS) as either sleeping less than normal, sleeping more than normal, or having trouble falling asleep. One-way analyses of variance were conducted to examine the effects that sleep duration as well as self reported sleep disturbance symptoms had on composite scores. A total of 1067 ImPACT tests were analyzed: test 1, 545; test 2, 380; and test 3, 142. RESULTS: Sleeping fewer than 7 hours the night before testing correlated with higher PCSS scores (P < .001), whereas sleeping longer than 9 hours correlated with worse visual memory (P = .01), visual motor speed (P <.001), and reaction time (P = .04) composite scores. With regard to self-reported sleep disturbance symptoms, patients demonstrated worse composite scores during ImPACT testing when they self reported sleeping more than normal (ImPACT test 1: verbal memory, P < .001; visual motor speed, P = .05; reaction time, P = .01; ImPACT test 2: verbal memory, P < .001; visual memory, P < .001; visual motor speed, P < .001; reaction time, P = .01). Adolescent patients recovering from SRC demonstrated higher (worse) PCSS scores (P < .001) when they sensed that their sleep had been disrupted. CONCLUSION: Adolescent patients who perceive that their sleep is somehow disrupted after SRC may report a greater number of concussion symptoms during their recovery. In addition, the study results suggest that sleeping more than normal may identify an individual who continues to be actively recovering from concussion, given the correlation between lower neurocognitive function and this self-reported symptom. PMID- 25520303 TI - Retraction: 'Ubiquitination of the GTPase Rap1B by the ubiquitin ligase Smurf2 is required for the establishment of neuronal polarity'. PMID- 25520302 TI - Anterior cruciate ligament reconstruction with contralateral autogenous patellar tendon graft: evaluation of donor site strength and subjective results. AB - BACKGROUND: Few surgeons use a contralateral patellar tendon autograft for primary anterior cruciate ligament (ACL) reconstruction because of concern for donor site morbidity. HYPOTHESIS: There will be no difference in quadriceps muscle strength or International Knee Documentation Committee (IKDC) subjective scores in patients with contralateral grafts compared with patients with ipsilateral grafts. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Between 2007 and 2009, a total of 279 patients who underwent primary ACL reconstruction with autogenous patellar tendon graft from the contralateral knee met the inclusion criteria of unilateral knee involvement, no arthritic changes preoperatively, and minimum 2-year follow-up objective and subjective evaluations. A control group was obtained of 58 patients who had the same inclusion criteria and were of the same age but who underwent surgery with ipsilateral graft. Patients underwent a goal-directed and sequential postoperative rehabilitation program that first emphasized controlling a hemarthrosis and obtaining full knee range of motion immediately after surgery, followed by increasing leg strength and performing functional activities. The rehabilitation for the contralateral donor site emphasized high-repetition/low resistance exercises beginning the day after surgery. The IKDC subjective data were compared between surgery groups. Quadriceps muscle strength was evaluated in both knees compared with the preoperative values obtained in the noninvolved knee and between knees at 2 years postoperatively. RESULTS: Quadriceps muscle strength compared with the preoperative normal value (mean +/- SD) was 105% +/- 29% in the ipsilateral ACL-reconstructed knee versus 114% +/- 28.4% in the contralateral donor knee (P < .01) and 116% +/- 25% in the contralateral ACL-reconstructed knee (P = .0339). Mean side-to-side strength (ACL-reconstructed knee/opposite knee) was 98.4% +/- 13.6% in the contralateral group versus 92.9% +/- 13.0% in the ipsilateral group (P < .01). The mean total IKDC score was 92.4 +/- 9.6 for the contralateral donor knee. The mean IKDC total score for the ACL-reconstructed knee was 88.8 +/- 12.3 in the contralateral group and 88.9 +/- 11.2 in the ipsilateral group (P = .626). CONCLUSION: After ACL reconstruction with contralateral patellar tendon graft, patients can achieve strength symmetry between legs after surgery without experiencing adverse subjective symptoms after graft harvest. Furthermore, strength return can be superior with a contralateral graft than with an ipsilateral graft. PMID- 25520304 TI - Validation of an UPLC-MS-MS Method for Quantitative Analysis of Vincristine in Human Urine After Intravenous Administration of Vincristine Sulfate Liposome Injection. AB - Vincristine sulfate liposome injection (VSLI) is a liposomal formulation of vincristine (VCR) sulfate, being developed for the systemic treatment of cancer. In this paper, we have developed and validated a method to quantify VCR in human urine to obtain the urinary excretion of VCR after intravenous administration of VSLI. The analyte was extracted from urine samples using liquid-liquid extraction after addition of vinblastine (VBL, used as internal standard) and chromatographed on an Acquity UPLC HSS T3 column with a gradient mobile phase at a flow rate of 0.4 mL/min. The multiple reactions monitoring transitions of m/z 413.2 -> 353.2 and m/z 406.2 -> 271.6 were used to quantify VCR and VBL, respectively. The lower limit of quantification was 0.5 ng/mL with a precision (RSD%) of 5.7% and an accuracy (RE%) of 6.7%. The calibration curve was linear up to 100.0 ng/mL. Intraday precision and accuracy ranged from 0.8 to 11.0% and from -12.4 to 11.3%, respectively. Interassay precision and accuracy ranged from 8.0 to 10.1% and from -7.7 to 3.6%, respectively. No significant matrix effect was observed for VCR. The method was successfully applied for pharmacokinetic study of VSLI to investigate the route and extent of VCR urinary excretion in Chinese subjects with lymphoma. PMID- 25520305 TI - Rapid Determination of Bile Acids in Bile from Various Mammals by Reversed-Phase Ultra-Fast Liquid Chromatography. AB - A valid and efficient reversed-phase ultra-fast liquid chromatography method was developed for the simultaneous determination of 13 bile acids in the bile of three mammal species, including rat, pig and human gallstone patients. Chromatographic separation was performed with a Shim-pack XR-ODS column, and the mobile phase consisted of acetonitrile and potassium phosphate buffer (pH 2.6) at a flow rate of 0.5 mL min(-1). The linear detection range of most bile acids ranged from 2 to 600 ng uL(-1) with a good correlation coefficient (>0.9995). The precision of each bile acid was <1.8% for intraday and <4.8% for interday. All bile acids were separated in 15 min with satisfactory resolution, and the total analysis time was 18 min, including equilibration. The method was successfully applied in rapid screening of bile samples from the three mammals. Significant metabolic frameworks of bile acids among various species were observed, whereas considerable quantitative variations in both inter- and intraspecies were also observed, especially for gallstone patients. Our results suggest that detecting the change of bile acid profiles could be applied for the diagnosis of gallstone disease. PMID- 25520306 TI - Impact of Pathologists and Evaluation Methods on Performance Assessment of the Kidney Injury Biomarker, Kim-1. AB - Attempts to characterize and formally qualify biomarkers for regulatory purposes have raised questions about how histological and histopathological methods impact the evaluation of biomarker performance. A group of pathologists was asked to analyze digitized images prepared from rodent kidney injury experiments in studies designed to investigate sources of variability in histopathology evaluations. Study A maximized variability by using samples from diverse studies and providing minimal guidance, contextual information, or opportunities for pathologist interaction. Study B was designed to limit interpathologist variability by using more uniform image sets from different locations within the same kidneys and allowing pathologist selected interactions to discuss and identify the location and injury to be evaluated but without providing a lexicon or peer review. Results from this study suggest that differences between pathologists and across models of disease are the largest sources of variability in evaluations and that blind evaluations do not generally make a significant difference. Results of this study generally align with recommendations from both industry and the U.S. Food and Drug Administration and should inform future studies examining the effects of common lexicons and scoring criteria, peer review, and blind evaluations in the context of biomarker performance assessment. PMID- 25520307 TI - Spontaneously Occurring Formation of Intranuclear and Cytoplasmic Inclusions in Renal Proximal Epithelium Due to Accumulation of D-Amino Acid Oxidase in Wistar Hannover Rats. AB - Intranuclear and cytoplasmic inclusions in the renal proximal tubular epithelium were observed in nontreated male and female Wistar Hannover rats in a 26-week study (32 weeks of age) and a 104-week study (110 weeks of age). The incidence rates were less than 5% in these two studies. In affected animals, the inclusions were observed in more than 60% of proximal tubular epithelium as various sized (approximately 1-8 MUm in diameter) round and eosinophilic materials, but not in distal tubules, Henle's loop, or collecting ducts. Ultrastructurally, inclusions appeared finely granular, homogenous with middle-electron density, and without a limiting membrane. These inclusions were determined to be protein histochemically stained by Azan-Mallory and immunoreactive with an antibody against D-amino acid oxidase (DAO). There was no abnormality in in-life observations or in clinical test values suggestive of renal dysfunction. There were no associated degenerative or inflammatory changes in the kidneys, and no similar inclusions were observed in the other organs. These inclusions are very similar to propiverine hydrochloride (propiverine) and norepinephreine/serotonin reuptake inhibitor-induced inclusions. This is the first report of accumulation of DAO and formation of inclusions occurring spontaneously in rat kidneys. The data are important for toxicological studies using Wistar Hannover rats. PMID- 25520308 TI - Neutrophil-Lymphocyte Ratio May Predict the Degree of Coronary Collateral Circulation. PMID- 25520309 TI - Retrospective Evaluation of Oral Anticoagulant Therapy may not Reveal the Reality. PMID- 25520310 TI - Recent syncope and unexplained falls are associated with poor cognitive performance. AB - OBJECTIVE: To compare cognitive performance in participants with and without syncope and unexplained falls in a large population representative sample aged 50 years or older. METHODS: Participants of the Irish longitudinal study on ageing (TILDA) were studied. Participants with a history of syncope and/or unexplained falls in the past 12 months were compared with those with no reported events. Cognitive performance was measured using the Montreal cognitive assessment (MoCA) score. Multivariate linear regression analysis controlling for potential confounders was performed to compare cognitive function by syncope and falls status. RESULTS: Five thousand eight hundred and forty-six participants were analysed, median age 62 years (inter-quartile range=14), and 54% were female. Five hundred and forty-nine (9.4%) had a syncopal event and/or an unexplained fall in past 12 months. One hundred and two (1.8%) subjects had two-plus syncopal events in the same period. There was a significant association between syncope/falls history and lower MoCA score, following adjustment for all confounders (B=-0.4; -0.69, -0.11; P=0.006). Higher syncope burden was also associated with lower performance; however, this was largely explained by confounders. There was no age interaction with these findings. CONCLUSION: Participants who experienced syncope and/or non-accidental falls in the previous year have poor global cognitive performance compared with case-controls. There was no effect of age on our results. Further investigation of the association between syncope burden, unexplained falls and cognitive decline is required to establish a relationship between these disorders. PMID- 25520311 TI - Fatal traumatic brain injury in older adults in Austria 1980-2012: an analysis of 33 years. AB - BACKGROUND: traumatic brain injury (TBI) is a significant public health problem. Developed countries report a significant increase of TBI in older adults in the past decades. The objective of this study was to investigate the changes in TBI related mortality in older Austrians (65 years or older) between 1980 and 2012 (33 years) and to identify possible causes for these changes. METHODS: data from Statistics Austria on mortality in Austria between 1980 and 2012 were screened and data on TBI-related mortality in adults aged 65 and older were extracted and analysed, based on the diagnostic codes of the International Classification of Diseases, 10th and 9th revision. Mortality rates were calculated for 5-year age groups; standardized mortality rates were calculated for the total. Mechanism of injury was analysed for all events, both sexes and individual age groups. RESULTS: between 1980 and 2012, 16,204 people aged 65 or older died from TBI in Austria; 61% of these were male. Fatal TBI cases and mortality rates increased in the oldest age groups (80 years or older). Half of the fatal TBI cases were caused by falls, 22% by traffic accidents and 17% by suicides. Rate of fall related fatal TBI increased and rate of traffic accident-related fatal TBI decreased with age. CONCLUSION: preventive measures introduced in the past decades in the developed countries have contributed to a decrease in traffic injuries. However, falls in the older population are on the rise, mainly due to ageing of the population, throughout the reported period. It is important to take preventive measures to stop the epidemics of fall-related TBIs and fatalities in older adults. PMID- 25520313 TI - Increased risk of Bell palsy in patients with migraine: a nationwide cohort study. AB - OBJECTIVE: To evaluate the association between migraine and Bell palsy and to examine the effects of age, sex, migraine subtype, and comorbid risk factors for Bell palsy. METHODS: This nationwide cohort study was conducted using data from the Taiwan National Health Insurance Research Database. Subjects aged 18 years or older with neurologist-diagnosed migraine from 2005 to 2009 were included. A nonheadache age- and propensity score-matched control cohort was selected for comparison. All subjects were followed until the end of 2010, death, or the occurrence of a Bell palsy event. Cox proportional hazards regression was used to calculate the adjusted hazard ratios and 95% confidence intervals to compare the risk of Bell palsy between groups. RESULTS: Both cohorts (n = 136,704 each) were followed for a mean of 3.2 years. During the follow-up period, 671 patients (424,372 person-years) in the migraine cohort and 365 matched control subjects (438,677 person-years) were newly diagnosed with Bell palsy (incidence rates, 158.1 and 83.2/100,000 person-years, respectively). The adjusted hazard ratio for Bell palsy was 1.91 (95% confidence interval, 1.68-2.17; p < 0.001). The association between migraine and Bell palsy remained significant in sensitivity analyses, and tests of interaction failed to reach significance in all subgroup analyses. CONCLUSION: Migraine is a previously unidentified risk factor for Bell palsy. The association between these 2 conditions suggests a linked disease mechanism, which is worthy of further exploration. PMID- 25520314 TI - Does migraine produce facial palsy? For whom the Bell tolls. PMID- 25520315 TI - Neuropathologic features of anti-dipeptidyl-peptidase-like protein-6 antibody encephalitis. PMID- 25520317 TI - Removal of floating inferior vena cava thrombus with the AngioVac device. PMID- 25520316 TI - Superoxide anion radicals induce IGF-1 resistance through concomitant activation of PTP1B and PTEN. AB - The evolutionarily conserved IGF-1 signalling pathway is associated with longevity, metabolism, tissue homeostasis, and cancer progression. Its regulation relies on the delicate balance between activating kinases and suppressing phosphatases and is still not very well understood. We report here that IGF-1 signalling in vitro and in a murine ageing model in vivo is suppressed in response to accumulation of superoxide anions (O2?-) in mitochondria, either by chemical inhibition of complex I or by genetic silencing of O2?--dismutating mitochondrial Sod2. The O2?--dependent suppression of IGF-1 signalling resulted in decreased proliferation of murine dermal fibroblasts, affected translation initiation factors and suppressed the expression of alpha1(I), alpha1(III), and alpha2(I) collagen, the hallmarks of skin ageing. Enhanced O2?- led to activation of the phosphatases PTP1B and PTEN, which via dephosphorylation of the IGF-1 receptor and phosphatidylinositol 3,4,5-triphosphate dampened IGF-1 signalling. Genetic and pharmacologic inhibition of PTP1B and PTEN abrogated O2?--induced IGF 1 resistance and rescued the ageing skin phenotype. We thus identify previously unreported signature events with O2?-, PTP1B, and PTEN as promising targets for drug development to prevent IGF-1 resistance-related pathologies. PMID- 25520318 TI - The relation of red blood cell fatty acids with vascular stiffness, cardiac structure and left ventricular function: the Framingham Heart Study. AB - Polyunsaturated fatty acids have been associated with beneficial influences on cardiovascular health. However, the underlying mechanisms are not clear, and data on the relations of polyunsaturated fatty acids to subclinical disease measures such as vascular stiffness and cardiac function are sparse and inconclusive. In a large community-based cohort, we examined the relations of omega-3 and other fatty acids to a comprehensive panel of vascular function measures (assessing microvascular function and large artery stiffness), cardiac structure and left ventricular function. Red blood cell (RBC) membrane fatty acid composition, a measure of long-term fatty acid intake, was assessed in participants of the Framingham Offspring Study and Omni cohorts and related to tonometry-derived measures of vascular stiffness and to a panel of echocardiographic traits using partial correlations. Up to n=3055 individuals (56% women, mean age 66 years) were available for analyses. In age- and sex-adjusted models, higher RBC omega-3 content was moderately associated (p<=0.002) with several measures of vascular stiffness and function in a protective direction. However, after multivariable adjustment, only an association of higher RBC omega-3 content with lower carotid femoral pulse wave velocity (a measure of aortic stiffness) remained significant (r = -0.06, p=0.002). In secondary analyses, higher linoleic acid, the major nutritional omega-6 fatty acid, was associated with smaller left atrial size, even after multivariable adjustment (r = -0.064, p<0.001). In conclusion, in our cross-sectional community-based study, we found several associations consistent with the notion of protective effects of omega-3 and linoleic acid. The clinical significance of these modest associations remains to be elucidated. PMID- 25520319 TI - The first 10 years of the American Board of Vascular Medicine. AB - The American Board of Vascular Medicine (ABVM) was conceived through the Society for Vascular Medicine and this year will complete 10 years of certifying physicians who practice vascular medicine and endovascular medicine. The value of certification to our physicians, patients, and field cannot be understated. This paper reviews the highlights of the test development process, quality assurance measures, and management of these high stakes examinations. PMID- 25520320 TI - Social support, collective efficacy, and child physical abuse: does parent gender matter? AB - Social support and collective efficacy are related to child physical abuse. However, little is known about whether these relationships differ by gender, although mothers and fathers differ in the quantity and quality of time spent with children. This study examined whether the relationship between social support, collective efficacy, and physical abuse is stronger for mothers than fathers. Telephone interviews were conducted with parent respondents in 50 California cities (N = 3,023). Data were analyzed via overdispersed multi-level Poisson models. Results suggest that high levels of emotional support were inversely associated with physical abuse for women and men, although this effect was stronger for women. High levels of companionship support were positively associated with physical abuse for women; however, the opposite was true for men. There were no significant interactions between collective efficacy variables and gender. The relationships between some types of social support and physical abuse appear to vary for men and women suggesting possibilities for more targeted intervention. PMID- 25520321 TI - Criminal investigations in child protective services cases: an empirical analysis. AB - This study analyzed the frequency and correlates of criminal investigation of child maltreatment in cases investigated by child protective service (CPS), using national probability data from the National Survey of Child and Adolescent Well Being. Criminal investigations were conducted in slightly more than 25% of cases. Communities varied substantially in percentage criminally investigated. Sexual abuse was the most frequent type of maltreatment criminally investigated followed by physical abuse. Logistic regression results indicated that criminal investigations were more likely when caseworkers perceived greater harm and more evidence; when CPS conducted an investigation rather than an assessment; when a parent or a legal guardian reported the maltreatment; and when cases were located in communities in which CPS and police had a memorandum of understanding (MOU) governing coordination. Most variation between communities in criminal investigation remained unexplained. The findings suggest the potential of MOUs for communities wanting to increase criminal investigation. PMID- 25520322 TI - Vesicle uncoating regulated by SH3-SH3 domain-mediated complex formation between endophilin and intersectin at synapses. AB - Neurotransmission involves the exo-endocytic cycling of synaptic vesicle (SV) membranes. Endocytic membrane retrieval and clathrin-mediated SV reformation require curvature-sensing and membrane-bending BAR domain proteins such as endophilin A. While their ability to sense and stabilize curved membranes facilitates membrane recruitment of BAR domain proteins, the precise mechanisms by which they are targeted to specific sites of SV recycling has remained unclear. Here, we demonstrate that the multi-domain scaffold intersectin 1 directly associates with endophilin A to facilitate vesicle uncoating at synapses. Knockout mice deficient in intersectin 1 accumulate clathrin-coated vesicles at synapses, a phenotype akin to loss of endophilin function. Intersectin 1/endophilin A1 complex formation is mediated by direct binding of the SH3B domain of intersectin to a non-canonical site on the SH3 domain of endophilin A1. Consistent with this, intersectin-binding defective mutant endophilin A1 fails to rescue clathrin accumulation at neuronal synapses derived from endophilin A1-3 triple knockout (TKO) mice. Our data support a model in which intersectin aids endophilin A recruitment to sites of clathrin-mediated SV recycling, thereby facilitating vesicle uncoating. PMID- 25520323 TI - Lessons in learning: An effective process for engaging 12- to 14-year-olds in stem cell biology. PMID- 25520325 TI - Public perception of cancer care in Poland and Austria. AB - BACKGROUND: We compared the public perception of cancer care in Poland and Austria. Both countries are members of the European Union (EU) but reflect two extremes in health-related per capita spending. Recently, the EUROCARE-5 study reported on very discrepant cancer outcomes between the two countries. METHODS: A one-time survey was conducted to compare the public perception of cancer treatment in Poland and Austria. In total, 3,649 subjects, representing the general population, cancer patients, and cancer patients' family members, were surveyed. RESULTS: In both countries, cancer was considered the most challenging problem of the health care system, and health care was indicated as the most important issue influencing political election decisions. Polish compared with Austrian cancer patients gave a significantly lower positive assessment of overall cancer treatment efficacy and detection methods. Cancer cure rates estimated by Polish and Austrian citizens were 29% and 44%, respectively. The majority of all citizens interviewed thought that cancer patients should have access to all available registered cancer drugs. However, only 18% of Poles versus 62% of Austrians agreed with the notion that the available cancer treatment in their countries is of a standard comparable to that of other EU countries. Consequently, 24% of Poles and 7% of Austrians identified financial status, age, gender, and residence as factors influencing the availability of cancer treatments. CONCLUSION: In both countries, cancer is considered the most challenging problem of the health care system, and health care issues may strongly influence decisions for political elections. Vast differences in the two populations' perceptions of cancer care reflect actual cancer outcomes and the national per capita spending on health-related issues. PMID- 25520326 TI - Assisting Older Persons With Adjusting to Hearing Aids. AB - This intervention study tested the feasibility and initial effect of Hearing Aid Reintroduction (HEAR) to assist persons aged 70 to 85 years adjust to hearing aids. Following this 30-day intervention, hearing aid use increased between 1 and 8 hr per day with 50% of participants able to wear them for at least 4 hr. Hearing aid satisfaction improved from not satisfied to satisfied overall. The study demonstrated that HEAR is feasible and could improve hearing aid use of a substantial number of older persons who had previously failed to adjust to their hearing aids and had given up. However, further testing among a larger and more diverse population is needed to better understand the effectiveness and sustainability of the intervention. PMID- 25520324 TI - Stem and progenitor cell dysfunction in human trisomies. AB - Trisomy 21, the commonest constitutional aneuploidy in humans, causes profound perturbation of stem and progenitor cell growth, which is both cell context dependent and developmental stage specific and mediated by complex genetic mechanisms beyond increased Hsa21 gene dosage. While proliferation of fetal hematopoietic and testicular stem/progenitors is increased and may underlie increased susceptibility to childhood leukemia and testicular cancer, fetal stem/progenitor proliferation in other tissues is markedly impaired leading to the characteristic craniofacial, neurocognitive and cardiac features in individuals with Down syndrome. After birth, trisomy 21-mediated premature aging of stem/progenitor cells may contribute to the progressive multi-system deterioration, including development of Alzheimer's disease. PMID- 25520327 TI - Physical fitness and hypertension in a population at risk for cardiovascular disease: the Henry Ford ExercIse Testing (FIT) Project. AB - BACKGROUND: Increased physical fitness is protective against cardiovascular disease. We hypothesized that increased fitness would be inversely associated with hypertension. METHODS AND RESULTS: We examined the association of fitness with prevalent and incident hypertension in 57 284 participants from The Henry Ford ExercIse Testing (FIT) Project (1991-2009). Fitness was measured during a clinician-referred treadmill stress test. Incident hypertension was defined as a new diagnosis of hypertension on 3 separate consecutive encounters derived from electronic medical records or administrative claims files. Analyses were performed with logistic regression or Cox proportional hazards models and were adjusted for hypertension risk factors. The mean age overall was 53 years, with 49% women and 29% black. Mean peak metabolic equivalents (METs) achieved was 9.2 (SD, 3.0). Fitness was inversely associated with prevalent hypertension even after adjustment (>=12 METs versus <6 METs; OR: 0.73; 95% CI: 0.67, 0.80). During a median follow-up period of 4.4 years (interquartile range: 2.2 to 7.7 years), there were 8053 new cases of hypertension (36.4% of 22 109 participants without baseline hypertension). The unadjusted 5-year cumulative incidences across categories of METs (<6, 6 to 9, 10 to 11, and >=12) were 49%, 41%, 30%, and 21%. After adjustment, participants achieving >=12 METs had a 20% lower risk of incident hypertension compared to participants achieving <6 METs (HR: 0.80; 95% CI: 0.72, 0.89). This relationship was preserved across strata of age, sex, race, obesity, resting blood pressure, and diabetes. CONCLUSIONS: Higher fitness is associated with a lower probability of prevalent and incident hypertension independent of baseline risk factors. PMID- 25520328 TI - Age, sex, and hospital factors are associated with the duration of cardiopulmonary resuscitation in hospitalized patients who do not experience sustained return of spontaneous circulation. AB - BACKGROUND: Variability in the duration of attempted in-hospital cardiopulmonary resuscitation (CPR) is high, but the factors influencing termination of CPR efforts are unknown. METHODS AND RESULTS: We examined the association between patient and hospital characteristics and CPR duration in 45 500 victims of in hospital cardiac arrest who did not experience return of spontaneous circulation (ROSC) and who were enrolled in the Get With the Guidelines registry between 2001 and 2010. In a secondary analysis, we performed analyses in 46 168 victims of in hospital cardiac arrest who experienced ROSC. We used ordered logistic regression to identify factors associated with CPR duration. Analyses were conducted by tertile of CPR duration (tertiles: ROSC group: 2 to 7, 8 to 17, and 18 to 120 minutes; no-ROSC group: 2 to 16, 17 to 26, 27 to 120 minutes). In those without ROSC, younger age (aged 18 to 40 versus >65 years; odds ratio [OR] 1.81; 95% CI 1.69 to 1.95; P<0.001), female sex (OR 1.05; 95% CI 1.02 to 1.09; P=0.005), ventricular tachycardia or fibrillation (OR 1.50; 95% CI 1.42 to 1.58; P<0.001), and the need to place an invasive airway (OR 2.59; 95% CI 2.46 to 2.72; P<0.001) were associated with longer CPR duration. In those with ROSC, ventricular tachycardia or fibrillation (OR 0.89; 95% CI 0.85 to 0.93; P<0.001) and witnessed events (OR 0.87; 95% CI 0.82 to 0.91; P<0.001) were associated with shorter duration. CONCLUSIONS: Age and sex were associated with attempted CPR duration in patients who do not experience ROSC after in-hospital cardiac arrest but not in those who experience ROSC. Understanding the mechanism of these interactions may help explain variability in outcomes for in-hospital cardiac arrest. PMID- 25520330 TI - Measuring what matters: CPR quality and resuscitation outcomes. PMID- 25520329 TI - Deficiency of ataxia telangiectasia mutated kinase delays inflammatory response in the heart following myocardial infarction. AB - BACKGROUND: Ataxia-telangiectasia results from mutations in ataxia telangiectasia mutated kinase (ATM) gene. We recently reported that ATM deficiency attenuates left ventricular (LV) dysfunction and dilatation 7 days after myocardial infarction (MI) with increased apoptosis and fibrosis. Here we investigated the role of ATM in the induction of inflammatory response, and activation of survival signaling molecules in the heart acute post-MI. METHODS AND RESULTS: LV structure, function, inflammatory response, and biochemical parameters were measured in wild-type (WT) and ATM heterozygous knockout (hKO) mice 1 and 3 days post-MI. ATM deficiency had no effect on infarct size. MI-induced decline in heart function, as measured by changes in percent fractional shortening, ejection fraction and LV end systolic and diastolic volumes, was lower in hKO-MI versus WT MI (n=10 to 12). The number of neutrophils and macrophages was significantly lower in the infarct LV region of hKO versus WT 1 day post-MI. Fibrosis and expression of alpha-smooth muscle actin (myofibroblast marker) were higher in hKO MI, while active TGF-beta1 levels were higher in the WT-MI 3 days post-MI. Myocyte cross-sectional area was higher in hKO-sham with no difference between the two MI groups. MMP-9 protein levels were similarly increased in the infarct LV region of both MI groups. Apoptosis was significantly higher in the infarct LV region of hKO at both time points. Akt activation was lower, while Bax expression was higher in hKO-MI infarct. CONCLUSION: ATM deficiency results in decreased dilative remodeling and delays inflammatory response acute post-MI. However, it associates with increased fibrosis and apoptosis. PMID- 25520331 TI - Ataxia-telangiectasia mutated kinase: a potential new target for suppressing inflammation in heart failure? PMID- 25520334 TI - Editorial commentary: Preventing aspiration pneumonia in high-risk nursing home residents: role of chlorhexidine-based oral care questioned again. PMID- 25520332 TI - Randomized trial of micafungin for the prevention of invasive fungal infection in high-risk liver transplant recipients. AB - BACKGROUND: Invasive fungal infection (IFI) following liver transplant is associated with significant morbidity and mortality. Antifungal prophylaxis is rational for liver transplant patients at high IFI risk. METHODS: In this open label, noninferiority study, patients were randomized 1:1 to receive intravenous micafungin 100 mg or center-specific standard care (fluconazole, liposomal amphotericin B, or caspofungin) posttransplant. The primary endpoint was clinical success (absence of a proven/probable IFI and no need for additional antifungals) at end of prophylaxis (EOP). Noninferiority (10% margin) of micafungin vs standard care was assessed in the per protocol and full analysis sets. Safety assessments included adverse events and liver and kidney function tests. RESULTS: The full analysis set comprised 344 patients (172 micafungin; 172 standard care). Mean age was 51.2 years; 48.0% had a Model for End-Stage Liver Disease score >=20. At EOP (mean treatment duration, 17 days), clinical success was 98.6% for micafungin and 99.3% for standard care (Delta standard care - micafungin [95% confidence interval], 0.7% [-2.7% to 4.4%]) in the per protocol set and 96.5% and 93.6%, respectively (-2.9% [-8.0% to 1.9%]), in the full analysis set. Incidences of drug-related adverse events for micafungin and standard care were 11.6% and 16.3%, leading to discontinuation in 6.4% and 11.6% of cases, respectively. At EOP, liver function tests were similar but creatinine clearance was higher in micafungin- vs standard care-treated patients. CONCLUSIONS: Micafungin was noninferior to standard care as antifungal prophylaxis in liver transplant patients at high risk for IFI. Adverse event profiles and liver function at EOP were similar, although kidney function was better with micafungin. CLINICAL TRIALS REGISTRATION: NCT01058174. PMID- 25520335 TI - Postoperative myocardial infarction and cardiac arrest following primary total knee and hip arthroplasty: rates, risk factors, and time of occurrence. AB - BACKGROUND: Cardiac complications are a major cause of postoperative morbidity. The purpose of this study was to determine the rates, risk factors, and time of occurrence for cardiac complications within thirty days after primary unilateral total knee arthroplasty and total hip arthroplasty. METHODS: The American College of Surgeons National Surgical Quality Improvement Program data set from 2006 to 2011 was used to identify all total knee arthroplasties and total hip arthroplasties. Cardiac complications occurring within thirty days after surgery were the primary outcome measure. Patients were designated as having a history of cardiac disease if they had a new diagnosis or exacerbation of chronic congestive heart failure or a history of angina within thirty days before surgery, a history of myocardial infarction within six months, and/or any percutaneous cardiac intervention or other major cardiac surgery at any time. An analysis of the occurrence of all major cardiac complications and deaths within the thirty-day postoperative time frame was performed. RESULTS: For the 46,322 patients managed with total knee arthroplasty or total hip arthroplasty, the cardiac complication rate was 0.33% (n = 153) at thirty days postoperatively. In both the total knee arthroplasty and total hip arthroplasty groups, an age of eighty years or more (odds ratios [ORs] = 27.95 and 3.72), hypertension requiring medication (ORs = 4.74 and 2.59), and a history of cardiac disease (ORs = 4.46 and 2.80) were the three most significant predictors for the development of postoperative cardiac complications. Of the patients with a cardiac complication, the time of occurrence was within seven days after surgery for 79% (129 of the 164 patients for whom the time of occurrence could be determined). CONCLUSIONS: An age of eighty years or more, a history of cardiac disease, and hypertension requiring medication are significant risk factors for developing postoperative cardiac complications following primary unilateral total knee arthroplasty and total hip arthroplasty. Consideration should be given to a preoperative cardiology evaluation and co-management in the perioperative period for individuals with these risk factors. PMID- 25520333 TI - A cluster-randomized controlled trial of a multicomponent intervention protocol for pneumonia prevention among nursing home elders. AB - BACKGROUND: Pneumonia remains an important public health problem among elderly nursing home residents. This clinical trial sought to determine if a multicomponent intervention protocol, including manual tooth/gum brushing plus 0.12% chlorhexidine oral rinse, twice per day, plus upright positioning during feeding, could reduce the incidence of radiographically documented pneumonia among nursing home residents, compared with usual care. METHODS: This cluster randomized clinical trial was conducted in 36 nursing homes in Connecticut. Eligible residents >65 years with at least 1 of 2 modifiable risk factors for pneumonia (ie, impaired oral hygiene, swallowing difficulty) were enrolled. Nursing homes were randomized to the multicomponent intervention protocol or usual care. Participants were followed for up to 2.5 years for development of the primary outcome, a radiographically documented pneumonia, and secondary outcome, a lower respiratory tract infection (LRTI) without radiographic documentation. RESULTS: A total of 834 participants were enrolled: 434 to intervention and 400 to usual care. The trial was terminated for futility. The number of participants in the intervention vs control arms with first pneumonia was 119 (27.4%) vs 94 (23.5%), respectively, and with first LRTI, 125 (28.8%) vs 100 (25.0%), respectively. In a multivariable Cox regression model, the hazard ratio in the intervention vs control arms, respectively, was 1.12 (95% confidence interval [CI], .84-1.50; P = .44) for first pneumonia and 1.07 (95% CI, .79-1.46, P = .65) for first LRTI. CONCLUSIONS: The multicomponent intervention protocol did not significantly reduce the incidence of first radiographically confirmed pneumonia or LRTI compared with usual care in nursing home residents. CLINICAL TRIALS REGISTRATION: NCT00975780. PMID- 25520336 TI - Preliminary results of a new test for rapid diagnosis of septic arthritis with use of leukocyte esterase and glucose reagent strips. AB - BACKGROUND: Most currently used tools to diagnose septic arthritis are either not readily available or fail to provide real-time results. Reagent strip tests have identified infections in various body fluids. We hypothesized that combined leukocyte esterase and glucose strip tests can aid in diagnosing septic arthritis in native synovial fluid because (1) leukocyte esterase concentrations would be elevated at the infection site because of secretion by recruited neutrophils, and (2) glucose concentrations would be reduced because of bacterial metabolism. METHODS: We prospectively investigated synovial fluid from consecutive patients with an atraumatic joint effusion who underwent arthrocentesis in our emergency department during a one-year period. Leukocyte esterase and glucose strip tests were performed on the synovial fluid. Synovial fluid leukocyte count, crystal analysis, Gram staining, culture, and glucose concentration results were also assessed. RESULTS: Nineteen fluids were classified as septic and 127 as aseptic. Considering septic arthritis to be present when the leukocyte esterase reading was positive (++ or +++) and the glucose reading was negative (-) yielded a sensitivity of 89.5% (95% confidence interval [CI], 66.9% to 98.7%), specificity of 99.2% (95% CI, 95.7% to 99.9%), positive predictive value of 94.4% (95% CI, 72.7% to 99.9%), negative predictive value of 98.4% (95% CI, 94.5% to 99.8%), positive likelihood ratio of 114, and negative likelihood ratio of 0.11. The synovial leukocyte counts and polymorphonuclear cell percentages were consistent with the semiquantitative readings on the leukocyte esterase strip tests, and the glucose concentrations were consistent with the glucose strip test results. CONCLUSIONS: Combined leukocyte esterase and glucose strip tests can be a useful additional tool to help confirm or rule out a diagnosis of septic arthritis. PMID- 25520337 TI - Surgical site infections after posterior spinal fusion for neuromuscular scoliosis: a thirty-year experience at a single institution. AB - BACKGROUND: Surgical site infection is a serious complication of posterior spinal fusion for neuromuscular scoliosis, with a reported prevalence of 6% to 24%. A single-institution experience over a thirty-year period was reviewed to determine the prevalence of surgical site infection after posterior spinal fusion for neuromuscular scoliosis, and to identify patient and treatment-related risk factors. METHODS: Our retrospective review included all patients treated with posterior spinal fusion (alone or in combination with an anterior procedure) for neuromuscular scoliosis from 1980 to 2009 and followed for a minimum of two years. Univariate and multivariate statistical analysis was performed to identify significant risk factors for occurrence of deep surgical site infection (p < 0.05). RESULTS: The study included 428 patients with an average duration of follow-up of 4.9 years. The mean Cobb angle was 74.3 degrees . Most (74%) were treated with posterior spinal fusion alone. Deep infection developed in forty four patients (10.3%); 57% of the infections occurred within three months after the surgery and 73%, within twelve months. Nearly half (45%) of the infections were polymicrobial; 59% of the organisms were gram-positive and 41% were gram negative. Implant removal was required in 58% of the patients. Surgical site infection was more frequent from 1980 to 1989 (20.3%) than it was from 1990 to 2009 (8.4%) (odds ratio [OR] = 2.8, p = 0.01 in univariate analysis). Surgical site infection was more common in patients with spina bifida (21.5%) than in those with other diagnoses (8.3%) (OR = 3.0, p = 0.001). Other patient factors associated with surgical site infection were a body mass index (BMI) of >25 kg/m(2) (OR = 2.4, p = 0.04) and incontinence (OR = 2.4, p = 0.009). Treatment factors associated with surgical site infection were inadequate prophylactic antibiotic dosing (cefazolin <= 20 mg/kg) (OR = 3.3, p = 0.0002), length of fusion (p = 0.002), pelvic fixation (OR = 2.4, p = 0.04), length of hospital stay (p = 0.005), and other complications (OR = 3.2, p = 0.0003). Drain output (p = 0.04) and lower hemoglobin levels (p = 0.008) were significantly associated with surgical site infection in patients with spina bifida, and drain use (superficial to the fascia) was protective in those without spina bifida (OR = 0.5, p = 0.046). CONCLUSIONS: This study identified modifiable factors, especially antibiotic dosing and drain use, associated with surgical site infection in patients with neuromuscular scoliosis. PMID- 25520338 TI - Risk factors for poor outcome of cervical laminoplasty for cervical spondylotic myelopathy in patients with diabetes. AB - BACKGROUND: Diabetes is one of the most frequent comorbidities in patients with cervical spondylotic myelopathy. The purpose of this study was to characterize the risk factors for poor treatment outcome following cervical laminoplasty for cervical spondylotic myelopathy in patients with diabetes. METHODS: A total of 105 consecutive patients with diabetes and cervical spondylotic myelopathy who underwent double-door laminoplasty were included in this study; there were sixty five male patients and forty female patients with a mean age of 68.2 years (range, forty-three to eighty-three years). All patients were followed for twelve months or more after surgery, with a mean follow-up time (and standard deviation) of 25.7 +/- 14.2 months. All patients had palliative controlled blood glucose levels in the immediate term during the perioperative period. We evaluated the recovery rate on the basis of the Japanese Orthopaedic Association score. Logistic regression analyses (univariate analysis and multivariate analysis) were performed to identify the risk factors for poor outcome. Poor outcome was defined as a postoperative recovery rate of <50%, and good outcome was defined as a postoperative recovery rate of >= 50%. RESULTS: Univariate logistic regression analysis showed that a patient age of sixty-five years or older (odds ratio, 3.111; p = 0.0085) and a duration of cervical spondylotic myelopathy symptoms for twelve months or more (odds ratio, 3.940; p = 0.0012) were associated with an increased risk of poor surgical outcome. High glycated hemoglobin levels of >= 6.5% (odds ratio, 2.591; p = 0.0193) and a duration of diabetes for ten years or more (odds ratio, 2.245; p = 0.0321) were significant risk factors for poor surgical outcome. Multivariate logistic regression analysis determined that glycated hemoglobin levels of >= 6.5% (odds ratio, 2.822; p = 0.0441) and a duration of diabetes for ten years or more (odds ratio, 2.240; p = 0.0410) were significant risk factors for poor treatment outcome. Fasting blood glucose levels did not affect treatment outcomes. CONCLUSIONS: Diabetes with advanced age and long-term cervical spondylotic myelopathy symptoms adversely affected cervical laminoplasty outcomes. High preoperative glycated hemoglobin levels and long-term diabetes are risk factors for poor cervical laminoplasty outcomes in patients with diabetes and cervical spondylotic myelopathy. PMID- 25520339 TI - Arthroscopic repair of anterosuperior rotator cuff tears: in-continuity technique vs. disruption of subscapularis-supraspinatus tear margin: comparison of clinical outcomes and structural integrity between the two techniques. AB - BACKGROUND: The purpose of this study was to compare the clinical outcomes and structural integrity after two techniques of arthroscopic anterosuperior rotator cuff repair: in continuity and disruption of the tear margin. METHODS: This study included fifty-nine patients who underwent arthroscopic repair of an anterosuperior rotator cuff tear that was done either by disrupting the margin between the subscapularis and supraspinatus tears (Group A) or by performing the repair in continuity without disrupting the margin (Group B). Clinical outcomes were assessed on the basis of a visual analog scale (VAS) pain score, subjective shoulder value (SSV), American Shoulder and Elbow Surgeons (ASES) score, University of California at Los Angeles (UCLA) shoulder score, and active range of motion of the shoulder. Subscapularis strength was assessed with use of the modified belly-press test. Magnetic resonance arthrography (MRA) or computed tomographic arthrography (CTA) was performed at six months after surgery to assess the structural integrity of the repair. RESULTS: At the two-year follow-up evaluation, VAS pain scores, SSVs, ASES scores, UCLA shoulder scores, subscapularis strength, and active range of motion improved significantly in both groups compared with preoperatively (p < 0.001). There were no significant differences between groups for any of these follow-up measurements. On follow-up MRA or CTA, the overall retear rate did not differ significantly different between Group A (22%; five of twenty-three) and Group B (19%; six of thirty-two). CONCLUSIONS: In conclusion, in patients treated with arthroscopic repair of anterosuperior full-thickness subscapularis and supraspinatus tears of the rotator cuff, the technique of in-continuity repair did not produce better clinical outcomes or structural integrity than the technique involving disruption of the tear margin. If the muscle in an anterosuperior rotator cuff tear is of good quality, it does not appear to matter whether the tear margin between the subscapularis and supraspinatus is preserved or disrupted. PMID- 25520340 TI - Metal-carbon fiber composite femoral stems in hip replacements: a randomized controlled parallel-group study with mean ten-year follow-up. AB - BACKGROUND: Attempts to improve proximal load transfer and minimize stress shielding have included reducing the stiffness of femoral stems and using alternative stem materials, including carbon fiber composites. An uncemented implant (SR71) composed of a carbon-fiber-composite distal section and a porous coated titanium-alloy proximal section, designed to improve proximal load transfer and provide good fixation, was clinically evaluated in a prospective randomized study. METHODS: Sixty patients were enrolled and randomized to receive either the SR71 stem or an all-metal stem (Stability). All patients received a cemented all-polyethylene acetabular component and a 28-mm metal femoral head. All uncemented stems were implanted by the same surgeon. Patients were followed for up to ten years with repeated assessments of bone mineral density, radiographs, Harris hip scores (HHS), and visual analog scale (VAS) pain scores. RESULTS: Ten years postoperatively, nineteen patients who had been treated with the SR71 stem and not lost to follow-up showed a significantly greater increase in proximal bone mineral density (Gruen zones 1 [p = 0.003] and 7 [p = 0.0007]) from baseline than did the twenty-two who had been treated with the Stability stem and not lost to follow-up. In contrast, the Stability group showed a significantly greater increase in distal bone mineral density (Gruen zones 2 [p = 0.0004], 3 [p = 0.0001], and 5 [p = 0.0035]) compared with the SR71 group. Radiographs demonstrated one case of progressive migration of an acetabular component used with an SR71 stem and one case of bone resorption in Gruen zones 7 and 14 in a patient treated with a Stability stem. There was no significant difference between the SR71 and Stability stems in terms of changes in the total HHS, HHS for pain, HHS for range of motion, or VAS pain scores ten years postoperatively relative to preoperative levels. There was one reported revision of an SR71 femoral stem at the ten-year review. CONCLUSIONS: The investigational SR71 implant provided increased proximal bone density and reduced distal bone density. The implant showed promising results at the time of early follow-up, and the clinical outcomes were similar to those of an all-metal stem at the time of a ten-year follow-up. PMID- 25520341 TI - Reverse shoulder arthroplasty for the treatment of nonunions of the surgical neck of the proximal part of the humerus (type-3 fracture sequelae). AB - BACKGROUND: Fracture sequelae of the proximal part of the humerus are challenging conditions, and various treatment options have been described. The purpose of this multicenter study was to analyze the clinical and radiographic outcomes as well as the complications following semiconstrained reverse total shoulder arthroplasty for the treatment of nonunion of a surgical neck fracture of the proximal part of the humerus. METHODS: Thirty-two patients with a mean age of sixty-eight years (range, forty-eight to eighty-three years) managed with a reverse shoulder arthroplasty for the treatment of nonunion of a proximal humeral fracture were analyzed clinically and radiographically. The mean duration of follow-up was four years (range, two to twelve years). The Constant score, active shoulder mobility, all complications, and revision procedures were recorded. RESULTS: The mean Constant score increased from 14.2 points (range, 2 to 35 points) to 46.6 points (range, 6 to 75 points) (p < 0.001). The mean shoulder flexion increased from 42.9 degrees (range, 0 degrees to 160 degrees ) to 109.7 degrees (range, 0 degrees to 170 degrees ) (p < 0.001), and the mean external rotation increased from 0.5 degrees (range, -40 degrees to 60 degrees ) to 13.1 degrees (range, -30 degrees to 60 degrees ) (p < 0.005). No component loosening occurred, but 50% (sixteen) of the patients had radiographic evidence of scapular notching. There were thirteen complications (41%) leading to nine revision surgical procedures (28%). The most common complication was a dislocation following reverse shoulder arthroplasty, which occurred in 34% (eleven) of the patients. An intraoperative resection of the humeral head fragment and the tuberosities was associated with increased risk of dislocation (p < 0.007). CONCLUSIONS: Nonunions of the proximal part of the humerus can be treated with reverse shoulder arthroplasty. Although clinical outcomes improved significantly, we found an unacceptably high rate of dislocations associated with intraoperative resection of the tuberosities. The tuberosities and the attached rotator cuff should be preserved if possible to reduce the risk of dislocation after reverse total shoulder arthroplasty. PMID- 25520342 TI - Topical cutaneous CO2 application by means of a novel hydrogel accelerates fracture repair in rats. AB - BACKGROUND: We previously demonstrated that topical cutaneous application of CO2, by means of a hydrogel in which the CO2 readily dissolves, increases blood flow and oxygen dissociation from hemoglobin in the soft tissues surrounding bone. In the present study, we utilized a rat fracture model to test the hypothesis that application of this treatment to fractured limbs would accelerate fracture repair. METHODS: A closed femoral shaft fracture was created in each rat. Topical cutaneous application of CO2 by means of a hydrogel was performed five times a week for up to four weeks in the CO2/hydrogel group (n = 60). Sham treatments were performed in the control group (n = 60). Radiographic, histological, immunohistochemical, laser Doppler perfusion imaging, real-time polymerase chain reaction, and biomechanical assessments were performed. RESULTS: Radiographic fracture union was evident at week 3 in twelve (86%) of fourteen animals in the CO2/hydrogel group compared with five (36%) of fourteen in the control group (p < 0.05; 95% CI [confidence interval] for the difference in union rate, 2.26% to 99.64%). Histological assessment revealed promotion of endochondral ossification in the CO2/hydrogel group. Immunohistochemical assessment at week 2 showed significantly greater capillary density in the CO2/hydrogel group (p < 0.05; 95% CI for the difference, 161 to 258 per mm(2)). Laser Doppler perfusion imaging demonstrated that the blood flow in the fractured limb was significantly greater at weeks 2 and 3 in the CO2/hydrogel group (p < 0.05; 95% CI for the difference, 8.4% to 22.4% and 6.7% to 19.0%, respectively). Gene expression of chondrogenic, osteogenic, and angiogenic markers was significantly greater in the CO2/hydrogel group at several time points. Ultimate stress, extrinsic stiffness, and failure energy (relative to the contralateral limb) were significantly greater in the CO2/hydrogel group at week 3 (p < 0.05; 95% CI for the difference, 24.8% to 67.5%, 4.0 % to 22.7%, and 9.6% to 58.8%, respectively). There were no significant differences between the groups with respect to any outcome measure at week 4. CONCLUSIONS: Topical cutaneous application of CO2 by means of a hydrogel accelerated fracture repair in association with the promotion of angiogenesis, blood flow, and endochondral ossification. . PMID- 25520343 TI - Repair techniques for acute distal biceps tendon ruptures: a systematic review. AB - BACKGROUND: There is a lack of consensus regarding the optimal surgical approach and fixation method for distal biceps tendon ruptures. The purpose of this study was to conduct a systematic review comparing the results of the various surgical approaches and repair techniques for acute distal biceps tendon ruptures. METHODS: We searched the MEDLINE, Cochrane, and Embase databases for all published randomized controlled trials, prospective cohort studies, or case series that involved primary repairs of acute distal biceps tendon ruptures with use of a cortical button, intraosseous screws, suture anchors, or bone tunnels for fixation. Exclusion criteria included case reports, cadaveric studies, repairs of partial ruptures, revision repairs, and multiple methods of fixation in the same patient. Statistical analysis was performed with use of the chi square test. RESULTS: Twenty-two studies met the inclusion criteria. The total number of patients was 494 (498 elbows). The complication rate was 24.5% (122 of 498 elbows) overall, and it was 23.9% (seventy-eight of 327) for one-incision procedures and 25.7% (forty-four of 171) for two-incision procedures (p = 0.32). The complication rate was 26.4% (seventy-five of 284) for suture anchors, 20.4% (thirty-four of 167) for bone tunnels, 44.8% (thirteen of twenty-nine) for intraosseous screws, and 0% (zero of eighteen) for cortical button fixation. The complication rate for use of bone tunnels was significantly lower than that for intraosseous screws (p < 0.01). Similarly, the cortical button method proved superior to intraosseous screws (p = 0.01). The most common complication was lateral antebrachial cutaneous nerve neurapraxia (9.6% across all studies, 11.6% for one incision, and 5.8% for two incisions). CONCLUSIONS: The complication rate did not differ significantly between one and two-incision distal biceps repairs; however, the bone tunnel and cortical button methods had significantly lower complication rates compared with suture anchors and intraosseous screws. Further studies are needed to determine the optimal number of incisions. PMID- 25520344 TI - Surgical management of metastatic disease of the proximal part of the femur. AB - ? Pathologic fracture of the proximal part of the femur resulting from metastatic disease causes severe pain and an inability to walk. Surgical stabilization can be challenging because of bone loss resulting from the underlying metastatic lesions, the potential for major blood loss, and the poor health of the patient.? The goal of surgical treatment is the creation of a stable construct to allow early weight-bearing.? Pathologic femoral neck fractures secondary to metastases are best managed with arthroplasty.? The treatment of intertrochanteric or subtrochanteric fractures is more controversial. Surgical stabilization may be performed with cephalomedullary nailing or arthroplasty. The choice of implant and operative technique is dependent on careful consideration of multiple factors, including the patient's life span, the type of tumor, the perceived response to other therapies, the need for adjuvant radiation therapy and chemotherapy, the location and number of metastatic lesions, and the degree of bone involvement.? While the potential for complications is high, surgical stabilization of the proximal part of the femur decreases pain and improves function. PMID- 25520345 TI - What's new in primary bone tumors. PMID- 25520347 TI - Osteotomies about the knee: AAOS exhibit selection. AB - Varus or valgus malalignment of the lower extremity can alter the load distribution across the knee and hasten the development of focal osteoarthritis. Although knee arthroplasty remains an effective option for end-stage arthritis, it is not typically recommended in the young, active patient. In the setting of painful unicompartmental cartilage injury in a mechanically malaligned limb, alignment correction by osteotomy has been shown to slow the progression of osteoarthritis and lessen pain. In this review, we will discuss the different options, indications, and techniques for osteotomies about the knee. PMID- 25520348 TI - Forced air warming devices in orthopaedics: a focused review of the literature. PMID- 25520349 TI - Reflection on infection: Commentary on an article by Brandon A. Ramo, MD, et al.: "Surgical site infections after posterior spinal fusion for neuromuscular scoliosis. a thirty-year experience at a single institution". PMID- 25520350 TI - Is the reverse shoulder prosthesis for proximal humeral nonunions really worth the risk? Commentary on an article by Patric Raiss, MD, et al.: "Reverse shoulder arthroplasty for the treatment of nonunions of the surgical neck of the proximal part of the humerus (type-3 fracture sequelae)". PMID- 25520351 TI - Genetic basis in motor skill and hand preference for tool use in chimpanzees (Pan troglodytes). AB - Chimpanzees are well known for their tool using abilities. Numerous studies have documented variability in tool use among chimpanzees and the role that social learning and other factors play in their development. There are also findings on hand use in both captive and wild chimpanzees; however, less understood are the potential roles of genetic and non-genetic mechanisms in determining individual differences in tool use skill and laterality. Here, we examined heritability in tool use skill and handedness for a probing task in a sample of 243 captive chimpanzees. Quantitative genetic analysis, based on the extant pedigrees, showed that overall both tool use skill and handedness were significantly heritable. Significant heritability in motor skill was evident in two genetically distinct populations of apes, and between two cohorts that received different early social rearing experiences. We further found that motor skill decreased with age and that males were more commonly left-handed than females. Collectively, these data suggest that though non-genetic factors do influence tool use performance and handedness in chimpanzees, genetic factors also play a significant role, as has been reported in humans. PMID- 25520352 TI - Sexual deception in a cannibalistic mating system? Testing the Femme Fatale hypothesis. AB - Animal communication theory holds that in order to be evolutionarily stable, signals must be honest on average, but significant dishonesty (i.e. deception) by a subset of the population may also evolve. A typical praying mantid mating system involves active mate searching by males, which is guided by airborne sex pheromones in most species for which mate-searching cues have been studied. The Femme Fatale hypothesis suggests that female mantids may be selected to exploit conspecific males as prey if they benefit nutritionally from cannibalism. Such a benefit exists in the false garden mantid Pseudomantis albofimbriata-females use the resources gained from male consumption to significantly increase their body condition and reproductive output. This study aimed to examine the potential for chemical deception among the subset of females most likely to benefit from cannibalism (poorly fed females). Females were placed into one of four feeding treatments ('Very Poor', 'Poor', 'Medium' and 'Good'), and males were given the opportunity to choose between visually obscured females in each of the treatments. Female body condition and fecundity varied linearly with food quantity; however, female attractiveness did not. That is, Very Poor females attracted significantly more males than any of the other female treatments, even though these females were in significantly poorer condition, less fecund (in this study) and more likely to cannibalise (in a previous study). In addition, there was a positive correlation between fecundity and attractiveness if Very Poor females were removed from the analysis, suggesting an inherently honest signalling system with a subset of dishonest individuals. This is the first empirical study to provide evidence of sexual deception via chemical cues, and the first to provide support for the Femme Fatale hypothesis. PMID- 25520353 TI - Himalayan 'yeti' DNA: polar bear or DNA degradation? A comment on 'Genetic analysis of hair samples attributed to yeti' by Sykes et al. (2014). PMID- 25520354 TI - Ablation of insulin-producing cells prevents obesity but not premature mortality caused by a high-sugar diet in Drosophila. AB - Ageing can be modulated by genetic as well as nutritional interventions. In female Drosophila melanogaster, lifespan is maximized at intermediate concentrations of sucrose as the carbohydrate source, and yeast as the protein source. Dampening the signal through the insulin/IGF signalling (IIS) pathway, by genetic ablation of median neurosecretory cells (mNSCs) that produce insulin-like peptides, extends lifespan and counteracts the detrimental effects of excess yeast. However, how IIS reduction impacts health on a high-sugar diet remains unclear. We find that, while the ablation of the mNSCs can extend lifespan and delay the age-related decline in the health of the neuromuscular system irrespective of the amount of dietary sugar, it cannot rescue the lifespan shortening effects of excess sugar. On the other hand, ablation of mNSCs can prevent adult obesity resulting from excess sugar, and this effect appears independent from the canonical effector of IIS, dfoxo. Our study indicates that while treatments that reduce IIS have anti-ageing effects irrespective of dietary sugar, additional interventions may be required to achieve full benefits in humans, where excessive sugar consumption is a growing problem. At the same time, pathways regulated by IIS may be suitable targets for treatment of obesity. PMID- 25520355 TI - Adenosine receptors mediate the hypoxic ventilatory response but not the hypoxic metabolic response in the naked mole rat during acute hypoxia. AB - Naked mole rats are the most hypoxia-tolerant mammals identified; however, the mechanisms underlying this tolerance are poorly understood. Using whole-animal plethysmography and open-flow respirometry, we examined the hypoxic metabolic response (HMR), hypoxic ventilatory response (HVR) and hypoxic thermal response in awake, freely behaving naked mole rats exposed to 7% O2 for 1 h. Metabolic rate and ventilation each reversibly decreased 70% in hypoxia (from 39.6 +/- 2.9 to 12.1 +/- 0.3 ml O2 min(-1) kg(-1), and 1412 +/- 244 to 417 +/- 62 ml min(-1) kg(-1), respectively; p < 0.05), whereas body temperature was unchanged and animals remained awake and active. Subcutaneous injection of the general adenosine receptor antagonist aminophylline (AMP; 100 mg kg(-1), in saline), but not control saline injections, prevented the HVR but had no effect on the HMR. As a result, AMP-treated naked mole rats exhibited extreme hyperventilation in hypoxia. These animals were also less tolerant to hypoxia, and in some cases hypoxia was lethal following AMP injection. We conclude that in naked mole rats (i) hypoxia tolerance is partially dependent on profound hypoxic metabolic and ventilatory responses, which are equal in magnitude but occur independently of thermal changes in hypoxia, and (ii) adenosine receptors mediate the HVR but not the HMR. PMID- 25520356 TI - Macronutrients mediate the functional relationship between Drosophila and Wolbachia. AB - Wolbachia are maternally inherited bacterial endosymbionts that naturally infect a diverse array of arthropods. They are primarily known for their manipulation of host reproductive biology, and recently, infections with Wolbachia have been proposed as a new strategy for controlling insect vectors and subsequent human transmissible diseases. Yet, Wolbachia abundance has been shown to vary greatly between individuals and the magnitude of the effects of infection on host life history traits and protection against infection is correlated to within-host Wolbachia abundance. It is therefore essential to better understand the factors that modulate Wolbachia abundance and effects on host fitness. Nutrition is known to be one of the most important mediators of host-symbiont interactions. Here, we used nutritional geometry to quantify the role of macronutrients on insect Wolbachia relationships in Drosophila melanogaster. Our results show fundamental interactions between diet composition, host diet selection, Wolbachia abundance and effects on host lifespan and fecundity. The results and methods described here open a new avenue in the study of insect-Wolbachia relationships and are of general interest to numerous research disciplines, ranging from nutrition and life-history theory to public health. PMID- 25520357 TI - Differential activation of serotonergic neurons during short- and long-term gregarization of desert locusts. AB - Serotonin is a neurochemical with evolutionarily conserved roles in orchestrating nervous system function and behavioural plasticity. A dramatic example is the rapid transformation of desert locusts from cryptic asocial animals into gregarious crop pests that occurs when drought forces them to accumulate on dwindling resources, triggering a profound alteration of behaviour within just a few hours. The onset of crowding induces a surge in serotonin within their thoracic ganglia that is sufficient and necessary to induce the switch from solitarious to gregarious behaviour. To identify the neurons responsible, we have analysed how acute exposure to three gregarizing stimuli--crowding, touching the hind legs or seeing and smelling other locusts--and prolonged group living affect the expression of serotonin in individual neurons in the thoracic ganglia. Quantitative analysis of cell body immunofluorescence revealed three classes of neurons with distinct expressional responses. All ganglia contained neurons that responded to multiple gregarizing stimuli with increased expression. A second class showed increased expression only in response to intense visual and olfactory stimuli from conspecifics. Prolonged group living affected a third and entirely different set of neurons, revealing a two-tiered role of the serotonergic system as both initiator and substrate of socially induced plasticity. This demonstrates the critical importance of ontogenetic time for understanding the function of serotonin in the reorganization of behaviour. PMID- 25520358 TI - How much does nasal cavity morphology matter? Patterns and rates of olfactory airflow in phyllostomid bats. AB - The morphology of the nasal cavity in mammals with a good sense of smell includes features that are thought to improve olfactory airflow, such as a dorsal conduit that delivers odours quickly to the olfactory mucosa, an enlarged olfactory recess at the back of the airway, and a clear separation of the olfactory and respiratory regions of the nose. The link between these features and having a good sense of smell has been established by functional examinations of a handful of distantly related mammalian species. In this paper, we provide the first detailed examination of olfactory airflow in a group of closely related species that nevertheless vary in their sense of smell. We study six species of phyllostomid bats that have different airway morphologies and foraging ecologies, which have been linked to differences in olfactory ability or reliance. We hypothesize that differences in morphology correlate with differences in the patterns and rates of airflow, which in turn are consistent with dietary differences. To compare species, we make qualitative and quantitative comparisons of the patterns and rates of airflow through the olfactory region during both inhalation and exhalation across the six species. Contrary to our expectations, we find no clear differences among species in either the patterns of airflow through the airway or in rates of flow through the olfactory region. By and large, olfactory airflow seems to be conserved across species, suggesting that morphological differences appear to be driven by other mechanical demands on the snout, such as breathing and feeding. Olfactory ability may depend on other aspects of the system, such as the neurobiological processing of odours that work within the existing morphology imposed by other functional demands on the nasal cavity. PMID- 25520359 TI - Discriminating signal from noise in the fossil record of early vertebrates reveals cryptic evolutionary history. AB - The fossil record of early vertebrates has been influential in elucidating the evolutionary assembly of the gnathostome bodyplan. Understanding of the timing and tempo of vertebrate innovations remains, however, mired in a literal reading of the fossil record. Early jawless vertebrates (ostracoderms) exhibit restriction to shallow-water environments. The distribution of their stratigraphic occurrences therefore reflects not only flux in diversity, but also secular variation in facies representation of the rock record. Using stratigraphic, phylogenetic and palaeoenvironmental data, we assessed the veracity of the fossil records of the jawless relatives of jawed vertebrates (Osteostraci, Galeaspida, Thelodonti, Heterostraci). Non-random models of fossil recovery potential using Palaeozoic sea-level changes were used to calculate confidence intervals of clade origins. These intervals extend the timescale for possible origins into the Upper Ordovician; these estimates ameliorate the long ghost lineages inferred for Osteostraci, Galeaspida and Heterostraci, given their known stratigraphic occurrences and stem-gnathostome phylogeny. Diversity changes through the Silurian and Devonian were found to lie within the expected limits predicted from estimates of fossil record quality indicating that it is geological, rather than biological factors, that are responsible for shifts in diversity. Environmental restriction also appears to belie ostracoderm extinction and demise rather than competition with jawed vertebrates. PMID- 25520360 TI - Response to Edward and Barnett. PMID- 25520362 TI - Correction to: Trade-offs between and within scales: environmental persistence and within-host fitness of avian influenza viruses. PMID- 25520361 TI - Variation in Drosophila melanogaster central metabolic genes appears driven by natural selection both within and between populations. AB - In this report, we examine the hypothesis that the drivers of latitudinal selection observed in the eastern US Drosophila melanogaster populations are reiterated within seasons in a temperate orchard population in Pennsylvania, USA. Specifically, we ask whether alleles that are apparently favoured in northern populations are also favoured early in the spring, and decrease in frequency from the spring to autumn with the population expansion. We use SNP data collected for 46 metabolic genes and 128 SNPs representing the central metabolic pathway and examine for the aggregate SNP allele frequencies whether the association of allele change with latitude and that with increasing days of spring-autumn season are reversed. Testing by random permutation, we observe a highly significant negative correlation between these associations that is consistent with this expectation. This correlation is stronger when we confine our analysis to only those alleles that show significant latitudinal changes. This pattern is not caused by association with chromosomal inversions. When data are resampled using SNPs for amino acid change the relationship is not significant but is supported when SNPs associated with cis-expression are only considered. Our results suggest that climate factors driving latitudinal molecular variation in a metabolic pathway are related to those operating on a seasonal level within populations. PMID- 25520363 TI - Osteoglycin prevents cardiac dilatation and dysfunction after myocardial infarction through infarct collagen strengthening. AB - RATIONALE: To maintain cardiac mechanical and structural integrity after an ischemic insult, profound alterations occur within the extracellular matrix. Osteoglycin is a small leucine-rich proteoglycan previously described as a marker of cardiac hypertrophy. OBJECTIVE: To establish whether osteoglycin may play a role in cardiac integrity and function after myocardial infarction (MI). METHODS AND RESULTS: Osteoglycin expression is associated with collagen deposition and scar formation in mouse and human MI. Absence of osteoglycin in mice resulted in significantly increased rupture-related mortality with tissue disruption, intramyocardial bleeding, and increased cardiac dysfunction, despite equal infarct sizes. Surviving osteoglycin null mice had greater infarct expansion in comparison with wild-type mice because of impaired collagen fibrillogenesis and maturation in the infarcts as revealed by electron microscopy and collagen polarization. Absence of osteoglycin did not affect cardiomyocyte hypertrophy in the remodeling remote myocardium. In cultured fibroblasts, osteoglycin knockdown or supplementation did not alter transforming growth factor-beta signaling. Adenoviral overexpression of osteoglycin in wild-type mice significantly improved collagen quality, thereby blunting cardiac dilatation and dysfunction after MI. In osteoglycin null mice, adenoviral overexpression of osteoglycin was unable to prevent rupture-related mortality because of insufficiently restoring osteoglycin protein levels in the heart. Finally, circulating osteoglycin levels in patients with heart failure were significantly increased in the patients with a previous history of MI compared with those with nonischemic heart failure and correlated with survival, left ventricular volumes, and other markers of fibrosis. CONCLUSIONS: Increased osteoglycin expression in the infarct scar promotes proper collagen maturation and protects against cardiac disruption and adverse remodeling after MI. In human heart failure, osteoglycin is a promising biomarker for ischemic heart failure. PMID- 25520364 TI - Annexin A1 counteracts chemokine-induced arterial myeloid cell recruitment. AB - RATIONALE: Chemokine-controlled arterial leukocyte recruitment is a crucial process in atherosclerosis. Formyl peptide receptor 2 (FPR2) is a chemoattractant receptor that recognizes proinflammatory and proresolving ligands. The contribution of FPR2 and its proresolving ligand annexin A1 to atherosclerotic lesion formation is largely undefined. OBJECTIVE: Because of the ambivalence of FPR2 ligands, we here investigate the role of FPR2 and its resolving ligand annexin A1 in atherogenesis. METHODS AND RESULTS: Deletion of FPR2 or its ligand annexin A1 enhances atherosclerotic lesion formation, arterial myeloid cell adhesion, and recruitment. Mechanistically, we identify annexin A1 as an endogenous inhibitor of integrin activation evoked by the chemokines CCL5, CCL2, and CXCL1. Specifically, the annexin A1 fragment Ac2-26 counteracts conformational activation and clustering of integrins on myeloid cells evoked by CCL5, CCL2, and CXCL1 through inhibiting activation of the small GTPase Rap1. In vivo administration of Ac2-26 largely diminishes arterial recruitment of myeloid cells in a FPR2-dependent fashion. This effect is also observed in the presence of selective antagonists to CCR5, CCR2, or CXCR2, whereas Ac2-26 was without effect when all 3 chemokine receptors were antagonized simultaneously. Finally, repeated treatment with Ac2-26 reduces atherosclerotic lesion sizes and lesional macrophage accumulation. CONCLUSIONS: Instructing the annexin A1-FPR2 axis harbors a novel approach to target arterial leukocyte recruitment. With the ability of Ac2-26 to counteract integrin activation exerted by various chemokines, delivery of Ac2-26 may be superior in inhibition of arterial leukocyte recruitment when compared with blocking individual chemokine receptors. PMID- 25520365 TI - Prevalence of Parental Smoking and Predictors of Cessation: A Study in the South Carolina Pediatric Practice Research Network. AB - BACKGROUND: Secondhand smoke exposure harms children. The objectives of the study were to determine the prevalence of secondhand smoke exposure in children <=2 years and determine the predictors of smoking and smoking cessation in parents. METHODS: We surveyed parents of children <=2 years of age, asking about parental smoking patterns, interest in quitting and children's respiratory symptoms. Data were analyzed with chi-square and multiple logistic regression. RESULTS: Thirteen percent were current smokers and 18% had quit. The most common reason for quitting was being pregnant (42%). Children's respiratory symptoms did not predict quitting. Parents on Medicaid were more likely to smoke than those on private insurance (OR = 5.7, 95% CI = 2.0-16.5) and less likely to quit (OR = 0.2, 95% CI = 0.1-0.9). CONCLUSION: Having a new baby may be a motivator for parents to quit. We must address socioeconomic factors to develop a successful intervention in pediatric practices. PMID- 25520366 TI - Zinc-fortified oral rehydration solution improved intestinal permeability and small intestinal mucosal recovery. AB - A randomized double-blind placebo-controlled study was conducted in children admitted to hospital with gastroenteritis (>=3 loose stools per day). All were treated for 5 days following admission with either zinc (Zn, 3 mg) or without Zn fortified rice-based oral rehydration solution (ORS). (13)C-sucrose breath test (SBT) and intestinal permeability (lactulose/rhamnose or L/R ratio) were performed concurrently prior to commencement of ORS with or without Zn and at day 5 post-admission. There was a significant improvement in the SBT results in both the Zn-fortified group, median (5th-95th percentile) 2.1% (0.4% to 8.3%) versus 4.4% (0.4% to 10.4%), P < .05, and control group, 1.4% (0.1% to 5.4%) versus 4.3% (0.4% to 11.4%), P < .05, between the day of admission and day 5 post-admission. In the Zn-fortified group, there was also a significant improvement in L/R ratio between the day of admission and day 5 post-admission, 53.0 (19.5-90.6) versus 17.7 (13.4-83.2), P < .05. Low levels of Zn improved intestinal permeability but did not enhance short-term recovery following diarrheal illness. PMID- 25520367 TI - Health-Related Quality of Life in Overweight/Obese Children Compared With Children With Inflammatory Bowel Disease. AB - PURPOSE: This study examined the health-related quality of life (HRQOL) of pediatric patients with overweight/obesity compared with that of patients with inflammatory bowel disease. METHODS: Differences between disease groups in their PedsQL 4.0 HRQOL survey scores were analyzed using unpaired t tests and analyses of variance. RESULTS: Scores of patients with overweight/obesity were as low as scores of patients with inflammatory bowel disease. Parent/guardian-proxy social functioning scores of the overweight/obese group were statistically significantly lower than scores of the inflammatory bowel disease group, and the parents/guardians reported significantly lower HRQOL scores than the patients. CONCLUSIONS: Overweight/obese children have HRQOL scores as impaired as those of children with inflammatory bowel disease. According to proxy-reported scores, overweight/obesity is associated with lower social functioning. Thus, it is important for health care providers to recognize obesity's relationship to patients' psychosocial health and provide holistic care that addresses the severity of this disease. PMID- 25520368 TI - A Kick in the Groin. PMID- 25520369 TI - Nine-year-old girl with a left flank mass. PMID- 25520370 TI - Emergence of Chinese drug discovery research: impact of hit and lead identification. AB - The identification of hits and the generation of viable leads is an early and yet crucial step in drug discovery. In the West, the main players of drug discovery are pharmaceutical and biotechnology companies, while in China, academic institutions remain central in the field of drug discovery. There has been a tremendous amount of investment from the public as well as private sectors to support infrastructure buildup and expertise consolidation relative to drug discovery and development in the past two decades. A large-scale compound library has been established in China, and a series of high-impact discoveries of lead compounds have been made by integrating information obtained from different technology-based strategies. Natural products are a major source in China's drug discovery efforts. Knowledge has been enhanced via disruptive breakthroughs such as the discovery of Boc5 as a nonpeptidic agonist of glucagon-like peptide 1 receptor (GLP-1R), one of the class B G protein-coupled receptors (GPCRs). Most of the original hit identification and lead generation were carried out by academic institutions, including universities and specialized research institutes. The Chinese pharmaceutical industry is gradually transforming itself from manufacturing low-end generics and active pharmaceutical ingredients to inventing new drugs. PMID- 25520371 TI - Detection of cell aggregation and altered cell viability by automated label-free video microscopy: a promising alternative to endpoint viability assays in high throughput screening. AB - Automated phase-contrast video microscopy now makes it feasible to monitor a high throughput (HT) screening experiment in a 384-well microtiter plate format by collecting one time-lapse video per well. Being a very cost-effective and label free monitoring method, its potential as an alternative to cell viability assays was evaluated. Three simple morphology feature extraction and comparison algorithms were developed and implemented for analysis of differentially time evolving morphologies (DTEMs) monitored in phase-contrast microscopy videos. The most promising layout, pixel histogram hierarchy comparison (PHHC), was able to detect several compounds that did not induce any significant change in cell viability, but made the cell population appear as spheroidal cell aggregates. According to recent reports, all these compounds seem to be involved in inhibition of platelet-derived growth factor receptor (PDGFR) signaling. Thus, automated quantification of DTEM (AQDTEM) holds strong promise as an alternative or complement to viability assays in HT in vitro screening of chemical compounds. PMID- 25520372 TI - CHO-S antibody titers >1 gram/liter using flow electroporation-mediated transient gene expression followed by rapid migration to high-yield stable cell lines. AB - In recent years, researchers have turned to transient gene expression (TGE) as an alternative to CHO stable cell line generation for early-stage antibody development. Despite advances in transfection methods and culture optimization, the majority of CHO-based TGE systems produce insufficient antibody titers for extensive use within biotherapeutic development pipelines. Flow electroporation using the MaxCyte STX Scalable Transfection System is a highly efficient, scalable means of CHO-based TGE for gram-level production of antibodies without the need for specialized expression vectors or genetically engineered CHO cell lines. CHO cell flow electroporation is easily scaled from milligram to multigram quantities without protocol reoptimization while maintaining transfection performance and antibody productivity. In this article, data are presented that demonstrate the reproducibility, scalability, and antibody production capabilities of CHO-based TGE using the MaxCyte STX. Data show optimization of posttransfection parameters such as cell density, media composition, and feed strategy that result in secreted antibody titers >1 g/L and production of multiple grams of antibody within 2 weeks of a single CHO-S cell transfection. In addition, data are presented to demonstrate the application of scalable electroporation for the rapid generation of high-yield stable CHO cell lines to bridge the gap between early- and late-stage antibody development activities. PMID- 25520373 TI - Risk factors for new infection with Leptospira in meat workers in New Zealand. AB - OBJECTIVE: To evaluate risk factors for new infection with Leptospira interrogans sv Pomona and Leptospira borgpetersenii sv Hardjo in meat workers. METHODS: Sera were collected twice approximately 12 months apart from 592 workers from eight abattoirs slaughtering sheep, cattle or deer and tested by microscopic agglutination for Pomona and Hardjo. Information on potential risk factors were recorded and analysed by multivariable logistic regression. RESULTS: Forty-nine (8.3%) participants, either seroconverted or had at least a titre increase by two dilutions against either serovar. While in sheep meat workers, the annual infection risk was 11.3% (95% CI 8.5% to 14.8%), in deer meat workers it was 0% (95% CI 0.0% to 10.9%) and in those processing beef cattle, 1.2% (95% CI 0.2% to 4.6%). Risk factors for new infection in sheep abattoirs were worker position, abattoir and time worked in the meat industry. The new infection risk was highest at the beginning of the slaughter line (stunning and hide removal; relative risk, RR 7.5, 95% CI 2.5 to 22.4), followed by positions on the line involving the removal of high-risk material (bladder, and kidneys; RR 5.2, 95% CI 1.7 to 16.0). Risk was lower in the offal/pet food area (RR 4.1, 95% CI 1.0 to 16.4), and lowest in the boning room or office. Wearing personal protective equipment did not reduce the risk of new infection. CONCLUSIONS: This study has demonstrated ongoing exposure to leptospires in meat workers and risk factors for challenge. We recommend measures such as improvement of personal protective equipment use, changes in slaughter procedure or vaccination of sheep against Leptospira to reduce the risk. PMID- 25520374 TI - Heart disease and stroke statistics--2015 update: a report from the American Heart Association. PMID- 25520376 TI - A follow-up cytogenetic study of workers highly exposed inside the Chernobyl sarcophagus. AB - Data are presented on some of the engineers and scientists who regularly entered highly radioactive areas of the sarcophagus chamber constructed around the ruins of the Chernobyl reactor. Previous investigations on six of them by unstable chromosomal aberrations, quartz fibre electrometers and, in some cases, tooth electron spin resonance have all indicated high doses accumulated over several years of work inside the sarcophagus. Here, the authors present the data on eleven of the men who agreed to be monitored cytogenetically although two have since died aged 45 and 66 y. The present data were combined with the previous to examine the time-courses of these individuals' changes in their aberration frequencies. As expected, dicentric aberrations showed a clear drop down to 2-3 per 100 cells since the men ceased working inside the sarcophagus. In contrast, the translocation yields remained at a high level showing no tendency to decrease and so proved reliable for retrospective biodosimetry. These data are particularly useful in demonstrating the value of FISH long after high but protracted and fractionated exposure. PMID- 25520377 TI - Response improved for neutron long counter. AB - A low-sensitivity neutron long counter was designed as a standard directional flow detector to monitor neutron fluence reference values of an accelerator-based 14-MeV D-T neutron source with yield of 10(13) n s(-1). The energy response over 6 MeV was improved using a tungsten radiator, which acts as an energy converter via the (n, xn) reaction. Different parameters were optimised to flatten the neutron energy response over a wide energy range. A simulation of the designed neutron long counter was performed using the Monte Carlo codes SuperMC. The response function is relatively flat in the energy range of 1 keV-20 MeV. The results show that the maximal relative variation is ~7.8 %. PMID- 25520375 TI - Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis. AB - BACKGROUND: A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. A better understanding of the molecular mechanisms leading to platelet activation is important for the development of improved therapies. Recently, protein tyrosine phosphatases have emerged as critical regulators of platelet function. METHODS AND RESULTS: This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated by the collagen receptor glycoprotein VI and the C-type lectin-like receptor 2. DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism compared with wild-type mice and showed severely impaired thrombus formation on ferric chloride induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of phospholipase Cgamma2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen- and C-type lectin-like receptor 2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells. CONCLUSIONS: DUSP3 plays a selective and essential role in collagen- and C-type lectin-like receptor 2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a protein tyrosine phosphatase, implicated in platelet signaling, has been targeted with a small-molecule drug. PMID- 25520378 TI - Whole-body dose evaluation with an adaptive treatment planning system for boron neutron capture therapy. AB - Dose evaluation for out-of-field organs during radiotherapy has gained interest in recent years. A team led by University of Tsukuba is currently implementing a project for advancing boron neutron capture therapy (BNCT), along with a radiation treatment planning system (RTPS). In this study, the authors used the RTPS (the 'Tsukuba-Plan') to evaluate the dose to out-of-field organs during BNCT. Computed tomography images of a whole-body phantom were imported into the RTPS, and a voxel model was constructed for the Monte Carlo calculations, which used the Particle and Heavy Ion Transport Code System. The results indicate that the thoracoabdominal organ dose during BNCT for a brain tumour and maxillary sinus tumour was 50-360 and 120-1160 mGy-Eq, respectively. These calculations required ~29.6 h of computational time. This system can evaluate the out-of-field organ dose for BNCT irradiation during treatment planning with patient-specific irradiation conditions. PMID- 25520379 TI - European low-dose radiation risk research strategy: future of research on biological effects at low doses. AB - In 2009, the European High Level and Expert Group identified key policy and scientific questions to be addressed through a strategic research agenda for low dose radiation risk. This initiated the establishment of a European Research Platform, called MELODI (Multidisciplinary European Low Dose Research Initiative). In 2010, the DoReMi Network of Excellence was launched in the Euratom 7th Framework Programme. DoReMi has acted as an operational tool for the sustained development of the MELODI platform during its early years. A long-term Strategic Research Agenda for European low-dose radiation risk research has been developed by MELODI. Strategic planning of DoReMi research activities is carried out in close collaboration with MELODI. The research priorities for DoReMi are designed to focus on objectives that are achievable within the 6-y lifetime of the project and that are in areas where stimulus and support can help progress towards the longer-term strategic objectives. PMID- 25520381 TI - Article-level metrics-it's not just about citations. PMID- 25520382 TI - An affinity for biochemical adaptation to temperature. PMID- 25520380 TI - Effects of drug and exercise intervention on functional capacity and quality of life in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials. AB - BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) are often elderly and their primary chronic symptom is severe exercise intolerance that results in a reduced quality of life (QOL).Thus, improvement of exercise capacity and QOL presents an important clinical outcome in HFpEF patients. Although the effects of interventions such as cardiovascular drugs and exercise training on exercise capacity and QOL in HFpEF patients have been examined in a number of clinical trials, the results are inconsistent due in part to limited power with small sample sizes. We aimed to conduct a meta-analysis of the randomized controlled trial (RCT)s on the effect of drug or exercise intervention on exercise capacity and QOL in HFpEF patients. METHOD AND RESULTS: The search of electronic databases identified five RCTs on exercise (245 patients) and eight RCTs on cardiovascular drugs (1080 patients). The pooled analysis showed that exercise training improved peak exercise oxygen uptake (VO2) (weighted mean difference (WMD) 2.283, 95% confidence interval (CI)) (1.318 3.248) ml/min/kg), six-minute walk distance (6MWD) (30.275 m (4.315-56.234)), and Minnesota Living with Heart Failure Questionnaire (MLHFQ) total score (8.974 points (3.321-14.627)) compared with usual care. In contrast, drug intervention did not improve peak VO2 (WMD (95% CI), -0.393 (-1.005-0.220) ml/min/kg), 6MWD ( 9.463 (-21.455-2.530) m), or MLHFQ total score (1.042 (-0.982-3.066) point) compared with placebo or no treatment. CONCLUSION: Our meta-analysis indicates that exercise training may be a therapeutic option to improve functional capacity and QOL in HFpEF patients. PMID- 25520383 TI - Sound production in Onuxodon fowleri (Carapidae) and its amplification by the host shell. AB - Onuxodon species are well known for living inside pearl oysters. As in other carapids, their anatomy highlights their ability to make sounds but sound production has never been documented in Onuxodon. This paper describes sound production in Onuxodon fowleri as well as the anatomy of the sound production apparatus. Single-pulsed sounds and multiple-pulsed sounds that sometimes last more than 3 s were recorded in the field and in captivity (Makemo Island, French Polynesia). These pulses are characterized by a broadband frequency spectrum from 100 to 1000 Hz. Onuxodon fowleri is mainly characterized by its ability to modulate the pulse period, meaning that this species can produce pulsed sounds and tonal-like sounds using the same mechanism. In addition, the sound can be remarkably amplified by the shell cavity (peak gain can exceed 10 dB for some frequencies). The sonic apparatus of O. fowleri is characterized by a rocker bone in front of the swimbladder, modified vertebrae and epineurals, and two pairs of sonic muscles, one of which (primary sonic muscle) inserts on the rocker bone. The latter structure, which is absent in other carapid genera, appears to be sexually dimorphic suggesting differences in sound production in males and females. Sound production in O. fowleri could be an example of adaptation where an animal exploits features of its environment to enhance communication. PMID- 25520384 TI - Prey fish escape by sensing the bow wave of a predator. AB - Prey fish possess a remarkable ability to sense and evade an attack from a larger fish. Despite the importance of these events to the biology of fishes, it remains unclear how sensory cues stimulate an effective evasive maneuver. Here, we show that larval zebrafish (Danio rerio) evade predators using an escape response that is stimulated by the water flow generated by an approaching predator. Measurements of the high-speed responses of larvae in the dark to a robotic predator suggest that larvae respond to the subtle flows in front of the predator using the lateral line system. This flow, known as the bow wave, was visualized and modeled with computational fluid dynamics. According to the predictions of the model, larvae direct their escape away from the side of their body exposed to more rapid flow. This suggests that prey fish use a flow reflex that enables predator evasion by generating a directed maneuver at high speed. These findings demonstrate a sensory-motor mechanism that underlies a behavior that is crucial to the ecology and evolution of fishes. PMID- 25520385 TI - The mechanics of elastic loading and recoil in anuran jumping. AB - Many animals use catapult mechanisms to produce extremely rapid movements for escape or prey capture, resulting in power outputs far beyond the limits of muscle. In these catapults, muscle contraction loads elastic structures, which then recoil to release the stored energy extremely rapidly. Many arthropods employ anatomical 'catch mechanisms' to lock the joint in place during the loading period, which can then be released to allow joint motion via elastic recoil. Jumping vertebrates lack a clear anatomical catch, yet face the same requirement to load the elastic structure prior to movement. There are several potential mechanisms to allow loading of vertebrate elastic structures, including the gravitational load of the body, a variable mechanical advantage, and moments generated by the musculature of proximal joints. To test these hypothesized mechanisms, we collected simultaneous 3D kinematics via X-ray Reconstruction of Moving Morphology (XROMM) and single-foot forces during the jumps of three Rana pipiens. We calculated joint mechanical advantage, moment and power using inverse dynamics at the ankle, knee, hip and ilio-sacral joints. We found that the increasing proximal joint moments early in the jump allowed for high ankle muscle forces and elastic pre-loading, and the subsequent reduction in these moments allowed the ankle to extend using elastic recoil. Mechanical advantage also changed throughout the jump, with the muscle contracting against a poor mechanical advantage early in the jump during loading and a higher mechanical advantage late in the jump during recoil. These 'dynamic catch mechanisms' serve to resist joint motion during elastic loading, then allow it during elastic recoil, functioning as a catch mechanism based on the balance and orientation of forces throughout the limb rather than an anatomical catch. PMID- 25520386 TI - How and how not to investigate the oxygen and capacity limitation of thermal tolerance (OCLTT) and aerobic scope-remarks on the article by Grans et al. PMID- 25520387 TI - Response to 'How and how not to investigate the oxygen and capacity limitation of thermal tolerance (OCLTT) and aerobic scope-remarks on the article by Grans et al.'. PMID- 25520389 TI - Aspirin, NSAIDs, and risk of prostate cancer: results from the REDUCE study. AB - PURPOSE: A recent meta-analysis showed that aspirin was associated with reduced prostate cancer risk. As anti-inflammatory medications lower PSA levels, whether these findings reflect reduced prostate cancer detection or lower prostate cancer risk is unknown. We tested the association between aspirin and nonaspirin NSAID use on prostate cancer diagnosis in REDUCE, where all men received biopsies at 2 and 4 years largely independent of PSA. REDUCE tested dutasteride for prostate cancer risk reduction in men with a PSA of 2.5 to 10.0 ng/mL and a negative prestudy biopsy. EXPERIMENTAL DESIGN: We examined the association between aspirin, NSAIDs, or both and total, low-grade (Gleason < 7), or high-grade (Gleason >= 7) prostate cancer versus no prostate cancer using multinomial logistic regression among 6,390 men who underwent >=1 on-study biopsy. Multivariable analyses were adjusted for age, race, geographic region, PSA, prostate volume, digital rectal examination, body mass index, treatment arm, smoking, alcohol, statins, hypertension, diabetes, and cardiovascular disease. RESULTS: Overall, 3,169 men (50%) were nonusers, 1,368 (21%) used aspirin, 1,176 (18%) used NSAIDs, and 677 (11%) used both. In unadjusted models, aspirin was associated with reduced prostate cancer risk (OR = 0.85, P = 0.036). In multivariable analyses, aspirin was associated with reduced total prostate cancer risk (OR = 0.81, P = 0.015). Use of NSAIDs or NSAIDs and aspirin was not associated with total, low-grade, or high-grade prostate cancer, though all ORs were <1 (all P >= 0.08). Therefore, we created a dichotomous variable of aspirin and/or NSAID users versus nonusers. On multivariable analysis, the use of aspirin and/or NSAIDs was significantly associated with decreased total (OR = 0.87, P = 0.030) and high-grade (OR = 0.80, P = 0.040), but not with low-grade, prostate cancer risk (OR = 0.90, P = 0.15). Results were similar in placebo and dutasteride arms. CONCLUSIONS: Among men with a negative biopsy, aspirin and/or NSAID use was associated with decreased prostate cancer risk. Additional studies are warranted. PMID- 25520388 TI - Differential gene expression and alternative splicing between diploid and tetraploid watermelon. AB - The exploitation of synthetic polyploids for producing seedless fruits is well known in watermelon. Tetraploid progenitors of triploid watermelon plants, compared with their diploid counterparts, exhibit wide phenotypic differences. Although many factors modulate alternative splicing (AS) in plants, the effects of autopolyploidization on AS are still unknown. In this study, we used tissues of leaf, stem, and fruit of diploid and tetraploid sweet watermelon to understand changes in gene expression and the occurrence of AS. RNA-sequencing analysis was performed along with reverse transcription quantitative PCR and rapid amplification of cDNA ends (RACE)-PCR to demonstrate changes in expression and splicing. All vegetative tissues except fruit showed an increased level of AS in the tetraploid watermelon throughout the growth period. The ploidy levels of diploids and the tetraploid were confirmed using a ploidy analyser. We identified 5362 and 1288 genes that were up- and downregulated, respectively, in tetraploid as compared with diploid plants. We further confirmed that 22 genes underwent AS events across tissues, indicating possibilities of generating different protein isoforms with altered functions of important transcription factors and transporters. Arginine biosynthesis, chlorophyllide synthesis, GDP mannose biosynthesis, trehalose biosynthesis, and starch and sucrose degradation pathways were upregulated in autotetraploids. Phloem protein 2, chloroplastic PGR5-like protein, zinc-finger protein, fructokinase-like 2, MYB transcription factor, and nodulin MtN21 showed AS in fruit tissues. These results should help in developing high-quality seedless watermelon and provide additional transcriptomic information related to other cucurbits. PMID- 25520390 TI - Nottingham Clinico-Pathological Response Index (NPRI) after neoadjuvant chemotherapy (Neo-ACT) accurately predicts clinical outcome in locally advanced breast cancer. AB - PURPOSE: There is a need to identify more sensitive clinicopathologic criteria to assess the response to neoadjuvant chemotherapy (Neo-ACT) and guide subsequent adjuvant therapy. EXPERIMENTAL DESIGN: We performed a clinicopathologic assessment of 426 patients who had completed Neo-ACT for locally advanced breast cancer (LABC) with a median follow-up of 70 months. Patients were divided into a training set treated with anthracycline combination chemotherapy (n = 172); an internal validation set treated with anthracycline and taxane (n = 129); and an external validation set treated with anthracycline with or without taxane (n = 125). RESULTS: A multivariate Cox regression model demonstrated the absence of fibrosis, presence of lymphovascular invasion, increasing number of lymph node metastases, and administration of hormone therapy were significantly associated with short breast cancer-specific survival (BCSS) and disease-free survival (DFS); Ps < 0.01, while reduction of tumor size was associated with DFS (P = 0.022). Nottingham Clinico-Pathological Response Indexes (NPRI) were calculated, and four prognostic groups (NPRI-PG) were identified. Patients in prognostic group 2 (NPRI-PG2) for BCSS (66 of 172; 38.4%) have the same prognosis as those who achieved pathologic complete response (pCR; NPRI-PG1; 15%). Receiver operating characteristic (ROC) curves indicated that the NPRI outperformed the currently used prognostic factors and adding the NPRI improved their performance as a predictor for both BCSS (area under the curve [AUC], 0.88) and DFS (AUC, 0.87). CONCLUSIONS: The NPRI predicts BCSS and DFS, with a higher sensitivity than pCR. The NPRI can also improve the sensitivity and specificity of clinicopathologic response as a study endpoint, for assessing response to Neo ACT, and can serve as a valuable tool for the discovery of future predictive molecular markers. PMID- 25520393 TI - The global fight against dementia. PMID- 25520391 TI - Gene expression markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance). AB - PURPOSE: Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis-related genes to identify prognostic or predictive biomarkers for cetuximab treatment. PATIENTS AND METHODS: Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy +/- cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models. RESULTS: High tumor mRNA levels of HER2 [hazard ratio (HR), 0.64; P = 0.002] and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025). CONCLUSIONS: Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity. PMID- 25520392 TI - Longitudinal noninvasive imaging of progesterone receptor as a predictive biomarker of tumor responsiveness to estrogen deprivation therapy. AB - PURPOSE: To investigate whether longitudinal functional PET imaging of mammary tumors using the radiopharmaceuticals [(18)F]FDG (to measure glucose uptake), [(18)F]FES [to measure estrogen receptor (ER) levels], or [(18)F]FFNP [to measure progesterone receptor (PgR) levels] is predictive of response to estrogen deprivation therapy. EXPERIMENTAL DESIGN: [(18)F]FDG, [(18)F]FES, and [(18)F]FFNP uptake in endocrine-sensitive and -resistant mammary tumors was quantified serially by PET before ovariectomy or estrogen withdrawal in mice, and on days 3 and 4 after estrogen-deprivation therapy. Specificity of [(18)F]FFNP uptake in ERalpha(+) mammary tumors was determined by competition assay using unlabeled ligands for PgR or glucocorticoid receptor (GR). PgR expression was also assayed by immunohistochemistry (IHC). RESULTS: The levels of [(18)F]FES and [(18)F]FDG tumor uptake remained unchanged in endocrine-sensitive tumors after estrogen deprivation therapy compared with those at pretreatment. In contrast, estrogen deprivation therapy led to a reduction in PgR expression and [(18)F]FFNP uptake in endocrine-sensitive tumors, but not in endocrine-resistant tumors, as early as 3 days after treatment; the changes in PgR levels were confirmed by IHC. Unlabeled PgR ligand R5020 but not GR ligand dexamethasone blocked [(18)F]FFNP tumor uptake, indicating that [(18)F]FFNP bound specifically to PgR. Therefore, a reduction in FFNP tumor to muscle ratio in mammary tumors predicts sensitivity to estrogen-deprivation therapy. CONCLUSIONS: Monitoring the acute changes in ERalpha activity by measuring [(18)F]FFNP uptake in mammary tumors predicts tumor response to estrogen-deprivation therapy. Longitudinal noninvasive PET imaging using [(18)F]FFNP is a robust and effective approach to predict tumor responsiveness to endocrine treatment. PMID- 25520395 TI - A rapid antimicrobial susceptibility test based on single-cell morphological analysis. AB - A rapid antibiotic susceptibility test (AST) is desperately needed in clinical settings for fast and appropriate antibiotic administration. Traditional ASTs, which rely on cell culture, are not suitable for urgent cases of bacterial infection and antibiotic resistance owing to their relatively long test times. We describe a novel AST called single-cell morphological analysis (SCMA) that can determine antimicrobial susceptibility by automatically analyzing and categorizing morphological changes in single bacterial cells under various antimicrobial conditions. The SCMA was tested with four Clinical and Laboratory Standards Institute standard bacterial strains and 189 clinical samples, including extended-spectrum beta-lactamase-positive Escherichia coli and Klebsiella pneumoniae, imipenem-resistant Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus, and vancomycin-resistant Enterococci from hospitals. The results were compared with the gold standard broth microdilution test. The SCMA results were obtained in less than 4 hours, with 91.5% categorical agreement and 6.51% minor, 2.56% major, and 1.49% very major discrepancies. Thus, SCMA provides rapid and accurate antimicrobial susceptibility data that satisfy the recommended performance of the U.S. Food and Drug Administration. PMID- 25520396 TI - Wide-field computational imaging of pathology slides using lens-free on-chip microscopy. AB - Optical examination of microscale features in pathology slides is one of the gold standards to diagnose disease. However, the use of conventional light microscopes is partially limited owing to their relatively high cost, bulkiness of lens-based optics, small field of view (FOV), and requirements for lateral scanning and three-dimensional (3D) focus adjustment. We illustrate the performance of a computational lens-free, holographic on-chip microscope that uses the transport of-intensity equation, multi-height iterative phase retrieval, and rotational field transformations to perform wide-FOV imaging of pathology samples with comparable image quality to a traditional transmission lens-based microscope. The holographically reconstructed image can be digitally focused at any depth within the object FOV (after image capture) without the need for mechanical focus adjustment and is also digitally corrected for artifacts arising from uncontrolled tilting and height variations between the sample and sensor planes. Using this lens-free on-chip microscope, we successfully imaged invasive carcinoma cells within human breast sections, Papanicolaou smears revealing a high-grade squamous intraepithelial lesion, and sickle cell anemia blood smears over a FOV of 20.5 mm(2). The resulting wide-field lens-free images had sufficient image resolution and contrast for clinical evaluation, as demonstrated by a pathologist's blinded diagnosis of breast cancer tissue samples, achieving an overall accuracy of ~99%. By providing high-resolution images of large-area pathology samples with 3D digital focus adjustment, lens-free on-chip microscopy can be useful in resource-limited and point-of-care settings. PMID- 25520398 TI - Target antigen density governs the efficacy of anti-CD20-CD28-CD3 zeta chimeric antigen receptor-modified effector CD8+ T cells. AB - The effectiveness of chimeric Ag receptor (CAR)-transduced T (CAR-T) cells has been attributed to supraphysiological signaling through CARs. Second- and later generation CARs simultaneously transmit costimulatory signals with CD3zeta signals upon ligation, but may lead to severe adverse effects owing to the recognition of minimal Ag expression outside the target tumor. Currently, the threshold target Ag density for CAR-T cell lysis and further activation, including cytokine production, has not yet been investigated in detail. Therefore, we determined the threshold target Ag density required to induce CAR-T cell responses using novel anti-CD20 CAR-T cells with a CD28 intracellular domain and a CD20-transduced CEM cell model. The newly developed CD20CAR-T cells demonstrated Ag-specific lysis and cytokine secretion, which was a reasonable level as a second-generation CAR. For lytic activity, the threshold Ag density was determined to be ~200 molecules per target cell, whereas the Ag density required for cytokine production of CAR-T cells was ~10-fold higher, at a few thousand per target cell. CD20CAR-T cells responded efficiently to CD20 downregulated lymphoma and leukemia targets, including rituximab- or ofatumumab refractory primary chronic lymphocytic leukemia cells. Despite the potential influence of the structure, localization, and binding affinity of the CAR/Ag, the threshold determined may be used for target Ag selection. An Ag density below the threshold may not result in adverse effects, whereas that above the threshold may be sufficient for practical effectiveness. CD20CAR-T cells also demonstrated significant lytic activity against CD20-downregulated tumor cells and may exhibit effectiveness for CD20-positive lymphoid malignancies. PMID- 25520397 TI - A Wnt-TGFbeta2 axis induces a fibrogenic program in muscle stem cells from dystrophic mice. AB - We have previously observed that Wnt signaling activates a fibrogenic program in adult muscle stem cells, called satellite cells, during aging. We genetically labeled satellite cells in a mouse model of Duchenne muscular dystrophy to follow their fate during the progression of the disease. We observed that a fraction of satellite cells had a reduced myogenic potential and showed enhanced expression of profibrotic genes compared to age-matched controls. By combining in vitro and in vivo results, we found that expression of transforming growth factor-beta2 (TGFbeta2) was induced in response to elevated canonical Wnt signaling in dystrophic muscles and that the resulting increase in TGFbeta activity affected the behavior of satellite cells in an autocrine or paracrine fashion. Indeed, pharmacological inhibition of the TGFbeta pathway in vivo reduced the fibrogenic characteristics of satellite cells. These studies shed new light on the cellular and molecular mechanisms responsible for stem cell dysfunction in dystrophic muscle and may contribute to the development of more effective and specific therapeutic approaches for the prevention of muscle fibrosis. PMID- 25520399 TI - Induction of potent CD8 T cell cytotoxicity by specific targeting of antigen to cross-presenting dendritic cells in vivo via murine or human XCR1. AB - Current subunit vaccines are incapable of inducing Ag-specific CD8(+) T cell cytotoxicity needed for the defense of certain infections and for therapy of neoplastic diseases. In experimental vaccines, cytotoxic responses can be elicited by targeting of Ag into cross-presenting dendritic cells (DC), but almost all available systems use target molecules also expressed on other cells and thus lack the desired specificity. In the present work, we induced CD8(+) T cell cytotoxicity by targeting of Ag to XCR1, a chemokine receptor exclusively expressed on murine and human cross-presenting DC. Targeting of Ag with a mAb or the chemokine ligand XCL1 was highly specific, as determined with XCR1-deficient mice. When applied together with an adjuvant, both vector systems induced a potent cytotoxic response preventing the outgrowth of an inoculated aggressive tumor. By generating a transgenic mouse only expressing the human XCR1 on its cross-presenting DC, we could demonstrate that targeting of Ag using human XCL1 as vector is fully effective in vivo. The specificity and efficiency of XCR1 mediated Ag targeting to cross-presenting DC, combined with its lack of adverse effects, make this system a prime candidate for the development of therapeutic cytotoxic vaccines in humans. PMID- 25520400 TI - Stable interactions and sustained TCR signaling characterize thymocyte-thymocyte interactions that support negative selection. AB - Negative selection is one of the primary mechanisms that render T cells tolerant to self. Thymic dendritic cells play an important role in negative selection, in line with their ability to induce migratory arrest and sustained TCR signals. Thymocytes themselves display self-peptide/MHC class I complexes, and although there is evidence that they can support clonal deletion, it is not clear whether they do so directly via stable cell-cell contacts and sustained TCR signals. In this study, we show that murine thymocytes can support surprisingly efficient negative selection of Ag-specific thymocytes. Furthermore, we observe that agonist-dependent thymocyte-thymocyte interactions occurred as stable, motile conjugates led by the peptide-presenting thymocyte and in which the trailing peptide-specific thymocyte exhibited persistent elevations in intracellular calcium concentration. These data confirm that self-Ag presentation by thymocytes is an additional mechanism to ensure T cell tolerance and further strengthen the correlation between stable cellular contacts, sustained TCR signals, and efficient negative selection. PMID- 25520402 TI - Psychiatric comorbidity in multiple sclerosis: It's not the genes. PMID- 25520401 TI - MiR-127 modulates macrophage polarization and promotes lung inflammation and injury by activating the JNK pathway. AB - A polarized macrophage response is presumed to have a pivotal role in a variety of immunological pathophysiology. However, the molecular mechanism underlying macrophage functional shaping remains largely unknown. In this study, we reveal a pivotal role of miR-127 in macrophage development and thereby the pathogenesis of inflammation and lung injury. In particular, miR-127 was demonstrated to be prominently induced upon TLR engagement and repressed by the M2-prone cytokines. Enforced expression of miR-127 in macrophages resulted in significantly increased production of proinflammatory cytokines, whereas deletion of miR-127 impaired M1 gene expression and led to a M2-biased response. Accordingly, intratracheal administration of miR-127 resulted in an exaggerated pulmonary inflammation and injury. Conversely, antagonizing of miR-127 suppressed production of the proinflammatory cytokines and rendered the mice more refractory to the inflammation-associated pathology. Mechanistically, miR-127 demonstrated to target B cell lymphoma 6 (Bcl6) and remarkably downregulated its expression and subsequently dual specificity phosphatase 1 (Dusp1), which in turn enhanced the activation of JNK kinase and hence the development of proinflammatory macrophages. Thereby, reconstitution with the expression of Bcl6 or Dusp1 or inhibition of JNK activity impaired miR-127-mediated skewing of M1 proinflammatory macrophages, whereas interference of Bcl6 or Dusp1 expression abrogated the anti-inflammatory property of anti-miR-127. Together, these data establish miR-127 as a molecular switch during macrophage development and as a potential target for treatment of inflammatory diseases. PMID- 25520403 TI - Genetic identification of ACC-RESISTANT2 reveals involvement of LYSINE HISTIDINE TRANSPORTER1 in the uptake of 1-aminocyclopropane-1-carboxylic acid in Arabidopsis thaliana. AB - 1-Aminocyclopropane-1-carboxylic acid (ACC) is a biosynthetic precursor of ethylene, a gaseous plant hormone which controls a myriad of aspects of development and stress adaptation in higher plants. Here, we identified a mutant in Arabidopsis thaliana, designated as ACC-resistant2 (are2), displaying a dose dependent resistance to exogenously applied ACC. Physiological analyses revealed that mutation of are2 impaired various aspects of exogenous ACC-induced ethylene responses, while not affecting sensitivity to other plant hormones during seedling development. Interestingly, the are2 mutant was normally sensitive to gaseous ethylene, compared with the wild type. Double mutant analysis showed that the ethylene-overproducing mutations, eto1 or eto3, and the constitutive ethylene signaling mutation, ctr1 were epistatic to the are2 mutation. These results suggest that the are2 mutant is not defective in ethylene biosynthesis or ethylene signaling per se. Map-based cloning of ARE2 demonstrated that LYSINE HISTIDINE TRANSPORTER1 (LHT1), encoding an amino acid transporter, is the gene responsible. An uptake experiment with radiolabeled ACC indicated that mutations of LHT1 reduced, albeit not completely, uptake of ACC. Further, we performed an amino acid competition assay and found that two amino acids, alanine and glycine, known as substrates of LHT1, could suppress the ACC-induced triple response in a LHT1-dependent way. Taken together, these results provide the first molecular genetic evidence supporting that a class of amino acid transporters including LHT1 takes part in transport of ACC, thereby influencing exogenous ACC-induced ethylene responses in A. thaliana. PMID- 25520404 TI - Elevated growth temperature can enhance photosystem I trimer formation and affects xanthophyll biosynthesis in Cyanobacterium Synechocystis sp. PCC6803 cells. AB - In the thylakoid membranes of the mesophilic cyanobacterium Synechocystis PCC6803, PSI reaction centers (RCs) are organized as monomers and trimers. PsaL, a 16 kDa hydrophobic protein, a subunit of the PSI RC, was previously identified as crucial for the formation of PSI trimers. In this work, the physiological effects accompanied by PSI oligomerization were studied using a PsaL-deficient mutant (DeltapsaL), not able to form PSI trimers, grown at various temperatures. We demonstrate that in wild-type Synechocystis, the monomer to trimer ratio depends on the growth temperature. The inactivation of the psaL gene in Synechocystis grown phototropically at 30 degrees C induces profound morphological changes, including the accumulation of glycogen granules localized in the cytoplasm, resulting in the separation of particular thylakoid layers. The carotenoid composition in DeltapsaL shows that PSI monomerization leads to an increased accumulation of myxoxantophyll, zeaxanthin and echinenone irrespective of the temperature conditions. These xanthophylls are formed at the expense of beta-carotene. The measured H2O->CO2 oxygen evolution rates in the DeltapsaL mutant are higher than those observed in the wild type, irrespective of the growth temperature. Moreover, circular dichroism spectroscopy in the visible range reveals that a peak attributable to long-wavelength-absorbing carotenoids is apparently enhanced in the trimer-accumulating wild-type cells. These results suggest that specific carotenoids are accompanied by the accumulation of PSI oligomers and play a role in the formation of PSI oligomer structure. PMID- 25520405 TI - Trafficking of plant plasma membrane aquaporins: multiple regulation levels and complex sorting signals. AB - Aquaporins are small channel proteins which facilitate the diffusion of water and small neutral molecules across biological membranes. Compared with animals, plant genomes encode numerous aquaporins, which display a large variety of subcellular localization patterns. More specifically, plant aquaporins of the plasma membrane intrinsic protein (PIP) subfamily were first described as plasma membrane (PM) resident proteins, but recent research has demonstrated that the trafficking and subcellular localization of these proteins are complex and highly regulated. In the past few years, PIPs emerged as new model proteins to study subcellular sorting and membrane dynamics in plant cells. At least two distinct sorting motifs (one cytosolic, the other buried in the membrane) are required to direct PIPs to the PM. Hetero-oligomerization and interaction with SNAREs (soluble N ethylmaleimide-sensitive factor protein attachment protein receptors) also influence the subcellular trafficking of PIPs. In addition to these constitutive processes, both the progression of PIPs through the secretory pathway and their dynamics at the PM are responsive to changing environmental conditions. PMID- 25520406 TI - Functional water flow pathways and hydraulic regulation in the xylem network of Arabidopsis. AB - In vascular plants, the xylem network constitutes a complex microfluidic system. The relationship between vascular network architecture and functional hydraulic regulation during actual water flow remains unexplored. Here, we developed a method to visualize individual xylem vessels of the 3D xylem network of Arabidopsis thaliana, and to analyze the functional activities of these vessels using synchrotron X-ray computed tomography with hydrophilic gold nanoparticles as flow tracers. We show how the organization of the xylem network changes dynamically throughout the plant, and reveal how the elementary units of this transport system are organized to ensure both long-distance axial water transport and local lateral water transport. Xylem vessels form distinct clusters that operate as functional units, and the activity of these units, which determines water flow pathways, is modulated not only by varying the number and size of xylem vessels, but also by altering their interconnectivity and spatial arrangement. Based on these findings, we propose a regulatory model of water transport that ensures hydraulic efficiency and safety. PMID- 25520407 TI - GLUCAN SYNTHASE-LIKE 5 (GSL5) plays an essential role in male fertility by regulating callose metabolism during microsporogenesis in rice. AB - Callose plays an important role in pollen development in flowering plants. In rice, 10 genes encoding putative callose synthases have been identified; however, none of them has been functionally characterized. In this study, a rice Glucan Synthase-Like 5 (GSL5) knock-out mutant was isolated that exhibited a severe reduction in fertility. Pollen viability tests indicated that the pollen of the mutant was abnormal while the embryo sac was normal. Further, GSL5-RNA interference transgenic plants phenocopied the gsl5 mutant. The RNA expression of GSL5 was found to be knocked out in the gsl5 mutant and knocked down in GSL5-RNA interference transgenic plants by real-time reverse transcripion-PCR (RT-PCR) analysis. The male sterility of the mutant was due to abnormal microspore development; an analysis of paraffin sections of the mutant anthers at various developmental stages revealed that abnormal microspore development began in late meiosis. Both the knock-out and knock-down of GSL5 caused a lack of callose in the primary cell wall of meiocytes and in the cell plate of tetrads. As a result, the callose wall of the microspores was defective. This was demonstrated by aniline blue staining and an immunogold labeling assay; the microspores could not maintain their shape, leading to premature swelling and even collapsed microspores. These data suggest that the callose synthase encoded by GSL5 plays a vital role in microspore development during late meiosis and is essential for male fertility in rice. PMID- 25520408 TI - A P4-ATPase gene GbPATP of cotton confers chilling tolerance in plants. AB - Members of the P4 subfamily of P-type ATPases are implicated in generating lipid asymmetry between the two lipid leaflets of the plasma membrane in Arabidopsis and are important for resistance to low temperatures, but the function of P4 ATPases in cotton remains unclear. In this study, we found using quantitative reverse transcription-PCR analysis that the expression of the P4-ATPase gene GbPATP in cotton was induced at low temperatures. In addition, GbPATP-silenced cotton plants were more sensitive to low temperatures and exhibited greater malondialdehyde (MDA) content and lower catalase (CAT) activity than the control plants. GbPATP transgenic tobacco plants showed better chilling tolerance, had a lower MDA content and had higher CAT activity than wild-type plants under low temperature treatment. The green fluorescent protein (GFP)-GbPATP fusion protein was found to be localized to the cell plasma membrane. Collectively, the results suggest that GbPATP functions as a P4-ATPase and plays an important role in improving chilling tolerance in plant. PMID- 25520409 TI - Long-Term Mortality Rates in Acute De Novo Versus Acute-on-Chronic Heart Failure: From the Heart Function Assessment Registry Trial in Saudi Arabia. AB - AIM: The heart function assessment registry trial in Saudi Arabia (HEARTS) is a national multicenter project that compared de novo versus acute-on-chronic heart failure (ACHF). METHODS AND RESULTS: This is a prospective registry in 18 hospitals in Saudi Arabia between October 2009 and December 2010. The study enrolled 2610 patients: 940 (36%) de novo and 1670 (64%) ACHF. Patients with ACHF were significantly older (62.2 vs 60 years), less likely to be males (64% vs 69%) or smokers (31.6% vs 36.7%), and more likely to have history of diabetes mellitus (65.7% vs 61.3%), hypertension (74% vs 65%), and severe left ventricular dysfunction (52% vs 40%). The ACHF group had a higher adjusted 3-year mortality rate (hazard ratio, 1.6; 95% confidence interval [CI] 1.3-2.0; P < .001). CONCLUSION: Patients with ACHF had significantly higher long-term mortality rates than those with de novo acute heart failure (HF). Multidisciplinary HF disease management programs are highly needed for such high-risk populations. PMID- 25520411 TI - Perspectives on parenteral micronutrient shortages. AB - Micronutrients are essential components of parenteral nutrition (PN). Problems related to deficiency and toxicity occur during routine practice, which could be related to the content of commercial sources, inadequate prescribed doses, and the high frequency of at-risk patients receiving PN. Shortages of commercial products result in increased risk of deficiency. Even though there are recommendations to conserve supplies for those at highest risk, practices that provide no micronutrients or doses less than desired are not safe. This article reviews the evidence describing patients at risk for micronutrient deficiency, the rationale for micronutrient product reformulation, and characteristics of deficiency observed during shortages of micronutrient products. PMID- 25520410 TI - Coronary Computed Tomographic Angiography in the Evaluation of Liver Transplant Candidates. AB - The feasibility, safety, and value of coronary computed tomographic angiography (CCTA) in evaluating orthotopic liver transplant (OLT) candidates are unknown. We studied a cohort of consecutive OLT candidates with intermediate-to-high risk of coronary artery disease (CAD). Intermediate risk candidates received CCTA, and those at high risk or with abnormal noninvasive testing underwent invasive coronary angiography (ICA). One hundred consecutive patients were evaluated. Fifty patients underwent a CCTA, 71.4% were beta-blocked, the image quality was "good" or "excellent" in 71.4% of cases, and there was no event of significant contrast-induced nephropathy. Twenty (20%) patients were found to have severe CAD (>=70% stenosis) by CCTA and/or ICA. Independent predictors of severe CAD were age (odds ratio [OR] = 5.4 per 10-year increment, 95% confidence interval [CI] = 1.7-17.0; P = .004), dyslipidemia (OR = 12.3, 95% CI = 2.6-57.6; P = .001), and chest pain (OR = 6.0, 95% CI = 1.2-29.1; P = .03). Implementing CCTA in the evaluation of intermediate/high CAD risk OLT candidates is challenging but feasible and seems safe. PMID- 25520412 TI - National and international postmarket research and surveillance implementation: achievements of the International Consortium of Orthopaedic Registries initiative. PMID- 25520413 TI - A distributed health data network analysis of survival outcomes: the International Consortium of Orthopaedic Registries perspective. AB - The International Consortium for Orthopaedic Registries is a multinational initiative established by the United States Food and Drug Administration to develop a health data network aimed at providing a robust infrastructure to facilitate evidence-based decision-making on performance of medical devices. Through the International Consortium for Orthopaedic Registries, individual data holders have complete control of their data and can choose to participate in studies of their choice. In this article, we present an overview of the data extraction process and the analytic strategy employed to answer several device performance-related questions in total hip arthroplasty and total knee arthroplasty. In the process, we discuss some nuances pertinent to International Consortium for Orthopaedic Registries data that pose certain statistical challenges, and we briefly suggest strategies to be adopted to address them. PMID- 25520414 TI - Effect of femoral head size on metal-on-HXLPE hip arthroplasty outcome in a combined analysis of six national and regional registries. AB - BACKGROUND: HXLPE (highly cross-linked polyethylene) has greater wear resistance compared with UHMWPE (ultra-high molecular weight polyethylene), which may contribute to improving the outcomes of total hip arthroplasty with a large femoral head. However, no information is available regarding the effect of femoral head size on the survivorship of HXLPE hip prostheses. The aim of the present study was to provide evidence regarding whether femoral head size has an effect on the risk of revision when an HXLPE liner is used on a metal head. METHODS: A distributed health data network was developed by the ICOR (International Consortium of Orthopaedic Registries). Six national and regional registries are participating in this network: Kaiser Permanente, HealthEast, the Emilia-Romagna region in Italy, the Catalan region in Spain, Norway, and Australia. Data from each registry were standardized and provided at an aggregate level for each of the variables of interest. Patients with osteoarthritis who were forty-five to sixty-four years of age and had undergone uncemented total hip arthroplasty were included in the present study. Analyses were performed on the basis of individual patient profiles, utilizing the variables collected from each registry. The outcome of interest was the time to the first revision (for any reason). Survival probabilities and their standard errors were extracted from each registry for each unique combination of the covariates and were combined through multivariate meta-analysis utilizing linear mixed models to compare survivorship for <32-mm, 32-mm, and >32-mm femoral head sizes. RESULTS: A total of 14,372 total hip arthroplasties were included in the study. The five-year rate of revision surgery varied from 1.9% to 3.2% among registries. The risk of revision did not differ significantly between <32-mm and 32-mm head sizes (HR [hazard ratio] = 0.91, 95% CI [confidence interval] = 0.69 to 1.19) or between >32-mm and 32-mm sizes (HR = 1.05, 95% CI = 0.70 to 1.55). CONCLUSIONS: The results of our study provide relevant data to orthopaedic surgeons deciding on the use of a larger articulation in a metal-on-polyethylene bearing. A larger head diameter should not be considered a detriment to device survival when an HXLPE liner is used. However, efforts to force the use of a large-size implant appear unsupported, as similar survivorship was observed for all head diameter groups. PMID- 25520415 TI - Risk of revision following total hip arthroplasty: metal-on-conventional polyethylene compared with metal-on-highly cross-linked polyethylene bearing surfaces: international results from six registries. AB - The results of randomized controlled trials and systematic reviews have suggested reduced radiographic wear in highly cross-linked polyethylene compared with conventional polyethylene in primary total hip arthroplasty. However, longer-term clinical results have not been thoroughly examined, to our knowledge. The purpose of this study was to compare the risk of revision for metal-on-conventional and metal-on-highly cross-linked total hip arthroplasty bearing surfaces with use of a distributed data network of six national and regional registries (Kaiser Permanente, HealthEast, the Emilia-Romagna region in Italy, the Catalan region in Spain, Norway, and Australia). Inclusion criteria were osteoarthritis as the primary diagnosis, cementless implant fixation, and a patient age of forty-five to sixty-four years. These criteria resulted in a sample of 16,571 primary total hip arthroplasties. Multivariate meta-analysis was performed with use of linear mixed models, with survival probability as the unit of analysis. The results of a fixed-effects model suggested that there was insufficient evidence of a difference in risk of revision between bearing surfaces (hazard ratio, 1.20 [95% confidence interval, 0.80 to 1.79]; p = 0.384). Highly cross-linked polyethylene does not appear to have a reduced risk of revision in this subgroup of total hip arthroplasty patients. Arthroplasties involving highly cross-linked polyethylene do not appear to have an increased risk of revision in this subgroup of total hip arthroplasty patients. PMID- 25520416 TI - Distributed analysis of hip implants using six national and regional registries: comparing metal-on-metal with metal-on-highly cross-linked polyethylene bearings in cementless total hip arthroplasty in young patients. AB - BACKGROUND: The regulation of medical devices has attracted controversy recently because of problems related to metal-on-metal hip implants. There is growing evidence that metal-on-metal implants fail early and cause local and systemic complications. However, the failure associated with metal-on-metal head size is not consistently documented and needs to be communicated to patients and surgeons. The purpose of this study is to compare implant survival of metal on metal with that of metal on highly cross-linked polyethylene. METHODS: Using a distributed health data network, primary total hip arthroplasties were identified from six national and regional total joint arthroplasty registries (2001 to 2010). Inclusion criteria were patient age of forty-five to sixty-four years, cementless total hip arthroplasties, primary osteoarthritis diagnosis, and exclusion of the well-known outlier implant ASR (articular surface replacement). The primary outcome was revision for any reason. A meta-analysis of survival probabilities was performed with use of a fixed-effects model. Metal-on-metal implants with a large head size of >36 mm were compared with metal-on-highly cross-linked polyethylene implants. RESULTS: Metal-on-metal implants with a large head size of >36 mm were used in 5172 hips and metal-on-highly cross-linked polyethylene implants were used in 14,372 hips. Metal-on-metal total hip replacements with a large head size of >36 mm had an increased risk of revision compared with metal-on-highly cross-linked polyethylene total hip replacements with more than two years of follow-up, with no difference during the first two years after implantation. The results of the hazard ratios (and 95% confidence intervals) from the multivariable model at various durations of follow-up were 0.95 (0.74 to 1.23) at zero to two years (p = 0.698), 1.42 (1.16 to 1.75) at more than two years to four years (p = 0.001), 1.78 (1.45 to 2.19) at more than four years to six years (p < 0.001), and 2.15 (1.63 to 2.83) at more than six years to seven years (p < 0.001). CONCLUSIONS: We conducted a comparison of large-head size, metal-on-metal implants and metal-on-highly cross-linked polyethylene implants in younger patients with uncemented fixation. We found consistent and strong evidence worldwide that large-head-size, metal-on-metal implants were associated with increased risk of revision after two years compared with metal-on highly cross-linked polyethylene implants, with the effect becoming more pronounced over time. PMID- 25520417 TI - Comparative effectiveness of ceramic-on-ceramic implants in stemmed hip replacement: a multinational study of six national and regional registries. AB - BACKGROUND: The rapid decline in use of conventional total hip replacement with a large femoral head size and a metal-on-metal bearing surface might lead to increased popularity of ceramic-on-ceramic bearings as another hard-on-hard alternative that allows implantation of a larger head. We sought to address comparative effectiveness of ceramic-on-ceramic and metal-on-HXLPE (highly cross linked polyethylene) implants by utilizing the distributed health data network of the ICOR (International Consortium of Orthopaedic Registries), an unprecedented collaboration of national and regional registries and the U.S. FDA (Food and Drug Administration). METHODS: A distributed health data network was developed by the ICOR and used in this study. The data from each registry are standardized and provided at a level of aggregation most suitable for the detailed analysis of interest. The data are combined across registries for comprehensive assessments. The ICOR coordinating center and study steering committee defined the inclusion criteria for this study as total hip arthroplasty performed without cement from 2001 to 2010 in patients forty-five to sixty-four years of age with osteoarthritis. Six national and regional registries (Kaiser Permanente and HealthEast in the U.S., Emilia-Romagna region in Italy, Catalan region in Spain, Norway, and Australia) participated in this study. Multivariate meta-analysis was performed with use of linear mixed models, with survival probability as the unit of analysis. We present the results of the fixed-effects model and include the results of the random-effects model in an appendix. SAS version 9.2 was used for all analyses. We first compared femoral head sizes of >28 mm and <=28 mm within ceramic-on-ceramic implants and then compared ceramic-on-ceramic with metal-on HXLPE. RESULTS: A total of 34,985 patients were included; 52% were female. We found a lower risk of revision associated with use of ceramic-on-ceramic implants when a larger head size was used (HR [hazard ratio] = 0.73, 95% CI [confidence interval] = 0.60 to 0.88, p = 0.001). Use of smaller-head-size ceramic-on-ceramic bearings was associated with a higher risk of failure compared with metal-on HXLPE bearings (HR = 1.36, 95% CI = 1.09 to 1.68, p = 0.006). Use of large-head size ceramic-on-ceramic bearings was associated with a small protective effect relative to metal-on-HXLPE bearings (not subdivided by head size) in years zero to two, but this difference dissipated over the longer term. CONCLUSIONS: Our multinational study based on a harmonized, distributed network showed that use of ceramic-on-ceramic implants with a smaller head size in total hip arthroplasty without cement was associated with a higher risk of revision compared with metal on-HXLPE and >28-mm ceramic-on-ceramic implants. These findings warrant careful reflection by regulatory and clinical communities and wide dissemination to patients for informed decision-making regarding such surgery. PMID- 25520418 TI - Multinational comprehensive evaluation of the fixation method used in hip replacement: interaction with age in context. AB - BACKGROUND: Fixation in total hip replacements remains a controversial topic, despite the high level of its success. Data obtained from major orthopaedic registries indicate that there are large differences among preferred fixation and survival results. METHODS: Using a distributed registry data network, primary total hip arthroplasties performed for osteoarthritis from 2001 to 2010 were identified from six national and regional total joint arthroplasty registries. A multivariate meta-analysis was performed using linear mixed models with the primary outcome revision for any reason. Survival probabilities and their standard errors were extracted from each registry for each unique combination of the covariates. Fixation strategies were compared with regard to age group, sex, bearing, and femoral-head diameter. All comparisons were based on the random effects model and the fixed-effects model. RESULTS: In patients who were seventy five years of age and older, uncemented fixation had a significantly higher risk of revision (p < 0.001) than hybrid fixation, with a hazard ratio of 1.575 (95% confidence interval, 1.389 to 1.786). We found a similar, if lesser, effect in the intermediate age group of sixty-five to seventy-four years (hazard ratio, 1.16 [95% confidence interval, 1.023 to 1.315]; p = 0.021) and in the younger age group of forty-five to sixty-four years (hazard ratio, 1.205 [95% confidence interval, 1.008 to 1.442]; p = 0.041). There were no significant differences between hybrid and cemented bearings across age groups. CONCLUSIONS: We conclude that cementless fixation should be avoided in older patients (those seventy-five years of age or older), although this evidence is less strong in patients of intermediate and younger ages. PMID- 25520419 TI - International comparative evaluation of knee replacement with fixed or mobile non posterior-stabilized implants. AB - BACKGROUND: Mobile-bearing total knee prostheses were designed to reduce wear and improve implant survivorship following total knee arthroplasty. However, the benefit of mobile-bearing total knee arthroplasty remains unproven. Both mobile bearing and fixed-bearing total knee arthroplasty implants are available in posterior-stabilized and non-posterior-stabilized designs. With the latter, the implant does not recreate the function of the posterior cruciate ligament (PCL) with a posterior-stabilizing cam mechanism. The purpose of the present study was to compare mobile-bearing, non-posterior-stabilized devices with fixed-bearing, non-posterior-stabilized devices used in total knee arthroplasty through a novel multinational study design. METHODS: Through the use of a distributed health data network, primary total knee arthroplasties performed for osteoarthritis from 2001 to 2010 were identified from six national and regional total joint arthroplasty registries. Multivariate meta-analysis was performed with use of linear mixed models, with the primary outcome of interest being revision for any reason. Survival probabilities and their standard errors were extracted from each registry for each unique combination of the covariates. RESULTS: A total of 319,616 patients (60% female) underwent non-posterior-stabilized total knee arthroplasty. A fixed-bearing, non-posterior-stabilized design was used in 258,190 (81%) of the knees and a mobile-bearing, non-posterior-stabilized design in 61,426 (19%) of the knees. Sixty-nine percent of the patients who received a fixed-bearing implant were over sixty-five years of age, compared with 63% of those who received a mobile-bearing implant. Mobile-bearing designs had a higher risk of revision, with a hazard ratio of 1.43 (95% confidence interval, 1.36 to 1.51; p < 0.001). CONCLUSIONS: Previous comparisons of mobile-bearing and fixed bearing total knee arthroplasty outcomes have been inconclusive. The current study utilized an advanced, harmonized distributed analysis of six national and regional joint-replacement registries. To our knowledge, it is the largest analysis of mobile-bearing total knee arthroplasty to date. Mobile-bearing, non posterior-stabilized designs presented a greater risk of failure than was found for fixed-bearing, non-posterior-stabilized designs. Caution should be used in the selection of the mobile-bearing non-posterior-stabilized design for total knee replacement. PMID- 25520420 TI - International comparative evaluation of knee replacement with fixed or mobile bearing posterior-stabilized prostheses. AB - BACKGROUND: Posterior-stabilized total knee prostheses were introduced to address instability secondary to loss of posterior cruciate ligament function, and they have either fixed or mobile bearings. Mobile bearings were developed to improve the function and longevity of total knee prostheses. In this study, the International Consortium of Orthopaedic Registries used a distributed health data network to study a large cohort of posterior-stabilized prostheses to determine if the outcome of a posterior-stabilized total knee prosthesis differs depending on whether it has a fixed or mobile-bearing design. METHODS: Aggregated registry data were collected with a distributed health data network that was developed by the International Consortium of Orthopaedic Registries to reduce barriers to participation (e.g., security, proprietary, legal, and privacy issues) that have the potential to occur with the alternate centralized data warehouse approach. A distributed health data network is a decentralized model that allows secure storage and analysis of data from different registries. Each registry provided data on mobile and fixed-bearing posterior-stabilized prostheses implanted between 2001 and 2010. Only prostheses associated with primary total knee arthroplasties performed for the treatment of osteoarthritis were included. Prostheses with all types of fixation were included except for those with the rarely used reverse hybrid (cementless tibial and cemented femoral components) fixation. The use of patellar resurfacing was reported. The outcome of interest was time to first revision (for any reason). Multivariate meta-analysis was performed with linear mixed models with survival probability as the unit of analysis. RESULTS: This study includes 137,616 posterior-stabilized knee prostheses; 62% were in female patients, and 17.6% had a mobile bearing. The results of the fixed-effects model indicate that in the first year the mobile bearing posterior-stabilized prostheses had a significantly higher hazard ratio (1.86) than did the fixed-bearing posterior-stabilized prostheses (95% confidence interval, 1.28 to 2.7; p = 0.001). For all other time intervals, the mobile bearing posterior-stabilized prostheses had higher hazard ratios; however, these differences were not significant. CONCLUSIONS: Mobile-bearing posterior stabilized prostheses had an increased rate of revision compared with fixed bearing posterior-stabilized prostheses. This difference was evident in the first year. PMID- 25520421 TI - International comparative evaluation of fixed-bearing non-posterior-stabilized and posterior-stabilized total knee replacements. AB - BACKGROUND: Differences in survivorship of non-posterior-stabilized compared with posterior-stabilized knee designs carry substantial economic consequences, especially with limited health-care resources. However, these comparisons have often been made between relatively small groups of patients, often with short term follow-up, with only small differences demonstrated between the groups. The goal of this study is to compare the outcomes of non-posterior-stabilized and posterior-stabilized total knee arthroplasties with use of a unique collaboration of multiple established knee arthroplasty registries. METHODS: A distributed health data network was developed by the International Consortium of Orthopaedic Registries and was used in this study to reduce barriers to participation (such as security, propriety, legal, and privacy issues) compared with a centralized data warehouse approach. The study included only replacements in osteoarthritis patients who underwent total knee procedures involving fixed-bearing devices from 2001 to 2010. The outcome of interest was time to first revision. RESULTS: On average, not resurfacing showed a more harmful effect than resurfacing did when posterior-stabilized and non-posterior-stabilized knee replacements were compared, while the risk of revision for posterior-stabilized compared with non posterior-stabilized knees was highest in year zero to one, followed by year one to two, years eight through ten, and years two through eight. Posterior stabilized knees did significantly worse than non-posterior-stabilized knees did when the patella was not resurfaced. This difference was most pronounced in the first two years (year zero to one: hazard ratio [HR] = 2.15, 95% confidence interval [CI] = 1.56 to 2.95, p < 0.001; year one to two: HR = 1.61, 95% CI = 1.48 to 1.75, p < 0.001). When the patella was resurfaced, posterior-stabilized knees did significantly worse than non-posterior-stabilized knees did. This was again most pronounced in the first two years (year zero to one: HR = 1.75, 95% CI = 1.27 to 2.42, p = 0.001; year one to two: HR = 1.31, 95% CI = 1.19 to 1.45, p < 0.001). There was a reduced risk of revision with a patient age of more than sixty-five years (HR = 0.57, 95% CI = 0.55 to 0.60, p < 0.001). CONCLUSIONS: We found that fixed non-posterior-stabilized total knee arthroplasty performed better with or without patellar resurfacing than did fixed posterior-stabilized total knee arthroplasty. This effect was most pronounced in the first two years. The risk of revision for posterior-stabilized total knee arthroplasties was reduced with patellar resurfacing. Also, a patient age of more than sixty-five years and female gender reduced the risk of revision. PMID- 25520422 TI - Survivorship of hip and knee implants in pediatric and young adult populations: analysis of registry and published data. AB - BACKGROUND: One of the least researched areas in orthopaedic pediatrics is the safety and effectiveness of joint replacement, in part because it is uncommon and is undertaken for a wide range of conditions not common for adult joint replacement. This study used data from the AOANJRR (Australian Orthopaedic Association National Joint Replacement Registry) to analyze the use of total hip arthroplasty (THA) and total knee arthroplasty (TKA) in the pediatric population and to provide preliminary data on the outcome of these procedures. METHODS: The AOANJRR, which is part of the ICOR (International Consortium of Orthopaedic Registries), provided information on pediatric procedures reported to the registry by hospitals undertaking arthroplasty procedures in Australia. All THA and TKA procedures reported to the registry from 1999 to 2012 were included. The cumulative percent revision and the hazard ratio from Cox proportional-hazards models were used for analysis. All tests were two-tailed, with a 5% level of significance. Additionally, an overview of the literature is presented to provide a point of reference. RESULTS: Primary conventional THA was performed in 297 patients twenty years of age or younger; the cumulative percent revision at five years was 4.5%. Primary conventional THA was performed in 975 young adults twenty one to thirty years of age; the cumulative percent revision at five years was 5.4%. Primary THA was performed in 105 patients twenty years of age or younger; the cumulative percent revision at five years was 4.6%. Primary TKA was performed in 159 young adults twenty-one to thirty years of age; the cumulative percent revision at five years was 10.3%. CONCLUSIONS: Compared with older adults, pediatric patients and young adults undergoing THA and TKA have very different diagnoses, including a high prevalence of tumor. Although the reported rate of revision surgery is currently similar to that for older patients, the number of reported procedures and the follow-up period remain limited. It is important for registries to continue to collect and analyze data relevant to this cohort and to coordinate these activities in order to better understand the safety and effectiveness of joint arthroplasty in the pediatric population. PMID- 25520423 TI - Which implant should we use for primary total hip replacement? A systematic review and meta-analysis. AB - BACKGROUND: Many total hip implants are currently available on the market worldwide. We aimed to estimate the probability of revision surgery at ten years for each individual total hip implant and to compare these estimates with the National Institute for Health and Care Excellence (NICE) benchmark. METHODS: We performed a meta-analysis of cohort studies. The methodological quality was assessed with use of the Assessment of Quality in Lower Limb Arthroplasty (AQUILA) checklist. We searched PubMed, Embase, Web of Science, and the Cochrane Library. Additionally, national joint registries that were full members of the International Society of Arthroplasty Registers (ISAR) were hand searched. Studies in which the authors reported the survival probability for either the acetabular or the femoral component of primary total hip replacements with use of revision for any reason or for aseptic loosening at ten years as the end point, with at least 100 implants at baseline, and in which at least 60% of the patients had primary osteoarthritis were eligible for inclusion. RESULTS: The search strategy revealed 5513 papers describing survival probabilities for thirty-four types of acetabular components and thirty-two types of femoral components. Eight types of acetabular cups and fifteen types of femoral stems performed better than the NICE benchmark. CONCLUSIONS: We recommend that surgeons performing a primary total hip replacement use an implant that outperforms the NICE benchmarks. PMID- 25520424 TI - Review of clinical outcomes-based anchors of minimum clinically important differences in hip and knee registry-based reports and publications. AB - Patient-reported outcome measures are tools that allow clinicians and researchers to gauge patients' level of satisfaction and quality of life after a medical intervention. The use of patient-reported outcome measures and the clinically relevant score differentials over time as they relate to outcomes (minimum clinically important differences) has been proposed as a way to understand success and failure rates in orthopaedics. We conducted a systematic appraisal of literature in peer-reviewed journals and registry reports to measure the use that registries and other large data repositories make of minimum clinically important differences and to understand methodological approaches for such uses. Of the nineteen registry reports and 1052 articles examined, we found that only one report and two studies mentioned the use of patient-reported outcome measures and minimum clinically important differences in the context of revision rates of total knee arthroplasty and total hip arthroplasty. We conclude that although the infrastructure and efforts to routinely collect patient-reported outcome measures at registry levels do exist, there is limited use of minimum clinically important differences to understand and potentially predict clinical outcomes. We suggest advancing the global infrastructure such as the International Consortium of Orthopaedic Registries to address how research related to patient-reported outcome measures can help individual registries collaborate in the development of tools and allow aggregation of data. PMID- 25520425 TI - Implementation of patient-reported outcome measures in U.S. Total joint replacement registries: rationale, status, and plans. AB - BACKGROUND: In the U.S. and abroad, the use of patient-reported outcome measures to evaluate the impact of total joint replacement surgery on patient quality of life is increasingly common. Analyses of patient-reported outcomes have documented substantial pain relief and functional gain among the vast majority of patients managed with total joint replacement. In addition, postoperative patient reported outcomes are useful to identify persistent pain and suboptimal outcomes in the minority of patients who have them. The leaders of five U.S. total joint replacement registries report the rationale, current status, and vision for the use of patient-reported outcome measures in U.S. total joint replacement registries. METHODS: Surgeon leaders of the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement registry, American Joint Replacement Registry, California Joint Replacement Registry, Michigan Arthroplasty Registry Collaborative Quality Initiative, and Virginia Joint Registry report the rationale supporting the adoption of patient-reported outcome measures, factors associated with the selection and successful implementation of patient-reported outcome measures, and barriers to complete and valid data. RESULTS: U.S. registries are at varied stages of implementation of preoperative surveys and postoperative total joint replacement outcome measures. Surgeon leaders report unified rationales for adopting patient-reported outcome measures: to capture data on pain relief and functional gain following total joint replacement as well as to identify suboptimal implant performance. Key considerations in the selection of a patient-reported outcome measure include its ability to measure both joint pain and physical function while limiting any burden on patients and surgeons related to its use. Complete patient-reported outcomes data will be associated with varied modes of survey completion, including options for home-based completion, to ensure consistent timing and data capture. CONCLUSIONS: The current stage of implementation of patient-reported outcome measures varies widely among U.S. registries. Nonetheless, evidence from the Function and Outcomes Research for Comparative Effectiveness in Total Joint Replacement registry supports the feasibility of successful implementation of patient-reported outcome measures with careful attention to the selection of the outcome measure, mode and timing of postoperative administration, and minimization of any burden on the patient and surgeon. PMID- 25520426 TI - Antiretroviral Pre-Exposure Prophylaxis Does Not Enhance Immune Responses to HIV in Exposed but Uninfected Persons. AB - BACKGROUND: Antiretroviral preexposure prophylaxis (PrEP), using daily oral combination tenofovir disoproxil fumarate plus emtricitabine, is an effective human immunodeficiency virus (HIV) prevention strategy for populations at high risk of HIV acquisition. Although the primary mode of action for the protective effect of PrEP is probably direct antiviral activity, nonhuman primate studies suggest that PrEP may also allow for development of HIV-specific immune responses, hypothesized to result from aborted HIV infections providing a source of immunologic priming. We sought to evaluate whether PrEP affects the development of HIV-specific immune response in humans. METHODS AND RESULTS: Within a PrEP clinical trial among high-risk heterosexual African men and women, we detected HIV-specific CD4(+) and CD8(+) peripheral blood T-cell responses in 10%-20% of 247 subjects evaluated. The response rate and magnitude of T-cell responses did not vary significantly between those assigned PrEP versus placebo, and no significant difference between those assigned PrEP and placebo was observed in measures of innate immune function. CONCLUSIONS: We found no evidence to support the hypothesis that PrEP alters either the frequency or magnitude of HIV-specific immune responses in HIV-1-exposed seronegative individuals. These results suggest that PrEP is unlikely to serve as an immunologic prime to aid protection by a putative HIV vaccine. PMID- 25520428 TI - Injury-Induced Neurogenesis: Mechanisms and Relevance. AB - Partial recovery from brain injury due to trauma, hypoxia, or stroke, is ubiquitous and occurs largely through unknown mechanisms. It is now well accepted that injury enhances proliferation of quiescent stem and progenitor cells in specialized niches within the brain. However, whether this injury-induced neurogenesis contributes to recovery after brain injury remains controversial. Recent evidence suggests that hippocampal neural stem/precursor cell activation and subsequent neurogenesis are responsible for at least some aspects of spontaneous recovery following brain injury from a variety of causes. However, other aspects of injury-induced neurogenesis, including its contribution to adverse sequelae such as seizures, are still being investigated. The purpose of this review is to provide an overview of adult hippocampal neurogenesis and how it relates to injury and explain how current mouse technology is allowing for better understanding of whether manipulating this natural process might eventually help inform therapy following brain injury. PMID- 25520427 TI - IFNgamma Responses to Pre-erythrocytic and Blood-stage Malaria Antigens Exhibit Differential Associations With Past Exposure and Subsequent Protection. AB - BACKGROUND: The malaria-specific T-cell response is believed to be important for protective immunity. Antimalarial chemoprevention may affect this response by altering exposure to malaria antigens. METHODS: We performed interferon gamma (IFNgamma) ELISpot assays to assess the cellular immune response to blood-stage and pre-erythrocytic antigens longitudinally from 1 to 3 years of age in 196 children enrolled in a randomized trial of antimalarial chemoprevention in Tororo, Uganda, an area of high transmission intensity. RESULTS: IFNgamma responses to blood-stage antigens, particularly MSP1, were frequently detected, strongly associated with recent malaria exposure, and lower in those adherent to chemoprevention compared to nonadherent children and those randomized to no chemoprevention. IFNgamma responses to pre-erythrocytic antigens were infrequent and similar between children randomized to chemoprevention or no chemoprevention. Responses to blood-stage antigens were not associated with subsequent protection from malaria (aHR 0.96, P = .83), but responses to pre-erythrocytic antigens were associated with protection after adjusting for prior malaria exposure (aHR 0.52, P = .009). CONCLUSIONS: In this high transmission setting, IFNgamma responses to blood-stage antigens were common and associated with recent exposure to malaria but not protection from subsequent malaria. Responses to pre-erythrocytic antigens were uncommon, not associated with exposure but were associated with protection from subsequent malaria. PMID- 25520430 TI - Learning and generalization in an isometric visuomotor task. AB - Adaptation is a prominent feature of the human motor system and has been studied extensively in reaching movements. This study characterizes adaptation and generalization during isometric reaching in which the arm remains stationary and the participant controls a virtual cursor via force applied by the hand. We measured how learning of a visual cursor rotation generalizes across workspace 1) to determine the coordinate system that predominates visual rotation learning, and 2) to ascertain whether mapping type, namely position or velocity control, influences transfer. Participants performed virtual reaches to one of two orthogonal training targets with the applied rotation. In a new workspace, participants reached to a single target, similar to the training target in either hand or joint space. Furthermore, a control experiment measured within-workspace generalization to an orthogonal target. Across position and velocity mappings, learning transferred predominantly in intrinsic (joint) space, although the transfer was incomplete. The velocity mapping resulted in significantly larger aftereffects and broader within-workspace generalization than the position mapping, potentially due to slower peak speeds, longer trial times, greater target overshoot, or other factors. Although we cannot rule out a mixed reference frame in our task, the predominance of intrinsic coding of cursor kinematics in the isometric environment opposes the extrinsic coding of arm kinematics in real reaching but matches the intrinsic coding of dynamics found in prior work. These findings have implications for the design of isometric control systems in human machine interaction or in rehabilitation when coordinated multi-degree-of-freedom movement is difficult to achieve. PMID- 25520429 TI - Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH. AB - Cholesterol crystals form within hepatocyte lipid droplets in human and experimental nonalcoholic steatohepatitis (NASH) and are the focus of crown-like structures (CLSs) of activated Kupffer cells (KCs). Obese, diabetic Alms1 mutant (foz/foz) mice were a fed high-fat (23%) diet containing 0.2% cholesterol for 16 weeks and then assigned to four intervention groups for 8 weeks: a) vehicle control, b) ezetimibe (5 mg/kg/day), c) atorvastatin (20 mg/kg/day), or d) ezetimibe and atorvastatin. Livers of vehicle-treated mice developed fibrosing NASH with abundant cholesterol crystallization within lipid droplets calculated to extend over 3.3% (SD, 2.2%) of liver surface area. Hepatocyte lipid droplets with prominent cholesterol crystallization were surrounded by TNFalpha-positive (activated) KCs forming CLSs (>= 3 per high-power field). KCs that formed CLSs stained positive for NLRP3, implicating activation of the NLRP3 inflammasome in response to cholesterol crystals. In contrast, foz/foz mice treated with ezetimibe and atorvastatin showed near-complete resolution of cholesterol crystals [0.01% (SD, 0.02%) of surface area] and CLSs (0 per high-power field), with amelioration of fibrotic NASH. Ezetimibe or atorvastatin alone had intermediate effects on cholesterol crystallization, CLSs, and NASH. These findings are consistent with a causative link between exposure of hepatocytes and KCs to cholesterol crystals and with the development of NASH possibly mediated by NLRP3 activation. PMID- 25520431 TI - Deconstructing multisensory enhancement in detection. AB - The mechanisms responsible for the integration of sensory information from different modalities have become a topic of intense interest in psychophysics and neuroscience. Many authors now claim that early, sensory-based cross-modal convergence improves performance in detection tasks. An important strand of supporting evidence for this claim is based on statistical models such as the Pythagorean model or the probabilistic summation model. These models establish statistical benchmarks representing the best predicted performance under the assumption that there are no interactions between the two sensory paths. Following this logic, when observed detection performances surpass the predictions of these models, it is often inferred that such improvement indicates cross-modal convergence. We present a theoretical analyses scrutinizing some of these models and the statistical criteria most frequently used to infer early cross-modal interactions during detection tasks. Our current analysis shows how some common misinterpretations of these models lead to their inadequate use and, in turn, to contradictory results and misleading conclusions. To further illustrate the latter point, we introduce a model that accounts for detection performances in multimodal detection tasks but for which surpassing of the Pythagorean or probabilistic summation benchmark can be explained without resorting to early cross-modal interactions. Finally, we report three experiments that put our theoretical interpretation to the test and further propose how to adequately measure multimodal interactions in audiotactile detection tasks. PMID- 25520433 TI - Cell-selective modulation of the Drosophila neuromuscular system by a neuropeptide. AB - Neuropeptides can modulate physiological properties of neurons in a cell-specific manner. The present work examines whether a neuropeptide can also modulate muscle tissue in a cell-specific manner using identified muscle cells in third-instar larvae of fruit flies. DPKQDFMRFa, a modulatory peptide in the fruit fly Drosophila melanogaster, has been shown to enhance transmitter release from motor neurons and to elicit contractions by a direct effect on muscle cells. We report that DPKQDFMRFa causes a nifedipine-sensitive drop in input resistance in some muscle cells (6 and 7) but not others (12 and 13). The peptide also increased the amplitude of nerve-evoked contractions and compound excitatory junctional potentials (EJPs) to a greater degree in muscle cells 6 and 7 than 12 and 13. Knocking down FMRFamide receptor (FR) expression separately in nerve and muscle indicate that both presynaptic and postsynaptic FR expression contributed to the enhanced contractions, but EJP enhancement was mainly due to presynaptic expression. Muscle ablation showed that DPKQDFMRFa induced contractions and enhanced nerve-evoked contractions more strongly in muscle cells 6 and 7 than cells 12 and 13. In situ hybridization indicated that FR expression was significantly greater in muscle cells 6 and 7 than 12 and 13. Taken together, these results indicate that DPKQDFMRFa can elicit cell-selective effects on muscle fibers. The ability of neuropeptides to work in a cell-selective manner on neurons and muscle cells may help explain why so many peptides are encoded in invertebrate and vertebrate genomes. PMID- 25520432 TI - Tracking the evolution of crossmodal plasticity and visual functions before and after sight restoration. AB - Visual deprivation leads to massive reorganization in both the structure and function of the occipital cortex, raising crucial challenges for sight restoration. We tracked the behavioral, structural, and neurofunctional changes occurring in an early and severely visually impaired patient before and 1.5 and 7 mo after sight restoration with magnetic resonance imaging. Robust presurgical auditory responses were found in occipital cortex despite residual preoperative vision. In primary visual cortex, crossmodal auditory responses overlapped with visual responses and remained elevated even 7 mo after surgery. However, these crossmodal responses decreased in extrastriate occipital regions after surgery, together with improved behavioral vision and with increases in both gray matter density and neural activation in low-level visual regions. Selective responses in high-level visual regions involved in motion and face processing were observable even before surgery and did not evolve after surgery. Taken together, these findings demonstrate that structural and functional reorganization of occipital regions are present in an individual with a long-standing history of severe visual impairment and that such reorganizations can be partially reversed by visual restoration in adulthood. PMID- 25520434 TI - The effect of face inversion for neurons inside and outside fMRI-defined face selective cortical regions. AB - It is widely believed that face processing in the primate brain occurs in a network of category-selective cortical regions. Combined functional MRI (fMRI) single-cell recording studies in macaques have identified high concentrations of neurons that respond more to faces than objects within face-selective patches. However, cells with a preference for faces over objects are also found scattered throughout inferior temporal (IT) cortex, raising the question whether face selective cells inside and outside of the face patches differ functionally. Here, we compare the properties of face-selective cells inside and outside of face selective patches in the IT cortex by means of an image manipulation that reliably disrupts behavior toward face processing: inversion. We recorded IT neurons from two fMRI-defined face-patches (ML and AL) and a region outside of the face patches (herein labeled OUT) during upright and inverted face stimulation. Overall, turning faces upside down reduced the firing rate of face selective cells. However, there were differences among the recording regions. First, the reduced neuronal response for inverted faces was independent of stimulus position, relative to fixation, in the face-selective patches (ML and AL) only. Additionally, the effect of inversion for face-selective cells in ML, but not those in AL or OUT, was impervious to whether the neurons were initially searched for using upright or inverted stimuli. Collectively, these results show that face-selective cells differ in their functional characteristics depending on their anatomicofunctional location, suggesting that upright faces are preferably coded by face-selective cells inside but not outside of the fMRI-defined face selective regions of the posterior IT cortex. PMID- 25520436 TI - Long-range GABAergic neurons in the prefrontal cortex modulate behavior. AB - Cortical glutamatergic projections are extensively studied in behavioral neuroscience, whereas cortical GABAergic projections to downstream structures have been overlooked. A recent study by Lee and colleagues (Lee AT, Vogt D, Rubenstein JL, Sohal VS. J Neurosci 34: 11519-11525, 2014) used optogenetic and electrophysiological techniques to characterize a behavioral role for long projecting GABAergic neurons in the medial prefrontal cortex. In this Neuro Forum, we discuss the potential implications of this study in several learning and memory models. PMID- 25520437 TI - Comparing brain structural MRI and metabolic FDG-PET changes in patients with ALS FTD: 'the chicken or the egg?' question. AB - OBJECTIVE: Our previous voxel based morphometry (VBM) studies in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (ALS-FTD) showed reduced motor and extramotor grey matter (GM) volume when compared to neurological controls. However, erroneously high GM values can result because VBM analysis includes both cortical gyri and sulci as a single GM region. In addition, the relationship between structural and functional changes is unknown. Therefore, we determined whether GM volumetric changes seen in patients with ALS FTD were due to changes in cortical thickness, area or both, and compared these structural changes with metabolic changes as revealed by positron emission tomography (PET). METHODS: T1-weighted MRIs were obtained in unaffected neurological controls and in patients with ALS-FTD; the latter also underwent PET imaging. We assessed brain GM structural changes using VBM and cortical thickness, and metabolic changes using PET images. Significant (p<0.05) reductions in GM volume and cortical thickness were observed in motor and extramotor regions in patients with ALS-FTD compared to controls. No significant difference in cortical surface area was observed in any of the brain regions. Results Significant (p<0.05) reductions in cerebral glucose metabolism rate were observed in brain regions where structural changes were also observed. Significant reductions primarily in cortical thickness were the likely reason for decreased GM volume in ALS-FTD. CONCLUSIONS: Metabolic changes corresponded well with structural changes in motor and extramotor areas, and sometimes occurred even in the absence of GM volume reduction. Coincident structural and functional GM changes suggest that neurodegeneration may occur as "neuronopathy" in patients with ALS-FTD. PMID- 25520435 TI - Adult spinal V2a interneurons show increased excitability and serotonin-dependent bistability. AB - In mice, most studies of the organization of the spinal central pattern generator (CPG) for locomotion, and its component neuron classes, have been performed on neonatal [postnatal day (P)2-P4] animals. While the neonatal spinal cord can generate a basic locomotor pattern, it is often argued that the CPG network is in an immature form whose detailed properties mature with postnatal development. Here, we compare intrinsic properties and serotonergic modulation of the V2a class of excitatory spinal interneurons in behaviorally mature (older than P43) mice to those in neonatal mice. Using perforated patch recordings from genetically tagged V2a interneurons, we revealed an age-dependent increase in excitability. The input resistance increased, the rheobase values decreased, and the relation between injected current and firing frequency (F/I plot) showed higher excitability in the adult neurons, with almost all neurons firing tonically during a current step. The adult action potential (AP) properties became narrower and taller, and the AP threshold hyperpolarized. While in neonates the AP afterhyperpolarization was monophasic, most adult V2a interneurons showed a biphasic afterhyperpolarization. Serotonin increased excitability and depolarized most neonatal and adult V2a interneurons. However, in ~30% of adult V2a interneurons, serotonin additionally elicited spontaneous intrinsic membrane potential bistability, resulting in alternations between hyperpolarized and depolarized states with a dramatically decreased membrane input resistance and facilitation of evoked plateau potentials. This was never seen in younger animals. Our findings indicate a significant postnatal development of the properties of locomotor-related V2a interneurons, which could alter their interpretation of synaptic inputs in the locomotor CPG. PMID- 25520438 TI - Ictal tachycardia in patients with hypothalamic hamartoma. PMID- 25520439 TI - Tsukamurella pulmonis bloodstream infection identified by secA1 gene sequencing. AB - Recurrent bloodstream infections caused by a Gram-positive bacterium affected an immunocompromised child. Tsukamurella pulmonis was the microorganism identified by secA1 gene sequencing. Antibiotic treatment in combination with removal of the subcutaneous port healed the patient. PMID- 25520440 TI - Rapid identification of microorganisms from sterile body fluids by use of FilmArray. AB - We evaluated the clinical performance of the FilmArray blood culture identification (BCID) panel in the identification of microorganisms from positive blood culture bottles inoculated with sterile body fluids. All organisms included in the FA BCID panel were accurately identified in 84/84 (100%) and 18/24 (75%) samples with mono- and polymicrobial growth, respectively. PMID- 25520441 TI - Isolation and enrichment of Cryptosporidium DNA and verification of DNA purity for whole-genome sequencing. AB - Whole-genome sequencing of Cryptosporidium spp. is hampered by difficulties in obtaining sufficient, highly pure genomic DNA from clinical specimens. In this study, we developed procedures for the isolation and enrichment of Cryptosporidium genomic DNA from fecal specimens and verification of DNA purity for whole-genome sequencing. The isolation and enrichment of genomic DNA were achieved by a combination of three oocyst purification steps and whole-genome amplification (WGA) of DNA from purified oocysts. Quantitative PCR (qPCR) analysis of WGA products was used as an initial quality assessment of amplified genomic DNA. The purity of WGA products was assessed by Sanger sequencing of cloned products. Next-generation sequencing tools were used in final evaluations of genome coverage and of the extent of contamination. Altogether, 24 fecal specimens of Cryptosporidium parvum, C. hominis, C. andersoni, C. ubiquitum, C. tyzzeri, and Cryptosporidium chipmunk genotype I were processed with the procedures. As expected, WGA products with low (<16.0) threshold cycle (CT) values yielded mostly Cryptosporidium sequences in Sanger sequencing. The cloning sequencing analysis, however, showed significant contamination in 5 WGA products (proportion of positive colonies derived from Cryptosporidium genomic DNA, <=25%). Following this strategy, 20 WGA products from six Cryptosporidium species or genotypes with low (mostly <14.0) CT values were submitted to whole-genome sequencing, generating sequence data covering 94.5% to 99.7% of Cryptosporidium genomes, with mostly minor contamination from bacterial, fungal, and host DNA. These results suggest that the described strategy can be used effectively for the isolation and enrichment of Cryptosporidium DNA from fecal specimens for whole genome sequencing. PMID- 25520442 TI - Proposing an empirically justified reference threshold for blood culture sampling rates in intensive care units. AB - Early and appropriate blood culture sampling is recommended as a standard of care for patients with suspected bloodstream infections (BSI) but is rarely taken into account when quality indicators for BSI are evaluated. To date, sampling of about 100 to 200 blood culture sets per 1,000 patient-days is recommended as the target range for blood culture rates. However, the empirical basis of this recommendation is not clear. The aim of the current study was to analyze the association between blood culture rates and observed BSI rates and to derive a reference threshold for blood culture rates in intensive care units (ICUs). This study is based on data from 223 ICUs taking part in the German hospital infection surveillance system. We applied locally weighted regression and segmented Poisson regression to assess the association between blood culture rates and BSI rates. Below 80 to 90 blood culture sets per 1,000 patient-days, observed BSI rates increased with increasing blood culture rates, while there was no further increase above this threshold. Segmented Poisson regression located the threshold at 87 (95% confidence interval, 54 to 120) blood culture sets per 1,000 patient days. Only one-third of the investigated ICUs displayed blood culture rates above this threshold. We provided empirical justification for a blood culture target threshold in ICUs. In the majority of the studied ICUs, blood culture sampling rates were below this threshold. This suggests that a substantial fraction of BSI cases might remain undetected; reporting observed BSI rates as a quality indicator without sufficiently high blood culture rates might be misleading. PMID- 25520443 TI - Utility of real-time PCR for detection of Exserohilum rostratum in body and tissue fluids during the multistate outbreak of fungal meningitis and other infections. AB - Exserohilum rostratum was the major cause of the multistate outbreak of fungal meningitis linked to contaminated injections of methylprednisolone acetate produced by the New England Compounding Center. Previously, we developed a fungal DNA extraction procedure and broad-range and E. rostratum-specific PCR assays and confirmed the presence of fungal DNA in 28% of the case patients. Here, we report the development and validation of a TaqMan real-time PCR assay for the detection of E. rostratum in body fluids, which we used to confirm infections in 57 additional case patients, bringing the total number of case patients with PCR results positive for E. rostratum to 171 (37% of the 461 case patients with available specimens). Compared to fungal culture and the previous PCR assays, this real-time PCR assay was more sensitive. Of the 139 identical specimens from case patients tested by all three methods, 19 (14%) were positive by culture, 41 (29%) were positive by the conventional PCR assay, and 65 (47%) were positive by the real-time PCR assay. We also compared the utility of the real-time PCR assay with that of the previously described beta-d-glucan (BDG) detection assay for monitoring response to treatment in case patients with serially collected CSF. Only the incident CSF specimens from most of the case patients were positive by real-time PCR, while most of the subsequently collected specimens were negative, confirming our previous observations that the BDG assay was more appropriate than the real-time PCR assay for monitoring the response to treatment. Our results also demonstrate that the real-time PCR assay is extremely susceptible to contamination and its results should be used only in conjunction with clinical and epidemiological data. PMID- 25520444 TI - Human adenovirus type 7 infection associated with severe and fatal acute lower respiratory illness and nosocomial transmission. AB - A 23-year-old male died of severe pneumonia and respiratory failure in a tertiary hospital in Beijing, and 4 out of 55 close contacts developed fever. Molecular analysis confirmed human adenovirus type 7 (HAdV7) as the causative agent. We highlight the importance of early diagnosis and treatment and proper transmission control of HAdV7. PMID- 25520445 TI - Rapid homogeneous immunoassay based on time-resolved Forster resonance energy transfer for serodiagnosis of acute hantavirus infection. AB - We recently introduced a homogeneous immunoassay based on time-resolved Forster resonance energy transfer (TR-FRET) elicited by fluorophore-labeled antigen and fluorophore-labeled protein L, bound by an immunoglobulin. As the first clinical application, we employ this approach (LFRET) in serodiagnosis of Puumala hantavirus (PUUV) infection. A reference panel containing serum from individuals with acute (n = 21) or past (n = 17) PUUV infection and from PUUV-seronegative individuals (n = 20) was used to define the parameters. The clinical assay performance was evaluated with a prospectively collected serum panel (panel 2; n = 153). Based on the results for panel 1, the threshold for positivity was set at a signal level that was 3-fold over background, while those with a signal <3-fold over the background level were considered PUUV seronegative. With panel 1, 20/21 acute- and 7/10 past-infection samples induced positive signals, compared to 0/20 seronegatives. With panel 2, a positive signal was obtained in 39/40 acute- and 4/10 past-infection samples, as opposed to 7/103 seronegatives. However, after IgG depletion, 58/61 acute-infection samples were LFRET positive, while all past infection and seronegative samples were negative, corresponding to 100% specificity and 95% sensitivity in detection of acute PUUV infection. We demonstrate that the novel immunoassay is a promising tool for rapid serodiagnosis of acute Puumala virus infection. PMID- 25520446 TI - Clinical and microbiological characteristics of Eggerthella lenta bacteremia. AB - Eggerthella lenta is an emerging pathogen that has been underrecognized due to historical difficulties with phenotypic identification. Until now, its pathogenicity, antimicrobial susceptibility profile, and optimal treatment have been poorly characterized. In this article, we report the largest cohort of patients with E. lenta bacteremia to date and describe in detail their clinical features, microbiologic characteristics, treatment, and outcomes. We identified 33 patients; the median age was 68 years, and there was no gender predominance. Twenty-seven patients (82%) had serious intra-abdominal pathology, often requiring a medical procedure. Of those who received antibiotics (28/33, 85%), the median duration of treatment was 21.5 days. Mortality from all causes was 6% at 7 days, 12% at 30 days, and 33% at 1 year. Of 26 isolates available for further testing, all were identified as E. lenta by both commercially available matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) systems, and none were found to harbor a vanA or vanB gene. Of 23 isolates which underwent susceptibility testing, all were susceptible to amoxicillin-clavulanate, cefoxitin, metronidazole, piperacillin-tazobactam, ertapenem, and meropenem, 91% were susceptible to clindamycin, 74% were susceptible to moxifloxacin, and 39% were susceptible to penicillin. PMID- 25520448 TI - Contribution of (1,3)-beta-D-glucan to diagnosis of invasive candidiasis after liver transplantation. AB - Invasive candidiasis (IC) causes high morbidity and mortality rates after liver transplantation, in part due to delayed diagnosis. The fungal cell wall component (1,3)-beta-d-glucan (BG) could be an early biomarker of IC. This preliminary prospective study was designed to evaluate the contribution of BG measurements to the diagnosis of IC after liver transplantation. All consecutive patients who underwent liver transplantation at Henri Mondor Hospital in France between January and June 2013 were enrolled prospectively in the study. They were monitored weekly for colonization by Candida, and colonization index values were calculated. Serum samples were tested for BG (Fungitell; Cape Cod Inc.) at least weekly between liver transplantation and discharge from the hospital. A total of 52 patients (including 39 male patients) were enrolled, with a median age of 55 years (range, 31 to 69 years). The median Model for End-Stage Liver Disease (MELD) score was 27 (range, 6 to 40). Cultures from 42 patients (81%) yielded Candida spp., with the most common Candida species isolated being Candida glabrata (47%). Six cases of documented IC were found for four of the 52 patients. On the day the clinical diagnosis of IC was made, analysis based on combining two sequential BG-positive samples (>146 pg/ml) and a colonization index of >=0.5 revealed sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) results of 83%, 89%, 50%, and 97.6%, respectively. The detection of BG associated with Candida colonization may be a promising tool based on a high NPV that can rule out IC among high-risk patients. PMID- 25520447 TI - Hepatitis C virus genotype 7, a new genotype originating from central Africa. AB - We report a new hepatitis C virus (HCV) genotype identified in patients originating from the Democratic Republic of Congo. The prototype QC69 virus is shown to be a new lineage distinct from genotypes 1 to 6. Three additional patients were also found to be infected by a virus from this lineage, confirming its circulation in humans. We propose that these viruses be classified into HCV genotype 7. PMID- 25520449 TI - Design and implementation of an external quality assessment program for HIV viral load measurements using dried blood spots. AB - An external quality assurance program was developed for HIV-1 RNA viral load measurements taken from dried blood spots using a reference panel and field collected specimens. The program demonstrated that accurate and reproducible quantitation can be obtained from field-collected specimens. Residual proviral DNA may confound interpretation in virologically suppressed subjects. PMID- 25520450 TI - Sonication of explanted prosthesis combined with incubation in BD bactec bottles for pathogen-based diagnosis of prosthetic joint infection. AB - Prosthetic joint infection (PJI) is a rare but refractory complication of arthroplasty. Accurate identification of pathogens is a key step for successful treatment of PJI, which remains a challenge for clinicians and laboratory workers. We designed a combined culture method with sonication of implants and incubation in a BD Bactec system to improve the effectiveness of pathogen diagnosis in PJI. The aims of this study were to investigate the diagnostic accuracy of sonicate fluid cultures in the BD Bactec system and to compare the results with those of synovial fluid cultures in the BD Bactec system. The prosthetic components removed were sonicated in Ringer's solution, and then sonicate fluid was incubated in Bactec bottles for 5 days. Synovial fluid was incubated in Bactec bottles for 5 days as a control. Synovial fluid cultures with Bactec bottles and sonicate fluid cultures with Bactec bottles showed sensitivities of 64% and 88%, respectively (P = 0.009), with specificities of 98% and 87% (P = 0.032), respectively. Sonicate fluid cultures with Bactec bottles were more sensitive than synovial fluid cultures with Bactec bottles regardless of whether antimicrobial agents were used within 14 days before surgery (81% versus 52%; P = 0.031) or not (93% versus 72%; P = 0.031). Sonication of explanted prostheses followed by incubation of the resulting sonicate fluid in Bactec bottles detected many more pathogens than did synovial fluid cultures with Bactec bottles. This method is also effective in cases with antibiotic treatment before surgery. PMID- 25520451 TI - Molecular epidemiology and genetic diversity of fluoroquinolone-resistant Escherichia coli isolates from patients with community-onset infections in 30 Chinese county hospitals. AB - The high frequency of fluoroquinolone resistance in Escherichia coli is a feature of clinical bacteriology in China, where the molecular epidemiology and genetic characteristics of this resistance in county hospitals remain unclear. A total of 590 nonduplicate E. coli isolates from 30 county hospitals located across seven Chinese regions were examined for plasmid-mediated quinolone resistance (PMQR) genes and mutations in quinolone resistance-determining regions (QRDRs). Multilocus sequence typing (MLST) and phylogenetic analysis of fluoroquinolone resistant isolates were used to determine their genetic relatedness. The ciprofloxacin resistance rate of community-onset E. coli was 51.2%, and at least one PMQR gene was carried by 220 (37.3%) isolates. These included qnr (3.7%), aac(6')-Ib-cr (19.7%), qepA (14.4%), and oqxAB (3.8%). Two novel oqxB mutants were identified and named oqxB20 and oqxB29. From 60 sequence types (STs) isolated, 5 novel STs (ST4499 to ST4503) were identified. ST1193 (7.9%) was the second most abundant ST among fluoroquinolone-resistant isolates (ST131 was the most common, with 14.6%), and this is the first report of it in China. This is also the first report of ST2115 and ST3014 isolates from human samples. Ciprofloxacin-resistant E. coli isolates fell mainly into phylogroups B2 and D. The rates of fluoroquinolone resistance and the prevalence of PMQR genes in community-onset E. coli isolates from Chinese county hospitals were high. The wide-ranging molecular epidemiology of E. coli isolates from scattered locations across China indicates that fluoroquinolone resistance evolved from different sources. PMID- 25520452 TI - Evaluation of the Cepheid Xpert C. difficile/Epi and meridian bioscience illumigene C. difficile assays for detecting Clostridium difficile ribotype 033 strains. AB - Clostridium difficile PCR ribotype 033 (RT033) is found in the gastrointestinal tracts of production animals and, occasionally, humans. The illumigene C. difficile assay (Meridian Bioscience, Inc.) failed to detect any of 52 C. difficile RT033 isolates, while all strains signaled positive for the binary toxin genes but were reported as negative for C. difficile by the Xpert C. difficile/Epi assay (Cepheid). PMID- 25520454 TI - Interdisciplinary and interprofessional: what are the differences? PMID- 25520453 TI - Performance of the 47-kilodalton membrane protein versus DNA polymerase I genes for detection of Treponema pallidum by PCR in ulcers. AB - Treponema pallidum PCR (Tp-PCR) is a direct diagnostic method for primary and secondary syphilis, but there is no recommendation regarding the best choice of target gene. In this study, we sequentially tested 272 specimens from patients with sexually transmitted ulcers using Tp-PCR targeting the tpp47 and then polA genes. The two methods showed similar accuracies and an almost-perfect agreement. PMID- 25520455 TI - Reverence--or not? PMID- 25520456 TI - Feeling disrespected: an exploration of the extant literature. AB - In this article, a comprehensive exploration of the literature on feeling disrespected is presented. Literature is reviewed from philosophy, sociology, psychology, education, business, and nursing. Four over-arching themes concerning feeling disrespected are identified. PMID- 25520457 TI - IRB reformation: is unfettered access the answer? AB - The purpose of this column is to consider if research using only an interview should be evaluated by an institutional review board (IRB) or if it may be considered exempt. A review of atrocities committed by researchers both in the biomedical and psychosocial domains will be considered as a backdrop to the discussion. Issues that plague IRBs will be examined including lack of transparency, overreach of the process, and stipulations that change the nature of research. Finally, recommendations for reform will be entertained. PMID- 25520458 TI - Ethics and academic integrity. AB - Academics from across the globe must navigate ever-increasing demands for research, practice, and educational productivity. With the increased demands, nurse faculty must choose value priorities and actions that reflect academic integrity. What does it mean to choose actions that reflect personal integrity in the academic arena? This article begins an important nursing philosophical and theoretical discussion that members and future members of the discipline of nursing must reflect upon and grapple with as they consider what it potentially means to act with straight thinking and integrity in academics. PMID- 25520459 TI - Incivility as bullying in nursing education. AB - Incivility as bullying in the workplace remains an important issue in need of attention. Nursing teaching-learning environments are no different. Acts of bullying can be disruptive and harmful to individuals and institutions. The author in this column discusses the prevalence of incivility as bullying within nursing communities with a focus on those in education. The humanbecoming ethical tenets, shame and betrayal are discussed as they relate to bullying. Suggested means of putting an end to this incivility are presented with a call for all nursing faculty to honor living quality as humanbecoming professionals. PMID- 25520460 TI - Why thinking is important to nursing. PMID- 25520461 TI - Theory to practice: the humanbecoming leading-following model. AB - Guided by the humanbecoming leading-following model, the author designed a nursing theories course with the intention of creating a meaningful nursing theory to practice link. The author perceived that with the implementation of Situation-Background-Assessment-Recommendations (SBAR) communication, nursing staff had drifted away from using the KardexTM in shift to shift reporting. Nurse students, faculty, and staff members supported the creation of a theories project which would engage nursing students in the pursuit of clinical excellence. The project chosen was to revise the existing KardexTM (predominant nursing communication tool). In the project, guided by a nursing theory, nursing students focused on the unique patient's experience, depicting the specific role of nursing knowledge and the contributions of the registered nurse to the patient's healthcare journey. The emphasis of this theoretical learning was the application of a nursing theory to real-life clinical challenges with communication of relevant, timely, and accurate patient information, recognizing that real problems are often complex and require multi-perspective approaches. This project created learning opportunities where a nursing theory would be chosen by the nursing student clinical group and applied in their clinical specialty area. This practice activity served to broaden student understandings of the role of nursing knowledge and nursing theories in their professional practice. PMID- 25520462 TI - Nursing science: an answer to lateral violence? AB - More emphasis on nursing theory in education and practice settings is suggested as an approach to reduce lateral violence in the workplace. PMID- 25520463 TI - Lateral violence in nursing: a review of the past three decades. AB - The author of this article reviews the literature on lateral violence in nursing. This concept was first discussed over three decades ago. Bullying and incivility are concepts similar to lateral violence that have become increasingly utilized in nursing research and scholarly writing. The research on these concepts suggests that the behavior still exists in the nursing workplace, and that few interventions have been developed to change the behaviors or the power dynamics that cause them. Suggestions are included to change practice and scholarship in this area. PMID- 25520464 TI - Martha E. Rogers: heretic and heroine. AB - Rhythms of Martha Rogers' life and work are presented showing her evolution as a heretic and a heroine through her heretical thinking. New concepts of unitariology, energyspirit, wellbecoming, integral presence, and soul are presented with their relevance for advancing Rogers' science of unitary human beings. New dimensions of practice make explicit pandimensional ministering to humankind and living in the universe. PMID- 25520465 TI - The living experience of difficulty telling the truth: a parse method study. AB - The purpose of this study was to investigate the living experience of difficulty telling the truth. Parse's research method was used to answer the question: What is the structure of the living experience of difficulty telling the truth? The participants were 9 nurses and 1 physician. The central finding of the study is the structure: difficulty telling the truth is uncomfortable dialogues with knowing silences arise with anguishing deliberations anticipating potential adversity, while contemplating intentional withholding gives rise to calm acquiescence. The findings are discussed in relation to the humanbecoming school of thought and extant literature. PMID- 25520466 TI - Moving beyond dwelling in suffering: a situation-specific theory of men's healing from childhood maltreatment. AB - The authors present an explanation of the development of a situation-specific theory of men's healing from maltreatment during childhood. Development of the theory was guided by Rogers' science of unitary human beings (SUHB). The four multidimensional concepts of the theory are interpreted within the context of the SUHB from themes discovered from the findings of a hermeneutic phenomenological study of men who had been exposed to childhood maltreatment, including neglect and abuse. The concepts are: moving beyond suffering, desiring release from suffering, dwelling in suffering, and experiencing wellbeing. Moving beyond suffering is the process of healing from childhood maltreatment. Desiring release from suffering is the facilitator of men's life experiences that speeds up the rate of evolution from moving beyond suffering to experiencing healing. Dwelling in suffering is the barrier in men's life experiences that slows down the rate of evolution from moving beyond suffering to experiencing wellbeing. PMID- 25520467 TI - The centricity of presence in scenario-based high fidelity human patient simulation: a model. AB - Enhancing immersive presence has been shown to have influence on learning outcomes in virtual types of simulation. Scenario-based human patient simulation, a mixed reality form, may pose unique challenges for inducing the centricity of presence among participants in simulation. A model for enhancing the centricity of presence in scenario-based human patient simulation is presented here. The model represents a theoretical linkage among the interaction of pedagogical, individual, and group factors that influence the centricity of presence among participants in simulation. Presence may have an important influence on the learning experiences and learning outcomes in scenario-based high fidelity human patient simulation. This report is a follow-up to an article published in 2014 by the author where connections were made to the theoretical basis of presence as articulated by nurse scholars. PMID- 25520468 TI - Nursing in Switzerland: struggling to maintain quality and ideals. AB - After an edited transcript of an interview with a nurse leader, Teodora Duarte, RN; MA, on nursing in Switzerland, the author further discusses the challenges and opportunities facing nursing in that country from a global perspective. Also discussed are some of the advantages and problems of international nursing, in particular nurses who migrate to work in other countries or commute across national borders. PMID- 25520469 TI - Nursing and Native Americans: sharing principles of healthcare. PMID- 25520470 TI - Linking Native American tribal policy to practice in mental health care. AB - The authors highlight approaches used in implementing tribal policy to provide a successful culturally-based modification of dialectical behavior therapy in the Suquamish Native American Tribe. The modified program was called Healthy and Whole. This work fostered greater tribal community resiliency despite the serious mental health problems of the community. It also strengthened tribal policies that support mental health treatment. PMID- 25520471 TI - Thoughts about conceptual models of nursing and health policies. AB - In this essay, we present a conceptual framework for analysis and evaluation of sexuality education health policies based on the conceptual model of nursing and health policy and the Neuman systems model. The framework is intended to facilitate understanding of sexuality education policies promulgated by the governments of any country in the world. PMID- 25520476 TI - Global ultrasound assessment of structural lesions in osteoarthritis: a reliability study by the OMERACT ultrasonography group on scoring cartilage and osteophytes in finger joints. AB - OBJECTIVE: Ultrasonography is sensitive for the evaluation of cartilage pathology and degree of osteophytes in patients with hand osteoarthritis (OA). High consistency of assessments is essential, and the OMERACT (Outcome Measures in Rheumatology) ultrasonography group took the initiative to explore the reliability of a global ultrasonography score in patients with hand OA using semiquantitative ultrasonography score of cartilage and osteophytes in finger joints. METHODS: Ten patients with hand OA were examined by 10 experienced sonographers over the course of two days. Semiquantitative scoring (0-3) was performed on osteophytes (carpo-metacarpal 1, metacarpo-phalangeal (MCP) 1-5, proximal interphalangeal 1-5 and distal interphalangeal 2-5 joints bilaterally with an ultrasonography atlas as reference) and cartilage pathology (MCP 2-5 bilaterally). A web-based exercise on static cartilage images was performed a month later. Reliability was assessed by use of weighted kappa analyses. RESULTS: Osteophyte scores were evenly distributed, and the intraobserver and interobserver reliabilities were substantial to excellent (kappa range 0.68-0.89 and mean kappa 0.65 (day 1) and 0.67 (day 2), respectively). Cartilage scores were unevenly distributed, and the intraobserver and interobserver reliability was fair to moderate (kappa range 0.46-0.66 and mean kappa 0.39 (day 1) and 0.33 (day 2), respectively). The web-based exercise showed acceptable agreement for cartilage being normal (kappa 0.47) or with complete loss (kappa 0.68), but poor for the intermediate scores (kappa 0.22-0.30). CONCLUSIONS: Use of the present semiquantitative ultrasonography scoring system for cartilage pathology in hand OA is not recommended (while normal or total loss of cartilage may be assessed). However, the OMERACT ultrasonography group will endorse the use of semiquantitative scoring of osteophytes with the ultrasonography atlas as reference. PMID- 25520477 TI - The importance of using patient experience to direct research. PMID- 25520478 TI - High time for human height. PMID- 25520480 TI - Does PTH offer additive value to ALP measurement in assessing CKD-MBD? PMID- 25520481 TI - Quality versus costs: a false paradigm. PMID- 25520482 TI - Should peritoneal resting be advised in ultrafiltration failure associated with a fast peritoneal solute transport status? PMID- 25520483 TI - Knowledge, attitudes, and practices with regard to PD access: a report from the Peritoneal Dialysis Access Subcommittee of the Ontario Renal Network Committee on Independent Dialysis. PMID- 25520484 TI - Effects of different mixing methods on the concentration of sodium in "fresh" dialysate. PMID- 25520486 TI - New-onset psoriasis during peritoneal dialysis. PMID- 25520485 TI - Stability of anidulafungin in two standard peritoneal dialysis fluids. PMID- 25520487 TI - Treatment of obturator hernia in a patient undergoing peritoneal dialysis. PMID- 25520488 TI - Intravenous antibiotics with adjunctive lavage in refractory peritonitis. PMID- 25520489 TI - Continuous ambulatory peritoneal dialysis (CAPD) in the management of persistent hepatic encephalopathy - more studies needed. PMID- 25520490 TI - The use of exchange-free periods alternating with daily exchanges of icodextrin in the initial treatment of peritoneal dialysis-associated peritonitis: a safety study. PMID- 25520491 TI - Peritonitis in a peritoneal dialysis patient due to Rhizobium radiobacter and Moraxella osleonsis: case report and literature review. PMID- 25520492 TI - Actinomyces neuii PD peritonitis--resolution of infection without catheter removal. PMID- 25520493 TI - Peritoneal dialysis-related peritonitis caused by Neisseria elongata subsp. nitroreducens, the first report. PMID- 25520494 TI - A tale of two patients: refractory peritonitis with umbilical hernias. PMID- 25520498 TI - A fine neuroscience vintage. PMID- 25520495 TI - Peritoneal dialysis-related peritonitis due to Kingella denitrificans: the first case report. PMID- 25520499 TI - Structural basis for the development of avian virus capsids that display influenza virus proteins and induce protective immunity. AB - Bioengineering of viruses and virus-like particles (VLPs) is a well-established approach in the development of new and improved vaccines against viral and bacterial pathogens. We report here that the capsid of a major avian pathogen, infectious bursal disease virus (IBDV), can accommodate heterologous proteins to induce protective immunity. The structural units of the ~70-nm-diameter T=13 IBDV capsid are trimers of VP2, which is made as a precursor (pVP2). The pVP2 C terminal domain has an amphipathic alpha helix that controls VP2 polymorphism. In the absence of the VP3 scaffolding protein, 466-residue pVP2 intermediates bearing this alpha helix assemble into genuine VLPs only when expressed with an N terminal His6 tag (the HT-VP2-466 protein). HT-VP2-466 capsids are optimal for protein insertion, as they are large enough (cargo space, ~78,000 nm(3)) and are assembled from a single protein. We explored HT-VP2-466-based chimeric capsids initially using enhanced green fluorescent protein (EGFP). The VLP assembly yield was efficient when we coexpressed EGFP-HT-VP2-466 and HT-VP2-466 from two recombinant baculoviruses. The native EGFP structure (~240 copies/virion) was successfully inserted in a functional form, as VLPs were fluorescent, and three dimensional cryo-electron microscopy showed that the EGFP molecules incorporated at the inner capsid surface. Immunization of mice with purified EGFP-VLPs elicited anti-EGFP antibodies. We also inserted hemagglutinin (HA) and matrix (M2) protein epitopes derived from the mouse-adapted A/PR/8/34 influenza virus and engineered several HA- and M2-derived chimeric capsids. Mice immunized with VLPs containing the HA stalk, an M2 fragment, or both antigens developed full protection against viral challenge. IMPORTANCE: Virus-like particles (VLPs) are multimeric protein cages that mimic the infectious virus capsid and are potential candidates as nonliving vaccines that induce long-lasting protection. Chimeric VLPs can display or include foreign antigens, which could be a conserved epitope to elicit broadly neutralizing antibodies or several variable epitopes effective against a large number of viral strains. We report the biochemical, structural, and immunological characterization of chimeric VLPs derived from infectious bursal disease virus (IBDV), an important poultry pathogen. To test the potential of IBDV VLPs as a vaccine vehicle, we used the enhanced green fluorescent protein and two fragments derived from the hemagglutinin and the M2 matrix protein of the human murine-adapted influenza virus. The IBDV capsid protein fused to influenza virus peptides formed assemblies able to protect mice against viral challenge. Our studies establish the basis for a new generation of multivalent IBDV-based vaccines. PMID- 25520500 TI - Severe acute respiratory syndrome-associated coronavirus vaccines formulated with delta inulin adjuvants provide enhanced protection while ameliorating lung eosinophilic immunopathology. AB - Although the severe acute respiratory syndrome-associated coronavirus (SARS-CoV) epidemic was controlled by nonvaccine measures, coronaviruses remain a major threat to human health. The design of optimal coronavirus vaccines therefore remains a priority. Such vaccines present major challenges: coronavirus immunity often wanes rapidly, individuals needing to be protected include the elderly, and vaccines may exacerbate rather than prevent coronavirus lung immunopathology. To address these issues, we compared in a murine model a range of recombinant spike protein or inactivated whole-virus vaccine candidates alone or adjuvanted with either alum, CpG, or Advax, a new delta inulin-based polysaccharide adjuvant. While all vaccines protected against lethal infection, addition of adjuvant significantly increased serum neutralizing-antibody titers and reduced lung virus titers on day 3 postchallenge. Whereas unadjuvanted or alum-formulated vaccines were associated with significantly increased lung eosinophilic immunopathology on day 6 postchallenge, this was not seen in mice immunized with vaccines formulated with delta inulin adjuvant. Protection against eosinophilic immunopathology by vaccines containing delta inulin adjuvants correlated better with enhanced T-cell gamma interferon (IFN-gamma) recall responses rather than reduced interleukin-4 (IL-4) responses, suggesting that immunopathology predominantly reflects an inadequate vaccine-induced Th1 response. This study highlights the critical importance for development of effective and safe coronavirus vaccines of selection of adjuvants based on the ability to induce durable IFN-gamma responses. IMPORTANCE: Coronaviruses such as SARS-CoV and Middle East respiratory syndrome-associated coronavirus (MERS-CoV) cause high case fatality rates and remain major human public health threats, creating a need for effective vaccines. While coronavirus antigens that induce protective neutralizing antibodies have been identified, coronavirus vaccines present a unique problem in that immunized individuals when infected by virus can develop lung eosinophilic pathology, a problem that is further exacerbated by the formulation of SARS-CoV vaccines with alum adjuvants. This study shows that formulation of SARS-CoV spike protein or inactivated whole-virus vaccines with novel delta inulin-based polysaccharide adjuvants enhances neutralizing-antibody titers and protection against clinical disease but at the same time also protects against development of lung eosinophilic immunopathology. It also shows that immunity achieved with delta inulin adjuvants is long-lived, thereby overcoming the natural tendency for rapidly waning coronavirus immunity. Thus, delta inulin adjuvants may offer a unique ability to develop safer and more effective coronavirus vaccines. PMID- 25520502 TI - LMP1 promotes expression of insulin-like growth factor 1 (IGF1) to selectively activate IGF1 receptor and drive cell proliferation. AB - Epstein-Barr Virus (EBV) is a gammaherpesvirus that infects the majority of the human population and is linked to the development of multiple cancers, including nasopharyngeal carcinoma. Latent membrane protein 1 (LMP1) is considered the primary oncoprotein of EBV, and in epithelial cells it induces the expression and activation, or phosphorylation, of the epidermal growth factor receptor kinase. To identify effects on additional kinases, an unbiased screen of receptor tyrosine kinases potentially activated by LMP1 was performed. Using a protein array, it was determined that LMP1 selectively activates insulin-like growth factor 1 receptor (IGF1R). This activation takes place in fibroblast, epithelial, and nasopharyngeal cell lines that express LMP1 stably and transiently. Of note, LMP1 altered the phosphorylation, but not the expression, of IGF1R. The use of LMP1 mutants with defective signaling domains revealed that the C-terminal activating region 2 domain of LMP1 increased the mRNA expression and the secretion of the ligand IGF1, which promoted phosphorylation of IGF1R. IGF1R phosphorylation was dependent upon activation of canonical NF-kappaB signaling and was suppressed by IkappaBalpha and a dominant negative form of TRAF6. Inhibition of IGF1R activation with two small-molecule inhibitors, AG1024 and picropodophyllin (PPP), or with short hairpin RNA (shRNA) directed against IGF1R selectively reduced proliferation, focus formation, and Akt activation in LMP1 positive cells but did not impair LMP1-induced cell migration. Expression of constitutively active Akt rescued cell proliferation in the presence of IGF1R inhibitors. These findings suggest that LMP1-mediated activation of IGF1R contributes to the ability of LMP1 to transform epithelial cells. IMPORTANCE: EBV is linked to the development of multiple cancers in both lymphoid and epithelial cells, including nasopharyngeal carcinoma. Nasopharyngeal carcinoma is a major cancer that develops in specific populations, with nearly 80,000 new cases reported annually. LMP1 is consistently expressed in early lesions and continues to be detected within 50 to 80% of these cancers at later stages. It is therefore of paramount importance to understand the mechanisms through which LMP1 alters cell growth and contributes to tumorigenesis. This study is the first to determine that LMP1 activates the IGF1R tyrosine kinase by regulating expression of the ligand IGF1. Additionally, the data in this paper reveal that specific targeting of IGF1R selectively impacts LMP1-positive cells. These findings suggest that therapies directed against IGF1R may specifically impair the growth of EBV-infected cells. PMID- 25520501 TI - Structure of an enteric pathogen, bovine parvovirus. AB - Bovine parvovirus (BPV), the causative agent of respiratory and gastrointestinal disease in cows, is the type member of the Bocaparvovirus genus of the Parvoviridae family. Toward efforts to obtain a template for the development of vaccines and small-molecule inhibitors for this pathogen, the structure of the BPV capsid, assembled from the major capsid viral protein 2 (VP2), was determined using X-ray crystallography as well as cryo-electron microscopy and three dimensional image reconstruction (cryo-reconstruction) to 3.2- and 8.8-A resolutions, respectively. The VP2 region ordered in the crystal structure, from residues 39 to 536, conserves the parvoviral eight-stranded jellyroll motif and an alphaA helix. The BPV capsid displays common parvovirus features: a channel at and depressions surrounding the 5-fold axes and protrusions surrounding the 3 fold axes. However, rather than a depression centered at the 2-fold axes, a raised surface loop divides this feature in BPV. Additional observed density in the capsid interior in the cryo-reconstructed map, compared to the crystal structure, is interpreted as 10 additional N-terminal residues, residues 29 to 38, that radially extend the channel under the 5-fold axis, as observed for human bocavirus 1 (HBoV1). Surface loops of various lengths and conformations extend from the core jellyroll motif of VP2. These loops confer the unique surface topology of the BPV capsid, making it strikingly different from HBoV1 as well as the type members of other Parvovirinae genera for which structures have been determined. For the type members, regions structurally analogous to those decorating the BPV capsid surface serve as determinants of receptor recognition, tissue and host tropism, pathogenicity, and antigenicity. IMPORTANCE: Bovine parvovirus (BPV), identified in the 1960s in diarrheic calves, is the type member of the Bocaparvovirus genus of the nonenveloped, single-stranded DNA (ssDNA) Parvoviridae family. The recent isolation of human bocaparvoviruses from children with severe respiratory and gastrointestinal infections has generated interest in understanding the life cycle and pathogenesis of these emerging viruses. We have determined the high-resolution structure of the BPV capsid assembled from its predominant capsid protein VP2, known to be involved in a myriad of functions during host cell entry, pathogenesis, and antigenicity for other members of the Parvovirinae. Our results show the conservation of the core secondary structural elements and the location of the N-terminal residues for the known bocaparvovirus capsid structures. However, surface loops with high variability in sequence and conformation give BPV a unique capsid surface topology. Similar analogous regions in other Parvovirinae type members are important as determinants of receptor recognition, tissue and host tropism, pathogenicity, and antigenicity. PMID- 25520503 TI - COMMD1/Murr1 reinforces HIV-1 latent infection through IkappaB-alpha stabilization. AB - The transcription factor NF-kappaB is important for HIV-1 transcription initiation in primary HIV-1 infection and reactivation in latently HIV-1-infected cells. However, comparative analysis of the regulation and function of NF-kappaB in latently HIV-1-infected cells has not been done. Here we show that the expression of IkappaB-alpha, an endogenous inhibitor of NF-kappaB, is enhanced by latent HIV-1 infection via induction of the host-derived factor COMMD1/Murr1 in myeloid cells but not in lymphoid cells by using four sets of latently HIV-1 infected cells and the respective parental cells. IkappaB-alpha protein was stabilized by COMMD1, which attenuated NF-kappaB signaling during Toll-like receptor ligand and tumor necrosis factor alpha treatment and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the phosphoinositol 3 kinase (PI3K)-JAK pathway is involved in COMMD1 induction in latently HIV-1 infected cells. Our findings indicate that COMMD1 induction is the NF-kappaB inhibition mechanism in latently HIV-1-infected cells that contributes to innate immune deficiency and reinforces HIV-1 latency. Thus, COMMD1 might be a double edged sword that is beneficial in primary infection but not beneficial in latent infection when HIV-1 eradication is considered. IMPORTANCE: HIV-1 latency is a major barrier to viral eradication in the era of combination antiretroviral therapy. In this study, we found that COMMD1/Murr1, previously identified as an HIV-1 restriction factor, inhibits the proteasomal degradation of IkappaB-alpha by increasing the interaction with IkappaB-alpha in latently HIV-1-infected myeloid cells. IkappaB-alpha protein was stabilized by COMMD1, which attenuated NF-kappaB signaling during the innate immune response and enhanced HIV-1 latency in latently HIV-1-infected cells. Activation of the PI3K-JAK pathway is involved in COMMD1 induction in latently HIV-1-infected cells. Thus, the host-derived factor COMMD1 is beneficial in suppressing primary infection but enhances latent infection, indicating that it may be a double-edged sword in HIV-1 eradication. PMID- 25520504 TI - Role of Cdk1 in the p53-independent abrogation of the postmitotic checkpoint by human papillomavirus E6. AB - Specific types of human papillomavirus (HPV) are strongly associated with the development of cervical carcinoma. The HPV E6 oncoprotein from HPV degrades p53 and abrogates cell cycle checkpoints. Nonetheless, functional p53 has been observed in cervical cancer. We have previously identified a p53-independent function of E6 in attenuating the postmitotic G1-like checkpoint that can lead to polyploidy, an early event during cervical carcinogenesis that predisposes cells to aneuploidy. How E6 promotes cell cycle progression in the presence of p53 and its target, p21, remains a mystery. In this study, we examined the expression of cell cycle-related genes in cells expressing wild-type E6 and the mutant that is defective in p53 degradation but competent in abrogating the postmitotic checkpoint. Our results demonstrated an increase in the steady-state levels of G1 and G2-related cyclins/Cdks in E6-expressing keratinocytes. Interestingly, only Cdk1 remained active in E6 mutant-expressing cells while bypassing the postmitotic checkpoint. Furthermore, the downregulation of Cdk1 impaired the ability of both wild-type and mutant E6 to induce polyploidy. Our study thus demonstrated an important role for Cdk1, which binds p21 with lower affinity than Cdk2, in abrogating the postmitotic checkpoint in E6-expressing cells. We further show that E2F1 is important for E6 to upregulate Cdk1. Moreover, reduced nuclear p21 localization was observed in the E6 mutant-expressing cells. These findings shed light on the mechanisms by which HPV induces genomic instability and hold promise for the identification of drug targets. IMPORTANCE: HPV infection is strongly associated with the development of cervical carcinoma. HPV encodes an E6 oncoprotein that degrades the tumor suppressor p53 and abrogates cell cycle checkpoints. Nonetheless, functional p53 has been observed in cervical cancer. We have recently demonstrated a p53-independent abrogation of the postmitotic checkpoint by HPV E6 that induces polyploidy. However, the mechanism is not known. In this study, we provide evidence that Cdk1 plays an important role in this process. Previously, Cdk2 was thought to be essential for the G1/S transition, while Cdk1 only compensated its function in the absence of Cdk2. Our studies have demonstrated a novel role of Cdk1 at the postmitotic G1-like checkpoint in the presence of Cdk2. These findings shed light on the mechanisms by which HPV induces genomic instability and hold promise for the identification of drug targets. PMID- 25520505 TI - Delayed inflammatory and cell death responses are associated with reduced pathogenicity in Lujo virus-infected cynomolgus macaques. AB - To identify host factors associated with arenavirus virulence, we used a cynomolgus macaque model to evaluate the pathogenesis of Lujo virus (LUJV), a recently emerged arenavirus that caused an outbreak of severe viral hemorrhagic fever in southern Africa. In contrast to human cases, LUJV caused mild, nonlethal illness in macaques. We then compared this to contrasting clinical outcomes during arenavirus infection, specifically to samples obtained from macaques infected with three highly pathogenic lines of Lassa virus (LASV), the causative agent of Lassa fever (LF). We assessed gene expression in peripheral blood mononuclear cells (PBMC) and determined genes that significantly changed expression relative to that in uninfected animals over the course of infection. We detected a 72-h delay in the induction of host responses to infection during LUJV infection compared to that of the animals infected with LASV. This included genes associated with inflammatory and antiviral responses and was particularly apparent among groups of genes promoting cell death. We also observed early differential expression of a subset of genes specific to LUJV infection that accounts for the delayed inflammatory response. Cell type enrichment analysis suggested that host response induction delay and an LUJV-specific profile are due to a different proportion of natural killer cells responding in LUJV infection than that in the LASV-infected animals. Together, these data indicate that delayed proinflammatory and proapoptotic host responses to arenavirus infection could ameliorate disease severity. This conclusion provides insight into the cellular and molecular mechanisms of arenaviral hemorrhagic fever and suggests potential strategies for therapeutic development. IMPORTANCE: Old World arenaviruses are significant human pathogens that often are associated with high mortality. However, mechanisms underlying disease severity and virulence in arenavirus hemorrhagic fever are largely unknown, particularly regarding host responses that contribute to pathogenicity. This study describes a comparison between Lujo and Lassa virus infection in cynomolgus macaques. Lujo virus infected macaques developed only mild illness, while Lassa virus-infected macaques developed severe illness consistent with Lassa fever. We determined that mild disease is associated with a delay in host expression of genes linked to virulence, such as those causing inflammation and cell death, and with distinct cell types that may mediate this delay. This is the first study to associate the timing and directionality of gene expression with arenaviral pathogenicity and disease outcome and evokes new potential approaches for developing effective therapeutics for treating these deadly emerging pathogens. PMID- 25520506 TI - Improving neutralization potency and breadth by combining broadly reactive HIV-1 antibodies targeting major neutralization epitopes. AB - The isolation of broadly neutralizing HIV-1 monoclonal antibodies (MAbs) to distinct epitopes on the viral envelope glycoprotein (Env) provides the potential to use combinations of MAbs for prevention and treatment of HIV-1 infection. Since many of these MAbs have been isolated in the last few years, the potency and breadth of MAb combinations have not been well characterized. In two parallel experiments, we examined the in vitro neutralizing activities of double-, triple , and quadruple-MAb combinations targeting four distinct epitopes, including the CD4-binding site, the V1V2-glycan region, the V3-glycan supersite, and the gp41 membrane-proximal external region (MPER), using a panel of 125 Env-pseudotyped viruses. All MAb combinations showed substantially improved neutralization breadth compared to the corresponding single MAbs, while the neutralization potency of individual MAbs was maintained. At a 50% inhibitory concentration (IC50) cutoff of 1 MUg/ml per antibody, double-MAb combinations neutralized 89 to 98% of viruses, and triple combinations neutralized 98 to 100%. Overall, the improvement of neutralization breadth was closely predicted by an additive-effect model and explained by complementary neutralization profiles of antibodies recognizing distinct epitopes. Subtle but consistent favorable interactions were observed in some MAb combinations, whereas less favorable interactions were observed on a small subset of viruses that are highly sensitive to V3-glycan MAbs. These data demonstrate favorable in vitro combinations of broadly neutralizing HIV-1 MAbs and suggest that such combinations could have utility for HIV-1 prevention and treatment. IMPORTANCE: Over the last 5 years, numerous broadly reactive HIV-1-neutralizing MAbs have been isolated from B cells of HIV-1 infected donors. Each of these MAbs binds to one of the major vulnerable sites (epitopes) on the surface of the viral envelope glycoprotein. Since antibodies to distinct viral epitopes could theoretically act together to provide greater potency and breadth of virus neutralization, we tested physical mixtures of double, triple, and quadruple combinations of neutralizing MAbs targeting four major epitopes on HIV-1 Env. When tested together, antibody combinations showed substantially improved neutralization breadth compared to single MAbs. This improvement could be explained by the complementary neutralization profiles of individual MAbs. We further demonstrated that each antibody maintained its full neutralization potency when used in combination with other MAbs. These data provide a rationale for clinical use of antibody-based combinations for HIV-1 prevention and therapy. PMID- 25520507 TI - A human herpesvirus 6A-encoded microRNA: role in viral lytic replication. AB - Human herpesvirus 6A (HHV-6A), a member of the betaherpesvirus family, is associated with several human diseases. Like all herpesviruses, HHV-6A establishes a lifelong, latent infection in its host. Reactivation of HHV-6A is frequent within the immunosuppressed and immunocompromised populations and results in lytic viral replication within multiple organs, often leading to severe disease. MicroRNAs (miRNAs) are key regulators of multiple cellular processes that regulate the translation of specific transcripts. miRNAs carried by herpesviruses play important roles in modulating the host cell, thereby facilitating a suitable environment for productive viral infection and/or latency. Currently, there are approximately 150 known human herpesvirus-encoded miRNAs, although an miRNA(s) encoded by HHV-6A has yet to be reported. We hypothesized that HHV-6A, like other members of the human herpesvirus family, encodes miRNAs, which function to promote viral infection. We utilized deep sequencing of small RNA species isolated from cells harboring HHV-6A to identify five novel small noncoding RNA species that originate from the viral genome, one of which has the characteristics of a viral miRNA. These RNAs are expressed during productive infection by either bacterial artificial chromosome (BAC) derived virus in Jjhan cells or wild-type HHV-6A strain U1102 virus in HSB2 cells and are associated with the RNA induced silencing complex (RISC) machinery. Growth analyses of mutant viruses that lack each individual miRNA revealed that a viral miRNA candidate (miR-U86) targets the HHV-6A IE gene U86, thereby regulating lytic replication. The identification and biological characterization of this HHV-6A-specific miRNA is the first step to defining how the virus regulates its life cycle. IMPORTANCE: A majority of the human population is infected with human herpesvirus 6A (HHV-6A), a betaherpesvirus family member. Infections usually occur in young children, and upon resolution, the virus remains in a latent state within the host. Importantly, during times of weakened immune responses, the virus can reactivate and is correlated with significant disease states. Viruses encode many different types of factors that both undermine the host antiviral response and regulate viral replication, including small RNA species called microRNAs (miRNAs). Here we report that HHV-6A encodes at least one miRNA, which we named miR-U86. We have characterized the requirement of this viral miRNA and its impact on the viral life cycle and found that it functions to regulate a viral protein important for efficient viral replication. Our data suggest that viral miRNAs are important for HHV-6A and that they may serve as an important therapeutic target to inhibit the virus. PMID- 25520508 TI - The stress granule protein G3BP1 recruits protein kinase R to promote multiple innate immune antiviral responses. AB - Stress granules (SGs) are cytoplasmic storage sites containing translationally silenced mRNPs that can be released to resume translation after stress subsides. We previously showed that poliovirus 3C proteinase cleaves the SG-nucleating protein G3BP1, blocking the ability of cells to form SGs late in infection. Many other viruses also target G3BP1 and inhibit SG formation, but the reasons why these functions evolved are unclear. Previously, we also showed a link between G3BP1-induced SGs and protein kinase R (PKR)-mediated translational control, but the mechanism of PKR interplay with SG and the antiviral consequences are unknown. Here, we show that G3BP1 exhibits antiviral activity against several enteroviruses, whereas truncated G3BP1 that cannot form SGs does not. G3BP1 induced SGs are linked to activation of innate immune transcriptional responses through NF-kappaB and JNK. The G3BP1-induced SGs also recruit PKR and other antiviral proteins. We show that the PXXP domain within G3BP1 is essential for the recruitment of PKR to SGs, for eIF2alpha phosphorylation driven by PKR, and for nucleating SGs of normal composition. We also show that deletion of the PXXP domain in G3BP1 compromises its antiviral activity. These findings tie PKR activation to its recruitment to SGs by G3BP1 and indicate that G3BP1 promotes innate immune responses at both the transcriptional and translational levels and integrates cellular stress responses and innate immunity. IMPORTANCE: Stress granules appear during virus infection, and their importance is not well understood. Previously, it was assumed that they were nonfunctional artifacts associated with cellular stress. PKR is a well-known antiviral protein; however, its regulation in cells is not well understood. Our work links cellular stress granules with activation of PKR and other innate immune pathways through the activity of G3BP1, a critical stress granule component. The ability of stress granules and G3BP1 to activate PKR and other innate immune transcriptional responses indicates that G3BP1 is an antiviral protein. This work helps to refine a longstanding paradigm indicating stress granules are inert structures and explains why G3BP1 is subverted by many viruses to promote a productive infection. PMID- 25520510 TI - Nanobody binding to a conserved epitope promotes norovirus particle disassembly. AB - Human noroviruses are icosahedral single-stranded RNA viruses. The capsid protein is divided into shell (S) and protruding (P) domains, which are connected by a flexible hinge region. There are numerous genetically and antigenically distinct noroviruses, and the dominant strains evolve every other year. Vaccine and antiviral development is hampered by the difficulties in growing human norovirus in cell culture and the continually evolving strains. Here, we show the X-ray crystal structures of human norovirus P domains in complex with two different nanobodies. One nanobody, Nano-85, was broadly reactive, while the other, Nano 25, was strain specific. We showed that both nanobodies bound to the lower region on the P domain and had nanomolar affinities. The Nano-85 binding site mainly comprised highly conserved amino acids among the genetically distinct genogroup II noroviruses. Several of the conserved residues also were recognized by a broadly reactive monoclonal antibody, which suggested this region contained a dominant epitope. Superposition of the P domain nanobody complex structures into a cryoelectron microscopy particle structure revealed that both nanobodies bound at occluded sites on the particles. The flexible hinge region, which contained ~10 to 12 amino acids, likely permitted a certain degree of P domain movement on the particles in order to accommodate the nanobodies. Interestingly, the Nano-85 binding interaction with intact particles caused the particles to disassemble in vitro. Altogether, these results suggested that the highly conserved Nano-85 binding epitope contained a trigger mechanism for particle disassembly. Principally, this epitope represents a potential site of norovirus vulnerability. IMPORTANCE: We characterized two different nanobodies (Nano-85 and Nano-25) that bind to human noroviruses. Both nanobodies bound with high affinities to the lower region of the P domain, which was occluded on intact particles. Nano-25 was specific for GII.10, whereas Nano-85 bound several different GII genotypes, including GII.4, GII.10, and GII.12. We showed that Nano-85 was able to detect norovirus virions in clinical stool specimens using a sandwich enzyme-linked immunosorbent assay. Importantly, we found that Nano-85 binding to intact particles caused the particles to disassemble. We believe that with further testing, Nano-85 not only will work as a diagnostic reagent in norovirus detection systems but also could function as a broadly reactive GII norovirus antiviral. PMID- 25520511 TI - Acanthamoeba polyphaga mimivirus prevents amoebal encystment-mediating serine proteinase expression and circumvents cell encystment. AB - Acanthamoeba is a genus of free-living amoebas distributed worldwide. Few studies have explored the interactions between these protozoa and their infecting giant virus, Acanthamoeba polyphaga mimivirus (APMV). Here we show that, once the amoebal encystment is triggered, trophozoites become significantly resistant to APMV. Otherwise, upon infection, APMV is able to interfere with the expression of a serine proteinase related to amoebal encystment and the encystment can no longer be triggered. PMID- 25520509 TI - Ataxia telangiectasia mutated kinase mediates NF-kappaB serine 276 phosphorylation and interferon expression via the IRF7-RIG-I amplification loop in paramyxovirus infection. AB - Respiratory syncytial virus (RSV) is a primary etiological agent of childhood lower respiratory tract disease. Molecular patterns induced by active infection trigger a coordinated retinoic acid-inducible gene I (RIG-I)-Toll-like receptor (TLR) signaling response to induce inflammatory cytokines and antiviral mucosal interferons. Recently, we discovered a nuclear oxidative stress-sensitive pathway mediated by the DNA damage response protein, ataxia telangiectasia mutated (ATM), in cytokine-induced NF-kappaB/RelA Ser 276 phosphorylation. Here we observe that ATM silencing results in enhanced single-strand RNA (ssRNA) replication of RSVand Sendai virus, due to decreased expression and secretion of type I and III interferons (IFNs), despite maintenance of IFN regulatory factor 3 (IRF3) dependent IFN-stimulated genes (ISGs). In addition to enhanced oxidative stress, RSV replication enhances foci of phosphorylated histone 2AX variant (gammaH2AX), Ser 1981 phosphorylation of ATM, and IKKgamma/NEMO-dependent ATM nuclear export, indicating activation of the DNA damage response. ATM-deficient cells show defective RSV-induced mitogen and stress-activated kinase 1 (MSK-1) Ser 376 phosphorylation and reduced RelA Ser 276 phosphorylation, whose formation is required for IRF7 expression. We observe that RelA inducibly binds the native IFN regulatory factor 7 (IRF7) promoter in an ATM-dependent manner, and IRF7 inducibly binds to the endogenous retinoic acid-inducible gene I (RIG-I) promoter. Ectopic IRF7 expression restores RIG-I expression and type I/III IFN expression in ATM-silenced cells. We conclude that paramyxoviruses trigger the DNA damage response, a pathway required for MSK1 activation of phospho Ser 276 RelA formation to trigger the IRF7-RIG-I amplification loop necessary for mucosal IFN production. These data provide the molecular pathogenesis for defects in the cellular innate immunity of patients with homozygous ATM mutations. IMPORTANCE: RNA virus infections trigger cellular response pathways to limit spread to adjacent tissues. This "innate immune response" is mediated by germ line-encoded pattern recognition receptors that trigger activation of two, largely independent, intracellular NF-kappaB and IRF3 transcription factors. Downstream, expression of protective antiviral interferons is amplified by positive-feedback loops mediated by inducible interferon regulatory factors (IRFs) and retinoic acid inducible gene (RIG-I). Our results indicate that a nuclear oxidative stress and DNA damage-sensing factor, ATM, is required to mediate a cross talk pathway between NF-kappaB and IRF7 through mediating phosphorylation of NF-kappaB. Our studies provide further information about the defects in cellular and innate immunity in patients with inherited ATM mutations. PMID- 25520512 TI - Modified vaccinia virus Ankara-infected dendritic cells present CD4+ T-cell epitopes by endogenous major histocompatibility complex class II presentation pathways. AB - CD4(+) T lymphocytes play a central role in the immune system and mediate their function after recognition of their respective antigens presented on major histocompatibility complex II (MHCII) molecules on antigen-presenting cells (APCs). Conventionally, phagocytosed antigens are loaded on MHCII for stimulation of CD4(+) T cells. Certain epitopes, however, can be processed directly from intracellular antigens and are presented on MHCII (endogenous MHCII presentation). Here we characterized the MHCII antigen presentation pathways that are possibly involved in the immune response upon vaccination with modified vaccinia virus Ankara (MVA), a promising live viral vaccine vector. We established CD4(+) T-cell lines specific for MVA-derived epitopes as tools for in vitro analysis of MHCII antigen processing and presentation in MVA-infected APCs. We provide evidence that infected APCs are able to directly transfer endogenous viral proteins into the MHCII pathway to efficiently activate CD4(+) T cells. By using knockout mice and chemical inhibitory compounds, we further elucidated the molecular basis, showing that among the various subcellular pathways investigated, proteasomes and autophagy are key players in the endogenous MHCII presentation during MVA infection. Interestingly, although proteasomal processing plays an important role, neither TAP nor LAMP-2 was found to be involved in the peptide transport. Defining the molecular mechanism of MHCII presentation during MVA infection provides a basis for improving MVA-based vaccination strategies by aiming for enhanced CD4(+) T-cell activation by directing antigens into the responsible pathways. IMPORTANCE: This work contributes significantly to our understanding of the immunogenic properties of pathogens by deciphering antigen processing pathways contributing to efficient activation of antigen-specific CD4(+) T cells. We identified autophagosome formation, proteasomal activity, and lysosomal integrity as being crucial for endogenous CD4(+) T-cell activation. Since poxvirus vectors such as MVA are already used in clinical trials as recombinant vaccines, the data provide important information for the future design of optimized poxviral vaccines for the study of advanced immunotherapy options. PMID- 25520513 TI - Inhibition of reactive oxygen species production ameliorates inflammation induced by influenza A viruses via upregulation of SOCS1 and SOCS3. AB - Highly pathogenic avian influenza virus infection is associated with severe mortality in both humans and poultry. The mechanisms of disease pathogenesis and immunity are poorly understood although recent evidence suggests that cytokine/chemokine dysregulation contributes to disease severity following H5N1 infection. Influenza A virus infection causes a rapid influx of inflammatory cells, resulting in increased reactive oxygen species production, cytokine expression, and acute lung injury. Proinflammatory stimuli are known to induce intracellular reactive oxygen species by activating NADPH oxidase activity. We therefore hypothesized that inhibition of this activity would restore host cytokine homeostasis following avian influenza virus infection. A panel of airway epithelial and immune cells from mammalian and avian species were infected with A/Puerto Rico/8/1934 H1N1 virus, low-pathogenicity avian influenza H5N3 virus (A/duck/Victoria/0305-2/2012), highly pathogenic avian influenza H5N1 virus (A/chicken/Vietnam/0008/2004), or low-pathogenicity avian influenza H7N9 virus (A/Anhui/1/2013). Quantitative real-time reverse transcriptase PCR showed that H5N1 and H7N9 viruses significantly stimulated cytokine (interleukin-6, beta interferon, CXCL10, and CCL5) production. Among the influenza-induced cytokines, CCL5 was identified as a potential marker for overactive immunity. Apocynin, a Nox2 inhibitor, inhibited influenza-induced cytokines and reactive oxygen species production, although viral replication was not significantly altered in vitro. Interestingly, apocynin treatment significantly increased influenza virus-induced mRNA and protein expression of SOCS1 and SOCS3, enhancing negative regulation of cytokine signaling. These findings suggest that apocynin or its derivatives (targeting host responses) could be used in combination with antiviral strategies (targeting viruses) as therapeutic agents to ameliorate disease severity in susceptible species. IMPORTANCE: Highly pathogenic avian influenza virus infection causes severe morbidity and mortality in both humans and poultry. Wide spread antiviral resistance necessitates the need for the development of additional novel therapeutic measures to modulate overactive host immune responses after infection. Disease severity following avian influenza virus infection can be attributed in part to hyperinduction of inflammatory mediators such as cytokines, chemokines, and reactive oxygen species. Our study shows that highly pathogenic avian influenza H5N1 virus and low-pathogenicity avian influenza H7N9 virus (both associated with human fatalities) promote inactivation of FoxO3 and downregulation of the TAM receptor tyrosine kinase, Tyro3, leading to augmentation of the inflammatory cytokine response. Inhibition of influenza induced reactive oxygen species with apocynin activated FoxO3 and stimulated SOCS1 and SOCS3 proteins, restoring cytokine homeostasis. We conclude that modulation of host immune responses with antioxidant and/or anti-inflammatory agents in combination with antiviral therapy may have important therapeutic benefits. PMID- 25520516 TI - ONE SIZE FITS ALL? ON PATIENT AUTONOMY, MEDICAL DECISION-MAKING, AND THE IMPACT OF CULTURE. AB - While both medical law and medical ethics have developed in a way that has sought to prioritise patient autonomy, it is less clear whether it has done so in a way that enhances the self-determination of patients from non-western backgrounds. In this article, we consider the desire of some patients from non-western backgrounds for family involvement in decision-making and argue that this desire is not catered for effectively in either medical law or medical ethics. We examine an alternative approach based on relational autonomy that might serve both to allow such patients to exercise their self-determination while still allowing them to include family members in the decision-making process. PMID- 25520514 TI - Clustered microRNAs of the Epstein-Barr virus cooperatively downregulate an epithelial cell-specific metastasis suppressor. AB - The Epstein-Barr virus (EBV) encodes its own microRNAs (miRNAs); however, their biological roles remain elusive. The commonly used EBV B95-8 strain lacks a 12-kb genomic region, known as BamHI A rightward transcripts (BART) locus, where a number of BART miRNAs are encoded. Here, bacterial artificial chromosome (BAC) technology was used to generate an EBV B95-8 strain in which the 12-kb region was fully restored at its native locus [BART(+) virus]. Epithelial cells were stably infected with either the parental B95-8 virus or the BART(+) virus, and BART miRNA expression was successfully reconstituted in the BART(+) virus-infected cells. Microarray analyses of cellular gene expression identified N-myc downstream regulated gene 1 (NDRG1) as a putative target of BART miRNAs. The NDRG1 protein was barely expressed in B cells, highly expressed in epithelial cells, including primary epithelial cells, and strongly downregulated in the BART(+) virus-infected epithelial cells of various origins. Although in vitro reporter assays identified BART22 as being responsible for the NDRG1 downregulation, EBV genetic analyses revealed that BART22 was not solely responsible; rather, the entire BART miRNA cluster 2 was responsible for the downregulation. Immunohistochemical analyses revealed that the expression level of the NDRG1 protein was downregulated significantly in EBV-positive nasopharyngeal carcinoma specimens. Considering that NDRG1 encodes an epithelial differentiation marker and a suppressor of metastasis, these data implicate a causative relationship between BART miRNA expression and epithelial carcinogenesis in vivo. IMPORTANCE: EBV-related epithelial cancers, such as nasopharyngeal carcinomas and EBV-positive gastric cancers, encompass more than 80% of EBV-related malignancies. Although it is known that they express high levels of virally encoded BART miRNAs, how these miRNAs contribute to EBV mediated epithelial carcinogenesis remains unknown. Although a number of screenings have been performed to identify targets of viral miRNAs, many targets likely have not been identified, especially in case of epithelial cell infection. This is the first study to use EBV genetics to perform unbiased screens of cellular genes that are differentially expressed in viral miRNA-positive and negative epithelial cells. The result indicates that multiple EBV-encoded miRNAs cooperatively downregulate NDRG1, an epithelial differentiation marker and suppressor of metastasis. The experimental system described in this study should be useful for further clarifying the mechanism of EBV-mediated epithelial carcinogenesis. PMID- 25520515 TI - Measles virus mutants possessing the fusion protein with enhanced fusion activity spread effectively in neuronal cells, but not in other cells, without causing strong cytopathology. AB - Subacute sclerosing panencephalitis (SSPE) is caused by persistent measles virus (MV) infection in the central nervous system (CNS). Since human neurons, its main target cells, do not express known MV receptors (signaling lymphocyte activation molecule [SLAM] and nectin 4), it remains to be understood how MV infects and spreads in them. We have recently reported that fusion-enhancing substitutions in the extracellular domain of the MV fusion (F) protein (T461I and S103I/N462S/N465S), which are found in multiple SSPE virus isolates, promote MV spread in human neuroblastoma cell lines and brains of suckling hamsters. In this study, we show that hyperfusogenic viruses with these substitutions also spread efficiently in human primary neuron cultures without inducing syncytia. These substitutions were found to destabilize the prefusion conformation of the F protein trimer, thereby enhancing fusion activity. However, these hyperfusogenic viruses exhibited stronger cytopathology and produced lower titers at later time points in SLAM- or nectin 4-expressing cells compared to the wild-type MV. Although these viruses spread efficiently in the brains of SLAM knock-in mice, they did not in the spleens. Taken together, the results suggest that enhanced fusion activity is beneficial for MV to spread in neuronal cells where no cytopathology occurs, but detrimental to other types of cells due to strong cytopathology. Acquisition of enhanced fusion activity through substitutions in the extracellular domain of the F protein may be crucial for MV's extensive spread in the CNS and development of SSPE. IMPORTANCE: Subacute sclerosing panencephalitis (SSPE) is a fatal disease caused by persistent measles virus (MV) infection in the central nervous system (CNS). Its cause is not well understood, and no effective therapy is currently available. Recently, we have reported that enhanced fusion activity of MV through the mutations in its fusion protein is a major determinant of efficient virus spread in human neuronal cells and brains of suckling hamsters. In this study, we show that those mutations render the conformation of the fusion protein less stable, thereby making it hyperfusogenic. Our results also show that enhanced fusion activity is beneficial for MV to spread in the CNS but detrimental to other types of cells in peripheral tissues, which are strongly damaged by the virus. Our findings provide important insight into the mechanism for the development of SSPE after MV infection. PMID- 25520518 TI - MicroRNA regulation of vascular smooth muscle function and phenotype: early career committee contribution. PMID- 25520519 TI - Long noncoding RNA-MicroRNA pathway controlling nuclear factor IA, a novel atherosclerosis modifier gene. PMID- 25520520 TI - Conflicting forces of warfarin and matrix gla protein in the artery wall. PMID- 25520522 TI - Regulation of endothelial cell metabolism: just go with the flow. PMID- 25520521 TI - Accelerating the pace of atherosclerosis research. PMID- 25520525 TI - "Low-Income Men and Fathers' Influences on Children?" PMID- 25520526 TI - How Do Small Things Make a Big Difference? Activities to Teach about Human Microbe Interactions. AB - Recent scientific studies are providing increasing evidence for how microbes living in and on us are essential to our good health. However, many students still think of microbes only as germs that harm us. The classroom activities presented here are designed to shift student thinking on this topic. In these guided inquiry activities, students investigate human-microbe interactions as they work together to interpret and analyze authentic data from published articles and develop scientific models. Through the activities, students learn and apply ecological concepts as they come to see the human body as a fascinatingly complex ecosystem. PMID- 25520528 TI - Cracking the Dual Code: Toward a Unitary Model of Phoneme Identification. AB - The results of five experiments on the nature of the speech code and on the role of sentence context on speech processing are reported. The first three studies test predictions from the dual code model of phoneme identification (Foss, D. J., & Blank, M. A. Cognitive Psychology, 1980, 12, 1-31). According to that model, subjects in a phoneme monitoring experiment respond to a prelexical code when engaged in a relatively easy task, and to a postlexical code when the task is difficult. The experiments controlled ease of processing either by giving subjects multiple targets for which to monitor or by preceding the target with a similar-sounding phoneme that draws false alarms. The predictions from the model were not sustained. Furthermore, evidence for a paradoxical nonword superiority effect was observed. In Experiment IV reaction times (RTs) to all possible /d/ initial CVCs were gathered. RTs were unaffected by the target item's status as a word or nonword. but they were affected by the internal phonetic structure of the target-bearing item. Vowel duration correlated highly (0.627) with RTs. Experiment V examined previous work purporting to demonstrate that semantic predictability affects how the speech code is processed, in particular that semantic predictability leads to responses based upon a postlexical code. That study found "predictability" effects when words occurred in isolation; further, it found that vowel duration and other phonetic factors can account parsimoniously for the existing results. These factors also account for the apparent nonword superiority effects observed earlier. Implications of the present work for theoretical models that stress the interaction between semantic context and speech processing are discussed, as are implications for use of the phoneme monitoring task. PMID- 25520529 TI - DETERMINANTS OF NETWORK OUTCOMES: THE IMPACT OF MANAGEMENT STRATEGIES. AB - The literature on network management is extensive. However, it generally explores network structures, neglecting the impact of management strategies. In this article we assess the effect of management strategies on network outcomes, providing empirical evidence from 119 urban revitalization networks. We go beyond current work by testing a path model for the determinants of network outcomes and considering the interactions between the constructs: management strategies, trust, complexity, and facilitative leadership. Our results suggest that management strategies have a strong effect on network outcomes and that they enhance the level of trust. We also found that facilitative leadership has a positive impact on network management as well as on trust in the network. Our findings also show that complexity has a negative impact on trust. A key finding of our research is that managers may wield more influence on network dynamics than previously theorized. PMID- 25520527 TI - Microbial community composition explains soil respiration responses to changing carbon inputs along an Andes-to-Amazon elevation gradient. AB - 1. The Andes are predicted to warm by 3-5 degrees C this century with the potential to alter the processes regulating carbon (C) cycling in these tropical forest soils. This rapid warming is expected to stimulate soil microbial respiration and change plant species distributions, thereby affecting the quantity and quality of C inputs to the soil and influencing the quantity of soil derived CO2 released to the atmosphere. 2. We studied tropical lowland, premontane and montane forest soils taken from along a 3200-m elevation gradient located in south-east Andean Peru. We determined how soil microbial communities and abiotic soil properties differed with elevation. We then examined how these differences in microbial composition and soil abiotic properties affected soil C cycling processes, by amending soils with C substrates varying in complexity and measuring soil heterotrophic respiration (RH). 3. Our results show that there were consistent patterns of change in soil biotic and abiotic properties with elevation. Microbial biomass and the abundance of fungi relative to bacteria increased significantly with elevation, and these differences in microbial community composition were strongly correlated with greater soil C content and C:N (nitrogen) ratios. We also found that RH increased with added C substrate quality and quantity and was positively related to microbial biomass and fungal abundance. 4. Statistical modelling revealed that RH responses to changing C inputs were best predicted by soil pH and microbial community composition, with the abundance of fungi relative to bacteria, and abundance of gram-positive relative to gram-negative bacteria explaining much of the model variance. 5. Synthesis. Our results show that the relative abundance of microbial functional groups is an important determinant of RH responses to changing C inputs along an extensive tropical elevation gradient in Andean Peru. Although we do not make an experimental test of the effects of climate change on soil, these results challenge the assumption that different soil microbial communities will be 'functionally equivalent' as climate change progresses, and they emphasize the need for better ecological metrics of soil microbial communities to help predict C cycle responses to climate change in tropical biomes. PMID- 25520530 TI - In Search of Complete Comprehension: Getting "Minimalists" to Work. AB - Three experiments illustrated that readers will not completely comprehend the sentences they read unless sufficiently motivated by situational demands. Complete comprehension of a topic is defined as the ability to accurately redescribe that topic in one's own words, and it entails three separate yet interdependent processing tasks: (a) activating the information contained in a topic, (b) resolving the topic as a new topic or as an anaphor referring to an old topic, and (c) modifying one's mental structures to organize the additional information that is received. Each process hinges on the outcome of those that preceded it, and comprehenders are not expected to initiate the next process in the sequence unless it is required or motivated by task demands. To test these predictions, three experiments were conducted in which participants were prompted to engage in one, two, or all three comprehension processes after reading two clause conjunctive sentences. The results suggested that experimental participants had a strategy of minimal task satisfaction: They did not resolve anaphors, build structures, or draw inferences unless it was necessary for completion of the experiment. PMID- 25520531 TI - Spatial Situation Models and Text Comprehension. AB - Three experiments examined how readers inferred spatial information that was relevant to a story character's movements through a previously memorized layout of a fictional building relative to various tasks. This study also examined how inference measures were related to spatial imagery and reading comprehension ability. Replicating the spatial separation effect reported by Morrow, Greenspan, and Bower (1987), probed objects were responded to faster when they were located in the same room of a building as the main character of a narrative than when the objects were located in different rooms. Experiment 2 ruled out a simple name based priming explanation of the spatial separation effect, and Experiment 3 demonstrated a facilitation for objects from the character's target room even when readers were provided with a spatially indeterminate list description of the building. The construction-integration model of text comprehension accounted for the spatial separation effect in terms of variations in the knowledge-integration process. It was concluded that the integration of an enriched knowledge network can facilitate the process of mapping text information onto a developing mental representation of a discourse situation, a process that gains further support from spatial imagery and reading comprehension ability. PMID- 25520532 TI - Suppression of Story Character Goals During Reading. AB - The objective of this study was to determine how readers process narrative texts when the main character has multiple, and changing, goals. Readers must keep track of such goals to understand the causal relations between text events, an important process for comprehension. The structure building framework theory of reading proposes that readers maintain the most relevant goal in focus using the mechanism of suppression. The results of this study confirm that readers maintain the activation of goal information that is rementioned in a text and suppress previous goal information when a new goal is introduced. Thus, in an attempt to understand the causal relations between events in a text, readers keep track of multiple story character goals by using suppression. PMID- 25520533 TI - Accessibility in Text and Discourse Processing. AB - Accessibility is one of the most important challenges at the intersection of linguistic and psycholinguistic studies of text and discourse processing. Linguists have shown how linguistic indicators of referential coherence show a systematic pattern: Longer linguistic forms (like full lexical NPs) tend to be used when referents are relatively low accessible, shorter forms (pronouns and zero anaphora) are used when referents are highly accessible. This linguistic theory fits in nicely with a dynamic view of text and discourse processing: When a reader proceeds through a text, the activation of concepts as part of the reader's representation fluctuates constantly. Hypotheses considering activation patterns can be tested with on-line research methods like reading time or eye movement recording. The articles in this special issue show how accessibility phenomena need to be studied from a linguistic and a psycholinguistic angle, and in the latter case from interpretation as well as production. PMID- 25520534 TI - Managing Mental Representations During Narrative Comprehension. AB - Three experiments investigated how readers manage their mental representations during narrative comprehension. The first experiment investigated whether readers' access to their mental representations of the main character in a narrative becomes enhanced (producing a "benefit") when the character is rementioned; the first experiment also investigated whether readers' access to the main character in a narrative becomes weakened or interfered with (producing a "cost") when a new character is introduced. The purpose of the second experiment was to ensure that there was nothing unusually salient about the accessibility of names; thus, we assessed readers' access to an object associated with the main character rather than the character's name. Again, readers demonstrated increased accessibility to the main character when it was rementioned in the narrative, and readers demonstrated reduced accessibility to the main character when a new character was introduced. A third experiment compared more-skilled and less-skilled readers' abilities to manage these mental representations during narrative comprehension. Findings were consistent with research suggesting that more-skilled readers are more skilled at attenuating interfering information (i.e., suppression). Data from all 3 experiments suggest that successful narrative comprehension involves managing mental representations of salient and often times interfering characters. PMID- 25520535 TI - Improving Written Communication Through Minimal Feedback. AB - We propose that writers must form accurate representations of how their readers will interpret their texts to convey their ideas successfully. In two experiments, we investigated whether getting feedback from their readers helps writers form better representations of how their texts are interpreted. In our first experiment, one group of subjects (writers) wrote descriptions of a set of geometric figures; another group of subjects (readers) read those descriptions and used them to select the figures from sets of similar looking distractor figures. Half the writers received feedback on how well their readers selected the figures, and half the writers did not receive this feedback. Those writers who received feedback improved their descriptions more than those writers who did not receive feedback. In our second experiment, half the writers received two treatments of feedback on their descriptions of one set of figures, whereas the other half of the writers did not receive feedback. Then, all the writers described a new set of figures. Those writers who had previously received feedback wrote better new descriptions than did those writers who had never received feedback. We concluded that feedback - even this minimal form of feedback - helps writers to envision how readers interpret their texts. PMID- 25520536 TI - How Natural are Conceptual Anaphors? AB - This paper reports three experiments on the interpretation of "conceptual" anaphors. These are anaphors that do not have an explicit linguistic antecedent, but one constructed from context. For instance, if one says "I need a knife. Where do you keep them?", them means something like "the knives that I presume you have in your house". In the first experiment, subjects rated sentences containing conceptual anaphors, of three different types, to be as natural as ones with a "linguistically correct" antecedent (e.g. "I need an iron. Where do you keep it?"), and as more natural than ones with neither a plausible conceptual antecedent nor a plausible linguistic one. In a second (self-paced) experiment, subjects judged whether the second sentence in such pairs was a sensible continuation from the first, and the time to make these judgements was measured. We found that acceptability judgements were high, and judgement times low, in just those sentences that were rated as more natural in the first experiment. These first two experiments showed that conceptual anaphors are quite easily understood. However, they did not show that such anaphors are processed without difficulty. In the third experiment, we therefore compared conceptual anaphors ("plate ... them") with matched plural anaphors whose antecedents were explicit ("some plates ... them"). The results were different for different types of anaphor: in one case (pronouns that referred to collective sets), the conceptual version followed by a plural pronoun was easier than the explicit plural version. For the other two types (references to generics and to implied multiple items), the explicit plurals were understood more rapidly than their conceptual counterparts. PMID- 25520537 TI - Knowledge Activation Versus Sentence Mapping when Representing Fictional Characters' Emotional States. AB - We investigated the role that knowledge activation and sentence mapping play in how readers represent fictional characters' emotional states. The subjects read stories that described concrete actions, such as a main character stealing money from a store where his best friend worked and later learning that his friend had been fired. By manipulating the content of the stories (i.e. writing stories that implied different emotional states), we affected what emotional knowledge would be activated. Following each story, the subjects read a target sentence that contained an emotion word. By manipulating the emotion word in each target sentence (i.e. whether it matched vs mismatched the emotional state implied by the story), we affected how easily subjects could map the target sentence onto their developing mental structures. In Experiment 1, we further isolated the role of knowledge activation from the role of sentence mapping with a density manipulation. When the subjects read many emotional stories, they more widely activated their knowledge of emotional states. Using a proportionality manipulation in Experiment 2, we demonstrated that this result was not due to the subjects' strategies. PMID- 25520539 TI - COGNITIVE FOUNDATIONS OF SECOND LANGUAGE ACQUISITION. PMID- 25520538 TI - Prevalence and predictors of emotional and behavioral problems reported by teachers among institutionally reared children and adolescents in Turkish orphanages compared with community controls. AB - We examined the prevalence of emotional and behavioral problems and associated risk and protective factors among children and adolescents ages 6 to 18 years reared in orphanages in Turkey (n = 461, 87.9% of all eligible subjects) compared with a nationally representative community sample of similarly-aged youngsters brought up by their own families (n = 2280). Using the 90th percentile as the cut off criterion, it was found that the Teacher's Report Form (TRF) Total Problem score was higher for children and adolescents in orphanage care than in the community (23.2%, orphanage v. 11%, community). Multiple regression models explained 73% of the total variance of TRF Total Problems score for children and adolescents in orphanages. Regular contact with parents or relatives, between classroom teachers and orphanage staff, appropriate task involvement, perceived social support and competency were significant protective factors against emotional and behavioral problems. Younger age at first admission, being small for age, and feelings of stigmatization were associated with higher TRF Problem Scores (P<.05). Parental psychiatric disorder was unrelated to emotional and behavioral problems in children reflecting that psychosocial adversity and parenting problems in of themselves lead to institutionalization, irrespective of identifiable parental mental disorder. The findings are interpreted in the light of an urgent need for development of early intervention programs that promote community care of children by preventing separation from families, provision of support services for families in need, and development of counseling programs to prevent abandonment, abuse and neglect. Finding ways for child welfare professionals to collaborate more closely with early intervention programs would also increase the viable opportunities and rights of children and adolescents currently cared for in the system. Finally, alternative cost-effective care models need to be promoted including foster care or adoption systems and family based homes in the community. PMID- 25520540 TI - The role of suppression in figurative language comprehension. AB - In this paper, we describe the crucial role that suppression plays in many aspects of language comprehension. We define suppression as a general, cognitive mechanism, the purpose of which is to attenuate the interference caused by the activation of extraneous, unnecessary, or inappropriate information. We illustrate the crucial role that suppression plays in general comprehension by reviewing numerous experiments. These experiments demonstrate that suppression attenuates interference during lexical access (how word meanings are 'accessed'), anaphoric reference (how referents for anaphors, like pronouns, are computed), cataphoric reference (how concepts that are marked by devices, such as spoken stress, gain a privileged status), syntactic parsing (how grammatical forms of sentences are decoded), and individual differences in (adult) language comprehension skill. We also review research that suggests that suppression plays a crucial role in the understanding of figurative language, in particular, metaphors, idioms, and proverbs. PMID- 25520541 TI - Accessing Sentence Participants: The Advantage of First Mention. AB - We investigate the following finding concerning the order in which participants are mentioned in sentences: In a probe recognition task, probe words are responded to considerably more rapidly when they are the names of the first- as opposed to the second-mentioned participants. Seven experiments demonstrated that this advantage is not attributable to the tendency in English for first-mentioned participants to be semantic agents; neither is it due to the fact that in many of our experiments, the first-mentioned participants were also the initial words of their stimulus sentences. Furthermore, the advantage is not attenuated when the first- and second-mentioned participants share syntactic subjecthood, or even when the first-mentioned participants are not the syntactic subjects. In sum, the effect does not appear to be attributable to linguistic factors. We suggest instead that it is the result of cognitive processes: Building a coherent mental representation requires first laying a foundation and then mapping subsequent information onto the developing representation. First-mentioned participants are more accessible because they form the foundations for their sentence. Level representations and because it is through them that subsequent information gets mapped onto the developing representations. PMID- 25520542 TI - Low-income minority mothers' and fathers' reading and children's interest: Longitudinal contributions to children's receptive vocabulary skills. AB - Using data from a diverse sample of low-income African American and Latino mothers, fathers, and their young children who participated in Early Head Start (n = 61), the current study explored the association between parents' reading quality (i.e. metalingual talk) while reading with their 2-year-old children and their children's receptive vocabulary skills at pre-kindergarten. It further examined whether children's interest in reading mediated this association. There were three main findings. First, most mothers and fathers in our sample read relatively often to their children (a few times a week) and used some metalingual talk; fathers used more than mothers. Second, controlling for parental education, mothers' and fathers' early reading quality significantly predicted children's receptive vocabulary skills at pre-kindergarten. Third, children's interest in reading mediated the association between mothers' and fathers' reading quality and children's receptive vocabulary scores. These findings have important implications for programs aimed at fostering low-income children's vocabularies and suggest that both mothers and fathers need to be included in programs. PMID- 25520543 TI - Non-Iterative Reconstruction with a Prior for Undersampled Radial MRI Data. AB - This paper develops an FBP-MAP (Filtered Backprojection, Maximum a Posteriori) algorithm to reconstruct MRI images from under-sampled data. An objective function is first set up for the MRI reconstruction problem with a data fidelity term and a Bayesian term. The Bayesian term is a constraint in the temporal dimension. This objective function is minimized using the calculus of variations. The proposed algorithm is non-iterative. Undersampled dynamic myocardial perfusion MRI data were used to test the feasibility of the proposed technique. It is shown that the non-iterative Fourier reconstruction method effectively incorporates the temporal constraint and significantly reduces the angular aliasing artifacts caused by undersampling. A significant advantage of the proposed non-iterative Fourier technique over the iterative techniques is its fast computation time. PMID- 25520544 TI - One-angle fluorescence tomography with in-and-out motion. AB - The usual tomography is achieved by acquiring measurements around an object with multiple angles. The possibility of obtaining a fluorescence tomographic image from measurements at only one angle is explored. Instead of rotating around the object, the camera (or the objective lens) moves toward (or away from) the object and takes photographs while the camera's focal plane passes through the object. The volume of stacked two-dimensional pictures forms a blurred three-dimensional image. The true image can be obtained by deconvolving the system's point spread function. Simplified computer simulations are carried out to verify the feasibility of the proposed method. The computer simulations indicate that it is feasible to obtain a tomographic image by using the in-and-out motion to acquire data. PMID- 25520545 TI - Going beyond 2D: Following membrane diffusion and topography in the IgE Fc[Epsilon]RI system using 3-dimensional tracking microscopy. AB - The ability to follow and observe single molecules as they function in live cells represents a major milestone for molecular-cellular biology. Here we present a tracking microscope that is able to track quantum dots in three dimensions and simultaneously record time-resolved emission statistics from a single dot. This innovative microscopy approach is based on four spatial filters and closed loop feedback to constantly keep a single quantum dot in the focal spot. Using this microscope, we demonstrate the ability to follow quantum dot labeled IgE antibodies bound to FcepsilonRI membrane receptors in live RBL-2H3 cells. The results are consistent with prior studies of two dimensional membrane diffusion (Andrews et al., Nat. Cell Biol., 10, 955, 2008). In addition, the microscope captures motion in the axial (Z) direction, which permits tracking of diffusing receptors relative to the "hills and valleys" of the dynamically changing membrane landscape. This approach is uniquely capable of following single molecule dynamics on live cells with three dimensional spatial resolution. PMID- 25520546 TI - Infantilizing Autism. AB - When members of the public envision the disability of autism, they most likely envision a child, rather than an adult. In this empirically based essay, three authors, one of whom is an autistic self-advocate, analyzed the role played by parents, charitable organizations, the popular media, and the news industry in infantilizing autism. Parents portrayed the face of autism to be that of a child 95% of the time on the homepages of regional and local support organizations. Nine of the top 12 autism charitable organizations restricted descriptions of autism to child-referential discourse. Characters depicted as autistic were children in 90% of fictional books and 68% of narrative films and television programs. The news industry featured autistic children four times as often as they featured autistic adults in contemporary news articles. The cyclical interaction between parent-driven autism societies, autism fundraising charities, popular media, and contemporary news silences adult self-advocates by denying their very existence. Society's overwhelming proclivity for depicting autism as a disability of childhood poses a formidable barrier to the dignity and well-being of autistic people of all ages. PMID- 25520547 TI - On Not Being Human. PMID- 25520548 TI - Care at the Crossroads: Navigating the HIV, HCV, and Substance Abuse Syndemic. AB - For patients with both HIV/HCV coinfection and substance addiction, multidisciplinary teams can facilitate coordination of care and improve clinical outcomes. Such teams should include HIV/HCV treatment providers, mental health specialists, case managers, social workers, and substance abuse counselors. PMID- 25520549 TI - How Automatically Do Readers Infer Fictional Characters' Emotional States? AB - We propose that reading stories, such as a narrative about a character who takes money from a store where his best friend works and who later learns that his best friend has been fired, stimulates readers to activate the knowledge of how the character feels when he finds out that his best friend has been fired from a job for something he did. In other words, we propose that readers infer fictional character's emotional states. In this article, we first review two series of laboratory experiments (Gernsbacher, Goldsmith, & Robertson, 1992; Gernsbacher & Robertson, 1992) that empirically tested this hypothesis by measuring participants' reading times to target sentences that contained emotion words that matched (e.g., guilt) or mismatched (e.g., pride) the implied emotional state. We then present a third series of laboratory experiments that tested how automatically such knowledge is activated by using a divided-attention task (tone identification, per-sentence memory load, or cumulative memory load) and by comparing target-sentence reading time when the emotional state is explicitly mentioned versus only implicit. PMID- 25520550 TI - Expressive Language Intratest Scatter of Preschool-Age Children Who Stutter. AB - PURPOSE: The purpose of this study was to assess intratest scatter (variability) on standardized tests of expressive language by preschool-age children who do (CWS) and do not stutter (CWNS). METHOD: Participants were 40 preschool-age CWS and 46 CWNS. Between-group comparisons of intratest scatter were made based on participant responses to the Expressive subtest of the Test of Early Language Development - 3 (TELD-Exp; Hresko, Reid, & Hamill, 1999) and the Expressive Vocabulary Test 2 (EVT-2; Williams, 2007). Within-group correlational analyses between intratest scatter and stuttering frequency and severity were also conducted for CWS. RESULTS: Findings indicated that, for CWS, categorical scatter on the EVT-2 was positively correlated with their stuttering frequency. No significant between-group differences in intratest scatter were found on the TELD Exp or the EVT-2. CONCLUSIONS: Consistent with earlier findings, variability in speech-language performance appears to be related to CWS' stuttering, a finding taken to suggest an underlying cognitive-linguistic variable (e.g., cognitive load) may be common to both variables. PMID- 25520551 TI - Revealing Biological Pathways Implicated in Lung Cancer from TCGA Gene Expression Data Using Gene Set Enrichment Analysis. AB - Analyzing biological system abnormalities in cancer patients based on measures of biological entities, such as gene expression levels, is an important and challenging problem. This paper applies existing methods, Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis, to pathway abnormality analysis in lung cancer using microarray gene expression data. Gene expression data from studies of Lung Squamous Cell Carcinoma (LUSC) in The Cancer Genome Atlas project, and pathway gene set data from the Kyoto Encyclopedia of Genes and Genomes were used to analyze the relationship between pathways and phenotypes. Results, in the form of pathway rankings, indicate that some pathways may behave abnormally in LUSC. For example, both the cell cycle and viral carcinogenesis pathways ranked very high in LUSC. Furthermore, some pathways that are known to be associated with cancer, such as the p53 and the PI3K-Akt signal transduction pathways, were found to rank high in LUSC. Other pathways, such as bladder cancer and thyroid cancer pathways, were also ranked high in LUSC. PMID- 25520552 TI - Streamlined Genome Sequence Compression using Distributed Source Coding. AB - We aim at developing a streamlined genome sequence compression algorithm to support alternative miniaturized sequencing devices, which have limited communication, storage, and computation power. Existing techniques that require heavy client (encoder side) cannot be applied. To tackle this challenge, we carefully examined distributed source coding theory and developed a customized reference-based genome compression protocol to meet the low-complexity need at the client side. Based on the variation between source and reference, our protocol will pick adaptively either syndrome coding or hash coding to compress subsequences of changing code length. Our experimental results showed promising performance of the proposed method when compared with the state-of-the-art algorithm (GRS). PMID- 25520553 TI - Semantically linking in silico cancer models. AB - Multiscale models are commonplace in cancer modeling, where individual models acting on different biological scales are combined within a single, cohesive modeling framework. However, model composition gives rise to challenges in understanding interfaces and interactions between them. Based on specific domain expertise, typically these computational models are developed by separate research groups using different methodologies, programming languages, and parameters. This paper introduces a graph-based model for semantically linking computational cancer models via domain graphs that can help us better understand and explore combinations of models spanning multiple biological scales. We take the data model encoded by TumorML, an XML-based markup language for storing cancer models in online repositories, and transpose its model description elements into a graph-based representation. By taking such an approach, we can link domain models, such as controlled vocabularies, taxonomic schemes, and ontologies, with cancer model descriptions to better understand and explore relationships between models. The union of these graphs creates a connected property graph that links cancer models by categorizations, by computational compatibility, and by semantic interoperability, yielding a framework in which opportunities for exploration and discovery of combinations of models become possible. PMID- 25520554 TI - Bayesian joint selection of genes and pathways: applications in multiple myeloma genomics. AB - It is well-established that the development of a disease, especially cancer, is a complex process that results from the joint effects of multiple genes involved in various molecular signaling pathways. In this article, we propose methods to discover genes and molecular pathways significantly associated with clinical outcomes in cancer samples. We exploit the natural hierarchal structure of genes related to a given pathway as a group of interacting genes to conduct selection of both pathways and genes. We posit the problem in a hierarchical structured variable selection (HSVS) framework to analyze the corresponding gene expression data. HSVS methods conduct simultaneous variable selection at the pathway (group level) and the gene (within-group) level. To adapt to the overlapping group structure present in the pathway-gene hierarchy of the data, we developed an overlap-HSVS method that introduces latent partial effect variables that partition the marginal effect of the covariates and corresponding weights for a proportional shrinkage of the partial effects. Combining gene expression data with prior pathway information from the KEGG databases, we identified several gene-pathway combinations that are significantly associated with clinical outcomes of multiple myeloma. Biological discoveries support this relationship for the pathways and the corresponding genes we identified. PMID- 25520555 TI - Assessment of subnetwork detection methods for breast cancer. AB - Subnetwork detection is often used with differential expression analysis to identify modules or pathways associated with a disease or condition. Many computational methods are available for subnetwork analysis. Here, we compare the results of eight methods: simulated annealing-based jActiveModules, greedy search based jActiveModules, DEGAS, BioNet, NetBox, ClustEx, OptDis, and NetWalker. These methods represent distinctly different computational strategies and are among the most widely used. Each of these methods was used to analyze gene expression data consisting of paired tumor and normal samples from 50 breast cancer patients. While the number of genes/proteins and protein interactions detected by the eight methods vary widely, a core set of 60 genes and 50 interactions was found to be shared by the subnetworks identified by five or more of the methods. Within the core set, 12 genes were found to be known breast cancer genes. PMID- 25520556 TI - Evidence for the Influence of the Iron Regulatory MHC Class I Molecule HFE on Tumor Progression in Experimental Models and Clinical Populations. AB - Proteins involved in iron regulation are modifiers of cancer risk and progression. Of these, the HFE protein (high iron gene and its protein product) is of particular interest because of its interaction with both iron handling and immune function and the high rate of genetic polymorphisms resulting in a mutant protein. Clinical studies suggest that HFE polymorphisms increase the risk of certain cancers, but the inconsistent outcomes suggest a more nuanced effect, possibly interacting with other genetic or environmental factors. Some basic science research has been conducted to begin to understand the implications of variant HFE genotype on cancer, but the story is far from complete. In particular, putative mechanisms exist for HFE to affect tumor progression through its role in iron handling and its major histocompatibility complex class I structural features. In this review, the current understanding of the role of HFE in cancer is described and models for future directions are identified. PMID- 25520557 TI - Randomized trial of hypnosis as a pain and symptom management strategy in adults with sickle cell disease. AB - Sickle cell disease (SCD) is the most common genetic disease in African Americans, characterized by recurrent painful vaso-occlusive crises. Medical therapies for controlling or preventing crises are limited because of efficacy and/or toxicity. This is a randomized, controlled, single-crossover protocol of hypnosis for managing pain in SCD patients. Participants receive hypnosis from a trained hypnosis therapist followed by six weeks of self-hypnosis using digital media. Those in the control arm receive SCD education followed by a six-week waiting period before crossing over to the hypnosis arm of the study. Outcome measures include assessments of pain (frequency, intensity and quality), anxiety, coping strategies, sleep, depression, and health care utilization. To date, there are no published randomized, controlled trials evaluating the efficacy of hypnosis on SCD pain modulation in adults. Self-hypnosis for pain management may be helpful in modulating chronic pain, improving sleep quality, and decreasing use of narcotics in patients with SCD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00393250. PMID- 25520558 TI - Damage to the optic chiasm in myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis mice. AB - Optic chiasm lesions in myelin oligodendrocyte glycoprotein (MOG)-experimental autoimmune encephalomyelitis (EAE) mice were characterized using magnetic resonance imaging (MRI) and validated using electron microscopy (EM). MR images were collected from 3 days after induction to remission, approximately 20 days after induction. Hematoxylin and eosin, solochrome cyanin-stained sections, and EM images were obtained from the optic chiasms of some mice approximately 4 days after disease onset when their scores were thought to be the highest. T2-weighted imaging and apparent diffusion coefficient map hyperintensities corresponded to abnormalities in the optic chiasms of EAE mice. Mixed inflammation was concentrated at the lateral surface. Degeneration of oligodendrocytes, myelin, and early axonal damage were also apparent. A marked increase in chiasm thickness was observed. T2-weighted and diffusion-weighted MRI can detect abnormalities in the optic chiasms of MOG-EAE mice. MRI is an important method in the study of this model toward understanding optic neuritis. PMID- 25520559 TI - Aedes aegypti and Aedes albopictus Habitat Preferences in South Texas, USA. AB - The South Texas region has a historical record of occasional dengue outbreaks. The recent introduction of chikungunya virus to the Caribbean suggests that this disease may be a concern as well. Six different cities and three field habitat types (residential, tire shops, and cemeteries) were examined for evidence of habitat and longitudinal preference of two vector species, Aedes aegypti and Aedes albopictus. A. aegypti was more prevalent in tire shop sites, while A. albopictus was more prevalent in cemetery sites. In residential sites, the relative abundance of the two species varied with longitude, with A. albopictus being more abundant near the coast, and A. aegypti being more abundant inland. There was also a temporal variation, with A. aegypti declining in frequency over time in residential sites. These results have implications for control strategies and disease risk and suggest a greater need for increased surveillance and research in the region. PMID- 25520560 TI - Mechanisms of the pellagragenic effect of leucine: stimulation of hepatic tryptophan oxidation by administration of branched-chain amino acids to healthy human volunteers and the role of plasma free tryptophan and total kynurenines. AB - The pellagragenic effect of leucine (Leu) has been proposed to involve modulation of L-tryptophan (Trp) metabolism along the hepatic kynurenine pathway. Here, we discuss some of the mechanisms suggested and report the effects in healthy volunteers of single doses of Leu (4.05-6.75 g) administered in a 16-amino acid mixture on concentrations of plasma Trp and its kynurenine metabolites. Flux of Trp through Trp 2,3-dioxygenase (TDO) is dose-dependently enhanced most probably by Leu and can be attributed to TDO activation. Trp oxidation is better expressed using plasma total kynure-nines, rather than kynurenine, and free, rather than total, Trp. Increased hepatic Trp oxidation may be an additional mechanism of action of branched-chain amino acids in the acute Trp depletion test. Inhibition of intestinal absorption or hepatic uptake of Trp by Leu can be excluded. Potential mechanisms of the aggravation of pellagra symptoms by Leu are discussed. PMID- 25520561 TI - A Role for the Cavin-3/Matrix Metalloproteinase-9 Signaling Axis in the Regulation of PMA-Activated Human HT1080 Fibrosarcoma Cell Neoplastic Phenotype. AB - Caveolae are specialized cell membrane invaginations known to regulate several cancer cell functions and oncogenic signaling pathways. Among other caveolar proteins, they are characterized by the presence of proteins of the cavin family. In this study, we assessed the impact of cavin-1, cavin-2, and cavin-3 on cell migration in a human HT-1080 fibrosarcoma model. We found that all cavin-1, -2 and -3 transcripts were expressed and that treatment with phorbol 12-myristate 13 acetate (PMA), which is known to prime cell migration and proliferation, specifically upregulated cavin-3 gene and protein expression. PMA also triggered matrix metalloproteinase (MMP)-9 secretion, but reduced the global cell migration index. Overexpression of recombinant forms of the three cavins demonstrated that only cavin-3 was able to reduce basal cell migration, and this anti-migratory effect was potentiated by PMA. Interestingly, cavin-3 overexpression inhibited PMA-induced MMP-9, while cavin-3 gene silencing led to an increase in MMP-9 gene expression and secretion. Furthermore, recombinant cavin-3 significantly prevented PMA-mediated dephosphorylation of AKT, a crucial regulator in MMP-9 transcription. In conclusion, our results demonstrate that cellular cavin-3 expression may repress MMP-9 transcriptional regulation in part through AKT. We suggest that the balance in cavin-3-to-MMP-9 expression regulates the extent of extracellular matrix degradation, confirming the tumor-suppressive role of cavin 3 in controlling the invasive potential of human fibrosarcoma cells. PMID- 25520562 TI - Allele and genotype distributions of DNA repair gene polymorphisms in South Indian healthy population. AB - Various DNA repair pathways protect the structural and chemical integrity of the human genome from environmental and endogenous threats. Polymorphisms of genes encoding the proteins involved in DNA repair have been found to be associated with cancer risk and chemotherapeutic response. In this study, we aim to establish the normative frequencies of DNA repair genes in South Indian healthy population and compare with HapMap populations. Genotyping was done on 128 healthy volunteers from South India, and the allele and genotype distributions were established. The minor allele frequency of Xeroderma pigmentosum group A (XPA) G23A, Excision repair cross-complementing 2 (ERCC2)/Xeroderma pigmentosum group D (XPD) Lys751Gln, Xeroderma pigmentosum group G (XPG) His46His, XPG Asp1104His, and X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln polymorphisms were 49.2%, 36.3%, 48.0%, 23.0%, and 34.0% respectively. Ethnic variations were observed in the frequency distribution of these polymorphisms between the South Indians and other HapMap populations. The present work forms the groundwork for cancer association studies and biomarker identification for treatment response and prognosis. PMID- 25520563 TI - Deep Sequencing of Serum Small RNAs Identifies Patterns of 5' tRNA Half and YRNA Fragment Expression Associated with Breast Cancer. AB - Small noncoding RNAs circulating in the blood may serve as signaling molecules because of their ability to carry out a variety of cellular functions. We have previously described tRNA- and YRNA-derived small RNAs circulating as components of larger complexes in the blood of humans and mice; the characteristics of these small RNAs imply specific processing, secretion, and physiological regulation. In this study, we have asked if changes in the serum abundance of these tRNA and YRNA fragments are associated with a diagnosis of cancer. We used deep sequencing and informatics analysis to catalog small RNAs in the sera of breast cancer cases and normal controls. 5' tRNA halves and YRNA fragments are abundant in both groups, but we found that a breast cancer diagnosis is associated with changes in levels of specific subtypes. This prompted us to look at existing sequence datasets of serum small RNAs from 42 breast cancer cases, taken at the time of diagnosis. We find significant changes in the levels of specific 5' tRNA halves and YRNA fragments associated with clinicopathologic characteristics of the cancer. Although these findings do not establish causality, they suggest that circulating 5' tRNA halves and YRNA fragments with known cellular functions may participate in breast cancer syndromes and have potential as circulating biomarkers. Larger studies with multiple types of cancer are needed to adequately evaluate their potential use for the development of noninvasive cancer screening. PMID- 25520564 TI - Plantar pressure as a risk assessment tool for diabetic foot ulceration in egyptian patients with diabetes. AB - BACKGROUND: Diabetic foot ulceration is a preventable long-term complication of diabetes. In the present study, peak plantar pressures (PPP) and other characteristics were assessed in a group of 100 Egyptian patients with diabetes with or without neuropathy and foot ulcers. The aim was to study the relationship between plantar pressure (PP) and neuropathy with or without ulceration and trying to clarify the utility of pedobarography as an ulceration risk assessment tool in patients with diabetes. SUBJECTS AND METHODS: A total of 100 patients having diabetes were selected. All patients had a comprehensive foot evaluation, including assessment for neuropathy using modified neuropathy disability score (MNDS), for peripheral vascular disease using ankle brachial index, and for dynamic foot pressures using the MAT system (Tekscan). The studied patients were grouped into: (1) diabetic control group (DC), which included 37 patients who had diabetes without neuropathy or ulceration and MNDS <=2; (2) diabetic neuropathy group (DN), which included 33 patients who had diabetes with neuropathy and MNDS >2, without current or a history of ulceration; and (3) diabetic ulcer group (DU), which included 30 patients who had diabetes and current ulceration, seven of those patients also gave a history of ulceration. RESULTS: PP parameters were significantly different between the studied groups, namely, forefoot peak plantar pressure (FFPPP), rearfoot peak plantar pressure (RFPPP), forefoot/rearfoot ratio (F/R), forefoot peak pressure gradient (FFPPG) rearfoot peak pressure gradient (RFPPG), and forefoot peak pressure gradient/rearfoot peak pressure gradient (FFPPG/RFPPG) (P < 0.05). FFPPP and F/R were significantly higher in the DU group compared to the DN and DC groups (P < 0.05), with no significant difference between DN and DC. FFPPG was significantly higher in the DU and DN groups compared to the DC group (P < 0.05). RFPPP and FFPPG/RFPPG were significantly higher in the DU and DN groups compared to the DC group (P < 0.05) with no significant difference between the DN and DU groups (P > 0.05). FFPPP, F/R ratio, FFPPG, and FFPPG/RFPPG correlated significantly with the severity of neuropathy according to MNDS (P < 0.05). These same variables as well as MNDS were also significantly higher in patients with foot deformity compared to those without deformity (P < 0.05). Using the receiver operating characteristic analysis, the optimal cut-point of PPP for ulceration risk, as determined by a balance of sensitivity, specificity, and accuracy was 335 kPa and was found at the forefoot. Multivariate logistical regression analysis for ulceration risk was statistically significant for duration of diabetes (odds ratio [OR] = 0.8), smoking (OR = 9.7), foot deformity (OR = 8.7), MNDS (OR = 1.5), 2-h postprandial plasma glucose (2 h PPG) (OR = 0.9), glycated hemoglobin (HbA1c) (OR = 2.1), FFPPP (OR = 1.0), and FFPPG (OR = 1.0). CONCLUSION: In conclusion, persons with diabetes having neuropathy and/or ulcers have elevated PPP. Risk of ulceration was highly associated with duration of diabetes, smoking, severity of neuropathy, glycemic control, and high PP variables especially the FFPPP, F/R, and FFPPG. We suggest a cut-point of 355 kPa for FFPPP to denote high risk for ulceration that would be more valid when used in conjunction with other contributory risk factors, namely, duration of diabetes, smoking, glycemic load, foot deformity, and severity of neuropathy. PMID- 25520565 TI - Monitoring HIV-infected Patients with Diabetes: Hemoglobin A1c, Fructosamine, or Glucose? AB - BACKGROUND: Published studies report inappropriately low hemoglobin A1C (HbA1c) values that underestimate glycemia in HIV patients. METHODS: We reviewed the charts of all HIV patients with diabetes mellitus (DM) at our clinic. Fifty-nine patients had HbA1c data, of whom 26 patients also had fructosamine data. We compared the most recent HbA1c to finger-stick (FS) glucose averaged over three months, and fructosamine to FS averaged over six weeks. Predicted average glucose (pAG) was calculated as reported by Nathan et al: pAG (mg/dL) = 28.7 * A1C% - 46.7. Data were analyzed using the Statistical Analysis System (SAS) and Kruskal Wallis test. RESULTS: HbA1c values underestimated (UE) actual average glucose (aAG) in 19% of these patients and overestimated (OE) aAG in 27%. HbA1c estimated aAG within the established range in only 54% of the patients. There were no statistical differences in the types of HIV medication used in patients with UE, OE, or accurately estimated (AE) glycemia. A Spearman correlation coefficient between HbA1c and aAG was r = 0.53 (P < 0.0001). Correlation between fructosamine and aAG was r = 0.47 (P = 0.016). CONCLUSIONS: The correlations between HbA1c and aAG and between fructosamine and aAG were weaker than expected, and fructosamine was not more accurate than HbA1c. PMID- 25520566 TI - Phase II Clinical Trial of Gefitinib for the Treatment of Chemonaive Patients with Advanced Non-small Cell Lung Cancer with Poor Performance Status. AB - BACKGROUND: Patients with advanced non-small cell lung cancer (NSCLC) have no curative treatment options; therefore, improving their quality of life (QOL) is an important goal. Gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, is a safe oral agent that may be of benefit to a specific population of NSCLC. PATIENTS AND METHODS: A Phase II clinical trial included chemonaive patients with advanced NSCLC and poor performance status (PS). Response rate, progression-free survival, overall survival, QOL using the Functional Assessment of Cancer Therapy - Lung (FACT-L) questionnaire, and Trial Outcome Index (TOI) were evaluated. RESULTS: Twelve out of 19 enrolled patients were evaluable. The median age for the evaluable patients was 68.8 years (59.7-74.6). Out of all the patients, 7 (58.3%) had adenocarcinoma and 5 (41.7%) had squamous cell carcinoma. The median duration of treatment was 62.5 days (26.5-115.0) in the evaluable patients. Grade 3/4 toxicities included fatigue, rash, diarrhea, and nausea. One patient had partial response, eight patients had stable disease (SD), and three patients progressed. The median overall survival for the evaluable population was 4.9 months (2.3-16). The median progression-free survival was 3.7 months (1.9 6.6). TOI was marginally associated with the overall survival, with a hazard ratio of 0.92 (95% confidence interval: 0.84, 1.0) (P = 0.061). FACT-L score and the TOI were highly correlated (r = 0.96, P < 0.0001). TOI scores were higher in African Americans compared to Caucasians and increased with age. CONCLUSION: Our results suggest that gefitinib use in patients with NSCLC and poor PS may improve the QOL of older patients and African American patients. PMID- 25520567 TI - Cancer-associated thrombosis: an overview. AB - Venous thromboembolism (VTE) is a common complication in patients with malignant disease. Emerging data have enhanced our understanding of cancer-associated thrombosis, a major cause of morbidity and mortality in patients with cancer. In addition to VTE, arterial occlusion with stroke and anginal symptoms is relatively common among cancer patients, and is possibly related to genetic predisposition. Several risk factors for developing venous thrombosis usually coexist in cancer patients including surgery, hospital admissions and immobilization, the presence of an indwelling central catheter, chemotherapy, use of erythropoiesis-stimulating agents (ESAs) and new molecular-targeted therapies such as antiangiogenic agents. Effective prophylaxis and treatment of VTE reduced morbidity and mortality, and improved quality of life. Low-molecular-weight heparin (LMWH) is preferred as an effective and safe means for prophylaxis and treatment of VTE. It has largely replaced unfractionated heparin (UFH) and vitamin K antagonists (VKAs). Recently, the development of novel oral anticoagulants (NOACs) that directly inhibit factor Xa or thrombin is a milestone achievement in the prevention and treatment of VTE. This review will focus on the epidemiology and pathophysiology of cancer-associated thrombosis, risk factors, and new predictive biomarkers for VTE as well as discuss novel prevention and management regimens of VTE in cancer according to published guidelines. PMID- 25520568 TI - The use of pharmacogenomics for selection of therapy in non-small-cell lung cancer. AB - INTRODUCTION: Performance status (PS) is the only known clinical predictor of outcome in patients with advanced non-small-cell lung cancer (NSCLC), although pharmacogenomic markers may also correlate with outcome. The aim of our study was to correlate clinical and pharmacogenomic measures with overall survival. METHODS: This was an IRB approved, retrospective study in which the medical records of 50 patients with advanced NSCLC from 1998-2008 were reviewed, and gender, race, PS, and chemotherapy regimens were documented. Stromal expression of pharmacogenomic markers (VEGFR, ERCC1, 14-3-3sigma, pAKT, and PTEN) was measured. Clinical factors and pharmacogenomics markers were compared to overall survival using a Cox proportional hazards model. RESULTS: Forty patients received platinum-based therapy. Median age was 65 years. Improved PS, female gender, and gemcitabine therapy were significantly associated with longer overall survival (P = 0.004, P = 0.04, and P = 0.003, respectively). Age was not associated with survival. Caucasians had better overall survival in comparison to African Americans with median survival of 14.8 months versus 10.4 months (P = 0.1). Patients treated with platinum-based therapy had better survival of 15 months versus 8 months for non-platinum based therapy (P = 0.01). There was no significant association between any of the pharmacogenomics markers and overall survival other than in patients treated with platinum, in whom ERCC1 negativity was strongly associated with longer survival (P = 0.007). CONCLUSION: ERCC1 negativity with platinum therapy, gemcitabine therapy, good PS, and female gender all correlated with improved overall survival in patients with advanced NSCLC. PMID- 25520569 TI - Micro-cost Analysis of ALK Rearrangement Testing by FISH to Determine Eligibility for Crizotinib Therapy in NSCLC: Implications for Cost Effectiveness of Testing and Treatment. AB - Break-apart fluorescence in situ hybridization (FISH) is the gold standard test for anaplastic lymphoma kinase (ALK) gene rearrangement. However, this methodology often is assumed to be expensive and potentially cost-prohibitive given the low prevalence of ALK-positive non-small cell lung cancer (NSCLC) cases. To more accurately estimate the cost of ALK testing by FISH, we developed a micro-cost model that accounts for all cost elements of the assay, including laboratory reagents, supplies, capital equipment, technical and pathologist labor, and the acquisition cost of the commercial test and associated reagent kits and controls. By applying a set of real-world base-case parameter values, we determined that the cost of a single ALK break-apart FISH test result is $278.01. Sensitivity analysis on the parameters of batch size, testing efficiency, and the cost of the commercial diagnostic testing products revealed that the cost per result is highly sensitive to batch size, but much less so to efficiency or product cost. This implies that ALK testing by FISH will be most cost effective when performed in high-volume centers. Our results indicate that testing cost may not be the primary determinant of crizotinib (Xalkori((r))) treatment cost effectiveness, and suggest that testing cost is an insufficient reason to limit the use of FISH testing for ALK rearrangement. PMID- 25520570 TI - The proposed role of suppression in simultaneous interpretation. AB - In this paper we suggest that the cognitive mechanism of suppression attenuates interference in many language comprehension phenomena, and is particularly crucial when comprehension must share processing capacity with other cognitive tasks, as is manifestly the case in simultaneous interpreting. During lexical access, the mechanism of suppression attenuates the interference caused by the activation of other lexical information, such as the inappropriate meanings of homonyms. During anaphoric reference, the mechanism of suppression attenuates the interference caused by the activation of other potential referents. In this way, the referent to which the anaphor does refer becomes the most activated concept. During syntactic parsing, the mechanism of suppression attenuates the interference caused by a previous syntactic form. During metaphor comprehension, the mechanism of suppression attenuates the interference caused by a literal interpretation. During inferencing, the mechanism of suppression attenuates the interference caused by an initial but inappropriate inference. We propose therefore that suppression - a general, cognitive mechanism that attenuates interference - plays a crucial role in language comprehension and simultaneous interpretation. PMID- 25520572 TI - Trabectedin as a single agent and in combination with pegylated liposomal doxorubicin - activity against ovarian cancer cells. AB - Over 225 000 new cases of ovarian cancer are diagnosed each year. Symptoms are often vague, so most cases are detected when the disease is at an advanced stage. There is a need to find new drugs which will be able to treat ovarian cancer effectively. One of the most promising antineoplastic agents is trabectedin (Yondelis), derived from the marine tunicate Ecteinascidia turbinata, approved by the European Union in July 2007 for the treatment of soft-tissue sarcomas. This drug shows a mechanism of action based on the inhibition of the nucleotide excision repair system. Trabectedin shows anti-tumour activity in vitro and in vivo in ovarian, breast, prostate, renal, melanoma and non-small cell lung cancer cell lines. Trabectedin in combination with pegylated liposomal doxorubicin demonstrates synergistic antineoplastic activity. PMID- 25520571 TI - Signalling pathways in endometrial cancer. AB - Carcinogenesis is a multistage process, during which the activity of signalling pathways responsible for cell cycle regulation and division is disrupted which leads to inhibition of apoptosis and enhanced proliferation. Improper activation of Wnt/beta-catenin and PI3K. Akt pathways play essential role in endometrial cancers (EC), mainly type I. Mutations in APC, axin or CTNBB1 may lead to beta catenin overactivation leading to excessive gene expression. PTEN inactivation, mutations in the PIK3CA or Akt result in increased transmission in the PI3K/Akt pathway, apoptosis inhibition, intensive cell division, mTOR excitation. In non endometrioid cancers, key mutations include suppressor gene TP53 responsible for repairing damaged DNA or apoptosis initiation. Irregularities in gene P16, encoding a protein forming the p16-cyclinD/CDK-pRb have also been described. Understanding the complex relations between specific proteins taking part in signal transduction of the abovementioned pathways is key to research on drugs used in targeted therapy. PMID- 25520573 TI - Cervical cancer screening and psychosocial barriers perceived by patients. A systematic review. AB - AIM OF THE STUDY: This study aimed at integrating research discussing the role of perceived psychosocial barriers in cervical cancer screening (CCS) uptake. In particular, we analyzed the evidence for the associations between CCS uptake and perceived psychosocial barriers and frequency of psychosocial barriers identified by women. MATERIAL AND METHODS: A systematic search of peer-reviewed papers published until 2011 in 8 databases yielded 48 original studies, analyzing data obtained from 155 954 women. The majority of studies (k = 43) applied correlational design, while 5 had experimental design. RESULTS: Experimental research indicated a positive effect of 75% of psychosocial interventions targeting barriers. The interventions resulted in a significant increase of CCS uptake. Overall 100% of correlational studies indicated that perceiving lower levels of barriers significantly predicted higher CCS uptake. 53 psychosocial barriers were listed in at least 2 original correlational studies: 9.5% of barriers were related to CCS facilities/environment, 67.9% dealt with personal characteristics of the patient, and 22.6% addressed social factors. As many as 35.9% of perceived barriers referred to negative emotions related to CCS examination procedures and collecting CCS results, whereas 25.7% of barriers referred to prior contacts with health professionals. CONCLUSIONS: Leaflets or discussion on psychosocial barriers between patients and health professionals involved in CCS might increase CCS uptake and thus reduce cervical cancer mortality rates. Communication skills training for health professionals conducting CCS might focus on the most frequently reported barriers, referring to emotions related to CCS examination and collecting CCS results. PMID- 25520574 TI - Risk for oral cancer from smokeless tobacco. AB - Tobacco products which are used in a way other than smoking are known as smokeless tobacco. The most common smokeless tobaccos are chewing tobacco, naswar, snuff, snus, gutka, and topical tobacco paste. Any product which contains tobacco is not safe for human health. There are more than twenty-five compounds in smokeless tobacco which have cancer causing activity. Use of smokeless tobacco has been linked with risk of oral cancer. Smokeless tobacco contains tobacco specific nitrosamines (TSNAs), polonium, formaldehyde, cadmium, lead, and benzo[a]pyrene, which are carcinogenic agents. Although there is presence of some compounds, carotenoids and phenolic compounds, that have cancer inhibiting properties, they are in low concentrations. Dry snuff use is linked with higher relative risks, while the use of other smokeless tobacco is of intermediate risk. Moist snuff and chewing tobacco have a very low risk for oral cancer. Therefore, from this review article, it was concluded that smokeless tobacco has risk for oral cancer - either low, medium or high depending on the balance between cancer causing agents and cancer inhibiting agents. PMID- 25520575 TI - Targeting osteosarcoma vasculature with peptide obtained by phage display. AB - AIM OF THE STUDY: Tumour endothelial cells have been proven to have molecular markers distinct from normal endothelial cells. These specific molecular markers allow for targeting of the tumour vasculature with specific pharmacological vehicles to direct diagnostic or therapeutic modalities at the endothelial cells. By performing a phage display-based screening, this study aimed to identify a certain short peptide that could specifically bind to osteosarcoma vasculature. MATERIAL AND METHODS: We performed in vivo screening in the murine models of osteosarcoma with annular Ph.D.-C7C library in the present study. To explore the in vivo binding specificity of the retrieved peptide, we conjugated the peptide with fluorescein isothiocyanate (FITC) and injected it intravenously into osteosarcoma-bearing BALB-c mice. RESULTS: CTKPDKGYC was the dominant sequence isolated from in vivo screening and was named as NF-1. Fluorescence staining found that FITC-NF-1 peptide could be specifically homed to osteosarcoma vasculature while being almost undetectable in the heart, brain, lung and liver. Simultaneously, a small amount of fluorescence could also be detected in the renal glomerulus and renal tubule but not in renal vascular endothelium, indicating that FITC-NF-1 peptide might be excreted mainly through the renal urinary route. CONCLUSIONS: Our data suggest that, with high binding specificity to osteosarcoma vasculature, peptide NF-1 may have potential value in early diagnosis or targeted therapy for osteosarcoma. PMID- 25520576 TI - Over-expression of beclin-1 in gallbladder carcinoma and its relationship with prognosis. AB - AIM OF THE STUDY: We determined the expression of beclin-1 in gallbladder carcinoma, analyzed the association of beclin-1 expression with clinicopathologic parameters and prognosis, and investigated the relationship between microvessel density and beclin-1 expression. MATERIAL AND METHODS: Tissue microarray blocks containing 118 primary gallbladder tumor sites were used. Clinical parameters and prognostic data were collected. Expression of beclin-1 in these specimens was analyzed by immunohistochemical studies and confirmed by Western blotting. Microvessel density was counted using immunohistochemical staining. RESULTS: The overall rate of over-expression of beclin-1 was 68.1% (80 of 118). Over expression of beclin-1 was significantly associated with TNM stage and liver metastasis. Over-expression of beclin-1 has no significant relationship with age, sex, lymphatic metastasis, or tumor differentiation. Based on the Kaplan-Meier method, over-expression of beclin-1 showed no significant difference for the overall survival rate in patients with gallbladder cancer. The multivariate Cox regression analysis demonstrated that beclin-1 was not an independent prognostic factor for gallbladder cancer. CONCLUSIONS: Beclin-1 might play roles in the development of gallbladder cancer. However, beclin-1 may not be an effective prognostic factor for gallbladder cancer. PMID- 25520577 TI - Lack of association between COX-2 8473T>C polymorphism and breast cancer risk: a meta-analysis. AB - AIM OF THE STUDY: Results of recent published studies on the association between the COX-2 8473T>C polymorphism and the risk of breast cancer have often been conflicting. To make a more precise estimation of the potential relationship, a meta-analysis was performed. MATERIAL AND METHODS: A total of seven case-control studies with 7,033 cases and 9,350 controls were included in the current meta analysis through searching the databases of PubMed, Embase, and Cochrane Library (up to March 1(st), 2013). The odds ratio (OR) and 95% confidence interval (95% CI) were calculated to assess the strength of the association. The meta-analysis was conducted in a fixed/random effect model. RESULTS: We found no significant associations for all genetic models after all studies were pooled into the meta analysis (for C vs. T: OR = 0.974, 95% CI: 0.906-1.047, p = 0.471; for CC vs. TT: OR = 0.957, 95% CI: 0.803-1.140, p = 0.62; for TC vs. TT: OR = 0.964, 95% CI: 0.881-1.055, p = 0.421; for CC + TC vs. TT: OR = 0.963, 95% CI: 0.880-1.053, p = 0.406; for CC vs. TT + TC: OR = 0.978, 95% CI: 0.831-1.15, p = 0.788). We also observed no obvious associations in the subgroup analyses by ethnicity (Caucasian) and source of controls (population based, PB) for all genetic models. CONCLUSIONS: Current evidence suggests that the COX-2 8473T>C polymorphism is not associated with breast cancer risk. PMID- 25520578 TI - Role of irradiation in combined treatment of head and neck paragangliomas at the Centre of Oncology in Krakow between 1970-2005. AB - AIM OF THE STUDY: Aim of the study is to evaluate the results of postoperative radiotherapy of paragangliomas, prognostic factors and causes of treatment failure. MATERIAL AND METHODS: Forty-four patients (39 females and 5 males) aged 20 to 74 years were treated for paraganglioma between 1970 and 2010 at the Centre of Oncology in Krakow. Patient survival probability was estimated with the Kaplan Meier method. Log-rank tests and Cox proportional hazard model were used in univariate and multivariate analysis, respectively. RESULTS: The most common locations of paragangliomas were the following: the ear, carotid body and internal jugular vein bulb. Forty (91%) out of them were benign and 4 - malignant. All patients underwent surgery followed by adjuvant radiotherapy. The delivered dose ranged from 50 to 72 Gy, the mean dose was 60 Gy. Five-year overall survival was 84%. Five-year relapse-free survival was 84%, either. The multivariate analysis has shown that the dose in an independent prognostic factor for the overall survival. The univariate analysis has shown significantly higher 5-year overall survival in patients who received a dose of 60 Gy or higher - 92% vs. 70% in patients who received a dose lower than 60 Gy. CONCLUSIONS: Postoperative radiotherapy with doses higher than 60 Gy in patients with paragangliomas is associated with longer overall survival. PMID- 25520579 TI - Feasibility of simultaneous integrated boost with forward intensity-modulated radiation therapy for multiple brain metastases. AB - AIM OF THE STUDY: To evaluate the feasibility of whole-brain radiotherapy (WBRT) with a simultaneous integrated boost (SIB) by forward intensity-modulated radiation therapy (IMRT) in patients with 1-3 brain metastases. MATERIAL AND METHODS: Two forward IMRT plans were implemented among 18 patients. In plan A, the prescribed dose was 30 Gy to the whole brain (PTVWBRT) and 50 Gy to individual brain metastases (PTVboost) delivered simultaneously in 10 fractions. In plan B, the prescribed dose was 30 Gy to the PTVWBRT and 40 Gy to the PTVboost. Plans were evaluated with regard to conformation number (CN), prescription isodose volume to target volume ratio (PITV), target coverage (TC), homogeneity index (HI), and the volume receiving at least 95% of the prescribed dose (V95). Plan A was implemented for 5 of these patients, and plan B was used for the remaining patients. RESULTS: The mean values of CN, PITV, TC, and HI for the PTVboost were 0.71, 1.32, 0.97, and 0.07, respectively, for plan A and 0.65, 1.47, 0.97, and 0.05, respectively, for plan B. The mean values of TC, HI, and V95 for the PTVWBRT were 0.98, 0.45, and 99.71%, respectively, for plan A and 0.97, 0.27, and 99.61%, respectively, for plan B. All patients completed the planned radiotherapy (RT) schedule with no acute and late RT-related toxicity greater than grade 2. CONCLUSIONS: It is feasible to deliver WBRT with a SIB via forward IMRT for patients with 1-3 brain metastases with good dose conformity and acceptable toxicity. PMID- 25520580 TI - Evaluation of alpha-fetoprotein-L3 and Golgi protein 73 detection in diagnosis of hepatocellular carcinoma. AB - AIM OF THE STUDY: Hepatocellular carcinoma (HCC) is common throughout the world. Most HCCs are diagnosed at an advanced stage. There is an urgent need to find new methods for screening and surveillance of individuals at risk for HCC. The aim of this study was to evaluate serum alpha-fetoprotein (AFP)-L3 and serum Golgi protein 73 (GP73) detection in diagnosis of HCC with different AFP concentration. MATERIAL AND METHODS: One hundred and eighty one patients were involved, including 102 with HCC and 79 with benign liver disease. The serum AFP-L3 and GP73 was measured by a liquid-phase binding assay and quantitative enzyme-linked immunosorbent assay, respectively. RESULTS: Of the 102 HCC patients, 53 were positive for AFP, 77 were positive for AFP-L3, and 79 were positive for GP73. The maximum area under the curve for AFP-L3% and for GP73 was significantly different from the AUC of 0.5525 for total AFP (p < 0.01). AFP-L3% was not detected for AFP < 20 ng/ml. However, elevated GP73 was detected in 87.50% of the patients. In the HCC patients with total AFP 20-400 ng/ml, elevated AFP-L3 was detected in 26 patients, whereas in 23 patients elevated GP73 could be detected. In the HCC patients with a total AFP > 400 ng/ml, AFP-L3% > 10% was present in 96.23%, and GP73 was detected in 87.50%. CONCLUSIONS: The determination of AFP-L3% and GP73 in combination with AFP can increase the sensitivity and specificity in diagnosis of HCC. alpha-fetoprotein-L3% and GP73, in combination with AFP, are useful biomarkers to confirm the diagnosis of HCC. PMID- 25520581 TI - Efficacy and safety of breast radiothermometry in the differential diagnosis of breast lesions. AB - AIM OF THE STUDY: The aim of this study is to research the contribution of radiothermometry (RTM) to the characterization of breast masses, the differentiation of malignant-benign masses and diagnosis of early stage breast cancer. MATERIAL AND METHODS: This prospective study comprised 182 cases of patients diagnosed with a breast mass and a control group of 55 cases: a total of 237. RESULTS: When histopathology is accepted as the gold standard among diagnostic methods, the sensitivity, specificity, and positive-negative predictive value for RTM were 90.9%, 20.8%, 61.2% and 62.5%, respectively. Consistency was 0.129. When compared with mammography the same values for RTM examination are 87%, 81.4%, 58% and 95.5%. Consistency was 0.582. Evaluating with respect to size of the mass accepting mammography as the gold standard, RTM examination had sensitivity, specificity, positive and negative predictive values for masses 2 cm and above of 88.9%, 83.3%, 88.9% and 83.3%. Consistency was 0.722. The consistency of RTM for lesion diagnosis in BI-RADS II breast structure is higher than the consistency of mammography. CONCLUSIONS: Identification of lesions in the breast and presence of microcalcification by RTM shows that it is more trustworthy compared to mammography. When compared with mammography the validity results for RTM show there is a good level of conformity between the two methods. When evaluated based on the area below the ROC cure and compared to mammography, RTM is sufficiently successful at evaluating positive and negative cases. PMID- 25520582 TI - Effects of comorbidities and functional living activities on survival in geriatric breast cancer patients. AB - AIM OF THE STUDY: We evaluated the possible effects of comorbid diseases and functional capacity on the survival of elderly female patients with breast cancer. MATERIAL AND METHODS: The study included 159 breast cancer patients aged 65 years or older. Functional status of the patients was evaluated using Katz's index of activities of daily living (ADL) and Lawton and Brody's Instrumental ADL (IADL) scale. RESULTS: ADL-based evaluation revealed 121 patients (76.1%) were independent, 34 (21.4%) semi-dependent and 4 (2.5%) dependent whereas IADL-based evaluation showed 69 patients (43.4%) were independent, 67 patients (42.1%) semi dependent and 23 patients (14.5%) dependent. Among the patients, 69 (43.4%) had one comorbid disease, 62 (39.0%) had two and 26 (16.4%) had three or more. Of the entire cohort, 60.4% received adjuvant chemotherapy. Based on ADL index, overall survival (OS) was significantly better in semi-dependent and independent patients than in dependent patients (p = 0.001). In the upfront non-metastatic patient subgroup, disease-free survival (DFS) was favourable in the independent patients according to ADL index (p = 0.001). Having more than one comorbid disease had an unfavourable effect on OS. In the multiple regression analysis of non-metastatic patients, stage, triple-negative histology and ADL index remained significant in terms of OS (p = 0.008, HR: 3.17, CI: 1.35-7.44; p = 0.027, HR: 2.78, CI: 1.172 6.91; and p = 0.006, HR: 0.29, CI: 0.12-0.70, respectively). CONCLUSIONS: In elderly patients with breast cancer, evaluation of daily living activities and comorbid diseases are as important as staging and subclassification of breast cancer in the determination of prognosis and survival. PMID- 25520583 TI - Beger procedure in a 20-year-old female with solid pseudopapillary tumour of the pancreas. AB - Solid pseudopapillary tumour is a rare indolent neoplasm of the pancreas (< 2% of exocrine pancreatic tumours), which predominantly affects young women at reproductive age, without significant clinical symptoms. We report a case of a 20 year-old Caucasian female who presented with upper abdominal pain of one-year duration. Ultrasound scans of the abdomen demonstrated enlarged pancreatic head and body containing a poorly separated mass (52 * 41 * 36 mm) with a multi-cystic component 20-24 mm in diameter. Laboratory tests including, tumour markers levels, were normal. She underwent complete resection of the tumour using a Beger procedure. By immunohistochemistry, the case stained strongly for CD10 and CD56 and was negative for cytokeratin-7 (CK-7), synaptophysin and chromogranin A. The proliferation index (Ki-67) was < 1%. The patient is being followed-up and remains healthy. CONCLUSIONS: Solid pseudopapillary tumour is a tumour with low potential of malignancy and with generally favourable prognosis; surgical resection is usually curative. PMID- 25520584 TI - Oxycodone/naloxone as a therapeutic option in a patient with chronic pain and opioid-induced bowel dysfunction. PMID- 25520586 TI - Language is More than Speech: A Case Study. AB - Some individuals face severe challenges with producing oral language (i.e., speech). In this article a case study of a child who experienced severe challenges with speech development is presented. Medical records, historical home videos, audio recordings, and photographs, in conjunction with an extensive journal maintained by the child's mother provide the basis for this report, which profiles the child's development from birth to age 8;0. This child's development demonstrates the necessity of distinguishing between language-the mental representation of concepts and their relations-and speech-one means for communicating mental representations. PMID- 25520585 TI - Osteoblast inhibition by chemokine cytokine ligand3 in myeloma-induced bone disease. AB - BACKGROUND: Multiple myeloma is a hematologic malignancy characterized by the accumulation of monoclonal plasma cells in the bone marrow. A common manifestation of the disease is myeloma bone disease (MBD), which is caused by increased osteoclastic bone resorption and decreased bone formation. The chemokine cytokine ligand 3 (CCL3) is a pro-inflammatory protein and chemokine that stimulates osteoclasts in MBD. However, little is known about the effect of CCL3 on osteoblasts (OB). METHODS: The OBs are induced from patients with MBD and healthy donors, cultured in vitro, and identified by histochemistry. The effects of CCL3 and CCL3 antibody on the OBs in vitro are observed. The CCL3 receptor (CCR1), osteocalcin (OCN), runt-related transcription factor 2 (Runx2), and osterix (Osx) are detected using flow cytometry, enzyme-linked immunosorbent assay, and real-time PCR. RESULTS: Proliferation and osteogenic potential of the OB in patients with MBD are suppressed. Moreover, the CCR1 expression is significantly higher in patients with MBD than in normal controls. The OCN level, quantity of calcium nodules, and Runx2 and Osx levels decrease after CCL3 stimulation, which indicates that CCL3 inhibits OB function. Furthermore, CCL3 antibody partially restores OB activity through the upregulation of the OCN, Runx2, and Osx. CONCLUSIONS: CCL3 contributes to the OB/OC imbalance by inhibiting OB differentiation and function in MBD. PMID- 25520587 TI - Does the Autistic Brain Lack Core Modules? AB - Researchers have hypothesized that autistics are missing core modules of the brain, critical neural tissue necessary for accomplishing various processes. In this article, we critically review the evidence supporting two such hypothesized deficits. We ask whether autistic brains lack a module for understanding the behavior of others (i.e., theory of mind) and whether they lack a module for processing faces. We illustrate that successful performance on theory of mind tasks depends on linguistic ability; therefore, it is not surprising that autistics are more likely to fail theory of mind tasks because a qualitative impairment in communication is one of the primary diagnostic criteria for autism. Similarly, we illustrate that autistics are less likely to fixate the eye region of facial photographs and that the amount of time spent fixating the eye region correlates with activation in the face processing "module"; therefore, it is not surprising that autistics are less likely to activate the putative face processing area. These illustrations cast doubt on the arguments that the autistic brain is missing the core modules responsible for understanding theory of mind and for processing faces. PMID- 25520588 TI - A composite CdS thin film/TiO2 nanotube structure by ultrafast successive electrochemical deposition toward photovoltaic application. AB - Fabricating functional compounds on substrates with complicated morphology has been an important topic in material science and technology, which remains a challenging issue to simultaneously achieve a high growth rate for a complex nanostructure with simple controlling factors. Here, we present a novel simple and successive method based on chemical reactions in an open reaction system manipulated by an electric field. A uniform CdS/TiO2 composite tubular structure has been fabricated in highly ordered TiO2 nanotube arrays in a very short time period (~90 s) under room temperature (RT). The content of CdS in the resultant and its crystalline structure was tuned by the form and magnitude of external voltage. The as-formed structure has shown a quite broad and bulk-like light absorption spectrum with the absorption of photon energy even below that of the bulk CdS. The as-fabricated-sensitized solar cell based on this composite structure has achieved an efficiency of 1.43% without any chemical doping or co sensitizing, 210% higher than quantum dot-sensitized solar cell (QDSSC) under a similar condition. Hopefully, this method can also easily grow nanostructures based on a wide range of compound materials for energy science and electronic technologies, especially for fast-deploying devices. PMID- 25520589 TI - Annealing effects on the optical and morphological properties of ZnO nanorods on AZO substrate by using aqueous solution method at low temperature. AB - Vertically aligned ZnO nanorods (NRs) on aluminum-doped zinc oxide (AZO) substrates were fabricated by a single-step aqueous solution method at low temperature. In order to optimize optical quality, the effects of annealing on optical and structural properties were investigated by scanning electron microscopy, X-ray diffraction, photoluminescence (PL), and Raman spectroscopy. We found that the annealing temperature strongly affects both the near-band-edge (NBE) and visible (defect-related) emissions. The best characteristics have been obtained by employing annealing at 400 degrees C in air for 2 h, bringing about a sharp and intense NBE emission. The defect-related recombinations were also suppressed effectively. However, the enhancement decreases with higher annealing temperature and prolonged annealing. PL study indicates that the NBE emission is dominated by radiative recombination associated with hydrogen donors. Thus, the enhancement of NBE is due to the activation of radiative recombinations associated with hydrogen donors. On the other hand, the reduction of visible emission is mainly attributed to the annihilation of OH groups. Our results provide insight to comprehend annealing effects and an effective way to improve optical properties of low-temperature-grown ZnO NRs for future facile device applications. PMID- 25520590 TI - Electrical characteristic fluctuation of 16-nm-gate high-kappa/metal gate bulk FinFET devices in the presence of random interface traps. AB - In this work, we study the impact of random interface traps (RITs) at the interface of SiO x /Si on the electrical characteristic of 16-nm-gate high kappa/metal gate (HKMG) bulk fin-type field effect transistor (FinFET) devices. Under the same threshold voltage, the effects of RIT position and number on the degradation of electrical characteristics are clarified with respect to different levels of RIT density of state (D it). The variability of the off-state current (I off) and drain-induced barrier lowering (DIBL) will be severely affected by RITs with high D it varying from 5 * 10(12) to 5 * 10(13) eV(-1) cm(-2) owing to significant threshold voltage (V th) fluctuation. The results of this study indicate that if the level of D it is lower than 1 * 10(12) eV(-1) cm(-2), the normalized variability of the on-state current, I off, V th, DIBL, and subthreshold swing is within 5%. PMID- 25520591 TI - Coupled nanowire-based hybrid plasmonic nanocavities on thin substrates. AB - We theoretically analyze nanowire-based hybrid plasmonic nanocavities on thin substrates at visible wavelengths. In the presence of thin suspended substrates, the hybrid plasmonic modes, formed by the coupling between a metal nanowire and a dielectric nanowire with optical gain, exhibit negligible substrate-mediated characteristics and overlap better with the gain region. Consequently, the confinement factor of the guided hybrid modes is enhanced by more than 42%. However, the presence of significant mirror loss remains the main challenge to lasing. By adding silver coatings with a sufficient thickness range on the two end facets, we show that the reflectivity is substantially enhanced to above 50%. For a coating thickness of 50 nm and cavity length of about 4 MUm, the quality factor is above 100. PMID- 25520593 TI - Electrical conductivity of poly(3,4-ethylenedioxythiophene):p-toluene sulfonate films hybridized with reduced graphene oxide. AB - Reduced graphene oxide-poly(3,4-ethylenedioxythiophene):p-toluene sulfonate (rGO PEDOT:PTS) hybrid electrode films were synthesized directly on a substrate by interfacial polymerization between an oxidizing solid layer and liquid droplets of 3,4-ethylenedioxythiophene (EDOT) produced by electrospraying. The EDOT reduced the graphene oxide by donating electrons during its transformation into PEDOT:PTS, and hybrid films consisting of rGO distributed in a matrix of PEDOT:PTS were obtained. These rGO-PEDOT:PTS hybrid films showed excellent electrical conductivities as high as 1,500 S/cm and a sheet resistance of 70 Omega sq(-1). The conductivity values are up to 50% greater than those of films containing conductive PEDOT:PTS alone. These results confirm that highly conductive rGO-PEDOT:PTS hybrid films can potentially be used as organic transparent electrodes. PMID- 25520592 TI - Size- and time-dependent alteration in metabolic activities of human hepatic cytochrome P450 isozymes by gold nanoparticles via microsomal coincubations. AB - Nano-sized particles are known to interfere with drug-metabolizing cytochrome P450 (CYP) enzymes, which can be anticipated to be a potential source of unintended adverse reactions, but the mechanisms underlying the inhibition are still not well understood. Herein we report a systematic investigation of the impacts of gold nanoparticles (AuNPs) on five major CYP isozymes under in vitro incubations of human liver microsomes (HLMs) with tannic acid (TA)-stabilized AuNPs in the size range of 5 to 100 nm. It is found that smaller AuNPs show more pronounced inhibitory effects on CYP2C9, CYP2C19, CYP2D6, and CYP3A4 in a dose dependent manner, while 1A2 is the least susceptible to the AuNP inhibition. The size- and dose-dependent CYP-specific inhibition and the nonspecific drug nanogold binding in the coincubation media can be significantly reduced by increasing the concentration ratio of microsomal proteins to AuNPs, probably via a noncompetitive mode. Remarkably, AuNPs are also found to exhibit a slow time dependent inactivation of 2D6 and 3A4 in a beta-nicotinamide adenine dinucleotide 2'-phosphate reduced tetrasodium salt hydrate (NADPH)-independent manner. During microsomal incubations, UV-vis spectroscopy, dynamic light scattering, and zeta potential measurements were used to monitor the changes in particle properties under the miscellaneous AuNP/HLM/CYP dispersion system. An improved stability of AuNPs by mixing HLM with the gold nanocolloid reveals that the stabilization via AuNP-HLM interactions may occur on a faster time scale than the salt-induced nanoaggregation by incubation in phosphate buffer. The results suggest that the AuNP induced CYP inhibition can be partially attributed to its adhesion onto the enzymes to alter their structural conformations or onto the HLM membrane therefore impairing the integral membrane proteins. Additionally, AuNPs likely block the substrate pocket on the CYP surface, depending on both the particle characteristics and the structural diversity of the isozymes. These findings may represent additional mechanisms for the differential inhibitory effects arising from the coincubated AuNPs on the metabolic activities of the hepatic CYP isozymes. PMID- 25520594 TI - Designed nitrogen doping of few-layer graphene functionalized by selective oxygenic groups. AB - Few-layer nitrogen doped graphene was synthesized originating from graphene oxide functionalized by selective oxygenic functional groups (hydroxyl, carbonyl, carboxyl etc.) under hydrothermal conditions, respectively. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) observation evidenced few layer feature of the graphene oxide. X-ray diffraction (XRD) pattern confirmed phase structure of the graphene oxide and reduced graphene oxide. Nitrogen doping content and bonding configuration of the graphene was determined by X-ray photoelectron spectroscopy (XPS), which indicated that different oxygenic functional groups were evidently different in affecting the nitrogen doping process. Compared with other oxygenic groups, carboxyl group played a crucial role in the initial stage of nitrogen doping while hydroxyls exhibited more evident contribution to the doping process in the late stage of the reaction. Formation of graphitic-like nitrogen species was controlled by a synergistic effect of the involved oxygenic groups (e.g., -COOH, -OH, C-O-C, etc.). The doping mechanism of nitrogen in the graphene was scrutinized. The research in this work may not only contribute to the fundamental understandings of nitrogen doping within graphene but promote the development of producing novel graphene based devices with designed surface functionalization. PMID- 25520595 TI - Synthesis and enhanced humidity detection response of nanoscale Au-particle decorated ZnS spheres. AB - We successfully prepared Au-nanoparticle-decorated ZnS (ZnS-Au) spheres by sputtering Au ultrathin films on surfaces of hydrothermally synthesized ZnS spheres and subsequently postannealed the samples in a high-vacuum atmosphere. The Au nanoparticles were distributed on ZnS surfaces without substantial aggregation. The Au nanoparticle diameter range was 5 to 10 nm. Structural information showed that the surface of the annealed ZnS-Au spheres became more irregular and rough. A humidity sensor constructed using the Au-nanoparticle decorated ZnS spheres demonstrated a substantially improved response to the cyclic change in humidity from 11% relative humidity (RH) to 33% to 95% RH at room temperature. The improved response was associated with the enhanced efficiency of water molecule adsorption onto the surfaces of the ZnS because of the surface modification of the ZnS spheres through noble-metal nanoparticle decoration. PMID- 25520596 TI - Hydrothermal synthesis of 3D hollow porous Fe3O4 microspheres towards catalytic removal of organic pollutants. AB - Three-dimensional hollow porous superparamagnetic Fe3O4 microspheres were synthesized via a facile hydrothermal process. A series of characterizations done with X-ray diffraction, Brunauer-Emmett-Teller method, Fourier transform infrared spectroscopy, scanning electron microscopy, and transmission electron microscopy indicated that the production of Fe3O4 microspheres possessed good monodispersity, uniform size distribution, hollow and porous structural characters, and strong superparamagnetic behavior. The obtained Fe3O4 microspheres have a diameter of ca. 300 nm, which is composed of many interconnected nanoparticles with a size of ca. 20 nm. The saturation magnetization is 80.6 emu.g(-1). The as-prepared products had promising applications as novel catalysts to remove organic pollutants (methylene blue) from wastewater in the presence of H2O2 and ultrasound irradiation. PMID- 25520597 TI - Pulsed laser deposition of single-crystalline Cu7In3/CuIn0.8Ga0.2Se2 core/shell nanowires. AB - Single-crystalline Cu7In3/CuIn0.8Ga0.2Se2 (CI/CIGS) core/shell nanowires are fabricated by pulsed laser deposition with Ni nanoparticles as catalyst. The CI/CIGS core/shell nanowires are made up of single-crystalline CI cores surrounded by single-crystalline CIGS shells. The CI/CIGS nanowires are grown at a considerably low temperature (350 degrees C ~ 450 degrees C) by vapor-liquid solid mode combined with vapor-solid mode. The distribution density of the nanowires increases with the increasing of the deposition duration, and the substrate temperature determines the lengths of the nanowires. The U-V absorption spectra of the CIGS thin films with and without the CI/CIGS core/shell nanowires demonstrate that the CI/CIGS nanowires can remarkably enhance the absorption of CIGS thin films in the spectrum range of 300 to 900 nm. PACS: 61.46. + w; 61.41.e; 81.15.Fg; 81.07.b. PMID- 25520598 TI - Size and surface modification of amorphous silica particles determine their effects on the activity of human CYP3A4 in vitro. AB - Because of their useful chemical and physical properties, nanomaterials are widely used around the world - for example, as additives in food and medicines - and such uses are expected to become more prevalent in the future. Therefore, collecting information about the effects of nanomaterials on metabolic enzymes is important. Here, we examined the effects of amorphous silica particles with various sizes and surface modifications on cytochrome P450 3A4 (CYP3A4) activity by means of two different in vitro assays. Silica nanoparticles with diameters of 30 and 70 nm (nSP30 and nSP70, respectively) tended to inhibit CYP3A4 activity in human liver microsomes (HLMs), but the inhibitory activity of both types of nanoparticles was decreased by carboxyl modification. In contrast, amine-modified nSP70 activated CYP3A4 activity. In HepG2 cells, nSP30 inhibited CYP3A4 activity more strongly than the larger silica particles did. Taken together, these results suggest that the size and surface characteristics of the silica particles determined their effects on CYP3A4 activity and that it may be possible to develop silica particles that do not have undesirable effects on metabolic enzymes by altering their size and surface characteristics. PMID- 25520599 TI - Numerical simulations of the current-matching effect and operation mechanisms on the performance of InGaN/Si tandem cells. AB - Numerical simulations are conducted to study the current-matching effect and operation mechanisms in and to design the optimized device structure of InGaN/Si tandem cells. The characteristics of short circuit current density (J sc), open circuit voltage (V oc), fill factor (FF), and conversion efficiency (eta) of InGaN/Si tandem cells are determined by the current-matching effect. The similar trend of eta to that of J sc shows that J sc is a dominant factor in determining the performance of InGaN/Si tandem cells. In addition, the combined effects of the J sc, V oc, and FF lead to an optimized eta in the medium-indium, [Formula: see text], InGaN/Si tandem cell. At [Formula: see text], the J sc of the InGaN subcell is equal to that of the Si subcell such that an InGaN/Si tandem cell reaches the current matching condition to operate at the maximum power point. Similar to the J sc and FF, the eta for low- [Formula: see text] and high-In [Formula: see text] InGaN/Si tandem cells are InGaN- and Si subcell-limited, respectively. Furthermore, the p- and n-layer thicknesses, indium content, and position of depletion region of InGaN subcell should be adjusted to reapportion the light between the two subcells and to achieve the maximum conversion efficiency. With appropriate thicknesses of p- and n-InGaN, In0.5-0.6Ga0.5-0.4 N/Si tandem cells can exhibit as high as approximately 34% to 36.5% conversion efficiency, demonstrating that a medium-indium InGaN/Si tandem cell results in a high-efficiency solar cell. Simulation results determine that the current matching effect and operation mechanisms of InGaN/Si tandem cells can be utilized for efficiency enhancement through the optimized device structures. PMID- 25520600 TI - Temperature-induced reversible self-assembly of diphenylalanine peptide and the structural transition from organogel to crystalline nanowires. AB - Controlling the self-assembly of diphenylalanine peptide (FF) into various nanoarchitectures has received great amounts of attention in recent years. Here, we report the temperature-induced reversible self-assembly of diphenylalanine peptide to microtubes, nanowires, or organogel in different solvents. We also find that the organogel in isopropanol transforms into crystalline flakes or nanowires when the temperature increases. The reversible self-assembly in polar solvents may be mainly controlled by electronic and aromatic interactions between the FF molecules themselves, which is associated with the dissociation equilibrium and significantly influenced by temperature. We found that the organogel in the isopropanol solvent made a unique transition to crystalline structures, a process that is driven by temperature and may be kinetically controlled. During the heating-cooling process, FF preferentially self-assembles to metastable nanofibers and organogel. They further transform to thermodynamically stable crystal structures via molecular rearrangement after introducing an external energy, such as the increasing temperature used in this study. The strategy demonstrated in this study provides an efficient way to controllably fabricate smart, temperature-responsive peptide nanomaterials and enriches the understanding of the growth mechanism of diphenylalanine peptide nanostructures. PMID- 25520601 TI - Periodic nano/micro-hole array silicon solar cell. AB - In this study, we applied a metal catalyst etching method to fabricate a nano/microhole array on a Si substrate for application in solar cells. In addition, the surface of an undesigned area was etched because of the attachment of metal nanoparticles that is dissociated in a solution. The nano/microhole array exhibited low specular reflectance (<1%) without antireflection coating because of its rough surface. The solar spectrum related total reflection was approximately 9%. A fabricated solar cell with a 40-MUm hole spacing exhibited an efficiency of 9.02%. Comparing to the solar cell made by polished Si, the external quantum efficiency for solar cell with 30 s etching time was increased by 16.7%. PMID- 25520602 TI - Silica-sol-based spin-coating barrier layer against phosphorous diffusion for crystalline silicon solar cells. AB - The phosphorus barrier layers at the doping procedure of silicon wafers were fabricated using a spin-coating method with a mixture of silica-sol and tetramethylammonium hydroxide, which can be formed at the rear surface prior to the front phosphorus spin-on-demand (SOD) diffusion and directly annealed simultaneously with the front phosphorus layer. The optimization of coating thickness was obtained by changing the applied spin-coating speed; from 2,000 to 8,000 rpm. The CZ-Si p-type silicon solar cells were fabricated with/without using the rear silica-sol layer after taking the sheet resistance measurements, SIMS analysis, and SEM measurements of the silica-sol material evaluations into consideration. For the fabrication of solar cells, a spin-coating phosphorus source was used to form the n(+) emitter and was then diffused at 930 degrees C for 35 min. The out-gas diffusion of phosphorus could be completely prevented by spin-coated silica-sol film placed on the rear side of the wafers coated prior to the diffusion process. A roughly 2% improvement in the conversion efficiency was observed when silica-sol was utilized during the phosphorus diffusion step. These results can suggest that the silica-sol material can be an attractive candidate for low-cost and easily applicable spin-coating barrier for any masking purpose involving phosphorus diffusion. PMID- 25520603 TI - Horizontal transfer of aligned Si nanowire arrays and their photoconductive performance. AB - An easy and low-cost method to transfer large-scale horizontally aligned Si nanowires onto a substrate is reported. Si nanowires prepared by metal-assisted chemical etching were assembled and anchored to fabricate multiwire photoconductive devices with standard Si technology. Scanning electron microscopy images showed highly aligned and successfully anchored Si nanowires. Current voltage tests showed an approximately twofold change in conductivity between the devices in dark and under laser irradiation. Fully reversible light switching ON/OFF response was also achieved with an I ON/I OFF ratio of 230. Dynamic response measurement showed a fast switching feature with response and recovery times of 10.96 and 19.26 ms, respectively. PMID- 25520604 TI - Improved Exciton Dissociation at Semiconducting Polymer:ZnO Donor:Acceptor Interfaces via Nitrogen Doping of ZnO. AB - Exciton dissociation at the zinc oxide/poly(3-hexylthiophene) (ZnO/P3HT) interface as a function of nitrogen doping of the zinc oxide, which decreases the electron concentration from approximately 1019 cm-3 to 1017 cm-3, is reported. Exciton dissociation and device photocurrent are strongly improved with nitrogen doping. This improved dissociation of excitons in the conjugated polymer is found to result from enhanced light-induced de-trapping of electrons from the surface of the nitrogen-doped ZnO. The ability to improve the surface properties of ZnO by introducing a simple nitrogen dopant has general applicability. PMID- 25520605 TI - Signet ring cell carcinoma of the extrahepatic bile duct diagnosed by preoperative biopsy: a case report. AB - A 73-year-old woman was admitted because of obstructive jaundice. Computed tomography revealed a stricture in the lower bile duct with enhanced bile duct wall. Endoscopic retrograde cholangiopancreatography (ERCP) revealed a tapering stenosis at the lower bile duct. Transpapillary histological biopsy using biopsy forceps through ERCP was performed; the diagnosis of signet ring cell carcinoma (SRCC) of the bile duct was established. Regional lymph node enlargement and distant metastases were not detected on diagnostic imaging. Pancreaticoduodenectomy with pylorus preservation was performed. Histological examination of the resected specimen confirmed SRCC of the extrahepatic bile duct coexisting with adenocarcinoma (ADC) of the extrahepatic bile duct with negative resection margins. However, tumor cells directly invaded the pancreatic parenchyma and the muscle layer of the duodenum, prompting us to administer adjuvant chemotherapy to the patient, with no sign of tumor recurrence at 1-year follow-up. Almost all tumors originating from the extrahepatic bile duct are ADC and other histological variants are rare. Of these, SRCC is extremely rare and only four cases have been reported. Furthermore, to the best of our knowledge, this is the first case report regarding the preoperative diagnosis of SRCC of the bile duct. Current reports indicate that younger age and Asian ethnicity are the clinical features of SRCC of the extrahepatic bile duct. Immunohistochemical staining of CK7, CK20 and MUC2 may be useful for predicting prognosis. Chemotherapy has not resulted in increased survival rates and only surgical resection currently serves as a curative treatment. PMID- 25520606 TI - Mind the sump! - diagnostic challenge of a rare complication of choledochoduodenostomy. AB - Sump syndrome is a rare long-term complication of side-to-side choledochoduodenostomy (CDD), a common surgical procedure in patients with biliary tract disease in the era before endoscopic retrograde cholangiopancreatography (ERCP). Frequently only pneumobilia, serving as sign for functioning biliary-enteric anastomosis, is reminiscent of the former surgery. We present the case of an 81-year-old patient with sump syndrome who presented with clinical signs of ascending cholangitis, decades after the initial CDD procedure. Finally the detailed medical history that was taken very thoroughly in combination with the presence of pneumobilia led to the suspicion of sump syndrome. Sump syndrome was diagnosed by ERCP, and after endoscopic debris extraction and antibiotic treatment the patient recovered quickly. In the ERCP era little is known about CDD and its long-term complications, especially by young colleagues and trainees. Therefore this report provides an excellent opportunity to refresh the knowledge and raise awareness for this syndrome. PMID- 25520607 TI - Do you hear where I hear?: isolating the individualized sound localization cues. AB - It is widely acknowledged that individualized head-related transfer function (HRTF) measurements are needed to adequately capture all of the 3D spatial hearing cues. However, many perceptual studies have shown that localization accuracy in the lateral dimension is only minimally decreased by the use of non individualized head-related transfer functions. This evidence supports the idea that the individualized components of an HRTF could be isolated from those that are more general in nature. In the present study we decomposed the HRTF at each location into average, lateral and intraconic spectral components, along with an ITD in an effort to isolate the sound localization cues that are responsible for the inter-individual differences in localization performance. HRTFs for a given listener were then reconstructed systematically with components that were both individualized and non-individualized in nature, and the effect of each modification was analyzed via a virtual localization test where brief 250 ms noise bursts were rendered with the modified HRTFs. Results indicate that the cues important for individualization of HRTFs are contained almost exclusively in the intraconic portion of the HRTF spectra and localization is only minimally affected by introducing non-individualized cues into the other HRTF components. These results provide new insights into what specific inter-individual differences in head-related acoustical features are most relevant to sound localization, and provide a framework for how future human-machine interfaces might be more effectively generalized and/or individualized. PMID- 25520608 TI - Artificial Neural Network classification of operator workload with an assessment of time variation and noise-enhancement to increase performance. AB - Workload classification-the determination of whether a human operator is in a high or low workload state to allow their working environment to be optimized-is an emerging application of passive Brain-Computer Interface (BCI) systems. Practical systems must not only accurately detect the current workload state, but also have good temporal performance: requiring little time to set up and train the classifier, and ensuring that the reported performance level is consistent and predictable over time. This paper investigates the temporal performance of an Artificial Neural Network based classification system. For networks trained on little EEG data good classification accuracies (86%) are achieved over very short time frames, but substantial decreases in accuracy are found as the time gap between the network training and the actual use is increased. Noise-enhanced processing, where artificially generated noise is deliberately added to the testing signals, is investigated as a potential technique to mitigate this degradation without requiring the network to be re-trained using more data. Small stochastic resonance effects are demonstrated whereby the classification process gets better in the presence of more noise. The effect is small and does not eliminate the need for re-training, but it is consistent, and this is the first demonstration of such effects for non-evoked/free-running EEG signals suitable for passive BCI. PMID- 25520609 TI - Brain-immune interactions in health and disease. PMID- 25520610 TI - Central regulation of food intake, body weight, energy expenditure, and glucose homeostasis. PMID- 25520613 TI - Synaptic vesicles are "primed" for fast clathrin-mediated endocytosis at the ribbon synapse. AB - Retrieval of synaptic vesicles can occur 1-10 s after fusion, but the role of clathrin during this process has been unclear because the classical mode of clathrin-mediated endocytosis (CME) is an order of magnitude slower, as during retrieval of surface receptors. Classical CME is thought to be rate-limited by the recruitment of clathrin, which raises the question: how is clathrin recruited during synaptic vesicle recycling? To investigate this question we applied total internal reflection fluorescence microscopy (TIRFM) to the synaptic terminal of retinal bipolar cells expressing fluorescent constructs of clathrin light-chain A. Upon calcium influx we observed a fast accumulation of clathrin within 100 ms at the periphery of the active zone. The subsequent loss of clathrin from these regions reflected endocytosis because the application of a potent clathrin inhibitor Pitstop2 dramatically slowed down this phase by ~3 fold. These results indicate that clathrin-dependent retrieval of synaptic vesicles is unusually fast, most probably because of a "priming" step involving a state of association of clathrin with the docked vesicle and with the endosomes and cisternae surrounding the ribbons. Fluorescence correlation spectroscopy (FCS) and fluorescence recovery after photobleaching (FRAP) showed that the majority of clathrin is moving with the same kinetics as synaptic vesicle proteins. Together, these results indicate that the fast endocytic mechanism operating to retrieve synaptic vesicles differs substantially from the classical mode of CME operating via formation of a coated pit. PMID- 25520611 TI - Neural pathways for visual speech perception. AB - This paper examines the questions, what levels of speech can be perceived visually, and how is visual speech represented by the brain? Review of the literature leads to the conclusions that every level of psycholinguistic speech structure (i.e., phonetic features, phonemes, syllables, words, and prosody) can be perceived visually, although individuals differ in their abilities to do so; and that there are visual modality-specific representations of speech qua speech in higher-level vision brain areas. That is, the visual system represents the modal patterns of visual speech. The suggestion that the auditory speech pathway receives and represents visual speech is examined in light of neuroimaging evidence on the auditory speech pathways. We outline the generally agreed-upon organization of the visual ventral and dorsal pathways and examine several types of visual processing that might be related to speech through those pathways, specifically, face and body, orthography, and sign language processing. In this context, we examine the visual speech processing literature, which reveals widespread diverse patterns of activity in posterior temporal cortices in response to visual speech stimuli. We outline a model of the visual and auditory speech pathways and make several suggestions: (1) The visual perception of speech relies on visual pathway representations of speech qua speech. (2) A proposed site of these representations, the temporal visual speech area (TVSA) has been demonstrated in posterior temporal cortex, ventral and posterior to multisensory posterior superior temporal sulcus (pSTS). (3) Given that visual speech has dynamic and configural features, its representations in feedforward visual pathways are expected to integrate these features, possibly in TVSA. PMID- 25520614 TI - Intracisternal delivery of NFkappaB-inducible scAAV2/9 reveals locoregional neuroinflammation induced by systemic kainic acid treatment. AB - We have previously demonstrated disease-dependent gene delivery in the brain using an AAV vector responding to NFkappaB activation as a probe for inflammatory responses. This vector, injected focally in the parenchyma prior to a systemic kainic acid (KA) injection mediated inducible transgene expression in the hippocampus but not in the cerebellum, regions, respectively, known to be affected or not by the pathology. However, such a focal approach relies on previous knowledge of the model parameters and does not allow to predict the whole brain response to the disease. Global brain gene delivery would allow to predict the regional distribution of the pathology as well as to deliver therapeutic factors in all affected brain regions. We show that self complementary AAV2/9 (scAAV2/9) delivery in the adult rat cisterna magna allows a widespread but not homogenous transduction of the brain. Indeed, superficial regions, i.e., cortex, hippocampus, and cerebellum were more efficiently transduced than deeper regions, such as striatum, and substantia nigra. These data suggest that viral particles penetration from the cerebrospinal fluid (CSF) into the brain is a limiting factor. Interestingly, AAV2/9-2YF a rationally designed capsid mutant (affecting surface tyrosines) increased gene transfer efficiency approximately fivefold. Neurons, astrocytes, and oligodendrocytes, but not microglia, were transduced in varying proportions depending on the brain region and the type of capsid. Finally, after a single intracisternal injection of scAAV2/9-2YF using the NFkappaB-inducible promoter, KA treatment induced transgene expression in the hippocampus and cortex but not in the cerebellum, corresponding to the expression of the CD11b marker of microglial activation. These data support the use of disease-inducible vectors administered in the cisterna magna as a tool to characterize the brain pathology in systemic drug induced or transgenic disease models. However, further improvements are required to enhance viral particles penetration into the brain. PMID- 25520615 TI - Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade. AB - Ketamine is a N-methyl-D-aspartate receptor (NMDAR) antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDAR activation at rest, which inhibits eukaryotic elongation factor 2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from adult animals. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDARs is sufficient to trigger this effect. These findings suggest that global blockade of NMDARs in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine. PMID- 25520616 TI - Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats. AB - The second messenger cyclic GMP affects synaptic transmission and modulates synaptic plasticity and certain types of learning and memory processes. The impact of the natriuretic peptide receptor B (NPR-B) and its ligand C-type natriuretic peptide (CNP), one of several cGMP producing signaling systems, on hippocampal synaptic plasticity and learning is, however, less well understood. We have previously shown that the NPR-B ligand CNP increases the magnitude of long-term depression (LTD) in hippocampal area CA1, while reducing the induction of long-term potentiation (LTP). We have extended this line of research to show that bidirectional plasticity is affected in the opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-BDeltaKC) lacking the intracellular guanylyl cyclase domain under control of a promoter for neuron-specific enolase. The brain cells of these transgenic rats express functional dimers of the NPR-B receptor containing the dominant-negative NPR-BDeltaKC mutant, and therefore show decreased CNP-stimulated cGMP-production in brain membranes. The NPR-B transgenic rats display enhanced LTP but reduced LTD in hippocampal slices. When the frequency-dependence of synaptic modification to afferent stimulation in the range of 1-100 Hz was assessed in transgenic rats, the threshold for both, LTP and LTD induction, was shifted to lower frequencies. In parallel, NPR-BDeltaKC rats exhibited an enhancement in exploratory and learning behavior. These results indicate that bidirectional plasticity and learning and memory mechanism are affected in transgenic rats expressing a dominant-negative mutant of NPR-B. Our data substantiate the hypothesis that NPR-B-dependent cGMP signaling has a modulatory role for synaptic information storage and learning. PMID- 25520617 TI - Local ubiquitin-proteasome-mediated proteolysis and long-term synaptic plasticity. AB - The ubiquitin-proteasome pathway (UPP) of protein degradation has many roles in synaptic plasticity that underlies memory. Work on both invertebrate and vertebrate model systems has shown that the UPP regulates numerous substrates critical for synaptic plasticity. Initial research took a global view of ubiquitin-protein degradation in neurons. Subsequently, the idea of local protein degradation was proposed a decade ago. In this review, we focus on the functions of the UPP in long-term synaptic plasticity and discuss the accumulated evidence in support of the idea that the components of the UPP often have disparate local roles in different neuronal compartments rather than a single cell-wide function. PMID- 25520618 TI - Olfactory impairment in the rotenone model of Parkinson's disease is associated with bulbar dopaminergic D2 activity after REM sleep deprivation. AB - Olfactory and rapid eye movement (REM) sleep deficits are commonly found in untreated subjects with a recent diagnosis of Parkinson's disease (PD). Additionally, different studies report declines in olfactory performance during a short period of sleep deprivation. Mechanisms underlying these clinical manifestations are poorly understood, and impairment of dopamine (DA) neurotransmission in the olfactory bulb and the nigrostriatal pathway may have important roles in olfaction and REM sleep disturbances. Therefore, we hypothesized that modulation of the dopaminergic D2 receptors in the olfactory bulb could provide a more comprehensive understanding of the olfactory deficits in PD and REM sleep deprivation (REMSD). We decided to investigate the olfactory, neurochemical, and histological alterations generated through the administration of piribedil (a selective D2 agonist) or raclopride (a selective D2 antagonist) within the glomerular layer of the olfactory bulb, in rats subjected to intranigral rotenone and REMSD. Our findings provide evidence of the occurrence of a negative correlation (r = -0.52, P = 0.04) between the number of periglomerular TH-ir neurons and the bulbar levels of DA in the rotenone, but not sham, groups. A significant positive correlation (r = 0.34, P = 0.03) was observed between nigrostriatal DA levels and olfactory discrimination index (DI) for the sham groups, indicating that increased DA levels in the substantia nigra pars compacta (SNpc) are associated with enhanced olfactory discrimination performance. Also, increased levels in bulbar and striatal DA were induced by piribedil in the rotenone control and rotenone REMSD groups, consistent with reductions in the DI. The present evidence reinforce the idea that DA produced by periglomerular neurons, particularly the bulbar dopaminergic D2 receptors, is an essential participant in olfactory discrimination processes, as the SNpc, and the striatum. PMID- 25520612 TI - "You Shall Not Pass"-tight junctions of the blood brain barrier. AB - The structure and function of the barrier layers restricting the free diffusion of substances between the central nervous system (brain and spinal cord) and the systemic circulation is of great medical interest as various pathological conditions often lead to their impairment. Excessive leakage of blood-borne molecules into the parenchyma and the concomitant fluctuations in the microenvironment following a transient breakdown of the blood-brain barrier (BBB) during ischemic/hypoxic conditions or because of an autoimmune disease are detrimental to the physiological functioning of nervous tissue. On the other hand, the treatment of neurological disorders is often hampered as only minimal amounts of therapeutic agents are able to penetrate a fully functional BBB or blood cerebrospinal fluid barrier. An in-depth understanding of the molecular machinery governing the establishment and maintenance of these barriers is necessary to develop rational strategies allowing a controlled delivery of appropriate drugs to the CNS. At the basis of such tissue barriers are intimate cell-cell contacts (zonulae occludentes, tight junctions) which are present in all polarized epithelia and endothelia. By creating a paracellular diffusion constraint TJs enable the vectorial transport across cell monolayers. More recent findings indicate that functional barriers are already established during development, protecting the fetal brain. As an understanding of the biogenesis of TJs might reveal the underlying mechanisms of barrier formation during ontogenic development numerous in vitro systems have been developed to study the assembly and disassembly of TJs. In addition, monitoring the stage-specific expression of TJ-associated proteins during development has brought much insight into the "developmental tightening" of tissue barriers. Over the last two decades a detailed molecular map of transmembrane and cytoplasmic TJ-proteins has been identified. These proteins not only form a cell-cell adhesion structure, but integrate various signaling pathways, thereby directly or indirectly impacting upon processes such as cell-cell adhesion, cytoskeletal rearrangement, and transcriptional control. This review will provide a brief overview on the establishment of the BBB during embryonic development in mammals and a detailed description of the ultrastructure, biogenesis, and molecular composition of epithelial and endothelial TJs will be given. PMID- 25520619 TI - Differentiation of pluripotent stem cells into striatal projection neurons: a pure MSN fate may not be sufficient. AB - Huntington's disease (HD) is an autosomal dominant inherited disorder leading to the loss inter alia of DARPP-32 positive medium spiny projection neurons ("MSNs") in the striatum. There is no known cure for HD but the relative specificity of cell loss early in the disease has made cell replacement by neural transplantation an attractive therapeutic possibility. Transplantation of human fetal striatal precursor cells has shown "proof-of-principle" in clinical trials; however, the practical and ethical difficulties associated with sourcing fetal tissues have stimulated the need to identify alternative source(s) of donor cells that are more readily available and more suitable for standardization. We now have available the first generation of protocols to generate DARPP-32 positive MSN-like neurons from pluripotent stem cells and these have been successfully grafted into animal models of HD. However, whether these grafts can provide stable functional recovery to the level that can regularly be achieved with primary fetal striatal grafts remains to be demonstrated. Of particular concern, primary fetal striatal grafts are not homogenous; they contain not only the MSN subpopulation of striatal projection neurons but also include all the different cell types that make up the mature striatum, such as the multiple populations of striatal interneurons and striatal glia, and which certainly contribute to normal striatal function. By contrast, present protocols for pluripotent stem cell differentiation are almost entirely targeted at specifying just neurons of an MSN lineage. So far, evidence for the functionality and integration of stem-cell derived grafts is correspondingly limited. Indeed, consideration of the features of full striatal reconstruction that is achieved with primary fetal striatal grafts suggests that optimal success of the next generations of stem cell-derived replacement therapy in HD will require that graft protocols be developed to allow inclusion of multiple striatal cell types, such as interneurons and/or glia. Almost certainly, therefore, more sophisticated differentiation protocols will be necessary, over and above replacement of a specific population of MSNs. A rational solution to this technical challenge requires that we re-address the underlying question-what constitutes a functional striatal graft? PMID- 25520620 TI - ER stress and unfolded protein response in amyotrophic lateral sclerosis-a controversial role of protein disulphide isomerase. AB - Accumulation of proteins in aberrant conformation occurs in many neurodegenerative diseases. Furthermore, dysfunctions in protein handling in endoplasmic reticulum (ER) and the following ER stress have been implicated in a vast number of diseases, such as amyotrophic lateral sclerosis (ALS). During excessive ER stress unfolded protein response (UPR) is activated to return ER to its normal physiological balance. The exact mechanisms of protein misfolding, accumulation and the following ER stress, which could lead to neurodegeneration, and the question whether UPR is a beneficial compensatory mechanism slowing down the neurodegenerative processes, are of interest. Protein disulphide isomerase (PDI) is a disulphide bond-modulating ER chaperone, which can also facilitate the ER-associated degradation (ERAD) of misfolded proteins. In this review we discuss the recent findings of ER stress, UPR and especially the role of PDI in ALS. PMID- 25520621 TI - Prenatal nicotine exposure enhances Cx43 and Panx1 unopposed channel activity in brain cells of adult offspring mice fed a high-fat/cholesterol diet. AB - Nicotine, the most important neuroteratogen of tobacco smoke, can reproduce brain and cognitive disturbances per se when administered prenatally. However, it is still unknown if paracrine signaling among brain cells participates in prenatal nicotine-induced brain impairment of adult offspring. Paracrine signaling is partly mediated by unopposed channels formed by connexins hemichannels (HCs) and pannexins serving as aqueous pores permeable to ions and small signaling molecules, allowing exchange between the intra- and extracellular milieus. Our aim was to address whether prenatal nicotine exposure changes the activity of those channels in adult mice offspring under control conditions or subjected to a second challenge during young ages: high-fat/cholesterol (HFC) diet. To induce prenatal exposure to nicotine, osmotic minipumps were implanted in CF1 pregnant mice at gestational day 5 to deliver nicotine bitartrate or saline (control) solutions. After weaning, offspring of nicotine-treated or untreated pregnant mice were fed ad libitum with chow or HFC diets for 8 weeks. The functional state of connexin 43 (Cx43) and pannexin 1 (Panx1) unopposed channels was evaluated by dye uptake experiments in hippocampal slices from 11-week-old mice. We found that prenatal nicotine increased the opening of Cx43 HCs in astrocytes, and Panx1 channels in microglia and neurons only if offspring mice were fed with HFC diet. Blockade of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2) and prostaglandin E receptor 1 (EP1), ionotropic ATP receptor type 7 (P2X7) and NMDA receptors, showed differential inhibition of prenatal nicotine-induced channel opening in glial cells and neurons. Importantly, inhibition of the above mentioned enzymes and receptors, or blockade of Cx43 and Panx1 unopposed channels greatly reduced adenosine triphosphate (ATP) and glutamate release from hippocampal slices of prenatally nicotine-exposed offspring. We propose that unregulated gliotransmitter release through Cx43 and Panx1 unopposed channels may participate in brain alterations observed in offspring of mothers exposed to tobacco smoke during pregnancy. PMID- 25520622 TI - Shedding of APP limits its synaptogenic activity and cell adhesion properties. AB - The amyloid precursor protein (APP) plays a central role in Alzheimer's disease (AD) and has essential synapse promoting functions. Synaptogenic activity as well as cell adhesion properties of APP presumably depend on trans-cellular dimerization via its extracellular domain. Since neuronal APP is extensively processed by secretases, it raises the question if APP shedding affects its cell adhesion and synaptogenic properties. We show that inhibition of APP shedding using cleavage deficient forms of APP or a dominant negative alpha-secretase strongly enhanced its cell adhesion and synaptogenic activity suggesting that synapse promoting function of APP is tightly regulated by alpha-secretase mediated processing, similar to other trans-cellular synaptic adhesion molecules. PMID- 25520623 TI - Transcriptional control of vertebrate neurogenesis by the proneural factor Ascl1. AB - Proneural transcription factors (TFs) such as Ascl1 function as master regulators of neurogenesis in vertebrates, being both necessary and sufficient for the activation of a full program of neuronal differentiation. Novel insights into the dynamics of Ascl1 expression at the cellular level, combined with the progressive characterization of its transcriptional program, have expanded the classical view of Ascl1 as a differentiation factor in neurogenesis. These advances resulted in a new model, whereby Ascl1 promotes sequentially the proliferation and differentiation of neural/stem progenitor cells. The multiple activities of Ascl1 are associated with the activation of distinct direct targets at progressive stages along the neuronal lineage. How this temporal pattern is established is poorly understood. Two modes of Ascl1 expression recently described (oscillatory vs. sustained) are likely to be of importance, together with additional mechanistic determinants such as the chromatin landscape and other transcriptional pathways. Here we revise these latest findings, and discuss their implications to the gene regulatory functions of Ascl1 during neurogenesis. PMID- 25520624 TI - The sacral networks and neural pathways used to elicit lumbar motor rhythm in the rodent spinal cord. AB - Identification of neural networks and pathways involved in activation and modulation of spinal central pattern generators (CPGs) in the absence of the descending control from the brain is important for further understanding of neural control of movement and for developing innovative therapeutic approaches to improve the mobility of spinal cord injury patients. Activation of the hindlimb innervating segments by sacrocaudal (SC) afferent input and by specific application of neurochemicals to the sacral networks is feasible in the isolated spinal cord preparation of the newborn rat. Here we review our recent studies of sacral relay neurons with lumbar projections and evaluate their role in linking the sacral and thoracolumbar (TL) networks during different motor behaviors. Our major findings show that: (1) heterogeneous groups of dorsal, intermediate and ventral sacral-neurons with ventral and lateral ascending funicular projections mediate the activation of the locomotor CPGs through sacral sensory input; and (2) rhythmic excitation of lumbar flexor motoneurons, produced by bath application of alpha-1 adrenoceptor agonists to the sacral segments is mediated exclusively by ventral clusters of sacral-neurons with lumbar projections through the ventral funiculus. PMID- 25520625 TI - Notch signaling and proneural genes work together to control the neural building blocks for the initial scaffold in the hypothalamus. AB - The vertebrate embryonic prosencephalon gives rise to the hypothalamus, which plays essential roles in sensory information processing as well as control of physiological homeostasis and behavior. While patterning of the hypothalamus has received much attention, initial neurogenesis in the developing hypothalamus has mostly been neglected. The first differentiating progenitor cells of the hypothalamus will give rise to neurons that form the nucleus of the tract of the postoptic commissure (nTPOC) and the nucleus of the mammillotegmental tract (nMTT). The formation of these neuronal populations has to be highly controlled both spatially and temporally as these tracts will form part of the ventral longitudinal tract (VLT) and act as a scaffold for later, follower axons. This review will cumulate and summarize the existing data available describing initial neurogenesis in the vertebrate hypothalamus. It is well-known that the Notch signaling pathway through the inhibition of proneural genes is a key regulator of neurogenesis in the vertebrate central nervous system. It has only recently been proposed that loss of Notch signaling in the developing chick embryo causes an increase in the number of neurons in the hypothalamus, highlighting an early function of the Notch pathway during hypothalamus formation. Further analysis in the chick and mouse hypothalamus confirms the expression of Notch components and Ascl1 before the appearance of the first differentiated neurons. Many newly identified proneural target genes were also found to be expressed during neuronal differentiation in the hypothalamus. Given the critical role that hypothalamic neural circuitry plays in maintaining homeostasis, it is particularly important to establish the targets downstream of this Notch/proneural network. PMID- 25520627 TI - Embryonic development of circadian clocks in the mammalian suprachiasmatic nuclei. AB - In most species, self-sustained molecular clocks regulate 24-h rhythms of behavior and physiology. In mammals, a circadian pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN) receives photic signals from the retina and synchronizes subordinate clocks in non-SCN tissues. The emergence of circadian rhythmicity during development has been extensively studied for many years. In mice, neuronal development in the presumptive SCN region of the embryonic hypothalamus occurs on days 12-15 of gestation. Intra-SCN circuits differentiate during the following days and retinal projections reach the SCN, and thus mediate photic entrainment, only after birth. In contrast the genetic components of the clock gene machinery are expressed much earlier and during midgestation SCN explants and isolated neurons are capable of generating molecular oscillations in culture. In vivo metabolic rhythms in the SCN, however, are observed not earlier than the 19th day of rat gestation, and rhythmic expression of clock genes is hardly detectable until after birth. Together these data indicate that cellular coupling and, thus, tissue-wide synchronization of single-cell rhythms, may only develop very late during embryogenesis. In this mini-review we describe the developmental origin of the SCN structure and summarize our current knowledge about the functional initiation and entrainment of the circadian pacemaker during embryonic development. PMID- 25520626 TI - Input transformation by dendritic spines of pyramidal neurons. AB - In the mammalian brain, most inputs received by a neuron are formed on the dendritic tree. In the neocortex, the dendrites of pyramidal neurons are covered by thousands of tiny protrusions known as dendritic spines, which are the major recipient sites for excitatory synaptic information in the brain. Their peculiar morphology, with a small head connected to the dendritic shaft by a slender neck, has inspired decades of theoretical and more recently experimental work in an attempt to understand how excitatory synaptic inputs are processed, stored and integrated in pyramidal neurons. Advances in electrophysiological, optical and genetic tools are now enabling us to unravel the biophysical and molecular mechanisms controlling spine function in health and disease. Here I highlight relevant findings, challenges and hypotheses on spine function, with an emphasis on the electrical properties of spines and on how these affect the storage and integration of excitatory synaptic inputs in pyramidal neurons. In an attempt to make sense of the published data, I propose that the raison d'etre for dendritic spines lies in their ability to undergo activity-dependent structural and molecular changes that can modify synaptic strength, and hence alter the gain of the linearly integrated sub-threshold depolarizations in pyramidal neuron dendrites before the generation of a dendritic spike. PMID- 25520628 TI - nkx2.1 and nkx2.4 genes function partially redundant during development of the zebrafish hypothalamus, preoptic region, and pallidum. AB - During ventral forebrain development, orthologs of the homeodomain transcription factor Nkx2.1 control patterning of hypothalamus, preoptic region, and ventral telencephalon. However, the relative contributions of Nkx2.1 and Nkx2.4 to prosencephalon development are poorly understood. Therefore, we analyzed functions of the previously uncharacterized nkx2.4-like zgc:171531 as well as of the presumed nkx2.1 orthologs nkx2.1a and nkx2.1b in zebrafish forebrain development. Our results show that zgc:171531 and nkx2.1a display overlapping expression patterns and a high sequence similarity. Together with a high degree of synteny conservation, these findings indicate that both these genes indeed are paralogs of nkx2.4. As a result, we name zgc:171531 now nkx2.4a, and changed the name of nkx2.1a to nkx2.4b, and of nkx2.1b to nkx2.1. In nkx2.1, nkx2.4a, and nkx2.4b triple morpholino knockdown (nkx2TKD) embryos we observed a loss of the rostral part of prosomere 3 and its derivative posterior tubercular and hypothalamic structures. Furthermore, there was a loss of rostral and intermediate hypothalamus, while a residual preoptic region still develops. The reduction of the ventral diencephalon was accompanied by a ventral expansion of the dorsally expressed pax6, revealing a dorsalization of the basal hypothalamus. Within the telencephalon we observed a loss of pallidal markers, while striatum and pallium are forming. At the neuronal level, nkx2TKD morphants lacked several neurosecretory neuron types, including avp, crh, and pomc expressing cells in the hypothalamus, but still form oxt neurons in the preoptic region. Our data reveals that, while nkx2.1, nkx2.4a, and nkx2.4b genes act partially redundant in hypothalamic development, nkx2.1 is specifically involved in the development of rostral ventral forebrain including the pallidum and preoptic regions, whereas nkx2.4a and nkx2.4b control the intermediate and caudal hypothalamus. PMID- 25520630 TI - Some predictions of Rafael Lorente de No 80 years later. AB - Rafael Lorente de No, the youngest of Santiago Ramon y Cajal disciples, was one of the last Century's more influential researches in neuroscience. This assay highlights two fundamental contributions of Rafael Lorente de No to neurobiology: the intrinsic organization of the mammalian cerebral cortex and the basic physiology of the neuron processes. PMID- 25520629 TI - Calbindin content and differential vulnerability of midbrain efferent dopaminergic neurons in macaques. AB - Calbindin (CB) is a calcium binding protein reported to protect dopaminergic neurons from degeneration. Although a direct link between CB content and differential vulnerability of dopaminergic neurons has long been accepted, factors other than CB have also been suggested, particularly those related to the dopamine transporter. Indeed, several studies have reported that CB levels are not causally related to the differential vulnerability of dopaminergic neurons against neurotoxins. Here we have used dual stains for tyrosine hydroxylase (TH) and CB in 3 control and 3 MPTP-treated monkeys to visualize dopaminergic neurons in the ventral tegmental area (VTA) and in the dorsal and ventral tiers of the substantia nigra pars compacta (SNcd and SNcv) co-expressing TH and CB. In control animals, the highest percentages of co-localization were found in VTA (58.2%), followed by neurons located in the SNcd (34.7%). As expected, SNcv neurons lacked CB expression. In MPTP-treated animals, the percentage of CB-ir/TH ir neurons in the VTA was similar to control monkeys (62.1%), whereas most of the few surviving neurons in the SNcd were CB-ir/TH-ir (88.6%). Next, we have elucidated the presence of CB within identified nigrostriatal and nigroextrastriatal midbrain dopaminergic projection neurons. For this purpose, two control monkeys received one injection of Fluoro-Gold into the caudate nucleus and one injection of cholera toxin (CTB) into the postcommissural putamen, whereas two more monkeys were injected with CTB into the internal division of the globus pallidus (GPi). As expected, all the nigrocaudate- and nigroputamen-projecting neurons were TH-ir, although surprisingly, all of these nigrostriatal-projecting neurons were negative for CB. Furthermore, all the nigropallidal-projecting neurons co-expressed both TH and CB. In summary, although CB-ir dopaminergic neurons seem to be less prone to MPTP-induced degeneration, our data clearly demonstrated that these neurons are not giving rise to nigrostriatal projections and indeed CB-ir/TH-ir neurons only originate nigroextrastriatal projections. PMID- 25520632 TI - Bottlenecks to clinical translation of direct brain-computer interfaces. AB - Despite several decades of research into novel brain-implantable devices to treat a range of diseases, only two-cochlear implants for sensorineural hearing loss and deep brain stimulation for movement disorders-have yielded any appreciable clinical benefit. Obstacles to translation include technical factors (e.g., signal loss due to gliosis or micromotion), lack of awareness of current clinical options for patients that the new therapy must outperform, traversing between federal and corporate funding needed to support clinical trials, and insufficient management expertise. This commentary reviews these obstacles preventing the translation of promising new neurotechnologies into clinical application and suggests some principles that interdisciplinary teams in academia and industry could adopt to enhance their chances of success. PMID- 25520633 TI - Endogenous fMRI default mode network fluctuations both positively and negatively correlate with individual transfer of learning. PMID- 25520631 TI - Short-term plasticity and modulation of synaptic transmission at mammalian inhibitory cholinergic olivocochlear synapses. AB - The organ of Corti, the mammalian sensory epithelium of the inner ear, has two types of mechanoreceptor cells, inner hair cells (IHCs) and outer hair cells (OHCs). In this sensory epithelium, vibrations produced by sound waves are transformed into electrical signals. When depolarized by incoming sounds, IHCs release glutamate and activate auditory nerve fibers innervating them and OHCs, by virtue of their electromotile property, increase the amplification and fine tuning of sound signals. The medial olivocochlear (MOC) system, an efferent feedback system, inhibits OHC activity and thereby reduces the sensitivity and sharp tuning of cochlear afferent fibers. During neonatal development, IHCs fire Ca(2+) action potentials which evoke glutamate release promoting activity in the immature auditory system in the absence of sensory stimuli. During this period, MOC fibers also innervate IHCs and are thought to modulate their firing rate. Both the MOC-OHC and the MOC-IHC synapses are cholinergic, fast and inhibitory and mediated by the alpha9alpha10 nicotinic cholinergic receptor (nAChR) coupled to the activation of calcium-activated potassium channels that hyperpolarize the hair cells. In this review we discuss the biophysical, functional and molecular data which demonstrate that at the synapses between MOC efferent fibers and cochlear hair cells, modulation of transmitter release as well as short term synaptic plasticity mechanisms, operating both at the presynaptic terminal and at the postsynaptic hair-cell, determine the efficacy of these synapses and shape the hair cell response pattern. PMID- 25520634 TI - Modulation of innate and learned sexual behaviors by the TRP channel Painless expressed in the fruit fly brain: behavioral genetic analysis and its implications. AB - Transient receptor potential (TRP) channels have attracted considerable attention because of their vital roles in primary sensory neurons, mediating responses to a wide variety of external environmental stimuli. However, much less is known about how TRP channels in the brain respond to intrinsic signals and are involved in neurophysiological processes that control complex behaviors. Painless (Pain) is the Drosophila TRP channel that was initially identified as a molecular sensor responsible for detecting noxious thermal and mechanical stimuli. Here, we review recent behavioral genetic studies demonstrating that Pain expressed in the brain plays a critical role in both innate and learned aspects of sexual behaviors. Several members of the TRP channel superfamily play evolutionarily conserved roles in sensory neurons as well as in other peripheral tissues. It is thus expected that brain TRP channels in vertebrates and invertebrates would have some common physiological functions. Studies of Pain in the Drosophila brain using a unique combination of genetics and physiological techniques should provide valuable insights into the fundamental principles concerning TRP channels expressed in the vertebrate and invertebrate brains. PMID- 25520635 TI - Neonatal pain and COMT Val158Met genotype in relation to serotonin transporter (SLC6A4) promoter methylation in very preterm children at school age. AB - Children born very preterm are exposed to repeated neonatal procedures that induce pain and stress during hospitalization in the neonatal intensive care unit (NICU). The COMT Val158Met genotype is involved with pain sensitivity, and early life stress is implicated in altered expression of methylation of the serotonin transporter. We examined: (1) whether methylation of the serotonin transporter gene (SLC6A4) promoter differs between very preterm children and full-term controls at school age, (2) relationships with child behavior problems, and (3) whether the extent of neonatal pain exposure interacts with the COMT Val158Met genotype to predict SLC6A4 methylation at 7 years in the very preterm children. We examined the associations between the COMT genotypes, neonatal pain exposure (adjusted for neonatal clinical confounders), SLC6A4 methylation and behavior problems. Very preterm children had significantly higher methylation at 7/10 CpG sites in the SLC6A4 promoter compared to full-term controls at 7 years. Neonatal pain (adjusted for clinical confounders) was significantly associated with total child behavior problems on the Child Behavior Checklist (CBCL) questionnaire (adjusted for concurrent stressors and 5HTTLPR genotype) (p = 0.035). CBCL Total Problems was significantly associated with greater SLC6A4 methylation in very preterm children (p = 0.01). Neonatal pain (adjusted for clinical confounders) and COMT Met/Met genotype were associated with SLC6A4 promoter methylation in very preterm children at 7 years (p = 0.001). These findings provide evidence that both genetic predisposition and early environment need to be considered in understanding susceptibility for developing behavioral problems in this vulnerable population. PMID- 25520636 TI - Changes in cerebral metabolism in patients with a minimally conscious state responding to zolpidem. AB - BACKGROUND: Zolpidem, a short-acting non-benzodiazepine GABA agonist hypnotic, has been shown to induce paradoxical responses in some patients with disorders of consciousness (DOC), leading to recovery of arousal and cognitive abilities. We here assessed zolpidem-induced changes in regional brain metabolism in three patients with known zolpidem response in chronic post-anoxic minimally conscious state (MCS). METHODS: [18F]-fluorodeoxyglucose positron emission tomography (FDG PET) and standardized clinical assessments using the Coma Recovery Scale-Revised were performed after administration of 10 mg zolpidem or placebo in a randomized double blind 2-day protocol. PET data preprocessing and comparison with a healthy age-matched control group were performed using statistical parametric mapping (SPM8). RESULTS: Behaviorally, all patients recovered functional communication after administration of zolpidem (i.e., emergence from the MCS). FDG-PET showed increased metabolism in dorsolateral prefrontal and mesiofrontal cortices after zolpidem but not after placebo administration. CONCLUSION: Our data show a metabolic activation of prefrontal areas, corroborating the proposed mesocircuit hypothesis to explain the paradoxical effect of zolpidem observed in some patients with DOC. It also suggests the key role of the prefrontal cortices in the recovery of functional communication and object use in hypoxic patients with chronic MCS. PMID- 25520637 TI - An allocentric exception confirms an egocentric rule: a comment on Taghizadeh and Gail (2014). PMID- 25520640 TI - Cost-sensitive Bayesian control policy in human active sensing. AB - An important but poorly understood aspect of sensory processing is the role of active sensing, the use of self-motion such as eye or head movements to focus sensing resources on the most rewarding or informative aspects of the sensory environment. Here, we present behavioral data from a visual search experiment, as well as a Bayesian model of within-trial dynamics of sensory processing and eye movements. Within this Bayes-optimal inference and control framework, which we call C-DAC (Context-Dependent Active Controller), various types of behavioral costs, such as temporal delay, response error, and sensor repositioning cost, are explicitly minimized. This contrasts with previously proposed algorithms that optimize abstract statistical objectives such as anticipated information gain (Infomax) (Butko and Movellan, 2010) and expected posterior maximum (greedy MAP) (Najemnik and Geisler, 2005). We find that C-DAC captures human visual search dynamics better than previous models, in particular a certain form of "confirmation bias" apparent in the way human subjects utilize prior knowledge about the spatial distribution of the search target to improve search speed and accuracy. We also examine several computationally efficient approximations to C DAC that may present biologically more plausible accounts of the neural computations underlying active sensing, as well as practical tools for solving active sensing problems in engineering applications. To summarize, this paper makes the following key contributions: human visual search behavioral data, a context-sensitive Bayesian active sensing model, a comparative study between different models of human active sensing, and a family of efficient approximations to the optimal model. PMID- 25520638 TI - Robotic exoskeletons: a perspective for the rehabilitation of arm coordination in stroke patients. AB - Upper-limb impairment after stroke is caused by weakness, loss of individual joint control, spasticity, and abnormal synergies. Upper-limb movement frequently involves abnormal, stereotyped, and fixed synergies, likely related to the increased use of sub-cortical networks following the stroke. The flexible coordination of the shoulder and elbow joints is also disrupted. New methods for motor learning, based on the stimulation of activity-dependent neural plasticity have been developed. These include robots that can adaptively assist active movements and generate many movement repetitions. However, most of these robots only control the movement of the hand in space. The aim of the present text is to analyze the potential of robotic exoskeletons to specifically rehabilitate joint motion and particularly inter-joint coordination. First, a review of studies on upper-limb coordination in stroke patients is presented and the potential for recovery of coordination is examined. Second, issues relating to the mechanical design of exoskeletons and the transmission of constraints between the robotic and human limbs are discussed. The third section considers the development of different methods to control exoskeletons: existing rehabilitation devices and approaches to the control and rehabilitation of joint coordinations are then reviewed, along with preliminary clinical results available. Finally, perspectives and future strategies for the design of control mechanisms for rehabilitation exoskeletons are discussed. PMID- 25520641 TI - Traces across the body: influence of music-dance synchrony on the observation of dance. AB - In previous studies investigating entrainment and person perception, synchronized movements were found to enhance memory for incidental person attributes. Although this effect is robust, including in dance, the process by which it is actuated are less well understood. In this study, two hypotheses are investigated: that enhanced memory for person attributes is the result of (1) increased gaze time between in-tempo dancers; and/or (2) greater attentional focus between in-tempo dancers. To explore these possible mechanisms in the context of observing dance, an eye-tracking study was conducted in which subjects watched videos of pairs of laterally positioned dancers; only one of the dancers was synchronized with the music, the other being asynchronous. The results were consistent with the first hypothesis-music-dance synchrony gives rise to increased visual inspection times. In addition, there was a preference for upper-body fixations over lower-body fixations across both synchronous and asynchronous conditions. A subsequent, single-dancer eye-tracking study investigated fixations across different body regions, including head, torso, legs and feet. Significantly greater dwell times were recorded for head than torso and legs; feet attracted significantly less dwell time than any other body region. Lastly, the study sought to identify dance gestures responsible for torso- and head-directed fixations. Specifically we asked whether there are features in dance that are specially designed to direct an observer's gaze towards the face-the main "communicative portal" with respect to the transmission of intent, affect and empathy. PMID- 25520639 TI - Changes in global and regional modularity associated with increasing working memory load. AB - Using graph theory measures common to complex network analyses of neuroimaging data, the objective of this study was to explore the effects of increasing working memory processing load on functional brain network topology in a cohort of young adults. Measures of modularity in complex brain networks quantify how well a network is organized into densely interconnected communities. We investigated changes in both the large-scale modular organization of the functional brain network as a whole and regional changes in modular organization as demands on working memory increased from n = 1 to n = 2 on the standard n-back task. We further investigated the relationship between modular properties across working memory load conditions and behavioral performance. Our results showed that regional modular organization within the default mode and working memory circuits significantly changed from 1-back to 2-back task conditions. However, the regional modular organization was not associated with behavioral performance. Global measures of modular organization did not change with working memory load but were associated with individual variability in behavioral performance. These findings indicate that regional and global network properties are modulated by different aspects of working memory under increasing load conditions. These findings highlight the importance of assessing multiple features of functional brain network topology at both global and regional scales rather than focusing on a single network property. PMID- 25520642 TI - The importance of being apt: metaphor comprehension in Alzheimer's disease. AB - We investigated the effect of aptness in the comprehension of copular metaphors (e.g., Lawyers are sharks) by Alzheimer's Disease (AD) patients. Aptness is the extent to which the vehicle (e.g., shark) captures salient properties of the topic (e.g., lawyers). A group of AD patients provided interpretations for metaphors that varied both in aptness and familiarity. Compared to healthy controls, AD patients produced worse interpretations, but interpretation ability was related to a metaphor's aptness rather than to its familiarity level, and patients with superior abstraction ability produced better interpretations. Therefore, the ability to construct figurative interpretations for metaphors is not always diminished in AD patients nor is it dependent only on the novelty level of the expression. We show that Alzheimer's patients' capacity to build figurative interpretations for metaphors is related to both item variables, such as aptness, and participant variables, such as abstraction ability. PMID- 25520643 TI - Behavioral dissociation between emotional and non-emotional facial expressions in congenital prosopagnosia. AB - Neuropsychological and neuroimaging studies have shown that facial recognition and emotional expressions are dissociable. However, it is unknown if a single system supports the processing of emotional and non-emotional facial expressions. We aimed to understand if individuals with impairment in face recognition from birth (congenital prosopagnosia, CP) can use non-emotional facial expressions to recognize a face as an already seen one, and thus, process this facial dimension independently from features (which are impaired in CP), and basic emotional expressions. To this end, we carried out a behavioral study in which we compared the performance of 6 CP individuals to that of typical development individuals, using upright and inverted faces. Four avatar faces with a neutral expression were presented in the initial phase. The target faces presented in the recognition phase, in which a recognition task was requested (2AFC paradigm), could be identical (neutral) to those of the initial phase or present biologically plausible changes to features, non-emotional expressions, or emotional expressions. After this task, a second task was performed, in which the participants had to detect whether or not the recognized face exactly matched the study face or showed any difference. The results confirmed the CPs' impairment in the configural processing of the invariant aspects of the face, but also showed a spared configural processing of non-emotional facial expression (task 1). Interestingly and unlike the non-emotional expressions, the configural processing of emotional expressions was compromised in CPs and did not improve their change detection ability (task 2). These new results have theoretical implications for face perception models since they suggest that, at least in CPs, non-emotional expressions are processed configurally, can be dissociated from other facial dimensions, and may serve as a compensatory strategy to achieve face recognition. PMID- 25520644 TI - A Markov model for the temporal dynamics of balanced random networks of finite size. AB - The balanced state of recurrent networks of excitatory and inhibitory spiking neurons is characterized by fluctuations of population activity about an attractive fixed point. Numerical simulations show that these dynamics are essentially nonlinear, and the intrinsic noise (self-generated fluctuations) in networks of finite size is state-dependent. Therefore, stochastic differential equations with additive noise of fixed amplitude cannot provide an adequate description of the stochastic dynamics. The noise model should, rather, result from a self-consistent description of the network dynamics. Here, we consider a two-state Markovian neuron model, where spikes correspond to transitions from the active state to the refractory state. Excitatory and inhibitory input to this neuron affects the transition rates between the two states. The corresponding nonlinear dependencies can be identified directly from numerical simulations of networks of leaky integrate-and-fire neurons, discretized at a time resolution in the sub-millisecond range. Deterministic mean-field equations, and a noise component that depends on the dynamic state of the network, are obtained from this model. The resulting stochastic model reflects the behavior observed in numerical simulations quite well, irrespective of the size of the network. In particular, a strong temporal correlation between the two populations, a hallmark of the balanced state in random recurrent networks, are well represented by our model. Numerical simulations of such networks show that a log-normal distribution of short-term spike counts is a property of balanced random networks with fixed in-degree that has not been considered before, and our model shares this statistical property. Furthermore, the reconstruction of the flow from simulated time series suggests that the mean-field dynamics of finite-size networks are essentially of Wilson-Cowan type. We expect that this novel nonlinear stochastic model of the interaction between neuronal populations also opens new doors to analyze the joint dynamics of multiple interacting networks. PMID- 25520645 TI - A novel computational framework for deducing muscle synergies from experimental joint moments. AB - Prior experimental studies have hypothesized the existence of a "muscle synergy" based control scheme for producing limb movements and locomotion in vertebrates. Such synergies have been suggested to consist of fixed muscle grouping schemes with the co-activation of all muscles in a synergy resulting in limb movement. Quantitative representations of these groupings (termed muscle weightings) and their control signals (termed synergy controls) have traditionally been derived by the factorization of experimentally measured EMG. This study presents a novel approach for deducing these weightings and controls from inverse dynamic joint moments that are computed from an alternative set of experimental measurements movement kinematics and kinetics. This technique was applied to joint moments for healthy human walking at 0.7 and 1.7 m/s, and two sets of "simulated" synergies were computed based on two different criteria (1) synergies were required to minimize errors between experimental and simulated joint moments in a musculoskeletal model (pure-synergy solution) (2) along with minimizing joint moment errors, synergies also minimized muscle activation levels (optimal-synergy solution). On comparing the two solutions, it was observed that the introduction of optimality requirements (optimal-synergy) to a control strategy solely aimed at reproducing the joint moments (pure-synergy) did not necessitate major changes in the muscle grouping within synergies or the temporal profiles of synergy control signals. Synergies from both the simulated solutions exhibited many similarities to EMG derived synergies from a previously published study, thus implying that the analysis of the two different types of experimental data reveals similar, underlying synergy structures. PMID- 25520647 TI - The possible role of contact sensitization to fragrances and preservatives in poikiloderma of civatte. AB - Numerous mechanisms have been postulated to play an important role in the pathogenesis of poikiloderma of Civatte (PC), including chronic exposure to ultraviolet radiation, menopause-related hormonal changes, contact hypersensitivity and genetic predisposition. Herein, we report a case of contact sensitization to fragrances and commonly used preservatives, methylchloroisothiazolinone and methylisothiazolinone, also widely known as Kathon CG, in a post-menopausal woman with PC, who denied excessive sun exposure and a family history. After abstaining from the use of her personal care products containing the documented allergens, not only the itching and burning symptoms, but also the cutaneous changes appeared to improve partially. This report underlines the possible influence of contact hypersensitivity in the pathogenesis of PC. PMID- 25520648 TI - Primary cutaneous amyloidoma: a case report. AB - Amyloidoma is defined as solitary, localized, tumor-like deposit of amyloid in diverse organs without evidence of systemic amyloidosis. Here we report the case of a 49-year-old male patient with a solitary amyloidoma of the skin seated on the left upper lip. Full medical examination showed no signs of systemic amyloidosis. The mass was removed surgically with tangential shave and so far no signs of recurrence have been found. PMID- 25520646 TI - A spiking network model of cerebellar Purkinje cells and molecular layer interneurons exhibiting irregular firing. AB - While the anatomy of the cerebellar microcircuit is well-studied, how it implements cerebellar function is not understood. A number of models have been proposed to describe this mechanism but few emphasize the role of the vast network Purkinje cells (PKJs) form with the molecular layer interneurons (MLIs) the stellate and basket cells. We propose a model of the MLI-PKJ network composed of simple spiking neurons incorporating the major anatomical and physiological features. In computer simulations, the model reproduces the irregular firing patterns observed in PKJs and MLIs in vitro and a shift toward faster, more regular firing patterns when inhibitory synaptic currents are blocked. In the model, the time between PKJ spikes is shown to be proportional to the amount of feedforward inhibition from an MLI on average. The two key elements of the model are: (1) spontaneously active PKJs and MLIs due to an endogenous depolarizing current, and (2) adherence to known anatomical connectivity along a parasagittal strip of cerebellar cortex. We propose this model to extend previous spiking network models of the cerebellum and for further computational investigation into the role of irregular firing and MLIs in cerebellar learning and function. PMID- 25520649 TI - Delayed intratumoral hemorrhage after drug-eluting bead transarterial chemoembolization for hepatocellular carcinoma. AB - Transarterial chemoembolization (TACE) using a drug-eluting bead (DEB-TACE) for hepatocellular carcinoma (HCC) is a new treatment method. We report on a case of delayed intratumoral hemorrhage after DEB-TACE. An 81-year-old male with hepatitis C virus-related cirrhosis was diagnosed with a HCC of 35 mm in diameter in S5 detected by dynamic computed tomography (CT) and contrast-enhanced ultrasonography (CEUS). DEB-TACE with DC Bead ((r)) and epirubicin hydrochloride was performed because the patient declined to undergo surgical resection. The treatment was completed, and the course after DEB-TACE was favorable. However, right hypochondriac pain suddenly developed about 1 month after DEB-TACE. Unenhanced CT showed an increase of the tumor diameter and intratumoral high intensity area, which was not enhanced in the arterial phase. CEUS performed at the time of right hypochondriac pain (5 weeks after DEB-TACE) showed nonenhancement of almost the entire tumor in the vascular phase. The cause of the symptom may have been DEB-TACE-associated intratumoral hemorrhage. Tumor hemorrhage has been reported after DEB-TACE with tumors >5 cm in diameter, and the tumor locations were subcapsular in all previous reports. There has been no case of a tumor with a diameter <5 cm distinct from the subcapsular, as was observed in our patient. Incomplete embolization might be the cause of the intratumoral hemorrhage experienced by this case presenting a few risks. To obtain the therapeutic effect of DEB-TACE while preventing the adverse events, it may be important to understand the characteristics of the beads and to apply the appropriate embolization to each individual case. PMID- 25520650 TI - Remarkable response to neoadjuvant therapy with methotrexate, vinblastine, adriamycin, and Cisplatin for undifferentiated bladder carcinoma: a case report and literature review. AB - We report a case of primary undifferentiated bladder carcinoma, which revealed a remarkable response to methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) therapy. A 46-year-old Japanese woman presented at the hospital with the chief complaints of gross hematuria and pain during urination. Cystoscopy revealed a large smooth-surfaced tumor in the urinary bladder. The histopathological diagnosis was undifferentiated carcinoma. The patient then received 3 courses of MVAC over a 3-month period. Hydronephrosis disappeared after the first course, and the tumor shrank rapidly. After completion of the third MVAC course, radical cystectomy and ileal conduit surgery were performed. After 7 years, the patient has still had no recurrences or metastases. We retrospectively review the relative efficacy of the two popular chemotherapeutic regimens in the management of muscle-invasive bladder cancer in patients who had had radical cystectomy. PMID- 25520652 TI - Association of cryptogenic organizing pneumonia in bilateral anterior uveitis. AB - Two female patients with histories of cancer who showed cryptogenic organizing pneumonia (COP) complications and bilateral anterior uveitis with hypopyon were examined. Both patients had suffered from COP and received intermitted systemic corticosteroid administration (SCA). The first patient, a 65-year-old woman with a history of breast cancer, showed bilateral uveitis with hypopyon. The topical corticosteroid treatment was ineffective. After SCA for the treatment of COP was started, the hypopyon gradually dissipated. Upon termination of SCA, uveitis relapses were controlled by renewed SCA. The other patient, a 69-year-old woman with a history of ovarian cancer, showed bilateral anterior uveitis with hypopyon. Her intraocular outcome did not improve by the topical corticosteroid administration, but SCA that was applied to treat COP led to remission of uveitis. Imaging examinations, biochemical analysis, symptoms or HLA-B27 antigen screenings in either patient did not explain the development of uveitis. Bilateral anterior uveitis is commonly related to autoimmune disease or systemic syndrome. We report two cases with COP that developed bilateral anterior uveitis with hypopyon resistant to topical administration but responsive to systemic administration of corticosteroid. These findings suggest that COP can be associated with the etiology of anterior uveitis. PMID- 25520651 TI - Papillary thyroid cancer in struma testis with malignant transformation in the lung associated with trisomy 17 successfully treated with total thyroidectomy and radioiodine ablation. AB - BACKGROUND: Struma testis is a rare entity, and there are only few reports on the malignant transformation of a testicular teratoma to papillary thyroid carcinoma in the literature. In this report, we describe the malignant transformation of struma testis with distant lung metastasis associated with trisomy 17 and a coexisting papillary microcarcinoma in the thyroid. CASE REPORT: A 56-year-old man presented after a left orchiectomy for an undescended left testicle. Pathologic examination identified a monodermal teratoma composed of thyroid parenchyma and associated with a 1.7-cm papillary thyroid carcinoma. Further evaluation showed a pulmonary mass on a chest CT scan. Total thyroidectomy revealed a 0.5-mm focus of papillary thyroid cancer, and removal of the lung mass confirmed metastatic papillary thyroid cancer. Array-comparative genomic hybridization of both tumors showed trisomy 17 in the struma testes and the lung metastasis. The patient responded well to radioactive iodine ablation and has no evidence of cancer 3 years later. CONCLUSION: To our knowledge, this is the first case of papillary thyroid cancer in struma testes metastatic to the lung. It highlights the difficulties in treating these patients. Surgery to remove cancer foci, followed by radioactive iodine ablation, resulted in an excellent response in our patient. Interestingly, trisomy 17, which has so far been observed only in noninvasive thyroid nodules, was associated with pulmonary metastasis in our patient. PMID- 25520653 TI - Trimanual Anterior Vitrectomy: A Novel Technique to Manage Vitreous Loss during Phacoemulsification. AB - We report 2 cases illustrating the use of a new technique to manage vitreous loss during phacoemulsification, which we have termed 'trimanual' anterior vitrectomy. In each case, after recognizing posterior capsule tear, the remaining nuclear pieces were removed with low-parameter phacoemulsification. The remaining cortical material was then removed using bimanual irrigation and aspiration handpieces while the assistant surgeon inserted the vitrectomy probe through a separate 1-mm limbal incision. The vitrectomy probe was held below the plane of the posterior capsule tear, used to cut the vitreous and to provide a mechanical blockade to potentially descending lens material. While this technique involves the potentially awkward simultaneous use of 3 intraocular instruments, we believe that there are several advantages over standard bimanual anterior vitrectomy. PMID- 25520654 TI - Framingham Coronary Heart Disease Risk Score Can be Predicted from Structural Brain Images in Elderly Subjects. AB - Recent literature has presented evidence that cardiovascular risk factors (CVRF) play an important role on cognitive performance in elderly individuals, both those who are asymptomatic and those who suffer from symptoms of neurodegenerative disorders. Findings from studies applying neuroimaging methods have increasingly reinforced such notion. Studies addressing the impact of CVRF on brain anatomy changes have gained increasing importance, as recent papers have reported gray matter loss predominantly in regions traditionally affected in Alzheimer's disease (AD) and vascular dementia in the presence of a high degree of cardiovascular risk. In the present paper, we explore the association between CVRF and brain changes using pattern recognition techniques applied to structural MRI and the Framingham score (a composite measure of cardiovascular risk largely used in epidemiological studies) in a sample of healthy elderly individuals. We aim to answer the following questions: is it possible to decode (i.e., to learn information regarding cardiovascular risk from structural brain images) enabling individual predictions? Among clinical measures comprising the Framingham score, are there particular risk factors that stand as more predictable from patterns of brain changes? Our main findings are threefold: (i) we verified that structural changes in spatially distributed patterns in the brain enable statistically significant prediction of Framingham scores. This result is still significant when controlling for the presence of the APOE 4 allele (an important genetic risk factor for both AD and cardiovascular disease). (ii) When considering each risk factor singly, we found different levels of correlation between real and predicted factors; however, single factors were not significantly predictable from brain images when considering APOE4 allele presence as covariate. (iii) We found important gender differences, and the possible causes of that finding are discussed. PMID- 25520656 TI - Aging increases flexibility of postural reactive responses based on constraints imposed by a manual task. AB - This study compared the effect of stability constraints imposed by a manual task on the adaptation of postural responses between 16 healthy elderly (mean age = 71.56 years, SD = 7.38) and 16 healthy young (mean age = 22.94 years, SD = 4.82) individuals. Postural stability was perturbed through unexpected release of a load attached to the participant's trunk while performing two versions of a voluntary task: holding a tray with a cylinder placed with its flat side down (low constraint) or with its rolling round side down (high constraint). Low and high constraint tasks were performed in alternate blocks of trials. Results showed that young participants adapted muscular activation and kinematics of postural responses in association with previous experience with the first block of manual task constraint, whereas the elderly modulated postural responses based on the current manual constraint. This study provides evidence for flexibility of postural strategies in the elderly to deal with constraints imposed by a manual task. PMID- 25520655 TI - Copper-uptake is critical for the down regulation of synapsin and dynamin induced by neocuproine: modulation of synaptic activity in hippocampal neurons. AB - Extracellular and intracellular copper and zinc regulate synaptic activity and plasticity, which may impact brain functionality and human behavior. We have found that a metal coordinating molecule, Neocuproine, transiently increases free intracellular copper and zinc levels (i.e., min) in hippocampal neurons as monitored by Phen Green and FluoZin-3 fluorescence, respectively. The changes in free intracellular zinc induced by Neocuproine were abolished by the presence of a non-permeant copper chelator, Bathocuproine (BC), indicating that copper influx is needed for the action of Neocuproine on intracellular Zn levels. Moreover, Neocuproine decreased the mRNA levels of Synapsin and Dynamin, and did not affect the expression of Bassoon, tubulin or superoxide dismutase (SOD). Western blot analysis showed that protein levels of synapsin and dynamin were also down regulated in the presence of Neocuproine and that these changes were accompanied by a decrease in calcium transients and neuronal activity. Furthermore, Neocuproine decreased the number of active neurons, effect that was blocked by the presence of BC, indicating that copper influx is needed for the action of Neocuproine. We finally show that Neocuproine blocks the epileptiform-like activity induced by bicuculline in hippocampal neurons. Collectively, our data indicates that presynaptic protein configuration and function of primary hippocampal neurons is sensitive to transient changes in transition metal homeostasis. Therefore, small molecules able to coordinate transition metals and penetrate the blood-brain barrier might modify neurotransmission at the Central Nervous System (CNS). This might be useful to establish therapeutic approaches to control the neuronal hyperexcitabiltity observed in brain conditions that are associated to copper dyshomeotasis such as Alzheimer's and Menkes diseases. Our work also opens a new avenue to find novel and effective antiepilepsy drugs based in metal coordinating molecules. PMID- 25520657 TI - The extraocular muscle stem cell niche is resistant to ageing and disease. AB - Specific muscles are spared in many degenerative myopathies. Most notably, the extraocular muscles (EOMs) do not show clinical signs of late stage myopathies including the accumulation of fibrosis and fat. It has been proposed that an altered stem cell niche underlies the resistance of EOMs in these pathologies, however, to date, no reports have provided a detailed characterization of the EOM stem cell niche. PW1/Peg3 is expressed in progenitor cells in all adult tissues including satellite cells and a subset of interstitial non-satellite cell progenitors in muscle. These PW1-positive interstitial cells (PICs) include a fibroadipogenic progenitor population (FAP) that give rise to fat and fibrosis in late stage myopathies. PICs/FAPs are mobilized following injury and FAPs exert a promyogenic role upon myoblasts in vitro but require the presence of a minimal population of satellite cells in vivo. We and others recently described that FAPs express promyogenic factors while satellite cells express antimyogenic factors suggesting that PICs/FAPs act as support niche cells in skeletal muscle through paracrine interactions. We analyzed the EOM stem cell niche in young adult and aged wild-type mice and found that the balance between PICs and satellite cells within the EOM stem cell niche is maintained throughout life. Moreover, in the adult mdx mouse model for Duchenne muscular dystrophy (DMD), the EOM stem cell niche is unperturbed compared to normal mice, in contrast to Tibialis Anterior (TA) muscle, which displays signs of ongoing degeneration/regeneration. Regenerating mdx TA shows increased levels of both PICs and satellite cells, comparable to normal unaffected EOMs. We propose that the increase in PICs that we observe in normal EOMs contributes to preserving the integrity of the myofibers and satellite cells. Our data suggest that molecular cues regulating muscle regeneration are intrinsic properties of EOMs. PMID- 25520659 TI - Editorial: New therapeutic targets for human placental angiogenesis disease. PMID- 25520660 TI - Phenotypic screening in the 21st century. PMID- 25520662 TI - Accommodating the cost of growth and swimming in fish-the applicability of exercise-induced growth to juvenile hapuku (Polyprion oxygeneios). AB - Induced-swimming can improve the growth and feed conversion efficiency of finfish aquaculture species, such as salmonids and Seriola sp., but some species, such as Atlantic cod, show no or a negative productivity response to exercise. As a possible explanation for these species-specific differences, a recent hypothesis proposed that the applicability of exercise training, as well as the exercise regime for optimal growth gain (ERopt growth), was dependent upon the size of available aerobic metabolic scope (AMS). This study aimed to test this hypothesis by measuring the growth and swimming metabolism of hapuku, Polyprion oxygeneios, to different exercise regimes and then reconciling the metabolic costs of swimming and specific dynamic action (SDA) against AMS. Two 8-week growth trials were conducted with ERs of 0.0, 0.25, 0.5, 0.75, 1, and 1.5 body lengths per second (BL s(-1)). Fish in the first trial showed a modest 4.8% increase in SGR over static controls in the region 0.5-0.75 BL s(-1) whereas the fish in trial 2 showed no significant effect of ER on growth performance. Reconciling the SDA of hapuku with the metabolic costs of swimming showed that hapuku AMS is sufficient to support growth and swimming at all ERs. The current study therefore suggests that exercise-induced growth is independent of AMS and is driven by other factors. PMID- 25520658 TI - Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders. AB - A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC)-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer's Disease, and the psychiatric disorder schizophrenia, we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature data in order to construct predictive disease network models that can (i) elucidate subtypes of syndromic diseases, (ii) provide insights into disease networks and targets and (iii) facilitate a novel drug screening strategy using patient-derived hiPSCs to discover novel therapeutics for CNS disorders. PMID- 25520661 TI - Antibodies to probe endogenous G protein-coupled receptor heteromer expression, regulation, and function. AB - Over the last decade an increasing number of studies have focused on the ability of G protein-coupled receptors to form heteromers and explored how receptor heteromerization modulates the binding, signaling and trafficking properties of individual receptors. Most of these studies were carried out in heterologous cells expressing epitope tagged receptors. Very little information is available about the in vivo physiological role of G protein-coupled receptor heteromers due to a lack of tools to detect their presence in endogenous tissue. Recent advances such as the generation of mouse models expressing fluorescently labeled receptors, of TAT based peptides that can disrupt a given heteromer pair, or of heteromer-selective antibodies that recognize the heteromer in endogenous tissue have begun to elucidate the physiological and pathological roles of receptor heteromers. In this review we have focused on heteromer-selective antibodies and describe how a subtractive immunization strategy can be successfully used to generate antibodies that selectively recognize a desired heteromer pair. We also describe the uses of these antibodies to detect the presence of heteromers, to study their properties in endogenous tissues, and to monitor changes in heteromer levels under pathological conditions. Together, these findings suggest that G protein-coupled receptor heteromers represent unique targets for the development of drugs with reduced side-effects. PMID- 25520663 TI - Micron-scale voltage and [Ca(2+)]i imaging in the intact heart. AB - Studies in isolated cardiomyocytes have provided tremendous information at the cellular and molecular level concerning regulation of transmembrane voltage (Vm) and intracellular calcium ([Ca(2+)]i). The ability to use the information gleaned to gain insight into the function of ion channels and Ca(2+) handling proteins in a more complex system, e.g., the intact heart, has remained a challenge. We have developed laser scanning fluorescence microscopy-based approaches to monitor, at the sub-cellular to multi-cellular level in the immobilized, Langendorff-perfused mouse heart, dynamic changes in [Ca(2+)]i and Vm. This article will review the use of single- or dual-photon laser scanning microscopy [Ca(2+)]i imaging in conjunction with transgenic reporter technology to (a) interrogate the extent to which transplanted, donor-derived myocytes or cardiac stem cell-derived de novo myocytes are capable of forming a functional syncytium with the pre-existing myocardium, using entrainment of [Ca(2+)]i transients by the electrical activity of the recipient heart as a surrogate for electrical coupling, and (b) characterize the Ca(2+) handling phenotypes of cellular implants. Further, we will review the ability of laser scanning fluorescence microscopy in conjunction with a fast-response voltage-sensitive to resolve, on a subcellular level in Langendorff-perfused mouse hearts, Vm dynamics that typically occur during the course of a cardiac action potential. Specifically, the utility of this technique to measure microscopic-scale voltage gradients in the normal and diseased heart is discussed. PMID- 25520664 TI - Structural and protein interaction effects of hypertrophic and dilated cardiomyopathic mutations in alpha-tropomyosin. AB - The potential alterations to structure and associations with thin filament proteins caused by the dilated cardiomyopathy (DCM) associated tropomyosin (Tm) mutants E40K and E54K, and the hypertrophic cardiomyopathy (HCM) associated Tm mutants E62Q and L185R, were investigated. In order to ascertain what the cause of the known functional effects may be, structural and protein-protein interaction studies were conducted utilizing actomyosin ATPase activity measurements and spectroscopy. In actomyosin ATPase measurements, both HCM mutants and the DCM mutant E54K caused increases in Ca(2+)-induced maximal ATPase activities, while E40K caused a decrease. Investigation of Tm's ability to inhibit actomyosin ATPase in the absence of troponin showed that HCM-associated mutant Tms did not inhibit as well as wildtype, whereas the DCM associated mutant E40K inhibited better. E54K did not inhibit the actomyosin ATPase activity at any concentration of Tm tested. Thermal denaturation studies by circular dichroism and molecular modeling of the mutations in Tm showed that in general, the DCM mutants caused localized destabilization of the Tm dimers, while the HCM mutants resulted in increased stability. These findings demonstrate that the structural alterations in Tm observed here may affect the regulatory function of Tm on actin, thereby directly altering the ATPase rates of myosin. PMID- 25520665 TI - Length-dependent changes in contractile dynamics are blunted due to cardiac myosin binding protein-C ablation. AB - Enhanced cardiac contractile function with increased sarcomere length (SL) is, in part, mediated by a decrease in the radial distance between myosin heads and actin. The radial disposition of myosin heads relative to actin is modulated by cardiac myosin binding protein-C (cMyBP-C), suggesting that cMyBP-C contributes to the length-dependent activation (LDA) in the myocardium. However, the precise roles of cMyBP-C in modulating cardiac LDA are unclear. To determine the impact of cMyBP-C on LDA, we measured isometric force, myofilament Ca(2+)-sensitivity (pCa50) and length-dependent changes in kinetic parameters of cross-bridge (XB) relaxation (k rel), and recruitment (k df) due to rapid stretch, as well as the rate of force redevelopment (k tr) in response to a large slack-restretch maneuver in skinned ventricular multicellular preparations isolated from the hearts of wild-type (WT) and cMyBP-C knockout (KO) mice, at SL's 1.9 MUm or 2.1 MUm. Our results show that maximal force was not significantly different between KO and WT preparations but length-dependent increase in pCa50 was attenuated in the KO preparations. pCa50 was not significantly different between WT and KO preparations at long SL (5.82 +/- 0.02 in WT vs. 5.87 +/- 0.02 in KO), whereas pCa50 was significantly different between WT and KO preparations at short SL (5.71 +/- 0.02 in WT vs. 5.80 +/- 0.01 in KO; p < 0.05). The k tr, measured at half-maximal Ca(2+)-activation, was significantly accelerated at short SL in WT preparations (8.74 +/- 0.56 s(-1) at 1.9 MUm vs. 5.71 +/- 0.40 s(-1) at 2.1 MUm, p < 0.05). Furthermore, k rel and k df were accelerated by 32% and 50%, respectively at short SL in WT preparations. In contrast, k tr was not altered by changes in SL in KO preparations (8.03 +/- 0.54 s(-1) at 1.9 MUm vs. 8.90 +/- 0.37 s(-1) at 2.1 MUm). Similarly, KO preparations did not exhibit length dependent changes in k rel and k df. Collectively, our data implicate cMyBP-C as an important regulator of LDA via its impact on dynamic XB behavior due to changes in SL. PMID- 25520667 TI - TonEBP/NFAT5 regulates ACTBL2 expression in biomechanically activated vascular smooth muscle cells. AB - Cytoskeletal reorganization and migration are critical responses which enable vascular smooth muscle cells (VSMCs) cells to evade, compensate, or adapt to alterations in biomechanical stress. An increase in wall stress or biomechanical stretch as it is elicited by arterial hypertension promotes their reorganization in the vessel wall which may lead to arterial stiffening and contractile dysfunction. This adaptive remodeling process is dependent on and driven by subtle phenotype changes including those controlling the cytoskeletal architecture and motility of VSMCs. Recently, it has been reported that the transcription factor nuclear factor of activated T-cells 5 (TonEBP/NFAT5) controls critical aspects of the VSMC phenotype and is activated by biomechanical stretch. We therefore hypothesized that NFAT5 controls the expression of gene products orchestrating cytoskeletal reorganization in stretch-stimulated VSMCs. Automated immunofluorescence and Western blot analyses revealed that biomechanical stretch enhances the expression and nuclear translocation of NFAT5 in VSMCs. Subsequent in silico analyses suggested that this transcription factor binds to the promotor region of ACTBL2 encoding kappa-actin which was shown to be abundantly expressed in VSMCs upon exposure to biomechanical stretch. Furthermore, ACTBL2 expression was inhibited in these cells upon siRNA-mediated knockdown of NFAT5. Kappa-actin appeared to be aligned with stress fibers under static culture conditions, dispersed in lamellipodia and supported VSMC migration as its knockdown diminishes lateral migration of these cells. In summary, our findings delineated biomechanical stretch as a determinant of NFAT5 expression and nuclear translocation controlling the expression of the cytoskeletal protein ACTBL2. This response may orchestrate the migratory activity of VSMCs and thus promote maladaptive rearrangement of the arterial vessel wall during hypertension. PMID- 25520666 TI - Membrane domain formation-a key factor for targeted intracellular drug delivery. AB - Protein molecules, toxins and viruses internalize into the cell via receptor mediated endocytosis (RME) using specific proteins and lipids in the plasma membrane. The plasma membrane is a barrier for many pharmaceutical agents to enter into the cytoplasm of target cells. In the case of cancer cells, tissue specific biomarkers in the plasma membrane, like cancer-specific growth factor receptors, could be excellent candidates for RME-dependent drug delivery. Recent data suggest that agent binding to these receptors at the cell surface, resulting in membrane domain formation by receptor clustering, can be used for the initiation of RME. As a result, these pharmaceutical agents are internalized into the cells and follow different routes until they reach their final intracellular targets like lysosomes or Golgi. We propose that clustering induced formation of plasma membrane microdomains enriched in receptors, sphingolipids, and inositol lipids, leads to membrane bending which functions as the onset of RME. In this review we will focus on the role of domain formation in RME and discuss potential applications for targeted intracellular drug delivery. PMID- 25520669 TI - Short term fat feeding rapidly increases plasma insulin but does not result in dyslipidaemia. AB - Although the association between obesity and hypertension is well-known, the underlying mechanism remains elusive. Previously, we have shown that 3 week fat feeding in rabbits produces greater visceral adiposity, hypertension, tachycardia and elevated renal sympathetic nerve activity (RSNA) compared to rabbits on a normal diet. Because hyperinsulinaemia, hyperleptinemia, and dyslipidaemia are independent cardiovascular risk factors associated with hypertension we compared plasma insulin, leptin, and lipid profiles in male New Zealand White rabbits fed a normal fat diet (NFD 4.3% fat, n = 11) or high fat diet (HFD 13.4% fat, n = 13) at days 1, 2, 3 and weeks 1, 2, 3 of the diet. Plasma concentrations of diacylglyceride (DG), triacylglyceride (TG), ceramide and cholesteryl esters (CE) were obtained after analysis by liquid chromatography mass spectrometry. Plasma insulin and glucose increased within the first 3 days of the diet in HFD rabbits (P < 0.05) and remained elevated at week 1 (P < 0.05). Blood pressure and heart rate (HR) followed a similar pattern. By contrast, in both groups, plasma leptin levels remained unchanged during the first few days (P > 0.05), increasing by week 3 in fat fed animals alone (P < 0.05). Concentrations of total DG, TG, CE, and Ceramide at week 3 did not differ between groups (P > 0.05). Our data show plasma insulin increases rapidly following consumption of a HFD and suggests that it may play a role in the rapid rise of blood pressure. Dyslipidaemia does not appear to contribute to the hypertension in this animal model. PMID- 25520668 TI - Enhanced carotid body chemosensory activity and the cardiovascular alterations induced by intermittent hypoxia. AB - The carotid body (CB) plays a main role in the maintenance of the oxygen homeostasis. The hypoxic stimulation of the CB increases the chemosensory discharge, which in turn elicits reflex sympathetic, cardiovascular, and ventilatory adjustments. An exacerbate carotid chemosensory activity has been associated with human sympathetic-mediated diseases such as hypertension, insulin resistance, heart failure, and obstructive sleep apnea (OSA). Indeed, the CB chemosensory discharge becomes tonically hypereactive in experimental models of OSA and heart failure. Chronic intermittent hypoxia (CIH), a main feature of OSA, enhances CB chemosensory baseline discharges in normoxia and in response to hypoxia, inducing sympathetic overactivity and hypertension. Oxidative stress, increased levels of ET-1, Angiotensin II and pro-inflammatory cytokines, along with a reduced production of NO in the CB, have been associated with the enhanced carotid chemosensory activity. In this review, we will discuss new evidence supporting a main role for the CB chemoreceptor in the autonomic and cardiorespiratory alterations induced by intermittent hypoxia, as well as the molecular mechanisms involved in the CB chemosensory potentiation. PMID- 25520670 TI - Impact and management of physiological calibration in spectral analysis of blood pressure variability. AB - Physiological calibration (Physiocal) improves the quality of continuous blood pressure (BP) signal from finger. However, the effects of Physiocal on spectral characteristics of systolic BP (SBP) variability are not well-known. We tested the hypothesis that the use of Physiocal may alter the results on SBP variability when compared with BP recording without Physiocal. Continuous BP was recorded simultaneously from fingers of both arms during 10-min standing by two Nexfin devices, one with (ON) and the other without (OFF) Physiocal (n = 19). Missing SBP values in ON signal were linearly interpolated over Physiocal sequences (ONinter). The OFF signal was analyzed without any corrections (OFFreference) and after linear interpolation of corresponding sequences when Physiocal appeared in the ON signal (OFFinter). Mean low frequency power of SBP oscillations (LFSBP, 0.04-0.15 Hz) did not differ between the OFFreference, OFFinter, and ONinter. However, LFSBP deviated more from OFFreference when analyzed from ONinter compared with the analysis from OFFinter [median (interquartile range): 14.7 (4.6 38.6) vs. 0.9 (0.5-1.8) %, p < 0.05]. In conclusion, the use of Physiocal had a significant effect on the spectral SBP variability that overwhelms the impact of linear interpolation of short data sequences. Therefore, caution is needed when comparing SBP variability between BP datasets acquired with and without Physiocal. PMID- 25520671 TI - Actigraphy, the alternative way? PMID- 25520672 TI - Frendak to phenis to breivik: an examination of the imposed insanity defense. AB - The imposition of the insanity defense is a complicated psycho-legal scenario. Globally, definitions of insanity differ from country to country. In a multitude of cases, a determination of insanity at the time of a criminal act means the offender will not be considered responsible for his or her action(s). In many jurisdictions, concerns have been raised that the insanity defense has been used to mitigate punishment, usually after a particularly heinous crime. In this review, the authors use three cases - Frendak, Phenis, and Breivik to demonstrate how the imposition of the insanity defense has been used for legal purposes in the past and present. In an effort to give more background to each of the above mentioned cases, the writers have provided some details to aid comprehension. The authors offer recommendations for the ethical forensic evaluator unburdened by partisan allegiance and invested in the search for truth. This review article relies on peer-reviewed articles available from PubMed, Meharry Online Library, and legal dictionaries. We also cross-referenced reputable news sources to ensure the validity of the facts we present. PMID- 25520674 TI - Prevalence of the catatonic syndrome in an acute inpatient sample. AB - OBJECTIVE: In this exploratory open label study, we investigated the prevalence of catatonia in an acute psychiatric inpatient population. In addition, differences in symptom presentation of catatonia depending on the underlying psychiatric illness were investigated. METHODS: One hundred thirty patients were assessed with the Bush-Francis Catatonia Rating Scale (BFCRS), the Positive and Negative Syndrome Scale, the Young Mania Rating Scale, and the Simpson-Angus Scale. A factor analysis was conducted in order to generate six catatonic symptom clusters. Composite scores based on this principal component analysis were calculated. RESULTS: When focusing on the first 14 items of the BFCRS, 101 patients (77.7%) had at least 1 symptom scoring 1 or higher, whereas, 66 patients (50.8%) had at least 2 symptoms. Interestingly, when focusing on the DSM-5 criteria of catatonia, 22 patients (16.9%) could be considered for this diagnosis. Furthermore, different symptom profiles were found, depending on the underlying psychopathology. Psychotic symptomatology correlated strongly with excitement symptomatology (r = 0.528, p < 0.001) and to a lesser degree with the stereotypy/mannerisms symptom cluster (r = 0.289; p = 0.001) and the echo/perseveration symptom cluster (r = 0.185; p = 0.035). Similarly, manic symptomatology correlated strongly with the excitement symptom cluster (r = 0.596; p < 0.001) and to a lesser extent with the stereotypy/mannerisms symptom cluster (r = 0.277; p = 0.001). CONCLUSION: There was a high prevalence of catatonic symptomatology. Depending on the criteria being used, we noticed an important difference in exact prevalence, which makes it clear that we need clear cut criteria. Another important finding is the fact that the catatonic presentation may vary depending on the underlying pathology, although an unambiguous delineation between these catatonic presentations cannot be made. Future research is needed to determine diagnostical criteria of catatonia, which are clinically relevant. PMID- 25520675 TI - Attention to local and global levels of hierarchical Navon figures affects rapid scene categorization. AB - In four experiments, we investigated how attention to local and global levels of hierarchical Navon figures affected the selection of diagnostic spatial scale information used in scene categorization. We explored this issue by asking observers to classify hybrid images (i.e., images that contain low spatial frequency (LSF) content of one image, and high spatial frequency (HSF) content from a second image) immediately following global and local Navon tasks. Hybrid images can be classified according to either their LSF, or HSF content; thus, making them ideal for investigating diagnostic spatial scale preference. Although observers were sensitive to both spatial scales (Experiment 1), they overwhelmingly preferred to classify hybrids based on LSF content (Experiment 2). In Experiment 3, we demonstrated that LSF based hybrid categorization was faster following global Navon tasks, suggesting that LSF processing associated with global Navon tasks primed the selection of LSFs in hybrid images. In Experiment 4, replicating Experiment 3 but suppressing the LSF information in Navon letters by contrast balancing the stimuli examined this hypothesis. Similar to Experiment 3, observers preferred to classify hybrids based on LSF content; however and in contrast, LSF based hybrid categorization was slower following global than local Navon tasks. PMID- 25520673 TI - Allostasis as a conceptual framework linking bipolar disorder and addiction. AB - Bipolar disorders (BDs) and addictions constitute reciprocal risk factors and are best considered under a unitary perspective. The concepts of allostasis and allostatic load (AL) may contribute to the understanding of the complex relationships between BD and addictive behaviors. Allostasis entails the safeguarding of reward function stability by recruitment of changes in the reward and stress system neurocircuitry and it may help to elucidate neurobiological underpinnings of vulnerability to addiction in BD patients. Conceptualizing BD as an illness involving the cumulative build-up of allostatic states, we hypothesize a progressive dysregulation of reward circuits clinically expressed as negative affective states (i.e., anhedonia). Such negative affective states may render BD patients more vulnerable to drug addiction, fostering a very rapid transition from occasional drug use to addiction, through mechanisms of negative reinforcement. The resulting addictive behavior-related ALs, in turn, may contribute to illness progression. This framework could have a heuristic value to enhance research on pathophysiology and treatment of BD and addiction comorbidity. PMID- 25520676 TI - Investigating diet and physical activity in Malaysia: education and family history of diabetes relate to lower levels of physical activity. AB - The National Health and Morbidity Survey (NHMS, 2011), estimates that the number of Malaysian adults suffering from type 2 diabetes has increased from 8.3 to 31.2% since 1996. This study is a preliminary investigation of possible factors contributing to this epidemic. Knowledge of diabetes, health locus of control, diet and exercise habits, as well as family history, education level and other demographic factors to better understand the correlates of risky and healthy behaviors. This was done as part of a larger initiative to improve prevention efforts. Questionnaires were completed by 770 individuals from three Malaysian states: Selangor, Penang, and Terengganu. Findings showed that people with better health knowledge and those who have a family history of type 2 diabetes were more likely to have healthy diets. Also, health knowledge related to lower alcohol consumption. Participants with diabetic family members, however, also reported higher levels of stress. Counterintuitively, higher educational levels, higher internal locus of control, better health knowledge, as well as a family history of diabetes all correlated with lower levels of physical activity. Thus, it is suggested that, while increasing health knowledge will be important in addressing the type 2 diabetes epidemic in Malaysia, especially in relation to diet, other cultural factors, specifically norms related to exercise and physical activity, also need to be addressed if the spread of type 2 diabetes is to be addressed over the long term. PMID- 25520677 TI - Capuchin monkeys do not show human-like pricing effects. AB - Recent work in judgment and decision-making has shown that a good's price can have irrational effects on people's preferences. People tend to prefer goods that cost more money and assume that such expensive goods will be more effective, even in cases where the price of the good is itself arbitrary. Although much work has documented the existence of these pricing effects, unfortunately little work has addressed where these price effects come from in the first place. Here we use a comparative approach to distinguish between different accounts of this bias and to explore the origins of these effects. Specifically, we test whether brown capuchin monkeys (Cebus apella) are also susceptible to pricing effects within the context of an experimentally trained token economy. Using a capuchin population previously trained in a token market, we explored whether monkeys used price as an indicator of value across four experiments. Although monkeys demonstrated an understanding of which goods had which prices (consistently shifting preferences to cheaper goods when prices were increased), we observed no evidence that such price information affected their valuation of different kinds of goods. These results suggest that human pricing effects may involve more sophisticated human-unique cognitive capacities, such as an understanding of market forces and signaling. PMID- 25520678 TI - Mental workload and driving. AB - The aim of this review is to identify the most representative measures of subjective and objective mental workload in driving, and to understand how the subjective and objective levels of mental workload influence the performance as a function of situation complexity and driving experience, i.e., to verify whether the increase of situation complexity and the lack of experience increase the subjective and physiological levels of mental workload and lead to driving performance impairments. This review will be useful to both researchers designing an experimental study of mental workload and to designers of drivers' training content. In the first part, we will broach the theoretical approach with two factors of mental workload and performance, i.e., situation complexity and driving experience. Indeed, a low complex situation (e.g., highways), or conversely a high complex situation (e.g., town) can provoke an overload. Additionally, performing the driving tasks implies producing a high effort for novice drivers who have not totally automated the driving activity. In the second part, we will focus on subjective measures of mental workload. A comparison of questionnaires usually used in driving will allow identifying the most appropriate ones as a function of different criteria. Moreover, we will review the empirical studies to verify if the subjective level of mental workload is high in simple and very complex situations, especially for novice drivers compared to the experienced ones. In the third part, we will focus on physiological measures. A comparison of physiological indicators will be realized in order to identify the most correlated to mental workload. An empirical review will also take the effect of situation complexity and experience on these physiological indicators into consideration. Finally, a more nuanced comparison between subjective and physiological measures will be established from the impact on situation complexity and experience. PMID- 25520679 TI - Emotional pictures and sounds: a review of multimodal interactions of emotion cues in multiple domains. AB - In everyday life, multiple sensory channels jointly trigger emotional experiences and one channel may alter processing in another channel. For example, seeing an emotional facial expression and hearing the voice's emotional tone will jointly create the emotional experience. This example, where auditory and visual input is related to social communication, has gained considerable attention by researchers. However, interactions of visual and auditory emotional information are not limited to social communication but can extend to much broader contexts including human, animal, and environmental cues. In this article, we review current research on audiovisual emotion processing beyond face-voice stimuli to develop a broader perspective on multimodal interactions in emotion processing. We argue that current concepts of multimodality should be extended in considering an ecologically valid variety of stimuli in audiovisual emotion processing. Therefore, we provide an overview of studies in which emotional sounds and interactions with complex pictures of scenes were investigated. In addition to behavioral studies, we focus on neuroimaging, electro- and peripher-physiological findings. Furthermore, we integrate these findings and identify similarities or differences. We conclude with suggestions for future research. PMID- 25520681 TI - Romantic ideals, mate preferences, and anticipation of future difficulties in marital life: a comparative study of young adults in India and America. AB - Previous studies have established that Indians tend to be greater in collectivism and gender role traditionalism than Americans. The purpose of the present study was to examine whether these differences explained further cultural differences in romantic beliefs, traditional mate preferences, and anticipation of future difficulties in marital life. Results revealed that Indians reported greater collectivism than Americans and, in turn, held stronger romantic beliefs. Additionally, Indians' greater collectivism and endorsement of more traditional gender roles in part predicted their preferences for a marital partner possessing traditional characteristics, and fully accounted for their heightened concerns about encountering future difficulties in marital life. These results shed light on the processes underlying cultural differences in relationship attitudes and preferences, and point to culture-specific therapies to enhance marital functioning. PMID- 25520680 TI - Does pronounceability modulate the letter string deficit of children with dyslexia? A study with the rate and amount model. AB - The locus of the deficit of children with dyslexia in dealing with strings of letters may be a deficit at a pre-lexical graphemic level or an inability to bind orthographic and phonological information. We evaluate these alternative hypotheses in two experiments by examining the role of stimulus pronounceability in a lexical decision task (LDT) and in a forced-choice letter discrimination task (Reicher-Wheeler paradigm). Seventeen fourth grade children with dyslexia and 24 peer control readers participated to two experiments. In the LDT children were presented with high-, low-frequency words, pronounceable pseudowords (such as DASU) and unpronounceable non-words (such as RNGM) of 4-, 5-, or 6- letters. No sign of group by pronounceability interaction was found when over-additivity was taken into account. Children with dyslexia were impaired when they had to process strings, not only of pronounceable stimuli but also of unpronounceable stimuli, a deficit well accounted for by a single global factor. Complementary results were obtained with the Reicher-Wheeler paradigm: both groups of children gained in accuracy in letter discrimination in the context of pronounceable primes (words and pseudowords) compared to unpronounceable primes (non-words). No global factor was detected in this task which requires the discrimination between a target letter and a competitor but does not involve simultaneous letter string processing. Overall, children with dyslexia show a selective difficulty in simultaneously processing a letter string as a whole, independent of its pronounceability; however, when the task involves isolated letter processing, also these children can make use of the ortho-phono-tactic information derived from a previously seen letter string. This pattern of findings is in keeping with the idea that an impairment in pre-lexical graphemic analysis may be a core deficit in developmental dyslexia. PMID- 25520682 TI - Tempo and walking speed with music in the urban context. AB - The study explored the effect of music on the temporal aspects of walking behavior in a real outdoor urban setting. First, spontaneous synchronization between the beat of the music and step tempo was explored. The effect of motivational and non-motivational music (Karageorghis et al., 1999) on the walking speed was also studied. Finally, we investigated whether music can mask the effects of visual aspects of the walking route environment, which involve fluctuation of walking speed as a response to particular environmental settings. In two experiments, we asked participants to walk around an urban route that was 1.8 km in length through various environments in the downtown area of Hradec Kralove. In Experiment 1, the participants listened to a musical track consisting of world pop music with a clear beat. In Experiment 2, participants were walking either with motivational music, which had a fast tempo and a strong rhythm, or with non-motivational music, which was slower, nice music, but with no strong implication to movement. Musical beat, as well as the sonic character of the music listened to while walking, influenced walking speed but did not lead to precise synchronization. It was found that many subjects did not spontaneously synchronize with the beat of the music at all, and some subjects synchronized only part of the time. The fast, energetic music increases the speed of the walking tempo, while slower, relaxing music makes the walking tempo slower. Further, it was found that listening to music with headphones while walking can mask the influence of the surrounding environment to some extent. Both motivational music and non-motivational music had a larger effect than the world pop music from Experiment 1. Individual differences in responses to the music listened to while walking that were linked to extraversion and neuroticism were also observed. The findings described here could be useful in rhythmic stimulation for enhancing or recovering the features of movement performance. PMID- 25520683 TI - The influence of imagery vividness on cognitive and perceptual cues in circular auditorily-induced vection. AB - In the absence of other congruent multisensory motion cues, sound contribution to illusions of self-motion (vection) is relatively weak and often attributed to purely cognitive, top-down processes. The present study addressed the influence of cognitive and perceptual factors in the experience of circular, yaw auditorily induced vection (AIV), focusing on participants imagery vividness scores. We used different rotating sound sources (acoustic landmark vs. movable types) and their filtered versions that provided different binaural cues (interaural time or level differences, ITD vs. ILD) when delivering via loudspeaker array. The significant differences in circular vection intensity showed that (1) AIV was stronger for rotating sound fields containing auditory landmarks as compared to movable sound objects; (2) ITD based acoustic cues were more instrumental than ILD based ones for horizontal AIV; and (3) individual differences in imagery vividness significantly influenced the effects of contextual and perceptual cues. While participants with high scores of kinesthetic and visual imagery were helped by vection "rich" cues, i.e., acoustic landmarks and ITD cues, the participants from the low-vivid imagery group did not benefit from these cues automatically. Only when specifically asked to use their imagination intentionally did these external cues start influencing vection sensation in a similar way to high-vivid imagers. These findings are in line with the recent fMRI work which suggested that high vivid imagers employ automatic, almost unconscious mechanisms in imagery generation, while low-vivid imagers rely on more schematic and conscious framework. Consequently, our results provide an additional insight into the interaction between perceptual and contextual cues when experiencing purely auditorily or multisensory induced vection. PMID- 25520685 TI - On extending experimental findings to clinical application: Never too late? An advantage on tests of auditory attention extends to late bilinguals. PMID- 25520684 TI - Can the computer replace the adult for storybook reading? A meta-analysis on the effects of multimedia stories as compared to sharing print stories with an adult. AB - The present meta-analysis challenges the notion that young children necessarily need adult scaffolding in order to understand a narrative story and learn words as long as they encounter optimally designed multimedia stories. Including 29 studies and 1272 children, multimedia stories were found more beneficial than encounters with traditional story materials that did not include the help of an adult for story comprehension (g+ = 0.40, k = 18) as well as vocabulary (g+ = 0.30, k = 11). However, no significant differences were found between the learning outcomes of multimedia stories and sharing traditional print-like stories with an adult. It is concluded that multimedia features like animated illustrations, background music and sound effects provide similar scaffolding of story comprehension and word learning as an adult. PMID- 25520686 TI - Specificity of the bilingual advantage for memory: examining cued recall, generalization, and working memory in monolingual, bilingual, and trilingual toddlers. AB - The specificity of the bilingual advantage in memory was examined by testing groups of monolingual, bilingual, and trilingual 24-month-olds on tasks tapping cued recall, memory generalization and working memory. For the cued recall and memory generalization conditions, there was a 24-h delay between time of encoding and time of retrieval. In addition to the memory tasks, parent-toddler dyads completed a picture-book reading task, in order to observe emotional responsiveness, and a parental report of productive vocabulary. Results indicated no difference between language groups on cued recall, working memory, emotional responsiveness, or productive vocabulary, but a significant difference was found in the memory generalization condition with only the bilingual group outperforming the baseline control group. These results replicate and extend results from past studies (Brito and Barr, 2012, 2014; Brito et al., 2014) and suggest a bilingual advantage specific to memory generalization. PMID- 25520687 TI - Reinforcement of perceptual inference: reward and punishment alter conscious visual perception during binocular rivalry. AB - Perception is an inferential process, which becomes immediately evident when sensory information is conflicting or ambiguous and thus allows for more than one perceptual interpretation. Thinking the idea of perception as inference through to the end results in a blurring of boundaries between perception and action selection, as perceptual inference implies the construction of a percept as an active process. Here we therefore wondered whether perception shares a key characteristic of action selection, namely that it is shaped by reinforcement learning. In two behavioral experiments, we used binocular rivalry to examine whether perceptual inference can be influenced by the association of perceptual outcomes with reward or punishment, respectively, in analogy to instrumental conditioning. Binocular rivalry was evoked by two orthogonal grating stimuli presented to the two eyes, resulting in perceptual alternations between the two gratings. Perception was tracked indirectly and objectively through a target detection task, which allowed us to preclude potential reporting biases. Monetary reward or punishments were given repeatedly during perception of only one of the two rivaling stimuli. We found an increase in dominance durations for the percept associated with reward, relative to the non-rewarded percept. In contrast, punishment led to an increase of the non-punished compared to a relative decrease of the punished percept. Our results show that perception shares key characteristics with action selection, in that it is influenced by reward and punishment in opposite directions, thus narrowing the gap between the conceptually separated domains of perception and action selection. We conclude that perceptual inference is an adaptive process that is shaped by its consequences. PMID- 25520689 TI - Attentional cueing in numerical cognition. PMID- 25520688 TI - Cross-cultural differences in somatic awareness and interoceptive accuracy: a review of the literature and directions for future research. AB - This review examines cross-cultural differences in interoception and the role of culturally bound epistemologies, historical traditions, and contemplative practices to assess four aspects of culture and interoception: (1) the extent to which members from Western and non-Western cultural groups exhibit differential levels of interoceptive accuracy and somatic awareness; (2) the mechanistic origins that can explain these cultural differences, (3) culturally bound behavioral practices that have been empirically shown to affect interoception, and (4) consequences for culturally bound psychopathologies. The following outlines the scope of the scientific review. Part 1 reviews studies on cultural variation in spontaneous somatic word use, linguistic expressions, traditional medical practices, and empirical laboratory studies to assess the evidence for cultural differences in somatic processes. Integration of these findings suggests a startling paradox: on the one hand, non-Western cultures consistently exhibit heightened somatic focus and awareness across a variety of contexts; on the other hand, non-Western cultures also exhibit less interoceptive accuracy in laboratory studies. Part 2 discusses the various mechanistic explanations that have been proposed to explain these cultural differences in somatic awareness and interoceptive accuracy, focusing on cultural schemas and epistemologies. Part 3 addresses the behavioral and contemplative practices that have been proposed as possible "interventions," or methods of cultivating bodily awareness and perceptual accuracy. Finally, Part 4 reviews the consequences of interoception for psychopathology, including somatization, body dysmorphia, eating disorders, and anxiety disorders. PMID- 25520690 TI - Among three different executive functions, general executive control ability is a key predictor of decision making under objective risk. AB - Executive functioning is supposed to have an important role in decision making under risk. Several studies reported that more advantageous decision-making behavior was accompanied by better performance in tests of executive functioning and that the decision-making process was accompanied by activations in prefrontal and subcortical brain regions associated with executive functioning. However, to what extent different components of executive functions contribute to decision making is still unclear. We tested direct and indirect effects of three executive functions on decision-making performance in a laboratory gambling task, the Game of Dice Task (GDT). Using Brand's model of decisions under risk (2006) we tested seven structural equation models with three latent variables that represent executive functions supposed to be involved in decision making. The latent variables were general control (represented by the general ability to exert attentional and behavioral self-control that is in accordance with task goals despite interfering information), concept formation (represented by categorization, rule detection, and set maintenance), and monitoring (represented by supervision of cognition and behavior). The seven models indicated that only the latent dimension general control had a direct effect on decision making under risk. Concept formation and monitoring only contributed in terms of indirect effects, when mediated by general control. Thus, several components of executive functioning seem to be involved in decision making under risk. However, general control functions seem to have a key role. They may be important for implementing the calculative and cognitively controlled processes involved in advantageous decision making under risk. PMID- 25520691 TI - Perceptual advantage for category-relevant perceptual dimensions: the case of shape and motion. AB - Category learning facilitates perception along relevant stimulus dimensions, even when tested in a discrimination task that does not require categorization. While this general phenomenon has been demonstrated previously, perceptual facilitation along dimensions has been documented by measuring different specific phenomena in different studies using different kinds of objects. Across several object domains, there is support for acquired distinctiveness, the stretching of a perceptual dimension relevant to learned categories. Studies using faces and studies using simple separable visual dimensions have also found evidence of acquired equivalence, the shrinking of a perceptual dimension irrelevant to learned categories, and categorical perception, the local stretching across the category boundary. These later two effects are rarely observed with complex non face objects. Failures to find these effects with complex non-face objects may have been because the dimensions tested previously were perceptually integrated. Here we tested effects of category learning with non-face objects categorized along dimensions that have been found to be processed by different areas of the brain, shape and motion. While we replicated acquired distinctiveness, we found no evidence for acquired equivalence or categorical perception. PMID- 25520693 TI - Keep meaning in conversational coordination. AB - Coordination is a widely employed term across recent quantitative and qualitative approaches to intersubjectivity, particularly approaches that give embodiment and enaction central explanatory roles. With a focus on linguistic and bodily coordination in conversational contexts, I review the operational meaning of coordination in recent empirical research and related theorizing of embodied intersubjectivity. This discussion articulates what must be involved in treating linguistic meaning as dynamic processes of coordination. The coordination approach presents languaging as a set of dynamic self-organizing processes and actions on multiple timescales and across multiple modalities that come about and work in certain domains (those jointly constructed in social, interactive, high order sense-making). These processes go beyond meaning at the level that is available to first-person experience. I take one crucial consequence of this to be the ubiquitously moral nature of languaging with others. Languaging coordinates experience, among other levels of behavior and event. Ethical effort is called for by the automatic autonomy-influencing forces of languaging as coordination. PMID- 25520692 TI - The impact of intermediate-term alcohol abstinence on memory retrieval and suppression. AB - BACKGROUND: The nature of episodic memory deficit in intermediate-term abstinence from alcohol in alcohol dependence (AD) is not yet clarified. Deficits in inhibitory control are commonly reported in substance use disorders. However, much less is known about cognitive control suppressing interference from memory. The Think/No-think (TNT) paradigm is a well established method to investigate inhibition of associative memory retrieval. METHODS: Thirty-six unmedicated patients with AD and 36 healthy controls (HCs) performed the TNT task. Thirty image-word pairs were trained up to a predefined accuracy level. Cued recall was examined in three conditions: Think (T) for items instructed to-be-remembered, No think (NT) assessing the ability to suppress retrieval and Baseline (B) for general relational memory. Premorbid IQ, clinical variables and impulsivity measures were quantified. RESULTS: AD patients had a significantly increased demand for training. Baseline memory abilities and effect of practice on retrieval were not markedly different between the groups. We found a significant main effect of group (HC vs. AD) * condition (B, T, and NT) and a significant difference in mean NT-B scores for the two groups. DISCUSSION: AD and HC groups did not differ essentially in their baseline memory abilities. Also, the instruction to focus on retrieval improved episodic memory performance in both groups. Crucially, control participants were able to suppress relational words in the NT condition supporting the critical effect of cognitive control processes over inhibition of retrieval. In contrast to this, the ability of AD patients to suppress retrieval was found to be impaired. PMID- 25520694 TI - The potential role of temporal dynamics in approach biases: delay-dependence of a general approach bias in an alcohol approach-avoidance task. AB - Attractive cues have been shown to evoke automatic approach biases in tasks such as the Automatic Approach Task or Stimulus Response Compatibility task. An important but as yet not studied question is the role of temporal dynamics in such tasks: the impact of automatic processes may depend on the interval between cue and response. The current proof of principle study tested this hypothesized time-dependence of the approach bias. Secondary goals included the exploration of effects of alcohol cues and virtual hand stimuli. 22 participants performed an SRC task in which the delay between the presentation of the cue and the possibility to select the response was manipulated. Results revealed an approach bias that decayed over longer delays. Thus, the approach bias was indeed dependent on processes that are transiently evoked by cues. The results did not show significant effects of alcohol cues or a virtual hand. Temporal dynamics may be an essential feature of approach biases. PMID- 25520695 TI - Cognitive control, cognitive reserve, and memory in the aging bilingual brain. AB - In recent years bilingualism has been linked to both advantages in executive control and positive impacts on aging. Such positive cognitive effects of bilingualism have been attributed to the increased need for language control during bilingual processing and increased cognitive reserve, respectively. However, a mechanistic explanation of how bilingual experience contributes to cognitive reserve is still lacking. The current paper proposes a new focus on bilingual memory as an avenue to explore the relationship between executive control and cognitive reserve. We argue that this focus will enhance our understanding of the functional and structural neural mechanisms underlying bilingualism-induced cognitive effects. With this perspective we discuss and integrate recent cognitive and neuroimaging work on bilingual advantage, and suggest an account that links cognitive control, cognitive reserve, and brain reserve in bilingual aging and memory. PMID- 25520696 TI - Cerebral microdialysis for protein biomarker monitoring in the neurointensive care setting - a technical approach. AB - Cerebral microdialysis (MD) was introduced as a neurochemical monitoring method in the early 1990s and is currently widely used for the sampling of low molecular weight molecules, signaling energy crisis, and cellular distress in the neurointensive care (NIC) setting. There is a growing interest in MD for harvesting of intracerebral protein biomarkers of secondary injury mechanisms in acute traumatic and neurovascular brain injury in the NIC community. The initial enthusiasm over the opportunity to sample protein biomarkers with high molecular weight cut-off MD catheters has dampened somewhat with the emerging realization of inherent methodological problems including protein-protein interaction, protein adhesion, and biofouling, causing an unstable in vivo performance (i.e., fluid recovery and extraction efficiency) of the MD catheter. This review will focus on the results of a multidisciplinary collaborative effort, within the Uppsala Berzelii Centre for Neurodiagnostics during the past several years, to study the features of the complex process of high molecular weight cut-off MD for protein biomarkers. This research has led to new methodology showing robust in vivo performance with optimized fluid recovery and improved extraction efficiency, allowing for more accurate biomarker monitoring. In combination with evolving analytical methodology allowing for multiplex biomarker analysis in ultra-small MD samples, a new opportunity opens up for high-resolution temporal mapping of secondary injury cascades, such as neuroinflammation and other cell injury reactions directly in the injured human brain. Such data may provide an important basis for improved characterization of complex injuries, e.g., traumatic and neurovascular brain injury, and help in defining targets and treatment windows for neuroprotective drug development. PMID- 25520697 TI - An Exploration of the Effect of Hemodynamic Changes Due to Normal Aging on the fNIRS Response to Semantic Processing of Words. AB - Like other neuroimaging techniques assessing cerebral blood oxygenation, near infrared spectroscopy (NIRS) has been applied in many neurocognitive studies. With NIRS, neural activation can be explored indirectly via hemodynamic changes in the imaged region. In studies of aging, changes in baseline physiology and brain anatomy confound NIRS measures seeking to investigate age-related changes in neuronal activity. The field is thus hampered by the complexity of the aging process itself, and statistical inferences from functional data acquired by optical imaging techniques must be interpreted with care. Multimodal integration of NIRS with both structural and baseline physiological assessments is crucial to avoid misinterpreting neuroimaging signals. In this study, a combination of two different optical techniques, anatomical MRI and Arterial Spin Labeling (ASL), was used to investigate age-related changes in activation during a lexical semantic processing task. Quantitative analysis revealed decreased baseline oxyhemoglobin and cerebral blood flow in the older adults. Using baseline physiology measures as regressors in the investigation of functional concentration changes when doing analyses of variance, we found significant changes in task-induced areas of activity. In the right hemisphere, more significant age-related activity was observed around the junction of the inferior frontal gyrus and inferior precentral sulcus, along with engagement of Wernicke's area. In the left hemisphere, the degree and extent of frontal activation, including the dorsolateral prefrontal cortex and inferior frontal gyrus, differed between age groups. Measuring background physiological differences and using their values as regressors in statistical analyses allowed a more appropriate, age-corrected understanding of the functional differentiations between age groups. Age-corrected baselines are thus essential to investigate which components of the NIRS signal are altered by aging. PMID- 25520698 TI - Perturbed glucose metabolism: insights into multiple sclerosis pathogenesis. AB - Multiple sclerosis (MS) is a complex debilitating disease of the central nervous system (CNS) perceived to result from the autoimmune effect of T cells in damaging myelin sheath. However, the exact pathogenesis of the disease remains elusive. Initial studies describing the possibility of defective pyruvate metabolism in MS were performed in 1950s. The group observed elevated blood pyruvate level in both fasting and postprandial times in MS patients with relapse. Similarly, other investigators also reported increased fasting pyruvate level in this disease. These reports hint to a possible abnormality of pyruvate metabolism in MS patients. In addition, increase in levels of Krebs cycle acids like alpha-ketoglutarate in fasting and citrate after glucose intake in MS patients further strengthened the connection of disturbed pyruvate metabolism with MS progression. These studies led the investigators to explore the role of disturbed glucose metabolism in pathophysiological brain function. Under normal circumstances, complex molecules are metabolized into simpler molecules through their respective pathways. Differential expression of genes encoding enzymes of the glucose metabolic pathway in CNS may result in neurological deficits. In this review article, we discuss the studies related to disturbed carbohydrate metabolism in MS and other neurodegenerative diseases. These observations open new perspectives for the understanding of metabolic dynamics in MS yet many puzzling aspects and critical questions need to be addressed. Much more research is required to fully unravel the disease mechanism, and a proper understanding of the disease could eventually lead to new treatments. PMID- 25520699 TI - Detection of protein aggregates in brain and cerebrospinal fluid derived from multiple sclerosis patients. AB - Studies of the properties of soluble oligomer species of amyloidogenic proteins, derived from different proteins with little sequence homology, have indicated that they share a common structure and may share similar pathogenic mechanisms. Amyloid beta, tau protein, as well as amyloid precursor protein normally associated with Alzheimer's disease and Parkinson's disease were found in lesions and plaques of multiple sclerosis patients. The objective of the study is to investigate whether brain and cerebrospinal fluid (CSF) samples derived from multiple sclerosis patients demonstrate the presence of soluble oligomers normally associated with protein-misfolding diseases such as Alzheimer's disease. We have used anti-oligomer monoclonal antibodies to immunodetect soluble oligomers in CSF and brain tissues derived from multiple sclerosis patients. In this report, we describe the presence of soluble oligomers in the brain tissue and cerebral spinal fluid of multiple sclerosis patients detected with our monoclonal anti-oligomer antibodies with Western blot and Sandwich enzyme-linked immunosorbent assay (sELISA). These results might suggest that protein aggregation plays a role in multiple sclerosis pathogenesis although further and more refined studies are needed to confirm the role of soluble aggregates in multiple sclerosis. PMID- 25520700 TI - Intracerebral hemorrhage after intravenous thrombolysis in patients with cerebral microbleeds and cardiac myxoma. AB - BACKGROUND AND PURPOSE: Cardiac myxoma is a rare etiology of stroke. Both cerebral microbleeds and cardiac myxoma may increase the risk of intracerebral hemorrhage after intravenous (IV) thrombolysis. However, data are still limited. We report a case of multiple cerebral microbleeds treated with IV thrombolysis with later findings of cardiac myxoma. SUMMARY OF CASE: A 58-year-old-man presented with right-sided hemiplegia and global aphasia. The presumptive diagnosis of acute left middle cerebral artery (MCA) infarction was made. Previous magnetic resonance imaging showed multiple cerebral microbleeds. The patient received IV thrombolysis. Bilateral cerebellar hemorrhage occurred after thrombolysis, and a median suboccipital craniectomy and hematoma removal was performed. Transthoracic echocardiogram found a left atrial myxoma. The tumor was then surgically removed. Six months later, neurological deficit improved. CONCLUSION: Cerebral microbleeds may be associated with atrial myxoma. IV thrombolysis could benefit acute ischemic stroke patients with both baseline cerebral microbleeds and atrial myxoma. PMID- 25520701 TI - A parametric approach to shape field-relevant blast wave profiles in compressed gas-driven shock tube. AB - Detonation of a high-explosive produces shock-blast wave, shrapnel, and gaseous products. While direct exposure to blast is a concern near the epicenter, shock blast can affect subjects, even at farther distances. When a pure shock-blast wave encounters the subject, in the absence of shrapnels, fall, or gaseous products the loading is termed as primary blast loading and is the subject of this paper. The wave profile is characterized by blast overpressure, positive time duration, and impulse and called herein as shock-blast wave parameters (SWPs). These parameters in turn are uniquely determined by the strength of high explosive and the distance of the human subjects from the epicenter. The shape and magnitude of the profile determine the severity of injury to the subjects. As shown in some of our recent works (1-3), the profile not only determines the survival of the subjects (e.g., animals) but also the acute and chronic biomechanical injuries along with the following bio-chemical sequelae. It is extremely important to carefully design and operate the shock tube to produce field-relevant SWPs. Furthermore, it is vital to identify and eliminate the artifacts that are inadvertently introduced in the shock-blast profile that may affect the results. In this work, we examine the relationship between shock tube adjustable parameters (SAPs) and SWPs that can be used to control the blast profile; the results can be easily applied to many of the laboratory shock tubes. Further, replication of shock profile (magnitude and shape) can be related to field explosions and can be a standard in comparing results across different laboratories. Forty experiments are carried out by judiciously varying SAPs such as membrane thickness, breech length (66.68-1209.68 mm), measurement location, and type of driver gas (nitrogen, helium). The effects SAPs have on the resulting shock-blast profiles are shown. Also, the shock-blast profiles of a TNT explosion from ConWep software is compared with the profiles obtained from the shock tube. To conclude, our experimental results demonstrate that a compressed-gas shock tube when designed and operated carefully can replicate the blast time profiles of field explosions accurately. Such a faithful replication is an essential first step when studying the effects of blast induced neurotrauma using animal models. PMID- 25520703 TI - Autonomic neuropathy in diabetes mellitus. AB - Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes, often overlooked and misdiagnosed. It is a systemic-wide disorder that may be asymptomatic in the early stages. The most studied and clinically important form of DAN is cardiovascular autonomic neuropathy defined as the impairment of autonomic control of the cardiovascular system in patients with diabetes after exclusion of other causes. The reported prevalence of DAN varies widely depending on inconsistent definition, different diagnostic method, different patient cohorts studied. The pathogenesis is still unclear and probably multifactorial. Once DAN becomes clinically evident, no form of therapy has been identified, which can effectively stop or reverse it. Prevention strategies are based on strict glycemic control with intensive insulin treatment, multifactorial intervention, and lifestyle modification including control of hypertension, dyslipidemia, stop smoking, weight loss, and adequate physical exercise. The present review summarizes the latest knowledge regarding clinical presentation, epidemiology, pathogenesis, and management of DAN, with some mention to childhood and adolescent population. PMID- 25520704 TI - O-GlcNAcase Expression is Sensitive to Changes in O-GlcNAc Homeostasis. AB - O-linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification involving an attachment of a single beta-N-acetylglucosamine moiety to serine or threonine residues in nuclear and cytoplasmic proteins. Cellular O-GlcNAc levels are regulated by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which add and remove the modification, respectively. The levels of O-GlcNAc can rapidly change in response to fluctuations in the extracellular environment; however, O-GlcNAcylation returns to a baseline level quickly after stimulus removal. This process termed O-GlcNAc homeostasis appears to be critical to the regulation of many cellular functions including cell cycle progress, stress response, and gene transcription. Disruptions in O-GlcNAc homeostasis are proposed to lead to the development of diseases, such as cancer, diabetes, and Alzheimer's disease. O-GlcNAc homeostasis is correlated with the expression of OGT and OGA. We reason that alterations in O-GlcNAc levels affect OGA and OGT transcription. We treated several human cell lines with Thiamet-G (TMG, an OGA inhibitor) to increase overall O-GlcNAc levels resulting in decreased OGT protein expression and increased OGA protein expression. OGT transcript levels slightly declined with TMG treatment, but OGA transcript levels were significantly increased. Pretreating cells with protein translation inhibitor cycloheximide did not stabilize OGT or OGA protein expression in the presence of TMG; nor did TMG stabilize OGT and OGA mRNA levels when cells were treated with RNA transcription inhibitor actinomycin D. Finally, we performed RNA Polymerase II chromatin immunoprecipitation at the OGA promoter and found that RNA Pol II occupancy at the transcription start site was lower after prolonged TMG treatment. Together, these data suggest that OGA transcription was sensitive to changes in O-GlcNAc homeostasis and was potentially regulated by O-GlcNAc. PMID- 25520702 TI - Natriuretic hormones, endogenous ouabain, and related sodium transport inhibitors. AB - The work of deWardener and colleagues stimulated longstanding interest in natriuretic hormones (NHs). In addition to the atrial peptides (APs), the circulation contains unidentified physiologically relevant NHs. One NH is controlled by the central nervous system (CNS) and likely secreted by the pituitary. Its circulating activity is modulated by salt intake and the prevailing sodium concentration of the blood and intracerebroventricular fluid, and contributes to postprandial and dehydration natriuresis. The other NH, mobilized by atrial stretch, promotes natriuresis by increasing the production of intrarenal dopamine and/or nitric oxide (NO). Both NHs have short (<35 min) circulating half lives, depress renotubular sodium transport, and neither requires the renal nerves. The search for NHs led to endogenous cardiotonic steroids (CTS) including ouabain-, digoxin-, and bufadienolide-like materials. These CTS, given acutely in high nanomole to micromole amounts into the general or renal circulations, inhibit sodium pumps and are natriuretic. Among these CTS, only bufalin is cleared sufficiently rapidly to qualify for an NH-like role. Ouabain-like CTS are cleared slowly, and when given chronically in low daily nanomole amounts, promote sodium retention, augment arterial myogenic tone, reduce renal blood flow and glomerular filtration, suppress NO in the renal vasa recta, and increase sympathetic nerve activity and blood pressure. Moreover, lowering total body sodium raises circulating endogenous ouabain. Thus, ouabain like CTS have physiological actions that, like aldosterone, support renal sodium retention and blood pressure. In conclusion, the mammalian circulation contains two non-AP NHs. Identification of the CNS NH should be a priority. PMID- 25520706 TI - Shotgun metagenomics reveals a wide array of antibiotic resistance genes and mobile elements in a polluted lake in India. AB - There is increasing evidence for an environmental origin of many antibiotic resistance genes. Consequently, it is important to identify environments of particular risk for selecting and maintaining such resistance factors. In this study, we described the diversity of antibiotic resistance genes in an Indian lake subjected to industrial pollution with fluoroquinolone antibiotics. We also assessed the genetic context of the identified resistance genes, to try to predict their genetic transferability. The lake harbored a wide range of resistance genes (81 identified gene types) against essentially every major class of antibiotics, as well as genes responsible for mobilization of genetic material. Resistance genes were estimated to be 7000 times more abundant than in a Swedish lake included for comparison, where only eight resistance genes were found. The sul2 and qnrD genes were the most common resistance genes in the Indian lake. Twenty-six known and 21 putative novel plasmids were recovered in the Indian lake metagenome, which, together with the genes found, indicate a large potential for horizontal gene transfer through conjugation. Interestingly, the microbial community of the lake still included a wide range of taxa, suggesting that, across most phyla, bacteria has adapted relatively well to this highly polluted environment. Based on the wide range and high abundance of known resistance factors we have detected, it is plausible that yet unrecognized resistance genes are also present in the lake. Thus, we conclude that environments polluted with waste from antibiotic manufacturing could be important reservoirs for mobile antibiotic resistance genes. PMID- 25520705 TI - Genetic resources for methane production from biomass described with the Gene Ontology. AB - Methane (CH4) is a valuable fuel, constituting 70-95% of natural gas, and a potent greenhouse gas. Release of CH4 into the atmosphere contributes to climate change. Biological CH4 production or methanogenesis is mostly performed by methanogens, a group of strictly anaerobic archaea. The direct substrates for methanogenesis are H2 plus CO2, acetate, formate, methylamines, methanol, methyl sulfides, and ethanol or a secondary alcohol plus CO2. In numerous anaerobic niches in nature, methanogenesis facilitates mineralization of complex biopolymers such as carbohydrates, lipids and proteins generated by primary producers. Thus, methanogens are critical players in the global carbon cycle. The same process is used in anaerobic treatment of municipal, industrial and agricultural wastes, reducing the biological pollutants in the wastes and generating methane. It also holds potential for commercial production of natural gas from renewable resources. This process operates in digestive systems of many animals, including cattle, and humans. In contrast, in deep-sea hydrothermal vents methanogenesis is a primary production process, allowing chemosynthesis of biomaterials from H2 plus CO2. In this report we present Gene Ontology (GO) terms that can be used to describe processes, functions and cellular components involved in methanogenic biodegradation and biosynthesis of specialized coenzymes that methanogens use. Some of these GO terms were previously available and the rest were generated in our Microbial Energy Gene Ontology (MENGO) project. A recently discovered non-canonical CH4 production process is also described. We have performed manual GO annotation of selected methanogenesis genes, based on experimental evidence, providing "gold standards" for machine annotation and automated discovery of methanogenesis genes or systems in diverse genomes. Most of the GO-related information presented in this report is available at the MENGO website (http://www.mengo.biochem.vt.edu/). PMID- 25520707 TI - Influenza virus and endothelial cells: a species specific relationship. AB - Influenza A virus (IAV) infection is an important cause of respiratory disease in humans. The original reservoirs of IAV are wild waterfowl and shorebirds, where virus infection causes limited, if any, disease. Both in humans and in wild waterbirds, epithelial cells are the main target of infection. However, influenza virus can spread from wild bird species to terrestrial poultry. Here, the virus can evolve into highly pathogenic avian influenza (HPAI). Part of this evolution involves increased viral tropism for endothelial cells. HPAI virus infections not only cause severe disease in chickens and other terrestrial poultry species but can also spread to humans and back to wild bird populations. Here, we review the role of the endothelium in the pathogenesis of influenza virus infection in wild birds, terrestrial poultry and humans with a particular focus on HPAI viruses. We demonstrate that whilst the endothelium is an important target of virus infection in terrestrial poultry and some wild bird species, in humans the endothelium is more important in controlling the local inflammatory milieu. Thus, the endothelium plays an important, but species-specific, role in the pathogenesis of influenza virus infection. PMID- 25520708 TI - Environmental cues and genes involved in establishment of the superinfective Pf4 phage of Pseudomonas aeruginosa. AB - Biofilm development in Pseudomonas aeruginosa is in part dependent on a filamentous phage, Pf4, which contributes to biofilm maturation, cell death, dispersal and variant formation, e.g., small colony variants (SCVs). These biofilm phenotypes correlate with the conversion of the Pf4 phage into a superinfection (SI) variant that reinfects and kills the prophage carrying host, in contrast to other filamentous phage that normally replicate without killing their host. Here we have investigated the physiological cues and genes that may be responsible for this conversion. Flow through biofilms typically developed SI phage approximately days 4 or 5 of development and corresponded with dispersal. Starvation for carbon or nitrogen did not lead to the development of SI phage. In contrast, exposure of the biofilm to nitric oxide, H2O2 or the DNA damaging agent, mitomycin C, showed a trend of increased numbers of SI phage, suggesting that reactive oxygen or nitrogen species (RONS) played a role in the formation of SI phage. In support of this, mutation of oxyR, the major oxidative stress regulator in P. aeruginosa, resulted in higher level of and earlier superinfection compared to the wild-type (WT). Similarly, inactivation of mutS, a DNA mismatch repair gene, resulted in the early appearance of the SI phage and this was four log higher than the WT. In contrast, loss of recA, which is important for DNA repair and the SOS response, also resulted in a delayed and decreased production of SI phage. Treatments or mutations that increased superinfection also correlated with an increase in the production of morphotypic variants. The results suggest that the accumulation of RONS by the biofilm may result in DNA lesions in the Pf4 phage, leading to the formation of SI phage, which subsequently selects for morphotypic variants, such as SCVs. PMID- 25520709 TI - Persistent viremia by a novel parvovirus in a slow loris (Nycticebus coucang) with diffuse histiocytic sarcoma. AB - Cancer is one of the leading health concerns for human and animal health. Since the tumorigenesis process is not completely understood and it is known that some viruses can induce carcinogenesis, it is highly important to identify novel oncoviruses and extensively study underlying oncogenic mechanisms. Here, we investigated a case of diffuse histiocytic sarcoma in a 22 year old slow loris (Nycticebus coucang), using a broad spectrum virus discovery technique. A novel parvovirus was discovered and the phylogenetic analysis performed on its fully sequenced genome demonstrated that it represents the first member of a novel genus. The possible causative correlation between this virus and the malignancy was further investigated and 20 serum and 61 organ samples from 25 animals (N. coucang and N. pygmaeus) were screened for the novel virus but only samples collected from the originally infected animal were positive. The virus was present in all tested organs (intestine, liver, spleen, kidneys, and lungs) and in all banked serum samples collected up to 8 years before death. All attempts to identify a latent viral form (integrated or episomal) were unsuccessful and the increase of variation in the viral sequences during the years was consistent with absence of latency. Since it is well known that parvoviruses are dependent on cell division to successfully replicate, we hypothesized that the virus could have benefitted from the constantly dividing cancer cells and may not have been the cause of the histiocytic sarcoma. It is also possible to conjecture that the virus had a role in delaying the tumor progression and this report might bring new exciting opportunities in recognizing viruses to be used in cancer virotherapy. PMID- 25520711 TI - DNA polymerases in biotechnology. PMID- 25520710 TI - Plasmodium attenuation: connecting the dots between early immune responses and malaria disease severity. AB - Sterile attenuation of Plasmodium parasites at the liver-stage either by irradiation or genetic modification, or at the blood-stage by chemoprophylaxis, has been shown to induce immune responses that can protect against subsequent wild-type infection. However, following certain interventions, parasite attenuation can be incomplete or non-sterile. Instead parasites are rendered developmentally stunted but still capable of establishing an acute infection. In experiments involving Plasmodium berghei ANKA, a model of experimental cerebral malaria, it has been observed that several forms of attenuated parasites do not induce cerebral pathology. In this perspective we collect evidence from studies on murine malaria in particular, and attempt to "connect the dots" between early immune responses and protection from severe cerebral disease, highlighting potential parallels to human infection. PMID- 25520712 TI - Molecular tools for differentiation of non-typeable Haemophilus influenzae from Haemophilus haemolyticus. AB - Non-typeable Haemophilus influenzae (NTHi) and Haemophilus haemolyticus are closely related bacteria that reside in the upper respiratory tract. NTHi is associated with respiratory tract infections that frequently result in antibiotic prescription whilst H. haemolyticus is rarely associated with disease. NTHi and H. haemolyticus can be indistinguishable by traditional culture methods and molecular differentiation has proven difficult. This current review chronologically summarizes the molecular approaches that have been developed for differentiation of NTHi from H. haemolyticus, highlighting the advantages and disadvantages of each target and/or technique. We also provide suggestions for the development of new tools that would be suitable for clinical and research laboratories. PMID- 25520713 TI - Silver polyvinyl pyrrolidone nanoparticles exhibit a capsular polysaccharide influenced bactericidal effect against Streptococcus pneumoniae. AB - Streptococcus pneumoniae remains a leading cause of morbidity and mortality worldwide. The highly adaptive nature of S. pneumoniae exemplifies the need for next generation antimicrobials designed to avoid high level resistance. Metal based nanomaterials fit this criterion. Our study examined the antimicrobial activity of gold nanospheres, silver coated polyvinyl pyrrolidone (AgPVP), and titanium dioxide (TiO2) against various serotypes of S. pneumoniae. Twenty nanometer spherical AgPVP demonstrated the highest level of killing among the tested materials. AgPVP (0.6 mg/mL) was able to kill pneumococcal serotypes 2, 3, 4, and 19F within 4 h of exposure. Detailed analysis of cultures during exposure to AgPVP showed that both the metal ions and the solid nanoparticles participate in the killing of the pneumococcus. The bactericidal effect of AgPVP was lessened in the absence of the pneumococcal capsular polysaccharide. Capsule negative strains, JD908 and RX1, were only susceptible to AgPVP at concentrations at least 33% higher than their respective capsule expressing counterparts. These findings suggest that mechanisms of killing used by nanomaterials are not serotype dependent and that the capsular polysaccharide participates in the inhibition. In the near future these mechanisms will be examined as targets for novel antimicrobials. PMID- 25520714 TI - Contrasting assembly processes in a bacterial metacommunity along a desiccation gradient. AB - Understanding the relative influence of deterministic and stochastic processes in driving community assembly is a major goal in microbial ecology. Here, we have investigated the influence of these processes on bacterial community assembly in the lateral sediments of a salt pan along a desiccation gradient over a three year period. We show that the role of deterministic processes increases in communities distant from the water line (shaped by drought), probably as a result of the interplay between abiotic and biotic factors. By contrast, the influence of stochastic processes on bacterial community assembly was higher in the sediments closest to the water line, more likely due to lower levels of abiotic stress. Our results demonstrate that both deterministic and stochastic processes influence bacterial community assembly in salt pan sediments, and that their relative influence varies along a desiccation gradient. PMID- 25520715 TI - Animal model studies on viral infections. PMID- 25520718 TI - Demonstration of Functional Heterogeneity of T lymphocytes and Identification of Their Two Major Subsets. PMID- 25520716 TI - Preterm birth, intrauterine infection, and fetal inflammation. AB - Preterm birth (PTB) (delivery before 37 weeks' gestation) is a leading cause of neonatal death and disease in industrialized and developing countries alike. Infection (most notably in high-risk deliveries occurring before 28 weeks' gestation) is hypothesized to initiate an intrauterine inflammatory response that plays a key role in the premature initiation of labor as well as a host of the pathologies associated with prematurity. As such, a better understanding of intrauterine inflammation in pregnancy is critical to our understanding of preterm labor and fetal injury, as well as on-going efforts to prevent PTB. Focusing on the fetal innate immune system responses to intrauterine infection, the present paper will review clinical and experimental studies to discuss the capacity for a fetal contribution to the intrauterine inflammation associated with PTB. Evidence from experimental studies to suggest that the fetus has the capacity to elicit a pro-inflammatory response to intrauterine infection is highlighted, with reference to the contribution of the lung, skin, and gastrointestinal tract. The paper will conclude that pathological intrauterine inflammation is a complex process that is modified by multiple factors including time, type of agonist, host genetics, and tissue. PMID- 25520719 TI - Spatial, Temporal, and Functional Aspects of Macrophages during "The Good, the Bad, and the Ugly" Phases of Inflammation. PMID- 25520717 TI - Extracellular vesicles: potential roles in regenerative medicine. AB - Extracellular vesicles (EV) consist of exosomes, which are released upon fusion of the multivesicular body with the cell membrane, and microvesicles, which are released directly from the cell membrane. EV can mediate cell-cell communication and are involved in many processes, including immune signaling, angiogenesis, stress response, senescence, proliferation, and cell differentiation. The vast amount of processes that EV are involved in and the versatility of manner in which they can influence the behavior of recipient cells make EV an interesting source for both therapeutic and diagnostic applications. Successes in the fields of tumor biology and immunology sparked the exploration of the potential of EV in the field of regenerative medicine. Indeed, EV are involved in restoring tissue and organ damage, and may partially explain the paracrine effects observed in stem cell-based therapeutic approaches. The function and content of EV may also harbor information that can be used in tissue engineering, in which paracrine signaling is employed to modulate cell recruitment, differentiation, and proliferation. In this review, we discuss the function and role of EV in regenerative medicine and elaborate on potential applications in tissue engineering. PMID- 25520720 TI - Stem cell transplantation as a dynamical system: are clinical outcomes deterministic? AB - Outcomes in stem cell transplantation (SCT) are modeled using probability theory. However, the clinical course following SCT appears to demonstrate many characteristics of dynamical systems, especially when outcomes are considered in the context of immune reconstitution. Dynamical systems tend to evolve over time according to mathematically determined rules. Characteristically, the future states of the system are predicated on the states preceding them, and there is sensitivity to initial conditions. In SCT, the interaction between donor T cells and the recipient may be considered as such a system in which, graft source, conditioning, and early immunosuppression profoundly influence immune reconstitution over time. This eventually determines clinical outcomes, either the emergence of tolerance or the development of graft versus host disease. In this paper, parallels between SCT and dynamical systems are explored and a conceptual framework for developing mathematical models to understand disparate transplant outcomes is proposed. PMID- 25520722 TI - NK receptors: tools for a polyvalent cell family. PMID- 25520723 TI - gammadelta T Cell-Mediated Antibody-Dependent Cellular Cytotoxicity with CD19 Antibodies Assessed by an Impedance-Based Label-Free Real-Time Cytotoxicity Assay. AB - gammadelta T cells are not MHC restricted, elicit cytotoxicity against various malignancies, are present in early post-transplant phases in novel stem cell transplantation strategies and have been shown to mediate antibody-dependent cellular cytotoxicity (ADCC) with monoclonal antibodies (mAbs). These features make gammadelta T cells promising effector cells for antibody-based immunotherapy in pediatric patients with B-lineage acute lymphoblastic leukemia (ALL). To evaluate combination of human gammadelta T cells with CD19 antibodies for immunotherapy of B-lineage ALL, gammadelta T cells were expanded after a GMP compliant protocol and ADCC of both primary and expanded gammadelta T cells with an Fc-optimized CD19 antibody (4G7SDIE) and a bi-specific antibody with the specificities CD19 and CD16 (N19-C16) was evaluated in CD107a-degranulation assays and intracellular cytokine staining. CD107a, TNFalpha, and IFNgamma expression of primary gammadelta T cells were significantly increased and correlated with CD16-expression of gammadelta T cells. gammadelta T cells highly expressed CD107a after expansion and no further increased expression by 4G7SDIE and N19-C16 was measured. Cytotoxicity of purified expanded gammadelta T cells targeting CD19-expressing cells was assessed in both europium-TDA release and in an impedance-based label-free method (using the xCELLigence system) measuring gammadelta T cell lysis in real-time. Albeit in the 2 h end-point europium-TDA release assay no increased lysis was observed, in real-time xCELLigence assays both significant antibody-independent cytotoxicity and ADCC of gammadelta T cells were observed. The xCELLigence system outperformed the end-point europium-TDA release assay in sensitivity and allows drawing of conclusions to lysis kinetics of gammadelta T cells over prolonged periods of time periods. Combination of CD19 antibodies with primary as well as expanded gammadelta T cells exhibits a promising approach, which may enhance clinical outcome of patients with pediatric B-lineage ALL and requires clinical evaluation. PMID- 25520725 TI - Frost resistance in alpine woody plants. AB - This report provides a brief review of key findings related to frost resistance in alpine woody plant species, summarizes data on their frost resistance, highlights the importance of freeze avoidance mechanisms, and indicates areas of future research. Freezing temperatures are possible throughout the whole growing period in the alpine life zone. Frost severity, comprised of both intensity and duration, becomes greater with increasing elevation and, there is also a greater probability, that small statured woody plants, may be insulated by snow cover. Several frost survival mechanisms have evolved in woody alpine plants in response to these environmental conditions. Examples of tolerance to extracellular freezing and freeze dehydration, life cycles that allow species to escape frost, and freeze avoidance mechanisms can all be found. Despite their specific adaption to the alpine environment, frost damage can occur in spring, while all alpine woody plants have a low risk of frost damage in winter. Experimental evidence indicates that premature deacclimation in Pinus cembra in the spring, and a limited ability of many species of alpine woody shrubs to rapidly reacclimate when they lose snow cover, resulting in reduced levels of frost resistance in the spring, may be particularly critical under the projected changes in climate. In this review, frost resistance and specific frost survival mechanisms of different organs (leaves, stems, vegetative and reproductive over-wintering buds, flowers, and fruits) and tissues are compared. The seasonal dynamics of frost resistance of leaves of trees, as opposed to woody shrubs, is also discussed. The ability of some tissues and organs to avoid freezing by supercooling, as visualized by high resolution infrared thermography, are also provided. Collectively, the report provides a review of the complex and diverse ways that woody plants survive in the frost dominated environment of the alpine life zone. PMID- 25520724 TI - Canopy architectural and physiological characterization of near-isogenic wheat lines differing in the tiller inhibition gene tin. AB - Tillering is a core constituent of plant architecture, and influences light interception to affect plant and crop performance. Near-isogenic lines (NILs) varying for a tiller inhibition (tin) gene and representing two genetic backgrounds were investigated for tillering dynamics, organ size distribution, leaf area, light interception, red: far-red ratio, and chlorophyll content. Tillering ceased earlier in the tin lines to reduce the frequencies of later primary and secondary tillers compared to the free-tillering NILs, and demonstrated the genetically lower tillering plasticity of tin-containing lines. The distribution of organ sizes along shoots varied between NILs contrasting for tin. Internode elongation commenced at a lower phytomer, and the peduncle was shorter in the tin lines. The flag leaves of tin lines were larger, and the longest leaf blades were observed at higher phytomers in the tin than in free tillering lines. Total leaf area was reduced in tin lines, and non-tin lines invested more leaf area at mid-canopy height. The tiller economy (ratio of seed bearing shoots to numbers of shoots produced) was 10% greater in the tin lines (0.73-0.76) compared to the free-tillering sisters (0.62-0.63). At maximum tiller number, the red: far-red ratio (light quality stimulus that is thought to induce the cessation of tillering) at the plant-base was 0.18-0.22 in tin lines and 0.09 0.11 in free-tillering lines at levels of photosynthetic active radiation of 49 53% and 30-33%, respectively. The tin lines intercepted less radiation compared to their free-tillering sisters once genotypic differences in tiller numbers had established, and maintained green leaf area in the lower canopy later into the season. Greater light extinction coefficients (k) in tin lines prior to, but reduced k after, spike emergence indicated that differences in light interception between NILs contrasting in tin cannot be explained by leaf area alone but that geometric and optical canopy properties contributed. The careful characterization of specifically-developed NILs is refining the development of a physiology-based model for tillering to improve understanding of the value of architectural traits for use in cereal improvement. PMID- 25520721 TI - Cysteine cathepsins as regulators of the cytotoxicity of NK and T cells. AB - Cysteine cathepsins are lysosomal peptidases involved at different levels in the processes of the innate and adaptive immune responses. Some, such as cathepsins B, L, and H are expressed constitutively in most immune cells. In cells of innate immunity they play a role in cell adhesion and phagocytosis. Other cysteine cathepsins are expressed more specifically. Cathepsin X promotes dendritic cell maturation, adhesion of macrophages, and migration of T cells. Cathepsin S is implicated in major histocompatibility complex class II antigen presentation, whereas cathepsin C, expressed in cytotoxic T lymphocytes and natural killer (NK) cells, is involved in processing pro-granzymes into proteolytically active forms, which trigger cell death in their target cells. The activity of cysteine cathepsins is controlled by endogenous cystatins, cysteine protease inhibitors. Of these, cystatin F is the only cystatin that is localized in endosomal/lysosomal vesicles. After proteolytic removal of its N-terminal peptide, cystatin F becomes a potent inhibitor of cathepsin C with the potential to regulate pro-granzyme processing and cell cytotoxicity. This review is focused on the role of cysteine cathepsins and their inhibitors in the molecular mechanisms leading to the cytotoxic activity of T lymphocytes and NK cells in order to address new possibilities for regulation of their function in pathological processes. PMID- 25520726 TI - Elucidation of the molecular responses to waterlogging in Jatropha roots by transcriptome profiling. AB - Jatropha (Jatropha curcas) is a promising oil-seed crop for biodiesel production. However, the species is highly sensitive to waterlogging, which can result in stunted growth and yield loss. To date, the molecular mechanisms underlying the responses to waterlogging in Jatropha remain elusive. Here, the transcriptome adjustment of Jatropha roots to waterlogging was examined by high-throughput RNA sequencing (RNA-seq). The results indicated that 24 h of waterlogging caused significant changes in mRNA abundance of 1968 genes. Comprehensive gene ontology and functional enrichment analysis of root transcriptome revealed that waterlogging promoted responses to hypoxia and anaerobic respiration. On the other hand, the stress inhibited carbohydrate synthesis, cell wall biogenesis, and growth. The results also highlighted the roles of ethylene, nitrate, and nitric oxide in waterlogging acclimation. In addition, transcriptome profiling identified 85 waterlogging-induced transcription factors including members of AP2/ERF, MYB, and WRKY families implying that reprogramming of gene expression is a vital mechanism for waterlogging acclimation. Comparative analysis of differentially regulated transcripts in response to waterlogging among Arabidopsis, gray poplar, Jatropha, and rice further revealed not only conserved but species-specific regulation. Our findings unraveled the molecular responses to waterlogging in Jatropha and provided new perspectives for developing a waterlogging tolerant cultivar in the future. PMID- 25520727 TI - Plant immunity in plant-aphid interactions. AB - Aphids are economically important pests that cause extensive feeding damage and transmit viruses. While some species have a broad host range and cause damage to a variety of crops, others are restricted to only closely related plant species. While probing and feeding aphids secrete saliva, containing effectors, into their hosts to manipulate host cell processes and promote infestation. Aphid effector discovery studies pointed out parallels between infection and infestation strategies of plant pathogens and aphids. Interestingly, resistance to some aphid species is known to involve plant resistance proteins with a typical NB-LRR domain structure. Whether these resistance proteins indeed recognize aphid effectors to trigger ETI remains to be elucidated. In addition, it was recently shown that unknown aphid derived elicitors can initiate reactive oxygen species (ROS) production and callose deposition and that these responses were dependent on BAK1 (BRASSINOSTERIOD INSENSITIVE 1-ASSOCIATED RECEPTOR KINASE 1) which is a key component of the plant immune system. In addition, BAK-1 contributes to non host resistance to aphids pointing to another parallel between plant-pathogen and - aphid interactions. Understanding the role of plant immunity and non-host resistance to aphids is essential to generate durable and sustainable aphid control strategies. Although insect behavior plays a role in host selection and non-host resistance, an important observation is that aphids interact with non host plants by probing the leaf surface, but are unable to feed or establish colonization. Therefore, we hypothesize that aphids interact with non-host plants at the molecular level, but are potentially not successful in suppressing plant defenses and/or releasing nutrients. PMID- 25520729 TI - Bud structure, position and fate generate various branching patterns along shoots of closely related Rosaceae species: a review. AB - Branching in temperate plants is closely linked to bud fates, either floral or vegetative. Here, we review how the fate of meristematic tissues contained in buds and their position along a shoot imprint specific branching patterns which differ among species. Through examples chosen in closely related species in different genera of the Rosaceae family, a panorama of patterns is apparent. Patterns depend on whether vegetative and floral buds are borne individually or together in mixed buds, develop as the shoot grows or after a rest period, and are located in axillary or terminal positions along the parent shoot. The resulting branching patterns are conserved among varieties in a given species but progressively change with the parent shoot length during plant ontogeny. They can also be modulated by agronomic and environmental conditions. The existence of various organizations in the topology and fate of meristematic tissues and their appendages in closely related species questions the between-species conservation of physiological and molecular mechanisms leading to bud outgrowth vs. quiescence and to floral induction vs. vegetative development. PMID- 25520731 TI - Autophagy in plants and algae. PMID- 25520728 TI - Shedding light on ethylene metabolism in higher plants. AB - Ethylene metabolism in higher plants is regulated by a wide array of endogenous and environmental factors. During most physiological processes, ethylene levels are mainly determined by a strict control of the rate-limiting biosynthetic steps responsible for the production of 1-aminocyclopropane-1-carboxylic acid (ACC) and its subsequent conversion to ethylene. Responsible for these reactions, the key enzymes ACC synthase and ACC oxidase are encoded by multigene families formed by members that can be differentially regulated at the transcription and post translational levels by specific developmental and environmental signals. Among the wide variety of environmental cues controlling plant ethylene production, light quality, duration, and intensity have consistently been demonstrated to influence the metabolism of this plant hormone in diverse plant tissues, organs, and species. Although still not completely elucidated, the mechanisms underlying the interaction between light signal transduction and ethylene evolution appears to involve a complex network that includes central transcription factors connecting multiple signaling pathways, which can be reciprocally modulated by ethylene itself, other phytohormones, and specific light wavelengths. Accumulating evidence has indicated particular photoreceptors as essential mediators in light-induced signaling cascades affecting ethylene levels. Therefore, this review specifically focuses on discussing the current knowledge of the potential molecular mechanisms implicated in the light-induced responses affecting ethylene metabolism during the regulation of developmental and metabolic plant responses. Besides presenting the state of the art in this research field, some overlooked mechanisms and future directions to elucidate the exact nature of the light-ethylene interplay in higher plants will also be compiled and discussed. PMID- 25520730 TI - Improving crop disease resistance: lessons from research on Arabidopsis and tomato. AB - One of the great challenges for food security in the 21st century is to improve yield stability through the development of disease-resistant crops. Crop research is often hindered by the lack of molecular tools, growth logistics, generation time and detailed genetic annotations, hence the power of model plant species. Our knowledge of plant immunity today has been largely shaped by the use of models, specifically through the use of mutants. We examine the importance of Arabidopsis and tomato as models in the study of plant immunity and how they help us in revealing a detailed and deep understanding of the various layers contributing to the immune system. Here we describe examples of how knowledge from models can be transferred to economically important crops resulting in new tools to enable and accelerate classical plant breeding. We will also discuss how models, and specifically transcriptomics and effectoromics approaches, have contributed to the identification of core components of the defense response which will be key to future engineering of durable and sustainable disease resistance in plants. PMID- 25520733 TI - Plant-Agrobacterium interaction mediated by ethylene and super-Agrobacterium conferring efficient gene transfer. AB - Agrobacterium tumefaciens has a unique ability to transfer genes into plant genomes. This ability has been utilized for plant genetic engineering. However, the efficiency is not sufficient for all plant species. Several studies have shown that ethylene decreased the Agrobacterium-mediated transformation frequency. Thus, A. tumefaciens with an ability to suppress ethylene evolution would increase the efficiency of Agrobacterium-mediated transformation. Some studies showed that plant growth-promoting rhizobacteria (PGPR) can reduce ethylene levels in plants through 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase, which cleaves the ethylene precursor ACC into alpha-ketobutyrate and ammonia, resulting in reduced ethylene production. The whole genome sequence data showed that A. tumefaciens does not possess an ACC deaminase gene in its genome. Therefore, providing ACC deaminase activity to the bacteria would improve gene transfer. As expected, A. tumefaciens with ACC deaminase activity, designated as super-Agrobacterium, could suppress ethylene evolution and increase the gene transfer efficiency in several plant species. In this review, we summarize plant Agrobacterium interactions and their applications for improving Agrobacterium mediated genetic engineering techniques via super-Agrobacterium. PMID- 25520732 TI - Transcriptional responses of Medicago truncatula upon sulfur deficiency stress and arbuscular mycorrhizal symbiosis. AB - Sulfur plays an essential role in plants' growth and development and in their response to various abiotic and biotic stresses despite its leachability and its very low abundance in the only form that plant roots can uptake (sulfate). It is part of amino acids, glutathione (GSH), thiols of proteins and peptides, membrane sulfolipids, cell walls and secondary products, so reduced availability can drastically alter plant growth and development. The nutritional benefits of symbiotic interactions can help the plant in case of S deficiency. In particular the arbuscular mycorrhizal (AM) interaction improves N, P, and S plant nutrition, but the mechanisms behind these exchanges are not fully known yet. Although the transcriptional changes in the leguminous model plant Medicago truncatula have been already assessed in several biotic and/or abiotic conditions, S deficiency has not been considered so far. The aim of this work is to get a first overview on S-deficiency responses in the leaf and root tissues of plants interacting with the AM fungus Rhizophagus irregularis. Several hundred genes displayed significantly different transcript accumulation levels. Annotation and GO ID association were used to identify biological processes and molecular functions affected by sulfur starvation. Beside the beneficial effects of AM interaction, plants were greatly affected by the nutritional status, showing various differences in their transcriptomic footprints. Several pathways in which S plays an important role appeared to be differentially affected according to mycorrhizal status, with a generally reduced responsiveness to S deficiency in mycorrhized plants. PMID- 25520734 TI - Novel dehydrins lacking complete K-segments in Pinaceae. The exception rather than the rule. AB - Dehydrins are thought to play an essential role in the plant response, acclimation and tolerance to different abiotic stresses, such as cold and drought. These proteins contain conserved and repeated segments in their amino acid sequence, used for their classification. Thus, dehydrins from angiosperms present different repetitions of the segments Y, S, and K, while gymnosperm dehydrins show A, E, S, and K segments. The only fragment present in all the dehydrins described to date is the K-segment. Different works suggest the K segment is involved in key protective functions during dehydration stress, mainly stabilizing membranes. In this work, we describe for the first time two Pinus pinaster proteins with truncated K-segments and a third one completely lacking K segments, but whose sequence homology leads us to consider them still as dehydrins. qRT-PCR expression analysis show a significant induction of these dehydrins during a severe and prolonged drought stress. By in silico analysis we confirmed the presence of these dehydrins in other Pinaceae species, breaking the convention regarding the compulsory presence of K-segments in these proteins. The way of action of these unusual dehydrins remains unrevealed. PMID- 25520735 TI - Sun leaves up-regulate the photorespiratory pathway to maintain a high rate of CO2 assimilation in tobacco. AB - The greater rate of CO2 assimilation (A n) in sun-grown tobacco leaves leads to lower intercellular and chloroplast CO2 concentrations and, thus, a higher rate of oxygenation of ribulose-1,5-bisphosphate (RuBP) than in shade-grown leaves. Impairment of the photorespiratory pathway suppresses photosynthetic CO2 assimilation. Here, we hypothesized that sun leaves can up-regulate photorespiratory pathway to enhance the A n in tobacco. To test this hypothesis, we examined the responses of photosynthetic electron flow (J T) and CO2 assimilation to incident light intensity and intercellular CO2 concentration (C i) in leaves of 'k326' tobacco plants grown at 95% sunlight (sun plants) or 28% sunlight (shade plants). The sun leaves had higher photosynthetic capacity and electron flow devoted to RuBP carboxylation (J C) than the shade leaves. When exposed to high light, the higher Rubisco (ribulose-1,5-bisphosphate carboxylase/oxygenase) content and lower C i in the sun leaves led to greater electron flow devoted to RuBP oxygenation (J O). The J O/J C ratio was significantly higher in the sun leaves than in the shade leaves under strong illumination. As estimated from CO2-response curves, the maximum J O was linearly correlated with the estimated Rubisco content. Based on light-response curves, the light-saturated J O was linearly correlated with light-saturated J T and light-saturated photosynthesis. These findings indicate that enhancement of the photorespiratory pathway is an important strategy by which sun plants maintain a high A n. PMID- 25520737 TI - Genetic trends in maternal and neonatal behaviors and their association with perinatal survival in French Large White swine. AB - Genetic trends in maternal abilities were studied in French Large White sows. Two lines representing old-type and modern-type pigs were obtained by inseminating modern sows with semen from boars born in 1977 or 1998. Successive generations were produced by inter-se mating. The maternal performance of sows from the second generation was compared in farrowing crates. Video analysis was performed for the 1st h after the onset of 43 and 36 farrowing events, and for the 6 first hours for 23 and 21 events, in old-type and modern-type sows, respectively. Genetic trends were estimated as twice the difference in estimates between the 2 lines. The contribution of behavior to the probability of stillbirth and piglet death in the first 2 days was estimated as the percentage of deviance reduction (DR) due to the addition of behavior traits as factors in the mortality model. Sow activity decreased strongly from the 1st to the 2nd h in both lines (P < 0.001). In the first 6 h, old-type sows sat (1st parity), stood (2nd parity) and rooted (both parities) for longer than modern-type sows, which were less active, especially in 2nd parity. In modern-type sows, stillbirth was associated positively with lying laterally in the first 6 h (4.6% DR) and negatively in the 1st h (9.1% DR). First-parity old-type sows were more attentive to piglets (P = 0.003) than modern-type sows which responded more to nose contacts at 2nd parity (P = 0.01). Maternal reactivity of modern-type sows was associated with a higher risk of piglet death (4.6% DR). Respiratory distress at birth tended to be higher in modern-type piglets than in old-type piglets (P < 0.10) and was associated with a higher risk of piglet death in both lines (2.7-3.1% DR). Mobility at birth was lower in modern-type than old-type piglets (P < 0.0001). Genetic trends show that sow and piglet behaviors at farrowing have changed. Our results indicate reduced welfare in parturient modern-type sows and their newborn piglets. PMID- 25520736 TI - Patterns of diversification amongst tropical regions compared: a case study in Sapotaceae. AB - Species diversity is unequally distributed across the globe, with the greatest concentration occurring in the tropics. Even within the tropics, there are significant differences in the numbers of taxa found in each continental region. Manilkara is a pantropical genus of trees in the Sapotaceae comprising c. 78 species. Its distribution allows for biogeographic investigation and testing of whether rates of diversification differ amongst tropical regions. The age and geographical origin of Manilkara are inferred to determine whether Gondwanan break-up, boreotropical migration or long distance dispersal have shaped its current disjunct distribution. Diversification rates through time are also analyzed to determine whether the timing and tempo of speciation on each continent coincides with geoclimatic events. Bayesian analyses of nuclear (ITS) and plastid (rpl32-trnL, rps16-trnK, and trnS-trnFM) sequences were used to reconstruct a species level phylogeny of Manilkara and related genera in the tribe Mimusopeae. Analyses of the nuclear data using a fossil-calibrated relaxed molecular clock indicate that Manilkara evolved 32-29 million years ago (Mya) in Africa. Lineages within the genus dispersed to the Neotropics 26-18 Mya and to Asia 28-15 Mya. Higher speciation rates are found in the Neotropical Manilkara clade than in either African or Asian clades. Dating of regional diversification correlates with known palaeoclimatic events. In South America, the divergence between Atlantic coastal forest and Amazonian clades coincides with the formation of drier Cerrado and Caatinga habitats between them. In Africa diversification coincides with Tertiary cycles of aridification and uplift of the east African plateaux. In Southeast Asia dispersal may have been limited by the relatively recent emergence of land in New Guinea and islands further east c. 10 Mya. PMID- 25520738 TI - On the processes generating latitudinal richness gradients: identifying diagnostic patterns and predictions. AB - We use a simulation model to examine four of the most common hypotheses for the latitudinal richness gradient and identify patterns that might be diagnostic of those four hypotheses. The hypotheses examined include (1) tropical niche conservatism, or the idea that the tropics are more diverse because a tropical clade origin has allowed more time for diversification in the tropics and has resulted in few species adapted to extra-tropical climates. (2) The ecological limits hypothesis suggests that species richness is limited by the amount of biologically available energy in a region. (3) The speciation rates hypothesis suggests that the latitudinal gradient arises from a gradient in speciation rates. (4) Finally, the tropical stability hypothesis argues that climatic fluctuations and glacial cycles in extratropical regions have led to greater extinction rates and less opportunity for specialization relative to the tropics. We found that tropical niche conservatism can be distinguished from the other three scenarios by phylogenies which are more balanced than expected, no relationship between mean root distance (MRD) and richness across regions, and a homogeneous rate of speciation across clades and through time. The energy gradient, speciation gradient, and disturbance gradient scenarios all produced phylogenies which were more imbalanced than expected, showed a negative relationship between MRD and richness, and diversity-dependence of speciation rate estimates through time. We found that the relationship between speciation rates and latitude could distinguish among these three scenarios, with no relation expected under the ecological limits hypothesis, a negative relationship expected under the speciation rates hypothesis, and a positive relationship expected under the tropical stability hypothesis. We emphasize the importance of considering multiple hypotheses and focusing on diagnostic predictions instead of predictions that are consistent with multiple hypotheses. PMID- 25520739 TI - Measuring eosinophiluria, urinary eosinophil cationic protein and urinary interleukin-5 in patients with Lupus Nephritis. AB - BACKGROUND: Urine is increasingly becoming an attractive biological fluid in clinical practice due to being an easily obtained, non-invasive sampling method, containing proteins and peptides. The aim of this study was to investigate eosinophiluria, urinary eosinophil cationic protein (uECP) and urinary IL-5 (uIL 5) in patients with Lupus Nephritis. METHODS: Seventy-four patients with SLE-20 with clinical and laboratory evidence of lupus nephritis (LN group) and 54 without evidence of renal involvement (non-LN group)-were analyzed regarding eosinophiluria, uECP and uIL-5. Eosinophiluria was observed by Hansel's stain, ECP by fluoroenzymeimmunoassay and uIL-5 by quantitative sandwich enzyme immunoassay. Both uECP and urinary IL-5 (uIL-5) were corrected by urinary creatinine. Eosinophiluria and uECP were compared with glomerular erythrocyturia, protein/creatinine ratio (Pr/Cr ratio), serum creatinine, estimated glomerular filtration rate (eGFR), anti-double-stranded DNA (anti-dsDNA), serum levels of complement (C3 and C4), uIL-5/Cr ratio, and SLE disease activity index. RESULTS: Patients of the LN group had higher eosinophiluria, uECP, uECP/Cr ratio levels, and uIL-5 than patients of the non-LN group (p<0.001 for all). These variables showed a statistically significant correlation with glomerular erythrocyturia, casts, Pr/Cr ratio, serum creatinine, eGFR, anti-dsDNA, uIL-5/Cr, and SLE disease activity index (all p<0.05). CONCLUSION: These results provide evidence of increased urinary eosinophils, ECP and IL-5 in patients with SLE and LN; uECP/Cr ratio showed better correlation with markers of renal function and SLE disease activity. PMID- 25520740 TI - Successful use of daily intravenous infusion of C1 esterase inhibitor concentrate in the treatment of a hereditary angioedema patient with ascites, hypovolemic shock, sepsis, renal and respiratory failure. AB - Hereditary angioedema (HAE) is a rare autosomal dominant disease most commonly associated with defects in C1 esterase inhibitor (C1-INH). HAE manifests as recurrent episodes of edema in various body locations. Atypical symptoms, such as ascites, acute respiratory distress syndrome, and hypovolemic shock, have also been reported. Management of HAE conventionally involves the treatment of acute attacks, as well as short- and long-term prophylaxis. Since attacks can be triggered by several factors, including stress and physical trauma, prophylactic therapy is recommended for patients undergoing surgery. Human plasma-derived C1 INH (pdC1-INH) concentrate is indicated for the treatment of both acute HAE attacks and pre-procedure prevention of HAE episodes in patients undergoing medical, dental, or surgical procedures. We report the first case of a patient with HAE who experienced an abdominal attack precipitated by a retroperitoneal bleed while being converted from warfarin to heparin in preparation for surgery. Subsequently, the patient had a protracted course in hospital with other complications, which included hypovolemic shock, ascites, severe sepsis from nosocomial pneumonia, renal and respiratory failure. Despite intensive interventions, the patient remained in a critical state for months; however, after a trial of daily intravenous infusion of pdC1-INH concentrate (Berinert(r), CSL Behring GmbH, Marburg, Germany), clinical status improved, particularly renal function. Therefore, pdC1-INH concentrate may be an effective treatment option to consider for critically-ill patients with HAE. PMID- 25520741 TI - Homocysteine downregulates gene expression of heme oxygenase-1 in hepatocytes. AB - BACKGROUND: Hyperhomocysteinemia (HHcy) is an independent risk factor for liver diseases, such as fatty liver and hepatic fibrosis. However, the mechanisms underlying this pro-oxidative effect of homocysteine (Hcy) in hepatocytes remain largely unknown. Thus, we investigated the effect of Hcy on the gene expression of heme oxygenase-1 (HO-1), the primary rate-limiting enzyme in heme catabolism and a key anti-oxidant detoxification enzyme in maintaining cellular redox homeostasis. METHODS: In vivo, twenty male C57BL/6 mice at 8 weeks of age were randomly divided into two groups. One group was fed a chow diet (chow group; n = 10), the other group of mice was fed a methionine-supplemented diet (Met group, 1 mg kg(-1) day(-1) L-methionine in drinking water; n = 10) for 4 weeks. In vitro, HepG2 cells were stimulated with different doses of homocysteine (Hcy). RESULTS: Four weeks' methionine supplementation caused a significant increase of plasma Hcy concentration and a decrease of HO-1 expression in the liver of C57BL/6 mice than mice received chow diet. Besides, SOD enzyme activities were impaired and the level of oxidative stress markers, such as malondialdehyde (MDA) were elevated in the liver from mice supplemented with methionine compared with control mice. In cultured hepatocytes, Hcy treatment reduced both the mRNA and protein levels of HO-1 dose-dependently. However, Hcy had no effect on the gene expression of Nrf2, the major transcriptional regulator of HO-1. Instead, Hcy induced the expression of Bach1, a transcriptional repressor of HO-1. In addition, Hcy stimulated the nuclear localization of Bach1 but prevented that of Nrf2. Furthermore, we found that knockdown of Bach1 attenuated the suppression of the HO-1 expression by Hcy. CONCLUSIONS: Collectively, our results demonstrated that Bach1 plays an important role in Hcy-triggered ROS generations through inhibiting HO-1 expression, likely, resulting from the disturbed interplay between Bach1 and Nrf2. PMID- 25520742 TI - Alexithymia, anxiety and depression in patients with psoriasis: a case-control study. AB - BACKGROUND: Alexithymia, the difficulty in describing or recognizing emotions, has been associated with various psychosomatic pathologies including psoriasis. The aim of this study was to examine the prevalence of alexithymia and its association with anxiety and depression in patients with psoriasis compared with healthy participants, while taking into consideration demographic and clinical variables. METHODS: One hundred and eight psoriatic patients and 100 healthy participants from the general population completed the Toronto Alexithymia Scale (TAS-20) and the Hospital Anxiety and Depression Scale (HADS). The severity of patients' psoriasis was clinically assessed using the Psoriasis Area and Severity Index (PASI). RESULTS: Psoriatic patients had higher levels of alexithymia compared with healthy participants. While a rather high rate of psoriatic patients presented anxiety and depression as defined by the HADS, the differences that were found in comparison with the control group were not significant. Neither alexithymia nor its dimensions, difficulty in identifying feelings (DIF), difficulty in describing feelings (DDF) and externally oriented thinking (EOT), were associated with gender or psoriasis severity. Age was associated only with EOT, which was independent of depression and anxiety. Higher anxiety and depression were connected with higher alexithymia and DIF, while higher anxiety with higher DDF as well. CONCLUSIONS: The alexithymia prevalence was higher in psoriatic patients than that in healthy participants, while it was positively correlated with anxiety and depression. Difficulty in identifying feelings was connected with both anxiety and depression, whereas difficulty in describing them was only with anxiety. Finally, externally oriented thinking was predicted only from age. PMID- 25520743 TI - Children, care, career - a cross-sectional study on the risk of burnout among German hospital physicians at different career stages. AB - BACKGROUND: With the increasing number of female medical students physicians' need for work-life balanced hospital jobs rises at all career stages. The Working Time Act (Arbeitszeitgesetz, ArbZG), an implementation of the European Working Time Directive into German law in 2004, should have improved the general conditions for creating flexible work. Nevertheless, the vast majority of female physicians still report an incompatibility of work and family. So far, little is known about mothers working on leading positions in the medical field. The presented study focuses on gender differences in the level of emotional exhaustion between child-rearing junior and senior physicians and different predictors of burnout. METHODS: Three years after the ArbZT-enactment, 994 physicians from the listed hospital physicians in the Medical Register of the city of Hamburg participated in the cross-sectional study and completed a 60-item questionnaire (return rate of 46,5%). The questionnaire included a 22-item version of the German translation of the Maslach Burnout Inventory whereat emotional exhaustion was interpreted as the crucial predictor of burnout. Results of an univariate covariance analysis and regression analyses are reported. RESULTS: In the level of emotional exhaustion no gender differences were found between junior and senior physicians with children in the overall analysis. Support by the superior was the only overall predictor of burnout. Female senior physicians having children presented the highest risk of burnout. Only in this group parenting contributed significantly to the risk of burnout. CONCLUSIONS: Support by the superior and the relationship to colleagues are generally important predictors of burnout among hospital physicians. Parenthood only gets a crucial influence on psychomental health for female senior physicians. Still conservative role models are common in this group, thus dealing with the triple burden of work, leadership responsibility and child rearing seems to be a special female challenge. Innovative approaches of human resource policy need to be implemented to improve the reconciliation of family and working life. PMID- 25520745 TI - Rasterstereographic measurement of scoliotic deformity. AB - BACKGROUND: Back surface topography has gained acceptance in recent decades. At the same time, the motivation to use this technique has increased. From the view of the patient, the cosmetic aspect has played and still plays a major role as it provides a comprehensive documentation of cosmetic impairment. From the view of the medical practitioner, the aspect of reducing X-ray exposures in diagnosis and follow-up has been dominant and still prevails. Meanwhile, new aspects have emerged: due to the consequent three-dimensional view of the scoliotic condition, treatment success can be visualized convincingly. Clinical diagnosis is supported by information otherwise not supplied by X-rays, such as when functional examinations and diagnostic tests are recorded. METHODS: Like rasterstereography, most techniques of actual back surface measurement refer to photogrammetry and the triangulation method. However, with respect to the particular clinical application, a wide spectrum of implementations exists. Applications in a clinic require high accuracy of measurement in a short time and comprehensive analysis providing data to be used to supplement and compare with radiographic data. This is exemplified by rasterstereography; the procedures of surface analysis and localization of landmarks using curvatures and the reconstruction of the spinal midline will be described. ORTHOPAEDIC RELEVANCE: Based on rasterstereographic analysis, different geometrical measures that characterize the back surface are given and underlying skeletal structures described. Furthermore, in analogy to radiological projection, a 3-D reconstruction of the spinal midline is visualized by a frontal and lateral projection, allowing comparison with pertinent X-rays. CONCLUSIONS: Surface topography and, in particular, rasterstereography provide reliable and consistent results that may be used to reduce X-ray exposure. Unfortunately, the correlation of shape parameters with the radiological Cobb angle is poor. However, the wealth of additional applications substantially enhances the spectrum of clinical value. PMID- 25520744 TI - Mirror Neuron Forum. PMID- 25520746 TI - Reliability and validity study of measurements on digital photography to evaluate shoulder balance in idiopathic scoliosis. AB - OBJECTIVE: To determine the validity of digital photography as an evaluation method for shoulder balance (ShB) in patients with idiopathic scoliosis. MATERIAL AND METHODS: A total of 80 patients were included (mean age 20.3 years; 85% women). We obtained a full x-ray of the vertebral column and front and back clinical photography for all patients. For antero-posterior x-rays we measured the proximal thoracic curve angles (CPT). To evaluate radiological shoulder balance we calculated the clavicle-rib intersection angle (CRIA) and T1-tilt. For clinical photography we measured shoulder height angle (SHA), axilla height angle (AHA) and the left right trapezium angle (LRTA). We analyzed the reliability of the different photographic measurements and the correlation between these and the radiological parameters. RESULTS: The mean magnitude of PTC, CRIA and T1-tilt were 19 degrees , -0.6 degrees and 1.4 degrees respectively. Mean SHA from the front was -1.7 degrees . All photographic measurements revealed an excellent-near perfect intra and inter-observer reliability in both photographic projections. No correlation was found between the ShB and the magnitude of the PTC. A statistically significant correlation was found between clinical balance of the shoulders and radiological balance (r between 0.37 and 0.51). CONCLUSIONS: Digital clinical photography appears to be a reliable method for objective clinical measurement of ShB. The correlation between clinical and radiological balance is statistically significant although moderate/weak. PMID- 25520748 TI - On Privileging the Role of Gaze in Infant Social Cognition. AB - Theories of early social-cognitive development privilege infants' use of gaze as a cue to others' attention and intentions. Mutual gaze is assumed to indicate social engagement, gaze following is believed to index understanding of others' attention, and gaze alternation (between an object and a caregiver) is used to assess joint attention. This article discusses other cues (e.g., vocal and postural) on which children in other cultures and atypically developing children in Western cultures probably rely. It proposes that it is quite likely that typically developing children in Western cultures also use nongaze cues-in conjunction with gaze-in their everyday interactions with others. PMID- 25520747 TI - Why Does Joint Attention Look Atypical in Autism? AB - This essay answers the question of why autistic children are less likely to initiate joint attention (e.g., use their index finger to point to indicate interest in something) and why they are less likely to respond to bids for their joint attention (e.g., turn their heads to look at something to which another person points). It reviews empirical evidence that autistic toddlers, children, adolescents, and adults can attend covertly, even to social stimuli, such as the direction in which another person's eyes are gazing. It also reviews empirical evidence that autistics of various ages understand the intentionality of other persons' actions. The essay suggests that autistics' atypical resistance to distraction, atypical skill at parallel perception, and atypical execution of volitional actions underlie their atypical manifestations of joint attention. PMID- 25520749 TI - Charge density analysis for crystal engineering. AB - This review reports on the application of charge density analysis in the field of crystal engineering, which is one of the most growing and productive areas of the entire field of crystallography. While methods to calculate or measure electron density are not discussed in detail, the derived quantities and tools, useful for crystal engineering analyses, are presented and their applications in the recent literature are illustrated. Potential developments and future perspectives are also highlighted and critically discussed. Graphical abstract? PMID- 25520751 TI - Carbon accumulation in Rhodotorula glutinis induced by nitrogen limitation. AB - BACKGROUND: Oleaginous microorganisms, such as bacterium, yeast and algal species, can represent an alternative oil source for biodiesel production. The composition of their accumulated lipid is similar to the lipid of an oleaginous plant with a predominance of unsaturated fatty acid. Moreover this alternative to conventional biodiesel production does not create competition for land use between food and oleo-chemical industry supplies. Despite this promising potential, development of microbial production processes are at an early stage. Nutritional limited conditions, such as nitrogen limitation, with an excess of carbon substrate is commonly used to induce lipid accumulation metabolism. Nitrogen limitation implies modification of the carbon-to-nitrogen ratio in culture medium, which impacts on carbon flow distribution in the metabolic network. RESULTS: The goal of the present study is to improve our knowledge of carbon flow distribution in oleaginous yeast metabolism by focusing carbon distribution between carbohydrate and lipid pools in order to optimize microbial lipid production. The dynamic effects of limiting nitrogen consumption flux according to carbon flow were studied to trigger lipid accumulation in the oleaginous yeast Rhodotorula glutinis. With a decrease of the specific nitrogen consumption rate from 0.052 Nmol.CmolX (-1).h(-1) to 0.003 Nmol.CmolX (-1).h(-1), a short and transitory intracellular carbohydrate accumulation occurred before the lipid accumulation phase. This phenomenon was studied in fed-batch culture under optimal operating conditions, with a mineral medium and using glucose as carbon source. Two different strategies of decreasing nitrogen flow on carbohydrate accumulation were investigated: an instantaneous decrease and a progressive decrease of nitrogen flow. CONCLUSIONS: Lipid production performance in these fed-batch culture strategies with R. glutinis were higher than those reported in the previous literature; the catalytic specific lipid production rate was 0.07 Cmollip.CmolX* (-1).h(-1). Experimental results suggested that carbohydrate accumulation was an intrinsic phenomenon connected to the limitation of growth by nitrogen when the nitrogen-to-carbon ratio in the feed flow was lower than 0.045 Nmol.Cmol(-1). Carbohydrate accumulation corresponded to a 440% increase of carbohydrate content. These results suggest that microbial lipid production can be optimized by culture strategy and that carbohydrate accumulation must be taken account for process design. PMID- 25520750 TI - Mental health training program for community mental health staff in Guangzhou, China: effects on knowledge of mental illness and stigma. AB - BACKGROUND: In order to reduce the huge treatment gap in mental health, WHO has called for integrating mental health into primary care. The purposes of this study are to provide a training course to improve the community mental health staff's knowledge of mental health and reduce stigma related to mental illness, as well as to evaluate the impact of this training on knowledge and stigma. METHODS: The training intervention was a one day course for community mental health staff in Guangzhou, China. Evaluation questionnaires were given before and after the training session. Mental health knowledge was assessed using two vignettes. Stigma was evaluated by the Mental Illness: Clinicians' Attitudes Scale (MICA) and the Reported and Intended Behavior Scale (RIBS). RESULTS: A total of 99 community mental health staff from eight regions in Guangzhou, China were recruited for the study. The training course did not lead to a significant improvement of participants' levels of mental health knowledge. The mean score of MICA decreased from 47.92 +/- 8.63 to 43.53 +/- 9.61 after the training (t = 6.64, P < 0.001). As for the RIBS, the mean scores increased from (14.12 +/- 3.90) to (15.38 +/- 3.41) at post-test (t = -5.44, P < 0.001), indicating a significant improvement. CONCLUSIONS: The results from this study show that the training course is an effective way to improve community mental health staff's attitudes toward people with mental illness in the short term, as well as to lessen the social distance between staff and people with mental illness. PMID- 25520752 TI - Techno-economics of integrating bioethanol production from spent sulfite liquor for reduction of greenhouse gas emissions from sulfite pulping mills. AB - BACKGROUND: Flow sheet options for integrating ethanol production from spent sulfite liquor (SSL) into the acid-based sulfite pulping process at the Sappi Saiccor mill (Umkomaas, South Africa) were investigated, including options for generation of thermal and electrical energy from onsite bio-wastes, such as bark. Processes were simulated with Aspen Plus(r) for mass- and energy-balances, followed by an estimation of the economic viability and environmental impacts. Various concentration levels of the total dissolved solids in magnesium oxide based SSL, which currently fuels a recovery boiler, prior to fermentation was considered, together with return of the fermentation residues (distillation bottoms) to the recovery boiler after ethanol separation. The generation of renewable thermal and electrical energy from onsite bio-wastes were also included in the energy balance of the combined pulping-ethanol process, in order to partially replace coal consumption. The bio-energy supplementations included the combustion of bark for heat and electricity generation and the bio-digestion of the calcium oxide SSL to produce methane as additional energy source. RESULTS: Ethanol production from SSL at the highest substrate concentration was the most economically feasible when coal was used for process energy. However this solution did not provide any savings in greenhouse gas (GHG) emissions for the concentration-fermentation-distillation process. Maximizing the use of renewable energy sources to partially replace coal consumption yielded a satisfactory economic performance, with a minimum ethanol selling price of 0.83 US$/l , and a drastic reduction in the overall greenhouse gas emissions for the entire facility. CONCLUSION: High substrate concentrations and conventional distillation should be used when considering integrating ethanol production at sulfite pulping mills. Bio-wastes generated onsite should be utilized at their maximum potential for energy generation in order to maximize the GHG emissions reduction. PMID- 25520754 TI - 8p23.1 duplication syndrome: narrowing of critical interval to 1.80 Mbp. AB - BACKGROUND: A 3.68 Mbp duplication of 8p23.1 defines the 8p23.1 duplication syndrome. The main features of this syndrome are developmental delay and/or learning problems. RESULTS: Here we present a patient with a 1.80 Mbp duplication in 8p23.1 and characteristic signs and symptoms of the syndrome, including delay of motor and speech development and intellectual disability. DISCUSSION: The case indicates that genes within this interval, in particular dosage sensitive genes SOX7 and TNKS1, and possibly MIR124-1 and MIR598 as well suffice to cause the pathognomonic features of the 8p23.1 duplication syndrome. PMID- 25520753 TI - Localized, non-random differences in chromatin accessibility between homologous metaphase chromosomes. AB - BACKGROUND: Condensation differences along the lengths of homologous, mitotic metaphase chromosomes are well known. This study reports molecular cytogenetic data showing quantifiable localized differences in condensation between homologs that are related to differences in accessibility (DA) of associated DNA probe targets. Reproducible DA was observed for ~10% of locus-specific, short (1.5-5 kb) single copy DNA probes used in fluorescence in situ hybridization. RESULTS: Fourteen probes (from chromosomes 1, 5, 9, 11, 15, 17, 22) targeting genic and intergenic regions were developed and hybridized to cells from 10 individuals with cytogenetically-distinguishable homologs. Differences in hybridization between homologs were non-random for 8 genomic regions (RGS7, CACNA1B, GABRA5, SNRPN, HERC2, PMP22:IVS3, ADORA2B:IVS1, ACR) and were not unique to known imprinted domains or specific chromosomes. DNA probes within CCNB1, C9orf66, ADORA2B:Promoter-Ex1, PMP22:IVS4-Ex 5, and intergenic region 1p36.3 showed no DA (equivalent accessibility), while OPCML showed unbiased DA. To pinpoint probe locations, we performed 3D-structured illumination microscopy (3D-SIM). This showed that genomic regions with DA had 3.3-fold greater volumetric, integrated probe intensities and broad distributions of probe depths along axial and lateral axes of the 2 homologs, compared to a low copy probe target (NOMO1) with equivalent accessibility. Genomic regions with equivalent accessibility were also enriched for epigenetic marks of open interphase chromatin (DNase I HS, H3K27Ac, H3K4me1) to a greater extent than regions with DA. CONCLUSIONS: This study provides evidence that DA is non-random and reproducible; it is locus specific, but not unique to known imprinted regions or specific chromosomes. Non-random DA was also shown to be heritable within a 2 generation family. DNA probe volume and depth measurements of hybridized metaphase chromosomes further show locus specific chromatin accessibility differences by super-resolution 3D-SIM. Based on these data and the analysis of interphase epigenetic marks of genomic intervals with DA, we conclude that there are localized differences in compaction of homologs during mitotic metaphase and that these differences may arise during or preceding metaphase chromosome compaction. Our results suggest new directions for locus-specific structural analysis of metaphase chromosomes, motivated by the potential relationship of these findings to underlying epigenetic changes established during interphase. PMID- 25520755 TI - Transcriptional fingerprints of antigen-presenting cell subsets in the human vaginal mucosa and skin reflect tissue-specific immune microenvironments. AB - BACKGROUND: Dendritic cells localize throughout the body, where they can sense and capture invading pathogens to induce protective immunity. Hence, harnessing the biology of tissue-resident dendritic cells is fundamental for the rational design of vaccines against pathogens. METHODS: Herein, we characterized the transcriptomes of four antigen-presenting cell subsets from the human vagina (Langerhans cells, CD14(-) and CD14(+) dendritic cells, macrophages) by microarray, at both the transcript and network level, and compared them to those of three skin dendritic cell subsets and blood myeloid dendritic cells. RESULTS: We found that genomic fingerprints of antigen-presenting cells are significantly influenced by the tissue of origin as well as by individual subsets. Nonetheless, CD14(+) populations from both vagina and skin are geared towards innate immunity and pro-inflammatory responses, whereas CD14(-) populations, particularly skin and vaginal Langerhans cells, and vaginal CD14(-) dendritic cells, display both Th2-inducing and regulatory phenotypes. We also identified new phenotypic and functional biomarkers of vaginal antigen-presenting cell subsets. CONCLUSIONS: We provide a transcriptional database of 87 microarray samples spanning eight antigen-presenting cell populations in the human vagina, skin and blood. Altogether, these data provide molecular information that will further help characterize human tissue antigen-presenting cell lineages and their functions. Data from this study can guide the design of mucosal vaccines against sexually transmitted pathogens. PMID- 25520756 TI - Plasmodium falciparum gene expression measured directly from tissue during human infection. AB - BACKGROUND: During the latter half of the natural 48-h intraerythrocytic life cycle of human Plasmodium falciparum infection, parasites sequester deep in endothelium of tissues, away from the spleen and inaccessible to peripheral blood. These late-stage parasites may cause tissue damage and likely contribute to clinical disease, and a more complete understanding of their biology is needed. Because these life cycle stages are not easily sampled due to deep tissue sequestration, measuring in vivo gene expression of parasites in the trophozoite and schizont stages has been a challenge. METHODS: We developed a custom nCounter(r) gene expression platform and used this platform to measure malaria parasite gene expression profiles in vitro and in vivo. We also used imputation to generate global transcriptional profiles and assessed differential gene expression between parasites growing in vitro and those recovered from malaria infected patient tissues collected at autopsy. RESULTS: We demonstrate, for the first time, global transcriptional expression profiles from in vivo malaria parasites sequestered in human tissues. We found that parasite physiology can be correlated with in vitro data from an existing life cycle data set, and that parasites in sequestered tissues show an expected schizont-like transcriptional profile, which is conserved across tissues from the same patient. Imputation based on 60 landmark genes generated global transcriptional profiles that were highly correlated with genome-wide expression patterns from the same samples measured by microarray. Finally, differential expression revealed a limited set of in vivo upregulated transcripts, which may indicate unique parasite genes involved in human clinical infections. CONCLUSIONS: Our study highlights the utility of a custom nCounter(r) P. falciparum probe set, validation of imputation within Plasmodium species, and documentation of in vivo schizont-stage expression patterns from human tissues. PMID- 25520757 TI - Clinicopathological analysis on small cell carcinoma of the prostate in chinese patients. AB - OBJECTIVE: To explore the clinical and pathological characteristics of small-cell carcinoma (SmCC) of the prostate and applicable treatment methods. METHODS: We reported three cases of SmCC of the prostate diagnosed from 1999 to 2011 at the Chinese PLA General Hospital. We also reviewed clinical and pathological data of 26 cases in China reported over the same period. RESULTS: Serum prostate-specific antigen (PSA) levels were normal in 20 cases (76.9%) and elevated in six (23.1%). There was local invasion in 12 cases (46.2%) at the time of diagnosis; lymphatic vessel invasion and distant metastases were detected in eight (30.8%) and nine cases (34.6%) respectively. At the end of follow-up, 16 cases (61.5%) had died, eight (30.8%) survived, and two (7.7%) were missing. The median survival time was 8 months, and the 1-year survival rate was 23.2%. Statistical analysis showed that survival time was significantly correlated with chemotherapy treatment (p<0.05). However, serum PSA levels, surgical approach, pathological type, local invasion, lymphatic vessel invasion, and distant metastasis had no significant relationship with survival (p>0.05). CONCLUSIONS: SmCC of the prostate is a rare neoplasm typified by high malignancy, rapid progress, and poor prognosis. Pathological analysis is an important tool for confirming a diagnosis. Pure SmCC is usually not associated with an increase in serum PSA. Surgery, mixed with acinar adenocarcinoma components, and clinical staging do not correlate with prognosis; and chemotherapy was the only prognostic factor. For patients, diagnosed by preoperative biopsy, administering chemotherapy as the first-line treatment may improve outcomes. PMID- 25520759 TI - APPLYING INSIGHTS FROM BEHAVIORAL ECONOMICS TO POLICY DESIGN. AB - The premise of this article is that an understanding of psychology and other social science disciplines can inform the effectiveness of the economic tools traditionally deployed in carrying out the functions of government, which include remedying market failures, redistributing income, and collecting tax revenue. An understanding of psychology can also lead to the development of different policy tools that better motivate desired behavior change or that are more cost effective than traditional policy tools. The article outlines a framework for thinking about the psychology of behavior change in the context of market failures. It then describes the research on the effects of a variety of interventions rooted in an understanding of psychology that have policy-relevant applications. The article concludes by discussing how an understanding of psychology can also inform the use and design of traditional policy tools for behavior change, such as financial incentives. PMID- 25520761 TI - Is One Style of Early Behavioral Treatment for Autism 'Scientifically Proven?' AB - Within the field of autism spectrum disorder, the attribute "scientifically proven' it moil commonly urn in reference to the results of early behavioral treatment, and in particular, one style of early behavioral treatment. In this brief article, such claims are evaluated. Concerns raised by other researchers about the methodology of the original Lovaas (1987) study are briefly summarized. A particular concern that has been raised repeatedly u the loch of random assignment of participants to treatment versus control group. A more recent study (Smith, Groen, & Wynn, ZOOO), which included the necessary random assignment of participants to treatment versus control group and assessed multiple outcome measures, is reviewed. The results of the Smith et al. (ZOOO) study with random assignment appear to be less dramatic than the results from the original Lovaas (1987) study. PMID- 25520758 TI - MicroRNA-21 Down-regulates Rb1 Expression by Targeting PDCD4 in Retinoblastoma. AB - Retinoblastoma (RB) is a children's ocular cancer caused by mutated retinoblastoma 1 (Rb1) gene on both alleles. Rb1 and other related genes could be regulated by microRNAs (miRNA) via complementarily pairing with their target sites. MicroRNA-21 (miR-21) possesses the oncogenic potential to target several tumor suppressor genes, including PDCD4, and regulates tumor progression and metastasis. However, the mechanism of how miR-21 regulates PDCD4 is poorly understood in RB. We investigated the expression of miRNAs in RB cell lines and identified that miR-21 is one of the most deregulated miRNAs in RB. Using qRT PCR, we verified the expression level of several miRNAs identified by independent microarray assays, and analyzed miRNA expression patterns in three RB cell lines, including Weri-Rb1, Y79 and RB355. We found that miR-19b, -21, -26a, -195 and 222 were highly expressed in all three cell lines, suggesting their potential role in RB tumorigenesis. Using the TargetScan program, we identified a list of potential target genes of these miRNAs, of which PDCD4 is one the targets of miR 21. In this study, we focused on the regulatory mechanism of miR-21 on PDCD4 in RB. We demonstrated an inverse correlation between miR-21 and PDCD4 expression in Weri-Rb1 and Y79 cells. These data suggest that miR-21 down-regulates Rb1 by targeting PDCD4 tumor suppressor. Therefore, miR-21 could serve as a therapeutic target for retinoblastoma. PMID- 25520762 TI - A study of sports related occurrence of traumatic orodental injuries and associated risk factors in high school students in north India. AB - BACKGROUND: Oral and dental injuries contribute to a major part of sports related injuries in children. Trauma occurring in developing years disrupts normal social functioning and brings about a major impact on quality of life due to their cumulative effect. OBJECTIVES: To assess the prevalence and causes of various sports related traumatic orodental injuries among 8 to 16 year school students along with identifying the associated risk factors in North India. PATIENTS AND METHODS: A cross sectional study consisting of high school students of different organized sports teams aged 8-16 years was carried out in geographical area of north India. The students were selected by multistage cluster sampling methodology. 1105 students from 19 school teams (sports teams) and sports academies participated in study through structured interview and clinical examination in different sports situations. RESULTS: 30.3% (n = 335) of students suffered from orodental injuries. A higher number of girls had injury (32%) than boys (29%), though the difference was not significant. Most of the students suffered from soft tissue injuries (48%) followed by tooth fractures (43%). Maximum numbers of injuries were reported in high velocity (44.1%) and medium intensity sports (46.6%) (P < 0.001) Maximum injuries occurred in basketball (50%) and lowest in the field of badminton (6.1%) (P < 0.05). Amateurs (52%) suffered the most from injuries as per level of coaching. Only 6% of boys and 2% of girls used mouthguards. CONCLUSIONS: The result of the present study confirmed that students participating in different organized sports at high school level are at a very high risk of getting orodental injury. Hence knowledge and education regarding prevention of traumatic injuries is of paramount importance. PMID- 25520763 TI - The influence of different modes of ventilation on standing balance of athletes. AB - BACKGROUND: The respiratory movements are one of the factors influencing standing balance. Although well-trained athletes have better postural performance compared to untrained men, it's not quite clear, if the formers' upright posture would be more stable during different ventilation modes, maximal voluntary hyperventilation and inspiratory breath-holding. There are no studies on this subject in the available literature. OBJECTIVES: The aim of this study was to investigate an influence of maximal inspiratory breath-holding and maximal voluntary hyperventilation on the standing balance of athletes. PATIENTS AND METHODS: We assessed the amplitude and the velocity of postural sway in the athletes (n = 38) and untrained subjects (n = 28) by the force platform. The frequency characteristics of the center of pressure (CP) oscillations' were also analyzed. The amplitude and the frequency of respiratory movements were estimated by the strain gauge. RESULTS: It was found that during quiet breath velocity and frequency of CP oscillations were lower in the athletes. Breath holding led to an increase of velocity and frequency of CP displacement in both groups, increase of these indices was more pronounced in the athletes. Maximal voluntary hyperventilation caused a significant increase of all stabilographic indices in both groups. Increase of frequency and amplitude of respiratory movements were mainly observed during hyperventilation in athletes and it caused an increase of the velocity of CP displacement. Changes of sway amplitude were the same in both groups. CONCLUSIONS: Breath holding led to activation of the postural control, which was more pronounced in the athletes. Hyperventilation caused an impairment of the postural stability. The athletes' postural system compensated the impact of hyperventilation more efficiently versus controls, but it was achieved at the expense of greater effort. PMID- 25520764 TI - Lack of Association Between ACE Indel Polymorphism and Cardiorespiratory Fitness in Physically Active and Sedentary Young Women. AB - BACKGROUND: Polymorphisms at the angiotensin-converting enzyme gene (ACE), such as the indel [rs1799752] variant in intron 16, have been shown to be associated with aerobic performance of athletes and non-athletes. However, the relationship between ACE indel polymorphism and cardiorespiratory fitness has not been always demonstrated. OBJECTIVES: The relationship between ACE indel polymorphism and cardiorespiratory fitness was investigated in a sample of young Caucasian Brazilian women. PATIENTS AND METHODS: This study investigated 117 healthy women (aged 18 to 30 years) who were grouped as physically active (n = 59) or sedentary (n = 58). All subjects performed an incremental exercise test (ramp protocol) on a cycle-ergometer with 20-25 W/min increments. Blood samples were obtained for DNA extraction and to analyze metabolic and hormonal profiles. ACE indel polymorphism was determined by polymerase chain reaction (PCR) and fragment size analysis. RESULTS: The physically active group had higher values of peak oxygen uptake (VO2 peak), carbon dioxide output (VCO2), ventilation (VE) and power output than the sedentary group (P < 0.05) at the peak of the exercise test. However, heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) did not differ between groups. There was no relationship between ACE indel polymorphism and cardiorespiratory variables during the test in both the physically active and sedentary groups, even when the dominant (DD vs. D1 + 2) and recessive (2 vs. DI + DD) models of inheritance were tested. CONCLUSIONS: These results do not support the concept that the genetic variation at the ACE locus contributes to the cardiorespiratory responses at the peak of exercise test in physically active or sedentary healthy women. This indicates that other factors might mediate these responses, including the physical training level of the women. PMID- 25520765 TI - Postural control impairments in individuals with autism spectrum disorder: a critical review of current literature. AB - CONTEXT: Motor impairments in individuals with autism spectrum disorder (ASD) have been frequently reported. In this review, we narrow our focus on postural control impairments to summarize current literature for patterns, underlying mechanisms, and determinants of posture in this population. EVIDENCE ACQUISITION: A literature search was conducted through Medline, ISI web of Knowledge, Scopus and Google Scholar to include studies between 1992 and February 2013. RESULTS: Individuals with ASD have problems in maintaining postural control in infancy that well persists into later years. However, the patterns and underlying mechanisms are still unclear. CONCLUSIONS: Examining postural control as an endophenotype or early diagnostic marker of autism is a conceptual premise which should be considered in future investigations. At the end of the review, methodological recommendations on the assessment of postural control have also been provided. PMID- 25520766 TI - Effect of preconditioning by light load eccentric exercise versus heat on markers of muscle damage in collegiate males. AB - BACKGROUND: Delayed onset muscle soreness (DOMS) occurs following unaccustomed or intense bouts of exercise. Previous research has demonstrated that that preconditioning with low load exercise or heat relieves muscle soreness. However, actively warming up the muscles with exercise may be an effective alternative. OBJECTIVES: This study compared preconditioning effect of light load eccentric exercise and heat using microwave diathermy on markers of muscle damage in collegiate males. PATIENTS AND METHODS: Thirty six sedentary collegiate males were randomly assigned into two experimental groups: 10% Eccentric exercise group (10% ECC group) and Microwave diathermy group (MWD group). Both the groups performed 30 repetitions of maximal eccentric exercise (Max-ECC) of the elbow flexors. The 10% ECC group performed light load eccentric exercise (10% ECC), five sets, six repetitions using a dumbbell set at 10% of maximal voluntary isometric contraction strength (MVC), 2 days prior to Max-ECC. The MWD group received heat using microwave diathermy (150 watts, 20 minutes) one day prior to Max-ECC. Changes in MVC, range of motion (ROM), upper arm circumference, soreness, were assessed before and 24-72 hours after whereas serum creatine kinase activity and lactate dehydrogenase (LDH) activity up to 48 hours following the Max-ECC were compared between groups by a mixed model ANOVA. RESULTS: No significant difference (P > 0.05) were found between the groups for changes in all variables post Max-ECC, except for LDH activity showing significant interaction effect (P = 0.04). CONCLUSIONS: Preconditioning with light load eccentric exercise and heat using microwave diathermy treatment did not differ in their effects on muscle damage markers after Max-ECC. However, with time their effects on LDH activity were found to be different. PMID- 25520767 TI - Injuries in iran futsal national teams: a comparative study of incidence and characteristics. AB - BACKGROUND: Futsal is a growing sport with lots of fans in many countries including Iran, but there are few papers in the literature which report injuries in top level futsal. OBJECTIVES: The aim of this study is to record and analyze the incidence and characteristics of injuries in Iran futsal national teams from March 2011 to September 2012. PATIENTS AND METHODS: 55 Iranian national futsal players participated in this prospective cohort study. Before entering the study, all players took part in Pre-Competition Medical Assessment (PCMA) in accordance with FIFA protocol. Team physicians recorded the injuries throughout the match and trainings in a special form which was designed for this purpose. Finally, data analysis was done with the SPSS software. RESULTS: The total exposure time for all players was 24326 hours (21138 hours during training and 3188 hours during matches). During the study period, 32 of the 55 national players (58.2%) incurred 54 injuries (incidence rate = 2.22 injuries per 1000 players-hours). The incidence rate of injury in female players was significantly higher than male players (P = 0.001). The majority of injuries (85.2%) were located on the lower extremities. The ankle was the most frequent injury location (40.7%) and sprain was the most frequent type of injury. CONCLUSIONS: Injuries are common among futsal players and female players are more prone to injuries than male players. The ankle is the most frequent site and sprain is the most frequent type of injury among futsal players. PMID- 25520768 TI - Analysis of the Three Most Prevalent Injuries in Australian Football Demonstrates a Season to Season Association Between Groin/Hip/Osteitis Pubis Injuries With ACL Knee Injuries. AB - BACKGROUND: Injuries are common in contact sports like Australian football. The Australian Football League (AFL) has developed an extensive injury surveillance database that can be used for epidemiological studies. OBJECTIVES: The purpose of this study is to identify any association between the three most prevalent injuries in the AFL. PATIENTS AND METHODS: From the AFL injury surveillance data 1997-2012 the injury incidence (new injuries per club per season) and the injury prevalence data (missed games per club per season) were analysed to detect the three most common injuries that would cause a player to miss a match in the AFL. The three most prevalent injuries in the AFL are hamstring strains, groin/hip/osteitis pubis injuries and Anterior Cruciate Ligament (ACL) knee injuries. Following this, further study was undertaken to detect the presence of any statistical relationship between injury incidences of the three most prevalent injuries over this sixteen year study period. RESULTS: Statistical analysis demonstrates for any given year that there was an association between having a groin/hip/osteitis pubis injuriy and having a knee ACL injury (P < 0.05) over the entire sixteen years. In other words if the number of groin/hip/osteitis pubis injuries in any given season were higher than average (alternatively lower) then the number of knee ACL injuries were also higher than average (alternatively lower) for that same season. Hamstring injuries had the highest variance of incidence of the three most prevalent injuries. CONCLUSIONS: Analysis of the AFL injury data demonstrates an association between incidence of groin/hip/osteitis pubis injuries and incidence of knee ACL injuries for any given playing season. This finding is difficult to explain with further research being required. PMID- 25520769 TI - Second to fourth digit ratio is a predictor of sporting ability in elite Indian male kabaddi players. AB - BACKGROUND: To determine the 2D:4D ratio in elite Indian male kabaddi players and compare them with non-athletes. OBJECTIVES: Our study was undertaken to find out a possible relation between digit ratio and sporting ability of male kabaddi players. This study also gives an insight into the possible ethnic differences between Indian sports personnel and other populations. PATIENTS AND METHODS: Both right and left hands of 33 male kabaddi players attending training camp at the Bangalore regional centre of Sports Authority of India were scanned. Lengths of second and fourth digits were measured and their ratio calculated. Age, weight, height and body mass index matched subjects (25 males) who did not participate in any sports formed the control group. RESULTS: A highly significant difference was found in 2D:4D ratios of both the hands with Kabaddi players having a lower ratio compared to their controls. There was no statistically significant difference in 2D:4D (Delta r-l) between Kabaddi players and controls. CONCLUSIONS: Kabaddi is an intermediate sport not requiring a high level of endurance but at the same time requires masculine traits because of combating nature of the game. 2D:4D ratios can be used as reliable additional criteria when screening for prospective players to be inducted into the team. PMID- 25520770 TI - Effect of ice massage on lower extremity functional performance and weight discrimination ability in collegiate footballers. AB - BACKGROUND: Cryotherapy, in the form of ice massge is used to reduce inflammation after acute musculoskeletal injury or trauma. The potential negative effects of ice massage on proprioception are unknown, despite equivocal evidence supporting its effectiveness. OBJECTIVES: The purpose of the study was to test the influence of cooling on weight discrimination ability and hence the performance in footballers. PATIENTS AND METHODS: The study was of same subject experimental design (pretest-posttest design). Thirty male collegiate football players, whose mean age was 21.07 years, participated in the study. The participants were assessed for two functional performance tests, single leg hop test and crossed over hop test and weight discrimination ability before and after ice massage for 5 minutes on hamstrings muscle tendon. RESULTS: Pre cooling scores of Single Leg Hop Test of the dominant leg in the subjects was 166.65 (+/- 10.16) cm and post cooling scores of the dominant leg was 167.25 (+/- 11.77) cm. Pre cooling scores of Crossed Over Hop Test of the dominant leg in the subjects was 174.14 (+/- 8.60) cm and post cooling scores of the dominant leg was 174.45 (+/- 9.28) cm. Pre cooling scores of Weight Discrimination Differential Threshold of the dominant leg in the subjects was 1.625 +/- 1.179 kg compared with post cooling scores of the dominant leg 1.85 (+/- 1.91) kg. Pre cooling scores of single leg hop and crossed over hop test of the dominant leg in the subjects compared with post cooling scores of the dominant leg showed no significant differences and it was also noted that the weight discrimination ability (weight discrimination differential threshold) didn't show any significant difference. All the values are reported as mean +/- SD. CONCLUSIONS: This study provides additional evidence that proprioceptive acuity in the hamstring muscles (biceps femoris) remains largely unaffected after ice application to the hamstrings tendon (biceps femoris). PMID- 25520771 TI - An unusual knee mass in a soccer player. AB - INTRODUCTION: Non-traumatic knee joint effusion and fullness is a relatively common presenting complaint among athletes and non-athletes. Due to its broad differential diagnosis, a comprehensive evaluation beginning with history and physical examination are recommended. Imaging including plain radiography, magnetic resonance imaging (MRI), and in some cases ultrasound are preferred modalities. If inflammatory arthritis is suspected, joint aspiration and analysis may help diagnosis. CASE PRESENTATION: A 37-year-old male soccer player presented with a complaint of left anterior knee pain and fullness for a few months. Physical examination revealed a healthy appearing male with obvious fullness of his left suprapatellar pouch and posterolateral knee. Plain radiographs were unremarkable. MRI demonstrated an effusion infiltrated by multiple, low intensity projections from a fatty mass in the suprapatellar pouch consistent with lipoma arborescens. CONCLUSIONS: Lipoma arborescens is a rare synovial disorder characterized by replacement of subsynovial tissue with mature fat cells, most commonly in the knee joint. MRI is the best diagnostic modality to evaluate and confirm the diagnosis as well as rule out other pathologies. More recent single case-reports and clinical series endorse arthroscopic synovectomy as the treatment of choice. PMID- 25520772 TI - On-Surface Cross Coupling Methods for the Construction of Modified Electrode Assemblies with Tailored Morphologies. AB - Controlling the molecular topology of electrode-catalyst interfaces is a critical factor in engineering devices with specific electron transport kinetics and catalytic efficiencies. As such, the development of rational methods for the modular construction of tailorable electrode surfaces with robust molecular wires (MWs) exhibiting well-defined molecular topologies, conductivities and morphologies is critical to the evolution and implementation of electrochemical arrays for sensing and catalysis. In response to this need, we have established modular on-surface Sonogashira and Glaser cross-coupling processes to synthetically install arrays of ferrocene-capped MWs onto electrochemically functionalized surfaces. These methods are of comparable convenience and efficiency to more commonly employed Huisgen methods. Furthermore, unlike the Huisgen reaction, this new surface functionalization chemistry generates modified electrodes that do not contain unwanted ancillary metal binding sites, while allowing the bridge between the ferrocenyl moiety and electrode surface to be synthetically tailored. Electrochemical and surface analytical characterization of these platforms demonstrate that the linker topology and connectivity influences the ferrocene redox potential and the kinetics of charge transport at the interface. PMID- 25520773 TI - How can we manage resistance to antiangiogenic drugs? PMID- 25520776 TI - Learning intrinsic excitability in medium spiny neurons. AB - We present an unsupervised, local activation-dependent learning rule for intrinsic plasticity (IP) which affects the composition of ion channel conductances for single neurons in a use-dependent way. We use a single compartment conductance-based model for medium spiny striatal neurons in order to show the effects of parameterization of individual ion channels on the neuronal activation function. We show that parameter changes within the physiological ranges are sufficient to create an ensemble of neurons with significantly different activation functions. We emphasize that the effects of intrinsic neuronal variability on spiking behavior require a distributed mode of synaptic input and can be eliminated by strongly correlated input. We show how variability and adaptivity in ion channel conductances can be utilized to store patterns without an additional contribution by synaptic plasticity (SP). The adaptation of the spike response may result in either "positive" or "negative" pattern learning. However, read-out of stored information depends on a distributed pattern of synaptic activity to let intrinsic variability determine spike response. We briefly discuss the implications of this conditional memory on learning and addiction. PMID- 25520775 TI - Cellular and molecular basis of Venous insufficiency. AB - Chronic venous disease (CVD) has a range of clinical presentations, including tortuous, distended veins in lower extremities, increasing skin pigmentation, and in severe cases ulceration of the affected skin. Venous insufficiency, a precursor to CVD characterized by improper return of blood from the lower extremities to the heart, must be studied in its earliest stages at a time when preventative measures could be applied in man. This underscores the need for basic research into biomarkers and genetic predisposing factors affecting the progression of venous disease. Investigation over the past decade has yielded insight into these specific genetic, cellular and molecular mechanisms underlying the development of venous disease. Among the many advances include the elucidation of an increasing role for matrix metalloproteinases as important mediators of the degenerative process involved with venous insufficiency. This may be preceded by an inflammatory process which further contributes to venular degeneration and endothelial dysfunction seen in advanced presentation of disease. Furthermore, genomic analyses have shed light upon temporal expression patterns of matrix remodeling proteins in diseased tissue samples. In this review we examine some of the current findings surrounding cellular, molecular and genetic advances in delineating the etiology of chronic venous disease. PMID- 25520774 TI - Sex differences in mood disorders: perspectives from humans and rodent models. AB - Mood disorders are devastating, often chronic illnesses characterized by low mood, poor affect, and anhedonia. Notably, mood disorders are approximately twice as prevalent in women compared to men. If sex differences in mood are due to underlying biological sex differences, a better understanding of the biology is warranted to develop better treatment or even prevention of these debilitating disorders. In this review, our goals are to: 1) summarize the literature related to mood disorders with respect to sex differences in prevalence, 2) introduce the corticolimbic brain network of mood regulation, 3) discuss strategies and challenges of modeling mood disorders in mice, 4) discuss mechanisms underlying sex differences and how these can be tested in mice, and 5) discuss how our group and others have used a translational approach to investigate mechanisms underlying sex differences in mood disorders in humans and mice. PMID- 25520778 TI - Cytoscape tools for the web age: D3.js and Cytoscape.js exporters. AB - In this paper we present new data export modules for Cytoscape 3 that can generate network files for Cytoscape.js and D3.js. Cytoscape.js exporter is implemented as a core feature of Cytoscape 3, and D3.js exporter is available as a Cytoscape 3 app. These modules enable users to seamlessly export network and table data sets generated in Cytoscape to popular JavaScript library readable formats. In addition, we implemented template web applications for browser-based interactive network visualization that can be used as basis for complex data visualization applications for bioinformatics research. Example web applications created with these tools demonstrate how Cytoscape works in modern data visualization workflows built with traditional desktop tools and emerging web based technologies. This interactivity enables researchers more flexibility than with static images, thereby greatly improving the quality of insights researchers can gain from them. PMID- 25520777 TI - Follow up: Compound data sets and software tools for chemoinformatics and medicinal chemistry applications: update and data transfer. AB - In 2012, we reported 30 compound data sets and/or programs developed in our laboratory in a data article and made them freely available to the scientific community to support chemoinformatics and computational medicinal chemistry applications. These data sets and computational tools were provided for download from our website. Since publication of this data article, we have generated 13 new data sets with which we further extend our collection of publicly available data and tools. Due to changes in web servers and website architectures, data accessibility has recently been limited at times. Therefore, we have also transferred our data sets and tools to a public repository to ensure full and stable accessibility. To aid in data selection, we have classified the data sets according to scientific subject areas. Herein, we describe new data sets, introduce the data organization scheme, summarize the database content and provide detailed access information in ZENODO (doi: 10.5281/zenodo.8451 and doi:10.5281/zenodo.8455). PMID- 25520779 TI - Active transmembrane drug transport in microgravity: a validation study using an ABC transporter model. AB - Microgravity has been shown to influence the expression of ABC (ATP-Binding Cassette) transporters in bacteria, fungi and mammals, but also to modify the activity of certain cellular components with structural and functional similarities to ABC transporters. Changes in activity of ABC transporters could lead to important metabolic disorders and undesired pharmacological effects during spaceflights. However, no current means exist to study the functionality of these transporters in microgravity. To this end, a Vesicular Transport Assay ((r)) (Solvo Biotechnology, Hungary) was adapted to evaluate multi-drug resistance-associated protein 2 (MRP2) trans-membrane estradiol-17-beta glucuronide (E17betaG) transport activity, when activated by adenosine-tri phosphate (ATP) during parabolic flights. Simple diffusion, ATP-independent transport and benzbromarone inhibition were also evaluated. A high accuracy engineering system was designed to perform, monitor and synchronize all procedures. Samples were analysed using a validated high sensitivity drug detection protocol. Experiments were performed in microgravity during parabolic flights, and compared to 1g on ground results using identical equipment and procedures in all cases. Our results revealed that sufficient equipment accuracy and analytical sensitivity were reached to detect transport activity in both gravitational conditions. Additionally, transport activity levels of on ground samples were within commercial transport standards, proving the validity of the methods and equipment used. MRP2 net transport activity was significantly reduced in microgravity, so was signal detected in simple diffusion samples. Ultra structural changes induced by gravitational stress upon vesicle membranes or transporters could explain the current results, although alternative explanations are possible. Further research is needed to provide a conclusive answer in this regard. Nevertheless, the present validated technology opens new and interesting research lines in biology and human physiology with the potential for significant benefits for both space and terrestrial medicine. PMID- 25520780 TI - Using Twitter to investigate opinions about multiple sclerosis treatments: a descriptive, exploratory study. AB - BACKGROUND: Multiple sclerosis (MS) is a common complex disorder, with new treatment options emerging each year. Social media is being increasingly used to investigate opinions about drugs, diseases and procedures. In this descriptive exploratory study, we sought to investigate opinions about currently available MS treatments. METHODS: The Twitter resource Topsy was searched for tweets mentioning the following MS treatments: Aubagio, Avonex, Betaferon or Betaseron, Copaxone, Extavia, Gilenya, Lemtrada, Novantrone, Rebif, Tysabri and Tecfidera between 1 Jan 2006 to 31 Jul 2014. Tweets were normalised and sentiment analysis performed. RESULTS: In total, there were 60037 unique tweets mentioning an MS treatment. About half of the tweets contained non-neutral sentiment. Mean sentiment scores were different for treatments ranging from -0.191to 0.282 when investigating all tweets. These differences in sentiment scores between treatments were statistically significant (P<0.001). Sentiment scores tended to be higher for oral MS treatments than injectable treatments. CONCLUSIONS: Many tweets about MS treatments have a non-neutral sentiment. The analysis of social media appears to be a potential avenue for exploring patient opinion about MS treatments. PMID- 25520781 TI - The proteasome activity reporter GFP-Cl1 is degraded by autophagy in the aging model Podospora anserina. AB - The degradation of damaged proteins is an important vital function especially during aging and stress. The ubiquitin proteasome system is one of the major cellular machineries for protein degradation. Health and longevity are associated with high proteasome activity. To demonstrate such a role in aging of Podospora anserina, we first analyzed the transcript and protein abundance of selected proteasome components in wild-type cultures of different age. No significant differences were observed. Next, in order to increase the overall proteasome abundance we generated strains overexpressing the catalytic proteasome subunits PaPRE2 and PaPRE3. Although transcript levels were strongly increased, no substantial effect on the abundance of the corresponding proteins was observed. Finally, the analysis of the P. anserina strains expressing the sequence coding for the CL1 degron fused to the Gfp gene revealed no evidence for degradation of the GFP-CL1 fusion protein by the proteasome. Instead, our results demonstrate the degradation of the CL1-degron sequence via autophagy, indicating that basal autophagy appears to be a very effective protein quality control pathway in P. anserina. PMID- 25520783 TI - Current scientific evidence for integrated community case management (iCCM) in Africa: Findings from the iCCM Evidence Symposium. AB - In March 2014, over 400 individuals from 35 countries in sub-Saharan Africa and 59 international partner organizations gathered in Accra, Ghana for an integrated Community Case Management (iCCM) Evidence Review Symposium. The objective was 2 fold: first, to review the current state of the art of iCCM implementation and second, to assist African countries to integrate lessons learned and best practices presented during the symposium into their programmes. Based on the findings from the symposium this supplement includes a comprehensive set of articles that provide the latest evidence for improving iCCM programs and ways to better monitor and evaluate such programs. PMID- 25520782 TI - It is not just muscle mass: a review of muscle quality, composition and metabolism during ageing as determinants of muscle function and mobility in later life. AB - Worldwide estimates predict 2 billion people will be aged over 65 years by 2050. A major current challenge is maintaining mobility and quality of life into old age. Impaired mobility is often a precursor of functional decline, disability and loss of independence. Sarcopenia which represents the age-related decline in muscle mass is a well-established factor associated with mobility limitations in older adults. However, there is now evidence that not only changes in muscle mass but other factors underpinning muscle quality including composition, metabolism, aerobic capacity, insulin resistance, fat infiltration, fibrosis and neural activation may also play a role in the decline in muscle function and impaired mobility associated with ageing. Importantly, changes in muscle quality may precede loss of muscle mass and therefore provide new opportunities for the assessment of muscle quality particularly in middle-aged adults who could benefit from interventions to improve muscle function. This review will discuss the accumulating evidence that in addition to muscle mass, factors underpinning muscle quality influence muscle function and mobility with age. Further development of tools to assess muscle quality in community settings is needed. Preventative diet, exercise or treatment interventions particularly in middle aged adults at the low end of the spectrum of muscle function may help preserve mobility in later years and improve healthspan. PMID- 25520787 TI - Routine monitoring systems for integrated community case management programs: Lessons from 18 countries in sub-Saharan Africa. PMID- 25520788 TI - Community health workers: A crucial role in newborn health care and survival. PMID- 25520789 TI - The way forward for integrated community case management programmes: A summary of lessons learned to date and future priorities. PMID- 25520790 TI - Where to from here? Policy and financing of integrated community case management (iCCM) of childhood illness in sub-Saharan Africa. PMID- 25520791 TI - Community case management of childhood illness in sub-Saharan Africa - findings from a cross-sectional survey on policy and implementation. AB - BACKGROUND: Community case management (CCM) involves training, supporting, and supplying community health workers (CHWs) to assess, classify and manage sick children with limited access to care at health facilities, in their communities. This paper aims to provide an overview of the status in 2013 of CCM policy and implementation in sub-Saharan African countries. METHODS: We undertook a cross sectional, descriptive, quantitative survey amongst technical officers in Ministries of Health and UNICEF offices in 2013. The survey aim was to describe CCM policy and implementation in 45 countries in sub-Saharan Africa, focusing on: CHW profile, CHW activities, and financing. RESULTS: 42 countries responded. 35 countries in sub-Saharan Africa reported implementing CCM for diarrhoea, 33 for malaria, 28 for pneumonia, 6 for neonatal sepsis, 31 for malnutrition and 28 for integrated CCM (treatment of 3 conditions: diarrhoea, malaria and pneumonia) - an increase since 2010. In 27 countries, volunteers were providing CCM, compared to 14 countries with paid CHWs. User fees persisted for CCM in 6 countries and mark ups on commodities in 10 countries. Most countries had a national policy, memo or written guidelines for CCM implementation for diarrhoea, malaria and pneumonia, with 20 countries having this for neonatal sepsis. Most countries plan gradual expansion of CCM but many countries' plans were dependent on development partners. A large group of countries had no plans for CCM for neonatal sepsis. CONCLUSION: 28 countries in sub-Saharan Africa now report implementing CCM for pneumonia, diarrhoea and malaria, or "iCCM". Most countries have developed some sort of written basis for CCM activities, yet the scale of implementation varies widely, so a focus on implementation is now required, including monitoring and evaluation of performance, quality and impact. There is also scope for expansion for newborn care. Key issues include financing and sustainability (with development partners still providing most funding), gaps in data on CCM activities, and the persistence of user fees and mark-ups in several countries. National health management information systems should also incorporate CCM activities. PMID- 25520792 TI - Spatial distribution and deployment of community-based distributors implementing integrated community case management (iCCM): Geographic information system (GIS) mapping study in three South Sudan states. AB - AIM: In late 2012 and in conjunction with South Sudan's Ministry of Health - National Malaria Control Program, PSI (Population Services International) conducted a comprehensive mapping exercise to assess geographical coverage of its integrated community case management (iCCM) program and consider scope for expansion. The operational research was designed to provide evidence and support for low-cost mapping and monitoring systems, demonstrating the use of technology to enhance the quality of programming and to allow for the improved allocation of resources through appropriate and need-based deployment of community-based distributors (CBDs). METHODS: The survey took place over the course of three months and program staff gathered GPS (global positioning system) data, along with demographic data, for over 1200 CBDs and 111 CBD supervisors operating in six counties in South Sudan. Data was collated, cleaned and quality assured, input into an Excel database, and subsequently uploaded to geographic information system (GIS) for spatial analysis and map production. RESULTS: The mapping results showed that over three-quarters of CBDs were deployed within a five kilometer radius of a health facility or another CBD, contrary to program planning and design. Other characteristics of the CBD and CBD supervisor profiles (age, gender, literacy) were more closely matched with other regional programs. CONCLUSIONS: The results of this mapping exercise provided a valuable insight into the contradictions found between a program "deployment plan" and the realities observed during field implementation. It also highlighted an important need for program implementers and national-level strategy makers to consider the natural and community-driven diffusion of CBDs, and take into consideration the strength of the local health facilities when developing a deployment plan. PMID- 25520793 TI - Training, supervision and quality of care in selected integrated community case management (iCCM) programmes: A scoping review of programmatic evidence. AB - AIM: To describe the training, supervision and quality of care components of integrated Community Case Management (iCCM) programmes and to draw lessons learned from existing evaluations of those programmes. METHODS: Scoping review of reports from 29 selected iCCM programmes purposively provided by stakeholders containing any information relevant to understand quality of care issues. RESULTS: The number of people reached by iCCM programmes varied from the tens of thousands to more than a million. All programmes aimed at improving access of vulnerable populations to health care, focusing on the main childhood illnesses, managed by Community Health Workers (CHW), often selected bycommunities. Training and supervision were widely implemented, in different ways and intensities, and often complemented with tools (eg, guides, job aids), supplies, equipment and incentives. Quality of care was measured using many outcomes (eg, access or appropriate treatment). Overall, there seemed to be positive effects for those strategies that involved policy change, organisational change, standardisation of clinical practices and alignment with other programmes. Positive effects were mostly achieved in large multi-component programmes. Mild or no effects have been described on mortality reduction amongst the few programmes for which data on this outcome was available to us. Promising strategies included teaming-up of CHW, micro-franchising or social franchising. On-site training and supervision of CHW have been shown to improve clinical practices. Effects on caregivers seemed positive, with increases in knowledge, care seeking behaviour, or caregivers' basic disease management. Evidence on iCCM is often of low quality, cannot relate specific interventions or the ways they are implemented with outcomes and lacks standardisation; this limits the capacity to identify promising strategies to improve quality of care. CONCLUSION: Large, multi-faceted, iCCM programmes, with strong components of training, supervision, which included additional support of equipment and supplies, seemed to improve selected quality of care outcomes. However, current evaluation and reporting practices need to be revised in a new research agenda to address the methodological challenges of iCCM evaluations. PMID- 25520794 TI - Integrated community case management of malaria, pneumonia and diarrhoea across three African countries: A qualitative study exploring lessons learnt and implications for further scale up. AB - Numerous studies highlight the effectiveness of an integrated approach for the management of malaria, pneumonia and diarrhoea at the community level. There has however been little study on lessons learnt from implementation in practice and stakeholder experiences which could inform future programmatic planning and evaluation frameworks. A participatory, qualitative evaluation was conducted in the three varied settings of South Sudan, Uganda and Zambia, which have seen the scale up of integrated community case management (iCCM) over the last five years. All key in-country stakeholders were consulted on study design, with a particular focus on scope and methodology. Data collection methods included stakeholder consultations (key informant interviews, focus group discussions), and a review of project and Ministry of Health documentation. Data analysis followed the Framework Approach. Results suggest that iCCM implementation generally followed national pre-agreed guidelines. Overarching key programmatic recommendations included: collaboration with implementing partners in planning stages to positively impact on community acceptance and ownership; adoption of participatory training methods adapted to low literacy populations; development of alternative support supervision methods such as peer support groups; full integration of community level data into the health management information system and emphasizing data analysis, use and feedback at all levels; strengthened supply chains through improved quantification and procurement of commodities in conjunction with the national distribution network; community engagement to establish a support system for community health workers to increase their motivation; enhanced sensitisation and behaviour change communication to raise awareness and usage of appropriate health services; and advocacy at the national level for funding and logistical support for the continuation and integration of iCCM. This qualitative study is a valuable contribution in understanding the 'hows' of iCCM implementation with key insights for improved feasibility and acceptability. Main findings show how community support to iCCM and community health workers is necessary for sustained health benefits coupled with a focus on strengthening and 'enabling' the public health system. The participatory study design and methodologies used enabled the scope of the research enquiry to effectively capture various stakeholder perspectives. PMID- 25520795 TI - Making products available among community health workers: Evidence for improving community health supply chains from Ethiopia, Malawi, and Rwanda. AB - BACKGROUND: A UNICEF review of the challenges to scaling up integrated community case management (iCCM) found that drug shortages were a common bottleneck. In many settings, little thought has gone into the design of supply chains to the community level and limited evidence exists for how to address these unique challenges. SC4CCM's purpose was to conduct intervention research to identify proven, simple, affordable solutions that address the unique supply chain challenges faced by CHWs and to demonstrate that supply chain constraints at the community level can be overcome. METHODS: SC4CCM selected three countries to implement supply chain innovations and developed a theory of change (TOC) framework for the learning phase, which identified the main drivers of product availability and was used for baseline assessments, design, implementation and evaluation of interventions in Ethiopia, Malawi, and Rwanda. Interventions were developed in each country and tested over 12-24 months. Mixed-method follow up assessments were conducted in each country in 2012-2013. The Supply Chain for Community Case Management (SC4CCM) Project then simplified the TOC into a Community Health Supply Chain (CHSC) framework to enable cross country analysis. RESULTS: The findings from interventions in the three countries suggest that the greatest supply chain benefits are realized when all three CHSC framework elements (data flow, product flow, and effective people) are in place and working together. The synergistic effect of these three elements on supply chain performance was most effectively demonstrated by results from the Enhanced Management and Quality Collaborative interventions in Malawi and Rwanda, respectively, which were characterized by lower mean stockout rates and higher in stock rates on day of visit, when compared to other interventions. CONCLUSIONS: Many conditions are necessary to ensure continuous product availability at the community level, however a supply chain works best when three key elements (product flow, data flow, and effective people) are deliberately included as an integral part of the system design. Although these elements may be designed differently in different settings, streamlining and synchronizing them while ensuring inclusion of all components for each element improves supply chain performance and promotes product availability at the community level. PMID- 25520796 TI - Strengthening community health supply chain performance through an integrated approach: Using mHealth technology and multilevel teams in Malawi. AB - BACKGROUND: In 2010, 7.6 million children under five died globally - largely due to preventable diseases. Majority of these deaths occurred in sub-Saharan Africa. As a strategy to reduce child mortality, the Government of Malawi, in 2008, initiated integrated community case management allowing health surveillance assistants (HSAs) to treat sick children in communities. Malawi however, faces health infrastructure challenges, including weak supply chain systems leading to low product availability. A baseline assessment conducted in 2010 identified data visibility, transport and motivation of HSAs as challenges to continuous product availability. The project designed a mHealth tool as part of two interventions to address these challenges. METHODS: A mobile health (mHealth) technology - cStock, for reporting on community stock data - was designed and implemented as an integral component of Enhanced Management (EM) and Efficient Product Transport (EPT) interventions. We developed a feasibility and acceptability framework to evaluate the effectiveness and predict the likelihood of scalability and ownership of the interventions. Mixed methods were used to conduct baseline and follow up assessments in May 2010 and February 2013, respectively. Routine monitoring data on community stock level reports, from cStock, were used to analyze supply chain performance over 18-month period in the intervention groups. RESULTS: Mean stock reporting rate by HSAs was 94% in EM group (n = 393) and 79% in EPT group (n = 253); mean reporting completeness was 85% and 65%, respectively. Lead time for HSA drug resupply over the 18-month period was, on average, 12.8 days in EM and 26.4 days in EPT, and mean stock out rate for 6 tracer products was significantly lower in EM compared to EPT group. CONCLUSIONS: Results demonstrate that cStock was feasible and acceptable to test users in Malawi, and that based on comparison with the EPT group, the team component of the EM group was an essential pairing with cStock to achieve the best possible supply chain performance and supply reliability. Establishing multi-level teams serves to connect HSAs with decision makers at higher levels of the health system, align objectives, clarify roles and promote trust and collaboration, thereby promoting country ownership and scalability of a cStock-like system. PMID- 25520797 TI - The costs of integrated community case management (iCCM) programs: A multi country analysis. AB - BACKGROUND: Integrated community case management (iCCM) can be an effective strategy for expanding the provision of diarrhea, pneumonia, and malaria services to children under 5 years old but there are concerns in some countries about the corresponding cost and impact. This paper presents and compares findings from a multi-country analysis of iCCM program costs. METHODS: Data on coverage, utilization, and costs were collected as part of two sets of studies conducted between 2011 and 2013 for iCCM programs in seven sub-Saharan African countries: Cameroon, the Democratic Republic of the Congo, Malawi, Senegal, Sierra Leone, South Sudan and Zambia. The data were used to compare some elements of program performance as well as costs per capita and costs per service (which are key indicators of resource allocation and efficiency). RESULTS: Among the seven countries, iCCM utilization ranged from a total of 0.26 to 3.05 contacts per capita (children 2-59 months) per year for the diseases treated, representing a range of 2.7% to 36.7% of the expected numbers of cases. The total recurrent cost per treatment ranged from US$ 2.44 to US$ 13.71 for diarrhea; from US$ 2.17 to US$ 17.54 for malaria (excluding rapid diagnostic testing); and from US$ 1.70 to US$ 12.94 for pneumonia. In some of the country programs, the utilization of iCCM services was quite low and this, together with significant fixed costs, particularly for management and supervision, resulted in services being quite costly. Given the differences across the countries and programs, however, these results should be treated as indicative and not definitive. CONCLUSION: A comprehensive understanding of iCCM program costs and results can help countries obtain resources and use them efficiently. To be cost-effective and affordable, iCCM programs must be well-utilized while program management and supervision should be organized to minimize costs and ensure quality of care. iCCM programs will not always be low-cost, however, particularly in small, remote villages where supervision and supply challenges are greater. Further research is needed to determine the cost-effectiveness of iCCM programs and corresponding patient and service delivery costs. PMID- 25520799 TI - A proposed model to conduct process and outcome evaluations and implementation research of child health programs in Africa using integrated community case management as an example. AB - AIM: To use a newly devised set of criteria to review the study design and scope of collection of process, outcomes and contextual data for evaluations and implementation research of integrated community case management (iCCM) in Sub Saharan African. METHODS: We examined 24 program evaluations and implementation research studies of iCCM in sub-Saharan Africa conducted in the last 5 years (2008-2013), assessed the design used and categorized them according to whether or not they collected sufficient information to conduct process and outcome evaluations. RESULTS: Five of the 24 studies used a stepped wedge design and two were randomized control trials. The remaining 17 were quasi-experimental of which 10 had comparison areas; however, not all comparison areas had a pre and post household survey. With regard to process data, 22 of the studies collected sufficient information to report on implementation strength, and all, except one, could report on program implementation. Most common missing data elements were health facility treatments, service costs, and qualitative data to assess demand. For the measurement of program outcomes, 7 of the 24 studies had a year or less of implementation at scale before the endline survey, 6 of the household surveys did not collect point of service, 10 did not collect timeliness (care seeking within 24 hours of symptoms) and 12 did not have socioeconomic (SES) information. Among the 16 studies with comparison areas, only 5 randomly selected comparison areas, while 10 had appropriate comparison areas. CONCLUSIONS: Several evaluations were done too soon after implementation, lacked information on health facility treatments, costs, demand, timeliness or SES and/or did not have a counterfactual. We propose several study designs and minimal data elements to be collected to provide sufficient information to assess whether iCCM increased timely coverage of treatment for the neediest children in a cost-efficient manner. PMID- 25520798 TI - Multi-country analysis of routine data from integrated community case management (iCCM) programs in sub-Saharan Africa. AB - AIM: To identify better performing iCCM programs in sub-Saharan Africa (SSA) and identify factors associated with better performance using routine data. METHODS: We examined 15 evaluations or studies of integrated community case management (iCCM) programs in SSA conducted between 2008 and 2013 and with information about the program; routine data on treatments, supervision, and stockouts; and, where available, data from community health worker (CHW) surveys on supervision and stockouts. Analyses included descriptive statistics, Fisher exact test for differences in median treatment rates, the Kruskal-Wallis test for differences in the distribution of treatment rates, and Spearman's correlation by program factors. RESULTS: The median percent of annual expected cases treated was 27% (1 74%) for total iCCM, 37% (1-80%) for malaria, 155% (7-552%) for pneumonia, and 27% (1-74%) for diarrhoea. Seven programs had above median total iCCM treatments rates. Four programs had above median treatment rates, above median treatments per active CHW per month, and above median percent of expected cases treated. Larger populations under-five targeted were negatively associated with treatment rates for fever, malaria, diarrhea, and total iCCM. The ratio of CHWs per population was positively associated with diarrhoea treatment rates. Use of rapid diagnostic tests (RDTs) was negatively associated with treatment rates for pneumonia. Treatment rates and percent of annual expected cases treated were equivalent between programs with volunteer CHWs and programs with salaried CHWs. CONCLUSIONS: There is large variation in iCCM program performance in SSA. Four programs appear to be higher performing in terms of treatment rates, treatments per CHW per month, and percent of expected cases treated. Treatment rates for diarrhoea are lower than expected across most programmes. CHWs in many programmes are overtreating pneumonia. Programs targeting larger populations under-five tend to have lower treatment rates. The reasons for lower pneumonia treatment rates where CHWs use RDTs need to be explored. Programs with volunteer CHWs and those with salaried CHWs can achieve similar treatment rates and percent of annual expected cases treated but to do so volunteer programs must manage more CHWs per population and salaried CHWs must provide more treatments per CHW per month. PMID- 25520800 TI - Demand generation and social mobilisation for integrated community case management (iCCM) and child health: Lessons learned from successful programmes in Niger and Mozambique. AB - AIM: We present the approaches used in and outcomes resulting from integrated community case management (iCCM) programmes in Niger and Mozambique with a strong focus on demand generation and social mobilisation. METHODS: We use a case study approach to describe the programme and contextual elements of the Niger and Mozambique programmes. RESULTS: Awareness and utilisation of iCCM services and key family practices increased following the implementation of the Niger and Mozambique iCCM and child survival programmes, as did care-seeking within 24 hours and care-seeking from appropriate, trained providers in Mozambique. These approaches incorporated interpersonal communication activities and community empowerment/participation for collective change, partnerships and networks among key stakeholder groups within communities, media campaigns and advocacy efforts with local and national leaders. CONCLUSIONS: iCCM programmes that train and equip community health workers and successfully engage and empower community members to adopt new behaviours, have appropriate expectations and to trust community health workers' ability to assess and treat illnesses can lead to improved care-seeking and utilisation, and community ownership for iCCM. PMID- 25520801 TI - Assessing the impact of integrated community case management (iCCM) programs on child mortality: Review of early results and lessons learned in sub-Saharan Africa. AB - AIM: To accelerate progress in reducing child mortality, many countries in sub Saharan Africa have adopted and scaled-up integrated community case management (iCCM) programs targeting the three major infectious killers of children under five. The programs train lay community health workers to assess, classify and treat uncomplicated cases of pneumonia with antibiotics, malaria with antimalarial drugs and diarrhea with Oral Rehydration Salts (ORS) and zinc. Although management of these conditions with the respective appropriate drugs has proven efficacious in randomized trials, the effectiveness of large iCCM scale-up programs in reducing child mortality is yet to be demonstrated. This paper reviews recent experience in documenting and attributing changes in under-five mortality to the specific interventions of a variety of iCCM programs. METHODS: Eight recent studies have been identified and assessed in terms of design, mortality measurement and results. Impact of the iCCM program on mortality among children age 2-59 months was assessed through a difference in differences approach using random effect Poisson regression. RESULTS: Designs used by these studies include cluster randomized trials, randomized stepped-wedge and quasi experimental trials. Child mortality is measured through demographic surveillance or household survey with full birth history conducted at the end of program implementation. Six of the eight studies showed a higher decline in mortality among children 2-59 months in program areas compared to comparison areas, although this acceleration was statistically significant in only one study with a decline of 76% larger in intervention than in comparison areas. CONCLUSION: Studies that evaluate large scale iCCM programs and include assessment of mortality impact must ensure an appropriate design. This includes required sample sizes and sufficient number of program and comparison districts that allow adequate inference and attribution of impact. In addition, large-scale program utilization, and a significant increase in coverage of care seeking and treatment of targeted childhood illnesses are preconditions to measurable mortality impact. Those issues need to be addressed before large investments in assessing changes in child mortality is undertaken, or the results of mortality impact evaluation will most likely be inconclusive. PMID- 25520802 TI - Using the Lives Saved Tool as part of evaluations of community case management programs. AB - BACKGROUND: Integrated community case management (iCCM) has been recommended by the World Health Organization to reduce mortality among children in populations with limited access to facility-based health care providers. Although many countries have introduced iCCM, interpretation of the impact is difficult due to many other activities occurring in the community. This paper suggests a method for using the Lives Saved Tool to model the independent impact of iCCM on child mortality. MODEL: The Lives Saved Tool (LiST) is a multi-cause model of mortality which allows users to look at the potential impacts of one or many interventions on one or many causes of death without double counting their impact. LiST uses changes in intervention coverage and cause-specific effectiveness estimates on mortality and risk factors to model overall changes in mortality as well as to attribute mortality reduction to specific interventions. Collecting data on the source of the care seeking behaviors is critical to being able to model and interpret the changes observed. DISCUSSION: The complexity of implementation of iCCM in the environment of broader health changes requires modeling to understand the program specific impacts. Using LiST results as additional data in combination with observed coverage change and mortality reduction can help explain the isolated impact of a given iCCM program when other changes are ongoing. LiST is unable to determine why the changes in health care seeking behaviors occur, but can be useful in helping to explain whether or not the changes were beneficial. PMID- 25520803 TI - Setting global research priorities for integrated community case management (iCCM): Results from a CHNRI (Child Health and Nutrition Research Initiative) exercise. AB - AIMS: To systematically identify global research gaps and resource priorities for integrated community case management (iCCM). METHODS: An iCCM Child Health and Nutrition Research Initiative (CHNRI) Advisory Group, in collaboration with the Community Case Management Operational Research Group (CCM ORG) identified experts to participate in a CHNRI research priority setting exercise. These experts generated and systematically ranked research questions for iCCM. Research questions were ranked using a "Research Priority Score" (RPS) and the "Average Expert Agreement" (AEA) was calculated for every question. Our groups of experts were comprised of both individuals working in Ministries of Health or Non Governmental Organizations (NGOs) in low- and middle-income countries (LMICs) and individuals working in high-income countries (HICs) in academia or NGO headquarters. A Spearman's Rho was calculated to determine the correlation between the two groups' research questions' ranks. RESULTS: The overall RPS ranged from 64.58 to 89.31, with a median score of 81.43. AEA scores ranged from 0.54 to 0.86. Research questions involving increasing the uptake of iCCM services, research questions concerning the motivation, retention, training and supervision of Community Health Workers (CHWs) and concerning adding additional responsibilities including counselling for infant and young child feeding (IYCF) and treatment of severe acute malnutrition (SAM) ranked highly. There was weak to moderate, statistically significant, correlation between scores by representatives of high-income countries and those working in-country or regionally (Spearman's rho = 0.35034, P < 0.01). CONCLUSIONS: Operational research to determine optimal training, supervision and modes of motivation and retention for the CHW is vital for improving iCCM, globally, as is research to motivate caregivers to take advantage of iCCM services. Experts working in country or regionally in LMICs prioritized different research questions than those working in organization headquarters in HICs. Further exploration is needed to determine the nature of this divergence. PMID- 25520804 TI - Systematic literature review of integrated community case management and the private sector in Africa: Relevant experiences and potential next steps. AB - BACKGROUND: Despite substantial investments made over the past 40 years in low income countries, governments cannot be viewed as the principal health care provider in many countries. Evidence on the role of the private sector in the delivery of health services is becoming increasingly available. In this study, we set out to determine the extent to which the private sector has been utilized in providing integrated care for sick children under 5 years of age with community acquired malaria, pneumonia or diarrhoea. METHODS: We reviewed the published literature for integrated community case management (iCCM) related experiences within both the public and private sector. We searched PubMed and Google/Google Scholar for all relevant literature until July 2014. The search terms used were "malaria", "pneumonia", "diarrhoea", "private sector" and "community case management". RESULTS: A total of 383 articles referred to malaria, pneumonia or diarrhoea in the private sector. The large majority of these studies (290) were only malaria related. Most of the iCCM-related studies evaluated introduction of only malaria drugs and/or diagnostics into the private sector. Only one study evaluated the introduction of drugs and diagnostics for malaria, pneumonia and diarrhoea in the private sector. In contrast, most iCCM-related studies in the public sector directly reported on community case management of 2 or more of the illnesses. CONCLUSIONS: While the private sector is an important source of care for children in low income countries, little has been done to harness the potential of this sector in improving access to care for non-malaria-associated fever in children within the community. It would be logical for iCCM programs to expand their activities to include the private sector to achieve higher population coverage. An implementation research agenda for private sector integrated care of febrile childhood illness needs to be developed and implemented in conjunction with private sector intervention programs. PMID- 25520806 TI - PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma. AB - In this study, we investigated the cytotoxic effects of a broad-spectrum histone deacetylase (HDAC) inhibitor, PCI-24781, alone and in combination with the proteasome inhibitor bortezomib in neuroblastoma cell lines. The combination was shown to induce synergistic cytotoxity involving the formation of reactive oxygen species. The cleavage of caspase-3 and PARP, as determined by western blotting, indicated that cell death was primarily due to apoptosis. Xenograft mouse models indicated increased survival among animals treated with this combination. The Notch signaling pathway and MYCN gene expression were quantified by reverse transcription-polymerase chain reaction (PCR) in cells treated with PCI-24781 and bortezomib, alone and in combination. Notch pathway expression increased in response to an HDAC inhibitor. NFKB1 and MYCN were both significantly down regulated. Our results suggest that PCI-24781 and bortezomib are synergistic in neuroblastoma cell lines and may be a new therapeutic strategy for this disease. PMID- 25520805 TI - Microbial shifts in the aging mouse gut. AB - BACKGROUND: The changes that occur in the microbiome of aging individuals are unclear, especially in light of the imperfect correlation of frailty with age. Studies in older human subjects have reported subtle effects, but these results may be confounded by other variables that often change with age such as diet and place of residence. To test these associations in a more controlled model system, we examined the relationship between age, frailty, and the gut microbiome of female C57BL/6 J mice. RESULTS: The frailty index, which is based on the evaluation of 31 clinical signs of deterioration in mice, showed a near-perfect correlation with age. We observed a statistically significant relationship between age and the taxonomic composition of the corresponding microbiome. Consistent with previous human studies, the Rikenellaceae family, which includes the Alistipes genus, was the most significantly overrepresented taxon within middle-aged and older mice. The functional profile of the mouse gut microbiome also varied with host age and frailty. Bacterial-encoded functions that were underrepresented in older mice included cobalamin (B12) and biotin (B7) biosynthesis, and bacterial SOS genes associated with DNA repair. Conversely, creatine degradation, associated with muscle wasting, was overrepresented within the gut microbiomes of the older mice, as were bacterial-encoded beta glucuronidases, which can influence drug-induced epithelial cell toxicity. Older mice also showed an overabundance of monosaccharide utilization genes relative to di-, oligo-, and polysaccharide utilization genes, which may have a substantial impact on gut homeostasis. CONCLUSION: We have identified taxonomic and functional patterns that correlate with age and frailty in the mouse microbiome. Differences in functions related to host nutrition and drug pharmacology vary in an age-dependent manner, suggesting that the availability and timing of essential functions may differ significantly with age and frailty. Future work with larger cohorts of mice will aim to separate the effects of age and frailty, and other factors. PMID- 25520808 TI - Caregiver stress in stroke survivor: data from a tertiary care hospital -a cross sectional survey. AB - BACKGROUND: A principal caregiver (CG) is directly affected by patient's health problems that lead to CG strain. Pakistan has an estimated 4.8% of the population suffering from strokes. The study objective was to evaluate the caregiver level of stress and the factors which make CGs more prone to stress and also to identify the predictive role of factors such as age, sex, educational, marital status on their burden. METHODS: This was a cross-sectional survey. 112 Participants were chosen on the basis of being directly involved in the care of patient and able to give consent for the study. Stroke patients had to have a more than 1 month history of stroke and treated in a tertiary care hospital. The severity of stress was rated using the Modified Caregiver Strain Index (MCSI). RESULTS: Out of a total of 112 stroke patients and their caregivers, 12 were exempted. Most of the CGs were between the ages 30-39 (48%) and male (70%). Out of the males, most were sons (89%). None of the female CGs was employed. The mean MCSI score was 13.8. Gender, age, marital status, and duration of care all did not have a significant effect on the total (P = 0.640, 0.848, 0.839, 0.110 respectively). Female gender (P = 0.0075) was a factor leading to increased emotional adjustments. Single CGs had increased changes in personal plans (P = 0.014), and married CGs found the behaviour of the patients less upsetting (P = 0.0425). There was no significant difference between the total (P = 0.906) or individual components between daughters and daughter-in-laws. Increased duration of care was significantly associated with decrease level of sleep disturbance (P = 0.026), physical strain (P = 0.050) and other demands on time (P = 0.044). Increase age of CG was associated with an increase feeling of being overwhelmed (P = 0.027). CONCLUSION: There is a need to identify the factors responsible for major CG stress by conducting similar studies and to define structured intervention for evaluating and preventing problems of caregivers. PMID- 25520807 TI - Randomized controlled trial of a health plan-level mood disorders psychosocial intervention for solo or small practices. AB - BACKGROUND: Mood disorders represent the most expensive mental disorders for employer-based commercial health plans. Collaborative care models are effective in treating chronic physical and mental illnesses at little to no net healthcare cost, but to date have primarily been implemented by larger healthcare organizations in facility-based models. The majority of practices providing commercially insured care are far too small to implement such models. Health plan level collaborative care treatment can address this unmet need. The goal of this study is to implement at the national commercial health plan level a collaborative care model to improve outcomes for persons with mood disorders. METHODS/DESIGN: A randomized controlled trial of a collaborative care model versus usual care will be conducted among beneficiaries of a large national health plan from across the country seen by primary care or behavioral health practices. At discharge 344 patients identified by health plan claims as hospitalized for unipolar depression or bipolar disorder will be randomized to receive collaborative care (patient phone-based self-management support, care management, and guideline dissemination to practices delivered by a plan-level care manager) or usual care from their provider. Primary outcomes are changes in mood symptoms and mental health-related quality of life at 12 months. Secondary outcomes include rehospitalization, receipt of guideline-concordant care, and work productivity. DISCUSSION: This study will determine whether a collaborative care model for mood disorders delivered at the national health plan level improves outcomes compared to usual care, and will inform a business case for collaborative care models for these settings that can reach patients wherever they receive treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02041962; registered January 3, 2014. PMID- 25520809 TI - The contribution of illness perception to psychological distress in heart failure patients. AB - BACKGROUND: The influences on the psychological well-being of heart failure (HF) patients have received limited attention. Illness perceptions are a specific set of cognitive representations that have been shown to predict health-related outcomes in other patient groups. This study sought to explore the role of illness perceptions in the psychological well-being of HF patients by creating a profile of illness perceptions in HF and examining their relations with anxiety and depression. METHODS: Participants were 95 consecutive outpatients. Indices of psychological well-being were depression and anxiety, measured using the Hospital Anxiety and Depression Scale (HADS). Illness perceptions were measured using the Illness Perception Questionnaire - Revised (IPQ-R). Functional status was also determined using the New York Heart Association (NYHA) classification. RESULTS: Illness perceptions were associated with indices of psychological well-being. Regression analyses showed that illness perceptions accounted for a significant proportion of the variance in both depression and anxiety. The contribution of illness perceptions was greater than that made by traditional covariates (socio demographic variables and functional status). CONCLUSIONS: Results highlight dynamic interrelations between perceptions of illness and mental health indices. They also suggest that in considering the role of illness perceptions in psychological well-being, the primary focus should be on the overall dynamic of an individual's illness experience rather than on specific illness dimensions. Findings highlight the potential role of illness perceptions in depression and anxiety in HF. This has implications for interventions to maximise psychological well-being in this patient group. PMID- 25520810 TI - Tympanic membrane temperature in adopted children associated with sleep problems and pre-adoption living arrangements: an exploratory study. AB - BACKGROUND: Tympanic membrane temperature (TMT) has been proposed as an indicator of cerebral activation and TMT asymmetry may indicate lateralization, which has been associated with specific (problem) behaviors in children and adults. The current study explored the relations between pre-adoption living arrangements, TMT, and behavior and sleep problems in a sample of adopted toddlers. METHODS: Ninety-two families who had adopted a Chinese girl who had previously been placed in an institution or foster care reported on behavior problems using the Child Behavior Checklist and TMT two months (Time 1) and six months (Time 2) after adoption. RESULTS: Structural equation modeling revealed that institutionalized children had significantly higher left than right TMTs compared with foster care children at Time 2. A higher left than right TMT was associated with increased sleep problems and total behavior problems at Time 1, but not at Time 2. CONCLUSIONS: Our findings with regard to pre-adoption living arrangements, TMT asymmetry, and sleep problems suggest that TMT is sensitive to early environmental influences and may be a biological marker of vulnerability to the development of sleep problems in children from adverse backgrounds. PMID- 25520811 TI - Suicidal ideation among surgeons in Italy and Sweden - a cross-sectional study. AB - BACKGROUND: Suicidal ideation is more prevalent among physicians, compared to the population in general, but little is known about the factors behind surgeons' suicidal ideation. A surgeon's work environment can be competitive and characterised by degrading experiences, which could contribute to burnout, depression and even thoughts of suicide. Being a surgeon has been reported to be predictor for not seeking help when psychological distressed. The aim of the present study was to investigate to what extent surgeons in Italy and Sweden are affected by suicidal ideation, and how suicidal ideation can be associated with psychosocial work conditions. METHODS: A cross-sectional study of surgeons was performed in Italy (N = 149) and Sweden (N = 272), where having suicidal ideation was the outcome variable. Work-related factors, such as harassment, depression and social support, were also measured. RESULTS: Suicidal ideation within the previous twelve months was affirmatively reported by 18% of the Italian surgeons, and by 12% of the Swedish surgeons in the present study. The strongest association with having recent suicidal ideation for both countries was being subjected to degrading experiences/harassment at work by a senior physician. Sickness presenteeism, exhaustion and disengagement were related to recent suicidal ideation among Italian surgeons, while role conflicts and sickness presenteeism were associated with recent suicidal ideation in the Swedish group. For both countries, regular meetings to discuss situations at work were found to be protective. CONCLUSIONS: A high percentage of surgeons at two university hospitals in Italy and Sweden reported suicidal ideation during the year before the investigation. This reflects a tough workload, including sickness presenteeism, harassment at work, exhaustion/disengagement and role conflicts. Regular meetings to discuss work situations might be protective. PMID- 25520812 TI - Transient windows for connectivity in a changing world. AB - The primary focus of studies examining metapopulation processes in dynamic or disturbance-dependent landscapes has been related to spatiotemporal changes in the habitat patches themselves. However, like the habitat patches, opportunities for movement between patches can also exist intermittently in dynamic landscapes, creating transient connectivity windows - which we define as a period of time during which matrix conditions increase the probability of one or more individuals moving successfully between habitat patches. Far less is known about the implications of dynamic changes in connectivity per se, and, to our knowledge, there are no connectivity metrics or metapopulation models that explicitly consider intermittent changes to connectivity between habitat patches. Consequently, in this paper, we examined the peer-reviewed, published literature up to November 2013 to better understand the consequences of variability in connectivity and to highlight knowledge gaps on this topic. First, we describe how connectivity per se can vary along a temporal gradient, offering examples of ecological systems that fall along this gradient. Second, we examine how temporal variability in connectivity is important for metapopulation dynamics, particularly given likely alterations to disturbance regimes as a result of global change. We conclude our review by briefly discussing key avenues for future connectivity-related research, all of which hinge on the need to perceive connectivity as a transient feature. PMID- 25520813 TI - Elephant movement closely tracks precipitation-driven vegetation dynamics in a Kenyan forest-savanna landscape. AB - BACKGROUND: This study investigates the ranging behavior of elephants in relation to precipitation-driven dynamics of vegetation. Movement data were acquired for five bachelors and five female family herds during three years in the Marsabit protected area in Kenya and changes in vegetation were mapped using MODIS normalized difference vegetation index time series (NDVI). In the study area, elevations of 650 to 1100 m.a.s.l experience two growth periods per year, while above 1100 m.a.s.l. growth periods last a year or longer. RESULTS: We find that elephants respond quickly to changes in forage and water availability, making migrations in response to both large and small rainfall events. The elevational migration of individual elephants closely matched the patterns of greening and senescing of vegetation in their home range. Elephants occupied lower elevations when vegetation activity was high, whereas they retreated to the evergreen forest at higher elevations while vegetation senesced. Elephant home ranges decreased in size, and overlapped less with increasing elevation. CONCLUSIONS: A recent hypothesis that ungulate migrations in savannas result from countervailing seasonally driven rainfall and fertility gradients is demonstrated, and extended to shorter-distance migrations. In other words, the trade-off between the poor forage quality and accessibility in the forest with its year-round water sources on the one hand and the higher quality forage in the low-elevation scrubland with its seasonal availability of water on the other hand, drives the relatively short migrations (the two main corridors are 20 and 90 km) of the elephants. In addition, increased intra-specific competition appears to influence the animals' habitat use during the dry season indicating that the human encroachment on the forest is affecting the elephant population. PMID- 25520815 TI - Applications of step-selection functions in ecology and conservation. AB - Recent progress in positioning technology facilitates the collection of massive amounts of sequential spatial data on animals. This has led to new opportunities and challenges when investigating animal movement behaviour and habitat selection. Tools like Step Selection Functions (SSFs) are relatively new powerful models for studying resource selection by animals moving through the landscape. SSFs compare environmental attributes of observed steps (the linear segment between two consecutive observations of position) with alternative random steps taken from the same starting point. SSFs have been used to study habitat selection, human-wildlife interactions, movement corridors, and dispersal behaviours in animals. SSFs also have the potential to depict resource selection at multiple spatial and temporal scales. There are several aspects of SSFs where consensus has not yet been reached such as how to analyse the data, when to consider habitat covariates along linear paths between observations rather than at their endpoints, how many random steps should be considered to measure availability, and how to account for individual variation. In this review we aim to address all these issues, as well as to highlight weak features of this modelling approach that should be developed by further research. Finally, we suggest that SSFs could be integrated with state-space models to classify behavioural states when estimating SSFs. PMID- 25520814 TI - Navigation outside of the box: what the lab can learn from the field and what the field can learn from the lab. AB - Space is continuous. But the communities of researchers that study the cognitive map in non-humans are strangely divided, with debate over its existence found among behaviorists but not neuroscientists. To reconcile this and other debates within the field of navigation, we return to the concept of the parallel map theory, derived from data on hippocampal function in laboratory rodents. Here the cognitive map is redefined as the integrated map, which is a construction of dual mechanisms, one based on directional cues (bearing map) and the other on positional cues (sketch map). We propose that the dual navigational mechanisms of pigeons, the navigational map and the familiar area map, could be homologous to these mammalian parallel maps; this has implications for both research paradigms. Moreover, this has implications for the lab. To create a bearing map (and hence integrated map) from extended cues requires self-movement over a large enough space to sample and model these cues at a high resolution. Thus a navigator must be able to move freely to map extended cues; only then should the weighted hierarchy of available navigation mechanisms shift in favor of the integrated map. Because of the paucity of extended cues in the lab, the flexible solutions allowed by the integrated map should be rare, despite abundant neurophysiological evidence for the existence of the machinery needed to encode and map extended cues through voluntary movement. Not only do animals need to map extended cues but they must also have sufficient information processing capacity. This may require a specific ontogeny, in which the navigator's nervous system is exposed to naturally complex spatial contingencies, a circumstance that occurs rarely, if ever, in the lab. For example, free-ranging, flying animals must process more extended cues than walking animals and for this reason alone, the integrated map strategy may be found more reliably in some species. By taking concepts from ethology and the parallel map theory, we propose a path to directly integrating the three great experimental paradigms of navigation: the honeybee, the homing pigeon and the laboratory rodent, towards the goal of a robust, unified theory of animal navigation. PMID- 25520816 TI - Optimizing acceleration-based ethograms: the use of variable-time versus fixed time segmentation. AB - BACKGROUND: Animal-borne accelerometers measure body orientation and movement and can thus be used to classify animal behaviour. To univocally and automatically analyse the large volume of data generated, we need classification models. An important step in the process of classification is the segmentation of acceleration data, i.e. the assignment of the boundaries between different behavioural classes in a time series. So far, analysts have worked with fixed time segments, but this may weaken the strength of the derived classification models because transitions of behaviour do not necessarily coincide with boundaries of the segments. Here we develop random forest automated supervised classification models either built on variable-time segments generated with a so called 'change-point model', or on fixed-time segments, and compare for eight behavioural classes the classification performance. The approach makes use of acceleration data measured in eight free-ranging crab plovers Dromas ardeola. RESULTS: Useful classification was achieved by both the variable-time and fixed time approach for flying (89% vs. 91%, respectively), walking (88% vs. 87%) and body care (68% vs. 72%). By using the variable-time segment approach, significant gains in classification performance were obtained for inactive behaviours (95% vs. 92%) and for two major foraging activities, i.e. handling (84% vs. 77%) and searching (78% vs. 67%). Attacking a prey and pecking were never accurately classified by either method. CONCLUSION: Acceleration-based behavioural classification can be optimized using a variable-time segmentation approach. After implementing variable-time segments to our sample data, we achieved useful levels of classification performance for almost all behavioural classes. This enables behaviour, including motion, to be set in known spatial contexts, and the measurement of behavioural time-budgets of free-living birds with unprecedented coverage and precision. The methods developed here can be easily adopted in other studies, but we emphasize that for each species and set of questions, the presented string of work steps should be run through. PMID- 25520817 TI - Secondary dispersal driven by overland flow in drylands: Review and mechanistic model development. AB - Seed dispersal alters gene flow, reproduction, migration and ultimately spatial organization of dryland ecosystems. Because many seeds in drylands lack adaptations for long-distance dispersal, seed transport by secondary processes such as tumbling in the wind or mobilization in overland flow plays a dominant role in determining where seeds ultimately germinate. Here, recent developments in modeling runoff generation in spatially complex dryland ecosystems are reviewed with the aim of proposing improvements to mechanistic modeling of seed dispersal processes. The objective is to develop a physically-based yet operational framework for determining seed dispersal due to surface runoff, a process that has gained recent experimental attention. A Buoyant OBject Coupled Eulerian - Lagrangian Closure model (BOB-CELC) is proposed to represent seed movement in shallow surface flows. The BOB-CELC is then employed to investigate the sensitivity of seed transport to landscape and storm properties and to the spatial configuration of vegetation patches interspersed within bare earth. The potential to simplify seed transport outcomes by considering the limiting behavior of multiple runoff events is briefly considered, as is the potential for developing highly mechanistic, spatially explicit models that link seed transport, vegetation structure and water movement across multiple generations of dryland plants. PMID- 25520818 TI - Coupling instantaneous energy-budget models and behavioural mode analysis to estimate optimal foraging strategy: an example with wandering albatrosses. AB - BACKGROUND: How foragers move across the landscape to search for resources and obtain energy is a central issue in ecology. Direct energetic quantification of animal movements allows for testing optimal foraging theory predictions which assumes that animals forage so as to maximise net energy gain. Thanks to biologging advances, we coupled instantaneous energy-budget models and behavioural mode analysis to test optimal foraging theory predictions on wandering albatross Diomedea exulans during the brooding period. Specifically, the instantaneous energy-budget model considered the energetic balance (i.e., the difference between empirical energy gain data and modelled energy expenditure via heart rate values) along the trajectory of a given individual. Four stereotypic instantaneous behavioural modes were identified based on trajectory properties (e.g., speed and turning angle) by applying a new algorithm called Expectation Maximization Binary Clustering. Previous studies on this species have shown that foraging-in-flight is the optimal foraging strategy during the incubation period when albatrosses undertake long-distance movements but no specific foraging strategy has been determined for shorter foraging movements (e.g., brooding period). RESULTS: The output of our energy-budget model (measured as net energy gain) highlighted the potential optimality of alternative search strategies (e.g., sit-and-wait) during brooding, when birds may be subjected to specific energetic trade-offs and have to adapt their foraging strategies accordingly. However, not all birds showed this pattern, revealing the importance of considering individual variability in foraging strategies, as well as any switching among strategies, before drawing population-level generalizations. Finally, our study unveils the importance of considering fine scale activities to make realistic estimates of trip energy expenditure for flying birds at sea. CONCLUSIONS: The up-scaling of accurately measured fine-scale energy patterns is essential to quantify energy balances, and their fluctuations by season of different activities among individuals or populations. In particular, we offer new insights for the energetic quantification of the effect of changing oceanic winds on the biology of pelagic predators in the southern oceans. PMID- 25520819 TI - An analysis of the relationship between Glasgow Coma Scale score and plasma glucose level according to the severity of hypoglycemia. AB - BACKGROUND: The Glasgow Coma Scale (GCS) score of an individual with hypoglycemia is expected to be low due to an insufficient glucose supply to the brain. However, we sometimes encounter hypoglycemic patients with high GCS scores. This study was undertaken to analyze the relationship between the GCS score and the plasma glucose level. METHODS: Among the patients with neurological impairments admitted to our institution between October 1, 2010 and March 31, 2013, the cases of 41 hypoglycemic patients were examined in this retrospective cohort study. The defined plasma glucose level for mild hypoglycemia was 41-60 mg/dL, that for moderate hypoglycemia was 21-40 mg/dL, and that for extreme hypoglycemia was below 20 mg/dL. We divided the patients into two groups: those with mild hypoglycemia (n = 14) and those with moderate/extreme hypoglycemia (n = 27). We compared the two groups' physiological data and assessed the relationship between the GCS score and the plasma glucose level by Spearman rank correlation (rho), the significance of which was determined by Spearman's rank sum test. We used the Mann-Whitney U-test and the chi-square (chi (2)) test to test for differences between the two groups when appropriate. RESULTS: Three hundred twenty-six patients with neurological impairments were admitted during the study period, and 41were eligible hypoglycemic patients. The GCS scores of the 14 patients with mild hypoglycemia were significantly higher than those of the 27 patients with moderate or extreme hypoglycemia (median score 12, range 7-15 vs. 10, 3-15, p = 0.0367). There were no significant differences in physiological data (including autonomic symptoms) between the two groups. Spearman's rank sum test was 0.491 in the total group of 41 hypoglycemic patients, 0.053 in the mild hypoglycemic patients, and 0.493 in the moderately or extremely hypoglycemic patients. CONCLUSIONS: The relationship between the GCS score and the plasma glucose level differed according to the severity of hypoglycemia. Even when a patient has a high GCS score, careful assessment of differential diagnosis should be conducted and the possibility of hypoglycemia should be considered in light of his or her neurogenous symptoms. PMID- 25520820 TI - Update in acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is characterized by permeability pulmonary edema and refractory hypoxemia. Recently, the new definition of ARDS has been published, and this definition suggested severity-oriented respiratory treatment by introducing three levels of severity according to PaO2/FiO2 and positive end-expiratory pressure. Lung-protective ventilation is still the key of better outcome in ARDS. Through randomized trials, short-term use of neuromuscular blockade at initial stage of mechanical ventilation, prone ventilation in severe ARDS, and extracorporeal membrane oxygenation in ARDS with influenza pneumonia showed beneficial efficacy. However, ARDS mortality still remains high. Therefore, early recognition of ARDS modified risk factors and the avoidance of aggravating factors during the patient's hospital stay can help decrease its development. In addition, efficient antifibrotic strategies in late stage ARDS should be developed to improve the outcome. PMID- 25520822 TI - Evaluation of noninvasive positive pressure ventilation after extubation from moderate positive end-expiratory pressure level in patients undergoing cardiovascular surgery: a prospective observational study. AB - BACKGROUND: It remains to be clarified if the application of noninvasive positive pressure ventilation (NPPV) is effective after extubation in patients with hypoxemic respiratory failure who require the sufficient level of positive end expiratory pressure (PEEP). This study was aimed at examining the effect and the safety of NPPV application following extubation in patients requiring moderate PEEP level for sufficient oxygenation after cardiovascular surgery. METHODS: With institutional ethic committee approval, the patients ventilated invasively for over 48 h after cardiovascular surgery were enrolled in this study. The patients who failed the first spontaneous breathing trial (SBT) at 5 cmH2O of PEEP, but passed the second SBT at 8 cmH2O of PEEP, received NPPV immediately after extubation following our weaning protocol. Respiratory parameters (partial pressure of arterial oxygen tension to inspiratory oxygen fraction ratio: P/F ratio, respiratory ratio, and partial pressure of arterial carbon dioxide: PaCO2) 2 h after extubation were evaluated with those just before extubation as the primary outcome. The rate of re-intubation, the frequency of respiratory failure and intolerance of NPPV, the duration of NPPV, and the length of intensive care unit (ICU) stay were also recorded. RESULTS: While 51 postcardiovascular surgery patients were screened, 6 patients who met the criteria received NPPV after extubation. P/F ratio was increased significantly after extubation compared with that before extubation (325 +/- 85 versus 245 +/- 55 mmHg, p < 0.05). The other respiratory parameters did not change significantly. Re-intubation, respiratory failure, and intolerance of NPPV never occurred. The duration of NPPV and the length of ICU stay were 2.7 +/- 0.7 (SD) and 7.5 (6 to 10) (interquartile range) days, respectively. CONCLUSIONS: While further investigation should be warranted, NPPV could be applied effectively and safely after extubation in patients requiring the moderate PEEP level after cardiovascular surgery. PMID- 25520823 TI - Landiolol reduces hemodynamic responses to bronchoscopy-assisted suctioning in intubated ICU patients. AB - Landiolol is an ultra-short-acting beta1-selective antagonist developed in Japan that was recently approved for the treatment of tachycardia in intensive care units (ICUs). This study investigated the protective effects of landiolol against the cardiovascular responses during bronchoscopic endotracheal suctioning. This study enrolled 15 patients requiring orotracheal intubation in an ICU. All of the patients required endotracheal suctioning using fiber bronchoscopy while sedated at a Ramsay Scale of 2-3. All subsequent suctioning procedures were assigned randomly to three groups using a cross-over design: saline as a placebo (group C) or 20 or 40 MUg kg(-1) min(-1) landiolol, respectively (groups L20 and L40). The infusion was started 3 min before bronchoscopy and continued for 6 min. The central venous pressure (CVP) heart rate (HR) and arterial blood pressure (BP) were recorded. Fourteen patients completed the investigation, and 30 procedures (n = 10/group) were analyzed. The suctioning significantly increased the CVP, HR, and BP in groups C and L20, although the changes in BP were of shorter duration in group L20. No significant increase in the hemodynamic parameters was observed in group L40. The administration of landiolol 40 MUg kg(-1) min(-1) prevented a harmful hyperdynamic circulatory response to bronchoscopic endotracheal suctioning, without obvious decreases in HR or BP after the intervention. PMID- 25520824 TI - Changes in endotracheal tube cuff pressure in mechanically ventilated adult patients. AB - During mechanical ventilation, endotracheal tube cuff pressure should be maintained within proper range. We investigated the effect of frequent adjustment on cuff pressure in 27 mechanically ventilated patients. Cuff pressure was recorded every 2 h and was adjusted to 24 cmH2O each time. We found that cuff pressure was decreased by 4.9 +/- 2.9 cmH2O from the target value. Cuff pressure decreased to less than 20 cmH2O in 45% of measurement occasions 2 h after adjusting it to 24 cmH2O. PMID- 25520825 TI - End-of-life considerations in the ICU in Japan: ethical and legal perspectives. AB - In Japan, the continuation of critical care at the end of life is a common practice due to the threat of legal action against physicians that may choose a palliative care approach. This is beginning to change due to public debate related to a series of controversial incidents concerning end-of-life care over the last decade. In this review we contrast and compare the history and evolution of end-of-life care in Japan vs. the USA and other Asian countries. Efforts by the Japanese Society of Intensive Care Medicine (JSICM) to establish better end of-life care systems, as well as future directions in palliative care in Japan, are discussed. PMID- 25520827 TI - Clinical experience with an active intravascular rewarming technique for near severe hypothermia associated with traumatic injury. AB - Hypothermia and acidosis are secondary causes of trauma-related coagulopathy. Here we report the case of a 72-year-old patient with severe trauma who suffered near-severe hypothermia despite the initiation of standard warming measures and was successfully managed with active intravascular rewarming. The patient was involved in a road traffic accident and was transported to a hospital. He was diagnosed with massive right-sided hemothorax, blunt aortic injury, burst fractures of the eighth and ninth thoracic vertebrae, and open fracture of the right tibia. He was referred to our hospital, where emergency surgery was performed to control bleeding from the right hemothorax. During surgery, the patient demonstrated progressive heat loss despite standard rewarming measures, and his temperature decreased to 32.4 degrees C. Severe acidosis was also observed. A Cool Line(r) catheter was inserted into the right femoral vein and lodged in the inferior vena cava, and an intravascular balloon catheter system was utilized for aggressive rewarming. The automated target core temperature was set at 37 degrees C, and the maximum flow rate was used. His core temperature reached 36.0 degrees C after 125 min of intravascular rewarming. The severe acidosis was also resolved. The main active bleeding site was not identified, and coagulation hemostasis as well as rewarming enabled us to control bleeding from the vertebral bodies, lung parenchyma, and pleura. The total volume of intraoperative bleeding was 5,150 mL, and 20 units of red cell concentrate and 16 units of fresh frozen plasma were transfused. After surgery, he was transferred to the intensive care unit under endotracheal intubation and mechanical ventilation. His hemodynamic condition stabilized after surgery. The rewarming catheter was removed on day 2 of admission, and no bleeding, infection, or thrombosis associated with catheter placement was observed. Extubation was performed on day 40, and his subsequent clinical course was uneventful. He recovered well following rehabilitation and was discharged on day 46. These findings suggest that active intravascular rewarming should be considered as an aggressive, additional rewarming technique in patients with near-severe hypothermia associated with traumatic injury. PMID- 25520828 TI - Low prevalence of active cytomegalovirus infection in a cardiovascular intensive care unit. AB - Active cytomegalovirus infection is not uncommon in critically ill non immunosuppressed patients. We conducted a preliminary observational study to determine the prevalence of active cytomegalovirus infection in cardiovascular surgical patients. One hundred patients admitted to the intensive care unit following cardiovascular surgery were enrolled between January 2010 and May 2010. Four patients (4%) were positive for serum pp65 antigens, though cytomegalovirus positive serology (immunoglobulin G, IgG) was found in 98 patients (98%) including those four patients. Active cardiac diseases and their operative procedures including cardiopulmonary bypass may not be significant risk factors for active cytomegalovirus infection unless systemic derangements are also present. PMID- 25520826 TI - The molecular mechanism of acute lung injury caused by Pseudomonas aeruginosa: from bacterial pathogenesis to host response. AB - Pseudomonas aeruginosa is the most common gram-negative pathogen causing pneumonia in immunocompromised patients. Acute lung injury induced by bacterial exoproducts is associated with a poor outcome in P. aeruginosa pneumonia. The major pathogenic toxins among the exoproducts of P. aeruginosa and the mechanism by which they cause acute lung injury have been investigated: exoenzyme S and co regulated toxins were found to contribute to acute lung injury. P. aeruginosa secretes these toxins through the recently defined type III secretion system (TTSS), by which gram-negative bacteria directly translocate toxins into the cytosol of target eukaryotic cells. TTSS comprises the secretion apparatus (termed the injectisome), translocators, secreted toxins, and regulatory components. In the P. aeruginosa genome, a pathogenic gene cluster, the exoenzyme S regulon, encodes genes underlying the regulation, secretion, and translocation of TTSS. Four type III secretory toxins, namely ExoS, ExoT, ExoU, and ExoY, have been identified in P. aeruginosa. ExoS is a 49-kDa form of exoenzyme S, a bifunctional toxin that exerts ADP-ribosyltransferase and GTPase-activating protein (GAP) activity to disrupt endocytosis, the actin cytoskeleton, and cell proliferation. ExoT, a 53-kDa form of exoenzyme S with 75% sequence homology to ExoS, also exerts GAP activity to interfere with cell morphology and motility. ExoY is a nucleotidal cyclase that increases the intracellular levels of cyclic adenosine and guanosine monophosphates, resulting in edema formation. ExoU, which exhibits phospholipase A2 activity activated by host cell ubiquitination after translocation, is a major pathogenic cytotoxin that causes alveolar epithelial injury and macrophage necrosis. Approximately 20% of clinical isolates also secrete ExoU, a gene encoded within an insertional pathogenic gene cluster named P. aeruginosa pathogenicity island-2. The ExoU secretory phenotype is associated with a poor clinical outcome in P. aeruginosa pneumonia. Blockade of translocation by TTSS or inhibition of the enzymatic activity of translocated toxins has the potential to decrease acute lung injury and improve clinical outcome. PMID- 25520829 TI - A case of purpura fulminans caused by Hemophilus influenzae complicated by reversible cardiomyopathy. AB - Here, we report a case of a 41-year-old male diagnosed as septic shock with purpura fulminans (PF) infection. The causative organism was beta-lactamase negative ampicillin-resistant Hemophilus influenzae. He developed fulminant cardiac dysfunction approximately 1 h after admission, and the cause was considered to be septic cardiomyopathy. Blood pressure and oxygenation were maintained at adequate levels with the aid of extracorporeal membrane oxygenation (ECMO). The cardiac dysfunction was reversible, and he was successfully weaned from ECMO on day 12 of hospitalization. However, he needed amputation for all extremities because the infection spread to his limbs and eventually, succumbed to sepsis caused by empyema on day 34 of hospitalization. To the best of our knowledge, this is only the second case of PF caused by H. influenzae in an adult to be reported worldwide. PMID- 25520830 TI - Body temperature abnormalities in non-neurological critically ill patients: a review of the literature. AB - Body temperature abnormalities, which occur because of several infectious and non infectious etiologies, are among the most commonly noted symptoms of critically ill patients. These abnormalities frequently trigger changes in patient management. The purpose of this article was to review the contemporary literature investigating the definition and occurrence of body temperature abnormalities in addition to their impact on illness severity and mortality in critically ill non neurological patients, particularly in patients with severe sepsis. Reports on the influence of fever on outcomes are inconclusive, and the presence of fever per se may not contribute to increased mortality in critically ill patients. In patients with severe sepsis, the impacts of elevated body temperature and hypothermia on mortality and the severity of physiologic decline are different. Hypothermia is significantly associated with an increased risk of mortality. In contrast, elevated body temperature may not be associated with increased disease severity or risk of mortality. In patients with severe sepsis, the effect of fever and fever control on outcomes requires further research. PMID- 25520832 TI - Safety and effective use of landiolol in the ICU. AB - Supplemental landiolol administration (20 or 40 MUg kg(-1) min(-1)) effectively diminished harmful hemodynamic changes during bronchoscopic endotracheal suctioning compared to normal saline. However, inappropriate use of landiolol (i.e., failure of evaluating factors that influence hemodynamic changes) may iatrogenically further complicate pathophysiology, and relatively higher doses of landiolol may be dangerous. We recommend that landiolol should not be routinely used to control cardiovascular responses during bronchoscopic endotracheal suctioning in the intensive care unit. Careful evaluation of factors influencing hemodynamic changes and close monitoring of the patient are mandatory following landiolol administration. Furthermore, a lower initiation dose is recommended. PMID- 25520833 TI - Comparison of the McGrath MAC video laryngoscope and the Pentax Airwayscope during chest compression: a manikin study. AB - We tested the utility of the McGrath MAC((r)) (McG) video laryngoscope during chest compression compared with the Pentax Airwayscope((r)) (AWS). We recruited 59 participants into the simulation study. The difference in the time to intubation (TTI [sec]) between without and with chest compression was significant for the AWS attempts (median 13, range 6-28 vs. median 15, range 6-72, p = 0.0247) but not significant for the McG attempts (median 16, range 6-75 vs. median 16, range 6-71); however, the difference of the TTIs is not serious clinically. The utility of the two devices during chest compressions is almost similar although their characteristics are different. PMID- 25520831 TI - Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines. AB - Disseminated intravascular coagulation (DIC) is categorized into bleeding, organ failure, massive bleeding, and non-symptomatic types according to the sum of vectors for hypercoagulation and hyperfibrinolysis. The British Committee for Standards in Haematology, Japanese Society of Thrombosis and Hemostasis, and the Italian Society for Thrombosis and Haemostasis published separate guidelines for DIC; however, there are several differences between these three sets of guidelines. Therefore, the International Society of Thrombosis and Haemostasis (ISTH) recently harmonized these differences and published the guidance of diagnosis and treatment for DIC. There are three different diagnostic criteria according to the Japanese Ministry Health, Labour and Welfare, ISTH, and Japanese Association of Acute Medicine. The first and second criteria can be used to diagnose the bleeding or massive bleeding types of DIC, while the third criteria cover organ failure and the massive bleeding type of DIC. Treatment of underlying conditions is recommended in three types of DIC, with the exception of massive bleeding. Blood transfusions are recommended in patients with the bleeding and massive bleeding types of DIC. Meanwhile, treatment with heparin is recommended in those with the non-symptomatic type of DIC. The administration of synthetic protease inhibitors and antifibrinolytic therapy is recommended in patients with the bleeding and massive bleeding types of DIC. Furthermore, the administration of natural protease inhibitors is recommended in patients with the organ failure type of DIC, while antifibrinolytic treatment is not. The diagnosis and treatment of DIC should be carried out in accordance with the type of DIC. PMID- 25520834 TI - Classifying types of disseminated intravascular coagulation: clinical and animal models. AB - Disseminated intravascular coagulation (DIC) has a common pathogenesis in terms of persistent widespread activation of coagulation in the presence of underlying disease, but the degree of fibrinolytic activation often differs by DIC type. DIC with suppressed fibrinolysis is a DIC type usually seen in sepsis. Coagulation activation is severe, but fibrinolytic activation is mild. DIC with enhanced fibrinolysis is a DIC type usually seen in acute promyelocytic leukemia (APL). Both coagulation activation and fibrinolytic activation are severe. DIC with balanced fibrinolysis is a DIC type usually seen in solid tumors, with an intermediate pathogenesis between the above two types. In animal DIC models, lipopolysaccharide (LPS)-induced models are similar to suppressed-fibrinolytic type DIC, whereas tissue factor (TF)-induced models are similar to enhanced fibrinolytic/balanced fibrinolytic DIC. Appropriate diagnosis and treatment may also differ depending on the DIC type. PMID- 25520835 TI - Pros and cons of tetrastarch solution for critically ill patients. AB - Proper fluid management is crucial for the management of critically ill patients. However, there is a continuing debate about the choice of the fluid, i.e., crystalloid vs. colloid. Colloid solution is theoretically advantageous to the crystalloid because of larger volume effect and less interstitial fluid accumulation, and hydroxyethyl starch (HES) is most frequently used for perioperative setting. Nevertheless, application of HES solution is relatively limited due to its side effects including renal toxicity and coagulopathy. Since prolonged presence of large HES molecule is responsible for these side effects, rapidly degradable HES solution with low degree of substitution (tetrastarch) supposedly has less potential for negative effects. Thus, tetrastarch may be more frequently used in the ICU setting. However, several large-scale randomized trials reported that administration of tetrastarch solution to the patients with severe sepsis has negative effects on mortality and renal function. These results triggered further debate and regulatory responses around the world. This narrative review intended to describe the currently available evidence about the advantages and disadvantages of tetrastarch in the ICU setting. PMID- 25520836 TI - Difference in pulmonary permeability between indirect and direct acute respiratory distress syndrome assessed by the transpulmonary thermodilution technique: a prospective, observational, multi-institutional study. AB - BACKGROUND: Acute respiratory distress syndrome (ARDS) is characterized by the increased pulmonary permeability secondary to diffuse alveolar inflammation and injuries of several origins. Especially, the distinction between a direct (pulmonary injury) and an indirect (extrapulmonary injury) lung injury etiology is gaining more attention as a means of better comprehending the pathophysiology of ARDS. However, there are few reports regarding the quantitative methods distinguishing the degree of pulmonary permeability between ARDS patients due to pulmonary injury and extrapulmonary injury. METHODS: A prospective, observational, multi-institutional study was performed in 23 intensive care units of academic tertiary referral hospitals throughout Japan. During a 2-year period, all consecutive ARDS-diagnosed adult patients requiring mechanical ventilation were collected in which three experts retrospectively determined the pathophysiological mechanisms leading to ARDS. Patients were classified into two groups: patients with ARDS triggered by extrapulmonary injury (ARDSexp) and those caused by pulmonary injury (ARDSp). The degree of pulmonary permeability using the transpulmonary thermodilution technique was obtained during the first three intensive care unit (ICU) days. RESULTS: In total, 173 patients were assessed including 56 ARDSexp patients and 117 ARDSp patients. Although the Sequential Organ Failure Assessment (SOFA) score was significantly higher in the ARDSexp group than in the ARDSp group, measurements of the pulmonary vascular permeability index (PVPI) were significantly elevated in the ARDSp group on all days: at day 0 (2.9 +/- 1.3 of ARDSexp vs. 3.3 +/- 1.3 of ARDSp, p = .008), at day 1 (2.8 +/- 1.5 of ARDSexp vs. 3.2 +/- 1.2 of ARDSp, p = .01), at day 2 (2.4 +/- 1.0 of ARDSexp vs. 2.9 +/- 1.3 of ARDSp, p = .01). There were no significant differences in mortality at 28 days, mechanical ventilation days, and hospital length of stay between the two groups. CONCLUSIONS: The results of this study suggest the existence of several differences in the increased degree of pulmonary permeability between patients with ARDSexp and ARDSp. TRIAL REGISTRATION: This report is a sub-group analysis of the study registered with UMIN-CTR (IDUMIN000003627). PMID- 25520837 TI - Global end-diastolic volume is an important contributor to increased extravascular lung water in patients with acute lung injury and acuterespiratory distress syndrome: a multicenter observational study. AB - BACKGROUND: Extravascular lung water (EVLW), as measured by the thermodilution method, reflects the extent of pulmonary edema. Currently, there are no clinically effective treatments for preventing increases in pulmonary vascular permeability, a hallmark of lung pathophysiology, in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). In this study, we examined the contributions of hemodynamic and osmolarity factors, for which appropriate interventions are expected in critical care, to EVLW in patients with ALI/ARDS. METHODS: We performed a subgroup analysis of a multicenter observational study of patients with acute pulmonary edema. Overall, 207 patients with ALI/ARDS were enrolled in the study. Multivariate regression analysis was used to evaluate the associations of hemodynamic and serum osmolarity parameters with the EVLW index (EVLWI; calculated as EVLW/Ideal body weight). We analyzed factors measured on the day of enrollment (day 0), and on days 1 and 2 after enrollment. RESULTS: Multivariate regression analysis showed that global end-diastolic volume index (GEDVI) was significantly associated with EVLWI measured on days 0, 1, and 2 (P = 0.002, P < 0.001, and P = 0.003, respectively), whereas other factors were not significantly associated with EVLWI measured on all 3 days. CONCLUSIONS: Among several hemodynamic and serum osmolarity factors that could be targets for appropriate intervention, GEDVI appears to be a key contributor to EVLWI in patients with ALI/ARDS. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000003627. PMID- 25520839 TI - Healthcare Technology Management (HTM) of mechanical ventilators by clinical engineers. AB - Mechanical ventilator failures expose patients to unacceptable risks, and maintaining mechanical ventilator safety is an important issue. We examined the usefulness of maintaining mechanical ventilators by clinical engineers (CEs) using a specialized calibrator. These evaluations and the ability to make in house repairs proved useful for obviating the need to rent ventilators which, in turn, might prove faulty themselves. The CEs' involvement in maintaining mechanical ventilators is desirable, ensures prompt service, and, most importantly, enhances safe management of mechanical ventilators. PMID- 25520838 TI - Perioperative fluid balance affects staging of acute kidney injury in postsurgical patients: a retrospective case-control study. AB - BACKGROUND: Although Acute Kidney Injury Network (AKIN) staging is widely used, it has been suggested that classification using serum creatinine levels, which fluctuate because of fluid balance, is not always appropriate for acute kidney injury (AKI) detection. We hypothesized that some patients are misdiagnosed as having no AKI due to dilution resulting from intraoperative infusion, and have worse outcomes than typical patients with no AKI. METHODS: We retrospectively selected patients who did not fulfill the AKI criteria from those who underwent cardiac surgery and remained in an intensive care unit (ICU) for >=7 days. The patients were divided into two groups: those with AKI (AKI group) and those without AKI (no-AKI group), classified using serum creatinine levels adjusted for fluid balance during the perioperative period. We compared the characteristics and outcomes of the two groups. RESULTS: After adjustment for serum creatinine, 7 of 26 patients were categorized as having AKI. The AKI group had significantly fewer ventilator-free days during a 28-day period and significantly longer ICU stays than the no-AKI group (5.86 +/- 10.0 days vs. 15.6 +/- 9.71 days, respectively, P = 0.050; 36.4 +/- 20.6 days vs. 14.9 +/- 10.7 days, respectively, P = 0.033). CONCLUSION: Adjustment of creatinine level for perioperative fluid balance could improve the accuracy of AKI diagnosis after cardiac surgery. PMID- 25520840 TI - Basic life support training for single rescuers efficiently augments their willingness to make early emergency calls with no available help: a cross-over questionnaire survey. AB - BACKGROUND: The aim of this study was to investigate effects of basic life support (BLS) training on willingness of single rescuers to make emergency calls during out-of-hospital cardiac arrests (OHCAs) with no available help from others. METHODS: A cross-over questionnaire survey was conducted with two questionnaires. Questionnaires were administered before and after two BLS courses in fire departments. One questionnaire included two scenarios which simulate OHCAs occurring in situations where help from other rescuers is available (Scenario-M) and not available (Scenario-S). The conventional BLS course was designed for multiple rescuers (Course-M), and the other was designed for single rescuers (Course-S). RESULTS: Of 2,312 respondents, 2,218 (95.9%) answered all questions and were included in the analysis. Although both Course-M and Course-S significantly augmented willingness to make early emergency calls not only in Scenario-M but also in Scenario-S, the willingness for Scenario-M after training course was significantly higher in respondents of Course-S than in those of Course-M (odds ratio 1.706, 95% confidential interval 1.301-2.237). Multiple logistic regression analysis for Scenario-M disclosed that post training (adjusted odds ratio 11.6, 95% confidence interval 7.84-18.0), age (0.99, 0.98 0.99), male gender (1.77, 1.39-2.24), prior BLS experience of at least three times (1.46, 1.25-2.59), and time passed since most recent training during 3 years or less (1.80, 1.25-2.59) were independently associated with willingness to make early emergency calls and that type of BLS course was not independently associated with willingness. Therefore, both Course-M and Course-S similarly augmented willingness in Scenario-M. However, in multiple logistic regression analyses for Scenario-S, Course-S was independently associated with willingness to make early emergency calls in Scenario-S (1.26, 1.00-1.57), indicating that Course-S more efficiently augmented willingness. Moreover, post training (2.30, 1.86-2.83) and male gender (1.26, 1.02-1.57) were other independent factors associated with willingness in Scenario-S. CONCLUSIONS: BLS courses designed for single rescuers with no help available from others are likely to augment willingness to make early emergency calls more efficiently than conventional BLS courses designed for multiple rescuers. PMID- 25520841 TI - Performance of the SAPS 3 admission score as a predictor of ICU mortality in a Philippine private tertiary medical center intensive care unit. AB - BACKGROUND: This study aimed to assess the performance of the Simplified Acute Physiology Score 3 (SAPS 3) as a predictor of ICU mortality in critically ill patients of different case mixes admitted to an intensive care unit. METHODS: This retrospective cohort study was performed from January 2011 to August 2013 in the intensive care unit of a private tertiary referral center in the Philippines. Predicted ICU mortality was calculated using the SAPS 3 global model. Observed versus predicted mortality rates were compared, and the standardized mortality ratio (SMR) was calculated. The discrimination and calibration characteristics of the SAPS 3 system to predict ICU mortality were assessed. RESULTS: A total of 2,426 patients were included. The observed ICU mortality was 277 (11.42%). The SAPS 3 global model had fair to good discrimination with an area under the receiver operating characteristic curve of 0.80 (CI 0.78-0.81). Good calibration was seen with the Hosmer-Lemeshow goodness of fit at C = 11.51 (p = 0.175). Standardized mortality ratio was 0.36 (0.26-0.81). CONCLUSION: The global SAPS 3 prediction model showed fair to good discrimination and good calibration in predicting mortality in our intensive care unit. Different levels of discrimination and calibration across the different subgroups analyzed suggest that overall ICU performance seemed to be affected by case mix variations. PMID- 25520842 TI - Post-marketing surveillance data of thrombomodulin alfa: sub-analysis in patients with sepsis-induced disseminated intravascular coagulation. AB - BACKGROUND: Thrombomodulin alfa (TM-alpha, recombinant thrombomodulin) significantly improved disseminated intravascular coagulation (DIC) when compared with heparin therapy in a phase III study. Post-marketing surveillance of TM alpha was performed to evaluate the effects and safety in patients with sepsis induced DIC. METHODS: From May 2008 to April 2010, a total of 1,787 patients with sepsis-induced DIC treated with TM-alpha were registered. DIC was diagnosed based on the Japanese Association for Acute Medicine (JAAM) criteria. The DIC resolution and survival rates on day 28 after the last TM-alpha administration, and changes in DIC, systemic inflammatory response syndrome (SIRS), and sequential organ failure assessment (SOFA) scores and coagulation and inflammation markers were evaluated. RESULTS: The most frequent underlying disease was infectious focus-unknown sepsis (29.8%). The mean +/- SD values of age, dose, and the duration of TM-alpha administration were 64.7 +/- 20.3 years, 297.3 +/- 111.4 U/kg/day, and 5.6 +/- 3.4 days, respectively. A total of 1,320 subjects (73.9%) received combined administration with other anticoagulants. Both coagulation and inflammation markers, such as fibrin/fibrinogen degradation products, prothrombin time ratio, thrombin-antithrombin complex, and C-reactive protein, as well as JAAM DIC, SIRS, and SOFA scores, significantly and simultaneously decreased after TM-alpha administration (p < 0.001). DIC resolution and 28-day survival rates were 44.4% and 66.0%, respectively. The 28 day survival rate decreased significantly according to the duration of DIC before TM-alpha administration (p < 0.001). Total adverse drug reactions (ADRs), bleeding ADRs, and serious bleeding adverse events occurred in 126 (7.1%), 98 (5.5%), and 121 (6.8%) subjects, respectively. On day 28, after the last TM-alpha administration available for an antibody test, only one patient was positive for anti-TM-alpha antibodies (0.11%). CONCLUSION: Our results suggest that TM-alpha is most effective for treating patients with sepsis-induced DIC when administered within the first 3 days after diagnosis. PMID- 25520843 TI - Estimation of renal function in the intensive care unit: the covert concepts brought to light. AB - Frantic efforts have been made up to this date to derive consensus for estimating renal function in critically ill patients, only to open the Pandora's box. This article tries to explore the various methods available to date, the newer concepts, and the uncared issues that may still prove to be useful in estimating renal function in intensive care unit patients. The concept of augmented renal clearance, which is frequently encountered in critically ill patients, should always be taken into account, as correct therapeutic dosage of drugs sounds vital which in turn depends on correctly calculated glomerular filtration rate. Serum creatinine and creatinine-based formulae have their own demerits that are well known and established. While Cockcroft-Gault and 4-variable modification of diet in renal diseases formulae are highly inadequate in the intensive care setup for estimating glomerular filtration rate, employing isotopic methods is impractical and cumbersome. The 6-variable modification of diet in renal diseases formula fairs better as it takes into account the serum albumin and blood urea nitrogen, too. Jelliffe's and modified Jelliffe's equations take into account the rate of creatinine production and volume of distribution which in turn fluctuates heavily in a critically ill patient. Twenty-four-hour and timed creatinine clearances offer values close to reality although not accurate and cannot provide immediate results. Cystatin C is a novel agent that offers a sure promise as it is least influenced by factors that affect serum creatinine to a major extent. Aminoglycoside clearance, although still in the dark area, may prove a simple yet precise way of estimating glomerular filtration rate in those patients in whom these drugs are therapeutically employed. Optic ratiometric method has emerged as the most sophisticated one in glomerular filtration rate estimation in critically ill patients. PMID- 25520844 TI - Pathophysiology and biomarkers of acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is defined as an acute-onset, progressive, hypoxic condition with radiographic bilateral lung infiltration, which develops after several diseases or injuries, and is not derived from hydrostatic pulmonary edema. One specific pathological finding of ARDS is diffuse alveolar damage. In 2012, in an effort to increase diagnostic specificity, a revised definition of ARDS was published in JAMA. However, no new parameters or biomarkers were adopted by the revised definition. Discriminating between ARDS and other similar diseases is critically important; however, only a few biomarkers are currently available for diagnostic purposes. Furthermore, predicting the severity, response to therapy, or outcome of the illness is also important for developing treatment strategies for each patient. However, the PaO2/FIO2 ratio is currently the sole clinical parameter used for this purpose. In parallel with progress in understanding the pathophysiology of ARDS, various humoral factors induced by inflammation and molecules derived from activated cells or injured tissues have been shown as potential biomarkers that may be applied in clinical practice. In this review, the current understanding of the basic pathophysiology of ARDS and associated candidate biomarkers will be discussed. PMID- 25520845 TI - Rhabdophis tigrinus is not a pit viper but its bites result in venom-induced consumptive coagulopathy similar to many viper bites. AB - As a response to the recent article by Hifumi et al. published in the Journal of Intensive Care, the present correspondence clarifies the family-level taxonomy of the yamakagashi (Rhabdophis tigrinus). Further, the relevance of the term 'venom induced consumptive coagulopathy,' instead of disseminated intravascular coagulation, in describing the procoagulant coagulopathy of R. tigrinus is highlighted. PMID- 25520846 TI - Effect of antivenom therapy of Rhabdophis tigrinus (Yamakagashi snake) bites. AB - BACKGROUND: Rhabdophis tigrinus (Yamakagashi snake) is a rear-fanged colubrid snake present throughout Russia and Asia. Its venom induces life-threatening hemorrhagic symptoms and severe disseminated intravascular coagulation with a fibrinolytic phenotype. R. tigrinus antivenom manufactured by the immunization of horses to neutralize the venom has the risk of adverse events such as anaphylaxis and serum sickness disease. It should be used when benefit is greater than the risk of adverse effects; however, its efficacy has not been well evaluated. Although our previous survey of nine cases demonstrated that seven of all cases treated with antivenom survived, the clinical characteristics and prognosis without antivenom administration remained unclear. We assumed that R. tigrinus antivenom administration overlaps self-recovery with supportive care. We aimed to determine the association between antivenom administration and outcome with further analyzed cases. METHODS: We retrospectively reviewed the records of the Japan Snake Institute between January 1, 1973 and December 31, 2013. Antivenom and without antivenom groups were compared with regard to baseline demographic features, treatment-related factors, and outcomes. RESULTS: In total, 34 patients were analyzed (97% male, median age 37.5 years). Twenty-five patients were further examined from our previous study. On admission, the median levels of fibrinogen and fibrinogen degradation products were 35 mg/dL and 200 MUg/mL, respectively, and platelet counts were 107,000/mm(3). The median disseminated intravascular coagulation score (defined by the Japanese Association of Acute Medicine) was 5. Antivenom was administered to 19 patients, with a median interval of 32 h between bite and antivenom administration. The in-hospital mortality rate was 12%. In univariate analysis, baseline characteristics and laboratory data were not significantly different between the antivenom and without antivenom groups. Hospital mortality in the antivenom group was significantly better than that in the without antivenom group (0% vs. 26.7%, P = 0.03). Moreover, the number of patients developing renal failure requiring hemodialysis was significantly lower in the antivenom group (5.3% vs. 40.0%, P = 0.03). CONCLUSIONS: In our small retrospective study, antivenom administration was likely to be effective in the management of R. tigrinus bites. Apparently, further research is required to confirm its efficacy. PMID- 25520847 TI - Delayed presentation of late-onset cerebrospinal fluid rhinorrhoea following dopamine agonist therapy for giant prolactinoma. AB - Therapeutic shrinkage of prolactinomas with dopamine agonists achieves clinical benefit but can expose fistulae that have arisen as a result of bony erosion of the sella floor and anterior skull base by the invasive tumour, resulting in the potential development of cerebrospinal fluid (CSF) rhinorrhoea, meningitis, and rarely pneumocephalus. Onset of symptoms is typically within 4 months of commencing therapy. The management is typically surgical repair via an endoscopic transnasal transsphenoidal approach. A 23-year-old man presented to the Emergency Department with acute left limb weakness and intermittent headaches. Visual fields were full to confrontation. Immediate computed tomography and subsequent magnetic resonance imaging (MRI), demonstrated a 5 cm lobular/cystic mass invading the right cavernous sinus, displacing and compressing the midbrain, with destruction of the bony sella. He was referred to the regional pituitary multidisciplinary team (MDT). Serum prolactin was 159 455 mIU/l (7514.37 ng/ml) (normal ranges 100-410 mIU/l (4.72-19.34 ng/ml)). Cabergoline was commenced causing dramatic reduction in tumour size and resolution of neurological symptoms. Further dose titrations were required as the prolactin level plateaued and significant residual tumour remained. After 13 months of treatment, he developed continuous daily rhinorrhea, and on presenting to his general practitioner was referred to an otolaryngologist. When next seen in the routine regional pituitary clinic six-months later he was admitted for urgent surgical repair. Histology confirmed a prolactinoma with a low proliferation index of 2% (Ki-67 antibody). In view of partial cabergoline resistance he completed a course of conventional radiotherapy. Nine months after treatment the serum prolactin had fallen to 621 mIU/l, and 12 months after an MRI showed reduced tumour volume. LEARNING POINTS: CSF rhinorrhoea occurred 13 months after the initiation of cabergoline, suggesting a need for vigilance throughout therapy.Dedicated bony imaging should be reviewed early in the patient pathway to assess the potential risk of CSF rhinorrhoea after initiation of dopamine agonist therapy.There was a significant delay before this complication was brought to the attention of the regional pituitary MDT, with associated risk whilst left untreated. This demonstrates a need for patients and healthcare professionals to be educated about early recognition and management of this complication to facilitate timely and appropriate referral to the MDT for specialist advice and management. We changed our nurse-led patient education programme as a result of this case.An excellent therapeutic response was achieved with conventional radiotherapy after limited surgery having developed partial cabergoline resistance and CSF rhinorrhoea. PMID- 25520848 TI - Glucagonoma-induced acute heart failure. AB - Neuroendocrine tumours (NETs) represent a broad spectrum of tumours, of which the serotonin-producing carcinoid is the most common and has been shown to cause right ventricular heart failure. However, an association between heart failure and NETs other than carcinoid has not been established so far. In this case report, we describe a 51-year-old patient with a glucagon-producing NET of the pancreas who developed acute heart failure and even cardiogenic shock despite therapy. Heart failure eventually regressed after initialising i.v. treatment with the somatostatin analogue octreotide. Chromogranin A as a tumour marker was shown to be significantly elevated, and it decreased with clinical improvement of the patient. The effects of long-time stimulation of glucagon on the myocardium have not been studied yet; however, sarcoplasmic reticulum calcium leak can be discussed as a possible mechanism for glucagon-induced heart failure. LEARNING POINTS: Glucagonoma can be a cause for heart failure.i.v. infusion of octreotide can be successfully used to treat glucagonoma-induced acute heart failure.We suggest that cardiac function should be monitored in all NET patients. PMID- 25520849 TI - Adrenal cancer in neurofibromatosis type 1: case report and DNA analysis. AB - Adrenal cortical carcinoma (ACC) has previously only been reported in eight patients with type 1 neurofibromatosis (NF1). There has not been any clear evidence of a causal association between NF1 gene mutations and adrenocortical malignancy development. We report the case of a 49-year-old female, with no family history of endocrinopathy, who was diagnosed with ACC on the background of NF1, due to a novel germline frame shift mutation (c.5452_5453delAT) in exon 37 of the NF1 gene. A left adrenal mass was detected by ultrasound and characterised by contrast computerised tomography (CT) scan. Biochemical tests showed mild hypercortisolism and androgen excess. A 24-h urinary steroid profile and (18)flouro deoxy glucose PET suggested ACC. An open adrenalectomy was performed and histology confirmed ACC. This is the first reported case with DNA analysis, which demonstrated the loss of heterozygosity (LOH) at the NF1 locus in the adrenal cancer, supporting the hypothesis of an involvement of the NF1 gene in the pathogenesis of ACC. LOH analysis of the tumour suggests that the loss of neurofibromin in the adrenal cells may lead to tumour formation. LEARNING POINTS: ACC is rare but should be considered in a patient with NF1 and adrenal mass when plasma metanephrines are normal.Urinary steroid metabolites and PET/CT are helpful in supporting evidence for ACC.The LOH at the NF1 region of the adrenal tumour supports the role of loss of neurofibromin in the development of ACC. PMID- 25520850 TI - Humic acid degradation by the synthesized flower-like Ag/ZnO nanostructure as an efficient photocatalyst. AB - Nano-sized flower-like Ag/ZnO was synthesized by a simple method using zinc acetate and silver acetate under hydrothermal condition. Powder X-ray diffraction (PXRD) and transmission electron microscopy (TEM) were used to characterize the structure and morphology of the synthesized powder. Nano flower-like Ag/ZnO was used as a photocatalyst for degradation of humic acid in aqueous solution. The disappearance of HA was analyzed by measuring the absorbance of sample at special wavelength (254 nm). The effects of various parameters such as amount of photocatalyst, pH, initial humic acid concentration and irradiation time on degradation rate were systematically investigated. Photodegradation efficiency was small when the photolysis was carried out in the absence of Ag/ZnO and it was also negligible in the absence of light. Approximately 70% of humic acid (50 mg/L) has been eliminated after 40 minutes in the presences of catalyst (catalyst dose o.6 g/L and pH =7) and UVA irradiation. While, 100% of humic acid has been eliminated with solar irradiation. PMID- 25520852 TI - Special Topic: Frontiers in RNA Research: The ever-expanding RNA world. PMID- 25520853 TI - An increase in mean platelet volume after admission is associated with higher mortality in critically ill patients. AB - BACKGROUND: Platelet activation and consumption are common in critically ill patients and are associated with poorer prognosis. Mean platelet volume is a simple surrogate for platelet activation, with higher MPV being associated with worse clinical condition on a large array of clinical diagnoses. We therefore aimed to investigate associations between changes in platelet count and mean platelet volume (MPV) with prognosis and inflammatory cytokine values in critically ill patients. METHODS: This study prospectively included 84 critically ill patients. Patients were stratified into four groups according to proportional changes in MPV (DeltaMPV24h) and platelet count (DeltaPlat24h) in the first 24 hours after admission. Mortality between groups was compared using the chi (2) test. Logistic regression was performed using hospital mortality as outcome and Simplified Acute Physiology Score (SAPS 3), DeltaPlat24h and DeltaMPV24h as covariates. Concentrations of the following inflammatory mediators were measured using Miliplex(r) technology: IL1beta, IL6, IL8, IL10, epidermal growth factor, vascular endothelial growth factor, TNFalpha and IFNalpha. Cytokine concentrations were compared between groups using the Kruskal-Wallis test with Bonferroni correction. RESULTS: Patients in whom MPV increased and platelet count decreased had higher mortality rates (46%). According to logistic regression, DeltaMPV24h was independently associated with increased mortality (OR 1.28 per 1% increase; 95% CI 1.08 to 1.48). No strong associations between inflammatory mediators and changes in MPV and platelet count were found. CONCLUSION: An increase in MPV after admission to an ICU is independently associated with higher hospital mortality. PMID- 25520851 TI - Why women see differently from the way men see? A review of sex differences in cognition and sports. AB - The differences of learning and memory between males and females have been well documented and confirmed by both human and animal studies. The sex differences in cognition started from early stage of neuronal development and last through entire life span. The major biological basis of the gender-dependent cognitive activity includes two major components: sex hormone and sex-related characteristics, such as sex-determining region of the Y chromosome (SRY) protein. However, the knowledge of how much biology of sex contributes to normal cognitive function and elite athletes in various sports are still pretty limited. In this review, we will be focusing on sex differences in spatial learning and memory - especially the role of male- and female-type cognitive behaviors in sports. PMID- 25520854 TI - Anticancer activity of essential oils and their chemical components - a review. AB - Essential oils are widely used in pharmaceutical, sanitary, cosmetic, agriculture and food industries for their bactericidal, virucidal, fungicidal, antiparasitical and insecticidal properties. Their anticancer activity is well documented. Over a hundred essential oils from more than twenty plant families have been tested on more than twenty types of cancers in last past ten years. This review is focused on the activity of essential oils and their components on various types of cancers. For some of them the mechanisms involved in their anticancer activities have been carried out. PMID- 25520856 TI - Mahanine, a novel mitochondrial complex-III inhibitor induces G0/G1 arrest through redox alteration-mediated DNA damage response and regresses glioblastoma multiforme. AB - The Electron transport chain (ETC) is responsible for oxidative phosphorylation mediated mitochondrial respiration. Here we wanted to address the mahanine induced targeted pathways in glioblastoma multiforme (GBM) in the context of G0/G1 phase arrest and redox alteration. We have demonstrated mahanine, as a novel mitochondrial complex-III inhibitor which induced G0/G1 phase arrest in GBM. This event was preceded by accumulation of intracellular ROS by the inhibition of mitochondrial ETC. The accumulated ROS induced DNA damage response (DDR), that mediated Chk1/Chk2 upregulation and activation which were essential factors for the G0/G1 arrest. NAC-mediated scavenging of ROS generation reduced the propensity of G0/G1 phase arrest in GBM cells by mahanine. Knockdown of Chk1/Chk2 also affected the cell cycle inhibitory potential of mahanine. During G0/G1 arrest, other hallmark proteins like, cyclin D1/cyclin D3, CDK4/CDK6 and CDC25A were also downregulated. The G0/G1 phase restriction property of mahanine was also established in in vivo mice model. Mahanine-induced complex-III inhibition triggered enhanced ROS in hypoxia responsible for higher G0/G1 arrest. Furthermore, we demonstrated that mahanine-treated G0/G1 arrested cells were less potent to form xenograft tumor in vivo. Additionally, they exhibited reduced ability to migrate and form intracellular tube-like structures. Moreover, they became susceptible to differentiate and astrocyte-like cells were generated from the epithelial lineage. Taken together, our results established that complex-III of ETC is one of the possible potential targets of mahanine. This nontoxic chemotherapeutic molecule enhanced ROS production, induced cell cycle arrest and thereafter regressed GBM without effecting normal astrocytes. PMID- 25520857 TI - Methylation-associated silencing of MicroRNA-335 contributes tumor cell invasion and migration by interacting with RASA1 in gastric cancer. AB - MicroRNAs (miRNAs) are small non-coding RNAs that function as endogenous silencers of target genes, previous studies have shown that miR-335 play an important role in suppressing metastasis and migration in human cancer including gastric cancer (GC). However, the mechanisms which result in aberrant expression of miR-335 in GC are still unknown. Recent studies have shown that the silencing of some miRNAs is associated with DNA hypermethylation. In this study, we find the promoter of miR-335 we embedded in CpG island by accessing to bioinformatics data and the low expression of miR-335 in 5 gastric cell lines can be restored by 5-aza-2'-deoxycytidine (5-Aza-dC) treatment. So we postulated that the miR-335 genes undergo epigenetic inactivation in GC. Subsequently, in GC cells and tissues, we performed quantitative real-time PCR (RTQ-PCR) to assess the expression of miR-335, and methylation-specific PCR (MSP) and bisulfite sequence PCR (BSP) to evaluate the DNA methylation status in the CpG islands upstream of MiR-335. The result showed that the expression of miR-335 was significantly reduce in gastric cancer cell lines and tumor tissues compared to matched normal gastric tissues, and cell lines, and which is inverse correlation with DNA hypermethylation of miR-335 both in GC cells lines and tissues, but not in normal tissues. In addition, we found that the lower miR-335 expression induced by abnormal methylation may be mainly involved in gastric cell invasion and metastasis in GC tissues. No statistical significance was found about miR-335 expression and methylation level between healthy individuals with and without H. pylori (HP) infection. Finally, we carry out miRNA transfection, RTQ-PCR and western blot assay to find the RAS p21 protein activator (GTPase activating protein) 1 (RASA1) may be the possible target genes which lead to the gastric cell invasion and metastasis, furthermore, the re-expression of endogenous miR 335 by 5-Aza-dC treatment can exert effects similar to exogenous miRNAs transfection. Taken together, our results suggest that miR-335 may be silenced by promoter hypermethylation and play important roles in gastric cell invasion and metastasis through its target genes, such as RASA1. Its methylation level might be a predictive epigenetic marker of GC and remodeling on the expression by demethylation can provided a potential therapeutic strategy. PMID- 25520858 TI - MicroRNAs in stool samples as potential screening biomarkers for pancreatic ductal adenocarcinoma cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90-95% exocrine malignant tumors of the pancreas. The high prevalence of metastasis and the difficulty of early diagnosis lead to a dismal prognosis. MicroRNAs (miRNAs) play a critical role in extensive biological processes. The purpose of this study was to evaluate the feasibility of stool miRNAs as novel biomarker for PDAC screening. MiRNAs were extracted from clinical specimens which included cancer and matched adjacent benign pancreatic tissues of 30 PDAC patients, pancreatic juice of 20 from the 30 PDAC patients and 10 chronic pancreatitis (CP) patients, stool samples of the 30 PDAC patients, the 10 CP patients and 15 healthy volunteers. Relative expression of a panel of 5 dysregulated miRNAs (miR-21, miR 155, miR-196a, miR-216 and miR-217) was analyzed with qRT-PCR. Receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosing value of stool miRNAs in PDAC patients. The study showed that our methods of extracting and detecting miRNAs from pancreatic juice and stool specimens had high reproducibility. Compared to matched adjacent benign pancreatic tissues and pancreatic juice of CP patients, the expression of miR-21 (P = 0.0021 and P = 0.0027) as well as miR-155 (P = 0.0087 and P = 0.0067) was significantly higher and the expression of miR-216 (P < 0.0001 and P = 0.0044) was significantly lower in primary tumor tissues and pancreatic juice of PDAC patients. PDAC patients had a significantly higher stool miR-21 and miR-155 (P = 0.0049 and P = 0.0112) and lower miR-216 level (P = 0.0002) compared to normal controls. The same results were obtained in the expression levels of stool miR-21, miR-155 and miR-216 between PDAC and CP patients (P = 0.0337, P = 0.0388 and P = 0.0117, respectively). Receiver operating characteristic (ROC) analysis by using stool miRNAs expression indicated that combination of miR-21 and miR-155 had best sensitivity of 93.33% while the combination of miR-21, miR-155 and miR-216 would be best for detecting and screening PDAC with area under the curve (AUC) of 0.8667 (95% CI: 0.7722-0.9612) and a better balance of sensitivity and specificity (83.33% vs. 83.33%). Our data indicate that miRNAs could be extracted and detected from pancreatic juice and stool efficiently and reproducibly. MiR 21, miR-155 and miR-216 in stool have the potential of becoming biomarkers for screening PDAC. PMID- 25520859 TI - Ligand-activated PPARdelta modulates the migration and invasion of melanoma cells by regulating Snail expression. AB - Peroxisome proliferator-activated receptor (PPAR) delta is implicated in the carcinogenesis of several types of cancer. However, the therapeutic efficacy of PPARdelta ligands against cancer progression is unclear. Here, we showed that PPARdelta modulates the migration and invasion of melanoma cells by up-regulating Snail expression. Activation of PPARdelta by GW501516, a specific ligand for PPARdelta, significantly increased the migration and invasion of highly metastatic A375SM cells, but not that of low metastatic A375P cells. The migration- and invasion-promoting effects of PPARdelta on A375SM cells was associated with increased Snail expression, which was accompanied by a decrease in E-cadherin expression. Furthermore, a significant concentration- and time dependent increase in the levels of Snail mRNA and protein was observed in A375SM cells (but not A375P cells) treated with GW501516. The effects of GW501516 were almost completely abrogated by a small interfering RNA against PPARdelta, suggesting that PPARdelta mediates the effects of GW501516. Activation of PPARdelta in SK-MEL-2 and SK-MEL-5 (but not SK-MEL-3) melanoma cell lines also led to significant increases in the expression of Snail mRNA and protein, which mirrored the invasive and migratory potential of these cell lines. These results suggest that PPARdelta promotes the aggressive phenotype observed in highly metastatic melanoma cells by up-regulating Snail. PMID- 25520855 TI - Redundant kinase activation and resistance of EGFR-tyrosine kinase inhibitors. AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown dramatic effects against that tumors harboring EGFR activating mutations in the EGFR intracytoplasmic tyrosine kinase domain and resulted in cell apoptosis. Unfortunately, a number of patients ultimately developed resistance by multiple mechanisms. Thus, elucidation of the mechanism of resistance to EGFR-TKIs can provide strategies for blocking or reversing the situation. Recent studies suggested that redundant kinase activation plays pivotal roles in escaping from the effects of EGFR-TKIs. Herein, we aimed to characterize several molecular events involved in the resistance to EGFR-TKIs mediated by redundant kinase activation. PMID- 25520860 TI - SPRY1 promotes the degradation of uPAR and inhibits uPAR-mediated cell adhesion and proliferation. AB - Urokinase plasminogen activator receptor (uPAR) is a GPI anchored cell surface protein that is closely associated with invasion, migration, and metastasis of cancer cells. Many functional extracellular proteins and transmembrane receptors interact with uPAR. However, few studies have examined the association of uPAR with cytoplasm proteins. We previously used yeast two-hybrid screening to isolate several novel uPAR-interacting cytoplasmic proteins, including Sprouty1 (SPRY1), an inhibitor of the (Ras-mitogen-activated protein kinase) MAPK pathway. In this study, we show that SPRY1 interacts with uPAR and directs it toward lysosomal mediated degradation. Overexpression of SPRY1 decreased the cell surface and cytoplasmic uPAR protein level. Moreover, SPRY1 overexpression augmented uPAR induced cell adhesion to vitronectin as well as proliferation of cancer cells. Our results also further support the critical role of SPRY1 contribution to tumor growth. In a subcutaneous tumor model, overexpression of SPRY1 in HCT116 or A549 xenograft in athymic nude mice led to great suppression of tumor growth. These results show that SPRY1 may affect tumor cell function through direct interaction with uPAR and promote its lysosomal degradation. PMID- 25520861 TI - ABCG2 regulated by MAPK pathways is associated with cancer progression in laryngeal squamous cell carcinoma. AB - ATP-binding cassette, subfamily G, member 2 (ABCG2) overexpression has been associated with multidrug resistance and cancer progression by promoting proliferation and/or suppressing apoptosis, but how this process happens remains to be determined. In this study, the roles and the mechanisms of ABCG2 in the progression of Laryngeal squamous cell carcinoma (LSCC) were investigated. We found that introduction of ABCG2 siRNA into Hep-2 and Hep-2T cells significantly enhanced the intracellular accumulation of mitoxantrone (MX). Down-regulation of ABCG2 by transient RNAi inhibited cell proliferation and blocked cell cycle progression by regulating the expression of cyclin D3 and p21 Cip1. ABCG2 silence also induced cell apoptosis by regulating the expression of surviving, bcl-2 and the cleavage of poly (ADP-ribose) polymerase (PARP) in Hep-2 and Hep-2T cells. ABCG2-specific inhibitor, fumitremorgin C (FTC), and mitogen-activated protein kinase (MAPK) pathway inhibitor, U0126, inhibited cell proliferation and promoted cell apoptosis by degrading endogenous ABCG2 in Hep-2T cells. Furthermore, inhibition of MAPK pathway by U0126 enhanced anti-cancer effects of MX in vivo. In conclusion, suppression of ABCG2 inhibits the procession of LSCC tumor growth by regulating cell proliferation and apoptosis. Our data also provide more evidence for the importance of the MAPK pathway as a suitable therapeutic target for LSCC. PMID- 25520862 TI - DACT2 is frequently methylated in human gastric cancer and methylation of DACT2 activated Wnt signaling. AB - Dapper, Dishevelled-associated antagonist of beta-catenin (DACT), is a key regulator of Wnt signaling pathway. The purpose of this study is to explore the epigenetic changes and the function ofDACT2 in human gastric cancer (GC). Eight human gastric cancer cell lines, 167 cases of primary gastric cancer and 8 cases of normal gastric mucosa were involved in this study. In addition, methylation Specific PCR (MSP), semi-quantitative RT-PCR, colony formation assay, flow cytometry assay, siRNA, immunofluorescence techniques and xenograft mice models were employed. The results indicate that DACT2 is frequently methylated in human primary gastric cancer (55.7%), and that methylation of DACT2 is associated with lost or reduction in its expression (X(2) test, P<0.01). We found that DACT2 expression was regulated by promoter region hypermethylation. Methylation of DACT2 is associated with tumor differentiation, invasion and intravascular cancerous emboli (X(2) test, P<0.05, P<0.05 and P<0.05). In gastric cancer patients treated with 5-FU and cisplatin, the five-year survival rates are higher in DACT2 methylated cases. DACT2 inhibits cell proliferation, migration and invasion in gastric cancer cells and suppresses gastric cancer xenografts in mice. Restoration of DACT2 expression inhibits both canonical and noncanonical WNT signaling in SGC7901 cells. Restoration of DACT2 expression sensitized gastric cancer cells to paclitaxel and 5-FU. In conclusion, DACT2 is frequently methylated in human gastric cancer and DACT2 expression is silenced by promoter region hypermethylation. DACT2 suppressed gastric cancer proliferation, invasion and metastasis by inhibiting Wnt signaling both in vitro and in vivo. PMID- 25520863 TI - RUNX3 site-specific hypermethylation predicts papillary thyroid cancer recurrence. AB - Papillary thyroid cancer (PTC) is the most common epithelial thyroid tumor, accounting for more than 80% of all thyroid cancers. Although PTC shows an indolent character and excellent prognosis, patients with aggressive characteristics are more likely to have a disease recurrence and die in the end. The aim of this study was to analyze BRAF(V600E) mutation and methylation levels of CpG sites in the promoters of CDH1, DAPK, RARbeta and RUNX3 genes in a cohort of PTCs, and investigate their association with tumor recurrence. In this study, we used pyrosequencing method to individually quantified methylation levels at multiple CpG sites within each gene promoter, and detect BRAF(V600E) mutation in 120 PTCs and 23 goiter tissues as normal control. Moreover, appropriate cut-off values for each CpG site were set up to predict disease recurrence. Our data showed that overall average methylation levels of CDH1 and RUNX3 genes were significantly higher in PTCs than that in control subjects. Conversely, overall average methylation levels of DAPK promoter were significantly lower in PTCs than that in control subjects. Moreover, BRAF(V600E) mutation and overall average methylation levels of all these genes were not significant difference between recurrent and non-recurrent cases. However, we found that hypermethylation of RUNX3 at CpG sites -1397, -1406, -1415 and -1417 significantly increased the risk of of disease recurrence by using appropriate site-specific cut-off values. Collectively, our findings suggest RUNX3 site-specific hypermethylation may offer value in predicting or monitoring postoperative recurrence of PTC patients. PMID- 25520864 TI - miR-199a-3p negatively regulates the progression of osteosarcoma through targeting AXL. AB - Dysregulation of micro-RNAs has been shown to contribute to multiple tumorigenic processes, as well as to correlate with tumor progression and prognosis. miR-199a has been shown to be dysregulated in many different tumor types; however, the association between miR-199a and the clinicopathological features of osteosarcoma is unknown, and the target gene for miR-199a and the regulatory mechanism are also unknown. In this study, we demonstrated that miR-199a-3p is expressed at low levels in osteosarcoma cells, which may inhibit the migration and invasion of these tumor cells. The downregulation of miR-199a-3p expression is significantly correlated with the recurrence and lung metastasis of patients with osteosarcoma. Using multivariate Cox regression analysis, low level of expression of miR-199a 3p was shown to be an independent predictor for worse prognosis in osteosarcoma. Furthermore, we showed that miR-199a-3p mimics can decrease the expression of the mRNA and protein of the receptor tyrosine kinase AXL, and miR-199a-3p targets directly the 3'-UTR of AXL mRNA, suggesting that miR-199a-3p may downregulate the expression of the AXL gene to inhibit the progression of osteosarcoma. In patients' osteosarcoma samples, we also showed a statistically significant inverse relation between the levels of miR-199a-3p and AXL, which is consistent with the results in osteosarcoma cell lines. Interestingly, miR-199a-3p mimics reduced the level of phosphorylation of AKT. Together with the previous data, we conclude that miR-199a-3p negatively contributes to the progression of osteosarcoma by downregulating the expression of AXL mRNA and protein. By this mechanism, a regulatory pathway comprised of miR-199a-3p and AXL may exist in osteosarcoma cells, which may as a result regulate the progression of osteosarcoma through the AKT pathway. PMID- 25520865 TI - Hepatic stellate cells secretes type I collagen to trigger epithelial mesenchymal transition of hepatoma cells. AB - Liver fibrosis is a risk factor for hepatoma. Activated hepatic stellate cells (HSCs) play a critical role in progression of hepatoma. Resected hepatoma patients with high alpha-SMA+HSCs infiltration had worse survival, OR: 2.2 and p=0.0434. We hypothesized that HSCs could increase the epithelial-mesenchymal transition (EMT) ability of hepatoma cells. In murine model of liver fibrosis with injection of ML1 mice HCC cell line, E-cadherin was lost at the margin of tumor nodule around alpha-SMA+HSC sites. In subcutaneous tumor model, HSCs could increase the metastatic nodules in the lung, and the expression of E-cadherin was decreased and the Slug was induced. To elucidate the effect of HSCs on hepatoma cells, HSC-T6 was co-cultured with ML1 and the condition medium of HSC-T6 can trigger ML1 cell morphological change, down-expression of E-cadherin, induction of Slug expression, and cell migration. Proteomic analysis of the condition medium showed that collagen I was the target molecule. Collagen type I alone also induced EMT of ML1 cells. Knockdown of collagen type I in HSC-T6 could decrease its induction of EMT on ML1 cells. In conclusion, HSC can secrete collagen type I to trigger hepatoma cells to undergo EMT for metastasis. PMID- 25520866 TI - Inhibition of mTOR reduce Stat3 and PAI related angiogenesis in salivary gland adenoid cystic carcinoma. AB - Angiogenesis is a complex biological process, which is involved in tumorigenesis and progression. However, the molecular mechanism of underlying angiogenesis remains largely unknown. In this study, we accessed the expression of proteins related angiogenesis by immunohistochemical staining of human tissue microarray which contains 72 adenoid cystic carcinoma (AdCC), 12 pleomorphic adenoma (PMA) and 18 normal salivary gland (NSG) using digital pathological scanner and scoring system. We found that the expression of p-S6(S235/236) (a downstream molecule of mTOR), p-Stat3(T705), PAI, EGFR, and HIF-1alpha was significantly increased in AdCC as compared with PMA and (or) NSG (p < 0.05). While, the expression of these proteins was not associated with pathological type of human AdCC (p > 0.05). Correlation analysis of these proteins revealed that p-S6(S235/236) up-regulates the expression of EGFR/p-Stat3(T705) (p < 0.05) and HIF-1alpha/PAI (p < 0.05). Moreover, the activation of p-S6(S235/236), EGFR/p-Stat3(T705) and HIF-1alpha/PAI associated with angiogenesis (CD34) and proliferation (Ki-67). In vitro, Rapamycin suppressed the expression of p-S6(S235/236), EGFR, p-Stat3(T705), HIF 1alpha and PAI. Further more, target inhibition of mTOR by rapamycin effectively reduced tumor growth of SACC-83 cells line nude mice xenograft and decreased the expression of p-S6(S235/236), EGFR/p-Stat3(T705) and HIF-1alpha/PAI. Taken together, these data revealed that mTOR signaling pathway regulates tumor angiogenesis by EGFR/p-Stat3(T705) and HIF-1alpha/PAI. Inhibition of mTOR by rapamycin could effectively reduced tumor growth. It is likely that mTOR inhibitors may be a potential candidate for treatment of AdCC. PMID- 25520867 TI - Activation of integrin-ERBB2 signaling in undifferentiated thyroid cancer. AB - Undifferentiated thyroid carcinoma is one of the most aggressive human cancers. Although genetic changes underlying this aggressive cancer remain to be elucidated, RAS mutations have been frequently identified in it. Mice harboring a mutant thyroid hormone receptor Thrb(PV) (Thrb(PV/PV) ) spontaneously develop differentiated follicular thyroid carcinoma similar to human thyroid cancer. We recently demonstrated that targeting a RAS mutation (Kras(G12D) ) to the thyroid of Thrb(PV/PV) mice (Thrb(PV/PV) Kras(G12D) mice) promotes initiation and progression of undifferentiated thyroid cancer. To uncover genes destined to drive the aggressive cancer phenotype, we used cDNA microarrays to compare the gene expression profiles of thyroid cells of Kras(G12D) mice and thyroid tumor lesions of Thrb(PV/PV) and Thrb(PV/PV) Kras(G12D) mice. Analyses of microarray data identified 14 upstream regulators that were significantly altered in thyroid tumors of Thrb(PV/PV) and Thrb(PV/PV) Kras(G12D) mice. Most of these genes with altered expression function as key regulators in growth factor-induced signaling. Further analysis identified gene expression profiles of markedly elevated integrin levels, acting as upstream activators to stimulate ERBB2-mediated downstream signaling in thyroid tumors of Thrb(PV/PV) Kras(G12D) mice. The present studies uncovered integrin-activated ERBB2 signaling as one of the mechanisms in synergy between TRbetaPV and KRASG12D signaling to promote aggressive tumor growth in undifferentiated thyroid cancer. PMID- 25520868 TI - Silencing of hypoxia-inducible tumor suppressor lysyl oxidase gene by promoter methylation activates carbonic anhydrase IX in nasopharyngeal carcinoma. AB - Lysyl oxidase (LOX) is an oxidative enzyme known to initiate the cross-linking of collagens and elastin, and suggested recently as a tumor suppressor for several tumor types including lung, pancreatic and gastric cancers. Previously we showed that LOX is strongly induced upon hypoxia in nasopharyngeal carcinoma (NPC) cell lines CNE2 and HONE1 but only slightly in HK1 and not in C666-1. Here, we further studied the regulatory mechanism and functions of LOX in NPC. LOX is widely expressed in human normal tissues with variations in expression levels. LOX was expressed in most NPC cell lines except for C666-1, while HK1 and FaDu (laryngeal cancer) only expressed low level of LOX. Methylation analysis showed that the LOX promoter was methylated in C666-1 and partially methylated in HK1. After demethylation with 5-aza-2'-deoxycytidine, LOX expression was reactivated along with increased unmethylated alleles. LOX promoter methylation was detected in 42/49 (85.7%) of NPC primary tumors but only 3/16 (18.75%) of nose swab samples from NPC patients. LOX overexpression reduced the clonogenicity and cell growth of NPC cells, and also inhibited the migration and invasion of the NPC cells. Carbonic anhydrase IX (CA9) mRNA level was obviously decreased in HK1 cells after transfection with LOX. The elevation of CA9 protein upon hypoxia was inhibited in LOX-transfected HK1 cells. The protein levels of an apoptosis marker cPARP were increased in LOX-transfected HK1 cells upon hypoxia treatment. Our data showed that silencing or down-regulation of LOX in NPC was due to its promoter methylation and LOX acts as a tumor suppressor in NPC. LOX silencing would facilitate NPC cells to escape from hypoxia-induced apoptosis and maintains a malignant and metastatic phenotype. PMID- 25520869 TI - Caveolin-1-dependent and -independent uPAR signaling pathways contribute to ganglioside GT1b induced early apoptosis in A549 lung cancer cells. AB - Urokinase receptor interacts with alpha5beta1-integrin and enhances cancer cell proliferation and metastasis. Activation of alpha5beta1-integrin requires caveolin-1 and is regulated by uPAR, which upregulates persistently the activated ERK necessary for tumor growth. In this study, we show that the ganglioside GT1b induces proapoptotic signaling through two uPAR-ERK signaling pathways in A549 lung cancer cells. GT1b downregulated the expression of alpha5beta1 integrin, caveolin-1, fibronectin, FAK, and ERK, whereas GT1b upregulated the expression of p53 and uPAR, suggesting GT1b mediated depletion of caveolin-1 in uPAR-expressing A549 cells also disrupts uPAR/integrin complexes, resulting in downregulation of fibronectin-alpha5beta1-integrin-ERK signaling. Following p53 siRNA treatment, FAK and ERK expression was recovered, meaning the presence of reentry uPAR-FAK ERK signaling pathway. These findings reveal that GT1b is involved in both caveolin-1-dependent uPAR-alpha5beta1-integrin-ERK signaling and caveolin-1 independent uPAR-FAK-ERK signaling. These results suggest a novel function of GT1b as a dual regulator of ERK by modulating caveolin-1 and p53. PMID- 25520870 TI - TrkC expression predicts favorable clinical outcome in invasive ductal carcinoma of breast independent of NT-3 expression. AB - BACKGROUND: TrkC, a member of neurotrophin receptor family, functions not only as an oncogene, but also act as a tumor suppressor via a manner of dependence receptor in human malignant tumors. Little is known on the action of TrkC for the clinical prognosis and the progression of breast cancer according to the availability of its ligand NT-3. We sought to investigate the prognostic relevance of NT-3-TrkC axis in breast cancer and estimate its role during the process of breast cancer progression. METHODS: 236 cases of invasive ductal carcinoma (IDC), 60 pure ductal carcinoma in situ (DCIS) and 30 normal breast tissue (NBT) between 2004 and 2005 were included in the study. Spearman's rank correlation test was used to analyze the association of NT-3-TrkC expression and breast cancer progression. The Kaplan-Meier method and Cox proportional hazards model were performed to identify the relevant prognostic factors. RESULTS: 50.4% IDC tumors displayed absent or low TrkC expression, while 49.6% was high TrkC expression. TrkC expression was negatively associated with lymph node metastasis (P = 0.029) and tumor proliferation (P = 0.015). Patients with lower TrkC expressing tumors had a higher risk of recurrence (odds ratio, 0.401; 95% confidence interval, 0.207-0.778; P = 0.007). The layered analysis indicated that patients with high TrkC expression tumors had a favor disease-free survival whether NT-3 and TrkC were co-expressed or solitarily expressed in the tumor (P = 0.000). NT-3 was demonstrated to be not a predictor of IDC patients' prognosis. But NT-3 expression was inversely correlated with the progression of breast cancer (r = -0.341, P = 0.000), since more IDC tumors showed high NT-3 expression than DCIS tumors (51.7% vs. 25.9%), while no NBT showed high NT-3 expression, as well. CONCLUSION: The study indicates TrkC expression reduces tumor relapse independent of NT-3 availability in the IDC. Elevated NT-3 expression contributes to the progression of breast cancer. PMID- 25520872 TI - HER4 is a novel prognostic biomarker in gastrointestinal stromal tumor specifically originated from stomach. AB - HER family has been implicated in a number of malignant tumors for predicting prognosis and potential targeted therapy purposes, however, the prognostic roles of HER family in GISTs have not been elaborated yet. Our study aims to fully evaluate the prognostic value of HER family in GIST patients and efficacy of imatinib adjuvant therapy. For HER family expression detection, qPCR were used in 33 flesh GIST specimens, and then, 453 GIST samples (405 GISTs with operation only and 48 with imatinib adjuvant therapy after radical surgery) were collected for tissue microarrays construction and immunohistochemistry (IHC). Clinicopathological data were confirmed by pathological diagnosis and clinical recorders, recurrence-free survivals (RFS) were evaluated in 453 GIST patients. With qPCR and IHC performed, EGFR, HER2 and HER4 are focused on examining prognostic value in remainder of our study by high positive expression rates in GISTs. In high-risk GISTs with or without imatinib adjuvant therapy, EGFR negative expression are associated with decreased RFS when compared to positive cases. HER2 present no relationship with GIST patients' prognosis. HER4 positive expression significantly associated with disease recurrence in GISTs. Further subgroup studies revealed HER4 was an independent prognostic indicator especially for gastric GISTs, and also for gastric high-risk GISTs. In our study, detection of EGFR expression helps to precisely subdivide high-risk GISTs for different prognosis and probably predict outcomes for imatinib treatment. HER4 is a novel independent prognostic biomarker for gastric GISTs specifically, which could be potential therapeutic target in GISTs originated from stomach. PMID- 25520871 TI - Establishment of genetically diverse patient-derived xenografts of colorectal cancer. AB - Preclinical compounds tested in animal models often show limited efficacy when transitioned into human clinical trials. As a result, many patients are stratified into treatment regimens that have little impact on their disease. In order to create preclinical models that can more accurately predict tumor responses, we established patient-derived xenograft (PDX) models of colorectal cancer (CRC). Surgically resected tumor specimens from colorectal cancer patients were implanted subcutaneously into athymic nude mice. Following successful establishment, fourteen models underwent further evaluation to determine whether these models exhibit heterogeneity, both at the cellular and genetic level. Histological review revealed properties not found in CRC cell lines, most notably in overall architecture (predominantly columnar epithelium with evidence of gland formation) and the presence of mucin-producing cells. Custom CRC gene panels identified somatic driver mutations in each model, and therapeutic efficacy studies in tumor-bearing mice were designed to determine how models with known mutations respond to PI3K, mTOR, or MAPK inhibitors. Interestingly, MAPK pathway inhibition drove tumor responses across most models tested. Noteworthy, the MAPK inhibitor PD0325901 alone did not significantly mediate tumor response in the context of a KRAS(G12D) model, and improved tumor responses resulted when combined with mTOR inhibition. As a result, these genetically diverse models represent a valuable resource for preclinical efficacy and drug discovery studies. PMID- 25520873 TI - Targeting CREB inhibits radiation-induced neuroendocrine differentiation and increases radiation-induced cell death in prostate cancer cells. AB - Neuroendocrine differentiation (NED) is a process by which prostate cancer cells transdifferentiate into neuroendocrine-like (NE-like) cancer cells. Accumulated evidence suggests that NED is associated with disease progression and therapy resistance in prostate cancer patients. We previously reported that by mimicking a clinical radiotherapy protocol, fractionated ionizing radiation (FIR) induces NED in prostate cancer cells. Interestingly, FIR-induced NED constitutes two distinct phases: a radioresistance phase in which a fraction of cells selectively survive during the first two week irradiation, and a neuroendocrine differentiation phase in which surviving cells differentiate into NE-like cancer cells during the second two week irradiation. We have also observed increased activation of the transcription factor cAMP response element binding (CREB) protein during the course of FIR-induced NED. To determine whether targeting NED can be explored as a radiosensitization approach, we employed two CREB targeting strategies, CREB knockdown and overexpression of ACREB, a dominant-negative mutant of CREB, to target both phases. Our results showed that ACREB expression increased FIR-induced cell death and sensitized prostate cancer cells to radiation. Consistent with this, knockdown of CREB also inhibited FIR-induced NED and sensitized prostate cancer cells to radiation. Molecular analysis suggests that CREB targeting primarily increases radiation-induced pre-mitotic apoptosis. Taken together, our results suggest that targeting NED could be developed as a radiosensitization approach for prostate cancer radiotherapy. PMID- 25520874 TI - A mathematical model for short-term vs. long-term survival in patients with glioma. AB - Gliomas, the most common primary brain tumors in adults, constitute clinically, histologically, and molecularly a most heterogeneous type of cancer. Owing to this, accurate clinical prognosis for short-term vs. long-term survival for patients with grade II or III glioma is currently nonexistent. A rigorous, multi method bioinformatic approach was used to identify the top most differentially expressed genes as captured by mRNA sequencing of tumor tissue. Mathematical modeling was employed to develop the model, and three different and independent methods of validation were used to assess its performance. I present here a mathematical model that can identify with a high accuracy (sensitivity=92.9%, specificity=96.0%) those patients with glioma (grade II or III) who will experience short-term survival (<= 1 year), as well as those with long-term survival (>= 3 years), at the time of diagnosis and prior to surgery and adjuvant chemotherapy. The 5 gene input variables to the model are: FAM120AOS, PDLIM4, OCIAD2, PCDH15, and MXI1. MXI1, a transcriptional repressor, represents the top biomarker of survival and the most promising target for the development of a pharmacological treatment. PMID- 25520875 TI - Identification and verification of Hsp90-beta as a potential serum biomarker for lung cancer. AB - BACKGROUND: Hsp90-beta was investigated as prognostic factor because of its apparent association with tumorigenesis. The aim of this study was to investigate the expression of Hsp90-beta in lung cancer patients, to analyze the relationship with respect to the clinicopathological features and to assess whether Hsp90-beta as a potential serum marker for lung cancer. METHODS: Expression of Hsp90-beta was examined using immunohistochemistry, in-situ hybridization, western blot and enzyme-linked immunosorbent assay. Sensitivities and specificities for Hsp90-beta serum test were determined using receiver operator characteristic curve and cutoff was defined based on 95% and 85% sensitivities. RESULTS: Lung cancer tissues exhibited higher expression of Hsp90-beta than the normal tissues (P < 0.05) and the serum Hsp90-beta of lung cancer patients also exhibited higher level than control groups (P < 0.05). Moreover, increased serum Hsp90-beta was significantly associated with the pathological grade and clinical stage of lung cancer patients (P < 0.05). Using receiver operator characteristic curve analysis, the cutoffs for distinguishing lung cancer from normal and benign groups were 1.155 and 1.158 ng/ml respectively. The sensitivities of Hsp90-beta for distinguishing lung cancer from normal and benign groups were 98.77% and 95.9%, and specificities were 88.33% and 72.7%. CONCLUSION: Up-regulation of serum Hsp90-beta was associated with pathological grade and clinical stage of lung cancer patients, which indicated that it could be considered molecular biomarker for diagnosis and prognosis of lung cancer. PMID- 25520876 TI - Involvement of different mechanisms for the association of CAG repeat length polymorphism in androgen receptor gene with prostate cancer. AB - While androgen and androgen receptor (AR) activity have been strongly implicated in prostate cancer development and therapy, the influence of the CAG repeat, which is found within the first exon of the AR gene, on prostate carcinogenesis is still unclear. We investigated the differences in the length of the CAG repeat between prostate cancer patients and controls in the Chinese population as well as between TMPRSS2:ERG fusion positive and negative samples. A general association between prostate cancer and either longer or shorter AR CAG repeat length was not observed in the Chinese population. However, our data suggest that certain CAG repeat lengths may increase or decrease prostate cancer risk. Shorter CAG repeat length was also not shown to be associated with a higher induction rate of TMPRSS2 and ERG proximity, an essential step for TMPRSS2:ERG fusion formation. However, samples with a CAG repeat of 17 were found more frequently in the TMPRSS2:ERG fusion positive than negative prostate cancer cases and mediated a higher rate of androgen-induced TMPRSS2 and ERG co-localisation than AR with longer (24) and shorter (15) CAG repeats. This suggests that 17 CAG repeats may be associated with TMPRSS2:ERG fusion positive prostate cancer, but may have a preventive role for prostate cancer in the Chinese population, which has a low TMPRSS2:ERG fusion frequency. This study suggests that different mechanisms for the association of CAG repeat length polymorphism and prostate cancer exist in different ethnic populations. PMID- 25520877 TI - MicroRNA-543 acts as an oncogene by targeting PAQR3 in hepatocellular carcinoma. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that can act as oncogenes or tumor suppressor genes in human cancer. Increasing evidences indicate that deregulation of miRNAs contributes to the hepatocarcinogenesis. In this study, we demonstrated that the levels of miR-543 were dramatically increased in clinical hepatocellular carcinoma (HCC) tissues and cell lines. Moreover, forced expression of miR-543 promoted the proliferative and invasive potential of HepG2. We also identified PAQR3 as a direct target gene for miR-543 using a fluorescent reporter assay and western blot. The levels of PAQR3 were dramatically decreased in clinical hepatocellular carcinoma (HCC) tissues and cell lines. The mRNA levels of PAQR3 were inversely correlated with the miR-543 expression level.Thus, our finding provides a new insight into the mechanism of hepatocarcinogenesis, indicating a therapeutic potential of miR-543 in the treatment of HCC. PMID- 25520878 TI - Methods to identify molecular expression of mTOR pathway: a rationale approach to stratify patients affected by clear cell renal cell carcinoma for more likely response to mTOR inhibitors. AB - Since target therapy with mTOR inhibitors plays an important role in the current management of clear cell renal cell carcinoma (RCC), there is an increasing demand for predictive biomarkers, which may help to select patients that are most likely to benefit from personalized treatment. When dealing with formalin-fixed paraffin-embedded (FFPE) cancer tissue specimens, several techniques may be used to identify potential molecular markers, yielding different outcome in terms of accuracy. We sought to investigate and compare the capability of three main techniques to detect molecules performing an active function in mTOR pathway in RCC. Immunohistochemistry (IHC), Western blot (WB) and immunofluorescence (IF) analyses were performed on FFPE RCC tissue specimens from 16 patients by using the following mTOR pathway-related: mTOR (Ser235/236), phospho-mTOR (p mTOR/Ser2448), phospho-p70S6k (p-p70S6k/Thr389), both monoclonal and polyclonal, phospho-S6Rb (p-S6Rb) and phospho-4EBP1 (p-4EBP1/Thr37/46). No single molecule was simultaneously revealed by all three techniques. Only p-p70S6k was detected by two methods (IHC and IF) using a monoclonal antibody. The other molecules were detected exclusively by one technique, as follows: p-mTOR and polyclonal p-p70S6K by IHC, p70S6K, p-S6Rb and p-4EBP1 by WB, and, finally, mTOR by IF. We found significant differences in detecting mTOR pathway-related active biomarkers by using three common techniques such as IHC, WB and IF on RCC samples. Such results have important implications in terms of predictive biomarker testing, and need to be related to clinical end-points such as responsiveness to targeted drugs by prospective studies. PMID- 25520879 TI - Methylation of ras association domain protein 10 (RASSF10) promoter negative association with the survival of gastric cancer. AB - OBJECTIVE: The present study was conducted to elucidate the prognostic prediction value of the methylation of the RASSF10 promoter in gastric cancer (GC). METHODS: A total of 300 patients with GC revealed the methylation degrees of the DNA of the RASSF10 promoter. Methylation-specific PCR (MSP) analysis was performed to qualitatively detect the methylated degrees of the DNA of the RASSF10 promoter of 300 patients with GC. Associations between molecular, clinicopathological and survival data were analyzed. RESULTS: The protein and mRNA expressions of RASSF10 in GC tissues were lower than those in normal gastric mucosal tissues. In the MSP analysis cohort, patients with methylated RASSF10 promoter exhibited significantly shorter median OS than those with unmethylated RASSF10 promoter (P < 0.001). Multivariate survival analysis results showed that methylated RASSF10 promoter was an independent predictor of the survival of patients with GC. CONCLUSIONS: The methylation of the RASSF10 promoter could be applied for the clinical prediction of the prognosis of GC. PMID- 25520880 TI - Changes of TCR repertoire diversity in colorectal cancer after Erbitux (cetuximab) in combination with chemotherapy. AB - We have previous found a positive correlation between post-therapy TCR repertoire normalization and remission of colorectal cancer (CRC) patients following fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab or Rh endostatin therapy. To further define the TCR repertoire diversity changes following treatment in CRC patients, and confirm its potential prognostic value, the present study extended the sample size of follow-up and used an alternative therapy regime to investigate changes of TCR repertoires following Erbitux plus FOLFIRI therapy. Inclusion and exclusion criteria have been established to screen out 26 patients to receive Erbitux plus FOLFIRI therapy. Efficacy and toxicity assessment have been made for them after 3 months' treatment as well as the TCR repertoire diversity has been determined. A CDR3 complex scoring system was used to quantify the diversity of TCR repertoire. The results showing that the diversity of CD4(+) T cells in PR group was significantly higher than that of SD and PD groups, and the difference was enlargement after treatment. The diversity of CD8(+) T cells in PR group has no difference before and after treatment, but significant decrease in SD and PD group after treatment. In conclusion, analysis the diversity of T cell repertoire has an important prognosis value for CRC patients. PMID- 25520881 TI - Genetic polymorphisms in oxidative stress-related genes are associated with clinical outcome in patients with advanced non-small cell lung cancer receiving tyrosine kinase inhibitors. AB - Many types of cancer have high antioxidant capacity that effectively scavenges reactive oxygen species and thus protect cancer cells against oxidative damage. The aim of this study was to examine the effect of 20 single nucleotide polymorphisms (SNPs) in 20 oxidative stress-related genes on clinical outcome in 219 patients with advanced non-small cell lung cancer (NSCLC) who were treated with EGFR tyrosine kinase inhibitors (TKIs). We assessed the associations of SNPs with prognosis in all patients as well as stratified by clinical characteristics. Three SNP (rs1695, rs2333227 and rs699512) were significantly associated with overall survival (OS). In a multivariate analysis, rs1695 AA and rs2333227 AG/GG genotypes were identified as independent prognostic factors for poor OS. Stratification analyses revealed that these 3 SNPs remained significantly associated with OS. Furthermore, there was a strong gene-dosage effect of these 3 SNPs on OS that patients with increasing number of unfavorable genotypes had significantly increased death risk. In conclusion, our findings provide the first evidence that genetic variants in oxidative stress-related genes may influence treatment outcome in advanced NSCLC patients receiving EGFR TKIs. PMID- 25520882 TI - Debio 1143, an antagonist of multiple inhibitor-of-apoptosis proteins, activates apoptosis and enhances radiosensitization of non-small cell lung cancer cells in vitro. AB - Inhibitors of apoptosis (IAPs) limit the effectiveness of radiation in non-small cell lung cancer (NSCLC). Debio 1143 (D1143) is an antagonist of IAPs. The purpose of this study was to investigate the potential of D1143 as a radiosensitizer in NSCLC. MTS assays were performed in two NSCLC cell lines: HCC193 and H460. Extent of apoptotic cell death was characterized by Annexin V assay and Western blot for cleaved caspase-3, -8, and IAPs. TNF-alpha release was determined by ELISA. Radiosensitivities were compared with dose enhancement ratios (DERs). HCC193 cells D1143 IC50 was 1 MUM. HCC193 cells demonstrated noticeable cleaved caspase-3, -8, and a decrease in IAP levels with 2.5 MUM D1143; H460 cells, with 10 MUM; both in a time-dependent manner. Additionally, HCC193 cells exhibited an increase in TNF-alpha. D1143 radiosensitized cells: HCC193, 2.5 MUM D1143, 24 h incubation, DER of 2.19, p = 0.001; H460 cells, 10 MUM D1143, 48 h incubation, DER of 1.29, p = 0.082. Treatment of H460 cells with radiation therapy, TNF-alpha, and D1143 further radiosensitized the cells (DER of 1.92, p = 0.026). D1143 significantly enhanced the radiosensitization of HCC193 and H460 cells in vitro. TNF-alpha contributed to the sensitization in the more sensitive cell line (HCC193). More research is warranted to test the mechanism of D1143, and to assess its potential in vivo in the clinical setting. PMID- 25520883 TI - Prostaglandin receptors EP1-4 as a potential marker for clinical outcome in urothelial bladder cancer. AB - Prostaglandins, especially prostaglandin E2 (PGE2), and COX-2 play an important role in carcinogenesis of many tumors including bladder cancer (BCA). The PGE2 receptors EP1-4 regulate tumor cell growth, invasion and migration in different tumor entities but EP expression in BCA remains to be determined. In the present study we examined the expression of EP1-4 in non-muscle invasive bladder cancer (NMIBC), muscle invasive bladder cancer (MIBC) and normal urothelial tissue (NU) using immunohistochemistry. Nuclear and cytoplasmic EP1-4 expression was correlated with clinicopathological parameters and survival of BCA patients. EP1, EP2 and EP3 were significantly less expressed in the cytoplasm und nucleus of NMIBC and MIBC than in NU; EP4 cytoplasmic staining in MIBC was significantly higher compared to NU. The cytoplasmic staining was significantly more abundant in MIBC than in NMIBC in all investigated receptors except EP2. The level of EP staining in NMIBC was correlated with staging and grading, especially cytoplasmic EP1. Nuclear staining of EP1 was an independent predictor of BCA recurrence-free survival in NMIBC patients. EP receptors are dysregulated in BCA. The increase of EP1 may be used as prognostic parameter in NMIBC patients and its dysregulation could be targeted by specific EP1 inhibitors. PMID- 25520885 TI - Prospective assessment of suicidal ideation and behavior: an internet survey of pharmaceutical sponsor practices. AB - OBJECTIVE: To survey the current approaches of clinical trial sponsors in prospective suicidal ideation and behavior assessments and challenges encountered. DESIGN: An internet-based survey. SETTING: Inclusion of prospective assessments of suicidal ideation and behavior in industry-sponsored clinical studies were required following the release of the September 2010 United States Federal Drug Administration draft guidance. The International Society for CNS Clinical Trials and Methodology Suicidal Ideation and Behavior Assessment Workgroup conducted an online survey to understand industry practices and experiences in implementing suicidal ideation and behavior assessments in clinical trials. PARTICIPANTS: The survey was sent to 1,447 industry employees at 178 pharmaceutical companies. A total of 89 evaluable responses, representing 39 companies, were obtained. MEASUREMENTS: A 30-item internet survey was developed asking about potential challenges and issues in implementing prospective suicidal ideation and behavior assessments. RESULTS: Common factors in deciding whether to include suicidal ideation and behavior assessments in a clinical trial were psychiatric or neurologic drug product (95%); central nervous system activity (78%); disease (74%) and patient population (71%); and regulatory announcements and policies (74%). The most common challenges in implementing suicidal ideation and behavior assessments included cross-cultural differences in acceptance of SIB assessments (40%); obtaining adequate baseline history (36.8%); obtaining translations (35%); investigator/rater discomfort with asking about suicidal ideation and behavior (32%); and inadequate training of raters to administer suicidal ideation and behavior ratings (30%). CONCLUSION: Among sponsors surveyed, the implementation rate of suicidal ideation and behavior assessment in central nervous systems studies is very high. Most have used the Columbia-Suicide Severity Rating Scale. Challenges regarding standardization of retrospective assessment timeframes and differing approaches to summarizing and analyzing suicidal ideation and behavior-related study data were frequently reported. These results suggest that inconsistent reports of suicidal ideation and behavior within study datasets may occur and that integration of data across studies remains a concern. PMID- 25520884 TI - Rab25 Small GTPase Mediates Secretion of Tumor Necrosis Factor Receptor Superfamily Member 11b (osteoprotegerin) Protecting Cancer Cells from Effects of TRAIL. AB - BACKGROUND: Expression of Rab25, which is located in the 1q amplicon present at high frequency in many cancer lineages, promotes cancer cell survival under multiple stress conditions. While Rab proteins play essential roles in all stages of vesicle trafficking, the functions and endogenous cargoes for Rab25 remain to be fully elucidated. Osteoprotegerin (OPG) is a secreted glycoprotein that binds the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) thus preventing it from activating the TNF-family death receptors. In the present study, we demonstrated that Rab25 regulates OPG at both the transcription and secretion level. METHODS: The effect of Rab25 on OPG expression and its effect on TRAIL-induced cell were examined in both ovarian and breast cells. Signal transduction pathways regulation of OPG expression was examined in cells using pharmacogenetic approaches. RESULTS: Expression of Rab25 to levels similar to those in tumors with RAB25 amplification, increased OPG mRNA expression and secretion from ovarian and breast cancer cell lines, whereas down regulation with Rab25 specific siRNA decreased OPG secretion and sensitized cells to TRAIL induced cell death. Critically, exogenous OPG mimicked the effects of Rab25 on cell death supporting the contention that Rab25-induced accumulation of OPG protects cancer cells from the effects of TRAIL. Rab25 cooperates with EGFR mediated MAPK signaling to increase TRAIL production and release. Importantly, priming cells with EGFR inhibitors increased sensitivity to TRAIL-induced cells death regardless of the Rab25 background. CONCLUSION: Increased OPG expression induced by Rab25 may provide a mechanistic advantage for cancer development and progression. PMID- 25520886 TI - Predictive Value of Baseline Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) Assessments for Identifying Risk of Prospective Reports of Suicidal Behavior During Research Participation. AB - OBJECTIVE: Examine the ability of baseline electronic Columbia-Suicide Severity Rating Scale lifetime suicidal ideation and behavior categories to predict prospective reports of suicidal behavior in psychiatric and non-psychiatric research participants. DESIGN: Meta-analysis of 74,406 eC-SSRS assessments completed between September 2009 and December 2012. SETTING: Thirty-three clinical research studies that used the electronic Columbia-Suicide Severity Rating Scale to assess suicidal ideation and behavior at baseline and prospectively during follow-up visits. PARTICIPANTS: Records from 6,760 patients with psychiatric disorders (opioid dependence, generalized anxiety, major depressive, and posttraumatic stress disorders) and 2,077 nonpsychiatric disorder patients (chronic obstructive pulmonary disease, epilepsy, fibromyalgia, human immunodeficiency virus, insomnia, multiple sclerosis, osteoarthritis, pain/back pain, Parkinson's disease, restless leg syndrome) were analyzed. MEASUREMENTS: Electronic Columbia-Suicide Severity Rating Scale assessment of lifetime suicidal ideation (5 severity levels) and suicidal behavior (4 types) at baseline and prospectively reported suicidal behavior during study participation. RESULTS: Increasingly more severe lifetime suicidal ideation at baseline was associated with a progressively greater likelihood of prospectively reported suicidal behavior during study participation. Intent to act on suicidal ideation was most predictive of reports of suicidal behavior. Reports of lifetime suicidal behaviors at baseline also predicted subsequent suicidal behavior, and multiple lifetime behaviors monotonically increased prospective risk of suicidal behavior. Baseline suicidal ideation and behavior predicted future suicidal behavior in both psychiatric and non-psychiatric trials. CONCLUSIONS: Lifetime reports of suicidal ideation and/or behavior at baseline significantly increased risk of prospectively reporting suicidal behavior during research trial participation in both psychiatric and nonpsychiatric patients. Lifetime prevalence of suicidal ideation and behavior is higher among psychiatric patients, but also presents a safety concern among nonpsychiatric patients when reported. PMID- 25520887 TI - Comparative Validation of the S-STS, the ISST-Plus, and the C-SSRS for Assessing the Suicidal Thinking and Behavior FDA 2012 Suicidality Categories. AB - OBJECTIVE: This exploratory study examines the concurrent validity for mapping symptoms of suicidal ideation, self-harm, and suicidal behavior as recorded on the InterSePT Scale for Suicidal Thinking-Plus, the Sheehan-Suicidality Tracking Scale (clinician- and patient-rated and reconciled patient/clinician versions), and the Columbia-Suicide Severity Rating Scale to the 11 United States Food and Drug Administration-Classification Algorithm of Suicide Assessment (September 2012) categories. METHOD: Forty subjects with varying degrees of suicidal ideation and behavior severity (from not present to extremely severe) were recruited from inpatient, outpatient, and emergency room settings. Each patient was interviewed using all three scales (InterSePT Scale for Suicidal Thinking Plus, the Sheehan-Suicidality Tracking Scale, and the Columbia-Suicide Severity Rating Scale) on the same day. The scales were administered in a random sequence by three independent raters who were blind to the ratings on the other scales. RESULTS: The Sheehan-Suicidality Tracking Scale and the InterSePT Scale for Suicidal Thinking-Plus show acceptable agreement with the Columbia-Suicide Severity Rating Scale in detecting the presence or absence of the 2012 Food and Drug Administration-Classification Algorithm of Suicide Assessment categories 1, 5, 6, 10, and 11 (passive ideation; active ideation with method, intent, and plan; completed suicide; preparatory actions; and self-injurious behavior) but not of categories 2, 3, and 4 (3 other active suicidal ideation combination categories) or to 8 and 9 (aborted and interrupted attempt). Despite the significant disagreement between the Columbia-Suicide Severity Rating Scale on the one side and the InterSePT Scale for Suicidal Thinking-Plus and the Sheehan Suicidality Tracking Scale on the other in the ability to accurately map to the 2012 Food and Drug Administration-Classification Algorithm of Suicide Assessment categories on some items, there was close agreement between the InterSePT Scale for Suicidal Thinking-Plus and the Sheehan-Suicidality Tracking Scale on these categories. CONCLUSION: The results of this exploratory study invite discussion and debate about the validity of the Columbia-Suicide Severity Rating Scale and its ability to accurately assess key active suicidal ideation categories, since it disagrees so much with the other two standardized scales that agree so closely with each other. PMID- 25520888 TI - Simple Measures of Hopelessness and Impulsivity are Associated with Acute Suicidal Ideation and Attempts in Patients in Psychiatric Crisis. AB - OBJECTIVE: To explore the authors' predictions 1) that hopelessness would positively correlate with suicidal ideation and that impulsivity (either transient urges to self-harm or impulsive acting out) would positively correlate with suicidal behavior, and 2) that the recent or long-standing nature of the traits will have corresponding effects on reported histories of suicidal ideation and behavior. DESIGN: Questionnaire validation trial in which each subject received every measure in counterbalanced fashion. SETTING: Inpatient and outpatient psychiatric settings associated with a medium-sized medical school in the southeastern United States. PARTICIPANTS: Forty-five subjects presenting with varying levels of suicidal ideation and behavior completed measures providing information about their histories of suicidal ideation and behavior, recent feelings of hopelessness, feelings of general hopelessness, recent feelings of difficulty controlling urges to self-harm, and feeling about general levels of impulsivity. MEASUREMENTS: The InterSePT Scale for Suicidal Thinking-Plus, the Sheehan-Suicidality Tracking Scale, the Columbia-Suicide Severity Rating Scale, and six additional questions to assess hopelessness and impulsivity. RESULTS: Recent and trait hopelessness correlated positively with suicidal ideation. Patients who reported any suicide attempt endorsed higher levels of general impulsivity than those who did not report a history of at least one suicide attempt. Those enrolled in the study secondary to a very recent suicide attempt reported more difficulties with recent suicidal impulses. CONCLUSION: Simple measures of hopelessness and impulsivity are associated with suicidal ideation and attempts and may add to determination of suicide risk. PMID- 25520889 TI - Current Assessment and Classification of Suicidal Phenomena using the FDA 2012 Draft Guidance Document on Suicide Assessment: A Critical Review. AB - OBJECTIVE: Standard international classification criteria require that classification categories be comprehensive to avoid type II error. Categories should be mutually exclusive and definitions should be clear and unambiguous (to avoid type I and type II errors). In addition, the classification system should be robust enough to last over time and provide comparability between data collections. This article was designed to evaluate the extent to which the classification system contained in the United States Food and Drug Administration 2012 Draft Guidance for the prospective assessment and classification of suicidal ideation and behavior in clinical trials meets these criteria. METHOD: A critical review is used to assess the extent to which the proposed categories contained in the Food and Drug Administration 2012 Draft Guidance are comprehensive, unambiguous, and robust. Assumptions that underlie the classification system are also explored. RESULTS: The Food and Drug Administration classification system contained in the 2012 Draft Guidance does not capture the full range of suicidal ideation and behavior (type II error). Definitions, moreover, are frequently ambiguous (susceptible to multiple interpretations), and the potential for misclassification (type I and type II errors) is compounded by frequent mismatches in category titles and definitions. These issues have the potential to compromise data comparability within clinical trial sites, across sites, and over time. CONCLUSION: These problems need to be remedied because of the potential for flawed data output and consequent threats to public health, to research on the safety of medications, and to the search for effective medication treatments for suicidality. PMID- 25520890 TI - The Columbia-Suicide Severity Rating Scale (C-SSRS): Has the "Gold Standard" Become a Liability? AB - OBJECTIVE: The Columbia- Suicide Severity Rating Scale has become the gold standard for the assessment of suicidal ideation and behavior in clinical trials. Criticism of the instrument has been mounting. We examine whether the instrument meets widely accepted psychometric standards and maps to the United States Food and Drug Administration's most recent 2012 algorithm for assessment of suicidal phenomena. Our goal is to determine if the Columbia-Suicide Severity Rating Scale should be retained as the preferred instrument for assessment of suicidal ideation and behavior. METHOD: Standard psychometric criteria dictate that categorizations to avoid type I and type II errors should be comprehensive and address the full spectrum (i.e., all dimensions) of a phenomenon. The criteria should also be well defined and consistent, and the wording throughout should be unambiguous. We examine the Columbia-Suicide Severity Rating Scale in terms of these criteria. RESULTS: The Columbia-Suicide Severity Rating Scale does not address the full spectrum of suicidal ideation or behavior. As a result, it has the potential to miss many combinations of suicidal ideation and behavior that present to clinicians in practice (type II error). Potential misclassifications (type I and II errors) are compounded by flawed navigation instructions; mismatches in category titles, definitions, and probes; and wording that is susceptible to multiple interpretations. Further, the Columbia-Suicide Severity Rating Scale in its current form does not map to the 2012 Food and Drug Administration's draft classification algorithm for suicidal ideation and behavior. CONCLUSION: The evidence suggests that the Columbia-Suicide Severity Rating Scale is conceptually and psychometrically flawed and does not map to the Food and Drug Administration's new standards. A new gold standard for assessment of suicidality may be warranted. PMID- 25520891 TI - Are suicide terrorists suicidal? A critical assessment of the evidence. AB - OBJECTIVE: Most of the research on suicide terrorism is conducted in the political science and international relations fields. The prevailing wisdom within this literature is that suicide terrorists are not suicidal. But how good is the evidence for this assumption? Knowing whether suicide terrorists are suicidal has implications for prevention, rehabilitation, and the "softer" side of counterterrorism designed to win minds and hearts. In addition it may deepen our understanding of suicide itself. DESIGN: This article uses a review of existing literature to examine the arguments and evidence for and against the possibility that suicide terrorists could be suicidal in the context of a broad range of explanations for suicide terrorism. RESULTS: Much of the evidence against the possibility that suicide terrorists are suicidal is based on anecdote or faulty assumptions about suicide. Relatively few formal systematic studies of suicidality in suicide terrorists have been conducted. Nonetheless, there is emerging evidence that suicidality may play a role in a significant number of cases. CONCLUSION: The field needs a more multidimensional approach, more systematic data at the individual level, and greater international cross disciplinary collaboration. Would-be suicide terrorists (intercepted and arrested on their way to an attack) should be routinely interviewed using standard internationally accepted psychiatric diagnostic interviews as well as suicidality and homicidality rating scales. Psychological autopsies should also be routinely conducted worldwide. Since no one research site can collect all of the information that is needed, the creation of an internationally shared database that focuses on suicide terrorists rather than simply incidents is encouraged. PMID- 25520892 TI - Status Update on the Sheehan-Suicidality Tracking Scale (S-STS) 2014. AB - There is a need for a choice of scales to evaluate the full range of suicidal phenomena. Such scales must be capable of use as both safety and efficacy outcome measures in research and in clinical settings. Central to the success in finding and developing effective anti-suicidal medications is having a sensitive suicidality scale that can detect an efficacy signal in conventional sample sizes used in clinical trials. The Sheehan-Suicidality Tracking Scale was developed for these purposes. This article provides a 2014 status update on the scale's progress, its use, and its properties. The authors review why and how the scale was developed; the scale structure, versions, and properties; the trials in which it was used; the time frames accommodated; its validation and reliability studies; its utility in screening and assessment; its utility in assessing treatment-emergent suicidal adverse events; its use as an efficacy outcome measure; its availability in self-rated and clinician-rated forms; the availability and linguistic validation of pediatric versions; linguistic validation in other languages; how it compares with global ratings of suicidality; and its possible utility and applications. PMID- 25520893 TI - Linguistic Validation of the Pediatric Versions of the Sheehan Suicidality Tracking Scale (S-STS). AB - OBJECTIVE: The United States Food and Drug Administration meta-analysis of registration trials of antidepressants found that emergent suicidality under the age of 25 years increases with decreasing age. This led to boxed warnings for antidepressants and the recommendation for careful assessment and monitoring of suicidality in children and adolescents. To address this need, we describe the development of a pediatric suicidality assessment and tracking scale and a novel, empirically based approach to its age-appropriate linguistic validation. METHOD: Starting with the adult version of the Sheehan-Suicidality Tracking Scale, we collaborated with reading specialists who use the sight word lists of Dolch and Fry and the grade level vocabulary lists of Beck, Farr, and Strickland to adapt the adult version to each age group. RESULTS: Our approach resulted in the development and documentation of a process for linguistically validating three age-appropriate pediatric versions of the Sheehan-Suicidality Tracking Scale from the adult version of the scale: one for 6- to 8-year-olds, a second for 9- to 12 year-olds, and a third for 13- to 17-year-olds. CONCLUSION: Further reliability and cognitive debriefing studies are needed in diverse demographic, ethnic, and cultural groups to make the pediatric versions of the Sheehan-Suicidality Tracking Scale more reliable, more generalizable, and more useful. PMID- 25520894 TI - The complexity of assessing overall severity of suicidality: a case study. AB - OBJECTIVES: This paper investigates the relationship between total scale scores and some other measures used to assess global severity of suicidality in order to determine if "global assessment" can be accomplished with one metric or if is it necessary to judge severity of suicidality in a multidimensional fashion. METHODS: For over a year, one subject with daily suicidality self-rated a global severity of suicidality score, the time spent in suicidality over 31,183 events of suicidality, the Sheehan-Suicidality Tracking Scale, Hopelessness Spectrum measure, and the Suicide Plan Tracking Scale. RESULTS: Relying on only one or two metrics to assess global severity of suicidality appears to have significant limitations. As with all single case reports, the findings may not be generalizable to other cases of suicidality. CONCLUSION: At the middle to high end of the suicidality spectrum, it is necessary to rely on multiple metrics, not just a global severity of suicidality rating, to properly assess the overall severity of suicidality. PMID- 25520895 TI - Do the Five Combinations of Suicidal Ideation in the FDA 2012 Draft Guidance Document and the C-SSRS Adequately Cover All Suicidal Ideation Combinations in Practice? A Case Study. AB - OBJECTIVE: The United States Food and Drug Administration's newest classification system for suicidality assessment anchors suicidal ideation to various combinations of passive suicidal ideation, active suicidal ideation, method, intent, and plan. This is based upon the suicidal ideation categories in the Columbia-Suicide Severity Rating Scale. Although there are 32 possible combinations of these suicidal ideation phenomena, the Food and Drug Administration's 2012 system and the Columbia-Suicide Severity Rating Scale accommodate six combinations. We use a case study to explore the impact of possible type II errors on suicidality classification posed by not including remaining 26 possible categories. METHODS: A suicidal subject kept detailed daily records of her experience of suicidality over two separate intervals of eight months' and nine-months' duration. These records permitted classification of individual events into each of the possible 32 suicidal ideation combinations. RESULTS: Although only a small percentage of all events of suicidality from either collection period fell outside of the Food and Drug Administration's classification system and the Columbia -Suicide Severity Rating Scale categories, those that were not so categorized constituted a large percentage of the time this subject experienced suicidality. When these two timeframes were aggregated, more than half of the subject's time spent experiencing suicidality fell into the suicidal ideation combinations not captured by the Food and Drug Administration's classification system and the Columbia-Suicide Severity Rating Scale categories. CONCLUSION: This case study suggests that type II errors in the Food and Drug Administration's classification system and in the Columbia-Suicide Severity Rating Scale categories for suicidal ideation may represent important omissions. PMID- 25520896 TI - Is a count of suicidal ideation and behavior events useful in assessing global severity of suicidality? A case study. AB - OBJECTIVE: Regulatory agencies and suicidality scales have focused on the value of a count of suicidal ideation and behavior events, even though the clinical usefulness and predictive value of the count of events in the global assessment of suicidality is unclear. This case study explores the value of this event count and offers a more sensitive alternative to tracking the count of events. METHODS: One subject documented her suicidality daily for 366 days. This documentation included the global severity of suicidality, the count of suicidal events, and the time spent experiencing those events. The relationship between both the count of events and the time spent were each compared to the global severity rating. RESULTS: We found the relationship between the time spent experiencing suicidality and the global severity of suicidality was much stronger than the relationship between the count of suicidal events and global severity. CONCLUSION: This case study suggests that tracking the time a patient spends experiencing suicidality may be more clinically useful and may have more value in assessing global severity of suicidality than tracking the count of events of suicidal ideation and behavior. PMID- 25520897 TI - Is There Value in Asking the Question "Do you think you would be better off dead?" in Assessing Suicidality? A Case Study. AB - OBJECTIVE: The author of the widely used suicidality scale, the Columbia-Suicide Severity Rating Scale, has repeatedly made the claim that asking the question, "Do you think you would be better off dead?" in suicidality assessment delivers false positive results. This case study investigates the value of this question as an immediate antecedent to impulsive suicidality and as a correlate of functional impairment. METHOD: One subject with daily suicidality and frequent impulsive suicidality rated five passive suicidal ideation phenomena and impulsive suicidality daily on a 0 to 4 Likert scale and rated weekly functional impairment scores for 13 weeks on a 0 to 10 Discan metric. RESULTS: Each of the five passive suicidal ideation phenomena studied frequently occurred at a different severity level, and the five phenomena did not move in synchrony. Most passive suicidal ideation phenomena were very low on dates of impulsive suicidality. Thoughts of being better off dead were a frequent antecedent to impulsive suicidality and were related to an increase in functional impairment. CONCLUSION: The relationship to both functional impairment and impulsive suicidality suggest that it is potentially dangerous to ignore thoughts of being better off dead in suicidality assessment. PMID- 25520898 TI - How the Timing of a Patient's Self-ratings of Suicidality and the Relationship to the Recipient Affect Patient Responses: A Case Study. AB - OBJECTIVE: This case study explores to what extent, if any, a subject's reporting varies depending upon whom the subject believes will view the data and the relationship the subject has with the reviewer. It also explores the variance in reporting if several days pass between the timeframe in question and the time of data collection. METHOD: The subject answered three suicidality-related scales (the Sheehan-Suicidality Tracking Scale, the Suicidality Modifiers, and the Alphs Dichotomous Impulsivity and Hopelessness Two Questions) for 24 distinct timeframes. The scales were rated three different ways for each timeframe. The first was for only the patient. Immediately afterward, the scales were answered for the subject's therapist. A few days later, the scales were again answered by the patient, but only for the patient. The three different interviews for the same timeframe were compared to investigate any deviations. RESULTS: This case study found clinically relevant deviations between the three ratings completed for the same timeframe. CONCLUSION: This case study illustrates that a patient's reporting of his or her symptoms of suicidality using a patient-rated scale can vary depending upon the context, distance from timeframe in question, and the patient's relationship with the reviewer of the data. PMID- 25520899 TI - Assessment of suicidal behavior in the emergency department. PMID- 25520900 TI - Effect of Intra-Medullar and Intra-Venous Infusions of Mesenchymal Stem Cells on Cell Engraftment by In-Vivo Cell Tracking and Osteoinductivity in Rabbit Long Bones: A Pilot Study. AB - OBJECTIVE: Stem cell therapy can be an efficacious treatment option for bone fragility disorders (eg, osteogenesis imperfecta, disuse osteopenia, and osteoporosis), and successful cell therapy application may be dependent on optimal cell engraftment in target bones. The objective of this study was to compare the efficiency of intra-medullar and intra-venous delivery of mesenchymal stem cells (MSC) to improve cell engraftment rate, bone mineral density, and micro-architecture. METHODS: By using six healthy juvenile New Zealand White rabbits, MSC were isolated from cancellous bone harvests and confirmed to have osteogenic capacity by inducing ectopic bone formation. The MSC were cultured, transduced by foamy viral vectors with marker genes for in vivo cell tracking, and expanded. All rabbits had one randomly selected limb receive intra-medullar infusion of 3*107 to 1*108 autologous MSC in the distal femur or the distal femur and proximal tibia. Two of six rabbits also received an intra-venous MSC infusion. At 28 days, MSC bone engraftment was assessed by PCR and the bone density and microstructure assessed by computed tomography and histomorphometry. RESULTS: The intra-medullar-infused MSC were detected in epiphysis or diaphysis of the distal femurs and/or proximal tibiae. Infused MSC comprised 0.01 to 0.3% of all cells in the bone tissues. The intra-venous-infused MSC were not detected in any location. Neither intra-medullar nor intra-venous MSC infusion altered bone volume, bone mineral density, or cortical bone porosity/thickness. Systemic biodistribution of intra-medullar-infused MSC was not evident. CONCLUSIONS: Our results indicated that intra-medullar infusion can be an effective cell delivery route for stem cell therapy potentially for orthopedic disorders, in preference to systemic administration. Further research is warranted to demonstrate an efficacy of intra-medullar MSC infusion on bone density and micro-architecture using animal models of bone disorders. PMID- 25520901 TI - Localized Principal Component Analysis based Curve Evolution: A Divide and Conquer Approach. AB - We propose a novel localized principal component analysis (PCA) based curve evolution approach which evolves the segmenting curve semi-locally within various target regions (divisions) in an image and then combines these locally accurate segmentation curves to obtain a global segmentation. The training data for our approach consists of training shapes and associated auxiliary (target) masks. The masks indicate the various regions of the shape exhibiting highly correlated variations locally which may be rather independent of the variations in the distant parts of the global shape. Thus, in a sense, we are clustering the variations exhibited in the training data set. We then use a parametric model to implicitly represent each localized segmentation curve as a combination of the local shape priors obtained by representing the training shapes and the masks as a collection of signed distance functions. We also propose a parametric model to combine the locally evolved segmentation curves into a single hybrid (global) segmentation. Finally, we combine the evolution of these semilocal and global parameters to minimize an objective energy function. The resulting algorithm thus provides a globally accurate solution, which retains the local variations in shape. We present some results to illustrate how our approach performs better than the traditional approach with fully global PCA. PMID- 25520902 TI - Why They Stay: Understanding Research Participant Retention in Studies of Aging, Cognitive Impairment and Dementia. AB - BACKGROUND: Retaining participants in longitudinal research in aging and Alzheimer's disease remains a significant challenge. "Study partners" are often required to insure participation and accuracy of information because cognitive impairment may interfere with accurate reporting. The purpose of the present report was to identify attitudes and reasons for continued participation in observational research. METHODS: 53 individuals (33 participants and 20 study partners) who were participating in the longitudinal cohort at the Mount Sinai Alzheimer's Disease Research Center were available for this survey. They were asked a single open-ended question about why they continued in our study. Seven categories of answers (e.g., Altruism, Value relationship with staff, and Concern about health) were identified and frequency of endorsement was summarized for participants and study partners separately. RESULTS: There were 82 responses from the 53 individuals. Forty five percent of the participants and 55% of the study partners identified altruism as one reason they participate in research over time, and 75% of study partners and 30% of participants mentioned valuing the relationship with staff as a reason they stayed in research. CONCLUSIONS: This data suggests that retention efforts should be directed toward fostering strong relationships between research staff and study participants and reinforcing the opportunity to contribute to others, which fosters a sense of altruism. PMID- 25520903 TI - (68)Ga-DOTA-Siglec-9 PET/CT imaging of peri-implant tissue responses and staphylococcal infections. AB - BACKGROUND: Staphylococcus epidermidis (S. epidermidis) has emerged as one of the leading pathogens of biomaterial-related infections. Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial molecule controlling extravasation of leukocytes. Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a leukocyte ligand of VAP-1. We hypothesized that (68)Ga-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated Siglec-9 motif containing peptide ((68)Ga-DOTA-Siglec-9) could detect inflammatory response due to S. epidermidis peri-implant infection by positron emission tomography (PET). METHODS: Thirty Sprague-Dawley rats were randomized into three groups. A sterile catheter was implanted into the medullary canal of the left tibia. In groups 1 and 2, the implantation was followed by peri-implant injection of S. epidermidis or Staphylococcus aureus (S. aureus) with adjunct injections of aqueous sodium morrhuate. In group 3, sterile saline was injected instead of bacteria and no aqueous sodium morrhuate was used. At 2 weeks after operation, (68)Ga-DOTA-Siglec-9 PET coupled with computed tomography (CT) was performed with the measurement of the standardized uptake value (SUV). The presence of the implant-related infection was verified by microbiological analysis, imaging with fluorescence microscope, and histology. The in vivo PET results were verified by ex vivo measurements by gamma counter. RESULTS: In group 3, the tibias with implanted sterile catheters showed an increased local uptake of (68)Ga-DOTA Siglec-9 compared with the intact contralateral bones (SUVratio +29.5%). (68)Ga DOTA-Siglec-9 PET detected inflammation induced by S. epidermidis and S. aureus catheter-related bone infections (SUVratio +58.1% and +41.7%, respectively). The tracer uptake was significantly higher in the S. epidermidis group than in group 3 without bacterial inoculation, but the difference between S. epidermidis and S. aureus groups was not statistically significant. The difference between the S. aureus group and group 3 was neither statistically significant. CONCLUSION: PET/CT imaging with novel (68)Ga-DOTA-Siglec-9 tracer was able to detect inflammatory tissue response induced by catheter implantation and staphylococcal infections. PMID- 25520904 TI - A methodology for stochastic analysis of share prices as Markov chains with finite states. AB - Price volatilities make stock investments risky, leaving investors in critical position when uncertain decision is made. To improve investor evaluation confidence on exchange markets, while not using time series methodology, we specify equity price change as a stochastic process assumed to possess Markov dependency with respective state transition probabilities matrices following the identified state pace (i.e. decrease, stable or increase). We established that identified states communicate, and that the chains are aperiodic and ergodic thus possessing limiting distributions. We developed a methodology for determining expected mean return time for stock price increases and also establish criteria for improving investment decision based on highest transition probabilities, lowest mean return time and highest limiting distributions. We further developed an R algorithm for running the methodology introduced. The established methodology is applied to selected equities from Ghana Stock Exchange weekly trading data. PMID- 25520905 TI - Factorials of real negative and imaginary numbers - A new perspective. AB - Presently, factorials of real negative numbers and imaginary numbers, except for zero and negative integers are interpolated using the Euler's gamma function. In the present paper, the concept of factorials has been generalised as applicable to real and imaginary numbers, and multifactorials. New functions based on Euler's factorial function have been proposed for the factorials of real negative and imaginary numbers. As per the present concept, the factorials of real negative numbers, are complex numbers. The factorials of real negative integers have their imaginary part equal to zero, thus are real numbers. Similarly, the factorials of imaginary numbers are complex numbers. The moduli of the complex factorials of real negative numbers, and imaginary numbers are equal to their respective real positive number factorials. Fractional factorials and multifactorials have been defined in a new perspective. The proposed concept has also been extended to Euler's gamma function for real negative numbers and imaginary numbers, and beta function. PMID- 25520906 TI - Strontium ranelate effect on bone mineral density is modified by previous bisphosphonate treatment. AB - The aim of this study was to evaluate the effect of strontium ranelate (SrR) on bone mineral density (BMD) and bone turnover markers after 1 year of treatment. Additionally, the effect of SrR in bisphosphonate-naive patients (BP-naive) compared to patients previously treated with bisphosphonates (BP-prior) was analyzed. This retrospective study included 482 postmenopausal women treated with SrR (2 g/day) for 1 year in ten Argentine centers; 41 patients were excluded due to insufficient data, while 441 were included. Participants were divided according to previous bisphosphonate treatment in two groups: BP-naive (n = 87) and BP-prior (n = 350). Data are expressed as mean +/- SEM. After 1 year of treatment with SrR the bone formation markers total alkaline phosphatase and osteocalcin were increased (p < 0.0001), while the bone resorption marker s-CTX was decreased (p = 0.0579). Also increases in BMD at the lumbar spine (LS, 3.73%), femoral neck (FN, 2.00%) and total hip (TH, 1.54%) [p < 0.0001] were observed. These increments were significant (p < 0.0001) both among BP-naive and BP-prior patients. Interestingly, the change in BMD after 1 year of SrR treatment was higher in BP-naive patients: LS: BP-naive = 4.58 +/- 0.62%; BP-prior = 3.45 +/- 0.28% (p = 0.078). FN: BP-naive = 2.79 +/- 0.56%; BP-prior = 2.13 +/- 0.29% (p = 0.161). TH: BP-naive = 3.01 +/- 0.55%; BP-prior = 1.22 +/- 0.27% (p = 0.0006). SrR treatment increased BMD and bone formation markers and decreased a bone resorption marker in the whole group, with better response in BP-naive patients. PMID- 25520907 TI - Novel uterine sarcoma preoperative diagnosis score predicts the need for surgery in patients presenting with a uterine mass. AB - Preoperative diagnosis of uterine sarcoma is very difficult, and currently, its diagnostic accuracy is not satisfactory. It is therefore important to perform surgery and establish the pathological diagnosis if the clinical findings and various examination findings indicate possible uterine sarcoma. We investigated the accuracy of the combination of various types of predictors of uterine sarcoma and the novel PREoperative Sarcoma Score (PRESS) for avoiding unnecessary surgery while diagnosing uterine sarcoma. We retrospectively analyzed the clinical findings, blood tests, imaging studies (ultrasonography and magnetic resonance imaging [MRI]), and endometrial cytology of 63 suspected uterine sarcoma cases that underwent surgery from 2006 to 2012. These cases were also scored retrospectively using PRESS. We analyzed the number of unnecessary surgeries that could be avoided using PRESS. Of 63 cases, 15 were diagnosed with uterine sarcoma (sarcoma group), and 48 had benign tumors (benign group). Univariate analysis indicated age, serum lactate dehydrogenase (LDH) values, and MRI and endometrial cytology findings as significant predictors of uterine sarcoma in both groups. In contrast, multivariable analysis identified only age, serum LDH value, and endometrial cytology findings as significant predictors. Accordingly, the latter were placed as 2 points, and the remaining MRI finding as 1 point. The accuracy rate of prediction was 84.1%, and the positive and negative predictive values were 63.2% and 93.2% respectively when the PRESS was interpreted as "positive" when it was 3 points or higher. Using multiple predictors for the preoperative diagnosis of uterine sarcoma, our proposed PRESS score is beneficial in the clinical setting while making treatment decisions in suspected uterine sarcoma cases as well as avoiding unnecessary surgery. PMID- 25520908 TI - Delayed abdominal wall abscess after abdomino-perineal resection simulating local recurrence of rectal cancer. AB - INTRODUCTION: We report a rare case of delayed abdominal wall abscess after abdominoperineal resection (APR) for rectal cancer. CASE DESCRIPTION: A 63-year old woman was diagnosed with rectal cancer and received chemo-radiotherapy, followed by APR. One year after surgery, the patient complained of pain and skin redness in the lower abdomen. A low-density mass lesion with 5.9-cm diameter was found in the lower abdominal wall by computed tomography, which showed high uptake on positron-emission tomography. These findings suggested the possibilities of either delayed abscess formation or abdominal wall recurrence of rectal cancer with central necrosis. Percutaneous drainage was performed. The content was a purulent exudate, without neoplastic cells in the cytology. The lesion quickly disappeared after the drainage, and no recurrence of the tumor was observed for more than 2 years. DISCUSSION AND EVALUATION: In this case, the un absorbable yarn, such as silk, has not been used during the operation, no foreign body was retained in the abdominal wall, and there was no associated inflammatory bowel disease. Use of neoadjuvant chemoradiotherapy was the only possible cause of delayed abscess formation in this case. CONCLUSION: In case local recurrence is suspected by imaging modalities in the postoperative of colorectal cancer, especially those with precedent chemoradiotherapy or radiotherapy, although rare, the possibility of a delayed abscess formation should also be considered. PMID- 25520909 TI - Unraveling the associations of osteoprotegerin gene with production traits in a paternal broiler line. AB - Improvements on growth and carcass traits in the poultry industry have been achieved by intense selection for heavier chickens at early ages. This faster growth has caused serious problems due to insufficient skeletal structure development needed to support the musculature of modern broilers. The osteoprotegerin gene (OPG), located on GGA2, is an important regulator of bone metabolism and reabsorption, being suggestive as a possible functional candidate gene associated with bone integrity in chickens. This study reports associations of a single nucleotide polymorphism (SNP) in the OPG gene with production traits in a parental broiler line. Different phenotypic groups were evaluated: performance, carcass and skeletal traits. SNPs were identified within the OPG gene and the most informative SNP g.9144C > G was chosen for association analyses. Chickens (n = 1230) were genotyped using PCR-RFLP. The association was carried out with QxPaK v4.0 software using a mixed model including sex, hatch and SNP as fixed effects, and the infinitesimal and residual as random effects. The OPG SNP was associated with important traits as body weight at 21 days, weights of tibia and drumstick skin, leg muscle yield, and tibia breaking strength (P < 0.05). Associations were explained by the additive effect of the SNP and the additive effect within sex. This SNP could be considered a potential marker to improve bone resistance in chickens; however, caution should be taken because of its negative effect in other important traits evaluated in this study. Furthermore, these findings suggest a possible involvement of the OPG gene in fat deposition in poultry. PMID- 25520910 TI - Compensatory growth responses to food restriction in the Chinese three-keeled pond turtle, Chinemys reevesii. AB - Juvenile Chinese three-keeled pond turtles (Chinemys reevesii) were subjected to one of four different feeding regimens: ad libitum (AL), restricted (R), ad libitum-restricted (AL-R), or restricted-ad libitum (R-AL) for 13 weeks, to assess the compensatory growth (CG) response to food restriction and subsequent re-alimentation. After switching to ad libitum feeding, the turtles in R-AL group ate more food and grew faster than those in other groups. At the end of the trial, R-AL turtles achieved the comparable body weight as AL turtles, indicating that a complete CG response occurred. Cumulative food consumption over the entire period did not differ between R-AL turtles and AL turtles. Experimental treatment affected carcass composition. Carcass lipid content of AL turtles was greater than that of R and AL-R turtles, with R-AL turtles in between. Carcass protein content of R-AL turtles was slightly greater than that of other groups without statistical differences. Stored lipids might be consumed firstly when animals underwent food restriction. Our results reconfirmed the CG of C. reevesii after food restriction. However, it is still difficult to achieve a reduction in the cost of farm-raised turtle production by adopting a restricted-satiation feeding protocol. PMID- 25520911 TI - Sensitivity of a harbor seal (Phoca vitulina) to coherent visual motion in random dot displays. AB - Motion vision is one of the fundamental properties of the visual system and is involved in numerous tasks. Previous work has shown that harbor seals are able to perceive visual motion. Tying in with this experimental finding, we assessed the sensitivity of harbor seals to visual motion using random dot displays. In these random dot displays, either all or a percentage of the dots plotted in the display area move into one direction which is referred to as percent coherence. Using random dot displays allows determining motion sensitivity free from form or position cues. Moreover, when reducing the lifetime of the dots, the experimental subjects need to rely on the global motion over the display area instead of on local motion events, such as the streaks of single dots. For marine mammals, the interpretation of global motion stimuli seems important in the context of locomotion, orientation and foraging. The first experiment required the seal to detect coherent motion directed upwards in one out of two stimulus displays and psychophysical motion coherence detection thresholds were obtained ranging from 5% to 35% coherence. At the beginning of the second experiment, which was conducted to reduce the differential flickering of the motion stimulus as secondary cue, the seal was directly able to transfer from coherent motion detection to a discrimination of coherent motion direction, leftward versus rightward. The seal performed well even when the duration of the local motion event was extremely short in the last experiment, in which noise was programmed as random position noise. Its coherence threshold was determined at 23% coherence in this experiment. This motion sensitivity compares well to the performance of most species tested so far excluding monkeys, humans and cats. To conclude, harbor seals possess an effective global motion processing system. For seals, the interpretation of global and coherent motion might e. g. play a role in the interpretation of optic flow information or when breaking the camouflage of cryptic prey items. PMID- 25520912 TI - Age and ultra-marathon performance - 50 to 1,000 km distances from 1969 - 2012. AB - We investigated age and performance in distance-limited ultra-marathons held from 50 km to 1,000 km. Age of peak running speed and running speed of the fastest competitors from 1969 to 2012 in 50 km, 100 km, 200 km and 1,000 km ultra marathons were analyzed using analysis of variance and multi-level regression analyses. The ages of the ten fastest women ever were 40 +/- 4 yrs (50 km), 34 +/ 7 yrs (100 km), 42 +/- 6 yrs (200 km), and 41 +/- 5 yrs (1,000 km). The ages were significantly different between 100 km and 200 km and between 100 km and 1,000 km. For men, the ages of the ten fastest ever were 34 +/- 6 yrs (50 km), 32 +/- 4 yrs (100 km), 44 +/- 4 yrs (200 km), and 47 +/- 9 yrs (1,000 km). The ages were significantly younger in 50 km compared to 100 km and 200 km and also significantly younger in 100 km compared to 200 km and 1,000 km. The age of the annual ten fastest women decreased in 50 km from 39 +/- 8 yrs (1988) to 32 +/- 4 yrs (2012) and in men from 35 +/- 5 yrs (1977) to 33 +/- 5 yrs (2012). In 100 km events, the age of peak running speed of the annual ten fastest women and men remained stable at 34.9 +/- 3.2 and 34.5 +/- 2.5 yrs, respectively. Peak running speed of top ten runners increased in 50 km and 100 km in women (10.6 +/- 1.0 to 15.3 +/- 0.7 km/h and 7.3 +/- 1.5 to 13.0 +/- 0.2 km/h, respectively) and men (14.3 +/- 1.2 to 17.5 +/- 0.6 km/h and 10.2 +/- 1.2 to 15.1 +/- 0.2 km/h, respectively). In 200 km and 1,000 km, running speed remained unchanged. In summary, the best male 1,000 km ultra-marathoners were ~15 yrs older than the best male 100 km ultra-marathoners and the best female 1,000 km ultra-marathoners were ~7 yrs older than the best female 100 km ultra-marathoners. The age of the fastest 50 km ultra-marathoners decreased across years whereas it remained unchanged in 100 km ultra-marathoners. These findings may help athletes and coaches to plan an ultra-marathoner's career. Future studies are needed on the mechanisms by which the fastest runners in the long ultra-marathons tend to be older than those in shorter ultra-marathons. PMID- 25520913 TI - Adverse drug reactions monitoring: prospects and impending challenges for pharmacovigilance. AB - Pharmacovigilance plays a consequential role in the surveillance of adverse drug reactions, which is provoked by the drugs used to cure diseases. Adverse drug reactions (ADRs) produce detrimental or undesirable effects to the body after administration of drugs. It has been reported that the number of patients dying because of contrary effects of drugs per year increased upto 2.6-fold. Moreover, rates of hospitalization of patients are increasing owing to adverse effects of drugs. Thus, it becomes challengeable for physician, health care providers, WHO and pharmaceutical industries to resolve the associated problem of ADRs. During the clinical trial of a novel drug, it is prominent to explore the dependability of drug. In this review, we documented the details required to identify the ADRs in patients along with reported banned drugs. PMID- 25520914 TI - EZH2: novel therapeutic target for human cancer. AB - Enhancer of Zeste homlog 2 (EZH2) is a catalytic subunit of epigenetic regulator Polycomb repressive complex 2 (PRC2), which trimethylates Lys 27 of histone H3, leading to silencing of the target genes that are involved in a variety of biological processes including tumor progression and stem cell maintenance. However, in addition to its canonical PRC2-dependent transcriptional repression function, EZH2 also acts as a gene activator in a noncanonical PRC2-independent manner. Overexpression of EZH2 has been detected in diverse cancers, and is associated with tumor malignancy. Moreover, activating mutations and inactivating mutations of EZH2 are also associated with certain types of cancer. Given EZH2's multi-faceted function and role in cancer, context-specific strategy for targeting EZH2/EZH2-mediated signaling could serve as future targeted therapy/personalized medicine for human cancer. PMID- 25520916 TI - Contribution of personalized Cyclin D1 genotype to triple negative breast cancer risk. AB - Aim: Cell cycle regulator cyclin D1 (CCND1) is a pivotal regulator for G1/S phase transition, playing a critical part in initiation of carcinogenesis. Triple negative breast cancer comprises a very heterogeneous group of cancer cells, but little is known about what is wrong in the genome of these patients. This study investigated contribution of CCND1 genotype to individual triple negative breast cancer susceptibility. Materials: In all, 2464 native Taiwan subjects consist of 1232 breast cancer cases and 1232 controls were enrolled in a hospital-based, case-control study. CCND1 A870G (rs9344) genotyping was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Risk stratified analyses correlated genotype and age-related characteristics of breast cancer subgroups. Results: No significant difference was found between patient and control groups in distribution of genotypic and allelic frequencies in CCND1 genotype, yet CCND1 A870G (rs9344) GG genotype was far less prevalent in breast cancer patients younger than 55 years (OR=0.62, 95%CI=0.43-0.89, P=0.0362), with first menarche earlier than 12.2 years (OR=0.61, 95% CI=0.42-0.87, P=0.0241), with menopause earlier than 49.0 years (OR=0.57, 95%CI=0.39-0.82, P=0.0093), or showing triple-negative breast cancer (OR=0.28, 95%CI=0.13-0.62, P=0.0006). Such valuable findings suggest CCND1 A870G (rs9344) as a predictive marker for triple negative breast cancer in Taiwanese women; the authors sincerely hope these help us fight the toughest subtype in clinical management. PMID- 25520915 TI - Evolving Personalized Therapy for Castration-Resistant Prostate Cancer. AB - With advances in molecular biologic and genomic technology, detailed molecular mechanisms for development of castration-resistant prostate cancer (CRPC) have surfaced. Metastatic prostate cancer (PCa) no longer represents an end stage, with many emerging therapeutic agents approved as effective in prolonging survival of patients from either pre- or post-docetaxel stage. Given tumor heterogeneity in patients, a one-size-fits-all theory for curative therapy remains questionable. With the support of evidence from continuing clinical trials, each treatment modality has gradually been found suitable for selective best-fit patients: e.g., new androgen synthesis inhibitor arbiraterone, androgen receptor signaling inhibitor enzalutamide, sipuleucel-T immunotherapy, new taxane carbazitaxel, calcium-mimetic radium-223 radiopharmaceutical agent. Moreover, several emerging immunomodulating agents and circulating tumor cell enumeration and analysis showed promise in animal or early phase clinical trials. While the era of personalized therapy for CRPC patients is still in infancy, optimal therapeutic agents and their sequencing loom not far in the future. PMID- 25520917 TI - Vascular Endothelial Growth Factor -460 C/T BstUI Gene Polymorphism is associated with Primary Open Angle Glaucoma. AB - BACKGROUND: Hypoxia and nitric oxide (NO) play important roles in the onset and progression of glaucoma. Vascular endothelial growth factor (VEGF) is one of the main factors responsive to hypoxia and NO. In this study, we investigated the association between the BstUI C/T VEGF gene polymorphism and primary open angle glaucoma (POAG). METHODS: 60 POAG patients and 78 healthy volunteers were enrolled in this study. The most frequently observed polymorphism in the VEGF gene is BstUI C/T, which was located 460 nucleotides upstream of the gene. The polymorphism was observed using polymerase chain reaction-based restriction analysis. RESULTS: Significant differences were observed in the distribution of the polymorphism between control subjects and POAG patients (p = 0.003). C/C homozygotes are absent in the control group; therefore, this genotype represents a suitable genetic maker for POAG. CONCLUSIONS: Hypoxia and NO may be involved in the pathway whereby the VEGF-460 polymorphism regulates POAG. Furthermore, homozygous C/C VEGF genotype is a useful maker for Chinese POAG. BACKGROUND: Hypoxia and nitric oxide (NO) play important roles in the onset and progression of glaucoma. Vascular endothelial growth factor (VEGF) is one of the main factors responsive to hypoxia and NO. In this study, we investigated the association between the BstUI C/T VEGF gene polymorphism and primary open angle glaucoma (POAG). METHODS: 60 POAG patients and 78 healthy volunteers were enrolled in this study. The most frequently observed polymorphism in the VEGF gene is BstUI C/T, which was located 460 nucleotides upstream of the gene. The polymorphism was observed using polymerase chain reaction-based restriction analysis. RESULTS: Significant differences were observed in the distribution of the polymorphism between control subjects and POAG patients (p = 0.003). C/C homozygotes are absent in the control group; therefore, this genotype represents a suitable genetic maker for POAG. CONCLUSIONS: Hypoxia and NO may be involved in the pathway whereby the VEGF-460 polymorphism regulates POAG. Furthermore, homozygous C/C VEGF genotype is a useful maker for Chinese POAG. PMID- 25520918 TI - Protective effects from Houttuynia cordata aqueous extract against acetaminophen induced liver injury. AB - BACKGROUND: Protective effects of Houttuynia cordata aqueous extract (HCAE) against acetaminophen-induced hepatotoxicity in Balb/cA mice were examined. METHODS: HCAE, at 1 or 2 g/L, was added into the drinking water for 4 weeks. Acute liver injury was induced by acetaminophen treatment intraperitoneally (350 mg/kg body weight). RESULTS: Acetaminophen treatment significantly depleted hepatic glutathione (GSH) content, increased hepatic malonyldialdehyde (MDA), reactive oxygen species (ROS) and oxidized glutathione (GSSG) levels, and decreased hepatic activity of glutathione peroxidase (GPX), catalase and superoxide dismutase (SOD) (p<0.05). The pre-intake of HCAE alleviated acetaminophen-induced oxidative stress by retaining GSH content, decreasing MDA, ROS and GSSG production, and maintaining activity of GPX, catalase and SOD in liver (p<0.05). The pre-intake of HCAE also significantly lowered acetaminophen induced increase in cytochrome P450 2E1 activity (p<0.05). Acetaminophen treatment increased hepatic release of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein-1 (p<0.05). HCAE intake significantly diminished acetaminophen-induced elevation of these cytokines (p<0.05). CONCLUSION: These results support that HCAE could provide hepato protection. PMID- 25520919 TI - Metabolic Abnormality and Sleep Disturbance are Associated with Clinical Severity of Patients with Schizophrenia. AB - Schizophrenic patients suffer from more metabolic or sleep problems. Little is known about risk factors. We recruited 17 patients with chronic schizophrenia from the rehabilitation center in a medical center in Taiwan and measured their demographic data, cognitive performance, and physical fitness, metabolic profiles and sleep parameters. They were divided into two groups according to clinical severity, then compared in terms of metabolic and sleep parameters. Those with more severe symptomatology had more metabolic abnormality and shorter slow wave sleep (SWS). Our findings suggest clinical symptoms as linked with heavier body weight, wider neck circumference, elevated blood pressure, and shorter SWS. Further studies are warranted to confirm the preliminary finding and to elucidate the underlying mechanism. PMID- 25520920 TI - Case report of Chromosome 3q25 deletion syndrome or Mucopolysaccharidosis IIIB. AB - Interstitial deletions of the long arm of chromosome 3 have, to our knowledge, been reported in only eleven patients; detailed genotype- phenotype correlations are not well established. Here we describe a case with interstitial deletion involving 3q25.33 region. Dysmorphic features and developmental delay lead to clinical genetic and enzyme assessment. Low alpha-hexosaminidase level is also noted, which imply Mucopolysaccharidosis(MPS) IIIB. PMID- 25520921 TI - Personalized medicine in Type 2 Diabetes. AB - Type 2 diabetes (T2D) is a global public health concern, its prevalence in Asia, especially Taiwan, rising every year. The risk of developing T2D and diabetes complications is not only controlled by environmental but also by genetic factors. Genetic association studies have shown polymorphisms at specific loci may help identify individuals at greatest risk and response to oral antidiabetic drugs. This review probes effect of genetic profiling on T2D and its complications, using our study population as examples. Also, pharmacogenetics and pharmacogenomics of oral anitdiabetic drug will be explored. PMID- 25520922 TI - Genetic susceptibility to idiopathic membranous nephropathy in high-prevalence Area, Taiwan. AB - Idiopathic membranous nephropathy (MN) is one common cause of idiopathic nephrotic syndrome in adults; 25% of MN patients proceed to end-stage renal disease. In adults, membranous nephropathy is a lead cause of nephrotic syndrome, with about 75% of the cases idiopathic. Secondary causes include autoimmune disease, infection, drugs and malignancy. Three hypotheses about pathogenesis have surfaced: preformed immune complex, in situ immune complex formation, and auto-antibody against podocyte membrane antigen. Pathogenesis does involve immune complex formation with later deposition in sub-epithelial sites, but definite mechanism is still unknown. Several genes were recently proven associated with primary membranous nephropathy in Taiwan: IL-6, NPHS1, TLR-4, TLR-9, STAT4, and MYH9 . These may provide a useful tool for diagnosis and prognosis. This article reviews epidemiology and lends new information on KIRREL2 (rs443186 and rs447707) polymorphisms as underlying causes of MN; polymorphisms revealed by this study warrant further investigation. PMID- 25520923 TI - Coronary artery aneurysms occurrence risk analysis between Kawasaki disease and LRP1B gene in Taiwanese children. AB - Background: Kawasaki disease (KD) is an acute and systemic vasculitis. Its complications in coronary artery aneurysms (CAA) make KD one of the leading causes of acquired cardiovascular diseases in childhood. Low density lipoprotein receptor-related protein 1B (LRP1B) is abundantly expressed in the medial layer of coronary arteries and involved in endothelium inflammations. Purpose: We aimed to identify the role of LRP1B in CAA formation during KD progression. Methods: we investigated genetic variations in LRP1B in a Taiwanese cohort of 258 KD patients (83 with CAA and 175 without CAA complications). We used univariate and multivariate regression analyses to identify the associations between LRP1B genetic variations and KD patients. Results: CAA formation in KD was significantly associated with the LRP1B (rs6707826) genetic variant (p = 0.007). By using multivariate regression analysis, significant correlations were observed between KD with CAA complications and the presence of the TT+TG genotypes for the LRP1B rs6707826 single-nucleotide polymorphism (full model: odds ratio = 2.82; 95% CI = 1.33-5.78). Conclusion: Our results suggest that genetic polymorphism of LRP1B gene may be used as a genetic marker for the diagnosis and prognosis of the CAA formation in KD and contribute to genetic profiling studies for personalized medicine. PMID- 25520924 TI - Mutant EXT1 in Taiwanese Patients with Multiple Hereditary Exostoses. AB - BACKGROUND: Multiple hereditary exostoses (MHE) is characterized by multiple benign projections of bone capped by cartilage, most numerous in metaphyses of long bones. HME are usually inherited in autosomal dominant mode, chief genes EXT1 and EXT2. METHODS: Two MHE patients were identified from clinic and enrolled in genetic study, complete coding regions of EXT1 and EXT2, including intron/exon boundaries, sequenced via DNA samples drawn from participants. RESULTS: DNA sequencing revealed mutant EXT1 gene in both cases, within which frame-shift mutation c.447delC (p.Ser149fsX156) in exon1 and nonsense mutation c.2034T>G (p.Tyr678X) in exon10, emerged. Neither mutation was detected in control group. CONCLUSIONS: Our results extended the spectrum of EXT1 mutations, revealing similar incidence of EXT1 and EXT2 in Taiwanese MHE patients. PMID- 25520925 TI - Auricularia polytricha aqueous extract supplementation decreases hepatic lipid accumulation and improves antioxidative status in animal model of nonalcoholic fatty liver. AB - Background: Amelioration effect of Auricularia polytricha water extract (AP) on hepatic injury in an animal model of NAFLD was investigated. Methods: Forty six week-old Wistar rats were housed and thirty-two fed ten percent lard high-fat diet to induce NAFLD. After eight weeks of induction, animals were divided into five groups of eight rats each: normal control, high-fat diet, RN (reversion to a normal diet), 1* AP (normal diet plus 0.75% AP, w/w), and 2*AP (normal diet plus 1.5% AP). Animals were sacrificed four weeks later. Results: Rats receiving either 0.75% or 1.5% AP exhibited effective interruption of NAFLD progression, as evidenced by decreased lipid accumulation and elevated antioxidative status. Histological examination proved AP anti-inflammatory function and lower level of related markers for tumor necrosis factor-alpha and interleukin-6. Besides abundant polysaccharides against lipid accumulation, AP had a specific high level of phenolic compounds and tannins thus may be a potent anti-inflammatory and antioxidative agent. Conclusion: Findings suggest that under normal diet recovery, AP supplement may represent novel, protective material against NAFLD by attenuating inflammatory response, oxidative stress and lipid deposition. PMID- 25520926 TI - Needling therapy for myofascial pain: recommended technique with multiple rapid needle insertion. AB - Myofascial trigger point (MTrP) is a major cause of muscle pain, characterized with a hyperirritable spot due to accumulation of sensitized nociceptors in skeletal muscle fibers. Many needling therapy techniques for MTrP inactivation exist. Based on prior human and animal studies, multiple insertions can almost completely eliminate the MTrP pain forthwith. It is an attempt to stimulate many sensitive loci (nociceptors) in the MTrP region to induce sharp pain, referred pain or local twitch response. Suggested mechanisms of needling analgesia include effects related to immune, hormonal or nervous system. Compared to slow-acting biochemical effects involving immune or hormonal system, neurological effects can act faster to provide immediate and complete pain relief. Most likely mechanism of multiple needle insertion therapy for MTrP inactivation is to encounter sensitive nociceptors with the high-pressure stimulation of a sharp needle tip to activate a descending pain inhibitory system. This technique is strongly recommended for myofasical pain therapy in order to resume patient's normal life rapidly, thus saving medical and social resources. PMID- 25520927 TI - Cross-species identification of in silico microsatellite biomarkers for genetic disease. AB - Microsatellites appear widely in genomes of diverse species. Variants of repeat number of microsatellites often correlate with risks of genetic disorder or severity of diseases. Using cross-species comparison, the proposed system comprehensively verifies microsatellites of specific genes related to 16 genetic disorders. Genomic information retrieved from 14 frequently used model organisms in biomedical study was thoroughly analyzed, emphasizing conserved and diverse traits. Features of microsatellite sequences among different organisms, including appearing frequency, position, pattern and distribution, could be determined automatically for stating genetically functional conservation and evolutionary correlation. This research found that among mammals and fishes, the microsatellite sequences are conserved in the genes of epidermal growth factor receptor, ataxia telangiectasia mutated and androgen receptor corresponding to cancers, ataxia telangiectasia and hepatocellular carcinoma, respectively. Still, except fruit fly conserved CAG repeats in Huntington and Spinocerebellar ataxia type 2 genes, no microsatellites were conserved in those genes linked to neurological/neurodegenerative disorders among mammal and fish species. In comparison of mammalian species, microsatellite biomarkers identified from 17 genetic disorder-related genes revealed high repeat conservation, especially in human, gorilla and macaque. Obviously, this comparative analysis illustrates microsatellite repeats affecting genetic disorders, highly correlated to evolutionary distance of species. Chief contribution of this in silico research lies in assisting biologists to identify disease-related microsatellite biomarkers and employ appropriate model organisms for further biomedical studies relying on microsatellite conservation information. Database http://ssrtc.cs.ntou.edu.tw is for academic use. PMID- 25520928 TI - Successful control with carbamazepine of family with paroxysmal kinesigenic dyskinesia of PRRT2 mutation. AB - Paroxysmal kinesigenic dyskinesia (PKD), a rare paroxysmal movement disorder often misdiagnosed as epilepsy, is characterized by recurrent, brief dyskinesia attacks triggered by sudden voluntary movement. Pathophysiological mechanism of PKD remains not well understood. Ion channelopathy has been suggested, since the disease responds well to ion channel blockers. Mutations in proline-rich transmembrane protein 2 (PRRT2) were recently identified in patients with familial PKD. To extend these genetic reports, we studied a family with clinical manifestations of familial PKD responding well to low dose carbamazepine. Therapeutic dose ranged from 1.5 to 2.0 mg/ kg/day, below that in seizure control. One insertion mutation c.649_650insC (p.P217fsX7) was identified in three patients of the family. This study avers PRRT2's high sensitivity for PKD phenotype. Identification of genes underlying pathogenesis will enhance diagnosis and treatment. Function of PRRT2 and its role in PKD warrant further investigation. PMID- 25520929 TI - Tissue distribution of naringenin conjugated metabolites following repeated dosing of naringin to rats. AB - Background: Naringin is a major antioxidant in Citrus fruits and herbs. To clarify molecular forms distributed to various tissues, we investigated tissue distribution of naringin and relevant metabolites in rats after repeated dosing. Methods: Male Sprague-Dawley rats were orally administered naringin (210 mg/kg) twice daily for eight days. At 6 h post the 17th dose, various tissues including liver, kidney, heart, spleen and brain were collected and analyzed by HPLC method before and after hydrolysis with beta-glucuronidase and sulfatase, individually. Results: The free forms of naringin and naringenin were not detected in all the tissues assayed. Liver contained the highest concentration of naringenin sulfates, followed by spleen, heart, brain and kidney. Naringenin glucuronides were present in liver and kidney, but not in spleen, brain and heart. Conclusion: The bioavailability of naringenin glucuronides and sulfates supported its application for personalized medicine. PMID- 25520930 TI - Effect of wild bitter gourd treatment on inflammatory responses in BALB/c mice with sepsis. AB - Background/Introduction: Wild bitter gourd (Momordica charantia L. var. abbreviate Seringe) common vegetable in Asia, is used in traditional medicine to treat various diseases, including inflammation. Extant literature indicates that wild bitter gourds have components that activate PPARalpha and PPARgamma. This research probed influence of adding wild bitter gourd to diets on inflammation responses in mice with sepsis. Purpose: This study evaluated influence of eating wild bitter gourd on inflammation responses in mice with sepsis. Methods: We injected intraperitoneal LPS to induce sepsis. Male BALB/c mice were divided normal, sepsis, positive control, and three experimental groups. The latter ate diets with low (1%), moderate (2%), and high (10%) ratios of wild bitter gourd lyophilized powder. Before mice were sacrificed, with the exception of the normal group, intraperitoneal injection of LPS induced sepsis in each group; positive control group was injected with LPS after PDTC. Results: This experiment revealed weights in groups with added wild bitter gourd starkly lower than those of the remaining groups. Blood lipids (TG, cholesterol, and NEFA) were also lower in comparison to the sepsis group, and blood glucose concentrations recovered and approached normal levels. Blood biochemistry values related to inflammation reactions indicated GOT, GPT, C-RP, and NO concentrations of groups with wild bitter gourd added all lower than that of the sepsis group. Secretion levels of the spleen pro-inflammatory cytokines IL-1, IL-6, and TNF-alpha tallied significantly lower in comparison to the sepsis group, whereas secretion levels of IL-10 anti-inflammatory cytokine increased. Expression level of proteins NF kappaB, iNOS, and COX-2 were inhibited significantly. Conclusion: Wild bitter gourd in diets promoted lipid metabolism, improved low blood glucose in sepsis, and attenuated inflammatory stress. These findings suggested that this plant food might provide medical benefits for certain persons. PMID- 25520931 TI - Renal protective effects of Porphyra dentate aqueous extract in diabetic mice. AB - Background: Purple laver ((Porphyra dentate) is a popular edible seaweed in Asia. This study examined protective effects of extract from purple laver extract (PLE) in diabetic mice. Methods: Content of carotenoids and anthocyanins in PLE was analyzed. PLE at 0.5 and 1% was supplied for 7 weeks. Results: PLE was rich in anthocyanins. PLE intake at 0.5 and 1% lowered plasma glucose level (P<0.05); only at 1% raised plasma insulin level, and decreased plasma triglyceride and total cholesterol levels (P<0.05). PLE treatments at 1% lowered hepatic triglyceride and total cholesterol (P<0.05); it reduced renal reactive oxygen species level (P<0.05); retained renal glutathione level, maintaining renal glutathione peroxidase and catalase activities (P<0.05). Conclusion: Porphyra dentate aqueous extract could attenuate diabetic progression via anti-oxidative and lipid lowering effects. This seaweed could be considered as potent healthy food, and used for personalized medicine. PMID- 25520932 TI - Anti-glycative effects of asiatic acid in human keratinocyte cells. AB - Background: Human skin keratinocyte (HaCaT) cells served to examine effects of asiatic acid (AA) at 1, 2, 4 and 8 MUM against advanced glycative endproduct (AGE)-modified bovine serum albumin (BSA) induced glycative stress. Results: AGE BSA treatment reduced cell viability; and increased reactive oxygen species, nitric oxide, protein carbonyl, interleukin (IL)-1beta and tumor necrosis factor alpha levels in HaCaT cells. Yet AA pretreatments decreased these oxidative and inflammatory factors, dose-dependently lowering nitric oxide synthase activity and expression. AGE-BSA raised activity and expression of caspase-3 and caspase 8. AA pretreatments at 2-8 MUM decreased activity and expression of these two caspases. AGE-BSA declined collagen I expression, but enhanced matrix metalloproteinase (MMP)-1, MMP-8 and MMP-9 protein expression. AA pretreatments at 2-8 MUM maintained collagen I expression, and reduced three MMPs expression. AGE-BSA also up-regulated RAGE (receptor of AGE), p-p38 and p-JNK expression. AA pretreatments at 2-8 MUM suppressed RAGE expression, and at 1-8 MUM down regulated p-p38 and p-JNK expression. Conclusion: Asiatic acid, via its anti glycative activity, could protect skin. Thus, this compound could be developed as an external agent and applied for personalized medicine. PMID- 25520933 TI - Polymorphism of gene cassette promoter variants of class 1 integron harbored in S. Choleraesuis and Typhimurium isolated from Taiwan. AB - Integrons, mobile genetic units, capture and incorporate antibiotic resistance gene cassette by site-specific recombination. Class 1 integrons are widespread and associated with dispersion of antibiotic resistance among Gram-negative bacteria. The expression of gene cassette in Class 1 can vary, based on the Pc promoter but seldom from another promoter hiding downstream of Pc, called P2. To probe distribution and prevalence of gene cassette promoter variants, we analyzed 169 S. Choleraesuis and 191 S. Typhimurium isolates from humans and animals, finding 95.27% occurrence of integrin among S. Choleraesuis, 83.25% among S. Typhimurium. PCR-RFLP analysis identified four promoters (PcS+P2, PcWTGN-10+P2, PcH1+P2, and PcWTGN-10+P2-GGG) in said integron-positive isolates; major types in S. Choleraesuis and S. Typhimurium were PcS+P2 and PcWTGN-10+P2, respectively. Likewise, beta-galactosidase assay rated promoter strength of variants by transcriptional fusion constructs to show extended -10 promoter (TGn/-10 promoter) in Pc and three-nucleotide insertion (GGG) between -35 and -10 region of P2 improving promoter strength of gene cassette. PMID- 25520934 TI - Medical students' awareness and perception of national health examinations. AB - Key ingredients for upgrading health care include bolstering and appraising professional medical education. Health examination as a crucial element of health care that we must incorporate into medical education. This research evaluates medical students' awareness of national health examinations. Two surveys, focused on health examination knowledge and perspective, were conducted for first- to fourthyear medical students, results analyzed by descriptive statistics, t-test and ANOVA. Research subjects scored maximum 11 (of possible 15): i.e., 76.2% accuracy for health examination knowledge questions and held positive views on seven (58%) perspective-related questions. Self-directed learning courses do provide a positive effect on students' learning. Respondents' varying backgrounds had insignificant impact on overall results, but in-depth analysis for each individual question does reveal differences among several backgrounds. Medical students' overall awareness level for health examination is above average in comparison to the general public. This research result can provide a basis to improve the related professional programs, courses and teachings or used as a reference for modifications on future classes. The above observations were discussed based on the medical education system in Taiwan. PMID- 25520935 TI - Retinoic acid and cancer treatment. AB - Retinoic acid which belongs to the retinoid class of chemical compounds is an important metabolite of vitamin A in diets. It is currently understood that retinoic acid plays important roles in cell development and differentiation as well as cancer treatment. Lung, prostate, breast, ovarian, bladder, oral, and skin cancers have been demonstrated to be suppressed by retinoic acid. Our results also show that low doses and high doses of retinoic acid may respectively cause cell cycle arrest and apoptosis of cancer cells. Also, the common cell cycle inhibiting protein, p27, and the new cell cycle regulator, Cdk5, are involved in retinoic acid's effects. These results provide new evidence indicating that the molecular mechanisms of/in retinoic acid may control cancer cells' fates. Since high doses of retinoic acid may lead to cytotoxicity, it is probably best utilized as a potential supplement in one's daily diet to prevent or suppress cancer progression. In this review, we have collected numerous references demonstrating the findings of retinoic acid in melanoma, hepatoma, lung cancer, breast cancer, and prostate cancer. We hope these observations will shed light on the future investigation of retinoic acid in cancer prevention and therapy. PMID- 25520937 TI - New mechanisms of antiplatelet activity of nifedipine, an L-type calcium channel blocker. AB - Platelet hyperactivity often occursd in hypertensive patients and is a key factor in the development of cardiovascular diseases including thrombosis and atherosclerosis. Nifedipine, an L-type calcium channel blocker, is widely used for hypertension and coronary heart disease therapy. In addition, nifedipine is known to exhibit an antiplatelet activity, but the underlying mechanisms involved remain unclear. Several transcription factors such as peroxisome proliferator activated receptors (PPARs) and nuclear factor kappa B (NF-kappaB) exist in platelets and have an ability to regulate platelet aggregation through a non genomic mechanism. The present article focuses on describing the mechanisms of the antiplatelet activity of nifedipine via PPAR activation. It has been demonstrated that nifedipine treatment increases the activity and intracellular amount of PPAR-beta/-gamma in activated platelets. Moreover, the antiplatelet activity of nifedipine is mediated by PPAR-beta/-gamma-dependent upon the up regulation of the PI3K/AKT/NO/cyclic GMP/PKG pathway, and inhibition of protein kinase Calpha (PKCalpha) activity via an interaction between PPAR-beta/-gamma and PKCalpha. Furthermore, suppressing NF-kappaB activation by nifedipine through enhanced association of PPAR-beta/-gamma with NF-kappaB has also been observed in collagen-stimulated platelets. Blocking PPAR-beta/-gamma activity or increasing NF-kappaB activation greatly reverses the antiplatelet activity and inhibition of intracellular Ca2+ mobilization, PKCalpha activity, and surface glycoprotein IIb/IIIa expression caused by nifedipine. Thus, PPAR-beta/-gamma- dependent suppression of NF-kappaB activation also contributes to the antiplatelet activity of nifedipine. Consistently, administration of nifedipine markedly reduces fluorescein sodium-induced vessel thrombus formation in mice, which is considerably inhibited when the PPAR-beta/-gamma antagonists are administrated simultaneously. Collectively, these results provide important information regarding the mechanism by which nifedipine inhibits platelet aggregation and thrombus formation through activation of PPAR-beta/-gamma- mediated signaling pathways. These findings highlight that PPARs are novel therapeutic targets for preventing and treating platelet-hyperactivity-related vascular diseases. PMID- 25520936 TI - Molecular targets for anti-oxidative protection of green tea polyphenols against myocardial ischemic injury. AB - Ischemic heart disease is the leading cause of death worldwide. An improved understanding of the mechanisms involved in myocardial injury would allow intervention downstream in the pathway where certain drugs including natural products could be efficiently applied to target the end effectors of the cell death pathway. Green tea polyphenols (GTPs) have potent anti-oxidative capabilities, which may account for their beneficial effects in preventing oxidative stress associated with ischemia injury. Although studies have provided convincing evidence to support the protective effects of GTPs in cardiovascular system, the potential end effectors that mediate cardiac protection are only beginning to be addressed. Proteomics analyses widely used to identify the protein targets for many cardiovascular diseases have advanced the discovery of the signaling mechanism for GTPs-mediated cardio-protection. This review focuses on putative triggers, mediators, and end effectors for the GTPs-mediated cardio protection signaling pathways engaged in myocardial ischemia crisis, allowing a promising natural product to be used for ameliorating oxidative stress associated with ischemic heart diseases. PMID- 25520939 TI - Lyophilized particles and ethanolic extracts of Antrodia cinnamomea mycelia suppress the tumorigenicity of head and neck cancer cells in vivo. AB - Head and neck cancer (HNC) is one of the most common forms of cancer in Taiwan. In addition, head and neck cancer cells (HNCs) are highly tumorigenic and resistant to conventional therapy. Therefore, development of new therapeutic regimens that are adjuvant to conventional treatments would benefit future head and neck cancer therapy. In this study, we found that the lyophilized particles and ethanolic extracts of Antrodia cinnamomea mycelia inhibited the tumor growth of HNCs by xenograft assay in vivo. Moreover, administration of lyophilized particles or ethanolic extracts to nude mice did not cause significant side effects. Our study revealed that the Antrodia cinnamomea mycelia extract (ACME) efficiently inhibited the tumorigenicity of HNCs without causing organ failure. Furthermore, it showed that ACME may work as a novel drug candidate for alternative treatments for head and neck cancer. PMID- 25520940 TI - Ectodermal dysplasia (ED) syndrome. AB - Ectodermal dysplasia (ED) syndrome comprises a large, heterogeneous group of inherited disorders that are defined by primary defects in the development of 2 or more tissues derived from the embryonic ectoderm. The tissues primarily involved are the skin and its appendages (including hair follicles, eccrine glands, sebaceous glands, nails) and teeth. The clinical features include sparse hair, abnormal or missing teeth, and an inability to sweat due to lack of sweat glands. One such case report of ectodermal dysplasia is presented here. PMID- 25520938 TI - Mass spectrometry-based proteomics in Chest Medicine, Gerontology, and Nephrology: subgroups omics for personalized medicine. AB - Mass spectrometry (MS) is currently the most promising tool for studying proteomics to investigate largescale proteins in a specific proteome. Emerging MS based proteomics is widely applied to decipher complex proteome for discovering potential biomarkers. Given its growing usage in clinical medicine for biomarker discovery to predict, diagnose and confer prognosis, MS-based proteomics can benefit study of personalized medicine. In this review we introduce some fundamental MS theory and MS-based quantitative proteomic approaches as well as several representative clinical MS-based proteomics issues in Chest Medicine, Gerontology, and Nephrology. PMID- 25520941 TI - New developments in treatment planning and verification of particle beam therapy. AB - Charged particle beam therapy has been used for almost 60 years. During the initial 40 years, the medical use of protons and heavy ions was explored at accelerator laboratories in a limited number of patients and for a limited number of cancerous and non-cancerous disease conditions. After the development of computed tomography and 3D treatment planning, it was time to move charged particle therapy into the clinical realm. This happened in October 1991 when an ocular melanoma patient became the first patient to be treated at Loma Linda University Medical Center in California. Due to the increased awareness of the advantages of charged particle therapy and promising results of single institution experiences, one currently observes a phase of rapid expansion of proton treatment centers throughout the world. A few of these centers are combined proton/carbon ion facilities. It is very important that the technological evolution of charged particle therapy will continue during this phase of clinical expansion to ensure that the increasing number of patients exposed to therapeutic charged particles will benefit most from the advantageous dose distributions that these particles afford. This report will give an overview of translational research activities related to planning and verification of proton therapy in which the authors have been involved for a number of years. While our activities focus on protons, these developments are to a large degree also applicable to carbon ion therapy. PMID- 25520942 TI - Optimization of heart block in the left-sided whole breast radiation treatments. AB - PURPOSE: Blocks have been used to protect heart from potential radiation damage in left-sided breast treatments. Since cardiac motion pattern may not be fully captured on conventional 3DCT or 4DCT simulation scans, this study was intended to investigate the optimization of the heart block design taking the cardiac motion into consideration. MATERIALS AND METHODS: Whole breast treatment plans using two opposed tangential fields were designed based on 4DCT simulation images for 10 left-sided breast cancer patients. Using an OBI system equipped to a Varian Linac, beam-eye viewed fluoroscopy images were acquired for each of the treatment beams after patient treatment setup, and the MLC heart blocks were overlaid onto the fluoroscopy images with an in-house software package. A non rigid image registration and tracking algorithm was utilized to track the cardiac motion on the fluoroscopy images with minimal manual delineation for initialization, and the tracked cardiac motion information was used to optimize the heart block design to minimize the radiation damage to heart while avoiding the over-shielding that may lead to underdosing certain breast tissues. RESULTS: Twenty-three sets of fluoroscopy images were acquired on 23 different days of treatment for the 10 patients. As expected, heart moved under the influences of both respiratory and cardiac motion. It was observed that for 16 out of the 23 treatments, heart moved beyond the planed heart block into treatment fields and MLC had to be adjusted to fully block heart. The adjustment was made for all but one patient. The number of the adjusted MLC leaves ranged from 1 to 16 (mean = 10), and the MLC leaf position adjustment ranged from 2 to 10 mm (mean = 6 mm). The added heart block areas ranged from 3 to 1230 mm(2) (mean = 331 mm(2)). CONCLUSION: In left-sided whole breast radiation treatments, simulation CT (and 4DCT) based heart block design may not provide adequate heart protection for all the treatments. A fluoroscopy-based method has been developed to adaptively optimize the heart MLC block to achieve optimal heart protection. PMID- 25520945 TI - Regulatory science needs for neonates: a call for neonatal community collaboration and innovation. PMID- 25520944 TI - Elevated positive end-expiratory pressure decreases cardiac index in a rhesus monkey model. AB - RATIONALE: Clinicians are often concerned that higher positive end-expiratory pressure (PEEP) will decrease cardiac index (CI). PEEP affects CI through multiple inter-related mechanisms. The adult Rhesus monkey is an excellent model to study cardiopulmonary interaction due to similar pulmonary and chest wall compliances to human infants. OBJECTIVE: Our goal was to examine the impact of increasing PEEP on CI in Rhesus monkeys as a model for critically ill children. METHODS: Prospective, experimental animal study. Nine healthy anesthetized, intubated Rhesus monkeys were allowed to breathe spontaneously at a PEEP of 0, 5, 10, and 15 cm H2O while CI was measured with an ultrasonic Doppler (USCOM). MEASUREMENTS AND MAIN RESULTS: Cardiac index decreased between PEEP levels of 5 and 15 cm H2O. The mean decrease in CI for the entire cohort of monkeys was 18% (p < 0.01) with a range of -11 to 49%. Stroke volume and oxygen delivery also decreased between PEEP levels of 5 and 15 cm H2O (p < 0.01). CONCLUSION: Between PEEP levels of 5 and 15 cm H2O, there was a decrease in CI, stroke volume, and oxygen delivery in intubated Rhesus monkeys. A plausible mechanism is that over distention of normally compliant lungs at increased PEEP resulted in decreased preload to the right ventricle, outweighing the potentially beneficial decrease in left ventricular afterload or pulmonary vascular resistance. Further investigation is warranted, particularly in children with lung injury, who have historically benefited from increased PEEP levels without over-distention. PMID- 25520943 TI - AZD5363 Inhibits Inflammatory Synergy between Interleukin-17 and Insulin/Insulin Like Growth Factor 1. AB - In the United States, one-third of population is affected by obesity and almost 29 million people are suffering from type 2 diabetes. Obese people have elevated serum levels of insulin, insulin-like growth factor 1 (IGF1), and interleukin-17 (IL-17). Insulin and IGF1 are known to enhance IL-17-induced expression of inflammatory cytokines and chemokines, which may contribute to the chronic inflammatory status observed in obese people. We have previously demonstrated that insulin/IGF1 signaling pathway crosstalks with IL-17-activated nuclear factor-kappaB pathway through inhibiting glycogen synthase kinase 3beta (GSK3beta) activity. However, it is unclear whether GSK3alpha also plays a role and whether this crosstalk can be manipulated by AZD5363, a novel pan-Akt inhibitor that has been shown to increase glycogen synthase kinase 3 activity through reducing phosphorylation of GSK3alpha and GSK3beta. In this study, we investigated IL-17-induced expression of C-X-C motif ligand 1 (Cxcl1), C-C motif ligand 20 (Ccl20), and interleukin-6 (Il-6) in wild-type, GSK3alpha(-/-), and GSK3beta(-/-) mouse embryonic fibroblast cells as well as in mouse prostate tissues by real-time quantitative PCR. We examined the proteins involved in the signaling pathways by Western blot analysis. We found that insulin and IGF1 enhanced IL-17-induced expression of Cxcl1, Ccl20, and Il-6, which was associated with increased phosphorylation of GSK3alpha and GSK3beta in the presence of insulin and IGF1. AZD5363 inhibited the synergy between IL-17 and insulin/IGF1 through reducing phosphorylation of GSK3alpha and GSK3beta by inhibiting Akt function. These findings imply that the cooperative crosstalk of IL-17 and insulin/IGF1 in initiating inflammatory responses may be alleviated by AZD5363. PMID- 25520946 TI - Legal requirements for human-health based appeals of wind energy projects in ontario. AB - In 2009, the government of the province of Ontario, Canada passed new legislation to promote the development of renewable energy facilities, including wind energy facilities in the province. Throughout the legislative process, concerns were raised with respect to the effect of wind energy facilities on human health. Ultimately, the government established setbacks and sound level limits for wind energy facilities and provided Ontario residents with the right to appeal the approval of a wind energy facility on the ground that engaging in the facility in accordance with its approval will cause serious harm to human health. The first approval of a wind facility under the new legislation was issued in 2010 and since then, Ontario's Environmental Review Tribunal as well as Ontario's courts has been considering evidence proffered by appellants seeking revocation of approvals on the basis of serious harm to human health. To date, the evidence has been insufficient to support the revocation of a wind facility approval. This article reviews the legal basis for the dismissal of human-health based appeals. PMID- 25520948 TI - Developing seventh grade students' systems thinking skills in the context of the human circulatory system. AB - Developing systems thinking skills in school can provide useful tools to deal with a vast amount of medical and health information that may help learners in decision making in their future lives as citizen. Thus, there is a need to develop effective tools that will allow learners to analyze biological systems and organize their knowledge. Here, we examine junior high school students' systems thinking skills in the context of the human circulatory system. A model was formulated for developing teaching and learning materials and for characterizing students' systems thinking skills. Specifically, we asked whether seventh grade students, who studied about the human circulatory system, acquired systems thinking skills, and what are the characteristics of those skills? Concept maps were used to characterize students' systems thinking components and examine possible changes in the students' knowledge structure. These maps were composed by the students before and following the learning process. The study findings indicate a significant improvement in the students' ability to recognize the system components and the processes that occur within the system, as well as the relationships between different levels of organization of the system, following the learning process. Thus, following learning students were able to organize the systems' components and its processes within a framework of relationships, namely the students' systems thinking skills were improved in the course of learning using the teaching and learning materials. PMID- 25520949 TI - Ebola viral disease outbreak-2014: implications and pitfalls. PMID- 25520950 TI - Chagas' disease: an emergent urban zoonosis. The caracas valley (Venezuela) as an epidemiological model. AB - The unprecedented emergence of important public health and veterinary zoonoses is usually a result of exponential population growth and globalization of human activities. I characterized Chagas' disease as an emergent zoonosis in the Caracas Valley (Venezuela) due to the following findings: the presence of reservoirs (Didelphis marsupialis, Rattus rattus) and vectors (Panstrongylus geniculatus, Panstrongylus rufotuberculatus) infected with Trypanosoma cruzi in urbanized or marginalized areas; the elevated contact between P. geniculatus and human beings detected by parasitological and molecular examinations of triatomine feces demonstrated the possibility of transmission risks; a study of outbreaks of urban Chagas' disease reported the first proven case of oral transmission of T. cruzi to human beings; the risk of transmission of glandular metacyclic stages from marsupials by experimental ocular and oral instillation; mice genitalia infected with T. cruzi contaminated blood resulted in the formation of amastigotes very close to the lumen suggesting that there may be a possibility of infection via their release into the urine and thence to the exterior; the ubiquitous histotropism and histopathology of T. cruzi was demonstrated using a mouse model; the presence of experimental T. cruzi pseudocysts in adipose, bone cartilage, and eye tissue indicated a potential risk for transplants. Socio sanitary programs that include improvements in housing, vector control, and access to medical treatment, as well as strategies aimed at combating social inequalities, poverty, and underdevelopment should be undertaken in those areas where zoonoses are most prevalent. Disciplines, such as Ecology, Epidemiology, Medical Entomology, Human and Veterinary Medicine, Environmental Studies, Public Health, Social and Political Studies, Immunology, Microbiology, and Pharmacology could all provide important contributions that aim to reduce the occurrence of factors governing the spread of emergent diseases. PMID- 25520951 TI - Emerging Vector-Borne Diseases - Incidence through Vectors. AB - Vector-borne diseases use to be a major public health concern only in tropical and subtropical areas, but today they are an emerging threat for the continental and developed countries also. Nowadays, in intercontinental countries, there is a struggle with emerging diseases, which have found their way to appear through vectors. Vector-borne zoonotic diseases occur when vectors, animal hosts, climate conditions, pathogens, and susceptible human population exist at the same time, at the same place. Global climate change is predicted to lead to an increase in vector-borne infectious diseases and disease outbreaks. It could affect the range and population of pathogens, host and vectors, transmission season, etc. Reliable surveillance for diseases that are most likely to emerge is required. Canine vector-borne diseases represent a complex group of diseases including anaplasmosis, babesiosis, bartonellosis, borreliosis, dirofilariosis, ehrlichiosis, and leishmaniosis. Some of these diseases cause serious clinical symptoms in dogs and some of them have a zoonotic potential with an effect to public health. It is expected from veterinarians in coordination with medical doctors to play a fundamental role at primarily prevention and then treatment of vector-borne diseases in dogs. The One Health concept has to be integrated into the struggle against emerging diseases. During a 4-year period, from 2009 to 2013, a total number of 551 dog samples were analyzed for vector-borne diseases (borreliosis, babesiosis, ehrlichiosis, anaplasmosis, dirofilariosis, and leishmaniasis) in routine laboratory work. The analysis was done by serological tests - ELISA for borreliosis, dirofilariosis, and leishmaniasis, modified Knott test for dirofilariosis, and blood smear for babesiosis, ehrlichiosis, and anaplasmosis. This number of samples represented 75% of total number of samples that were sent for analysis for different diseases in dogs. Annually, on average more then half of the samples brought to the laboratory to analysis for different infectious diseases are analyzed for vector-borne diseases. In the region of Vojvodina (northern part of Serbia), the following vector-borne infectious diseases have been found in dogs so far borreliosis, babesiosis, dirofilariosis, leishmaniasis, and anaplasmosis. PMID- 25520952 TI - The application of magnetic nanoparticles for the treatment of brain tumors. PMID- 25520954 TI - Rituximab as a first-line preventive treatment in pediatric NMOSDs: Preliminary results in 5 children. AB - OBJECTIVE: No established therapeutic protocol has been proposed to date for childhood-onset neuromyelitis optica (NMO) spectrum disorders (NMOSDs). We report the response of 5 NMO immunoglobulin (Ig)G-positive pediatric cases to a standardized B-cell-targeted first-line immunosuppressive protocol with rituximab for prevention of relapses. METHODS: Retrospective observational cohort study. RESULTS: All patients included in the study showed disease remission after rituximab induction. Relapses always occurred in conjunction with CD19(+) B-cell repopulation and appeared less severe than prior to treatment. At the end of follow-up, neurologic disability and MRI findings stabilized or improved in all the patients, with only minor and transient side effects. Oral steroid discontinuation was possible in all the patients. CONCLUSIONS: Our protocol is well-tolerated and has provided encouraging results in terms of control of relapses and progression of disability. An early intervention with rituximab might affect the disease course in pediatric NMO-IgG-positive NMOSDs. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for children with NMOSDs, rituximab is well-tolerated and stabilizes or improves neurologic disability. PMID- 25520947 TI - Ixodes ricinus and Its Transmitted Pathogens in Urban and Peri-Urban Areas in Europe: New Hazards and Relevance for Public Health. AB - Tick-borne diseases represent major public and animal health issues worldwide. Ixodes ricinus, primarily associated with deciduous and mixed forests, is the principal vector of causative agents of viral, bacterial, and protozoan zoonotic diseases in Europe. Recently, abundant tick populations have been observed in European urban green areas, which are of public health relevance due to the exposure of humans and domesticated animals to potentially infected ticks. In urban habitats, small and medium-sized mammals, birds, companion animals (dogs and cats), and larger mammals (roe deer and wild boar) play a role in maintenance of tick populations and as reservoirs of tick-borne pathogens. Presence of ticks infected with tick-borne encephalitis virus and high prevalence of ticks infected with Borrelia burgdorferi s.l., causing Lyme borreliosis, have been reported from urbanized areas in Europe. Emerging pathogens, including bacteria of the order Rickettsiales (Anaplasma phagocytophilum, "Candidatus Neoehrlichia mikurensis," Rickettsia helvetica, and R. monacensis), Borrelia miyamotoi, and protozoans (Babesia divergens, B. venatorum, and B. microti) have also been detected in urban tick populations. Understanding the ecology of ticks and their associations with hosts in a European urbanized environment is crucial to quantify parameters necessary for risk pre-assessment and identification of public health strategies for control and prevention of tick-borne diseases. PMID- 25520955 TI - Natalizumab-related anaphylactoid reactions in MS patients are associated with HLA class II alleles. AB - OBJECTIVES: We aimed to investigate potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic/anaphylactoid reactions in patients with multiple sclerosis (MS) treated with natalizumab. METHODS: HLA class I and II genotyping was performed in patients with MS who experienced anaphylactic/anaphylactoid reactions and in patients who did not develop infusion-related allergic reactions following natalizumab administration. RESULTS: A total of 119 patients with MS from 3 different cohorts were included in the study: 54 with natalizumab-related anaphylactic/anaphylactoid reactions and 65 without allergic reactions. HLA DRB1*13 and HLA-DRB1*14 alleles were significantly increased in patients who developed anaphylactic/anaphylactoid reactions (p M-H = 3 * 10(-7); odds ratio [OR]M-H = 8.96, 95% confidence interval [CI] = 3.40-23.64), with a positive predictive value (PPV) of 82%. In contrast, the HLA-DRB1*15 allele was significantly more represented in patients who did not develop anaphylactic/anaphylactoid reactions to natalizumab (p M-H = 6 * 10(-4); ORM-H = 0.2, 95% CI = 0.08-0.50), with a PPV of 81%. CONCLUSIONS: HLA-DRB1 genotyping before natalizumab treatment may help neurologists to identify patients with MS at risk for developing serious systemic hypersensitivity reactions associated with natalizumab administration. PMID- 25520953 TI - Metabolic network discovery by top-down and bottom-up approaches and paths for reconciliation. AB - The primary focus in the network-centric analysis of cellular metabolism by systems biology approaches is to identify the active metabolic network for the condition of interest. Two major approaches are available for the discovery of the condition-specific metabolic networks. One approach starts from genome-scale metabolic networks, which cover all possible reactions known to occur in the related organism in a condition-independent manner, and applies methods such as the optimization-based Flux-Balance Analysis to elucidate the active network. The other approach starts from the condition-specific metabolome data, and processes the data with statistical or optimization-based methods to extract information content of the data such that the active network is inferred. These approaches, termed bottom-up and top-down, respectively, are currently employed independently. However, considering that both approaches have the same goal, they can both benefit from each other paving the way for the novel integrative analysis methods of metabolome data- and flux-analysis approaches in the post genomic era. This study reviews the strengths of constraint-based analysis and network inference methods reported in the metabolic systems biology field; then elaborates on the potential paths to reconcile the two approaches to shed better light on how the metabolism functions. PMID- 25520957 TI - Occurrence of hemolytic anemia in patients with GBS treated with high-dose IVIg. AB - OBJECTIVE: We describe an underrecognized side effect of high-dose IV immunoglobulin (IVIg), hemolytic anemia. BACKGROUND: There are no established guidelines on treating patients with Guillain-Barre syndrome (GBS) who relapse or do not improve after a standard course of treatment (IVIg or plasma exchange). Some centers will opt for a second course of the initial treatment. There is an ongoing trial of a second course of IVIg in patients with severe GBS. METHODS: We retrospectively reviewed 4 patients with severe GBS who received high-dose IVIg. One patient inadvertently received a high dose of IVIg for Miller Fisher syndrome. All patients received a total of at least 2 courses of the standard dose of IVIg (total >4 g/kg). We review their clinical course and side effects. RESULTS: All patients with non-O blood types developed clinically significant hemolytic anemia requiring blood transfusion. CONCLUSION: Hemolytic anemia may limit doses of IVIg for treatment of severe GBS in patients with non-O blood types. PMID- 25520956 TI - CB1 receptor affects cortical plasticity and response to physiotherapy in multiple sclerosis. AB - OBJECTIVES: Therapeutic effects of physical therapy in neurologic disorders mostly rely on the promotion of use-dependent synaptic plasticity in damaged neuronal circuits. Genetic differences affecting the efficiency of synaptic plasticity mechanisms could explain why some patients do not respond adequately to the treatment. It is known that physical exercise activates the endocannabinoid system and that stimulation of cannabinoid CB1 receptors (CB1Rs) promotes synaptic plasticity in both rodents and humans. We thus tested whether CB1R genetic variants affect responsiveness to exercise therapy. METHODS: We evaluated the effect of a genetic variant of the CB1R associated with reduced receptor expression (patients with long AAT trinucleotide short tandem repeats in the CNR1 gene) on long-term potentiation (LTP)-like cortical plasticity induced by transcranial magnetic theta burst stimulation (TBS) of the motor cortex and, in parallel, on clinical response to exercise therapy in patients with multiple sclerosis. RESULTS: We found that patients with long AAT CNR1 repeats do not express TBS-induced LTP-like cortical plasticity and show poor clinical benefit after exercise therapy. CONCLUSIONS: Our results provide the first evidence that genetic differences within the CB1R may influence clinical responses to exercise therapy, and they strengthen the hypothesis that CB1Rs are involved in the regulation of synaptic plasticity and in the control of spasticity in humans. This information might be of great relevance for patient stratification and personalized rehabilitation treatment programs. PMID- 25520959 TI - The genetics of natalizumab hypersensitivity: One learns to itch where one can scratch. PMID- 25520958 TI - Leucine-rich glioma-inactivated protein 1 antibody encephalitis: A case report. AB - OBJECTIVE: To describe a case of leucine-rich glioma-inactivated protein 1 (LGI1) antibody-associated encephalitis. METHODS: The clinical and ancillary data and brain MRIs were gathered retrospectively by chart review. Relevant literature on similar cases was also reviewed. RESULTS: The diagnosis of LGI1 antibody associated autoimmune encephalitis was based on the typical clinical presentation of seizures, psychiatric symptoms, and memory loss as well as negative diagnostic testing for cancer; the diagnosis was confirmed by positive LGI1 antibody. The patient responded favorably to treatment with IV immunoglobulin and continues to do well. CONCLUSION: LGI1 antibody-associated encephalitis has increasingly been recognized as a primary autoimmune disorder with good prognosis and response to treatment. PMID- 25520960 TI - Species composition and temporal distribution of mosquito populations in Ibadan, Southwestern Nigeria. AB - Nigeria has a high burden of vector borne diseases such as malaria and lymphatic filariasis (LF). This study aimed to determine the species composition of mosquitoes in Ibadan, Southwest Nigeria as well as determine their role in malaria and LF transmission. Adult mosquitoes were collected by Pyrethrum Spray Catch (PSC) and identified and graded according to their abdominal conditions. The mosquitoes were dissected to determine the parity status and to check for microfilariae of Wuchereria bancrofti. The presence of circumsporozoite protein of Plasmodium falciparum was examined using ELISA. A total of 1600 mosquitoes were collected of which 31 (1.9%) were Anopheles gambiae s.l. while 1756 (98%) were Culex sp. None of the mosquitoes examined was positive for Plasmodium falciparum and Wuchereria bancrofti. The lack of adequate sanitary conditions in the area could be responsible for the large number of mosquitoes collected. Health education could help in sensitizing the inhabitants. PMID- 25520961 TI - Efficient Discovery of De-identification Policies Through a Risk-Utility Frontier. AB - Modern information technologies enable organizations to capture large quantities of person-specific data while providing routine services. Many organizations hope, or are legally required, to share such data for secondary purposes (e.g., validation of research findings) in a de-identified manner. In previous work, it was shown de-identification policy alternatives could be modeled on a lattice, which could be searched for policies that met a prespecified risk threshold (e.g., likelihood of re-identification). However, the search was limited in several ways. First, its definition of utility was syntactic - based on the level of the lattice - and not semantic - based on the actual changes induced in the resulting data. Second, the threshold may not be known in advance. The goal of this work is to build the optimal set of policies that trade-off between privacy risk (R) and utility (U), which we refer to as a R-U frontier. To model this problem, we introduce a semantic definition of utility, based on information theory, that is compatible with the lattice representation of policies. To solve the problem, we initially build a set of policies that define a frontier. We then use a probability-guided heuristic to search the lattice for policies likely to update the frontier. To demonstrate the effectiveness of our approach, we perform an empirical analysis with the Adult dataset of the UCI Machine Learning Repository. We show that our approach can construct a frontier closer to optimal than competitive approaches by searching a smaller number of policies. In addition, we show that a frequently followed de-identification policy (i.e., the Safe Harbor standard of the HIPAA Privacy Rule) is suboptimal in comparison to the frontier discovered by our approach. PMID- 25520962 TI - Discrete dynamic system oriented on the formation of prebiotic dipeptides from Rode's experiment. AB - This work attempts to rationalize the possible prebiotic profile of the first dipeptides of about 4 billion years ago based on a computational discrete dynamic system that uses the final yields of the dipeptides obtained in Rode's experiments of salt-induced peptide formation (Rode et al., 1999, Peptides 20: 773-786). The system built a prebiotic scenario that allowed us to observe that (i) the primordial peptide generation was strongly affected by the abundances of the amino acid monomers, (ii) small variations in the concentration of the monomers have almost no effect on the final distribution pattern of the dipeptides and (iii) the most plausible chemical reaction of prebiotic peptide bond formation can be linked to Rode's hypothesis of a salt-induced scenario. The results of our computational simulations were related to former simulations of the Miller, and Fox & Harada experiments on amino acid monomer and oligomer generation, respectively, offering additional information to our approach. PMID- 25520963 TI - Antimutagenic effects of aqueous fraction of Myristica fragrans (Houtt.) leaves on Salmonella typhimurium and Mus musculus. AB - Natural plant extracts offer a promising hope in the prevention/treatment of cancer arising from genetic mutations. This study evaluated in vitro and in vivo mutagenic and antimutagenic effects of aqueous fraction of Myristica fragrans (AFMF) leaves on TA100 strain of Salmonella typhimurium and Mus musculus (Male Swiss albino mice), respectively. The antioxidant activity of AFMF against 2,2 diphenyl-1-picrylhydrazyl (DPPH), total phenolic and flavonoid contents were determined, followed by its phytochemical elucidation using the Ultra Performance Liquid Chromatography technique (UPLC). The mutagenicity of AFMF at 4, 20, 50, 100, 200, 500, and 1000 ug/well was <2.0 in S. typhimurium and the induced micronucleated polychromatic and normochromatic erythrocytes at 500, 1000, 2000, and 4000 mg/kg were not significantly different from the negative control (p>=0.05). The mutagenic activity of benzo[a]pyrene and cyclophosphamide was significantly suppressed above 50.0% throughout the tested concentrations. Fifty percent of the free radicals from DPPH were scavenged by AFMF at 0.11 mg/ml. Total phenolic and flavonoid contents of AFMF were 51.0 mg GAE/g and 27 mg QE/g, respectively. Rutin was elucidated by the UPLC technique, and thereby suspected to be the phytochemical responsible for the observed antimutagenic activity. Thus far, AFMF seems to contain a promising chemotherapeutic agent for the prevention of genetic damage that is crucial for cancer development. PMID- 25520964 TI - Administration wants more restraint over antimicrobial use. PMID- 25520965 TI - Dispute benefits of onychectomy. PMID- 25520966 TI - Serial laboratory testing in Scottish Terriers with vacuolar hepatopathy. PMID- 25520967 TI - The authors respond. PMID- 25520968 TI - Bipolar staining of gram-negative bacillus in cerebrospinal fluid. PMID- 25520969 TI - AVMA COE accreditation. PMID- 25520970 TI - In memoriam: Hugh Malcolm Douglas Gurling. PMID- 25520971 TI - Sugar consumption reduction needed to prevent caries, study says. PMID- 25520972 TI - Extreme exercise can affect oral health, say researchers. PMID- 25520973 TI - Ectoparasite immunology. PMID- 25520974 TI - California veterinarian's death ruled a homicide. PMID- 25520975 TI - Mass spectrometry imaging of small molecules. Preface. PMID- 25520976 TI - Health and life purpose: What's the connection? PMID- 25520977 TI - Effective coaching, the power of purpose, and communities of support. PMID- 25520978 TI - Living in the temple of the spirit of God. PMID- 25520979 TI - Finding purpose in the Kingdom of Tonga. PMID- 25520980 TI - Evidence-based review and discussion points. PMID- 25520981 TI - Relationship between soil temperature and fruit colour development of 'Clemenpons' Clementine mandarin (Citrus clementina Hort ex. Tan). AB - BACKGROUND: In Citrus, root temperature regulates rind colouration. However, few studies have investigated the range of temperatures and timing which determine rind colour break. The objective of this study was to determine the relationship between range of soil temperature (ST) and rind colour development in the precocious 'Clemenpons' Clementine mandarin. Reflective white plastic mulch was used to modify root temperature. RESULTS: Mulching increased reflected light and reduced daily maximum ST and temperature range, major differences being established 70-30 days before harvest. Rind colour-break correlated positively with 20 degrees C < ST < 23 degrees C; thus, 20-23 degrees C appears to be the ST threshold interval for fruit colouration. The sooner the soil reached it, the sooner the fruit changed rind colour. In our experiments, control trees accumulated 565 h at this ST interval before fruit changed colour, whereas in treated trees it occurred 2 weeks earlier. Hence, in treated trees the colour break was advanced by 2 weeks and this increased the percentage of fruit harvested at the first picking date by up to 2.5-fold. CONCLUSIONS: Fruit colour break does not take place at a certain ST, but after several hours at a ST of 20 23 degrees C. In our experiments, reducing ST during the 2 months before harvest advances the first picking date in the 'Clemenpons' Clementine mandarin. PMID- 25520982 TI - Chemical composition, antioxidant and cytotoxicity activities of the essential oils of Myristica fragrans and Morinda citrifolia. AB - BACKGROUND: In this study the chemical composition, antioxidant activities and cytotoxic effect of the essential oils of Myristica fragrans (nutmeg) and Morinda citrifolia (mengkudu) were determined. RESULTS: Thirty-eight compounds in nutmeg oil and six compounds in mengkudu oil were identified by gas chromatography-mass spectrometry. The free radical scavenging activity of nutmeg oil was superior of that mengkudu oil. The MTT assay of nutmeg oil on human colorectal carcinoma (HCT 116) and human breast carcinoma (MCF-7) cell lines showed IC50 values of 78.61 and 66.45 ug mL-1, respectively. The mengkudu oil exhibited IC50 values of 91.46 and 78.15 ug mL-1 for HCT-116 and MCF-7, respectively. CONCLUSION: The results showed that nutmeg oil can be developed as potent anti-cancer and antioxidant drugs. PMID- 25520983 TI - Vitamin D3 regulation of body fat, cytokines, and calpain gene expression. AB - BACKGROUND: We conducted an in vivo experiment to determine whether vitamin D3 acts as a fat synthesizer and/or meat tenderizer in mice. At 6 weeks of age, 20 male C57BL/6 wild-type mice were randomly divided into two groups (10 mice per group) and fed a modified AIN93G diet with (vitamin D3 diet) or without (basal diet) 10 IU 25-OH-cholecalciferol kg-3 for 3 weeks. RESULTS: When vitamin D3 was fed to mice for 3 weeks, body fat was significantly increased compared to mice fed a basal diet. There was, however, no difference in body weight between the two groups. Vitamin D3 increased the gene expressions of pro-inflammatory cytokines and peroxisome proliferator-activated receptor gamma, but decreased interleukin-15 in adipose tissue through nuclear vitamin D receptor and uncoupling protein-2 signals. The muscle inducible nitrate oxide synthase content of mice fed vitamin D3 was higher than those fed a basal diet, while muscle arginase l showed a reverse phenomenon. longissimuss dorsi muscle of vitamin D3 fed mice showed more severe fat deposition than those fed a basal diet. Vitamin D3 amplified muscle u- and m-calpain protein content and suppressed muscle calpastatin protein content. CONCLUSION: These findings suggest that vitamin D3 can be used as a fat synthesizer and meat tenderizer in meat-producing animals. PMID- 25521005 TI - Zoogeography of the San Andreas Fault system: Great Pacific Fracture Zones correspond with spatially concordant phylogeographic boundaries in western North America. AB - The purpose of this article is to provide an ultimate tectonic explanation for several well-studied zoogeographic boundaries along the west coast of North America, specifically, along the boundary of the North American and Pacific plates (the San Andreas Fault system). By reviewing 177 references from the plate tectonics and zoogeography literature, I demonstrate that four Great Pacific Fracture Zones (GPFZs) in the Pacific plate correspond with distributional limits and spatially concordant phylogeographic breaks for a wide variety of marine and terrestrial animals, including invertebrates, fish, amphibians, reptiles, birds, and mammals. These boundaries are: (1) Cape Mendocino and the North Coast Divide, (2) Point Conception and the Transverse Ranges, (3) Punta Eugenia and the Vizcaino Desert, and (4) Cabo Corrientes and the Sierra Transvolcanica. However, discussion of the GPFZs is mostly absent from the zoogeography and phylogeography literature likely due to a disconnect between biologists and geologists. I argue that the four zoogeographic boundaries reviewed here ultimately originated via the same geological process (triple junction evolution). Finally, I suggest how a comparative phylogeographic approach can be used to test the hypothesis presented here. PMID- 25521006 TI - Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group. AB - This prospective multi-institutional phase II study was designed to assess the efficacy and safety of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphomas. Eighty-one patients diagnosed with diffuse large B-cell lymphoma (DLBCL, n = 68), primary mediastinal DLBCL (n = 6) and follicular lymphoma Grade 3b (n = 7), with an age-adjusted International Prognostic Index >1, were eligible for analysis. Median age was 60 years (range: 21-77). Sixty-five patients (80.2%) achieved complete response. After a median follow-up time of 64 months, 10-year event-free survival and overall survival (OS) were 47.8% and 63.6%, respectively. None of the studied clinical and biological characteristics were associated with poorer outcome. Interestingly, patients with BCL6 rearrangement achieved a 10-year OS of 100%, while patients with BCL2 rearrangement exhibited a poorer outcome compared to activated B-cell tumours and germinal centre B-cell without BCL2 rearranged tumours. Results achieved with DA-EPOCH-R showed a good long-term outcome and a tolerable toxicity profile in high-risk large B cell lymphoma patients. Outcome was not affected by tumour cell proliferation or by cell of origin, highlighting the requirement of new biological markers for patient subclassification of high risk DLBCL patients. PMID- 25521007 TI - Landmark clinical trials influencing surgical management of non-invasive and invasive breast cancer. AB - The surgical management of breast cancer has changed considerably since the use of the Halstedian radical mastectomy early in the 20th century. Over the last 50 years, several landmark clinical trials from the USA and Europe have resulted in a paradigm shift in the management of breast cancer toward less radical forms of surgery with the combined use of multi-modality treatments including systemic chemotherapy, endocrine therapy, and radiotherapy. Advances in such research have established a new worldwide standard of care for breast cancer surgical management and treatment, which has become more patient centric and which places a higher emphasis on cosmesis and improved patient quality of life. In this chapter, we review the landmark clinical trials that have influenced surgical management for non-invasive and invasive breast cancer and that serve to guide current clinical practices to date. PMID- 25521008 TI - Sequential healing at implants installed immediately into extraction sockets. An experimental study in dogs. AB - OBJECTIVE: To compare the sequential healing at implants installed in a healed alveolar bony ridge or immediately after tooth extraction without functional load. MATERIAL AND METHODS: In the mandible of 12 dogs, the mesial roots of the first molars were endodontically treated, the tooth hemisected, and the distal roots extracted. After 3 months, the mesial roots of the fourth premolars were endodontically treated, the tooth hemisected, and the distal roots extracted in one side of the mandible. Implants were placed immediately into extraction sockets (IPIES) of the fourth premolar and in the healed sites in the molar regions. Healing abutments were placed, and the flaps were sutured to allow a non submerged healing. The time of surgery and of sacrifices were planned in such a way to obtain biopsies representing the healing after 1 and 2 weeks and 1 and 3 months, respectively. Ground sections were prepared for histological evaluation of tissues components on the implant surface and the coronal termination level of osseointegration (M-B). RESULTS: New bone apposition on the implant surface was slightly higher at the healed compared to the IPIES sites, being 7.4% and 4.1% after 1 week, and 67.3% and 65.3% after 3 months, respectively. Old bone was progressively resorbed, from 27.0% and 21.9% after 1 week, to 2.5% and 2.0% after 3 months, at healed and IPIES sites, respectively. M-B was 1.4 mm and 2.6 mm after 1 week, 1.2 mm and 1.2 mm after 3 months, at healed and IPIES sites, respectively. CONCLUSIONS: Similar patterns of sequential osseointegration were found at implants installed in healed alveolar bone or in alveolar sockets immediately after tooth extraction. The coronal termination level of osseointegration, that was different after 1 week, was found similar at the 3 month observation. PMID- 25521009 TI - A MAT1-2 wild-type strain from Penicillium chrysogenum: functional mating-type locus characterization, genome sequencing and mating with an industrial penicillin-producing strain. AB - In heterothallic ascomycetes, mating is controlled by two nonallelic idiomorphs that determine the 'sex' of the corresponding strains. We recently discovered mating-type loci and a sexual life cycle in the penicillin-producing fungus, Penicillium chrysogenum. All industrial penicillin production strains worldwide are derived from a MAT1-1 isolate. No MAT1-2 strain has been investigated in detail until now. Here, we provide the first functional analysis of a MAT1-2 locus from a wild-type strain. Similar to MAT1-1, the MAT1-2 locus has functions beyond sexual development. Unlike MAT1-1, the MAT1-2 locus affects germination and surface properties of conidiospores and controls light-dependent asexual sporulation. Mating of the MAT1-2 wild type with a MAT1-1 high penicillin producer generated sexual spores. We determined the genomic sequences of parental and progeny strains using next-generation sequencing and found evidence for genome-wide recombination. SNP calling showed that derived industrial strains had an uneven distribution of point mutations compared with the wild type. We found evidence for meiotic recombination in all chromosomes. Our results point to a strategy combining the use of mating-type genes, genetics, and next-generation sequencing to optimize conventional strain improvement methods. PMID- 25521010 TI - Effects of downstream genes on synthetic genetic circuits. AB - BACKGROUND: In order to understand and regulate complex genetic networks in living cells, it is important to build simple and well-defined genetic circuits. We designed such circuits using a synthetic biology approach that included mathematical modeling and simulation, with a focus on the effects by which downstream reporter genes are involved in the regulation of synthetic genetic circuits. RESULTS: Our results indicated that downstream genes exert two main effects on genes involved in the regulation of synthetic genetic circuits: (1) competition for regulatory proteins and (2) protein degradation in the cell. CONCLUSIONS: Our findings regarding the effects of downstream genes on regulatory genes and the role of impedance in driving large-scale and complex genetic circuits may facilitate the design of more accurate genetic circuits. This design will have wide applications in future studies of systems and synthetic biology. PMID- 25521011 TI - One-pot process that efficiently generates single stereoisomers of 1,3 bisphosphinylpropanes having five chiral centers. AB - P,C-stereogenic 1,3-bisphosphinylpropanes 3 that have up to five stereogenic centers could be obtained stereoselectively in high yields by a one-step reaction of (RP)-menthylphenylphosphine oxide 1 with alpha,beta-unsaturated aldehydes 2 catalyzed by KOH at room temperature. A mechanism was proposed as to involve a stereoselective intermolecular 1,3'-phosphorus migration from the 1,2-adduct of 1 with 2 to another 2 generating a 1,4-adduct that subsequently reacts with 1 to produce 3. PMID- 25521012 TI - Agreement between adolescents and parents/caregivers in rating the impact of malocclusion on adolescents' quality of life. AB - OBJECTIVE: To assess the agreement between adolescents and their parents/caregivers regarding the impact of malocclusion on adolescents' oral health-related quality of life (OHRQoL). MATERIALS AND METHODS: A consecutive sample of 141 adolescent and parent/caregiver pairs was selected. Adolescents answered the short version of the Child Perceptions Questionnaire (CPQ11-14), while parents answered the Parental-Caregiver Perceptions Questionnaire (P-CPQ). The CPQ11-14 and the P-CPQ have 14 items in common that are organized through four subscales: oral symptoms (OS), functional limitations (FL), emotional well being (EW), and social well-being (SW). Agreement on the overall score and agreement on the subscales were determined using comparison and correlation analysis. The comparison analysis was carried out by comparing the mean directional and absolute differences, and the correlation analysis was performed using the intraclass correlation coefficient (ICC). RESULTS: A total of 135 pairs of adolescents and parents/caregivers agreed to answer the questionnaires, providing a response rate of 95.7%. The mean age of the adolescents was 11.50 years. The mean directional difference was significant for the OS (P < .001) and FL (P = .040) subscales as well as for the overall score (P = .007). Adolescents' reports were higher than parents/caregivers' reports. The mean absolute difference for the overall score was 7.26, representing 12.9% of the maximum possible overall score. The ICC was 0.16 for the overall score, indicating poor agreement. CONCLUSION: Poor agreement was observed between adolescents and their parents/caregivers in rating the impact of malocclusion on adolescents' OHRQoL. PMID- 25521013 TI - Proteasome-associated autoinflammatory syndromes: advances in pathogeneses, clinical presentations, diagnosis, and management. AB - The disease spectrum currently known as the proteasome-associated autoinflammatory syndromes (PRAAS) was first described in 1939 in patients who presented with recurrent fevers beginning in infancy or early childhood, which were accompanied by nodular erythema, a pernio-like rash, and joint contractures. Since then, several syndromes, such as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, Nakajo-Nishimura syndrome (NNS), joint contractures, muscle atrophy, microcytic anemia and panniculitis-induced lipodystrophy (JMP) syndrome, and Japanese autoinflammatory syndrome with lipodystrophy (JASL), have been used to categorize patients with diseases within the same spectrum. Recently, independent studies have identified mutations in the human proteasome subunit beta type 8 (PSMB8) gene, which result in a sustained inflammatory response in all syndromes. Further functional studies not only suggest a causative role of PSMB8 mutations but also imply that they represent one disease spectrum, referred to as PRAAS. In this paper, we review the clinical presentations and laboratory findings of PRAAS, as well as the most recent advances in pathogeneses, diagnosis, and treatment options for patients with diseases in this spectrum. PMID- 25521014 TI - Effect of dietary histidine on contents of carnosine and anserine in muscles of broilers. AB - Carnosine (beta-alanyl-L-histidine) and anserine (beta-alanyl-1-methyl-L histidine) are dipeptides mainly found in skeletal muscle and brain of many vertebrates, and particularly high concentrations are observed in chicken pectoral muscles. It was reported that these peptides have many functions, such as antioxidant activity. In this study, we examined the effect of different levels of dietary histidine on carnosine and anserine contents in broiler muscles. The 14-days-old female Chunky strain broilers were given feeds containing three different levels of histidine; 67% (Low-His), 100% (Control) and 200% (High-His) of histidine requirement according to the NRC (1994). Chicks were fed experimental diets for 10 days. Both dipeptides in muscle were significantly decreased. In particular, carnosine was not detected at all in the Low-His group and was significantly increased in the High-His group. Both dipeptides were not detected in plasma. These results indicated the possibility to produce chicken meat with enhanced amount of these dipeptides by high histidine feeding. PMID- 25521015 TI - Revisiting the link between breeding effort and oxidative balance through field evaluation of two sympatric sibling insect species. AB - The idea that oxidative stress could be a major force governing evolutionary trade-offs has recently been challenged by experimental approaches in laboratory conditions, triggering extensive debates centered on theoretical and methodological issues. Here, we revisited the link between oxidative stress and reproduction by measuring multiple antioxidant and oxidative damages in wild caught females of two sibling weevil species (Curculio elephas, C. glandium). The strength of our study arised from (1) studied species that were sympatric and exploited similar resource, but displayed contrasting reproductive strategies and (2) individuals were sampled throughout adult life so as to relate oxidative status to breeding effort. We found that the short-lived C. elephas sacrifices red-ox homeostasis for immediate reproduction upon emergence as characterized by low antioxidant defenses and elevated oxidative damage. Comparatively, C. glandium massively invests in antioxidant and maintains low oxidative damage, which may contribute to their extended prereproductive period. Intriguingly, we also reveal, for the first time in a field study, an unexpected reactivation of antioxidant defenses with the onset of reproduction. Our results thus support the existence of a strong, but complex relationship between oxidative stress and life history evolution and highlight the need for a finer-scale picture of antioxidant strategies. PMID- 25521016 TI - Isolation of B subunit-specific monoclonal antibody clones that strongly neutralize the toxicity of Shiga toxin 2. AB - Shiga toxin 2 (Stx2)-specific mAb-producing hybridoma clones were generated from mice. Because mice tend to produce small amounts of B subunit (Stx2B)-specific antibodies at the polyclonal antibody level after immunization via the parenteral route, mice were immunized intranasally with Stx2 toxoids with a mutant heat labile enterotoxin as a mucosal adjuvant; 11 different hybridoma clones were obtained in two trials. Six of them were A subunit (Stx2A)-specific whereas five were Stx2B-specific antibody-producing clones. The in vitro neutralization activity of Stx2B-specific mAbs against Stx2 was greater than that of Stx2A specific mAbs on HeLa229 cells. Furthermore, even at low concentrations two of the Stx2B-specific mAbs (45 and 75D9) completely inhibited receptor binding and showed in vivo neutralization activity against a fivefold median lethal dose of Stx2 in mice. In western blot analysis, these Stx2B-specific neutralization antibodies did not react to three different mutant forms of Stx2, each amino acid residue of which was associated with receptor binding. Additionally, the nucleotide sequences of the VH and VL regions of clones 45 and 75D9 were determined. Our Stx2B-specific mAbs may be new candidates for the development of mouse-human chimeric Stx2-neutralizing antibodies which have fewer adverse effects than animal antibodies for enterohemorrhagic Escherichia coli infection. PMID- 25521017 TI - Superficial vein thrombosis: a current approach to management. AB - Superficial vein thrombosis (SVT) was considered to be a benign and self-limiting condition. However, it is now appreciated that a significant proportion of those presenting with SVT will have concomitant deep vein thrombosis or pulmonary embolism, or are at significant risk of developing deep venous thromboembolism. Potential therapeutic options include topical preparations, compression therapy (stockings, bandages), medication such as non-steroidal anti-inflammatory drugs (NSAIDs) or anticoagulants (therapeutic or prophylactic doses) and surgery, ligation or stripping, of superficial veins. The treatment of choice is therapeutic/intermediate dose low molecular weight heparin or prophylactic dose fondaparinux administered for 4-6 weeks. The cost-effectiveness of treatment is a concern and more targeted therapy is required. PMID- 25521040 TI - The high costs of "free" drug samples. PMID- 25521038 TI - Homopharma: a new concept for exploring the molecular binding mechanisms and drug repurposing. AB - BACKGROUND: Drugs that simultaneously target multiple proteins often improve efficacy, particularly in the treatment of complex diseases such as cancers and central nervous system disorders. Many approaches have been proposed to identify the potential targets of a drug. Recently, we have introduced Space-Related Pharmamotif (SRPmotif) method to recognize the proteins that share similar binding environments. In addition, compounds with similar topology may bind to similar proteins and have similar protein-compound interactions. However, few studies have focused on exploring the relationships between binding environments and protein-compound interactions, which is important for understanding molecular binding mechanisms and helpful to be used in discovering drug repurposing. RESULTS: In this study, we propose a new concept of "Homopharma", combining similar binding environments and protein-compound interaction profiles, to explore the molecular binding mechanisms and drug repurposing. A Homopharma consists of a set of proteins which have the conserved binding environment and a set of compounds that share similar structures and functional groups. These proteins and compounds present conserved interactions and similar physicochemical properties. Therefore, these compounds are often able to inhibit the proteins in a Homopharma. Our experimental results show that the proteins and compounds in a Homopharma often have similar protein-compound interactions, comprising conserved specific residues and functional sites. Based on the Homopharma concept, we selected four flavonoid derivatives and 32 human protein kinases for enzymatic profiling. Among these 128 bioassays, the IC50 of 56 and 25 flavonoid-kinase inhibitions are less than 10 MUM and 1 MUM, respectively. Furthermore, these experimental results suggest that these flavonoids can be used as anticancer compounds, such as oral and colorectal cancer drugs. CONCLUSIONS: The experimental results show that the Homopharma is useful for identifying key binding environments of proteins and compounds and discovering new inhibitory effects. We believe that the Homopharma concept can have the potential for understanding molecular binding mechanisms and providing new clues for drug development. PMID- 25521039 TI - Stimulation of Mucin, Mucus, and Viscosity during Lubiprostone in Patients with Chronic Constipation may Potentially Lead to Increase of Lubrication. AB - OBJECTIVES: The purpose of this clinical trial was to explore whether lubiprostone increases the rate of mucus and mucin secretion and its viscosity in chronic constipation (CC) patients. The secretion of chloride (CS) into the gastrointestinal tract lumen is pivotal in the body's ability to process non digestible food components. CS sets the optimal rate of hydration for non digestible food components, their fluidity, and their adequate propulsion along the alimentary tract. Chloride is also instrumental in the secretion of alimentary tract mucus, and the formation of a gel-like, viscous mucus-buffer layer. This layer acts as the first line and vanguard of the mucosal barrier. This barrier is essential in mucosal lubrication and protection. Lubiprostone, a novel chloride channel stimulator ClC-2, is currently approved for the treatment of CC. Its impact on mucus, mucus secretion, and viscosity is not established. METHODS: A double-blind, crossover trial was approved by the IRBs at the Kansas University Medical Center (Kansas City, KS) (study site) and at the Texas Tech University HSC (El Paso, TX) (analysis site). The study included 20 patients (17 females (F); mean age: 37 years) with symptoms of CC diagnosed according to the Rome III criteria. Patients were randomized to 1 week of therapy with lubiprostone or placebo followed by a 1 week washout and 1 week of the alternative therapy. Gastric juice was collected basally and during stimulation with pentagastrin (6 MUg/kg body weight subcutaneously) at the end of weeks 1 and 3. Pentagastrin stimulation mimics food stimulation. The mucus content in gastric juice was assessed gravimetrically. The mucin content was measured after its purification using ultracentrifugation. The viscosity of the gastric secretion was measured using a digital viscometer. RESULTS: In comparison with placebo, the volume of gastric secretion in patients with CC during administration of lubiprostone increased significantly by 50% (86.3 vs. 57.5 ml/h) (P<0.001) in basal conditions and increased by 25% (210.0 vs. 167.6 ml/h) (P=0.024) during stimulation with pentagastrin. The rate of gastric mucus secretion during therapy with lubiprostone was 91% higher (257.3 vs. 135 mg/h) (P=0.001) in basal conditions and 28% higher (348.1 vs. 270.8 mg/h) (NS) in stimulated conditions, although the latter was not statistically significant. The rate of gastric mucin secretion during lubiprostone therapy was 85% higher (98.4 vs. 65.5 mg/h) (P=0.011) in basal conditions and 38% (98.3 vs. 71.7 mg/h) (NS) higher in stimulated conditions. In basal conditions, the viscosity of gastric secretion during administration of lubiprostone increased by 240% at the lowest (P<0.001) and by 106% at the highest shear rate (P<0.001). In stimulated conditions, it increased by 226% (P<0.01) at the lowest shear rate and by 67% (P<0.01) at the highest shear rate. CONCLUSIONS: The significantly higher content of gastric mucus and mucin during therapy in basal conditions with lubiprostone in patients with CC suggests and supports the potentially leading role of lubiprostone and ClC-2 stimulation in their secretion. This increased stimulation results in profoundly increased viscosity, which in turn facilitates and/or accelerates the transit and evacuation of non-digestible food components. Although increases in mucus and mucin were observed in stimulated conditions, neither increase was statistically significant. Based on this experiment, we hypothesize that, in CC patients, the significantly increased rate of mucus and its major component, mucin secretion, during lubiprostone administration may partially explain its clinical effectiveness and also have additional clinically important effects. We propose that since the increased mucus production enhances the protective quality of the mucosal barrier, it also boosts its potential to withstand luminal aggressive components such as acid/pepsin duet, Helicobacter pylori and/or nonsteroidal anti-inflammatory drugs/aspirin, or a combination of all. Further trials are needed to test this hypothesis. As this was crossover clinical trial, the patients serve as their own controls. No interaction was found with body mass index (BMI) and treatment. The observed relationships of BMI and mucus and mucin secretions and gastric juice volume are important considerations in the design of future trials, particularly if a crossover design is not used. PMID- 25521041 TI - Factors affecting actualisation of the WHO breastfeeding recommendations in urban poor settings in Kenya. AB - Poor breastfeeding practices are widely documented in Kenya, where only a third of children are exclusively breastfed for 6 months and only 2% in urban poor settings. This study aimed to better understand the factors that contribute to poor breastfeeding practices in two urban slums in Nairobi, Kenya. In-depth interviews (IDIs), focus group discussions (FGDs) and key informant interviews (KIIs) were conducted with women of childbearing age, community health workers, village elders and community leaders and other knowledgeable people in the community. A total of 19 IDIs, 10 FGDs and 11 KIIs were conducted, and were recorded and transcribed verbatim. Data were coded in NVIVO and analysed thematically. We found that there was general awareness regarding optimal breastfeeding practices, but the knowledge was not translated into practice, leading to suboptimal breastfeeding practices. A number of social and structural barriers to optimal breastfeeding were identified: (1) poverty, livelihood and living arrangements; (2) early and single motherhood; (3) poor social and professional support; (4) poor knowledge, myths and misconceptions; (5) HIV; and (6) unintended pregnancies. The most salient of the factors emerged as livelihoods, whereby women have to resume work shortly after delivery and work for long hours, leaving them unable to breastfeed optimally. Women in urban poor settings face an extremely complex situation with regard to breastfeeding due to multiple challenges and risk behaviours often dictated to them by their circumstances. Macro-level policies and interventions that consider the ecological setting are needed. PMID- 25521042 TI - 137Cs concentrations in foliose lichens within Tsukuba-city as a reflection of radioactive fallout from the Fukushima Dai-ichi Nuclear Power Plant accident. AB - (137)Cs concentrations in ten species of foliose lichens collected within Tsukuba city in August 2013 ranged from 1.7 to 35 kBq/kg. The relationships between (137)Cs in two dominant species, Dirinaria applanata and Physcia orientalis, and the air dose rate (MUSv/h) at the sampling sites were investigated. (137)Cs in P. orientalis measured about 1 year after the Fukushima nuclear accident was correlated (r(2) = 0.80) more closely with the air dose rate than those measured after about 2 years (r(2) = 0.65), possibly demonstrating its continued value as a biomonitor to reflect ambient fall-out levels. In contrast, those of Dirinaria applanata were not correlated with the air dose rate in either year. PMID- 25521043 TI - Strain-promoted oxidation-controlled cyclooctyne-1,2-quinone cycloaddition (SPOCQ) for fast and activatable protein conjugation. AB - A main challenge in the area of bioconjugation is to devise reactions that are both activatable and fast. Here, we introduce a temporally controlled reaction between cyclooctynes and 1,2-quinones, induced by facile oxidation of 1,2 catechols. This so-called strain-promoted oxidation-controlled cyclooctyne-1,2 quinone cycloaddition (SPOCQ) shows a remarkably high reaction rate when performed with bicyclononyne (BCN), outcompeting the well-known cycloaddition of azides and BCN by 3 orders of magnitude, thereby allowing a new level of orthogonality in protein conjugation. PMID- 25521044 TI - Using hidden Markov models to investigate G-quadruplex motifs in genomic sequences. AB - BACKGROUND: G-quadruplexes are four-stranded structures formed in guanine-rich nucleotide sequences. Several functional roles of DNA G-quadruplexes have so far been investigated, where their putative functional roles during DNA replication and transcription have been suggested. A necessary condition for G-quadruplex formation is the presence of four regions of tandem guanines called G-runs and three nucleotide subsequences called loops that connect G-runs. A simple computational way to detect potential G-quadruplex regions in a given genomic sequence is pattern matching with regular expression. Although many putative G quadruplex motifs can be found in most genomes by the regular expression-based approach, the majority of these sequences are unlikely to form G-quadruplexes because they are unstable as compared with canonical double helix structures. RESULTS: Here we present elaborate computational models for representing DNA G quadruplex motifs using hidden Markov models (HMMs). Use of HMMs enables us to evaluate G-quadruplex motifs quantitatively by a probabilistic measure. In addition, the parameters of HMMs can be trained by using experimentally verified data. Computational experiments in discriminating between positive and negative G quadruplex sequences as well as reducing putative G-quadruplexes in the human genome were carried out, indicating that HMM-based models can discern bona fide G quadruplex structures well and one of them has the possibility of reducing false positive G-quadruplexes predicted by existing regular expression-based methods. Furthermore, our results show that one of our models can be specialized to detect G-quadruplex sequences whose functional roles are expected to be involved in DNA transcription. CONCLUSIONS: The HMM-based method along with the conventional pattern matching approach can contribute to reducing costly and laborious wet-lab experiments to perform functional analysis on a given set of potential G quadruplexes of interest. The C++ and Perl programs are available at http://tcs.cira.kyoto-u.ac.jp/~ykato/program/g4hmm/. PMID- 25521045 TI - Binder-free V2O5 cathode for greener rechargeable aluminum battery. AB - This letter reports on the investigation of a binder-free cathode material to be used in rechargeable aluminum batteries. This cathode is synthesized by directly depositing V2O5 on a Ni foam current collector. Rechargeable aluminum coin cells fabricated using the as-synthesized binder-free cathode delivered an initial discharge capacity of 239 mAh/g, which is much higher than that of batteries fabricated using a cathode composed of V2O5 nanowires and binder. An obvious discharge voltage plateau appeared at 0.6 V in the discharge curves of the Ni V2O5 cathode, which is slightly higher than that of the V2O5 nanowire cathodes with common binders. This improvement is attributed to reduced electrochemical polarization. PMID- 25521046 TI - Two-dimensional coordination polymers constructed using, simultaneously, linear and angular spacers and cobalt(II) nodes. New examples of networks of single-ion magnets. AB - Two novel bidimensional coordination polymers, [Co(azbbpy)(4,4' bipy)0.5(DMF)(NCS)2].MeOH (1) and [Co(azbbpy)(bpe)0.5(DMF)(NCS)2].0.25H2O (2), resulted from the assembling of cobalt(II) ions by 1,3-bis(4-pyridyl)azulene, using either 4,4'-bipyridyl or 1,2-bis(4-pyridyl)ethylene as neutral spacers. The cobalt(II) nodes in 1 and 2 act as single-ion magnets (SIMs). PMID- 25521047 TI - Celebrity appeal: reaching women to promote colorectal cancer screening. AB - The Centers for Disease Control and Prevention's Screen for Life: National Colorectal Cancer Action Campaign works with the Entertainment Industry Foundation's National Colorectal Cancer Research Alliance to develop public service announcements (PSAs) featuring celebrities. Selection of Screen for Life celebrity spokespersons is based on a variety of factors, including their general appeal and personal connection to colorectal cancer. Screen for Life PSAs featuring celebrities have been disseminated exclusively through donated media placements and have been formatted for television, radio, print, and out-of-home displays such as dioramas in airports, other transit stations, and shopping malls. A 2012 national survey with women aged 50-75 years (n=772) investigated reported exposure to Screen for Life PSAs featuring actor Terrence Howard. In total, 8.3% of women recalled exposure to the PSAs. Celebrity spokespersons can attract the attention of both target audiences and media gatekeepers who decide which PSAs will receive donated placements. PMID- 25521052 TI - In-fiber photo-immobilization of a bioactive surface. AB - We demonstrate the first in-fiber light-induced bioactive biotin functionalization via photobleaching fluorophore-conjugated biotin. Photobleaching the fluorophores generated free radicals that bind to the albumin passivated inner surface of pure silica photonic crystal fiber. The subsequent attachment of dye-conjugated streptavidin to the bound biotin qualified the photo immobilization process and demonstrated a potential for the construction of in fiber macromolecular assemblies or multiplexes. Compared with other in-fiber bioactive coating methods, the proposed light-induced technique requires only a low-power light source, without the need for additional preactivation steps or toxic chemical reagents. This method, hence, enables a simple and compact implementation for potential biomedical applications. PMID- 25521053 TI - Differences in fluorescence profiles from breast cancer tissues due to changes in relative tryptophan content via energy transfer: tryptophan content correlates with histologic grade and tumor size but not with lymph node metastases. AB - The correlation between histologic grade, an increasingly important measure of prognosis for patients with breast cancer, and tryptophan levels from tissues of 15 breast carcinoma patients was investigated. Changes in the relative content of key native organic biomolecule tryptophan were seen from the fluorescence spectra of cancerous and paired normal tissues with excitation wavelengths of 280 and 300 nm. Due to a large spectral overlap and matching excitation-emission spectra, fluorescence resonance energy transfer from tryptophan-donor to reduced nicotinamide adenine dinucleotides-acceptor was noted. We used the ratios of fluorescence intensities at their spectral emission peaks, or spectral fingerprint peaks, at 340, 440, and 460 nm. Higher ratios correlated strongly with high histologic grade, while lower-grade tumors had low ratios. Large tumor size also correlated with high ratios, while the number of lymph node metastases, a major factor in staging, was not correlated with tryptophan levels. High histologic grade correlates strongly with increased content of tryptophan in breast cancer tissues and suggests that measurement of tryptophan content may be useful as a part of the evaluation of these patients. PMID- 25521054 TI - Controlling pharmaceutical crystallization with designed polymeric heteronuclei. AB - To investigate the hypothesis that molecules acting as crystallization inhibitors in solution could be transformed into crystallization promoters, additives were synthesized that mimic the pharmaceuticals acetaminophen and mefenamic acid and also possess polymerizable functionality. It was found that, in solution, these additives face-selectively inhibit crystal growth and lead to overall slower crystal appearance. In contrast, when the tailor-made additives were incorporated into an insoluble polymer, the induction time for the onset of crystal formation for both pharmaceuticals was substantially decreased. This approach now allows for the synthesis of tailor-made polymers that decrease the induction time for crystal appearance and may find application in compounds that are resistant to crystallization or in improving the fidelity of heteronucleation approaches to solid form discovery. PMID- 25521055 TI - InCoB2014: bioinformatics to tackle the data to knowledge challenge. Introduction. AB - Since 2006, the International Conference on Bioinformatics (InCoB) has been publishing selected papers in BMC Bioinformatics. Papers within the scope of the journal from the 13th InCoB July 31-2 August, 2014 in Sydney, Australia have been compiled in this supplement. These span protein and proteome informatics, structural bioinformatics, software development and bioimaging to pharmacoinformatics and disease informatics, representing the breadth of bioinformatics research in the Asia-Pacific. PMID- 25521057 TI - Prevalence of self-reported stroke and disability in the French adult population: a transversal study. AB - In France, the prevalence of stroke and the level of disability of stroke survivors are little known. The aim of this study was to evaluate functional limitations in adults at home and in institutions, with and without self-reported stroke. A survey named "the Disability Health survey" was carried out in people's homes (DHH) and in institutions (DHI). Medical history and functional level (activities-of-daily-living, ADL and instrumented-activities-of-daily-living IADL) were collected through interviews. The modified Rankin score (mRS) and the level of dependence and disability were compared between participants with and without stroke. 33896 subjects responded. The overall prevalence of stroke was 1.6% (CI95% [1.4%-1.7%]). The mRS was over 2 for 34.4% of participants with stroke (28.7% of participants at home and 87.8% of participants in institutions) versus respectively 3.9%, 3.1% and 71.6% without stroke. Difficulty washing was the most frequently reported ADL for those with stroke (30.6% versus 3% for those without stroke). Difficulty with ADL and IADL increased with age but the relative risk was higher below the age of 60 (17 to 25) than over 85 years (1.5 to 2.2), depending on the ADL. In the overall population, 22.6% of those confined to bed or chair reported a history of stroke. These results thus demonstrate a high national prevalence of stroke. Older people are highly dependent, irrespective of stroke history and the relative risk of dependence in young subjects with a history of stroke is high compared with those without. PMID- 25521058 TI - Seroepidemiology and occult hepatitis B virus infection in young adults in Banjarmasin, Indonesia. AB - Hepatitis B virus (HBV) infection remains a public health problem in Indonesia. There has been limited data regarding HBV infection in young adult population. This study aimed to evaluate the seroepidemiology of HBV infection and characterize occult HBV variants in healthy young adults in Banjarmasin, Indonesia, who were born before the implementation of the universal infant hepatitis B vaccination. Serum samples of 195 healthy young adults were tested for HBsAg, anti-HBc, and anti-HBs. The prevalence of HBsAg, anti-HBc, and anti HBs was 9 (4.6%), 62 (31.8%), and 96 (49.2%), respectively. Seventy four (37.9%) samples were seronegative for all three parameters, indicating the susceptibility to HBV infection. Among 66 samples positive for HBsAg and/or anti-HBc, 13 (19.7%) were HBV DNA positive; of these, four were HBsAg positive and nine were HBsAg negative, and categorized as occult HBV infection. Most occult HBV cases had high level anti-HBs (>100 IU/l), suggesting that blood with positive anti-HBs and anti HBc could not be regarded as noninfectious. Thirteen amino acid substitutions were identified: T126S, P127S, Q129R, T131N, M133T, and Y161S in the HBsAg positive group; P120T, T126I, G145S, Y161F, E164V, and V168F in the occult-HBV group; and T143S in both groups. More studies are required to provide data on the prevalence and characteristics of mutants to ensure reliable diagnosis. The occult HBV infection, combined with the HBsAg prevalence, could indicate the high HBV carriage among young adults in this area. The high percentage of individuals susceptible to HBV infection reiterates the need for catch-up immunization strategies targeted at young adults. PMID- 25521059 TI - Detection of Dobrava hantavirus RNA in Apodemus mice in Bulgaria. AB - Several Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) in Europe: Dobrava-Belgrade virus (DOBV), Puumala, Saaremaa, Sochi, and Seoul virus. Although HFRS is endemic in Bulgaria, genome sequences of hantaviruses have never been detected in wild rodents. To identify rodent reservoirs, a total of 691 rodents from three endemic regions were trapped in 2011-2012 and screened by TaqMan RT-PCR for detection of hantaviral genomic RNA. Partial small (S) and/or large (L)-segment sequences were recovered from six Apodemus mice: five of the species A. flavicollis and one A. agrarius. Phylogenetic analysis revealed that all recovered sequences belonged to DOBV. On the phylogenetic trees, the novel Bulgarian hantavirus sequences clustered together with sequences of established previously DOBV variants recovered from Bulgarian HFRS patients and also with variants found in wild rodents trapped in Slovenia, Greece, and Slovakia. One of the novel Bulgarian DOBV S-sequences from A. agrarius was related closely to DOBV sequences recovered from A. flavicollis, suggesting a spillover of DOBV from its natural host to A. agrarius mice. The results of this study confirmed the circulation of DOBV in wild rodents in Bulgaria. The complexity of the epidemiological situation in the Balkans requires further studies of hantaviruses in rodent hosts and human HFRS cases. PMID- 25521060 TI - Response. PMID- 25521061 TI - Combining spatial and chemical information for clustering pharmacophores. AB - BACKGROUND: A pharmacophore model consists of a group of chemical features arranged in three-dimensional space that can be used to represent the biological activities of the described molecules. Clustering of molecular interactions of ligands on the basis of their pharmacophore similarity provides an approach for investigating how diverse ligands can bind to a specific receptor site or different receptor sites with similar or dissimilar binding affinities. However, efficient clustering of pharmacophore models in three-dimensional space is currently a challenge. RESULTS: We have developed a pharmacophore-assisted Iterative Closest Point (ICP) method that is able to group pharmacophores in a manner relevant to their biochemical properties, such as binding specificity etc. The implementation of the method takes pharmacophore files as input and produces distance matrices. The method integrates both alignment-dependent and alignment independent concepts. CONCLUSIONS: We apply our three-dimensional pharmacophore clustering method to two sets of experimental data, including 31 globulin-binding steroids and 4 groups of selected antibody-antigen complexes. Results are translated from distance matrices to Newick format and visualised using dendrograms. For the steroid dataset, the resulting classification of ligands shows good correspondence with existing classifications. For the antigen-antibody datasets, the classification of antigens reflects both antigen type and binding antibody. Overall the method runs quickly and accurately for classifying the data based on their binding affinities or antigens. PMID- 25521062 TI - Synthesis and evaluation of novel lipidated neuromedin U analogs with increased stability and effects on food intake. AB - Neuromedin U (NMU) is a 25 amino acid peptide expressed and secreted in the brain and gastrointestinal tract. Data have shown that peripheral administration of human NMU decreases food intake and body weight and improves glucose tolerance in mice, suggesting that NMU receptors constitute a possible anti-diabetic and anti obesity drug target. However, the clinical use of native NMU is hampered by a poor pharmacokinetic profile. In the current study, we report in vitro and in vivo data from a series of novel lipidated NMU analogs. In vitro plasma stability studies of native NMU were performed to investigate the proteolytic stability and cleavage sites using LC-MS. Native NMU was found to be rapidly cleaved at the C terminus between Arg(24) and Asn(25) , followed by cleavage between Arg(16) and Gly(17) . Lipidated NMU analogs were generated using solid-phase peptide synthesis, and in vitro potency was investigated using a human embryonic kidney 293-based inositol phosphate accumulation assay. All lipidated analogs had preserved in vitro activity on both NMU receptors with potency improving as the lipidation site was moved away from the receptor-interacting C-terminal octapeptide segment. In vivo efficacy was assessed in lean mice as reduction in food intake after acute subcutaneous administration of 1, 0.3, 0.1, and 0.03 umol/kg. These lipidated NMU analogs prolonged the anorectic effect of NMU in a dose-dependent manner. This was likely an effect of improved pharmacokinetic properties because of improved vitro plasma stability. Accordingly, the data demonstrate that lipidated NMU analogs may represent drug candidates for the treatment of obesity. PMID- 25521063 TI - Capillary zone electrophoresis method for a highly glycosylated and sialylated recombinant protein: development, characterization and application for process development. AB - A purity method based on capillary zone electrophoresis (CZE) has been developed for the separation of isoforms of a highly glycosylated protein. The separation was found to be driven by the number of sialic acids attached to each isoform. The method has been characterized using orthogonal assays and shown to have excellent specificity, precision and accuracy. We have demonstrated the CZE method is a useful in-process assay to support cell culture and purification development of this glycoprotein. Compared to isoelectric focusing (IEF), the CZE method provides more quantitative results and higher sample throughput with excellent accuracy, qualities that are required for process development. In addition, the CZE method has been applied in the stability testing of purified glycoprotein samples. PMID- 25521064 TI - Mothers' expressed emotion towards children with autism spectrum disorder and their siblings. AB - BACKGROUND: Expressed emotion (EE) is a construct used to measure the emotional climate within families. EE is of interest to researchers in the field of autism spectrum disorder (ASD) because of its putative implications for child development. The aim was to explore whether maternal EE differs towards a child with ASD and a non-disabled sibling. METHODS: We adopted a within-family design with 143 mothers of children with ASD and a non-disabled sibling. EE was measured using the Five-Minute Speech Sample. RESULTS: Wilcoxon signed-rank tests were utilised. Mothers were coded as significantly more critical and less warm towards their child with ASD than towards the sibling. There were no significant differences in maternal emotional overinvolvement or overall EE towards the child with ASD and a sibling. CONCLUSIONS: The data support the results of previous research suggesting that EE is linked to the relationship a mother has with individual children, rather than being evidence of the character disposition of mothers. More research is needed to understand the emotional dimensions of parent child relationships in families with children with ASD. PMID- 25521066 TI - Stomatal function has an element of hysteresis. PMID- 25521065 TI - Word structures of Granada Spanish-speaking preschoolers with typical versus protracted phonological development. AB - BACKGROUND: Research on children's word structure development is limited. Yet, phonological intervention aims to accelerate the acquisition of both speech sounds and word structure, such as word length, stress or shapes in CV sequences. Until normative studies and meta-analyses provide in-depth information on this topic, smaller investigations can provide initial benchmarks for clinical purposes. AIMS: To provide preliminary reference data for word structure development in a variety of Spanish with highly restricted coda use: Granada Spanish (similar to many Hispano-American varieties). To be clinically applicable, such data would need to show differences by age, developmental typicality and word structure complexity. Thus, older typically developing (TD) children were expected to show higher accuracy than younger children and those with protracted phonological development (PPD). Complex or phonologically marked forms (e.g. multisyllabic words, clusters) were expected to be late developing. METHODS & PROCEDURES: Participants were 59 children aged 3-5 years in Granada, Spain: 30 TD children, and 29 with PPD and no additional language impairments. Single words were digitally recorded by a native Spanish speaker using a 103-word list and transcribed by native Spanish speakers, with confirmation by a second transcriber team and acoustic analysis. The program Phon 1.5 provided quantitative data. OUTCOMES & RESULTS: In accordance with expectations, the TD and older age groups had better-established word structures than the younger children and those with PPD. Complexity was also relevant: more structural mismatches occurred in multisyllabic words, initial unstressed syllables and clusters. Heterosyllabic consonant sequences were more accurate than syllable initial sequences. The most common structural mismatch pattern overall was consonant deletion, with syllable deletion most common in 3-year-olds and children with PPD. CONCLUSIONS & IMPLICATIONS: The current study provides preliminary reference data for word structure development in a Spanish variety with restricted coda use, both by age and types of word structures. Between ages 3 and 5 years, global measures (whole word match, word shape match) distinguished children with typical versus protracted phonological development. By age 4, children with typical development showed near-mastery of word structures, whereas 4- and 5-year-olds with PPD continued to show syllable deletion and cluster reduction, especially in multisyllabic words. The results underline the relevance of multisyllabic words and words with clusters in Spanish phonological assessment and the utility of word structure data for identification of protracted phonological development. PMID- 25521067 TI - Location, location, location--no more! The unravelling of chromatin remodeling regulatory aspects of plant metabolic gene clusters. PMID- 25521068 TI - Belowground fine root productivity, traits, and trees. PMID- 25521069 TI - A snapshot of molecular plant-microbe interaction research. PMID- 25521070 TI - Five decades of invasion genetics. PMID- 25521071 TI - Graphene oxide liquid crystals for reflective displays without polarizing optics. AB - The recent emergence of liquid crystals of atomically thin two-dimensional (2D) materials not only has allowed us to explore novel phenomena of macroscopically aligned 2D nanomaterials but also has provided a route toward their controlled assembly into three-dimensional functional macrostructures. Using flow-induced mechanical alignment, we prepared flakes of graphene oxide (GO) in different orientational orders and demonstrated that GO liquid crystals (LC) can be used as rewritable media for reflective displays without polarizing optics. With a wire or stick as a pen, we can make the surface of GO LC reflective and bright, and we can then manually draw lines, curves, and any patterns with dark appearance. The contrast between bright and dark features is due to anisotropic optical responses of ordered GO flakes. Since optical anisotropy is an intrinsic property of 2D structures, our observations and demonstration represent one of many potential applications of macroscopically aligned 2D nanomaterials. PMID- 25521073 TI - Tuning the crystal polymorphs of alkyl thienoacene via solution self-assembly toward air-stable and high-performance organic field-effect transistors. AB - The first example for thienoacene derivatives with selective growth of different crystal polymorphs is simply achieved by solution-phase self-assembly. Compared with platelet-shaped alpha-phase crystals, organic field-effect transistors (OFETs) based on microribbon-shaped beta-phase crystals show a hole mobility up to 18.9 cm(2) V(-1) s(-1), which is one of the highest values for p-type organic semiconductors measured under ambient conditions. PMID- 25521072 TI - Dynamic ordering of early generated striatal cells destined to form the striosomal compartment of the striatum. AB - The mature striatum is divided into a labyrinthine system of striosomes embedded in a surrounding matrix compartment. We pulse-labeled striosomal cells (S cells) and matrix cells (M cells) in cats with (3) H-thymidine and followed their distributions during fetal and postnatal development. We identified three maturational phases in S-cell distributions. The early phase (sampled at embryonic day [E]27-E35 following E24-E28 (3) H-thymidine) was characterized by a transient medial accumulation of synchronously generated S cells within the caudate nucleus adjoining the ganglionic eminence, potentially a waiting compartment. Band-like arrangements of synchronously generated S cells then formed beyond this medial band. During the second phase (sampled at E38-E45), the loosely banded S-cell distributions were transformed into clustered arrangements typical of developing striosomes. In the third phase (sampled from E52 into the postnatal period), these developed into the typical mature striosomal architecture. At adulthood, gentle mediolateral birthdate-gradients in S cells were still evident, but M cells, produced over mid to late prenatal ages, became broadly distributed, without apparent gradients or banding arrangements. These findings suggest that the maturational histories of the striosomal and matrix neurons are influenced by their generation times and local environments, and that future S cells have transient, nonstriosomal distributions prior to their aggregation into striosomal clusters, including a putative waiting compartment. Further, the eventual patterning of the striosomal compartment reflects outside in, band-like gradient patterns of settling of synchronously generated S cells, patterns that could be related both to neural processing in the mature striatum and to patterns of vulnerability of striatal neurons. PMID- 25521074 TI - Regional disparities in obesity prevalence in the United States: A spatial regime analysis. AB - OBJECTIVE: Significant clusters of high- and low-obesity counties have been demonstrated across the United States (US). This study examined regional disparities in obesity prevalence and differences in the related structural characteristics across regions of the US. METHODS: Drawing on model-based estimates from the Centers for Disease Control and Prevention, regional differences in county-level adult obesity prevalence (percent of the adult population [>= 20 years] that was obese [BMI >= 30 kg/m(2) ] within a county, 2009) were assessed with a LISA (Local Indicators of Spatial Association) analysis to identify geographic concentrations of high and low obesity levels. Regional regime analysis was utilized to identify factors that were differentially associated with obesity prevalence between regions of the US. RESULTS: High- and low-obesity county clusters and the effect of a number of county-level characteristics on obesity prevalence differed significantly by region. These included the positive effect of African American populations in the South, the negative effect of Hispanic populations in the Northeast, and the positive effect of unemployed workers in the Midwest and West. CONCLUSIONS: Our findings suggest the need for public health policies and interventions that account for different regional characteristics underlying obesity prevalence variation across the US. PMID- 25521076 TI - Bifunctional Zn(II) complexes for recognition of non-canonical thymines in DNA bulges and G-quadruplexes. AB - Six Zn(II) complexes of derivatives of 1,4,7,10-tetraazacyclododecane (cyclen) were studied for binding to DNA sequences containing non-canonical thymines, including a hairpin with a single thymine bulge (T-bulge) and a G-quadruplex (H telo) containing thymine loops. The cyclen-based macrocycles contained pendents with either two fused rings to give planar groups including quinolinone (QMC), coumarin (MCC) and quinoline (CQC) derivatives or a non-planar dansyl group (DSC). Macrocyclic complexes with three fused rings including an anthraquinone pendent (ATQ) were also studied. All Zn(II) complexes were stable in solution at micromolar concentrations and neutral pH with the Zn(L)(OH2) species prevailing for L = QMC and CQC at pH 7.5 and 100 mM NaCl. Immobilized T-bulge or H-telo G quadruplex was used to study binding of the complexes by surface plasmon resonance (SPR) for several of the complexes. For the most part, data matched well with that obtained by isothermal calorimetry (ITC) and, for fluorescent complexes, by fluorescence titrations. Data showed that Zn(II) complexes containing planar aromatic pendents with two fused rings bound to T-bulge more tightly than complexes with non-planar pendents such as DSC. The H-telo DNA exhibited multiple binding sites for all complexes containing aromatic pendents. The complexes with two fused rings bound with low micromolar dissociation constants and two binding sites whereas a complex with three fused rings (ATQ) bound to three sites. This study shows that different pendent groups on Zn(II) cyclen complexes impart selectivity for recognition of non-canonical DNA structures. PMID- 25521075 TI - Synergistic anti-tumour effects of tetrandrine and chloroquine combination therapy in human cancer: a potential antagonistic role for p21. AB - BACKGROUND AND PURPOSE: Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the Chinese medicinal herb Stephaniae tetrandrae, has a long history in Chinese clinical applications to treat diverse diseases. Tetrandrine induced apoptosis or, at low concentrations, autophagy of human hepatocellular carcinoma cells. Here we have tested the effects of inhibitors of autophagy such as chloroquine, on the response to low concentrations of tetrandrine in cancer cells. EXPERIMENTAL APPROACH: Cultures of several cancer cell lines, including Huh7, U251, HCT116 and A549 cells, were exposed to tetrandrine, chloroquine or a combination of these compounds. Cell viability and content of reactive oxygen species (ROS) were measured and synergy assessed by calculation of the combination index. Western blot and RT-PCR assays were also used along with fluorescence microscopy and histochemical techniques. KEY RESULTS: Combinations of tetrandrine and chloroquine were more cytotoxic than the same concentrations used separately and these effects showed synergy. Such effects involved increased ROS generation and were dependent on caspase-3 but independent of Akt activity. Blockade of tetrandrine-induced autophagy with 3-methyladenine or bafilomycin-A1 induced apoptosis in cancer cells. Lack of p21 protein (p21(-/-) HCT116 cells) increased sensitivity to the apoptotic effects of the combination of tetrandrine and chloroquine. In a tumour xenograft model in mice, combined treatment with tetrandrine and chloroquine induced ROS accumulation and cell apoptosis, and decreased tumour growth. CONCLUSIONS AND IMPLICATIONS: The combinations of tetrandrine and chloroquine exhibited synergistic anti-tumour activity, in vitro and in vivo. Our results suggest a novel therapeutic strategy for tumour treatment. PMID- 25521077 TI - Concise total syntheses of amphidinolides C and F. AB - The marine natural products amphidinolide C (1) and F (4) differ in their side chains but share a common macrolide core with a signature 1,4-diketone substructure. This particular motif inspired a synthesis plan predicating a late stage formation of this non-consonant ("umpoled") pattern by a platinum-catalyzed transannular hydroalkoxylation of a cycloalkyne precursor. This key intermediate was assembled from three building blocks (29, 41 and 47 (or 65)) by Yamaguchi esterification, Stille cross-coupling and a macrocyclization by ring-closing alkyne metathesis (RCAM). This approach illustrates the exquisite alkynophilicity of the catalysts chosen for the RCAM and alkyne hydroalkoxylation steps, which activate triple bonds with remarkable ease but left up to five other pi-systems in the respective substrates intact. Interestingly, the inverse chemoselectivity pattern was exploited for the preparation of the tetrahydrofuran building blocks 47 and 65 carrying the different side chains of the two target macrolides. These fragments derive from a common aldehyde precursor 46 formed by an exquisitely alkene-selective cobalt-catalyzed oxidative cyclization of the diunsaturated alcohol 44, which left an adjacent acetylene group untouched. The northern sector 29 was prepared by a two-directional Marshall propargylation strategy, whereas the highly adorned acid subunit 41 derives from D-glutamic acid by an intramolecular oxa-Michael addition and a proline-mediated hydroxyacetone aldol reaction as the key steps; the necessary Me3 Sn-group on the terminus of 41 for use in the Stille coupling was installed via enol triflate 39, which was obtained by selective deprotonation/triflation of the ketone site of the precursor 38 without competing enolization of the ester also present in this particular substrate. PMID- 25521079 TI - Treatment costs for advanced prostate cancer using luteinizing hormone-releasing hormone agonists: a solid biodegradable leuprorelin implant versus other formulations. AB - AIM: To compare treatment costs with alternative luteinizing hormone-releasing hormone (LHRH) agonist preparations and determine whether a leuprorelin solid implant is associated with potential cost savings. PATIENTS & METHODS: A hypothetical population of 1000 prostate cancer patients was apportioned between the three most commonly-prescribed LHRH agonist preparations. Differentiated annual costs for 1- and 3-monthly formulations were calculated for France, Germany, Italy, Spain, the UK (EU5) and Sweden, and compared with the leuprorelin solid implant. RESULTS: Compared with alternative formulations, leuprorelin solid implants had potential annual cost savings/1000 patients of ?353,000 (EU5) and ?699,000 (Sweden; 1-month formulations), and ?259,000 (EU5) and ?300,000 (Sweden; 3-month formulations). CONCLUSION: The leuprorelin solid implant was associated with potential cost savings compared with the most commonly used LHRH agonist preparations. PMID- 25521081 TI - Easy-to-fabricate thin-film coating on PDMS substrate with super hydrophilicity and stability. AB - With the fast expansion of microfluidic applications, stable, and easy-to fabricate PDMS surface coating with super hydrophilicity is highly desirable. In this study, we introduce a new kind of copolymer-based, single-layer thin-film coating for PDMS. The coating can exist in air at room temperature for at least 6 months without any noticeable deterioration in the super hydrophilicity (water contact angle ~7 degrees ), resistance of protein adsorption, or inhibition of the EOF. In addition, this coating enables arbitrary patterning of cells on planar surfaces. PMID- 25521080 TI - Hen egg-white lysozyme crystallisation: protein stacking and structure stability enhanced by a Tellurium(VI)-centred polyoxotungstate. AB - As synchrotron radiation becomes more intense, detectors become faster and structure-solving software becomes more elaborate, obtaining single crystals suitable for data collection is now the bottleneck in macromolecular crystallography. Hence, there is a need for novel and advanced crystallisation agents with the ability to crystallise proteins that are otherwise challenging. Here, an Anderson-Evans-type polyoxometalate (POM), specifically Na6 [TeW6 O24 ]?22 H2 O (TEW), is employed as a crystallisation additive. Its effects on protein crystallisation are demonstrated with hen egg-white lysozyme (HEWL), which co-crystallises with TEW in the vicinity (or within) the liquid-liquid phase separation (LLPS) region. The X-ray structure (PDB ID: 4PHI) determination revealed that TEW molecules are part of the crystal lattice, thus demonstrating specific binding to HEWL with electrostatic interactions and hydrogen bonds. The negatively charged TEW polyoxotungstate binds to sites with a positive electrostatic potential located between two (or more) symmetry-related protein chains. Thus, TEW facilitates the formation of protein-protein interfaces of otherwise repulsive surfaces, and thereby the realisation of a stable crystal lattice. In addition to retaining the isomorphicity of the protein structure, the anomalous scattering of the POMs was used for macromolecular phasing. The results suggest that hexatungstotellurate(VI) has great potential as a crystallisation additive to promote both protein crystallisation and structure elucidation. PMID- 25521078 TI - Cellular oxidative stress response controls the antiviral and apoptotic programs in dengue virus-infected dendritic cells. AB - Dengue virus (DENV) is a re-emerging arthropod borne flavivirus that infects more than 300 million people worldwide, leading to 50,000 deaths annually. Because dendritic cells (DC) in the skin and blood are the first target cells for DENV, we sought to investigate the early molecular events involved in the host response to the virus in primary human monocyte-derived dendritic cells (Mo-DC). Using a genome-wide transcriptome analysis of DENV2-infected human Mo-DC, three major responses were identified within hours of infection - the activation of IRF3/7/STAT1 and NF-kappaB-driven antiviral and inflammatory networks, as well as the stimulation of an oxidative stress response that included the stimulation of an Nrf2-dependent antioxidant gene transcriptional program. DENV2 infection resulted in the intracellular accumulation of reactive oxygen species (ROS) that was dependent on NADPH-oxidase (NOX). A decrease in ROS levels through chemical or genetic inhibition of the NOX-complex dampened the innate immune responses to DENV infection and facilitated DENV replication; ROS were also essential in driving mitochondrial apoptosis in infected Mo-DC. In addition to stimulating innate immune responses to DENV, increased ROS led to the activation of bystander Mo-DC which up-regulated maturation/activation markers and were less susceptible to viral replication. We have identified a critical role for the transcription factor Nrf2 in limiting both antiviral and cell death responses to the virus by feedback modulation of oxidative stress. Silencing of Nrf2 by RNA interference increased DENV-associated immune and apoptotic responses. Taken together, these data demonstrate that the level of oxidative stress is critical to the control of both antiviral and apoptotic programs in DENV-infected human Mo-DC and highlight the importance of redox homeostasis in the outcome of DENV infection. PMID- 25521082 TI - Mesenteric and Mediastinal Lymphadenopathy in Egyptian Children With Gaucher Disease Types 1 and 3 Treated With Enzyme Replacement Therapy. AB - Gaucher disease (GD) is characterized by 3 clinical subtypes; type 1 GD (non neuronopathic) and types 2 and 3 GD (acute and chronic neuronopathic forms, respectively). There are few reports of mesenteric and mediastinal lymphadenopathy, and none in type 1 GD or in African people. We report 8 Egyptian GD children (3 type 1 GD and 5 type 3 GD) who developed mesenteric and mediastinal lymphadenopathy despite receiving enzyme replacement therapy. Biopsy showed infiltration with Gaucher cells and no malignant changes. Pediatric physicians should be aware of possible lymphadenopathy associated with both types 1 and 3 GD as it can mimic malignancy. PMID- 25521083 TI - Cytomegalovirus Disease in Children With Acute Lymphoblastic Leukemia in the Nontransplant Setting: Case Series and Review of the Literature. AB - Cytomegalovirus (CMV) disease in pediatric acute lymphoblastic leukemia in the nontransplant setting is very rare. We report our experience with 4 such cases, and review the literature (n=12). The median age at diagnosis was 10 years and 50% of patients were males. Among the 11 cases with available information at the time of diagnosis, CMV disease occurred during maintenance therapy in 10 patients. Fever was present in 9 cases. CMV disease manifested as retinitis in 6, hepatosplenic disease in 3, pneumonitis in 1, and hemophagocytic lymphohistiocytosis in 1 patient. One patient had both CMV retinitis and CMV related hemophagocytic lymphohistiocytosis. Four of the 7 patients with retinitis complained of visual disturbance at diagnosis. CMV viremia was present in 10 patients. Three patients had at least 1 relapse and developed permanent visual defects, and 1 patient developed recurrent retinal detachment. In conclusion, prolonged immunosuppression is the major etiology and retinitis is the most common manifestation of CMV disease. As a significant number of patients with retinitis are asymptomatic, early diagnosis and treatment is important to prevent permanent visual loss. PMID- 25521084 TI - Neuroblastoma and spinal muscular atrophy. PMID- 25521085 TI - Does admission via an acute medical unit influence hospital mortality? 12 years' experience in a large Dublin hospital. AB - BACKGROUND: Following an emergency medical admission, patients may be admitted an acute medical assessment unit (AMAU) or directly into a ward. An AMAU provides a structured environment for their initial assessment and treatment. METHODS: All emergency admissions (66,933 episodes in 36,271 patients) to an Irish hospital over an 12-year period (2002-2013) were studied with 30-day in-hospital mortality as the outcome measure. Univariate Odds Ratios, by initial patient allocation, and the fully adjusted Odds Ratios were calculated, using a validated logistic regression model. RESULTS: Patients, by design, were intended to be admitted initially to the AMAU (<= 5 day stay). Capacity constraints dictated that only 39.8% of patients were so admitted; the remainder bypassed the AMAU to a ward (60.2%). All patients remained under the care of the admitting consultant/team. We computed the risk profile for each group, using a multiple variable validated model of 30-day in-hospital mortality; the model indicated the same risk profile between these groups. The univariate OR of an in-hospital death by day 30 for a patient initially allocated to the AMAU, compared with an initial ward allocation was 0.76 (95% CI: 0.71, 0.82- p<0.001). The fully adjusted risk for patients was 0.67 (95% CI: 0.62, 0.73- p<0.001). CONCLUSION: Patients, with equivalent mortality risk, allocated initially to AMAU or a more traditional ward, appeared to have substantially different outcomes. PMID- 25521086 TI - Developing and evaluating nurse led discharge in acute medicine. AB - AIMS: To develop and evaluate nurse-led discharge criteria for a clinical decision unit in a large NHS Foundation Trust METHOD: Criteria for nurse led discharge were developed for patients presenting to hospital via the emergency department with chest pain, headache and deliberate self poisoning. Data on length of stay on CDU and readmission were collected for these patient groups during a 2 month period, during which the nurse-led criteria were introduced. Following introduction of the criteria a survey was conducted to evaluate staff opinions of the new system. RESULTS: A trend towards reduced length of stay was noted during the month after introduction of nurse-led discharge (18.26 hrs vs 20 hours p=0.582). Our staff survey indicated that the process was popular and has been continued since the study period. CONCLUSION: Nurse-led discharge using defined criteria is feasible and popular with staff in an acute medical setting. PMID- 25521087 TI - The perils of Grandma's medication: colchicine toxicity causing pneumomediastinum. AB - A 19 year old male presented with a deliberate overdose of colchicine (50mg). He had no other significant medical history. 36 hours following admission he developed widespread surgical emphysema. An urgent CT scan of his chest and abdomen demonstrated mediastinal gas of lung origin. He also developed bone marrow suppression and disseminated intravascular coagulopathy. He was treated supportively with intravenous fluids, high flow oxygen and intravenous antibiotics and made a full recovery. Colchicine toxicity is a rare, but important presentation with high levels of morbidity and mortality. Pneumomediastinum is a potentially important complication. It may be appropriate to monitor patients in the later stages of the condition through an ambulatory setting. PMID- 25521088 TI - A patient with pleuritic chest pain and abnormal blood clotting tests. AB - We present the case of a 58 year old man who developed pleuritic chest while an in-patient; investigations revealed pulmonary embolism, despite a significantly raised Activated Partial Thromboplastin Time (APTT), which was subsequently attributed to Antiphospholipid syndrome (APS). The diagnosis and initial management of APS in the acute setting is discussed. PMID- 25521089 TI - Weil's disease presenting as atypical pneumonia. AB - Leptospirosis is a disease caused by spp. Leptospira, also known as Weil's disease if it manifests with jaundice. It can be associated with respiratory, renal, hepatic and haematological complications and most importantly carries a high mortality when untreated. We describe a case of a 53 year old man presenting with myalgia and fever in whom the diagnosis of leptospirosis was not initially considered. Following a deterioration in his condition a careful history revealed an apparent brief exposure to animal urine and subsequent grossly positive Leptospira serology. Treatment of his condition led to complete resolution after a brief stay on the intensive care unit. This case highlights the atypical nature of a presentation of Leptospirosis, its respiratory complications, and importance of serological testing in its diagnosis. PMID- 25521090 TI - Are the skills of neurological assessment in need of resuscitation? AB - The aim of this paper is to outline the background to several recent papers which highlight deficiencies in acute neurological care-all of which highlight (to differing degrees) issues in relation to neurological assessment with some proposed solutions. Given that 10% of acute emergency admissions are for neurological conditions (up to 20% if stroke included), this should be of concern to all acute medical physicians. PMID- 25521091 TI - Block copolypeptide nanoparticles for the delivery of ocular therapeutics. AB - Self-assembling block copolypeptides were prepared by sequential ring-opening polymerization of N-carboxyanhydride (NCA) derivatives of gamma-benzyl-L-glutamic acid and epsilon-carbobenzyloxy-L-lysine, followed by selective deprotection of the benzyl glutamate block. The synthesized polymers had number average molecular weights close to theoretical values, and had low dispersities (DM = 1.15-1.28). Self-assembly of the amphiphilic block copolymers into nanoparticles was achieved using the "solvent-switch" method, whereby the polymer was dissolved in THF and water and the organic solvent removed by rotary evaporation. The type of nanostructures formed varied from spherical micelles to a mixture of spherical and worm-like micelles, depending on copolymer composition. The spherical micelles had an average diameter of 43 nm by dynamic light scattering, while the apparent diameter of the mixed phase system was around 200 nm. Reproducibility of nanoparticle preparation was demonstrated to be excellent; almost identical DLS traces were obtained over three repeats. Following qualitative dye-solubilization experiments, the nanoparticles were loaded with the ocular anti-inflammatory drug dexamethasone. Loading efficiency of the nanoparticles was 90% and the cumulative drug release was 94% over 16 d, with a 20% burst release in the first 24 h. PMID- 25521092 TI - Bulk graphdiyne powder applied for highly efficient lithium storage. AB - Here, we prepared bulk graphdiyne (GDY) powder with porous structure and explored its lithium storage properties. The assembled lithium ion batteries exhibited superior electrochemical performance, including high specific capacity, excellent rate performance and long cycle life, which should be attributed to the unique structure, high electronic conductivity and chemical stability of GDY. PMID- 25521094 TI - Across the board: Licheng Sun. AB - In this series of articles the board members of ChemSusChem discuss recent research articles that they consider of exceptional quality and importance for sustainability. In this entry, Prof. Licheng Sun discusses how solar fuel production (such as water splitting) can be made more efficient and economic on an industrial scale. Recommended is the work by Prof. Xuping Sun, who use non noble metal-phosphorus-based nanostructures as efficient electrocatalysts for hydrogen generation from water. PMID- 25521093 TI - Relative expression of vascular endothelial growth factor isoforms in squamous cell carcinoma of the head and neck. AB - BACKGROUND: Alternative splicing of the vascular endothelial growth factor (VEGF) gene results in a family of antiangiogenic isoforms (VEGFxxx b), not yet investigated in squamous cell carcinoma of the head and neck (SCCHN). We examined, therefore, the prognostic value of the relative expression of VEGF isoforms in SCCHN. METHODS: A tissue microarray comprising 187 SCCHNs was studied by immunohistochemistry with total VEGF (panVEGF) and VEGFxxx b-specific antibodies, and scored by 2 assessors for intensity and proportion. Scores were combined and expression ratios calculated. RESULTS: No meaningful significant differences were observed between panVEGF, VEGFxxx b, or expression ratio, and presence of lymphatic metastasis, or overall survival. This held true when tumor subsites were analyzed independently and when human papillomavirus (HPV) was accounted for in the oropharyngeal subgroup. CONCLUSION: Differential VEGF isoform expression is not a reliable prognostic biomarker for either the clinically node negative/pathologically node-positive neck or overall survival in pharyngeal and laryngeal SCCHNs. PMID- 25521095 TI - The next generation of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of lung cancer. AB - The discovery of "driver" genomic alterations in patients with non-small cell lung cancer (NSCLC) has dramatically changed the field of thoracic oncology in recent years. The best understood of these molecular drivers are those involving the epidermal growth factor receptor (EGFR), which when aberrantly activated are integral to the development of a subset of NSCLC tumors. First-generation and second-generation tyrosine kinase inhibitors (TKIs) specific to the activated EGFR have shown significant efficacy and have brought about the era of targeted therapy for NSCLC. The most common resistance mechanism is a threonine-to methionine substitution (T790M) in exon 20 of the EGFR gene. Although the previous standard of care in patients with EGFR-mutated NSCLC that progressed on initial TKI therapy was chemotherapy, third-generation EGFR TKIs have now been developed and have yielded promising results for this population of patients with NSCLC. This article reviews the emerging data regarding third-generation agents in the treatment of patients with advanced NSCLC. PMID- 25521096 TI - Deep reads: strands in the history of molecular genetics. PMID- 25521097 TI - Complete response of huge buccal malignant melanoma in an octogenarian patient to arterial chemotherapy. AB - BACKGROUND: Primary oral mucosal melanoma is uncommon. However, it is an aggressive entity, and the absence of a standardized treatment protocol makes for an extremely poor prognosis. METHODS: We described the clinical course and treatment by arterial chemotherapy of an 87-year-old patient with nonresectable huge buccal malignant melanoma. Continuous intra-arterial infusion of fluorouracil (50 mg/24 hours) and 1 intermittent weekly 10-mg shot of cisplatin were given. RESULTS: The patient with oral melanoma presented with a roughly 6- * 4-cm exophytic mass that was noticed on the right buccal mucosa. The buccal tumor regressed dramatically until complete disappearance of the tumor mass was achieved at 2.5 months after intra-arterial chemotherapy was initiated. In total, 2880 mg of fluorouracil and 80 mg of cisplatin were administrated. The side effects of intra-arterial chemotherapy were mild and tolerable. CONCLUSION: Our data demonstrate that intra-arterial chemotherapy could be an alternative treatment for nonresectable buccal malignant melanoma. PMID- 25521098 TI - Prediction of postoperative pain after Mohs micrographic surgery with 2 validated pain anxiety scales. AB - BACKGROUND: Anxiety toward pain has been shown in several studies to increase postoperative pain after surgical procedures. This anxiety can be measured by several validated questionnaires, the Pain Catastrophizing Scale (PCS) and the Pain Anxiety Symptoms Scale (PASS). Higher scores on these scales correlate with increased pain after surgery, but this has not yet been demonstrated in dermatologic surgery. OBJECTIVE: To assess whether pain anxiety will predict postoperative pain after Mohs micrographic surgery (MMS). MATERIALS AND METHODS: Patients at 2 private Mohs practices were recruited to fill out 2 pain questionnaires, the PCS and the PASS. Their postoperative pain was assessed after MMS. RESULTS: Three hundred fifty-six patients completed the study. Overall, most patients experienced little postoperative pain after Mohs surgery. However, for people with high anxiety toward pain, they also experienced statistically significant greater postoperative pain. Other factors that contributed to greater postoperative pain included female gender and lower extremity location. Second intention healing had lower pain than other repair types. CONCLUSION: This study shows that postoperative pain is affected by pain anxiety, even in dermatologic surgery. However, most patients still had very little discomfort after surgery, further supporting MMS as an effective and safe procedure with relatively few postoperative problems. PMID- 25521099 TI - Anatomy of facial and trigeminal nerve branches associated with the corrugator supercilii muscle: microdissection and modified Sihler staining. AB - BACKGROUND: Deactivation of the corrugator supercilii for the treatment of unintentional glabellar lines requires high selectivity to avoid sensory complications. OBJECTIVE: The aim of this study was to delineate the topographic anatomy of facial and trigeminal nerves in relation to the corrugator supercilii to improve the selectivity and safety of deactivation of the corrugator supercilii muscle. MATERIALS AND METHODS: The number, courses, and attachments of the facial nerve to the corrugator supercilii muscle were investigated by dissection of 27 cadaveric hemifaces. Twelve cadaveric hemiforehead flaps were stained using a modified Sihler method to trace the supraorbital and supratrochlear branches. RESULTS: On average, 1.8 branches of the facial nerve at the zygomatic arch were associated with the corrugator supercilii muscle through 1 (29.3%) or 2 terminal rami (70.7%). The trigeminal nerve gave off 7.7 supraorbital and 5.1 supratrochlear branches emerging from orbit. The majority of the supraorbital branches became intramuscular branches (60.4%), whereas the majority of the supratrochlear branches became superficial branches (67.8%). CONCLUSION: Resection of the muscle may damage the intramuscular trigeminal branches, leading to sensory changes. The course of the facial nerve branches to the corrugator supercilii muscle was much more predictable at their distal part than the proximal part. PMID- 25521100 TI - Sebaceous carcinoma: review of the literature. AB - BACKGROUND: Sebaceous carcinoma is an uncommon adnexal neoplasm with a documented capability for regional and distant metastasis. Traditionally, sebaceous carcinoma has been associated with high rates of recurrence after excision. OBJECTIVE: To review the current literature on sebaceous carcinoma and detail its epidemiology, pathogenesis, clinical presentation, histopathology, diagnostic workup, treatment, and prognosis. MATERIALS AND METHODS: Literature review using PubMed search for articles related to sebaceous carcinoma. RESULTS: Sebaceous carcinoma typically presents as a painless pink or yellow nodule. Diagnosis requires histopathologic examination, and immunohistochemical analysis often assists in the differentiation of sebaceous carcinoma from other benign and malignant skin neoplasms. Sebaceous carcinoma should prompt a workup for Muir Torre syndrome. Periorbital sebaceous carcinoma has an increased tendency for regional metastasis, although cancer-specific mortality rates are similar among all anatomic locations. CONCLUSION: Surgery is the preferred treatment for local disease. Limited data suggest that Mohs micrographic surgery may provide superior clinical outcomes, but more research is needed regarding the long-term outcomes. Radiation and systemic chemotherapy are reserved for recurrent or metastatic disease. PMID- 25521101 TI - A review of the aesthetic treatment of abdominal subcutaneous adipose tissue: background, implications, and therapeutic options. AB - BACKGROUND: The demand for aesthetic body sculpting procedures has expanded precipitously in recent years. Subcutaneous adipose tissue (SAT) deposits of the central abdomen are especially common areas of concern for both males and females. OBJECTIVE: To review the available literature regarding the underlying pathophysiology of subcutaneous fat accumulation in the abdominal area and available treatment options. METHODS: A MEDLINE and Google Scholar search was performed accordingly. RESULTS: The preferential accumulation of SAT in the central abdomen is attributable to the reduced lipolytic sensitivity of its adipocytes. A number of therapeutic options are available for the treatment of central abdominal adiposity. Cryolipolysis, high-intensity focused ultrasound, nonthermal ultrasound, radiofrequency, and injection adipolysis lead to adipocyte destruction through multiple different mechanisms. Nonablative modalities such as injection lipolysis mobilize fat stores from viable adipocytes, although its effects may be curtailed in obese patients. Liposuction through tumescent technique, however, mechanically extricates SAT. CONCLUSION: Although tumescent liposuction remains the gold standard for SAT removal, less invasive ablative and nonablative options for targeting localized deposits of adipose tissue now permeate the aesthetic marketplace. Limited results associated with these modalities mandate multiple sessions or combination treatment paradigms. PMID- 25521102 TI - An analysis of 72% chromated glycerin used for sclerotherapy: sterility, potency, and cost after extended shelf life. AB - BACKGROUND: Sclerotherapy is the treatment of reticular veins and telangiectasias of the lower extremities. Sclerosants destroy endothelial tissue and expose subendothelial collagen fibers, which lead to subsequent fibrosis of vessels, thus preventing recanalization. There are several available sclerosants including sodium tetradecyl sulfate (STS), polidocanol (POL), and chromated glycerin (CG) with varying efficacy, potency, side effect profile, and cost. OBJECTIVE: To identify the possible bacterial contamination and potency of CG beyond the current recommended shelf life of 3 months and to prove if CG is as cost effective as other available sclerosants. METHODS: Samples of 72% CG underwent bacterial endotoxin, sterility, and potency analysis at Days 0, 24, and 183. In addition, cost comparison was performed with other commercially available sclerosants including STS and POL. RESULTS: No samples of CG showed any bacterial contamination. All aliquots of glycerin remained sterile at Day 14. Potency at Day 24 was 99.2%, which was the same at Day 183. Cost comparison with other sclerosants revealed that CG is lower cost per milliliter than STS and POL. CONCLUSION: Seventy-two percent CG has no contamination and maintains its reported potency up to 6 months while comparable with the cost of other commercially available sclerosants. PMID- 25521103 TI - A multicenter, randomized, double-blind clinical study to evaluate the efficacy and safety of PP-501-B in correction of nasolabial folds. AB - BACKGROUND: Many new brands of hyaluronic acid (HA) fillers are being produced, but comparative research on the characteristics of similar products is limited. OBJECTIVE: To test the efficacy, tolerability, and safety of a new HA filler, PP 501-B (Cleviel Contour; Pacific Pharma, Seoul, Korea), which is used for correcting nasolabial folds (NLFs), and to compare the performance of PP-501-B with that of Restylane Perlane (Q-Med). MATERIALS AND METHODS: A total of 103 subjects with visible NLFs were enrolled in this randomized, multicenter, patient/evaluator-blind, active-controlled, matched-pair clinical study. Each subject was injected with PP-501-B in 1 NLF and Restylane Perlane in the other. All participants were reassessed for cosmetic changes at 8, 16, and 24 weeks. Wrinkle severity was rated using the 5-point Wrinkle Severity Rating Scale (WSRS). RESULTS: At Week 24, the mean improvement in the WSRS compared with baseline was 1.87 +/- 0.73 for the PP-501-B side and 1.92 +/- 0.71 for the Restylane Perlane side. Both fillers were well tolerated, and adverse reactions were mild. CONCLUSION: The new HA filler, PP-501-B, to the market, with suitable characteristics and ample safety profiles, will widen the selection of agents for physicians and patients because the purpose, area, and depth of filler injections vary. PMID- 25521104 TI - Antiseptic use in Mohs and reconstructive surgery: an American College of Mohs Surgery member survey. PMID- 25521105 TI - Effects of lidocaine on random skin flap survival in rats. AB - BACKGROUND: Use of a random skin flap is common for repairing wounds and for reconstruction. Lidocaine is a traditional local anesthetic that blocks sodium channels and has positive effects on ischemia-reperfusion injury. OBJECTIVE: To investigate the effects of lidocaine on random skin flap survival in rats. MATERIALS AND METHODS: McFarlane flaps were established in 20 rats divided into 2 groups. Lidocaine was injected in the lidocaine group, and the same concentration of saline was injected in the control group. The survival area of the flaps was measured on Day 7. Levels of inflammation were evaluated by hematoxylin and eosin (H&E)-stained slices, and superoxide dismutase and malonyldialdehyde contents were examined. RESULTS: The mean survival area of the flaps in the lidocaine group was significantly larger than that in the control group. Superoxide dismutase activity increased significantly in the lidocaine group compared with that in the control group. Malonyldialdehyde level in the lidocaine group was significantly lower than that in the control group. The H&E-stained slices showed that inflammation was clearly inhibited in the lidocaine group. CONCLUSION: Lidocaine improved the survival of random skin flaps. PMID- 25521106 TI - Nail melanoma in situ: clinical, dermoscopic, pathologic clues, and steps for minimally invasive treatment. AB - BACKGROUND: Nail unit melanoma (NUM) is a variant of acral lentiginous melanoma. The differential diagnosis is wide but an acquired brown streak in the nail of a fair-skinned adult person must be considered a potential melanoma. Dermoscopy helps clinicians to more accurately decide if a nail apparatus biopsy is necessary. OBJECTIVE: Detailed evaluation of clinical and dermoscopy features and description of conservative surgery of in situ NUM. METHODS: Retrospective study of in situ NUM diagnosed and treated with conservative surgical management in the authors' center from 2008 to 2013. RESULTS: Six cases of NUM were identified: 2 male and 4 female patients, age range at diagnosis of 44 to 76 years. All patients underwent complete nail unit removal with at least 6-mm security margins around the anatomic boundaries of the nail. The follow-up varies from 4 to 62 months. CONCLUSION: Nail unit melanomas pose a difficult diagnostic and therapeutic challenge. Wide excision is sufficient, whereas phalanx amputation is unnecessary and associated with significant morbidity for patients with in situ or early invasive melanoma. Full-thickness skin grafting or second-intention healing after total nail unit excision is a simple procedure providing a good functional and cosmetic outcome. PMID- 25521107 TI - Carbon arc lamp non-solar UV-B radiation and mathematical comparison to solar UV B as a cause of basal cell carcinoma. PMID- 25521108 TI - CO2 laser treatment for regional cutaneous malignant melanoma metastases. AB - BACKGROUND: Cutaneous in-transit and satellite metastases are distressing presentations of melanoma progression. OBJECTIVE: The purpose of this study was to analyze the efficacy of carbon dioxide (CO2) lasers in patients with melanoma with cutaneous in-transit and satellite metastases. MATERIALS AND METHODS: Results of CO2 laser therapy were retrospectively evaluated in 22 patients between January 2004 and January 2008. The number of laser treatments, postoperative morbidity, regional control, and overall survival were analyzed. RESULTS: Twenty-two patients received a total of 42 CO2 laser treatments. The number of lesions treated per session varied from 3 to 329. The median duration of regional control in all patients was 14 weeks (range, 3-117). In 9 of 22 patients, only 1 treatment with CO2 laser was performed resulting in a mean regional control of 11 weeks. In 10 patients, an average of 4 laser treatments (range, 1-17) was necessary to achieve regional control. Three of the 22 patients underwent isolated limb perfusion after laser treatment for disease control. CONCLUSION: This study shows that (repeated) laser treatment can achieve adequate regional control with little morbidity. CO2 laser is recommended as a first-line treatment to patients with small but numerous cutaneous satellite or in-transit lesions in whom other surgery would induce substantial morbidity. PMID- 25521109 TI - Symmetry restoring bifurcation in collective decision-making. AB - How social groups and organisms decide between alternative feeding sites or shelters has been extensively studied both experimentally and theoretically. One key result is the existence of a symmetry-breaking bifurcation at a critical system size, where there is a switch from evenly distributed exploitation of all options to a focussed exploitation of just one. Here we present a decision-making model in which symmetry-breaking is followed by a symmetry restoring bifurcation, whereby very large systems return to an even distribution of exploitation amongst options. The model assumes local positive feedback, coupled with a negative feedback regulating the flow toward the feeding sites. We show that the model is consistent with three different strains of the slime mold Physarum polycephalum, choosing between two feeding sites. We argue that this combination of feedbacks could allow collective foraging organisms to react flexibly in a dynamic environment. PMID- 25521110 TI - Improved optical sintering efficiency at the contacts of silver nanowires encapsulated by a graphene layer. AB - Graphene/silver nanowire (AgNWs) stacked electrodes, i.e., graphene/AgNWs, are fabricated on a glass substrate by air-spray coating of AgNWs followed by subsequent encapsulation via a wet transfer of single-layer graphene (SLG) and multilayer graphene (MLG, reference specimen) sheets. Here, graphene is introduced to improve the optical sintering efficiency of a xenon flash lamp by controlling optical transparency and light absorbing yield in stacked graphene/AgNW electrodes, facilitating the fusion at contacts of AgNWs. Intense pulsed light (IPL) sintering induced ultrafast (<20 ms) welding of AgNW junctions encapsulated by graphene, resulting in approximately a four-fold reduction in the sheet resistance of IPL-treated graphene/AgNWs compared to that of IPL-treated AgNWs. The role of graphene in IPL-treated graphene/AgNWs is further investigated as a passivation layer against thermal oxidation and sulfurization. This work demonstrates that optical sintering is an efficient way to provide fast welding of Ag wire-to-wire junctions in stacked electrodes of graphene/AgNWs, leading to enhanced conductivity as well as superior long-term stability under oxygen and sulfur atmospheres. PMID- 25521111 TI - An accurate molecular structure of phenyl, the simplest aryl radical. AB - The phenyl radical (C6H5(.)) is the prototypical sigma-type aryl radical and one of the most common aromatic building blocks for larger ring molecules. Using a combination of rotational spectroscopy of singly substituted isotopic species and vibrational corrections calculated theoretically, an extremely accurate molecular structure has been determined. Relative to benzene, the phenyl radical has a substantially larger C-Cipso-C bond angle [125.8(3) degrees vs. 120 degrees ], and a shorter distance [2.713(3) A vs. 2.783(2) A] between the ipso and para carbon atoms. PMID- 25521113 TI - Urinary LTE4 levels as a diagnostic marker for IgE-mediated asthma in preschool children: a birth cohort study. AB - OBJECTIVES: Leukotrienes play a central pathophysiological role in allergic asthma. The aim of this study was to investigate the utility of measuring urinary leukotriene E4 (LTE4) levels in the diagnosis of atopic diseases in early childhood. METHODS: Children aged 0 through 4 years from a birth cohort in the Prediction of Allergies in Taiwanese Children (PATCH) study were enrolled. Urinary LTE4 levels were measured and its association between total serum IgE levels, allergen-specific IgE sensitization and atopic diseases were assessed. RESULTS: A total of 182 children were regular followed up at clinics for a four year follow-up period. Urinary LTE4 levels appeared to be elevated in children with total serum IgE levels exceeding 100 kU/L, allergen-specific IgE sensitization after 2 years of age. Elevation of urinary LTE4 levels (>=500 pg/mg of creatinine) significantly discriminated high serum total IgE levels (>=100 kU/L) at age 2 (P = 0.027). A higher level of total serum IgE or urinary LTE4 was significantly associated with the risk of developing allergic rhinitis and asthma at age 3. A significantly higher urinary LTE4 level was found in children with a combination of IgE sensitization and asthma at age 4. CONCLUSIONS: Urinary LTE4 levels appear to be highly associated with IgE sensitization and its related allergic airway diseases after age 2. The measurement of urinary LTE4 (>=500 pg/mg of creatinine) could not only be a non-invasive method for atopic predisposition but also potentially provide a strategy for the diagnosis and management of asthma in preschool children. PMID- 25521112 TI - Generation of antigenic diversity in Plasmodium falciparum by structured rearrangement of Var genes during mitosis. AB - The most polymorphic gene family in P. falciparum is the ~60 var genes distributed across parasite chromosomes, both in the subtelomeres and in internal regions. They encode hypervariable surface proteins known as P. falciparum erythrocyte membrane protein 1 (PfEMP1) that are critical for pathogenesis and immune evasion in Plasmodium falciparum. How var gene sequence diversity is generated is not currently completely understood. To address this, we constructed large clone trees and performed whole genome sequence analysis to study the generation of novel var gene sequences in asexually replicating parasites. While single nucleotide polymorphisms (SNPs) were scattered across the genome, structural variants (deletions, duplications, translocations) were focused in and around var genes, with considerable variation in frequency between strains. Analysis of more than 100 recombination events involving var exon 1 revealed that the average nucleotide sequence identity of two recombining exons was only 63% (range: 52.7-72.4%) yet the crossovers were error-free and occurred in such a way that the resulting sequence was in frame and domain architecture was preserved. Var exon 1, which encodes the immunologically exposed part of the protein, recombined in up to 0.2% of infected erythrocytes in vitro per life cycle. The high rate of var exon 1 recombination indicates that millions of new antigenic structures could potentially be generated each day in a single infected individual. We propose a model whereby var gene sequence polymorphism is mainly generated during the asexual part of the life cycle. PMID- 25521114 TI - Prevalence of hypertension in rural areas of china: a meta-analysis of published studies. AB - BACKGROUND: Hypertension is one of the leading causes of disease burden across the world. In China, the latest nationwide survey of prevalence of hypertension was ten year ago, and data in rural areas is little known. More information about hypertension prevalence could help to improve overall antihypertensive health care. We aimed to estimate the pooled prevalence of hypertension in rural areas of China. METHODS: Comprehensive electronic searches of PubMed, Web of Knowledge, Chinese Web of Knowledge, Wangfang, Weipu and SinoMed databases were conducted to identify any study in each database published from January 1, 2004 to December 31, 2013, reporting the prevalence of hypertension in Chinese rural areas. Prevalence estimates were stratified by age, area, sex, publication year, and sample size. All statistical calculations were made using the Stata Version 11.0 (College Station, Texas) and Statsdirect Version 2.7.9. RESULTS: We identified 124 studies with a total population of 3,735,534 in the present meta-analysis. Among people aged 18 years old in Chinese rural areas, the summarized prevalence is 22.81% (19.41%-26.41%). Subgroup analysis shows the following results: for male 24.46% (21.19%-27.89%, for female 22.17% (18.25%-26.35%). For 2004-2006: 18.94% (14.41%-23.94%), for 2007-2009, 21.24% (15.98%-27.01%) for 2010-2013: 26.68%, (20.79%-33.02%). For Northern region 25.76% (22.36%-29.32%), for Southern region 19.30%, (15.48%-24.08%). CONCLUSIONS: The last decade witnessed the growth in prevalence of hypertension in rural areas of China compared with the fourth national investigation, which has climbed the same level as the urban area. Guidelines for screening and treatment of hypertension in rural areas need to be given enough attention. PMID- 25521115 TI - Curcumin and inflammatory bowel disease: potential and limits of innovative treatments. AB - Curcumin belongs to the family of natural compounds collectively called curcuminoids and it possesses remarkable beneficial anti-oxidant, anti inflammatory, anti-cancer, and neuroprotective properties. Moreover it is commonly assumed that curcumin has also been suggested as a remedy for digestive diseases such as inflammatory bowel diseases (IBD), a chronic immune disorder affecting the gastrointestinal tract and that can be divided in two major subgroups: Crohn's disease (CD) and Ulcerative Colitis (UC), depending mainly on the intestine tract affected by the inflammatory events. The chronic and intermittent nature of IBD imposes, where applicable, long-term treatments conducted in most of the cases combining different types of drugs. In more severe cases and where there has been no good response to the drugs, a surgery therapy is carried out. Currently, IBD-pharmacological treatments are generally not curative and often present serious side effects; for this reason, being known the relationship between nutrition and IBD, it is worthy of interesting the study and the development of new dietary strategy. The curcumin principal mechanism is the suppression of IBD inflammatory compounds (NF-kappaB) modulating immune response. This review summarizes literature data of curcumin as anti-inflammatory and anti oxidant in IBD, trying to understand the different effects in CD e UC. PMID- 25521116 TI - In vitro and in vivo evaluation of the antioxidant and prooxidant activity of phenolic compounds obtained from grape (Vitis vinifera) pomace. AB - The antioxidant and/or prooxidant ability of extracts obtained from wine waste were analyzed using in vitro and in vivo assays. Cyclic voltammetry was used as the in vitro assay to determine the antioxidant and/or prooxidant properties and, the in vivo effect on mycelial growth of the fungus Botrytis cinerea was evaluated. In addition, the prooxidant activity was evaluated by intracellular oxidation of compound 2,7-dichlorodihydrofluorescein diacetate (DCFH-DA) in B. cinerea. The extracts used in this study were obtained from grape pomace of Cabernet Sauvignon, Carmenere and Syrah varieties from the Misiones de Rengo Vineyard by simple extraction, using methanol/HCl 1% (v/v), ethanol 70% (v/v), or Soxhlet extraction. According to the results obtained, gallic acid was the most represented phenolic compound independent of grape variety and extraction method. In addition, vanillic acid; protocatechuic acid, syringic acid, quercetin and kaempferol were found in the extracts. From this study it was possible concluded that, depending of the method of extraction of the grape residues and the grape variety (Cabernet Sauvignon, Carmenere and Syrah), the extracts showed antioxidant and/or prooxidant activity. However, no correlation can be established between the anodic oxidation potentials of the extracts and their effect on the fungus B. cinerea. PMID- 25521117 TI - Toxicity of Evodiae fructus on rat liver mitochondria: the role of oxidative stress and mitochondrial permeability transition. AB - Evodiae fructus (EF) has been used in China for thousands of years as an analgesic, antiemetic, anti-inflammatory and antidiarrheal drug. EF is a toxic drug and causes hepatotoxicity in humans. Although recent chronic toxicity studies performed on aqueous extract of EF has revealed that it can produce obvious cumulative hepatotoxicity, the mechanism behind this toxicity is still uncertain. In the present study, we investigated the influence of EF on oxidative stress, mitochondrial permeability transition, adenosine triphosphate (ATP), and cytochrome C release of hepatic mitochondria. Rats were divided into four groups and fed distilled water, 6, 12, 24 g/kg of aqueous extract of EF daily for 15 days. Evodiamine, rutaecarpine and evodine were quantified in the aqueous extract by high performance liquid chromatography with ultraviolet detection (HPLC/UV). The results showed that aqueous extract of EF could significantly (p < 0.05) decrease MnSOD levels to 56.50%, 46.77% and 19.67% of control group, GSH level was decreased to 74.24%, 53.97% and 47.91% of control group and MDA level was increased to 131.55%, 134.34% and 150.81% of control group in the 6, 12 and 24 g/kg groups, respectively; extract also induced mitochondria swelling, vacuolation, MPT pore opening and a significant decrease (p < 0.05) in mitochondrial potential, while ATP levels were significant decreased (p < 0.05) to 65.24%, 38.08% and 34.59% of control group in the 6, 12 and 24 g/kg groups, respectively, resulting in ATP depletion and CytC release, finally trigger cell death signaling, which are the partial hepatotoxicity mechanisms of EF. PMID- 25521118 TI - Hydrogen sulfide and endothelium-dependent vasorelaxation. AB - In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H2S), synthesized enzymatically from l-cysteine or l-homocysteine, is the third gasotransmitter in mammals. Endogenous H2S is involved in the regulation of many physiological processes, including vascular tone. Although initially it was suggested that in the vascular wall H2S is synthesized only by smooth muscle cells and relaxes them by activating ATP-sensitive potassium channels, more recent studies indicate that H2S is synthesized in endothelial cells as well. Endothelial H2S production is stimulated by many factors, including acetylcholine, shear stress, adipose tissue hormone leptin, estrogens and plant flavonoids. In some vascular preparations H2S plays a role of endothelium-derived hyperpolarizing factor by activating small and intermediate-conductance calcium activated potassium channels. Endothelial H2S signaling is up-regulated in some pathologies, such as obesity and cerebral ischemia-reperfusion. In addition, H2S activates endothelial NO synthase and inhibits cGMP degradation by phosphodiesterase 5 thus potentiating the effect of NO-cGMP pathway. Moreover, H2S-derived polysulfides directly activate protein kinase G. Finally, H2S interacts with NO to form nitroxyl (HNO)-a potent vasorelaxant. H2S appears to play an important and multidimensional role in endothelium-dependent vasorelaxation. PMID- 25521119 TI - Design and synthesis of a series of truncated neplanocin fleximers. AB - In an effort to study the effects of flexibility on enzyme recognition and activity, we have developed several different series of flexible nucleoside analogues in which the purine base is split into its respective imidazole and pyrimidine components. The focus of this particular study was to synthesize the truncated neplanocin A fleximers to investigate their potential anti-protozoan activities by inhibition of S-adenosylhomocysteine hydrolase (SAHase). The three fleximers tested displayed poor anti-trypanocidal activities, with EC50 values around 200 MUM. Further studies of the corresponding ribose fleximers, most closely related to the natural nucleoside substrates, revealed low affinity for the known T. brucei nucleoside transporters P1 and P2, which may be the reason for the lack of trypanocidal activity observed. PMID- 25521120 TI - Evaluation of the diagnostic accuracy of prototype rapid tests for human African trypanosomiasis. AB - BACKGROUND: Diagnosis of human African trypanosomiasis (HAT) remains a challenge both for active screening, which is critical in control of the disease, and in the point-of-care scenario where early and accurate diagnosis is essential. Recently, the first field deployment of a lateral flow rapid diagnostic test (RDT) for HAT, "SD BIOLINE HAT" has taken place. In this study, we evaluated the performance of "SD BIOLINE HAT" and two new prototype RDTs. METHODOLOGY/PRINCIPAL FINDINGS: The performance of "SD BIOLINE HAT" and 2 prototype RDTs was tested using archived plasma from 250 Trypanosoma brucei gambiense patients, and 250 endemic controls. As well as comparison of the sensitivity and specificity of each device, the performance of individual antigens was assessed and the hypothetical performance of novel antigen combinations extrapolated. Neither of the prototype devices were inferior in sensitivity or specificity to "SD BIOLINE HAT" (sensitivity 0.82+/-0.01, specificity 0.97+/-0.01, 95% CI) at the 5% margins, while one of the devices (BBI) had significantly superior sensitivity (0.88+/-0.03). Analysis of the performance of individual antigens was used to model new antigen combinations to be explored in development of the next generation of HAT RDTs. The modelling showed that an RDT using two recombinant antigens (rLiTat1.5 and rISG65) would give a performance similar to the best devices in this study, and would also offer the most robust performance under deteriorating field conditions. CONCLUSIONS/SIGNIFICANCE: Both "SD BIOLINE HAT" and the prototype devices performed comparably well to one another and also to the published performance range of the card agglutination test for trypanosomiasis in sensitivity and specificity. The performance of individual antigens enabled us to predict that an all-recombinant antigen RDT can be developed with an accuracy equivalent to " SD BIOLINE HAT." Such an RDT would have advantages in simplified manufacture, lower unit cost and assured reproducibility. PMID- 25521121 TI - Improved quantification of cerebral hemodynamics using individualized time thresholds for assessment of peak enhancement parameters derived from dynamic susceptibility contrast enhanced magnetic resonance imaging. AB - PURPOSE: Assessment of cerebral ischemia often employs dynamic susceptibility contrast enhanced magnetic resonance imaging (DSC-MRI) with evaluation of various peak enhancement time parameters. All of these parameters use a single time threshold to judge the maximum tolerable peak enhancement delay that is supposed to reliably differentiate sufficient from critical perfusion. As the validity of this single threshold approach still remains unclear, in this study, (1) the definition of a threshold on an individual patient-basis, nevertheless (2) preserving the comparability of the data, was investigated. METHODS: The histogram of time-to-peak (TTP) values derived from DSC-MRI, the so-called TTP distribution curve (TDC), was modeled using a double-Gaussian model in 61 patients without severe cerebrovascular disease. Particular model-based zf-scores were used to describe the arterial, parenchymal and venous bolus-transit phase as time intervals Ia,p,v. Their durations (delta Ia,p,v), were then considered as maximum TTP-delays of each phase. RESULTS: Mean-R2 for the model-fit was 0.967. Based on the generic zf-scores the proposed bolus transit phases could be differentiated. The Ip-interval reliably depicted the parenchymal bolus-transit phase with durations of 3.4 s-10.1 s (median = 4.3s), where an increase with age was noted (~30 ms/year). CONCLUSION: Individual threshold-adjustment seems rational since regular bolus-transit durations in brain parenchyma obtained from the TDC overlap considerably with recommended critical TTP-thresholds of 4 s-8 s. The parenchymal transit time derived from the proposed model may be utilized to individually correct TTP-thresholds, thereby potentially improving the detection of critical perfusion. PMID- 25521122 TI - Further contributions to nitrogen removal modelling in waste stabilization ponds. AB - A large database from an experimental maturation pond system in Brazil was used to verify the agreement of field results with values predicted by some of the most widely accepted models to describe ammonium and total nitrogen (TN) removal in facultative and maturation ponds. The same database was used to derive a pH independent linear model to predict ammonium removal in ponds, which was proved to be, essentially, a function of ammonium surface loading rate. In general, all these models made reasonable predictions of ammonium or TN removal but tended to overestimate low ammonium effluent concentrations while underestimating higher values of field data. PMID- 25521123 TI - The performance of enhanced coagulation for treating slightly polluted raw water combining polyaluminum chloride with variable charge soil. AB - The feasibility and effectiveness of treating pollutants in slightly polluted raw water by variable charge soil and polyaluminum chloride (PAC) was investigated. Removal efficiencies of turbidity, phenol, aniline, algae and heavy metals (Cu(2+), Zn(2+) and Pb(2+)) were used to evaluate the coagulation performance. The results indicated that the addition of variable charge soil as a coagulant aid is advantageous due to the improvement of removal efficiencies. The tests also demonstrated that the presence of variable charge soil increased the removal of turbidity rather than adding residuary turbidity. The use of variable charge soil produced settleable flocs of greater density and bigger size. The main mechanism involved in the PAC coagulation was supposed to be sweep flocculation as well as charge-neutralization. Variable charge soil played a promoted aid role by adsorption in the enhanced coagulation process. It is concluded that the enhanced coagulation by PAC and variable charge soil, as coagulant and adsorbent, is more effective and efficient than traditional coagulation. PMID- 25521124 TI - Simultaneous preconcentration of cadmium and chromium(III) in water samples by cloud point extraction and their determination by flame atomic absorption spectrometry. AB - A sensitive and simple method for flame atomic absorption spectrometry determination of traces of cadmium and chromium(III) species in water samples after preconcentration by cloud point extraction has been developed. A novel complex agent of alizarin complexone with cadmium (Cd) and chromium (Cr(III)) was quantitatively extracted in surface primary alcohol ethoxylate-rich phase at 33 degrees C. The effects of experimental conditions including pH of sample solution, concentration of chelating agent and salt, equilibration temperature and time, and foreign ions were evaluated in order to enhance sensitivity of the method. Under optimal conditions, the low limit detections were 6.7 and 3.2 MUg/L, and the enrichment factors were 24 and 20 for Cd and Cr(III), respectively. The relative standard deviations were 3.8 and 2.5% for Cd and Cr(II), respectively (n = 11). The high recoveries of the spiked Cd and Cr(III) ions were obtained in the range of 90-116%. The proposed method has been successfully applied for the determination of Cd and Cr(III) in water samples. PMID- 25521125 TI - Biohydrogen production from tequila vinasses using a fixed bed reactor. AB - In Mexico, the industrial production of tequila leads to the discharge of more than 31.2 million of m(3) of vinasse, which causes serious environmental issues because of its acidity, high organic load and the presence of recalcitrant compounds. The aim of this research was to study the feasibility of a fixed bed reactor for the production of biohydrogen by using tequila vinasse as substrate. The experiments were carried out in a continuous mode under mesophilic and acidic conditions. The maximum hydrogen yield and hydrogen production rate were 1.3 mol H2 mol/mol glucose and 72 +/- 9 mL H2/(Lreactor h), respectively. Biogas consisted of carbon dioxide (36%) and hydrogen (64%); moreover methane was not observed. The electron-equivalent mass balance fitted satisfactorily (sink of electrons from 0.8 to 7.6%). For vinasses, hydrogen production accounted for 10.9% of the total available electron-equivalents. In the liquid phase, the principal metabolites identified were acetic, butyric and iso-butyric acids, which indicated a butyrate-acetate type fermentation. Tequila vinasses did not result in potential inhibition of the fermentative process. Considering the process as a water treatment system, only 20% of the original carbon was removed (as carbon dioxide and biomass) when the tequila vinasses are used. PMID- 25521126 TI - Crucial elements and technical implementation of intelligent monitoring networks. AB - Growing complexity of water monitoring instrumentation leads to specialized solutions in respect to sensor integration across several measurement device suppliers. Despite efforts of standardization for data interfaces and protocols, problems regarding the combination of several devices to gain the complete picture in terms of water quality remain. This assessment, especially accomplished from the perspective of a catchment area, requires a transition from sole use of data collectors toward an implementation of intelligent measurement networks. Several challenges and bottlenecks concerning distributed data collection are discussed starting with data acquisition up to the user-scope of utilizing data processing software. Finally, experiences using automated data inspection and export tools are discussed and a brief overview of expectable long term data availability is given. PMID- 25521127 TI - Enhanced decomposition of 1,4-dioxane in water by ozonation under alkaline condition. AB - 1,4-Dioxane is a probable human carcinogenic and refractory substance that is widely detected in aquatic environments. Traditional wastewater treatment processes, including activated sludge, cannot remove 1,4-dioxane. Removing 1,4 dioxane with a reaction kinetic constant of 0.32 L/(mol.s) by using ozone, a strong oxidant, is difficult. However, under alkaline environment, ozone generates a hydroxyl radical (*OH) that exhibits strong oxidative potential. Thus, the ozonation of 1,4-dioxane in water under different pH conditions was investigated in this study. In neutral solution, with an inlet ozone feed rate of 0.19 mmol/(L.min), the removal efficiency of 1,4-dioxane was 7.6% at 0.5 h, whereas that in alkaline solution was higher (16.3-94.5%) within a pH range of 9 12. However, the removal efficiency of dissolved organic carbon was considerably lower than that of 1,4-dioxane. This result indicates that several persistent intermediates were generated during 1,4-dioxane ozonation. The pseudo first-order reaction further depicted the reaction of 1,4-dioxane. The obvious kinetic constants (kobs) at pH 9, 10, 11 and 12 were 0.94, 2.41, 24.88 and 2610 L/(mol.s), respectively. Scavenger experiments on radical species indicated that *OH played a key role in removing 1,4-dioxane during ozonation under alkaline condition. PMID- 25521129 TI - Multi-chamber microbial desalination cell for improved organic matter and dissolved solids removal from wastewater. AB - A five-chamber microbial desalination cell (MDC) with anode, cathode, one central desalination chamber and two concentrate chambers separated by ion exchange membranes was operated in batch mode for more than 60 days. The performance of the MDC was evaluated for chemical oxygen demand (COD) removal, total dissolved solids (TDS) removal and energy production. An average COD removal of 81 +/- 2.1% was obtained using acetate-fed wastewater as substrate in the anodic chamber inoculated with mixed anaerobic sludge. TDS removals of 58, 70 and 78% were observed with salt concentration of 8, 20 and 30 g/L, respectively, in the middle desalination chamber. The MDC produced a maximum power output of 16.87 mW/m(2) during polarization. The highest Coulombic efficiency of 12 +/- 2.4% was observed in this system using mixed anaerobic sludge as inoculum. The system effectively demonstrated capability for simultaneous organic matter removal and desalination along with power generation. PMID- 25521128 TI - Aerobic co-treatment of landfill leachate and domestic wastewater - are slowly biodegradable organics removed or simply diluted? AB - This study investigated the co-treatment of landfill leachate/domestic wastewater in bench-scale activated sludge (AS) reactors to determine whether the slowly biodegradable organic matter (SBOM) was removed rather than diluted. The AS reactors were loaded with mixtures of raw leachate and leachate that was pretreated by air stripping. The tested volumetric ratios were 0%, 0.2%, 2% and 5%. For all of the tested conditions, the reactors performed better when pretreated leachate was used rather than raw leachate, and the best volumetric ratio was 2%. The following removals were obtained: 97% for the biochemical oxygen demand (BOD5,20), 79% for total suspended solids, 77% for dissolved organic carbon and 84% for soluble chemical oxygen demand. Most of the pretreated leachate SBOM (65%) was removed rather than diluted or adsorbed into the sludge, as confirmed by Fourier transform infrared (FTIR) spectroscopy analyses. PMID- 25521130 TI - Evaluation of diarrheagenic E. coli in riversheds by quantitative PCR in combination with enrichment. AB - Diarrheagenic Escherichia coli (DEC) is a group of the most common agents of diarrhea. Highly virulent DEC strains could cause illness with dozens of organisms. Waterborne DEC may be detected using polymerase chain reaction (PCR); however, environmental contaminants can interfere with PCR reaction, thus causing the prevalence of DEC to be underestimated. In this study, we propose an approach to efficiently quantify trace amounts of DEC. An enrichment procedure was performed to amplify total E. coli including DEC in the water samples. By normalizing the number of pathotype-specific genes to the amplification rate of a housekeeping gene in all E. coli, the quantity of DEC in original samples could be assessed. This method allows detection of trace amounts of DEC in receiving waters. The results showed that the presence of DEC in water samples was partially associated with riverside settlement. The DEC concentration was substantially higher at a few sampling sites, suggesting that evaluation of DEC along the river may help identify previously unknown pollution sources. Although the sustainability of DEC in the receiving waters may be low, the risk of DEC infection from the watershed warrants further examination. PMID- 25521131 TI - Wastewater retreatment and reuse system for agricultural irrigation in rural villages. AB - Climate changes and continuous population growth increase water demands that will not be met by traditional water resources, like surface and ground water. To handle increased water demand, treated municipal wastewater is offered to farmers for agricultural irrigation. This study aimed to enhance the effluent quality from worn-out sewage treatment facilities in rural villages, retreat effluent to meet water quality criteria for irrigation, and assess any health-related and environmental impacts from using retreated wastewater irrigation on crops and in soil. We developed the compact wastewater retreatment and reuse system (WRRS), equipped with filters, ultraviolet light, and bubble elements. A pilot greenhouse experiment was conducted to evaluate lettuce growth patterns and quantify the heavy metal concentration and pathogenic microorganisms on lettuce and in soil after irrigating with tap water, treated wastewater, and WRRS retreated wastewater. The purification performance of each WRRS component was also assessed. The study findings revealed that existing worn-out sewage treatment facilities in rural villages could meet the water quality criteria for treated effluent and also reuse retreated wastewater for crop growth and other miscellaneous agricultural purposes. PMID- 25521132 TI - Strengthening the growth of Rubrivivax gelatinosus in sewage purification through ferric ion regulated photophosphorylation and respiration. AB - Rubrivivax gelatinosus has the potential of biomass resource recycling combined with sewage purification. However, low biomass production and yield restricts the potential for sewage purification. Thus, this research investigated the improvement of biomass production and yield and organics reduction by Fe(3+) in R. gelatinosus wastewater treatment. Results showed that 10-30 mg/L Fe(3+) improved biomass yield in wastewater to a level found in culture medium. With optimal dosage (20 mg/L), biomass production reached 4,300 mg/L, which was 1.67 times that of the control group. Biomass yield was improved by 43.3%. Chemical oxygen demand (COD) removal reached above 91%. Hydraulic retention time was shortened by 25%. Mechanism analysis indicated that Fe(3+) enhanced the succinate and NADH dehydrogenase activities and, bacteriochlorophyll content in three energy metabolism pathways. These effects then enhanced adenosine triphosphate (ATP) production, which led to more biomass accumulation and COD removal. With 20 mg/L Fe(2+) dosage, succinate and NADH dehydrogenase, coproporphyrinogen III oxidase activities, bacteriochlorophyll content and ATP production were improved, respectively, by 48.4, 50.8, 50, 67 and 56% compared to those of the control group. PMID- 25521133 TI - Transformation characteristics of organic pollutants in Fered-Fenton process for dry-spun acrylic fiber wastewater treatment. AB - The Fered-Fenton process using Ti sheet as cathode and RuO2/Ti as anode was employed for the pretreatment of dry-spun acrylic fiber manufacturing wastewater. The effects of feeding mode and concentration of H2O2 on chemical oxygen demand (COD) removal efficiency as well as the biodegradability variation during the Fered-Fenton process were investigated. The feeding mode of H2O2 had significant influence on COD removal efficiency: the removal efficiency was 44.8% if all the 60.0 mM H2O2 was fed at once, while it could reach 54.1% if the total H2O2 was divided into six portions and fed six times. The biochemical oxygen demand/COD ratio increased from 0.29 to above 0.68 after 180 min treatment. The transformation characteristics of organic pollutants during the Fered-Fenton process were evaluated by using gas chromatography-mass spectrometry (GC-MS), Fourier transform infrared spectroscopy (FTIR) and fluorescence excitation emission matrix (EEM) spectroscopy. Most of the refractory organic pollutants with aromatic structure or large molecular weight were decomposed during the Fered-Fenton process. PMID- 25521134 TI - Comparative study on adsorption of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) by different adsorbents in water. AB - Perfluorinated compounds (PFCs) are emerging environmental pollutants. Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are the two primary PFC contaminants that are widely found in water, particularly in groundwater. This study compared the adsorption behaviors of PFOS and PFOA on several commercially available adsorbents in water. The tested adsorbents include granular activated carbon (GAC: Filtrasorb 400), powdered activated carbon, multi walled carbon nanotube (MCN), double-walled carbon nanotube, anion-exchange resin (AER: IRA67), non-ion-exchange polymer, alumina, and silica. The study demonstrated that adsorption is an effective technique for the removal of PFOS/PFOA from aqueous solutions. The kinetic tests showed that the adsorption onto AER reaches equilibrium rapidly (2 h), while it takes approximately 4 and 24 h to reach equilibrium for MCN and GAC, respectively. In terms of adsorption capacity, AER and GAC were identified as the most effective adsorbents to remove PFOS/PFOA from water. Furthermore, MCN, AER, and GAC proved to have high PFOS/PFOA removal efficiencies (>=98%). AER (IRA67) and GAC (Filtrasorb 400) were thus identified as the most promising adsorbents for treating PFOS/PFOA contaminated groundwater at mg L(-1) level based on their equilibrium times, adsorption capacities, removal efficiencies, and associated costs. PMID- 25521135 TI - A novel application of modified bamboo charcoal to treat oil-containing wastewater and its modified mechanism. AB - Three conventional coalescence filters including walnut shells (WS), polystyrene resin particles (PR), and quartz sand (QS) were compared with bamboo charcoal (BC) to treat oily wastewater in a coalescence system process. The results showed the order of oil removal efficiency was QS>BC>WS>PR. To improve the oil removal efficiency of BC further, six types of modified BC were prepared. The results showed that the modified BC using silane coupling agent (SCA) significantly increased oil removal efficiency, but the other types (including the use of NaOH, HNO3, H2O2, FeCl3 and ultrasound) of modified BC exhibited nearly the same level of efficiency as that of pure BC. Infra-red, X-ray diffraction, scanning electron microscopy, and the contact angle for modified BC were measured to reveal the modified mechanism. It was found that the higher oil removal efficiency of the SCA-modified BC occurred due to the changed crystal structure of the BC and the increase in its surface hydrophobicity, which resulted in higher oil removal efficiency. Therefore, modified bamboo charcoal is an attractive filter candidate for oil removal in a coalescence system process. PMID- 25521136 TI - Alternative energy efficient membrane bioreactor using reciprocating submerged membrane. AB - A novel membrane bioreactor (MBR) pilot system, using membrane reciprocation instead of air scouring, was operated at constant high flux and daily fluctuating flux to demonstrate its application under peak and diurnal flow conditions. Low and stable transmembrane pressure was achieved at 40 l/m(2)/h (LMH) by use of repetitive membrane reciprocation. The results reveal that the inertial forces acting on the membrane fibers effectively propel foulants from the membrane surface. Reciprocation of the hollow fiber membrane is beneficial for the constant removal of solids that may build up on the membrane surface and inside the membrane bundle. The membrane reciprocation in the reciprocating MBR pilot consumed less energy than coarse air scouring used in conventional MBR systems. Specific energy consumption for the membrane reciprocation was 0.072 kWh/m(3) permeate produced at 40 LMH flux, which is 75% less than for a conventional air scouring system as reported in literature without consideration of energy consumption for biological aeration (0.29 kWh/m(3)). The daily fluctuating flux test confirmed that the membrane reciprocation is effective to handle fluctuating flux up to 50 LMH. The pilot-scale reciprocating MBR system successfully demonstrated that fouling can be controlled via 0.43 Hz membrane reciprocation with 44 mm or higher amplitude. PMID- 25521137 TI - Kinetics of lead and copper removal from oil-field brine by potential sorption. AB - The present study investigates the kinetics of lead and copper removal from oil field brine by potential sorption. A population balance equation, coupled with a mass balance equation, was used in the estimation of kinetic parameters. Metal removal was performed by potential sorption of lead and copper through CaCO3 precipitates induced by the reaction of Na2CO3 and CaCl2. The oil-field brine was selected from an oil well in Gachsaran, Iran. The crystal size distribution of the solid phase was measured by dynamic laser scattering analyzer, and the liquor phase was analyzed using atomic adsorption. The morphology of calcium carbonate particles was illustrated using scanning electron microscopy and X-ray diffraction. The results showed that the presence of copper and lead decreases the average size distribution of calcium carbonate particles by influencing the kinetic parameters. Lead and copper concentrations were reduced from 2.911 to 0.127 ppm (95.63% removal) and 0.476 to 0.025 ppm (94.74% removal), respectively, in exchange for 12 g CaCO3 consumption per 100 ml oil-field brine. PMID- 25521138 TI - The construction of an engineered bacterium to remove cadmium from wastewater. AB - The removal of cadmium (Cd) from wastewater before it is released from factories is important for protecting human health. Although some researchers have developed engineered bacteria, the resistance of these engineered bacteria to Cd have not been improved. In this study, two key genes involved in glutathione synthesis (gshA and gshB), a serine acetyltransferase gene (cysE), a Thlaspi caerulescens phytochelatin synthase gene (TcPCS1), and a heavy metal ATPase gene (TcHMA3) were transformed into Escherichia coli BL21. The resistance of the engineered bacterium to Cd was significantly greater than that of the initial bacterium and the Cd accumulation in the engineered bacterium was much higher than in the initial bacterium. In addition, the Cd resistance of the bacteria harboring gshB, gshA, cysE, and TcPCS1 was higher than that of the bacteria harboring gshA, cysE, and TcPCS1. This finding demonstrated that gshB played an important role in glutathione synthesis and that the reaction catalyzed by glutathione synthase was the limiting step for producing phytochelatins. Furthermore, TcPCS1 had a greater specificity and a higher capacity for removing Cd than SpPCS1, and TcHMA3 not only played a role in T. caerulescens but also functioned in E. coli. PMID- 25521139 TI - Removal of toxic elements from aqueous solution using bentonite modified with L histidine. AB - This study proposes the use of bentonite modified with L-histidine for the removal of Cu, Co, Cr, Fe, Hg, Ni, U and Zn from aqueous solutions such as those impacted by acidic drainage. The surface areas of natural bentonite and bentonite histidine were 73.8 and 61.2 m(2) g(-1), respectively. Elemental analysis showed an increase in the amount of carbon (0.258%) and nitrogen (0.066%) for the bentonite-histidine. At a fixed solid/solution ratio, the operating variables affecting the adsorption of metal ions from aqueous solution such as pH, initial concentration, contact time and temperature were studied in batch mode. The Freundlich isotherm model yielded a better fit than the Langmuir for the adsorption of Cu, Co, Ni and Zn, implying adsorption on a heterogeneous surface. Adsorption kinetics followed a pseudo-second-order model, suggesting chemisorption as the rate-limiting step. The apparent activation energy was greater than 40 kJ mol(-1) for Cu, Zn, Ni, Co and U, which is characteristic of a chemically controlled reaction. Thermodynamic constants DeltaG and DeltaH showed that the adsorption of metals was endothermic and spontaneous. Adsorption of heavy metals onto bentonite-histidine was efficient at low pH values, meaning that the adsorbent could be useful for remediating acid mine water. PMID- 25521140 TI - Potential for nutrient removal by integrated remediation methods in a eutrophicated artificial lake - a case study in Dishui Lake, Lingang New City, China. AB - A new integrated water remediation technology, including a floating bed, a buffer zone of floating plants, enclosed 'water hyacinth' purification, economic aquatic plants and near-shore aquatic plant purification, was used in Dishui Lake to improve its water quality. A channel of 1,000 m length and 30 m width was selected to implement pilot-scale experiments both in the static period and the continuous water diversion period. The results showed that the new integrated water remediation technology exhibited the highest removal rate for permanganate index in a static period, which achieved 40.6%. The average removal rates of total nitrogen (TN), ammonia nitrogen (NH3-N) and total phosphorus (TP) in a static period were 23.2, 21.6 and 19.1%, respectively. However, it did not exhibit an excellent removal rate for pollutants in the continuous water diversion period. The average removal rates for all pollutants were below 10%. In winter, the new integrated remediation technology showed efficient effects compared to others. The average removal rate for CODMn, TN, NH3-N and TP were 7, 5.3, 7.6 and 6.5%, respectively. Based on our results, the new integrated water remediation technology was highly efficient as a purification system, especially during the static period in winter. PMID- 25521141 TI - Stability of Fe-oxide nanoparticles coated with natural organic matter under relevant environmental conditions. AB - Manufactured nanoparticles (MNPs) are increasingly released into the environment and thus research on their fate and behaviour in complex environmental samples is urgently needed. The fate of MNPs in the aquatic environment will mainly depend on the physico-chemical characteristics of the medium. The presence and concentration of natural organic matter (NOM) will play a significant role on the stability of MNPs by either decreasing or exacerbating the aggregation phenomenon. In this study, we firstly investigated the effect of NOM concentration on the aggregation behaviour of manufactured Fe-oxide nanoparticles. Then, the stability of the coated nanoparticles was assessed under relevant environmental conditions. Flow field-flow fractionation, an emerging method which is gaining popularity in the field of nanotechnology, has been employed and results have been compared to another size-measurement technique to provide increased confidence in the outcomes. Results showed enhanced stability when the nanoparticles are coated with NOM, which was due to electrosteric stabilisation. However, the presence of divalent cations, even at low concentration (i.e. less than 1 mM) was found to induce aggregation of NOM-coated nanoparticles via bridging mechanisms between NOM and Ca(2+). PMID- 25521142 TI - Effective detoxification of hexavalent chromium using sulfate-crosslinked chitosan. AB - A sulfate-crosslinked chitosan (SCC) was prepared for effective detoxification of hexavalent chromium (Cr(VI)) from effluents. SCC was characterized using Fourier transform infrared, X-ray diffraction, scanning electron microscopy and energy dispersive X-ray studies. The maximum adsorption of Cr(VI) was observed at pH 6.0 with adsorption capacity of 157 mg/g in accordance with the Langmuir adsorption isotherm model. The adsorption process was found to follow the pseudo-second order rate kinetics. From the study of various thermodynamic parameters (Gibbs energy, entropy and enthalpy changes), the adsorption capacity was found to decrease with increase in temperature. Column studies were carried out to obtain a breakthrough point of the adsorbent. The adsorbent was regenerated using sodium hydroxide with no change in the adsorption efficiency for up to 10 cycles. Effect of diverse ions on adsorption efficiency was studied and SCC was applied for Cr(VI) removal in synthetic effluents. PMID- 25521143 TI - Evaluation of acute ecotoxicity removal from industrial wastewater using a battery of rapid bioassays. AB - The present study compares conventional wastewater treatment technologies (coagulation-flocculation and activated sludge) and powdered activated carbon (PAC) treatment for the removal of acute ecotoxicity from wastewater generated by tank truck cleaning (TTC) processes. Ecotoxicity was assessed with a battery of four commercially available rapid biological toxicity testing systems, verified by the US Environmental Protection Agency. Chemical coagulation-flocculation of raw TTC wastewater had no impact on the inhibition of the bioluminescence by Vibrio fischeri (BioTox assay). Subsequent biological treatment with activated sludge without PAC resulted in BioTox inhibition-free effluent (<10% inhibition). In contrast, activated sludge treatment without PAC produced an effluent that significantly inhibited (>50%) (i) the bioluminescence by Photobacterium leiognathi (ToxScreen3 test kit), (ii) the photosynthesis by the green algae Chlorella vulgaris (LuminoTox SAPS test kit), and (iii) the particle ingestion by the crustacean Thamnocephalus platyurus (Rapidtoxkit test kit). The lowest inhibition was measured after activated sludge treatment with the highest PAC dose (400 mg/L), demonstrating the effectiveness of PAC treatment for ecotoxicity removal from TTC wastewater. In conclusion, the combination of bioassays applied in the present study represents a promising test battery for rapid ecotoxicty assessment in wastewater treatment. PMID- 25521156 TI - Identification of estrogenic compounds in oil sands process waters by effect directed analysis. AB - Using effect directed analysis, the presence of estrogenic components in untreated and biologically treated oil sands process water (OSPW) was detected with the yeast estrogenic screening assay after fractionation with solid phase extraction followed by reversed phase high performance liquid chromatography. Comparison of the composition, as determined by electrospray ionization combined with high-resolution linear trap quadropole (LTQ)-Orbitrap Velos Pro hybrid mass spectrometry (negative ion) of selected estrogenic and nonestrogenic fractions identified compounds that were uniquely present in the estrogenic samples, biologically treated and untreated. Of the 30 most abundant compounds, there were 14 possible nonaromatic structures and 16 possible aromatic structures. Based on the published literature, the latter are the most likely to cause estrogenicity and were O2, O3 and O4 C17 to C20 compounds with double bond equivalents between 6 and 10 and chemical formulas similar to estrone- and estradiol-like compounds. This study shows exact formulas and masses of possible estrogenic compounds in OSPW. These findings will help to focus study on the most environmentally significant components in OSPW. PMID- 25521158 TI - Palladium-catalyzed synthesis of six-membered benzofuzed phosphacycles via carbon phosphorus bond cleavage. AB - The palladium-catalyzed synthesis of dibenzofused six-membered phosphacycles via carbon-phosphorus bond cleavage is developed. This method is compatible with a range of functional groups, such as esters, amides, and carbamates, which is in sharp contrast to the limitations of the classical method using organolithium reagents. PMID- 25521157 TI - Copper nanowires as nanoscale interconnects: their stability, electrical transport, and mechanical properties. AB - Application of copper nanowires (Cu NWs) for interconnects in future nanodevices must meet the following needs: environmental stability and superior electrical transport properties. Here, we demonstrate a kind of Cu NW that possesses the both properties. The Cu NWs were synthesized through a hydrothermal route with the reduction of copper chloride using octadecylamine (ODA). The reasons for their environmental stability could be due to interaction of ODA(+) molecules with the surface of Cu NWs and forming strong N-Cu chemical bonds. Electrical transport properties of individual Cu NW were investigated by using the four probe measurement, showing the temperature-dependent resistance of the Cu NW was fairly linear in the temperature range from 25 to 300 K and the Cu NW retained the low resistivity of approximately 3.5 * 10(-6) Omega . cm at room temperature, near the resistivity value of bulk copper. The maximum transport current density for the Cu NW should be superior to 1.06 * 10(7) A . cm(-2). In addition, the Cu NWs have ultralow junction resistance. The present study indicates that the Cu NWs could act as a multifunctional building blocks for interconnects in future nanoscale devices. PMID- 25521159 TI - Paper-based microfluidic approach for surface-enhanced raman spectroscopy and highly reproducible detection of proteins beyond picomolar concentration. AB - Although microfluidic approach is widely used in various point of care diagnostics, its implementation in surface enhanced Raman spectroscopy (SERS) based detection is challenging. This is because SERS signal depends on plasmonic nanoparticle aggregation induced generation of stable electromagnetic hot spots and in currently available microfluidic platform this condition is difficult to adapt. Here we show that SERS can be adapted using simple paper based microfluidic system where both the plasmonic nanomaterials and analyte are used in mobile phase. This approach allows analyte induced controlled particle aggregation and electromagnetic hot spot generation inside the microfluidic channel with the resultant SERS signal, which is highly reproducible and sensitive. This approach has been used for reproducible detection of protein in the pico to femtomolar concentration. Presented approach is simple, rapid, and cost-effective, and requires low sample volume. Method can be extended for SERS based detection of other biomolecules. PMID- 25521160 TI - Redox cycling of copper-amyloid beta 1-16 peptide complexes is highly dependent on the coordination mode. AB - Copper (Cu)-amyloid beta (Abeta) interactions play a role in the etiology of Alzheimer's disease. This work presents a spectroscopic and electrochemical study of two physiologically relevant Abeta-Cu(II) complexes, as a function of pH and relative Cu-Abeta(1-16) concentrations. Our results reveal that these coordination modes display distinct redox behaviors and provide experimental evidence for the existence of an intermediate Cu(I) species. A mechanism for the redox cycling of these complexes is proposed, providing further insight into the redox relevance of Abeta-Cu interactions. PMID- 25521161 TI - Transport of Triplet Excitons along Continuous 100 nm Polyfluorene Chains. AB - Triplet excitons created in poly-2,7-(9,9-dihexyl)fluorene (pF) chains with end trap groups in solution are efficiently transported to and captured by the end groups. The triplets explore the entire lengths of the chains, even for ~100 nm long chains, enabling determination of the completeness of end-capping. The results show that the chains are continuous: they may contain transient barriers or traps, such as those from fluctuations of dihedral angles, but they are free of major defects that stop motion of the triplets. Quantitative determinations are aided by the addition of a strong electron donor, TMPD, which removes absorption bands of the end-trapped triplets. For chains having at least one end trap, triplet capture is quantitative on the 1 MUs time scale imposed by the use of the donor. Fractions of chains having no end traps were 0.15 for pF samples with anthraquinone (AQ) end traps and 0.063 with naphthylimide (NI) end traps. These determinations agreed with measurements by NMR for short (<40 polymer repeat units (PRU)) chains, where NMR determinations are accurate. The results find no evidence for traps or barriers to the transport of triplets, and places limits on the possible presence of defects as impenetrable barriers to less than one per 300 PRU. The present results present a paradigm different from the current consensus, derived from observations of singlet excitons, that conjugated chains are divided into "segments," perhaps by some kind of defects. For the present pF chains, the segmentation either does not apply to triplet excitons or is transient so that the defects are healed or surmounted in times much shorter than 1 MUs. Triplets on chains without end trap groups transfer to chains with end traps on a slower time scale. Rate constants for these bimolecular triplet transfer reactions were found to increase with the length of the accepting chain, as did rate constants for triplet transfer to the chains from small molecules like biphenyl. A second set of polyfluorenes with 2-butyloctyl side chains was found to have a much lower completeness of end-capping. PMID- 25521162 TI - First reported duplication of the entire beta globin gene cluster causing an unusual sickle cell trait phenotype. PMID- 25521163 TI - Resonance frequency analysis of implants placed with osteotome sinus floor elevation in posterior maxillae. AB - OBJECTIVES: To test the reliability and validity of implant stability quotient (ISQ) values used for assessment of the condition of bone-to-implant interface in the osteotome sinus floor elevation (OSFE) model and to evaluate the influence of residual bone height (RBH) on ISQ values. MATERIAL AND METHODS: Forty-six Straumann((r)) tissue-level SLA implants (Phi4.8 mm*8 mm, wide neck, standard plus) placed in 39 patients applying OSFE without grafting were included in the study. Patients were assigned to three groups based on the RBH with one implant per patient randomly chosen: (1) 2 <= RBH < 4 mm (n = 14); (2) 4 <= RBH < 6 mm (n = 15); (3) 6 <= RBH < 8 mm (n = 10). ISQ values were determined with Osstell ISQ((r)) at 0, 2, 4, 8, 12, 16, and 20 weeks postoperation. The reliability of RFA measurements was tested by the degree of dispersion of ISQ values at each time point, and the validity was tested by linear correlation between ISQ and RBH. ISQ values were then compared among groups at all observed time points. RESULTS: The implants achieved a mean ISQ value of 63.6 immediately after surgery and reached a higher ISQ level of 70 after 20 weeks with a dip at 4 weeks. A higher degree of dispersion of ISQ values was observed immediately after surgery compared to the other time points. No significant correlations were found between RBH and ISQ values and no significant difference in ISQ values among groups at all the time points. CONCLUSION: Within the limits of the study, it may be implied that ISQ values are not able to assess the condition of bone-to-implant interface and the role of single RFA measurement in determining loading protocol is questionable. PMID- 25521164 TI - The molecular spectrum and clinical impact of DIS3 mutations in multiple myeloma. AB - Multiple myeloma (MM) is a plasma cell neoplasm that presents with a major biological and clinical heterogeneity. We here investigated the spectrum of clonal and subclonal mutations of DIS3, an active part of the exosome complex, that may play a role in the development or progression of MM. The whole coding sequence of DIS3 was subjected to deep sequencing in 81 uniformly-treated MM patients and 12 MM cell lines and the overall occurrence of DIS3 mutations as well as the presence of DIS3 mutations in minor and major subclones were correlated with cytogenetic alterations and clinical parameters. Our study identified DIS3 mutations in 9/81 patients that were associated with 13q14 deletions and IGH translocations on the cytogenetic level. Specifically, we detected seven novel somatic DIS3 single nucleotide variants (SNVs) and defined three hot spot mutations within the RNB domain. Lastly, we found a trend towards a shorter median overall survival for patients with DIS3 mutations, and patients carrying DIS3 mutations in minor subclones of their tumours showed a significantly worse response to therapy compared to patients with DIS3 mutations in the major subclone. PMID- 25521165 TI - A definition of refractory pain to help determine suitability for device implantation. PMID- 25521166 TI - Neurotech report. PMID- 25521167 TI - Neuromodulation of the great auricular nerve: a case report. PMID- 25521169 TI - Effects of video exposure to cluttering on undergraduate students' perceptions of a person who clutters. AB - BACKGROUND: Previous research suggests a negative stereotype toward people with fluency disorders (i.e. stuttering and/or cluttering), although recent findings suggest that exposure to an actual person who stutters (e.g. a live or video presentation) leads to more positive perceptions of some personality traits. However, there is a paucity of research examining perceptions of a person who clutters and whether these perceptions can be modified via video exposure to cluttering. AIMS: To examine the effects of video exposure to cluttering on university students' perceptions of a person who clutters. It was hypothesized that participants in the video condition would rate personality traits more positively than those who did not view the video clip. METHODS & PROCEDURES: A total of 105 undergraduate students served as participants; 54 were provided with written definition of cluttering, whereas 51 were provided with both a definition and short segment of an instructional DVD on cluttering. Students then rated a person who clutters on a variety of speech skills and personality scales. OUTCOMES & RESULTS: Independent samples t-tests yielded no significant group differences in ratings of any speech skills or personality traits. However, a significantly greater number of students who viewed the video clip reported a reluctance to hire a person who clutters specifically because of the individual's fluency disorder. Additionally, participants who did not view the video clip reported having more previous instructors who cluttered than those who did view the video clip; this increased familiarity with persons who clutter may have impacted perceptions of a person who clutters. CONCLUSIONS & IMPLICATIONS: The present results indicate that viewing the brief video clip did not significantly influence ratings towards more positive perceptions, but also did not influence ratings to be significantly more negative on any traits. Further research is needed to compare the differences in the perceptions of listeners who have had long-term exposure to cluttered speech with those of listeners who have had brief exposure. Implications discussed include the impact of prior exposure to fluency disorders, as well as potential confusion between cluttering and 'fast speech'. These two factors may have influenced the identification rate of individuals with who clutter in the present study, which may have affected perceptions of a person who clutters. PMID- 25521171 TI - Depressive symptoms, cognitive impairment, and metabolic syndrome in community dwelling elderly in Southern Taiwan. AB - OBJECTIVE: Metabolic syndrome and depression are both thought to be associated with cognitive impairment in the elderly. Metabolic syndrome is also correlated with depression. We examined their possible pathways in a population-based sample. METHODS: We recruited 300 older community participants from Southern Taiwan. Demographics, medical history, severity of depressive symptoms, cognitive function, apolipoprotein genotyping, and lipid profile were collected. The presence of metabolic syndrome was confirmed with the Third Report of the National Cholesterol Education Program's Adult Treatment Panel. Possible relationships between metabolic syndrome, depressive symptoms, and cognitive dysfunction were explored using logistic regression and structured equation modelling. RESULTS: When gender, age, education, marital status, and apolipoprotein genotype were adjusted for logistic regression, metabolic syndrome and depressive symptoms were independent and significant predictors of cognitive dysfunction for community-dwelling elderly. In structural equation modelling, metabolic syndrome and depressive symptoms were correlated to each other, and both contributed to the presence of cognitive dysfunction. CONCLUSIONS: Depressive symptoms and metabolic syndrome are independently associated with cognitive impairment among community-dwelling elderly. PMID- 25521170 TI - A 15-year-old boy with silvery white hair, hepatosplenomegaly, and pancytopenia. PMID- 25521168 TI - Denial of prescription analgesia among people who inject drugs in a Canadian setting. AB - INTRODUCTION AND AIMS: Despite the high prevalence of pain among people who inject drugs (PWIDs), clinicians may be reluctant to prescribe opioid-based analgesia to those with a history of drug use or addiction. We sought to examine the prevalence and correlates of PWIDs reporting being denied of prescription analgesia (PA). We also explored reported reasons for and actions taken after being denied PA. DESIGN AND METHODS: Using data from two prospective cohort studies of PWIDs, multivariate logistic regression was used to identify the prevalence and correlates of reporting being denied PA. Descriptive statistics were used to characterise reasons for denials and subsequent actions. RESULTS: Approximately two-thirds (66.5%) of our sample of 462 active PWIDs reported having ever been denied PA. We found that reporting being denied PA was significantly and positively associated with having ever been enrolled in methadone maintenance treatment (adjusted odds ratio 1.76, 95% confidence interval 1.11-2.80) and daily cocaine injection (adjusted odds ratio 2.38, 95% confidence interval 1.00-5.66). The most commonly reported reason for being denied PA was being accused of drug seeking (44.0%). Commonly reported actions taken after being denied PA included buying the requested medication off the street (40.1%) or obtaining heroin to treat pain (32.9%). DISCUSSION AND CONCLUSIONS: These findings highlight the challenges of addressing perceived pain and the need for strategies to prevent high-risk methods of self-managing pain, such as obtaining diverted medications or illicit substances for pain. Such strategies may include integrated pain management guidelines within methadone maintenance treatment and other substance use treatment programs. PMID- 25521172 TI - A Video Recall Study of In-session Changes in Sentiment Override. AB - This study examines in-session changes in sentiment override over the first three sessions of couple therapy. Couples viewed a video recording of therapy sessions immediately after each of the first three sessions and continuously rated their level of sentiment override. Ninety-eight changes were randomly chosen for analysis. Three talk turns prior to each change was coded using the Family Relational Communication Control Coding System. Results show that changes in sentiment override occur frequently. Repeated incidents of communication control were related to negative change in sentiment override for females. Repeated incidents of being left out of the conversation were related to negative changes in sentiment override for females and positive changes for males. PMID- 25521174 TI - White matter damage in dementia. Introduction. PMID- 25521173 TI - The utility of the corticotropin test to diagnose adrenal insufficiency in critical illness: an update. AB - OBJECTIVE: One of the most common dynamic testing procedures for assessment of adrenocortical function is the standard corticotropin or the cosyntropin test. The aim of this review was to examine the evidence base underlying the corticotropin test in the management of the critically ill patient. DATA SYNTHESIS: The principle behind the corticotropin test is the demonstration of an inappropriately low cortisol production in response to exogenous ACTH, a situation analogous to physiological stress. The corticotropin test was originally described in nonstressed subjects, and its applicability and interpretation in the setting of critical illness continues to generate controversy. Attempting to determine the prevalence of an abnormal corticotropin test in critical illness is complicated by the use of different end-points and different populations. Moreover, the test result is also influenced by the assay used for measurement of plasma cortisol. Trials assessing the relationship between corticotropin response and severity of stress and organ dysfunction have produced divergent results, which may reflect differences in the methodology and the association being measured. Moreover, controversy exists with respect to the methodology and the interpretation with respect to the following variables: dose of corticotropin, end-points for assessment of total or free cortisol, effect of plasma cortisol variability, adrenal blood flow and its equivalence with other tests of adrenocortical function. CONCLUSIONS: The corticotropin test is used widely in the evaluation of adrenocortical function in the endocrine clinics. Its role in the critically ill patient is less well established. Several confounding variables exist and to have a 'one-size-fits-all' approach with a single end point in the face of several methodological and pathophysiological confounders may be flawed and may result in the institution of inappropriate therapy. The current evidence does not support the use of the corticotrophin test in critical illness to assess adrenocortical function and guiding steroid therapy in critical illness. PMID- 25521175 TI - Age-associated white matter lesions: the MRC Cognitive Function and Ageing Study. AB - Cerebral white matter lesions (WML) are common in the aging brain and are associated with dementia and depression. They are associated with vascular risk factors and small vessel disease, suggesting an ischemic origin, but recent pathology studies suggest a more complex pathogenesis. Studies using samples from the population-representative Medical Research Council Cognitive Function and Ageing Study neuropathology cohort used post-mortem magnetic resonance imaging to identify WML for further study. Expression of hypoxia-related molecules and other injury and protective cellular pathways in candidate immunohistochemical and gene expression microarray studies support a role for hypoxia/ischemia. However, these approaches also suggest that immune activation, blood-brain barrier dysfunction, altered cell metabolic pathways and glial cell injury contribute to pathogenesis. These abnormalities are not confined to WML, but are also found in apparently normal white matter in brains with lesions, suggesting a field effect of white matter abnormality within which lesions arise. WML are an active pathology with a complex pathogenesis that may potentially offer a number of primary and secondary intervention targets. PMID- 25521176 TI - Endothelial cells and human cerebral small vessel disease. AB - Brain endothelial cells have unique properties in terms of barrier function, local molecular signaling, regulation of local cerebral blood flow (CBF) and interactions with other members of the neurovascular unit. In cerebral small vessel disease (arteriolosclerosis; SVD), the endothelial cells in small arteries survive, even when mural pathology is advanced and myocytes are severely depleted. Here, we review aspects of altered endothelial functions that have been implicated in SVD: local CBF dysregulation, endothelial activation and blood brain barrier (BBB) dysfunction. Reduced CBF is reported in the diffuse white matter lesions that are a neuroradiological signature of SVD. This may reflect an underlying deficit in local CBF regulation (possibly via the nitric oxide/cGMP signaling pathway). While many laboratories have observed an association of symptomatic SVD with serum markers of endothelial activation, it is apparent that the origin of these circulating markers need not be brain endothelium. Our own neuropathology studies did not confirm local endothelial activation in small vessels exhibiting SVD. Local BBB failure has been proposed as a cause of SVD and associated parenchymal lesions. Some groups find that computational analyses of magnetic resonance imaging (MRI) scans, following systemic injection of a gadolinium-based contrast agent, suggest that extravasation into brain parenchyma is heightened in people with SVD. Our recent histochemical studies of donated brain tissue, using immunolabeling for large plasma proteins [fibrinogen, immunoglobulin G (IgG)], do not support an association of SVD with recent plasma protein extravasation. It is possible that a trigger leakage episode, or a size selective loosening of the BBB, participates in SVD pathology. PMID- 25521177 TI - Cerebral amyloid angiopathy, subcortical white matter disease and dementia: literature review and study in OPTIMA. AB - Cerebral amyloid angiopathy (CAA) is of increasing clinical and research interest as the ability to detect it and its consequences by neuroimaging in living subjects has advanced. There is also increasing interest in understanding its possible role in the development of intracerebral hemorrhage, Alzheimer's disease (AD) and vascular dementia. In this article, the literature on this subject is reviewed and novel findings relating CAA to subcortical white matter damage in 224 subjects in the Oxford project to Investigate Memory and Ageing (OPTIMA) are reported. The relationship between CAA and subcortical tissue damage in the OPTIMA subjects was found to be critically dependent on ApoE genotype, there being a positive relationship between measures of CAA and subcortical small vessel disease in ApoEepsilon4 carriers and a significant negative relationship in ApoEepsilon2 carriers. These findings draw attention, as have many other studies, to the importance of ApoE genotype as a major risk factor not only for dementia but also for damage to blood vessels in the aging brain. PMID- 25521178 TI - White matter changes in dementia: role of impaired drainage of interstitial fluid. AB - White matter abnormalities on magnetic resonance imaging (MRI) are associated with dementia and include white matter hyperintensities (WMH; also termed leukoaraiosis) and visible perivascular spaces (PVS). We review the potential role of impaired drainage of interstitial fluid in the pathogenesis of WMH and PVS. Whereas the volume of extracellular space in the grey matter is tightly controlled, fluid accumulates and expands the extracellular spaces of the white matter in acute hydrocephalus, vasogenic edema and WMH. Although there are no conventional lymphatic vessels in the brain, there is very effective lymphatic drainage for fluid and solutes along restricted pathways in the basement membranes of cerebral capillaries and arteries in young individuals. Lymphatic drainage of the brain is impaired with age and in association with apolipoprotein E epsilon4, risk factors for Alzheimer's disease and cerebral amyloid angiopathy (CAA). Deposition of proteins in the lymphatic drainage pathways in the walls of cerebral arteries with age is recognized as protein elimination failure angiopathy (PEFA), as in CAA and cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL). Facilitating perivascular lymphatic drainage from the aging brain may play a significant role in the prevention of CAA, WMH and Alzheimer's disease and may enhance the efficacy of immunotherapy for Alzheimer's disease. PMID- 25521179 TI - Cognitive impairment in multiple sclerosis: clinical, radiologic and pathologic insights. AB - Cognitive impairment is a common and debilitating feature of multiple sclerosis (MS) that has only recent gained considerable attention. Clinical neuropsychological studies have made apparent the multifaceted nature of cognitive troubles often encountered in MS and continue to broaden our understanding of its complexity. Radiographic studies have started to decipher the neuroanatomic substrate of MS-related cognitive impairment and have shed light onto its pathogenesis. Where radiographic studies have been limited by inadequate resolution or non-specificity, pathological studies have come to the fore. This review aims to provide an overview of the nature of cognitive impairment typically seen in MS and to explore the literature on imaging and pathological studies relevant to its evolution. In particular, the relative contributions of gray (i.e., cerebral cortex, hippocampus, thalamus and basal ganglia) and white matter to MS-related cognitive impairment will be discussed and the importance of interconnectivity between structures highlighted. The pressing need for longitudinal studies combining standardized neuropsychometric, paraclinical and radiographic outcomes obtained during life with post-mortem tissue analysis after death is presented. PMID- 25521180 TI - White matter hypoperfusion and damage in dementia: post-mortem assessment. AB - Neuroimaging has revealed a range of white matter abnormalities that are common in dementia, some that predict cognitive decline. The abnormalities may result from structural diseases of the cerebral vasculature, such as arteriolosclerosis and amyloid angiopathy, but can also be caused by nonstructural vascular abnormalities (eg, of vascular contractility or permeability), neurovascular instability or extracranial cardiac or vascular disease. Conventional histopathological assessment of the white matter has tended to conflate morphological vascular abnormalities with changes that reflect altered interstitial fluid dynamics or white matter ischemic damage, even though the latter may be of extracranial or nonstructural etiology. However, histopathology is being supplemented by biochemical approaches, including the measurement of proteins involved in the molecular responses to brain ischemia, myelin proteins differentially susceptible to ischemic damage, vessel-associated proteins that allow rapid measurement of microvessel density, markers of blood-brain barrier dysfunction and axonal injury, and mediators of white matter damage. By combining neuroimaging with histopathology and biochemical analysis, we can provide reproducible, quantitative data on the severity of white matter damage, and information on its etiology and pathogenesis. Together these have the potential to inform and improve treatment, particularly in forms of dementia to which white matter hypoperfusion makes a significant contribution. PMID- 25521181 TI - 48 year-old woman with right leg and arm numbness. Ganglioneurocytoma, WHO grade 2. PMID- 25521182 TI - 77-year-old woman with a dural-based mass. Marginal zone B-cell lymphoma (MZBCL). PMID- 25521183 TI - A 44-year old male with right-sided facial numbness. Dura-associated extranodal marginal zone B cell lymphoma (MALT lymphoma). PMID- 25521184 TI - A 24 year-old woman with relapsing brainstem manifestations and multiple focal brain lesions. Natural killer cell lymphoblastic lymphoma/leukemia. PMID- 25521187 TI - Exercise-Induced Abnormal Increase of Systolic Pulmonary Artery Pressure in Adult Patients With Sickle Cell Anemia: An Exercise Stress Echocardiography Study. AB - BACKGROUND: Pulmonary hypertension (PH) at rest is a risk factor for death in patients with sickle cell anemia (SCA). Exercise echocardiography (EE) can detect latent PH. We sought to investigate the occurrence of exercise-induced abnormal response of systolic pulmonary artery pressure (SPAP) in adult patients with SCA and normal SPAP at rest, and to identify the independent predictors of this abnormal response. METHODS AND RESULTS: Forty-four adult patients with SCA and normal SPAP at rest (tricuspid regurgitant jet flow velocity [TRV] <2.5 m/sec) were studied and divided into 2 groups: exhibiting normal SPAP after treadmill EE (TRV <= 2.7 m/sec) (G1), and exhibiting abnormal exercise-induced increase of SPAP (TRV > 2.7 m/sec) (G2). TRV cutoff points at rest and during EE were based on data from healthy-matched control subjects. Abnormal response of SPAP with exercise occurred in 57% of the sample (G2), with mean TRV level of 3.39 +/- 0.41 m/sec (range 2.8-4.5 m/sec), significantly higher than those of G1 (2.29 +/- 0.25 m/sec, range 2.0-2.7 m/sec; P < 0.001). Multivariate analysis identified TRV value in resting conditions >=2.25 m/sec (P < 0.05), left atrial volume index >=41 mL/m2 (P < 0.05), and a E/e'-waves ratio >=6.3 (P < 0.05) as independent predictors of exercise-induced increase of SPAP. CONCLUSION: We concluded that adult patients with SCA and normal SPAP at rest may exhibit abnormal exercise induced increase in SPAP, which was independently related to resting TRV levels, and indices of diastolic impairment and left ventricular filling pressure. PMID- 25521188 TI - Comparison of methods to assess adherence to small-quantity lipid-based nutrient supplements (SQ-LNS) and dispersible tablets among young Burkinabe children participating in a community-based intervention trial. AB - Adherence to supplementation provided during an intervention trial can affect interpretation of study outcomes. We compared different approaches for estimating adherence to small-quantity lipid-based nutrient supplements (SQ-LNS) and dispersible tablets in a randomised clinical trial in Burkina Faso. A total of 2435 children (9-18 months) were randomly assigned to receive daily 20 g SQ-LNS with varying contents of zinc and a dispersible tablet containing 0 or 5 mg zinc. Adherence to SQ-LNS and tablets was assessed for all children through weekly caregiver interviews, and disappearance rate was calculated based on empty and unused packages returned during home visits. Additional adherence data were collected in different randomly selected subgroups of children: 12-h home observations were completed for children 11 and 16 months of age (n = 192) to assess consumption of SQ-LNS and dispersible tablets, and plasma zinc concentration was measured at baseline and 18 months (n = 310). Apparent adherence to SQ-LNS and dispersible tablets differed according to the assessment method used. Average daily caregiver-reported adherence to both SQ-LNS and dispersible tablets was 97 +/- 6%. Disappearance rates showed similarly high average weekly adherence (98 +/- 4%). In contrast, only 63% and 54% of children at 11 and 16 months, respectively, received SQ-LNS during the 12-h home observation periods, and fewer (32% and 27%) received a tablet. The lack of change in plasma zinc concentration after 9 months of supplementation suggests low adherence to the zinc tablet. Better methods are needed to assess adherence in community-based supplementation trials. PMID- 25521190 TI - The soil microbial community predicts the importance of plant traits in plant soil feedback. AB - Reciprocal interaction between plant and soil (plant-soil feedback, PSF) can determine plant community structure. Understanding which traits control interspecific variation of PSF strength is crucial for plant ecology. Studies have highlighted either plant-mediated nutrient cycling (litter-mediated PSF) or plant-microbe interaction (microbial-mediated PSF) as important PSF mechanisms, each attributing PSF variation to different traits. However, this separation neglects the complex indirect interactions between the two mechanisms. We developed a model coupling litter- and microbial-mediated PSFs to identify the relative importance of traits in controlling PSF strength, and its dependency on the composition of root-associated microbes (i.e. pathogens and/or mycorrhizal fungi). Results showed that although plant carbon: nitrogen (C : N) ratio and microbial nutrient acquisition traits were consistently important, the importance of litter decomposability varied. Litter decomposability was not a major PSF determinant when pathogens are present. However, its importance increased with the relative abundance of mycorrhizal fungi as nutrient released from the mycorrhizal-enhanced litter production to the nutrient-depleted soils result in synergistic increase of soil nutrient and mycorrhizal abundance. Data compiled from empirical studies also supported our predictions. We propose that the importance of litter decomposability depends on the composition of root associated microbes. Our results provide new perspectives in plant invasion and trait-based ecology. PMID- 25521189 TI - The catalytic topoisomerase II inhibitor dexrazoxane induces DNA breaks, ATF3 and the DNA damage response in cancer cells. AB - BACKGROUND AND PURPOSE: The catalytic topoisomerase II inhibitor dexrazoxane has been associated not only with improved cancer patient survival but also with secondary malignancies and reduced tumour response. EXPERIMENTAL APPROACH: We investigated the DNA damage response and the role of the activating transcription factor 3 (ATF3) accumulation in tumour cells exposed to dexrazoxane. KEY RESULTS: Dexrazoxane exposure induced topoisomerase IIalpha (TOP2A)-dependent cell death, gamma-H2AX accumulation and increased tail moment in neutral comet assays. Dexrazoxane induced DNA damage responses, shown by enhanced levels of gamma H2AX/53BP1 foci, ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), Chk1 and Chk2 phosphorylation, and by p53 accumulation. Dexrazoxane-induced gamma H2AX accumulation was dependent on ATM. ATF3 protein was induced by dexrazoxane in a concentration- and time-dependent manner, which was abolished in TOP2A depleted cells and in cells pre-incubated with ATM inhibitor. Knockdown of ATF3 gene expression by siRNA triggered apoptosis in control cells and diminished the p53 protein level in both control and dexrazoxane -treated cells. This was accompanied by increased gamma-H2AX accumulation. ATF3 knockdown also delayed the repair of dexrazoxane -induced DNA double-strand breaks. CONCLUSIONS AND IMPLICATIONS: As with other TOP2A poisons, dexrazoxane induced DNA double-strand breaks followed by activation of the DNA damage response. The DNA damage triggered ATF3 controlled p53 accumulation and generation of double-strand breaks and is proposed to serve as a switch between DNA damage and cell death following dexrazoxane treatment. These findings suggest a mechanistic explanation for the diverse clinical observations associated with dexrazoxane. PMID- 25521191 TI - A multicenter study of key stakeholders' perspectives on communicating with surrogates about prognosis in intensive care units. AB - RATIONALE: Surrogates of critically ill patients often have inaccurate expectations about prognosis. Yet there is little research on how intensive care unit (ICU) clinicians should discuss prognosis, and existing expert opinion-based recommendations give only general guidance that has not been validated with surrogate decision makers. OBJECTIVE: To determine the perspectives of key stakeholders regarding how prognostic information should be conveyed in critical illness. METHODS: This was a multicenter study at three academic medical centers in California, Pennsylvania, and Washington. One hundred eighteen key stakeholders completed in-depth semistructured interviews. Participants included 47 surrogates of adult patients with acute respiratory distress syndrome; 45 clinicians working in study ICUs, including physicians, nurses, social workers, and spiritual care providers; and 26 experts in health communication, decision science, ethics, family-centered care, geriatrics, healthcare disparities, palliative care, psychology, psychiatry, and critical care. MEASUREMENTS AND MAIN RESULTS: There was broad support among surrogates for existing expert recommendations, including truthful prognostic disclosure, emotional support, tailoring the disclosure strategy to each family's needs, and checking for understanding. In addition, stakeholders offered suggestions that add specificity to existing recommendations, including: (1) In addition to conveying prognostic estimates, clinicians should help families "see the prognosis for themselves" by showing families radiographic images and explaining the clinical significance of physical manifestations of severe disease at the bedside. (2) Many physicians did not support using numeric estimates to convey prognosis to families, whereas many surrogates, clinicians from other disciplines, and experts believed numbers could be helpful. (3) Clinicians should conceptualize prognostic communication as an iterative process that begins with a preliminary mention of the possibility of death early in the ICU stay and becomes more detailed as the clinical situation develops. (4) Although prognostic information should be initially disclosed by physicians, other members of the multidisciplinary team-nurses, social workers, and spiritual care providers-should be given explicit role responsibilities to reinforce physicians' prognostications and help families process a poor prognosis emotionally. CONCLUSIONS: Family members, clinicians, and experts identified specific communication behaviors that clinicians should use to discuss prognosis in the critical care setting. These findings extend existing opinion-based recommendations and should guide interventions to improve communication about prognosis in ICUs. PMID- 25521198 TI - MHC2MIL: a novel multiple instance learning based method for MHC-II peptide binding prediction by considering peptide flanking region and residue positions. AB - BACKGROUND: Computational prediction of major histocompatibility complex class II (MHC-II) binding peptides can assist researchers in understanding the mechanism of immune systems and developing peptide based vaccines. Although many computational methods have been proposed, the performance of these methods are far from satisfactory. The difficulty of MHC-II peptide binding prediction comes mainly from the large length variation of binding peptides. METHODS: We develop a novel multiple instance learning based method called MHC2MIL, in order to predict MHC-II binding peptides. We deem each peptide in MHC2MIL as a bag, and some substrings of the peptide as the instances in the bag. Unlike previous multiple instance learning based methods that consider only instances of fixed length 9 (9 amino acids), MHC2MIL is able to deal with instances of both lengths of 9 and 11 (11 amino acids), simultaneously. As such, MHC2MIL incorporates important information in the peptide flanking region. For measuring the distances between different instances, furthermore, MHC2MIL explicitly highlights the amino acids in some important positions. RESULTS: Experimental results on a benchmark dataset have shown that, the performance of MHC2MIL is significantly improved by considering the instances of both 9 and 11 amino acids, as well as by emphasizing amino acids at key positions in the instance. The results are consistent with those reported in the literature on MHC-II peptide binding. In addition to five important positions (1, 4, 6, 7 and 9) for HLA(human leukocyte antigen, the name of MHC in Humans) DR peptide binding, we also find that position 2 may play some roles in the binding process. By using 5-fold cross validation on the benchmark dataset, MHC2MIL outperforms two state-of-the-art methods of MHC2SK and NN-align with being statistically significant, on 12 HLA DP and DQ molecules. In addition, it achieves comparable performance with MHC2SK and NN-align on 14 HLA DR molecules. MHC2MIL is freely available at http://datamining iip.fudan.edu.cn/service/MHC2MIL/index.html. PMID- 25521199 TI - Actions of the pyrethroid insecticide bifenthrin on sodium channels expressed in rat cerebral cortical neurons. AB - Voltage-gated sodium channels are important sites for the neurotoxic actions of pyrethroid insecticides in mammals. Here, we studied the mode of action of bifenthrin on the native sodium channels in cerebral cortical neurons prepared from newborn rat brain, where the toxic effects are largely generated. Bifenthrin caused a pronounced late current that persisted at the end of a depolarizing pulse, a slowly-decaying tail current following repolarization and significant resting modification (25.3% modification at 10 MUM). No significant bifenthrin induced effect was observed at the peak current. Bifenthrin also caused a concentration-dependent hyperpolarizing shift in steady-state activation and inactivation as well as slowed recovery from channel inactivation. Repetitive depolarization increased the potency of bifenthrin with high frequency. There was approximately 64% inhibition of modification upon repetitive activation by 10-Hz trains of depolarizing pulses. These results suggest that bifenthrin binds to and modifies sodium channels in both the closed and open states and exhibits the behavior between type I and type II. PMID- 25521197 TI - Lymphaticovenous bypass decreases pathologic skin changes in upper extremity breast cancer-related lymphedema. AB - INTRODUCTION: Recent advances in microsurgery such as lymphaticovenous bypass (LVB) have been shown to decrease limb volumes and improve subjective symptoms in patients with lymphedema. However, to date, it remains unknown if these procedures can reverse the pathological tissue changes associated with lymphedema. Therefore, the purpose of this study was to analyze skin tissue changes in patients before and after LVB. METHODS AND RESULTS: Matched skin biopsy samples were collected from normal and lymphedematous limbs of 6 patients with unilateral breast cancer-related upper extremity lymphedema before and 6 months after LVB. Biopsy specimens were fixed and analyzed for inflammation, fibrosis, hyperkeratosis, and lymphangiogenesis. Six months following LVB, 83% of patients had symptomatic improvement in their lymphedema. Histological analysis at this time demonstrated a significant decrease in tissue CD4(+) cell inflammation in lymphedematous limb (but not normal limb) biopsies (p<0.01). These changes were associated with significantly decreased tissue fibrosis as demonstrated by decreased collagen type I deposition and TGF-beta1 expression (all p<0.01). In addition, we found a significant decrease in epidermal thickness, decreased numbers of proliferating basal keratinocytes, and decreased number of LYVE-1(+) lymphatic vessels in lymphedematous limbs after LVB. CONCLUSIONS: We have shown, for the first time, that microsurgical LVB not only improves symptomatology of lymphedema but also helps to improve pathologic changes in the skin. These findings suggest that the some of the pathologic changes of lymphedema are reversible and may be related to lymphatic fluid stasis. PMID- 25521200 TI - Network-based biomarkers enhance classical approaches to prognostic gene expression signatures. AB - BACKGROUND: Classical approaches to predicting patient clinical outcome via gene expression information are primarily based on differential expression of unrelated genes (single-gene approaches) or genes related by, for example, biologic pathway or function (gene-sets). Recently, network-based approaches utilising interaction information between genes have emerged. An open problem is whether such approaches add value to the more traditional methods of signature modelling. We explored this question via comparison of the most widely employed single-gene, gene-set, and network-based methods, using gene expression microarray data from two different cancers: melanoma and ovarian. We considered two kinds of network approaches. The first of these identifies informative genes using gene expression and network connectivity information combined, the latter drawn from prior knowledge of protein-protein interactions. The second approach focuses on identification of informative sub-networks (small networks of interacting proteins, again from prior knowledge networks). For all methods we performed 100 rounds of 5-fold cross-validation under 3 different classifiers. For network-based approaches, we considered two different protein-protein interaction networks. We quantified resulting patterns of misclassification and discussed the relative value of each relative to ongoing development of prognostic biomarkers. RESULTS: We found that single-gene, gene-set and network methods yielded similar error rates in melanoma and ovarian cancer data. Crucially, however, our novel and detailed patient-level analyses revealed that the different methods were correctly classifying alternate subsets of patients in each cohort. We also found that the network-based NetRank feature selection method was the most stable. CONCLUSIONS: Next-generation methods of gene expression signature modelling harness data from external networks and are foreshadowed as a standard mode of analysis. But what do they add to traditional approaches? Our findings indicate there is value in the way in which different subspaces of the patient sample are captured differently among the various methods, highlighting the possibility of 'combination' classifiers capable of identifying which patients will be more accurately classified by one particular method over another. We have seen this clearly for the first time because of our in-depth analysis at the level of individual patients. PMID- 25521202 TI - Validity of the assessment method of skeletal maturation by cervical vertebrae: a systematic review and meta-analysis. AB - OBJECTIVES: To perform a systematic review with meta-analysis to answer the question: is the cervical vertebrae maturation index (CVMI) effective to replace hand-wrist radiograph (gold standard) in determining the pubertal growth spurt in patients undergoing bone growth? METHODS: A search in three databases was performed, in which studies were selected that compared one of the two main assessment methods for cervical vertebrae (Hassel B, Farman AG. Skeletal maturation evaluation using cervical vertebrae. Am J Orthod Dentofacial Orthop 1995; 107: 58-66, or Baccetti T, Franchi L, McNamara JA Jr. An improved version of the cervical vertebral maturation (CVM) method for the assessment of mandibular growth. Angle Orthod 2002; 72: 316-23) to a carpal assessment method. The main methodological data from each of the texts were collected and tabulated after. Later, the meta-analysis of the correlation coefficients obtained was performed. RESULTS: 19 articles were selected from an initial 206 articles collected. Regardless of the method used, the results of the meta-analysis showed that every article selected presented a positive correlation between skeletal maturation assessment performed by cervical vertebrae and carpal methods, with discrepancy of values between genders indicating higher correlation for the female gender (0.925; 0.878) than for the male (0.879; 0.842). When the assessment was performed without gender separation, correlation was significant (0.592; 0.688) but lower in the cases when genders were separated. CONCLUSIONS: With the results of this meta-analysis, it is safe to affirm that both CVMIs used in the present study are reliable to replace the hand-wrist radiograph in predicting the pubertal growth spurt, considering that the highest values were found in female samples, especially in the method by Hassel and Farman. PMID- 25521201 TI - Rule discovery and distance separation to detect reliable miRNA biomarkers for the diagnosis of lung squamous cell carcinoma. AB - BACKGROUND: Altered expression profiles of microRNAs (miRNAs) are linked to many diseases including lung cancer. miRNA expression profiling is reproducible and miRNAs are very stable. These characteristics of miRNAs make them ideal biomarker candidates. METHOD: This work is aimed to detect 2-and 3-miRNA groups, together with specific expression ranges of these miRNAs, to form simple linear discriminant rules for biomarker identification and biological interpretation. Our method is based on a novel committee of decision trees to derive 2-and 3 miRNA 100%-frequency rules. This method is applied to a data set of lung miRNA expression profiles of 61 squamous cell carcinoma (SCC) samples and 10 normal tissue samples. A distance separation technique is used to select the most reliable rules which are then evaluated on a large independent data set. RESULTS: We obtained four 2-miRNA and three 3-miRNA top-ranked rules. One important rule is that: If the expression level of miR-98 is above 7.356 and the expression level of miR-205 is below 9.601 (log2 quantile normalized MirVan miRNA Bioarray signals), then the sample is normal rather than cancerous with specificity and sensitivity both 100%. The classification performance of our best miRNA rules remarkably outperformed that by randomly selected miRNA rules. Our data analysis also showed that miR-98 and miR-205 have two common predicted target genes FZD3 and RPS6KA3, which are actually genes associated with carcinoma according to the Online Mendelian Inheritance in Man (OMIM) database. We also found that most of the chromosomal loci of these miRNAs have a high frequency of genomic alteration in lung cancer. On the independent data set (with balanced controls), the three miRNAs miR-126, miR-205 and miR-182 from our best rule can separate the two classes of samples at the accuracy of 84.49%, sensitivity of 91.40% and specificity of 77.14%. CONCLUSION: Our results indicate that rule discovery followed by distance separation is a powerful computational method to identify reliable miRNA biomarkers. The visualization of the rules and the clear separation between the normal and cancer samples by our rules will help biology experts for their analysis and biological interpretation. PMID- 25521203 TI - FMAj: a tool for high content analysis of muscle dynamics in Drosophila metamorphosis. AB - BACKGROUND: During metamorphosis in Drosophila melanogaster, larval muscles undergo two different developmental fates; one population is removed by cell death, while the other persistent subset undergoes morphological remodeling and survives to adulthood. Thanks to the ability to perform live imaging of muscle development in transparent pupae and the power of genetics, metamorphosis in Drosophila can be used as a model to study the regulation of skeletal muscle mass. However, time-lapse microscopy generates sizeable image data that require new tools for high throughput image analysis. RESULTS: We performed targeted gene perturbation in muscles and acquired 3D time-series images of muscles in metamorphosis using laser scanning confocal microscopy. To quantify the phenotypic effects of gene perturbations, we designed the Fly Muscle Analysis tool (FMAj) which is based on the ImageJ and MySQL frameworks for image processing and data storage, respectively. The image analysis pipeline of FMAj contains three modules. The first module assists in adding annotations to time lapse datasets, such as genotypes, experimental parameters and temporal reference points, which are used to compare different datasets. The second module performs segmentation and feature extraction of muscle cells and nuclei. Users can provide annotations to the detected objects, such as muscle identities and anatomical information. The third module performs comparative quantitative analysis of muscle phenotypes. We applied our tool to the phenotypic characterization of two atrophy related genes that were silenced by RNA interference. Reduction of Drosophila Tor (Target of Rapamycin) expression resulted in enhanced atrophy compared to control, while inhibition of the autophagy factor Atg9 caused suppression of atrophy and enlarged muscle fibers of abnormal morphology. FMAj enabled us to monitor the progression of atrophic and hypertrophic phenotypes of individual muscles throughout metamorphosis. CONCLUSIONS: We designed a new tool to visualize and quantify morphological changes of muscles in time-lapse images of Drosophila metamorphosis. Our in vivo imaging experiments revealed that evolutionarily conserved genes involved in Tor signalling and autophagy, perform similar functions in regulating muscle mass in mammals and Drosophila. Extending our approach to a genome-wide scale has the potential to identify new genes involved in muscle size regulation. PMID- 25521204 TI - Characterization and identification of protein O-GlcNAcylation sites with substrate specificity. AB - BACKGROUND: Protein O-GlcNAcylation, involving the attachment of single N acetylglucosamine (GlcNAc) to the hydroxyl group of serine or threonine residues. Elucidation of O-GlcNAcylation sites on proteins is required in order to decipher its crucial roles in regulating cellular processes and aid in drug design. With an increasing number of O-GlcNAcylation sites identified by mass spectrometry (MS)-based proteomics, several methods have been proposed for the computational identification of O-GlcNAcylation sites. However, no development that focuses on the investigation of O-GlcNAcylated substrate motifs has existed. Thus, we were motivated to design a new method for the identification of protein O GlcNAcylation sites with the consideration of substrate site specificity. RESULTS: In this study, 375 experimentally verified O-GlcNAcylation sites were collected from dbOGAP, which is an integrated resource for protein O GlcNAcylation. Due to the difficulty in characterizing the substrate motifs by conventional sequence logo analysis, a recursively statistical method has been applied to obtain significant conserved motifs. To construct the predictive models learned from the identified substrate motifs, we adopted Support Vector Machines (SVMs). A five-fold cross validation was used to evaluate the predictive model, achieving sensitivity, specificity, and accuracy of 0.76, 0.80, and 0.78, respectively. Additionally, an independent testing set, which was really blind to the training data of predictive model, was used to demonstrate that the proposed method could provide a promising accuracy (0.94) and outperform three other O GlcNAcylation site prediction tools. CONCLUSION: This work proposed a computational method to identify informative substrate motifs for O-GlcNAcylation sites. The evaluation of cross validation and independent testing indicated that the identified motifs were effective in the identification of O-GlcNAcylation sites. A case study demonstrated that the proposed method could be a feasible means of conducting preliminary analyses of protein O-GlcNAcylation. We also anticipated that the revealed substrate motif may facilitate the study of extensive crosstalk between O-GlcNAcylation and phosphorylation. This method may help unravel their mechanisms and roles in signaling, transcription, chronic disease, and cancer. PMID- 25521207 TI - Peptide-induced affinity binding of carbonic anhydrase to carbon nanotubes. AB - Although affinity binding between short chain peptides and carbon nanotube (CNT) has been reported, little is known for the study of proteins with CNT recognition and specific binding capabilities. Herein, carbonic anhydrase (CA) was functionalized via protein fusion with a single-walled carbon nanotube (SWNTs) binding peptide, thereby forming a bioactive protein with high affinity binding capability. TEM and AFM analyses showed that the fusion CA could firmly coat to SWNTs with a surface coverage over 51%, while the enzyme maintained its catalytic activity. Structural analysis revealed that slight conformation changes were induced as a result of the fusion; however, the affinity binding of CA to the hydrophobic surface of SWNTs restored the native structure of the protein, with the conformation of the SWNT-bound CA largely resembling that of the native parent enzyme. Interfacial interactions between the fusion CA and SWNT were further investigated with Raman spectrometry and microscopic analysis. The results suggested that such peptide-induced CNT-protein binding allows the development of bioactive hybrid materials with the native structures of the protein moieties largely undisrupted. PMID- 25521206 TI - Effects of resveratrol supplementation on bone growth in young rats and microarchitecture and remodeling in ageing rats. AB - Osteoporosis is a highly prevalent skeletal disorder in the elderly that causes serious bone fractures. Peak bone mass achieved at adolescence has been shown to predict bone mass and osteoporosis related risk fracture later in life. Resveratrol, a natural polyphenol compound, may have the potential to promote bone formation and reduce bone resorption. However, it is unclear whether it can aid bone growth and bone mass accumulation during rapid growth and modulate bone metabolism during ageing. Using rat models, the current study investigated the potential effects of resveratrol supplementation during the rapid postnatal growth period and in late adulthood (early ageing) on bone microarchitecture and metabolism. In the growth trial, 4-week-old male hooded Wistar rats on a normal chow diet were given resveratrol (2.5 mg/kg/day) or vehicle control for 5 weeks. In the ageing trial, 6-month-old male hooded Wistar rats were treated with resveratrol (20 mg/kg/day) or vehicle for 3 months. Treatment effects in the tibia were examined by MU-computer tomography (MU-CT) analysis, bone histomorphometric measurements and reverse transcription-polymerase chain reaction (RT-PCR) gene expression analysis. Resveratrol treatment did not affect trabecular bone volume and bone remodeling indices in the youth animal model. Resveratrol supplementation in the early ageing rats tended to decrease trabecular bone volume, Sirt1 gene expression and increased expression of adipogenesis-related genes in bone, all of which were statistically insignificant. However, it decreased osteocalcin expression (p = 0.03). Furthermore, serum levels of bone resorption marker C-terminal telopeptides type I collagen (CTX-1) were significantly elevated in the resveratrol supplementation group (p = 0.02) with no changes observed in serum levels of bone formation marker alkaline phosphatase (ALP). These results in rat models suggest that resveratrol supplementation does not significantly affect bone volume during the rapid growth phase but may potentially have negative effects on male skeleton during early ageing. PMID- 25521205 TI - Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population. AB - BACKGROUND: Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel. METHODOLOGY/PRINCIPAL FINDINGS: A total of 365 PSC cases and 368 healthy controls of Scandinavian ancestry were included in the study. We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n = 18,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRbeta, a MICA microsatellite polymorphism and HLA-C and HLA-B according to their ligand properties for killer immunoglobulin-like receptors. Breakdowns of the association signal by unconditional and conditional logistic regression analyses demarcated multiple PSC associated MHC haplotypes, and for eight of these classical HLA class I and II alleles represented the strongest association. A novel independent risk locus was detected near NOTCH4 in the HLA class III region, tagged by rs116212904 (odds ratio [95% confidence interval] = 2.32 [1.80, 3.00], P = 1.35*10-11). CONCLUSIONS/SIGNIFICANCE: Our study shows that classical HLA class I and II alleles, predominantly at HLA-B and HLA-DRB1, are the main risk factors for PSC in the MHC. In addition, the present assessments demonstrated for the first time an association near NOTCH4 in the HLA class III region. PMID- 25521208 TI - Time- and spectrally resolved characteristics of flavin fluorescence in U87MG cancer cells in culture. AB - Early detection of cancer is crucial for the successful diagnostics of its presence and its subsequent treatment. To improve cancer detection, we tested the progressive multimodal optical imaging of U87MG cells in culture. A combination of steady-state spectroscopic methods with the time-resolved approach provides a new insight into the native metabolism when focused on endogenous tissue fluorescence. In this contribution, we evaluated the metabolic state of living U87MG cancer cells in culture by means of endogenous flavin fluorescence. Confocal microscopy and time-resolved fluorescence imaging were employed to gather spectrally and time-resolved images of the flavin fluorescence. We observed that flavin fluorescence in U87MG cells was predominantly localized outside the cell nucleus in mitochondria, while exhibiting a spectral maximum under 500 nm and fluorescence lifetimes under 1.4 ns, suggesting the presence of bound flavins. In some cells, flavin fluorescence was also detected inside the cell nuclei in the nucleoli, exhibiting longer fluorescence lifetimes and a red shifted spectral maximum, pointing to the presence of free flavin. Extra-nuclear flavin fluorescence was diminished by 2-deoxyglucose, but failed to increase with 2,4-dinitrophenol, the uncoupler of oxidative phosphorylation, indicating that the cells use glycolysis, rather than oxidative phosphorylation for functioning. These gathered data are the first step toward monitoring the metabolic state of U87MG cancer cells. PMID- 25521209 TI - In defense of the employer mandate: hedging against uninsurance. PMID- 25521210 TI - Spatially resolved photoexcited charge-carrier dynamics in phase-engineered monolayer MoS2. AB - A fundamental understanding of the intrinsic optoelectronic properties of atomically thin transition-metal dichalcogenides (TMDs) is crucial for its integration into high performance semiconductor devices. Here, we investigate the transport properties of chemical vapor deposition (CVD) grown monolayer molybdenum disulfide (MoS2) under photoexcitation using correlated scanning photocurrent microscopy and photoluminescence imaging. We examined the effect of local phase transformation underneath the metal electrodes on the generation of photocurrent across the channel length with diffraction-limited spatial resolution. While maximum photocurrent generation occurs at the Schottky contacts of semiconducting (2H-phase) MoS2, after the metallic phase transformation (1T phase), the photocurrent peak is observed toward the center of the device channel, suggesting a strong reduction of native Schottky barriers. Analysis using the bias and position dependence of the photocurrent indicates that the Schottky barrier heights are a few millielectron volts for 1T- and ~ 200 meV for 2H-contacted devices. We also demonstrate that a reduction of native Schottky barriers in a 1T device enhances the photoresponsivity by more than 1 order of magnitude, a crucial parameter in achieving high-performance optoelectronic devices. The obtained results pave a way for the fundamental understanding of intrinsic optoelectronic properties of atomically thin TMDs where ohmic contacts are necessary for achieving high-efficiency devices with low power consumption. PMID- 25521211 TI - Photochemical formation and cleavage of C-N bond. AB - A new photochemical method of C-N bond formation has been developed. A properly substituted trityl alcohol can cleave the benzylic C-O bond and replace it with a C-N bond which is stable under the irradiation conditions. The C-N bond can then be photochemically cleaved with the same light source when the nitrogen is protonated. PMID- 25521212 TI - Electrochemiluminescent immune-modified electrodes based on Ag2Se@CdSe nanoneedles loaded with polypyrrole intercalated graphene for detection of CA72 4. AB - This work described a new electrochemiluminescence (ECL) immunosensor based on polypyrrole intercalated graphene and Ag2Se@CdSe nanoneedles. The novel nanomaterial Ag2Se@CdSe, with needle-like morphology, was synthesized for the first time. The prepared Ag2Se@CdSe nanoneedles exhibited good luminous performance in the presence of K2S2O8. Polypyrrole intercalated amination graphene with high specific binding sites and excellent electrochemical performance was used as the platform for the sensor. The developed ECL immunosensor was used for the detection of CA72-4 with good linear relation in the range from 10(-4) to 20 U/mL and low detection limit of 2.1 * 10(-5) U/mL (S/N = 3). The developed ECL immunosensor with high sensitivity and spectral selectivity can be used for detection of real samples. Ag2Se@CdSe nanoneedles could be promising candidate emitter for ECL biosensors in the future. PMID- 25521213 TI - Fully and partially Li-stuffed diamond polytypes with Ag-Ge structures: Li2AgGe and Li2.53AgGe2. AB - In view of the search for and understanding of new materials for energy storage, the Li-Ag-Ge phase diagram has been investigated. High-temperature syntheses of Li with reguli of premelted Ag and Ge led to the two new compounds Li(2)AgGe and Li(2.80-x)AgGe(2) (x = 0.27). The compounds were characterized by single-crystal X-ray diffraction. Both compounds show diamond-polytype-like polyanionic substructures with tetrahedrally coordinated Ag and Ge atoms. The Li ions are located in the channels provided by the network. The compound Li(2)AgGe crystallizes in the space group R3m (No. 166) with lattice parameters of a = 4.4424(6) A and c = 42.7104(6) A. All atomic positions are fully occupied and ordered. Li(2.80-x)AgGe(2) crystallizes in the space group I4(1)/a (No. 88) with lattice parameters of a = 9.7606(2) A and c = 18.4399(8) A. The Ge substructure consists of unique (1)(infinity)[Ge(10)] chains that are interconnected by Ag atoms to build a three-dimensional network. In the channels of this diamond-like network, not all of the possible positions are occupied by Li ions. Li atoms in the neighborhood of the vacancies show considerably enlarged displacement vectors. The occurrence of the vacancy is traced back to short Li-Li distances in the case of the occupation of the vacancy with Li. Both compounds are not electron-precise Zintl phases. The density of states, band structure, and crystal orbital Hamilton population analyses of Li(2.80-x)AgGe(2 )reveal metallic properties, whereas a full occupation of all Li sites leads to an electron precise Zintl compound within a rigid-band model. Li(2)AgGe reveals metallic character in the ab plane and is a semiconductor with a small band gap along the c direction. PMID- 25521214 TI - How to assess kidney function in outpatient clinics. AB - BACKGROUND: In 2002, a new definition and classification of chronic kidney disease was published, and glomerular filtration rate < 60 ml/min/1.73 m(2) for 3 months or more was adapted to define chronic kidney disease irrespective of other signs of kidney damage. AIMS: To discuss different ways to assess kidney function in outpatient clinics and especially in primary care. METHODS: The PubMed database was searched for relevant articles. RESULTS: The estimated glomerular filtration rate equations which take into account plasma creatinine, age, sex, race and body size have been developed to identify patients with chronic kidney disease formerly overlooked if the renal function had been assessed by plasma creatinine alone. Cystatin C-based equations have also been developed to enhance accuracy for individuals with whom creatinine-based estimates for kidney function are acknowledged to be less accurate. DISCUSSION: The characteristics of the patients to whom the diagnostic test is applied can influence the sensitivity of the test. Thus, there is nowadays controversy over the best method to assess kidney function in general population. CONCLUSION: In the overwhelming majority of patients currently treated in primary care, the CKD-EPI creatinine equation is suitable for estimating renal function. The CKD-EPIcr-cys equation would provide further reliability in individuals with a CKD-EPI creatinine eGFR of 45-59 ml/min/1.73 m(2) , but the cost of serum cystatin C analysis limits its use in everyday general practice. PMID- 25521215 TI - Caregiving across the lifespan: comparing caregiver burden, mental health, and quality of life. AB - BACKGROUND: Care can be considered a lifelong process, but caring for a child is different from caring for an older adult. The present study aims to compare the caregiving process from infancy through old age by evaluating differences in caregiver burden, mental health, and quality of life and to describe the factors that could impact these outcomes. METHODS: To compare different groups of caregivers, we included 300 caregivers recruited from admissions to a tertiary acute hospital: 100 caregivers of children, 100 caregivers of adults, and 100 caregivers of older adults. A self-administered questionnaire was used that covered the following: sociodemographics, depression (Beck Depression Inventory), anxiety (Beck Anxiety Inventory), quality of life (Short Form Health Survey (SF 36)), religiosity (Duke Religion Index) and caregiver burden (Zarit Caregiver Burden Interview). RESULTS: A comparison between groups was performed (through chi2 and anova), and a linear regression analysis was used to assess the related factors. We found that children's caregivers had more depressive symptoms (higher Beck Depression Inventory scores), better physical health (SF-36: physical functioning and SF-36: Physical Component Summary), and lower pain (SF-36: bodily pain) than other caregivers. We found that caregivers of adults had better mental health (SF-36: mental health and SF-36: Mental Component Summary) than other caregivers and that caregivers of older adult had a higher caregiver burden (Zarit Caregiver Burden Interview scores) than other caregivers. After we controlled for baseline characteristics, only depressive symptoms and caregiver burden remained statistically significant. CONCLUSION: In conclusion, there are important differences between caregiving across the lifespan. Caregiving for children was associated with more depressive symptoms, and caregiving for older adults was associated with higher caregiver burden. Further studies are needed to replicate these findings in other settings. PMID- 25521216 TI - Long-term patterns of dental attendance and caries experience among British adults: a retrospective analysis. AB - There is inconclusive evidence on the value of regular dental attendance. This study explored the relationship between long-term patterns of dental attendance and caries experience. We used retrospective data from 3,235 adults, >= 16 yrs of age, who participated in the Adult Dental Health Survey in the UK. Participants were classified into four groups (always, current, former, and never regular attenders) based on their responses to three questions on lifetime dental attendance patterns. The association between dental-attendance patterns and caries experience, as measured using the decayed, missing, or filled teeth (DMFT) index, was tested in negative binomial regression models, adjusting for demographic (sex, age, and country of residence) and socio-economic (educational attainment, household income, and social class) factors. A consistent pattern of association between long-term dental attendance and caries experience was found in adjusted models. Former and never regular-attenders had a significantly higher DMFT score and numbers of decayed and missing teeth, but fewer filled teeth, than always regular-attenders. No differences in DMFT or its components were found between current and always regular-attenders. The findings of this study show that adults with different lifetime trajectories of dental attendance had different dental statuses. PMID- 25521217 TI - Effects of anodic titanium dioxide nanotubes of different diameters on macrophage secretion and expression of cytokines and chemokines. AB - OBJECTIVES: To investigate effects of TiO2 nanotubes of different diameters on J744A.1 macrophage behaviour, secretion and expression of pro-inflammatory cytokines and chemokines. MATERIALS AND METHODS: Macrophage-like J744A.1 cells were cultured on three types of Ti surface: mechanically polished titanium plus 30 and 80 nm TiO2 nanotube surfaces, for 4, 24 and 48 h. Macrophage adhesion and proliferation were assessed using CCK-8 assay. Levels of pro-inflammatory cytokines (TNF-alpha, IL-1beta and IL-6) and chemokines (MCP-1 and MIP-1alpha) secreted into the supernatant were measured using the Cytometric Bead Arrays kit. TNF-alpha, MCP-1 and MIP-1alpha gene expression were quantitatively analysed by real-time PCR. RESULTS: These show that TiO2 nanotube surfaces, especially of 80 nm TiO2 nanotube, benefited macrophage adhesion and proliferation, and reduced protein secretion and mRNA expression of TNF-alpha, MCP-1 and MIP-1alpha. IL 1beta and IL-6 were undetectable on all the surfaces at all times. CONCLUSIONS: TiO2 nanotube surfaces, especially of 80 nm TiO2 nanotube, reduced inflammatory response in vitro, which might be part of a basis for rapid osseointegration in implants with TiO2 nanotube surfaces in animal studies. PMID- 25521218 TI - The atypical MAPK ERK3 controls positive selection of thymocytes. AB - Extracellular signal-regulated kinase 3 (ERK3 )is an atypical member of the mitogen-activated protein kinase (MAPK) family. We have previously shown that ERK3 is expressed during thymocyte differentiation and that its expression is induced in mature peripheral T cells following activation of ERK1/2 by T-cell receptor (TCR) signalling. Herein, we have investigated whether ERK3 expression is required for proper T-cell selection. Using a knock-in mouse model in which the coding sequence of ERK3 is replaced by the gene encoding for the beta galactosidase reporter, we show that ERK3 is expressed by double-positive (DP) thymocytes undergoing positive selection. In ERK3-deficient mice with a polyclonal TCR repertoire, we observe a decrease in positive selection. This reduction in positive selection was also observed when ERK3-deficient mice were backcrossed to class I- and class II-restricted TCR transgenic mice. Furthermore, the response of DP thymocytes to in vitro TCR stimulation was strongly reduced in ERK3-deficient mice. Together, these results show that ERK3 expression following TCR signalling is critical for proper thymic positive selection. PMID- 25521219 TI - Prophylactic versus reactive transfusion of thawed plasma in patients undergoing surgical repair of craniosynostosis: a randomized clinical trial. AB - BACKGROUND: Surgical repair of craniosynostosis in young children is associated with copious bleeding and often coagulopathy. Typically, a reactive transfusion strategy is used to treat coagulopathy whereby fresh frozen plasma (FFP) is given only after clinical manifestation of clotting abnormality. This prospective, randomized clinical trial was designed to test the hypothesis that prophylactic FFP during craniofacial surgery reduces blood loss and blood transfusion requirements compared to a reactive FFP transfusion strategy. METHODS: Eighty-one patients less than 2 years of age requiring primary repair of craniosynostosis were randomized to receive FFP using either a prophylactic or reactive strategy. Laboratory values were measured at four standardized time points. The volume of blood products transfused, length of stay in the pediatric intensive care unit (PICU), hospital length of stay, and number of donor exposures were recorded for each patient. RESULTS: The prophylactic FFP group received a significantly greater average volume of FFP compared to the reactive group (29.7 ml.kg(-1) vs 16.1 ml.kg(-1) ; P < 0.001), which was associated with improvement in coagulation values at multiple time points. However, there was no difference in blood transfusion requirements or blood loss between the two groups. The two transfusion strategies resulted in similar median donor exposures. There was no difference in PICU or hospital length of stay. CONCLUSION: A reactive FFP transfusion strategy required less plasma transfusion and was associated with similar rates of blood loss and PRBC transfusion as prophylactic FFP despite improvement in coagulation values in the prophylactic FFP group. PMID- 25521220 TI - Coagulation activation during air travel is not initiated via the extrinsic pathway. PMID- 25521221 TI - Autoimmune response as a side effect of treatment with interferon-alpha in melanoma: does this have prognostic implications? PMID- 25521222 TI - RE: Association between habitual physical activity and brown adipose tissue activity in individuals undergoing PET-CT scan. PMID- 25521223 TI - Pilomyxoid Astrocytoma (PMA) Shows Significant Differences in Gene Expression vs. Pilocytic Astrocytoma (PA) and Variable Tendency Toward Maturation to PA. AB - Pilomyxoid astrocytomas (PMAs) manifest a more aggressive clinical course than pilocytic astrocytomas (PAs). Development of effective therapies demands a better biological understanding of PMA. We first conducted gene expression microarray analysis of 9 PMA and 13 PA from infra- and supratentorial sites. Unsupervised hierarchical clustering analysis demonstrated that tumors are grouped according to anatomic site, not diagnosis. Gene expression profiles were then contrasted between eight PMAs and six PAs, all supratentorial/hypothalamic/chiasmal. Clinical outcome of PMAs varied, with four out of four patients with diencephalic syndrome succumbing to disease, one of whom showed bulky metastatic leptomeningeal spread at autopsy, with bimodal maturation to PA in some areas and de-differentiation to glioblastoma in others. A surviving child has undergone multiple surgical debulking, with progressive maturation to PA over time. Ontology-enrichment analysis identified overexpression in PMAs of extracellular matrix and mitosis-related genes. Genes overexpressed in PMA vs. PA, ranked according to fold-change, included developmental genes H19, DACT2, extracellular matrix collagens (COL2A1; COL1A1) and IGF2BP3 (IMP3), the latter previously identified as an adverse prognostic factor in PMA and PA. PMID- 25521224 TI - A6V polymorphism of the human MU-opioid receptor decreases signalling of morphine and endogenous opioids in vitro. AB - BACKGROUND AND PURPOSE: Polymorphisms of the MU opioid receptor (MOPr) may contribute to the variation in responses to opioid drugs in clinical and unregulated situations. The A6V variant of MOPr (MOPr-A6V) is present in up to 20% of individuals in some populations, and may be associated with heightened susceptibility to drug abuse. There are no functional studies examining the acute signalling of MOPr-A6V in vitro, so we investigated potential functional differences between MOPr and MOPr-A6V at several signalling pathways using structurally distinct opioid ligands. EXPERIMENTAL APPROACH: CHO and AtT-20 cells stably expressing MOPr and MOPr-A6V were used. AC inhibition and ERK1/2 phosphorylation were assayed in CHO cells; K channel activation was assayed in AtT-20 cells. KEY RESULTS: Buprenorphine did not inhibit AC or stimulate ERK1/2 phosphorylation in CHO cells expressing MOPr-A6V, but buprenorphine activation of K channels in AtT-20 cells was preserved. [D-Ala2, N-MePhe4, Gly-ol]-enkephalin, morphine and beta-endorphin inhibition of AC was significantly reduced via MOPr A6V, as was signalling of all opioids to ERK1/2. However, there was little effect of the A6V variant on K channel activation. CONCLUSIONS AND IMPLICATIONS: Signalling to AC and ERK via the mutant MOPr-A6V was decreased for many opioids, including the clinically significant drugs morphine, buprenorphine and fentanyl, as well endogenous opioids. The MOPr-A6V variant is common and this compromised signalling may affect individual responses to opioid therapy, while the possible disruption of the endogenous opioid system may contribute to susceptibility to substance abuse. PMID- 25521225 TI - Meta-analysis of the TNFAIP3 region in psoriasis reveals a risk haplotype that is distinct from other autoimmune diseases. AB - Tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) encodes a ubiquitin modifying protein, A20, that is a critical regulator of inflammatory responses. TNFAIP3 polymorphisms are associated with the susceptibility to multiple autoimmune diseases (AIDs) including psoriasis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and celiac disease. In order to refine the TNFAIP3 association signal in psoriasis and identify candidate causal variants, we performed imputation and meta-analysis of the TNFAIP3 region in five European ancestry cohorts totaling 4704 psoriasis cases and 7805 controls. We identified 49 variants whose significance exceeded a corrected Bonferroni threshold, with the top variant being rs582757 (P = 6.07 * 10(-12), odds ratio (OR) = 1.23). Conditional analysis revealed a suggestive independent association at rs6918329 (P(cond) = 7.22 * 10(-5), OR = 1.15). Functional annotation of the top variants identified several with a strong evidence of regulatory potential and several within long noncoding RNAs. Analysis of TNFAIP3 haplotypes revealed that the psoriasis risk haplotype is distinct from other AIDs. Overall, our findings identify novel candidate causal variants of TNFAIP3 in psoriasis and highlight the complex genetic architecture of this locus in autoimmune susceptibility. PMID- 25521226 TI - Genome-wide significant linkage to IgG subclass responses against Plasmodium falciparum antigens on chromosomes 8p22-p21, 9q34 and 20q13. AB - A genome-wide scan was conducted for the levels of total immunoglobulin G (IgG) and IgG subclasses directed against Plasmodium falciparum antigens in an urban population living in Burkina Faso. Non-parametric multipoint linkage analysis provided three chromosomal regions with genome-wide significant evidence (logarithm of the odds (LOD) score >3.6), and five chromosomal regions with genome-wide suggestive evidence (LOD score >2.2). IgG3 levels were significantly linked to chromosomes 8p22-p21 and 20q13, whereas IgG4 levels were significantly linked to chromosome 9q34. In addition, we detected suggestive linkage of IgG1 levels to chromosomes 18p11-q12 and 18q12-q21, IgG4 levels to chromosomes 1p31 and 12q24 and IgG levels to chromosome 6p24-p21. Moreover, we genotyped genetic markers located within the regions of interest in a rural population living in Burkina Faso. We detected genome-wide significant and suggestive linkage results when combining the two study populations for chromosomes 1p31, 6p24-p21, 8p22 p21, 9q34, 12q24 and 20q13. Because high anti-parasite IgG3 and low anti-parasite IgG4 levels were associated with malaria resistance, the chromosomal regions linked to IgG3 and IgG4 levels are of special interest. Although the results should be confirmed in an independent population, they may provide new insights in understanding both the genetic control of IgG production and malaria resistance. PMID- 25521227 TI - Association of the LRRK2 genetic polymorphisms with leprosy in Han Chinese from Southwest China. AB - Leprosy is a chronic infectious and neurological disease that is caused by infection of Mycobacterium leprae (M. leprae). A recent genome-wide association study indicated a suggestive association of LRRK2 genetic variant rs1873613 with leprosy in Chinese population. To validate this association and further identify potential causal variants of LRRK2 with leprosy, we genotyped 13 LRRK2 variants in 548 leprosy patients and 1078 healthy individuals from Yunnan Province and (re )analyzed 3225 Han Chinese across China. Variants rs1427267, rs3761863, rs1873613, rs732374 and rs7298930 were significantly associated with leprosy per se and/or paucibacillary leprosy (PB). Haplotype A-G-A-C-A was significantly associated with leprosy per se (P=0.018) and PB (P=0.020). Overexpression of the protective allele (Thr2397) of rs3761863 in HEK293 cells led to a significantly increased nuclear factor of activated T-cells' activity compared with allele Met2397 after lipopolysaccharides stimulation. Allele Thr2397 could attenuate 1 methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced autophagic activity in U251 cells. These data suggest that the protective effect of LRRK2 variant p.M2397T on leprosy might be mediated by increasing immune response and decreasing neurotoxicity after M. leprae loading. Our findings confirm that LRRK2 is a susceptible gene to leprosy in Han Chinese population. PMID- 25521229 TI - Risk factors associated with potentially antibiotic-resistant pathogens in community-acquired pneumonia. AB - RATIONALE: To identify pathogens that require different treatments in community acquired pneumonia (CAP), we propose an acronym, "PES" (Pseudomonas aeruginosa, Enterobacteriaceae extended-spectrum beta-lactamase-positive, and methicillin resistant Staphylococcus aureus). OBJECTIVES: To compare the clinical characteristics and outcomes between patients with CAP caused by PES versus other pathogens, and to identify the risk factors associated with infection caused by PES. METHODS: We conducted an observational prospective study evaluating only immunocompetent patients with CAP and an established etiological diagnosis. We included patients from nursing homes. We computed a score to identify patients at risk of PES pathogens. MEASUREMENT AND MAIN RESULTS: Of the 4,549 patients evaluated, we analyzed 1,597 who presented an etiological diagnosis. Pneumonia caused by PES was identified in 94 (6%) patients, with 108 PES pathogens isolated (n = 72 P. aeruginosa, n = 15 Enterobacteriaceae extended-spectrum beta-lactamase positive, and n = 21 methicillin-resistant Staphylococcus aureus). These patients were older (P = 0.001), had received prior antibiotic treatment more frequently (P < 0.001), and frequently presented with acute renal failure (P = 0.004). PES pathogens were independently associated with increased risk of 30-day mortality (adjusted odds ratio = 2.51; 95% confidence interval = 1.20-5.25; P = 0.015). The area under the curve for the score we computed was 0.759 (95% confidence interval, 0.713-0.806; P < 0.001). CONCLUSIONS: PES pathogens are responsible for a small proportion of CAP, resulting in high mortality. These pathogens require a different antibiotic treatment, and identification of specific risk factors could help to identify these microbial etiologies. PMID- 25521228 TI - Polymorphisms in TICAM2 and IL1B are associated with TB. AB - Human genetic susceptibility for tuberculosis (TB) has been demonstrated by several studies, but few have examined the multiple innate and adaptive immunity genes comprehensively, age-specific effects and/or resistance to Mycobacterium tuberculosis (Mtb) infection (resistors (RSTRs)). We hypothesized that RSTRs, defined by a persistently negative tuberculin skin test, may have different genetic influences than Mtb disease. We examined 29 candidate genes in pathways that mediate immune responses to Mtb in subjects in a household contact study in Kampala, Uganda. We genotyped 546 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 835 individuals from 481 families; 28.7% had TB, 10.5% were RSTRs, and the remaining 60.8% had latent Mtb infection. Among our most significant findings were SNPs in TICAM2 (P = 3.6 * 10(-6)) and IL1B (P = 4.3 * 10(-5)) associated with TB. Multiple SNPs in IL4 and TOLLIP were associated with TB (P < 0.05). Age-genotype interaction analysis revealed SNPs in IL18 and TLR6 that were suggestively associated with TB in children aged ? 10 years (P = 2.9 * 10(-3)). By contrast, RSTR was associated with SNPs in NOD2, SLC6A3 and TLR4 (nominal P < 0.05); these genes were not associated with TB, suggesting distinct genetic influences. We report the first association between TICAM2 polymorphisms and TB and between IL18 and pediatric TB. PMID- 25521230 TI - A community assessment of privacy preserving techniques for human genomes. AB - To answer the need for the rigorous protection of biomedical data, we organized the Critical Assessment of Data Privacy and Protection initiative as a community effort to evaluate privacy-preserving dissemination techniques for biomedical data. We focused on the challenge of sharing aggregate human genomic data (e.g., allele frequencies) in a way that preserves the privacy of the data donors, without undermining the utility of genome-wide association studies (GWAS) or impeding their dissemination. Specifically, we designed two problems for disseminating the raw data and the analysis outcome, respectively, based on publicly available data from HapMap and from the Personal Genome Project. A total of six teams participated in the challenges. The final results were presented at a workshop of the iDASH (integrating Data for Analysis, 'anonymization,' and SHaring) National Center for Biomedical Computing. We report the results of the challenge and our findings about the current genome privacy protection techniques. PMID- 25521237 TI - Multiple shifts to different pollinators fuelled rapid diversification in sexually deceptive Ophrys orchids. AB - Episodes of rapid speciation provide unique insights into evolutionary processes underlying species radiations and patterns of biodiversity. Here we investigated the radiation of sexually deceptive bee orchids (Ophrys). Based on a time calibrated phylogeny and by means of ancestral character reconstruction and divergence time estimation, we estimated the tempo and mode of this radiation within a state-dependent evolutionary framework. It appears that, in the Pleistocene, the evolution of Ophrys was marked by episodes of rapid diversification coinciding with shifts to different pollinator types: from wasps to Eucera bees to Andrena and other bees. An abrupt increase in net diversification rate was detected in three clades. Among these, two phylogenetically distant lineages switched from Eucera to Andrena and other bees in a parallel fashion and at about the same time in their evolutionary history. Lack of early radiation associated with the evolution of the key innovation of sexual deception suggests that Ophrys diversification was mainly driven by subsequent ecological opportunities provided by the exploitation of novel pollinator groups, encompassing many bee species slightly differing in their sex pheromone communication systems, and by spatiotemporal fluctuations in the pollinator mosaic. PMID- 25521238 TI - The effects of walnut supplementation on hippocampal NMDA receptor subunits NR2A and NR2B of rats. AB - OBJECTIVES: Walnuts contain numerous selected dietary factors that have an impact on brain functions, especially learning and memory formation in the hippocampus. Hippocampal N-methyl d-aspartate receptors (NMDARs) are involved in the formation of cognitive functions. In this study, we aimed to investigate the molecular effects of walnut supplementation on the hippocampal expressions of NMDARs involved in cognitive functions and lipid peroxidation levels in rats. METHODS: The male Sprague-Dawley rats (6 months old, n = 24) were fed with a walnut supplemented diet (6% walnut diet, n = 12) and a control diet (rat food, n = 12) as ad libitum for 8 weeks. At the end of this period, NMDAR subunits NR2A and NR2B in the hippocampi were assayed by western blotting. Lipid peroxidation levels were measured using the thiobarbituric acid. RESULTS: The expression of NR2A and NR2B was elevated in the walnut-supplemented rats compared with the control group (P < 0.05). In addition, the levels of lipid peroxidation in the walnut-supplemented group were significantly decreased compared with the control group. DISCUSSION: We suggested that walnut supplementation may have protective effects against the decline of cognitive functions by regulating NMDAR and lipid peroxidation levels in the hippocampus. The study provides evidence that selected dietary factors (polyunsaturated fatty acids, melatonin, vitamin E, and flavonoids) within walnut may help to trigger hippocampal neuronal signal transduction for the formation of learning and memory. PMID- 25521240 TI - Contribution of Meat Inspection to the surveillance of poultry health and welfare in the European Union. AB - In the European Union, Meat Inspection (MI) aims to protect public health by ensuring that minimal hazardous material enters in the food chain. It also contributes to the detection and monitoring of animal diseases and welfare problems but its utility for animal surveillance has been assessed partially for some diseases only. Using the example of poultry production, we propose a complete assessment of MI as a health surveillance system. MI allows a long-term syndromic surveillance of poultry health but its contribution is lowered by a lack of data standardization, analysis and reporting. In addition, the probability of case detection for 20 diseases and welfare conditions was quantified using a scenario tree modelling approach, with input data based on literature and expert opinion. The sensitivity of MI appeared to be very high to detect most of the conditions studied because MI is performed at batch level and applied to a high number of birds per batch. PMID- 25521239 TI - An integrated assessment of histopathological changes of the enteric neuromuscular compartment in experimental colitis. AB - Bowel inflammatory fibrosis has been largely investigated, but an integrated assessment of remodelling in inflamed colon is lacking. This study evaluated tissue and cellular changes occurring in colonic wall upon induction of colitis, with a focus on neuromuscular compartment. Colitis was elicited in rats by 2,4 dinitrobenzenesulfonic acid (DNBS). After 6 and 21 days, the following parameters were assessed on paraffin sections from colonic samples: tissue injury and inflammatory infiltration by histology; collagen and elastic fibres by histochemistry; HuC/D, glial fibrillar acidic protein (GFAP), proliferating cell nuclear antigen (PCNA), nestin, substance P (SP), von Willebrand factor, c-Kit and transmembrane 16A/Anoctamin1 (TMEM16A/ANO1) by immunohistochemistry. TMEM16A/ANO1 was also examined in isolated colonic smooth muscle cells (ICSMCs). On day 6, inflammatory alterations and fibrosis were present in DNBS-treated rats; colonic wall thickening and fibrotic remodelling were evident on day 21. Colitis was associated with both an increase in collagen fibres and a decrease in elastic fibres. Moreover, the neuromuscular compartment of inflamed colon displayed a significant decrease in neuron density and increase in GFAP/PCNA positive glia of myenteric ganglia, enhanced expression of neural SP, blood vessel remodelling, reduced c-Kit- and TMEM16A/ANO1-positive interstitial cells of Cajal (ICCs), as well as an increase in TMEM16A/ANO1 expression in muscle tissues and ICSMCs. The present findings provide an integrated view of the inflammatory and fibrotic processes occurring in the colonic neuromuscular compartment of rats with DNBS-induced colitis. These morphological alterations may represent a suitable basis for understanding early pathophysiological events related to bowel inflammatory fibrosis. PMID- 25521241 TI - Whole-body imaging of a hypercholesterolemic female zebrafish by using synchrotron X-ray micro-CT. AB - Zebrafish has been used as a powerful model system in biological and biomedical studies studying development and diseases. Comparative, functional, and developmental studies on zebrafish morphology require precise visualization of 3D morphological structures. Few methods that can visualize whole-volume of zebrafish tissues are available because optical bio-imaging methods are limited by pigmentation and hard tissues. To overcome these limitations, the 3D microstructures of a hypercholesterolemic zebrafish model are visualized using synchrotron X-ray micro-computed tomography (SR-MUCT). The model spatial resolution ranged from sub- to several microns. The microstructures of various zebrafish organs are observed by combining high-contrast staining (osmium tetroxide and uranyl acetate) and embedding a protocol to enhance the image contrast of soft tissues. Furthermore, blood vessels are identified using a barium sulfate injection technique. The internal organs and cells, such as liver, intestine, oocytes, and adipocytes, of a hypercholesterolemic zebrafish are compared with those of normal organs and cells. The SR-MUCT is useful for understanding the pathogenesis of circulatory vascular diseases by detecting the modifications in the 3D morphological structures of the whole body of the zebrafish. This bio-imaging technique can be readily used to study other disease models. PMID- 25521242 TI - Semi-supervised multi-label collective classification ensemble for functional genomics. AB - BACKGROUND: With the rapid accumulation of proteomic and genomic datasets in terms of genome-scale features and interaction networks through high-throughput experimental techniques, the process of manual predicting functional properties of the proteins has become increasingly cumbersome, and computational methods to automate this annotation task are urgently needed. Most of the approaches in predicting functional properties of proteins require to either identify a reliable set of labeled proteins with similar attribute features to unannotated proteins, or to learn from a fully-labeled protein interaction network with a large amount of labeled data. However, acquiring such labels can be very difficult in practice, especially for multi-label protein function prediction problems. Learning with only a few labeled data can lead to poor performance as limited supervision knowledge can be obtained from similar proteins or from connections between them. To effectively annotate proteins even in the paucity of labeled data, it is important to take advantage of all data sources that are available in this problem setting, including interaction networks, attribute feature information, correlations of functional labels, and unlabeled data. RESULTS: In this paper, we show that the underlying nature of predicting functional properties of proteins using various data sources of relational data is a typical collective classification (CC) problem in machine learning. The protein functional prediction task with limited annotation is then cast into a semi-supervised multi-label collective classification (SMCC) framework. As such, we propose a novel generative model based SMCC algorithm, called GM-SMCC, to effectively compute the label probability distributions of unannotated protein instances and predict their functional properties. To further boost the predicting performance, we extend the method in an ensemble manner, called EGM SMCC, by utilizing multiple heterogeneous networks with various latent linkages constructed to explicitly model the relationships among the nodes for effectively propagate the supervision knowledge from labeled to unlabeled nodes. CONCLUSION: Experimental results on a yeast gene dataset predicting the functions and localization of proteins demonstrate the effectiveness of the proposed method. In the comparison, we find that the performances of the proposed algorithms are better than the other compared algorithms. PMID- 25521243 TI - Highly sensitive inference of time-delayed gene regulation by network deconvolution. AB - BACKGROUND: Gene regulatory network (GRN) is a fundamental topic in systems biology. The dynamics of GRN can shed light on the cellular processes, which facilitates the understanding of the mechanisms of diseases when the processes are dysregulated. Accurate reconstruction of GRN could also provide guidelines for experimental biologists. Therefore, inferring gene regulatory networks from high-throughput gene expression data is a central problem in systems biology. However, due to the inherent complexity of gene regulation, noise in measuring the data and the short length of time-series data, it is very challenging to reconstruct accurate GRNs. On the other hand, a better understanding into gene regulation could help to improve the performance of GRN inference. Time delay is one of the most important characteristics of gene regulation. By incorporating the information of time delays, we can achieve more accurate inference of GRN. RESULTS: In this paper, we propose a method to infer time-delayed gene regulation based on cross-correlation and network deconvolution (ND). First, we employ cross correlation to obtain the probable time delays for the interactions between each target gene and its potential regulators. Then based on the inferred delays, the technique of ND is applied to identify direct interactions between the target gene and its regulators. Experiments on real-life gene expression datasets show that our method achieves overall better performance than existing methods for inferring time-delayed GRNs. CONCLUSION: By taking into account the time delays among gene interactions, our method is able to infer GRN more accurately. The effectiveness of our method has been shown by the experiments on three real-life gene expression datasets of yeast. Compared with other existing methods which were designed for learning time-delayed GRN, our method has significantly higher sensitivity without much reduction of specificity. PMID- 25521244 TI - Interaction potential of the multitargeted receptor tyrosine kinase inhibitor dovitinib with drug transporters and drug metabolising enzymes assessed in vitro. AB - Dovitinib (TKI-258) is under development for the treatment of diverse cancer entities. No published information on its pharmacokinetic drug interaction potential is available. Thus, we assessed its interaction with important drug metabolising enzymes and drug transporters and its efficacy in multidrug resistant cells in vitro. P-glycoprotein (P-gp, MDR1, ABCB1) inhibition was evaluated by calcein assay, inhibition of breast cancer resistance protein (BCRP, ABCG2) by pheophorbide A efflux, and inhibition of organic anion transporting polypeptides (OATPs) by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 3A4, 2C19, and 2D6 was assessed by using commercial kits. Induction of transporters and enzymes was quantified by real-time RT-PCR. Possible aryl hydrocarbon receptor (AhR) activating properties were assessed by a reporter gene assay. Substrate characteristics were evaluated by growth inhibition assays in cells over-expressing P-gp or BCRP. Dovitinib weakly inhibited CYP2C19, CYP3A4, P gp and OATPs. The strongest inhibition was observed for BCRP (IC50 = 10.3 +/- 4.5 MUM). Among the genes investigated, dovitinib only induced mRNA expression of CYP1A1, CYP1A2, ABCC3 (coding for multidrug resistance-associated protein 3), and ABCG2 and suppressed mRNA expression of some transporters and drug metabolising enzymes. AhR reporter gene assay demonstrated that dovitinib is an activator of this nuclear receptor. Dovitinib retained its efficacy in cell lines over expressing P-gp or BCRP. Our analysis indicates that dovitinib will most likely retain its efficacy in tumours over-expressing P-gp or BCRP and gives first evidence that dovitinib might act as a perpetrator drug in pharmacokinetic drug drug interactions. PMID- 25521245 TI - Bhageerath-H: a homology/ab initio hybrid server for predicting tertiary structures of monomeric soluble proteins. AB - BACKGROUND: The advent of human genome sequencing project has led to a spurt in the number of protein sequences in the databanks. Success of structure based drug discovery severely hinges on the availability of structures. Despite significant progresses in the area of experimental protein structure determination, the sequence-structure gap is continually widening. Data driven homology based computational methods have proved successful in predicting tertiary structures for sequences sharing medium to high sequence similarities. With dwindling similarities of query sequences, advanced homology/ ab initio hybrid approaches are being explored to solve structure prediction problem. Here we describe Bhageerath-H, a homology/ ab initio hybrid software/server for predicting protein tertiary structures with advancing drug design attempts as one of the goals. RESULTS: Bhageerath-H web-server was validated on 75 CASP10 targets which showed TM-scores >= 0.5 in 91% of the cases and Calpha RMSDs <= 5 A from the native in 58% of the targets, which is well above the CASP10 water mark. Comparison with some leading servers demonstrated the uniqueness of the hybrid methodology in effectively sampling conformational space, scoring best decoys and refining low resolution models to high and medium resolution. CONCLUSION: Bhageerath-H methodology is web enabled for the scientific community as a freely accessible web server. The methodology is fielded in the on-going CASP11 experiment. PMID- 25521246 TI - iPhos: a toolkit to streamline the alkaline phosphatase-assisted comprehensive LC MS phosphoproteome investigation. AB - BACKGROUND: Comprehensive characterization of the phosphoproteome in living cells is critical in signal transduction research. But the low abundance of phosphopeptides among the total proteome in cells remains an obstacle in mass spectrometry-based proteomic analysis. To provide a solution, an alternative analytic strategy to confidently identify phosphorylated peptides by using the alkaline phosphatase (AP) treatment combined with high-resolution mass spectrometry was provided. While the process is applicable, the key integration along the pipeline was mostly done by tedious manual work. RESULTS: We developed a software toolkit, iPhos, to facilitate and streamline the work-flow of AP assisted phosphoproteome characterization. The iPhos tookit includes one assister and three modules. The iPhos Peak Extraction Assister automates the batch mode peak extraction for multiple liquid chromatography mass spectrometry (LC-MS) runs. iPhos Module-1 can process the peak lists extracted from the LC-MS analyses derived from the original and dephosphorylated samples to mine out potential phosphorylated peptide signals based on mass shift caused by the loss of some multiples of phosphate groups. And iPhos Module-2 provides customized inclusion lists with peak retention time windows for subsequent targeted LC-MS/MS experiments. Finally, iPhos Module-3 facilitates to link the peptide identifications from protein search engines to the quantification results from pattern-based label-free quantification tools. We further demonstrated the utility of the iPhos toolkit on the data of human metastatic lung cancer cells (CL1-5). CONCLUSIONS: In the comparison study of the control group of CL1-5 cell lysates and the treatment group of dasatinib-treated CL1-5 cell lysates, we demonstrated the applicability of the iPhos toolkit and reported the experimental results based on the iPhos-facilitated phosphoproteome investigation. And further, we also compared the strategy with pure DDA-based LC-MS/MS phosphoproteome investigation. The results of iPhos-facilitated targeted LC-MS/MS analysis convey more thorough and confident phosphopeptide identification than the results of pure DDA-based analysis. PMID- 25521249 TI - The moyamoya optic disc. PMID- 25521248 TI - Extreme resilience in cochleate nanoparticles. AB - Cochleates, prospective nanoscale drug delivery vehicles, are rolls of negatively charged phospholipid membrane layers. The membrane layers are held together by calcium ions; however, neither the magnitude of membrane interaction forces nor the overall mechanical properties of cochleates have been known. Here, we manipulated individual nanoparticles with atomic force microscopy to characterize their nanomechanical behavior. Their stiffness (4.2-12.5 N/m) and membrane rupture forces (45.3-278 nN) are orders of magnitude greater than those of the tough viral nanoshells. Even though the fundamental building material of cochleates is a fluid membrane, the combination of supramolecular geometry, the cross-linking action of calcium, and the tight packing of the ions apparently lead to extreme mechanical resilience. The supramolecular design of cochleates may provide efficient protection for encapsulated materials and give clues to understanding biomolecular structures of similar design, such as the myelinated axon. PMID- 25521250 TI - Torquoselectivity in the Nazarov reactions of allenyl vinyl ketones. AB - Nazarov reactions mediated by BF3-etherate of a series of carbon-substituted allenyl vinyl ketones provided intermediates in which substituents on the termini of the allenes had rotated away from the vinyl moieties, and these intermediates were trapped by (4 + 3)-cyclizations. A computational examination of the torquoselectivity of these Nazarov reactions confirmed a kinetic preference for the observed isomers and pointed to steric interactions and the degree of allene deformation as significant factors in determining the torquoselectivity. The study also suggested that the high proportion of one geometrical isomer in the Nazarov products might also be due to some preferential trapping of the major Nazarov intermediate. PMID- 25521247 TI - Mechanical design principles of a mitotic spindle. AB - An organised spindle is crucial to the fidelity of chromosome segregation, but the relationship between spindle structure and function is not well understood in any cell type. The anaphase B spindle in fission yeast has a slender morphology and must elongate against compressive forces. This 'pushing' mode of chromosome transport renders the spindle susceptible to breakage, as observed in cells with a variety of defects. Here we perform electron tomographic analyses of the spindle, which suggest that it organises a limited supply of structural components to increase its compressive strength. Structural integrity is maintained throughout the spindle's fourfold elongation by organising microtubules into a rigid transverse array, preserving correct microtubule number and dynamically rescaling microtubule length. PMID- 25521251 TI - Impact of distributions and mixtures on the charge transfer properties of graphene nanoflakes. AB - Many of the promising new applications of graphene nanoflakes are moderated by charge transfer reactions occurring between defects, such as edges, and the surrounding environment. In this context the sign and value of properties such as the ionization potential, electron affinity, electronegativity and chemical hardness can be useful indicators of the efficiency of graphene nanoflakes for different reactions, and can help identify new application areas. However, as samples of graphene nanoflakes cannot necessarily be perfectly monodispersed, it is necessary to predict these properties for polydispersed ensembles of flakes, and provide a statistical solution. In this study we use some simple statistical methods, in combination with electronic structure simulations, to predict the charge transfer properties of different types of ensembles where restrictions have been placed on the diversity of the structures. By predicting quality factors for a variety of cases, we find that there is a clear motivation for restricting the sizes and suppressing certain morphologies to increase the selectivity and efficiency of charge transfer reactions; even if samples cannot be completely purified. PMID- 25521255 TI - A heterometallic macrocycle as a redox-controlled molecular hinge. AB - The ability to modify the structure of nanoscopic assemblies in a controlled fashion is an important prerequisite for the creation of functional supramolecular systems. Here, we describe a heterometallic Pt2Cu2-macrocycle which behaves as a molecular hinge. A square-planar Pt(ii) complex with pendent 2 formylpyridine groups was synthesized and structurally characterized. Condensation of the complex with benzylamine followed by reaction with Cu(MeCN)4BF4 resulted in the formation of a rectangular Pt2Cu2-macrocycle. Upon chemical oxidation of the Cu centers, the macrocycle folds up to adopt a butterfly-like geometry in which the Pt centers approach each other. This process can be reversed by chemical reduction. PMID- 25521256 TI - Mass spectrometry imaging of fingerprint sweat on nanostructured silicon. AB - Desorption ionisation on porous silicon mass spectrometry imaging (DIOS-MSI) was used on fingerprints to map the distribution of exogenous and endogenous molecules present in sweat. Our attention was focused on the proof-of-principle to detect illicit drugs and their metabolites to exemplify the technique's potential in the area of forensic and workplace testing. PMID- 25521257 TI - Nearly exclusive growth of small diameter semiconducting single-wall carbon nanotubes from organic chemistry synthetic end-cap molecules. AB - The inability to synthesize single-wall carbon nanotubes (SWCNTs) possessing uniform electronic properties and chirality represents the major impediment to their widespread applications. Recently, there is growing interest to explore and synthesize well-defined carbon nanostructures, including fullerenes, short nanotubes, and sidewalls of nanotubes, aiming for controlled synthesis of SWCNTs. One noticeable advantage of such processes is that no metal catalysts are used, and the produced nanotubes will be free of metal contamination. Many of these methods, however, suffer shortcomings of either low yield or poor controllability of nanotube uniformity. Here, we report a brand new approach to achieve high efficiency metal-free growth of nearly pure SWCNT semiconductors, as supported by extensive spectroscopic characterization, electrical transport measurements, and density functional theory calculations. Our strategy combines bottom-up organic chemistry synthesis with vapor phase epitaxy elongation. We identify a strong correlation between the electronic properties of SWCNTs and their diameters in nanotube growth. This study not only provides material platforms for electronic applications of semiconducting SWCNTs but also contributes to fundamental understanding of the growth mechanism and controlled synthesis of SWCNTs. PMID- 25521258 TI - Primary and Radiation-induced Breast Angiosarcoma: Clinicopathologic Predictors of Outcomes and the Impact of Adjuvant Radiation Therapy. AB - BACKGROUND: Mammary angiosarcoma (AS) is an aggressive malignancy with high recurrence rates and poor overall survival. Limited data exist to guide treatment. We aimed to identify patterns of failure in the context of adjuvant radiation and to identify prognostic indicators to better guide management. METHODS: Thirty-five patients with breast AS at UPMC Magee Women's Hospital from June 1994 to March 2011 were retrospectively reviewed. Pathology was rereviewed for 22 patients by an expert breast pathologist using an objective scoring system, partly based on the Rosen grading scheme. All patients completed R0 resection, with 14 of them receiving adjuvant radiotherapy (RT) (82% of which represented reirradiation for radiation-induced AS). RESULTS: At a median follow up of 20 months (range, 3 to 178 mo), the primary mode of failure was local with 32% local first failure. Tumor size >5 cm, radiation-induced etiology, and the omission of adjuvant RT were important prognostic factors of tumor control and survival. Histopathology including necrosis, number of mitotic figures, endothelial tufting, solid/spindle cell foci, and the combined scoring system were prognostic for recurrence patterns. CONCLUSIONS: Breast AS has high rates of local failure despite R0 resection, which may be improved with adjuvant RT, even in the reirradiation setting. Histopathology is prognostic for recurrence patterns. PMID- 25521259 TI - Open posterior dislocation of hip in a 6-year-old boy: a rare case report. AB - Open hip dislocation in pediatric patients is a rare injury. Open posterior dislocation because of soft tissue damage is unstable after reduction. There is no treatment protocol in the literature for this injury in pediatric patients. We treated a 6-year-old boy presented with open posterior hip dislocation. Thorough debridement was performed and antibiotics were administered to prevent infection, and fixation of reduction with Kirschner-wires (K-wires) was performed. Nonthreaded K-wires were used under an image intensifier to minimize the risk of physeal injury. A hip spica cast was used to prevent the breakage of K-wires into the joint because of movements at the hip. PMID- 25521260 TI - What's trending in service delivery. PMID- 25521261 TI - The scope of pediatric physical therapy practice in health promotion and fitness for youth with disabilities. AB - PURPOSE: The purpose of this report is to discuss the scope of pediatric physical therapy practice in health promotion and fitness for youth with disabilities. SUMMARY OF KEY POINTS: Evidence is provided that supports integration of health promotion and fitness strategies in physical therapy clinical management. Physical therapists' roles in community-based adapted sports and fitness interventions and reimbursement considerations are discussed. CONCLUSIONS: Physical therapists are in a unique position to provide expertise in the design and implementation of health promotion and fitness programs for youth with disabilities. These programs are important to promote active, healthy lifestyles and reduce comorbidities associated with sedentary behaviors and unhealthy weight, which are often seen in youth with disabilities. RECOMMENDATIONS FOR CLINICAL PRACTICE: Pediatric physical therapists should incorporate health promotion and fitness strategies into practice. PMID- 25521262 TI - Maximal respiratory pressures of healthy children: comparison between obtained and predicted values. AB - PURPOSE: To compare maximal inspiratory and expiratory pressures (PImax and PEmax, respectively) obtained in Brazilian children who are healthy with reference and predicted values from previous studies. METHODS: Respiratory muscle strength of 144 children (63 boys), aged 7 to 11 years, was assessed. A digital manovacuometer was used to measure PImax and PEmax from residual volume and total lung capacity, respectively. Children were assessed in the sitting position while wearing a nose clip. RESULTS: Mean values of PImax for boys and girls were 81.6 +/- 20.2 and 66.1 +/- 19.5 cmH2O, respectively. Mean values of PEmax in boys and girls were 95.6 +/- 21.1 and 78.9 +/- 19.7 cmH2O, respectively. CONCLUSIONS: Published reference values demonstrated a wide diversity across age groups studied, and published equations were not successful in predicting maximal respiratory pressures; thus, the assessment of respiratory muscle strength of children should consider the minimization of ethnic and methodological differences. PMID- 25521263 TI - Commentary on "Maximal respiratory pressures of healthy children: comparison between obtained and predicted values". PMID- 25521264 TI - Responsiveness of clinical and laboratory measures to intervention effects in children with developmental coordination disorder. AB - PURPOSE: To compare responsiveness of the Movement Assessment Battery for Children-2 (MABC-2) and segment kinematics and center of pressure measures in detecting intervention effects in children with developmental coordination disorder. METHODS: Motion Analysis Laboratory (MAL) data from 21 children with developmental coordination disorder (mean age 11.0 years) in a randomized control trial were analyzed using effect size, minimal detectable difference, and parent and child report of meaningfulness (chi2 tests). RESULTS: The MABC-2 and MAL data showed moderate-large effect sizes (0.7-1.8). The MABC-2 detected large portions of children whose change exceeded the minimal detectable difference (47.6% 71.4%); MAL data detected small portions (0%-19.0%). Neither tool correlated well with meaningfulness (chi2 = 0.186-5.724; P > .10). Both tools detected change in the overall group; however, only the MABC-2 detected individual change exceeding potential measurement error. CONCLUSIONS: Although both assessment tools are responsive, they may be responsive to different types of change. Therefore, assessment constructs should be matched to intervention goals. PMID- 25521265 TI - Commentary on "Responsiveness of clinical and laboratory measures to intervention effects in children with developmental coordination disorder". PMID- 25521266 TI - Short-term, intensive neurodevelopmental treatment program experiences of parents and their children with disabilities. AB - PURPOSE: Parents' perspectives on intervention and functional changes in children were investigated following an intensive neurodevelopmental treatment (NDT) program of 1 to 2 weeks (5 consecutive days per week; 2-4 h/d). METHODS: Thirteen parents and their children (aged 1-17 years) with neuromotor conditions participated in a short-term, intensive program conducted by NDT certified pediatric therapists. A mixed-method design was used: a qualitative phenomenological approach of inquiry for parent perspectives and a pre/posttest quasi-experimental design for weekly intervention changes using Goal Attainment Scaling and the Canadian Occupational Performance Measure. RESULTS: Through interviews, parents reported positive experiences with the intensive NDT program. Child participants demonstrated significant improvements in Goal Attainment Scaling (P < .001) and Canadian Occupational Performance Measure (P < .001) scores pre- to postintervention. CONCLUSIONS: A short-term, intensive NDT program was perceived by parents as beneficial and supported functional improvements. Valued were expert, compassionate therapists; collaboration; objective goals; home programming; and individualized intervention. Scheduling, financial support, and fatigue were difficulties. PMID- 25521267 TI - Commentary on "Short-term intensive neurodevelopmental treatment program experiences of parents and their children with disabilities". PMID- 25521268 TI - Constraint-induced movement therapy in children aged 5 to 9 years with cerebral palsy: a day camp model. AB - PURPOSE: To examine the effectiveness of a modified form of constraint-induced movement therapy (mCIMT) in the context of a day camp model in 6 children aged 5 9 years with spastic hemiplegic cerebral palsy. METHODS: Before, 1 week after, and 3 months after 9 consecutive days of mCIMT, participants were assessed using the Quality of Upper Extremity Skills Test (QUEST) and assessments of range of motion and grip strength. Caregiver perceptions were assessed using the Pediatric Evaluation of Disability Inventory (PEDI) and a parent questionnaire. RESULTS: Significant improvements were observed on the "grasps" and "protective extension" subsections of the QUEST after the intervention. Increased social function was also observed as measured by the PEDI. All improvements were maintained at the 3 month follow-up assessment. Analysis of individual participants yielded additional information on clinically significant improvements as a result of the mCIMT intervention. CONCLUSIONS: The day camp model of mCIMT was effective in inducing lasting and meaningful changes in the children with hemiplegic cerebral palsy. PMID- 25521269 TI - Commentary on "Constraint-induced movement therapy in children aged 5 to 9 years with cerebral palsy: a day camp model". PMID- 25521270 TI - Reliability of measuring hip and knee power and movement velocity in active youth. AB - PURPOSE: The purpose of this study was to determine the reliability of measuring neuromuscular power and movement velocity of the hip and knee in young, active individuals using an isokinetic dynamometer. METHODS: Peak power, average power, and peak velocity (PV) data were recorded for the hip in the standing position and the knee in the sitting position in 52 youth aged 10 to 14 years on 2 occasions approximately 1 week apart. RESULTS: The PV measures demonstrated the best absolute reliability of all variables tested (coefficients of variation of the typical error [CV(TE)] = 5.0%-8.5%; standard errors of measurement = 18.1 21.1 degrees /s). Hip flexion and knee extension peak power and average power exhibited acceptable reliability (CV(TE) = 8.7%-10.8%) compared with the other isokinetic tests (CV(TE) = 16.9%-32.8%). CONCLUSIONS: Peak velocity appears to be a reliable means of indirectly measuring neuromuscular power in active youth, whereas direct measurement of power is only reliable for certain movements. PMID- 25521271 TI - Commentary on "Reliability of measuring hip and knee power and movement velocity in active youth". PMID- 25521272 TI - Developmental presentation, medical complexities, and service delivery for a child with 16p11.2 deletion syndrome. AB - PURPOSE: To discuss the developmental presentation, complicating factors, and delivery of physical therapy services through the Birth to Three System, for 1 child with 16p11.2 deletion syndrome. KEY POINTS: History, presenting problems, medical complexities, developmental and behavioral characteristics, interventions, and implications for service delivery are reviewed. CONCLUSIONS: The child experienced many difficulties reported in the literature related to the wide phenotype of 16p11.2 deletion syndrome. Focus on caregiver instruction and education to accomplish family-driven, functional outcomes increased carryover and allowed the greatest potential for success. RECOMMENDATIONS FOR CLINICAL PRACTICE: Genetic disorders such as 16p11.2 deletion syndrome are increasingly being recognized as etiologic factors in neurodevelopmental conditions. It is critical for physical therapists to be aware of the varied manifestations and effects of this genetic disorder. Advanced problem solving and decision-making, ongoing assessment, and collaboration are required to comprehensively support the family in meeting the child's medical, behavioral, and developmental needs. PMID- 25521273 TI - Letter to the editor. PMID- 25521274 TI - Optical and electrochemical applications of silicon-carbon dots/silicon dioxide nanocomposites. AB - Various colors of photoluminescent SiC-dots/SiO2 prepared through a simple heating process have been employed for optical and electrochemical applications. Blue (B)-, green (G)-, and tan (T)-SiC-dots/SiO2 powders have been prepared from SiC-dots that had been prepared from 3-aminopropyl trimethoxysilane through a hydrothermal route by simply controlling heating at 60 degrees C for 60 min and 300 degrees C for 10 and 20 min, respectively. The B-, G-, and T-SiC-dots/SiO2 nanocomposites emit at 455, 534, and 574 nm, respectively, under excitation at 360 nm. B-, G-, and T-SiC-dots/SiO2 glass films show at least seven colors when excited at 360, 460, and 520 nm. Through a heat-induced photoluminescence (PL) change, a representative lithographic pattern of B-SiC-dots/SiO2 films has been fabricated using a near-infrared laser. The B-, G-, and T-SiC-dots/SiO2 also possess high electrocatalytic activity for the oxygen reduction reaction. Having such interesting PL and electrical properties, the stable, low-toxic, and cost effective B-, G-, and T-SiC-dots/SiO2 nanocomposites show great economic potential in many applications such as light-emitting diodes, photoluminescent windows, and fuel cells. PMID- 25521275 TI - Comparison of nerve growth factor-induced sensitization pattern in lumbar and tibial muscle and fascia. AB - INTRODUCTION: Nerve growth factor (NGF) induces profound hyperalgesia. In this study we explored patterns of NGF sensitization in muscle and fascia of distal and paraspinal sites. METHODS: We injected 1 ug of NGF into human (n = 8) tibialis anterior and erector spinae muscles and their fasciae. The spatial extent of pressure sensitization, pressure pain threshold, and mechanical hyperalgesia (150 kPa, 10 s) was assessed at days 0.25, 1, 3, 7, 14, and 21. Chemical sensitization was explored by acidic buffer injections (pH 4, 100 ul) at days 7 and 14. RESULTS: The mechanical hyperalgesia area was larger in tibial fascia than in muscle. Pressure pain thresholds were lower, tonic pressure pain ratings, and citrate buffer evoked pain higher in fascia than in muscle. CONCLUSIONS: Spatial mechanical sensitization differs between muscle and fascia. Thoracolumbar fasciae appear more sensitive than tibial fasciae and may be major contributors to low back pain, but the temporal sensitization profile is similar between paraspinal and distal sites. Muscle Nerve 52: 265-272, 2015. PMID- 25521276 TI - Synthesis of a new class of fused cyclotetraphosphazene ring systems. AB - Octachlorocyclotetraphosphazene (1) was reacted with butylamines [n-butyl, i butyl, sec-butyl, and t-butyl] in a 1:0.8 mol ratio in THF to obtain cyclotetraphosphazenes bearing a P-NH group, N4P4Cl7(NHR) [R = n-butyl (2a), i butyl (2b), sec-butyl (2c), t-butyl (2d)](2a-d). The cyclotetraphosphazene derivatives 2a, 2b, and 2c were treated with sodium hydride giving rise to a new type of cyclophosphazene compounds (P8N8 ring) consisting of three fused tetramer rings (3a-c). Whereas reaction of sodium hydride with the t butylaminocyclophosphazene derivative (2d) gave a P-O-P bridged compound (4) presumably as a result of hydrolysis reaction associated with moisture in the solvent. It is likely that the 16-membered cyclooctaphosphazene derivatives (3a c) are formed by a proton abstraction/chloride ion elimination, intramolecular nucleophilic attack, ring opening and intermolecular condensation processes, respectively. PMID- 25521278 TI - Is plate clearing a risk factor for obesity? A cross-sectional study of self reported data in US adults. AB - OBJECTIVES: Identifying eating behaviors which contribute to excess weight gain will inform obesity prevention strategies. A tendency to clear one's plate when eating may be a risk factor for obesity in an environment where food is plentiful. Whether plate clearing is associated with increased body weight in a cohort of US participants was examined. METHODS: Nine hundred and ninety-three US adults (60% male, 80% American European, mean age=31 years) completed self-report measures of habitual plate clearing together with behavioral and demographic characteristics known to be associated with obesity. RESULTS: Plate clearing tendencies were positively associated with BMI and remained so after accounting for a large number of other demographic and behavioral predictors of BMI in analyses (beta=0.18, 95% CIs=0.07, 0.29, P<0.001); an increased tendency to plate clear was associated with a significantly higher body weight. CONCLUSIONS: The tendency to clear one's plate when eating is associated with increased body weight and may constitute a risk factor for weight gain. PMID- 25521279 TI - Evaporation of sessile drops containing colloidal rods: coffee-ring and order disorder transition. AB - Liquid drops containing insoluble solutes when dried on solid substrates leave distinct ring-like deposits at the periphery or along the three-phase contact line-a phenomena popularly known as the coffee-ring or the coffee stain effect. The formation of such rings as well as their suppression is shown to have applications in particle separation and disease diagnostics. We present an experimental study of the evaporation of sessile drops containing silica rods to elucidate the structural arrangement of particles in the ring, an effect of the addition of surfactant and salt. To this end, the evaporation of aqueous sessile drops containing model rod-like silica particles of aspect ratio ranging from ~4 to 15 on a glass slide is studied. We first show that when the conditions such as (1) solvent evaporation, (2) nonzero contact angle, (3) contact line pinning, (4) no surface tension gradient driven flow, and (5) repulsive particle particle/particle-substrate interactions, that are necessary for the formation of the coffee-ring are met, the suspension drops containing silica rods upon evaporation leave a ring-like deposit. A closer examination of the ring deposits reveals that several layers of silica rods close to the edge of the drop are ordered such that the major axis of the rods are oriented parallel to the contact line. After the first few layers of ordered arrangement of particles, a random arrangement of particles in the drop interior is observed indicating an order disorder transition in the ring. We monitor the evolution of the ring width and particle velocity during evaporation to elucidate the mechanism of the order disorder transition. Moreover, when the evaporation rate is lowered, the ordering of silica rods is observed to extend over large areas. We demonstrate that the nature of the deposit can be tuned by the addition of a small quantity of surfactant or salt. PMID- 25521280 TI - Influence of the molecular weight and size dispersion of the electroluminescent polymer on the performance of air-stable hybrid light-emitting diodes. AB - The influence of the chain length and the molecular weight distribution of the electroluminescent polymer on the carrier transport properties and morphology of air stable hybrid light-emitting diodes is reported. It is found that variations between diverse as-received commercial batches play a major role in the performance of the devices, whose maximum luminance can differ up to 2 orders of magnitude. Through complementary optoelectronic, structural, and morphological characterization techniques, we provide insights into the relationship between charge dynamics and the structure of polymeric electroluminescent materials. The carrier dynamics are found to be dominated by both the polymeric chain length and the hole transport, which in turn is dependent on the concentration of trap states. Furthermore, the chain length is seen to affect the morphology of the active layer. PMID- 25521277 TI - 3,3'-Diindolylmethane attenuates LPS-mediated acute liver failure by regulating miRNAs to target IRAK4 and suppress Toll-like receptor signalling. AB - BACKGROUND AND PURPOSE: Acute liver failure (ALF) is a severe and potentially lethal clinical syndrome. 3,3'-Diindolylmethane (DIM) is a natural plant-derived compound with anti-cancer activities. Recently, DIM has also been shown to have anti-inflammatory properties. Here, we tested the hypothesis that DIM would suppress endotoxin-induced ALF. EXPERIMENTAL APPROACH: We investigated the therapeutic potential of DIM in a mouse model of D galactosamine/Lipopolysaccharide (GalN/LPS)-induced ALF. The efficacy of DIM treatment was assessed by survival, liver histopathology, serum levels of alanine transaminase, pro-inflammatory cytokines and number of activated liver macrophages. Effects of DIM on the expression of two miRNAs, 106a and 20b, and their predicted target gene were measured by qRT-PCR and Western blotting. Effects of DIM on the release of TNF-alpha from RAW264.7 macrophages transfected with mimics of these miRNAs and activated by LPS was assessed by elisa. KEY RESULTS: DIM treatment protected mice from ALF symptoms and reduced the number of activated liver macrophages. DIM increased expression of miR-106a and miR-20b in liver mononuclear cells and decreased expression of their predicted target gene IL-1 receptor-associated kinase 4 (IRAK4), involved in signalling from Toll-like receptor 4 (TLR4). In vitro transfection of RAW264.7 cells using miRNA mimics of miR-106a and 20b decreased expression of IRAK4 and of TNF-alpha secretion, following LPS stimulation. CONCLUSIONS AND IMPLICATIONS: DIM attenuated GalN/LPS induced ALF by regulating the expression of unique miRNAs that target key molecules in the TLR4 inflammatory pathway. DIM may represent a potential novel hepatoprotective agent. PMID- 25521281 TI - Isoquinoline synthesis by heterocyclization of tosylmethyl isocyanide derivatives: total synthesis of mansouramycin B. AB - A new method for the synthesis of isoquinolines through a catalytic acid-mediated cyclization of alpha-benzyl TosMIC derivatives has been developed. This methodology has been successfully applied to the total synthesis of mansouramycin B. This is the first total synthesis of this compound to be reported in the literature. PMID- 25521282 TI - Imine macrocycle with a deep cavity: guest-selected formation of syn/anti configuration and guest-controlled reconfiguration. AB - A dynamic covalent bond is one of the ideal linkages for the construction of large and robust organic architectures. In the present article, we show how organic templates can efficiently transform a complex dynamic imine library into a dynamic imine macrocycle. Not only is the constitution well controlled, but also the syn/anti host configuration is efficiently selected and even the orientation of the guest in the asymmetric cavity of the host can be well aligned. This is attributed to the delicate balance and the cooperation of multiple noncovalent interactions between the hosts and the guests. Through sequential additions of three guests in appropriate amounts, controlled structural reconfiguration of dynamic covalent architectures has been achieved for the first time. PMID- 25521283 TI - Spatially gradated hydrogel platform as a 3D engineered tumor microenvironment. AB - There is an acute need for biomaterial tools that recreate the heterogeneous brain-tumor microenvironment. A microfluidic mixing tool is reported to encapsulate glioblastoma multiforme cells within miniaturized gelatin hydrogels containing overlapping patterns of tumor-inspired matrix signals. This approach permits in situ analysis of glioma cells at the molecular and genomic level as well as the potential for clinical insight. PMID- 25521284 TI - Cone bipolar cells in the retina of the microbat Carollia perspicillata. AB - We studied the retinal cone bipolar cells of Carollia perspicillata, a microchiropteran bat of the phyllostomid family. Microchiroptera are strongly nocturnal, with small eyes and rod-dominated retinae. However, they also possess a significant cone population (2-4%) comprising two spectral types, which are hence the basis for daylight and color vision. We used antibodies against the calcium-binding protein recoverin and the carbohydrate epitope 15 (CD15) as reliable markers for certain cone bipolar cells. Dye injections of recoverin- or CD15-prelabeled cone bipolar cells in vertical slices revealed the morphology of the axon terminal system of individual bipolar cells. Seven distinct cone bipolar cell types were identified. They differed in the morphology and stratification level of their axon terminal system in the inner plexiform layer and in immunoreactivity for recoverin and/or CD15. Additional immunocytochemical markers were used to assess the functional ON/OFF subdivision of the inner plexiform layer. In line with the extended thickness of the ON sublayer of the inner plexiform layer in the microbat retina, more ON than OFF cone bipolar cell types were found, namely, four versus three. Most likely, in the bats' predominantly dark environment, ON signals have greater importance for contrast perception. We conclude that the microbat retina conforms to the general mammalian blueprint, in which light signals of intensities above rod sensitivity are detected by cones and transmitted to various types of ON and OFF cone bipolar cells. PMID- 25521285 TI - Third heart sound in hospitalised patients with acute heart failure: insights from the ATTEND study. AB - BACKGROUND: Several previous studies have suggested that detection of a third heart sound (S3) in patients with chronic congestive heart failure is associated with adverse long-term outcomes. However, the short-term prognostic value of identifying an S3 on admission in patients with acute heart failure (AHF) is not well established. We therefore analysed the in-hospital prognostic value of detecting an S3 on admission in hospitalised patients with AHF. METHODS: The Acute Decompensated Heart Failure Syndromes (ATTEND) study investigators enrolled 4107 patients hospitalised with AHF. Investigators evaluated the presence or absence of an S3 during routine physical examination. RESULTS: On admission to hospital, 1673 patients (41%) had an S3. Patients with an S3 had a higher heart rate, higher serum level of B-type natriuretic peptide and higher creatinine levels than patients without an S3. However, there were no significant differences of systolic blood pressure, serum sodium, haemoglobin, C-reactive protein and total bilirubin between the two groups. Multivariate analysis adjusted for various markers of disease severity revealed that only the presence of an S3 was independently associated with an increase of in-hospital all cause death [adjusted odds ratio (OR), 1.69; 95% confidence interval (CI), 1.19-2.41; p = 0.003] and cardiac death (adjusted OR, 1.66; 95% CI, 1.08-2.54; p = 0.020) among the congestive physical findings related to heart failure (S3, rales, jugular venous distension and peripheral oedema). CONCLUSIONS: Detecting an S3 on admission was independently associated with adverse in-hospital outcomes in patients with AHF. Our findings suggest that careful bedside assessment is clinically meaningful. PMID- 25521287 TI - Silver-assisted chemical etching on silicon with polyvinylpyrrolidone-mediated formation of silver dendrites. AB - Metal-assisted chemical etching (MaCE) on silicon (Si)-mediated by polyvinylpyrrolidone (PVP)-is systematically investigated herein. It is found that the morphologies and crystallographic natures of the grown silver (Ag) dendrites can be significantly modulated, with the presence of PVP in the MaCE process leading to the formation of faceted Ag dendrites preferentially along the (111) crystallographic phase, rather than along the (200) phase. Further explorations of the PVP-mediated effect on Si etching are also revealed. In contrast to the aligned Si nanowires formed by MaCE without PVP addition, only distributed nanopores with sizes of 200 to 400 nm appear on the Si surfaces in the presence of PVP. The origin of surface polishing on Si in the PVP-mediated MaCE process can be attributed to the distinct transport pathway of holes supplied by the Ag(+) ions, where the holes are injected directly into the primary Ag seeds, rather than through Ag dendrites, thus leading to the isotropic etching of the Si surface. PMID- 25521286 TI - The use of nonsteroidal anti-inflammatory drugs in critically ill horses. AB - OBJECTIVE: To review the physiology of the cyclooxygenase (COX) enzymes with reference to the beneficial effects of nonsteroidal anti-inflammatory drugs (NSAIDs) related to their analgesic and antiendotoxic properties as well as the mechanisms responsible for adverse gastrointestinal, renal, and coagulation effects. DATA SOURCES: Human and veterinary peer reviewed literature VETERINARY DATA SYNTHESIS: NSAIDs are frequently administered to critically ill horses for their analgesic and anti-inflammatory effects. However, NSAIDs have significant side effects principally on the gastrointestinal mucosa and kidneys. These side effects may be exacerbated in critically ill horses if they have gastrointestinal damage or are volume depleted CONCLUSIONS: This review provides important information for equine veterinarians and criticalists on the advantages and disadvantages of using traditional NSAIDs and newer equine COX-2 selective NSAIDs for the management of different conditions in critically ill horses. PMID- 25521288 TI - New vinylester-based monoliths as a new stationary phase for capillary electrochromatography. AB - Vinyl ester-based monoliths are proposed as a new group of stationary phase for CEC. The capillary monolithic columns were prepared by using two vinyl ester monomers, vinyl pivalate (VPV), and vinyl decanoate (VDC) by using ethylene dimethacrylate (EDMA) as the cross-linking agent, and 2-acrylamido-2 methylpropane sulfonic acid as the charge-bearing monomer. The monoliths with different pore structures and permeabilities were obtained by varying the type and composition of the porogen mixture containing isoamyl alcohol and 1,4 butanediol. The electrochromatographic separation of alkylbenzenes was successfully performed by using an acetonitrile/aqueous buffer system as the mobile phase in a CEC system. Vinyl ester monoliths with short alkyl chain length (i.e. poly(VPV-co-EDMA) exhibited better separation performance compared with the monolith with long alkyl chain length (i.e. poly(VDC-co-EDMA). In the case of VPV based monoliths, the theoretical plate numbers higher than 250 000 plates/m were achieved by using a porogen mixture containing 33% v/v of isoamyl alcohol. For both VDC and VPV-based monoliths, the column efficiency was almost independent of the superficial velocity in the range of 2-12 cm/min. PMID- 25521290 TI - The effect of age on the key parameters in the Chicago classification: a study using high-resolution esophageal manometry in asymptomatic normal individuals. AB - BACKGROUND: High-resolution manometry using the Chicago classification, which utilizes parameters including integrated relaxation pressure (IRP), distal contractile integral (DCI), and contractile front velocity (CFV), shows better diagnostic ability than previous conventional criteria. However, the current normal cut-off values for the Chicago classification are based on individuals aged 19-48 years and do not include older people. Here, we aimed to assess the normal values for the Chicago classification in individuals aged 20-67 years and compare the parameters across age groups. METHODS: Fifty-four asymptomatic healthy individuals (27 male and 27 female; age range. 20-67 years) were prospectively enrolled. To evaluate the effect of age and sex on manometric profiles, we attempted to enroll equal numbers of male and female subjects for each decade. Manometry was performed in both the supine and sitting positions. KEY RESULTS: The distal latency (DL) was significantly shorter with increasing age in both measurement positions. Furthermore, IRP was significantly higher with increasing age in both positions. Spearman's ranked correlation coefficient analysis indicated that DCI and IRP in both positions were positively correlated with age. CONCLUSIONS & INFERENCES: Age affects the key parameters currently used in the Chicago classification, including IRP, DCI, and DL. Larger prospective studies with older subjects are needed to determine the age-related normal values for the Chicago classification system. PMID- 25521289 TI - Notch signaling mediates the age-associated decrease in adhesion of germline stem cells to the niche. AB - Stem cells have an innate ability to occupy their stem cell niche, which in turn, is optimized to house stem cells. Organ aging is associated with reduced stem cell occupancy in the niche, but the mechanisms involved are poorly understood. Here, we report that Notch signaling is increased with age in Drosophila female germline stem cells (GSCs), and this results in their removal from the niche. Clonal analysis revealed that GSCs with low levels of Notch signaling exhibit increased adhesiveness to the niche, thereby out-competing their neighbors with higher levels of Notch; adhesiveness is altered through regulation of E-cadherin expression. Experimental enhancement of Notch signaling in GSCs hastens their age dependent loss from the niche, and such loss is at least partially mediated by Sex lethal. However, disruption of Notch signaling in GSCs does not delay GSC loss during aging, and nor does it affect BMP signaling, which promotes self renewal of GSCs. Finally, we show that in contrast to GSCs, Notch activation in the niche (which maintains niche integrity, and thus mediates GSC retention) is reduced with age, indicating that Notch signaling regulates GSC niche occupancy both intrinsically and extrinsically. Our findings expose a novel role of Notch signaling in controlling GSC-niche adhesion in response to aging, and are also of relevance to metastatic cancer cells, in which Notch signaling suppresses cell adhesion. PMID- 25521291 TI - Anti-cancer drugs reactivate tumor suppressor miR-375 expression in tongue cancer cells. AB - Head and neck cancer is one of the deadliest malignant diseases and chemotherapy is a common treatment option. Despite the development of chemotherapies for several decades, how these drugs affect the dynamics of gene regulation is still largely unknown. In our previous study, miR-375 was shown to be underexpressed in oral cancers and thus unable to serve as a tumor suppressor microRNA to regulate certain putative oncogenes. In this study, we found that common anti-cancer drugs reactivated miR-375 in tongue cancer cells. Incubation of tongue cancer cells CAL 27 and SCC-25 in medium containing doxorubicin, 5-fluorouracil, trichostatin A, or etoposide significantly increased the expression of miR-375 and its primary transcript pri-miR-375. The dose- and time-dependent effects of doxorubicin in CAL 27 were demonstrated by miR-375 increases in response to the drug. Significant suppression of pri-miR-375 expression was observed in human tongue cancer specimens and this decrease was more prominent in advanced stage tumors. Bioinformatics from four publicly available mRNA microarray data sets suggested that these candidate miR-375 targets are mainly involved in cancer biology, indicating that these targets are likely to be suppressed via miR-375 due to the treatment with these drugs. Together, our data suggest that the four anti-cancer drugs examined in this study induce the expression of tumor suppressor miR-375 in tongue cancer. PMID- 25521292 TI - First-in-human trial of a novel suprachoroidal retinal prosthesis. AB - Retinal visual prostheses ("bionic eyes") have the potential to restore vision to blind or profoundly vision-impaired patients. The medical bionic technology used to design, manufacture and implant such prostheses is still in its relative infancy, with various technologies and surgical approaches being evaluated. We hypothesised that a suprachoroidal implant location (between the sclera and choroid of the eye) would provide significant surgical and safety benefits for patients, allowing them to maintain preoperative residual vision as well as gaining prosthetic vision input from the device. This report details the first-in human Phase 1 trial to investigate the use of retinal implants in the suprachoroidal space in three human subjects with end-stage retinitis pigmentosa. The success of the suprachoroidal surgical approach and its associated safety benefits, coupled with twelve-month post-operative efficacy data, holds promise for the field of vision restoration. TRIAL REGISTRATION: Clinicaltrials.gov NCT01603576. PMID- 25521293 TI - (R)-Desmolactone is a sex pheromone or sex attractant for the endangered valley elderberry longhorn beetle Desmocerus californicus dimorphus and several congeners (Cerambycidae: Lepturinae). AB - We report here that (4R,9Z)-hexadec-9-en-4-olide [(R)-desmolactone] is a sex attractant or sex pheromone for multiple species and subspecies in the cerambycid genus Desmocerus. This compound was previously identified as a female-produced sex attractant pheromone of Desmocerus californicus californicus. Headspace volatiles from female Desmocerus aureipennis aureipennis contained (R) desmolactone, and the antennae of adult males of two species responded strongly to synthetic (R)-desmolactone in coupled gas chromatography-electroantennogram analyses. In field bioassays in California, Oregon, and British Columbia, traps baited with synthetic (R)-desmolactone captured males of several Desmocerus species and subspecies. Only male beetles were captured, indicating that this compound acts as a sex-specific attractant, rather than as a signal for aggregation. In targeted field bioassays, males of the US federally threatened subspecies Desmocerus californicus dimorphus responded to the synthetic attractant in a dose dependent manner. Our results represent the first example of a "generic" sex pheromone used by multiple species in the subfamily Lepturinae, and demonstrate that pheromone-baited traps may be a sensitive and efficient method of monitoring the threatened species Desmocerus californicus dimorphus, commonly known as the valley elderberry longhorn beetle. PMID- 25521294 TI - Deep neural networks rival the representation of primate IT cortex for core visual object recognition. AB - The primate visual system achieves remarkable visual object recognition performance even in brief presentations, and under changes to object exemplar, geometric transformations, and background variation (a.k.a. core visual object recognition). This remarkable performance is mediated by the representation formed in inferior temporal (IT) cortex. In parallel, recent advances in machine learning have led to ever higher performing models of object recognition using artificial deep neural networks (DNNs). It remains unclear, however, whether the representational performance of DNNs rivals that of the brain. To accurately produce such a comparison, a major difficulty has been a unifying metric that accounts for experimental limitations, such as the amount of noise, the number of neural recording sites, and the number of trials, and computational limitations, such as the complexity of the decoding classifier and the number of classifier training examples. In this work, we perform a direct comparison that corrects for these experimental limitations and computational considerations. As part of our methodology, we propose an extension of "kernel analysis" that measures the generalization accuracy as a function of representational complexity. Our evaluations show that, unlike previous bio-inspired models, the latest DNNs rival the representational performance of IT cortex on this visual object recognition task. Furthermore, we show that models that perform well on measures of representational performance also perform well on measures of representational similarity to IT, and on measures of predicting individual IT multi-unit responses. Whether these DNNs rely on computational mechanisms similar to the primate visual system is yet to be determined, but, unlike all previous bio inspired models, that possibility cannot be ruled out merely on representational performance grounds. PMID- 25521295 TI - Mucolipin co-deficiency causes accelerated endolysosomal vacuolation of enterocytes and failure-to-thrive from birth to weaning. AB - During the suckling period, intestinal enterocytes are richly endowed with endosomes and lysosomes, which they presumably utilize for the uptake and intracellular digestion of milk proteins. By weaning, mature intestinal enterocytes replace those rich in lysosomes. We found that mouse enterocytes before weaning express high levels of two endolysosomal cation channels, mucolipins 3 and 1 -products of Trpml3 and Trpml1 genes; moreover neonatal enterocytes of mice lacking both mucolipins (Trpml3-/-;Trpml1-/-) vacuolated pathologically within hours of birth and remained so until weaning. Ultrastructurally and chemically these fast-forming vacuoles resembled those that systemically appear in epithelial cells of mucolipidosis type IV (MLIV) patients, which bear mutations in Trpml1. Hence, lack of both mucolipins 1 and 3 causes an accelerated MLIV-type of vacuolation in enterocytes. The vacuoles were aberrant hybrid organelles with both endosomal and lysosomal components, and were not generated by alterations in endocytosis or exocytosis, but likely by an imbalance between fusion of lysosomes and endosomes and their subsequent scission. However, upon extensive vacuolation enterocytes displayed reduced endocytosis from the intestinal lumen, a defect expected to compromise nutrient uptake. Mice lacking both mucolipins suffered a growth delay that began after birth and continued through the suckling period but recovered after weaning, coinciding with the developmental period of enterocyte vacuolation. Our results demonstrate genetic redundancy between lysosomal mucolipins 3 and 1 in neonatal enterocytes. Furthermore, our Trpml3-/-;Trpml1-/- mice represent a polygenic animal model of the poorly-understood, and often intractable, neonatal failure-to-thrive with intestinal pathology. Our results implicate lysosomes in neonatal intestinal pathologies, a major cause of infant mortality worldwide, and suggest transient intestinal dysfunction might affect newborns with lysosomal storage disorders. Finally, we conclude that mucolipin-endowed lysosomes in the young play an evolutionarily-conserved role in the intracellular digestion of maternally provided nutrients, whether milk in mammals or yolk in oviparous species. PMID- 25521297 TI - Where and how are roads endangering mammals in Southeast Asia's forests? AB - Habitat destruction and overhunting are two major drivers of mammal population declines and extinctions in tropical forests. The construction of roads can be a catalyst for these two threats. In Southeast Asia, the impacts of roads on mammals have not been well-documented at a regional scale. Before evidence-based conservation strategies can be developed to minimize the threat of roads to endangered mammals within this region, we first need to locate where and how roads are contributing to the conversion of their habitats and illegal hunting in each country. We interviewed 36 experts involved in mammal research from seven Southeast Asian countries to identify roads that are contributing the most, in their opinion, to habitat conversion and illegal hunting. Our experts highlighted 16 existing and eight planned roads - these potentially threaten 21% of the 117 endangered terrestrial mammals in those countries. Apart from gathering qualitative evidence from the literature to assess their claims, we demonstrate how species-distribution models, satellite imagery and animal-sign surveys can be used to provide quantitative evidence of roads causing impacts by (1) cutting through habitats where endangered mammals are likely to occur, (2) intensifying forest conversion, and (3) contributing to illegal hunting and wildlife trade. To our knowledge, ours is the first study to identify specific roads threatening endangered mammals in Southeast Asia. Further through highlighting the impacts of roads, we propose 10 measures to limit road impacts in the region. PMID- 25521296 TI - Inhibition of autoimmune Chagas-like heart disease by bone marrow transplantation. AB - BACKGROUND: Infection with the protozoan Trypanosoma cruzi manifests in mammals as Chagas heart disease. The treatment available for chagasic cardiomyopathy is unsatisfactory. METHODS/PRINCIPAL FINDINGS: To study the disease pathology and its inhibition, we employed a syngeneic chicken model refractory to T. cruzi in which chickens hatched from T. cruzi inoculated eggs retained parasite kDNA (1.4 kb) minicircles. Southern blotting with EcoRI genomic DNA digests revealed main 18 and 20 kb bands by hybridization with a radiolabeled minicircle sequence. Breeding these chickens generated kDNA-mutated F1, F2, and F3 progeny. A targeted primer TAIL-PCR (tpTAIL-PCR) technique was employed to detect the kDNA integrations. Histocompatible reporter heart grafts were used to detect ongoing inflammatory cardiomyopathy in kDNA-mutated chickens. Fluorochromes were used to label bone marrow CD3+, CD28+, and CD45+ precursors of the thymus-dependent CD8alpha+ and CD8beta+ effector cells that expressed TCRgammadelta, vbeta1 and vbeta2 receptors, which infiltrated the adult hearts and the reporter heart grafts. CONCLUSIONS/SIGNIFICANCE: Genome modifications in kDNA-mutated chickens can be associated with disruption of immune tolerance to compatible heart grafts and with rejection of the adult host's heart and reporter graft, as well as tissue destruction by effector lymphocytes. Autoimmune heart rejection was largely observed in chickens with kDNA mutations in retrotransposons and in coding genes with roles in cell structure, metabolism, growth, and differentiation. Moreover, killing the sick kDNA-mutated bone marrow cells with cytostatic and anti-folate drugs and transplanting healthy marrow cells inhibited heart rejection. We report here for the first time that healthy bone marrow cells inhibited heart pathology in kDNA+ chickens and thus prevented the genetically driven clinical manifestations of the disease. PMID- 25521299 TI - El Nino Southern Oscillation (ENSO) enhances CO2 exchange rates in freshwater Marsh ecosystems in the Florida everglades. AB - This research examines the relationships between El Nino Southern Oscillation (ENSO), water level, precipitation patterns and carbon dioxide (CO2) exchange rates in the freshwater wetland ecosystems of the Florida Everglades. Data was obtained over a 5-year study period (2009-2013) from two freshwater marsh sites located in Everglades National Park that differ in hydrology. At the short hydroperiod site (Taylor Slough; TS) and the long-hydroperiod site (Shark River Slough; SRS) fluctuations in precipitation patterns occurred with changes in ENSO phase, suggesting that extreme ENSO phases alter Everglades hydrology which is known to have a substantial influence on ecosystem carbon dynamics. Variations in both ENSO phase and annual net CO2 exchange rates co-occurred with changes in wet and dry season length and intensity. Combined with site-specific seasonality in CO2 exchanges rates, El Nino and La Nina phases magnified season intensity and CO2 exchange rates at both sites. At TS, net CO2 uptake rates were higher in the dry season, whereas SRS had greater rates of carbon sequestration during the wet season. As La Nina phases were concurrent with drought years and extended dry seasons, TS became a greater sink for CO2 on an annual basis (-11 to -110 g CO2 m 2 yr-1) compared to El Nino and neutral years (-5 to -43.5 g CO2 m-2 yr-1). SRS was a small source for CO2 annually (1.81 to 80 g CO2 m-2 yr-1) except in one exceptionally wet year that was associated with an El Nino phase (-16 g CO2 m-2 yr-1). Considering that future climate predictions suggest a higher frequency and intensity in El Nino and La Nina phases, these results indicate that changes in extreme ENSO phases will significantly alter CO2 dynamics in the Florida Everglades. PMID- 25521298 TI - HSV-2-driven increase in the expression of alpha4beta7 correlates with increased susceptibility to vaginal SHIV(SF162P3) infection. AB - The availability of highly susceptible HIV target cells that can rapidly reach the mucosal lymphoid tissues may increase the chances of an otherwise rare transmission event to occur. Expression of alpha4beta7 is required for trafficking of immune cells to gut inductive sites where HIV can expand and it is expressed at high level on cells particularly susceptible to HIV infection. We hypothesized that HSV-2 modulates the expression of alpha4beta7 and other homing receptors in the vaginal tissue and that this correlates with the increased risk of HIV acquisition in HSV-2 positive individuals. To test this hypothesis we used an in vivo rhesus macaque (RM) model of HSV-2 vaginal infection and a new ex vivo model of macaque vaginal explants. In vivo we found that HSV-2 latently infected RMs appeared to be more susceptible to vaginal SHIVSF162P3 infection, had higher frequency of alpha4beta7high CD4+ T cells in the vaginal tissue and higher expression of alpha4beta7 and CD11c on vaginal DCs. Similarly, ex vivo HSV-2 infection increased the susceptibility of the vaginal tissue to SHIVSF162P3. HSV 2 infection increased the frequencies of alpha4beta7high CD4+ T cells and this directly correlated with HSV-2 replication. A higher amount of inflammatory cytokines in vaginal fluids of the HSV-2 infected animals was similar to those found in the supernatants of the infected explants. Remarkably, the HSV-2-driven increase in the frequency of alpha4beta7high CD4+ T cells directly correlated with SHIV replication in the HSV-2 infected tissues. Our results suggest that the HSV-2-driven increase in availability of CD4+ T cells and DCs that express high levels of alpha4beta7 is associated with the increase in susceptibility to SHIV due to HSV-2. This may persists in absence of HSV-2 shedding. Hence, higher availability of alpha4beta7 positive HIV target cells in the vaginal tissue may constitute a risk factor for HIV transmission. PMID- 25521301 TI - Glowing graphene quantum dots and carbon dots: properties, syntheses, and biological applications. AB - The emerging graphene quantum dots (GQDs) and carbon dots (C-dots) have gained tremendous attention for their enormous potentials for biomedical applications, owing to their unique and tunable photoluminescence properties, exceptional physicochemical properties, high photostability, biocompatibility, and small size. This article aims to update the latest results in this rapidly evolving field and to provide critical insights to inspire more exciting developments. We comparatively review the properties and synthesis methods of these carbon nanodots and place emphasis on their biological (both fundamental and theranostic) applications. PMID- 25521300 TI - Geographical variability in the likelihood of bloodstream infections due to gram negative bacteria: correlation with proximity to the equator and health care expenditure. AB - OBJECTIVE: Infections due to Gram-negative bacteria exhibit seasonal trends, with peak infection rates during warmer months. We hypothesized that the likelihood of a bloodstream infection due to Gram-negative bacteria increases with proximity to the equator. We tested this hypothesis and identified geographical, climatic and social factors associated with this variability. DESIGN: We established a network of 23 international centers in 22 cities. SETTING: De-identified results of positive blood cultures from 2007-2011 and data sources for geographic, climatic and socioeconomic factors were assembled for each center. PARTICIPANTS: Patients at the 23 centers with positive blood cultures. MAIN OUTCOME: Due to variability in the availability of total culture volumes across sites, our primary outcome measure was the fraction of positive blood cultures that yielded Gram-negative bacteria; sources of variability in this outcome measure were explored using meta regression techniques. RESULTS: The mean fraction of bacteremia associated with Gram-negative bacteria was 48.4% (range 26.4% to 61.8%). Although not all sites displayed significant seasonality, the overall P-value for seasonal oscillation was significant (P<0.001). In univariate meta-regression models, temperature, latitude, latitude squared, longitude, per capita gross domestic product and percent of gross domestic product spent on healthcare were all associated with the fraction of bacteremia due to Gram-negative bacteria. In multivariable models, only percent of gross domestic product spent on healthcare and distance from the equator (ie. latitude squared) were significantly associated with the fraction of bacteremia due to Gram-negative bacteria. CONCLUSIONS: The likelihood of bacteremia due to Gram-negative bacteria varies markedly between cities, in a manner that appears to have both geographic (latitude) and socioeconomic (proportion gross domestic product devoted to health spending) determinants. Thus, the optimal approach to initial management of suspected bacteremia may be geographically specific. The rapid emergence of highly antibiotic-resistant Gram negative pathogens may have geographically specific impacts. PMID- 25521302 TI - Leptomeningeal melanomatosis associated with neurocutaneous melanosis: an autopsy case report. AB - An autopsy case of leptomeningeal melanomatosis associated with neurocutaneous melanosis (NCM) involving a 44-year-old male is reported. The autopsy showed that the leptomeningeal surface of the brain and the spinal cord were covered with a diffuse black lesion. A histological examination detected diffusely distributed, proliferating, melanin-containing cells and demonstrated that the lesion consisted of three different components; i.e. regions of melanomatosis, melanocytosis, and melanocyte hyperplasia. In the leptomeningeal melanomatosis component, tumor cells with pleomorphic nuclei and prominent nucleoli had infiltrated into the cerebral parenchyma via Virchow-Robin spaces. The Ki-67 labeling index and the nuclear accumulation of p53 and p16 protein were immunohistochemically examined in each component. The Ki-67 labeling indices of the melanomatosis, melanocytosis, and melanocyte hyperplasia components were 8.7%, 0.8%, and 0%, respectively. Immunostaining of nuclear p16 produced a negative result in the melanomatosis component, but positive results in the melanocytosis and melanocyte hyperplasia components, whereas nuclear p53 expression was not detected in any of the components. This case suggests that p16(INK4) /CDKN2 may play a significant role in progression of leptomeningeal melanocytic neoplasms. We also reviewed previously reported cases of leptomeningeal neoplasms associated with NCM and discussed the relationship between the biological behavior and proliferative activity of such lesions. PMID- 25521303 TI - The importance of disclosure: lesbian, gay, bisexual, transgender/transsexual, queer/questioning, and intersex individuals and the cancer continuum. PMID- 25521304 TI - Levocetirizine and rupatadine in chronic idiopathic urticaria. AB - BACKGROUND: Chronic idiopathic urticaria (CIU) is a common dermatological condition. Its pathogenesis involves mainly histamine and also other mediators, including platelet-activating factor (PAF) and tumor necrosis factor-alpha (TNF alpha). In the absence of an exact etiology, H1 -antihistaminics are the mainstay of treatment. Levocetirizine is widely prescribed for CIU. Rupatadine, a newer antihistaminic, has PAF receptor antagonist activity and has shown anti-TNF-alpha activity in vitro. These additional anti-inflammatory effects may improve its efficacy. OBJECTIVES: This study was conducted to compare the efficacy and safety of rupatadine and levocetirizine, respectively, in CIU patients. METHODS: A prospective, open, comparative, randomized study was conducted in 100 patients, of whom 50 were treated with levocetirizine and 50 were treated with rupatadine. Efficacy parameters used were urticarial activity score (UAS) and Dermatology Life Quality Index (DLQI) values. Safety was evaluated by monitoring for adverse drug reactions and by using the critical flicker fusion threshold (CFFT) test and a visual analog scale (VAS) at baseline, and at 2, 4, and 6 weeks. RESULTS: The mean UAS decreased to 0.10 in the levocetirizine group and to 0.38 in the rupatadine group. Patients in the levocetirizine group showed a more significant (P < 0.001) improvement, although symptoms improved in both groups. Significant reductions in mean DLQI scores were observed in both groups, but the decrease was statistically significant in the levocetirizine group (P < 0.05). Somnolence was the most common side effect in both groups. Patients in the levocetirizine group showed more psychomotor impairment based on the CFFT test. Findings on the VAS showed sedative effects in both groups (P < 0.05). CONCLUSIONS: Levocetirizine was found to be more efficacious than rupatadine in CIU patients, but both drugs caused mild sedation. PMID- 25521305 TI - A compendium of cytogenetic abnormalities in myelofibrosis: molecular and phenotypic correlates in 826 patients. AB - Among 826 patients with primary myelofibrosis (PMF) and analysable metaphases on cytogenetic studies, 352 (42.6%) had abnormal karyotype, of which 240 (68.2%) were sole aberrations and 48 (13.6%) were complex; the most frequent abnormalities were 20q- (23.3%), 13q- (18.2%), +8 (11.1%), +9 (9.9%), chromosome 1q+ (9.7%) and -7/7q- (7.1%). Phenotypic correlates included: abnormal karyotype with anaemia (P = 0.02), leucopenia (P < 0.01) and thrombocytopenia (P < 0.01); complex karyotype with younger age (P = 0.04) and thrombocytopenia (P < 0.01); leucopenia with 20q-, +8 and -7/7q- and thrombocytopenia with 20q- and -7/7q-. Cytopenias were less likely to occur with 13q-. 476 patients were annotated for JAK2/CALR/MPL mutations; abnormal karyotype frequencies were 43% in JAK2, 42% CALR, 33% MPL mutated and 34% triple-negative cases (P = 0.3). A proportion of patients were also screened for ASXL1, EZH2, IDH1, IDH2, SRSF2, U2AF1 and SF3B1 mutations; in all instances, mutational frequencies were higher in patients with normal karyotype, reaching significance for ASXL1 (P = 0.02) and U2AF1 (P = 0.01). 13q- was associated with mutant CALR (P = 0.03), +9 with mutant JAK2 (P = 0.02) and 20q- with mutant SRSF2 (P = 0.02). The current PMF study provides detailed cytogenetic information and correlations with mutations and clinical phenotype. PMID- 25521307 TI - Time, place, and people: composition of the EPIET Alumni Network and its contribution to the European public health resource in 2013. AB - The EPIET Alumni Network (EAN) is an association of professionals who have completed field epidemiology or public health microbiology training programmes in the European Union. In 2013, we conducted a survey of EAN members to investigate this network's role within European public health. We distributed an online questionnaire to members registered at the time, collecting data on demographics, professional background, and attitudes towards EAN. Out of 362 registered members, 189 (52%) responded; 97% were from Europe; 65% were female. Their mean age was 39 years. The highest academic qualification was PhD for 44% and Master's degree for 55%. The majority (60%) worked in public health institutes. They were especially satisfied with having access to job offers and professional networking via EAN, but requested more learning opportunities and knowledge-sharing between members. EAN is a unique platform where highly skilled professionals can connect to control infectious diseases locally and internationally. Having a network of professionals that know each other, speak the same 'language', and can easily access each other's expertise, represents an important resource for European and global public health, which should be nurtured by encouraging more collaborations devoted to professional development. PMID- 25521306 TI - Differentially private genome data dissemination through top-down specialization. AB - Advanced sequencing techniques make large genome data available at an unprecedented speed and reduced cost. Genome data sharing has the potential to facilitate significant medical breakthroughs. However, privacy concerns have impeded efficient genome data sharing. In this paper, we present a novel approach for disseminating genomic data while satisfying differential privacy. The proposed algorithm splits raw genome sequences into blocks, subdivides the blocks in a top-down fashion, and finally adds noise to counts to preserve privacy. The experimental results suggest that the proposed algorithm can retain certain data utility in terms of a high sensitivity. PMID- 25521308 TI - Highly enantioselective (-)-sparteine-mediated lateral metalation functionalization of remote silyl protected ortho-ethyl N,N-dialkyl aryl O carbamates. AB - We report the enantioselective, lateral deprotonation of ortho-protected or functionalized tertiary N,N-dialkyl aryl O-carbamates 5-7 (Scheme 2 ) and meta protected carbamates 14, 15, and 20 (Schemes 5 and 7 ) by s-BuLi/(-)-sparteine and subsequent quench with a variety of electrophiles to give products 11-13 and 16, 17, and 21 in yields up to 96% and enantiomeric ratios up to 99:1. The influence of organolithium reagents, ratio of organolithium/(-)-sparteine pair versus N,N-dialkyl aryl O-carbamate starting materials, temperature, solvents, electrophiles, substituents located ortho or meta to the O-carbamate moiety, and O-carbamate N-substituents was investigated. The identical absolute configuration of the stereogenic center of the major enantiomers of the products, as established by single-crystal X-ray analysis for substrates (S)-11c, (S)-19, and (S)-21a, provides evidence for a consistent stereochemical course in the enantioselective deprotonation. Mechanistic investigations, including an estimate of the configurational stability of the benzyllithium species 9 (starting from 12e; Scheme 8 ) and 23 (starting from 17e; Scheme 9 ), both derived by tin lithium exchange, and 24 (starting from 20; Scheme 9 ) are reported. The experimental results, together with semiempirical molecular orbital calculations (PM3/SMD), are consistent with a process in which enantioinduction occurs in the deprotonation step (Scheme 11 ). PMID- 25521309 TI - Increased vascular endothelial growth factor level in the subretinal fluid of eye with vasoproliferative retinal tumors. AB - PURPOSE: To describe a level of vascular endothelial growth factor (VEGF) in the subretinal fluid obtained from a case with vasoproliferative retinal tumors (VPRTs). METHODS: A 30-year-old male patient presented with VPRTs subsequent to long-standing rhegmatogenous retinal detachment. RESULTS: The patient was treated with encircling scleral buckling, cryopexy, and intravitreal bevacizumab injection. The protein level of VEGF in the subretinal fluid was measured and compared with those in the subretinal fluid obtained from patients with rhegmatogenous retinal detachment. Vascular endothelial growth factor level in the subretinal fluid from a patient with VPRTs was 12,997.9 pg/mL, whereas the mean VEGF concentration in the subretinal fluid from 4 patients with rhegmatogenous retinal detachment was 2.1 +/- 2.8 pg/mL. CONCLUSION: The current data provide the evidence that VEGF production has increased in eyes with VPRTs and anti-VEGF therapy is theoretically effective for the treatment of VPRTs. PMID- 25521310 TI - Investigations of the effect of the non-manganese metal in heterometallic-oxido cluster models of the oxygen evolving complex of photosystem II: lanthanides as substitutes for calcium. AB - We report the syntheses and electrochemical properties of nine new clusters ([LLnMn(IV)3O4(OAc)3(DMF)n](+) (Ln = La(3+), Ce(3+), Nd(3+), Eu(3+), Gd(3+), Tb(3+), Dy(3+), Yb(3+), and Lu(3+), n = 2 or 3)) supported by a ligand (L(3-)) based on a 1,3,5-triarylbenzene motif appended with alkoxide and pyridine donors. All complexes were obtained by metal substitution of Ca(2+) with lanthanides upon treatment of previously reported LMn3CaO4(OAc)3(THF) with Ln(OTf)3. Structural characterization confirmed that the clusters contain the [LnMn3O4] cubane motif. The effect of the redox-inactive centers on the electronic properties of the Mn3O4 cores was investigated by cyclic voltammetry. A linear correlation between the redox potential of the cluster and the ionic radii or pKa of the lanthanide metal ion was observed. Chemical reduction of the LMn(IV)3GdO4(OAc)3(DMF)2 cluster with decamethylferrocene, resulted in the formation of LGdMn(IV)2Mn(III)O4(OAc)3(DMF)2, a rare example of mixed-valence [MMn3O4] cubane. The lanthanide-coordinated ligands can be substituted with other donors, including water, the biological substrate. PMID- 25521313 TI - Covalent attachment of cyclic TAT peptides to GFP results in protein delivery into live cells with immediate bioavailability. AB - The delivery of free molecules into the cytoplasm and nucleus by using arginine rich cell-penetrating peptides (CPPs) has been limited to small cargoes, while large cargoes such as proteins are taken up and trapped in endocytic vesicles. Based on recent work, in which we showed that the transduction efficiency of arginine-rich CPPs can be greatly enhanced by cyclization, the aim was to use cyclic CPPs to transport full-length proteins, in this study green fluorescent protein (GFP), into the cytosol of living cells. Cyclic and linear CPP-GFP conjugates were obtained by using azido-functionalized CPPs and an alkyne functionalized GFP. Our findings reveal that the cyclic-CPP-GFP conjugates are internalized into live cells with immediate bioavailability in the cytosol and the nucleus, whereas linear CPP analogues do not confer GFP transduction. This technology expands the application of cyclic CPPs to the efficient transport of functional full-length proteins into live cells. PMID- 25521314 TI - Predicting sumoylation sites using support vector machines based on various sequence features, conformational flexibility and disorder. AB - BACKGROUND: Sumoylation, which is a reversible and dynamic post-translational modification, is one of the vital processes in a cell. Before a protein matures to perform its function, sumoylation may alter its localization, interactions, and possibly structural conformation. Abberations in protein sumoylation has been linked with a variety of disorders and developmental anomalies. Experimental approaches to identification of sumoylation sites may not be effective due to the dynamic nature of sumoylation, laborsome experiments and their cost. Therefore, computational approaches may guide experimental identification of sumoylation sites and provide insights for further understanding sumoylation mechanism. RESULTS: In this paper, the effectiveness of using various sequence properties in predicting sumoylation sites was investigated with statistical analyses and machine learning approach employing support vector machines. These sequence properties were derived from windows of size 7 including position-specific amino acid composition, hydrophobicity, estimated sub-window volumes, predicted disorder, and conformational flexibility. 5-fold cross-validation results on experimentally identified sumoylation sites revealed that our method successfully predicts sumoylation sites with a Matthew's correlation coefficient, sensitivity, specificity, and accuracy equal to 0.66, 73%, 98%, and 97%, respectively. Additionally, we have showed that our method compares favorably to the existing prediction methods and basic regular expressions scanner. CONCLUSIONS: By using support vector machines, a new, robust method for sumoylation site prediction was introduced. Besides, the possible effects of predicted conformational flexibility and disorder on sumoylation site recognition were explored computationally for the first time to our knowledge as an additional parameter that could aid in sumoylation site prediction. PMID- 25521312 TI - Rising prevalence of human papillomavirus-related oropharyngeal cancer in Australia over the last 2 decades. AB - BACKGROUND: This study provides Australian data on the characteristics of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) over the last 2 decades. METHODS: The HPV status of 515 patients with oropharyngeal SCC diagnosed between 1987 and 2010 was determined by HPV E6-targeted multiplex real time polymerase chain reaction assay (PCR) and p16 immunohistochemistry. RESULTS: The HPV positivity rate increased from 20.2% (1987-1995) to 63.5% (2006-2010). Among HPV-positive oropharyngeal SCC over the study period, the median age increased from 55.4 years to 59.8 years (p = .004) and there was a trend of an increasing proportion of never smokers (19.2% to 34.0%). The use of radiation therapy (RT) in patients with HPV-positive oropharyngeal cancer increased from 26.9% to 68.1% (p = .007) and we also observed a trend of improved outcomes. CONCLUSION: Our data show a rising prevalence of HPV-positive oropharyngeal SCC in Australia over the last 2 decades. These patients with HPV-positive oropharyngeal SCC are now presenting at an older age and about one third have never smoked. PMID- 25521311 TI - High-affinity sigma1 protein agonist reduces clinical and pathological signs of experimental autoimmune encephalomyelitis. AB - BACKGROUND AND PURPOSE: Selective agonists of the sigma-1 receptor (sigma1 protein) are generally reported to protect against neuronal damage and modulate oligodendrocyte differentiation. Human and rodent lymphocytes possess saturable, high-affinity binding sites for compounds binding to the sigma1 protein and potential immunomodulatory properties have been described for sigma1 protein ligands. Experimental autoimmune encephalomyelitis (EAE) is recognized as a valuable model of the inflammatory aspects of multiple sclerosis (MS). Here, we have assessed the role of a sigma1 protein agonist, containing the tetrahydroisoquinoline-hydantoin structure, in EAE. EXPERIMENTAL APPROACH: EAE was induced in SJL/J female mice by active immunization with myelin proteolipid protein (PLP)139-151 peptide. The sigma1 protein agonist was injected i.p. at the time of immunization (day 0). Disease severity was assessed clinically and by histopathological evaluation of the CNS. Phenotyping of B-cell subsets and regulatory T-cells were performed by flow cytometry in spleen and cervical lymph nodes. KEY RESULTS: Prophylactic treatment of EAE mice with the sigma1 protein agonist prevented mononuclear cell accumulation and demyelination in brain and spinal cord and increased T2 B-cells and regulatory T-cells, resulting in an overall reduction in the clinical progression of EAE. CONCLUSIONS AND IMPLICATIONS: This sigma1 protein agonist, containing the tetrahydroisoquinoline hydantoin structure, decreased the magnitude of inflammation in EAE. This effect was associated with increased proportions of B-cell subsets and regulatory T cells with potential immunoregulatory functions. Targeting of the sigma1 protein might thus provide new therapeutic opportunities in MS. PMID- 25521321 TI - Highlights of topic "Creations and innovations in interventional endoscopy". PMID- 25521315 TI - Transforming growth factor-beta-activated kinase 1 resistance limits glucocorticoid responsiveness to Toll-like receptor 4-mediated inflammation. AB - Glucocorticoids (GC) are among the most effective anti-inflammatory drugs, but are often associated with serious adverse effects or inadequate therapeutic responses. Here, we use activation of different Toll-like receptors (TLRs) by their respective ligands to evaluate context-specific GC sensitivity in the macrophage. Recruitment and activation of transforming growth factor-beta activated kinase 1 (TAK1), downstream of TLR engagement, is crucial in activating multiple inflammatory pathways, and contributes to inflammatory disorders. We hypothesize that GC exert anti-inflammatory effects through regulation of TAK1. Both in vivo and in vitro, in comparison to other TLRs, there was limited GC potency in restricting TLR4 ligand-mediated secretion of interleukin-6, tumour necrosis factor-alpha and interleukin-12. Also, we found that inactivation of TAK1 both in vivo and in vitro strongly inhibits TLR4-induced inflammation associated genes beyond the suppressive effects from GC treatment. However, there was no effect of TAK1 inactivation on GC inhibition of TLR3- or TLR9-initiated inflammatory actions. Together, our findings demonstrate that GC resistance for TAK1 activation associated with TLR4 engagement may be an important contributor to GC resistance in inflammatory disorders. PMID- 25521323 TI - Occupational cholangiocarcinoma. PMID- 25521324 TI - Re: Occupational cholangiocarcinoma. PMID- 25521325 TI - Re: Push-out bond strength of a nano-modified mineral trioxide aggregate. PMID- 25521326 TI - Erythema elevatum diutinum: an atypical presentation. PMID- 25521327 TI - Homozygous deletions at 3p22, 5p14, 6q15, and 9p21 result in aberrant expression of tumor suppressor genes in gastric cancer. AB - Homozygous deletion is a frequent mutational mechanism of silencing tumor suppressor genes in cancer. Therefore, homozygous deletions have been analyzed for identification of tumor suppressor genes that can be utilized as biomarkers or therapeutic targets for cancer treatment. In this study, to elucidate potential tumor suppressor genes involved in gastric cancer (GC), we analyzed the entire set of large homozygous deletions in six human GC cell lines through genome- and transcriptome-wide approaches. We identified 51 genes in homozygous deletion regions of chromosomes and confirmed the deletion frequency in tumor tissues of 219 GC patients from The Cancer Genome Atlas database. We evaluated the effect of homozygous deletions on the mRNA level and found significantly affected genes in chromosome bands 9p21, 3p22, 5p14, and 6q15. Among the genes in 9p21, we investigated the potential tumor suppressive effect of KLHL9. We demonstrated that ectopic expression of KLHL9 inhibited cell proliferation and tumor formation in KLHL9-deficient SNU-16 cell line. In addition, we observed that homozygous focal deletions generated truncated transcripts of TGFBR2, CTNNA1, and STXBP5. Ectopic expression of two kinds of TGFBR2-reverse GADL1 fusion genes suppressed TGF-beta signaling, which may lead to the loss of sensitivity to TGF-beta tumor suppressive activity. In conclusion, our findings suggest that novel tumor suppressor genes that are aberrantly expressed through homozygous deletions may play important roles in gastric tumorigenesis. PMID- 25521329 TI - Protein inter-domain linker prediction using Random Forest and amino acid physiochemical properties. AB - BACKGROUND: Protein chains are generally long and consist of multiple domains. Domains are distinct structural units of a protein that can evolve and function independently. The accurate prediction of protein domain linkers and boundaries is often regarded as the initial step of protein tertiary structure and function predictions. Such information not only enhances protein-targeted drug development but also reduces the experimental cost of protein analysis by allowing researchers to work on a set of smaller and independent units. In this study, we propose a novel and accurate domain-linker prediction approach based on protein primary structure information only. We utilize a nature-inspired machine-learning model called Random Forest along with a novel domain-linker profile that contains physiochemical and domain-linker information of amino acid sequences. RESULTS: The proposed approach was tested on two well-known benchmark protein datasets and achieved 68% sensitivity and 99% precision, which is better than any existing protein domain-linker predictor. Without applying any data balancing technique such as class weighting and data re-sampling, the proposed approach is able to accurately classify inter-domain linkers from highly imbalanced datasets. CONCLUSION: Our experimental results prove that the proposed approach is useful for domain-linker identification in highly imbalanced single- and multi-domain proteins. PMID- 25521328 TI - Altered chromatin occupancy of master regulators underlies evolutionary divergence in the transcriptional landscape of erythroid differentiation. AB - Erythropoiesis is one of the best understood examples of cellular differentiation. Morphologically, erythroid differentiation proceeds in a nearly identical fashion between humans and mice, but recent evidence has shown that networks of gene expression governing this process are divergent between species. We undertook a systematic comparative analysis of six histone modifications and four transcriptional master regulators in primary proerythroblasts and erythroid cell lines to better understand the underlying basis of these transcriptional differences. Our analyses suggest that while chromatin structure across orthologous promoters is strongly conserved, subtle differences are associated with transcriptional divergence between species. Many transcription factor (TF) occupancy sites were poorly conserved across species (~25% for GATA1, TAL1, and NFE2) but were more conserved between proerythroblasts and cell lines derived from the same species. We found that certain cis-regulatory modules co-occupied by GATA1, TAL1, and KLF1 are under strict evolutionary constraint and localize to genes necessary for erythroid cell identity. More generally, we show that conserved TF occupancy sites are indicative of active regulatory regions and strong gene expression that is sustained during maturation. Our results suggest that evolutionary turnover of TF binding sites associates with changes in the underlying chromatin structure, driving transcriptional divergence. We provide examples of how this framework can be applied to understand epigenomic variation in specific regulatory regions, such as the beta-globin gene locus. Our findings have important implications for understanding epigenomic changes that mediate variation in cellular differentiation across species, while also providing a valuable resource for studies of hematopoiesis. PMID- 25521331 TI - Optimal pharmacologic pain management in the older adult: an ongoing quagmire. PMID- 25521330 TI - ZEB1 Promotes Invasion in Human Fetal Neural Stem Cells and Hypoxic Glioma Neurospheres. AB - Diffuse spread through brain parenchyma and the presence of hypoxic foci rimmed by neoplastic cells are two cardinal features of glioblastoma, and low oxygen is thought to drive movement of malignant gliomas in the core of the lesions. Transcription factors associated with epithelial-to-mesenchymal transition (EMT) have been linked to this invasion, and we found that hypoxia increased in vitro invasion up to fourfold in glioblastoma neurosphere lines and induced the expression of ZEB1. Immunohistochemical assessment of 295 surgical specimens consisting of various types of pediatric and adult brain cancers showed that ZEB1 expression was significantly higher in infiltrative lesions than less invasive tumors such as pilocytic astrocytoma and ependymoma. ZEB1 protein was also present in human fetal periventricular stem and progenitor cells and ZEB1 inhibition impaired migration of in vitro propagated human neural stem cells. The induction of ZEB1 protein in hypoxic glioblastoma neurospheres could be partially blocked by the HIF1alpha inhibitor digoxin. Targeting ZEB1 blocked hypoxia augmented invasion of glioblastoma cells in addition to slowing them in normoxia. These data support the role for ZEB1 in invasive and high-grade brain tumors and suggest its key role in promoting invasion in the hypoxic tumor core as well as in the periphery. PMID- 25521332 TI - The Ca(2+) channel inhibitor 2-APB reverses beta-amyloid-induced LTP deficit in hippocampus by blocking BAX and caspase-3 hyperactivation. AB - BACKGROUND AND PURPOSE: At the early stage of Alzheimer's disease (AD), the accumulation of beta-amyloid (Abeta) oligomers disturbs intracellular Ca(2+) homeostasis and disrupts synaptic plasticity of brain neurons. Prevention of Abeta-induced synaptic failure remains an unsolved problem for the treatment of AD. Here, the effects of 2-aminoethoxydiphenyl borate (2-APB), a non-specific, but moderately potent Ca(2+) channel inhibitor, on Abeta-induced deficit of synaptic long-term potentiation (LTP) and the underlying molecular mechanisms were explored. EXPERIMENTAL APPROACH: We used hippocampal slices and primary cultures of hippocampal neurons from C57BL/6 mice. Methods applied in our study included electrophysiological recording, membrane protein extraction, Western blot assay and Ca(2+) imaging. KEY RESULTS: 2-APB at 10 MUM effectively reversed suppression by oligomeric Abeta1-42 (500 nM) of LTP in hippocampal slices. 2-APB also restored phosphorylation and trafficking of the glutamate receptor subunit GluA1 in Abeta-treated hippocampal slices, supporting its protective action on synaptic function. Abeta-mediated abnormal neuronal [Ca(2+) ]i elevation and hyperactivation of the mitochondrial apoptotic proteins BAX, caspase-3, and glycogen synthase kinase-3beta, were blocked by 2-APB pretreatment. Moreover, the defict in long term potentiation deficit in hippocampal slices from APPswe /PS1DeltaE 9 gene mutant mice was rescued by 2-APB at 10 MUM. CONCLUSIONS AND IMPLICATION: These data demonstrate that 2-APB is a potentially useful chemical to protect synaptic plasticity against neurotoxic effects of Abeta in AD. PMID- 25521333 TI - Guidance for pharmacogenomic biomarker testing in labels of FDA-approved drugs. AB - PURPOSE: The aim of this study was to compare guidance for genetic testing in US Food and Drug Administration (FDA)-approved drug labels in oncology to those of drugs for other therapeutic areas. METHODS: We reviewed labels of all the FDA approved drugs with labels containing pharmacogenomic information. We assessed whether genetic testing was required or recommended before prescription and, if not, the reason for pharmacogenomic labeling. RESULTS: We included 140 drugs corresponding to 158 drug-biomarker pairs. Overall, 46 (29%) of 158 pairs stated a requirement or recommendation for genetic biomarker testing in the label. This proportion was higher in oncology than in other areas (62 vs. 12%; P < 0.001). For the 112 drug-biomarker pairs (including 20 in oncology) without recommendation or requirement for genetic testing, the main reasons for pharmacogenomic labeling were change in pharmacologic end points (32%) and higher risk of toxicity (30%). For 11 (10%) pairs (including 1 in oncology), a genetic biomarker was mentioned only to inform that it was not relevant. In oncology, the main reasons for pharmacogenomic labeling were higher risk of toxicity (55%) and definition of the mechanism of action (25%). CONCLUSION: Inclusion of biomarkers in drug labels does not always correspond to required or recommended genetic testing, especially outside oncology.Genet Med 17 9, 733-738. PMID- 25521334 TI - SG-ADVISER CNV: copy-number variant annotation and interpretation. AB - PURPOSE: Copy-number variants have been associated with a variety of diseases, especially cancer, autism, schizophrenia, and developmental delay. The majority of clinically relevant events occur de novo, necessitating the interpretation of novel events. In this light, we present the Scripps Genome ADVISER CNV annotation pipeline and Web server, which aims to fill the gap between copy number variant detection and interpretation by performing in-depth annotations and functional predictions for copy number variants. METHODS: The Scripps Genome ADVISER CNV suite includes a Web server interface to a high-performance computing environment for calculations of annotations and a table-based user interface that allows for the execution of numerous annotation-based variant filtration strategies and statistics. RESULTS: The annotation results include details regarding location, impact on the coding portion of genes, allele frequency information (including allele frequencies from the Scripps Wellderly cohort), and overlap information with other reference data sets (including ClinVar, DGV, DECIPHER). A summary variant classification is produced (ADVISER score) based on the American College of Medical Genetics and Genomics scoring guidelines. We demonstrate >90% sensitivity/specificity for detection of pathogenic events. CONCLUSION: Scripps Genome ADVISER CNV is designed to allow users with no prior bioinformatics expertise to manipulate large volumes of copy-number variant data. Scripps Genome ADVISER CNV is available at http://genomics.scripps.edu/ADVISER/. PMID- 25521335 TI - Preliminary validation of a consumer-oriented colorectal cancer risk assessment tool compatible with the US Surgeon General's My Family Health Portrait. AB - PURPOSE: This study examines the analytic validity of a software tool designed to provide individuals with risk assessments for colorectal cancer based on personal health and family history information. The software is compatible with the US Surgeon General's My Family Health Portrait (MFHP). METHODS: An algorithm for risk assessment was created using accepted colorectal risk assessment guidelines and programmed into a software tool (MFHP). Risk assessments derived from 150 pedigrees using the MFHP tool were compared with "gold standard" risk assessments developed by three expert cancer genetic counselors. RESULTS: Genetic counselor risk assessments showed substantial, but not perfect, agreement. MFHP risk assessments for colorectal cancer yielded a sensitivity for colorectal cancer risk of 81% (95% confidence interval: 54-96%) and specificity of 90% (95% confidence interval: 83-94%), as compared with genetic counselor pedigree review. The positive predictive value for risk for MFHP was 48% (95% confidence interval: 29-68%), whereas the negative predictive value was 98% (95% confidence interval: 93-99%). Agreement between MFHP and genetic counselor pedigree review was moderate (kappa = 0.54). CONCLUSION: The analytic validity of the MFHP colorectal cancer risk assessment software is similar to those of other types of screening tools used in primary care. Future investigations should explore the clinical validity and utility of the software in diverse population groups.Genet Med 17 9, 753-756. PMID- 25521336 TI - Variables associated with change in quality of life among persons with dementia in nursing homes: a 10 months follow-up study. AB - AIM: To investigate variables associated with change in quality of life (QOL), measured by QUALID scale and three subscales; tension, sadness and wellbeing, among dementia patients in nursing homes. METHOD: A 10 months follow-up study including 198 (female 156, 79%) nursing home patients, mean age 87 (s.d 7.7) years. Scales applied; quality of life in late stage dementia (QUALID) scale and three subscales (wellbeing, sadness and tension), neuropsychiatric inventory questionnaire 10 items (NPI-10-Q), clinical dementia rating (CDR) scale, physical self-maintenance (PSMS) scale and a scale of general medical health. Use of psychotropic medication, gender and age was collected from the patient's records. RESULTS: Mean baseline QUALID score: 20.6 (s.d.7.0), follow-up score: 22.9 (s.d.7.4), mean change 2.8 (s.d.7.4). QOL improved in 30.8%, were unchanged in 14.7%, deteriorated in 54.6% of patients. A regression analysis revealed that change in QUALID score was significantly associated with: QUALID baseline score (beta -.381, p-value.000), change in NPI score (beta.421, p-value.000), explained variance 38.1%. Change in score on wellbeing subscale associated with: change in PSMS score (beta.185, p-value.019), wellbeing baseline score (beta -.370, p value.000), change in NPI score (beta.186, p-value.017), explained variance 25.3%. Change in score on tension subscale associated with: change in CDR sum-of boxes (beta.214, p-value.003), change in NPI score (beta.270, p-value.000), tension baseline score (beta -.423, p-value.000), explained variance 34.6%. Change in score on sadness subscale associated with: change in NPI score (beta.404, p-value.000), sadness baseline score (beta -.438, p-value.000), explained variance 38.8%. CONCLUSION: The results imply that a lower baseline score (better QOL) results in a larger change in QOL (towards worse QOL). Change in QOL is mostly associated with change in neuropsychiatric symptoms. In almost 50% of patients QOL did not deteriorate. PMID- 25521337 TI - Histopathological and biochemical evidence of hepatopancreatic toxicity caused by cadmium in white shrimp, Palaemonetes argentinus. AB - Cadmium (Cd) is one of the most common pollutants in the environment and induces a range of tissue changes or damages and organ dysfunction. The histopathological effects of Cd and lipid peroxidation (LPO) on hepatopancreas of the freshwater shrimp, Palaemonetes argentinus, were studied. Shrimp were obtained from two lagoons with contrasting environmental quality, De los Padres (LP, impacted site) and Nahuel Ruca (NR, reference site), and were exposed to 3.06 and 12.24ugCdL(-1) for 3, 7, 10 and 15 days. The health status of both populations was also evaluated by histological analysis of control individuals. After exposure, shrimp were transferred to clean water for 28 days to evaluate the recuperation capacity of hepatopancreas. Control shrimp from NR exhibited a normal hepatopancreas structure; unlike control shrimp from LP which showed several alterations. These results were attributed to the different environmental quality of lagoons. The exposure to Cd resulted in several alterations in the histological structure of the hepatopancreas of both populations. The observed alterations included haemocytic and connective infiltrations in the intertubular space, erosioned microvilli, ripple of basal lamina, atrophied epithelium and necrosis, however, the latter was only observed in shrimp from LP. The exposure also caused an increase of LPO levels in both populations. P. argentinus was able to repair the hepatopancreas structure from the damage caused by Cd, evidenced by the histopathological results and LPO levels. Obtained results are indicating that the histological analysis of the hepatopancreas proved to be a highly sensitive method for evaluating water quality, in both environmental and laboratory conditions. PMID- 25521338 TI - Histopathological biomarkers in juvenile silver catfish (Rhamdia quelen) exposed to a sublethal lead concentration. AB - The aim of this study was to determine the 96-h lethal concentration (96-h LC50) of lead (Pb) in silver catfish, Rhamdia quelen, and to determine histopathological biomarkers in fish exposed for 96-h to a sublethal concentration at 25% of the LC50. The 96-h LC50 was 108 mgl(-1). In gills, the length and thickness of lamella and thickness of the filament epithelium were significantly higher in fish exposed to Pb for 48-h than in control fish whereas the interlamellar distance decreased. In the liver, the area occupied by lipid droplets and size of hepatocytes showed significantly higher values after 24-h of exposure. The percentage of abnormal renal tubules was higher in fish exposed to Pb, exhibiting a time-dependent increase. These variations in histopathological biomarkers permit the definition of the overall response of R. quelen to Pb and the potential usefulness in the monitoring of Pb contamination. PMID- 25521339 TI - Comparison of produced water toxicity to Arctic and temperate species. AB - Produced water is the main discharge stream from oil and gas production. For offshore activities this water is usually discharged to the marine environment. Produced water contains traces of hydrocarbons such as polycyclic aromatic hydrocarbons as well as alkylphenols, which are relatively resistant to biodegradation and have been reported to cause adverse effects to marine organisms in laboratory studies. For management of produced water, risk-based tools have been developed using toxicity data for mainly non-Arctic species. Reliable risk assessment approaches for Arctic environments are requested to manage potential impacts of produced water associated with increased oil and gas activities in Arctic regions. In order to assess the applicability of existing risk tools for Arctic areas, basic knowledge on the sensitivity of Arctic species has to be developed. In the present study, acute and chronic toxicity of artificial produced water for 6 Arctic and 6 temperate species was experimentally tested and evaluated. The hazardous concentrations affecting 5% and 50% of the species were calculated from species sensitivity distribution curves. Hazardous concentrations were compared to elucidate whether temperate toxicity data used in risk assessment are sufficiently representative for Arctic species. From the study it can be concluded that hazardous concentration derived from individual species' toxicity data of temperate and Arctic species are comparable. However, the manner in which Arctic and non-Arctic populations and communities respond to exposure levels above established thresholds remains to be investigated. Hence, responses at higher levels of biological organization should be studied to reveal potential differences in sensitivities to produced water between Arctic and non Arctic ecosystems. PMID- 25521340 TI - Coping styles of parents of children and adolescents with acquired brain injury in the chronic phase. AB - OBJECTIVE: To investigate the types of coping strategies used by parents of children with acquired brain injury in the chronic phase and the relationship between their coping styles and psychosocial functioning. DESIGN: Cross-sectional study (April-May 2013). SUBJECTS: Parents (n = 42) of 28 children with acquired brain injury (> 6 months post-injury). METHODS: Parents completed the Utrecht Coping List, Life Satisfaction Questionnaire 9, Caregiver Strain Index, and Family Assessment Device. RESULTS: The use of coping strategies among fathers did not differ from that among men from the standardization population (t14 = 0.96, p = 0.35 and t14 = 0.61, p = 0.55, respectively). However, mothers used more emotion-focused coping strategies than women in the standardization population (t26 = 3.27, p = 0.00), while there was no difference on the problem-focused coping strategies (t26 = -1.75, p = 0.09). Parents who used emotion-focused coping styles exhibited lower family functioning, higher strain and lower quality of life, while those who used problem-focused coping styles exhibited higher strain. CONCLUSION: Parents of children with acquired brain injury need proper treatment to improve their psychosocial functioning. In particular, treatments should be developed that aim at changing the parents' maladaptive coping styles into less maladaptive ones. Thus, more attention should be focused on the psychological well-being of parents of children with acquired brain injury in the chronic phase. PMID- 25521341 TI - Experimental charge density evidence for pnicogen bonding in a crystal of ammonium chloride. AB - Chemical binding in crystalline ammonium chloride, a simple inorganic salt with an unexpectedly complex bonding pattern, was studied by using a topological analysis of electron density function derived from high-resolution X-ray diffraction. Supported by periodic quantum chemical calculations, it provided experimental evidence for weak sigma-hole bonds (1.5 kcal mol(-1) ) that involve ammonium cations in a crystal. Our results show this type of supramolecular interaction to be more numerous than has been found to date by using gas-phase calculations or statistical analysis of CSD. PMID- 25521342 TI - Flavonoids in oral cancer prevention and therapy. AB - Oral cancer, representing all the malignancies arising in the oral cavity, is the eighth most diffused neoplasm worldwide. Despite therapeutic improvements, its survival rate has not changed significantly over the past few decades, with a 5 year survival rate slightly above 50%. In this context, a search for new therapeutic strategies is mandatory. Flavonoids, polyphenolic compounds derived from plants, have a broad spectrum of biological activities, including antioxidant and anticancer. They have been proved to counteract the growth of several types of cancer through multiple mechanisms including the inhibition of cell cycle progression, apoptosis induction, and the modulation of intracellular pathways. Because of their multiple biological activities and their safe toxicological profile, flavonoids have been studied widely in the last decade as potential leads for anticancer therapy. Several studies have reported different flavonoid effects according to cancer cell type. In the present review, therefore, we have evaluated the data available on the effect of flavonoids on oral cancer, with the aim of identifying the molecular mechanisms underlying their potential anticancer properties. PMID- 25521343 TI - Structural variations in metal complexes of a tertiary alpha-hydroxyoxime. AB - Despite the long term interest in hydroxyoximes as metal ion extractants, there is a lack of information on the possible coordination modes these ligands can assume, particularly in concert with a co-ligand. This is pertinent to the use of these extractants in synergistic systems, where a combination of extractants can achieve commercially useful results. We report here the structures of some metal complexes (M = Mn, Co, Ni, Cu, and Zn) with (1-hydroxycyclohexyl)-phenyl ketone oxime. The results demonstrate that this ligand can support complexes ranging from mononuclear to trinuclear, in association with anionic and neutral co ligands in some cases. While these results have been obtained in the solid state, they illustrate a range of possible species that may be formed in extractant solutions. PMID- 25521344 TI - Glutamate mediated astrocytic filtering of neuronal activity. AB - Neuron-astrocyte communication is an important regulatory mechanism in various brain functions but its complexity and role are yet to be fully understood. In particular, the temporal pattern of astrocyte response to neuronal firing has not been fully characterized. Here, we used neuron-astrocyte cultures on multi electrode arrays coupled to Ca2+ imaging and explored the range of neuronal stimulation frequencies while keeping constant the amount of stimulation. Our results reveal that astrocytes specifically respond to the frequency of neuronal stimulation by intracellular Ca2+ transients, with a clear onset of astrocytic activation at neuron firing rates around 3-5 Hz. The cell-to-cell heterogeneity of the astrocyte Ca2+ response was however large and increasing with stimulation frequency. Astrocytic activation by neurons was abolished with antagonists of type I metabotropic glutamate receptor, validating the glutamate-dependence of this neuron-to-astrocyte pathway. Using a realistic biophysical model of glutamate-based intracellular calcium signaling in astrocytes, we suggest that the stepwise response is due to the supralinear dynamics of intracellular IP3 and that the heterogeneity of the responses may be due to the heterogeneity of the astrocyte-to-astrocyte couplings via gap junction channels. Therefore our results present astrocyte intracellular Ca2+ activity as a nonlinear integrator of glutamate-dependent neuronal activity. PMID- 25521345 TI - Radiofrequency configuration to facilitate bilateral breast (31) P MR spectroscopic imaging and high-resolution MRI at 7 Tesla. AB - PURPOSE: High-resolution MRI combined with phospholipid detection may improve breast cancer grading. Currently, configurations are optimized for either high resolution imaging or (31) P spectroscopy. To be able to perform both imaging as well as spectroscopy in a single session, we integrated a (1) H receiver array into a (1) H-(31) P transceiver at 7T. To ensure negligible signal loss due to coupling between elements, we investigated the use of a floating decoupling loop to enable bilateral MRI and (31) P MRS. METHODS: Two quadrature double-tuned radiofrequency coils were designed for bilateral breast MR with active detuning at the (1) H frequency. The two coils were placed adjacent to each other and decoupled for both frequencies with a single resonant floating loop. Sensitivity of the bilateral configuration, facilitating space for a 26-element (1) H receive array, was compared with a transceiver configuration. RESULTS: The floating loop was able to decouple the elements over 20 dB for both frequencies. Enlargement of the elements, to provide space for the receivers, and the addition of detuning electronics altered the (31) P sensitivity by 0.4 dB. CONCLUSION: Dynamic contrast-enhanced scans of 0.7 mm isotropic, diffusion-weighted imaging, and (31) P MR spectroscopic imaging can be acquired at 7T in a single session as demonstrated in a patient with invasive ductal carcinoma. PMID- 25521346 TI - HbA1C variability and the risk of renal status progression in Diabetes Mellitus: a meta-analysis. AB - OBJECTIVE: To explore the association between glycated hemoglobin (A1C) variability and renal disease progression in patients with diabetes mellitus. METHODS: A comprehensive search was performed using the PubMed and Embase databases (up to April 26, 2014). The hazard ratio (HR) was pooled per unit increase in the standard deviation of A1C (A1C-SD) to evaluate the dose-response relationship between A1C-SD and the risk of nephropathy. RESULTS: Eight studies with a total of 17,758 subjects provided the HR for A1C-SD and were included in the final meta-analysis. The pooled HR results demonstrated that A1C-SD was significantly associated with the progression of renal status (HR for both T1DM and T2DM 1.43, 95% confidence interval [CI] 1.24-1.64; HR for T1DM 1.70, 95%CI 1.41-2.05; HR for T2DM 1.20, 95%CI 1.12-1.28). A1C-SD was significantly correlated with new-onset microalbuminuria (HR for T1DM 1.63, 95%CI 1.28-2.07; HR for T2DM 1.23, 95%CI 1.08-1.39). These outcomes were also supported in subgroup analyses. Furthermore, sensitivity analyses demonstrated that the results were robust. CONCLUSIONS: A1C variability is independently associated with the development of microalbuminuria and the progression of renal status in both type 1 and 2 diabetes patients. A standard method for measuring A1C variability is essential for further and deeper analyses. In addition, future studies should assess the effect of reducing A1C variability on nephropathy complication. PMID- 25521347 TI - Biochar production and applications in sub-Saharan Africa: opportunities, constraints, risks and uncertainties. AB - Sub-Saharan Africa (SSA) experiences soil degradation, food and livelihood insecurity, environmental pollution and lack of access to energy. Biochar has gained international research attention, but few studies have investigated the potential of biochar to address the challenges in SSA. This paper seeks to identify and evaluate generic potential opportunities and constraints associated with biochar application in sub-Saharan Africa using Zimbabwe as case study. Specific objectives were to; (1) identify and quantify feedstocks for biochar production; (2) review literature on the biochar properties, and evaluate its potential applications in agriculture, environmental remediation and energy provision, and (3) identify research gaps, risks and constraints associated with biochar technology. Biochar feedstocks in Zimbabwe were estimated to be 9.9 Mton yr(-1), predominantly derived from manure (88%) and firewood (10%). This will yield 3.5, 1.7 and 3.1 Mton yr(-1) of biochar, bio-oil and synthetic gas, respectively. Land application of the 3.5 Mton yr(-1) of biochar (~63% C) would sequester approximately 2.2 Mton yr(-1) of soil carbon in Zimbabwe alone, while simultaneously minimizing the environmental and public health risks, and greenhouse gas emissions associated with solid organic wastes. Biochar potentially enhances soil and crop productivity through enhanced nutrient and soil moisture availability, amelioration of acidic soils and stimulation of microbial diversity and activity. Due to its excellent adsorption properties, biochar has potential applications in industrial and environmental applications including water and wastewater treatment, remediation and revegetation of contaminated soils and water. Biochar products have energy values comparable or higher than those of traditional biomass fuels; thereby making them ideal alternative sources of energy especially for poor households without access to electricity. Before the benefits of biochar can be realized in SSA, there is need to overcome multiple risks and constraints such as lack of finance, socio economic constraints including negative perceptions and attitudes among both researchers and consumers, and environmental and public health risks. Therefore, there is need to conduct fundamental research to demonstrate the benefits of biochar applications, and develop policy framework and criteria for its production and subsequent adoption. PMID- 25521348 TI - Treatment of hepatic amyloid light-chain amyloidosis with bortezomib and dexamethasone in a liver transplant patient. AB - Hepatic amyloid light-chain (AL) amyloidosis is characterized by abnormal deposition of amyloid fibrils in the liver. As this precursor protein is produced by a proliferative plasma cell clone in the bone marrow, liver transplantation (LT) does not affect the disease's progression. Here, we describe the successful treatment using bortezomib- and dexamethasone-based chemotherapy, following LT, of hepatic AL amyloidosis in a 65-year-old woman with progressive liver failure. The patient presented with progressive hepatic dysfunction accompanied by hepatorenal syndrome requiring hemodialysis, and living donor LT was successfully performed. Histology revealed amyloid deposits in the liver and stomach, and serum immunofixation revealed AL amyloidosis (kappa-type). The patient began chemotherapy on day 45 after the LT, and remission was achieved after one course. She was subsequently discharged 83 days after the LT, with normal liver and renal function, and no clinical evidence of recurrent disease was observed at the latest follow up (22 months post-LT). PMID- 25521349 TI - The effects of marijuana exposure on expiratory airflow. A study of adults who participated in the U.S. National Health and Nutrition Examination Study. AB - RATIONALE: Given the inconclusive science on the long-term effects of marijuana exposure on lung function, the increasing tetrahydrocannabinol composition of marijuana over time, and the increasing legal accessibility of the substance, continued investigation is needed. OBJECTIVES: To determine the independent association between recent and chronic marijuana smoke exposure with spirometric parameters of lung function and symptoms of respiratory health in a large cohort of U.S. adults. METHODS: This is a cross-sectional study of U.S. adults who participated in the National Health and Nutrition Examination Survey cycles from 2007-2008 and 2009-2010, using the data from standardized spirometry and survey questions performed during these years. MEASUREMENTS AND MAIN RESULTS: In the combined 2007-2010 cohort, 59.1% replied that they had used marijuana at least once, and 12.2% had used in the past month. For each additional day of marijuana use in the prior month, there were no changes in percent predicted FEV1 (0.002 +/ 0.04%; P = 0.9), but there was an associated increase in percent predicted FVC (0.13 +/- 0.03%, P = 0.0001) and decrease in the FEV1/FVC ratio (-0.1 +/- 0.04%; P < 0.0001). In multivariable regressions, 1-5 and 6-20 joint-years of marijuana use were not associated with an FEV1/FVC less than 70% (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 0.7-1.6, P = 0.8, and OR = 1.2, 95% CI = 0.8-1.8, P = 0.4, respectively), whereas over 20 joint-years was associated with an FEV1/FVC less than 70% (OR = 2.1; 95% CI = 1.1-3.9; P = 0.02). For each additional marijuana joint-year smoked, there was no associated change in the mean percent predicted FEV1 (0.02 +/- 0.02%; P = 1.00), an increase in percent predicted FVC (0.07 +/- 0.02%; P = 0.004), and a decrease in FEV1/FVC (-0.03 +/- 0.01%; P = 0.02). CONCLUSIONS: In a large cross-section of U.S. adults, cumulative lifetime marijuana use, up to 20 joint-years, is not associated with adverse changes in spirometric measures of lung health. Although greater than 20 joint-years of cumulative marijuana exposure was associated with a twofold increased odds of a FEV1/FVC less than 70%, this was the result of an increase in FVC, rather than a disproportional decrease in FEV1 as is typically associated with obstructive lung diseases. PMID- 25521350 TI - Cadmium delays puberty onset and testis growth in adolescents. AB - OBJECTIVE: Cadmium (Cd) has been shown to impair pubertal development in experimental animals. However, no data are available for male adolescents with increased urinary cadmium levels. DESIGN: The aim of this cross-sectional study was to evaluate pubertal onset and pituitary-gonadal axis hormones in male adolescents with increased urinary levels of Cd. SUBJECTS: We studied 111 males, aged 12-14 years living in the Milazzo-Valle del Mela area. A control age-matched population (n = 60) living 28-45 km far from the industrial site was also enrolled. MEASUREMENTS: Pubertal stages were assessed by clinical examination according to Tanner's score. Mean testicular volume was also investigated by ultrasound examination. Urinary Cd concentration and blood levels of FSH, LH, testosterone and inhibin B were also investigated. RESULTS: Cd levels were significantly higher in adolescents living in the Milazzo-Valle del Mela area, compared to both age-matched subjects living far from the industrial plants and the reference values. Our population showed also a delayed onset of puberty, a smaller testicular volume and lower testosterone levels. An inverse correlation was found between urinary Cd and testicular volume (r = -0.25; P = 0.0008), testosterone levels (Spearman's r = -0.0.37; two-tailed P < 0.0001) and LH levels (Spearman's r = 0.048; P < 0.05). Testosterone levels were positively correlated with testicular volume (Spearman's r = 0.48; P < 0.0001). CONCLUSIONS: This study, for the first time, suggests that increased Cd burden is associated with delayed onset of puberty in male adolescents and impaired testicular growth. PMID- 25521353 TI - Exploiting combinatorial patterns in cancer genomic data for personalized therapy and new target discovery. PMID- 25521351 TI - High prevalence of Schistosoma mansoni in six health areas of - Kasansa health zone, Democratic Republic of the Congo: short report. AB - School-aged children suffer the most from schistosomiasis infection in sub Saharan Africa due to poverty and limited sanitary conditions. Mapping of disease burden is recommended and there is a need of updating prevalence data which is as old as 20 years in the Democratic Republic of Congo. An epidemiological and parasitological study was carried out in 2011 in the health zone of Kasansa. Six health areas (HA) were included in the study. In each health area, one primary school was selected. School-aged children were screened for S. mansoni infection using parallel Kato-Katz and direct microscopy techniques. A total of 335 school aged children were screened. The average prevalence was 82.7% and ranged between 59.5-94.9%. Four of the six HAs had a prevalence level over 91%. Of all infected children, about half 112 (43.2%) had light parasite density. These results demonstrate that Schistosoma mansoni infection is a bigger problem than anticipated and there is an urgent need to implement effective control measures. PMID- 25521352 TI - Evoked emotions predict food choice. AB - In the current study we show that non-verbal food-evoked emotion scores significantly improve food choice prediction over merely liking scores. Previous research has shown that liking measures correlate with choice. However, liking is no strong predictor for food choice in real life environments. Therefore, the focus within recent studies shifted towards using emotion-profiling methods that successfully can discriminate between products that are equally liked. However, it is unclear how well scores from emotion-profiling methods predict actual food choice and/or consumption. To test this, we proposed to decompose emotion scores into valence and arousal scores using Principal Component Analysis (PCA) and apply Multinomial Logit Models (MLM) to estimate food choice using liking, valence, and arousal as possible predictors. For this analysis, we used an existing data set comprised of liking and food-evoked emotions scores from 123 participants, who rated 7 unlabeled breakfast drinks. Liking scores were measured using a 100-mm visual analogue scale, while food-evoked emotions were measured using 2 existing emotion-profiling methods: a verbal and a non-verbal method (EsSense Profile and PrEmo, respectively). After 7 days, participants were asked to choose 1 breakfast drink from the experiment to consume during breakfast in a simulated restaurant environment. Cross validation showed that we were able to correctly predict individualized food choice (1 out of 7 products) for over 50% of the participants. This number increased to nearly 80% when looking at the top 2 candidates. Model comparisons showed that evoked emotions better predict food choice than perceived liking alone. However, the strongest predictive strength was achieved by the combination of evoked emotions and liking. Furthermore we showed that non-verbal food-evoked emotion scores more accurately predict food choice than verbal food-evoked emotions scores. PMID- 25521355 TI - POR*28 SNP is associated with lipid response to atorvastatin in children and adolescents with familial hypercholesterolemia. AB - BACKGROUND: In children and adolescents with familial hypercholesterolemia (FH) pharmacotherapy with statins is the cornerstone in the current regimen to reduce low-density lipoprotein cholesterol (LDLc) and premature coronary heart disease risk. There is, however, a great interindividual variation in response to therapy, partially attributed to genetic factors. The polymorphic enzyme POR transfers electrons from NADPH to CYP450 enzymes including CYP3A, which metabolize atorvastatin. POR*28 polymorphism is associated with increased CYP3A enzyme activity. We analyzed the association of POR*28 allele with response to atorvastatin. MATERIALS & METHODS: One hundred and five FH children and adolescents treated with atorvastatin at doses 10-40 mg were included in the study. Total cholesterol (TChol) and LDLc were measured at baseline and after 6 months of treatment. POR*28 allele was analyzed with TaqMan assay. CYP3A4*22, CYP3A5*3 and SLCO1B1 521T>C and 388A>G genotypes were also determined with TaqMan or PCR-RFLP methods. RESULTS: POR*28 carriers had significantly lower percent mean reduction of TChol (33.1% in *1/*1, 29.8% in *1/*28 and 25.9% in *28/*28 individuals, p = 0.045) and of LDLc (43.9% in *1/*1, 40.9% in *1/*28 and 30.8% in *28/*28 individuals, p = 0.013). In multivariable linear regression adjusted for confounding factors, POR*28 genotypes, additionally to baseline cholesterol level, accounted for an estimated 8.3% and 7.3% of overall variability in % TChol and LDLc reduction (beta: 4.05; 95% CI: 1.73-6.37; p = 0.001 and beta: 5.08; 95% CI: 1.62-8.54; p = 0.004, respectively). CYP3A4*22, CYP3A5*3 and SLCO1B1 521T>C and 388A>G polymorphisms were not associated with lipid reductions and did not modify the effect of POR*28 on atorvastatin response. CONCLUSION: In children with FH, carriage of POR*28 allele is associated with reduced effect of atorvastatin on TChol and LDLc and therefore identifies FH children that may require higher atorvastatin doses to achieve full therapeutic benefits. Additional studies in different populations are needed to replicate this association. PMID- 25521354 TI - Detection of an endogenous urinary biomarker associated with CYP2D6 activity using global metabolomics. AB - AIM: We sought to discover endogenous urinary biomarkers of human CYP2D6 activity. PATIENTS & METHODS: Healthy pediatric subjects (n = 189) were phenotyped using dextromethorphan and randomized for candidate biomarker selection and validation. Global urinary metabolomics was performed using liquid chromatography quadrupole time-of-flight mass spectrometry. Candidate biomarkers were tested in adults receiving fluoxetine, a CYP2D6 inhibitor. RESULTS: A biomarker, M1 (m/z 444.3102) was correlated with CYP2D6 activity in both the pediatric training and validation sets. Poor metabolizers had undetectable levels of M1, whereas it was present in subjects with other phenotypes. In adult subjects, a 9.56-fold decrease in M1 abundance was observed during CYP2D6 inhibition. CONCLUSION: Identification and validation of M1 may provide a noninvasive means of CYP2D6 phenotyping. PMID- 25521356 TI - Genotype and risk of major bleeding during warfarin treatment. AB - AIM: To determine whether genetic variants associated with warfarin dose variability were associated with increased risk of major bleeding during warfarin therapy. MATERIALS & METHODS: Using Vanderbilt's DNA biobank we compared the prevalence of CYP2C9, VKORC1 and CYP4F2 variants in 250 cases with major bleeding and 259 controls during warfarin therapy. RESULTS: CYP2C9*3 was the only allele that differed significantly among cases (14.2%) and controls (7.8%; p = 0.022). In the 214 (85.6%) cases with a major bleed 30 or more days after warfarin initiation, CYP2C9*3 was the only variant associated with bleeding (adjusted odds ratio: 2.05; 95% CI: 1.04, 4.04). CONCLUSION: The CYP2C9*3 allele may double the risk of major bleeding among patients taking warfarin for 30 or more days. PMID- 25521357 TI - Pharmacogenetic interaction analysis of VEGFR-2 and IL-8 polymorphisms in advanced breast cancer patients treated with paclitaxel and bevacizumab. AB - AIM: To investigate pharmacogenetic interactions among VEGF-A, VEGFR-2, IL-8, HIF 1alpha, EPAS-1 and TSP-1 SNPs and their role on progression-free survival in a population of metastatic breast cancer patients treated with bevacizumab in combination with first-line paclitaxel. PATIENTS & METHODS: Analyses were performed on germline DNA obtained from blood samples and SNPs were investigated by real-time polymerase chain reaction technique. The multifactor dimensionality reduction methodology was applied to investigate the interaction between SNPs. RESULTS: One hundred and thirteen patients were enrolled from eight Italian Oncology Units ( clinicaltrial.gov : NCT01935102). The multifactor dimensionality reduction software provided two pharmacogenetic interaction profiles consisting of the combination between specific VEGFR-2 rs11133360 and IL-8 rs4073 genotypes. The median progression-free survival was 14.1 months (95% CI: 11.4-16.8) and 10.2 months (95% CI: 8.8-11.5) for the favorable and the unfavorable genetic profile, respectively (HR: 0.44, 95% CI: 0.29-0.66, p < 0.0001). CONCLUSION: The pharmacogenetic statistical interaction between VEGFR-2 rs11133360 and IL-8 rs4073 genotypes may identify a population of patients with a better outcome. PMID- 25521358 TI - Dopaminergic pathway polymorphisms and heroin addiction: further support for association of CSNK1E variants. AB - BACKGROUND & AIM: The dopaminergic pathways have been implicated in the etiology of drug addictions. The aim of this study was to determine if variants in dopaminergic genes are associated with heroin addiction. MATERIALS & METHODS: The study includes 828 former heroin addicts and 232 healthy controls, of predominantly European ancestry. Ninety seven SNPs (13 genes) were analyzed. RESULTS: Nine nominally significant associations were observed at CSNK1E, ANKK1, DRD2 and DRD3. CONCLUSION: The results support our previous report of association of CSNK1E SNP rs1534891 with protection from heroin addiction. CSNK1E interacts with circadian rhythms and DARPP-32 and has been implicated in negative regulation of sensitivity to opioids in rodents. It may be a target for drug addiction treatment. Original submitted 8 August 2014; Revision submitted 8 October 2014. PMID- 25521359 TI - Donor ABCB1 genetic polymorphisms influence epithelial-to-mesenchyme transition in tacrolimus-treated kidney recipients. AB - AIM: The contribution of epithelial-mesenchymal transition (EMT) has been suggested in renal transplant recipients receiving calcineurin inhibitors and developing nephrotoxicity. MATERIALS & METHODS: We assessed whether interindividual variability in tacrolimus pharmacokinetics is associated with the occurrence in tubular cells of two EMT markers (vimentin, beta-catenin) detected at 3-month in 140 allograft biopsies. We investigated whether genetic polymorphisms affecting CYP3A5 and ABCB1 influence EMT and kidney fibrosis. RESULTS: In univariate analysis, the donor CYP3A5*1 allele was significantly associated with a lower vimentin expression. In multivariate analysis, grafts carrying ABCB1 3435T allele(s) developed significantly less EMT and less interstitial fibrosis. CONCLUSION: Donor SNPs significantly influence the epithelial program in the context of kidney transplantation, and the epithelial metabolism of tacrolimus is one key to understand graft fibrogenesis. PMID- 25521361 TI - Pharmacogenetics of inflammatory bowel disease. AB - Pharmacogenetic studies have been performed for almost all classes of drugs that have been used in IBD but very few have generated consistent findings or have been replicated. The genetic test that has been approved for clinical practice is TPMT testing prior to starting treatment with thiopurine drugs. Research in IBD pharmacogenetics has focused on prediction of drug efficacy and toxicity by identifying polymorphisms in the genes encoding enzymes that are involved in metabolic pathways. Recent research has mainly focused on therapeutic agents such as azathioprine, methotrexate, aminosalicylates, corticosteroids, infliximab and adalimumab. Future pharmaceutical trials should include pharmacogenetic research to test appropriate candidate genes in a prospective manner and correlate genetic associations with trial outcomes and relevant functional data. PMID- 25521363 TI - Microbial biogeography: the end of the ubiquitous dispersal hypothesis? PMID- 25521360 TI - Genomic architecture of pharmacological efficacy and adverse events. AB - The pharmacokinetic and pharmacodynamic disciplines address pharmacological traits, including efficacy and adverse events. Pharmacogenomics studies have identified pervasive genetic effects on treatment outcomes, resulting in the development of genetic biomarkers for optimization of drug therapy. Pharmacogenomics-based tests are already being applied in clinical decision making. However, despite substantial progress in identifying the genetic etiology of pharmacological response, current biomarker panels still largely rely on single gene tests with a large portion of the genetic effects remaining to be discovered. Future research must account for the combined effects of multiple genetic variants, incorporate pathway-based approaches, explore gene-gene interactions and nonprotein coding functional genetic variants, extend studies across ancestral populations, and prioritize laboratory characterization of molecular mechanisms. Because genetic factors can play a key role in drug response, accurate biomarker tests capturing the main genetic factors determining treatment outcomes have substantial potential for improving individual clinical care. PMID- 25521364 TI - New-generation narrow band imaging system for detection of a laterally spreading tumor in the colon. PMID- 25521362 TI - Pharmacogenomics and pharmacogenetics of thiazolidinediones: role in diabetes and cardiovascular risk factors. AB - The most important goal in the treatment of patients with diabetes is to prevent the risk of cardiovascular disease (CVD), the first cause of mortality in these subjects. Thiazolidinediones (TZDs), a class of antidiabetic drugs, act as insulin sensitizers increasing insulin-dependent glucose disposal and reducing hepatic glucose output. TZDs including pioglitazone, rosiglitazone and troglitazone, by activating PPAR-gamma have shown pleiotropic effects in reducing vascular risk factors and atherosclerosis. However, troglitazone was removed from the market due to its hepatoxicity, and rosiglitazone and pioglitazone both have particular warnings due to being associated with heart diseases. Specific genetic variations in genes involved in the pathways regulated by TDZs have demonstrated to modify the variability in treatment with these drugs, especially in their side effects. Therefore, pharmacogenomics and pharmacogenetics are an important tool in further understand intersubject variability per se but also to assess the therapeutic potential of such variability in drug individualization and therapeutic optimization. PMID- 25521365 TI - Development and Reliability of the Functional Evaluation Scale for Duchenne Muscular Dystrophy, Gait Domain: A Pilot Study. AB - BACKGROUND AND PURPOSE: The progression of Duchenne muscular dystrophy (DMD) results in the emergence of multiple and varied synergies to compensate muscle weakness and to deal with the demands of the functional tasks (e.g. gait). No functional evaluation instrument for individuals with DMD allows the detailed description (subjective qualitative evaluation) and compensatory movement scoring (objective quantitative evaluation) exclusively of gait. For this reason, clinicians and therapists face difficulties in assessment and decision-making of this functional activity. This study aimed to elaborate the gait domain of the Functional Evaluation Scale for DMD (FES-DMD-GD) and test its intra-rater and inter-rater reliabilities and its relationship with age and timed motor performance. METHOD: We listed all the compensatory movements observed in 102 10 m gait videos of 51 children with DMD. Based on this report, the FES-DMD-GD was created and submitted to the review of 10 experts. After incorporating the experts suggestions, three examiners scored the videos using the FES-DMD-GD. The intra-rater and inter-rater reliabilities was calculated. Spearman correlation tests investigated the relationships between FES-DMD-GD and age and timed motor performance (p < 0.05). RESULTS: The FES-DMD-GD was composed of three phases and had 14 items to quantify compensatory movements on gait. Intra-class correlation coefficients ranged from acceptable (0.74) to excellent (0.99). FES-DMD-GD correlated to age and timed motor performance. CONCLUSION: This pilot version of FES-DMD-GD showed reliability and correlated to age and timed motor performance. PMID- 25521366 TI - Molecular understanding of ion specificity at the peptide bond. AB - The Hofmeister series has remained a mystery for more than a century. A detailed understanding of the interactions in ion-dissolved systems is still needed because the classical theories have failed to accommodate the specific ion effects. In this study, the interactions between ions, solvent and a model compound for proteins were explored using a direct nuclear magnetic resonance (NMR) approach along with density functional theory (DFT) calculations. It was found that the chaotropic anions caused increasing chemical shifts of the model compound, while kosmotropic anions resulted in decreasing shifts; this suggests that the kosmotropic anions were prevented from interacting with the model compound. The experimental results can be explained by a combination of local electrostatic interactions and hydrogen bonding. Although more effort are required to justify the NMR method applied in this study, the results could give a quantitative standard for defining kosmotropes/chaotropes and might provide a new way for predicting the effects of unfamiliar ions in the future. PMID- 25521367 TI - Scalable privacy-preserving data sharing methodology for genome-wide association studies: an application to iDASH healthcare privacy protection challenge. AB - In response to the growing interest in genome-wide association study (GWAS) data privacy, the Integrating Data for Analysis, Anonymization and SHaring (iDASH) center organized the iDASH Healthcare Privacy Protection Challenge, with the aim of investigating the effectiveness of applying privacy-preserving methodologies to human genetic data. This paper is based on a submission to the iDASH Healthcare Privacy Protection Challenge. We apply privacy-preserving methods that are adapted from Uhler et al. 2013 and Yu et al. 2014 to the challenge's data and analyze the data utility after the data are perturbed by the privacy-preserving methods. Major contributions of this paper include new interpretation of the chi2 statistic in a GWAS setting and new results about the Hamming distance score, a key component for one of the privacy-preserving methods. PMID- 25521369 TI - Please mind the gap: axonal transport deficits in multiple sclerosis neurodegeneration. AB - In this issue, Sorbara et al. (2014) demonstrate that axonal transport impairment is an early feature of neurodegeneration in multiple sclerosis models. This transport deficit is reversible by anti-inflammatory intervention but, if untreated, can contribute to late-stage axonal dystrophy. PMID- 25521370 TI - Strides toward a structure-function understanding of cortical representations of allocentric space. AB - Grid cells, border cells, head-directions cells, and conjunctive correlates found in the Medial Entorhinal Cortex (MEC) indicate the presence of highly specialized neural circuits that process allocentric space. New technical advancements, as described by Tang et al. (2014) in this issue, offer an integrated approach to charting the function and organization of these circuits. PMID- 25521371 TI - Unveiling the secret lives of glutamate transporters: VGLUTs engage in multiple transport modes. AB - Accumulation of glutamate in synaptic vesicles is mediated by vesicular glutamate transporters called VGLUTs. In the current issue of Neuron, Preobraschenski et al. (2014) show that the VGLUTs, in addition to transporting glutamate, also provide the conductances necessary to maintain the appropriate voltage and pH inside these vesicles. PMID- 25521368 TI - Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in the regulation of circulating serum chemerin. AB - Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total N = 2,791). In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs) at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) locus reached genome-wide significance (p<5.0*10-8) in the meta-analysis (the strongest evidence for association at rs7806429 with p = 7.8*10-14, beta = -0.067, explained variance 2.0%). All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2 = 0.43 in the Sorbs cohort). The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p<0.05 after adjusting for age and body mass index). In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations. PMID- 25521372 TI - Looks can be deceiving: reconsidering the evidence for gliotransmission. AB - Gliotransmission, a process involving active vesicular release of glutamate and other neurotransmitters by astrocytes, is thought to play a critical role in many brain functions. A new paper by Nedergaard et al. (2014) identifies an experimental flaw in these previous studies suggesting that astrocytes may not perform active vesicular release after all. PMID- 25521373 TI - The 2014 Nobel Prize in Chemistry: a large-scale prize for achievements on the nanoscale. AB - The 2014 Nobel Prize in Chemistry awarded to Eric Betzig, Stefan W. Hell, and William E. Moerner "for the development of superresolved fluorescence microscopy" can be seen as a combined prize for single-molecule detection and superresolution imaging. Neurons, arguably the most morphologically complex cell type, are the subject of choice for this application, now generically called "nanoscopy." PMID- 25521374 TI - The 2014 Nobel Prize in Physiology or Medicine: a spatial model for cognitive neuroscience. AB - Understanding how the cognitive functions of the brain arise from its basic physiological components has been an enticing final frontier in science for thousands of years. The Nobel Prize in Physiology or Medicine 2014 was awarded one half to John O'Keefe, the other half jointly to May-Britt Moser and Edvard I. Moser "for their discoveries of cells that constitute a positioning system in the brain." This prize recognizes both a paradigm shift in the study of cognitive neuroscience, and some of the amazing insights that have followed from it concerning how the world is represented within the brain. PMID- 25521375 TI - Mitochondrial DNA: impacting central and peripheral nervous systems. AB - Because of their high-energy metabolism, neurons are strictly dependent on mitochondria, which generate cellular ATP through oxidative phosphorylation. The mitochondrial genome encodes for critical components of the oxidative phosphorylation pathway machinery, and therefore, mutations in mitochondrial DNA (mtDNA) cause energy production defects that frequently have severe neurological manifestations. Here, we review the principles of mitochondrial genetics and focus on prototypical mitochondrial diseases to illustrate how primary defects in mtDNA or secondary defects in mtDNA due to nuclear genome mutations can cause prominent neurological and multisystem features. In addition, we discuss the pathophysiological mechanisms underlying mitochondrial diseases, the cellular mechanisms that protect mitochondrial integrity, and the prospects for therapy. PMID- 25521376 TI - The orbitofrontal oracle: cortical mechanisms for the prediction and evaluation of specific behavioral outcomes. AB - The orbitofrontal cortex (OFC) has long been associated with the flexible control of behavior and concepts such as behavioral inhibition, self-control, and emotional regulation. These ideas emphasize the suppression of behaviors and emotions, but OFC's affirmative functions have remained enigmatic. Here we review recent work that has advanced our understanding of this prefrontal area and how its functions are shaped through interaction with subcortical structures such as the amygdala. Recent findings have overturned theories emphasizing behavioral inhibition as OFC's fundamental function. Instead, new findings indicate that OFC provides predictions about specific outcomes associated with stimuli, choices, and actions, especially their moment-to-moment value based on current internal states. OFC function thereby encompasses a broad representation or model of an individual's sensory milieu and potential actions, along with their relationship to likely behavioral outcomes. PMID- 25521377 TI - Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. AB - Expanded GGGGCC (G4C2) nucleotide repeats within the C9ORF72 gene are the most common genetic mutation associated with both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Sense and antisense transcripts of these expansions are translated to form five dipeptide repeat proteins (DRPs). We employed primary cortical and motor neuron cultures, live-cell imaging, and transgenic fly models and found that the arginine-rich dipeptides, in particular Proline-Arginine (PR), are potently neurotoxic. Factors that anticipated their neurotoxicity included aggregation in nucleoli, decreased number of processing bodies, and stress granule formation, implying global translational dysregulation as path accountable for toxicity. Nuclear PR aggregates were also found in human induced motor neurons and postmortem spinal cord tissues from C9ORF72 ALS and ALS/FTD patients. Intronic G4C2 transcripts, but not loss of C9ORF72 protein, are also toxic to motor and cortical neurons. Interestingly, G4C2 transcript-mediated neurotoxicity synergizes with that of PR aggregates, suggesting convergence of mechanisms. PMID- 25521378 TI - Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors. AB - Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development. PMID- 25521379 TI - Katanin p80 regulates human cortical development by limiting centriole and cilia number. AB - Katanin is a microtubule-severing complex whose catalytic activities are well characterized, but whose in vivo functions are incompletely understood. Human mutations in KATNB1, which encodes the noncatalytic regulatory p80 subunit of katanin, cause severe microlissencephaly. Loss of Katnb1 in mice confirms essential roles in neurogenesis and cell survival, while loss of zebrafish katnb1 reveals specific roles for katnin p80 in early and late developmental stages. Surprisingly, Katnb1 null mutant mouse embryos display hallmarks of aberrant Sonic hedgehog signaling, including holoprosencephaly. KATNB1-deficient human cells show defective proliferation and spindle structure, while Katnb1 null fibroblasts also demonstrate a remarkable excess of centrioles, with supernumerary cilia but deficient Hedgehog signaling. Our results reveal unexpected functions for KATNB1 in regulating overall centriole, mother centriole, and cilia number, and as an essential gene for normal Hedgehog signaling during neocortical development. PMID- 25521382 TI - A malicious pattern detection engine for embedded security systems in the Internet of Things. AB - With the emergence of the Internet of Things (IoT), a large number of physical objects in daily life have been aggressively connected to the Internet. As the number of objects connected to networks increases, the security systems face a critical challenge due to the global connectivity and accessibility of the IoT. However, it is difficult to adapt traditional security systems to the objects in the IoT, because of their limited computing power and memory size. In light of this, we present a lightweight security system that uses a novel malicious pattern-matching engine. We limit the memory usage of the proposed system in order to make it work on resource-constrained devices. To mitigate performance degradation due to limitations of computation power and memory, we propose two novel techniques, auxiliary shifting and early decision. Through both techniques, we can efficiently reduce the number of matching operations on resource constrained systems. Experiments and performance analyses show that our proposed system achieves a maximum speedup of 2.14 with an IoT object and provides scalable performance for a large number of patterns. PMID- 25521380 TI - Fmr1 KO and fenobam treatment differentially impact distinct synapse populations of mouse neocortex. AB - Cognitive deficits in fragile X syndrome (FXS) are attributed to molecular abnormalities of the brain's vast and heterogeneous synapse populations. Unfortunately, the density of synapses coupled with their molecular heterogeneity presents formidable challenges in understanding the specific contribution of synapse changes in FXS. We demonstrate powerful new methods for the large-scale molecular analysis of individual synapses that allow quantification of numerous specific changes in synapse populations present in the cortex of a mouse model of FXS. Analysis of nearly a million individual synapses reveals distinct, quantitative changes in synaptic proteins distributed across over 6,000 pairwise metrics. Some, but not all, of these synaptic alterations are reversed by treatment with the candidate therapeutic fenobam, an mGluR5 antagonist. These patterns of widespread, but diverse synaptic protein changes in response to global perturbation suggest that FXS and its treatment must be understood as a networked system at the synapse level. PMID- 25521383 TI - Effects of reduced terrestrial LiDAR point density on high-resolution grain crop surface models in precision agriculture. AB - 3D geodata play an increasingly important role in precision agriculture, e.g., for modeling in-field variations of grain crop features such as height or biomass. A common data capturing method is LiDAR, which often requires expensive equipment and produces large datasets. This study contributes to the improvement of 3D geodata capturing efficiency by assessing the effect of reduced scanning resolution on crop surface models (CSMs). The analysis is based on high-end LiDAR point clouds of grain crop fields of different varieties (rye and wheat) and nitrogen fertilization stages (100%, 50%, 10%). Lower scanning resolutions are simulated by keeping every n-th laser beam with increasing step widths n. For each iteration step, high-resolution CSMs (0.01 m2 cells) are derived and assessed regarding their coverage relative to a seamless CSM derived from the original point cloud, standard deviation of elevation and mean elevation. Reducing the resolution to, e.g., 25% still leads to a coverage of >90% and a mean CSM elevation of >96% of measured crop height. CSM types (maximum elevation or 90th-percentile elevation) react differently to reduced scanning resolutions in different crops (variety, density). The results can help to assess the trade off between CSM quality and minimum requirements regarding equipment and capturing set-up. PMID- 25521381 TI - Choice certainty is informed by both evidence and decision time. AB - "Degree of certainty" refers to the subjective belief, prior to feedback, that a decision is correct. A reliable estimate of certainty is essential for prediction, learning from mistakes, and planning subsequent actions when outcomes are not immediate. It is generally thought that certainty is informed by a neural representation of evidence at the time of a decision. Here we show that certainty is also informed by the time taken to form the decision. Human subjects reported simultaneously their choice and confidence about the direction of a noisy display of moving dots. Certainty was inversely correlated with reaction times and directly correlated with motion strength. Moreover, these correlations were preserved even for error responses, a finding that contradicts existing explanations of certainty based on signal detection theory. We also contrived a stimulus manipulation that led to longer decision times without affecting choice accuracy, thus demonstrating that deliberation time itself informs the estimate of certainty. We suggest that elapsed decision time informs certainty because it serves as a proxy for task difficulty. PMID- 25521384 TI - Nanocrystalline tin oxide nanofibers deposited by a novel focused electrospinning method. Application to the detection of TATP precursors. AB - A new method of depositing tin dioxide nanofibers in order to develop chemical sensors is presented. It involves an electrospinning process with in-plane electrostatic focusing over micromechanized substrates. It is a fast and reproducible method. After an annealing process, which can be performed by the substrate heaters, it is observed that the fibers are intertwined forming porous networks that are randomly distributed on the substrate. The fiber diameters oscillate from 100 nm to 200 nm and fiber lengths reach several tens of microns. Each fiber has a polycrystalline structure with multiple nano-grains. The sensors have been tested for the detection of acetone and hydrogen peroxide (precursors of the explosive triacetone triperoxide, TATP) in air in the ppm range. High and fast responses to these gases have been obtained. PMID- 25521385 TI - A high-Q resonant pressure microsensor with through-glass electrical interconnections based on wafer-level MEMS vacuum packaging. AB - This paper presents a high-Q resonant pressure microsensor with through-glass electrical interconnections based on wafer-level MEMS vacuum packaging. An approach to maintaining high-vacuum conditions by integrating the MEMS fabrication process with getter material preparation is presented in this paper. In this device, the pressure under measurement causes a deflection of a pressure sensitive silicon square diaphragm, which is further translated to stress build up in "H" type doubly-clamped micro resonant beams, leading to a resonance frequency shift. The device geometries were optimized using FEM simulation and a 4-inch SOI wafer was used for device fabrication, which required only three photolithographic steps. In the device fabrication, a non-evaporable metal thin film as the getter material was sputtered on a Pyrex 7740 glass wafer, which was then anodically bonded to the patterned SOI wafer for vacuum packaging. Through glass via holes predefined in the glass wafer functioned as the electrical interconnections between the patterned SOI wafer and the surrounding electrical components. Experimental results recorded that the Q-factor of the resonant beam was beyond 22,000, with a differential sensitivity of 89.86 Hz/kPa, a device resolution of 10 Pa and a nonlinearity of 0.02% F.S with the pressure varying from 50 kPa to 100 kPa. In addition, the temperature drift coefficient was less than -0.01% F.S/ degrees C in the range of -40 degrees C to 70 degrees C, the long-term stability error was quantified as 0.01% F.S over a 5-month period and the accuracy of the microsensor was better than 0.01% F.S. PMID- 25521386 TI - Influence of fiber Bragg grating spectrum degradation on the performance of sensor interrogation algorithms. AB - The working principle of fiber Bragg grating (FBG) sensors is mostly based on the tracking of the Bragg wavelength shift. To accomplish this task, different algorithms have been proposed, from conventional maximum and centroid detection algorithms to more recently-developed correlation-based techniques. Several studies regarding the performance of these algorithms have been conducted, but they did not take into account spectral distortions, which appear in many practical applications. This paper addresses this issue and analyzes the performance of four different wavelength tracking algorithms (maximum detection, centroid detection, cross-correlation and fast phase-correlation) when applied to distorted FBG spectra used for measuring dynamic loads. Both simulations and experiments are used for the analyses. The dynamic behavior of distorted FBG spectra is simulated using the transfer-matrix approach, and the amount of distortion of the spectra is quantified using dedicated distortion indices. The algorithms are compared in terms of achievable precision and accuracy. To corroborate the simulation results, experiments were conducted using three FBG sensors glued on a steel plate and subjected to a combination of transverse force and vibration loads. The analysis of the results showed that the fast phase correlation algorithm guarantees the best combination of versatility, precision and accuracy. PMID- 25521387 TI - Rapid detection of protein phosphatase activity using Zn(II)-coordinated gold nanosensors based on His-tagged phosphopeptides. AB - We report a rapid colorimetric assay to detect protein phosphatase (PP) activity based on the controlled assembly and disassembly of gold nanoparticles (AuNPs) via Zn(II)-specific coordination in the presence of His6-tagged phosphopeptides. Among divalent metal ions including Ni(II), Cu(II), Co(II), Mg(II), Mn(II), and Zn(II), only Zn(II) triggered a strong association between phosphopeptides with hexahistidine at a single end and nitrilotriacetic acid (NTA)-modified AuNPs (21.3 nm in core diameter), leading to the self-assembly of AuNPs and consequently changes in color of the AuNP solution. In contrast, unphosphorylated peptides and His6-deficient phosphopeptides did not change the color of the AuNP solution. As a result, protein phosphatase 1 (PP1) activity and its inhibition were easily quantified with high sensitivity by determining the extinction ratio (E520/E700) of colloidal AuNPs. Most importantly, this method was capable of detecting protein phosphatase 2A (PP2A) activity in immunoprecipitated plant extracts. Because PPs play pivotal roles in mediating diverse signal transduction pathways as primary effectors of protein dephosphorylation, we anticipate that our method will be applied as a rapid format method to analyze the activities of various PPs and their inhibition. PMID- 25521388 TI - Neutral sphingomyelinase in physiological and measles virus induced T cell suppression. AB - T cell paralysis is a main feature of measles virus (MV) induced immunosuppression. MV contact mediated activation of sphingomyelinases was found to contribute to MV interference with T cell actin reorganization. The role of these enzymes in MV-induced inhibition of T cell activation remained equally undefined as their general role in regulating immune synapse (IS) activity which relies on spatiotemporal membrane patterning. Our study for the first time reveals that transient activation of the neutral sphingomyelinase 2 (NSM2) occurs in physiological co-stimulation of primary T cells where ceramide accumulation is confined to the lamellum (where also NSM2 can be detected) and excluded from IS areas of high actin turnover. Genetic ablation of the enzyme is associated with T cell hyper-responsiveness as revealed by actin dynamics, tyrosine phosphorylation, Ca2+-mobilization and expansion indicating that NSM2 acts to suppress overshooting T cell responses. In line with its suppressive activity, exaggerated, prolonged NSM2 activation as occurring in co-stimulated T cells following MV exposure was associated with aberrant compartmentalization of ceramides, loss of spreading responses, interference with accumulation of tyrosine phosphorylated protein species and expansion. Altogether, this study for the first time reveals a role of NSM2 in physiological T cell stimulation which is dampening and can be abused by a virus, which promotes enhanced and prolonged NSM2 activation to cause pathological T cell suppression. PMID- 25521389 TI - Clinical and genetic associations of autoantibodies to 3-hydroxy-3-methyl glutaryl-coenzyme a reductase in patients with immune-mediated myositis and necrotizing myopathy. AB - INTRODUCTION: Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune mediated necrotizing myopathy (IMNM). Anti-HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti-HMGCR in IIM/IMNM. METHODS: Anti-HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. RESULTS: Anti-HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti-HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA-DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti-HMGCR antibodies was among HLA-DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti-HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti-HMGCR(+) patients there was a trend toward increased malignancy (P = 0.15). CONCLUSIONS: Anti-HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA DR11. Muscle Nerve 52: 196-203, 2015. PMID- 25521391 TI - Cooperative Ge-N Bond activation in aluminium-functionalised aminogermanes and spontaneous imine elimination via an intermediate germyl cation. AB - Hydrometallation of iPr2 N-Ge(CMe3 )(C=C-CMe3 )2 with H-M(CMe3 )2 (M=Al, Ga) affords alkenyl-alkynylgermanes in which the Lewis-acidic metal atoms are not coordinated by the amino N atoms but by the alpha-C atoms of the ethynyl groups. These interactions result in a lengthening of the Ge-C bonds by approximately 10 pm and a comparably strong deviation of the Ge-C?C angle from linearity (154.3(1) degrees ). This unusual behaviour may be caused by steric shielding of the N atoms. Coordination of the metal atoms by the amino groups is observed upon hydrometallation of Et2 N-Ge(C6 H5 )(C=C-CMe3 )2 , bearing a smaller NR2 group. Strong M-N interactions lead to a lengthening of the Ge-N bonds by 10 to 15 pm and a strong deviation of the M atoms from the MC3 plane by 52 and 47 pm, for Al and Ga, respectively. Dual hydrometallation is achieved only with HAl(CMe3 )2 . In the product, there is a strong Al-N bond with converging Al-N and Ge-N distances (208 vs. 200 pm) and an interaction of the second Al atom to the phenyl group. Addition of chloride anions terminates the latter interaction while the activated Ge-N bond undergoes an unprecedented elimination of EtN=C(H)Me at room temperature, leading to a germane with a Ge-H bond. State-of-the-art DFT calculations reveal that the unique mechanism comprises the transfer of the amino group from Ge to Al to yield an intermediate germyl cation as a strong Lewis acid, which induces beta-hydride elimination, with chloride binding being crucial for providing the thermodynamic driving force. PMID- 25521390 TI - Ethenoguanines undergo glycosylation by nucleoside 2'-deoxyribosyltransferases at non-natural sites. AB - Deoxyribosyl transferases and functionally related purine nucleoside phosphorylases are used extensively for synthesis of non-natural deoxynucleosides as pharmaceuticals or standards for characterizing and quantitating DNA adducts. Hence exploring the conformational tolerance of the active sites of these enzymes is of considerable practical interest. We have determined the crystal structure at 2.1 A resolution of Lactobacillus helveticus purine deoxyribosyl transferase (PDT) with the tricyclic purine 8,9-dihydro-9-oxoimidazo[2,1-b]purine (N2,3 ethenoguanine) at the active site. The active site electron density map was compatible with four orientations, two consistent with sites for deoxyribosylation and two appearing to be unproductive. In accord with the crystal structure, Lactobacillus helveticus PDT glycosylates the 8,9-dihydro-9 oxoimidazo[2,1-b]purine at N7 and N1, with a marked preference for N7. The activity of Lactobacillus helveticus PDT was compared with that of the nucleoside 2'-deoxyribosyltransferase enzymes (DRT Type II) from Lactobacillus leichmannii and Lactobacillus fermentum, which were somewhat more effective in the deoxyribosylation than Lactobacillus helveticus PDT, glycosylating the substrate with product profiles dependent on the pH of the incubation. The purine nucleoside phosphorylase of Escherichia coli, also commonly used in ribosylation of non-natural bases, was an order of magnitude less efficient than the transferase enzymes. Modeling based on published active-site structures as templates suggests that in all cases, an active site Phe is critical in orienting the molecular plane of the purine derivative. Adventitious hydrogen bonding with additional active site residues appears to result in presentation of multiple nucleophilic sites on the periphery of the acceptor base for ribosylation to give a distribution of nucleosides. Chemical glycosylation of O9-benzylated 8,9 dihydro-9-oxoimidazo[2,1-b]purine also resulted in N7 and N1 ribosylation. Absent from the enzymatic and chemical glycosylations is the natural pattern of N3 ribosylation, verified by comparison of spectroscopic and chromatographic properties with an authentic standard synthesized by an unambiguous route. PMID- 25521392 TI - Digital microscopy of seborrheic keratosis. PMID- 25521393 TI - Nonenzymatic modification of Ubiquitin under high-pressure and -temperature treatment: mass spectrometric studies. AB - The effect of high-pressure and/or high-temperature on the glycation of a model protein (ubiquitin) was investigated by mass spectrometry. This paper reports the impact of high pressure (up to 1200 MPa) on the modification of a ubiquitin using ESI-MS measurements. The application of glucose labeled with stable isotope allows a quantitative assessment of modification under the conditions of high pressure (HPG) and high-temperature (HTG) glycation. A higher degree of modification was observed for the sample heated at 80 degrees C for 25 min under atmospheric pressure than for sample treated under high pressure. In samples treated at pressure below 400 MPa an insignificant increase of glycation level was observed, whereas high pressure (>600 MPa) has only a minor effect on the number of hexose moieties (Fru) attached to the lysine residue side chain. PMID- 25521396 TI - International Association for the Study of Lung Cancer (IASLC): celebrating 40 years with scientific and educational achievements! PMID- 25521394 TI - Genetic algorithm with logistic regression for prediction of progression to Alzheimer's disease. AB - BACKGROUND: Assessment of risk and early diagnosis of Alzheimer's disease (AD) is a key to its prevention or slowing the progression of the disease. Previous research on risk factors for AD typically utilizes statistical comparison tests or stepwise selection with regression models. Outcomes of these methods tend to emphasize single risk factors rather than a combination of risk factors. However, a combination of factors, rather than any one alone, is likely to affect disease development. Genetic algorithms (GA) can be useful and efficient for searching a combination of variables for the best achievement (eg. accuracy of diagnosis), especially when the search space is large, complex or poorly understood, as in the case in prediction of AD development. RESULTS: Multiple sets of neuropsychological tests were identified by GA to best predict conversions between clinical categories, with a cross validated AUC (area under the ROC curve) of 0.90 for prediction of HC conversion to MCI/AD and 0.86 for MCI conversion to AD within 36 months. CONCLUSIONS: This study showed the potential of GA application in the neural science area. It demonstrated that the combination of a small set of variables is superior in performance than the use of all the single significant variables in the model for prediction of progression of disease. Variables more frequently selected by GA might be more important as part of the algorithm for prediction of disease development. PMID- 25521397 TI - Consensus report of a joint NCI thoracic malignancies steering committee: FDA workshop on strategies for integrating biomarkers into clinical development of new therapies for lung cancer leading to the inception of "master protocols" in lung cancer. AB - On February 2, 2012, the National Cancer Institute (NCI) sponsored a 2-day workshop with the NCI Thoracic Malignancies Steering Committee and the Food and Drug Administration to bring together leading academicians, clinicians, industry and government representatives to identify challenges and potential solutions in the clinical development of novel targeted therapies for lung cancer. Measures of success are rapidly evolving from a scientific and regulatory perspective and the objectives of this workshop were to achieve initial consensus on a high priority biomarker-driven clinical trial designed to rapidly assess the activity of targeted agents in molecularly defined lung cancer subsets and to facilitate generation of data leading to approval of these new therapies. Additionally, the meeting focused on identification of the barriers to conduct such a trial and the development of strategies to overcome those barriers. The "Lung Master Protocols" recently launched by NCI were the direct outcome of this workshop. PMID- 25521398 TI - Safety and efficacy of dacomitinib in korean patients with KRAS wild-type advanced non-small-cell lung cancer refractory to chemotherapy and erlotinib or gefitinib: a phase I/II trial. AB - INTRODUCTION: Dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor ([HER]-1/EGFR, HER-2, and HER-4) tyrosine kinase inhibitor, demonstrated antitumor activity in Western patients with non-small cell lung cancer (NSCLC) at a dose of 45 mg once daily. We report data from a phase I/II, multicenter, open-label study of Korean patients with refractory KRAS wild-type adenocarcinoma NSCLC (defined as patients with evidence of disease progression during or within 6 months of treatment with chemotherapy and gefitinib or erlotinib). METHODS: The phase I dose-finding portion identified the recommended phase II dose (RP2D) in Korean patients, evaluated safety, and characterized the pharmacokinetics of dacomitinib. In the phase II portion, patients received dacomitinib at the RP2D. The primary end point was progression free survival at 4 months (PFS4m). RESULTS: Twelve patients enrolled in phase I, and 43 patients enrolled in phase II at the RP2D of 45 mg once daily. In phase II, PFS4m was 47.2% (95% confidence interval [CI], 31.6-61.3; one-sided p-value = 0.0007). Median PFS was 15.4 weeks (95% CI, 9.7-17.6); median overall survival was 46.3 weeks (95% CI, 32.7-not reached); and the objective response rate was 17.1% (95% CI, 7.2-32.1). Common treatment-related adverse events were dermatitis acneiform, diarrhea, and paronychia; there were no treatment-related grade 4 or 5 adverse events. Pharmacokinetic parameters of dacomitinib in Korean patients were similar to those reported in Western patients. By patient report, NSCLC symptoms "cough" and "pain" showed improvement within 3 weeks of initiating treatment. CONCLUSIONS: Dacomitinib was well tolerated and had antitumor activity in Korean patients with NSCLC who had previously progressed on chemotherapy and an epidermal growth factor receptor tyrosine kinase inhibitor. PMID- 25521399 TI - Impact of non-small-cell lung cancer-not otherwise specified immunophenotyping on treatment outcome. AB - INTRODUCTION: The vast majority of non-small-cell lung cancers (NSCLCs) presents as advanced disease, and histological diagnosis is widely based on small samples. The differential activity and toxicity profile of new cytotoxic and molecular targeted therapies according to histotypes requires a precise subtyping of NSCLC. Immunohistochemistry (IHC) contributes to define the most probable histotype; however, the real impact of IHC characterization of NSCLC-not otherwise specified (NOS) in terms of outcome is not well established. METHODS: A large series of 224 advanced "nonsquamous" NSCLC diagnosed on small biopsy or cytological samples and homogeneously treated was retrospectively selected, all having adequate follow-up data available. Reviewed diagnoses resulted into two groups: adenocarcinoma (ADC) and NSCLC-NOS. The latter was further characterized by IHC (TTF-1, Napsin-A, p40, and Desmocollin-3) -identify a possible, most probable differentiation lineage. RESULTS: Sixty-seven percentage of cases were classified as ADC based on morphological examination only ("morphological ADC") and 33% as NSCLC-NOS. IHC profiling of NSCLC-NOS identified 43.2% of cases with an ADC immunophenotype ("NSCLC favor ADC"), 10.8% with a phenotype favoring squamous lineage, and 46% lacking differentiation features. Survival curves confirmed no difference in terms of outcome between the morphological ADC and the NSCLC favor ADC groups, while a significantly poorer outcome was found in the "null" group in terms of best response, progression-free survival or overall survival (OS). CONCLUSION: Tumors with an IHC profile ADC-like had an OS comparable with that of morphological ADCs. These findings support the use of IHC to optimize lung cancer histological typing and therapy. PMID- 25521400 TI - Prospective exploratory analysis of cardiac biomarkers and electrocardiogram abnormalities in patients receiving thoracic radiation therapy with high-dose heart exposure. AB - INTRODUCTION: Acute effects of incidental cardiac irradiation in patients treated for thoracic cancer are not well characterized. We evaluated longitudinal changes in cardiac biomarkers for patients undergoing conformal radiation therapy (RT) with thoracic malignancies with high-dose cardiac exposure. METHODS: Twenty-five patients enrolled in a prospective trial (February 2009-December 2012) received more than or equal to 45 Gy to the thorax, with pretreatment estimates of more than or equal to 20 Gy to the heart. Chemotherapy was allowed except for doxorubicin or fluorouracil. Electrocardiographic (ECG), troponin-I (TnI), and brain natriuretic peptide (BNP) measurements were obtained before RT, within 24 hours of the first fraction, at the end of RT, and at first follow-up (1-2 months). These biomarkers were quantified at specific times and changes from baseline were evaluated with paired t tests. RESULTS: The median heart dose was 25.9 Gy (range 10.1-35.1 Gy). After the first RT fraction, no changes were noted in ECG or median TnI or BNP levels; at the end of RT, two patients had elevated TnI and BNP, but neither difference was statistically significant. At first follow-up, TnI had returned to normal but the median BNP remained elevated (p = 0.042). BNP did not increase over time in the 18 patients who received only RT. Twelve patients experienced acute ECG changes during RT, which resolved in seven patients by the next measurement. No patients experienced clinically significant RT-related events. CONCLUSION: Increases in BNP and ECG changes were observed during high doses of radiation to the heart. The findings of this pilot study warrant further investigation and validation. PMID- 25521401 TI - Serum thymidine kinase 1 activity in the prognosis and monitoring of chemotherapy in lung cancer patients: a brief report. AB - INTRODUCTION: Thymidine kinase 1 (TK1) is a metabolic enzyme involved in DNA synthesis. Most standard treatment protocols for lung cancer (LC) include cytotoxic agents, which are potential modulators of TK1. We aimed to assess the prognostic significance of serum TK1 activity and its role in monitoring chemotherapy in LC patients. METHODS: TK1 activity was measured using the DiviTum (Biovica) assay in sera from 233 patients with non-small-cell lung cancer (NSCLC), 91 with small-cell lung cancer (SCLC), and 90 with benign lung disease. RESULTS: TK1 activity was significantly associated with age, performance status, and stage in NSCLC and with stage and weight loss in SCLC. In multivariate analysis, pretreatment TK1 activity, adjusted for performance status, stage, and weight loss, independently affected survival in NSCLC (relative risk =1.45, p = 0.031) and SCLC (relative risk = 2.49, p = 0.001). In NSCLC patients, adjusted elevated TK1 activity (>100 Du/L) at pretreatment was a significant predictor of treatment failure (odds ratio = 2.55, p = 0.01). A small (less than twofold) increase in TK1 activity after the first and second cycle of chemotherapy was significantly associated with treatment failure and poor overall survival. CONCLUSIONS: Elevated pretreatment serum TK1 activity was an independent, adverse prognostic factor, based on survival, in the two main histological types of LC. A small (less than twofold) increase in TK1 activity after the first and second cycle of chemotherapy was associated with treatment failure and poor overall survival. PMID- 25521402 TI - Development of the international thymic malignancy interest group international database: an unprecedented resource for the study of a rare group of tumors. AB - BACKGROUND: Our knowledge of thymic malignancies has largely been derived from small, single-institution series. Recognition of the need for broad collaboration led to the creation of the International Thymic Malignancy Interest Group (ITMIG) and the development of a large, centralized database to advance knowledge of these rare tumors. METHODS: A multidisciplinary Database Committee was convened to define a common set of data elements a priori. Retrospective data were solicited from ITMIG members and collated using standardized fields. Patients with thymoma, thymic carcinoma, or thymic carcinoid were included. RESULTS: Over a 6-month period, 47 institutions spanning 15 countries contributed a total of 6097 cases (mean, 129 [range, 10-1209]). The sex distribution was equal for thymomas, but there was a greater proportion of men with thymic carcinoma and thymic carcinoid (p < 0.0001). Nearly all cases (99%) were treated surgically. WHO type B2 was the most frequent histologic classification among thymomas, whereas squamous was the most common among thymic carcinomas. In total, 38% of patients with thymoma had myasthenia gravis compared with less than or equal to 5% for thymic carcinoma and thymic carcinoid. Median overall survival was 18.9 years (95% confidence interval [CI], 17.4-20.3) for thymoma, 6.8 years (95% CI, 5.5-7.9) for thymic carcinoma, and 7.5 years (95% CI, 6.5-8.5) for thymic carcinoid. CONCLUSIONS: The rapid creation of the ITMIG database demonstrates the feasibility of international collaboration for this rare set of malignancies and attests to the engagement of its membership. This database represents the largest collective data set ever assembled and provides an unprecedented resource for research of these tumors. PMID- 25521403 TI - Bronchoscopic delivery of lipiodol as a fiducial marker in lung tumors before radiotherapy. AB - Definitive radiotherapy treatment of thoracic tumors may be hampered by poor tumor visualization on radiological imaging and the effects of tumor motion. Fiducial markers act to enhance tumor visualization and tracking. Traditional solid fiducial markers, however, may result in complications, particularly in proximal lung lesions. These complications may be mitigated through the use of a liquid fiducial marker. This article presents four cases which demonstrate the feasibility of bronchoscopic delivery of lipiodol as a fiducial marker, to aid in guided radiotherapy for certain lung tumors. PMID- 25521404 TI - Iris metastasis from small-cell lung cancer. PMID- 25521405 TI - Clinical and in vivo evidence that EGFR S768I mutant lung adenocarcinomas are sensitive to erlotinib. PMID- 25521406 TI - Rare EGFR exon 20 S768I mutation predicts resistance to targeted therapy: a report of two cases. PMID- 25521407 TI - Elderly former smoker with HRAS mutant non-small-cell lung cancer. PMID- 25521408 TI - Two cases of non-small-cell lung cancer with rare complex mutation of EGFR exon 18 but different response to targeted therapy. PMID- 25521409 TI - Size matters in the water uptake and hygroscopic growth of atmospherically relevant multicomponent aerosol particles. AB - Understanding the interactions of water with atmospheric aerosols is crucial for determining the size, physical state, reactivity, and climate impacts of this important component of the Earth's atmosphere. Here we show that water uptake and hygroscopic growth of multicomponent, atmospherically relevant particles can be size dependent when comparing 100 nm versus ca. 6 MUm sized particles. It was determined that particles composed of ammonium sulfate with succinic acid and of a mixture of chlorides typical of the marine environment show size-dependent hygroscopic behavior. Microscopic analysis of the distribution of components within the aerosol particles show that the size dependence is due to differences in the mixing state, that is, whether particles are homogeneously mixed or phase separated, for different sized particles. This morphology-dependent hygroscopicity has consequences for heterogeneous atmospheric chemistry as well as aerosol interactions with electromagnetic radiation and clouds. PMID- 25521411 TI - In silico analysis and experimental validation of active compounds from fructus Schisandrae chinensis in protection from hepatic injury. AB - OBJECTIVES: The aim of this study was to explore mechanisms by which fructus Schisandrae chinensis (Wuweizi) is able to reveal its protective capacity against hepatocyte injury. MATERIALS AND METHODS: Identification of candidate small molecular compounds was performed by text-mining, extraction and isolation, reverse-docking, network construction, molecular docking and molecular dynamics (MD) simulation. In vitro cytological examination and western blotting were used to validate efficacy of selected compounds. RESULTS: We analyzed chemical composition of fructus Schisandrae chinensis and constructed protein-protein networks of key targets. Networks of miRNA-protein were constructed. Molecular docking and MD simulation results supported good interaction between selected compound 11/12 and GBA3/SHBG. Further in vitro examination divulged molecular mechanisms involved. CONCLUSIONS: In silico analysis and experimental validation together demonstrated that compound 11/12 of fructus Schisandrae chinensis targetted GBA3/SHBG in hepatocytes. Hopefully this will shed light on exploration of its complex molecular mechanisms. PMID- 25521410 TI - Asymmetric syntheses of three-membered heterocycles using chiral amide-based ammonium ylides. AB - The use of carbonyl-stabilised ammonium ylides to access chiral glycidic amides and the corresponding aziridines has so far been limited to racemic trans selective protocols. We herein report the development of an asymmetric approach to access such compounds with high levels of stereoselectivity using easily accessible chiral auxiliary-based ammonium ylides. The use of phenylglycinol as the chiral auxiliary was found to be superior to Evans or pseudoephedrine-based auxiliaries resulting in good to excellent stereoselectivities in both, epoxidation and aziridination reactions. PMID- 25521412 TI - Translocation and biotransformation of CuO nanoparticles in rice (Oryza sativa L.) plants. AB - Metal-based nanoparticles (MNPs) may be translocated and biochemically modified in vivo, which may influence the fate of MNPs in the environment. Here, synchrotron-based techniques were used to investigate the behavior of CuO NPs in rice plants exposed to 100 mg/L CuO NPs for 14 days. Micro X-ray fluorescence (MU XRF) and micro X-ray absorption near edge structure (MU-XANES) analysis revealed that CuO NPs moved into the root epidermis, exodermis, and cortex, and they ultimately reached the endodermis but could not easily pass the Casparian strip; however, the formation of lateral roots provided a potential pathway for MNPs to enter the stele. Moreover, bulk-XANES data showed that CuO NPs were transported from the roots to the leaves, and that Cu (II) combined with cysteine, citrate, and phosphate ligands and was even reduced to Cu (I). CuO NPs and Cu-citrate were observed in the root cells using soft X-ray scanning transmission microscopy (STXM). PMID- 25521413 TI - Uptake and transformation of arsenic during the vegetative life stage of terrestrial fungi. AB - Many species of terrestrial fungi produce fruiting bodies that contain high proportions of arsenobetaine (AB), an arsenic compound of no known toxicity. It is unknown whether fungi produce or accumulate AB from the surrounding environment. The present study targets the vegetative life stage (mycelium) of fungi, to examine the role of this stage in arsenic transformations and potential formation of AB. The mycelia of three different fungi species were cultured axenically and exposed to AB, arsenate (As(V)) and dimethylarsinoyl acetic acid for 60 days. Agaricus bisporus was additionally exposed to hypothesized precursors for AB and the exposure time to As(V) and dimethlyarsinic acid was also extended to 120 days. The mycelia of all fungi species accumulated all arsenic compounds with two species accumulating significantly more AB than other compounds. Few biotransformations were observed in these experiments indicating that it is unlikely that the mycelium of the fungus is responsible for biosynthesizing AB. PMID- 25521414 TI - Ectomycorrhizal colonization and growth of the hybrid larch F1 under elevated CO2 and O3. AB - We studied the colonization of ectomycorrhizal fungi and species abundance of a hybrid larch (F1) under elevated CO2 and O3. Two-year-old seedlings were planted in an Open-Top-Chamber system with treatments: Control (O3 < 6 nmol/mol), O3 (60 nmol/mol), CO2 (600 MUmol/mol), and CO2 + O3. After two growing seasons, ectomycorrhiza (ECM) colonization and root biomass increased under elevated CO2. Additionally, O3 impaired ECM colonization and species richness, and reduced stem biomass. However, there was no clear inhibition of photosynthetic capacity by O3. Concentrations of Al, Fe, Mo, and P in needles were reduced by O3, while K and Mg in the roots increased. This might explain the distinct change in ECM colonization rate and diversity. No effects of combined fumigation were observed in any parameters except the P concentration in needles. The tolerance of F1 to O3 might potentially be related to a shift in ECM community structure. PMID- 25521415 TI - Microbial community pattern detection in human body habitats via ensemble clustering framework. AB - BACKGROUND: The human habitat is a host where microbial species evolve, function, and continue to evolve. Elucidating how microbial communities respond to human habitats is a fundamental and critical task, as establishing baselines of human microbiome is essential in understanding its role in human disease and health. Recent studies on healthy human microbiome focus on particular body habitats, assuming that microbiome develop similar structural patterns to perform similar ecosystem function under same environmental conditions. However, current studies usually overlook a complex and interconnected landscape of human microbiome and limit the ability in particular body habitats with learning models of specific criterion. Therefore, these methods could not capture the real-world underlying microbial patterns effectively. RESULTS: To obtain a comprehensive view, we propose a novel ensemble clustering framework to mine the structure of microbial community pattern on large-scale metagenomic data. Particularly, we first build a microbial similarity network via integrating 1920 metagenomic samples from three body habitats of healthy adults. Then a novel symmetric Nonnegative Matrix Factorization (NMF) based ensemble model is proposed and applied onto the network to detect clustering pattern. Extensive experiments are conducted to evaluate the effectiveness of our model on deriving microbial community with respect to body habitat and host gender. From clustering results, we observed that body habitat exhibits a strong bound but non-unique microbial structural pattern. Meanwhile, human microbiome reveals different degree of structural variations over body habitat and host gender. CONCLUSIONS: In summary, our ensemble clustering framework could efficiently explore integrated clustering results to accurately identify microbial communities, and provide a comprehensive view for a set of microbial communities. The clustering results indicate that structure of human microbiome is varied systematically across body habitats and host genders. Such trends depict an integrated biography of microbial communities, which offer a new insight towards uncovering pathogenic model of human microbiome. PMID- 25521416 TI - Fabrication of gold nanorods with tunable longitudinal surface plasmon resonance peaks by reductive dopamine. AB - Hydroxyphenol compounds are often used as reductants in controlling the growth of nanoparticles. Herein, dopamine was used as an effective reductant in seed mediated synthesis of gold nanorods (GNRs). The as-prepared GNRs (83 * 16 nm) were monodisperse and had a high degree of purity. The conversion ratio from gold ions to GNRs was around 80%. In addition, dopamine worked as an additive. At a very low concentration of hexadecyltrimethylammonium bromide (CTAB; 0.025 M), thinner and shorter GNRs (60 * 9 nm) were successfully prepared. By regulating the concentration of silver ions, CTAB, seeds, and reductant, GNRs with longitudinal surface plasmon resonance (LSPR) peaks ranging from 680 to 1030 nm were synthesized. The growth process was tracked using UV-vis-NIR spectroscopy, and it was found that a slow growth rate was beneficial to the formation of GNRs. PMID- 25521417 TI - Topological Crystalline Insulator Pb1-x Snx Se Nanowires with {100} Facets. AB - Surface states properties of topological crystalline insulator Pb1-x Snx Se are strongly dependent on crystallographic plane orientation. Rectangular prismatic Pbx Sn1-x Se nanowires and nanoplates are grown with distinct {100} surfaces on mica sheets. Substrate surface chemical properties are found to be the critical factors that affect the vapor deposition process and final shapes of Pb1-x Snx Se nanostructures. PMID- 25521418 TI - Inter- and intrarater reliability of the Chicago Classification in pediatric high resolution esophageal manometry recordings. AB - BACKGROUND: The Chicago Classification (CC) facilitates interpretation of high resolution manometry (HRM) recordings. Application of this adult based algorithm to the pediatric population is unknown. We therefore assessed intra and interrater reliability of software-based CC diagnosis in a pediatric cohort. METHODS: Thirty pediatric solid state HRM recordings (13M; mean age 12.1 +/- 5.1 years) assessing 10 liquid swallows per patient were analyzed twice by 11 raters (six experts, five non-experts). Software-placed anatomical landmarks required manual adjustment or removal. Integrated relaxation pressure (IRP4s), distal contractile integral (DCI), contractile front velocity (CFV), distal latency (DL) and break size (BS), and an overall CC diagnosis were software-generated. In addition, raters provided their subjective CC diagnosis. Reliability was calculated with Cohen's and Fleiss' kappa (kappa) and intraclass correlation coefficient (ICC). KEY RESULTS: Intra- and interrater reliability of software generated CC diagnosis after manual adjustment of landmarks was substantial (mean kappa = 0.69 and 0.77 respectively) and moderate-substantial for subjective CC diagnosis (mean kappa = 0.70 and 0.58 respectively). Reliability of both software generated and subjective diagnosis of normal motility was high (kappa = 0.81 and kappa = 0.79). Intra- and interrater reliability were excellent for IRP4s, DCI, and BS. Experts had higher interrater reliability than non-experts for DL (ICC = 0.65 vs ICC = 0.36 respectively) and the software-generated diagnosis diffuse esophageal spasm (DES, kappa = 0.64 vs kappa = 0.30). Among experts, the reliability for the subjective diagnosis of achalasia and esophageal gastric junction outflow obstruction was moderate-substantial (kappa = 0.45-0.82). CONCLUSIONS & INFERENCES: Inter- and intrarater reliability of software-based CC diagnosis of pediatric HRM recordings was high overall. However, experience was a factor influencing the diagnosis of some motility disorders, particularly DES and achalasia. PMID- 25521419 TI - Co-micellization behavior in poloxamers: dissipative particle dynamics study. AB - Dissipative particle dynamics simulations are applied to investigate co micellization behavior for binary mixtures of Poloxamers in dilute aqueous solution. In view of block length similarity/dissimilarity, four representative mixture cases are considered: F127/P123, F127/P105, P123/P84, and F127/L64. With appropriate interaction parameters, the simulations enable us to examine the formation of micelles, their types, size, shape, and composition. In the investigated concentration range, we find that pure and mixed micelles, both ellipsoidal, always coexist for all cases. At similar concentrations, both species form pure micelles of their own together with mixed micelles. In the case of F127/L64, it is found that the L64 chains are involved in the mixed micelles, even when the L64 concentration is below its CMC. The fraction of L64 involved in the mixed micelles is lower as compared to the other systems studied. For all cases, the proportion of mixed micelles can be increased when the two polymer species have similar concentrations. Moreover, shorter chains may prefer to straddle the core and corona in the region of ellipsoidal interface that is closer to the center of mixed micelle. PMID- 25521421 TI - Journal of Fish Diseases. Editorial. PMID- 25521422 TI - Spatial extended hazard model with application to prostate cancer survival. AB - This article develops a Bayesian semiparametric approach to the extended hazard model, with generalization to high-dimensional spatially grouped data. County level spatial correlation is accommodated marginally through the normal transformation model of Li and Lin (2006, Journal of the American Statistical Association 101, 591-603), using a correlation structure implied by an intrinsic conditionally autoregressive prior. Efficient Markov chain Monte Carlo algorithms are developed, especially applicable to fitting very large, highly censored areal survival data sets. Per-variable tests for proportional hazards, accelerated failure time, and accelerated hazards are efficiently carried out with and without spatial correlation through Bayes factors. The resulting reduced, interpretable spatial models can fit significantly better than a standard additive Cox model with spatial frailties. PMID- 25521420 TI - Distributions of vesicular glutamate transporters 1 and 2 in the visual system of tree shrews (Tupaia belangeri). AB - Vesicular glutamate transporter (VGLUT) proteins regulate the storage and release of glutamate from synapses of excitatory neurons. Two isoforms, VGLUT1 and VGLUT2, are found in most glutamatergic projections across the mammalian visual system, and appear to differentially identify subsets of excitatory projections between visual structures. To expand current knowledge on the distribution of VGLUT isoforms in highly visual mammals, we examined the mRNA and protein expression patterns of VGLUT1 and VGLUT2 in the lateral geniculate nucleus (LGN), superior colliculus, pulvinar complex, and primary visual cortex (V1) in tree shrews (Tupaia belangeri), which are closely related to primates but classified as a separate order (Scandentia). We found that VGLUT1 was distributed in intrinsic and corticothalamic connections, whereas VGLUT2 was predominantly distributed in subcortical and thalamocortical connections. VGLUT1 and VGLUT2 were coexpressed in the LGN and in the pulvinar complex, as well as in restricted layers of V1, suggesting a greater heterogeneity in the range of efferent glutamatergic projections from these structures. These findings provide further evidence that VGLUT1 and VGLUT2 identify distinct populations of excitatory neurons in visual brain structures across mammals. Observed variations in individual projections may highlight the evolution of these connections through the mammalian lineage. PMID- 25521423 TI - NMR studies of active-site properties of human carbonic anhydrase II by using (15) N-labeled 4-methylimidazole as a local probe and histidine hydrogen-bond correlations. AB - By using a combination of liquid and solid-state NMR spectroscopy, (15) N-labeled 4-methylimidazole (4-MI) as a local probe of the environment has been studied: 1) in the polar, wet Freon CDF3 /CDF2 Cl down to 130 K, 2) in water at pH 12, and 3) in solid samples of the mutant H64A of human carbonic anhydrase II (HCA II). In the latter, the active-site His64 residue is replaced by alanine; the catalytic activity is, however, rescued by the presence of 4-MI. For the Freon solution, it is demonstrated that addition of water molecules not only catalyzes proton tautomerism but also lifts its quasidegeneracy. The possible hydrogen-bond clusters formed and the mechanism of the tautomerism are discussed. Information about the imidazole hydrogen-bond geometries is obtained by establishing a correlation between published (1) H and (15) N chemical shifts of the imidazole rings of histidines in proteins. This correlation is useful to distinguish histidines embedded in the interior of proteins and those at the surface, embedded in water. Moreover, evidence is obtained that the hydrogen-bond geometries of His64 in the active site of HCA II and of 4-MI in H64A HCA II are similar. Finally, the degeneracy of the rapid tautomerism of the neutral imidazole ring His64 reported by Shimahara et al. (J. Biol. Chem.- 2007, 282, 9646) can be explained with a wet, polar, nonaqueous active-site conformation in the inward conformation, similar to the properties of 4-MI in the Freon solution. The biological implications for the enzyme mechanism are discussed. PMID- 25521424 TI - Relationships among structural empowerment, psychological empowerment, intent to stay and burnout in nursing field in mainland China-based on a cross-sectional questionnaire research. AB - The aim of the study was to explore the relationship among perceived structural empowerment, psychological empowerment, burnout and intent to stay by nurses in mainland China.With the shortage of nurses in many countries, including China, intent to stay is a dominant factor to influence the quality of care. Also, burnout is identified to negatively affect the quality of care. Empowered clinical nurse practical environment is related to intent to stay and burnout. In the current literature, there is a lack of data based on empowering environment discussing the relationship between burnout and intent to stay. The study used an anonymous questionnaire, filled voluntarily by 219 nurses from different sections in a city in mainland China, 2012.Structural equation modelling (SEM) was used to test the proposed hypotheses. Based on the SEM model, structural empowerment and psychological empowerment had significant positive effects on intent to stay of nurses and negative effects on burnout. Burnout had a significant negative effect on intent to stay. The final modified models yielded chi(2) = 58.580, P > 0.05, chi(2) /df = 1.046, root mean square error of approximation = 0.015, Tucker-Lewis Index = 0.996, comparative fit index = 0.998,which indicated good fit indices. Creating a positive empowering workplace can encourage nurses to stay long and prevent burnout. Therefore, higher level of empowering environment is required. PMID- 25521425 TI - Verification and classification bias interactions in diagnostic test accuracy studies for fine-needle aspiration biopsy. AB - BACKGROUND: Reliable estimates of accuracy are important for any diagnostic test. Diagnostic accuracy studies are subject to unique sources of bias. Verification bias and classification bias are 2 sources of bias that commonly occur in diagnostic accuracy studies. Statistical methods are available to estimate the impact of these sources of bias when they occur alone. The impact of interactions when these types of bias occur together has not been investigated. METHODS: We developed mathematical relationships to show the combined effect of verification bias and classification bias. A wide range of case scenarios were generated to assess the impact of bias components and interactions on total bias. RESULTS: Interactions between verification bias and classification bias caused overestimation of sensitivity and underestimation of specificity. Interactions had more effect on sensitivity than specificity. Sensitivity was overestimated by at least 7% in approximately 6% of the tested scenarios. Specificity was underestimated by at least 7% in less than 0.1% of the scenarios. CONCLUSIONS: Interactions between verification bias and classification bias create distortions in accuracy estimates that are greater than would be predicted from each source of bias acting independently. PMID- 25521426 TI - Application of 2-substituted benzyl groups in stereoselective glycosylation. AB - The use of 2-O-(2-nitrobenzyl) and 2-O-(2-cyanobenzyl) groups controls stereoselective formation of 1,2-trans-glycosidic linkages via the arming participation effect. The observed stereoselectivity likely arises from the intramolecular formation of cyclic intermediate between the electron-rich substituent and the donor oxacarbenium ion providing the expected facial selectivity for attack of the glycoside acceptor. The stereodirecting effect of the 2-nitro- and 2-cyanobenzyl groups attached at the remote position (C-3, C-4, and C-6) of the donor molecule have also been investigated. To prove the postulated mechanism based on the participation effect of 2-substituted benzyl groups in the glycosylation stereoselectivity we used DFT theoretical calculation methodology. PMID- 25521427 TI - In vivo cross-sectional imaging of a degrading dexamethasone intravitreal implant that became attached to the macula. PMID- 25521428 TI - Secular trends of obesity prevalence in Chinese children from 1985 to 2010: Urban rural disparity. AB - OBJECTIVE: To examine the trend of urban-rural disparity in obesity prevalence among Chinese children from 1985 to 2010. METHODS: The data were from five cross sectional surveys (1985, 1995, 2000, 2005, and 2010) of Chinese National Surveys on Students' Constitution and Health. Logistic regression was used to estimate the prevalence odds ratio (POR) of urban-rural areas for obesity prevalence in different surveys. RESULTS: The standardized prevalence of obesity in Chinese children increased rapidly from 0.1% in 1985 to 5.0% in 2010, and significant differences were found between two adjacent surveys in most of the age subgroups (P<0.01). Although the obesity prevalence was significantly higher in urban than in rural children of all age subgroups at different survey points, the changing pace was faster in rural than in urban areas from 1995 to 2010. The PORs had increased in 1995 in most age subgroups and then began to decline in all age subgroups after 1995. CONCLUSIONS: The gradually decreasing urban-rural disparity suggests that the obesity prevalence in rural areas would contribute to a growing proportion of obese children. Therefore, rural children should be included in obesity prevention efforts even though obesity rates are still lower in rural than in urban areas. PMID- 25521430 TI - Interactions between muscle tissues and bone metabolism. AB - Sarcopenia and osteoporosis have recently been noted for their relationship with locomotive syndrome and increased number of older people. Sarcopenia is defined by decreased muscle mass and impaired muscle function, which may be associated with frailty. Several clinical data have indicated that increased muscle mass is related to increased bone mass and reduced fracture risk. Genetic, endocrine and mechanical factors as well as inflammatory and nutritional states concurrently affect muscle tissues and bone metabolism. Several genes, including myostatin and alpha-actinin 3, have been shown in a genome-wide association study (GWAS) to be associated with both sarcopenia and osteoporosis. Vitamin D, growth hormone and testosterone as well as pathological disorders, such as an excess in glucocorticoid and diabetes, affect both muscle and bone. Basic and clinical research of bone metabolism and muscle biology suggests that bone interacts with skeletal muscle via signaling from local and humoral factors in addition to their musculoskeletal function. However, the physiological and pathological mechanisms related to muscle and bone interactions remain unclear. We found that Tmem119 may play a critical role in the commitment of myoprogenitor cells to the osteoblast lineage. We also reported that osteoglycin and FAM5C might be muscle-derived humoral osteogenic factors. Other factors, including myostatin, osteonectin, insulin-like growth factor I, irisin and osteocalcin, may be associated with the interactions between muscle tissues and bone metabolism. PMID- 25521429 TI - Structural apelin analogues: mitochondrial ROS inhibition and cardiometabolic protection in myocardial ischaemia reperfusion injury. AB - BACKGROUND AND PURPOSE: Mitochondria-derived oxidative stress is believed to be crucially involved in cardiac ischaemia reperfusion (I/R) injury, although currently no therapies exist that specifically target mitochondrial reactive oxygen species (ROS) production. The present study was designed to evaluate the potential effects of the structural analogues of apelin-12, an adipocyte-derived peptide, on mitochondrial ROS generation, cardiomyocyte apoptosis, and metabolic and functional recovery to myocardial I/R injury. EXPERIMENTAL APPROACH: In cultured H9C2 cardiomyoblasts and adult cardiomyocytes, oxidative stress was induced by hypoxia reoxygenation. Isolated rat hearts were subjected to 35 min of global ischaemia and 30 min of reperfusion. Apelin-12, apelin-13 and structural apelin-12 analogues, AI and AII, were infused during 5 min prior to ischaemia. KEY RESULTS: In cardiac cells, mitochondrial ROS production was inhibited by the structural analogues of apelin, AI and AII, in comparison with the natural peptides, apelin-12 and apelin-13. Treatment of cardiomyocytes with AI and AII decreased cell apoptosis concentration-dependently. In a rat model of I/R injury, pre-ischaemic infusion of AI and AII markedly reduced ROS formation in the myocardial effluent and attenuated cell membrane damage. Prevention of oxidative damage by AI and AII was associated with the improvement of functional and metabolic recovery after I/R in the heart. CONCLUSIONS AND IMPLICATIONS: These data provide the evidence for the potential of the structural apelin analogues in selective reduction of mitochondrial ROS generation and myocardial apoptosis and form the basis for a promising therapeutic strategy in the treatment of oxidative stress-related heart disease. PMID- 25521431 TI - Incidence and long-term survival of patients with de novo head and neck carcinoma after liver transplantation. AB - BACKGROUND: Liver transplant recipients have an increased risk of developing de novo malignancies. METHODS: We conducted a prospective evaluation of clinicopathological data and predictors for overall survival (OS) in patients with head and neck squamous cell carcinoma (HNSCC) after liver transplantation (1988 to 2010). RESULTS: Thirty-three of 2040 patients who underwent liver transplantation (1.6%) developed de novo HNSCC. The incidence of HNSCC in liver transplant recipients with end-stage alcoholic liver disease (26) was 5%. After a median follow-up of 9 years, 1-year, 3-year, and 5-year OS rates were 74%, 47%, and 34%, respectively. Tumor size, cervical lymph node metastases, tumor site, and therapy (surgery only vs surgery and adjuvant radiotherapy [RT]/chemoradiotherapy [CRT] vs RT/CRT only; p < .0001) were significantly associated with OS in univariate analysis. However, surgery only predicted OS independently in multivariate analysis. CONCLUSION: Early diagnosis and surgical treatment of de novo HNSCC are crucial to the outcome. HNSCC risk should be taken into close consideration during posttransplantation follow-up examinations, especially among patients with a positive history of smoking and alcohol consumption. PMID- 25521432 TI - Paediatric acute lymphoblastic leukaemia mimicking Langerhans cell histiocytosis of bone. PMID- 25521433 TI - CCRL1/ACKR4 is expressed in key thymic microenvironments but is dispensable for T lymphopoiesis at steady state in adult mice. AB - Thymus colonisation and thymocyte positioning are regulated by interactions between CCR7 and CCR9, and their respective ligands, CCL19/CCL21 and CCL25. The ligands of CCR7 and CCR9 also interact with the atypical receptor CCRL1 (also known as ACKR4), which is expressed in the thymus and has recently been reported to play an important role in normal alphabetaT-cell development. Here, we show that CCRL1 is expressed within the thymic cortex, predominantly by MHC-II(low) CD40(-) cortical thymic epithelial cells and at the subcapsular zone by a population of podoplanin(+) thymic epithelial cells in mice. Interestingly, CCRL1 is also expressed by stromal cells which surround the pericytes of vessels at the corticomedullary junction, the site for progenitor cell entry and mature thymocyte egress from the thymus. We show that CCRL1 suppresses thymocyte progenitor entry into the thymus, however, the thymus size and cellularity are the same in adult WT and CCRL1(-/-) mice. Moreover, CCRL1(-/-) mice have no major perturbations in T-cell populations at different stages of thymic differentiation and development, and have a similar rate of thymocyte migration into the blood. Collectively, our findings argue against a major role for CCRL1 in normal thymus development and function. PMID- 25521434 TI - N400 brain responses to spoken phrases paired with photographs of scenes: implications for visual scene displays in AAC systems. AB - Augmentative and alternative communication (AAC) systems are often implemented for individuals whose speech cannot meet their full communication needs. One type of aided display is called a Visual Scene Display (VSD). VSDs consist of integrated scenes (such as photographs) in which language concepts are embedded. Often, the representations of concepts on VSDs are perceptually similar to their referents. Given this physical resemblance, one may ask how well VSDs support development of symbolic functioning. We used brain imaging techniques to examine whether matches and mismatches between the content of spoken messages and photographic images of scenes evoke neural activity similar to activity that occurs to spoken or written words. Electroencephalography (EEG) was recorded from 15 college students who were shown photographs paired with spoken phrases that were either matched or mismatched to the concepts embedded within each photograph. Of interest was the N400 component, a negative deflecting wave 400 ms post-stimulus that is considered to be an index of semantic functioning. An N400 response in the mismatched condition (but not the matched) would replicate brain responses to traditional linguistic symbols. An N400 was found, exclusively in the mismatched condition, suggesting that mismatches between spoken messages and VSD-type representations set the stage for the N400 in ways similar to traditional linguistic symbols. PMID- 25521435 TI - Changes in total and central adiposity and body fat distribution among 7-10-year old schoolchildren in Brazil. AB - OBJECTIVE: To describe changes in total and central adiposity and body fat distribution in children over a 5-year period by investigating variations in BMI, waist circumference (WC), waist-to-height ratio (WHtR) and skinfold thicknesses (SFT). DESIGN: A school-based sample of children from 2nd to 5th grades of elementary schools participated in two cross-sectional studies in 2002 (n 2936) and 2007 (n 1232). SETTING: Public and private schools of Florianopolis, Brazil. SUBJECTS: Schoolchildren aged 7-10 years had their weight, height, WC and SFT measured according to standard procedures. Body fat distribution was assessed by triceps, subscapular, suprailiac and medial calf skinfold measurements. Changes in BMI, WC, WHtR and SFT were analysed, adjusting for type of school and monthly family income. RESULTS: Adjusted mean differences between 2002 and 2007 for BMI and WC were always positive and of similar magnitude between boys and girls. However, a statistically significant increase was observed only for BMI (raw and Z-score values) in boys. WHtR remained stable in both sexes. Adjusted median values for SFT also increased in boys and girls, except for triceps skinfold. BMI, WC and SFT tended to increase across age classes in both sexes. The relative change observed for the median central skinfolds (subscapular and suprailiac) was greater than that of peripheral skinfolds (triceps and medial calf). CONCLUSIONS: The subcutaneous adipose tissue (SFT) appeared to increase at a faster rate than total adiposity (BMI). The increase in central SFT indicates that the relative change is due primarily to a rise in central adiposity. PMID- 25521436 TI - Taylor dispersion in equilibrium gradient focusing at steady state. AB - An analytic expression is presented for the effective dispersion coefficient in the case where a solute is focused in a parabolic flow against a linear gradient in a restoring force. This expression was derived by employing a minor variation on the method of moments used by Aris in his development of the dispersion coefficients for a time-dependent, isocratic system. In the present case, dispersion is controlled by two dimensionless groups, a Peclet number which is proportional to the parabolic component of the flow, and a gradient number which is proportional to the slope of the restoring force. These results confirm that the Aris-Taylor expression for the dispersion coefficient should not be applied in cases where a solute is focused to a stationary steady state. PMID- 25521438 TI - Colorectal Cancer Screening and State Health Insurance Mandates. AB - Colorectal cancer (CRC) is the third most deadly cancer in the USA. CRC screening is the most effective way to prevent CRC death, but compliance with recommended screenings is very low. In this study, we investigate whether CRC screening behavior changed under state mandated private insurance coverage of CRC screening in a sample of insured adults from the 1997 to 2008 Behavioral Risk Factor Surveillance Survey (BRFSS). We present difference-in-difference-in-differences (DDD) estimates that compare insured individuals age 51 to 64 to Medicare age eligible individuals (ages 66 to 75) in mandate and non-mandate states over time. Our DDD estimates suggest endoscopic screening among men increased by 2 to 3 percentage points under mandated coverage among 51 to 64 year olds relative to their Medicare age-eligible counterparts. We find no clear evidence of changes in screening behavior among women. DD estimates suggest no evidence of a mandate effect on either type of CRC screening for men or women. PMID- 25521437 TI - Escherichia coli-induced immune paralysis is not exacerbated during chronic filarial infection. AB - Sepsis initially starts with a systemic inflammatory response (SIRS phase) and is followed by a compensatory anti-inflammatory response syndrome (CARS) that causes impaired adaptive T-cell immunity, immune paralysis and an increased susceptibility to secondary infections. In contrast, parasitic filariae release thousands of microfilariae into the peripheral blood without triggering inflammation, as they induce regulatory, anti-inflammatory host responses. Hence, we investigated the impact of chronic filarial infection on adaptive T-cell responses during the SIRS and CARS phases of a systemic bacterial infection and analysed the development of T-cell paralysis following a subsequent adenovirus challenge in BALB/c mice. Chronic filarial infection impaired adenovirus-specific CD8(+) T-cell cytotoxicity and interferon-gamma responses in the absence of a bacterial challenge and led to higher numbers of splenic CTLA-4(+) CD4(+) T cells, whereas splenic T-cell expression of CD69 and CD62 ligand, serum cytokine levels and regulatory T-cell frequencies were comparable to naive controls. Irrespective of filarial infection, the SIRS phase dominated 6-24 hr after intravenous Escherichia coli challenge with increased T-cell activation and pro inflammatory cytokine production, whereas the CARS phase occurred 6 days post E. coli challenge and correlated with high levels of transforming growth factor-beta and increased CD62 ligand T-cell expression. Escherichia coli-induced impairment of adenovirus-specific CD8(+) T-cell cytotoxicity and interferon-gamma production was not additionally impaired by chronic filarial infection. This suggests that filarial immunoregulation does not exacerbate E. coli-induced T-cell paralysis. PMID- 25521439 TI - Comparing functional and morphologic characteristics of lamellar macular holes with and without lamellar hole-associated epiretinal proliferation. AB - PURPOSE: To compare the functional and morphologic characteristics and evolution of lamellar macular holes (LMHs) with and without lamellar hole-associated epiretinal proliferation (LHEP). METHODS: This was a retrospective observational case review of 145 eyes of 136 patients with LMH seen in a vitreoretinal clinical practice, and the eyes were subdivided into 2 groups based on the presence or absence of LHEP. Main outcome measures were logarithm of minimal angle of resolution (logMAR) visual acuity and morphologic characteristics as seen with spectral domain optical coherence tomography over retrospective follow-up. RESULTS: In 62 eyes (42.7%), LHEP was detected, while 83 eyes (57.3%) had the presence of epiretinal membrane without LHEP. The mean logMAR visual acuity in eyes with LHEP was 0.51 (20/65 Snellen equivalent), which was significantly poorer than that in the eyes without LHEP at 0.33 (20/43 Snellen equivalent, P = 0.002). Multivariate analysis showed that the presence of LHEP was significantly associated with larger LMH diameter at the middle retinal level (P = 0.01) and thinner retinal thickness at the base of the LMH (P < 0.001). A higher proportion of eyes with LHEP (88%) had ellipsoid disruption compared with eyes without LHEP (24%, P = 0.001). Over the mean retrospective follow-up of 26 months, 5% of eyes with LHEP had functional decline of 0.3 logMAR visual acuity compared with 4% of eyes without LHEP (P = 0.99), whereas 18% of eyes with LHEP had morphologic progression compared with 13% of eyes without LHEP (P = 0.49). CONCLUSION: Eyes with LMH and LHEP were associated with poorer visual acuity, larger LMH diameters, thinner retinal thickness, and higher incidence of ellipsoid disruption compared with eyes without LHEP, suggesting a process involving more severe retinal tissue loss and injury. Both LMH with and without LHEP seemed to be stable configurations over time. PMID- 25521440 TI - Response from the authors. PMID- 25521441 TI - IFACEwat: the interfacial water-implemented re-ranking algorithm to improve the discrimination of near native structures for protein rigid docking. AB - BACKGROUND: Protein-protein docking is an in silico method to predict the formation of protein complexes. Due to limited computational resources, the protein-protein docking approach has been developed under the assumption of rigid docking, in which one of the two protein partners remains rigid during the protein associations and water contribution is ignored or implicitly presented. Despite obtaining a number of acceptable complex predictions, it seems to-date that most initial rigid docking algorithms still find it difficult or even fail to discriminate successfully the correct predictions from the other incorrect or false positive ones. To improve the rigid docking results, re-ranking is one of the effective methods that help re-locate the correct predictions in top high ranks, discriminating them from the other incorrect ones. RESULTS: Our results showed that the IFACEwat increased both the numbers of the near-native structures and improved their ranks as compared to the initial rigid docking ZDOCK3.0.2. In fact, the IFACEwat achieved a success rate of 83.8% for Antigen/Antibody complexes, which is 10% better than ZDOCK3.0.2. As compared to another re-ranking technique ZRANK, the IFACEwat obtains success rates of 92.3% (8% better) and 90% (5% better) respectively for medium and difficult cases. When comparing with the latest published re-ranking method F2Dock, the IFACEwat performed equivalently well or even better for several Antigen/Antibody complexes. CONCLUSIONS: With the inclusion of interfacial water, the IFACEwat improves mostly results of the initial rigid docking, especially for Antigen/Antibody complexes. The improvement is achieved by explicitly taking into account the contribution of water during the protein interactions, which was ignored or not fully presented by the initial rigid docking and other re-ranking techniques. In addition, the IFACEwat maintains sufficient computational efficiency of the initial docking algorithm, yet improves the ranks as well as the number of the near native structures found. As our implementation so far targeted to improve the results of ZDOCK3.0.2, and particularly for the Antigen/Antibody complexes, it is expected in the near future that more implementations will be conducted to be applicable for other initial rigid docking algorithms. PMID- 25521442 TI - Integrated one-flow synthesis of heterocyclic thioquinazolinones through serial microreactions with two organolithium intermediates. AB - The synthesis of pharmaceutical compounds via short-lived intermediates in a microreactor is attractive, because of the fast flow and high throughput. Additionally, intermediates can be utilized sequentially to efficiently build up a library in a short time. Here we present an integrated microfluidic synthesis of biologically active thioquinazolinone libraries. Generation of o-lithiophenyl isothiocyanate and subsequent reaction with aryl isocyanate is optimized by controlling the residence time in the microreactor to 16 ms at room temperature. Various S-benzylic thioquinazolinone derivatives are synthesized within 10 s in high yields (75-98%) at room temperature. These three-step reactions involve two organolithium intermediates, an isothiocyanate-functionalized aryllithium intermediate, and a subsequent lithium thiolate intermediate. We also demonstrate the gram-scale synthesis of a multifunctionalized thioquinazolinone in the microfluidic device with a high yield (91%) and productivity (1.25 g in 5 min). PMID- 25521444 TI - The bacterial proteogenomic pipeline. AB - BACKGROUND: Proteogenomics combines the cutting-edge methods from genomics and proteomics. While it has become cheap to sequence whole genomes, the correct annotation of protein coding regions in the genome is still tedious and error prone. Mass spectrometry on the other hand relies on good characterizations of proteins derived from the genome, but can also be used to help improving the annotation of genomes or find species specific peptides. Additionally, proteomics is widely used to find evidence for differential expression of proteins under different conditions, e.g. growth conditions for bacteria. The concept of proteogenomics is not altogether new, in-house scripts are used by different labs and some special tools for eukaryotic and human analyses are available. RESULTS: The Bacterial Proteogenomic Pipeline, which is completely written in Java, alleviates the conducting of proteogenomic analyses of bacteria. From a given genome sequence, a naive six frame translation is performed and, if desired, a decoy database generated. This database is used to identify MS/MS spectra by common peptide identification algorithms. After combination of the search results and optional flagging for different experimental conditions, the results can be browsed and further inspected. In particular, for each peptide the number of identifications for each condition and the positions in the corresponding protein sequences are shown. Intermediate and final results can be exported into GFF3 format for visualization in common genome browsers. CONCLUSIONS: To facilitate proteogenomics analyses the Bacterial Proteogenomic Pipeline is a set of comprehensive tools running on common desktop computers, written in Java and thus platform independent. The pipeline allows integrating peptide identifications from various algorithms and emphasizes the visualization of spectral counts from different experimental conditions. PMID- 25521450 TI - Seizures and transient neurological deficits during epiduroscopy in a patient with failed back surgery syndrome. PMID- 25521443 TI - Merging photoredox and nickel catalysis: decarboxylative cross-coupling of carboxylic acids with vinyl halides. AB - Decarboxylative cross-coupling of alkyl carboxylic acids with vinyl halides has been accomplished through the synergistic merger of photoredox and nickel catalysis. This new methodology has been successfully applied to a variety of alpha-oxy and alpha-amino acids, as well as simple hydrocarbon-substituted acids. Diverse vinyl iodides and bromides give rise to vinylation products in high efficiency under mild, operationally simple reaction conditions. PMID- 25521451 TI - Three isostructural one-dimensional Ln(III) chains with distorted cubane motifs showing dual fluorescence and slow magnetic relaxation/magnetocaloric effect. AB - Three new homometallic lanthanide complexes with mixed carboxylate-modified rigid ligands, [Ln(MU3-OH)(na)(pyzc)]n (na(-) = 1-naphtholate, pyzc(-) = 2 pyrazinecarboxylate, Ln = Dy (1), Yb (2), and Gd (3)), were solvothermally synthesized, and their structures and magnetic as well as photophysical properties were completely investigated. Complexes 1-3 are crystallographically isostructural, exhibiting linear chains with four bidentate bridging MU-COO(-) moieties encapsulated cubic {Ln4(MU3-OH)4}(8+) clusters repeatedly extended by 4 fold chelating-bridging-pyzc(-) connectors. Magnetically, the former two complexes with highly anisotropic Dy(III) and weak anisotropic Yb(III) ions in the distorted NO7 triangular dodecahedron coordination environment display field induced slow relaxation of magnetization. Fitting the dynamic magnetic data to the Arrhenius law gives energy barrier DeltaE/kB = 39.6 K and pre-exponential factor tauo = 1.52 * 10(-8) s for 1 and DeltaE/kB = 14.1 K and tauo = 2.13 * 10( 7) s for 2. By contrast, complex 3 with isotropic Gd(III) ion and weak intracluster antiferromagnetic coupling shows a significant cryogenic magnetocaloric effect, with a maximum -DeltaSm value of 30.0 J kg(-1) K(-1) at 2.5 K and 70 kOe. Additionally, the chromophoric na(-) and pyzc(-) ligands can serve as antenna groups, selectively sensitizing the Dy(III)- and Yb(III)-based luminescence of 1 and 2 in the UV-visible region by an intramolecular energy transfer process. Thus, complexes 1-3, incorporating field-induced slow magnetic magnetization and interesting luminescence together, can be used as composite magneto-optical materials. More importantly, these interesting results further demonstrate that the mixed-ligand system with rigid carboxylate-functionalized chromophores can be excellent candidates for the preparations of new bifunctional magneto-optical materials. PMID- 25521453 TI - Aspirin and nonsteroidal anti-inflammatory drugs can prevent cutaneous squamous cell carcinoma: a systematic review and meta-analysis. AB - Nonsteroidal anti-inflammatory drugs (NSAIDS) have received increasing attention as potential chemopreventive agents of skin cancer, but evidence is inconsistent. To investigate whether the use of aspirin and other NSAIDS reduces the risk of squamous cell carcinoma (SCC), we conducted a systematic review on the basis of published epidemiologic studies and calculated summary estimates for aspirin, nonaspirin NSAIDS, and any NSAIDS use. Summary estimates from nine studies (five case-control, three cohort, and one intervention) indicated significantly reduced risks of SCC among users of nonaspirin NSAIDS (relative risk (RR) 0.85, 95% confidence interval (CI) 0.78-0.94) and among users of any NSAIDS (RR 0.82, 95% CI 0.71-0.94) compared with nonusers with the effect seen particularly in those with previous actinic skin tumors. A reduced risk was also observed among aspirin users, although with borderline statistical significance (RR 0.88 95% CI 0.75 1.03). There was significant heterogeneity between studies regarding SCC risk estimates for aspirin use and any NSAIDS use. These findings suggest that NSAIDS collectively have the potential to prevent the development of cutaneous SCC. PMID- 25521454 TI - Assessment of cancer cell line representativeness using microarrays for Merkel cell carcinoma. AB - When using cell lines to study cancer, phenotypic similarity to the original tumor is paramount. Yet, little has been done to characterize how closely Merkel cell carcinoma (MCC) cell lines model native tumors. To determine their similarity to MCC tumor samples, we characterized MCC cell lines via gene expression microarrays. Using whole transcriptome gene expression signatures and a computational bioinformatic approach, we identified significant differences between variant cell lines (UISO, MCC13, and MCC26) and fresh frozen MCC tumors. Conversely, the classic WaGa and Mkl-1 cell lines more closely represented the global transcriptome of MCC tumors. When compared with publicly available cancer lines, WaGa and Mkl-1 cells were similar to other neuroendocrine tumors, but the variant cell lines were not. WaGa and Mkl-1 cells grown as xenografts in mice had histological and immunophenotypical features consistent with MCC, whereas UISO xenograft tumors were atypical for MCC. Spectral karyotyping and short tandem repeat analysis of the UISO cells matched the original cell line's description, ruling out contamination. Our results validate the use of transcriptome analysis to assess the cancer cell line representativeness and indicate that UISO, MCC13, and MCC26 cell lines are not representative of MCC tumors, whereas WaGa and Mkl-1 more closely model MCC. PMID- 25521455 TI - Dermal CD14(+) Dendritic Cell and Macrophage Infection by Dengue Virus Is Stimulated by Interleukin-4. AB - Dengue virus (DENV) is responsible for the most prevalent arthropod-borne viral infection in humans. Events decisive for disease development occur in the skin after virus inoculation by the mosquito. Yet, the role of human dermis-resident immune cells in dengue infection and disease remains elusive. Here we investigated how dermal dendritic cells (dDCs) and macrophages (dMs) react to DENV and impact on immunopathology. We show that both CD1c(+) and CD14(+) dDC subsets were infected, but viral load greatly increased in CD14(+) dDCs upon IL-4 stimulation, which correlated with upregulation of virus-binding lectins Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Nonintegrin (DC-SIGN/CD209) and mannose receptor (CD206). IL-4 also enhanced T-cell activation by dDCs, which was further increased upon dengue infection. dMs purified from digested dermis were initially poorly infected but actively replicated the virus and produced TNF-alpha upon lectin upregulation in response to IL-4. DC-SIGN(+) cells are abundant in inflammatory skin with scabies infection or Th2-type dermatitis, suggesting that skin reactions to mosquito bites heighten the risk of infection and subsequent immunopathology. Our data identify dDCs and dMs as primary arbovirus target cells in humans and suggest that dDCs initiate a potent virus-directed T-cell response, whereas dMs fuel the inflammatory cascade characteristic of dengue fever. PMID- 25521456 TI - BAP1 has a survival role in cutaneous melanoma. AB - Although the pattern of BAP1 inactivation in ocular melanoma specimens and in the BAP1 cutaneous melanoma (CM)/ocular melanoma predisposition syndrome suggests a tumor suppressor function, the specific role of this gene in the pathogenesis of CM is not fully understood. We thus set out to characterize BAP1 in CM and discovered an unexpected pro-survival effect of this protein. Tissue and cell lines analysis showed that BAP1 expression was maintained, rather than lost, in primary melanomas compared with nevi and normal skin. Genetic depletion of BAP1 in melanoma cells reduced proliferation and colony-forming capability, induced apoptosis, and inhibited melanoma tumor growth in vivo. On the molecular level, suppression of BAP1 led to a concomitant drop in the protein levels of survivin, a member of anti-apoptotic proteins and a known mediator of melanoma survival. Restoration of survivin in melanoma cells partially rescued the growth-retarding effects of BAP1 loss. In contrast to melanoma cells, stable overexpression of BAP1 into immortalized but non-transformed melanocytes did suppress proliferation and reduce survivin. Taken together, these studies demonstrate that BAP1 may have a growth-sustaining role in melanoma cells, but that its impact on ubiquitination underpins a complex physiology, which is context and cell dependent. PMID- 25521457 TI - A spontaneous KRT16 mutation in a dog breed: a model for human focal non epidermolytic palmoplantar keratoderma (FNEPPK). PMID- 25521458 TI - The psychological burden of skin diseases: a cross-sectional multicenter study among dermatological out-patients in 13 European countries. AB - The contribution of psychological disorders to the burden of skin disease has been poorly explored, and this is a large-scale study to ascertain the association between depression, anxiety, and suicidal ideation with various dermatological diagnoses. This international multicenter observational cross sectional study was conducted in 13 European countries. In each dermatology clinic, 250 consecutive adult out-patients were recruited to complete a questionnaire, reporting socio-demographic information, negative life events, and suicidal ideation; depression and anxiety were assessed with the Hospital Anxiety and Depression Scale. A clinical examination was performed. A control group was recruited among hospital employees. There were 4,994 participants--3,635 patients and 1,359 controls. Clinical depression was present in 10.1% patients (controls 4.3%, odds ratio (OR) 2.40 (1.67-3.47)). Clinical anxiety was present in 17.2% (controls 11.1%, OR 2.18 (1.68-2.82)). Suicidal ideation was reported by 12.7% of all patients (controls 8.3%, OR 1.94 (1.33-2.82)). For individual diagnoses, only patients with psoriasis had significant association with suicidal ideation. The association with depression and anxiety was highest for patients with psoriasis, atopic dermatitis, hand eczema, and leg ulcers. These results identify a major additional burden of skin disease and have important clinical implications. PMID- 25521459 TI - Simvastatin prevents and reverses depigmentation in a mouse model of vitiligo. AB - Vitiligo is a common autoimmune disease of the skin that results in disfiguring white spots. There are no Food and Drug Administration (FDA)-approved treatments, and current treatments are time-consuming, expensive, and of low efficacy. We sought to identify new treatments for vitiligo, and first considered repurposed medications because of the availability of safety data and expedited regulatory approval. We previously reported that the IFN-gamma-induced chemokine CXCL10 is expressed in lesional skin from vitiligo patients, and that it is critical for the progression and maintenance of depigmentation in our mouse model of vitiligo. We hypothesized that targeting IFN-gamma signaling might be an effective new treatment strategy. Activation of signal transducer and activator of transcription 1 (STAT1) is required for IFN-gamma signaling and recent studies revealed that simvastatin, an FDA-approved cholesterol-lowering medication, inhibited STAT1 activation in vitro. Therefore, we hypothesized that simvastatin may be an effective treatment for vitiligo. We found that simvastatin both prevented and reversed depigmentation in our mouse model of vitiligo, and reduced the number of infiltrating autoreactive CD8(+) T cells in the skin. Treatment of melanocyte-specific, CD8(+) T cells in vitro decreased proliferation and IFN gamma production, suggesting additional effects of simvastatin directly on T cells. Based on these data, simvastatin may be a safe, targeted treatment option for patients with vitiligo. PMID- 25521460 TI - Maintenance therapy of adult vitiligo with 0.1% tacrolimus ointment: a randomized, double blind, placebo-controlled study. AB - The risk of relapse after successful repigmentation in vitiligo is estimated to 40% within the first year. It has been shown in atopic dermatitis that continuous low-level use of topical corticosteroids and calcineurin inhibitors in previously affected skin can prevent new flares. We hypothesized that a twice-weekly application of 0.1% tacrolimus ointment might be effective for maintaining repigmentation in therapeutically repigmented lesions of vitiligo patients. After randomization, sixteen patients with 31 patches were assigned to the placebo group and 19 patients with 41 patches were assigned to the tacrolimus group. In the intention-to-treat analysis, 48.4% of lesions showed depigmentation in the placebo group, whereas 26.8% did in the tacrolimus group (P=0.059). The intention to-treat results did not remain significant after adjustment for within-patient clustering, odds ratio (OR) 2.55; 95% confidence interval (CI; 0.65-9.97); P=0.1765. The per-protocol analysis (n=56) showed that 40% of lesions had some depigmentation in the placebo group, whereas only 9.7% did in the tacrolimus group (P=0.0075). The per-protocol results remained significant after adjustment for within-patient clustering: OR 6.22; 95% CI (1.48-26.12); P=0.0299. Our study shows that twice-weekly application of 0.1% tacrolimus ointment is effective in preventing the depigmentation of vitiligo patches that have been previously successfully repigmented. PMID- 25521462 TI - Microbiota and the human nature: know thyself. AB - Biology has been driven by the human desire for self-knowledge. The discovery of our intimate symbiosis with microbes raises the question about our identity. A central issue is whether the microbiome associated with humans changes our phenotype in an observable way. As we deal with a great multitude of colonizing microbes and as even monozygotic twins differ substantially for their microbiome, we might deal with a dynamic system that is highly sensitive to initial conditions for which long-term prediction are impossible according to chaos theory. The overall colonization of the human alimentary tract can be teleological rationalized by a strong antimicrobial activity in the proximal and a mutualistic but controlled relationship with the microbiome in the distal gut segments. Yet the association of a specific microbiome with physiological traits turned out to be complicated and became frequently only clear after microbiota transfer experiments into gnotobiotic mice as a reductionist approach. As pathogenic bacteria create human phenotypes by their presence, mutualistic bacteria create symptoms (phenotypes) by their absence as exemplified by lactobacilli in bacterial vaginosis. PMID- 25521461 TI - Dendritic cells loaded with pancreatic Cancer Stem Cells (CSCs) lysates induce antitumor immune killing effect in vitro. AB - According to the cancer stem cells (CSCs) theory, malignant tumors may be heterogeneous in which a small population of CSCs drive the progression of cancer. Because of their intrinsic abilities, CSCs may survive a variety of treatments and then lead to therapeutic resistance and cancer recurrence. Pancreatic CSCs have been reported to be responsible for the malignant behaviors of pancreatic cancer, including suppression of immune protection. Thus, development of immune strategies to eradicate pancreatic CSCs may be of great value for the treatment of pancreatic cancer. In this study, we enriched pancreatic CSCs by culturing Panc-1 cells under sphere-forming conditions. Panc-1 CSCs expressed low levels of HLA-ABC and CD86, as measured by flow cytometry analysis. We further found that the Panc-1 CSCs modulate immunity by inhibiting lymphocyte proliferation which is promoted by phytohemagglutinin (PHA) and anti CD3 monoclonal antibodies. The monocyte derived dendritic cells (DCs) were charged with total lysates generated from Panc-1 CSCs obtained from tumor sphere culturing. After co-culturing with lymphocytes at different ratios, the Panc-1 CSCs lysates modified DC effectively promoted lymphocyte proliferation. The activating efficiency reached 72.4% and 74.7% at the ratios of 1?10 and 1?20 with lymphocytes. The activated lymphocytes secreted high levels of INF-gamma and IL 2, which are strong antitumor cytokines. Moreover, Panc-1 CSCs lysates modified DC induced significant cytotoxic effects of lymphocytes on Panc-1 CSCs and parental Panc-1 cells, respectively, as shown by lactate dehydrogenase (LDH) assay. Our study demonstrates that the development of CSCs-based vaccine is a promising strategy for treating pancreatic cancer. PMID- 25521463 TI - Intensive rehabilitation in selected hip fracture patients may optimize care efficiency: A retrospective comparison study. AB - OBJECTIVE: To gather preliminary data on the effectiveness of intensive rehabilitation after hip fracture surgery, as provided in the Transfer Unit (TU) in Leiden, The Netherlands, compared with the effectiveness of rehabilitation in a regular nursing home. Intensive rehabilitation in the TU consists of physical therapy twice daily by dedicated medical staff and aims to shorten hospital stay and duration of rehabilitation, in order to increase the hospital admission capacity and reduce waiting lists for nursing homes. DESIGN: Retrospective cohort study. PATIENTS: A total of 173 hip fracture patients, selected postoperatively for intensive rehabilitation in the TU. Of these, 156 received TU rehabilitation (TU+ group), while 17 were rehabilitated in regular nursing homes for logistic reasons (TU- group). METHODS: Length of hospital stay, rehabilitation duration and survival were compared between TU+ and TU-. RESULTS: Both groups appeared comparable at baseline. TU+ patients had a mean hospital stay of 10.4 vs 12.3 days for TU- patients (p = 0.29), while their rehabilitation duration was 25.2 days shorter: 42.0 vs 67.2 days (p = 0.001). One-year survival was similar (87%). CONCLUSION: Intensive rehabilitation in selected hip fracture patients may reduce rehabilitation duration by almost 4 weeks. Differentiated aftercare appears to increase care efficiency for hip fracture patients in both hospitals and nursing homes and may result in a significant reduction in costs. PMID- 25521464 TI - Li[B(OCH2CF3)4]: synthesis, characterization and electrochemical application as a conducting salt for LiSB batteries. AB - A new Li salt with views to success in electrolytes is synthesized in excellent yields from lithium borohydride with excess 2,2,2-trifluorethanol (HOTfe) in toluene and at least two equivalents of 1,2-dimethoxyethane (DME). The salt Li[B(OTfe)4 ] is obtained in multigram scale without impurities, as long as DME is present during the reaction. It is characterized by heteronuclear magnetic resonance and vibrational spectroscopy (IR and Raman), has high thermal stability (Tdecomposition >271 degrees C, DSC) and shows long-term stability in water. The concentration-dependent electrical conductivity of Li[B(OTfe)4 ] is measured in water, acetone, EC/DMC, EC/DMC/DME, ethyl acetate and THF at RT In DME (0.8 mol L(-1) ) it is 3.9 mS cm(-1) , which is satisfactory for the use in lithium-sulfur batteries (LiSB). Cyclic voltammetry confirms the electrochemical stability of Li[B(OTfe)4 ] in a potential range of 0 to 4.8 V vs. Li/Li(+) . The performance of Li[B(OTfe)4 ] as conducting salt in a 0.2 mol L(-1) solution in 1:1 wt % DME/DOL is investigated in LiSB test cells. After the 40th cycle, 86 % of the capacity remains, with a coulombic efficiency of around 97 % for each cycle. This indicates a considerable performance improvement for LiSB, if compared to the standard Li[NTf2 ]/DOL/DME electrolyte system. PMID- 25521465 TI - Quality of life in women who use pessaries for longer than 12 months. AB - OBJECTIVES: Pessaries are an effective treatment for pelvic organ prolapse and urinary incontinence; however, few data exist describing long-term pessary use. Our aim was to describe symptom bother and quality of life (QoL) in women using pessaries for urinary incontinence and/or prolapse for at least 12 months. METHODS: Consecutive women who met inclusion criteria were approached for this observational cross-sectional study. Wilson and Cleary's Health-Related Quality of Life Model guided the inclusion of biologic, functional, and individual factors that impact the health-related QoL. Consenting participants completed a generalized QoL index, the Center for Epidemiologic Depression Symptoms, Medical Outcomes Study Social Support Survey, and condition-specific measures; the Pelvic Floor Distress Inventory (PFDI-20-SF) and the Pelvic Floor Impact Questionnaire. RESULTS: Fifty-six women, mean age 74.4 years (range, 47-89 years), completed the survey. Mean length of time for pessary use was 4.5 years (1-15 years). Most of the women (n = 31, 55.4%) returned to the clinic for pessary care every 3 months. There was no difference in generalized QoL nor condition-specific total PFDI-20 in women performing self-care versus routine follow-up. Almost one third (29%) of participants reported complications related to pessary use (eg, vaginal erosion), and 41%were considering surgical repair in the near future. Women who were considering surgery had higher PFDI-20 scores relating to more bothersome prolapse symptoms than those not considering surgery (Pelvic Organ Prolapse Distress Inventory 6, 33.91 vs 24.73, P = 0.03). CONCLUSIONS: Pessaries can be used to control pelvic floor symptoms for extended periods. Complication rates in this study were lower than previously reported, even in women not doing self care. Not surprisingly, women considering surgical intervention reported greater symptom bother despite pessary use. PMID- 25521466 TI - The Quality of Health Information Available on the Internet for Patients With Pelvic Organ Prolapse. AB - OBJECTIVE: This study aimed to assess the quality of Web sites that provide information on pelvic organ prolapse using validated quality measurement tools. METHODS: The Google search engine was used to perform a search of the following 4 terms: "pelvic organ prolapse," "dropped bladder," "cystocele," and "vaginal mesh." The DISCERN appraisal tool and JAMA benchmark criteria were used to determine the quality of health information of each Web site. Cohen kappa was performed to determine interrater reliability between reviewers. Kruskal-Wallis and Wilcoxon rank sum tests were used to compare DISCERN scores and JAMA criteria among search terms. RESULTS: Interrater reliability between the two reviewers using DISCERN was kappa = 0.71 [95% confidence interval (CI), 0.68-0.74] and using JAMA criteria was kappa = 0.98 (95% CI, 0.74-1.0). On the basis of the DISCERN appraisal tool, the search term "vaginal mesh" had significantly lower Web site quality than "pelvic organ prolapse" and "cystocele," respectively [mean difference of DISCERN score, -14.65 (95% CI, -25.50 to 8.50, P < 0.0001) and 12.55 (95% CI, -24.00 to 7.00, P = 0.0007)]. "Dropped bladder" had significantly lower Web site quality compared to "pelvic organ prolapse" and "cystocele," respectively (mean difference of DISCERN score, -9.55 (95% CI, -20.00 to 3.00, P = 0.0098) and -7.80 (95% CI, -18.00 to 1.00, P = 0.0348). Using JAMA criteria, there were no statistically significant differences between Web sites. CONCLUSIONS: Web sites queried under search terms "vaginal mesh" and "dropped bladder" are lower in quality compared with the Web sites found using the search terms "pelvic organ prolapse" and "cystocele." PMID- 25521467 TI - Utility of intraoperative cystoscopy in detecting ureteral injury during vaginal hysterectomy. AB - OBJECTIVES: The aim of this study was to determine the utility of intraoperative cystoscopy in detecting and managing ureteral injury among women undergoing vaginal hysterectomy. METHODS: We performed a secondary analysis of a retrospective cohort study of 593 patients who underwent vaginal hysterectomy for benign indications, with or without additional pelvic floor reconstructive surgery, from January 2, 2004, through December 30, 2005. A logistic regression model determining the propensity to undergo intraoperative cystoscopy was constructed. Comparisons of ureteral injury and cost between patients with and without cystoscopy were adjusted for the cystoscopy propensity score. We further explored the feasibility of using perioperative change in creatinine level to detect ureteral injury. RESULTS: In total, 230 (38.8%) of 593 patients underwent cystoscopy. Six patients (2.6%) in the cystoscopy group and 5 (1.4%) in the no cystoscopy group had ureteral injuries (odds ratio, 1.92; 95% confidence interval [CI], 0.58-6.36). This association was further attenuated after adjusting for the propensity to undergo cystoscopy (odds ratio, 1.31; 95% CI, 0.19-9.09). Four injuries detected cystoscopically were managed intraoperatively. Adjusted mean predicted costs for patients undergoing cystoscopy were $10,686 (95% CI, $7500 $13,872) versus $10,217 (95% CI, $6894-$13,540). In the no-cystoscopy group, patients with ureteral injury had a median increase in creatinine level of 0.2 mg/dL, whereas patients without injury had a median decrease of 0.1 mg/dL (P < 0.001). CONCLUSIONS: The level of selection for cystoscopy did not significantly increase the mean predicted costs for patients. Reliance on postoperative creatinine level to detect ureteral injury, while highly sensitive, is limited by a low positive predictive value and variable range. PMID- 25521468 TI - Traumatic labial bladder diverticulum and vesico-vulvar fistula. AB - BACKGROUND: Injuries to the female urinary tract are rare after pelvic trauma. The sequelae of these injuries are often delayed, and misdiagnosis is common. CASE: A woman with a history of pelvic trauma presented with a labial mass that was found to be a large bladder diverticulum. In addition, she was ultimately diagnosed with a traumatic vesico-vulvar fistula that was successfully repaired using a novel surgical technique. CONCLUSIONS: In patients with a history of pelvic trauma and genitourinary symptoms, it is important to consider injury to the female bladder and urethra. Further, successful repair of vesico-vulvar fistulas can be accomplished with cystoscopic fulguration and dissection of the supraurethral fistulous tract. PMID- 25521469 TI - Laparoscopic colpotomy using monopolar electrocautery: does power really matter? AB - OBJECTIVE: The purpose of this study was to assess the extent and rate of vaginal tissue injury associated with the utilization of various monopolar electrosurgical power settings when laparoscopically transecting vaginal tissue. METHODS: This is an Institutional Animal Care and Use Committee-approved prospective, paired, single-blinded study. Externalized porcine vagina was transected using monopolar energy at 30, 50, and 80 W in the cut mode with laparoscopic Endo Shears. The slides were prepared and stained with both hematoxylin-eosin and Masson trichrome and were examined by board-certified veterinary pathologists blinded to the study. RESULTS: There were 18 swine; each animal was tested on all 3 power settings (n = 54). Tissue injury was measured to a mean (SD) of 767 (519) MUm at 30 W, 690 (600) MUm at 50 W, and 556 (470) MUm at 80 W. When comparing the monopolar settings, the results were as follows: 30 versus 50 W (P = 0.33), 30 versus 80 W (P = 0.067), and 50 versus 80 W (P = 0.17). The mean (SD) time for complete transection was measured at each power setting (n = 18), with 35.8 (5.4) seconds for 30 W, 13.5 (5.5) seconds for 50 W, and 8.4 (5.1) seconds for 80 W (P < 0.001). There was a statistically significant difference in the mean (SD) rates of injury, with 20.8 (8.8) MUm/s at 30 W, 39.8 (11.8) MUm/s at 50 W, and 50.1 (19.2) MUm/s at 80 W (P = 0.01). CONCLUSIONS: Using various power settings of monopolar energy may not make a significant difference in swine vaginal tissue damage at the time of colpotomy. However, there was a significant difference in the times and rates at which tissue was transected when using higher powers. We recommend using the 50- or 80-W setting, as this will likely decrease surgical times without altering vaginal tissue damage. PMID- 25521470 TI - Urinary Retention After Hysterectomy and Postoperative Analgesic Use. AB - OBJECTIVE: This study aimed to determine risk factors, including postoperative analgesic use, for the development of postoperative urinary retention (PUR) after hysterectomy for routine gynecologic indications using a case-control study design. METHODS: Cases of PUR after hysterectomy were identified from billing data. Cases were those patients requiring recatheterization for inability to void. Controls were similarly identified and matched by age and date of surgery in a 3:1 control-to-case ratio. Chart review was performed to obtain demographic, medical, surgical, anesthetic, and medication data. Cumulative and interval doses of postoperative narcotic were recorded and converted into morphine equivalents. Crude odds ratios (ORs) were determined for potential risk factors for PUR using standard statistical analysis. Conditional logistic regression was used on multivariate models, including cumulative postoperative narcotic use, to determine adjusted ORs for risk factors. RESULTS: Twenty-six cases of PUR were matched with 78 controls. The cases had a higher body mass index (32 vs 28 kg/m2, P = 0.02), had a higher preoperative use of tricyclic antidepressants (TCA; 19.2% vs 1.3%, P = 0.004), were more likely to present preoperative urinary retention associated with fibroids (19.2% vs 0%, P < 0.01), and received a higher cumulative narcotic dose in the postoperative period (109 vs 73.6 mg, P < 0.001). In a multivariate model, preoperative TCA use (OR, 30.1; 95% confidence interval, 1.99-456; P = 0.01) and cumulative narcotic dose (OR, 2.54; 95% confidence interval, 1.44-4.56; P < 0.01) were significantly associated with PUR. CONCLUSIONS: Postoperative urinary retention after hysterectomy is associated with higher postoperative narcotic dose, preoperative TCA use, and preoperative urinary retention. PMID- 25521471 TI - The Effect of Age on Postoperative Morbidity in Women Undergoing Urogynecologic Surgery. AB - OBJECTIVES: The objectives of this study were to estimate the effect of older age on postoperative morbidity and to assess other factors associated with postoperative complications after urogynecologic surgery. METHODS: We conducted a retrospective cohort study of 508 women who underwent pelvic floor reconstructive surgery between March 2011 and June 2013. Our 2 cohorts were based on age--women younger than 65 years and women aged 65 years or older. Our primary outcome was clinically significant postoperative complications defined as Dindo-Clavien grade greater than or equal to 2. We compared the risk of postoperative morbidity between the cohorts and constructed a logistic regression analysis to adjust for potential confounders. RESULTS: Of the 508 patients, 300 (59.1%) were in the younger cohort and 208 (40.9%) were in the older cohort. For our primary outcome, we found that older women had a significantly higher rate of clinically significant postoperative complications (12.5% vs. 6.7%, P = 0.02). In a multivariate logistic regression model that included advanced prolapse, smoking status, Charlson Comorbidity Index, body mass index, and operative time, older age remained significantly associated with greater postoperative morbidity (odds ratio, 2.06; 95% confidence interval, 1.03-4.11). The length of surgery in hours was also associated with greater morbidity (odds ratio, 1.47; 95% confidence interval, 1.14-1.66). CONCLUSIONS: Women aged 65 years and older who underwent urogynecologic surgery had a higher risk of clinically significant postoperative complications based on the Dindo-Clavien Scale when compared with women younger than 65 years. PMID- 25521472 TI - Effect of a Decision Aid on Decision Making for the Treatment of Pelvic Organ Prolapse. AB - OBJECTIVES: The aim of this study was to evaluate if the addition of a decision aid (DA) decreases decisional conflict in women presenting for the management and treatment of pelvic organ prolapse (POP). METHODS: Women scheduled for the evaluation and management of POP were randomized into either of 2 groups: standard counseling (SC) alone (n = 51) or SC plus a DA (n = 53). Upon completion of their initial visit, patients filled out a 16-item decisional conflict scale and short form general health survey. Values were assessed for normality and compared between groups. Normally distributed, continuous data were evaluated with a Student t test. A chi2 test was used to compare selected categorical characteristics between groups. Differences in distributions of low and high decisional conflict were assessed with a Mann-Whitney U test. RESULTS: One hundred four women were randomized for this analysis. Baseline characteristics, including pelvic prolapse examination measurements, did not significantly differ between groups. The addition of a DA to SC did not significantly lower the level decisional conflict patients faced when deciding on a treatment plan (P = 0.566). There were no significant differences between groups in the following subscores: uncertainty, values clarity, support, effective decision, and informed. In addition, there were no between-group differences in choice of treatment plan (conservative management, pelvic floor physical therapy, pessary, and surgery; P = 0.835). CONCLUSIONS: In this relatively small sample, the addition of a DA to SC for women with POP does not significantly decrease the level of decisional conflict in making treatment-related decisions. PMID- 25521473 TI - The CROWN Initiative: journal editors invite researchers to develop core outcomes in women's health: the Core Outcomes in Women's Health Initiative. PMID- 25521474 TI - What a long, strange trip it's been. PMID- 25521475 TI - A lung-on-a-chip array with an integrated bio-inspired respiration mechanism. AB - We report a lung-on-a-chip array that mimics the pulmonary parenchymal environment, including the thin alveolar barrier and the three-dimensional cyclic strain induced by breathing movements. The micro-diaphragm used to stretch the alveolar barrier is inspired by the in vivo diaphragm, the main muscle responsible for inspiration. The design of this device aims not only at best reproducing the in vivo conditions found in the lung parenchyma but also at making the device robust and its handling easy. An innovative concept, based on the reversible bonding of the device, is presented that enables accurate control of the concentration of cells cultured on the membrane by easily accessing both sides of the membranes. The functionality of the alveolar barrier could be restored by co-culturing epithelial and endothelial cells that form tight monolayers on each side of a thin, porous and stretchable membrane. We showed that cyclic stretch significantly affects the permeability properties of epithelial cell layers. Furthermore, we also demonstrated that the strain influences the metabolic activity and the cytokine secretion of primary human pulmonary alveolar epithelial cells obtained from patients. These results demonstrate the potential of this device and confirm the importance of the mechanical strain induced by breathing in pulmonary research. PMID- 25521476 TI - Tapping the potential of polymer brushes through synthesis. AB - CONSPECTUS: Polymer brushes are becoming increasing popular in the chemical literature, because scientists can control their chemical configuration, density, architecture, and thickness down to nanoscale precision with even simple laboratory setups. A polymer brush is made up of a layer of polymers attached to a substrate surface at one end with the other end dangling into a solvent. In a suitable solvent, the polymer chains stretch away from the surface due to both steric and osmotic repulsion between the chain segments. In an inadequate solvent, however, the polymer chains collapse due to enough interior free space after desolvation. This unique class of materials exhibit interesting physicochemical properties at interfaces and have numerous applications from sensing to surface/interface property control. Chemists have made recent advances in surface modification and specific application of polymer brushes, due to both profound mechanistic understanding and synthetic strategies. The commonly used synthetic strategies for generating polymer brushes are surface-initiated polymerizations (SIPs), which resemble planting rice. That is, the assembly of initiator on the surface is similar to transplanting rice seedlings, and the subsequent polymerizations are akin to rice growth. Among different SIP methods, researchers mostly use surface-initiated atom transfer radical polymerization (SI ATRP) because it provides many advantages in the preparation of well-defined polymer brushes, including easy initiator synthesis, fair control over polymer growth, a "living" end for copolymer grafting, and polymerization in aqueous solution. However, chemists gradually realized that there still room for improvement in this method, since the conventional SI-ATRP method suffers several drawbacks. These include having limited availability on various materials surfaces, rigorous synthetic protocols, heavy consumption and waste of unreacted monomers, and limited ability to control a polymerization process. Moreover, applications of polymer brushes as model surfaces must benefit from the synergistic strategies and profound insights into the fundamental understanding of the polymerization. This is not only to optimize the SI-ATRP process but also to expand the range of monomers, simplify reaction setups, reduce the cost, and ultimately gain control of the synthesis of well-defined polymeric surfaces for material science and engineering. In this Account, we provide an overview of our and others' recent advances in the fabrication of polymer brushes by using SI ATRP, to promote the widespread application of SI-ATRP and practical applications of the polymer brushes. We aim to provide fundamental mechanistic and synthetic features of SI-ATRP, while emphasizing the various externally applied stimuli mediated catalytic and initiation systems, including electrochemistry, chemical reducing agents, and photochemistry. In addition, we discuss how chemists can advantageously exploit these methods to synthesize functional polymeric surfaces in environmentally friendly media and facilitate in situ regulation of a dynamic polymerization process. We also discuss structural polymer brushes, such as block copolymers and patterned and gradient structures. Finally, we provide examples that highlight some practical applications of polymer brushes using SI-ATRP, especially the emerging polymerization methods. Overall, recently developed SI ATRP systems overcome many limitations that permit less rigorous synthetic protocols and facilitate scientific community-wide access to surface modifications. By using these methodologies, chemists are tapping the potential of polymer brushes in surface/interface research areas. PMID- 25521477 TI - Combined outer volume suppression and T2 preparation sequence for coronary angiography. AB - PURPOSE: To develop a magnetization preparation sequence for simultaneous outer volume suppression (OVS) and T2 weighting in whole-heart coronary magnetic resonance angiography. METHODS: A combined OVS and T2 preparation sequence (OVS T2 Prep) was designed with a nonselective adiabatic 90 degrees tipdown pulse, two adiabatic 180 degrees refocusing pulses, and a 2D spiral -90 degrees tipup pulse. The OVS-T2 Prep preserves the magnetization inside an elliptic cylinder with T2 weighting, while saturating the magnetization outside the cylinder. Its performance was tested on phantoms and on 13 normal subjects with coronary magnetic resonance angiography using 3D cones trajectories. RESULTS: Phantom studies showed expected T2 -dependent signal amplitude in the spatial passband and suppressed signal in the spatial stopband. In vivo studies with full-field-of view cones yielded a passband-to-stopband signal ratio of 3.18 +/- 0.77 and blood myocardium contrast-to-noise ratio enhancement by a factor of 1.43 +/- 0.20 (P < 0.001). In vivo studies with reduced-field-of-view cones showed that OVS-T2 Prep well suppressed the aliasing artifacts, as supported by significantly reduced signal in the regions with no tissues compared to the images acquired without preparation (P < 0.0001). CONCLUSION: OVS-T2 Prep is a compact sequence that can accelerate coronary magnetic resonance angiography by suppressing signals from tissues surrounding the heart while simultaneously enhancing the blood-myocardium contrast. PMID- 25521478 TI - Local and systemic regulation of plant root system architecture and symbiotic nodulation by a receptor-like kinase. AB - In plants, root system architecture is determined by the activity of root apical meristems, which control the root growth rate, and by the formation of lateral roots. In legumes, an additional root lateral organ can develop: the symbiotic nitrogen-fixing nodule. We identified in Medicago truncatula ten allelic mutants showing a compact root architecture phenotype (cra2) independent of any major shoot phenotype, and that consisted of shorter roots, an increased number of lateral roots, and a reduced number of nodules. The CRA2 gene encodes a Leucine Rich Repeat Receptor-Like Kinase (LRR-RLK) that primarily negatively regulates lateral root formation and positively regulates symbiotic nodulation. Grafting experiments revealed that CRA2 acts through different pathways to regulate these lateral organs originating from the roots, locally controlling the lateral root development and nodule formation systemically from the shoots. The CRA2 LRR-RLK therefore integrates short- and long-distance regulations to control root system architecture under non-symbiotic and symbiotic conditions. PMID- 25521479 TI - Phylogeography of Chinese cherry (Prunus pseudocerasus Lindl.) inferred from chloroplast and nuclear DNA: insights into evolutionary patterns and demographic history. AB - Chinese cherry (Prunus pseudocerasus Lindl.) is a commercially valuable fruit crop in China. In order to obtain new insights into its evolutionary history and provide valuable recommendations for resource conservation, phylogeographic patterns of 26 natural populations (305 total individuals) from six geographic regions were analyzed using chloroplast and nuclear DNA fragments. Low levels of haplotype and nucleotide diversity were found in these populations, especially in landrace populations. It is likely that a combined effect of botanical characteristics impact the effective population size, such as inbreeding mating system, long life span, as well as vegetative reproduction. In addition, strong bottleneck effect caused by domestication, together with founder effect after dispersal and subsequent demographic expansion, might also accelerate the reduction of the genetic variation in landrace populations. Interestingly, populations from Longmen Mountain (LMM) and Daliangshan Mountain (DLSM) exhibited relatively higher levels of genetic diversity, inferring the two historical genetic diversity centers of the species. Moreover, moderate population subdivision was also detected by both chloroplast DNA (GST = 0.215; NST = 0.256) and nuclear DNA (GST = 0.146; NST = 0.342), respectively. We inferred that the episodes of efficient gene flow through seed dispersal, together with features of long generation cycle and inbreeding mating system, were likely the main contributors causing the observed phylogeographic patterns. Finally, factors that led to the present demographic patterns of populations from these regions and taxonomic varieties were also discussed. PMID- 25521480 TI - Selective interaction of heparin with the variable region 3 within surface glycoprotein of laboratory-adapted feline immunodeficiency virus. AB - Heparan sulfate proteoglycans (HSPG) can act as binding receptors for certain laboratory-adapted (TCA) strains of feline immunodeficiency virus (FIV) and human immunodeficiency virus (HIV). Heparin, a soluble heparin sulfate (HS), can inhibit TCA HIV and FIV entry mediated by HSPG interaction in vitro. In the present study, we further determined the selective interaction of heparin with the V3 loop of TCA of FIV. Our current results indicate that heparin selectively inhibits infection by TCA strains, but not for field isolates (FS). Heparin also specifically interferes with TCA surface glycoprotein (SU) binding to CXCR4, by interactions with HSPG binding sites on the V3 loop of the FIV envelope protein. Peptides representing either the N- or C-terminal side of the V3 loop and containing HSPG binding sites were able to compete away the heparin block of TCA SU binding to CXCR4. Heparin does not interfere with the interaction of SU with anti-V3 antibodies that target the CXCR4 binding region or with the interaction between FS FIV and anti-V3 antibodies since FS SU has no HSPG binding sites within the HSPG binding region. Our data show that heparin blocks TCA FIV infection or entry not only through its competition of HSPG on the cell surface interaction with SU, but also by its interference with CXCR4 binding to SU. These studies aid in the design and development of heparin derivatives or analogues that can inhibit steps in virus infection and are informative regarding the HSPG/SU interaction. PMID- 25521482 TI - Distress and patient-centered communication among veterans with incidental (not screen-detected) pulmonary nodules. A cohort study. AB - RATIONALE: Incidental pulmonary nodule detection is postulated to cause distress, but the frequency and magnitude of that distress have not been reported. The quality of patient-clinician communication and the perceived risk of lung cancer may influence distress Objectives: To evaluate the association of communication processes with distress and the perceived risk of lung cancer using validated instruments. METHODS: We conducted a prospective cohort study of patients with incidentally detected nodules who received care at one Department of Veterans Affairs Medical Center. We measured distress with the Impact of Event Scale and patient-centered communication with the Consultation Care Measure, both validated instruments. Risk of lung cancer was self-reported by participants. We used multivariable adjusted logistic regression to measure the association of communication quality with distress. MEASUREMENTS AND MAIN RESULTS: Among 122 Veterans with incidental nodules, 23%, 12%, and 4% reported experiencing mild, moderate, and severe distress, respectively, at the time they were informed of the pulmonary nodule. Participant-reported risk of lung cancer was not associated with distress. In the adjusted model, high-quality communication was associated with decreased distress (odds ratio [OR] = 0.28, 95% confidence interval [CI] = 0.08-1.00, P = 0.05). Among participants who reported a risk of malignancy of 30% or less, high-quality communication was associated with decreased distress (OR = 0.15, 95% CI = 0.02-0.92, P = 0.04), but was not associated with distress for those who reported a risk greater than 30% (OR = 0.12 (95% CI = 0.00-3.97, P = 0.24), although the P value for interaction was not significant. CONCLUSIONS: Veterans with incidental pulmonary nodules frequently reported inadequate information exchange regarding their nodule. Many patients experience distress after they are informed that they have a pulmonary nodule, and high-quality patient-clinician communication is associated with decreased distress. Communication strategies that only target improved knowledge of the risk of malignancy may not be sufficient to reduce the distress associated with nodule detection. PMID- 25521481 TI - Combinations of serum prostate-specific antigen and plasma expression levels of let-7c, miR-30c, miR-141, and miR-375 as potential better diagnostic biomarkers for prostate cancer. AB - In the current study, expression levels of let-7c, miR-30c, miR-141, and miR-375 in plasma from 59 prostate cancer (PC) patients with different clinicopathological characteristics and two groups of controls: 16 benign prostatic hyperplasia (BPH) samples and 11 young asymptomatic men (YAM) were analyzed to evaluate their diagnostic and prognostic value in comparison to prostate-specific antigen (PSA). miR-375 was significantly downregulated in 83.5% of patients compared to BPH controls and showed stronger diagnostic accuracy (area under the curve [AUC]=0.809, 95% CI: 0.697-0.922, p=0.00016) compared with PSA (AUC=0.710, 95% CI: 0.559-0.861, p=0.013). Expression levels of let-7c showed potential to distinguish PC patients from BPH controls with AUC=0.757, but the result did not reach significance. Better discriminating performance was observed when combinations of studied biomarkers were used. Sensitivity of 86.8% and specificity of 81.8% were reached when all biomarkers were combined (AUC=0.877) and YAM were used as calibrators. None of the studied microRNAs (miRNAs) showed correlation with clinicopathological characteristics. PSA levels were significantly correlated with the Gleason score, tumor stage, and lymph node metastasis with Spearman correlation coefficients: 0.612, 0.576, and 0.458. In conclusion, the combination of the studied circulating plasma miRNAs and serum PSA has the potential to be used as a noninvasive diagnostic biomarker for PC screening outperforming the PSA testing alone. PMID- 25521483 TI - Protective role of dietary-supplemented selenium and vitamin E in heat-induced apoptosis and oxidative stress in mice testes. AB - This study evaluated the role of selenium (0.5 ppm selenium/kg diet) and vitamin E (200 mg alpha-tocopherol/kg diet) on spermatogenesis after scrotal hyperthermia (42 degrees C, 30 min) in six different groups of male Balb/c mice; Control, Heat shock, Selenium, Selenium+heat shock, Vitamin E and Vitamin E+heat shock. Markers of the stress responses, hypoxia and oxidative stress, were evaluated in testis after the hyperthermic shock. Hyperthermia caused an elevated mRNA expression of hypoxia-inducible factor-1 alpha, haem oxygenase-1 (HMOX-1) and also glutathione peroxidase activity and reactive oxygen species (ROS). Apoptosis was evaluated by TUNEL assay and further by mRNA expression of Bcl-2, caspase 3, 8, 9, bid and AKT. TUNEL assay showed significant increase in apoptotic index of spermatogenic cells, whereas decrease in mRNA expression of Bcl-2, AKT and increase in caspase 3, 8, 9 and Bid in heat-shock group were observed. A significant decrease in sperm motility was also seen in heat-shock group in comparison with control group. These observations clearly indicate the development of oxidative stress and apoptosis after hyperthermia. Further analysis in Selenium+heat shock and Vitamin E+heat shock groups showed protective behaviour as compared to effects in heat-shock group which could be of therapeutic interest in future studies. PMID- 25521487 TI - Phenolic resin-grafted reduced graphene oxide as a highly stable anode material for lithium ion batteries. AB - A novel and effective route for preparing phenol formaldehyde resin grafted reduced graphene oxide (rGO-g-PF) electrode materials with highly enhanced electrochemical properties is reported. In order to prepare rGO-g-PF, hydroxymethyl-terminated PF is initially grafted to graphene oxide (GO) via esterification reaction. Subsequently, the grafted GO is reduced by the carbonization process under an inert gas atmosphere. The covalent linkage, morphology, thermal stability and electrochemical properties of rGO-g-PF are systematically investigated by Fourier transform infrared spectroscopy, scanning electron microscopy, thermal gravimetric analysis, differential scanning calorimetry and a variety of electrochemical testing techniques. In the constructed architecture, the amorphous carbon shell can inhibit the co intercalation of solvated lithium ion and avoid partial exfoliation of the graphene layers, thus effectively reducing the irreversible capacity and preserving the structural integrity. Meanwhile, the carbon coating layer leading to a decreased thickness of SEI film can improve the conductivity of electrode materials. As a result, the rGO-g-PF electrode exhibits impressive high cycling stability at various large current densities (376.5 mA h g(-1) at 50 mA g(-1) for 250 cycles, 337.8 mA h g(-1) at 200 mA g(-1) and 267.8 mA h g(-1) at 1 A g(-1) for 200 cycles), in combination with high rate capability. PMID- 25521486 TI - The Influence of a Constraint and Bimanual Training Program Using a Variety of Modalities, on Upper Extremity Functions and Gait Parameters Among Children with Hemiparetic Cerebral Palsy: A Case Series. AB - AIM: To assess the influence of an intensive combined constraint and bimanual upper extremity (UE) training program using a variety of modalities including the fitness room and pool, on UE functions as well as the effects of the program on gait parameters among children with hemiparetic cerebral palsy. METHODS: Ten children ages 6-10 years participated in the program for 2 weeks, 5 days per week for 6 hr each day. Data from the Assisting Hand Assessment (AHA) for bimanual function , the Jebsen-Taylor Test of Hand Function (JTTHF) for unimanual function, the six-minute walk test (6MWT), and the temporal-spatial aspects of gait using the GAITRite walkway were collected prior to, immediately post and 3 months post-intervention. RESULTS: A significant improvement was noted in both unimanual as well as bimanual UE performance; A significant improvement in the 6MWT was noted, from a median of 442 meter [range: 294-558] at baseline to 466 [432-592] post intervention and 528 [425-609] after 3 months (p = .03). CONCLUSION: Combining intensive practice in a variety of modalities, although targeting to the UE is associated with substantial improvement both in the upper as well as in the lower extremity function. PMID- 25521491 TI - Second-generation autofluorescence imaging for colorectal neoplasia. PMID- 25521484 TI - Evolution of integrated causal structures in animats exposed to environments of increasing complexity. AB - Natural selection favors the evolution of brains that can capture fitness relevant features of the environment's causal structure. We investigated the evolution of small, adaptive logic-gate networks ("animats") in task environments where falling blocks of different sizes have to be caught or avoided in a 'Tetris like' game. Solving these tasks requires the integration of sensor inputs and memory. Evolved networks were evaluated using measures of information integration, including the number of evolved concepts and the total amount of integrated conceptual information. The results show that, over the course of the animats' adaptation, i) the number of concepts grows; ii) integrated conceptual information increases; iii) this increase depends on the complexity of the environment, especially on the requirement for sequential memory. These results suggest that the need to capture the causal structure of a rich environment, given limited sensors and internal mechanisms, is an important driving force for organisms to develop highly integrated networks ("brains") with many concepts, leading to an increase in their internal complexity. PMID- 25521492 TI - Abstracts of the Seventh Scientific Meeting of The TMJ Association, 7-9 September 2014, Bethesda, Maryland. PMID- 25521493 TI - Synchronous seasonal change in fin whale song in the North Pacific. AB - Fin whale (Balaenoptera physalus) song consists of down-swept pulses arranged into stereotypic sequences that can be characterized according to the interval between successive pulses. As in blue (B. musculus) and humpback whales (Megaptera novaeangliae), these song sequences may be geographically distinct and may correlate with population boundaries in some regions. We measured inter-pulse intervals of fin whale songs within year-round acoustic datasets collected between 2000 and 2006 in three regions of the eastern North Pacific: Southern California, the Bering Sea, and Hawaii. A distinctive song type that was recorded in all three regions is characterized by singlet and doublet inter-pulse intervals that increase seasonally, then annually reset to the same shorter intervals at the beginning of each season. This song type was recorded in the Bering Sea and off Southern California from September through May and off Hawaii from December through April, with the song interval generally synchronized across all monitoring locations. The broad geographic and seasonal occurrence of this particular fin whale song type may represent a single population broadly distributed throughout the eastern Pacific with no clear seasonal migratory pattern. Previous studies attempting to infer population structure of fin whales in the North Pacific using synchronous individual song samples have been unsuccessful, likely because they did not account for the seasonal lengthening in song intervals observed here. PMID- 25521495 TI - Differential mobility spectrometry-mass spectrometry for atomic analysis. AB - Analysis and separation of atomic ions within a portable setting are studied in forensic applications of radiological debris analysis. Ion mobility spectrometry (IMS) may be used to show separation of atomic ions, while the related method of differential mobility spectrometry (DMS) has focused on fractionation of primarily molecular components. We set out to investigate DMS as a means for separating atomic ions. We initially derived the differential ion mobility parameter, alpha, from classic empirical IMS data of atomic ions, cesium and potassium, each showing its own distinct form of alpha. These alpha functions were applied to DMS simulations and supported by analytical treatment that suggested a means for a rapid disambiguation of atomic ions using DMS. We validated this hypothesis through the prototype cesium-potassium system investigated experimentally by DMS coupled to mass spectrometry (MS). Such a feature would be advantageous in a field portable instrument for rapid atomic analyses especially in the case of isobaric ions that cannot be distinguished by MS. Herein, we first report this novel method for the derivation of alpha from existing field dependent drift tube ion mobility data. Further, we translate experimental DMS data into alpha parameters by expanding upon existing methods. Refining the alpha parameter in this manner helps convey the interpretation of the alpha parameter particularly for those new to the DMS field. PMID- 25521496 TI - Multiphoton microscopic imaging of rabbit dorsal skin. AB - Rabbits are often preferred to be experimental animals during the skin research. The visualizing and understanding the full-thickness structure of rabbit skin has significance in biology, medicine, and animal husbandry. In this study, multiphoton microscopy (MPM) was employed to examine the rabbit skin on the back, which was based on second harmonic generation and two-photon excited fluorescence. High-resolution images were achieved from the fresh, unfixed, and unstained tissues, showing detailed microstructure of the skin without the administration of exogenous contrast agents. The morphology and distribution of the main components of epidermis and dermis, such as keratin, collagen fibers, elastic fibers, and hair follicles, can be distinctly identified in MPM images. Since the changes in these components are tightly related to skin diseases and wound healing, the noninvasive nature of MPM enables it become a valuable tool in skin research for detecting and monitoring. PMID- 25521494 TI - Direct activation of ribosome-associated double-stranded RNA-dependent protein kinase (PKR) by deoxynivalenol, anisomycin and ricin: a new model for ribotoxic stress response induction. AB - Double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a critical upstream mediator of the ribotoxic stress response (RSR) to the trichothecene deoxynivalenol (DON) and other translational inhibitors. Here, we employed HeLa cell lysates to: (1) characterize PKR's interactions with the ribosome and ribosomal RNA (rRNA); (2) demonstrate cell-free activation of ribosomal associated PKR and (3) integrate these findings in a unified model for RSR. Robust PKR-dependent RSR was initially confirmed in intact cells. PKR basally associated with 40S, 60S, 80S and polysome fractions at molar ratios of 7, 2, 23 and 3, respectively. Treatment of ATP-containing HeLa lysates with DON or the ribotoxins anisomycin and ricin concentration-dependently elicited phosphorylation of PKR and its substrate eIF2alpha. These phosphorylations could be blocked by PKR inhibitors. rRNA immunoprecipitation (RNA-IP) of HeLa lysates with PKR-specific antibody and sequencing revealed that in the presence of DON or not, the kinase associated with numerous discrete sites on both the 18S and 28S rRNA molecules, a number of which contained double-stranded hairpins. These findings are consistent with a sentinel model whereby multiple PKR molecules basally associate with the ribosome positioning them to respond to ribotoxin induced alterations in rRNA structure by dimerizing, autoactivating and, ultimately, evoking RSR. PMID- 25521497 TI - General and practical formation of thiocyanates from thiols. AB - A new method for the cyanation of thiols and disulfides using cyanobenziodoxol(on)e hypervalent iodine reagents is described. Both aliphatic and aromatic thiocyanates can be accessed in good yields in a few minutes at room temperature starting from a broad range of thiols with high chemioselectivity. The complete conversion of disulfides to thiocyanates was also possible. Preliminary computational studies indicated a low energy concerted transition state for the cyanation of the thiolate anion or radical. The developed thiocyanate synthesis has broad potential for various applications in synthetic chemistry, chemical biology and materials science. PMID- 25521498 TI - A woman with night sweats, arthritis, and two distinct eruptions. Adult-onset Still's disease (AOSD). PMID- 25521499 TI - Functional activity of monocytes and macrophages in HTLV-1 infected subjects. AB - The Human T lymphotropic virus type-1 (HTLV-1) infects predominantly T cells, inducing proliferation and lymphocyte activation. Additionally, HTLV-1 infected subjects are more susceptible to other infections caused by other intracellular agents. Monocytes/macrophages are important cells in the defense against intracellular pathogens. Our aims were to determine the frequency of monocytes subsets, expression of co-stimulatory molecules in these cells and to evaluate microbicidal ability and cytokine and chemokine production by macrophages from HTLV-1 infected subjects. Participants were 23 HTLV-1 carriers (HC), 22 HAM/TSP patients and 22 healthy subjects (HS) not infected with HTLV-1. The frequencies of monocyte subsets and expression of co-stimulatory molecules were determined by flow cytometry. Macrophages were infected with L. braziliensis or stimulated with LPS. Microbicidal activity of macrophages was determined by optic microscopy. Cytokines/chemokines from macrophage supernatants were measured by ELISA. HAM/TSP patients showed an increase frequency of intermediate monocytes, but expression of co-stimulatory molecules was similar between the groups. Macrophages from HTLV 1 infected individuals were infected with L. braziliensis at the same ratio than macrophages from HS, and all the groups had the same ability to kill Leishmania parasites. However, macrophages from HTLV-1 infected subjects produced more CXCL9 and CCL5, and less IL-10 than cells from HS. While there was no correlation between IFN-gamma and cytokine/chemokine production by macrophages, there was a correlation between proviral load and TNF and CXCL10. These data showed a dissociation between the inflammatory response and microbicidal ability of macrophages from HTLV-1 infected subjects. While macrophages ability to kill an intracellular pathogen did not differ among HTLV-1 infected subjects, these cells secreted high amount of chemokines even in unstimulated cultures. Moreover the increasing inflammatory activity of macrophages was similar in HAM/TSP patients and HC and it was related to HTLV-1 proviral load rather than the high IFN-gamma production observed in these subjects. PMID- 25521501 TI - A novel triterpenoid isolated from apple functions as an anti-mammary tumor agent via a mitochondrial and caspase-independent apoptosis pathway. AB - A novel triterpenoid, named 3beta-trans-cinnamoyloxy-2alpha-hydroxy-urs-12-en-28 oic acid (CHUA), was one of the main components of apple peels and showed potent in vitro antitumor activity against human tumor cells. In vivo antitumor experiments showed that CHUA could significantly inhibit the growth of mammary tumor in a nude mouse xenograft model at a dose of 50 mg/kg/day without body weight loss and mortality. In vitro, CHUA could induce apoptosis in MDA-MB-231 cells through the detection of DNA fragments and LDH activity. Simultaneously, mitochondrial transmembrane potential was markedly reduced and the release of cytochrome c was increased after CHUA treatment. It also up-regulated the expression ratio of mitochondrial Bax/Bcl-2 regulated by SIRT1 and p53. Interestingly, z-VAD-fmk and z-DEVD-fmk augmented cell death after CHUA treatment. Other protease(s) different from caspase-3 might be responsible for the degradation of PARP. These results suggested that the pro-apoptotic activity of CHUA may be adjusted by mitochondrial and caspase-independent pathways. PMID- 25521500 TI - Structure and biological roles of Sinorhizobium fredii HH103 exopolysaccharide. AB - Here we report that the structure of the Sinorhizobium fredii HH103 exopolysaccharide (EPS) is composed of glucose, galactose, glucuronic acid, pyruvic acid, in the ratios 5?2?2?1 and is partially acetylated. A S. fredii HH103 exoA mutant (SVQ530), unable to produce EPS, not only forms nitrogen fixing nodules with soybean but also shows increased competitive capacity for nodule occupancy. Mutant SVQ530 is, however, less competitive to nodulate Vigna unguiculata. Biofilm formation was reduced in mutant SVQ530 but increased in an EPS overproducing mutant. Mutant SVQ530 was impaired in surface motility and showed higher osmosensitivity compared to its wild type strain in media containing 50 mM NaCl or 5% (w/v) sucrose. Neither S. fredii HH103 nor 41 other S. fredii strains were recognized by soybean lectin (SBL). S. fredii HH103 mutants affected in exopolysaccharides (EPS), lipopolysaccharides (LPS), cyclic glucans (CG) or capsular polysaccharides (KPS) were not significantly impaired in their soybean-root attachment capacity, suggesting that these surface polysaccharides might not be relevant in early attachment to soybean roots. These results also indicate that the molecular mechanisms involved in S. fredii attachment to soybean roots might be different to those operating in Bradyrhizobium japonicum. PMID- 25521502 TI - Improving protein fold recognition using the amalgamation of evolutionary-based and structural based information. AB - Deciphering three dimensional structure of a protein sequence is a challenging task in biological science. Protein fold recognition and protein secondary structure prediction are transitional steps in identifying the three dimensional structure of a protein. For protein fold recognition, evolutionary-based information of amino acid sequences from the position specific scoring matrix (PSSM) has been recently applied with improved results. On the other hand, the SPINE-X predictor has been developed and applied for protein secondary structure prediction. Several reported methods for protein fold recognition have only limited accuracy. In this paper, we have developed a strategy of combining evolutionary-based information (from PSSM) and predicted secondary structure using SPINE-X to improve protein fold recognition. The strategy is based on finding the probabilities of amino acid pairs (AAP). The proposed method has been tested on several protein benchmark datasets and an improvement of 8.9% recognition accuracy has been achieved. We have achieved, for the first time over 90% and 75% prediction accuracies for sequence similarity values below 40% and 25%, respectively. We also obtain 90.6% and 77.0% prediction accuracies, respectively, for the Extended Ding and Dubchak and Taguchi and Gromiha benchmark protein fold recognition datasets widely used for in the literature. PMID- 25521503 TI - Valuation and Modeling of EQ-5D-5L Health States Using a Hybrid Approach. AB - BACKGROUND: The EQ-5D instrument is the most widely used preference-based health related quality of life questionnaire in cost-effectiveness analysis of health care technologies. Recently, a version called EQ-5D-5L with 5 levels on each dimension was developed. This manuscript explores the performance of a hybrid approach for the modeling of EQ-5D-5L valuation data. METHODS: Two elicitation techniques, the composite time trade-off, and discrete choice experiments, were applied to a sample of the Spanish population (n=1000) using a computer-based questionnaire. The sampling process consisted of 2 stages: stratified sampling of geographic area, followed by systematic sampling in each area. A hybrid regression model combining composite time trade-off and discrete choice data was used to estimate the potential value sets using main effects as starting point. The comparison between the models was performed using the criteria of logical consistency, goodness of fit, and parsimony. RESULTS: Twenty-seven participants from the 1000 were removed following the exclusion criteria. The best-fitted model included 2 significant interaction terms but resulted in marginal improvements in model fit compared to the main effects model. We therefore selected the model results with main effects as a potential value set for this methodological study, based on the parsimony criteria. The results showed that the main effects hybrid model was consistent, with a range of utility values between 1 and -0.224. CONCLUSION: This paper shows the feasibility of using a hybrid approach to estimate a value set for EQ-5D-5L valuation data. PMID- 25521504 TI - Reactions of Mg and Mg2 with SO2 in low-temperature matrices: association or insertion? AB - Laser-ablated magnesium species were codeposited with SO2 in excess argon or neon on the substrate at 4 K. The reactions mainly produced Mg(eta(2)-O2S), Mg(eta(2) O2S)2, Mg2(eta(2)-O2S), OMg2(eta(2)-SO), and Mg(eta(2)-SO) complexes, which were identified by isotopic substitutions and density functional frequency calculations (B3LYP and BPW91). In addition, the collected infrared spectra suggest that the single Mg atoms could react with SO2 to form the Mg(eta(2)-O2S) complex on annealing, which further reacts with SO2 to produce the Mg(eta(2) O2S)2 complex on irradiation. In contrast, the reactions of magnesium dimers lead to cleavage of the S?O bond in SO2 on irradiating. Structural and bonding characteristics of these generated complexes, which shed light on the different performances of single Mg atom and its dimer in their reactions with small molecules, are discussed. PMID- 25521505 TI - Help-seeking experiences of men diagnosed with colorectal cancer: a qualitative study. AB - Advanced-stage diagnosis of colorectal cancer (CRC) leads to poor prognosis and reduced survival rates. The current study seeks to explore the reasons for diagnostic delays in a sample of Australian men with CRC. Semi-structured interviews were conducted in a purposive sample of 20 male CRC patients. Data collection ceased when no new data emerged. Interviews were audiotaped, transcribed and thematically analysed using Andersen's Model of Total Patient Delay as the theoretical framework. Most participants (18/20) had experienced lower bowel symptoms prior to diagnosis. Patient-related delays were more common than delays attributable to the health-care system. Data regarding patient delays fit within the first four stages of Andersen's model. The barriers to seeking timely medical advice were mainly attributed to misinterpretation of symptoms, fear of cancer diagnosis, reticence to discuss the symptoms or consulting a general practitioner. Treatment delays were a minor cause for delayed diagnosis. Delay in referral and scheduling for colonoscopy were among the system-delay factors. In many instances, delays resulted from men's failure to attribute their symptoms to cancer and, subsequently, delay in diagnosis. PMID- 25521506 TI - Practices used for recommending sickness certification by general practitioners: a conversation analytic study of UK primary care consultations. AB - Existing research indicates that many patients and doctors find the process of negotiating sickness certification for time off work to be a difficult one. This study examined how patients and general practitioners (GPs) managed these negotiations in a sample of UK primary care consultations. The study made use of an existing dataset of audio-recorded consultations between 13 GPs and 506 unselected adult patients in five general practices in London. Forty-nine consultations included discussions for both initial and repeat sickness certification across a wide range of conditions. Here we report our findings on doctor practices for recommending, as opposed to patient practices for advocating for, sickness certification (n = 26 cases). All cases were transcribed in detail and analysed using conversation analytic methods. Four main communication practices were observed: (1) declarative statements of need for sickness certification; (2) 'do you need' offers for sickness certification; (3) 'do you want' offers for sickness certification; and (4) conditional 'If X, Y' offers for sickness certification. These different communication practices indexed doctor agency, doctor endorsement and patient entitlement to varying degrees. In the main, recommendations to patients presenting with biomedical problems or a repeat occurrence of a psychosocial problem displayed stronger doctor endorsement and patient entitlement. Contrastingly, recommendations to patients presenting with new psychosocial and biopsychosocial problems, displayed weaker endorsement and patient entitlement. This study offers new evidence to support the Parsonian argument that becoming sick involves entering a social role with special rights and obligations. Through documenting doctors' orientations to their gatekeeping role as well as patients' orientations to differential rights vis a vis legitimacy, we demonstrate the contrasting stances of doctors in situ when giving sick notes for biomedical problems as opposed to difficulties of a more psychosocial nature. PMID- 25521507 TI - cisMEP: an integrated repository of genomic epigenetic profiles and cis regulatory modules in Drosophila. AB - BACKGROUND: Cis-regulatory modules (CRMs), or the DNA sequences required for regulating gene expression, play the central role in biological researches on transcriptional regulation in metazoan species. Nowadays, the systematic understanding of CRMs still mainly resorts to computational methods due to the time-consuming and small-scale nature of experimental methods. But the accuracy and reliability of different CRM prediction tools are still unclear. Without comparative cross-analysis of the results and combinatorial consideration with extra experimental information, there is no easy way to assess the confidence of the predicted CRMs. This limits the genome-wide understanding of CRMs. DESCRIPTION: It is known that transcription factor binding and epigenetic profiles tend to determine functions of CRMs in gene transcriptional regulation. Thus integration of the genome-wide epigenetic profiles with systematically predicted CRMs can greatly help researchers evaluate and decipher the prediction confidence and possible transcriptional regulatory functions of these potential CRMs. However, these data are still fragmentary in the literatures. Here we performed the computational genome-wide screening for potential CRMs using different prediction tools and constructed the pioneer database, cisMEP (cis regulatory module epigenetic profile database), to integrate these computationally identified CRMs with genomic epigenetic profile data. cisMEP collects the literature-curated TFBS location data and nine genres of epigenetic data for assessing the confidence of these potential CRMs and deciphering the possible CRM functionality. CONCLUSIONS: cisMEP aims to provide a user-friendly interface for researchers to assess the confidence of different potential CRMs and to understand the functions of CRMs through experimentally-identified epigenetic profiles. The deposited potential CRMs and experimental epigenetic profiles for confidence assessment provide experimentally testable hypotheses for the molecular mechanisms of metazoan gene regulation. We believe that the information deposited in cisMEP will greatly facilitate the comparative usage of different CRM prediction tools and will help biologists to study the modular regulatory mechanisms between different TFs and their target genes. PMID- 25521509 TI - Exploiting the wall-induced non-inertial lift in electrokinetic flow for a continuous particle separation by size. AB - Separating particles from a heterogeneous mixture is important and necessary in many engineering and biomedical applications. Electrokinetic flow-based continuous particle separation has thus far been realized primarily by the use of particle dielectrophoresis induced in constricted and/or curved microchannels. We develop in this work a new electrokinetic method that exploits the wall-induced non-inertial lift in a straight uniform microchannel to continuously separate particles by intrinsic properties (e.g., size and surface charge). Such an electrically originated lift force arises from the asymmetric electric field distribution around a particle nearby a planar dielectric wall. We demonstrate this method through separating both a binary and ternary mixture of dispersed polystyrene microspheres by size in a T-shaped microchannel. A semi-analytical model is also developed to simulate and understand the particle separation process. The predicted particle trajectories in the entire microchannel agree reasonably well with the experimental measurements. PMID- 25521508 TI - SEEDSTICK is a master regulator of development and metabolism in the Arabidopsis seed coat. AB - The role of secondary metabolites in the determination of cell identity has been an area of particular interest over recent years, and studies strongly indicate a connection between cell fate and the regulation of enzymes involved in secondary metabolism. In Arabidopsis thaliana, the maternally derived seed coat plays pivotal roles in both the protection of the developing embryo and the first steps of germination. In this regard, a characteristic feature of seed coat development is the accumulation of proanthocyanidins (PAs - a class of phenylpropanoid metabolites) in the innermost layer of the seed coat. Our genome-wide transcriptomic analysis suggests that the ovule identity factor SEEDSTICK (STK) is involved in the regulation of several metabolic processes, providing a strong basis for a connection between cell fate determination, development and metabolism. Using phenotypic, genetic, biochemical and transcriptomic approaches, we have focused specifically on the role of STK in PA biosynthesis. Our results indicate that STK exerts its effect by direct regulation of the gene encoding BANYULS/ANTHOCYANIDIN REDUCTASE (BAN/ANR), which converts anthocyanidins into their corresponding 2,3-cis-flavan-3-ols. Our study also demonstrates that the levels of H3K9ac chromatin modification directly correlate with the active state of BAN in an STK-dependent way. This is consistent with the idea that MADS-domain proteins control the expression of their target genes through the modification of chromatin states. STK might thus recruit or regulate histone modifying factors to control their activity. In addition, we show that STK is able to regulate other BAN regulators. Our study demonstrates for the first time how a floral homeotic gene controls tissue identity through the regulation of a wide range of processes including the accumulation of secondary metabolites. PMID- 25521511 TI - Reversed-phase vortex-assisted liquid-liquid microextraction: a new sample preparation method for the determination of amygdalin in oil and kernel samples. AB - A novel, simple, and rapid reversed-phase vortex-assisted liquid-liquid microextraction coupled with high-performance liquid chromatography has been introduced for the extraction, clean-up, and preconcentration of amygdalin in oil and kernel samples. In this technique, deionized water was used as the extracting solvent. Unlike the reversed-phase dispersive liquid-liquid microextraction, dispersive solvent was eliminated in the proposed method. Various parameters that affected the extraction efficiency, such as extracting solvent volume and its pH, vortex, and centrifuging times were evaluated and optimized. The calibration curve shows good linearity (r(2) = 0.9955) and precision (RSD < 5.2%) in the range of 0.07-20 MUg/mL. The limit of detection and limit of quantitation were 0.02 and 0.07 MUg/mL, respectively. The recoveries were in the range of 96.0 102.0% with relative standard deviation values ranging from 4.0 to 5.1%. Unlike the conventional extraction methods for plant extracts, no evaporative and re solubilizing operations were needed in the proposed technique. PMID- 25521512 TI - High temperatures result in smaller nurseries which lower reproduction of pollinators and parasites in a brood site pollination mutualism. AB - In a nursery pollination mutualism, we asked whether environmental factors affected reproduction of mutualistic pollinators, non-mutualistic parasites and seed production via seasonal changes in plant traits such as inflorescence size and within-tree reproductive phenology. We examined seasonal variation in reproduction in Ficus racemosa community members that utilise enclosed inflorescences called syconia as nurseries. Temperature, relative humidity and rainfall defined four seasons: winter; hot days, cold nights; summer and wet seasons. Syconium volumes were highest in winter and lowest in summer, and affected syconium contents positively across all seasons. Greater transpiration from the nurseries was possibly responsible for smaller syconia in summer. The 3 5 degrees C increase in mean temperatures between the cooler seasons and summer reduced fig wasp reproduction and increased seed production nearly two-fold. Yet, seed and pollinator progeny production were never negatively related in any season confirming the mutualistic fig-pollinator association across seasons. Non pollinator parasites affected seed production negatively in some seasons, but had a surprisingly positive relationship with pollinators in most seasons. While within-tree reproductive phenology did not vary across seasons, its effect on syconium inhabitants varied with season. In all seasons, within-tree reproductive asynchrony affected parasite reproduction negatively, whereas it had a positive effect on pollinator reproduction in winter and a negative effect in summer. Seasonally variable syconium volumes probably caused the differential effect of within-tree reproductive phenology on pollinator reproduction. Within-tree reproductive asynchrony itself was positively affected by intra-tree variation in syconium contents and volume, creating a unique feedback loop which varied across seasons. Therefore, nursery size affected fig wasp reproduction, seed production and within-tree reproductive phenology via the feedback cycle in this system. Climatic factors affecting plant reproductive traits cause biotic relationships between plants, mutualists and parasites to vary seasonally and must be accorded greater attention, especially in the context of climate change. PMID- 25521510 TI - HTLV-1 Tax-mediated inhibition of FOXO3a activity is critical for the persistence of terminally differentiated CD4+ T cells. AB - The mechanisms involved in the persistence of activated CD4+ T lymphocytes following primary human T leukemia/lymphoma virus type 1 (HTLV-1) infection remain unclear. Here, we demonstrate that the HTLV-1 Tax oncoprotein modulates phosphorylation and transcriptional activity of the FOXO3a transcription factor, via upstream activation of the AKT pathway. De novo HTLV-1 infection of CD4+ T cells or direct lentiviral-mediated introduction of Tax led to AKT activation and AKT-dependent inactivation of FOXO3a, via phosphorylation of residues Ser253 and Thr32. Inhibition of FOXO3a signalling led to the long-term survival of a population of highly activated, terminally differentiated CD4+Tax+CD27negCCR7neg T cells that maintained the capacity to disseminate infectious HTLV-1. CD4+ T cell persistence was reversed by chemical inhibition of AKT activity, lentiviral mediated expression of a dominant-negative form of FOXO3a or by specific small interfering RNA (siRNA)-mediated silencing of FOXO3a. Overall this study provides new mechanistic insight into the strategies used by HTLV-1 to increase long-term maintenance of Tax+CD4+ T lymphocytes during the early stages of HTLV-1 pathogenesis. PMID- 25521514 TI - Tribology of Si/SiO2 in humid air: transition from severe chemical wear to wearless behavior at nanoscale. AB - Wear at sliding interfaces of silicon is a main cause for material loss in nanomanufacturing and device failure in microelectromechanical system (MEMS) applications. However, a comprehensive understanding of the nanoscale wear mechanisms of silicon in ambient conditions is still lacking. Here, we report the chemical wear of single crystalline silicon, a material used for micro/nanoscale devices, in humid air under the contact pressure lower than the material hardness. A transmission electron microscopy (TEM) analysis of the wear track confirmed that the wear of silicon in humid conditions originates from surface reactions without significant subsurface damages such as plastic deformation or fracture. When rubbed with a SiO2 ball, the single crystalline silicon surface exhibited transitions from severe wear in intermediate humidity to nearly wearless states at two opposite extremes: (a) low humidity and high sliding speed conditions and (b) high humidity and low speed conditions. These transitions suggested that at the sliding interfaces of Si/SiO2 at least two different tribochemical reactions play important roles. One would be the formation of a strong "hydrogen bonding bridge" between hydroxyl groups of two sliding interfaces and the other the removal of hydroxyl groups from the SiO2 surface. The experimental data indicated that the dominance of each reaction varies with the ambient humidity and sliding speed. PMID- 25521513 TI - Duodenal rather than antral motility contractile parameters correlate with symptom severity in gastroparesis patients. AB - BACKGROUND: Studies of symptomatic gastroparetics consistently find poor correlation with gastric emptying. We hypothesized that concomitant small bowel dysmotility may play a role in symptom causation in gastroparesis and sought to test this hypothesis by using wireless motility capsule (WMC) testing to simultaneously measure antral and duodenal area under pressure curve (AUC) in patients with delayed gastric emptying. METHODS: Using a cohort from a multicenter clinical trial and a separate tertiary clinical database, we identified gastroparetics that underwent concurrent WMC testing and completed the Gastroparesis Cardinal Symptom Index, a validated questionnaire. Our study included 35 gastroparetics defined by a gastric emptying time (GET) >= 5 h. Antral and duodenal AUC were assessed at 1-h windows pre-GET and post-GET, respectively. KEY RESULTS: We found moderate correlations between duodenal AUC and symptom severity in the combined cohort (n = 35; R = -0.42; p = 0.01; 95% CI 0.7, -0.1). Removing patients with colonic delay resulted in a stronger correlation of duodenal AUC to symptom severity (n = 21; R = -0.63; p < 0.01; 95% CI -0.81, -0.31). The multicenter trial (n = 20) and clinical practice cohorts (n = 15) had significantly different symptom severity and exclusion criteria. When analyzed separately, significant correlations between duodenal AUC and symptom severity were observed (R = -0.71; p < 0.01; 95% CI -0.9, -0.4 and R = -0.72; p < 0.01; 95% CI -0.9, -0.3, respectively). Symptom severity and antral motility showed no correlation. CONCLUSIONS & INFERENCES: We found significant correlations between duodenal AUC and symptom severity in two cohorts of gastroparetics. Small bowel motility may contribute to symptom generation in gastroparetic patients and this may inform therapeutic considerations. PMID- 25521515 TI - A second corticotropin-releasing hormone gene (CRH2) is conserved across vertebrate classes and expressed in the hindbrain of a basal neopterygian fish, the spotted gar (Lepisosteus oculatus). AB - To investigate the origins of the vertebrate stress-response system, we searched sequenced vertebrate genomes for genes resembling corticotropin-releasing hormone (CRH). We found that vertebrate genomes possess, in addition to CRH, another gene that resembles CRH in sequence and syntenic environment. This paralogous gene was previously identified only in the elephant shark (a holocephalan), but we find it also in marsupials, monotremes, lizards, turtles, birds, and fishes. We examined the relationship of this second vertebrate CRH gene, which we name CRH2, to CRH1 (previously known as CRH) and urocortin1/urotensin1 (UCN1/UTS1) in primitive fishes, teleosts, and tetrapods. The paralogs CRH1 and CRH2 likely evolved via duplication of CRH during a whole-genome duplication early in the vertebrate lineage. CRH2 was subsequently lost in both teleost fishes and eutherian mammals but retained in other lineages. To determine where CRH2 is expressed relative to CRH1 and UTS1, we used in situ hybridization on brain tissue from spotted gar (Lepisosteus oculatus), a neopterygian fish closely related to teleosts. In situ hybridization revealed widespread distribution of both crh1 and uts1 in the brain. Expression of crh2 was restricted to the putative secondary gustatory/secondary visceral nucleus, which also expressed calcitonin-related polypeptide alpha (calca), a marker of parabrachial nucleus in mammals. Thus, the evolutionary history of CRH2 includes restricted expression in the brain, sequence changes, and gene loss, likely reflecting release of selective constraints following whole-genome duplication. The discovery of CRH2 opens many new possibilities for understanding the diverse functions of the CRH family of peptides across vertebrates. PMID- 25521516 TI - Basic and applied problems in developmental biology and immunobiology of cestode infections: Hymenolepis, Taenia and Echinococcus. AB - Differentiation and development of parasites, including longevity in host animals, are thought to be governed by host-parasite interactions. In this review, several topics on the developmental biology of cestode infections are discussed from immunobiological perspective with a focus on Hymenolepis, Taenia and Echinococcus infections. The basic premise of this review is that 'differentiation and development of cestodes' are somehow affected by host immune responses with an evolutionary history. PMID- 25521517 TI - Anti-cancer iron(II) complexes of pentadentate N-donor ligands: cytotoxicity, transcriptomics analyses, and mechanisms of action. AB - Two cytotoxic iron(II) complexes [Fe(L)(CH3 CN)n ](ClO4 )2 (L=qpy for Fe-1 a, Py5 -OH for Fe-2 a) were synthesized. Both complexes are stable against spontaneous demetalation and oxidation in buffer solutions. Cyclic voltammetry measurements revealed the higher stability of Fe-2 a (+0.82 V vs Fc) against Fe(II) to Fe(III) oxidation than Fe-1 a (+0.57 V vs Fc). These two complexes display potent cytotoxicity at micromolar level against a panel of cancer cell lines (Fe-1 a=0.8 3.1 MUM; Fe-2 a=0.6-3.4 MUM), and induce apoptosis that involves caspase activation. Transcriptomic and Connectivity Map analyses revealed that the changes of gene expression induced by Fe-1 a and Fe-2 a are similar to that induced by ciclopirox, an antifungal compound whose mode of action involves formation of intracellular cytotoxic iron chelates. Both Fe-1 a and Fe-2 a caused cellular nuclear DNA damage, as revealed by Comet assay and H2 AX immunofluorescence experiments. The cytotoxicity is associated with production of reactive oxygen species (for Fe-1 a), cell cycle regulation, and stress kinase pathways. The relative contributions of these to the overall cytotoxic mechanism is significantly affected by the structure of penta-N-donor ligand. PMID- 25521518 TI - Factors influencing women's attitudes towards midwifery: Tool validation. AB - The purpose of this study was to validate a tool that explores the factors influencing women's opinion of and attitudes towards midwifery. A descriptive, cross-sectional design was used. The sample consisted of 526 Jordanian women. Cluster sampling was used to ensure a representative sample; then, convenience sampling was performed. The instrument asked non-identifying demographic questions and covered factors reported in literature to influence women's attitudes towards and views of the profession. The resulting instrument consisted of five factors explained by 29 items. These factors were women's general view of midwives, midwife duties, professional ethics, media influence and demotivating factors associated with working as a midwife. Although the instrument is valid and reliable, it needs further testing in other studies. Taking the factors reported on by the present study into account in public policy-making could promote better understanding of midwifery and improve its status in the community. PMID- 25521519 TI - The epidemiology, clinical course and outcome of febrile cytopenia in children. AB - AIM: Transient infectious neutropenia of mild-to-moderate severity is common and resolves spontaneously within weeks. This was the first prospective study of the whole spectrum of febrile cytopenia in noncancer patients followed-up for 2 years. It aimed to assess its aetiology, duration and outcome. METHODS: We evaluated 116 children with febrile cytopenia aged 4 +/- 3.8 years, admitted to a paediatric ward over 2 years, using inflammatory markers, cultures and serological tests. RESULTS: An infectious agent was identified in 74 (63.8%) cases: 44.8% viral, 11.2% bacterial and 7.8% parasitic. One cell line was affected in 26.7% of patients and >=2 cell lines in 73.3%. Cytopenia was transient in 82.75% of cases and chronic in 17.24%. The transient cytopenia subgroups - exhibited differences in severity (mild in bacterial cases and moderate in viral and parasitic cases, p = 0.018) and the number of affected cell lines, (predominantly two in viral and bacterial cases and pancytopenia in parasitic cases, p = 0.001). Chronic patients had severe cytopenia (p = 0.004) with >=2 cell lines affected, while transient patients had mild-to-moderate cytopenia, with 1-3 cell lines affected. CONCLUSION: Childhood febrile cytopenia is usually transient, of mild-to-moderate severity, and resolves spontaneously, but patients with severe cytopenia affecting >=2 cell lines need further evaluation and follow-up. PMID- 25521520 TI - Clinical heterogeneity in a family with mutations in USH2A. PMID- 25521521 TI - In quest of the unified field theory of exercise training. PMID- 25521522 TI - Structure and function of G protein-coupled receptor oligomers: implications for drug discovery. AB - G protein-coupled receptor (GPCR) oligomers are promising targets for the design of new highly selective therapeutics. GPCRs have historically been attractive drug targets for their role in nearly all cellular processes, and their localization at the cell surface makes them easily accessible to most small molecule therapeutics. However, GPCRs have traditionally been considered a monomeric entity, a notion that greatly oversimplifies their function. As evidence accumulates that GPCRs tune function through oligomer formation and protein-protein interactions, we see a greater demand for structural information about these oligomers to facilitate oligomer-specific drug design. These efforts are slowed by difficulties inherent to studying membrane proteins, such as low expression yield, in vitro stability and activity. Such obstacles are amplified for the study of specific oligomers, as there are limited tools to directly isolate and characterize these receptor complexes. Thus, there is a need to develop new interdisciplinary approaches, combining biochemical and biophysical techniques, to address these challenges and elucidate structural details about the oligomer and ligand binding interfaces. In this review, we provide an overview of mechanistic models that have been proposed to underlie the function of GPCR oligomers, and perspectives on emerging techniques to characterize GPCR oligomers for structure-based drug design. PMID- 25521523 TI - Self-weighing in weight management: a systematic literature review. AB - OBJECTIVE: Regular self-weighing, which in this article is defined as weighing oneself regularly over a period of time (e.g., daily, weekly), is recommended as a weight loss strategy. However, the published literature lacks a review of the recent evidence provided by prospective, longitudinal studies. Moreover, no paper has reviewed the psychological effects of self-weighing. Therefore, the objective is to review the literature related to longitudinal associations between self weighing and weight change as well as the psychological outcomes. METHODS: Electronic literature searches in PubMed, Ovid PsycINFO, and Ebscohost CINAHL were conducted. Keywords included overweight, obesity, self-weighing, etc. Inclusion criteria included trials that were published in the past 25 years in English; participants were adults seeking weight loss treatment; results were based on longitudinal data. RESULTS: The results (N=17 studies) revealed that regular self-weighing was associated with more weight loss and not with adverse psychological outcomes (e.g., depression, anxiety). Findings demonstrated that the effect sizes of association between self-weighing and weight change varied across studies and also that the reported frequency of self-weighing varied across studies. CONCLUSIONS: The findings from prospective, longitudinal studies provide evidence that regular self-weighing has been associated with weight loss and not with negative psychological outcomes. PMID- 25521526 TI - Studies on the formal [3 + 2] cycloaddition of aziridines with alkenes for the synthesis of 1-azaspiroalkanes. AB - The Lewis acid-mediated [3 + 2] cycloaddition of N-sulfonyl- and N sulfamoylaziridines with alkenes provides a rapid and efficient access to 1 azaspiro[4.n]alkanes. Experimental studies have been combined with DFT calculations to explore the mechanism of the reaction. They demonstrate that the nature of the electron-withdrawing nitrogen protecting group has a very limited influence on the course of the reaction and, particularly, on the initial formation of the 1,3-zwitterionic species through C-N bond cleavage, which has been found to be the rate-determining step. Compared to N-sulfonylaziridines, N sulfamoylaziridines have proved to be more synthetically useful synthons that afford crystalline polycyclic structures in good yields. A short sequence of catalytic C(sp(3))-H amination-cyclization-[3 + 2] cycloaddition has then been successfully designed to afford the homologue 1-azaspiro[5.n]alkanes, thereby illustrating the higher versatility of sulfamates in these cycloadditions. PMID- 25521525 TI - SRC family kinase inhibition through a new pyrazolo[3,4-d]pyrimidine derivative as a feasible approach for glioblastoma treatment. AB - Glioblastoma (GB) is the most common and aggressive primary tumor of the central nervous system. The current standard of care for GB consists of surgical resection, followed by radiotherapy combined with temozolomide chemotherapy. However, despite this intensive treatment, the prognosis remains extremely poor. Therefore, more effective therapies are urgently required. Recent studies indicate that SRC family kinases (SFKs) could represent promising molecular targets for GB therapy. Here, we challenged four GB cell lines with a new selective pyrazolo[3,4-d]pyrimidine derivative SFK inhibitor, called SI221. This compound exerted a significant cytotoxic effect on GB cells, without significantly affecting non-tumor cells (primary human skin fibroblasts), as evaluated by MTS assay. We also observed that SI221 was more effective than the well-known SFK inhibitor PP2 in GB cells. Notably, despite the high intrinsic resistance to apoptosis of GB cells, SI221 was able to induce this cell death process in all the GB cell lines, as observed through cytofluorimetric analysis and caspase-3 assay. SI221 also exerted a long-term inhibition of GB cell growth and was able to reduce GB cell migration, as shown by clonogenic assay and scratch test, respectively. Moreover, through in vitro pharmacokinetic assays, SI221 proved to have a high metabolic stability and a good potential to cross the blood brain barrier, which is an essential requirement for a drug intended to treat brain tumors. Therefore, despite the need of developing strategies to improve SI221 solubility, our results suggest a potential application of this selective SFK inhibitor in GB therapy. PMID- 25521524 TI - Enhanced GABAergic synaptic transmission at VLPAG neurons and potent modulation by oxycodone in a bone cancer pain model. AB - BACKGROUND AND PURPOSE: We demonstrated previously that oxycodone has potent antinociceptive effects at supraspinal sites. In this study, we investigated changes in neuronal function and antinociceptive mechanisms of oxycodone at ventrolateral periaqueductal gray (VLPAG) neurons, which are a major site of opioid action, in a femur bone cancer (FBC) model with bone cancer-related pain. EXPERIMENTAL APPROACH: We characterized the supraspinal antinociceptive profiles of oxycodone and morphine on mechanical hypersensitivity in the FBC model. Based on the disinhibition mechanism underlying supraspinal opioid antinociception, the effects of oxycodone and morphine on GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in VLPAG neurons were evaluated in slices from the FBC model. KEY RESULTS: The supraspinal antinociceptive effects of oxycodone, but not morphine, were abolished by blocking G protein-gated inwardly rectifying potassium1 (Kir 3.1) channels. In slices from the FBC model, GABAergic synaptic transmission at VLPAG neurons was enhanced, as indicated by a leftward shift of the input-output relationship curve of evoked IPSCs, the increased paired-pulse facilitation and the enhancement of miniature IPSC frequency. Following treatment with oxycodone and morphine, IPSCs were reduced in the FBC model, and the inhibition of presynaptic GABA release by oxycodone, but not morphine was enhanced and dependent on Kir 3.1 channels. CONCLUSION AND IMPLICATIONS: Our results demonstrate that Kir 3.1 channels are important for supraspinal antinociception and presynaptic GABA release inhibition by oxycodone in the FBC model. Enhanced GABAergic synaptic transmission at VLPAG neurons in the FBC model is an important site of supraspinal antinociception by oxycodone via Kir 3.1 channel activation. PMID- 25521528 TI - Overall survival and competing risks of death in patients with Waldenstrom macroglobulinaemia: an analysis of the Surveillance, Epidemiology and End Results database. AB - Waldenstrom macroglobulinaemia (WM) is a rare and incurable lymphoma. Given that the survival of WM patients can be prolonged, our objective was to describe trends in overall survival (OS) and analyse competing risks of death in patients with WM. The analysis included 5784 patients diagnosed with WM between 1991 and 2010 from the Surveillance, Epidemiology and End Results (SEER) database. Multivariate hazard models for OS and cumulative incidence of death were fitted according to epoch of diagnosis (1991-2000 vs. 2001-10) while adjusting for age, sex, race, histology, site of involvement and registry. Median OS for the 1991 2000 and the 2001-10 cohorts was 6 and 8 years, respectively (P < 0.001). In the multivariate analysis, better OS [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.67-0.79; P < 0.001] was seen in the 2001-10 cohort. Survival benefits were identified, for the 2001-10 cohort, in almost every stratum analysed, with the exception of patients aged <50 years and blacks. In the multivariate competing risk analysis, the 2001-10 cohort experienced lower rates of WM-related (HR 0.57, 95% CI 0.49-0.66; P < 0.001) and non-WM-related deaths (HR 0.72, 95% CI 0.66 0.79; P < 0.001). In conclusion, there have been significant improvements in OS, WM-related and non-WM-related mortality in patients with WM diagnosed in the last decade. PMID- 25521529 TI - Changing epistemologies under conditions of social change in two Arab communities in Israel. AB - The study of epistemic thinking focuses on how people understand and coordinate objective and subjective aspects of knowing and make sense of multiple and discrepant knowledge claims. Typically described in terms of normative development, cross-cultural studies show differences in epistemic development and characteristics of epistemic thinking. This study focuses on within-culture variations of epistemic thinking, with the assumption that social change will produce changes in development. Arab society in Israel has undergone notable change over the last half century. In this cross-sectional research design, cross generational comparison and rural-urban comparison were used as proxies for longitudinal social change. Three generations of Muslim Arab women in a village in Israel (20 adolescents, 20 mothers and 20 grandmothers) and 20 Muslim Arab adolescents from a large, mixed city in the same region responded to six dilemmas invoking epistemic thinking. Village adolescents were more subjectivist than their mothers and grandmothers. Sociodemographic characteristics representing greater exposure to diverse people and ideas accounted for generational differences. Both urban and rural adolescents tended towards subjectivist perspectives, and they did not differ. Parents' education levels emerged as the sociodemographic variables most consistently related to epistemic thinking. Epistemic thinking mediated the relationship between generation and gender role/cross-sex relation values. PMID- 25521527 TI - Tobacco use and surgical outcomes in patients with head and neck cancer. AB - BACKGROUND: Tobacco use is a risk factor for head and neck cancer, but effects on postoperative outcomes are unclear. METHODS: Patients with head and neck cancer (n = 89) were recruited before surgery. We assessed self-reported tobacco use status (never, former, or current) at study entry and recent tobacco exposure via urinary cotinine on surgery day. Outcomes included hospital length of stay (LOS) and complications. RESULTS: Most participants reported current (32.6%) or former (52.8%) tobacco use; 43.2% were cotinine-positive on surgery day. Complications occurred in 41.6% and mean LOS was 4.0 and 8.8 days in patients who received low and high acuity procedures, respectively. Current and former smokers were over 6 times more likely to have complications than never smokers (p = .03). For high acuity procedures, LOS was increased in current (by 4.4 days) and former smokers (by 2.3 days; p = .02). CONCLUSION: Tobacco use status is associated with postoperative complications and may distinguish at-risk patients. PMID- 25521531 TI - Treatment of chronic conditions with traditional Chinese medicine: findings from traditional Chinese medicine hospitals in Hubei, China. AB - OBJECTIVES: This study aimed to document clinical use of Traditional Chinese Medicine (TCM) for chronic conditions in all TCM hospitals in a Chinese province and to recommend treatments most in need of evaluation for use in community health centers. DESIGN: A cross-sectional survey was conducted in the summer of 2010. It included 119 of 132 TCM hospitals in Hubei Province, China. TCM physicians were asked to recommend specific TCM treatments for common chronic conditions. Nine types of chronic conditions recommended more than 3.7 times (mean of frequencies of chronic conditions) are included in this analysis. Frequency of each TCM treatment and the number of visits by type of chronic conditions were calculated. RESULTS: The total number of recommendations by TCM physicians was 411. For seven types of treatments, six were recommended for musculoskeletal pain, five for soft tissue injuries, four for visceral pain and fractures, three for stroke and asthma, two for hemorrhoids, and one for hypertension. The most frequently recommended treatments for specific conditions include orally ingested herbs for visceral pain (n=3), type 2 diabetes (n=5), and hypertension (n=7); herbs for external use for soft tissue injuries (n=10), asthma (n=6), and hemorrhoids (n=8); acupuncture for musculoskeletal pains (n=43) and for stroke (n=10); and Chinese external fixation for fractures (n=24). The number of visits for recommended treatments per year of was 671,759. The most frequently recommended treatments for specific chronic conditions have most visits, except for chronic conditions such as musculoskeletal pains, visceral pains, soft tissue injuries, and asthma. CONCLUSIONS: Patients with musculoskeletal pain have more treatment options than other patients. Herbal medicine is the option most commonly used for chronic conditions. These treatments for these conditions should be targeted for further evaluation of effectiveness and, only if found effective, considered for use in primary care settings. PMID- 25521532 TI - Determination of zeta-potential, charge, and number of organic ligands on the surface of water soluble quantum dots by capillary electrophoresis. AB - The number of charges and/or organic ligands covalently attached to the surface of CdTe quantum dot nanoparticles has been determined from their electrophoretic mobilities measured in capillaries filled with free electrolyte buffers. Three sizes of water soluble CdTe quantum dots with 3-mercaptopropionic and thioglycolic acids as surface ligands were prepared. Their electrophoretic mobilities in different pH and ionic strength values of separation buffers were measured by capillary electrophoresis with laser induced fluorescence detection. The zeta-potentials determined from electrophoretic mobilities using analytical solution of Henry function proposed by Ohshima were in the range from -30 to -100 mV. Charges of QDs were calculated from zeta-potentials. As a result, numbers of organic ligands bonded to QDs surface were determined to be 13, 14, and 15 for the sizes of 3.1, 3.5, and 3.9 nm, respectively. The dissociation constants of organic ligands bonded on QDs surfaces estimated from the dependence of QDs charge on pH of the separation buffer were 7.8 and 7.9 for 3-mercaptopropionic acid and 6.9 for thioglycolic acid. PMID- 25521530 TI - Time trends in socio-economic inequalities in stunting prevalence: analyses of repeated national surveys. AB - OBJECTIVE: Much is known about national trends in child undernutrition, but there is little information on how socio-economic inequalities are evolving over time. We aimed to assess socio-economic inequalities in stunting prevalence over time. DESIGN: We selected nationally representative surveys carried out since the mid 1990s for which information was available on asset indices and on child anthropometry. We identified twenty-five countries that had at least two surveys over an interval of 10 years or more, totalling eighty-seven surveys. Stunting prevalence was calculated according to wealth quintiles. Absolute and relative inequalities were calculated and time trends were obtained by regression. Setting Nationally representative household surveys from twenty-five low- and middle income countries. SUBJECTS: Children <5 years of age. RESULTS: National prevalence declined significantly in twenty-two of the twenty-five countries. In eighteen out of twenty-five countries, relative reductions were higher among the rich than among the poor. Overall, there was no indication that inequalities improved. Striking examples are Nepal, with a 17.0 percentage points decline in stunting per decade, but where inequalities increased sharply; and Brazil, where stunting fell by 6.7 percentage points and inequalities were all but eliminated. CONCLUSIONS: Global progress in reducing stunting has not been accompanied by improved equity, but countries varied markedly in how successful they were in reducing prevalence among the poorest children. It is important to document how some countries were able to reduce inequalities, so that these lessons can be used to foster global progress, particularly in light of the increased importance of within-country inequalities in the post-2015 agenda. PMID- 25521533 TI - Response Patterns in Health State Valuation Using Endogenous Attribute Attendance and Latent Class Analysis. AB - Not accounting for simplifying decision-making heuristics when modelling data from discrete choice experiments has been shown potentially to lead to biased inferences. This study considers two ways of exploring the presence of attribute non-attendance (that is, respondents considering only a subset of the attributes that define the choice options) in a health state valuation discrete choice experiment. The methods used include the latent class (LC) and endogenous attribute attendance (EAA) models, which both required adjustment to reflect the structure of the quality-adjusted life year (QALY) framework for valuing health outcomes. We find that explicit consideration of attendance patterns substantially improves model fit. The impact of allowing for non-attendance on the estimated QALY weights is dependent on the assumed source of non-attendance. If non-attendance is interpreted as a form of preference heterogeneity, then the inferences from the LC and EAA models are similar to those from standard models, while if respondents ignore attributes to simplify the choice task, the QALY weights differ from those using the standard approach. Because the cause of non attendance is unknown in the absence of additional data, a policymaker may use the range of weights implied by the two approaches to conduct a sensitivity analysis. PMID- 25521534 TI - Attitudes of adolescents towards sexual health in three cities from Croatia and Bosnia and Herzegovina. AB - AIM: This study aimed to determine the attitudes of adolescents towards sexual health and to assess their understanding of contraception use and knowledge about sexually transmitted infections in three ethnically different areas of Croatia and Bosnia and Herzegovina. METHODS: A total of 146 adolescent high school students between 17 and 19 years of age from three different cities were enrolled in this cross-sectional study. The participants completed two anonymous questionnaires: one that measured attitudes towards safe sex practice and another that measured contraception and general sexual health knowledge. RESULTS: Shame was identified as the main factor why adolescents did not seek information about sexual health and contraception. On average, respondents correctly answered only 35% of questions regarding sexual health. Adolescents from East Mostar, with a predominantly Bosniak population, had more positive attitudes towards safe sex and showed less contraception knowledge in comparison to their colleagues from two cities in Croatia. LIMITATIONS: Our study design might be burdened by socially desirable reporting and other biases inherent to the survey design. CONCLUSION: Adolescents from Croatia and Bosnia and Herzegovina, countries that experienced war and are still undergoing post-communist socio-economic transition, generally did not have adequate knowledge with respect to safe sex lifestyles. Respondents had major problems identifying sexually transmitted infections and their knowledge about contraception was insufficient. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Providing care for adolescent populations should address specificities in local ethnical and socio-economical circumstances. There is a need for further studies to determine social, cultural and religious factors influencing the knowledge and attitudes towards sexual health in order to provide most effective interventions for specific adolescent populations. PMID- 25521536 TI - Subacute Oxidative Stress and Glial Reactivity in the Amygdala are Associated with Increased Anxiety Following Blast Neurotrauma. AB - Behavioral symptoms, such as anxiety, are widely reported after blast overpressure (BOP) exposure. Amygdalar vulnerability to increasing magnitudes of BOP has not been investigated, and single exposures to blast have been limited to acute (<72 h) assessment. Rats were exposed to a single low, moderate, or high BOP (10, 14, or 24 psi) with an advanced blast simulator to test the susceptibility of the amygdala. Anxiety-like behavior was observed in the low- and moderate-pressure groups when subjected to the light/dark box assessment 7 days after the blast but not in high-pressure group. Immunohistochemistry was performed to measure apoptosis (cleaved caspase-3), neuronal loss (NeuN), reactive astrocytes (glial fibrillary acidic protein), microglia (Iba-1), and oxidative stress (CuZn superoxide dismutase). Slower progression of injury cascades was associated with a significant increase in anxiety, apoptosis, and astrogliosis in the low pressure group compared with others. A significant increase of CuZn superoxide dismutase in the low pressure group could be associated with neuroprotection from cell death caused by oxidative stress because neuronal loss was significant in the moderate- and high- but not the low pressure group. Overall, this study demonstrated that overpressure as low as 10 psi can induce subacute anxiety, in addition to neuropathologic changes in the amygdala. PMID- 25521535 TI - Five-year outcomes in kidney transplant patients converted from cyclosporine to everolimus: the randomized ZEUS study. AB - ZEUS study was an open-label, 12-month, multicenter study in which 300 de novo kidney transplant recipients were randomized to continue receiving cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant. Five-year follow-up data were available for 245/269 patients (91.1%) who completed the core 12-month study (123 everolimus, 109 CsA). At 5 years, adjusted estimated GFR was 66.2 mL/min/1.73 m(2) with everolimus versus 60.9 mL/min/1.73 m(2) with CsA; the mean difference was 5.3 mL/min/1.73 m(2) in favor of everolimus (95% CI 2.4, 8.3; p < 0.001 [intent-to-treat population]). In a post hoc analysis of patients remaining on study drug at 5 years (everolimus 77, CsA 86), mean difference was 8.2 mL/min/1.73 m(2) (95% CI 4.3, 12.1; p < 0.001) in favor of everolimus. The cumulative incidence of biopsy-proven acute rejection postrandomization was 13.6% with everolimus versus 7.5% with CsA (p = 0.095), largely accounted for by grade I rejection (16/21 patients and 7/11 patients, respectively). Postrandomization, graft loss, mortality, serious adverse events and neoplasms were similar in both arms. In conclusion, conversion of kidney transplant patients to everolimus at 4.5 months posttransplant is associated with a significant improvement in renal function that is maintained to at least 5 years. The increase in early mild acute rejection did not affect long-term graft function. PMID- 25521537 TI - Trending, Accuracy, and Precision of Noninvasive Hemoglobin Monitoring During Human Hemorrhage and Fixed Crystalloid Bolus. AB - Automated critical care systems for en route care will rely heavily on noninvasive continuous monitoring. It has been reported that noninvasive assessment of blood hemoglobin via CO-oximetry (SpHb) assessed by spot measurements lacks sufficient accuracy for clinical decision making in trauma patients. However, the precision and utility of trending of continuous hemoglobin have not been evaluated in hemorrhaging humans. This study measured the trending and concordance of SpHb changes during dynamic variations resulting from controlled hemorrhage with concomitant fluid infusion. With institutional review board approval and informed consent, 12 healthy volunteers under general anesthesia were subjected to hemorrhage (10 mL/kg for 15 min) accompanied by Ringer's lactate solution infusion (30 mL/kg for 20 min). The SpHb was measured continuously by the Masimo Radical-7, whereas total blood hemoglobin was measured by arterial blood sampling. Trend analysis, assessed by plots of SpHb against time of 12 subjects, shows consistent falls in SpHb during hemodilution without exception. Four-quadrant concordance analysis was 95.4% with an exclusion zone of 1 g/dL. Spot comparisons of 106 data pairs (SpHb and total blood hemoglobin) showed that 50% exhibited an error of more than 1 g/dL with bias of 1.08 +/- 0.82 g/dL and 95% limits of agreement of -0.5 to 2.6. Both trend analysis and concordance analysis suggest high precision of pulse CO-oximetry during hemodilution by hemorrhage and fluid bolus in human volunteers. However, accuracy was similar to other studies and therefore the use of pulse CO-oximetry alone is likely insufficient to make transfusion decisions. PMID- 25521538 TI - Intramolecular frustrated Lewis pair with the smallest boryl site: reversible H2 addition and kinetic analysis. AB - Ansa-aminoborane 1 (ortho-TMP-C6H4-BH2; TMP = 2,2,6,6-tetramethylpiperid-1-yl), a frustrated Lewis pair with the smallest possible Lewis acidic boryl site (-BH2), is prepared. Although it is present in quenched forms in solution, and BH2 represents an acidic site with reduced hydride affinity, 1 reacts with H2 under mild conditions producing ansa-ammonium trihydroborate 2. The thermodynamic and kinetic features as well as the mechanism of this reaction are studied by variable-temperature NMR spectroscopy, spin-saturation transfer experiments, and DFT calculations, which provide comprehensive insight into the nature of 1. PMID- 25521539 TI - InCoB2014: mining biological data from genomics for transforming industry and health. AB - The 13th International Conference on Bioinformatics (InCoB2014) was held for the first time in Australia, at Sydney, July 31-2 August, 2014. InCoB is the annual scientific gathering of the Asia-Pacific Bioinformatics Network (APBioNet), hosted since 2002 in the Asia-Pacific region. Of 106 full papers submitted to the BMC track of InCoB2014, 50 (47.2%) were accepted in BMC Bioinformatics, BMC Genomics and BMC Systems Biology supplements, with three papers in a new BMC Medical Genomics supplement. While the majority of presenters and authors were from Asia and Australia, the increasing number of US and European conference attendees augurs well for the international flavour of InCoB. Next year's InCoB will be held jointly with the Genome Informatics Workshop (GIW), September 9-11, 2015 in Tokyo, Japan, with a view to integrate bioinformatics communities in the region. PMID- 25521540 TI - Cancer cell death induced by the intracellular self-assembly of an enzyme responsive supramolecular gelator. AB - We report cancer cell death initiated by the intracellular molecular self assembly of a peptide lipid, which was derived from a gelator precursor. The gelator precursor was designed to form nanofibers via molecular self-assembly, after cleavage by a cancer-related enzyme (matrix metalloproteinase-7, MMP-7), leading to hydrogelation. The gelator precursor exhibited remarkable cytotoxicity to five different cancer cell lines, while the precursor exhibited low cytotoxicity to normal cells. Cancer cells secrete excessive amounts of MMP-7, which converted the precursor into a supramolecular gelator prior to its uptake by the cells. Once inside the cells, the supramolecular gelator formed a gel via molecular self-assembly, exerting vital stress on the cancer cells. The present study thus describes a new drug where molecular self-assembly acts as the mechanism of cytotoxicity. PMID- 25521547 TI - Topical capsaicin response as a phenotypic measure in patients with pain. PMID- 25521546 TI - Urinary excretion of C5b-9 is associated with the anti-angiogenic state in severe preeclampsia. AB - PROBLEM: Severe preeclampsia has been independently linked to complement dysregulation and angiogenic imbalance; however, the relationship between complement and angiogenic factors in human pregnancy is unclear. METHOD OF STUDY: Utilizing existing biomarkers, our study sought to better understand this relationship in active disease. We performed a case-control study, enrolling 25 cases with severe preeclampsia, 25 controls with chronic hypertension, and 25 healthy controls without hypertension. Levels of complement components (C3a, C5a, and C5b-9) and angiogenic markers [basic fibroblast growth factor (bFGF), placental growth factor (PlGF), vascular endothelial growth factor (VEGF), and soluble fms-like tyrosine kinase-1 (sFlt-1)] were measured simultaneously. RESULTS: Compared to both hypertensive and non-hypertensive controls, severe preeclampsia was associated with increased plasma sFlt-1, decreased plasma VEGF and PlGF, decreased urinary PlGF, and increased urinary C5b-9. Urinary marker C5b 9 correlated strongly with the anti-angiogenic condition. In subjects with detectable urinary excretion of C5b-9, median plasma levels of sFlt-1 were significantly greater (32,029 versus 4556 pg/mL, P < 0.0001) and levels of PlGF (15.6 versus 226 pg/mL, P < 0.0001) and VEGF (119 versus 153 pg/mL, P = 0.001) were significantly lower. CONCLUSION: More so than plasma complement markers, urinary C5b-9 may a useful measure to link complement dysregulation with angiogenic imbalance in severe preeclampsia. PMID- 25521550 TI - Influence of microgel packing on raspberry-like heteroaggregate assembly. AB - We describe the influence of microgel packing on colloidal-phase mediated heteroaggregation using poly(N-isopropylacrylamide) and poly(N isopropylmethacrylamide) microgels with 1% mol or 5% mol N,N' methylenebis(acrylamide) cross-linker. This system is uniquely designed to interrogate the influence of microgel structure and stiffness on microgel deformation at a curved interface by elminating the necessity of electrostatic charge pairing. Microgel monomer and cross-linker content is expected to influence deformation at a curved interface. Microgel deformation and swelling were characterized via atomic force microscopy (AFM) and viscometry. A systematic study of colloidal-phase mediated heteroaggregation was performed at varied effective volume fractions with all microgel compositions. Scanning electron microscopy (SEM) and qNano pore translocation experiments were used to asses the microgel coverage on the resultant raspberry-like particles (RLPs). Results reveal that microgel composition has a strong influence on the efficiency (as determined by microgel coverage) of RLP fabrication. The compositional effects appear to be related to the degree of microgel spreading/deformation at the interface, which is coupled to the influence of packing on assembly fidelity. These findings are widely applicable to systems where microgel deformation occurs at a curved interface. We also demonstrate that qNano pore translocation experiments can be used as a high-throughput method to analyze RLP microgel coverage. PMID- 25521551 TI - Graphene oxide (GO) nanosheets as oil-in-water emulsion stabilizers: influence of oil phase polarity. AB - HYPOTHESIS: Two-dimensional nanoparticles such as graphene oxide (GO) can serve as emulsion stabilizers due their ability to adsorb at oil-water (o/w) interfaces with high atom efficiency. The ability for GO to act as a surfactant is hypothesized to be highly dependent on the nature (i.e. polarity) of the oil phase, which has not considered previously. MODELLING AND EXPERIMENTS: The stabilization energy associated with adsorption of GO sheets at an o/w interface was modelled as a function of the polarity of the oil phase using surface tension contributions terms and Hansen solubility parameters (HSPs). Oil-in-water (o/w) miniemulsions were prepared via ultrasonication in the presence of GO for a variety of different oil phases, and were studied using dynamic light scattering (DLS). FINDINGS: The stabilization energy associated with GO adsorption was greater for non-polar oil phases compared to more polar oils. This behaviour is driven by the significant reduction in the oil-water interfacial tension as the polarity of the oil increases, to the point where GO adsorption is no longer thermodynamically favourable. This was verified by DLS measurements experiments, as GO-stabilized emulsion were successfully prepared for hydrophobic and aromatic oil phases (e.g. styrene), but not for polar oil phases such as methyl methacrylate. PMID- 25521548 TI - TINAGL1 and B3GALNT1 are potential therapy target genes to suppress metastasis in non-small cell lung cancer. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) remains lethal despite the development of numerous drug therapy technologies. About 85% to 90% of lung cancers are NSCLC and the 5-year survival rate is at best still below 50%. Thus, it is important to find drugable target genes for NSCLC to develop an effective therapy for NSCLC. RESULTS: Integrated analysis of publically available gene expression and promoter methylation patterns of two highly aggressive NSCLC cell lines generated by in vivo selection was performed. We selected eleven critical genes that may mediate metastasis using recently proposed principal component analysis based unsupervised feature extraction. The eleven selected genes were significantly related to cancer diagnosis. The tertiary protein structure of the selected genes was inferred by Full Automatic Modeling System, a profile-based protein structure inference software, to determine protein functions and to specify genes that could be potential drug targets. CONCLUSIONS: We identified eleven potentially critical genes that may mediate NSCLC metastasis using bioinformatic analysis of publically available data sets. These genes are potential target genes for the therapy of NSCLC. Among the eleven genes, TINAGL1 and B3GALNT1 are possible candidates for drug compounds that inhibit their gene expression. PMID- 25521552 TI - Viscosity of soft spherical micro-hydrogel suspensions. AB - The rheology of soft particle suspensions is considered to be a function of particle micromechanics and phase volume. However, soft particles such as microgels present a challenge because they typically contain solvent in their polymeric network structure, and their specific volume can alter in response to mechanical forces and physiochemical effects. We investigate how particle elasticity affects the viscosity of microgel suspensions as a function of effective phase volume (phi0) using non-colloidal hydrogel spheres that, unlike many colloidal-scale microgels, are not highly responsive to physiochemical effects. In our unique approach, we compare the viscosity of microgel suspensions to a theoretical hard sphere viscosity model that defines the maximum packing fraction using the geometric random close packing fraction (phircp) obtained from the measured particle size distribution. We discover that our harder microgels follow the hard sphere model up to random close packing, but softer microgels deviate around phi0/phircp~50% which indicates that their specific volume is decreasing with increasing phi0. This effect arises because microgels at high phase volumes do not fully re-swell during their preparation. We conclude that particle elasticity does not directly affect the viscosity of soft sphere suspensions up to the random close packing fraction. We highlight a convenient method for analysing the viscosity of microgel suspensions with potential to be applied to a wide variety of soft sphere suspensions. PMID- 25521553 TI - Two-dimensional self-assembly of amphiphilic peptides; adsorption-induced secondary structural transition on hydrophilic substrate. AB - Adsorption of sequential amphiphilic peptides on solid substrates triggered the spontaneous construction of nanoscaled architecture. An amphiphilic peptide designed with a cationic amino acid as a hydrophilic residue turned an anionic mica substrate into a water-repellent surface, simply by adsorbing it on the substrate surface. In contrast, an amphiphilic peptide designed with an anionic amino-acid residue formed a precisely controlled fiber array comprising a beta sheet fiber monolayer at the anionic substrate/water interface. This phenomenon was based on the secondary structural transition from random-coil to beta-sheet, which occurred specifically when amphiphilic peptide adsorbed on the substrate surface. Such surface-specific nonorder/order transition was implemented by exploiting the strength of adsorption between the peptide and the substrate. A strategic design exploiting weak bonding such as hydrophobic interactions is essential for constructing precisely controlled nano-architectures in two dimensions. PMID- 25521554 TI - Preparation of small size palladium nanoparticles by picosecond laser ablation and control of metal concentration in the colloid. AB - We assessed a method for the preparation of small, highly stable and unprotected Pd nanoparticles by picosecond laser ablation in 2-propanol. The nanoparticles can be extracted from 2-propanol by centrifugation and redispersed in water, where a strongly negative zeta-potential assures long term stability. The proposed procedure permits reduction of particle size down to 1.6nm and optimization of the Pd(0):Pd(II) ratio which, in the best cases, was of the order of 6:1. The increase of this ratio with ablation times has been correlated to the high temperature conversion of PdO to metallic Pd by a simple theoretical model. A study of the relationship between colloid absorption at 400nm and Pd concentration permitted the role of PdO in the determination of the UV-vis spectra to be clarified and the limits of the Mie theory for the evaluation of colloid concentration to be established. The absorption at 400nm can be used as a fast method to estimate the Pd content in the colloids, provided that a calibration of the ablation process is preliminarily performed. PMID- 25521555 TI - Hydrothermal synthesis of C3N4/BiOIO3 heterostructures with enhanced photocatalytic properties. AB - The C3N4/BiOIO3 composites with heterostructures have been fabricated by simply depositing BiOIO3 on the surface of C3N4 at hydrothermal conditions, using bismuth nitrate and potassium iodate as precursors. C3N4 is an excellent organic semiconductor, which can be excited by visible light. BiOIO3 is a layered bismuth based compound that has an internal polar field. Coupling C3N4 with BiOIO3 can combine the advantages of the two compounds and obtain better photocatalytic properties. X-ray diffraction, scanning electron microscopy, transmission electron microscopy and Fourier transformation infrared spectra have been carried out to confirm the structures and morphologies of as-prepared products. The absorption properties have been characterized by diffuse reflectance spectra and the photocatalytic activities have been evaluated by photodegradation of methyl orange, Rhodamine B and 2,4-dichlorophenol. Compared with C3N4, all C3N4/BiOIO3 composites exhibit better visible-light-driven photocatalytic properties. It is a synergetic effect that enables the composites to harvest light and promote charge separation, which eventually leads to the enhancement of the photocatalytic efficiencies. Under UV-vis light irradiation, C3N4/BiOIO3 composites also exhibit better activities, and the charge transfer process is similar to a redox mediator free Z-scheme system. PMID- 25521556 TI - Child maltreatment and children's developmental trajectories in early to middle childhood. AB - Associations between experiencing child maltreatment and adverse developmental outcomes are widely studied, yet conclusions regarding the extent to which effects are bidirectional, and whether they are likely causal, remain elusive. This study uses the Fragile Families and Child Wellbeing Study, a birth cohort of 4,898 children followed from birth through age 9. Hierarchical linear modeling and structural equation modeling are employed to estimate associations of maltreatment with cognitive and social-emotional well-being. Results suggest that effects of early childhood maltreatment emerge immediately, though developmental outcomes are also affected by newly occurring maltreatment over time. Additionally, findings indicate that children's early developmental scores predict their subsequent probability of experiencing maltreatment, though to a lesser extent than early maltreatment predicts subsequent developmental outcomes. PMID- 25521557 TI - AG4, a compound isolated from Radix Ardisiae Gigantifoliae, induces apoptosis in human nasopharyngeal cancer CNE cells through intrinsic and extrinsic apoptosis pathways. AB - 3beta-O-{alpha-L-Pyran rhamnose-(1->3)-[beta-D-xylopyranose-(1->2)]-beta-D glucopyranose-(1->4)-[beta-D-lucopyranose-(1->2)]-alpha-L-pyran arabinose} cyclamiretin A (AG4) is a saponin component obtained from the Giantleaf Ardisia Rhizome (Rhizoma Ardisiae Gigantifoliae). The present study aimed to investigate the antitumor potential of AG4 and its possible mechanisms in human nasopharyngeal carcinoma cells (CNE). We exposed tumor cells to AG4 to investigate which cell line was the most sensitive to AG4. Cell viability was assessed using the MTT reduction assay, and the effects of AG4 on apoptosis, reactive oxygen species (ROS) content, mitochondrial membrane potential (MMP), and cell cycle were detected using a flow cytometer; the glutathione, superoxide dismutase and malondialdehyde activities were measured using colorimetric methods. The relative expressions of Bax, Bad, Bid, Bcl-2, and Fas mRNA were calculated using the (Equation is included in full-text article.)comparative method by real-time PCR studies and protein was detected by western blotting. AG4 markedly inhibited the growth of CNE cells by decreasing cell proliferation, inducing apoptosis, and blocking the cell cycle in the S phase. The release of caspase-3, caspase-8, and caspase-9 was stimulated by AG4 in CNE, and the decreased proliferation induced by AG4 was blocked by the inhibitor of pan caspase (Z-VAD-FMK). Moreover, the MMP was decreased in AG4-treated cells, and AG4-induced cell apoptosis was accompanied by a rapid and lasting increase in ROS, which was abolished by N-acetyl-L-cysteine (NAC); glutathione, superoxide dismutase, and malondialdehyde were regulated by AG4. AG4 inhibited Bcl-2 mRNA and protein expression and stimulated Bax, Bad, Bid, Fas mRNA, and protein expression in CNE cultures, suggesting an effect at the transcriptional and protein level. In addition, both the FasL inhibitor (AF-016) and the Bcl-2 family inhibitor (GX15-070) could prevent the cell apoptosis induced by AG4. The findings suggested that AG4-induced apoptosis in CNE cells involved a death receptor pathway and a Bcl-2 family-mediated mitochondrial signaling pathway by decreasing the MMPs in an ROS-dependent manner and regulating genes and proteins relative to apoptosis; also, regulation of cell cycles may also play a role in the antitumor mechanism of AG4. PMID- 25521558 TI - The therapeutic potential of a novel non-ATP-competitive fibroblast growth factor receptor 1 inhibitor on gastric cancer. AB - Previous studies showed that fibroblast growth factor receptor 1 (FGFR1) is an attractive target in gastric cancer therapy. In the current study, we aimed to investigate whether the compound L6123, a novel non-ATP-competitive FGFR1 inhibitor, could show better antitumor activity than the leading compound, nordihydroguaiaretic acid (NDGA), in FGFR1-overexpressing gastric cancer cells. Using an MTT assay, we investigated the inhibitory effect of L6123 on the viability of three gastric cancer cells (MGC-803, SGC-7901, and BGC-823) overexpressing FGFR1, wild-type mouse embryonic fibroblast (MEF), and MEF expressing FGFR1, FGFR2, and FRS2alpha gene knockout (MEF). We studied the antitumor mechanism of L6123 against the gastric cancer cell line SGC-7901 by western blot analysis. The antitumor effects of L6123 on the gastric cancer cell line SGC-7901 were detected by flow cytometry, Hoechst staining, western blot analysis, and Transwell invasion assay. L6123 had lower IC50 in all three gastric cancer cells than NDGA and showed better inhibitory activity against MEF cells than against MEF cells. In the SGC-7901 gastric cell, L6123 inhibited the FGF2 induced phosphorylation of FGFR1/FRS2alpha/ERK1/2 in a dose-dependent manner, induced the activation of the apoptosis-related proteins, cleaved-PARP and cleaved-caspase-3, decreased the expression of pro-caspase-3 and Bcl-2, and induced tumor cell apoptosis. L6123 also dose-dependently reduced cell invasion ability, and showed better activity than NDGA at the same concentration. A novel non-ATP-competitive inhibitor L6123 showed excellent antigastric cancer activity by inhibiting the FGFR1 signaling pathway. Thus, we discovered a potential agent for the treatment of FGFR1-overexpressing gastric cancer. PMID- 25521559 TI - Serum caffeine concentrations and short-term outcomes in premature infants of ?29 weeks of gestation. AB - OBJECTIVE: Caffeine is effective in the treatment of apnea of prematurity but it is not well known if the therapeutic concentration of the drug has an impact on other neonatal outcomes such as chronic lung disease (CLD). The aim of this study was to determine if there is an association between caffeine concentrations and the incidence of CLD in premature infants of ?29 weeks of gestation. STUDY DESIGN: A retrospective chart review of all the infants born ?29 weeks of gestation from 2007 to 2011, who survived until discharge or 36 weeks postmenstrual age, was conducted. Caffeine concentrations were obtained weekly on infants getting the drug. Average caffeine concentrations (ACCs) were determined for the duration of caffeine therapy and correlated with CLD, length of stay (LOS), oxygen at discharge (OD), duration of ventilation (DV) and total charges for hospitalization for each patient. RESULTS: Of the 222 eligible infants, 198 met the inclusion criteria. ACC for infants without CLD was 17.0+/-3.8 MUg ml(-1) compared with infants with CLD 14.3+/-6.1 MUg ml(-1) (P<0.001). Infants receiving high ACC (>14.5 MUg ml(-1)) had lower incidence of patent ductus arteriosus, lesser number of days on ventilator and oxygen, lesser need for diuretics, lower incidence of CLD, were more likely to go home without supplemental OD and had lower LOS and lower total hospital charges (all differences were significant P<0.05) Multiple logistic regression modeling after adjusting for confounding variables indicated that higher caffeine concentrations were significantly associated with decrease in CLD. Receiver operating curve analysis confirmed a significant predictive ability of caffeine concentration for CLD with a cutoff concentration of 14.5 MUg ml(-1) (sensitivity of 42.6 and specificity of 86.8). The AUC (area under the curve) for the prediction of CLD was 0.632 (95% confidence interval 0.56-0.69, P=0.009). CONCLUSIONS: Caffeine concentrations >14.5 MUg ml(-1) were strongly correlated with reduced CLD in infants born at ?29 weeks of gestation. Higher caffeine concentrations were associated with decreased total hospital charges, DV, OD and LOS. Additional randomized trials are needed to confirm these findings, to identify ideal serum concentrations and determine possible long-term neurologic benefits. PMID- 25521560 TI - Are trends in the proportions of non-medically indicated inductions different by Medicaid status? AB - OBJECTIVE: To determine whether Medicaid status influenced the effect of a quality improvement effort. STUDY DESIGN: Using a data set consisting of the 2006 to 2010 vital statistics data linked with Medicaid status data, we identified non medically indicated inductions between 36 0/7 and 38 6/7 weeks gestational age and compared rates of non-medically indicated inductions between women with Medicaid and all other payers. We also compared these rates in hospitals that did and did not participate in the Ohio Perinatal Quality Collaborative (OPQC). RESULTS: A total of 232 935 births with gestational ages between 36 0/7 and 38 6/7 weeks were included in this study. In the sample, 32 371 births (13.9%) were non-medically indicated inductions. Overall, rates of non-medically indicated deliveries for all insurance types dropped over the course of the initiative. Interestingly, in OPQC participating hospitals, the Medicaid mothers' rates of non-medically indicated inductions prior to 39 weeks were well below rates for other insurance types prior to the initiative. By the end of the initiative, rates for all insurance types had dropped significantly but non-medically indicated inductions<39 weeks rates dropped more dramatically in the non-Medicaid mothers, resulting in higher rates for Medicaid than for non-Medicaid mothers. CONCLUSIONS: Non-medically indicated deliveries decreased for women irrespective of Medicaid enrollment status. However, non-medically indicated delivery rates did not drop as sharply for women enrolled in Medicaid. PMID- 25521561 TI - Normative amplitude-integrated EEG measures in preterm infants. AB - OBJECTIVE: Assessing qualitative patterns of amplitude-integrated electroencephalography (aEEG) maturation of preterm infants requires personnel with training in interpretation and an investment of time. Quantitative algorithms provide a method for rapidly and reproducibly assessing an aEEG recording independent of provider skill level. Although there are several qualitative and quantitative normative data sets in the literature, this study provides the broadest array of quantitative aEEG measures in a carefully selected and followed cohort of preterm infants with mild or no visible injury on term equivalent magnetic resonance imaging (MRI) and subsequently normal neurodevelopment at 2 and 7 years of age. STUDY DESIGN: A two-channel aEEG recording was obtained on days 4, 7, 14 and 28 of life for infants born ?30 weeks estimated gestational age. Measures of amplitude and continuity, spectral edge frequency, percentage of trace in interburst interval (IBI), IBI length and frequency counts of smooth delta waves, delta brushes and theta bursts were obtained. MRI was obtained at term-equivalent age and neurodevelopmental testing was conducted at 2 and 7 years of corrected age. RESULT: Correlations were found between increasing postmenstrual age (PMA) and decreasing maximum amplitude (R= 0.23, P=0.05), increasing minimum amplitude (R=0.46, P=0.002) and increasing spectral edge frequency (R=0.78, P=4.17 * 10(-14)). Negative correlations were noted between increasing PMA and counts of smooth delta waves (R= -0.39, P=0.001), delta brushes (R= -0.37, P=0.003) and theta bursts (R= -0.61, P=5.66 * 10(-8)). Increasing PMA was also associated with a decreased amount of time spent in the IBI (R= -0.38, P=0.001) and a shorter length of the maximum IBI (R= -0.27, P=0.03). CONCLUSION: This analysis supports a strong correlation between quantitatively determined aEEG measures and PMA, in a cohort of preterm infants with normal term-equivalent age neuroimaging and neurodevelopmental outcomes at 7 years of age, which is both predictable and reproducible. These 'normative' quantitative values support the pattern of maturation previously identified by qualitative analysis. PMID- 25521562 TI - Doppler abnormalities in monochorionic diamniotic twin pregnancies with discordant growth. AB - OBJECTIVE: We studied whether abnormal umbilical artery (UA) Doppler flow velocity waveforms occur with higher frequency in monochorionic diamniotic (MCDA) twin gestations with discordant fetal growth and whether this impacted neonatal outcome. STUDY DESIGN: We performed a retrospective study of MCDA twin pairs. We collected data from an electronic medical record. We classified pregnancies as discordant if there was at least 20% birth weight discordance. Abnormal UA Doppler velocity waveforms included absent or reversed end diastolic flow. We analyzed the data with chi square, Student's t-test and analysis of variance as appropriate. RESULT: Seventy-three twin pairs met criteria for inclusion, including 16 with discordant growth. The discordant group was significantly more affected with twin-to-twin transfusion syndrome (TTTS) (P=0.02). The smaller fetuses in discordant pairs were more likely to display abnormal UA Doppler flow velocity waveforms (P<0.01). These neonates also had lower Apgar scores (P=0.03) and were more likely to require care in a neonatal intensive care unit. Our findings persisted after excluding pregnancies with TTTS. CONCLUSION: In MCDA twin gestations complicated by discordant growth, there is an increased frequency of abnormal UA Doppler flow velocity waveforms in small fetuses, and these neonates face clinical challenges after birth. PMID- 25521564 TI - Salty worlds underwater. PMID- 25521563 TI - Outcomes of extremely preterm infants after delivery room cardiopulmonary resuscitation in a population-based cohort. AB - OBJECTIVE: To describe the relationship of delivery room cardiopulmonary resuscitation (DR-CPR) to short-term outcomes of extremely preterm infants. STUDY DESIGN: This was a cohort study of 22 to 27+6/7 weeks gestational age (GA) infants during 2005 to 2011. DR-CPR was defined as chest compressions and/or epinephrine administration. Multivariable logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) associated with DR CPR; analysis was stratified by GA. RESULT: Of the 13 758 infants, 856 (6.2%) received DR-CPR. Infants 22 to 23+6/7 weeks receiving DR-CPR had similar outcomes to non-recipients. Infants 24 to 25+6/7 weeks receiving DR-CPR had more severe intraventricular hemorrhage (OR 1.36, 95% CI 1.07, 1.72). Infants 26 to 27+6/7 weeks receiving DR-CPR were more likely to die (OR 1.81, 95% CI 1.30, 2.51) and have intraventricular hemorrhage (OR 2.10, 95% CI 1.56, 2.82). Adjusted hospital DR-CPR rates varied widely (median 5.7%). CONCLUSION: Premature infants receiving DR-CPR had worse outcomes. Mortality and morbidity varied by GA. PMID- 25521565 TI - Induction of domoic acid production in the toxic diatom Pseudo-nitzschia seriata by calanoid copepods. AB - The toxic diatom Pseudo-nitzschia seriata was exposed directly and indirectly (separated by a membrane) to copepods, Calanus hyperboreus and C. finmarchicus, to evaluate the effects of the copepods on domoic acid production and chain formation in P. seriata. The toxicity of P. seriata increased in the presence of the copepods. This response was chemically mediated without physical contact between the organisms suggesting that it was induced by potential waterborne cues from the copepods or changes in water chemistry. Domoic acid production may be related to defense against grazing in P. seriata although it was not shown in the present study. To evaluate if the induction of domoic acid production was mediated by the chemical cues from damaged P. seriata cells, live P. seriata cells were exposed to a P. seriata cell homogenate, but no effect was observed. Chain formation in P. seriata was affected only when in direct contact with the copepods. This study suggests that the presence of zooplankton may be one of the factors affecting the toxicity of Pseudo-nitzschia blooms in the field. PMID- 25521566 TI - Copper-induced intra-specific oxidative damage and antioxidant responses in strains of the brown alga Ectocarpus siliculosus with different pollution histories. AB - Inter- and intra-specific variation in metal resistance has been observed in the ecologically and economically important marine brown macroalgae (Phaeophyceae), but the mechanisms of cellular tolerance are not well elucidated. To investigate inter-population responses of brown seaweeds to copper (Cu) pollution, the extent of oxidative damage and antioxidant responses were compared in three strains of the filamentous brown seaweed Ectocarpus siliculosus, the model organism for the algal class Phaeophyceae that diverged from other major eukaryotic groups over a billion year ago. Strains isolated from locations with different pollution histories (i.e. LIA, from a pristine site in Scotland; REP and Es524 from Cu contaminated sites in England and Chile, respectively) were exposed to total dissolved Cu concentrations (CuT) of up to 2.4 MUM (equivalent to 128 nM Cu(2+)) for 10 d. LIA exhibited oxidative stress, with increases in hydrogen peroxide (H2O2) and lipid peroxidation (measured as TBARS levels), and decreased concentrations of photosynthetic pigments. Es524 presented no apparent oxidative damage whereas in REP, TBARS increased, revealing some level of oxidative damage. Adjustments to activities of enzymes and antioxidant compounds concentrations in Es524 and REP were strain and treatment dependent. Mitigation of oxidative stress in Es524 was by increased activities of superoxide dismutases (SOD) at low CuT, and catalase (CAT) and ascorbate peroxidase (APX) at all CuT, accompanied by higher levels of antioxidants (ascorbate, glutathione, phenolics) at higher CuT. In REP, only APX activity increased, as did the antioxidants. For the first time evidence is presented for distinctive oxidative stress defences under excess Cu in two populations of a species of brown seaweed from environments contaminated by Cu. PMID- 25521567 TI - Single-molecule methods to study membrane receptor oligomerization. AB - Membrane receptors control fundamental cellular processes. Binding of a specific ligand to a receptor initiates communication through the membrane and activation of signaling cascades. This activation process often leads to a spatial rearrangement of receptors in the membrane at the molecular level. Single molecule techniques contributed significantly to the understanding of receptor organization and rearrangement in membranes. Here, we review four prominent single-molecule techniques that have been applied to membrane receptors, namely, stepwise photobleaching, Forster resonance energy transfer, sub-diffraction localization microscopy and co-tracking. We discuss the requirements, benefits and limitations of each technique, discuss target labeling, present a selection of applications and results and compare the different methodologies. PMID- 25521568 TI - Balloon overtube-assisted stenting in difficult upper and lower gastrointestinal locations using a modified over-the-wire technique. AB - In this series of four patients, some modifications of the standard over-the-wire (OTW) technique for stent deployment using the balloon overtube normally used in single-balloon enteroscopy are presented. This modified technique allowed the use of OTW stents in patients where there were difficulties that meant the standard technique was unsuccessful. For each patient, the authors describe different small novel adaptations of this modified technique that enabled self-expanding metal stents (SEMSs) and biodegradable stents to be successfully deployed in different gastrointestinal locations. Moreover, in one patient the stent was placed without fluoroscopic guidance. PMID- 25521569 TI - Use of a cap in single-balloon enteroscopy-assisted endoscopic retrograde cholangiography. AB - BACKGROUND AND STUDY AIM: Cannulation of the native papilla in surgically altered anatomy is difficult in endoscopic retrograde cholangiography (ERC). There are limited data regarding the success of single-balloon enteroscopy-assisted ERC (SBE-ERC) in patients with a native papilla and Roux-en-Y gastric bypass. Use of a plastic cap may assist cannulation in these cases. The aim of the current study was to investigate the use of SBE-ERC with a cap (Cap-SBE-ERC) in patients with surgically altered anatomy referred for ERC. PATIENTS AND METHODS: Patients with surgically altered anatomy (hepaticojejunostomy, gastric bypass surgery, and Whipple's surgery) who underwent Cap-SBE-ERC were identified from a prospectively maintained database. Outcomes were diagnostic and procedural success. Patients with a native papilla were compared with those with a biliary-enteric anastomosis. RESULTS: Among 56 patients with surgically altered anatomy, high rates of diagnostic and procedural success were observed (78.6 % and 71.4 %, respectively). High diagnostic and procedural success rates of 72.7 % and 65.9 %, respectively, were also observed for patients with Roux-en-Y gastric bypass anatomy with a native papilla (n = 44). CONCLUSION: High rates of diagnostic and procedural success were reported for SBE-ERC with the use of a cap, including a large subgroup of patients with Roux-en-Y gastric bypass and a native papilla. PMID- 25521570 TI - Endoscopic treatment of nonstricture-related benign biliary diseases using covered self-expandable metal stents. AB - BACKGROUND AND STUDY AIMS: Nonstricture benign biliary diseases (BBDs) such as leaks, perforations, and bleeding, have been traditionally managed by placement of one or more plastic stents. Emerging data support the use of covered, self expandable, metal stents (CSEMSs). The aim of this study was to assess the outcomes of endoscopic temporary placement of CSEMS in patients with nonstricture BBD. PATIENTS AND METHODS: This was a retrospective study of CSEMS placement for BBD between May 2005 and August 2013 at two tertiary care centers. The main outcome measures were resolution of perforation, bleeding, leak, and adverse events related to CSEMS treatment. RESULTS: A total of 87 patients were included (median age 62 years [range 18 - 86]). Indications for stent placement were bile leaks (n = 35, 40 %), bleeding (n = 27, 31 %), perforation (n = 18, 21 %), and other conditions (n = 7, 8 %). Fully and partially covered 8 - 10-mm diameter CSEMS were placed and subsequently removed in all 87 patients (100 %). Resolution of the underlying problem was achieved for 33 bile leaks (94 %), 25 bleedings (93 %), 18 perforations (100 %), and for 3 cases with other indications (43 %). The median duration of stenting was 9 weeks in patients with biliary leaks, 3 weeks for bleeding, and 9.5 weeks for perforations. Median follow-up was 82 weeks after stent removal. Seven adverse events occurred, including cholangitis in six patients (7 %), and tissue hyperplasia leading to difficulty in the removal of a partially covered SEMS in one patient. CONCLUSIONS: Nonstricture BBD can be effectively and safely treated with the short term placement of CSEMS. . PMID- 25521571 TI - Risk of neoplastic progression in Barrett's esophagus diagnosed as indefinite for dysplasia: a nationwide cohort study. AB - BACKGROUND AND STUDY AIMS: A histological diagnosis of "indefinite for dysplasia" (IND) in Barrett's esophagus is used when a diagnosis of genuine dysplasia is equivocal. The aim of the present study was to assess the risk of progression to high grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) after a diagnosis of IND in a nationwide cohort of patients with Barrett's esophagus. PATIENTS AND METHODS: Patients with a first diagnosis of IND in Barrett's esophagus between 2002 and 2011 were selected from a nationwide registry of histopathology diagnoses in The Netherlands. Patients were followed up until treatment for HGD, detection of EAC, or date of last endoscopy contact with biopsy sampling. RESULTS: In total, 1258 patients met the inclusion criteria, of whom 842 (66.9 %) underwent endoscopic follow-up. Patients were followed for a total of 2585 person years (mean +/- SD 3.01 +/- 2.6). Median duration until first follow-up endoscopy was 1.2 years (interquartile range 0.3 - 1.8 years). The progression rate from IND to the combined end point of HGD or EAC was 2.0 (95 % confidence interval [CI] 1.5 - 2.6) per 100 person-years and progression to EAC was 1.2 (95 %CI 0.8 - 1.6). After excluding cases with HGD or EAC within 1 year after IND diagnosis (n = 16), the progression rates were 1.4 (95 %CI 1.0 - 1.9) and 0.8 (95 %CI 0.5 - 1.2) per 100 person-years for HGD or EAC and EAC, respectively. CONCLUSION: In this large, population-based, cohort of patients with Barrett's esophagus, the incidence rate of HGD or EAC following a diagnosis of IND was 1.4 per 100 person years. The results demonstrate the need for additional studies to select the subgroup of IND patients with an increased risk of neoplastic progression. PMID- 25521572 TI - Interobserver agreement and accuracy of preoperative endoscopic ultrasound-guided biopsy for histological grading of pancreatic cancer. AB - BACKGROUND AND STUDY AIM: Poorly differentiated/high grade pancreatic ductal adenocarcinoma (PDAC) is associated with an early unfavorable outcome, and patients with these tumors may be candidates for neo-adjuvant treatment. Endoscopic ultrasound-guided pancreatic fine-needle biopsy (EUS-FNB) may, in theory, allow preoperative assessment of PDAC histological grading. The aim of the current study was to assess the interobserver agreement and accuracy of preoperative PDAC grading from EUS-FNB specimens. METHODS: Data from 42 postsurgical PDAC patients who had undergone preoperative EUS-FNB were retrieved. Four experienced pathologists independently reviewed the EUS-FNB slides and reported tumor grading (well, moderately, or poorly differentiated). Agreement among pathologists for grading of preoperative EUS-FNB samples was expressed by using Cohen's or Fleiss' kappa statistic, as appropriate. Postsurgical PDAC grading was used as the gold standard to assess the cumulative accuracy of EUS FNB for the preoperative prediction of PDAC grading. RESULTS: The kappa values for PDAC grading on EUS-FNB specimens ranged from 0.09 to 0.41. The total agreement among the four pathologists was only fair (kappa = 0.27; 95 % confidence interval [CI] 0.14 - 0.38). When tumor grades were grouped as well or moderately differentiated vs. poorly differentiated, kappa values ranged from 0.19 to 0.50, with only a fair overall agreement (kappa = 0.27; 95 %CI 0.21 - 0.49). The accuracy of preoperative grading from EUS-FNB was 56 % (75/134 readings; 95 %CI 40 % - 65 %), with mean sensitivity and specificity to detect a high grade, poorly differentiated tumor of 41 % (95 %CI 19 % - 54 %) and 78 % (53/68 readings; 95 %CI 60 % - 99 %), respectively. CONCLUSIONS: Preoperative EUS FNB-based histological grading of PDAC is unreliable, and current results do not support the use of this information in clinical practice. This appears to be due to suboptimal interobserver agreement among pathologists and an overall low accuracy in predicting postsurgical grading. PMID- 25521573 TI - Confocal laser endomicroscopy for the differential diagnosis of ulcerative colitis and Crohn's disease: a pilot study. AB - BACKGROUND AND STUDY AIM: The differential diagnosis of ulcerative colitis from Crohn's disease is of pivotal importance for the management of inflammatory bowel diseases, as both entities involve specific therapeutic management strategies. Confocal laser endomicroscopy (CLE) allows on-demand, in vivo characterization of architectural and cellular details during endoscopy. The aim of this study was to assess the efficacy of CLE to differentiate between ulcerative colitis and Crohn's disease. PATIENTS AND METHODS: This was a prospective study involving consecutive patients with a well-established diagnosis of ulcerative colitis or Crohn's disease who underwent colonoscopy with fluorescein-aided confocal imaging. RESULTS: Overall, 79 patients were included (40 Crohn's disease, 39 ulcerative colitis). CLE findings in patients with Crohn's disease, showed significantly more discontinuous inflammation (87.5 % vs. 5.1 %), focal cryptitis (75.0 % vs. 12.8 %), and discontinuous crypt architectural abnormality (87.5 % vs. 10.3 %) than in ulcerative colitis (P < 0.0001). Conversely, ulcerative colitis was associated with severe, widespread crypt distortion (87.2 % vs. 17.5 % in Crohn's disease), decreased crypt density (79.5 % vs. 22.5 %), and frankly irregular surface (89.7 % vs. 17.5 %; P < 0.0001 for all comparisons). Statistically significant differences were not seen for heavy, diffuse lamina propria cell increase or mucin preservation. No granulomas were visible. Based on these findings, a CLE scoring system was developed that revealed excellent accuracy (93.7 %) when compared with the historical clinical diagnosis and the histopathological gold standard. CONCLUSIONS: CLE could visualize several disease specific microscopic features, which are conventionally used in standard histopathology to differentiate between ulcerative colitis and Crohn's disease. However, because of the limited penetration depth of CLE, submucosal details or granulomas were not visible. The new scoring system may allow in vivo diagnosis of ulcerative colitis or Crohn's disease. Trial registered at ClinicalTrials.gov: NCT 02238665. PMID- 25521574 TI - Magnetic endoscopic imaging as an adjuvant to elective colonoscopy: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND AND STUDY AIMS: The use of magnetic endoscopic imaging (MEI) to visualize scope configuration in three dimensions is thought to increase procedural efficiency and diminish discomfort associated with colonoscopy. The aim of this systematic review and meta-analysis was to evaluate the performance of MEI in colonoscopy. METHODS: The electronic databases Medline, EMBASE, and the Cochrane Library of Randomized Trials were searched. Methodological quality was assessed using the Jadad score. Odds ratios (OR) or risk differences for dichotomous variables and mean differences for continuous outcomes were calculated with 95 % confidence intervals (CIs). RESULTS: A total of 13 randomized studies met eligibility criteria and were included in qualitative and quantitative synthesis. MEI was associated with a significantly lower risk of failed cecal intubation (risk difference 4 %, 95 %CI 0 % - 7 %; P = 0.03), lower cecal intubation time (mean difference 0.58 minutes, 95 %CI 0.28 - 0.88; P < 0.001), and lower pain scores as estimated by visual analog scales (mean difference 0.45 cm, 95 %CI 0.03 - 0.86; P = 0.03) compared with conventional colonoscopy. On subgroup stratification of outcome according to endoscopist experience, failure rates were unaffected, but experienced colonoscopists reduced intubation times with MEI (mean difference 0.78 minutes, 95 %CI 0.12 - 1.43; P = 0.02). Sensitivity analyses of high-quality studies (Jadad score >= 3) showed no significant difference in failure rate (risk difference 4 %, 95 %CI 0 % - 8 %; P = 0.07) or intubation time (mean difference 0.56 minutes, 95 %CI - 0.15 to 1.28; P = 0.12). CONCLUSION: Adjuvant MEI is associated with a lower failure risk and shorter time to cecal intubation during elective colonoscopy compared with conventional colonoscopy. PMID- 25521575 TI - Identification and molecular structure analysis of a new noncoding RNA, a sbRNA homolog, in the silkworm Bombyx mori genome. AB - The small noncoding group of RNAs called stem-bulge RNAs (sbRNAs), first reported in Caenorhabditis elegans, is described as molecules homologous to the Y RNAs, a specific class of noncoding RNAs that is present in vertebrates. This homology indicates the possibility of the existence of sbRNAs in other invertebrate organisms. In this work, we used bioinformatic tools and conserved sequences of sbRNAs from C. Elegans and Y RNAs to search for homologous sbRNA sequences in the Bombyx mori genome. This analysis led to the discovery of one noncoding gene, which was translated into RNA segments and comparatively analysed with segments from human and hamster Y RNAs and C. elegans sbRNAs in molecular dynamic simulations. This gene represents the first evidence for a new sbRNA-like noncoding RNA, the BmsbRNA gene, in this Lepidoptera genome. PMID- 25521576 TI - The construct validity of the Short Form-36 Health Survey for patients with nonspecific chronic neck pain. AB - Self-reported disability related to neck pain can be measured using general health questionnaires. The validity of the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) in patients with nonspecific chronic neck pain (CNP) in a tertiary outpatient rehabilitation setting is unknown. This study investigates construct validity of the SF-36 in these patients using 16 a-priori formulated hypotheses. Ninety-one patients admitted for rehabilitation completed the SF-36 before the rehabilitation program. SF-36 domain scores of patients with CNP were compared with general population reference values and standardized differences were calculated. For both the SF-36 physical and the mental component summary (PCS and MCS), differences between primary and tertiary care setting, men and women, age groups, litigants and nonlitigants, patients with and without compensation, and with >=3 versus<=2 concomitant complaints were analyzed using independent t-tests. Differences between PCS and MCS scores were analyzed using a paired t-test. Twelve hypotheses were not rejected and four were rejected. All SF 36 domain scores were significantly lower than the general population references values. The domain scores 'role physical', 'bodily pain', 'vitality', 'social functioning,' and 'role emotional' were relevantly (>=1 SD) lower. SF-36-PCS and SF-36-MCS scores were significantly lower in tertiary care. The SF-36-PCS score was significantly lower for patients with workers compensation and patients with at least three concomitant complaints. The SF-36-MCS score was significantly lower for the age group of at least 39 years. The SF-36 has good construct validity and can be used to measure self-reported general health in patients with nonspecific CNP in outpatient tertiary rehabilitation. PMID- 25521577 TI - NMR in cultural heritage. PMID- 25521579 TI - Careful cone counting critical for clinical care. PMID- 25521578 TI - Niacin reverses migratory macrophage foam cell arrest mediated by oxLDL in vitro. AB - INTRODUCTION: Niacin reduces vascular oxidative stress and down regulates inducible nitric oxide synthase, an enzyme mediating proatherosclerotic effects in part by increasing oxidative stress. Here, we evaluate whether Niacin reverses the redox sensitive migratory arrest of macrophages in response to oxidised(ox) LDL uptake. MATERIAL AND METHODS: Migration of RAW264.7 cells, a murine macrophage cell line and bone marrow derived macrophages from wildtype and iNOS knockout mice was quantified using a modified Boyden chamber. Unstimulated cells or cells preincubated with oxLDL or non-oxidised (n)LDL were treated with Nicotinic acid or Nicotinamide. Nitric oxide, peroxynitrite and ROS production were assessed using electron paramagnetic resonance (ESR). Additionally, flow cytometry analysis of apoptosis, fokal adhesion kinase (FAK), phalloidin, CD36, F4/80 macrophage marker and iNOS gene expression (PCR) were assessed. RESULTS: Migration of Nicotinic acid, Nicotinamide treated cells or unstimulated cells did not differ (P>0.05). oxLDL treatment significantly reduced migration vs. unstimulated cells (p<0.05). In contrast, migratory arrest in response to oxLDL treatment was reversed by co-incubation with Nicotinic acid and Nicotinamide. The oxLDL-induced peroxynitrite formation in RAW264.7 cells was abolished by Niacin and glutathion (GSH) oxidation was significantly reduced. However, nitric oxide (NO)- and reactive oxygen species (ROS) production induced by oxLDL were not affected by Niacin treatment of RAW264.7 cells. In addition, Nicotinic acid and Nicotinamide reduced actin polymerization, a marker for migratory arrest. DISCUSSION: Our data shows that oxLDL induced inhibition of macrophage migration in vitro can be reversed by Niacin. Furthermore, Niacin reduces peroxynitite formation and improves antioxidant GSH. PMID- 25521581 TI - Leptin normalizes photic synchronization in male ob/ob mice, via indirect effects on the suprachiasmatic nucleus. AB - Mounting evidence indicates a strong link between metabolic diseases and circadian dysfunctions. The metabolic hormone leptin, substantially increased in dietary obesity, displays chronobiotic properties. Here we investigated whether leptin is involved in the alteration of timing associated with obesity, via direct or indirect effects on the suprachiasmatic nucleus (SCN), the site of the master clock. Photic synchronization was studied in obese ob/ob mice (deficient in leptin), either injected or not with high doses of recombinant murine leptin (5 mg/kg). This was performed first at a behavioral level, by shifting the light dark cycle and inducing phase shifts by 30-minute light pulses and then at molecular levels (c-FOS and P-ERK1/2). Moreover, to characterize the targets mediating the chronomodulatory effects of leptin, we studied the induction of phosphorylated signal transducer and activator of transcription 3 (P-STAT3) in the SCN and in different structures projecting to the SCN, including the medial hypothalamus. Ob/ob mice showed altered photic synchronization, including augmented light-induced phase delays. Acute leptin treatment normalized the photic responses of the SCN at both the behavioral and molecular levels (decrease of light-induced c-FOS). Leptin-induced P-STAT3 was modulated by light in the arcuate nucleus and both the ventromedial and dorsomedial hypothalamic nuclei, whereas its expression was independent of the presence of leptin in the SCN. These results suggest an indirect action of leptin on the SCN, possibly mediated by the medial hypothalamus. Taken together, these results highlight a central role of leptin in the relationship between metabolic disturbances and circadian disruptions. PMID- 25521582 TI - Hypoxia inhibits Cavin-1 and Cavin-2 expression and down-regulates caveolae in adipocytes. AB - During obesity, a hypoxic state develops within the adipose tissue, resulting in insulin resistance. To understand the underlying mechanism, we analyzed the involvement of caveolae because they play a crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disappearance of caveolae and inhibits the expression of Cavin-1 and Cavin-2, two proteins necessary for the formation of caveolae. In mice, hypoxia induced by the ligature of the spermatic artery results in the decrease of cavin-1 and cavin-2 expression in the epididymal adipose tissue. Down-regulation of the expression of cavins in response to hypoxia is dependent on hypoxia-inducible factor-1. Indeed, the inhibition of hypoxia-inducible factor-1 restores the expression of cavins and caveolae formation. Expression of cavins regulates insulin signaling because the silencing of cavin-1 and cavin-2 impairs insulin signaling pathway. In human, cavin-1 and cavin-2 are decreased in the sc adipose tissue of obese diabetic patients compared with lean subjects. Moreover, the expression of cavin-2 correlates negatively with the homeostatic model assessment index of insulin resistance and glycated hemoglobin level. In conclusion, we propose a new mechanism in which hypoxia inhibits cavin-1 and cavin-2 expression, resulting in the disappearance of caveolae. This leads to the inhibition of insulin signaling and the establishment of insulin resistance. PMID- 25521583 TI - Role of WNT16 in the regulation of periosteal bone formation in female mice. AB - In this study, we evaluated the role of WNT16 in regulating bone size, an important determinant of bone strength. Mice with targeted disruption of the Wnt16 gene exhibited a 24% reduction in tibia cross-sectional area at 12 weeks of age compared with that of littermate wild-type (WT) mice. Histomorphometric studies revealed that the periosteal bone formation rate and mineral apposition rate were reduced (P < .05) by 55% and 32%, respectively, in Wnt16 knockout (KO) vs WT mice at 12 weeks of age. In contrast, the periosteal tartrate resistant acid phosphatase-labeled surface was increased by 20% in the KO mice. Because mechanical strain is an important physiological regulator of periosteal bone formation (BF), we determined whether mechanical loading-induced periosteal BF is compromised in Wnt16 KO mice. Application of 4800-MUe strain to the right tibia using a 4-point bending loading method for 2 weeks (2-Hz frequency, 36 cycles per day, 6 days/wk) produced a significant increase in cross-sectional area (11% above that of the unloaded left tibia, P < .05, n = 6) in the WT but not in the KO mice (-0.2% change). Histomorphometric analyses revealed increases in the periosteal bone formation rate and mineral apposition rate in the loaded bones of WT but not KO mice. Wnt16 KO mice showed significant (20%-70%) reductions in the expression levels of markers of canonical (beta-catenin and Axin2) but not noncanonical (Nfatc1 and Tnnt2) WNT signaling in the periosteum at 5 weeks of age. Our findings suggest that WNT16 acting via canonical WNT signaling regulates mechanical strain-induced periosteal BF and bone size. PMID- 25521587 TI - Negative isotope effect for charge transport in acenes and derivatives--a theoretical conclusion. AB - The isotope effect (IE) on charge transport in polyacenes was proposed in 1970 to judge the transport mechanism. However, there had not been a definitive answer for more than 40 years as to whether such an IE is positive or negative, both theoretically and experimentally, because either theory was too approximate or the experimental estimate was too rough to make a judgment. Employing the quantum nuclear tunneling model for organic semiconductors, we investigate the IE on both hole and electron transport for acenes and their derivatives. We show that both (13)C-substitution and deuteration lead to a negative IE. By introducing phenyl, chlorine, or alkyl side-chains into acenes, the IE becomes more remarkable, especially for hole transport. The vibrational relaxation processes involving in plane bending of ring or alkyl side-chain motions are found to be responsible for the IE. PMID- 25521584 TI - Male bovine GH transgenic mice have decreased adiposity with an adipose depot specific increase in immune cell populations. AB - White adipose tissue (WAT) is composed of mature adipocytes and a stromal vascular fraction (SVF), which contains a variety of cells, including immune cells that vary among the different WAT depots. Growth hormone (GH) impacts immune function and adiposity in an adipose depot-specific manner. However, its effects on WAT immune cell populations remain unstudied. Bovine GH transgenic (bGH) mice are commonly used to study the in vivo effects of GH. These giant mice have an excess of GH action, impaired glucose metabolism, decreased adiposity, increased lean mass, and a shortened lifespan. Therefore, the purpose of this study was to characterize the WAT depot-specific differences in immune cell populations in the presence of excess GH in vivo. Three WAT depots were assessed: inguinal (sc), epididymal (EPI), and mesenteric (MES). Subcutaneous and MES bGH WAT depots showed a significantly higher number of total SVF cells, yet only MES bGH WAT had higher leukocyte counts compared with control samples. By means of flow cytometry analysis of the SVF, we detected greater macrophage and regulatory T-cell infiltration in sc and MES bGH WAT depots compared with controls. However, no differences were observed in the EPI WAT depot. RNA-sequencing confirmed significant alterations in pathways related to T-cell infiltration and activation in the sc depot with fewer significant changes in the EPI bGH WAT depot. These findings collectively point to a previously unrecognized role for GH in influencing the distribution of WAT immune cell populations in a depot-specific manner. PMID- 25521586 TI - Genetic basis of haloperidol resistance in Saccharomyces cerevisiae is complex and dose dependent. AB - The genetic basis of most heritable traits is complex. Inhibitory compounds and their effects in model organisms have been used in many studies to gain insights into the genetic architecture underlying quantitative traits. However, the differential effect of compound concentration has not been studied in detail. In this study, we used a large segregant panel from a cross between two genetically divergent yeast strains, BY4724 (a laboratory strain) and RM11_1a (a vineyard strain), to study the genetic basis of variation in response to different doses of a drug. Linkage analysis revealed that the genetic architecture of resistance to the small-molecule therapeutic drug haloperidol is highly dose-dependent. Some of the loci identified had effects only at low doses of haloperidol, while other loci had effects primarily at higher concentrations of the drug. We show that a major QTL affecting resistance across all concentrations of haloperidol is caused by polymorphisms in SWH1, a homologue of human oxysterol binding protein. We identify a complex set of interactions among the alleles of the genes SWH1, MKT1, and IRA2 that are most pronounced at a haloperidol dose of 200 uM and are only observed when the remainder of the genome is of the RM background. Our results provide further insight into the genetic basis of drug resistance. PMID- 25521588 TI - DNA switches: from principles to applications. AB - The base sequence of nucleic acid encodes structural and functional properties into the biopolymer. Structural information includes the formation of duplexes, G quadruplexes, i-motif, and cooperatively stabilized assemblies. Functional information encoded in the base sequence involves the strand-displacement process, the recognition properties by aptamers, and the catalytic functions of DNAzymes. This Review addresses the implementation of the information encoded in nucleic acids to develop DNA switches. A DNA switch is a supramolecular nucleic acid assembly that undergoes cyclic, switchable, transitions between two distinct states in the presence of appropriate triggers and counter triggers, such as pH value, metal ions/ligands, photonic and electrical stimuli. Applications of switchable DNA systems to tailor switchable DNA hydrogels, for the controlled drug-release and for the activation of switchable enzyme cascades, are described, and future perspectives of the systems are addressed. PMID- 25521589 TI - Effects of epigallocatechin gallate on lipid metabolism and its underlying molecular mechanism in broiler chickens. AB - The objective of this study was to investigate the effects of epigallocatechin gallate (EGCG) on fat metabolism and to establish the molecular mechanism of these effects in broilers. Seventy-two 28-day-old male Ross 308 broiler chickens were divided into three groups with different levels of EGCG supplementation for 4 weeks: normal control (NC) group, L-EGCG (a low-level supplement of EGCG, 40 mg/kg body weight daily) and H-EGCG (a high-level supplement of EGCG, 80 mg/kg body weight daily). After 4 weeks of oral administration, EGCG significantly reduced the level of abdominal fat deposition in broilers. The serum triglycerides and low-density lipoprotein cholesterol of chickens in H-EGCG group were also significantly decreased compared with the NC group, and the high density lipoprotein cholesterol was notably increased at the same time. Moreover, the vital role of the liver and abdominal adipose tissue in lipid metabolism of poultry animals was examined through gene expression and enzyme activities related to fat anabolism and catabolism in these organs. Our data show that EGCG supplementation for 2 weeks significantly downregulated the expression of fatty acid synthesis and fat deposition-related genes, and upregulated the expression of genes involved in fatty acid beta-oxidation and lipolysis genes. Simultaneously, the activities of hepatic fatty acid synthesis enzymes (fatty acid synthase and acetyl CoA carboxylase) were significantly decreased, and the activity of carnitine palmitoyl transferase-1 was notably elevated. The results suggest that EGCG could alleviate fat deposition in broilers through inhibiting fat anabolism and stimulating lipid catabolism in broilers. PMID- 25521591 TI - InCoB2014: Systems Biology update from the Asia-Pacific. Introduction. AB - Selected papers from the 13th International Conference on Bioinformatics (InCoB2014), July 31-2 August, 2014 in Sydney, Australia have been compiled in this supplement. These range from network analysis and gene regulatory networks to systems level biological analysis, providing the 2014 update to InCoB's computational systems biology research. PMID- 25521590 TI - Reward associated with singing behavior correlates with opioid-related gene expression in the medial preoptic nucleus in male European starlings. AB - Birdsong consists of species-specific learned vocal sequences that are used primarily to attract mates and to repel competitors during the breeding season. However, many birds continue to sing at times when vocal production has no immediate or obvious impact on conspecific behavior. The mechanisms that ensure that animals produce important behaviors in contexts in which the function of these behaviors is not immediate or obvious are not known. One possibility is that animals engage in such behaviors because they are associated with pleasure. Here we examined the hypothesis that male European starlings sing outside of the breeding season in part because the act of singing in this context is facilitated and/or maintained by opioid-mediated reward. We measured song-associated reward using a conditioned place preference (CPP) test in male starlings producing fall, non-breeding season-typical song. We used quantitative real time PCR to measure expression of the enkephalin opioid precursor preproenkephalin (PENK) and mu opioid receptors (MOR) in the medial preoptic nucleus (POM; a region in which opioids are implicated in both reward and starling fall song) and additionally the song control region HVC as a control. Starlings developed a strong preference for a place that had been paired previously with the act of producing fall typical song, indicating that fall song production was associated with a positive affective state. Both PENK and MOR mRNA expression in the POM, but not HVC, correlated positively with both individual reward state (as reflected in CPP) and undirected singing behavior. These results suggest that singing induces opioid receptor and enkephalin expression in the POM and consequent reward, and/or that opioid release in the POM induced by individual or environmental factors (e.g., the presence of food, safety of a flock or the absence of predators) induces a positive affective state which then facilitates singing behavior. PMID- 25521593 TI - Segregating complex sound sources through temporal coherence. AB - A new approach for the segregation of monaural sound mixtures is presented based on the principle of temporal coherence and using auditory cortical representations. Temporal coherence is the notion that perceived sources emit coherently modulated features that evoke highly-coincident neural response patterns. By clustering the feature channels with coincident responses and reconstructing their input, one may segregate the underlying source from the simultaneously interfering signals that are uncorrelated with it. The proposed algorithm requires no prior information or training on the sources. It can, however, gracefully incorporate cognitive functions and influences such as memories of a target source or attention to a specific set of its attributes so as to segregate it from its background. Aside from its unusual structure and computational innovations, the proposed model provides testable hypotheses of the physiological mechanisms of this ubiquitous and remarkable perceptual ability, and of its psychophysical manifestations in navigating complex sensory environments. PMID- 25521592 TI - CPB1 of Aedes aegypti interacts with DENV2 E protein and regulates intracellular viral accumulation and release from midgut cells. AB - Aedes aegypti is a principal vector responsible for the transmission of dengue viruses (DENV). To date, vector control remains the key option for dengue disease management. To develop new vector control strategies, a more comprehensive understanding of the biological interactions between DENV and Ae. aegypti is required. In this study, a cDNA library derived from the midgut of female adult Ae. aegypti was used in yeast two-hybrid (Y2H) screenings against DENV2 envelope (E) protein. Among the many interacting proteins identified, carboxypeptidase B1 (CPB1) was selected, and its biological interaction with E protein in Ae. aegypti primary midgut cells was further validated. Our double immunofluorescent assay showed that CPB1-E interaction occurred in the endoplasmic reticulum (ER) of the Ae. aegypti primary midgut cells. Overexpression of CPB1 in mosquito cells resulted in intracellular DENV2 genomic RNA or virus particle accumulation, with a lower amount of virus release. Therefore, we postulated that in Ae. aegypti midgut cells, CPB1 binds to the E protein deposited on the ER intraluminal membranes and inhibits DENV2 RNA encapsulation, thus inhibiting budding from the ER, and may interfere with immature virus transportation to the trans-Golgi network. PMID- 25521594 TI - A retrospective analysis of 141 patients with liver metastases from uveal melanoma: a two-cohort study comparing transarterial chemoembolization with CPT 11 charged microbeads and historical treatments. AB - We retrospectively evaluated the benefit of transarterial chemoembolization with CPT-11 charged microbeads (TACE) in 58 of 141 uveal melanoma patients with liver metastases. This was a retrospective analysis of a prospectively maintained database ranging from September 1990 to April 2014. Statistical analyses adjusting for possible confounding effects of extent of liver metastases were carried out using the Cox regression model under the verified hypothesis of proportional hazards. Among 141 patients with liver metastases, 58 were treated with TACE as first-line therapy and 36 were dead at the time of the analysis; 83 patients received other first-line treatments (deaths=83). The treatment with TACE conferred a survival advantage (median 16.5 vs. 12.2 months, respectively); when the two cohorts were analyzed comparing the two groups according to the percentage of liver involvement, there was significant evidence that patients with worse hepatic involvement benefited most from the treatment (liver metastases=20-50%: hazard ratio=0.50, P=0.048 and liver metastases >=50%: hazard ratio=0.17, P=0.009). Liver function tests (transaminases and gamma-glutamyl transpeptidase) and age were higher in the historic group, and LDH tended to show higher values. There were no high-grade toxicities with TACE. TACE seems to be a tolerable regimen that confers an improvement in the survival of uveal melanoma patients with liver metastases. Confirmation of the clinical efficacy of TACE is recommended in a phase III trial, possibly with the inclusion of a targeted therapy such as a MEK inhibitor. PMID- 25521596 TI - When health means suffering: mammograms, pain and compassionate care. AB - The X-ray mammogram remains the cornerstone of most public health programmes aimed at the early diagnosis of breast cancer. Its virtues of safety, reliability and cheapness maintain its established position, and Western social and cultural traditions of ambivalence to pain push any questions concerning the painfulness of the procedure into the background. As part of a larger UK/USA-based empirical study, we undertook a qualitative analysis of women's accounts of pain experienced in mammograms and their reaction to it, comparing their accounts with professional views and advice to patients as reflected in interviews, patient leaflets and practice guidelines. We found considerable variability of experience and reaction to pain among patients, and indications of similar variability in professionals' views and practice, contrasting with a uniformly reassuring message in formal institutional advice. We suggest that in practice professional work-arounds and patients' felt obligation to tolerate pain bridge this gap, but that action to tackle the problems of dropout and the emotional and operational costs of the current system is nonetheless needed. The need is for concerned groups to combine to establish a serious and sustained programme of amelioration and innovative technological development to assure more compassionate patient care and operational efficiency. PMID- 25521595 TI - Evaluating multiplexed quantitative phosphopeptide analysis on a hybrid quadrupole mass filter/linear ion trap/orbitrap mass spectrometer. AB - As a driver for many biological processes, phosphorylation remains an area of intense research interest. Advances in multiplexed quantitation utilizing isobaric tags (e.g., TMT and iTRAQ) have the potential to create a new paradigm in quantitative proteomics. New instrumentation and software are propelling these multiplexed workflows forward, which results in more accurate, sensitive, and reproducible quantitation across tens of thousands of phosphopeptides. This study assesses the performance of multiplexed quantitative phosphoproteomics on the Orbitrap Fusion mass spectrometer. Utilizing a two-phosphoproteome model of precursor ion interference, we assessed the accuracy of phosphopeptide quantitation across a variety of experimental approaches. These methods included the use of synchronous precursor selection (SPS) to enhance TMT reporter ion intensity and accuracy. We found that (i) ratio distortion remained a problem for phosphopeptide analysis in multiplexed quantitative workflows, (ii) ratio distortion can be overcome by the use of an SPS-MS3 scan, (iii) interfering ions generally possessed a different charge state than the target precursor, and (iv) selecting only the phosphate neutral loss peak (single notch) for the MS3 scan still provided accurate ratio measurements. Remarkably, these data suggest that the underlying cause of interference may not be due to coeluting and cofragmented peptides but instead from consistent, low level background fragmentation. Finally, as a proof-of-concept 10-plex experiment, we compared phosphopeptide levels from five murine brains to five livers. In total, the SPS-MS3 method quantified 38 247 phosphopeptides, corresponding to 11 000 phosphorylation sites. With 10 measurements recorded for each phosphopeptide, this equates to more than 628 000 binary comparisons collected in less than 48 h. PMID- 25521598 TI - The effects of UV irradiation on collagen D-band revealed by atomic force microscopy. AB - The objective of this paper was to investigate the influence of UV irradiation on collagen D-band periodicity by using the AFM imaging and nanoindentation methods. It is well known than UV irradiation is one of the main factors inducing destabilization of collagen molecules. Due to the human's skin chronic exposure to sun light, the research concerning the influence of UV radiation on collagen is of great interest. The impact of UV irradiation on collagen can be studied in nanoscale using Atomic Force Microscopy (AFM). AFM is a powerful tool as far as surface characterization is concerned, due to its ability to relate high resolution imaging with mechanical properties. Hence, high resolution images of individual collagen fibrils and load-displacement curves on the overlapping and gap regions, under various time intervals of UV exposure, were obtained. The results demonstrated that the UV rays affect the height level differences between the overlapping and gap regions. Under various time intervals of UV exposure, the height difference between overlaps and gaps reduced from ~3.7 nm to ~0.8 nm and the fibril diameters showed an average of 8-10% reduction. In addition, the irradiation influenced the mechanical properties of collagen fibrils. The Young's modulus values were reduced per 66% (overlaps) and 61% (gaps) compared to their initial values. The observed alterations on the structural and the mechanical properties of collagen fibrils are probably a consequence of the polypeptide chain scission due to the impact of the UV irradiation. PMID- 25521597 TI - Computational identification of novel natural inhibitors of glucagon receptor for checking type II diabetes mellitus. AB - BACKGROUND: Interaction of the small peptide hormone glucagon with glucagon receptor (GCGR) stimulates the release of glucose from the hepatic cells during fasting; hence GCGR performs a significant function in glucose homeostasis. Inhibiting the interaction between glucagon and its receptor has been reported to control hepatic glucose overproduction and thus GCGR has evolved as an attractive therapeutic target for the treatment of type II diabetes mellitus. RESULTS: In the present study, a large library of natural compounds was screened against 7 transmembrane domain of GCGR to identify novel therapeutic molecules that can inhibit the binding of glucagon with GCGR. Molecular dynamics simulations were performed to study the dynamic behaviour of the docked complexes and the molecular interactions between the screened compounds and the ligand binding residues of GCGR were analysed in detail. The top scoring compounds were also compared with already documented GCGR inhibitors- MK-0893 and LY2409021 for their binding affinity and other ADME properties. Finally, we have reported two natural drug like compounds PIB and CAA which showed good binding affinity for GCGR and are potent inhibitor of its functional activity. CONCLUSION: This study contributes evidence for application of these compounds as prospective small ligand molecules against type II diabetes. Novel natural drug like inhibitors against the 7 transmembrane domain of GCGR have been identified which showed high binding affinity and potent inhibition of GCGR. PMID- 25521599 TI - Modeling systems with pi-pi interactions using the Hartree-Fock method with an empirical dispersion correction. AB - The accuracy of the Hartree-Fock method with an empirical dispersion correction, HF-D3, to model interaction energies and locate constrained minimum geometries is tested against more conventional correlation methods, such as second-order perturbation theory and coupled cluster theory, and against the sophisticated effective fragment potential model. HF-D3 was applied to substituted-benzene dimers in both sandwich and T-shaped configurations and to DNA base pair complexes in both hydrogen bonded and stacked geometries. Overall, HF-D3 is found to be a plausible and cost efficient substitute for higher levels of electronic structure theory, such as MP2, in systems with pi-pi interactions. PMID- 25521601 TI - A theoretical study of the UV absorption of 4-methylbenzylidene camphor: from the UVB to the UVA region. AB - In this study, a theoretical approach was used to study the UV absorption of the UVB filter, 4-methylbenzylidene camphor. The main objective of this work was to design new UVA filters based on this rather photo-stable compound, so that photo degradation in this UV region can be avoided without the use of other molecules. This objective was achieved by the simultaneous addition of two appropriate substituents, which led to red-shifts of up to 0.69 eV while maintaining appreciable oscillator strength. Also, useful structure-energy relationships were derived, which allow for the development of more UVA filters based on 4 methylbenzylidene camphor. PMID- 25521600 TI - Transcranial direct current stimulation promotes the mobility of engrafted NSCs in the rat brain. AB - Transcranial direct current stimulation (tDCS) is used in numerous clinical studies and considered an effective and versatile add-on therapy in neurorehabilitation. To date, however, the underlying neurobiological mechanisms remain elusive. In a rat model of tDCS, we recently observed a polarity-dependent accumulation of endogenous neural stem cells (NSCs) in the stimulated cortex. Based upon these findings, we hypothesized that tDCS may exert a direct migratory effect on endogenous NSCs towards the stimulated cortex. Using noninvasive imaging, we here investigated whether tDCS may also cause a directed migration of engrafted NSCs. Murine NSCs were labeled with superparamagnetic particles of iron oxide (SPIOs) and implanted into rat striatum and corpus callosum. MRI was performed (i) immediately after implantation and (ii) after 10 tDCS sessions of anodal or cathodal polarity. Sham-stimulated rats served as control. Imaging results were validated ex vivo using immunohistochemistry. Overall migratory activity of NSCs almost doubled after anodal tDCS. However, no directed migration within the electric field (i.e. towards or away from the electrode) could be observed. Rather, an undirected outward migration from the center of the graft was detected. Xenograft transplantation induced a neuroinflammatory response that was significantly enhanced following cathodal tDCS. This inflammatory response did not impact negatively on the survival of implanted NSCs. Data suggest that anodal tDCS increases the undirected migratory activity of implanted NSCs. Since the electric field did not guide implanted NSCs over large distances, previously observed polarity-dependent accumulation of endogenous NSCs in the cortex might have originated from local proliferation. Results enhance our understanding of the neurobiological mechanisms underlying tDCS, and may thereby help to develop a targeted and sustainable application of tDCS in clinical practice. PMID- 25521602 TI - DNA adsorption by indium tin oxide nanoparticles. AB - The high conductivity and optical transparency of indium tin oxide (ITO) has made it a popular material in the electronic industry. Recently, its application in biosensors is also explored. To understand its biointerface chemistry, we herein investigate its interaction with fluorescently labeled single-stranded oligonucleotides using ITO nanoparticles (NPs). The fluorescence of DNA is efficiently quenched after adsorption, and the interaction between DNA and ITO NPs is strongly dependent on the surface charge of ITO. At low pH, the ITO surface is positively charged to afford a high DNA adsorption capacity. Adsorption is also influenced by the sequence and length of DNA. For its components, In2O3 adsorbs DNA more strongly while SnO2 repels DNA at neutral pH. The DNA adsorption property of ITO is an averaging result from both components. DNA adsorption is confirmed to be mainly by the phosphate backbone via displacement experiments using free phosphate or DNA bases. Last, DNA-induced DNA desorption by forming duplex DNA is demonstrated on ITO, while the same reaction is more difficult to achieve on other metal oxides including CeO2, TiO2, and Fe3O4 because these particles adsorb DNA more tightly. PMID- 25521603 TI - Liquid chromatography with tandem mass spectrometry for the simultaneous identification and quantification of cardiovascular drugs applied to the detection of substandard and falsified drugs. AB - The counterfeiting of pharmaceuticals has been detected since about 1990 and has alarmingly continued to pick up steam. We have been recently involved in an evaluation program of some of the most commonly prescribed cardiovascular drugs in Africa, for analysing an important number of tablets or capsules obtained from different places in seven African countries. A reversed-phase high-performance liquid chromatography with tandem mass spectrometry method was developed and validated to simultaneously control the identity and the quantity of acenocoumarol, amlodipine, atenolol, captopril, furosemide, hydrochlorothiazide and simvastatin in tablets. Their separation was performed on a Kinetex(r) C(18) (100 mm * 2.1 mm inside diameter, 2.6 MUm) column using a gradient elution of 20 mM ammonium formate buffer and acetonitrile (90:10 10:90 v/v) at a flow rate of 0.5 mL/min. The analytes were detected using electrospray ionisation tandem mass spectrometry in both positive and negative modes with multiple reaction monitoring. Tandem mass spectrometry fragmentation patterns of captopril, furosemide and acenocoumarol, up to now not detailed in the literature, were also studied to assist in the selection of the most relevant transitions towards the objectives. The developed method was validated as per International Conference on Harmonisation guidelines with respect to specificity, linearity, trueness, precision, limits of detection and quantification. It has been successfully applied to the control of oral forms of seven cardiovascular drugs collected in African countries. PMID- 25521604 TI - A comprehensive performance evaluation on the prediction results of existing cooperative transcription factors identification algorithms. AB - BACKGROUND: Eukaryotic transcriptional regulation is known to be highly connected through the networks of cooperative transcription factors (TFs). Measuring the cooperativity of TFs is helpful for understanding the biological relevance of these TFs in regulating genes. The recent advances in computational techniques led to various predictions of cooperative TF pairs in yeast. As each algorithm integrated different data resources and was developed based on different rationales, it possessed its own merit and claimed outperforming others. However, the claim was prone to subjectivity because each algorithm compared with only a few other algorithms and only used a small set of performance indices for comparison. This motivated us to propose a series of indices to objectively evaluate the prediction performance of existing algorithms. And based on the proposed performance indices, we conducted a comprehensive performance evaluation. RESULTS: We collected 14 sets of predicted cooperative TF pairs (PCTFPs) in yeast from 14 existing algorithms in the literature. Using the eight performance indices we adopted/proposed, the cooperativity of each PCTFP was measured and a ranking score according to the mean cooperativity of the set was given to each set of PCTFPs under evaluation for each performance index. It was seen that the ranking scores of a set of PCTFPs vary with different performance indices, implying that an algorithm used in predicting cooperative TF pairs is of strength somewhere but may be of weakness elsewhere. We finally made a comprehensive ranking for these 14 sets. The results showed that Wang J's study obtained the best performance evaluation on the prediction of cooperative TF pairs in yeast. CONCLUSIONS: In this study, we adopted/proposed eight performance indices to make a comprehensive performance evaluation on the prediction results of 14 existing cooperative TFs identification algorithms. Most importantly, these proposed indices can be easily applied to measure the performance of new algorithms developed in the future, thus expedite progress in this research field. PMID- 25521605 TI - Concurrent psychological stress and infectious colitis is key to sustaining enhanced peripheral sensory signaling. AB - BACKGROUND: The development of postinfectious-irritable bowel syndrome is associated with psychological stress but this relationship is poorly understood. The mouse Citrobacter rodentium model enhances the postinfectious excitability of colonic nociceptors, which can be further amplified by water-avoidance stress (WAS). This study tested whether concurrent infectious colitis and chronic stress enhance and sustain nociceptor excitability more than stress after resolution of infection. METHODS: Male C57 mice were gavaged with C. rodentium. WAS (1 h/day) was performed at different time-points relative to the infection. After the final session of WAS, T9-T13 colonic-projecting DRG neurons were isolated, cultured overnight and patch-clamped to assess excitability. To investigate potential mechanisms, histological damage scores and colonic cytokine production were assessed. KEY RESULTS: WAS more than 30 days after C. rodentium infection produced no greater DRG excitability than WAS in uninfected mice. However, when overlapped with chronic stress (3 sessions of WAS; 7 days before, 9 days during and 9 days after C. rodentium or sham gavage), C. rodentium significantly enhanced DRG excitability vs saline-gavaged chronically stressed mice. Bodyweights and colonic damage scores were unchanged. Both WAS and C. rodentium gavage were found to significantly alter colonic cytokines at postinfection day 30. CONCLUSIONS & INFERENCES: Chronic stress and infectious colitis combine in an additive manner to heighten and prolong the sensitivity of visceral nociceptors. The effect relies on temporal coincidence of stress and infection, does not involve substantial exacerbation of inflammation, and may involve combined direct stress hormone and immune signaling on DRG neurons. PMID- 25521606 TI - Single-chain semiconducting polymer dots. AB - This work describes the preparation and validation of single-chain semiconducting polymer dots (sPdots), which were generated using a method based on surface immobilization, washing, and cleavage. The sPdots have an ultrasmall size of ~3.0 nm as determined by atomic force microscopy, a size that is consistent with the anticipated diameter calculated from the molecular weight of the single-chain semiconducting polymer. sPdots should find use in biology and medicine as a new class of fluorescent probes. The FRET assay this work presents is a simple and rapid test to ensure methods developed for preparing sPdot indeed produced single chain Pdots as designed. PMID- 25521607 TI - The prevalence of NAFLD and NASH among patients with psoriasis in a tertiary care dermatology and rheumatology clinic. AB - BACKGROUND: Psoriasis has been linked to metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Data suggest that the prevalence of NAFLD is increased in patients with psoriasis. The aim of this study was to determine the prevalence and severity of NAFLD in this patient population. AIM: To determine the prevalence of both NAFLD and non-alcoholic steatohepatitis (NASH) in patients with psoriasis. METHODS: Patients between the ages of 18 and 70 years with a diagnosis of psoriasis or psoriatic arthritis and followed by either the Dermatology or Rheumatology Division within the Department of Medicine at San Antonio Military Medical Center were considered for enrollment. Each patient completed a questionnaire, underwent a thorough skin evaluation, and had a right upper quadrant ultrasound and fasting blood work. If the liver enzymes were elevated or fatty liver detected on imaging, percutaneous liver biopsy was recommended. RESULTS: One hundred and twenty-nine patients were enrolled and 103 completed all necessary studies. The participants were predominantly middle aged (52.7 +/- 12) and overweight or obese (average BMI 30.1 +/- 5.9, range: 19.8-52.5 kg/m(2)). 53% (n = 54) were male while 15% (n = 15) of participants identified themselves as being a diabetic. The overall prevalence of NAFLD was 47%. The overall prevalence of NASH was 22% in those who underwent biopsy. CONCLUSIONS: Non-alcoholic fatty liver disease is very common among our cohort of patients with psoriasis, occurring in roughly 47% of patients. The more progressive form of the disease, NASH, is found in approximately one in five patients. Health care providers should be mindful of this association given the high prevalence of both NAFLD and NASH in this cohort of patients. PMID- 25521611 TI - Microporous La-metal-organic framework (MOF) with large surface area. AB - A microporous La-metal-organic framework (MOF) has been synthesized by the reaction of La(NO3 )3 ?6 H2 O with a ligand 4,4',4''-s-triazine-1,3,5-triyltri-p aminobenzoate (TATAB) featuring three carboxylate groups. Crystal structure analysis confirms the formation of 3D MOF with hexagonal micropores, a Brunauer Emmett-Teller (BET) surface area of 1074 m(2) g(-1) and high thermal and chemical stability. The CO2 adsorption capacities are 76.8 cm(3) g(-1) at 273 K and 34.6 cm(3) g(-1) at 293 K, a highest measured CO2 uptake for a Ln-MOFs. PMID- 25521610 TI - Derivation of iPSCs after culture of human dental pulp cells under defined conditions. AB - Human dental pulp cells (hDPCs) are a promising resource for regenerative medicine and tissue engineering and can be used for derivation of induced pluripotent stem cells (iPSCs). However, current protocols use reagents of animal origin (mainly fetal bovine serum, FBS) that carry the potential risk of infectious diseases and unwanted immunogenicity. Here, we report a chemically defined protocol to isolate and maintain the growth and differentiation potential of hDPCs. hDPCs cultured under these conditions showed significantly less primary colony formation than those with FBS. Cell culture under stringently defined conditions revealed a donor-dependent growth capacity; however, once established, the differentiation capabilities of the hDPCs were comparable to those observed with FBS. DNA array analyses indicated that the culture conditions robustly altered hDPC gene expression patterns but, more importantly, had little effect on neither pluripotent gene expression nor the efficiency of iPSC induction. The chemically defined culture conditions described herein are not perfect serum replacements, but can be used for the safe establishment of iPSCs and will find utility in applications for cell-based regenerative medicine. PMID- 25521608 TI - Characterization of the Ca2+-gated and voltage-dependent K+-channel Slo-1 of nematodes and its interaction with emodepside. AB - The cyclooctadepsipeptide emodepside and its parent compound PF1022A are broad spectrum nematicidal drugs which are able to eliminate nematodes resistant to other anthelmintics. The mode of action of cyclooctadepsipeptides is only partially understood, but involves the latrophilin Lat-1 receptor and the voltage and calcium-activated potassium channel Slo-1. Genetic evidence suggests that emodepside exerts its anthelmintic activity predominantly through Slo-1. Indeed, slo-1 deficient Caenorhabditis elegans strains are completely emodepside resistant. However, direct effects of emodepside on Slo-1 have not been reported and these channels have only been characterized for C. elegans and related Strongylida. Molecular and bioinformatic analyses identified full-length Slo-1 cDNAs of Ascaris suum, Parascaris equorum, Toxocara canis, Dirofilaria immitis, Brugia malayi, Onchocerca gutturosa and Strongyloides ratti. Two paralogs were identified in the trichocephalids Trichuris muris, Trichuris suis and Trichinella spiralis. Several splice variants encoding truncated channels were identified in Trichuris spp. Slo-1 channels of trichocephalids form a monophyletic group, showing that duplication occurred after the divergence of Enoplea and Chromadorea. To explore the function of a representative protein, C. elegans Slo 1a was expressed in Xenopus laevis oocytes and studied in electrophysiological (voltage-clamp) experiments. Incubation of oocytes with 1-10 uM emodepside caused significantly increased currents over a wide range of step potentials in the absence of experimentally increased intracellular Ca2+, suggesting that emodepside directly opens C. elegans Slo-1a. Emodepside wash-out did not reverse the effect and the Slo-1 inhibitor verruculogen was only effective when applied before, but not after, emodepside. The identification of several splice variants and paralogs in some parasitic nematodes suggests that there are substantial differences in channel properties among species. Most importantly, this study showed for the first time that emodepside directly opens a Slo-1 channel, significantly improving the understanding of the mode of action of this drug class. PMID- 25521612 TI - Evening media exposure reduces night-time sleep. AB - AIM: To investigate whether evening media exposure, bedroom media use and night time sleep duration at age 6 months are associated with night-time sleep duration in 12-month-old Thai infants. METHODS: We enrolled 208 infants in this study at 6 months of age. They were followed-up at 12 months of age. A sleep diary was used to document the infant's sleep onset and wake time at each visit. Night-time sleep duration was then calculated at both ages. Screen media exposure in the household was assessed in depth at both visits. RESULTS: Infants who were exposed to screen media in the evening at 12 months of age had a 28-min decrease in 12 month night-time sleep duration on weekdays. Moreover, infants who were exposed to screen media in the evening at age 6 months and 12 months had shorter 12-month night-time sleep duration compared with those who were not exposed to screen media after 7 pm at both ages. Night-time sleep duration at 12 months of age was also directly related to 6-month night-time sleep duration. CONCLUSION: Infants exposed to screen media in the evening at 12 months of age had decreased 12-month night-time sleep duration. To promote good sleep hygiene and optimal sleep for infants at this age, screen media exposure after 7 pm should be avoided. PMID- 25521613 TI - Notions of quality and standards for qualitative research reporting. AB - The utility of qualitative research findings in the health sciences has been the subject of considerable debate, particularly with the advent of qualitative systematic reviews in recent years. There has been a significant investment in the production of guidance to improve the reporting of quantitative research; however, comparatively little time has been spent on developing the same for qualitative research reporting. This paper sets out to examine the possibility of developing a framework for refereed journals to utilize when guiding authors on how to report the results of qualitative studies in the hope that this will improve the quality of reports and subsequently their inclusion in qualitative syntheses and guidelines to inform practice at the point of care. PMID- 25521614 TI - Raman spectroscopic studies of vitamin A content in the liver: a biomarker of healthy liver. AB - Confocal Raman microspectroscopy was used in this study to identify hepatic stellate cells (HSCs) from healthy mice and mice with untreated and treated liver steatosis. We have identified the main form of occurrence of vitamin A in healthy liver and confirmed its absence in the pathological state. Additionally, we have reported the reappearance of vitamin A in the tissue after treatment of liver steatosis. PMID- 25521615 TI - Inverse metal-assisted chemical etching produces smooth high aspect ratio InP nanostructures. AB - Creating high aspect ratio (AR) nanostructures by top-down fabrication without surface damage remains challenging for III-V semiconductors. Here, we demonstrate uniform, array-based InP nanostructures with lateral dimensions as small as sub 20 nm and AR > 35 using inverse metal-assisted chemical etching (I-MacEtch) in hydrogen peroxide (H2O2) and sulfuric acid (H2SO4), a purely solution-based yet anisotropic etching method. The mechanism of I-MacEtch, in contrast to regular MacEtch, is explored through surface characterization. Unique to I-MacEtch, the sidewall etching profile is remarkably smooth, independent of metal pattern edge roughness. The capability of this simple method to create various InP nanostructures, including high AR fins, can potentially enable the aggressive scaling of InP based transistors and optoelectronic devices with better performance and at lower cost than conventional etching methods. PMID- 25521616 TI - Comparison of retinal and choriocapillaris thicknesses following sitting to supine transition in healthy individuals and patients with age-related macular degeneration. AB - IMPORTANCE: The effects of position on retinal and choroidal structure are absent from the literature yet may provide insights into disease states such as age related macular degeneration (AMD). OBJECTIVE: To evaluate the effect of postural change on retinal and choroidal structures in healthy volunteers and patients with non-neovascular AMD. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational case series at an academic tertiary care retina service from September 2013 to April 2014 involving 4 unaffected volunteers (8 eyes) and 7 patients (8 eyes) with intermediate AMD. Healthy volunteers selected for the study had no evidence of ocular disease. Patients with AMD were required to have at least 10 intermediate-sized drusen. EXPOSURES: Spectral-domain optical coherence tomography with enhanced depth imaging in upright (sitting) and supine positions. Stable imaging was achieved using a rotating adjustable mechanical arm that we constructed to allow the optical coherence tomography transducer to rotate 90 degrees . The Iowa Reference Algorithms were used to quantify choroid and choriocapillaris thicknesses. MAIN OUTCOMES AND MEASURES: Changes in sitting and supine position central macular thickness (in micrometers), total macular volume (in cubic millimeters), choroidal thickness (in micrometers), and choriocapillaris-equivalent thickness (CCET, in micrometers). RESULTS: Choriocapillaris-equivalent thickness was thinner in healthy participants (9.89 MUm; range, 7.15-12.5 MUm) compared with patients with intermediate AMD (16.73 MUm; range, 10.31-27.38 MUm) (P = .02); there was no difference in overall choroidal thickness between the 2 groups (P = .38). There was a 15% CCET reduction among healthy participants when transitioning from a sitting (9.89 MUm) to supine (8.4 MUm; range, 6.92-10.7 MUm) position (P = .02) vs a CCET reduction of 11.1% from sitting (16.73 MUm) to supine (14.88 MUm; range, 8.76-20.8 MUm) positioning (P = .10) in patients with intermediate AMD. CONCLUSIONS AND RELEVANCE: Intermediate AMD appears to be associated with an increase in CCET and with a lack of positional responses that are observed in the CCET of normal eyes. Our results suggest that although outer portions of the choroid do not appear to be responsive to modest positional or hydrostatic pressure, the choriocapillaris capacity is, and this is measurable in vivo. Whether this physiologic deviation that occurs in AMD is related to atrophy, inflammation, or changes in autoregulatory factors or growth factors remains to be determined. PMID- 25521618 TI - Therapeutic gold, silver, and platinum nanoparticles. AB - There are an abundance of nanoparticle technologies being developed for use as part of therapeutic strategies. This review focuses on a narrow class of metal nanoparticles that have therapeutic potential that is a consequence of elemental composition and size. The most widely known of these are gold nanoshells that have been developed over the last two decades for photothermal ablation in superficial cancers. The therapeutic effect is the outcome of the thickness and diameter of the gold shell that enables fine tuning of the plasmon resonance. When these metal nanoparticles are exposed to the relevant wavelength of light, their temperature rapidly increases. This in turn induces a localized photothermal ablation that kills the surrounding tumor tissue. Similarly, gold nanoparticles have been developed to enhance radiotherapy. The high-Z nature of gold dramatically increases the photoelectric cross-section. Thus, the photoelectric effects are significantly increased. The outcome of these interactions is enhanced tumor killing with lower doses of radiation, all while sparing tissue without gold nanoparticles. Silver nanoparticles have been used for their wound healing properties in addition to enhancing the tumor-killing effects of anticancer drugs. Finally, platinum nanoparticles are thought to serve as a reservoir for platinum ions that can induce DNA damage in cancer cells. The future is bright with the path to clinical trials is largely cleared for some of the less complex therapeutic metal nanoparticle systems. PMID- 25521617 TI - Enhanced longevity by ibuprofen, conserved in multiple species, occurs in yeast through inhibition of tryptophan import. AB - The common non-steroidal anti-inflammatory drug ibuprofen has been associated with a reduced risk of some age-related pathologies. However, a general pro longevity role for ibuprofen and its mechanistic basis remains unclear. Here we show that ibuprofen increased the lifespan of Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster, indicative of conserved eukaryotic longevity effects. Studies in yeast indicate that ibuprofen destabilizes the Tat2p permease and inhibits tryptophan uptake. Loss of Tat2p increased replicative lifespan (RLS), but ibuprofen did not increase RLS when Tat2p was stabilized or in an already long-lived strain background impaired for aromatic amino acid uptake. Concomitant with lifespan extension, ibuprofen moderately reduced cell size at birth, leading to a delay in the G1 phase of the cell cycle. Similar changes in cell cycle progression were evident in a large dataset of replicatively long-lived yeast deletion strains. These results point to fundamental cell cycle signatures linked with longevity, implicate aromatic amino acid import in aging and identify a largely safe drug that extends lifespan across different kingdoms of life. PMID- 25521619 TI - Extreme divergence of Wolbachia tropism for the stem-cell-niche in the Drosophila testis. AB - Microbial tropism, the infection of specific cells and tissues by a microorganism, is a fundamental aspect of host-microbe interactions. The intracellular bacteria Wolbachia have a peculiar tropism for the stem cell niches in the Drosophila ovary, the microenvironments that support the cells producing the eggs. The molecular underpinnings of Wolbachia stem cell niche tropism are unknown. We have previously shown that the patterns of tropism in the ovary show a high degree of conservation across the Wolbachia lineage, with closely related Wolbachia strains usually displaying the same pattern of stem cell niche tropism. It has also been shown that tropism to these structures in the ovary facilitates both vertical and horizontal transmission, providing a strong selective pressure towards evolutionary conservation of tropism. Here we show great disparity in the evolutionary conservation and underlying mechanisms of stem cell niche tropism between male and female gonads. In contrast to females, niche tropism in the male testis is not pervasive, present in only 45% of niches analyzed. The patterns of niche tropism in the testis are not evolutionarily maintained across the Wolbachia lineage, unlike what was shown in the females. Furthermore, hub tropism does not correlate with cytoplasmic incompatibility, a Wolbachia-driven phenotype imprinted during spermatogenesis. Towards identifying the molecular mechanism of hub tropism, we performed hybrid analyses of Wolbachia strains in non-native hosts. These results indicate that both Wolbachia and host derived factors play a role in the targeting of the stem cell niche in the testis. Surprisingly, even closely related Wolbachia strains in Drosophila melanogaster, derived from a single ancestor only 8,000 years ago, have significantly different tropisms to the hub, highlighting that stem cell niche tropism is rapidly diverging in males. These findings provide a powerful system to investigate the mechanisms and evolution of microbial tissue tropism. PMID- 25521620 TI - Earlier menarche is associated with fatty liver and abdominal ectopic fat in midlife, independent of young adult BMI: The CARDIA study. AB - OBJECTIVE: The hypothesis that earlier menarche is associated with higher non alcoholic fatty liver disease (NAFLD) and ectopic adiposity, independent of young adult body mass index (BMI), was tested. METHODS: The data from 1,214 black and white women in the Coronary Artery Risk Development in Young Adults (CARDIA) study who reliably reported menarche age at exam years 0 and 2, who had multiple slice abdominal computed tomography (CT) at exam year 25, and who had no known liver disease or secondary causes of steatosis were included. Women were aged 18 30 at year 0 and 43-55 at year 25. Liver attenuation, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and inter-muscular adipose tissue (IMAT) were derived from CT. NAFLD was defined as liver attenuation less than 51 Hounsfield units. RESULTS: One-year earlier menarche was associated with higher NAFLD (RR = 1.15; 95% CI: 1.07, 1.24), and VAT (6.7 cc; 95% CI: 4.3, 9.0 cc), IMAT (1.0 cc; 95% CI: 0.6, 1.4 cc), and SAT (19.6 cc; 95% CI: 13.2, 26.0 cc) after confounder adjustment. Associations remained significant (P < 0.05) after further adjustment for year 0 BMI. Only VAT remained significant (P = 0.047) after adjustment for weight gain between years 0 and 25. CONCLUSIONS: Earlier menarche is positively associated with NAFLD and ectopic fat independent of confounders and young adult BMI. Weight gain between young adulthood and midlife explains some of this association. PMID- 25521621 TI - The prevalence and risk factors for gallstone disease in taiwanese vegetarians. AB - INTRODUCTION: Gallstone disease (GSD) and its complications are major public health issues globally. Although many community-based studies had addressed the risk factors for GSD, little is known about GSD prevalence and risk factors among Taiwanese vegetarians. METHODS: This study included 1721 vegetarians who completed a questionnaire detailing their demographics, medical history, and life styles. GSD was ascertained by ultrasonography or surgical history of cholecystectomy for GSD. The predictive probability of GSD for male and female vegetarians was estimated from the fitted model. RESULTS: The prevalence of GSD was 8.2% for both male and female vegetarians. The risk of GSD is similar in men and women across all age groups, and increases steadily with increasing age. For male vegetarians, age (OR: 1.04; 95% CI: 1.00-1.08) and serum total bilirubin level (OR: 2.35; 95% CI: 1.31-4.22) predict risk for GSD. For female vegetarians, age (OR: 1.03; 95% CI: 1.01-1.05), BMI (OR: 1.07; 95% CI: 1.01-1.13), and alcohol consumption (OR: 7.85; 95% CI: 1.83-33.73) are associated with GSD. GSD is not associated with type of vegetarian diet, duration of vegetarianism, low education level, physical inactivity, diabetes, coronary artery disease, cerebral vascular accident, chronic renal failure, hepatitis C virus infection, and lipid abnormalities. GSD is also not associated with age at menarche, postmenopausal status, and multiparity in female vegetarians. CONCLUSIONS: Risk factors useful for predicting GSD in vegetarians are (1) age and total bilirubin level in men, and (2) age, BMI, and alcohol consumption in women. Many previously identified risk factors for general population does not seem to apply to Taiwanese vegetarians. PMID- 25521623 TI - Selective transfer semihydrogenation of alkynes with nanoporous gold catalysts. AB - A facile, highly chemo- and stereoselective transfer semihydrogenation of alkynes to Z-olefins has been achieved by use of unsupported nanoporous gold (AuNPore) as a heterogeneous catalyst together with formic acid as a hydrogen donor. A variety of terminal/internal and aromatic/aliphatic alkynes were reduced to the corresponding alkenes in high chemical yields with good functional-group tolerance. The catalyst is robust enough to be reused without leaching. PMID- 25521624 TI - First Asian Invertebrate Immunity Symposium (Busan, Korea). Preface to the Special Issue. PMID- 25521625 TI - Symbiotic factors in Burkholderia essential for establishing an association with the bean bug, Riptortus pedestris. AB - Symbiotic bacteria are common in insects and intimately affect the various aspects of insect host biology. In a number of insect symbiosis models, it has been possible to elucidate the effects of the symbiont on host biology, whereas there is a limited understanding of the impact of the association on the bacterial symbiont, mainly due to the difficulty of cultivating insect symbionts in vitro. Furthermore, the molecular features that determine the establishment and persistence of the symbionts in their host (i.e., symbiotic factors) have remained elusive. However, the recently established model, the bean bug Riptortus pedestris, provides a good opportunity to study bacterial symbiotic factors at a molecular level through their cultivable symbionts. Bean bugs acquire genus Burkholderia cells from the environment and harbor them as gut symbionts in the specialized posterior midgut. The genome of the Burkholderia symbiont was sequenced, and the genomic information was used to generate genetically manipulated Burkholderia symbiont strains. Using mutant symbionts, we identified several novel symbiotic factors necessary for establishing a successful association with the host gut. In this review, these symbiotic factors are classified into three categories based on the colonization dynamics of the mutant symbiont strains: initiation, accommodation, and persistence factors. In addition, the molecular characteristics of the symbiotic factors are described. These newly identified symbiotic factors and on-going studies of the Riptortus Burkholderia symbiosis are expected to contribute to the understanding of the molecular cross-talk between insects and bacterial symbionts that are of ecological and evolutionary importance. PMID- 25521626 TI - Paralytic peptide: an insect cytokine that mediates innate immunity. AB - Host animals combat invading pathogens by activating various immune responses. Modulation of the immune pathways by cytokines is critical for efficient pathogen elimination. Insects and mammals possess common innate immune systems, and individual immune pathways have been intensively studied over the last two decades. Relatively less attention, however, has been focused on the functions of cytokines in insect innate immunity. Here, we summarize our recent findings from studies of the insect cytokine, paralytic peptide, in the silkworm Bombyx mori. The content of this report was presented at the First Asian Invertebrate Immunity Symposium. Acute activation of paralytic peptide occurs via proteolysis after stimulation with the cell wall components of pathogens, leading to the induction of a wide range of cellular and humoral immune responses. The pathogenic bacterium Serratia marcescens suppresses paralytic peptide-dependent immune activation, which impairs host resistance. Studies of insect cytokines will broaden our understanding of the basic mechanisms underlying the interaction between host innate immunity and pathogenic agents. PMID- 25521622 TI - WMJ-S-001, a novel aliphatic hydroxamate derivative, exhibits anti-inflammatory properties via MKP-1 in LPS-stimulated RAW264.7 macrophages. AB - BACKGROUND AND PURPOSE: Hydroxamate derivatives have attracted considerable attention because of their broad pharmacological properties. Recent studies reported their potential use in the treatment of cardiovascular diseases, arthritis and infectious diseases. However, the mechanisms of the anti inflammatory effects of hydroxamate derivatives remain to be elucidated. In an effort to develop a novel pharmacological agent that could suppress abnormally activated macrophages, we investigated a novel aliphatic hydroxamate derivative, WMJ-S-001, and explored its anti-inflammatory mechanisms. EXPERIMENTAL APPROACH: RAW264.7 macrophages were exposed to LPS in the absence or presence of WMJ-S-001. COX-2 expression and signalling molecules activated by LPS were assessed. KEY RESULTS: LPS-induced COX-2 expression was suppressed by WMJ-S-001. WMJ-S-001 inhibited p38MAPK, NF-kappaB subunit p65 and CCAAT/enhancer-binding protein (C/EBP)beta phosphorylation in cells exposed to LPS. Treatment of cells with a p38MAPK inhibitor (p38MAPK inhibitor III) markedly inhibited LPS-induced p65 and C/EBPbeta phosphorylation and COX-2 expression. LPS-increased p65 and C/EBPbeta binding to the COX-2 promoter region was suppressed in the presence of WMJ-S-001. In addition, WMJ-S-001 suppression of p38MAPK, p65 and C/EBPbeta phosphorylation, and subsequent COX-2 expression were restored in cells transfected with a dominant-negative (DN) mutant of MAPK phosphatase-1 (MKP-1). WMJ-S-001 also caused an increase in MKP-1 activity in RAW264.7 macrophages. CONCLUSIONS AND IMPLICATIONS: WMJ-S-001 may activate MKP-1, which then dephosphorylates p38MAPK, resulting in a decrease in p65 and C/EBPbeta binding to the COX-2 promoter region and COX-2 down-regulation in LPS-stimulated RAW264.7 macrophages. The present study suggests that WMJ-S-001 may be a potential drug candidate for alleviating LPS-associated inflammatory diseases. PMID- 25521627 TI - Cloning, expression, and characterization of prophenoloxidase from Antheraea pernyi. AB - Prophenoloxidase (PPO) is an essential enzyme in insect innate immunity because of its role in humoral defense. In this study, we have cloned a full-length cDNA of Antheraea pernyi prophenoloxidase (ApPPO) with an open-reading frame encoding 683 amino acids, and the deduced amino acid sequence of ApPPO exhibited a high similarity with those of lepidoptera. The expression of ApPPO was inducible so that the mRNA level was significantly upregulated in the microbial challenged tissues, including fat body, hemocytes, and midgut. To better investigate the enzymatic and immunological properties of ApPPO, recombinant ApPPO (rApPPO) was produced in Escherichia coli. Several functional verification experiments were performed after studying the enzymatic properties. It was found that rApPPO could be stimulated by the microbial challenged larvae hemolymph and then killed bacteria in the radial diffusion assay. Furthermore, rApPPO also induced the transcription of cecropins after injected into the larvae 24 h later. PMID- 25521630 TI - Use of eltrombopag after romiplostim in primary immune thrombocytopenia. AB - The thrombopoietin receptor agonists (THPO-RAs), romiplostim and eltrombopag, are effective and safe in immune thrombocytopenia (ITP). However, the value of their sequential use when no response is achieved or when adverse events occur with one THPO-RA has not been clearly established. Here we retrospectively evaluated 51 primary ITP adult patients treated with romiplostim followed by eltrombopag. The median age of our cohort was 49 (range, 18-83) years. There were 32 women and 19 men. The median duration of romiplostim use before switching to eltrombopag was 12 (interquartile range 5-21) months. The reasons for switching were: lack of efficacy (n = 25), patient preference (n = 16), platelet-count fluctuation (n = 6) and side-effects (n = 4). The response rate to eltrombopag was 80% (41/51), including 67% (n = 35) complete responses. After a median follow-up of 14 months, 31 patients maintained their response. Efficacy was maintained after switching in all patients in the patient preference, platelet-count fluctuation and side effect groups. 33% of patients experienced one or more adverse events during treatment with eltrombopag. We consider the use of eltrombopag after romiplostim for treating ITP to be effective and safe. Response to eltrombopag was related to the cause of romiplostim discontinuation. PMID- 25521632 TI - Inside the cell: one of a series, but something special.... PMID- 25521629 TI - Surgical molecular navigation with ratiometric activatable cell penetrating peptide for intraoperative identification and resection of small salivary gland cancers. AB - BACKGROUND: We evaluated the use of intraoperative fluorescence guidance by enzymatically cleavable ratiometric activatable cell-penetrating peptide (RACPPPLGC(Me)AG) containing Cy5 as a fluorescent donor and Cy7 as a fluorescent acceptor for salivary gland cancer surgery in a mouse model. METHODS: Surgical resection of small parotid gland cancers in mice was performed with fluorescence guidance or white light (WL) imaging alone. Tumor identification accuracy, operating time, and tumor-free survival were compared. RESULTS: RACPP guidance aided tumor detection (positive histology in 90% [27/30] vs 48% [15/31] for WL; p < .001). An approximate 25% ratiometric signal increase as the threshold to distinguish between tumor and adjacent tissue, yielded >90% detection sensitivity and specificity. Operating time was reduced by 54% (p < .001), and tumor-free survival was increased with RACPP guidance (p = .025). CONCLUSION: RACPP provides real-time intraoperative guidance leading to improved survival. Ratiometric signal thresholds can be set according to desired detection accuracy levels for future RACPP applications. PMID- 25521631 TI - Phospholipase C epsilon (PLCepsilon) induced TRPC6 activation: a common but redundant mechanism in primary podocytes. AB - In eukaryotic cells, activation of phospholipase C (PLC)-coupled membrane receptors by hormones leads to an increase in the intracellular Ca(2+) concentration [Ca(2+) ]i . Catalytic activity of PLCs results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) which opens DAG-sensitive classical transient receptor channels 3, 6, and 7 (TRPC3/6/7), initiating Ca(2+) influx from the extracellular space. Patients with focal segmental glomerulosclerosis (FSGS) express gain-of-function mutants of TRPC6, while others carry loss-of-function mutants of PLCepsilon, raising the intriguing possibility that both proteins interact and might work in the same signalling pathway. While TRPC6 activation by PLCbeta and PLCgamma isozymes was extensively studied, the role of PLCepsilon in TRPC6 activation remains elusive. TRPC6 was co-immunoprecipitated with PLCepsilon in a heterologous overexpression system in HEK293 cells as well as in freshly isolated murine podocytes. Receptor-operated TRPC6 currents in HEK293 cells expressing TRPC6 were reduced by a specific PLCepsilon siRNA and by a PLCepsilon loss-of-function mutant isolated from a patient with FSGS. PLCepsilon-induced TRPC6 activation was also identified in murine embryonic fibroblasts (MEFs) lacking Galphaq/11 proteins. Further analysis of the signal transduction pathway revealed a Galpha12/13 Rho-GEF activation which induced Rho-mediated PLCepsilon stimulation. Therefore, we identified a new pathway for TRPC6 activation by PLCepsilon. PLCepsilon-/- podocytes however, were undistinguishable from WT podocytes in their angiotensin II-induced formation of actin stress fibers and their GTPgammaS-induced TRPC6 activation, pointing to a redundant role of PLCepsilon-mediated TRPC6 activation at least in podocytes. PMID- 25521633 TI - A century of phage research: bacteriophages and the shaping of modern biology. AB - 2015 marks the centennial of the discovery of bacteriophages, viruses that infect bacteria. Phages have been central to some of biology's most meaningful advances over the past hundred years (shown here); they greatly influence the workings of the biosphere, and are poised to play expanded roles in biomedicine, biotechnology, and ecology. PMID- 25521637 TI - Pathway analysis and transcriptomics improve protein identification by shotgun proteomics from samples comprising small number of cells--a benchmarking study. AB - BACKGROUND: Proteomics research is enabled with the high-throughput technologies, but our ability to identify expressed proteome is limited in small samples. The coverage and consistency of proteome expression are critical problems in proteomics. Here, we propose pathway analysis and combination of microproteomics and transcriptomics analyses to improve mass-spectrometry protein identification from small size samples. RESULTS: Multiple proteomics runs using MCF-7 cell line detected 4,957 expressed proteins. About 80% of expressed proteins were present in MCF-7 transcripts data; highly expressed transcripts are more likely to have expressed proteins. Approximately 1,000 proteins were detected in each run of the small sample proteomics. These proteins were mapped to gene symbols and compared with gene sets representing canonical pathways, more than 4,000 genes were extracted from the enriched gene sets. The identified canonical pathways were largely overlapping between individual runs. Of identified pathways 182 were shared between three individual small sample runs. CONCLUSIONS: Current technologies enable us to directly detect 10% of expressed proteomes from small sample comprising as few as 50 cells. We used knowledge-based approaches to elucidate the missing proteome that can be verified by targeted proteomics. This knowledge-based approach includes pathway analysis and combination of gene expression and protein expression data for target prioritization. Genes present in both the enriched gene sets (canonical pathways collection) and in small sample proteomics data correspond to approximately 50% of expressed proteomes in larger sample proteomics data. In addition, 90% of targets from canonical pathways were estimated to be expressed. The comparison of proteomics and transcriptomics data, suggests that highly expressed transcripts have high probability of protein expression. However, approximately 10% of expressed proteins could not be matched with the expressed transcripts. PMID- 25521639 TI - Hypothermic machine preservation facilitates successful transplantation of "orphan" extended criteria donor livers. AB - Hypothermic machine preservation (HMP) remains investigational in clinical liver transplantation. It is widely used to preserve kidneys for transplantation with improved results over static cold storage (SCS). At our center, we have used HMP in 31 adults receiving extended criteria donor (ECD) livers declined by the originating United Network for Organ Sharing region ("orphan livers"). These cases were compared to ECD SCS cases in a matched cohort study design. Livers were matched for donor age, recipient age, cold ischemic time, donor risk index and Model for End-Stage Liver Disease (MELD) score. HMP was performed for 3-7 h at 4-8 degrees C using our previously published protocol. Early allograft dysfunction rates were 19% in the HMP group versus 30% in the control group (p = 0.384). One-year patient survival was 84% in the HMP group versus 80% in the SCS group (p = NS). Post hoc analysis revealed significantly less biliary complications in the HMP group versus the SCS group (4 vs. 13, p = 0.016). Mean hospital stay was significantly shorter in the HMP group (13.64 +/- 10.9 vs. 20.14 +/- 11.12 days in the SCS group, p = 0.001). HMP provided safe and reliable preservation in orphan livers transplanted at our center. PMID- 25521640 TI - Small steps to new drugs for bugs. AB - Governments, academics and industry are beginning to listen to the medical communities call for new anti-bacterials. This special issue brings together diverse review articles on topics from economics and pricing to new discovery methods. PMID- 25521638 TI - Immunoglobulins: 25 years of immunoinformatics and IMGT-ONTOLOGY. AB - IMGT(r), the international ImMunoGeneTics information system(r) (CNRS and Montpellier University) is the global reference in immunogenetics and immunoinformatics. By its creation in 1989, IMGT(r) marked the advent of immunoinformatics, which emerged at the interface between immunogenetics and bioinformatics. IMGT(r) is specialized in the immunoglobulins (IG) or antibodies, T cell receptors (TR), major histocompatibility (MH), and IgSF and MhSF superfamilies. IMGT(r) has been built on the IMGT-ONTOLOGY axioms and concepts, which bridged the gap between genes, sequences and three-dimensional (3D) structures. The concepts include the IMGT(r) standardized keywords (identification), IMGT(r) standardized labels (description), IMGT(r) standardized nomenclature (classification), IMGT unique numbering and IMGT Colliers de Perles (numerotation). IMGT(r) comprises seven databases, 15,000 pages of web resources and 17 tools. IMGT(r) tools and databases provide a high-quality analysis of the IG from fish to humans, for basic, veterinary and medical research, and for antibody engineering and humanization. They include, as examples: IMGT/V-QUEST and IMGT/JunctionAnalysis for nucleotide sequence analysis and their high throughput version IMGT/HighV-QUEST for next generation sequencing, IMGT/DomainGapAlign for amino acid sequence analysis of IG domains, IMGT/3Dstructure-DB for 3D structures, contact analysis and paratope/epitope interactions of IG/antigen complexes, and the IMGT/mAb-DB interface for therapeutic antibodies and fusion proteins for immunological applications (FPIA). PMID- 25521641 TI - Cost-effectiveness and pricing of antibacterial drugs. AB - Growing resistance to antibacterial agents has increased the need for the development of new drugs to treat bacterial infections. Given increasing pressure on limited health budgets, it is important to study the cost-effectiveness of these drugs, as well as their safety and efficacy, to find out whether or not they provide value for money and should be reimbursed. In this article, we systematically reviewed 38 cost-effectiveness analyses of new antibacterial agents. Most studies showed the new antibacterial drugs were cost-effective compared to older generation drugs. Drug pricing is a complicated process, involving different stakeholders, and has a large influence on cost effectiveness. Value-based pricing is a method to determine the price of a drug at which it can be cost-effective. It is currently unclear what the influence of value-based pricing will be on the prices of new antibacterial agents, but an important factor will be the definition of 'value', which as well as the impact of the drug on patient health might also include other factors such as wider social impact and the health impact of disease. PMID- 25521642 TI - Machine-learning techniques applied to antibacterial drug discovery. AB - The emergence of drug-resistant bacteria threatens to revert humanity back to the preantibiotic era. Even now, multidrug-resistant bacterial infections annually result in millions of hospital days, billions in healthcare costs, and, most importantly, tens of thousands of lives lost. As many pharmaceutical companies have abandoned antibiotic development in search of more lucrative therapeutics, academic researchers are uniquely positioned to fill the pipeline. Traditional high-throughput screens and lead-optimization efforts are expensive and labor intensive. Computer-aided drug-discovery techniques, which are cheaper and faster, can accelerate the identification of novel antibiotics, leading to improved hit rates and faster transitions to preclinical and clinical testing. The current review describes two machine-learning techniques, neural networks and decision trees, that have been used to identify experimentally validated antibiotics. We conclude by describing the future directions of this exciting field. PMID- 25521644 TI - Development of antivirulence compounds: a biochemical review. AB - There is an urgent requirement for new anti-infective compounds that can be used to prevent or treat bacterial pathogens. In particular, Gram-negative pathogens, which are most commonly associated with hospital-acquired infections, are of major concern. In this review, we cover recent developments in the screening and testing of new anti-infective compounds that interfere with aspects of bacterial pathogenicity. This so-called antivirulence approach is very different to traditional antibiotic development and testing. Moreover, antivirulence compounds vary considerably in their chemical structures, ranging from small compounds to large natural products. The challenge of understanding the precise mechanism of action of any such compound is also highlighted. PMID- 25521645 TI - Histidine-containing peptide catalysts developed by a facile library screening method. AB - Although peptide catalysts have a high potential for the use as organocatalysts, the optimization of peptide sequences is laborious and time-consuming. To address this issue, a facile screening method for finding efficient aminocatalysts from a peptide library has been developed. In the screening for the Michael addition of a malonate to an enal, a dye-labeled product is immobilized on resin-bound peptides through reductive amination to visualize active catalysts. This procedure allows for the monitoring of the reactivity of entire peptides without modifying the resin beads beforehand. Peptides containing histidine at an appropriate position were identified by this method. A novel function of the histidyl residue, which enhances the binding of a substrate to the catalyst by capturing an iminium intermediate, was indicated. PMID- 25521643 TI - The bacterial type III secretion system as a target for developing new antibiotics. AB - Antibiotic resistance in pathogens requires new targets for developing novel antibacterials. The bacterial type III secretion system (T3SS) is an attractive target for developing antibacterials as it is essential in the pathogenesis of many Gram-negative bacteria. The T3SS consists of structural proteins, effectors, and chaperones. Over 20 different structural proteins assemble into a complex nanoinjector that punctures a hole on the eukaryotic cell membrane to allow the delivery of effectors directly into the host cell cytoplasm. Defects in the assembly and function of the T3SS render bacteria non-infective. Two major classes of small molecules, salicylidene acylhydrazides and thiazolidinones, have been shown to inhibit multiple genera of bacteria through the T3SS. Many additional chemically and structurally diverse classes of small molecule inhibitors of the T3SS have been identified as well. While specific targets within the T3SS of a few inhibitors have been suggested, the vast majority of specific protein targets within the T3SS remain to be identified or characterized. Other T3SS inhibitors include polymers, proteins, and polypeptides mimics. In addition, T3SS activity is regulated by its interaction with biologically relevant molecules, such as bile salts and sterols, which could serve as scaffolds for drug design. PMID- 25521651 TI - Serum ferritin is elevated in amyotrophic lateral sclerosis patients. AB - Our objective was to measure serum ferritin levels, which reflect iron metabolism, in ALS patients versus healthy and disease controls, and determine whether serum ferritin levels correlate with survival. We retrospectively analyzed data from 138 ALS patients, 152 healthy controls, and 82 disease controls. Gender, age, site of onset, and dates of symptom onset and death were recorded. Survival was defined as the time from symptom onset to death. Serum ferritin levels were measured using immunoassay. ANOVA and Pearson's correlation were used to compare ferritin levels between groups and test the association between ferritin levels and age and survival. Ferritin levels were categorized into high and low groups, and Kaplan-Meier analysis performed. Results showed that gender proportions differed between ALS patients versus healthy and disease controls, and gender affected serum ferritin levels. Ferritin comparisons were stratified for gender. In both males and females, ferritin levels were higher in ALS patients versus healthy and disease controls. However, ferritin levels were unrelated to survival in either gender, by tests of association or survival analysis. In conclusion, ALS patients have altered iron metabolism that is not simply due to the presence of neurological disease. Serum ferritin levels alone are not sufficient to predict survival. PMID- 25521653 TI - It's complicated. PMID- 25521652 TI - Avenaciolides: potential MurA-targeted inhibitors against peptidoglycan biosynthesis in methicillin-resistant Staphylococcus aureus (MRSA). AB - Discovery of new antibiotics for combating methicillin-resistant Staphylococcus aureus (MRSA) is of vital importance in the post-antibiotic era. Here, we report four avenaciolide derivatives (1-4) isolated from Neosartorya fischeri, three of which had significant antimicrobial activity against MRSA. The morphology of avenaciolide-treated cells was protoplast-like, which indicated that cell wall biosynthesis was interrupted. Comparing the structures and minimum inhibitory concentrations of 1-4, the alpha,beta-unsaturated carbonyl group seems to be an indispensable moiety for antimicrobial activity. Based on a structural similarity survey of other inhibitors with the same moiety, we revealed that MurA was the drug target. This conclusion was validated by (31)P NMR spectroscopy and MS/MS analysis. Although fosfomycin, which is the only clinically used MurA-targeted antibiotic, is ineffective for treating bacteria harboring the catalytically important Cys-to-Asp mutation, avenaciolides 1 and 2 inhibited not only wild-type but also fosfomycin-resistant MurA in an unprecedented way. Molecular simulation revealed that 2 competitively perturbs the formation of the tetrahedral intermediate in MurA. Our findings demonstrated that 2 is a potent inhibitor of MRSA and fosfomycin-resistant MurA, laying the foundation for the development of new scaffolds for MurA-targeted antibiotics. PMID- 25521654 TI - Kristen F. Sobota and Micah J. Sobota: this couple both found careers in geriatric pharmacy. PMID- 25521655 TI - Pharmacists' Stellar experience can create Five-Star Success. AB - The evolving health care system has put an increasing emphasis on balancing quality, outcomes, and costs. As part of this evolution, the Centers for Medicare & Medicaid Services (CMS) is using a Five-Star Quality Rating System to evaluate the quality of care provided by Medicare Advantage and Part D prescription drug plans. At the same time, drug plans are using a Five-Star system to rate pharmacies, which contribute to the CMS ratings of nursing facilities. More than ever, pharmacists can play a significant role in helping facilities, plans, and even pharmacies achieve the highest possible ratings and maintain those standards over time. PMID- 25521656 TI - Improving the management of disruptive behavior and reducing antipsychotic medications in nursing facility residents. AB - OBJECTIVE: The objective of this work is to improve the management of disruptive behavior in the nursing facility setting through an interdisciplinary team (IDT) approach to reduce the use of antipsychotic medications in accordance with the Centers for Medicare & Medicaid Services initiative. DATA SOURCES, EXTRACTION, AND SYNTHESIS: The process began with a search and review of more than 100 peer reviewed articles, government, and association resources that focused on the management of disruptive behavior in older adults. While data were limited to the past 10 years, the vast majority of data reviewed were within the past 5 years. This information was reviewed and discussed by all of the coauthors who meet in person at the American Society of Consultant Pharmacists as a work group. This group was tasked with identifying strategies through an IDT to improve the management of disruptive behavior and reduce the use of antipsychotic medications in nursing facility residents. In addition, significant follow-up work was accomplished following the live working session. CONCLUSION: Through an IDT, strategies can be implemented for long-term care residents to prevent and better manage disruptive behavior. These strategies can result in the reduction of the use of antipsychotic medications. The field of long-term care would benefit from further research to identify additional nonpharmacologic and pharmacologic treatments for managing disruptive behavior. PMID- 25521657 TI - Comparison of vials and prefilled pens of a rapid-acting insulin analog on pharmacy budgets in a long-term care setting. AB - OBJECTIVE: Estimate budgetary impact for skilled nursing facility converting from individual patient supply (IPS) delivery of rapid-acting insulin analog (RAIA) 10 mL vials or 3-mL prefilled pens to 3-mL vials. DESIGN: A budget-impact model used insulin volume purchased and assumptions of length of stay (LOS), daily RAIA dose, and delivery protocol to estimate the cost impact of using 3-mL vials. SETTING: Skilled nursing facility. PARTICIPANTS: Medicare Part A patients. INTERVENTIONS: Simulations conducted using 12-month current and future scenarios. Comparisons of RAIA use for 13- and 28-day LOS. MAIN OUTCOME MEASURES: RAIA costs and savings, waste reduction. RESULTS: For patients with 13-day LOS using 20 units/day of IPS insulin, the model estimated a 70% reduction in RAIA costs and units purchased and a 95% waste reduction for the 3-mL vial compared with the 10 mL vial. The estimated costs for prefilled pen use were 58% lower than for use of 10-mL vials. The incremental savings associated with 3-mL vial use instead of prefilled pens was 28%, attributable to differences in per-unit cost of insulin in vials versus prefilled pens. Using a more conservative scenario of 28-day LOS at 20 units/day, the model estimated a 40% reduction in RAIA costs and units purchased, resulting in a 91% reduction in RAIA waste for the 3-mL vial, compared with 10-mL vial. CONCLUSION: Budget-impact analysis of conversion from RAIA 10-mL vials or 3-mL prefilled pens to 3-mL vials estimated reductions in both insulin costs and waste across multiple scenarios of varying LOS and patient daily doses for skilled nursing facility stays. PMID- 25521659 TI - The pharmacist's role in preventing medication errors in older adults. AB - Approximately 1.5 million medication errors occur each year in the United States. Older adults may be at increased risk for these errors as a result of a variety of contributing factors such as inappropriate medication use, polymorbidity, and complexities in managing dosage adjustments for geriatric patients. Pharmacists, as trained medication experts, are uniquely poised to lead efforts to prevent, detect, and resolve medications errors. As the American population continues to age, future pharmacists are likely to play an even greater role in promoting safe and effective medication use in older adults. In this paper, we highlight common settings for medication errors in older individuals, explore tools and solutions for error prevention, and outline the unique role that pharmacists have in preventing medication errors in older adults. PMID- 25521658 TI - Mirabegron: a Beta-3 agonist for overactive bladder. AB - OBJECTIVE: To review the literature regarding the efficacy and safety of mirabegron for the treatment of overactive bladder (OAB). DATA SOURCES: A literature search was performed using MEDLINE (PubMed) prior to December 31, 2013, using the terms "mirabegron" and "randomized-controlled trial." STUDY SELECTION/DATA EXTRACTION: All published, double-blind, randomized-controlled trials assessing mirabegron were included. Articles were reviewed and included if mirabegron was used as monotherapy and if the primary outcome analyzed drug efficacy. DATA SYNTHESIS: The efficacy of mirabegron for the treatment of OAB has been demonstrated in the selected five randomized, placebo-controlled trials. The majority of these trials lasted 12 weeks and compared various doses of mirabegron with placebo and/or tolterodine extended-release (ER). Primary efficacy outcomes for the trials included mean number of micturitions per 24 hours and mean number of incontinence episodes per 24 hours. Included trials showed statistically significant reductions in both efficacy outcomes for various doses of mirabegron when compared with placebo. CONCLUSION: Based on the trials reviewed, mirabegron has been efficacious in reducing mean number of micturitions and incontinence episodes per 24 hours, as well as in improving other secondary outcomes such as OAB symptoms and quality-of-life measures. Common adverse drug events seen with mirabegron include: hypertension, nasopharyngitis, urinary tract infections, headache, constipation, upper respiratory tract infection, arthralgia, diarrhea, tachycardia, abdominal pain, and fatigue. Given the efficacy and safety data currently available, mirabegron represents a reasonable alternative to antimuscarinics for patients with OAB. Future studies are needed to determine the utility of mirabegron for OAB in a variety of demographics. PMID- 25521661 TI - Project connect online: user and visitor experiences of an Internet-based intervention for women with breast cancer. AB - OBJECTIVE: This study's purpose was to characterize the experience of patients with breast cancer randomly assigned to the intervention arm of Project Connect Online (PCO), a randomized controlled trial of an Internet-based intervention, and to examine relationships between website use variables and psychosocial outcomes. METHODS: In the larger PCO trial, patients with breast cancer (n = 88) were randomly assigned to an intervention or a waiting-list control. This report pertains to the 46 women in the intervention arm, a 3-h workshop for creation of personal websites with a blog function to communicate with their interpersonal network and chronicle their breast cancer experience. Participants completed assessments at 1 and 6 months. Visitors to the websites (n = 66) completed an online questionnaire. RESULTS: Reactions to website use were positive, although lack of time was a barrier for some. Women with advanced cancer were more likely to use their websites. Women found the websites useful for telling the story of their experience and expressing emotions. Positive word use was associated with heightened positive mood at 6 months; negative word use was associated with improved depressive symptoms. Visitors were most commonly female friends of participants who valued the websites as a way to connect emotionally with participants and receive information about their health. CONCLUSIONS: Specific aspects of patients' blogs predicted improvements in psychosocial functioning. Personal websites can help women with breast cancer construct a narrative of their experience, express emotions, and receive the social support they need, particularly from friends and extended family. PMID- 25521662 TI - Computational analyses of arteriovenous malformations in neuroimaging. AB - Computational models have been investigated for the analysis of the physiopathology and morphology of arteriovenous malformation (AVM) in recent years. Special emphasis has been given to image fusion in multimodal imaging and 3-dimensional rendering of the AVM, with the aim to improve the visualization of the lesion (for diagnostic purposes) and the selection of the nidus (for therapeutic aims, like the selection of the region of interest for the gamma knife radiosurgery plan). Searching for new diagnostic and prognostic neuroimaging biomarkers, fractal-based computational models have been proposed for describing and quantifying the angioarchitecture of the nidus. Computational modeling in the AVM field offers promising tools of analysis and requires a strict collaboration among neurosurgeons, neuroradiologists, clinicians, computer scientists, and engineers. We present here some updated state-of-the-art exemplary cases in the field, focusing on recent neuroimaging computational modeling with clinical relevance, which might offer useful clinical tools for the management of AVMs in the future. PMID- 25521663 TI - Do male and female general practitioners differently prescribe chronic pain drugs to older patients? AB - OBJECTIVE: The aim of this study was to identify the relationship between general practitioner (GP) gender and prescribing practice of chronic pain drugs in older adults. DESIGN: Cross-sectional observational study. SETTING: GPs in private practice throughout France. SUBJECTS: Two hundred and sixty GPs (80.8% male and 19.2% female) enrolled 1,379 (28.4% male and 71.6% female) noninstitutionalized patients over 65 years of age, suffering from chronic pain. METHODS: A comparison of prescribing habits between male and female GPs was performed on baseline data with univariate analyses followed by multivariate analyses after taking several confounding factors into account. RESULTS: No significant differences were found when comparing male and female GPs' prescriptions of World Health Organization step 1, step 2, and step 3 analgesics. Male GPs were more likely than female GPs to prescribe antineuropathic pain drugs (11.3% of patients with male GPs versus 4.8% of patients with female GPs, P = 0.004) and less likely to prescribe symptomatic slow-acting drugs for osteoarthritis (SySADOA) (10.2% of male GPs' patients versus 18.8% of female GPs' patients, P = 0.0003). After adjusting for several confounding factors, male GPs were still more likely to prescribe antineuropathic pain drugs (OR 2.43, 95% CI 1.15-5.14, P = 0.02) and less likely to prescribe symptomatic slow-acting drugs (OR 0.64, 95% CI 0.42-0.97, P = 0.03). CONCLUSION: Male and female GPs prescribe analgesics in a similar manner. However, male GPs prescribe more antineuropathic pain drugs, but fewer SySADOA. PMID- 25521664 TI - Novel SNP improves differential survivability and mortality in non-small cell lung cancer patients. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide due to poor patient prognosis and clinical outcome. Here, we studied the genetic variations underlying NSCLC pathogenesis based on their association to patient outcome after gemcitabine therapy. RESULTS: Bioinformatics analysis was used to investigate possible effects of POLA2 G583R (POLA2+1747 GG/GA, dbSNP ID: rs487989) in terms of protein function. Using biostatistics, POLA2+1747 GG/GA (rs487989, POLA2 G583R) was identified as strongly associated with mortality rate and survival time among NSCLC patients. It was also shown that POLA2+1747 GG/GA is functionally significant for protein localization via green fluorescent protein (GFP)-tagging and confocal laser scanning microscopy analysis. The single nucleotide polymorphism (SNP) causes DNA polymerase alpha subunit B to localize in the cytoplasm instead of the nucleus. This inhibits DNA replication in cancer cells and confers a protective effect in individuals with this SNP. CONCLUSIONS: The results suggest that POLA2+1747 GG/GA may be used as a prognostic biomarker of patient outcome in NSCLC pathogenesis. PMID- 25521665 TI - Refining the quantitative pathway of the Pathways to Mathematics model. AB - In the current study, we adopted the Pathways to Mathematics model of LeFevre et al. (2010). In this model, there are three cognitive domains--labeled as the quantitative, linguistic, and working memory pathways--that make unique contributions to children's mathematical development. We attempted to refine the quantitative pathway by combining children's (N=141 in Grades 2 and 3) subitizing, counting, and symbolic magnitude comparison skills using principal components analysis. The quantitative pathway was examined in relation to dependent numerical measures (backward counting, arithmetic fluency, calculation, and number system knowledge) and a dependent reading measure, while simultaneously accounting for linguistic and working memory skills. Analyses controlled for processing speed, parental education, and gender. We hypothesized that the quantitative, linguistic, and working memory pathways would account for unique variance in the numerical outcomes; this was the case for backward counting and arithmetic fluency. However, only the quantitative and linguistic pathways (not working memory) accounted for unique variance in calculation and number system knowledge. Not surprisingly, only the linguistic pathway accounted for unique variance in the reading measure. These findings suggest that the relative contributions of quantitative, linguistic, and working memory skills vary depending on the specific cognitive task. PMID- 25521666 TI - Comparison of the Diagnostic Performance of Four Quantitative Myocardial Perfusion Estimation Methods Used in Cardiac MR Imaging: CE-MARC Substudy. AB - PURPOSE: To compare the diagnostic performance of four tracer kinetic analysis methods to quantify myocardial perfusion from magnetic resonance (MR) imaging cardiac perfusion data sets in terms of their ability to lead to the diagnosis of myocardial ischemia. MATERIALS AND METHODS: The study was approved by the regional ethics committee, and all patients gave written consent. A representative sample of 50 patients with suspected ischemic heart disease was retrospectively selected from the Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease trial data set. Quantitative myocardial blood flow (MBF) was estimated from rest and adenosine stress MR imaging perfusion data sets by using four established methods. A matching diagnosis of both an inducible defect as assessed with single photon emission computed tomography and a luminal stenosis of 70% or more as assessed with quantitative x-ray angiography was used as the reference standard for the presence of myocardial ischemia. Diagnostic performance was evaluated with receiver operating characteristic (ROC) curve analysis for each method, with stress MBF and myocardial perfusion reserve (MPR) serving as continuous measures. RESULTS: Area under the ROC curve with stress MBF and MPR as the outcome measures, respectively, was 0.86 and 0.92 for the Fermi model, 0.85 and 0.87 for the uptake model, 0.85 and 0.80 for the one-compartment model, and 0.87 and 0.87 for model-independent deconvolution. There was no significant difference between any of the models or between MBF and MPR, except that the Fermi model outperformed the one-compartment model if MPR was used as the outcome measure (P = .02). CONCLUSION: Diagnostic performance of quantitative myocardial perfusion estimates is not affected by the tracer kinetic analysis method used. PMID- 25521667 TI - Coronary In-Stent Restenosis: Assessment with Corrected Coronary Opacification Difference across Coronary Stents Measured with CT Angiography. AB - PURPOSE: To determine whether changes in coronary opacification normalized to the aorta (corrected coronary opacification [CCO]) across stents can help identify in stent restenosis (ISR) severity with use of invasive coronary angiography as the standard of reference. MATERIALS AND METHODS: This study was approved by the institutional review board, and the requirement to obtain informed consent was waived. The authors retrospectively analyzed 106 patients (88 men, 18 women; mean age, 59.6 years +/- 10.4; age range, 36-84 years) who had previously undergone stent implantation within 3 months of coronary computed tomographic (CT) angiography. Attenuation values in the coronary lumen were measured proximal and distal to the stents and normalized to the descending aorta. The CCO difference across the stent was compared with the severity of ISR. One-way analysis of variance least significant difference was used for comparison. RESULTS: A total of 141 stents were assessed. Seventy-six stents were normally patent, 18 had ISR of less than 50%, 28 had ISR of 50%-99%, and 19 were fully occluded. The median CCO differences in the four groups were 0.078, 0.163, 0.346, and 0.606, respectively. There was no significant difference between stents with an ISR of at least 50% and those with total occlusion (P = .056), although the other groups had significant differences at pairwise comparison (P < .01 for all). For stents smaller than 3 mm in diameter, the median CCO differences in the four groups were 0.086, 0.136, 0.390, and 0.471, respectively. The CCO differences across normal stents and stents with ISR of less than 50% were significantly less than those across stents with an ISR of at least 50% and those with total occlusion (P < .01 for all). There were no significant differences between stents with no ISR and those with an ISR of less than 50% (P = .821) and between stents with an ISR of at least 50% and those with an ISR of 100% (P = .836). CONCLUSION: The CCO difference across coronary stents is related to ISR severity in obstructive ISR in stents smaller than 3 mm in diameter. PMID- 25521668 TI - Modifications of recognition memory processes in preterm children: an event related potential study. AB - Prematurity may cause hippocampal compromise. Therefore, hippocampus-dependent memory processes (recollection-based retrieval) may be more impaired than hippocampus-independent processes (familiarity-based retrieval). The memory of 18 children born preterm with reduced hippocampal volumes, without neonatal complications (weeks of gestation < 34, weight < 1,600 g), and 15 controls (8-10 years) was tested using an item recognition task. While groups were equal in memory performance, dissociation was found: The event-related potential (ERP) correlate of familiarity was intact in the preterm group, whereas the correlate of recollection was attenuated. A follow-up experiment ruled out that this was due to general cognitive deficits. Furthermore, gestational age correlated with the ERP index of recollection. Thus, recognition memory in preterm children may be characterized by a compensation of attenuated recollection by familiarity. PMID- 25521669 TI - Incremental Cost of Emergency Versus Elective Surgery. AB - OBJECTIVE: To determine hospital costs and the adjusted risk of death associated with emergent versus elective surgery. BACKGROUND: Emergency surgery has a higher cost and worse outcomes compared with elective surgery. However, no national estimates of the excess burden of emergency surgery exist. METHODS: Nationwide Inpatient Sample (NIS) data from 2001 to 2010 were analyzed. Patients aged 18 years or older who underwent abdominal aortic aneurysm repair, coronary artery bypass graft, or colon resection for neoplasm were included. Using generalized linear models with propensity scores, cost differences for emergent versus elective admission were calculated for each procedure. Multivariable logistic regression was performed to investigate the adjusted odds of mortality comparing elective and emergent cases. Discharge-level weights were applied to analyses. RESULTS: A total of 621,925 patients, representing a weighted population of 3,057,443, were included. The adjusted mean cost difference for emergent versus elective care was $8741.22 (30% increase) for abdominal aortic aneurysm repair, $5309.78 (17% increase) for coronary artery bypass graft, and $7813.53 (53% increase) for colon resection. If 10% of the weighted estimates of emergency procedures had been performed electively, the cost benefit would have been nearly $1 billion, at $996,169,160 (95% confidence interval [CI], $985,505,565 $1,006,834,104). Elective surgery patients had significantly lower adjusted odds of mortality for all procedures. CONCLUSIONS: Even a modest reduction in the proportion of emergent procedures for 3 conditions is estimated to save nearly $1 billion over 10 years. Preventing emergency surgery through improved care coordination and screening offers a tremendous opportunity to save lives and decrease costs. PMID- 25521670 TI - The brave new world of innate lymphoid cells. PMID- 25521671 TI - Stop the executioners. PMID- 25521672 TI - A surprising role for TLR7. PMID- 25521673 TI - The subtle hands of self-reactivity in peripheral T cells. PMID- 25521680 TI - The lungs at the frontlines of immunity. PMID- 25521681 TI - Antiviral B cell and T cell immunity in the lungs. AB - Respiratory viruses are frequent causes of repeated common colds, bronchitis and pneumonia, which often occur unpredictably as epidemics and pandemics. Despite those decimating effects on health and decades of intensive research, treatments remain largely supportive. The only commonly available vaccines are against influenza virus, and even these need improvement. The lung shares some features with other mucosal sites, but preservation of its especially delicate anatomical structures necessitates a fine balance of pro- and anti-inflammatory responses; well-timed, appropriately placed and tightly regulated T cell and B cell responses are essential for protection from infection and limitation of symptoms, whereas poorly regulated inflammation contributes to tissue damage and disease. Recent advances in understanding adaptive immunity should facilitate vaccine development and reduce the global effect of respiratory viruses. PMID- 25521682 TI - Respiratory epithelial cells orchestrate pulmonary innate immunity. AB - The epithelial surfaces of the lungs are in direct contact with the environment and are subjected to dynamic physical forces as airway tubes and alveoli are stretched and compressed during ventilation. Mucociliary clearance in conducting airways, reduction of surface tension in the alveoli, and maintenance of near sterility have been accommodated by the evolution of a multi-tiered innate host defense system. The biophysical nature of pulmonary host defenses are integrated with the ability of respiratory epithelial cells to respond to and 'instruct' the professional immune system to protect the lungs from infection and injury. PMID- 25521683 TI - The development and function of lung-resident macrophages and dendritic cells. AB - Gas exchange is the vital function of the lungs. It occurs in the alveoli, where oxygen and carbon dioxide diffuse across the alveolar epithelium and the capillary endothelium surrounding the alveoli, separated only by a fused basement membrane 0.2-0.5 MUm in thickness. This tenuous barrier is exposed to dangerous or innocuous particles, toxins, allergens and infectious agents inhaled with the air or carried in the blood. The lung immune system has evolved to ward off pathogens and restrain inflammation-mediated damage to maintain gas exchange. Lung-resident macrophages and dendritic cells are located in close proximity to the epithelial surface of the respiratory system and the capillaries to sample and examine the air-borne and blood-borne material. In communication with alveolar epithelial cells, they set the threshold and the quality of the immune response. PMID- 25521692 TI - Comprehensive experiment-clinical biochemistry: determination of blood glucose and triglycerides in normal and diabetic rats. AB - For second year medical students, we redesigned an original laboratory experiment and developed a combined research-teaching clinical biochemistry experiment. Using an established diabetic rat model to detect blood glucose and triglycerides, the students participate in the entire experimental process, which is not normally experienced during a standard clinical biochemistry exercise. The students are not only exposed to techniques and equipment but are also inspired to think more about the biochemical mechanisms of diseases. When linked with lecture topics about the metabolism of carbohydrates and lipids, the students obtain a better understanding of the relevance of abnormal metabolism in relation to diseases. Such understanding provides a solid foundation for the medical students' future research and for other clinical applications. PMID- 25521693 TI - Nickel-responsive regulation of two novel Helicobacter pylori NikR-targeted genes. AB - Nickel is an essential transition metal for the survival of Helicobacter pylori in the acidic human stomach. The nickel-responsive transcriptional regulator HpNikR is important for maintaining healthy cytosolic nickel concentrations through the regulation of multiple genes, but its complete regulon and role in nickel homeostasis are not well understood. To investigate potential gene targets of HpNikR, ChIP sequencing was performed using H. pylori grown at neutral pH in nickel-supplemented media and this experiment identified HPG27_866 (frpB2) and HPG27_1499 (ceuE). These two genes are annotated to encode a putative iron transporter and a nickel-binding, periplasmic component of an ABC transporter, respectively. In vitro DNA-binding assays revealed that HpNikR binds both gene promoter sequences in a nickel-responsive manner with affinities on the order of ~10(-7) M. The recognition sites of HpNikR were identified and loosely correlate with the HpNikR pseudo-consensus sequence (TATTATT-N11-AATAATA). Quantitative PCR experiments revealed that HPG27_866 and HPG27_1499 are transcriptionally repressed following growth of H. pylori G27 in nickel-supplemented media, and that this response is dependent on HpNikR. In contrast, iron supplementation results in activation of HPG27_1499, but no impact on the expression of HPG27_866 was observed. Metal analysis of the Delta866 strain revealed that HPG27_866 has an impact on nickel accumulation. These studies demonstrate that HPG27_866 and HPG27_1499 are both direct targets of HpNikR and that HPG27_866 influences nickel uptake in H. pylori. PMID- 25521685 TI - The balance between protective and pathogenic immune responses in the TB-infected lung. AB - Tuberculosis is a disease of the lung, and efficient transmission is dependent on the generation of a lesion in the lung, which results in a bacterium-laden cough. Mycobacterium tuberculosis (Mtb) is able to manipulate both the innate and acquired immune response of the host. This manipulation results in an effective CD4(+) T cell response that limits disease throughout the body but can also promote the development of progressively destructive lesions in the lung. In this way Mtb infection can result in an ambulatory individual who has a lesion in the lung capable of transmitting Mtb. The inflammatory environment within the lung lesion is manipulated by Mtb throughout infection and can limit the expression of acquired immunity by a variety of pathways. PMID- 25521684 TI - The immunology of asthma. AB - Asthma is a common disease that affects 300 million people worldwide. Given the large number of eosinophils in the airways of people with mild asthma, and verified by data from murine models, asthma was long considered the hallmark T helper type 2 (TH2) disease of the airways. It is now known that some asthmatic inflammation is neutrophilic, controlled by the TH17 subset of helper T cells, and that some eosinophilic inflammation is controlled by type 2 innate lymphoid cells (ILC2 cells) acting together with basophils. Here we discuss results from in-depth molecular studies of mouse models in light of the results from the first clinical trials targeting key cytokines in humans and describe the extraordinary heterogeneity of asthma. PMID- 25521694 TI - Sex-specific factors for bone density in patients with schizophrenia. AB - Patients with schizophrenia are susceptible to low bone mineral density (BMD). Many risk factors have been suggested. However, it remains uncertain whether the risk factors differ between men and women. In addition, the study of bone density in men is neglected more often than that in women. This study aims to examine specific risk factors of low BMD in different sexes. Men (n=80) and women (n=115) with schizophrenia, similar in demographic and clinical characteristics, were enrolled in three centers. Clinical and laboratory variables (including blood levels of prolactin, sex and thyroid hormones, cortisol, calcium, and alkaline phosphatase) were collected. BMD was measured using a dual-energy X-ray absorptiometer. Men had lower BMD than women. Predictors for BMD in men included hyperprolactinemia (B=-0.821, P=0.009), body weight (B=0.024, P=0.046), and Global Assessment of Functioning score (B=0.027, P=0.043); in women, BMD was associated with menopause (B=-1.070, P<0.001), body weight (B=0.027, P=0.003), and positive symptoms (B=0.094, P<0.001). In terms of the effect of psychotic symptoms, positive symptoms were related positively to BMD in women, but not in men. The findings suggest that sex-specific risk factors should be considered for an individualized intervention of bone loss in patients with schizophrenia. Physicians should pay particular attention to bone density in men with hyperprolactinemia and postmenopausal women. Further prospective studies in other populations are warranted to confirm these findings. PMID- 25521695 TI - Spectral domain optical coherence tomography evidence on the mechanism of diode laser peripheral iridoplasty. PMID- 25521697 TI - Peer support for parents of disabled children part 1: perceived outcomes of a one to-one service, a qualitative study. AB - BACKGROUND: Parents of disabled children are encouraged to seek peer support. Delivering one-to-one support requires resources; therefore, investigating how these services may impact on families and those providing the service is important when evaluating such services. METHODS: We carried out a qualitative study involving semi-structured interviews and focus groups. Participants were 12 parents and 23 befrienders who had contact with the Face2Face one-to-one befriending service in Devon and Cornwall during a 12-month period, and 10 professionals from health, social care and education services. FINDINGS: Shared experience was perceived central to successful peer support and was a catalyst for other elements of support, enabling parents to (i) learn from the experience of others; (ii) speak freely in a safe and non-judgemental environment; and (iii) receive support and encouragement from their befriender. These elements underpinned perceived outcomes for both parents providing and receiving support. Outcomes for parents receiving support centred on emotional stability, personal growth and reduced isolation. Supporting parents experienced positive outcomes through their training, mutual support and the feeling that they were helping others. Parents and befrienders appeared to benefit through expanding their social network. Nevertheless providing support was reported to create emotional burden and concerns for befrienders around their performance, and also required a substantial time commitment. CONCLUSIONS: Befrienders as well as parents perceived positive outcomes from their involvement in peer support although there is also potential for less positive impact on those offering support. PMID- 25521696 TI - Effect of public reporting on intensive care unit discharge destination and outcomes. AB - RATIONALE: Public reporting of hospital performance is designed to improve healthcare outcomes by promoting quality improvement and informing consumer choice, but these programs may carry unintended consequences. OBJECTIVE: To determine whether publicly reporting in-hospital mortality rates for intensive care unit (ICU) patients influenced discharge patterns or mortality. METHODS: We performed a retrospective cohort study taking advantage of a natural experiment in which California, but not other states, publicly reported hospital-specific severity-adjusted ICU mortality rates between 2007 and 2012. We used multivariable logistic regression adjusted for patient, hospital, and regional characteristics to compare mortality rates and discharge patterns between California and states without public reporting for Medicare fee-for-service ICU admissions from 2005 through 2009 using a difference-in-differences approach. MEASUREMENTS AND MAIN RESULTS: We assessed discharge patterns using post-acute care use and acute care hospital transfer rates and mortality using in-hospital and 30-day mortality rates. The study cohort included 936,063 patients admitted to 646 hospitals. Compared with control subjects, admission to a California ICU after the introduction of public reporting was associated with a reduced odds of post-acute care use in post-reform year 2 (ratio of odds ratios [ORs], 0.94; 95% confidence interval [CI], 0.91-0.96) and increased odds of transfer to another acute care hospital in both post-reform years (year 1: ratio of ORs, 1.08; 95% CI, 1.01-1.16; year 2: ratio of ORs, 1.43; 95% CI, 1.33-1.53). There were no significant differences in in-hospital or 30-day mortality. CONCLUSIONS: Public reporting of ICU in-hospital mortality rates was associated with changes in discharge patterns but no change in risk-adjusted mortality. PMID- 25521698 TI - Pnicogen and hydrogen bonds: complexes between PH3X(+) and PH2X systems. AB - The charge-assisted complexes between PH3X(+) and PH2X have been analyzed. MP2/aug'-cc-pVTZ calculations were performed and the results were supported by the Quantum Theory of Atoms in Molecules approach and the Natural Bond Orbitals method. It was found that three different configurations could be formed, i.e. those linked through a P...P or a P...X pnicogen bond and those linked through a P-H...P hydrogen bond. The P...P configurations are the most stable ones corresponding to the strongest interactions; for all complexes the P...P configuration exists, while the P...X and P-H...P ones are present only for some of them. Different relations between the parameters were found, especially for the P...P interactions where there are correlations between the P...P distance and the electron density at the P...P bond critical point (rhoPP) as well as between rhoPP and the charge transfer energy. PMID- 25521699 TI - Chemical and structural stability of zirconium-based metal-organic frameworks with large three-dimensional pores by linker engineering. AB - The synthesis of metal-organic frameworks with large three-dimensional channels that are permanently porous and chemically stable offers new opportunities in areas such as catalysis and separation. Two linkers (L1=4,4',4'',4'''-([1,1' biphenyl]-3,3',5,5'-tetrayltetrakis(ethyne-2,1-diyl)) tetrabenzoic acid, L2=4,4',4'',4'''-(pyrene-1,3,6,8-tetrayltetrakis(ethyne-2,1-diyl))tetrabenzoic acid) were used that have equivalent connectivity and dimensions but quite distinct torsional flexibility. With these, a solid solution material, [Zr6 O4 (OH)4 (L1)2.6 (L2)0.4 ]?(solvent)x , was formed that has three-dimensional crystalline permanent porosity with a surface area of over 4000 m(2) g(-1) that persists after immersion in water. These properties are not accessible for the isostructural phases made from the separate single linkers. PMID- 25521700 TI - Standardized ileal digestibility of proteins and amino acids in sesame expeller and soya bean meal in weaning piglets. AB - Apparent ileal digestibility (AID) of diets containing sesame expeller (SE) and soya bean meal (SBM) was determined using 15 piglets (Genetiporc((r))), weaned at 17 +/- 0.4 days with average body weight of 6.4 +/- 0.7 kg (Fertilis 20 * G Performance, Genetiporc((r)), PIC Mexico, Queretaro, Mexico). Piglets were randomly assigned to three treatments: (i) a reference diet with casein as the sole protein source; (ii) a mixed diet of casein-SE; and (iii) a mixed diet of casein-SBM. The chemical composition of SE and SBM was determined, and AID and standardized ileal digestibility (SID) of crude protein (CP) and amino acids (AAs) were determined for each protein source. SE contained greater quantities of ether extract, neutral detergent fibre, phytic acid, methionine and arginine than SBM. Lysine and proline contents and trypsin inhibitor activity were higher in SBM than in SE. The AID and SID of CP and AA (except for lysine and proline) were similar in SE and SBM. The AID of lysine and proline was higher in SBM than in SE (p < 0.05), and the SID of proline was higher in SE than in SBM (p < 0.05). These findings indicate that SE is an appropriate alternative protein source for early weaned pigs. PMID- 25521701 TI - Complex-based analysis of dysregulated cellular processes in cancer. AB - BACKGROUND: Differential expression analysis of (individual) genes is often used to study their roles in diseases. However, diseases such as cancer are a result of the combined effect of multiple genes. Gene products such as proteins seldom act in isolation, but instead constitute stable multi-protein complexes performing dedicated functions. Therefore, complexes aggregate the effect of individual genes (proteins) and can be used to gain a better understanding of cancer mechanisms. Here, we observe that complexes show considerable changes in their expression, in turn directed by the concerted action of transcription factors (TFs), across cancer conditions. We seek to gain novel insights into cancer mechanisms through a systematic analysis of complexes and their transcriptional regulation. RESULTS: We integrated large-scale protein interaction (PPI) and gene-expression datasets to identify complexes that exhibit significant changes in their expression across different conditions in cancer. We devised a log-linear model to relate these changes to the differential regulation of complexes by TFs. The application of our model on two case studies involving pancreatic and familial breast tumour conditions revealed: (i) complexes in core cellular processes, especially those responsible for maintaining genome stability and cell proliferation (e.g. DNA damage repair and cell cycle) show considerable changes in expression; (ii) these changes include decrease and countering increase for different sets of complexes indicative of compensatory mechanisms coming into play in tumours; and (iii) TFs work in cooperative and counteractive ways to regulate these mechanisms. Such aberrant complexes and their regulating TFs play vital roles in the initiation and progression of cancer. CONCLUSIONS: Complexes in core cellular processes display considerable decreases and countering increases in expression, strongly reflective of compensatory mechanisms in cancer. These changes are directed by the concerted action of cooperative and counteractive TFs. Our study highlights the roles of these complexes and TFs and presents several case studies of compensatory processes, thus providing novel insights into cancer mechanisms. PMID- 25521703 TI - Current research funding methods dumb down health care and rehabilitation for disabled people and aging population: a call for a change. AB - Health care systems in Western societies are faced with two major challenges: aging populations and the growing burden of chronic conditions. This translates into more persons with disabilities and the need for more Physical and Rehabilitation Medicine (PRM) services. We raise the point of how these emerging needs are faced by the actual research funding. We briefly present the results of an analysis we made about research funding by the Italian National Health Service as an interesting case study, since it relates to Italy (the financer) and the United States, where National Institutes of Health (NIH) reviewers were identified according to their classification of research topics. The topics of potentially greatest interest for aging Western societies, like chronicity, disability and rehabilitation, were among those least often funded and considered in the traditional method of financing research projects. These results could be based on those PRM peculiarities that make the specialty different from all other classical biomedical specialties, namely the bio-psycho-social approach and its specific research methodologies. Moreover, PRM researchers are spread among the different topics as usually classified, and it is probable that PRM projects are judged by non-PRM reviewers. There are at least two possible ways in which research can be better placed to meet the emerging needs of Western societies (chronicity, disability and consequently also rehabilitation). One is to create specific keywords on these topics so as to improve the match between researchers and reviewers; the second is to allocate specific funds to research in these areas. In fact, the not coherence between emerging needs and research priorities have already been periodically addressed in the past with specific "political" and/or "social" initiatives, when researchers were forced to respond to new emergencies: some historical examples include cancer or HIV and viral diseases or the recent Ebola outbreak. PMID- 25521702 TI - Assessing the assessment in emergency care training. AB - OBJECTIVE: Each year over 1.5 million health care professionals attend emergency care courses. Despite high stakes for patients and extensive resources involved, little evidence exists on the quality of assessment. The aim of this study was to evaluate the validity and reliability of commonly used formats in assessing emergency care skills. METHODS: Residents were assessed at the end of a 2-week emergency course; a subgroup was videotaped. Psychometric analyses were conducted to assess the validity and inter-rater reliability of the assessment instrument, which included a checklist, a 9-item competency scale and a global performance scale. RESULTS: A group of 144 residents and 12 raters participated in the study; 22 residents were videotaped and re-assessed by 8 raters. The checklists showed limited validity and poor inter-rater reliability for the dimensions "correct" and "timely" (ICC = .30 and.39 resp.). The competency scale had good construct validity, consisting of a clinical and a communication subscale. The internal consistency of the (sub)scales was high (alpha = .93/.91/.86). The inter-rater reliability was moderate for the clinical competency subscale (.49) and the global performance scale (.50), but poor for the communication subscale (.27). A generalizability study showed that for a reliable assessment 5-13 raters are needed when using checklists, and four when using the clinical competency scale or the global performance scale. CONCLUSIONS: This study shows poor validity and reliability for assessing emergency skills with checklists but good validity and moderate reliability with clinical competency or global performance scales. Involving more raters can improve the reliability substantially. Recommendations are made to improve this high stakes skill assessment. PMID- 25521704 TI - Solid-phase extraction and nanoflow liquid chromatography-nanoelectrospray ionization mass spectrometry for improved global urine metabolomics. AB - Global urine metabolomics is a rapidly expanding field with the potential to discover biomarkers of disease and exposure. To date, most methods focus on rapid sample preparation, using neat or diluted urine, together with high-throughput analyses, and are poorly suited for detection of low abundance metabolites present in urine samples. In this study, novel methods have been developed to analyze urine by splitless nanoflowUHPLC-nanoESI-TOFMS (nUHPLC-nESI-TOFMS) after preconcentration by solid-phase extraction (SPE), thus enabling significant improvements in analytical sensitivity and coverage of the urinary metabolome. In initial work, urine samples were extracted by both anion and cation exchange mixed-mode polymeric SPE cartridges and qualitatively compared with those using conventional sample preparations using UHPLC-ESI-TOFMS analyses. Compared with neat or diluted urine samples, SPE concentration of urine resulted in detection of additional metabolites including bile acids, lipids, pharmaceuticals, and markers of lifestyle, with little loss of other components of the metabolome. Analyses of SPE preparations by nUHPLC-nESI-TOFMS revealed excellent retention time repeatability with <1% coefficient of variation (CV) for 96% of analyzed peaks. The repeatability of the MS response was <30% CV for >79% of MS features in both negative and positive nESI modes. Compared with UHPLC-ESI-TOFMS, analysis by the nanoplatform enabled detection of signaling molecules important in disease processes including sex steroids, glucocorticoids, eicosanoids, and neurotransmitter metabolites. The significant improvement in sensitivity arising from use of splitless nUHPLC-nESI-TOFMS analyses of SPE-concentrated samples represents a step change in coverage of the urinary metabolome, thereby increasing the potential for biomarker discovery. PMID- 25521705 TI - Introducing TreeCollapse: a novel greedy algorithm to solve the cophylogeny reconstruction problem. AB - BACKGROUND: Cophylogeny mapping is used to uncover deep coevolutionary associations between two or more phylogenetic histories at a macro coevolutionary scale. As cophylogeny mapping is NP-Hard, this technique relies heavily on heuristics to solve all but the most trivial cases. One notable approach utilises a metaheuristic to search only a subset of the exponential number of fixed node orderings possible for the phylogenetic histories in question. This is of particular interest as it is the only known heuristic that guarantees biologically feasible solutions. This has enabled research to focus on larger coevolutionary systems, such as coevolutionary associations between figs and their pollinator wasps, including over 200 taxa. Although able to converge on solutions for problem instances of this size, a reduction from the current cubic running time is required to handle larger systems, such as Wolbachia and their insect hosts. RESULTS: Rather than solving this underlying problem optimally this work presents a greedy algorithm called TreeCollapse, which uses common topological patterns to recover an approximation of the coevolutionary history where the internal node ordering is fixed. This approach offers a significant speed-up compared to previous methods, running in linear time. This algorithm has been applied to over 100 well-known coevolutionary systems converging on Pareto optimal solutions in over 68% of test cases, even where in some cases the Pareto optimal solution has not previously been recoverable. Further, while TreeCollapse applies a local search technique, it can guarantee solutions are biologically feasible, making this the fastest method that can provide such a guarantee. CONCLUSION: As a result, we argue that the newly proposed algorithm is a valuable addition to the field of coevolutionary research. Not only does it offer a significantly faster method to estimate the cost of cophylogeny mappings but by using this approach, in conjunction with existing heuristics, it can assist in recovering a larger subset of the Pareto front than has previously been possible. PMID- 25521706 TI - Using administrative data to estimate time to breast cancer diagnosis and percent of screen-detected breast cancers - a validation study in Alberta, Canada. AB - Appropriate use of administrative data enables the assessment of care quality at the population level. Our objective was to develop/validate methods for assessing quality of breast cancer diagnostic care using administrative data, specifically by identifying relevant medical tests to estimate the percentage screen/symptom detected cancers and time to diagnosis. Two databases were created for all women diagnosed with a first-ever breast cancer in years 2007-2010 in Alberta, Canada, with dates of medical tests received in years 2006-2010. One purchased database had test results and was used to determine the 'true' first relevant test of a cancer diagnosis. The other free administrative database had test types but no test results. Receiver operating characteristic curves and concordance rates were used to assess estimates of percent screen/symptom-detected breast cancers; Log rank test was used to assess time to diagnosis obtained from the two databases. Using a look-back period of 4-6 months from cancer diagnosis to identify relevant tests resulted in over 94% concordance, sensitivity and specificity for classifying patients into screen/symptom-detected group; good agreement between the distributions of time to diagnosis was also achieved. Our findings support the use of administrative data to accurately identify relevant tests for assessing the quality of breast cancer diagnostic care. PMID- 25521707 TI - Father attendance in nurse home visitation. AB - Our aim was to examine the rates and predictors of father attendance at nurse home visits in replication sites of the Nurse-Family Partnership (NFP). Early childhood programs can facilitate father involvement in the lives of their children, but program improvements require an understanding of factors that predict father involvement. The sample consisted of 29,109 low-income, first-time mothers who received services from 694 nurses from 80 sites. We conducted mixed model multiple regression analyses to identify population, implementation, site, and nurse influences on father attendance. Predictors of father attendance included a count of maternal visits (B = 0.12, SE = 0.01, F = 3101.77), frequent contact between parents (B = 0.61, SE = 0.02, F = 708.02), cohabitation (B = 1.41, SE = 0.07, F = 631.51), White maternal race (B = 0.77, SE = 0.06, F = 190.12), and marriage (B = 0.42, SE = 0.08, F = 30.08). Random effects for sites and nurses predicted father-visit participation (2.7 & 6.7% of the variance, respectively), even after controlling for population sociodemographic characteristics. These findings suggest that factors operating at the levels of sites and nurses influence father attendance at home visits, even after controlling for differences in populations served. Further inquiry about these influences on father visit attendance is likely to inform program-improvement efforts. PMID- 25521708 TI - Gas-phase acidities of nitrated azoles as determined by the extended kinetic method and computations. AB - Making use of the extended kinetic method and the alternative method for data analysis, we have experimentally determined DeltaH degrees acid (kcal/mol) for six mononitrated azole species (2-nitropyrrole = 337.0, 3-nitropyrrole = 335.8, 3 nitropyrazole = 330.5, 4-nitropyrazole = 329.5, 2-nitroimidazole = 327.4, and 4 nitroimidazole = 325.0). We report an absolute uncertainty of +/-2.2 kcal/mol that arises from the uncertainties of the reference acids; the relative values are known within 0.4 kcal/mol. Combining these experimental DeltaH degrees acid values with DeltaS degrees acid values calculated at the B3LYP/aug-cc-pVTZ level of theory, we report DeltaG degrees acid (kcal/mol) for the nitroazoles (2 nitropyrrole = 329.4, 3-nitropyrrole = 328.4, 3-nitropyrazole = 323.1, 4 nitropyrazole = 322.0, 2-nitroimidazole = 319.7, and 4-nitroimidazole = 317.6); the absolute uncertainties are +/-2.4 kcal/mol. In addition to the experimental studies, we have computationally investigated the gas-phase acidities and electron affinities of the azoles in this work, as well as higher-order aza- and dinitro-substituted azoles. We discuss trends in the stabilities of the deprotonated azoles based on aza substitution and nitro group placement. 4 Nitroimidazole has already found use as the anionic component in ionic liquids, and we propose that the additional nitrated azolate ions are potential candidates for the anionic component of ionic liquids. PMID- 25521710 TI - Yemen: fighting neglected tropical diseases against all odds. PMID- 25521709 TI - Measurement of cerebral oxygenation in preterm infants: is it useful? PMID- 25521711 TI - Dynamic intravoxel incoherent motion imaging of skeletal muscle at rest and after exercise. AB - The purpose of this work was to demonstrate the feasibility of intravoxel incoherent motion imaging (IVIM) for non-invasive quantification of perfusion and diffusion effects in skeletal muscle at rest and following exercise. After IRB approval, eight healthy volunteers underwent diffusion-weighted MRI of the forearm at 3 T and eight different b values between 0 and 500 s/mm(2) with a temporal resolution of 57 s per dataset. Dynamic images were acquired before and after a standardized handgrip exercise. Diffusion (D) and pseudodiffusion (D*) coefficients as well as the perfusion fraction (FP ) were measured in regions of interest in the flexor digitorum superficialis and profundus (FDS/FDP), brachioradialis, and extensor carpi radialis longus and brevis muscles by using a multi-step bi-exponential analysis in MATLAB. Parametrical maps were calculated voxel-wise. Differences in D, D*, and FP between muscle groups and between time points were calculated using a repeated measures analysis of variance with post hoc Bonferroni tests. Mean values and standard deviations at rest were the following: D*, 28.5 +/- 11.4 * 10(-3) mm(2) /s; FP , 0.03 +/- 0.01; D, 1.45 +/- 0.09 * 10(-3) mm(2) /s. Changes of IVIM parameters were clearly visible on the parametrical maps. In the FDS/FDP, D* increased by 289 +/- 236% (p < 0.029), FP by 138 +/- 58% (p < 0.01), and D by 17 +/- 9% (p < 0.01). A significant increase of IVIM parameters could also be detected in the brachioradialis muscle, which however was significantly lower than in the FDS/FDP. After 20 min, all parameters were still significantly elevated in the FDS/FDP but not in the brachioradialis muscle compared with the resting state. The IVIM approach allows simultaneous quantification of muscle perfusion and diffusion effects at rest and following exercise. It may thus provide a useful alternative to other non-invasive methods such as arterial spin labeling. Possible fields of interest for this technique include perfusion-related muscle diseases, such as peripheral arterial occlusive disease. PMID- 25521712 TI - A master equation for the probability distribution functions of forces in soft particle packings. AB - We study the microscopic response of force-chain networks in jammed soft particles to quasi-static isotropic (de)compressions by molecular dynamics simulations. We show that not only contacts but also interparticle gaps between the nearest neighbors must be considered for the stochastic evolution of the probability distribution functions (PDFs) of forces, where the mutual exchange of contacts and interparticle gaps, i.e. opening and closing contacts, are also crucial to the incremental system behavior. By numerically determining the transition rates for all changes of contacts and gaps, we formulate a Master equation for the PDFs of forces, where the insight one gets from the transition rates is striking: the mean change of forces reflects non-affine system responses, while their fluctuations obey uncorrelated Gaussian statistics. In contrast, interparticle gaps react mostly affine in average, but imply multi scale correlations according to a much wider stable distribution function. PMID- 25521713 TI - Target-specific native/decoy pose classifier improves the accuracy of ligand ranking in the CSAR 2013 benchmark. AB - As part of the CSAR 2013 benchmark exercise, we have implemented a hybrid docking and scoring workflow to rank 10 steroid ligands of an engineered digoxigenin binding protein. Schrodinger's Glide docking software was used to generate poses for each steroid ligand and rank them according to both standard docking precision (SP) and extra docking precision (XP) scoring functions. The unique component of our approach was the use of a target-specific pose classifier trained to discriminate nativelike from decoy poses. To build the classifier, a single cognate ligand with a known native pose (PDB code 4J8T) was docked multiple times into its target protein, and the generated poses were divided into two classes (nativelike and decoy) using a root-mean-square deviation threshold of 2 A. All of the poses were characterized by the MCT-Tess descriptors of the protein-ligand interface, and random forest (RF) models were trained to discriminate the two classes of poses on the basis of their descriptors. The consensus pose classifier was then applied to the Glide-generated poses of each CSAR ligand in order to filter out those poses predicted as decoys and rerank the remaining ones using both XP and SP scoring functions. The best-scoring pose for each ligand following this filtering step was used for final ligand ranking. Overall, the ranking accuracy for the 10 ligands evaluated by the Spearman correlation coefficient was 0.64 for SP and 0.52 for XP but reached 0.75 for SP/RF consensus scoring (ranked third in the CSAR 2013 benchmark exercise). This study reconfirms that target-specific pose scoring models are capable of enhancing the reliability of structure-based molecular docking by discarding decoy poses. PMID- 25521714 TI - Performance of young children on ''traveling salesperson'' navigation tasks presented on a touch screen. AB - BACKGROUND: The traveling salesperson problem (TSP) refers to a task in which one finds the shortest path when traveling through multiple spatially distributed points. Little is known about the developmental course of the strategies used to solve TSPs. The present study examined young children's performance and route selection strategies in one-way TSPs using a city-block metric. A touch screen based navigation task was applied. METHODOLOGY/PRINCIPAL FINDINGS: Children (39 70 months) and adults (21-35 years) made serial responses on a touch screen to move a picture of a dog (the target) to two or three identical pictures of a bone (the goals). For all the versions of the tasks, significant improvement in measures of performance was observed from younger to older participants. In TSPs in which a specific route selection strategy such as the nearest-neighbor strategy minimized the total traveling distance, older participants used that strategy more frequently than younger ones. By contrast, in TSPs in which multiple strategies equally led to the minimal traveling distance, children tended to use strategies different from those used by adults, such as traveling straight to the farthest goal first. CONCLUSIONS/SIGNIFICANCE: The results primarily suggest development of efficient route selection strategies that can optimize total numbers of movements and/or solution time. Unlike adults, children sometimes prioritized other strategies such as traveling straight ahead until being forced to change directions. This may reflect the fact that children were either less attentive to the task or less efficient at perceiving the overall shape of the problem and/or the relative distance from the starting location to each goal. PMID- 25521715 TI - Screening antiallergic components from Carthamus tinctorius using rat basophilic leukemia 2H3 cell membrane chromatography combined with high-performance liquid chromatography and tandem mass spectrometry. AB - Carthamus tinctorius, used in traditional Chinese medicine, has many pharmacological effects, such as anticoagulant effects, antioxidant effects, antiaging effects, regulation of gene expression, and antitumor effects. However, there is no report on the antiallergic effects of the components in C. tinctorius. In the present study, we investigated the antiallergic components of C. tinctorius and its mechanism of action. A rat basophilic leukemia 2H3/cell membrane chromatography coupled online with high-performance liquid chromatography and tandem mass spectrometry method was developed to screen antiallergic components from C. tinctorius. The screening results showed that Hydroxysafflor yellow A, from C. tinctorius, was the targeted component that retained on the rat basophilic leukemia 2H3/cell membrane chromatography column. We measured the amount of beta-hexosaminidase and histamine released in mast cells and the key markers of degranulation. The release assays showed that Hydroxysafflor yellow A could attenuate the immunoglobulin E induced release of allergic cytokines without affecting cell viability from 1.0 to 50.0 MUM. In conclusion, the established rat basophilic leukemia 2H3 cell membrane chromatography coupled with online high-performance liquid chromatography and tandem mass spectrometry method successfully screened and identified Hydroxysafflor yellow A from C. tinctorius as a potential antiallergic component. Pharmacological analysis elucidated that Hydroxysafflor yellow A is an effective natural component for inhibiting immunoglobulin E-antigen-mediated degranulation. PMID- 25521716 TI - Competing ParA structures space bacterial plasmids equally over the nucleoid. AB - Low copy number plasmids in bacteria require segregation for stable inheritance through cell division. This is often achieved by a parABC locus, comprising an ATPase ParA, DNA-binding protein ParB and a parC region, encoding ParB-binding sites. These minimal components space plasmids equally over the nucleoid, yet the underlying mechanism is not understood. Here we investigate a model where ParA ATP can dynamically associate to the nucleoid and is hydrolyzed by plasmid associated ParB, thereby creating nucleoid-bound, self-organizing ParA concentration gradients. We show mathematically that differences between competing ParA concentrations on either side of a plasmid can specify regular plasmid positioning. Such positioning can be achieved regardless of the exact mechanism of plasmid movement, including plasmid diffusion with ParA-mediated immobilization or directed plasmid motion induced by ParB/parC-stimulated ParA structure disassembly. However, we find experimentally that parABC from Escherichia coli plasmid pB171 increases plasmid mobility, inconsistent with diffusion/immobilization. Instead our observations favor directed plasmid motion. Our model predicts less oscillatory ParA dynamics than previously believed, a prediction we verify experimentally. We also show that ParA localization and plasmid positioning depend on the underlying nucleoid morphology, indicating that the chromosomal architecture constrains ParA structure formation. Our directed motion model unifies previously contradictory models for plasmid segregation and provides a robust mechanistic basis for self-organized plasmid spacing that may be widely applicable. PMID- 25521717 TI - Man o' war mutation in UDP-alpha-D-xylose synthase favors the abortive catalytic cycle and uncovers a latent potential for hexamer formation. AB - The man o' war (mow) phenotype in zebrafish is characterized by severe craniofacial defects due to a missense mutation in UDP-alpha-d-xylose synthase (UXS), an essential enzyme in proteoglycan biosynthesis. The mow mutation is located in the UXS dimer interface ~16 A away from the active site, suggesting an indirect effect on the enzyme mechanism. We have examined the structural and catalytic consequences of the mow mutation (R236H) in the soluble fragment of human UXS (hUXS), which shares 93% sequence identity with the zebrafish enzyme. In solution, hUXS dimers undergo a concentration-dependent association to form a tetramer. Sedimentation velocity studies show that the R236H substitution induces the formation of a new hexameric species. Using two new crystal structures of the hexamer, we show that R236H and R236A substitutions cause a local unfolding of the active site that allows for a rotation of the dimer interface necessary to form the hexamer. The disordered active sites in the R236H and R236A mutant constructs displace Y231, the essential acid/base catalyst in the UXS reaction mechanism. The loss of Y231 favors an abortive catalytic cycle in which the reaction intermediate, UDP-alpha-d-4-keto-xylose, is not reduced to the final product, UDP-alpha-d-xylose. Surprisingly, the mow-induced hexamer is almost identical to the hexamers formed by the deeply divergent UXS homologues from Staphylococcus aureus and Helicobacter pylori (21% and 16% sequence identity, respectively). The persistence of a latent hexamer-building interface in the human enzyme suggests that the ancestral UXS may have been a hexamer. PMID- 25521718 TI - Predicting host tropism of influenza A virus proteins using random forest. AB - BACKGROUND: Majority of influenza A viruses reside and circulate among animal populations, seldom infecting humans due to host range restriction. Yet when some avian strains do acquire the ability to overcome species barrier, they might become adapted to humans, replicating efficiently and causing diseases, leading to potential pandemic. With the huge influenza A virus reservoir in wild birds, it is a cause for concern when a new influenza strain emerges with the ability to cross host species barrier, as shown in light of the recent H7N9 outbreak in China. Several influenza proteins have been shown to be major determinants in host tropism. Further understanding and determining host tropism would be important in identifying zoonotic influenza virus strains capable of crossing species barrier and infecting humans. RESULTS: In this study, computational models for 11 influenza proteins have been constructed using the machine learning algorithm random forest for prediction of host tropism. The prediction models were trained on influenza protein sequences isolated from both avian and human samples, which were transformed into amino acid physicochemical properties feature vectors. The results were highly accurate prediction models (ACC>96.57; AUC>0.980; MCC>0.916) capable of determining host tropism of individual influenza proteins. In addition, features from all 11 proteins were used to construct a combined model to predict host tropism of influenza virus strains. This would help assess a novel influenza strain's host range capability. CONCLUSIONS: From the prediction models constructed, all achieved high prediction performance, indicating clear distinctions in both avian and human proteins. When used together as a host tropism prediction system, zoonotic strains could potentially be identified based on different protein prediction results. Understanding and predicting host tropism of influenza proteins lay an important foundation for future work in constructing computation models capable of directly predicting interspecies transmission of influenza viruses. The models are available for prediction at http://fluleap.bic.nus.edu.sg. PMID- 25521719 TI - Supramolecular Photochemistry in Solution and on Surfaces: Encapsulation and Dynamics of Guest Molecules and Communication between Encapsulated and Free Molecules. AB - Supramolecular assemblies that help to preorganize reactant molecules have played an important role in the development of concepts related to the control of excited-state processes. This has led to a persistent search for newer supramolecular systems (hosts), and this review briefly presents our work with octa acid (OA) to a host to control excited-state processes of organic molecules. Octa acid, a water-soluble host, forms 1:1, 2:1, and 2:2 (host-guest) complexes with various organic molecules. A majority of the guest molecules are enclosed within a capsule made up of two molecules of OA whereas OA by itself remains as a monomer or aggregates. Luminescence and (1)H NMR spectroscopy help to characterize the structure and dynamics of these host-guest complexes. The guest molecule as well as the host-guest complex as a whole undergoes various types of motion, suggesting that the guests possess freedom inside the confined space of the octa acid capsule. In addition, the confined guests are not isolated but are able to communicate (energy, electron, and spin) with molecules present closer to the capsule. The host-guest complexes are stable even on solid surfaces such as silica, clay, alpha-Zr phosphate, TiO2, and gold nanoparticles. This opens up new opportunities to explore the interaction between confined guests and active surfaces of TiO2 and gold nanoparticles. In addition, this allows the possibility of performing energy and electron transfer between organic molecules that do not adsorb on inert surfaces of silica, clay, or alpha-Zr phosphate. The results summarized here, in addition to providing a fundamental understanding of the behavior of molecules in a confined space provided by the host OA, are likely to have a long-range effect on the capture and release of solar energy. PMID- 25521720 TI - Monitoring bypassing agent therapy - a prospective crossover study comparing thromboelastometry and thrombin generation assay. AB - The aim of this study was to evaluate the capability of thromboelastometry (ROTEM) and thrombin generation assay (TGA) to monitor the treatment response of bypassing agent (BPA) therapy and to study whether one method is superior to another. In a prospective crossover study haemophilia A patients with high titre inhibitors were included to receive a dose of 75 U kg(-1) activated prothrombin complex concentrates (aPCC) intravenously. Blood sampling was performed at baseline, 15, 30 min, 1, 2, 3 and 4 h post-infusion for TGA and ROTEM analysis. After a washout period of 14 days the subjects received recombinant FVIIa (rFVIIa) at a dose of 90 MUg kg(-1) and similar blood sampling was performed. Healthy subjects were used as controls. Six haemophilia A patients with inhibitors were included. We found that TGA parameters endogenous thrombin potential (ETP) and peak thrombin increased 2-3 folds from baseline 15-30 min after infusion. ROTEM parameters MaxVel and maximum clot firmness increased to a level comparable to that of healthy controls. An individual difference in response was observed for different parameters among participants. ETP and peak thrombin were almost two-fold greater following aPCC infusion compared to rFVIIa, whereas ROTEM parameters showed no difference in response between the two products. The study showed that ROTEM and TGA have a great potential to evaluate the effect of BPA in haemophilia patients with inhibitors. TGA seemed to be more sensitive than ROTEM in reflecting the difference in treatment response between aPCC and rFVIIa. Additional prospective clinical studies are needed to clarify which assay and what parameters are clinically predictive. PMID- 25521722 TI - Organocatalytic asymmetric cascade reactions of 7-vinylindoles: diastereo- and enantioselective synthesis of C7-functionalized indoles. AB - The first catalytic asymmetric cascade reaction of 7-vinylindoles has been established by the rational design of such substrates. Cascade reactions with isatin-derived 3-indolylmethanols in the presence of a chiral phosphoric acid derivative allow the diastereo- and enantioselective synthesis of C7 functionalized indoles as well as the construction of cyclopenta[b]indole and spirooxindole frameworks (all >95:5 d.r., 94->99 % ee). This approach not only addresses the great challenge of the catalytic asymmetric synthesis of C7 functionalized indoles, but also provides an efficient method for constructing biologically important cyclopenta[b]indole and spirooxindole scaffolds with excellent optical purity. Investigation of the reaction pathway and activation mode has suggested that this cascade reaction proceeds through a vinylogous Michael addition/Friedel-Crafts process, in which dual H-bonding activation of the two reactants plays a crucial role. PMID- 25521721 TI - Frequent proviral integration of the human betaretrovirus in biliary epithelium of patients with autoimmune and idiopathic liver disease. AB - BACKGROUND: A human betaretrovirus (HBRV) has been linked with primary biliary cirrhosis (PBC) following the detection of viral particles in biliary epithelium by electron microscopy and cloning of the betaretrovirus genome from biliary epithelium and peri-hepatic lymph nodes. Evidence for viral infection was found in the majority of PBC patients' peri-hepatic lymph node samples. However, less than a third of the liver samples had detectable HBRV, whereas others were unable to detect betaretrovirus infection or noted the presence of virus in the liver of patients with other diagnoses. AIMS: To address the hypothesis that the betaretrovirus may be below the limits of detection in the liver, biliary epithelial cells (BEC) were investigated for the evidence of infection. METHODS: Ligation-mediated PCR and next generation sequencing were used to detect proviral integrations in liver, lymph nodes and BEC isolated from liver transplant recipients. Hybridisation-based assays were used to detect betaretroviral RNA in BEC. RESULTS: Unique HBRV integrations and betaretrovirus RNA were detected in the majority of biliary epithelia derived from patients with PBC, autoimmune hepatitis and cryptogenic liver disease but rarely in other liver transplant recipients with primary sclerosing cholangitis and other hepatic disorders. HBRV integrations were commonly found in PBC patients' lymph nodes but rarely in whole liver samples. CONCLUSIONS: Human betaretrovirus infection is frequently observed at the site of disease in patients with primary biliary cirrhosis and also in biliary epithelium of patients with autoimmune hepatitis and cryptogenic liver disease. PMID- 25521723 TI - Factors contributing to malnutrition in patients with Parkinson's disease. AB - Our objective in this study was to evaluate the nutritional status and to identify clinical, psychosocial, and nutritional factors contributing to malnutrition in Korean patients with Parkinson's disease. We used a descriptive, cross-sectional study design. Of 102 enrolled patients, 26 (25.5%) were malnourished and 27 (26.5%) were at risk of malnutrition based on Mini Nutritional Assessment scores. Malnutrition was related to activity of daily living score, Hoehn and Yahr stage, duration of levodopa therapy, Beck Depression Inventory and Spielberger's Anxiety Inventory scores, body weight, body weight at onset of Parkinson's disease, and body mass index. On multiple logistic regression analysis, anxiety score, duration of levodopa therapy, body weight at onset of Parkinson's disease, and loss of body weight were significant factors predicting malnutrition in Parkinson's disease patients. Therefore, nutritional assessment, including psychological evaluation, is required for Parkinson's disease patients to facilitate interdisciplinary nutritional intervention for malnourished patients. PMID- 25521724 TI - Label-free aptasensor for adenosine deaminase sensing based on fluorescence turn on. AB - A label-free and fluorescence turn-on aptamer biosensor has been developed for the detection of adenosine deaminase (ADA) activity with simplicity and selectivity. Adenosine aptamer will form a tight stem-loop structure upon binding with adenosine. In the absence of ADA, only a small quantity of picagreen intercalates into the stem section of aptamer, resulting in a low fluorescence of picagreen when excited at 490 nm. Interestingly, after the addition of ADA, adenosine is hydrolyzed to inosine, and the released aptamer forms double stranded DNA (dsDNA) with its complementary single-stranded DNAc, followed by the intercalation of picagreen to dsDNA. When the solution is excited, picagreen emits strong green fluorescence. The increased fluorescence intensity of picagreen is dependent on the concentration of ADA. The detection limit of the ADA is determined to be 2 U L(-1), which is lower than ADA cutoff value (4 U L( 1)) in the clinical requirement and more sensitive than most of the reported methods. Compared to other previous ADA sensors, the assay is not only label-free but also a turn-on signal, and possesses properties of lower cost and simpler detection system. Furthermore, this label-free strategy is also applicable to the assay of other enzymes and screening of corresponding inhibitors. PMID- 25521725 TI - Importance of cyclooxygenase-1/prostacyclin in modulating gastric mucosal integrity under stress conditions. AB - BACKGROUND AND AIM: We investigated the roles of cyclooxygenase (COX) isozymes and prostaglandins (PGs) and their receptors in mucosal defense against cold restraint stress (CRS)-induced gastric lesions. METHODS: Male C57BL/6 wild-type (WT) mice and those lacking COX-1 or COX-2 as well as those lacking EP1, EP3, or IP receptors were used after 18 h fasting. Animals were restrained in Bollman cages and kept in a cold room at 10 degrees C for 90 min. RESULTS: CRS induced multiple hemorrhagic lesions in WT mouse stomachs. The severity of these lesions was significantly worsened by pretreatment with the nonselective COX inhibitors (indomethacin, loxoprofen) or selective COX-1 inhibitor (SC-560), while neither of the selective COX-2 inhibitors (rofecoxib and celecoxib) had any effect. These lesions were also aggravated in animals lacking COX-1, but not COX-2. The expression of COX-2 mRNA was not detected in the stomach after CRS, while COX-1 expression was observed under normal and stressed conditions. The gastric ulcerogenic response to CRS was similar between EP1 or EP3 knockout mice and WT mice, but was markedly worsened in animals lacking IP receptors. Pretreating WT mice with iloprost (the PGI2 analog) significantly prevented CRS-induced gastric lesions in the presence of indomethacin. PGE2 also reduced the severity of these lesions, and the effect was mimicked by the EP4 agonist, AE1-329. CONCLUSIONS: These results suggest that endogenous PGs derived from COX-1 play a crucial role in gastric mucosal defense during CRS, and this action is mainly mediated by PGI2 /IP receptors and partly by PGE2 /EP4 receptors. PMID- 25521726 TI - Comparison of teprenone and famotidine against gastroduodenal mucosal damage in patients taking low-dose aspirin. AB - BACKGROUND AND AIM: Proton-pump inhibitors are known to be effective in the treatment and prevention of ulcers related to low-dose aspirin (LDA), but few reports address H2 -receptor antagonists (H2RAs) and gastroprotective agents (GPs). This study was intended to compare the therapeutic effects of an H2RA and a GP against gastroduodenal mucosal injuries in patients taking LDA. METHODS: The subjects consisted of patients requiring continuous LDA treatment, in whom no peptic ulcer was found on endoscopy at enrollment. The patients were randomized to either famotidine 20 mg/day (group F) or teprenone 150 mg/day (group T). The study medication was administered for 12 weeks. The patients underwent endoscopy after administration of the study medication in order to obtain a Lanza score. RESULTS: A total of 66 patients (38 in group F, 28 in group T) were included in the efficacy analysis population. The Lanza score changed as follows: in group F, it improved significantly, from 0.89+/-1.03 (mean+/-standard deviation) before medication to 0.39+/-0.75 after medication (P=0.006); in group T, no significant difference was observed: 0.75+/-0.93 before medication and 0.68+/-0.82 after medication. CONCLUSION: Famotidine is better than teprenone in terms of reducing the number of the erosions under use of LDA. PMID- 25521727 TI - Prevalence of Helicobacter pylori infection with healthy subjects in Japan. AB - BACKGROUND AND AIM: Only few large-scale epidemiological studies have examined the prevalence of Helicobacter pylori (H. pylori) infection in Japan. The aim of the present study was to estimate the prevalence and incidence of H. pylori infection in Japan in terms of gender, age and region. METHODS: Serum anti-H. pylori antibody testing was included in workers' annual health checks conducted by T-company's health insurance association in 2008. The testing was continued for the next 5 years in 35-year-old subjects. RESULTS: The total number of subjects was 21 144 (18 398 males and 2746 females). Stratified for age, there were 5016 subjects (male:female=4219:797) in their 30s, 8748 (7770:978) in their 40s, 5589 (4807:782) in their 50s, and 1769 (1584:185) in their 60s. The H. pylori seropositive rate (male:female) was 27.5% (27.5:27.7) overall, 18.0% (18.3:16.1) in subjects in their 30s, 22.9% (22.7:24.7) in those in their 40s, 37.4% (37.2:38.2) in those in their 50s, and 46.1% (45.7:49.2) in those in their 60s. The prevalence of H. pylori seropositivity increased as age increased; however, no significant differences were seen between genders or among regions (chi2 test). The numbers of 35-year-old subjects from 2008 to 2012 were 1072, 1107, 941, 1065, and 940, respectively. The corresponding H. pylori seropositive rates were 17.4, 17.4, 14.3, 13.3, and 14.0%, respectively. CONCLUSION: The Japanese H. pylori infection rate had already declined to 27.5% in 2008, with subjects in the 35-70 age range. The prevalence of H. pylori infection is also decreasing gradually from 2008 to 2012. PMID- 25521728 TI - Effect of supplementation with rebamipide for Helicobacter pylori eradication therapy: a systematic review and meta-analysis. AB - BACKGROUND AND AIM: Several studies have reported that the application of rebamipide during the eradication of Helicobacter pylori can improve the eradication rate. However, the efficacy and safety are controversial. The present study systematically evaluated whether rebamipide improves the eradication rate of H. pylori by conducting a meta-analysis based on randomized controlled trials (RCTs). METHODS: Literature searches were conducted in the following database: PubMed, the Cochrane Library, and the Igaku-chuo-zasshi database in Japan. A meta analysis of all RCTs comparing rebamipide supplementation with non-rebamipide containing therapy was performed. RESULTS: We identified six randomized trials (611 patients). Pooled H. pylori eradication rates by per-protocol analysis were 73.3% and 61.4% for patients with or without rebamipide, respectively. The odds ratio was 1.74 (95% confidence interval. 1.19-2.53). CONCLUSIONS: Supplementation with rebamipide might be effective in increasing the H. pylori eradication rates of proton-pump inhibitor-amoxicillin dual therapy. PMID- 25521729 TI - Decrease of serum level of gastrin in healthy Japanese adults by the change of Helicobacter pylori infection. AB - BACKGROUND AND AIM: In Japan, the prevalence of Helicobacter pylori infection is decreasing and the number of patients who receive eradication therapy is increasing. Although the serum level of gastrin is affected by H. pylori infection, the normal level has been unchanged for more than 20 years. The aim of this study was to study whether the present normal range for the serum gastrin level is appropriate for Japanese at present or in the near future. METHODS: We studied 810 adults (40-80 years old) who participated in a health survey in 2012. We measured H. pylori stool antigen, titer of serum antibody to H. pylori, and serum level of gastrin. The patient's H. pylori status was defined as positive or negative when the results of both stool antigen and serology were concordant. Subjects who were taking proton-pump inhibitor and had a previous history of gastric surgery were excluded. RESULTS: Mean serum level of gastrin was 66.2+/ 49.6 pg/mL in 281 H. pylori-negative subjects and 69.7+/-42.2 pg/mL in 115 patients who had H. pylori eradicated at least 2 years ago. The level of gastrin was 134.4+/-145.6 pg/mL in 224 patients with H. pylori infection and the level was significantly higher when compared with those in uninfected subjects and eradicated patients (P<0.01). CONCLUSIONS: Because the situation of H. pylori infection has changed remarkably in Japan, a new appropriate normal range of gastrin should be established using current Japanese populations. PMID- 25521730 TI - Changes in the first line Helicobacter pylori eradication rates using the triple therapy-a multicenter study in the Tokyo metropolitan area (Tokyo Helicobacter pylori study group). AB - BACKGROUND AND AIM: Helicobacter pylori (H. pylori) infection is a strong risk factor for the development of gastric cancer. In 2013, the Japanese government approved H. pylori eradication therapy in patients with chronic gastritis as well as peptic ulcer. However, the continuing decline in eradication rates for first line H. pylori eradication therapies is an urgent problem. In this study, we investigated changes in the first-line eradication rate from 2001 to 2010. METHODS: Eradication rates for 7-day triple therapy [proton pump inhibitor (rabeprazole 20 mg, lansoprazole 60 mg, or omeprazole 40 mg)+amoxicillin 1500 mg + clarithromycin (CAM) 400 or 800 mg, daily] were collated from 14 hospitals in the Tokyo metropolitan area. The urea breath test was used for the evaluation of eradication. The cut-off value was less than 2.5%. RESULTS: The yearly eradication rates (intention to treat/per protocol) were 78.5/79.5% (2001, n=242), 71.2%/72.9% (2002, n=208), 67.8%/70.5% (2003, n=183), 75.6%/84.6% (2004, n=131), 56.4%/70.5% (2005, n=114), 70.5%/75.8% (2006, n=271), 67.4%/82.0% (2007, n=135), 64.0%/76.3% (2008, n=261), 60.5%/74.3% (2009, n=329), and 66.5%/78.8% (2010, n=370), respectively. Examination of eradication rates according to CAM dosage revealed an eradication rate of 65.6% (383/584) for CAM 400 mg daily, and 68.5% (1124/1642) for CAM 800 mg daily, with no significant difference seen between dosages. CONCLUSION: In recent years, eradication rates for first-line triple therapy have obviously decreased, but no noticeable decrease has occurred after 2001. PMID- 25521731 TI - Evaluation of gastric cancer diagnosis using new ultrathin transnasal endoscopy with narrow-band imaging: preliminary study. AB - BACKGROUND AND AIM: The new developed ultrathin transnasal endoscope, the GIF XP290N, makes possible a resolving power similar to the GIF-H260 at a distance of 3 mm. In this study, using the GIF-XP290N, we evaluated whether endoscopic diagnosis (discrimination between benign and malignant) of gastric lesions is possible using nonmagnified narrow-band imaging (NBI) endoscopy. METHODS: The subjects were 255 consecutive patients who underwent screening of the gastrointestinal tract using new ultrathin transnasal endoscopy. Their average age was 65.2 +/- 11.4 years. The male-female ratio was 2.5:1. All cases were examined using conventional white-light imaging (WLI) and nonmagnified NBI. When a depressed lesion was detected in the stomach, it was examined using WLI, then NBI close examination (at about 3 mm). We observed the mucosal structure of the lesion using close visualization with NBI. Concerning mucosal structural changes, we looked for a clear demarcation line between the lesion and the surrounding mucosa, and loss, irregularity, or nonuniformity of the lesion mucosal microsurface pattern. RESULTS: A total of 52 depressed lesions were examined. The histological diagnosis was cancer for 8 lesions, and noncancer for 44 lesions. WLI examination yielded a sensitivity of 50.0% (4/8), specificity of 63.6% (28/44), and accuracy 61.5% (32/52). On the other hand, NBI close examination yielded a sensitivity of 87.5% (7/8), specificity of 93.2% (41/44), and accuracy of 92.3% (48/52), significantly higher. CONCLUSION: NBI close examination using ultrathin transnasal endoscopy enables mucosal diagnosis even without magnification and was considered to be an effective technique for improving endoscopic diagnosis. PMID- 25521732 TI - Effect of rebamipide on gastric bleeding and ulcerogenic responses induced by aspirin plus clopidogrel under stimulation of acid secretion in rats. AB - BACKGROUND AND AIM: We examined the prophylactic effect of rebamipide on gastric bleeding induced by the perfusion of aspirin (acetylsalicylic acid [ASA]) plus clopidogrel under the stimulation of acid secretion in rats. METHODS: Under urethane anesthesia, acid secretion was stimulated by the i.v. infusion of histamine (8 mg/kg/h), and the stomach was perfused with 25 mmol/L ASA at a rate of 0.4 mL/min. Gastric bleeding was evaluated as the concentration of hemoglobin in the perfusate. Clopidogrel (30 mg/kg) was given p.o. 24 h before the perfusion. Rebamipide (3-30 mg/kg) or other antiulcer drugs were given i.d. before the ASA perfusion. RESULTS: Slight gastric bleeding or damage was observed with the perfusion of ASA under the stimulation of acid secretion, whereas these responses were significantly increased in the presence of clopidogrel. Both omeprazole and famotidine inhibited acid secretion and prevented these responses to ASA plus clopidogrel. Rebamipide had no effect on acid secretion, but dose dependently prevented gastric bleeding in response to ASA plus clopidogrel, with the degree of inhibition being almost equivalent to that of the antisecretory drugs, and the same effects were obtained with the gastroprotective drugs, irsogladine and teprenone. These agents also reduced the severity of gastric lesions, although the effects were less than those of the antisecretory drugs. CONCLUSIONS: These results suggest that the antiplatelet drug, clopidogrel, increases gastric bleeding induced by ASA under the stimulation of acid secretion, and the gastroprotective drug, rebamipide, is effective in preventing the gastric bleeding induced under such conditions, similar to antisecretory drugs. PMID- 25521733 TI - Single nucleotide polymorphism markers for low-dose aspirin-associated peptic ulcer and ulcer bleeding. AB - BACKGROUND AND AIM: In our previous study, the SLCO1B1 521TT genotype and the SLCO1B1*1b haplotype were significantly associated with the risk of peptic ulcer in patients taking low-dose aspirin (LDA). The aim of the present study was to investigate pharmacogenomic profile of LDA-induced peptic ulcer and ulcer bleeding. METHODS: Patients taking 100 mg of enteric-coated aspirin for cardiovascular diseases and with a peptic ulcer or ulcer bleeding and patients who also participated in endoscopic surveillance were studied. Genome-wide analysis of single nucleotide polymorphisms (SNPs) was performed using the Affymetrix DME Plus Premier Pack. SLCO1B1*1b haplotype and candidate genotypes of genes associated with ulcer bleeding or small bowel bleeding identified by genome wide analysis were determined using TaqMan SNP Genotyping Assay kits, polymerase chain reaction-restriction fragment length polymorphism, and direct sequencing. RESULTS: Of 593 patients enrolled, 111 patients had a peptic ulcer and 45 had ulcer bleeding. The frequencies of the SLCO1B1*1b haplotype and CHST2 2082 T allele were significantly greater in patients with peptic ulcer and ulcer bleeding compared to the controls. After adjustment for significant factors, the SLCO1B1*1b haplotype was associated with peptic ulcer (OR 2.20, 95% CI 1.24-3.89) and CHST2 2082 T allele with ulcer bleeding (2.57, 1.07-6.17). CONCLUSION: The CHST2 2082 T allele as well as SLCO1B1*1b haplotype may identify patients at increased risk for aspirin-induced peptic ulcer or ulcer bleeding. PMID- 25521734 TI - Mucosal expression of aquaporin-4 in the stomach of histamine type 2 receptor knockout mice and Helicobacter pylori-infected mice. AB - BACKGROUND AND AIM: Basolateral water channel, aquaporin-4 (AQP4), is known to be expressed in gastric parietal cells, especially in the basal side of gastric mucosa. However, the role of AQP4 in the stomach is still unknown. Histamine type 2 receptor (H2R) knockout mice, which are characterized by suppressed gastric acid secretion, are known as formation of mucosal hyperplasia with cystic dilatation and spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach. The aim of the present study is to investigate whether the expression of AQP4 is changed by the condition of acid suppression and Helicobacter pylori infection. METHODS: Male H2 R knockout mice and their controls (C57BL/6) were used. H. pylori was orally infected at the age of 5 weeks. The distributions of AQP4 and H+/K+-ATPase in the gastric mucosa were investigated by fluorescent immunohistochemistry. The mRNA expressions of AQP4, H+/K+-ATPase, sonic hedgehog (Shh), and trefoil factor-2 (TFF2) were investigated by quantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS: In the H2 R knockout mice, the distribution of AQP4-positive parietal cells was extended toward the surface of the fundic glands. Although the mRNA expression levels of AQP4 and H+/K+ATPase were elevated in H2 R knockout mice at the age of 20 weeks, the elevations were not maintained by aging or H. pylori infection. In H2 R knockout mice with H. pylori infection, the expression level of TFF2 mRNA was elevated while the ratio between AQP4 and H+/K+ ATPase mRNA expression was decreased compared with the H2 R knockout mice without H. pylori infection. CONCLUSIONS: In the H2 R knockout mice, massive SPEM was induced by H. pylori colonization and the ratio between AQP4 and H+/K+ATPase mRNA expression was decreased. PMID- 25521735 TI - Usefulness of Helicobacter pylori eradication for precancerous lesions of the gastric remnant. AB - BACKGROUND AND AIM: Secondary stomach cancer in lesions of the remnant stomach occurs relatively soon after distal gastrectomy using the Billroth I reconstruction procedure. Prophylactic eradication of Helicobacter pylori after endoscopic resection of early gastric cancer should be used to prevent the development of metachronous gastric carcinoma. However, the effect of H. pylori eradication on the gastric remnant has not been clearly determined. METHODS: Eight patients who were H. pylori-positive after distal gastrectomy for primary gastric cancer underwent eradication therapy and were followed by endoscopy for 9 years. Upper gastroenteroscopy series were done before and at 1, 3, 5, 7 and 9 years after eradication, and biopsy specimens were taken from the lesser and greater curvatures, respectively. Histological changes, including chronic inflammation, activity, atrophy, and intestinal metaplasia, were evaluated using the updated Sydney system. RESULTS: Successful eradication was confirmed using the urea breath test in all eight patients. Chronic inflammation scores were improved after eradication at both the lesser (mean scores +/- SD: before eradication, 2.9+/-0.5; 1 year after, 2.3+/-0.4; 3 years, 1.8+/-0.3; 5 years, 1.5+/-0.3; 7 years, 1.3+/-0.3; and 9 years, 1.0+/-0.3) and greater curvatures (before, 2.9+/-0.4; 1 year after, 1.9+/-0.3; 3 years, 1.4+/-0.4; 5 years, 1.3+/ 0.3; 7 years, 1.1+/-0.2; and 9 years, 0.6+/-0.3). Atrophy scores improved more quickly after eradication than chronic inflammation scores at both the lesser (before, 2.4+/-0.5; 1 year after, 1.8+/-0.4; 3 years, 0.8+/-0.3; 5 years, 0.3+/ 0.1; 7 years, 0.0; and 9 years, 0.0) and greater curvatures (before, 2.2+/-0.4; 1 year after, 1.3+/-0.3; 3 years, 0.5+/-0.3; 5 years, 0.0; 7 years, 0.0; and 9 years, 0.0). No secondary stomach cancers were found on endoscopy. CONCLUSIONS: Undergoing H. pylori eradication improved possible precancerous lesions of the gastric remnant among patients who had undergone distal gastrectomy. Prophylactic H. pylori eradication in the gastric remnant may be useful in preventing the development of metachronous gastric carcinoma. PMID- 25521736 TI - Acetic acid induces cell death: an in vitro study using normal rat gastric mucosal cell line and rat and human gastric cancer and mesothelioma cell lines. AB - BACKGROUND AND AIM: We recently reported that topical application of acetic acid promptly caused tumor necrosis in a mouse model of gastric cancer. The aim of the present study was to examine whether acetic acid can directly induce cancer cell death. METHODS: Rat gastric epithelial cell line (RGM-1), rat gastric carcinoma cell line (RGK-1), human gastric cancer cell line (KATO III), and human mesothelioma cell lines (ACC-MESO1 and MSTO-211H) were used. Acetic acid was added into the cell culture at different concentrations for different time periods. Cell death was analyzed by MTT assay, flow cytometry, and trypan blue exclusion test. RESULTS: Acetic acid promptly induced the cell death of RGM-1, RGK-1 cells, and KATO III cells in a concentration-dependent manner from 0.01% to 0.5%. Acetic acid at 0.5% for 1 min induced the cell death by 80%. RGK-1 cells were more sensitive to acetic acid than RGM-l cells. KATO III cells were more sensitive to acetic acid than RGK-1 cells. Acetic acid at 0.5% for 10 min induced almost complete cell death of ACC-MESO1 and MSTO-211H. CONCLUSIONS: Acetic acid is a powerful anticancer agent. Topical application of acetic acid may be a feasible approach for the treatments of gastric cancer and possibly other malignancies. PMID- 25521737 TI - Alteration of angiogenesis in Helicobacter heilmannii-induced mucosa-associated lymphoid tissue lymphoma: interaction with c-Met and hepatocyte growth factor. AB - BACKGROUND AND AIM: The hepatocyte growth factor (HGF)/c-Met pathway has attracted attention in the formation of malignant tumors, as HGF secreted from the microcirculatory components as well as residing macrophages has been suggested to act on the c-Met receptors of cancer cells to decrease apoptosis and increase proliferation, invasion, and metastasis. The present study was undertaken to elucidate the interaction of the gastric, hepatic, and pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma induced by Helicobacter heilmannii infection with c-Met and HGF. METHODS: C57BL/6 female mice, infected with H. heilmannii for 3 months were used. The localization of the HGF, c-Met, and HGF activator immunoreactivities was observed by the indirect immunohistochemical methods. In addition, the effect of c-Met antibody and c-Met inhibitor, PHA-665752, was also investigated. RESULTS: c-Met immunoreactivity was found in the lymphocytes composing the MALT lymphoma, and HGF immunoreactivity was recognized mostly in the endothelial cells and macrophages in the MALT lymphoma. HGFA was localized on mesenchymal cells other than the lymphocytes. The administration of the antibody against c-Met or the c-Met inhibitor to the infected mice induced the significant suppression of hepatic and pulmonary MALT lymphoma, while the gastric MALT lymphoma showed only a tendency to decrease in size, while the active caspase 3 positive cells markedly decreased in the gastric, hepatic, and pulmonary MALT lymphoma after the treatment with the c-Met antibody or the c-Met antagonist. CONCLUSIONS: HGF and c-Met pathway were suggested to contribute to the lymphomagenesis in the MALT lymphoma after H. heilmannii infection. PMID- 25521738 TI - Initial clinical trial of a novel hemostat, TDM-621, in the endoscopic treatments of the gastric tumors. AB - BACKGROUND AND AIM: The feasibility of TDM-621, the synthetic infectious agent free peptides, was tested in hemostasis of the bleeding after endoscopic treatments of the gastric tumors. METHODS: The patients who underwent endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) were enrolled in the present study. The subject of hemostasis was the oozing after the EMR or ESD. The hemostatic effect, the secondary hemorrhage from one postoperative day to the day before discharge and operability were studied. RESULTS: The hemostatic effects were assessed in 12 patients. It was "remarkably effective" in 11 patients and "effective" in 1 patient. The operability was "very easy" in two patients, "easy" in eight patients and "acceptable" in two patients. No secondary hemorrhage was observed in all of 12 patients. No adverse effect considered to be related to TDM-621 was observed. CONCLUSION: It was shown that hemostasis using TDM-621 was feasible after endoscopic treatments of the gastric tumors without any technical trouble or adverse event. PMID- 25521739 TI - S-allyl cysteine alleviates nonsteroidal anti-inflammatory drug-induced gastric mucosal damages by increasing cyclooxygenase-2 inhibition, heme oxygenase-1 induction, and histone deacetylation inhibition. AB - BACKGROUND AND AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs), the most highly prescribed drugs in the world for the treatment of pain, inflammation, and fever, are associated with gastric mucosal damages including ulcer directly or indirectly. This study was aimed to document the preventive effects of an organosulfur constituent of garlic, S-allyl cysteine (SAC), against NSAIDs induced gastric damages, as well the elucidation of its pharmacological actions, such as anti-inflammatory, anti-oxidative, and cytoprotective actions. METHODS: Different doses of SAC were administrated intragastrically before the indomethacin administration. After killing, in addition to gross and pathological evaluations of ulcer, the expressions of inflammatory mediators, including cyclooxygenase-2, prostaglandin E2 , IL-1beta, tumor necrosis factor-alpha, IL-6, and anti-oxidant capacity, were analyzed by Western blot analysis or ELISA, respectively. Transferase deoxytidyl uridine end labeling assay, periodic acid and Schiff staining, F4/80 staining, and CD31 staining were compared among doses of SAC. Detailed documentation of in vitro biological actions of SAC, including NF-kappaB, histone deacetylator inhibition, phase 2 enzyme, and MAPKs, was performed. RESULTS: SAC was very effective in preventing indomethacin-induced gastric damages in a low dose through significant decreases in macrophage infiltration as well as restorative action. Indomethacin-induced expressions of inflammatory mediators were all significantly attenuated with SAC in accordance with histone deacetylator inhibition. In addition, SAC significantly increased the total anti-oxidant concentration and mucus secretion, and allows for a significant induction of HO-1. However, these preventive effects of SAC were dependent on dosage of SAC; higher dose above 10 MUM paradoxically aggravated NSAID-induced inflammation. CONCLUSION: Synthetic SAC can be promising therapeutics agent to provide potent anti-inflammatory, anti-oxidative, and mucosa protective effects against NSAID-induced damages. PMID- 25521741 TI - Naturally occurring phenethyl isothiocyanate-induced inhibition of gastric cancer cell growth by disruption of microtubules. AB - BACKGROUND AND AIM: Phenethyl isothiocyanate (PEITC) derives from vegetables commonly consumed by man and has been demonstrated as a promising chemopreventive agent against several types of cancer. However, the potential in preventing gastric cancer as well as the underlying mechanisms are to date not fully understood. The present study aimed at elucidating the cellular effects induced by PEITC in gastric cancer cells leading to apoptosis. METHODS: The human gastric cancer cell lines Kato-III and MKN74 were employed. Cell proliferation was assayed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Morphology and migration were investigated through a contrast microscope. Cell cycle distribution was analyzed using flow cytometry of PI-stained cells. Microtubules were studied by confocal detection of Kato-III cells transfected to express GFP-tagged microtubules. Commercial kits were employed to study the effect of PEITC on apoptosis, caspase-3 activity, and glutathione content in MKN74 cells. RESULTS: Kato-III and MKN74 cells responded, with different sensitivity, dose- and time-dependently in inhibition of cell proliferation to PEITC treatment. Further, PEITC induced aberrated cell morphologies and inhibited migration of MKN74 cells. Kato-III cells treated with PEITC accumulated in G2 /M phase and displayed a loss of microtubuli with the subsequent formation of apoptotic bodies. Although weak responses, MKN74 cells also accumulated in G2 /M phase, became apoptotic, increased caspase-3 activity, and suffered a reduction of glutathione pool. CONCLUSION: Our findings demonstrate that PEITC induces disintegration of microtubules in human gastric cancer cells contributing to cell cycle arrest and ultimately apoptosis, contributing to an increased understanding of PEITC-induced inhibition of gastric cancer cell growth. PMID- 25521743 TI - Angiogenesis in gastric mucosa: an important component of gastric erosion and ulcer healing and its impairment in aging. AB - Angiogenesis (also referred to as neovascularization-formation of new blood vessels from existing vessels) is a fundamental process essential for healing of tissue injury and ulcers because regeneration of blood microvessels is a critical requirement for oxygen and nutrient delivery to the healing site. This review article updates the current views on angiogenesis in gastric mucosa following injury and during ulcer healing, its sequential events, the underlying mechanisms, and the impairment of angiogenesis in aging gastric mucosa. We focus on the time sequence and ultrastructural features of angiogenesis, hypoxia as a trigger, role of vascular endothelial growth factor signaling (VEGF), serum response factor, Cox2 and prostaglandins, nitric oxide, and importin. Recent reports indicate that gastric mucosa of aging humans and experimental animals exhibits increased susceptibility to injury and delayed healing. Gastric mucosa of aging rats has increased susceptibility to injury by a variety of damaging agents such as ethanol, aspirin, and other non-steroidal anti-inflammatory drugs because of structural and functional abnormalities including: reduced gastric mucosal blood flow, hypoxia, reduced expression of vascular endothelial growth factor and survivin, and increased expression of early growth response protein 1 (egr-1) and phosphatase and tensin homolog (PTEN). Until recently, postnatal neovascularization was assumed to occur solely through angiogenesis sprouting of endothelial cells and formation of new blood vessels from pre-existing blood vessels. New studies in the last decade have challenged this paradigm and indicate that in some tissues, including gastric mucosa, the homing of bone marrow-derived endothelial progenitor cells to the site of injury can also contribute to neovascularization by a process termed vasculogenesis. PMID- 25521742 TI - Lymphangiogenesis in early and advanced gastric cancer: is there any difference? AB - BACKGROUND AND AIM: Gastric cancer (GC) in Poland is on the third place of men's mortality and on the fifth place of women's mortality in malignant neoplasms, and the percentage of diagnosed early GC is less than 20%. In this study, the relationship among lymphatic vessel density, marked with D2-40, expression of vascular endothelial growth factor (VEGF)-C/D, VEGF receptor 3 VEGFR-3, and the stage of GC patient were investigated. METHODS: This study examined the relationships between the peritumoral lymphatic vessels (PTL) density and intratumoral lymphatic vessels (ITL) density stained immunohistochemically with D2-40/podoplanin, the expression of VEGF-C/D and VEGFR-3, and the stage of 58 GC patients. RESULTS: Lymphatic vessel density measured by D2-40 decreases outside the tumor (PTL) and increases within the tumor (ITL) as the staging grows from I to III, whereas in the case of patients belonging to stage IV group, lymphatic vessel density decreases outside the tumor as well as within the tumor in comparison with the stage III group (not statistically significant). We observed a difference between morphology of the vessels within the tumor (ITLs) and vessels that are located outside the tumor (PTLs). PTLs were enlarged and unsqueezed as opposed to ITLs, which were collapsed. CONCLUSIONS: (i) There is no significant correlation between the density of ITL nor PTL marked with D2-40 and the stage of GC. (ii) We did not observe relationship between expression of VEGF C/D and VEGFR-3 and the stage of GC. (iii) Further studies are needed to fully determine the role of PTL and ITL. PMID- 25521740 TI - Prostaglandin pathways in duodenal chemosensing. AB - Acid-sensing pathways, which trigger mucosal defense mechanisms in response to luminal acid, involve the rapid afferent-mediated "capsaicin pathway" and the sustained "prostaglandin (PG) pathway." Luminal acid quickly increases protective PG synthesis and release from epithelia, although the mechanism by which luminal acid induces PG synthesis is still mostly unknown. Acid exposure augments purinergic ATP-P2Y signaling by inhibition of intestinal alkaline phosphatase activity. Since P2Y activation increases intracellular Ca2+, we further hypothesized that ATP-P2Y signals increase the generation of H2O2 derived from dual oxidase, a member of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family activated by Ca2+. Our recent studies suggest that acid exposure increases H2O2 output, followed by phospholipase A2 and cyclooxygenase activation, increasing PG synthesis. Released prostaglandin E2 augments protective HCO3- and mucus secretion via EP4 receptor activation. Thus, the PG pathway as a component of duodenal acid sensing consists of acid-related intestinal alkaline phosphatase inhibition, ATP-P2Y signals, dual oxidase 2 derived H2O2 production, phospholipase A2 activation, prostaglandin E2 synthesis, and EP4 receptor activation. The PG pathway is also involved in luminal bacterial sensing in the duodenum via activation of pattern recognition receptors, including Toll-like receptors and nucleotide-binding oligomerization domain 2. The presence of acute mucosal responses to luminal bacteria suggests that the duodenum is important for host defenses and may reduce bacterial loading to the hindgut using H2O2, complementing gastric acidity and anti-bacterial bile acids. PMID- 25521744 TI - "Gastric cytoprotection" is still relevant. AB - Although Andre Robert's historic article on "gastric cytoprotection" in 1979 introduced this new name and concept, gastroprotective drugs (e.g. sofalcone, sucralfate), which prevent and/or accelerate healing of gastric ulcers without inhibiting acid secretion, were known in Japan before or around that time. But since Robert's studies were solely focused on prostaglandins (PG), they became the center of gastrointestinal research for more than 30 years. As endogenous products, PG were implicated in mediating the gastroprotective effect of other drugs such as sofalcone and sucralfate, despite that the cyclooxygenase inhibitor indomethacin diminished but never abolished gastroprotection by other drugs. Another group of endogenous substances, that is, sulfhydryls (SH), investigated in parallel with PG, also seem to play a mechanistic role in gastroprotection, especially since SH alkylators like N-ethylmaleimide counteract virtually any form of gastroprotection. In Robert's terms of "prevention of chemically induced acute mucosal lesions," so far no single mechanism could explain the beneficial effects of diverse protective agents, but I argue that these two endogenous substances (i.e. PG, SH), in addition to histamine, are the main mechanistic mediators of acute gastroprotection: PG and histamine, because as mediators of acute inflammation, they increase vascular permeability (VP), and SH scavenge free radicals. This is contrary to the search for a single mechanism of action, long focused on enhanced secretion of mucus and/or bicarbonate that may contribute but cannot explain all forms of gastroprotection. Nevertheless, based on research work of the last 30 years, in part from our lab, a new mechanistic explanation of gastroprotection may be formulated: it's a complex but orderly and evolution-based physiologic response of the gastric mucosa under pathologic conditions. Namely, one of the first physiologic defense responses of any organ is inflammation that starts with rapid vascular changes (e.g. increased VP and blood flow), followed by cellular events (e.g. infiltration by acute and chronic inflammatory cells). Thus, PG and histamine, by increasing VP create a perivascular edema that dilutes and delays toxic agents reaching the subepithelial capillaries. Otherwise, damaging chemicals may induce severe early vascular injury resulting in blood flow stasis, hypoxia, and necrosis of surrounding epithelial and mesenchymal cells. In this complex response, increased mucus and/or bicarbonate secretion seem to cause luminal dilution of gastrotoxic chemicals that is further reinforced by a perivascular, histodilutional component. This mechanistic explanation would encompass the protective actions of diverse agents as PG, small doses of histamine, motility stimulants, and dilute irritants (i.e. "adaptive cytoprotection"). Thus, although markedly increased VP is pathologic, slight increase in VP seems to be protective, that is, a key element in the complex pathophysiologic response during acute gastroprotection. Over the years, "gastroprotection" was also applied to accelerated healing of chronic gastroduodenal ulcers without reduction of acid secretion. The likely main mechanism here is the binding of angiogenic growth factors (e.g. basic fibroblast growth factor, vascular endothelial growth factor) to the heparin-like structures of sucralfate and sofalcone. Thus, despite intensive research of the last 30 years, gastroprotection is incompletely understood, and we are still far away from effectively treating Helicobacter pylori-negative ulcers and preventing nonsteroidal anti-inflammatory drugs-caused erosions and ulcers in the upper and lower gastrointestinal tract; hence "gastric cytoprotection" research is still relevant. PMID- 25521745 TI - Second-harmonic generation from metal nanoparticles: resonance enhancement versus particle geometry. AB - We demonstrate that optical second-harmonic generation (SHG) from arrays of noncentrosymmetric gold nanoparticles depends essentially on particle geometry. We prepare nanoparticles with different geometrical shapes (L and T) but similar wavelengths for the polarization-dependent plasmon resonances. In contrast to recent interpretations emphasizing resonances at the fundamental frequency, the T shape leads to stronger SHG when only one, instead of both, polarization component of the fundamental field is resonant. This is explained by the character of plasmon oscillations supported by the two shapes. Our numerical simulations for both linear and second-order responses display unprecedented agreement with measurements. PMID- 25521747 TI - Virus-based scaffolds for tissue engineering applications. AB - One of the major research directions of tissue engineering is to develop artificial scaffolds that can mimic extracellular matrix (ECM) and support the growth of functional cells for the repair of damaged tissues and organs. Recently, virus particles have expanded as nanosized building blocks for materials applications. Viruses represent monodispersed supramolecular assemblies with organized three-dimensional architecture, which can be isolated in high yield and purity with batch-to-batch consistency. In addition, virus particles can be re-engineered by chemical and genetic modification to incorporate multivalent functional ligands with high density and ordered arrangement. In this review, we highlight that the self-assembly of the reengineered viruses can form two-dimensional and three-dimensional scaffolds, which can be employed to support cell growth and regulate cellular functions such as adhesion, spreading and proliferation. In particular, the application of virus-based scaffolds for directed differentiation of pluripotent stem cells for bone and neural regeneration is discussed. Finally, the in vivo behaviors of virus nanoparticles will be discussed for the consideration of tissue engineering applications. PMID- 25521748 TI - Weight gain in pregnancy and application of the 2009 IOM guidelines: toward a uniform approach. AB - OBJECTIVE: There is an urgent need to adopt standardized nomenclature as it relates to gestational weight gain (GWG), a more uniform approach to calculate it, and hence quantifying adherence to the 2009 Institute of Medicine (IOM) guidelines. METHODS: This perspective highlights the varying methods used to estimate GWG and discuss the advantages and limitations of each. RESULTS: While these calculations could be argued to have a minimal impact on data at the population level, on the patient level, incorrectly estimating weight at conception can result in misclassification of preconception body mass index (BMI) and assignment of the IOM guidelines which inherently affect the prospective management of weight gain (and potential outcomes) during the current pregnancy. CONCLUSIONS: This study recommends that preconception BMI and total GWG be determined objectively and total GWG be adjusted for length of gestation before assessing adherence to the IOM GWG guidelines. PMID- 25521750 TI - Multicomponent strategy to indeno[2,1-c]pyridine and hydroisoquinoline derivatives through cleavage of carbon-carbon bond. AB - A concise and efficient three-component domino reaction has been developed for the synthesis of polyfunctionalized indenopyridine and hydroisoquinoline derivatives via the cleavage of a C-C bond under transition-metal-free conditions. This reaction provides facile access to complex nitrogen-containing heterocycles by simply mixing three common starting materials in EtOH in the presence of 20 mol % NaOH under microwave irradiation conditions. PMID- 25521746 TI - Predictors for the development of referral-warranted retinopathy of prematurity in the telemedicine approaches to evaluating acute-phase retinopathy of prematurity (e-ROP) study. AB - IMPORTANCE: Detection of treatment-requiring retinopathy of prematurity (ROP) involves serial eye examinations. An ROP prediction model using predictive factors could identify high-risk infants and reduce required eye examinations. OBJECTIVE: To determine predictive factors for the development of referral warranted (RW) ROP. DESIGN, SETTING, AND PARTICIPANTS: This multicenter observational cohort study included secondary analysis of data from the Telemedicine Approaches to Evaluating Acute-Phase Retinopathy of Prematurity Study. Infants included in the study had a birth weight (BW) of less than 1251 g. EXPOSURES: Serial ROP examinations of premature infants who had 2 or more ROP examinations. MAIN OUTCOMES AND MEASURES: Incidence of RW-ROP (defined as the presence of plus disease, zone I ROP, or ROP stage 3 or greater in either eye) and associations with predictive factors. RESULTS: Among 979 infants without RW ROP at first study-related eye examination (median postmenstrual age, 33 weeks; range, 29-40 weeks) who underwent at least 2 eye examinations, 149 (15.2%) developed RW-ROP. In a multivariate model, significant predictors for RW-ROP were male sex (odds ratio [OR], 1.80; 95% CI, 1.13-2.86 vs female), nonblack race (OR, 2.76; 95% CI, 1.50-5.08 for white vs black race and OR, 4.81; 95% CI, 2.19-10.6 for other vs black race), low BW (OR, 5.16; 95% CI, 1.12-7.20 for <=500 g vs >1100 g), younger gestational age (OR, 9.79; 95% CI, 3.49-27.5 for <=24 weeks vs >=28 weeks), number of quadrants with preplus disease (OR, 7.12; 95% CI, 2.53 20.1 for 1-2 quadrants and OR, 18.4; 95% CI, 4.28-79.4 for 3-4 quadrants vs no preplus disease), stage 2 ROP (OR, 4.13; 95% CI, 2.13-8.00 vs no ROP), the presence of retinal hemorrhage (OR, 4.36; 95% CI, 1.57-12.1 vs absence), the need for respiratory support (OR, 4.99; 95% CI, 1.89-13.2 for the need for controlled mechanical ventilator; OR, 11.0; 95% CI, 2.26-53.8 for the need for high frequency oscillatory ventilation vs no respiratory support), and slow weight gain (OR, 2.44; 95% CI, 1.22-4.89 for weight gain <=12 g/d vs >18 g/d). These characteristics predicted the development of RW-ROP significantly better than BW and gestational age (area under receiver operating characteristic curve, 0.88 vs 0.78; P < .001). CONCLUSIONS AND RELEVANCE: When controlling for very low BW and prematurity, the presence of preplus disease, stage 2 ROP, retinal hemorrhage, and the need for ventilation at time of first study-related eye examination were strong independent predictors for RW-ROP. These predictors may help identify infants in need of timely eye examinations. PMID- 25521749 TI - Proteinases, their receptors and inflammatory signalling: the Oxford South Parks Road connection. AB - In keeping with the aim of the Paton Memorial Lecture to 'facilitate the historical study of pharmacology', this overview, which is my distinct honour to write, represents a 'Janus-like' personal perspective looking both backwards and forwards at the birth and growth of 'receptor molecular pharmacology' with special relevance to inflammatory diseases. The overview begins in the Oxford Department of Pharmacology in the mid-1960s and then goes on to provide a current perspective of signalling by proteinases. Looking backwards, the synopsis describes the fruitful Oxford Pharmacology Department infrastructure that Bill Paton generated in keeping with the blueprint begun by his predecessor, J H Burn. Looking forwards, the overview illustrates the legacy of that environment in generating some of the first receptor ligand-binding data and providing the inspiration and vision for those like me who were training in the department at the same time. With apologies, I mention only in passing a number of individuals who benefitted from the 'South Parks Road connection' using myself as one of the 'outcome study' examples. It is also by looking forward that I can meet the complementary aim of summarizing the lecture presented at a 'BPS 2014 Focused Meeting on Cell Signalling' to provide an overview of the role of proteinases and their signalling mechanisms in the setting of inflammation. PMID- 25521751 TI - Controlling radiofrequency-induced currents in guidewires using parallel transmit. AB - PURPOSE: Elongated conductors, such as pacemaker leads, neurostimulator leads, and conductive guidewires used for interventional procedures can couple to the MRI radiofrequency (RF) transmit field, potentially causing dangerous tissue heating. The purpose of this study was to demonstrate the feasibility of using parallel transmit to control induced RF currents in elongated conductors, thereby reducing the RF heating hazard. METHODS: Phantom experiments were performed on a four-channel parallel transmit system at 1.5T. Parallel transmit "null mode" excitations that induce minimal wire current were designed using coupling measurements derived from axial B1 (+) maps. The resulting current reduction performance was evaluated with B1 (+) maps, current sensor measurements, and fluoroptic temperature probe measurements. RESULTS: Null mode excitations reduced the maximum coupling mode current by factors ranging from 2 to 80. For the straight wire experiment, a current null imposed at a single wire location was sufficient to reduce tip heating below detectable levels. For longer insertion lengths and a curved geometry, imposing current nulls at two wire locations resulted in more distributed current reduction along the wire length. CONCLUSION: Parallel transmit can be used to create excitations that induce minimal RF current in elongated conductors, thereby decreasing the RF heating risk, while still allowing visualization of the surrounding volume. PMID- 25521752 TI - Golgi-located NTPDase1 of Leishmania major is required for lipophosphoglycan elongation and normal lesion development whereas secreted NTPDase2 is dispensable for virulence. AB - Parasitic protozoa, such as Leishmania species, are thought to express a number of surface and secreted nucleoside triphosphate diphosphohydrolases (NTPDases) which hydrolyze a broad range of nucleoside tri- and diphosphates. However, the functional significance of NTPDases in parasite virulence is poorly defined. The Leishmania major genome was found to contain two putative NTPDases, termed LmNTPDase1 and 2, with predicted NTPDase catalytic domains and either an N terminal signal sequence and/or transmembrane domain, respectively. Expression of both proteins as C-terminal GFP fusion proteins revealed that LmNTPDase1 was exclusively targeted to the Golgi apparatus, while LmNTPDase2 was predominantly secreted. An L. major LmNTPDase1 null mutant displayed increased sensitivity to serum complement lysis and exhibited a lag in lesion development when infections in susceptible BALB/c mice were initiated with promastigotes, but not with the obligate intracellular amastigote stage. This phenotype is characteristic of L. major strains lacking lipophosphoglycan (LPG), the major surface glycoconjugate of promastigote stages. Biochemical studies showed that the L. major NTPDase1 null mutant synthesized normal levels of LPG that was structurally identical to wild type LPG, with the exception of having shorter phosphoglycan chains. These data suggest that the Golgi-localized NTPase1 is involved in regulating the normal sugar-nucleotide dependent elongation of LPG and assembly of protective surface glycocalyx. In contrast, deletion of the gene encoding LmNTPDase2 had no measurable impact on parasite virulence in BALB/c mice. These data suggest that the Leishmania major NTPDase enzymes have potentially important roles in the insect stage, but only play a transient or non-major role in pathogenesis in the mammalian host. PMID- 25521753 TI - Comorbidity and performance status as independent prognostic factors in patients with head and neck squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to evaluate the individual and combined relationship of comorbidity and performance status (PS) on head and neck squamous cell carcinoma (HNSCC) survival. METHODS: Six hundred patients with HNSCC were prospectively recruited. Comorbidity and PS were measured using the Charlson Comorbidity Index (CCI) and the Eastern Cooperative Oncology Group (ECOG) Scale. Outcomes were overall survival (OS) and cancer-specific survival (CSS). RESULTS: A total of 48.3% of the patients had at least 1 comorbidity, and 42.3% had impaired PS at baseline. There was no correlation between CCI and ECOG (Spearman's rho = 0.033; p = .42). In multivariate analysis, CCI score was significantly associated with OS (p = .01). ECOG was not associated with OS, but seems to act as an effect modifier in the association between comorbidity and OS. CCI and ECOG were not associated with CSS. CONCLUSION: CCI and ECOG scores both provide prognostic information in predicting OS in HNSCC, but a significant association with CSS was not observed. PMID- 25521755 TI - Ginsenoside Rg3 inhibits melanoma cell proliferation through down-regulation of histone deacetylase 3 (HDAC3) and increase of p53 acetylation. AB - Malignant melanoma is an aggressive and deadly form of skin cancer, and despite recent advances in available therapies, is still lacking in completely effective treatments. Rg3, a monomer extracted from ginseng roots, has been attempted for the treatment of many cancers. It is reported that the expressions of histone deacetylase 3 (HDAC3) and p53 acetylation correlate with tumor cell growth. However, the antitumor effect of Rg3 on melanoma and the mechanism by which it regulates HDAC3 expression and p53 acetylation remain unknown. We found high expression of HDAC3 in human melanoma tissues to be significantly correlated to lymph node metastasis and clinical stage of disease (p<0.05). In melanoma cells, Rg3 inhibited cell proliferation and induced G0/G1 cell cycle arrest. Rg3 also decreased the expression of HDAC3 and increased the acetylation of p53 on lysine (k373/k382). Moreover, suppression of HDAC3 by either siRNA or a potent HDAC3 inhibitor (MS-275) inhibited cell proliferation, increased p53 acetylation and transcription activity. In A375 melanoma xenograft studies, we demonstrated that Rg3 and HDAC3 short hairpin RNA (shHDAC3) inhibited the growth of xenograft tumors with down-regulation of HDAC3 expression and up-regulation of p53 acetylation. In conclusion, Rg3 has antiproliferative activity against melanoma by decreasing HDAC3 and increasing acetylation of p53 both in vitro and in vivo. Thus, Rg3 serves as a potential therapeutic agent for the treatment of melanoma. PMID- 25521756 TI - Combined cord blood and bone marrow transplantation from the same human leucocyte antigen-identical sibling donor for children with malignant and non-malignant diseases. AB - Umbilical cord blood (UCB) from an human leucocyte antigen (HLA)-identical sibling can be used for transplantation of patients with malignant and non malignant diseases. However, the low cellular content of most UCB units represents a limitation to this approach. An option to increase cell dose is to harvest bone marrow (BM) cells from the same donor and infuse them along with the UCB. We studied 156 children who received such a combined graft between 1992 and 2011. Median age was 7 years and 78% of patients (n = 122) were transplanted for non-malignant diseases, mainly haemoglobinopathies. Acute leukaemia (n = 26) was the most frequent malignant diagnosis. Most patients (91%) received myeloablative conditioning. Median donor age was 1.7 years, median infused nucleated cell dose was 24.4 * 10(7) /kg and median follow-up was 41 months. Sixty-days neutrophil recovery occurred in 96% of patients at a median of 17 d. The probabilities of grade-II-IV acute and chronic graft-versus-host disease (GVHD) were 19% and 10%, respectively. Four-year overall survival was 90% (68% malignant; 97% non malignant diseases) with 3% probability of death. In conclusion, combined UCB and BM transplantation from an HLA-identical sibling donor is an effective treatment for children with malignant and non-malignant disorders with high overall survival and low incidence of GVHD. PMID- 25521758 TI - Mixl1 and Flk1 Are Key Players of Wnt/TGF-beta Signaling During DMSO-Induced Mesodermal Specification in P19 cells. AB - Dimethyl sulfoxide (DMSO) is widely used to induce multilineage differentiation of embryonic and adult progenitor cells. To date, little is known about the mechanisms underlying DMSO-induced mesodermal specification. In this study, we investigated the signaling pathways and lineage-determining genes involved in DMSO-induced mesodermal specification in P19 cells. Wnt/beta-catenin and TGF-beta superfamily signaling pathways such as BMP, TGF-beta and GDF1 signaling were significantly activated during DMSO-induced mesodermal specification. In contrast, Nodal/Cripto signaling pathway molecules, required for endoderm specification, were severely downregulated. DMSO significantly upregulated the expression of cardiac mesoderm markers but inhibited the expression of endodermal and hematopoietic lineage markers. Among the DMSO-activated cell lineage markers, the expression of Mixl1 and Flk1 was dramatically upregulated at both the transcript and protein levels, and the populations of Mixl1+, Flk1+ and Mixl1+/Flk1+ cells also increased significantly. DMSO modulated cell cycle molecules and induced cell apoptosis, resulting in significant cell death during EB formation of P19 cells. An inhibitor of Flk1, SU5416 significantly blocked expressions of TGF-beta superfamily members, mesodermal cell lineage markers and cell cycle molecules but it did not affect Wnt molecules. These results demonstrate that Mixl1 and Flk1 play roles as key downstream or interacting effectors of Wnt/TGF-beta signaling pathway during DMSO-induced mesodermal specification in P19 cells. PMID- 25521757 TI - Vangl2-regulated polarisation of second heart field-derived cells is required for outflow tract lengthening during cardiac development. AB - Planar cell polarity (PCP) is the mechanism by which cells orient themselves in the plane of an epithelium or during directed cell migration, and is regulated by a highly conserved signalling pathway. Mutations in the PCP gene Vangl2, as well as in other key components of the pathway, cause a spectrum of cardiac outflow tract defects. However, it is unclear why cells within the mesodermal heart tissue require PCP signalling. Using a new conditionally floxed allele we show that Vangl2 is required solely within the second heart field (SHF) to direct normal outflow tract lengthening, a process that is required for septation and normal alignment of the aorta and pulmonary trunk with the ventricular chambers. Analysis of a range of markers of polarised epithelial tissues showed that in the normal heart, undifferentiated SHF cells move from the dorsal pericardial wall into the distal outflow tract where they acquire an epithelial phenotype, before moving proximally where they differentiate into cardiomyocytes. Thus there is a transition zone in the distal outflow tract where SHF cells become more polarised, turn off progenitor markers and start to differentiate to cardiomyocytes. Membrane-bound Vangl2 marks the proximal extent of this transition zone and in the absence of Vangl2, the SHF-derived cells are abnormally polarised and disorganised. The consequent thickening, rather than lengthening, of the outflow wall leads to a shortened outflow tract. Premature down regulation of the SHF-progenitor marker Isl1 in the mutants, and accompanied premature differentiation to cardiomyocytes, suggests that the organisation of the cells within the transition zone is important for maintaining the undifferentiated phenotype. Thus, Vangl2-regulated polarisation and subsequent acquisition of an epithelial phenotype is essential to lengthen the tubular outflow vessel, a process that is essential for on-going cardiac morphogenesis. PMID- 25521760 TI - Prostatic angiogenic responses in late life: antiangiogenic therapy influences and relation with the glandular microenvironment in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. AB - BACKGROUND: Aging is considered one of the main predisposing factors for the development of prostate malignancies. Angiogenesis is fundamental for tumor growth and its inhibition represents a promising therapeutic approach in cancer treatment. Thus, we sought to determine angiogenic responses and the effects of antiangiogenic therapy in the mouse prostate during late life, comparing these findings with the prostatic microenvironment in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. METHODS: Male mice (52 week-old FVB) were submitted to treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c.). Finasteride was administered (20 mg/kg; s.c.), alone or in association to both inhibitors. The dorsolateral prostate was collected for VEGF, HIF-1alpha, FGF-2 and endostatin immunohistochemical and Western Blotting analyses and for microvessel density (MVD) count. RESULTS: Senescence led to increased MVD and VEGF, HIF-1alpha and FGF-2 protein levels in the prostatic microenvironment, similarly to what was observed in TRAMP mice prostate. The angiogenic process was impaired in all the treated groups, demonstrating significantly decreased MVD. Antiangiogenic and/or finasteride treatments resulted in decreased VEGF and HIF 1alpha levels, especially following TNP-470 administration, either alone or associated to SU5416. The combination of these agents resulted in increased endostatin levels, regardless of the presence of finasteride. CONCLUSIONS: Prostatic angiogenesis stimulation during senescence favored the development of neoplastic lesions, considering the pro-angiogenic microenvironment as a common aspect also observed during cancer progression in TRAMP mice. The combined antiangiogenic therapy was more efficient, leading to enhanced imbalance towards angiogenic inhibition in the organ. Finally, finasteride administration might secondarily upregulate the expression of pro-angiogenic factors, pointing to the harmful effects of this therapy. PMID- 25521759 TI - Loss of Arabidopsis thaliana Dynamin-Related Protein 2B reveals separation of innate immune signaling pathways. AB - Vesicular trafficking has emerged as an important means by which eukaryotes modulate responses to microbial pathogens, likely by contributing to the correct localization and levels of host components necessary for effective immunity. However, considering the complexity of membrane trafficking in plants, relatively few vesicular trafficking components with functions in plant immunity are known. Here we demonstrate that Arabidopsis thaliana Dynamin-Related Protein 2B (DRP2B), which has been previously implicated in constitutive clathrin-mediated endocytosis (CME), functions in responses to flg22 (the active peptide derivative of bacterial flagellin) and immunity against flagellated bacteria Pseudomonas syringae pv. tomato (Pto) DC3000. Consistent with a role of DRP2B in Pattern Triggered Immunity (PTI), drp2b null mutant plants also showed increased susceptibility to Pto DC3000 hrcC-, which lacks a functional Type 3 Secretion System, thus is unable to deliver effectors into host cells to suppress PTI. Importantly, analysis of drp2b mutant plants revealed three distinct branches of the flg22-signaling network that differed in their requirement for RESPIRATORY BURST OXIDASE HOMOLOGUE D (RBOHD), the NADPH oxidase responsible for flg22 induced apoplastic reactive oxygen species production. Furthermore, in drp2b, normal MAPK signaling and increased immune responses via the RbohD/Ca2+-branch were not sufficient for promoting robust PR1 mRNA expression nor immunity against Pto DC3000 and Pto DC3000 hrcC-. Based on live-cell imaging studies, flg22 elicited internalization of the plant flagellin-receptor, FLAGELLIN SENSING 2 (FLS2), was found to be partially dependent on DRP2B, but not the closely related protein DRP2A, thus providing genetic evidence for a component, implicated in CME, in ligand-induced endocytosis of FLS2. Reduced trafficking of FLS2 in response to flg22 may contribute in part to the non-canonical combination of immune signaling defects observed in drp2b. In conclusion, this study adds DRP2B to the relatively short list of known vesicular trafficking proteins with roles in flg22-signaling and PTI in plants. PMID- 25521761 TI - Profiling of exome mutations associated with progression of HBV-related hepatocellular carcinoma. AB - Recent advances in sequencing technology have allowed us to profile genome-wide mutations of various cancer types, revealing huge heterogeneity of cancer genome variations. However, its heterogeneous landscape of somatic mutations according to liver cancer progression is not fully understood. Here, we profiled the mutations and gene expressions of early and advanced hepatocellular carcinoma (HCC) related with Hepatitis B-viral infection. Integrative analysis was performed with whole-exome sequencing and gene expression profiles of the 12 cases of early and advanced HCCs and paired non-tumoral adjacent liver tissues. A total of 293 tumor-specific somatic variants and 202 non-tumoral variants were identified. The tumor-specific variants were found to be enriched at chromosome 1q particularly in the advanced HCC, compared to the non-tumoral variants. Functional enrichment analysis revealed frequent mutations at the genes encoding cytoskeleton organization, cell adhesion, and cell cycle-related genes. In addition, to elucidate actionable somatic mutations, we performed an integrative analysis of gene mutations and gene expression profiles together. This revealed the 48 mutated genes which were differentially mutated with concomitant gene expression enrichment. Of these, CTNNB1 was found to have a pivotal role in the differential progression of the HCC subgroup. In conclusion, our integrative analysis of whole-exome sequencing and transcriptome profiles could provide actionable mutations which might play pivotal roles in the heterogeneous progression of HCC. PMID- 25521762 TI - Assessment of de novo assemblers for draft genomes: a case study with fungal genomes. AB - BACKGROUND: Recently, large bio-projects dealing with the release of different genomes have transpired. Most of these projects use next-generation sequencing platforms. As a consequence, many de novo assembly tools have evolved to assemble the reads generated by these platforms. Each tool has its own inherent advantages and disadvantages, which make the selection of an appropriate tool a challenging task. RESULTS: We have evaluated the performance of frequently used de novo assemblers namely ABySS, IDBA-UD, Minia, SOAP, SPAdes, Sparse, and Velvet. These assemblers are assessed based on their output quality during the assembly process conducted over fungal data. We compared the performance of these assemblers by considering both computational as well as quality metrics. By analyzing these performance metrics, the assemblers are ranked and a procedure for choosing the candidate assembler is illustrated. CONCLUSIONS: In this study, we propose an assessment method for the selection of de novo assemblers by considering their computational as well as quality metrics at the draft genome level. We divide the quality metrics into three groups: g1 measures the goodness of the assemblies, g2 measures the problems of the assemblies, and g3 measures the conservation elements in the assemblies. Our results demonstrate that the assemblers ABySS and IDBA-UD exhibit a good performance for the studied data from fungal genomes in terms of running time, memory, and quality. The results suggest that whole genome shotgun sequencing projects should make use of different assemblers by considering their merits. PMID- 25521764 TI - Correlation between portal vein anatomy and bile duct variation in 407 living liver donors. AB - Our aim was to determine whether variant bile duct (BD) anatomy is associated with portal vein (PV) and/or hepatic artery (HA) anatomy. We examined the associations between BD anatomy and PV and/or HA anatomy in 407 living donor transplantation donors. We also examined whether the right posterior BD (RPBD) course was associated with the PV and/or HA anatomy. Variant PV, HA and BD anatomies were found in 11%, 25% and 25%, respectively, of 407 donors enrolled in this study. The presence of a variant BD was more frequently associated with a variant PV than with a normal PV (61% vs. 20%, p < 0.0001). By contrast, the presence of a variant HA was not associated with a variant BD. A supraportal RPBD was found in 357 donors (88%) and an infraportal RPBD was found in 50 donors (12%). An infraportal RPBD was significantly more common in donors with a variant PV than in donors with a normal PV (30% vs. 10%, p = 0.0004). Variant PV, but not variant HA, anatomies were frequently associated with variant BD anatomy. Additionally, an infraportal RPBD was more common in donors with a variant PV than in donors with a normal PV. PMID- 25521765 TI - Changes in salmon (Oncorhynchus keta) flesh quality following ultra-high pressure treatment and 30 d of chilled storage. AB - The approximately 1.5 million tons of salmon traded in 31 countries in 2008 provides clear evidence that salmon is a popular food source throughout the world. There are many methods for the preservation of salmon flesh, such as vacuum-packaging, smoking, and freezing. Ultra-high pressure (UHP) does not require heat, preserves the quality of salmon flesh, and allows for an increase in the chilled storage period. In this study, the quality of salmon flesh was assessed after exposure to UHP (200, 400, or 600 MPa compared with no UHP) and 30 d of storage at 4 degrees C. Salmon flesh quality analyses included the degree of changes in the interspacing of muscle bundles, color, texture profiles (hardness, chewiness, cohesiveness, and elasticity), and microbial growth. The use of UHP (>400 MPa) improved the color, hardness, and chewiness of the flesh. Study results suggested that the application of UHP (>=400 MPa) may be useful in preserving salmon flesh, and could be used by the salmon aquaculture and distribution industries. PMID- 25521763 TI - A mechanistic approach to cross-domain perceptual narrowing in the first year of life. AB - Language and face processing develop in similar ways during the first year of life. Early in the first year of life, infants demonstrate broad abilities for discriminating among faces and speech. These discrimination abilities then become tuned to frequently experienced groups of people or languages. This process of perceptual development occurs between approximately 6 and 12 months of age and is largely shaped by experience. However, the mechanisms underlying perceptual development during this time, and whether they are shared across domains, remain largely unknown. Here, we highlight research findings across domains and propose a top-down/bottom-up processing approach as a guide for future research. It is hypothesized that perceptual narrowing and tuning in development is the result of a shift from primarily bottom-up processing to a combination of bottom-up and top down influences. In addition, we propose word learning as an important top-down factor that shapes tuning in both the speech and face domains, leading to similar observed developmental trajectories across modalities. Importantly, we suggest that perceptual narrowing/tuning is the result of multiple interacting factors and not explained by the development of a single mechanism. PMID- 25521770 TI - From anilines to isatins: oxidative palladium-catalyzed double carbonylation of C H bonds. AB - A novel palladium-catalyzed C-H double carbonylation introduces two adjacent carbonyl groups for the synthesis of isatins from readily available anilines. The reaction proceeds under atmospheric pressure of CO with high regioselectivity and without any additives. Density functional theory investigations indicate that the palladium-catalyzed double carbonylation catalytic cycle is plausible. PMID- 25521771 TI - Evolving tRNA(Sec) for efficient canonical incorporation of selenocysteine. AB - Bacterial selenocysteine incorporation occurs in response to opal stop codons and is dependent on the presence of a selenocysteine insertion sequence (SECIS) element, which recruits the selenocysteine specific elongation factor and tRNA(Sec) needed to reassign the UGA codon. The SECIS element is a stem-loop RNA structure immediately following the UGA codon and forms part of the coding sequence in bacterial selenoproteins. Although the site specific incorporation of selenocysteine is of great interest for protein engineering, the sequence constraints imposed by the adjoining SECIS element severely limit its use. We have evolved an E. coli tRNA(Sec) that is compatible with the canonical translation machinery and can suppress amber stop codons to incorporate selenocysteine with high efficiency. This evolved tRNA(Sec) allows the production of new recombinant selenoproteins containing structural motifs such as selenyl sulfhydryl and diselenide bonds. PMID- 25521772 TI - Emotion episodes during psychotherapy sessions among women newly diagnosed with gynecological cancers. AB - OBJECTIVE: The aim of this study was to describe emotion episodes during early and late psychotherapy sessions among women newly diagnosed with gynecological cancer and to examine whether the total number of emotion episodes during early and later sessions was associated with baseline psychological distress, dispositional emotion expressivity, and patient-rated therapeutic progress. METHODS: The study utilized data from an ongoing study examining the efficacy of two psychotherapy interventions, a coping and communication intervention and a supportive counseling intervention, for women diagnosed with gynecological cancer. Emotion episode coding was completed for the first and sixth psychotherapy sessions for each patient randomized to receive psychotherapy (N = 173). Patients completed baseline survey measures of psychological distress and dispositional emotional expressivity and post-session ratings of therapeutic progress. RESULTS: The average number of emotion episodes was 7.4 in the first session and 5.2 episodes in the sixth session. In both sessions, the majority of emotion episodes contained only negative emotions and focused on a cancer-related topic. A higher number of emotion episodes in the first session was associated with higher psychological distress reported in the baseline survey (p = 0.02). A higher number of emotion episodes in the sixth session was associated with a higher number of emotion episodes in the first session (p < 0.001) and higher patient-rated progress as rated in the sixth session (p = 0.016). CONCLUSION: The findings highlight the importance of expressed emotions, particularly negative emotions about cancer-related topics, in therapeutic progress during psychotherapy among women diagnosed with gynecological cancer. PMID- 25521773 TI - Opioid-related adverse effects in children undergoing surgery: unequal burden on younger girls with higher doses of opioids. AB - OBJECTIVE: Unpredictable interindividual variability in response to opioids results in inadequate analgesia and opioid-related adverse effects. The effects of the child's sex on opioid response have not been well studied. The aim of this study is to determine the effects of sex on opioid-related adverse effects in children undergoing tonsillectomy. DESIGN: Prospective observational clinical study. SETTING: Outpatient pediatric surgery. SUBJECTS: Two hundred and seventy five children between 6 and 15 years of age undergoing outpatient tonsillectomy. METHODS: All children received standard perioperative care with a standard intraoperative dose of morphine. Opioid-related analgesia and safety outcomes included incidences of respiratory depression (RD), postoperative nausea and vomiting (PONV) and incidence of prolonged stay in the, post-anesthesia recovery unit (PACU) due to opioid related adverse effects. RESULTS: Given the small sample of minority population, we focused our study on 219 white children. Significant morphine effect was observed in girls but not boys for PONV (P = 0.001) and prolonged PACU stay due to PONV (P = 0.010). Although the overall incidence of RD is not statistically different between boys and girls, the incidence of RD (52% vs 32%) and PONV (43% vs 4%) tended to be more in white girls than boys as the total perioperative morphine dose increased to 0.3 mg/kg or more. CONCLUSIONS: This study demonstrates that child's sex influences morphine's dose response and adverse effects. White girls have an unequal burden with higher incidences of PONV, RD, and prolonged PACU stays following tonsillectomy from PONV and RD as total morphine doses are increased. PMID- 25521774 TI - Comparison of Stresses Generated within the Supporting Structures of Mandibular Second Molars Restored with Different Crown Materials: 3-D Finite Element Analysis (FEA). AB - PURPOSE: This study compares the FEA-calculated stresses generated within the supporting periodontal structure of a mandibular second molar restored with a full ceramic crown and with a porcelain-fused-to-metal (PFM) crown, each resisting occlusal forces acting at different inclinations. MATERIALS AND METHODS: Three-dimensional finite element models representing the crown of an unrestored mandibular second molar and two relevant restoration designs were constructed. Two designs represented the molar restored with a full ceramic crown and with a PFM crown, each cemented with the same resin cement. Occlusion was assumed at three contact areas, which equally shared a 100 N force. The analysis was carried out for forces located in the bucco-axial-lingual plane at five inclinations, 0, 22.5 degrees , 45 degrees , 67.5 degrees , and 90 degrees , measured from the axial direction of the tooth. The magnitudes and sites of the maximum equivalent stress (MES) generated within the supporting periodontium of each analyzed model were collected. RESULTS: Generally, there were no significant differences in the site and magnitude of MES in the regions of the supporting structure for the analyzed models. The MES was located at the tooth periodontal ligament (PDL) bifurcation area and distal root apex, crestal bone at the junction between cortical and cancellous bone, and the distal wall of the mesial root socket of cancellous bone. The highest stresses corresponded to a horizontal load, followed by the axial load in the PDL and cortical zones. The results show opposite observations for the cancellous bone. The lowest stresses were generated under a load inclination between 22.5 degrees and 45 degrees . CONCLUSION: Considering the stresses generated within the supporting structures, the present work validates, by calculation, the proposed clinical use of either a full ceramic crown or a PFM crown as a restoration for mandibular second molars. PMID- 25521776 TI - Multimodal Surgical Guidance during Sentinel Node Biopsy for Melanoma: Combined Gamma Tracing and Fluorescence Imaging of the Sentinel Node through Use of the Hybrid Tracer Indocyanine Green-(99m)Tc-Nanocolloid. AB - Purpose To evaluate the hybrid approach in a large population of patients with melanoma in the head and neck, on the trunk, or on an extremity who were scheduled for sentinel node (SN) biopsy. Materials and Methods This prospective study was approved by the institutional review board. Between March 2010 and March 2013, 104 patients with a melanoma, including 48 women (average age, 54.3 years; range, 18.5-87.4 years) and 56 men (average age, 55.2 years; range, 22.4 77.4 years) (P = .76) were enrolled after obtaining written informed consent. Following intradermal hybrid tracer administration, lymphoscintigraphy and single photon emission computed tomography/computed tomography were performed. Blue dye was intradermally injected prior to the start of the surgical operation (excluding patients with a facial melanoma). Intraoperatively, SNs were initially pursued by using gamma tracing followed by fluorescence imaging (FI) and, when applicable, blue-dye detection. A portable gamma camera was used to confirm SN removal. Collected data included number and location of the preoperatively and intraoperatively identified SNs and the intraoperative number of SNs that were radioactive, fluorescent, and blue. A two-sample test for equality of proportions was performed to evaluate differences in intraoperative SN visualization through FI and blue-dye detection. Results Preoperative imaging revealed 2.4 SNs (range, 1-6) per patient. Intraoperatively, 93.8% (286 of 305) of the SNs were radioactive, 96.7% (295 of 305) of the SNs were fluorescent, while only 61.7% (116 of 188) of the SNs stained blue (P < .0001). FI was of value for identification of near-injection-site SNs (two patients), SNs located in complex anatomic areas (head and neck [28 patients]), and SNs that failed to accumulate blue dye (19 patients). Conclusion The hybrid tracer enables both preoperative SN mapping and intraoperative SN identification in melanoma patients. In the setup of this study, optical identification of the SNs through the fluorescent signature of the hybrid tracer was superior compared with blue dye-based SN visualization. PMID- 25521775 TI - Fragment based group QSAR and molecular dynamics mechanistic studies on arylthioindole derivatives targeting the alpha-beta interfacial site of human tubulin. AB - BACKGROUND: A number of microtubule disassembly blocking agents and inhibitors of tubulin polymerization have been elements of great interest in anti-cancer therapy, some of them even entering into the clinical trials. One such class of tubulin assembly inhibitors is of arylthioindole derivatives which results in effective microtubule disorganization responsible for cell apoptosis by interacting with the colchicine binding site of the beta-unit of tubulin close to the interface with the alpha unit. We modelled the human tubulin beta unit (chain D) protein and performed docking studies to elucidate the detailed binding mode of actions associated with their inhibition. The activity enhancing structural aspects were evaluated using a fragment-based Group QSAR (G-QSAR) model and was validated statistically to determine its robustness. A combinatorial library was generated keeping the arylthioindole moiety as the template and their activities were predicted. RESULTS: The G-QSAR model obtained was statistically significant with r2 value of 0.85, cross validated correlation coefficient q2 value of 0.71 and pred_r2 (r2 value for test set) value of 0.89. A high F test value of 65.76 suggests robustness of the model. Screening of the combinatorial library on the basis of predicted activity values yielded two compounds HPI (predicted pIC50 = 6.042) and MSI (predicted pIC50 = 6.001) whose interactions with the D chain of modelled human tubulin protein were evaluated in detail. A toxicity evaluation resulted in MSI being less toxic in comparison to HPI. CONCLUSIONS: The study provides an insight into the crucial structural requirements and the necessary chemical substitutions required for the arylthioindole moiety to exhibit enhanced inhibitory activity against human tubulin. The two reported compounds HPI and MSI showed promising anti cancer activities and thus can be considered as potent leads against cancer. The toxicity evaluation of these compounds suggests that MSI is a promising therapeutic candidate. This study provided another stepping stone in the direction of evaluating tubulin inhibition and microtubule disassembly degeneration as viable targets for development of novel therapeutics against cancer. PMID- 25521777 TI - Papillary thyroid cancer: dual-energy spectral CT quantitative parameters for preoperative diagnosis of metastasis to the cervical lymph nodes. AB - PURPOSE: To evaluate the use of dual-energy spectral computed tomographic (CT) quantitative parameters compared with the use of conventional CT imaging features for preoperative diagnosis of metastasis to the cervical lymph nodes in patients with papillary thyroid cancer. MATERIALS AND METHODS: This study was approved by the ethics committee and all patients provided written informed consent. Analyses of quantitative gemstone spectral imaging data and qualitative conventional CT imaging features were independently performed by different groups of radiologists. Excised lymph nodes were located and labeled during surgery according to location on preoperative CT images and were evaluated histopathologically. Single and combined parameters were fitted to simple and multiple logistic regression models, respectively, by means of the generalized estimating equations method. Sensitivity and specificity analyses were performed by using receiver operating characteristic curves and were compared with data from the qualitative analysis. RESULTS: The slope of the spectral Hounsfield unit curve ( lambdaHU slope of the spectral Hounsfield unit curve ), normalized iodine concentration, and normalized effective atomic number measured during both arterial and venous phases were significantly higher in metastatic than in benign lymph nodes. The best single parameter for detection of metastatic lymph nodes was venous phase lambdaHU, with sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 62.0%, 91.1%, 80.6%, 79.7%, and 81.0%, respectively. The best combination of parameters was venous phase lambdaHU slope of the spectral Hounsfield unit curve and arterial phase normalized iodine concentration, with values of 73.0%, 88.4%, 82.9%, 78.0%, and 85.3%, respectively. Compared with qualitative analysis, the venous phase lambdaHU slope of the spectral Hounsfield unit curve showed higher specificity (91.1% vs 83.0%, P < .001) and similar sensitivity (62.0% vs 61.9%, P > .99), and the combined venous phase lambdaHU slope of the spectral Hounsfield unit curve and arterial phase normalized iodine concentration showed higher sensitivity (73.0% vs 61.9%, P < .001) and specificity (88.4% vs 83.0%, P < .001). CONCLUSION: Quantitative assessment with gemstone spectral imaging quantitative parameters showed higher accuracy than qualitative assessment of conventional CT imaging features for preoperative diagnosis of metastatic cervical lymph nodes in patients with papillary thyroid cancer. PMID- 25521779 TI - Heeding the past, leading the future. PMID- 25521778 TI - Probabilistic Air Segmentation and Sparse Regression Estimated Pseudo CT for PET/MR Attenuation Correction. AB - PURPOSE: To develop a positron emission tomography (PET) attenuation correction method for brain PET/magnetic resonance (MR) imaging by estimating pseudo computed tomographic (CT) images from T1-weighted MR and atlas CT images. MATERIALS AND METHODS: In this institutional review board-approved and HIPAA compliant study, PET/MR/CT images were acquired in 20 subjects after obtaining written consent. A probabilistic air segmentation and sparse regression (PASSR) method was developed for pseudo CT estimation. Air segmentation was performed with assistance from a probabilistic air map. For nonair regions, the pseudo CT numbers were estimated via sparse regression by using atlas MR patches. The mean absolute percentage error (MAPE) on PET images was computed as the normalized mean absolute difference in PET signal intensity between a method and the reference standard continuous CT attenuation correction method. Friedman analysis of variance and Wilcoxon matched-pairs tests were performed for statistical comparison of MAPE between the PASSR method and Dixon segmentation, CT segmentation, and population averaged CT atlas (mean atlas) methods. RESULTS: The PASSR method yielded a mean MAPE +/- standard deviation of 2.42% +/- 1.0, 3.28% +/- 0.93, and 2.16% +/- 1.75, respectively, in the whole brain, gray matter, and white matter, which were significantly lower than the Dixon, CT segmentation, and mean atlas values (P < .01). Moreover, 68.0% +/- 16.5, 85.8% +/- 12.9, and 96.0% +/- 2.5 of whole-brain volume had within +/-2%, +/-5%, and +/-10% percentage error by using PASSR, respectively, which was significantly higher than other methods (P < .01). CONCLUSION: PASSR outperformed the Dixon, CT segmentation, and mean atlas methods by reducing PET error owing to attenuation correction. PMID- 25521780 TI - Examining relationship/family planning factors and sexual relationship power among immigrant Latino couples in the United States. AB - The ability to influence partners' actions within an intimate relationship (sexual relationship power [SRP]) is a key concept in achieving optimum family planning (FP) among U.S. Latinos. The purpose of this study was to examine the associations between relationship/FP factors and SRP. The actor-partner interdependence model was used to analyze data for 40 couples. Both men's and women's sexual communications were positively associated with SRP, only women's relationship satisfaction was positively associated with SRP, women's general communication was negatively associated with men's SRP, and men's contraception attitudes were negatively associated with SRP. Couples interventions are needed, which account for SRP and gender differences. These findings provide direction for developing targeted interventions to achieve better FP for Latino couples. PMID- 25521782 TI - Cardiac genetic testing: a single-center pilot study of a Dominican population. AB - The impact of undergoing genetic testing in a Dominican population is not well understood. The objective of this investigation was to evaluate the psychological well-being and perceived cardiac risk among Dominicans who underwent genetic testing. Participants completed a qualitative interview and the Short Form-36 (SF 36) questionnaire after cardiac genetic testing. There were 31 subjects evaluated (mean age 42 +/- 11 years). Participants revealed three common themes: (a) fear of dying prematurely, (b) guilt of possibly passing on a mutation to their children, and (c) fear of having an implantable cardioverter defibrillator (ICD) shock. Physical components of the SF-36 were within normal limits (46.2 +/- 6.6) but elevated for mental components (59.9 +/- 5.3). The quality of life and specific themes results determined in this investigation warrant further research in the Dominican population. PMID- 25521781 TI - "You are not fat, you are hermosa": Mexican caregivers share their perceptions about their role supporting their morbidly obese children. AB - This qualitative study reports the findings from 6 focus groups conducted at a clinic in Southern Mexico with caregivers of morbidly obese children. This study was developed with the purpose of gaining a further understanding of caregivers' perceived role in addressing their children's obesity within the family context and identifying topics that could be considered when providing health care in similar sociocultural environments. We identified that although caregivers acknowledge the role of modifiable factors in obesity prevention and treatment, they held beliefs about determinism in obesity. In addition, diet was the more frequently identified means of reducing the impact of obesity. The importance of role modeling and promoting healthy behaviors in the family context are topics that could be addressed in clinical practice. PMID- 25521783 TI - Rural Latino parents offer preschool children few nutrient-dense snacks: a community-based study in Western Illinois. AB - The aims of this descriptive study were to identify the snacks offered to preschool children by Latino parents living in a rural community, assess the overall healthfulness of those snacks, and measure related psychosocial correlates. Data were collected using Spanish-language questionnaires and interviews completed by 96 parents. Thirty-two percent of snack offerings were nutrient dense. The energy-dense snacks offered most often by the greatest proportion of parents were regular yogurt (17%), whole milk (16%), and fruit drinks (16%); the nutrient-dense snacks offered most often were fresh fruit (43%), low-fat milk (37%), and fruit juice (34%). Two-thirds of parents felt confident about offering healthy snacks, and 67% self-classified in the action stages. The primary barrier to offering healthy snacks was children's refusal to eat these products. These parents would benefit from interventions that teach how to overcome perceived barriers and how to purchase and prepare healthy snacks appealing to preschoolers. PMID- 25521784 TI - Latinos and political advocacy for cancer control in a United States-Mexico border community. AB - Health policy interventions provide powerful tools for addressing health disparities. The Latino community is one of the fastest growing communities in the United States yet is largely underrepresented in government and advocacy efforts. This study includes 42 Latino adults (M age = 45 years) who participated in focus group discussions and completed a brief questionnaire assessing their experiences with political health advocacy. Qualitative analyses revealed participants considered cancer a concern for the Latino community, but there was a lack of familiarity with political advocacy and its role in cancer control. Participants identified structural, practical, cultural, and contextual barriers to engaging in political health advocacy. This article presents a summary of the findings that suggest alternative ways to engage Latinos in cancer control advocacy. PMID- 25521785 TI - The enduring predictive significance of early maternal sensitivity: social and academic competence through age 32 years. AB - This study leveraged data from the Minnesota Longitudinal Study of Risk and Adaptation (N = 243) to investigate the predictive significance of maternal sensitivity during the first 3 years of life for social and academic competence through age 32 years. Structural model comparisons replicated previous findings that early maternal sensitivity predicts social skills and academic achievement through midadolescence in a manner consistent with an enduring effects model of development and extended these findings using heterotypic indicators of social competence (effectiveness of romantic engagement) and academic competence (educational attainment) during adulthood. Although early socioeconomic factors and child gender accounted for the predictive significance of maternal sensitivity for social competence, covariates did not fully account for associations between early sensitivity and academic outcomes. PMID- 25521787 TI - Blogged nursing: analysis of the phenomenon and contextualization in the Spanish setting. AB - Blogging within the health profession has grown in the recent past. This article aims to perform an analysis of the theoretical aspects of blogging, the use by professional nurses and students, benefits for patients, and, finally, an approach to the activities of Spanish nursing blogs. Blogs have great advantages as social communication tools. Immediacy in content update, closeness to information consumers, and compatibility with other Web 2.0 tools are points to be highlighted. Nurses use blogs for education and communication with other health professionals, students, and patients. For patients, therapeutic effects have been demonstrated in using blogging to share their health problems and express their experiential viewpoints. There are about 80 blogs written by Spanish nurses; most of them originated in the period between 2010 and 2012. These blogs are targeted to professionals (59%), patients (20%), or mixed (13%). There is a great heterogeneity in content: informative style (20%), opinion (28%), narrative (9%), experiential (2%), or humorous (2%). Nursing language is present in 15%, research and evidence-based practice in 13%, and protocols, guidelines, and procedures in 11% of them. We propose the need to plan institutional strategies for effective use of Web 2.0 resources as well as the need to unify criteria to provide quality content. PMID- 25521786 TI - Mining soil metagenomes to better understand the evolution of natural product structural diversity: pentangular polyphenols as a case study. AB - Sequence-guided mining of metagenomic libraries provides a means of recovering specific natural product gene clusters of interest from the environment. In this study, we use ketosynthase gene (KS) PCR amplicon sequences (sequence tags) to explore the structural and biosynthetic diversities of pentangular polyphenols (PP). In phylogenetic analyses, eDNA-derived sequence tags often fall between closely related clades that are associated with gene clusters known to encode distinct chemotypes. We show that these common "intermediate" sequence tags are useful for guiding the discovery of not only novel bioactive metabolites but also collections of closely related gene clusters that can provide new insights into the evolution of natural product structural diversity. Gene clusters corresponding to two eDNA-derived KSbeta sequence tags that reside between well defined KSbeta clades associated with the biosynthesis of (C24)-pradimicin and (C26)-xantholipin type metabolites were recovered from archived soil eDNA libraries. Heterologous expression of these gene clusters in Streptomyces albus led to the isolation of three new PPs (compounds 1-3). Calixanthomycin A (1) shows potent antiproliferative activity against HCT-116 cells, whereas arenimycins C (2) and D (3) display potent antibacterial activity. By comparing genotypes and chemotypes across all known PP gene clusters, we define four PP subfamilies, and also observe that the horizontal transfer of PP tailoring genes has likely been restricted to gene clusters that encode closely related chemical structures, suggesting that only a fraction of the "natural product-like" chemical space that can theoretically be encoded by these secondary metabolite tailoring genes has likely been sampled naturally. PMID- 25521788 TI - Using interactive computer simulation for teaching the proper use of personal protective equipment. AB - The use of personal protective equipment is one of the basic infection control precautions in health care. The effectiveness of personal protective equipment is highly dependent on adequate staff training. In this project, a computer simulation program, as a supplement to conventional training approaches, was developed to facilitate the learning of the proper use of personal protective equipment. The simulation program was a Web-based interactive software with user friendly graphical interface for users to practice the use of personal protective equipment usage via drag-and-drop metaphors and respond to questions online. The effectiveness of the computer simulation software was investigated by a controlled study. Fifty healthcare workers were randomly assigned into two groups: one received conventional personal protective equipment training only (control group), whereas the other also received the same conventional training but followed by using the developed simulation program for self-learning (experimental group). Their performance was assessed by personal protective equipment donning and doffing evaluation before and after the training. The results showed that the computer simulation program is able to improve the healthcare workers' understanding and competence in using personal protective equipment. PMID- 25521789 TI - A survey of university students' perceptions of learning management systems in a low-resource setting using a technology acceptance model. AB - Learning management systems have been widely advocated for the support of distance learning. In low-resource settings, the uptake of these systems by students has been mixed. This study aimed to identify, through the use of the Technology Acceptance Model, the individual, organizational, and technological factors that could be influencing the use of learning management systems. A simple quantitative descriptive survey was conducted of nursing and health science students at a university in South Africa as part of their first exposure to a learning management system. A total of 274 respondents (56.7%) completed the survey questionnaire, made up of 213 nursing respondents (87.7%) and 61 health sciences respondents (25%). Overall, the respondents found the learning management system easy to use and useful for learning. There were significant differences between the two groups of respondents, with the respondents from health sciences being both younger and more computer literate. The nursing respondents, who received more support and orientations, reported finding the learning management system more useful. Recommendations are made for training and support to ensure uptake. PMID- 25521790 TI - Hydrodynamic size-based separation and characterization of protein aggregates from total cell lysates. AB - Herein we describe a protocol that uses hollow-fiber flow field-flow fractionation (FFF) coupled with multiangle light scattering (MALS) for hydrodynamic size-based separation and characterization of complex protein aggregates. The fractionation method, which requires 1.5 h to run, was successfully modified from the analysis of protein aggregates, as found in simple protein mixtures, to complex aggregates, as found in total cell lysates. In contrast to other related methods (filter assay, analytical ultracentrifugation, gel electrophoresis and size-exclusion chromatography), hollow-fiber flow FFF coupled with MALS allows a flow-based fractionation of highly purified protein aggregates and simultaneous measurement of their molecular weight, r.m.s. radius and molecular conformation (e.g., round, rod-shaped, compact or relaxed). The polyethersulfone hollow fibers used, which have a 0.8-mm inner diameter, allow separation of as little as 20 MUg of total cell lysates. In addition, the ability to run the samples in different denaturing and nondenaturing buffer allows defining true aggregates from artifacts, which can form during sample preparation. The protocol was set up using Paraquat-induced carbonylation, a model that induces protein aggregation in cultured cells. This technique will advance the biochemical, proteomic and biophysical characterization of molecular weight aggregates associated with protein mutations, as found in many CNS degenerative diseases, or chronic oxidative stress, as found in aging, and chronic metabolic and inflammatory conditions. PMID- 25521791 TI - Antibody-based detection of protein phosphorylation status to track the efficacy of novel therapies using nanogram protein quantities from stem cells and cell lines. AB - This protocol describes a highly reproducible antibody-based method that provides protein level and phosphorylation status information from nanogram quantities of protein cell lysate. Nanocapillary isoelectric focusing (cIEF) combines with UV activated linking chemistry to detect changes in phosphorylation status. As an example application, we describe how to detect changes in response to tyrosine kinase inhibitors (TKIs) in the phosphorylation status of the adaptor protein CrkL, a major substrate of the oncogenic tyrosine kinase BCR-ABL in chronic myeloid leukemia (CML), using highly enriched CML stem cells and mature cell populations in vitro. This protocol provides a 2.5 pg/nl limit of protein detection (<0.2% of a stem cell sample containing <10(4) cells). Additional assays are described for phosphorylated tyrosine 207 (pTyr207)-CrkL and the protein tyrosine phosphatase PTPRC/CD45; these assays were developed using this protocol and applied to CML patient samples. This method is of high throughput, and it can act as a screen for in vitro cancer stem cell response to drugs and novel agents. PMID- 25521793 TI - Biologics, colchicine, corticosteroids, immunosuppressants and interferon-alpha for Neuro-Behcet's Syndrome. AB - BACKGROUND: Neuro-Behcet Syndrome (NBS) is a severe chronic inflammatory vascular disease involving the Central Nervous System (CNS), and it is an invalidating condition with disability and a huge impact on quality of life. Recommendations on treatments for NBS include the use of disease-modifying therapies in general, although they are not supported by a systematic review of the evidence. OBJECTIVES: To assess the benefit and harms of available treatments for NBS, including biologics, colchicine, corticosteroids, immunosuppressants and interferon-alpha. SEARCH METHODS: We searched the following databases up to 30 September 2014: Trials Specialised Register of The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group, CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, ORPHANET, Clinicaltrials.gov and World Health Organization (WHO) International Clinical Trials Registry Portal. SELECTION CRITERIA: Randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective controlled cohort studies were eligible to assess the benefit. Patients over 13 years of age with a diagnosis of NBS. For assessment of harms, open-label extension (OLE), case-control studies, population-based registries, case-series and case-reports were additionally planned to be evaluated. DATA COLLECTION AND ANALYSIS: Selection of studies, data extraction and assessment of risk of bias were planned to be carried out independently by two review authors. Standard methodological procedures expected by The Cochrane Collaboration were followed. We planned to perform standard pair-wise meta-analyses for RCTs, and meta-analyses based on the adjusted estimates using the inverse-variance weighted average method for non-randomised studies (NRSs). We planned to present the main results of the review in a 'Summary of Findings' table using the GRADE approach. MAIN RESULTS: No RCTs, CCTs or controlled cohort studies on the benefit of the treatments for NBS met the inclusion criteria of the review. Only one potentially eligible study was identified, but it did not report sufficient details on the patient characteristics. The author of this study did not provide additional data on request, and therefore it was excluded. Hence, no studies were included in the present review. Since no studies were included in the assessment of benefit, no further search was performed in order to collect data on harms. AUTHORS' CONCLUSIONS: There is no evidence to support or refute the benefit of biologics, colchicine, corticosteroids, immunosuppressants and interferon-alpha for the treatment of patients with NBS. Thus, well-designed multicentre RCTs are needed in order to inform and guide clinical practice. PMID- 25521792 TI - An improved toolbox to unravel the plant cellular machinery by tandem affinity purification of Arabidopsis protein complexes. AB - Tandem affinity purification coupled to mass spectrometry (TAP-MS) is one of the most advanced methods to characterize protein complexes in plants, giving a comprehensive view on the protein-protein interactions (PPIs) of a certain protein of interest (bait). The bait protein is fused to a double affinity tag, which consists of a protein G tag and a streptavidin-binding peptide separated by a very specific protease cleavage site, allowing highly specific protein complex isolation under near-physiological conditions. Implementation of this optimized TAP tag, combined with ultrasensitive MS, means that these experiments can be performed on small amounts (25 mg of total protein) of protein extracts from Arabidopsis cell suspension cultures. It is also possible to use this approach to isolate low abundant protein complexes from Arabidopsis seedlings, thus opening perspectives for the exploration of protein complexes in a plant developmental context. Next to protocols for efficient biomass generation of seedlings (~7.5 months), we provide detailed protocols for TAP (1 d), and for sample preparation and liquid chromatography-tandem MS (LC-MS/MS; ~5 d), either from Arabidopsis seedlings or from cell cultures. For the identification of specific co-purifying proteins, we use an extended protein database and filter against a list of nonspecific proteins on the basis of the occurrence of a co-purified protein among 543 TAP experiments. The value of the provided protocols is illustrated through numerous applications described in recent literature. PMID- 25521795 TI - Multifunctional NaYF4:Yb, Er@mSiO2@Fe3O4-PEG nanoparticles for UCL/MR bioimaging and magnetically targeted drug delivery. AB - A low toxic multifunctional nanoplatform, integrating both mutimodal diagnosis methods and antitumor therapy, is highly desirable to assure its antitumor efficiency. In this work, we show a convenient and adjustable synthesis of multifunctional nanoparticles NaYF4:Yb, Er@mSiO2@Fe3O4-PEG (MFNPs) based on different sizes of up-conversion nanoparticles (UCNPs). With strong up-conversion fluorescence offered by UCNPs, superparamagnetism properties attributed to Fe3O4 nanoparticles and porous structure coming from the mesoporous SiO2 shell, the as obtained MFNPs can be utilized not only as a contrast agent for dual modal up conversion luminescence (UCL)/magnetic resonance (MR) bio-imaging, but can also achieve an effective magnetically targeted antitumor chemotherapy both in vitro and in vivo. Furthermore, the UCL intensity of UCNPs and the magnetic properties of Fe3O4 in the MFNPs were carefully balanced. Silica coating and further PEG modifying can improve the hydrophilicity and biocompatibility of the as synthesized MFNPs, which was confirmed by the in vitro/in vivo biocompatibility and in vivo long-time bio-distributions tests. Those results revealed that the UCNPs based magnetically targeted drug carrier system we synthesized has great promise in the future for multimodal bio-imaging and targeted cancer therapy. PMID- 25521794 TI - Triggering of RNA interference with RNA-RNA, RNA-DNA, and DNA-RNA nanoparticles. AB - Control over cellular delivery of different functionalities and their synchronized activation is a challenging task. We report several RNA and RNA/DNA based nanoparticles designed to conditionally activate the RNA interference in various human cells. These nanoparticles allow precise control over their formulation, stability in blood serum, and activation of multiple functionalities. Importantly, interferon and pro-inflammatory cytokine activation assays indicate the significantly lower responses for DNA nanoparticles compared to the RNA counterparts, suggesting greater potential of these molecules for therapeutic use. PMID- 25521796 TI - Combining cell transplants or gene therapy with deep brain stimulation for Parkinson's disease. AB - Cell transplantation and gene therapy each show promise to enhance the treatment of Parkinson's disease (PD). However, because cell transplantation and gene therapy generally require direct delivery to the central nervous system, clinical trial design involves unique scientific, ethical, and financial concerns related to the invasive nature of the procedure. Typically, such biologics have been tested in PD patients who have not received any neurosurgical intervention. Here, we suggest that PD patients undergoing deep brain stimulation (DBS) device implantation are an ideal patient population for the clinical evaluation of cell transplantation and gene therapy. Randomizing subjects to an experimental group that receives the biologic concurrently with the DBS implantation-or to a control group that receives the DBS treatment alone-has several compelling advantages. First, this study design enables the participation of patients likely to benefit from DBS, many of whom simultaneously meet the inclusion criteria of biologic studies. Second, the need for a sham neurosurgical procedure is eliminated, which may reduce ethical concerns, promote patient recruitment, and enhance the blinding of surgical trials. Third, testing the biologic by "piggybacking" onto an established, reimbursable procedure should reduce the cost of clinical trials, which may allow a greater number of biologics to reach this critical stage of research translation. Finally, this clinical trial design may lead to combinatorial treatment strategies that provide PD patients with more durable control over disabling motor symptoms. By combining neuromodulation with biologics, we may also reveal important treatment paradigms relevant to other diseases of the brain. PMID- 25521797 TI - Management and outcomes of axial isolated distal deep vein thrombosis at North Shore Hospital, New Zealand: a retrospective audit. AB - BACKGROUND: It is standard of care to treat proximal vein deep vein thrombosis (DVT) for a minimum of 3 months. Conversely, management of isolated distal DVT (IDDVT) is controversial, with options including observation and repeat ultrasound scan within 1 week to detect and anticoagulate those with proximal propagation, or anticoagulation for periods of up to 3 months. AIM: The aim was to assess the rates of proximal propagation and venous thromboembolism (VTE) recurrence within 3 months of diagnosis of IDDVT, and to examine how the duration of treatment might influence this. METHODS: Study patients were identified by retrospective audit of data from the North Shore Hospital VTE database. All patients presenting with established axial vein distal DVT from July 2007 to June 2012 were included. A 6-week treatment duration cut-off was used to separate the treatment arms (<6 weeks vs 6 weeks vs >6 weeks), and Fisher's exact or Pearson's Chi-squared tests were used to assess between-group comparisons. RESULTS: Five hundred and seven patients were included in the study, mean age 59.7 years; 53% female. There were three cases of proximal propagation, all occurring in those receiving <6 weeks treatment. There were six VTE recurrences, three in the <6 week and three in the >=6 week treatment groups respectively. Malignancy was the only significant predictor of VTE recurrence (P = 0.001). CONCLUSION: A 6-week duration of anticoagulation appears to be an effective and safe treatment for isolated axial distal DVT, with low rates of VTE recurrence and proximal propagation. PMID- 25521798 TI - In response: incident depression increases medical utilization in Medicaid patients with hypertension. PMID- 25521799 TI - Darapladib for the treatment of cardiovascular disease. AB - Elevated levels of phospholipase A2 have been linked to atherosclerotic plaque progression, instability via promoting inflammation and subsequent acute coronary events. Epidemiological studies have demonstrated the correlation between elevated levels associated phospholipase A2 and cardiovascular events. Therefore, specific inhibition of lipoprotein-associated phospholipase A2 with darapladib has been tested as a therapeutic option for atherosclerosis. The aim of this profile is to review the physiologic aspects of lipoprotein-associated phospholipase A2 and to revisit the clinical evidence of darapladib as therapeutic option for atherosclerosis. PMID- 25521801 TI - The Processing of Surgical Specimens With Forensic Evidence: Lessons Learned From the Boston Marathon Bombings. AB - CONTEXT: Following the Boston Marathon bombings in April 2013, pathology departments at hospitals across Boston, Massachusetts received numerous amputated limbs, as well as other surgical specimens from trauma surgeries. In the absence of clear guidelines, each department faced uncertainties in performing gross examination of these specimens. OBJECTIVE: To develop a protocol for processing surgical specimens with forensic evidence. DESIGN: We collaborated with representatives who knew the practices at 3 major Boston hospitals, the Office of the Chief Medical Examiner of Massachusetts, and a senior team leader for the evidence response team for the Boston, Massachusetts division of the US Federal Bureau of Investigation to construct a protocol for processing specimens with forensic evidence. RESULTS: A simple and robust protocol approved by experts in forensic evidence collection was developed. Important points in this protocol include (1) assigning the task of processing the specimens to one individual or one team of individuals, (2) photographing all specimens before and after washing, (3) obtaining a radiograph of each specimen, and (4) identifying a secure area to store forensic evidence. CONCLUSIONS: When acts of terror occur, protocols provide order and clarification to the processing of surgical specimens. We propose a protocol that provides guidance for pathology departments across the country to handle trauma-related surgical specimens with forensic evidence in an efficient manner to allow optimal patient care and a secure way of gathering forensic evidence. PMID- 25521800 TI - Initial therapy, persistence and regimen change in a cohort of newly treated type 2 diabetes patients. AB - AIMS: The aim was to describe the utilization of antidiabetic agents, in terms of persistence and regimen change, in the management of a cohort of newly treated type 2 diabetes patients and to investigate associated socio-demographic and treatment factors. METHODS: A population-based retrospective cohort study was conducted using the national pharmacy claims database in Ireland. Subjects were analyzed for persistence and regimen change. Cox proportional hazards regression examined associations of socio-demographic and treatment factors on treatment patterns. Hazard ratios (HR) and 95% CIs are presented. RESULTS: A total of 20947 subjects were identified in the study over a 2 year period. Most were initiated on metformin (76%) or sulphonylureas (22%) and 77% were persistent with therapy 12 months after initiation. The likelihood of non-persistence was significantly lower in the youngest (40-49 years) age groups (reference 60-69 years) (HR 1.62, 95% CI 1.42, 1.84) and those on sulphonylureas (HR 1.49, 95% CI 1.36, 1.64). The likelihood of receiving a regimen change was significantly lower in the older (80+ years) age groups (HR 0.63, 95% CI 0.56, 0.71), females (HR 0.91, 95% CI 0.86, 0.95), and those with pre-existing CVD (1 vs. 0 CVD medicines) (HR 0.82, 95% CI 0.74, 0.90), and higher in those on sulphonylureas (HR 1.83, 95% CI 1.73, 1.94). CONCLUSIONS: Type of treatment, pre-existing CVD and demographic factors are shown to be associated with the observed treatment patterns. Guideline recommended agents were widely used on treatment initiation though a substantial minority were not initiated on the recommended first line agent. Use of guideline recommended agents was not as evident during treatment progression. Further optimization of initial and subsequent antidiabetic agent prescribing may be possible. PMID- 25521802 TI - Depletion of Core Needle Biopsy Cellularity and DNA Content as a Result of Vigorous Touch Preparations. AB - CONTEXT: Touch preparations (TP) of core needle biopsies (CNBs) are used at some institutions for on-site assessment of CNB adequacy. In our clinical practice, we have encountered instances in which TPs resulted in substantial depletion of CNB cellularity. OBJECTIVE: To examine the effect of increasingly vigorous TPs on cellularity and DNA content of CNBs. DESIGN: Ex vivo CNBs (n = 56) were performed on resected lung and kidney tumor specimens. For each specimen, CNBs were performed in quadruplicate on tumor and nontumor tissue and subjected to 1 of 4 TP methods: imprint, 1-cm drag, 2-cm drag, or full-slide drag. Overall cellularity in TPs relative to corresponding CNBs was estimated semiquantitatively. DNA was extracted and quantified from 12 TPs and corresponding CNBs. Two cytopathologists performed a blinded diagnostic assessment of Diff-Quik-stained TPs. RESULTS: Cellularity of imprint, 1-cm, 2-cm, and full-slide TPs represented, on average, 19%, 33%, 41%, and 46% of total CNB cellularity, respectively (p = .003). Average DNA content in imprint, 1-cm, and 2 cm TPs was 0.3 MUg (range, 0.1-0.8 MUg), 0.4 MUg (range, 0.1-1 MUg), and 0.6 MUg (range, 0.2-1.3 MUg), respectively, which represented on average 15%, 36%, and 50%, respectively, of total CNB DNA content. Diagnostic accuracy was not inferior for less-extensive TPs, compared with more-extensive TPs. CONCLUSIONS: Vigorous TPs may contain a substantial fraction of CNB cellularity and DNA content, whereas more-limited TPs are less disruptive to CNBs but remain suitable for cytologic assessment. We suggest avoiding excessively forceful TPs and, whenever clinically feasible, obtaining additional samples to ensure sufficient cellularity for potential ancillary studies. PMID- 25521803 TI - Nonspecific reactivity of polyclonal napsin a antibody in mucinous adenocarcinomas of various sites: a word of caution. PMID- 25521804 TI - Prediction of enhanced solvent-induced enantioselectivity for a ring opening with a bifurcating reaction path. AB - Classical molecular dynamics simulations are reported for the deazetisation and ring opening of meso-2,3-difluoro-2,3-dimethyldiazocyclopropane in three solvents: CHCl3, CHFClBr and CH3CH(OH)CF3 (TFIPA). The achiral reactant leads to enantiomeric allene products, and the question addressed in the study is whether either of the chiral, enantiomerically pure solvents can induce significant enantiomeric excess in the products. The direct dynamics calculations use an empirical valence bond potential for the solute, with empirical parameters optimised against M06-2X/cc-pVTZ density functional results. The results reveal that the exothermic N2 loss and ring opening promote transient strong solvent solute interactions within the first ~100 fs of the reaction. Because of the bifurcating reaction path, these interactions occur at time when the "decision" about which enantiomer of the product to form has yet to be made (at least for many of the trajectories). Hence, it is possible in principle that the solvent could exert a larger-than-normal influence on the course of the reaction. In fact, the results reveal no such effect for CHFClBr but do predict that TFIPA should induce 15.2 +/- 2.1% enantiomeric excess. This is roughly an order of magnitude larger than solvent-induced enantiomeric excesses found experimentally in reactions where the conversion of reactant(s) to enantiomeric products occur over separate transition states. PMID- 25521805 TI - Functional materials from cellulose-derived liquid-crystal templates. AB - Cellulose nanocrystals (CNCs), known for more than 50 years, have attracted attention because of their unique properties such as high specific strength and modulus, high surface area, and fascinating optical properties. Just recently, however, their potential in supramolecular templating was identified by making use of their self-assembly behavior in aqueous dispersions in the presence of compatible precursors. The combination of the mesoporosity, photonic properties, and chiral nematic order of the materials, which are available as freestanding films, has led to a significant number of interesting and promising discoveries towards new functional materials. This Review summarizes the use of cellulose derivatives, especially CNCs, as novel templates and gives an overview of the recent developments toward new functional materials. PMID- 25521806 TI - Perinatal maternal feeding with an energy dense diet and/or micronutrient mixture drives offspring fat distribution depending on the sex and growth stage. AB - Maternal nutrition during pregnancy and lactation influences offspring development and health. Novel studies have described the effects on next generation obesity-related features depending on maternal macro- and micro nutrient perinatal feeding. We hypothesized that the maternal obesogenic diet during pregnancy and lactation programs an obese phenotype, while maternal micronutrient supplementation at these stages could partially prevent these features. Thus, the aim was to assess the influence of a perinatal maternal feeding with an obesogenic diet enriched in fat and sucrose and a micronutrient supplementation during pregnancy and lactation on offspring growth and obese phenotypical features during life course. Female Wistar rats were assigned to four dietary groups during pregnancy and lactation: control, control supplemented with micronutrients (choline, betaine, folic acid and vitamin B12 ), high-fat sucrose (HFS) and HFS supplemented. At weaning, the offspring were transferred to a chow diet, and weight and fat mass were measured at weeks 3, 12 and 20. At birth, both male and female offspring from mothers fed the obesogenic diet showed lower body weight (-5 and -6%, respectively), while only female offspring weight decreased by maternal micronutrient supplementation (-5%). During lactation, maternal HFS diet was associated with increased body weight, while micronutrient supplementation protected against body weight gain. Whole body fat mass content increased at weeks 3, 12 and 20 (from 16 to 65%) due to maternal HFS diet. Maternal micronutrient supplementation decreased offspring fat mass content at week 3 (-8%). Male offspring showed higher adiposity than females at weeks 12 and 20. In conclusion, maternal HFS feeding during pregnancy and lactation was associated with a low offspring weight at birth and obese phenotypical features during adult life in a sex- and time-dependent manner. Furthermore, maternal methyl donor supplementation protected against body weight gain in male offspring during lactation and in female offspring also during juvenile period. PMID- 25521807 TI - A graph kernel method for DNA-binding site prediction. AB - BACKGROUND: Protein-DNA interactions play important roles in many biological processes. Computational methods that can accurately predict DNA-binding sites on proteins will greatly expedite research on problems involving protein-DNA interactions. RESULTS: This paper presents a method for predicting DNA-binding sites on protein structures. The method represents protein surface patches using labeled graphs and uses a graph kernel method to calculate the similarities between graphs. A new surface patch is predicted to be interface or non-interface patch based on its similarities to known DNA-binding patches and non-DNA-binding patches. The proposed method achieved high accuracy when tested on a representative set of 146 protein-DNA complexes using leave-one-out cross validation. Then, the method was applied to identify DNA-binding sites on 13 unbound structures of DNA-binding proteins. In each of the unbound structure, the top 1 patch predicted by the proposed method precisely indicated the location of the DNA-binding site. Comparisons with other methods showed that the proposed method was competitive in predicting DNA-binding sites on unbound proteins. CONCLUSIONS: The proposed method uses graphs to encode the feature's distribution in the 3-dimensional (3D) space. Thus, compared with other vector-based methods, it has the advantage of taking into account the spatial distribution of features on the proteins. Using an efficient kernel method to compare graphs the proposed method also avoids the demanding computations required for 3D objects comparison. It provides a competitive method for predicting DNA-binding sites without requiring structure alignment. PMID- 25521808 TI - Treatment adherence and real-life effectiveness of topical therapy in patients with mild or moderate psoriasis: uptake of scientific evidence in clinical practice and dermatologists' preferences for alternative treatment options. AB - AIM: Topical corticosteroids and the vitamin D analogue calcipotriol are the cornerstone of therapy for patients with mild-to-moderate plaque psoriasis. Lack of patients' adherence leads to suboptimal effectiveness of topical therapy in real-life practice. The fixed combination betamethasone/calcipotriol gel is more effective and safe than the administration of single components and may enhance patients' adherence. We aimed at evaluating the pattern of care and dermatologists' expert opinion toward the available topical treatments for the management of mild-to-moderate psoriasis in Italy. METHODS: We enrolled 242 Italian dermatologists and collected information related to their practice pattern and opinion toward available topical treatments with a face-to-face structured interview. We evaluated dermatologists' ratings of therapy with 16 items tapping their opinion toward the relevance and satisfaction toward 8 therapy attributes in clinical practices which tapped aspects of real-life effectiveness, adherence promotion, toxicity, convenience of use. Ratings occurred along a 10-point scale. We compared single-attribute and weighted overall therapy ratings across alternative treatment options with random intercept linear models to account for ratings clustering within dermatologists. RESULTS: There was a wide variation in practice patterns: 1/3 of dermatologist had seen more than 30 patients with psoriasis while around 1/4 had seen less than 10 patients. The fixed combination betamethasone/calcipotriol gel was considered superior to monotherapies in all the eight attributes considered which tapped aspects of real-life effectiveness, adherence promotion, toxicity, convenience of use. CONCLUSION: Participant dermatologists' strongly preferred the fixed betamethasone/calcipotriol combination gel over both the fixed combination ointment formulation and corticosteroid or vitamin D analogues monotherapies. Such findings are in line with evidence from randomized controlled trials and few observational studies demonstrating superior clinical outcomes, quality of life, tolerability and lower risk of side effect in patients treated with the fixed combination of betamethasone/calcipotriol gel. PMID- 25521809 TI - Assessing consciousness with auditory event-related potential during coma recovery: a case study. AB - To observe changes in mismatch negativity (MMN) and P300 in a patient transitioning from a vegetative state (VS) to a minimally conscious state (MCS). One patient with intracerebral hemorrhage and an 8-month disease course was evaluated as being in the VS using the Coma Recovery Scale-Revised. Two weeks after the patient was admitted to the hospital, another evaluation was performed, and the patient was determined to be in an MCS. Using the Oddball paradigm, pure tone and name stimuli were presented to the patient to study event-related potentials (ERPs). A 15-week clinical follow-up was carried out, and four ERP examinations were performed at 2 days and 2, 6, and 15 weeks after admission. One healthy individual was assessed as a control participant. MMN and P300 were elicited in all four ERP examinations. MMN and P300 may occur earlier than believed in patients in persistent VS and MCS; their predictive values for prognosis need to be further confirmed by follow-up studies on a large clinical sample. PMID- 25521810 TI - Verification and validation of bioinformatics software without a gold standard: a case study of BWA and Bowtie. AB - BACKGROUND: Bioinformatics software quality assurance is essential in genomic medicine. Systematic verification and validation of bioinformatics software is difficult because it is often not possible to obtain a realistic "gold standard" for systematic evaluation. Here we apply a technique that originates from the software testing literature, namely Metamorphic Testing (MT), to systematically test three widely used short-read sequence alignment programs. RESULTS: MT alleviates the problems associated with the lack of gold standard by checking that the results from multiple executions of a program satisfy a set of expected or desirable properties that can be derived from the software specification or user expectations. We tested BWA, Bowtie and Bowtie2 using simulated data and one HapMap dataset. It is interesting to observe that multiple executions of the same aligner using slightly modified input FASTQ sequence file, such as after randomly re-ordering of the reads, may affect alignment results. Furthermore, we found that the list of variant calls can be affected unless strict quality control is applied during variant calling. CONCLUSION: Thorough testing of bioinformatics software is important in delivering clinical genomic medicine. This paper demonstrates a different framework to test a program that involves checking its properties, thus greatly expanding the number and repertoire of test cases we can apply in practice. PMID- 25521811 TI - Consumer attitudes towards and satisfaction with emergency contraception counselling: experience from clinic and retail pharmacy settings. AB - OBJECTIVE: To collectively assess consumer attitudes towards and satisfaction with emergency contraception (EC) counselling by student pharmacists in two different locations: an academic healthcare clinic and a retail pharmacy. METHODS: EC counselling was provided by trained student pharmacists utilizing a standardized education toolkit. Participants were asked to rate the counselling at the end of the knowledge survey. In addition to descriptive statistics, we compared the self-reported attitudes and satisfaction with the counselling between the two sites. KEY FINDINGS: The majority of participants from both settings rated 'strongly agree' on the attitude and satisfaction statements for the EC counselling. Participants from the clinic setting rated higher in two of the four statements than the participants from the retail setting. CONCLUSIONS: Participants had positive attitudes towards and were highly satisfied with the EC counselling in both settings. EC counselling should be encouraged in practice settings. PMID- 25521813 TI - Acid-base strength and acidochromism of some dimethylamino-azinium iodides. An integrated experimental and theoretical study. AB - The effects of pH on the spectral properties of stilbazolium salts bearing dimethylamino substituents, namely, trans isomers of the iodides of the dipolar E [2-(4-dimethylamino)styryl]-1-methylpyridinium, its branched quadrupolar analogue E,E-[2,6-di-(p-dimethylamino)styryl]-1-methylpyridinium, and three analogues, chosen to investigate the effects of the stronger quinolinium acceptor, the longer butadiene pi bridge, or both, were investigated through a joint experimental and computational approach. A noticeable acidochromism of the absorption spectra (interesting for applications) was observed, with the basic and protonated species giving intensely colored and transparent solutions, respectively. The acid-base equilibrium constants for the protonation of the dimethylamino group in the ground state (pKa) were experimentally derived. Theoretical calculations according to the thermodynamic Born-Haber cycle provided pKa values in good agreement with the experimental values. The very low fluorescence yield did not allow a direct investigation of the changes in the acid-base properties in the excited state (pKa*) by fluorimetric titrations. Their values were derived by quantum-mechanical calculations and estimated experimentally on the basis of the Forster cycle. PMID- 25521812 TI - Centrifugal microfluidic platform for ultrasensitive detection of botulinum toxin. AB - We present an innovative centrifugal microfluidic immunoassay platform (SpinDx) to address the urgent biodefense and public health need for ultrasensitive point of-care/incident detection of botulinum toxin. The simple, sample-to-answer centrifugal microfluidic immunoassay approach is based on binding of toxins to antibody-laden capture particles followed by sedimentation of the particles through a density-media in a microfluidic disk and quantification by laser induced fluorescence. A blind, head-to-head comparison study of SpinDx versus the gold-standard mouse bioassay demonstrates 100-fold improvement in sensitivity (limit of detection = 0.09 pg/mL), while achieving total sample-to-answer time of <30 min with 2-MUL required volume of the unprocessed sample. We further demonstrate quantification of botulinum toxin in both exogeneous (human blood and serum spiked with toxins) and endogeneous (serum from mice intoxicated via oral, intranasal, and intravenous routes) samples. SpinDx can analyze, without any sample preparation, multiple sample types including whole blood, serum, and food. It is readily expandable to additional analytes as the assay reagents (i.e., the capture beads and detection antibodies) are disconnected from the disk architecture and the reader, facilitating rapid development of new assays. SpinDx can also serve as a general-purpose immunoassay platform applicable to diagnosis of other conditions and diseases. PMID- 25521815 TI - A statistical model of intra-chromosome contact maps. AB - A statistical model describing a fine structure of the intra-chromosome maps obtained by a genome-wide chromosome conformation capture method (Hi-C) is proposed. The model combines hierarchical chain folding with a quenched heteropolymer structure of primary chromatin sequences. It is conjectured that the observed Hi-C maps are statistical averages over many different ways of hierarchical genome folding. It is shown that the existence of a quenched primary structure coupled with hierarchical folding induces a full range of features observed in experimental Hi-C maps: hierarchical elements, chess-board intermittency and large-scale compartmentalization. PMID- 25521814 TI - ZTE imaging with long-T2 suppression. AB - Three-dimensional radial zero echo time (ZTE) imaging enables efficient direct MRI of tissues with rapid transverse relaxation. Yet, the feature of capturing signals with a wide range of T2 and T2 * values is accompanied by a lack of contrast between the corresponding tissues. In particular, the targeted short-T2 tissues may not be easily identified, and various approaches have been proposed to generate T2 contrast by reducing the long-T2 signal of water and/or fat. The aim of this work was to provide efficient long-T2 suppression for selective direct MRI of short-T2 tissues using the ZTE technique. For magnetization preparation, suppression pulses for water and fat were designed to provide both good T2 selectivity and off-resonance performance. To obtain high efficiency at short TRs, the pulses were applied in a segmented sequence scheme with minimized timing overhead, thus leading to a quasi-steady state of magnetization. The sequence timing was adjusted for optimal tissue contrast in musculoskeletal applications by means of simulations and experiments, incorporating both T2 and T1 of the involved tissues. The developed technique was employed for imaging of a lamb joint sample at 4.7 T. ZTE images were obtained with effective suppression of signals from tissues with long-T2 water, such as muscle or articular spaces, and fat. Hence, primarily short-T2 tissues were visible, such as bone and tendon. The MR image intensity of bone showed strong similarity with bone density imaged with micro-computed tomography. PMID- 25521816 TI - Cardiogel: a nano-matrix scaffold with potential application in cardiac regeneration using mesenchymal stem cells. AB - 3-Dimensional conditions for the culture of Bone Marrow-derived Stromal/Stem Cells (BMSCs) can be generated with scaffolds of biological origin. Cardiogel, a cardiac fibroblast-derived Extracellular Matrix (ECM) has been previously shown to promote cardiomyogenic differentiation of BMSCs and provide protection against oxidative stress. To determine the matrix composition and identify significant proteins in cardiogel, we investigated the differences in the composition of this nanomatrix and a BMSC-derived ECM scaffold, termed as 'mesogel'. An optimized protocol was developed that resulted in efficient decellularization while providing the maximum yield of ECM. The proteins were sequentially solubilized using acetic acid, Sodium Dodecyl Sulfate (SDS) and Dithiothreitol (DTT). These proteins were then analyzed using surfactant-assisted in-solution digestion followed by nano-liquid chromatography and tandem mass spectrometry (nLC-MS/MS). The results of these analyses revealed significant differences in their respective compositions and 17 significant ECM/matricellular proteins were differentially identified between cardiogel and mesogel. We observed that cardiogel also promoted cell proliferation, adhesion and migration while enhancing cardiomyogenic differentiation and angiogenesis. In conclusion, we developed a reproducible method for efficient extraction and solubilization of in vitro cultured cell-derived extracellular matrix. We report several important proteins differentially identified between cardiogel and mesogel, which can explain the biological properties of cardiogel. We also demonstrated the cardiomyogenic differentiation and angiogenic potential of cardiogel even in the absence of any external growth factors. The transplantation of Bone Marrow derived Stromal/Stem Cells (BMSCs) cultured on such a nanomatrix has potential applications in regenerative therapy for Myocardial Infarction (MI). PMID- 25521818 TI - Liquid chromatography with diode array detection combined with spectral deconvolution for the analysis of some diterpene esters in Arabica coffee brew. AB - In this manuscript, the separation of kahweol and cafestol esters from Arabica coffee brews was investigated using liquid chromatography with a diode array detector. When detected in conjunction, cafestol, and kahweol esters were eluted together, but, after optimization, the kahweol esters could be selectively detected by setting the wavelength at 290 nm to allow their quantification. Such an approach was not possible for the cafestol esters, and spectral deconvolution was used to obtain deconvoluted chromatograms. In each of those chromatograms, the four esters were baseline separated allowing for the quantification of the eight targeted compounds. Because kahweol esters could be quantified either using the chromatogram obtained by setting the wavelength at 290 nm or using the deconvoluted chromatogram, those compounds were used to compare the analytical performances. Slightly better limits of detection were obtained using the deconvoluted chromatogram. Identical concentrations were found in a real sample with both approaches. The peak areas in the deconvoluted chromatograms were repeatable (intraday repeatability of 0.8%, interday repeatability of 1.0%). This work demonstrates the accuracy of spectral deconvolution when using liquid chromatography to mathematically separate coeluting compounds using the full spectra recorded by a diode array detector. PMID- 25521817 TI - Design and characterization of novel recombinant listeriolysin O-protamine fusion proteins for enhanced gene delivery. AB - To improve the efficiency of gene delivery for effective gene therapy, it is essential that the vector carries functional components that can promote overcoming barriers in various steps leading to the transport of DNA from extracellular to ultimately nuclear compartment. In this study, we designed genetically engineered fusion proteins as a platform to incorporate multiple functionalities in one chimeric protein. Prototypes of such a chimera tested here contain two domains: one that binds to DNA; the other that can facilitate endosomal escape of DNA. The fusion proteins are composed of listeriolysin O (LLO), the endosomolytic pore-forming protein from Listeria monocytogenes, and a 22 amino acid sequence of the DNA-condensing polypeptide protamine (PN), singly or as a pair: LLO-PN and LLO-PNPN. We demonstrate dramatic enhancement of the gene delivery efficiency of protamine-condensed DNA upon incorporation of a small amount of LLO-PN fusion protein and further improvement with LLO-PNPN in vitro using cultured cells. Additionally, the association of anionic liposomes with cationic LLO-PNPN/protamine/DNA complexes, yielding a net negative surface charge, resulted in better in vitro transfection efficiency in the presence of serum. An initial, small set of data in mice indicated that the observed enhancement in gene expression could also be applicable to in vivo gene delivery. This study suggests that incorporation of a recombinant fusion protein with multiple functional components, such as LLO-protamine fusion protein, in a nonviral vector is a promising strategy for various nonviral gene delivery systems. PMID- 25521821 TI - Ten-year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan. AB - Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries. PMID- 25521822 TI - Altered faecal and mucosal microbial composition in post-infectious irritable bowel syndrome patients correlates with mucosal lymphocyte phenotypes and psychological distress. AB - BACKGROUND: A subset of irritable bowel syndrome (IBS) patients, denoted post infectious IBS (PI-IBS), develop symptoms after an enteric infection. Bacterial dysbiosis and mucosal inflammation have been proposed to be involved in the pathophysiology of this entity. AIM: To characterise the mucosal and faecal microbiota in PI-IBS, general IBS and healthy controls, and to investigate associations between the microbiota and the mucosal immune system. METHODS: Mucosal biopsies and faeces were collected from 13 PI-IBS patients, 19 general IBS patients and 16 healthy controls. Global bacterial composition was determined by generating 16S rRNA amplicons that were examined by phylogenetic microarray hybridisation, principal component and redundancy analysis. We correlated previously reported lymphocyte proportions with the microbiota. RESULTS: Faecal microbiota composition of PI-IBS patients differed significantly from both general IBS patients and healthy controls (P < 0.02). Both mucosal (P < 0.01) and faecal (P = 0.05) microbial diversity were reduced in PI-IBS compared to healthy controls. In the intraepithelial lymphocytes the previously published proportion of CD8(+) CD45RA(+) was negatively correlated with mucosal microbial diversity (P < 0.005). The previously published number of lamina propria lymphocytes was negatively correlated with mucosal microbial diversity (P < 0.05). Faecal microbial diversity was significantly negatively correlated with the Hospital Anxiety and Depression scale (P < 0.05). CONCLUSIONS: We present data that distinguishes the intestinal microbiota of PI-IBS patients from that of both general IBS patients and HC. The microbial composition is significantly associated with the HADs score and alterations in lymphocyte subsets proportions. PMID- 25521820 TI - Detection of venom after antivenom is not associated with persistent coagulopathy in a prospective cohort of Russell's viper (Daboia russelii) envenomings. AB - BACKGROUND: Venom recurrence or persistence in the circulation after antivenom treatment has been documented many times in viper envenoming. However, it has not been associated with clinical recurrence for many snakes, including Russell's viper (Daboia spp.). We compare the recovery of coagulopathy to the recurrence or persistence of venom in patients with Russell's viper envenoming. METHODOLOGY/PRINCIPAL FINDINGS: The study included patients with Russell's viper (D. russelii) envenoming presenting over a 30 month period who had Russell's viper venom detected by enzyme immunoassay. Demographics, information on the snake bite, and clinical effects were collected for all patients. All patients had serum collected for venom specific enzyme immunoassay and citrate plasma to measure fibrinogen levels and prothrombin time (international normalised ratio; INR). Patients with venom recurrence/persistence were compared to those with no detectable recurrence of venom. There were 55 patients with confirmed Russell's viper envenoming and coagulopathy with low fibrinogen concentrations: 31 with venom recurrence/persistence, and 24 with no venom detected post-antivenom. Fibrinogen concentrations increased and INR decreased after antivenom in both the recurrence and non-recurrence patients. Clinical features, laboratory parameters, antivenom dose and length of hospital were similar for both groups. Pre-antivenom venom concentrations were higher in patients with venom recurrence/persistence with a median venom concentration of 385 ng/mL (16-1521 ng/mL) compared to 128 ng/mL (14-1492 ng/mL; p = 0.008). CONCLUSION: Recurrence of Russell's viper venom was not associated with a recurrence of coagulopathy and length of hospital stay. Further work is required to determine if the detection of venom recurrence is due to the venom specific enzyme immunoassay detecting both venom-antivenom complexes as well as free venom. PMID- 25521819 TI - Tumor antigens as proteogenomic biomarkers in invasive ductal carcinomas. AB - BACKGROUND: The majority of genetic biomarkers for human cancers are defined by statistical screening of high-throughput genomics data. While a large number of genetic biomarkers have been proposed for diagnostic and prognostic applications, only a small number have been applied in the clinic. Similarly, the use of proteomics methods for the discovery of cancer biomarkers is increasing. The emerging field of proteogenomics seeks to enrich the value of genomics and proteomics approaches by studying the intersection of genomics and proteomics data. This task is challenging due to the complex nature of transcriptional and translation regulatory mechanisms and the disparities between genomic and proteomic data from the same samples. In this study, we have examined tumor antigens as potential biomarkers for breast cancer using genomics and proteomics data from previously reported laser capture microdissected ER+ tumor samples. RESULTS: We applied proteogenomic analyses to study the genetic aberrations of 32 tumor antigens determined in the proteomic data. We found that tumor antigens that are aberrantly expressed at the genetic level and expressed at the protein level, are likely involved in perturbing pathways directly linked to the hallmarks of cancer. The results found by proteogenomic analysis of the 32 tumor antigens studied here, capture largely the same pathway irregularities as those elucidated from large-scale screening of genomics analyses, where several thousands of genes are often found to be perturbed. CONCLUSION: Tumor antigens are a group of proteins recognized by the cells of the immune system. Specifically, they are recognized in tumor cells where they are present in larger than usual amounts, or are physiochemically altered to a degree at which they no longer resemble native human proteins. This proteogenomic analysis of 32 tumor antigens suggests that tumor antigens have the potential to be highly specific biomarkers for different cancers. PMID- 25521823 TI - Combined experimental and computational investigations of rhodium-catalysed C - H functionalisation of pyrazoles with alkenes. AB - Detailed experimental and computational studies have been carried out on the oxidative coupling of the alkenes C2 H3 Y (Y=CO2 Me (a), Ph (b), C(O)Me (c)) with 3-aryl-5-R-pyrazoles (R=Me (1 a), Ph (1 b), CF3 (1 c)) using a [Rh(MeCN)3 Cp*][PF6 ]2 /Cu(OAc)2 ?H2 O catalyst system. In the reaction of methyl acrylate with 1 a, up to five products (2 aa-6 aa) were formed, including the trans monovinyl product, either complexed within a novel Cu(I) dimer (2 aa) or as the free species (3 aa), and a divinyl species (6 aa); both 3 aa and 6 aa underwent cyclisation by an aza-Michael reaction to give fused heterocycles 4 aa and 5 aa, respectively. With styrene, only trans mono- and divinylation products were observed, whereas with methyl vinyl ketone, a stronger Michael acceptor, only cyclised oxidative coupling products were formed. Density functional theory calculations were performed to characterise the different migratory insertion and beta-H transfer steps implicated in the reactions of 1 a with methyl acrylate and styrene. The calculations showed a clear kinetic preference for 2,1-insertion and the formation of trans vinyl products, consistent with the experimental results. PMID- 25521824 TI - Effects of a seven day overload-period of high-intensity training on performance and physiology of competitive cyclists. AB - OBJECTIVES: Competitive endurance athletes commonly undertake periods of overload training in the weeks prior to major competitions. This investigation examined the effects of two seven-day high-intensity overload training regimes (HIT) on performance and physiological characteristics of competitive cyclists. DESIGN: The study was a matched groups, controlled trial. METHODS: Twenty-eight male cyclists (mean +/- SD, Age: 33+/-10 years, Mass 74+/-7 kg, VO2 peak 4.7+/-0.5 L.min-1) were assigned to a control group or one of two training groups for seven consecutive days of HIT. Before and after training cyclists completed an ergometer based incremental exercise test and a 20-km time-trial. The HIT sessions were ~120 minutes in duration and consisted of matched volumes of 5, 10 and 20 second (short) or 15, 30 and 45 second (long) maximal intensity efforts. RESULTS: Both the short and long HIT regimes led to significant (p<0.05) gains in time trial performance compared to the control group. Relative to the control group, the mean changes (+/-90% confidence limits) in time-trial power were 8.2%+/-3.8% and 10.4%+/-4.3% for the short and long HIT regimes respectively; corresponding increases in peak power in the incremental test were 5.5%+/-2.7% and 9.5%+/-2.5%. Both HIT (short vs long) interventions led to non-significant (p>0.05) increases (mean +/- SD) in VO2 peak (2.3%+/-4.7% vs 3.5%+/-6.2%), lactate threshold power (3.6%+/-3.5% vs 2.9%+/-5.3%) and gross efficiency (3.2%+/ 2.4% vs 5.1%+/-3.9%) with only small differences between HIT regimes. CONCLUSIONS: Seven days of overload HIT induces substantial enhancements in time trial performance despite non-significant increases in physiological measures with competitive cyclists. PMID- 25521825 TI - Differentiation of prostate cancer from normal tissue in radical prostatectomy specimens by desorption electrospray ionization and touch spray ionization mass spectrometry. AB - Radical prostatectomy is a common treatment option for prostate cancer before it has spread beyond the prostate. Examination for surgical margins is performed post-operatively with positive margins reported to occur in 6.5-32% of cases. Rapid identification of cancerous tissue during surgery could improve surgical resection. Desorption electrospray ionization (DESI) is an ambient ionization method which produces mass spectra dominated by lipid signals directly from prostate tissue. With the use of multivariate statistics, these mass spectra can be used to differentiate cancerous and normal tissue. The method was applied to 100 samples from 12 human patients to create a training set of MS data. The quality of the discrimination achieved was evaluated using principal component analysis - linear discriminant analysis (PCA-LDA) and confirmed by histopathology. Cross validation (PCA-LDA) showed >95% accuracy. An even faster and more convenient method, touch spray (TS) mass spectrometry, not previously tested to differentiate diseased tissue, was also evaluated by building a similar MS data base characteristic of tumor and normal tissue. An independent set of 70 non-targeted biopsies from six patients was then used to record lipid profile data resulting in 110 data points for an evaluation dataset for TS-MS. This method gave prediction success rates measured against histopathology of 93%. These results suggest that DESI and TS could be useful in differentiating tumor and normal prostate tissue at surgical margins and that these methods should be evaluated intra-operatively. PMID- 25521826 TI - Current resources for evidence-based practice, January/February 2015. PMID- 25521827 TI - Intractable erosive lichen planus treated successfully with rituximab. PMID- 25521828 TI - Erbin interacts with c-Cbl and promotes tumourigenesis and tumour growth in colorectal cancer by preventing c-Cbl-mediated ubiquitination and down-regulation of EGFR. AB - The epidermal growth factor receptor (EGFR) is implicated in many types of cancer, including colorectal cancer (CRC), and has become one of the most common candidates for targeted therapy. Here, we found that Erbin, a member of the leucine-rich repeat and PDZ domain (LAP) family, plays a key role in EGFR signalling. Erbin inhibited EGFR ubiquitination and stabilized the EGFR protein by interacting with c-Cbl. Moreover, the PDZ domain of Erbin was critical for the interaction between Erbin and c-Cbl and EGFR ubiquitination. Interestingly, Erbin expression was elevated in tumour samples from CRC patients, increased in advanced clinical stage disease and correlated with EGFR expression. In vivo studies using mouse xenograft models of CRC showed that Erbin promotes tumour growth, and that the effects of Erbin on tumour growth are mainly related to the regulatory effects of Erbin on EGFR. The azoxymethane (AOM)-induced colon carcinogenesis model in Erbin(DeltaC) (/) (DeltaC) mice, with the PDZ domain of Erbin deleted, demonstrated that the PDZ domain of Erbin and its regulation of EGFR signalling are necessary for the tumourigenesis and tumour growth of CRC. We found that Erbin promotes tumourigenesis and tumour growth in CRC by stabilizing EGFR. Our study sheds light on developing Erbin, especially its PDZ domain, as a potential target for CRC treatment. PMID- 25521829 TI - Midline approach to pediatric nasofrontal dermoid cysts. AB - IMPORTANCE: To highlight the advantages of the vertical midline incision in providing satisfactory cosmesis with complete excision of pediatric nasofrontal dermoid cysts. OBSERVATIONS: Retrospective case series of nasofrontal dermoid cysts in 4 patients treated at a single tertiary medical center from June 1, 2010, through July 31, 2012. The mean age at surgery was 2.5 years. The anatomical location of the nasofrontal dermoid cysts differed: (1) supratip extending through the upper lateral cartilages to the cartilaginous septum, (2) upper dorsum and subcutaneous tissue, (3) tip and supratip extending deep to the nasal bones with involvement of the anterior cranial fossae and dura, and (4) nasal tip extending deep to the level of the rhinion and involving the upper lateral cartilages and below the left medial canthus. Preoperative imaging was performed on all patients. There was one case of intracranial extension. All patients underwent surgical excision with the vertical midline incision. Nasal reconstruction was performed with local soft-tissue flaps (1 patient), regenerative tissue matrix (2 patients), and bone dust pate (1 patient). The patient with intracranial involvement also underwent a frontal craniotomy. All lesions were histologically confirmed as dermoid cysts. Mean follow-up was 1.5 years. There were no complications or recurrences. All patients had cosmetically acceptable scars. CONCLUSIONS AND RELEVANCE: A vertical midline incision with modifications to excise involved skin provides a satisfactory and cosmetically sound approach to congenital lesions of the nasofrontal region. It affords adequate exposure for complete excision and reconstruction. A multidisciplinary team consisting of a neurosurgeon, facial plastic surgeon, and pediatric otolaryngologist is needed to optimize outcomes. PMID- 25521830 TI - Analog computing using reflective plasmonic metasurfaces. AB - Motivated by the recent renewed interest in compact analog computing using light and metasurfaces ( Silva, A. et al. Science 2014 , 343, 160 - 163), we suggest a practical approach to its realization that involves reflective metasurfaces consisting of arrayed gold nanobricks atop a subwavelength-thin dielectric spacer and optically thick gold film, a configuration that supports gap-surface plasmon resonances. Using well-established numerical routines, we demonstrate that these metasurfaces enable independent control of the light phase and amplitude, and design differentiator and integrator metasurfaces featuring realistic system parameters. Proof-of-principle experiments are reported along with the successful realization of a high-quality poor-man's integrator metasurface operating at the wavelength of 800 nm. PMID- 25521831 TI - Gestational weight gain according to Institute of Medicine recommendations in relation to infant size and body composition. AB - BACKGROUND: Intrauterine life may be a critical period for programming childhood obesity; however, there is insufficient knowledge concerning how gestational weight gain (GWG) affects infant fat mass (FM) and fat-free mass (FFM). OBJECTIVES: The aim of this study was to investigate relationships between GWG according to Institute of Medicine (IOM) recommendations and infant size, FM and FFM. We also investigated if the associations were different for normal-weight and overweight/obese women. METHODS: This study included 312 healthy Swedish mother-infant pairs. Infant body composition at 1 week of age was assessed using air-displacement plethysmography. Maternal GWG was defined as below, within or above the 2009 IOM recommendations. Multiple regression analyses were used. RESULTS: Compared with women whose weight gain was within IOM recommendations, women with weight gain below the recommendations had infants that were shorter ( 0.7 cm, P = 0.008) when adjusting for confounders. Normal-weight women exceeding IOM recommendations had infants with higher FM (+58 g, P = 0.008) compared with normal-weight women who gained within the recommendations. No corresponding association was observed for overweight/obese women. CONCLUSIONS: Inadequate GWG was associated with shorter infants, while excessive GWG was associated with greater infant FM for women who were of normal weight before pregnancy. PMID- 25521832 TI - Bilinearity in spatiotemporal integration of synaptic inputs. AB - Neurons process information via integration of synaptic inputs from dendrites. Many experimental results demonstrate dendritic integration could be highly nonlinear, yet few theoretical analyses have been performed to obtain a precise quantitative characterization analytically. Based on asymptotic analysis of a two compartment passive cable model, given a pair of time-dependent synaptic conductance inputs, we derive a bilinear spatiotemporal dendritic integration rule. The summed somatic potential can be well approximated by the linear summation of the two postsynaptic potentials elicited separately, plus a third additional bilinear term proportional to their product with a proportionality coefficient [Formula: see text]. The rule is valid for a pair of synaptic inputs of all types, including excitation-inhibition, excitation-excitation, and inhibition-inhibition. In addition, the rule is valid during the whole dendritic integration process for a pair of synaptic inputs with arbitrary input time differences and input locations. The coefficient [Formula: see text] is demonstrated to be nearly independent of the input strengths but is dependent on input times and input locations. This rule is then verified through simulation of a realistic pyramidal neuron model and in electrophysiological experiments of rat hippocampal CA1 neurons. The rule is further generalized to describe the spatiotemporal dendritic integration of multiple excitatory and inhibitory synaptic inputs. The integration of multiple inputs can be decomposed into the sum of all possible pairwise integration, where each paired integration obeys the bilinear rule. This decomposition leads to a graph representation of dendritic integration, which can be viewed as functionally sparse. PMID- 25521833 TI - FABP4 is secreted from adipocytes by adenyl cyclase-PKA- and guanylyl cyclase-PKG dependent lipolytic mechanisms. AB - OBJECTIVE: Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes, and elevated plasma FABP4 level is associated with obesity-mediated metabolic phenotype. Postprandial regulation and secretory signaling of FABP4 has been investigated. METHODS: Time courses of FABP4 levels were examined during an oral glucose tolerance test (OGTT; n=53) or a high-fat test meal eating (n=35). Effects of activators and inhibitors of adenyl cyclase (AC)-protein kinase A (PKA) signaling and guanylyl cyclase (GC)-protein kinase G (PKG) signaling on FABP4 secretion from mouse 3T3-L1 adipocytes were investigated. RESULTS: FABP4 level significantly declined after the OGTT or a high-fat meal eating, while insulin level was increased. Treatment with low and high glucose concentration or palmitate for 2 h did not affect FABP4 secretion from 3T3-L1 adipocytes. FABP4 secretion was increased by stimulation of lipolysis using isoproterenol, a beta3 adrenoceptor agonist (CL316243), forskolin, dibutyryl-cAMP and atrial natriuretic peptide, and the induced FABP4 secretion was suppressed by insulin or an inhibitor of PKA (H-89), PKG (KT5823) or hormone sensitive lipase (CAY10499). CONCLUSIONS: FABP4 is secreted from adipocytes in association with lipolysis regulated by AC-PKA- and GC-PKG-mediated signal pathways. Plasma FABP4 level declines postprandially, and suppression of FABP4 secretion by insulin-induced anti-lipolytic signaling may be involved in this decline in FABP4 level. PMID- 25521835 TI - C-H arylation of unsubstituted furan and thiophene with acceptor bromides: access to donor-acceptor-donor-type building blocks for organic electronics. AB - Pd-catalyzed direct arylation (DA) reaction conditions have been established for unsubstituted furan (Fu) and thiophene (Th) with three popular acceptor building blocks to be used in materials for organic electronics, namely 4,7-dibromo-2,1,3 benzothiadiazole (BTBr2), N,N'-dialkylated 2,6-dibromonaphthalene-1,4,5,8 bis(dicarboximide) (NDIBr2), and 1,4-dibromotetrafluorobenzene (F4Br2). Reactions with BTBr2, F4Br2, and NDIBr2 require different solvents to obtain high yields. The use of dimethylacetamide (DMAc) is essential for the successful coupling of BTBr2 and F4Br2, but detrimental for NDIBr2, as the electron-deficient NDI core is prone to nucleophilic core substitution in DMAc as solvent but not in toluene. NDIFu2 is much more planar compared to NDITh2, resulting in an enhanced charge transfer character, which makes it an interesting building block for conjugated systems designed for organic electronics. This study highlights direct arylation as a simple and inexpensive method to construct a series of important donor acceptor-donor building blocks to be further used for the preparation of a variety of conjugated materials. PMID- 25521837 TI - Effect-Based Screening Methods for Water Quality Characterization Will Augment Conventional Analyte-by-Analyte Chemical Methods in Research As Well As Regulatory Monitoring. PMID- 25521836 TI - Spectral-editing measurements of GABA in the human brain with and without macromolecule suppression. AB - PURPOSE: The conventional spectral-editing experiment used to measure GABA in the human brain also contains a contribution from macromolecules (MM), and the combined GABA plus MM signal is often referred to as "GABA+". More recently, methods have been developed to estimate GABA free from MM contamination. In this study, the relationship between GABA acquired with MM suppression and conventional GABA+ measurements was examined. METHODS: GABA-edited MEGA-PRESS experiments with and without MM suppression were performed in the sensorimotor and occipital cortex of 12 healthy subjects at 3 Tesla. The correlation between GABA+ and MM-suppressed GABA measures was then determined. RESULTS: Across all data, a significant correlation between GABA+ and MM-suppressed GABA was found (r = 0.48; P = 0.02). Regionally, the sensorimotor voxel showed a trend toward a correlation of r = 0.53, P = 0.07 and the occipital voxel did not show a correlation, r = 0.058, P = 0.9. CONCLUSION: GABA+ and MM-suppressed GABA are moderately correlated, but statistical power to reveal this relationship may vary regionally. The MM signal, while often assumed to be functionally irrelevant, appears to show inter-individual and inter-regional variance that impacts the correlation of GABA+ and MM-suppressed GABA. PMID- 25521838 TI - Osteoradionecrosis of mandible bone in patients with oral cancer--associated factors and treatment outcomes. AB - BACKGROUND: The purpose of this study was to investigate factors associated with osteoradionecrosis (ORN) of the mandible bone in a large cohort of patients with oral cancer. METHODS: We reviewed the medical records of patients with oral cancer and identified those with ORN of the mandible bone. Variables of patients with and without ORN were compared and associated factors were investigated by logistic regression model. RESULTS: A total of 1692 patients were included in the final analysis and 105 patients (6.2%) developed ORN in the mandible bone. Primary site, including mouth floor, buccal mucosa, retromolar trigone, or gum, segmental mandibulectomy, and total radiation dose to the primary site >=75 Gy were independent factors associated with ORN. After aggressive treatment using surgical intervention with/without hyperbaric oxygen, 93.3% of the patients healed completely. CONCLUSION: Among patients with oral cancer after radiation, ORN is an uncommon and dreaded complication. Recognition of associated factors can help physicians to identify those at risk. PMID- 25521839 TI - 18F-FDG-PET/CT in implant-associated anaplastic large cell lymphoma of the breast. PMID- 25521834 TI - Opioid receptors and cardioprotection - 'opioidergic conditioning' of the heart. AB - Ischaemic heart disease (IHD) remains a major cause of morbidity/mortality globally, firmly established in Westernized or 'developed' countries and rising in prevalence in developing nations. Thus, cardioprotective therapies to limit myocardial damage with associated ischaemia-reperfusion (I-R), during infarction or surgical ischaemia, is a very important, although still elusive, clinical goal. The opioid receptor system, encompassing the delta (vas deferens), kappa (ketocyclazocine) and MU (morphine) opioid receptors and their endogenous opioid ligands (endorphins, dynorphins, enkephalins), appears as a logical candidate for such exploitation. This regulatory system may orchestrate organism and organ responses to stress, induces mammalian hibernation and associated metabolic protection, triggers powerful adaptive stress resistance in response to ischaemia/hypoxia (preconditioning), and mediates cardiac benefit stemming from physical activity. In addition to direct myocardial actions, central opioid receptor signalling may also enhance the ability of the heart to withstand I-R injury. The delta- and kappa-opioid receptors are strongly implicated in cardioprotection across models and species (including anti-infarct and anti arrhythmic actions), with mixed evidence for MU opioid receptor-dependent protection in animal and human tissues. A small number of clinical trials have provided evidence of cardiac benefit from morphine or remifentanil in cardiopulmonary bypass or coronary angioplasty patients, although further trials of subtype-specific opioid receptor agonists are needed. The precise roles and utility of this GPCR family in healthy and diseased human myocardium, and in mediating central and peripheral survival responses, warrant further investigation, as do the putative negative influences of ageing, IHD co morbidities, and relevant drugs on opioid receptor signalling and protective responses. PMID- 25521840 TI - 15-Lipoxygenase promotes chronic hypoxia-induced phenotype changes of PASMCs via positive feedback-loop of BMP4. AB - Our laboratory has previously demonstrated that 15-lipoxygenase (15-LO)/15 hydroxyeicosatetr-aenoic acid (15-HETE) is involved in hypoxic pulmonary arterial hypertension (PAH). Phenotypical alterations of vascular smooth muscle cells are considered to be an important stage in the development of PAH, whereas the underlying mechanisms and signaling systems are still unclear. Here, we determined the contribution of 15-LO/15-HETE signaling in the hypoxia-induced phenotype changes of pulmonary arterial smooth muscle cells (PASMCs). To accomplish this, cellular and molecular changes in pulmonary vascular remodeling were detected in PAH patients and rats exposed to hypoxia. We found that the hypoxia-induced alterations in PASMCs phenotypes were reversed by the inhibition of 15-LO/15-HETE or inhibition of BMP4/BMPRI. Hypoxia-induced 15-LO1/2 expression in rat PASMCs was significantly abolished by small interfering RNA targeted at BMP4. Meanwhile, BMP4/BMPRI-15-LO/15-HETE had a positive feedback mechanism. Furthermore, ERK and p38MAPK act as the downstream of the 15-LO/15-HETE BMP4/BMPRI signaling. Our results suggest that chronic hypoxia promotes phenotypical alterations of PASMCs due to the interaction between 15-LO/15-HETE and BMP4/BMPRI. Our study reveals a novel mechanism of hypoxia-induced pulmonary vascular remodeling and suggested new therapeutic strategies for the targeting of 15-LO/15-HETE and BMP4/BMPRI in PAH treatment. PMID- 25521841 TI - Optimizing multimodal analgesia with intravenous acetaminophen and opioids in postoperative bariatric patients. AB - STUDY OBJECTIVE: To evaluate the effect of therapeutic doses of intravenous acetaminophen (IV APAP) on postoperative opioid use following bariatric surgery. DESIGN: Retrospective review of medical records. SETTING: A 654-bed academic hospital. PATIENTS: Records for 104 patients who underwent laparoscopic sleeve gastrectomy (LSG; 44 patients) or laparoscopic Roux-en-Y gastric bypass (LRYGB; 60 patients) were reviewed. Patients received IV APAP 1 g every 6 hours postoperatively (22 LSG patients and 30 LRYGB patients) or no IV APAP (22 LSG patients and 30 LRYGB patients). MEASUREMENTS AND MAIN RESULTS: Baseline demographic features were similar for both groups. Patients receiving IV APAP required fewer intravenous morphine equivalents than patients treated with opioids alone. Reductions in morphine equivalents with IV APAP were 21 mg (LSG), 33 mg (LRYGB), and 28 mg (all patients) (p<0.001 for all comparisons). IV APAP was associated with a shorter hospital length of stay (LOS) for the LRYGB (mean difference 1.47 days; p=0.039) and combined groups (mean difference 0.95 days; p=0.025). Patients who received IV APAP had earlier return of bowel sounds and flatus. IV APAP did not reduce mean pain scores in any group. CONCLUSION: Patients undergoing bariatric surgery who received IV APAP during the 24-hour postoperative period consumed fewer intravenous morphine equivalents and had similar pain scores as patients who were treated with opioids alone. Use of IV APAP reduced the hospital LOS and resulted in earlier return of bowel sounds and passage of flatus. PMID- 25521842 TI - Introduction. PMID- 25521843 TI - Opioid use in knee arthroplasty after receiving intravenous acetaminophen. AB - BACKGROUND: Intravenous (IV) acetaminophen may be an effective component of multimodal postoperative pain management. The primary objective of this study was to evaluate the impact of IV acetaminophen on total opioid use in postoperative patients. The secondary objective was to evaluate the effect of IV acetaminophen on hospital length of stay. METHODS: This retrospective, case-control study evaluated the impact of IV acetaminophen on total opioid use in surgical patients. Patients were included if they received at least one perioperative dose of IV acetaminophen and underwent a surgical knee procedure. Controls were matched and randomly selected based on procedure type, age, and severity of illness. Postoperative opioids were converted into oral morphine equivalents, and overall use was compared between groups. RESULTS: One hundred patients were enrolled, with 25 patients receiving IV acetaminophen and 75 matched controls. A total of 135 mg versus 112.5 mg oral morphine equivalents were used in the IV acetaminophen group and control group, respectively (p=0.987). There were 45 mg/day oral morphine equivalents used in the IV acetaminophen group versus 37.5 mg in the control group (p=0.845). The median hospital length of stay in both groups was 3 days (p=0.799). CONCLUSION: IV acetaminophen did not significantly decrease postoperative opioid use in patients who underwent surgical knee procedures. In addition, there was a nonsignificant trend toward increased opioid use in the IV acetaminophen group. There was no significant difference in hospital length of stay between the IV acetaminophen group and the control group. These findings require further study in larger patient populations and in other orthopedic procedures that typically require longer hospital stays. PMID- 25521844 TI - Impact of intravenous acetaminophen on reducing opioid use after hysterectomy. AB - STUDY OBJECTIVE: To examine the impact of intravenous acetaminophen on the total quantity of opioids (in morphine equivalents) administered within the first 48 hours postoperatively and perioperatively, while still affording patients adequate analgesia, in women who underwent total abdominal hysterectomies. DESIGN: Retrospective chart review. SETTING: Tertiary care community hospital. PATIENTS: One hundred women underwent total abdominal hysterectomies performed by a single surgeon: 50 patients received opioids only (fentanyl, morphine, hydromorphone, meperidine, or oxycodone), without the addition of any acetaminophen, between January 1 and March 28, 2011, and 50 patients received intravenous acetaminophen 1000 mg every 6 hours in addition to opioids (multimodal group) between May 1 and July 16, 2012 (time period coincided with the addition of intravenous acetaminophen to the hospital formulary). Patients in both groups were also given nonopioids (celecoxib, dexmedetomidine, aspirin, or tizanidine) perioperatively. MEASUREMENTS AND MAIN RESULTS: Patients in both groups had a mean age of 55 years (mean+/-SD 55+/-13 yrs in the multimodal group, 55+/-15 yrs in the opioids-only group), surgery time of ~2 hours (116+/-51 min in the multimodal group, 118+/-40 min in the opioids-only group), and an anesthesia time of ~3.5 hours (209+/-79 min in the multimodal group, 207+/-79 min in the opioids-only group). During postoperative days 1-2, intravenous acetaminophen reduced opioid use by 31% (mean+/-SD 47+/-24 mg in the multimodal group vs 68+/ 37 mg in the opioids-only group, p=0.003) and by 26% during the total perioperative period, defined as preoperative, intraoperative, recovery room, and postoperative days 1-2 (73+/-24 mg in the multimodal group vs 99+/-39 mg in the opioids-only group, p=0.001). CONCLUSION: The multimodal approach to perioperative analgesic management, which includes concurrent administration of intravenous acetaminophen and opioids, is effective in reducing the total average amount of opioids administered on postoperative days 1-2 and perioperatively. Limitations of this study include its short duration, retrospective design, and single-site setting. These results may not be generalized to patients undergoing other types of obstetric-gynecologic surgeries. PMID- 25521845 TI - Postmarketing review of intravenous acetaminophen dosing based on Food and Drug Administration prescribing guidelines. AB - STUDY OBJECTIVES: To evaluate the appropriateness of intravenous acetaminophen dosing-prescribed dose, frequency, duration, and indication-based on United States Food and Drug Administration (FDA)-approved prescribing guidelines and to evaluate the adverse effect profile of intravenous acetaminophen. DESIGN: Retrospective chart review. SETTING: United States Navy medical center. PATIENTS: Three hundred patients who received intravenous acetaminophen from August 1, 2011, to August 1, 2012. MEASUREMENTS AND MAIN RESULTS: The indications, dose, frequency, and duration of intravenous acetaminophen were recorded for each patient. Adverse effects of intravenous acetaminophen were analyzed by thoroughly reviewing any adverse effects documented, including nausea, vomiting, headache, or any symptom specifically attributed to the drug. Baseline liver function tests, including aspartate aminotransferase and alanine aminotransferase levels, and elevations 3 times the upper limit of normal during intravenous acetaminophen therapy were recorded. The average patient weight was 78+/-21 kg, with 12 patients (4%) weighing less than 50 kg and 288 (96%) patients weighing 50 kg or greater. Two hundred forty-one patients (80%) were appropriately dosed, whereas 59 (20%) patients were not appropriately dosed based on the FDA-approved dosing. No patients exceeded the FDA-approved maximum daily dosing recommendations for intravenous acetaminophen (4 g). Sixty-five patients (22%) received intravenous acetaminophen for longer than 24 hours. Intravenous acetaminophen was well tolerated, without any reported adverse effects, including the commonly reported adverse effects of nausea, vomiting, headache, and insomnia. Ten patients (3%) had a documented history of liver disease and did not experience any adverse effects or increases in liver function tests after the administration of intravenous acetaminophen. CONCLUSION: Intravenous acetaminophen appeared to be a safe and effective analgesic and antipyretic agent. Dosing for patients weighing less than 50 kg needs to be appropriately weight adjusted. Intravenous acetaminophen can be used alone or in conjunction with opioids and other analgesics. Limitations of this study include its retrospective design, inability to assess outcomes of reducing opioid use, and short-term observation period. PMID- 25521846 TI - Medication use evaluations as a research tool. PMID- 25521847 TI - Medication use evaluation: pharmacist rubric for performance improvement. AB - Despite rigorous expert review, medications often fall into routine use with unrecognized and unwanted complications. Use of some medications remains controversial because information to support efficacy is conflicting, scant, or nonexistent. Medication use evaluation (MUE) is a performance improvement tool that can be used when there is uncertainty regarding whether a medication will be beneficial. It is particularly useful when limited evidence is available on how best to choose between two or more medications. MUEs can analyze the process of medication prescribing, preparation, dispensing, administration, and monitoring. MUEs can be part of a structured or mandated multidisciplinary quality management program that focuses on evaluating medication effectiveness and improving patient safety. Successful MUE programs have a structure in place to support completion of rapid-cycle data collection, analysis, and intervention that supports practice change. PMID- 25521849 TI - Characterization of M. tuberculosis SerB2, an essential HAD-family phosphatase, reveals novel properties. AB - M. tuberculosis harbors an essential phosphoserine phosphatase (MtSerB2, Rv3042c) that contains two small- molecule binding ACT-domains (Pfam 01842) at the N terminus followed by the phosphoserine phosphatase (PSP) domain. We found that exogenously added MtSerB2 elicits microtubule rearrangements in THP-1 cells. Mutational analysis demonstrates that phosphatase activity is co-related to the elicited rearrangements, while addition of the ACT-domains alone elicits no rearrangements. The enzyme is dimeric, exhibits divalent metal- ion dependency, and is more specific for l- phosphoserine unlike other classical PSPases. Binding of a variety of amino acids to the ACT-domains influences MtSerB2 activity by either acting as activators/inhibitors/have no effects. Additionally, reduced activity of the PSP domain can be enhanced by equimolar addition of the ACT domains. Further, we identified that G18 and G108 of the respective ACT-domains are necessary for ligand-binding and their mutations to G18A and G108A abolish the binding of ligands like l- serine. A specific transition to higher order oligomers is observed upon the addition of l- serine at ~0.8 molar ratio as supported by Isothermal calorimetry and Size exclusion chromatography experiments. Mutational analysis shows that the transition is dependent on binding of l- serine to the ACT-domains. Furthermore, the higher-order oligomeric form of MtSerB2 is inactive, suggesting that its formation is a mechanism for feedback control of enzyme activity. Inhibition studies involving over eight inhibitors, MtSerB2, and the PSP domain respectively, suggests that targeting the ACT-domains can be an effective strategy for the development of inhibitors. PMID- 25521851 TI - Recent technological advances in computed tomography and the clinical impact therein. AB - Current technological advances in CT, specifically those with a major impact on clinical imaging, are discussed. The intent was to provide for both medical physicists and practicing radiologists a summary of the clinical impact of each advance, offering guidance in terms of utility and day-to-day clinical implementation, with specific attention to radiation dose reduction. PMID- 25521852 TI - Distinct genealogies for plasmids and chromosome. PMID- 25521850 TI - Long-term survival and virulence of Mycobacterium leprae in amoebal cysts. AB - Leprosy is a curable neglected disease of humans caused by Mycobacterium leprae that affects the skin and peripheral nerves and manifests clinically in various forms ranging from self-resolving, tuberculoid leprosy to lepromatous leprosy having significant pathology with ensuing disfiguration disability and social stigma. Despite the global success of multi-drug therapy (MDT), incidences of clinical leprosy have been observed in individuals with no apparent exposure to other cases, suggestive of possible non-human sources of the bacteria. In this study we show that common free-living amoebae (FLA) can phagocytose M. leprae, and allow the bacillus to remain viable for up to 8 months within amoebic cysts. Viable bacilli were extracted from separate encysted cocultures comprising three common Acanthamoeba spp.: A. lenticulata, A. castellanii, and A. polyphaga and two strains of Hartmannella vermiformis. Trophozoites of these common FLA take up M. leprae by phagocytosis. M. leprae from infected trophozoites induced to encyst for long-term storage of the bacilli emerged viable by assessment of membrane integrity. The majority (80%) of mice that were injected with bacilli extracted from 35 day cocultures of encysted/excysted A. castellanii and A. polyphaga showed lesion development that was similar to mice challenged with fresh M. leprae from passage mice albeit at a slower initial rate. Mice challenged with coculture-extracted bacilli showed evidence of acid-fast bacteria and positive PCR signal for M. leprae. These data support the conclusion that M. leprae can remain viable long-term in environmentally ubiquitous FLA and retain virulence as assessed in the nu/nu mouse model. Additionally, this work supports the idea that M. leprae might be sustained in the environment between hosts in FLA and such residence in FLA may provide a macrophage-like niche contributing to the higher than-expected rate of leprosy transmission despite a significant decrease in human reservoirs due to MDT. PMID- 25521853 TI - Dynamic changes in numbers and properties of circulating tumor cells and their potential applications. AB - Circulating tumor cells (CTCs) can be detected in the blood of different types of early or advanced cancer using immunology-based assays or nucleic acid methods. The detection and quantification of CTCs has significant clinical utility in the prognosis of metastatic breast, prostate, and colorectal cancers. CTCs are a heterogeneous population of cells and often different from those of their respective primary tumor. Understanding the biology of CTCs may provide useful predictive information for the selection of the most appropriate treatment. Therefore, CTC detection and characterization could become a valuable tool to refine prognosis and serve as a "real-time biopsy" and has the potential to guide precision cancer therapies, monitor cancer treatment, and investigate the process of metastasis. PMID- 25521854 TI - Met in urological cancers. AB - Met is a tyrosine kinase receptor that is considered to be a proto-oncogene. The hepatocyte growth factor (HGF)-Met signaling system plays an important role in tumor growth, invasion, and metastasis in many types of malignancies. Furthermore, Met expression has been reported to be a useful predictive biomarker for disease progression and patient survival in these malignancies. Many studies have focused on the clinical significance and prognostic role of Met in urological cancers, including prostate cancer (PCa), renal cell carcinoma (RCC), and urothelial cancer. Several preclinical studies and clinical trials are in progress. In this review, the current understanding of the pathological role of Met in cancer cell lines, its clinical significance in cancer tissues, and its predictive value in patients with urological cancers are summarized. In particular, Met-related malignant behavior in castration-resistant PCa and the different pathological roles Met plays in papillary RCC and other histological types of RCC are the subjects of focus. In addition, the pathological significance of phosphorylated Met in these cancers is shown. In recent years, Met has been recognized as a potential therapeutic target in various types of cancer; therapeutic strategies used by Met-targeted agents in urological cancers are summarized in this review. PMID- 25521857 TI - Preservation of Hypermobile Teeth by Establishing Posterior Occlusal Support Using Implant Prostheses: A 5-Year Follow-Up. AB - For patients with periodontally compromised, hypermobile teeth, implant-supported fixed dental prostheses (FDPs) or removable dentures are often used after extracting mobile teeth. The loss of native teeth may carry social consequences, depending upon the patient's age, state of health, and degree of social functioning. This report represents successful stabilization and preservation of questionable, hypermobile teeth that have been damaged by traumatic occlusion due to the loss of posterior support with a cross-arch splinted FDP, as well as the implementation of posterior support using implant-supported prostheses. PMID- 25521855 TI - Revealing editing and SNPs of microRNAs in colon tissues by analyzing high throughput sequencing profiles of small RNAs. AB - BACKGROUND: Editing and mutations in microRNAs (miRNAs) can change the stability of pre-miRNAs and/or complementarities between miRNAs and their targets. Small RNA (sRNA) high-throughput sequencing (HTS) profiles contain miRNAs that are originated from mutated DNAs or are edited during their biogenesis procedures. It is largely unknown whether miRNAs are edited in colon tissues since existing studies mainly focused their attention on the editing of miRNAs in brain tissues. RESULTS: Through comprehensive analysis of four high-throughput sequencing profiles of normal and cancerous colon tissues, we identified 548 editing and/or SNPs in miRNAs that are significant in at least one of the sequencing profiles used. Our results show that the most abundant editing events of miRNAs in colon tissues are 3'-A and 3'-U. In addition to four known A-to-I editing sites previously reported in brain tissues, four novel A-to-I editing sites are also identified in colon tissues. CONCLUSIONS: This suggests that A-to-I editing of miRNAs potentially is a commonly existing mechanism in different tissues to diversify the possible functional roles of miRNAs, but only a small portion of different miRNAs are edited by the A-to-I mechanism at a significant level. Our results suggest that there are other types of editing in miRNAs through unknown mechanisms. Furthermore, several SNPs in miRNAs are also identified. PMID- 25521856 TI - HLA-DR and -DQ eplet mismatches and transplant glomerulopathy: a nested case control study. AB - We conducted a nested case-control study from a cohort of adult kidney transplant recipients to assess the risk of transplant glomerulopathy (TG) as a function of donor and recipient HLA-DR and -DQ incompatibility at the eplet level. Cases (n = 52) were defined as patients diagnosed with transplant glomerulopathy based on biopsies showing glomerular basement membrane duplication without immune complex deposition. Controls (n = 104) with a similar follow-up from transplantation were randomly selected from the remaining cohort. HLAMatchmaker was used to ascertain the number of DRB1/3/4/5, DQA1 and DQB1 related eplet mismatches (eplet load). Multivariable conditional logistic regression models demonstrated an increase in the odds of TG (odds ratios [OR] of 2.84 [95% confidence interval (CI): 1.03, 7.84] and 4.62 [95% CI: 1.51, 14.14]) in the presence of 27-43 and >43 HLA-DR + DQ related eplet mismatches versus <27 eplet mismatches, respectively. When the eplet load was modeled as a continuous variable, the OR for TG was 1.25 (95% CI: 1.04, 1.50) for every 10 additional HLA-DR + DQ eplet mismatches. Our study suggests that minimization of HLA-DR + DQ eplet mismatches may decrease the incidence of transplant glomerulopathy diagnosed by indication biopsies. The role of eplet immunogenicity/antigenicity as determinants of allograft outcomes requires further study. PMID- 25521859 TI - Adaptive striping watershed segmentation method for processing microscopic images of overlapping irregular-shaped and multicentre particles. AB - Oversegmentation is a major drawback of the morphological watershed algorithm. Here, we study and reveal that the oversegmentation is not only because of the irregular shapes of the particle images, which people are familiar with, but also because of some particles, such as ellipses, with more than one centre. A new parameter, the striping level, is introduced and the criterion for striping parameter is built to help find the right markers prior to segmentation. An adaptive striping watershed algorithm is established by applying a procedure, called the marker searching algorithm, to find the markers, which can effectively suppress the oversegmentation. The effectiveness of the proposed method is validated by analysing some typical particle images including the images of gold nanorod ensembles. PMID- 25521864 TI - Controversies in the management of sudden sensorineural hearing loss: an evidence based review. AB - BACKGROUND: Sudden sensorineural hearing loss (SSNHL) is considered an otological emergency. It may present as an isolated condition or be the presenting feature of a systemic disease process. Idiopathic sudden sensorineural hearing loss (ISSNHL) is diagnosed when an underlying cause or condition cannot be identified. OBJECTIVE OF REVIEW: To review the current literature on SSNHL and propose a treatment algorithm based on the highest quality evidence. SEARCH STRATEGY AND TYPE OF REVIEW: An evidence-based literature review using medline (search terms 'sudden sensorineural hearing loss' and 'acute sensorineural hearing loss'). RESULTS: (i) Baseline Investigations: All patients should be assessed with a thorough history and examination. This should include a pure tone audiogram (PTA) where possible. Baseline and targeted laboratory tests should be carried out to diagnose specific conditions. (ii) Imaging: MRI should be carried out in all cases of ISSNHL. If MRI imaging is contraindicated either CT or auditory brainstem response (ABR) testing should be performed. (iii) Medical Management: If a specific cause for a SSNHL is found, the patient should be managed accordingly. If idiopathic in nature, patients may be offered a course of oral steroid. If systemic steroids are contraindicated and/or there is no improvement with initial oral therapy, intratympanic steroids (IT) as either primary or salvage therapy may be considered. (iv) Further Management: There is no evidence to support the routine use of antiviral therapy. The cost, limited availability and lack of strong evidence for hyperbaric oxygen therapy (HBOT) make it impractical at present. Due to the variability in the vasodilator and vasoactive agents used, there is insufficient evidence to support the routine use of these agents. Consideration should be given to both temporary and permanent hearing amplification when required. CONCLUSIONS: SSNHL is an important condition that can have a significant impact on quality of life. Some patients respond spontaneously without intervention; however, evidence tells us that certain interventions such as corticosteroid treatment may improve outcomes. Further high quality research is required. Meanwhile, an interim indicative treatment algorithm for SSNHL based on the current best evidence available is outlined. PMID- 25521866 TI - Hydrodeoxygenation of vicinal OH groups over heterogeneous rhenium catalyst promoted by palladium and ceria support. AB - Heterogeneous ReOx-Pd/CeO2 catalyst showed excellent performance for simultaneous hydrodeoxygenation of vicinal OH groups. High yield (>99%), turnover frequency (300 h(-1)), and turnover number (10,000) are achieved in the reaction of 1,4 anhydroerythritol to tetrahydrofuran. This catalyst can be applied to sugar alcohols, and mono-alcohols and diols are obtained in high yields (>=85%) from substrates with even and odd numbers of OH groups, respectively. The high catalytic performance of ReOx-Pd/CeO2 can be assigned to rhenium species with +4 or +5 valence state, and the formation of this species is promoted by H2/Pd and the ceria support. PMID- 25521865 TI - Whole genome sequence and analysis of the Marwari horse breed and its genetic origin. AB - BACKGROUND: The horse (Equus ferus caballus) is one of the earliest domesticated species and has played an important role in the development of human societies over the past 5,000 years. In this study, we characterized the genome of the Marwari horse, a rare breed with unique phenotypic characteristics, including inwardly turned ear tips. It is thought to have originated from the crossbreeding of local Indian ponies with Arabian horses beginning in the 12th century. RESULTS: We generated 101 Gb (~30 * coverage) of whole genome sequences from a Marwari horse using the Illumina HiSeq2000 sequencer. The sequences were mapped to the horse reference genome at a mapping rate of ~98% and with ~95% of the genome having at least 10 * coverage. A total of 5.9 million single nucleotide variations, 0.6 million small insertions or deletions, and 2,569 copy number variation blocks were identified. We confirmed a strong Arabian and Mongolian component in the Marwari genome. Novel variants from the Marwari sequences were annotated, and were found to be enriched in olfactory functions. Additionally, we suggest a potential functional genetic variant in the TSHZ1 gene (p.Ala344>Val) associated with the inward-turning ear tip shape of the Marwari horses. CONCLUSIONS: Here, we present an analysis of the Marwari horse genome. This is the first genomic data for an Asian breed, and is an invaluable resource for future studies of genetic variation associated with phenotypes and diseases in horses. PMID- 25521867 TI - A water availability intervention in New York City public schools: influence on youths' water and milk behaviors. AB - OBJECTIVES: We determined the influence of "water jets" on observed water and milk taking and self-reported fluid consumption in New York City public schools. METHODS: From 2010 to 2011, before and 3 months after water jet installation in 9 schools, we observed water and milk taking in cafeterias (mean 1000 students per school) and surveyed students in grades 5, 8, and 11 (n=2899) in the 9 schools that received water jets and 10 schools that did not. We performed an observation 1 year after implementation (2011-2012) with a subset of schools. We also interviewed cafeteria workers regarding the intervention. RESULTS: Three months after implementation we observed a 3-fold increase in water taking (increase of 21.63 events per 100 students; P<.001) and a much smaller decline in milk taking (-6.73 events per 100 students; P=.012), relative to comparison schools. At 1 year, relative to baseline, there was a similar increase in water taking and no decrease in milk taking. Cafeteria workers reported that the water jets were simple to clean and operate. CONCLUSIONS: An environmental intervention in New York City public schools increased water taking and was simple to implement. PMID- 25521868 TI - Comparison of smoking cessation between education groups: findings from 2 US National Surveys over 2 decades. AB - OBJECTIVES: We examined smoking cessation rate by education and determined how much of the difference can be attributed to the rate of quit attempts and how much to the success of these attempts. METHODS: We analyzed data from the National Health Interview Survey (NHIS, 1991-2010) and the Tobacco Use Supplement to the Current Population Survey (TUS-CPS, 1992-2011). Smokers (>= 25 years) were divided into lower- and higher-education groups (<= 12 years and >12 years). RESULTS: A significant difference in cessation rate between the lower- and the higher-education groups persisted over the last 2 decades. On average, the annual cessation rate for the former was about two thirds that of the latter (3.5% vs 5.2%; P<.001, for both NHIS and TUS-CPS). About half the difference in cessation rate can be attributed to the difference in quit attempt rate and half to the difference in success rate. CONCLUSIONS: Smokers in the lower-education group have consistently lagged behind their higher-education counterparts in quitting. In addition to the usual concern about improving their success in quitting, tobacco control programs need to find ways to increase quit attempts in this group. PMID- 25521870 TI - Diverging trends in the incidence of occupational and nonoccupational injury in Ontario, 2004-2011. AB - OBJECTIVES: We describe trends in occupational and nonoccupational injury among working-age adults in Ontario. METHODS: We conducted an observational study of adults aged 15 to 64 over the period 2004 through 2011, estimating the incidence of occupational and nonoccupational injury from emergency department (ED) records and, separately, from survey responses to 5 waves of a national health interview survey. RESULTS: Over the observation period, the annual percentage change (APC) in the incidence of work-related injury was -5.9% (95% confidence interval [CI] = -7.3, -4.6) in ED records and -7.4% (95% CI=-11.1, -3.5) among survey participants. In contrast, the APC in the incidence of nonoccupational injury was -0.3% (95% CI=-0.4, 0.0) in ED records and 1.0% (95% CI=0.4, 1.6) among survey participants. Among working-age adults, the percentage of all injuries attributed to work exposures declined from 20.0% in 2004 to 15.2% in 2011 in ED records and from 27.7% in 2001 to 16.9% in 2010 among survey participants. CONCLUSIONS: Among working-age adults in Ontario, nearly all of the observed decline in injury incidence over the period 2004 through 2011 is attributed to reductions in occupational injury. PMID- 25521869 TI - Tobacco-, alcohol-, and drug-attributable deaths and their contribution to mortality disparities in a cohort of homeless adults in Boston. AB - OBJECTIVES: We quantified tobacco-, alcohol-, and drug-attributable deaths and their contribution to mortality disparities among homeless adults. METHODS: We ascertained causes of death among 28 033 adults seen at the Boston Health Care for the Homeless Program in 2003 to 2008. We calculated population-attributable fractions to estimate the proportion of deaths attributable to tobacco, alcohol, or drug use. We compared attributable mortality rates with those for Massachusetts adults using rate ratios and differences. RESULTS: Of 1302 deaths, 236 were tobacco-attributable, 215 were alcohol-attributable, and 286 were drug attributable. Fifty-two percent of deaths were attributable to any of these substances. In comparison with Massachusetts adults, tobacco-attributable mortality rates were 3 to 5 times higher, alcohol-attributable mortality rates were 6 to 10 times higher, and drug-attributable mortality rates were 8 to 17 times higher. Disparities in substance-attributable deaths accounted for 57% of the all-cause mortality gap between the homeless cohort and Massachusetts adults. CONCLUSIONS: In this clinic-based cohort of homeless adults, over half of all deaths were substance-attributable, but this did not fully explain the mortality disparity with the general population. Interventions should address both addiction and non-addiction sources of excess mortality. PMID- 25521871 TI - Recall of anti-tobacco advertisements and effects on quitting behavior: results from the California smokers cohort. AB - OBJECTIVES: We assessed whether an anti-tobacco television advertisement called "Stages," which depicted a woman giving a brief emotional narrative of her experiences with tobacco use, would be recalled more often and have a greater effect on smoking cessation than 3 other advertisements with different intended themes. METHODS: Our data were derived from a sample of 2596 California adult smokers. We used multivariable log-binomial and modified Poisson regression models to calculate respondents' probability of quitting as a result of advertisement recall. RESULTS: More respondents recalled the "Stages" ad (58.5%) than the 3 other ads (23.1%, 23.4%, and 25.6%; P<.001). Respondents who recalled "Stages" at baseline had a higher probability than those who did not recall the ad of making a quit attempt between baseline and follow-up (adjusted risk ratio [RR]=1.18; 95% confidence interval [CI]=1.03, 1.34) and a higher probability of being in a period of smoking abstinence for at least a month at follow-up (adjusted RR=1.55; 95% CI=1.02, 2.37). CONCLUSIONS: Anti-tobacco television advertisements that depict visceral and personal messages may be recalled by a larger percentage of smokers and may have a greater impact on smoking cessation than other types of advertisements. PMID- 25521872 TI - Randomized Trial of Two Dissemination Strategies for a Skin Cancer Prevention Program in Aquatic Settings. AB - OBJECTIVES: We compared 2 strategies for disseminating an evidence-based skin cancer prevention program. METHODS: We evaluated the effects of 2 strategies (basic vs enhanced) for dissemination of the Pool Cool skin cancer prevention program in outdoor swimming pools on (1) program implementation, maintenance, and sustainability and (2) improvements in organizational and environmental supports for sun protection. The trial used a cluster-randomized design with pools as the unit of intervention and outcome. The enhanced group received extra incentives, reinforcement, feedback, and skill-building guidance. Surveys were collected in successive years (2003-2006) from managers of 435 pools in 33 metropolitan areas across the United States participating in the Pool Cool Diffusion Trial. RESULTS: Both treatment groups improved their implementation of the program, but pools in the enhanced condition had significantly greater overall maintenance of the program over 3 summers of participation. Furthermore, pools in the enhanced condition established and maintained significantly greater sun-safety policies and supportive environments over time. CONCLUSIONS: This study found that more intensive, theory-driven dissemination strategies can significantly enhance program implementation and maintenance of health-promoting environmental and policy changes. Future research is warranted through longitudinal follow-up to examine sustainability. PMID- 25521873 TI - Cross-sectional and longitudinal effects of racism on mental health among residents of Black neighborhoods in New York City. AB - OBJECTIVES: We investigated the impact of reported racism on the mental health of African Americans at cross-sectional time points and longitudinally, over the course of 1 year. METHODS: The Black Linking Inequality, Feelings, and the Environment (LIFE) Study recruited Black residents (n = 144) from a probability sample of 2 predominantly Black New York City neighborhoods during December 2011 to June 2013. Respondents completed self-report surveys, including multiple measures of racism. We conducted assessments at baseline, 2-month follow-up, and 1-year follow-up. Weighted multivariate linear regression models assessed changes in racism and health over time. RESULTS: Cross-sectional results varied by time point and by outcome, with only some measures associated with distress, and effects were stronger for poor mental health days than for depression. Individuals who denied thinking about their race fared worst. Longitudinally, increasing frequencies of racism predicted worse mental health across all 3 outcomes. CONCLUSIONS: These results support theories of racism as a health defeating stressor and are among the few that show temporal associations with health. PMID- 25521874 TI - Anemia in Puerto Rico at the turn of the twentieth century. PMID- 25521876 TI - Tobacco industry use of personal responsibility rhetoric in public relations and litigation: disguising freedom to blame as freedom of choice. AB - We examined the tobacco industry's rhetoric to frame personal responsibility arguments. The industry rarely uses the phrase "personal responsibility" explicitly, but rather "freedom of choice." When freedom of choice is used in the context of litigation, the industry means that those who choose to smoke are solely to blame for their injuries. When used in the industry's public relations messages, it grounds its meaning in the concept of liberty and the right to smoke. The courtroom "blame rhetoric" has influenced the industry's larger public relations message to shift responsibility away from the tobacco companies and onto their customers. Understanding the rhetoric and framing that the industry employs is essential to combating this tactic, and we apply this comprehension to other industries that act as disease vectors. PMID- 25521875 TI - The role of stigma and medical mistrust in the routine health care engagement of black men who have sex with men. AB - Objectives: We assessed how health care-related stigma, global medical mistrust, and personal trust in one's health care provider relate to engaging in medical care among Black men who have sex with men (MSM). METHODS: In 2012, we surveyed 544 Black MSM attending a community event. We completed generalized linear modeling and mediation analyses in 2013. RESULTS: Twenty-nine percent of participants reported experiencing racial and sexual orientation stigma from heath care providers and 48% reported mistrust of medical establishments. We found that, among HIV-negative Black MSM, those who experienced greater stigma and global medical mistrust had longer gaps in time since their last medical exam. Furthermore, global medical mistrust mediated the relationship between stigma and engagement in care. Among HIV-positive Black MSM, experiencing stigma from health care providers was associated with longer gaps in time since last HIV care appointment. CONCLUSIONS: Interventions focusing on health care settings that support the development of greater awareness of stigma and mistrust are urgently needed. Failure to address psychosocial deterrents will stymie progress in biomedical prevention and cripple the ability to implement effective prevention and treatment strategies. PMID- 25521877 TI - Awareness of HCV infection among persons who inject drugs in San Diego, California. AB - We asked persons who inject drugs questions about HCV, including past testing and diagnosis followed by HCV testing. Of 540 participants, 145 (27%) were anti-HCV positive, but of those who were positive, only 46 (32%) knew about their infection. Asking about previous HCV testing results yielded better results than did asking about prior HCV diagnosis. Factors associated with knowing about HCV infection included older age, HIV testing, and drug treatment. Comprehensive approaches to educating and screening this population for HCV need implementation. PMID- 25521878 TI - Incarcerated Youths' Perspectives on Protective Factors and Risk Factors for Juvenile Offending: A Qualitative Analysis. AB - OBJECTIVES: We sought to understand incarcerated youths' perspectives on the role of protective factors and risk factors for juvenile offending. METHODS: We performed an in-depth qualitative analysis of interviews (conducted October December 2013) with 20 incarcerated youths detained in the largest juvenile hall in Los Angeles. RESULTS: The adolescent participants described their homes, schools, and neighborhoods as chaotic and unsafe. They expressed a need for love and attention, discipline and control, and role models and perspective. Youths perceived that when home or school failed to meet these needs, they spent more time on the streets, leading to incarceration. They contrasted the path through school with the path to jail, reporting that the path to jail felt easier. All of them expressed the insight that they had made bad decisions and that the more difficult path was not only better but also still potentially achievable. CONCLUSIONS: Breaking cycles of juvenile incarceration will require that the public health community partner with legislators, educators, community leaders, and youths to determine how to make success, rather than incarceration, the easier path for disadvantaged adolescents. PMID- 25521879 TI - Prescription drug insurance coverage and patient health outcomes: a systematic review. AB - Previous reviews have shown that changes in prescription drug insurance benefits can affect medication use and adherence. We conducted a systematic review of the literature to identify studies addressing the association between prescription drug coverage and health outcomes. Studies were included if they collected empirical data on expansions or restrictions of prescription drug coverage and if they reported clinical outcomes. We found 23 studies demonstrating that broader prescription drug insurance reduces use of other health care services and has a positive impact on patient outcomes. Coverage gaps or caps on drug insurance generally led to worse outcomes. States should consider implementing the Affordable Care Act expansions in drug coverage to improve the health of low income patients receiving state-based health insurance. PMID- 25521880 TI - Public health, science, and policy debate: being right is not enough. AB - Public health is usually enacted through public policies, necessitating that the public engage in debates that, ideally, are grounded in solid scientific findings. Mistrust in science, however, has compromised the possibility of deriving sound policy from such debates, partially owing to justified concerns regarding undue interference and even outright manipulation by commercial interests. This situation has generated problematic impasses, one of which is the emergence of an anti-vaccination movement that is already affecting public health, with a resurgence in the United States of preventable diseases thought to have been eradicated. Drawing on British sociologist Harry Collins' work on expertise, we propose a theoretical framework in which the paralyzing, undue public distrust of science can be analyzed and, it is hoped, overcome. PMID- 25521881 TI - Store Impulse Marketing Strategies and Body Mass Index. AB - OBJECTIVES: We quantified the use of placement and price reduction marketing strategies in different food retail outlets to identify associations between these strategies and the risk of overweight and obesity among customers. METHODS: In 2011 we collected dietary and health information from 1372 residents in "food deserts" in Pittsburgh, PA. We audited neighborhood restaurants and food stores (n = 40) including 16 distant food venues at which residents reported shopping. We assessed end-aisle displays, special floor displays, cash register displays, and price reductions for sugar-sweetened beverages (SSBs); foods high in saturated oils, fats, and added sugars; and nutritious foods such as fruits, vegetables, and products with at least 51% whole grains. RESULTS: Supermarkets and superstores had the largest numbers of displays and price reductions for low nutrient foods. Exposure to displays of SSBs and foods high in saturated oils, fats, and added sugars and price reduction of SSBs was associated with increased body mass index. CONCLUSIONS: In-store marketing strategies of low-nutrient foods appear to be risk factors for a higher body mass index among regular shoppers. Future research is needed to confirm the causal role of marketing strategies in obesity. PMID- 25521883 TI - A qualitative content analysis of cigarette health warning labels in Australia, Canada, the United Kingdom, and the United States. AB - The legislation of health warning labels on cigarette packaging is a major focus for tobacco control internationally and is a key component of the World Health Organization's Framework Convention on Tobacco Control. This population-level intervention is broadly supported as a vital measure for warning people about the health consequences of smoking. However, some components of this approach warrant close critical inspection. Through a qualitative content analysis of the imagery used on health warning labels from 4 countries, we consider how this imagery depicts people that smoke. By critically analyzing this aspect of the visual culture of tobacco control, we argue that this imagery has the potential for unintended consequences, and obscures the social and embodied contexts in which smoking is experienced. PMID- 25521882 TI - Shape Up Somerville: change in parent body mass indexes during a child-targeted, community-based environmental change intervention. AB - OBJECTIVES: We investigated the body mass index (BMI; weight in pounds/[height in inches](2) * 703) of parents whose children participated in Shape Up Somerville (SUS), a community-based participatory research study that altered household, school, and community environments to prevent and reduce childhood obesity. METHODS: SUS was a nonrandomized controlled trial with 30 participating elementary schools in 3 Massachusetts communities that occurred from 2002 to 2005. It included first-, second-, and third-grade children. We used an inverse probability weighting estimator adjusted for clustering effects to isolate the influence of SUS on parent (n=478) BMI. The model's dependent variable was the change in pre- and postintervention parent BMI. RESULTS: SUS was significantly associated with decreases in parent BMIs. SUS decreased treatment parents' BMIs by 0.411 points (95% confidence interval=-0.725, -0.097) relative to control parents. CONCLUSIONS: The benefits of a community-based environmental change childhood obesity intervention can spill over to parents, resulting in decreased parental BMI. Further research is warranted to examine the effects of this type of intervention on parental health behaviors and health outcomes. PMID- 25521884 TI - Second-generation antipsychotics and tardive syndromes in affective illness: a public health problem with neuropsychiatric consequences. AB - Food and Drug Administration-approved information and public advertisements belie neurodegenerative risks for second-generation antipsychotics in affective illness. Package inserts label tardive syndromes "potentially reversible" while uniformly omitting patient counseling for long-term neurodegenerative side effects. I found that only 2 of 78 outpatients exposed to second-generation antipsychotics reported awareness of tardive syndromes. Updated literature challenges safety advantages of atypical versus typical antipsychotics. Physician and patient information regarding tardive syndromes from second-generation antipsychotics approved for affective illness is inadequate. PMID- 25521885 TI - Psychological well-being during the great recession: changes in mental health care utilization in an occupational cohort. AB - OBJECTIVES: We examined the mental health effects of the Great Recession of 2008 to 2009 on workers who remained continuously employed and insured. METHODS: We examined utilization trends for mental health services and medications during 2007 to 2012 among a panel of workers in the 25 largest plants, located in 15 states, of a US manufacturing firm. We used piecewise regression to compare trends from 2007 to 2010 in service and medication use before and after 2009, the year of mass layoffs at the firm and the peak of the recession. Our models accounted for changes in county-level unemployment rates and individual-level fixed effects. RESULTS: Mental health inpatient and outpatient visits and the yearly supply of mental health-related medications increased among all workers after 2009. The magnitude of the increase in medication usage was higher for workers at plants with more layoffs. CONCLUSIONS: The negative effects of the recession on mental health extend to employed individuals, a group considered at lower risk of psychological distress. PMID- 25521886 TI - The impact of local immigration enforcement policies on the health of immigrant hispanics/latinos in the United States. AB - OBJECTIVES: We sought to understand how local immigration enforcement policies affect the utilization of health services among immigrant Hispanics/Latinos in North Carolina. METHODS: In 2012, we analyzed vital records data to determine whether local implementation of section 287(g) of the Immigration and Nationality Act and the Secure Communities program, which authorizes local law enforcement agencies to enforce federal immigration laws, affected the prenatal care utilization of Hispanics/Latinas. We also conducted 6 focus groups and 17 interviews with Hispanic/Latino persons across North Carolina to explore the impact of immigration policies on their utilization of health services. RESULTS: We found no significant differences in utilization of prenatal care before and after implementation of section 287(g), but we did find that, in individual-level analysis, Hispanic/Latina mothers sought prenatal care later and had inadequate care when compared with non-Hispanic/Latina mothers. Participants reported profound mistrust of health services, avoiding health services, and sacrificing their health and the health of their family members. CONCLUSIONS: Fear of immigration enforcement policies is generalized across counties. Interventions are needed to increase immigrant Hispanics/Latinos' understanding of their rights and eligibility to utilize health services. Policy-level initiatives are also needed (e.g., driver's licenses) to help undocumented persons access and utilize these services. PMID- 25521887 TI - From patchwork to package: implementing foundational capabilities for state and local health departments. AB - Daily public health responses are threatened by the inadequate capacity of public health agencies. A 2012 Institute of Medicine report defined a package of foundational capabilities that support all programs and services within a health department. Standardizing foundational capabilities may help address the increasing disparity in health department performance nationally. During the Fall of 2013, we collected information on how much state and local health departments knew about foundational capabilities. To our knowledge, this was the first study to assess current health department infrastructure as it relates to foundational capabilities. PMID- 25521888 TI - Martens et al. respond. PMID- 25521889 TI - Smoking cessation and social justice. PMID- 25521890 TI - Health outcomes for HIV-infected persons released from the New York City jail system with a transitional care-coordination plan. AB - OBJECTIVES: We sought to assess 6-month outcomes for HIV-infected people released from New York City jails with a transitional care plan. METHODS: Jail detainees in New York City living with HIV who accepted a transitional care plan during incarceration were asked to participate in a multi-site evaluation aimed at improving linkages to community-based care. The evaluation included a 6-month follow-up; HIV surveillance data were used to assess outcomes for those considered lost to follow-up. RESULTS: Participants (n=434) completed baseline surveys during incarceration in a jail in New York City. Of those seen at 6 months (n=243), a greater number were taking antiretroviral medications (92.6% vs 55.6%), had improved antiretroviral therapy adherence (93.2% vs 80.7%), and reported significant reductions in emergency department visits (0.20 vs 0.60 visits), unstable housing (4.15% vs 22.4%), and food insecurity (1.67% vs 20.7%) compared with baseline. CONCLUSIONS: Transitional care coordination services facilitate continuity of care and improved health outcomes for HIV-positive people released from jail. PMID- 25521891 TI - More money, fewer lives: the cost effectiveness of welfare reform in the United States. AB - OBJECTIVES: We evaluated the economic benefits of Temporary Assistance to Needy Families (TANF) relative to the previous program, Aid to Families with Dependent Children (AFDC). METHODS: We used pooled mortality hazard ratios from 2 randomized controlled trials-Connecticut Jobs First and the Florida Transition Program, which had follow-up from the early and mid-1990s through December 2011 and previous estimates of health and economic benefits of TANF and AFDC. We entered them into a Markov model to evaluate TANF's economic benefits relative to AFDC and weigh them against the potential health threats of TANF. RESULTS: Over the working life of the average cash assistance recipient, AFDC would cost approximately $28000 more than TANF from the societal perspective. However, it would also bring 0.44 additional years of life. The incremental cost effectiveness of AFDC would be approximately $64000 per life-year saved relative to TANF. CONCLUSIONS: AFDC may provide more value as a health investment than TANF. Additional attention given to the neediest US families denied cash assistance could improve the value of TANF. PMID- 25521892 TI - Public health in the Vilna Ghetto as a form of Jewish resistance. AB - We describe the system of public health that evolved in the Vilna Ghetto as an illustrative example of Jewish innovation and achievement during the Holocaust. Furthermore, we argue that by cultivating a sophisticated system of public health, the ghetto inmates enacted a powerful form of Jewish resistance, directly thwarting the intention of the Nazis to eliminate the inhabitants by starvation, epidemic, and exposure. In doing so, we aim to highlight applicable lessons for the broader public health literature. We hope that this unique story may gain its rightful place in the history of public health as an insightful case study of creative and progressive solutions to universal health problems in one of the most challenging environments imaginable. PMID- 25521893 TI - Peter Bourne's drug policy and the perils of a public health ethic, 1976-1978. AB - As President Jimmy Carter's advisor for health issues, Peter Bourne promoted a rational and comprehensive drug strategy that combined new supply-side efforts to prevent drug use with previously established demand-side addiction treatment programs. Using a public health ethic that allowed the impact of substances on overall population health to guide drug control, Bourne advocated for marijuana decriminalization as well as increased regulations for barbiturates. A hostile political climate, a series of rumors, and pressure from both drug legalizers and prohibitionists caused Bourne to resign in disgrace in 1978. We argue that Bourne's critics used his own public health framework to challenge him, describe the health critiques that contributed to Bourne's resignation, and present the story of his departure as a cautionary tale for today's drug policy reformers. PMID- 25521895 TI - The National Prevention Strategy: leveraging multiple sectors to improve population health. PMID- 25521894 TI - Adolescents' and adults' experiences of being surveyed about violence and abuse: a systematic review of harms, benefits, and regrets. AB - The neuroscience and psychological literatures suggest that talking about previous violence and abuse may not only be beneficial, as previously believed, but may also be associated with risks. Thus, studies on such topics introduce ethical questions regarding the risk-benefit ratio of sensitive research. We performed a systematic review of participants' experiences related to sensitive research and compared consequent harms, benefits, and regrets among victims and nonvictims of abuse. Thirty studies were included (4 adolescent and 26 adult studies). In adolescent studies, 3% to 37% of participants (median: 6%) reported harms, but none of these studies measured benefits or regrets. Among adults, 4% to 50% (median: 25%) reported harms, 23% to 100% (median: 92%) reported benefits, and 1% to 6% (median: 2%) reported regrets. Our results suggest that the risk benefit ratio related to sensitive research is not unfavorable, but there are gaps in the evidence among adolescents. PMID- 25521896 TI - Work safety culture of youth farmworkers in North Carolina: a pilot study. AB - OBJECTIVES: We analyzed aspects of the behavioral, situational, and psychological elements of work safety culture of hired youth farmworkers in North Carolina. METHODS: Data were from interviewer-administered questionnaires completed with 87 male and female hired farmworkers aged 10 to 17 years in North Carolina in 2013. We computed means, SDs, and Cronbach alpha values for the perceived work safety climate and safety perception summary scores. RESULTS: Hired youth farmworkers in North Carolina described a negative work safety culture. Most engaged in unsafe general and unsafe work behaviors, few received training, and many were sexually harassed at work. They had mixed safety attitudes and knew that their employment was precarious. They reported a poor perceived work safety climate characterized by the perception that their supervisors "are only interested in doing the job fast and cheaply." However, we could not detect statistically significant associations between work safety culture and injuries among these farmworkers. CONCLUSIONS: Increased scrutiny of agriculture as a suitable industry for workers as young as 10 years and additional regulations to protect hired youth farmworkers, if not to remove them from this environment, are warranted. Additional research is needed. PMID- 25521897 TI - Health effects of unemployment benefit program generosity. AB - OBJECTIVES: We assessed the impact of unemployment benefit programs on the health of the unemployed. METHODS: We linked US state law data on maximum allowable unemployment benefit levels between 1985 and 2008 to individual self-rated health for heads of households in the Panel Study of Income Dynamics and implemented state and year fixed-effect models. RESULTS: Unemployment was associated with increased risk of reporting poor health among men in both linear probability (b=0.0794; 95% confidence interval [CI]=0.0623, 0.0965) and logistic models (odds ratio=2.777; 95% CI=2.294, 3.362), but this effect is lower when the generosity of state unemployment benefits is high (b for interaction between unemployment and benefits=-0.124; 95% CI=-0.197, -0.0523). A 63% increase in benefits completely offsets the impact of unemployment on self-reported health. CONCLUSIONS: Results suggest that unemployment benefits may significantly alleviate the adverse health effects of unemployment among men. PMID- 25521898 TI - Asian American women in California: a pooled analysis of predictors for breast and cervical cancer screening. AB - OBJECTIVES: We examined patterns of cervical and breast cancer screening among Asian American women in California and assessed their screening trends over time. METHODS: We pooled weighted data from 5 cycles of the California Health Interview Survey (2001, 2003, 2005, 2007, 2009) to examine breast and cervical cancer screening trends and predictors among 6 Asian nationalities. We calculated descriptive statistics, bivariate associations, multivariate logistic regressions, predictive margins, and 95% confidence intervals. RESULTS: Multivariate analyses indicated that Papanicolaou test rates did not significantly change over time (77.9% in 2001 vs 81.2% in 2007), but mammography receipt increased among Asian American women overall (75.6% in 2001 vs 81.8% in 2009). Length of time in the United States was associated with increased breast and cervical cancer screening among all nationalities. Sociodemographic and health care access factors had varied effects, with education and insurance coverage significantly predicting screening for certain groups. Overall, we observed striking variation by nationality. CONCLUSIONS: Our results underscore the need for intervention and policy efforts that are targeted to specific Asian nationalities, recent immigrants, and individuals without health care access to increase screening rates among Asian women in California. PMID- 25521900 TI - Crowding as a possible factor for health outcomes in children. PMID- 25521899 TI - Diabetes and hypertension prevalence in homeless adults in the United States: a systematic review and meta-analysis. AB - We estimated hypertension and diabetes prevalence among US homeless adults compared with the general population, and investigated prevalence trends. We systematically searched 5 databases for published studies (1980-2014) that included hypertension or diabetes prevalence for US homeless adults, pooled disease prevalence, and explored heterogeneity sources. We used the National Health Interview Survey for comparison. We included data from 97366 homeless adults. The pooled prevalence of self-reported hypertension was 27.0% (95% confidence interval=23.8%, 29.9%; n=43 studies) and of diabetes was 8.0% (95% confidence interval=6.8%, 9.2%; n=39 studies). We found no difference in hypertension or diabetes prevalence between the homeless and general population. Additional health care and housing resources are needed to meet the significant, growing burden of chronic disease in the homeless population. PMID- 25521901 TI - Association of campus tobacco policies with secondhand smoke exposure, intention to smoke on campus, and attitudes about outdoor smoking restrictions. AB - College campus tobacco-free policies are an emerging trend. Between September 2013 and May 2014, we surveyed 1309 college students at 8 public 4-year institutions across California with a range of policies (smoke-free indoors only, designated outdoor smoking areas, smoke-free, and tobacco-free). Stronger policies were associated with fewer students reporting exposure to secondhand smoke or seeing someone smoke on campus. On tobacco-free college campuses, fewer students smoked and reported intention to smoke on campus. Strong majorities of students supported outdoor smoking restrictions across all policy types. Comprehensive tobacco-free policies are effective in reducing exposure to smoking and intention to smoke on campus. PMID- 25521902 TI - System for rapid assessment of pneumonia and influenza-related mortality-Ohio, 2009-2010. AB - Rapid mortality surveillance is critical for state emergency preparedness. To enhance timeliness during the 2009-2010 influenza A H1N1 pandemic, the Ohio Department of Health activated a drop-down menu within Ohio's Electronic Death Registration System for reporting of pneumonia- or influenza-related deaths approximately 5 days postmortem. We used International Classification of Diseases Tenth Revision (ICD-10) codes, available 2-3 months postmortem as the standard, and assessed their agreement with drop-down-menu codes for pneumonia- or influenza-related deaths. Among 56 660 Ohio deaths during September 2009-March 2010, agreement was 97.9% for pneumonia (kappa = 0.85) and 99.9% for influenza (kappa = 0.79). Sensitivity was 80.2% for pneumonia and 73.9% for influenza. Drop down menu coding enhanced timeliness while maintaining high agreement with ICD-10 codes. PMID- 25521903 TI - Lavinia Dock (1858-1956): picketing, parading, and protesting. PMID- 25521904 TI - An evaluation of voluntary 2-dose varicella vaccination coverage in New York City public schools. AB - OBJECTIVES: We assessed coverage for 2-dose varicella vaccination, which is not required for school entry, among New York City public school students and examined characteristics associated with receipt of 2 doses. METHODS: We measured receipt of either at least 1 or 2 doses of varicella vaccine among students aged 4 years and older in a sample of 336 public schools (n = 223 864 students) during the 2010 to 2011 school year. Data came from merged student vaccination records from 2 administrative data systems. We conducted multivariable regression to assess associations of age, gender, race/ethnicity, and school location with 2 dose prevalence. RESULTS: Coverage with at least 1 varicella dose was 96.2% (95% confidence interval [CI] = 96.2%, 96.3%); coverage with at least 2 doses was 64.8% (95% CI = 64.6%, 64.9%). Increasing student age, non-Hispanic White race/ethnicity, and attendance at school in Staten Island were associated with lower 2-dose coverage. CONCLUSIONS: A 2-dose varicella vaccine requirement for school entry would likely improve 2-dose coverage, eliminate coverage disparities, and prevent disease. PMID- 25521906 TI - Alfred Yankauer (1913-2004): advocate for public health and social justice. PMID- 25521905 TI - Labor unions: a public health institution. AB - Using a social-ecological framework, we drew on a targeted literature review and historical and contemporary cases from the US labor movement to illustrate how unions address physical and psychosocial conditions of work and the underlying inequalities and social determinants of health. We reviewed labor involvement in tobacco cessation, hypertension control, and asthma, limiting articles to those in English published in peer-reviewed public health or medical journals from 1970 to 2013. More rigorous research is needed on potential pathways from union membership to health outcomes and the facilitators of and barriers to union public health collaboration. Despite occasional challenges, public health professionals should increase their efforts to engage with unions as critical partners. PMID- 25521907 TI - Socioeconomic disparities in sleep duration among veterans of the US wars in Iraq and Afghanistan. AB - We characterized socioeconomic disparities in short sleep duration, which is linked to multiple adverse health outcomes, in a population-based sample of veterans of the US wars in Iraq and Afghanistan who had interacted with the Minneapolis VA Health Care System. Lower reported household assets, lower food security, greater reported discrimination, and lower subjective social status were significantly (P<.05) related to less sleep, even after adjusting for demographics, health behaviors, and posttraumatic stress disorder diagnosis. Assisting veterans to navigate social and socioeconomic stressors could promote healthful sleep and overall health. PMID- 25521908 TI - Family Caregivers of Patients With a High-Grade Glioma: A Qualitative Study of Their Lived Experience and Needs Related to Professional Care. AB - BACKGROUND: The poor prognosis and disabling symptoms of a high-grade glioma (HGG) affect not only the patient but place high demands on family caregivers. OBJECTIVE: The objective of this study was to explore the experience of family caregivers of patients with HGG and their needs related to professional care. METHODS: A qualitative research using semistructured interviews was conducted. Sixteen family caregivers of patients with an HGG who were treated or in follow up at a Belgian hospital were interviewed. RESULTS: Family caregivers reported experiencing loss of their old life and the patient's old self. They were saddened to see the patient's disabilities and the change in their relationship, which in turn contributed to feelings of loneliness. At the same time, they reported a strong commitment and determination to provide the patient with the best possible care. Many, however, felt unprepared to do so, and they reported feeling insecure. Caregivers expressed the need for information and for consideration and support. CONCLUSIONS: The diagnosis of an HGG is disruptive to the life of family caregivers. They strongly commit but at the same time struggle to care for the patient. IMPLICATIONS FOR PRACTICE: Professional caregivers should be aware of the subtle balance between family caregivers' wish to care and the burden of caregiving. Professional caregivers can be of great value to family caregivers by providing guidance and assistance for this new caregiving role while being considerate of their commitment and their grief. PMID- 25521909 TI - The Effectiveness of Psychoeducational Interventions Focused on Sexuality in Cancer. AB - BACKGROUND: Although sexual health is a common concern for oncology patients, no practical guidelines to sexual intervention exist, perhaps because of a lack of systematic reviews or meta-analyses. OBJECTIVES: The objectives of this study were to determine the effect size for psychoeducational intervention focused on sexuality and to compare effect sizes according to intervention outcomes and characteristic. METHODS: We explored quantitative evidence for the effects of sexual intervention for cancer patients or partners by using the electronic databases. Among them, we considered 15 eligible articles. RESULTS: The meta analysis provided 133 effect sizes from 15 primary studies. The analysis revealed significant improvements after intervention, with a random-effects standardized mean difference of 0.75. Psychoeducational interventions focused on sexuality after cancer diagnosis were effective for compliance (2.40), cognitive aspect (1.29), and psychological aspect (0.83). Individual-based interventions (0.85) were more effective in improving outcomes than group approach and group combined with individual intervention. With regard to intervention providers, registered nurse only (2.22) and team approach including the registered nurse (2.38) had the highest effect size. Face-to-face intervention combined with telephone or the Internet (1.04) demonstrated a higher effect size than face-to-face (0.62) and telephone (0.58) independently. CONCLUSION: We conducted an analysis of data from various subgroups of preexisting studies, obtained an overall estimate of the effectiveness of the intervention, and compared its effectiveness across variables that affect intervention outcomes. IMPLICATIONS FOR PRACTICE: These results provide empirical data for evidence-based practice and inform the development of useful intervention programs through a comprehensive review and meta-analysis of the results. PMID- 25521910 TI - Breast Self-examination and Health Beliefs in Grenadian Women. AB - BACKGROUND: Breast cancer incidence and mortality are rising in Grenada, and there is a lack of knowledge about women's beliefs about breast self-examination (BSE). OBJECTIVE: The objective of this study was to quantify and identify patterns of beliefs about health and BSE in Grenadian women to help plan targeted community interventions. METHODS: In this descriptive cross-sectional study of 110 women in a community parish in Grenada, sociodemographic data and health beliefs were collected using a self-administered questionnaire. The Champion revised Health Belief Model Scale was used to measure general health motivation (5 items), perceived susceptibility to breast cancer (4 items), seriousness of breast cancer (7 items), confidence in performing BSE (7 items), benefits of BSE (2 items), and barriers to BSE (6 items). RESULTS: Younger women were motivated to perform BSE (P = .018), and divorced/separated/widowed women felt more susceptible to breast cancer (P = .014) but perceived fewer benefits in performing BSE (P = .032). Women who did not attend church were more motivated (P = .015) and saw greater benefit (P = .033) in BSE. Frequent church attendees perceived that they were more susceptible (P = .01), were less confident (P < .001), and saw less benefit in BSE (P = .024). CONCLUSIONS: There are groups of women in Grenada with belief patterns and sociodemographic characteristics that may benefit from targeted community intervention, perhaps in partnership with other stakeholders such as the church. IMPLICATIONS FOR PRACTICE: Beliefs about health and BSE affect BSE uptake and are culture dependent. These data help identify the at-risk population to guide the development of targeted community based and culturally appropriate breast screening programs. PMID- 25521911 TI - Resilience, Positive Coping, and Quality of Life Among Women Newly Diagnosed With Gynecological Cancers. AB - BACKGROUND: Resilience has been linked to psychological adaptation to many challenging life events. OBJECTIVE: The goal was to examine 3 coping strategies- expressing positive emotions, positive reframing of the cancer experience, and cultivating a sense of peace and meaning in life--as potential mechanisms by which resilience translates to quality of life among women recently diagnosed with gynecological cancer. METHODS: This cross-sectional study utilized baseline data from women diagnosed with gynecological cancer participating in an ongoing randomized clinical trial (n = 281; mean age, 55 years; 80% were white). Participants completed measures of resilience, positive emotional expression, positive reappraisal, cultivating a sense of peace and meaning, and quality of life. Univariate and multiple mediation analyses were conducted. RESULTS: Greater resilience was related to higher quality of life (P < .001). Multiple mediation analyses indicated that the coping strategies, as a set, accounted for 62.6% of the relationship between resilience and quality of life. When considered as a set, cultivating a sense of peace and meaning had the strongest indirect effect (b = 0.281, SE = 0.073, P < .05). CONCLUSION: The findings suggested that resilient women may report higher quality of life during gynecological cancer diagnosis because they are more likely to express positive emotions, reframe the experience positively, and cultivate a sense of peace and meaning in their lives. IMPLICATIONS FOR PRACTICE: Interventions promoting a sense of purpose in one's life and facilitating expression of positive emotions may prove beneficial, particularly for women reporting higher levels of resilience. PMID- 25521912 TI - Generation of functional RNAs from inactive oligonucleotide complexes by non enzymatic primer extension. AB - The earliest genomic RNAs had to be short enough for efficient replication, while simultaneously serving as unfolded templates and effective ribozymes. A partial solution to this paradox may lie in the fact that many functional RNAs can self assemble from multiple fragments. Therefore, in early evolution, genomic RNA fragments could have been significantly shorter than unimolecular functional RNAs. Here, we show that unstable, nonfunctional complexes assembled from even shorter 3'-truncated oligonucleotides can be stabilized and gain function via non enzymatic primer extension. Such short RNAs could act as good templates due to their minimal length and complex-forming capacity, while their minimal length would facilitate replication by relatively inefficient polymerization reactions. These RNAs could also assemble into nascent functional RNAs and undergo conversion to catalytically active forms, by the same polymerization chemistry used for replication that generated the original short RNAs. Such phenomena could have substantially relaxed requirements for copying efficiency in early nonenzymatic replication systems. PMID- 25521913 TI - Children use nonverbal cues to make inferences about social power. AB - Four studies (N = 192) tested whether young children use nonverbal information to make inferences about differences in social power. Five- and six-year-old children were able to determine which of two adults was "in charge" in dynamic videotaped conversations (Study 1) and in static photographs (Study 4) using only nonverbal cues. Younger children (3-4 years) were not successful in Study 1 or Study 4. Removing irrelevant linguistic information from conversations did not improve the performance of 3- to 4-year-old children (Study 3), but including relevant linguistic cues did (Study 2). Thus, at least by 5 years of age, children show sensitivity to some of the same nonverbal cues adults use to determine other people's social roles. PMID- 25521914 TI - A feasibility study of Fricke dosimetry as an absorbed dose to water standard for 192Ir HDR sources. AB - High dose rate brachytherapy (HDR) using 192Ir sources is well accepted as an important treatment option and thus requires an accurate dosimetry standard. However, a dosimetry standard for the direct measurement of the absolute dose to water for this particular source type is currently not available. An improved standard for the absorbed dose to water based on Fricke dosimetry of HDR 192Ir brachytherapy sources is presented in this study. The main goal of this paper is to demonstrate the potential usefulness of the Fricke dosimetry technique for the standardization of the quantity absorbed dose to water for 192Ir sources. A molded, double-walled, spherical vessel for water containing the Fricke solution was constructed based on the Fricke system. The authors measured the absorbed dose to water and compared it with the doses calculated using the AAPM TG-43 report. The overall combined uncertainty associated with the measurements using Fricke dosimetry was 1.4% for k = 1, which is better than the uncertainties reported in previous studies. These results are promising; hence, the use of Fricke dosimetry to measure the absorbed dose to water as a standard for HDR 192Ir may be possible in the future. PMID- 25521915 TI - The economic burden and health-related quality of life associated with systemic sclerosis in France. AB - OBJECTIVES: To provide data on the economic burden and health-related quality of life (HRQoL) associated with systemic sclerosis (SSc) in France and to raise awareness of the repercussions of this disease for patients and caregivers and on the health and social care system. METHOD: A cross-sectional study was carried out on 147 patients recruited through the Association des Sclerodermiques de France (ASF), the French association for SSc patients. Data on the patients' use of resources were obtained retrospectively from an online questionnaire and costs were estimated by a bottom-up approach. The HRQoL patients and caregivers was assessed with the five-level EURQol-5 Dimension (EQ-5D-5L) health questionnaire. RESULTS: The average annual cost of SSc was estimated at EUR 22,459 per patient. Direct healthcare costs amounted to EUR 8452, direct non-healthcare formal costs to EUR 1606, direct non-healthcare informal costs to EUR 1875, and indirect costs resulting from patients' absence from the labour market to EUR 10,526. The main contributors to SSc costs were hospitalizations and early retirement. Mean EQ-5D utility scores were 0.49 for patients and 0.66 for caregivers. CONCLUSIONS: Although SSc is a rare disease, its economic burden from a societal perspective is substantial and the consequences for HRQoL are significant for both patients and caregivers in France, underscoring the need to develop tailored policies targeted at improving patients' care and reducing the long-term impact of SSc. PMID- 25521916 TI - Altered prostanoid metabolism contributes to impaired angiogenesis in persistent pulmonary hypertension in a fetal lamb model. AB - BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is associated with decreased lung angiogenesis and impaired pulmonary vasodilatation at birth. Prostanoids are important modulators of vascular tone and angiogenesis. We hypothesized that altered levels of prostacyclin (PGI2), a potent vasodilator, and thromboxane A2 (TXA2), a vasoconstrictor, contribute to impaired angiogenesis of pulmonary artery endothelial cells (PAEC) in PPHN. METHODS: PAEC were isolated from fetal lambs with PPHN induced by prenatal ductus arteriosus constriction or from sham operated controls. Expression and activity of PGI2 synthase (PGIS) and TXA2 synthase (TXAS), expression of cyclooxygenases 1 and 2 (COX-1 and COX-2), and the role of PGIS/TXAS alterations in angiogenesis were investigated in PAEC from PPHN and control lambs. RESULTS: PGIS protein and activity were decreased and PGIS protein tyrosine nitration was increased in PPHN PAEC. In contrast, TXAS protein and its stimulated activity were increased in PPHN PAEC. COX-1 and COX-2 proteins were decreased in PPHN PAEC. Addition of PGI2 improved in vitro tube formation by PPHN PAEC, whereas indomethacin decreased tube formation by control PAEC. PGIS knockdown decreased the in vitro angiogenesis in control PAEC, whereas TXAS knockdown increased the in vitro angiogenesis in PPHN PAEC. CONCLUSION: Reciprocal alterations in PGI2 and TXA2 may contribute to impaired angiogenesis in PPHN. PMID- 25521919 TI - Spatial regulation of gene expression during growth of articular cartilage in juvenile mice. AB - BACKGROUND: In juvenile mammals, the epiphyses of long bones grow by chondrogenesis within the articular cartilage. A better understanding of the molecular mechanisms that regulate the growth of articular cartilage may give insight into the antecedents of joint disease, such as osteoarthritis. METHODS: We used laser capture microdissection to isolate chondrocytes from the superficial, middle, and deep zones of growing tibial articular cartilage in the 1-wk-old mouse and then investigated expression patterns by microarray. To identify molecular markers for each zone of the growing articular cartilage, we found genes showing zone-specific expression and confirmed by real-time PCR and in situ hybridization. RESULTS: Bioinformatic analyses implicated ephrin receptor signaling, Wnt signaling, and bone morphogenetic protein signaling in the spatial regulation of chondrocyte differentiation during growth. Molecular markers were identified for superficial (e.g., Cilp, Prg4), middle (Cxcl14, Tnn), and deep zones (Sfrp5, Frzb). Comparison between juvenile articular and growth plate cartilage revealed that the superficial-to-deep zone transition showed similarity with the hypertrophic-to-resting zone transition. CONCLUSION: Laser capture microdissection combined with microarray analysis identified novel signaling pathways that are spatially regulated in growing mouse articular cartilage and revealed similarities between the molecular architecture of the growing articular cartilage and that of growth plate cartilage. PMID- 25521918 TI - Genetic variation in CYB5R3 is associated with methemoglobin levels in preterm infants receiving nitric oxide therapy. AB - BACKGROUND: In recent years, increasing numbers of preterm infants have been exposed to inhaled nitric oxide (iNO). This population has decreased methemoglobin (MetHb) reductase activity in their erythrocytes, which may increase the risk of MetHb toxicity. We sought to determine if genetic factors are associated with the observed variance in MetHb levels. METHODS: A population of 127 preterm infants was genotyped for five single-nucleotide polymorphisms (SNPs) in the CYB5A and CYB5R3 genes. iNO dose and levels of MetHb were obtained by chart abstraction. ANOVA was performed to identify genetic associations with MetHb levels. RESULTS: An association was found between the heterozygous genotype (GA) of rs916321 in the CYB5R3 gene and the mean of the first recorded MetHb levels in Caucasian infants (P = 0.01). This result remained significant after adjustment for the iNO dose (P = 0.009), gender (P = 0.03), multiple gestation (P = 0.03), birth weight (P = 0.02), and gestational age (P = 0.02). No significant associations were found with the other SNPs. CONCLUSION: We demonstrate a novel genetic association with neonatal MetHb levels. Identification of genetic risk factors may be useful in determining which preterm infants are most at risk of developing MetHb toxicity with the use of iNO. PMID- 25521917 TI - Toll-like receptor-4 in human and mouse colonic epithelium is developmentally regulated: a possible role in necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is an immature intestinal condition resulting in devastating intestinal inflammation due to unknown mechanisms. Evidence has suggested that intestinal maturation attenuates the severity of NEC and Toll-like receptor 4 (TLR4) has been suggested to play a critical role in its pathogenesis. We investigated whether maturational effects of TLR4 expression in immature colon might contribute to the development of NEC. METHODS: TLR4 colonocyte expression was detected by immunofluorescence confocal microscopy. Interleukin-6 (IL-6) levels were assayed by an enzyme-linked immunosorbent assay (ELISA). RESULTS: TLR4 expression was high in fetal colonic epithelium in human and mouse, with earlier gestation having a higher surface/cytoplasm distribution. TLR4 remained high in mouse postnatal day 1 but the surface/cytoplasm distribution was reduced. TLR4 decreased in amount and then was expressed in crypts in the mature human and mouse colon. Hydrocortisone (HC) reduced the surface/cytoplasm distribution of TLR4 in human fetal colon. Elevated IL-6 levels in immature colon after lipopolysaccharide were attenuated by HC in human and mouse. CONCLUSION: Expression, localization, and signaling of TLR4 in colonic epithelium may be developmentally regulated. HC may accelerate the TLR developmental pathway change to an adult type, which may account for its impact on TLR4 signaling. PMID- 25521920 TI - Acute kidney injury and progression of renal failure after fetal programming in the offspring of diabetic rats. AB - BACKGROUND: Diseases of adulthood, such as diabetes and hypertension, may be related to changes during pregnancy, particularly in kidney. We hypothesized that acute kidney injury progresses more rapidly in cases of fetal programming. METHODS: Diabetic dams' offspring were divided into: CC (controls, receiving vehicle); DC (diabetics, receiving vehicle); CA (controls receiving folic Acid solution, 250 mg/kg); and DA (diabetics receiving folic acid solution). Renal function tests, morphometry, gene, and protein expression of epithelial mesenchymal transition (EMT) markers were analyzed by qPCR and immunohistochemistry, respectively. RESULTS: Creatinine, urea, Bowman's space, and EMT markers were increased in CA and DA groups. TGF-beta3, actin, and fibronectin expression was higher in CA and DA, with significant increase in DA compared to CA 2-mo offspring. There was higher expression level of TGF-beta1, TGF-beta3, fibronectin, and vimentin in the offspring of diabetic dams at 5 mo. Increases in TGF-beta1 and TGF-beta3 were more evident in the offspring of diabetic dams. CONCLUSION: Fetal programming promotes remarkable changes in kidney morphology, and function in offspring and renal failure progression may be faster in younger offspring of diabetic dams subjected to an additional injury. PMID- 25521921 TI - Maternal LC-PUFA status during pregnancy and child problem behavior: the Generation R Study. AB - BACKGROUND: Omega 3 (n-3) and 6 (n-6) long-chain polyunsaturated fatty acids (LC PUFAs) and the n-3:n-6 ratio are important for brain development. Whether maternal LC-PUFA status during pregnancy affects risk of problem behavior in later childhood is unclear. METHODS: Within a population-based cohort, we measured maternal plasma docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) concentrations and n-3:n-6-ratio in mid-pregnancy. Child emotional and behavioral problems at 6 y of age were assessed by parents (child behavior checklist), teachers (teacher report form), and combined parent/teacher report. RESULTS: Higher maternal DHA and n-3:n-6 ratio were associated with fewer child emotional problems using parent (odds ratio (OR)DHA = 0.82; 95% confidence interval (CI): 0.70, 0.96; P = 0.02 and OR(n-3:n-6) = 0.83; 95% CI: 0.71, 0.96; P = 0.01; n = 5,307) and combined parent/teacher scores (ORDHA = 0.79; 95% CI: 0.66, 0.95; P = 0.01 and OR(n-3:n-6) = 0.77; 95% CI: 0.65, 0.92; P < 0.01; n = 2,828). Higher AA was associated with more child behavioral problems using teacher (OR = 1.10; 95% CI: 1.00, 1.20; P = 0.04; n = 3,365) and combined parent/teacher scores (OR = 1.12; 95% CI: 1.02, 1.22; P = 0.02; n = 2,827). Maternal EPA was not associated with child problem behavior. CONCLUSION: Indications of associations of maternal LC-PUFA status with child emotional and behavioral problems were found. Future research is needed to identify LC-PUFA sensitive periods of fetal brain development by including multiple assessments of prenatal LC-PUFA status. PMID- 25521922 TI - Diagnostic methods and recommendations for the cerebral creatine deficiency syndromes. AB - Primary care pediatricians and a variety of specialist physicians strive to define an accurate diagnosis for children presenting with impairment of expressive speech and delay in achieving developmental milestones. Within the past two decades, a group of disorders featuring this presentation have been identified as cerebral creatine deficiency syndromes (CCDS). Patients with these disorders were initially discerned using proton magnetic resonance spectroscopy of the brain within a magnetic resonance imaging (MRI) examination. The objective of this review is to provide the clinician with an overview of the current information available on identifying and treating these conditions. We explain the salient features of creatine metabolism, synthesis, and transport required for normal development. We propose diagnostic approaches for confirming a CCDS diagnosis. Finally, we describe treatment approaches for managing patients with these conditions. PMID- 25521923 TI - Chronic spinal and oral morphine-induced neuroendocrine and metabolic changes in noncancer pain patients. AB - OBJECTIVE: Interactions between opioid use and hormonal function are documented in the literature. However, it is unclear if therapeutic intrathecal opioid therapy can induce hormonal changes, compared to oral opioid therapy. METHODS: The authors studied hormone and metabolic changes in 22 women (18-60 years) and 38 men (18-45 years) who were referred to a pain center. The patients were allocated to different treatment groups (based on assistant physicians' decision), as follows: 20 patients received oral morphine (60-120 mg/day); 20 patients, spinal morphine (0.2-10 mg/day); and 20 patients, nonopioid analgesic treatment. RESULTS: All three groups experienced substantial improvement in pain scores during the whole follow-up period. Significantly impaired libido, reduced potency, hot flashes, and menstrual cycle dysfunction occurred more often in both morphine groups than in the nonopioid group. Significantly low serum total testosterone levels were more prevalent in the spinal morphine group and the oral morphine group (58.3% and 70.0%, respectively) than in the control group (16.7%). Total cholesterol values above 200 mg/dL and higher ultrasensitive C-reactive protein levels were significantly more frequent in the morphine groups than in the controls. Total body bone mineral density was below normal in men receiving spinal morphine (P = 0.014). CONCLUSIONS: Hypogonadotrophic hypogonadism was more prevalent in the morphine groups and was correlated with clinical findings. Significant bone mass loss occurred in morphine users, even without hormone dysfunction when compared to nonopioid treatment. Growth hormone, thyroid stimulating hormone, adrenocorticotrophic hormones, and cardiovascular risk parameters were less compromised in morphine users. PMID- 25521924 TI - Complex PCI: when the going gets tough the tough gets going. PMID- 25521925 TI - Thinking about stent thrombosis: how does angiographic flow relate to outcome? PMID- 25521926 TI - Bridging antiplatelet therapy prior to surgery in DES patients: is less more? PMID- 25521927 TI - Optimal DAPT duration: each in their own time. PMID- 25521928 TI - Lipid-laden plaques: lesions "at-risk" for distal embolization during PCI. PMID- 25521929 TI - High dose statins prior to PCI--change our modus operandis and start guideline therapy earlier? PMID- 25521930 TI - Bleeding that BARCs may bite... PMID- 25521931 TI - A radial resolution to a warfarin worry. PMID- 25521932 TI - Whither platelets after TAVR? PMID- 25521933 TI - Fluoroscopy and CT fusion overlay--greater than the sum of their parts. PMID- 25521934 TI - Spatial patterning of bone stiffness in the anterior mandibular corpus of Macaca fascicularis: Implications for models of bone adaptation. AB - Elastic modulus of bone from the anterior mandibular corpus was determined via microindentation in a mixed-sex ontogenetic sample (N = 14) of Macaca fascicularis. This investigation focused on the hypothesis that material heterogeneity in the macaque mandibular symphysis-provided an accounting of age and sex variation-is explicable as a means to homogenize strains in this region. Experimental data and theoretical models of masticatory loading indicate that in the absence of material compensation, large strain gradients exist in the anterior mandibular corpus of macaques, particularly between lingual and labial cortical plates owing to the effects of lateral transverse bending. Microindentation data indicate that juvenile macaques possess less stiff bone than their subadult and adult counterparts; however, sex differences in elastic modulus are not apparent. Anisotropy variation is idiosyncratic; that is, there is not a common pattern of variation in stiffness sampled among orthogonal planes across individuals. Similarly, differences in stiffness between lingual and labial cortical plates, as well as differences among alveolar, midcorpus, and basal regions are inconsistently observed. Consequently, we find little evidence in support of the hypothesis that spatial variation in bone stiffness functions to homogenize strains in the anterior corpus; in fact, in some individuals, this spatial variation serves to exacerbate, rather than to minimize, strain gradients. The mechanical benefit of elastic modulus variation in the macaque mandibular symphysis is unclear; this variation may not confer adaptive benefit in terms of structural integrity despite the fact that such variation has discernible functional consequences. PMID- 25521935 TI - Cognitive Behavioral Therapies in older adults with depression and cognitive deficits: a systematic review. AB - OBJECTIVES: The objective of this study is to investigate the effectiveness of cognitive behavioral therapies (CBTs) in improving depressive symptoms, disability, and cognition in older adults with depression and cognitive deficits. DESIGN: It was performed a systematic search for articles published between 1994 and February 2014 in the MEDLINE/Pubmed, PsycINFO, and SCIELO. The studies should have provided information about benefits after CBTs to older adults with depression and cognitive deficits. RESULTS: Cognitive behavioral therapy focused on problem solving is the main approach studied, having better effectiveness than supportive therapy in randomized clinical trials. Significant improvements in mood and disability were consistent, although evidence of changes in cognitive measures is controversial, less studied, and limited. Nevertheless, improvements in executive functions, processing speed, and changes in patients' perspectives of problem solving skills, such as generating alternatives and decision-making, were described. Also, it would be necessary that future studies more often evaluate cognitive status of depressed elders, as well as cognitive changes after psychotherapy. It should be emphasized that there is a lack of studies in this field, and more approaches in CBTs need to be investigated to this population. CONCLUSION: Older adults with depression and cognitive deficits can benefit from CBTs. Improvements in mood and disability are more consistent than changes in cognition, which are little studied after CBTs. It is necessary more studies in the field, as well as, to investigate more approaches in CBTs to older adults with depression and cognitive deficits. PMID- 25521936 TI - Enhanced reactive oxygen species overexpression by CuO nanoparticles in poorly differentiated hepatocellular carcinoma cells. AB - Copper oxide nanoparticles (CuO NPs) are known to exhibit toxic effects on a variety of cell types and organs. To determine the oxidative impact of CuO NPs on hepatocellular carcinoma (HCC) cells, well-differentiated (HepG2) and poorly differentiated (SK-Hep-1) cells were exposed to CuO NPs. Cell viability assay showed that the median inhibition concentration (IC50) for SK-Hep-1 and HepG2 cells was 25 MUg ml(-1) and 85 MUg ml(-1), respectively. Cellular fluorescence intensity using DCFH-DA staining analysis revealed significant intracellular reactive oxygen species (ROS) generation of up to 242% in SK-Hep-1 cells, compared with 86% in HepG2 cells. HPLC analysis demonstrated that a CuO NP treatment caused cellular GSH depletion of 58% and a GSH/GSSG ratio decrease to ~0.1 in SK-Hep-1 cells. The oxidative stress caused by enhanced superoxide anion production was observed in both HepG2 (146%) and SK-Hep-1 (192%) cells. The Griess assay verified that CuO NPs induced NO production (170%) in SK-Hep-1 cells. Comet assay and western blot further demonstrated that CuO NPs induced severe DNA strand breakage (70%) in SK-Hep-1 cells and caused DNA damage via increased gamma-H2AX levels. These results suggest that well-differentiated HepG2 cells possess a robust antioxidant defense system against CuO NP-induced ROS stress and exhibit more tolerance to oxidative stress. Conversely, poorly differentiated SK-Hep-1 cells exhibited a deregulated antioxidant defense system that allowed accumulation of CuO NP-induced ROS and resulted in severe cytotoxicity. PMID- 25521937 TI - Engaging women at risk for poor perinatal mental health outcomes: a mixed-methods study. AB - Risk factors for poor perinatal mental health are well known. Psychosocial assessment and depression screening during the perinatal period aim to identify women at risk for poor perinatal outcomes. Early intervention programmes are known to improve the mental health outcomes of women and infants. Key to any intervention is initial and ongoing engagement in the therapeutic process. This mixed-methods study reports the proportion of women who engage/do not engage with services and their characteristics, as well as the strategies clinicians use to engage women. Data were collected by reviewing medical records, interviewing perinatal and infant mental health (PIMH) clinicians, their managers, key stakeholders, and women service users. Analyses identified that most (71.3%) women referred engaged with the PIMH service. Themes related to non-engagement are 'time to rethink' and 'stigma'. Themes reflecting the engagement strategies used by PIMH clinicians are initial engagement: 'back to basics' and 'building trust', therapeutic engagement: 'making myself useful', engagement at discharge: 'woman or clinician led', and models that facilitate engagement. PMID- 25521939 TI - Laser-induced fast fusion of gold nanoparticle-modified polyelectrolyte microcapsules. AB - In this study we investigated the effect of laser-induced membrane fusion of polyelectrolyte multilayer (PEM) based microcapsules bearing surface-attached gold nanoparticles (AuNPs) in aqueous media. We demonstrate that a dense coating of the capsules with AuNPs leads to enhanced light absorption, causing an increase of local temperature. This enhances the migration of polyelectrolytes within the PEMs and thus enables a complete fusion of two or more capsules. The encapsulated substances can achieve complete merging upon short-term laser irradiation (30 s, 30 mW @ 650 nm). The whole fusion process is followed by optical microscopy and scanning electron microscopy. In control experiments, microcapsules without AuNPs do not show a significant capsule fusion upon irradiation. It was also found that the duration of capsule fusion is affected by the density of AuNPs on the shell - the higher the density of AuNPs the shorter the fusion time. All these findings confirm that laser-induced microcapsule fusion is a new type of membrane fusion. This effect helps to study the interior exchange reactions of functional microcapsules, micro-reactors and drug transport across multilayers. PMID- 25521940 TI - Scanning-tunneling-spectroscopy-directed design of tailored deep-blue emitters. AB - Frontier molecular orbitals can be visualized and selectively set to achieve blue phosphorescent metal complexes. For this purpose, the HOMOs and LUMOs of tridentate Pt(II) complexes were measured using scanning tunneling microscopy and spectroscopy. The introduction of electron-accepting or -donating moieties enables independent tuning of the frontier orbital energies, and the measured HOMO-LUMO gaps are reproduced by DFT calculations. The energy gaps correlate with the measured and the calculated energies of the emissive triplet states and the experimental luminescence wavelengths. This synergetic interplay between synthesis, microscopy, and spectroscopy enabled the design and realization of a deep-blue triplet emitter. Finding and tuning the electronic "set screws" at molecular level constitutes a useful experimental method towards an in-depth understanding and rational design of optoelectronic materials with tailored excited state energies and defined frontier-orbital properties. PMID- 25521938 TI - STING, nanoparticles, autoimmune disease and cancer: a novel paradigm for immunotherapy? AB - DNA has potent immunogenic properties that are useful to enhance vaccine efficacy. DNA also incites hyperinflammation and autoimmunity if DNA sensing is not regulated. Paradoxically, DNA regulates immunity and autoimmunity when administered systemically as DNA nanoparticles. DNA nanoparticles regulated immunity via cytosolic DNA sensors that activate the signaling adaptor stimulator of interferon genes. In this review, we describe how DNA sensing to activate stimulator of interferon genes promotes regulatory responses and discuss the biological and clinical implications of these responses for understanding disease progression and designing better therapies for patients with chronic inflammatory diseases, such as autoimmune syndromes or cancer. PMID- 25521941 TI - cytoHubba: identifying hub objects and sub-networks from complex interactome. AB - BACKGROUND: Network is a useful way for presenting many types of biological data including protein-protein interactions, gene regulations, cellular pathways, and signal transductions. We can measure nodes by their network features to infer their importance in the network, and it can help us identify central elements of biological networks. RESULTS: We introduce a novel Cytoscape plugin cytoHubba for ranking nodes in a network by their network features. CytoHubba provides 11 topological analysis methods including Degree, Edge Percolated Component, Maximum Neighborhood Component, Density of Maximum Neighborhood Component, Maximal Clique Centrality and six centralities (Bottleneck, EcCentricity, Closeness, Radiality, Betweenness, and Stress) based on shortest paths. Among the eleven methods, the new proposed method, MCC, has a better performance on the precision of predicting essential proteins from the yeast PPI network. CONCLUSIONS: CytoHubba provide a user-friendly interface to explore important nodes in biological networks. It computes all eleven methods in one stop shopping way. Besides, researchers are able to combine cytoHubba with and other plugins into a novel analysis scheme. The network and sub-networks caught by this topological analysis strategy will lead to new insights on essential regulatory networks and protein drug targets for experimental biologists. According to cytoscape plugin download statistics, the accumulated number of cytoHubba is around 6,700 times since 2010. PMID- 25521945 TI - Social structure varies with elevation in an Alpine ant. AB - Insect societies vary greatly in social organization, yet the relative roles of ecological and genetic factors in driving this variation remain poorly understood. Identifying how social structure varies along environmental gradients can provide insights into the ecological conditions favouring alternative social organizations. Here, we investigate how queen number variation is distributed along elevation gradients within a socially polymorphic ant, the Alpine silver ant Formica selysi. We sampled low- and high-elevation populations in multiple Alpine valleys. We show that populations belonging to different drainage basins are genetically differentiated. In contrast, there is little genetic divergence between low- and high-elevation populations within the same drainage basin. Thus, elevation gradients in each of the drainage basins represent independent contrasts. Whatever the elevation, all well-sampled populations are socially polymorphic, containing both monogynous (= one queen) and polygynous (= multiple queen) colonies. However, the proportion of monogynous colonies per population increases at higher elevation, while the effective number of queens in polygynous colonies decreases, and this pattern is replicated in each drainage basin. The increased prevalence of colonies with a single queen at high elevation is correlated with summer and winter average temperature, but not with precipitation. The colder, unpredictable and patchy environment encountered at higher elevations may favour larger queens with the ability to disperse and establish incipient monogynous colonies independently, while the stable and continuous habitat in the lowlands may favour large, fast-growing polygynous colonies. By highlighting differences in the environmental conditions favouring monogynous or polygynous colonies, this study sheds light on the ecological factors influencing the distribution and maintenance of social polymorphism. PMID- 25521946 TI - High resolution solid state 2D NMR analysis of biomass and biochar. AB - Solid state NMR methods are required to analyze biomass as a function of its chemical or biological treatment for biofuels, chemicals, or biochar production. The native polymers network in lignocellulosic biomass and other solid materials, such as coal, coke, or biochar, can hardly be analyzed by liquid state NMR due to their poor swelling ability without chemical modification. A (1)H-(13)C two dimensional heteronuclear correlation (HETCOR) experiment with frequency-switched Lee-Goldburg (FSLG) irradiation is performed on a high field spectrometer (750 MHz). This method leads to previously unattained resolution for biomass and biochar and offers a unique ability to reveal their chemical composition. The formation of aromatic moieties from carbohydrates and lignin thermal conversion is clearly distinguished. This method can be applied to all other carbonaceous materials. PMID- 25521947 TI - Supervised prediction of drug-induced nephrotoxicity based on interleukin-6 and 8 expression levels. AB - BACKGROUND: Drug-induced nephrotoxicity causes acute kidney injury and chronic kidney diseases, and is a major reason for late-stage failures in the clinical trials of new drugs. Therefore, early, pre-clinical prediction of nephrotoxicity could help to prioritize drug candidates for further evaluations, and increase the success rates of clinical trials. Recently, an in vitro model for predicting renal-proximal-tubular-cell (PTC) toxicity based on the expression levels of two inflammatory markers, interleukin (IL)-6 and -8, has been described. However, this and other existing models usually use linear and manually determined thresholds to predict nephrotoxicity. Automated machine learning algorithms may improve these models, and produce more accurate and unbiased predictions. RESULTS: Here, we report a systematic comparison of the performances of four supervised classifiers, namely random forest, support vector machine, k-nearest neighbor and naive Bayes classifiers, in predicting PTC toxicity based on IL-6 and -8 expression levels. Using a dataset of human primary PTCs treated with 41 well-characterized compounds that are toxic or not toxic to PTC, we found that random forest classifiers have the highest cross-validated classification performance (mean balanced accuracy = 87.8%, sensitivity = 89.4%, and specificity = 85.9%). Furthermore, we also found that IL-8 is more predictive than IL-6, but a combination of both markers gives higher classification accuracy. Finally, we also show that random forest classifiers trained automatically on the whole dataset have higher mean balanced accuracy than a previous threshold-based classifier constructed for the same dataset (99.3% vs. 80.7%). CONCLUSIONS: Our results suggest that a random forest classifier can be used to automatically predict drug-induced PTC toxicity based on the expression levels of IL-6 and -8. PMID- 25521949 TI - [Health governance and social protection indicators in Latin-America: strengths, weaknesses and lessons-learned from six Mexican states]. AB - OBJECTIVE: Evaluative research projects for identifying good practice have been postponed regarding health system reform. This study was thus aimed at identifying health governance and social protection indicators. METHODS: This study involved evaluative research regarding the health system for the uninsured part of the population in six Mexican states. The primary data was obtained from in-depth interviews with key players from the participating states; official statistics and the results of a macro-project concerned with Mexican health and governance reform and policy was used for secondary. Atlas Ti and Policy Maker software were used for processing and analysing the data. RESULTS: A list of strengths and weaknesses was presented as evidence of health system governance. Accountability at federal level (even though not lacking) was of a prescriptive nature and a system of accountability and transparency regarding the assignment of resources and strategies for the democratisation of health in the states and municipalities was still lacking. CONCLUSIONS: All six states had low levels of governance and experienced difficulty in conducting effective reform programmes and strategies involving a lack of precision regarding the rules and roles adopted by different health system actors. PMID- 25521948 TI - Measurement of parenchymal extravascular R2* and tissue oxygen extraction fraction using multi-echo vascular space occupancy MRI at 7 T. AB - Parenchymal extravascular R2* is an important parameter for quantitative blood oxygenation level-dependent (BOLD) studies. Total and intravascular R2* values and changes in R2* values during functional stimulations have been reported in a number of studies. The purpose of this study was to measure absolute extravascular R2* values in human visual cortex and to estimate the intra- and extravascular contributions to the BOLD effect at 7 T. Vascular space occupancy (VASO) MRI was employed to separate out the extravascular tissue signal. Multi echo VASO and BOLD functional MRI (fMRI) with visual stimulation were performed at 7 T for R2* measurement at a spatial resolution of 2.5 * 2.5 * 2.5 mm(3) in healthy volunteers (n = 6). The ratio of changes in extravascular and total R2* (DeltaR2*) was used to estimate the extravascular fraction of the BOLD effect. Extravascular R2* values were found to be 44.66 +/- 1.55 and 43.38 +/- 1.51 s(-1) (mean +/- standard error of the mean, n = 6) at rest and activation, respectively, in human visual cortex at 7 T. The extravascular BOLD fraction was estimated to be 91 +/- 3%. The parenchymal oxygen extraction fraction (OEF) during activation was estimated to be 0.24 +/- 0.01 based on the R2* measurements, indicating an approximately 37% decrease compared with OEF at rest. PMID- 25521950 TI - [Equity-based considerations for transforming the Ecuadorian health system]. AB - OBJECTIVE: The present study was aimed at analysing socioeconomic inequity regarding the use of health services in Ecuador, inequity regarding the geographic distribution of healthcare-related human resources and reflecting on the challenges concerning equity which the Ecuadorian health system is currently facing. METHODS: The Ecuadorian Demographic, Maternal and Infant Health Survey (2004) was used as the main data source, as its sample was representative of the Ecuadorian population. Multilevel multivariate analysis (MLWiN 2.02 statistical software) and spatial data analysis regarding health resources (GeoDa 1.0.1) were used for estimating the effects of using health services. RESULTS: It was found that social, economic and geographic inequity limited access to health services in Ecuador. People living in low economic resource households or indigenous housing and people living in rural areas (many of them having all three characteristics at the same time) had less possibility of using health services. In spite of a marked concentration of health-service providers in urban areas, it was found that the presence of healthcare personnel (excluding doctors) in rural public entities increased the possibility of using preventative and curative services. CONCLUSIONS: Efforts at transforming the Ecuadorian health system must be aimed at reducing social, cultural and financial barriers and inequality regarding the distribution de healthcare-related human resources, particularly in rural areas. Community and family orientation of the services and increasing spaces for citizen participation are necessary for reducing such inequity. PMID- 25521951 TI - [The judicialisation of health as a means ensuring access to medicines]. AB - OBJECTIVE: A systematic review, focusing on the judicialisation of health regarding gaining access to medicines, was aimed at understanding the impact of lawsuits on the organisation of public health services. METHOD: Original articles published between 2007 and 2011 in the pertinent national and international literature were analysed, resulting in 49,239 articles being found in Science Direct and BIREME databases. Results The survey indicated a predominance of literature from Brazil, mainly the southeast, as well as a study from Colombia. DISCUSSION: The aforementioned chronic disease-related claims involved diabetes, high blood pressure, cancer and rheumatoid arthritis. Forming part of specific Unified Healthcare System programmes highlighted the difficulty in gaining access to the appropriate medicine and consequent health judicialisation demonstrated the fragility of existing public policy. CONCLUSION: It was concluded that the courts (despite being a strategy for ensuring access to medicine) were unable to deal with the current spate of lawsuits, thereby leading to disruption regarding the flow of public systems. PMID- 25521952 TI - [Cooperative learning for improving healthy housing conditions in Bogota: a case study]. AB - OBJECTIVE: This was a community-based effort at constructing an educational proposal orientated towards self-empowerment aimed at improving the target population's sanitary, housing and living conditions through cooperative learning. METHODS: A constructivist approach was adopted based on a programme called "Habitat community manger". The project involved working with fifteen families living in the Mochuelo Bajo barrio in Ciudad Bolivar in Bogota, Colombia, for identifying the most relevant sanitary aspects for improving their homes and proposing a methodology and organisation for an educational proposal. RESULTS: Twenty-one poor housing-related epidemiological indicators were identified which formed the basis for defining specific problems and establishing a methodology for designing an educational proposal. DISCUSSION: The course which emerged from the cooperative learning experience was designed to promote the community's skills and education regarding health aimed at improving households' living conditions and ensuring a healthy environment which would allow them to develop an immediate habitat ensuring their own welfare and dignity. PMID- 25521953 TI - Sociodemographic determinants of university students' lifestyles. AB - OBJECTIVE: It has been observed during recent decades that a large percentage of the population has an inadequate lifestyle and that there is a need for identifying factors determining such behavior pattern. This study was thus aimed at determining the association between lifestyle and sociodemographic variables of freshmen attending a state university in southern Brazil. METHODS: The sample consisted of 716 students (59.6 % female). The Fantastic questionnaire was used for evaluating the students' lifestyles; their lifestyle was classified as being suitable or inadequate. The sociodemographic variables of interest were gender, age group (<20 and >= 20 years), paid work (yes or no), maternal education (<= 4 years of study, 5-8 years and >= 9 years), study shift (daytime or night-time) and marital status (single and married). Binary logistic regression was used for determining associations between lifestyle and sociodemographic characteristics (p<0.05 being significant). RESULTS: Inadequate lifestyle prevalence was 5.3 %. Adjusted analysis results indicated that students over 20 years-old (OR=2.87: 1.37-6.03 95 %CI) whose mothers' formal education had lasted less than nine years (OR=2.23: 1.29-3.88 95 %CI) had a higher risk of having an inadequate lifestyle. CONCLUSION: These findings may be useful for developing university healthcare promotion programs, paying special attention to older freshmen whose mothers have had less formal education. PMID- 25521954 TI - [Social, demographic, family and economic factors related to adolescent pregnancy in the urban area of Briceno, 2012]. AB - OBJECTIVE: To establish the relationship between the social, demographic, economic and family with pregnancy in adolescents 13 to 19 years in urban areas in the municipality of Briceno, 2012, for the purpose of obtaining information for the formulation of public health policies sexual and reproductive health. Methods: Cross sectional study, conducted in the urban area of Antioquia Briceno, between April and May 2012. A survey was conducted to gather information on factors: social, demographic, economic and family. Implemented a logistic regression model. RESULTS: The adolescents who were 193 survey respondents. Factors associated by multivariate analysis with increased risk of teenage pregnancy were age (OR: 8.33 CI, 1.82 to 38.14), socioeconomic status (OR: 12.52 CI, 1.58 to 98, 91), occupation (OR: 7.60 CI 3.0 to 19.27), living with a partner (OR: 17.47 CI, 3.63 to 83.94), early initiation of sex (OR: 1.95 CI, 0.69 to 5.5), the number of sexual partners (OR: 1.70 CI, 0.74 to 3.86), the father's education level (OR: 3.05 CI 1.01 to 9.22), the fact of having been raped (OR: 3.66 CI, 1.12 to 11.96) and family income (OR: 3.98 CI, 1,45-10, 92). CONCLUSIONS: The study found that age, socioeconomic status, occupation, living with the couple, early initiation of sexual intercourse, number of sexual partners, the educational level of the father, having been raped and the family income were associated with teenage pregnancy in the urban area of Briceno. PMID- 25521955 TI - [Cost-effectiveness analysis (CEA) regarding vitamin A in children aged less than 5 years-old in Colombia]. AB - OBJECTIVE: Evaluating the relative cost-effectiveness of using vitamin A in children aged less than 5-years-old regarding the reduction of events involving diarrhoea, malaria and mortality from the Colombian health-related social security system (CHSSS). MATERIALS AND METHODS: A decision tree was constructed, using deaths averted as outcome. Probabilities were taken from the pertinent literature and costs from official sources. The cost-effectiveness threshold was three times greater than the per capita Colombian gross domestic product (GDP) in 2012. Probabilistic and deterministic sensitivity analyses were made and cost effectiveness acceptability curves were drawn. RESULTS: Providing a cohort of 100,000 children with vitamin A (as opposed to not doing so) would represent a saving regarding medical attention costs of $ 340,306,917 due to the number of events involving diarrhea (4,268) and malaria (76), having become reduced, as well as cases requiring hospitalization. A saving for the CHSSS was consistently obtained in sensitivity analysis. CONCLUSION: Providing vitamin supplements for children aged less than 5 years-old would seem to be the least costly and most effective (dominant) strategy for the CHSSS, i.e. compared to not doing so). PMID- 25521956 TI - [Validating and standardizing children's box and block test normal values]. AB - OBJECTIVE: Evaluating gross motor skills forms part of a child's functional examination. The box and block test is a simple, useful method for evaluating upper limb functionality. This study was aimed at validating and standardising the test's normal values in 6 to 11 year-old Colombian children. METHODS: The test was used on 411 children from two schools in Bogota catering for children different socioeconomic classes. A questionnaire directed towards parents and teachers was used for evaluating the children's performance on every-day life and school-related activities for validating the construct; correlation with the test was established. RESULTS: Data related to 386 children (55.4% male) was analysed; 67.9% of these children were attending a public school and 90.2% had right dominance. Average test score with the right hand was 60.9 and 57.8 with the left hand. DISCUSSION: Girls' average test scores were significantly higher. A table was constructed from (and showing) the average values, standard deviation and range of normality. A positive correlation was found regarding test result with age and every-day life activities and the teachers' appreciation of children's scholastic abilities. The test was reliable, having 0.84 intraclass correlation for the right hand and 0.83 for the left hand. PMID- 25521957 TI - [Using equations for identifying and classifying children and adolescents' body fat]. AB - OBJECTIVE: Determining the correlation between equations for estimating body fat percentage (BFP) based on Slaughter's anthropometric equation, which deals with skinfold measurement, and Deurenberg's equations for predicting total percentage body fat (%BF) which use body mass index (BMI) results. METHODS: This study used data concerning 1,341 children and adolescents aged seven to 15 years-old (564 boys and 777 girls). Slaughter and Deurenberg's equations were used for calculating BFP and the Wilcoxon test, Spearman correlation, Bland-Altman scatter plot and Kappa index were used for analyzing the data. RESULTS: A high correlation was identified (>0.75); however, there was a statistically significant difference between BFP values obtained by both equations for males and females. The results also indicated slight agreement (k<=0.4) between percentage fat obtained from the equations used here. CONCLUSION: Slaughter and Deurenberg's equations had little agreement in terms of fat percentage values they gave differing results at all body fat levels. PMID- 25521958 TI - [Young adults' lower limb neuroconduction study reference values]. AB - OBJECTIVE: Establishing reference values for neuroconduction studies regarding the peroneal, tibial and sural nerves in a group of young adults. MATERIALS AND METHODS: Neuroconduction was tested (also known as nerve conduction velocity (NCV) tests) on 155 asymptomatic subjects' tibial, peroneal and sural nerves using current conventional techniques, after informed written consent had been obtained. Reference values were obtained and presented as averages, standard deviations and percentiles, along with their correlation with parameters such as age, weight and height, via bivariate analysis of linear correlation using Spearman's rank correlation test. RESULTS: Peroneal nerve average distal latency was 3.6 ms (0.4 SD), amplitude 6.1 mV (2.0 SD) and conduction velocity 54.8m/s (4.2 SD). Average tibial nerve distal latency was 3.5 ms (0.4 SD), amplitude 16.7mV (4.7 SD) and conduction velocity 53 m/s (3.8 SD). Average sural nerve peak latency was 3.4 ms (0.3 SD) and amplitude 21.3V (5.0 SD). Peroneal and tibial nerve upper limit of normal side to side variation was 0.8ms (average+2DE) and 0.4 ms (average + 2 SD) for the sural nerve. A statistically significant relationship was found with variables such as weight, height and age. CONCLUSIONS: The values so obtained could be used in Colombia's electrophysiology laboratories as reference in evaluating patients' suffering musculoskeletal pathologies and different types of polyneuropathy. PMID- 25521959 TI - [Evaluating language acquisition using the Early Language Milestone (ELM) and Munich developmental scales]. AB - OBJECTIVE: Evaluating language development by comparing the Munich Development method to the Early Language Milestone scale for identifying both diagnostic tests' agreement and enriching neurodevelopmental consultation. METHODS: The clinical histories of a cohort of 129 children were evaluated, as prematurity is a risk factor for deviation in children's language development. The children had less than 40 weeks gestational age and 0 to 12 months corrected age. They were given both tests between 2008 and 2011. The results from both scales were compared regarding receptive and expressive language and visual response (Early Language Milestone scale) and evaluation of verbal response, vocal play, understanding and expression (Munich scale). Student's T-test was used for comparing means for paired samples. Results: A statistically significant correlation (p<0.05) was found between both tests and between them and corrected age. It was seen that the higher the corrected age, the greater correlation there was between tests. CONCLUSION: The Early Language Milestone and Munich Development scales, regarding their components dealing with language, both represent useful tools for following-up premature children's language development. PMID- 25521960 TI - [Compliance with current standards for the early detection of neonatal hearing loss]. AB - OBJECTIVE: Assessing compliance with the section "Assessment of hearing" stipulated in the Technical Standard to Detect Alteration in children aged less than 10 years-old in Bogota. METHODS: This was a cross-sectional study which involved reviewing the medical records of all children born between July 1st and December 31st 2010 in two healthcare institutions in Bogota. Records were selected in which any of the following risk factors appeared: neonatal hyperbilirubinaemia involving phototherapy, neonatal exposure to ototoxic substances and/or <1.500 gr low birth weight. It was also ascertained whether children had been referred to an auditory evoked potential test as the prescribed screening test for neonatal hearing, as stipulated in mandatory Colombian technical standards for detecting abnormal growth and developmental in children aged less than ten years-old. RESULTS: Neither of the two institutions was making the aforementioned referral test. DISCUSSION: The results indicated significant difficulties in adherence to the protocol for the early detection of hearing loss regarding pertinent/current neonatal Colombian regulations. PMID- 25521961 TI - A complexity-based approach to batterer intervention programmes. AB - This paper was aimed at providing opinion by adopting a complexity-based approach to coordinating nursing science and psychology concerning psycho-educational intervention for batterers regarding their partner or ex-partner. Improving both disciplines' interrelationship should facilitate implementing relevant action, thereby engendering motivation for change in participants and modifying sexist attitudes and beliefs. The document has analyzed the importance of coordinating scientific disciplines' action and defined guidelines for an approach involving intervention as well as highlighting implications for practice and research. PMID- 25521962 TI - Nanotopography alters nuclear protein expression, proliferation and differentiation of human mesenchymal stem/stromal cells. AB - Mesenchymal stem/stromal cells respond to physical cues present in their microenvironment such as substrate elasticity, geometry, or topography with respect to morphology, proliferation, and differentiation. Although studies have demonstrated the role of focal adhesions in topography-mediated changes of gene expression, information linking substrate topography to the nucleus remains scarce. Here we show by two-dimensional gel electrophoresis and western blotting that A-type lamins and retinoblastoma protein are downregulated in mesenchymal stem/stromal cells cultured on 350 nm gratings compared to planar substrates; these changes lead to a decrease in proliferation and changes in differentiation potential. PMID- 25521963 TI - Synthesis and biological evaluation of 2-aryliminopyrrolidines as selective ligands for I1 imidazoline receptors: discovery of new sympatho-inhibitory hypotensive agents with potential beneficial effects in metabolic syndrome. AB - New 2-aryliminopyrrolidines (1-18) were synthesized and tested for their binding properties on I1 imidazoline receptors vs alpha2-adrenergic receptors and their blood pressure effects after both systemic and intracerebral administrations. The purposes of this study were: (i) to analyze structure-activity and affinity relationships on I1 imdazoline receptors and (ii) to propose some leader compounds for the development of new sympatho-inhibitory drugs with potential applications in hypertension and/or metabolic syndrome, i.e., a cluster of cardiovascular (hypertension) and metabolic disorders. Our study highlights decisive arguments of SAR concerning both the affinity for I1Rs and the hypotensive activity of 2-aryliminopyrrolidines. Binding assays showed high affinity and selectivity of some compounds for I1 imidazoline receptors over alpha2-adreergic receptors. Compound 13 (laboratory reference LNP599; Ki = 3.2 nM on I1imidazoline receptors) is the prototype for the development of new centrally acting agents targeting specifically I1imidazoline receptors to be used in the management of hypertension and/or metabolic syndrome. PMID- 25521964 TI - Effect of solvent and protonation/deprotonation on electrochemistry, spectroelectrochemistry and electron-transfer mechanisms of N-confused tetraarylporphyrins in nonaqueous media. AB - A series of N-confused free-base meso-substituted tetraarylporphyrins was investigated by electrochemistry and spectroelectrochemistry in nonaqueous media containing 0.1 M tetra-n-butylammonium perchlorate (TBAP) and added acid or base. The investigated compounds are represented as (XPh)4 NcpH2 , in which "Ncp" is the N-confused porphyrin macrocycle and X is a OCH3 , CH3 , H, or Cl substituent on the para position of each meso-phenyl ring of the macrocycle. Two distinct types of UV/Vis spectra are initially observed depending upon solvent, one corresponding to an inner-2H form and the other to an inner-3H form of the porphyrin. Both forms have an inverted pyrrole with a carbon inside the cavity and a nitrogen on the periphery of the pi-system. Each porphyrin undergoes multiple irreversible reductions and oxidations. The first one-electron addition and first one-electron abstraction are located on the porphyrin pi-ring system to give pi-anion and pi-cation radicals with a potential separation of 1.52 to 1.65 V between the two processes, but both electrogenerated products are unstable and undergo a rapid chemical reaction to give new electroactive species, which were characterized in the present study. The effect of the solvent and protonation/deprotonation reactions on the UV/Vis spectra, redox potentials and reduction/oxidation mechanisms is discussed with comparisons made to data and mechanisms for the structurally related free-base corroles and porphyrins. PMID- 25521965 TI - Molecular profiling of thyroid cancer subtypes using large-scale text mining. AB - BACKGROUND: Thyroid cancer is the most common endocrine tumor with a steady increase in incidence. It is classified into multiple histopathological subtypes with potentially distinct molecular mechanisms. Identifying the most relevant genes and biological pathways reported in the thyroid cancer literature is vital for understanding of the disease and developing targeted therapeutics. RESULTS: We developed a large-scale text mining system to generate a molecular profiling of thyroid cancer subtypes. The system first uses a subtype classification method for the thyroid cancer literature, which employs a scoring scheme to assign different subtypes to articles. We evaluated the classification method on a gold standard derived from the PubMed Supplementary Concept annotations, achieving a micro-average F1-score of 85.9% for primary subtypes. We then used the subtype classification results to extract genes and pathways associated with different thyroid cancer subtypes and successfully unveiled important genes and pathways, including some instances that are missing from current manually annotated databases or most recent review articles. CONCLUSIONS: Identification of key genes and pathways plays a central role in understanding the molecular biology of thyroid cancer. An integration of subtype context can allow prioritized screening for diagnostic biomarkers and novel molecular targeted therapeutics. Source code used for this study is made freely available online at https://github.com/chengkun-wu/GenesThyCan. PMID- 25521966 TI - Novel therapeutic approaches for haemophilia. AB - The major therapy for haemophilia is plasma derived or recombinant clotting factors which are evolving steadily to increase potency, stability and half-life. Research in the area of haemophilia therapeutics, however, is not restricted only to modifications in the recombinant products, but alternate therapeutic strategies are being developed which are in different phases of experimental and clinical trials. This chapter reviews the diverse molecular innovations which are being developed for alternate therapeutic approaches in haemophilia. The data is mainly extracted from the literature and the Conference abstracts. Some of the novel therapeutic approaches include inhibition of anticoagulant pathway factors (activated protein C, antithrombin, tissue factor pathway inhibitor) by monoclonal antibodies, peptide inhibitors, DNA or RNA aptamers, use of variant coagulation factors (factor Xa, factor Va) which are more resistant to inactivation or enzymatically more active and antibody-mediated therapy including a humanized anti-factor IXa/X bispecific antibody mimicking factor VIII. Other approaches include nonsense mutation suppression, induction of prothrombotic microparticles by P-selectin-immunoglobulin chimeras, suppression of fibrinolytic potential either by antifibrinolytics or by the use of mutant molecules of fibrinolytic inhibitors. Few products are proposed as 'stand alone' treatment for haemophilia, while a few can be used as adjuvant therapies to recombinant factors with an aim to reduce the amount of factor intake. All efforts are underway to produce an alternate, novel drug for haemophilia which will have an increased half-life, subcutaneously injectable, non-immunogenic and effective both in the presence and absence of inhibitors. PMID- 25521967 TI - Quality evaluation of Hypericum ascyron extract by two-dimensional high performance liquid chromatography coupled with the colorimetric 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. AB - In this paper, a heart-cutting two-dimensional high-performance liquid chromatography coupled with the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) method was established for controlling the quality of different batches of Hypericum ascyron extract for the first time. In comparison with the common one-dimensional fingerprint, the second-dimensional fingerprint compiled additional spectral data and was hence more informative. The quality of H. ascyron extract was further evaluated by similarity measures and the same results were achieved, the correlation coefficients of the similarity of ten batches of H. ascyron extract were >0.99. Furthermore, we also evaluated the quality of the ten batches of H. ascyron extract by antibacterial activity. The result demonstrated that the quality of the ten batches of H. ascyron extract was not significantly different by MTT. Finally, we demonstrated that the second dimensional fingerprint coupled with the MTT method was a more powerful tool to characterize the quality of samples of batch to batch. Therefore the proposed method could be used to comprehensively conduct the quality control of traditional Chinese medicines. PMID- 25521968 TI - Prenatal screening: current practice, new developments, ethical challenges. AB - Prenatal screening pathways, as nowadays offered in most Western countries consist of similar tests. First, a risk-assessment test for major aneuploides is offered to pregnant women. In case of an increased risk, invasive diagnostic tests, entailing a miscarriage risk, are offered. For decades, only conventional karyotyping was used for final diagnosis. Moreover, several foetal ultrasound scans are offered to detect major congenital anomalies, but the same scans also provide relevant information for optimal support of the pregnancy and the delivery. Recent developments in prenatal screening include the application of microarrays that allow for identifying a much broader range of abnomalities than karyotyping, and non-invasive prenatal testing (NIPT) that enables reducing the number of invasive tests for aneuploidies considerably. In the future, broad NIPT may become possible and affordable. This article will briefly address the ethical issues raised by these technological developments. First, a safe NIPT may lead to routinisation and as such challenge the central issue of informed consent and the aim of prenatal screening: to offer opportunity for autonomous reproductive choice. Widening the scope of prenatal screening also raises the question to what extent 'reproductive autonomy' is meant to expand. Finally, if the same test is used for two different aims, namely detection of foetal anomalies and pregnancy related problems, non-directive counselling can no longer be taken as a standard. Our broad outline of the ethical issues is meant as an introduction into the more detailed ethical discussions about prenatal screening in the other articles of this special issue. PMID- 25521969 TI - Psychological aspects of individualized choice and reproductive autonomy in prenatal screening. AB - Probably the main purpose of reproductive technologies is to enable people who choose to do so to avoid the birth of a baby with a disabling condition. However the conditions women want information about and the 'price' they are willing to pay for obtaining that information vary enormously. Individual women have to arrive at their own prenatal testing choices by 'trading off' means and ends in order to resolve the dilemmas facing them. We know very little about how individuals make these trade-offs, so it is difficult to predict how new technologies will affect their choices and preferences. Uptake decisions can be expected to change, especially in the group of women who now are put off by some aspect of the current screening approach, where the avoidance of miscarriage risk may have provided a kind of 'psychological shelter', protecting a lot of people from having to make other decisions. Technologies such as Pre-implantation Genetic Diagnosis may remove a second 'psychological shelter' because they offer the means of avoiding the birth of an affected child without terminating a pregnancy. Even if new technologies will make some decisions easier in terms of their cognitive demands, they will also create new dilemmas and decision making will not necessarily become less stressful in emotional terms. Key challenges concern information and decision-making. PMID- 25521970 TI - For your interest? The ethical acceptability of using non-invasive prenatal testing to test 'purely for information'. AB - Non-invasive prenatal testing (NIPT) is an emerging form of prenatal genetic testing that provides information about the genetic constitution of a foetus without the risk of pregnancy loss as a direct result of the test procedure. As with other prenatal tests, information from NIPT can help to make a decision about termination of pregnancy, plan contingencies for birth or prepare parents to raise a child with a genetic condition. NIPT can also be used by women and couples to test purely 'for information'. Here, no particular action is envisaged following the test; it is motivated entirely by an interest in the result. The fact that NIPT can be performed without posing a risk to the pregnancy could give rise to an increase in such requests. In this paper, we examine the ethical aspects of using NIPT 'purely for information', including the competing interests of the prospective parents and the future child, and the acceptability of testing for 'frivolous' reasons. Drawing on several clinical scenarios, we claim that arguments about testing children for genetic conditions are relevant to this debate. In addition, we raise ethical concerns over the potential for objectification of the child. We conclude that, in most cases, using NIPT to test for adult-onset conditions, carrier status or non-serious traits presenting in childhood would be unacceptable. PMID- 25521971 TI - Prenatal screening, reproductive choice, and public health. AB - One widely held view of prenatal screening (PNS) is that its foremost aim is, or should be, to enable reproductive choice; this is the Pure Choice view. The article critiques this position by comparing it with an alternative: Public Health Pluralism. It is argued that there are good reasons to prefer the latter, including the following. (1) Public Health Pluralism does not, as is often supposed, render PNS more vulnerable to eugenics-objections. (2) The Pure Choice view, if followed through to its logical conclusions, may have unpalatable implications, such as extending choice well beyond health screening. (3) Any sensible version of Public Health Pluralism will be capable of taking on board the moral seriousness of abortion and will advocate, where practicable, alternative means of reducing the prevalence of disease and disability. (4) Public Health Pluralism is at least as well-equipped as the Pure Choice model to deal with autonomy and consent issues. PMID- 25521972 TI - A new ethical landscape of prenatal testing: individualizing choice to serve autonomy and promote public health: a radical proposal. AB - A new landscape of prenatal testing (PNT) is presently developing, including new techniques for risk-reducing, non-invasive sampling of foetal DNA and drastically enhanced possibilities of what may be rapidly and precisely analysed, surrounded by a growing commercial genetic testing industry and a general trend of individualization in healthcare policies. This article applies a set of established ethical notions from past debates on PNT for analysing PNT screening programmes in this new situation. While some basic challenges of PNT stay untouched, the new development supports a radical individualization of how PNT screening is organized. This reformation is, at the same time, difficult to reconcile with responsible spending of resources in a publicly funded healthcare context. Thus, while the ethical imperative of individualization holds and applies to PNT, the new landscape of PNT provides reasons to start rolling back the type of mass-screening programmes currently established in many countries. Instead, more limited offers are suggested, based on considerations of severity of conditions and optimized to simultaneously serve reproductive autonomy and public health within an acceptable frame of priorities. The new landscape of PNT furthermore underscores the ethical importance of supporting and including people with disabilities. For the very same reason, no ban on what may be analysed using PNT in the new landscape should be applied, although private offers must, of course, conform to strict requirements of respecting reproductive autonomy and what that means in terms of counselling. PMID- 25521973 TI - Prenatal screening: an ethical agenda for the near future. AB - Prenatal screening for foetal abnormalities such as Down's syndrome differs from other forms of population screening in that the usual aim of achieving health gains through treatment or prevention does not seem to apply. This type of screening leads to no other options but the choice between continuing or terminating the pregnancy and can only be morally justified if its aim is to provide meaningful options for reproductive choice to pregnant women and their partners. However, this aim should not be understood as maximizing reproductive choice per se. Only if understood as allowing prospective parents to avoid suffering related to living with (a child with) serious disorders and handicaps can prenatal screening be a publicly or collectively funded programme. The alternative of moving prenatal testing outside the healthcare system into the private sector is problematic, as it makes these tests accessible only to those who can afford to pay for it. New developments in prenatal screening will have to be assessed in terms of whether and to what extent they either contribute to or undermine the stated aim of providing meaningful options for reproductive choice. In the light of this criterion, this article discusses the introduction of the new non-invasive prenatal test (NIPT), the tendency to widen the scope of follow up testing, as well as the possible future scenarios of genome-wide screening and 'prenatal personalised medicine'. The article ends with recommendations for further debate, research and analysis. PMID- 25521974 TI - Dynamics of prenatal screening: new developments challenging the ethical framework. PMID- 25521975 TI - Rare cause of absence of femoral arterial pulse: bilateral common iliac artery hypoplasia. AB - Congenital anomaly of the iliac arteries is rare, and, given that patients are generally asymptomatic, diagnosis in the newborn period is difficult. Herein is presented the case of a newborn with bilateral hypoplasia of the common iliac arteries, seen on multi-slice computed tomography while investigating the absence of femoral pulse. This anomaly is a rare cause of absence of femoral arterial pulse. PMID- 25521976 TI - Transitional cell carcinoma in a patient with X-linked hyperimmunoglobulin M syndrome. AB - Patients with X-linked hyperimmunoglobulin M syndrome (XHIGM) have a defective CD40-CD40 ligand system and further immunoglobulin class-switching. They may present with recurrent infection and malignancy involving the liver, pancreas or biliary tract. We report here a case of poorly differentiated transitional cell carcinoma in a young man with XHIGM even on regular treatment and discuss the possible pathogenesis. Given that the triggering of the CD40-CD40 ligand system has been found to improve tumor immunogenicity in recent studies, future immunotherapy targeting the CD40 ligand for these patients may be feasible to prolong their survival. PMID- 25521977 TI - Successful treatment of relapsing autoimmune thrombotic thrombocytopenic purpura with rituximab. AB - Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening condition characterized by thrombotic microangiopathy. The standard treatment for TTP is plasmapheresis. For refractory or relapsing cases, various immunosuppressive agents have been tried, and among them rituximab has shown promising results. TTP is rarer in the pediatric age group and the use of rituximab in children with TTP is limited. Reported herein is the successful treatment of relapsing autoimmune TTP with rituximab in a 12-year-old girl. PMID- 25521978 TI - Rare but threatening complication of otitis media: lateral sinus thrombosis. AB - Although appropriate use of antibiotics has decreased mortality, lateral sinus thrombosis is a rare, important intracranial complication of acute otitis media. Herein is described the case of a 5-year-old patient with lateral sinus thrombosis after acute otitis media. We emphasize the need to be alert for lateral sinus thrombosis when treating acute otitis media. PMID- 25521979 TI - Diffuse cerebral vasospasm with infarct after intrathecal cytarabine in childhood leukemia. AB - Although the varied neurotoxicity of intrathecal (IT) chemotherapy for treatment of childhood acute leukemia is well known, most are related to transient post puncture headache, drug-induced arachnoiditis, or leukoencephalopathy after methotrexate or cytarabine. Cerebral vasospasm leading to acute infarct after IT chemotherapy is very uncommon in children. Reported herein is a rare case of diffuse cerebral vasospasm with subsequent cerebral infarct after IT cytarabine in a 7-year-old boy with acute lymphoblastic leukemia, who successfully recovered with supportive management, and a review of the literature. PMID- 25521980 TI - Novel TRAPPC2 mutation in a boy with X-linked spondylo-epiphyseal dysplasia tarda. AB - X-linked spondylo-epiphyseal dysplasia tarda (SEDT) is an X-linked recessive, late-onset, progressive skeletal disorder characterized by mild-to-moderate short trunked short stature. X-linked SEDT is caused by mutations in the gene TRAPPC2, which is located on chromosome Xp22. In the present study, we identified a novel splice-site mutation, c.93+1G>A, in TRAPPC2 in a 9-year-old Japanese patient who had X-linked SEDT and no family history of the disease. On reverse transcription polymerase chain reaction, the mutation resulted in a 4 bp frame-shift insertion between exon 3 and exon 4. The present case highlights the importance of genetic analysis for confirmatory diagnosis of X-linked SEDT, especially in cases without a positive family history. PMID- 25521981 TI - Antenatal ultrasound visualization of left testis that then vanished after birth. AB - A 10-month-old infant was referred for disappearance of the left testis, which had been confirmed as present on antenatal ultrasound at 38 weeks of gestation, as well as at the newborn physical exam and the 4 month exam. The right testis was enlarged, whereas the left testis was palpated as a nubbin. The right testis measured on ultrasound was 1.6 * 0.8 * 1.0 cm; the testicular volume was 0.67 cm(3). The left nubbin was hyperechoic, and accurate measurement of testicular components was difficult. At the age of 1 year 8 months, with the diagnosis of left vanishing testis, inguinal exploration was undertaken to rule out intra abdominal cryptorchidism. A fibrous nodule that connected to the spermatic vessels and the vas deferens was resected. Histopathology indicated a testicular remnant containing seminiferous tubules, hemosiderin deposits, calcification and marked fibrosis of the stroma, suggesting hemorrhagic infarction in utero. PMID- 25521982 TI - Fibroadenoma in Beckwith-Wiedemann syndrome with paternal uniparental disomy of chromosome 11p15.5. AB - Herein is described a case of breast fibroadenomas in a 16-year-old girl with Beckwith-Wiedemann syndrome (BWS) and uniparental disomy (UPD) of chromosome 11p15.5. She was clinically diagnosed with BWS and direct closure was performed for an omphalocele at birth. Subtotal and 90% pancreatectomy were performed for nesidioblastosis at the ages 2 months and 8 years, respectively. Bilateral multiple breast fibroadenomas were noted at the age of 16 and 17 years. In this case, paternal UPD of chromosome 11p15.5 was identified on microsatellite marker analysis. The relevant imprinted chromosomal region in BWS is 11p15.5, and UPD of chromosome 11p15 is a risk factor for BWS-associated tumorigenicity. Chromosome 11p15.5 consists of imprinting domains of IGF2, the expression of which is associated with the tumorigenesis of various breast cancers. This case suggests that fibroadenomas occurred in association with BWS. PMID- 25521984 TI - Trisomy 8 mosaicism with pyloric atresia and situs ambiguous. PMID- 25521983 TI - Cyclic fluctuation of blood pressure in neonatal neuroblastoma. AB - Herein is described a case of neonatal neuroblastoma with cyclic blood pressure fluctuation and elevated catecholamines. The fluctuations stabilized after treatment with alpha-adrenergic blocker and the perioperative course was uneventful. The possibility of catecholamine-related symptoms including hypertension, heart failure, and blood pressure fluctuations should be considered in the treatment for neuroblastoma; if they are present, treatment with alpha blockers is effective. PMID- 25521985 TI - Diabetic ketoacidosis and severe hypoglycemia in management of type 1 diabetes during 2003-2013. PMID- 25521987 TI - Hepatic focal nodular hyperplasia with congenital portosystemic shunt. AB - Hepatic focal nodular hyperplasia (FNH) is a rare benign tumor in children. Vascular anomalies have been identified as pathological features of FNH, but the etiology remains unclear. We describe a rare case including the time course of formation of hepatic FNH in response to congenital portosystemic shunt (PSS). A 4 month-old girl was identified on newborn mass screening to have hypergalactosemia, but no inherited deficiencies in galactose-metabolizing enzymes were found. Ultrasonography and per-rectal portal scintigraphy showed intrahepatic PSS of the right lobe as a cause of the hypergalactosemia. At age 12 months, the patient had elevated hepatic enzymes and small hypoechoic hepatic lesions around the shunt. On abdominal contrast-enhanced ultrasonography spoke wheel sign and central stellate scar were seen, which are typical features of hepatic FNH without biopsy. Congenital intrahepatic PSS should be evaluated on abdominal contrast-enhanced ultrasonography and observed over time because of its potential to develop into hepatic FNH. PMID- 25521988 TI - Prolonged incubation period in neonatal Pasteurella multocida meningitis and bacteremia. AB - Pasteurella multocida, often found as part of the human oral flora and in finger/toenails, also exists in many animals, especially cats, dogs, and pigs. Although rare, pasteurella infection in neonates can cause serious systemic disease, such as meningitis. In this article, a 23-day-old girl presented with decreased appetite and irritability for >2 days. Eighteen days previously her pet cat had jumped onto the left side of her head while she was sleeping. On laboratory data C-reactive protein was high, and on cerebrospinal fluid (CSF) analysis leukocyte count was extremely high, with low glucose and high protein. P. multocida grew out of the blood and CSF cultures, and she was successfully treated with antibiotics for 3 weeks. Although pasteurellosis rarely occurs, it can sometimes lead to life-threatening situations, so parents should exercise caution when having pets around their children. PMID- 25521989 TI - Postoperative mitral leaflet rupture in an infant with Loeys-Dietz syndrome. AB - This report describes an infantile case of Loeys-Dietz syndrome (LDS) with spontaneous mitral leaflet rupture. The patient was diagnosed with a type B interruption of the aortic arch. Bilateral pulmonary artery banding was performed 5 days after birth. On the 53rd day, intra-cardiac repair was performed without valvuloplasty. Although the operation was successful, mitral regurgitation deteriorated at 4 weeks after operation. On the 88th day, a mitral valvuloplasty was performed and a severely ruptured anterior leaflet was observed. Seven days after valvuloplasty, the mitral valve insufficiency again worsened and a fourth operation was performed. Two tears were observed in the anterior and posterior mitral valve leaflets, and a mitral valve replacement was required. Subsequently, the patient was diagnosed with LDS according to gene mutational status. LDS is known to have a poor prognosis with cardiovascular complications, but valve rupture has not been previously reported in other cases. PMID- 25521990 TI - Opsoclonus-myoclonus syndrome following rotavirus gastroenteritis. AB - Opsoclonus-myoclonus syndrome (OMS) is a rare neurologic disorder characterized by opsoclonus, myoclonus, ataxia and behavioral disturbance. In the pathogenesis, an autoimmune process with infectious or paraneoplastic trigger has been suggested. We describe the case of a 22-month-old girl with OMS following rotavirus gastroenteritis. Rotavirus should be considered in the differential diagnosis of OMS in children. PMID- 25521991 TI - Rare coincidence of familial central core disease and hemophagocytic lymphohistiocytosis. AB - Central core disease is a congenital myopathy caused by mutations in RYR1. A 6 year-old girl was admitted due to difficulty in running and climbing stairs. Another 13 members through the four generations had similar symptoms, indicating autosomal dominant inheritance. Muscle biopsy showed the characteristic central cores in predominant type 1 fibers. She later developed hemophagocytic lymphohistiocytosis. Mutation analysis identified c.14582G>A in RYR1, and c.1693delG and c.2954 + 5G>A in UNC13D. To our knowledge, this is the first case of a patient with central core disease, carrying a RYR1 mutation in a Korean large family, who had concurrent familial hemophagocytic lymphohistiocytosis. PMID- 25521992 TI - Wheezing as a sign of cor triatriatum sinister culminating in multiple organ failure. AB - Cardiac asthma or cardiac wheezing (CW) refers to a syndrome of dyspnea and wheezing that mimicks asthma clinically. Reported herein is the case of a 2-month old boy who presented with refractory wheezing as a sign of cor triatriatum sinister (CTS) that culminated in overwhelming multiple organ failure in a short time. On the day of admission, oxygen saturation (SpO2 ) was <80%. Heart rate was 198 beats/min and respiratory rate 58 breaths/min. Chest radiogram showed pulmonary edema. Electrocardiogram showed right atrial enlargement and right ventricular hypertrophy. N-terminal pro-brain natriuretic peptide (NTproBNP) was very high at >20,000 pg/mL. Two-dimensional echocardiography with Doppler showed CTS, which was complicated with severe pulmonary arterial hypertension due to flagrant pulmonary venous obstruction. Cardiac surgery was undertaken, after which pulmonary edema subsided, SpO2 increased to >=96%, and NTproBNP dropped to normal. He was discharged 11 days later, and was free of cardiac, pulmonary, renal, and neurological sequelae at 24 month follow up. PMID- 25521993 TI - Mycobacterium avium complex-associated peritonitis with CAPD after unrelated bone marrow transplantation. AB - Peritonitis remains an important complication of peritoneal dialysis and is mostly caused by aerobic enteric bacteria. Non-tuberculous mycobacteria (NTM) associated peritonitis is an unusual but serious infection, requiring special culture techniques to avoid delay in diagnosis. We report the case of an 11-year old girl with aplastic anemia on ambulatory peritoneal dialysis who had Mycobacterium avium complex-associated peritonitis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This case emphasizes that we should be constantly cautious about NTM infection in allo-HSCT recipients, especially when standard cultures are negative and the infection is refractory to empirical antibiotic therapy. PMID- 25521994 TI - Obesity hypoventilation syndrome in a 12-year-old child requiring therapeutic phlebotomy: case report and review of the literature. AB - The childhood obesity epidemic involves unusual and underrecognized complications associated with this clinical and public health problem. Obesity hypoventilation syndrome (OHS) is defined as the triad of obesity, daytime hypoventilation, and sleep-disordered breathing in the absence of an alternative neuromuscular, mechanical or metabolic explanation for hypoventilation. We herewith report a 12 year-old boy who was diagnosed with OHS. The patient improved with phlebotomy and bi-level positive airway pressure. To the best of our knowledge, this is the first reported case of secondary polycythemia due to OHS requiring therapeutic phlebotomy. PMID- 25521995 TI - PNGase F-mediated incorporation of (18)O into glycans for relative glycan quantitation. AB - PNGase F-catalyzed glycosylation site (18)O-labeling is a widely used method for glycoprotein quantitation owing to its efficiency and simplicity. However, PNGase F-catalyzed glycan (18)O-labeling, which offers advantages for glycomics, has not yet been developed. In this study, PNGase F-mediated incorporation of (18)O into glycans during the N-glycan release from glycoproteins by PNGase F was finally realized, named as PCGOL (PNGase F-catalyzed glycan (18)O-labeling), which offers a potential strategy for relative glycan quantitation. This new method showed good linearity and high reproducibility within at least 2 orders of magnitude in the dynamic range. Furthermore, PCGOL combined with our previously developed TOSIL method (tandem (18)O stable isotope labeling for N-glycoproteome quantitation) can be used for comprehensive N-glycosylation quantification, achieving simultaneous quantification of glycans, glycopeptides and glycoproteins in a single workflow, which was also used to analyze glycosylation changes in immunoglobulin G (IgG) associated with hepatocellular carcinoma in the present work. PMID- 25521996 TI - Interprofessional collaboration and co-publishing. PMID- 25521997 TI - Simple fecal flotation is a superior alternative to guadruple Kato Katz smear examination for the detection of hookworm eggs in human stool. AB - BACKGROUND: Microscopy-based identification of eggs in stool offers simple, reliable and economical options for assessing the prevalence and intensity of hookworm infections, and for monitoring the success of helminth control programs. This study was conducted to evaluate and compare the diagnostic parameters of the Kato-Katz (KK) and simple sodium nitrate flotation technique (SNF) in terms of detection and quantification of hookworm eggs, with PCR as an additional reference test in stool, collected as part of a baseline cross-sectional study in Cambodia. METHODS/PRINCIPLE FINDINGS: Fecal samples collected from 205 people in Dong village, Rovieng district, Preah Vihear province, Cambodia were subjected to KK, SNF and PCR for the detection (and in case of microscopy-based methods, quantification) of hookworm eggs in stool. The prevalence of hookworm detected using a combination of three techniques (gold standard) was 61.0%. PCR displayed a highest sensitivity for hookworm detection (92.0%) followed by SNF (44.0%) and quadruple KK smears (36.0%) compared to the gold standard. The overall eggs per gram feces from SNF tended to be higher than for quadruple KK and the SNF proved superior for detecting low egg burdens. CONCLUSION/SIGNIFICANCE: As a reference, PCR demonstrated the higher sensitivity compared to SNF and the quadruple KK method for detection of hookworm in human stool. For microscopic-based quantification, a single SNF proved superior to the quadruple KK for the detection of hookworm eggs in stool, in particular for low egg burdens. In addition, the SNF is cost-effective and easily accessible in resource poor countries. PMID- 25521999 TI - An analysis of common indications for bronchoscopy in neonates and findings over a 10-year period. AB - IMPORTANCE: There is a perceived increase in the number of microdirect laryngoscopies and bronchoscopies (MLBs) required on premature infants, infants with syndromic conditions, and those with complex congenital heart defects. Determining which neonates with certain underlying conditions require more aggressive interventions like tracheostomy, intubation, or supraglottoplasty might be useful for future preoperative planning and counseling of the families of newborns with complex medical conditions involving the airway. OBJECTIVES: To evaluate features and findings in neonates undergoing MLB in the first 28 days of life over a 10-year period and compare these findings with past publications. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case series of 162 consecutive patients 28 days or younger undergoing MLB between January 1, 2002, and December 31, 2012, at a tertiary care children's hospital. INTERVENTION: Microdirect laryngoscopy and bronchoscopy. MAIN OUTCOMES AND MEASURES: Frequencies of common indications and findings in neonates undergoing MLB. To determine if findings on MLB had significant associations with gestational age, neonates with cardiac defects or syndromic conditions, and neonates who had at least 1 other comorbid condition, chi2 and Fisher exact tests were performed. Similar associations were analyzed between neonates with other comorbid conditions and need for interventions such as supraglottoplasty, tracheostomy, and intubation. RESULTS: Of the 162 patients, 101 were male (55.5%). The mean age at their procedure was 14.1 days. The mean weight of patients at MLB was 3.31 kg, and 32 (17.6%) were premature. Congenital conditions were noted in 114 patients (62.6%), and of these, 55 (30.2%) had congenital cardiac disease and 30 (16.4%) had syndromic conditions. Common indications for surgery were respiratory distress (n = 145 [79.7%]), stridor (n = 102 [56.0%]), and cyanosis or an acute life-threatening event (n = 67 [36.8%]). The most common findings at the time of surgery were laryngomalacia (n = 71 [39.0%]), subglottic stenosis (n = 58 [31.9%]), and tracheomalacia (n = 47 [25.8%]). Seventeen neonates (9.3%) required a tracheostomy, and 11 (6.0%) required a supraglottoplasty. Neonates with congenital heart defects were statistically significantly more likely to require long-term intubation (n = 9 [16.4%]; P = .03). Those with syndromic conditions were more likely to require long-term intubation and tracheostomy (n = 7 [23.3%] [P = .004] and n = 7 [23.3%] [P = .01], respectively). Premature infants who required MLB had a decreased incidence of laryngomalacia (n = 7 [21.9%]; P = .03), and those with comorbid conditions, an increased incidence (n = 43 [33.3%]; P = .01). There was minimal morbidity directly associated with the procedure. CONCLUSIONS AND RELEVANCE: Neonates undergoing MLB most commonly presented with respiratory distress and stridor and were most commonly found to have laryngomalacia and subglottic stenosis. More than half of the patients studied had other comorbid conditions. Those with cardiac defects and syndromic conditions were more likely to require intubation, and those with syndromic conditions were more likely to eventually undergo tracheostomy. PMID- 25521998 TI - Epistasis and the sensitivity of phenotypic screens for beta thalassaemia. AB - Genetic disorders of haemoglobin, particularly the sickle cell diseases and the alpha and beta thalassaemias, are the commonest inherited disorders worldwide. The majority of affected births occur in low-income and lower-middle income countries. Screening programmes are a vital tool to counter these haemoglobinopathies by: (i) identifying individual carriers and allowing them to make informed reproductive choices, and (ii) generating population level gene frequency estimates, to help ensure the optimal allocation of public health resources. For both of these functions it is vital that the screen performed is suitably sensitive. One popular first-stage screening option to detect carriers of beta thalassaemia in low-income countries is the One Tube Osmotic Fragility Test (OTOFT). Here we introduce a population genetic framework within which to quantify the likely sensitivity and specificity of the OTOFT in different epidemiological contexts. We demonstrate that interactions between the carrier states for beta thalassaemia and alpha thalassaemia, glucose-6-phosphate dehydrogenase deficiency and Southeast Asian Ovalocytosis have the potential to reduce the sensitivity of OTOFTs for beta thalassaemia heterozygosity to below 70%. Our results therefore caution against the widespread application of OTOFTs in regions where these erythrocyte variants co-occur. PMID- 25522001 TI - Chemoenzymatic synthesis of the enantiomer of 4,12-dihydroxysterpurene, the structure assigned to a metabolite isolated from the culture broth of Stereum purpureum. AB - Compound ent-1 has been prepared by engaging a derivative of the enantiomerically enriched and microbially derived cis-1,2-dihydrocatechol 6 in an intramolecular Diels-Alder reaction, elaboration of the adduct so-formed to the cyclopentannulated bicyclo[2.2.2]octenone 3, and photochemical rearrangement of this to the cyclobutanone 2. By such means it has been established that 4,12 dihydroxysterpurene (1) is not the structure of the natural product isolated by Xie and co-workers from a culture broth of Stereum purpureum. PMID- 25522000 TI - Characterization of the physical stability of a lyophilized IgG1 mAb after accelerated shipping-like stress. AB - Upon exposure to shaking stress, an IgG1 mAb formulation in both the liquid and lyophilized state formed subvisible particles. Because freeze-drying was expected to minimize protein physical instability under these conditions, the extent and nature of aggregate formation in the lyophilized preparation were examined using a variety of particle characterization techniques. The effects of formulation variables such as residual moisture content, reconstitution rate, and reconstitution medium were also examined. Upon reconstitution of shake-stressed lyophilized mAb, differences in protein particle size and number were observed by microflow digital imaging, with the reconstitution medium having the largest impact. Shake stress had minor effects on the structure of protein within the particles as shown by SDS-PAGE and FTIR analysis. The lyophilized mAb was shake stressed to different extents and stored for 3 months at different temperatures. Both extent of cake collapse and storage temperature affected the physical stability of the shake-stressed lyophilized mAb upon subsequent storage. These findings demonstrate that physical degradation upon shaking of a lyophilized IgG1 mAb formulation includes not only cake breakage, but also results in an increase in subvisible particles and turbidity upon reconstitution. The shake-induced cake breakage of the lyophilized IgG1 mAb formulation also resulted in decreased physical stability upon storage. PMID- 25522002 TI - Fatty liver disease, glucose tolerance and insulin resistance in obese adolescents. AB - BACKGROUND/OBJECTIVES: Adult studies suggest that intra-hepatic fat predicts 2-h blood glucose levels and type 2 diabetes, and may have a role in the development of insulin resistance. Our study objective was to explore relationships between intra-hepatic fat and (i) blood glucose levels and (ii) insulin resistance determined by homeostasis model assessment (HOMA) in a group of obese adolescents. METHODS: Subjects were 61 obese non-diabetic male and female volunteers aged 12-18 years inclusive with a body mass index >95th percentile for age and 2-h blood glucose <200 mg dL(-1) . Each subject underwent 2-h glucose tolerance testing and measurement of haemoglobin A1c, ultrasensitive C-reactive protein and fasting insulin. Visceral, subcutaneous abdominal and intra-hepatic fat were determined by magnetic resonance imaging. Intra-hepatic fat was measured by gradient echo chemical shift imaging. RESULTS: Alanine aminotransferase levels and hepatic phase difference were not significant correlates of fasting or 2-h glucose. In a multiple regression model including hepatic phase difference and visceral fat volume, visceral fat volume was the sole predictor of HOMA. CONCLUSIONS: This study provides no support to the notion that intra-hepatic fat has a role in the regulation of fasting blood glucose, 2-h postprandial blood glucose or systemic insulin resistance. PMID- 25522003 TI - HCV 3a core protein increases lipid droplet cholesteryl ester content via a mechanism dependent on sphingolipid biosynthesis. AB - Hepatitis C virus (HCV) infected patients often develop steatosis and the HCV core protein alone can induce this phenomenon. To gain new insights into the pathways leading to steatosis, we performed lipidomic profiling of HCV core protein expressing-Huh-7 cells and also assessed the lipid profile of purified lipid droplets isolated from HCV 3a core expressing cells. Cholesteryl esters, ceramides and glycosylceramides, but not triglycerides, increased specifically in cells expressing the steatogenic HCV 3a core protein. Accordingly, inhibitors of cholesteryl ester biosynthesis such as statins and acyl-CoA cholesterol acyl transferase inhibitors prevented the increase of cholesteryl ester production and the formation of large lipid droplets in HCV core 3a-expressing cells. Furthermore, inhibition of de novo sphingolipid biosynthesis by myriocin - but not of glycosphingolipid biosynthesis by miglustat - affected both lipid droplet size and cholesteryl ester level. The lipid profile of purified lipid droplets, isolated from HCV 3a core-expressing cells, confirmed the particular increase of cholesteryl ester. Thus, both sphingolipid and cholesteryl ester biosynthesis are affected by the steatogenic core protein of HCV genotype 3a. These results may explain the peculiar lipid profile of HCV-infected patients with steatosis. PMID- 25522005 TI - A convergent approach to the total synthesis of telmisartan via a Suzuki cross coupling reaction between two functionalized benzimidazoles. AB - A direct and efficient total synthesis has been developed for telmisartan, a widely prescribed treatment for hypertension. This approach brings together two functionalized benzimidazoles using a high-yielding Suzuki reaction that can be catalyzed by either a homogeneous palladium source or graphene-supported palladium nanoparticles. The ability to perform the cross-coupling reaction was facilitated by the regio-controlled preparation of the 2-bromo-1 methylbenzimidazole precursor. This convergent approach provides telmisartan in an overall yield of 72% while circumventing many issues associated with previously reported processes. PMID- 25522004 TI - Metadynamics simulations reveal a Na+ independent exiting path of galactose for the inward-facing conformation of vSGLT. AB - Sodium-Galactose Transporter (SGLT) is a secondary active symporter which accumulates sugars into cells by using the electrochemical gradient of Na+ across the membrane. Previous computational studies provided insights into the release process of the two ligands (galactose and sodium ion) into the cytoplasm from the inward-facing conformation of Vibrio parahaemolyticus sodium/galactose transporter (vSGLT). Several aspects of the transport mechanism of this symporter remain to be clarified: (i) a detailed kinetic and thermodynamic characterization of the exit path of the two ligands is still lacking; (ii) contradictory conclusions have been drawn concerning the gating role of Y263; (iii) the role of Na+ in modulating the release path of galactose is not clear. In this work, we use bias-exchange metadynamics simulations to characterize the free energy profile of the galactose and Na+ release processes toward the intracellular side. Surprisingly, we find that the exit of Na+ and galactose is non-concerted as the cooperativity between the two ligands is associated to a transition that is not rate limiting. The dissociation barriers are of the order of 11-12 kcal/mol for both the ion and the substrate, in line with kinetic information concerning this type of transporters. On the basis of these results we propose a branched six state alternating access mechanism, which may be shared also by other members of the LeuT-fold transporters. PMID- 25522006 TI - Microscopic diffusion properties of fixed breast tissue: Preliminary findings. AB - PURPOSE: To investigate the microscopic diffusion properties of formalin-fixed breast tissue. METHODS: Diffusion microimaging was performed at 16.4T with 40-MUm isotropic voxels on two normal and two cancer tissue samples from four patients. Results were correlated with histology of the samples. RESULTS: Diffusion weighted images and mean diffusivity maps demonstrated distinct diffusivity differences between breast tissue components. Mean diffusivity (MD) in normal tissue was 0.59 +/- 0.24 MUm(2) /ms for gland lobule (voxels containing epithelium and intralobular stroma) and 1.23 +/- 0.34 MUm(2) /ms for interlobular fibrous stroma. In the cancer samples, MD = 0.45 +/- 0.23 MUm(2) /ms for invasive ductal carcinoma (voxels contain epithelium and intralobular stroma) and 0.61 +/- 0.35 MUm(2) /ms for ductal carcinoma in situ. There were significant MD differences between all tissue components (P < 0.005), except between gland lobule and ductal carcinoma in situ (P = 0.71). The low diffusivity of epithelium rich cancer tissue and of normal epithelium relative to its supporting fibrous stroma was similar to that reported for prostate tissue and the esophageal wall. CONCLUSION: Diffusion microimaging demonstrates distinct diffusivity differences between breast tissue glandular structures. Low diffusivity may be a distinctive feature of mammalian epithelia. PMID- 25522007 TI - Bayesian risk mapping and model-based estimation of Schistosoma haematobium Schistosoma mansoni co-distribution in Cote d'Ivoire. AB - BACKGROUND: Schistosoma haematobium and Schistosoma mansoni are blood flukes that cause urogenital and intestinal schistosomiasis, respectively. In Cote d'Ivoire, both species are endemic and control efforts are being scaled up. Accurate knowledge of the geographical distribution, including delineation of high-risk areas, is a central feature for spatial targeting of interventions. Thus far, model-based predictive risk mapping of schistosomiasis has relied on historical data of separate parasite species. METHODOLOGY: We analyzed data pertaining to Schistosoma infection among school-aged children obtained from a national, cross sectional survey conducted between November 2011 and February 2012. More than 5,000 children in 92 schools across Cote d'Ivoire participated. Bayesian geostatistical multinomial models were developed to assess infection risk, including S. haematobium-S. mansoni co-infection. The predicted risk of schistosomiasis was utilized to estimate the number of children that need preventive chemotherapy with praziquantel according to World Health Organization guidelines. PRINCIPAL FINDINGS: We estimated that 8.9% of school-aged children in Cote d'Ivoire are affected by schistosomiasis; 5.3% with S. haematobium and 3.8% with S. mansoni. Approximately 2 million annualized praziquantel treatments would be required for preventive chemotherapy at health districts level. The distinct spatial patterns of S. haematobium and S. mansoni imply that co-infection is of little importance across the country. CONCLUSIONS/SIGNIFICANCE: We provide a comprehensive analysis of the spatial distribution of schistosomiasis risk among school-aged children in Cote d'Ivoire and a strong empirical basis for a rational targeting of control interventions. PMID- 25522008 TI - A recombinant avian leukosis virus subgroup j for directly monitoring viral infection and the selection of neutralizing antibodies. AB - Avian leukosis virus subgroup J (ALV-J) has induced serious clinical outbreaks and has become a serious infectious disease of chickens in China. We describe here the creation of a recombinant ALV-J tagged with the enhanced green fluorescent protein (named rHPRS-103EGFP). We successfully utilize the rHPRS 103EGFP to visualize viral infection and for development of a simplified serum neutralization test. PMID- 25522009 TI - Clinical predictive circulating peptides in rectal cancer patients treated with neoadjuvant chemoradiotherapy. AB - Preoperative chemoradiotherapy is worldwide accepted as a standard treatment for locally advanced rectal cancer. Current standard of treatment includes administration of ionizing radiation for 45-50.4 Gy in 25-28 fractions associated with 5-fluorouracil administration during radiation therapy. Unfortunately, 40% of patients have a poor or absent response and novel predictive biomarkers are demanding. For the first time, we apply a novel peptidomic methodology and analysis in rectal cancer patients treated with preoperative chemoradiotherapy. Circulating peptides (Molecular Weight <3 kDa) have been harvested from patients' plasma (n = 33) using nanoporous silica chip and analyzed by Matrix-Assisted Laser Desorption/Ionization-Time of Flight mass spectrometer. Peptides fingerprint has been compared between responders and non-responders. Random Forest classification selected three peptides at m/z 1082.552, 1098.537, and 1104.538 that were able to correctly discriminate between responders (n = 16) and non-responders (n = 17) before therapy (T0) providing an overall accuracy of 86% and an area under the receiver operating characteristic (ROC) curve of 0.92. In conclusion, the nanoporous silica chip coupled to mass spectrometry method was found to be a realistic method for plasma-based peptide analysis and we provide the first list of predictive circulating biomarker peptides in rectal cancer patients underwent preoperative chemoradiotherapy. PMID- 25522011 TI - How malaria parasites avoid running out of ammo. PMID- 25522010 TI - Measles immune suppression: functional impairment or numbers game? PMID- 25522013 TI - Large-scale automated analysis of news media: a novel computational method for obesity policy research. AB - OBJECTIVE: Analyzing news media allows obesity policy researchers to understand popular conceptions about obesity, which is important for targeting health education and policies. A persistent dilemma is that investigators have to read and manually classify thousands of individual news articles to identify how obesity and obesity-related policy proposals may be described to the public in the media. A machine learning method called "automated content analysis" that permits researchers to train computers to "read" and classify massive volumes of documents was demonstrated. METHODS: 14,302 newspaper articles that mentioned the word "obesity" during 2011-2012 were identified. Four states that vary in obesity prevalence and policy (Alabama, California, New Jersey, and North Carolina) were examined. The reliability of an automated program to categorize the media's framing of obesity as an individual-level problem (e.g., diet) and/or an environmental-level problem (e.g., obesogenic environment) was tested. RESULTS: The automated program performed similarly to human coders. The proportion of articles with individual-level framing (27.7-31.0%) was higher than the proportion with neutral (18.0-22.1%) or environmental-level framing (16.0-16.4%) across all states and over the entire study period (P<0.05). CONCLUSIONS: A novel approach to the study of how obesity concepts are communicated and propagated in news media was demonstrated. PMID- 25522014 TI - Trisomy 12 is associated with an abbreviated redistribution lymphocytosis during treatment with the BTK inhibitor ibrutinib in patients with chronic lymphocytic leukaemia. PMID- 25522015 TI - Record-breaking Lake Erie hypoxia during 2012 drought. AB - Hypoxia has been observed in the central basin of Lake Erie for decades. To understand the impact of various controlling factors, we analyze a record of hypoxic extents for Lake Erie for 1985-2012 and develop a parsimonious model of their interannual variability. We find that the 2012 North American drought and accompanying low tributary discharge was associated with a record-breaking hypoxic event in Lake Erie, whereas a record-setting harmful algal bloom in 2011 was likely associated with only mild hypoxia. River discharge and the timing of nutrient input therefore impact western basin bloom growth and central basin oxygen demand in distinct ways that merit further investigation. Overall, April to June tributary discharge, May to July soluble reactive phosphorus loading, July wind stress, and June northwesterly wind duration explain 82% of the interannual variability of hypoxia, and discharge alone explains 39%, indicating that meteorological factors need to be considered in the development of nutrient management strategies, especially as both extreme precipitation events and droughts become more frequent under a changing climate. PMID- 25522016 TI - Anterolateral approach to the upper cervical spine: Case report and operative technique. AB - BACKGROUND: Transcervical approaches to the upper cervical spine are challenging because several upper anterior neurovascular structures need to be displaced to provide access. Although various techniques have been described, the anterolateral approach is one of the safest and most effective methods available to access the anterior C2-C3 disc space. Despite the approach's efficacy, however, it can cause postoperative complications because of, at least partly, the inter-surgeon differences in the methods by which the larynx and hypopharynx are displaced medially. METHODS AND RESULTS: We present a case report of a patient treated with a modified anterolateral approach to C2-C3. The approach provided excellent visualization while protecting vital structures. The patient recovered without any postoperative dysphagia or other surgical complications. CONCLUSION: The anterolateral approach to C2-C3 described herein safely protects the contents of the submandibular triangle while providing a wide exposure for direct access to the C2-C3 disc space. PMID- 25522017 TI - Human genetic variation in HIV disease: beyond genome-wide association studies. AB - PURPOSE OF REVIEW: Rapid expansion of genomic technologies has resulted in an unprecedented ability to interrogate the impact of human genetic variation on disease. HIV-1 infection is a unique model for studying this impact because host genetic variation influences both clinical outcome and the genetic sequence and evolution of the pathogen itself. RECENT FINDINGS: Several candidate gene studies have proposed novel associations with HIV acquisition and/or disease progression; however, many of these are not supported by larger genome-wide association studies. Thus, controversy remains as to which host and viral genetic factors truly impact HIV infection. Novel methods for assessing the genetic (viral and host) component of disease progression are becoming important areas of investigation. SUMMARY: To fully understand the impact of human genetic variation in HIV disease, the field will need to come together to set a standard for discovery of new genes. Additionally, novel avenues of investigation such as sequencing studies (to define the role of rare variants), studies of epistasis and host/viral genome interaction will be of great value. PMID- 25522022 TI - A lesson in empathy. PMID- 25522018 TI - Sirolimus use and cancer incidence among US kidney transplant recipients. AB - Sirolimus has anti-carcinogenic properties and can be included in maintenance immunosuppressive therapy following kidney transplantation. We investigated sirolimus effects on cancer incidence among kidney recipients. The US transplant registry was linked with 15 population-based cancer registries and national pharmacy claims. Recipients contributed sirolimus-exposed time when sirolimus claims were filled, and unexposed time when other immunosuppressant claims were filled without sirolimus. Cox regression was used to estimate associations with overall and specific cancer incidence, excluding nonmelanoma skin cancers (not captured in cancer registries). We included 32,604 kidney transplants (5687 sirolimus-exposed). Overall, cancer incidence was suggestively lower during sirolimus use (hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.70 1.11). Prostate cancer incidence was higher during sirolimus use (HR = 1.86, 95% CI = 1.15-3.02). Incidence of other cancers was similar or lower with sirolimus use, with a 26% decrease overall (HR = 0.74, 95% CI = 0.57-0.96, excluding prostate cancer). Results were similar after adjustment for demographic and clinical characteristics. This modest association does not provide strong evidence that sirolimus prevents posttransplant cancer, but it may be advantageous among kidney recipients with high cancer risk. Increased prostate cancer diagnoses may result from sirolimus effects on screen detection. PMID- 25522023 TI - Which oral valproic acid formulation is best for my patient? AB - The various oral formulations of valproic acid vary in dosing frequency, form, indication, and cost. This article describes how to determine which formulation to prescribe based on factors including the patient's diagnosis and financial situation. PMID- 25522024 TI - What is the physician assistant's role in Mohs micrographic surgery? PMID- 25522019 TI - Steric parameters, molecular modeling and hydropathic interaction analysis of the pharmacology of para-substituted methcathinone analogues. AB - BACKGROUND AND PURPOSE: There is growing concern over the abuse of certain psychostimulant methcathinone (MCAT) analogues. This study extends an initial quantitative structure-activity relationship (QSAR) investigation that demonstrated important steric considerations of seven 4- (or para-)substituted analogues of MCAT. Specifically, the steric character (Taft's steric ES ) of the 4-position substituent affected in vitro potency to induce monoamine release via dopamine and 5-HT transporters (DAT and SERT) and in vivo modulation of intracranial self-stimulation (ICSS). Here, we have assessed the effects of other steric properties of the 4-position substituents. EXPERIMENTAL APPROACH: Definitive steric parameters that more explicitly focus on the volume, width and length of the MCAT 4-position substituents were assessed. In addition, homology models of human DAT and human SERT based upon the crystallized Drosophila DAT were constructed and docking studies were performed, followed by hydropathic interaction (HINT) analysis of the docking results. KEY RESULTS: The potency of seven MCAT analogues at DAT was negatively correlated with the volume and maximal width of their 4-position substituents, whereas potency at SERT increased as substituent volume and length increased. SERT/DAT selectivity, as well as abuse related drug effects in the ICSS procedure, also correlated with the same parameters. Docking solutions offered a means of visualizing these findings. CONCLUSIONS AND IMPLICATIONS: These results suggest that steric aspects of the 4 position substituents of MCAT analogues are key determinants of their action and selectivity, and that the hydrophobic nature of these substituents is involved in their potency at SERT. PMID- 25522020 TI - dCaP: detecting differential binding events in multiple conditions and proteins. AB - BACKGROUND: Current ChIP-seq studies are interested in comparing multiple epigenetic profiles across several cell types and tissues simultaneously for studying constitutive and differential regulation. Simultaneous analysis of multiple epigenetic features in many samples can gain substantial power and specificity than analyzing individual features and/or samples separately. Yet there are currently few tools can perform joint inference of constitutive and differential regulation in multi-feature-multi-condition contexts with statistical testing. Existing tools either test regulatory variation for one factor in multiple samples at a time, or for multiple factors in one or two samples. Many of them only identify binary rather than quantitative variation, which are sensitive to threshold choices. RESULTS: We propose a novel and powerful method called dCaP for simultaneously detecting constitutive and differential regulation of multiple epigenetic factors in multiple samples. Using simulation, we demonstrate the superior power of dCaP compared to existing methods. We then apply dCaP to two datasets from human and mouse ENCODE projects to demonstrate its utility. We show in the human dataset that the cell-type specific regulatory loci detected by dCaP are significantly enriched near genes with cell-type specific functions and disease relevance. We further show in the mouse dataset that dCaP captures genomic regions showing significant signal variations for TAL1 occupancy between two mouse erythroid cell lines. The novel TAL1 occupancy loci detected only by dCaP are highly enriched with GATA1 occupancy and differential gene expression, while those detected only by other methods are not. CONCLUSIONS: Here, we developed a novel approach to utilize the cooperative property of proteins to detect differential binding given multivariate ChIP-seq samples to provide better power, aiming for complementing existing approaches and providing new insights in the method development in this field. PMID- 25522026 TI - Malignant hyperthermia in a trauma patient. AB - Malignant hyperthermia is a life-threatening disorder caused by exposure to certain anesthetics. Prompt recognition and intervention is crucial. This article focuses on preoperative patient screening as well as perioperative and postoperative recognition and management. PMID- 25522027 TI - Identifying and managing chest pain in women. AB - Heart disease continues to be the leading cause of death in women in the United States. Sex disparities remain despite research highlighting the unique aspects of managing women with ischemic heart disease. Increased mortality in women may be related to the critical differences in the clinical presentation of ischemic heart disease between the sexes. Sex-related differences in the pathophysiology of ischemic heart disease also influence diagnostic testing and management. This article reviews the differences in diagnosis and management between men and women with ischemic heart disease. PMID- 25522028 TI - Medical anthropology and the physician assistant profession. AB - Medical anthropology is a subfield of anthropology that investigates how culture influences people's ideas and behaviors regarding health and illness. Medical anthropology contributes to the understanding of how and why health systems operate the way they do, how different people understand and interact with these systems and cultural practices, and what assets people use and challenges they may encounter when constructing perceptions of their own health conditions. The goal of this article is to highlight the methodological tools and analytical insights that medical anthropology offers to the study of physician assistants (PAs). The article discusses the field of medical anthropology; the advantages of ethnographic and qualitative research; and how medical anthropology can explain how PAs fit into improved health delivery services by exploring three studies of PAs by medical anthropologists. PMID- 25522029 TI - Managing traumatic injury in an acute setting. PMID- 25522030 TI - Levels of supervision among practicing physician assistants. PMID- 25522031 TI - What is the probable cause of this genital ulcer? PMID- 25522032 TI - A few gray hairs. PMID- 25522033 TI - Sample size and robust marginal methods for cluster-randomized trials with censored event times. AB - In cluster-randomized trials, intervention effects are often formulated by specifying marginal models, fitting them under a working independence assumption, and using robust variance estimates to address the association in the responses within clusters. We develop sample size criteria within this framework, with analyses based on semiparametric Cox regression models fitted with event times subject to right censoring. At the design stage, copula models are specified to enable derivation of the asymptotic variance of estimators from a marginal Cox regression model and to compute the number of clusters necessary to satisfy power requirements. Simulation studies demonstrate the validity of the sample size formula in finite samples for a range of cluster sizes, censoring rates, and degrees of within-cluster association among event times. The power and relative efficiency implications of copula misspecification is studied, as well as the effect of within-cluster dependence in the censoring times. Sample size criteria and other design issues are also addressed for the setting where the event status is only ascertained at periodic assessments and times are interval censored. PMID- 25522034 TI - Long-term results of endoscopic-assisted cranionasal resection for olfactory neuroblastoma - single centre experience of fourteen patients. PMID- 25522035 TI - The Yeast Nucleosome Atlas (YNA) database: an integrative gene mining platform for studying chromatin structure and its regulation in yeast. AB - BACKGROUND: Histone modification and remodeling play crucial roles in regulating gene transcription. These post-translational modifications of histones function in a combinatorial fashion and can be recognized by specific histone-binding proteins, thus regulating gene transcription. Therefore, understanding the combinatorial patterns of the histone code is vital to understanding the associated biological processes. However, most of the datasets regarding histone modification and chromatin regulation are scattered across various studies, and no comprehensive search and query tool has yet been made available to retrieve genes bearing specific histone modification patterns and regulatory proteins. DESCRIPTION: For this reason, we developed the Yeast Nucleosome Atlas database, or the YNA database, which integrates the available experimental data on nucleosome occupancy, histone modifications, the binding occupancy of regulatory proteins, and gene expression data, and provides the genome-wide gene miner to retrieve genes with a specific combination of these chromatin-related datasets. Moreover, the biological significance analyzer, which analyzes the enrichments of histone modifications, binding occupancy, transcription rate, and functionality of the retrieved genes, was constructed to help researchers to gain insight into the correlation among chromatin regulation and transcription. CONCLUSIONS: Compared to previously established genome browsing databases, YNA provides a powerful gene mining and retrieval interface, and is an investigation tool that can assist users to generate testable hypotheses for studying chromatin regulation during transcription. YNA is available online at http://cosbi3.ee.ncku.edu.tw/yna/. PMID- 25522037 TI - EPR-based approach for the localization of paramagnetic metal ions in biomolecules. AB - Metal ions play an important role in the catalysis and folding of proteins and oligonucleotides. Their localization within the three-dimensional fold of such biomolecules is therefore an important goal in understanding structure-function relationships. A trilateration approach for the localization of metal ions by means of long-range distance measurements based on electron paramagnetic resonance (EPR) is introduced. The approach is tested on the Cu(2+) center of azurin, and factors affecting the precision of the method are discussed. PMID- 25522036 TI - Phainanoids A-F, a new class of potent immunosuppressive triterpenoids with an unprecedented carbon skeleton from Phyllanthus hainanensis. AB - Phainanoids A-F (1-6), six highly modified triterpenoids with a new carbon skeleton by incorporating two unique motifs of a 4,5- and a 5,5-spirocyclic systems, were isolated from Phyllanthus hainanensis. Their structures with absolute configurations were determined by spectroscopic data, chemical methods, and X-ray crystallography. Compounds 1-6 exhibited exceptionally potent immunosuppressive activities in vitro against the proliferation of T and B lymphocytes. The most potent one, phainanoid F (6), showed activities against the proliferation of T cells with IC50 value of 2.04 +/- 0.01 nM (positive control CsA = 14.21 +/- 0.01 nM) and B cells with IC50 value of <1.60 +/- 0.01 nM (CsA = 352.87 +/- 0.01 nM), which is about 7 and 221 times as active as CsA, respectively. The structure-activity relationships of 1-6 are discussed. PMID- 25522047 TI - Interdisciplinary Care for a Patient with Amelogenesis Imperfecta: A Clinical Report. AB - This manuscript describes an interdisciplinary approach over a period of 8 years combining surgical and prosthodontic treatment of a young patient diagnosed with hypocalcified-type amelogenesis imperfecta and anterior open bite. The treatment procedures included transitional restorations, orthodontic treatment, and maxillofacial surgery with a one-piece Le Fort I osteotomy, bilateral mandibular osteotomy, and genioplasty. The definitive prosthetic rehabilitation consisted of 28 zirconia-based ceramic single crowns restoring both esthetics and function. Photographs and radiographs associated with clinical evaluation were used in the maintenance period. Two-year follow-up revealed satisfactory results and no deterioration in the restorations. PMID- 25522048 TI - Difference in health inequity between two population groups due to a social determinant of health. AB - The World Health Organization defines social determinants of health as "complex, integrated, and overlapping social structures and economic systems" that are responsible for most health inequities. Similar to the individual-level risk factors such as behavioral and biological risk factors that influence disease, we consider social determinants of health such as the distribution of income, wealth, influence and power as risk factors for risk of disease. We operationally define health inequity in a disease within a population due to a risk factor that is unfair and avoidable as the difference between the disease outcome with and without the risk factor in the population. We derive expressions for difference in health inequity between two populations due to a risk factor that is unfair and avoidable for a given disease. The difference in heath inequity between two population groups due to a risk factor increases with increasing difference in relative risks and the difference in prevalence of the risk factor in the two populations. The difference in health inequity could be larger than the difference in health outcomes between the two populations in some situations. Compared to health disparities which are typically measured and monitored using absolute or relative disparities of health outcomes, the methods presented in this manuscript provide a different, yet complementary, picture because they parse out the contributions of unfair and avoidable risk factors. PMID- 25522049 TI - Metabolic influence of psychrophilic diatoms on travertines at the Huanglong Natural Scenic District of China. AB - Diatoms are a highly diversified group of algae that are widely distributed in aquatic ecosystems, and various species have different nutrient and temperature requirements for optimal growth. Here, we describe unusual psychrophilic diatoms of Cymbella in a travertine deposition environment in southwestern China in winter season. Travertine surfaces are colonized by these psychrophilic diatoms, which form biofilms of extracellular polysaccharide substances (EPS) with active metabolic activities in extremely cold conditions. The travertine in Huanglong, is a typical single crystalline calcite with anisotropic lattice distortions of unit cell parameters along axes of a and c, and this structure is suggestive of some level of metabolic mediation on mineralization. Near-edge X-ray absorption fine structure spectroscopy (NEXAFS) results further confirmed the occurrence of biogenic distortion of the crystal lattice of travertine calcite. Overall, our results imply that the metabolic influence of psychrophilic diatoms may be particularly important for promoting formation and dissolution of travertine in extremely cold environments of Huanglong. The EPS of psychrophilic diatoms will protect travertine from HCO3- etching and provide template for forming travertine when water re-flowing, in warm season. PMID- 25522050 TI - Health care facilities resilient to climate change impacts. AB - Climate change will increase the frequency and magnitude of extreme weather events and create risks that will impact health care facilities. Health care facilities will need to assess climate change risks and adopt adaptive management strategies to be resilient, but guidance tools are lacking. In this study, a toolkit was developed for health care facility officials to assess the resiliency of their facility to climate change impacts. A mixed methods approach was used to develop climate change resiliency indicators to inform the development of the toolkit. The toolkit consists of a checklist for officials who work in areas of emergency management, facilities management and health care services and supply chain management, a facilitator's guide for administering the checklist, and a resource guidebook to inform adaptation. Six health care facilities representing three provinces in Canada piloted the checklist. Senior level officials with expertise in the aforementioned areas were invited to review the checklist, provide feedback during qualitative interviews and review the final toolkit at a stakeholder workshop. The toolkit helps health care facility officials identify gaps in climate change preparedness, direct allocation of adaptation resources and inform strategic planning to increase resiliency to climate change. PMID- 25522051 TI - Chlorpyrifos exposure and respiratory health among adolescent agricultural workers. AB - Chlorpyrifos (CPF) is a commonly used organophosphate insecticide (OP). In adults, exposure to OPs has been inconsistently associated with reduced lung function. OP exposure and lung function has not been assessed in adolescents. The objective of this study was to assess CPF exposure and lung function among Egyptian adolescents. We conducted a 10-month study of male adolescent pesticide applicators (n = 38) and non-applicators of similar age (n = 24). Urinary 3,5,6 trichloro-2-pyridinol (TPCy), a CPF-specific metabolite, was analyzed in specimens collected throughout the study. Spirometry was performed twice after pesticide application: day 146, when TCPy levels were elevated and day 269, when TCPy levels were near baseline. Applicators had higher levels of TCPy (mean cumulative TCPy day 146 = 33,217.6; standard deviation (SD) = 49,179.3) than non applicators (mean cumulative TCPy day 146 = 3290.8; SD = 3994.9). Compared with non-applicators, applicators had higher odds of reporting wheeze, odds ratio = 3.41 (95% CI: 0.70; 17.41). Cumulative urinary TCPy was inversely associated with spirometric measurements at day 146, but not at day 269. Although generally non significant, results were consistent with an inverse association between exposure to CPF and lung function. PMID- 25522052 TI - The role of social context in shaping student-athlete opinions. AB - How do student-athletes form opinions? This is a particularly important question given ongoing debates about whether student-athletes should be paid and/or allowed to unionize. These debates concern the rights and benefits accrued directly to student-athletes, and thus, understanding their attitudes is of obvious import. Yet, virtually no recent work has delved into how student athletes form opinions on these issues. We fill this gap with a theoretical framework that predicts changes in social context alter opinions. This leads to the hypothesis that opinions will change once a student-athlete completes his/her career and finds him/herself in a distinct social network. We test the prediction with a survey, implemented in 2012, of one of the most notable athletic conferences in the National Collegiate Athletic Association (NCAA): the Big Ten. We find that post-career student-athletes demonstrate higher levels of support for pay for play and unionization. Our results suggest that student-athletes' opinions seem to depend on their extant social contexts. While our data, from 2012, neither speak to current opinions - given the quickly evolving landscape of college athletics - nor demonstrate what reforms may be "best," they do accentuate the power of social context in shaping student-athletes' attitudes. PMID- 25522053 TI - Active printed materials for complex self-evolving deformations. AB - We propose a new design of complex self-evolving structures that vary over time due to environmental interaction. In conventional 3D printing systems, materials are meant to be stable rather than active and fabricated models are designed and printed as static objects. Here, we introduce a novel approach for simulating and fabricating self-evolving structures that transform into a predetermined shape, changing property and function after fabrication. The new locally coordinated bending primitives combine into a single system, allowing for a global deformation which can stretch, fold and bend given environmental stimulus. PMID- 25522055 TI - Validation of a simplified provocation instrument for diagnosis and threshold testing of symptomatic dermographism. AB - BACKGROUND: Symptomatic dermographism is a common urticarial condition, which requires determination of provocation thresholds to confirm diagnosis and allow physicians to individualize management and therapy for optimal control of symptoms. To determine provocation thresholds, we have developed a provocation test device, the FricTest((r)) 4.0. This simple and inexpensive device, which is stroked across the skin to produce a response, consists of a flat plastic comb with four round-ended plastic pins, 3 mm in diameter, and of differing lengths. AIM: To validate the FricTest((r)) 4.0 by comparison with FricTest 3.0 in determining provocation thresholds in symptomatic dermographism, METHODS: Dermal provocation with the FricTest 4.0 and FricTest 3.0 was performed in parallel on the volar forearm of 30 patients with symptomatic dermographism and 30 healthy controls. The widths of the resulting weals were measured, and weals with a width of >= 3 mm were considered positive. Accompanying pruritus was assessed using a 10-point verbal rating scale. RESULTS: All 30 patients with symptomatic dermographism, but none of the healthy volunteers, showed positive responses to provocation with the strongest trigger strength, showing that FricTest((r)) 4.0 has 100% sensitivity and specificity for diagnosing symptomatic dermographism. Quantitatively, both devices were similar in the number of patients who responded positively to different pin lengths. Results for pruritus were also similar with both instruments. CONCLUSIONS: The FricTest 4.0 is a simple and inexpensive instrument for determining provocation thresholds in patients with symptomatic dermographism. It should find a place in both routine clinical investigation and in therapeutic trials. PMID- 25522054 TI - Critical care bed growth in the United States. A comparison of regional and national trends. AB - RATIONALE: Although the number of intensive care unit (ICU) beds in the United States is increasing, it is unknown whether this trend is consistent across all regions. OBJECTIVES: We sought to better characterize regional variation in ICU bed changes over time and identify regional characteristics associated with these changes. METHODS: We used data from the Centers for Medicare and Medicaid Services and the U.S. Census to summarize the numbers of hospitals, hospital beds, ICU beds, and ICU occupancy at the level of Dartmouth Atlas hospital referral region from 2000 to 2009. We categorized regions into quartiles of bed change over the study interval and examined the relationship between change categories, regional characteristics, and population characteristics over time. MEASUREMENTS AND MAIN RESULTS: From 2000 to 2009 the national number of ICU beds increased 15%, from 67,579 to 77,809, mirroring population. However, there was substantial regional variation in absolute changes (median, +16 ICU beds; interquartile range, -3 to +51) and population-adjusted changes (median, +0.9 ICU beds per 100,000; interquartile range, -3.8 to +5.9), with 25.0% of regions accounting for 74.8% of overall growth. At baseline, regions with increasing numbers of ICU beds had larger populations, lower ICU beds per 100,000 capita, higher average ICU occupancy, and greater market competition as measured by the Herfindahl-Hirschman Index (P < 0.001 for all comparisons). CONCLUSIONS: National trends in ICU bed growth are not uniformly reflected at the regional level, with most growth occurring in a small number of highly populated regions. PMID- 25522056 TI - Fitting a distribution to microbial counts: making sense of zeroes. AB - The accurate estimation of true prevalence and concentration of microorganisms in foods is an important element of quantitative microbiological risk assessment (QMRA). This estimation is often based on microbial detection and enumeration data. Among such data are artificial zero counts, that originated by chance from contaminated food products. When these products are not differentiated from uncontaminated products that originate true zero counts, the estimates of true prevalence and concentration may be inaccurate. This inaccuracy is especially relevant in situations where highly pathogenic bacteria are involved and where growth can occur along the food pathway. Our aim was to develop a method that provides accurate estimates of concentration parameters and differentiates between artificial and true zeroes, thus also accurately estimating true prevalence. We first show the disadvantages of using a limit of quantification (LOQ) threshold for the analysis of microbial enumeration data. We show that, depending on the original distribution of concentrations and the LOQ value, it may be incorrect to treat artificial zeroes as censored below a quantification threshold. Next, a method is developed that estimates the true prevalence of contamination within a food lot and the parameters characterizing the within-lot distribution of concentrations, without assuming a LOQ, and using raw plate count data as an input. Counts resulting both from contaminated and uncontaminated sample units are analysed together. This procedure allows the estimation of the proportion of artificial zeroes among the total of zero counts, and therefore the estimation of true prevalence from enumeration results. We observe that this method yields best estimates of mean, standard deviation and prevalence at low true prevalence levels and low expected standard deviation. Furthermore, we conclude that the estimation of prevalence and the estimation of the distribution of concentrations are interrelated and therefore should be estimated simultaneously. We also conclude that one of the keys to an accurate characterization of the overall microbial contamination is the correct identification and separation of true and artificial zeroes. Our method for the analysis of quantitative microbial data shows a good performance in the estimation of true prevalence and the parameters of the distribution of concentrations, which indicates that it is a useful data analysis tool in the field of QMRA. PMID- 25522057 TI - Exploitation of the nutritional and functional characteristics of traditional Italian legumes: the potential of sourdough fermentation. AB - This study aimed at evaluating the composition of nineteen traditional Italian legumes and at investigating the potential of the sourdough fermentation with selected lactic acid bacteria to improve the nutritional and functional features. Traditional Italian legumes, all with product certifications and belonging to Phaseolus vulgaris, Cicer arietinum, Lathyrus sativus, Lens culinaris and Pisum sativum species, were used in this study. Seeds were milled, and flours were analyzed for proximate composition and subjected to sourdough fermentation at 30 degrees C for 24h. Lactobacillus plantarum C48 and Lactobacillus brevis AM7 were used as selected starters. Compared to control doughs, without bacterial inoculum, the concentrations of free amino acids (FAA), soluble fibres, and total phenols increased for all legume sourdoughs. Raffinose decreased of up to ca. 64%. During sourdough fermentation, the level of GABA markedly increased and reached values up to 624mg/kg. Condensed tannins decreased. At the same time, almost all legume sourdoughs showed increases of the antioxidant and phytase activities. As shown by PCA analysis based on data of total FAA, GABA, raffinose, soluble/insoluble dietary fibre, condensed tannins and antioxidant and phytase activities, all legume sourdoughs were clearly differentiated from control doughs. The traditional Italian legumes are bio-diverse, and all showed high levels of nutritional elements and suitability for optimal sourdough fermentation. Legume flours subjected to sourdough fermentation would be suitable to be used alone or better in mixture with cereals, and as gluten-free ingredients for making novel and healthy foods. PMID- 25522058 TI - Incorporating single molecules into electrical circuits. The role of the chemical anchoring group. AB - Constructing electronic circuits containing singly wired molecules is at the frontier of electrical device miniaturisation. When a molecule is wired between a pair of electrodes, the two points of contact are determined by the chemical anchoring groups, located at the ends of the molecule. At this point, when a bias is applied, electrons are channelled from a metallic environment through an extremely narrow constriction, essentially a single atom, into the molecule. The fact that this is such an abrupt change in the electron pathway makes the nature of the chemical anchoring groups critically important regarding the propagation of electrons from the electrode across the molecule. A delicate interplay of phenomena can occur when a molecule binds to the electrodes, which can produce profound differences in conductance properties depending on the anchoring group. This makes answering the question "what is the best anchoring group for single molecule studies" far from straight forward. In this review, we firstly take a look at techniques developed to 'wire-up' single molecules, as understanding their limitations is key when assessing a molecular wire's performance. We then analyse the various chemical anchoring groups, and discuss their merits and disadvantages. Finally we discuss some theoretical concepts of molecular junctions to understand how transport is affected by the nature of the chemical anchor group. PMID- 25522060 TI - Abstracts from the International Surgical Congress of the ASGBI, 30 April-2 May 2014, Harrogate, UK. PMID- 25522059 TI - Infant attachment security and early childhood behavioral inhibition interact to predict adolescent social anxiety symptoms. AB - Insecure attachment and behavioral inhibition (BI) increase risk for internalizing problems, but few longitudinal studies have examined their interaction in predicting adolescent anxiety. This study included 165 adolescents (ages 14-17 years) selected based on their reactivity to novelty at 4 months. Infant attachment was assessed with the Strange Situation. Multimethod BI assessments were conducted across childhood. Adolescents and their parents independently reported on anxiety. The interaction of attachment and BI significantly predicted adolescent anxiety symptoms, such that BI and anxiety were only associated among adolescents with histories of insecure attachment. Exploratory analyses revealed that this effect was driven by insecure-resistant attachment and that the association between BI and social anxiety was significant only for insecure males. Clinical implications are discussed. PMID- 25522061 TI - A nanoscale resolution view on synaptic vesicle dynamics. AB - The ability of synapses to sustain neurotransmitter release during continuous activity critically relies on an efficient vesicle recycling program. Despite extensive research on synaptic function, the basic mechanisms of vesicle recycling remain poorly understood due to the relative inaccessibility of central synapses to conventional recording techniques. The extremely small size of synaptic vesicles, nearly five times below the diffraction-limited resolution of conventional light microscopy, has hampered efforts to define the mechanisms controlling their cycling. The complex sequence of dynamic processes that occur within the nerve terminals and link vesicle endocytosis and the subsequent round of release has been particularly difficult to study. The recent development of nanoscale-resolution imaging techniques has provided an opportunity to overcome these limitations and begin to reveal the mechanisms controlling vesicle recycling within individual nerve terminals. Here we summarize the recent advances in the implementation of super-resolution imaging and single-particle tracking approaches to study the dynamic steps of the vesicle recycling process within presynaptic terminals. PMID- 25522062 TI - Consumer sexual relationships in a forensic mental health hospital: perceptions of nurses and consumers. AB - The management of consumer-related risk is paramount in a secure forensic mental health facility. However, the consequent risk aversion presents a major barrier to consumers forming sexual relationships in a manner that is open and accepted. Investigation of the views of nurses working in forensic mental health settings on this topic is limited, and even more so for consumers of services. This qualitative exploratory study was undertaken to elicit the views of consumers and nurses about forming sexual relationships within this long-term and secure setting. Individual in-depth interviews were conducted with 12 nurses and 10 consumers. The benefits of, and barriers to, sexual relationships was identified as a major theme, and these findings are the focus of this paper. Nurse responses included the subthemes 'supportive factors' and 'potential dangers', reflecting their qualified support. Consumer responses included the subthemes 'therapeutic', 'feeling normal', 'restrictions and barriers', and 'lack of support and secrecy'. The importance of sexual relationships was clearly articulated, as was the difficulties in forming and maintaining them within the forensic setting. More open discussion about this commonly-avoided issue and the education of nurses and other health professionals is required. PMID- 25522064 TI - 3D graphene nanomaterials for binder-free supercapacitors: scientific design for enhanced performance. AB - Because of the excellent intrinsic properties, especially the strong mechanical strength, extraordinarily high surface area and extremely high conductivity, graphene is deemed as a versatile building block for fabricating functional materials for energy production and storage applications. In this article, the recent progress in the assembly of binder-free and self-standing graphene-based materials, as well as their application in supercapacitors are reviewed, including electrical double layer capacitors, pseudocapacitors, and asymmetric supercapacitors. Various fabrication strategies and the influence of structures on the capacitance performance of 3D graphene-based materials are discussed. We finally give concluding remarks and an outlook on the scientific design of binder free and self-standing graphene materials for achieving better capacitance performance. PMID- 25522063 TI - TimeXNet: identifying active gene sub-networks using time-course gene expression profiles. AB - BACKGROUND: Time-course gene expression profiles are frequently used to provide insight into the changes in cellular state over time and to infer the molecular pathways involved. When combined with large-scale molecular interaction networks, such data can provide information about the dynamics of cellular response to stimulus. However, few tools are currently available to predict a single active gene sub-network from time-course gene expression profiles. RESULTS: We introduce a tool, TimeXNet, which identifies active gene sub-networks with temporal paths using time-course gene expression profiles in the context of a weighted gene regulatory and protein-protein interaction network. TimeXNet uses a specialized form of the network flow optimization approach to identify the most probable paths connecting the genes with significant changes in expression at consecutive time intervals. TimeXNet has been extensively evaluated for its ability to predict novel regulators and their associated pathways within active gene sub networks in the mouse innate immune response and the yeast osmotic stress response. Compared to other similar methods, TimeXNet identified up to 50% more novel regulators from independent experimental datasets. It predicted paths within a greater number of known pathways with longer overlaps (up to 7 consecutive edges) within these pathways. TimeXNet was also shown to be robust in the presence of varying amounts of noise in the molecular interaction network. CONCLUSIONS: TimeXNet is a reliable tool that can be used to study cellular response to stimuli through the identification of time-dependent active gene sub networks in diverse biological systems. It is significantly better than other similar tools. TimeXNet is implemented in Java as a stand-alone application and supported on Linux, MS Windows and Macintosh. The output of TimeXNet can be directly viewed in Cytoscape. TimeXNet is freely available for non-commercial users. PMID- 25522065 TI - Novel MCH1 receptor antagonists: a patent review. AB - INTRODUCTION: The cyclic neuropeptide melanin-concentrating hormone (MCH) shows appetite-stimulating effects indicating an involvement in obesity. Large efforts have been invested in discovery programs to identify novel MCH1 receptor (MCHR1) antagonists. Other indications where MCHR1 antagonists may have a potential use include: anxiety/depression and, more recently, inflammatory responses in the gastrointestinal tract. AREAS COVERED: The current review covers the patent literature on MCHR1 antagonists published from November 2010 to March 2014. The applications have been grouped by filing company, and weight has been put on commenting compounds with disclosed in vivo biological data. EXPERT OPINION: Achieving sufficient separation of the human EtheR-a-Go-go channel has prevented many programs from reaching the clinic. For clinical programs, CNS exposure seems to have been a major challenge. Although clinical studies of MCHR1 antagonists have not been able to conclusively evaluate the concept, the body of evidence suggesting a role for MCHR1 antagonists in weight management is strong and novel chemical series still appear in the patent literature. An MCHR1 antagonist with the appropriate physical chemical properties is needed to convincingly evaluate the MCHR1 concept for obesity treatment and, as knowledge from previous programs are shared, the discovery of such a compound should be achievable. PMID- 25522066 TI - CD64 expression by neutrophil granulocytes. PMID- 25522067 TI - Ebola: when a nightmare becomes reality. PMID- 25522068 TI - The future of e-learning in healthcare professional education: some possible directions. Commentary. AB - E-learning in healthcare professional education still seems like it is a new innovation but the reality is that e-learning has been around for as long as the internet has been around. This is approximately twenty years and so it is probably appropriate to now take stock and consider what the future of e-learning in healthcare professional education might be. One likely occurrence is that there will be more formats, more interactive technology, and sometimes game-based learning. Another future of healthcare professional education will likely be in simulation. Like other forms of technology outside of medicine, the cost of e learning in healthcare professional education will fall rapidly. E-learning will also become more adaptive in the future and so will deliver educational content based on learners' exact needs. The future of e-learning will also be mobile. Increasingly in the future e-learning will be blended with face to face education. PMID- 25522069 TI - Incidental findings, genetic screening and the challenge of personalisation. AB - Genetic tests frequently produce more information than is initially expected. Several documents have addressed this issue and offer suggestions regarding how this information should be managed and, in particular, concerning the expedience of revealing (or not revealing) it to the persons concerned. While the approaches to the management of these incidental findings (IFs) vary, it is usually recommended that the information be disclosed if there is confirmed clinical utility and the possibility of treatment or prevention. However, this leaves unsolved some fundamental issues such as the different ways of interpreting "clinical utility", countless sources of uncertainty and varying ways of defining the notion of "incidental". Guidelines and other reference documents can offer indications to those responsible for managing IFs but should not be allowed to relieve researchers and healthcare professionals of their responsibilities. PMID- 25522070 TI - Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use: an overview. AB - For the 28 member states of the European Union, Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use, which repeals Directive 2001/20/EC, represents a substantial innovation in the procedures for authorising clinical trials and for handling all the subsequent stages. It introduces a single authorisation that will be valid for all EU member states, as well as a single portal through which all data concerning all clinical trials performed throughout the EU will pass. The present article offers an overview of the general aspects of the new procedures. It does not address the specific issues involved, each of which merits separate examination. PMID- 25522071 TI - Mesothelioma incidence in the neighbourhood of an asbestos-cement plant located in a national priority contaminated site. AB - BACKGROUND: An epidemic of asbestos-related disease is ongoing in most industrialized countries, mainly attributable to past occupational exposure but partly due to environmental exposure. In this perspective, the incidence of pleural mesothelioma close to a former asbestos-cement plant in a national contaminated site was estimated. METHODS: The census-tracts interested by atmospheric dispersion of facilities in the contaminated site were identified. Two subareas with different estimated environmental asbestos impact were distinguished. An ecological study at micro-geographic level was performed. The standardized incidence ratios (SIR) for study area and the two subareas, in comparison with region and municipality were computed. The standardized incidence rate ratio (IRR) between the two subareas was computed. RESULTS: Mesothelioma incidence in the study area was increased: 46 cases were observed with respect to 22.23 expected (SIR: 2.02). The increase was confirmed in analysis considering only the subjects without an occupationally exposure to asbestos: 19 cases among men (SIR = 2.48; 95% CI: 1.49-3.88); 11 case among women (SIR = 1.34; 95% CI: 0.67-2.40). The IRR between the two subareas is less than one in overall population considering all age-classes and of 3 fold (IRR = 3.14, 95% CI: 0.65 9.17) in the age-classes below 55 years. CONCLUSIONS: The findings indicate an increased incidence of pleural mesothelioma in the neighbourhood of asbestos cement plant, and a possible etiological contribution of asbestos environmental exposure in detected risks. PMID- 25522072 TI - A five years study on drug-related deaths in Campania (Italy). AB - OBJECTIVES: The study regards n. 267 drug related deaths submitted to toxicological analyses for forensic purpose, since 2008 to 2012, at the Laboratory of Forensic Toxicology of the Second University of Napoli (SUN), Italy. Among the cases studied (94% males and 6% females) the 13.1% regards foreign citizens. METHODS: For each case autopsy findings and all drugs detected were recorded. In addition other epidemiological data such as age, race, gender, place and circumstance of death were also supplied. A systematic toxicological analysis (STA) for illicit drug, other pharmaceuticals, new psychotropic substances and ethanol has been applied on the specimens collected at autopsy and all positive results were confirmed by a quantitative analysis (GC/MS or LC MS/MS). RESULTS: Toxicological results shows that simultaneous use of multiple illicit drugs was responsible of the largest mortality rate (57.7%), in both males and females. In the polydrug use the cocaine was the most detected substance. The association of heroin/cocaine was identified in the 22.5% of deaths. The finding of only one drug was correlated with an opiate drug for the 14.2% and with cocaine for the 4.5% of cases. The distribution by age and gender demonstrates an increase in deaths among males aged over 30 years and among women older than 35 years. The territorial distribution of the deaths in the different surrounding areas and in the residential quarters of the Naples city demonstrates that the 76% of deaths occurred in a place different from the usual residence. CONCLUSION: Results obtained demonstrate that prevails, at present, the need to specifically explore the changing patterns of polydrug use among addicts, because studying the prevalence of mortality subsequent to the consumption of a single illicit drug may be insufficient to guide preventive policies in public health. PMID- 25522073 TI - Generic substitution of antidiabetic drugs in the elderly does not affect adherence. AB - INTRODUCTION: The possibility that variation in packaging and pill appearance may reduce adherence is a reason for concern, especially for chronic diseases. The objectives of the study were to quantify the extent of switches between generic antidiabetics and to verify whether switching between different products of the same substance affects adherence. MATERIALS AND METHODS: All elderly residents of the Umbria Region who received at least 2 prescriptions of antidiabetics in 2010 and 2011 were included in the study. Switching was defined as the dispensing of two different products of the same substance in a series of two prescriptions. Single and multiple switchers were identified according to the number of switches during 2011. Switching relevant to the three off-patent substances with generic use >= 5% (metformin, gliclazide and repaglinide) was quantified. The effect of switching on adherence, defined as the proportion of days in 2011 covered by prescriptions (Medication Possession Ratio, MPR), was estimated. RESULTS: Among the 15 964 patients receiving antidiabetics (14.4% of the elderly population) 9211 were prescribed at least one of the generic substances. Of these patients, 23.3% experienced a single switch and 15.7% were multiple switchers (61.0% never switched). The proportion of multiple switchers increased with the number of prescriptions, reaching 26% among patients with >= 11 prescriptions. MPR was 62%, 62% and 72%, respectively among non-switchers, single and multiple switchers. CONCLUSIONS: In elderly patients treated with antidiabetics, the substitution between branded and unbranded products (as well as between generics) of the same substance, did not negatively affect adherence. PMID- 25522074 TI - Measles in Italy, laboratory surveillance activity during 2010. AB - INTRODUCTION: The European Regional Office of the World Health Organization (WHO/Europe) developed a strategic approach to stop the indigenous transmission of measles in its 53 Member States by 2015. This study describes the measles laboratory surveillance activity performed by the National Reference Laboratory for Measles and Rubella at the Italian National Institute of Health (Istituto Superiore di Sanita) during 2010. METHODS: Urine, oral fluid and capillary blood samples from 211 suspected measles cases arrived to the NRL from different regions of Italy for confirmation of the clinical diagnosis. Serological and/or molecular assays were performed; after molecular detection, positive samples were sequenced and genotyped. RESULTS AND DISCUSSION: 85% (180/211) of the specimens were confirmed as measles cases and 139 of these were analyzed phylogenetically. The phylogenetic analysis revealed a co-circulation of D4 and D8 genotypes for the reviewed period. PMID- 25522075 TI - Genotyping of circulating measles strains in Italy in 2010. AB - INTRODUCTION: The European Regional Office of the World Health Organization developed a strategic approach to stop the indigenous transmission of measles in its 53 Member States by 2015. In Italy, laboratory surveillance activity is implemented by the National Reference Laboratory for Measles and Rubella at the Italian National Institute of Health (Istituto Superiore di Sanita, Rome). The role of the National Reference Laboratory is to strengthen surveillance systems through rigorous case investigation and laboratory confirmation of suspected sporadic cases and outbreaks. Genetic characterization of wild-type measles virus is an essential component of the laboratory-based surveillance. This study describes the molecular characterization of measles virus strains isolated during 2010. METHODS: Dried blood spots, urine and oral fluid samples were collected from patients with a suspected measles infection. Serological tests were performed on capillary blood, and viral detection was performed on urine and oral fluid samples through molecular assay. Positive samples were sequenced and phylogenetically analysed. RESULTS AND DISCUSSION: The phylogenetic analysis showed a co-circulation of genotypes D4 and D8, and sporadic cases associated to genotypes D9 and B3. Then, molecular epidemiology of measles cases permitted to establish that D4 and D8 were the endemic genotypes in Italy during 2010. PMID- 25522076 TI - Estimating measles transmission potential in Italy over the period 2010-2011. AB - BACKGROUND: Recent history of measles epidemiology in Italy is characterized by the recurrence of spatially localized epidemics. AIM: In this study we investigate the three major outbreaks occurred in Italy over the period 2010-2011 and estimate the measles transmission potential. The epidemics mainly involved individuals aged 10-28 years and the transmission potential, measured as effective reproduction number - i.e. the number of new infections generated by a primary infector - was estimated to be 1.9-5.9. RESULTS: Despite such high values, we found that, in all investigated outbreaks, the reproduction number has remained above the epidemic threshold for no more than twelve weeks, suggesting that measles may hardly have the potential to give rise to new nationwide epidemics. CONCLUSION: In conclusion, the performed analysis highlights the need of planning additional vaccination programs targeting those age classes currently showing a higher susceptibility to infection, in order not to compromise the elimination goal by 2015. PMID- 25522077 TI - Frequency and trends of hospital discharges against medical advice (DAMA) in a large administrative database. AB - OBJECTIVE: The aim of this research was to characterize hospitalizations associated with discharges against medical advice (DAMA) in a large, population based data system. MATERIALS AND METHODS: This was a retrospective cohort study on 11 436 500 hospital admissions. The hospital discharge records for residents of the Veneto region (north-east Italy) discharged from 2001 to 2012, from both public and accredited private hospitals, were considered. The DAMA rate was calculated by type of hospital admission, excluding patients who died. The time trend of the DAMA rate was charted from the average annual percent changes. RESULTS: During the period considered, 66 549 DAMA were recorded, amounting to an overall DAMA rate of 6.00/00 admissions. Analyzing the diagnostic categories, admissions for substance abuse (drugs or alcohol) and dependence coincided with the highest DAMA rate (83.50/00), followed by poisoning (40.20/00), psychiatric disorders (24.7 0/00), traumas (21.10/00), HIV-related diseases (19.90/00), burns (10.50/00), and - for women - issues relating to pregnancy, childbirth and the postnatal period (11.20/00). The DAMA rate dropped from 6.72 to 5.55 from 2000 to 2008, then remained stable. CONCLUSION: The DAMA rate dropped slightly over the period considered. Several diagnostic categories are associated with a higher likelihood of patients leaving hospital against their doctor's advice. PMID- 25522078 TI - Sex workers clients in Italy: results of a phone survey on hiv risk behaviour and perception. AB - INTRODUCTION: Sex workers (SW) clients represent a bridge population for HIV transmission from high risk to low risk general population. MATERIALS AND METHODS: A cross-sectional anonymous telephone survey was carried out at the AIDS and Sexually Transmitted Infections Helpline of National Institute of Health in Italy. The questionnaire was proposed on a voluntary basis to a sample of 119 subjects from helpline users. RESULTS: The 119 participants were all males, aged between 19 and 59 years and mostly accessed female prostitutes. Vaginal intercourses with SW were more frequently reported, followed by passive oral, active oral sex and active anal intercourses. Cumulatively, 86.6% and 84.6% of vaginal and anal intercourses were respectively reported as regularly protected by condom. DISCUSSION: The telephone interview allowed an eased access, a high response rate and a standardised evaluation of questions. CONCLUSIONS: It is necessary a constant monitoring of the characteristics, behaviour, risk perception and testing of SW clients in Italian and other populations. PMID- 25522079 TI - Visiting Friends and Relatives (VFRs) travelers and imported malaria in the Palermo district (Sicily). AB - INTRODUCTION: Although Italy has been malaria-free since 1970, the infection is commonly introduced into the country by travelers and immigrants from endemic areas. The term VFRs refers to immigrants from malaria-endemic countries who are regularly resident in a malaria-free area, and who travel to their countries of origin to visit friends and relatives (VFRs). This group is at special risk of malaria as they are unaware of having lost their transitory immunity to the disease. METHODS: We conducted a retrospective study at the International Travelers Department of Palermo (Italy), examining records of malaria cases (67) reported over the period from 1998 to 2013. RESULTS: VFRs represent the highest number of cases (77.6%), followed by workers (16.4%) and tourists (6.0%). All female patients and patients under the age of 18 were VFRs. Plasmodium falciparum was the most frequently-identified species. In all cases, chemoprophylaxis was not taken or was incomplete. CONCLUSIONS: VFRs are at high risk of contracting malaria. This is probably related to an inequality in health care available to immigrants, as well as to ethnic and cultural conditions. PMID- 25522080 TI - The use of fenestrated and branched endovascular aneurysm repair for juxtarenal and thoracoabdominal aneurysms: a systematic review and cost-effectiveness analysis. AB - BACKGROUND: Patients with large abdominal aortic aneurysms (AAAs) are usually offered reparative treatment given the high mortality risk. There is uncertainty about how to treat juxtarenal AAAs (JRAAAs) or thoracoabdominal aortic aneurysms (TAAAs). Endovascular repair of an abdominal aortic aneurysm (EVAR) is often seen as safer and easier than open surgical repair (OSR). However, endovascular treatment of JRAAAs or TAAAs requires specially manufactured stent grafts, with openings to allow blood to reach branches of the aorta. Commissioners are receiving increasing requests for fenestrated EVAR (fEVAR) and branched EVAR (bEVAR), but it is unclear whether or not the extra cost of fEVAR or bEVAR is justified by advantages for patients. OBJECTIVE(S): To assess the clinical effectiveness, safety and cost-effectiveness of fEVAR and bEVAR in comparison with conventional treatment (i.e. no surgery) or OSR for two populations: JRAAAs and TAAAs. DATA SOURCES: Resources were searched from inception to October 2013, including MEDLINE (OvidSP), EMBASE (OvidSP) and the Cochrane Central Register of Controlled Trials (Wiley) and, additionally, for cost-effectiveness, NHS Economic Evaluation Database (NHS EED; Wiley) and EconLit (EBSCOhost). Conference abstracts were also searched. REVIEW METHODS: Studies were included based on an intervention of either fEVAR or bEVAR and a comparator of either OSR or no surgery. For clinical effectiveness, observational studies were excluded only if they were not comparative, i.e. explicitly selected on the basis of prognosis. RESULTS: For clinical effectiveness, searches retrieved 5253 records before deduplication. Owing to overlap between the databases, 1985 duplicate records were removed. Of the remaining 3268 records, based on titles and abstracts, 3244 records were excluded, leaving 24 publications to be ordered. All 24 studies were excluded as none of them satisfied the inclusion criteria. Sixteen studies were excluded on study design, six on intervention and two on comparator. Five out of 16 studies excluded on study design reported a comparison. However, all of the studies acknowledged that they had groups that were not comparable at baseline given that they had selectively assigned younger, fitter patients to OSR. Therefore, these studies were considered 'non-comparative'. For cost effectiveness, searches identified 104 references before deduplication. Owing to overlap between the databases, 34 duplicate records were removed. Of the remaining 70 records, seven were included for the full assessment based on initial screening. After a full-text review, no studies were included. Because of the lack of clinical effectiveness evidence and difficulty in estimating costs given the rapidly changing and variable technology, a cost-effectiveness analysis (CEA) was not performed. Instead a detailed description of modelling methods was provided. CONCLUSIONS: Despite a thorough search, no studies could be found that met the inclusion criteria. All studies that compared either fEVAR or bEVAR with either OSR or no surgery explicitly selected patients based on prognosis, i.e. essentially the populations for each comparator were not the same. Despite not being able to conduct a CEA, we have provided detailed methods for the conduct if data becomes available. FUTURE WORK: We recommend at least one clinical trial to provide an unbiased estimate of effect for fEVAR/bEVAR compared with OSR or no surgery. This trial should also collect data for a CEA. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013006051. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 25522081 TI - Unusual ultra-hydrophilic, porous carbon cuboids for atmospheric-water capture. AB - There is significant interest in high-performance materials that can directly and efficiently capture water vapor, particularly from air. Herein, we report a class of novel porous carbon cuboids with unusual ultra-hydrophilic properties, over which the synergistic effects between surface heterogeneity and micropore architecture is maximized, leading to the best atmospheric water-capture performance among porous carbons to date, with a water capacity of up to 9.82 mmol g(-1) at P/P0 =0.2 and 25 degrees C (20% relative humidity or 6000 ppm). Benefiting from properties, such as defined morphology, narrow pore size distribution, and high heterogeneity, this series of functional carbons may serve as model materials for fundamental research on carbon chemistry and the advance of new types of materials for water-vapor capture as well as other applications requiring combined highly hydrophilic surface chemistry, developed hierarchical porosity, and excellent stability. PMID- 25522082 TI - The control of reactive oxygen species influences porcine oocyte in vitro maturation. AB - The aim of this study was to examine the effect of varying intracellular reactive oxygen species (ROS) levels during oocyte in vitro maturation with enzymatic ROS production systems (xanthine + xanthine oxidase or xanthine + xanthine oxidase + catalase), scavenger systems (catalase or superoxide dismutase + catalase) or cysteine on porcine oocyte maturation. Oocyte ROS levels showed an increase when H2O2 or O2?(-) production systems were added to the culture medium (p < 0.05). On the other hand, the presence of ROS scavengers in the maturation medium did not modify oocyte ROS levels compared with the control after 48 h of maturation, but the addition of cysteine induced a decrease in oocyte ROS levels (p < 0.05). The ROS production systems used in this work did not modified the percentage of oocyte nuclear maturation, but increased the decondensation of sperm head (p < 0.05) and decreased the pronuclear formation (p < 0.05). In turn, the addition of O2?(-) and H2O2 scavenging systems during in vitro maturation did not modify the percentage of oocytes reaching metaphase II nor the oocytes with decondensed sperm head or pronuclei after fertilization. However, both parameters increased in the presence of cysteine (p < 0.05). The exogenous generation of O2?(-) and H2O2 during oocyte in vitro maturation would not affect nuclear maturation or later sperm penetration, but most of the spermatozoa cannot progress to form the pronuclei after fusion with the oocyte. The decrease in endogenous ROS levels by the addition of cysteine would improve pronuclear formation after sperm penetration. PMID- 25522083 TI - Building heterogeneous core-satellite chiral assemblies for ultrasensitive toxin detection. AB - A chiral-aptasensor for ochratoxin A (OTA) detection based on Au core-Ag nanoparticle satellite assemblies was fabricated for the first time. High yields of Au core-Ag NP satellite assemblies were prepared in the aqueous phase and the optical properties of the Au core-Ag NP satellite assemblies were investigated in detail. Because of the different concentrations of the OTA target, the assembly degree of the architecture varied which led to the corresponding chiral signals. The developed method for OTA detection with excellent linear range from 1 to 50pg/mL showed high selectivity for OTA and the limit of detection as low as 0.16pg/mL. The feasibility of this method was demonstrated by performing recovery experiment using negative red wine samples, excellent recovery ranged from 90% to 105% was achieved, and indicated promising applications. PMID- 25522084 TI - Magnetic bead and gold nanoparticle probes based immunoassay for beta-casein detection in bovine milk samples. AB - In this work, a double-probe based immunoassay was developed for rapid and sensitive determination of beta-casein in bovine milk samples. In the method, magnetic beads (MBs), employed as supports for the immobilization of anti-beta casein polyclonal antibody (PAb), were used as the capture probe. Colloidal gold nanoparticles (AuNPs), employed as a bridge for loading anti-beta-casein monoclonal antibody (McAb) and horseradish peroxidase (HRP), were used as the amplification probe. The presence of beta-casein causes the sandwich structures of MBs-PAb-beta-casein-McAb-AuNPs through the interaction between beta-casein and the anti-beta-casein antibodies. The HRP, used as an enzymatic-amplified tracer, can catalytically oxidize the substrate 3,3',5,5'-tetramethylbenzidine (TMB), generating optical signals that are proportional to the quantity of beta-casein. The linear range of the immunoassay was from 6.5 to 1520ngmL(-1). The limit of detection (LOD) was 4.8ngmL(-1) which was 700 times lower than that of MBs antibody-HRP based immunoassay and 6-7 times lower than that from the microplate antibody-HRP based assay. The recoveries of beta-casein from bovine milk samples were from 95.0% to 104.3% that had a good correlation coefficient (R(2)=0.9956) with those obtained by an official standard Kjeldahl method. For higher sensitivity, simple sample pretreatment and shorter time requirement of the antigen-antibody reaction, the developed immunoassay demonstrated the viability for detection of beta-casein in bovine milk samples. PMID- 25522085 TI - Outbreak of cryptosporidiosis among responders to a rollover of a truck carrying calves - Kansas, April 2013. AB - In April 2013, the Thomas County Health Department notified the Kansas Department of Health and Environment's Infectious Disease Epidemiology and Response section (KDHE) of two cases of cryptosporidiosis among emergency responders to a tractor trailer rollover. The truck was carrying approximately 350 preweaned Holstein calves. An outbreak investigation was led by KDHE with assistance from the county health department; six cases of cryptosporidiosis were identified among the 15 emergency responders. No additional primary cases with this exposure or secondary cases were identified. Disease was associated with carrying calves (relative risk [RR] = 3.0) and contact with fecal matter (RR = 4.5). The calves were aged <10 days and reportedly suffered from scours (diarrheal disease), which is often caused by Cryptosporidium spp., a chlorine-tolerant protozoan parasite. Because of the age of the calves and the conditions at the rollover scene, a high potential existed for fecal contamination and subsequent transmission of Cryptosporidium. This outbreak is the first report of both law enforcement and volunteer emergency responders contracting cryptosporidiosis, with transmission of Cryptosporidium attributed solely to direct contact with animals and their feces. Human illness resulting from contact with animals during an emergency response might be minimized if 1) all responders are aware of the potential for zoonotic transmission, 2) education is provided on proper animal handling including the use of appropriate personal protective equipment, and 3) responders practice thorough hand hygiene and decontaminate clothing and equipment following contact with feces. PMID- 25522086 TI - Update: influenza activity - United States, September 28- December 6, 2014. AB - CDC collects, compiles, and analyzes data on influenza activity year-round in the United States (http://www.cdc.gov/flu/weekly/fluactivitysurv.htm). The influenza season generally begins in the fall and continues through the winter and spring months; however, the timing and severity of circulating influenza viruses can vary by geographic location and season. Influenza activity in the United States increased starting mid-October through December. This report summarizes U.S. influenza activity during September 28-December 6, 2014. PMID- 25522087 TI - Illnesses and deaths among persons attending an electronic dance-music festival - New York City, 2013. AB - Outdoor electronic dance-music festivals (EDMFs) are typically summer events where attendees can dance for hours in hot temperatures. EDMFs have received increased media attention because of their growing popularity and reports of illness among attendees associated with recreational drug use. MDMA (3,4 methylenedioxymethamphetamine) is one of the drugs often used at EDMFs. MDMA causes euphoria and mental stimulation but also can cause serious adverse effects, including hyperthermia, seizures, hyponatremia, rhabdomyolysis, and multiorgan failure. In this report, MDMA and other synthetic drugs commonly used at dance festivals are referred to as "synthetic club drugs." On September 1, 2013, the New York City (NYC) Department of Health and Mental Hygiene (DOHMH) received reports of two deaths of attendees at an EDMF (festival A) held August 31-September 1 in NYC. DOHMH conducted an investigation to identify and characterize adverse events resulting in emergency department (ED) visits among festival A attendees and to determine what drugs were associated with these adverse events. The investigation identified 22 cases of adverse events; nine cases were severe, including two deaths. Twenty-one (95%) of the 22 patients had used drugs or alcohol. Of 17 patients with toxicology testing, MDMA and other compounds were identified, most frequently methylone, in 11 patients. Public health messages and strategies regarding adverse health events might reduce illnesses and deaths at EDMFs. PMID- 25522088 TI - Update: ebola virus disease epidemic - West Africa, December 2014. AB - CDC is assisting ministries of health and working with other organizations to end the ongoing epidemic of Ebola virus disease (Ebola) in West Africa. The updated data in this report were compiled from situation reports from the Guinea Interministerial Committee for Response Against the Ebola Virus, the World Health Organization, the Liberia Ministry of Health and Social Welfare, and the Sierra Leone Ministry of Health and Sanitation. Total case counts include all suspected, probable, and confirmed cases, which are defined similarly by each country. These data reflect reported cases, which make up an unknown proportion of all cases, and reporting delays that vary from country to country. PMID- 25522089 TI - Challenges in responding to the ebola epidemic - four rural counties, Liberia, August-November 2014. AB - The first cases of Ebola virus disease (Ebola) in West Africa were identified in Guinea on March 22, 2014. On March 30, the first Liberian case was identified in Foya Town, Lofa County, near the Guinean border. Because the majority of early cases occurred in Lofa and Montserrado counties, resources were concentrated in these counties during the first several months of the response, and these counties have seen signs of successful disease control. By October 2014, the epidemic had reached all 15 counties of Liberia. During August 27-September 10, 2014, CDC in collaboration with the Liberian Ministry of Health and Social Welfare assessed county Ebola response plans in four rural counties (Grand Cape Mount, Grand Bassa, Rivercess, and Sinoe, to identify county-specific challenges in executing their Ebola response plans, and to provide recommendations and training to enhance control efforts. Assessments were conducted through interviews with county health teams and health care providers and visits to health care facilities. At the time of assessment, county health teams reported lacking adequate training in core Ebola response strategies and reported facing many challenges because of poor transportation and communication networks. Development of communication and transportation network strategies for communities with limited access to roads and limited means of communication in addition to adequate training in Ebola response strategies is critical for successful management of Ebola in remote areas. PMID- 25522090 TI - Support services for survivors of ebola virus disease - Sierra Leone, 2014. AB - As of December 6, 2014, Sierra Leone reported 6,317 laboratory-confirmed cases of Ebola virus disease (Ebola), the highest number of reported cases in the current West Africa epidemic. The Sierra Leone Ministry of Health and Sanitation reported that as of December 6, 2014, there were 1,181 persons who had survived and were discharged. Survivors from previous Ebola outbreaks have reported major barriers to resuming normal lives after release from treatment, such as emotional distress, health issues, loss of possessions, and difficulty regaining their livelihoods. In August 2014, a knowledge, attitude, and practice survey regarding the Ebola outbreak in Sierra Leone, administered by a consortium of partners that included the Ministry of Health and Sanitation, UNICEF, CDC, and a local nongovernmental organization, Focus 1000, found that 96% of the general population respondents reported some discriminatory attitude towards persons with suspected or known Ebola. Access to increased psychosocial support, provision of goods, and family and community reunification programs might reduce these barriers. Survivors also have unique potential to contribute to the Ebola response, particularly because survivors might have some immunity to the same virus strain. In previous outbreaks, survivors served as burial team members, contact tracers, and community educators promoting messages that seeking treatment improves the chances for survival and that persons who survived Ebola can help their communities. As caregivers in Ebola treatment units, survivors have encouraged patients to stay hydrated and eat and inspired them to believe that they, too, can survive. Survivors regaining livelihood through participation in the response might offset the stigma associated with Ebola. PMID- 25522091 TI - Reintegration of ebola survivors into their communities - Firestone District, Liberia, 2014. AB - The current Ebola virus disease (Ebola) epidemic in West Africa is unprecedented in size and duration. Since the outbreak was recognized in March 2014, the World Health Organization (WHO) has reported 17,145 cases with 6,070 deaths, primarily in Guinea, Liberia, and Sierra Leone. Combined data show a case-fatality rate of approximately 70% in patients with a recorded outcome; a 30% survival rate means that thousands of patients have survived Ebola. An important component of a comprehensive Ebola response is the reintegration of Ebola survivors into their communities. PMID- 25522092 TI - Notes from the field: fatal rat-bite fever in a child - San Diego County, California, 2013. AB - In August 2013, the County of San Diego Health and Human Services Agency was notified of a fatal case of rat-bite fever (RBF) in a previously healthy male, aged 10 years, who owned pet rats. Two days before his death, the patient experienced rigors, fevers, vomiting, headaches, and leg pains. His physician noted a fever of 102.6 degrees F (39.2oC), documented a normal examination, diagnosed viral gastroenteritis, and prescribed anti-nausea medication. During the next 24 hours, the patient experienced vomiting and persistent fever. He was confused and weak before collapsing at home. Paramedics reported the patient was unresponsive and had dilated pupils; resuscitation was initiated in the field and was continued for >1 hour after arrival at the emergency department but was unsuccessful. A complete blood count performed during resuscitation revealed anemia (hemoglobin 10.0 g/dL [normal = 13.5-18.0 g/dL], thrombocytopenia (platelets 40,000/uL [normal = 140,000-440,000/uL]), leukocytosis (white blood cells 17,900 cells/uL [normal = 4,000-10,500/uL]) with 16% band neutrophils; the patient also had evidence of disseminated intravascular coagulation. No rash or skin breakdown was noted. Lung, liver, and epiglottis tissue collected postmortem was positive for Streptobacillus moniliformis DNA by polymerase chain reaction. PMID- 25522093 TI - Notes from the field: measles transmission at a domestic terminal gate in an international airport - United States, January 2014. AB - In March 2014, CDC identified a possible cluster of four laboratory-confirmed measles cases among passengers transiting a domestic terminal in a U.S. international airport. Through epidemiologic assessments conducted by multiple health departments and investigation of flight itineraries by CDC, all four patients were linked to the same terminal gate during a 4-hour period on January 17, 2014. Patient 1, an unvaccinated man aged 21 years with rash onset February 1, traveled on two domestic flights on January 17 and 18 that connected at the international airport. Patient 2, an unvaccinated man aged 49 years with rash onset February 1, traveled from the airport on January 17. Patient 3, an unvaccinated man aged 19 years with rash onset January 30, traveled domestically with at least a 4-hour layover at the airport on January 17. Patient 4, an unvaccinated man aged 63 years with rash onset February 5, traveled on a flight to the airport on January 17. PMID- 25522095 TI - Natural flanking sequences for peptides included in a quantification concatamer internal standard. AB - Quantification by targeted proteomics has largely depended on mass spectrometry and isotope-labeled internal standards. In addition to traditionally used recombinant proteins or synthetic peptides, concatenated peptides (QconCATs) were introduced as a conceptually new source of internal standard. In the present study, we focused on assessing the length of natural flanking sequences, which surround each peptide included in QconCAT and provide for identical rates of analyte and standard digestion by trypsin. We have expressed, purified, and characterized a set of seven (15)N-labeled QconCATs that cover seven tryptic peptides from human clusterin with a length of natural flanking sequences ranging from none (+0) to six amino acid residues (+6) for each tryptic peptide. Individual QconCATs were mixed with recombinant human clusterin at a 1:1 molar ratio and digested, and the actual ratios for each combination of peptide/flanking sequence were measured with a multiple reaction monitoring assay. Data analysis suggested that natural flanking sequences shorter than +6 residues can cause a quantitative error because the random appearance of other amino acid residues in close proximity to trypsin cleavage sites has unpredictable consequences for the digestion rates of QconCATs. PMID- 25522096 TI - Quantitative trait locus mapping identifies candidate alleles involved in adaptive introgression and range expansion in a wild sunflower. AB - The wild North American sunflowers Helianthus annuus and H. debilis are participants in one of the earliest identified examples of adaptive trait introgression, and the exchange is hypothesized to have triggered a range expansion in H. annuus. However, the genetic basis of the adaptive exchange has not been examined. Here, we combine quantitative trait locus (QTL) mapping with field measurements of fitness to identify candidate H. debilis QTL alleles likely to have introgressed into H. annuus to form the natural hybrid lineage H. a. texanus. Two 500-individual BC1 mapping populations were grown in central Texas, genotyped for 384 single nucleotide polymorphism (SNP) markers and then phenotyped in the field for two fitness and 22 herbivore resistance, ecophysiological, phenological and architectural traits. We identified a total of 110 QTL, including at least one QTL for 22 of the 24 traits. Over 75% of traits exhibited at least one H. debilis QTL allele that would shift the trait in the direction of the wild hybrid H. a. texanus. We identified three chromosomal regions where H. debilis alleles increased both female and male components of fitness; these regions are expected to be strongly favoured in the wild. QTL for a number of other ecophysiological, phenological and architectural traits colocalized with these three regions and are candidates for the actual traits driving adaptive shifts. G * E interactions played a modest role, with 17% of the QTL showing potentially divergent phenotypic effects between the two field sites. The candidate adaptive chromosomal regions identified here serve as explicit hypotheses for how the genetic architecture of the hybrid lineage came into existence. PMID- 25522097 TI - An integrative model of multi-organ drug-induced toxicity prediction using gene expression data. AB - BACKGROUND: In practice, some drugs produce a number of negative biological effects that can mitigate their effectiveness as a remedy. To address this issue, several studies have been performed for the prediction of drug-induced toxicity from gene-expression data, and a significant amount of work has been done on predicting limited drug-induced symptoms or single-organ toxicity. Since drugs often lead to some injuries in several organs like liver or kidney, however, it would be very useful to forecast the drug-induced injuries for multiple organs. Therefore, in this work, our aim was to develop a multi-organ toxicity prediction model using an integrative model of gene-expression data. RESULTS: To train our integrative model, we used 3708 in-vivo samples of gene-expression profiles exposed to one of 41 drugs related to 21 distinct physiological changes divided between liver and kidney (liver 11, kidney 10). Specifically, we used the gene expression profiles to learn an ensemble classifier for each of 21 pathology prediction models. Subsequently, these classifiers were combined with weights to generate an integrative model for each pathological finding. The integrative model outputs the likeliness of presenting the trained pathology in a given test sample of gene-expression profile, called an integrative prediction score (IPS). For the evaluation of an integrative model, we estimated the prediction performance with the k-fold cross-validation. Our results demonstrate that the proposed integrative model is superior to individual pathology prediction models in predicting multi-organ drug-induced toxicities over all the targeted pathological findings. On average, the AUC of the integrative models was 88% while the AUC of individual pathology prediction models was 68%. CONCLUSIONS: Not only does this integrative model produce comparable prediction performance to existing approaches, but also it produces very stable performance overall. In addition, our approach is easily expandable to a variety of other multi-organ toxicology applications. PMID- 25522099 TI - [Gender, health professions and society]. PMID- 25522098 TI - Hepatic arterial spin labelling MRI: an initial evaluation in mice. AB - The development of strategies to combat hepatic disease and augment tissue regeneration has created a need for methods to assess regional liver function. Liver perfusion imaging has the potential to fulfil this need, across a range of hepatic diseases, alongside the assessment of therapeutic response. In this study, the feasibility of hepatic arterial spin labelling (HASL) was assessed for the first time in mice at 9.4 T, its variability and repeatability were evaluated, and it was applied to a model of colorectal liver metastasis. Data were acquired using flow-sensitive alternating inversion recovery-arterial spin labelling (FAIR-ASL) with a Look-Locker readout, and analysed using retrospective respiratory gating and a T1 -based quantification. This study shows that preclinical HASL is feasible and exhibits good repeatability and reproducibility. Mean estimated liver perfusion was 2.2 +/- 0.8 mL/g/min (mean +/- standard error, n = 10), which agrees well with previous measurements using invasive approaches. Estimates of the variation gave a within-session coefficient of variation (CVWS) of 7%, a between-session coefficient of variation (CVBS) of 9% and a between animal coefficient of variation (CVA) of 15%. The within-session Bland-Altman repeatability coefficient (RCWS) was 18% and the between-session repeatability coefficient (RCBS) was 29%. Finally, the HASL method was applied to a mouse model of liver metastasis, in which significantly lower mean perfusion (1.1 +/- 0.5 mL/g/min, n = 6) was measured within the tumours, as seen by fluorescence histology. These data indicate that precise and accurate liver perfusion estimates can be achieved using ASL techniques, and provide a platform for future studies investigating hepatic perfusion in mouse models of disease. PMID- 25522100 TI - [The gender perspective and health professionals: notes from the Brazilian collective health field]. AB - We examine the incorporation of the gender perspective in the health field, considering scientific production, health policies and programs and everyday professional practices within the health services. These distinct layers are necessary given the different possibilities each presents for the incorporation of gender. In scientific production, we identify increasing inclusion of the gender perspective, but with little methodological use of the concept; in health policies and programs, the incorporation of the gender perspective is not comprehensive and varies temporally; and in professional practices, incorporation is anchored more in practical knowledge than in a technical and scientific basis. In the daily work of health professionals, this set of difficulties generates different tensions regarding the scientific and technological basis and the moral basis for intervention. PMID- 25522101 TI - [Gender and career paths of female primary care physicians in Andalusia, Spain, at the beginning of 21st century]. AB - The purpose of this article was to study, from a feminist perspective, the diversity and homogeneity in the career paths of female primary care physicians from Andalusia, Spain in the early 21st century, by analyzing the meanings they give to their careers and the influence of personal, family and professional factors. We conducted a qualitative study with six discussion groups. Thirty-two female primary care physicians working in urban health centers of the public health system of Andalusia participated in the study. The discourse analysis revealed that most of the female physicians did not plan for professional goals and, when they did plan for them, the goals were intertwined with family needs. Consequently, their career paths were discontinuous. In contrast, career paths oriented towards professional development and the conscious planning of goals were more common among the female doctors acting as directors of health care centers. PMID- 25522102 TI - ["The fact that there are more women doesn't guarantee anything": the feminization of obstetrics and gynecology and the experiences of female medical professionals in Mexico]. AB - In the framework of an increasing feminization of the medical profession in Mexico, this article explores the characteristics of this process in the obstetrics and gynecology specialty. Understanding feminization as a process of change to be analyzed both quantitatively and qualitatively, the article focuses special attention on the experiences of female obstetrician-gynecologists within a medical specialty that has since its origins functioned as a mechanism of control over women's bodies. Based on ethnographic research, the article combines statistical and archival sources and field observation. The interviews reveal the experiences and tensions women obstetrician-gynecologists encounter in this context. PMID- 25522103 TI - [Gender norms and the development of the medical habitus: in the years of medical schooling and residency]. AB - This article documents the gender abuse that Mexican medical students face. The concept of medical socialization is analyzed, with emphasis on the problem of the mistreatment of medical students. The theoretical framework articulates ideas from Foucault and Goffman with the nodal points of Bourdieu using a gender focus. Numerous examples are employed to show that the formal program of study also contains a hidden curriculum which serves to reproduce gender hierarchies. Women face numerous types of socially induced discouragement in choosing and completing their course of study, particularly in certain specialties. Discrimination is present in affectivized as well as in authoritarian interactions. They face sexual harassment in the classroom and in their years of specialization, and are constantly constructed as subordinated subjects. The importance of these findings in the constitution of a medical habitus is discussed. PMID- 25522104 TI - [Relationships between health care professionals and users from a gender perspective]. AB - The objective of this article is to analyze relationships between health professionals and users from a gender perspective. Using Pierre Bourdieu as a theoretical reference, we critically analyze data from two studies carried out in Brazil in which we took part as authors. The first of these studies was based in Rio de Janeiro and the second was a multicenter and ethnographical study carried out in eight health care facilities distributed throughout four Brazilian states, two in the Southeast region and two in the Northeast region. Among the principal results of the present study, we found that although the relationships between health professionals and users demonstrate varied opinions, all are marked by a gendered habitus. We conclude that, among other aspects, the construction of diverse femininities and masculinities and the way in which these are exercised in health care contexts are the product of process that is both socio-historical and personal. PMID- 25522105 TI - [Transsexuality: law and health-related aspects in the Spanish legal system]. AB - The social weight of transsexual groups has been and continues to be crucial in many aspects regarding transsexuality, from the progressive elimination of discrimination to influence in the legislative branch. This paper especially discusses a classic demand of these groups, comprehensive medical treatment of transsexual people within the National Health System. Thus, progress in the development of an adequate healthcare system for these groups, their treatment in the legal systems of Spain in general and of some of its autonomous communities with more noteworthy laws (especially in Andalusia, an autonomous community that has been pioneering in this regard, as well as the Basque Country and Navarre) and remaining challenges will be observed in this work. The article will also take particular note of the substantial developments that the publication of the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders has established in this area. PMID- 25522106 TI - [Dialogue and respect: the basis for constructing an intercultural health system for indigenous communities in Puerto Narino, Amazonas, Colombia]. AB - This paper presents the ideas on health and disease as well as proposals regarding the health care system voiced by indigenous communities belonging to the Tikunas, Cocama and Yagua ethnicities of the Puerto Narino municipality in the department of Amazonas, Colombia. The study was conducted between 2010 and 2013. The tools used to obtain the data were participant observation, interviews and discussion groups. The study evidenced a profound lack of information and understanding on the part of state health agencies. As a principal demand, indigenous communities ask to be heard when decisions affecting their health or their way of understanding health are made. These results should be taken into account in the development of future health programs and provide a basis for the construction of an adequate intercultural health system for the town of Port Narino. PMID- 25522107 TI - [Marking bourdaries as a strategy of social control: the case of homicidal violence in Medellin, Colombia]. AB - As part of a research study undertaken in the period 2003-2011 to understand situations of homicidal violence based in perceptions regarding the act of violence and the surrounding context, we reflect on the meaning of "invisible bourdaries" in the neighborhoods of Medellin (Colombia). Using a qualitative approach that combines documentary sources and interviews, the experiences of 8 participants are analyzed. In the primary results we can see how control over neighborhoods is exercised by different actors through bourdaries not visible to ordinary people. Nevertheless, around these lines people are recruited and controlled and strategies to illegally generate economic resources and to regulate the cultural and social activities of inhabitants are consolidated, thus affecting the social dynamics and imaginary of the neighborhood. In this way, the territories, friendships, and affects of young victims - who are not linked to illegal groups and/or do not have "information" - and of defenseless older adults are controlled. PMID- 25522108 TI - [The State, waiting and political domination among the poor: interview with the sociologist Javier Auyero]. AB - The extensive work of Javier Auyero regarding the poor in Latin America is disturbing in its sociological and political complexity. Instead of falling into the commonplace explorations of how inhabitants at the margins of our cities live, suffer and relate, his twenty years of research have focused on the consequences of neoliberalism in urban marginality. In light of the publication of his last book Patients of the State (2013), Salud Colectiva invited Auyero to reflect on the connections, not always observed, between waiting and political domination in government offices, schools and hospitals. His ethnographic strategy allows him to enter without prejudices into a social universe marked by polarizing political positions. He affirms that in the everyday encounters of poor people with the diverse forms of state power, practices are reproduced - not all of which are equally conscious and planned - that impart a political education and end up turning those who should be citizens into patients of the State. PMID- 25522111 TI - Experimental and theoretical studies on the rearrangement of 2-oxoazepane alpha,alpha-amino acids into 2'-oxopiperidine beta(2,3,3) -amino acids: an example of intramolecular catalysis. AB - Enantiopure beta-amino acids represent interesting scaffolds for peptidomimetics, foldamers and bioactive compounds. However, the synthesis of highly substituted analogues is still a major challenge. Herein, we describe the spontaneous rearrangement of 4-carboxy-2-oxoazepane alpha,alpha-amino acids to lead to 2' oxopiperidine-containing beta(2,3,3) -amino acids, upon basic or acid hydrolysis of the 2-oxoazepane alpha,alpha-amino acid ester. Under acidic conditions, a totally stereoselective synthetic route has been developed. The reordering process involved the spontaneous breakdown of an amide bond, which typically requires strong conditions, and the formation of a new bond leading to the six membered heterocycle. A quantum mechanical study was carried out to obtain insight into the remarkable ease of this rearrangement, which occurs at room temperature, either in solution or upon storage of the 4-carboxylic acid substituted 2-oxoazepane derivatives. This theoretical study suggests that the rearrangement process occurs through a concerted mechanism, in which the energy of the transition states can be lowered by the participation of a catalytic water molecule. Interestingly, it also suggested a role for the carboxylic acid at position 4 of the 2-oxoazepane ring, which facilitates this rearrangement, participating directly in the intramolecular catalysis. PMID- 25522110 TI - Structure-based design of bacterial nitric oxide synthase inhibitors. AB - Inhibition of bacterial nitric oxide synthase (bNOS) has the potential to improve the efficacy of antimicrobials used to treat infections by Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis. However, inhibitor specificity toward bNOS over the mammalian NOS (mNOS) isoforms remains a challenge because of the near identical NOS active sites. One key structural difference between the NOS isoforms is the amino acid composition of the pterin cofactor binding site that is adjacent to the NOS active site. Previously, we demonstrated that a NOS inhibitor targeting both the active and pterin sites was potent and functioned as an antimicrobial ( Holden , , Proc. Natl. Acad. Sci. U.S.A. 2013 , 110 , 18127 ). Here we present additional crystal structures, binding analyses, and bacterial killing studies of inhibitors that target both the active and pterin sites of a bNOS and function as antimicrobials. Together, these data provide a framework for continued development of bNOS inhibitors, as each molecule represents an excellent chemical scaffold for the design of isoform selective bNOS inhibitors. PMID- 25522112 TI - Differential regulation of mGlu5 R and MUOPr by priming- and cue-induced reinstatement of cocaine-seeking behaviour in mice. AB - The key problem for the treatment of drug addiction is relapse to drug use after abstinence that can be triggered by drug-associated cues, re-exposure to the drug itself and stress. Understanding the neurobiological mechanisms underlying relapse is essential in order to develop effective pharmacotherapies for its prevention. Given the evidence implicating the metabotropic glutamate receptor 5 (mGlu5 R), MU-opioid receptor (MOPr), kappa-opioid receptor (KappaOPr) and oxytocin receptor (OTR) systems in cocaine addiction and relapse, our aim was to assess the modulation of these receptors using a mouse model of cue- and priming induced reinstatement of cocaine seeking. Male mice were trained to self administer cocaine (1 mg/kg/infusion, i.v.) and were randomized into different groups: (1) cocaine self-administration; (2) cocaine extinction; (3) cocaine primed (10 mg/kg i.p.); or (4) cue-induced reinstatement of cocaine seeking. Mice undergoing the same protocols but receiving saline instead of cocaine were used as controls. Quantitative autoradiography of mGlu5 R, MOPr, KOPr and OTR showed a persistent cocaine-induced upregulation of the mGlu5 R and OTR in the lateral septum and central amygdala, respectively. Moreover, a downregulation of mGlu5 R and MOPr was observed in the basolateral amygdala and striatum, respectively. Further, we showed that priming- but not cue-induced reinstatement upregulates mGlu5 R and MOPr binding in the nucleus accumbens core and basolateral amygdala, respectively, while cue- but not priming-induced reinstatement downregulates MOPr binding in caudate putamen and nucleus accumbens core. This is the first study to provide direct evidence of reinstatement-induced receptor alterations that are likely to contribute to the neurobiological mechanisms underpinning relapse to cocaine seeking. PMID- 25522113 TI - Predictive factors for the presence of malignant transformation of pelvic endometriosis. AB - OBJECTIVES: To determine predictive factors for the presence of malignant transformation in ovarian endometriotic cysts. STUDY DESIGN: This was an IRB approved, case control study analyzing patient data from 2004 to 2013. Pathology database records were searched to identify patients with benign endometrioma and ovarian carcinoma arising in the background of endometriosis. Inclusion criteria required each patient to have a preoperative diagnosis of adnexal mass and no other findings concerning for malignancy. Patient clinical records were queried for preoperative symptoms, serum CA125 levels and radiologic findings. Pathologic data were collected including histology, tumor grade and stage. RESULTS: A total of 138 patients met inclusion criteria; 42 women with ovarian cancer arising in the background of endometriosis and 96 women with benign endometrioma. Women diagnosed with ovarian cancer were significantly older than women with endometriosis (53.6 vs. 39.2 years). There was no difference in presence of symptoms between the two groups. Women with malignant tumors were found to have significantly larger cysts (14 cm vs. 7.5 cm; p<0.0001) that were more often multilocular (45.7% vs. 12.2%; p<0.0001), and contained solid components (77.1% vs. 14.5%; p<0.0001). Among patients that were observed prior to surgery there was a significant difference in the change in size of the mass over time with 4.2 cm increase for cases vs. 1.0 cm increase for controls (p=0.02). Multiple logistic regression analysis indicated that for every 5 years increase in age there was an adjusted OR of 2.17 (p=0.003). An age of 49 years or greater had an 80.6% sensitivity (95% CI: 62.5-92.5%) and an 82.9% specificity (95% CI: 67.9 92.8%) for malignancy, and solid component on imaging had an adjusted OR of 23.7 (p<0.0001). Serum CA125 levels tended to be higher in patients with malignant tumors but did not reach statistical significance with a mean of 204.9 vs. 66.9 (p=0.1). CONCLUSIONS: Significant predictors for malignant transformation of endometriosis include cyst characteristics and age. Women above the age of 49 with multilocular cysts and solid components are at high risk for malignant transformation of endometriosis. Serum CA125 level is not a significant predictor of malignant transformation. PMID- 25522114 TI - Identifying patients who can improve fertility with myomectomy. AB - OBJECTIVE: To identify the characteristics of cases and fibroids that will indicate which patients should undergo myomectomy to improve fertility. MATERIALS AND METHODS: We recruited patients (n=101) who had undergone myomectomy to improve fertility and received follow-up care for at least six months by the hospital. Medical records were retrospectively reviewed to analyze the pregnancy rates after myomectomy and to identify clinical factors that correlate with pregnancy rates. Cumulative pregnancy rates were analyzed using the Kaplan-Meier method and the Log rank test. The patients were then divided into three groups according to the timing of the myomectomy. The analysis was performed for all patients, for patients in the post-superovulation and/or intrauterine insemination (post-SO/IUI) group and the post-assisted reproductive technology (post-ART) group combined, and for patients in the post-ART group. RESULTS: Sixty three pregnancies were achieved by 58 patients (57.4%) who underwent myomectomy. The mean time period between surgery and conception was 9.8 months. Most pregnancies (91.5%) were achieved within two years after surgery. Pregnancy rates were higher in patients aged less than 36 years, with no male factors, and without severe endometriosis, in comparison with patients 36 years of age or older (p<0.05), with male factor (p<0.05), and severe endometriosis (p<0.05). In the analysis of the post-ART group, pregnancy rates were higher (p<0.05) in cases where enucleation had penetrated the endometrial cavity in comparison with patients where the cavity was not penetrated; however, fibroid characteristics did not correlate with the post-myomectomy pregnancy rate in the post-SO/IUI plus post-ART group. CONCLUSION: Post-myomectomy pregnancy rates were higher in women who did not have additional infertility factors. These results suggest that the removal of fibroids benefits especially patients who suffer from infertility of an otherwise unknown cause: surgery should be strongly recommended for these patients. Our study also shows the difficulty in identifying fibroids for removal to improve fertility. Further studies are needed to develop new diagnostic techniques for identifying patients who can improve fertility with myomectomy. PMID- 25522115 TI - Intra-abortion contraception with etonogestrel subdermal implant. AB - OBJECTIVES: Etonogestrel subdermal implant is a highly effective, reversible and safe form of contraception. Immediate placement during abortion visit could increase contraception use in women at high risk for unintended pregnancy. Our purpose was to evaluate patient acceptability, user continuation rate and efficacy of medical termination of pregnancy when the implant is inserted during medical termination of pregnancy. STUDY DESIGN: Prospective observational study comparing patients who chose the subdermal implant for post-abortion contraception, inserted at the time of administration of mifepristone, with patients who chose delayed placement after the termination was complete. RESULTS: After contraceptive counseling 119 women chose the implant as their post-abortion contraceptive method. In the intra-abortion implant insertion group the user continuation rate after 6 months was 73.7% (42/57). In the delayed placement group 59.7% (37/62) missed the follow-up after abortion visit, 24.2% (15/62) chose another method and only 16.1% (10/62) had the implant inserted. The efficacy of medical termination was 96.5% in the group of intra-abortion implant insertion and 98.4% in the delayed placement group. CONCLUSIONS: Intra-abortion subdermal implant insertion significantly increases the likelihood of effective long-acting contraception use following abortion. The efficacy of medical termination was not significantly changed by intra-abortion implant insertion. PMID- 25522116 TI - Evaluation of the selective use of abdomino-pelvic drains at laparoscopic myomectomy: in enhanced recovery, do drains delay discharge home? AB - OBJECTIVE: To assess whether the use of abdominal drains at laparoscopic myomectomy (LM) influences length of hospital stay. The primary outcome was to determine whether the use of intra-abdominal drains after LM was associated with prolonged hospital stay after surgery. Secondary outcomes were to identify factors that influence the use of abdomino-pelvic drains during LM. STUDY DESIGN: Retrospective cohort study of 217 consecutive single surgeon LMs in a London university teaching hospital. Abdominal drains were used selectively after LM. Of the 217 patients, 123 (57%) had a drain left in situ at the end of the operation. RESULTS: The two cohorts of patients were not significantly different in their demographics. The use of a drain was significantly associated with an increased number of fibroids (4.6+/-3.8 vs. 2.8+/-2.1, p<0.0001), increased weight of fibroids (277+/-211 g vs. 133+/-153 g, p<0.0001), increased surgical time (133+/ 40 min vs. 90+/-35 min, p<0.0001) and increased estimated blood loss (406+/-265 ml vs. 199+/-98 ml, p<0.0001). There was no statistically significant difference in length of hospital stay (mean duration of admission 2.1 days+/-0.98 with drain, vs. 2.1 days+/-0.97 without a drain, p=0.98). CONCLUSION: We conclude that although the use of a drain may be associated with a more complex operation, this does not delay the patient's discharge. PMID- 25522117 TI - Translation and validation of the Endometriosis Health Profile (EHP-5) in patients with laparoscopically diagnosed endometriosis. AB - OBJECTIVES: To validate the Turkish-translated versions of the Endometriosis Health Profile 5 (EHP-5) for use in patients with laparoscopically proven endometriosis. STUDY DESIGN: This case control study was conducted in a tertiary referral teaching institution between April and June 2014. Fifty-eight patients with surgically proven endometriosis were enrolled. The EHP-5 questionnaire was evaluated for patients with laparoscopically diagnosed endometriosis. Test-retest reliability, descriptive statistics, reliability analysis (internal consistency and item-total correlation), data completeness, and known-group comparison were all assessed in the validation of the EHP-5 form as translated into the Turkish language. RESULTS: Two weeks test-retest reliability showed statistically significant correlation; Spearman's rho was 0.885 (p<0.001) for the EHP-5 core questionnaire and 0.896 (p<0.001) for the EHP-5 modular questionnaire. Cronbach's alpha values for the translated form of the EHP-5 core and modular questionnaires were 0.829 and 0.804, respectively, with a high level of internal consistency. In known group comparison, there were statistically significant differences in all subgroups except in the infertility group on the core questionnaire. Pain scales on the core questionnaire and infertility scales on the modular questionnaire showed the highest mean scores (1.14+/-1.16 and 1.78+/-1.77). CONCLUSION: Like the original English questionnaire, the Turkish-translated version of the EHP-5 is a reliable and valid instrument for assessing symptom severity and the impact of endometriosis on health-related quality of life in Turkish-speaking women. PMID- 25522118 TI - Health status and quality of life in postpartum women: a systematic review of associated factors. AB - Since health care is becoming more and more patient centered, patient-reported outcomes such as quality of life (QOL) and health status (HS) are becoming increasingly important. The aim of this systematic review was to provide an overview of physical, psychological, and social domains of QOL and HS in postpartum women, and to assess which factors are associated with QOL and HS domains postpartum. A computerized literature search was performed using the PubMed, PsycINFO, and Cochrane databases. Studies were selected if the three domains of QOL or HS were measured in a (sub)group of postpartum women, by using validated standardized questionnaires. The methodological quality of the 66 included studies was examined by two independent reviewers. All three domains of QOL were impaired in postpartum women with urinary incontinence, with even worse QOL in women with mixed urinary incontinence. Mental QOL was impaired in women with urge urinary incontinence after cesarean section. Social QOL was decreased in HIV-positive women. HS was impaired in all three domains in postpartum depressed women. Physical HS was impaired after cesarean section for at least two months postpartum. Additional supportive interventions from health care social support were not associated with improved HS. Urinary incontinence and being HIV positive seemed to be associated with impaired QOL. Postpartum depression and a cesarean section seemed to be associated with impaired HS. Prospective longitudinal research is needed in order to draw valid conclusions regarding postpartum HS and QOL, and the predictive value of the associated factors. PMID- 25522119 TI - Elucidation of conformer preferences for a hydrophobic antimicrobial peptide by vesicle capture-freeze-drying: a preparatory method coupled to ion mobility-mass spectrometry. AB - A novel sample preparation method to probe the solution phase structure of dimerized Gramicidin A (GA) inserted into lipid vesicle bilayers is described. This method, termed vesicle capture-freeze-drying (VCFD), when coupled with electrospray ionization-ion mobility-mass spectrometry (ESI-IM-MS), successfully demonstrates the first evidence for the preservation of membrane-bound structure in the analysis of solution phase conformers retained into the gas phase. The extremely hydrophobic character of GA ensures that only membrane-bound conformations are captured and subsequently monitored when samples are prepared using VCFD, removing a barrier that has prevented previous attempts at direct analysis using mass spectrometry. Solution-phase physicochemical interactions of GA influenced by lipid acyl chain length and extent of acyl chain unsaturation can now be probed by monitoring the conformer preferences using IM-MS. Increasing the acyl chain length from 12 to 22 carbons yields [2GA + 2Na](2+) IM-MS profiles with reduced conformer microheterogeneity. POPC (16:0, 18:1 PC), a lipid possessing a single acyl chain unsaturation point, yields the highest abundance of the single stranded head to head (SSHH) conformer. Conformer preferences adopted in the lipid bilayer are maintained as GA dimers travel from the solution phase to fully desolvated gas-phase ions demonstrating that distributions observed using ESI-IM-MS unambiguously reflect the ensemble of conformers observed in the solution phase. VCFD-ESI-IM-MS yields novel biophysical insight into the influence of lipid bilayer membranes on conformer preferences and conformer heterogeneity of an important channel-forming membrane peptide. PMID- 25522120 TI - Hydride generation atomic absorption spectrometric determination of bismuth after separation and preconcentration with modified alumina. AB - A simple and sensitive method has been developed for the trace determination of bismuth in aqueous samples by a combination of solid-phase extraction and hydride generation atomic absorption spectrometry. The method is based on the use of a column packed with 2-mercaptobenzothiazole immobilized on sodium dodecyl sulfate coated alumina. Different parameters influencing the separation and preconcentration of bismuth such as pH, sample volume, type, and concentration of eluent, and the flow rate of sample and eluent were studied. A sample volume of 500.0 mL resulted in a preconcentration factor of 100. The precision (relative standard deviation, N = 10) at the 300 ng/L level and the limit of detection (3s) were found to be 2.3% and 12 ng/L, respectively. The developed method was successfully applied to the determination of bismuth in natural water samples and two certified reference materials. PMID- 25522121 TI - Organoclays in water cause expansion that facilitates caffeine adsorption. AB - This study investigates the adsorption of caffeine in water on organically modified clays (a natural montmorillonite and synthetic saponite, which are smectite group of layered clay minerals). The organoclays were prepared by cation exchange reactions of benzylammonium and neostigmine with interlayer exchangeable cations in the clay minerals. Although less caffeine was uptaken on neostigmine modified clays than on raw clay minerals, uptake was increased by adding benzylammonium to the clays. The adsorption equilibrium constant was considerably higher on benzylammonium-modified saponite (containing small quantities of intercalated benzylammonium) than on its montmorillonite counterpart. These observations suggest that decreasing the size and number of intercalated cations enlarges the siloxane surface area available for caffeine adsorption. When the benzylammonium-smectite powders were immersed in water, the intercalated water molecules expanded the interlayer space. Addition of caffeine to the aqueous dispersion further expanded the benzylammonium-montmorillonite system but showed no effect on benzylammonium-saponite. We assume that intercalated water molecules were exchanged with caffeine molecules. By intercalating benzylammonium into smectites, we have potentially created an adaptable two-dimensional nanospace that sequesters caffeine from aqueous media. PMID- 25522122 TI - Monofunctional polymer nanoparticles prepared through intramolecularly cross linking the polymer chains sparsely grafted on the surface of sacrificial silica spheres. AB - Herein we report preparation of polymeric monofunctional nanoparticles (PMNs) through intramolecularly cross-linking the polymer chains sparsely grafted on the surface of sacrificial silica spheres, and a one-to-one coupling reaction between PMNs and linear polymer chains and that between two PMNs. PMID- 25522123 TI - Assisted Gestation and Transgender Women. AB - Developments in uterus transplant put assisted gestation within meaningful range of clinical success for women with uterine infertility who want to gestate children. Should this kind of transplantation prove routine and effective for those women, would there be any morally significant reason why men or transgender women should not be eligible for the same opportunity for gestation? Getting to the point of safe and effective uterus transplantation for those parties would require a focused line of research, over and above the study of uterus transplantation for non-transgender women. Some commentators object to the idea that the state has any duty to sponsor research of this kind. They would limit all publicly-funded fertility research to sex-typical ways of having children, which they construe as the basis of reproductive rights. This objection has no force against privately-funded research, of course, and in any case not all social expenditures are responses to 'rights' properly speaking. Another possible objection raised against gestation by transgender women is that it could alter the social meaning of sexed bodies. This line of argument fails, however, to substantiate a meaningful objection to gestation by transgender women because social meanings of sexed bodies do not remain constant and because the change in this case would not elicit social effects significant enough to justify closing off gestation to transgender women as a class. PMID- 25522124 TI - Neurobrucellosis in children: Case series from Turkey. AB - BACKGROUND: Brucellosis is a multisystem disease that may present with a broad spectrum of clinical manifestations and complications. Neurobrucellosis is an uncommon and serious complication of pediatric brucellosis. METHODS: We describe seven cases of neurobrucellosis. RESULTS: Ataxia (one patient), diplopia (one patient) and hearing loss (one patient) were among the neurological signs and symptoms. The most common diagnoses were acute meningitis and meningoencephalitis. Five of the patients fully recovered, one was lost to follow up and the other had hearing loss as a sequela. CONCLUSION: Neurobrucellosis should be kept in mind in patients with any neurological or neuropsychiatric diseases who live in endemic areas of brucellosis. PMID- 25522125 TI - Congenital heart surgery in patients with ventricular noncompaction. AB - BACKGROUND: Noncompaction of the ventricular myocardium (NVM) is exceedingly rare and associated with a high morbidity and mortality. This pathology has been associated with other congenital heart diseases (CHDs). The efficacy of surgical treatment of patients with NVM and other CHDs is largely unknown. The aim of the present study was to describe surgical outcomes of 16 patients. METHODS AND RESULTS: Between April 2009 and October 2011, 16 patients with NVM and CHD were admitted to our hospital. Through a clinical chart review, we analyzed results of surgical treatment of NVM with other CHDs retrospectively. The median age was 3.9 years (range 2 m-11 y). The follow-up time was 23.93 months (range 3 m-36 m). Two patients (12.5%) died after the surgery, the remaining patients (87.5%) had an uneventful postoperative course. An additional patient died due to sudden death three months after surgery. Two patients developed recurrent heart failure after surgery. Congestive heart failure, severe arrhythmias, and the range of NVM may be risk factors for death. At 6 months after the operation, the NYHA functional class was significantly improved (2.38 +/- 0.89 vs. 1.62 +/- 0.65, p = 0.009). The cardiothoracic ratio was significantly reduced when compared to before the operation (p < 0.001). CONCLUSIONS: Surgery in patients with NVM and other CHDs can be effective in relieving heart failure, improving heart function, and decreasing heart size. PMID- 25522126 TI - Effect of Haemophilus influenzae exposure on Staphylococcus aureus tympanostomy tube attachment and biofilm formation. AB - IMPORTANCE: Tympanostomy tube (TT) biofilm formation may lead to sequelae. OBJECTIVE: To determine whether the acute pathogen Haemophilus influenzae promotes TT attachment and biofilm formation by the chronic pathogen Staphylococcus aureus. DESIGN AND SETTING: Controlled, in vitro microbiological study at an academic research laboratory using TTs treated with 0 (untreated), 10, or 3000 ug/mL ciprofloxacin or ethylene oxide and TTs with and without prior H influenzae exposure. INTERVENTIONS: Fluoroplastic TTs (18 per treatment) were cultured with H influenzae. The TTs were gas-sterilized or exposed to 0, 10, or 3000 ug/mL ciprofloxacin. One-third of the TTs from each treatment group underwent H influenzae counts or scanning electron microscopy (SEM). Another one third were used for an S aureus attachment assay. The remainder, as well as TTs not exposed to H influenzae, were cultured with S aureus and then treated with oxacillin to kill planktonic S aureus. S aureus counts and SEM were performed. MAIN OUTCOMES AND MEASURES: Attachment and biofilm formation of S aureus on TTs assessed by quantitative bacterial counts and SEM. RESULTS: Mean (SD) H influenzae counts were lower on TTs treated with 3 mg/mL than with 10 ug/mL ciprofloxacin (2.06 * 103 [1.00 * 103] vs 4.21 * 105 [1.67 * 105]; P < .001). Mean (SD) S aureus attachment was higher on TTs with untreated preexisting H influenzae (8.88 * 105 [3.20 * 105]; P < .001) and lower on TTs with prior exposure to H influenzae treated with 10 (3.43 * 104 [2.10 * 104]; P = .006) or 3000 ug/mL ciprofloxacin (6.41 * 102 [3.59 * 102]; P < .001). S aureus biofilm formation was similar across groups, except TTs with prior exposure to H influenzae treated with ciprofloxacin 3 mg/mL, which had significantly less (9.30 * 101 [3.51 * 102]; P < .001). CONCLUSIONS AND RELEVANCE: Exposure to live H influenzae may promote S aureus attachment on TTs. Treatment of H influenzae on TTs with ciprofloxacin, 3 mg/mL, as found in ototopical therapy, may reduce subsequent S aureus attachment and biofilm formation. PMID- 25522127 TI - Psychometric evaluation of the HIV stigma scale in a Swedish context. AB - BACKGROUND: HIV-related stigma has negative consequences for infected people's lives and is a barrier to HIV prevention. Therefore valid and reliable instruments to measure stigma are needed to enable mapping of HIV stigma. This study aimed to evaluate the psychometric properties of the HIV stigma scale in a Swedish context with regard to construct validity, data quality, and reliability. METHODS: The HIV stigma scale, developed by Berger, Ferrans, and Lashley (2001), was distributed to a cross-sectional sample of people living with HIV in Sweden (n = 194). The psychometric evaluation included exploratory factor analysis together with an analysis of the distribution of scores, convergent validity by correlations between the HIV stigma scale and measures of emotional well-being, and an analysis of missing items and floor and ceiling effects. Reliability was assessed using Cronbach's alpha. RESULTS: The exploratory factor analysis suggested a four-factor solution, similar to the original scale, with the dimensions personalised stigma, disclosure concerns, negative self-image, and concerns with public attitudes. One item had unacceptably low loadings and was excluded. Correlations between stigma dimensions and emotional well-being were all in the expected direction and ranged between -0.494 and -0.210. The instrument generated data of acceptable quality except for participants who had not disclosed their HIV status to anybody. In line with the original scale, all subscales demonstrated acceptable internal consistency with Cronbach's alpha 0.87 0.96. CONCLUSION: A 39-item version of the HIV stigma scale used in a Swedish context showed satisfactory construct validity and reliability. Response alternatives are suggested to be slightly revised for items assuming the disclosure of diagnosis to another person. We recommend that people that have not disclosed should skip all questions belonging to the dimension personalised stigma. Our analysis confirmed construct validity of the instrument even without this dimension. PMID- 25522129 TI - Cu(I)-catalyzed highly enantioselective [3 + 3] cycloaddition between two different 1,3-dipoles, phthalazinium dicyanomethanides and iminoester-derived azomethine ylides. AB - The Cu(I)-catalyzed highly enantioselective [3 + 3] cycloaddition between two different 1,3-dipoles, phthalazinium dicyanomethanides and iminoester-derived azomethine ylides, has been achieved under mild reaction conditions, providing novel chiral heterocyclic compounds, 2,3,4,11b-tetrahydro-1H-pyrazino[2,1 a]phthalazine derivatives, in high yields with excellent diastereo- and enantioselectivies (up to 99% yield, 99% ee, >20:1 dr). PMID- 25522128 TI - Post-transplant maintenance therapy with azacitidine and gemtuzumab ozogamicin for high-risk acute myeloid leukaemia. PMID- 25522130 TI - Matrix Rigidity Mediates TGFbeta1-Induced Epithelial-Myofibroblast Transition by Controlling Cytoskeletal Organization and MRTF-A Localization. AB - Myofibroblasts mediate normal wound healing and upon chronic activation can contribute to the development of pathological conditions including organ fibrosis and cancer. Myofibroblasts can develop from epithelial cells through an epithelial-mesenchymal transition (EMT) during which epithelial cells exhibit drastic morphological changes and upregulate cytoskeletal associated proteins that enable exertion of large contractile forces and remodeling of the surrounding microenvironment. Increased matrix rigidity is a hallmark of fibrosis and tumor progression and mechanical tension has been identified as a regulator of EMT; however, the mechanisms governing the mechanical regulation of EMT are not completely understood. Here, we find that matrix rigidity regulates transforming growth factor (TGF)-beta1-induced EMT, with rigid substrata enabling increased myofibroblast marker expression, cell morphology changes, and cytoskeletal reorganization while soft matrices block these changes. Furthermore, we find that matrix rigidity controls the subcellular localization of myocardin related transcription factor (MRTF)-A, a regulator of cytoskeletal protein expression that contributes to the acquisition of myogenic features during EMT. Results from these studies provide insight into how biophysical cues contribute to myofibroblast development from epithelial cells and may suggest ways to enhance wound healing or to engineer therapeutic solutions for fibrosis and cancer. PMID- 25522131 TI - Dehydrative thiolation of allenols: indium vs gold catalysis. AB - Intermolecular additions of thiols to allenols via formal S(N)2' selectivity to produce functionalized dienes are described. Although this dehydrative reaction was initially developed using gold(I) catalysis, indium(III) proves to be a far superior catalyst in terms of selectivity and substrate scope. PMID- 25522132 TI - The effects of SENSE on PROPELLER imaging. AB - PURPOSE: To study how sensitivity encoding (SENSE) impacts periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) image quality, including signal-to-noise ratio (SNR), robustness to motion, precision of motion estimation, and image quality. METHODS: Five volunteers were imaged by three sets of scans. A rapid method for generating the g-factor map was proposed and validated via Monte Carlo simulations. Sensitivity maps were extrapolated to increase the area over which SENSE can be performed and therefore enhance the robustness to head motion. The precision of motion estimation of PROPELLER blades that are unfolded with these sensitivity maps was investigated. An interleaved R factor PROPELLER sequence was used to acquire data with similar amounts of motion with and without SENSE acceleration. Two neuroradiologists independently and blindly compared 214 image pairs. RESULTS: The proposed method of g-factor calculation was similar to that provided by the Monte Carlo methods. Extrapolation and rotation of the sensitivity maps allowed for continued robustness of SENSE unfolding in the presence of motion. SENSE-widened blades improved the precision of rotation and translation estimation. PROPELLER images with a SENSE factor of 3 outperformed the traditional PROPELLER images when reconstructing the same number of blades. CONCLUSION: SENSE not only accelerates PROPELLER but can also improve robustness and precision of head motion correction, which improves overall image quality even when SNR is lost due to acceleration. The reduction of SNR, as a penalty of acceleration, is characterized by the proposed g-factor method. PMID- 25522133 TI - Discovery of mono- and disubstituted 1H-pyrazolo[3,4]pyrimidines and 9H-purines as catalytic inhibitors of human DNA topoisomerase IIalpha. AB - Human DNA topoisomerase IIalpha (htIIalpha) is a validated target for the development of anticancer agents. Based on structural data regarding the binding mode of AMP-PNP (5'-adenylyl-beta,gamma-imidodiphosphate) to htIIalpha, we designed a two-stage virtual screening campaign that combines structure-based pharmacophores and molecular docking. In the first stage, we identified several monosubstituted 9H-purine compounds and a novel class of 1H pyrazolo[3,4]pyrimidines as inhibitors of htIIalpha. In the second stage, disubstituted analogues with improved cellular activities were discovered. Compounds from both classes were shown to inhibit htIIalpha-mediated DNA decatenation, and surface plasmon resonance (SPR) experiments confirmed binding of these two compounds on the htIIalpha ATPase domain. Proposed complexes and interaction patterns between both compounds and htIIalpha were further analyzed in molecular dynamics simulations. Two compounds identified in the second stage showed promising anticancer activities in hepatocellular carcinoma (HepG2) and breast cancer (MCF-7) cell lines. The discovered compounds are suitable starting points for further hit-to-lead development in anticancer drug discovery. PMID- 25522134 TI - Field evaluation of picaridin repellents reveals differences in repellent sensitivity between Southeast Asian vectors of malaria and arboviruses. AB - Scaling up of insecticide treated nets has contributed to a substantial malaria decline. However, some malaria vectors, and most arbovirus vectors, bite outdoors and in the early evening. Therefore, topically applied insect repellents may provide crucial additional protection against mosquito-borne pathogens. Among topical repellents, DEET is the most commonly used, followed by others such as picaridin. The protective efficacy of two formulated picaridin repellents against mosquito bites, including arbovirus and malaria vectors, was evaluated in a field study in Cambodia. Over a period of two years, human landing collections were performed on repellent treated persons, with rotation to account for the effect of collection place, time and individual collector. Based on a total of 4996 mosquitoes collected on negative control persons, the overall five hour protection rate was 97.4% [95%CI: 97.1-97.8%], not decreasing over time. Picaridin 20% performed equally well as DEET 20% and better than picaridin 10%. Repellents performed better against Mansonia and Culex spp. as compared to aedines and anophelines. A lower performance was observed against Aedes albopictus as compared to Aedes aegypti, and against Anopheles barbirostris as compared to several vector species. Parity rates were higher in vectors collected on repellent treated person as compared to control persons. As such, field evaluation shows that repellents can provide additional personal protection against early and outdoor biting malaria and arbovirus vectors, with excellent protection up to five hours after application. The heterogeneity in repellent sensitivity between mosquito genera and vector species could however impact the efficacy of repellents in public health programs. Considering its excellent performance and potential to protect against early and outdoor biting vectors, as well as its higher acceptability as compared to DEET, picaridin is an appropriate product to evaluate the epidemiological impact of large scale use of topical repellents on arthropod borne diseases. PMID- 25522136 TI - Comparison of negative pressure wound therapy and conventional dressing methods for fibula free flap donor site management in patients with head and neck cancer. AB - BACKGROUND: Evaluation of the efficacy of negative pressure wound therapy in fibula free flap donor site management in head and neck cancer. METHODS: We conducted a single-center retrospective study from 2007 to 2013 comparing fibula free flap donor site healing time after conventional bolster dressing or negative pressure wound therapy. RESULTS: Thirteen patients were treated by conventional dressing and 16 patients were treated by negative pressure wound therapy. The mean graft loss rate was higher in the bolster group (37%) than in the negative pressure wound therapy group (19%). The mean total healing time was significantly shorter in the negative pressure wound therapy group than in the bolster group (67 days vs 163 days; p = .02). CONCLUSION: The use of negative pressure wound therapy for fibula free flap donor site management facilitates early patient mobilization, ensures better graft acceptance, and significantly decreases the healing time. PMID- 25522135 TI - Association of breastfeeding with postmenopausal visceral adiposity among three racial/ethnic groups. AB - OBJECTIVE: We examined the association between breastfeeding and postmenopausal visceral adiposity. METHODS: Participants were community-dwelling women aged 55 80 from the Caucasian Rancho Bernardo Study, the Filipino Women's Health Study, and the Health Assessment Study of African-American Women who had visceral adipose tissue (VAT) measurements by computed tomography between 2000 and 2002. Linear regression was used to determine the association between average breastfeeding duration per child and VAT. RESULTS: In Caucasian, Filipino, and African-American women, average number of live births was 3, 4, and 3; average breastfeeding duration was 4.3, 1.8, and 5.1 months, respectively. Filipino women had more live births, were more likely to breastfeed, and breastfed shorter durations. African-American women had lower VAT, despite higher subcutaneous adipose tissue (SAT), BMI, and waist girth. Women who breastfed >3 months on average had 8.8 cm(3) lower VAT than women who breastfed <=3 months, independent of covariates. Women who initiated breastfeeding had lower BMI and waist girth than those who did not, but they did not differ by VAT unless they breastfed >3 months. Associations were independent of race/ethnicity. CONCLUSIONS: Results suggest breastfeeding initiation is associated with reduced BMI and smaller waist girth, and breastfeeding >3 months is associated with lower postmenopausal VAT. PMID- 25522137 TI - Groundwater chemistry determines the prokaryotic community structure of waterworks sand filters. AB - Rapid sand filtration is essential at most waterworks that treat anaerobic groundwater. Often the filtration depends on microbiological processes, but the microbial communities of the filters are largely unknown. We determined the prokaryotic community structures of 11 waterworks receiving groundwater from different geological settings by 16S rRNA gene-based 454 pyrosequencing and explored their relationships to filtration technology and raw water chemistry. Most of the variation in microbial diversity observed between different waterworks sand filters could be explained by the geochemistry of the inlet water. In addition, our findings suggested four features of particular interest: (1) Nitrospira dominated over Nitrobacter at all waterworks, suggesting that Nitrospira is a key nitrifying bacterium in groundwater-treating sand filters. (2) Hyphomicrobiaceae species were abundant at all waterworks, where they may be involved in manganese oxidation. (3) Six of 11 waterworks had significant concentrations of methane in their raw water and very high abundance of the methanotrophic Methylococcaceae. (4) The iron-oxidizing bacteria Gallionella was present at all waterworks suggesting that biological iron oxidation is occurring in addition to abiotic iron oxidation. Elucidation of key members of the microbial community in groundwater-treating sand filters has practical potential, for example, when methods are needed to improve filter function. PMID- 25522138 TI - Pluripotent stem cells and tolerance induction in organ transplantation. AB - PURPOSE OF REVIEW: Ongoing research is constantly looking for means to modulate the immune system for long-lasting engraftment of pluripotent stem cells (PSC) during stem cell-based therapies. This study reviews data on in-vitro and in-vivo immunogenicity of embryonic and induced-PSC and describes how their immunological properties can be harnessed for tolerance induction in organ transplantation. RECENT FINDINGS: Although PSC display immunomodulatory properties in vitro, they are capable of eliciting an immune response that leads to cell rejection when transplanted into immune-competent recipients. Nevertheless, long-term acceptance of PSC-derived cells/tissues in an allogeneic environment can be achieved using minimal host conditioning. Protocols for differentiating PSC towards haematopoietic stem cells, thymic epithelial precursors, dendritic cells, regulatory T cells and myeloid-derived suppressor cells are being developed, suggesting the possibility to use PSC-derived immunomodulatory cells to induce tolerance to a solid organ transplant. SUMMARY: PSC and/or their derivatives possess unique immunological properties that allow for acceptance of PSC-derived tissue with minimal host conditioning. Investigators involved either in regenerative or in transplant medicine must join their efforts with the ultimate aim of using PSC as a source of donor-specific cells that would create a protolerogenic environment to achieve tolerance in solid organ transplantation. PMID- 25522139 TI - Facilitating cells in tolerance induction for kidney transplantation. AB - PURPOSE OF REVIEW: To describe the clinical outcomes and science behind a CD8/TCR facilitating cell-based hematopoietic stem cell transplant approach (termed FCRx) to induce tolerance to renal allografts without graft-versus-host disease (GVHD) and avoidance of long-term immunosuppressant drugs in living donor kidney transplant recipients. RECENT FINDINGS: Successful solid organ transplantation currently requires the life-long use of medications to suppress the immune system to prevent transplant rejection. Drug-based immunosuppression significantly increases the risk of infection and cancer, as well as being very costly. Development of new therapies to minimize or eliminate entirely the need for antirejection drugs is of great interest to the transplant community. Therapeutic cell transfer for the control of the human immune system represents a compelling approach to reduce or eliminate the need for antirejection drugs. SUMMARY: Establishment of durable hematopoietic macrochimerism under nonmyeloablative conditioning is achievable in mismatched recipients using facilitating cells and stem cells obtained from donor mobilized peripheral blood mononuclear cells. Persistently chimeric recipients developed donor-specific tolerance and were weaned off of immunosuppressive drugs over 12 months. They maintained stable renal function without development of acute or chronic GVHD. PMID- 25522141 TI - Universal prophylaxis or preemptive strategy for cytomegalovirus disease after liver transplantation: a systematic review and meta-analysis. AB - We systematically reviewed and meta-analyze the efficacy of universal prophylaxis (UP) and preemptive (PE) strategies (using ganciclovir or valganciclovir) in preventing cytomegalovirus (CMV) disease (CMD) among liver transplant recipients (LTRs). We performed an electronic search of MEDLINE, EMBASE and the Cochrane Database till December 2013. Studies that assessed UP or PE for preventing CMD in LTRs were included. The risk of bias was assessed using the Newcastle-Ottawa scale. The primary outcome was CMD, secondary outcomes being acute cellular rejection (ACR), graft loss (GL) and mortality. Due to the heterogeneity of comparative studies, an indirect comparison was performed. Pooled incidence rates with 95% confidence interval (CI) are calculated for each outcome using a random effects model. Thirty-two studies involving 2456 LTRs were included. The majority of the studies were of low risk of bias. Irrespective of donor/recipient CMV sero status, CMD was 10% with UP (95% CI: 6-14; I(2) = 87%; 16 studies, n = 1581) and 7% with PE (95% CI: 3-10; I(2) = 84%; 16 studies, n = 875) (mean difference 2.6; 95% CI: -3.25 to 8.45, p = 0.34). Likewise, ACR and mortality were similar with the two strategies. However, GL was significantly lower in the UP group, regardless of donor/recipient sero-status. In indirect comparison, the incidence of CMD, ACR and mortality in LTRs were similar with two strategies. Trials comparing the two strategies directly are needed. PMID- 25522142 TI - Pregnancy outcome in patients with sickle cell disease in the UK--a national cohort study comparing sickle cell anaemia (HbSS) with HbSC disease. AB - We describe the findings from a national study of maternal and fetal outcomes of pregnancy in women with sickle cell disease (SCD). Data were collected via the United Kingdom Obstetric Surveillance System between 1 February 2010 and 31 January 2011 from 109 women, of whom 51 (46.8%) had HbSS and 44 (40.4%) had HbSC. Data included antenatal, maternal and fetal outcomes. Comparisons were made between women with HbSS and HbSC. Incidence of complications were acute pain (57%), blood transfusion (26%), urinary tract infection (UTI; 12%) and critical care unit admission (23%) and these were all more common in women with HbSS than HbSC. There was no difference in the incidence of acute chest syndrome, hypertension and venous thromboembolism between HbSS and HbSC. Women with HbSS were more likely to deliver at <37 weeks gestation (P = 0.01) and their babies were more likely to have reduced birth weight. Delivery at <34 weeks was increased in both HbSS and HbSC women (5.9% vs. 4.6%) compared to national data. This study confirms a high rate of maternal and fetal complications in mothers with SCD, even in women with HbSC, which has previously been considered to have a more benign phenotype in pregnancy. PMID- 25522140 TI - Selective activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis. AB - BACKGROUND AND PURPOSE: Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right-heart failure and death. A dys-regulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin AT2 receptor in PH has not been fully elucidated. We have taken advantage of a recently identified non-peptide AT2 receptor agonist, Compound 21 (C21), to investigate its effects on the well-established monocrotaline (MCT) rat model of PH. EXPERIMENTAL APPROACH: A single s.c. injection of MCT (50 mg.kg(-1) ) was used to induce PH in 8-week-old male Sprague Dawley rats. After 2 weeks of MCT administration, a subset of animals began receiving either 0.03 mg.kg(-1) C21, 3 mg.kg(-1) PD-123319 or 0.5 mg.kg(-1) A779 for an additional 2 weeks, after which right ventricular haemodynamic parameters were measured and tissues were collected for gene expression and histological analyses. KEY RESULTS: Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT-induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro-inflammatory cytokines and favourable modulation of the lung RAS. Conversely, co-administration of the AT2 receptor antagonist, PD-123319, or the Mas antagonist, A779, abolished the protective actions of C21. CONCLUSIONS AND IMPLICATIONS: Taken together, our results suggest that the AT2 receptor agonist, C21, may hold promise for patients with PH. PMID- 25522143 TI - Plasmid flux in Escherichia coli ST131 sublineages, analyzed by plasmid constellation network (PLACNET), a new method for plasmid reconstruction from whole genome sequences. AB - Bacterial whole genome sequence (WGS) methods are rapidly overtaking classical sequence analysis. Many bacterial sequencing projects focus on mobilome changes, since macroevolutionary events, such as the acquisition or loss of mobile genetic elements, mainly plasmids, play essential roles in adaptive evolution. Existing WGS analysis protocols do not assort contigs between plasmids and the main chromosome, thus hampering full analysis of plasmid sequences. We developed a method (called plasmid constellation networks or PLACNET) that identifies, visualizes and analyzes plasmids in WGS projects by creating a network of contig interactions, thus allowing comprehensive plasmid analysis within WGS datasets. The workflow of the method is based on three types of data: assembly information (including scaffold links and coverage), comparison to reference sequences and plasmid-diagnostic sequence features. The resulting network is pruned by expert analysis, to eliminate confounding data, and implemented in a Cytoscape-based graphic representation. To demonstrate PLACNET sensitivity and efficacy, the plasmidome of the Escherichia coli lineage ST131 was analyzed. ST131 is a globally spread clonal group of extraintestinal pathogenic E. coli (ExPEC), comprising different sublineages with ability to acquire and spread antibiotic resistance and virulence genes via plasmids. Results show that plasmids flux in the evolution of this lineage, which is wide open for plasmid exchange. MOBF12/IncF plasmids were pervasive, adding just by themselves more than 350 protein families to the ST131 pangenome. Nearly 50% of the most frequent gamma proteobacterial plasmid groups were found to be present in our limited sample of ten analyzed ST131 genomes, which represent the main ST131 sublineages. PMID- 25522145 TI - Parasitic nematode-induced CD4+Foxp3+T cells can ameliorate allergic airway inflammation. AB - BACKGROUND: The recruitment of CD4+CD25+Foxp3+T (Treg) cells is one of the most important mechanisms by which parasites down-regulate the immune system. METHODOLOGY/PRINCIPAL FINDINGS: We compared the effects of Treg cells from Trichinella spiralis-infected mice and uninfected mice on experimental allergic airway inflammation in order to understand the functions of parasite-induced Treg cells. After four weeks of T. spiralis infection, we isolated Foxp3-GFP expressing cells from transgenic mice using a cell sorter. We injected CD4+Foxp3+ cells from T. spiralis-infected [Inf(+)Foxp3+] or uninfected [Inf(-)Foxp3+] mice into the tail veins of C57BL/6 mice before the induction of inflammation or during inflammation. Inflammation was induced by ovalbumin (OVA)-alum sensitization and OVA challenge. The concentrations of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchial alveolar lavage fluid and the levels of OVA-specific IgE and IgG1 in the serum were lower in mice that received intravenous application of Inf(+)Foxp3+ cells [IV(inf):+(+) group] than in control mice. Some features of allergic airway inflammation were ameliorated by the intravenous application of Inf(-)Foxp3+ cells [IV(inf):+(-) group], but the effects were less distinct than those observed in the IV(inf):+(+) group. We found that Inf(+)Foxp3+ cells migrated to inflammation sites in the lung and expressed higher levels of Treg-cell homing receptors (CCR5 and CCR9) and activation markers (Klrg1, Capg, GARP, Gzmb, OX40) than did Inf(-)Foxp3+ cells. CONCLUSION/SIGNIFICANCE: T. spiralis infection promotes the proliferation and functional activation of Treg cells. Parasite-induced Treg cells migrate to the inflammation site and suppress immune responses more effectively than non parasite-induced Treg cells. The adoptive transfer of Inf(+)Foxp3+ cells is an effective method for the treatment and prevention of allergic airway diseases in mice and is a promising therapeutic approach for the treatment of allergic airway diseases. PMID- 25522144 TI - Lack of exercise of "moderate to vigorous" intensity in people with low levels of physical activity is a major discriminant for sociodemographic factors and morbidity. AB - INTRODUCTION: The aim is to examine the differences between participation at low and zero moderate to vigorous physical activity (MVPA) in relation to their trends and associations with known socio-demographic and health factors. We hypothesised that the number of people at zero MVPA level could be rising despite a parallel increase in the population meeting the recommended MVPA level. We also hypothesised that graded associations of sociodemographic and health factors exist across MVPA levels. METHODS: Two independent population-based samples (n = 4320 [2004] and n = 2176 [1997]), were recruited with a stratified and random sampling procedure and interviewed at home by professional interviewers. The MVPA was assessed by validated questionnaire. The participants were classified into three MVPA levels: zero, low and recommended MVPA. The trend of each MVPA level was analysed with the standardized prevalence ratios. Correlates of low and zero MVPA levels were examined using multinomial logistic regression. RESULTS: The population at zero and recommended MVPA levels rose between 1997-2004 by 12% (95% CI, 5-20%) and 7% (95% CI,-4-19%) respectively, while the population at low MVPA level decreased. At zero MVPA level, associative patterns were observed with sociodemographic and health factors which were different when compared to the population at low MVPA level. CONCLUSIONS: Despite the slight increase of population meeting the recommended MVPA level, a higher trend of increase was observed at zero MVPA level. Both recommended and low MPVA levels increased their participation by absorbing participants from the low MVPA level. The sociodemographic profile of those with low MVPA was more similar to the population at recommended MVPA than at zero MVPA level. Methodological implications about the combination of light and moderate-intensity PA could be derived. The prevention of decline in actual low MVPA could change the trend of increase in the population at zero MVPA level, particularly among young adults. PMID- 25522147 TI - Complete chloroplast genome of Macadamia integrifolia confirms the position of the Gondwanan early-diverging eudicot family Proteaceae. AB - BACKGROUND: Sequence data from the chloroplast genome have played a central role in elucidating the evolutionary history of flowering plants, Angiospermae. In the past decade, the number of complete chloroplast genomes has burgeoned, leading to well-supported angiosperm phylogenies. However, some relationships, particulary among early-diverging lineages, remain unresolved. The diverse Southern Hemisphere plant family Proteaceae arose on the ancient supercontinent Gondwana early in angiosperm history and is a model group for adaptive radiation in response to changing climatic conditions. Genomic resources for the family are limited, and until now it is one of the few early-diverging 'basal eudicot' lineages not represented in chloroplast phylogenomic analyses. RESULTS: The chloroplast genome of the Australian nut crop tree Macadamia integrifolia was assembled de novo from Illumina paired-end sequence reads. Three contigs, corresponding to a collapsed inverted repeat, a large and a small single copy region were identified, and used for genome reconstruction. The complete genome is 159,714 bp in length and was assembled at deep coverage (3.29 million reads; ~2000 x). Phylogenetic analyses based on 83-gene and inverted repeat region alignments, the largest sequence-rich datasets to include the basal eudicot family Proteaceae, provide strong support for a Proteales clade that includes Macadamia, Platanus and Nelumbo. Genome structure and content followed the ancestral angiosperm pattern and were highly conserved in the Proteales, whilst size differences were largely explained by the relative contraction of the single copy regions and expansion of the inverted repeats in Macadamia. CONCLUSIONS: The Macadamia chloroplast genome presented here is the first in the Proteaceae, and confirms the placement of this family with the morphologically divergent Plantanaceae (plane tree family) and Nelumbonaceae (sacred lotus family) in the basal eudicot order Proteales. It provides a high-quality reference genome for future evolutionary studies and will be of benefit for taxon-rich phylogenomic analyses aimed at resolving relationships among early-diverging angiosperms, and more broadly across the plant tree of life. PMID- 25522146 TI - Live cell imaging reveals novel functions of Salmonella enterica SPI2-T3SS effector proteins in remodeling of the host cell endosomal system. AB - Intracellular Salmonella enterica induce a massive remodeling of the endosomal system in infected host cells. One dramatic consequence of this interference is the induction of various extensive tubular aggregations of membrane vesicles, and tubules positive for late endosomal/lysosomal markers are referred to as Salmonella-induced filaments or SIF. SIF are highly dynamic in nature with extension and collapse velocities of 0.4-0.5 um x sec-1. The induction of SIF depends on the function of the Salmonella Pathogenicity Island 2 (SPI2) encoded type III secretion system (T3SS) and a subset of effector proteins. In this study, we applied live cell imaging and electron microscopy to analyze the role of individual effector proteins in SIF morphology and dynamic properties of SIF. SIF in cells infected with sifB, sseJ, sseK1, sseK2, sseI, sseL, sspH1, sspH2, slrP, steC, gogB or pipB mutant strains showed a morphology and dynamics comparable to SIF induced by WT Salmonella. SIF were absent in cells infected with the sifA-deficient strain and live cell analyses allowed tracking of the loss of the SCV membrane of intracellular sifA Salmonella. In contrast to analyses in fixed cells, in living host cells SIF induced by sseF- or sseG deficient strains were not discontinuous, but rather continuous and thinner in diameter. A very dramatic phenotype was observed for the pipB2-deficient strain that induced very bulky, non-dynamic aggregations of membrane vesicles. Our study underlines the requirement of the study of Salmonella-host interaction in living systems and reveals new phenotypes due to the intracellular activities of Salmonella. PMID- 25522148 TI - Unique features of HIV-1 spread through T cell virological synapses. PMID- 25522149 TI - The inventiveness of nature: an interview with Werner Arber. PMID- 25522150 TI - Urban-Rural Dichotomy of Burn Patients in Georgia and South Carolina: A Geographic Information System Study. AB - This study uses a 4-year (2006-2009) cross-section of epidemiological burn injury data from Georgia and South Carolina. The results from the study show that the burn patients from rural areas differ from their urban counterparts in terms of relative burn injury incidence. Younger population groups that live in lower socioeconomic status communities especially in the urban areas are at a higher risk than other population groups. The differences in the types of burns in the urban-rural communities can give us further insights to the patients' association with injury sites. The presence of fewer burn injury treatment and care facilities in rural areas and the high incidence of burn in low-income communities in the urban areas should carry important policy implications for health planners. This study will enable researchers to understand the epidemiology of burn injuries at the local and national levels in the United States. It also carries important implications for using Geographic Information Systems for studying spatial distribution of burn injuries for disaster planning and mitigation of burn injuries. PMID- 25522151 TI - Hydrogen sulfide suicide: a new trend and threat to healthcare providers. AB - First popularized in Japan, hydrogen sulfide (H2S) gas suicide is an underreported form of suicide with known risk for secondary disaster. Mortality rate commonly exceeds 90% because of the gas's lethal, noncontained nature. Instances in the United States are increasing, up from 2 cases in 2008 to 18 in 2010. Because H2S poisonings remain rare, there exists a lack of knowledge regarding the residual effects of gas venting after victim extrication. Identifying instances of the efficacious use of personal protection equipment (PPE) is critical in the effort to alleviate risks faced by hospital and rescue personnel. The current case demonstrates the effective use of PPEs after prolonged H2S exposure. In 2011, a 20-year-old man threatened suicide using H2S gas inside a vehicle on a remote rural highway. First responders identified a "rotten egg smell" and subsequently experienced low poisoning symptoms. After prolonged Hazmat-assisted extrication (4 hours) the patient was unconscious and experiencing seizures. He was decontaminated on-scene (20 minutes) and transported to the closest hospital (22 minutes). Ambulance personnel who wore PPE and used the ambulance's reverse ventilation system (RVS)reported no adverse effects. The patient was transferred to the authors' burn facility by helicopter (38 minutes). Life-flight personnel, who did not wear PPE (no ventilatory system available), complained of watery eyes, headache, and dizziness. Hospital personnel, who did not use PPE (or RVS), complained of watery eyes or headache. Exposed personnel demonstrated no deficits or residual effects. In spite of spontaneous movement, the patient began to seize and died. This case is unique given the multiple primary and secondary H2S gas exposures involved. Exposed personnel without RVS and not using PPE demonstrated moderate H2S symptoms. PPE (self-contained breathing apparatuses) and RVS were shown to be effective during an H2S emergency; however, there are currently limited data supporting their appropriate use. Until data demonstrating duration of H2S venting for small enclosed spaces are made available, PPEs should be required. PMID- 25522152 TI - Measuring the burden of pediatric burn injury for parents and caregivers: informed burn center staff can help to lighten the load. AB - This study sought to identify which commonly experienced burn-related issues parents/caregivers of burn-injured youth deemed most stressful, difficult, and disruptive during their child's initial acute burn care hospitalization, and following the child's discharge. Parents completed an 11-item survey, asking them to rate the difficulty of items regarding their child's burn injury. The scale was created by burn doctors, nurses, and psychologists with an average of 10.5 (SD +/- 4.8) years of experience. Items selected were among common parental problems reported in the burn literature. Respondents included 69 parents/caregivers of previously hospitalized, burn-injured youth. The majority were mothers, n = 51 (74%), and n = 34 (49%) were Caucasian. The most represented age group was 37 to 45 years, n = 31 (45%). Children were on average, 6.04 years out from their initial injury. All parents reported their child's pain as the most difficult part of the injury, n = 69 (100%). The second most common issue was the child's first hospital stay. The other two items found to be "very hard" or "pretty hard" were the time spent away from their other children, and feelings of hopelessness in being unable to fix everything for their child. In this study, key parental problems occurred during the child's initial hospitalization. Burn staff cannot alleviate all problems, however, staff education regarding distressing problems faced by parents, as well as possible solutions, can be made available. PMID- 25522153 TI - A 365-day view of the difficult patients treated in an Australian adult burn center. AB - Although the effect of burns on mental health has been well examined, the aims of this study were to determine the prevalence of pre-existing mental health, drug and alcohol, and forensic problems in an Australian burn patient population; examine differences between these groups in terms of burns characteristics and healing; and also establish any patterns of presentation amongst these groups. Retrospective case notes of all the acute burn admissions, 273 patients, into a busy tertiary adults burn center in a full year were reviewed. Almost half of the patients admitted had underlying complex issues. Those with psychotic, forensic, and/or drug and alcohol problems tended to stay longer in hospital and required more procedures, despite burn sizes comparable with those in the general population. These patients also tended to sustain their burn injuries, and present to hospital, on a Saturday, Sunday, or Monday, rarely coming later in the week. Those with depression/anxiety had similar lengths of stay, number of procedures and random temporal presentations to the general burns population. Burn centers should be well staffed and educated in how to deal with patients with complex needs; this staffing should be actively structured to deal with a clear pattern of presentation over the weekend and Monday. PMID- 25522154 TI - Postburn neck anterior contracture treatment in children with scar-fascial local trapezoid flaps: a new approach. AB - One of the dramatic consequences of burns is scar contracture and deformities of the neck. Cervical contracture in children is especially dangerous, leading to face disfigurement and kyphosis; therefore, early reconstruction is indicated. Despite the existence of many various surgical techniques, the successful neck contracture treatment in pediatric patients remains a challenge for surgeons. Eleven children (aged 5 to 14 years) with postburn neck anterior contractures were studied to develop a new approach for reconstruction that would employ the use of local scar-fascial flaps. The new approach and technique for postburn pediatric contracture treatment was developed which is especially effective in the treatment of children who cannot undergo complex and long surgical procedures that are aimed at both contracture elimination and neck skin restoration. The technique consists of two trapezoid scar-fascial flaps mobilization which includes all the anterior neck surfaces and consists of scars, fat layer, platysma, and deep cervical fascia. Counter transposition of flaps with tension elongated neck anterior surface was 100 to 200%. The contracture was fully eliminated, and neck contours, mentocervical angle, and head movement were restored. In case of severe contracture, residual wound in submandibular region and above clavicles were skin-grafted. The full range of head motion (functional results) was achieved in all the 11 patients. The flaps continued to grow and the skin grafts shrinkage was moderate. Local trapeze-flap plasty allows neck contracture elimination in children in the cases when a more complex technique is impossible or undesirable to use. Early surgical intervention prevents secondary complications, allotting enough time for patients to mature and be ready for more complex procedures. PMID- 25522155 TI - Intraalveolar TNF-alpha in combined burn and inhalation injury compared with intraalveolar interleukin-6. AB - The objective of this study was to evaluate the role of intraalveolar tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in a combination of skin burn and smoke inhalation injuries because this combined trauma is associated with an increased morbidity and mortality compared with either of these traumas alone. We used a standardized small animal model (rats n = 84) to investigate the early intraalveolar excretion of TNF-alpha during the first one, three, and six hours after a singular skin burn injury, singular smoke inhalation injury, and a combination involving both the traumas. The data were compared with the data from control rats that only received preparation and mechanical ventilation. The TNF-alpha serum levels and intraalveolar IL-6 concentrations were also measured. One hour after trauma, there was a significant difference in the TNF-alpha concentration between the controls and both the singular traumas (control vs burn P < .0444 and control vs smoke P < .005) and between the inhalation injury and the combined trauma (smoke vs burn + smoke P < .0084). After three and six hours, no significant differences among the groups were observed. Compared with the controls, both the singular skin burn and smoke inhalation injuries led to increased intraalveolar TNF-alpha excretion, whereas the combined trauma showed the least intraalveolar TNF-alpha levels at three and six hours post-trauma. These findings differed from the serum TNF-alpha levels. Compared with the IL-6 levels, we observed a negative correlation within the intraalveolar cytokine concentrations after one hour (r = -.809), three hours (r = -.627), and six hours (r = -.746). This study confirms the importance of the intraalveolar cytokine reaction in the early posttraumatic stage after a combined burn and inhalation injury. The differences between the combined and singular traumas indicate that TNF-alpha plays a role in the immunologic hyporesponsiveness of the lung and therefore in the systemic pathophysiological pathway, that often leads to patient mortality. In addition, an inverse correlation between TNF-alpha and IL-6, both classical markers of inflammation, in the intraalveolar space was observed. PMID- 25522156 TI - Fat grafting for thermal injury: current state and future directions. PMID- 25522157 TI - The paired neuroglial and interglial membranes in the crayfish stretch receptor and their local disorganization. AB - The paired neuronal and glial membranes, or interglial membranes, which are separated by the narrow layer of the extracellular medium, are involved in intercellular communications. In the crayfish stretch receptor, the paired neuroglial membranes contain thin protein bridges (septate junctions) that maintain the intermembrane gap. In some places the paired membranes are locally disorganized. In the altered regions, they comprise the diffuse material in which a few 10-15 nm vesicles are embedded. The development of these defects can lead to formation of 20-30 nm vesicles and perforations in the paired membranes. The presence of such holes can, in principle, disturb ionic gradients and neuronal activity. However, a free passage between contacting neurons and glia is prevented by the diffuse proteolipid material (the product of the membrane disorganization) that seals perforations. As a result, the neuroglial border does not lose its integrity and impermeability for ions so that the sensory neurons save the capability for prolonged regular firing. Unlike the neuroglial border, some perforations in the paired glia-glial membranes are not sealed. This can create the interglial syncytial connections providing the shortcut pathway for transport of ions and metabolites across the glial layers in the crayfish stretch receptor. PMID- 25522159 TI - Structural evidence for asymmetrical nucleotide interactions in nitrogenase. AB - The roles of ATP hydrolysis in electron-transfer (ET) reactions of the nitrogenase catalytic cycle remain obscure. Here, we present a new structure of a nitrogenase complex crystallized with MgADP and MgAMPPCP, an ATP analogue. In this structure the two nucleotides are bound asymmetrically by the Fe-protein subunits connected to the two different MoFe-protein subunits. This binding mode suggests that ATP hydrolysis and phosphate release may proceed by a stepwise mechanism. Through the associated Fe-protein conformational changes, a stepwise mechanism is anticipated to prolong the lifetime of the Fe-protein-MoFe-protein complex and, in turn, could orchestrate the sequence of intracomplex ET required for substrate reduction. PMID- 25522160 TI - Cyclic alkyl amino carbene (CAAC) ruthenium complexes as remarkably active catalysts for ethenolysis. AB - An expanded family of ruthenium-based metathesis catalysts bearing cyclic alkyl amino carbene (CAAC) ligands was prepared. These catalysts exhibited exceptional activity in the ethenolysis of the seed-oil derivative methyl oleate. In many cases, catalyst turnover numbers (TONs) of more than 100,000 were achieved, at a catalyst loading of only 3 ppm. Remarkably, the most active catalyst system was able to achieve a TON of 340,000, at a catalyst loading of only 1 ppm. This is the first time a series of metathesis catalysts has exhibited such high performance in cross-metathesis reactions employing ethylene gas, with activities sufficient to render ethenolysis applicable to the industrial-scale production of linear alpha-olefins (LAOs) and other terminal-olefin products. PMID- 25522158 TI - Transcriptome alterations of mitochondrial and coagulation function in schizophrenia by cortical sequencing analysis. AB - BACKGROUND: Transcriptome sequencing of brain samples provides detailed enrichment analysis of differential expression and genetic interactions for evaluation of mitochondrial and coagulation function of schizophrenia. It is implicated that schizophrenia genetic and protein interactions may give rise to biological dysfunction of energy metabolism and hemostasis. These findings may explain the biological mechanisms responsible for negative and withdraw symptoms of schizophrenia and antipsychotic-induced venous thromboembolism. RESULTS: Published BA22 RNA-Seq brain data of 9 schizophrenic patients and 9 controls samples were analyzed. The differentially expressed genes in the BA22 brain samples of schizophrenia are proposed as schizophrenia candidate marker genes (SCZCGs). The genetic interactions between mitochondrial genes and many under expressed SCZCGs indicate the genetic predisposition of mitochondria dysfunction in schizophrenia. The biological functions of SCZCGs, as listed in the Pathway Interaction Database (PID), indicate that these genes have roles in DNA binding transcription factor, signal and cancer-related pathways, coagulation and cell cycle regulation and differentiation pathways. CONCLUSIONS: It is implicated that the energy metabolism and hemostatic process have important roles in the pathogenesis for schizophrenia. The cross-talk of genetic interaction by these co expressed genes and reached candidate genes may address the key network in disease pathology. The accuracy of candidate genes evaluated from different quantification tools could be improved by crosstalk analysis of overlapping genes in genetic networks. PMID- 25522161 TI - Complex chronic conditions in Rhode Island's pediatric populace: implications for palliative and hospice services, 2000-2012. AB - BACKGROUND: Pediatric patients with complex chronic conditions (CCC) can benefit from pediatric palliative and hospice care (PP/HC) services. PP/HC can be delivered in a variety of health care settings and for a multitude of conditions, but data on hospitalization patterns and on secondary illnesses in pediatric CCC patients remains scant. OBJECTIVE: The study objective was to describe mortality trends for Rhode Island resident children aged 0-17 years, along with the demographics, subtypes, sites of death, and comorbidities of those with CCC. METHODS: This was a retrospective cohort study using demographic, hospitalization, and clinical data from all Rhode Island Department of Health death certificates from 2000 to 2012. RESULTS: Among the 1422 Rhode Island children aged 0-17 years old who died from 2000 to 2012, CCCs accounted for 27% (279/1049) of medically related deaths and 62% (145/233) of such deaths after infancy. CCC deaths were more likely at home (OR 5.202, 95% CI 2.984-9.203, p<0.001) and to have had a secondary cause of death documented (OR 3.032, 95% CI 2.259-4.067, p<0.001) than were other medically related deaths. Infants with CCCs were more likely to die in an inpatient setting (OR 5.141, 95% CI 2.718-10.026, p<0.001), whereas 1-17 year-olds with CCCs were more likely to die at home (OR 5.346, 95% CI 2.200-14.811, p<0.001) or in an emergency department (OR 3.281, 95% CI 1.363-8.721, p<0.040). CONCLUSIONS: CCCs constitute a significant proportion of medically related pediatric deaths in Rhode Island and are associated with both secondary comorbidities and death at home. Specialized, multidisciplinary services are warranted and PP/HC is crucial for patient and family support. PMID- 25522163 TI - Human umbilical cord blood mesenchymal stem cell-derived PGE2 and TGF-beta1 alleviate atopic dermatitis by reducing mast cell degranulation. AB - Mesenchymal stem cell (MSC) is a promising tool for the therapy of immune disorders. However, their efficacy and mechanisms in treating allergic skin disorders are less verified. We sought to investigate the therapeutic efficacy of human umbilical cord blood-derived MSCs (hUCB-MSCs) against murine atopic dermatitis (AD) and to explore distinct mechanisms that regulate their efficacy. AD was induced in mice by the topical application of Dermatophagoides farinae. Naive or activated-hUCB-MSCs were administered to mice, and clinical severity was determined. The subcutaneous administration of nucleotide-binding oligomerization domain 2 (NOD2)-activated hUCB-MSCs exhibited prominent protective effects against AD, and suppressed the infiltration and degranulation of mast cells (MCs). A beta-hexosaminidase assay was performed to evaluate the effect of hUCB MSCs on MC degranulation. NOD2-activated MSCs reduced the MC degranulation via NOD2-cyclooxygenase-2 signaling. In contrast to bone marrow-derived MSCs, hUCB MSCs exerted a cell-to-cell contact-independent suppressive effect on MC degranulation through the higher production of prostaglandin E2 (PGE2 ). Additionally, transforming growth factor (TGF)-beta1 production from hUCB-MSCs in response to interleukin-4 contributed to the attenuation of MC degranulation by downregulating FcepsilonRI expression in MCs. In conclusion, the subcutaneous application of NOD2-activated hUCB-MSCs can efficiently ameliorate AD, and MSC derived PGE2 and TGF-beta1 are required for the inhibition of MC degranulation. PMID- 25522164 TI - Chemicals eluting from disposable plastic syringes and syringe filters alter neurite growth, axogenesis and the microtubule cytoskeleton in cultured hippocampal neurons. AB - Cultures of dissociated hippocampal neurons are often used to study neuronal cell biology. We report that the development of these neurons is strongly affected by chemicals leaching from commonly used disposable medical-grade syringes and syringe filters. Contamination of culture medium by bioactive substance(s) from syringes and filters occurred with multiple manufacturing lots and filter types under normal use conditions and resulted in changes to neurite growth, axon formation and the neuronal microtubule cytoskeleton. The effects on neuronal morphology were concentration dependent and significant effects were detected even after substantial dilution of the contaminated medium. Gas chromatography mass spectrometry analyses revealed many chemicals eluting from the syringes and filters. Three of these chemicals (stearic acid, palmitic acid and 1,2-ethanediol monoacetate) were tested but showed no effects on neurite growth. Similar changes in neuronal morphology were seen with high concentrations of bisphenol A and dibutyl phthalate, two hormonally active plasticisers. Although no such compounds were detected by gas chromatography-mass spectrometry, unknown plasticisers in leachates may affect neurites. This is the first study to show that leachates from laboratory consumables can alter the growth of cultured hippocampal neurons. We highlight important considerations to ensure leachate contamination does not compromise cell biology experiments. PMID- 25522165 TI - Effect of Tooth-Colored Restorative Materials on Reliability of Heat-Pressed Lithium Disilicate. AB - PURPOSE: Restorative material selection in complete mouth rehabilitation is an important factor in long-term management of potential technical complications. The aim of this study was to evaluate in vitro the reliability (fracture resistance) of lithium disilicate fatigued with different restorative materials. MATERIALS AND METHODS: A step-stress accelerated life-testing model was used. Seventy disc specimens were heat-pressed. Five groups of different indenter materials fatigued the lithium-disilicate specimens: group WC (tungsten carbide served as a control), group PR (interpenetrating polymer network [IPN] resin based denture tooth), group POM (heat-pressed leucite glass-ceramic), group LD (heat-pressed lithium disilicate), and group ZR (zirconium dioxide). Lithium disilicate specimens were randomly divided into four groups (n = 14). Specimens were fatigued to failure according to three step-stress profiles: light, moderate, and aggressive. Use level probability Weibull plots were generated, and each group's reliability, failure rate, and mean life to failure were calculated. RESULTS: The IPN resin-based denture tooth group had the highest reliability and mean life to failure, and lowest failure rate as compared to lithium disilicate and zirconium dioxide. No significant difference existed between the reliability of the tungsten carbide and leucite glass-ceramic groups and the IPN resin-based denture tooth group. CONCLUSIONS: Lithium-disilicate specimens fatigued with IPN resin-based denture teeth exhibited higher reliability than specimens fatigued with lithium disilicate and zirconium dioxide. There was a difference in fracture characteristics in lithium-disilicate specimens fatigued with tungsten carbide, lithium disilicate, and zirconium dioxide, versus those fatigued with IPN resin based denture teeth and leucite glass-ceramic material. PMID- 25522166 TI - Comparative transcriptome analysis to reveal genes involved in wheat hybrid necrosis. AB - Wheat hybrid necrosis is an interesting genetic phenomenon that is found frequently and results in gradual death or loss of productivity of wheat. However, the molecular basis and mechanisms of this genetic phenomenon are still not well understood. In this study, the transcriptomes of wheat hybrid necrosis F1 and its parents (Neimai 8 and II469) were investigated using digital gene expression (DGE). A total of 1300 differentially expressed genes were identified, indicating that the response to hybrid necrosis in wheat is complicated. The assignments of the annotated genes based on Gene Ontology (GO) revealed that most of the up-regulated genes belong to "universal stress related", "DNA/RNA binding", "protein degradation" functional groups, while the down-regulated genes belong to "carbohydrate metabolism" and "translation regulation" functional groups. These findings suggest that these pathways were affected by hybrid necrosis. Our results provide preliminarily new insight into the underlying molecular mechanisms of hybrid necrosis and will help to identify important candidate genes involved in wheat hybrid necrosis. PMID- 25522167 TI - OPN induces FoxM1 expression and localization through ERK 1/2, AKT, and p38 signaling pathway in HEC-1A cells. AB - Mammalian embryo implantation is an extremely complex process and requires endometrial receptivity. In order to establish this receptivity, sequential proliferation and differentiation during the menstrual cycle is necessary. Forkhead box M1 (FoxM1) is described as a major oncogenic transcription factor in tumor initiation, promotion and progression. According to these functions, we believe that FoxM1 should also play an essential role in embryo implantation. Osteopontin (OPN), an adhesion molecule, has been studied extensively in reproduction. In this study, we observed the expression and distribution of FoxM1 during the proliferative-phase and secretory-phase human endometrium and the pre implantation mouse uterus firstly. Then we observed the relationship between OPN and FoxM1. Our results showed that FoxM1 was mainly distributed in glandular epithelium. OPN increased the expression of FoxM1 in the human uterine epithelial cell line HEC-1A cells in a time- and concentration-dependent manner. OPN regulates FoxM1 to influence HEC-1A cell proliferation through extracellular regulated protein kinases (ERK 1/2), protein kinase B (PKB, AKT), and the p38 mitogen activated protein kinases (p38MAPK, p38) signaling pathway. Inhibition of ERK 1/2, AKT and p38 suppressed OPN-induced FoxM1 expression and location. Our data indicate that FoxM1 might be regulated by OPN to influence endometrial proliferation to establish endometrial receptivity. PMID- 25522168 TI - Evaluation of posterolateral lumbar fusion in sheep using mineral scaffolds seeded with cultured bone marrow cells. AB - The objective of this study is to investigate the efficacy of hybrid constructs in comparison to bone grafts (autograft and allograft) for posterolateral lumbar fusion (PLF) in sheep, instrumented with transpedicular screws and bars. Hybrid constructs using cultured bone marrow (BM) mesenchymal stem cells (MSCs) have shown promising results in several bone healing models. In particular, hybrid constructs made by calcium phosphate-enriched cells have had similar fusion rates to bone autografts in posterolateral lumbar fusion in sheep. In our study, four experimental spinal fusions in two animal groups were compared in sheep: autograft and allograft (reference group), hydroxyapatite scaffold, and hydroxyapatite scaffold seeded with cultured and osteoinduced bone marrow MSCs (hybrid construct). During the last three days of culture, dexamethasone (dex) and beta-glycerophosphate (beta-GP) were added to potentiate osteoinduction. The two experimental situations of each group were tested in the same spinal segment (L4-L5). Spinal fusion and bone formation were studied by clinical observation, X ray, computed tomography (CT), histology, and histomorphometry. Lumbar fusion rates assessed by CT scan and histology were higher for autograft and allograft (70%) than for mineral scaffold alone (22%) and hybrid constructs (35%). The quantity of new bone formation was also higher for the reference group, quite similar in both (autograft and allograft). Although the hybrid scaffold group had a better fusion rate than the non-hybrid scaffold group, the histological analysis revealed no significant differences between them in terms of quantity of bone formation. The histology results suggested that mineral scaffolds were partly resorbed in an early phase, and included in callus tissues. Far from the callus area the hydroxyapatite alone did not generate bone around it, but the hybrid scaffold did. In nude mice, labeled cells were induced to differentiate in vivo and monitored by bioluminescence imaging (BLI). Although the cultured MSCs had osteogenic potential, their contribution to spinal fusion when seeded in mineral scaffolds, in the conditions disclosed here, remains uncertain probably due to callus interference with the scaffolds. At present, bone autografts are better than hybrid constructs for posterolateral lumbar fusion, but we should continue to seek better conditions for efficient tissue engineering. PMID- 25522170 TI - Homogenized finite element analysis on effective elastoplastic mechanical behaviors of composite with imperfect interfaces. AB - A three-dimensional (3D) representative volume element (RVE) model was developed for analyzing effective mechanical behavior of fiber-reinforced ceramic matrix composites with imperfect interfaces. In the model, the fiber is assumed to be perfectly elastic until its tensile strength, and the ceramic material is modeled by an elasto-plastic Drucker-Prager constitutive law. The RVE model is then used to study the elastic properties and the tensile strength of composites with imperfect interfaces and validated through experiments. The imperfect interfaces between the fiber and the matrix are taken into account by introducing some cohesive contact surfaces. The influences of the interface on the elastic constants and the tensile strengths are examined through these interface models. PMID- 25522169 TI - RNA recognition and stress granule formation by TIA proteins. AB - Stress granule (SG) formation is a primary mechanism through which gene expression is rapidly modulated when the eukaryotic cell undergoes cellular stresses (including heat, oxidative, viral infection, starvation). In particular, the sequestration of specifically targeted translationally stalled mRNAs into SGs limits the expression of a subset of genes, but allows the expression of heatshock proteins that have a protective effect in the cell. The importance of SGs is seen in several disease states in which SG function is disrupted. Fundamental to SG formation are the T cell restricted intracellular antigen (TIA) proteins (TIA-1 and TIA-1 related protein (TIAR)), that both directly bind to target RNA and self-associate to seed the formation of SGs. Here a summary is provided of the current understanding of the way in which TIA proteins target specific mRNA, and how TIA self-association is triggered under conditions of cellular stress. PMID- 25522172 TI - Functionalization of boron diiminates with unique optical properties: multicolor tuning of crystallization-induced emission and introduction into the main chain of conjugated polymers. AB - In this article, we report the unique optical characteristics of boron diiminates in the solid states. We synthesized the boron diiminates exhibiting aggregation induced emission (AIE). From the series of optical measurements, it was revealed that the optical properties in the solid state should be originated from the suppression of the molecular motions of the boron diiminate units. The emission colors were modulated by the substitution effects (lambda(PL,crystal) = 448-602 nm, lambda(PL,amorphous) = 478-645 nm). Strong phosphorescence was observed from some boron diiminates deriving from the effects of two imine groups. Notably, we found some of boron diiminates showed crystallization-induced emission (CIE) properties derived from the packing differences from crystalline to amorphous states. The 15-fold emission enhancement was observed by the crystallization (Phi(PL,crystal) = 0.59, Phi(PL,amorphous) = 0.04). Next, we conjugated boron diiminates with fluorene. The synthesized polymers showed good solubility in the common solvents, film formability, and thermal stability. In addition, because of the expansion of main-chain conjugation, the peak shifts to longer wavelength regions were observed in the absorption/emission spectra of the polymers comparing to those of the corresponding boron diiminate monomers (lambda(abs) = 374-407 nm, lambda(PL) = 509-628 nm). Furthermore, the absorption and the emission intensities were enhanced via the light-harvesting effect by the conjugation with fluorene. Finally, we also demonstrated the dynamic reversible alterations of the optical properties of the polymer thin films by exposing to acidic or basic vapors. PMID- 25522171 TI - PRRT2 mutations are related to febrile seizures in epileptic patients. AB - Previous studies reported that the proline-rich transmembrane protein 2 (PRRT2) gene was identified to be related to paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions with PKD, PKD with migraine and benign familial infantile epilepsy (BFIE). The present study explores whether the PRRT2 mutation is a potential cause of febrile seizures, including febrile seizures plus (FS+), generalized epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS); thus, it may provide a new drug target for personalized medicine for febrile seizure patients. We screened PRRT2 exons in a cohort of 136 epileptic patients with febrile seizures, including FS+, GEFS+ and DS. PRRT2 genetic mutations were identified in 25 out of 136 (18.4%) febrile seizures in epileptic patients. Five loss-of-function and coding missense mutations were identified: c.649delC (p.R217Efs*12), c.649_650insC (p.R217Pfs*8), c.412C>G (p.Pro138Ala), c.439G>C (p.Asp147His) and c.623C>A (p.Ser208Tyr). PRRT2 variants were probably involved in the etiology of febrile seizures in epileptic patients. PMID- 25522173 TI - Gold-catalyzed cyclopropanation reactions using a carbenoid precursor toolbox. AB - Homogeneous gold-catalyzed cyclopropanation has emerged as a powerful method in organic synthesis due to its rich chemistry and fascinating reactivity. This thriving strategy is remarkable for its mild conditions, good selectivity, and high efficiency, which provides complementarity and orthogonality to traditional metal-catalyzed cyclopropanation. This review summarizes recent advances in gold catalyzed cyclopropanation divided by the type of carbenoid precursors. Besides the commonly used diazo compounds, current approaches enable readily available enynes, propargyl esters, cyclopropenes, cycloheptatrienes, alkynes, and sulfonium ylides as safer surrogates in the realm of gold carbenoid chemistry. Meanwhile, these reactions allow for the rapid building of molecular complexity including synthetically useful and intricate cyclic, heterocyclic, and polycyclic skeletons. The combination of the new reactivity of gold complexes with their capability to catalyze cyclopropanations may lead to myriad opportunities for the design of new reactions. Furthermore, the synthetic utilities of such superior methods have also been illustrated by the total syntheses of selected natural and biologically interesting products and the asymmetric formation of challenging target molecules. PMID- 25522174 TI - Granulomatous pigmented purpuric dermatosis. AB - The granulomatous variant of the pigmented purpuric dermatoses (PPDs) is a rare and infrequently described condition, with a total of 16 cases published to date. We report a case of granulomatous PPD in a 59-year-old white woman who demonstrated involvement of the arms, legs, chest and back with concurrent hyperlipidaemia. Histopathological examination revealed a lymphohistiocytic infiltrate obscuring the dermoepidermal junction, and loose granuloma formation in the superficial dermis, with extravasated erythrocytes. Other conditions within the differential diagnosis such as atypical infection, papular sarcoidosis and generalized granuloma annulare were excluded on clinical and histological grounds. Our patient represents the ninth patient reported to have granulomatous PPD with coexisting hyperlipidaemia, and the fifth patient with granulomatous PPD and a lichenoid infiltrate. PMID- 25522176 TI - Risk factors for complications after laparoscopic major hepatectomy. AB - BACKGROUND: Although laparoscopic major hepatectomy (MH) is becoming increasingly common in several specialized centres, data regarding outcomes are limited. The aim of this study was to identify the risk factors for postoperative complications of purely laparoscopic MH at a single centre. METHODS: All patients who underwent purely laparoscopic MH between January 1998 and March 2014 at the authors' institution were enrolled. Demographic, clinicopathological and perioperative factors were collected prospectively, and data were analysed retrospectively. The dependent variables studied were the occurrence of overall and major complications (Dindo-Clavien grade III or above). RESULTS: A total of 183 patients were enrolled. The types of MH included left-sided hepatectomy in 40 patients (21.9 per cent), right-sided hepatectomy in 135 (73.8 per cent) and central hepatectomy in eight (4.4 per cent). Median duration of surgery was 255 (range 100-540) min, and median blood loss was 280 (10-4500) ml. Complications occurred in 100 patients (54.6 per cent), and the 90-day all-cause mortality rate was 2.7 per cent. Liver-specific and general complications occurred in 62 (33.9 per cent) and 38 (20.8 per cent) patients respectively. Multivariable analysis identified one independent risk factor for global postoperative complications: intraoperative simultaneous radiofrequency ablation (RFA) (odds ratio (OR) 6.93, 95 per cent c.i. 1.49 to 32.14; P = 0.013). There were two independent risk factors for major complications: intraoperative blood transfusion (OR 2.50, 1.01 to 6.23; P = 0.049) and bilobar resection (OR 2.47, 1.00 to 6.06; P = 0.049). CONCLUSION: Purely laparoscopic MH is feasible and safe. Simultaneous RFA and bilobar resection should probably be avoided. PMID- 25522175 TI - Lung cancer in patients with chronic obstructive pulmonary disease. Development and validation of the COPD Lung Cancer Screening Score. AB - RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) are at high risk for lung cancer (LC) and represent a potential target to improve the diagnostic yield of screening programs. OBJECTIVES: To develop a predictive score for LC risk for patients with COPD. METHODS: The Pamplona International Early Lung Cancer Detection Program (P-IELCAP) and the Pittsburgh Lung Screening Study (PLuSS) databases were analyzed. Only patients with COPD on spirometry were included. By logistic regression we determined which factors were independently associated with LC in PLuSS and developed a COPD LC screening score (COPD-LUCSS) to be validated in P-IELCAP. MEASUREMENTS AND MAIN RESULTS: By regression analysis, age greater than 60, body mass index less than 25 kg/m(2), pack-years history greater than 60, and emphysema presence were independently associated with LC diagnosis and integrated into the COPD-LUCSS, which ranges from 0 to 10 points. Two COPD-LUCSS risk categories were proposed: low risk (scores 0-6) and high risk (scores 7-10). In comparison with low-risk patients, in both cohorts LC risk increased 3.5-fold in the high-risk category. CONCLUSIONS: The COPD-LUCSS is a good predictor of LC risk in patients with COPD participating in LC screening programs. Validation in two different populations adds strength to the findings. PMID- 25522177 TI - Expanding the phenotype of a recurrent de novo variant in PACS1 causing intellectual disability. PMID- 25522178 TI - Cannabinoid CB1 receptors activation and coactivation with D2 receptors modulate GABAergic neurotransmission in the globus pallidus and increase motor asymmetry. AB - The cannabinoid CB1 (CB1R) and dopaminergic D2 (D2R) receptors modify GABAergic transmission in the globus pallidus. Although dopaminergic denervation produces changes in the expression and supersensitization of these receptors, the consequences of these changes on GABAergic neurotransmission are unknown. The aim of this study was to show the effects of CB1R and D2R activation and coactivation on the uptake and release of [(3) H]GABA in the globus pallidus of hemiparkinsonian rats as well as their effects on motor behavior. The activation of CB1R blocked GABA uptake and decreased GABA release in the globus pallidus in the dopamine denervated side, whereas the co-activation of CB1R-D2R increased GABA release and had no effect on GABA uptake. A microinjection of the CB1R agonist ACEA into the globus pallidus ipsilaterally to a 6-OHDA lesion potentiated turning behavior that was induced by methamphetamine. However, a microinjection of the D2R agonist quinpirole did not modify this behavior, and a microinjection of a mixture of CB1R and D2R agonists significantly potentiated turning behavior. The behavioral effects produced after the activation of the CB1R and the co-activation of CB1R and D2R can be explained by increased GABAergic neurotransmission produced by a block of GABA uptake and an increase in the release of GABA in the globus pallidus, respectively. PMID- 25522179 TI - Working with people who have killed: the experience and attitudes of forensic mental health clinicians working with forensic patients. AB - Forensic mental health (FMH) clinicians sometimes feel unsupported and unprepared for their work. This article explores their experiences of working in a FMH setting in Australia. The research examined the clinical context of clinicians working with forensic patients (FP), particularly those individuals who have killed while experiencing a mental illness. A qualitative, exploratory design was selected. Data were collected through focus groups and individual interviews with hospital and community-based forensic clinicians from all professional groups: psychiatric medicine, social work, psychology, mental health nursing, occupational therapy, and psychiatric service officers. The main themes identified were orientation and adjustment to FMH, training in FMH, vicarious traumatization, clinical debriefing and clinical supervision, and therapeutic relationships. Participants described being frustrated and unsupported in making the transition to working with FP and felt conflicted by the emotional response that was generated when developing therapeutic relationships. Recommendations include the development of programmes that might assist clinicians and address gaps in service delivery, such as clinical governance, targeted orientation programmes, and clinical supervision. PMID- 25522181 TI - Bimodal frequency-modulated atomic force microscopy with small cantilevers. AB - Small cantilevers with ultra-high resonant frequencies (1-3 MHz) have paved the way for high-speed atomic force microscopy. However, their potential for multi frequency atomic force microscopy is unexplored. Because small cantilevers have small spring constants but large resonant frequencies, they are well-suited for the characterisation of delicate specimens with high imaging rates. We demonstrate their imaging capabilities in a bimodal frequency modulation mode in constant excitation on semi-crystalline polypropylene. The first two flexural modes of the cantilever were simultaneously excited. The detected frequency shift of the first eigenmode was held constant for topographical feedback, whereas the second eigenmode frequency shift was used to map the local properties of the specimen. High-resolution images were acquired depicting crystalline lamellae of approximately 12 nm in width. Additionally, dynamic force curves revealed that the contrast originated from different interaction forces between the tip and the distinct polymer regions. The technique uses gentle forces during scanning and quantified the elastic moduli Eam = 300 MPa and Ecr = 600 MPa on amorphous and crystalline regions, respectively. Thus, multimode measurements with small cantilevers allow one to map material properties on the nanoscale at high resolutions and increase the force sensitivity compared with standard cantilevers. PMID- 25522180 TI - A phase Ia study to assess the safety and immunogenicity of new malaria vaccine candidates ChAd63 CS administered alone and with MVA CS. AB - BACKGROUND: Plasmodium falciparum (P. falciparum) malaria remains a significant cause of mortality and morbidity throughout the world. Development of an effective vaccine would be a key intervention to reduce the considerable social and economic impact of malaria. METHODOLOGY: We conducted a Phase Ia, non randomized, clinical trial in 24 healthy, malaria-naive adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication deficient viral vectored vaccines encoding the circumsporozoite protein (CS) of P. falciparum. RESULTS: ChAd63-MVA CS administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to CS. With a priming ChAd63 CS dose of 5*109 vp responses peaked at a mean of 1947 SFC/million PBMC (median 1524) measured by ELIspot 7 days after the MVA boost and showed a mixed CD4+/CD8+ phenotype. With a higher priming dose of ChAd63 CS dose 5*1010 vp T cell responses did not increase (mean 1659 SFC/million PBMC, median 1049). Serum IgG responses to CS were modest and peaked at day 14 post ChAd63 CS (median antibody concentration for all groups at day 14 of 1.3 ug/ml (range 0-11.9), but persisted throughout late follow-up (day 140 median antibody concentration groups 1B & 2B 0.9 ug/ml (range 0-4.7). CONCLUSIONS: ChAd63-MVA is a safe and highly immunogenic delivery platform for the CS antigen in humans which warrants efficacy testing. TRIAL REGISTRATION: ClinicalTrials.gov NCT01450280. PMID- 25522182 TI - Diagnostic utility of biomarkers for neonatal sepsis--a systematic review. AB - Neonatal sepsis is a major cause of morbidity and mortality. Early diagnosis and treatment of the neonate with suspected sepsis are essential to prevent life threatening complications. Diagnosis of neonatal sepsis is a challenge due to non specific clinical signs and the fact that infection markers are difficult to interpret in the first and critical phase of neonatal sepsis. The objective of the present study was to systematically evaluate existing evidence of the diagnostic utility of biomarkers for prediction of sepsis in neonates. We conducted a systematic literature search performed in PubMed and Embase. The study population was neonates with gestation age > 24 weeks in their first 28 days of life with suspected sepsis. The included manuscripts were rated due to criteria from a modified rating scale developed by Douglas Altman. Of 292 potentially relevant manuscripts, 77 fulfilled the inclusion and exclusion criteria; 16 (21%) were rated as high-quality studies. C-reactive protein (CRP) was the most extensively studied biomarker evaluated. The high-quality studies indicated that the acute phase protein serum amyloid A had high sensitivity, both at onset of symptoms and 2 days after. The studies evaluating serum amyloid A presented a variable positive predictive value (PPV, 0.67 and 0.92) with a high negative predictive value (NPV, 0.97 and 1.00). The existing evidence of the diagnostic value of serum amyloid A for neonatal sepsis showed promising results, and should be further investigated in clinical settings. PMID- 25522183 TI - High faecal calprotectin levels in intestinal tuberculosis are associated with granulomas in intestinal biopsies. AB - BACKGROUND: The diagnosis of intestinal tuberculosis (ITB) is sometimes difficult to establish and requires endoscopic investigation with biopsies for histopathological examination. This study aimed to evaluate calprotectin as a marker of inflammation in ITB. METHODS: Patients with ITB were prospectively recruited in Southern India from October 2009 until July 2012. Demographic, clinical, endoscopic and histological features were examined along with faecal calprotectin (FC), serum calprotectin (SC) and C-reactive protein (CRP). RESULTS: Thirty patients (median age 34.5 years, 19 men) were included. Clinical features were abdominal pain (97%), weight loss (83%), cachexia (75%), fatigue (63%), watery diarrhoea (62%), nausea (55%) and fever (53%). Endoscopy showed transverse ulcers (61%), nodularity of mucosa (55%), aphthous ulcers (39%), strictures (10%) and fissures (10%). The terminal ileum and right colon harboured 81% of the lesions. Histology revealed granulomas in biopsies from 10 of the patients. FC and CRP levels showed a strong positive correlation (rs = 0.70, p < 0.01). FC, SC and CRP levels were higher in the granulomatous than the non-granulomatous patients, respectively (median FC 988 MUg/g, interquartile range (IQR) 940 vs 87 MUg/g, IQR 704, p < 0.01; median SC 8.2 MUg/ml, IQR 7.3 vs 3.8 MUg/ml, IQR 8.9, p = 0.23; median CRP 38.8 mg/L, IQR 42.9 vs 2.3 mg/L, IQR 13.5, p < 0.01). Higher median calprotectin and CRP levels were detected in patients with extensive than localized disease, but the differences did not reach statistical significance. CONCLUSION: ITB patients with granulomas on histology have high levels of faecal calprotectin and CRP. PMID- 25522184 TI - Immuno-epidemiological modeling of HIV-1 predicts high heritability of the set point virus load, while selection for CTL escape dominates virulence evolution. AB - It has been suggested that HIV-1 has evolved its set-point virus load to be optimized for transmission. Previous epidemiological models and studies into the heritability of set-point virus load confirm that this mode of adaptation within the human population is feasible. However, during the many cycles of replication between infection of a host and transmission to the next host, HIV-1 is under selection for escape from immune responses, and not transmission. Here we investigate with computational and mathematical models how these two levels of selection, within-host and between-host, are intertwined. We find that when the rate of immune escape is comparable to what has been observed in patients, immune selection within hosts is dominant over selection for transmission. Surprisingly, we do find high values for set-point virus load heritability, and argue that high heritability estimates can be caused by the 'footprints' left by differing hosts' immune systems on the virus. PMID- 25522186 TI - Computational analysis of the roles of ER-Golgi network in the cell cycle. AB - BACKGROUND: ER-Golgi network plays an important role in the processing, sorting and transport of proteins, and it's also a site for many signaling pathways that regulate the cell cycle. Accumulating evidence suggests that, the stressed ER and malfunction of Golgi apparatus are associated with the pathogenesis of cancer and Alzheimer's disease (AD). Our previous work discovered and verified that altering the expression levels of target SNARE and GEF could modulate the size of Golgi apparatus. Moreover, Golgi's structure and size undergo dramatic changes during the development of several diseases. It is of importance to investigate the roles of ER-Golgi network in the cell cycle progression and some diseases. RESULTS: In this work, we first develop a computational model to study the ER stress-induced and Golgi-related apoptosis-survival signaling pathways. Then, we propose and apply both asynchronous and synchronous model checking methods, which extend our previous verification technique, to automatically and formally analyze the ER Golgi-regulated signaling pathways in the cell cycle progression through verifying some computation tree temporal logic formulas. CONCLUSIONS: The proposed asynchronous and synchronous verification technique has advantages for large network analysis and verification over traditional simulation methods. Using the model checking method, we verified several Alzheimer's disease and cancer-related properties, and also identified important proteins (NFkappaB, ATF4, ASK1 and TRAF2) in the ER-Golgi network, which might be responsible for the pathogenesis of cancer and AD. Our studies indicate that targeting the ER stress induced and Golgi-related pathways might serve as potent therapeutic targets for the treatment of cancer and Alzheimer's disease. PMID- 25522188 TI - Synthesis of inorganic structural isomers by diffusion-constrained self-assembly of designed precursors: a novel type of isomerism. AB - The structure of precursors is used to control the formation of six possible structural isomers that contain four structural units of PbSe and four structural units of NbSe2: [(PbSe)1.14]4[NbSe2]4, [(PbSe)1.14]3[NbSe2]3[(PbSe)1.14]1[NbSe2]1, [(PbSe)1.14]3[NbSe2]2[(PbSe)1.14]1[NbSe2]2, [(PbSe)1.14]2[NbSe2]3[(PbSe)1.14]2[NbSe2]1, [(PbSe)1.14]2[NbSe2]2[(PbSe)1.14]1[NbSe2]1[(PbSe)1.14]1[NbSe2]1, [(PbSe)1.14]2[NbSe2]1[(PbSe)1.14]1[NbSe2]2[(PbSe)1.14]1[NbSe2]1. The electrical properties of these compounds vary with the nanoarchitecture. For each pair of constituents, over 20,000 new compounds, each with a specific nanoarchitecture, are possible with the number of structural units equal to 10 or less. This provides opportunities to systematically correlate structure with properties and hence optimize performance. PMID- 25522185 TI - Dietary lipids modulate the expression of miR-107, an miRNA that regulates the circadian system. AB - SCOPE: The increased prevalence of cardiovascular diseases (CVDs) has been hypothesized to be the result of an increased exposure to a host of atherogenic environmental factors, paramount among them being unhealthy dietary habits. Long chain n-3 polyunsaturated fatty acids have been shown to have cardio protective effects, partially due to their ability to regulate gene expression. In this regard, increasing attention has been devoted to the role of miRNAs as regulators of multiple metabolic pathways whose deregulation has been associated with CVD risk. METHODS AND RESULTS: In this work, we investigated whether miRNA expression was regulated by docosahexanoic acid, conjugated linoleic acid, and cholesterol in Caco-2 cells. The modulated miRNAs, miR-107 was differentially expressed by all treatments and this modulation was independent of its hosting gene, PANK1, possibly through its own promoter, which contains binding sites for metabolically relevant transcription factors. Among the putative target genes of miR-107, we found some genes with key roles in circadian rhythm. Specifically, we demonstrated that binding of miR-107 to the CLOCK gene results in the deregulation of the circadian rhythm of the cells. CONCLUSION: Since chronodisruption has been linked to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and CVD, our findings suggests that miR-107 could represent a new approach for pharmacological treatment of these diseases. PMID- 25522189 TI - Serial transrectal ultrasonography for monitoring the reproductive activity of the Asiatic black bear (Ursus thibetanus ussuricus). AB - This study evaluated the structural changes in the reproductive tract of Asiatic black bears using serial transrectal ultrasonography. In addition, the ultrasonographic observations were compared with the results of vaginal cytology and hormonal analyses. The collection of blood for hormonal analysis, vaginal cytology and transrectal ultrasonography was performed in two bears (Bears 1 and 2) from June 2011 to August 2013 without mating and in a third bear (Bear 3) from April to December 2012, allowing natural mating. Serial ultrasonographic observations showed cyclic changes in ovarian structures (e.g. emergence of small follicles, growth and ovulation of dominant follicles and corpus luteum (CL) formation) during the reproductive cycles of the three bears. The diameter of the uterine horns remained similar throughout the reproductive cycle in Bears 1 and 2, and it remained similar from April until October, but an enlargement containing foetuses was observed in Bear 3 in December. The ultrasonographic observations were consistent with the data obtained through vaginal cytology and progesterone analysis during the reproductive cycle. An average of 4.0 (+/-0.4) dominant follicles was observed during the oestrous stage (May-August), during which the superficial cells accounted for >90% of the total vaginal cells. In addition, the detection of an average of 2.6 (+/-0.2) CL was associated with increased plasma progesterone concentrations (3.0 +/- 0.4 ng/ml) between June and December (near hibernation). In conclusion, serial transrectal ultrasonography demonstrated yearly oestrous (ovulation) cycles via follicular dynamics and CL formation on ovaries, accordingly with vaginal cytology and hormonal level in the Asiatic black bear. PMID- 25522192 TI - Variation in dual-task performance reveals late initiation of speech planning in turn-taking. AB - The smooth transitions between turns in natural conversation suggest that speakers often begin to plan their utterances while listening to their interlocutor. The presented study investigates whether this is indeed the case and, if so, when utterance planning begins. Two hypotheses were contrasted: that speakers begin to plan their turn as soon as possible (in our experiments less than a second after the onset of the interlocutor's turn), or that they do so close to the end of the interlocutor's turn. Turn-taking was combined with a finger tapping task to measure variations in cognitive load. We assumed that the onset of speech planning in addition to listening would be accompanied by deterioration in tapping performance. Two picture description experiments were conducted. In both experiments there were three conditions: (1) Tapping and Speaking, where participants tapped a complex pattern while taking over turns from a pre-recorded speaker, (2) Tapping and Listening, where participants carried out the tapping task while overhearing two pre-recorded speakers, and (3) Speaking Only, where participants took over turns as in the Tapping and Speaking condition but without tapping. The experiments differed in the amount of tapping training the participants received at the beginning of the session. In Experiment 2, the participants' eye-movements were recorded in addition to their speech and tapping. Analyses of the participants' tapping performance and eye movements showed that they initiated the cognitively demanding aspects of speech planning only shortly before the end of the turn of the preceding speaker. We argue that this is a smart planning strategy, which may be the speakers' default in many everyday situations. PMID- 25522191 TI - HIV Risk, prevention, and testing behaviors among heterosexuals at increased risk for HIV infection--National HIV Behavioral Surveillance System, 21 U.S. cities, 2010. AB - PROBLEM/CONDITION: At the end of 2010, an estimated 872,990 persons in the United States were living with a diagnosis of human immunodeficiency virus (HIV) infection. Approximately one in four of the estimated HIV infections diagnosed in 2011 were attributed to heterosexual contact. Heterosexuals with a low socioeconomic status (SES) are disproportionately likely to be infected with HIV. REPORTING PERIOD: June-December 2010. DESCRIPTION OF SYSTEM: The National HIV Behavioral Surveillance System (NHBS) collects HIV prevalence and risk behavior data in selected metropolitan statistical areas (MSAs) from three populations at high risk for HIV infection: men who have sex with men, injecting drug users, and heterosexuals at increased risk for HIV infection. Data for NHBS are collected in rotating cycles in these three different populations. For the 2010 NHBS cycle among heterosexuals, men and women were eligible to participate if they were aged 18-60 years, lived in a participating MSA, were able to complete a behavioral survey in English or Spanish, and reported engaging in vaginal or anal sex with one or more opposite-sex partners in the 12 months before the interview. Persons who consented to participate completed an interviewer-administered, standardized questionnaire about HIV-associated behaviors and were offered anonymous HIV testing. Participants were sampled using respondent-driven sampling, a type of chain-referral sampling. Sampling focused on persons of low SES (i.e., income at the poverty level or no more than a high school education) because results of a pilot study indicated that heterosexual adults of low SES were more likely than those of high SES to be infected with HIV. To assess risk and testing experiences among persons at risk for acquiring HIV infection through heterosexual sex, analyses excluded participants who were not low SES, those who reported ever having tested positive for HIV, and those who reported recent (i.e., in the 12 months before the interview) male-male sex or injection drug use. This report summarizes unweighted data regarding HIV-associated risk, prevention, and testing behaviors from 9,278 heterosexual men and women interviewed in 2010 (the second cycle of NHBS data collection among heterosexuals). RESULTS: The median age of participants was 35 years; 47% were men. The majority of participants were black or African American (hereafter referred to as black) (72%) or Hispanic/Latino (21%). Most participants (men: 88%; women: 90%) reported having vaginal sex without a condom with one or more opposite-sex partners in the past 12 months; approximately one third (men: 30%; women: 29%) reported anal sex without a condom with one or more opposite-sex partners. The majority of participants (59%) reported using noninjection drugs in the 12 months before the interview; nearly one in seven (15%) had used crack cocaine. Although most participants (men: 71%; women: 77%) had ever been tested for HIV, this percentage was lower among Hispanic/Latino participants (men: 52%; women: 62%). Approximately one third (34%) of participants reported receiving free condoms in the 12 months before the interview; 11% reported participating in a behavioral HIV prevention program. INTERPRETATION: A substantial proportion of heterosexuals interviewed for the 2010 NHBS heterosexual cycle reported engaging in behaviors that increase the risk for HIV infection. However, HIV testing was suboptimal among the overall sample, including among groups disproportionately affected by HIV infection (i.e., blacks and Hispanics/Latinos). PUBLIC HEALTH ACTION: Increasing coverage of HIV testing and other HIV prevention services among heterosexuals at increased risk is important, especially among groups disproportionately affected by HIV infection, such as blacks and Hispanics/Latinos. The National HIV/AIDS Strategy for the United States delineates a coordinated national response to reduce infections and HIV-related health disparities among disproportionately affected groups. NHBS data can guide national and local planning efforts to maximize the impact of HIV prevention programs. PMID- 25522193 TI - A novel bio-orthogonal cross-linker for improved protein/protein interaction analysis. AB - The variety of protein cross-linkers developed in recent years illustrates the current requirement for efficient reagents optimized for mass spectrometry (MS) analysis. To date, the most widely used strategy relies on commercial cross linkers that bear an isotopically labeled tag and N-hydroxysuccinimid-ester (NHS ester) moieties. Moreover, an enrichment step using liquid chromatography is usually performed after enzymatic digestion of the cross-linked proteins. Unfortunately, this approach suffers from several limitations. First, it requires large amounts of proteins. Second, NHS-ester cross-linkers are poorly efficient because of their fast hydrolysis in water. Finally, data analysis is complicated because of uneven fragmentation of complex isotopic cross-linked peptide mixtures. We therefore synthesized a new type of trifunctional cross-linker to overrule these limitations. This reagent, named NNP9, comprises a rigid core and bears two activated carbamate moieties and an azido group. NNP9 was used to establish intra- and intermolecular cross-links within creatine kinase, then to map the interaction surfaces between alpha-Synuclein (alpha-Syn), the aggregation of which leads to Parkinson's disease, and the molecular chaperone Hsc70. We show that NNP9 cross-linking efficiency is significantly higher than that of NHS-ester commercial cross-linkers. The number of cross-linked peptides identified was increased, and a high quality of MS/MS spectra leading to high sequence coverage was observed. Our data demonstrate the potential of NNP9 for an efficient and straightforward characterization of protein-protein interfaces and illustrate the power of using different cross-linkers to map thoroughly the surface interfaces within protein complexes. PMID- 25522194 TI - Long-term experimental warming alters community composition of ascomycetes in Alaskan moist and dry arctic tundra. AB - Arctic tundra regions have been responding to global warming with visible changes in plant community composition, including expansion of shrubs and declines in lichens and bryophytes. Even though it is well known that the majority of arctic plants are associated with their symbiotic fungi, how fungal community composition will be different with climate warming remains largely unknown. In this study, we addressed the effects of long-term (18 years) experimental warming on the community composition and taxonomic richness of soil ascomycetes in dry and moist tundra types. Using deep Ion Torrent sequencing, we quantified how OTU assemblage and richness of different orders of Ascomycota changed in response to summer warming. Experimental warming significantly altered ascomycete communities with stronger responses observed in the moist tundra compared with dry tundra. The proportion of several lichenized and moss-associated fungi decreased with warming, while the proportion of several plant and insect pathogens and saprotrophic species was higher in the warming treatment. The observed alterations in both taxonomic and ecological groups of ascomycetes are discussed in relation to previously reported warming-induced shifts in arctic plant communities, including decline in lichens and bryophytes and increase in coverage and biomass of shrubs. PMID- 25522195 TI - Evolution of equal division among unequal partners. AB - One of the hallmarks of human fairness is its insensitivity to power: although strong individuals are often in a position to coerce weak individuals, fairness requires them to share the benefits of cooperation equally. The existence of such egalitarianism is poorly explained by current evolutionary models. We present a model based on cooperation and partner choice that can account for the emergence of a psychological disposition toward fairness, whatever the balance of power between the cooperative partners. We model the evolution of the division of a benefit in an interaction similar to an ultimatum game, in a population made up of individuals of variable strength. The model shows that strong individuals will not receive any advantage from their strength, instead having to share the benefits of cooperation equally with weak individuals at the evolutionary equilibrium, a result that is robust to variations in population size and the proportion of weak individuals. We discuss how this model suggests an explanation for why egalitarian behaviors toward everyone, including the weak, should be more likely to evolve in humans than in any other species. PMID- 25522196 TI - Use B-factor related features for accurate classification between protein binding interfaces and crystal packing contacts. AB - BACKGROUND: Distinction between true protein interactions and crystal packing contacts is important for structural bioinformatics studies to respond to the need of accurate classification of the rapidly increasing protein structures. There are many unannotated crystal contacts and there also exist false annotations in this rapidly expanding volume of data. Previous tools have been proposed to address this problem. However, challenging issues still remain, such as low performance when the training and test data contain mixed interfaces having diverse sizes of contact areas. METHODS AND RESULTS: B factor is a measure to quantify the vibrational motion of an atom, a more relevant feature than interface size to characterize protein binding. We propose to use three features related to B factor for the classification between biological interfaces and crystal packing contacts. The first feature is the sum of the normalized B factors of the interfacial atoms in the contact area, the second is the average of the interfacial B factor per residue in the chain, and the third is the average number of interfacial atoms with a negative normalized B factor per residue in the chain. We investigate the distribution properties of these basic features and a compound feature on four datasets of biological binding and crystal packing, and on a protein binding-only dataset with known binding affinity. We also compare the cross-dataset classification performance of these features with existing methods and with a widely-used and the most effective feature interface area. The results demonstrate that our features outperform the interface area approach and the existing prediction methods remarkably for many tests on all of these datasets. CONCLUSIONS: The proposed B factor related features are more effective than interface area to distinguish crystal packing from biological binding interfaces. Our computational methods have a potential for large-scale and accurate identification of biological interactions from the experimentally determined structural data stored at PDB which may have diverse interface sizes. PMID- 25522197 TI - Magnetic Resonance Imaging Evaluation of Endolymphatic Hydrops in Cases With Otosclerosis. AB - OBJECTIVE: Endolymphatic hydrops (EH) has been reported in cases with otosclerosis, and preoperative EH could be a risk factor for inner ear disturbances after stapes surgery. Visualization of EH has recently become possible using magnetic resonance imaging (MRI) with contrast agents. This study investigated the presence of EH on MRI in ears with clinical otosclerosis. STUDY DESIGN: Retrospective case series. SETTING: University hospital. PATIENTS: 27 ears of 15 cases diagnosed with otosclerosis. INTERVENTION: Ears were evaluated by 3-T MRI performed 4 hours after intravenous injection of gadolinium. The degree of EH in the vestibule and cochlea was classified into three grades (none, mild, and significant). Imaging data were compared with clinical findings for all ears. MAIN OUTCOME MEASURES: Imaging and clinical findings. RESULTS: Varying degrees of cochlear EH and vestibular EH were observed in 20 and 15 ears, respectively. Episodes of acute sensorineural hearing loss with rotatory vertigo occurred in four ears that showed severe EH in the cochleae and vestibules. Severe EH, however, was also observed in ears without such symptoms. CONCLUSIONS: The presence of EH in ears with otosclerosis was clearly visualized in the present patient series. Such MRI evaluation could provide useful information for managing symptoms related to EH. PMID- 25522198 TI - Assessment of nasal-noise masking audiometry as a diagnostic test for patulous Eustachian tube. AB - OBJECTIVE: The primary objective is to assess the validity of nasal-noise masking audiometry (NNMA) as a clinical diagnostic tool in our patient population. STUDY DESIGN: Retrospective case review. SETTING: Tertiary ambulatory referral center. PATIENTS: Patients with patulous Eustachian tube (PET) were identified from referrals to our Eustachian tube disorders clinic primarily with symptoms including autophony, aural fullness, and hearing their own breathing. The healthy subjects had no history of ear disease. INTERVENTION: NNMA was measured in 20 ears of 10 healthy subjects as well as in 42 ears of 21 patients with suspected PET. MAIN OUTCOME MEASURE: NNMA mean auditory thresholds were measured at frequencies ranging from 250 to 8,000 Hz. RESULTS: When stratified as definitive or probable PET based on observed tympanic membrane movement with breathing, both Definitive and Probable PET groups had significantly higher NNMA mean auditory thresholds compared to Normal ears at 250 Hz (p = 0.001, p = 0.003), 1,000 Hz (p = 0.019, p = 0.001), and 6,000 Hz (p = 0.4, p = 0.001). When stratified based on symptoms on the day of testing, both Symptomatic Ears and Non-Symptomatic Ears had significantly higher mean auditory thresholds compared to Normal ears at 250 Hz (p = 0.001, p = 0.015) and at 1,000 Hz (p = 0.002, p = 0.004). CONCLUSION: Our results demonstrate a larger masking effect in patients with PET compared to normal subjects in the low-frequency region. In clinical practice, the relatively small effect and the wide variability of results between patients have made this test be of little value clinically in our patient population. PMID- 25522199 TI - The anatomical orientation of the middle turn of the cochlea: importance during surgical implantation of the ossified cochlea. AB - HYPOTHESIS: The physical relationship between anatomical landmarks such as the tympanic portion of the facial nerve and the orientation of the middle turn of the cochlea are sufficiently constant to provide guidance to surgeons performing cochlear implantation in the ossified cochlea. BACKGROUND: Placing an implant in an ossified cochlea is technically difficult. The surgeon needs to drill two tunnels through the promontory bone to insert electrode arrays in the region of the basal and middle turns of the cochlea. However, few studies describe the orientation of these tunnels or how to use anatomical landmarks to guide the surgeon during their creation. This problem is particularly true for the superior (middle turn) tunnel. DESIGN: Twenty human temporal bones from adult cadavers were analyzed. They were dissected with exposure of all middle ear structures, followed by the removal of the tympanic ring, tympanic membrane, malleus, and incus. We measured the angle between the tympanic segment of the fallopian canal and a line passing through the lower portion of the middle turn of the cochlea. RESULTS: The measured angles varied from 123 and 152 degrees with an average of 133.85 degrees and the standard deviation of +/- 6.83 degrees. CONCLUSION: The tunnel for the middle turn should be created with an inclination of about 134 degrees in relation to the tympanic segment of the facial nerve. PMID- 25522200 TI - Was Cheselden's One-Century-Long Otological Writings Concordant With His Time? AB - William Cheselden's famous anatomical treatise spanned the entire 18th century period with its 15 editions. The aim of this study is to analyze the otological knowledge described in all these editions, to identify key 18th century otological advancements, and to study their concordance.In the first edition (1713), Cheselden notably mentioned four middle ear ossicles: malleus, incus, fourth ossicle, and stapes; four auditory muscles: "external tympani," "external oblique," tensor tympani, and stapedial; and a small opening in the tympanic membrane. In subsequent editions, minimal changes appeared, except for nomenclature changes and the proposal of an artificial opening of the tympanic membrane. Virtually no changes were performed up to the last edition (1806). All Cheselden's Editions confirm the uncertain presence of a fourth ossicle, the disputable presence of a tympanic membrane opening and the "usual" accepted presence of three muscles to the malleus. Key otologic advancements, not found in any of Cheselden's writings, were catherization of the Eustachian tube, presence of fluid in the inner ear, and the surgical opening of the mastoid.This study demonstrates that Cheselden, and his subsequent editors, were unaware of some important otologic developments that revolutionized the field of otology. Description of key advancements lacking in his treatise includes catherization of the Eustachian tube, the presence of fluid in the inner ear, and the surgical opening of the mastoid. Nevertheless, Cheselden is first in proposing to artificially open the tympanic membrane in humans. PMID- 25522201 TI - Self-regulation in flow-induced structure formation of polypropylene. AB - Flow-induced structure formation is investigated with in situ wide-angle X-ray diffraction with high acquisition rate (30 Hz) using isotactic polypropylene in a piston-driven slit flow with high wall shear rates (up to ~900 s(-1) ). We focus on crystallization within the shear layers that form in the high shear rate regions near the walls. Remarkably, the kinetics of the crystallization process show no dependence on either flow rate or flow time; the crystallization progresses identically regardless. Stronger or longer flows only increase the thickness of the layers. A conceptual model is proposed to explain the phenomenon. Above a certain threshold, the number of shish-kebabs formed affects the rheology such that further structure formation is halted. The critical amount is reached already within 0.1 s under the current flow conditions. The change in rheology is hypothesized to be a consequence of the "hairy" nature of shish. Our results have large implications for process modelling, since they suggest that for injection molding type flows, crystallization kinetics can be considered independent of deformation history. PMID- 25522202 TI - Engineering of the function of diamond-like carbon binding peptides through structural design. AB - The use of phage display to select material-specific peptides provides a general route towards modification and functionalization of surfaces and interfaces. However, a rational structural engineering of the peptides for optimal affinity is typically not feasible because of insufficient structure-function understanding. Here, we investigate the influence of multivalency of diamond-like carbon (DLC) binding peptides on binding characteristics. We show that facile linking of peptides together using different lengths of spacers and multivalency leads to a tuning of affinity and kinetics. Notably, increased length of spacers in divalent systems led to significantly increased affinities. Making multimers influenced also kinetic aspects of surface competition. Additionally, the multivalent peptides were applied as surface functionalization components for a colloidal form of DLC. The work suggests the use of a set of linking systems to screen parameters for functional optimization of selected material-specific peptides. PMID- 25522205 TI - Cationic zinc organyls as precatalysts for hydroamination reactions. AB - The cationic zinc triple-decker complex [Zn2 Cp*3 ](+) [BAr(F) 4 ](-) (BAr(F) 4 =B(3,5-(CF3 )2 C6 H3 )4 ) exhibits catalytic activity in intra- and intermolecular hydroamination reactions in the absence of a cocatalyst. These hydroaminations presumably proceed through the activation of the C-C multiple bond of the alkene or alkyne by a highly electrophilic zinc species, which is formed upon elimination of the Cp* ligands. The reaction of [Zn2 Cp*3 ](+) [BAr(F) 4 ](-) with henylacetylene gives the hydrocarbonation product (Cp*)(Ph)CCH2 , which might be formed via a similar reaction pathway. Additionally, several other structurally well-defined cationic zinc organyls have been examined as precatalysts for intermolecular hydroamination reactions without the addition of a cocatalyst. These studies reveal that the highest activity is achieved in the absence of any donor ligands. The neutral complex [ZnCp(2S) 2 ] (Cp(2S) =C5 Me4 (CH2 )2 SMe) shows a remarkably high catalytic activity in the presence of a Bronsted acid. PMID- 25522204 TI - Design, synthesis, biochemical, and antiviral evaluations of C6 benzyl and C6 biarylmethyl substituted 2-hydroxylisoquinoline-1,3-diones: dual inhibition against HIV reverse transcriptase-associated RNase H and polymerase with antiviral activities. AB - Reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not targeted by current chemotherapy against human immunodeficiency virus (HIV). Although numerous chemotypes have been reported to inhibit HIV RNase H biochemically, few show significant antiviral activity against HIV. We report herein the design, synthesis, and biological evaluations of a novel variant of 2-hydroxyisoquinoline-1,3-dione (HID) scaffold featuring a crucial C-6 benzyl or biarylmethyl moiety. The synthesis involved a recently reported metal-free direct benzylation between tosylhydrazone and boronic acid, which allowed the generation of structural diversity for the hydrophobic aromatic region. Biochemical studies showed that the C-6 benzyl and biarylmethyl HID analogues, previously unknown chemotypes, consistently inhibited HIV RT-associated RNase H and polymerase with IC50s in low to submicromolar range. The observed dual inhibitory activity remained uncompromised against RT mutants resistant to non-nucleoside RT inhibitors (NNRTIs), suggesting the involvement of binding site(s) other than the NNRTI binding pocket. Intriguingly, these same compounds inhibited the polymerase, but not the RNase H function of Moloney Murine Leukemia Virus (MoMLV) RT and also inhibited Escherichia coli RNase H. Additional biochemical testing revealed a substantially reduced level of inhibition against HIV integrase. Molecular docking corroborates favorable binding of these analogues to the active site of HIV RNase H. Finally, a number of these analogues also demonstrated antiviral activity at low micromolar concentrations. PMID- 25522206 TI - Inactivation, aggregation, secondary and tertiary structural changes of germin like protein in Satsuma mandarine with high polyphenol oxidase activity induced by ultrasonic processing. AB - The inhibition of Polyphenol oxidase (PPO) in plants has been widely researched for their important roles in browning reaction. A newly found germin-like protein (GLP) with high PPO activity in Satsuma mandarine was inactivated by low frequency high-intensity ultrasonic (20 kHz) processing. The effects of ultrasound on PPO activity and structure of GLP were investigated using dynamic light scattering (DLS) analysis, transmission electron microscopy (TEM), circular dichroism (CD) spectral measurement and fluorescence spectral measurement. The lowest PPO activity achieved was 27.4% following ultrasonication for 30 min at 400 W. DLS analysis showed ultrasound caused both aggregation and dissociation of GLP particles. TEM images also demonstrated protein aggregation phenomena. CD spectra exhibited a certain number of loss in alpha-helix structure content. Fluorescence spectra showed remarkable increase in fluorescence intensity with tiny blue-shift following ultrasonication. In conclusion, ultrasound applied in this study induced structural changes of GLP and eventually inactivated PPO activity. PMID- 25522208 TI - Norovirus Dose-Response: Are Currently Available Data Informative Enough to Determine How Susceptible Humans Are to Infection from a Single Virus? AB - Two forms of single-hit infection dose-response models have previously been developed to assess available data from human feeding trials and estimate the norovirus dose-response relationship. The mechanistic interpretations of these models include strong assumptions that warrant reconsideration: the first study includes an implicit assumption that there is no immunity to Norwalk virus among the specific study population, while the recent second study includes assumptions that such immunity could exist and that the nonimmune have no defensive barriers to prevent infection from exposure to just one virus. Both models addressed unmeasured virus aggregation in administered doses. In this work, the available data are reanalyzed using a generalization of the first model to explore these previous assumptions. It was hypothesized that concurrent estimation of an unmeasured degree of virus aggregation and important dose-response parameters could lead to structural nonidentifiability of the model (i.e., that a diverse range of alternative mechanistic interpretations yield the same optimal fit), and this is demonstrated using the profile likelihood approach and by algebraic proof. It is also demonstrated that omission of an immunity parameter can artificially inflate the estimated degree of aggregation and falsely suggest high susceptibility among the nonimmune. The currently available data support the assumption of immunity within the specific study population, but provide only weak information about the degree of aggregation and susceptibility among the nonimmune. The probability of infection at low and moderate doses may be much lower than previously asserted, but more data from strategically designed dose response experiments are needed to provide adequate information. PMID- 25522207 TI - Regulation of dopaminergic markers expression in response to acute and chronic morphine and to morphine withdrawal. AB - Dopamine (DA) is thought to represent a teaching signal and has been implicated in the induction of addictive behaviours. Dysfunction of DA homeostasis leading to high or low DA levels is causally linked to addiction. Previously, it has been proposed that the transcription factors Nurr1 and Pitx3, which are critical for transcription of a set of genes involved in DA metabolism in the mesolimbic pathway, are associated with addiction pathology. Using quantitative real-time polymerase chain reaction, immunofluorescence and Western blotting, we studied the effects of single morphine administration, morphine dependence and withdrawal on the DA markers DA transporters (DAT), vesicular monoamine transporters (VMAT2) and DA 2 receptor subtype (DRD2), DA 1 receptor subtype as well as tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and/or nucleus accumbens (NAc). In addition, Nurr1 and Pitx3 expression was also measured. Present data showed a high degree of colocalization of Nurr1 and Pitx3 with TH(+) neurons in the VTA. We found that the increased Nurr1 and/or Pitx3 levels during morphine dependence and in morphine-withdrawn rats were associated to an increase of DAT, VMAT2 and DRD2. Altogether, present data indicate that morphine dependence and withdrawal induced consistent alterations of most of the DA markers, which was correlated with transcription factors involved in the maintenance of DA neurons in drug-reward pathways, suggesting that Nurr1 and Pitx3 regulation might be associated with controlling adaptation to chronic morphine and to morphine withdrawal-induced alterations of DA neurons activity in the mesolimbic pathway. PMID- 25522209 TI - Controlled and sustained release of pharmaceuticals via single step solvent-free encapsulation. AB - Herein, we report a novel and solvent-free technique for the encapsulation of pharmaceuticals that allows achieving controllable release rates. This method utilizes the deposition of a plasma polymer coating of controlled chemistry and thickness on the outer surface of drug particles placed under continuous agitation. PMID- 25522203 TI - Tools for assessing outcomes in studies of chronic cough: CHEST guideline and expert panel report. AB - BACKGROUND: Since the publication of the 2006 American College of Chest Physicians (CHEST) cough guidelines, a variety of tools has been developed or further refined for assessing cough. The purpose of the present committee was to evaluate instruments used by investigators performing clinical research on chronic cough. The specific aims were to (1) assess the performance of tools designed to measure cough frequency, severity, and impact in adults, adolescents, and children with chronic cough and (2) make recommendations or suggestions related to these findings. METHODS: By following the CHEST methodologic guidelines, the CHEST Expert Cough Panel based its recommendations and suggestions on a recently published comparative effectiveness review commissioned by the US Agency for Healthcare Research and Quality, a corresponding summary published in CHEST, and an updated systematic review through November 2013. Recommendations or suggestions based on these data were discussed, graded, and voted on during a meeting of the Expert Cough Panel. RESULTS: We recommend for adults, adolescents (>= 14 years of age), and children complaining of chronic cough that validated and reliable health-related quality-of-life (QoL) questionnaires be used as the measurement of choice to assess the impact of cough, such as the Leicester Cough Questionnaire and the Cough-Specific Quality of-Life Questionnaire in adult and adolescent patients and the Parent Cough Specific Quality of Life Questionnaire in children. We recommend acoustic cough counting to assess cough frequency but not cough severity. Limited data exist regarding the performance of visual analog scales, numeric rating scales, and tussigenic challenges. CONCLUSIONS: Validated and reliable cough-specific health related QoL questionnaires are recommended as the measurement of choice to assess the impact of cough on patients. How they compare is yet to be determined. When used, the reporting of cough severity by visual analog or numeric rating scales should be standardized. Previously validated QoL questionnaires or other cough assessments should not be modified unless the new version has been shown to be reliable and valid. Finally, in research settings, tussigenic challenges play a role in understanding mechanisms of cough. PMID- 25522210 TI - Gold nanoparticles supported in zirconia-ceria mesoporous thin films: a highly active reusable heterogeneous nanocatalyst. AB - Gold nanoparticles (NP) trapped in the mesopores of mixed zirconia-ceria thin films are prepared in a straightforward and reproducible way. The films exhibit enhanced stability and excellent catalytic activity in nitro-group reduction by borohydride and electrocatalytic activity in CO and ethanol oxidation and oxygen reduction. PMID- 25522211 TI - Complex cerebellopontine angle mass in a patient with a history of falls. PMID- 25522213 TI - Sex chromosome loss in adults with haematological neoplasms. PMID- 25522212 TI - A Claisen approach to 4'-Ed4T. AB - An efficient, stereoselective synthesis of 4'-Ed4T is demonstrated. The synthesis is highlighted by a regioselective TMSOTf-mediated acetal opening, a Claisen rearrangement to set the key 4'-stereocenter as well as the olefin, and a one-pot nonaflation/elimination to deliver the alkyne moiety. The synthesis proceeds in eight steps from 5-methyluridine and occurs in 37% overall yield. PMID- 25522214 TI - Laser 3D printing with sub-microscale resolution of porous elastomeric scaffolds for supporting human bone stem cells. AB - A reproducible method is needed to fabricate 3D scaffold constructs that results in periodic and uniform structures with precise control at sub-micrometer and micrometer length scales. In this study, fabrication of scaffolds by two-photon polymerization (2PP) of a biodegradable urethane and acrylate-based photoelastomer is demonstrated. This material supports 2PP processing with sub micrometer spatial resolution. The high photoreactivity of the biophotoelastomer permits 2PP processing at a scanning speed of 1000 mm s(-1), facilitating rapid fabrication of relatively large structures (>5 mm(3)). These structures are custom printed for in vitro assay screening in 96-well plates and are sufficiently flexible to enable facile handling and transplantation. These results indicate that stable scaffolds with porosities of greater than 60% can be produced using 2PP. Human bone marrow stromal cells grown on 3D scaffolds exhibit increased growth and proliferation compared to smooth 2D scaffold controls. 3D scaffolds adsorb larger amounts of protein than smooth 2D scaffolds due to their larger surface area; the scaffolds also allow cells to attach in multiple planes and to completely infiltrate the porous scaffolds. The flexible photoelastomer material is biocompatible in vitro and is associated with facile handling, making it a viable candidate for further study of complex 3D-printed scaffolds. PMID- 25522215 TI - Hyperpolarized [U-(2) H, U-(13) C]Glucose reports on glycolytic and pentose phosphate pathway activity in EL4 tumors and glycolytic activity in yeast cells. AB - PURPOSE: A resonance at ~181 ppm in the (13) C spectra of tumors injected with hyperpolarized [U-(2) H, U-(13) C]glucose was assigned to 6-phosphogluconate (6PG), as in previous studies in yeast, whereas in breast cancer cells in vitro this resonance was assigned to 3-phosphoglycerate (3PG). These peak assignments were investigated here using measurements of 6PG and 3PG (13) C-labeling using liquid chromatography tandem mass spectrometry (LC-MS/MS) METHODS: Tumor-bearing mice were injected with (13) C6 glucose and the (13) C-labeled and total 6PG and 3PG concentrations measured. (13) C MR spectra of glucose-6-phosphate dehydrogenase deficient (zwf1Delta) and wild-type yeast were acquired following addition of hyperpolarized [U-(2) H, U-(13) C]glucose and again (13) C-labeled and total 6PG and 3PG were measured by LC-MS/MS RESULTS: Tumor (13) C-6PG was more abundant than (13) C-2PG/3PG and the resonance at ~181 ppm matched more closely that of 6PG. (13) C MR spectra of wild-type and zwf1Delta yeast cells showed a resonance at ~181 ppm after labeling with hyperpolarized [U-(2) H, U (13) C]glucose, however, there was no 6PG in zwf1Delta cells. In the wild-type cells 3PG was approximately four-fold more abundant than 6PG CONCLUSION: The resonance at ~181 ppm in (13) C MR spectra following injection of hyperpolarized [U-(2) H, U-(13) C]glucose originates predominantly from 6PG in EL4 tumors and 3PG in yeast cells. PMID- 25522216 TI - Intrinsic resistance triggered under acid loading within normal esophageal epithelial cells: NHE1- and ROS-mediated survival. AB - The transition to a pathological phenotype such as Barrett's esophagus occurs via induction of resistance upon repeated contact with gastric refluxate in esophagus. This study examined the molecular changes within normal esophageal epithelial cells (EECs) under short-term acid loading and the role of these changes in defensive resistance against acidic cytotoxicity. After primary cultured EECs were exposed to pH 4-acidified medium (AM4), cell viability was determined by the MTT assay. Reactive oxygen species (ROS) and NAD(P)H oxidase (NOX) activity were measured. Activation of the mitogen-activated protein kinases (MAPKs) MEK/ERK1/2, p38 and JNK; phosphoinositol-3-kinase (PI3K)/Akt, and nuclear factor-kappa B (NF-kappaB) were detected by Western blot analysis or immunofluorescence staining. AM4 incubation induced intracellular ROS generation accompanied by increase in NOX activity, which was further increased by Na(+) /H(+) exchange-1 (NHE1)-dependent inhibition but was prevented by inhibition of NOX or mitochondria complex I. AM4 also induced phosphorylation of MEK/ERK1/2, p38 MAPK, PI3K/Akt, and nuclear translocation of NF-kappaB, and all these effects, except for p38 MAPK phosphorylation, were abolished by inhibition of ROS. ROS-dependent PI3K/Akt activation, which mediates NF-kappaB nuclear translocation, was inhibited by protein tyrosine kinase (PTK) inhibitors and NHE1 specific inhibitor. All inhibitors of NHE, ROS, PTK, PI3K, or NF-kappaB further decreased AM4-induced cell viability. Acid loading in the presence of NHE1 dependent protection induced ROS generation by activating NOX and mitochondria complex I, which stimulated PTK/PI3K/Akt/NF-kappaB-dependent survival in EEC. Our data indicate that normal EEC initially respond to acid loading through intrinsic survival activation. PMID- 25522217 TI - Congenital and postnatal CMV and EBV acquisition in HIV-infected Zimbabwean infants. AB - BACKGROUND: HIV-infected infants in sub-Saharan Africa have rapid disease progression. We hypothesized that co-infection with cytomegalovirus (CMV) or Epstein Barr virus (EBV) increases mortality in HIV-infected infants. METHODS: 257 antiretroviral therapy-naive HIV-infected Zimbabwean infants were tested for CMV and EBV at 6 weeks of age by real-time PCR; if positive, birth samples were retrieved where available to distinguish congenital and postnatal infection. The impact of co-infection on mortality through 6 months was estimated using Kaplan Meier and Cox proportional hazards methods. RESULTS: At 6 weeks, 203/257 (79%) HIV-infected infants were CMV-positive; 27 (11%) had congenital CMV, 108 (42%) postnatal CMV and 68 (26%) indeterminate timing of infection. By 6 months, 37/108 (34%) infants with postnatal CMV versus 16/54 (30%) CMV-negative infants died (adjusted hazard ratio (aHR) 1.1 [95%CI 0.6, 2.2]). At 6 weeks, 33/257 (13%) HIV infected infants had EBV co-infection; 6 (2%) had congenital EBV, 18 (7%) postnatal EBV and 9 (4%) indeterminate timing of infection. By 6 months, 5/18 (28%) infants with postnatal EBV versus 72/224 (32%) EBV-negative infants died (aHR 0.8 [95%CI 0.3, 2.3]). CONCLUSIONS: The vast majority of HIV-infants had acquired CMV by 6 weeks, and EBV co-infection occurred earlier than expected, with one in eight HIV-infected infants positive for EBV by 6 weeks. There was a high prevalence of congenital CMV infection and we identified 6 infants with congenital EBV infection, which has not previously been reported in Africa or in the context of HIV infection. Neither CMV nor EBV co-infection was associated with increased mortality. PMID- 25522219 TI - Visceral and subcutaneous adipose tissue FDG uptake by PET/CT in metabolically healthy obese subjects. AB - OBJECTIVE: To measure FDG uptake in visceral (VAT) and subcutaneous (SAT) adipose tissue of metabolically healthy obese (MHO) and metabolically abnormal obese (MAO) compared to metabolically healthy lean (MHL) subjects. Given that MHO has increased metabolic risk, it was hypothesized that MHO and MAO display similar VAT FDG uptake. METHODS: The 18F-FDG-PET/CT studies of 141 adults (n = 60 MHL, n = 20 MHO, n = 61 MAO) were examined to determine VAT and SAT volumes and FDG uptake. Data on CVD risk factors (BMI, abdominal circumference, blood pressure, serum lipids, and fasting plasma glucose) were collected. RESULTS: MHO and MAO had similar VAT FDG uptake (P = 0.74), both significantly lower than MHL (P < 0.01) independent of age and gender. SAT FDG uptake was similar across all groups (P > 0.2) independent of age and gender. In all groups, VAT FDG uptake was higher than SAT (P < 0.0001). In separate sub-analyses of obese groups, VAT FDG uptake was more broadly negatively associated with whole-body adiposity than SAT FDG uptake, and FDG uptake in abdominal adipose depots was positively associated with liver density (P < 0.05). CONCLUSIONS: FDG uptake in VAT of MHO is similar to MAO and lower than MHL, suggesting these subjects may present similar VAT dysfunction. PMID- 25522220 TI - Interpretation of the Swedish Self Evaluation of Communication Experiences after Laryngeal cancer: Cutoff levels and minimum clinically important differences. AB - BACKGROUND: The purpose of this study was to establish minimum clinically important difference (MCID) scores for the Swedish Self-Evaluation of Communication Experiences after Laryngeal Cancer (S-SECEL) in order to facilitate clinical interpretation and identify cutoff values for voice rehabilitation. METHOD: One hundred nineteen patients with laryngeal cancer completed the S-SECEL instrument and an anchor question regarding acceptability of speech in a social context pretreatment and 12-month postoncologic treatment. Receiver operating characteristic (ROC) curves analysis was used for calculation of cutoff values. RESULTS: Voice rehabilitation cutoff values were identified for all domains (Total = 20; General = 4; Environmental = 16, and Attitudinal = 5), presenting acceptable sensitivity and specificity. Initial MCID estimates were obtained for all domains; improvement of -13 points (p < .0001) or a deterioration of +8 points (p = .035) for the Total domain. CONCLUSION: MCID and cutoff scores for the S-SECEL have been identified and may be used in clinical practice to help identify patients with laryngeal cancer in need of voice rehabilitation. PMID- 25522221 TI - Oral steroid therapy as an adjuvant treatment for severe epidemic keratoconjunctivitis in patients younger than 3 years. AB - PURPOSE: To evaluate the therapeutic effect of oral steroids given to patients younger than 3 years with epidemic keratoconjunctivitis (EKC) accompanied by severe eyelid edema and inflammatory ptosis, in whom eye drops were not feasible. METHODS: This study included 9 patients treated for EKC in local clinics whose condition failed to improve due to severe eyelid swelling together with difficulties in application of eye drops and pseudomembrane removal. We analyzed the extent of eyelid swelling, corneal damage, follicles, chemosis, and pseudomembrane formation in these patients before and after oral corticosteroid therapy in collaboration with the pediatrics department. RESULTS: After a mean of 1.8 +/- 0.7 days of oral steroid treatment, eyelid edema, corneal damage, conjunctival injection, follicles, and chemosis improved in all patients. CONCLUSIONS: Oral steroids are an effective adjuvant treatment for EKC in patients younger than 3 years in whom eye drops could not be administered frequently due to severe eyelid edema. PMID- 25522222 TI - Evaluation of broadband spectral transmission characteristics of fresh and gamma irradiated corneal tissues. AB - PURPOSE: The aim of this study was to evaluate the clarity of gamma-irradiated sterile corneal donor lenticules. METHODS: Broadband UV, visible, and near infrared (200-850 nm) light transmission was measured through gamma-irradiated, sterile partial-thickness, and full-thickness donor lenticules and fresh corneal tissues and compared with standard acrylic intraocular lens (IOL) implants using a conventional spectrophotometer technique. RESULTS: All tissues had high light transmission (>= 90%) in the visible and near-infrared regions and very low (<2%) transmission below 290 nm. Differences in light transmission between irradiated and fresh cornea types were observed between 300 and 450 nm, which mirrored differences in light transmission through their respective storage solutions. Light transmission through partial-thickness irradiated donor lenticules was greatest across all wavelengths. All corneal tissues exhibited higher transmission than acrylic IOL implant across all wavelengths. CONCLUSIONS: Gamma irradiated donor lenticules are comparable with fresh corneas regarding light transmission, with both partial-thickness and full-thickness lenticules having greater transmission than standard IOL. We would expect the optical performance of gamma-irradiated donor lenticules to be comparable to fresh cornea if used for lamellar corneal procedures that do not require a viable endothelium. PMID- 25522218 TI - Targeted methods for quantitative analysis of protein glycosylation. AB - Quantification of proteins by LC-MS/MS-MRM has become a standard method with broad projected clinical applicability. MRM quantification of protein modifications is, however, far less utilized, especially in the case of glycoproteins. This review summarizes current methods for quantitative analysis of protein glycosylation with a focus on MRM methods. We describe advantages of this quantitative approach, analytical parameters that need to be optimized to achieve reliable measurements, and point out the limitations. Differences between major classes of N- and O-glycopeptides are described and class-specific glycopeptide assays are demonstrated. PMID- 25522223 TI - Evaluation of internationally shipped prestripped donor tissue for descemet membrane endothelial keratoplasty by vital dye staining. AB - PURPOSE: The aim of this study was to evaluate endothelial cell damage of internationally shipped prestripped donor tissue for Descemet membrane endothelial keratoplasty (DMEK) using vital dye staining. METHODS: Six internationally shipped prestripped DMEK donors were stained with trypan blue and were subsequently photographed before they were cut with a trephine. Quantitative analysis assessment of endothelial damage of the donor graft area (8.0 mm in diameter) was performed using Adobe Photoshop CS6 Extended software. Seven internationally shipped precut Descemet stripping automated endothelial keratoplasty (DSAEK) donors were used as controls. RESULTS: No statistical differences were noted between prestripped DMEK donors and precut DSAEK donors in mean donor age (67.7 vs. 56.4 years, P = 0.222), mean donor endothelial cell density (2687.3 vs. 2894.6 cells, P = 0.353), and death-to-preservation time (405.3 vs. 558.4 minutes, P = 0.173). However, the mean time of death-to experiment time in DMEK donors was significantly longer than that of DSAEK donors (8.7 vs. 6.6 days, P = 0.031). Mean endothelial cell damage of prestripped DMEK donors was as low as 0.3%. However, DMEK donor endothelial damage (0.3%) was significantly higher compared with that of precut DSAEK donor tissue (0.01%, P = 0.029). CONCLUSIONS: Although endothelial damage of internationally shipped prestripped donor tissue for DMEK was higher than that of precut DSAEK donor, it was extremely low. Further evaluation using another vital dye and clinical studies may be needed to confirm this study. PMID- 25522224 TI - Speciation of radiocesium and radioiodine in aerosols from Tsukuba after the Fukushima nuclear accident. AB - Aerosol samples were collected from Tsukuba, Japan, soon after the 2011 Fukushima nuclear accident and analyzed for speciation of radiocesium and radioiodine to explore their chemical behavior and isotopic ratios after the release. Most (134)Cs and (137)Cs were bound in organic matter (53-91%) and some in water soluble fractions (5-15%), whereas a negligible proportion of radiocesium remained in minerals. This pattern suggests that sulfate salts and organic matter may be the main carrier of Cs-bearing particles. The (129)I in aerosol samples is contained in various proportions as soluble inorganic iodine (I(-) and IO3(-)), soluble organic iodine, and unextractable iodine. The measured mean (129)I/(131)I atomic ratio of 16.0 +/- 2.2 is in good agreement with that measured from rainwater and consistent with ratios measured in surface soil samples. Together with other aerosols and seawater samples, an initial (129)I/(137)Cs activity ratio of ~4 * 10(-7) was obtained. In contrast to the effectively constant (134)Cs/(137)Cs activity ratios (1.04 +/- 0.04) and (129)I/(131)I atomic ratios (16.0 +/- 2.2), the (129)I/(137)Cs activity ratios scattered from 3.5 * 10(-7) to 5 * 10(-6) and showed temporally and spatially different dispersion and deposition patterns between radiocesium and radioiodine. These findings confirm that (129)I, instead of (137)Cs, should be considered as a proxy for (131)I reconstruction. PMID- 25522225 TI - Factors affecting decision concerning influenza vaccination among students of medical faculties. AB - Influenza is one of the most common cyclic respiratory diseases in humans. Methods of prevention are multidirectional, but the most effective and most efficacious way to prevent influenza and its complications is through preventive vaccination. This work aims to determine different factors affecting the decision concerning influenza vaccine. The percentage of people vaccinated against the flu was evaluated, as well as their knowledge of post-influenza complications, etc. among full-time students and bridging studies of nursing and physiotherapy (full time and part-time) at the University of Technology and Life Sciences in Radom, and students of medicine and pharmacy at the Medical University of Lodz. The research tool was the authors' questionnaire with 18 questions. The surveys conducted, consisting of multiple choice questions, were anonymous. In total, the survey involved 470 students. Overall, the number of people who were vaccinated against influenza in the 2012/13 epidemic season numbered 15 respondents, representing 5.84% of the total group of respondents. For the group of nursing students it was 6%, for physiotherapy students 5%, for students of medicine and pharmacy 14%. The percentage of respondents who said they would get vaccinated if the vaccinaton was free of charge was also low. Increasing the percentage of people vaccinated against influenza (immunization coverage) is a very important measure in preventing influenza epidemics. Therefore, it is necessary to identify the reasons why people are reluctant to be vaccinated against influenza, particularly among students who will work in the future in the health care services sector. PMID- 25522226 TI - Organometallic iron complexes as potential cancer therapeutics. AB - Metal-containing drugs have long been used for medicinal purposes in more or less empirical way. The potential of these anticancer agents has only been fully realised and explored since the discovery of the biological activity of cisplatin. Cisplatin and carboplatin have been two of the most successful anti cancer agents ever developed, and are currently used to treat ovarian, lung and testicular cancers. They share certain side effects, so their clinical use is severely limited by dose-limiting toxicity. Inherent or acquired resistance is a second problem often associated with platinum-based drugs, with further limits of their clinical use. These problems have prompted chemists to employ different strategies in development of the new metal-based anticancer agents with different mechanisms of action. There are various metal complexes still under development and investigation for the future cancer treatment use. In the search for novel bio-organometallic molecules, iron containing anti-tumoral agents are enjoying an increasing interest and appear very promising as the potential drug candidates. Iron, as an essential cofactor in a number of enzymes and physiological processes, may be less toxic than non essential metals, such as platinum. Up to now, some of iron complexes have been tested as cytotoxic agents and found to be endowed with an antitumor activity in several in vitro tests (on cultured cancer cell lines) and few in vivo experiments (e. g. on Ehrlich's ascites carcinoma). Although the precise molecular mechanism is yet to be defined, a number of observations suggest that the reactive oxygen species can play important role in iron-induced cytotoxicty. This review covers some relevant examples of research on the novel iron complexes. PMID- 25522227 TI - Purinergic signaling in the pancreas and the therapeutic potential of ecto nucleotidases in diabetes. AB - It is widely accepted that purinergic signaling is involved in the regulation of functions of all known tissues and organs. Extracellular purines activate two classes of receptors, P1-adenosine receptors and P2-nucleotide receptors, in a concentration-dependent manner. Ecto-enzymes metabolizing nucleotides outside the cell are involved in the termination of the nucleotide signaling pathway through the release of ligands from their receptors. The pancreas is a central organ in nutrient and energy homeostasis with endocrine, exocrine and immunoreactive functions. The disturbances in cellular metabolism in diabetes mellitus lead also to changes in concentrations of intra- and extracellular nucleotides. Purinergic receptors P1 and P2 are present on the pancreatic islet cells as well as on hepatocytes, adipocytes, pancreatic blood vessels and nerves. The ATP-dependent P2X receptor activation on pancreatic beta-cells results in a positive autocrine signal and subsequent insulin secretion. Ecto-NTPDases play the key role in regulation of extracellular ATP concentration. These enzymes, in cooperation with 5'-nucleotidase can significantly increase ecto-adenosine concentration. It has been demonstrated that adenosine, through activation of P1 receptors present on adipocytes and pancreatic islets cells, inhibits the release of insulin. Even though we know for 50 years about the regulatory role of nucleotides in the secretion of insulin, an integrated understanding of the involvement of purinergic signaling in pancreas function is still required. This comprehensive review presents our current knowledge about purinergic signaling in physiology and pathology of the pancreas as well as its potential therapeutic relevance in diabetes. PMID- 25522228 TI - The influence of father's child feeding knowledge and practices on children's dietary diversity: a study in urban and rural districts of Northern Ethiopia, 2013. AB - Infant and young child feeding has been recognised as an essential element to improve growth of children, especially in developing countries where malnutrition among children and its dire consequences are very prevalent. However, little attention has been paid on the influence of fathers on child feeding practices, although fathers are very important in raising well-adjusted, happy and successful children. Therefore, this study aimed to assess the influence of fathers' child feeding knowledge and practice on children's dietary diversity. A community-based comparative cross-sectional study was conducted among 850 eligible urban and rural households with children of 6-23 months. The father and mother of the child were interviewed on children's dietary diversity and fathers' knowledge and practice of child feeding. Nearly half (46%) of the children in the rural district did not meet the minimum dietary diversity, and in the urban district, the rate was even worse (72%). Grains were the common food group given to the children in both districts, whereas flesh food was the least commonly consumed food group. Additionally, low vitamin A-rich food and other fruit and vegetable consumption seem to be a problem in both districts. Almost all dimensions of fathers' knowledge and practice were significantly related to children's minimum dietary diversity; especially, fathers' knowledge of food groups was an important predictor (P-value < 0.001) in both districts. Interventions that focus on the fathers' knowledge of child feeding, especially about food groups, are recommended to improve children's dietary diversity in the study communities. PMID- 25522229 TI - Lack of bone lesions at diagnosis is associated with inferior outcome in multisystem langerhans cell histiocytosis of childhood. AB - Skeletal involvement is generally, but not universally, characteristic of Langerhans cell histiocytosis (LCH). We investigated whether the presence of bone lesions at diagnosis is a prognostic factor for survival in LCH. Nine hundred and thirty-eight children with multisystem (MS) LCH, both high (386 RO+) and low (RO ) risk, were evaluated for bone lesions at diagnosis. Risk organ (RO+) involvement was defined as: haematopoietic system (haemoglobin <100 g/l, and/or white blood cell count <4.0 * 10(9) /l and/or platelet count <100 * 10(9) /l), spleen (>2 cm below the costal margin), liver (>3 cm and/or hypoproteinaemia, hypoalbuminaemia, hyperbilirubinaemia, and/or increased aspartate transaminase/alanine transaminase). Given the general view that prognosis in LCH worsens with increasing extent of disease, the surprising finding was that in MS+RO+ LCH the probability of survival with bone involvement 74 +/- 3% (n = 230, 56 events) was reduced to 62 +/- 4% (n = 156, 55 events) if this was absent (P = 0.007). An even greater difference was seen in the subgroup of patients with both liver and either haematopoiesis or spleen involvement: 61 +/- 5% survival (n = 105; 52 events) if patients had bony lesions, versus 47 +/- 5% (n = 111; 39 events) if they did not (P = 0.014). This difference was retained in multivariate analysis (P = 0.048). Although as yet unexplained, we conclude that bone involvement at diagnosis is a previously unrecognized favourable prognostic factor in MS+RO+ LCH. PMID- 25522230 TI - Rapid and sensitive detection of Bartonella bacilliformis in experimentally infected sand flies by loop-mediated isothermal amplification (LAMP) of the Pap31 gene. AB - BACKGROUND: Carrion' disease, caused by Bartonella bacilliformis, remains truly neglected due to its focal geographical nature. A wide spectrum of clinical manifestations, including asymptomatic bacteremia, and lack of a sensitive diagnostic test can potentially lead to a spread of the disease into non-endemic regions where competent sand fly vectors may be present. A reliable test capable of detecting B. bacilliformis is urgently needed. Our objective is to develop a loop-mediated isothermal amplification (LAMP) assay targeting the pap31 gene to detect B. bacilliformis. METHODS AND FINDINGS: The sensitivity of the LAMP was evaluated in comparison to qPCR using plasmid DNA containing the target gene and genomic DNA in the absence and presence of human or sand fly DNA. The detection limit of LAMP was 1 to 10 copies/uL, depending on the sample metrics. No cross reaction was observed when testing against a panel of various closely related bacteria. The utility of the LAMP was further compared to qPCR by the examination of 74 Lutzomyia longipalpis sand flies artificially fed on blood spiked with B. bacilliformis and harvested at days (D) 1, 3, 5, 7 and 9 post feeding. Only 86% of sand flies at D1 and 63% of flies at D3 were positive by qPCR. LAMP was able to detect B. bacilliformis in all those flies confirmed positive by qPCR. However, none of the flies after D3 were positive by either LAMP or qPCR. In addition to demonstrating the sensitivity of the LAMP assay, these results suggest that B. bacilliformis cannot propagate in artificially fed L. longipalpis. CONCLUSIONS: The LAMP assay is as sensitive as qPCR for the detection of B. bacilliformis and could be useful to support diagnosis of patients in low-resource settings and also to identify B. bacilliformis in the sand fly vector. PMID- 25522232 TI - Heterothermy in large mammals: inevitable or implemented? AB - Advances in biologging techniques over the past 20 years have allowed for the remote and continuous measurement of body temperatures in free-living mammals. While there is an abundance of literature on heterothermy in small mammals, fewer studies have investigated the daily variability of body core temperature in larger mammals. Here we review measures of heterothermy and the factors that influence heterothermy in large mammals in their natural habitats, focussing on large mammalian herbivores. The mean 24 h body core temperatures for 17 species of large mammalian herbivores (>10 kg) decreased by ~1.3 degrees C for each 10 fold increase in body mass, a relationship that remained significant following phylogenetic correction. The degree of heterothermy, as measured by the 24 h amplitude of body core temperature rhythm, was independent of body mass and appeared to be driven primarily by energy and water limitations. When faced with the competing demands of osmoregulation, energy acquisition and water or energy use for thermoregulation, large mammalian herbivores appear to relax the precision of thermoregulation thereby conserving body water and energy. Such relaxation may entail a cost in that an animal moves closer to its thermal limits for performance. Maintaining homeostasis requires trade-offs between regulated systems, and homeothermy apparently is not accorded the highest priority; large mammals are able to maintain optimal homeothermy only if they are well nourished, hydrated, and not compromised energetically. We propose that the amplitude of the 24 h rhythm of body core temperature provides a useful index of any compromise experienced by a free-living large mammal and may predict the performance and fitness of an animal. PMID- 25522231 TI - funRNA: a fungi-centered genomics platform for genes encoding key components of RNAi. AB - BACKGROUND: RNA interference (RNAi) is involved in genome defense as well as diverse cellular, developmental, and physiological processes. Key components of RNAi are Argonaute, Dicer, and RNA-dependent RNA polymerase (RdRP), which have been functionally characterized mainly in model organisms. The key components are believed to exist throughout eukaryotes; however, there is no systematic platform for archiving and dissecting these important gene families. In addition, few fungi have been studied to date, limiting our understanding of RNAi in fungi. Here we present funRNA http://funrna.riceblast.snu.ac.kr/, a fungal kingdom-wide comparative genomics platform for putative genes encoding Argonaute, Dicer, and RdRP. DESCRIPTION: To identify and archive genes encoding the abovementioned key components, protein domain profiles were determined from reference sequences obtained from UniProtKB/SwissProt. The domain profiles were searched using fungal, metazoan, and plant genomes, as well as bacterial and archaeal genomes. 1,163, 442, and 678 genes encoding Argonaute, Dicer, and RdRP, respectively, were predicted. Based on the identification results, active site variation of Argonaute, diversification of Dicer, and sequence analysis of RdRP were discussed in a fungus-oriented manner. funRNA provides results from diverse bioinformatics programs and job submission forms for BLAST, BLASTMatrix, and ClustalW. Furthermore, sequence collections created in funRNA are synced with several gene family analysis portals and databases, offering further analysis opportunities. CONCLUSIONS: funRNA provides identification results from a broad taxonomic range and diverse analysis functions, and could be used in diverse comparative and evolutionary studies. It could serve as a versatile genomics workbench for key components of RNAi. PMID- 25522234 TI - Exploring the future of neurologic physical therapy: the emergence of technological and scientific contributions. PMID- 25522235 TI - Making the most of every repetition. PMID- 25522236 TI - Applications of electroencephalography to characterize brain activity: perspectives in stroke. AB - A wide array of neuroimaging technologies are now available that offer unprecedented opportunities to study the brain in health and disease. Each technology has associated strengths and weaknesses that need to be considered to maximize their utility, especially when used in combination. One imaging technology, electroencephalography (EEG), has been in use for more than 80 years, but as a result of recent technologic advancements EEG has received renewed interest as an inexpensive, noninvasive and versatile technique to evaluate neural activity in the brain. In part, this is due to new opportunities to combine EEG not only with other imaging modalities, but also with neurostimulation and robotics technologies. When used in combination, noninvasive brain stimulation and EEG can be used to study cause-and-effect relationships between interconnected brain regions providing new avenues to study brain function. Although many of these approaches are still in the developmental phase, there is substantial promise in their ability to deepen our understanding of brain function. The ability to capture the causal relationships between brain function and behavior in individuals with neurologic disorders or injury has important clinical implications for the development of novel biomarkers of recovery and response to therapeutic interventions. The goals of this paper are to provide an overview of the fundamental principles of EEG; discuss past, present, and future applications of EEG in the clinical management of stroke; and introduce the technique of combining EEG with a form of noninvasive brain stimulation, transcranial magnetic stimulation, as a powerful synergistic research paradigm to characterize brain function in both health and disease.Video Abstract available (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A87) for more insights from the authors. PMID- 25522233 TI - SCL, LMO1 and Notch1 reprogram thymocytes into self-renewing cells. AB - The molecular determinants that render specific populations of normal cells susceptible to oncogenic reprogramming into self-renewing cancer stem cells are poorly understood. Here, we exploit T-cell acute lymphoblastic leukemia (T-ALL) as a model to define the critical initiating events in this disease. First, thymocytes that are reprogrammed by the SCL and LMO1 oncogenic transcription factors into self-renewing pre-leukemic stem cells (pre-LSCs) remain non malignant, as evidenced by their capacities to generate functional T cells. Second, we provide strong genetic evidence that SCL directly interacts with LMO1 to activate the transcription of a self-renewal program coordinated by LYL1. Moreover, LYL1 can substitute for SCL to reprogram thymocytes in concert with LMO1. In contrast, inhibition of E2A was not sufficient to substitute for SCL, indicating that thymocyte reprogramming requires transcription activation by SCL LMO1. Third, only a specific subset of normal thymic cells, known as DN3 thymocytes, is susceptible to reprogramming. This is because physiological NOTCH1 signals are highest in DN3 cells compared to other thymocyte subsets. Consistent with this, overexpression of a ligand-independent hyperactive NOTCH1 allele in all immature thymocytes is sufficient to sensitize them to SCL-LMO1, thereby increasing the pool of self-renewing cells. Surprisingly, hyperactive NOTCH1 cannot reprogram thymocytes on its own, despite the fact that NOTCH1 is activated by gain of function mutations in more than 55% of T-ALL cases. Rather, elevating NOTCH1 triggers a parallel pathway involving Hes1 and Myc that dramatically enhances the activity of SCL-LMO1 We conclude that the acquisition of self renewal and the genesis of pre-LSCs from thymocytes with a finite lifespan represent a critical first event in T-ALL. Finally, LYL1 and LMO1 or LMO2 are co expressed in most human T-ALL samples, except the cortical T subtype. We therefore anticipate that the self-renewal network described here may be relevant to a majority of human T-ALL. PMID- 25522240 TI - Evaluating the interaction of faecal pellet deposition rates and DNA degradation rates to optimize sampling design for DNA-based mark-recapture analysis of Sonoran pronghorn. AB - Knowledge of population demographics is important for species management but can be challenging in low-density, wide-ranging species. Population monitoring of the endangered Sonoran pronghorn (Antilocapra americana sonoriensis) is critical for assessing the success of recovery efforts, and noninvasive DNA sampling (NDS) could be more cost-effective and less intrusive than traditional methods. We evaluated faecal pellet deposition rates and faecal DNA degradation rates to maximize sampling efficiency for DNA-based mark-recapture analyses. Deposition data were collected at five watering holes using sampling intervals of 1-7 days and averaged one pellet pile per pronghorn per day. To evaluate nuclear DNA (nDNA) degradation, 20 faecal samples were exposed to local environmental conditions and sampled at eight time points from one to 124 days. Average amplification success rates for six nDNA microsatellite loci were 81% for samples on day one, 63% by day seven, 2% by day 14 and 0% by day 60. We evaluated the efficiency of different sampling intervals (1-10 days) by estimating the number of successful samples, success rate of individual identification and laboratory costs per successful sample. Cost per successful sample increased and success and efficiency declined as the sampling interval increased. Results indicate NDS of faecal pellets is a feasible method for individual identification, population estimation and demographic monitoring of Sonoran pronghorn. We recommend collecting samples <7 days old and estimate that a sampling interval of four to seven days in summer conditions (i.e., extreme heat and exposure to UV light) will achieve desired sample sizes for mark-recapture analysis while also maximizing efficiency [Corrected]. PMID- 25522241 TI - HOXD-AS1 is a novel lncRNA encoded in HOXD cluster and a marker of neuroblastoma progression revealed via integrative analysis of noncoding transcriptome. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) constitute a major, but poorly characterized part of human transcriptome. Recent evidence indicates that many lncRNAs are involved in cancer and can be used as predictive and prognostic biomarkers. Significant fraction of lncRNAs is represented on widely used microarray platforms, however they have usually been ignored in cancer studies. RESULTS: We developed a computational pipeline to annotate lncRNAs on popular Affymetrix U133 microarrays, creating a resource allowing measurement of expression of 1581 lncRNAs. This resource can be utilized to interrogate existing microarray datasets for various lncRNA studies. We found that these lncRNAs fall into three distinct classes according to their statistical distribution by length. Remarkably, these three classes of lncRNAs were co-localized with protein coding genes exhibiting distinct gene ontology groups. This annotation was applied to microarray analysis which identified a 159 lncRNA signature that discriminates between localized and metastatic stages of neuroblastoma. Analysis of an independent patient cohort revealed that this signature differentiates also relapsing from non-relapsing primary tumors. This is the first example of the signature developed via the analysis of expression of lncRNAs solely. One of these lncRNAs, termed HOXD-AS1, is encoded in HOXD cluster. HOXD-AS1 is evolutionary conserved among hominids and has all bona fide features of a gene. Studying retinoid acid (RA) response of SH-SY5Y cell line, a model of human metastatic neuroblastoma, we found that HOXD-AS1 is a subject to morphogenic regulation, is activated by PI3K/Akt pathway and itself is involved in control of RA-induced cell differentiation. Knock-down experiments revealed that HOXD-AS1 controls expression levels of clinically significant protein-coding genes involved in angiogenesis and inflammation, the hallmarks of metastatic cancer. CONCLUSIONS: Our findings greatly extend the number of noncoding RNAs functionally implicated in tumor development and patient treatment and highlight their role as potential prognostic biomarkers of neuroblastomas. PMID- 25522242 TI - Identification of c-MYC SUMOylation by mass spectrometry. AB - The c-MYC transcription factor is a master regulator of many cellular processes and deregulation of this oncogene has been linked to more than 50% of all cancers. This deregulation can take many forms, including altered post translational regulation. Here, using immunoprecipitation combined with mass spectrometry, we identified a MYC SUMOylation site (K326). Abrogation of signaling through this residue by substitution with arginine (K326R) has no obvious effects on MYC half-life, intracellular localization, transcriptional targets, nor on the biological effects of MYC overexpression in two different cell systems assessed for soft agar colony formation, proliferation, and apoptosis. While we have definitively demonstrated that MYC SUMOylation can occur on K326, future work will be needed to elucidate the mechanisms and biological significance of MYC regulation by SUMOylation. PMID- 25522245 TI - beta-CuN3: the overlooked ground-state polymorph of copper azide with heterographene-like layers. AB - An unexpected polymorph of the highly energetic phase CuN3 has been synthesized and crystallizes in the orthorhombic space group Cmcm with a=3.3635(7), b=10.669(2), c=5.5547(11) A and V=199.34(7) A(3). The layered structure resembles graphite with an interlayer distance of 2.777(1) A (=1/2 c). Within a single layer, considering N3(-) as one structural unit, there are 10-membered almost hexagonal rings with a heterographene-like motif. Copper and nitrogen atoms are covalently bonded with Cu-N bonds lengths of 1.91 and 2.00 A, and the N3(-) group is linear but with N-N 1.14 and 1.20 A. Electronic-structure calculations and experimental thermochemistry show that the new polymorph termed beta-CuN3 is more stable than the established alpha-CuN3 phase. Also, beta-CuN3 is dynamically, and thus thermochemically, metastable according to the calculated phonon density of states. In addition, beta-CuN3 exhibits negative thermal expansion within the graphene-like layer. PMID- 25522243 TI - Ligand-receptor interaction catalyzes the aggregation of small molecules to induce cell necroptosis. AB - Because they exhibit important biological functions, from unfolding proteins to activating enzymes to controlling cell fates, aggregates of small molecules are able to serve as functional molecular entities in cellular environments. However, the inability to precisely control their production has hampered the understanding and exploration of their biological functions. Here we show that the well-established ligand-receptor interaction between vancomycin and d-Ala-d Ala catalyzes the aggregation of a d-Ala-d-Ala-containing small peptide derivative in water. The resulting aggregates largely adhere to the cell surface to induce cell necroptosis. Mutation of d-Ala-d-Ala to l-Ala-l-Ala or removal of the aromatic group in the derivative results in innocuous compounds, confirming that the aromatic-aromatic and ligand-receptor interactions are responsible for the formation and corresponding cytotoxicity of the aggregates. In addition to being the first example of ligand-receptor interaction-catalyzed aggregation of small molecules on the surface of mammalian cells, this work provides useful insights for understanding the cytotoxicity of molecular aggregates of small molecules. PMID- 25522244 TI - Comparison of safety and immunogenicity of PVRV and PCECV immunized in patients with WHO category II animal exposure: a study based on different age groups. AB - BACKGROUND: The aim of this study was to compare the safety and immunogenicity between purified vero cell rabies vaccine (PVRV) and purified chick embryo cell vaccine (PCECV) in patients with WHO category II animal exposure, especially in different age groups. METHODOLOGY/PRINCIPAL FINDINGS: In one-year clinical observation after vaccination with PVRV or PCECV under Zagreb (2-1-1) or Essen (1 1-1-1-1) regimens, information collection for the demographic and adverse events (AEs) and rabies virus laboratory examination of neutralizing antibody (RVNA) titers were performed for all patients with WHO category II animal exposure in Wuhan city. The results showed no significant differences of safety and immunogenicity between PVRV and PCECV both in Zagreb and Essen regimens. However, when compared with other age groups, most systemic AEs (36/61) occurred in <5 year-old patients, and <5-year-old patients have significant lower RVNA titer and seroconversion rate (RVNA >=0.5 IU/ml) at day 7 both in Zagreb and Essen regimens or PVRV and PCECV groups. CONCLUSIONS: Our data showed that vaccination with PVRV is as safe and immunogenic as PCECV in patients of all age groups, but might be more popular for clinical use. When performing a vaccination with rabies vaccine in young children, the most optimal vaccine regimen should be selected. PMID- 25522246 TI - Patient navigation to improve follow-up of abnormal mammograms among disadvantaged women. AB - BACKGROUND: Patient navigation (PN) can improve breast cancer care among disadvantaged women. We evaluated the impact of a PN program on follow-up after an abnormal mammogram. METHODS: Between 2007 and 2010, disadvantaged women with an abnormal mammogram (Breast Imaging-Reporting and Data System [BI-RADS] codes 0, 3, 4, 5) cared for in a community health center (CHC) with PN were compared to those receiving care in 11 network practices without PN. Multivariable logistic regression and Cox proportional hazards modeling were used to compare the percentages receiving appropriate follow-up and time to follow-up between the groups. RESULTS: Abnormal mammography findings were reported for 132 women in the CHC with PN and 168 from practices without PN. The percentage of women with appropriate follow-up care was higher in the practice with PN than in non-PN practices (90.4% vs. 75.3%, adjusted p=0.006). RESULTS varied by BI-RADS score for women in PN and non-PN practices (BI-RADS 0, 93.7% vs. 90.2%, p=0.24; BI-RADS 3, 85.7% vs. 49.2%, p=0.003; BI-RADS 4/5, 95.1% vs. 82.8%, p=0.26). Time to follow-up was similar for BI-RADS 0 and occurred sooner for women in the PN practice than in non-PN practices for BI-RADS 3 and 4/5 (BI-RADS 3, adjusted hazard ratio [aHR], 95% confidence interval [CI]: 2.41 [1.36-4.27], BI-RADS 4/5, aHR [95% CI]: 1.41 [0.88-2.24]). CONCLUSIONS: Disadvantaged women from a CHC with PN were more likely to receive appropriate follow-up after an abnormal mammogram than were those from practices without PN. Expanding PN to include all disadvantaged women within primary care networks could improve equity in cancer care. PMID- 25522247 TI - HPGCD outperforms HPBCD as a potential treatment for Niemann-Pick disease type C during disease modeling with iPS cells. AB - Niemann-Pick disease type C (NPC) is a lysosomal storage disease characterized by abnormal accumulation of free cholesterol and glycolipids. Here, we established induced pluripotent stem cell (iPSC) lines from NPC patients. Hepatocyte-like cells (HLCs) and neural progenitors derived from the iPSC lines accumulated cholesterol and displayed impaired autophagy and ATP production. A molecular signature related to lipid metabolism was also impaired in the NPC-iPSC-derived HLCs. These findings indicate that iPSC-derived cells can phenocopy human NPC. We also newly found that 2-hydroxypropyl-gamma-cyclodextrin (HPGCD) could reduce the cholesterol accumulation and restore the functional and molecular abnormalities in the NPC patient-derived cells, and do so more effectively than 2-hydroxypropyl beta-cyclodextrin treatment. In addition, NPC model mice showed an improved liver status and prolonged survival with HPGCDs. Thus, iPSC lines derived from patient cells are powerful tools to study cellular models of NPC, and HPGCD is a potential new drug candidate for future treatment of this disease. PMID- 25522248 TI - Non-surgical periodontal therapy with systemic antibiotics in patients with untreated aggressive periodontitis: a systematic review and meta-analysis. AB - OBJECTIVE: The purpose of this meta-analysis is to evaluate the effectiveness of different systemic antibiotics in combination with scaling and root planing (SRP) compared to SRP alone in patients with untreated aggressive periodontitis. BACKGROUND: In patients with aggressive periodontitis, SRP is often combined with the use of systemic antibiotics. However, the effectiveness of these antibiotics over time and differences in effectiveness between different antibiotics are hardly known. MATERIAL AND METHODS: The MEDLINE-PubMed database was searched from their earliest records until January 20, 2014. Several journals were hand searched and some authors were contacted for additional information. The following outcome measures were analysed: mean probing pocket depth reduction, mean clinical attachment level gain and mean bleeding on probing change. Extracted data were pooled using a random effect model. Weighted mean differences were calculated and heterogeneity was assessed. RESULTS: The search yielded 296 abstracts. Ultimately, 101 articles were selected of which 14 articles met the eligibility criteria. Systemic antibiotics showed a significant (p < 0.05) additional pocket depth reduction for moderate (0.36 +/- 0.22 mm at 3 mo, 6 mo 0.42 +/- 0.22 mm and 12 mo 0.88 +/- 0.27 mm) and deep pockets (0.74 +/- 0.36 mm at 3 mo, 6 mo 0.85 +/- 0.55 mm and 12 mo 1.26 +/- 0.81 mm) and a significant clinical attachment gain for moderate (0.26 +/- 0.18 at 3 mo, 6 mo 0.52 +/- 0.15 and 12 mo 0.83 +/- 0.38) and deep pockets (0.59 +/- 0.18 at 3 mo, 0.96 +/- 0.21 at 6 mo and 1.00 +/- 0.80 at 12 mo). CONCLUSION: For the treatment of patients with aggressive periodontitis, systemic antibiotics combined with non-surgical periodontal therapy resulted in a significant additional effect compared to non surgical therapy alone. There is a visible trend that showed metronidazole + amoxicillin is the most potent antibiotic combination. PMID- 25522249 TI - Surface Detail Reproduction and Effect of Disinfectant and Long-Term Storage on the Dimensional Stability of a Novel Vinyl Polyether Silicone Impression Material. AB - PURPOSE: This study investigated the surface detail reproduction and dimensional stability of a vinyl polyether silicone (VPES) in comparison to a vinylpolysiloxane (VPS) material as a function of prolonged storage for up to 2 weeks. MATERIALS AND METHODS: Heavy-body VPES (EXA'lence(TM) Fast Set) and VPS (Imprint(TM) 3 Quick Step) were compared. Forty impression ingots of each material were made using a stainless steel die as described by ANSI/ADA specification No. 19. Twenty impressions of each material were disinfected by immersion in a 2.5% buffered glutaraldehyde solution. Surface quality was assessed and scored immediately after making the ingots. Dimensional stability measurements were made immediately and repeated on the same ingots after 7 and 14 days storage in ambient laboratory conditions. Data were analyzed using the D'Agostino and Pearson omnibus normality test followed by two-way repeated measures ANOVA with post hoc Bonferroni tests. Values of p < 0.01 were deemed to be significant. RESULTS: Disinfected VPES and VPS specimens had significantly reduced dimensional changes at 7 and 14 days when compared with the nondisinfected ones (p < 0.0001). The dimensional stability of both materials was within ANSI/ADA specification No. 19's acceptable limit throughout the 2-week test period, regardless of whether they were disinfected. Out of the initial 80 ingots, 8 VPES and 1 VPS ingot scored a 2 on the surface detail test, while the remaining 71 ingots scored 1. CONCLUSIONS: Heavy-body fast-set VPES experienced minimal contraction in vitro after prolonged storage, though surface detail scores were not as consistent as those of the VPS tested. The least contraction occurred when the material was examined immediately after ingot production. PMID- 25522250 TI - The central role of cAMP in regulating Plasmodium falciparum merozoite invasion of human erythrocytes. AB - All pathogenesis and death associated with Plasmodium falciparum malaria is due to parasite-infected erythrocytes. Invasion of erythrocytes by P. falciparum merozoites requires specific interactions between host receptors and parasite ligands that are localized in apical organelles called micronemes. Here, we identify cAMP as a key regulator that triggers the timely secretion of microneme proteins enabling receptor-engagement and invasion. We demonstrate that exposure of merozoites to a low K+ environment, typical of blood plasma, activates a bicarbonate-sensitive cytoplasmic adenylyl cyclase to raise cytosolic cAMP levels and activate protein kinase A, which regulates microneme secretion. We also show that cAMP regulates merozoite cytosolic Ca2+ levels via induction of an Epac pathway and demonstrate that increases in both cAMP and Ca2+ are essential to trigger microneme secretion. Our identification of the different elements in cAMP dependent signaling pathways that regulate microneme secretion during invasion provides novel targets to inhibit blood stage parasite growth and prevent malaria. PMID- 25522252 TI - The stereochemical basis of the genetic code and the (mostly) autotrophic origin of life. AB - Spark-tube experiments and analysis of meteorite contents have led to the widespread notion that abiotic organic molecules were the first life components. However, there is a contradiction between the abundance of simple molecules, such as the amino acids glycine and alanine, observed in these studies, and the minimal functional complexity that even the least sophisticated living system should require. I will argue that although simple abiotic molecules must have primed proto-metabolic pathways, only Darwinian evolving systems could have generated life. This condition may have been initially fulfilled by both replicating RNAs and autocatalytic reaction chains, such as the reductive citric acid cycle. The interactions between nucleotides and biotic amino acids, which conferred new functionalities to the former, also resulted in the progressive stereochemical recognition of the latter by cognate anticodons. At this point only large enough amino acids would be recognized by the primordial RNA adaptors and could polymerize forming the first peptides. The gene duplication of RNA adaptors was a crucial event. By removing one of the anticodons from the acceptor stem the new RNA adaptor liberated itself from the stereochemical constraint and could be acylated by smaller amino acids. The emergence of messenger RNA and codon capture followed. PMID- 25522253 TI - Distribution and ecology of cyanobacteria in the rocky littoral of an english lake district water body, devoke water. AB - Cyanobacteria were sampled along two vertical and two horizontal transects in the littoral of Devoke Water, English Lake District. Profiles of cyanobacterium diversity and abundance showed that both attained a maximum close to the water line, but declined rapidly 20-40 cm above it. The distribution of individual species with height together with species and site ordinations showed that several taxa occurred in well-defined zones. A narrow "black zone" in the supralittoral was colonised mainly by species of Calothrix, Dichothrix and Gloeocapsa with pigmented sheaths. There was no evidence of lateral variation of species around the lake, but the height of the black zone correlated positively with wind exposure. The flora of Devoke Water is that of a base-poor mountain lake with some elements of a lowland, more alkaline water-body. PMID- 25522251 TI - Inhibition of nicotinic acetylcholine receptors, a novel facet in the pleiotropic activities of snake venom phospholipases A2. AB - Phospholipases A2 represent the most abundant family of snake venom proteins. They manifest an array of biological activities, which is constantly expanding. We have recently shown that a protein bitanarin, isolated from the venom of the puff adder Bitis arietans and possessing high phospholipolytic activity, interacts with different types of nicotinic acetylcholine receptors and with the acetylcholine-binding protein. To check if this property is characteristic to all venom phospholipases A2, we have studied the capability of these enzymes from other snakes to block the responses of Lymnaea stagnalis neurons to acetylcholine or cytisine and to inhibit alpha-bungarotoxin binding to nicotinic acetylcholine receptors and acetylcholine-binding proteins. Here we present the evidence that phospholipases A2 from venoms of vipers Vipera ursinii and V. nikolskii, cobra Naja kaouthia, and krait Bungarus fasciatus from different snake families suppress the acetylcholine- or cytisine-elicited currents in L. stagnalis neurons and compete with alpha-bungarotoxin for binding to muscle- and neuronal alpha7 types of nicotinic acetylcholine receptor, as well as to acetylcholine-binding proteins. As the phospholipase A2 content in venoms is quite high, under some conditions the activity found may contribute to the deleterious venom effects. The results obtained suggest that the ability to interact with nicotinic acetylcholine receptors may be a general property of snake venom phospholipases A2, which add a new target to the numerous activities of these enzymes. PMID- 25522255 TI - Brain energy metabolism measured by (13)C magnetic resonance spectroscopy in vivo upon infusion of [3-(13)C]lactate. AB - The brain uses lactate produced by glycolysis as an energy source. How lactate originated from the blood stream is used to fuel brain metabolism is not clear. The current study measures brain metabolic fluxes and estimates the amount of pyruvate that becomes labeled in glial and neuronal compartments upon infusion of [3-(13)C]lactate. For that, labeling incorporation into carbons of glutamate and glutamine was measured by (13)C magnetic resonance spectroscopy at 14.1 T and analyzed with a two-compartment model of brain metabolism to estimate rates of mitochondrial oxidation, glial pyruvate carboxylation, and the glutamate glutamine cycle as well as pyruvate fractional enrichments. Extracerebral lactate at supraphysiological levels contributes at least two-fold more to replenish the neuronal than the glial pyruvate pools. The rates of mitochondrial oxidation in neurons and glia, pyruvate carboxylase, and glutamate-glutamine cycles were similar to those estimated by administration of (13)C-enriched glucose, the main fuel of brain energy metabolism. These results are in agreement with primary utilization of exogenous lactate in neurons rather than astrocytes. PMID- 25522254 TI - Syd/JIP3 and JNK signaling are required for myonuclear positioning and muscle function. AB - Highlighting the importance of proper intracellular organization, many muscle diseases are characterized by mispositioned myonuclei. Proper positioning of myonuclei is dependent upon the microtubule motor proteins, Kinesin-1 and cytoplasmic Dynein, and there are at least two distinct mechanisms by which Kinesin and Dynein move myonuclei. The motors exert forces both directly on the nuclear surface and from the cell cortex via microtubules. How these activities are spatially segregated yet coordinated to position myonuclei is unknown. Using Drosophila melanogaster, we identified that Sunday Driver (Syd), a homolog of mammalian JNK-interacting protein 3 (JIP3), specifically regulates Kinesin- and Dynein-dependent cortical pulling of myonuclei without affecting motor activity near the nucleus. Specifically, Syd mediates Kinesin-dependent localization of Dynein to the muscle ends, where cortically anchored Dynein then pulls microtubules and the attached myonuclei into place. Proper localization of Dynein also requires activation of the JNK signaling cascade. Furthermore, Syd functions downstream of JNK signaling because without Syd, JNK signaling is insufficient to promote Kinesin-dependent localization of Dynein to the muscle ends. The significance of Syd-dependent myonuclear positioning is illustrated by muscle specific depletion of Syd, which impairs muscle function. Moreover, both myonuclear spacing and locomotive defects in syd mutants can be rescued by expression of mammalian JIP3 in Drosophila muscle tissue, indicating an evolutionarily conserved role for JIP3 in myonuclear movement and highlighting the utility of Drosophila as a model for studying mammalian development. Collectively, we implicate Syd/JIP3 as a novel regulator of myogenesis that is required for proper intracellular organization and tissue function. PMID- 25522256 TI - Lipocalin-2 and matrix metalloproteinase-9 expression in high-grade endometrial cancer and their prognostic value. AB - AIMS: To demonstrate lipocalin-2 (LCN-2) immunohistochemical expression together with matrix metalloproteinase-9 (MMP-9) protein in high-grade endometrial cancer and determine their correlations with FIGO (International Federation of Gynecology and Obstetrics) stage, histological subtype, presence of vascular invasion, patient age and overall and disease-free survival. METHODS AND RESULTS: Immunohistochemical staining was performed using LCN-2 and MMP-9 antibodies on high-grade endometrial cancer (n = 85) diagnosed at Split University Hospital Centre during 1998-2010. Immunohistochemical expression was determined on archived paraffin-embedded samples and scored semiquantitatively. Survival time was analysed using the Kaplan-Meier method, and the log-rank test was used to assess between-group differences. The Cox proportional hazard regression model was used on multivariate survival analysis. Patients were followed from the time of primary surgery until death or last follow-up until December 2012. LCN-2 and MMP-9 were highly expressed in high-grade endometrial cancer. Univariate analysis showed positive immunohistochemical staining for LCN-2 and MMP-9 to be associated with shorter survival in patients with high-grade endometrial cancer. Multivariate analysis showed LCN-2 overexpression to be associated with shorter overall and disease-free survival in high-grade endometrial cancer. CONCLUSIONS: Our findings suggest that LCN-2 expression may be an important independent indicator of shorter survival in patients with high-grade endometrial cancer. PMID- 25522258 TI - Attorneys as advocates: organizations step up to help patients navigate the legal and financial issues that often accompany a cancer diagnosis. PMID- 25522259 TI - Breast cancer gene increases risk to 1 in 3 by age 70. PMID- 25522260 TI - Immigration associated with an increase in smoking among Latinos, Asians. PMID- 25522257 TI - Survival of patients with stage IV lung cancer with diabetes treated with metformin. AB - RATIONALE: Prior studies have shown an anticancer effect of metformin in patients with breast and colorectal cancer. It is unclear, however, whether metformin has a mortality benefit in lung cancer. OBJECTIVES: To compare overall survival of patients with diabetes with stage IV non-small cell lung cancer (NSCLC) taking metformin versus those not on metformin. METHODS: Using data from the Surveillance, Epidemiology, and End Results registry linked to Medicare claims, we identified 750 patients with diabetes 65-80 years of age diagnosed with stage IV NSCLC between 2007 and 2009. We used propensity score methods to assess the association of metformin use with overall survival while controlling for potential confounders. MEASUREMENTS AND MAIN RESULTS: Overall, 61% of patients were on metformin at the time of lung cancer diagnosis. Median survival in the metformin group was 5 months, compared with 3 months in patients not treated with metformin (P < 0.001). Propensity score analyses showed that metformin use was associated with a statistically significant improvement in survival (hazard ratio, 0.80; 95% confidence interval, 0.71-0.89), after controlling for sociodemographics, diabetes severity, other diabetes medications, cancer characteristics, and treatment. CONCLUSIONS: Metformin is associated with improved survival among patients with diabetes with stage IV NSCLC, suggesting a potential anticancer effect. Further research should evaluate plausible biologic mechanisms and test the effect of metformin in prospective clinical trials. PMID- 25522261 TI - Integrated nanotubes, etch tracks, and nanoribbons in crystallographic alignment to a graphene lattice. AB - Carbon nanotubes, few-layer graphene, and etch tracks exposing insulating SiO2 regions are integrated into nanoscale systems with precise crystallographic orientations. These integrated systems consist of nanotubes grown across nanogap etch tracks and nanoribbons formed within the few-layer graphene films. This work is relevant to the integration of semiconducting, conducting, and insulating nanomaterials together into precise intricate systems. PMID- 25522262 TI - Stamping colloidal photonic crystals: a facile way towards complex pixel colour patterns for sensing and displays. AB - Patterning of colloidal photonic crystals (CPCs) has been strongly investigated in recent years for sensing and image displays. Rather than using traditional template-directed approaches, here microimprint lithography along with convective self-assembly is applied to generate complex CPC patterns that can be adjusted to show single- or dual-colour patterns or composite CPC patterns possessing two different colours. These composite CPC patterns show different wettability with water because of the surface chemistry of the polymers and silica used. This dramatically transforms the structural colours upon liquid infiltration. By mixing different ethanol concentrations with water, the infiltration efficiency can be further improved and easily read out from changes in reflection intensity and spectral peak shifts. Integrating these nano-architectures into devices can thus yield function as image displays and as sensors for solvents. PMID- 25522263 TI - Alterations of cortisol homeostasis may link changes of the sociocultural environment to an increased diabetes and metabolic risk in developing countries: a prospective diagnostic study performed in cooperation with the Ovahimba people of the Kunene region/northwestern Namibia. AB - CONTEXT: Diabetes mellitus is increasingly affecting Africa. OBJECTIVE: Urbanization of the Ovahimba people in Namibia is associated with an increased prevalence of disorders of glucose metabolism, and may thus be attributed to changes of cortisol homeostasis. DESIGN: A prospective, cross-sectional, diagnostic study was applied. SETTING: The study was conducted in the field. Location of the Diabetes Epidemic: Africa and Namibia. PARTICIPANTS: Ovahimba people: group 1 "urban" n = 60, 42 females, 46.3 +/- 11.3 years (town); group 2 "rural" n = 63, 44 females, 51.1 +/- 12.0 years (seminomadic). INTERVENTIONS: oGTT, sunrise and sunset saliva cortisol, metabolic parameters, questionnaire. MAIN OUTCOME MEASURE: The prevalence of disorders of glucose metabolism (DM, IGT, IFT). RESULTS: The prevalence of disorders of glucose metabolism differed significantly: urban group n = 17(28.3%) vs rural group n = 8(12.7%) (P = 0.04). The saliva cortisol concentrations also differed significantly: sunrise 0.34 +/- 0.18 vs 0.12 +/- 0.15 MUg/dL, sunset 0.18 +/- 0.20 vs 0.07 +/- 0.09 MUg/dL, area under the curve 6.16 +/- 3.48 vs 2.28 +/- 2.56 MUg/dL * 24 h (all P < 0.001). Further metabolic parameters were unfavorably changed in the urban group: hip circumference (P < 0.001), waist circumference (P < 0.001), body mass index (P = 0.014), systolic BP at rest (P < 0.001), diastolic BP at rest (P = 0.002), systolic BP after exercise (P < 0.001), heart rate after exercise (P = 0.007), fasting glucose (P < 0.001), 2-h-glucose by OGTT (P = 0.002), triglycerides (P = 0.04), HDL-cholesterol (P = 0.014), prevalence of the metabolic syndrome (P < 0.001). Physical activity was higher in the rural group, and intake of fast food and sweets were higher in the urban group. CONCLUSIONS: Urbanization of the Ovahimba people is associated with an increasing prevalence of disorders of glucose metabolism and other unfavorable metabolic parameters. Besides changes of lifestyle, this may be attributed to an increased cortisol exposure of the Ovahimba people living in an urban environment. PMID- 25522264 TI - Associations of menopausal vasomotor symptoms with fracture incidence. AB - CONTEXT: Vasomotor symptoms (VMS) are common. Whether VMS are associated with fracture incidence or bone mineral density (BMD) levels is unknown. OBJECTIVE: This study aimed to examine associations of baseline VMS with fracture incidence and BMD. DESIGN: This was a prospective observational study with mean (SD) followup of 8.2 (1.7) years (1993-2005). SETTING: Forty United States clinical centers. PARTICIPANTS: We examined data from Women's Health Initiative Clinical Trial participants (n = 23 573) age 50-79 years not using menopausal hormone therapy, and 4,867 participants of the BMD sub-study. INTERVENTIONS: None. MAIN OUTCOME MEASURES: We measured baseline VMS, incident adjudicated fractures, and BMD (baseline, annual visits 1, 3, 6, and 9). RESULTS: After adjustment for baseline age, body mass index, race/ethnicity, smoking, and education, the hazard ratio for hip fracture among women with baseline moderate/severe VMS (vs no VMS) was 1.78 (95% confidence interval [CI], 1.20-2.64; P = .01). There was no association between VMS and vertebral fracture. VMS severity was inversely associated with BMD during followup (P = .004 for femoral neck, P = .045 for lumbar spine). In repeated measures models, compared with women who reported no VMS, women with moderate/severe VMS had 0.015 g/cm(2) lower femoral neck BMD (95% CI, -0.025--0.005) and 0.016 g/cm(2) lower lumbar spine BMD (95% CI, -0.032- 0.004). CONCLUSIONS: Women with moderate/severe VMS have lower BMD and increased hip fracture rates. Elucidation of the biological mechanisms underlying these associations may inform the design of preventive strategies for at-risk women prior to occurrence of fracture. PMID- 25522266 TI - Self-templated formation of uniform NiCo2O4 hollow spheres with complex interior structures for lithium-ion batteries and supercapacitors. AB - Despite the significant advancement in preparing metal oxide hollow structures, most approaches rely on template-based multistep procedures for tailoring the interior structure. In this work, we develop a new generally applicable strategy toward the synthesis of mixed-metal-oxide complex hollow spheres. Starting with metal glycerate solid spheres, we show that subsequent thermal annealing in air leads to the formation of complex hollow spheres of the resulting metal oxide. We demonstrate the concept by synthesizing highly uniform NiCo2O4 hollow spheres with a complex interior structure. With the small primary building nanoparticles, high structural integrity, complex interior architectures, and enlarged surface area, these unique NiCo2O4 hollow spheres exhibit superior electrochemical performances as advanced electrode materials for both lithium-ion batteries and supercapacitors. This approach can be an efficient self-templated strategy for the preparation of mixed-metal-oxide hollow spheres with complex interior structures and functionalities. PMID- 25522265 TI - Absorption and chemopreventive targets of sulforaphane in humans following consumption of broccoli sprouts or a myrosinase-treated broccoli sprout extract. AB - SCOPE: Sulforaphane (SFN), an isothiocyanate derived from crucifers, has numerous health benefits. SFN bioavailability from dietary sources is a critical determinant of its efficacy in humans. A key factor in SFN absorption is the release of SFN from its glucosinolate precursor, glucoraphanin, by myrosinase. Dietary supplements are used in clinical trials to deliver consistent SFN doses, but myrosinase is often inactivated in available supplements. We evaluated SFN absorption from a myrosinase-treated broccoli sprout extract (BSE) and are the first to report effects of twice daily, oral dosing on SFN exposure in healthy adults. METHODS AND RESULTS: Subjects consumed fresh broccoli sprouts or the BSE, each providing 200 MUmol SFN daily, as a single dose and as two 100-MUmol doses taken 12 h apart. Using HPLC-MS/MS, we detected ~3 x higher SFN metabolite levels in plasma and urine of sprout consumers, indicating enhanced SFN absorption from sprouts. Twelve-hour dosing retained higher plasma SFN metabolite levels at later time points than 24-hour dosing. No dose responses were observed for molecular targets of SFN (i.e. heme oxygenase-1, histone deacetylase activity, p21). CONCLUSION: We conclude that the dietary form and dosing schedule of SFN may impact SFN absorption and efficacy in human trials. PMID- 25522267 TI - Defective sarcoplasmic reticulum-mitochondria calcium exchange in aged mouse myocardium. AB - Mitochondrial alterations are critically involved in increased vulnerability to disease during aging. We investigated the contribution of mitochondria sarcoplasmic reticulum (SR) communication in cardiomyocyte functional alterations during aging. Heart function (echocardiography) and ATP/phosphocreatine (NMR spectroscopy) were preserved in hearts from old mice (>20 months) with respect to young mice (5-6 months). Mitochondrial membrane potential and resting O2 consumption were similar in mitochondria from young and old hearts. However, maximal ADP-stimulated O2 consumption was specifically reduced in interfibrillar mitochondria from aged hearts. Second generation proteomics disclosed an increased mitochondrial protein oxidation in advanced age. Because energy production and oxidative status are regulated by mitochondrial Ca2+, we investigated the effect of age on mitochondrial Ca2+ uptake. Although no age dependent differences were found in Ca2+ uptake kinetics in isolated mitochondria, mitochondrial Ca2+ uptake secondary to SR Ca2+ release was significantly reduced in cardiomyocytes from old hearts, and this effect was associated with decreased NAD(P)H regeneration and increased mitochondrial ROS upon increased contractile activity. Immunofluorescence and proximity ligation assay identified the defective communication between mitochondrial voltage dependent anion channel and SR ryanodine receptor (RyR) in cardiomyocytes from aged hearts associated with altered Ca2+ handling. Age-dependent alterations in SR Ca2+ transfer to mitochondria and in Ca2+ handling could be reproduced in cardiomyoctes from young hearts after interorganelle disruption with colchicine, at concentrations that had no effect in aged cardiomyocytes or isolated mitochondria. Thus, defective SR-mitochondria communication underlies inefficient interorganelle Ca2+ exchange that contributes to energy demand/supply mistmach and oxidative stress in the aged heart. PMID- 25522269 TI - Tax contributes apoptosis resistance to HTLV-1-infected T cells via suppression of Bid and Bim expression. AB - The human T-lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). HTLV-1 Tax has been shown to have a prosurvival role in infected T cells by enhancing expression of the Bcl-2 family of antiapoptotic proteins. In this study, we show that the expression of proapoptotic BH3-only proteins Bim (Bcl-2-interacting mediator of cell death) and Bid (BH3-interacting domain death agonist) is diminished in HTLV-1-infected leukemic cells. Using a Tax-inducible system and a transient overexpression approach, we demonstrate that Tax downregulates Bid and Bim expression at the transcriptional level. We show that reinforced expression of Bim and Bid in HTLV-1-infected T-cell lines sensitizes CD95/TRAIL- and anticancer drug-induced apoptosis. Furthermore, we show that Tax suppresses Bid and Bim expression by enhancing hypoxia-inducible factor-1alpha (HIF-1alpha) protein expression. siRNA knockdown of HIF-1alpha or chemical inhibition of the transactivation activity of HIF-1alpha resulted in an increase in Bid and Bim expression and, consequently, in an increase in CD95/TRAIL- and anticancer drug-induced apoptosis in HTLV-1-infected leukemic T cell lines. Our study provides evidence that besides upregulation of prosurvival Bcl-2 proteins, Tax may also confer apoptosis resistance to HTLV-1-infected T cells by suppressing the expression of the proapoptotic BH3-only proteins Bim and Bid. PMID- 25522268 TI - TLR4-mediated inflammation promotes foam cell formation of vascular smooth muscle cell by upregulating ACAT1 expression. AB - Vascular smooth muscle cell (VSMC) foam cell formation is an important hallmark, especially in advanced atherosclerosis lesions. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) promotes foam cell formation by promoting intracellular cholesteryl ester synthesis. The present study tests the hypothesis that oxidized low-density lipoprotein (oxLDL) increases the ACAT1 expression by activating the Toll-like receptor 4 (TLR4)-mediated inflammation, and ultimately promotes VSMC foam cell formation. Wild-type, ApoE(-/-), TLR4(-/-) and ACAT1(-/-) mice on a C57BL/6J background were used. Increased TLR4, proinflammatory cytokines and ACAT1 were observed in high-fat (HF) diet-induced atherosclerotic plaque formation and in oxLDL-stimulated VSMCs. ACAT1 deficiency impeded the HF diet induced atherosclerotic plaque formation and impaired the TLR4-manipulated VSMC foam cell formation in response to oxLDL. TLR4 deficiency inhibited the upregulation of myeloid-differentiating factor 88 (MyD88), nuclear factor-kappaB (NF-kappaB), proinflammatory cytokines and ACAT1, and eventually attenuated the HF diet-induced atherosclerotic plaque formation and suppressed the oxLDL-induced VSMC foam cell formation. Knockdown of MyD88 and NF-kappaB, respectively, impaired the TLR4-manipulated VSMC foam cell formation in response to oxLDL. Rosiglitazone (RSG) attenuated HF diet-induced atherosclerotic plaque formation in ApoE(-/-) mice, accompanied by reduced expression of TLR4, proinflammatory cytokines and ACAT1 accordingly. Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) suppressed oxLDL-induced VSMC foam cell formation and inhibited the expression of TLR4, MyD88, NF-kappaB, proinflammatory cytokines and ACAT1, whereas inhibition of PPARgamma exerted the opposite effect. TLR4(-/-) mice and VSMCs showed impaired atherosclerotic plaque formation and foam cell formation, and displayed no response to PPARgamma manipulation. In conclusion, our data showed that oxLDL stimulation can activate the TLR4/MyD88/NF-kappaB inflammatory signaling pathway in VSMCs, which in turn upregulates the ACAT1 expression and finally promotes VSMC foam cell formation. PMID- 25522270 TI - Resveratrol regulates mitochondrial reactive oxygen species homeostasis through Sirt3 signaling pathway in human vascular endothelial cells. AB - Mitochondrial reactive oxygen species (mtROS) homeostasis plays an essential role in preventing oxidative injury in endothelial cells, an initial step in atherogenesis. Resveratrol (RSV) possesses a variety of cardioprotective activities, however, little is known regarding the effects of RSV on mtROS homeostasis in endothelial cells. Sirt3 is a mitochondrial deacetylase, which plays a key role in mitochondrial bioenergetics and is closely associated with oxidative stress. The goal of the study is to investigate whether RSV could attenuate oxidative injury in endothelial cells via mtROS homeostasis regulation through Sirt3 signaling pathway. We found that pretreatment with RSV suppressed tert-butyl hydroperoxide (t-BHP)-induced oxidative damage in human umbilical vein endothelial cells (HUVECs) by increasing cell viability, inhibiting cell apoptosis, repressing collapse of mitochondrial membrane potential and decreasing mtROS generation. Moreover, the enzymatic activities of isocitrate dehydrogenase 2 (IDH2), glutathione peroxidase (GSH-Px) and manganese superoxide dismutase (SOD2) as well as deacetylation of SOD2 were increased by RSV pretreatment, suggesting RSV notably enhanced mtROS scavenging in t-BHP-induced endothelial cells. Meanwhile, RSV remarkably reduced mtROS generation by promoting Sirt3 enrichment within the mitochondria and subsequent upregulation of forkhead box O3A (FoxO3A)-mediated mitochondria-encoded gene expression of ATP6, CO1, Cytb, ND2 and ND5, thereby leading to increased complex I activity and ATP synthesis. Furthermore, RSV activated the expressions of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha) and Sirt3, as well as estrogen-related receptor-alpha (ERRalpha)-dependent Sirt3 mRNA transcription, which were abolished in the presence of AMPK inhibitor and AMPK, PGC-1alpha or Sirt3 siRNA transfection, indicating the effects of RSV on mtROS homeostasis regulation were dependent on AMPK-PGC-1alpha-ERRalpha-Sirt3 signaling pathway. Our findings indicated a novel mechanism that RSV-attenuated oxidative injury in endothelial cells through the regulation of mtROS homeostasis, which, in part, was mediated through the activation of the Sirt3 signaling pathway. PMID- 25522271 TI - Level of macroautophagy drives senescent keratinocytes into cell death or neoplastic evasion. AB - Senescence is a non-proliferative state reached by normal cells in response to various stresses, including telomere uncapping, oxidative stress or oncogene activation. In previous reports, we have highlighted that senescent human epidermal keratinocytes have two opposite outcomes: either they die by autophagic programmed cell death or they evade in the form of neoplastic postsenescence emergent (PSNE) cells. Herein, we show that partially reducing macroautophagy in senescent keratinocytes using 3-methyl adenine or anti-Atg5 siRNAs increases the PSNE frequency, suggesting that senescent keratinocytes have to escape autophagic cell death to generate PSNE cells. However, totally inhibiting macroautophagy impairs PSNE and leads to a huge accumulation of oxidative damages, indicating that senescent keratinocytes need to achieve quality-control macroautophagy for PSNE to occur. In accordance, we demonstrate that the progenitors of PSNE cells display a level of macroautophagy slightly lower than that of the average senescent population, which is directly dictated by their level of reactive oxygen species, their level of upregulation of MnSOD, their level of activation of NF-kappaB transcription factors and their level of dysfunctional mitochondria. Macroautophagy thus has antagonistic roles during senescence, inducing cell death or promoting neoplastic transformation, depending on its level of activation. Taken together, these data suggest that levels of oxidative damages and ensuing macroautophagic activity could be two main determinants of the very initial phases of neoplastic transformation by senescence evasion. PMID- 25522272 TI - An activated unfolded protein response promotes retinal degeneration and triggers an inflammatory response in the mouse retina. AB - Recent studies on the endoplasmic reticulum stress have shown that the unfolded protein response (UPR) is involved in the pathogenesis of inherited retinal degeneration caused by mutant rhodopsin. However, the main question of whether UPR activation actually triggers retinal degeneration remains to be addressed. Thus, in this study, we created a mouse model for retinal degeneration caused by a persistently activated UPR to assess the physiological and morphological parameters associated with this disease state and to highlight a potential mechanism by which the UPR can promote retinal degeneration. We performed an intraocular injection in C57BL6 mice with a known unfolded protein response (UPR) inducer, tunicamycin (Tn) and examined animals by electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT) and histological analyses. We detected a significant loss of photoreceptor function (over 60%) and retinal structure (35%) 30 days post treatment. Analysis of retinal protein extracts demonstrated a significant upregulation of inflammatory markers including interleukin-1beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1) and IBA1. Similarly, we detected a strong inflammatory response in mice expressing either Ter349Glu or T17M rhodopsin (RHO). These mutant rhodopsin species induce severe retinal degeneration and T17M rhodopsin elicits UPR activation when expressed in mice. RNA and protein analysis revealed a significant upregulation of pro- and anti inflammatory markers such as IL-1beta, IL-6, p65 nuclear factor kappa B (NF-kB) and MCP-1, as well as activation of F4/80 and IBA1 microglial markers in both the retinas expressing mutant rhodopsins. We then assessed if the Tn-induced inflammatory marker IL-1beta was capable of inducing retinal degeneration by injecting C57BL6 mice with a recombinant IL-1beta. We observed ~19% reduction in ERG a-wave amplitudes and a 29% loss of photoreceptor cells compared with control retinas, suggesting a potential link between pro-inflammatory cytokines and retinal pathophysiological effects. Our work demonstrates that in the context of an established animal model for ocular disease, the persistent activation of the UPR could be responsible for promoting retinal degeneration via the UPR-induced pro-inflammatory cytokine IL-1beta. PMID- 25522273 TI - Mitochondrial inhibitor sensitizes non-small-cell lung carcinoma cells to TRAIL induced apoptosis by reactive oxygen species and Bcl-X(L)/p53-mediated amplification mechanisms. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for anticancer therapy; however, non-small-cell lung carcinoma (NSCLC) cells are relatively TRAIL resistant. Identification of small molecules that can restore NSCLC susceptibility to TRAIL-induced apoptosis is meaningful. We found here that rotenone, as a mitochondrial respiration inhibitor, preferentially increased NSCLC cells sensitivity to TRAIL-mediated apoptosis at subtoxic concentrations, the mechanisms by which were accounted by the upregulation of death receptors and the downregulation of c-FLIP (cellular FLICE-like inhibitory protein). Further analysis revealed that death receptors expression by rotenone was regulated by p53, whereas c-FLIP downregulation was blocked by Bcl-X(L) overexpression. Rotenone triggered the mitochondria-derived reactive oxygen species (ROS) generation, which subsequently led to Bcl-X(L) downregulation and PUMA upregulation. As PUMA expression was regulated by p53, the PUMA, Bcl-X(L) and p53 in rotenone-treated cells form a positive feedback amplification loop to increase the apoptosis sensitivity. Mitochondria-derived ROS, however, promote the formation of this amplification loop. Collectively, we concluded that ROS generation, Bcl-X(L) and p53-mediated amplification mechanisms had an important role in the sensitization of NSCLC cells to TRAIL-mediated apoptosis by rotenone. The combined TRAIL and rotenone treatment may be appreciated as a useful approach for the therapy of NSCLC that warrants further investigation. PMID- 25522274 TI - Suppression of BRCA1 sensitizes cells to proteasome inhibitors. AB - BRCA1 is a multifunctional protein best known for its role in DNA repair and association with breast and ovarian cancers. To uncover novel biologically significant molecular functions of BRCA1, we tested a panel of 198 approved and experimental drugs to inhibit growth of MDA-MB-231 breast cancer cells depleted for BRCA1 by siRNA. 26S proteasome inhibitors bortezomib and carfilzomib emerged as a new class of selective BRCA1-targeting agents. The effect was confirmed in HeLa and U2OS cancer cell lines using two independent siRNAs, and in mouse embryonic stem (ES) cells with inducible deletion of Brca1. Bortezomib treatment did not cause any increase in nuclear foci containing phosphorylated histone H2AX, and knockdown of BRCA2 did not entail sensitivity to bortezomib, suggesting that the DNA repair function of BRCA1 may not be directly involved. We found that a toxic effect of bortezomib on BRCA1-depleted cells is mostly due to deregulated cell cycle checkpoints mediated by RB1-E2F pathway and 53BP1. Similar to BRCA1, depletion of RB1 also conferred sensitivity to bortezomib, whereas suppression of E2F1 or 53BP1 together with BRCA1 reduced induction of apoptosis after bortezomib treatment. A gene expression microarray study identified additional genes activated by bortezomib treatment only in the context of inactivation of BRCA1 including a critical involvement of the ERN1-mediated unfolded protein response. Our data indicate that BRCA1 has a novel molecular function affecting cell cycle checkpoints in a manner dependent on the 26S proteasome activity. PMID- 25522276 TI - Establishing the evolutionary compatibility of potential sources of colonizers for overfished stocks: a population genomics approach. AB - Identifying fish stock structure is fundamental to pinpoint stocks that might contribute colonizers to overfished stocks. However, a stock's potential to contribute to rebuilding hinges on demographic connectivity, a challenging parameter to measure. With genomics as a new tool, fisheries managers can detect signatures of natural selection and thus identify fishing areas likely to contribute evolutionarily compatible colonizers to an overfished area (i.e. colonizers that are not at a fitness disadvantage in the overfished area and able to reproduce at optimal rates). Identifying evolutionarily compatible stocks would help narrow the focus on establishing demographic connectivity where it matters. Here, we genotype 4723 SNPs in 616 orange roughy (Hoplostethus atlanticus) across five fishing areas off the Tasmanian coast in Australia. We ask whether these areas form a single genetic unit, and test for signatures of local adaptation. Results from amova, structure, discriminant analysis of principal components, BAYESASS and isolation by distance suggest that sampled locations are subjected to geneflow amounts that are above what is needed to establish 'drift connectivity'. However, it remains unclear whether there is a single panmictic population or several highly connected populations. Most importantly, we did not find any evidence of local adaptation, suggesting that the examined orange roughy stocks are evolutionarily compatible. The data have helped test an assumption of the orange roughy management programme and to formulate hypotheses regarding stock demographic connectivity. Overall, our results demonstrate the potential of genomics to inform fisheries management, even when evidence for stock structure is sparse. PMID- 25522275 TI - SBF-1 exerts strong anticervical cancer effect through inducing endoplasmic reticulum stress-associated cell death via targeting sarco/endoplasmic reticulum Ca(2+)-ATPase 2. AB - Cervical cancer is one of the most common carcinomas in the genital system. In the present study, we report that SBF-1, a synthetic steroidal glycoside, has a strong antigrowth activity against human cervical cancer cells in vitro and in vivo. SBF-1 suppressed the growth, migration and colony formation of HeLa cells. In addition, severe endoplasmic reticulum (ER) stress was triggered by SBF-1, and 4-phenyl-butyric acid, a chemical chaperone, partially reversed SBF-1-induced cell death. To uncover the target protein of SBF-1, the compound was labeled with biotin. The biotin-labeled SBF-1 bound to sarco/ER Ca(2+)-ATPase 2 (SERCA2) and colocalized with SERCA2 in HeLa cells. Moreover, SBF-1 inhibited SERCA activity, depleted ER Ca2+ and increased cytosolic Ca2+ levels. 1,2-Bis(o aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, a chelator of Ca2+, partially blocked SBF-1-induced ER stress and growth inhibition. Importantly, knockdown of SERCA2 increased the sensitivity of HeLa cells to SBF-1-induced ER stress and cell death, whereas overexpression of SERCA2 decreased this sensitivity. Furthermore, SBF-1 induced growth suppression and apoptosis in HeLa xenografts, which is closely related to the induction of ER stress and inhibition of SERCA activity. Finally, SERCA2 expression was elevated in human cervical cancer tissues (n=299) and lymph node metastasis (n=8), as compared with normal cervix tissues (n=23), with a positive correlation with clinical stages. In all, these results suggest that SBF-1 disrupts Ca2+ homeostasis and causes ER stress associated cell death through directly binding to SERCA2 and inhibiting SERCA activity. Our findings also indicate that SERCA2 is a potential therapeutic target for human cervical cancer. PMID- 25522277 TI - Identifying expectations about the strength of causal relationships. AB - When we try to identify causal relationships, how strong do we expect that relationship to be? Bayesian models of causal induction rely on assumptions regarding people's a priori beliefs about causal systems, with recent research focusing on people's expectations about the strength of causes. These expectations are expressed in terms of prior probability distributions. While proposals about the form of such prior distributions have been made previously, many different distributions are possible, making it difficult to test such proposals exhaustively. In Experiment 1 we used iterated learning-a method in which participants make inferences about data generated based on their own responses in previous trials-to estimate participants' prior beliefs about the strengths of causes. This method produced estimated prior distributions that were quite different from those previously proposed in the literature. Experiment 2 collected a large set of human judgments on the strength of causal relationships to be used as a benchmark for evaluating different models, using stimuli that cover a wider and more systematic set of contingencies than previous research. Using these judgments, we evaluated the predictions of various Bayesian models. The Bayesian model with priors estimated via iterated learning compared favorably against the others. Experiment 3 estimated participants' prior beliefs concerning different causal systems, revealing key similarities in their expectations across diverse scenarios. PMID- 25522278 TI - A new double digestion ligation mediated suppression PCR method for simultaneous bacteria DNA-typing and confirmation of species: an Acinetobacter sp. model. AB - We have designed a new ddLMS PCR (double digestion Ligation Mediated Suppression PCR) method based on restriction site polymorphism upstream from the specific target sequence for the simultaneous identification and differentiation of bacterial strains. The ddLMS PCR combines a simple PCR used for species or genus identification and the LM PCR strategy for strain differentiation. The bacterial identification is confirmed in the form of the PCR product(s), while the length of the PCR product makes it possible to differentiate between bacterial strains. If there is a single copy of the target sequence within genomic DNA, one specific PCR product is created (simplex ddLMS PCR), whereas for multiple copies of the gene the fingerprinting patterns can be obtained (multiplex ddLMS PCR). The described ddLMS PCR method is designed for rapid and specific strain differentiation in medical and microbiological studies. In comparison to other LM PCR it has substantial advantages: enables specific species' DNA-typing without the need for pure bacterial culture selection, is not sensitive to contamination with other cells or genomic DNA, and gives univocal "band-based" results, which are easy to interpret. The utility of ddLMS PCR was shown for Acinetobacter calcoaceticus-baumannii (Acb) complex, the genetically closely related and phenotypically similar species and also important nosocomial pathogens, for which currently, there are no recommended methods for screening, typing and identification. In this article two models are proposed: 3' recA-ddLMS PCR MaeII/RsaI for Acb complex interspecific typing and 5' rrn-ddLMS PCR-HindIII/ApaI for Acinetobacter baumannii intraspecific typing. ddLMS PCR allows not only for DNA-typing but also for confirmation of species in one reaction. Also, practical guidelines for designing a diagnostic test based on ddLMS PCR for genotyping different species of bacteria are provided. PMID- 25522280 TI - A comparative study of capillary electrophoresis and isothermal titration calorimetry for the determination of binding constant of human serum albumin to monoclonal antibody. AB - This paper focuses on the investigation of the interactions between the anti-HSA mAb and its protein antigen using CZE, ACE, and isothermal titration calorimetry. The CZE revealed the formation of the anti-HSA-mAb.HSA and anti-HSA-mAb.(HSA)2 complexes and the binding constants determined by plotting the amount of the bound anti-HSA-mAb as a function of the concentration of HSA. The ACE provided information on the binding strength from the change in effective electrophoretic mobility of the anti-HSA-mAb. These two separation techniques estimated the presence of two binding sites. The equilibrium dissociation constant values obtained by CZE and ACE were found to be 2.26 * 10(-6) M for anti-HSA-mAb.HSA, 1.22 * 10(-6) M for anti-HSA-mAb.(HSA)2 and 4.45 * 10(-8) M for anti-HSA-mAb.HSA, 1.08 * 10(-7) M for anti-HSA-mAb.(HSA)2 , respectively. The dissociation constant data obtained by ACE were in congruence with the values obtained by isothermal titration calorimetry (2.74 * 10(-8) M, 1.04 * 10(-7) M). PMID- 25522279 TI - SCMHBP: prediction and analysis of heme binding proteins using propensity scores of dipeptides. AB - BACKGROUND: Heme binding proteins (HBPs) are metalloproteins that contain a heme ligand (an iron-porphyrin complex) as the prosthetic group. Several computational methods have been proposed to predict heme binding residues and thereby to understand the interactions between heme and its host proteins. However, few in silico methods for identifying HBPs have been proposed. RESULTS: This work proposes a scoring card method (SCM) based method (named SCMHBP) for predicting and analyzing HBPs from sequences. A balanced dataset of 747 HBPs (selected using a Gene Ontology term GO:0020037) and 747 non-HBPs (selected from 91,414 putative non-HBPs) with an identity of 25% was firstly established. Consequently, a set of scores that quantified the propensity of amino acids and dipeptides to be HBPs is estimated using SCM to maximize the predictive accuracy of SCMHBP. Finally, the informative physicochemical properties of 20 amino acids are identified by utilizing the estimated propensity scores to be used to categorize HBPs. The training and mean test accuracies of SCMHBP applied to three independent test datasets are 85.90% and 71.57%, respectively. SCMHBP performs well relative to comparison with such methods as support vector machine (SVM), decision tree J48, and Bayes classifiers. The putative non-HBPs with high sequence propensity scores are potential HBPs, which can be further validated by experimental confirmation. The propensity scores of individual amino acids and dipeptides are examined to elucidate the interactions between heme and its host proteins. The following characteristics of HBPs are derived from the propensity scores: 1) aromatic side chains are important to the effectiveness of specific HBP functions; 2) a hydrophobic environment is important in the interaction between heme and binding sites; and 3) the whole HBP has low flexibility whereas the heme binding residues are relatively flexible. CONCLUSIONS: SCMHBP yields knowledge that improves our understanding of HBPs rather than merely improves the prediction accuracy in predicting HBPs. PMID- 25522281 TI - An extra dimension to decision-making in animals: the three-way trade-off between speed, effort per-unit-time and accuracy. AB - The standard view in biology is that all animals, from bumblebees to human beings, face a trade-off between speed and accuracy as they search for resources and mates, and attempt to avoid predators. For example, the more time a forager spends out of cover gathering information about potential food sources the more likely it is to make accurate decisions about which sources are most rewarding. However, when the cost of time spent out of cover rises (e.g. in the presence of a predator) the optimal strategy is for the forager to spend less time gathering information and to accept a corresponding decline in the accuracy of its decisions. We suggest that this familiar picture is missing a crucial dimension: the amount of effort an animal expends on gathering information in each unit of time. This is important because an animal that can respond to changing time costs by modulating its level of effort per-unit-time does not have to accept the same decrease in accuracy that an animal limited to a simple speed-accuracy trade-off must bear in the same situation. Instead, it can direct additional effort towards (i) reducing the frequency of perceptual errors in the samples it gathers or (ii) increasing the number of samples it gathers per-unit-time. Both of these have the effect of allowing it to gather more accurate information within a given period of time. We use a modified version of a canonical model of decision-making (the sequential probability ratio test) to show that this ability to substitute effort for time confers a fitness advantage in the face of changing time costs. We predict that the ability to modulate effort levels will therefore be widespread in nature, and we lay out testable predictions that could be used to detect adaptive modulation of effort levels in laboratory and field studies. Our understanding of decision-making in all species, including our own, will be improved by this more ecologically-complete picture of the three-way tradeoff between time, effort per-unit-time and accuracy. PMID- 25522282 TI - A decrease in miR-150 regulates the malignancy of pancreatic cancer by targeting c-Myb and MUC4. AB - OBJECTIVES: Pancreatic cancer is an aggressive cancer with high mortality. Conventional treatments have little impact on its progression. Limited research investigating the role of oncogene miR-150 specifically in pancreatic cancer has been published. The purpose of this study was to determine the tumorigenesis of miR-150 in pancreatic cancer. METHODS: One hundred six pancreatic ductal adenocarcinomas were analyzed together with their adjacent benign pancreatic tissues. The associations of miR-150, c-Myb, and MUC4 expression with survival rates were determined. Functional studies on miR-150 in pancreatic cancer were used to assess its effect on proliferation and malignancy in several pancreatic cell lines. RESULTS: miR-150 expression was significantly down-regulated in pancreatic ductal adenocarcinoma tissues compared with adjacent benign pancreatic tissues. Patients with low miR-150 expression had significantly higher mortality rates than those with high miR-150 expression. The in vitro and in vivo assays of pancreatic cancer cells showed that miR-150 overexpression leads to reduced cell growth, clonogenicity, migration, invasion, modular cell cycles, and induced apoptosis. Moreover, miR-150 expression was inversely correlated with c-Myb and MUC4 activities in pancreatic tissue, cell lines, and nude mouse model. CONCLUSIONS: miR-150 is an important suppressor of pancreatic ductal carcinoma and acts as a regulator of c-Myb and MUC4 in aggressive progress. PMID- 25522284 TI - Bronchial thermoplasty: ready for prime time--the evidence is there! PMID- 25522283 TI - Chitosan-PEG hydrogel with sol-gel transition triggerable by multiple external stimuli. AB - Smart hydrogels play an increasingly important role in biomedical applications, since materials that are both biocompatible and multi-stimuli-responsive are highly desirable. A simple, organic solvent-free method is presented to synthesize a biocompatible hydrogel that undergoes a sol-gel transition in response to multiple stimuli. Methoxy-poly(ethylene glycol) (mPEG) is modified into carboxylic-acid-terminated-methoxy-poly(ethylene glycol) (mPEG-acid), which is then grafted onto chitosan via amide linkages yielding mPEG-g-chitosan. Grafting of mPEG onto hydrophobic chitosan imparts hydrophilic properties to the resultant polymer. The mPEG-g-chitosan gel exhibits a controllable multi-stimuli responsive property. The balance between hydrophilicity and hydrophobicity is believed to confer mPEG-g-chitosan with stimuli-responsive behavior. The effect of salt concentration, solute concentration, temperature, and pH on the sol-gel transition of mPEG-g-chitosan is evaluated and the underlying mechanisms of mPEG g-chitosan polymer packing and gelation property is discussed. PMID- 25522294 TI - Multistep energy and electron transfer in a "V-configured" supramolecular BODIPY azaBODIPY-fullerene triad: mimicry of photosynthetic antenna reaction-center events. AB - A new photosynthetic antenna-reaction-center model compound composed of covalently linked BF2 -chelated dipyrromethene (BODIPY), BF2 -chelated azadipyrromethene (azaBODIPY), and fullerene (C60 ), in a "V-configuration", has been newly synthesized and characterized by using a multistep synthetic procedure. Optical absorbance and steady-state fluorescence, computational, and electrochemical studies were systematically performed in nonpolar, toluene, and polar, benzonitrile, solvents to establish the molecular integrity of the triad and to construct an energy-level diagram revealing different photochemical events. The geometry obtained by B3LYP/6-31G* calculations revealed the anticipated V-configuration of the BODIPY-azaBODIPY-C60 triad. The location of the frontier orbitals in the triad tracked the site of electron transfer determined from electrochemical studies. The different photochemical events originated from (1) BODIPY* were realized from the energy-level diagram. Accordingly, (1) BODIPY* resulted in competitive ultrafast energy transfer to produce BODIPY-(1) azaBODIPY*-C60 and electron transfer to produce BODIPY(.) (+) azaBODIPY-C60 (.) (-) as major photochemical events. The charge-separated state persisted for few nanoseconds prior populating (3) C60 *, which in turn revealed an unusual triplet-triplet energy transfer to produce (3) azaBODIPY* prior returning to the ground state. These findings delineate the importance of multimodular systems in energy harvesting, and more importantly, their utility in building multifunction performing optoelectronic devices. PMID- 25522295 TI - Reconstructing the gauge earlobe defect. AB - IMPORTANCE: The use of gauge earrings causes earlobe defects and, at times, significant contour distortion. Simple closure leads to inadequate results in most cases. We describe a stratified approach to assessing the earlobe deformity as well as specific reconstructive techniques tailored to each type of deformity to restore normal size and contour, which, to our knowledge, has not been discussed in the literature thus far. OBSERVATIONS: This case series reviewed the last 20 patients who requested earlobe reconstruction with at least 1 year of follow-up. Earlobe deformity can be classified into 3 groups: small, which can be closed primarily; medium (with radial earlobe distortion and thinning), which requires advancement flaps or wedge excisions; and large (with inferior displacement of earlobe border and vertical axis abnormalities), which requires advancement flaps and excision of redundant tissue. Excellent final earlobe appearance is usually observed at 6 months postoperatively. CONCLUSIONS AND RELEVANCE: Soft-tissue loss and contour abnormalities of medium and large defects require more complex repairs to prevent excessively narrowed lobes with loss of normal rounded contours. Obtaining a normal-appearing ear is of the utmost importance for patients who require a more professional appearance. PMID- 25522296 TI - Robust superhydrophobic silicon without a low surface-energy hydrophobic coating. AB - Superhydrophobic surfaces without low surface-energy (hydrophobic) modification such as silanization or (fluoro)polymer coatings are crucial for water-repellent applications that need to survive under harsh UV or IR exposures and mechanical abrasion. In this work, robust low-hysteresis superhydrophobic surfaces are demonstrated using a novel hierarchical silicon structure without a low surface energy coating. The proposed geometry produces superhydrophobicity out of silicon that is naturally hydrophilic. The structure is composed of collapsed silicon nanowires on top and bottom of T-shaped micropillars. Collapsed silicon nanowires cause superhydrophobicity due to nanoscale air pockets trapped below them. T shaped micropillars significantly decrease the water contact angle hysteresis because microscale air pockets are trapped between them and can not easily escape. Robustness is studied under mechanical polishing, high-energy photoexposure, high temperature, high-pressure water shower, and different acidic and solvent environments. Mechanical abrasion damages the nanowires on top of micropillars, but those at the bottom survive. Small increase of hysteresis is seen, but the surface is still superhydrophobic after abrasion. PMID- 25522297 TI - Renal impairment at presentation in multiple myeloma continues to be associated with poor survival. PMID- 25522298 TI - Targeting and microenvironment-responsive lipid nanocarrier for the enhancement of tumor cell recognition and therapeutic efficiency. AB - Poor recognition and penetration of chemotherapeutic agents in solid tumors have been recognized as one of the major challenges limiting the efficacy of cancer therapies. Folic acid and tumor microenvironment-sensitive polypeptide (TMSP) co modified lipid-nanocarrier (F/TMSP-NLC) are successfully formulated in response to the overexpression of folate receptor (FR) and the upregulation of matrix metalloproteinase-2 (MMP-2) in tumor microenvironment. The F/TMSP-NLC accumulates in tumor via the enhanced permeability and retention (EPR) effect, and folate moiety binds selectively to the FR once it reaches the tumor. In addition, cell penetrating peptide (CPP)-penetrating activity is initiated by MMP-2 protease oversecretion tumor. The specificity and efficacy of the co-modified nanocarriers to tumor are investigated in KB, HT-1080 and A549 cells in vitro. Multivalent interactions induce the enhancement of cancer cell recognition and internalization, which subsequently result in cancer cell apoptosis or death. The F/TMSP-NLC shows long-circulation effect, high accumulation in tumor, strong tumor inhibition, increased apoptotic indices, and negligible toxicity in vivo. In conclusion, the present nanocarrier modified with both TMSP and folic acid is a potential drug delivery system for tumor cell recognition and therapy, implying that using more than one target from the pool of tumor-stroma interactions is profoundly beneficial to therapeutic approaches. PMID- 25522299 TI - Highly undersampled contrast-enhanced MRA with iterative reconstruction: Integration in a clinical setting. AB - PURPOSE: To integrate, optimize, and evaluate a three-dimensional (3D) contrast enhanced sparse MRA technique with iterative reconstruction on a standard clinical MR system. METHODS: Data were acquired using a highly undersampled Cartesian spiral phyllotaxis sampling pattern and reconstructed directly on the MR system with an iterative SENSE technique. Undersampling, regularization, and number of iterations of the reconstruction were optimized and validated based on phantom experiments and patient data. Sparse MRA of the whole head (field of view: 265 * 232 * 179 mm(3) ) was investigated in 10 patient examinations. RESULTS: High-quality images with 30-fold undersampling, resulting in 0.7 mm isotropic resolution within 10 s acquisition, were obtained. After optimization of the regularization factor and of the number of iterations of the reconstruction, it was possible to reconstruct images with excellent quality within six minutes per 3D volume. Initial results of sparse contrast-enhanced MRA (CEMRA) in 10 patients demonstrated high-quality whole-head first-pass MRA for both the arterial and venous contrast phases. CONCLUSION: While sparse MRI techniques have not yet reached clinical routine, this study demonstrates the technical feasibility of high-quality sparse CEMRA of the whole head in a clinical setting. Sparse CEMRA has the potential to become a viable alternative where conventional CEMRA is too slow or does not provide sufficient spatial resolution. PMID- 25522300 TI - Dispositional mindfulness, spirituality, and substance use in predicting depressive symptoms in a treatment-seeking sample. AB - OBJECTIVE: It is imperative that research identifies factors related to depression among individuals in substance use treatment, as depression is associated with substance use relapse. Dispositional mindfulness and spirituality may bear an important role in the relationship between depression and substance use. METHOD: Using preexisting patient medical records (N = 105), the current study investigated dispositional mindfulness and spirituality in relation to depressive symptom clusters (affective, cognitive, and physiological) among men in residential substance use treatment. The mean age of the sample was 41.03 (standard deviation = 10.75). RESULTS: Findings demonstrated that dispositional mindfulness and spirituality were negatively associated with depressive symptoms. After controlling for age, alcohol use, and drug use, dispositional mindfulness remained negatively associated with all of the depression clusters. Spirituality only remained associated with the cognitive depression cluster. CONCLUSION: Mindfulness-based interventions may hold promise as an effective intervention for reducing substance use and concurrent depressive symptoms. PMID- 25522301 TI - Pressure-accelerated azide-alkyne cycloaddition: micro capillary versus autoclave reactor performance. AB - Pressure effects on regioselectivity and yield of cycloaddition reactions have been shown to exist. Nevertheless, high pressure synthetic applications with subsequent benefits in the production of natural products are limited by the general availability of the equipment. In addition, the virtues and limitations of microflow equipment under standard conditions are well established. Herein, we apply novel-process-window (NPWs) principles, such as intensification of intrinsic kinetics of a reaction using high temperature, pressure, and concentration, on azide-alkyne cycloaddition towards synthesis of Rufinamide precursor. We applied three main activation methods (i.e., uncatalyzed batch, uncatalyzed flow, and catalyzed flow) on uncatalyzed and catalyzed azide-alkyne cycloaddition. We compare the performance of two reactors, a specialized autoclave batch reactor for high-pressure operation up to 1800 bar and a capillary flow reactor (up to 400 bar). A differentiated and comprehensive picture is given for the two reactors and the three methods of activation. Reaction speedup and consequent increases in space-time yields is achieved, while the process window for favorable operation to selectively produce Rufinamide precursor in good yields is widened. The best conditions thus determined are applied to several azide-alkyne cycloadditions to widen the scope of the presented methodology. PMID- 25522303 TI - Ultrasound-guided percutaneous laser ablation in treating symptomatic solid benign thyroid nodules: Our experience in 45 patients. AB - BACKGROUND: Laser ablation may be useful in debulking of benign thyroid nodules. METHODS: In order to retrospectively evaluate the effectiveness and safety of laser ablation, 45 patients with benign solid thyroid nodules, with a fluid component <=20%, were included in our series between October 2009 and January 2011. All reported pressure and/or cosmetic complaints. Nd:YAG laser at 1064 nm was used, with a fix-power (3W), changing the application time. All patients were evaluated at baseline, 6 months, and 12 months and any complications were recorded. RESULTS: Mean nodule volume reduction decreased from 24.2 mL +/- 19.4 to 4.5 +/- 5.2 at 12 months (p < .001). Mean nodule volume reduction was 84% +/- 13. Cosmetic signs were completely resolved in 87%, reduced in 9%, unchanged in 2%, and pressure symptoms were resolved in 88%. One patient experienced transient dysphonia. CONCLUSION: Ultrasound-guided laser ablation is an effective tool for treatment of symptomatic benign thyroid nodules in patients not eligible for surgery. PMID- 25522302 TI - Genetic susceptibility testing and readiness to control weight: Results from a randomized controlled trial. AB - OBJECTIVE: To test the hypothesis that adding obesity gene feedback (FTO) to simple weight control advice at a life stage with raised risk of weight gain (university) increases readiness to control weight. METHODS: Individually randomized controlled trial comparing the effect of: (i) simple weight control advice plus FTO feedback (FA) and (ii) simple weight control advice only (AO) on readiness to engage with weight control. Differences in stage of change by genotype and differential weight control behaviors were secondary outcomes. RESULTS: Of 1,016 participants randomized, only 279 completed follow-up, yielding 90% power to detect a small effect for readiness to control weight. As predicted, FA participants were more likely to be in the contemplation stage than AO participants (P = 0.023). Participants receiving higher-risk genetic results were at a higher stage of change than controls (P = 0.003), with a trend toward a higher stage of change than those getting lower-risk results (P = 0.051). Lower risk results did not decrease weight control intentions compared with controls (P = 0.55). There were no group differences in adherence to recommended weight control behaviors (P = 0.87). CONCLUSIONS: Adding FTO feedback to weight control advice enhanced readiness to control weight, without evidence for genetic determinism, but had no more effect on behavior than weight control advice alone. PMID- 25522304 TI - Stakeholder views regarding patient discharge from intensive care: Suboptimal quality and opportunities for improvement. AB - OBJECTIVE: To provide the first description of intensive care unit (ICU) discharge practices from the perspective of Canadian ICU administrators, and ICU providers from Canada, the United States and the United Kingdom. METHODS: The authors identified 140 Canadian ICUs and administered a survey to ICU administrators (unit manager, director) to obtain an institutional perspective. Also surveyed were members of professional critical care associations in Canada, the United States and the United Kingdom, using membership distribution lists, to obtain a provider perspective. RESULTS: A total of 118 ICU administrators (114 ICUs [81%]) and 737 ICU providers (denominator unknown) responded to the survey. Administrator and provider respondents reported that ICU physicians are primarily responsible for determining the timing (70% and 77%, respectively) and safety (94% and 96%) for patients discharged from ICU. The majority of respondents indicated that patient summaries (87% and 85%) and medication reconciliation (78% and 79%) were part of their institutions' discharge process. One-half of respondents reported the use of discharge protocols, while a minority indicated that checklists (46% and 44%), electronic tools (19% and 28%) or outreach follow up (44% and 33%) were used. The majority of respondents rated current ICU discharge practices to be of medium quality (57% and 58% scored 3 on a five-point scale). Suggested opportunities for improvement included the information provided to patients and families (71% and 59%) and collaboration among hospital units (65% and 66%). CONCLUSION: Findings from the present study revealed the complexity of the ICU discharge process, considerable practice variation, perception of only medium quality and several proposed opportunities for improvement. PMID- 25522305 TI - Effectiveness of phosphodiesterase-5 inhibitor therapy for portopulmonary hypertension. AB - BACKGROUND: Portopulmonary hypertension is associated with significant morbidity and mortality. Phosphodiesterase-5 inhibitor therapy is efficacious in other causes of WHO group I pulmonary arterial hypertension. OBJECTIVE: To evaluate the efficacy and safety of phosphodiesterase-5 inhibitor therapy in patients with portopulmonary hypertension. METHODS: A single-centre retrospective cohort study that included patients with a diagnosis of portopulmonary hypertension was performed. The primary outcome was change in pulmonary vascular resistance after six months of phosphodiesterase-5 inhibitor therapy. A secondary evaluation investigated the effect on other hemodynamic measurements, 6 min walk distance, functional class, safety outcomes and survival. RESULTS: Of 1385 patients screened, 25 patients with portopulmonary hypertension were identified, of whom 20 received a phosphodiesterase-5 inhibitor. After six months, there was a significant decrease in pulmonary vascular resistance (-236 dyn * s * cm(-5) [95% CI -343 dyn * s * cm(-5) to -130 dyn * s * cm(-5)]; P<0.001), mean pulmonary artery pressure (-8.9 mmHg [95% CI -13.7 mmHg to -4.2 mmHg]; P=0.001) and an increase in Fick cardiac output (0.9 L/min [95% CI 0.1 L/min to 1.6 L/min]; P=0.02). There was no change in 6 min walk distance. The proportion of subjects with a WHO functional class III or IV was significantly reduced at six months compared with baseline (18% versus 61%; P=0.002). Safety outcomes did not reveal any adverse events. CONCLUSIONS: Phosphodiesterase-5 inhibitor therapy improved hemodynamics and functional class at six months in a cohort of patients with portopulmonary hypertension. PMID- 25522306 TI - Validity of birth certificate-derived maternal weight data in twin pregnancies. AB - Birth certificates are an important source of pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) data for surveillance and aetiologic studies, but little is known about their validity in twin pregnancies. Twins experience high rates of adverse perinatal outcomes that have been associated with BMI and GWG in singletons. Our objective was to evaluate the accuracy of birth certificate-derived pre-pregnancy BMI and GWG compared with medical record derived data in a sample of 186 twin pregnancies at a teaching hospital in Pennsylvania (2003-2010). Twelve strata were created by simultaneous stratification on pre-pregnancy BMI (underweight, normal weight/overweight, obese class 1, obese classes 2 and 3) and GWG (<20th, 20-80th, >80th percentile). The agreement of birth certificate-derived pre-pregnancy BMI category with medical record BMI category was lowest among underweight mothers [75% (95% confidence interval 51-91%) ] and highest among normal/overweight [97% (90-99%) ] and obese classes 2 and 3 mothers [97% (85-99%) ]. Agreement for GWG category from the birth certificate varied from 57% (41-70%) for GWG >80th percentile to 80% (65 91%) and 82% (72-89%) for GWG <20th and 20th-80th percentiles, respectively. The misclassification of BMI and GWG was primarily due to error in pre-pregnancy weight rather than weight at delivery or height. Agreement proportions for twins were not meaningfully different from the proportions in a comparable sample of singleton pregnancies. These data suggest that birth certificate-based BMI and GWG data are prone to error in twin pregnancies. Those who use these data should conduct internal validation studies and adjust their results using bias analyses. PMID- 25522307 TI - GWAS-Identified Common Variants With Nonalcoholic Fatty Liver Disease in Chinese Children. AB - OBJECTIVES: Three genome-wide association studies were previously done for nonalcoholic fatty liver disease (NAFLD) among individuals of Western countries and identified several genetic variants associated with NAFLD. The study aimed to identify whether 7 GWAS-identified common variants (GCKR rs780094, PDGFA rs343064, FDFT1 rs2645424, COL13A1 rs1227756, EHBP1L1 rs6591182, NCAN rs2228603, and PNPLA3 rs738409) were associated with NAFLD in Chinese children. METHODS: This case-control study recruited 1027 Chinese children of age 7 to 18 years, including 162 children with NAFLD and 865 children without NAFLD. Anthropometric measurements, alanine transaminase (ALT) detection, liver ultrasound examination, and genotyping of 7 variants were performed. RESULTS: The G-allele of PNPLA3 rs738409 was associated with NAFLD (odds ratio [OR] 1.55, 95% confidence interval 1.13-2.11, P = 0.006) and moderate-to-severe steatosis (OR 3.77, 95% confidence interval 1.78-7.98, P = 0.001) adjusted for age, sex, and BMI standard deviation score. In addition, we found each G-allele of rs738409 increased ALT level by 1.09 IU/L (P = 0.011). Subjects carrying 10 or more risk alleles of 7 variants had an OR of 4.76 (P = 0.025) for NAFLD compared with subjects carrying 3 or fewer risk alleles. CONCLUSIONS: The PNPLA3 rs738409 G-allele was associated with NAFLD and ALT level in Chinese children. It had stronger association with moderate-to-severe steatosis. Children carrying 10 or more risk alleles of 7 variants were susceptible for NAFLD. PMID- 25522309 TI - Reevaluation of acetylcholinesterase staining for the diagnosis of Hirschsprung disease and allied disorders. AB - OBJECTIVES: Acetylcholinesterase (AChE) staining has become the gold standard for definitively diagnosing Hirschsprung disease (HD), although some pitfalls have been reported. We reevaluated a large series at our institute in order to validate the accuracy of AChE staining for detecting HD. METHODS: A retrospective study of the rectal mucosal specimens of all of the children with suspected HD during a 13-year period was performed. The specimens were stained according to the modified Karnovsky-Roots method for AChE staining. The final diagnosis, prognosis, and management after the histopathological diagnosis were analyzed with a questionnaire sent to the patient's original hospital. RESULTS: Three hundred and fifty-eight specimens were collected. One hundred twenty-two (34%) specimens were diagnosed as HD, 198 (55%) as nonHD, 25 (7%) as "undetermined," and 13 (4%) as "inappropriate." The non-HD group contained 190 (96%) specimens with a normal appearance and 8 (4%) specimens with suspected intestinal neuronal dysplasia (IND). Three hundred and six of 358 questionnaires were returned. The final diagnosis showed that no specimens first diagnosed as HD were identified as non-HD and vice versa, for a sensitivity and specificity of 100%. Four cases were finally diagnosed as chronic idiopathic intestinal pseudo-obstruction (CIIP) in the non-HD group. All of the patients with HD underwent radical surgery. Most non HD patients were managed conservatively, although some continued to have constipation. CONCLUSIONS: AChE staining is an accurate tool for differentiating between HD and non-HD with high sensitivity and specificity. CIIP can be included in cases of non-HD; therefore, careful follow-up is mandatory. PMID- 25522310 TI - Satisfaction in open access versus traditional referral for upper endoscopy in children. AB - OBJECTIVES: In traditional access endoscopy (TAE), patients are booked for endoscopy following a gastroenterology clinic assessment. In contrast, open access endoscopy (OAE) patients are seen for the first time on the day of the procedure, providing same day procedural consent. Controversy exists over the use of OAE in adults, both with the consent process and with patient satisfaction. No literature exists describing satisfaction with OAE in pediatrics. We therefore aimed to assess pediatric patient and caregiver satisfaction in OAE compared with TAE. METHODS: Consecutive pediatric patients, and their caregivers, undergoing elective upper endoscopy from May to December 2012 at the Stollery Children's Hospital (Edmonton, Alberta, Canada) were consented for a cross-sectional survey. Seven preprocedure and 5 postprocedure questions were completed regarding mood and satisfaction with the wait time and the information provided. Group demographics and endoscopy wait times were collected. RESULTS: Median wait time with OAE was less compared with TAE (57 days vs 196 days, P < 0.001). OAE patients reported worse mood preprocedure than TAE patients (35.3% vs 10.7%, P = 0.046). OAE caregivers and patients reported more mood disturbance if required to wait longer for endoscopy by attending clinic preprocedure (OAE caregivers 62.2%, OAE patients 64.7%). CONCLUSIONS: OAE is associated with worse preendoscopy patient mood; however, children and caregivers seem concerned about longer wait times associated with TAE. Given the significantly shorter wait times in OAE, identifying methods to minimize present limitations of OAE will be useful to improve clinical practices in pediatric gastroenterology. PMID- 25522308 TI - Antibodies to deamidated gliadin peptide in diagnosis of celiac disease in children. AB - OBJECTIVES: Determination of antibodies to synthetic deamidated gliadin peptides (anti-DGPs) may work as an alternative or complement the commonly used test for tissue transglutaminase antibodies (TGA) in the diagnosis of celiac disease (CD). We analyzed the performance of a time-resolved immunofluorometric anti-DGP assay (TR-IFMA) in the diagnosis of CD in children and also retrospectively analyzed the appearance of anti-DGP antibodies before TGA seroconversion. METHODS: The study included 92 children with biopsy-confirmed CD. Serum samples were taken at the time or just before the clinical diagnosis. The control group comprised 82 TGA-negative children who were positive for human leucocyte antigen-DQ2 or -DQ8. RESULTS: Based on receiver operating characteristic curves, the optimal cutoff value for immunoglobulin (Ig) A anti-DGP positivity was 153 arbitrary units (AUs) with a sensitivity of 92.4% and specificity of 97.6% and that for IgG anti-DGP 119 AU, with a sensitivity of 97.8% and specificity of 97.6%. All 92 children with CD were either IgA or IgG anti-DGP positive at the time of diagnosis. Sera from 48 children with CD were also analyzed retrospectively before the diagnosis. Anti-DGP antibodies preceded TGA positivity in 35 of the 48 children with CD and appeared a median of 1 year earlier. CONCLUSIONS: The TR-IFMA assay for detecting anti-DGP antibodies shows high sensitivity and specificity for the diagnosis of CD in children. In a majority of our study population, anti-DGP seropositivity preceded TGA positivity, indicating that earlier detection of CD may be possible by monitoring anti-DGP antibodies frequently in genetically susceptible children. PMID- 25522311 TI - Phosphorus-doped graphitic carbon nitrides grown in situ on carbon-fiber paper: flexible and reversible oxygen electrodes. AB - Flexible non-metal oxygen electrodes fabricated from phosphorus-doped graphitic carbon nitride nano-flowers directly grown on carbon-fiber paper exhibit high activity and stability in reversibly catalyzing oxygen reduction and evolution reactions, which is a result of N, P dual action, enhanced mass/charge transfer, and high active surface area. The performance is comparable to that of the state of-the-art transition-metal, noble-metal, and non-metal catalysts. Remarkably, the flexible nature of these oxygen electrodes allows their use in folded and rolled-up forms, and directly as cathodes in Zn-air batteries, featuring low charge/discharge overpotential and long lifetime. PMID- 25522312 TI - Forced expression of Nanog or Esrrb preserves the ESC status in the absence of nucleostemin expression. AB - Nucleostemin (NS) is a nucleolar GTP-binding protein that is involved in a plethora of functions including ribosomal biogenesis and maintenance of telomere integrity. In addition to its expression in cancerous cells, the NS gene is expressed in stem cells including embryonic stem cells (ESCs). Previous knockdown and knockout studies have demonstrated that NS is important to preserve the self renewality and high expression levels of pluripotency marker genes in ESCs. Here, we found that forced expression of Nanog or Esrrb, but not other pluripotency factors, resulted in the dispensability of NS expression in ESCs. However, the detrimental phenotypes of ESCs associated with ablation of NS expression were not mitigated by forced expression of Rad51 or a nucleolar localization-defective NS mutant that counteracts the damage associated with loss of NS expression in other NS-expressing cells such as neural stem/progenitor cells. Thus, our results indicate that NS participates in preservation of the viability and integrity of ESCs, which is distinct from that in other NS-expressing cells. PMID- 25522313 TI - Serum IgG antibody levels to periodontal microbiota are associated with incident Alzheimer disease. AB - BACKGROUND: Periodontitis and Alzheimer disease (AD) are associated with systemic inflammation. This research studied serum IgG to periodontal microbiota as possible predictors of incident AD. METHODS: Using a case-cohort study design, 219 subjects (110 incident AD cases and 109 controls without incident cognitive impairment at last follow-up), matched on race-ethnicity, were drawn from the Washington Heights-Inwood Columbia Aging Project (WHICAP), a cohort of longitudinally followed northern Manhattan residents aged >65 years. Mean follow up was five years (SD 2.6). In baseline sera, serum IgG levels were determined for bacteria known to be positively or negatively associated with periodontitis (Porphyromonas gingivalis, Tannerella forsythia, Actinobacillus actinomycetemcomitans Y4, Treponema denticola, Campylobacter rectus, Eubacterium nodatum, and Actinomyces naeslundii genospecies-2). In all analyses, we used antibody threshold levels shown to correlate with presence of moderate-severe periodontitis. RESULTS: Mean age was 72 years (SD 6.9) for controls, and 79 years (SD 4.6) for cases (p<0.001). Non-Hispanic Whites comprised 26%, non-Hispanic Blacks 27%, and Hispanics 48% of the sample. In a model adjusting for baseline age, sex, education, diabetes mellitus, hypertension, smoking, prior history of stroke, and apolipoprotein E genotype, high anti-A. naeslundii titer (>640 ng/ml, present in 10% of subjects) was associated with increased risk of AD (HR = 2.0, 95%CI: 1.1-3.8). This association was stronger after adjusting for other significant titers (HR = 3.1, 95%CI: 1.5-6.4). In this model, high anti-E. nodatum IgG (>1755 ng/ml; 19% of subjects) was associated with lower risk of AD (HR = 0.5, 95%CI: 0.2-0.9). CONCLUSIONS: Serum IgG levels to common periodontal microbiota are associated with risk for developing incident AD. PMID- 25522314 TI - Nano- and microdelivery systems for marine bioactive lipids. AB - There is an increasing body of evidence of the positive impact of several marine lipids on human health. These compounds, which include omega-3 polyunsaturated fatty acids, have been shown to improve blood lipid profiles and exert anti inflammatory and cardioprotective effects. The high instability of these compounds to oxidative deterioration and their hydrophobicity have a drastic impact in their pharmacokinetics. Thus, the bioavailability of these compounds may be affected, resulting in their inability to reach the target sites at effective concentrations. In this regard, micro/nanoparticles can offer a wide range of solutions that can prevent the degradation of targeted molecules, increase their absorption, uptake and bioavailability. In this work we will present the options currently available concerning micro- and nanodelivery systems for marine lipids; with emphasis on micro/nanoparticles; such as micro/nanocapsules and emulsions. A wide range of bottom-up approaches using casein, chitosan, cyclodextrins, among others; will be discussed. PMID- 25522315 TI - Secocrassumol, a seco-cembranoid from the Dongsha Atoll soft coral Lobophytum crassum. AB - Chemical investigations on the Dongsha Atoll soft coral Lobophytum crassum led to the purification of a new seco-cembranoid, secocrassumol. The structural elucidation was established by extensive NMR, HRESIMS and CD data. The absolute configuration at C-12 was determined as S using a modified Mosher's acylation. Secocrassumol differs from previously known marine seco-cembranoid in that it possesses an unprecedented skeleton functionalized at C11-C12 bond cleavage. Secocrassumol showed antiviral activity against human cytomegalovirus (HCMV) with an IC50 value of 5.0 MUg/mL. PMID- 25522316 TI - Glycol chitosan-based fluorescent theranostic nanoagents for cancer therapy. AB - Theranostics is an integrated nanosystem that combines therapeutics with diagnostics in attempt to develop new personalized treatments with enhanced therapeutic efficacy and safety. As a promising therapeutic paradigm with cutting edge technologies, theranostic agents are able to simultaneously deliver therapeutic drugs and diagnostic imaging agents and also monitor the response to therapy. Polymeric nanosystems have been intensively explored for biomedical applications to diagnose and treat various cancers. In recent years, glycol chitosan-based nanoagents have been developed as dual-purpose materials for simultaneous diagnosis and therapy. They have shown great potential in cancer therapies, such as chemotherapeutics and nucleic acid and photodynamic therapies. In this review, we summarize the recent progress and potential applications of glycol chitosan-based fluorescent theranostic nanoagents for cancer treatments and discuss their possible underlying mechanisms. PMID- 25522318 TI - Anti-mycobacterial nucleoside antibiotics from a marine-derived Streptomyces sp. TPU1236A. AB - Five new nucleoside antibiotics, named streptcytosines A-E (1-5), and six known compounds, de-amosaminyl-cytosamine (6), plicacetin (7), bamicetin (8), amicetin (9), collismycin B (10), and SF2738 C (11), were isolated from a culture broth of Streptomyces sp. TPU1236A collected in Okinawa, Japan. The structures of new compounds were elucidated on the basis of their spectroscopic data (HRFABMS, IR, UV, and 2D NMR experiments including 1H-1H COSY, HMQC, HMBC, and NOESY spectra). Streptcytosine A (1) belonged to the amicetin group antibiotics, and streptcytosines B-E (2-5) were derivatives of de-amosaminyl-cytosamine (6), 2,3,6 trideoxyglucopyranosyl cytosine. Compound 1 inhibited the growth of Mycobacterium smegmatis (MIC = 32 ug/mL), while compounds 2-5 were not active at 50 ug/disc. Bamicetin (8) and amicetin (9) showed the MICs of 16 and 8 ug/mL, respectively. PMID- 25522319 TI - Territrem and butyrolactone derivatives from a marine-derived fungus Aspergillus terreus. AB - Seventeen lactones including eight territrem derivatives (1-8) and nine butyrolactone derivatives (9-17) were isolated from a marine-derived fungus Aspergillus terreus SCSGAF0162 under solid-state fermentation of rice. Compounds 1-3 and 9-10 were new, and their structures were elucidated by spectroscopic analysis. The acetylcholinesterase inhibitory activity and antiviral activity of compounds 1-17 were evaluated. Among them, compounds 1 and 2 showed strong inhibitory activity against acetylcholinesterase with IC50 values of 4.2 +/- 0.6, 4.5 +/- 0.6 nM, respectively. This is the first time it has been reported that 3, 6, 10, 12 had evident antiviral activity towards HSV-1 with IC50 values of 16.4 +/- 0.6, 6.34 +/- 0.4, 21.8 +/- 0.8 and 28.9 +/- 0.8 MUg.mL-1, respectively. Antifouling bioassay tests showed that compounds 1, 11, 12, 15 had potent antifouling activity with EC50 values of 12.9 +/- 0.5, 22.1 +/- 0.8, 7.4 +/- 0.6, 16.1 +/- 0.6 MUg.mL-1 toward barnacle Balanus amphitrite larvae, respectively. PMID- 25522317 TI - Conotoxin gene superfamilies. AB - Conotoxins are the peptidic components of the venoms of marine cone snails (genus Conus). They are remarkably diverse in terms of structure and function. Unique potency and selectivity profiles for a range of neuronal targets have made several conotoxins valuable as research tools, drug leads and even therapeutics, and has resulted in a concerted and increasing drive to identify and characterise new conotoxins. Conotoxins are translated from mRNA as peptide precursors, and cDNA sequencing is now the primary method for identification of new conotoxin sequences. As a result, gene superfamily, a classification based on precursor signal peptide identity, has become the most convenient method of conotoxin classification. Here we review each of the described conotoxin gene superfamilies, with a focus on the structural and functional diversity present in each. This review is intended to serve as a practical guide to conotoxin superfamilies and to facilitate interpretation of the increasing number of conotoxin precursor sequences being identified by targeted-cDNA sequencing and more recently high-throughput transcriptome sequencing. PMID- 25522321 TI - Simultaneous determination of non-steroidal anti-inflammatory drugs and oestrogenic hormones in environmental solid samples. AB - Pharmaceuticals are continually being released into the environment. Because of their physical and chemical properties, many of them or their bioactive metabolites can accumulate in sediments, sludge and soils, and induce adverse effects in terrestrial organisms. However, due to the very limited methods permitting the detection of these low-level concentration compounds in such complex matrices, their concentrations in natural solids remain largely unknown. In this paper, an analytical method for the simultaneous determination of thirteen pharmaceuticals (eight non-steroidal anti-inflammatory drugs and five oestrogenic hormones) in solid matrices was developed. The proposed MAE-SPE-GC MS(SIM) method has been successfully validated providing a linear response over a concentration range of 1(17)-1000(1200)ng/g, depending on the pharmaceuticals, with correlation coefficients above 0.991. The method detection limits were in the range of 0.3-5.7 ng/g, absolute recoveries above 50%, except estrone. The developed method was applied in the analysis of the target compounds in sediment, sludge and soils collected in Poland giving primary data on their concentrations in such matrices in Poland. The obtained results confirmed that the proposed method can be successfully used in the analysis of real environmental solid samples. PMID- 25522320 TI - Dissemination of cephalosporin resistance genes between Escherichia coli strains from farm animals and humans by specific plasmid lineages. AB - Third-generation cephalosporins are a class of beta-lactam antibiotics that are often used for the treatment of human infections caused by Gram-negative bacteria, especially Escherichia coli. Worryingly, the incidence of human infections caused by third-generation cephalosporin-resistant E. coli is increasing worldwide. Recent studies have suggested that these E. coli strains, and their antibiotic resistance genes, can spread from food-producing animals, via the food-chain, to humans. However, these studies used traditional typing methods, which may not have provided sufficient resolution to reliably assess the relatedness of these strains. We therefore used whole-genome sequencing (WGS) to study the relatedness of cephalosporin-resistant E. coli from humans, chicken meat, poultry and pigs. One strain collection included pairs of human and poultry associated strains that had previously been considered to be identical based on Multi-Locus Sequence Typing, plasmid typing and antibiotic resistance gene sequencing. The second collection included isolates from farmers and their pigs. WGS analysis revealed considerable heterogeneity between human and poultry associated isolates. The most closely related pairs of strains from both sources carried 1263 Single-Nucleotide Polymorphisms (SNPs) per Mbp core genome. In contrast, epidemiologically linked strains from humans and pigs differed by only 1.8 SNPs per Mbp core genome. WGS-based plasmid reconstructions revealed three distinct plasmid lineages (IncI1- and IncK-type) that carried cephalosporin resistance genes of the Extended-Spectrum Beta-Lactamase (ESBL)- and AmpC-types. The plasmid backbones within each lineage were virtually identical and were shared by genetically unrelated human and animal isolates. Plasmid reconstructions from short-read sequencing data were validated by long-read DNA sequencing for two strains. Our findings failed to demonstrate evidence for recent clonal transmission of cephalosporin-resistant E. coli strains from poultry to humans, as has been suggested based on traditional, low-resolution typing methods. Instead, our data suggest that cephalosporin resistance genes are mainly disseminated in animals and humans via distinct plasmids. PMID- 25522322 TI - Human African trypanosomiasis presenting at least 29 years after infection--what can this teach us about the pathogenesis and control of this neglected tropical disease? PMID- 25522323 TI - Different arms of the adaptive immune system induced by a combination vaccine work in concert to provide enhanced clearance of influenza. AB - Current split influenza virus vaccines that induce strain-specific neutralising antibodies provide some degree of protection against influenza infection but there is a clear need to improve their effectiveness. The constant antigenic drift of influenza viruses means that vaccines are often not an exact match to the circulating strain and so levels of relevant antibodies may not be sufficiently high to afford protection. In the situation where the emergent influenza virus is completely novel, as is the case with pandemic strains, existing vaccines may provide no benefit. In this study we tested the concept of a combination vaccine consisting of sub-optimal doses of split influenza virus vaccine mixed with a cross-protective T-cell inducing lipopeptide containing the TLR2 ligand Pam2Cys. Mice immunised with combination vaccines showed superior levels of lung viral clearance after challenge compared to either split virus or lipopeptide alone, mediated through activation of enhanced humoral and/or additional cellular responses. The mechanism of action of these vaccines was dependent on the route of administration, with intranasal administration being superior to subcutaneous and intramuscular routes, potentially through the induction of memory CD8+ T cells in the lungs. This immunisation strategy not only provides a mechanism for minimising the dose of split virus antigen but also, through the induction of cross-protective CD8+ T cells, proves a breadth of immunity to provide potential benefit upon encounter with serologically diverse influenza isolates. PMID- 25522324 TI - Phosphorescent biscyclometallated iridium(III) ethylenediamine complexes functionalised with polar ester or carboxylate groups as bioimaging and visualisation reagents. AB - We report the synthesis, characterisation and photophysical properties of new phosphorescent biscyclometallated iridium(III) ethylenediamine (en) complexes functionalised with polar ester or carboxylate groups [Ir(N^C)2(en)](n)(X) (n = +1, X = Cl(-), HN^C = methyl 4-(2-pyridyl)benzoate Hppy-COOMe (1a), methyl 2 phenyl-4-quinolinecarboxylate Hpq-COOMe (2a); n = -1, X = Li(+), HN^C = 4-(2 pyridyl)benzoate Hppy-COO(-) (1b), 2-phenyl-4-quinolinecarboxylate Hpq-COO(-) (2b)). In aqueous solutions, the carboxylate complexes 1b and 2b displayed emission quenching (ca. 7 and 74 fold, respectively) and lifetime shortening upon protonation, and their pKa values were determined to be 5.13 and 3.46, respectively. The pq complexes 2a and 2b exhibited hypsochromic shifts in their emission maxima and a significant increase in emission intensity (ca. 84 and 15 fold, respectively) upon nonspecific binding to the protein bovine serum albumin (BSA). Inductively coupled plasma-mass spectroscopy (ICP-MS) and laser-scanning confocal microscopy (LSCM) results revealed that the ester complexes 1a and 2a were efficiently internalised by the human cervix epithelioid carcinoma (HeLa) cells through energy-requiring pathways and subsequently localised in endosomes and mitochondria, respectively. They showed good biocompatibility in the dark, but became significantly cytotoxic upon photoirradiation due to the generation of singlet oxygen. In contrast, in aqueous solutions of physiological pH, the carboxylate complexes 1b and 2b existed as the anionic form and hardly entered cells due to limited membrane permeability, as evidenced by the intense emission surrounding the plasma membrane of the cells. They showed negligible cytotoxicity and the cell viability remained over 95% for an incubation period of 24 hours. In view of the low cytotoxicity and strongly emissive nature of the hydrophilic ppy COO(-) complex 1b in an aqueous medium, the potential application of the complex as a visualisation reagent has been demonstrated using zebrafish (Danio rerio) as an animal model. PMID- 25522325 TI - Universal single-probe RT-PCR assay for diagnosis of dengue virus infections. AB - BACKGROUND: Dengue is a mosquito-borne viral disease that has become more prevalent in the last few decades. Most patients are viremic when they present with symptoms, and early diagnosis of dengue is important in preventing severe clinical complications associated with this disease and also represents a key factor in differential diagnosis. Here, we designed and validated a hydrolysis probe-based one-step real-time RT-PCR assay that targets the genomes of dengue virus serotypes 1-4. METHODOLOGY/PRINCIPAL FINDINGS: The primers and probe used in our RT-PCR assay were designed to target the 3' untranslated region of all complete genome sequences of dengue virus available in GenBank (n = 3,305). Performance of the assay was evaluated using in vitro transcribed RNA, laboratory adapted virus strains, external control panels, and clinical specimens. The linear dynamic range was found to be 104-1011 GCE/mL, and the detection limit was between 6.0*102 and 1.1*103 GCE/mL depending on target sequence. The assay did not cross-react with human RNA, nor did it produce false-positive results for other human pathogenic flaviviruses or clinically important etiological agents of febrile illnesses. We used clinical serum samples obtained from returning travelers with dengue-compatible symptomatology (n = 163) to evaluate the diagnostic relevance of our assay, and laboratory diagnosis performed by the RT PCR assay had 100% positive agreement with diagnosis performed by NS1 antigen detection. In a retrospective evaluation including 60 archived serum samples collected from confirmed dengue cases 1-9 days after disease onset, the RT-PCR assay detected viral RNA up to 9 days after appearance of symptoms. CONCLUSIONS/SIGNIFICANCE: The validation of the RT-PCR assay presented here indicates that this technique can be a reliable diagnostic tool, and hence we suggest that it be introduced as the method of choice during the first 5 days of dengue symptoms. PMID- 25522327 TI - Coping with shifting nest predation refuges by European reed Warblers Acrocephalus scirpaceus. AB - Predation, the most important source of nest mortality in altricial birds, has been a subject of numerous studies during past decades. However, the temporal dynamics between changing predation pressures and parental responses remain poorly understood. We analysed characteristics of 524 nests of European reed warblers monitored during six consecutive breeding seasons in the same area, and found some support for the shifting nest predation refuge hypothesis. Nest site characteristics were correlated with nest fate, but a nest with the same nest site attributes could be relatively safe in one season and vulnerable to predation in another. Thus nest predation refuges were ephemeral and there was no between-season consistency in nest predation patterns. Reed warblers that lost their first nests in a given season did not disperse farther for the subsequent reproductive attempt, compared to successful individuals, but they introduced more changes to their second nest sites. In subsequent nests, predation risk remained constant for birds that changed nest-site characteristics, but increased for those that did not. At the between-season temporal scale, individual birds did not perform better with age in terms of reducing nest predation risk. We conclude that the experience acquired in previous years may not be useful, given that nest predation refuges are not stable. PMID- 25522328 TI - Exfoliation at the liquid/air interface to assemble reduced graphene oxide ultrathin films for a flexible noncontact sensing device. AB - Reduced graphene oxide ultrathin films are fabricated by a reproducible exfoliation method at the liquid/air interface, and they show high transparency, tunable sheet resistance, uniform electric conductivity, and structural homogeneity over a large area. A flexible relative humidity sensing matrix is demonstrated and it is shown to be excellent for close proximity sensing without touching it. This method opens up a novel avenue for future human-machine interaction applications. PMID- 25522326 TI - Molecular evolution of broadly neutralizing Llama antibodies to the CD4-binding site of HIV-1. AB - To date, no immunization of humans or animals has elicited broadly neutralizing sera able to prevent HIV-1 transmission; however, elicitation of broad and potent heavy chain only antibodies (HCAb) has previously been reported in llamas. In this study, the anti-HIV immune responses in immunized llamas were studied via deep sequencing analysis using broadly neutralizing monoclonal HCAbs as a guides. Distinct neutralizing antibody lineages were identified in each animal, including two defined by novel antibodies (as variable regions called VHH) identified by robotic screening of over 6000 clones. The combined application of five VHH against viruses from clades A, B, C and CRF_AG resulted in neutralization as potent as any of the VHH individually and a predicted 100% coverage with a median IC50 of 0.17 ug/ml for the panel of 60 viruses tested. Molecular analysis of the VHH repertoires of two sets of immunized animals showed that each neutralizing lineage was only observed following immunization, demonstrating that they were elicited de novo. Our results show that immunization can induce potent and broadly neutralizing antibodies in llamas with features similar to human antibodies and provide a framework to analyze the effectiveness of immunization protocols. PMID- 25522330 TI - Co3O4 nanoparticles decorated carbon nanofiber mat as binder-free air-cathode for high performance rechargeable zinc-air batteries. AB - An efficient, durable and low cost air-cathode is essential for a high performance metal-air battery for practical applications. Herein, we report a composite bifunctional catalyst, Co3O4 nanoparticles-decorated carbon nanofibers (CNFs), working as an efficient air-cathode in high performance rechargeable Zn air batteries (ZnABs). The particles-on-fibers nanohybrid materials were derived from electrospun metal-ion containing polymer fibers followed by thermal carbonization and a post annealing process in air at a moderate temperature. Electrochemical studies suggest that the nanohybrid material effectively catalyzes oxygen reduction reaction via an ideal 4-electron transfer process and outperforms Pt/C in catalyzing oxygen evolution reactions. Accordingly, the prototype ZnABs exhibit a low discharge-charge voltage gap (e.g. 0.7 V, discharge charge at 2 mA cm(-2)) with higher stability and longer cycle life compared to their counterparts constructed using Pt/C in air-cathode. Importantly, the hybrid nanofiber mat readily serves as an integrated air-cathode without the need of any further modification. Benefitting from its efficient catalytic activities and structural advantages, particularly the 3D architecture of highly conductive CNFs and the high loading density of strongly attached Co3O4 NPs on their surfaces, the resultant ZnABs show significantly improved performance with respect to the rate capability, cycling stability and current density, promising good potential in practical applications. PMID- 25522331 TI - Precisely Tailoring the Stoichiometric Stacking of Perylene-TCNQ Co-Crystals towards Different Nano and Microstructures with Varied Optoelectronic Performances. AB - Organic charge-transfer co-crystals with varied donor-acceptor stoichiometric ratios and molecular packing structures are controllably prepared with the morphology of nanowires or microblocks. They have distinct charge transport behavior and photoresponsivity. These interesting results pave the way for rational design and preparation of co-crystals with desired functions. PMID- 25522332 TI - Cell-penetrating and neurotargeting dendritic siRNA nanostructures. AB - We report the development of dendritic siRNA nanostructures that are able to penetrate even difficult to transfect cells such as neurons with the help of a special receptor ligand. The nanoparticles elicit strong siRNA responses, despite the dendritic structure. An siRNA dendrimer directed against the crucial rabies virus (RABV) nucleoprotein (N protein) and phosphoprotein (P protein) allowed the suppression of the virus titer in neurons below the detection limit. The cell penetrating siRNA dendrimers, which were assembled using click chemistry, open up new avenues toward finding novel molecules able to cure this deadly disease. PMID- 25522333 TI - Controlling pre-leukemic thymocyte self-renewal. PMID- 25522334 TI - Neural network study for standardizing pulse-taking depth by the width of artery. AB - To carry out a pulse diagnosis, a traditional Chinese medicine (TCM) physician presses the patient's wrist artery at three incremental depths, namely Fu (superficial), Zhong (medium), and Chen (deep). However, the definitions of the three depths are insufficiently clear for use with modern pulse diagnosis instruments (PDIs). In this paper, a quantitative method is proposed to express the pulse-taking depths based on the width of the artery (WA). Furthermore, an index, alpha, is developed for estimating WA for PDI application. The alpha value is obtained using an artificial neural network (ANN) model with contact pressure (CP) and sensor displacement (SD) as the inputs. The WA and SD data from an ultrasound instrument and CP and SD data from a PDI were analyzed. The results show that the mean prediction error and the standard deviation (STD) of the ANN model was 1.19% and 0.0467, respectively. Comparing the ANN model with the SD model by statistical method, it showed significant difference and the improvement in the mean prediction error and the STD was 71.62% and 29.78%, respectively. The alpha value can thus map WA with less individual variation than that of the values estimated directly using the SD model. Pulse signals at different depths thus can be acquired according to alpha value while using a PDI, providing TCM physicians with more reliable pulse information. PMID- 25522335 TI - Clinical activity of androgen deprivation therapy in patients with metastatic/relapsed androgen receptor-positive salivary gland cancers. AB - BACKGROUND: Androgen deprivation therapy has some clinical activity in selected salivary gland cancer histotypes, with androgen receptor expression. METHODS: We retrospectively analyzed patients with androgen receptor-expressing recurrent/metastatic salivary gland cancer, treated with androgen deprivation therapy. Protein expression of androgen receptor and ErbB family members was investigated. Progression-free survival (PFS) and overall survival (OS) were the main endpoints. RESULTS: Seventeen patients were identified. No significant toxicities were reported. Overall response rate was 64.7%; 3-year PFS and 5-year OS were 11.8% and 19.3%, respectively. Androgen receptor overexpression may be sustained by gain of chromosome X (58%) and TP53 mutation (44%). No association between response to androgen deprivation therapy and epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER)2, HER3 expression, PIK3CA mutations, or phosphatase and tensin homolog (PTEN) deletion was identified. CONCLUSION: We confirm the activity of androgen deprivation therapy in androgen receptor-expressing recurrent/metastatic salivary gland cancers. The hypothesis that an androgen receptor increased gene copy number may represent a possible mechanism of primary resistance should be further investigated. PMID- 25522336 TI - Improving chip-to-chip precision in disposable microchip capillary electrophoresis devices with internal standards. AB - To realize portable systems for routine measurements in point-of-care settings, MCE methods are required to be robust across many single-use chips. While it is well-known internal standards (ISTDs) improve run-to-run precision, a systematic investigation is necessary to determine the significance of chip-to-chip imprecision in MCE and how ISTDs account for it. This paper addresses this question by exploring the reproducibility of Na quantification across six basic, in-house fabricated microchips. A dataset of 900 electrophoerograms was collected from analyzing five concentrations of NaCl with two ISTDs (CsCl and LiCl). While both improved the peak area reproducibility, the Na/Cs ratio was superior to the Na/Li ratio (improving the RSD by a factor of 2-4, depending on the Na concentration). We attribute this to the significant variation in microchannel surface properties, which was accounted for by cesium but not lithium. Microchip dimension and detector variations were only a few percent, and could be improved through commercial fabrication over in-house made microchips. These results demonstrate that ISTDs not only correct for intrachip imprecision, but are also a viable means to correct for chip-to-chip imprecision inherent in disposable, point-of-care MCE devices. However, as expected, the internal standard must be carefully chosen. PMID- 25522337 TI - Response. PMID- 25522339 TI - Germacyclobutenes: generation by 1,1-carbalumination or 1,1-carbagallation and their photophysical properties. AB - Aluminium- and gallium-functionalised alkenylalkynylgermanes, R(1) 2 Ge(C=C-R(2) )[C{E(CMe3 )2 }=C(H)-R(2) ] (E=Al, Ga), exhibit a close contact between the coordinatively unsaturated Al or Ga atoms and the alpha-C atoms of the intact ethynyl groups. These interactions activate the Ge-C(alkynyl) bonds and favour the thermally induced insertion of these C atoms into the E-C(vinyl) bonds by means of 1,1-carbalumination or 1,1-carbagallation reactions. For the first time the latter method was shown to be a powerful alternative to known metallation processes. Germacyclobutenes with an unsaturated GeC3 heterocycle and endo- and exocyclic C=C bonds resulted from concomitant Ge-C bond formation to the beta-C atoms of the alkynyl groups. These heterocyclic compounds show an interesting photoluminescence behaviour with Stokes shifts of >110 nm. The fascinating properties are based on extended pi-delocalisation including sigma*-orbitals localised at Ge and Al. High-level quantum chemical DFT and TD-DFT calculations for an Al compound were applied to elucidate their absorption and emission properties. They revealed a biradical excited state with the transfer of a pi electron into the empty p-orbital at Al and a pyramidalisation of the metal atom. PMID- 25522338 TI - Autism spectrum disorder and particulate matter air pollution before, during, and after pregnancy: a nested case-control analysis within the Nurses' Health Study II Cohort. AB - BACKGROUND: Autism spectrum disorder (ASD) is a developmental disorder with increasing prevalence worldwide, yet has unclear etiology. OBJECTIVE: We explored the association between maternal exposure to particulate matter (PM) air pollution and odds of ASD in her child. METHODS: We conducted a nested case control study of participants in the Nurses' Health Study II (NHS II), a prospective cohort of 116,430 U.S. female nurses recruited in 1989, followed by biennial mailed questionnaires. Subjects were NHS II participants' children born 1990-2002 with ASD (n = 245), and children without ASD (n = 1,522) randomly selected using frequency matching for birth years. Diagnosis of ASD was based on maternal report, which was validated against the Autism Diagnostic Interview Revised in a subset. Monthly averages of PM with diameters <= 2.5 MUm (PM2.5) and 2.5-10 MUm (PM10-2.5) were predicted from a spatiotemporal model for the continental United States and linked to residential addresses. RESULTS: PM2.5 exposure during pregnancy was associated with increased odds of ASD, with an adjusted odds ratio (OR) for ASD per interquartile range (IQR) higher PM2.5 (4.42 MUg/m3) of 1.57 (95% CI: 1.22, 2.03) among women with the same address before and after pregnancy (160 cases, 986 controls). Associations with PM2.5 exposure 9 months before or after the pregnancy were weaker in independent models and null when all three time periods were included, whereas the association with the 9 months of pregnancy remained (OR = 1.63; 95% CI: 1.08, 2.47). The association between ASD and PM2.5 was stronger for exposure during the third trimester (OR = 1.42 per IQR increase in PM2.5; 95% CI: 1.09, 1.86) than during the first two trimesters (ORs = 1.06 and 1.00) when mutually adjusted. There was little association between PM10-2.5 and ASD. CONCLUSIONS: Higher maternal exposure to PM2.5 during pregnancy, particularly the third trimester, was associated with greater odds of a child having ASD. PMID- 25522340 TI - Ebola in children: epidemiology, clinical features, diagnosis and outcomes. AB - Ebola virus disease is caused by a highly contagious and pathogenic threadlike RNA virus of the Filoviridae family. The index human case is usually a zoonosis that launches human-to-human transmission interface with varying levels of sustainability of the epidemic depending on the level of public health preparedness of the affected country and the Ebola virus strain. The disease affects all age groups in the population. Clinical diagnosis is challenging in index cases especially in the early stages of the disease when the presenting features are usually nonspecific and only similar to a flu-like illness. However, in the agonal stages, hemorrhage frequently occurs in a high proportion of cases. The diagnostic gold standard is by detecting the antigen using reverse transcription-polymerase chain reaction. Mortality rates in the past 28 outbreaks since 1976 have ranged from 30% to 100% in different settings among adults, but lower mortality rates have been documented in children. This review aims to describe Ebola virus infection, clinical presentation, diagnosis and outcomes in children. PMID- 25522341 TI - Proteomics equipped with multiplexing toward ultra high throughput. AB - MS-based quantitative proteomics is a powerful technology to study virtually almost all biological and clinical samples. Although it has been known to be a high-throughput method, an MS analysis of a higher number of samples remains to be challenging practically and economically. In this issue, the use of multiplexing strategy for quantitative analysis of proteomes and phosphoproteomes has been demonstrated by Paulo et al. (Proteomics 2015, 15, 462-473) to better understand in vivo effects of two small molecule inhibitors on a mouse model. Within the short period of drug treatment, it has been found that the protein alteration is minimal in three tissues tested, whereas the phosphorylation level was widely altered. PMID- 25522342 TI - Delivery of mitogen-activated protein kinase inhibitor for hepatocellular carcinoma stem cell therapy. AB - Hepatocellular carcinoma (HCC) is one of the most common malignant human tumors worldwide, but no effective therapeutic options are currently available. The cancer stem cell (CSC) has proven to play a central role in the development, metastasis, and recurrence of HCC. In this study, we report a dual functional mitogen-activated protein kinase inhibitor (U0126)-based therapy for treating both bulk HCC and HCC CSCs, using poly(ethylene glycol)-b-poly(d,l-lactide) (PEG PLA) nanoparticles as the drug carrier. It is demonstrated that nanoparticle encapsulation enhanced the cell uptake of U0126 in HCC CSCs and that enhanced endocytosis lead to augmented cytotoxicity of U0126 in HCC CSCs. Moreover, the nanoparticle encapsulation increased the inhibition of self-renewal capability, prolonged the circulation time, and increased the tumor accumulation of U0126 when compared with the use of the free inhibitor. The systemic delivery of U0126 remarkably enhanced the suppression of tumor development with decreased CSCs in the HepG2 xenograft simultaneously with reduced systemic toxicity. PMID- 25522344 TI - Centrality of positive and negative deployment memories predicts posttraumatic growth in danish veterans. AB - OBJECTIVE: The purpose of the present study was to examine theoretically motivated predictors for the development of positive changes following potentially traumatic experiences (i.e., posttraumatic growth). Specifically, we wanted to examine the prediction that memories of highly negative and positive deployment events predict subsequent posttraumatic growth. METHOD: A total of 251 Danish soldiers (7% female, mean age 26.4) deployed to forward operating bases in Afghanistan filled out questionnaires before, during, and after deployment. This allowed us to perform prospective as well as cross-sectional analyses of the data. RESULTS: The main findings were that the centrality of highly emotional memories from deployment predicted growth alongside openness to experience, combat exposure, and social support. Importantly, the centrality of both positive and negative memories predicted growth equally well. CONCLUSION: The perceived importance of both negative and positive events may play an important part in the development of posttraumatic growth. PMID- 25522345 TI - Rho-associated protein kinases play an important role in the differentiation of rat adipose-derived stromal cells into cardiomyocytes in vitro. AB - Adipose-derived stromal cells (ADSCs) represent a readily available abundant supply of mesenchymal stem cells and have the ability to differentiate into cardiomyocytes in mice and human, making ADSCs a promising source of cardiomyocytes for transplantation. However, there has been no report of differentiation of rat ADSCs into cardiomyocytes. In addition, signaling pathways in the differentiation process from ADSCs to cardiomyocytes are unknown. In this study, we first demonstrated that rat ADSCs spontaneously differentiated into cardiomyocytes in vitro, when cultured on a complete medium formulation MethoCult GF M3534. These differentiated cells possessed cardiomyocyte phenotype and expressed cardiac markers. Moreover, these cells showed open excitation contracting coupling and Ca2+ transient and contracted spontaneously. The role of Rho-associated protein kinases (ROCKs) in the differentiation process was then studied by using ROCK-specific inhibitor Y-27632 and ROCK siRNAs. These agents changed the arrangement of cytoskeleton and diminished appearance of cardiomyocyte phenotype, accompanied by inhibition of c-Jun N-terminal kinase (JNK) phosphorylation and promotion of Akt phosphorylation. Collectively, this is the first study to demonstrate that rat ADSCs could spontaneously differentiate into cardiomyocytes in vitro and ROCKs play an important role in the differentiation of ADSCs into beating cardiomyocytes in conjunction of the PI3K/Akt pathway and the JNK pathway. PMID- 25522346 TI - Selective oxidation of n-butanol using gold-palladium supported nanoparticles under base-free conditions. AB - The base-free selective catalytic oxidation of n-butanol by O2 in an aqueous phase has been studied using Au-Pd bimetallic nanoparticles supported on titania. Au-Pd/TiO2 catalysts were prepared by different methods: wet impregnation, physical mixing, deposition-precipitation and sol immobilisation. The sol immobilisation technique, which used polyvinyl alcohol (PVA) as the stabilizing agent, gave the catalyst with the smallest average particle size and the highest stable activity and selectivity towards butyric acid. Increasing the amount of PVA resulted in a decrease in the size of the nanoparticles. However, it also reduced activity by limiting the accessibility of reactants to the active sites. Heating the catalyst to reflux with water at 90 degrees C for 1 h was the best method to enhance the surface exposure of the nanoparticles without affecting their size, as determined by TEM, X-ray photoelectron spectroscopy and CO chemisorption analysis. This catalyst was not only active and selective towards butyric acid but was also stable under the operating conditions. PMID- 25522343 TI - Engineering an effective Mn-binding MRI reporter protein by subcellular targeting. AB - PURPOSE: Manganese (Mn) is an effective contrast agent and biologically active metal, which has been widely used for Mn-enhanced MRI (MEMRI). The purpose of this study was to develop and test a Mn binding protein for use as a genetic reporter for MEMRI. METHODS: The bacterial Mn-binding protein, MntR was identified as a candidate reporter protein. MntR was engineered for expression in mammalian cells, and targeted to different subcellular organelles, including the Golgi Apparatus where cellular Mn is enriched. Transfected HEK293 cells and B16 melanoma cells were tested in vitro and in vivo, using immunocytochemistry, MR imaging and relaxometry. RESULTS: Subcellular targeting of MntR to the cytosol, endoplasmic reticulum and Golgi apparatus was verified with immunocytochemistry. After targeting to the Golgi, MntR expression produced robust R1 changes and T1 contrast in cells, in vitro and in vivo. Co-expression with the divalent metal transporter DMT1, a previously described Mn-based reporter, further enhanced contrast in B16 cells in culture, but in the in vivo B16 tumor model tested was not significantly better than MntR alone. CONCLUSION: This second-generation reporter system both expands the capabilities of genetically encoded reporters for imaging with MEMRI and provides important insights into the mechanisms of Mn biology which create endogenous MEMRI contrast. PMID- 25522347 TI - The weight of stigma: cortisol reactivity to manipulated weight stigma. AB - OBJECTIVE: Rates of weight-based stigmatization have steadily increased over the past decade. The psychological and physiological consequences of weight stigma remain understudied. METHODS: This study examined the effects of experimentally manipulated weight stigma on the stress-responsive hypothalamic-pituitary-adrenal axis (HPA) in 110 female undergraduate participants (BMI: M=19.30, SD=1.55). Objective BMI and self-perceived body weight were examined as moderators of the relationship between stigma and HPA reactivity. RESULTS: Results indicated participants' perceptions of their own body weight (but not objective BMI) moderated the effect of weight stigma on cortisol reactivity: F(1,102)=13.48, P<0.001, eta(2) p =0.12 (interaction 95% CI range [-2.06 to -1.44, -1.31 to 0.99]). Specifically, participants who perceived themselves as heavy exhibited sustained cortisol elevation post-manipulation compared with individuals who did not experience the weight-related stigma. Cortisol change did not vary by condition for participants who perceived themselves as average weight. CONCLUSIONS: In the first study to examine physiological consequences of active interpersonal exposure to weight stigma, experiencing weight stigma was stressful for participants who perceived themselves as heavy, regardless of their BMI. These results are important because stress and cortisol are linked to deleterious health outcomes, stimulate eating, and contribute to abdominal adiposity. PMID- 25522348 TI - Detection of Helicobacter pylori in patients with head and neck cancer: Results from a prospective comparative study combining serology, polymerase chain reaction, and rapid urease test. AB - BACKGROUND: The purpose of this study was to evaluate prospectively the presence and impact of the gastric carcinogen Helicobacter pylori (H. pylori) in the upper aerodigestive tract. Previous studies suggested it could represent a risk factor for head and neck squamous cell carcinoma (HNSCC). METHODS: Serology, rapid urease test, and quantitative polymerase chain reaction (qPCR) for H. pylori were performed in patients with head and neck cancer (N = 56) and cancer-free controls (N = 90). Comparison between groups was done using logistic regression analysis. RESULTS: Rates of positive serology and rapid urease test did not differ between the 2 groups in logistic regression analysis (p = .677 and p = .633, respectively). Birth in a developing country and age above 50 years old were predictors of positive serology (p < .001 and p = .040, respectively). Using qPCR, no biopsy showed the presence of H. pylori. CONCLUSION: This study challenges the concept that H. pylori may be a risk factor for HNSCC. PMID- 25522350 TI - Screening of non-steroidal anti-inflammatory drugs for inhibitory effects on the activities of six UDP-glucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC-MS/MS. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely to relieve pain and to decrease inflammation. Several clinical studies have reported that NSAIDs inhibit uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, the study evaluated the inhibitory potential of 15 NSAIDs on the activities of six UGT isoforms (i.e. UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes (HLMs). Among the 15 NSAIDs tested here, mefenamic acid and diclofenac inhibited all UGTs tested in this study. Piroxicam and niflumic acid inhibited UGT1A9 activity (IC50 = 73.8 MUm and 0.38 MUm, respectively) and naproxen selectively inhibited UGT2B7 activity (IC50 = 53.1 MUm), whereas it did not inhibit the other UGTs tested (IC50 > 200 MUm). Diflunisal inhibited the UGT1A1 (IC50 = 33.0 MUm) and UGT1A9 (IC50 = 19.4 MUm). Acetaminophen, fenoprofen, ibuprofen, ketoprofen, meloxicam, phenylbutazone, salicylic acid and sulindac showed negligible inhibitory effects on the six UGTs (IC50 > 100 MUm). These results suggest that some NSAIDs have the potential to inhibit UGTs in vitro. PMID- 25522351 TI - Secondary antifungal prophylaxis in pediatric hematopoietic stem cell transplants. AB - Invasive fungal infections (IFIs) constitute a leading cause of morbidity and infection-related mortality among hematopoietic stem cell transplant (HSCT) recipients. With the use of secondary prophylaxis, a history of IFI is not an absolute contraindication to allo-HSCT. However, still, IFI recurrence remains a risk factor for transplant-related mortality. In this study, of the 105 children undergoing HSCT between April 2010 and February 2013, 10 patients who had IFI history before transplantation and had undergone allo-HSCT were evaluated retrospectively to investigate results of secondary prophylaxis. In conclusion, our study shows that amphotericin B and caspofungin was successful as secondary antifungal prophylaxis agents with no relapse of IFI. In addition, after engraftment, secondary prophylaxis was continued with voriconazole orally in 4 patients that yielded good results. PMID- 25522349 TI - Multitask learning of signaling and regulatory networks with application to studying human response to flu. AB - Reconstructing regulatory and signaling response networks is one of the major goals of systems biology. While several successful methods have been suggested for this task, some integrating large and diverse datasets, these methods have so far been applied to reconstruct a single response network at a time, even when studying and modeling related conditions. To improve network reconstruction we developed MT-SDREM, a multi-task learning method which jointly models networks for several related conditions. In MT-SDREM, parameters are jointly constrained across the networks while still allowing for condition-specific pathways and regulation. We formulate the multi-task learning problem and discuss methods for optimizing the joint target function. We applied MT-SDREM to reconstruct dynamic human response networks for three flu strains: H1N1, H5N1 and H3N2. Our multi task learning method was able to identify known and novel factors and genes, improving upon prior methods that model each condition independently. The MT SDREM networks were also better at identifying proteins whose removal affects viral load indicating that joint learning can still lead to accurate, condition specific, networks. Supporting website with MT-SDREM implementation: http://sb.cs.cmu.edu/mtsdrem. PMID- 25522353 TI - Achieving single-nucleotide resolution of 5-methylcytosine detection with TALEs. AB - We report engineered transcription-activator-like effectors (TALEs) as the first DNA-binding molecules that detect 5-methylcytosine (mC) at single-nucleotide resolution with fully programmable sequence selectivity. This is achieved by a design strategy such that a single cytosine (C) in a DNA sequence is selectively interrogated for its mC-modification level by targeting with a discriminatory TALE repeat; other Cs are ignored by targeting with universal-binding TALE repeats. PMID- 25522352 TI - Canadian Orofacial Pain Team workshop report on the global year against orofacial pain. AB - The year 2013-2014 has been designated the Global Year Against Orofacial Pain by the International Association for the Study of Pain. Accordingly, a multidisciplinary Canadian and international group of clinical, research and knowledge-transfer experts attended a workshop in Montreal, Quebec. The workshop had two aims: to identify new pathways for innovative diagnosis and management of chronic orofacial pain states; and to identify opportunities for further collaborative orofacial pain research and education in Canada. Three topics related to chronic orofacial pain were explored: biomarkers and pain signatures for chronic orofacial pain; misuse of analgesic and opioid pain medications for managing chronic orofacial pain; and complementary alternative medicine, topical agents and the role of stress in chronic orofacial pain. It was determined that further research is needed to: identify biomarkers of chronic orofacial post traumatic neuropathic pain, with a focus on psychosocial, physiological and chemical-genetic factors; validate the short- and long-term safety (i.e., no harm to health, and avoidance of misuse and addiction) of opioid use for two distinct conditions (acute and chronic orofacial pain, respectively); and promote the use of topical medications as an alternative treatment in dentistry, and further document the benefits and safety of complementary and alternative medicine, including stress management, in dentistry. It was proposed that burning mouth syndrome, a painful condition that is not uncommon and affects mainly postmenopausal women, should receive particular attention. PMID- 25522354 TI - Lipid-dependent pore formation by antimicrobial peptides arenicin-2 and melittin demonstrated by their proton transfer activity. AB - This work presents a comparative study of proton transfer activity (PTA) of two cationic (+6) antimicrobial peptides, beta-structural arenicin-2 and alpha helical melittin. A new approach was proposed for the detection of passive proton transfer by using proteoliposomes containing bacteriorhodopsin, which creates a small light-induced electrochemical proton gradient ?DeltapH. Addition of several nanomoles of the peptides lowers ?DeltapH that is proximately indicative of the pore formation. The quantitative analysis of sigmoidal dependences of ?pH on the peptides concentration was carried out using liposomes prepared from PC, PC/PE, PC/PE/PI and PC/PG. Substitution of PC-containing liposomes with PE-containing ones, having negative spontaneous curvature, reduced the PTA of alpha-helical melittin and increased that of beta-structural arenicin-2. This result indicates an essential difference in the pore formation by these peptides. Further increase of PTA in response to arenicin-2 (in contrast to melittin) was observed in the liposomes prepared from PC/PE/PI. The data analysis leads to the conclusion that PTA is influenced by (i) efficiency of the pore assemblage, which depends on the structure of pore-forming peptides, and the spontaneous curvature of lipids and (ii) the presence of mobile protons in the polar head groups of phospholipids. PMID- 25522356 TI - Electric field control of the magnetocaloric effect. AB - Through strain-mediated magnetoelectric coupling, it is demonstrated that the magnetocaloric effect of a ferromagnetic shape-memory alloy can be controlled by an electric field. Large hysteresis and the limited operating temperature region are effectively overcome by applying an electric field on a laminate comprising a piezoelectric and the alloy. Accordingly, a model for an active magnetic refrigerator with high efficiency is proposed in principle. PMID- 25522355 TI - Spatiotemporal changes of CVOC concentrations in karst aquifers: analysis of three decades of data from Puerto Rico. AB - We studied the spatial and temporal distribution patterns of Chlorinated Volatile Organic Compounds (CVOCs) in the karst aquifers in northern Puerto Rico (1982 2013). Seventeen CVOCs were widely detected across the study area, with the most detected and persistent contaminated CVOCs including trichloroethylene (TCE), tetrachloroethylene (PCE), carbon tetrachloride (CT), chloroform (TCM), and methylene chloride (DCM). Historically, 471 (76%) and 319 (52%) of the 615 sampling sites have CVOC concentrations above the detection limit and maximum contamination level (MCL), respectively. The spatiotemporal patterns of the CVOC concentrations showed two clusters of contaminated areas, one near the Superfund site "Upjohn" and another near "Vega Alta Public Supply Wells." Despite a decreasing trend in concentrations, there is a general northward movement and spreading of contaminants even beyond the extent of known sources of the Superfund and landfill sites. Our analyses suggest that, besides the source conditions, karst characteristics (high heterogeneity, complex hydraulic and biochemical environment) are linked to the long-term spatiotemporal patterns of CVOCs in groundwater. PMID- 25522357 TI - Association between levels of serum ferritin and bone mineral density in Korean premenopausal and postmenopausal women: KNHANES 2008-2010. AB - BACKGROUND: As women go through menopause, serum estrogen decreases and ferritin increases. Decreased serum estrogen is well known to cause detrimental effects on bone health; however, data on the associations of serum ferritin with BMD before and after menopause are still lacking. Therefore, this study aimed to investigate the association between serum ferritin levels and BMD in premenopausal and postmenopausal Korean women. METHODS: This study was performed using data from the 2008-2010 Korean National Health and Nutrition Examination Survey, including 7300 women (4229 premenopausal and 3071 postmenopausal). BMD was measured using dual X-ray absorptiometry at the femur and the lumbar spine, and serum ferritin levels were measured by chemiluminescent immunoassay. RESULTS: Median serum ferritin levels in postmenopausal women were higher than those in premenopausal women despite the same age ranges. Serum ferritin levels were only significantly correlated with BMD on the lumbar spine (beta = -0.189, p-value = 0.005) in premenopausal women after adjusting confounding factors. Additionally, BMD on the lumbar spine had tended to decrease as serum ferritin quartiles increase (P for trend = 0.035) in premenopausal women after adjusting confounding factors. On the other hand, there were no significant associations between serum ferritin levels and BMD on the total femur and, femur neck in premenopausal women, and BMD on the total femur, femur neck, and lumbar spine in postmenopausal women. CONCLUSION: Increased serum ferritin levels were significantly associated with BMD in premenopausal women, particularly on the lumbar spine, but not in postmenopausal women. PMID- 25522359 TI - Revealing halogen bonding interactions with anomeric systems: an ab initio quantum chemical studies. AB - A computational study has been performed using MP2 and CCSD(T) methods on a series of O?X (X=Br, Cl and I) halogen bonds to evaluate the strength and characteristic of such highly directional noncovalent interactions. The study has been carried out on a series of dimeric complexes formed between interhalogen compounds (such as BrF, BrCl and BrI) and oxygen containing electron donor molecule. The existence and consequences of the anomeric effect of the electron donor molecule has also been investigated through an exploration of halogen bonding interactions in this halogen bonded complexes. The ab initio quantum chemical calculations have been employed to study both the nature and directionality of the halogen molecules toward the sp(3) oxygen atom in anomeric systems. The presence of anomeric nO->sigma*CN interaction involves a dominant role for the availability of the axial and equatorial lone pairs of donor O atom to participate with interhalogen compounds in the halogen-bonded complexes. The energy difference between the axial and equatorial conformers with interhalogen compounds reaches up to 4.60 kJ/mol, which however depends upon the interacting halogen atoms and its attaching atoms. The energy decomposition analysis further suggests that the total halogen bond interaction energies are mainly contributed by the attractive electrostatic and dispersion components. The role of substituents attached with the halogen atoms has also been evaluated in this study. With the increase of halogen atom size and the positive nature of sigma hole, the halogen atom interacted more with the electron donor atom and the electrostatic contribution to the total interaction energy enhances appreciably. Further, noncovalent interaction (NCI) studies have been carried out to locate the noncovalent halogen bonding interactions in real space. PMID- 25522358 TI - ABA-mediated ROS in mitochondria regulate root meristem activity by controlling PLETHORA expression in Arabidopsis. AB - Although research has determined that reactive oxygen species (ROS) function as signaling molecules in plant development, the molecular mechanism by which ROS regulate plant growth is not well known. An aba overly sensitive mutant, abo8-1, which is defective in a pentatricopeptide repeat (PPR) protein responsible for the splicing of NAD4 intron 3 in mitochondrial complex I, accumulates more ROS in root tips than the wild type, and the ROS accumulation is further enhanced by ABA treatment. The ABO8 mutation reduces root meristem activity, which can be enhanced by ABA treatment and reversibly recovered by addition of certain concentrations of the reducing agent GSH. As indicated by low ProDR5:GUS expression, auxin accumulation/signaling was reduced in abo8-1. We also found that ABA inhibits the expression of PLETHORA1 (PLT1) and PLT2, and that root growth is more sensitive to ABA in the plt1 and plt2 mutants than in the wild type. The expression of PLT1 and PLT2 is significantly reduced in the abo8-1 mutant. Overexpression of PLT2 in an inducible system can largely rescue root apical meristem (RAM)-defective phenotype of abo8-1 with and without ABA treatment. These results suggest that ABA-promoted ROS in the mitochondria of root tips are important retrograde signals that regulate root meristem activity by controlling auxin accumulation/signaling and PLT expression in Arabidopsis. PMID- 25522360 TI - Fear-potentiated startle during extinction is associated with white matter microstructure and functional connectivity. AB - BACKGROUND: Extinction of conditioned fear is an associative learning process that involves communication among the hippocampus, medial prefrontal cortex, and amygdala. Strength of connectivity between the hippocampus and the anterior cingulate cortex (ACC), and between the amygdala and ventromedial prefrontal cortex (vmPFC), may influence fear-potentiated startle (FPS) responses during extinction. Specific white matter tracts, the cingulum and uncinate fasciculus (UF), serve as primary routes of communication for these areas. Our objective was to investigate associations between FPS during extinction and cingulum and UF connectivity. METHOD: Diffusion tensor imaging (DTI) and probabilistic tractography analyses were used to examine cingulum and UF structural connectivity in 40 female African-Americans with psychological trauma exposure. FPS responses during fear conditioning and extinction were assessed via electromyography (EMG) of the right orbicularis oculi muscle. Secondarily, functional connectivity analyses were performed with the seed regions of interest (ROIs) used for tractography. RESULTS: A significant negative association between cingulum microstructure and FPS during early extinction (r = -.42, p = .01) and late extinction (r = -.36, p = .03) was observed after accounting for the effects of age, trauma exposure, and psychopathology (post-traumatic stress disorder symptoms); this pattern was similar for early extinction and functional connectivity between these regions (p < .05(corrected)). No significant correlations were observed between FPS and UF microstructure. CONCLUSIONS: These data indicate that structural integrity of the cingulum is directly associated with extinction learning and appears to influence functional connectivity between these regions. Decrements in cingulum microstructure may interfere with extinction learning, thereby increasing risk for the development of pathological anxiety. PMID- 25522361 TI - Using a non-image-based medium-throughput assay for screening compounds targeting N-myristoylation in intracellular Leishmania amastigotes. AB - We have refined a medium-throughput assay to screen hit compounds for activity against N-myristoylation in intracellular amastigotes of Leishmania donovani. Using clinically-relevant stages of wild type parasites and an Alamar blue-based detection method, parasite survival following drug treatment of infected macrophages is monitored after macrophage lysis and transformation of freed amastigotes into replicative extracellular promastigotes. The latter transformation step is essential to amplify the signal for determination of parasite burden, a factor dependent on equivalent proliferation rate between samples. Validation of the assay has been achieved using the anti-leishmanial gold standard drugs, amphotericin B and miltefosine, with EC50 values correlating well with published values. This assay has been used, in parallel with enzyme activity data and direct assay on isolated extracellular amastigotes, to test lead-like and hit-like inhibitors of Leishmania N-myristoyl transferase (NMT). These were derived both from validated in vivo inhibitors of Trypanosoma brucei NMT and a recent high-throughput screen against L. donovani NMT. Despite being a potent inhibitor of L. donovani NMT, the activity of the lead T. brucei NMT inhibitor (DDD85646) against L. donovani amastigotes is relatively poor. Encouragingly, analogues of DDD85646 show improved translation of enzyme to cellular activity. In testing the high-throughput L. donovani hits, we observed macrophage cytotoxicity with compounds from two of the four NMT-selective series identified, while all four series displayed low enzyme to cellular translation, also seen here with the T. brucei NMT inhibitors. Improvements in potency and physicochemical properties will be required to deliver attractive lead-like Leishmania NMT inhibitors. PMID- 25522362 TI - Membrane morphology is actively transformed by covalent binding of the protein Atg8 to PE-lipids. AB - Autophagy is a cellular degradation pathway involving the shape transformation of lipid bilayers. During the onset of autophagy, the water-soluble protein Atg8 binds covalently to phosphatdylethanolamines (PEs) in the membrane in an ubiquitin-like reaction coupled to ATP hydrolysis. We reconstituted the Atg8 conjugation system in giant and nm-sized vesicles with a minimal set of enzymes and observed that formation of Atg8-PE on giant vesicles can cause substantial tubulation of membranes even in the absence of Atg12-Atg5-Atg16. Our findings show that ubiquitin-like processes can actively change properties of lipid membranes and that membrane crowding by proteins can be dynamically regulated in cells. Furthermore we provide evidence for curvature sorting of Atg8-PE. Curvature generation and sorting are directly linked to organelle shapes and, thus, to biological function. Our results suggest that a positive feedback exists between the ubiquitin-like reaction and the membrane curvature, which is important for dynamic shape changes of cell membranes, such as those involved in the formation of autophagosomes. PMID- 25522363 TI - Functional cardiomyocytes derived from Isl1 cardiac progenitors via Bmp4 stimulation. AB - As heart failure due to myocardial infarction remains a leading cause of morbidity worldwide, cell-based cardiac regenerative therapy using cardiac progenitor cells (CPCs) could provide a potential treatment for the repair of injured myocardium. As adult CPCs may have limitations regarding tissue accessibility and proliferative ability, CPCs derived from embryonic stem cells (ESCs) could serve as an unlimited source of cells with high proliferative ability. As one of the CPCs that can be derived from embryonic stem cells, Isl1 expressing cardiac progenitor cells (Isl1-CPCs) may serve as a valuable source of cells for cardiac repair due to their high cardiac differentiation potential and authentic cardiac origin. In order to generate an unlimited number of Isl1-CPCs, we used a previously established an ESC line that allows for isolation of Isl1 CPCs by green fluorescent protein (GFP) expression that is directed by the mef2c gene, specifically expressed in the Isl1 domain of the anterior heart field. To improve the efficiency of cardiac differentiation of Isl1-CPCs, we studied the role of Bmp4 in cardiogenesis of Isl1-CPCs. We show an inductive role of Bmp directly on cardiac progenitors and its enhancement on early cardiac differentiation of CPCs. Upon induction of Bmp4 to Isl1-CPCs during differentiation, the cTnT+ cardiomyocyte population was enhanced 2.8+/-0.4 fold for Bmp4 treated CPC cultures compared to that detected for vehicle treated cultures. Both Bmp4 treated and untreated cardiomyocytes exhibit proper electrophysiological and calcium signaling properties. In addition, we observed a significant increase in Tbx5 and Tbx20 expression in differentiation cultures treated with Bmp4 compared to the untreated control, suggesting a link between Bmp4 and Tbx genes which may contribute to the enhanced cardiac differentiation in Bmp4 treated cultures. Collectively these findings suggest a cardiomyogenic role for Bmp4 directly on a pure population of Isl1 expressing cardiac progenitors, which could lead to enhancement of cardiac differentiation and engraftment, holding a significant therapeutic value for cardiac repair in the future. PMID- 25522366 TI - Electronically type-sorted carbon nanotube-based electrochemical biosensors with glucose oxidase and dehydrogenase. AB - An electrochemical enzyme biosensor with electronically type-sorted (metallic and semiconducting) single-walled carbon nanotubes (SWNTs) for use in aqueous media is presented. This research investigates how the electronic types of SWNTs influence the amperometric response of enzyme biosensors. To conduct a clear evaluation, a simple layer-by-layer process based on a plasma-polymerized nano thin film (PPF) was adopted because a PPF is an inactive matrix that can form a well-defined nanostructure composed of SWNTs and enzyme. For a biosensor with the glucose oxidase (GOx) enzyme in the presence of oxygen, the response of a metallic SWNT-GOx electrode was 2 times larger than that of a semiconducting SWNT GOx electrode. In contrast, in the absence of oxygen, the response of the semiconducting SWNT-GOx electrode was retained, whereas that of the metallic SWNT GOx electrode was significantly reduced. This indicates that direct electron transfer occurred with the semiconducting SWNT-GOx electrode, whereas the metallic SWNT-GOx electrode was dominated by a hydrogen peroxide pathway caused by an enzymatic reaction. For a biosensor with the glucose dehydrogenase (GDH; oxygen-independent catalysis) enzyme, the response of the semiconducting SWNT-GDH electrode was 4 times larger than that of the metallic SWNT-GDH electrode. Electrochemical impedance spectroscopy was used to show that the semiconducting SWNT network has less resistance for electron transfer than the metallic SWNT network. Therefore, it was concluded that semiconducting SWNTs are more suitable than metallic SWNTs for electrochemical enzyme biosensors in terms of direct electron transfer as a detection mechanism. This study makes a valuable contribution toward the development of electrochemical biosensors that employ sorted SWNTs and various enzymes. PMID- 25522364 TI - Granulocytes impose a tight bottleneck upon the gut luminal pathogen population during Salmonella typhimurium colitis. AB - Topological, chemical and immunological barriers are thought to limit infection by enteropathogenic bacteria. However, in many cases these barriers and their consequences for the infection process remain incompletely understood. Here, we employed a mouse model for Salmonella colitis and a mixed inoculum approach to identify barriers limiting the gut luminal pathogen population. Mice were infected via the oral route with wild type S. Typhimurium (S. Tm) and/or mixtures of phenotypically identical but differentially tagged S. Tm strains ("WITS", wild type isogenic tagged strains), which can be individually tracked by quantitative real-time PCR. WITS dilution experiments identified a substantial loss in tag/genetic diversity within the gut luminal S. Tm population by days 2-4 post infection. The diversity-loss was not attributable to overgrowth by S. Tm mutants, but required inflammation, Gr-1+ cells (mainly neutrophilic granulocytes) and most likely NADPH-oxidase-mediated defense, but not iNOS. Mathematical modelling indicated that inflammation inflicts a bottleneck transiently restricting the gut luminal S. Tm population to approximately 6000 cells and plating experiments verified a transient, inflammation- and Gr-1+ cell dependent dip in the gut luminal S. Tm population at day 2 post infection. We conclude that granulocytes, an important clinical hallmark of S. Tm-induced inflammation, impose a drastic bottleneck upon the pathogen population. This extends the current view of inflammation-fuelled gut-luminal Salmonella growth by establishing the host response in the intestinal lumen as a double-edged sword, fostering and diminishing colonization in a dynamic equilibrium. Our work identifies a potent immune defense against gut infection and reveals a potential Achilles' heel of the infection process which might be targeted for therapy. PMID- 25522365 TI - The application of the open pharmacological concepts triple store (open PHACTS) to support drug discovery research. AB - Integration of open access, curated, high-quality information from multiple disciplines in the Life and Biomedical Sciences provides a holistic understanding of the domain. Additionally, the effective linking of diverse data sources can unearth hidden relationships and guide potential research strategies. However, given the lack of consistency between descriptors and identifiers used in different resources and the absence of a simple mechanism to link them, gathering and combining relevant, comprehensive information from diverse databases remains a challenge. The Open Pharmacological Concepts Triple Store (Open PHACTS) is an Innovative Medicines Initiative project that uses semantic web technology approaches to enable scientists to easily access and process data from multiple sources to solve real-world drug discovery problems. The project draws together sources of publicly-available pharmacological, physicochemical and biomolecular data, represents it in a stable infrastructure and provides well-defined information exploration and retrieval methods. Here, we highlight the utility of this platform in conjunction with workflow tools to solve pharmacological research questions that require interoperability between target, compound, and pathway data. Use cases presented herein cover 1) the comprehensive identification of chemical matter for a dopamine receptor drug discovery program 2) the identification of compounds active against all targets in the Epidermal growth factor receptor (ErbB) signaling pathway that have a relevance to disease and 3) the evaluation of established targets in the Vitamin D metabolism pathway to aid novel Vitamin D analogue design. The example workflows presented illustrate how the Open PHACTS Discovery Platform can be used to exploit existing knowledge and generate new hypotheses in the process of drug discovery. PMID- 25522367 TI - Epistatic adaptive evolution of human color vision. AB - Establishing genotype-phenotype relationship is the key to understand the molecular mechanism of phenotypic adaptation. This initial step may be untangled by analyzing appropriate ancestral molecules, but it is a daunting task to recapitulate the evolution of non-additive (epistatic) interactions of amino acids and function of a protein separately. To adapt to the ultraviolet (UV)-free retinal environment, the short wavelength-sensitive (SWS1) visual pigment in human (human S1) switched from detecting UV to absorbing blue light during the last 90 million years. Mutagenesis experiments of the UV-sensitive pigment in the Boreoeutherian ancestor show that the blue-sensitivity was achieved by seven mutations. The experimental and quantum chemical analyses show that 4,008 of all 5,040 possible evolutionary trajectories are terminated prematurely by containing a dehydrated nonfunctional pigment. Phylogenetic analysis further suggests that human ancestors achieved the blue-sensitivity gradually and almost exclusively by epistasis. When the final stage of spectral tuning of human S1 was underway 45-30 million years ago, the middle and long wavelength-sensitive (MWS/LWS) pigments appeared and so-called trichromatic color vision was established by interprotein epistasis. The adaptive evolution of human S1 differs dramatically from orthologous pigments with a major mutational effect used in achieving blue sensitivity in a fish and several mammalian species and in regaining UV vision in birds. These observations imply that the mechanisms of epistatic interactions must be understood by studying various orthologues in different species that have adapted to various ecological and physiological environments. PMID- 25522368 TI - Sex differences in lateralization of semantic verbal fluency in temporal lobe epilepsy. AB - When differences exist, women tend to outperform men on measures of verbal fluency, possibly due to greater bilateral language representation. Patients with temporal lobe epilepsy (TLE) have a higher rate of atypical cortical language representation than the general population, making them a population of interest for the study of language. For the current study, 78 TLE patients (51% male, 51% left temporal focus) underwent pre-surgical neuropsychological evaluations. Retrospective data analyses investigated the impact of seizure laterality and sex on letter and semantic verbal fluency. Results indicated an interaction between sex and laterality for semantic, but not letter, verbal fluency. Males with left TLE exhibited significantly worse semantic fluency than males with right TLE, whereas females' semantic fluency did not differ by seizure focus. These data indicate that females with TLE may indeed engage in more bilateral hemispheric processing of semantic verbal fluency, whereas males may be more reliant on left temporal cortical function for this task. PMID- 25522370 TI - Electronic structure and stability of fluorophore-nitroxide radicals from ultrahigh vacuum to air exposure. AB - Thin film processes of organic radicals remain widely unknown, although these materials may have a significant technological potential. In aiming at their use in applications, we explore the electronic structure of thin films of a nitronyl nitroxide radical attached to a fluorophore core. According to our findings, this molecule maintains its radical function and, consequently, its sensing capabilities in the thin films. The films are characterized by a high structural degree of the molecular arrangement, coupled to strong vacuum and air stability that make this fluorophore-nitroxide radical an extremely promising candidate for application in electronics. Our work also identifies a quantitative correlation between the results obtained by the simultaneous use of X-ray photoemission and electron paramagnetic resonance spectroscopy. This result can be used as a standard diagnostic tool in order to link the (in situ-measured) electronic structure with classical ex situ paramagnetic investigations. PMID- 25522369 TI - Suppression of Th1-mediated autoimmunity by embryonic stem cell-derived dendritic cells. AB - We herein demonstrate the immune-regulatory effect of embryonic stem cell-derived dendritic cells (ES-DCs) using two models of autoimmune disease, namely non-obese diabetic (NOD) mice and experimental autoimmune encephalomyelitis (EAE). Treatment of pre-diabetic NOD mice with ES-DCs exerted almost complete suppression of diabetes development during the observation period for more than 40 weeks. The prevention of diabetes by ES-DCs was accompanied with significant reduction of insulitis and decreased number of Th1 and Th17 cells in the spleen. Development of EAE was also inhibited by the treatment with ES-DCs, and the therapeutic effect was obtained even if ES-DCs were administrated after the onset of clinical symptoms. Treatment of EAE-induced mice with ES-DCs reduced the infiltration of inflammatory cells into the spinal cord and suppressed the T cell response to the myelin antigen. Importantly, the ES-DC treatment did not affect T cell response to an exogenous antigen. As the mechanisms underlying the reduction of the number of infiltrating Th1 cells, we observed the inhibition of differentiation and proliferation of Th1 cells by ES-DCs. Furthermore, the expression of VLA-4alpha on Th1 cells was significantly inhibited by ES-DCs. Considering the recent advances in human induced pluripotent stem cell-related technologies, these results suggest a clinical application for pluripotent stem cell-derived dendritic cells as a therapy for T cell-mediated autoimmune diseases. PMID- 25522371 TI - Assessing the consistency and microbiological effectiveness of household water treatment practices by urban and rural populations claiming to treat their water at home: a case study in Peru. AB - BACKGROUND: Household water treatment (HWT) can improve drinking water quality and prevent disease if used correctly and consistently by vulnerable populations. Over 1.1 billion people report treating their water prior to drinking it. These estimates, however, are based on responses to household surveys that may exaggerate the consistency and microbiological performance of the practice-key factors for reducing pathogen exposure and achieving health benefits. The objective of this study was to examine how HWT practices are actually performed by households identified as HWT users, according to international monitoring standards. METHODS AND FINDINGS: We conducted a 6-month case study in urban (n = 117 households) and rural (n = 115 households) Peru, a country in which 82.8% of households report treating their water at home. We used direct observation, in depth interviews, surveys, spot-checks, and water sampling to assess water treatment practices among households that claimed to treat their drinking water at home. While consistency of reported practices was high in both urban (94.8%) and rural (85.3%) settings, availability of treated water (based on self-report) at time of collection was low, with 67.1% and 23.0% of urban and rural households having treated water at all three sampling visits. Self-reported consumption of untreated water in the home among adults and children <5 was common and this was corroborated during home observations. Drinking water of self-reported users was significantly better than source water in the urban setting and negligible but significantly better in the rural setting. However, only 46.3% and 31.6% of households had drinking water <1 CFU/100 mL at all follow-up visits. CONCLUSIONS: Our results raise questions about the usefulness of current international monitoring of HWT practices and their usefulness as a proxy indicator for drinking water quality. The lack of consistency and sub-optimal microbiological effectiveness also raises questions about the potential of HWT to prevent waterborne diseases. PMID- 25522374 TI - Strengthening new graduate nurse residency programs in critical care: recommendations from nurse residents and organizational stakeholders. AB - BACKGROUND: Thirty-four new graduate nurses participated in a critical care nurse residency program in preparation for opening a new intensive care unit. At the end of the program, multi-constituent focus groups were held to assess program effectiveness. METHOD: Participants included 34 new graduate nurses, 18 preceptors and staff nurse partners, five clinical nurse specialists, and five nurse directors. Twelve focus groups were held; groups included four to eight nurses from the same role group. Two independent reviewers analyzed recordings and transcripts of focus group content to identify themes. RESULTS: Five themes were identified: program design, developing nursing expertise, program impact on the unit, future expectations, and communication. Comments were used to guide program improvements and offer new insights for residency programs in acute and critical care. CONCLUSION: Obtaining structured input from multiple program stakeholders is beneficial in evaluating a program's impact and identifying areas for improvement. PMID- 25522373 TI - Triplet-triplet annihilation upconversion in CdS-decorated SiO2 nanocapsules for sub-bandgap photocatalysis. AB - This study reports the first successful nanoscale encapsulation of triplet triplet annihilation upconversion (TTA-UC) medium within a rigid silica shell using a self-assembly microemulsion process. These newly synthesized nanocapsules present a few critical advances that could be instrumental for a wide range of aqueous-based photonics applications, including photocatalysis, artificial photosynthesis, and bioimaging. The nanocapsules form a homogeneous suspension that can produce intense, diffuse UC emission in water without deoxygenation, closely resembling conventional TTA-UC processes that have been performed in deoxygenated organic solvents. The silica shell provides sites for further surface modification, which allows, when combined with its nanoscale dimension and structural rigidity, this TTA-UC system to acquire various useful functionalities. A benchmark TTA-UC pair, palladium(II) tetraphenyltetrabenzoporphyrin as a sensitizer and perylene as an acceptor, was used to demonstrate efficient red-to-blue (635 nm, 1.95 eV -> 470 nm, 2.6 eV) upconversion in the oxygen-rich aqueous phase. The nanocapsule surface was further functionalized with cadmium sulfide nanoparticles (Eg = 2.4 eV) to demonstrate sub-bandgap sensitization and subsequent aqueous-phase catalytic oxidation. PMID- 25522375 TI - The scholarship of application: recognizing and promoting nurses' contribution to knowledge development. AB - The generation of knowledge is fundamental to the practice of nursing and occurs through various forms of scholarship. Boyer recognized this and described knowledge production through research, integration, teaching, and application. The focus of this article is on the scholarship of application and its role in the development of nursing knowledge. Examples of achievement in the scholarship of application are provided with outcomes of work between community and education partners and innovative clinical practice changes. The scholarship of application is of particular importance to nursing as it bridges research, practice, and education, and documents and disseminates nursing knowledge to enable peer critique. Approaches for developing a climate of scholarship are discussed, including differentiating scholarly practice from clinical scholarship and how the scholarship of application is situated in practice arenas. The role of clinical scholars and clinical leaders and the continuing development of future scholars are proposed. PMID- 25522372 TI - Development of noncytotoxic chitosan-gold nanocomposites as efficient antibacterial materials. AB - This work describes the synthesis and characterization of noncytotoxic nanocomposites either colloidal or as films exhibiting high antibacterial activity. The biocompatible and biodegradable polymer chitosan was used as reducing and stabilizing agent for the synthesis of gold nanoparticles embedded in it. Herein, for the first time, three different chitosan grades varying in the average molecular weight and deacetylation degree (DD) were used with an optimized gold precursor concentration. Several factors were analyzed in order to obtain antimicrobial but not cytotoxic nanocomposite materials. Films based on chitosan with medium molecular weight and the highest DD exhibited the highest antibacterial activity against biofilm forming strains of Staphylococcus aureus and Pseudomonas aeruginosa. The resulting nanocomposites did not show any cytotoxicity against mammalian somatic and tumoral cells. They produced a disruptive effect on the bacteria wall while their internalization was hindered on the eukaryotic cells. This selectivity and safety make them potentially applicable as antimicrobial coatings in the biomedical field. PMID- 25522376 TI - Compassion fatigue resiliency training: the experience of facilitators. AB - This qualitative evaluation examined compassion fatigue facilitators' perceptions of the effects of a compassion fatigue resiliency training program in an urban medical center in the midwestern United States. Nine months after completing a compassion fatigue resiliency facilitator training program, 15 participants wrote short narratives describing how the program affected them. Participants described how the training program benefited them both personally and professionally. Two main themes were identified from the narrative analysis: self-improvement and application of resiliency. All of the participants described one or more self improvements as a result of the program, particularly in regard to emotional health. All of the participants also described how they regularly applied one or more of the resiliency skills taught in the class to improve their ability to manage stress and prevent compassion fatigue. This program shows promise in ameliorating compassion fatigue and burnout in health care providers. PMID- 25522377 TI - Enhancing midwives' scope of practice: an innovative educational program for delivery suite operating rooms. AB - BACKGROUND: This retrospective study examined the enhancement of practice, knowledge, and skill of delivery suite midwives undertaking the circulating and instrument roles during emergent caesarean sections following a tailored educational program implemented to the benchmark standard. METHOD: All midwives who attended the educational program were invited to participate (N = 48); a total of 20 responses were received. Descriptive data analysis of the bivariate nominal data was performed. RESULTS: Clinically significant outcomes were noted across all theme areas: knowledge of the Australian College of Operating Room Nurses standards, competence and knowledge of the main roles during a caesarean section, knowledge of policies and procedures, and patient safety. An improved working relationship between the perioperative and delivery ward staff also was identified. CONCLUSION: An educational program for midwives on the instrument and circulating roles for caesarean sections provides the knowledge and skill development required for clinically safe practice. PMID- 25522378 TI - DREADD: a chemogenetic GPCR signaling platform. AB - Recently, we created a family of engineered G protein-coupled receptors (GPCRs) called DREADD (designer receptors exclusively activated by designer drugs) which can precisely control three major GPCR signaling pathways (Gq, Gi, and Gs). DREADD technology has been successfully applied in a variety of in vivo studies to control GPCR signaling, and here we describe recent advances of DREADD technology and discuss its potential application in drug discovery, gene therapy, and tissue engineering. PMID- 25522379 TI - Effects of alpha-pyrrolidinopentiophenone and 4-methyl-N-ethylcathinone, two synthetic cathinones commonly found in second-generation "bath salts," on intracranial self-stimulation thresholds in rats. AB - BACKGROUND: Use of synthetic cathinones, which are designer stimulants found in "bath salts," has increased dramatically in recent years. Following governmental bans of methylenedioxypyrovalerone, mephedrone, and methylone, a second generation of synthetic cathinones with unknown abuse liability has emerged as replacements. METHODS: Using a discrete trials current intensity threshold intracranial self-stimulation procedure, the present study assessed the effects of 2 common second-generation synthetic cathinones, alpha pyrrolidinopentiophenone (0.1-5 mg/kg) and 4-methyl-N-ethcathinone (1-100 mg/kg) on brain reward function. Methamphetamine (0.1-3 mg/kg) was also tested for comparison purposes. RESULTS: Results revealed both alpha pyrrolidinopentiophenone and 4-methyl-N-ethcathinone produced significant intracranial self-stimulation threshold reductions similar to that of methamphetamine. alpha-Pyrrolidinopentiophenone (1 mg/kg) produced a significant maximal reduction in intracranial self-stimulation thresholds (~19%) most similar to maximal reductions produced by methamphetamine (1 mg/kg, ~20%). Maximal reductions in intracranial self-stimulation thresholds produced by 4-methyl-N ethcathinone were observed at 30 mg/kg (~15%) and were comparable with those observed with methamphetamine and alpha-pyrrolidinopentiophenone tested at the 0.3-mg/kg dose (~14%). Additional analysis of the ED50 values from log transformed data revealed the rank order potency of these drugs as methamphetamine ~ alpha-pyrrolidinopentiophenone>4-methyl-N-ethcathinone. CONCLUSIONS: These data suggest that the newer second-generation synthetic cathinones activate the brain reward circuitry and thus may possess a similar degree of abuse potential as prototypical illicit psychostimulants such as methamphetamine as well as the first generation synthetic cathinone methylenedioxypyrovalerone, as previously reported. PMID- 25522380 TI - Evaluation of the individual safe correction of antipsychotic agent polypharmacy in Japanese patients with chronic schizophrenia: validation of safe corrections for antipsychotic polypharmacy and the high-dose method. AB - BACKGROUND: Polypharmacy for schizophrenia treatment is not justified by the available clinical evidence. We evaluated a treatment reduction approach that reduces the dose and number of antipsychotic medications simultaneously prescribed to patients. METHODS: In a randomized open study of the Safe Correction of Antipsychotic Polypharmacy and High-Dose Prescriptions program funded by the Japanese Ministry of Health, Labour, and Welfare, we evaluated a drug reduction method consisting of a dose reduction intervention performed on 163 patients with schizophrenia for twelve or 24 weeks. One antipsychotic medication was removed each week from each patient's treatment regimen by reducing the dose by 0 to 50 chlorpromazine equivalents. Data on health-related indices of quality of life, clinical symptoms, and risk of side effects were analyzed using a two-way repeated-measures mixed linear model. RESULTS: Despite a 23% reduction in antipsychotic dose, no differences in outcomes were observed between the dose reduction and observation groups (effect size = 0.001 - 0.085, P = .24-.97), despite high statistical power (1-beta = 0.48-0.97). The findings are limited by the nonuniformity of the participants' treatment history, duration, and dose reduction amount. Dose reduction protocol patients exhibited no difference in psychotic symptoms or adverse events compared with the observation group. CONCLUSIONS: Importantly, the low dropout rate in our study (6.9% of participants withdrew because of patient factors and 23.8% for all secondary reasons) indicates that our "slowly" method is well tolerated. We hope that this approach will result in therapeutic improvements. PMID- 25522382 TI - Chronic stimulation of the tone of endogenous anandamide reduces cue- and stress induced relapse in rats. AB - BACKGROUND: The endogenous cannabinoid system plays an important role in motivation, stress, and drug abuse. Pharmacologically, the endocannabinoid system can be stimulated by either agonists of CB1 receptors or inhibition of metabolic degradation of endogenous cannabinoids and consequent increases in their brain levels. METHODS: Here, we investigated whether chronic administration during a period of withdrawal of the fatty acid amide hydrolase inhibitor URB597, which increases anandamide levels, would decrease the risks of relapse to cocaine seeking. Rats were allowed to self-administer cocaine and then they underwent forced withdrawal for 28 days, during which they were treated with URB597 or vehicle. One day after the last injection, we investigated cocaine seeking in one 6h extinction session and relapse triggered by re-exposure to drug-associated cues or a pharmacological stressor. RESULTS: We found that administration of URB597 significantly decreases cocaine-seeking behavior and cue- and stress induced relapse. CONCLUSION: These results suggest that stimulation of the endocannabinoid system could be helpful to prevent relapse to cocaine addiction. PMID- 25522381 TI - Effects of pubertal cannabinoid administration on attentional set-shifting and dopaminergic hyper-responsivity in a developmental disruption model of schizophrenia. AB - BACKGROUND: Adolescent exposure to cannabinoids in vulnerable individuals is proposed to be a risk factor for psychiatric conditions later in life, particularly schizophrenia. Evidence from studies in animals has indicated that a combination of repeated pubertal cannabinoid administration with either neonatal prefrontocortical lesion, isolation rearing, or chronic NMDA receptor antagonism administration induces enhanced schizophrenia-like behavioral disruptions. The effects of adolescent exposure to CB1 receptor agonists, however, have not been tested in a developmental disruption model of schizophrenia. METHODS: This was tested in the methylazoxymethanol (MAM) model, in which repeated treatment with the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 1.2mg/kg) was extended over 25 days throughout puberty (postnatal days 40-65) in control and MAM rats. The rats received 20 injections, which were delivered irregularly to mimic the human condition. Adult rats were tested for attentional set-shifting task and locomotor response to amphetamine, which was compared with in vivo recording from ventral tegmental area (VTA) dopamine (DA) neurons. RESULTS: MAM-treated rats showed impairment in the attentional set-shifting task, augmented locomotor response to amphetamine administration, and an increased number of spontaneously active DA neurons in the VTA. Interestingly, pubertal WIN treatment in normal animals induced similar changes at adulthood as those observed in MAM-treated rats, supporting the notion that adolescence exposure to cannabinoids may represent a risk factor for developing schizophrenia-like signs at adulthood. However, contrary to expectations, pubertal WIN administration did not exacerbate the behavioral and electrophysiological changes in MAM-treated rats beyond that observed in WIN-treated saline rats (Sal). Indeed, WIN treatment actually attenuated the locomotor response to amphetamine in MAM rats without impacting DA neuron activity states. CONCLUSIONS: Taken together, the present results indicate that the impact of cannabinoids during puberty/adolescence on schizophrenia models is more complex than may be predicted. PMID- 25522383 TI - Preclinical to clinical translation of CNS transporter occupancy of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor. AB - BACKGROUND: Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters. METHODS: We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor. RESULTS: TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD 9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC50 of 11.7 ng/mL and 50.8 ng/mL, respectively, consistent with modest selectivity for NET in vivo. Accounting for species differences in protein binding, the projected human NET and SERT plasma EC50 values were 5.5 ng/mL and 23.9 ng/mL, respectively. A single-dose, open label PET study (4-20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [(11)C]-3-amino-4- [2 [(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [(11)C]-(S,S) methylreboxetine for NET. The long pharmacokinetic half-life (30-40 h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC50 for NET was estimated to be 1.21 ng/mL, and at doses of greater than 4 mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (+/-8)% at a plasma level of 6.35 ng/mL. CONCLUSIONS: These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation. PMID- 25522385 TI - Knockdown of dopamine D2 receptors in the nucleus accumbens core suppresses methamphetamine-induced behaviors and signal transduction in mice. AB - BACKGROUND: Addictive drugs lead to reinforcing properties by increasing dopamine in the nucleus accumbens, which is composed of a core and shell regions. Neurons in the nucleus accumbens are divided into 2 subtypes based on the differential gene expression of the dopamine D1 receptors and D2 receptors. METHODS: In the present study, we investigated the role of D2 receptors in the nucleus accumbens core in behaviors and signal transduction induced by psychostimulant methamphetamine in mice that were microinjected with adeno-associated virus vectors containing a microRNA (miRNA) sequence for D2 receptor (adeno-associated virus-miD2r vectors) in the nucleus accumbens core. The adeno-associated virus vectors containing a miRNA sequence for D2 receptor-treated mice (miD2r mice) were assessed at a reduction in D2 receptor, but at no change in dopamine D1 receptor, in the nucleus accumbens core compared with the adeno-associated virus Mock vectors-treated mice (Mock mice). RESULTS: miD2r mice exhibited a reduction in hyperlocomotion that was induced by a single treatment with methamphetamine. The development of locomotor sensitization induced by repeated treatment with methamphetamine exhibited less extension in miD2r mice. In a place conditioning paradigm, the preferred effects of methamphetamine were significantly weaker in miD2r mice than in Mock mice. Furthermore, the single treatment with methamphetamine-induced phosphorylation of extracellular signal regulated kinase and cyclic adenosine monophosphate response element-binding protein in the nucleus accumbens core of miD2r mice was decreased compared with that in Mock mice. Repeated treatment with methamphetamine-induced delta FBJ murine osteosarcoma viral oncogene homolog B accumulation in the nucleus accumbens core of miD2r mice was also attenuated. CONCLUSIONS: These findings suggest that a D2 receptor-mediated neuronal pathway from the nucleus accumbens core plays an inhibitory role in the development of reinforcing properties. PMID- 25522384 TI - Familial risk for major depression is associated with lower striatal 5-HT4 receptor binding. AB - BACKGROUND: The 5-HT4 receptor provides a novel potential target for antidepressant treatment. No studies exist to elucidate the 5-HT4 receptor's in vivo distribution in the depressed state or in populations that may display trait markers for major depression disorder (MDD). The aim of this study was to determine whether familial risk for MDD is associated with cerebral 5-HT4 receptor binding as measured with [(11)C]SB207145 brain PET imaging. Familial risk is the most potent risk factor of MDD. METHODS: We studied 57 healthy individuals (mean age 36 yrs, range 20-86; 21 women), 26 of which had first degree relatives treated for MDD. RESULTS: We found that having a family history of MDD was associated with lower striatal 5-HT4 receptor binding (p = 0.038; in individuals below 40 years, p = 0.013). Further, we found evidence for a "risk dose effect" on 5-HT4 receptor binding, since the number of first-degree relatives with a history of MDD binding correlated negatively with 5-HT4 receptor binding in both the striatum (p = 0.001) and limbic regions (p = 0.012). CONCLUSIONS: Our data suggest that the 5-HT4 receptor is involved in the neurobiological mechanism underlying familial risk for depression, and that lower striatal 5-HT4 receptor binding is associated with increased risk for developing MDD. The finding is intriguing considering that the 5-HT4 receptor has been suggested to be an effective target for antidepressant treatment. PMID- 25522386 TI - Effects of risperidone on cytokine profile in drug-naive first-episode psychosis. AB - BACKGROUND: There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naive first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder. METHODS: The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-gamma, TNF alpha, and IL-17) in drug-naive FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naive FEP patients who had repeated measurements of cytokine levels and 57 healthy controls. RESULTS: We found that FEP patients had significantly higher IL-6, IL-10 and TNF-alpha levels than healthy controls. After risperidone treatment, these three cytokines and additionally IL-4 decreased significantly. No significant difference was found between the post-treatment cytokine levels in FEP patients and in healthy controls, suggesting that these alterations in cytokine profiles are a state marker of FEP. No significant association was found between risperidone-induced changes in cytokines and the clinical response to treatment or the presence of depression. There was a significant inverse association between the risperidone induced changes in IL-10 and the negative symptoms. CONCLUSIONS: In conclusion, our results show a specific cytokine profile in FEP patients (monocytic and regulatory T-cell activation) and suggest immunoregulatory effects of risperidone treatment, characterized by suppressant effects on monocytic, Th2, and T regulatory functions. PMID- 25522387 TI - Hypothalamic-pituitary-adrenal axis dysfunction and illness progression in bipolar disorder. AB - BACKGROUND: Impaired stress resilience and a dysfunctional hypothalamic-pituitary adrenal (HPA) axis are suggested to play key roles in the pathophysiology of illness progression in bipolar disorder (BD), but the mechanisms leading to this dysfunction have never been elucidated. This study aimed to examine HPA axis activity and underlying molecular mechanisms in patients with BD and unaffected siblings of BD patients. METHODS: Twenty-four euthymic patients with BD, 18 siblings of BD patients, and 26 healthy controls were recruited for this study. All subjects underwent a dexamethasone suppression test followed by analyses associated with the HPA axis and the glucocorticoid receptor (GR). RESULTS: Patients with BD, particularly those at a late stage of illness, presented increased salivary post-dexamethasone cortisol levels when compared to controls (p = 0.015). Accordingly, these patients presented reduced ex vivo GR responsiveness (p = 0.008) and increased basal protein levels of FK506-binding protein 51 (FKBP51, p = 0.012), a co-chaperone known to desensitize GR, in peripheral blood mononuclear cells. Moreover, BD patients presented increased methylation at the FK506-binding protein 5 (FKBP5) gene. BD siblings presented significantly lower FKBP51 protein levels than BD patients, even though no differences were found in FKBP5 basal mRNA levels. CONCLUSIONS: Our data suggest that the epigenetic modulation of the FKBP5 gene, along with increased FKBP51 levels, is associated with the GR hyporesponsiveness seen in BD patients. Our findings are consistent with the notion that unaffected first-degree relatives of BD patients share biological factors that influence the disorder, and that such changes are more pronounced in the late stages of the illness. PMID- 25522389 TI - A randomized controlled trial of brief and ultrabrief pulse right unilateral electroconvulsive therapy. AB - BACKGROUND: Some studies suggest better overall outcomes when right unilateral electroconvulsive therapy (RUL ECT) is given with an ultrabrief, rather than brief, pulse width. METHODS: The aim of the study was to test if ultrabrief-pulse RUL ECT results in less cognitive side effects than brief- pulse RUL ECT, when given at doses which achieve comparable efficacy. One hundred and two participants were assigned to receive ultrabrief (at 8 times seizure threshold) or brief (at 5 times seizure threshold) pulse RUL ECT in a double-blind, randomized controlled trial. Blinded raters assessed mood and cognitive functioning over the ECT course. RESULTS: Efficacy outcomes were not found to be significantly different. The ultrabrief group showed less cognitive impairment immediately after a single session of ECT, and over the treatment course (autobiographical memory, orientation). CONCLUSIONS: In summary, when ultrabrief RUL ECT was given at a higher dosage than brief RUL ECT (8 versus 5 times seizure threshold), efficacy was comparable while cognitive impairment was less. PMID- 25522388 TI - Prenatal exposure to methylphenidate affects the dopamine system and the reactivity to natural reward in adulthood in rats. AB - BACKGROUND: Methylphenidate (MPH) is a commonly-used medication for the treatment of children with Attention-Deficit/Hyperactivity Disorders (ADHD). However, its prescription to adults with ADHD and narcolepsy raises the question of how the brain is impacted by MPH exposure during pregnancy. The goal of this study was to elucidate the long-term neurobiological consequences of prenatal exposure to MPH using a rat model. METHODS: We focused on the effects of such treatment on the adult dopamine (DA) system and on the reactivity of animals to natural rewards. RESULTS: This study shows that adult male rats prenatally exposed to MPH display elevated expression of presynaptic DA markers in the DA cell bodies and the striatum. Our results also suggest that MPH-treated animals could exhibit increased tonic DA activity in the mesolimbic pathway, altered signal-to-noise ratio after a pharmacological stimulation, and decreased reactivity to the locomotor effects of cocaine. Finally, we demonstrated that MPH rats display a decreased preference and motivation for sucrose. CONCLUSIONS: This is the first preclinical study reporting long-lasting neurobiological alterations of DA networks as well as alterations in motivational behaviors for natural rewards after a prenatal exposure to MPH. These results raise concerns about the possible neurobiological consequences of MPH treatment during pregnancy. PMID- 25522390 TI - Agonist and antagonist effects of aripiprazole on D2-like receptors controlling rat brain dopamine synthesis depend on the dopaminergic tone. AB - BACKGROUND: The atypical antipsychotic drug aripiprazole binds with high affinity to a number of G protein coupled receptors, including dopamine D2 receptors, where its degree of efficacy as a partial agonist remains controversial. METHODS: We examined the properties of aripiprazole at D2-like autoreceptors by monitoring the changes of dopamine synthesis in adult rat brain striatal minces incubated ex vivo. The effects of the dopaminergic tone on the properties of aripiprazole were assayed by comparing a basal condition (2 mM K(+), low dopaminergic tone) and a stimulated condition (15 mM K(+), where dopamine release mimics a relatively higher dopaminergic tone). We also used 2 reference compounds: quinpirole showed a clear agonistic activity and preclamol (S-(-)-PPP) showed partial agonism under both basal and stimulated conditions. RESULTS: Aripiprazole under the basal condition acted as an agonist at D2-like autoreceptors and fully activated them at about 10 nM, inhibiting dopamine synthesis similarly to quinpirole. Higher concentrations of aripiprazole had effects not restricted to D2-like autoreceptor activation. Under the stimulated (15 mM K(+)) condition, nanomolar concentrations of aripiprazole failed to decrease dopamine synthesis but could totally block the effect of quinpirole. CONCLUSIONS: Under high dopaminergic tone, aripiprazole acts as a D2-like autoreceptor antagonist rather than as an agonist. These data show that, ex vivo, alteration of dopaminergic tone by depolarization affects the actions of aripiprazole on D2-like autoreceptors. Such unusual effects were not seen with the typical partial agonist preclamol and are consistent with the hypothesis that aripiprazole is a functionally selective D2R ligand. PMID- 25522391 TI - Cellular and molecular mechanisms of action of transcranial direct current stimulation: evidence from in vitro and in vivo models. AB - Transcranial direct current stimulation is a noninvasive technique that has been experimentally tested for a number of psychiatric and neurological conditions. Preliminary observations suggest that this approach can indeed influence a number of cellular and molecular pathways that may be disease relevant. However, the mechanisms of action underlying its beneficial effects are largely unknown and need to be better understood to allow this therapy to be used optimally. In this review, we summarize the physiological responses observed in vitro and in vivo, with a particular emphasis on cellular and molecular cascades associated with inflammation, angiogenesis, neurogenesis, and neuroplasticity recruited by direct current stimulation, a topic that has been largely neglected in the literature. A better understanding of the neural responses to transcranial direct current stimulation is critical if this therapy is to be used in large-scale clinical trials with a view of being routinely offered to patients suffering from various conditions affecting the central nervous system. PMID- 25522392 TI - Primate phencyclidine model of schizophrenia: sex-specific effects on cognition, brain derived neurotrophic factor, spine synapses, and dopamine turnover in prefrontal cortex. AB - BACKGROUND: Cognitive deficits are a core symptom of schizophrenia, yet they remain particularly resistant to treatment. The model provided by repeatedly exposing adult nonhuman primates to phencyclidine has generated important insights into the neurobiology of these deficits, but it remains possible that administration of this psychotomimetic agent during the pre-adult period, when the dorsolateral prefrontal cortex in human and nonhuman primates is still undergoing significant maturation, may provide a greater understanding of schizophrenia-related cognitive deficits. METHODS: The effects of repeated phencyclidine treatment on spine synapse number, dopamine turnover and BDNF expression in dorsolateral prefrontal cortex, and working memory accuracy were examined in pre-adult monkeys. RESULTS: One week following phencyclidine treatment, juvenile and adolescent male monkeys demonstrated a greater loss of spine synapses in dorsolateral prefrontal cortex than adult male monkeys. Further studies indicated that in juvenile males, a cognitive deficit existed at 4 weeks following phencyclidine treatment, and this impairment was associated with decreased dopamine turnover, decreased brain derived neurotrophic factor messenger RNA, and a loss of dendritic spine synapses in dorsolateral prefrontal cortex. In contrast, female juvenile monkeys displayed no cognitive deficit at 4 weeks after phencyclidine treatment and no alteration in dopamine turnover or brain derived neurotrophic factor messenger RNA or spine synapse number in dorsolateral prefrontal cortex. In the combined group of male and female juvenile monkeys, significant linear correlations were detected between dopamine turnover, spine synapse number, and cognitive performance. CONCLUSIONS: As the incidence of schizophrenia is greater in males than females, these findings support the validity of the juvenile primate phencyclidine model and highlight its potential usefulness in understanding the deficits in dorsolateral prefrontal cortex in schizophrenia and developing novel treatments for the cognitive deficits associated with schizophrenia. PMID- 25522393 TI - A single brain-derived neurotrophic factor infusion into the dorsomedial prefrontal cortex attenuates cocaine self-administration-induced phosphorylation of synapsin in the nucleus accumbens during early withdrawal. AB - BACKGROUND: Dysregulation in the prefrontal cortex-nucleus accumbens pathway has been implicated in cocaine addiction. We have previously demonstrated that one intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor (BDNF) infusion immediately following the last cocaine self-administration session caused a long-lasting inhibition of cocaine-seeking and normalized the cocaine induced disturbance of glutamate transmission in the nucleus accumbens after extinction and a cocaine prime. However, the molecular mechanism mediating the brain-derived neurotrophic factor effect on cocaine-induced alterations in extracellular glutamate levels is unknown. METHODS: In the present study, we determined the effects of brain-derived neurotrophic factor on cocaine-induced changes in the phosphorylation of synapsin (p-synapsin), a family of presynaptic proteins that mediate synaptic vesicle mobilization, in the nucleus accumbens during early withdrawal. RESULTS: Two hours after cocaine self-administration, p synapsin Ser9 and p-synapsin Ser62/67, but not p-synapsin Ser603, were increased in the nucleus accumbens. At 22 hours, only p-synapsin Ser9 was still elevated. Elevations at both time points were attenuated by an intra-dorsomedial prefrontal cortex brain-derived neurotrophic factor infusion immediately after the end of cocaine self-administration. Brain-derived neurotrophic factor also reduced cocaine self-administration withdrawal-induced phosphorylation of the protein phosphatase 2A C-subunit, suggesting that brain-derived neurotrophic factor disinhibits protein phosphatase 2A C-subunit, consistent with p-synapsin Ser9 dephosphorylation. Further, co-immunoprecipitation demonstrated that protein phosphatase 2A C-subunit and synapsin are associated in a protein-protein complex that was reduced after 2 hours of withdrawal from cocaine self-administration and reversed by brain-derived neurotrophic factor. CONCLUSIONS: Taken together, these findings demonstrate that brain-derived neurotrophic factor normalizes the cocaine self-administration-induced elevation of p-synapsin in nucleus accumbens that may underlie a disturbance in the probability of neurotransmitter release or represent a compensatory neuroadaptation in response to the hypofunction within the prefrontal cortex-nucleus accumbens pathway during cocaine withdrawal. PMID- 25522394 TI - Restoration of serotonin neuronal firing following long-term administration of bupropion but not paroxetine in olfactory bulbectomized rats. AB - BACKGROUND: Olfactory bulbectomized rats generally manifest many of the neurochemical, physiological, and behavioral features of major depressive disorder in humans. Another interesting feature of this model is that it responds to chronic but not acute antidepressant treatments, including selective serotonin reuptake inhibitors. The purpose of the present study was first to characterize the firing activity of dorsal raphe serotonin neurons in olfactory bulbectomized rats and then examine the effects of 2 antidepressants, bupropion and paroxetine. METHODS: Olfactory bulbectomy was performed by aspirating olfactory bulbs in anesthetized rats. Vehicle and drugs were delivered for 2 and 14 days via subcutaneously implanted minipumps. In vivo electrophysiological recordings were carried out in male anesthetized Sprague-Dawley rats. RESULTS: Following ablation of olfactory bulbs, the firing rate of serotonin neurons was decreased by 36%, leaving those of norepinephrine and dopamine neurons unchanged. In olfactory bulbectomized rats, bupropion (30 mg/kg/d) restored the firing rate of serotonin neurons to the control level following 2- and 14-day administration and also induced an increase in the tonic activation of serotonin(1A) receptors; paroxetine (10 mg/kg/d) did not result in a return to normal of the attenuated firing of serotonin neurons in olfactory bulbectomized rats. In the hippocampus, although at a higher dose of WAY 100635 than that required in bupropion-treated animals, paroxetine administration also resulted in an increase in the tonic activation of serotonin(1A) receptors. CONCLUSIONS: The present results indicate that unlike paroxetine, bupropion administration normalized serotonin neuronal activity and increased tonic activation of the serotonin(1A) receptors in hippocampus. PMID- 25522395 TI - Oxytocin affects the connectivity of the precuneus and the amygdala: a randomized, double-blinded, placebo-controlled neuroimaging trial. AB - BACKGROUND: Although oxytocin is one of the most widely studied neuropeptides in recent times, the mechanistic process by which it modulates social-affective behavior in the brain is not yet clearly understood. Thus, to understand the neurophysiological basis of oxytocin effects, we used resting-state functional MRI to examine the effects of intranasal oxytocin on brain connectivity in healthy males. METHODS: Using a randomized, double-blinded, placebo-controlled, crossover design, 15 healthy male volunteers received 24 IU intranasal oxytocin or placebo prior to resting-state functional MRI acquisition at 3T. RESULTS: We found that oxytocin significantly reduced the degree centrality of the right precuneus (P<.05). Oxytocin also reduced connectivity between the bilateral amygdalae and between the right precuneus and the right and left amygdala (P<.05). Although there were no significant changes in regional homogeneity at the whole brain level, posthoc results showed a reduction involving the right precuneus (P<.05). CONCLUSIONS: These results show that oxytocin affects one of the key centers in the brain for social cognition and introspective processing, the precuneus, and enhances our understanding of how oxytocin can modulate brain networks at rest. An improved understanding of the neurophysiological effects of oxytocin can be important in terms of evaluating the mechanisms that are likely to underlie the clinical responses observed upon long-term oxytocin administration. PMID- 25522397 TI - Prenatal nutritional deficiency reprogrammed postnatal gene expression in mammal brains: implications for schizophrenia. AB - BACKGROUND: Epidemiological studies have identified prenatal exposure to famine as a risk factor for schizophrenia, and animal models of prenatal malnutrition display structural and functional brain abnormalities implicated in schizophrenia. METHODS: The offspring of the RLP50 rat, a recently developed animal model of prenatal famine malnutrition exposure, was used to investigate the changes of gene expression and epigenetic modifications in the brain regions. Microarray gene expression analysis was carried out in the prefrontal cortex and the hippocampus from 8 RLP50 offspring rats and 8 controls. MBD-seq was used to test the changes in DNA methylation in hippocampus depending on prenatal malnutrition exposure. RESULTS: In the prefrontal cortex, offspring of RLP50 exhibit differences in neurotransmitters and olfactory-associated gene expression. In the hippocampus, the differentially-expressed genes are related to synaptic function and transcription regulation. DNA methylome profiling of the hippocampus also shows widespread but systematic epigenetic changes; in most cases (87%) this involves hypermethylation. Remarkably, genes encoded for the plasma membrane are significantly enriched for changes in both gene expression and DNA methylome profiling screens (p = 2.37*10(-9) and 5.36*10(-9), respectively). Interestingly, Mecp2 and Slc2a1, two genes associated with cognitive impairment, show significant down-regulation, and Slc2a1 is hypermethylated in the hippocampus of the RLP50 offspring. CONCLUSIONS: Collectively, our results indicate that prenatal exposure to malnutrition leads to the reprogramming of postnatal brain gene expression and that the epigenetic modifications contribute to the reprogramming. The process may impair learning and memory ability and result in higher susceptibility to schizophrenia. PMID- 25522396 TI - Blunted autonomic reactivity to pharmacological panic challenge under long-term escitalopram treatment in healthy men. AB - BACKGROUND: Central serotonergic pathways influence brain areas involved in vagal cardiovascular regulation and, thereby, influence sympathetic efferent activity. Selective serotonin reuptake inhibitors (SSRIs) affect multiple serotonergic pathways, including central autonomic pathways. However, only a few studies have assessed SSRI-mediated effects on autonomic reactivity in healthy individuals using heart rate variability (HRV). METHODS: The present study assessed the influence of long-term treatment with escitalopram (ESC) on autonomic reactivity to an intravenous application of 50 ug cholecystokinin tetrapeptide (CCK-4) in 30 healthy young men using a double-blind, placebo (PLA)-controlled, randomized, within-subject cross-over design. Main outcome measures were time- and frequency domain HRV parameters, assessed at both baseline and immediately after CCK-4 application. RESULTS: Results showed substantial effects for the treatment * CCK 4 challenge interaction with respect to heart rate (p < 0.001; peta(2) = 0.499), SDNN (p < 0.001; peta(2) = 576), RMSSD (p = 0.015; peta(2) = 194), NN50% (p = 0.008; peta(2) = 0.224), and LF% (p = 0.014; peta(2) = 0.196), and moderate effects with respect HF% (p = 0.099; peta(2) = 0.094), with PLA subjects showing a higher increase in HR and SDNN and a higher decrease in RMSSD, NN50, LF and HF than subjects in the ESC condition. Thus, ESC treatment significantly blunted the autonomic reactivity to CCK-4. Secondary analysis indicated no effect of the 5 HTTLPR polymorphism on CCK-4-induced autonomic response. CONCLUSIONS: Our results support findings suggesting an effect of SSRI treatment on autonomic regulation and provide evidence that ESC treatment is associated with blunted autonomic reactivity in healthy men. PMID- 25522398 TI - 5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidence. AB - BACKGROUND: Desensitization and blockade of 5-HT2C receptors (5-HT2CR) have long been thought to be central in the therapeutic action of antidepressant drugs. However, besides behavioral pharmacology studies, there is little in vivo data documenting antidepressant-induced 5-HT2CR desensitization in specific brain areas. METHODS: Mice lacking the 5-HT reuptake carrier (5-HTT(-/-)) were used to model the consequences of chronic 5-HT reuptake inhibition with antidepressant drugs. The effect of this mutation on 5-HT2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding, and 5-HT2CR-induced hypolocomotion tests), the neurochemical, and the cellular (RT-qPCR, mRNA editing, and c-fos-induced expression) levels. RESULTS: Although 5-HTT(-/-) mice had an anxiogenic profile in the novelty-suppressed feeding test, they displayed less 5-HT2CR-mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT2CR-mediated inhibition of a stress-induced increase in 5-HT turnover, measured in various brain areas, was markedly reduced in 5-HTT(-/-) mutants. These indices of tolerance to 5-HT2CR stimulation were associated neither with altered levels of 5-HT2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c fos mRNA production in cells expressing 5-HT2CR was higher in 5-HTT(-/-) mutants, suggesting an altered basal activity of these cells following sustained 5-HT reuptake carrier inactivation. Furthermore, the increased c-fos mRNA expression in 5-HT2CR-like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT2CR agonist RO-60,0175 was absent in 5-HTT(-/-) mutants. CONCLUSIONS: Such blunted responsiveness of the 5-HT2CR system, observed at the cell signaling level, probably contributes to the moderation of the anxiety phenotype in 5-HTT(-/-) mice. PMID- 25522399 TI - Bimodal effect of lithium plasma levels on hippocampal glutamate concentrations in bipolar II depression: a pilot study. AB - BACKGROUND: The hippocampus has been highly implicated in the pathophysiology of bipolar disorder (BD). Nevertheless, no study has longitudinally evaluated hippocampal metabolite levels in bipolar depression under treatment with lithium. METHODS: Nineteen medication-free BD patients (78.9% treatment-naive and 73.7% with BD type II) presenting an acute depressive episode and 17 healthy controls were studied. Patients were treated for 6 weeks with lithium in an open-label trial. N-acetyl aspartate (NAA), creatine, choline, myo-Inositol, and glutamate levels were assessed in the left hippocampus before (week 0) and after (week 6) lithium treatment using 3T proton magnetic resonance spectroscopy (1H-MRS). The metabolite concentrations were estimated using internal water as reference and voxel segmentation for partial volume correction. RESULTS: At baseline, acutely depressed BD patients and healthy controls exhibited similar hippocampal metabolites concentrations, with no changes after 6 weeks of lithium monotherapy. A significant correlation between antidepressant efficacy and increases in NAA concentration over time was observed. Also, there was a significant positive correlation between the changes in glutamate concentrations over follow-up and plasma lithium levels at endpoint. Mixed effects model analysis revealed a bimodal effect of lithium plasma levels in hippocampal glutamate concentrations: levels of 0.2 to 0.49 mmol/L (n=9) were associated with a decrease in glutamate concentrations, whereas the subgroup of BD subjects with "standard" lithium levels (>= 0.50 mmol/L; n = 10) showed an overall increase in glutamate concentrations over time. CONCLUSIONS: These preliminary results suggest that lithium has a bimodal action in hippocampal glutamate concentration depending on the plasma levels. PMID- 25522400 TI - Glutamatergic neurometabolites during early abstinence from chronic methamphetamine abuse. AB - BACKGROUND: The acute phase of abstinence from methamphetamine abuse is critical for rehabilitation success. Proton magnetic resonance spectroscopy has detected below-normal levels of glutamate+glutamine in anterior middle cingulate of chronic methamphetamine abusers during early abstinence, attributed to abstinence induced downregulation of the glutamatergic systems in the brain. This study further explored this phenomenon. METHODS: We measured glutamate+glutamine in additional cortical regions (midline posterior cingulate, midline precuneus, and bilateral inferior frontal cortex) putatively affected by methamphetamine. We examined the relationship between glutamate+glutamine in each region with duration of methamphetamine abuse as well as the depressive symptoms of early abstinence. Magnetic resonance spectroscopic imaging was acquired at 1.5 T from a methamphetamine group of 44 adults who had chronically abused methamphetamine and a control group of 23 age-, sex-, and tobacco smoking-matched healthy volunteers. Participants in the methamphetamine group were studied as inpatients during the first week of abstinence from the drug and were not receiving treatment. RESULTS: In the methamphetamine group, small but significant (5-15%, P<.05) decrements (vs control) in glutamate+glutamine were observed in posterior cingulate, precuneus, and right inferior frontal cortex; glutamate+glutamine in posterior cingulate was negatively correlated (P<.05) with years of methamphetamine abuse. The Beck Depression Inventory score was negatively correlated (P<.005) with glutamate+glutamine in right inferior frontal cortex. CONCLUSIONS: Our findings support the idea that glutamatergic metabolism is downregulated in early abstinence in multiple cortical regions. The extent of downregulation may vary with length of abuse and may be associated with severity of depressive symptoms emergent in early recovery. PMID- 25522401 TI - Effects of the trace amine associated receptor 1 agonist RO5263397 on abuse related behavioral indices of methamphetamine in rats. AB - BACKGROUND: Methamphetamine is a major drug of abuse with no effective pharmacotherapy available. Trace amine associated receptor 1 is implicated in cocaine addiction and represents a potential therapeutic target. However, the effects of trace amine associated receptor 1 agonists on addiction-related behavioral effects of methamphetamine are unknown. METHODS: This study examined the effects of a trace amine associated receptor 1 agonist RO5263397 on methamphetamine-induced behavioral sensitization, methamphetamine self administration, cue- and methamphetamine-induced reinstatement of drug seeking, and cue-induced reinstatement of sucrose-seeking behaviors in rats. Male Sprague Dawley rats were used to examine the effects of methamphetamine alone and in combination with the trace amine associated receptor 1 agonist RO5263397 (3.2 10mg/kg). RESULTS: RO5263397 dose-dependently attenuated the expression of behavioral sensitization to methamphetamine, reduced methamphetamine self administration, and decreased both cue- and a priming dose of methamphetamine induced reinstatement of drug-seeking behaviors. However, RO5263397 did not alter cue-induced reinstatement of sucrose-seeking behavior. CONCLUSIONS: Taken together, trace amine associated receptor 1 agonists attenuate some abuse-related behavioral effects of methamphetamine, strongly suggesting that drugs activating trace amine associated receptor 1 may be potentially useful for the treatment of methamphetamine addiction and warrant further studies. PMID- 25522402 TI - Lurasidone exerts antidepressant properties in the chronic mild stress model through the regulation of synaptic and neuroplastic mechanisms in the rat prefrontal cortex. AB - BACKGROUND: Major depression is associated with several alterations, including reduced neuronal plasticity and impaired synaptic function, which represent an important target of pharmacological intervention. METHODS: In the present study, we have investigated the ability of the antipsychotic drug lurasidone to modulate behavioral and neuroplastic alterations in the chronic mild stress model of depression. RESULTS: Rats that show reduced sucrose consumption after 2 weeks of chronic mild stress have reduced expression of the pool of Bdnf transcripts with the long 3' untranslated region (3'-UTR) that may be targeted to the synaptic compartment, suggesting the contribution of the neurotrophin to the behavioral dysfunction produced by chronic mild stress. The downregulation of Bdnf expression persisted also after 7 weeks of chronic mild stress, whereas chronic lurasidone treatment improved anhedonia in chronic mild stress rats and restored Bdnf mRNA levels in the prefrontal cortex. Moreover, chronic lurasidone treatment was able to normalize chronic mild stress-induced defects of Psd95 and Gfap as well as changes in molecular regulators of protein translation at the synapse, including mTOR and eEF2. CONCLUSIONS: These results demonstrate that lurasidone shows antidepressant properties in the chronic mild stress model through the modulation of synaptic and neuroplastic proteins. Such changes may contribute to the amelioration of functional capacities, which are deteriorated in patients with major depression and stress-related disorders. PMID- 25522403 TI - Effects of Silexan on the serotonin-1A receptor and microstructure of the human brain: a randomized, placebo-controlled, double-blind, cross-over study with molecular and structural neuroimaging. AB - BACKGROUND: Recently, Silexan, a patented active substance comprised of an essential oil produced from Lavandula angustifolia flowers, has been authorized in Germany as a medicinal product for the treatment of states of restlessness related to anxious mood. Its efficacy has been shown in several forms of anxiety disorders. Findings from preclinical and clinical studies attribute a major role to the serotonin-1A receptor in the pathogenesis and treatment of anxiety. METHODS: To elucidate the effect of Silexan on serotonin-1A receptor binding, 17 healthy men underwent 2 positron emission tomography measurements using the radioligand [carbonyl-(11)C]WAY-100635 following the daily intake of 160 mg Silexan or placebo for a minimum of 8 weeks (randomized, double-blind, cross-over design). Additionally, structural magnetic resonance imaging and voxel-based morphometry analysis was performed to determine potential effects on gray matter microstructure. RESULTS: Serotonin-1A receptor binding potential was shown to be significantly reduced following the intake of Silexan compared with placebo in 2 large clusters encompassing the temporal gyrus, the fusiform gyrus and the hippocampus on one hand as well as the insula and anterior cingulate cortex on the other hand. No effects of Silexan on gray matter volume could be detected in this investigation. CONCLUSION: This positron emission tomography study proposes an involvement of the serotonin-1A receptor in the anxiolytic effects of Silexan. The study was registered in the International Standard Randomized Controlled Trial Number Register as ISRCTN30885829 (http://www.controlled trials.com/isrctn/). PMID- 25522404 TI - A role for galanin N-terminal fragment (1-15) in anxiety- and depression-related behaviors in rats. AB - BACKGROUND: Galanin (GAL) plays a role in mood regulation. In this study we analyzed the action of the active N-terminal fragment [GAL(1-15)] in anxiety- and depression-related behavioral tests in rats. METHODS: The effect of GAL(1-15) was analyzed in the forced swimming test, tail suspension test, open field test, and light/dark test. The proximity of GAL1 and GAL2 receptors was examined with the proximity ligation assay (PLA). We tested the GAL receptors involved in GAL(1-15) effects with the GAL2 receptor antagonist M871 and with an in vivo model of siRNA GAL2 receptor knockdown or siRNA GAL1 receptor knockdown rats. The effects of GAL(1-15) were also studied in the cell line RN33B. RESULTS: GAL(1-15) induced strong depression-like and anxiogenic-like effects in all the tests. These effects were stronger than the ones induced by GAL. The involvement of the GAL2 receptor was demonstrated with M871 and with the siRNA GAL2 receptor knockdown rats. The PLA indicated the possible existence of GAL1 and GAL2 heteroreceptor complexes in the dorsal hippocampus and especially in the dorsal raphe nucleus. In the siRNA GAL1 receptor knockdown rats the behavioral actions of GAL(1-15) disappeared, and in the siRNA GAL2 receptor knockdown rats the reductions of the behavioral actions of GAL(1-15) was linked to a disappearance of PLA. In the cell line RN33B, GAL(1-15) decreased 5-HT immunoreactivity more strongly than GAL. CONCLUSIONS: Our results indicate that GAL(1-15) exerts strong depression-related and anxiogenic-like effects and may give the basis for the development of drugs targeting GAL1 and GAL2 heteroreceptor complexes in the raphe-limbic system for the treatment of depression and anxiety. PMID- 25522405 TI - Incongruent reduction of serotonin transporter associated with suicide attempts in patients with major depressive disorder: a positron emission tomography study with 4-[18F]-ADAM. AB - BACKGROUND: Much evidence supports the role of the serotonin transporter (SERT) in the pathophysiology and pharmacotherapy of major depressive disorder (MDD) and suicidal behaviors. METHODS: In this study, we recruited 17 antidepressant-naive patients with MDD and 17 age- and gender-matched healthy controls. SERT availability was measured in vivo with N,N-dimethyl-2-(2-amino-4 [(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) positron emission tomography (PET) imaging. The 21-item Hamilton Depression Rating Scale (HDRS) and Beck Scale for Suicide Ideation were used to assess the severity of depression and the intent of suicide ideation prior to PET imaging. All subjects with MDD were in a current state of depression with HDRS scores ?18. Subjects who attempted suicide within two weeks of the study onset were recruited in the depressed suicidal group (n = 8). Subjects with MDD who denied any prior suicide attempt were recruited into the depressed non-suicidal group (n = 9). RESULTS: A significant reduction of SERT availability in the midbrain, thalamus, and striatum was noted in the MDD group relative to the control group (Bonferroni-adjusted p-value < 0.05). Moreover, this effect was more pronounced in the depressed suicidal group compared to the control group (Bonferroni-adjusted p-value < 0.01). Relative to both the depressed non-suicidal and control groups, the depressed suicidal group showed an increased prefrontal cortex (PFC)/midbrain SERT binding ratio (Bonferroni-adjusted p-value < 0.01). CONCLUSIONS: This study suggests an incongruent reduction of PFC SERT binding relative to the midbrain might discriminate between depressed suicide attempters and non-attempters in patients with MDD and may be involved in the pathophysiology of suicide behaviors. PMID- 25522406 TI - Schizophrenia gene expression profile reverted to normal levels by antipsychotics. AB - BACKGROUND: Despite the widespread use of antipsychotics, little is known of the molecular bases behind the action of antipsychotic drugs. A genome-wide study is needed to characterize the genes that affect the clinical response and their adverse effects. METHODS: Here we show the analysis of the blood transcriptome of 22 schizophrenia patients before and after medication with atypical antipsychotics by next-generation sequencing. RESULTS: We found that 17 genes, among the 21 495 genes analyzed, have significantly-altered expression after medication (p-value adjusted [Padj] <0.05). Six genes (ADAMTS2, CD177, CNTNAP3, ENTPD2, RFX2, and UNC45B) out of the 17 are among the 200 genes that we characterized with differential expression in a previous study between antipsychotic-naive schizophrenia patients and controls (Sainz et al., 2013). This number of schizophrenia-altered expression genes is significantly higher than expected by chance (Chi-test, Padj 1.19E-50), suggesting that at least part of the antipsychotic beneficial effects is exerted by modulating the expression of these genes. Interestingly, all six of these genes were overexpressed in patients and reverted to control levels of expression after treatment. We also found a significant enrichment of genes related to obesity and diabetes, known adverse affects of antipsychotics. CONCLUSIONS: These results may facilitate understanding of unknown molecular mechanisms behind schizophrenia symptoms and the molecular mechanisms of antipsychotic drugs. PMID- 25522407 TI - Synaptoproteomic analysis of a rat gene-environment model of depression reveals involvement of energy metabolism and cellular remodeling pathways. AB - BACKGROUND: Major depression is a severe mental illness that causes heavy social and economic burdens worldwide. A number of studies have shown that interaction between individual genetic vulnerability and environmental risk factors, such as stress, is crucial in psychiatric pathophysiology. In particular, the experience of stressful events in childhood, such as neglect, abuse, or parental loss, was found to increase the risk for development of depression in adult life. Here, to reproduce the gene x environment interaction, we employed an animal model that combines genetic vulnerability with early-life stress. METHODS: The Flinders Sensitive Line rats (FSL), a validated genetic animal model of depression, and the Flinders Resistant Line (FRL) rats, their controls, were subjected to a standard protocol of maternal separation (MS) from postnatal days 2 to 14. A basal comparison between the two lines for the outcome of the environmental manipulation was performed at postnatal day 73, when the rats were into adulthood. We carried out a global proteomic analysis of purified synaptic terminals (synaptosomes), in order to study a subcellular compartment enriched in proteins involved in synaptic function. Two-dimensional gel electrophoresis (2 DE), mass spectrometry, and bioinformatic analysis were used to analyze proteins and related functional networks that were modulated by genetic susceptibility (FSL vs. FRL) or by exposure to early-life stress (FRL + MS vs. FRL and FSL + MS vs. FSL) RESULTS: We found that, at a synaptic level, mainly proteins and molecular pathways related to energy metabolism and cellular remodeling were dysregulated. CONCLUSIONS: The present results, in line with previous works, suggest that dysfunction of energy metabolism and cytoskeleton dynamics at a synaptic level could be features of stress-related pathologies, in particular major depression. PMID- 25522408 TI - Adjunctive treatment with asenapine augments the escitalopram-induced effects on monoaminergic outflow and glutamatergic neurotransmission in the medial prefrontal cortex of the rat. AB - BACKGROUND: Substantial clinical data support the addition of low doses of atypical antipsychotic drugs to selective serotonin reuptake inhibitors (SSRIs) to rapidly enhance the antidepressant effect in treatment-resistant depression. Preclinical studies suggest that this effect is at least partly explained by an increased catecholamine outflow in the medial prefrontal cortex (mPFC). METHODS: In the present study we used in vivo microdialysis in freely moving rats and in vitro intracellular recordings of pyramidal cells of the rat mPFC to investigate the effects of adding the novel atypical antipsychotic drug asenapine to the SSRI escitalopram with regards to monoamine outflow in the mPFC and dopamine outflow in nucleus accumbens as well as glutamatergic transmission in the mPFC. RESULTS: The present study shows that addition of low doses (0.05 and 0.1 mg/kg) of asenapine to escitalopram (5 mg/kg) markedly enhances dopamine, noradrenaline, and serotonin release in the rat mPFC as well as dopamine release in the nucleus accumbens. Moreover, this drug combination facilitated both N-methyl-d-Aspartate (NMDA)- and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) induced currents as well as electrically evoked excitatory postsynaptic potentials in pyramidal cells of the rat mPFC. CONCLUSIONS: Our results support the notion that the augmentation of SSRIs by atypical antipsychotic drugs in treatment-resistant depression may, at least in part, be related to enhanced catecholamine output in the prefrontal cortex and that asenapine may be clinically used to achieve this end. In particular, the subsequent activation of the D1 receptor may be of importance for the augmented antidepressant effect, as this mechanism facilitated both NMDA and AMPA receptor-mediated transmission in the mPFC. Our novel observation that the drug combination, like ketamine, facilitates glutamatergic transmission in the mPFC may contribute to explain the rapid and potent antidepressant effect obtained when atypical antipsychotic drugs are added to SSRIs. PMID- 25522409 TI - Paliperidone prevents brain toll-like receptor 4 pathway activation and neuroinflammation in rat models of acute and chronic restraint stress. AB - BACKGROUND: Alterations in the innate immune/inflammatory system have been proposed to underlie the pathophysiology of psychotic disease, but the mechanisms implicated remain elusive. The main agents of the innate immunity are the family of toll-like receptors (TLRs), which detect circulating pathogen-associated molecular patterns and endogenous damage-associated molecular patterns (DAMPS). Current antipsychotics are able to modulate pro- and anti-inflammatory pathways, but their actions on TLRs remain unexplored. METHODS: This study was conducted to elucidate the effects of paliperidone (1mg/Kg i.p.) on acute (6 hours) and chronic (6 hours/day during 21 consecutive days) restraint stress-induced TLR-4 pathway activation and neuroinflammation, and the possible mechanism(s) related (bacterial translocation and/or DAMPs activation). The expression of the elements of a TLR-4-dependent proinflammatory pathway was analyzed at the mRNA and protein levels in prefrontal cortex samples. RESULTS: Paliperidone pre-treatment prevented TLR-4 activation and neuroinflammation in the prefrontal cortices of stressed rats. Regarding the possible mechanisms implicated, paliperidone regulated stress-induced increased intestinal inflammation and plasma lipopolysaccharide levels. In addition, paliperidone also prevented the activation of the endogenous activators of TLR-4 HSP70 and HGMB-1. CONCLUSIONS: Our results showed a regulatory role of paliperidone on brain TLR-4, which could explain the therapeutic benefits of its use for the treatment of psychotic diseases beyond its effects on dopamine and serotonin neurotransmission. The study of the mechanisms implicated suggests that gut-increased permeability, inflammation, and bacterial translocation of Gram-negative microflora and HSP70 and HGMB1 expression could be potential adjuvant therapeutic targets for the treatment of psychotic and other stress-related psychiatric pathologies. PMID- 25522410 TI - Learning induces sonic hedgehog signaling in the amygdala which promotes neurogenesis and long-term memory formation. AB - BACKGROUND: It is known that neurogenesis occurs throughout the life mostly in the subgranular zone of the hippocampus and the subventricular zone of the lateral ventricle. We investigated whether neurogenesis occurred in the amygdala and its function in fear memory formation. METHODS: For detection of newborn neurons, mice were injected intraperitoneally with 5-bromo-2'-deoxyuridine (BrdU) 2h before receiving 15 tone-footshock pairings, and newborn neurons were analyzed 14 and 42 days after training. To determine the relationship between neurogenesis and memory formation, mice were given a proliferation inhibitor methylazoxymethanol (MAM) or a DNA synthesis inhibitor cytosine arabinoside (Ara C). To test whether sonic hedgehog (Shh) signaling was required for neurogenesis, Shh-small hairpin-interfering RNA (shRNA) was inserted into a retroviral vector (Retro-Shh-shRNA). RESULTS: The number of BrdU(+)/Neuronal nuclei (NeuN)(+) cells was significantly higher in the conditioned mice, suggesting that association of tone with footshock induced neurogenesis. MAM and Ara-C markedly reduced neurogenesis and impaired fear memory formation. Shh, its receptor patched 1 (Ptc1), and transcription factor Gli1 protein levels increased at 1 day and returned to baseline at 7 days after fear conditioning. Retro-Shh-shRNA, which knocked down Shh specifically in the mitotic neurons, reduced the number of BrdU(+)/NeuN(+) cells and decreased freezing responses. CONCLUSIONS: These results suggest that fear learning induces Shh signaling activation in the amygdala, which promotes neurogenesis and fear memory formation. PMID- 25522411 TI - Epigenetic mechanisms are involved in the regulation of ethanol consumption in mice. AB - BACKGROUND: Repeated alcohol exposure is known to increase subsequent ethanol consumption in mice. However, the underlying mechanisms have not been fully elucidated. One postulated mechanism involves epigenetic modifications, including histone modifications and DNA methylation of relevant genes such as NR2B or BDNF. METHODS: To investigate the role of epigenetic mechanisms in the development of alcohol drinking behavior, an established chronic intermittent ethanol exposure reinforced ethanol drinking mouse model with vapor inhalation over two 9-day treatment regimens was used. The DNA methyltransferase inhibitor, 5-azacytidine or the histone deacetylase inhibitor, Trichostatin A was administered (intraperitoneally) to C57BL/6 mice 30 min before daily exposure to chronic intermittent ethanol. Changes in ethanol consumption were measured using the 2 bottle choice test. RESULTS: The results indicated that systemic administration of Trichostatin A (2.5 ug/g) facilitated chronic intermittent ethanol-induced ethanol drinking, but systemic administration of 5-azacytidine (2 ug/g) did not cause the same effect. However, when 5-azacytidine was administered by intracerebroventricular injection, it facilitated chronic intermittent ethanol induced ethanol drinking. Furthermore, the increased drinking caused by chronic intermittent ethanol was prevented by injection of a methyl donor, S-adenosyl-L methionine. To provide evidence that chronic intermittent ethanol- or Trichostatin A-induced DNA demethylation and histone modifications of the NR2B promoter may underlie the altered ethanol consumption, we examined epigenetic modifications and NR2B expression in the prefrontal cortex of these mice. Chronic intermittent ethanol or Trichostatin A decreased DNA methylation and increased histone acetylation in the NR2B gene promoter, as well as mRNA levels of NR2B in these mice. CONCLUSIONS: Taken together, these results indicate that epigenetic modifications are involved in regulating ethanol drinking behavior, partially through altering NR2B expression. PMID- 25522412 TI - Methamphetamine self-administration in mice decreases GIRK channel-mediated currents in midbrain dopamine neurons. AB - BACKGROUND: Methamphetamine is a psychomotor stimulant with abuse liability and a substrate for catecholamine uptake transporters. Acute methamphetamine elevates extracellular dopamine, which in the midbrain can activate D2 autoreceptors to increase a G-protein gated inwardly rectifying potassium (GIRK) conductance that inhibits dopamine neuron firing. These studies examined the neurophysiological consequences of methamphetamine self-administration on GIRK channel-mediated currents in dopaminergic neurons in the substantia nigra and ventral tegmental area. METHODS: Male DBA/2J mice were trained to self-administer intravenous methamphetamine. A dose response was conducted as well as extinction and cue induced reinstatement. In a second study, after at least 2 weeks of stable self administration of methamphetamine, electrophysiological brain slice recordings were conducted on dopamine neurons from self-administering and control mice. RESULTS: In the first experiment, ad libitum-fed, nonfood-trained mice exhibited a significant increase in intake and locomotion following self-administration as the concentration of methamphetamine per infusion was increased (0.0015 0.15mg/kg/infusion). Mice exhibited extinction in responding and cue-induced reinstatement. In the second experiment, dopamine cells in both the substantia nigra and ventral tegmental area from adult mice with a history of methamphetamine self-administration exhibited significantly smaller D2 and GABAB receptor-mediated currents compared with control mice, regardless of whether their daily self-administration sessions had been 1 or 4 hours. Interestingly, the effects of methamphetamine self-administration were not present when intracellular calcium was chelated by including BAPTA in the recording pipette. CONCLUSIONS: Our results suggest that methamphetamine self-administration decreases GIRK channel-mediated currents in dopaminergic neurons and that this effect may be calcium dependent. PMID- 25522413 TI - Strain-dependent variations in stress coping behavior are mediated by a 5-HT/GABA interaction within the prefrontal corticolimbic system. AB - BACKGROUND: Serotonin and gamma-aminobutyric acid (GABA) transmission is crucial in coping strategies. METHODS: Here, using mice from 2 inbred strains widely exploited in behavioral neurochemistry, we investigated whether serotonin transmission in medial prefrontal cortex and GABA in basolateral amygdala determine strain-dependent liability to stress response and differences in coping. RESULTS: C57BL/6J mice displayed greater immobility in the forced swimming test, higher serotonin outflow in medial prefrontal cortex, higher GABA outflow in basolateral amygdala induced by stress, and higher serotonin 1A receptor levels in medial prefrontal cortex accompanied by lower GABAb receptor levels in basolateral amygdala than DBA/2J mice. In assessing whether serotonin in medial prefrontal cortex determines GABA functioning in response to stress and passive coping behavior in C57BL/6J and DBA/2J mice, we observed that selective prefrontal serotonin depletion in C57BL/6J and DBA/2J reduced stress-induced GABA outflow in basolateral amygdala and immobility in the forced swimming test. CONCLUSIONS: These results show that strain-dependent prefrontal corticolimbic serotonin/GABA regulation determines the strain differences in stress-coping behavior in the forced swimming test and point to a role of a specific neuronal system in genetic susceptibility to stress that opens up new prospects for innovative therapies for stress disorders. PMID- 25522414 TI - Antidepressant compounds can be both pro- and anti-inflammatory in human hippocampal cells. AB - BACKGROUND: The increasingly recognized role of inflammation in the pathogenesis and prognosis of depression has led to a renewed focus on the immunomodulatory properties of compounds with antidepressant action. Studies have, so far, explored such properties in human blood samples and in animal models. METHODS: Here we used the more relevant model of human hippocampal progenitor cells exposed to an inflammatory milieu, induced by treatment with IL-1beta. This increased the levels of a series of cytokines and chemokines produced by the cells, including a dose- and time-dependent increase of IL-6. We investigated the immunomodulatory properties of four monoaminergic antidepressants (venlafaxine, sertraline, moclobemide, and agomelatine) and two omega-3 polyunsaturated fatty acids (n-3 PUFAs; eicosapentanoic acid [EPA] and docosahexanoic acid [DHA]). RESULTS: We found that venlafaxine and EPA were anti-inflammatory: venlafaxine decreased IL-6, with a trend for decreases of IL-8 and IP-10, while EPA decreased the levels of IL-6, IL-15, IL-1RA, and IP-10. These effects were associated with a corresponding decrease in NF-kB activity. Unexpectedly, sertraline and DHA had pro-inflammatory effects, with sertraline increasing IFN-alpha and IL-6 and DHA increasing IL-15, IL-1RA, IFN-alpha, and IL-6, though these changes were also associated with a decrease in NF-kB activity, suggesting distinct modes of action. Agomelatine and moclobemide had no effect on IL-6 secretion. CONCLUSIONS: These observations indicate that monoaminergic antidepressants and n-3 PUFAs have distinctive effects on immune processes in human neural cells. Further characterization of these actions may enable more effective personalization of treatment based on the inflammatory status of patients. PMID- 25522415 TI - Treatment implications of predominant polarity and the polarity index: a comprehensive review. AB - BACKGROUND: Bipolar disorder (BD) is a serious and recurring condition that affects approximately 2.4% of the global population. About half of BD sufferers have an illness course characterized by either a manic or a depressive predominance. This predominant polarity in BD may be differentially associated with several clinical correlates. The concept of a polarity index (PI) has been recently proposed as an index of the antimanic versus antidepressive efficacy of various maintenance treatments for BD. Notwithstanding its potential clinical utility, predominant polarity was not included in the DSM-5 as a BD course specifier. METHODS: Here we searched computerized databases for original clinical studies on the role of predominant polarity for selection of and response to pharmacological treatments for BD. Furthermore, we systematically searched the Pubmed database for maintenance randomized controlled trials (RCTs) for BD to determine the PI of the various pharmacological agents for BD. RESULTS: We found support from naturalistic studies that bipolar patients with a predominantly depressive polarity are more likely to be treated with an antidepressive stabilization package, while BD patients with a manic-predominant polarity are more frequently treated with an antimanic stabilization package. Furthermore, predominantly manic BD patients received therapeutic regimens with a higher mean PI. The calculated PI varied from 0.4 (for lamotrigine) to 12.1 (for aripiprazole). CONCLUSIONS: This review supports the clinical relevance of predominant polarity as a course specifier for BD. Future studies should investigate the role of baseline, predominant polarity as an outcome predictor of BD maintenance RCTs. PMID- 25522416 TI - Cardiovascular adverse reactions during antidepressant treatment: a drug surveillance report of German-speaking countries between 1993 and 2010. AB - BACKGROUND: Antidepressants (ADs) are known to have the potential to cause various cardiovascular adverse drug reactions (ADRs). The tricyclic antidepressants (TCAs) were first revealed to be a possible source of cardiovascular ADRs. In recent years, newer classes of ADs were also suggested to have a higher risk of cardiovascular adverse effects. In particular, the selective serotonin reuptake inhibitors (SSRIs) were suspected to have the potential to induce QTc interval prolongation, and therefore increase the risk of ventricular arrhythmia. This descriptive study is based on the continuous pharmacovigilance program of German-speaking countries (Austria, Germany, and Switzerland), the Arzneimittelsicherheit in der Psychiatrie (AMSP), which assesses severe ADRs occurring in clinical routine situations. METHODS: Of 169,278 psychiatric inpatients treated with ADs between 1993 and 2010, 198 cases of cardiovascular ADRs (0.12%) were analyzed. RESULTS: Our study showed that the incidence rates of cardiovascular ADRs were highest during treatment with monoamine oxidase inhibitors (0.27%), TCAs (0.15%), and serotonin noradrenaline reuptake inhibitors (0.14%); the risk of occurring during treatment with SSRIs (0.08%) was significantly lower. The noradrenergic and specific serotonergic AD mirtazapine (0.07%) had a significantly lower risk of cardiovascular ADRs than all other ADs. Severe hypotension was the most frequent ADR, followed by hypertension, arrhythmia, and in some rare cases heart failure. CONCLUSIONS: Despite certain limitations due to the AMSP study design, our observations on cardiovascular ADRs can contribute to a better knowledge of the cardiovascular risk profiles of antidepressants in the clinical routine setting. However, prospective studies are needed to verify our findings. PMID- 25522417 TI - Amphetamine decreases alpha2C-adrenoceptor binding of [11C]ORM-13070: a PET study in the primate brain. AB - BACKGROUND: The neurotransmitter norepinephrine has been implicated in psychiatric and neurodegenerative disorders. Examination of synaptic norepinephrine concentrations in the living brain may be possible with positron emission tomography (PET), but has been hampered by the lack of suitable radioligands. METHODS: We explored the use of the novel alpha2C-adrenoceptor antagonist PET tracer [(11)C]ORM-13070 for measurement of amphetamine-induced changes in synaptic norepinephrine. The effect of amphetamine on [(11)C]ORM-13070 binding was evaluated ex vivo in rat brain sections and in vivo with PET imaging in monkeys. RESULTS: Microdialysis experiments confirmed amphetamine-induced elevations in rat striatal norepinephrine and dopamine concentrations. Regional [(11)C]ORM-13070 receptor binding was high in the striatum and low in the cerebellum. After injection of [(11)C]ORM-13070 in rats, mean striatal specific binding ratios, determined using cerebellum as a reference region, were 1.4+/-0.3 after vehicle pretreatment and 1.2+/-0.2 after amphetamine administration (0.3mg/kg, subcutaneous). Injection of [(11)C]ORM-13070 in non-human primates resulted in mean striatal binding potential (BP ND) estimates of 0.65+/-0.12 at baseline. Intravenous administration of amphetamine (0.5 and 1.0mg/kg, i.v.) reduced BP ND values by 31-50%. Amphetamine (0.3mg/kg, subcutaneous) increased extracellular norepinephrine (by 400%) and dopamine (by 270%) in rat striata. CONCLUSIONS: Together, these results indicate that [(11)C]ORM-13070 may be a useful tool for evaluation of synaptic norepinephrine concentrations in vivo. Future studies are required to further understand a potential contribution of dopamine to the amphetamine-induced effect. PMID- 25522418 TI - Milnacipran remediates impulsive deficits in rats with lesions of the ventromedial prefrontal cortex. AB - BACKGROUND: Deficits in impulse control are often observed in psychiatric disorders in which abnormalities of the prefrontal cortex are observed, including attention-deficit/hyperactivity disorder and bipolar disorder. We recently found that milnacipran, a serotonin/noradrenaline reuptake inhibitor, could suppress impulsive action in normal rats. However, whether milnacipran could suppress elevated impulsive action in rats with lesions of the ventromedial prefrontal cortex, which is functionally comparable with the human prefrontal cortex, remains unknown. METHODS: Selective lesions of the ventromedial prefrontal cortex were made using quinolinic acid in rats previously trained on a 3-choice serial reaction time task. Sham rats received phosphate buffered saline. Following a period of recovery, milnacipran (0 or 10mg/kg/d * 14 days) was orally administered 60 minutes prior to testing on the 3-choice task. After 7 days of drug cessation, Western blotting, immunohistochemistry, electrophysiological analysis, and morphological analysis were conducted. RESULTS: Lesions of the ventromedial prefrontal cortex induced impulsive deficits, and repeated milnacipran ameliorated the impulsive deficit both during the dosing period and after the cessation of the drug. Repeated milnacipran remediated the protein levels of mature brain-derived neurotrophic factor and postsynaptic density-95, dendritic spine density, and excitatory currents in the few surviving neurons in the ventromedial prefrontal cortex of ventromedial prefrontal cortex-lesioned rats. CONCLUSIONS: The findings of this study suggest that milnacipran treatment could be a novel strategy for the treatment of psychiatric disorders that are associated with a lack of impulse control. PMID- 25522419 TI - Chronic desipramine prevents acute stress-induced reorganization of medial prefrontal cortex architecture by blocking glutamate vesicle accumulation and excitatory synapse increase. AB - BACKGROUND: Although a clear negative influence of chronic exposure to stressful experiences has been repeatedly demonstrated, the outcome of acute stress on key brain regions has only just started to be elucidated. Although it has been proposed that acute stress may produce enhancement of brain plasticity and that antidepressants may prevent such changes, we still lack ultrastructural evidence that acute stress-induced changes in neurotransmitter physiology are coupled with structural synaptic modifications. METHODS: Rats were pretreated chronically (14 days) with desipramine (10mg/kg) and then subjected to acute foot-shock stress. By means of serial section electron microscopy, the structural remodeling of medial prefrontal cortex glutamate synapses was assessed soon after acute stressor cessation and stress hormone levels were measured. RESULTS: Foot-shock stress induced a remarkable increase in the number of docked vesicles and small excitatory synapses, partially and strongly prevented by desipramine pretreatment, respectively. Acute stress-induced corticosterone elevation was not affected by drug treatment. CONCLUSIONS: Since desipramine pretreatment prevented the stress-induced structural plasticity but not the hormone level increase, we hypothesize that the preventing action of desipramine is located on pathways downstream of this process and/or other pathways. Moreover, because enhancement of glutamate system remodeling may contribute to overexcitation dysfunctions, this aspect could represent a crucial component in the pathophysiology of stress related disorders. PMID- 25522420 TI - FKBP5 genotype-dependent DNA methylation and mRNA regulation after psychosocial stress in remitted depression and healthy controls. AB - BACKGROUND: Polymorphisms in the FK506 binding protein 5 (FKBP5) gene have been shown to influence glucocorticoid receptor sensitivity, stress response regulation, and depression risk in traumatized subjects, with most consistent findings reported for the functional variant rs1360780. In the present study, we investigated whether the FKBP5 polymorphism rs1360780 and lifetime history of major depression are associated with DNA methylation and FKBP5 gene expression after psychosocial stress. METHODS: A total of 116 individuals with a positive (n = 61) and negative (n = 55) lifetime history of major depression participated in the Trier Social Stress Test. We assessed plasma cortisol concentrations, FKBP5 mRNA expression, and CpG methylation of FKBP5 intron 7 in peripheral blood cells. RESULTS: Genotype-dependent plasma cortisol response to psychosocial stress exposure was observed in healthy controls, with the highest and longest-lasting cortisol increase in subjects with the TT genotype of the FKBP5 polymorphism rs1360780, and healthy controls carrying the T risk allele responded with a blunted FKBP5 mRNA expression after psychosocial stress. No genotype effects could be found in remitted depression. CONCLUSIONS: The FKBP5 rs1360780 polymorphism is associated with plasma cortisol and FKBP5 mRNA expression after psychosocial stress in healthy controls but not in remitted depression. Preliminary results of the DNA methylation analysis suggest that epigenetic modifications could be involved. PMID- 25522421 TI - Temporal regulation of peripheral BDNF levels during cocaine and morphine withdrawal: comparison with a natural reward. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that has long been studied in the field of addiction and its importance in regulating drug addiction-related behavior has been widely demonstrated. The aim of our study was to analyze the consequences of a repeated exposure to drugs of abuse or natural reward on plasma BDNF levels during withdrawal. METHODS: Rats were chronically injected with morphine (subcutaneously, 5mg/kg) or cocaine (intraperitoneally, 20mg/kg) or fed with a butter biscuit (per os, 4g) once per day for 14 days. Blood collection was performed on the 1st (withdrawal day 1 or WD1) or on (WD14), either at the same time point rats had been exposed to drugs or natural reward or at a different time point (used to quantify basal brain-derived neurotrophic factor levels). RESULTS: Cocaine treatment led to a rapid (WD1) and persistent (WD14) decrease of basal BDNF levels compared with saline-treated animals, whereas morphine induced an increase on WD14 without any alteration on WD1. On the contrary, the natural reward induced a significant increase of basal brain derived neurotrophic factor levels only on WD1. The analysis of BDNF levels at the usual time point at which animals had been exposed showed that both drugs, but not the natural reward, increased BDNF levels compared with basal levels. CONCLUSION: Our data highlight that only drugs of abuse are able to persistently alter BDNF levels and to induce specific variations of this neurotrophic factor at the usual hour of injection. PMID- 25522423 TI - Measuring adherence to medication in schizophrenia: the relationship between attitudes toward drug therapy and plasma levels of new-generation antipsychotics. AB - BACKGROUND: Nonadherence to medication is still a major problem in the treatment of schizophrenia. The current longitudinal study investigated whether the patients' attitudes toward treatment correlated with the ratio of observed vs expected plasma levels of antipsychotic drugs as an objective measurement of adherence. METHODS: Data of patients starting monotherapy with a new-generation antipsychotic were collected 2, 4, and 12 weeks after the initiation of treatment. Next to the assessment of patients' attitudes toward medication by means of the Drug Attitude Inventory, the ratio of the observed vs expected plasma level was calculated. Antipsychotic-induced side effects were evaluated by means of the Udvalg for Kliniske Undersogelser Side Effect Rating Scale. RESULTS: A total of 93 patients were eligible for statistical analysis. About one-half of the ratios of observed vs expected plasma levels ranged from 0.5 to 2 and were considered normal, whereas the other ratios were considered either too low (<0.5) or too high (>2). No consistent correlation between patients' attitude toward drug therapy and the individual ratios of observed vs expected plasma levels of medication was detected. This finding was not affected by side effects. CONCLUSIONS: Our results highlight the importance of recognizing the complex nature of adherence to medication in schizophrenia patients. Importantly, we found no consistent correlation between subjective and objective measures of medication adherence. Therefore, monitoring adherence to medication remains a challenge in clinical practice. PMID- 25522422 TI - The morphological and molecular changes of brain cells exposed to direct current electric field stimulation. AB - BACKGROUND: The application of low-intensity direct current electric fields has been experimentally used in the clinic to treat a number of brain disorders, predominantly using transcranial direct current stimulation approaches. However, the cellular and molecular changes induced by such treatment remain largely unknown. METHODS: Here, we tested various intensities of direct current electric fields (0, 25, 50, and 100V/m) in a well-controlled in vitro environment in order to investigate the responses of neurons, microglia, and astrocytes to this type of stimulation. This included morphological assessments of the cells, viability, as well as shape and fiber outgrowth relative to the orientation of the direct current electric field. We also undertook enzyme-linked immunosorbent assays and western immunoblotting to identify which molecular pathways were affected by direct current electric fields. RESULTS: In response to direct current electric field, neurons developed an elongated cell body shape with neurite outgrowth that was associated with a significant increase in growth associated protein-43. Fetal midbrain dopaminergic explants grown in a collagen gel matrix also showed a reorientation of their neurites towards the cathode. BV2 microglial cells adopted distinct morphological changes with an increase in cyclooxygenase-2 expression, but these were dependent on whether they had already been activated with lipopolysaccharide. Finally, astrocytes displayed elongated cell bodies with cellular filopodia that were oriented perpendicularly to the direct current electric field. CONCLUSION: We show that cells of the central nervous system can respond to direct current electric fields both in terms of their morphological shape and molecular expression of certain proteins, and this in turn can help us to begin understand the mechanisms underlying the clinical benefits of direct current electric field. PMID- 25522424 TI - The role of BDNF, leptin, and catecholamines in reward learning in bulimia nervosa. AB - BACKGROUND: A relationship between bulimia nervosa and reward-related behavior is supported by several lines of evidence. The dopaminergic dysfunctions in the processing of reward-related stimuli have been shown to be modulated by the neurotrophin brain derived neurotrophic factor (BDNF) and the hormone leptin. METHODS: Using a randomized, double-blind, placebo-controlled, crossover design, a reward learning task was applied to study the behavior of 20 female subjects with remitted bulimia nervosa and 27 female healthy controls under placebo and catecholamine depletion with alpha-methyl-para-tyrosine (AMPT). The plasma levels of BDNF and leptin were measured twice during the placebo and the AMPT condition, immediately before and 1 hour after a standardized breakfast. RESULTS: AMPT induced differences in plasma BDNF levels were positively correlated with the AMPT-induced differences in reward learning in the whole sample (P=.05). Across conditions, plasma brain derived neurotrophic factor levels were higher in remitted bulimia nervosa subjects compared with controls (diagnosis effect; P=.001). Plasma BDNF and leptin levels were higher in the morning before compared with after a standardized breakfast across groups and conditions (time effect; P<.0001). The plasma leptin levels were higher under catecholamine depletion compared with placebo in the whole sample (treatment effect; P=.0004). CONCLUSIONS: This study reports on preliminary findings that suggest a catecholamine-dependent association of plasma BDNF and reward learning in subjects with remitted bulimia nervosa and controls. A role of leptin in reward learning is not supported by this study. However, leptin levels were sensitive to a depletion of catecholamine stores in both remitted bulimia nervosa and controls. PMID- 25522425 TI - A conjugate vaccine attenuates morphine- and heroin-induced behavior in rats. AB - BACKGROUND: Currently approved medications for opioid addiction have shown clinical efficacy, but undesired side effects, dependence induced by the medications themselves, and low treatment compliance necessitate the need for novel therapies. METHODS: A novel morphine-keyhole limpet hemocyanin conjugate vaccine was synthesized with 6-glutarylmorphine as the hapten and a lengthened linker of 6 carbon atoms. The titer and specificity of the triggered antibody were assessed by enzyme-linked immunosorbent assay. The effects of the vaccine on the morphine-induced elevation of dopamine levels in the nucleus accumbens were determined by high-performance liquid chromatography. The effects of the vaccine on morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin self-administration were also assessed. RESULTS: After subcutaneous administration in rats, the vaccine triggered a high antibody titer, with comparable specificity for morphine, 6-acetylmorphine, and heroin, but no interaction with dissimilar therapeutic opioid compounds, including buprenorphine, naloxone, and nalorphine, was observed. The vaccine significantly prevented the elevation of dopamine levels in the nucleus accumbens induced by a single morphine challenge. Moreover, the vaccine prevented the expression of morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin seeking, suggesting its potential for preventing relapse. CONCLUSION: These results demonstrate that active immunization with the present vaccine induces a robust morphine/heroin-specific antibody response in rats and attenuates the behavioral effects of morphine and heroin. PMID- 25522426 TI - Diurnal oscillation of amygdala clock gene expression and loss of synchrony in a mouse model of depression. AB - BACKGROUND: Disturbances in circadian rhythm-related physiological and behavioral processes are frequently observed in depressed patients and several clock genes have been identified as risk factors for the development of mood disorders. However, the particular involvement of the circadian system in the pathophysiology of depression and its molecular regulatory interface is incompletely understood. METHODS: A naturalistic animal model of depression based upon exposure to chronic mild stress was used to induce anhedonic behavior in mice. Micro-punch dissection was used to isolate basolateral amygdala tissue from anhedonic mice followed by quantitative real-time PCR-based analysis of gene expression. RESULTS: Here we demonstrate that chronic mild stress-induced anhedonic behavior is associated with disturbed diurnal oscillation of the expression of Clock, Cry2, Per1, Per3, Id2, Rev-erbalpha, Ror-beta and Ror-gamma in the mouse basolateral amygdala. Clock gene desynchronization was accompanied by disruption of the diurnal expressional pattern of vascular endothelial growth factor A expression in the basolateral amygdala of anhedonic mice, also reflected in alterations of circulating vascular endothelial growth factor A levels. CONCLUSION: We propose that aberrant control of diurnal rhythmicity related to depression may indeed directly result from the illness itself and establish an animal model for the further exploration of the molecular mechanisms mediating the involvement of the circadian system in the pathophysiology of mood disorders. PMID- 25522427 TI - SKF83959 produces antidepressant effects in a chronic social defeat stress model of depression through BDNF-TrkB pathway. AB - BACKGROUND: SKF83959 stimulates the phospholipase Cbeta/inositol phosphate 3 pathway, resulting in the activation of Ca(2+)/calmodulin-dependent kinase IIalpha, which affects the synthesis of brain-derived neurotrophic factor, a neurotrophic factor critical for the pathophysiology of depression. Previous reports showed that SKF83959 elicited antidepressant activity in the forced swim test and tail suspension test as a novel triple reuptake inhibitor. However, there are no studies showing the effects of SKF83959 in a chronic stress model of depression and the role of phospholipase C/inositol phosphate 3/calmodulin dependent kinase IIalpha/brain-derived neurotrophic factor pathway in SKF83959 mediated antidepressant effects. METHODS: In this study, SKF83959 was firstly investigated in the chronic social defeat stress model of depression. The changes in hippocampal neurogenesis, dendrite spine density, and brain-derived neurotrophic factor signaling pathway after chronic social defeat stress and SKF83959 treatment were then investigated. Pharmacological inhibitors and small interfering RNA/short hairpin RNA methods were further used to explore the antidepressive mechanisms of SKF83959. RESULTS: We found that SKF83959 produced antidepressant effects in the chronic social defeat stress model and also restored the chronic social defeat stress-induced decrease in hippocampal brain derived neurotrophic factor signaling pathway, dendritic spine density, and neurogenesis. By using various inhibitors and siRNA/shRNA methods, we further demonstrated that the hippocampal dopamine D5 receptor, phospholipase C/inositol phosphate 3/ calmodulin-dependent kinase IIalpha pathway, and brain-derived neurotrophic factor system are all necessary for the SKF83959 effects. CONCLUSION: These results suggest that SKF83959 can be developed as a novel antidepressant and produces antidepressant effects via the hippocampal D5/ phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIalpha/brain derived neurotrophic factor pathway. PMID- 25522429 TI - Fluoxetine regulates neurogenesis in vitro through modulation of GSK-3beta/beta catenin signaling. AB - BACKGROUND: It is generally accepted that chronic treatment with antidepressants increases hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. Recently, glycogen synthase kinase-3 beta (GSK-3beta)/beta catenin signaling was shown to be involved in the mechanism of how antidepressants might influence hippocampal neurogenesis. METHODS: The aim of this study was to determine whether GSK-3beta/beta-catenin signaling is involved in the alteration of neurogenesis as a result of treatment with fluoxetine, a selective serotonin reuptake inhibitor. The mechanisms involved in fluoxetine's regulation of GSK-3beta/beta-catenin signaling pathway were also examined. RESULTS: Our results demonstrated that fluoxetine increased the proliferation of embryonic neural precursor cells (NPCs) by up-regulating the phosphorylation of Ser9 on GSK-3beta and increasing the level of nuclear beta-catenin. The overexpression of a stabilized beta-catenin protein (DeltaN89 beta-catenin) significantly increased NPC proliferation, while inhibition of beta-catenin expression in NPCs led to a significant decrease in the proliferation and reduced the proliferative effects induced by fluoxetine. The effects of fluoxetine induced up-regulation of both phosphorylation of Ser9 on GSK-3beta and nuclear beta-catenin were significantly prevented by the 5-hydroxytryptamine-1A (5-HT1A) receptor antagonist WAY-100635. CONCLUSIONS: The results demonstrate that fluoxetine may increase neurogenesis via the GSK-3beta/beta-catenin signaling pathway that links postsynaptic 5-HT1A receptor activation. PMID- 25522430 TI - Reduced mRNA expression of PTGDS in peripheral blood mononuclear cells of rapid cycling bipolar disorder patients compared with healthy control subjects. AB - BACKGROUND: Disturbances related to the arachidonic acid cascade and prostaglandin metabolism may be involved in the pathophysiology of bipolar disorder, as supported by a recent genome-wide association study meta-analysis; however, evidence from clinical studies on a transcriptional level is lacking. Two enzymes in the arachidonic acid cascade are the prostaglandin D synthase (PTGDS), which catalyzes the conversion of prostaglandin H2 to prostaglandin D2 (PGD2), and the aldo-keto reductase family 1 member C3 (AKR1C3), which catalyzes the reduction of PGD2. We aimed to test the hypothesis that mRNA expression of PTGDS and AKR1C3 is deregulated in rapid-cycling disorder patients in a euthymic or current affective state compared with healthy control subjects, and that expression alters with affective states. METHODS: PTGDS and AKR1C3 mRNA expression in peripheral blood mononuclear cells was measured in 37 rapid-cycling bipolar disorder patients and 40 age- and gender-matched healthy control subjects using reverse transcription quantitative real-time polymerase chain reaction. Repeated measurements of PTGDS and AKR1C3 mRNA expression were obtained in various affective states during 6-12 months and compared with repeated measurements in healthy control subjects. RESULTS: Adjusted for age and gender, PTGDS mRNA expression was down-regulated in rapid-cycling bipolar disorder patients in a euthymic, depressive, and manic/hypomanic state compared with healthy control subjects. No difference in PTGDS mRNA expression was observed between affective states. AKR1C3 mRNA expression did not differ between bipolar disorder patients in any affective state or in comparison with healthy control subjects. CONCLUSIONS: The results suggest a role for aberrantly-regulated PTGDS mRNA expression in rapid-cycling bipolar disorder. The sample size was limited; replication of the findings in larger, independent samples is warranted to further explore the role of the arachidonic acid cascade and prostaglandin metabolism as a potential therapeutic target in bipolar disorder. PMID- 25522428 TI - Behavioral and neurochemical changes in mesostriatal dopaminergic regions of the rat after chronic administration of the cannabinoid receptor agonist WIN55,212-2. AB - BACKGROUND: The endocannabinoid system interacts extensively with other neurotransmitter systems and has been implicated in a variety of functions, including regulation of basal ganglia circuits and motor behavior. The present study examined the effects of repeated administration of the nonselective cannabinoid receptor 1 agonist WIN55,212-2 on locomotor activity and on binding and mRNA levels of dopamine receptors and transporters and GABAA receptors in mesostriatal dopaminergic regions of the rat. METHODS: Rats received systemic injections of WIN55,212-2 (0, 0.1, 0.3, or 1mg/kg, intraperitoneally) for 20 consecutive days. Locomotor activity was measured on days 1, 10, and 20. Following the last measurement, rats were euthanized and prepared for in vitro binding and in situ hybridization experiments. RESULTS: Acutely, 0.3 and 1mg/kg of WIN55,212-2 produced hypolocomotion, which was sustained for the next 2 measurements, compared to vehicle. Repeated administration of WIN55,212-2 decreased the mRNA levels of the D2 autoreceptors in substantia nigra and ventral tegmental area and increased D1 receptor mRNA and binding in nucleus accumbens. Furthermore, both dopamine receptor and transporter binding and mRNA levels were decreased in substantia nigra. Moreover, repeated administration of WIN55,212-2 decreased GABAA receptor binding levels in dorsal striatum and substantia nigra. CONCLUSIONS: Our data indicate that chronic WIN55,212-2 administration results in sustained effects on locomotor activity, similar to those observed after acute administration, and modulates the dopaminergic and GABAergic systems in a region , dose-, and neurotransmitter-selective manner. PMID- 25522431 TI - Toll-like receptor expression in the blood and brain of patients and a mouse model of Parkinson's disease. AB - BACKGROUND: Accumulating evidence supports a role for the immune system in the pathogenesis of Parkinson's disease. Importantly, recent preclinical studies are now suggesting a specific contribution of inflammation to the alpha-synuclein induced pathology seen in this condition. METHODS: We used flow cytometry and western blots to detect toll-like receptor 2 and 4 expression in blood and brain samples of Parkinson's disease patients and mice overexpressing human alpha synuclein. To further assess the effects of alpha-synuclein overexpression on the innate immune system, we performed a longitudinal study using Thy1.2-alpha synuclein mice that expressed a bicistronic DNA construct (reporter genes luciferase and green fluorescent protein) under the transcriptional control of the murine toll-like receptor 2 promoter. RESULTS: Here, we report increases in toll-like receptors 2 and 4 expression in circulating monocytes and of toll-like receptor 4 in B cells and in the caudate/putamen of Parkinson's disease patients. Monthly bioluminescence imaging of Thy1.2-alpha-synuclein mice showed increasing toll-like receptor 2 expression from 10 months of age, although no change in toll like receptor 2 and 4 expression was observed in the blood and brain of these mice at 12 months of age. Dexamethasone treatment starting at 5 months of age for 1 month significantly decreased the microglial response in the brain of these mice and promoted functional recovery as observed using a wheel-running activity test. CONCLUSION: Our results show that toll-like receptors 2 and 4 are modulated in the blood and brain of Parkinson's disease patients and that overexpression of alpha-synuclein leads to a progressive microglial response, the inhibition of which has a beneficial impact on some motor phenotypes of an animal model of alpha-synucleinopathy. PMID- 25522432 TI - Manganese-enhanced magnetic resonance imaging reveals differential long-term neuroadaptation after methamphetamine and the substituted cathinone 4 methylmethcathinone (mephedrone). AB - BACKGROUND: In recent years there has been a large increase in the use of substituted cathinones such as mephedrone (4-methylmethcathinone, 4-MMC), a psychostimulant drug that shows a strong resemblance to methamphetamine (METH). Unlike METH, which can produce clear long-term effects, the effects of 4-MMC have so far remained elusive. We employ manganese-enhanced magnetic resonance imaging (MEMRI), a highly sensitive method for detecting changes in neuronal activation, to investigate the effects of METH and 4-MMC on the brain. METHODS: In Wistar rats we performed a MEMRI scan two weeks after binge treatments (twice daily for 4 consecutive days) of METH (5 mg/kg) or 4-MMC (30 mg/kg). Furthermore, locomotor activity measurements and novel object recognition tests were performed. RESULTS: METH produced a widespread pattern of decreased bilateral activity in several regions, including the nucleus accumbens, caudate putamen, globus pallidus, thalamus, and hippocampus, as well as several other cortical and subcortical areas. Conversely, 4-MMC produced increased bilateral activity, anatomically limited to the hypothalamus and hippocampus. Drug treatments did not affect the development of locomotor sensitization or novel object recognition performance. CONCLUSIONS: The pattern of decreased brain activity seen after METH corresponds closely to regions known to be affected by this drug and confirms the validity of MEMRI for detecting neuroadaptation two weeks after amphetamine binge treatment. 4-MMC, unlike METH, produced increased activity in a limited number of different brain regions. This highlights an important difference in the long-term effects of these drugs on neural function and shows precisely the anatomical localization of 4-MMC-induced neuroadaptation. PMID- 25522433 TI - Genotypes do not confer risk for delinquency but rather alter susceptibility to positive and negative environmental factors: gene-environmentinteractions of BDNF Val66Met, 5-HTTLPR, and MAOA-uVNTR [corrected]. AB - BACKGROUND: Previous evidence of gene-by-environment interactions associated with emotional and behavioral disorders is contradictory. Differences in findings may result from variation in valence and dose of the environmental factor, and/or failure to take account of gene-by-gene interactions. The present study investigated interactions between the brain-derived neurotrophic factor gene (BDNF Val66Met), the serotonin transporter gene-linked polymorphic region (5 HTTLPR), the monoamine oxidase A (MAOA-uVNTR) polymorphisms, family conflict, sexual abuse, the quality of the child-parent relationship, and teenage delinquency. METHODS: In 2006, as part of the Survey of Adolescent Life in Vastmanland, Sweden, 1 337 high-school students, aged 17-18 years, anonymously completed questionnaires and provided saliva samples for DNA analyses. RESULTS: Teenage delinquency was associated with two-, three-, and four-way interactions of each of the genotypes and the three environmental factors. Significant four way interactions were found for BDNF Val66Met * 5-HTTLPR*MAOA-uVNTR * family conflicts and for BDNF Val66Met * 5-HTTLPR*MAOA-uVNTR * sexual abuse. Further, the two genotype combinations that differed the most in expression levels (BDNF Val66Met Val, 5-HTTLPR LL, MAOA-uVNTR LL [girls] and L [boys] vs BDNF Val66Met Val/Met, 5-HTTLPR S/LS, MAOA-uVNTR S/SS/LS) in interaction with family conflict and sexual abuse were associated with the highest delinquency scores. The genetic variants previously shown to confer vulnerability for delinquency (BDNF Val66Met Val/Met * 5-HTTLPR S * MAOA-uVNTR S) were associated with the lowest delinquency scores in interaction with a positive child-parent relationship. CONCLUSIONS: Functional variants of the MAOA-uVNTR, 5-HTTLPR, and BDNF Val66Met, either alone or in interaction with each other, may be best conceptualized as modifying sensitivity to environmental factors that confer either risk or protection for teenage delinquency. PMID- 25522434 TI - The impact of musculoskeletal pain on health-related quality of life in Fort Prajaksilapakom Hospital. AB - OBJECTIVE: To investigate the prevalence of musculoskeletal pain and its impact on health-related quality of life (HRQoL) in workers of Fort Prajaksilapakom Hospital. MATERIAL AND METHOD: A cross-sectional study was conducted. Participants completed self-reported questionnaires requesting demographic data and report ofpain symptoms occurring within the last one month. In addition, the HRQoL questionnaire (Thai SF-36v2) was used to study the SF-36v2 score. Musculoskeletal pain was divided into five groups: (1) no pain, 2) pain at one site, 3) pain at two sites, 4) pain at three sites and 5) pain at four sites. The association between the SF-36v2 score and mnusculoskeletal pain was evaluated using multivariable linear regression analysis. RESULTS: Of 726 hospital workers, 485 (66.8%) participated in the present study. The majority of participants were female (65.3%) and comprised non-health care providers (56.3%) with a mean age of 37 +/- 11.5 years (range: 20-59). The prevalence of musculoskeletal pain during the last one month was 77.0%. Musculoskeletal pain was mostly reported at the lower extremities (50.8%),followed by low back (48.2), the neck (40.5%) and the upper extremities (33.0%). Multiple sites pain (pain at more than one site) was 51%. Each subscale score of the Thai SF-36v2 was significantly lower in participants with pain than in those without pain (physical functioning; p<0.001, physical role; p = 0.001, bodily pain; p<0.001, general health; p<0.001, vitality; p<0.001, social functioning; p = 0.02, emotion role; p = 0.003 and mental health; p<0.001). Multiple pain sites were more likely to be associated with lower HRQoL. CONCLUSION: The present study showed the high prevalence of musculoskeletal pain and negative impact on HRQoL in workers ofFort Prajaksilapakom Hospital. The number of sites of musculoskeletal pain was associated with a reduction in the quality oflife. PMID- 25522435 TI - A non-catalytic role of choline kinase alpha is important in promoting cancer cell survival. AB - Choline kinase alpha (ChoKalpha) is regarded as an attractive cancer target. The enzyme catalyses the formation of phosphocholine(PCho), an important precursor in the generation of phospholipids essential for cell growth. ChoKalpha has oncogenic properties and is critical for the survival of cancer cells. Overexpression of the ChoKalpha protein can transform noncancer cells into cells with a cancerous phenotype, and depletion of the ChoKalpha protein can result in cancer cell death. However, the mechanisms underlying the tumourigenic properties of ChoKalpha are not fully understood. ChoKalpha was recently demonstrated to associate with other oncogenic proteins, raising the possibility that a non catalytic protein scaffolding function drives the tumourigenic properties of ChoKalpha rather than a catalytic function. In order to differentiate these two roles, we compared the impact on cancer cell survival using two tools specific for ChoKalpha: (1) small interfering RNA (siRNA) to knockdown the ChoKalpha protein levels; and (2) compound V-11-0711, a novel potent and selective ChoKalpha inhibitor (ChoKalpha IC50 20 nM), to impede the catalytic activity. Both treatments targeted the endogenous ChoKalpha protein in HeLa cells, as demonstrated by a substantial reduction in the PCho levels. siRNA knockdown of the ChoKalpha protein in HeLa cells resulted in significant cell death through apoptosis. In contrast, compound V-11-0711 caused a reversible growth arrest. This suggests that inhibition of ChoKalpha catalytic activity alone is not sufficient to kill cancer cells, and leads us to conclude that there is a role for the ChoKalpha protein in promoting cancer cell survival that is independent of its catalytic activity. PMID- 25522436 TI - Ultraviolet differences between the Sulphur Butterflies, Colias eurytheme and C. philodice, and a possible isolating mechanism. PMID- 25522437 TI - Sequencing of the 3'-terminal region of a 16S rRNA gene from Zea mays chloroplast reveals homology with E. coli 16S rRNA. PMID- 25522438 TI - [A case of infant visceral leishmaniasis in Yan'an City]. PMID- 25522439 TI - [Two cases of imported falciparum malaria]. PMID- 25522440 TI - Federal Employees Health Benefits Program miscellaneous changes: Medically Underserved Areas. Direct final rule. AB - The U.S. Office of Personnel Management (OPM) is issuing a direct final rule to discontinue the annual determination of the Medically Underserved Areas (MUAs) for the Federal Employees Health Benefits (FEHB) Program. PMID- 25522441 TI - [Not Available]. PMID- 25522443 TI - [In Process Citation]. PMID- 25522442 TI - [Not Available]. PMID- 25522444 TI - [Not Available]. PMID- 25522445 TI - Editorial comment from Dr. Tsurumaki Sato to "Length of site-specific positive surgical margins as a risk factor for biochemical recurrence following radical prostatectomy". PMID- 25522446 TI - Editorial comment to "Solitary and small (< or = 3 mm) apical positive surgical margins are related to biochemical recurrence after radical prostatectomy". PMID- 25522447 TI - Comment on 'Multivariate meta-analysis: potential and promise'. PMID- 25522448 TI - Multivariate meta-analysis: a comment. PMID- 25522449 TI - Comments on 'Multivariate meta-analysis: potential and promise' by Jackson et al, Statistics in Medicine. PMID- 25522451 TI - Urology in Asia--Hong Kong. PMID- 25522450 TI - Treatment of brain metastases from renal cell carcinoma with sunitinib and radiotherapy: our experience and review of the literature. AB - The present study reports our experience with five renal cell carcinoma (RCC) patients with brain metastases treated with sunitinib and radiotherapy. All patients had undergone radical nephrectomy. Before treatment with sunitinib, radiotherapy for brain metastases, either by gamma-knife surgery or whole brain radiation, was carried out. After treatment with sunitinib, shrinkage of brain metastases was achieved in all patients with complete response, partial response and stable disease in two, one and two patients, respectively. Although progression of brain metastases occurred in four of the five patients, additional gamma-knife surgery was effective in three patients. Over a 12.5-month follow up, four patients, including three who maintained their best response, remained alive. The remaining one patient died of disease progression. Despite the observation of several adverse events after treatment with sunitinib, there was no intracerebral hemorrhage in any patient. These findings suggest that sunitinib combined with radiation therapy can be safely carried out in RCC patients with brain metastases and provides a favorable prognosis in these cases. However, considering their frequent progression, it would be important to carry out careful follow up for these patients by focusing on the control of brain metastases. PMID- 25522452 TI - Stereoselective metabolism and toxicity of the herbicide fluroxypyr methylheptyl ester in rat hepatocytes. AB - We investigated the stereoselective degradation kinetics and toxicity of fluroxypyr methylheptyl ester (FPMH) in rat hepatocytes using a chiral high performance liquid chromatographic method. The T1/2 of (-)-FPMH was about two times longer than that of (+)-FPMH after the rat hepatocytes were incubated with 10, 20, and 50 MUM of rac-FPMH. There was no chiral conversion or transformation during their incubation with the hepatocytes. Toxicity differences were observed among the two enantiomers of FPMH and fluroxypyr (FP) in their EC50 values in rat hepatocytes. Of all the tested compounds, FP was most toxic to the rat hepatocytes. The (-)-FPMH enantiomer showed higher toxicity than the (+)-FPMH, whereas the racemic mixture displayed intermediate toxicity. The data presented here are important for a more thorough understanding of this pesticide and should be useful for its full environmental assessment. PMID- 25522453 TI - Commentary on Nayernouri's "sense and nonsense". PMID- 25522454 TI - Author's reply: To PMID 24329147. PMID- 25522455 TI - On the paper by E. R. Muslikhov, I. F. Sukhanova, and P. V. Avdonin entitled "arachidonic acid activates release of calcium ions from reticulum via ryanodine receptor channels in C2C12 skeletal myotubes" published in Biochemistry (Moscow), Vol. 79, No. 5, pp. 435-439 (2014). AB - A recent study published by Muslikhov et al. (Biochemistry (Moscow), 79, 435439 (2014)) showed that arachi donic acid increases cytosolic Ca2+ concentrations in C2C12 skeletal myotubes mainly via activation of the ryanodine (RY) receptor 1. These results are consistent with the data from another study demonstrating that arachidonic acid targets RY receptor 2 in clonal and primary pancreatic betacells (Woolcott et al., 2006). A novel and intriguing finding by Muslikhov's group is that arachidonic acid also appears to activate the twopore ion channel (TPC), suggesting that arachidonic acid could be a mediator in the interaction between TPCs and RY receptors. PMID- 25522456 TI - Failure to launch. PMID- 25522457 TI - Reframing what we tell parents about normal infant sleep and how we support them. PMID- 25522458 TI - Infant feeding practices among Sudanese women now living in regional south east Queensland, Australia. AB - The purpose of this research was to highlight and compare immigrant Sudanese women's infant feeding choices and patterns before and after moving to a regional city in Queensland, Australia. Semi-structured interviews were conducted with 10 Sudanese mothers who had birthed and breastfed babies both in Africa and Toowoomba. This qualitative research project supported previous research indicating a trend for immigrant women's breastfeeding duration to decline when they moved to another country. The outcomes of this research suggest that the reasons for this decline are complex. The authors conclude that a lack of social support, language difficulties and wanting to fit in with particular Western practices are contributing factors. PMID- 25522459 TI - Existential vulnerability can be evoked by severe difficulties with initial breastfeeding: a lifeworld hermeneutical single case study for research on complex breastfeeding phenomena. AB - Many mothers initiate breastfeeding, but some of these experience difficulties. This study has two aims in order to contribute to the development of optimal care for these mothers: firstly to explain and understand the existential meanings of one mother's severe initial breastfeeding difficulties and how these meanings affected her continued breastfeeding and secondly, to reflect on a method for applying lifeworld hermeneutics to research on complex breastfeeding phenomena. This is an approach that acknowledges and focuses on the concrete and lived existence and what it means for humans. Within this approach, humans are understood as whole human beings interacting in the world. The study was conducted using lifeworld interviews with Anna, focusing on meanings of her difficult lived experience of initial breastfeeding. The existential interpretation suggests that such an experience can evoke existential vulnerability, a vulnerability that becomes evident in shameful feelings, such as dislike of breastfeeding, aversion to the milk-producing body and anger towards the child. Anna continued breastfeeding as a way to rid herself of the shame, hoping to be confirmed as a good mother. Such an experience may have negative consequences for the mother-child relationship and it can create fear for future breastfeeding. This study concludes that carers should be aware of individual existential dimensions for breastfeeding mothers. PMID- 25522460 TI - Probiotics are the new black. PMID- 25522461 TI - ["Died suddenly and unexpectedly..."]. PMID- 25522462 TI - [It is a disgrace for the western world]. PMID- 25522463 TI - [Our image of dying and of death is subject to a time of change. Our author reviews the development and presents an outlook. Doubting the natural course]. PMID- 25522464 TI - [Subjective perception plays a central role]. PMID- 25522465 TI - [Emergencies in palliative medicine. It is always about the optimum of the possibilities]. PMID- 25522466 TI - [We will never lie]. PMID- 25522467 TI - [The family as proxy]. PMID- 25522468 TI - [Preserving dignity]. PMID- 25522469 TI - [It depends on nursing intervention]. PMID- 25522470 TI - [Reducing loud respiratory sounds of dying patients]. PMID- 25522471 TI - [Taking new pathways]. PMID- 25522472 TI - [German problems - international routes]. PMID- 25522473 TI - [Palliative care in family life: a systematic literature review about unmet needs]. PMID- 25522474 TI - [Ethically relevant decisions at the end of life: the question of indications. Leaving the formal level]. PMID- 25522475 TI - [The personal reserve is taboo]. PMID- 25522477 TI - [In focus: Chronic hepatitis and liver cirrhosis. When physical strength fails]. PMID- 25522478 TI - [Nursing and providing care at the end of life: every person decides for himself]. PMID- 25522479 TI - [Follow up protocol for post augmentation mammaplasty patients ]. PMID- 25522480 TI - [Reconstruction of facial soft tissue defects with pedicled expanded flaps]. AB - OBJECTIVE: To investigate the application of pedicled expanded flaps for the reconstruction of facial soft tissue defects. METHODS: The expanded skin flaps, pedicled with orbicularis oculi muscle, submental artery, the branch of facial artery, superficial temporal artery, interior upper arm artery, had similar texture and color as facial soft tissue. The pedicled expanded flaps have repaired the facial soft tissue defects. RESULTS: Between Jan. 2003 to Dec. 2013, 157 cases with facial soft tissue defects were reconstructed by pedicled expanded flaps. Epidermal necrosis happened at the distal end of 8 expanded flaps, pedicled with interior upper arm artery(4 cases), orbicularis oculi muscle(3 cases) and submental artery(1 case), which healed spontaneously after dressing. All the other flaps survived completely with similar color and inconspicuous scar. 112 cases were followed up for 8 months to 8 years. Satisfactory results were achieved in 75 cases. 37 cases with hypertrophic scar at incisions need secondary operation. CONCLUSIONS: Island pedicled expanded flap with similar texture and color as facial soft tissue is suitable for facial soft tissue defects. The facial extra-incision and large dog-ear deformity could be avoided. PMID- 25522481 TI - [The classification and surgical treatment of the terminal phalanx of congenital thumb duplication ]. AB - OBJECTIVE: To study the classification and individualized treatment of the terminal phalanx of thumb duplication. METHODS: From Apr. 2003 to Dec. 2012, 76 patients with 77 involved thumbs duplication at the level which is distal to the interphalangeal joint were retrospectively studied. Based on the morphology (the nail width and the thumb circumference) and the deviation of the thumb, we classified the terminal phalanx of thumb duplication into 5 types as Type A (no bony connection called floating thumb), Type B(asymmetry and no deviation), Type C(asymmetry and deviation), Type D (symmetry and no deviation) and Type E(symmetry and deviation). Different surgical procedures were selected according to different types. Simple excision of the smaller thumb was adopted for Type A case. Removement of the smaller thumb (usually the radial) and of the collateral ligament of the interphalangeal joint were selected for Type B. Removement of the smaller thumb (usually the radial) and reconstruction of the collateral ligament of the interphalangeal joint, as well as corrective osteotomies at the neck of the proximal phalanx were performed for Type C. The modified Bilhaut-Cloquet procedure with reconstruction of the collateral ligament of the interphalangeal joint were adopted in Type D. The classical Bilhaut-Cloquet procedure, or the modified Bilhaut-Cloquet procedure with reconstruction of the collateral ligament of the interphalangeal joint and corrective osteotomies at the neck of the proximal phalanx were performed in Type E. The results were assessed by an evaluation form for thumb duplication by the Japanese Society for Surgery of the Hand. RESULTS: According to our new classification standard, there were 3 cases with Type A duplicated thumbs, 36 with Type B, 13 with Type C, 15 with Type D, 10 with Type E. All the 76 patients underwent the individualized surgical treatment. The patients were followed up for 6-60 months. According to the evaluation form, excellent results were achieved in 66 thumbs, good in 9 thumbs and fair in 2 thumbs. CONCLUSIONS: The new classification could comprehensively describe the clinical features of the terminal phalanx of congenital thumb duplication. Individualized therapy, including basic and repeated surgical procedure could be adopted for each type with satisfactory results. PMID- 25522482 TI - [Treatment of skin and soft tissue defect in the hallex with flaps ]. AB - OBJECTIVE: To summarize the therapeutic effect of 5 kinds of flaps for the treatment of skin and soft tissue defect in the hallex. METHODS: From Jan. 2008 to Jun. 2013, 24 cases with skin and soft tissue defects in the hallex were treated with 5 kinds of reversed flaps, including medial foot dorsal neurocutaneous flaps, medial foot neurocutaneous flaps, lateral tarsal flaps, anterior malleous flaps, medial cross leg and saphenous nerve flaps. The defects size ranged from 3 cm x 2 cm to 5 cm x 3 cm, with the flap size from 3. 5 cm x 2. 5 cm to 5. 5 cm x 4. 0 cm. RESULTS: Partial superficial necroisis happened at the distal end of one foot dorsal medial neurocutaneous flap. One third flap necrosis occurred in 1 foot medial neurocutaneous flap due to too tight suture at flap pedicle and resulted thrombosis. All the other 23 flaps survived completely. 15 cases were followed up for 3-36 months with normal walking function and satisfactory appearance. Among the 8 cases with nerve anastomosis, 4 cases were followed up with 2-point discrimination distance of 8-11 mm. the flaps without nerve anastomosis also had protective sense due to nerve ingrowth. CONCLUSIONS: Skin and soft tissue defects in the hallex can be treated with different appropriate flaps. The hallex length can be reserved with satisfactory function and appearance. PMID- 25522483 TI - [Flow-through deep inferior epigastric perforator flaps transplantation for reconstruction of large defects at the extremities]. AB - OBJECTIVE: To investigate the clinical application of flow-through deep inferior epigastric perforator flaps for reconstruction of large defects at the extremities. METHODS: The deep inferior and superior epigastric arteries were designed as the axial vessel and the arterial supply to the flap was the paraumbilical perforator artery. Free deep inferior epigastric perforator flaps were harvested in flow- through manners to reconstruct associated arterial defect in the wound. The sensation assessment,Enneking score,and questionnaire of the flap aesthetic were all performed during follow-up period. RESULTS: From December 2011 to September 2012, 5 patients with large defects at extremities were treated. The deep inferior and superior epigastric arteries were designed as the axial vessel and the arterial supply to the flap was the paraumbilical perforator artery. The wound defects ranged form 11 cm x 5 cm to 30 cm x 11 cm. And the flap size ranged from 13 cm x7 cm to 33 cm x 13 cm. All flaps survived completely. The recipient arteries were all bypassed well documented by color Doppler examinations. All cases had 12-24 months' follow-up period. The flaps had good appearance and high aesthetic satisfactory(100%). 12 months after operations, sensation assessment were all S3+, and the Enneking score ratios were 82%-95% ,with 87.2% in average. CONCLUSIONS: Flow-through deep inferior epigastric perforator flaps are reliable and effective for reconstruction of large defects at the extremities with maintenance of the vascular status of the extremities. The flaps can also be designed in transverse or oblique mode for clinical application. PMID- 25522484 TI - [Application and therapeutic effect of frontal muscle fascia compound flap suspension for congenital blepharoptosis in children]. AB - OBJECTIVE: To investigate the application and therapeutic effect of frontal muscle fascia compound flap suspension for congenital blepharoptosis in children. METHODS: From July 2010 to March 2012, 21 children (23 eyes) with congenital blepharoptosis were treated with frontal muscle fascia compound flap suspension. The therapeutic effect was observed and followed up. RESULTS: 17 patients were followed up for 3-6 months with relapse in one case. The ptosis was corrected in the other 1 cases. CONCLUSION: The frontal muscle fascia compound flap suspension is effective and practical with minimal morbidity and lower complication for the correction of congenital blepharoptosis. PMID- 25522485 TI - [The middle-forearm flap based on perforator of ulnar artery for electrical burn wound on the wrist ]. AB - OBJECTIVE: To dicuss the application and therapeutic effect of middle-forearm flap based on perforator of ulnar artery for electrical burn wound on the wrist. METHODS: From Oct. 2009 to Oct. 2012, 10 cases of electrical burn wounds on the wrist were treated. A line from radialis medial epicondyle of humerus to the interior radialis pisiform bone was connected as flap axis. At the midpoint of the line, Doppler flow imaging meter was used to detect the emerging point of perforator vessel. The flap was designed and harvested. The flap was transferred reversely, with superficial vein retaining which was anastomosed with vein at recipient sites in 3 cases. The wounds in the donor sites were closed directly in 2 cases, and with skin graft in 8 cases. RESULTS: All the 10 flaps survived completely. 7 cases without vein anastomosis underwent obvious flap edema during 2-4 days postoperatively, which resovled 1 week later. Sub-flap tissue necrosis and infection happened in 2 cases, which healed after dressing and drainage. Patients were followed up for 3-36 months with satisfactory results. CONCLUSIONS: The middle-forearm flap based on perforator of ulnar artery has a stable and reliable blood supply. It offers a new choice for the electric burn wound on the wrist, especially at the ulnar side. PMID- 25522486 TI - [The imaging study of internal mammary artery and its branches ]. AB - OBJECTIVE: To investigate the distribution of the internal mammary artery and its branches by the multi-slice spiral CT angiography, and to explore the feasibility of transferring pedicled transverse rectus abdomials myocataneous (TRAM) flap for breast reconstruction through resection of inferior costicartilages. METHODS: 30 female patients received abdominal CT angiography. (1) The distance between internal mammary artery and the sternum midline were recorded; (2) The position and the numbers of branches from bilateral internal mammary arteries at the level of 5th, 6th, 7th rib was observed; (3) The points where the superior epigastric artery gets through the rectus abdominis muscle were located. RESULTS: ( The average distance between left internal mammary artery to the sternum midline is from 1. 66 cm (0. 62-2. 39 cm ) to 2.34 cm (0.69-3.36 cm) at the level from 4th to 6th intercostal space. The average distance between right internal mammary artery to the sternum midline is from 1.55 cm(0. 66-2. 29 cm) to 2.29 cm(0. 73-3. 67 cm) at the level from 4th to 6th intercostal space; ) The number of branches is the most at the level of 6th intercostal space; (3) There are 235 branches in the superior epigastric artery. CONCLUSIONS: This imaging study of internal mammary artery explores the feasibility of transferring pedicled transverse rectus abdominals myocataneous flap for breast reconstruction. It has important significance in the breast reconstruction using TRAM flap with lengthened pedicle. PMID- 25522487 TI - [Application of three-diinensional CT in the treatment of oblique facial clefts with mandibular outer cortex]. AB - OBJECTIVE: To investigate the application of three-dimensional CT(3D-CT) in the treatment of oblique facial clefts with mandibular outer cortex, including the surgical design and results assessment. METHODS: From Jan. 2003 to Dec. 2013, 22 cases with oblique facial cleft, who underwent mandibular outer cortex onlay bone graft were retrospectively studied. 3D images from CT data were reconstructed before operation for design. Then the mandibular outer cortex onlay bone transplant was performed to reconstruct the bone defect and cleft. 3D CT was performed 5-10 days postoperatively and 6- 12 months postoperatively to assess the facial symmetry. RESULTS: According to the results of CT measurement, the average volume of the orbital bone defects on the affected side decreased by(64. 6 +/- 14. 4)% 5 to 10 days after operation. The average volume of the maxillary and zygomatic bone defects on the affected side decreased by(71.4 +/- 15.7)% after surgery. After 6 to 12 months,the average recovery of the mandibular donor site was (57. 9 +/- 13. 9)% of the removed mandibular outer cortex. The average absorption of grafted bones was(24.7 +/- 25.6 )%. The average height difference between the centre of pupils on both sides before surgery was(3.76 +/- 1.27) mm,which decreased to( 1. 15 +/- 1.00) mm 5 to 10 days after surgery(P =0. 000) , and( 1.35 +/- 1. 13) mm 6 to 12 months after surgery(P = 0. 003). The relapse may be caused by the absorption of the grafted bones. CONCLUSIONS: 3D-CT can be used for preoperative design and postoperative assessment in the treatment of oblique facial cleft with mandibular outer cortex. PMID- 25522488 TI - [Effect of lentivirus-mediated hIL-24 gene on proliferation, migration and invasion of keloid fibroblasts]. AB - OBJECTIVE: To investigate the effect of hIL-24 gene on proliferation, migration and invasion activity of human keloid fibroblasts (KFs). METHODS: hIL-24 gene was cloned into lentivirus vector, then the lentivirus particles expressing hlL-24 were infected into KF cells. Real-time PCR and Western blot were performed to examine the expression of hIL-24 in lentivirus infected cells. The growth ability was detected by MTT assay. The cell cycle was analyzed by flow cytometry, The invasion and migration were detected by matrigel invasion assay and wound healing assay. RESULTS: Comparing to controls group and KF-NC group, the expression levels of hIL-24 mRNA and protein were both significantly up-regulated after 4 days of hIL-24 lentivims infection. Comparing with the KF-NC group, MTT assay showed that the A490 of KF-hlL-24 group was down-regulated after lentivims infection ( P < 0. 05 ). Comparing with the KF-NC group, Cell cycle test revealed hlL-24 gene could block KF cells in G1 [(75. 40 +/-2. 10)% ] , the proportion of KF cells was decreased in S phase [(4. 96 +/- 1. 60)% ] and G2 phase [(0.01 +/- 0.01)% ]. After KF cells were infected(P <0.01). Transfection of hlL-24 lentivirus inhibited the migration and invasion activity of KF cells. CONCLUSION: Lentivirus-mediated hlL-24 gene efficiently inhibits proliferation, cell cycle progression, migration and invasion activity of KF cells. PMID- 25522489 TI - [Effects of gene transfection at different time on the expression of bone morphogenetic protein-2 during mandibular distraction]. AB - OBJECTIVE: To investgate the expression patterns of bone morphogenetic protein-2 (BMP-2) in the distraction area following plRES-hBMP2-VEGFI65 gene transfection at different time during mandibular distraction osteogenesis in a rabbit model. METHODS: 48 New-Zeland rabbits were employed to underwent osteotomy and distraction devices implantation on mandible bilaterly. After 3 days of latency period, the devices were activated at the rate of 0. 8 mm per day for 10 days. The rabbits were randomly divided into 4 groups (group A, B, C and D). Group A, B and C were transfected recombinant plasmids pIRES-hBMP2-hVEGF165 via electroporation-mediated approach at latency period, distraction period, consolidation period respectively. Group D was used as control group without gene transfection. Three rabbits in each group were sacrificed at 1, 2, 4 weeks of consolidation respectively. The mandibles were harvested for immunohistochemical staining detection of BMP-2 expression respectively, which were analyzed by CMIAS series multifunction color quantitative analysis of pathological image analysis system. RESULTS: BMP-2 expression was found to be mainly located in the monocyte, fibroblast of the granulation tissue, the osteoblasts, osteocyte on the surface of new formed trabecular, and the connective tissues surrounding the new formed bone. The expression in group B was superior to other groups. Image analysis showed that, at the first week and second week of consolidation, the expression abosordbance A in group B (0. 58 +/- 0. 03 and 0. 34 +/- 0. 02) was relatively higher, when compared with that in group A (0. 42 +/- 0. 02 and. 31 +/-0.01), C(0.32 +/-0.01 and 0.30 +/-0.01)and D(0.27 +/-0.01 and 0.23 +/-0.02), showing a significant difference(P <0. 05). It was also relatively higher in group A(0. 42 +/- 0. 02 and 0. 31 +/- 0. 01) and C(0. 32 +/- 0.01 and 0.30 +/- 0.01), when compared with that in group D(0. 27 +/-0.01 and 0.23 +/- 0. 02), showing a significant difference( P < 0. 05) , but there was no significant difference ( P > 0. 05) between group A and group C. At the fourth week of consolidation, the expression decreased and there was no significant difference among group A, B, C, D. CONCLUSIONS: The electroporation-mediated gene transfection which is transfected at the beginning of traction can promote BMP-2 expression effectively, stimulate bone marrix synthesis and induce proliferation and differentiation of fibroblasts, osteoblasts, endothelial cells, which further effectively promote the new bone formation. It suggests that the distraction stage is the optimal time for gene therapy. PMID- 25522490 TI - [The role of histone H3 acetylation on cleft palate in mice induced by 2, 3, 7, 8 tetrachlorodibenzopdioxin ]. AB - OBJECTIVE: To explore the role of histone H3 acetylation in cleft palate induced by 2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD) in C57BL/6J mice, and its mechanism. METHODS: On gestation day 10 (GD10), 36 pregnant mice were randomly divided into two groups as the treated group(n = 18) and the control group( n = 18). The mice in the treated group received intragastric administration with TCDD 28 MUg/kg, while the mice in the control group received equivalent corn oil. The pregnant mice were sacrificed on GD13. 5, GD14. 5 and GD15. 5, collecting fetal palates to determine the activities of histone acetyltransferases (HATs) by Colorimetric and the expression level of acetylated histone H3 (Acetylated histone H3, Ac-H3) by Western-blot. RESULTS: The activity of HATs was 0.409 7 +/- 0.0147, 0.522 3 +/- 0.017 1 and 0.643 5 +/- 0.013 9 in control group on GD13.5, GD14.5 and GD15.5; 0.865 0 +/- 0.0129, 0.719 1 +/- 0.017 8 and 0.551 2 +/- 0.016 8 in TCDD group. The activity of HATs in TCDD group was higher than that in control group on GD13. 5, GD14. 5, showing significantly difference between the two groups (t = - 56. 932, t = - 19. 516, P < 0.01); however, the activity of HATs in TCDD group was significantly lower than that in control group on GD15. 5 (t = 10. 382, P < 0.01). The expression level of Ac-H3 was 0.745 0 +/- 0.113 5, 1.055 9 +/- 0.249 4 and 1.795 5 +/- 0.081 9 in control group on GD13. 5, GD14. 5 and GD15. 5; while 1.4490 +/- 0. 1460, 1. 641 8 +/- 0.099 7 and 1. 512 1 +/- 0. 150 2 in TCDD group. The expression of Ac-H3 in TCDD group was higher than that in control group on GD13. 5, GD14. 5, showing significantly difference( t = -6. 593, -3. 779, P <0. 01, P <0.05) ; However, the expression of Ac-H3 in TCDD group was statistically lower than that in control group (t = 2. 870, P <0. 05). CONCLUSION: The acetylation of histone H3 was involved in the cleft palate of C57BL/6J mice induced by TCDD, which may be one of the mechanisms in TCDD-induced cleft palate. PMID- 25522491 TI - [Effects of propranolol on proliferation of hemangioma-derived mesenchymal stem cells ]. AB - OBJECTIVE: To explore the new mechanism of propranolol for treatment of hemangioma and the effects of propranolol on proliferation of hemangioma-derived mesenchymal stem cells ( Hem- MSCs). METHODS: We isolated Hem-MSCs from hemangioma in the proliferating phase by their selective adhesion to plastic culture dishes. Immunofluorescence staining was used to examine the expression of marker antigens in Hem-MSCs. Human umbilical vein endothelial cells(HUVECs) were used as control. Indiuction of multi-lineage differentiation including osteogenesis and adipogeneis was performed with appropriate medium to identify the multi-lineage differentiation potential. MTT cell counting was used to observe the effects of different concentrations of propranolol on proliferation of Hem-MSCs. RESULTS: Hem- MSCs were fibroblast-like morphology. All of them expressed vimentin, most expressed alpha-SMA,CD133, some expressed Glutl, and none of them expressed VEGF. Osteogenic, adipogenic differentiations of Hem- MSCs were induced successfully. Effects of low concentration of propranolol on proliferation of Hem-MSCs were not obvious, while high concentration of propranolol can inhibit the proliferation of Hem-MSCs. CONCLUSIONS: The cells we isolated from hemangioma are Hem-MSCs. High concentration of propranolol can inhibit the proliferation of Hem-MSCs. PMID- 25522492 TI - [Anatomical basis of the flap based on the perforator of the first plantar metatarsal artery ]. AB - OBJECTIVE: To investigate the morphological features of the perforator from the first plantar metatarsal artery, so as to provide anatomic basis for the reconstruction of soft-tissue defects of the forefoot. METHODS: The first metatarsophalangeal joint was chosen as the landmark on 30 human cadaveric feet prefused with red latex. The following contents were observed under surgical magnifier: (1)The origin, courses,branches,distribution of the perforator of the first plantar metatarsal artery; (2)The anastomoses among the perforator of the first plantar metatarsal artery and other arteries on the medial aspect of the foot. Simulated operation was performed on one fresh specimen. RESULTS: The perforator of the first plantar metatarsal artery passed through the space between the tendon, the abductor hallucis and the first metatarsal bone, and its entry point into the deep fascia was located (2. 3 +/- 0.7 ) cm proximal to the first metatarsophalangeal joint. The perforator anastomosed with either the medial tarsal artery, the medial anterior malleolus artery or the branch of the medial plantar artery on the superior margin of the abductor hallucis, forming a longitudinal arterial chain,through which small branches were given off to the skin of the medial aspect of the foot. The perforator was( 1. 1 +/- 0.2) mm in diameter and(3.2 +/- 0.2) cm in length. CONCLUSION: The flap based on the perforator of the first plantar metatarsal artery can be harvested as an axial flap to repair the defects of soft tissue on the forefoot. PMID- 25522493 TI - With strengthened guidelines for health care workers, the CDC ups its game against the deadly Ebola virus. AB - Informed by the cases of two nurses who contracted Ebola virus disease (EVD) while caring for a patient with the disease in Dallas, TX, the Centers for Disease Control and Prevention (CDC) in Atlanta, GA, has unveiled strengthened guidance for health care workers. Further, nursing organizations are pledging to work together to identify gaps and make system-level improvements to protect both patients and caregivers. The CDC's new recommendations emphasize rigorous training for health care workers in how to put on and take off personal protective equipment (PPE), and they state that this activity should always be carefully supervised by a monitor. The guidance also states that health care workers should use either an N-95' respirator mask or a powered air purifying respirator (PAPR) when they are providing care to a patient with Ebola. Experts stress that the new guidance does not change the fundamental issue that Ebola is transmitted through contact with infectious substances from patients. Nursing organizations are pledging to work together to identify problems and improve safety for both caregivers and patients. PMID- 25522494 TI - State, local authorities in the driver's seat for much of the Ebola response. PMID- 25522495 TI - Hospitals prepare plans, drill staff to ensure that potential Ebola patients are identified, isolated, and managed safely. AB - Hospitals around the country have stepped up their efforts to train staff and implement procedures to ensure the safe identification and management of any patients with signs of Ebola virus disease (EVD). Ronald Reagan UCLA Medical Center in Los Angeles, CA, held an "Ebola preparedness exercise" to give staff an opportunity to walk through the hospital's protocol for handling a simulated patient with EVD. The University of Alabama at Birmingham (UAB) Medical Center has held similar exercises, and is now holding twice-weekly meetings of its leadership team to make sure that all new developments in the Ebola outbreak are communicated. UCLA Medical Center has prepared PPE kits based on the practices developed at Emory University Hospital, which has thus far had the most experience in this country in caring for patients with EVD. The UCLA Health System has adjusted its medical record system so that a red flag is placed on the electronic medical record [EMR] of any patient who has recently traveled to a high-risk area. UAB Medical Center has incorporated what had been a paper-and pencil screening tool for EVD into its electronic medical record. Training on PPE as well as EVD screening is being provided to first-responders and 911 call center dispatchers in the UAB system. PMID- 25522496 TI - From the trenches--finding lost ED revenue. PMID- 25522497 TI - TJC: plan and prepare for the transition to new tubing connectors to minimize the risk of dangerous misconnections, clinician frustration. AB - To reduce the risk of dangerous tubing misconnections, the ISO is rolling out new tubing connector standards that will eventually make it nearly impossible for tubing associated with one delivery system to be connected to a delivery system that serves a different purpose. Experts welcome the change, noting that tubing misconnections that cause injury and even death have been happening for years. However, TJC has issued a Sentinel Event Alert, warning that health care organizations need to be vigilant in managing the risk posed by these misconnections during the phased-in transition to the new connectors. Experts explain that tubing misconnections occur because many different types of tubing utilize the same Leur connector, making it possible for a clinician to mistakenly connect a tube to the wrong delivery system. The most common type of tubing misconnection reported to the ISMP is when a clinician wants to administer something to a patient through a feeding tube, but accidently administers the substance through an IV tube instead. The first new connector, called the ENFit, is going to be for enteral feeding tubes. It will not connect to IV tubing, making that type of misconnection unlikely. The new connector should be available early next year. Since hospitals will continue to use older tubing until their supplies are exhausted, manufacturers will temporarily provide adapters capable of making new administration sets compatible with older tubing. PMID- 25522498 TI - Seize upon mistakes/errors as opportunities for system improvement. PMID- 25522499 TI - Preliminary study on avian fauna of the Krishna River basin Sangli District, Western Maharashtra, India. AB - The present study on avifaunal diversity carried out for three years at the Krishna River Basin, Sangli District revealed a total of 126 species of birds belonging to 30 families, of which 91 species were resident, 16 migratory, 12 resident and local migratory and 7 species were resident and migratory. Among the migrant birds, Rosy Starling Sturnus roseus was dominant in the study area. Commonly recorded resident bird species were, Red vented bulbul, Jungle crow, House sparrow, Common myna, Brahminy myna, Rock pigeon, Spotted dove, Rose ringed parakeet, Indian robin, White-browed fantail-flycatcher and Small sunbird. Most of the families had one or two species, whereas Muscicapidae family alone had 16 species. Forty one species of waterfowls were recorded in this small landscape. Out of 126 bird species, 38 were insectivorous, 28 piscivorous, 25 omnivorous, 19 carnivorous, 9 granivorous, 5 frugivorous and 2 species were nectar sucker and insectivorous. These results suggest that richness of avifauna in the Krishna River Basin, Western Maharashtra might be due to large aquatic ground, varied vegetations and favourable environmental conditions. PMID- 25522500 TI - Feeding and filtration rates of zooplankton (rotifers and cladocerans) fed toxic cyanobacterium (Microcystis aeruginosa). AB - Microcystis aeruginosa is generally dominant in many Mexican freshwater ecosystems interacting with zooplankton species. Hence, feeding and filtration rates were quantified for three cladoceran (Daphnia pulex, Moina micrura and Ceriodaphnia dubia) and three rotifer species (Brachionus calyciflorus, Brachionus rubens and Plationus patulus) using sonicated M. aeruginosa alone or mixed with Scenedesmus acutus in different proportions (25, 50 and 75%, based on cell density), offering a combined initial density of 100,000 cells.ml(-1). All the three cladoceran species ingested M. aeruginosa (100-300 cells ind(-1) min( 1)) when fed exclusively with cyanobacterium. When green alga offered as exclusive diet, the number of cells ingested by the tested cladocerans varied from 80 to 400 cells ind(-1) min(-1). Compared to cladocerans, rotifers in general consumed much lower quantity (< 200 cells ind(-1) min(-1)) of M. aeruginosa and S. acutus. The filtration rate for Daphnia pulex was inversely related to the proportion of green alga in the diet. For other tested cladocerans, no such clear trend was evident. In mixed treatments containing M. aeruginosa, the filtration rate of Daphnia was highest (about 220 MUl ind(-1) min(-1)) when the medium contained 75% of S. acutus. Among the rotifer species, P. patulus filtered highest volume (100 MUl ind(-1) min(-1) from mixed diets containing higher proportions (50 or 75%) of M. aeruginosa. Thus, there were species-specific differences in the filtration and feeding rates of zooplankton when offered mixed diets of green algae and toxic cyanobacteria. These probably explain the coexistence of different zooplankton species in Microcystis-dominant waterbodies. PMID- 25522501 TI - Effect of alpha-naphthalene acetic acid and thidiazuron on seedling of economic crops grown in endosulfan sulfate-spiked sand. AB - The effect of two plant growth regulators, alpha-naphthalene acetic acid (NAA) and thidiazuron (TDZ) on the growth of sweet corn (Zea mays), cowpea (Vigna sinensis) and cucumber (Cucurmis sativus) seedling planted in 1-100 mg kg(-1) of endosulfan sulfate spiked sand was investigated. Endosulfan sulfate had no apparent toxicity as seedlings of these crop plants grew normally in endosulfan sulfate spiked sand. Concentration of endosulfan sulfate in sand affected the response of seedling induction by NAA or TDZ. Induction of crop seeds by NAA or TDZ did not promote growth of sweet corn, cowpea and cucumber to an appreciable extent. Both plant regulators at concentration of 10 mg l(-1) seemed to exert adverse effect on crop seedling. TDZ decreased shoot length, root length and chlorophyll contents in leaves of sweet corn and cowpea growing in endosulfan sulfate spiked sand. In contrast, NAA was not toxic and promoted growth of sweet corn and cowpea seedling. However, cucumber was affected by NAA and TDZ more than other plants. TDZ significantly decreased biomass and root length of cucumber. Also, NAA significantly decreased cucumber root length and tended to increase cucumber root dried weight when grown in 100 mg kg(-1) of endosulfan sulfate spiked sand. PMID- 25522502 TI - Biodecolourisation of reactive red an industrial dye by Phlebia spp. . AB - Four white rot fungi namely Phanerochaete chrysosporium, Phlebia floridensis, P. radiata and P. brevispora were selected for their ligninolytic enzymes viz., lignin peroxidase, manganese peroxidase and laccase. Cell free enzyme extracts (as such and concentrated) obtained from these fungi were tested for their ability to decolourise reactive red 28 (Congo red), an industrial dye. The use of cell free enzyme extracts helped to overcome the problem of adsorption of dye to mycelia. Laccase production was best expressed in P. brevispora. Increase in decolourisation percentage by concentrated culture extract was comparable to increase in enzyme activity. P. floridensis proved to be a better dye decolouriser in comparison to Pha. chrysosporium, thus showing its potential for biocleaning of industrial wastes and wastewaters. PMID- 25522503 TI - Induced changes in the antioxidative compounds of Vigna mungo genotypes due to infestation by Bemisia tabaci (Gennadius). AB - Antioxidative compounds were quantified from the leaves of nine black gram (Vigna mungo (L.) Hepper) genotypes over a period of two years, for potential whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleryrodidae) resistance. Oviposition preference, nymphal and adult development were evaluated under screen-house conditions. Biochemical analysis revealed that higher per cent increase in the total phenol and o-dihydroxy phenol contents both at 30 and 50 days after sowing was evident in moderately resistant genotypes NDU 5-7 (49.6 and 50.8%, respectively) and KU 99-20 (47.8 and 50.8%, respectively) under whitefly stress conditions as compared to non-stressed plants. Tannin and flavonol contents in leaves increased to varying degrees (up to 11.1 and 7.1%, respectively) in resistant plants after whitefly infestation, indicating that the changes in tannin and flavonol contents were closely associated with the resistance to whitefly. Correlation studies relating leaf content of black gram antioxidative compounds from different genotypes with whitefly population were also worked out. Total phenols (r = -0.71 & -0.88), o- dihydroxy phenols (r = -0.56 & -0.76), flavonols (r = -0.80 & -0.81) and tannins (r= -0.16 & -0.26) showed significant negative correlation with whitefly population (nymphs and adults) suggesting that enhanced level of these biochemicals may contribute to bioprotection of black gram plants against B. tabaci infestation. Comparatively higher level of resistance in genotype NDU 5-7 and KU 99-20 can serve as base for genetic improvement of black gram, focusing on the development of resistant varieties to B. tabaci. PMID- 25522504 TI - Effect of different concentrations of benzyladenine and frequency of watering on growth and quality of Dracaena sanderiana and Codiaeum variegatum. AB - The effect of benzyladenine concentration and watering frequency on the growth and quality of Dracaena sanderiana and Codiaeum variegatum was evaluated. Plants were treated with different benzyladenine concentrations of (0, 75, 150, 225 or 300 mg l(-1)) and watering frequencies, daily, every 4, 7 or 10 days interval. Benzyladenine concentration and watering frequency interacted significantly for plant grade on both species. This interaction resulted in the highest grade at 225 mg l(-1) benzyladenine and daily watering for D. sanderiana and 150 mgl(-1) benzyladenine and daily watering for C. variegatum. No significant interactions between benzyladenine concentration and watering frequency were observed for photosynthesis rate, stomatal conductance, specific leaf area and fresh weight of either species. For D. sanderiana, the highest photosynthesis rate (5.70 mmolm( 2)s(-1)) occurred at 225 mg l(-1) and decreased with increasing watering frequency. For C. variegatum, the highest photosynthesis rate (4.49 mmolm(-2)s( 1)) was recorded with benzyladenine concentration of 150 mg l(-1), and photosynthesis rate was found independent of watering frequency. For both species, stomatal conductance was recorded highest at 225 mg l(-1), but watering frequency failed to influence stomatal conductance. For better quality, D. sanderiana should be sprayed with benzyladenine at 225 mg l(-1), and C. variegatum with benzyladenine at 150 mg l(-1) in combinations with watering at 4 days interval. PMID- 25522505 TI - Water quality assessment of the Sinchun stream based on epilithic diatom communities. AB - Water quality was assessed 11 sites on the Sinchun Stream, in the region of Daegu City (South Korea), from May 2007 to March 2008 using Diatom Assemblage Index to Organic Water Pollution (DAIpo) and Trophic Diatom Index (TDI). The reference sites were unaffected by effluent from a closed mine or treated sewage and had, epilithic diatom communities that were dominated by saproxenous taxa such as Achnanthes convergens and Cocconeisplacentula var. lineata. The water quality of these sites had DAIpo values ranging between 77.5-93.8 and TDI values between 51.3-67.6, indicating beta-oligosaprobic and mesotrophic environments, respectively. Study sites affected by effluent from the closed mine had epilithic diatom communities that were dominated by acidobiontic diatoms, such as Eunotia exigua and Achnanthidium minutissimum. The water quality of these sites had DAlpo values of 45.9-70.8, indicating beta-mesosaprobic to alpha-oligosaprobic environments, whereas TDI ranged between 1.7-66.9, indicating an oligotrophic to mesotrophic environment. Downstream sites affected by the influx of mine effluent and treated sewage had many species and a high percentage of saprophilous taxa, including Fragilaria construens var. venter and Nitzschia amphibia. The water quality of these regions had DAIpo values ranging between 21.8-33.1 and TDI values between 67.5-76.7, indicating alpha-mesosaprobic and eutrophic environments, respectively. PMID- 25522506 TI - Antioxidative enzymes and biochemical changes in paclobutrazol induced flowering in mango (M. indica) cultivars. AB - A study was conducted to examine the level of nonstructural carbohydrate, protein concentration and the activity of antioxidative enzymes viz. catalase and peroxidase in buds of different stages (Stages: I-before flower bud differentiation, II-flower bud differentiation, III-bud burst, IV-panicle elongation) and their adjacent leaves of biennial (Chausa, Dashehari, Langra) and the regular (Amrapali) cultivars. In the present study, Amrapali being the regular cultivar, contained higher levels of total and reducing sugar (4.49 to 12.67 mg g(-1) f.wt.) and protein content (1.90 to 6.78 mg g(-1)) in all the developmental stages of flowering as compared to biennial cultivars. However, in leaves gradual reduction in sugar and protein content was noticed in the advance stages of flowering. Paclobutrazol (2-8 g.a.i.), a flower inducing chemical, enhanced the catalase and peroxidase activities over the untreated control and maximum enhancement was recorded at 8 g.a.i. On the other hand, decreasing trend of protein with paclobutrazol treatment was recorded in adjacent leaves of flower buds. The results implicated the possible role of catalase and peroxidase and other associated biochemical changes in paclobutrazol induced flowering in mango. PMID- 25522507 TI - Control of wilt disease of lentil through bio control agents and organic amendments in Tarai region of Uttarakhand, India. AB - The present work aimed at evaluating the efficacy of bioagents and organic amendments against lentil wilt pathogen. Field trials were carried out consecutively during Rabi 2010-11 and 2011-12 crop seasons in Randomized Block Design (RBD) with three replications, using 'Pant L-639' a popular cultivar. The plot size was 3.0 x 1.5 m2 with row spacing of 30 cm. Effect of selected bioagents and organic amendments on disease incidence, 1000 grain weight and yield kg ha' of lentil was recorded. It was observed that seed treatment with Trichoderma harizanum + Pseudomonas fluorescens significant by reduced 1.73% (2010-11) and 1.93% (2011-12) in Fusarium wilt disease incidence and increase in grain yield 507.6 kg ha(-1) and 496.0 kg ha(-1) respectively during both crop seasons. Among organic amendments, minimum wilt disease incidence of 1.69% (2010 11) and 1.81% (2011-12) and maximum grain yield 496.3 kg ha(-1) (2010-11) and 484.0 kg ha(-1) (2011-12) were observed in farm yard manure + spent compost treated plots. This indicates that these treatments have important roles in biologically based management strategies for controling Fusarium wilt disease under organic mode of lentil cultivation in Uttarakhand State. PMID- 25522508 TI - Invasive alien species water hyacinth Eichhornia crassipes as abode for macroinvertebrates in hypertrophic Ramsar Site, Lake Xochimilco, Mexico. AB - This paper presents information on the density, diversity and functional feeding groups of macroinvertebrate assemblages associated with water hyacinth in Antiguo Canal Cuemanco, part of Lake Xochimilco in Mexico City. Rare (low frequency and density) and dominant (high frequency and density) taxa prevailed in the assemblages, with the most predominant being Hyalella azteca, Chironomus plumosus and Ischnura denticollis. Nonmetric Multidimensional Scaling confirmed two climatic seasons: warm-rainy and cold-dry; the former with the highest diversity and density of taxa. Canonical Correspondence Analysis showed that conductivity, nitrates and turbidity explained the density variations of taxa. Antiguo Canal Cuemanco waters are spatially homogeneous with the characteristics of hypertrophic shallow lakes, inhabited by scrapers and gathering-collectors. The species found were tolerant to organic pollution. PMID- 25522509 TI - Effects of organic acids on growth and phosphorus utilization in rainbow trout, Oncorhynchus mykiss. . AB - The present study aimed to investigate the effect of phosphorus and various organic acids supplementation on growth, nutrient retention and loading in rainbow trout fed on low fishmeal based diets. Five experimental diets were formulated, Diet D1 (0.5P) was positive control with 0.5% inorganic phosphorus addition and D2 (0P, negative control) without addition of inorganic phosphorus. D3, D4 and D5 were supplemented with 1% fumaric (FuA), formic (FoA) and acetic (AA) acids, respectively. All the diets were fed until satiation to duplicate groups of 25 fish for 12 weeks. Feed conversion ratio (FCR) was recorded best with FoA diet and absorption of phosphorus was significantly higher (P < 0.05) in all the diets supplemented with organic acids and was similar to positive control. The phosphorus and nitrogen retention with FoA diet was significantly high (P < 0.05) as compared to 0P diet, in turn reducing their excretion. Hence, the present study demonstrated that, without additional phosphorus in the low fish meal-based diets, FoA supplement improved growth performance, absorption and retention of phosphorus and nitrogen and reducing excretion; thus it can be better incorporated to develop environment-friendly feed for rainbow trout. PMID- 25522510 TI - Characterization of sophorolipid biosurfactant produced by Cryptococcus sp. VITGBN2 and its application on Zn(II) removal from electroplating wastewater. AB - The present study aimed at elucidating the role of biosurfactant produced by yeast for the removal of Zn(II) ions from electroplating wastewater. The yeast species isolated from CETP, Vellore, Tamilnadu was identified as Cryptococcus sp.VITGBN2, based on molecular techniques, and was found to be potent producer of biosurfactant in mineral salt media containing vegetable oil as additional carbon source. Chemical structure of the purified biosurfactant was identified as acidic diacetate sophorolipid through GC-MS analysis. Interaction of Zn(II) ions with biosurfactant was monitored using FT-IR, SEM and EDS analysis. Zn (II) removal at 100 mg l(-1) concentration was 84.8% compared were other synthetic surfactants (Tween 80 and sodium dodecyl sulphate), yeast mediated biosurfactant showed enhanced Zn (II) removal in batch mode. The role of biosurfactant on Zn(II) removal was evaluated in column mode packed with biosurfactant entrapped in sodium alginate beads. At a flow rate of 1 ml min(-1) and bed height of 12 cm, immobilized biosurfactant showed 94.34% Zn(II) removal from electroplating wastewater. The present study confirmed that Zn(II) removal was biosurfactant mediated. This is the first report establishing the involvement of yeast mediated biosurfactant in Zn(II) removal from wastewater. PMID- 25522511 TI - Isolation and identification of antagonistic bacteria from phylloplane of rice as biocontrol agents for sheath blight. AB - A total of 325 bacteria were isolated from both healthy and sheath blight infected leaf samples of rice plants, collected from different places of Malaysia, following dilution technique. Sheath blight pathogen was isolated from infected samples by tissue plating method. Out of 325, 14 isolates were found to be antagonist against the pathogen in pre evaluation test. All the 14 isolates were morphologically characterized. Antagonistic activity of these isolates was further confirmed by adopting the standard dual culture and extracellular metabolite tests. The best isolates were selected, based on the results. In dual culture test, the selected bacterial isolates KMB25, TMB33, PMB38, UMB20 and BMB42 showed 68.44%, 60.89%, 60.22%, 50.00% and 48.22% fungal growth inhibition, respectively and in extracellular metabolite test these bacterial isolates exhibited 93.33%, 84.26%, 69.82%, 67.96% and 39.26% of the same, respectively. Biochemical tests of selected isolates were performed following standard procedure. These bacterial isolates were tentatively identified as fluorescent pseudomonas by morphological and biochemical characterization. The identities were further confirmed by Biolog microstation system as P. fluorescens (UMB20), P. aeruginosa (KMB25, TMB33 and PMB38) and P. asplenii (BMB42) with similarity index ranging from 0.517 to 0.697. The effective bacterial isolates obtained from the present study can be used in the management of soil borne fungal pathogen Rhizoctonia solani, causing sheath blight of rice. PMID- 25522512 TI - Ecology of Baskandi anua, an oxbow lake of South Assam, North East India. AB - A study was made on the physico-chemical properties of water and phyto and zooplankton communities of Baskandi anua, an oxbow lake of South Assam during March to August, 2009. Analyses of water showed acidic to slightly alkaline pH (5.4-7.9) with dissolved oxygen ranging from 4.26 to 11.83 mgl(-1) and total alkalinity from 31.25 to 65 mg l(-1), indicating the productive nature of water. Free CO2 fluctuated from 2.93 to 15.04 mgl(-1). PO4 and NO3 concentration ranged from 0.15 to 1.4 mg l(-1) and 0.06 mg l(-1) to 4.94 mg l(-1), respectively. Conductivity, pH and free CO2 were found higher at the sites surrounded by paddy fields. Mean values of physico-chemical parameters significantly varied between the sites and were found to be influenced by one or more of the following factors viz. rainfall, depth and influx from adjacent paddy field. A total of 30 phytoplankton taxa and 12 zooplankton taxa with qualitative dominance of Chlorophyceae were recorded. The study revealed that water quality of the lake was good for aquaculture. Hence, the lake should be protected and best management practices should be implemented for sustainable production. PMID- 25522513 TI - Toxicity assessment of effluent from flash light manufacturing industry by bioassay tests in Trigonella foenumgracum. AB - A rapid bioassay test was conducted to study heavy metal accumulation and biochemical changes in Trigonella foenumgracum (methi) irrigated with 25, 50, 75 and 100% of effluent from flash light manufacturing industry at 60 days after sowing. Total metal concentration in effluent samples was: Cr = 0.12 < Cd = 0.18 < Pb = 0.24 < Cu = 2.68 mg l(-1) whereas, metals were not detected in control. An increase in photosynthetic pigments of exposed plant was noticed up to 50% concentrations of the effluent followed by a decrease at higher concentration as compared to their respective control.An enhanced lipid peroxidation in the treated plants was observed, which was evident by increased level of antioxidants: proline, cysteine, malondialdehyde and ascorbic acid content. The treated plants accumulated metals in the following order: Cu > Pb > Cr > Cd in the roots and shoots. PMID- 25522514 TI - Study of population genetic polymorphism and gene flow rate in Indian snow trout, Schizothorax richardsonii fish of Himalaya, India. AB - The genetic polymorphism and gene flow rate among the Indian snow trout fish population S. richadsonii from three different locations viz., Chirapani stream of Champawat district, Kosi and Gola river of Nainital district, Uttarakhand State, India were assessed by employing twenty numbers of Randomly Amplified Polymorphic DNA (RAPD) markers. The overall percent polymorphisms among these three populations were 14.76 with 6.56, 4.92 and 3.28 in Chirapani, Kosi and Gola river population, respectively. Chirapani population had higher proportion of polymorphic loci as compared to the Kosi and Gola. The higher value of genetic distance (0.1565) was obtained between Chirapani and Gola population and the lower value of genetic distance was observed between Chirapani and Kosi (0.1058) river population. The cluster analysis revealed that in the formation of two clusters, one consisted of Chirapani and Kosi and the other was Gola fish population. Gst estimates among these populations showed some extent of homogeneity with lower genetic differentiation rate between populations and further suggested that higher tolerance to mutation, as expected that RAPD bands, arose from both coding and non-coding DNA regions. The findings revealed that the rate of gene flow in three populations seemed very low i.e. highly conserved its genetic diversity in their natural waterbodies and indicative of little migration among populations (geographically isolated and not the possibilities man made interventions/introduction of similar kind of fish species). It is further concluded that the Chirapani, Kosi and Gola river populations of S. richardsonii were being conserved naturally in their habitat and the species actual genetic potential were being maintained (adaptation to local climatic conditions, reproduction, production traits and disease resistance trait etc) in their natural habitat. PMID- 25522515 TI - Regeneration and reuse of leachate from a municipal solid waste landfill. AB - Landfill leachate is deep brown in color with extremely complex composition and difficult to treat in order to meet the effluent standards. The leachate of Keelung City Tien Wai Tien landfill has an average flow of 350 CMD. In the present study following serially connected devices: Activated sludge/contact aeration (AS/CA) combined system, reverse osmosis (RO) and an ammonia stripping tower were used to treat the leachate. After treatment, the COD (removal rate of 91%), BOD (removal rate of 83%), SS (removal rate of 86%) and NH(4+)-N level (removal rate of 98%) significantly reduced in the leachate. The treated effluent was further recycled and used as RO back washing water and for sprinkling roads and watering plants in Keelung City. It is further required to evaluate whether the treated effluent can be reutilized for agriculture and extinguishing fire during shortage of water. PMID- 25522516 TI - Isolation and molecular characterization of butanol tolerant bacterial strains for improved biobutanol production. AB - Butanol tolerance is a complex mechanism affecting the ability of microorganisms to generate economically viable quantities of butanol. The objective of this study was to isolate and characterize butanol tolerant bacterial strains which can act as potential alternative hosts for butanol production. The potential bacterial isolates were screened, based on the non toxic effect on cell growth rate and degradation ability of sago waste which was used as a sole carbon source with butanol enrichment. During this study, it was found that a growth barrier existed between 1 to 5% butanol concentrations and only few selected isolates could tolerate upto 5% butanol after long term adaptation. Screening of five isolates proved to be more tolerant, which were identified as Bacillusmegaterium, B. aryabhattai, B. tequilensis, and B. circulans using 16S rDNA sequence. These isolates were markedly attractive to identify butanol tolerance specific stress response genes and further engineered to act as a genetic host for biobutanol production. PMID- 25522517 TI - An appraisal of physico-chemical and microbiological characteristics of Nanmangalam Reserve Forest soil. AB - A detailed evaluation was performed on the soils of Nanmangalam Reserve Forest (NRF) in order to understand its physico-chemical, microbiological and enzymatic characteristics. The results of analysis showed that soil pH was directly proportional to the soil depth and the soil moisture content was irreversibly related to varying soil depth. Soil organic carbon was positively correlated with (p < 0.01) with total nitrogen, total bacterial count, cellulytic microbes, nitrogen-fixing bacteria, microbial biomass carbon, dehydrogenase activity and soil respiration. During summer, microbial population in the organic layer was more diverse than in the deepest layer. Analysis showed that NRF had low organic carbon content (less than 1%), microbial biomass, nutrient and functional microbes. The overall results of the analysis reinstate that Nanmangalam forest soil is undergoing degradation. PMID- 25522518 TI - Enhanced isolation and culture of highly efficient psychrophilic oil-degrading bacteria from oil-contaminated soils in South Korea. AB - It is known that isolation of oil-degrading bacterial strains is difficult at low temperatures, and the biodegradation efficiency of oil-contaminated soil is significantly reduced in cold weather. In this study, 14 strains were isolated from oil-contaminated soil that grew well at 10 degrees C by using a newly developed culture method. 11 of the 14 isolates were successfully cultured in mineral salts medium containing 1,500 ppm of oil components, 500 ppm each kerosene, gasoline, and diesel as carbon sources, at 10 degrees C for 2 weeks. The oil degradation efficiencies of these 11 isolates ranged from 36% to 100%, as measured by total petroleum hydrocarbon (TPH) degradation analyses. Three strains (Pseudomonas simiae G1-10O, P. taiwanensis Y1-4, and P. koreensis Gwa2) displayed complete degradation (100%), and six others (R frederiksbergensis G2-2, P arsenicoxydans Y2-1, R umsongensis Gwa3, P. migulae Gwa5, RhodococcusjialingiaeY 1-l , and R. qingshengii Y2-2) showed relatively high degradation efficiencies (> 70%). This study suggests that these isolates can be effectively utilised in thetreatment of oil-contaminated soil in landfarming, especially during winter. PMID- 25522519 TI - Factors influencing production of lipase under metal supplementation by bacterial strain, Bacillus subtilis BDG-8. AB - Lipases are biocatalyst having wide applications in industries due to their versatile properties. In the present study, a lipolytic bacterial strain, Bacillus subtilis BDG-8 was isolated from an oil based industrial soil. The effect of selenium and nickel as a media supplement on enhancement of lipase production, was studied individually with the isolated strain by varying the concentration of selected metal. 60 MUg l(-1) selenium enhanced lipase production to an enzyme activity measuring 7.8 U ml(-1) while 40 MUgI(-1) nickel gave the maximum enzyme activity equivalent to 7.5 U ml(-1). However, nickel and selenium together at a range of concentration with an equal w/v ratio, at 60 MUg l(-1) each, showed the maximum lipase activity of 8.5 U ml(-1). The effect of pH and temperature on lipase production showed maximum enzyme activity in the presence of each of the metals at pH 7 and 35 degrees C among the other tested ranges. After optimisation of the parameters such as metal concentration, pH and temperature lipase production by Bacillus subtilis BDG-8 had increased several folds. This preliminary investigation may consequently lead as to various industrial applications such as treatment of wastewater contaminated with metal or oil with simultaneous lipase production. PMID- 25522520 TI - Changes in growth, photosynthetic activities, biochemical parameters and amino acid profile of Thompson Seedless grapes (Vitis vinifera L.). AB - The study on photosynthetic activity and biochemical parameters in Thompson Seedless grapes grafted on Dog Ridge rootstock and its impact on growth, yield and amino acid profile at various stages of berry development was conducted during the year 2012-2013. Leaf and berry samples from ten year old vines of Thompson Seedless were collected at different growth and berry developmental stages. The analysis showed difference in photosynthetic activity, biochemical parameters and amino acid status with the changes in berry development stage. Higher photosynthetic rate of 17.39 umol cm(-2) s(-1) was recorded during 3-4mm berry size and the lowest (10.08 umol cm(-2) s(-1)) was recorded during the veraison stage. The photosynthetic activity showed gradual decrease with the onset of harvest while the different biochemical parameters showed increase and decrease from one stage to another in both berry and leaves. Changes in photosynthetic activity and biochemical parameters thereby affected the growth, yield and amino acid content of the berry. Positive correlation of leaf area and photosynthetic rate was recorded during the period of study. Reducing sugar (352.25 mg g(-1)) and total carbohydrate (132.52 mg g(-1)) was more in berries as compared to leaf. Amino acid profile showed variations in different stages of berry development. Marked variations in photosynthetic as well as biochemical and amino acid content at various berry development stages was recorded and thereby its cumulative effect on the development of fruit quality. PMID- 25522521 TI - Intercropping of aromatic crop Pelargonium graveolens with Solanum tuberosum for better productivity and soil health. AB - Farmers in hilly regions experience low production potential and resource use efficiency due to low valued crops and poorsoil health. Geranium (Pelargonium graveolens L.) is a vegetatively propagated initially slow growing, high value aromatic crop. Potato (Solanum tuberosum L.) is also vegetatively propagated high demand cash crop. A field experiment was carried out in temperate climate to investigate the influence of geranium intercropping at different row strips (1:1 and 1:2) and plant density (60 x 45, 75 x 45 and 90 x 45 cm) with potato intercrop on biomass, oil yield, monetary advantage and soil quality parameters. The row spacing 60x45cm and row strip 1:1 was found to be superior and produced 92 t ha(-1) and 14 kg ha(-1) biomass and oil yield, respectively. The row strip 1:2 intercrop earned a maximum $2107, followed by $1862 with row strip 1:1 at 60 x 45 cm plant density. Significant variations were noticed in soil organic carbon (Corg), total N (Nt), available nutrients, soil microbial biomass (Cmic) and nitrogen (Nmic) content. Maximum improvement of Corg (41.0%) and Nt (27.5%)with row strip 1:1 at 75 x 45 cm plant density. While higher soil respiration rate, Cmic, Nmic, and qCO2 was found with 1:2 row strip at 60 x 45 plant density. The buildup of Corg and Cmic potato intercrop can promote long term sustainability on productivity and soil health. PMID- 25522522 TI - Investigation and assessment of heavy metals in surface sediments of Ganjiang River, China. AB - Surface sediment samples were collected from four sampling areas (Ganzhou nonferrous metal processing zones (GZ), Jian city sewage discharge areas (JA), Non city areas (NC) and Zhangshu middle-city areas (ZS)) to investigate the degree and chemical partitioning of heavy metals. Samples were analyzed for Cu, Zn, Pb, Cd, Cr, As and Ni using sequential extraction scheme. Based on geo statistics analyses, the results showed maximum values of Cu (131.84 MUg g(-1)), Zn (290.68 MUg g(-1)), Cd (99.57 MUg g(-1)), Cr (53.75 MUg g(-1)), As (25.58 MUg g(-1)) and Ni (64.75 MUg g(11)) were in sediments dated at GZ areas, while ZS areas had the highest concentrations of Pb (128.51 MUg g(-1)). Almost all metal values were higher than their corresponding background values in the following order: Ni < Cr < Zn < Pb < As < Cu < Cd. Meanwhile, sediments showed that heavy metals were predominantly occured in Fe-Mn oxide, residual, organic, exchangeable and carbonate fractions respectively. It was found that concentration in carbonate fractions were generally low for most of the studied metals. The geo accumulation index and sediment quality values were used to determine the potential risk of heavy metal contamination. The results of geo-accumulation index indicated that contamination degree ranged from uncontaminated to extremely contaminated degrees. When metal partitioning characteristics were also considered, over 60% of metals showed potential bioavailability and toxic effects were probable. PMID- 25522523 TI - Characteristic monitoring of groundwater-salt transportation and input-output in inland arid irrigation area. AB - The rules of microscopic water-salt transportation can be revealed and the impact on the macroscopic water and soil resources can be further predicted by selecting a typical study area and carrying out continuous monitoring. In this paper, Jingtaichuan Electrical Lifting Irrigation District in Gansu Province (hereinafter called as JingDian irrigation district (JID)) located at the inland desert region of northwest China was selected as study area. Based on the groundwater-salt transportation data of representative groundwater monitoring wells in different hydrogeological units, the groundwater-salt evolution and transportation tendency in both closed and unclosed hydrogeological units were analyzed and the quantity relative ratio relationship of regional water-salt input-excretion was calculated. The results showed that the salt brought in by artificial irrigation accounts for the highest proportion of about 63.99% and the salt carried off by the discharge of irrigation water accounts for 66.42%, namely, the water-salt evolution and transportation were mainly controlled by artificial irrigation. As the general features of regional water-salt transportation, groundwater salinity and soil salt content variation were mainly decided by the transportation of soil soluble salt which showed an obvious symbiosis gathering regularity, but the differentiation with insoluble salt components was significant in the transportation process. Besides, groundwater salinity of the unclosed hydrogeological unit presented a periodically fluctuating trend, while the groundwater salinity and soil salt content in water and salt accumulation zone of the closed hydrogeological unit showed an increasing tendency, which formed the main occurrence area of soil secondary salinization. PMID- 25522524 TI - Anti-obesity effect of (8-E)-niizhenide, a secoiridoid from Ligustrum lucidum, in high-fat diet-induced obese mice. AB - The effect of the extract of Ligustrumn lucidum fruits (LFE) and its major secoiridoid (LFS), (8-E)-nuzhenide, on obesity was investigated using high fat diet (HFD)-induced C58BL/6J obese mice. LFE and LFS were administered at the doses of 300 mg/kg and 30 mg/kg, respectively, for 6 weeks. The anti-obesity activity was evaluated by measuring body weight, epididymal fat and metabolic plasma parameters. On Day 42, the body weight of the LFS-treated group was significantly lower compared with the HFD-treated group. Body weight gain was also reduced by 23.2% and 32.0% in the LFE- and LFS-treated groups, respectively, compared with the HFD group. In addition, the weight of the epididymal fat in the mice was significantly decreased in the HFD+LFS group. The food efficiency ratios (FERs) of the HFD+LFE and HFD+LFS groups were also lower compared with the HFD group with the same food intake. Metabolic parameters that had increased in the HFD group were decreased in the HFD+LFE and HFD+LFS groups. In particular, the increased triglyceride values were significantly reduced in the HFD+LFS group. These results show that treatment with LFE and LFS decreased HFD-induced obesity, mainly by improving metabolic parameters, such as fats and triglycerides. Therefore, LFE and LFS have potential benefits in regulation of obesity. PMID- 25522525 TI - Antiproliferative and antimalarial sesquiterpene lactones from Piptocoma antillana from Puerto Rico. AB - Bioassay-directed fractionation of an antiproliferative ethanol extract of the leaves and twigs of Piptocoma antillana (Asteraceae) afforded two new goyazensolide-type sesquiterpene lactones named 5-O-methyl-5-epiisogoyazensolide (1) and 15-O-methylgoyazensolide (2), together with the known compounds 1-oxo 3,10-epoxy-8-(2-methylacr1 0-epoxy-8-(2-methylacryloxy)-l 5-acetoxygermacra-2,4, 11(1 3)-trien-6(12)-olide (3) and 5-epiisogoyazensolide (4). The structure elucidation of all compounds was carried out based on NMR and mass spectroscopic data analyses. The relative and absolute configurations of all the isolated compounds were determined from their CD and NOESY NMR spectra. Compounds 1-4 showed moderately potent antiproliferative activities against A2780 ovarian cancer cells, with IC50 values of 1.5 +0.5, 0.6 +/- 0.3, 1.62 +/- 0.05, and 1.56 +/- 0.04 MUM, respectively. They also displayed antimalarial activity against Plasmodiumfalciparum, with IC50 values of 6.2 05 22 +/- 0.5, 2.2+/- 0.5, 8.0 +/- 0.4, and 9.0 +/- 0.6 MUM, respectively. PMID- 25522526 TI - Diterpene Foliar exudates of Blakiella bartsiifolia and phytotoxicity of clerodanes. AB - Blakiella bartsiifolia (S.F. Blake), an endemic and rare high altitude plant of the northern Andes, appears well adapted to the prevailing harsh environment owing in part to a thick glandular trichome cover. From foliar exudates, two new clerodanes, 15,16-epoxy-2-hydroxy-3,13(16),14-clerodatrien-20-oic acid (bartsiifolic acid) (2) and Z-15,16-dihydroxy-3,13-clerodien-20-oic acid (barthydrolic acid) (3), were isolated in addition to the known junceic acid (1). In addition, three new alicyclic furanoditerpenes: 1,20-epoxy 1,3(20),6(E),10(E),14-phytapentaen-18-methyl-19-oic acid (blakielic acid) (4), 1,20-epoxy- 1,3(20),10(E),14-phytapentaen-18-methyl-19-oic acid (blakifolic acid) (5) and 1,20-epoxy-1,3(20),6,14-phytatetraen-19-methyl-18-oic acid (dihydrocentipedic acid) (6) were obtained in minor quantity. Seed germination and plantlet growth bioassays on Allium cepa and Lactuca sativa to monitor bioactivity during isolation procedures revealed compounds 1-3 with substantial inhibition comparable with synthetic linuron. PMID- 25522527 TI - Variations of carnosic acid and carnosol concentrations in ethanol extracts of wild Lepechinia salviae in Spring (2008-2011). AB - Ethanol extracts from dried leaves of wild Lepechinia salvia (Lindl) Epling, collected during the flowering period (September-November), contained 15% to 25% carnosic acid and 2 to 8% carnosol, depending on the month of collection. The highest concentration of carnosic acid in extracts was in October, while carnosol concentration had a peak in September, which suggests that it is not a product of carnosic acid oxidation. A comparison of extracts obtained in September 2008 to 2011 shows that the production of both abietanes increased in years with less winter rainfall and higher temperatures, which induced an early blooming. EC50 values in DPPH radical scavenging and antiproliferative (CCRF-CEM tumor cells) bioassays confirm that the high bioactivity of the extracts of rosemary, sage and L. salviae does not arise only from carnosol and carnosic acid. The cytotoxic activity was significantly higher in extracts of L. salviae, probably due to water stress differences between the cultivars and the wild species. These results correlate well with the close phylogenetic relationship between the three species, and their similar medicinal uses. PMID- 25522528 TI - One-pot synthesis of hollongdione from dipterocarpol. AB - A one-pot synthesis of a hybrid triterpenoid-steroid molecule, hollongdione (22,23,24,25,26,27-hexanordammar-3,20-dion), was achieved in a yield of 89%, based on the selective dehydration of dipterocarpol following ozonolysis. The structure of hollongdione was confirmed by X-ray analysis for the first time. Dammar-20(22),24(25)-dien inhibited the growth of Mycobacterium tuberculosis (strain H37Rv) in vitro with a MIC of 50 MUg/mL. PMID- 25522529 TI - Triterpene glycosides from the sea cucumber Cladolabes schmeltzii. II. Structure and biological action of cladolosides A1-A6 . AB - Six new triterpene glycosides, cladolosides Al-A6 (1-6), have been isolated from the Vietnamese sea cucumber Cladolabes schmeltzii (Cladolabinae, Sclerodactylidae, Dendrochirotida). Structures of the glycosides were elucidated by 2D NMR spectroscopy and MS. All the glycosides have nonsulfated tetrasaccharide linear carbohydrate moieties. Glycoside 6 has a glucose residue as the third monosaccharide unit, while the rest of the compounds comprise a xylose in this postion of the carbohydrate chain. Glycosides 1-6 differ from each other in the structures of their holostane aglycones. Cytotoxic activities of glycosides 1-6 were studied against mouse spleenocytes, along with hemolytic activities against mouse erythrocytes. All the compounds, except cladoloside A5 (5) posessing a hydroxy-group in the aglycone side chain, demonstrated rather strong cytotoxic and hemolytic effects. The most active glycosides were cladolosides A1 (1) and A2 (2) having two O-acetic groups and the xylose residue in the third position of the sugar chain. PMID- 25522530 TI - History of gymnemic acid, a molecule that does not exist. . AB - In the literature there are hundreds of articles, the first dating back to 1866 and the last to 2014, on gymnemic acid, isolated from Gymnnema sylvestre, from its isolation to the determination of its biological activities. Gymnemic acid has a CAS number but its structure is not specified. Studies during the second half of the 1970s clearly demonstrated that what was being referred to as gymnemic acid is actually a very complex mixture of dozens of substances, belonging to different classes of natural compounds. This plant, whose infusions or complex mixtures of its metabolites are the basis for many formulas sold in pharmacies and by herbalists, has anti-diabetic and slimming effects. It is certainly misleading to talk about gymnemic acid as a specific molecule. There may be doubts about the exact composition of the products, and consequently about their origin and the claimed effects. PMID- 25522531 TI - A new 1,6-benzoxazocine-5-one alkaloid isolated from the aerial parts of Peristrophe lanceolaria. AB - A new 1,6-benzoxazocine-5-one alkaloid has been isolated as its butyl acetal derivative (1) along with peristrophine from the n-BuOH and EtOAc fractions of the crude MeOH extract of the aerial parts of Peristrophe lanceolaria growing in Thailand. The structures of these compounds were elucidated on the basis of their spectroscopic data. These compounds were isolated for the first time from P. lanceolaria. The EtOAc and n-BuOH fractions also possessed significant antioxidant activity with IC50 values of 57 and 50 MUg/mL, respectively (DPPH method), whereas 1 had an IC50 value of 23 MUg/mL. PMID- 25522532 TI - Comparative analysis of therapeutically important indole compounds in in vitro cultures of Hypericum perforatum cultivars by HPLC and TLC analysis coupled with densitometric detection. AB - Five indole compounds (5-hydroxy-L-tryptophan, L-tryptophan, indole-3-acetic acid, melatonin, serotonin) and hypericin were identified and quantified in methanolic extracts of shoot cultures of three Hypericum perforatum cultivars (Helos, Elixir, Topas) growing on two variants of Murashige -Skoog medium differing in concentrations of growth regulators (naphthalene-l-acetic acid and 6 benzylaminopurine). Extracts of the aboveground parts of field-grown plants (Hyperici herba) were also analyzed by HPLC and TLC analysis coupled with densitometric detection. Determination of four compounds was based on our assay described earlier. The methods of determination of 5-hydroxy-L-tryptophan and hypericin were developed and validated in this study. The composition and contents of the metabolites under study differed between the cultivars cultured in vitro and between medium variants containing diverse contents of growth regulators. The contents of individual indole compounds in the biomass from in vitro cultures ranged from 39.6 to 343.2 mg/100 g dry mass. 5-Hydroxy-L- tryptophan was the dominating metabolite (from 78.2 to 343.2 mg/100 g dry mass). Extracts from shoots of the cultivar Helos also contained high contents of serotonin (319.9 and 197.4 mg/100 g dry mass). The contents of indole compounds in Hyperici herba were also diverse (from 7.1 to 55.3 mg/100 g dry mass). 5 Hydroxy-L-tryptophan was the dominating metabolite as well. Hypericin content ofHyperici herba, equaling 12.2 mg/100 g dry mass was from 3.3 to 10 times higher than in extracts from shoots cultured in vitro. The present report is the first analysis of endogenous accumulation of indole compounds in Hyperici herba which involves, apart from melatonin, four other compounds. PMID- 25522533 TI - Monoterpene indole alkaloids from the twigs of Kopsia arborea. AB - The phytochemistry of Kopsia arborea Blume has received considerable attention, which has resulted in the isolation of a number of new unusual indole alkaloids with intriguing structures. In this study, a new eburnane-type alkaloid, phutdonginin (1), together with eight known alkaloids: 19-OH-(-)- eburnamonine (2), melodinine E (3), kopsinine (4), kopsilongine (5), kopsamine (6), (-) methylenedioxy-1 1,12-kopsinaline (7), decarbomethoxykopsiline (8), and vincadifformine (9), were isolated from the twigs of K. arborea. Their structures were characterized extensively by 1D and 2D NMR spectroscopy and HR-ESI-MS. All compounds were submitted to TLC screening for acetylcholinesterase inhibitory activities. Only kopsamine and decarbomethoxykopsiline showed AChE inhibition with MIR values of 12.5 and 6.25 MUg, respectively, compared with galanthamine (positive control, 0.004 MUg). In addition, compounds 1 and 2 inhibited moderate antibacterial activity against E. coli TISTR 780 with the MIC value of 32 .g/mL. PMID- 25522534 TI - Two new alkaloids from Melodinus suaveolens. AB - Two new Melodinus-type alkaloids, 15beta-hydroxy-14,15-dihydroscandine (1) and 14,15-dihydroscandine (2), together with 6 known ones were isolated from Melodinus suaveolens. The structures of the new compounds were identified from spectroscopic (NMR, UV, IR, CD) and mass spectrometric data and Mosher's method. The new compounds exhibited significant, dose-dependent inhibition of the production of lipopolysaccharide (LPS)-induced NO, IL-6 and IL-8 in mice macrophages. PMID- 25522535 TI - Flavone induces cell death in human hepatoma HepG2 cells. AB - Flavones have received considerable attention because of their antiproliferative properties and selective effects on cancer cells, making them good candidates for use in cancer therapy. In contrast to other flavones, little is known about the effects of the flavone core structure (2-phenyl-4H-1-benzopyran-4one) on cancer cells. Here, we report that flavone induces cell death in human hepatoma HepG2 cells. Furthermore, annexin-V+/PI- and SubG1 populations of HepG2 cells increased after flavone treatment. Exposure of HepG2 to flavone did not result in either cytochrome c release into the cytosol or changes in the mitochondrial membrane potential. Treatment of HepG2 cells with flavone for 24 h reduced the accumulation of intracellular ROS, which correlated with upregulation of Gred, CuZnSOD and MnSOD mRNA levels. Taken together, our results provided useful insights into the mechanism of cell death caused by flavones, in order to evaluate their future application in hepatocarcinoma therapy. PMID- 25522536 TI - Isolation, identification and usefulness of antifungal compounds from Zuccagnia punctata for control of toxigenic ear rot pathogens. AB - Infusion, tincture and decoction of leaves of Zuccagnia punctata Cav. were assayed on growth of Fusarium verticillioides, F. graminearum sensu stricto, F. boothii, F. meridionale, F. subglutinans and F. thapsinum. The tincture showed the lowest IC50 on mycelial growth. A diethyl ether fraction of the tincture showed the highest antifungal activity in microdilution assays on F. verticillioides and F. graminearum. The antifungal constituents were separated by silica gel chromatography and identified as 2',4'-dihydroxychalcone, 2',4' dihydroxy-3'-methoxychalcone and 7-hydroxy-3',4'-dimethoxyflavone. These chalcones had the lowest MIC and MFC values on F. verticillioides and F. graminearum sensu stricto. 2',4'-Dihydroxychalcone was mildly toxic and the remaining identified compounds were non-toxic in the brine shrimp assay. 2',4' Dihydroxychalcone in mixtures with commercial food preservatives showed additive effects on F. graminearum sensu stricto and synergistic ones on F. verticillioides. 2',4'-Dihydroxy-3'-methoxychalcone showed synergistic effects in mixtures. Our results suggest that addition of chalcones to food preservatives allows reduction in the doses of the preservatives required for control of Fusarium species. PMID- 25522537 TI - Cell cycle control by natural phenols in cisplatin-resistant cell lines. AB - Fifteen plant polyphenols, including flavonoids, cinnamic acids, coumarins and capsaicin, were investigated for their capacity to suppress cell growth and regulate the cell cycle of in vitro human ovarian carcinoma (2008 cell line) and cervix squamous carcinoma cells (A431), and their cisplatin (CDDP)-resistant subclones (C13 and A431Pt, respectively). Evaluation of the cytotoxic effects of the polyphenols (0.01-100 MUM) indicated that especially rhein and quercetin were almost equiactive in wild type and CDDP-resistant cells, indicating lack of cross resistance with cisplatin. Capsaicin was more potent in CDDP-resistant subclones than in wild type cells. The order of their potencies is flavonoids > anthraquinones > vanilloids > coumarins > phenols, cinnamic acids. The natural phenols which were most cytotoxic (rhein, quercetin and capsaicin) were able to cause the arrest of the cancer cell cycle, suggesting that specific cell cycle regulatory proteins are possibly involved in their intracellular mechanism of action. In particular, the natural compounds were revealed to be more active in CDDP-resistant cells than in wild types, especially inducing apoptotic death. PMID- 25522538 TI - Identification and evaluation of flavone-glucosides isolated from barley sprouts and their inhibitory activity against bacterial neuraminidase. AB - Neuraminidase (NA) is one of the key enzymes responsible for bacterial infection and pathogenesis. This study aimed to gain deeper insights into the inhibitory effects of flavone-glucosides (1-9) isolated from barley sprouts (BS) on neuraminidase activity. The isolated compounds were identified as, lutonarin (1), saponarin (2), isoorientin (3), orientin (4), isovitexin (5), isoscoparin-7-O-[6 sinapoyl]-glucoside (6), isoscoparin-7-O-[6-feruloyl]-glucoside (7), isovitexin-7 O-[6-sinapoyl]-glucoside (8), and isovitexin-7-O-[6-feruloyl]-glucoside (9). Among them, compounds 1-5 exhibited neuraminidase-inhibitory activities in a dose dependent manner, with IC50 values ranging from 20.1 to 32.7 MUM, in a non competitive inhibition mode according to kinetic studies. Moreover, the individual flavone-glucoside levels differed notably, in particular, lutonarin (1) and saponarin (2) were shown to be present in the greatest amounts, according to UPLC analysis. Consequently, our results suggest that BS may be utilized as an effective NA inhibitor in human health food, additives, and feed. PMID- 25522539 TI - Polyphenol composition and antioxidant capacity of three Lysimachia species. AB - The polyphenol composition and antioxidant properties of three Lysimachia species (L. nummularia L., L. vulgaris L. and L. punctata L.) and their column chromatographic fractions were investigated. The antioxidant activity of herb extracts and 54 different column chromatographic fractions was evaluated using in vitro DPPH and ABTS+ decolorization tests. The total polyphenol content was determined by spectrophotometric methods. The phenolic compounds of extracts of different Lysimachia species and their bioactive fractions were characterized by online chromatographic methods. For identification of the compounds, UV spectral data, accurate molecular mass and formula, as well as MS and fragmentation patterns given by LC-DAD-ESI/MS/MS and LC-ESI- TOF analyses were used. Quantification of the compounds was performed by LC-DAD using an external standard method. In the extracts, caffeic acid derivatives, chlorogenic acid, free flavonoid aglycones, and 11 various flavonoid glycosides were identified. Flavonoid composition of Lysimachia extracts showed significant differences. L. punctata extracts had the strongest DPPH and ABTS+ radical scavenger activity (IC50=43.3 MUg/mL and 21.3 MUg/mL), due to their high myricitrin and quercetin hexoside content. Correlation between polyphenol content and radical scavenging activity of each column chromatographic fractions is also included. PMID- 25522540 TI - Phenolic content, antioxidant and astroprotective response to oxidative stress of ethanolic extracts of Mentha longifolia from Sinai. AB - The aerial parts ofMentha longifolia L. are used as herbal remedies for curing different diseases through traditional Bedouin medicine. The antioxidant activity of the ethanolic extracts of M longifolia was investigated measuring peroxyl radical-scavenging activity by ORAC assay, with Trolox (a water-soluble analogue of alpha-tocopherol) employed as reference compound. In addition, the total content of phenolic compounds estimated by the Folin-Ciocalteau method and the identification of the polyphenols using high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) have been performed. Furthermore, the effect of these extracts on cell viability and intracellular ROS production was assayed using the U373-MG human astrocytoma cell line in a H2O2-induced oxidative stress model. Results showed that the major type of polyphenols found were benzoic acids, cinnamic acids, flavones and flavanones. The total phenolic content was 37.7 mg gallic acid/g sample and the ORAC value was 1.355 .mol TE/mg sample. The data obtained in cellular assays demonstrated that these ethanolic extracts protected H2O2-induced astrocyte damage by increasing cell viability and inhibiting production of intracellular ROS. These results suggest that the investigated extracts obtained from the aerial parts of M longifolia have antioxidant potential related to their phenol content which have important beneficial health effects, especially in those disease associated with ROS. PMID- 25522541 TI - Chemical constituents from Pterocarpus soyauxii. AB - Three new benzofurans (1-3) and one new isoflavan (4), pteroyanin G, H, I and J, together with 21 known compounds, were isolated from the heartwood of Pterocarpus soyauxii. Their structures were determined by the NMR and MS spectral data in comparison with literature data. Compounds (1-25) did not show cytotoxicity against three human cancer cell lines, A549, Panc-28, and HCT-116 (Gl50 > 50 MUM). PMID- 25522542 TI - Antibacterial compounds from the roots of Cratoxylumformosum spp. pruniflorum. AB - Phytochemical investigation of the roots of Cratoxylum formosum spp. pruniflolnnm led to the isolation and identification of a new xanthone, namely cratopruniforone (1), together with 13 known compounds (2-14). Some of these more abundant compounds were evaluated for their antibacterial activities. PMID- 25522543 TI - Stimulation of phosphorylation of ERK and CREB by phellopterin and auraptene isolated from Citrusjunos. AB - Bioactive compounds from citrus fruits contribute many benefits to human health. Extracellular signal-regulated kinase (ERK) signaling plays an important role in the regulation of multiple cellular processes. Activation of the ERK-cAMP response element binding protein (CREB) signaling is required for long- term memory formation. In this study, auraptene, phellopterin, thymol, coniferyl alcohol 9-methyl ether and methyl ferulate were isolated from Citrus junos. Among the five compounds isolated, auraptene and phellopterin increased the phosphorylation of ERK and CREB. This study provides, to our knowledge, the first evidence that phellopterin potently stimulates the phosphorylation of ERK and CREB. Phellopterin could be a novel neuroprotective agent. PMID- 25522544 TI - Isolation of (-)-avenaciolide as the antifungal and antimycobacterial constituent of a Seimatosporium sp. Endophyte from the medicinal plant Hypericum perforatum . AB - An extract of Seimatosporium sp., an endophyte from the Canadian medicinal plant Hypericum perforatum, exhibited significant antifungal and antimycobacterial activity against Candida albicans and Mycobacterium tuberculosis H37Ra. Bioassay guided fractionation led to the isolation of (-)-avenaciolide as the only bioactive constituent of the extract. This is the first report of both the antimycobacterial activity of avenaciolide and its isolation from a Seimatosporium sp. fungus. PMID- 25522545 TI - Two new pyrone derivatives from the plant endophytic fungus Exserohilum sp. AB - Two new a-pyrones, Exserolide G-H (1-2), together with one known metabolite, stemphypyrone (3), were isolated from the solid-substrate fermentation cultures of the plant endophytic fungus Exserohilum sp. The structures of the new compounds were elucidated primarily by analysis of NMR data. Compounds 1-3 were tested for cytotoxicity against a small panel of human carcinoma cell lines. Compound 1 showed cytotoxicity against HeLa, A549 and HCT116 cells. PMID- 25522546 TI - A New Aggreceride analogue and a peltogynoid isolated from the stem bark of Entada abyssinica (Fabaceae). AB - A new monoglyceride, l',26'-bis-[(S)-2,3-dihydroxypropyl] hexacosanedioate (1a) and the new peltogynoid, entadanin (3), along with eight known compounds, were isolated from the stem bark of Entada abyssinica (Fabaceae). The structures of the new compounds were determined by detailed analyses of 1D and 2D NMR spectra, in combination with high-resolution mass spectrometry data, and by comparison with related data from the literature. The stereochemistry of la was derived by comparison of the optical rotation with reference data. Peltogynoids have been reported previously from other Fabaceae, however this is the first report ofa peltogynoid from the genus Entada. PMID- 25522547 TI - Protective effect ofAgave salmiana fructans in azoxymethane- induced colon cancer in Wistar rats. AB - Colon cancer is a world concerning disease; it shows a high mortality rate and may be related to eating habits. Studies using inulin-like fructans, which are produced as energy supplies by several plants, have demonstrated a chemo protective effect of these fructans in colon cancer. However, agavins a structurally different type of fructans from the Agave genus with demonstrated prebiotic effects, have been poorly studied for their possible protective effects in cancer. The aim of the present study was to evaluate the effect ofAgave fructan-rich diets in colon cancer progress using a rat model and "Agave mezcalero potosino" A. salmiana Otto ex Salm Dick, which is widely distributed in Mexico. Results showed a significant decrease (p<0.05) in early lesions of colon cancer (aberrant crypt foci) compared with the control group. These data suggest that fructans from A. salmiana may contribute to a reduction in the risk of colon cancer as well as inulin-like compounds. PMID- 25522548 TI - Compositional variability and antifungal potentials of ocimum basilicum, O. tenuiflorum, O. gratissimum and O. kilimandscharicum essential oils against Rhizoctonia solani and Choanephora cucurbitarum. AB - The composition of hydrodistilled essential oils of Ocimum basilicum L. (four chemovariants), O. tenuiflorum L., O. gratissimum L., and O. kilimandscharicum Guerke were analyzed and compared by using capillary gas chromatography (GC/FID) and GC-mass spectrometry (GC/MS). Phenyl propanoids (upto 87.0%) and monoterpenoids (upto 83.3%) were prevalent constituents distributed in the studied Ocimum taxa. The major constituents of the four distinct chemovariants of O. basilicum were methyl chavicol (86.3%), methyl chavicol (61.5%)/linalool (28.6%), citral (65.9%); and linalool (36.1%)/citral (28.8%). Eugenol (66.5% and 78.0%) was the major constituent of O. tenuiflorum and O. gratissimum. Eugenol (34.0%), beta-bisabolene (15.4%), (E)-alpha-bisabolene (10.9%), methyl chavicol (10.2%) and 1,8-cineole (8.2%) were the major constituents of O. kilimandscharicum. In order to explore the potential for industrial use, the extracted essential oils were assessed for their antifungal potential through poison food technique against two phytopathogens, Rhizoctonia solani and Choanephora cucurbitarum, which cause root and wet rot diseases in various crops. O. tenuiflorum, O. gratissimum, and O. kilimandscharicum exhibited complete growth inhibition against R. solani and C. cucurbitarum after 24 and 48 h of treatment. O. basilicum chemotypes showed variable levels of growth inhibition (63.0%-100%) against these two phytopathogens. PMID- 25522549 TI - Chemical composition of the essential oil of Ligularia hodgsonii and free radical scavenging activity of the oil and crude extracts. AB - The chemical composition of the essential oil from roots and rhizomes of Ligularia hodgsonii was analyzed by gas chromatography (GC) and GC-mass spectrometry (MS). Forty-seven components were identified, representing 77.0% of the total oil. The main constituents were l-(+)-ascorbic acid 2,6- dihexadecanoate (15.7%), selina-6-en-4-ol (8.4%) and 9,10-dimethyl 1,2,3,4,5,6,7,8-octahydroanthracene (6.6%). The free radical scavenging activities of the essential oil, aqueous extract, ethanolic extract, and crude polysaccharides of L. hodgsonii, as well as some of their major components, were investigated using DPPH and ABTS assays. The essential oil displayed a lower capacity to quench free radicals than the extracts; the ethanolic and aqueous extracts showed considerably higher antioxidant potential that deserves further study. PMID- 25522550 TI - Repellent Constituents of essential oil from Citrus wilsonii stem barks against Tribolium castaneum. AB - The essential oil obtained from Citrus wilsonii Tanaka stem barks with hydrodistillation was investigated by GC-FID and GC-MS. The main components of the essential oil were identified to be nerol acetate (44.5%), nerol (13.6%), citronellyl propionate (13.5%) and alpha-terpineol (3.6%). Among them, the four active constituents, predicted with a bioactivity-test, were isolated and identified as nerolacetate, nerol, citronellyl propionate and alpha-terpineol. It was found that the essential oil of C. wilsonii stem barks possessed strong repellency (86% and 92%, respectively, at 78.6 nL/cm2, after 2 and 4 h treatment) against Tribolium castaneum adults. Repellency of the four active compounds was also determined. Nerolacetate, nerol, citronellyl propionate and alpha-terpineol were strongly repellent (100%, 100%, 90% and 96%, respectively, at 15.7 nL/cm2, after 2h treatment) against T. castaneum. Nerol exhibited the same level of repellency as the positive control, DEET. The results indicate that the essential oil of C. wilsonii stem barks and its active compounds have the potential to be developed as natural repellents for control of T. castaneum. PMID- 25522551 TI - Essential oil from the heartwood of Taiwan fir ameliorates LPS-induced inflammatory response by inhibiting the activation of mitogen-activated protein kinase. AB - The essential oil from the heartwood of Taiwan fir (EOTC) was demonstrated to exhibit anti-inflammatory activity in lipopolysaccharide (LPS)-activated mouse macrophages. EOTC reduced nitrite oxide levels and inducible nitrite oxide synthase expression in, and tumor necrosis factor-alpha and interleukin-6 secretion by, LPS-activated macrophages without affecting cyclooxygenase-2 expression. EOTC reduced the levels of interleukin-lbeta precursor induced by LPS and decreased the NLRP3 inflammasome-derived interleukin-lbeta secretion induced by LPS and adenosine triphosphate. In addition, the phosphorylation levels of ERKI/2, JNK1/2, and p38 in LPS-activated macrophages were reduced by EOTC. Furthermore, EOTC was composed of oxygenated sesquiterpenes (68.4%), sesquiterpene hydrocarbons (28.9%) and diterpenes (0.9%). The major compounds of the oxygenated sesquiterpenes were tau-cadinol (23.9%), alpha-cadinol (21.1%) and cedrol (16.9%). These findings suggest that EOTC may be a candidate for the development of anti-inflammatory agents for preventing and ameliorating inflammation-related diseases. PMID- 25522552 TI - Melissopalynological and volatile analysis of honeys from Corsican Arbutus unedo habitat. AB - Thirty Corsican "autumn maquis" honeys were characterized by the typical combination of autumnal taxa: Arbutus unedo, Hedera helix, Smilax aspera, Rosmarinus officinalis, and two Asteraceae pollen forms. Corsican origin was characterized by the diversity of the taxa's biogeographical origins and significant presence of Castanea sativa and Quercus sp. Volatile fractions of "autumn maquis" honeys were dominated by isophorone and 3,4,5-trimethylphenol. The latter is reported in A. unedo honey for the first time. Otherwise, both A. unedo flower and "autumn maquis" honeys exhibited high contents of isophorone derivatives. H. helix honey exhibited phenylacetaldehyde, benzyl nitrile, 3 hydroxy-4-phenylbutan-2-one and nonanal as major compounds, which were scarcely represented in the studied "autumn maquis" honey samples. PMID- 25522553 TI - Chemical composition and insecticidal properties of essential oils of Piper septuplinervium and P. subtomentosum (Piperaceae). AB - Essential oils of Piper subtomentosum (leaves and inflorescences) and Piper septuplinervium (aerial parts) were analyzed by GC-MS; sixty-three compounds were determined, representing 92.0%, 86.9 %, and 91.8 % of the total relative oil composition of the leaves, inflorescences, and aerial parts, respectively. The most abundant component in the aerial parts and inflorescence oils was alpha pinene (27.3%, 21.0%, respectively), and delta-cadinene was the main component of the leaf oil. Insecticidal activity of the essential oils were determined on the Spodoptera frugiperda second instar larvae; the essential oil from the aerial parts of P. septuplinervium was the most active against insect pests (LC50= 9.4 MUL/L of air). Statistical analysis by direct Pearson correlation showed that the insecticidal activity of the essential oils was primarily due to camphene and alpha- and beta-pinene. The effect of the oils on the insect life cycle was also evaluated, and in some cases, a delay in growth and inhibition of the oviposition in the females were observed. PMID- 25522554 TI - Chemical Composition of the essential oils from Vietnamese Clausena indica and C. anisum-olens. AB - The chemical composition of Vietnamese oil samples of the aerial parts of Clausena indica (Dalz.) Oliver and C. anisum-olens (Blanco) Merryll have been investigated using a combination of chromatographic and spectroscopic techniques. C. indica essential oil contained mainly terpinolene (53.9 and 56.1%), and myristicin (17.9 and 7.3%), whereas the major components of C. anisun-olens essential were citronellal (22.8%), geranial (21.4%) and neral (16.8%). The compositions of the investigated samples have been compared with those of essential oils from various origins. PMID- 25522555 TI - Chemical Constituents from Sinningia canescens and S. warmingii. AB - A new naphthoquinone, 6-methoxy-7-hydroxy-a-dunnione (1), along with four known compounds (2, 4, 10, and 11) were isolated from Sinningia canescens (Mart.) Wiehler tubers, while S. warmingii (Hiern.) Chautems furnished eight known compounds (3-10). The known compounds were identified as 7-hydroxy- alpha dunnione (2), lapachenole (3), tectoquinone (4), 7-methoxytectoquinone (5), 1 hydroxytectoquinone (6), 7-hydroxytectoquinone (7), aggregatin C (8), aggregatin D (9), halleridone (10), and cedrol (11). In addition, S. canescens yielded a volatile fraction, which was analyzed by GC/FID and GC/MS. This fraction was constituted mainly by sesquiterpene hydrocarbons (82.6%). The major components were beta-santalene (14.6%), beta-cedrene (10.4%), and trans-cadina-1(6)-4-diene (10.0%). PMID- 25522556 TI - [Research advances of laryngeal cancer stem cells]. PMID- 25522557 TI - [The clinical relationship between allergic rhinitis and allergic factors and chronic rhinosinusitis with or without nasal polyps]. AB - OBJECTIVE: To investigate the clinical relationship between allergic rhinitis and allergic factors with chronic rhinosinusitis with or without nasal polyps. METHOD: Two hundred patients were divided into A and B two groups. Group A of 110 patients was diagnosed allergic rhinitis. Group B of 90 patients was diagnosed chronic sinusitis with or without nasal polyps. Serums sIgE was detected with EUROIMMUN, and observe the recurrence rate of chronic sinusitis with or without nasal polyps patients who accept operation treatment and observe the incidence of allergic rhinitis superinduced chronic sinusitis with or without nasal polyps. RESULT: The total positive rate of group A sIgE was 89.09%. The total positive rate of group B sIgE was 74.44%. The postoperative recurrence rate of sIgE positive group was 58.21% and the postoperative recurrence rate of sIgE negative group was 8.70% in the group B. In the group A, the positive rate of serums sIgE in allergic rhinitis with chronic sinusitis with or without nasal polyps (37.27%) was 97.56%, while the positive rate of serums sIgE in allergic rhinitis without chronic sinusitis (62.73%) was 79.71%, there is a significant difference in allergic rhinitis with or without chronic sinusitis (chi2 = 6.96, P < 0.01). CONCLUSION: There is a certain correlation between allergic rhinitis and allergic factors with chronic sinusitis with or without nasal polyps. Therefore, through avoiding allergen exposure, the treatment of allergic rhinitis can effectively control recurrence rate of chronic sinusitis and nasal polyp. PMID- 25522558 TI - [Factors influencing olfactory dysfunction in patients with chronic rhinosinusitis]. AB - OBJECTIVE: To evaluate the relative factors influencing olfactory dysfunction in patients with chronic rhinosinusitis (CRS). METHOD: Visual analogue scale (VAS) was applied to measure the severity of olfactory dysfunction of 270 patients with CRS. Patients were divided into two groups, one was that the quality of life (QOL) of patients was affected by olfactory dysfunction (VAS > 5), the other was that without QOL affected by olfactory dysfunction (VAS <= 5). The association between age, gender, nasal polyps, allergic rhinitis, smoking history, early nasal surgery history and other clinical factors, and serum total IgE level, peripheral blood eosinophil count, peripheral blood mononuclear cell count and olfactory dysfunction was analyzed. RESULT: The number of patients with nasal polyps, allergic rhinitis, previous nasal surgeries, the level of serum total IgE, and the severity of edema were significantly increased in patients with impaired QOL associated with olfactory dysfunction (P < 0.05). Sex distribution, age, smoking history, deviation of nasal septum, eosinophil and mononuclear cell count did no statistically differ between the groups with and without impaired QOL associated with olfactory dysfunctions (P > 0.05). Serum total IgE increased (OR = 1.003, P < 0.01) and severe edema (OR = 2.483, P < 0.01) were the risk factors for the impairment of olfactory function, more notably for edema; whereas previous nasal surgeries was a protective factor (OR = 0.408, P < 0.01). CONCLUSION: Sever edema and increased serum total IgE are risk factors, whereas previous nasal surgeries history is a protective factor for the olfactory dysfunction. PMID- 25522559 TI - [Expression and significance of Toll like receptor 2 and Toll like receptor 4 in chronic rhinosinusitis]. AB - OBJECTIVE: To explore the role of the innate immune factors TLR2 and TLR4 in the pathogenesis of chronic rhinosinusitis (CRS) by detecting their expression in different clinical types of CRS and the normal control group. METHOD: Immunohistochemistry was used to detect the expression of TLR2 and TLR4 respectively in 21 cases (chronic rhinosinusitis with nasal polyps, CRSwNP) group, 15 cases (chronic rhinosinusitis without nasal polyos, CRSsNP) group, 11 cases recurrent CRSwNP group and 13 cases control group. Positive cells were counted under the microscope artificially, Mann-Whitney U analysis was applied for the ranked data, and one-way anova analysis was adopted to analyze the experimental group and control group. RESULT: (1) TLR2 and TLR4 expression had the same characteristics. Expression mainly concentrated in parts of the whole layer of epithelial basement membrane, cytoplasm of glandular cells, very few inflammatory cells such as monocytes and plasma cells in the cytoplasm, sometimes unknown cell nuclei positive expression. (2) The glandular cells were stained manual counting and color grading. TLR2 and TLR4 packet application Wilcoxon rank test Mann-Whitney U test analysis was not statistically significant (P > 0.05), measurement data within the group variance statistical difference between the groups (P < 0.05). CONCLUSION: The Nasal mucosa can produce the innate immune factors TLR2 and TLR4. The different expression of TLR2 and TLR4 in the various clinical types of CRS suggests that they play the certain role in the pathogenesis of CRS. PMID- 25522560 TI - [A randomized controlled study of treating chronic rhinosinusitis with macrolides]. AB - OBJECTIVE: Invastigation of macrolides in the treatment of drug effects in chronic rhinosinusit. METHOD: The 165 patients with chronic rhinosinusit were randomly divided into 80 cases of macrolides drug group and 85 cases of cephalosporins group, and therapeutic effect was observed. The therapeutic effect of macrolides was also observed in refractory chronic rhinosinusit. RESULT: Comparing macrolides group and cephalosporins group,there is not statistically significant (P > 0.05). Treatment with macrolides cefixime tablet ineffective treatment of patients for 3 months, compared before and after treatment was statistically significant (P < 0.01). Treatment with cefixime tablet macrolides ineffective treatment of patients for 3 months, compared before and after treatment was not statistically significant (P > 0.05). CONCLUSION: Long-term low dose applications of macrolides have a good effect in patients with chronic rhinosinusit, particularly for refractory chronic rhinosinusit have a significant effect. PMID- 25522561 TI - [Application of the xenogenic acellular dermal matrix membrane application used in the postoperative tissue shortage repair]. AB - OBJECTIVE: To observe the short-term and long-term curative effect of the xenogenic acellular dermal matrix membrane (or joint muscle flap transfer) application used in the 82 cases postoperative tissue shortage repair that after the head neck carcinoma resection. METHOD: To held the 82 cases head neck carcinoma postoperative mucosa shortage repaired after resection by the xenogenic acellular dermal matrix membrane (or joint muscle flap transfer), 65 cases mucosa shortage wound be directly covered by the repair membrane and the other 17 cases mucosa shortage wound be repaired by the tranfered muscle tissue flap with the repair membrane covered; 53 cases underwent additional postoperative radiotherapy between 2-4 weeks and follow-up in 1, 3, 6, 12, 18, 24, 30, 36, 48, 60 months and observed the operation site repair process through the electronic laryngoscope, observed the patients respiration, swallow, phonation function. RESULT: Seventy seven cases patients operation incision reached I phase healing standard, another 5 cases patients operation incision reached II phase healing standard because of the wound infection and fully-recovered through the local wound drainage,dressing process. All the patients tracheal cannula,the stomach tube be extubated successfully and without the local cicatricial constriction occurred. Seventy eight cases follow up period reached 1 year including 53 cases who underwent postoperative radiotherapy, 49 cases follow up period reached 3 years including 32 cases who underwent postoperative radiotherapy, 14 cases follow up period reached 5 years including 12 cases who underwent postoperative radiotherapy. The patients with static local lesions discovered no reaction such as exclusion, allergy. CONCLUSION: The application of xenogenic acellular dermal matrix membrane (or joint muscle flap transfer used in in the postoperative tissue shortage repair that after the head neck carcinoma resection have several advantage such as comparatively easily implementation, operation safety edge enough,well preserved organ function, comparatively low incidence about the laryngeal stenosis, the short-term and long-term repair effect are all exact. PMID- 25522562 TI - [Morphologic feature and cochlear implant surgical approach for cochlear modiolus deficiency]. AB - OBJECTIVE: To review the classification of cochlear modiolus deficiency and decision on surgical approach for above case,in order to provide mastery for cochlear implant (CI) indication. METHOD: Basing on temporal bone HRCT pre operation, CI subjects with modiolus deficiency were defined as following groups: (1) deficiency caused by cochlear dysplasia (Mondini malformation); (2) deficiency caused by dysplasia of cochlear and vestibule (Common cavity malformation); (3) deficiency caused by absence of internal acoustic meatus fundus (IP-III malformation). Three types of surgical approach were utilized: type I, electrode array was introduced through facial recess, enlarged the round window, type II, opened the surface of chchlea, electrode array was introduced through facial recess, fenestration on posterior promontory and then inserted around lateral wall of inner-cochlear cavity. type III, electrode array was introduce through fenestration of lateral semicircular canal and then placed close to the bony wall of common cavity. RESULT: One hundred and sixty-six cochlear modiolus deficiency cases were identified into 3 groups as following: 135 Mondini malformation cases into group a, 18 common cavity malformation cases into group b, and 13 IP-III malformation cases into group c. Surgical approach: type I were used in 136 cases (123 Mondini cases and 13 IP-III cases), while approach type II in 12 cases (12 Mondini cases), and approach type III in 18 cases (18 common cavity cases). Income post-operation of CI: For group a (Mondini malformation), post-activation mean hearing threshold in sound field was 65 dB, speech recognition score is 95% (single finals test) and 25% (signal initials test), while it was 80 dB, 60% and 0 for group b (Conmon cavity malformation), and it was 55 dB, 100% and 45% for group c (IP-III malformation). CONCLUSION: The income of speech recognition score for cochlear modiolus deficiency was relatively poor, group b was worst and group c was best, while group a moderate. PMID- 25522563 TI - [The expression and significance of programmed cell death 5 and Bcelllymphoma/lewkmia-2 in sinonasal squamous cell carcinoma]. AB - OBJECTIVE: To explore the expression and significance of programmed cell death 5 (PDCD5) and Bcelllymphoma/lewkmia-2(Bcl-2) in sinonasal squamous cell carcinoma (SNSCC). METHOD: Immunohistochemical method and Western Blot method was used to determine the expression of PDCD5 and Bcl-2 in specimen of SNSCC in thirty cases, sinonasal inverted papillomas (SNIP) in thirty-eight cases, and normal nasal mucosa in twenty cases. RESULT: (1) The expression of PDCD5 protein in SNSCC significantly decreased compared with SNIP and normal nasal mucosa. (2) The expression of Bcl-2 protein in SNSCC up-regulated obviously compared with SNIP and normal nasal mucosa. (3) Positive rate of PDCD5 protein and Bcl-2 protein in well, moderate and low differentiatied group is respectively 100.00%, 83.33%, 38.89% and 50.00%, 70.83% and 100.00%, the difference was statistically significant (P < 0.05). (4) In the follow-up cases, the survival rate of the patients with higher expression of PDCD5 protein was higher, but that with lower expression of Bcl-2 protein was higher. CONCLUSION: The inactivation of PDCD5 protein and the activation of Bcl-2 protein may play an important role in the development of SNSCC, and there are a positive correlation between PDCD5 and Bcl 2 protein in SNSCC, which may be identified as a new therapeutic target. PMID- 25522564 TI - [Computed tomographic images analysis of frontal recess anatomy based on three dimension reconstruction]. AB - OBJECTIVE: To observe the CT three-dimensional imaging features of the frontal recess region with advanced three-dimensional reconstruction, and develop the real image of the important anatomical structures around the region to conduct surgery. METHOD: Thirty patients were undergone spiral CT by 16 line high speed spiral CT, and multiplanar reconstruction images using standard three-dimensional reconstruction protocol on a computer workstation. The structure of the frontal recess, the agger nasi cell and adhere style of the uncinate process were observed. The parameter of the important anatomic structure of frontal recess was measured precisely. RESULT: After the reconstruction, we get the three dimensional model very close to the true state of the nasal cavity-sinuses cell, in which parts of the frontal recess can clearly identify the agger nasi cell, frontal cell and other important structures. In these patients, the height, width and depth of the agger nasi and frontal sinus were (9.45 +/- 3.60)mm, (8.08 +/- 3.37)mm, (26.98 +/- 6.82)mm and (26.86 +/- 9.45)mm, respectively. CONCLUSION: This study tried to develop the standardized techniques and measurements from three-dimensional reconstructed images of the frontal sinus and to ascertain the usefulness of the frontal sinus in identification of patients. The project results in better preoperative patient counselling and in predicting postoperative improvement in clinical status. PMID- 25522565 TI - [Study on the preemptive analgesia effects of both the parecoxib sodium and the pentazocine in patients undergoing nasal endoscopic surgery]. AB - OBJECTIVE: To evaluate the preemptive analgesia effects of both the parecoxib sodium and the pentazocine in patients undergoing nasal endoscopic surgery. METHOD: In the randomized, double blind, controlled study, 120 patients undergoing septoplasty were divided into 3 groups (n = 40): group A received parecoxib 40 mg by muscle injection 30 min before the operation; group B received pentazocine 30 mg; group C received an equal volume of saline. The preemptive analgesia effect was evaluated with VAS scores which recorded at different time points. The proportion of participants using rescue analgesia after the operation were recorded as additional measures of preemptive analgesia. RESULT: Intra operative as well as the postoperative pain scores were less in the group A and group B than in the control group. Fewer participants required rescue medication after operation with parecoxib as well as pentazocine than placebo. However there were no difference in the preemptive effects between the group A and group B. CONCLUSION: Administration of both the parecoxib and pentazocine before the nasal endoscopic surgery can provide preemptive analgesia without serious adverse side effects that deserves popularization in the clinic. PMID- 25522566 TI - [Different methods of antigen retrieval impact on Pan of sinonasal inverted papilloma]. AB - OBJECTIVE: To explore different conditions and buffers of antigen retrieval which affect the CK of SNIP on immunohistochemical staining results. METHOD: Dividing paraffin tissue sections of 11 patients into four groups. Using the Image-Pro Plus Image analyzer and taking five horizons for each section to calculate an average of 200 areas, measured standard optical density of the positive reaction areas. RESULT: It is divided into four groups: high temperature and high pressure citrate buffer retrieval, microwave EDTA buffer retrieval, microwave citrate retrieval, high temperature and high pressure EDTA buffer retrieval. The standard optical density of positive reaction areas respectively express: 0.324 +/- 0.051, 0.325 +/- 0.056, 0.303 +/- 0.061, 0.365 +/- 0.023. The rates of CK positive expression with high temperature and high pressure EDTA buffer retrieval is batter than other repairing groups in the same paraffin tissue sections (P < 0.05). CONCLUSION: For the Pan of Sinonasal inverted papilloma, the method of high temperature and high pressure EDTA buffer antigen retrieval can achieve the ideal staining results? which is worth while to promote and maybe as a bet? ter guide of clinic work. PMID- 25522567 TI - [The influence of hypothermia plasma radiofrequency ablation on synechia nasal after nasopharyngeal carcinoma radiotherapy]. AB - OBJECTIVE: To observe the effect of hypothermia plasma radiofrequency ablation to the adhesion of nasal cavity after radiotherapy of nasopharyngeal carcinoma. METHOD: The subjective score combined with nasal ventilation function test were used to reflect the degree of patients with nasal adhesion. RESULT: There is a significant improvement in subjective feeling after treatment. Nasal cavity volume began to increase and nasal expiratory resistance decrease obviously 3M later. CONCLUSION: Hypothermia plasma radiofrequency ablation technology can improve the nasal cavity adhesion in patients with nasopharyngeal carcinoma after radiotherapy, and also the patients quality of life. PMID- 25522568 TI - [The role of medical imaging plus carbon nanoparticles to manage the cervical lymph nodes in patients with thyroid carcinoma]. AB - OBJECTIVE: The purpose of this study was to discuss the role of the combination of carbon nanoparticles and medical imaging to manage the cervical lymph nodes in patients with thyroid carcinoma. METHOD: Eighty one patients with thyroid carcinoma that primary treated were divided into two groups: trial group and control group. Carbon nanoparticles were injected into the thyroid gland of trial group patients. Central compartment (level VI) dissection, levels IIl and IV dissection, lateral node (levels II-V) dissection were performed respectively in all the patients on the basis of medical imaging and pathology. Total lymph nodes, metastasis lymph nodes, black stained lymph nodes and black stained metastasis lymph nodes of trial group were counted respectively in different dissection specimens. Total lymph nodes and metastasis lymph nodes of control group were counted respectively in different dissection specimens. Parathyroid glands of thyroid or central compartment dissection specimens were counted in two groups. RESULT: In trial group, rate of staining lymph node was 80.0% in central neck dissection tissue, 54.9% in levels III and IV dissection specimen, 39.1% in lateral node dissection specimen. In central compartment dissection tissue, lymph nodes on average in control group were less than in trial group (3.03 +/- 2.07 vs. 4.72 +/- 2.97) (P < 0.01). The same was in levels III and lV dissection specimen (5.53 +/- 3.78 vs. 10.29 +/- 3.36) (P < 0.01). As for lateral node dissection specimen,there was no statistic difference in the two group (13.4 +/- 9.67 vs. 14.56 +/- 6.28) (P > 0.05). There was no statistic difference between control group and trial group for the metastasis lymph nodes in difference dissection specimens. Parathyroid gland was found in 3 thyroid or central compartment dissection specimens among trial group, which was found in 9 specimens among control group, the difference had statistical significance (P < 0.05). CONCLUSION: During levels III and IV dissection in cN0 patients or central compartment dissection, lymph nodes can be signed well by carbon nanoparticles, which can improve the lymph node detection rate, but can not increase the lymph node detection rate in cN+ patients. Parathyroid gland can be preserved by carbon nanoparticles during the thyroid gland resection and central neck dissection. PMID- 25522569 TI - [Clinical features of ocular symptom in patients with allergic rhinitis]. AB - OBJECTIVE: To investigate the clinical characteristics of ocular symptoms in patients with allergic rhinitis (AR) and the impact of the ocular symptoms on patients' quality of life. METHOD: AR patients' history and clinical data were collected and analyzed. One hundred cases were extracted from adult patients with and without ocular symptoms in each group and their quality of life were evaluated using rhino-conjunctivitis quality of life questionnaire (RQLQ). RESULT: Totally 1119 cases were collected and 859 cases had ocular symptoms. Of the patients with ocular symptoms, 582 cases were mild, 234 cases were moderate, 43 cases were severe. Eye itching was the most common symptom, followed by tears, hyperemia and swelling. Patients with ocular symptoms had longer disease history than non ocular symptom group (P < 0.05). There was a positive correlation between ocular and nasal symptoms (P < 0.01); patients with ocular symptoms had more severe nasal symptoms than patients without ocular problems; while patients with moderate to severe AR had more severe ocular symptoms than mild AR patients (P < 0.01). Female patients had higher incidence (P < 0.05) and ocular symptoms score (P < 0.05) than male. Children less than 10 years old had a relative lower incidence and score of ocular symptoms. While the incidence and score had an increasing trend for patients older than fifty. There was no difference regarding the type and number of allergen in the patients with and without ocular symptom. Moreover, patients with ocular symptoms had higher scores in the domains of non nose/eye symptoms, practical problems, ocular symptoms, emotional function and total score in RQLQ than patients without ocular symptom. CONCLUSION: It was common for the AR patients to have ocular symptoms, and ocular symptoms had obvious influence on the patients' quality of life. So controlling of the ocular symptoms should not be ignored during the diagnosis and treatment of AR. PMID- 25522570 TI - [Growth inhibition effection of perlecan anti-sense cDNA on human laryngeal carcinoma xnograft in nude mice]. AB - OBJECTIVE: To observe growth inhibition effect of perlecan anti-sense cDNA (pAP) on human laryngeal carcinoma xnografted in nude mice. To vertify its antitumor effect and mechanism in vivo, and it may be useful as a biomarker in carcinoma of larynx cancer. METHOD: Created the model of human laryngeal carcinoma xnograft in nude mice. To observe growth of those xnografts in nude mice and draw growth curve of xnografted. The expression of perlecan mRNA and portein in xnografts were examined by RT-PCR and immunohistochemistry. RESULT: Volume of xnografts in the group transfected by the plasmids of pAP were significant small as compared with other two groups made by the wild type cells and phpApr-neol cells (P < 0.05). It was showed that the expression of perlecan mRNA and protein were significantly reduced in the tumor of pAP transfected Hep-2 cells as compared with the tumors transfected by the wild type cells and phbetaApr-neol cells (P < 0.01). CONCLUSION: These data raise the possibility that pAP many play key roles in the growth of those xnografts in nude mice. PMID- 25522571 TI - [Effects of staphylococcal enterotoxin of different concentrations on the expression of GATA-3 and Th1/Th2 cytokines in the maxillary sinus mucosa of rabbits]. AB - OBJECTIVE: The aim of this study was to determine the expression of GATA-3 and the level of Th1 and Th2 cytokines upon repeated exposure to staphylococcal enterotoxin B(SEB) of different concentrations in the maxillary sinus mucosa of rabbits. METHOD: The rabbits were randomly divided into 2 groups (24 rabbits per group): low-dose SEB group and high-dose SEB group. The low-dose SEB group and high-dose SEB group received daily injections of 0.6 ng of SEB (2 ml) and 60 ng of SEB (2 ml) into the left maxillary sinus of rabbits for 28 days, respectively. Concurrent treatment of the right maxillary sinus with normal saline was used as a control. Six rabbits chosen randomly in two groups were killed on days 3, 7, 14, and 28, and to obtain the sinus mucosa from the two-side maxillary sinuses for measurement. Mucosal levels of IL-2, IL-4, IL-5, and IFN-gamma were measured using ABC-ELISA. Tissue expression of GATA-3 were examined using Real-time PCR and immunohistochemistry. RESULT: IFN-gamma and IL-2 levels were significantly elevated in the high-dose SEB group compared with the low-dose SEB and control groups on days 7, 14, and 28 (P < 0.05). However, IL-4 and IL-5 levels were markedly enhanced in the low-dose SEB group compared with the high-dose SEB and control groups on days 14 and 28 (P < 0.05). Real-time PCR showed that the expression of GATA-3 mRNA in the low-dose SEB group was markedly enhanced, and immunohistochemical staining illustrated that the number of GATA-3 positive cells was markedly increased in the low-dose SEB group as compared with the high-dose SEB group (P < 0.05). No significant differences were observed in GATA-3 expression between the high-dose SEB and the control groups (P > 0.05). CONCLUSION: SEB promoted Th1 cytokines production at high concentrations, and enhanced Th2 cytokines expression and Th2 immune response at low concentrations. PMID- 25522572 TI - [Blood supply of the pedicle nasal septum mucosa flap of rabbit in experiment]. AB - OBJECTIVE: To explore the blood supply of the pedicle nasal septum mucosa flap of rabbit, in order to supply the theory and experiment basis for making the pedicle nasal septum mucosa flap to repair nasal cavity and skull base defect. METHOD: Twenty rabbits corpses were induced into the experimental subject, and inject 5 ml blue ink into the external carotid artery, then longitudinal cut apart the middle head of rabbit, finally observe the blood supply of the pedicle nasal septum mucosa flap. RESULT: The blood supply of the pedicle nasal septum mucosa flap mostly come from the vessels of extremitas anterior part of nasal septum. CONCLUSION: Keep the he vessels of extremitas anterior part of nasal septum can guarantee the blood supply of mucous membrane, enhance the survival rate of nasal septum mucous membrane. PMID- 25522573 TI - [Distribution change of mast cells in human nasal polyps]. AB - OBJECTIVE: To investigate the distribution of mast cells in nasal polyps. METHOD: Biopsy specimens from patients with nasal polyps (n = 20) and control patients (n = 8) were obtained and included in this study. The distribution of mast cells in nasal polyps and the expression of chemokines (CCL5, CCL11, CX3CL1, IL-8, IL-6) in the epithelial cells of normal nasal mucosa and nasal polyps was determined by immunohistochemistry. RESULT: Mast cells migrate to intraepithelial in nasal polyps and the expression of chemokines (CCL5, CCL11, CX3CL1, IL-8) was up regulated in the epithelial cells of nasal polyps compare to normal nasal mucosa. CONCLUSION: Our findings showed that mast cells migrate to intraepithelial in nasal polyps and the over expression of chemotaxins (CCL5, CCL11, CX3CL1, IL-8) may be response for mast cells' migration in nasal polyps. Mast cells might be associated with the development of nasal polyps. PMID- 25522574 TI - [Painless esophagoscopy in extraction of foreign bodies in the esophagus]. AB - OBJECTIVE: To evaluate the effects of intravenous anesthesia in painless esophagoscopy for extraction of foreign bodies in the esophagus. METHOD: Forty two patients underwent painless esophagoscopy, and extracted the foreign bodies in the esophagus. RESULT: Thirty-two cases had their foreign bodies extracted smoothly and no serious complication occurred,the other 10 cases were mucosal injuries of esophagus with no obvious foreign body. CONCLUSION: Intravenous sedation with propofol in extraction of foreign bodies in the esophagus can relieve the suffering and adverse reactions, and it is safe, quick, comfortable and effective for extraction of foreign bodies in the esophagus and is worthy to be applied in the clinic. PMID- 25522575 TI - [Endoscopic endonasal dacryocystorhinostomy assisted by image guidance system to chronic dacryocystistis]. AB - OBJECTIVE: To estimate the value of nasal endoscopic dacryocystorhinostomy combined image guidance system in treating chronic dacryocystistis. METHOD: Thirteen cases (14 eyes) performed surgeries with nasal endoscopic dacryocystorhinostomy combined image guidance system from January 2010 to August 2013 were retrospectively analyzed. Their clinical data were analyzed and the effect of the surgery was evaluated. RESULT: All patients were followed-up for more than half a year. Of all patients,12 eyes were cured, 2 eyes were improved and 0 eyes were noneffective. The total treatment effectiveness was 100%. There was no complication for all cases. CONCLUSION: Nasal endoscopic dacryocystorhinostomy combined image guidance system is an effective and reliable treatment method for chronic dacryocystistis, especially for intraoperative location of lacrimal sac and control of operating process. PMID- 25522576 TI - [Angle of titanium clip next turbinate resection without filling in the clinical observation]. AB - OBJECTIVE: To observe the self-developed horn type of titanium clamp used for inferior turbinate resection from filling effect. METHOD: Choose the cases of inferior turbinate resection of 152 cases randomly selected 92 cases (group) in 2 4 angle type titanium clip head-tail closed wound middle turbinate, and therefore more than nasal passages in the surgical wound, just as in the nasal passages above micro tamponade, bare breathing zone, keep the ventilation, 1- 3 days to take out the angle titanium clamp; 60 cases (control group) with vaseline oil gauze or postoperative Merocel hemostatic sponge tamponade nasal bleeding. Observation of 1-3 days after nasal ventilation, headache, nasal bleeding, dry mouth, tolerance is painful, aural fullness tinnitus, a total of 7 indicators of sleep. RESULT: The team outside the there was no difference in blood loss and the control group, the rest of the indicators is better than the control group. CONCLUSION: The angle of titanium clamp used in inferior turbinate resection from stuffing, patients get better comfort, avoid drawn yarn of pain, improve the quality of perioperative patients with life. PMID- 25522577 TI - [Prevalence of allergic rhinitis in Beijing--a community survey]. AB - OBJECTIVE: To estimate the prevalence of allergic rhinitis (AR) in a community center in Beijing. METHOD: We randomly investigated a community with 13 900 inhabitents in Beijing by means of questionnaire survey. RESULT: A total of 2000 questionnaires was send out, and 1988 of them were collected, which included 952 males and 1036 females (age: 1 to 96 years old, 128 cases are younger than 14 years old. Among of them, 194 cases (9.76%) were diagnosed as having AR according to epidemiologic definition, including 14 children. The prevalence of AR was 9.68% in adults, with male 10.21% and female 9.18%, 10.94% in children. The prevalence in male are slightly higher than in female both with adults and children but without statistic significance. CONCLUSION: The survey showed the incidence of AR in Beijing are 9.76% in population, adults 9.68%, children (younger than 12) 10.94%. AR patients are more likely to have other allergic diseases. PMID- 25522578 TI - [Study on nose correlated quality of life in patients with pituitary tumor endoscopic resection via sphenoid sinus]. PMID- 25522579 TI - [The clinical study of fracture of child condylar process]. PMID- 25522580 TI - [Nasopharyngeal cyst treatment by low temperature coblation on endoscope]. PMID- 25522581 TI - [Pituitary adenoma with initial symptom of cerebrospinal fluid rhinorrhea: a case report]. AB - Pituitary adenoma with cerebrospinal fluid rhinorrhea is rare clinically. In this paper, through the analysis of a pituitary adenoma patient with initial symptom of cerebrospinal fluid rhinorrhea, we look forward to provide evidence for clinical diagnosis, so that we can avoid misdiagnosis. PMID- 25522582 TI - [A case of selective embolization in treatment of advanced tonsillar cancer hemorrhage]. AB - This paper reports a case of recurrence of tonsillar cancer on the right 6 months after radiotherapy with pharyngeal hemorrhage for 4 days and aggravation in the next day. The pharyngeal hemorrhage was severe in the case and the maximum of single amount of bleeding was approximately 200 ml. The examination showed active bleeding on the ulcer with a diameter of 2 cm in the right tonsil and the depth of 1 cm. After repeated compression hemostasis proved to be invalid, selective embolization was applied on the patient and the symtoms of pharyngeal hemorrhage disappeared without complications. The patient was discharged after 2 weeks of observation without any recurrence of hemorrhage. PMID- 25522583 TI - [Maxillary sinus malformations (double wall bone) lead to chronic sinusitis in a case]. AB - Chronic rhinosinusitis is a common otorhinolaryngological disease, although the incidence of chronic sinusitis is the result of many factors, the local anatomic abnormalities is one of the most important reasons. When maxillary sinus dysplasia that sinus cavity becomes small. These was some sinus cavity partial or complete bony septum malformation used to be reported occasionally, according to reports in the literature of this malformation rate is below 2%, bony divides sinus cavity is divided into 2 to 3 independent lacunar deformity are very rare, next we will introduce a case of sinus cavity that been divided into double deck by bone wall. PMID- 25522584 TI - [The promoting research of phospholipase C epsilon-1 on nasal Th2 cell polarization]. AB - Phospholipase C epsilon-1 (PLCE1) is a phospholipase C isoenzyme encoded by PLCE1 gene, and has more complicated molecular structure and function than other subtypes. Phospholipase C epsilon-1 is accepted the dual regulation by the upstream G proteins and GTP enzymes of Ras family. The downstream signal of PLCE1 is not only cause the Ca2+ flow and protein kinase C(PKC) activation, but also can be used as the GTP enzyme guanylic acid conversion factor of Ras superfamily, so as to regulate the expression of certain genes, adjusting cell growth and differentiation processes. PLCE1 plays a very important role in the signal transduction in the regulation of cell growth, differentiation, proliferation and apoptosis. Previous studies showed that phospholipase C epsilon-1 played an important role in the development of malignant tumors (especially the digestive tumors), heart disease, nephrotic syndrome and other diseases, but there are some questions about the mechanisms of PLCE1 involved in allergic rhinitis, this article will make an overview about PLCE1 promotes allergic rhinitis CD4+ T cells differentiate to Th2 cells by PKC-NF-kappaB pathway and Ras-MAPK pathway. PMID- 25522585 TI - [Regulation of the O-antigen polysaccharide chain length by Wzz- a review ]. AB - The O-antigen of Gram-negative bacterium plays an important role in the signal identification, adhesion, immune evasion and other processes. There are three O antigen polysaccharides biosynthesis mechanisms according to the type of the flippase that is involved. The Wzy-dependent mechanism is more commonly seen. In Wzy-dependent mechanism, the wzz gene is involved in regulating the length of O antigen polysaccharide chain which can affect antigenicity of the pathogen and immune response of the host. Based on the crystal structure of Wzz (regulator of the O- antigen polysaccharides length) , different length of O-antigen chain can be obtained through molecular modification of the gene wzz. Conjugating O-antigen or its mutants of a pathogen to a carrier protein could help to develop a vaccine that have both a good target specificity and a strong immunogenicity. Therefore, it is important to understand the function, structure and mechanism of Wzz for the development and production of glycoconjugates vaccine. PMID- 25522586 TI - [Research progress on biofilm formation by Bacillus subtilis- a review ]. AB - Biofilm is a prevalent lifestyle in nature and closely related to the life and production of humans. Bacillus subtilis is an important industrial strain and a good model for biofilm research. Combined with our current studies, we reviewed significant progress on biofilm formation by Bacillus subtilis, including main process, characteristics of biofilm formation, research models, and regulatory pathway for biofilm formation. In addition, further research focuses are addressed. PMID- 25522587 TI - [LAH-3, a transcriptional factor involved in osmotic regulation in Neurospora crassa]. AB - [OBJECTIVE] In order to identify the function of lah-3 in osmotic regulation, we generated lah-3 deletion strain and analyzed its phenotype by osmostress treatment. [METHODS] We used homologous recombination to replace lah-3gene by hph gene and treated these cells with 4% NaCl and 1 M sorbitol to analyze the phenotype. Northern blot was used to detect the expressions of osmoresponsing genes. Western blot was used to examine the phosphorylation level of LAH-3 and OS 2 and the expression of OS-2. [RESULTS] In the deletion strain of transcription factor lah-3 gene, the expressions of osmoresponsing genes gcy-1, stl-1 and pck-1 were significantly reduced. Besides, the phosphorylation level of LAH-3 protein increased under the osmostress treatment. The phosphorylation of LAH-3 was not mediated by OS-2. The deletion of lah-3 did not affect the os-2 expression and the phosphorylation level of OS-2 upon osmostress. [ CONCLUSION] LAH-3 involved in osmoresponsing was independent of OS-2 MAPK pathway. PMID- 25522588 TI - [Phylogenomic analysis reveals the significant expansion of gene families of Volvariella volvacea ]. AB - [OBJECTIVE] Cryogenic autolysis of Volvariella volvacea is an unusual phenomenon of abnormal metabolism. The aim of this study was to describe this molecular feature of abnormal metabolism at the genome-level. [METHODS] We used 21 fungal species for the phylogenomic analysis and then selected 9 representative species in basidiomycetes for the comparative genomic analysis. [ RESULTS] The phylogenomic analysis shows that V. volvacea was located at the bottom of the cluster consisting of grass-degrading fungi. Phylogenetic tree shows that basidiomycetes and ascomycetes fungi have independent evolutionary trajectories. Therefore, nine representative species in basidiomycetes were chosen for the comparative genomic analysis. The result shows that compared to other grass degrading fungi, V. volvacea has the tendency of contraction. The comparison of the number of gene families on a different scale shows that there was a significant expansion of 3 large size ( > 200) gene families (faml, fam4 and fam6) in V. volvacea with their total number significantly more than other species, representing that the molecular feature of V. volvacea is correlated with its abnormal metabolism. [ CONCLUSION] The significant expansion of 3 gene families ( > 200) in V. volvacea indicates the enhancement of their function in specific gene families, which is most likely associated with cryogenic autolysis of V. volvacea. PMID- 25522589 TI - [Development of PhaP-tagged protein expression and purification systems for extremely halophilic archaea ]. AB - [ OBJECTIVE] To establish a convenient halophilic protein expression and purification system based on the haloarchaeal-type PhaP and polyhydroxyalkanoate (PHA) granule. [METHODS] We cloned a strong haloarchaeal promoter and the phaP tag into the haloarchaea- Escherichia coli shuttle vector pWL502, and then used the constructed vector to express the PhaP-tagged haloarchaeal proteins in the phaP-deleted strain Haloferax mediterranei AphaP. We purified the PhaP-fusion proteins, which were associated with PHA granules, by sucrose density gradient centrifugation. We also inserted a haloarchaeal intein-containing fragment between phaP and multiple cloning sites, and modulated the intein splicing activity by site-directed mutagenesis. [RESULTS] We successfully constructed two expression vectors, pPM and pIP, in which PhaP was used as N-terminal and C terminal fusion tag, respectively. The haloarchaeal proteins were effectively expressed by both vectors. The PhaP-tagged proteins were easily purified through the strategy of PHA granulemediated protein purification. In addition, we found that the intein-containing fragment Hbt21 from Halobacterium sp. NRC-1 had maintained splicing activity in H. mediterranei, and its C-terminal cleavage could be blocked or attenuated by mutating the conserved asparagine ( N182) or serine (S183) , respectively. [ CONCLUSION] We have established a convenient and economical halophilic protein expression and purification system. We have also identified the splicing active sites of a haloarchaeal intein, which showed potential for removing the PhaP-tag from the purified proteins. PMID- 25522590 TI - [De novotranscriptomic analysis of Chlorella sorokiniana: Pathway description and gene discovery for lipid production ]. AB - [ OBJECTIVE] The paucity of genomic information limits the metabolic engineering of non-model microalgae Chlorella sorokiniana. Our study aimed to elucidate the fatty acid, triacylglycerol and starch biosynthetic pathways in the microalgae C. sorokiniana based on de novo transcriptomic analysis. [METHODS] We cultured C. sorokiniana with different nitrogen concentrations (KNO3: 8g/L and 2g/L) , then sequenced the transcriptomeusing Illumina Hiseq2000 platform. We used Trinity to de novo assemble the reads so as to obtain transcripts, aligned all the transcripts with Nr database, UniProtKB/Swiss-Prot database and COG database to annotate the function and classify using BLASTx algorithm, and assigned the transcript with metabolic pathway by aligning with KEGG database. Then we used RSEM to calculate FPKM value, and used it for preliminary analysis of different gene expression in the related pathways. [RESULTS] Over 49M high quality raw reads were produced with the length of 100bp, We used Trinity to assembled these reads into 49885 transcripts with an N50 of 1941bp, ranging from 300bp to 14100bp. 26479 transcripts were annotated through BLASTx similarity search, 2357 transcripts were assigned with EC number, and 207 metabolic pathways were assigned in total. Based on these analyses, we reconstructed the fatty acids, triacylglycerol and starch biosynthetic pathways in C. sorokiniana. We also identified preliminarily different geneexpression in the pathways. [CONCLUSION] Using RNA-seq technology, we reconstructed the metabolic pathways involving in the fatty acid, triacylglycerol and starch biosynthesis in non-model microalgae C. sorokiniana without genomic data, which is consistent with those in model microalgae Chlamydomonas reinhardtii, and compared the gene expression level under different conditions. These information is very useful for the metabolic engineering of C. sorokiniana and other microalgae to enhance the production of lipids. PMID- 25522591 TI - [Purification, characterization and application of epsilon-poly-L. lysine- degrading enzyme from Streptomyces sp. M-Z18 ]. AB - [OBJECTIVE] The epsilon-poly-L-lysine-degrading enzyme (Pld) derived from Streptomyces sp. M-Z18 was purified and characterized. Furthermore, Pld was used to produce the low polymerization of epsilon-poly-L-lysine (epsilon-PL). [METHODS] Pld was purified to electrophoretical homogeneity through HiTrapTM Butyl HP hydrophobic chromatography after pretreated by ultrasonic and NaSCN dissolving. Subsequently, enzymatic characteristics, kinetic parameters and the time profile of epsilon-PL degradation by the purified Pld were studied. Meanwhile, we examined the effect of epsilon-PL with different degrees of polymerization on the minimal inhibitory concentration of bacteria and fungi. [RESULTS] Pld was purified to homogeneity with a final fold of 80.4 and an overall yield of 59.3%. The optimal temperature and pH for the purified Pld were 370C and 7. 0, respectively. Moreover, the Km with L-lysyl-p-nitroanilide as substrate was calculated to be 0. 621 mmol/L, and the Vmax was 701. 16 nmol/min.mg. Pld was stable in the range of pH 7. 0 - 10. 0, and temperature up to 500 C, respectively. Time profile of epsilon-PL degradation by the purified Pld indicated that Pld catalyzed endo-type degradation of epsilon- PL. The experiments of minimal inhibitory showed that epsilon-PL with high degree of polymerization (30 - 35) had a superior antibacterial effect on bacteria and the low degree of polymerization epsilon-PL (8 -20) had a better antibacterial effect on yeasts. However, epsilon-PL with various degrees of polymerization had a poor antibacterial effect on mould. [ CONCLUSION] The present result showed that an endo-type Pld from epsilon-PL-producing strain was purified. Meanwhile, it is proved that epsilon-PL with different degrees of polymerization have exhibited significant different antibacterial effects on microorganism. PMID- 25522592 TI - [Microbial metabolism in typical flooded paddy soils ]. AB - [OBJECTIVE] The object of this study is to reveal the composition of active microorganism and their metabolic activities in flooded paddy soils with long term fertilization ( Mineral nitrogen, phosphorus, and potassium, NPK) and without fertilizer (Control check, CK) by environmental transcriptomics. [METHODS] Flooded soil microcosms were incubated in the laboratory for two weeks, then total RNA were extracted from the soil for transcriptome sequencing. Resulting fastq files were uploaded to the Metagenomics Analysis Server (MG-RAST) for taxonomic analysis, gene annotation and function classification. [RESULTS] Transcripts from diverse active microorganism, including bacteria ( > 95% ) , archaea, eukaryotes and viruses, were detected in both flooded paddy soils of CK and NPK treatments. Most of the transcripts (active genes) of bacteria and archaea were derived from Proteobacteria (more than 50% of total bacterial transcripts) and Thaumarchaaeota (about 70% of total archaeal transcripts ) respectively in both treatments. Transcriptional activity of Acidobacteria in NPK treatment paddy soil was significantly higher than that in CK treatment paddy soil. As for other phyla of bacteria and archaea, there were no significant differences of transcriptional activity of them between CK and NPK treatment paddy soils. The highest expressed gene in both CK and NPK treatment paddy soils is ABC transporter encoding gene which related to the transmembrane transport of substances. Based on gene function category of COG (Clusters of Orthologous Genes), Subsystem and KEGG (Kyoto Encyclopedia of Genes and Genomes) database, we found that the main metabolic activities of microorganisms in both CK and NPK treatment paddy soils were related to energy production and conversion, carbohydrate metabolism, protein metabolism and amino acid metabolism, and the dominant KEGG pathways were oxidative phosphorylation and aminoacyl-tRNA biosynthesis. [ CONCLUSION] Composition of active microorganism in CK and NPK treatment paddy soils was generally similar, except Acidobacteria whose transcriptional activity was significantly different between these two treatment paddy soils. It was also very similar between CK and NPK treatment paddy soils considering the metabolic activities of microorganisms in them, for dominant metabolic processes in these two soils were both related to energy obtaining and protein metabolism. So, dominant metabolic activities of microorganism in flooded paddy soils used in this study were not altered significantly under long - term inorganic fertilization. PMID- 25522593 TI - [Isolation and characterization of 27 polymorphic microsatellite markers in Armillaria luteo-virens ( Physalacriaceae)]. AB - [OBJECTIVE] The objectives of this study were to use Roche 454 GS FLX system to develop SSR markers for Armillaria luteo-virens. These datasets will be valuable for detecting genetic diversity and population structure of this species. [METHODS] We collected Armillaria luteo-virens samples from Yushu in Qinghai province, China. Total RNA was isolated by using the TRIzol reagent, after that we constructed cDNA library and performed one quarter plate of the whole run 454 pyrosequencing. We selected 98 primer pairs randomly from the 321 SSRs to evaluate their application and the polymorphism across 66 individuals (Armillaria luteo-virens) representing 3 wild populations. [RESULTS] Roche 454 sequencing yielded 197,121 reads with a total nucleotide size of 88,585,965bp. 27 of 98 SSRs loci were polymorphic. Numbers of alleles (Na) ranged from 2 to 8. Expected heterozygosity (HE) ranged from less than 0. 001 to 0. 810 at locus ALV65, while observed heterozygosity (Ho) from 0 at loci AIV64 and AIV92 to 0. 900 at loci ALV8. We found no evidence of linkage disequiliburium, however 10 of 27 SSR markers showed significant deviation from Hardy-weinberg equilibrium. [CONCLUSION] These remaining 17 pairs of Armillaria luteo-virens SSR markers will be valuable for future research on detecting population structure and conservation of this species. PMID- 25522594 TI - [Nitrate removal from recirculating aquaculture system using polyhydroxybutyrate co-hydroxyvalerate as carbon source ]. AB - [ OBJECTIVE] Polyhydroxybutyrate-co-hydroxyvalerate (PHBV) was used as solid carbon source and biofilm carrier to remove nitrate from recirculating aquaculture system (RAS). Dynamics of microbial community structure in biofilm coating on carbon source packed into denitrification reactor were investigated. [METHODS] Polymerase chain reaction-denaturing gradient gel electrophoresis (PCR DGGE) was used to analyze the microbial community in biofilm from denitrifiation reactor. Bacteria degrading PHBV were isolated from the reactor using pure culture method. [RESULTS] Nitrate decreased remarkably in the RAS connected with dentrification reactor. In contrast, Nitrate increased continuously in the conventional RAS without dentrification reactor. According to the phylogenetic analysis, the microbes in the biofilm samples from denitrification reactor were divided into Proteobacteria ( p-proteobacteria, gamma-proteobacteria and delta- proteobacteria) , Firmicutes and Bacteroidetes. The major advantageous populations were Acidovorax and Bacillus in the 40-day reactor. The advantageous populations in the 150-day reactor were in order of Clostridium, Desulfitobacterium, Dechloromonas, Pseudoxanthomonas and Flavobacterium. Pure cultures of bacteria degrading PHBV isolated from denitrification reactor were classified into Acidovorax, Methylibium, Pseudoxanthomonas and Dechloromonas. [CONCLUSION] Nitrate could be removed effectively from RAS using PHBV as carbon source. Advantageous bacteria and their dynamic changes were ascertained in biofilm from denitrification reactor packed with PHBV. PMID- 25522595 TI - [Degradation of halogenated compounds by haloalkane dehalogenase DadA from Alcanivorax dieselolei B-5 ]. AB - [OBJECTIVE] Alcanivorax dieselolei B-5 is an important oil-degrading bacterium. We studied its substrate range and degradation of halogenated compounds. [METHODS] Growth capability of B-5 was examined with different halogenated substrates as sole carbon source. A putative haloalkane dehalogenase (HLD) gene named dadA was found from the genome of strain B-5 and analyzed by sequence alignment, phylogenetic analysis and homologous modeling. After heterologous expression in Escherichia coli and purification, the activity of DadA towards 46 substrates was determined. [RESULTS] Strain B-5 was capable of utilizing various halogenated compounds (C3-C,8) as the sole carbon source. DadA had typical catalytic pentad residues of HLD-II subfamily, but it was independent from other members of this subfamily according to phylogenetic analysis. Activity assay showed that DadA has higher specificity and narrower substrate range than other characterized HLDs and it only showed activity toward 1,2,3-tribromopropane, 1,2 dibromo-3-chloropropane and 2,3-dichloroprop-1-ene among 46 tested substrates. [CONCLUSIONS] Strain B-5 and its HLD DadA can degrade halogenated aliphatic pollutants although. PMID- 25522596 TI - [Evolution of non-coding nucleotide sequences in Newcastle disease virus genomes ]. AB - [OBJECTIVE] Although much is done in the coding genes of Newcastle disease virus (NDV) , limited papers can be found with non-coding sequences. In this paper, the evolution tendency of non-coding sequences was studied. [METHODS] NDV strain LC12 isolated from duck with egg drop syndrome in 2012, and others 35 strains genome cDNA of different NDV genotype were sought and obtained from GenBank. Analytical approaches including nucleotide homology, nucleotide alignment and phylogenetic tree were associated with the leading sequences, trailer sequences, intergenic sequences (IGS), and coding gene between 5 'and 3' UTR nucleotide, respectively. [RESULTS] The location and the length of the non-coding sequences highly conserve, and the variation trend of non-coding sequences is synchronous with the entire genomes and coding genes. [ CONCLUSION] The molecular variation of the coding gene was indistinguishable with the non-coding gene in view of the NDV genome. PMID- 25522597 TI - [Molecular characteristic of duck hepatitis A virus type 1 causing pancreatitis ]. AB - [OBJECTIVE] We studied the molecular characteristics of the full-length genome of duck hepatitis A virus type 1 causing pancreatitis in Muscovy ducklings. [METHODS] We determined the entire genomic sequence of duck hepatitis A virus type 1 strain MPZJ1206 using reverse transcription polymerase chain reaction assay and analyzed the bioinformatics of the viral genome sequence. [ RESULTS] The genome length of strain MPZJ1206 comprised 7703 bases, with a G + C content of 43.05%. The genome of MPZJ1206 contains a single, long open reading frame encoding a polypeptide of 2249 amino acids, with a genomic orgariization similar to those of other isolates of duck hepatitis A virus type 1. MPZJ1206 is identical with previously isolates by 93. 5% - 99. 6% in nucleotide sequence and 97. 9% - 99. 6% in amino acid sequence and shares genetic distance no more than 7%. Phylogenetic analysis based on genome sequence indicates that MPZJ1206 shares a close genetic relationship with two strains isolated in 2011. [CONCLUSION] Although pathotype caused by MPZJ1206 strain is significantly distinct from those induced by classical isolates of duck hepatitis A virus type 1, the genome of MPZJ1206 shares high homology with those of previous isolates. The change of pathotype may result from an alteration in viral tissue tropism of MPZJ1206. PMID- 25522598 TI - [Diversity of ammonia-oxidizing archaea in Tibetan Zoige plateau wetland ]. AB - [ OBJECTIVE ] Investigation of ammonia-oxidizing archaea (AOA) in nature environments is important to understand the global nitrogen cycling. However, little is known about the AOA community in plateau wetland. Therefore, we studied the composition and diversity of AOA in Zoige plateau wetland swamp soil. [METHODS] Total DNA was extracted from the swamp soil of three typical wetlands including A'xi pastoral area, Maixi pastoral area and Fenqu pastoral area locate in Zoige plateau wetland, and amoA gene was amplified with universally AOA amoA gene primers and then cloned. Then 80 positive clones for each clone library were chosen for further restriction fragment length polymorphism (RFLP) analysis, and the typical RFLP types were selected for sequencing and clustered into operational taxonomic units (OTUs) at 98% cutoff using the Mothur software. The MEGA 5. 0 software was used for the amoA gene phylogeny analysis. [RESULTS] A total of 240 positive clones for all 3 libraries were used for RFLP analysis, and 15 specific amoA sequences were sequenced and clustered into 7 OTUs at 98% cutoff. Among them, OTU6 was detected in all of the 3 libraries and included 27% of the total specific clones. The phylogeny analysis showed that the 15 amoA sequences were grouped into 3 subgroups consisted of Zoige Wetland Clade 1 (4 OTUs), Zoige Wetland Clade 2 (2 OTUs) and Zoige Wetland Clade 3 (1 OTU). BLAST analysis showed that all OTUs were affiliated with the phylum Crenarchaeota. Correlation analysis showed that the Shannon diversity index (H') was significantly correlated with ammonia, nitrate/nitrite (P <0. 05). [ CONCLUSION] AOA in the Zoige plateau wetland swamp soil are all belonged to the Crenarchaeota, and their diversity is significantly correlated with soil ammonia, nitrate/nitrite content. PMID- 25522599 TI - [MicroRNA and left ventricular hypertrophy]. AB - MicroRNAs (miRNA) plays an important role in biological development and disease occurrence and development, and acts as a "main switch" in biology. Among patients of essential hypertension, around 1/3 would suffer left ventricular hypertrophy (LVH). Hence, essential hypertension becomes an independent risk factor for cardiovascular diseases. And miRNAs plays an important role in the occurrence and development of LVH. This paper reviewed the role of miRNA in regulating the stress signaling pathway, defined its impact on the occurrence of LVH, and further emphasized the opportunities and challenges of miRNA as a biomarker and therapeutic target. PMID- 25522600 TI - [Advance in studies on molecular mechanisms of cisplatin resistance and intervention with traditional Chinese medicines]. AB - Cisplatin is a first-line anticancer drug widely used in clinic. However, its resistance reduces its efficacy. With a non-specific cell cycle, cisplatin's main targets are nucleophilic protein, DNA and RNA in cells. Among cisplatin's multi factorial resistance mechanisms, abnormal expression of transport protein, intracellular detoxification enhancement, DNA repair capacity increase and apoptosis blocking are the main mechanisms. Because traditional Chinese medicines (TCMs) have unique advantages in cancer treatment, their combination with cisplatin can improve the efficacy. In this paper, the authors summarized the advance in studies on cisplatin's resistance and the combination of TCMs and cisplatin in recent years. PMID- 25522601 TI - [Safety evaluation of niuhuang jiedu tablet]. AB - Realgar-containing Niuhuang Jiedu tablet (NHJD) has been applied in clinic for more than 800 years. However, because realgar contains arsenic (As), it has aroused wide concerns and controversies both at home and abroad. Currently, there are two misunderstandings about realgar-containing Chinese patent medicines. First, some people exaggerated realgar's toxicity as that of arsenic. Second, they recommended to remove realgar from traditional Chinese medicine compounds. In this paper, the authors summarized the advance in studies on NHJD, and proposed different opinions: (1) It is inappropriate to take total As as the index in safety evaluation of NHJD. (2) The toxicity of NHJD is dependent on the dose and duration of administration. (3) Realgar is an active ingredient of NHJD, and shall be deeply studied. Classic realgar-containing traditional Chinese medicine prescriptions, such as Niuhuang Jiedu tablet, shall be evaluated with rigorous modern scientific basis, with the aim to guide rational and safe application. PMID- 25522602 TI - [Advanced in solubilization methods of water-insoluble natural drugs]. AB - With the development of natural products, the research activities on the solubilization methods of water-insoluble natural products have been carried out worldwide. Big molecular weight and poor solubility of most natural active ingredients lead to a very poor oral absorption and low bioavailability, which has extremely limited their development in pharmaceutical fields and clinical application. As a result, it is necessary to find out a suitable technique to improve the solubility and enhance the oral bioavailability of insoluble natural drugs. Based on the related references published in these years, this review introduced some new techniques to improve the solubility and bioavailability of natural drugs, including prodrugs, inclusion complex, solid dispersion, cocrystals, osmotic pump, liquisolid compacts, micronization, self microemulsifying, nanosuspensions, lipsomes, polymeric micelles and so on, and summarized the theory, characteristics, application range, application examples, problems and development direction of each technique. PMID- 25522603 TI - [Screening and identification of endophytic fungi with growth promoting effect on Dendrobium officinale]. AB - The endophytic fungi with plant growth promoting effects were screened by co culture of each endophytic fungus and seedlings of Dendrobium officinale. Anatomical features of the inoculated roots were studied by paraffin sectioning. Morphological characteristics and rDNA ITS1-5. 8S-ITS2 sequences were applied for the taxonomy of endophytic fungi. The results showed that 8 strains inoculated to D. officinale seedlings greatly enhanced plant height, stem diameter, new roots number and biomass. According to the anatomical features of the inoculated roots, each fungus could infect the velamina of seedlings. The hyphae or pelotons were existed in the exodermis passage cells and cortex cells. The effective fungi could not infect the endodermis and vascular bundle sheath, but which was exception for other fungi with harmful to seedlings. Combined with classic morphologic classification, 2 effective strains were identified which were subjected to Pestalotiopsis and Eurotium. Six species of fungi without conidiophore belonged to Pyrenochaeta, Coprinellus, Pholiota, Alternaria, Helotiales, which were identified by sequencing the PCR-amplified rDNA ITS1-5. 8S ITS2 regions. The co-culture technology of effective endophytic fungi and plant can apply to cultivate the seedlings of D. officinale. It is feasible to shorten growth cycle of D. officinale and increase the resource of Chinese herbs. PMID- 25522604 TI - [Effects of different fungi on symbiotic seed germination of two Dendrobium species]. AB - The epiphytic orchid, Dendrobium aphyllum and D. devonianum are used as traditional Chinese medicine, and became locally endangered in recent years because of over-collection. We test the effect of inoculations of endophytic fungi FDaI7 (Tulasnella sp.), FDd1 (Epulorhiza sp. ) and FCb4 (Epulorhiza sp.), which isolated from D. aphyllum, D. denonianum and Cymbidium mannii, respectively, on artificial substrate in these two Dendrobium species. In the symbiotic germination experiment, FDaI7 and FDd1 were effective for protocorm formation and seedling development of D. aphyllum and D. denonianum separately. After 60 days, 14.46% of the D. aphyllum seeds grown to protocorms and 12.07% developed to seedlings inoculated only with FDaI7, while contrasted with 0 when inoculated the other two isolates and non-inoculation treatment. However, in D. denonianum, seeds only grown to protocorms and developed to seedlings when inoculated with FDd1, the percentages were 44.36% and 42.91% distinguishingly. High specificity was shown in symbiotic germination on artificial substrate of Dendrobium. Protocorms could further develop to seedlings within or without light when inoculated the compatible fungi. However, light condition (12/12 h Light/Dark) produced the normal seedlings, while dark condition (0/24 h L/D) produced the abnormal seedlings. These may suggest that the development of young seedlings require light based on the effective symbiotic fungi. These findings will aid in seedling production of simulation-forestry ecology cultivation, conservation and reintroduction of Dendrobium. PMID- 25522605 TI - [Observation of prime position and driving zones in process of tuberous root expanding and expression analysis of phytohormone relative genes in Rehmannia glutinosa]. AB - In order to study the development characteristics of Rehmannia glutinosa tuberous root expansion and reveal the regulation mechanism of the genes related to hormones in this process, R. glutinosa "wen-85" was used as the experimental material in this study. R. glutinosa tuberous roots of different developmental stages were collected to observe phenotype and tissue morphology using resin semi thin sections method. The genes related to hormone biosynthesis and response were chosen from the transcriptome of R. glutinosa, which was previously constructed by our laboratory, their expression levels at different development stages were measured by real-time quantitative PCR. The results showed that the root development could be divided into six stages: seeding, elongation, pre-expanding, mid-expanding, late-expanding and maturity stage. The anatomic characteristics indicated that the fission of secondary cambium initiated the tuberous root expansion, and the continuous and rapid division of secondary cambium and accessory cambium kept the sustained and rapid expansion of tuberous root. In addition, a large number oleoplasts were observed in root on the semi-thin and ultra-thin section. The quantitative analysis suggested that the genes related to biosynthesis and response of the IAA, CK, ABA,ethylene, JA and EB were up regulated expressed, meanwhile, GA synthesis and response genes were down regulated expressed and the genes of GA negative regulation factors were up regulated expressed. The maximum levels of most genes expression occurred in the elongation and pre-expansion stage, indicating these two stages were the key periods to the formation and development of tuberous roots. Oleoplasts might be the essential cytological basis for the formation and storage of the unique medicinal components in R. glutinosa. The results of the study are helpful for explanation of development and the molecular regulation mechanism of the tuberous root in R. glutinosa. PMID- 25522606 TI - [Genetic structure and genetic diversity of Artemisia annua varieties (strains) populations based on SCoT markers]. AB - To reveal the genetic diversity and genetic structure in Artemisia annua varieties (strains) populations, we detected the genetic polymorphism within and among eight varieties (strains) populations (192 individuals) by the approach of Start Codon Targeted Polymorphism (SCoT). The associated genetic parameters were calculated by POPGENE1.31 and the relationship was constructed based on UPGMA method. The results showed that, using 20 screened primers, a total of 145 bands were produced, of which 122 were polymorphic loci. At species level, there was a high level of genetic diversity among eight varieties (strains) populations (PPB = 84.1% ,H = 0.217 3 and H(sp) = 0.341 9). However, at the variety (strains) population level, genetic diversity was lower, the average of genetic parameters was PPB = 41.9%, H = 0.121 5, H(pop) = 0.186 8. The Nei's genetic differentiation coefficient was 0.441 0, indicate that most of the genetic variation in this species existed within the variety populations. The gene flow (N(m) = 0.633 9) was less among populations, indicating that the degree of genetic differentiation was higher. Genetic similarity coefficient were changed from 0.755 1 to 0.985 7. By clustering analysis, eight varieties (strains) were clustered into two major categories and it was also showed the same or similar genetic background varieties (strains) have a tendency to gather in the same group. Results suggest that, in variety breeding, breeders should strengthen the exchange of bred germplasm and increase mutual penetration of excellent genes, which would broaden the genetic base of A. annua. PMID- 25522607 TI - [Study on identification of Sarcandra glabra and Chloranthus spicatus's leaves by PCR amplification of specific alleles]. AB - The paper is aimed to identify SNP in Sarcandra glabra and Chloranthus spicatus, and authenticate S. glabra from Ch. spicatus and the mixture by using PCR amplification of specific alleles. SNPs in the ITS sequences of S. glabra and Ch. spicatus were found by ClustulX 2. 1 program and Bioedit software. Primers for authentic S. glabra and Ch. spicatus was designed according to the SNP site, and ITS sequence universal primers plus to the authentic primer to construct a multi PCR reaction system, and then optimized the PCR reaction system. Five hundred and eighty band special for S. glabra and 470 bp band special for Ch. spicatus were found by using multi-PCR reaction. The multi-PCR reaction system could be applied to identify S. glabra and Ch. spicatus's leaves. PMID- 25522608 TI - [Effects of nitrogen form on growth and quality of Chrysanthemums morifolium]. AB - This paper is aimed to study the effects of nitrogen form on the growth and quality of Chrysanthemums morifolium at the same nitrogen level. In order to provide references for nutrition regulation of Ch. morifolium in field production, pot experiments were carried out in the greenhouse at experimental station of Nanjing Agricultural University. Five proportions of ammonium and nitrate nitrogen were set up and a randomized block design was applied four times repeatedly. The results showed that the growth and quality of Ch. morifolium were significantly influenced by the nitrogen form. The content of chlorophyll and photosynthesis rate were the highest at the NH4(+) -N /NO3(-) -N ratio of 25:75; The activities of NR in different parts of Ch. -morifolium reached the highest at the NH4(+) - N/NO3(-) -N ratio of 0: 100. The contents of nitrate nitrogen in the root and leaves reached the highest at the NH4(+) -N/NO3(-) -N ratio of 50:50. The activities of GS, GOGAT and the content of amylum increased with the ratio of NO3(-) -N decreasing and reached it's maximum at the NH4 + -N/NO3 - -N ratio of 100: 0. The content of ammonium nitrogen were the highest at the NH4 + -N /NO3 - N ratio of 75: 25, while the content of soluble sugar reached the highest at the NH4(+)-N/NO3(-) -N ratio of 25: 75. The content of flavones, chlorogenic acid and 3,5-O-dicoffeoylqunic acid were 57.2 mg x g(-1), 0.673% and 1.838% respectively, reaching the maximum at the NH4(+) -N /NO3(-) -N ratio of 25:75; The content of luteoloside increased with the ratio of NO3(-) -N increasing and reached it's maximum at the NH4(+) -N/NO3(-) -N ratio of 0: 100. The yield of Ch. morifolium reached it's maximum at the NH4(+) -N /NO3(-) -N ratio of 25:75. Nitrogen form has some remarkable influence on the nitrogen metabolism, photosynthesis and growth, Nitrogen form conducive to the growth and quality of Ch. morifolium at the NH4(+) -N /NO3(-) -N ratio of 25: 75. PMID- 25522609 TI - [Phylogenetic analysis for Fritillaria hupehensis: evidence from ITS, rpl16 and matK sequences]. AB - The systematic position of Fritillaria hupehensis has been in dispute. Phylogentic analyses were conducted on sequences of ITS, rpl16, matK sequences for species of F. hupehensis and allies. Lilium davidii was designed as outgroup. The analyses were performed using MP and ML methods. Conclusions could be achieved as follow. The topologies of MP and ML are consistent. The samples of F. hepehensis from different places form a supported clade with a strong bootstrap. And then form a strongly supported clade with F. anhuiensis, F. monantha. The results suggests that although F. hupehensis has a closet relation with the two ones, it exists some difference. PMID- 25522610 TI - [Studies on release behavior of sustained release tablets of extracts of Gardenia by antioxidant activity]. AB - Using sustained release tablets of gardenia extract as model drug and DPPH radical scavenging capacity as antioxidant index, the feasibility of using pharmacodynamics index was explored to evaluate sustained release tablets. Applying the established quantifiable method of DPPH radical scavenging to the dissolved liquid of model drug, release profiles and biological effects profiles were drawn, and their correlation was discussed. A good correlation was observed by linear regression and f2 actor, suggesting that the indicator could be used to evaluate sustained release tabletsofextracts of gardenia in which iridoids were mainly involved. PMID- 25522611 TI - [Effect of suet oil on formation of self-assembled micelles of flavonoids in Epimedium]. AB - In this paper, the action of suet oil in the preparation of self-assembled micelles of the active flavonoids in Epimedium in the simulated human environment was researched. Twelve suet oil samples were collected from different growing areas and different positions of sheep or goat to simulate the formation of micelles. Then the effects of the fatty acids in suet oil on the preparation of self-assembled micelles were studied furthermore. The results showed that the micelles had a dispersed state and spherical smooth surface. To compare the diameter, potential, encapsulation efficiency and drug loading of the 12 batches micelles, the micelles prepared by the suet oil from Qinghai were more stable and had a higher encapsulation efficiency. The fatty acids in suet oil could promote the formation of self-assembled micelles, but the whole suet oil had a better effect. Above all the study, we confirmed that the suet oil promoted the formation of self-assembled micelles of the flavonoids in Epimedium, it laid foundation for further research about increasing the efficacy of Epimedium and improved the absorption of the active flavonoids in Epimedium. PMID- 25522612 TI - [Preliminary study of odor change mechanism in Crataegi fructus stir-fried process based on correlation analysis]. AB - In order to investigate the mechanism, the correlation between the odor change in Crataegi Fructus stir-fried process and 5-HMF were studied. Required samples were retrieved from Crataegi Fructus stir-fried process. Statistical quality control (SQC) was used to analyze the response values acquired by the electronic nose. At the same time, the content of 5-HMF was detected by high performance liquid chromatography (HPLC). Correlation analysis was used to analyze the relationship between the above two. Experimental results showed that SQC model established by response values of all samples could show the change law of odor in Crataegi Fructus stir-fried process and changes of 5-HMF content was dropped after the first increase. Correlation analysis showed that the odor change in Crataegi Fructus stir-fried process and 5-HMF were significantly correlated (P < 0.05). Sugar degradation reaction and the Maillard reaction may be one of the mechanisms of the odor change in Crataegi Fructus stir-fried process. PMID- 25522613 TI - [Network analysis of ethanol precipitation process for Schisandrae chinensis fructus]. AB - A set of central composite design experiments were designed by using four factors which were ethanol amount, ethanol concentration, refrigeration temperature and refrigeration time. The relation between these factors with the target variables of the retention rate of schizandrol A, the soluble solids content, the removal rate of fructose and the removal rate of glucose were analyzed with Bayesian networks, and ethanol amount and ethanol concentration were found as the critical process parameters. Then a network model was built with 2 inputs and 4 outputs using back propagation artificial neural networks which was optimized by genetic algorithms. The R2 and MSE from the training set were 0.983 8 and 0.001 1. The R2 and MSE from the test set were 0.975 9 and 0.001 8. The results showed that network analysis method could be used for modeling of Schisandrae Chinensis Fructus ethanol precipitation process and identify critical operating parameters. PMID- 25522614 TI - [Identification of marine-derived shell TCM by near infrared spectroscopy]. AB - The identification of five marine-derived shell traditional Chinese medicine (TCM) recorded in the Chinese Pharmacopoeia were studied. Using near infrared technology (NIR) combined with principal component analysis (PCA) methods, Ostreae Concha, Haliotidis Concha, and Margaritifera Concha could be efficiently distinguished from Meretricis Concha together with Arcae Concha. In the first principal components, Ostreae Concha exhibited obvious differences with high loadings in 4 236, 5 263, 7 142 cm(-1) concerning to the contents of CaCO3 and H2O in the samples. Arcae Concha and Meretricis Concha displayed significant differences with others in the second principal components, which can be illustrated by high loadings in 5 000 -4 430 cm(-1) areas. It is indicated that the second principal components might be related to organics which contained NH and CH groups, for example proteins. Meanwhile, our data showed a correlation between the function of these shell TCM and their distribution in the PCA plot. These results suggested that organic components in marine-derived shell TCM could not be neglected for their quality control. PMID- 25522615 TI - [Separation and evaluation of antioxidant constituents from Carthamus tinctorius]. AB - Bio-active components from Carthamus tinctorius were separated on the basis of antioxidant capacities in vitro. The antioxidant capacity was investigated on the basis of the ability to scavenge DPPH radical, ABTS radical and reduce Fe3+ of different polar fractions. Furthermore, the chemical compounds were isolated from bio-active fraction, and were evaluated for the antioxidative effects. Five major components were isolated and identified from water extract as 6-hydroxykaempferol 3,6,7-tri-O-beta-D-glucoside(1), 6-hydroxykaempferol 3-O-beta-rutinoside-6-O-beta D-glucoside (2), 6-hydroxykaempferol 3-O-beta-D-glucoside (3), hydroxysafflor yellow A (4) and anhydrosafflor yellow B (5). By evaluating and comparing the antioxidative effects of different fractions and obtained compounds, the results showed that water extract displayed significantly high antioxidative activities and 6-hydroxykaempferol glycosides and quinochalcone C-glycosides were found as main contribution for antioxidant property. PMID- 25522616 TI - [Chemical constituents of flavonoids and their glycosides in Melastoma dodecandrum]. AB - The chemical constituents of 95% ethanol extract of Melastoma dodecandrum were isolated and purified by chromatography on silica gel, Sephadex LH-20, and HPLC, to obtain thirteen compounds eventually. On the basis of their physico-chemical properties and spectroscopic data, these compounds were identified as quercetin (1), quercetin-3-O-beta-D-glucopyranoside (2), quercetin-3-O-(6"-O-p-coumaroyl) beta-D-glucopyranoside (3), kaempferol (4), kaempferol-3-O-beta-D-glucopyranoside (5), kaempferol-3-O- [2",6"-di-O-(E)-coumaroyl]-beta-D-glucopyra-noside (6), luteolin (7), luteolin-7-O-(6"-p-coumaroyl) -beta-D-glucopyranoside (8), apigenin (9), apigenin-7-(6"-acetyl-glucopyranoside) (10) , naringenin (11), isovitexin (12), and epicatechin-[8,7-e] -4beta-(4-hydroxyphenyl)-3,4-dyhydroxyl-2(3H) pyranone (13). Eight compounds(3,5,6,8-11 and 13) were obtained from M. dodecandrum for the first time. PMID- 25522617 TI - [Simultaneous quantitation of artemisinin, arteannuin B, artemisic acid, and scopoletin in mice plasma by HPLC-MS]. AB - The objective of this study is to develop a sensitive and reliable high performance liquid chromatography mass spectrometry (LC-MS) method for simultaneous determination of artemisinin, arteannuin B, artemisic acid, and scopoletin, and study the pharmacokinetics of the four constituents in mouse serum after oral administration of the four components to mice. The analytical column used was Agilent Zorbax SB-C18 (2.1 mm x 150 mm, 5 mm). The mobile phase was acetonitrile: 0.5% acetic acid (60: 40) and the flow rate was 0.3 mL x min( 1). The temperature of the column was 40.0 degrees C. In this condition, we established an analysis method to simultaneously determine the four components. A sensitive and specific liquid chromatography-mass spectrometric (LC-MS) method was developed and validated for the determination of artemisin in derivatives in mice plasma. The method we established has a linear range of 5-3 000 MUg x L(-1) with a good sensitivity and specificity for all of the four components. This method is simple, rapid, accurate and suitable for the determination of the content of the four compounds. PMID- 25522618 TI - [FTIR fingerprint spectrograms of traditional Chinese medicine Marsdenia tenacissima]. AB - In this paper, Fourier transform infrared spectroscopy fingerprint analysis of Marsdenia tenacissima samples was used to develop a reliable method of tracing the geographical origins. Forty-eight samples from four provinces of China were analyzed by FTIR. We analyzed and characterized the fingerprints in both the full spectrum peaks and characteristic peaks, then the principal component analysis and the cluster analysis were carried out. The results of fingerprint analysis, correlation analysis, principal component analysis and cluster analysis can identify the geographic origins correctly, which verified and supplemented each other; the identification results and the actual location showed a high degree of consistency, namely the lower the space distance, the greater the similarity of different samples. These results revealed the obvious superiority and practical value in comparison to the more tedious and time-consuming wet chemistry method normally used. Using appropriate metrology methods can trace the geographical source correctly. The M. tenacissima materials from the region of Maguan should be considered as genuine medicinal materials taking into account the good quality. PMID- 25522619 TI - [Separation, purification and primary reverse cholesterol transport study of Cordyceps militaris polysaccharide]. AB - The authors designed to separate, purify and determine the monosaccharide composition of the polysaccharide from Cordyceps militaris, and study its effect on reverse cholesterol transport in vivo by isotope tracing assay. Polysaccharides were separate and purify by ion exchange column Q-sepharose Fast Flow and size exclusion column Sephacryl S200HR; the molecular weight and monosaccharide composition of the polysaccharides were determined by high performance gel permeation chromatography and high performance liquid chromatography coming with pre-column derivation, respectively. Finally, three purified polysaccharides CMBW1, CMBW2 and CMYW1 were obtained, their total carbohydrate contents were 87%, 89%, 95%, respectively; their protein contents were 6.5%, 1.3%, 2.8%, respectively; their molecular weights were 772.1, 20.9, 13.2 kDa, respectively; CMBW1 was composed of mannose, glucosamine, rhamnose, glucuronic acid, glucose, galactose and arabinose with a molar ratio of 7.25: 0.17: 1.29: 0.23: 6.30: 11.08: 0.79; CMBW2 was composed of mannose, glucosamine, galactose and arabinose with a molar ratio of 2.40: 0.16: 2.92: 0.24; CMYW1 was composed of mannose, glucosamine, glucuronic acid and glucose with a molar ratio of 0.59: 0.57: 0.45: 25.61. Polysaccharide at 50 mg x kg(-1) could significantly improve the transport of 3H- cholesterol to blood and excretion from feces. All of the three purified polysaccharides CMBW1, CMBW2 and CMYW1 were heteropolysaccharide; and they could improve reverse cholesterol transport in vivo, the underlying mechanisms are being studied. PMID- 25522620 TI - [Comparative analysis of seven marine biological source of mineral drugs]. AB - The marine biological source of mineral drugs recorded in Chinese Pharmacopoeia (2010 version) mainly including pearl, nacre, clam shell, common oyster shell, ark shell, cuttle bone, and sea-ear shell are widely used in clinical. Calcium carbonate and a small amount of protein are the main components in this type of drugs. In this paper, a systematical and comparable study were carried out by determination of calcium carbonate by EDTA titration method, the crystal of calcium carbonate by X-Ray powder diffraction and the total amino acids (TAAs) of the hydrolyzed samples by ultraviolet spectrophotometry method. As a result, the crystal structure is calcite for common oyster shell, mixture of calcite and aragonite for nacre and sea-ear shell, aragonite for the other drugs. The content of calcium carbonate ranged from 86% to 96%. Cuttle bone has the highest amount of TAAs among the seven drugs which reached 1.7% while clam shell has the lowest content of 0.16% on average. In conclusion, an effective method was developed for the quality control of marine mineral drugs by comprehensive analysis of calcium carbonate and TAAs in the seven marine mineral drugs. PMID- 25522621 TI - [Research on bitter components from Coptis chinensis based on electronic tongue]. AB - Isolated alkaloids from Coptis chinensis Franch. The compounds were identified as berberine, columbamine, groenlandicine, jatrorrhizine, magnoflorine, corydaldine and ferulic acid methylester. Then measured their bitter degree based on the electronic tongue and evaluated the antibacterial. The results based on the Electronic Tongue showed that berberine, columbamine, groenlandicine and jatrorrhizine have higher bitter degree than magnoflorine and corydaldine. And they also appeared better antibacterial activity on E. coli and S. aureus. The correlation coefficients between bitter degree and the two bacteria antibacterial activity were 0.983 and 0.911. So there was close relationship between the bitter degree and antibacterial activity of bitter components. Thus, it is confirmed further that bitter components are the material foundation of medicinal effectiveness of bitter herbs. PMID- 25522622 TI - [Application of support vector machine in screening neurotoxic compounds from traditional Chinese medicine]. AB - In this study, based on web database, 324 neurotoxic compounds and 234 non neurotoxic compounds were selected as a data set for neurotoxicity discriminative model. 6 122 molecular descriptors, including charge distribution, physicochemical and geometrical descriptors,were calculated to characterize the molecular structure of neurotoxic compounds. The combination of Cfs Subset Evaluation and Best First-D1-N5 searching was used to select molecular descriptors. A discrimination model with high accuracy was built based on the support vector machine (SVM) approach. Meanwhile, the model accuracy, sensitivity and specificity were all above 80%. Besides, 30 traditional Chinese medicine compositions with neurotoxicity were set as external validation to further verify the model accuracy,with anaccuracy of 73.333%. Using the model, 13 potential neurotoxic compounds were screened from Sophorae subprostrate Radix,4 of them were verified by literatures. The results demonstrated that the discrimination model can be applied to screen neurotoxic compounds from Chinese medicinal materials. PMID- 25522623 TI - [Study on correlation between trace elements and active ingredient in glycyrrhizae radix et rhizome]. AB - To clear the kinds of trace elements which is closely related with the active ingredient, proclaim the effects of trace elements on the quality of the Glycyrrhizae Radix et Rhizoma, provide the theoretical foundation to the further quality control of cultivation, take the advantage of the HPLC to determine the contents of glycyrrhizic acid and the liquiritin according to Chinese pharmacopoeia, use the inductively coupled plasma mass spectrometry to test the contents of Cu, Zn, Mn, Pb, Se, Cd, Ni, La, Na, Cr, M, Fe, Ca, Al, K, Sr, then, use SPSS statistical software for active ingredient and trace elements Correlation Analysis. The result of correlation analysis showed that Liquiritin contents of Glycyrrhizae Radix et Rhizoma have strong a positive correlation with the Mn, Pb contents, well, have a negative correlation with the Cu, Na contents; Glycyrrhizic acid contents showed a positive correlation with Mg, Cd, La contents, however, it showed a negative correlation with K, Fe contents. Comprehensive analysis of the results of the study, a preliminary thought that the active ingredient of Glycyrrhizae Radix et Rhizoma closely related with the trace elements, but the exact conclusion still need further study concentration response relationship analysis. PMID- 25522624 TI - [Effect of andrographolide on Candida albicans biofilm dispersion]. AB - Along with the increase in fungal infections, Candida albicans prevention and control become the focus of anti-fungal infection at present. This study aims to discuss the effect monomer andrographolide (AG) on C. albicans biofilm dispersion. In the experiment, micro-well plates and medical catheter pieces were used to establish the C. albicans biofilm model. It was discovered by XTT assay and flat band method that 1 000, 500, 250 mg x L(-1) AG could impact the activity of C. albicans biofilm dispersion cells. The morphological structures of residual biofilms on catheter pieces were observed with scanning electron microscopy, which showed that 1 000, 500, 250 mg x L(-1) AG could induce C. albicans biofilm dispersion in a dose-dependent manner, and the dispersed cells were dominated by the yeast phase. According to the real-time fluorescence quantification PCR (qRT PCR) test, AG could up-regulate HSP90 expression and down-regulate UME6 and PES1 expressions. This study demonstrates that AG could induce C. albicans biofilm dispersion to some extent. PMID- 25522625 TI - [Effect of carnosol against proliferative activity of breast cancer cells and its estrogen receptor subtype's mediation and regulation mechanisms]. AB - Carnosol has been proved to have anti-breast cancer effect in previous research. But its ER subtype's specific regulation and mediation mechanisms remain unclear. The aim of this study is to observe the effect of carnosol on cell proliferation and its estrogen receptor alpha and beta's specific regulation and mediation mechanisms with ER positive breast cancer T47D cell. With estrogen receptor alpha and beta antagonists MPP and PHTPP as tools, the MTT cell proliferation assay was performed to observe the effect of carnosol on T47D cell proliferation. The changes in the T47D cell proliferation cycle were detected by flow cytometry. The effect of carnosol on ERalpha and ERbeta expressions of T47D cells was measured by Western blot. The findings showed that 1 x 10(-5)-1 x 10(-7) mol x L(-1) carnosol could significantly inhibit the T47D cell proliferation, which could be enhanced by MPP or weakened by PHTPP. Meanwhile, 1 x 10(-5) mol x L(-1) or 1 x 10(-6) mol x L(-1) carnosol could significantly increase ERalpha and ERbeta expressions of T47D cells, and remarkably increase ERalpha/ERbeta ratio. The results showed that carnosol showed the inhibitory effect on the proliferation of ER positive breast cancer cells through target cell ER, especially ERbeta pathway. In the meantime, carnosol could regulate expressions and proportions of target cell ER subtype ERalpha and ERbeta. PMID- 25522626 TI - [Study on impact of ethanol extracts from Sedum sarmentosum in inhibiting STAT-3 signaling and inducing apoptosis of human hepatocellular carcinoma cell line HepG2]. AB - OBJECTIVE: To investigate the impact of ethanol extracts from Sedum sarmentosum (ESB) on STAT-3 signaling and its probable molecular mechanism in inducing apoptosis. METHOD: MTT assay was used to detect the impact of ESB on HepG2 cell proliferation. FITC-Annexin V-FITC /PI double-labeling were used to investigate the impact on hepatoma carcinoma cell apoptosis. Western blot analysis was used to test the expression levels of cell apoptosis-related proteins Caspase-3, Caspase-9, PARP, P-STAT-3 (Tyr705) , STAT-3, Bcl-2, Mcl-1. RESULT: ESB could notably inhibit proliferation of HepG2 cells, and induce HepG2 cell apoptosis, with the dose-dependent inhibitory effect. In addition, ESB could inhibit STAT-3 signaling, down-regulate Mcl-1 and Bcl-2 expressions, and induce degradation/activation of apoptosis-related proteins Caspase-3 and Caspase-9 and PARP degradation in a dose-dependent manner. CONCLUSION: ESB inhibits HepG2 cell proliferation and induces apoptosis by inhibiting STAT-3 signaling and Mcl-1 and Bcl-2 expressions. PMID- 25522627 TI - [Study on discrimination mode of cold and hot properties of traditional Chinese medicines based on biological effects]. AB - OBJECTIVE: To observe the effect of cold or hot properties of traditional Chinese medicines (TCM) on biological effect indexes, and analyze the contribution of variables on cold or hot properties, in order to preliminarily establish the discrimination mode for the biological effects of cold or hot properties. METHOD: Rats were randomly divided into the blank control group, cold TCM groups (Coptidis Rhizoma, Scutellariae Radix, Phellodendri Cortex, Gardeniae Fructus, Sophorae Flavescentis Radix and Gentianae Radix) and hot TCM groups (Aconiti Lateralis Preparata Radix, Zingiberis Rhizoma, Alpiniae Officinarum Rhizoma, Zanthoxyli Pericarpium, Cinnamomi Cortex and Evodiae Fructus), and orally administered with 10 mL x kg(-1) of corresponding TCM water decoctions for 30 d, twice a day. Altogether 53 biological effect indexes correlated to cold or hot properties of traditional Chinese medicines were founded by searching literatures. The data warehouse were established by using data-mining software Clementine12.0. Data of the blank control group, cold TCM groups (Coptidis Rhizoma, Phellodendri Cortex, Gardeniae Fructus, Sophorae Flavescentis Radix, Gentianae Radix) and hot TCM groups (Aconiti Lateralis Preparata Radix, Zingiberis Rhizoma, Alpiniae Officinarum Rhizoma, Zanthoxyli Pericarpium, Cinnamomi Cortex) were selected into a training set. C5.0 algorithm and C&R classification and regression algorithm were adopted to define the importance of variable, create the decision trees, and test hot or cold properties of Evodiae Fructus and Scutellariae Radix. RESULT: According to C&R classification and regression algorithm, SDH activity of livers was the most important hot or cold property, with the significance closed to 30%. It was followed by triglyceride, liver Na' -K' -ATPase enzyme, muscle glycogen and platelet distribution width, with the accuracy up to 97.39% in models. C5.0 algorithm showed that liver SDH activity was the most important hot or cold property, with the significance closed to 40%. It was followed by triglyceride, GOT, muscle glycogen and liver Na(+)-K(+)-ATPase enzyme, with the accuracy up to 98.26% in models. The possibilities that Evodiae Fructus is in hot property and Scutellariae Radix is in cold property were 100. 00% and 77.78% by using both C&R classification and regression algorithm and C5.0 algorithm. CONCLUSION: The SDH activity of liver is the most important biological effect index to distinguish cold and hot properties of TCMs. The discrimination pathway or mode of cold and hot properties is closely related to energy metabolism. PMID- 25522628 TI - [Study on effect of four traditional Chinese medicines distributed along lung meridian on TLR2 and NF-kappaB expressions in mice with lung heat syndrome]. AB - OBJECTIVE: To investigate the effect of four traditional Chinese medicines distributed along lung meridian, namely Ephedrae Hebra, Zingiberis Rhizoma, Scutellariae Radix and Mori Cortex, on TLR2 and NF-kappaB expressions in mice with lung heat syndrome, in order to study the intervention effect of the four traditional Chinese medicines (TCMs) on the lung heat syndrome. METHOD: One hundred KM mice were randomly divided into the normal control group, the model group, the Ephedrae Hebra group, the Zingiberis Rhizoma group, the Scutellariae Radix group and the Mori Cortex group (20, 10 g x kg(-1)), nasally dripped with streptococcus pneumoniae to establish the mouse lung heat syndrome model, and then administered with different TCMs. The expressions of TLR2, NF-kappaB p65 proteins in lung tissues were analyzed by the immunohistochemical method. The expressions of TLR2, NF-kappaB p65 mRNA were measured by real time PCR. RESULT: Compared with the normal control group, the expressions of TLR2 and NF-kappaB p65 proteins in lung tissues in the model group were higher (P < 0.01), and the expressions of TLR2 and NF-kappaB p65 mRNA in lung tissues were up-regulated (P < 0.01 or P < 0.05). Compared with the model group, Ephedrae Hebra high and low dose groups, the Zingiberis Rhizoma low dose group and the Scutellariae Radix high dose group showed decreased expression of TLR2 protein (P < 0.05 or P < 0.01); Ephedrae Hebra high and low dose groups, the Zingiberis Rhizoma low dose group, Scutellariae Radix high and low dose groups and Mori Cortex high and low dose groups showed reduced expression of NF-kappaB p65 protein (P < 0.05 or P < 0.01). Ephedrae Hebra high and low dose groups, Zingiberis Rhizoma high and low dose groups, Scutellariae Radix high dose group and Mori Cortex high dose group showed down-regulated expression of TLR2 mRNA (P < 0.01 or P < 0.05). CONCLUSION: Ephedrae Hebra, Zingiberis Rhizoma, Scutellariae Radix and Mori Cortex can induce the TLR2/NF-kappaB inflammatory signal pathways by down-regulating the expressions of TLR2 and NF-kappaB p65 in protein and mRNA, so as to alleviate the lung tissue injury in mice with lung heat syndrome. PMID- 25522629 TI - [Comparative study of main components of ginseng on immune function of rats]. AB - Ginseng and its effective components are famous for their influence to enhance human immunity, regulate endocrine and antioxidant action. However, the different effects of different components are not clear. In this study, Wistar rats were used to study the effects of main components of ginseng, including total ginsenoside, panaxadiol saponins, panaxtrol saponin and ginseng polysaccharide. The results showed that the effects of panaxadiol saponins and ginseng polysaccharide on improving animal immune organ weight, plasma interleukin 2 (IL 2), interleukin 6 (IL-6), plasma gamma-interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha) were better than that of the other groups. Total ginsenoside and panaxtrol saponin can effectively increase the concentration of spleen NK cells (NKC) while panaxadiol saponins and ginseng polysaccharide can significantly increase the concentrations of rat plasma adrenocorticotrophic hormone (ACTH), corticosterone (CORT) and thyroid stimulating hormone (TSH). As for the effect of increasing organization nitric oxide (NO) and superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA), total ginsenoside is better than that of other groups. In brief, different components in ginseng possess different effects on enhancing immunity, regulating endocrine and resisting oxidation. Panaxadiol saponins and ginseng polysaccharide are better in enhancing immune, and total ginsenoside shows advantages in resisting oxidation and stress. PMID- 25522630 TI - [Build of focal cerebral ischemia model in different varieties of mice with modification monofilament]. AB - OBJECTIVE: To establish a general method of focal cerebral ischemia model in different varieties of mice. METHOD: Each group of healthy adult KM and C57BL/6 mice were randomly divided into control group (n = 10) and MCAO group (n = 10). The mice in MCAO group were applied in the preparation of the MCAO model by intraluminal occlusion using monofilament. Twenty-four hours after operation,the neurologic function was evaluated,middle cerebral artery blood flow was monitored and the infarction volume was calculated by TTC staining, to evaluate the reliability of the model. RESULT: In the MCAO group, the base value of the cerebral blood flow down of KM and C57BL/6 mice respectively was (81.65 +/- 4.59)%, (83.68 +/- 6.25)%. The neurological deficit score respectively was (2.30 +/- 0.82), (2.50 +/- 0.80). TTC staining can clearly show the infarction area, and relatively stable, 24 hours of the survival rate of KM and C57BL/6 mice were 100% and 80% respectively. CONCLUSION: The key link is the optimization and improvement of monofilament, temperature, anesthesia and so on. The modified intraluminal occlusion of MCAO using monofilament is a kind of reliable and simple method to establish experimental cerebral ischemia model in mice. PMID- 25522631 TI - [Mongolian medicine cha gan beng ga regulated activity of biomarker PGC-1alpha]. AB - OBJECTIVE: To investigate the regulation of Cha Gan Beng Ga on the activity of biomarker PGC-1alpha in vivo and in vitro, and lay the foundation for studying the efficacy result of Cha Gan Beng Ga on xenograft tumor model and extracting active constituents. METHOD: (1) The coarse powder of Cha Gan Beng Ga was extracted with 70% ethanol solution through heating and refluxing, and finally was used to freeze dry powder. (2) 50 mg x kg(-1) of freeze-dried power was orally administrated to KM and C57BL/6J mice once daily, lasting for 5 consecutive days; different concentrations of extracted materials was given to non-small cell lung cells A549. (3) The expression level of PGC-1alpha mRNA was quantitatively determined in lung tissue of mice and non-small cell lung cells A549. RESULT: The expression levels of PGC-1alpha in lung tissue of different mice strains had an increasing tendency. Furthermore, the expression levels of PGC-1alpha in non-small cell lung cells A549 also had an increasing tendency, showing dose and time-dependent relationships. CONCLUSION: Mongolian Medicine Cha Gan Beng Ga could induce the over-expression of PGC-1alpha mRNA in lung tissue of mice and in non-small cell lung cells A549. The present results will lay foundation for studying the efficacy result of antitumor and active constitutes in future. PMID- 25522632 TI - [Discussion on application of Chinese medicine treatment of gynecological diseases]. AB - With rapid social development rhythm, the incidence of gynecological diseases gradually rise. Traditional Chinese medicine has made irreplaceable position in the treatment of gynecological disease. Due to the characteristics of gynecological diseases, the syndrome differentiation and treatment has unique characteristics. In this paper, according to menstrual disease, leukorrheal diseases, pregnancy diseases, puerperal diseases and miscellaneous diseases in order, combining documents discussion and old doctors of traditional Chinese medicine treatment of gynecological disease experiences, illustrate the key points of drug selection in the treatment process. We can get a revelation that appropriate choice of tradition Chinese medicine is an indispensable part for healing effects. Through the analysis of characteristics of drugs, we can understand the feature of each period in disease of department of gynecology, increase the ability of usinig traditional Chinese medicine and improve the level of clinical treatment. PMID- 25522633 TI - [Application characteristics and situation analysis of volatile oils in database of Chinese patent medicine]. AB - Aromatic traditional Chinese medicines have a long history in China, with wide varieties. Volatile oils are active ingredients extracted from aromatic herbal medicines, which usually contain tens or hundreds of ingredients, with many biological activities. Therefore, volatile oils are often used in combined prescriptions and made into various efficient preparations for oral administration or external use. Based on the sources from the database of Newly Edited National Chinese Traditional Patent Medicines (the second edition), the author selected 266 Chinese patent medicines containing volatile oils in this paper, and then established an information sheet covering such items as name, dosage, dosage form, specification and usage, and main functions. Subsequently, on the basis of the multidisciplinary knowledge of pharmaceutics, traditional Chinese pharmacology and basic theory of traditional Chinese medicine, efforts were also made in the statistics of the dosage form and usage, variety of volatile oils and main functions, as well as the status analysis on volatile oils in terms of the dosage form development, prescription development, drug instruction and quality control, in order to lay a foundation for the further exploration of the market development situations of volatile oils and the future development orientation. PMID- 25522634 TI - [SCHWABE Company's patent portfolio of Ginkgo biloba preparation]. AB - SCHWABE Company in German is the first and largest manufacturer of Ginkgo biloba preparation. The company not only has leading technology in this field, but also protects its own market effectively through the high quality of patent drafting and exactly patent layout. Based on multi-angle analysis for patent portfolio of G. biloba preparation at application time, legal status, globally layout, Chinese layout, the article provides technical reference of research and development of G. biloba, also provides valuable experience of traditonal Chinese medicine patent portfolio layout for Chinese enterprises. PMID- 25522635 TI - [Problems in quality standard research of new traditional Chinese medicine compound]. AB - The new traditional Chinese medicine compound is the main part of the research of new drug of traditional Chinese medicine (TCM), and the new Chinese herbal compound reflects the characteristics of TCM theory. The new traditional Chinese medicine compound quality standard research is one of the main content of pharmaceutical research, and is also the focus of the new medicine pharmaceutical evaluation content. Although in recent years the research level of new traditional Chinese medicine compound has been greatly improved, but the author during the review found still some common problems existing in new traditional Chinese medicine compound quality standard research data, this paper analyzed the current quality standards for new traditional Chinese medicine compound and the problems existing in the research data, respectively from measurement of the content of index selection, determine the scope of the content, and the quality standard design concept, the paper expounds developers need to concern. The quality of new traditional Chinese medicine compound quality standard is not only itself can be solved, but quality standards is to ensure the key and important content of product quality, improving the quality of products cannot do without quality standards. With the development of science and technology, on the basis of quality by design under the guidance of the concept, new traditional Chinese medicine compound quality standard system will be more scientific, systematic and perfect. PMID- 25522636 TI - [Discussion on polysaccharide determination methods in new Chinese drug research]. AB - According to existing problems in polysaccharide determination methods in new Chinese drug applications, the method suitability, chemical reference selection, components interference and method research were introduced. The author suggests that suitable determination method should be selected according to the structure and property of the polysaccharide, and validated. Some influent factors should be examined to assure the accuracy of the method, such as the stability and using amount of the visualizing reagent, visualizing time, maximum detection wavelength etc. Monosaccharide and other water soluble components should be removed from polysaccharide sample, and suitable reference substance and detection wavelength should be selected. It should pay attention to mutual interference of neutral and acidic saccharide, and use inhibitor to eliminate the interference. Because the slopes of the standard curves are different for different monosaccharide, it is proposed that the types and ratios of the monosaccharide in heteroglycan should be understood, and mixed reference substance solution in the ratio is prepared for determination. PMID- 25522637 TI - [Common questions and suggestions of evaluation for NDA of TCM]. AB - According to the existing Provisions for Drug Registration (SFDA Order No. 28), applications for new drugs of traditional Chinese medicine are divided into two parts: the applications for drug clinical trial and for drug production (including new drug certificate). It will last for about 10 years from the application for drug clinical trial to get approving, and it also remains many problems and the low probability to succeed. From the sight of pharmaceutical review, there are mainly two aspects of regulatory compliance and technical issues, mainly for changes without approval of the competent authorities of the country. For example, sample preparation and approval of clinical trial process are significant changes. Technical problems are reporting incomplete data or information submitted does not comply with the technical requirements for review, such as: production process validation does not provide information, the preparation of samples for clinical trials and field inspection, production information, or the information provided does not meet the technical requirements. This paper summarizes the frequently asked questions and to make recommendations to advise applicants concerned, timely detection of problems, avoid risk, improving the quality and efficiency of the application for registration. PMID- 25522638 TI - [Herbal textual research on origin and development of traditional Chinese medicine "duhuo" and "qianghuo"]. AB - To clarify the origin and development of the traditional Chinese medicine "Duhuo" and "Qianghuo" with medicinal literatures. Medical literatures of past dynasties were analysed and combined with the modern material. The "Duhuo" in Herbal writing Shen Nong Ben Cao Jing include traditional Chinese medicine "Duhuo" and "Qianghuo", "Qianghuo" was separated from "Duhuo" due to the distinguish of clinical application. The origin of "Qianghuo" is Notopterygium incisum and N. forbesii, However, The origin of "Duhuo" is very complex, Angelica pubescens f. biserrata as authentic "Duhuo" was used from Song Dynasty. "Qianghuo" was originated from "Duhuo". PMID- 25522639 TI - [Discussion on research and development of new traditional Chinese medicine preparation process based on idea of QbD]. AB - Traditional processes are mostly adopted in traditional Chinese medicine (TCM) preparation production and the quality of products is mostly controlled by terminal. Potential problems of the production in the process are unpredictable and is relied on experience in most cases. Therefore, it is hard to find the key points affecting the preparation process and quality control. A pattern of research and development of traditional Chinese medicine preparation process based on the idea of Quality by Design (QbD) was proposed after introducing the latest research achievement. Basic theories of micromeritics and rheology were used to characterize the physical property of TCM raw material. TCM preparation process was designed in a more scientific and rational way by studying the correlation among enhancing physical property of raw material, preparation process and product quality of preparation. So factors affecting the quality of TCM production would be found out and problems that might occur in the pilot process could be predicted. It would be a foundation for the R&D and production of TCM preparation as well as support for the "process control" of TCMIs gradually realized in the future. PMID- 25522640 TI - [NIRS-based total quality control system construction of Tanreqing injection and relative thinking]. AB - In this paper, NIRS (near infrared spectroscopy)-based total quality control system for the Tanreqing injection was introduced briefly. By analyzing and summing up the significance and difficulties, several important problems of the practical applications which need urgent solutions are proposed. And also the applicationprospect of NIRS is fully discussed and put forward in the end. PMID- 25522641 TI - [Issues of large scale tissue culture of medicinal plant]. AB - In order to increase the yield and quality of the medicinal plant and enhance the competitive power of industry of medicinal plant in our country, this paper analyzed the status, problem and countermeasure of the tissue culture of medicinal plant on large scale. Although the biotechnology is one of the most efficient and promising means in production of medicinal plant, it still has problems such as stability of the material, safety of the transgenic medicinal plant and optimization of cultured condition. Establishing perfect evaluation system according to the characteristic of the medicinal plant is the key measures to assure the sustainable development of the tissue culture of medicinal plant on large scale. PMID- 25522642 TI - [Interpretation of contemporary positioning of traditional Chinese medicine injections and analysis of key problems]. AB - According to the current situations and development of (TCMIs), the author of the article reveals the scientific connotation of TCMIs in theory, preparations and clinic application, and points out that TCMIs are an innovative and breakthrough of conventional dosage forms of traditional Chinese medicines, the combination of traditional theory and modern technology as well as a type of modern dosage form with the characteristics of traditional Chinese medicines, which conforms to the principle of including the essence and excluding the wastes for traditional Chinese medicine preparations, meets the demands for quick-acting of traditional Chinese medicines and guides one of the development orientation of traditional Chinese medicines. In the meantime, an analysis was also made on key issues, such as adverse reactions of TCMIs, modern clinical application, special drug delivery route and diversity of components and ingredients. PMID- 25522643 TI - Postsecondary education in the United States: introducing the issue. PMID- 25522644 TI - An overview of American higher education. AB - This overview of postsecondary education in the United States reviews the dramatic changes over the past fifty years in the students who go to college, the institutions that produce higher education, and the ways it is financed. The article, by Sandy Baum, Charles Kurose, and Michael McPherson, creates the context for the articles that follow on timely issues facing the higher education community and policy makers. The authors begin by observing that even the meaning of college has changed. The term that once referred primarily to a four-year period of academic study now applies to virtually any postsecondary study- academic or occupational, public or private, two-year or four-year-- that can result in a certificate or degree. They survey the factors underlying the expansion of postsecondary school enrollments; the substantial increases in female, minority, disadvantaged, and older students; the development of public community colleges; and the rise of for-profit colleges. They discuss the changing ways in which federal and state governments help students and schools defray the costs of higher education as well as more recent budget tensions that are now reducing state support to public colleges. And they review the forces that have contributed to the costs of producing higher education and thus rising tuitions. The authors also cite evidence on broad measures of college persistence and outcomes, including low completion rates at community and for-profit colleges, the increasing need for remedial education for poorly prepared high school students, and a growing gap between the earnings of those with a bachelor's degree and those with less education. They disagree with critics who say that investments in higher education, particularly for students at the margin, no longer pay off. A sustained investment in effective education at all levels is vital to the nation's future, they argue. But they caution that the American public no longer seems willing to pay more for more students to get more education. They therefore urge the higher education community to make every effort to find innovations, including creative uses of information technology, that can hold down costs while producing quality education. PMID- 25522645 TI - Making college worth it: a review of the returns to higher education. AB - Despite a general rise in the return to college, likely due to technological change, the cost-benefit calculus facing prospective students can make the decision to invest in and attend college dauntingly complex. Philip Oreopoulos and Uros Petronijevic review research on the varying costs and benefits of higher education and explore in full the complexity of the decision to invest in and attend college. Optimal college attainment decisions are different for all prospective students, who diverge in terms of what they are likely to get out of higher education and what specific options might be best for them. Earnings of college graduates depend in important measure on the program of study and eventual occupation they choose. Students uninterested in or unable to complete a four-year college degree appear to benefit from completing a two-year degree. Prospective students may also face both financial constraints, which prohibit them from taking advantage of more education, and information problems and behavioral idiosyncrasies, such as reluctance to take on debt, which keep them from making optimal decisions about attending college. In their discussion of how student debt figures in the college investment, the authors note that some students borrow too little and, as a result, underinvest in their education. Carefully calculating the return on the college investment can help determine the "appropriate" amount of debt. Students are more likely to benefit from postsecondary education the more informed they are about the expenses associated with college and the potential options for financial aid, which can be extremely complex. To make the best college investment, Oreopoulos and Petronijevic stress, prospective students must give careful consideration to selecting the institution itself, the major to follow, and the eventual occupation to pursue. For any particular program at a particular school, anticipated future labor market earnings, the likelihood of completion, the costs, and the value of any student debt must all be factored into the assessment. PMID- 25522646 TI - Financial aid policy: lessons from research. AB - In the nearly fifty years since the adoption of the Higher Education Act of 1965, financial aid programs have grown in scale, expanded in scope, and multiplied in form. As a result, financial aid has become the norm among college enrollees. Aid now flows not only to traditional college students but also to part-time students, older students, and students who never graduated from high school. Today aid is available not only to low-income students but also to middle- and even high-income families, in the form of grants, subsidized loans, and tax credits. The increasing size and complexity of the nation's student aid system has generated questions about effectiveness, heightened confusion among students and parents, and raised concerns about how program rules may interact. In this article, Susan Dynarski and Judith Scott-Clayton review what is known, and just as important, what is not known, about how well various student aid programs work. The evidence, the authors write, clearly shows that lowering costs can improve college access and completion. But this general rule is not without exception. First, they note, the complexity of program eligibility and delivery appears to moderate the impact of aid on college enrollment and persistence after enrollment. Second, for students who have already decided to enroll, grants that tie financial aid to academic achievement appear to boost college outcomes such as persistence more than do grants with no strings attached. Third, compared with grant aid, relatively little rigorous research has been conducted on the effectiveness of student loans. The paucity of evidence on student loans is particularly problematic both because they represent a large share of student aid overall and because their low cost (relative to grant aid) makes them an attractive option for policy makers. Future research is likely to focus on several issues: the importance of program design and delivery, whether there are unanticipated interactions between programs, and to what extent program effects vary across different types of students. The results of this evidence will be critical, the authors say, as politicians look for ways to control spending. PMID- 25522647 TI - Student supports: developmental education and other academic programs. AB - Low rates of college completion are a major problem in the United States. Less than 60 percent of students at four-year colleges graduate within six years, and at some colleges, the graduation rate is less than 10 percent. Additionally, many students enter higher education ill-prepared to comprehend college-level course material. Some estimates suggest that only one-third of high school graduates finish ready for college work; the proportion is even lower among older students. Colleges have responded to the poor preparation of incoming students by placing approximately 35 to 40 percent of entering freshmen into remedial or developmental courses, along with providing academic supports such as summer bridge programs, learning communities, academic counseling, and tutoring, as well as student supports such as financial aid and child care. Eric Bettinger, Angela Boatman, and Bridget Terry Long describe the role, costs, and impact of these college remediation and academic support programs. According to a growing body of research, the effects of remedial courses are considerably nuanced. The courses appear to help or hinder students differently by state, institution, background, and academic preparedness. The mixed findings from earlier research have raised questions ranging from whether remedial programs, on average, improve student academic outcomes to which types of programs are most effective. Administrators, practitioners, and policy makers are responding by redesigning developmental courses and searching for ways to implement effective remediation programs more broadly. In addition, recent research suggests that colleges may be placing too many students into remedial courses unnecessarily, suggesting the need for further examining the placement processes used to assign students to remedial courses. The authors expand the scope of remediation research by discussing other promising areas of academic support commonly offered by colleges, including advising, tutoring, and mentoring programs, as well as supports that target the competing responsibilities of students, namely caring for dependents and balancing employment with schoolwork. They conclude that the limited resources of institutions and equally limited funds of students make it imperative for postsecondary institutions to improve student academic supports and other services. PMID- 25522648 TI - Transitions from high school to college. AB - The vast majority of high school students aspire to some kind of postsecondary education, yet far too many of them enter college without the basic content knowledge, skills, or habits of mind they need to succeed. Andrea Venezia and Laura Jaeger look at the state of college readiness among high school students, the effectiveness of programs in place to help them transition to college, and efforts to improve those transitions. Students are unprepared for postsecondary coursework for many reasons, the authors write, including differences between what high schools teach and what colleges expect, as well as large disparities between the instruction offered by high schools with high concentrations of students in poverty and that offered by high schools with more advantaged students. The authors also note the importance of noncurricular variables, such as peer influences, parental expectations, and conditions that encourage academic study. Interventions to improve college readiness offer a variety of services, from academic preparation and information about college and financial aid, to psychosocial and behavioral supports, to the development of habits of mind including organizational skills, anticipation, persistence, and resiliency. The authors also discuss more systemic programs, such as Middle College High Schools, and review efforts to allow high school students to take college classes (known as dual enrollment). Evaluations of the effectiveness of these efforts are limited, but the authors report that studies of precollege support programs generally show small impacts, while the more systemic programs show mixed results. Dual-enrollment programs show promise, but the evaluation designs may overstate the results. The Common Core State Standards, a voluntary set of goals and expectations in English and math adopted by most states, offer the potential to improve college and career readiness, the authors write. But that potential will be realized, they add, only if the standards are supplemented with the necessary professional development to enable educators to help all students meet academic college readiness standards, a focus on developing strong noncognitive knowledge and skills for all students, and the information and supports to help students prepare and select the most appropriate postsecondary institution. PMID- 25522649 TI - For-profit colleges. AB - For-profit, or proprietary, colleges are the fastest-growing postsecondary schools in the nation, enrolling a disproportionately high share of disadvantaged and minority students and those ill-prepared for college. Because these schools, many of them big national chains, derive most of their revenue from taxpayer funded student financial aid, they are of interest to policy makers not only for the role they play in the higher education spectrum but also for the value they provide their students. In this article, David Deming, Claudia Goldin, and Lawrence Katz look at the students who attend for-profits, the reasons they choose these schools, and student outcomes on a number of broad measures and draw several conclusions. First, the authors write, the evidence shows that public community colleges may provide an equal or better education at lower cost than for-profits. But budget pressures mean that community colleges and other nonselective public institutions may not be able to meet the demand for higher education. Some students unable to get into desired courses and programs at public institutions may face only two alternatives: attendance at a for-profit or no postsecondary education at all. Second, for-profits appear to be at their best with well-defined programs of short duration that prepare students for a specific occupation. But for-profit completion rates, default rates, and labor market outcomes for students seeking associate's or higher degrees compare unfavorably with those of public postsecondary institutions. In principle, taxpayer investment in student aid should be accompanied by scrutiny concerning whether students complete their course of study and subsequently earn enough to justify the investment and pay back their student loans. Designing appropriate regulations to help students navigate the market for higher education has proven to be a challenge because of the great variation in student goals and types of programs. Ensuring that potential students have complete and objective information about the costs and expected benefits of for-profit programs could improve postsecondary education opportunities for disadvantaged students and counter aggressive and potentially misleading recruitment practices at for-profit colleges, the authors write. PMID- 25522650 TI - E-Learning in postsecondary education. AB - Over the past decade postsecondary education has been moving increasingly from the classroom to online. During the fall 2010 term 31 percent of U.S. college students took at least one online course. The primary reasons for the growth of e learning in the nation's colleges and universities include the desire of those institutions to generate new revenue streams, improve access, and offer students greater scheduling flexibility. Yet the growth of e-learning has been accompanied by a continuing debate about its effectiveness and by the recognition that a number of barriers impede its widespread adoption in higher education. Through an extensive research review, Bradford Bell and Jessica Federman examine three key issues in the growing use of e-learning in postsecondary education. The first is whether e-learning is as effective as other delivery methods. The debate about the effectiveness of e-learning, the authors say, has been framed in terms of how it compares with other means of delivering instruction, most often traditional instructor-led classroom instruction. Bell and Federman review a number of meta analyses and other studies that, taken together, show that e-learning produces outcomes equivalent to other delivery media when instructional conditions are held constant. The second issue is what particular features of e-learning influence its effectiveness. Here the authors move beyond the "does it work" question to examine how different instructional features and supports, such as immersion and interactivity, influence the effectiveness of e-learning programs. They review research that shows how these features can be configured to create e learning programs that help different types of learners acquire different types of knowledge. In addressing the third issue--the barriers to the adoption of e learning in postsecondary education--Bell and Federman discuss how concerns about fraud and cheating, uncertainties about the cost of e-learning, and the unique challenges faced by low-income and disadvantaged students have the potential to undermine the adoption of e-learning instruction. Based on their research review, the authors conclude that e-learning can be an effective means of delivering postsecondary education. They also urge researchers to examine how different aspects of these programs influence their effectiveness and to address the numerous barriers to the adoption of online instruction in higher education. PMID- 25522651 TI - Access and success with less: improving productivity in broad-access postsecondary institutions. AB - Achieving national goals for increased college completion in a time of scarce resources will require the postsecondary institutions that enroll the majority of undergraduates--community colleges and less-selective public universities--to graduate more students at a lower cost. Davis Jenkins and Olga Rodriguez examine research on how these "broad-access" institutions can do so without sacrificing access or quality. Research indicates that the strategies broad-access institutions have relied on in the past to cut costs--using part-time instructors and increasing student-faculty ratios--may in fact reduce productivity and efficiency. The limited evidence available suggests that some of the most popular strategies for improving student success are not cost-effective. New strategies to cut costs and improve college success are therefore imperative. Some believe that redesigning courses to make use of instructional technologies will lead to better outcomes at lower cost, although the evidence is mixed. Recently, a growing number of institutions are going beyond redesigning courses and instead changing the way they organize programs and supports along the student's "pathway" through college. These efforts are promising, but their effects on cost per completion are not yet certain. Meager funding has so far hampered efforts by policy makers to fund colleges based on outcomes rather than how many students they enroll, but some states are beginning to increase the share of appropriations tied to outcomes. Jenkins and Rodriquez argue that as policy makers push colleges to lower the cost per graduate, they must avoid providing incentives to lower academic standards. They encourage policy makers to capitalize on recent research on the economic value of postsecondary education to measure quality, and urge colleges and universities to redouble efforts to define learning outcomes and measure student mastery. PMID- 25522652 TI - Current role of rituximab in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by periods of flares and remission, resulting in organ damage over time caused by persistent disease activity and treatment-related complications. Conventional therapies are not ideal in terms of efficacy and safety. Novel biological therapies are being developed to enhance therapeutic efficacy, minimize disease exacerbation and reduce toxicities. As dysregulation of B cells is the hallmark of SLE, B-cell targeted therapies are the focus of recent clinical research. Rituximab, a chimeric anti-CD20 monoclonal antibody, has been used with success in recalcitrant lupus manifestations. However, randomized controlled trials have failed to reveal its benefit in renal and non-renal SLE when combined with conventional immunosuppressive protocols. Although heterogeneity of SLE manifestations, pitfalls in study design and the limitations of the assessment tools for various clinical end points may have contributed to the discouraging results, rituximab remains an option in patients who are refractory or intolerant to conventional therapies. Recently, a regimen consisting of rituximab and mycophenolate mofetil without oral corticosteroids was reported to be effective in lupus nephritis. While the efficacy of this regimen has to be confirmed, future controlled trials should focus on the efficacy of rituximab in refractory lupus manifestations and its synergistic effect with other immunosuppressive agents such as cyclophosphamide. In short-term randomized controlled trials, a non-significant increase in serious adverse events was observed in SLE patients treated with rituximab. Long-term safety data of rituximab in SLE, in particular the incidence of hypogammaglobulinemia and serious/opportunistic infections, have to be continuously surveyed. PMID- 25522653 TI - Long-term prediction of changes in health status, frailty, nursing care and mortality in community-dwelling senior citizens-results from the Longitudinal Urban Cohort Ageing Study (LUCAS). AB - BACKGROUND: The detection of incipient functional decline in elderly persons is not an easy task. Here, we propose the self-reporting Functional Ability Index (FA index) suitable to screen functional competence in senior citizens in the community setting. Its prognostic validity was investigated in the Longitudinal Urban Cohort Ageing Study (LUCAS). METHODS: This index is based equally on both, resources and risks/functional restrictions which precede ADL limitations. Since 2001, the FA index was tested in the LUCAS cohort without any ADL restrictions at baseline (n = 1,679), and followed up by repeated questionnaires in Hamburg, Germany. RESULTS: Applying the index, 1,022 LUCAS participants were initially classified as Robust (60.9%), 220 as postRobust (13.1%), 172 as preFrail (10.2%) and 265 as Frail (15.8%). This classification correlated with self-reported health, chronic pain and depressive mood (rank correlations 0.42, 0.26, 0.21; all p < .0001). Survival analyses showed significant differences between these classes as determined by the FA index: the initially Robust survived longest, the Frail shortest (p < .0001). Analyses of the time to need of nursing care revealed similar results. Significant differences persisted after adjustment for age, sex and self-reported health. CONCLUSIONS: Disability free lifetime and its development over time are important topics in public health. In this context, the FA index presented here provides answers to two questions. First, how to screen the heterogeneous population of community-dwelling senior citizens, i.e. for their functional ability/competence, and second, how far away they are from disability/dependency. Furthermore, the index provides a tool to address the urgent question whether incipient functional decline/incipient frailty can be recognized early to be influenced positively. The FA index predicted change in functional status, future need of nursing care, and mortality in an unselected population of community-dwelling seniors. It implies an operational specification of the classification into Robust, postRobust, preFrail and Frail. Based on a self-administered questionnaire, the FA index allows easy screening of elderly persons for declining functional competence. Thereby, incipient functional decline is recognized, e.g. in GPs' practices and senior community health centers, to initiate early appropriate preventive action. PMID- 25522654 TI - Gene variations in oestrogen pathways, CYP19A1, daily 17beta-estradiol and mammographic density phenotypes in premenopausal women. AB - INTRODUCTION: High mammographic density is an established breast cancer risk factor, and circulating oestrogen influences oestrogen-regulating gene expression in breast cancer development. However, less is known about the interrelationships of common variants in the CYP19A1 gene, daily levels of oestrogens, mammographic density phenotypes and body mass index (BMI) in premenopausal women. METHODS: Based on plausible biological mechanisms related to the oestrogen pathway, we investigated the association of single nucleotide polymorphisms (SNPs) in CYP19A1, 17beta-estradiol and mammographic density in 202 premenopausal women. DNA was genotyped using the Illumina Golden Gate platform. Daily salivary 17beta estradiol concentrations were measured throughout an entire menstrual cycle. Mammographic density phenotypes were assessed using a computer-assisted method (Madena). We determined associations using multivariable linear and logistic regression models. RESULTS: The minor alleles of rs749292 were positively (P = 0.026), and the minor alleles of rs7172156 were inversely (P = 0.002) associated with daily 17beta-estradiol. We observed an 87% lower level of daily 17beta estradiol throughout a menstrual cycle in heavier women (BMI >23.6 kg/m(2)) of rs7172156 with minor genotype aa compared with major genotype AA. Furthermore, the rs749292 minor alleles were inversely associated with absolute mammographic density (P = 0.032). Lean women with rs749292 minor alleles had 70 to 80% lower risk for high absolute mammographic density (>32.4 cm(2)); Aa: odds ratio (OR) = 0.23 (95% CI 0.07 to 0.75). Lean women with rs7172156 minor homozygous genotype had OR 5.45 for high absolute mammographic density (aa: OR = 5.45 (95% CI 1.13 to 26.3)). CONCLUSION: Our findings suggest that two SNPs in CYP19A1, rs749292 and rs7172156, are associated with both daily oestrogen levels and mammographic density phenotypes. BMI may modify these associations, but larger studies are needed. PMID- 25522655 TI - "A renewed sense of purpose": mothers' and fathers' experience of having a child following a recent stillbirth. AB - BACKGROUND: Most research has focused on mothers' experiences of perinatal loss itself or on the subsequent pregnancy, whereas little attention has been paid to both parents' experiences of having a child following late perinatal loss and the experience of parenting this child. The current study therefore explored mothers' and fathers' experiences of becoming a parent to a child born after a recent stillbirth, covering the period of the second pregnancy and up to two years after the birth of the next baby. METHOD: In depth interviews were conducted with 7 couples (14 participants). Couples were eligible if they previously had a stillbirth (after 24 weeks of gestation) and subsequently had another child (their first live baby) who was now under the age of 2 years. Couples who had more than one child after experiencing a stillbirth and those who were not fluent in English were excluded. Qualitative analysis of the interview data was conducted using Interpretive Phenomenological Analysis. RESULTS: Five superordinate themes emerged from the data: Living with uncertainty; Coping with uncertainty; Relationship with the next child; The continuing grief process; Identity as a parent. Overall, fathers' experiences were similar to those of mothers', including high levels of anxiety and guilt during the subsequent pregnancy and after the child was born. Coping strategies to address these were identified. Differences between mothers and fathers regarding the grief process during the subsequent pregnancy and after their second child was born were identified. Despite difficulties with bonding during pregnancy and at the time when the baby was born, parents' perceptions of their relationship with their subsequent child were positive. CONCLUSIONS: Findings highlight the importance of tailoring support systems not only according to mothers' but also to fathers' needs. Parents', and particularly fathers', reported lack of opportunities for grieving as well as the high level of anxiety of both parents about their baby's wellbeing during pregnancy and after birth implies a need for structured support. Difficulties experienced in bonding with the subsequent child during pregnancy and once the child is born need to be normalised. PMID- 25522656 TI - Levels of PAH-DNA adducts in cord blood and cord tissue and the risk of fetal neural tube defects in a Chinese population. AB - INTRODUCTION: Maternal exposure to polycyclic aromatic hydrocarbons (PAHs) has been shown to be associated with an elevated risk for neural tube defects (NTDs). In the human body, PAHs are bioactivated and the resultant reactive epoxides can covalently bind to DNA to form PAH-DNA adducts, which may, in turn, cause transcription errors, changes in gene expression or altered patterns of apoptosis. During critical developmental phases, these changes can result in abnormal morphogenesis. OBJECTIVES: We aimed to examine the relationship between the levels of PAH-DNA adducts in cord blood and cord tissue and the risk of NTDs. METHODS: From 2010 to 2012, 60 NTD cases and 60 healthy controls were recruited from a population-based birth defects surveillance system in five counties of Shanxi Province in Northern China, where the emission of PAHs remains one of the highest in the country and PAHs exposure is highly prevalent. PAH-DNA adducts in cord blood of 15 NTD cases and 15 control infants, and in cord tissue of 60 NTD cases and 60 control infants were measured using the (32)P-postlabeling method. RESULTS: PAH-DNA adduct levels in cord blood tend to be higher in the NTD group (28.5 per 10(8) nucleotides) compared with controls (19.7 per 10(8) nucleotides), although the difference was not statistically significant (P=0.377). PAH-DNA adducts in cord tissue were significantly higher in the NTD group (24.6 per 10(6) nucleotides) than in the control group (15.3 per 10(6) nucleotides), P=0.010. A positive dose-response relationship was found between levels of PAH-DNA adducts in cord tissue and the risk of NTDs (P=0.009). When the lowest tertile was used as the referent and potential confounding factors were adjusted for, a 1.03-fold (95% CI, 0.37-2.89) and 2.96-fold (95% CI, 1.16-7.58) increase in the risk of NTDs was observed for fetuses whose cord tissue PAH-DNA adduct levels were in the second and highest tertile, respectively. CONCLUSIONS: High levels of PAH-DNA adducts in fetal tissues were associated with increased risks of NTDs. PMID- 25522657 TI - The herbicide glyphosate causes behavioral changes and alterations in dopaminergic markers in male Sprague-Dawley rat. AB - Glyphosate (Glyph) is the active ingredient of several herbicide formulations. Reports of Glyph exposure in humans and animal models suggest that it may be neurotoxic. To evaluate the effects of Glyph on the nervous system, male Sprague Dawley rats were given six intraperitoneal injections of 50, 100, or 150 mg Glyph/kg BW over 2 weeks (three injections/week). We assessed dopaminergic markers and their association with locomotor activity. Repeated exposure to Glyph caused hypoactivity immediately after each injection, and it was also apparent 2 days after the last injection in rats exposed to the highest dose. Glyph did not decrease monoamines, tyrosine hydroxylase (TH), or mesencephalic TH+ cells when measured 2 or 16 days after the last Glyph injection. In contrast, Glyph decreased specific binding to D1 dopamine (DA) receptors in the nucleus accumbens (NAcc) when measured 2 days after the last Glyph injection. Microdialysis experiments showed that a systemic injection of 150 mg Glyph/kg BW decreased basal extracellular DA levels and high-potassium-induced DA release in striatum. Glyph did not affect the extracellular concentrations of 3,4 dihydroxyphenylacetic acid or homovanillic acid. These results indicate that repeated Glyph exposure results in hypoactivity accompanied by decreases in specific binding to D1-DA receptors in the NAcc, and that acute exposure to Glyph has evident effects on striatal DA levels. Additional experiments are necessary in order to unveil the specific targets of Glyph on dopaminergic system, and whether Glyph could be affecting other neurotransmitter systems involved in motor control. PMID- 25522658 TI - Effect of reversible ligands on oxime-induced reactivation of sarin- and cyclosarin-inhibited human acetylcholinesterase. AB - Poisoning by organophosphorus compounds (OP) used as pesticides and nerve agents is due to irreversible inhibition of the enzyme acetylcholinesterase (AChE). Oximes have been widely recognized for their potency to reactivate the inhibited enzyme. The limited efficacy of currently available oximes against a broad spectrum of OP-compounds initiated novel research efforts to improve oxime-based treatment. Hereby, oxime-induced reactivation of OP-inhibited non-human AChE was reported to be accelerated by different AChE-ligands. To investigate this concept with AChE from human source, the inhibitory potency, binding properties and the potential enhancement of oxime-induced reactivation of OP-inhibited AChE by structurally different AChE-ligands was assessed. Several ligands competed with the oxime for the AChE binding-site impairing reactivation of OP-inhibited AChE whereas a markedly accelerated reactivation of sarin-inhibited enzyme by obidoxime was recorded in the presence of edrophonium, galanthamine and donepezil. Enhancement of oxime-induced reactivation with ligands was presumably subject to prevention of re-inhibition by the reaction product phosphonyloxime (POX). In the end, the results of the present study did not confirm that AChE ligands directly accelerate the reactivation of OP-inhibited AChE by oximes, but indirectly by prevention of re-inhibition by the reaction product POX. This may be due to different experimental conditions and species differences between human and non-human AChE of previous experiments with non-human AChE. PMID- 25522659 TI - In vitro permeation of platinum through African and Caucasian skin. AB - The majority of the South African workforce are Africans, therefore potential racial differences should be considered in risk and exposure assessments in the workplace. Literature suggests African skin to be a superior barrier against permeation and irritants. Previous in vitro studies on metals only included skin from Caucasian donors, whereas this study compared the permeation of platinum through African and Caucasian skin. A donor solution of 0.3 mg/ml of potassium tetrachloroplatinate (K2PtCl4) dissolved in synthetic sweat was applied to the vertical Franz diffusion cells with full thickness abdominal skin. Skin from three female African and three female Caucasian donors were included (n=21). The receptor solution was removed at various intervals during the 24 h experiment, and analysed with high resolution inductively coupled plasma-mass spectrometry (ICP-MS). Skin was digested and analysed by inductively coupled plasma-optical emission spectrometry (ICP-OES). Significantly higher permeation of platinum through intact African skin (p=0.044), as well as a significantly higher mass of platinum retention in African skin in comparison with Caucasian skin (p=0.002) occurred. Significant inter-donor variation was found in both racial groups (p<0.02). Results indicate that African workers have increased risk of dermal permeation and therefore possible sensitisation caused by dermal exposure to platinum salts. These results are contradictory to limited literature suggesting a superior barrier in African skin and further investigation is necessary to explain the higher permeation through African skin. PMID- 25522660 TI - Cholinergic induction of perspiration attenuates nonhistaminergic pruritus in the skin of patients with atopic dermatitis and healthy controls. PMID- 25522661 TI - High-throughput profiling of point mutations across the HIV-1 genome. AB - BACKGROUND: The HIV-1 pandemic is not the result of a static pathogen but a large genetically diverse and dynamic viral population. The virus is characterized by a highly mutable genome rendering efforts to design a universal vaccine a significant challenge and drives the emergence of drug resistant variants upon antiviral pressure. Gaining a comprehensive understanding of the mutational tolerance of each HIV-1 genomic position is therefore of critical importance. RESULTS: Here we combine high-density mutagenesis with the power of next generation sequencing to gauge the replication capacity and therefore mutational tolerability of single point mutations across the entire HIV-1 genome. We were able to achieve the evaluation of point mutational effects on viral replicative capacity for 5,553 individual HIV-1 nucleotide positions - representing 57% of the viral genome. Replicative capacity was assessed at 3,943 nucleotide positions for a single alternate base change, 1,459 nucleotide positions for two alternate base changes, and 151 nucleotide positions for all three possible alternate base changes. This resulted in the study of how a total of 7,314 individual point mutations impact HIV-1 replication on a single experimental platform. We further utilize the dataset for a focused structural analysis on a capsid inhibitor binding pocket. CONCLUSION: The approach presented here can be applied to any pathogen that can be genetically manipulated in a laboratory setting. Furthermore, the methodology can be utilized under externally applied selection conditions, such as drug or immune pressure, to identify genetic elements that contribute to drug or host interactions, and therefore mutational routes of pathogen resistance and escape. PMID- 25522662 TI - Psychometric properties of two measures of childhood internalizing problems in a Bangladeshi sample. AB - OBJECTIVES: In order to assist mental health services in developing countries, a key issue is the availability of psychometrically sound, brief, and cost effective measures that have been tested within the relevant context. The present study was designed to evaluate within a young Bangladeshi population, the psychometric properties of two widely used Western measures of internalizing distress in young people: the short form of the Spence Children's Anxiety Scale and the Short Moods and Feelings Questionnaire. METHOD: The sample included 1,360 children and adolescents aged 9-17 years (M = 12.3 years, SD = 2.12) recruited from six districts of Bangladesh, including both community and emotionally at risk participants. A total of 179 children were re-tested on the measures within 3-4 weeks. RESULTS: Confirmatory factor analyses showed single-factor structures for both scales in the total sample and in both community and at-risk participants separately. Multiple group analyses across gender and age-group within the at-risk and community samples showed that the single-factor structure was suitable regardless of subgroup. Analyses also indicated acceptable internal consistency, test-retest reliability and construct validity for both scales. CONCLUSION: The two measures show promise as brief, reliable, and valid instruments for the assessment of internalizing distress among young people from Bangla-speaking communities. PRACTITIONER POINTS: Positive clinical implications: These two measures of internalizing distress in young people showed solid psychometric properties within samples collected from various parts of Bangladesh. The measures can therefore be used to assess anxiety and depression in Bangla-speaking youth. These measures should be of value in both clinical settings and at a community level to assess the need for services. Cautions and limitations: Resource limitations did not allow comparison against diagnostic criteria and therefore cut-off scores to indicate clinical status among Bangladeshi youth will require further research. PMID- 25522663 TI - Effect of topical ophthalmic dorzolamide(2%)-timolol(0.5%) solution and ointment on intraocular pressure in normal horses. AB - OBJECTIVE: To compare the effect of commercially available solution and compounded ointment formulations of dorzolamide(2%)-timolol(0.5%) on intraocular pressure (IOP) of normal horses. ANIMALS: Eighteen clinically normal horses. PROCEDURES: A randomized, masked prospective design was used with horses divided into two equal groups. One eye of each horse was selected for topical ophthalmic treatment with either 0.2 mL of dorzolamide(2%)-timolol(0.5%) solution or 0.2 g of dorzolamide(2%)-timolol(0.5%) ointment every 12 h for 5 days. The contralateral eye of horses in both groups was untreated. Rebound tonometry was performed every 6 h starting 2 days prior to and ending 2 days after the treatment period. RESULTS: The mean IOP reduction in eyes treated with the solution or ointment formulations was 13%. Untreated eyes in both groups experienced a lesser but still statistically significant reduction in IOP. The IOP values did not return to baseline within 48 h of the last treatment. CONCLUSIONS AND CLINICAL RELEVANCE: The commercially available solution and compounded ointment formulations of ophthalmic dorzolamide(2%)-timolol(0.5%) had similar effects on IOP in normal horses. Persistent IOP reduction following cessation of treatment may indicate prolonged drug effect or acclimation of horses to tonometry. PMID- 25522664 TI - Perinatal Dyadic Psychotherapy for postpartum depression: a randomized controlled pilot trial. AB - An integrated approach addressing maternal depression and associated mother infant relationship dysfunction may improve outcomes. This study tested Perinatal Dyadic Psychotherapy (PDP), a dual-focused mother-infant intervention to prevent/decrease maternal postpartum depression and improve aspects of the mother infant relationship related to child development. Women recruited from hospital postpartum units were screened using a three-stage process. Forty-two depressed first-time mothers and their 6-week-old infants were enrolled and randomized to receive the PDP intervention or usual care plus depression monitoring by phone. The intervention consisted of eight home-based, nurse-delivered mother-infant sessions consisting of (a) supportive, relationship-based, mother-infant psychotherapy, and (b) a developmentally based infant-oriented component focused on promoting positive mother-infant interactions. Data collected at baseline, post-intervention, and three-month follow-up included measures of maternal depression, anxiety, maternal self-esteem, parenting stress, and mother-infant interaction. Depression and anxiety symptoms and diagnoses decreased significantly, and maternal self-esteem increased significantly across the study time frame with no between-group differences. There were no significant differences between groups on parenting stress or mother-infant interaction at post-intervention and follow-up. No participants developed onset of postpartum depression during the course of the study. PDP holds potential for treating depression in the context of the mother-infant relationship; however, usual care plus depression monitoring showed equal benefit. Further research is needed to explore using low-intensity interventions as a first step in a stepped care approach and to determine what subset of at-risk or depressed postpartum mothers might benefit most from the PDP intervention. PMID- 25522665 TI - Regulation of T cells by mTOR: the known knowns and the known unknowns. AB - Mammalian/mechanistic target of rapamycin (mTOR) is emerging as an important integrator of environmental cues critical for the regulation of T cell activation, differentiation, and function. Recent studies leveraging pharmacologic inhibition or T cell specific genetic deletion of signaling components in the mTOR pathway have provided important insights into the mechanisms involved, and have been informative in defining targets downstream of mTOR that promote immune regulation. However, these studies have also presented confusing and, at times, contradictory findings, highlighting the complexities involved in examining the mTOR pathway in distinct contexts. Here, we review current understanding of the roles of mTOR in T cell biology, highlighting emerging concepts and areas of investigation where the precise role of mTOR has yet to be fully discerned. PMID- 25522666 TI - Subchondral fracture of the femoral head after acetabular fracture: a case report. AB - INTRODUCTION: Preventing post-traumatic osteoarthritis is a challenging problem following acetabular fracture. Progressive osteoarthritis is considered to be caused by an irregular articular surface of the acetabular roof or cartilage injury, but little is known about the pathogenesis of collapse of the femoral head after acetabular fracture. We report a case of post-traumatic osteoarthritis after acetabular fracture in which subchondral fracture of the femoral head contributed to the progressive collapse of the femoral head and osteoarthritis. To the best of our knowledge, there has been no previous report of subchondral fracture of the femoral head after acetabular fracture. CASE PRESENTATION: A 58 year-old Japanese man fell from a ladder. He was diagnosed with a left acetabular fracture, which was managed conservatively. He developed left coxalgia six months after injury and was seen at our institution one year after the onset of pain. The left acetabular fracture had fused, but his left femoral head had collapsed. The images at the time of injury showed a fracture of the acetabular roof, and an approximately 2mm step-off existed in the articular surface. Retrospective evaluation of the plain radiographs and computed tomography images showed that his femoral head had progressively collapsed. Our patient underwent total hip arthroplasty. Histopathologic findings demonstrated that the collapse of his femoral head was caused by a subchondral fracture of his femoral head. CONCLUSION: Our experience with this case indicates that in addition to post traumatic osteonecrosis, subchondral fracture may need to be considered in cases with progressive collapse of the femoral head after acetabular fracture. PMID- 25522667 TI - Transfusion-associated circulatory overload in Ireland: a review of cases reported to the National Haemovigilance Office 2000 to 2010. AB - BACKGROUND: Transfusion-associated circulatory overload (TACO) is an increasingly reported condition but symptoms and signs are still unrecognized. We present a review of the incidence and clinical features of TACO reported to the National Haemovigilance Office at the Irish Blood Transfusion Service. STUDY DESIGN AND METHODS: Between 2000 and 2010, a total of 1071 cases of serious transfusion related reactions were reported, of which 221 (21%) cases were TACO. RESULTS: A total of 2,000,684 blood components were issued, with a TACO incidence of one in 9177. The TACO incidence per red blood cells, plasma, and platelet components issued was one in 8000, one in 16,000, and one in 57,884, respectively. The majority of cases (68%, n = 151) were elderly patients, while no sex difference was seen. Twenty-eight (13%) patients experienced severe morbidity; 31 (14%) deaths were reported, of which five (2%) were considered due to TACO and the other deaths considered due to and underlying conditions, which in most cases were cardiovascular (76%). An increased risk of mortality was found in patients on diuretics either before transfusion as part of their routine therapy or given as pretransfusion medication (odds ratio, 2.49; 95% confidence interval, 1.06 6.01). In 19 (21%) cases, TACO reaction was due to human error. CONCLUSIONS: The strong association between TACO and human errors supports the role of hemovigilance and of adequate transfusion medicine teaching for preventing morbidity and mortality associated with TACO. PMID- 25522668 TI - Cervical adenocarcinoma secondary to primary vulval Paget's disease: an unusual form of retrograde spread. PMID- 25522669 TI - The future perspectives of natural materials for pulmonary drug delivery and lung tissue engineering. AB - INTRODUCTION: Search for new, functional biomaterials that can be used to synergistically deliver a drug, enhance its adsorption and stimulate the post injury recovery of tissue function, is one of the priorities in biomedicine. Currently used materials for drug delivery fail to satisfy one or more of these functionalities, thus they have limited potential and new classes of materials are urgently needed. AREAS COVERED: Natural materials, due to their origin, physical and chemical structure can potentially fulfill these requirements and there is already strong evidence of their usefulness in drug delivery. They are increasingly utilized in various therapeutic applications due to the obvious advantages over synthetic materials. Particularly in pulmonary drug delivery, there have been limitations in the use of synthetic materials such as polymers and lipids, leading to an increase in the use of natural and protein-based materials such as silk, keratin, elastin and collagen. Literature search in each specialized field, namely, silk, keratin and collagen was conducted, and the benefits of each material for future application in pulmonary drug delivery are highlighted. EXPERT OPINION: The natural materials discussed in this review have been well established in their use for other applications, yet further studies are required in the application of pulmonary drug delivery. The properties exhibited by these natural materials seem positive for their application in lung tissue engineering, which may allow for more extensive testing for validation of pulmonary drug delivery systems. PMID- 25522670 TI - siRNA targeting TCTP suppresses osteosarcoma cell growth and induces apoptosis in vitro and in vivo. AB - Osteosarcoma (OS) remains the most frequent primary malignant bone tumor in adolescents. However, the molecular cause of the disease is poorly elucidated. In the present study, we primarily found that translationally controlled tumor protein (TCTP) was overexpressed in human OS tissues and cell lines. To investigate the function of TCTP in OS cell growth, an RNA interference lentivirus system was employed to deplete TCTP expression in Saos-2 and U2OS cell lines. Specific knockdown of TCTP significantly impaired cell proliferation and colony-formation capacity in both OS cell lines. Moreover, depletion of TCTP caused a significant accumulation of OS cells in the S phase and eventually induced cell apoptosis. Expression levels of the G2/M phase regulators cyclin B1 and Cdc25A were decreased, and apoptotic markers Bad and caspase-3 were increased in both OS cell lines after depletion of TCTP. Furthermore, depletion of TCTP potently inhibited the growth of xenografts in nude mice. Our results indicate that inhibition of TCTP expression exerts potential antitumor activity and may be a novel therapeutic approach in human OS. PMID- 25522671 TI - Infusion of DDAVP does not improve primary hemostasis in patients with cirrhosis. AB - BACKGROUND & AIMS: Cirrhosis frequently affects multiple components of hemostasis. Reversal of the coagulopathy of these patients is frequently required in case of bleeding episodes, or as prophylaxis before invasive procedures. Although 1-deamino-8-D-arginine vasopressin (DDAVP) is widely used as a pro hemostatic agent in patients with cirrhosis, it is unclear whether DDAVP truly enhances hemostasis in these patients. Here we investigated the hemostatic effects of a single bolus of DDAVP in patients with cirrhosis. METHODS: Ten patients with cirrhosis (child B or C) and ten patients with mild haemophilia A received an intravenous single bolus of 0.3 microgram/kg DDAVP. Plasma was collected prior to and at 1, 3, 6, and 24 h after DDAVP administration. Levels of Von Willebrand factor (VWF), VWF propeptide, factor VIII (FVIII), and ADAMTS13 were measured in all plasma samples, whereas VWF multimers and functional VWF dependent platelet adhesion were determined in the samples pre- and 1 h after DDAVP administration. RESULTS: Following DDAVP administration, VWF, FVIII, and VWF propeptide levels increased in patients with haemophilia, while patients with cirrhosis only showed an increase in VWF propeptide and FVIII levels. High molecular weight VWF multimers and VWF-dependent platelet adhesion increased in patients with haemophilia one hour after DDAVP administration, but did not change in the patients with cirrhosis. Levels of ADAMTS13 were unaffected in both patient groups after DDAVP. CONCLUSION: The lack of relevant effects of DDAVP on laboratory indices of primary hemostasis in patients with cirrhosis is in line with previous clinical study results in these patients. PMID- 25522672 TI - Sheep prions with molecular properties intermediate between classical scrapie, BSE and CH1641-scrapie. AB - Efforts to differentiate bovine spongiform encephalopathy (BSE) from scrapie in prion infected sheep have resulted in effective methods to decide about the absence of BSE. In rare instances uncertainties remain due to assumptions that BSE, classical scrapie and CH1641-a rare scrapie variant-could occur as mixtures. In field samples including those from fallen stock, triplex Western blotting analyses of variations in the molecular properties of the proteinase K resistant part of the disease-associated form of prion protein (PrP(res)) represents a powerful tool for quick discrimination purposes. In this study we examined 7 deviant ovine field cases of scrapie for some typical molecular aspects of PrP(res) found in CH1641-scrapie, classical scrapie and BSE. One case was most close to scrapie with respect to molecular mass of its non-glycosylated fraction and N-terminally located 12B2-epitope content. Two cases were unlike classical scrapie but too weak to differentiate between BSE or CH1641. The other 4 cases appeared intermediate between scrapie and CH1641 with a reduced molecular mass and 12B2-epitope content, together with the characteristic presence of a second PrP(res) population. The existence of these 2 PrP(res) populations was further confirmed through deglycosylation by PNGaseF. The findings indicate that discriminatory diagnosis between classical scrapie, CH1641 and BSE can remain inconclusive with current biochemical methods. Whether such intermediate cases represent mixtures of TSE strains should be further investigated e.g. in bioassays with rodent lines that are varying in their susceptibility or other techniques suitable for strain typing. PMID- 25522673 TI - Challenges to developing diabetes self-management skills in a low-income sample in North Carolina, USA. AB - High rates of diabetes diagnosis and poor diabetes outcomes are particularly significant in low-income, socially disadvantaged populations. Although many social and economic predictors of poor self-management outcomes are known, few studies have examined how these elements impact the ability to develop self management capacities in low-income populations. This article presents new insights into low-income women's challenges and successes to becoming more adept self-managers. Interview data were collected in 2012 with a sample of low-income, middle-age women with type II diabetes recruited from a non-profit medical clinic serving low-income clients in North Carolina, United States. Data were analysed using a grounded theory approach. Developing self-management skills within disadvantaged life contexts involved negotiating three related, overlapping sub processes: negotiating access to care systems, negotiating disruptions to diabetes self-management patterns, and negotiating self-care knowledge. Developing diabetes self-management skills is a long and arduous process. Data and analysis presented here help explain how disadvantaged life contexts can impact self-managers' efforts to develop self-management skills and why continued support is important for reducing and preventing future problems. These initial findings suggest that future studies and intervention development on the topic are warranted. PMID- 25522674 TI - Detox diets for toxin elimination and weight management: a critical review of the evidence. AB - Detox diets are popular dieting strategies that claim to facilitate toxin elimination and weight loss, thereby promoting health and well-being. The present review examines whether detox diets are necessary, what they involve, whether they are effective and whether they present any dangers. Although the detox industry is booming, there is very little clinical evidence to support the use of these diets. A handful of clinical studies have shown that commercial detox diets enhance liver detoxification and eliminate persistent organic pollutants from the body, although these studies are hampered by flawed methodologies and small sample sizes. There is preliminary evidence to suggest that certain foods such as coriander, nori and olestra have detoxification properties, although the majority of these studies have been performed in animals. To the best of our knowledge, no randomised controlled trials have been conducted to assess the effectiveness of commercial detox diets in humans. This is an area that deserves attention so that consumers can be informed of the potential benefits and risks of detox programmes. PMID- 25522675 TI - Twin studies advance the understanding of gene-environment interplay in human nutrigenomics. AB - Investigations into the genetic architecture of diet-disease relationships are particularly relevant today with the global epidemic of obesity and chronic disease. Twin studies have demonstrated that genetic makeup plays a significant role in a multitude of dietary phenotypes such as energy and macronutrient intakes, dietary patterns, and specific food group intakes. Besides estimating heritability of dietary assessment, twins provide a naturally unique, case control experiment. Due to their shared upbringing, matched genes and sex (in the case of monozygotic (MZ) twin pairs), and age, twins provide many advantages over classic epidemiological approaches. Future genetic epidemiological studies could benefit from the twin approach particularly where defining what is 'normal' is problematic due to the high inter-individual variability underlying metabolism. Here, we discuss the use of twins to generate heritability estimates of food intake phenotypes. We then highlight the value of discordant MZ pairs to further nutrition research through discovery and validation of biomarkers of intake and health status in collaboration with cutting-edge omics technologies. PMID- 25522676 TI - Editorial for the special issue on mechanisms in metal-based organic chemistry. PMID- 25522678 TI - Tumor-suppressive microRNA-206 as a dual inhibitor of MET and EGFR oncogenic signaling in lung squamous cell carcinoma. AB - Expression of the oncogene hepatocyte growth factor receptor (MET) and phosphorylation of the MET protein have been associated with both primary and acquired resistance to tyrosine kinase inhibitors (TKIs) used in therapy targeting the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancers (NSCLCs). Therefore, simultaneous inhibition of both of these receptor tyrosine kinases (RTKs) should improve disease treatment. Our previous study of microRNA (miRNA) expression signatures of lung squamous cell carcinoma (lung-SCC) revealed that microRNA-206 (miR-206) was significantly reduced in lung SCC tissues, suggesting that miR-206 functions as a tumor suppressor in the disease. Furthermore, putative miR-206 binding sites were annotated in the 3' UTRs of MET and EGFR RTKs in miRNA databases. The aim of the study was to investigate the functional significance of miR-206 in lung-SCC and to confirm the inhibition of both MET and EGFR oncogenic signaling by expression of miR-206 in cancer cells. We found that restoration of mature miR-206 inhibited cancer cell proliferation, migration, and invasion in EBC-1 cells through downregulation of both mRNA and protein levels of MET and EGFR. Interestingly, phosphorylation of ERK1/2 and AKT signaling were inhibited by restoration of miR-206 in cancer cells. Overexpression of MET and EGFR were observed in clinical specimens of lung SCC. Tumor-suppressive miR-206 inhibited dual signaling networks activated by MET and EGFR, and these findings will provide new insights into the novel molecular mechanisms of lung-SCC oncogenesis and new therapeutic approaches for the treatment of this disease. PMID- 25522679 TI - Posterior single-incision semitendinosus harvest for a quadrupled anterior cruciate ligament graft construct: determination of graft length and diameter based on patient sex, height, weight, and body mass index. AB - PURPOSE: This study aimed to determine final graft length and diameter for a quadrupled semitendinosus anterior cruciate ligament (ACL) construct harvested from a single-incision posterior approach with correlation to preoperative patient variables of sex, height, weight, and body mass index (BMI). METHODS: This was a retrospective review of data collected prospectively on 60 patients undergoing all-inside quadrupled semitendinosus autograft ACL reconstruction. RESULTS: The mean values of the final quadrupled constructs were a length of 70.3 mm and a diameter of 9.0 mm. Separated based on sex, female versus male final mean graft length was 68.1 mm versus 71.7 mm, and final mean graft diameter was 8.6 mm and 9.3 mm, respectively. In both sexes, patient height and weight were strongly correlated to final construct diameter (r = 0.60 and r = 0.56) and length (r = 0.47 and r = 0.44), respectively. CONCLUSIONS: A single-incision posterior harvest approach allowed for retrieval of semitendinosis tendon autografts of sufficient dimension to allow for construction of quadrupled ACL grafts of a diameter of 8 mm or more in 95% of cases. In addition, desired graft length was achieved in all cases. Graft dimensions had moderately strong direct correlations to patient height and weight, with significant size differences noted between the sexes. We believe this to be helpful data for surgeons who might consider performing a quadrupled semitendinosus autograft ACL reconstruction. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25522680 TI - The prevalence of meniscal tears in young athletes undergoing revision anterior cruciate ligament reconstruction. AB - PURPOSE: The purpose of this study was to determine the incidence of meniscal injury, specifically medial meniscal injury, in US Army soldiers undergoing revision anterior cruciate ligament (ACL) reconstruction. METHODS: A retrospective review was performed of all patients who underwent revision ACL reconstruction from 2002 to 2011 at our institution. A complete chart review was performed to identify the prevalence of meniscal pathology identified at the time of revision ACL surgery. Patient demographic data and meniscal injury patterns were analyzed. RESULTS: Sixty-seven patients were identified, with a mean age of 28 years. The mean time to revision reconstruction was 67 months. Most patients (64.1%) reported a distinct reinjury. Reinjury was reported as the cause for revision ACL reconstruction in 43 patients. In this subgroup the mean time from reinjury to revision surgery was 13.9 months. Meniscal pathology was identified in 50 patients (74.6%). Medial meniscal tears were noted in 38 patients (56.7%), a rate significantly greater than that previously described (P = .008). Lateral meniscal tears were noted in 26 patients (38.8%), which was similar to previously published data (P = .52). CONCLUSIONS: The prevalence of meniscal injury at the time of revision ACL reconstruction in active-duty US Army soldiers is nearly identical to that of previously published data looking at a civilian population (74.6% v 74%) in the Multicenter ACL Revision Study (MARS) cohort. However, the incidence of medial meniscal injury was greater in the active-duty population than in the civilian population (56.7% v 40%). The observed increase in the prevalence of medial meniscal pathology is likely multifactorial, relating to the unique demands on young military athletes in both combat and training environments, rate of reinjury, and various delays to treatment after reinjury. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 25522681 TI - Total intravenous general anaesthesia vs. spinal anaesthesia for total hip arthroplasty: a randomised, controlled trial. AB - BACKGROUND: The choice of anaesthetic technique for patients undergoing joint arthroplasty is debatable. The hypothesis of this study was that general anaesthesia would generate a more favourable recovery profile than spinal anaesthesia. METHODS: We randomly allocated 120 patients to either intrathecal bupivacaine or general anaesthesia with target-controlled infusion of remifentanil and propofol. Length of hospital stay assessed as meeting discharge criteria was the primary outcome parameter. Other outcome parameters were actual time of discharge, pain, use of rescue pain medication, blood loss, length of stay in the post-operative care unit, dizziness, post-operative nausea, need of urinary catheterisation and patient satisfaction. RESULTS: General anaesthesia resulted in slightly reduced length of hospital stay (26 vs. 30 h, P = 0.004), less nausea (P = 0.043) and dizziness (P < 0.001). General anaesthesia patients had higher pain scores during the first two post-operative hours (P < 0.001) but lower after 6 h compared with the spinal anaesthesia group (P < 0.01 and P < 0.05). General anaesthesia patients had better orthostatic function compared with spinal anaesthesia patients (P = 0.008). Patients in the spinal anaesthesia group fulfilled the discharge criteria from the post-operative care unit earlier compared with the general anaesthesia patients (P = 0.004). General anaesthesia patients requested a change in the method of anaesthesia for a subsequent operation less often than the spinal anaesthesia patients (5 vs. 13, P = 0.022). CONCLUSION: General anaesthesia resulted in a more favourable recovery profile compared with spinal anaesthesia. PMID- 25522682 TI - Comparison of intrarenal renin-angiotensin system activity in diabetic versus non diabetic patients with overt proteinuria. AB - AIM: The intrarenal renin-angiotensin system (RAS) has been reported to be activated in chronic proteinuria patients. This study aimed to compare intrarenal RAS activity between diabetic nephropathy (DN) and non-diabetic nephropathy (NDN) patients with overt proteinuria. METHODS: A multicenter, cross-sectional study was conducted in 116 patients with overt proteinuria (urinary protein/creatinine ratio [uPCR] > 1 mg/mg Cr). To estimate intrarenal RAS activity we measured urinary excretion of angiotensinogen (uAGT) and renin (uRenin) in patients with DN (n = 38) and NDN (n = 78). RESULTS: Both natural logarithms of uAGT/urinary creatinine (ln[uAGT/uCr]) and uRenin (ln[uRenin/uCr]) levels were significantly higher in patients with DN compared with those with NDN (ln[uAGT/uCr]: 4.16 +/- 1.13 in DN vs. 3.52 +/- 1.21 in NDN, P = 0.007; ln[uRenin/uCr]: 5.66 +/- 1.60 in DN vs. 4.29 +/- 1.48 in NDN, P < 0.001), when estimated glomerular filtration rate (eGFR) and uPCR showed no significant difference between the two groups. In a subgroup analysis, according to amount of proteinuria, both uAGT and uRenin were higher in DN in patients with subnephrotic-range proteinuria (uPCR < 3.5 mg/mg Cr). However, in patients with nephrotic-range proteinuria (uPCR >= 3.5 mg/mg Cr), only uRenin was higher in DN compared to NDN. In a multiple regression analysis, diabetes showed independent association with uRenin. CONCLUSION: Consistently elevated uRenin in DN, regardless of the amount of proteinuria, indicates that intrarenal RAS activity may be higher in DN compared to NDN in patients with overt proteinuria. PMID- 25522683 TI - Radiological imaging of congenital hand anomalies--a 6-year single-centre experience and what the hand surgeons want to know. AB - OBJECTIVE: Congenital hand anomalies present a rare but important physical and emotional challenge for children and parents. Radiological imaging is important for accurate diagnosis, to aid decision making and to monitor changes in the growing hand. The goal of any treatment is to help the child achieve his/her maximum potential, to provide a useful hand with attention to cosmesis. We investigated the range of congenital hand anomalies imaged in a tertiary referral centre. We examined the timing of imaging and the key clinical questions. METHODS: The radiology imaging system was searched retrospectively for radiographs of congenital hand anomalies over a 6-year period. The images were reviewed and patient demographics, diagnosis and other imaging recorded. RESULTS: Over 6 years, 85 patients had imaging. Twenty-three patients had bilateral problems and 11 had recognised syndromes. The most common abnormalities imaged were duplicated thumbs (28 %), followed by syndactyly (18 %). Children were first imaged as early as 1 day old, with the median age of initial imaging 12 months. CONCLUSIONS: Thumb duplication and syndactyly are the most common conditions for which radiographs are requested at our hospital, although overall syndactyly is considered the most common congenital hand anomaly. For a variety of reasons, children are often imaged very early, before review by the Specialist in Children's Hand Surgery (despite surgery being unlikely before 1 year of age.) We discuss the classification systems and specific issues that hand surgeons want to know from the radiologists. PMID- 25522684 TI - Globe rupture despite correctly worn American standard-approved eye protective device. PMID- 25522685 TI - Anti-staphylococcal, anti-HIV and cytotoxicity studies of four South African medicinal plants and isolation of bioactive compounds from Cassine transvaalensis (Burtt. Davy) codd. AB - BACKGROUND: Medicinal plants represent an important opportunity to rural communities in Africa, as a source of affordable medicine and as a source of income. Increased patient awareness about safe usage is important as well as more training with regards to traditional medicine. The aim of this study was to evaluate the ethnomedicinal prowess of some indigenous South African plants commonly used in Eastern Cape Province of South Africa for the treatment of skin and respiratory tract infections, HIV and their toxicity potential. METHODS: Cassine transvaalensis, Vangueria infausta, Croton gratissimus and Vitex ferruginea were tested for antibacterial activities against Staphylococcus aureus and Staphylococcus epidermidis using Kirby-Bauer disk diffusion and minimum inhibition concentration (MIC). Cytotoxic and anti-HIV-1 activities of plants were tested using MTT Assay (3- (Dimethylthiozole-2-yl-2,5-diphenyltetrazolium bromide)) and anti- HIV-1iib assay. In search of bioactive lead compounds, Cassine transvaalensis which was found to be the most active plant extract against the two Staphylocoous bacteria was subjected to various chromatographic. Thin layer chromatography, Column chromatography and Nuclear Magnetic Resonance (NMR), (1H-1H, 13C-13C, in DMSO_d6, Bruker 600 MHz) were used to isolate and characterize 3-Oxo-28-hydroxylbetuli-20(29)-ene and 3,28-dihydroxylbetuli-20(29) ene bioactive compounds from C. transvaalensis. RESULTS: The four plants studied exhibited bioactive properties against the test isolates. The zones of inhibition ranged between 16 mm to 31 mm for multi-drug resistant staphylococci species. MIC values varied between 0.6 and 0.02 MUg/ml. C. gratissimus and C. transvaalensis exhibited the abilities to inhibit HIV-1iib. Two bioactive compounds were isolated from C. transvaalensis. CONCLUSION: Data from this study reveals the use of these plant by traditional healers in the Eastern Cape. Furthermore, C. transvaalensis and C. gratissimus were found to be more active as against HIV 1iib. While C. transvaalensis was most active against the two Staphylococcus bacteria. PMID- 25522686 TI - Lactosucrose attenuates intestinal inflammation by promoting Th2 cytokine production and enhancing CD86 expression in colitic rats. AB - Some oligosaccharides have immunoregulatory and anti-inflammatory functions in the intestine. This study investigated the immunoregulatory effect of lactosucrose (LS) on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitic rats. Alkaline phosphatase activity was increased but myeloperoxidase activity was decreased in the LS-TNBS group, as compared with the TNBS group (colitis rats without receiving LS). LS supplementation stimulated IL-4 and IL-10 production, while up-regulating CD86 expression in dendritic cells. LS supplementation reduced the ratio of CD80/CD86 and the ratio of IFN-gamma/IL-4 compared to the TNBS group. Moreover, IFN-gamma was significantly correlated with CD80 (r = 0.764, p < 0.01), whereas IL-4 was significantly correlated with CD86 (r = 0.489, p < 0.05). These results indicated that LS attenuated colitis by promoting the production of Th2-type cytokines and rebalancing the ratio of Th1/Th2 and that enhanced IL-4 production is correlated with enhanced CD86 expression in the gut. Therefore, LS is a functional food for patients with inflammatory bowel disease. PMID- 25522687 TI - Cholesterol-mediated surfactant dysfunction is mitigated by surfactant protein A. AB - The ability of pulmonary surfactant to reduce surface tension at the alveolar surface is impaired in various lung diseases. Recent animal studies indicate that elevated levels of cholesterol within surfactant may contribute to its inhibition. It was hypothesized that elevated cholesterol levels within surfactant inhibit human surfactant biophysical function and that these effects can be reversed by surfactant protein A (SP-A). The initial experiment examined the function of surfactant from mechanically ventilated trauma patients in the presence and absence of a cholesterol sequestering agent, methyl-beta cyclodextrin. The results demonstrated improved surface activity when cholesterol was sequestered in vitro using a captive bubble surfactometer (CBS). These results were explored further by reconstitution of surfactant with various concentrations of cholesterol with and without SP-A, and testing of the functionality of these samples in vitro with the CBS and in vivo using surfactant depleted rats. Overall, the results consistently demonstrated that surfactant function was inhibited by levels of cholesterol of 10% (w/w phospholipid) but this inhibition was mitigated by the presence of SP-A. It is concluded that cholesterol-induced surfactant inhibition can actively contribute to physiological impairment of the lungs in mechanically ventilated patients and that SP-A levels may be important to maintain surfactant function in the presence of high cholesterol within surfactant. PMID- 25522688 TI - A facile synthesis of highly luminescent nitrogen-doped graphene quantum dots for the detection of 2,4,6-trinitrophenol in aqueous solution. AB - A facile bottom-up method for the synthesis of highly fluorescent nitrogen-doped graphene quantum dots (N-GQDs) has been developed via a one-step pyrolysis of citric acid and tris(hydroxymethyl)aminomethane. The obtained N-GQDs emitted strong blue fluorescence under 365 nm UV light excitation with a high quantum yield of 59.2%. They displayed excitation-independent behavior, high resistance to photobleaching and high ionic strength. In addition to the good linear relationship between the fluorescence intensity of the N-GQDs and pH in the range 2-7, the fluorescence intensity of the N-GQDs could be greatly quenched by the addition of a small amount of 2,4,6-trinitrophenol (TNP). A sensitive approach has been developed for the detection of TNP with a detection limit of 0.30 MUM, and a linearity ranging from 1 to 60 MUM TNP could be obtained. The approach was highly selective and suitable for TNP analysis in natural water samples. PMID- 25522689 TI - Charge order and its connection with Fermi-liquid charge transport in a pristine high-T(c) cuprate. AB - Electronic inhomogeneity appears to be an inherent characteristic of the enigmatic cuprate superconductors. Here we report the observation of charge density-wave correlations in the model cuprate superconductor HgBa2CuO(4+delta) (T(c)=72 K) via bulk Cu L3-edge-resonant X-ray scattering. At the measured hole doping level, both the short-range charge modulations and Fermi-liquid transport appear below the same temperature of about 200 K. Our result points to a unifying picture in which these two phenomena are preceded at the higher pseudogap temperature by q=0 magnetic order and the build-up of significant dynamic antiferromagnetic correlations. The magnitude of the charge modulation wave vector is consistent with the size of the electron pocket implied by quantum oscillation and Hall effect measurements for HgBa2CuO(4+delta) and with corresponding results for YBa2Cu3O(6+delta), which indicates that charge-density wave correlations are universally responsible for the low-temperature quantum oscillation phenomenon. PMID- 25522690 TI - Triterpene saponins from Eryngium kotschyi. AB - Four new oleanane-type saponins 3-O-alpha-L-rhamnopyranosyl-(1 -> 4)-beta-D glucuronopyranosyl-22-O-beta,beta-dimethylacryloylA1-barrigenol (1), 3-O-alpha-L rhamnopyranosyl-(1 -> 4)-beta-D-glucuronopyranosyl-22-O-angeloylA1-barrigenol (2), 3-O-beta-D-glucopyranosyl-(1 -> 2)-[beta-D-glucopyranosyl-(1 -> 6)]-beta-D glucopyranosyl-21,22,28-O-triacetyl-(3beta,21beta,22alpha)-olean-12-en-16-one (3), and 3-O-beta-D-glucopyranosyl-(1 -> 2)-glucopyranosyl-22-O-beta-D glucopyranosylsteganogenin (4), along with the known 3-O-beta-D-galactopyranosyl (1 -> 2)-[alpha-L-arabinopyranosyl-(1 -> 3)]-beta-D-glucuronopyranosyl-22-O angeloylA1-barrigenol and 3-O-alpha-L-rhamnopyranosyl-(1 -> 4)-beta-D glucuronopyranosyloleanolic acid, were isolated from a methanol extract of the roots of Eryngium kotschyi by multiple chromatographic steps. Saponins 3 and 4 are unusual by the original structure of their aglycon. Compound 3 possessed an oleanane-type skeleton with a 21,22,28-triacetylation and a ketone function at the C-16 position. For compound 4, the 17,22-seco-oleanolic acid skeleton is rarely found in natural saponins. PMID- 25522691 TI - SCF(Slmb) E3 ligase-mediated degradation of Expanded is inhibited by the Hippo pathway in Drosophila. AB - Deregulation of the evolutionarily conserved Hippo pathway has been implicated in abnormal development of animals and in several types of cancer. One mechanism of Hippo pathway regulation is achieved by controlling the stability of its regulatory components. However, the executive E3 ligases that are involved in this process, and how the process is regulated, remain poorly defined. In this study, we identify, through a genetic candidate screen, the SCF(Slmb) E3 ligase as a novel negative regulator of the Hippo pathway in Drosophila imaginal tissues via mediation of the degradation of Expanded (Ex). Mechanistic study shows that Slmb-mediated degradation of Ex is inhibited by the Hippo signaling. Considering the fact that Hippo signaling suppresses the transcription of ex, we propose that the Hippo pathway employs a double security mechanism to ensure fine-tuned homeostasis during development. PMID- 25522692 TI - The effects of cancer and racial disparities in health-related quality of life among older Americans: a case-control, population-based study. AB - BACKGROUND: Understanding the impact of the cancer care system on racial/ethnic disparities in health-related quality of life (HRQOL) is increasingly important as the number of cancer survivors in the United States grows. The authors prospectively assessed changes in HRQOL before and after a first cancer diagnosis among non-Hispanic whites (NHWs), African Americans (AAs), Hispanics, and Asians in a cohort of Medicare beneficiaries with and without cancer. METHODS: Data from the Surveillance, Epidemiology, and End Results linked with the Medicare Health Outcomes Survey were used to identify 1778 individuals aged >=65 years with prostate, breast, or colorectal cancer from 1998 to 2007. The Medical Outcomes Trust Short Form 36 (SF-36) instrument was used to measure HRQOL. By using propensity scores, each patient with cancer (case) was matched to 5 individuals without cancer (noncancer controls), and differences in HRQOL according to race/ethnicity were assessed. Mixed effects analysis of covariance models was used to assess differences in HRQOL, adjusting for baseline HRQOL, demographics, and self-reported comorbid conditions while controlling for each individual's managed care plan. Stratified analyses were used to assess racial/ethnic disparities between cases and noncancer controls. RESULTS: Before cancer diagnosis, NHWs had better HRQOL scores than AAs and Hispanics on the Role Physical and Role-Emotional SF-36 subscales. Cancer diagnosis/treatment negatively impacted individuals' lives regardless of race/ethnicity. However, among cases, gaps between racial/ethnic groups narrowed (compared with controls) before and after cancer diagnosis for some SF-36 HRQOL measures. CONCLUSIONS: Racial/ethnic HRQOL gaps exist among cancer survivors but may narrow because of exposure to the cancer care system. Further research to understand why this occurs will help inform initiatives to manage the impact of cancer on HRQOL among elderly cancer survivors. PMID- 25522693 TI - PMP22-Related neuropathies and other clinical manifestations in Chinese han patients with charcot-marie-tooth disease type 1. AB - INTRODUCTION: Most cases of Charcot-Marie-Tooth (CMT) disease are caused by mutations in the peripheral myelin protein 22 gene (PMP22), including heterozygous duplications (CMT1A), deletions (HNPP), and point mutations (CMT1E). METHODS: Single-nucleotide polymorphism (SNP) arrays were used to study PMP22 mutations based on the results of multiplex ligation-dependent probe amplification (MLPA) and polymerase chain reaction-restriction fragment length polymorphism methods in 77 Chinese Han families with CMT1. PMP22 sequencing was performed in MLPA-negative probands. Clinical characteristics were collected for all CMT1A/HNPP probands and their family members. RESULTS: Twenty-one of 77 CMT1 probands (27.3%) carried duplication/deletion (dup/del) copynumber variants. No point mutations were detected. SNP array and MLPA seem to have similar sensitivity. Fifty-seven patients from 19 CMT1A families had the classical CMT phenotype, except for 1 with concomitant CIDP. Two HNPP probands presented with acute ulnar nerve palsy or recurrent sural nerve palsy, respectively. CONCLUSIONS: The SNP array has wide coverage, high sensitivity, and high resolution and can be used as a screening tool to detect PMP22 dup/del as shown in this Chinese Han population. PMID- 25522694 TI - Functional and structural balances of homologous sensorimotor regions in multiple sclerosis fatigue. AB - Fatigue in multiple sclerosis (MS) is a highly disabling symptom. Among the central mechanisms behind it, an involvement of sensorimotor networks is clearly evident from structural and functional studies. We aimed at assessing whether functional/structural balances of homologous sensorimotor regions-known to be crucial for sensorimotor networks effectiveness-decrease with MS fatigue increase. Functional connectivity measures at rest and during a simple motor task (weak handgrip of either the right or left hand) were derived from primary sensorimotor areas electroencephalographic recordings in 27 mildly disabled MS patients. Structural MRI-derived inter-hemispheric asymmetries included the cortical thickness of Rolandic regions and the volume of thalami. Fatigue symptoms increased together with the functional inter-hemispheric imbalance of sensorimotor homologous areas activities at rest and during movement, in absence of any appreciable parenchymal asymmetries. This finding supports the development of compensative interventions that may revert these neuronal activity imbalances to relieve fatigue in MS. PMID- 25522695 TI - CT perfusion on admission and cognitive functioning 3 months after aneurysmal subarachnoid haemorrhage. AB - Many survivors of aneurysmal subarachnoid haemorrhage (aSAH) have persistent cognitive deficits. Underlying causes of these deficits have not been elucidated. We aimed to investigate if cerebral perfusion in the acute phase after aSAH measured with CT perfusion (CTP) is associated with cognitive outcome 3 months after aSAH. We included 71 patients admitted to the University Medical Center Utrecht who had CTP performed within 24 h after ictus and neuropsychological examination after 3 months. Perfusion values were measured in predefined regions of interest for cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and time to peak (TTP). The relationship with global cognitive functioning, as measured with a mean z score of all cognitive tests, was examined by linear regression analyses. Adjustments were made for age, education, method of aneurysm treatment, and presence of non-acute medical complications. TTP was associated with cognitive functioning in the univariable analysis (B = -0.042, 95 % CI -0.076 to -0.008), but not after adjustment for age (B = -0.030, 95 % CI -0.065 to 0.004). For CBF, CBV and MTT no relationship with cognitive functioning was observed. Cerebral perfusion measured with CTP within 24 h after onset of aSAH is not associated with cognitive outcome after 3 months. The lack of an association might be explained by the delay between onset of aSAH and CTP. However, CTP assessment within the first minutes after aSAH is impossible in large series of patients. PMID- 25522696 TI - Sniff nasal inspiratory pressure as a prognostic factor of tracheostomy or death in amyotrophic lateral sclerosis. AB - Forced vital capacity (FVC) shows limitations in detecting respiratory failure in the early phase of amyotrophic lateral sclerosis (ALS). In fact, mild-to-moderate respiratory muscle weakness may be present even when FVC is normal, and ALS patients with bulbar involvement might not be able to perform correctly the spirometry test. Sniff nasal inspiratory pressure (SNIP) is correlated with transdiaphragmatic strength. We evaluated SNIP at baseline as a prognostic factor of tracheostomy or death in patients with ALS. In a multidisciplinary tertiary care center for motorneuron disease, we enrolled 100 patients with ALS diagnosed with El Escorial criteria in the period between January 2006 and December 2010. Main outcome measures were tracheostomy or death. RECursive Partitioning and AMalgamation (RECPAM) analysis was also used to identify subgroups at different risks for the tracheostomy or death. Twenty-nine patients with ALS reached the outcome (12 died and 17 had tracheostomy). Using a multivariate model SNIP correctly classified the risk of the composite event within 1 year of follow-up with a continuous Net Reclassification Improvement cNRI of 0.58 (p = 0.03). Sex, Amyotrophic Lateral Sclerosis Functional Rating Scale revisited, site of onset, and FVC did not improve the classification of prognostic classes. SNIP <=18 cmH2O identified the RECPAM class with the highest risk (Class 1, hazard ratio = 9.85, 95 % confidence interval: 2.67-36.29, p < 0.001). SNIP measured at baseline identified patients with ALS with initial respiratory failure. Finally, using only ALS patients with spinal onset of the disease, our findings were mostly overlapping with those reported in the models including the whole sample. At baseline, SNIP appeared to be the best predictor of death or tracheostomy within 1 year of follow-up. The measurement of SNIP in the early phase of the disease may contribute to identify patients with high risk of mortality or intubation. SNIP may also provide an additional tool for baseline stratification of patients with ALS in clinical trials. PMID- 25522697 TI - Esophoria or esotropia in adulthood: a sign of cerebellar dysfunction? AB - Convergent strabismus is a common diagnosis in early childhood, when it is mostly considered benign. If it develops later in life, strabismus can, however, be a sign of neurological disease. In these cases the underlying pathophysiological mechanisms are largely unknown. In this retrospective case-control study we analyzed the neuro-ophthalmological examination reports of 400 adult patients who presented at the German Center for Vertigo and Balance Disorders to determine an association between ocular misalignment and cerebellar dysfunction. Patients with cerebellar signs (i.e., cerebellar ataxia and/or cerebellar ocular motor signs) had a 4.49 (95 % CI [1.60; 13.78]) times higher frequency of ocular misalignment and specifically a 13.3 (95 % CI [3.80; 55.73]) times increased frequency of esophoria/esotropia (ESO) during distant gaze than patients without cerebellar dysfunction. ESO when looking into the distance was associated with saccadic smooth pursuit, dysmetria of saccades, and downbeat nystagmus (DBN) (chi (2) test, p < 0.0001 for all associations). Patients with cerebellar dysfunction also showed mildly impaired eye abduction (chi (2) test, left eye and right eye: p < 0.0001), associated with horizontal gaze-evoked nystagmus (chi (2) test, p < 0.0001). The association of ESO and DBN implicates a pathophysiological involvement of the cerebellar flocculus, while the association with dysmetric saccades suggests involvement of the oculomotor vermis. This is compatible with animal studies showing that the pathways of the flocculus/posterior interposed nucleus and vermis/nucleus fastigii are both involved in vergence movements and static binocular alignment. From a clinical point of view, a newly diagnosed esophoria/esotropia only during distant gaze may be a sign of a cerebellar disease. PMID- 25522698 TI - Familial Creutzfeldt-Jakob disease with the E200K mutation: longitudinal neuroimaging from asymptomatic to symptomatic CJD. AB - Familial Creutzfeldt-Jakob disease (fCJD) in Jews of Libyan ancestry is caused by an E200K mutation in the PRNP gene. While carriers are born with this mutation, they usually remain asymptomatic until middle age. Early detection of conversion is crucial for understanding and eventually for the treatment of the disease. The aim of this study was to report longitudinal MRI data in E200K individuals who eventually converted from healthy mutation carriers to clinically symptomatic CJD. As a part of a prospective study, asymptomatic E200K mutation carriers were scanned annually until their conversion to symptomatic disease. Standardized diffusion and anatomical MR sequences were performed before and after clinical conversion in the subjects and those were compared to 15 non-carrier siblings ("healthy controls"). Blinded radiological readings and region of interest analyses were performed. Radiological readings of individual cases failed to detect characteristic changes in the scans taken before the conversion. Region of interest analysis of diffusion changes in pre-symptomatic stage was inconclusive; however, ADC reduction was found in early and late stages of the disease. Computerized volumetric analysis revealed monotonic volume reductions in thalamus, putamen and caudate following conversion, and the lateral ventricles showed dilatation of up to 62 % after clinical conversion. Although the clinical manifestations at disease onset are variable, the diffusion abnormalities and/or volume changes in the thalamus and basal ganglia during conversion may indicate early involvement of the thalamostriatal neuronal circuit. PMID- 25522699 TI - Obsessive-compulsive personality disorder in drug-naive Parkinson's disease patients. PMID- 25522700 TI - Qualification of ship doctors: a German approach. AB - BACKGROUND: While a steady growth of cruise tourism since the 1970s created an increasing demand for ship doctors medical postgraduate specialty training did not sufficiently reflect the scope of skills and knowledge required from a physician being left to himself at sea. The German Maritime Health Association therefore tasked a working group with analysing the situation and coming up with suggestions for an adequate postgraduate training for ship doctors. MATERIALS AND METHODS: The working group consisted of 19 experts with various backgrounds in maritime medicine. A literature review was done on cruise ship epidemiology as well as an assessment of tasks and environmental factors influencing medical care on board of cruise ships. Necessary knowledge and skills were derived and compared with those imparted by standard German medical education. RESULTS: Mandatory knowledge and skills were identified as well as elements of standard medical education contributing to these goals. Those aspects that would or could not be adequately covered by German standard education were catalogued and summarised in a course curriculum. CONCLUSIONS: In 2013 after approval by its board of directors the German Maritime Health Association published a qualification and training recommendation addressing colleagues planning to muster as ship doctors. PMID- 25522701 TI - A research on obesity among Turkish seafarers. AB - BACKGROUND: Obesity and overweight threaten not only seafarer's health but also the safety of operations on board a ship. The aim of the study was to investigate the statistical distribution of obesity and overweight among Turkish seafarers by using the health examination reports data collected between 2009 and 2012. MATERIALS AND METHODS: The data on weight, height and age obtained from 143,341 medical examination reports of Turkish seafarers were used with the official permission of Directorate General of Health for Border and Coastal Areas. Considering the data in the health reports, body mass index (BMI) values were calculated, analysed and compared with Turkish general population and Danish seafarers. RESULTS: It has been found that BMI values of Turkish seafarers were boomed over the years. While Turkish male seafarers get older, their BMI values rise progressively. After the age of 28, BMI scores exceed the acceptable level. In addition, they reach maximum average 27.8 BMI value in their 50s. CONCLUSIONS: The activities, which will provide awareness to Turkish seafarers and the ship operators about the dangers of obesity, should be done. Also convenient environments and time for physical exercise on board a ship must be provided for seafarers. PMID- 25522702 TI - Prevalence of oral mucosal lesions among fishermen of Kutch coast, Gujarat, India. AB - BACKGROUND: The aim of the study was to assess the prevalence of oral mucosal lesions among fishermen population in the coastal region of Kutch, Gujarat, India. MATERIALS AND METHODS: A descriptive cross-sectional survey was conducted to assess the prevalence of oral mucosal lesions among the 979 fishermen of Kutch District, Gujarat, India. The proforma included information on demographic details, habits (tobacco and alcohol), oral hygiene practices and presence and location of oral mucosal lesions according to World Health Organisation, 2013. Chi-square test was used for comparisons. Confidence level and p-value were set at 95% and 5%, respectively. RESULTS: The majority of study population consumed tobacco and alcohol (88.1%) in some or the other form and used chewsticks (42.9%) for cleaning their teeth. Amongst all, 30.03% of the study subjects suffered from oral mucosal lesions. Leukoplakia (13.8%) was found to be the most prevalent lesion. The most affected sites were lips and vermillion border. The prevalence of oral mucosal lesions was found to be significantly associated with age, gender, oral hygiene practices and adverse habits. CONCLUSIONS: Oral mucosal lesions were prevalent among 30.03% of the study population. More detailed studies probing this issue should be conducted and efforts should be directed towards primordial prevention of the conditions. PMID- 25522703 TI - Consumption of addictive substances in mariners. AB - BACKGROUND: For many years, studies have confirmed that there is a high prevalence of addiction amongst seafarers. The effect of this is even more serious when one considers their isolated and even hostile living environment presenting risks which require vigilance and rapid reactions. The purpose of this article is to determine the extent of knowledge about addiction among seafarers. MATERIALS AND METHODS: This is a review of the literature between 1993 and 2013 with respect to the prevalence of consumption of alcohol, tobacco, cannabis, cocaine, heroin, and other drugs amongst seafarers. Total prevalence was calculated using the virtual population represented by the subjects of each article, when drug consumption definition was the same between articles and when mariners studied were different. RESULTS: 63.1% (range 38.4-96.3%) of seafarers smoked tobacco. 14.5% (range 8.8-75%) of seafarers drank alcohol. 3.4% (range 9 45%) had used cannabis during the previous month. Few studies concerned other drugs; 3-10% of seafarers used drugs on board. CONCLUSIONS: The prevalence of tobacco and alcohol consumption amongst seafarers was higher than that in the general population. Further studies on the use of drugs at work would be valuable for this population who are subject to significant occupational risk. PMID- 25522704 TI - Medical assistance at the sea: legal and medico-legal problems. AB - BACKGROUND: In case of pathologies or accidents on board which require medical intervention but lacking on-board medical or paramedical personnel, the ship's captain, or his delegate can contact a Telemedical Maritime Assistance Service (TMAS). International Maritime Organisation considers telemedicine at sea as an integral part of rescue procedures. Five key elements contribute to the delivery of good medical assistance at sea: one or more coordination and rescue centres; the TMAS; the possibility of intervention at sea; an organisation of appropriate institutions on ground and common operating procedures. This paper analyses the responsibility of the ship's captain and of the TMAS doctor in case of diseases or injuries on board in the frame of the main important international regulations. RESPONSIBILITY OF THE SHIP CAPTAIN: In case of a disease or injury on board a ship, the captain must contact the TMAS as soon as possible. A captain not acting promptly and not doing whatever it is possible for the ill/injured person by consulting the TMAS or a physician and/or not following prescriptions received, could be charged for omission of responsibility. A captain underestimating a medical problem and knowing that the patient's condition could worsen, but still not consulting a medical centre for assistance, should be ready to accept the consequences of his choices. RESPONSIBILITY OF THE PHYSICIAN: The doctor of TMAS has full responsibility for the diagnosis, prescription and treatment, while the ship's captain is responsible for the final decision. Regarding the medical treatment and assistance on board a ship, the TMAS doctor should pay attention not only for the diagnosis, but also for the prognosis. Telemedicine implies that the doctor should make decisions without a clinical examination, often without some additional medical examinations and by maintaining a contact with other people who are in direct contact with the patient. The physician usually has to rely on the account of colleagues of the sick seafarer as far as medical history is concerned. This may make harder to take a decision. CONCLUSIONS: The ship's captain is guilty if he fails to contact a TMAS in case of diseases or accidents on board. Similar to a traditional relationship between a patient and a physician, the doctor consulted via telecommunication systems is also responsible for his diagnosis and treatment. However, in telemedicine the contrasts with the most basic principles of the traditional medicine are obvious. This makes the delivery of medical care of seafarers on board ships quite complicated. PMID- 25522705 TI - Reasons for medical evacuations of soldiers serving in International Security Assistance Force (ISAF) operation in Afghanistan. AB - BACKGROUND: The article presents the results of a research study into the reasons for medical evacuations of Polish military personnel taking part in the International Security Assistance Force (ISAF) operation in Afghanistan from 2007 to 2013. MATERIALS AND METHODS: The authors have analysed medical records of 485 soldiers who were medically evacuated out of a combat zone in Afghanistan for battle injuries, non-battle injuries and diseases. Each medically evacuated Polish soldier was subjected to statistical analysis. The study population comprised 25,974 soldiers assigned to the Polish Military Contingent Afghanistan in the given period. RESULTS: From 2007 to 2013, 1.9% of the Polish military personnel (n = 485) participating in the ISAF operation in Afghanistan were evacuated for medical reasons before the scheduled termination of their contract. 40.6% of all medical evacuations were due to battle injuries, 32.4% due to non battle injuries, and 27.0% due to diseases. CONCLUSIONS: ISAF is an example of a combat operation, in which battle injuries remain the leading health problem in mission participants. 3 of 4 Polish soldiers who were medically evacuated from Afghanistan were no longer fit for military service in the area of operations due to the traumas they had suffered. PMID- 25522706 TI - Intestinal parasites in Polish community on the example of military environment. AB - BACKGROUND: The epidemiological situation concerning the prevalence of the majority of intestinal parasites in Poland has not been investigated in recent years and therefore is not known. Information on the prevalence of nematodes and most of cestodes is acquired from the studies carried out in Polish research centres. The aim of this study was to evaluate the occurrence of intestinal parasites among Polish soldiers who served in harsh environmental conditions in Afghanistan and their families living in Poland. The relation between the rates of infections in military personnel and in their families in the context of the risk of importing intestinal parasites from Afghanistan to Poland was also analysed in this article. MATERIALS AND METHODS: 264 families consisting of 803 persons took part in the study which was conducted in the period May 2011 - December 2012. Stool samples were subjected to parasitological examination in the Military Institute of Medicine, Poland. The tests were performed by means of three diagnostic methods (direct smear, decantation, flotation). The study population comprised 264 married soldiers and 539 civilians (soldiers' wives and children) living permanently in urban areas in Poland. RESULTS: Intestinal parasites were diagnosed in 4/264 studied soldiers (1.5% infected with Ascaris lumbricoides, Giardia intestinalis), in 9/253 studied women (3.6% infected with A. lumbricoides, Hymenolepis nana, Taenia spp.) and in 5/286 children (1.7% infected with A. lumbricoides, G. intestinalis). There was no more than one infection per one household. CONCLUSIONS: The occurrence of intestinal parasites among Polish soldiers shows the possibility of importing pathogens from the Third World countries. It also indicates, in the context of infected women and children, that the source of infection of parasites of the digestive tract can be present in Poland. PMID- 25522707 TI - Longitudinal change in professional divers' lung function: literature review. AB - BACKGROUND: The aim of this study was to assess changes in lung function of professional divers. MATERIALS AND METHODS: This is a review of the literature. Only studies about professional divers were included. All published studies between 01.01.1984 and 07.01.2014 were systematically searched. The search was performed in Medline and Embase databases and in the "Medicina Maritima" journal. The results of pulmonary function tests were extracted from each study. RESULTS: Fifteen articles were found. Four studies showed a significant decrease in forced vital capacity (FVC). Five studies demonstrated a significant decrease in forced expiratory flows (FEF) at 75% and 50% of FVC expired (FEF75% and FEF50%) after 3 years of diving. Seven studies demonstrated a significant decrease in forced expiratory volume in 1 second (FEV1) after 3 years of diving. But only 2 studies did an age-standardisation so that only 1 study demonstrated a significant decrease in FEV1 after age-standardisation. Three articles showed a decrease in transfer factor for carbon monoxide (TLCO) after 5 years. Dives parameters (like depth, number by year) were not always related to variations on the different lung variables. CONCLUSIONS: This literature review showed a decrease in TLCO, FEF75% and FEF25-75%. One wonders whether these variations are due to the age or to diving. The results of such a long-term study would be interesting and might help to guide fundamental research. PMID- 25522709 TI - Commentary to the article by Korzeniewski et al. PMID- 25522708 TI - Sea piracy sequelae: assessment according to the Diagnostic and Statistical Manual of Mental Disorders-5. AB - BACKGROUND: Our previous studies have investigated the psychological consequences of kidnapping in a group of Italian seafarers assaulted by sea pirates and held in captivity and in their family members by the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM)-4. These studies have shown that both the victims and the family members showed significant psychological disturbances, corresponding to a chronic Post-Traumatic Stress Disorder (PTSD), in the victims, and a pattern of anxiety and depression in their family members. After publication of these studies, an updated edition of the DSM became available, namely, the DSM-5. The DSM-5 redefines some diagnostic criteria, including those related to the PTSD. This work was focused on the re-evaluation of the results of our previous studies in the light of the DSM-5 diagnostic criteria. MATERIALS AND METHODS: Sixteen Italians including 4 kidnapped seafarers and 12 family members were examined by a semi-structured interview followed by Clinician-Administered PTSD Scale (CAPS-DX) and the Cognitive Behaviour al Assessment (CBA 2.0) for victims and by State-Trait Anxiety Inventory (STAI) X-1 and X-2 of CBA 2.0 and the Hamilton Depression Rating Scale (HDRS) for family members. Data already obtained were reviewed and re-analysed according to the DSM 5 criteria and the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). RESULTS: The use of the CAPS-5 did not modify the diagnosis for the victims' group: 3 of 4 had a PTSD diagnosis performed through the CAPS-5. Seven of 12 family members had PTSD diagnosis performed through the CAPS-5, with negative cognitions and mood symptoms being those obtaining the highest score. CONCLUSIONS: Using DSM-5 criteria, the diagnosis of PTSD in the direct victims of piracy was confirmed. The same diagnosis could apply to a group of their family members. Besides anxiety and fear, in fact, we found in 7 out 12 subjects the presence of symptoms included by the DSM-5 in the PTSD spectrum. These symptoms were: avoidance, negative alterations in mood and cognition, blame of self or others. The use of updated diagnostic criteria may enable more correct assessment of the consequences of piracy acts. This may be also useful for establishing proper compensations for the damage suffered by seafarers, depending on the degree of disability resulting from the criminal acts they suffered. PMID- 25522710 TI - Aksel Schreiner in memoriam. PMID- 25522711 TI - Effects of resveratrol on growth and skeletal muscle physiology of juvenile southern flounder. AB - Resveratrol is a naturally occurring antioxidant that has been widely studied in mammals due to its potential to extend lifespan. However, antioxidants may also limit protein damage and therefore reduce rates of protein degradation, providing a potential avenue for enhancing growth in an aquaculture setting. The present study tested the hypotheses that in Southern flounder, Paralichthys lethostigma, resveratrol would decrease protein carbonylation and 4-HNE (indicators of protein and lipid oxidative damage, respectively), levels of ubiquitinylation and LC3 (indicators of non-lysosomal and lysosomal protein degradation, respectively), while having no effect on S6K activation (indicator of protein synthesis). These effects were predicted to increase growth rate. Mitochondrial volume density was also examined since resveratrol may lead to the proliferation of mitochondria, which are the principal source of reactive oxygen species (ROS) that cause oxidative damage. Juvenile fish (n=142) were fed a control diet or a diet supplemented with 600 MUg resveratrol per g of food for 16 weeks. Fish treated with resveratrol had a 9% greater length and 33% greater body mass than control fish after 16 weeks. Additionally, there was lower protein carbonylation and lipid 4-HNE within the muscle tissues of treated fish, indicating decreased oxidative damage, and reduced protein ubiquitinylation in the resveratrol fed flounder, indicating less protein degradation. However, there was not a significant difference in LC3, S6K activation, or mitochondrial volume density. These results suggest that resveratrol has positive effects on growth due to its antioxidant properties that reduce non-lysosomal protein degradation. PMID- 25522712 TI - Regulation of salmonid fish sperm motility by osmotic shock-induced water influx across the plasma membrane. AB - The motility of salmonid fish sperm is initiated by a decrease in the extracellular K(+) concentration. However, our previous studies revealed that salmonid fish sperm motility could be initiated in the presence of an inhibitory concentration of K(+) by drastic osmotic shock induced by suspension in a hypertonic glycerol solution and subsequent dilution in a hypotonic solution (glycerol-treatment). In the present study, we examined if an osmotic shock induced water influx is involved in the regulation of salmonid fish sperm motility. HgCl2, a common inhibitor of aquaporins (AQPs), decreased the duration of salmonid fish sperm motility. Dilution of sperm cells in a hypotonic solution increased the cellular volume, whereas HgCl2 inhibited such an increase in cellular volume. Furthermore, the expression of AQP 1a and 10 in rainbow trout testes was confirmed. In contrast, HgCl2 did not affect glycerol-treated sperm motility, indicating that AQPs are not involved in glycerol-treated sperm motility. We also explored the possibility of aquaporin-independent water influx in glycerol-treated sperm by assessing the sperm membrane permeability using propidium iodide. The plasma membrane of glycerol-treated sperm was considerably permeabilized. The cellular volume was decreased in a hypertonic glycerol solution and increased upon subsequent hypoosmotic shock, indicating an AQP independent water flux across the plasma membrane upon glycerol-treatment. Taken together, these results showed that water influx across the plasma membrane via AQP is crucial for the maintenance of salmonid fish sperm motility under normal conditions, whereas water influx by osmotic shock-induced membrane permeation is critical for the initiation of glycerol-treated sperm motility. PMID- 25522713 TI - The SMART model: Soft Membranes Adapt and Respond, also Transiently, in the presence of antimicrobial peptides. AB - Biophysical and structural studies of peptide-lipid interactions, peptide topology and dynamics have changed our view on how antimicrobial peptides insert and interact with membranes. Clearly, both the peptides and the lipids are highly dynamic, change and mutually adapt their conformation, membrane penetration and detailed morphology on a local and a global level. As a consequence, the peptides and lipids can form a wide variety of supramolecular assemblies in which the more hydrophobic sequences preferentially, but not exclusively, adopt transmembrane alignments and have the potential to form oligomeric structures similar to those suggested by the transmembrane helical bundle model. In contrast, charged amphipathic sequences tend to stay intercalated at the membrane interface where they cause pronounced disruptions of the phospholipid fatty acyl packing. At increasing local or global concentrations, the peptides result in transient membrane openings, rupture and ultimately lysis. Depending on peptide-to-lipid ratio, lipid composition and environmental factors (temperature, buffer composition, ionic strength, etc.), the same peptide sequence can result in a variety of those responses. Therefore, the SMART model has been introduced to cover the full range of possibilities. With such a view in mind, novel antimicrobial compounds have been designed from amphipathic polymers, peptide mimetics, combinations of ultra-short polypeptides with hydrophobic anchors or small designer molecules. PMID- 25522715 TI - Bioinformatic analyses and conceptual synthesis of evidence linking ZNF804A to risk for schizophrenia and bipolar disorder. AB - Advances in molecular genetics, fueled by the results of large-scale genome-wide association studies, meta-analyses, and mega-analyses, have provided the means of identifying genetic risk factors for human disease, thereby enriching our understanding of the functionality of the genome in the post-genomic era. In the past half-decade, research on neuropsychiatric disorders has reached an important milestone: the identification of susceptibility genes reliably associated with complex psychiatric disorders at genome-wide levels of significance. This age of discovery provides the groundwork for follow-up studies designed to elucidate the mechanism(s) by which genetic variants confer susceptibility to these disorders. The gene encoding zinc-finger protein 804 A (ZNF804A) is among these candidate genes, recently being found to be strongly associated with schizophrenia and bipolar disorder via one of its non-coding mutations, rs1344706. Neurobiological, molecular, and bioinformatic analyses have improved our understanding of ZNF804A in general and this variant in particular; however, more work is needed to establish the mechanism(s) by which ZNF804A variants impinge on the biological substrates of the two disorders. Here, we review literature recently published on ZNF804A, and analyze critical concepts related to the biology of ZNF804A and the role of rs1344706 in schizophrenia and bipolar disorder. We synthesize the results of new bioinformatic analyses of ZNF804A with key elements of the existing literature and knowledge base. Furthermore, we suggest some potentially fruitful short- and long-term research goals in the assessment of ZNF804A. PMID- 25522716 TI - 3 Tesla high-resolution and delayed gadolinium enhanced MR imaging of cartilage (dGEMRIC) after autologous chondrocyte transplantation in the hip. AB - BACKGROUND: To evaluate the feasibility of 3 Tesla (T) high-resolution and gadolinium enhanced MRI of cartilage (dGEMRIC) in the thin and rounded hip cartilage of patients after acetabular matrix-based autologous chondrocyte transplantation (MACT). METHODS: Under general ethics approval, 24 patients were prospectively examined 6-31 months after acetabular MACT at 3T using high resolution proton-density weighted (PDw) images (bilateral PD SPACE, 0.8 mm isotropic; unilateral PD-TSE coronal/sagittal, 0.8 * 0.8 resp. 0.5 * 0.5 * 2.5 mm) as well as T1 mapping (3D-FLASH, 0.78 mm isotropic) in dGEMRIC technique, and clinically scored. The cartilage transplant was evaluated using an adapted MOCART score (maximum 85 points). T1 relaxation times were measured independently by two radiologists. Here, regions of interest were placed manually in automatically calculated relaxation-maps, both in the transplant and adjacent healthy cartilage regions. Interobserver reliability was estimated by means of intraclass correlation (ICC). RESULTS: The transplant was morphologically definable in the PDw images of 23 patients with a mean MOCART score of 69 points (60-80 points, SD 6.5). T1 maps showed a clear differentiation between acetabular and femoral cartilage, but correlation with PDw images was necessary to identify the transplant. Mean T1 relaxation times of the transplant were 616.3 ms (observer 1) resp. 610.1 ms (observer 2), and of adjacent healthy acetabular cartilage 574.5 ms (observer 1) resp. 604.9 ms (observer 2). Interobserver reliability of the relaxation times in the transplant was excellent (ICC-coefficient 0.88) and in adjacent healthy regions good (0.77). CONCLUSION: High-resolution PDw imaging with adapted MOCART scoring and dGEMRIC is feasible after MACT in the thin and rounded hip cartilage. PMID- 25522717 TI - An easy acronym to improve the check-list: CALPE. PMID- 25522718 TI - Enterocutaneous fistula secondary to an error in placement of a negative-pressure abdominal dressing. PMID- 25522719 TI - High-frequency stimulation of the hippocampus blocks fear learning sensitization and return of extinguished fear. AB - Patients with post-traumatic stress disorder (PTSD) present hippocampal (HPC) dysfunction, which may facilitate fear-related phenomena such as fear learning sensitization (i.e. potentiation of fear acquisition by initial fear conditioning (FC1)) and fear return (i.e. reactivation of extinguished fear). Fear return is sensitive to HPC high-frequency stimulation (HFS) in rats. The goal of the present study was to examine whether fear learning sensitization is also sensitive to HPC HFS in rats. We found in control conditions that, after FC1 (with 15 shock administrations) and extinction, conditioning in a different context with one shock administration was potentiated (proactive effect) and associated with fear return in the initial context (retroactive effect). Both phenomena were prevented by HPC HFS applied before the second conditioning. We also found that the effect of HPC HFS on fear learning sensitization required initial extinction. These findings suggest a pivotal role of the HPC in preventing proactive and retroactive effects of successive fear conditionings. These data also support the concept that HPC deactivation may be involved in fear learning sensitization and fear return in PTSD patients. PMID- 25522720 TI - Region and context-specific intracellular responses associated with cocaine induced conditioned place preference expression. AB - The development and maintenance of cocaine addiction depend heavily on learned reward-environment associations that can induce drug-seeking behavior and relapse. Understanding the mechanisms underlying these cue-induced conditioned responses is important for relapse prevention. To test whether intracellular responses measured after cocaine conditioned place preference (CPP) expression are context-dependent, we re-exposed cocaine-treated rats (drug-free) to an environment previously paired with cocaine or saline, 24h after the CPP test. After 8 days of cocaine CPP training with one of two cocaine doses (5mg/kg or 20mg/kg, i.p.), CPP was expressed only after conditioning with the higher cocaine dose. In CPP expressing rats, locomotor responses after re-exposure to the cocaine-chamber were greater than in rats re-exposed to the saline-paired chamber. Nucleus Accumbens (NAc) phosphorylated ERK (pERK) levels were increased after re-exposure to the cocaine-paired, but not the saline-paired chamber, regardless of whether or not CPP behavior was expressed. Caudate Putamen (CPu) pERK and FosB protein levels increased after re-exposure to the cocaine chamber only after conditioning with the higher cocaine dose. Conversely, the higher cocaine dose, independent of environment, resulted in increased NAc FosB, DeltaFosB and phosphorylated CREB (pCREB) protein levels compared to those conditioned with 5mg/kg cocaine (non-CPP-expressing). Our results suggest that NAc ERK phosphorylation may be involved with retrieving the contextual information of a cocaine-association, without necessarily motivating the expression of CPP behavior. Additionally, we show distinct patterns of intracellular responses in the NAc and CPu indicating a region-specific role for pERK/pCREB/FosB intracellular signaling in the retrieval of cocaine-context associations. PMID- 25522722 TI - Microbial resource research infrastructure (MIRRI): infrastructure to foster academic research and biotechnological innovation. AB - The coordinated collaboration between public culture collections within the MIRRI infrastructure will support research and development in the field of academic as well as industrial biotechnology. Researchers working with microorganisms using the envisioned MIRRI portal will have facilitated access to microbial resources, associated data and expertise. By addressing the users' specific needs MIRRI will provide the basis for biotechnological innovation in Europe. PMID- 25522721 TI - Assessment of hemodialysis impact by Polysulfone membrane on brain plasticity using BOLD-fMRI. AB - PURPOSE: Hemodialysis (HD) is considered the most common alternative for overcoming renal failure. Studies have shown the involvement of HD membrane in the genesis of oxidative stress (OS) which has a direct impact on the brain tissue and is expected to be involved in brain plasticity and also reorganization of brain function control. The goal of this paper was to demonstrate the sensitivity of the blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) to characterize the OS before and after the HD session. PATIENTS, MATERIALS AND METHODS: Twelve male patient-volunteers following chronic HD for more than 6months were recruited among 86 HD-patients. All patients underwent identical assessment immediately before and after the full HD-session. This consisted of full biological assessment, including malondialdehyde (MDA) and total antioxidant activity (TAOA); and brain BOLD-fMRI using the motor paradigm in block-design. RESULTS: Functional BOLD-fMRI maps of motor area M1 were obtained from the HD patient before and after the hemodialysis session, important decrease in the intensity of brain activation of the motor area after HD, and important increase of the size of the volume of brain activation were observed, these changes are reflecting brain plasticity that is well correlated to OS levels. Individual patients MDA and TAOA before and after the hemodialysis sessions demonstrated a clear and systematic increase of the OS after HD (P-value=0.03). Correlation of BOLD-fMRI maximal signal intensity and volume of activated cortical brain area behaviors to MDA and total TAOA were close to 1. CONCLUSION: OS is systematically increased in HD-patients after the HD-process. Indeed, the BOLD-fMRI shows a remarkable sensitivity to brain plasticity studied cortical areas. Our results confirm the superiority of the BOLD-fMRI quantities compared to the biological method used for assessing the OS while not being specific, and reflect the increase in OS generated by the HD. BOLD-fMRI is expected to be a suitable tool for evaluating the plasticity process evolution in hemodialysis brain patients. PMID- 25522723 TI - Time course of IL-15 expression after acute resistance exercise in trained rats: effect of diabetes and skeletal muscle phenotype. AB - Type 1 diabetes is associated with skeletal muscle atrophy. Skeletal muscle is an endocrine organ producing myokines such as interleukin-15 (IL-15) and interleukin 6 (IL-6) in response to contraction. These factors may mediate the effects of exercise on skeletal muscle metabolism and anabolic pathways. Lack of correlation between muscle IL-15 mRNA and protein levels after exercise training has been observed, while regulatory effects of IL-6 on IL-15 expression have also been suggested. This study determined post-exercise changes in muscle IL-15 and IL-6 mRNA expression and IL-15 protein levels in healthy and streptozotocin-induced diabetic rats in both the fast flexor hallucis longus (FHL) and slow soleus muscles. Resistance training preserved FHL muscle weight in diabetic rats and increased IL-15 protein levels in both the soleus and FHL muscles. However, the temporal pattern of this response was distinct in normal and diabetic rats. Moreover, discordance between post-exercise muscle IL-15 mRNA and protein expression was observed in our study, and diabetes suppressed post-exercise increases in FHL muscle IL-6 mRNA expression. Our study indicates that training, skeletal muscle phenotype, and metabolic status all influence the temporal pattern of post-exercise changes in IL-15 expression. Muscle IL-15 protein levels increase following training, suggesting this may be an adaptation contributing to increased capacity for secretion of this myokine that is not depressed by the diabetic state. PMID- 25522724 TI - Frequency of nodular goiter and autoimmune thyroid disease in patients with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS), and nodular and autoimmune thyroid diseases are frequently seen disorders. Previous studies reported conflicting results regarding possible association between PCOS and thyroid disorders. In this study, we investigated the frequency of autoimmune thyroid disease (AITD) and nodular goiter in patients with PCOS. Seventy-three PCOS patients and 60 age-matched controls were enrolled in the study. In PCOS group, body mass index values (27.45 +/- 5.73 vs. 22.55 +/- 3.78 kg/m(2), p < 0.001, respectively), systolic [110 mmHg (90-130) vs. 100 mmHg (90-140), p = 0.016, respectively] and diastolic (72.67 +/- 6.52 vs. 66.42 +/- 8.88 mmHg, p < 0.001, respectively) blood pressure, waist circumference (86.27 +/- 14.41 vs. 78.78 +/- 8.87 cm, p < 0.001, respectively), and homeostasis model assessment-insulin resistance (HOMA-IR) levels (2.96 +/- 2.11 and 1.77 +/- 0.83 p < 0.001, respectively) were higher than controls. However, thyroid nodule frequency was similar in both groups [22 (30.1 %) vs. 12 (20 %)], also thyroid gland volume was not significantly different [9.23 ml (3.08 32.40) vs. 8.52 ml (4.28-50.29)] among groups. The percentages of patients with thyroid parenchymal heterogeneity, positive anti-thyroid peroxidase, anti thyroglobulin, and AITD were similar. Cases were reclassified according to the presence of thyroid nodule in which similar HOMA-IR levels were detected (median 2.39 and 1.89, p = 0.093, respectively) despite the fact that the group with nodules had higher mean age (26.5 (18-37) vs. 21 (18-34), p = 0.013, respectively). Similar ratios of thyroid nodule and AITD were found in patients with PCOS and controls. PMID- 25522725 TI - The use of random projections for the analysis of mass spectrometry imaging data. AB - The 'curse of dimensionality' imposes fundamental limits on the analysis of the large, information rich datasets that are produced by mass spectrometry imaging. Additionally, such datasets are often too large to be analyzed as a whole and so dimensionality reduction is required before further analysis can be performed. We investigate the use of simple random projections for the dimensionality reduction of mass spectrometry imaging data and examine how they enable efficient and fast segmentation using k-means clustering. The method is computationally efficient and can be implemented such that only one spectrum is needed in memory at any time. We use this technique to reveal histologically significant regions within MALDI images of diseased human liver. Segmentation results achieved following a reduction in the dimensionality of the data by more than 99% (without peak picking) showed that histologic changes due to disease can be automatically visualized from molecular images. PMID- 25522726 TI - Focus on harsh environment and field-portable mass spectrometry: editorial. PMID- 25522728 TI - Corrigendum. PMID- 25522727 TI - Multiple antigenic polypeptide composed of heparanase B-cell epitopes shrinks human hepatocellular carcinoma in mice. AB - The purpose of this study was to evaluate the anti-growth effect of the self designed multiple antigenic polypeptide (MAP) vaccine comprising B-cell epitopes of heparanase (HPSE) on HCC97-H hepatocellular carcinoma (HCC) in mice. The polyclonal antibodies against the B-cell epitopes of HPSE were prepared by immunizing rabbits with freshly synthesized MAP vaccine. HCC-bearing models were constructed on BALB/c nude mice. Anti-MAP antibodies were administrered to the models to assess the effects on HPSE activity, HCC growth, the expression of VEGF/bFGF and the value of micro-vessel density (MVD). The anti-MAP antibodies were harvested, purified and identified. These antibodies were able to specifically bind with the dominant epitopes of the precursor protein and large subunit monomer of HPSE, decrease HPSE activity, suppress the expressions of VEGF and bFGF, reduce the MVD, and markedly shrink the HCC volume. Based on these findings, MAP vaccine based on the B-cell epitopes of HPSE seemed to provide theoretical evidence for further study of the synthesized HPSE MAP vaccine in the treatment of HCC. PMID- 25522729 TI - Symptom variation on the trauma symptom checklist for children: a within-scale meta-analytic review. AB - Trauma exposure in youth is widespread, yet symptom expression varies. The present study employs a within-scale meta-analytic framework to explore determinants of differential responses to trauma exposure. The meta-analysis included 74 studies employing samples of youth exposed to traumatic events and who completed the Trauma Symptom Checklist for Children (TSCC). Mean weighted T scores across all TSCC subscales for U.S. samples ranged between 49 and 52. Youth outside the U.S. reported higher posttraumatic stress, anxiety, and depressive symptoms, whereas those exposed to sexual abuse reported the highest posttraumatic stress, anxiety, depressive, and dissociative symptoms. Higher female representation in samples was associated with higher symptoms on all TSCC subscales except anger. In contrast, ethnic minority representation was associated with lower depressive symptoms. Moderator analyses revealed that sexual abuse, increased percentage of females, and older age were all associated with higher posttraumatic symptoms. The present meta-analytic results help elucidate some of the divergent findings on symptom expression in youth exposed to traumatic events. PMID- 25522730 TI - Psychophysiological predictors of working alliance among treatment-seeking women with complex trauma exposure. AB - Research has established that trauma-related symptoms may impede the formation of a strong working alliance (i.e., interpersonal connection, trust, and shared goals between therapist and client). As the alliance is critical in trauma focused therapy, we studied how clients' pretherapy factors, including symptoms and psychophysiological arousal, predict treatment alliance. We examined symptoms and physiological responses in 27 women who had exposure to extreme interpersonal violence; all of whom were enrolled in therapy. All had symptoms consistent with a diagnosis of posttraumatic stress disorder. Clients completed measures of working alliance and were assessed before and after treatment on measures of symptoms and autonomic arousal. Autonomic assessment included measures of skin conductance and respiratory sinus arrhythmia (RSA), taken during baseline, while viewing positive and then trauma-related slides, and during recovery. Higher alliance ratings were predicted by lower pretherapy skin conductance during trauma slides (r = -.41, p = .049) and recovery (r = -.44, p = .047) and higher RSA during baseline (r = .47, p = .027) and positive slides (r = .43, p = .044). Findings remained significant even after partialling pretherapy symptoms. These data on a high-need but understudied population suggest that sympathetic and parasympathetic arousal may help traumatized clients effectively engage in therapy, further supporting the role of parasympathetic activity in social engagement. PMID- 25522731 TI - Online self-administered training of PTSD treatment providers in cognitive behavioral intervention skills: results of a randomized controlled trial. AB - Despite potential advantages in scalability and efficiency of web-based training for trauma providers, few controlled trials of feasibility and effectiveness of web-based mental health training have been performed. Our study compared web based training in 3 intervention skills (motivation enhancement [ME], goal setting [GS], behavioral task assignment [BTA]) with web-based training plus telephone consultation, and a no-training control. The primary outcome measures included objective measures of skills acquisition (standardized patient assessments). Results showed significant differences among the training conditions. The overall tests of differences among the groups were statistically significant for ME and BTA skills (p < .001 and p = .005, respectively), but not for GS (p = .245). The web training plus consultation group improved in ME skills by 0.35 units compared to 0.12 units in the web only group (p < .001) and no change in the control group (p = .001). For BTA skills, the web training plus consultation improved by 0.27 units compared to 0.17 units in the web only group (p = .175) and no change in the control group (p = .004). Overall, these findings support the use of web-based dissemination for large-scale training programs for trauma providers in health care delivery systems. Further studies are needed to clarify the specific role of consultation as an adjunct to web-based training. PMID- 25522732 TI - Iron nanoparticles significantly affect the in vitro and in vivo expression of Id genes. AB - In recent DNA microarray studies, we found that the transcription of the Id3 gene was significantly down-regulated in five cell lines (RAW264.7, Hepa1-6, THP-1, HepG2, and HL7702) treated with two doses (50 and 100 MUg/mL) of a DMSA-coated magnetite nanoparticle. Given the regulatory roles of Id genes in the cell cycle, growth, and differentiation, we wanted to do more investigations on the effect of the nanoparticle upon the Id genes. This study detected the expression of Id genes in six cell lines (the above cell lines plus HeLa) treated with the nanoparticle at the same doses using quantitative PCR. The results revealed that the expression of Id genes was significantly affected by the nanoparticle in these cell lines. Under each treatment, the Id3 gene was significantly (p < 0.01) down-regulated in all cell lines, the Id1 gene was significantly down-regulated in all cell lines except the RAW264.7 cells, and the Id2 gene was significantly down-regulated in the HepG2, HL7702, and HeLa cells. Because the Id1, Id2, and Id3 genes were significantly down-regulated in three liver-derived cell lines (Hepa1-6, HepG2, and HL7702) in both microarray and PCR detections, this study then detected the expression of Id genes in the liver tissues of mice that were intravenously injected with the nanoparticle at two doses (2 and 5 mg/kg body weight). The results revealed that the expression of Id1, Id2, and Id3 genes was also significantly down-regulated in the liver tissues under each treatment. Another Id gene, Id4, was also significantly regulated in some cells or liver tissues treated with the nanoparticle. These results reveal that the nanoparticle exerts a significant effect on the in vitro and in vivo expression of Id genes. This study thus provides new insights into the Id-related nanotoxicity of the nanoparticle and the close relationship between the regulation of Id genes and iron. PMID- 25522733 TI - Identification and functional characterization of Siberian wild rye (Elymus sibiricus L.) small heat shock protein 16.9 gene (EsHsp16.9) conferring diverse stress tolerance in prokaryotic cells. AB - Small heat shock proteins (Hsps) protect against stress-inducible denaturation of substrates. Our objectives were to clone and examine the mRNA expression of the Hsp16.9 gene from Siberian wild rye grown under diverse stress treatments. We characterized EsHsp16.9 from Elymus sibiricus L. EsHsp16.9 has a 456-bp open reading frame that encodes a 151-amino acid protein with a conserved alpha crystallin domain. Northern blot analysis showed that EsHsp16.9 transcripts were enhanced by heat, drought, arsenate, methyl viologen, and H2O2 treatment. In addition, recombinant EsHsp16.9 protein acts as a molecular chaperone to prevent the denaturation of malate dehydrogenase. Growth of cells overexpressing EsHsp16.9 was up to 200% more rapid in the presence of NaCl, arsenate, and polyethylene glycol than that of cells harboring an empty vector. These data suggest that EsHsp16.9 acts as a molecular chaperone that enhances stress tolerance in living organisms. PMID- 25522734 TI - Xylose fermentation as a challenge for commercialization of lignocellulosic fuels and chemicals. AB - Fuel ethanol production from lignocellulosic materials is at a level where commercial biofuel production is becoming a reality. The solubilization of the hemicellulose fraction in lignocellulosic-based feedstocks results in a large variety of sugar mixtures including xylose. However, allowing xylose fermentation in yeast that normally is used for fuel ethanol production requires genetic engineering. Moreover, the efficiency of lignocellulosic pretreatment, together with the release and generation of inhibitory compounds in this step, are some of the new challenges faced during second generation ethanol production. Successful advances in all these aspects will improve ethanol yield, productivity and titer, which will reduce the impact on capital and operating costs, leading to the consolidation of the fermentation of lignocellulosic biomass as an economically feasible option for the production of renewable fuels. Therefore the development of yeast strains capable of fermenting a wide variety of sugars in a highly inhibitory environment, while maintaining a high ethanol yield and production rate, is required. This review provides an overview of the current status in the use of xylose-engineered yeast strains and describes the remaining challenges to achieve an efficient deployment of lignocellulosic-based ethanol production. PMID- 25522735 TI - Cortical phase changes measured using 7-T MRI in subjects with subjective cognitive impairment, and their association with cognitive function. AB - Studies have suggested that, in subjects with subjective cognitive impairment (SCI), Alzheimer's disease (AD)-like changes may occur in the brain. Recently, an in vivo study has indicated the potential of ultra-high-field MRI to visualize amyloid-beta (Abeta)-associated changes in the cortex in patients with AD, manifested by a phase shift on T2 *-weighted MRI scans. The main aim of this study was to investigate whether cortical phase shifts on T2 *-weighted images at 7 T in subjects with SCI can be detected, possibly implicating the deposition of Abeta plaques and associated iron. Cognitive tests and T2 *-weighted scans using a 7-T MRI system were performed in 28 patients with AD, 18 subjects with SCI and 27 healthy controls (HCs). Cortical phase shifts were measured. Univariate general linear modeling and linear regression analysis were used to assess the association between diagnosis and cortical phase shift, and between cortical phase shift and the different neuropsychological tests, adjusted for age and gender. The phase shift (mean, 1.19; range, 1.00-1.35) of the entire cortex in AD was higher than in both SCI (mean, 0.85; range, 0.73-0.99; p < 0.001) and HC (mean, 0.94; range, 0.79-1.10; p < 0.001). No AD-like changes, e.g. increased cortical phase shifts, were found in subjects with SCI compared with HCs. In SCI, a significant association was found between memory function (Wechsler Memory Scale, WMS) and cortical phase shift (beta = -0.544, p = 0.007). The major finding of this study is that, in subjects with SCI, an increased cortical phase shift measured at high field is associated with a poorer memory performance, although, as a group, subjects with SCI do not show an increased phase shift compared with HCs. This increased cortical phase shift related to memory performance may contribute to the understanding of SCI as it is still unclear whether SCI is a sign of pre-clinical AD. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25522737 TI - A Minimal tight-binding model for ferromagnetic canted bilayer manganites. AB - Half-metallicity in materials has been a subject of extensive research due to its potential for applications in spintronics. Ferromagnetic manganites have been seen as a good candidate, and aside from a small minority-spin pocket observed in La(2-2x)Sr(1+2x)Mn(2)O(7) (x = 0.38), transport measurements show that ferromagnetic manganites essentially behave like half metals. Here we develop robust tight-binding models to describe the electronic band structure of the majority as well as minority spin states of ferromagnetic, spin-canted antiferromagnetic, and fully antiferromagnetic bilayer manganites. Both the bilayer coupling between the MnO2 planes and the mixing of the |x(2) - y(2) > and |3 z(2) - r(2) > Mn 3d orbitals play an important role in the subtle behavior of the bilayer splitting. Effects of kz dispersion are included. PMID- 25522736 TI - Microbe-associated molecular pattern-induced calcium signaling requires the receptor-like cytoplasmic kinases, PBL1 and BIK1. AB - BACKGROUND: Plant perception of conserved microbe-derived or damage-derived molecules (so-called microbe- or damage-associated molecular patterns, MAMPs or DAMPs, respectively) triggers cellular signaling cascades to initiate counteracting defence responses. Using MAMP-induced rise in cellular calcium levels as one of the earliest biochemical readouts, we initiated a genetic screen for components involved in early MAMP signaling in Arabidopsis thaliana. RESULTS: We characterized here the "changed calcium elevation 5" (cce5) mutant, where five allelic cce5 mutants were isolated. They all show reduced calcium levels after elicitation with peptides representing bacteria-derived MAMPs (flg22 and elf18) and endogenous DAMP (AtPep1), but a normal response to chitin octamers. Mapping, sequencing of the mutated locus and complementation studies revealed CCE5 to encode the receptor-like cytoplasmic kinase (RLCK), avrPphB sensitive 1-like 1 (PBL1). Kinase activities of PBL1 derived from three of the cce5 alleles are abrogated in vivo. Validation with T-DNA mutants revealed that, besides PBL1, another RLCK, Botrytis-induced kinase 1 (BIK1), is also required for MAMP/DAMP induced calcium elevations. CONCLUSIONS: Hence, PBL1 and BIK1 (but not two related RLCKs, PBS1 and PBL2) are required for MAMP/DAMP-induced calcium signaling. It remains to be investigated if the many other RLCKs encoded in the Arabidopsis genome affect early calcium signal transduction - perhaps in dependence on the type of MAMP/DAMP ligands. A future challenge would be to identify the substrates of these various RLCKs, in order to elucidate their signaling role between the receptor complexes at the plasma membrane and downstream cellular signaling components. PMID- 25522738 TI - Brain protection conferred by long-term administration of 2-(2-benzofuranyl)-2 imidazoline against experimental autoimmune encephalomyelitis. AB - Our previous studies showed that 2-(2-benzofuranyl)-2-imidazoline (2-BFI), a ligand to type 2 imidazoline receptor, was protective against brain and spinal cord injury caused by experimental autoimmune encephalomyelitis (EAE). In the present study, we investigated the effect of long-term administration of 2-BFI and the dose-dependent response relationship of long-term administration of 2-BFI with neuroprotection. Treatment with 2-BFI at doses of 5, 10, and 20 mg/kg for 14 days significantly reduced hind limb paralysis and the severity of EAE compared with the EAE control group. Long-term use of 2-BFI was not only safe to mice, but also dose-dependently reduced the expression of inflammatory cytokines, including TNF-alpha, Interferon-gamma and Interleukin-17A, compared with the EAE control group. Expressions of neuronal injury markers, including cytochrome c, AIF and beta-APP, were also reduced significantly in response to long-term 2-BFI treatment. Together, these results provided new evidence to demonstrate that 2 BFI is a safe and effective candidate for further development as a therapeutic drug for treatment of multiple sclerosis. PMID- 25522739 TI - CD4+ lymphocyte adenosine triphosphate--a new marker in sepsis with acute kidney injury? AB - BACKGROUND: AKI frequently develops in sepsis patients, significantly decreasing the overall prognosis. There are currently no diagnostic markers available which reliably predict the prognosis of sepsis-associated AKI. Recently, ATP content of CD4+ T cells (ATP_CD4) has been shown to correlate with survival in sepsis. The aim of the study was to determine ATP_CD4 in sepsis-associated AKI. METHODS: Thirty-three patients with sepsis were prospectively analyzed for ATP_CD4 at three different time points. Results were related to survival, renal recovery, and further clinical/laboratory findings. RESULTS: ATP_CD4 tended to lower in concentration at 48 h after onset of sepsis in those patients with complete renal recovery. There were no differences between patients with no AKI and those with AKI of different severity (AKIN 1-3). Urinary NGAL did not correlate with renal prognosis. CONCLUSION: ATP_CD4 may serve as risk predictor in sepsis-associated AKI. Lower concentrations may indicate a higher chance of complete renal recovery in sepsis. PMID- 25522740 TI - Once upon a time the cell membranes: 175 years of cell boundary research. AB - All modern cells are bounded by cell membranes best described by the fluid mosaic model. This statement is so widely accepted by biologists that little attention is generally given to the theoretical importance of cell membranes in describing the cell. This has not always been the case. When the Cell Theory was first formulated in the XIX(th) century, almost nothing was known about the cell membranes. It was not until well into the XX(th) century that the existence of the plasma membrane was broadly accepted and, even then, the fluid mosaic model did not prevail until the 1970s. How were the cell boundaries considered between the articulation of the Cell Theory around 1839 and the formulation of the fluid mosaic model that has described the cell membranes since 1972? In this review I will summarize the major historical discoveries and theories that tackled the existence and structure of membranes and I will analyze how these theories impacted the understanding of the cell. Apart from its purely historical relevance, this account can provide a starting point for considering the theoretical significance of membranes to the definition of the cell and could have implications for research on early life. PMID- 25522741 TI - Ancillary benefits of antenatal ultrasound: an association between the introduction of a low-cost ultrasound program and an increase in the numbers of women receiving recommended antenatal treatments. AB - BACKGROUND: In June of 2010, an antenatal ultrasound program was introduced to perform basic screening examinations at a health care clinic in rural Uganda. The impact of the program on the existing antenatal care infrastructure including the proportion and number of women receiving recommended antenatal care at clinic visits was unknown. The aim of this study was to investigate the relationship between the advent of the ultrasound program and the proportion of women receiving recommended antenatal interventions at their clinic visits. Change in the absolute numbers of antenatal services provided was also assessed. METHODS: Records at the Nawanyago clinic were reviewed to determine the total numbers of women receiving specific interventions before and after the advent of the ultrasound program including HIV testing, intermittent preventive therapy for malaria, presumptive anti-parasitic treatment, and provision of iron and folate for anemia. The rate at which these interventions were provided (number of interventions per clinic visit) was also assessed. The differences in absolute numbers of antenatal interventions before and after the introduction of the ultrasound program were assessed using the Wilcoxon rank-sum test. Differences in intervention rate were assessed using negative binomial regression modeling. RESULTS: The mean monthly numbers of women receiving each of these interventions increased significantly with the greatest increase seen in numbers of women receiving anemia and deworming treatments at +113% and +102% respectively (p < 0.001). The intervention rate increased for anemia treatment, deworming treatment, and 2nd dose of intermittent preventive therapy for malaria. A slight decrease in intervention rate was observed for 1st dose of malaria treatment with a rate ratio of 0.88 (0.79 - 0.98, 95% CI). Intervention rate for HIV testing was not significantly changed. CONCLUSION: The introduction of a low-cost antenatal ultrasound program at a health care clinic in rural Uganda was associated with increases in the number of women receiving specific recommended antenatal care interventions. Effect on intervention rates was mixed but showed an overall increase. The use of ultrasound in this context may provide a benefit to the maternal and neonatal health of the community. PMID- 25522743 TI - Immediate effect of three different electroacupuncture protocols on fasting blood glucose in obese patients: a pilot study. AB - BACKGROUND: Obesity is an increasing global health problem, and current methods of management are limited. Preliminary research data suggest that acupuncture may have an influence on metabolic parameters related to obesity. OBJECTIVE: To determine the electroacupuncture (EA) protocol to be used in a future clinical trial examining the effect of acupuncture on metabolic parameters related to obesity and to examine whether a single EA treatment can change fasting blood glucose in obese subjects. METHODS: 16 obese women aged 30-52 years with body mass index >30 kg/m(2) were assigned consecutively into three groups and their fasting blood glucose was measured before and after administering a single session, lasting 30 min, of one of three EA treatment protocols. The Dorsal group received EA to dorsal segmental acupuncture points BL18-23 bilaterally (corresponding to the segmental levels innervating the pancreas); the Ear group received EA to ear points in the cavum conchae; and the Limb group received EA to points in the arms and legs (LI10-LI11, ST36-Zongping). RESULTS: After a single session of EA there was a statistically significant decrease in fasting blood glucose in the Dorsal and Limb groups, but there was no change and even a trend towards an increase in the glucose level in the Ear group. CONCLUSIONS: The findings of this small pilot study suggest that EA to either dorsal segmental points corresponding to the pancreas or to muscle points in all four limbs may exert a beneficial effect on glucose metabolism in obese women. PMID- 25522744 TI - Plasma lipid profile in Nigerians with high--normal blood pressure. AB - BACKGROUND: High blood pressure levels have been associated with elevated atherogenic blood lipid fraction, but epidemiological surveys often give inconsistent results across population sub-groups. To determine the extent to which there are differences in lipid profile based on blood pressure levels, we assessed lipid profile of subjects with high-normal blood pressure and compared with those of hypertensives and optimally normal blood pressure. METHODS: The study was a cross-sectional comparative study conducted at Aminu Kano Teaching Hospital, Kano, Nigeria. Fasting lipid levels were examined among randomly selected patients with optimally normal blood pressure (group 1), high-normal blood pressure (group 2) and those with hypertension (group 3). Optimal blood pressure was defined as systolic blood pressure (SBP) of <120 mmHg/or diastolic blood pressure (DBP) of <80 mmHg; and high-normal blood pressure as SBP of 130 139 mmHg and/or DBP of 85-89 mmHg. RESULTS: A total of 300 subjects were studied, 100 in each group. The mean age of subjects in group 1 was 27.32+/-8.20 years and 60% were female, while that of group 2 was 34.04+/-6.25 years, and 53% were female, and that for group 3 was 52.81+/-13.3 years and 56% were female. The mean total cholesterol (TC) for subjects in group1 (3.96+/-0.40 mmol/L) was significantly lower than levels in group2 (4.55+/-1.01 mmol/L); P=<0.001. Subjects in group 3 (5.20+/-1.88 mmol/L), however had statistically significant higher mean TC when compared with group 2; (P=0.03). The difference between the groups for low density lipoprotein cholesterol (LDL-C) and triglycerides (TG) followed the same pattern as that of TC, with statistically significant increasing trend across the blood pressure categories. Levels of high density lipoprotein cholesterol (HDL-C) were however similar across the three groups (group 2 versus group 1; P=0.49, group 2 versus group 3; P=0.9). Increased TC (>5.2 mmol/L) was absent in group1, but found among 11% of group2 subjects and 40% of those in group 3 (P-value for trend<0.001). Mean fasting plasma glucose (FPG) was 3.8+/-0.4 mmol/L, 4.7+/-1.1 mmol/L, 5.1+/-1.9 mmol/L and for subjects in groups 1, 2 and 3 respectively (p>0.05 for groups 2 Vs 1 and p<0.001 for groups 2 Vs 3). The differences in mean body mass index (BMI) between the groups followed a similar trend as that of FPG. Multivariate logistic regression analysis showed that FPG, TG and BMI were the strongest predictors of prehypertension [odds ratio (OR) 10.14, 95% CI (confidence interval) 3.63-28.33, P=0.000; OR 5.75, 95% CI 2.20-15.05, P=0.000; and OR 2.03, 95% CI 1.57-2.62, P=0.000 respectively]. CONCLUSION: The study has shown a significant increase in plasma TC, LDL-C and TG values as blood pressure levels increased from optimally normal, across high-normal to hypertensive levels. There was a similar trend for FPG and BMI, demonstrating the central role that blood pressure plays in these metabolic disorders in Nigerians. These findings are relevant in terms of both prevention and treatment of cardiovascular morbidities and mortality. PMID- 25522745 TI - First-in-man analysis of the i-cor assist device in patients with cardiogenic shock. AB - OBJECTIVE: In patients with refractory cardiogenic shock (CS) mechanical assistance by venous-arterial extracorporeal membrane oxygenation (VA-ECMO) therapy may be considered to reach haemodynamic stabilization. In this first-in man study, we analysed the applicability of the new i-cor VA-ECMO assist device equipped with a diagonal pump system. METHODS AND RESULTS: In total, 15 patients with refractory CS were treated with the i-cor assist device in three tertiary care centres. In 71%, CS was due to acute myocardial infarction (AMI). At baseline, patients were hypotensive (systolic/diastolic blood pressure 97 +/- 4/62 +/- 4 mm Hg) despite high doses of catecholamines. Under ECMO therapy, a significant reduction in vasopressor therapy and serum lactate levels was observed (norepinephrine: 0.69 +/- 0.1 ug/kg/min at baseline vs 0.21 +/- 0.08 ug/kg/min on the last day of treatment, p<0.0001; serum lactate: 6.7 +/- 1.4 mmol/l at baseline versus 1.3 +/- 0.1 mmol/l on the last day, p<0.001). Inspiratory oxygen concentration was significantly reduced during the course of VA-ECMO support (80.4 +/- 7.0% at baseline vs 42.7 +/- 2.4% on final day; p<0.001). At baseline, three patients (20%) were on continuous haemodialysis treatment. Of the 12 patients without haemodialysis at baseline, only one patient required haemodialysis during the course of ECMO treatment. Glomerular filtration rate (GFR) significantly increased with treatment (41.2 +/- 7.4 at baseline vs 69.0 +/- 10.8 on last day; p=0.006). Bleeding at the insertion site was recorded in two patients (13.3%). Overall, 11 patients (73.3%) needed blood transfusion. Three patients (20%) developed signs of limb ischaemia that were fully reversible. Haemolysis was recorded in five patients (33%). None of the complications required the interruption of ECMO therapy. Overall mortality was 33.3% (five patients); two patients died during, and three patients after, ECMO therapy. CONCLUSION: This first-in-man analysis suggests that the i-cor ECMO device is successfully applicable in humans. The data set the stage for further evaluation of this novel system and provide the necessary basis to design randomised evaluations. PMID- 25522746 TI - Combining therapeutic hypothermia and emergent coronary angiography in out-of hospital cardiac arrest survivors: Optimal post-arrest care for the best patient. AB - BACKGROUND: Aggressive post-resuscitation care, in particular combining mild therapeutic hypothermia (MTH) with early coronary angiography (CAG) and percutaneous coronary intervention (PCI), may improve prognosis after out-of hospital cardiac arrest (OHCA). OBJECTIVES: The study aims to assess the value of immediate CAG or PCI in comatose survivors after OHCA treated with MTH and their association with outcomes. METHODS: Observational, prospective analysis of all comatose, resuscitated patients treated with MTH at a tertiary centre and undergoing CAG or PCI <=6 hours after OHCA, or non-invasively managed. Primary outcomes were 30-day and 1-year survival. RESULTS: From March 2004-December 2012, 141 (51%) out of 278 comatose patients after cardiac OHCA were treated with MTH (median age: 64.5 (interquartile range 55-73) years, males: 67%, first shockable rhythm: 70%, witnessed OHCA: 94%, interval OHCA-resuscitation <=20 min: 81%). Ninety-seven patients (69%) underwent early CAG, and 45 (32%) of them PCI. Patients undergoing CAG or PCI had a more favourable risk profile than subjects non-invasively managed. PCI treated patients had more bleedings, but no stent thrombosis occurred. Thirty-day and one-year unadjusted total mortality rates were 50% and 72% for non-invasively managed patients, 26% and 38.7% for patients submitted only to CAG and 32% and 36.6% for patients treated with PCI (p=0.0435 for early death, and p<0.0001 for one-year mortality, respectively). However, a propensity-matched score analysis did not confirm the survival advantage of invasive management (p=0.093). At multivariable analysis, clinical and OHCA related variables as well as CAG, but not PCI, were associated with outcomes. CONCLUSIONS: Comatose patients cooled after OHCA and submitted to emergency CAG or PCI are a favourable outcome population that receives optimal post-arrest care. PMID- 25522747 TI - Response to letter to the editor, "Clinical trial registration in oral health journals". PMID- 25522748 TI - Letter to the editor, "Clinical trial registration in oral health journals". PMID- 25522749 TI - Aberrant expression of long noncoding RNAs in chronic thromboembolic pulmonary hypertension. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the primary causes of severe pulmonary hypertension. In order to identify long noncoding RNAs (lncRNAs) that may be involved in the development of CTEPH, comprehensive lncRNA and messenger RNA (mRNA) profiling of endothelial tissues from the pulmonary arteries of CTEPH patients was conducted with microarray analysis. Differential expression of 185 lncRNAs was observed in the CTEPH tissues compared with healthy control tissues. Further analysis identified 464 regulated enhancer-like lncRNAs and overlapping, antisense or nearby mRNA pairs. Coexpression networks were subsequently constructed and investigated. The expression levels of the lncRNAs, NR_036693, NR_027783, NR_033766 and NR_001284, were significantly altered. Gene ontology and pathway analysis demonstrated the potential role of lncRNAs in the regulation of central process, including inflammatory response, response to endogenous stimulus and antigen processing and presentation. The use of bioinformatics may help to uncover and analyze large quantities of data identified by microarray analyses, through rigorous experimental planning, statistical analysis and the collection of more comprehensive data regarding CTEPH. The results of the present study provided evidence which may be helpful in future studies on the diagnosis and management of CTEPH. PMID- 25522750 TI - A 6-year follow-up study of adult patients with congenitally corrected transposition. AB - The aims of this study were to assess the development of heart failure in patients with congenitally corrected transposition of the great arteries in a medium-term follow-up, to identify the impact of tricuspid regurgitation on the development of heart failure, and to determine the most reliable marker for its identification. The prospective 6-year follow-up study included 19 adult patients. All patients were evaluated clinically by the determination of N terminal pro-hormone brain natriuretic peptide levels, exercise stress testing, echocardiography magnetic resonance, or CT. Among them, two patients died of heart failure. There was a decline in exercise capacity and systolic systemic ventricular function (p=0.011). Systemic ventricular ejection fraction decreased (48.3+/-13.7 versus 42.7+/-12.7%, p=0.001). Tissue Doppler imaging showed a decline in peak tricuspid systolic annular velocity (10.3+/-2.0 versus 8.3+/-2.5 cm/second, p=0.032) and peak tricuspid early diastolic annular velocity (14.6+/ 4.3 versus 12.0+/-4.5 cm/second, p=0.048). The tricuspid regurgitation did not increase significantly. N-terminal pro-hormone brain natriuretic peptide levels increased (127.0 ng/L(82.3-305.8) versus 226.0 ng/L(112.5-753.0), p=0.022). Progressive exercise intolerance in congenitally corrected transposition of the great arteries appears to be driven mainly by a progression in systemic right ventricular dysfunction. Tricuspid regurgitation is likely to play a role, especially in patients with structural abnormalities of the tricuspid valve - Ebstein anomaly. The N-terminal pro-hormone brain natriuretic peptide levels and tissue Doppler parameters appear sensitive in detecting changes over time and may guide management. PMID- 25522752 TI - Transcatheter left atrial appendage occlusion in the prevention of stroke and death in patients with atrial fibrillation. PMID- 25522751 TI - Pooled PCR testing strategy and prevalence estimation of submicroscopic infections using Bayesian latent class models in pregnant women receiving intermittent preventive treatment at Machinga District Hospital, Malawi, 2010. AB - BACKGROUND: Low malaria parasite densities in pregnancy are a diagnostic challenge. PCR provides high sensitivity and specificity in detecting low density of parasites, but cost and technical requirements limit its application in resources-limited settings. Pooling samples for PCR detection was explored to estimate prevalence of submicroscopic malaria infection in pregnant women at delivery. Previous work uses gold-standard based methods to calculate sensitivity and specificity of tests, creating a challenge when newer methodologies are substantially more sensitive than the gold standard. Thus prevalence was estimated using Bayesian latent class models (LCMs) in this study. METHODS: Nested PCR (nPCR) for the 18S rRNA gene subunit of Plasmodium falciparum was conducted to detect malaria infection in microscopy-negative Malawian women on IPTp. Two-step sample pooling used dried blood spot samples (DBSs) collected from placenta or periphery at delivery. Results from nPCR and histology as well as previously published data were used to construct LCMs to estimate assay sensitivity and specificity. Theoretical confidence intervals for prevalence of infection were calculated for two-step and one-step pooling strategies. RESULTS: Of 617 microscopy-negative Malawian women, 39 (6.3%) were identified as actively infected by histology while 52 (8.4%) were positive by nPCR. One hundred forty (22.7%) individuals had past infection assessed by histology. With histology as a reference, 72% of women in the active infection group, 7.1% in the past infection group and 3.2% in histology-negative group were nPCR positive. Using latent class models without a gold standard, histology had a median sensitivity of 49.7% and specificity of 97.6% for active infection while PCR had a median sensitivity of 96.0% and specificity of 99.1%. The true prevalence of active infection was estimated at 8.0% (CI: 5.8-10.5%) from PCR. PCR also had similar sensitivity for detecting either peripheral or placental malaria for submicroscopic infections. One-step pooling would give similar confidence intervals for pool sizes less than 20 while reducing the number of tests performed. CONCLUSIONS: Pooled nPCR testing was a sensitive and resource-efficient strategy and LCMs provided precise prevalence estimates of submicroscopic infections. Compared to two-step pooling, one-step pooling could provide similar prevalence estimates at population levels with many fewer tests required. PMID- 25522753 TI - Influence of left atrial size on the outcome of pulmonary vein isolation in patients with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most frequent sustained supraventricular tachyarrhythmia. Radiofrequency (RF) ablation is one of the options used to prevent the recurrence of AF. Despite thorough studies, the relation between left atrial (LA) size and the results of RF ablation remains controversial. AIM: To estimate the relation between LA size assessed by echocardiography and the AF recurrence rate after pulmonary vein isolation (PVI). METHODS: Our analysis comprised 175 AF patients subjected to PVI between June 2011 and March 2012. Inclusion criteria comprised: symptomatic AF with no reversible cause, and age < 70, LA < 5.5 cm (anteroposterior). PVI was performed with a 4-mm non-irrigated catheter or irrigated catheter and circular mapping catheter (electroanatomic mapping with LocaLisa or CARTO systems). Recurrence was defined as any atrial tachyarrhythmia episode that lasted more than 30 s after three months of blanking period. Standard echocardiographic post-ablation anteroposterior LA measurements were performed with additional parameters such as systolic and diastolic LA area and volume (on sinus rhythm). RESULTS: The analysis included 198 procedures performed in 175 patients. Median follow-up time was 17 months. Median age was 56 years. After the first procedure, AF recurred in 88 (52.4%) patients. Efficacy after the last procedure was 55.2% (43.5% for persistent AF and 59.7% for paroxysmal AF). No significant relation between any of the LA parameters and the recurrence rate was found. Cox univariate and multivariate analysis revealed only very early AF recurrence as a prognostic factor for AF recurrence in the long term. CONCLUSIONS: In patients with AF, no relation could be observed between the recurrence rate after PVI and the echocardiographic LA measurement parameters. PMID- 25522754 TI - Subclinical left atrium remodelling in patients with frequent premature ventricular contractions. AB - BACKGROUND: Premature ventricular contractions (PVCs) may cause subtle changes in left atrium (LA) structure and function which may not be readily detected by conventional parameters. AIM: To explore the relationship between PVCs and LA shape and size remodelling in patients without known structural heart disease. METHODS: PVC frequency per 24 h was divided into tertiles. Echocardiographic measurements included left ventricular ejection fraction (LVEF) and volume, LA volume (LAV), mid-LA transverse diameter (LAt), and basal LA maximal transverse diameter (LAb). Trapezoidal LA shape was defined by LAt less than LAb. The association between PVCs and LA shape was explored by multivariable adjusted logistic regression. RESULTS: The 121 patients had a mean age of 43.1 years (63% male) and mean LVEF of 56%. Mean LAV was 57.7 mL in the lowest PVC tertile, 70.9 mL in the middle, and 87.1 mL in the highest PVC tertile (p < 0.001). Trapezoidal LA shape was documented in 32 patients. Five per cent of patients in the lowest and 65% in the highest PVC tertile had trapezoidal LA shape (p < 0.001). PVC frequency correlated with LAV (r = 0.87, p < 0.001) and LAb (r = 0.56, p < 0.001). Each 10% increase in PVCs was significantly associated with trapezoidal LA shape (OR = 1.32, 95% CI 1.17-1.48), after adjustment for age, sex, mean blood pressure, LVEF, and LV end-diastolic diameter. CONCLUSIONS: Frequent PVCs are associated with larger LAV and trapezoidal LA shape in otherwise healthy patients, suggesting LA remodelling in response to increased LV filling pressure. PMID- 25522755 TI - Idiopathic ventricular arrhythmia in children and adolescents: early effectiveness of radiofrequency current ablation. AB - BACKGROUND AND AIM: The aim of the study was to evaluate early effectiveness of radiofrequency (RF) current ablation for idiopathic ventricular arrhythmia (iVA) in children and to identify factors affecting treatment results. METHODS: Among over 600 children, 30 ablation procedures were performed for iVA. Patient age ranged from 2.0 to 17.9 years (mean 14.7 +/- 3.1). We analysed arrhythmia recurrences at 24 h and the effect of patient age, arrhythmia location, type of anaesthesia, and the presence of spontaneous arrhythmia during the procedure on the treatment results. RESULTS: Sixteen (53%) children had right ventricular (RV) arrhythmia, including RV outflow tract arrhythmia in 9 of them (56%). In 14 (47%) children, arrhythmia was located in the left ventricle (LV), including LV outflow tract in 2 children, and the posterior fascicle in 4 children. The procedure was effective in 13 (81%) children in the RV arrhythmia group and in 11 (78%) children in the LV arrhythmia group, including all children with fascicular tachycardia. The only variable that affected the treatment results was the presence of spontaneous arrhythmia during the procedure (p = 0.012). No procedural complications were noted. CONCLUSIONS: RF current ablation of iVA is a safe procedure with high early effectiveness. The only variable that affected the treatment results was the presence of spontaneous arrhythmia during the procedure. PMID- 25522756 TI - Vitamin D and systemic lupus erythematosus: continued evolution. AB - Vitamin D is a steroid hormone that has well-established roles in calcium and bone metabolism. Vitamin D has more recently become recognized for its role in the immune response and its potential immunomodulatory effects in autoimmune diseases, including systemic lupus erythematosus (SLE). This review provides a summary of the recent literature regarding vitamin D and SLE, as well as current recommendations for vitamin D supplementation in patients with SLE. PMID- 25522757 TI - Cardiac patients' perception of patient-centred care: a qualitative study. AB - AIM: The aim of this study was to explore cardiac patients' perception of patient centred care. BACKGROUND: Despite patient's importance in the process of care, less attention has been paid to experiences and expectations of patients in definitions of patient-centred care. As patients are an important element in process of patient-centred care, organizing care programs according to their perceptions and expectations will lead to enhanced quality of care and greater patient satisfaction. DESIGN: This study is a descriptive qualitative study. METHODS: Content analysis approach was performed for data analysis. Participants were 18 cardiac patients (10 women and 8 men) hospitalized in coronary care units of teaching hospitals affiliated to Tehran University of Medical Sciences. We collected the study data through conducting personal face-to-face semi-structured interviews. FINDINGS: The participants' perceptions of patient-centred care fell into three main themes including managing patients uncertainty, providing care with more flexibility and establishing a therapeutic communication. The second theme consisted of two sub-themes: empathizing with patients and having the right to make independent decisions. CONCLUSIONS: Receiving patient-centred care is essential for cardiac patients. Attention to priorities and preferences of cardiac patients and making decisions accordingly is among effective strategies for achieving patient-centred care. IMPLICATIONS FOR PRACTICE: Cardiac care unit nurses ought to be aware that in spite of technological developments and advances, it is still important to pay attention to patients' needs and expectations in order to achieve patient satisfaction. In planning care programs, they should consider accountability towards patients' needs, flexibility in process of care and establishing medical interactions as an effective strategy for improving quality of care. PMID- 25522758 TI - Retinal dysplasia in American pit bull terriers--phenotypic characterization and breeding study. AB - OBJECTIVE: The purpose of this study was to investigate the inheritance and phenotype of retinal dysplasia (RD) in the American pit bull terrier. ANIMALS STUDIED: A breeding colony established from a single female pure-bred American pit bull terrier dog with RD. PROCEDURES: A female pure-bred American pit bull terrier with RD was donated to the Veterinary Hospital of Federal University of Parana, Curitiba, Brazil. A breeding colony was established and the phenotype and inheritance of the condition investigated. Regular ophthalmic examinations and fundus photography were performed on three generations of offspring from the founder animal. Some animals were additionally studied by optical coherence tomography. Ocular histopathology was performed on some animals from the colony. RESULTS: Fifty-seven offspring were produced in two generations from the affected founder female. Thirty-two were diagnosed with RD and showed a spectrum of severity of lesions including multifocal, and or geographic lesions and some developed retinal detachment. Histologic examination demonstrated retinal folds, rosettes, and areas of retinal detachment. The affected dogs were shorter in stature than the unaffected littermates. Breeding studies suggested the trait has an autosomal dominant mode of inheritance. DNA testing showed that the affected dogs were negative for the known gene mutations for canine dwarfism with RD. CONCLUSION: This is a report of a novel inherited form of RD that affects American pit bull terriers. PMID- 25522759 TI - The use of steam explosion to increase the nutrition available from rice straw. AB - In the present study, rice straw was pretreated using steam-explosion (ST) technique to improve the enzymatic hydrolysis of potential reducing sugars for feed utilization. The response surface methodology based on central composite design was used to optimize the effects of steam pressure, pressure retention time, and straw moisture content on the yield of reducing sugar. All the investigated variables had significant effects (P < 0.001) on the reducing sugar yield. The optimum yield of 30.86% was obtained under the following pretreatment conditions: steam pressure, 1.54 MPa; pressure retention time, 140.5 Sec; and straw moisture content, 41.6%. The yield after thermal treatment under the same conditions was approximately 16%. Infrared (IR) radiation analysis showed a decrease in the cellulose IR crystallization index. ST noticeably increases reducing sugars in rice straw, and this technique may also be applicable to other cellulose/lignin sources of biomass. PMID- 25522760 TI - The road to automated peritoneal dialysis: a personal reflection. PMID- 25522762 TI - A study protocol of a randomized controlled trial examining the efficacy of a symptom self-management programme for people with acute myocardial infarction. AB - AIM: To report a study protocol of a randomized controlled trial examining if a symptom self-management programme helps patients with acute myocardial infarction self-manage their physical and psychological symptoms. BACKGROUND: In addition to physical conditions, people with acute myocardial infarction often experience psychological symptoms. However, there is limited empirical evidence on how to help individuals self-manage these psychological symptoms. DESIGN: A single blinded, randomized controlled trial is proposed. METHODS: A convenience sample of 90 will be recruited. Eligible participants will be adult patients with acute myocardial infarction hospitalized at a tertiary hospital in Singapore. Participants will be randomly assigned to one of the three treatment groups: Intervention 1 and standard care (n = 30), Intervention 2 and standard care (n = 30) and standard care alone (n = 30). Data will be collected by self-reported questionnaires, physiological measures and open-ended questions. Quantitative data will be analysed by descriptive statistics, t-test, analysis of covariance and repeated measures analysis of variance. Open-ended questions will be analysed by content analysis. DISCUSSION: This study will identify a potentially efficacious symptom self-management programme for patients with acute myocardial infarction. If the efficacy of the programme is demonstrated, the programme can be integrated into hospital services to improve patient care. A new teaching method (virtual reality-based teaching) and new teaching materials (virtual reality videos and relaxation videos) derived from this study can be offered to patients. Future research with larger samples and multi-centre recruitment can be undertaken to further test the efficacy of the interventions. PMID- 25522763 TI - A novel compound, NK150460, exhibits selective antitumor activity against breast cancer cell lines through activation of aryl hydrocarbon receptor. AB - Antiestrogen agents are commonly used to treat patients with estrogen receptor (ER)-positive breast cancer. Tamoxifen has been the mainstay of endocrine treatment for patients with early and advanced breast cancer for many years. Following tamoxifen treatment failure, however, there are still limited options for subsequent hormonal therapy. We discovered a novel compound, NK150460, that inhibits 17beta-estradiol (E2)-dependent transcription without affecting binding of E2 to ER. Against our expectations, NK150460 inhibited growth of not only most ER-positive, but also some ER-negative breast cancer cell lines, while never inhibiting growth of non-breast cancer cell lines. Cell-based screening using a random shRNA library, identified aryl hydrocarbon receptor nuclear translocator (ARNT) as a key gene involved in NK150460's antitumor mechanism. siRNAs against not only ARNT but also its counterpart aryl hydrocarbon receptor (AhR) and their target protein, CYP1A1, dramatically abrogated NK150460's growth-inhibitory activity. This suggests that the molecular cascade of AhR/ARNT plays an essential role in NK150460's antitumor mechanism. Expression of ERalpha was decreased by NK150460 treatment, and this was inhibited by an AhR antagonist. Unlike two other AhR agonists now undergoing clinical developmental stage, NK150460 did not induce histone H2AX phosphorylation or p53 expression, suggesting that it did not induce a DNA damage response in treated cells. Cell lines expressing epithelial markers were more sensitive to NK150460 than mesenchymal marker-expressing cells. These data indicate that NK150460 is a novel AhR agonist with selective antitumor activity against breast cancer cell lines, and its features differ from those of the other two AhR agonists. PMID- 25522764 TI - Radiotherapy followed by aurora kinase inhibition targets tumor-propagating cells in human glioblastoma. AB - Glioblastoma (GBM) is the most common malignant primary brain tumor. Radiotherapy fails to eliminate subpopulations of stem-like tumor-propagating cells (TPC), resulting in tumor regrowth. To identify kinases that promote TPC self-renewal rather than increasing proliferation in human GBM cultures, we screened a library of 54 nonselective tool compounds and determined their kinase inhibitor profiles in vitro. Most compounds inhibited aurora kinase (AURK) activity and blocked TPC self-renewal, while inducing GBM cell polynucleation and apoptosis. To prevent regrowth by TPCs, we used a priming dose of radiation followed by incubation with the pan-AURK inhibitor VX680 to block self-renewal and induce apoptosis in GBM cultures. In mice xenografted with human GBM cells, radiotherapy followed by VX680 treatment resulted in reduced tumor growth and increased survival relative to either monotherapy alone or VX680 treatment before radiation. Our results indicate that AURK inhibition, subsequent to radiation, may enhance the efficacy of radiotherapy by targeting radioresistant TPCs in human GBMs. PMID- 25522765 TI - Combining onartuzumab with erlotinib inhibits growth of non-small cell lung cancer with activating EGFR mutations and HGF overexpression. AB - Erlotinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI), benefits survival of patients with non-small cell lung cancer (NSCLC) who harbor activating EGFR mutations. However, elevated expression of hepatocyte growth factor (HGF), a ligand of the MET receptor tyrosine kinase, causes erlotinib resistance. Because onartuzumab, a monovalent antibody to MET, blocks HGF-induced MET activation, the addition of onartuzumab to erlotinib may improve therapeutic efficacy. We engineered the human NSCLC cell line PC-9 (MET-positive cells harboring an exon 19 deletion of EGFR) to overexpress hHGF and evaluated the effects of an onartuzumab and erlotinib combination in vitro and in vivo in xenograft models. A stable clone of PC-9/hHGF was less sensitive to erlotinib than the parental PC-9, and the addition of onartuzumab to erlotinib suppressed the proliferation of these cells in vitro. In PC-9/hHGF xenograft tumors, onartuzumab or erlotinib alone minimally inhibited tumor growth; however, combining onartuzumab and erlotinib markedly suppressed tumor growth. The total MET protein level was decreased in PC-9/hHGF cells, because MET is constitutively phosphorylated by autocrine HGF, leading to its ubiquitination and degradation. Onartuzumab reduced phospho-MET levels, inhibited MET ubiquitination, and consequently restored MET protein levels. Moreover, in NSCLC clinical specimens harboring activating EGFR mutations, more than 30% of patients expressed high levels of HGF. Our findings raised the possibility that patients with NSCLC with EGFR mutations who express high levels of HGF may benefit from onartuzumab and erlotinib combination therapy, and that HGF can be a novel biomarker for selecting such patients. PMID- 25522766 TI - Clinical and cellular roles for TDP1 and TOP1 in modulating colorectal cancer response to irinotecan. AB - Colorectal cancer is the third most common cancer in the world. Despite surgery, up to 50% of patients relapse with incurable disease. First-line chemotherapy uses the topoisomerase 1 (TOP1) poison irinotecan, which triggers cell death by trapping TOP1 on DNA. The removal of TOP1 peptide from TOP1-DNA breaks is conducted by tyrosyl-DNA phosphodiesterase 1 (TDP1). Despite putative roles for TDP1 and TOP1 in colorectal cancer, their role in cellular and clinical responses to TOP1-targeting therapies remains unclear. Here, we show varying expression levels of TOP1 and TDP1 polypeptides in multiple colorectal cancer cell lines and in clinical colorectal cancer samples. TDP1 overexpression or TOP1 depletion is protective. Conversely, TDP1 depletion increases DNA-strand breakage and hypersensitivity to irinotecan in a TOP1-dependent manner, presenting a potential therapeutic opportunity in colorectal cancer. TDP1 protein levels correlate well with mRNA and with TDP1 catalytic activity. However, no correlation is observed between inherent TDP1 or TOP1 levels alone and irinotecan sensitivity, pointing at their limited utility as predictive biomarkers in colorectal cancer. These findings establish TDP1 as a potential therapeutic target for the treatment of colorectal cancer and question the validity of TOP1 or TDP1 on their own as predictive biomarkers for irinotecan response. PMID- 25522767 TI - Safely expanding the donor pool: brain dead donors with history of temporary cardiac arrest. AB - BACKGROUND & AIMS: Cardiac arrest (CA) in deceased organ donors can potentially be associated with ischaemic organ injury, resulting in allograft dysfunction after liver transplantation (LT). The aim of this study was to analyse the influence of cardiac arrest in liver donors. METHODS: We evaluated 884 consecutive adult patients undergoing LT at our Institution from September 2003 to December 2011. Uni- and multivariable analyses was performed to identify predictive factors of outcome and survival for organs from donors with (CA donor) and without (no CA donor) a history of cardiac arrest. RESULTS: We identified 77 (8.7%) CA donors. Median resuscitation time was 16.5 (1-150) minutes. Allografts from CA donors had prolonged CIT (p = 0.016), were obtained from younger individuals (p < 0.001), and had higher terminal preprocurement AST and ALT (p < 0.001) than those of no CA donors. 3-month, 1-year and 5-year survival for recipients of CA donor grafts was 79%, 76% and 57% and 72.1%, 65.1% and 53% for no CA donor grafts (log rank p = 0.435). Peak AST after LT was significantly lower in CA donor organs than in no CA donor ones (886U/l vs 1321U/l; p = 0.031). Multivariable analysis identified CIT as a risk factor for both patient and graft survival in CA donors. CONCLUSION: This analysis represents the largest cohort of liver donors with a history of cardiac arrest. Reasonable selection of these donors constitutes a safe approach to the expansion of the donor pool. Rapid allocation and implantation with diminution of CIT may further improve the outcomes of livers from CA donors. PMID- 25522768 TI - Internal medicine resident knowledge of transfusion medicine: results from the BEST-TEST international education needs assessment. AB - BACKGROUND: Blood transfusion is the most common hospital procedure performed in the United States. While inadequate physician transfusion medicine knowledge may lead to inappropriate practice, such an educational deficit has not been investigated on an international scale using a validated assessment tool. Identifying specific deficiencies is critical for developing curricula to improve patient care. STUDY DESIGN AND METHODS: Rasch analysis, a method used in high stakes testing, was used to validate an assessment tool consisting of a 23 question survey and a 20-question examination. The assessment tool was administered to internal medicine residents to determine prior training, attitudes, perceived ability, and actual knowledge related to transfusion medicine. RESULTS: A total of 474 residents at 23 programs in nine countries completed the examination. The overall mean score of correct responses was 45.7% (site range, 32%-56%). The mean score for Postgraduate Year (PGY)1 (43.9%) was significantly lower than for PGY3 (47.1%) and PGY4 (50.6%) residents. Although 89% of residents had participated in obtaining informed consent from a patient for transfusion, residents scored poorly (<25% correct) on questions related to transfusion reactions. The majority of residents (65%) would find additional transfusion medicine training "very" or "extremely" helpful. CONCLUSION: Internationally, internal medicine residents have poor transfusion medicine knowledge and would welcome additional training. The especially limited knowledge of transfusion reactions suggests an initial area for focused training. This study not only represents the largest international assessment of transfusion medicine knowledge, but also serves as a model for rigorous, collaborative research in medical education. PMID- 25522769 TI - Qualitative evaluation of the implementation of the Interdisciplinary Management Tool: a reflective tool to enhance interdisciplinary teamwork using Structured, Facilitated Action Research for Implementation. AB - Reflective practice is used increasingly to enhance team functioning and service effectiveness; however, there is little evidence of its use in interdisciplinary teams. This paper presents the qualitative evaluation of the Interdisciplinary Management Tool (IMT), an evidence-based change tool designed to enhance interdisciplinary teamwork through structured team reflection. The IMT incorporates three components: an evidence-based resource guide; a reflective implementation framework based on Structured, Facilitated Action Research for Implementation methodology; and formative and summative evaluation components. The IMT was implemented with intermediate care teams supported by independent facilitators in England. Each intervention lasted 6 months and was evaluated over a 12-month period. Data sources include interviews, a focus group with facilitators, questionnaires completed by team members and documentary feedback from structured team reports. Data were analysed qualitatively using the Framework approach. The IMT was implemented with 10 teams, including 253 staff from more than 10 different disciplines. Team challenges included lack of clear vision; communication issues; limited career progression opportunities; inefficient resource use; need for role clarity and service development. The IMT successfully engaged staff in the change process, and resulted in teams developing creative strategies to address the issues identified. Participants valued dedicated time to focus on the processes of team functioning; however, some were uncomfortable with a focus on teamwork at the expense of delivering direct patient care. The IMT is a relatively low-cost, structured, reflective way to enhance team function. It empowers individuals to understand and value their own, and others' roles and responsibilities within the team; identify barriers to effective teamwork, and develop and implement appropriate solutions to these. To be successful, teams need protected time to take for reflection, and executive support to be able to broker changes that are beyond the scope of the team. PMID- 25522770 TI - Genetic susceptibility variants for chronic lymphocytic leukaemia in Mexican mestizos. PMID- 25522771 TI - Nutritional care after critical illness: a qualitative study of patients' experiences. AB - BACKGROUND: The present qualitative study aimed to explore the factors influencing nutritional recovery in patients after critical illness and to develop a model of care to improve current management of nutrition for this patient group. METHODS: Patients were recruited into the study on discharge from a general intensive care unit (ICU) of a large teaching hospital in central Scotland. Semi-structured interviews were carried out after discharge from the ICU, weekly for the duration of their ward stay, and at 3 months post ICU discharge. Observations of ward practice were undertaken thrice weekly for the duration of the ward stay. RESULTS: Seventeen patients were recruited into the study and, using a grounded theory approach, 'inter-related system breakdowns during the nutritional recovery process' emerged as the overarching core category that influenced patients' experiences of eating after critical illness. This encompassed the categories, 'experiencing a dysfunctional body', 'experiencing socio-cultural changes in relation to eating' and 'encountering nutritional care delivery failures'. CONCLUSIONS: The findings from the present study provide a unique contribution to knowledge by offering important insights into patients' experiences of eating after critical illness. The study has identified numerous nutritional problems and raises questions about the efficacy of current nutritional management in this patient group. Adopting a more individualised approach to nutritional care could ameliorate the nutritional issues experienced by post ICU patients. This will be evaluated in future work. PMID- 25522772 TI - A comparative analysis of island floras challenges taxonomy-based biogeographical models of speciation. AB - Speciation on islands, and particularly the divergence of species in situ, has long been debated. Here, we present one of the first, complete assessments of the geographic modes of speciation for the flora of a small oceanic island. Cocos Island (Costa Rica) is pristine; it is located 550 km off the Pacific coast of Central America. It harbors 189 native plant species, 33 of which are endemic. Using phylogenetic data from insular and mainland congeneric species, we show that all of the endemic species are derived from independent colonization events rather than in situ speciation. This is in sharp contrast to the results of a study carried out in a comparable system, Lord Howe Island (Australia), where as much as 8.2% of the plant species were the product of sympatric speciation. Differences in physiography and age between the islands may be responsible for the contrasting patterns of speciation observed. Importantly, comparing phylogenetic assessments of the modes of speciation with taxonomy-based measures shows that widely used island biogeography approaches overestimate rates of in situ speciation. PMID- 25522773 TI - Gastric adenocarcinoma of pyloric gland type with high-grade malignancy. PMID- 25522774 TI - AOGS: an international journal with Scandinavian quality. PMID- 25522775 TI - A new beginning. PMID- 25522776 TI - Enhancing access to emergency obstetric care through surgical task shifting in Sierra Leone: confrontation with Ebola during recovery from civil war. PMID- 25522777 TI - Salinomycin inhibits hepatocellular carcinoma cell invasion and migration through JNK/JunD pathway-mediated MMP9 expression. AB - The antibiotic salinomycin (Salin) was recently identified as an antitumor drug for the treatment of several types of solid tumors. However, the effects of Salin on the migratory and invasive properties of hepatocellular carcinoma (HCC) cells are unclear. The present study aimed to determine the antitumor efficacy and mechanism of Salin in HCC cells. Human HCC cells (HCCLM3) treated with Salin showed a concentration-dependent reduction in cell migration and invasion, and this was associated with reduced MMP9 expression. The MMP9 promoter and enhancer in a luciferase reporter assay revealed that Salin can regulate MMP9 expression through an activator protein (AP-1) site within the MMP9 enhancer. JunD, one of the AP-1 components, was significantly decreased by Salin in a concentration- and time-dependent manner. Salin was able to induce c-Jun NH2-kinase (JNK) phosphorylation and to block both JunD and MMP9 expression. Our results showed that JNK phosphorylation and JunD may be involved in the Salin-regulated MMP9 signaling pathway in HCCLM3 cells and may mediate HCC cell biological characteristics. Our studies provide new insight into the antitumor effects of Salin. PMID- 25522778 TI - Quantifying ecological memory in plant and ecosystem processes. AB - The role of time in ecology has a long history of investigation, but ecologists have largely restricted their attention to the influence of concurrent abiotic conditions on rates and magnitudes of important ecological processes. Recently, however, ecologists have improved their understanding of ecological processes by explicitly considering the effects of antecedent conditions. To broadly help in studying the role of time, we evaluate the length, temporal pattern, and strength of memory with respect to the influence of antecedent conditions on current ecological dynamics. We developed the stochastic antecedent modelling (SAM) framework as a flexible analytic approach for evaluating exogenous and endogenous process components of memory in a system of interest. We designed SAM to be useful in revealing novel insights promoting further study, illustrated in four examples with different degrees of complexity and varying time scales: stomatal conductance, soil respiration, ecosystem productivity, and tree growth. Models with antecedent effects explained an additional 18-28% of response variation compared to models without antecedent effects. Moreover, SAM also enabled identification of potential mechanisms that underlie components of memory, thus revealing temporal properties that are not apparent from traditional treatments of ecological time-series data and facilitating new hypothesis generation and additional research. PMID- 25522779 TI - Allelic diversity in the transcriptomes of contrasting rust-infected genotypes of Lathyrus sativus, a lasting resource for smart breeding. AB - BACKGROUND: Grass pea (Lathyrus sativus L.) is a valuable resource for potentially durable partial resistance to rust. To gain insight into the resistance mechanism and identify potential resistance genes, we generated the first comprehensive transcriptome assemblies from control and Uromyces pisi inoculated leafs of a susceptible and a partially rust-resistant grass pea genotype by RNA-seq. RESULTS: 134,914 contigs, shared by both libraries, were used to analyse their differential expression in response to rust infection. Functional annotation grouped 60.4% of the contigs present in plant databases (37.8% of total) to 33 main functional categories, being "protein", "RNA", "signalling", "transport" and "stress" the most represented. Transcription profiles revealed considerable differences in regulation of major phytohormone signalling pathways: whereas Salicylic and Abscisic Acid pathways were up regulated in the resistant genotype, Jasmonate and Ethylene pathways were down regulated in the susceptible one. As potential Resistance-genes we identified a mildew resistance locus O (MLO)-like gene, and MLO-related transcripts. Also, several pathogenesis-related genes were up-regulated in the resistant and exclusively down regulated in the susceptible genotype. Pathogen effectors identified in both inoculated libraries, as e.g. the rust Rtp1 transcript, may be responsible for the down-regulation of defence-related transcripts. The two genotypes contained 4,892 polymorphic contigs with SNPs unevenly distributed between different functional categories. Protein degradation (29.7%) and signalling receptor kinases (8.2%) were the most diverged, illustrating evolutionary adaptation of grass pea to the host/pathogens arms race. CONCLUSIONS: The vast array of novel, resistance-related genomic information we present here provides a highly valuable resource for future smart breeding approaches in this hitherto under-researched, valuable legume crop. PMID- 25522780 TI - Two color DNA barcode detection in photoluminescence suppressed silicon nitride nanopores. AB - Optical sensing of solid-state nanopores is a relatively new approach that can enable high-throughput, multicolor readout from a collection of nanopores. It is therefore highly attractive for applications such as nanopore-based DNA sequencing and genotyping using DNA barcodes. However, to date optical readout has been plagued by the need to achieve sufficiently high signal-to-noise ratio (SNR) for single fluorophore sensing, while still maintaining millisecond resolution. One of the main factors degrading the optical SNR in solid-state nanopores is the high photoluminescence (PL) background emanating from the silicon nitride (SiNx) membrane in which pores are commonly fabricated. Focusing on the optical properties of SiNx nanopores we show that the local membrane PL intensity is substantially reduced, and its spectrum is shifted toward shorter wavelengths with increasing e-beam dose. This phenomenon, which is correlated with a marked photocurrent enhancement in these nanopores, is utilized to perform for the first time single molecule fluorescence detection using both green and red laser excitations. Specifically, the reduction in PL and the concurrent measurement of the nanopore photocurrent enhancement allow us to maximize the background suppression and to detect a dual color, five-unit DNA barcode with high SNR levels. PMID- 25522781 TI - Exploring non-Condon effects in a covalent tetracene dimer: how important are vibrations in determining the electronic coupling for singlet fission? AB - Singlet fission (SF) offers opportunities for wavelength-selective processing of solar photons with an end goal of achieving higher efficiency inexpensive photovoltaic or solar-fuels-producing devices. In order to evaluate new molecular design strategies and for theoretical exploration of dynamics, it is important to put in place tools for efficient calculation of the electronic coupling between single-exciton reactant and multiexciton product states. For maximum utility, the couplings should be calculated at multiple nuclear geometries (rather than assumed constant everywhere, i.e., the Condon approximation) and we must be able to evaluate couplings for covalently linked multichromophore systems. With these requirements in mind, here we discuss the simplest methodology possible for rapid calculation of diabatic one-electron coupling matrix elements-based on Boys localization and rediagonalization of molecular orbitals. We focus on a covalent species called BT1 that juxtaposes two tetracene units in a partially cofacial geometry via a norbornyl bridge. In BT1, at the equilibrium C2v structure, the "nonhorizontal" couplings between HOMOs and LUMOs (t(HL) and t(LH)) vanish by symmetry. We then explore the impact of molecular vibrations through the calculation of t(AB) coupling gradients along 183 normal modes of motion. Rules are established for the types of motions (irreducible representations in the C2v point group) that turn on tHL and tLH values as well as for the patterns that emerge in constructive versus destructive interference of pathways to the SF product. For the best modes, calculated electronic coupling magnitudes for SF (at root-mean-squared deviation in position at 298 K), are within a factor of 2 of that seen for noncovalent tetracene dimers relevant to the molecular crystal. An overall "effective" electronic coupling is also given, based on the Stuchebrukhov formalism for non-Condon electron transfer rates. PMID- 25522782 TI - Inhibition of porcine reproductive and respiratory syndrome virus infection by recombinant adenovirus- and/or exosome-delivered the artificial microRNAs targeting sialoadhesin and CD163 receptors. AB - BACKGROUND: The current vaccines failed to provide substantial protection against porcine reproductive and respiratory syndrome (PRRS) and the new vaccine development faces great challenges. Sialoadhesin (Sn) and CD163 are the two key receptors for PRRS virus (PRRSV) infection of porcine alveolar macrophages (PAMs), but the artificial microRNA (amiRNA) strategy targeting two viral receptors has not been described. METHODS: The candidate miRNAs targeting Sn or CD163 receptor were predicted using a web-based miRNA design tool and validated by transfection of cells with each amiRNA expression vector plus the reporter vector. The amiRNA-expressing recombinant adenoviruses (rAds) were generated using AdEasy Adenoviral Vector System. The rAd transduction efficiencies for pig cells were measured by flow cytometry and fluorescent microscopy. The expression and exosome-mediated secretion of amiRNAs were detected by RT-PCR. The knock-down of Sn or CD163 receptor by rAd- and/or exosome-delivered amiRNA was detected by quantitative RT-PCR and flow cytometry. The additive anti-PRRSV effect between the two amiRNAs was detected by quantitative RT-PCR and viral titration. RESULTS: All 18 amiRNAs validated were effective against Sn or CD163 receptor mRNA expression. Two rAds expressing Sn- or CD163-targeted amiRNA were generated for further study. The maximal rAd transduction efficiency was 62% for PAMs at MOI 800 or 100% for PK-15 cells at MOI 100. The sequence-specific amiRNAs were expressed efficiently in and secreted from the rAd-transduced cells via exosomes. The expression of Sn and CD163 receptors was inhibited significantly by rAd transduction and/or amiRNA-containing exosome treatment at mRNA and protein levels. Both PRRSV ORF7 copy number and viral titer were reduced significantly by transduction of PAMs with the two rAds and/or by treatment with the two amiRNA containing exosomes. The additive anti-PRRSV effect between the two amiRNAs was relatively long-lasting (96 h) and effective against three different viral strains. CONCLUSION: These results suggested that Sn- and CD163-targeted amiRNAs had an additive anti-PRRSV effect against different viral strains. Our findings provide new evidence supporting the hypothesis that exosomes can also serve as an efficient small RNA transfer vehicle for pig cells. PMID- 25522784 TI - Relationship between anthropometric measures and early electrocardiographic changes in obese rats. AB - BACKGROUND: The degree of cardiovascular function impairment parallels the degree of obesity and obese subjects have abnormal changes on the electrocardiogram (ECG). Early ECG changes in obesity have not been previously studied. The objective of the present study was to determine the early ECG changes in obese rats and their relationship with anthropometric measurements. RESULTS: At seven weeks all rats in the experiment were obese and in sinus rhythm. In the experiment resting heart rate was increased (364+/-13 vs. 313+/-12 bpm, P<0.01). In contrast, the following parameters were shortened: QRS duration (77+/-3.6 vs. 65+/-2.6 ms, P<0.01); QT interval (102+/-5.2 vs. 88+/-3.7 ms, P<0.05); Q wave amplitude (-12.8+/-1.0 vs. -5.1+/-0.9 MUv, P<0.01); and T wave amplitude (18.8+/ 1.4 vs. 5.8+/-0.6, P<0.01). All other ECG parameters remained unchanged. With increased weight the resting heart rate (r=0.46, P<0.01) and R wave amplitude (r=0.60, P<0.01) increased. CONCLUSION: Early in obesity there are no rhythm disturbances, but resting heart rate is increased. The QRS duration is shortened and Q and T-wave amplitudes reduced signifying ventricular changes related to impaired myocardial depolarization and repolarization. Furthermore, weight gain is correlated with an increase in heart rate and accentuation of the R wave amplitude. PMID- 25522783 TI - Overexpression of SIRT1 promotes metastasis through epithelial-mesenchymal transition in hepatocellular carcinoma. AB - BACKGROUND: SIRT1 is a member of the mammalian sirtuin family with the ability to deacetylate histone and nonhistone proteins. The correlation between SIRT1 expression and tumor metastasis in several types of cancer has aroused widespread concern. This study investigated SIRT1 expression and its prognostic value in hepatocellular carcinoma (HCC). The function of SIRT1 in hepatocarcinogenesis was further investigated in cell culture and mouse models. METHODS: Western blotting and immunohistochemistry were used to explore SIRT1 expression in HCC cell lines and primary HCC clinical specimens. The functions of SIRT1 in the migration and invasion in the HCC cell line were analyzed by infecting cells with adenovirus containing full-length SIRT1 or sh-RNA. The effect of SIRT1 on tumorigenicity in nude mice was also investigated. RESULTS: SIRT1 expression was significantly overexpressed in the tumor tissues and HCC cell lines. SIRT1 significantly promoted the ability of migration and invasion in HCC cells. In addition, experiments with a mouse model revealed that SIRT1 overexpression enhanced HCC tumor metastasis in vivo. Furthermore, we demonstrated that SIRT1 significantly enhanced the invasive and metastatic potential by inducing epithelial-mesenchymal transition in HCC cells. A clinicopathological analysis showed that SIRT1 expression was significantly correlated with tumor size, tumor number, and TNM staging. Kaplan-Meier survival curves revealed that positive SIRT1 expression was associated with poor prognosis in patients with HCC. CONCLUSIONS: Our data suggest that SIRT1 may play an important role in HCC progression and could be a potential molecular therapy target for HCC. PMID- 25522785 TI - Number of osteoporotic sites as a modifying factor for bone mineral density. AB - Discordance has been proposed as a new predictor of fracture risk that may affect fracture risk via bone mineral density (BMD). With an emphasis on better understanding the relationship between discordance and BMD, the aim of this study was to determine the effect of the number of osteoporotic sites, as an indicator of discordance, on BMD and to explore the clinical significance of BMD modification by this factor. This study was based on data obtained from the Korea National Health and Nutrition Examination Survey 2008-2011, which is a nationwide cross-sectional study. Among postmenopausal women aged 50 years or older, 3,849 women whose BMD was measured at three sites (lumbar spine, femoral neck, and total hip) were included in the study. The diagnosis was consistent across sites in only 39.2-59.0 % of cases. Lumbar spine T-score was reduced by 0.163 for two osteoporotic sites and by 0.462 for three osteoporotic sites, compared with having one osteoporotic site at the lumbar spine only. Femoral neck T-score was reduced by 0.609 for three osteoporotic sites compared with one or two osteoporotic sites. Using BMD adjusted for discordance, we found fracture risk probability changed significantly. Our results confirmed that BMD discordance was considerably high among Korean women in their 50s and older owing to site dependent differences in the pattern of BMD reduction with age. Mean BMD decreased with increasing number of osteoporotic sites. Using a modified BMD adjusted for the number of osteoporotic sites may offer more accurate fracture risk assessment. PMID- 25522786 TI - Sodium intake in US ethnic subgroups and potential impact of a new sodium reduction technology: NHANES Dietary Modeling. AB - BACKGROUND: Because excessive dietary sodium intake is a major contributor to hypertension, a reduction in dietary sodium has been recommended for the US population. Using the National Health and Nutrition Examination Survey (NHANES) 2007-2010 data, we estimated current sodium intake in US population ethnic subgroups and modeled the potential impact of a new sodium reduction technology on sodium intake. METHODS: NHANES 2007-2010 data were analyzed using The National Cancer Institute method to estimate usual intake in population subgroups. Potential impact of SODA-LO(r) Salt Microspheres sodium reduction technology on sodium intake was modeled using suggested sodium reductions of 20-30% in 953 foods and assuming various market penetrations. SAS 9.2, SUDAAN 11, and NHANES survey weights were used in all calculations with assessment across age, gender and ethnic groups. RESULTS: Current sodium intake across all population subgroups exceeds the Dietary Guidelines 2010 recommendations and has not changed during the last decade. However, sodium intake measured as a function of food intake has decreased significantly during the last decade for all ethnicities. "Grain Products" and "Meat, Poultry, Fish, & Mixtures" contribute about 2/3rd of total sodium intake. Sodium reduction, using SODA-LO(r) Salt Microspheres sodium reduction technology (with 100% market penetration) was estimated to be 185-323 mg/day or 6.3-8.4% of intake depending upon age, gender and ethnic group. CONCLUSIONS: Current sodium intake in US ethnic subgroups exceeds the recommendations and sodium reduction technologies could potentially help reduce dietary sodium intake among those groups. PMID- 25522787 TI - Cell-cell contact viral transfer contributes to HIV infection and persistence in astrocytes. AB - Astrocytes are the most abundant cells in the central nervous system and play important roles in human immunodeficiency virus (HIV)/neuro-acquired immunodeficiency syndrome. Detection of HIV proviral DNA, RNA, and early gene products but not late structural gene products in astrocytes in vivo and in vitro indicates that astrocytes are susceptible to HIV infection albeit in a restricted manner. We as well as others have shown that cell-free HIV is capable of entering CD4- astrocytes through human mannose receptor-mediated endocytosis. In this study, we took advantage of several newly developed fluorescence protein-based HIV reporter viruses and further characterized HIV interaction with astrocytes. First, we found that HIV was successfully transferred to astrocytes from HIV infected CD4+ T cells in a cell-cell contact- and gp120-dependent manner. In addition, we demonstrated that, compared to endocytosis-mediated cell-free HIV entry and subsequent degradation of endocytosed virions, the cell-cell contact between astrocytes and HIV-infected CD4+ T cells led to robust HIV infection of astrocytes but retained the restricted nature of viral gene expression. Furthermore, we showed that HIV latency was established in astrocytes. Lastly, we demonstrated that infectious progeny HIV was readily recovered from HIV latent astrocytes in a cell-cell contact-mediated manner. Taken together, our studies point to the importance of the cell-cell contact-mediated HIV interaction with astrocytes and provide direct evidence to support the notion that astrocytes are HIV latent reservoirs in the central nervous system. PMID- 25522788 TI - Physiology-based pharmacokinetics of caspofungin for adults and paediatrics. AB - PURPOSE: Caspofungin (CAS) is an antifungal agent for intravenous application in adults and children. Our aim was the development and validation of a physiology based pharmacokinetic (PBPK) model in order to predict the pharmacokinetics in different patient populations, particularly in paediatrics. METHODS: A PBPK model for adults was built and validated with raw data of the two clinical trials CASLAMB and CASMTD. Afterwards, the model was scaled for paediatric patients under the consideration of known biochemical differences between adults and paediatrics. RESULTS: The simulated results of the PBPK model were in good agreement with the observed values of the CASLAMB and CASMTD trial. Patients of the CASLAMB trial received CAS in combination with cyclosporine A (CsA), which leads to an increased AUC0-24h of CAS hypothetically due to an inhibition of the hepatic transport protein OATP1B1 by CsA. However, there was no difference in the transport rate of OATP1B1 between CASLAMB and CASMTD patients in the PBPK model, suggesting that CsA might not influence OATP1B1. Furthermore, the model was able to sufficiently predict the pharmacokinetics of paediatric patients compared to published data. CONCLUSION: The final PBPK model of CAS without individualized parameter is able to predict the pharmacokinetics in different patient populations correctly. Thus, the model provides a basis for investigators to choose doses and sampling times for special populations such as infants and small children. PMID- 25522789 TI - Genomic Knockout of Endogenous Canine P-Glycoprotein in Wild-Type, Human P Glycoprotein and Human BCRP Transfected MDCKII Cell Lines by Zinc Finger Nucleases. AB - PURPOSE: To investigate whether it is possible to specifically suppress the expression and function of endogenous canine P-glycoprotein (cPgp) in Madin-Darby canine kidney type II cells (MDCKII) transfected with hPGP and breast cancer resistance protein (hBCRP) by zinc finger nuclease (ZFN) producing sequence specific DNA double strand breaks. METHODS: Wild-type, hPGP-transfected, and hBCRP-transfected MDCKII cells were transfected with ZFN targeting for cPgp. Net efflux ratios (NER) of Pgp and Bcrp substrates were determined by dividing efflux ratios (basal-to-apical / apical-to-basal) in over-expressing cell monolayers by those in wild-type ones. RESULTS: From ZFN-transfected cells, cell populations (ko-cells) showing knockout of cPgp were selected based on genotyping by PCR. qRT PCR analysis showed the significant knock-downs of cPgp and interestingly also cMrp2 expressions. Specific knock-downs of protein expression for cPgp were shown by western blotting and quantitative targeted absolute proteomics. Endogenous canine Bcrp proteins were not detected. For PGP-transfected cells, NERs of 5 Pgp substrates in ko-cells were significantly greater than those in parental cells not transfected with ZFN. Similar result was obtained for BCRP-transfected cells with a dual Pgp and Bcrp substrate. CONCLUSION: Specific efflux mediated by hPGP or hBCRP can be determined with MDCKII cells where cPgp has been knocked out by ZFN. PMID- 25522790 TI - Endoplasmic reticulum stress is involved in the lidocaine-induced apoptosis in SH SY5Y neuroblastoma cells. AB - Lidocaine has been indicated to promote apoptosis and to promote endoplasmic reticulum (ER) stress. However, the mechanism underlining ER stress-mediated apoptosis is unclear. In the present study, we investigated the promotion to ER stress in the lidocaine-induced apoptosis in human neuroblastoma SH-SY5Y cells. Firstly, we confirmed that lidocaine treatment induced apoptosis in SH-SY5Y cells, time-dependently and dose-dependently, via MTT cell viability assay and annexin V/FITC apoptosis detection with a FACScan flow cytometer. And the anti apoptosis Bcl-2 and Bcl-xL were downregulated, whereas the apoptosis-executive caspase 3 was promoted through Western blot assay and caspase 3 activity assay. Moreover, the ER stress-associated binding immunoglobulin protein (BiP), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4) and CCAAT/enhancer binding protein homologous protein (CHOP) were also upregulated at both mRNA and protein levels by lidocaine treatment. On the other hand, downregulation of the ER stress-associated BiP by RNAi method not only blocked the lidocaine-promoted ER stress but also attenuated the lidocaine-induced SH-SY5Y cell apoptosis. In conclusion, the present study confirmed the involvement of ER stress in the lidocaine-induced apoptosis in human neuroblastoma SH-SY5Y cells. Our study provides a better understanding on the mechanism of lidocaine's neurovirulence. PMID- 25522791 TI - Right ventricular failure with high echoic ventricular wall change after foetoscopic laser photocoagulation: a case report of a donor in twin-to-twin transfusion syndrome. AB - The introduction of foetoscopic laser photocoagulation has dramatically improved the prognosis of patients with severe twin-to-twin transfusion syndrome. We present the case of a donor who exhibited right-heart failure with a high echoic wall change of the right ventricle after the foetoscopic laser photocoagulation procedure. The prenatal and 1-year postnatal follow-up revealed the gradual recovery of the right ventricular function. PMID- 25522792 TI - Estimation of trace metal elements in oral mucosa specimens by using SR-XRF, PIXE, and XAFS. AB - The effects of dissolved elements from metal dental restorations are a major concern in lesions of the oral mucosa, and the evaluation of accumulated metal elements, especially their distribution and chemical state, is essential for determining the precise effects of trace metals. In this study, X-ray fluorescence with synchrotron radiation (SR-XRF) and particle-induced X-ray emission (PIXE) were applied for distribution analysis of the trace metal elements contained in the oral mucosa, and the chemical states of the elements were estimated using X-ray absorption fine structure (XAFS) analysis. Appropriate combination of these analysis techniques, particularly SR-XRF and PIXE, to visualize the distributions of the elements in the oral mucosa allowed for the observation and evaluation of accumulated metal ions and debris. Importantly, the analyses in this study could be carried out using conventional histopathological specimens without damaging the specimens. Therefore, this method would be applicable for the detection of accumulated trace metal elements in biopsy specimens from the oral mucosa. PMID- 25522793 TI - Percutaneous cervical cordotomy in cancer pain. AB - The aim of this study was to review all published articles in the literature in English regarding percutaneous cervical cordotomy in cancer pain. Percutaneous cordotomy may be used to relieve unilateral pain below the level of the neck arising from a variety of causes. It is particularly indicated for unilateral chest pain associated with malignant disease. We searched for reports on MEDLINE and EMBASE using the terms 'percutaneous cordotomy', 'fluoroscopy', 'computed tomography,' and 'cancer pain' up to and including 2013. Reports were also located through references of articles. This review leads us to conclude that percutaneous cervical cordotomy can be recommended even before considering the use of strong opioids. PMID- 25522794 TI - Induction of plant virus defense response by brassinosteroids and brassinosteroid signaling in Arabidopsis thaliana. AB - MAIN CONCLUSION: Our study demonstrated that CMV resistance was upregulated by brassinosteroids (BRs) treatment, and BR signaling was needed for this BRs induced CMV tolerance. Plant steroid hormones, brassinosteroids (BRs), play essential roles in variety of plant developmental processes and adaptation to various biotic and abiotic stresses. BR signal through plasma membrane-localized receptor and other components to modulate several transcription factors that modulate thousands of target genes including certain stress-responsive genes. To study the effects of BRs on plant virus defense and how BRs induce plant virus stress tolerance, we manipulated the BRs levels in Arabidopsis thaliana and found that BRs levels were positively correlated with the tolerance to Cucumber mosaic virus (CMV). We also showed that BRs treatment alleviated photosystem damage, enhanced antioxidant enzymes activity and induced defense-associated genes expression under CMV stress in Arabidopsis. To see whether BR signaling is essential for the plant virus defense response, we made use of BR signaling mutants (a weak allele of the BRs receptor mutant bri1-5 and constitutive BRs response mutant bes1-D). Compared with wild-type Arabidopsis plants, bri1-5 displayed reversed tolerance to CMV, but the resistance was enhanced in bes1-D. Together our results suggest that BRs can induce plant virus defense response through BR signaling. PMID- 25522795 TI - Molecular identification and functional analysis of a maize (Zea mays) DUR3 homolog that transports urea with high affinity. AB - MAIN CONCLUSION: Successful molecular cloning and functional characterization of a high-affinity urea permease ZmDUR3 provide convincing evidence of ZmDUR3 roles in root urea acquisition and internal urea-N-remobilization of maize plants. Urea occurs ubiquitously in both soils and plants. Being a major form of nitrogen fertilizer, large applications of urea assist cereals in approaching their genetic yield potential, but due to the low nitrogen-use efficiency of crops, this practice poses a severe threat to the environment through their hypertrophication. To date, except for paddy rice, little is known about the biological basis for urea movement in dryland crops. Here, we report the molecular and physiological characterization of a maize urea transporter, ZmDUR3. We show using gene prediction, PCR-based cloning and yeast complementation, that a functional full-length cDNA encoding a 731 amino acids-containing protein with putative 15 transmembrane alpha-helixes for ZmDUR3 was successfully cloned. Root influx studies using (15)N-urea demonstrated ZmDUR3 catalyzes urea transport with a K m at ~9 uM when expressed in the Arabidopsis dur3-mutant. qPCR analysis revealed that ZmDUR3 mRNA in roots was significantly upregulated by nitrogen depletion and repressed by reprovision of nitrogen after nitrogen starvation, indicating that ZmDUR3 is a nitrogen-responsive gene and relevant to plant nitrogen nutrition. Moreover, detection of higher urea levels in senescent leaves and obvious occurrence of ZmDUR3 transcripts in phloem-cells of mature/aged leaves strongly implies a role for ZmDUR3 in urea vascular loading. Significantly, expression of ZmDUR3 complemented atdur3-mutant of Arabidopsis, improving plant growth on low urea and increasing urea acquisition. As it also targets to the plasma membrane, our data suggest that ZmDUR3 functions as an active urea permease playing physiological roles in effective urea uptake and nitrogen remobilization in maize. PMID- 25522796 TI - Time to initiation of antiretroviral therapy in HIV-infected patients diagnosed with an opportunistic disease: a cohort study. AB - OBJECTIVES: The aim of the study was to identify factors associated with the time between opportunistic disease (OD) diagnosis and antiretroviral therapy (ART) initiation in HIV-infected patients presenting for care with an OD, and to evaluate the outcomes associated with any delay. METHODS: A multicentre cohort study was undertaken in London, Paris and Lille/Tourcoing. The medical records of patients diagnosed from 2002 to 2012 were reviewed. RESULTS: A total of 437 patients were enrolled in the study: 70% were male, the median age was 40 years, 42% were from sub-Saharan Africa, 68% were heterosexual, the median CD4 count was 40 cells/MUL, and the most common ODs were Pneumocystis pneumonia (37%), tuberculosis (24%), toxoplasmosis (12%) and Kaposi's sarcoma (11%). Of these patients, 400 (92%) started ART within 24 weeks after HIV diagnosis, with a median time from OD diagnosis to ART initiation of 30 [interquartile range (IQR) 16-58] days. Patients diagnosed between 2009 and 2012 had a shorter time to ART initiation than those diagnosed in earlier years [hazard ratio (HR) 2.07; 95% confidence interval (CI) 1.58-2.72]. Factors associated with a longer time to ART initiation were a CD4 count >= 200 cells/MUL (HR 0.30; 95% CI 0.20-0.44), tuberculosis (HR 0.40; 95% CI 0.30-0.55) and diagnosis in London (HR 0.62; 95% CI 0.48-0.80). Patients initiating 'deferred' ART (by >= 30 days) exhibited no difference in disease progression or immunovirological response compared with patients who had shorter times to ART initiation. Patients in the 'deferred' group were less likely to have ART modifications (HR 0.69; 95% CI 0.48-1.00) and had shorter in-patient stays (mean 14.2 days shorter; 95% CI 8.9-19.5 days) than patients in the group whose ART was not deferred. CONCLUSIONS: The time between OD diagnosis and ART initiation remains heterogeneous and relatively long, particularly in individuals with a high CD4 count or tuberculosis or those diagnosed in London. Deferring ART was associated with fewer ART modifications and shorter in-patient stays. PMID- 25522797 TI - From hesitation to appreciation: the transformation of a single, local donation nurse project into an established organ-donation service. AB - This study evaluates the transition from a local project to promote organ donation to a permanent county-based donation service inspired by the Spanish model. To address the problem of declining donation rates, a project with one donation-specialized nurse (DOSS) was initiated at a single neuro-intensive care unit. This project was later expanded into a permanent on-call service consisting of seven DOSSes, covering a large urban county. During the different periods (before, during project and during permanent service), the DOSS function's effect on donation rates was significant, and the number of eligible donors that became actual donors increased from 37% to 73% and 74%, respectively. The effect on family vetoes was as prominent with a decrease from 34% to 8% and 14%. The staff appreciation of the DOSS function was also evident during the periods; all areas included in the questionnaire (family care, donor care and staff support) have improved greatly owing to the DOSS. The transition from a single, local donation nurse project, to an on-call service with several DOSSes covering a large urban county was a success considering the donation rates as well as the staff's appreciation. Hence, organizational models from abroad can be adjusted and successfully adopted. PMID- 25522798 TI - Recent advances in systemic lupus erythematosus genetics in an Asian population. AB - Recent advances in systemic lupus erythematosus (SLE) genetics in Asian populations have been achieved by genome-wide association studies (GWASs) and following replication studies, which expanded the genetic information about shared or population-specific risk genes between ethnic groups. Meta-analyses and multi-ethnic replication studies may be possible approaches that could demonstrate stronger or more suggestive evidence for multiple variants for SLE. In addition to the susceptibility of SLE itself, several genotype-phenotype analyses have shown that the specific phenotypes of SLE can also be influenced by genetic factors. Almost all SLE genetic loci are involved in the potential pathways of SLE pathogenesis, such as Toll-like receptor/type I interferon signaling, nuclear factor kappaB signaling, immune complex clearing mechanism, immune cell (B, T cell, neutrophil and monocyte) function and signaling, cell cycle regulation, DNA methylation and autophagy. Further studies, including the next generation sequencing technology and the systematic strategy using bioinformatics, in addition to international collaboration among SLE genetic researchers, will give us better understanding of the genetic basis of SLE. PMID- 25522799 TI - Offset and anteversion reconstruction after cemented and uncemented total hip arthroplasty: an evaluation with the low-dose EOS system comparing two- and three dimensional imaging. AB - PURPOSE: Accurate evaluation of femoral offset is difficult with conventional anteroposterior (AP) X-rays. The EOS imaging system is a system that makes the acquisition of simultaneous and orthogonal AP and lateral images of the patient in the standing position possible. These two-dimensional (2D) images are equivalent to standard plane X-rays. Three-dimensional (3D) reconstructions are obtained from these paired images according to a validated protocol. This prospective study explores the value of the EOS imaging system for comparing measurements of femoral offset from these 2D images and the 3D reconstructions. METHODS: We included 110 patients with unilateral total hip arthroplasty (THA). The 2D offset was measured on the AP view with the same protocol as for standard X-rays. The 3D offset was calculated from the reconstructions based on the orthogonal AP and lateral views. Reproducibility and repeatability studies were conducted for each measurement. We compared the 2D and 3D offset for both hips (with and without THA). RESULTS: For the global series (110 hips with and 110 without THA), 2D offset was 40 mm (SD 7.3; 7-57 mm). The standard deviation was 6.5 mm for repeatability and 7.5 mm for reproducibility. Three-dimensional offset was 43 mm (SD 6.6; 22-62 mm), with a standard deviation of 4.6 for repeatability and 5.5 for reproducibility. Two-dimensional offset for the hips without THA was 40 mm (SD 7.0; 26-56 mm), and 3D offset 43 mm (SD 6.6; 28-62 mm). For THA side, 2D offset was 41 mm (SD 8.2; 7-57 mm) and 3D offset 45 mm (SD 4.8; 22-61 mm). Comparison of the two protocols shows a significant difference between the 2D and 3D measurements, with the 3D offset having higher values. Comparison of the side with and without surgery for each case showed a 5-mm deficit for the offset in 35 % of the patients according to the 2D measurement but in only 26 % according to the 3D calculation. CONCLUSIONS: This study points out the limitations of 2D measurements of femoral offset on standard plane X-rays. The reliability of the EOS 3D models has been previously demonstrated with CT scan reconstructions as a reference. The EOS imaging system could be an option for obtaining accurate and reliable offset measurements while significantly limiting the patient's exposure to radiation. PMID- 25522800 TI - Long-term functional outcome and quality of life after successful surgical treatment of tibial nonunions. AB - PURPOSE: Our aim was to evaluate quality of life (QoL) and functional outcome of patients with tibial nonunions after completion of surgical treatment with an average follow-up of five years. METHODS: The following data of 64 patients were retrospectively evaluated: fracture type, type and duration of surgical therapy, range of motion of the knee and ankle and American Orthopaedic Foot and Ankle Society (AOFAS) score. QoL was evaluated with the Short-Form Health Survey (SF 36) questionnaire; pain intensity, patient satisfaction and impairments of daily, professional and sport activities with a ten point visual analogue scale. RESULTS: QoL, even in cases with successfully completed treatment, was significantly reduced compared with the normal general population. Pain intensity and limited ankle dorsal extension, despite the absence of intra-articular fractures, were significantly correlated with inferior QoL. CONCLUSIONS: This study emphasises the long-term negative impact of tibial nonunions on patient QoL, even after successful surgical treatment. PMID- 25522801 TI - Reconstruction of femoro-acetabular offsets using a short-stem. AB - PURPOSE: Despite the fact that new and modern short-stems allow bone sparing and saving of soft-tissue and muscles, we still face the challenge of anatomically reconstructing the femoro-acetabular offset and leg length. Therefore a radiological and clinical analysis of a short-stem reconstruction of the femoro acetabular offset and leg length was performed. METHODS: Using an antero-lateral approach, the optimys short-stem (Mathys Ltd, Bettlach, Switzerland) was implanted in 114 consecutive patients in combination with a cementless cup (Fitmore, Zimmer, Indiana, USA; vitamys RM Pressfit, Mathys Ltd, Bettlach, Switzerland). Pre- and postoperative X-rays were done in a standardized technique. In order to better analyse and compare X-ray data a special double coordinate system was developed for measuring femoral- and acetabular offset. Harris hip score was assessed before and six weeks after surgery. Visual analogue scale (VAS) satisfaction, leg length difference and the existence of gluteal muscle insufficiency were also examined. RESULTS: Postoperative femoral offset was significantly increased by a mean of 5.8 mm. At the same time cup implantation significantly decreased the acetabular offset by a mean of 3.7 mm, which resulted in an increased combined femoro-acetabular offset of 2.1 mm. Postoperatively, 81.7% of patients presented with equal leg length. The maximum discrepancy was 10 mm. Clinically, there were no signs of gluteal insufficiency. No luxation occurred during hospitalization. The Harris hip score improved from 47.3 before to 90.1 points already at six weeks after surgery while the mean VAS satisfaction was 9.1. CONCLUSION: The analysis showed that loss of femoro acetabular offset can be reduced with an appropriate stem design. Consequently, a good reconstruction of anatomy and leg length can be achieved. In the early postoperative stage the clinical results are excellent. PMID- 25522802 TI - Health professionals' decision-making in wound management: a grounded theory. AB - AIM: To develop a conceptual understanding of the decision-making processes used by healthcare professionals in wound care practice. BACKGROUND: With the global move towards using an evidence-base in standardizing wound care practices and the need to reduce hospital wound care costs, it is important to understand health professionals' decision-making in this important yet under-researched area. DESIGN: A grounded theory approach was used to explore clinical decision-making of healthcare professionals in wound care practice. METHODS: Interviews were conducted with 20 multi-disciplinary participants from nursing, surgery, infection control and wound care who worked at a metropolitan hospital in Australia. Data were collected during 2012-2013. Constant comparative analysis underpinned by Strauss and Corbin's framework was used to identify clinical decision-making processes. FINDINGS: The core category was 'balancing practice based knowledge with evidence-based knowledge'. Participants' clinical practice and actions embedded the following processes: 'utilizing the best available information', 'using a consistent approach in wound assessment' and 'using a multidisciplinary approach'. The substantive theory explains how practice and evidence knowledge was balanced and the variation in use of intuitive practice based knowledge versus evidence-based knowledge. Participants considered patients' needs and preferences, costs, outcomes, technologies, others' expertise and established practices. Participants' decision-making tended to be more heavily weighted towards intuitive practice-based processes. CONCLUSION: These findings offer a better understanding of the processes used by health professionals' in their decision-making in wound care. Such an understanding may inform the development of evidence-based interventions that lead to better patient outcomes. PMID- 25522803 TI - Antibacterial activity and mode of action of the Artemisia capillaris essential oil and its constituents against respiratory tract infection-causing pathogens. AB - Inhalation therapy using essential oils has been used to treat acute and chronic sinusitis and bronchitis. The aim of the present study was to determine the chemical composition of the essential oil of Artemisia capillaris, and evaluate the antibacterial effects of the essential oil and its main components, against common clinically relevant respiratory bacterial pathogens. Gas chromatography and gas chromatography-mass spectrometry revealed the presence of 25 chemical constituents, the main constituents being: alpha-pinene, beta-pinene, limonene, 1,8-cineole, piperitone, beta-caryophyllene and capillin. The antibacterial activities of the essential oil, and its major constituents, were evaluated against Streptococcus pyogenes, methicillin-resistant Staphylococcus aureus (MRSA), MRSA (clinical strain), methicillin-gentamicin resistant Staphylococcus aureus (MGRSA), Streptococcus pneumoniae, Klebsiella pneumoniae, Haemophilus influenzae and Escherichia coli. The essential oil and its constituents exhibited a broad spectrum and variable degree of antibacterial activity against the various strains. The essential oil was observed to be much more potent, as compared with any of its major chemical constituents, exhibiting low minimum inhibitory and bacteriocidal concentration values against all of the bacterial strains. The essential oil was most active against S. pyogenes, MRSA (clinical strain), S. pneumoniae, K. pneumoniae, H. influenzae and E. coli. Piperitone and capillin were the most potent growth inhibitors, among the major chemical constituents. Furthermore, the essential oil of A. capillaris induced significant and dose-dependent morphological changes in the S. aureus bacterial strain, killing >90% of the bacteria when administered at a higher dose; as determined by scanning electron microscopy. In addition, the essential oil induced a significant leakage of potassium and phosphate ions from the S. aureus bacterial cultures. These results indicate that the antibacterial action of A. capillaris essential oil may be mediated through the leakage of these two important ions. In conclusion, A. capillaris essential oil exhibits potent antibacterial activity by inducing morphological changes and leakage of ions in S. aureus bacterial cultures. PMID- 25522804 TI - Short-Term Outcome of Multiple Port Laparoscopic Splenectomy in 10 Dogs. AB - OBJECTIVE: To describe surgical techniques for multiple port laparoscopic splenectomy (MLS) in dogs and report short-term outcome. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs (n = 10) with naturally occurring splenic disease. METHODS: Medical records (March 2012-March 2013) of dogs that had MLS were reviewed. Data retrieved included signalment, weight, clinical signs, physical examination findings, preoperative laboratory and ultrasonographic findings, port number, size, and location, patient positioning, additional procedures performed, surgical duration, histopathologic diagnosis, duration of hospitalization, and perioperative complications. RESULTS: Ten dogs (median weight, 28.7 kg; range, 20.2-46.0 kg) had MLS using a 3 or 4 port technique and a vessel-sealing device for tissue dissection along the splenic hilus. Dog positioning varied because of additional laparoscopic or laparoscopic assisted procedures including adrenalectomy (n = 2), ovariectomy (1), gastropexy (1), and intestinal resection and anastomosis (1). Conversion to an open approach was necessary in 1 dog because of inadequate visibility caused by omental adhesions. One dog had hemorrhage from an omental vessel, but open conversion was not required. CONCLUSIONS: MLS was associated with little perioperative morbidity and few complications in this cohort of dogs and may be a reasonable option for surgical management of dogs requiring elective splenectomy. PMID- 25522805 TI - A phase 1, multicentre, open-label study to evaluate ovarian follicular activity and hormone levels with an extended-regimen combined oral contraceptive with low dose ethinyl estradiol supplementation. AB - OBJECTIVES: To evaluate the effect on ovarian follicular activity of the 91-day extended-regimen combined oral contraceptive (COC), consisting of 84 days of levonorgestrel (LNG)/ethinylestradiol (EE) 150 MUg/30 MUg tablets plus seven days of EE 10 MUg tablets in place of placebo. METHODS: This was a phase 1, open-label study. Ovarian follicular activity was classified via the Hoogland and Skouby method. Safety and tolerability as well as return to ovulation were assessed. RESULTS: Of the 35 subjects included in the efficacy analysis, luteinized, unruptured follicles, or ovulation were detected in 0 of 35 cycles during the first 28-day interval; 1 of 35 cycles (2.9%) in the second 28-day interval; and 2 of 35 cycles (5.7%) in the final 35-day interval. The ovarian activity rate over the entire 91-day treatment period was 2.9%. There was a low incidence of treatment-emergent adverse events. Ovulation returned in most subjects (77.1%, 27/35) within 32 days following the last dose of COC. CONCLUSIONS: The 91-day extended-regimen COC with low-dose EE supplementation was found to be effective in suppressing ovarian activity and inhibiting ovulation and was well tolerated. Return to ovulation was rapid, occurring within approximately one month after discontinuation of COC. PMID- 25522806 TI - In-house preparation and evaluation of (125)I-histamine progesterone tracer for radioimmunoassay of progesterone. AB - The progesterone tracer for the development of in-house radioimmunoassay was prepared in two steps clearly described. First, activation of 11alpha hemisuccinate progesterone (progesterone-11 alpha HS) and labeling of histamine with (125)I, and second, conjugation of activated 11alpha-HS progesterone with iodinated histamine. The purification of the tracer was carried out by gel filtration on Sephadex G-25. The radiochemical purity of purified the tracer was 95%. The maximum binding using solid phase (coated tubes) reached 41% and the non specific binding didn't exceed 5%. The tracer stored at different temperatures 10 degrees C and -6 degrees C was stable during 12 weeks. The skim milk provided assay better sensitivity (0.22 ng/mL) than serum (0.28 ng/mL). PMID- 25522807 TI - Identification of the region of rice 13 kDa prolamin essential for the formation of ER-derived protein bodies using a heterologous expression system. AB - Cereal prolamins, which are alcohol-soluble seed storage proteins, can induce ER derived protein bodies (PBs) in heterologous tissue. Like maize and wheat prolamins, rice prolamins can form ER-derived PBs, but the region of mature polypeptides that is essential for PB formation has not been identified. In this study, we examined the formation mechanisms of ER-derived PB-like structures by expressing rice 13 kDa prolamin-deletion mutants fused to green fluorescent protein (GFP) in heterologous tissues such as yeast. The 13 kDa prolamin-GFP fusion protein was stably accumulated in transgenic yeast and formed an ER derived PB-like structure. In contrast, rice alpha-globulin-GFP fusion protein was transported to vacuoles. In addition, the middle and COOH-terminal regions of 13 kDa prolamin formed ER-derived PB-like structures, whereas the NH2-terminal region of 13 kDa prolamin did not form such structures. These results suggest that the middle and COOH-terminal regions of 13 kDa prolamin can be retained and thus can induce ER-derived PB in yeast. PMID- 25522808 TI - A CAD system for B-mode fatty liver ultrasound images using texture features. AB - The present study proposes a computer-aided diagnosis (CAD) system for the diagnosis of grades of fatty liver disease, namely mild, moderate and severe fatty liver along with normal liver tissue. Fifty-three B-mode ultrasound images consisting of 12 normal, 14 mild, 14 moderate and 13 severe fatty liver images are used. Based on the visual interpretations by the radiologists, region of interests (ROIs) from within the liver and one ROI from the diaphragm region are considered from each image. The texture features of these ROIs are combined in three ways to form ratio features, inverse ratio features and additive features. The sub-sets of optimal features are obtained by a differential evolution feature selection (DEFS) algorithm and a support vector machine (SVM) has been used for the classification task. The Laws ratio features have shown better performance with an average accuracy and standard deviation of 84.9+/-3.2. Hence, the CAD system could be useful to the radiologists in diagnosing grades of fatty liver disease. PMID- 25522809 TI - Risk factors for hepatocellular carcinoma in Caucasian patients with non-viral cirrhosis: the importance of prior obesity. AB - BACKGROUND & AIMS: In patients with cirrhosis, the risk of hepatocellular carcinoma (HCC) depends upon age, gender and the etiology of liver disease. Few studies are available in Caucasian patients with alcoholic or metabolic cirrhosis without viral hepatitis. METHODS: Cross-sectional clinical data from 905 HCV- and HBV-negative Caucasian patients with alcoholic or metabolic cirrhosis were prospectively collected in four French centres. The risk factors for HCC were identified by logistic regression analysis in the whole population and in a nested case-control study. RESULTS: The etiology of cirrhosis was alcoholic (48%), metabolic (7%) or mixed (45%). Patients were predominantly male (80%), mean age 62 years old and 31% had HCC. Mean body mass index (BMI) was 27 +/- 5 and 30% were obese at inclusion. The maximum BMI reached throughout life was 31 +/- 6 and 63% had been obese. Ninety percent of the population had daily alcohol consumption, 73% were smokers. Hepatocellular carcinoma was independently related to male gender (P < 0.0001), older age (P < 0.0001), past obesity (P = 0.007), diabetes (P = 0.037), abnormal levels of transaminases (P < 0.0001) and tobacco consumption (P = 0.007). The case-control study (200 HCC cases matched with 400 non-HCC cases for gender, age and Child-Pugh score) confirmed past obesity, tobacco and abnormal levels of transaminases. CONCLUSIONS: Beside diabetes, male gender and age, a past history of obesity, but not an existing overweight, as well as exposure to tobacco and elevated transaminases were three risk factors which could improve the strategy for HCC screening in Caucasian cirrhotic patients without hepatitis B or C. PMID- 25522810 TI - A new ABCG2 null allele with a 27-kb deletion including the promoter region causing the Jr(a-) phenotype. AB - BACKGROUND: The high-prevalence antigen Jr(a) is carried on the ATP-binding cassette transporter ABCG2. The ABCG2 gene consists of 16 exons and its translation start codon is located on the second exon. Although the occurrence of the Jr(a-) phenotype is rare, several ABCG2 null alleles have been reported. We report a new ABCG2 null allele having a large deletion in this study. STUDY DESIGN AND METHODS: The Jr(a) status was determined by standard serologic tests and genomic DNA was isolated from whole blood. Exons 1 to 16 and the 5' untranslated region of the ABCG2 gene were analyzed by polymerase chain reaction and sequencing. Expression of the ABCG2 protein on red blood cells was examined by immunoblotting. RESULTS: A Jr(a-) blood donor had a novel allele having a 27 kb deletion including noncoding Exon 1 and the promoter region of ABCG2, and the donor was apparently homozygous for the allele. In addition, we found three more individuals having heterozygosity for the same allele, with ABCG2*01N.01 having c.376C>T (p.Q126X), but did not find the allele having the 27-kb deletion in 3000 Jr(a+) individuals. Immunoblotting revealed that the ABCG2 protein was not found to be expressed in the individual with homozygosity for the ABCG2 27-kb deleted and in two individuals with an ABCG2 27-kb deleted/ABCG2*01N.01 genotype, which indirectly allows to conclude that the 27-kb deletion is responsible for a null ABCG2 allele. CONCLUSION: We first identified an ABCG2 null allele (provisional ISBT allele number ABCG2*01N.23) having a large deletion including the promoter region. PMID- 25522811 TI - Are species differences in maternal effects arising from maternal care adaptive? AB - Parental care benefits offspring through maternal effects influencing their development, growth and survival. However, although parental care in general is likely the result of adaptive evolution, it does not follow that specific differences in the maternal effects that arise from care are also adaptive. Here, we used an interspecific cross-fostering design in the burying beetle species Nicrophorus orbicollis and N. vespilloides, both of which have elaborate parental care involving direct feeding of regurgitated food to offspring, to test whether maternal effects are optimized within a species and therefore adaptive. Using a full-factorial design, we first demonstrated that N. orbicollis care for offspring longer regardless of recipient species. We then examined offspring development and mass in offspring reared by hetero- or conspecific parents. As expected, there were species-specific direct effects independent of the maternal effects, as N. orbicollis larvae were larger and took longer to develop than N. vespilloides regardless of caregiver. We also found significant differences in maternal effects: N. vespilloides maternal care caused more rapid development of offspring of either species. Contrary to expectations if maternal effects were species-specific, there were no significant interactions between caretaker and recipient species for either development time or mass, suggesting that these maternal effects are general rather than optimized within species. We suggest that rather than coadaptation between parents and offspring performance, the species differences in maternal effects may be correlated with direct effects, and that their evolution is driven by selection on those direct effects. PMID- 25522812 TI - c.1058C>T variant in the SERPINC1 gene is pathogenic for antithrombin deficiency. PMID- 25522813 TI - Exploring associations between anthropometric indices and graft function in patients receiving renal transplant. AB - BACKGROUND: The aim of the present study was to identify indicators of malnutrition, as obtained by anthropometric measurements, that might be potential predictors of transplant outcomes. METHODS: One hundred and three patients receiving a graft from a living or a deceased donor were included in this prospective study. Body mass index (BMI) based on pretransplant dry body weight, triceps skinfold, mid-arm muscle circumference and corrected mid-arm muscle area were measured. Post-transplant data on delayed graft function (DGF) and glomerular filtration rate (GFR) at discharge were collected until patient discharge. RESULTS: Delayed graft function developed in 36.9% of the patients. BMI was the only anthropometric variable associated with a higher likelihood of DGF (odds ratio = 1.25, 95% confidence interval = 1.07-1.47) after adjusting for age, gender, donor group, donor age and years of dialysis before transplantation. Obesity was associated with a higher frequency of DGF (83.3% versus 31.1%, P = 0.001) compared to normal weight. GFR at discharge was negatively associated with BMI [beta = -0.014 (0.005), P = 0.004], being overweight [beta = -0.151 (0.041), P < 0.001] and obesity [beta = -0.188 (0.053), P = 0.001], after adjusting for age, gender, donor group, donor age and years of dialysis, but was not associated with indices of muscle reserves. CONCLUSIONS: The likelihood of DGF was higher among obese patients, whereas GFR at discharge was negatively associated with being overweight and obesity. PMID- 25522814 TI - Exploiting transcriptome data for the development and characterization of gene based SSR markers related to cold tolerance in oil palm (Elaeis guineensis). AB - BACKGROUND: The oil palm (Elaeis guineensis, 2n = 32) has the highest oil yield of any crop species, as well as comprising the richest dietary source of provitamin A. For the tropical species, the best mean growth temperature is about 27 degrees C, with a minimal growth temperature of 15 degrees C. Hence, the plantation area is limited into the geographical ranges of 10 degrees N to 10 degrees S. Enhancing cold tolerance capability will increase the total cultivation area and subsequently oil productivity of this tropical species. Developing molecular markers related to cold tolerance would be helpful for molecular breeding of cold tolerant Elaeis guineensis. RESULTS: In total, 5791 gene-based SSRs were identified in 51,452 expressed sequences from Elaeis guineensis transcriptome data: approximately one SSR was detected per 10 expressed sequences. Of these 5791 gene-based SSRs, 916 were derived from expressed sequences up- or down-regulated at least two-fold in response to cold stress. A total of 182 polymorphic markers were developed and characterized from 442 primer pairs flanking these cold-responsive SSR repeats. The polymorphic information content (PIC) of these polymorphic SSR markers across 24 lines of Elaeis guineensis varied from 0.08 to 0.65 (mean = 0.31 +/- 0.12). Using in silico mapping, 137 (75.3%) of the 182 polymorphic SSR markers were located onto the 16 Elaeis guineensis chromosomes. Total coverage of 473 Mbp was achieved, with an average physical distance of 3.4 Mbp between adjacent markers (range 96 bp - 20.8 Mbp). Meanwhile, Comparative analysis of transcriptome under cold stress revealed that one ICE1 putative ortholog, five CBF putative orthologs, 19 NAC transcription factors and four cold-induced orhologs were up-regulated at least two fold in response to cold stress. Interestingly, 5' untranslated region of both Unigene21287 (ICE1) and CL2628.Contig1 (NAC) both contained an SSR markers. CONCLUSIONS: In the present study, a series of SSR markers were developed based on sequences differentially expressed in response to cold stress. These EST-SSR markers would be particularly useful for gene mapping and population structure analysis in Elaeis guineensis. Meanwhile, the EST-SSR loci were inducible expressed in response to low temperature, which may have potential application in identifying trait-associated markers in oil palm in the future. PMID- 25522815 TI - Whose truffle is this? Distribution patterns of ectomycorrhizal fungal diversity in Tuber melanosporum brules developed in multi-host Mediterranean plant communities. AB - In the Mediterranean region, patches of vegetation recovering from disturbance and transiently dominated by shrubs produce one of the world's most prized fungi, the black truffle (Tuber melanosporum). In these successional plant communities, we have fragmentary knowledge of the distribution of T. melanosporum in space among ectomycorrhizal (ECM) host species and in time. Molecular identification of hosts (Restriction Fragment Length Polymorphism) and fungi (Internal Transcribed Spacer sequencing) and quantification of T. melanosporum mycelium (quantitative Polymerase Chain Reaction) were employed to evaluate the presence of T. melanosporum on four dominant ECM host species (Quercus ilex, Quercus coccifera, Arbutus unedo, Cistus albidus) and the extent to which their respective ECM communities shared fungal diversity, over the course of development of truffle grounds, from recent unproductive brules to senescent ones where production has stopped. We found that truffle grounds host rich communities in which multi-host fungal species dominate in frequency. When considering both ECM tips and soil mycelia, we documented a dynamic and spatially heterogeneous pattern of T. melanosporum distribution in soils and a presence of ECM tips restricted to Q. ilex roots. This study advances our knowledge of the ecology of T. melanosporum, and provides insight into the extent of ECM fungal sharing among plant species that dominate Mediterranean landscapes. PMID- 25522816 TI - Evaluating effect of symptoms heterogeneity on decision-making ability in obsessive-compulsive disorder. AB - AIMS: Despite having a univocal definition, obsessive-compulsive disorder (OCD) shows a remarkably phenotypic heterogeneity. The published reports show impaired decision-making in OCD patients, using tasks such as the Iowa Gambling Task (IGT). We wanted to verify the hypothesis of an IGT worse performance in a large sample of OCD patients and healthy control (HC) subjects and to examine the relation between neuropsychological performance in IGT and the OCD symptoms heterogeneity. METHODS: Binary data from the Yale-Brown Obsessive Compulsive Scale collected on a large sample of OCD patients were analyzed using a multidimensional item response theory model to explore the underlying structure of data, thus revealing latent factors. Factor scores were categorized into quartiles. Then, for each factor, we identified patients respectively with the highest versus lowest score. We evaluated whether symptom dimensions affect the probability of a correct answer over time generalized, during IGT performance, fitting a generalized linear mixed model. RESULTS: We found a general deficit in ambiguous decision-making in OCD compared to HC. Moreover, our findings suggested that OCD symptoms heterogeneity affects decision-making learning abilities during IGT. In fact, while 'Symmetry' and 'Washing' patients showed a learning curve during the task, other subgroups did not. CONCLUSIONS: Our study confirmed previous findings suggesting that OCD is characterized by a deficit in decision making under uncertainty. Moreover, our study gave evidence about biological specificity for each symptom dimension in OCD. Data were discussed in the context of the somatic marker hypothesis, which was hypothesized to be reduced in OCD patients. PMID- 25522817 TI - Why does the hemolytic activity of silica predict its pro-inflammatory activity? AB - BACKGROUND: The hemolytic activity of inhaled particles such as silica has been widely investigated in the past and represents a usual toxicological endpoint to characterize particle reactivity despite the fact that red blood cells (RBCs) are not involved in the pathogenesis of pulmonary inflammation or fibrosis caused by some inhaled particles. The inflammatory process induced by silica starts with the activation of the inflammasome, which leads to the release of mature IL 1beta. One of the upstream mechanisms causing activation of the inflammasome is the labilization of the phagolysosomal membrane after particle phagocytosis. Considering RBC lysis as a model of membrane damage, we evaluated the relationship between hemolytic activity and inflammasome-dependent release of IL 1beta for a panel of selected silica particles, in search of the toxicological significance of the hemolytic activity of an inhaled particle. METHODS: Well characterized silica particles, including four quartz samples and a vitreous silica, with different surface properties and hemolytic potential were tested for their capacity to induce inflammasome-dependent release of IL-1beta in LPS-primed primary murine peritoneal macrophages by ELISA and Western blot analysis. The mechanisms of IL-1beta maturation and release were clarified by using ASC deficient cells and inhibitors of phagocytosis and cathepsin B. RESULTS: The silica samples induced dose-dependent hemolysis and IL-1beta release of different amplitudes. A significant correlation between IL-1beta release and hemolytic activity was evidenced (r = 0.827) by linear regression analysis. IL-1beta release was completely abolished in ASC-deficient cells and reduced by inhibitors, confirming the involvement of the inflammasome and the requirement of phagocytosis and cathepsin B for activation. CONCLUSIONS: The same physico chemical properties of silica particles which are relevant for the lysis of the RBC membrane also appear implicated in the labilization of the phagolysosome, leading to inflammasome activation and release of the pro-inflammatory cytokine IL-1beta. These findings strengthen the relevance of the hemolysis assay to predict the pro-inflammatory activity of silica dusts. PMID- 25522818 TI - A sensitive and specific Raman probe based on bisarylbutadiyne for live cell imaging of mitochondria. AB - We previously showed that bisarylbutadiyne (BADY), which has a conjugated diyne structure, exhibits an intense peak in the cellular Raman-silent region. Here, we synthesized a mitochondria-selective Raman probe by linking bisphenylbutadiyne with triphenylphosphonium, a well-known mitochondrial targeting moiety. This probe, named MitoBADY, has a Raman peak 27 times more intense than that of 5 ethynyl-2'-deoxyuridine. Raman microscopy using submicromolar extracellular probe concentrations successfully visualized mitochondria in living cells. A full Raman spectrum is acquired at each pixel of the scanned sample, and we showed that simultaneous Raman imaging of MitoBADY and endogenous cellular biomolecules can be achieved in a single scan. MitoBADY should be useful for the study of mitochondrial dynamics. PMID- 25522819 TI - Synthesis, analgesic, anti-inflammatory and anti-ulcerogenic activities of certain novel Schiff's bases as fenamate isosteres. AB - A series of certain novel Schiff bases as fenamate isosteres (VI:a-k) were synthesized to locate analgesic, anti-inflammatory agent with minimal ulcerogenic potential. The structures of the newly synthesized compounds were elucidated on the basis of their elemental analysis as well as IR, and NMR and mass spectroscopic data. All the compounds were evaluated for their anti-inflammatory activity by carrageenan induced paw oedema method. The compounds possessing good anti-inflammatory activity were further tested for analgesic, ulcerogenic, lipid peroxidation potentials and liver toxicity. Compounds (VI-c), (VI-f), (VI-h) and (VI-i) showed the best anti-inflammatory and significant analgesic activities at doses comparable to that of the standard drug Indomethacin. However, compounds (VI-c) and (VI-f) could be considered the most potent anti-inflammatory and analgesic molecules with maximum reduction in gastro-intestinal ulceration with no hepatocyte necrosis or liver degeneration. PMID- 25522820 TI - Diversity oriented synthesis and IKK inhibition of aminobenzimidazole tethered quinazoline-2,4-diones, thioxoquinazolin-4-ones, benzodiazepine-2,3,5-triones, isoxazoles and isoxazolines. AB - The derivatization of resin-bound aminobenzimidazole toward the parallel solid phase synthesis of aminobenzimidazole tethered pharmacologically important heterocycles such as quinazoline-2,4-diones, thioxoquinazolin-4-ones, benzodiazepine-2,3,5-triones, isoxazoles and isoxazolines is reported. All the compounds were tested for IKK inhibition. Only one compound elicited significant inhibition of IKKepsilon, TBK-1 and IKK2. PMID- 25522821 TI - Antitumor effect of boron nitride nanotubes in combination with thermal neutron irradiation on BNCT. AB - The first BNCT antitumor effects of BNNTs toward B16 melanoma cells were demonstrated. The use of DSPE-PEG2000 was effective for preparation of the BNNT suspended aqueous solution. BNNT-DSPE-PEG2000 accumulated in B16 melanoma cells approximately three times higher than BSH and the higher BNCT antitumor effect was observed in the cells treated with BNNT-DSPE-PEG2000 compared to those treated with BSH, indicating that BNNT-DSPE-PEG2000 would be a possible candidate as a boron delivery vehicle for BNCT. PMID- 25522822 TI - Individual-Oriented Relationship Education: An Evaluation Study in Community Based Settings. AB - The effects of relationship education aimed at individuals, rather than couples, have not yet been widely investigated. However, increasingly, relationship education is provided to large and diverse groups of individuals who may be in varying stages of relationships. Several programs have been developed to strengthen relationship competencies among single individuals as well as among partnered individuals who, for a variety of reasons, seek relationship education without their partners. The current study is an exploratory evaluation study that examined self-reported outcomes for 706 single and partnered individuals who attended Within My Reach classes delivered in community-based agencies. Participants were from diverse backgrounds and exhibited many of the risk factors for poor relationship outcomes including unemployment, low income, and childhood experience of abuse or neglect. Pre-post analyses indicated that the program was beneficial for both singles and partnered individuals. Singles reported increased belief in ability to obtain healthy relationships. Partnered individuals reported increased relationship quality, relationship confidence, and reduced conflict. Regardless of relationship status, participants also reported improvement in general relationship and communication skill. Results support the utility of individual-oriented relationship education for singles and partnered individuals with diverse background characteristics. PMID- 25522823 TI - Paired related homeobox 1 is associated with the invasive properties of glioblastoma cells. AB - Glioblastoma is a highly proliferative and invasive tumor. Despite extensive efforts to develop treatments for glioblastoma, the currently available therapies have only limited effects. To develop novel strategies for glioblastoma treatment, it is crucial to elucidate the molecular mechanisms that promote the invasive properties of glioblastoma. In the present study, we showed that the paired related homeobox 1 (PRRX1) is associated with glioblastoma cell invasion. The depletion of PRRX1 suppressed the invasion and neurosphere formation of glioblastoma cells. Conversely, the exogenous expression of PRRX1 promoted invasion. The Notch signaling pathway, which is an evolutionarily conserved pathway that is essential for developmental processes, plays an important role in the tumorigenesis of glioblastoma. The expression of PRRX1 induced the activation of Notch signaling, and the inhibition of Notch signaling suppressed PRRX1 mediated cell invasion. Our results indicate that activation of Notch signaling by PRRX1 is associated with the promotion of glioblastoma cell invasion. PMID- 25522824 TI - Frequency-modulated steady-state visual evoked potentials: a new stimulation method for brain-computer interfaces. AB - BACKGROUND: Steady-state visual evoked potentials (SSVEPs) are widely used for brain-computer interfaces. However, users experience fatigue due to exposure to flickering stimuli. High-frequency stimulation has been proposed to reduce this problem. We adapt frequency-modulated (FM) stimulation from the auditory domain, where it is commonly used to evoke steady-state responses, and compare the EEG as well as behavioral flicker perceptibility ratings. NEW METHOD: We evoke SSVEPs with a green light-emitting diode (LED) driven by FM signals. RESULTS: FM-SSVEPs with different carrier and modulation frequencies can reliably be evoked with spectral peaks at the lower FM sideband. Subjective perceptibility ratings decrease with increasing FM carrier frequencies, while the peak amplitude and signal-to-noise ratio (SNR) remain the same. COMPARISON WITH EXISTING METHOD: There are neither amplitude nor SNR differences between SSVEPs evoked rectangularly, sinusoidally or via FM. Perceptibility ratings were lower for FM SSVEPs with carrier frequencies of 20Hz and above than for sinusoidally evoked SSVEPs. CONCLUSIONS: FM-SSVEPs seem to be beneficial for BCI usage. Reduced flicker perceptibility in FM-SSVEPs suggests reduced fatigue, which leads to an enhanced user experience and performance. PMID- 25522825 TI - Asymmetric total synthesis of (-)-leuconoxine via chiral phosphoric acid catalyzed desymmetrization of a prochiral diester. AB - The asymmetric total synthesis of (-)-leuconoxine has been achieved. The desymmetrization of a prochiral diester using a chiral phosphoric acid catalyst produced a highly enantioenriched lactam with excellent yield. The ring construction featuring an intramolecular N-acyliminium cyclization and the one step pyrrolidone formation using Bestmann's ylide was successfully accomplished. PMID- 25522826 TI - Excited states of ladder-type pi-conjugated dyes with a joint SOS-CIS(D) and PCM TD-DFT approach. AB - First-principle simulations aimed at accurately reproducing the excited state properties of a large series of ladder-type pi-conjugated organic molecules containing heteroatoms (Si, S, B, O, and N) have been performed. In particular, time-dependent density functional theory (TD-DFT) calculations relying on several global and range-separated hybrid functionals have been carried out in conjunction with three variations of the polarizable continuum model (PCM), namely, the linear-response (LR), corrected linear-response (cLR), and state specific (SS) approaches. For this series of molecules, similar to many borate derivatives, the cLR-PCM-TD-M06-2X approach can be used to reproduce the auxochromic effects that tune the 0-0 energies. However, TD-DFT yields rather large absolute deviations with respect to the experimental 0-0 energies. These systematic errors can be reduced by more than 0.1 eV when scaled opposite spin configuration interaction singles with a double correction [SOS-CIS(D)] vertical calculations are combined to the PCM-TD-DFT results. This study demonstrates that such a "hybrid" scheme, where the geometrical and vibrational parameters, as well as the solvation effects, are determined with PCM-TD-DFT, whereas the transition energies are obtained with a wavefunction-based method, offers a useful compromise between accuracy and computational cost. PMID- 25522827 TI - Legal problem worry. PMID- 25522828 TI - Fast dissolving cyclodextrin complex of piroxicam in solid dispersion part I: influence of beta-CD and HPbeta-CD on the dissolution rate of piroxicam. AB - Sublingual drug delivery is an interesting route for drug having significant hepatic first-pass metabolism or requiring rapid pharmacological effect as for patients suffering from swallowing difficulties, nausea or vomiting. Sublingual absorption could however be limited by the kinetic of drug dissolution. This study evaluated influences of cyclodextrins (beta-CD or HP-beta-CD) and their different inclusion process (spray-drying or freeze-drying) on the drug dissolution kinetic of solid dispersions in poly(ethylene glycol) (PEG, Mw 6000Da) of piroxicam, used as poor hydrosoluble drug model. A secondary objective was to determine influences of drug dispersion process in PEG (evaporation or melting methods) on the drug dissolution kinetic of piroxicam. Piroxicam solid dispersions containing or not cyclodextrins were characterized by different scanning calorimetry (DSC), Thermogravometry analyser (TGA) and Fourier transform infrared spectroscopy (FT-IR) spectroscopy. In vitro drug dissolution study of these solid dispersions was then performed. The results demonstrated the high potential and interest of solid dispersions of drug previously included in cyclodextrins for sublingual delivery of hydrophobic drugs. This study also showed the advantages of evaporation method on the melting ones during drug dispersion in PEG. Indeed, drug complexation with cyclodextrins as dispersion by melting prevented the presence in solid dispersions of drug in crystalline form which can represent up to 63%. Moreover, dispersion in PEG by evaporation method gave more porous drug delivery system than with melting methods. This allowed complete (limited at most at 80-90% with melting methods) and quick drug dissolution without rebound effect like with melting ones. PMID- 25522829 TI - Lamination of pharmaceutical tablets due to air entrapment: direct visualization and influence of the compact thickness. AB - Capping and lamination are two problems that are often faced during the industrial manufacturing of pharmaceutical tablets. Several reasons have been proposed to explain these phenomena. Among them, air entrapment is supposed to play a role in some cases. Nevertheless, no direct proof were given to prove that air entrapment can promote lamination or capping and various publications have questioned this hypothesis. In this article, using a model product compacted on a compression simulator, a direct proof of the implication of air entrapment during lamination was given. In fact, at the surface of the compact, defects with a spherical shape, clearly linked with an entrapped bubble of air, began to appear on the surface of the compact just below the pressure level to which lamination was observed. Moreover it was also observed that, when the compact thickness increased, the lamination pressure decreased, meaning that the compact thickness can promote lamination. As a conclusion, contrary to what is said in some publications, air entrapment can be involved when problems of lamination occur, and, in this case, powder desaeration should be considered. PMID- 25522830 TI - Time for a change: what dominance durations reveal about adaptation effects in the perception of a bi-stable reversible figure. AB - The effect of adaptation on the perception of a reversible figure was examined in the context of the so-called "reverse-bias effect" in which prolonged exposure to an unambiguous version of a bi-stable ambiguous stimulus serves to bias an observer to report the alternative version of the subsequently viewed ambiguous stimulus. Exposure to the unambiguous stimulus presumably selectively adapts and weakens the neural structures underlying that particular interpretation of the ambiguous figure. We extended previous research by examining the dominance durations for the two alternatives of the reversible figure (i.e., how long each alternative was perceived when it was dominant) in addition to the measures of response rate and choice preference used by other researchers. We replicated earlier findings with the previously used measures. Interestingly, adaptation with an unambiguous version of the ambiguous stimulus produced an asymmetrical effect on the dominance durations of the subsequently presented ambiguous stimulus, relative to a no-adaptation control. The dominance durations were lengthened for the perceptual organization that was the opposite of the adaptation stimulus while they were relatively unaffected for the perceptual organization that was the same as the adaptation stimulus. Our findings are consistent with the argument that adaptation effects play an important role in perceptual bistability. The asymmetrical dominance-duration findings further suggest that adaptation operates in a perceptual system in which the alternative perceptual representations of an ambiguous figure reciprocally inhibit one another via cross-inhibitory processes, consistent with views developed in other forms of bistable perception (e.g., binocular rivalry). PMID- 25522831 TI - Auditory frequency perception adapts rapidly to the immediate past. AB - Frequency modulation is critical to human speech. Evidence from psychophysics, neurophysiology, and neuroimaging suggests that there are neuronal populations tuned to this property of speech. Consistent with this, extended exposure to frequency change produces direction specific aftereffects in frequency change detection. We show that this aftereffect occurs extremely rapidly, requiring only a single trial of just 100-ms duration. We demonstrate this using a long, randomized series of frequency sweeps (both upward and downward, by varying amounts) and analyzing intertrial adaptation effects. We show the point of constant frequency is shifted systematically towards the previous trial's sweep direction (i.e., a frequency sweep aftereffect). Furthermore, the perception of glide direction is also independently influenced by the glide presented two trials previously. The aftereffect is frequency tuned, as exposure to a frequency sweep from a set centered on 1,000 Hz does not influence a subsequent trial drawn from a set centered on 400 Hz. More generally, the rapidity of adaptation suggests the auditory system is constantly adapting and "tuning" itself to the most recent environmental conditions. PMID- 25522832 TI - The subjective postural vertical in standing: reliability and normative data for healthy subjects. AB - Impaired verticality perception can cause falls, or even the inability to stand, due to lateropulsion or retropulsion. The internal estimate of verticality can be assessed through the subjective visual, haptic, or postural vertical (SPV). The SPV reflects impaired upright body orientation, but has primarily been assessed in sitting position. The internal representations of body orientation might be different between sitting and standing, mainly because of differences in somatosensory input for the estimation of SPV. To test the SPV during standing, we set up a paradigm using a device that allows movement in three dimensions (the Spacecurl). This study focused on the test-retest and interrater reliabilities of SPV measurements (n = 25) and provides normative values for the age range 20-79 years (n = 60; 10 healthy subjects per decade). The test-retest and interrater reliabilities for SPV measurements in standing subjects were good. The normality values ranged from -1.7 degrees to 2.3 degrees in the sagittal plane, and from 1.6 degrees to 1.2 degrees in the frontal plane. Minor alterations occurred with aging: SPV shifted backward with increasing age, and the variability of verticality estimates increased. Assessment of SPV in standing can be done with reliable results. SPV should next be used to test patients with an impaired sense of verticality, to determine its diagnostic value in comparison to established tools. PMID- 25522833 TI - Does object view influence the scene consistency effect? AB - Traditional research on the scene consistency effect only used clearly recognizable object stimuli to show mutually interactive context effects for both the object and background components on scene perception (Davenport & Potter in Psychological Science, 15, 559-564, 2004). However, in real environments, objects are viewed from multiple viewpoints, including an accidental, hard-to-recognize one. When the observers named target objects in scenes (Experiments 1a and 1b, object recognition task), we replicated the scene consistency effect (i.e., there was higher accuracy for the objects with consistent backgrounds). However, there was a significant interaction effect between consistency and object viewpoint, which indicated that the scene consistency effect was more important for identifying objects in the accidental view condition than in the canonical view condition. Therefore, the object recognition system may rely more on the scene context when the object is difficult to recognize. In Experiment 2, the observers identified the background (background recognition task) while the scene consistency and object views were manipulated. The results showed that object viewpoint had no effect, while the scene consistency effect was observed. More specifically, the canonical and accidental views both equally provided contextual information for scene perception. These findings suggested that the mechanism for conscious recognition of objects could be dissociated from the mechanism for visual analysis of object images that were part of a scene. The "context" that the object images provided may have been derived from its view-invariant, relatively low-level visual features (e.g., color), rather than its semantic information. PMID- 25522834 TI - The genetic background of left ventricular hypertrabeculation/noncompaction remains vague. Response. PMID- 25522835 TI - Magnetic Resonance for Noninvasive Detection of Microcirculatory Disease Associated With Allograft Vasculopathy: Intracoronary Measurement Validation. AB - INTRODUCTION AND OBJECTIVES: Cardiac allograft vasculopathy affects both epicardial and microcirculatory coronary compartments. Magnetic resonance perfusion imaging has been proposed as a useful tool to assess microcirculation mostly outside the heart transplantation setting. Instantaneous hyperemic diastolic flow velocity-pressure slope, an intracoronary physiology index, has demonstrated a better correlation with microcirculatory remodelling in cardiac allograft vasculopathy than other indices such as coronary flow velocity reserve. To investigate the potential of magnetic resonance perfusion imaging to detect the presence of microcirculatory remodeling in cardiac allograft vasculopathy, we compared magnetic resonance perfusion data with invasive intracoronary physiological indices to study microcirculation in a population of heart transplantation recipients with macrovascular nonobstructive disease demonstrated with intravascular ultrasound. METHODS: We studied 8 heart transplantation recipients (mean age, 61 [12] years, 100% male) with epicardial allograft vasculopathy defined by intravascular ultrasound, nonsignificant coronary stenoses and negative visually-assessed wall-motion/perfusion dobutamine stress magnetic resonance. Quantitative stress and rest magnetic resonance perfusion data to build myocardial perfusion reserve index, noninvasively, and 4 invasive intracoronary physiological indices were determined. RESULTS: Postprocessed data showed a mean (standard deviation) myocardial perfusion reserve index of 1.22 (0.27), while fractional flow reserve, coronary flow velocity reserve, hyperemic microvascular resistance and instantaneous hyperemic diastolic flow velocity pressure slope were 0.98 (0.02), cm/s/mmHg, 2.34 (0.55) cm/s/mmHg, 2.00 (0.69) cm/s/mmHg and 0.91 (0.65) cm/s/mmHg, respectively. The myocardial perfusion reserve index correlated strongly only with the instantaneous hyperemic diastolic flow velocity-pressure slope (r=0.75; P=.033). CONCLUSIONS: Myocardial perfusion reserve index derived from a comprehensive dobutamine stress magnetic resonance appears to be a reliable technique for noninvasive detection of microcirculatory coronary disease associated with cardiac allograft vasculopathy. PMID- 25522836 TI - Comments on exercise echocardiography and multidetector computed tomography for the evaluation of acute chest pain. PMID- 25522837 TI - Cloning and functional characterization of two abiotic stress-responsive Jerusalem artichoke (Helianthus tuberosus) fructan 1-exohydrolases (1-FEHs). AB - Two fructan hydrolases were previously reported to exist in Jerusalem artichoke (Helianthus tuberosus) and one native fructan-beta-fructosidase (1-FEH) was purified to homogeneity by SDS-PAGE, but no corresponding cDNA was cloned. Here, we cloned two full-length 1-FEH cDNA sequences from Jerusalem artichoke, named Ht1-FEH I and Ht1-FEH II, which showed high levels of identity with chicory 1-FEH I and 1-FEH II. Functional characterization of the corresponding recombinant proteins in Pichia pastoris X-33 demonstrated that both Ht1-FEHs had high levels of hydrolase activity towards beta(2,1)-linked fructans, but low or no activity towards beta(2,6)-linked levan and sucrose. Like other plant FEHs, the activities of the recombinant Ht1-FEHs were greatly inhibited by sucrose. Real-time quantitative PCR analysis showed that Ht1-FEH I transcripts accumulated to high levels in the developing leaves and stems of artichoke, whereas the expression levels of Ht1-FEH II increased in tubers during tuber sprouting, which implies that the two Ht1-FEHs play different roles. The levels of both Ht1-FEH I and II transcript were significantly increased in the stems of NaCl-treated plants. NaCl treatment also induced transcription of both Ht1-FEHs in the tubers, while PEG treatments slightly inhibited the expression of Ht1-FEH II in tubers. Analysis of sugar-metabolizing enzyme activities and carbohydrate concentration via HPLC showed that the enzyme activities of 1-FEHs were increased but the fructose content was decreased under NaCl and PEG treatments. Given that FEH hydrolyzes fructan to yield Fru, we discuss possible explanations for the inconsistency between 1-FEH activity and fructan dynamics in artichokes subjected to abiotic stress. PMID- 25522838 TI - An objective assessment method for frequency selectivity of the human auditory system. AB - BACKGROUND: Frequency selectivity (FS) is an important aspect of auditory function, and is typically described by a tuning curve function. Sharply tuned curves represent a higher acuity in detecting frequency differences, and conversely, broadly tuned curves demonstrate a lower acuity. One way of obtaining tuning curves is from techniques based on subjective behavioral responses, which yields psychophysical tuning curves (PTCs). In contrast, other methods rely on objective auditory responses to sound, such as neuron responses and otoacoustic emissions, amongst others. The present study introduces an objective method that uses stimulus frequency otoacoustic emissions (SFOAEs) to assemble suppression tuning curves (STCs). Finding an objective method of accurately measuring human FS is very important, as it would permit the FS to be assayed in non-responsive patients (e.g., neonates or comatose patients). However, before the objective method can be applied, it must be demonstrated that its ability to estimate the FS, gives comparable results to those obtained by subjective procedures i.e. PTCs. METHODS: SFOAEs responses, generated in the peripheral auditory system, were used to produce STCs. PTCs were measured by behavioral responses. The validity of the objective measures of human FS were determined by comparing stimulus frequency otoacoustic emission suppression tuning curves (SFOAE STCs) to PTCs at common stimulus parameters in 10 individuals with normal hearing, at low probe-tone levels. RESULTS: The average Q10 ratios measured between PTCs and SFOAE STCs from subjects were close to 1 at various center frequencies (F2,24 = .15, p = .858). The estimates of FS provided by SFOAE STCs and PTCs were similar. CONCLUSIONS: This system could be used to estimate auditory FS by both objective and subjective methods. SFOAE STCs have the potential to provide an objective estimate of auditory FS. PMID- 25522839 TI - The effects of psychological treatment of maternal depression on children and parental functioning: a meta-analysis. AB - Successful treatment of parental depression may have a positive effect on the functioning and psychopathology of their children. We conducted a meta-analysis to examine the effects of psychotherapy for depressed mothers on their children and parental functioning. We used a database of randomized controlled trials examining the effects of psychotherapy for adult depression and selected trials comparing psychotherapy and control conditions in depressed mothers and reporting outcomes in their children and parental functioning. Nine studies were included. The quality of these studies was not optimal and the outcome instruments differed considerably from each other. The therapies resulted in significantly decreased levels of depression (g = 0.66) in the mothers. In the seven studies that reported outcomes on the mental health of children, a significant effect size was also found (g = 0.40). The eight studies examining mother-child interactions resulted in a significant effect size of g = 0.35, and the five studies examining parenting/marital distress had a pooled effect size of g = 0.67. We found that psychotherapy leads to decreased levels of depression in depressed mothers and also found indications that psychotherapy may have a positive effect on the mental health of their children and parenting/marital distress. However, more high-quality research is needed before a definite answer can be given. PMID- 25522840 TI - Behavior in children with Prader-Willi syndrome before and during growth hormone treatment: a randomized controlled trial and 8-year longitudinal study. AB - Information on behavior of children with Prader-Willi syndrome (PWS) and the effect of growth hormone (GH) treatment is scarce. Parents report less problem behavior during GH treatment. Forty-two pre-pubertal children, aged 3.5-14 years were studied in a randomized controlled GH trial (RCT) during 2 years, followed by a longitudinal study during 8 years of GH treatment. Behavior was measured annually by the Developmental Behavior Checklist for children with intellectual disability (DBC) and a Dutch questionnaire to evaluate social behavioral problems in children, the Children's Social Behavior Questionnaire (CSBQ). Problem behavior measured by the DBC in children with PWS was similar compared to peers with comparable intellectual disability. Scores on 'Social disabilities' subscale were however significantly higher compared to the DBC total score (p < 0.01). A lower IQ was associated with more self-absorbed behavior, more communication problems and more problem behavior in general. Problem behavior measured by the CSBQ was similar compared to peers with a comparable intellectual disability, but children with PWS scored significantly higher on the 'Not tuned', 'Understanding', and 'Stereotyped' subscales than the CSBQ total score (p < 0.05 for all subscales and p = 0.001 for the 'Not tuned'-subscale). There were no significant effects of GH treatment during the RCT and 8 years of GH treatment. Children with PWS showed similar problem behavior as a reference population with a comparable intellectual disability. Social problems were the most pronounced within-problem behavior in PWS. In contrast to our expectations and parents reports, our study shows no improvement but also no deterioration of behavioral problems in children with PWS during long-term GH treatment. PMID- 25522841 TI - Genetic diversity of Mycobacterium tuberculosis isolated from tuberculosis patients in the Serengeti ecosystem in Tanzania. AB - This study was part of a larger cross-sectional survey that was evaluating tuberculosis (TB) infection in humans, livestock and wildlife in the Serengeti ecosystem in Tanzania. The study aimed at evaluating the genetic diversity of Mycobacterium tuberculosis isolates from TB patients attending health facilities in the Serengeti ecosystem. DNA was extracted from 214 sputum cultures obtained from consecutively enrolled newly diagnosed untreated TB patients aged >=18 years. Spacer oligonucleotide typing (spoligotyping) and Mycobacterium Interspersed Repetitive Units and Variable Number Tandem Repeat (MIRU-VNTR) were used to genotype M. tuberculosis to establish the circulating lineages. Of the214 M. tuberculosis isolates genotyped, 55 (25.7%) belonged to the Central Asian (CAS) family, 52 (24.3%) were T family (an ill-defined family), 38 (17.8%) belonged to the Latin American Mediterranean (LAM) family, 25 (11.7%) to the East African Indian (EAI) family, 25 (11.7%) comprised of different unassigned ('Serengeti') strain families, while 8 (3.7%) belonged to the Beijing family. A minority group that included Haarlem, X, U and S altogether accounted for 11 (5.2%) of all genotypes. MIRU-VNTR typing produced diverse patterns within and between families indicative of unlinked transmission chains. We conclude that, in the Serengeti ecosystem only a few successful families predominate namely CAS, T, LAM and EAI families. Other types found in lower prevalence are Beijing, Haarlem, X, S and MANU. The Haarlem, EAI_Somalia, LAM3 and S/convergent and X2 subfamilies found in this study were not reported in previous studies in Tanzania. PMID- 25522842 TI - Correlating Minimum Inhibitory Concentrations of ofloxacin and moxifloxacin with gyrA mutations using the genotype MTBDRsl assay. AB - OBJECTIVE: To correlate gyrA mutations found on the Genotype MTBDRsl assay in Mycobacterium tuberculosis (MTB) isolates with Minimum Inhibitory Concentrations (MICs) to the fluoroquinolones compounds ofloxacin (OFX) and moxifloxacin (MXF). METHODS: MICs for OFX and MXF were ascertained for 93 archived clinical MTB isolates that showed gyrA mutations at Ala90Val, Ser91Pro, Asp94Ala, Asn/Tyr, Gly and His. Thirty fluoroquinolones susceptible isolates as determined by presence of all wild-type gyrA bands on the Genotype MTBDRsl assay were also included. RESULTS: gyrA mutations at Ala90Val (n = 25), Ser91Pro (n = 6), Asp94Ala (n = 4), Asp94Asn/Tyr (n = 13), Asp94Gly (n = 42) and Asp94His (n = 3) were observed. Isolates with mutations at Ala90Val or Ser91Pro had MIC90 of 4.0 MUg/ml and 1.0 MUg/ml for OFX and MXF, respectively, and isolates with mutations at Asp 94Ala, Asn/Tyr, Gly and His had MIC90 of 8.0 MUg/ml, and 2.5 MUg/ml for OFX and MXF, respectively. CONCLUSIONS: MTB MICs were found to be consistently lower for MXF than for OFX among isolates with the same gyrA mutation (e.g. Ala90Val). The majority of MTB isolates containing mutations at Asp94Ala, Asn/Tyr, Gly and His in gyrA were associated with a moderate level of resistance to MXF (MIC = 2.5 MUg/ml), although 3 isolates with the mutations Asp94Asn/Tyr/Gly were associated with a high level of resistance to both fluoroquinolones (MXF MICs = 5.0-8.0 MUg/ml, OFX MICs = >=10.0 MUg/ml). PMID- 25522843 TI - Alpha-lipoic acid protects against methylmercury-induced neurotoxic effects via inhibition of oxidative stress in rat cerebral cortex. AB - MeHg is one of the environmental pollutants that lead to oxidative stress and an indirect excitotoxicity caused by altered glutamate (Glu) concentration. However, little was known of the interaction. Therefore, we developed a rat model of MeHg poisoning to explore its neurotoxic effects, and whether LA could attenuate MeHg induced neurotoxicity. Seventy-two rats were randomly divided into four groups: control group, MeHg-treated groups (4 and 12MUmol/kg), and LA pre-treatment group. Administration of the 12MUmol/kg MeHg for 4 weeks significantly increased ROS formation that might be critical to aggravate oxidative damages in cerebral cortex. Meanwhile, Glu metabolism as well as GLAST and GLT-1 appeared to be disrupted by MeHg exposure. Pre-treatment of the 35MUmol/kg LA significantly prevented MeHg-induced oxidative stress and Glu dyshomoestasis. In conclusion, findings indicated that MeHg could induce oxidative stress and Glu uptake/metabolism disorders in cerebral cortex, LA might antagonize these neurotoxic effects induced by MeHg. PMID- 25522844 TI - A semi-automated magnetic capture probe based DNA extraction and real-time PCR method applied in the Swedish surveillance of Echinococcus multilocularis in red fox (Vulpes vulpes) faecal samples. AB - BACKGROUND: Following the first finding of Echinococcus multilocularis in Sweden in 2011, 2985 red foxes (Vulpes vulpes) were analysed by the segmental sedimentation and counting technique. This is a labour intensive method and requires handling of the whole carcass of the fox, resulting in a costly analysis. In an effort to reduce the cost of labour and sample handling, an alternative method has been developed. The method is sensitive and partially automated for detection of E. multilocularis in faecal samples. The method has been used in the Swedish E. multilocularis monitoring program for 2012-2013 on more than 2000 faecal samples. METHODS: We describe a new semi-automated magnetic capture probe DNA extraction method and real time hydrolysis probe polymerase chain reaction assay (MC-PCR) for the detection of E. multilocularis DNA in faecal samples from red fox. The diagnostic sensitivity was determined by validating the new method against the sedimentation and counting technique in fox samples collected in Switzerland where E. multilocularis is highly endemic. RESULTS: Of 177 foxes analysed by the sedimentation and counting technique, E. multilocularis was detected in 93 animals. Eighty-two (88%, 95% C.I 79.8-93.9) of these were positive in the MC-PCR. In foxes with more than 100 worms, the MC-PCR was positive in 44 out of 46 (95.7%) cases. The two MC-PCR negative samples originated from foxes with only immature E. multilocularis worms. In foxes with 100 worms or less, (n = 47), 38 (80.9%) were positive in the MC-PCR. The diagnostic specificity of the MC-PCR was evaluated using fox scats collected within the Swedish screening. Of 2158 samples analysed, two were positive. This implies that the specificity is at least 99.9% (C.I. = 99.7-100). CONCLUSIONS: The MC-PCR proved to have a high sensitivity and a very high specificity. The test is partially automated but also possible to perform manually if desired. The test is well suited for nationwide E. multilocularis surveillance programs where sampling of fox scats is done to reduce the costs for sampling and where a test with a high sensitivity and a very high specificity is needed. PMID- 25522846 TI - Multiple recurrences of ipsilateral facial palsy in a patient with widening of the facial canal. AB - The incidence of facial palsy (FP) is 6-12/100,000 in children, however only one in twenty experience recurrences. This report describes the clinical approach and diagnostic considerations in a child with multiple ipsilateral FP. The first occurrence of FP in conjunction with fever occurred at age 13 months, and was succeeded by more than 20 recurrences. Imaging revealed widening of the facial canal along with thickening of the facial nerve, allowing collateral inflammation and edema to induce pressure on the nerve. This is the first case describing the association between an abnormally widened facial canal and recurrent FP in childhood. PMID- 25522845 TI - Consequences of the JAK2V617F allele burden for the prediction of transformation into myelofibrosis from polycythemia vera and essential thrombocythemia. AB - Patients diagnosed with polycythemia vera (PV) or essential thrombocythemia (ET) sometimes suffer transformation of the disease into myelofibrosis (MF), which is associated with a poorer prognosis. This study investigated the prognostic value of the allele burden of JAK2V617F, a somatic driver mutation in these diseases, by comparing the allele burden between formalin-fixed paraffin-embedded bone marrow collected at initial diagnosis and peripheral blood from follow-up visits. Although the annual changes in the JAK2V617F allele burden were comparable between MF-transformed (n = 11) and untransformed (n = 23) patients, the burden was significantly increased in MF-transformed patients exhibiting a longer disease duration than untransformed patients. Furthermore, MF transformation was only observed in patients whose JAK2V617F allele burden exceeded the mean values for each disease (PV, 71.7 %; ET, 35.5 %) at initial diagnosis or during follow up. Finally, we showed that hydroxycarbamide treatment exerted neither a preventive effect on MF transformation nor a suppressive effect on the increased JAK2V617F allele burden. In conclusion, a high JAK2V617F allele burden at initial diagnosis or during follow-up is predictive of MF transformation in PV and ET. Therefore, routine measurement of the JAK2V617F allele burden using an accurate assay system is recommended to predict MF transformation. PMID- 25522847 TI - Use of fiberoptic endoscopic evaluation of swallowing (FEES) in the management of psychogenic dysphagia in children. AB - OBJECTIVES: To describe the use of fiberoptic endoscopic evaluation of swallowing (FEES) as an adjunct in the management of children presenting with psychogenic dysphagia, defined as food avoidance and excessive fear of eating without identifiable anatomic or functional swallowing abnormalities. METHODS: Case series of patients presenting to the otolaryngology clinic of a tertiary pediatric teaching hospital between 2007 and 2008 that were evaluated and managed with the utilization of FEES. The outcomes measured were age, gender, duration of symptoms, findings of FEES, additional work-up and resolution of symptoms at follow-up. RESULTS: Five patients (4 males, 1 female) with ages ranging from 5 to 13 years old (mean=8.6). The median duration of symptoms before presentation was 3 weeks. Four families described refusal of solids starting after choking episode and variable estimated weight loss (mean 2.8kg). One child presented with vague complaints of intermittent odynophagia and food refusal. Fiberoptic endoscopic evaluation of swallowing was performed on all patients. No abnormalities of the oropharyngeal swallow were appreciated. Additional management included different combinations of modified barium swallow study, esophagastroduodenoscopy (EGD), upper GI series, antibiotics, and psychotherapy. Mean follow-up with clinic visit was 4.2 months. Three of the five children reported complete resolution of symptoms after FEES at follow-up visit. CONCLUSION: Fiberoptic endoscopic evaluation of swallowing can be a useful management tool in children with psychogenic dysphagia as it provides direct visualization of the oropharyngeal swallowing mechanism. This can be used to provide visual reassure and biofeedback to patients and parents. Additional workup should be decided on an individual basis. PMID- 25522848 TI - Relationship of prenatal depression and comorbidities to infant outcomes. AB - OBJECTIVE: The purpose of this study was to provide information on the effect of prenatal depression and anxiety as assessed in the context of obstetrical care on key infant outcomes (gestational age at birth, birth weight, and APGAR scores), while simultaneously considering interactions with maternal medical conditions among primarily Medicaid enrollees. METHODS: Obstetrical medical records of 419 women presenting consecutively for prenatal care at a health system serving primarily Medicaid patients were examined. Information on maternal characteristics (age, race, education) and maternal medical health (BMI, high blood pressure, diabetes, and kidney problems), as well as mental health information, was extracted. Depression was assessed as part of routine care using the Patient Health Questionnaire-9 (PHQ-9), and any documentation of depression or anxiety by the obstetrics clinician was also used in the analyses. RESULTS: Approximately one-third of the sample showed some evidence of prenatal depression, either based on PHQ-9 score (>=10) or clinician documentation of depression, and close to 10% showed evidence of anxiety. Multivariate analyses showed significant interactions between depression and anxiety on gestational age and birth weight, between depression and high blood pressure on gestational age, and also between anxiety and kidney problems on gestational age. CONCLUSION: Among this sample, the effect of maternal depression and anxiety on birth outcomes was more evident when considered along with maternal chronic medical conditions. This information may be used to assist prenatal care clinicians to develop risk assessment based on knowledge of multiple risk factors that may exert and additive influence on poor birth outcomes. PMID- 25522849 TI - Experimental assessment of the bioconcentration of (15)N-tamoxifen in Pseudokirchneriella subcapitata. AB - Nowadays, pharmaceutical compounds (PC) are ubiquitous in aquatic ecosystems. In addition to direct ecotoxicity, the bioconcentration of PC in organisms is a phenomenon which could have an impact on the whole ecosystem. In order to study this phenomenon, we exposed unicellular algae (Pseudokirchneriella subcapitata) to (15)N-tamoxifen, an anticancer drug labelled with a stable nitrogen isotope used as a tracer. By measuring (15)N enrichment over time, we were able to measure the increase of tamoxifen content in algae. This enrichment was measured by an elemental analyser coupled with an isotopic ratio mass spectrometer (EA IRMS). Algal cells were exposed for 7d to 3 concentrations of tamoxifen: 1, 10 and 100MUgL(-1). Our result shows a high bioconcentration in algae from the first minutes of contact. The highest bioconcentration factor measured is around 26500. We also observe that bioconcentration is not linked to the exposure concentration. This study is the first to use stable isotopes in order to monitor PCs in aquatic organisms such as algae. The use of stable isotopes in ecotoxicology offers interesting perspectives in the field of contaminant transfer in organisms and along the trophic web. PMID- 25522850 TI - Permanganate oxidation of diclofenac: The pH-dependent reaction kinetics and a ring-opening mechanism. AB - In this work, the fate of diclofenac (DCF) during permanganate (Mn(VII)) oxidation was investigated at environmentally relevant pH conditions (from 5 to 9). The batch experiments showed that the kinetics of the Mn(VII)/DCF reaction follows a second-order rate law with an apparent rate constant of 1.57+/-0.02 M( 1) s(-1) at pH 7 and 20 degrees C. The half-value of DCF was calculated to be 37.5 min, when the concentration of Mn(VII) (0.4 mM) was 20-fold excess of DCF. The pH-dependence of the reaction kinetics was investigated, and the DCF reactivity with Mn(VII) was found to decrease with increasing pH. The second order rate constants were then quantitatively described by incorporating the species distribution of DCF. A lower reactivity of the anionic DCF (DCF(-)) in comparison with its neutral counterpart (DCF(0)) was most likely attributable to the interaction between the ionized carboxylate group and amine nitrogen position, which can reduce the nucleophilicity of amine nitrogen by inductive and resonance effects. Moreover, a range of degradation products and the corresponding structures were proposed on the basis of the LC-Q-TOF-MS analysis. A detailed ring-opening reaction mechanism was proposed as follows: Mn(VII) acts as an electrophile to attack the amine moiety, leading to the formation of the primary intermediate products 2,6-dichloroaniline and 5-hydroxy-diclofenac, which can be further transformed. The further degradation proceeded through a multistep process including ring-opening, decarboxylation, hydroxylation, and cyclation reactions. PMID- 25522851 TI - Sample pretreatment to differentiate between bioconcentration and atmospheric deposition of polycyclic aromatic hydrocarbons in mosses. AB - In this first approach a comparison using different sample pretreatment methodologies has been made to differentiate between total atmospheric deposition and bioconcentration of polycyclic aromatic hydrocarbons (PAHs) in moss samples (Brachythecium rutabulum). Samples were collected in a densely polluted urban area in Barakaldo (Biscay, Basque Country) and submitted to different cleaning procedures with the aim to remove as many deposited atmospheric particles as possible. Analysis by means of Scanning Electron Microscopy coupled to Energy Dispersive Spectroscopy (SEM-EDS) allowed to quantify the removal efficiency of each cleaning procedure and to chemically characterise particles still present in the pre-cleaned sample. Cleaning moss samples twice with deionised water in an ultrasound bath showed up as the most suitable way to remove solid particles deposited on their surface. Discerning between bioconcentration and atmospheric deposition is therefore possible after GC-MS quantitative analysis of non-washed and washed moss samples. PMID- 25522852 TI - Extracellular compounds produced by bacterial consortium promoting elements mobilization from polymetallic Kupferschiefer black shale (Fore-Sudetic Monocline, Poland). AB - Culture experiments employing Fe-deficient medium showed that a consortium of indigenous microorganisms isolated from Kupferschiefer black shale produced a mixture of extracellular compounds containing siderophores which could form complexes with a wide range of elements and were able to mediate element mobilization from polymetallic black shale. The mobilization of a diverse array of elements including a number of essential trace elements (Co, Cu, Mn, Mo, Zn) and toxic species (As) was shown. Since the bacteria used in this study were originally obtained from a subsurface copper deposit, these results highlight the potential importance of extracellular compounds in biogeochemical cycles of elements in underground environment and their ecological significance in promoting the uptake of essential trace metals and resistance to toxic elements. PMID- 25522853 TI - Dioxins and dioxin-like compounds in composts and digestates from European countries as determined by the in vitro bioassay and chemical analysis. AB - Aerobic composting and anaerobic digestion plays an important role in reduction of organic waste by transforming the waste into humus, which is an excellent soil conditioner. However, applications of chemical-contaminated composts on soils may have unwanted consequences such as accumulation of persistent compounds and their transfer into food chains. The present study investigated burden of composts and digestates collected in 16 European countries (88 samples) by the compounds causing dioxin-like effects as determined by use of an in vitro transactivation assay to quantify total concentrations of aryl hydrocarbon receptor-(AhR) mediated potency. Measured concentrations of 2,3,7,8-Tetrachlorodibeno-p-dioxin (2,3,7,8-TCDD) equivalents (TEQbio) were compared to concentrations of polycyclic aromatic hydrocarbons (PAHs) and selected chlorinated compounds, including polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs), co-planar polychlorinated biphenyls (PCBs), indicator PCB congeners and organochlorine pesticides (OCPs). Median concentrations of TEQbio (dioxin-like compounds) determined by the in vitro assay in crude extracts of various types of composts ranged from 0.05 to 1.2 with a maximum 8.22MUg (TEQbio)kg(-1) dry mass. Potencies were mostly associated with less persistent compounds such as PAHs because treatment with sulfuric acid removed bioactivity from most samples. The pan-European investigation of contamination by organic contaminants showed generally good quality of the composts, the majority of which were in compliance with conservative limits applied in some countries. Results demonstrate performance and added value of rapid, inexpensive, effect-based monitoring, and points out the need to derive corresponding effect-based trigger values for the risk assessment of complex contaminated matrices such as composts. PMID- 25522854 TI - Application of immobilized TiO2 photocatalysis to improve the inactivation of Heterosigma akashiwo in ballast water by intense pulsed light. AB - Ballast water exotic discharge has been identified as a leading vector for marine species invasion. Here immobilized TiO2 photocatalysis is introduced to improve the performance of intense pulsed light. For intense pulsed light/TiO2 photocatalysis, a typical inactivation of 99.89+/-0.46% can be achieved under treatment condition of 1.78 L min(-1) flow rate, 300 V pulse peak voltage, 15 Hz pulse frequency and 5 ms pulse width. Moreover, within tested 220-260 V peak voltage, 18.37-40.51% elevation in inactivation is observed in comparison with intense pulsed light treatment alone. The rough energy consumption of the tested intense pulsed light/TiO2 treatment system is about 1.51-2.51 times higher than that of the typical commercial UV ballast water treatment system. The stability of the photocatalytic reactivity and intactness of loaded TiO2 film is proved within 20-d's test, while local erosion on stainless steel support is observed after 30-d's test. The results indicate that intense pulsed light/TiO2 photocatalysis is likely to be a competitive ballast water treatment technique, while further measures is needed to reduce the energy consumption and ensure the performance of TiO2 film in a long run. PMID- 25522855 TI - Green remediation and recycling of contaminated sediment by waste-incorporated stabilization/solidification. AB - Navigational/environmental dredging of contaminated sediment conventionally requires contained marine disposal and continuous monitoring. This study proposed a green remediation approach to treat and recycle the contaminated sediment by means of stabilization/solidification enhanced by the addition of selected solid wastes. With an increasing amount of contaminated sediment (20-70%), the 28-d compressive strength of sediment blocks decreased from greater than 10MPa to slightly above 1MPa. For augmenting the cement hydration, coal fly ash was more effective than lime and ground seashells, especially at low sediment content. The microscopic and spectroscopic analyses showed varying amounts of hydration products (primarily calcium hydroxide and calcium silicate hydrate) in the presence of coal fly ash, signifying the influence of pozzolanic reaction. To facilitate the waste utilization, cullet from beverage glass bottles and bottom ashes from coal combustion and waste incineration were found suitable to substitute coarse aggregate at 33% replacement ratio, beyond which the compressive strength decreased accordingly. The mercury intrusion porosimetry analysis indicated that the increase in the total pore area and average pore diameter were linearly correlated with the decrease of compressive strength due to waste replacement. All the sediment blocks complied with the acceptance criteria for reuse in terms of metal leachability. These results suggest that, with an appropriate mixture design, contaminated sediment and waste materials are useful resources for producing non-load-bearing masonry units or fill materials for construction uses. PMID- 25522856 TI - Commensal Streptococcus mitis is a unique vector for oral mucosal vaccination. AB - The development of vaccine approaches that induce mucosal and systemic immune responses is critical for the effective prevention of several infections. Here, we report on the use of the abundant human oral commensal bacterium Streptococcus mitis as a delivery vehicle for mucosal immunization. Using homologous recombination we generated a stable rS. mitis expressing a Mycobacterium tuberculosis protein (Ag85b). Oral administration of rS. mitis in gnotobiotic piglets resulted in efficient oral colonization and production of oral and systemic anti-Ag85b specific IgA and IgG antibodies. These results support that the commensal S. mitis is potentially a useful vector for mucosal vaccination. PMID- 25522857 TI - Incidence of breast and gynaecological cancers by ethnic group in England, 2001 2007: a descriptive study. AB - BACKGROUND: Although international comparisons reveal large geographical differences in the incidence of breast and gynaecological cancers, incidence data for ethnic groups in England remains scarce. METHODS: We compared the incidence of breast, ovarian, cervical and endometrial cancer in British Indians, Pakistanis, Bangladeshis, Black Africans, Black Caribbeans, Chinese and Whites between 2001 and 2007. We identified 357,476 cancer registrations from which incidence rates were calculated using mid-year population estimates from 2001 to 2007. Ethnicity was obtained through linkage to the Hospital Episodes Statistics database. Incidence rate ratios were calculated, comparing the 6 non-White ethnic groups to Whites, and were adjusted for age and income. RESULTS: We found evidence of differences in the incidence of all 4 cancers by ethnic group (p<0.001). Relative to Whites, South Asians had much lower rates of breast, ovarian and cervical cancer (IRRs of 0.68, 0.66 and 0.33 respectively), Blacks had lower rates of breast, ovarian and cervical cancer but higher rates of endometrial cancer (IRRs of 0.85, 0.62, 0.72 and 1.16 respectively), and Chinese had lower rates of breast and cervical cancer (IRRs of 0.72 and 0.68 respectively). There were also substantial intra-ethnic differences, particularly among South Asians, with Bangladeshis experiencing the lowest rates of all 4 cancers. CONCLUSIONS: Our study provides evidence that the risk of breast and gynaecological cancers varies by ethnic group and that those groups typically grouped together are not homogenous with regards to their cancer risk. Furthermore, several of our findings cannot be readily explained by known risk factors and therefore warrant further investigation. PMID- 25522858 TI - [Reliability and validity of the Severe Impairment Battery, short form (SIB-s), in patients with dementia in Spain]. AB - INTRODUCTION: People with progressive dementia evolve into a state where traditional neuropsychological tests are not effective. Severe Impairment Battery (SIB) and short form (SIB-s) were developed for evaluating the cognitive status in patients with severe dementia. AIM: To evaluate the psychometric attributes of the SIB-s in patients with severe dementia. PATIENTS AND METHODS: 127 institutionalized patients (female: 86.6%; mean age: 82.6 +/- 7.5 years-old) with dementia were assessed with the SIB-s, the Global Deterioration Scale (GDS), Mini Mental State Examination (MMSE), Severe Mini-Mental State Examination (sMMSE), Barthel Index and FAST. RESULTS: SIB-s acceptability, reliability, validity and precision were analyzed. The mean total score for scale was 19.1 +/- 15.34 (range: 0-48). Floor effect was 18.1%, only marginally higher than the desirable 15%. Factor analysis identified a single factor explaining 68% of the total variance of the scale. Cronbach's alpha coefficient was 0.96 and the item-total corrected correlation ranged from 0.27 to 0.83. The item homogeneity value was 0.43. Test-retest and inter-rater reliability for the total score was satisfactory (ICC: 0.96 and 0.95, respectively). The SIB-s showed moderate correlation with functional dependency scales (Barthel Index: 0.48, FAST: -0.74). Standard error of measurement was 3.07 for the total score. CONCLUSIONS: The SIB s is a reliable and valid instrument for evaluating patients with severe dementia in the Spanish population of relatively brief instruments. PMID- 25522859 TI - [Sexual dysfunction in migraine patients who receive preventive treatment: identification by means of two screening tests]. AB - INTRODUCTION: Sexual dysfunctions are one of the most important problems affecting sexual health and are associated with low levels of quality of life. AIM: To assess the sexual functioning in migraine patients and the sexual dysfunction that can be attributed to its preventive treatment. PATIENTS AND METHODS: The patients attended in the headache units of two general hospitals who visited for the first time after being prescribed preventive treatment. They answered the Massachusetts General Hospital-Sexual Functioning Questionnaire (MGH SFQ) and the Psychotropic-Related Sexual Dysfunction Questionnaire (SALSEX). RESULTS: The sample used in the study consisted of 79 patients (17 males, 62 females) aged 37.6 +/- 9.1 years (range: 19-57 years), 31 (39.2%) of them with chronic migraine. As preventive treatment, 23 (29.1%) received beta blockers; 42 (53.2%) neuromodulators; 8 (10.1%), calcium antagonists; and 6 (7.6%), antidepressants. The MGH-SFQ detected diminished overall sexual satisfaction that was at least moderate in 24 patients (30.4%). SALSEX showed changes in sexual functioning that was attributable to the preventive treatment in 36 cases (45.5%), which only exceptionally appeared spontaneously. In patients with at least moderate dysfunction on the MGH-SFQ, the mean ages at the time of testing, the number of days with pain per month and the excessive use of medication for their symptoms were all higher (53.3% versus 46.7%; p = 0.03). CONCLUSIONS: Simple sexual dysfunction screening tests often detect sexual dysfunctions in patients with migraine on preventive treatment and changes in their sex life that can be attributed to these drugs. PMID- 25522860 TI - [Spanish validation of the Iowa Rating Scale for Personality Change (IRSPC) for the appraisal of changes in personality in patients with acquired brain injury]. AB - INTRODUCTION: The Iowa Rating Scale for Personality Change (IRSPC) presents some features (puts an emphasis on the motivational and emotional functions; evaluates the 'cognitive' executive functions in the daily life; estimates the premorbid personality; values the informant reliability) that make it use really interesting for both clinical and research. AIM: The aim of this study was the Spanish validation of the IRSPC, which evaluates the 'personality changes' secondary to prefrontal cortex brain injury and particularly those located in the ventromedial area. PATIENTS AND METHODS: After the translation and the Spanish adaptation of the scale guide, we carried out a validation study with 31 patients suffering from traumatic brain injury, getting good reliability. RESULTS: The data obtained by measuring the internal consistency of the IRSPC and the inter rater and test-retest reliability support this statement. The instrument validity is confirmed by the results of the concurrent validity (comparing IRSPC and Neuropsychiatric Inventory) and the construct validity (scores before and after the trauma). CONCLUSIONS: The IRSPC is a valid and reliable instrument for clinical examination in the context of a comprehensive evaluation of the symptoms resulting from neurological diseases and particularly from the ventromedial prefrontal cortex injury. PMID- 25522861 TI - [Temporal lobe epilepsy and active neurocysticercosis: two representative case reports]. AB - INTRODUCTION: There are limited evidences reported of temporal lobe epilepsy associated with active cysticercosis in cystic stage. The objective is to present the correlation between active cysticercosis in topographical zones associated with temporal lobe epilepsy, with neuropsychiatric manifestations and pattern of secondarily generalized partial seizures. CASE REPORTS: Two cases of adult patients with neuropsychiatric manifestations of one year evolution, refractory to antipsychotic drug treatment, and who subsequently appear late onset partial secondarily generalized seizures. Cysticercosis active presence in the temporal lobe in one patient, and the insula in the other, is identified. A better clinical control after albendazol treatment and subsequently anticonvulsant therapy only remained to evaluate pertinence of pharmacological withdrawal criteria. CONCLUSIONS: Active neurocysticercosis, may be the cause of acquired neuropsychiatric disorders and temporal lobe epilepsy of late onset when the topography is in the mesolimbic circuit. Early etiologic diagnosis and appropriate treatment allows adequate control of their symptoms and potentially final cure. PMID- 25522862 TI - [Latrepirdine: a systematic review of the preclinical studies]. AB - We conduct a systematic review of the preclinical studies published to date involving the use of latrepirdine (Dimebon (r)). Latrepirdine is capable of modulating different targets, such as those related with mitochondria, acetylcholinesterase activity or intraneuronal calcium levels, perhaps thanks to its action upon the N-methyl-D-aspartate-type receptor, which belongs to the glutamate family. The findings published on the possible effect of latrepirdine in protein aggregation processes in disorders such as Alzheimer's disease and Parkinson's disease are quite controversial. Likewise, the possible neuroprotective effect of latrepirdine has been evaluated in animal models of neurodegenerative diseases, again with heterogeneous results. Consequently, it can be concluded that no preclinical scientific evidence has been found to justify carrying out clinical trials. PMID- 25522863 TI - [Aqueductal stenosis]. PMID- 25522864 TI - [Fat embolism syndrome in the brain: a clinical case triggered after fracture of the humerus and without any associated respiratory distress]. PMID- 25522865 TI - [A specific on-call stroke service?]. PMID- 25522866 TI - [A specific on-call stroke service? Reply]. PMID- 25522867 TI - Nociceptive spinal cord neurons of laminae I-III exhibit oxidative stress damage during diabetic neuropathy which is prevented by early antioxidant treatment with epigallocatechin-gallate (EGCG). AB - Spinal cord neurons located in laminae I-III respond to nociceptive stimuli and participate in the transmission of painful information to the brain. In the present study we evaluated if nociceptive laminae I-III neurons are affected by oxidative stress damage in a model of diabetic neuropathic pain (DNP), the streptozotocin-induced diabetic rat (STZ rat). Additionally, we evaluated the effects of a preventive antioxidant treatment with epigallocatechin-gallate (EGCG) in nociceptive neuronal activation and behavioural signs of DNP. Three days after diabetes induction, a treatment protocol of STZ rats with an aqueous solution of EGCG in the drinking water was initiated. Ten weeks after the onset of treatment, the spinal cords were immunoreacted against validated markers of oxidative stress damage (8-hydroxy-2'-deoxyguanosine; 8-OHdG) and of nociceptive neuronal activation (Fos). Mechanical hypersensitivity was assessed before and after EGCG treatment. Untreated STZ rats presented increased levels of 8-OHdG immunoreaction, higher numbers of Fos-immunoreacted neurons and high levels of co localization of 8-OHdG and Fos in laminae I-III. Treatment with EGCG normalized the increase of the above mentioned parameters and ameliorated mechanical hypersensitivity. The present study shows that nociceptive neurons in spinal cord laminae I-III exhibit oxidative stress damage during diabetic neuropathy, which probably affects ascending pain transmission during DNP. The neurobiological mechanisms and translational perspectives of the beneficial effects of a preventive and sustained EGCG treatment in DNP need to be evaluated in the future. PMID- 25522868 TI - Development of TEM and SEM high brightness electron guns using cold-field emission from a carbon nanotip. AB - A newly developed carbon cone nanotip (CCnT) has been used as field emission cathode both in low voltage SEM (30 kV) electron source and high voltage TEM (200 kV) electron source. The results clearly show, for both technologies, an unprecedented stability of the emission and the probe current with almost no decay during 1h, as well as a very small noise (rms less than 0.5%) compared to standard sources which use tungsten tips as emitting cathode. In addition, quantitative electric field mapping around the FE tip have been performed using in situ electron holography experiments during the emission of the new tip. These results show the advantage of the very high aspect ratio of the new CCnT which induces a strong enhancement of the electric field at the apex of the tip, leading to very small extraction voltage (some hundred of volts) for which the field emission will start. The combination of these experiments with emission current measurements has also allowed to extract an exit work function value of 4.8 eV. PMID- 25522869 TI - Towards weighing individual atoms by high-angle scattering of electrons. AB - We consider theoretically the energy loss of electrons scattered to high angles when assuming that the primary beam can be limited to a single atom. We discuss the possibility of identifying the isotopes of light elements and of extracting information about phonons in this signal. The energy loss is related to the mass of the much heavier nucleus, and is spread out due to atomic vibrations. Importantly, while the width of the broadening is much larger than the energy separation of isotopes, only the shift in the peak positions must be detected if the beam is limited to a single atom. We conclude that the experimental case will be challenging but is not excluded by the physical principles as far as considered here. Moreover, the initial experiments demonstrate that the separation of gold and carbon based on a signal that is related to their mass, rather than their atomic number. PMID- 25522870 TI - To be or not to be an organ donor: differences in attitudes between freshmen and senior medical students. AB - Despite a plethora of studies on overall attitudes related to organ donation in a health care setting, little is known as to whether or not medical students at various levels of undergraduate training have distinctive attitudes towards donation. The purpose of this study was to analyze attitudes of first- and sixth year students towards organ donation. A total of 988 students in first (573) and the final, sixth, year (415) were recruited at the Faculty of Medicine, University of Belgrade (Serbia), in the period 2-9 December, 2013. Data were collected using an anonymous questionnaire. There were 3.0% of first-year and 3.9% of sixth-year students who were registered donors (p = 0.019). Sixth-year students felt statistically significantly more positive towards signing an organ donor card [odds ratio (OR) 1.45, 95% confidence interval (CI) 1.13-1.88]. Sixth year students also considered that organ donation was sufficiently promoted, as well as that organ donation should be practiced unless there is a written notice of objection. In addition, sixth-year students had more confidence in local organ transplant institutions. In a multivariate logistic regression analysis significant predictor of positive attitude for signing organ donor card was being blood donor (OR 1.55, 95% CI 1.03-2.35). Undergraduate training and increase in overall medical knowledge seem to contribute in shaping positive attitudes towards being an organ donor. It would be beneficial that strategies for organ donation promotion target local centers for blood donor recruitment. Nevertheless, further promotion of organ donation is necessary to expand the total donor pool. PMID- 25522871 TI - A case of visceral leishmaniasis and pulmonary tuberculosis in a post-partum woman. AB - Visceral leishmaniasis due to Leishmania infantum is a vector-borne zoonotic disease transmitted by sand fly bites endemic in rural or periurban areas of the Mediterranean basin. Pregnancy is accompanied by changes in immune response, mainly a decrease in cellular immunity and a proportional increase in humoral immunity. These physiological events result in increased risk of infection by pathogens whose immunity is based on a T-helper 1 predominant response. We describe a case of visceral leishmaniasis and pulmonary tuberculosis diagnosed in a post-partum woman four days after delivery. The diagnosis of leishmaniasis should be considered in pregnant women with fever and haematologic abnormalities in endemic regions or if a history of exposure in endemic areas is reported. PMID- 25522872 TI - The effect and acceptability of tympanometry and pneumatic otoscopy in general practitioner diagnosis and management of childhood ear disease. AB - BACKGROUND: Tympanometry and pneumatic otoscopy are recommended for diagnosis of otitis media, but are not frequently used by general practitioners (GPs). We examined how, after targeted short training, GP diagnosis and management of childhood ear disease was changed by the addition of these techniques to non pneumatic otoscopy. We further explored factors influencing the uptake of these techniques. METHODS: Between 2011 and 2012, we used a crossover experimental design to determine associations between tympanometry and pneumatic otoscopy and the GP diagnosis and management of ear disease in children aged 6 months to 6 years. GPs recorded a diagnosis and management plan after examining ears using non-pneumatic otoscopy, and another after using either tympanometry or pneumatic otoscopy. We compared diagnosis, prescription of oral antibiotics and planned GP follow-up at these two steps between the tympanometry and pneumatic otoscopy groups. We interviewed participants about their views regarding these techniques and analysed these data thematically. RESULTS: Thirteen GPs recorded 694 ear examinations on 347 children: 347 examinations with non-pneumatic otoscopy; then 196 using tympanometry; and 151 using pneumatic otoscopy. Tympanometry was more likely to be associated with changes in diagnosis (chi (2) = 28.64, df 1, p < 0.001) and planned GP follow-up (chi (2) = 9.24, df 1, p < 0.01) than pneumatic otoscopy. Change in oral antibiotic prescription was no different between the two techniques. GPs preferred tympanometry to pneumatic otoscopy, but cost was a barrier to ongoing use. Pneumatic otoscopy was considered the more difficult skill. GPs were not convinced that the increased detection of middle ear effusion afforded by tympanometry and pneumatic otoscopy resulted in benefit to general practice patients. CONCLUSION: Tympanometry was more likely than pneumatic otoscopy to change GP diagnoses and follow-up plans of childhood ear disease. Tympanometry may require less training than pneumatic otoscopy. GPs preferred tympanometry due to ease of use and interpretation; however, perceived high cost inhibited their intent to use it in the future. Training, cost and perceived lack of patient benefit are barriers to the use of tympanometry and pneumatic otoscopy in general practice. PMID- 25522873 TI - The next trial will be conflicting! Effects of explicit congruency pre-cues on cognitive control. AB - The dual mechanisms of control account proposed a role for proactive and reactive mechanisms in minimizing or resolving interference in conflict tasks. Proactive mechanisms are activated in advance of stimulus onset and lead to preparatory biasing of attention in a goal-directed fashion. Reactive mechanisms are triggered post-stimulus onset. Using an explicit, trial-by-trial pre-cueing procedure in a 4-choice color-word Stroop task, we investigated effects of congruency pre-cues on cognitive control. Under conditions of stimulus uncertainty (i.e., each word was associated with multiple, equally probable responses), pre-cue benefits were observed on incongruent trials when cues were 100% valid but not when they were 75% valid. These benefits were selectively found at the longest cue-to-stimulus interval (2,000 ms), consistent with a preparation-dependent proactive control mechanism. By contrast, when a reactive strategy of switching attention to the irrelevant dimension to predict the single correlated response was viable, pre-cue benefits were observed on incongruent trials for all cue-to-stimulus intervals including the shortest that afforded only 500 ms to prepare. The findings (a) suggest a restricted role for the preparation-dependent biasing of attention via proactive control in response to explicit, trial-by-trial pre-cues while (b) highlighting strategies that lead to pre-cue benefits but which appear to reflect primarily reactive use of the information afforded by the pre-cues. We conclude that pre-cues, though available in advance of stimulus onset, may stimulate proactive or reactive minimization of interference. PMID- 25522875 TI - A cell-free system toward deciphering the post-translational modification barcodes of Oct4 in different cellular contexts. AB - The octamer-binding transcription factor 4 (Oct4) is essential for maintaining the self-renewal and pluripotency of embryonic stem cells (ESCs). Post translational modifications (PTMs) of Oct4 critically control its structure, function and intracellular localization. However, determination of Oct4 PTM profiles has largely been restricted by the quantity and purity of the Oct4 protein samples required for mass spectrometric analyses. In this study, by incubating the Escherichia coli-derived His-tagged Oct4 proteins with the whole cell lysates of a variety of human cells followed by retrieving the reacted Oct4 proteins with the Ni-NTA beads, we developed a labor- and cost-effective in vitro PTM method that allowed for mass spectrometric determination of the phosphorylation profiles of Oct4 proteins exposed to various cell-free systems. A number of Oct4 phosphorylation sites that were commonly present in all the cell free systems or specifically present in a particular cellular context were identified, indicating that Oct4 is controlled by both common and distinct PTM regulatory pathways. Our work provided a proof-of-concept that such a cell-free system-based in vitro PTM approach can be applied to systematically map out the physiologically-relevant PTM sites in Oct4 proteins, which opened up an avenue to fully decipher the Oct4 PTM barcodes in various cellular contexts. PMID- 25522876 TI - Crystal structure of the Locusta migratoria odorant binding protein. AB - Locusta migratoria (Lmig) causes enormous losses to agricultural products, especially because it often infests the world with great swarms as locust plagues. Locusts find their plant hosts on which they feed through their olfactory system, in which odorant binding proteins (OBPs) play an important role. Previous study indicated that the amino acid sequences of LmigOBP showed low similarity to OBPs from other insect orders and we speculated that it might perform unique binding behavior. Here, we solved the first LmigOBP1 structure at 1.65A, which is a monomer in solution and disulfide bonds play a key role in maintaining its function. We show that LmigOBP1 possesses a unique seventh alpha helix, which is located at the surface with strong interactions with the LmigOBP1 scaffold consisting of other six alpha-helices. Moreover, the seventh alpha-helix forms a wall of an "L" shaped internal hydrophobic cavity to accommodate linear ligands, which is consistent with the binding experiments. We also demonstrate that the ligand-binding pocket in LmigOBP1 is greatly different from that in the closest homologs mosquito OBPs. Taken together, this study provides a structural basis for designing small inhibitors to control locust. PMID- 25522877 TI - Treatment of murine mast cells with IgEkappa and protein L enhances apoptotic cell death induced by IL-3 withdrawal. AB - Engagement of the high-affinity IgE receptor (FcepsilonRI) can be either protective or non-protective against apoptotic cell death (ACD) in bone marrow derived murine mast cells (BMMCs) after IL-3 withdrawal, depending on the avidity between IgE and its antigen. We recently reported that protein L (PpL), a bacterial Igkappa-binding soluble protein, is able to stimulate intracellular signaling to induce activation of BMMCs by interacting with the IgEkappa FcepsilonRI complex. However, it is unclear if cross-linking of FcepsilonRI with IgEkappa and PpL prevents or enhances IL-3-dependent ACD in BMMCs. In the present study, we found that IL-3-dependent ACD of BMMCs is accelerated by loading soluble PpL in the presence of IgEkappa-occupied FcepsilonRIalpha. For this purpose, soluble PpL was incorporated into the BMMCs. Unlike soluble PpL, immobilized PpL failed to enhance ACD, although both forms of PpL induced IL-6 production equally in BMMCs. In addition, we observed that DNS5-BSA protected anti-DNS IgE-sensitized BMMCs from IL-3 depletion-mediated ACD by inducing the production of autocrine IL-3. In contrast, DNS5-PpL enhanced IL-3 withdrawal induced ACD of anti-DNS IgE-sensitized BMMCs and reduced the production of autocrine IL-3. These findings suggest that PpL increases IL-3 withdrawal-induced ACD of IgEkappa-sensitized BMMCs by incorporating PpL into the BMMCs and that this internalized PpL may interfere with survival signals via FcepsilonRI. PMID- 25522874 TI - Liver-related deaths in HIV-infected patients between 1995 and 2010 in France: the Mortavic 2010 study in collaboration with the Agence Nationale de Recherche sur le SIDA (ANRS) EN 20 Mortalite 2010 survey. AB - OBJECTIVES: The aim of this study was to describe the proportion of liver-related diseases (LRDs) as a cause of death in HIV-infected patients in France and to compare the results with data from our five previous surveys. METHODS: In 2010, 24 clinical wards prospectively recorded all deaths occurring in around 26 000 HIV-infected patients who were regularly followed up. Results were compared with those of previous cross-sectional surveys conducted since 1995 using the same design. RESULTS: Among 230 reported deaths, 46 (20%) were related to AIDS and 30 (13%) to chronic liver diseases. Eighty per cent of patients who died from LRDs had chronic hepatitis C, 16.7% of them being coinfected with hepatitis B virus (HBV). Among patients who died from an LRD, excessive alcohol consumption was reported in 41%. At death, 80% of patients had undetectable HIV viral load and the median CD4 cell count was 349 cells/MUL. The proportion of deaths and the mortality rate attributable to LRDs significantly increased between 1995 and 2005 from 1.5% to 16.7% and from 1.20/00 to 2.00/00, respectively, whereas they tended to decrease in 2010 to 13% and 1.10/00, respectively. Among liver-related causes of death, the proportion represented by hepatocellular carcinoma (HCC) dramatically increased from 5% in 1995 to 40% in 2010 (p = 0.019). CONCLUSIONS: The proportion of LRDs among causes of death in HIV-infected patients seems recently to have reached a plateau after a rapid increase during the decade 1995 2005. LRDs remain a leading cause of death in this population, mainly as a result of hepatitis C virus (HCV) coinfection, HCC representing almost half of liver related causes of death. PMID- 25522878 TI - DNL1, encodes cellulose synthase-like D4, is a major QTL for plant height and leaf width in rice (Oryza sativa L.). AB - To better understand the genetic of rice agronomic traits, we selected two different rice germplasms in phenotypes, Xian80 and Suyunuo, to construct genetic population for QTL analysis. A total of 25 QTLs for six traits were found in a 175 F2 population. Major QTLs, qPH12,qLW12.2, qLL12 and qGW12.1, explaining 50.00%, 57.08%, 15.41% and 22.51% phenotypic variation for plant height, leaf width, leaf length and grain width, respectively, were located on the same interval of chromosome 12 flanking SSR markers RM519 and RM1103. In consideration of the great effects on plant height and leaf width, the locus was named DNL1 (Dwarf and Narrowed Leaf 1). Using a segregating population derived from F2 heterozygous individuals, a total of 1363 dwarfism and narrowed-leaf individuals was selected for screening recombinants. By high-resolution linkage analysis in 141 recombination events, DNL1 was narrowed to a 62.39kb region of InDel markers ID12M28 and HF43. The results of ORF analysis in target region and nucleotide sequence alignment indicated that DNL1 encodes cellulose synthase-like D4 protein, and a single nucleotide substitution (C2488T) in dnl1 result in decrease in plant height and leaf width. Bioinformatical analysis demonstrated that a conserved role for OsCSLD4 in the regulation of plant growth and development. Expression analysis for OsCSLDs showed OsCSLD4 highly expressed in roots, while other CSLD members had comparatively lower expression levels. However, no clear evidence about CSLD4/DNL1 expression was associated with its function. PMID- 25522879 TI - Evidence for nucleolar subcompartments in Dictyostelium. AB - The nucleolus is a multifunctional nuclear compartment usually consisting of two to three subcompartments which represent stages of ribosomal biogenesis. It is linked to several human diseases including viral infections, cancer, and neurodegeneration. Dictyostelium is a model eukaryote for the study of fundamental biological processes as well as several human diseases however comparatively little is known about its nucleolus. Unlike most nucleoli it does not possess visible subcompartments at the ultrastructural level. Several recently identified nucleolar proteins in Dictyostelium leave the nucleolus after treatment with the rDNA transcription inhibitor actinomycin-D (AM-D). Different proteins exit in different ways, suggesting that previously unidentified nucleolar subcompartments may exist. The identification of nucleolar subcompartments would help to better understand the nucleolus in this model eukaryote. Here, we show that Dictyostelium nucleolar proteins nucleomorphin isoform NumA1 and Bud31 localize throughout the entire nucleolus while calcium binding protein 4a localizes to only a portion, representing nucleolar subcompartment 1 (NoSC1). SWI/SNF complex member Snf12 localizes to a smaller area within NoSC1 representing a second nucleolar subcompartment, NoSC2. The nuclear/nucleolar localization signal KRKR from Snf12 localized GFP to NoSC2, and thus also appears to function as a nucleolar subcompartment localization signal. FhkA localizes to the nucleolar periphery displaying a similar pattern to that of Hsp32. Similarities between the redistribution patterns of Dictyostelium nucleolar proteins during nucleolar disruption as a result of either AM-D treatment or mitosis support these subcompartments. A model for the AM-D-induced redistribution patterns is proposed. PMID- 25522880 TI - A cyclic peptide accelerates the loading of peptide antigens in major histocompatibility complex class II molecules. AB - Major histocompatibility complex (MHC)-loading enhancers (MLE) have recently attracted attention because of their ability to enhance the efficacy of peptide immunotherapeutics. As small molecular weight compounds, they influence the loading of peptides in MHC molecules by converting them from a non-receptive to a receptive state. Herein, we report a 14-mer cyclic peptide 1 (CP-1) as a new class of MLE-peptide. This peptide was used to investigate its loading on human leukocyte antigen (HLA)-DR molecules. It was found that CP-1 strongly accelerates peptide-loading on both soluble and cell surface HLA-DR molecules in a dose dependent manner. The effect was evident for all subsets of HLA-DR tested, including HLA-DRB1*1501, indicating that it acts independently of P1-pocket size, which is the canonical MLE-binding site. Importantly, increased peptide-loading by CP-1 was correlated with improved CD4(+) T cell responses in vitro, while propidium iodide staining indicated low peptide-induced cytotoxicity. Thus, this study revealed a new class of peptide-based enhancers that catalyze peptide loading by allosteric interactions with MHC molecules. Because of its low cellular cytotoxicity and high MLE activity, it may be useful in stimulating antigen-specific T cell responses for therapeutic purposes. PMID- 25522881 TI - De novo design based pharmacophore query generation and virtual screening for the discovery of Hsp-47 inhibitors. AB - Heat shock protein-47 (Hsp-47) is exclusive collagen specific molecular chaperone involved in the maturation, processing and secretion of procollagen. Hsp-47 is consistently upregulated in several fibrotic diseases. Till date there is no potential antifibrotic small molecule drug available and Hsp-47 is known to be potential therapeutic target for fibrotic disorder and drug designing. We used the de novo drug design approach followed by pharmacophore generation and virtual screening to propose Hsp-47 based antifibrotic molecules. We used e-LEAD server for de novo drug design and ZINCPharmer for 3D pharmacophore generation and virtual screening. The virtually screened molecule may inhibit direct recruitment of collagen triple helix to interact with Hsp-47 and act as antifibrotic drug. PMID- 25522882 TI - Solution structure of 6aJL2 and 6aJL2-R24G amyloidogenics light chain proteins. AB - AL amyloidosis is the most common amyloid systemic disease and it is characterized by the deposition of immunoglobulin light chain amyloid fibers in different organs, causing organ failure. The immunoglobulin light chain germinal line 6a has been observed to over-express in AL patients, moreover, it was observed that, out of these amyloidogenic proteins, 25% present a mutation of an Arg to Gly in position 24. In vitro studies have shown that this mutation produces proteins with a higher amyloid fiber propensity. It was proposed that this difference was due, in part, to the formation of a non-canonical structural element. In order to get a more detailed understanding of the structural and dynamic properties that govern the amyloid fibers formation process, we have determined the solution structure by NMR for the two constructs, showing that the difference in amyloid fibril formation is not due to sequence or structure. PMID- 25522883 TI - Unusual pairing between assistants: interaction of the twin-arginine system specific chaperone DmsD with the chaperonin GroEL. AB - DmsD is a system-specific chaperone that mediates the biogenesis and maturation of DMSO reductase in Escherichia coli. It is required for DmsAB holoenzyme formation and its targeting to the cytoplasmic membrane for translocation by the twin-arginine translocase. Previous studies suggested that DmsD also interacts with general molecular chaperones to assist in folding of the reductase subunits. Here, the interaction between DmsD and GroEL was further characterized to understand the role of GroEL in DMSO reductase maturation. The inherently weak interaction between the two was strengthened in vivo under growth conditions that induce DMSO reductase expression, and the DmsD-GroEL complex showed negligible change in hydrodynamic diameter by dynamic light scattering when cross-linked. Mapping the cross-linked sites on DmsD shows that the GroEL binding site is in close proximity to the previously characterized DmsA leader binding site. These findings support a role of GroEL in DMSO reductase maturation that likely involves its chaperonin function for assisting in folding of the DmsA preprotein. PMID- 25522884 TI - [Mesenteric panniculitis: a rare cause of chronic abdominal pain]. PMID- 25522885 TI - Environmental Smoking Restrictions and Light Cigarette Adoption Among Chinese Urban Smokers. AB - Light cigarette adoption involves complex psychological and behavioral processes with many underlying factors. While numerous studies have shown that environmental restrictions on smoking are associated with higher probability of smoking cessation, it is also possible that some smokers may switch from regular to light cigarettes due to environmental pressures. The current study evaluates whether smoking restrictions in households, workplaces, and public places were respectively associated with light cigarette adoption. A cross-sectional multistage sampling process was used to recruit participants and collect data about demographics and smoking characteristics and environmental restriction variables. Multiple logistic models were employed to examine the association between environmental smoking restrictions and light cigarette adoption. Of 4735 respondents, 1592 (30.3 %) were current smokers, and 69.7 % (N = 1141) of the smokers were identified as light cigarette adopters. In a multivariate model, smoking restrictions in households, workplaces, and public places were significantly associated with higher light cigarette adoption. Under environmental smoking restrictions, which pose unique challenges to tobacco control efforts, light cigarette adoption may increase. The study findings are essential for health policy makers in designing and implementing targeted smoking cessation interventions and health education programs. PMID- 25522886 TI - Follow-up of post-transplant minimal residual disease and chimerism in childhood lymphoblastic leukaemia: 90 d to react. AB - Relapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days -30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre- or post transplant MRD status >=10(-3) . Only nine patients received DLI. Pre- and post transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62.07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52.3% vs. 14.3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2.57, P = 0.04) and duration of ciclosporin treatment (P < 0.001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post transplantation was a valuable prognostic tool to guide therapeutic intervention. PMID- 25522887 TI - Takotsubo cardiomyopathy: ten year experience at a tertiary care hospital in Pakistan. AB - OBJECTIVE: There is very little literature regarding Takotsubo Cardiomyopathy (TTC) from the Asian Countries other than Japan and Korea. We conducted this study to determine the demographics, clinical presentations, complications and recovery of left ventricular (LV) systolic function in TTC patients of Pakistani origin. METHODS: A ten years retrospective case series study of TTC was conducted at the Aga Khan University Hospital. Patients were followed for up to six months after presentation, with special emphasis on the recovery of LV function. CONCLUSION: TTC is classically triggered by an acute illness or by extreme stress and a triggering incident may not always be identified. It usually presents in the guise of an acute coronary syndrome (ACS). Our data was congruent with the existing literature, except for more heart failure and cardiogenic shock. Average Troponin-I (Tn-I) levels were also higher as compared to western population. The reason for more severity in our patients may be late presentation or different level of response to stress. PMID- 25522888 TI - A multicenter study of plasma use in the United States. AB - BACKGROUND: Detailed information regarding plasma use in the United States is needed to identify opportunities for practice improvement and design of clinical trials of plasma therapy. STUDY DESIGN AND METHODS: Ten US hospitals collected detailed medical information from the electronic health records for 1 year (2010 2011) for all adult patients transfused with plasma. RESULTS: A total of 72,167 units of plasma were transfused in 19,596 doses to 9269 patients. The median dose of plasma was 2 units (interquartile range, 2-4; range 1-72); 15% of doses were 1 unit, and 45% were 2 units. When adjusted by patient body weight (kg), the median dose was 7.3 mL/kg (interquartile range, 5.5-12.0). The median pretransfusion international normalized ratio (INR) was 1.9 (25%-75% interquartile range, 1.6 2.6). A total of 22.5% of plasma transfusions were given to patients with an INR of less than 1.6 and 48.5% for an INR of 2.0 or more. The median posttransfusion INR was 1.6 (interquartile range, 1.4-2.0). Only 42% of plasma transfusions resulted in a posttransfusion INR of less than 1.6. Correction of INR increased as the plasma dose increased from 1 to 4 units (p < 0.001). There was no difference in the INR response to different types of plasma. The most common issue locations were general ward (38%) and intensive care unit (ICU; 42%). CONCLUSION: This large database describing plasma utilization in the United States provides evidence for both inadequate dosing and unnecessary transfusion. Measures to improve plasma transfusion practice and clinical trials should be directed at patients on medical and surgical wards and in the ICU where plasma is most commonly used. PMID- 25522889 TI - A VEP study in sleeping and awake one-month-old infants and its relation with social behavior. AB - With the present study we aimed to analyze the relationship between infants' behavior and their visual evoked-potential (VEPs) response. Specifically, we want to verify differences regarding the VEP response in sleeping and awake infants and if an association between VEP components, in both groups, with neurobehavioral outcome could be identified. To do so, thirty-two full-term and healthy infants, approximately 1-month of age, were assessed through a VEP unpatterned flashlight stimuli paradigm, offered in two different intensities, and were assessed using a neurobehavioral scale. However, only 18 infants have both assessments, and therefore, these is the total included in both analysis. Infants displayed a mature neurobehavioral outcome, expected for their age. We observed that P2 and N3 components were present in both sleeping and awake infants. Differences between intensities were found regarding the P2 amplitude, but only in awake infants. Regression analysis showed that N3 amplitude predicted an adequate social interactive and internal regulatory behavior in infants who were awake during the stimuli presentation. Taking into account that social orientation and regulatory behaviors are fundamental keys for social-like behavior in 1-month-old infants, this study provides an important approach for assessing physiological biomarkers (VEPs) and its relation with social behavior, very early in postnatal development. Moreover, we evidence the importance of the infant's state when studying differences regarding visual threshold processing and its association with behavioral outcome. PMID- 25522890 TI - Autoimmunity after liver transplantation: a frequent event but a rare clinical problem. AB - Autoantibodies are frequently detected after liver transplantation (LT), but their role is unclear. This study was designed to address three points: autoantibody prevalence pre-LT and over time up to five yr after LT, identification of possible predictors of autoantibody formation, and correlation between autoantibodies and graft dysfunction. To these aims, we retrospectively evaluated 92 consecutive LT recipients for whom prospectively stored frozen sera were available for autoantibodies assessment by immunofluorescence. The overall autoantibody prevalence resulted significantly higher after LT than before LT (64% vs. 27%, p < 0.001 and 35.9% vs. 8.7%, p < 0.001 considering cutoff titer of >= 1:80 and >= 1:160, respectively). Recipient gender, donor age and gender, and indication for LT and main immunosuppressant (cyclosporine vs. tacrolimus) were not associated with the presence of autoantibodies. Patients with graft dysfunction had a significantly higher autoantibody prevalence irrespective of the etiology of liver injury as compared to those patients with persistently normal liver biochemistry, but only for cutoff titers >= 1:160 (p = 0.004). No cases of de novo autoimmune hepatitis were observed. In conclusion, autoantibodies are very frequently detected after LT also at high titers and their association with graft dysfunction likely represents an aspecific indicator of liver injury. PMID- 25522891 TI - Wrestling with the hymen: consultations and practical solutions. AB - OBJECTIVE: To study the consultation and treatment options for young women who desire revirgination surgery, and to offer recommendations. METHODS: During her initial visit to a Dutch clinic, each of these women discussed with a physician her reasons for consulting and the treatment options. RESULTS: One hundred and fifty-four women sought advice for virginity-related issues. They were planning to marry or had experienced some form of sexual violence. Of these, 48 chose hymen reconstruction (HR), 26 a temporary hymen suture (THS), and 27 to resort to some expedient for staining the sheets or to another alternative for surgery. At follow-up, 13 of the 17 women who had THS and six of the 11 who had HR reported blood loss on their wedding night, whereas all six women who inserted a capsule with food colouring stated they had stained the sheets. CONCLUSIONS: Cost effective procedures help young women who are no longer virgins to avoid reprisals by their husband or family. Pelvic floor exercises will tighten the vaginal opening. THS seems more effective than HR for producing blood loss. There are alternatives should no blood loss occur during penetration. PMID- 25522892 TI - Urine Spiking in a Pain Medicine Clinic: An Attempt to Simulate Adherence. PMID- 25522893 TI - Clinical trials update 2014: year in review. AB - This section of Headache annually reviews the status of recently completed and ongoing major clinical trials involving common headache disorders. The review will focus on multicenter trials of new therapies as well as novel formulations of previously approved therapeutics. Table 1 summarizes the major therapeutic headache trials that were ongoing at the end of 2014, according to data obtained from both the "ClinicalTrials.Gov" website and from corporate press releases and presentations. PMID- 25522894 TI - Molecular evolution of candidate genes involved in post-mating-prezygotic reproductive isolation. AB - Traits involved in post-copulatory interactions between the sexes may evolve rapidly as a result of sexual selection and/or sexual conflict, leading to post mating-prezygotic (PMPZ) reproductive isolating barriers between diverging lineages. Although the importance of PMPZ isolation is recognized, the molecular basis of such incompatibilities is not well understood. Here, we investigate molecular evolution of a subset of Drosophila mojavensis and Drosophila arizonae reproductive tract genes. These include genes that are transcriptionally regulated by conspecific mating in females, many of which are misregulated in heterospecific crosses, and a set of male genes whose transcripts are transferred to females during mating. As a group, misregulated female genes are not more divergent and do not appear to evolve under different selection pressures than other female reproductive genes. Male transferred genes evolve at a higher rate than testis-expressed genes, and at a similar rate compared to accessory gland protein genes, which are known to evolve rapidly. Four of the individual male transferred genes show patterns of divergent positive selection between D. mojavensis and D. arizonae. Three of the four genes belong to the sperm-coating protein-like family, including an ortholog of antares, which influences female fertility and receptivity in Drosophila melanogaster. Synthesis of these molecular evolutionary analyses with transcriptomics and predicted functional information makes these genes candidates for involvement in PMPZ reproductive incompatibilities between D. mojavensis and D. arizonae. PMID- 25522895 TI - Erratum to: Preventing Inguinodynia After Hernia Surgery: Does the Type of Mesh Matter? PMID- 25522896 TI - Near-infrared fluorescence imaging for real-time intraoperative anatomical guidance in minimally invasive surgery: a systematic review of the literature. AB - INTRODUCTION: Near-infrared fluorescence (NIRF) imaging, using contrast agents with fluorescent characteristics in the near-infrared (NIR: 700-900 nm) window, is considered to possess great potential for clinical practice in the future of minimally invasive surgery (MIS), given its capacity for intraoperative, real time anatomical navigation, and identification. The aim of this review is to provide an overview of the literature concerning the current and potential future applications of fluorescence imaging in supporting anatomical guidance during MIS, and thereby guiding future research. METHODS: A systematic literature search was performed in the PubMed and Embase databases. All identified articles were screened and checked for eligibility by two authors. In addition, literature was sought by screening references of eligible articles. RESULTS: After administration of a fluorescent dye (e.g., indocyanine green), NIRF imaging can be helpful to improve the visualization of vital anatomical structures during MIS. Extra-hepatic bile ducts, arteries, ureters, sentinel lymph nodes, and lymph vessels have successfully been identified using NIRF imaging. A uniform approach regarding timing and route of dye administration has not yet been established. Optimization of both imaging systems and fluorescent dyes is needed to improve current shortcomings. New preclinical dyes are considered for optimization of NIRF imaging. CONCLUSION: Future implementation of new intraoperative optical methods, such as NIRF, could significantly contribute to intraoperative anatomy navigation and facilitate critical decision-making in MIS. Further research (i.e., large multi-center randomized controlled trials) is needed to establish the true value of this innovative optical imaging technique in standard clinical practice. PMID- 25522897 TI - Is it a time to modify the BCLC guidelines in terms of the role of surgery? PMID- 25522898 TI - Delights and let-downs in the management of tumor necrosis factor receptor associated periodic syndrome: the canakinumab experience in a patient with a high penetrance T50M TNFRSF1A variant. PMID- 25522899 TI - Placebo-induced decrease in fatigue: evidence for a central action on the preparatory phase of movement. AB - Placebos have been found to affect a number of pathological processes and physiological functions through expectations of clinical improvement. Recently, the study of the placebo effect has moved from the clinical to the physical performance setting, wherein placebos can boost performance by increasing muscle work and by decreasing perceived exertion. However, nothing is known about the neurobiological underpinnings of this phenomenon. Here we show for the first time that a placebo, which subjects believed to be endurance-increasing caffeine, reduces fatigue by acting at the central level on the preparatory phase of movement. In fact, we recorded the readiness potential, which is the expression of the preparatory phase of movement at the level of the supplementary motor area, during repeated flexions of the index finger in a control group that did not receive any treatment and in a placebo group that received placebo caffeine. In the control group, as the number of flexions increased, both fatigue and readiness potential amplitude increased. By contrast, in the placebo group, as the number of flexions increased we found a decrease in perceived exertion along with no increase in readiness potential amplitude. This placebo-induced modulation of the readiness potential suggests that placebos reduce fatigue by acting centrally during the anticipatory phase of movement, thus emphasizing the important role of the central nervous system in the generation of fatigue. PMID- 25522900 TI - Acute colitis: differential diagnosis using multidetector CT. AB - AIM: To investigate the utility of multidetector CT (MDCT) in helping to establish the underlying cause of acute colitis. METHODS AND MATERIALS: All patients who had acute colitis with a well-identified cause and underwent abdomen 64-MDCT were included in the study. MDCT images were retrospectively analysed in a blinded fashion and the CT findings were correlated with the eventual aetiological diagnosis. RESULTS: The study population included 105 patients. Acute colitis was related to inflammatory bowel disease in 43 cases. MDCT was used to identify six relevant signs of inflammatory colitis: the "comb" sign (p < 0.001), enlarged lymph nodes (p < 0.001), abscess (p = 0.026), fibro-fatty infiltration (p = 0.007), small bowel involvement (p < 0.001), and the absence of an "empty colon" sign (p = 0.045). Multivariate logistic regression analysis identified three independent signs of inflammatory colitis: the "comb" sign, small bowel involvement, and enlarged lymph nodes. Acute colitis was related to bacterial infection in 35 cases. Five signs were significantly associated with infectious colitis: continuous distribution (p = 0.020), an "empty colon" sign (p = 0.002), absence of fat stranding (p = 0.013), and absence of a "comb" sign (p = 0.010) and absence of enlarged lymph nodes (p = 0.035). Multivariate analysis identified three independent signs: the "empty colon" sign and absence of fat stranding and of a "comb" sign. The remaining causes were ischaemic colitis (n = 21) and drug-related colitis (n = 6). MDCT examination provided five relevant signs of ischaemic colitis: fat stranding (p = 0.002), discontinuous distribution (p < 0.001), and absence of enlarged lymph node (p < 0.001), a "comb" sign (p = 0.006) and small bowel involvement (p = 0.037). CONCLUSIONS: MDCT provides certain suggestive signs that may be helpful in distinguishing the underlying aetiological cause of acute colitis. PMID- 25522901 TI - Detectability of hepatocellular carcinoma on gadoxetic acid-enhanced MRI at 3 T in patients with severe liver dysfunction: clinical impact of dual-source parallel radiofrequency excitation. AB - AIM: To clarify the detectability of hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced MRI at 3 T with dual-source parallel radiofrequency (RF) excitation. MATERIALS AND METHODS: Twelve patients with 26 HCCs who each underwent multidetector row CT (MDCT), gadoxetic acid-enhanced MRI with dual source parallel RF excitation, and angiography-assisted CT prior to living related-liver transplantation. Three blinded readers independently reviewed the images obtained by each imaging technique for the presence of HCC on a segment-by segment basis using a five-point confidence scale. The area under the receiver operating characteristic curve (Az), sensitivity, and specificity were compared among the three techniques. RESULTS: The Az values of gadoxetic acid-enhanced MRI were highest for all readers, although no significant difference in Az value among the three methods was obtained. No significant differences in sensitivity or specificity were observed among the three techniques for each reader. CONCLUSION: Gadoxetic acid-enhanced MRI at 3 T with dual-source parallel RF excitation has relatively high-level diagnostic potential for the detection of HCC in patients with severe liver dysfunction, which was equivalent to that of MDCT and angiography-assisted CT. Dual-source parallel RF excitation would have a clinical impact on 3 T MRI of the liver. PMID- 25522903 TI - New Approaches in Immunotherapy for the Treatment of Lung Cancer. AB - Despite the several advances in the last few years into treatment of advanced lung cancer, the 5-year survival remains extremely low. New therapeutic strategies are currently under investigation, and immunotherapy seems to offer a promising treatment alternative. In the last decade, therapeutic cancer vaccines in lung cancer have been rather disappointing, mainly due to the lack of efficient predictive biomarkers. A better refinement of the patient population that might respond to treatment might finally lead to a success story. For the first time, the immune checkpoint inhibitors are demonstrating sustained antitumor response and improved survival and they may be the first immunotherapeutics available for patients with lung cancer. PMID- 25522902 TI - Interactive simulator for e-Learning environments: a teaching software for health care professionals. AB - There is an established tradition of cardiovascular simulation tools, but the application of this kind of technology in the e-Learning arena is a novel approach. This paper presents an e-Learning environment aimed at teaching the interaction of cardiovascular and lung systems to health-care professionals. Heart-lung interaction must be analyzed while assisting patients with severe respiratory problems or with heart failure in intensive care unit. Such patients can be assisted by mechanical ventilatory assistance or by thoracic artificial lung."In silico" cardiovascular simulator was experimented during a training course given to graduate students of the School of Specialization in Cardiology at 'Sapienza' University in Rome.The training course employed CARDIOSIM(c): a numerical simulator of the cardiovascular system. Such simulator is able to reproduce pathophysiological conditions of patients affected by cardiovascular and/or lung disease. In order to study the interactions among the cardiovascular system, the natural lung and the thoracic artificial lung (TAL), the numerical model of this device has been implemented. After having reproduced a patient's pathological condition, TAL model was applied in parallel and hybrid model during the training course.Results obtained during the training course show that TAL parallel assistance reduces right ventricular end systolic (diastolic) volume, but increases left ventricular end systolic (diastolic) volume. The percentage changes induced by hybrid TAL assistance on haemodynamic variables are lower than those produced by parallel assistance. Only in the case of the mean pulmonary arterial pressure, there is a percentage reduction which, in case of hybrid assistance, is greater (about 40%) than in case of parallel assistance (20 30%).At the end of the course, a short questionnaire was submitted to students in order to assess the quality of the course. The feedback obtained was positive, showing good results with respect to the degree of students' learning and the ease of use of the software simulator. PMID- 25522904 TI - [Practical guidelines for peer support programmes for mental health problems]. AB - INTRODUCTION: This study aims to determine the guiding principles for the implementation of peer support programmes in Portugal. MATERIAL AND METHODS: The study was divided in 2 phases. In the first phase a systematic review of 112 papers indexed in ISI and EBSCO databases (2001 to 2012) was conducted. In the second phase clinicians, researchers, and people with psychiatric disabilities were invited to take part in a two-round online survey based on the Delphi process to rate the importance of statements generated from the systematic review. Data were analysed with NVivo 9 and SPSS 19. RESULTS: During the Delphi round 72 experts were contacted, 44 participated in the second round. A consensus was achieved on major statements, with 84% of the sentences obtaining a consensus and 8 key recommendations covering goals of peer support, selection of peer supporters, training and accreditation, role of mental health professionals, role of peer supporters, access to peer supporters, looking after peer supporters, and programme evaluation were based on these statements. CONCLUSIONS: Use of peer support for mental health problems is still underexplored and surrounded by some controversy and ambiguity. However, its organization and proper monitoring appears to enhance the quality of life and social inclusion of people with mental illness. This highlights the importance of conducting studies that increase our knowledge of these programmes and determining guidelines for their implementation. This national consensus may be used as a starting point for the design and implementation of peer support programmes in mental health organizations. PMID- 25522905 TI - Generation and application of a novel InsP(3)R(1) mono-antibody from mouse. AB - Inositol 1, 4, 5-Trisphosphate Receptor (InsP3R) is an intracellular Ca(2+) release channel, which widely participates in cellular processes. Three isoforms of InsP3R were identified as InsP3R1, InsP3R2, and InsP3R3. They share 60-0% protein sequence homology and form a channel in a manner of homotetramer or heterotetramer. Several InsP3R isoform-specific rabbit antibodies have been generated to distinguish their localization and functions. However, there is no report of such a valid antibody raised from other species. In his article, we prepare a mouse monoclonal antibody against a synthetic peptide with rat InsP3R1 specific carboxyl terminus sequence. This monoclonal antibody of InsP3R1 (R1-mAb) was purified and characterized as IgG2b, which can recognize InsP3R1 by Western blot (WB) analysis and immunoprecipitate (IP) InsP3R1 from moue brain lysate tested. Applied in immunofluorescent (IF) and immunohistochemical (IHC) assays, this antibody and rabbit polyclonal antibody could give the consistent results in SH-SY5Y cells, human sperm, and mouse brain paraffin section. In summary, we generate a mouse InsP3R1-specific IgG 2b antibody identifying InsP3R1 in WB, IF, IHC, and IP analysis, which provides a possible choice for detection of InsP3R1, especially in application of co-localization analysis with other InsP3R isoforms or other proteins. PMID- 25522906 TI - Breast cancer in younger women in Switzerland 1996-2009: a longitudinal population-based study. AB - BACKGROUND: Breast cancer (BC) is the most commonly diagnosed cancer and a leading cause of death in younger women. METHODS: We analysed incidence, mortality and relative survival (RS) in women with BC aged 20-49 years at diagnosis, between 1996 and 2009 in Switzerland. Trends are reported as estimated annual percentage changes (EAPC). RESULTS: Our findings confirm a slight increase in the incidence of BC in younger Swiss women during the period 1996-2009. The increase was largest in women aged 20-39 years (EAPC 1.8%). Mortality decreased in both age groups with similar EAPCs. Survival was lowest among women 20-39 years (10-year RS 73.4%). We observed no notable differences in stage of disease at diagnosis that might explain these differences. CONCLUSIONS: The increased incidence and lower survival in younger women diagnosed with BC in Switzerland indicates possible differences in risk factors, tumour biology and treatment characteristics that require additional examination. PMID- 25522907 TI - Tumor necrosis factor receptor-associated factor 6 promotes migration of rheumatoid arthritis fibroblast-like synoviocytes. AB - Fibroblast-like synoviocytes (FLSs) have a pivotal role in the destruction of joints in rheumatoid arthritis (RA). Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a critical mediator in the inflammatory pathway and of the activity of osteoclasts. The aim of the present study was to investigate whether TRAF6 is involved in the progression of RA in mouse collagen-induced arthritis (CIA) and human RA FLSs in vitro. In vivo mouse models were transfected with TRAF6 small interfering (si)RNA (siTRAF6) and TRAF6 inhibition was achieved in FLSs using an anti-TRAF6 monoclonal antibody in vitro in order to assess the effects of TRAF6 inhibition on the migration and invasion of FLSs. Inhibition of TRAF6 using mouse specific siTRAF6 reduced the severity of arthritis and joint inflammation. Serum anti-collagen II antibodies, matrix metalloproteinase (MMP) 1, MMP-3 and MMP-9 were also inhibited in CIA mice by siTRAF6. The levels of MMPs produced by IL-1beta-stimulated human RA-FLSs were reduced by anti-TRAF6 monoclonal antibody. TRAF6 blockade significantly suppressed the IL-1beta stimulated migration and invasion of human RA-FLSs. These results support a role for TRAF6 in the pathogenesis of RA, and suggest that the TRAF6 blockade may be a potential strategy in the management of RA. PMID- 25522908 TI - At will or not at will: Electrophysiological correlates of preparation for voluntary and instructed task-switching paradigms. AB - The present study investigated whether the advanced reconfiguration processes of the voluntary switching (VTS) paradigm were different from those of the instructed task switching (ITS) paradigm by examining event-related potentials (ERPs) in a within-subjects design. Of importance, given that effector-to-task mapping might lead to differential preparatory strategies, two effector-to-task mapping groups were studied: the hand-to-task (HAND) and finger-to-task (FINGER) groups. Intriguingly, we found the increased posterior negativity for voluntary switch (and/or increased posterior positivity for voluntary repeat) was exclusive to the HAND group, whereas the increased switch-related late posterior positivity in the ITS paradigm was independent of the effector manipulation. Moreover, the lateralized readiness potentials (LRP) and the mu and beta motor-related amplitude asymmetries indicated that the differential switch-related modulations were not the byproduct of hand-specific preparation. The advanced preparatory strategies in the VTS and ITS paradigms are discussed. PMID- 25522909 TI - Drainage failure of Bakri balloon: no drainage does not indicate no bleeding. PMID- 25522910 TI - Cyanobacterial distributions along a physico-chemical gradient in the Northeastern Pacific Ocean. AB - The cyanobacteria Prochlorococcus and Synechococcus are important marine primary producers. We explored their distributions and covariance along a physico chemical gradient from coastal to open ocean waters in the Northeastern Pacific Ocean. An inter-annual pattern was delineated in the dynamic transition zone where upwelled and eastern boundary current waters mix, and two new Synechococcus clades, Eastern Pacific Clade (EPC) 1 and EPC2, were identified. By applying state-of-the-art phylogenetic analysis tools to bar-coded 16S amplicon datasets, we observed higher abundance of Prochlorococcus high-light I (HLI) and low-light I (LLI) in years when more oligotrophic water intruded farther inshore, while under stronger upwelling Synechococcus I and IV dominated. However, contributions of some cyanobacterial clades were proportionally relatively constant, e.g. Synechococcus EPC2. In addition to supporting observations that Prochlorococcus LLI thrive at higher irradiances than other LL taxa, the results suggest LLI tolerate lower temperatures than previously reported. The phylogenetic precision of our 16S rRNA gene analytical approach and depth of bar-coded sequencing also facilitated detection of clades at low abundance in unexpected places. These include Prochlorococcus at the coast and Cyanobium-related sequences offshore, although it remains unclear whether these came from resident or potentially advected cells. Our study enhances understanding of cyanobacterial distributions in an ecologically important eastern boundary system. PMID- 25522911 TI - Ethyl gallate suppresses proliferation and invasion in human breast cancer cells via Akt-NF-kappaB signaling. AB - Euphorbia fischeriana Steud is a traditional Chinese Medicine that is known to possess a variety of anticarcinogenic properties. However, the bioactive constituents in Euphorbia fischeriana Steud and molecular mechanisms underlying this action in cancer treatment remain poorly understood. The present study investigated the chemotherapy activity and molecular targets of Ethyl gallate, which is identified as the major constituent extracted from the roots of Euphorbia fischeriana Steud in breast cancer cell lines in vitro. The results showed Ethyl gallate obviously decreased cell proliferation in MDA-MB-231 and MCF 7 cells in a dose- and time-dependent manner. Highly invasive MDA-MB-231 cells were found to be highly sensitive to treatment. Furthermore, significantly decreased metastatic potential of highly metastatic MDA-MB-231 cells by Ethyl gallate was identified via the inhibition of cell motility using invasion and migration through a polyethylene terephthalate membrane. Ethyl gallate treatment decreased the activity of matrix metalloproteinase-2 (MMP-2) and MMP-9 by the downregulation of mRNA levels using RT-PCR, enzymes that are critical to tumor invasion. Treatment with Ethyl gallate decreased phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappaB (NF-kappaB) activation in MDA-MB-231 cells. These results indicate that Ethyl gallate suppresses proliferation and invasion in human breast cancer cells by modulating the PI3K/Akt pathway, which may contribute to inhibiting their downstream targets such as NF-kappaB p-65, Bcl 2/Bax, and mRNA levels of MMP-2 and MMP-9 in breast cancer cells. Thus, the present study shed new light on Ethyl gallate, an important bioactive constituent of Euphorbia fischeriana Steud, in human breast cancer treatment. The findings may provide basal theories for wide therapeutic application in human breast cancer. PMID- 25522913 TI - Hybrid inorganic-organic materials with an optoelectronically active aromatic cation: (C7H7)2SnI6 and C7H7PbI3. AB - Inorganic materials with organic constituents-hybrid materials-have shown incredible promise as chemically tunable functional materials with interesting optical and electronic properties. Here, the preparation and structure are reported of two hybrid materials containing the optoelectronically active tropylium ion within tin- and lead-iodide inorganic frameworks with distinct topologies. The crystal structures of tropylium tin iodide, (C7H7)2SnI6, and tropylium lead iodide, C7H7PbI3, were solved using high-resolution synchrotron powder X-ray diffraction informed by X-ray pair distribution function data and high-resolution time-of-flight neutron diffraction. Tropylium tin iodide contains isolated tin(IV)-iodide octahedra and crystallizes as a deep black solid, while tropylium lead iodide presents one-dimensional chains of face-sharing lead(II) iodide octahedra and crystallizes as a bright red-orange powder. Experimental diffuse reflectance spectra are in good agreement with density functional calculations of the electronic structure. Calculations of the band decomposed charge densities suggest that the deep black color of tropylium tin iodide is attributed to iodide ligand to tin metal charge transfer, while the bright red orange color of tropylium lead iodide arises from charge transfer between iodine and tropylium states. Understanding the origins of the observed optoelectronic properties of these two compounds, with respect to their distinct topologies and organic-inorganic interactions, provides insight into the design of tropylium containing compounds for potential optical and electronic applications. PMID- 25522912 TI - Molecular identification of Trichinella spiralis nudix hydrolase and its induced protective immunity against trichinellosis in BALB/c mice. AB - BACKGROUND: Nudix hydrolases (Nd) is a widespread superfamily, which is found in all classes of organism, hydrolyse a wide range of organic pyrophosphates and has a 'housecleaning' function. The previous study showed that Trichinella spiralis Nd (TsNd) bound to intestinal epithelial cells (IECs), and the vaccination of mice with T7 phage-displayed TsNd polypeptides produced protective immunity. The aim of this study was to clone, express and identify the full-length TsNd and to investigate its immune protection against T. spiralis infection. METHODS: The full-length cDNA sequence of TsNd gene encoding a 46 kDa protein from T. spiralis intestinal infective larvae (IIL) was cloned and identified. The antigenicity of rTsNd was analyzed by Western blot. Transcription and expression of TsNd at T. spiralis different stages were observed by RT-PCR and IFT. The levels of the specific total IgG, IgG1 and IgG2a antibodies to rTsNd were determined by ELISA. The immune protection of rTsNd against T. spiralis infection was investigated. RESULTS: Sequence and phylogenetic analysis revealed that TsNd had a nudix motif located at 226-244aa, which had high homology and the closest evolutionary status with T. pseudospiralis. The rTsNd was obtained after expression and purification. Western blot analysis showed that anti-rTsNd serum recognized the native TsNd protein in crude antigens of muscle larvae (ML), IIL, adult worms (AW) and newborn larvae (NBL), and ES antigens of ML. Transcription and expression of TsNd gene was observed in all developmental stages of T. spiralis (ML, IIL, AW and NBL), with high level expression in IIL. An immunolocalization analysis identified TsNd in the cuticle, stichocytes and reproductive organs of the parasite. Following immunization, anti-rTsNd IgG levels were increased, and the levels of IgG1 were more significantly higher than that of IgG2a. After a challenge infection with T. spiralis, mice immunized with the rTsNd displayed a 57.7% reduction in adult worms and a 56.9% reduction in muscle larval burden. CONCLUSIONS: TsNd induced a partial protective immunity in mice and could be considered as a novel candidate vaccine antigen against trichinellosis. PMID- 25522914 TI - How is the AIE mechanism profoundly changed in an ESIPT family: the novel introduction of a tetraphenylethene group onto (Z)-3-(quinolin-2-ylmethylene)-3,4 dihydroquinoxalin-2(1H)-one. AB - It is reported that two derivatives of (Z)-3-(quinolin-2-ylmethylene)-3,4 dihydroquinoxalin-2-(1H)-one (1) with a tetraphenylethene (TPE) group introduced at amide N atom of the dihydroquinoxalinone moiety (2) or at phenyl ring of the quinoline fragment (3) are synthesized, and the derivatives exhibit a remarkably enhanced aggregation-induced emission (AIE) activity than the parent. Although both the parent and the derivatives have the characteristic of an excited state intramolecular proton transfer (ESIPT), the AIE mechanism of 2 and 3 is totally different from that of 1. The considerably stronger emission of 3 than that of 2 should be attributed to the unique crystallization-induced emission enhancement (CIEE) effect. PMID- 25522916 TI - MRS measured fatty acid composition of periprostatic adipose tissue correlates with pathological measures of prostate cancer aggressiveness. AB - PURPOSE: To investigate the association between magnetic resonance (MR) spectroscopically measured fatty acid composition of periprostatic adipose tissue and pathological markers of prostate cancer aggressiveness. MATERIALS AND METHODS: Periprostatic adipose (PPA) and subcutaneous adipose (SQA) tissue from prostate cancer patients undergoing radical prostatectomy were examined ex vivo by proton MR spectroscopy at 14.1T (n = 31). Fractions of monounsaturated, polyunsaturated, total unsaturated, and saturated fatty acids, as well as T2 relaxation times were measured from the spectra. Univariate and multivariate analyses based on receiver operating characteristic (ROC) and support vector machines (SVM) were used to evaluate the association between differential measures of fatty acid levels in the PPA and SQA tissues and Gleason score and extracapsular extension (ECE), which are pathological measures of prostate cancer aggressiveness. RESULTS: Both pathological markers for aggressive prostate cancer have separable patterns in the MRS features space. The association between ECE and PPA tissue fatty acid composition is linear (area under receiver operating characteristic curve (AROC) and 95% confidence intervals [CIs]: 1.00, [1.00, 1.00]), along the Delta(fM /fS ) measure, and is marked by elevated monounsaturated and reduced saturated fatty acids in the PPA tissue relative to SQA. In contrast, the association between Gleason score and PPA tissue fatty acid composition is nonlinear (classifier AROC and 95% CIs: 0.86, [0.71, 1.00]). CONCLUSION: Fatty acid composition is altered in the PPA tissue of patients with aggressive prostate cancer. Ex vivo MR spectroscopy may be a useful tool in studying the altered fatty acid metabolism in prostate cancer. PMID- 25522915 TI - Breast cancer stromal elastosis is associated with mammography screening detection, low Ki67 expression and favourable prognosis in a population-based study. AB - BACKGROUND: Mammography screen-detected breast cancers have a better prognosis than predicted from established prognostic markers. A search for additional features that are characteristic for these tumours and their prognosis is needed to reduce overtreatment, a recognized challenge in breast cancer patient management today. Here, we have investigated the occurrence and importance of tumour elastosis. METHODS: We performed a population based retrospective study of breast cancers detected in the Norwegian Breast Cancer Screening Programme in Vestfold County during 2004-2009. In total, 197 invasive screen-detected cancers and 75 interval cancers in patients aged 50-69 years were compared with regard to standard clinico-pathological parameters and tumour shape, as well as ER, PR, HER2 and Ki67 expression. In particular, the presence of elastotic material in tumours was graded on a 4-tiered scale (score 0-3). RESULTS: Screen-detected cancers had a significantly higher content of stromal elastosis than interval cancers (p < 0.001). High content of elastosis (score 3) correlated strongly with stellate tumour shape, low histological grade, and ER+/HER2- status. Further, high elastosis score was significantly associated with lower Ki67 expression. In survival analyses, cases with high elastosis demonstrated increased recurrence free (p = 0.03) and disease-specific survival (p = 0.11) compared to cases with low elastosis. CONCLUSION: There is a strong correlation between the presence of tumour elastosis, stellate tumour shape and mammography detection of breast cancers. To our knowledge, this is the first time elastosis has been studied in relation to breast cancer detection method. Presence of elastosis is associated with low tumour cell proliferation (Ki67) and a good prognosis. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_230. PMID- 25522917 TI - Cooperative dyads for two-photon uncaging. AB - A series of dyads that combine a photolabile protecting group (PPG) 4,5-dimethoxy 2-nitrobenzyl and different bis-donor or bis-acceptor dissymmetric chromophores acting as two-photon (2P) absorbers were synthesized. Even for low energy transfer efficiency from the 2PA subunit to the uncaging one, improvement of the 2P uncaging sensitivity in the NIR is achieved as compared to isolated PPG. Moreover enhancement of the 2PA response is achieved by tuning the electronic dissymmetry of the 2PA subunit and the arrangement of the complementary subunits in the dyads. PMID- 25522918 TI - Phase 2 trial of the cyclin-dependent kinase 4/6 inhibitor palbociclib in patients with retinoblastoma protein-expressing germ cell tumors. AB - BACKGROUND: Alterations in the retinoblastoma pathway in germ cell tumors (GCTs) have been described. In the phase 1 trials of the selective cyclin-dependent kinase 4/6 inhibitor palbociclib, 3 patients with unresectable, growing, mature teratoma syndrome achieved prolonged disease stabilization. The authors conducted an open-label, phase 2 study to determine the efficacy and safety of palbociclib in patients with incurable, refractory, retinoblastoma protein (pRB)-expressing GCTs. METHODS: Patients who had incurable, refractory GCTs that demonstrated pRB expression by immunohistochemistry received oral palbociclib 125 mg daily for 21 days followed by a 7-day break. The primary endpoint was the 24-week progression free survival (PFS) rate. A 24-week PFS rate >=15% was considered promising, and a PFS rate <=5% was not considered promising. RESULTS: Thirty patients received treatment, and 29 were evaluable for the primary endpoint. The estimated 24-week PFS rate was 28% (90% exact confidence interval, 15%-44%). Patients who had teratoma and teratoma with malignant transformation had significantly better PFS than patients who had nonteratomatous GCTs. Toxicity was manageable and was principally hematologic. CONCLUSIONS: Treatment with palbociclib was associated with a favorable 24-week PFS rate in patients with refractory, pRB-expressing GCTs. Benefit was mainly observed in patients who had unresectable teratomas and teratomas with malignant transformation. PMID- 25522919 TI - Corticosteroid injection in patients with ulnar neuropathy at the elbow: A randomized, double-blind, placebo-controlled trial. AB - INTRODUCTION: We conducted a randomized, double-blind, placebo-controlled trial to evaluate the effect of ultrasound-guided corticosteroid injection in patients with ulnar neuropathy at the elbow (UNE). METHODS: Fifty-five patients were randomized between an ultrasound-guided injection of 1 ml containing 40 mg methylprednisolone acetate and 10 mg lidocaine hydrochloride or a placebo injection. The primary outcome was the subjective change of symptoms after 3 months. The secondary outcomes were change in electrodiagnostic studies and ultrasonography findings. RESULTS: A success rate of 30% was found in the corticosteroid injection group versus 28% in the placebo injection group. Only the nerve cross-sectional area changed significantly in the intervention group, from a mean of 11.9 mm(2) to 10.9 mm(2) . CONCLUSIONS: We could not demonstrate a positive effect of ultrasound-guided corticosteroid injection in UNE compared with placebo. Favorable outcomes may be attributed to the natural course of UNE or the effect of patient education. PMID- 25522920 TI - Organic component vapor pressures and hygroscopicities of aqueous aerosol measured by optical tweezers. AB - Measurements of the hygroscopic response of aerosol and the particle-to-gas partitioning of semivolatile organic compounds are crucial for providing more accurate descriptions of the compositional and size distributions of atmospheric aerosol. Concurrent measurements of particle size and composition (inferred from refractive index) are reported here using optical tweezers to isolate and probe individual aerosol droplets over extended timeframes. The measurements are shown to allow accurate retrievals of component vapor pressures and hygroscopic response through examining correlated variations in size and composition for binary droplets containing water and a single organic component. Measurements are reported for a homologous series of dicarboxylic acids, maleic acid, citric acid, glycerol, or 1,2,6-hexanetriol. An assessment of the inherent uncertainties in such measurements when measuring only particle size is provided to confirm the value of such a correlational approach. We also show that the method of molar refraction provides an accurate characterization of the compositional dependence of the refractive index of the solutions. In this method, the density of the pure liquid solute is the largest uncertainty and must be either known or inferred from subsaturated measurements with an error of <+/-2.5% to discriminate between different thermodynamic treatments. PMID- 25522921 TI - Development and application of a real-time PCR assay for the detection and quantitation of lymphocystis disease virus. AB - Lymphocystis disease virus (LCDV) is responsible for a chronic self-limiting disease that affects more than 125 teleosts. Viral isolation of LCDV is difficult, time-consuming and often ineffective; the development of a rapid and specific tool to detect and quantify LCDV is desirable for both diagnosis and pathogenic studies. In this study, a quantitative real-time PCR (qPCR) assay was developed using a Sybr-Green-based assay targeting a highly conserved region of the MCP gene. Primers were designed on a multiple alignment that included all known LCDV genotypes. The viral DNA segment was cloned within a plasmid to generate a standard curve. The limit of detection was as low as 2.6DNA copies/MUl of plasmid and the qPCR was able to detect viral DNA from cell culture lysates and tissues at levels ten-times lower than conventional PCR. Both gilthead seabream and olive flounder LCDV has been amplified, and an in silico assay showed that LCDV of all genotypes can be amplified. LCDV was detected in target and non-target tissues of both diseased and asymptomatic fish. The LCDV qPCR assay developed in this study is highly sensitive, specific, reproducible and versatile for the detection and quantitation of Lymphocystivirus, and may also be used for asymptomatic carrier detection or pathogenesis studies of different LCDV strains. PMID- 25522922 TI - Diagnosis of human metapneumovirus in patients hospitalized with acute lower respiratory tract infection using a metal-enhanced fluorescence technique. AB - Human metapneumovirus (hMPV) is a common respiratory tract infection in children. However, conventional immunofluorescence assays (IFAs) for detecting hMPV in respiratory samples have limited reliability with a sensitivity and false negative predictive value of 58.1% and approximately 17.8%, respectively. In this study, hMPV was measured in 91 clinical respiratory samples (55 sputum and 36 nasopharyngeal aspirate samples), which were obtained from children under three years of age, utilizing our previously developed high-throughput metal-enhanced fluorescence (MEF)-based biosensor (HT-MEFB). The sensitivity of HT-MEFB for hMPV detection in the 91 samples was improved by up to 77.4% compared with that obtained with IFAs, and the specificity of HT-MEFB for hMPV detection was 91.7%. In addition, the specificity and accuracy obtained after the selection of 55 sputum samples as the analyzed specimen reached 92.3% and 90.9%, respectively. Thus, in terms of accuracy, high throughput, and sensitivity, HT-MEFB exhibits considerable potential for hMPV detection in clinical settings. PMID- 25522923 TI - A high-throughput drop microfluidic system for virus culture and analysis. AB - High mutation rates and short replication times lead to rapid evolution in RNA viruses. New tools for high-throughput culture and analysis of viral phenotypes will enable more effective studies of viral evolutionary processes. A water-in oil drop microfluidic system to study virus-cell interactions at the single event level on a massively parallel scale is described here. Murine norovirus (MNV-1) particles were co-encapsulated with individual RAW 264.7 cells in 65 pL aqueous drops formed by flow focusing in 50 MUm microchannels. At low multiplicity of infection (MOI), viral titers increased greatly, reaching a maximum 18 h post encapsulation. This system was employed to evaluate MNV-1 escape from a neutralizing monoclonal antibody (clone A6.2). Further, the system was validated as a means for testing escape from antibody neutralization using a series of viral point mutants. Finally, the replicative capacity of single viral particles in drops under antibody stress was tested. Under standard conditions, many RNA virus stocks harbor minority populations of genotypic and phenotypic variants, resulting in quasispecies. These data show that when single cells are encapsulated with single viral particles under antibody stress without competition from other virions, the number of resulting infectious particles is nearly equivalent to the number of viral genomes present. These findings suggest that lower fitness virions can infect cells successfully and replicate, indicating that the microfluidics system may serve as an effective tool for isolating mutants that escape evolutionary stressors. PMID- 25522924 TI - Role of vertical segregation in semitransparent organic photovoltaics. AB - In this work, the efficiency of semitransparent organic photovoltaic (OPV) devices for low intensity applications is investigated as a function of the processing conditions. It is observed that a thermal treatment of the organic layer induces fullerene migration toward the active layer/air interface. This physical process gives rise to different vertical segregation profiles of donor and acceptor molecules. Once the back contact is deposited, the amount of fullerene covering the surface will determine the contact selectivity and leakage current of the device. Control of this leakage current may not be essential for devices fabricated for high illumination condition applications. However, devices to be used under low illumination conditions may be highly influenced by the presence of this parasitic dark current which flows in the opposite direction to photogenerated current. At the proximity of the contacts, the vertical segregation profile is inferred from optical and electrical measurements. In particular, external quantum efficiency (EQE) measurements carried out from a relatively opaque back contact provide local information on the materials spatially close to the light source. Alternatively, capacitance-voltage measurements enable calculation of the percentage of fullerene molecules covering the cathode contact. Overall, a versatile method that can be used in regular and inverted configuration is presented that explains the different behavior observed for devices to be used under low illumination conditions. PMID- 25522925 TI - Small-molecule inhibitors of JC polyomavirus infection. AB - The JC polyomavirus (JCPyV) infects approximately 50% of the human population. In healthy individuals, the infection remains dormant and asymptomatic, but in immuno-suppressed patients, it can cause progressive multifocal leukoencephalopathy (PML), a potentially fatal demyelinating disease. Currently, there are no drugs against JCPyV infection nor for the treatment of PML. Here, we report the development of small-molecule inhibitors of JCPyV that target the initial interaction between the virus and host cell and thereby block viral entry. Utilizing a combination of computational and NMR-based screening techniques, we target the LSTc tetrasaccharide binding site within the VP1 pentameric coat protein of JCPyV. Four of the compounds from the screen effectively block viral infection in our in vitro assays using SVG-A cells. For the most potent compound, we used saturation transfer difference NMR to determine the mode of binding to purified pentamers of JCPyV VP1. Collectively, these results demonstrate the viability of this class of compounds for eventual development of JCPyV-antiviral therapeutics. PMID- 25522926 TI - Tumor-associated inflammation as a potential prognostic tool in BRCA1/2 associated breast cancer. AB - The prognosis of BRCA1/2-associated breast cancer partly depends on histologic characteristics. Most of these breast cancers, however, are poorly differentiated. BRCA1-associated cancers are mainly negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Consequently, the use of these histologic features for risk stratification in BRCA1/2 breast cancer is limited. We assessed the prognostic value of additional histologic features, including tumor-associated inflammation and tumor-associated stroma in BRCA1/2 breast cancer patients. From the Rotterdam Family Cancer Clinic database, we collected demographics, tumor characteristics, and follow-up data from female BRCA1/2 breast cancer patients. Tumor samples were centrally reviewed including histologic subtype, differentiation grade, tumor-associated inflammation density, amount of tumor-associated stroma, and intratumor necrosis. The impact of these factors on recurrence-free survival (RFS) was evaluated using univariate and multivariate Cox regression, adjusted for established prognostic features and year of diagnosis. We included 138 BRCA1 and 37 BRCA2 breast cancer patients. Median follow-up after diagnosis was 9.7 years. Independent prognostic factors for RFS were tumor size (hazard ratio [HR], 2.47 for >2 versus <=2 cm; 95% confidence interval [95% CI], 1.10-5.57), tumor-associated inflammation (HR, 0.18 for moderate/marked versus absent/mild; 95% CI, 0.05-0.61), and intratumor necrosis (HR, 2.60 for presence versus absence; 95% CI, 1.12-6.05). Established prognostic factors as nodal status and differentiation grade were not significantly related to RFS. Subgroup analyses of 138 BRCA1 and 118 triple negative breast cancer cases showed similar results. Tumor-associated inflammation density was the strongest predictor for RFS in this series of BRCA1/2 breast cancer patients. This provides a potential risk stratification tool that can easily be implemented in routine histologic examination. PMID- 25522927 TI - Chromosome 13q14 deletion in a mammary-type myofibroblastoma of the big toe Reply. PMID- 25522928 TI - Comparison of the effects of water- and land-based exercises on the physical function and quality of life in community-dwelling elderly people with history of falling: a single-blind, randomized controlled trial. AB - PURPOSE: The purpose of this study was to identify the effects of water-based exercises on the physical functions and quality of life (QOL) in community dwelling elderly people with history of falling. MATERIALS AND METHODS: Participants were randomly assigned to the water-based exercise group (n=34) or land-based exercise groups (n=32). To identify the effects on physical functions, muscle strength, flexibility, and mobility were measured. QOL and fear of falling were evaluated using the Short Form 36-item questionnaire and the modified falls efficacy scale (M-FES). The measurements were performed before and after the 10 week training period. RESULTS: Within-group analysis indicated that hip abduction and adduction strength improved significantly in both groups (p=0.005; p=0.007). However, no statistically significant within-group differences were found in the back scratch test (p=0.766) and chair sit-and-reach test (p=0.870). QOL was significantly different in both groups (health transition: p=0.014, physical functioning: p<0.001, role physical: p<0.001, role emotional: p=0.002, bodily pain: p<0.001, vitality: p<0.001, and mental health: p<0.001). There was a significant difference in the M-FES in both groups (p=0.040). CONCLUSIONS: These results indicate that water-based exercises are beneficial to improve the QOL, as well as physical activities, of community-dwelling elderly compared with land based exercise. Water-based exercises would be useful to improve physical and psychological health in the elderly people with history of falling. PMID- 25522929 TI - In commemoration of the 20th anniversary. PMID- 25522930 TI - Transition metal catalyzed meta-C-H functionalization of aromatic compounds. AB - Direct functionalization of C-H bonds represents a powerful strategy for the synthesis of complex organic compounds due to its inherent efficiency. Among various approaches, transition metal catalyzed direct activation of unreactive C H bonds is particularly effective for this purpose. However, the development of practical methods for transition metal catalyzed direct C-H functionalization has been challenging. Apart from identifying the reaction conditions that allow the activation of relatively unreactive C-H bonds, these reactions need to be selective, allowing one C-H bond to be differentiated from the rest of the ubiquitous C-H bonds of the compound. Whereas directing group guided, transition metal catalyzed ortho-C-H functionalization of aromatic compounds has seen significant growth in the past few decades, methods for meta-C-H functionalization of arenes have also emerged. This review summarizes approaches for directing group guided, transition metal catalyzed meta-C-H functionalization of aromatic compounds. Some steric-controlled, transition metal catalyzed formal meta-C-H functionalization reactions without coordinating directing groups are also discussed. PMID- 25522931 TI - Secular trend and epidemiology of measles in the Kingdom of Saudi Arabia: 2009 2012. AB - PURPOSE: To determine incidence of measles and progress towards its elimination in Saudi Arabia. METHODS: A retrospective analysis of routinely collected active and passive surveillance data on measles at the Ministry of Health, Saudi Arabia. All laboratory confirmed measles from (2009-2012) were analyzed to determine measles annual incidences and distribution by age, gender, nationality, seasonality, vaccination status and spatial distribution by region. RESULTS: Measles incidence per 1,000,000 populations increased from 3.2 in 2009 to a peak of 12.8in 2011 and a slight fall to 9.9 in 2012. About 50% of cases were in children under-five years, 12% were infants and 33% were 15 years and above. Of the total, 39%were unvaccinated and16% had unknown vaccination status. Fifty-five percent of infants were not due for vaccination. Of children <5 years, 42% received vaccination. Spatial distribution is not countrywide in each of the four years but seemed to concentrate in the central and South West regions with40% in Jizan and Jeddah. CONCLUSION: High incidence of confirmed measles among unvaccinated infants requires strengthening of the immunization services. Improvement in measles case surveillance for completeness of vaccination status, vaccination of unvaccinated youths and comprehensive immunization are needed for measles elimination. PMID- 25522932 TI - Food system sustainability for health and well-being of Indigenous Peoples. AB - OBJECTIVE: To describe how Indigenous Peoples understand how to enhance use of their food systems to promote sustainability, as demonstrated in several food based interventions. DESIGN: Comments contributed by partners from case studies of Indigenous Peoples and their food systems attending an international meeting were implemented with public health interventions at the community level in nine countries. SETTING: The Rockefeller Foundation Bellagio Conference Center in Bellagio, Italy, where experiences from case studies of Indigenous Peoples were considered and then conducted in their home communities in rural areas. SUBJECTS: Leaders of the Indigenous Peoples' case studies, their communities and their academic partners. RESULTS: Reported strategies on how to improve use of local food systems in case study communities of Indigenous Peoples. CONCLUSIONS: Indigenous Peoples' reflections on their local food systems should be encouraged and acted upon to protect and promote sustainability of the cultures and ecosystems that derive their food systems. Promoting use of local traditional food biodiversity is an essential driver of food system sustainability for Indigenous Peoples, and contributes to global consciousness for protecting food biodiversity and food system sustainability more broadly. Key lessons learned, key messages and good practices for nutrition and public health practitioners and policy makers are given. PMID- 25522933 TI - RANBP2 mutation and acute necrotizing encephalopathy: 2 cases and a literature review of the expanding clinico-radiological phenotype. AB - BACKGROUND: Acute necrotising encephalopathy (ANE) is a rapidly progressive encephalopathy associated with acute viral illness. A missense mutation in nuclear pore gene RANBP2 has been identified as a major cause of familial and recurrent ANE, which is now termed as ANE1. First presentation of ANE can mimic an acute disseminated encephalomyelitis (ADEM), although ANE presents in a slightly younger age group. Identification of this disorder at radiological study is the most important determinant of the outcome. ANE1 is inherited as autosomal dominant, but shows incomplete penetrance. METHODS: We report two female children who presented with atypical clinical presentation (afebrile) and atypical radiological presentation (lack of bilateral thalamic involvement), not fitting into the original diagnostic criteria for ANE1. Both received steroid therapy for a presumed diagnosis of ADEM and made good clinical recovery. We also reviewed the available literature on ANE1, including the clinical profile, MRI brain descriptions, CSF characteristics and common mutations. RESULTS: A total of 59 patients are reported in patients with ANE1 were identified, the incidence of ANE was higher in younger age group (<4 yrs) as compared to ADEM 5.3 yrs (3.6-7). Male and female were equally affected. High CSF protein (>0.45 g/l) was reported in 44/47 (94%) in absence CSF pleocytosis (Cells > 5 * 10(6)/L). Neuroimaging findings showed multifocal involvement across different studies, and bilateral thalamic involvement was seen in 77% of patients. CONCLUSION: Based on the literature review of ANE1 with RANBP2 mutation, we propose a threshold for RANBP2 mutation testing. PMID- 25522934 TI - The fungal microbiota of de-novo paediatric inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is characterised by an inappropriate chronic immune response against resident gut microbes. This may be on account of distinct changes in the gut microbiota termed as dysbiosis. The role of fungi in this altered luminal environment has been scarcely reported. We studied the fungal microbiome in de-novo paediatric IBD patients utilising next generation sequencing and compared with adult disease and normal controls. We report a distinct difference in fungal species with Ascomycota predominating in control subjects compared to Basidiomycota dominance in children with IBD, which could be as a result of altered tolerance in these patients. PMID- 25522935 TI - Reduction of carbon dioxide to oxalate by a binuclear copper complex. AB - Reduction of carbon dioxide to products such as oxalate (C2O4(2-)) is an active area of research, as the process converts an environmental pollutant into more useful organic compounds. However, carbon dioxide reduction remains a major challenge. Here we demonstrate a three-step reaction sequence in which a copper complex converts carbon dioxide to oxalate under mild conditions. The copper(II) complex is reduced to copper(I) in solution, either electrochemically or using sodium ascorbate. The reduced complex selectively reacts with carbon dioxide from air and fixes it into oxalate, with the oxalate ion bridging between two copper atoms. The bound oxalate ion is released as oxalic acid on treatment with mineral acids, regenerating the original copper(II) complex. This completes the process for conversion of carbon dioxide into oxalate using a binuclear copper complex and a mild reducing agent. PMID- 25522936 TI - Moderate evidence support a relationship between sugar intake and dental caries. AB - DATA SOURCES: Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), LILACS (Latin American and Caribbean Health Sciences), CNKI (China National Knowledge Infrastructure), Wanfang (China) and the South African Department of Health databases were searched. In addition the archives at the WHO Collaborating Centre for Nutrition and Oral Health at Newcastle University and reference lists of reviews were searched and experts contacted for further relevant papers. STUDY SELECTION: Intervention, cohort population or cross sectional studies were considered where there was any intervention to alter the intake of sugar or the intake of sugars or change of sugar intake was monitored. The main outcome was caries incidence. The GRADE (Grading of Recommendations Assessment Development and Evaluation) system was used to assess study quality. DATA EXTRACTION AND SYNTHESIS: Separate data abstraction forms were designed for RCTs and observational studies and meta-analyses were to be conducted where possible. RESULTS: Sixty-five papers reporting 55 studies were included. No RCTs were identified. Three studies (four papers) were interventional, eight (12 papers) were prospective cohort, 20 (25 papers) were population based and 24 (25 papers) were cross-sectional. Data variability limited meta-analysis. Of the studies, 42 out of 50 of those in children and five out of five in adults reported at least one positive association between sugars and caries.Five of the eight cohort studies allowed comparison of dental caries development when sugars consumption was equivalent to a level < 10% E (Energy) or > 10% E. All eight studies found higher caries with sugars intake > 10% E compared with < 10% E. CONCLUSIONS: This in-depth systematic review shows consistent evidence of moderate quality supporting a relationship between the amount of sugars consumed and dental caries development. There is evidence of moderate quality to show that dental caries is lower when free-sugars intake is < 10% E. Dental caries progresses with age, and the effects of sugars on the dentition are lifelong. Even low levels of caries in childhood are of significance to levels of caries throughout the life course. Analysis of the data suggests that there may be benefit in limiting sugars to < 5% E to minimise the risk of dental caries throughout the life course. PMID- 25522937 TI - No clear evidence of superiority regarding pulp medicaments in primary molars. AB - DATA SOURCES: Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, the Web of Science, OpenGrey, the US National Institutes of Health Trials Register and the World Health Organization (WHO) Clinical Trials Registry Platform. STUDY SELECTION: Two reviewers independently selected studies. Randomised controlled trials comparing different pulp interventions combining a pulp treatment technique and a medicament in primary teeth were considered. DATA EXTRACTION AND SYNTHESIS: Data abstraction and risk of bias assessment were carried out independently by two reviewers. The primary outcomes were clinical failure and radiological failure, as defined in trials, at six, 12 and 24 months. Pairwise meta-analysis using fixed-effect models was conducted with statistical heterogeneity being assessed using I2 coefficients. RESULTS: Forty-seven trials involving 3910 teeth were included. All were small single centre studies. The overall level of evidence was low with only one trial having a low risk of bias, 20 a high risk and 26 unclear risk of bias.The 47 trials examined 53 different comparisons: 25 for pulpotomy, 13 for pulpectomy, 13 for direct pulp capping and two comparisons between pulpotomy and pulpectomy.Regarding pulpotomy, 14 trials compared mineral trioxide aggregate (MTA) with formocresol (FC). MTA reduced both clinical and radiological failures at six, 12 and 24 months, although the difference was not statistically significant. MTA also showed favourable results for all secondary outcomes measured, although again, differences between MTA and FC were not statistically significant (with the exception of pathological root resorption at 24 months and dentine bridge formation at six months). MTA showed favourable results compared with calcium hydroxide (CH) (two trials) for all outcomes measured, but the differences were not statistically significant (with the exception of radiological failure at 12 months). When comparing MTA with ferric sulphate (FS) (three trials), MTA had statistically significantly fewer clinical, radiological and overall failures at 24 months. This difference was not shown at six or 12 months.FC was compared with CH in seven trials and with FS in seven trials. There was a statistically significant difference in favour of FC for clinical failure at six and 12 months, and radiological failure at six, 12 and 24 months. FC also showed favourable results for all secondary outcomes measured, although differences between FC and CH were not consistently statistically significant across time points. The comparisons between FC and FS showed no statistically significantly difference between the two medicaments for any outcome at any time point.For all other comparisons of medicaments used during pulpotomies, pulpectomies or direct pulp capping, the small numbers of studies and the inconsistency in results limits any interpretation. CONCLUSIONS: We found no evidence to identify one superior pulpotomy medicament and technique clearly. Two medicaments may be preferable: MTA or FS. The cost of MTA may preclude its clinical use and therefore FS could be used in such situations. Regarding other comparisons for pulpectomies or direct pulp capping, the small numbers of studies undertaking the same comparison limits any interpretation. PMID- 25522938 TI - Evidence unclear on whether Type I or II diabetes increases the risk of implant failure. AB - DATA SOURCES: PubMed, Web of Science and the Cochrane Oral Health Group Trials Register, www.clinicaltrials.gov, www.centerwatch.com and www.clinicalconnection.com databases. Manual searches of a number of dental journals and the reference lists of identified studies were undertaken. STUDY SELECTION: Human clinical studies comparing implant failure rates in diabetic and non-diabetic patients were considered. Three reviewers independently selected studies. DATA EXTRACTION AND SYNTHESIS: The definition of implant failure used was complete loss of the implant. Study quality was assessed using the Cochrane risk of bias approach. A narrative summary of the studies and meta-analysis are presented. RESULTS: Fourteen studies were included (one randomised controlled trial, six controlled clinical trials and seven retrospective analysis); all 14 were considered to be at high risk of bias. Meta-analysis (14 studies) found no significant difference between diabetic and non-diabetic patients; risk ratio of 1.07 (95% CI = 0.80, 1.44)(p = 65). A meta-analysis of two studies found a statistically significant difference (mean difference =0.20, 95% CI = 0.08, 0.31 p = 001;) between diabetic and non-diabetic patients concerning marginal bone loss, favouring non-diabetic patients. Meta-analysis was not possible for postoperative infections. CONCLUSIONS: The results of the present systematic review should be interpreted with caution because of the presence of uncontrolled confounding factors in the included studies. Within the limits of the existing investigations, the difference between the insertion of dental implants in non diabetic and diabetic patients did not statistically affect the implant failure rates. PMID- 25522939 TI - Insufficient evidence of the effect of systemic antibiotics on adults with symptomatic apical periodontitis or acute apical abscess. AB - DATA SOURCES: The Cochrane Oral Health Groups Trials Register, Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL, OpenGrey, ZETOC Conference Proceedings World Health Organization (WHO) International Trials Registry Platform and the US National Institutes of Health Trials Registry databases were searched with no restrictions on the language or date of publication. STUDY SELECTION: Randomised controlled trials of systemic antibiotics in adults with a clinical diagnosis of symptomatic apical periodontitis or acute apical abscess, with or without surgical intervention (considered in this situation to be extraction, incision and drainage or endodontic treatment) and with or without analgesics. DATA EXTRACTION AND SYNTHESIS: Study selection, data abstraction and risk of bias assessment were carried out independently by two reviewers. RESULTS: Two trials involving 62 patients were included. They compared the effects of oral penicillin V potassium versus a matched placebo given in conjunction with a surgical intervention and analgesics to adults with an acute apical abscess or symptomatic necrotic tooth. One study was considered to have a high risk of bias and the other an unclear risk of bias. The primary outcomes were patient-reported pain and swelling. There were no statistically significant differences in participant-reported measures of pain or swelling at any of the time points assessed within the review. The body of evidence was assessed as at very low quality. CONCLUSIONS: There is very low quality evidence that is insufficient to determine the effects of systemic antibiotics on adults with symptomatic apical periodontitis or acute apical abscess. PMID- 25522940 TI - Ibuprofen is superior to paracetamol for pain relief following third molar removal. AB - DATA SOURCES: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase and the metaRegister of Controlled Trials were searched with no language restrictions. STUDY SELECTION: Randomised controlled double-blinded clinical trials using the third molar model were included. DATA EXTRACTION AND SYNTHESIS: Two review authors independently and in duplicate extracted data. The proportion of patients with at least 50% pain relief (based on total pain relief (TOTPAR) and summed pain intensity difference (SPID) data) was calculated for all three drugs at both two and six hours post-dosing and meta-analysed for comparison. RESULTS: Seven studies involving 2241 patients were included. Two studies were considered to be at low risk of bias, three at high risk and two unclear risk of bias. Ibuprofen was found to be a superior analgesic to paracetamol at several doses, with high quality evidence suggesting that ibuprofen 400 mg is superior to 1000 mg paracetamol based on pain relief (estimated from TOTPAR data) and the use of rescue medication meta-analyses. Risk ratio (RR) for at least 50% pain relief (based on TOTPAR) at six hours was 1.47 (95% confidence interval (CI) 1.28 to 1.69; five trials) favouring 400 mg ibuprofen over 1000 mg paracetamol, RR for not using rescue medication (also favouring ibuprofen) was 1.50 (95% CI 1.25 to 1.79; four trials). For combined drug RR for at least 50% of the maximum pain relief over six hours of 1.77 (95% CI 1.32 to 2.39) (paracetamol 1000 mg and ibuprofen 400 mg) (one trial; moderate quality evidence). RR not using rescue medication 1.60 (95% CI 1.36 to 1.88) (two trials; moderate quality evidence). Adverse events were comparable between the treatment groups, but no formal analysis could be undertaken. CONCLUSIONS: There is high quality evidence that ibuprofen is superior to paracetamol at doses of 200 mg to 512 mg and 600 mg to 1000 mg respectively based on pain relief and use of rescue medication data collected at six hours postoperatively. The majority of this evidence (five out of six trials) compared ibuprofen 400 mg with paracetamol 1000 mg, these are the most frequently prescribed doses in clinical practice. The novel combination drug is showing encouraging results based on the outcomes from two trials when compared to the single drugs. PMID- 25522941 TI - Moderate quality evidence that surgical anchorage more effective than conventional anchorage during orthodontic treatment. AB - DATA SOURCES: Cochrane Oral Health Groups Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, key international orthodontic and dental journals and the World Health Organization (WHO) International Clinical Trials Registry Platform. STUDY SELECTION: Randomised controlled trials comparing surgical anchorage with conventional anchorage in orthodontic patients. Trials comparing two types of surgical anchorage were also included. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed independently and in duplicate by three review authors and the Cochrane risk of bias tool was used to assess bias. Random-effects meta-analysis was used for more than three studies when pooling of the data was clinically and statistically appropriate. Fixed-effect analysis was undertaken with two or three studies. RESULTS: Fifteen studies, involving 543 analysed participants, were included. Five ongoing studies were identified. Eight studies were assessed to be at high overall risk of bias, six at unclear risk and one study at low risk of bias. Ten studies (407 randomised and 390 analysed patients) compared surgical anchorage with conventional anchorage for the primary outcome. A random-effects meta analysis of seven studies for the primary outcome found strong evidence of an effect of surgical anchorage. Compared with conventional anchorage, surgical anchorage was more effective in the reinforcement of anchorage by 1.68 mm (95% CI -2.27 mm to -1.09 mm) (moderate quality evidence). This result should be interpreted with some caution, however, as there was a substantial degree of heterogeneity for this comparison. There was no evidence of a difference in overall duration of treatment between surgical and conventional anchorage (low quality of evidence).Information on patient-reported outcomes such as pain and acceptability was limited and inconclusive. When direct comparisons were made between two types of surgical anchorage, there was a lack of evidence to suggest that any one technique was better than another. CONCLUSIONS: There is moderate quality evidence that reinforcement of anchorage is more effective with surgical anchorage than conventional anchorage, and that results from mini-screw implants are particularly promising. While surgical anchorage is not associated with the inherent risks and compliance issues related to extra-oral headgear, none of the included studies reported on harms of surgical or conventional anchorage. PMID- 25522942 TI - Hawley or vacuum-formed retainers following orthodontic treatment? AB - DATA SOURCES: Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, ISI Web of Science, LILACS. In addition, Pro-Quest Dissertation and Thesis database and Pro-Quest Science Journals. Hand searches were also carried out in American Journal of Orthodontics and Dentofacial Orthopedics, Angle Orthodontist, European Journal of Orthodontics and Journal of Orthodontics. STUDY SELECTION: Two reviewers independently selected studies, and randomised, quasi randomised (RCTs) and controlled clinical trials (CCTs) were considered. Studies with at least six months follow-up were included. DATA EXTRACTION AND SYNTHESIS: Data extraction and risk of bias assessment were carried out independently by two reviewers. A narrative summary was presented as a meta-analysis could not be performed. RESULTS: Seven studies were included (five RCTs, two CCTs). Three were considered to be at low risk of bias, three at moderate risk and one at high risk. There was some evidence to suggest that no difference exists to distinguish between the HRs and VFRs with respect to changes in intercanine and intermolar widths after orthodontic retention. There was insufficient evidence to support the use of VFRs over HRs in relation to occlusal contacts, cost effectiveness, patient satisfaction and survival time. CONCLUSIONS: This systematic review suggests that further high-quality RCTs regarding the differences between HRs and VFRs during orthodontic retention are necessary to determine which retainer is the better selection for orthodontists. PMID- 25522943 TI - Little evidence to guide initial arch wire choice for fixed appliance therapy. AB - DATA SOURCES: Medline, Cochrane Library, Biomed Central, BBO including LILACS, Ind Med, Sceilo, Clinical trials.gov, Conference paper Index, Digital Dissertations, German National Library of Medicine (ZB MED), Google Scholar, ISI Web of Knowledge, metaRegister of Controlled Trials, OpenSIGLE, Scirus.Study selectionTwo reviewers independently selected studies. Only randomised controlled trials (RCTs) and quasi-RCTs of parallel or split-mouth design were considered. DATA EXTRACTION AND SYNTHESIS: Data abstraction and risk of bias assessment were carried out independently by two reviewers. Data were considered suitable for pooling if similar interventions were used in the same way and similar outcomes were reported. A random-effects model was used. RESULTS: Sixteen studies involving 1108 patients were included. Thirteen trials (863 patients) considered initial archwires assessing cross-section of archwires, ion implantation of archwires and archwire materials.A meta-analysis of two trials found slightly greater irregularity correction with an austenitic-active nickel-titanium (NiTi) compared with a martensitic-stabilised NiTi archwire (corresponding to MD: 1.11 mm, 95% CI: 0.38 to 2.61).Four trials (394 patients) considered archwire sequences. A meta-analysis of two trials found it took patients treated with a sequence of martensitic-active copper-nickel-titanium (CuNiTi) slightly longer to reach the working archwire (MD: 0.54 months, 95% CI: -0.87 to 1.95 ; p= 0.45) compared with a martensitic-stabilised NiTi sequence. However, patients treated with a sequence of martensitic-active CuNiTi archwires reported general greater pain intensity on the Likert scale four hours and one day after placement of each archwire, compared with a martensitic-stabilised NiTi sequence. CONCLUSIONS: There are insufficient data at present to make recommendations for the use of any available archwire type regarding effectiveness, efficacy, treatment outcome or potential side effects. The meta-analyses conducted are limited by the small number of trials and methodological issues and must therefore be subsequently confirmed. PMID- 25522944 TI - Accelerating orthodontic tooth movement using surgical and non-surgical approaches. AB - DATA SOURCES: Pubmed, Embase, Google scholar beta and the Cochrane Databases. STUDY SELECTION: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) reporting on results or treatment parameters related to accelerated orthodontic tooth movement were considered. DATA EXTRACTION AND SYNTHESIS: Data abstraction and quality assessment using the Cochrane risk of bias tool were carried out independently by two reviewers. A meta-analysis and narrative synthesis was presented. RESULTS: Eighteen studies (342 patients ) were included. Eight involved low intensity laser, seven corticotomy, and interseptal bone reduction, pulsed electromagnetic fields and photobiomodulation were each investigated by a single trial. Twelve RCTs and six CCTs were included. Two RCTs were considered to be at low risk of bias, five at unclear risk and five at high risk of bias. Three CCTS were at high risk of bias and three at unclear risk. Two studies on corticotomy and two on low intensity laser were combined in a random effects model. Higher canine retraction rate was evident with corticotomy during the first month of therapy (WMD=0.73; 95% CI: 0.28, 1.19, p<0.01) and with low intensity laser (WMD=0.42mm/month; 95% CI: 0.26, 0.57, p<0.001) in a period longer than three months. The quality of evidence supporting the interventions is moderate for laser therapy and low for corticotomy intervention. CONCLUSIONS: There is some evidence that low intensity laser therapy and corticotomy are effective, whereas the evidence is weak for interseptal bone reduction and very weak for photobiomodulation and pulsed electromagnetic fields. Overall, the results should be interpreted with caution given the small number of studies, allied to limited quality and heterogeneity of the included studies. Further research is required in this field with additional attention to application protocols, adverse effects and cost-benefit analysis. PMID- 25522945 TI - Are interventions for accelerating orthodontic tooth movement effective? AB - DATA SOURCES: Pubmed, Embase, Sciences Citation Index, Cochrane Central Register of Controlled Trials (CENTRAL) and grey literature database of SIGLE were searched from January 1, 1990 to August 20, 2011 with no language restrictions. STUDY SELECTION: Randomised controlled trials (RCTs) or quasi-RCTs in which the participants were healthy and received additional interventions to conventional orthodontic treatment for accelerating tooth movements were included. Subjects with defects in oral and maxillofacial regions (ie, cleft lip/palate), dental pathologies and medical conditions were excluded. DATA EXTRACTION AND SYNTHESIS: Studies were selected by two independent reviewers and disagreements were resolved by discussion with a third reviewer. The primary outcomes included accumulative moved distance (AMD) or movement rate (MR) and time required to move the tooth to its destination. Secondary outcomes were pain improvement, anchorage loss, periodontal health, orthodontic caries, pulp vitality and root resorption. The reviewers performed statistical pooling, where possible, according to a priori criteria on the basis of comparability of patient type, treatments and outcomes measured and risk of bias. The reviewers tested for heterogeneity, publication bias and sensitivity. A quality assessment test was conducted to evaluate the method used to measure AMD. RESULTS: The authors selected seven RCTs and two quasi-RCTs, which included a total of 101 patients with an age range of 12-26.3 years. Eight studies compared four intervention methods to no intervention group (control group). From them, four studies assessed low laser therapy (LLL), two evaluated corticotomy (CC), one assessed electrical current therapy (EC) and one evaluated pulsed electromagnetic field (PEF). Another study compared dentoalveolar distraction (DAD) vs periodontal distraction (PDD).Quality assessment scores showed that only two studies were of high quality, five studies were of medium quality, while two studies were of low quality. All studies, except one, compared left and right sides of the same participant (split mouth design), and measured the AMD.The method for measuring AMD was reliable in three studies, relatively reliable in one study and unreliable in four studies. The authors only performed pooled AMD mean meta-analysis for the LLL studies. The meta-analysis showed pooled mean AMD of 0.32 (95% confidence interval (CI), 20.04, 0.68), 0.76 (95% CI, 20.14, 1.65), and 0.73 (95% CI, 20.68, 2.14) for one month, two months and three months, respectively. Two LLL studies showed no differences regarding periodontal health and two LLL studies showed no differences in root resorption between LLL intervention and control groups. Compared to control group, one study reported that CS had significantly higher MR and another study showed that CS exhibited larger AMD for one month, two months, three months and four months. Two studies revealed that CS did not show any difference in the periodontal health status. One study reported the EC showed significantly larger AMD for one month, whereas another study reported that PEF induced larger AMD for five + 0.6 months. DAD showed faster MR and less anchorage loss compared to PDD. Teeth remained vital in both DAD and PDD interventions and one out of six cases presented root resorption in the PDD group. CONCLUSIONS: Among the five interventions corticotomy is effective and safe to accelerate orthodontic tooth movement, low-level laser therapy was unable to accelerate orthodontic tooth movement. The level of evidence does not support whether electrical current and pulsed electromagnetic fields are effective in accelerating orthodontic tooth movement and dentoalveolar or periodontal distraction is promising in accelerating orthodontic tooth movement. PMID- 25522946 TI - Caries risk and number of restored surfaces have impact on the survival of posterior composite restorations. AB - DATA SOURCES: Cochrane Library, PubMed, the Web of Science (ISI) and Scopus. STUDY SELECTION: Longitudinal studies of direct class II or classes I and II restorations in permanent dentition of at least five years duration, a minimum of 20 restorations at final recall and the original datasets available were considered. Only English language studies were included. Two reviewers screened titles independently. DATA EXTRACTION AND SYNTHESIS: Multivariate Cox regression method to analyse the variables of interest and hazard ratios with respective 95% confidence intervals were determined. The annual failure rate (AFR) of the investigated restorations and subgroups was calculated. RESULTS: Twelve studies, nine prospective and three retrospective were included. A total of 2,816 restorations (2,585 Class II and 231 Class I restorations) were included in the analysis. Five hundred and sixty-nine restorations failed during the observation period, and the main reasons for failure were caries and fracture. Regression analyses showed a significantly higher risk of failure for restorations in high caries-risk individuals and those with a higher number of restored surfaces. The overall annual failure rate at five years and ten years was 1.8% and 2.4% respectively. The rates were higher in high-caries-rate individuals at 3.2% and 4.6% respectively. CONCLUSIONS: The conclusion of the present meta-analysis of 12 clinical studies based on raw data is that caries risk and number of restored surfaces play a significant role in restoration survival, and that, on average, posterior resin composite restorations show a good survival, with annual failure rates of 1.8% at five years and 2.4% after ten years of service. PMID- 25522947 TI - Use of electronic apex locators may improve determination of working length. AB - DATA SOURCES: PubMed, LILACS, Science Direct, Cochrane Collaboration, NHS Evidence databases and in Evidence Based Dentistry and Journal of Evidence-Based Dental Practice. STUDY SELECTION: Randomised controlled trials (RCTs), clinical trials (CTs), diagnostic comparative studies and evaluation studies undertaken in adults where working length determination by both electronic and radiographic methods were used were considered. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently assessed study quality. RESULTS: Twenty-one studies were included, five RCTs and 16 in vivo diagnostic test studies. There was considerable heterogeneity between the EALs used and the study designs and a narrative summary of the findings were presented. Working length measurement was compared using three different methods: distance to the radiographic apex in teeth undergoing root canal treatment, (11 studies); concordance between the comparative measurements with EAL and radiography, (two studies); distance to specific anatomic apical reference points evaluated after tooth extraction (four studies)ded. The body of evidence was once again assessed as of low quality. CONCLUSIONS: Within the limitations of this review, it is suggested that working length determination by using EAL may perform better than radiography alone. PMID- 25522951 TI - Prognostic impact of neuroendocrine differentiation in high-grade serous ovarian carcinoma. AB - Neuroendocrine differentiation in high-grade serous ovarian carcinomas has only rarely been described. However, in our consultancy experience, we have been pointed at a case of neuroendocrine relapse in a patient with high-grade serous ovarian carcinoma where retrospectively, a minor neuroendocrine component in the primary tumor could be detected. Hypothesizing that immunohistochemical evidence of neuroendocrine differentiation might be more frequent in ovarian carcinoma than suspected by morphology, we immunophenotyped the tissue microarrays (TMAs) of a cohort of 178 high-grade serous carcinomas for chromogranin and synaptophysin expression. Synaptophysin expression was found in 12 (6.7 %) out of 172 patients, and chromogranin A expression was seen in 36 (20.7 %) out of 174 patients. Kaplan-Meier analysis revealed that carcinomas with synaptophysin expression of >20 % of positive cells (n = 4) had a significantly shorter survival time than those with 0-20 % of positive cells (p < 0.0001). Synaptophysin expression remained a significant prognostic factor in multivariate analysis (HR = 10.82, 95 % confidence interval 3.10-37.71, p < 0.0001), independently of age, FIGO stage, and residual tumor after surgery. A trend toward shorter survival was seen in patients with tumors that expressed chromogranin, irrespective of the amount of positive cells (p = 0.173). A neuroendocrine differentiation is important to keep in mind when a neuroendocrine tumor of unknown primary is detected in regional or temporal connection with an ovarian carcinoma. A minor neuroendocrine component in ovarian high-grade serous carcinomas might imply a dismal prognosis. PMID- 25522953 TI - Effects of tannins on fruit selection in three southern African frugivorous birds. AB - Tannins are common secondary compounds in plant material and are known for their ability to bind to protein which reduces nitrogen availability in the diet. In fruits, these compounds are responsible for their astringency which is thought to result in reduced food intake. In this study, the repellent effects of tannins were examined in three species of frugivorous birds: red-winged starlings Onychognathus morio, speckled mousebirds Colius striatus and Cape white-eyes Zosterops virens. Birds were fed artificial fruit diets containing varying levels of tannins in paired choice tests with the amount of food eaten by birds used to determine preference. Red-winged starlings were attracted to the control diet, indifferent to the medium tannin diet and deterred by the high tannin diet whereas speckled mousebirds and Cape white-eyes were not deterred at all concentrations. The discrepancy in the results was attributed to differences in taste sensitivity, tolerance levels and detoxification mechanisms of secondary compounds between species. Because fruit selection and ultimately fruit removal rates affect plant community composition, the disparity in the results suggests that frugivorous birds do not contribute equally to plant community dynamics. However, plant secondary compounds in fruits are diverse and their effects are similarly diverse and there is potential that different groups of secondary compounds generate disparate effects. Similar studies on other types of secondary compounds may thus contribute towards a broader understanding of the role of secondary compounds in mediating fruit-frugivore interactions. PMID- 25522952 TI - Plasma cell granuloma of the oral cavity: a mucosal manifestation of immunoglobulin G4-related disease or a mimic? AB - The aim of the study was to test the hypothesis that oral plasma cell granuloma may represent a mucosal manifestation of immunoglobulin (Ig)G4-related disease (IgG4-RD) in the oral cavity. The study sample comprised two males and four females, aged 54-79 years (median 62 years). The lesions were localized on gingival/alveolar mucosa (four cases), hard palate, and floor of the mouth, measuring 17-40 mm (median 31 mm). The duration of the lesions ranged from 3 months to several years. Information on IgG4 serum levels was available for two patients, and these were increased to 1.85 and 1.65 g/L, respectively. The follow up period ranged 11-30 months (median 13 months). None of the lesions recurred, and none of the patients developed any manifestation of IgG4-RD. Microscopically, all cases presented as nodular lesions composed of numerous polyclonal plasma cells admixed with lymphocytes, histiocytes, mast cells, and eosinophils, set within collagenized stroma in variable proportions. Obliterative phlebitis was observed in two cases. The number of IgG4-positive plasma cells ranged between 51 and 142 per HPF (median 114), while the IgG4/IgG ratio values ranged between 0.16 and 0.72 (median 0.44) and were above 0.40 in three cases. Based on international criteria, two cases were diagnosed as definite and one as probable IgG4-RD. Oral plasma cell granuloma is a heterogeneous group of lesions, and a subset may represent a mucosal manifestation of IgG4-RD in the oral cavity. PMID- 25522954 TI - Gasterophilus spp. infections in horses from northern and central Kazakhstan. AB - A cross-sectional survey was performed to obtain current data on the gastrointestinal myiasis of horses in the provinces of Kostanay, Akmola and Karagandy, northern and central Kazakhstan. The stomach, small intestine and rectum of 148 slaughter horses were examined for Gasterophilus spp. larvae during a 26-month study period. All horses were infected with 2nd and 3rd stage larvae (mean intensity: 803+/-350), and 22% of them harboured >1000 Gasterophilus spp. larvae each. Four species were identified: G. intestinalis (prevalence: 100%; mean intensity: 361+/-240 larvae), G. haemorrhoidalis (100%; 353+/-191), G. nasalis (100%; 73+/-36) and G. pecorum (91.2%; 18+/-10). Horses aged<2 years were higher infected with Gasterophilus larvae than 2-4 years old animals. Both the prevalence and extremely high intensity of Gasterophilus infections of horses in these Kazakh regions suggest respective control measurements to improve the health and performance of the animals and to increase the economic income of horse owners. PMID- 25522956 TI - Patient specific instrumentation. PMID- 25522955 TI - UP12, a novel ursolic acid derivative with potential for targeting multiple signaling pathways in hepatocellular carcinoma. AB - Targeting cancer cell glucose metabolism is a promising strategy for cancer therapy. In past approaches to cancer drug discovery, ursolic acid (UA) has been chemically modified to improve its antitumor activities and bioavailability. Here, a novel ursolic acid (UA) derivative UP12 was developed via computer-aided drug design to explore potent anti-cancer agents and to examine possible mechanisms. The structural docking analyses suggested that UP12 could bind to the active sites of glucokinase (GK), glucose transporter 1 (GLUT1) and ATPase, which are the main enzymes involved in cancer glucose metabolism. We further investigated the synergistic effect between UP12 and glycolysis inhibitor 2-deoxy d-glucose (2-DG) in inhibiting glucose metabolism of cancer cells. The pharmacological results showed that the combination enhanced depletion of intracellular ATP and decrease in lactate production, and pushed more cancer cells arrested in the S and G2/M cycle phases. The combination selectively down regulated the expression of Bcl-2 and HKII proteins, up-regulated the expression of Bax and p53, and collectively resulted in enhanced apoptosis related to caspase-3, -8, and -9 activities, in addition to inhibition on the cell mitochondrial membrane potential. The animal studies further demonstrated that the combination exhibited significant antitumor activity without obvious toxicity. In summary, UP12 can interfere cancer cell metabolism pathway and further enhance the therapeutic effects of 2-DG likely through synergistic suppression of cancer cell glucose metabolism, making UP12 a likely new candidate for anti-cancer drug development. PMID- 25522957 TI - The effects of different mixing speeds on the elution and strength of high-dose antibiotic-loaded bone cement created with the hand-mixed technique. AB - We evaluated the effects of the mixing speed of hand-mixed bone cement and the different phases of antibiotic mixing on the elution, mechanical properties, and porosity of antibiotic-loaded bone cement. Vancomycin-loaded Palacos LV bone cement was prepared at two hand-mixing speeds, normal and high-speed, and with antibiotic addition during three phases (directly mixing with the PMMA powder, in the liquid phase, and in the dough phase). The cumulative antibiotic elution over 15 days in the high-speed group was increased by 24% compared with the normal speed group (P < 0.001). The delayed antibiotic addition produced higher vancomycin elution (P < 0.05), but no difference was observed between the liquid and dough phases (P > 0.05). Our study demonstrated that bone cement prepared with high-speed hand mixing and delayed antibiotic addition can exhibit increased vancomycin release. PMID- 25522958 TI - Postthaw characterization of umbilical cord blood: markers of storage lesion. AB - BACKGROUND: The continued growth in the uses of umbilical cord blood (UCB) will require the development of meaningful postthaw quality assays. This study examines both conventional and new measures for assessing UCB quality after long term storage. STUDY DESIGN AND METHODS: The first arm of the study involved thawing UCB in storage for short (approx. 1 year) and long periods of time (>11 years). Conventional postthaw measures (colony-forming units [CFU], total nucleated cell counts, CD34+45+) were quantified in addition to apoptosis. The second arm of the study involved taking units stored in liquid nitrogen and imposing a storage lesion by storing the units in -80 degrees C for various periods of time. After storage lesion, the units were thawed and assessed. RESULTS: In the first arm of the study, there was little difference in the postthaw measures between UCB stored for short and long periods of time. There was a slight increase in the percentage of CD34+45+ cells with time in storage and a reduction in the number of cells expressing apoptosis markers. When moved from liquid nitrogen to -80 degrees C storage, the nucleated cell count varied little but there was a distinct decrease in frequency of CFUs and increase in percentage of cells expressing both early and late markers of apoptosis. CONCLUSION: Nucleated cell counts do not reflect damage to hematopoietic progenitors during long-term storage. Expression of caspases and other markers of apoptosis provide an early biomarker of damage during storage, which is consistent with other measures such as CFU and percentage of CD34+45+ cells. PMID- 25522959 TI - Morphometrics and behavior of a wild Asian elephant exhibiting disproportionate dwarfism. AB - BACKGROUND: Dwarfism is a condition characterized by shorter stature, at times accompanied by differential skeletal growth proportions relative to the species typical physical conformation. Causes vary and are well-documented in humans as well as certain mammalian species in captive or laboratory conditions, but rarely observed in the wild. CASE PRESENTATION: We report on a single case of apparent dwarfism in a free-ranging adult male Asian elephant in Sri Lanka, comparing physical dimensions to those of other males in the population as well as in previous literature. The subject M459 was found to have a shoulder height of approximately 195 cm, is shorter than the average height of typical mature males, with a body length of 218 cm. This ratio of body length to height deviates from what is typically observed, which is approximately 1:1, but was similar to the attributes of a dwarf elephant in captivity documented in 1955. We report on behavior including the surprising observation that M459 appears to have a competitive advantage in intrasexual contests. We discuss how this phenotype compares to cases of dwarfism in other non-human animals. CONCLUSION: M459 exemplifies a rare occurrence of disproportionate dwarfism in a free-ranging wild mammal that has survived to reproductive maturity and appears otherwise healthy. PMID- 25522960 TI - Enhanced retention and anti-tumor efficacy of liposomes by changing their cellular uptake and pharmacokinetics behavior. AB - Although PEGylated liposome-based drug delivery systems hold great promising applications for cancer therapy due to their prolonged blood circulation time, PEGylation significantly reduces their cellular uptake, which markedly impairs the in vivo tumor retention and antitumor efficiency of drug-loaded liposomes. Most importantly, it has been proved that repeated injections of PEGylated liposomes with cell cycle specific drug such as topotecan (TPT) in the same animal at certain time intervals will induce "accelerated blood clearance" (ABC) phenomenon, which decreases the tumor accumulation of drug-loaded liposomes and presents a tremendous challenge to the clinical use of liposome-based drug delivery systems. Herein, we developed a zwitterionic poly(carboxybetaine) (PCB) modified liposome-based drug delivery system. The presence of PCB could avoid protein adsorption and enhance the stability of liposomes as that for PEG. Quite different from the PEGylated liposomes, the pH-sensitive PCBylated liposomes were internalized into cells via endocytosis with excellent cellular uptake and drug release ability. Furthermore, the PCBylated liposomes would avoid ABC phenomenon, which promoted the tumor accumulation of drug-loaded liposomes in vivo. With higher tumor accumulation and cellular uptake, the PCBylated drug-loaded liposomes significantly inhibited tumor growth and provided a promising approach for cancer therapy. PMID- 25522961 TI - The effects of spheroid formation of adipose-derived stem cells in a microgravity bioreactor on stemness properties and therapeutic potential. AB - Adipose-derived stem cells (ADSCs) represent a valuable source of stem cells for regenerative medicine, but the loss of their stemness during in vitro expansion remains a major roadblock. We employed a microgravity bioreactor (MB) to develop a method for biomaterial-free-mediated spheroid formation to maintain the stemness properties of ADSCs. ADSCs spontaneously formed three-dimensional spheroids in the MB. Compared with monolayer culture, the expression levels of E cadherin and pluripotent markers were significantly upregulated in ADSC spheroids. Spheroid-derived ADSCs exhibited increased proliferative ability and colony-forming efficiency. By culturing the spheroid-derived ADSCs in an appropriate induction medium, we found that the multipotency differentiation capacities of ADSCs were significantly improved by spheroid culture in the MB. Furthermore, when ADSCs were administered to mice with carbon tetrachloride induced acute liver failure, spheroid-derived ADSCs showed more effective potentials to rescue liver failure than ADSCs derived from constant monolayer culture. Our results suggest that spheroid formation of ADSCs in an MB enhances their stemness properties and increases their therapeutic potential. Therefore, spheroid culture in an MB can be an efficient method to maintain stemness properties, without the involvement of any biomaterials for clinical applications of in vitro cultured ADSCs. PMID- 25522963 TI - Minimizing antibody surface density on liposomes while sustaining cytokine activated EC targeting. AB - Liposomes may be engineered to target inflamed endothelium by mimicking ligand receptor interactions between leukocytes and cytokine-activated endothelial cells (ECs). The upregulation and assembly of vascular cell adhesion molecule-1 (VCAM1) and E-selectin on the cell membrane upon exposure to cytokines have shown potential for drug delivery vehicles to target sites of chronic endothelial inflammation, such as atherosclerosis and cancer. Herein, we characterized EC surfaces by measuring the E-selectin and VCAM1 surface densities and adhesion forces of aVCAM1 and aE-selectin to ECs. We quantified the antibody density, ratio, and diffusivity of liposomes to achieve significant binding and internalization. At 1 h, the 1:1 ratio of VCAM1:E-selectin antibodies was significantly higher than 1:0 and 0:1. Significant binding and uptake was achieved at aE-selectin densities as low as 400 molecules/MUm(2). The highest levels of binding and uptake were achieved when using a 1:1 ratio of VCAM1:E selectin antibodies at a density of 1000 molecules/MUm(2); this density is 85% lower than previous reports. The binding and uptake of functionalized liposomes were reduced to levels comparable to IgG functionalized liposomes upon a 10-fold reduction in liposome membrane diffusivity. We conclude with a liposomal design that discriminates between healthy and inflamed endothelium while reducing antibody surface presentation. PMID- 25522962 TI - Linking the foreign body response and protein adsorption to PEG-based hydrogels using proteomics. AB - Poly(ethylene glycol) (PEG) hydrogels with their highly tunable properties are promising implantable materials, but as with all non-biological materials, they elicit a foreign body response (FBR). Recent studies, however, have shown that incorporating the oligopeptide RGD into PEG hydrogels reduces the FBR. To better understand the mechanisms involved and the role of RGD in mediating the FBR, PEG, PEG-RGD and PEG-RDG hydrogels were investigated. After a 28-day subcutaneous implantation in mice, a thinner and less dense fibrous capsule formed around PEG RGD hydrogels, while PEG and PEG-RDG hydrogels exhibited stronger, but similar FBRs. Protein adsorption to the hydrogels, which is considered the first step in the FBR, was also characterized. In vitro experiments confirmed that serum proteins adsorbed to PEG-based hydrogels and were necessary to promote macrophage adhesion to PEG and PEG-RDG, but not PEG-RGD hydrogels. Proteins adsorbed to the hydrogels in vivo were identified using liquid chromatography-tandem mass spectrometry. The majority (245) of the total proteins (>=300) that were identified was present on all hydrogels with many proteins being associated with wounding and acute inflammation. These findings suggest that the FBR to PEG hydrogels may be mediated by the presence of inflammatory-related proteins adsorbed to the surface, but that macrophages appear to sense the underlying chemistry, which for RGD improves the FBR. PMID- 25522964 TI - Manipulation of cell mechanotaxis by designing curvature of the elasticity boundary on hydrogel matrix. AB - Directional cell migration induced by the stiffness gradient of cell culture substrates is known as a subset of the mechanical-cue-induced taxis, so-called mechanotaxis, typically durotaxis toward hard region. To establish the general conditions of biomaterials to manipulate the mechanotaxis, the effect of the shape of the elasticity transition boundary between hard and soft regions of a substrate on mechanotaxis should be systematically determined as well as the conditions of elasticity gradient strength. Here, as a simplified factor of expressing variations in the shape of the elasticity boundary in living tissues, we focus on the curvature of the elasticity boundary. Mask-free photolithographic microelasticity patterning of photocurable gelatin gel was employed to systematically prepare elasticity boundaries with various curvatures, and the efficiency of mechanotaxis of fibroblast cells around each curved boundary was examined. Highly efficient usual durotaxis was induced on a convex boundary with 100 MUm in radius and on a concave boundary with 750 MUm in radius of curvature. Interestingly, biased migration toward soft regions of the gel, i.e., inverse durotaxis, was first observed for concave boundaries with 50 MUm or 100 MUm in radius of curvature, which was named as "negative mechanotaxis". The curvature of the elasticity boundary was found to markedly affect the efficiency of induction and the direction of mechanotaxis. The mechanism responsible for this phenomenon and the implication for the curvature effect in in vivo systems are discussed. PMID- 25522965 TI - Dual tumor targeting with pH-sensitive and bioreducible polymer-complexed oncolytic adenovirus. AB - Oncolytic adenoviruses (Ads) have shown great promise in cancer gene therapy but their efficacy has been compromised by potent immunological, biochemical, and specific tumor-targeting limitations. To take full advantage of the innate cancer specific killing potency of oncolytic Ads but also exploit the subtleties of the tumor microenvironment, we have generated a pH-sensitive and bio-reducible polymer (PPCBA)-coated oncolytic Ad. Ad-PPCBA complexes showed higher cellular uptake at pH 6.0 than pH 7.4 in both high and low coxsackie and adenovirus receptor-(CAR)-expressing cells, thereby demonstrating Ad-PPCBA's ability to target the low pH hypoxic tumor microenvironment and overcome CAR dependence for target cell uptake. Endocytic mechanism studies indicated that Ad-PPCBA internalization is mediated by macropinocytosis instead of the CAR-dependent endocytic pathway that internalizes naked Ad. VEGF-specific shRNA-expressing oncolytic Ad complexed with PPCBA (RdB/shVEGF-PPCBA) elicited much more potent suppression of U87 human brain cancer cell VEGF gene expression in vitro, and human breast cancer MCF7 cell/Matrigel plug vascularization in a mouse model, when cancer cells had been previously infected at pH 6.0 versus pH 7.4. Moreover, intratumorally and intravenously injected RdB/shVEGF-PPCBA nanocomplexes elicited significantly higher therapeutic efficacy than naked virus in U87-tumor mouse xenograft models, reducing IL-6, ALT, and AST serum levels. These data demonstrated PPCBA's biocompatibility and capability to shield the Ad surface to prevent innate immune response against Ad after both intratumoral and systemic administration. Taken together, these results demonstrate that smart, tumor specific, oncolytic Ad-PPCBA complexes can be exploited to treat both primary and metastatic tumors. PMID- 25522966 TI - Magnetic resonance beacon to detect intracellular microRNA during neurogenesis. AB - Magnetic resonance imaging (MRI) offers great spatial resolution for viewing deep tissues and anatomy. We developed a self-assembling signal-on magnetic fluorescence nanoparticle to visualize intracellular microRNAs (miRNAs or miRs) during neurogenesis using MRI. The self-assembling nanoparticle (miR124a MR beacon) was aggregated by the incubation of three different oligonucleotides: a 3' adaptor, a 5' adaptor, and a linker containing miR124a-binding sequences. The T2-weighted magnetic resonance (MR) signal of the self-assembled nanoparticle was quenched when miR124a was absent from test tubes or was minimally expressed in cells and tissues. When miR124a was present in test tubes or highly expressed in vitro and in vivo during P19 cell neurogenesis, it hybridized with the miR124a MR beacon, causing the linker to detach, resulting in increased signal-on MRI intensity. This MR beacon can be used as a new imaging probe to monitor the miRNA mediated regulation of cellular processes. PMID- 25522967 TI - Immunomodulation by mesenchymal stem cells combats the foreign body response to cell-laden synthetic hydrogels. AB - The implantation of non-biological materials, including scaffolds for tissue engineering, ubiquitously leads to a foreign body response (FBR). We recently reported that this response negatively impacts fibroblasts encapsulated within a synthetic hydrogel and in turn leads to a more severe FBR, suggesting a cross talk between encapsulated cells and inflammatory cells. Given the promise of mesenchymal stem cells (MSCs) in tissue engineering and recent evidence of their immunomodulatory properties, we hypothesized that MSCs encapsulated within poly(ethylene glycol) (PEG) hydrogels will attenuate the FBR. In vitro, murine MSCs encapsulated within PEG hydrogels attenuated classically activated primary murine macrophages by reducing gene expression and protein secretion of pro inflammatory cytokines, most notably tumor necrosis factor-alpha. Using a COX2 inhibitor, prostaglandin E2 (PGE2) was identified as a mediator of MSC immunomodulation of macrophages. In vivo, hydrogels laden with MSCs, osteogenically differentiating MSCs, or no cells were implanted subcutaneously into C57BL/6 mice for 28 days to assess the impact of MSCs on the fibrotic response of the FBR. The presence of encapsulated MSCs reduced fibrous capsule thickness compared to acellular hydrogels, but this effect diminished with osteogenic differentiation. The use of MSCs prior to differentiation in tissue engineering may therefore serve as a dynamic approach, through continuous cross talk between MSCs and the inflammatory cells, to modulate macrophage activation and attenuate the FBR to implanted synthetic scaffolds thus improving the long term tissue engineering outcome. PMID- 25522968 TI - The linear-ordered collagen scaffold-BDNF complex significantly promotes functional recovery after completely transected spinal cord injury in canine. AB - Spinal cord injury (SCI) is still a worldwide clinical challenge for which there is no viable therapeutic method. We focused on developing combinatorial methods targeting the complex pathological process of SCI. In this study, we implanted linear-ordered collagen scaffold (LOCS) fibers with collagen binding brain derived neurotrophic factor (BDNF) by tagging a collagen-binding domain (CBD) (LOCS + CBD-BDNF) in completely transected canine SCI with multisystem rehabilitation to validate its potential therapeutic effect through a long-term (38 weeks) observation. We found that LOCS + CBD-BDNF implants strikingly promoted locomotion and functional sensory recovery, with some dogs standing unassisted and transiently moving. Further histological analysis showed that administration of LOCS + CBD-BDNF reduced lesion volume, decreased collagen deposits, promoted axon regeneration and improved myelination, leading to functional recovery. Collectively, LOCS + CBD-BDNF showed striking therapeutic effect on completely transected canine SCI model and it is the first time to report such breakthrough in the war with SCI. Undoubtedly, it is a potentially promising therapeutic method for SCI paralysis or other movement disorders caused by neurological diseases in the future. PMID- 25522969 TI - Cathodic voltage-controlled electrical stimulation of titanium implants as treatment for methicillin-resistant Staphylococcus aureus periprosthetic infections. AB - Effective treatment options are often limited for implant-associated orthopedic infections. In this study we evaluated the antimicrobial effects of applying cathodic voltage-controlled electrical stimulation (CVCES) of -1.8 V (vs. Ag/AgCl) to commercially pure titanium (cpTi) substrates with preformed biofilm like structures of methicillin-resistant Staphylococcus aureus (MRSA). The in vitro studies showed that as compared to the open circuit potential (OCP) conditions, CVCES of -1.8 V for 1 h significantly reduced the colony-forming units (CFU) of MRSA enumerated from the cpTi by 97% (1.89 * 106 vs 6.45 * 104 CFU/ml) and from the surrounding solution by 92% (6.63 * 105 vs. 5.15 * 104 CFU/ml). The in vivo studies, utilizing a rodent periprosthetic infection model, showed that as compared to the OCP conditions, CVCES at -1.8 V for 1 h significantly reduced MRSA CFUs in the bone tissue by 87% (1.15 * 105 vs. 1.48 * 104 CFU/ml) and reduced CFU on the cpTi implant by 98% (5.48 * 104 vs 1.16 * 103 CFU/ml). The stimulation was not associated with histological changes in the host tissue surrounding the implant. As compared to the OCP conditions, the -1.8 V stimulation significantly increased the interfacial capacitance (18.93 vs. 98.25 MUF/cm(2)) and decreased polarization resistance (868,250 vs. 108 Omega-cm(2)) of the cpTi. The antimicrobial effects are thought to be associated with these voltage-dependent electrochemical surface properties of the cpTi. PMID- 25522970 TI - A novel soft tissue model for biomaterial-associated infection and inflammation - bacteriological, morphological and molecular observations. AB - Infection constitutes a major risk for implant failure, but the reasons why biomaterial sites are more vulnerable than normal tissue are not fully elucidated. In this study, a soft tissue infection model was developed, allowing the analysis of cellular and molecular responses in each of the sub-compartments of the implant-tissue interface (on the implant surface, in the surrounding exudate and in the tissue). Smooth and nanostructured titanium disks with or without noble metal chemistry (silver, gold, palladium), and sham sites, were inoculated with Staphylococcus epidermidis and analysed with respect to number of viable bacteria, number, viability and gene expression of host cells, and using different morphological techniques after 4 h, 24 h and 72 h. Non-infected rats were controls. Results showed a transient inflammatory response at control sites, whereas bacterial administration resulted in higher recruitment of inflammatory cells (mainly polymorphonuclear), higher, continuous cell death and higher gene expression of tumour necrosis factor-alpha, interleukin-6, interleukin-8, Toll like receptor 2 and elastase. At all time points, S. epidermidis was predominantly located in the interface zone, extra- and intracellularly, and lower levels were detected on the implants compared with surrounding exudate. This model allows detailed analysis of early events in inflammation and infection associated to biomaterials in vivo leading to insights into host defence mechanisms in biomaterial-associated infections. PMID- 25522971 TI - 3D culture of murine neural stem cells on decellularized mouse brain sections. AB - Transplantation of neural stem cells (NSC) in diseased or injured brain tissue is widely studied as a potential treatment for various neurological pathologies. However, effective cell replacement therapy relies on the intrinsic capacity of cellular grafts to overcome hypoxic and/or immunological barriers after transplantation. In this context, it is hypothesized that structural support for grafted NSC will be of utmost importance. With this study, we present a novel decellularization protocol for 1.5 mm thick mouse brain sections, resulting in the generation of acellular three-dimensional (3D) brain sections. Next, the obtained 3D brain sections were seeded with murine NSC expressing both the eGFP and luciferase reporter proteins (NSC-eGFP/Luc). Using real-time bioluminescence imaging, the survival and growth of seeded NSC-eGFP/Luc cells was longitudinally monitored for 1-7 weeks in culture, indicating the ability of the acellular brain sections to support sustained ex vivo growth of NSC. Next, the organization of a 3D maze-like cellular structure was examined using confocal microscopy. Moreover, under mitogenic stimuli (EGF and hFGF-2), most cells in this 3D culture retained their NSC phenotype. Concluding, we here present a novel protocol for decellularization of mouse brain sections, which subsequently support long-term 3D culture of undifferentiated NSC. PMID- 25522972 TI - PEDOT nanocomposites mediated dual-modal photodynamic and photothermal targeted sterilization in both NIR I and II window. AB - PEDOT nanoparticles with a suitable nanosize of 17.2 nm, broad adsorption from 700 to 1250 nm, and photothermal conversion efficiency (eta) of 71.1%, were synthesized using an environmentally friendly hydrothermal method. Due to the electrostatic attraction between indocyanine green (ICG) and PEDOT, the stability of ICG in aqueous solution was effectively improved. The PEDOT nanoparticles modified with glutaraldehyde (GTA) targeted bacteria directly, and MTT experiments demonstrated the low toxicity of PEDOT:ICG@PEG-GTA in different bacteria and cells. Pathogenic bacteria were effectively killed by photodynamic therapy (PDT) and photothermal therapy (PTT) with PEDOT:ICG@PEG-GTA in the presence of near-infrared (NIR) irradiation (808 nm for PDT, and 1064 nm for PTT). The combination of the two different bacteriostatic methods was significantly more effective than PTT or PDT alone. The obtained PEDOT:ICG@PEG GTA may be used as a novel synergistic agent in combination photodynamic and photothermal therapy to inactivate pathogenic bacteria in both the NIR I and II window. PMID- 25522973 TI - Pharmacodynamics of long-acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations. AB - Long-acting nanoformulated antiretroviral therapy (nanoART) that targets monocyte macrophages could improve the drug's half-life and protein-binding capacities while facilitating cell and tissue depots. To this end, ART nanoparticles that target the folic acid (FA) receptor and permit cell-based drug depots were examined using pharmacokinetic and pharmacodynamic (PD) tests. FA receptor targeted poloxamer 407 nanocrystals, containing ritonavir-boosted atazanavir (ATV/r), significantly increased drug bioavailability and PD by five and 100 times, respectively. Drug particles administered to human peripheral blood lymphocyte reconstituted NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ mice and infected with HIV-1ADA led to ATV/r drug concentrations that paralleled FA receptor beta staining in both the macrophage-rich parafollicular areas of spleen and lymph nodes. Drug levels were higher in these tissues than what could be achieved by either native drug or untargeted nanoART particles. The data also mirrored potent reductions in viral loads, tissue viral RNA and numbers of HIV-1p24+ cells in infected and treated animals. We conclude that FA-P407 coating of ART nanoparticles readily facilitates drug carriage and antiretroviral responses. PMID- 25522974 TI - Microchannel-based regenerative scaffold for chronic peripheral nerve interfacing in amputees. AB - Neurally controlled prosthetics that cosmetically and functionally mimic amputated limbs remain a clinical need because state of the art neural prosthetics only provide a fraction of a natural limb's functionality. Here, we report on the fabrication and capability of polydimethylsiloxane (PDMS) and epoxy based SU-8 photoresist microchannel scaffolds to serve as viable constructs for peripheral nerve interfacing through in vitro and in vivo studies in a sciatic nerve amputee model where the nerve lacks distal reinnervation targets. These studies showed microchannels with 100 MUm * 100 MUm cross-sectional areas support and direct the regeneration/migration of axons, Schwann cells, and fibroblasts through the microchannels with space available for future maturation of the axons. Investigation of the nerve in the distal segment, past the scaffold, showed a high degree of organization, adoption of the microchannel architecture forming 'microchannel fascicles', reformation of endoneurial tubes and axon myelination, and a lack of aberrant and unorganized growth that might be characteristic of neuroma formation. Separate chronic terminal in vivo electrophysiology studies utilizing the microchannel scaffolds with permanently integrated microwire electrodes were conducted to evaluate interfacing capabilities. In all devices a variety of spontaneous, sensory evoked and electrically evoked single and multi-unit action potentials were recorded after five months of implantation. Together, these findings suggest that microchannel scaffolds are well suited for chronic implantation and peripheral nerve interfacing to promote organized nerve regeneration that lends itself well to stable interfaces. Thus this study establishes the basis for the advanced fabrication of large-electrode count, wireless microchannel devices that are an important step towards highly functional, bi-directional peripheral nerve interfaces. PMID- 25522975 TI - ROS-responsive microspheres for on demand antioxidant therapy in a model of diabetic peripheral arterial disease. AB - A new microparticle-based delivery system was synthesized from reactive oxygen species (ROS)-responsive poly(propylene sulfide) (PPS) and tested for "on demand" antioxidant therapy. PPS is hydrophobic but undergoes a phase change to become hydrophilic upon oxidation and thus provides a useful platform for ROS-demanded drug release. This platform was tested for delivery of the promising anti inflammatory and antioxidant therapeutic molecule curcumin, which is currently limited in use in its free form due to poor pharmacokinetic properties. PPS microspheres efficiently encapsulated curcumin through oil-in-water emulsion and provided sustained, on demand release that was modulated in vitro by hydrogen peroxide concentration. The cytocompatible, curcumin-loaded microspheres preferentially targeted and scavenged intracellular ROS in activated macrophages, reduced in vitro cell death in the presence of cytotoxic levels of ROS, and decreased tissue-level ROS in vivo in the diabetic mouse hind limb ischemia model of peripheral arterial disease. Interestingly, due to the ROS scavenging behavior of PPS, the blank microparticles also showed inherent therapeutic properties that were synergistic with the effects of curcumin in these assays. Functionally, local delivery of curcumin-PPS microspheres accelerated recovery from hind limb ischemia in diabetic mice, as demonstrated using non-invasive imaging techniques. This work demonstrates the potential for PPS microspheres as a generalizable vehicle for ROS-demanded drug release and establishes the utility of this platform for improving local curcumin bioavailability for treatment of chronic inflammatory diseases. PMID- 25522977 TI - Thyroid-specific questions on work ability showed known-groups validity among Danes with thyroid diseases. AB - PURPOSE: We aimed to identify the best approach to work ability assessment in patients with thyroid disease by evaluating the factor structure, measurement equivalence, known-groups validity, and predictive validity of a broad set of work ability items. METHODS: Based on the literature and interviews with thyroid patients, 24 work ability items were selected from previous questionnaires, revised, or developed anew. Items were tested among 632 patients with thyroid disease (non-toxic goiter, toxic nodular goiter, Graves' disease (with or without orbitopathy), autoimmune hypothyroidism, and other thyroid diseases), 391 of which had participated in a study 5 years previously. Responses to select items were compared to general population data. We used confirmatory factor analyses for categorical data, logistic regression analyses and tests of differential item function, and head-to-head comparisons of relative validity in distinguishing known groups. RESULTS: Although all work ability items loaded on a common factor, the optimal factor solution included five factors: role physical, role emotional, thyroid-specific limitations, work limitations (without disease attribution), and work performance. The scale on thyroid-specific limitations showed the most power in distinguishing clinical groups and time since diagnosis. A global single item proved useful for comparisons with the general population, and a thyroid-specific item predicted labor market exclusion within the next 5 years (OR 5.0, 95 % CI 2.7-9.1). CONCLUSIONS: Items on work limitations with attribution to thyroid disease were most effective in detecting impact on work ability and showed good predictive validity. Generic work ability items remain useful for general population comparisons. PMID- 25522976 TI - Confirmatory factor analysis of the Patient Assessment of Constipation-Symptoms (PAC-SYM) among patients with chronic constipation. AB - BACKGROUND AND AIM: PAC-SYM is widely adopted to asses constipation severity. However, it has been validated in a small sample, few items have been included based on expert opinion and not on empirical grounds, and its factor structure has never been replicated. We aimed at evaluating the psychometric properties of PAC-SYM in patients with chronic constipation. METHODS: We enrolled 2,203 outpatients with chronic constipation in two waves. We used wave I sample to test the psychometric properties of the PAC-SYM and wave II sample to cross-validate its factor structure, to assess criterion validity, responsiveness to clinical change, and its minimal clinically important difference. RESULTS: Only a minority of patients reported any rectal tearing (38 %). Deletion of such item leads to a 11-item version (M:PAC-SYM). The remaining items in the rectal domain were moderately correlated with the stool domain. Exploratory factor analysis and confirmatory factor analysis revealed a bifactor structure with two subscales (stool and abdominal symptoms) and a general severity factor. The M:PAC-SYM demonstrated excellent reliability, moderate correlation with SF-12 and treatment satisfaction (r = 0.28-0.45), discrimination across Rome III criteria for functional constipation and abdominal pain, and responsiveness to clinical change (beta = -0.49; omega (2) = 0.25). M:PAC-SYM minimal clinically important difference was 0.24. CONCLUSION: Our analysis shows that the rectal domain may not represent a relevant cluster of symptoms for patients with chronic constipation. We developed a modified version of the PAC-SYM which might better represent symptom severity of most patients seeking care in gastroenterology referral centers. PMID- 25522979 TI - New pharmacotherapy for the treatment of onychomycosis: an update. AB - INTRODUCTION: Onychomycosis is an infection of the nail plate that is an important priority area for the development of antifungal drugs. The high incidence of relapse and reinfection often makes onychomycosis a chronic condition. The current gold standard is oral therapy, but the development of effective topical agents remains a priority as they have fewer systemic interactions. AREAS COVERED: This review summarizes development of antifungals from early phase development through Phase III clinical trials for onychomycosis. The oral molecules in development are azole molecules. Topical drugs in development include azoles, allylamines, benzoxaboroles and nanoemulsions. Photosensitizers for photodynamic therapy and new laser systems are also emerging therapeutic options. There is a diverse array of antifungal drugs in the early phases of development. EXPERT OPINION: The goals of onychomycosis therapy are a mycological cure and a normal appearing nail. The recent development of topical antifungals has been successful at improving the nail permeation and efficacy. The diversification of molecular targets is the next primary goal of antifungal development. Incomplete treatment of onychomycosis provides an environment conducive to the development of antifungal resistance. New topical agents and device-based therapies expand the therapeutic options. Combination therapy using multiple drug classes may improve the overall efficacy of antifungal treatment in onychomycosis. PMID- 25522978 TI - Laboratory evaluation of anti-phospholipid syndrome: a preliminary prospective study of phosphatidylserine/prothrombin antibodies in an at-risk patient cohort. AB - Immunoglobulin (Ig)G/IgM autoantibodies to phosphatidylserine/prothrombin (aPS/PT) were evaluated individually and in combination with criteria anti phospholipid (aPL) tests in a prospectively ascertained cohort of patients at risk for anti-phospholipid syndrome (APS). One hundred and sixty (160) consecutive requests for lupus anti-coagulant (LAC) from the University of Utah Health Sciences Center were identified during 8 weeks. Of these, 104 unique patients had additional requests for cardiolipin (aCL) and/or beta2 glycoprotein I (abeta2 GPI) IgG and/or IgM; samples were retained and analysed for aPS/PT, aCL and/or abeta2 GPI IgG and IgM antibodies. Following testing, a comprehensive chart review was performed and patients categorized according to their clinical diagnosis. Individual and combined sensitivities, specificities, odd ratios (OR), diagnostic accuracy for specific tests or combinations by receiver operating characteristic (ROC), area under the curve (AUC) analyses and correlations between test results were determined. The sensitivities of aPS/PT IgG/IgM (54.6/45.5%) were lower than LAC (81.8%) but higher relative to aCL IgG/IgM (27.3/0%) or abeta2 GPI IgG/IgM (27.3/0%). The best correlation between LAC and any aPL test was observed with aPS/PT (P = 0.002). There was no significant difference in the diagnostic accuracies for any panel with LAC: LAC/abeta2 GPI IgG/aCL IgG [AUC 0.979, OR 475.4, 95% confidence interval (CI) 23.1-9056.5, P = 0.0001 and LAC/abeta2 GPI IgG/aPS/PT IgG or LAC/aPS/PT IgG/aCL IgG (AUC 0.962, OR 265.3, 14.2-4958.2, P = 0.0001). The high correlation between LAC and aPS/PT IgG/IgM in this preliminary study suggest that this marker may be useful in the evaluation of APS. More studies to determine the optimal aPL antibody tests combination are needed. PMID- 25522980 TI - Furan formation during storage and reheating of sterilised vegetable purees. AB - To this day, research for furan mitigation has mostly targeted the levels of food production and handling of prepared foods by the consumer. However, part of the furan concentrations found in commercially available food products might originate from chemical deterioration reactions during storage. A range of individual vegetable purees was stored at two different temperatures to investigate the effects of storage on the furan concentrations of shelf-stable, vegetable-based foods. After 5 months of storage at 35 degrees C (temperature abuse conditions), a general increase in furan concentrations was observed. The furan formation during storage could be reduced by storing the vegetable purees at a refrigerated temperature of 4 degrees C, at which the furan concentrations remained approximately constant for at least 5 months. Following storage, the vegetable purees were briefly reheated to 90 degrees C to simulate the effect of the final preparation step before consumption. Contrary to storage, furan concentrations decreased as a result of evaporative losses. Both refrigerated storage and the reheating step prior to consumption showed the potential of mitigation measures for furan formation in vegetable-based foods (e.g. canned vegetables, ready-to-eat soups, sauces or baby foods). Next to furan, the vegetable purees were analysed for 2- and 3-methylfuran. Tomato was very susceptible to the formation of both alkylated derivatives of furan, as opposed to the other vegetables in this study. Methylfuran concentrations rapidly decreased during storage, which was contrary to the results observed for furan. PMID- 25522981 TI - Profunda anchor technique for ipsilateral antegrade approach in endovascular treatment of superficial femoral artery ostial occlusion. AB - Endovascular treatment of the superficial femoral artery (SFA) is challenging in the presence of flush ostial occlusion. One of the main challenges is the availability of access sites for intervention. Contralateral retrograde femoral access followed by cross-over and antegrade intervention while commonly used, may not be feasible in cases of altered iliac anatomy (e.g. kissing iliac stents). Ipsilateral antegrade intervention using common femoral artery (CFA) access in these instances while possible is typically challenging due to inadequate working length of the CFA for interrogation of the SFA ostium, compounded by the lack of sheath stability. The "profunda anchor" technique uses a buddy wire in the profunda femoris artery (PFA) to stabilize the sheath and allow catheter manipulation for antegrade intervention at the level of the SFA ostium. The PFA is further used as a conduit for deployment of closure device to avoid interference with the treated SFA. PMID- 25522982 TI - Identifying the Learning Curve for Uterine Artery Embolisation in an Interventional Radiological Training Unit. AB - AIM: A clear understanding of operator experience is important in improving technical success whilst minimising patient risk undergoing endovascular procedures, and there is the need to ensure that trainees have the appropriate skills as primary operators. The aim of the study is to retrospectively analyse uterine artery embolisation (UAE) procedures performed by interventional radiology (IR) trainees at an IR training unit analysing fluoroscopy times and radiation dose as surrogate markers of technical skill. METHODS: Ten IR fellows were primary operator in 200 UAE procedures over a 5-year period. We compared fluoroscopy times, radiation dose and complications, after having them categorised according to three groups: Group 1, initial five, Group 2, >5 procedures and Group 3, penultimate five UAE procedures. We documented factors that may affect screening time (number of vials employed and use of microcatheters). RESULTS: Mean fluoroscopy time was 18.4 (+/- 8.1), 17.3 (+/- 9.0), 16.3 (+/- 8.4) min in Groups 1, 2 and 3, respectively. There was no statistically significant difference between these groups (p > 0.05) with respect to fluoroscopy time or radiation dose. Analysis after correction for confounding factors showed no statistical significance (p > 0.05). All procedures were technically successful, and total complication rate was 4%. CONCLUSION: UAE was chosen as a highly standardised procedure followed by IR practitioners. Although there is a non-significant trend for shorter screening times with experience, technical success and safety were not compromised with appropriate Consultant supervision, which illustrates a safe construct for IR training. This is important and reassuring information for patients undergoing a procedure in a training unit. PMID- 25522983 TI - A "Lifesaving" Migraine Attack. PMID- 25522985 TI - Structure of HDL: particle subclasses and molecular components. AB - A molecular understanding of high-density lipoprotein (HDL) will allow a more complete grasp of its interactions with key plasma remodelling factors and with cell-surface proteins that mediate HDL assembly and clearance. However, these particles are notoriously heterogeneous in terms of almost every physical, chemical and biological property. Furthermore, HDL particles have not lent themselves to high-resolution structural study through mainstream techniques like nuclear magnetic resonance and X-ray crystallography; investigators have therefore had to use a series of lower resolution methods to derive a general structural understanding of these enigmatic particles. This chapter reviews current knowledge of the composition, structure and heterogeneity of human plasma HDL. The multifaceted composition of the HDL proteome, the multiple major protein isoforms involving translational and posttranslational modifications, the rapidly expanding knowledge of the HDL lipidome, the highly complex world of HDL subclasses and putative models of HDL particle structure are extensively discussed. A brief history of structural studies of both plasma-derived and recombinant forms of HDL is presented with a focus on detailed structural models that have been derived from a range of techniques spanning mass spectrometry to molecular dynamics. PMID- 25522984 TI - Protective effect of arachidonic acid and linoleic acid on 1-methyl-4 phenylpyridinium-induced toxicity in PC12 cells. AB - BACKGROUND: Parkinson's disease is a neurodegenerative disorder that is being characterized by the progressive loss of dopaminergic neurons of the nigrostriatal pathway in the brain. The protective effect of omega-6 fatty acids is unclear. There are lots of contradictions in the literature with regard to the cytoprotective role of arachidonic acid. To date, there is no solid evidence that shows the protective role of omega-6 fatty acids in Parkinson's disease. In the current study, the potential of two omega-6 fatty acids (i.e. arachidonic acid and linoleic acid) in alleviating 1-methyl-4-phenylpyridinium (MPP+)-induced cytotoxicity in PC12 cells was examined. METHODS: Cultured PC12 cells were either treated with MPP+ alone or co-treated with one of the omega-6 fatty acids for 1 day. Cell viability was then assessed by using the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: Cells treated with 500 MUM MPP+ for a day reduced cell viability to ~70% as compared to control group. Linoleic acid (50 and 100 MUM) significantly reduced MPP+-induced cell death back to ~85-90% of the control value. The protective effect could be mimicked by arachidonic acid, but not by ciglitazone. CONCLUSIONS: Both linoleic acid and arachidonic acid are able to inhibit MPP+-induced toxicity in PC12 cells. The protection is not mediated via peroxisome proliferator-activated receptor gamma (PPAR-gamma). Overall, the results suggest the potential role of omega-6 fatty acids in the treatment of Parkinson's disease. PMID- 25522986 TI - HDL biogenesis, remodeling, and catabolism. AB - In this chapter, we review how HDL is generated, remodeled, and catabolized in plasma. We describe key features of the proteins that participate in these processes, emphasizing how mutations in apolipoprotein A-I (apoA-I) and the other proteins affect HDL metabolism. The biogenesis of HDL initially requires functional interaction of apoA-I with the ATP-binding cassette transporter A1 (ABCA1) and subsequently interactions of the lipidated apoA-I forms with lecithin/cholesterol acyltransferase (LCAT). Mutations in these proteins either prevent or impair the formation and possibly the functionality of HDL. Remodeling and catabolism of HDL is the result of interactions of HDL with cell receptors and other membrane and plasma proteins including hepatic lipase (HL), endothelial lipase (EL), phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), apolipoprotein M (apoM), scavenger receptor class B type I (SR BI), ATP-binding cassette transporter G1 (ABCG1), the F1 subunit of ATPase (Ecto F1-ATPase), and the cubulin/megalin receptor. Similarly to apoA-I, apolipoprotein E and apolipoprotein A-IV were shown to form discrete HDL particles containing these apolipoproteins which may have important but still unexplored functions. Furthermore, several plasma proteins were found associated with HDL and may modulate its biological functions. The effect of these proteins on the functionality of HDL is the topic of ongoing research. PMID- 25522987 TI - Regulation of HDL genes: transcriptional, posttranscriptional, and posttranslational. AB - HDL regulation is exerted at multiple levels including regulation at the level of transcription initiation by transcription factors and signal transduction cascades; regulation at the posttranscriptional level by microRNAs and other noncoding RNAs which bind to the coding or noncoding regions of HDL genes regulating mRNA stability and translation; as well as regulation at the posttranslational level by protein modifications, intracellular trafficking, and degradation. The above mechanisms have drastic effects on several HDL-mediated processes including HDL biogenesis, remodeling, cholesterol efflux and uptake, as well as atheroprotective functions on the cells of the arterial wall. The emphasis is on mechanisms that operate in physiologically relevant tissues such as the liver (which accounts for 80% of the total HDL-C levels in the plasma), the macrophages, the adrenals, and the endothelium. Transcription factors that have a significant impact on HDL regulation such as hormone nuclear receptors and hepatocyte nuclear factors are extensively discussed both in terms of gene promoter recognition and regulation but also in terms of their impact on plasma HDL levels as was revealed by knockout studies. Understanding the different modes of regulation of this complex lipoprotein may provide useful insights for the development of novel HDL-raising therapies that could be used to fight against atherosclerosis which is the underlying cause of coronary heart disease. PMID- 25522988 TI - Cholesterol efflux and reverse cholesterol transport. AB - Both alterations of lipid/lipoprotein metabolism and inflammatory events contribute to the formation of the atherosclerotic plaque, characterized by the accumulation of abnormal amounts of cholesterol and macrophages in the artery wall. Reverse cholesterol transport (RCT) may counteract the pathogenic events leading to the formation and development of atheroma, by promoting the high density lipoprotein (HDL)-mediated removal of cholesterol from the artery wall. Recent in vivo studies established the inverse relationship between RCT efficiency and atherosclerotic cardiovascular diseases (CVD), thus suggesting that the promotion of this process may represent a novel strategy to reduce atherosclerotic plaque burden and subsequent cardiovascular events. HDL plays a primary role in all stages of RCT: (1) cholesterol efflux, where these lipoproteins remove excess cholesterol from cells; (2) lipoprotein remodeling, where HDL undergo structural modifications with possible impact on their function; and (3) hepatic lipid uptake, where HDL releases cholesterol to the liver, for the final excretion into bile and feces. Although the inverse association between HDL plasma levels and CVD risk has been postulated for years, recently this concept has been challenged by studies reporting that HDL antiatherogenic functions may be independent of their plasma levels. Therefore, assessment of HDL function, evaluated as the capacity to promote cell cholesterol efflux may offer a better prediction of CVD than HDL levels alone. Consistent with this idea, it has been recently demonstrated that the evaluation of serum cholesterol efflux capacity (CEC) is a predictor of atherosclerosis extent in humans. PMID- 25522989 TI - Functionality of HDL: antioxidation and detoxifying effects. AB - High-density lipoproteins (HDL) are complexes of multiple talents, some of which have only recently been recognised but all of which are under active investigation. Clinical interest initially arose from their amply demonstrated role in atherosclerotic disease with their consequent designation as a major cardiovascular disease (CVD) risk factor. However, interest is no longer confined to vascular tissues, with the reports of impacts of the lipoprotein on pancreatic, renal and nervous tissues, amongst other possible targets. The ever widening scope of HDL talents also encompasses environmental hazards, including infectious agents and environmental toxins. In almost all cases, HDL would appear to have a beneficial impact on health. It raises the intriguing question of whether these various talents emanate from a basic ancestral function to protect the cell.The following chapter will illustrate and review our current understanding of some of the functions attributed to HDL. The first section will look at the antioxidative functions of HDL and possible mechanisms that are involved. The second section will focus specifically on paraoxonase-1 (PON1), which appears to bridge the divide between the two HDL functions discussed herein. This will lead into the final section dealing with HDL as a detoxifying agent protecting against exposure to environmental pathogens and other toxins. PMID- 25522990 TI - Signal transduction by HDL: agonists, receptors, and signaling cascades. AB - Numerous epidemiologic studies revealed that high-density lipoprotein (HDL) is an important risk factor for coronary heart disease. There are several well documented HDL functions such as reversed cholesterol transport, inhibition of inflammation, or inhibition of platelet activation that may account for the atheroprotective effects of this lipoprotein. Mechanistically, these functions are carried out by a direct interaction of HDL particle or its components with receptors localized on the cell surface followed by generation of intracellular signals. Several HDL-associated receptor ligands such as apolipoprotein A-I (apoA I) or sphingosine-1-phosphate (S1P) have been identified in addition to HDL holoparticles, which interact with surface receptors such as ATP-binding cassette transporter A1 (ABCA1); S1P receptor types 1, 2, and 3 (S1P1, S1P2, and S1P3); or scavenger receptor type I (SR-BI) and activate intracellular signaling cascades encompassing kinases, phospholipases, trimeric and small G-proteins, and cytoskeletal proteins such as actin or junctional protein such as connexin43. In addition, depletion of plasma cell cholesterol mediated by ABCA1, ATP-binding cassette transporter G1 (ABCG1), or SR-BI was demonstrated to indirectly inhibit signaling over proinflammatory or proliferation-stimulating receptors such as Toll-like or growth factor receptors. The present review summarizes the current knowledge regarding the HDL-induced signal transduction and its relevance to athero- and cardioprotective effects as well as other physiological effects exerted by HDL. PMID- 25522991 TI - Epidemiology: disease associations and modulators of HDL-related biomarkers. AB - Epidemiological studies have shown an inverse association between high-density lipoprotein cholesterol (HDL-C) levels and risk of ischemic heart disease. In addition, a low level of HDL-C has been shown to be a risk factor for other diseases not related to atherosclerosis. However, recent studies have not supported a causal effect of HDL-C in the development of atherosclerosis. Furthermore, new drugs markedly elevating HDL-C levels have been disappointing with respect to clinical endpoints. Earlier, most studies have focused almost exclusively on the total HDL-C without regard to the chemical composition or multiple subclasses of HDL particles. Recently, there have been efforts to dissect the HDL fraction into as many well-defined subfractions and individual molecules of HDL particles as possible. On the other hand, the focus is shifting from the structure and composition to the function of HDL particles. Biomarkers and mechanisms that could potentially explain the beneficial characteristics of HDL particles unrelated to their cholesterol content have been sought with sophisticated methods such as proteomics, lipidomics, metabonomics, and function studies including efflux capacity. These new approaches have been used in order to resolve the complex effects of diseases, conditions, environmental factors, and genes in relation to the protective role of HDL but high-throughput methods are still needed for large-scale epidemiological studies. PMID- 25522992 TI - Beyond the genetics of HDL: why is HDL cholesterol inversely related to cardiovascular disease? AB - There is unequivocal evidence that high-density lipoprotein (HDL) cholesterol levels in plasma are inversely associated with the risk of cardiovascular disease (CVD). Studies of families with inherited HDL disorders and genetic association studies in general (and patient) population samples have identified a large number of factors that control HDL cholesterol levels. However, they have not resolved why HDL cholesterol and CVD are inversely related. A growing body of evidence from nongenetic studies shows that HDL in patients at increased risk of CVD has lost its protective properties and that increasing the cholesterol content of HDL does not result in the desired effects. Hopefully, these insights can help improve strategies to successfully intervene in HDL metabolism. It is clear that there is a need to revisit the HDL hypothesis in an unbiased manner. True insights into the molecular mechanisms that regulate plasma HDL cholesterol and triglycerides or control HDL function could provide the handholds that are needed to develop treatment for, e.g., type 2 diabetes and the metabolic syndrome. Especially genome-wide association studies have provided many candidate genes for such studies. In this review we have tried to cover the main molecular studies that have been produced over the past few years. It is clear that we are only at the very start of understanding how the newly identified factors may control HDL metabolism. In addition, the most recent findings underscore the intricate relations between HDL, triglyceride, and glucose metabolism indicating that these parameters need to be studied simultaneously. PMID- 25522993 TI - Mouse models of disturbed HDL metabolism. AB - High-density lipoprotein (HDL) is considered to be an anti-atherogenic lipoprotein moiety. Generation of genetically modified (total body and tissue specific knockout) mouse models has significantly contributed to our understanding of HDL function. Here we will review data from knockout mouse studies on the importance of HDL's major alipoprotein apoA-I, the ABC transporters A1 and G1, lecithin:cholesterol acyltransferase, phospholipid transfer protein, and scavenger receptor BI for HDL's metabolism and its protection against atherosclerosis in mice. The initial generation and maturation of HDL particles as well as the selective delivery of its cholesterol to the liver are essential parameters in the life cycle of HDL. Detrimental atherosclerosis effects observed in response to HDL deficiency in mice cannot be solely attributed to the low HDL levels per se, as the low HDL levels are in most models paralleled by changes in non-HDL-cholesterol levels. However, the cholesterol efflux function of HDL is of critical importance to overcome foam cell formation and the development of atherosclerotic lesions in mice. Although HDL is predominantly studied for its atheroprotective action, the mouse data also suggest an essential role for HDL as cholesterol donor for steroidogenic tissues, including the adrenals and ovaries. Furthermore, it appears that a relevant interaction exists between HDL-mediated cellular cholesterol efflux and the susceptibility to inflammation, which (1) provides strong support for the novel concept that inflammation and metabolism are intertwining biological processes and (2) identifies the efflux function of HDL as putative therapeutic target also in other inflammatory diseases than atherosclerosis. PMID- 25522994 TI - Dysfunctional HDL: from structure-function-relationships to biomarkers. AB - Reduced plasma levels of HDL-C are associated with an increased risk of CAD and myocardial infarction, as shown in various prospective population studies. However, recent clinical trials on lipid-modifying drugs that increase plasma levels of HDL-C have not shown significant clinical benefit. Notably, in some recent clinical studies, there is no clear association of higher HDL-C levels with a reduced risk of cardiovascular events observed in patients with existing CAD. These observations have prompted researchers to shift from a cholesterol centric view of HDL towards assessing the function and composition of HDL particles. Of importance, experimental and translational studies have further demonstrated various potential antiatherogenic effects of HDL. HDL has been proposed to promote macrophage reverse cholesterol transport and to protect endothelial cell functions by prevention of oxidation of LDL and its adverse endothelial effects. Furthermore, HDL from healthy subjects can directly stimulate endothelial cell production of nitric oxide and exert anti-inflammatory and antiapoptotic effects. Of note, increasing evidence suggests that the vascular effects of HDL can be highly heterogeneous and HDL may lose important anti-atherosclerotic properties and turn dysfunctional in patients with chronic inflammatory disorders. A greater understanding of mechanisms of action of HDL and its altered vascular effects is therefore critical within the context of HDL targeted therapies. PMID- 25522995 TI - HDL and atherothrombotic vascular disease. AB - High-density lipoproteins (HDLs) exert many beneficial effects which may help to protect against the development or progression of atherosclerosis or even facilitate lesion regression. These activities include promoting cellular cholesterol efflux, protecting low-density lipoproteins (LDLs) from modification, preserving endothelial function, as well as anti-inflammatory and antithrombotic effects. However, questions remain about the relative importance of these activities for atheroprotection. Furthermore, the many molecules (both lipids and proteins) associated with HDLs exert both distinct and overlapping activities, which may be compromised by inflammatory conditions, resulting in either loss of function or even gain of dysfunction. This complexity of HDL functionality has so far precluded elucidation of distinct structure-function relationships for HDL or its components. A better understanding of HDL metabolism and structure-function relationships is therefore crucial to exploit HDLs and its associated components and cellular pathways as potential targets for anti-atherosclerotic therapies and diagnostic markers. PMID- 25522996 TI - HDLs, diabetes, and metabolic syndrome. AB - The prevalence of type 2 diabetes mellitus and of the metabolic syndrome is rising worldwide and reaching epidemic proportions. These pathologies are associated with significant morbidity and mortality, in particular with an excess of cardiovascular deaths. Type 2 diabetes mellitus and the cluster of pathologies including insulin resistance, central obesity, high blood pressure, and hypertriglyceridemia that constitute the metabolic syndrome are associated with low levels of HDL cholesterol and the presence of dysfunctional HDLs. We here review the epidemiological evidence and the potential underlying mechanisms of this association. We first discuss the well-established association of type 2 diabetes mellitus and insulin resistance with alterations of lipid metabolism and how these alterations may lead to low levels of HDL cholesterol and the occurrence of dysfunctional HDLs. We then present and discuss the evidence showing that HDL modulates insulin sensitivity, insulin-independent glucose uptake, insulin secretion, and beta cell survival. A dysfunction in these actions could play a direct role in the pathogenesis of type 2 diabetes mellitus. PMID- 25522997 TI - High-density lipoprotein: structural and functional changes under uremic conditions and the therapeutic consequences. AB - High-density lipoprotein (HDL) has attracted interest as a therapeutic target in cardiovascular diseases in recent years. Although many functional mechanisms of the vascular protective effects of HDL have been identified, increasing the HDL plasma level has not been successful in all patient cohorts with increased cardiovascular risk. The composition of the HDL particle is very complex and includes diverse lipids and proteins that can be modified in disease conditions. In patients with chronic kidney disease (CKD), the accumulation of uremic toxins, high oxidative stress, and chronic micro-inflammatory conditions contribute to changes in the HDL composition and may also account for protein/lipid modifications. These conditions are associated with a decreased protective function of HDL. Therefore, the HDL quantity and the functional quality of the particle must be considered. This review summarizes the current knowledge of dyslipidemia in CKD patients, the effects of lipid-modulating therapy, and the structural modifications of HDL that are associated with dysfunction. PMID- 25522998 TI - Impact of systemic inflammation and autoimmune diseases on apoA-I and HDL plasma levels and functions. AB - The cholesterol of high-density lipoproteins (HDLs) and its major proteic component, apoA-I, have been widely investigated as potential predictors of acute cardiovascular (CV) events. In particular, HDL cholesterol levels were shown to be inversely and independently associated with the risk of acute CV diseases in different patient populations, including autoimmune and chronic inflammatory disorders. Some relevant and direct anti-inflammatory activities of HDL have been also recently identified targeting both immune and vascular cell subsets. These studies recently highlighted the improvement of HDL function (instead of circulating levels) as a promising treatment strategy to reduce inflammation and associated CV risk in several diseases, such as systemic lupus erythematosus and rheumatoid arthritis. In these diseases, anti-inflammatory treatments targeting HDL function might improve both disease activity and CV risk. In this narrative review, we will focus on the pathophysiological relevance of HDL and apoA-I levels/functions in different acute and chronic inflammatory pathophysiological conditions. PMID- 25522999 TI - HDL in infectious diseases and sepsis. AB - During infection significant alterations in lipid metabolism and lipoprotein composition occur. Triglyceride and VLDL cholesterol levels increase, while reduced HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels are observed. More importantly, endotoxemia modulates HDL composition and size: phospholipids are reduced as well as apolipoprotein (apo) A-I, while serum amyloid A (SAA) and secretory phospholipase A2 (sPLA2) dramatically increase, and, although the total HDL particle number does not change, a significant decrease in the number of small- and medium-size particles is observed. Low HDL-C levels inversely correlate with the severity of septic disease and associate with an exaggerated systemic inflammatory response. HDL, as well as other plasma lipoproteins, can bind and neutralize Gram-negative bacterial lipopolysaccharide (LPS) and Gram positive bacterial lipoteichoic acid (LTA), thus favoring the clearance of these products. HDLs are emerging also as a relevant player during parasitic infections, and a specific component of HDL, namely, apoL-1, confers innate immunity against trypanosome by favoring lysosomal swelling which kills the parasite. During virus infections, proteins associated with the modulation of cholesterol bioavailability in the lipid rafts such as ABCA1 and SR-BI have been shown to favor virus entry into the cells. Pharmacological studies support the benefit of recombinant HDL or apoA-I mimetics during bacterial infection, while apoL-1-nanobody complexes were tested for trypanosome infection. Finally, SR-BI antagonism represents a novel and forefront approach interfering with hepatitis C virus entry which is currently tested in clinical studies. From the coming years, we have to expect new and compelling observations further linking HDL to innate immunity and infections. PMID- 25523000 TI - High-density lipoproteins in stroke. AB - Besides their well-documented function of reverse transport of cholesterol, high density lipoproteins (HDLs) display pleiotropic effects due to their antioxidant, antithrombotic, anti-inflammatory and antiapoptotic properties that may play a major protective role in acute stroke, in particular by limiting the deleterious effects of ischaemia on the blood-brain barrier (BBB) and on the parenchymal cerebral compartment. HDLs may also modulate leukocyte and platelet activation, which may also represent an important target that would justify the use of HDL based therapy in acute stroke. In this review, we will present an update of all the recent findings in HDL biology that could support a potential clinical use of HDL therapy in ischaemic stroke. PMID- 25523001 TI - Therapeutic potential of HDL in cardioprotection and tissue repair. AB - Epidemiological studies support a strong association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. Experimental evidence from different angles supports the view that low HDL is unlikely an innocent bystander in the development of heart failure. HDL exerts direct cardioprotective effects, which are mediated via its interactions with the myocardium and more specifically with cardiomyocytes. HDL may improve cardiac function in several ways. Firstly, HDL may protect the heart against ischaemia/reperfusion injury resulting in a reduction of infarct size and thus in myocardial salvage. Secondly, HDL can improve cardiac function in the absence of ischaemic heart disease as illustrated by beneficial effects conferred by these lipoproteins in diabetic cardiomyopathy. Thirdly, HDL may improve cardiac function by reducing infarct expansion and by attenuating ventricular remodelling post-myocardial infarction. These different mechanisms are substantiated by in vitro, ex vivo, and in vivo intervention studies that applied treatment with native HDL, treatment with reconstituted HDL, or human apo A-I gene transfer. The effect of human apo A-I gene transfer on infarct expansion and ventricular remodelling post-myocardial infarction illustrates the beneficial effects of HDL on tissue repair. The role of HDL in tissue repair is further underpinned by the potent effects of these lipoproteins on endothelial progenitor cell number, function, and incorporation, which may in particular be relevant under conditions of high endothelial cell turnover. Furthermore, topical HDL therapy enhances cutaneous wound healing in different models. In conclusion, the development of HDL-targeted interventions in these strategically chosen therapeutic areas is supported by a strong clinical rationale and significant preclinical data. PMID- 25523002 TI - HDL and lifestyle interventions. AB - The main lifestyle interventions to modify serum HDL cholesterol include physical exercise, weight loss with either caloric restriction or specific dietary approaches, and smoking cessation. Moderate alcohol consumption can be permitted in some cases. However, as these interventions exert multiple effects, it is often difficult to discern which is responsible for improvement in HDL outcomes. It is particularly noteworthy that recent data questions the use of HDL cholesterol as a risk factor and therapeutic target since randomised interventions and Mendelian randomisation studies failed to provide evidence for such an approach. Therefore, these current data should be considered when reading and interpreting this review. Further studies are needed to document the effect of lifestyle changes on HDL structure-function and health. PMID- 25523003 TI - Effects of established hypolipidemic drugs on HDL concentration, subclass distribution, and function. AB - The knowledge of an inverse relationship between plasma high-density lipoprotein cholesterol (HDL-C) concentrations and rates of cardiovascular disease has led to the concept that increasing plasma HDL-C levels would be protective against cardiovascular events. Therapeutic interventions presently available to correct the plasma lipid profile have not been designed to specifically act on HDL, but have modest to moderate effects on plasma HDL-C concentrations. Statins, the first-line lipid-lowering drug therapy in primary and secondary cardiovascular prevention, have quite modest effects on plasma HDL-C concentrations (2-10%). Fibrates, primarily used to reduce plasma triglyceride levels, also moderately increase HDL-C levels (5-15%). Niacin is the most potent available drug in increasing HDL-C levels (up to 30%), but its use is limited by side effects, especially flushing.The present chapter reviews the effects of established hypolipidemic drugs (statins, fibrates, and niacin) on plasma HDL-C levels and HDL subclass distribution, and on HDL functions, including cholesterol efflux capacity, endothelial protection, and antioxidant properties. PMID- 25523004 TI - Emerging small molecule drugs. AB - Dyslipidaemia is a major risk factor for cardiovascular diseases. Pharmacological lowering of LDL-C levels using statins reduces cardiovascular risk. However, a substantial residual risk persists especially in patients with type 2 diabetes mellitus. Because of the inverse association observed in epidemiological studies of HDL-C with the risk for cardiovascular diseases, novel therapeutic strategies to raise HDL-C levels or improve HDL functionality are developed as complementary therapy for cardiovascular diseases. However, until now most therapies targeting HDL-C levels failed in clinical trials because of side effects or absence of clinical benefits. This chapter will highlight the emerging small molecules currently developed and tested in clinical trials to pharmacologically modulate HDL-C and functionality including new CETP inhibitors (anacetrapib, evacetrapib), novel PPAR agonists (K-877, CER-002, DSP-8658, INT131 and GFT505), LXR agonists (ATI-111, LXR-623, XL-652) and RVX-208. PMID- 25523005 TI - ApoA-I mimetics. AB - A wealth of evidence indicates that plasma levels of high-density lipoprotein cholesterol (HDL-C) are inversely related to the risk of cardiovascular disease (CVD). Consequently, HDL-C has been considered a target for therapy in order to reduce the residual CVD burden that remains significant, even after application of current state-of-the-art medical interventions. In recent years, however, a number of clinical trials of therapeutic strategies that increase HDL-C levels failed to show the anticipated beneficial effect on CVD outcomes. As a result, attention has begun to shift toward strategies to improve HDL functionality, rather than levels of HDL-C per se. ApoA-I, the major protein component of HDL, is considered to play an important role in many of the antiatherogenic functions of HDL, most notably reverse cholesterol transport (RCT), and several therapies have been developed to mimic apoA-I function, including administration of apoA-I, mutated variants of apoA-I, and apoA-I mimetic peptides. Based on the potential anti-inflammatory effects, apoA-I mimetics hold promise not only as anti atherosclerotic therapy but also in other therapeutic areas. PMID- 25523006 TI - Antisense oligonucleotides, microRNAs, and antibodies. AB - The specificity of Watson-Crick base pairing and the development of several chemical modifications to oligonucleotides have enabled the development of novel drug classes for the treatment of different human diseases. This review focuses on promising results of recent preclinical or clinical studies on targeting HDL metabolism and function by antisense oligonucleotides and miRNA-based therapies. Although many hurdles regarding basic mechanism of action, delivery, specificity, and toxicity need to be overcome, promising results from recent clinical trials and recent approval of these types of therapy to treat dyslipidemia suggest that the treatment of HDL dysfunction will benefit from these unique clinical opportunities. Moreover, an overview of monoclonal antibodies (mAbs) developed for the treatment of dyslipidemia and cardiovascular disease and currently being tested in clinical studies is provided. Initial studies have shown that these compounds are generally safe and well tolerated, but ongoing large clinical studies will assess their long-term safety and efficacy. PMID- 25523007 TI - Interspecific and intraspecific gene variability in a 1-Mb region containing the highest density of NBS-LRR genes found in the melon genome. AB - BACKGROUND: Plant NBS-LRR -resistance genes tend to be found in clusters, which have been shown to be hot spots of genome variability. In melon, half of the 81 predicted NBS-LRR genes group in nine clusters, and a 1 Mb region on linkage group V contains the highest density of R-genes and presence/absence gene polymorphisms found in the melon genome. This region is known to contain the locus of Vat, an agronomically important gene that confers resistance to aphids. However, the presence of duplications makes the sequencing and annotation of R gene clusters difficult, usually resulting in multi-gapped sequences with higher than average errors. RESULTS: A 1-Mb sequence that contains the largest NBS-LRR gene cluster found in melon was improved using a strategy that combines Illumina paired-end mapping and PCR-based gap closing. Unknown sequence was decreased by 70% while about 3,000 SNPs and small indels were corrected. As a result, the annotations of 18 of a total of 23 NBS-LRR genes found in this region were modified, including additional coding sequences, amino acid changes, correction of splicing boundaries, or fussion of ORFs in common transcription units. A phylogeny analysis of the R-genes and their comparison with syntenic sequences in other cucurbits point to a pattern of local gene amplifications since the diversification of cucurbits from other families, and through speciation within the family. A candidate Vat gene is proposed based on the sequence similarity between a reported Vat gene from a Korean melon cultivar and a sequence fragment previously absent in the unrefined sequence. CONCLUSIONS: A sequence refinement strategy allowed substantial improvement of a 1 Mb fragment of the melon genome and the re-annotation of the largest cluster of NBS-LRR gene homologues found in melon. Analysis of the cluster revealed that resistance genes have been produced by sequence duplication in adjacent genome locations since the divergence of cucurbits from other close families, and through the process of speciation within the family a candidate Vat gene was also identified using sequence previously unavailable, which demonstrates the advantages of genome assembly refinements when analyzing complex regions such as those containing clusters of highly similar genes. PMID- 25523008 TI - Intracortical modulation, and not spinal inhibition, mediates placebo analgesia. AB - Suppression of spinal responses to noxious stimulation has been detected using spinal fMRI during placebo analgesia, which is therefore increasingly considered a phenomenon caused by descending inhibition of spinal activity. However, spinal fMRI is technically challenging and prone to false-positive results. Here we recorded laser-evoked potentials (LEPs) during placebo analgesia in humans. LEPs allow neural activity to be measured directly and with high enough temporal resolution to capture the sequence of cortical areas activated by nociceptive stimuli. If placebo analgesia is mediated by inhibition at spinal level, this would result in a general suppression of LEPs rather than in a selective reduction of their late components. LEPs and subjective pain ratings were obtained in two groups of healthy volunteers - one was conditioned for placebo analgesia while the other served as unconditioned control. Laser stimuli at three suprathreshold energies were delivered to the right hand dorsum. Placebo analgesia was associated with a significant reduction of the amplitude of the late P2 component. In contrast, the early N1 component, reflecting the arrival of the nociceptive input to the primary somatosensory cortex (SI), was only affected by stimulus energy. This selective suppression of late LEPs indicates that placebo analgesia is mediated by direct intracortical modulation rather than inhibition of the nociceptive input at spinal level. The observed cortical modulation occurs after the responses elicited by the nociceptive stimulus in the SI, suggesting that higher order sensory processes are modulated during placebo analgesia. PMID- 25523009 TI - Twelve tips to support the development of clinical reasoning skills using virtual patient cases. AB - Clinical reasoning is a critical core competency in medical education. Strategies to support the development of clinical reasoning skills have focused on methodologies used in traditional settings, including lectures, small groups, activities within Simulation Centers and the clinical arena. However, the evolving role and growing utilization of virtual patients (VPs) in undergraduate medical education; as well as an increased emphasis on blended learning, multi modal models that include VPs in core curricula; suggest a growing requirement for strategies or guidelines that directly focus on VPs. The authors have developed 12 practical tips that can be used in VP cases to support the development of clinical reasoning. These are based on teaching strategies and principles of instructional design and pedagogy, already used to teach and assess clinical reasoning in other settings. Their application within VPs will support educators who author or use VP cases that promote the development of clinical reasoning. PMID- 25523010 TI - Assessing competencies using milestones along the way. AB - This paper presents perspectives and controversies surrounding the use of milestones to assess competency in outcomes-based medical education. Global perspectives (Canada, Europe, and the United States) and developments supporting their rationales are discussed. In Canada, there is a significant movement away from conceptualizing competency based on time, and a move toward demonstration of specific competencies. The success of this movement may require complex (rather than reductionist) milestones that reflect students' progression through complexity and context and a method to narrate their journey. European countries (United Kingdom, France, and Germany) have stressed the complexity associated with time and milestones for medical students to truly achieve competence. To meet the changing demands of medicine, they view time as actually providing students with knowledge and exposure to achieve various milestones. In the United States, milestones are based on sampling throughout professional development to initiate lifelong learning. However, the use of milestones may not imply overall competence (reductionism). Milestones must be developed alongside outcomes-based curriculum with use of faculty and competency committees. The perspectives outlined in this paper underscore emerging challenges for implementing outcomes based medical education and call for new conceptualizations of competence. PMID- 25523011 TI - Sea monsters & whirlpools: Navigating between examination and reflection in medical education. AB - The 16th International Ottawa Conference/Canadian Conference on Medical Education (2014) featured a keynote deconstructing the rising discourse of competence-as reflection in medical education. This paper, an elaborated version of the presentation, is an investigation into the theoretical roots of the diverse forms of reflective practice that are being employed by medical educators. It also raises questions about the degree to which any of these practices is compatible with assessment. PMID- 25523012 TI - Twitter as a tool for communication and knowledge exchange in academic medicine: A guide for skeptics and novices. AB - Twitter is a tool for physicians to increase engagement of learners and the public, share scientific information, crowdsource new ideas, conduct, discuss and challenge emerging research, pursue professional development and continuing medical education, expand networks around specialized topics and provide moral support to colleagues. However, new users or skeptics may well be wary of its potential pitfalls. The aims of this commentary are to discuss the potential advantages of the Twitter platform for dialogue among physicians, to explore the barriers to accurate and high-quality healthcare discourse and, finally, to recommend potential safeguards physicians may employ against these threats in order to participate productively. PMID- 25523013 TI - Antisense oligonucleotides targeting human telomerase mRNA increases the radiosensitivity of nasopharyngeal carcinoma cells. AB - Nasopharyngeal carcinoma (NPC) is associated with a high incidence rate in South China and is predominantly treated with radiotherapy; however, the survival rate remains low. The therapeutic effects of radiation and chemotherapy may be enhanced when combined with anti-sense oligonucleotides targeting human telomerase RNA (hTR ASODN). However, the influence of hTR ASODN on the anti-tumor effects of radiation in NPC remain unknown. The present study investigated the effects of hTR ASODN on the proliferation and radiosensitivity of NPC cells, and further explored the underlying mechanisms. hTR ASODN significantly inhibited the proliferation and decreased the telomere length of CNE-2 human NPC cells. Furthermore, combined treatment of hTR ASODN with radiation significantly enhanced anti-tumor efficacy. The apoptotic rate and cleavage of caspase 9 were increased in the cells treated with the combined therapy, as compared with the cells treated with hTR ASODN or radiotherapy alone. In conclusion, these results suggest that hTR ASODN may inhibit the proliferation of NPC cells and enhance the anti-tumor effects of radiation by inducing cell apoptosis. Therefore hTR ASODN may be a potential adjuvant agent for the treatment of NPC combined with radiation therapy, and these findings are of translational importance. PMID- 25523014 TI - Development, validation and psychometric analysis of the diabetic foot self-care questionnaire of the University of Malaga, Spain (DFSQ-UMA). AB - This paper assessed the reliability and construct validity of a tool to evaluate the foot self-care of diabetic patients. The education of diabetic patients about their foot care is a major issue to avoid complications like amputations and ulcers. Specific tools aimed to assess patient's knowledge in this area are needed. The study had two phases: in Phase 1, item-generation was carried out through a literature review, expert review by a Delphi technique and cognitive interviews with diabetic patients for testing readability and comprehension. In Phase 2, diabetic patients participated in a cross-sectional study for a psychometric evaluation (reliability and construct validity) was carried out on a sample of type I and II diabetic patients. The study was conducted at the University of Malaga (Spain), podiatric clinics and a Diabetic Foot Unit between October 2012 and March 2013. After psychometric-test analyses on a sample of 209 diabetic patients, the questionnaire resulted in 16 questions. Cronbach's alpha was 0.89 after removing 4 items because of their low reliability. Inter-item correlations gave a mean value of 0.34 (range: 0.06-0.74). The rotated solution showed a 3-factor structure (self-care, foot care, and footwear and socks) that jointly accounted for 60.88% of the variance observed. The correlation between the questionnaire scores and HbA1c was significant and inverse, (r = -0.15; p < 0.01). The findings show that the questionnaire is a valid and reliable tool for evaluating foot self-care behavior in diabetic patients. PMID- 25523016 TI - Tribute to a great obstetrician: in memory of Ingemar Ingemarsson. PMID- 25523015 TI - Peptide-based vaccination and induction of CD8+ T-cell responses against tumor antigens in breast cancer. AB - Tumor-associated antigens (TAAs) have been identified in many malignant tumors. Within these TAAs are peptide sequences that bind major histocompatibility complex (MHC) class I and class II molecules recognized by T cells triggering antigen-specific CD8+ cytotoxic T-cell and CD4+ T-helper cell responses. Efforts to develop vaccines for breast cancer have been underway for more than 20 years, including peptide and whole inactivated tumor cell vaccines as well as antigen loaded dendritic cell vaccines. The majority of vaccine trials have used peptides, including single-peptide and multiple-peptide formulations using either MHC class I and class II epitopes in oil-based emulsions alone or in combination with an adjuvant, such as granulocyte-macrophage colony-stimulating factor, and Toll-like receptor agonists. Preclinical research in vitro and in animal models has been aimed at improving vaccine efficacy by identifying more immunogenic peptides and combinations of peptides and adjuvants and cytokine adjuvants that induce stronger immune responses and prolong T-cell memory. Clinical studies investigating the therapeutic potential of active immunization using peptide vaccines has found no serious side effects. In this review, we examine TAA peptide-based vaccination regimens showing promise in breast cancer patients that are also being investigated in clinical trials of safety and efficacy. We also discuss the current limitations in the peptide vaccination field and areas for future development. PMID- 25523017 TI - Zinc porphyrin-Re(I) bipyridyl-fullerene triad: synthesis, characterization, and kinetics of the stepwise electron-transfer processes initiated by visible excitation. AB - A new triad system featuring one zinc porphyrin and one fullerene moieties attached to a central redox-active Re(I) connector was obtained in remarkable yield by cleverly exploiting a facile two-step synthesis. Detailed description and discussion on the characterization of this multicomponent system and of its parent free-base analogue are presented, along with a kinetic study of the stepwise electron-transfer processes occurring upon visible excitation. PMID- 25523018 TI - Insights from genomes of representatives of the human gut commensal Bifidobacterium bifidum. AB - Bifidobacteria are bacterial gut commensals of mammals, birds and social insects that are perceived to influence the metabolism/physiology of their host. In this context, members of the Bifidobacterium bifidum species are believed to significantly contribute to the overall microbiota of the human gut at infant stage. However, the molecular reasons for their adaptation to this environment are poorly understood. In this study, we analysed the pan-genome of B. bifidum species by decoding genomes of 15 B. bifidum strains, which highlighted the existence of a conserved gene uniquely present in this bifidobacterial taxon, underscoring a nutrient acquisition strategy that targets host-derived glycans, such as those present in mucin. Growth experiments and corresponding transcriptomic analyses confirmed the in silico data and supported these intriguing and unique host glycan-specific saccharolytic features. The ubiquity of the genetic features of B. bifidum for the breakdown of host glycans was confirmed by interrogating metagenomic datasets, thereby supporting the notion that metabolic access to host-derived glycans is a potent evolutionary force that has shaped B. bifidum genomes and consequently the ecology of the infant intestinal microbiota. PMID- 25523020 TI - The Welfare Cost of Homicides in Brazil: Accounting for Heterogeneity in the Willingness to Pay for Mortality Reductions. AB - This paper estimates the health dimension of the welfare cost of homicides in Brazil incorporating age, gender, educational, and regional heterogeneities. We use a marginal willingness to pay approach to assign monetary values to the welfare cost of increased mortality due to violence. Results indicate that the present discounted value of the welfare cost of homicides in Brazil corresponds to roughly 78% of the GDP or, in terms of yearly flow, 2.3%. The analysis also shows that reliance on aggregate data to perform such calculations can lead to biases of around 20% in the estimated social cost of violence. PMID- 25523021 TI - Atomic force microscopy in biomaterials surface science. AB - Recent progress in surface science, nanotechnology and biophysics has cast new light on the correlation between the physicochemical properties of biomaterials and the resulting biological response. One experimental tool that promises to generate an increasingly more sophisticated knowledge of how proteins, cells and bacteria interact with nanostructured surfaces is the atomic force microscope (AFM). This unique instrument permits to close in on interfacial events at the scale at which they occur, the nanoscale. This perspective covers recent developments in the exploitation of the AFM, and suggests insights on future opportunities that can arise from the exploitation of this powerful technique. PMID- 25523019 TI - Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer's disease and frontotemporal lobar degeneration. AB - A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer's disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296-390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology. PMID- 25523022 TI - Cigarette, alcohol, and illicit drug use down among US teens but e-cigarette use common, survey finds. PMID- 25523024 TI - The concise synthesis of unsymmetric triarylacetonitriles via Pd-catalyzed sequential arylation: a new synthetic approach to tri- and tetraarylmethanes. AB - The selective synthesis of multiarylated acetonitriles via sequential palladium catalyzed arylations of chloroacetonitrile is reported. The three aryl groups are installed via a Pd-catalyzed Suzuki-Miyaura cross coupling reaction followed by back-to-back C-H arylations to afford triarylacetonitriles in three steps with no over-arylation at any step. The triarylacetonitrile products can be converted into highly functionalized species including tetraarylmethanes. This new strategy provides rapid access to a variety of unsymmetrical tri- and tetraarylmethane derivatives from simple, readily available starting materials. PMID- 25523023 TI - Surgical skills simulation in trauma and orthopaedic training. AB - Changing patterns of health care delivery and the rapid evolution of orthopaedic surgical techniques have made it increasingly difficult for trainees to develop expertise in their craft. Working hour restrictions and a drive towards senior led care demands that proficiency be gained in a shorter period of time whilst requiring a greater skill set than that in the past. The resulting conflict between service provision and training has necessitated the development of alternative methods in order to compensate for the reduction in 'hands-on' experience. Simulation training provides the opportunity to develop surgical skills in a controlled environment whilst minimising risks to patient safety, operating theatre usage and financial expenditure. Many options for simulation exist within orthopaedics from cadaveric or prosthetic models, to arthroscopic simulators, to advanced virtual reality and three-dimensional software tools. There are limitations to this form of training, but it has significant potential for trainees to achieve competence in procedures prior to real-life practice. The evidence for its direct transferability to operating theatre performance is limited but there are clear benefits such as increasing trainee confidence and familiarity with equipment. With progressively improving methods of simulation available, it is likely to become more important in the ongoing and future training and assessment of orthopaedic surgeons. PMID- 25523025 TI - Economic modelling of a public health programme for fall prevention. AB - BACKGROUND: despite evidence on what works in falls prevention, falls in older people remain an important public health problem. AIMS: the purpose of this study was to model the impact and cost-effectiveness of a public health falls prevention programme, from the perspective of the health funder. METHODS: a decision analytic Markov model compared the health benefits in quality-adjusted life years (QALYs) and costs of treatment and residential aged care with and without a population heath falls prevention programme. Different intervention costs, uptake levels and programme effectiveness were modelled in sensitivity analyses. Uncertainty was explored using univariate and probabilistic sensitivity analysis. RESULTS: widespread rollout of a public health fall prevention programme could result in an incremental cost-effectiveness ratio (ICER) of $A28,931 per QALY gained, assuming a programme cost of $700 per person and at a fall prevention risk ratio of 0.75. This ICER would be considered cost-effective at a threshold value of $A50,000 per QALY gained. Sensitivity analyses for programme cost and effectiveness indicated that the public health programme produced greater health outcomes and was less costly than no programme when programme costs were $A500 or lower and risk ratio for falls was 0.70 or lower. At a cost of $A2,500, the public health falls prevention programme ceases to be a cost-effective option. CONCLUSION: serious consideration should be given to implementation of a public health programme of falls prevention as a cost effective option that enables population-wide access to the intervention strategies. PMID- 25523027 TI - Improved single pellet grasping using automated ad libitum full-time training robot. AB - The single pellet grasping (SPG) task is a skilled forelimb motor task commonly used to evaluate reaching and grasp kinematics and recovery of forelimb function in rodent models of CNS injuries and diseases. To train rats in the SPG task, the animals are usually food restricted then placed in an SPG task enclosure and presented food pellets on a platform located beyond a slit located at the front of the task enclosure for 10-30 min, normally every weekday for several weeks. When the SPG task is applied in studies involving various experimental groups, training quickly becomes labor intensive, and can yield results with significant day-to-day variability. Furthermore, training is frequently done during the animals' light-cycle, which for nocturnal rodents such as mice and rats could affect performance. Here we describe an automated pellet presentation (APP) robotic system to train and test rats in the SPG task that reduces some of the procedural weaknesses of manual training. We found that APP trained rats performed significantly more trials per 24 h period, and had higher success rates with less daily and weekly variability than manually trained rats. Moreover, the results show that success rates are positively correlated with the number of dark cycle trials, suggesting that dark-cycle training has a positive effect on success rates. These results demonstrate that automated training is an effective method for evaluating and training skilled reaching performance of rats, opening up the possibility for new approaches to investigating the role of motor systems in enabling skilled forelimb use and new approaches to investigating rehabilitation following CNS injury. PMID- 25523026 TI - NSAIDs: learning new tricks from old drugs. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) comprise a heterogeneous group of pharmacological agents used for the symptomatic treatment of fever, pain, and inflammation. Although the main mechanism of action of NSAIDs consists of inhibiting prostaglandin synthesis by blocking the enzyme cyclooxygenase (COX), clinical, and experimental data strongly indicate the existence of additional mechanisms. Some of the COX-independent effects are related to the ability of NSAIDs to penetrate biological membranes and disrupt important molecular interactions necessary for a wide array of cellular functions, including cell adhesion. These effects, in particular those that interfere with L-selectin function in neutrophils during the inflammatory response, may contribute to the anti-inflammatory properties that NSAIDs exert in vivo. Recent contributions in this field have shown that the anti-L-selectin effect of NSAIDs is related to the NADPH-oxidase-dependent generation of superoxide anion at the plasma membrane. These findings might represent a novel approach for developing new and effective anti-inflammatory compounds with a better safety profile than the currently available NSAIDs. PMID- 25523028 TI - Drug-, dose- and sex-dependent effects of chronic fluoxetine, reboxetine and venlafaxine on open-field behavior and spatial memory in rats. AB - In an effort to address the need to include both sexes in studies of effects of the SSRI fluoxetine, the NRI reboxetine and the SNRI venlafaxine on anxiety related behavior and memory along with the use of chronic drug administration, male and female PVG/c rats were fed diets containing two doses of each drug for 21 days. The rats' anxiety level was then assessed in an open field. Short-term spatial memory for a brightness change in a Y maze was also measured. While there was little evidence of anxiolytic effects of any of the drugs, both fluoxetine and, to a lesser extent, venlafaxine appeared to be mainly anxiogenic in their action depending on both dose and sex. Reboxetine was relatively ineffective in this respect. Ability to locate the Y-maze arm that had changed (from white to black) seemed to be impaired for male (but not female) rats by both fluoxetine and venlafaxine and, to a much lesser extent, by reboxetine. Given the relative ineffectiveness of reboxetine in either test, it is possible that the effects of the other two drugs on both anxiety and memory were mainly due to their serotonin reuptake inhibiting properties. The differences that occurred between males and females in responsiveness to all three drugs supported the long-held view that both sexes should be investigated in studies of this sort, especially in view of reports of sex differences in effects of clinically prescribed antidepressants. PMID- 25523029 TI - Establishment of an animal model of depression contagion. AB - BACKGROUND: Depression is a common and important cause of morbidity, and results in a significant economic burden. Recent human studies have demonstrated that that depression is contagious, and depression in family and friends might cumulatively increase the likelihood that a person will exhibit depressive behaviors. The mechanisms underlying contagion depression are poorly understood, and there are currently no animal models for this condition. METHODS: Rats were divided into 3 groups: depression group, contagion group, and control group. After induction of depression by 5 weeks of chronic unpredictable stress, rats from the contagion group were housed with the depressed rats (1 naive rat with 2 depressed rats) for 5 weeks. Rats were then subjected to sucrose preference, open field, and forced swim tests. RESULTS: The sucrose preference was significantly reduced in the depressed rats (p<0.01) and contagion depression rats (p<0.01). Climbing time during forced swim test was reduced in the depression and contagion depression groups (p<0.001), whereas immobility time was significantly prolonged in only the depression group (p<0.001). Rats in both the depression (p<0.05) and depression contagion group (p<0.005) had decreased total travel distance and decreased mean velocity in the open field test, whereas the time spent in the central part was significantly shorter in only the depression group (p<0.001). CONCLUSIONS: In this study, for the first time we demonstrated depression contagion in an animal model. A reliable animal model may help better understand the underlying mechanisms of contagion depression, and may allow for future investigations of the studying therapeutic modalities. PMID- 25523030 TI - Impairment of social behavior and communication in mice lacking the Uba6 dependent ubiquitin activation system. AB - The Uba6-Use1 ubiquitin enzyme cascade is a poorly understood arm of the ubiquitin-proteasome system required for mouse development. Recently, we reported that Uba6 brain-specific knockout (termed NKO) mice display abnormal social behavior and neuronal development due to a decreased spine density and accumulation of Ube3a and Shank3. To better characterize a potential role for NKO mice in autism spectrum disorders (ASDs), we performed a comprehensive behavioral characterization of the social behavior and communication of NKO mice. Our behavioral results confirmed that NKO mice display social impairments, as indicated by fewer vocalizations and decreased social interaction. We conclude that UBA6 NKO mice represent a novel ASD mouse model of anti-social and less verbal behavioral symptoms. PMID- 25523031 TI - A mutation in the intracellular loop III/IV of mosquito sodium channel synergizes the effect of mutations in helix IIS6 on pyrethroid resistance. AB - Activation and inactivation of voltage-gated sodium channels are critical for proper electrical signaling in excitable cells. Pyrethroid insecticides promote activation and inhibit inactivation of sodium channels, resulting in prolonged opening of sodium channels. They preferably bind to the open state of the sodium channel by interacting with two distinct receptor sites, pyrethroid receptor sites PyR1 and PyR2, formed by the interfaces of domains II/III and I/II, respectively. Specific mutations in PyR1 or PyR2 confer pyrethroid resistance in various arthropod pests and disease vectors. Recently, a unique mutation, N(1575)Y, in the cytoplasmic loop linking domains III and IV (LIII/IV) was found to coexist with a PyR2 mutation, L(1014)F in IIS6, in pyrethroid-resistant populations of Anopheles gambiae. To examine the role of this mutation in pyrethroid resistance, N(1575)Y alone or N(1575)Y + L(1014)F were introduced into an Aedes aegypti sodium channel, AaNav1-1, and the mutants were functionally examined in Xenopus oocytes. N(1575)Y did not alter AaNav1-1 sensitivity to pyrethroids. However, the N(1575)Y + L(1014)F double mutant was more resistant to pyrethroids than the L(1014)F mutant channel. Further mutational analysis showed that N(1575)Y could also synergize the effect of L(1014)S/W, but not L(1014)G or other pyrethroid-resistant mutations in IS6 or IIS6. Computer modeling predicts that N(1575)Y allosterically alters PyR2 via a small shift of IIS6. Our findings provide the molecular basis for the coexistence of N(1575)Y with L(1014)F in pyrethroid resistance, and suggest an allosteric interaction between IIS6 and LIII/IV in the sodium channel. PMID- 25523032 TI - Antiangiogenic and anticancer effect of an orally active low molecular weight heparin conjugates and its application to lung cancer chemoprevention. AB - Angiogenesis is well recognized as a pivotal process in tumor progression from the very early premalignant stages, thus making it an important target in cancer chemoprevention as well as in cancer treatment. In the present study, we introduce a recently developed oral heparin conjugate (LHTD4) for use as an inhibitor of angiogenesis and evaluate its therapeutic and preventive effects in two different animal models of lung cancer. The antiangiogenic activities of LHTD4 were evaluated using tube formation and Matrigel plug assays. VEGF- and bFGF-induced tube formations were reduced up to 77.2 and 67.3%, respectively, by LHTD4. Hemoglobin content was also significantly decreased by LHTD4 in the Matrigel plugs that were transplanted into mice. We observed that the VEGF- and bFGF-mediated phosphorylations of the receptors, VEGFR-2 and FGFR-1, were also inhibited by LHTD4. The in vivo antiangiogenic and anticancer effects of LHTD4 that developed following oral administration were verified in a tumor xenograft model of human A549 lung cancer cells: tumor volume was found to have decreased by 60.2% and the expressions of CD34 and Ki-67 in the LHTD4-treated group were affected. Finally, in a chemically induced lung carcinogenesis model, the number and area of each nodule were significantly reduced in the LHTD4-treated groups by 49.2% and 30.1%, respectively. In addition, the degree of angiogenesis in the lung tissue itself was decreased in the drug treatment group by 52.9%. Taken together, these results suggest that LHTD4 could be a promising candidate for angiogenesis inhibitor for the treatment and prevention of cancer. PMID- 25523033 TI - Trg-deficient Salmonella colonize quiescent tumor regions by exclusively penetrating or proliferating. AB - Chemotherapeutics fail to effectively treat tumors because they cannot reach quiescent regions far from blood vessels. Motile Salmonella are an attractive delivery system that could break this therapeutic barrier. However, little is known about the dissemination and tissue penetration of individual bacteria in tumors after intravenous administration. We hypothesized that eliminating the Trg receptor would improve accumulation in tumor quiescence. To test this hypothesis, we deleted the trg gene from nonpathogenic Salmonella. To quantify individual bacterial behavior, we measured tissue penetration in a tumor-on-a-chip device and measured colony localization in mouse tumors using immunofluorescence. In tumors in vitro and in mice, trg(-) Salmonella penetrated farther into tissue than control bacteria. This difference in localization was caused by the inability to sense sugars in well perfused tissue. Three distinct bacterial phenotypes were observed: proliferating, penetrating, and inactive. Large proliferating colonies, containing more than 40% of individual bacteria, only formed less than 60MUm from blood vessels. Small colonies, in comparison, were present both near (inactive) and far (penetrating) from vessels. The farthest was 361.2MUm from a vessel, demonstrating the ability to target avascular regions. In addition, colonization was most pronounced in poorly vascularized tumor regions. We show that deletion of trg amplifies Salmonella accumulation in quiescent tumor regions, and, for the first time, identify biological processes that control bacterial distribution in tumors. Understanding how Salmonella penetrate tissue, target quiescence and specifically replicate in tumors are essential steps toward creating a tightly controlled, tunable bacterial therapy. PMID- 25523034 TI - PCR diagnostic system in the treatment of prosthetic joint infections. AB - In our prospective study, we examined whether a multiplex PCR diagnostic method is suitable for the primary detection of pathogens. We also examined the possibility and sensitivity of detecting genes responsible for biofilm production and methicillin resistance. From 2007 to 2009, 94 patients were included in the study. A UNB (universal detection of 16S ribosomal bacterial DNA) and UNF (universal detection of pathogenic fungi) were used in the primary detection. A multiplex assay for biofilm production, methicillin resistance allowed us to distinguish between Gram positivity and negativity and to detect Staphylococci. From all the samples, the culture was positive in 53.2 % of cases, and by using the UNB method, we detected bacteria in 79.8 % of cases-the UNF detection of fungi was positive in 10.6 % of cases. In 75 % of positive findings, we detected a Gram-negative bacterium in 65.3 % of cases. In 47.2 % of Staphylococci detected, the ability to produce biofilm was confirmed. 61.1 % of the Staphylococci exhibited a methicillin resistance. Our multiplex scheme cannot yet fully replace microbial cultivation but can be a rational guide when choosing an appropriate antibiotic therapy in cases where the microbial culture is negative. PMID- 25523035 TI - "Squalenoylcurcumin" nanoassemblies as water-dispersible drug candidates with antileishmanial activity. AB - Curcumin, a natural polyphenolic compound, showed antiparasitic potential, including trypanocidal and leishmanicidal activity, in several in vitro and in vivo models. The molecule is well tolerated in humans. However, it is insoluble in water and displays poor oral bioavailability as a result of low absorption. New derivatives of curcumin were prepared by esterification of one or two of its phenolic groups with 1,1',2-tris-norsqualenic acid. These "squalenoylcurcumins" were formulated as water-dispersible nanoassemblies of homogeneous size, and they proved to be stable. Squalenoylcurcumins were inactive against Trypanosoma brucei brucei trypomastigotes, even as nanoassemblies, in contrast with curcumin. However, against Leishmania donovani promastigotes, the activities of the squalenoylcurcumins and their nanoassemblies were enhanced relative to that of curcumin. In L. donovani axenic and intramacrophagic amastigotes, they showed activity in the range of miltefosine, with good selectivity indexes. In regard to their dispersibility in water and to the safety of curcumin, these nanoassemblies are promising candidates for preclinical study toward the treatment of visceral leishmaniasis. PMID- 25523037 TI - Comparative and population mitogenomic analyses of Madagascar's extinct, giant 'subfossil' lemurs. AB - Humans first arrived on Madagascar only a few thousand years ago. Subsequent habitat destruction and hunting activities have had significant impacts on the island's biodiversity, including the extinction of megafauna. For example, we know of 17 recently extinct 'subfossil' lemur species, all of which were substantially larger (body mass ~11-160 kg) than any living population of the ~100 extant lemur species (largest body mass ~6.8 kg). We used ancient DNA and genomic methods to study subfossil lemur extinction biology and update our understanding of extant lemur conservation risk factors by i) reconstructing a comprehensive phylogeny of extinct and extant lemurs, and ii) testing whether low genetic diversity is associated with body size and extinction risk. We recovered complete or near-complete mitochondrial genomes from five subfossil lemur taxa, and generated sequence data from population samples of two extinct and eight extant lemur species. Phylogenetic comparisons resolved prior taxonomic uncertainties and confirmed that the extinct subfossil species did not comprise a single clade. Genetic diversity estimates for the two sampled extinct species were relatively low, suggesting small historical population sizes. Low genetic diversity and small population sizes are both risk factors that would have rendered giant lemurs especially susceptible to extinction. Surprisingly, among the extant lemurs, we did not observe a relationship between body size and genetic diversity. The decoupling of these variables suggests that risk factors other than body size may have as much or more meaning for establishing future lemur conservation priorities. PMID- 25523038 TI - Interpretation biases in chronic pain patients: an incidental learning task. AB - BACKGROUND: The aim of this study was to investigate the impact of chronic pain on interpretation bias for ambiguous faces, using a recently developed paradigm with ecologically valid stimuli. METHODS: Fifty patients with chronic pain and 25 healthy controls were trained to respond to probes following the presentation of happy or painful faces, using an incidental learning task. During a test phase, ambiguous faces were presented. The degree to which participants were faster to respond to probes presented where painful (rather than happy) faces had previously been presented was taken as an indication of the interpretation bias towards painful faces. RESULTS: All participants had learnt the originally presented contingency. As predicted, chronic pain patients showed a greater bias towards interpreting ambiguous faces as painful than control participants. Further, there were correlations between fear of pain and catastrophizing and interpretation bias, indicating that participants with higher fear of pain and higher scores on a measure of catastrophizing were more likely to interpret ambiguous faces as painful. Severity of pain was inversely associated with increased interpretation bias for pain. CONCLUSION: These results show clear evidence that chronic pain patients do demonstrate an interpretation bias towards painful faces and that this bias is greater for those who catastrophize more and have higher levels of fear of pain, but experienced less pain in the preceding week. Given the recent potential shown for interventions that modify cognitive biases, this paradigm would seem to be well suited to future efforts to modify interpretation biases in pain. PMID- 25523039 TI - Self-poled transparent and flexible UV light-emitting cerium complex-PVDF composite: a high-performance nanogenerator. AB - Cerium(III)-N,N-dimethylformamide-bisulfate [Ce(DMF)(HSO4)3] complex is doped into poly(vinylidene fluoride) (PVDF) to induce a higher yield (99%) of the electroactive phases (beta- and gamma-phases) of PVDF. A remarkable enhancement of the output voltage (~32 V) of a nanogenerator (NG) based on a nonelectrically poled cerium(III) complex containing PVDF composite film is achieved by simple repeated human finger imparting, whereas neat PVDF does not show this kind of behavior. This high electrical output resembles the generation of self-poled electroactive beta-phase in PVDF due to the electrostatic interactions between the fluoride of PVDF and the surface-active positive charge cloud of the cerium complex via H-bonding and/or bipolar interaction among the opposite poles of cerium complex and PVDF, respectively. The capacitor charging capability of the flexible NG promises its applicability as piezoelectric-based energy harvester. The cerium(III) complex doped PVDF composite film exhibit an intense photoluminescence in the UV region, which might be due to a participation of electron cloud from negative pole of bipolarized PVDF. This fact may open a new area for prospective development of high-performance energy-saving flexible solid state UV light emitters. PMID- 25523036 TI - Interest of preoperative immunonutrition in liver resection for cancer: study protocol of the PROPILS trial, a multicenter randomized controlled phase IV trial. AB - BACKGROUND: Malnutrition is an independent risk factor of postoperative morbidity and mortality and it's observed in 20 to 50% of surgical patients. Preoperative interventions to optimize the nutritional status, reduce postoperative complications and enteral nutrition has proven to be superior to the parenteral one. Moreover, regardless of the nutritional status of the patient, surgery impairs the immunological response, thus increasing the risk of postoperative sepsis. Immunonutrition has been developed to improve the immunometabolic host response in perioperative period and it has been proven to reduce significantly postoperative infectious complications and length of hospital stay in patients undergoing elective gastrointestinal surgery for tumors. We hypothesize that a preoperative oral immunonutrition (ORAL IMPACT(r)) can reduce postoperative morbidity in liver resection for cancer. METHODS/DESIGN: Prospective multicenter randomized placebo-controlled double-blind phase IV trial with two parallel treatment groups receiving either study product (ORAL IMPACT(r)) or control supplement (isocaloric isonitrogenous supplement--IMPACT CONTROL(r)) for 7 days before liver resection for cancer. A total of 400 patients will be enrolled. Patients will be stratified according to the type of hepatectomy, the presence of chronic liver disease and the investigator center. The main end-point is to evaluate in intention-to-treat analysis the overall 30-day morbidity. Secondary end-points are to assess the 30-day infectious and non-infectious morbidity, length of antibiotic treatment and hospital stay, modifications on total food intake, compliance to treatment, side-effects of immunonutrition, impact on liver regeneration and sarcopenia, and to perform a medico-economic analysis. DISCUSSION: The overall morbidity rate after liver resection is 22% to 42%. Infectious post-operative complications (12% to 23%) increase the length of hospital stay and costs and are responsible for a quarter of 30-day mortality. Various methods have been advocated to decrease the rate of postoperative complications but there is no evidence to support or refute the use of any treatment and further trials are required. The effects of preoperative oral immunonutrition in non-cirrhotic patients undergoing liver resection for cancer are unknown. The present trial is designed to evaluate whether the administration of a short-term preoperative oral immunonutrition can reduce postoperative morbidity in non-cirrhotic patients undergoing liver resection for cancer. TRIAL REGISTRATION: Clinicaltrial.gov: NCT02041871. PMID- 25523040 TI - Convex nonnegative matrix factorization with manifold regularization. AB - Nonnegative Matrix Factorization (NMF) has been extensively applied in many areas, including computer vision, pattern recognition, text mining, and signal processing. However, nonnegative entries are usually required for the data matrix in NMF, which limits its application. Besides, while the basis and encoding vectors obtained by NMF can represent the original data in low dimension, the representations do not always reflect the intrinsic geometric structure embedded in the data. Motivated by manifold learning and Convex NMF (CNMF), we propose a novel matrix factorization method called Graph Regularized and Convex Nonnegative Matrix Factorization (GCNMF) by introducing a graph regularized term into CNMF. The proposed matrix factorization technique not only inherits the intrinsic low dimensional manifold structure, but also allows the processing of mixed-sign data matrix. Clustering experiments on nonnegative and mixed-sign real-world data sets are conducted to demonstrate the effectiveness of the proposed method. PMID- 25523041 TI - Towards an intelligent framework for multimodal affective data analysis. AB - An increasingly large amount of multimodal content is posted on social media websites such as YouTube and Facebook everyday. In order to cope with the growth of such so much multimodal data, there is an urgent need to develop an intelligent multi-modal analysis framework that can effectively extract information from multiple modalities. In this paper, we propose a novel multimodal information extraction agent, which infers and aggregates the semantic and affective information associated with user-generated multimodal data in contexts such as e-learning, e-health, automatic video content tagging and human computer interaction. In particular, the developed intelligent agent adopts an ensemble feature extraction approach by exploiting the joint use of tri-modal (text, audio and video) features to enhance the multimodal information extraction process. In preliminary experiments using the eNTERFACE dataset, our proposed multi-modal system is shown to achieve an accuracy of 87.95%, outperforming the best state-of-the-art system by more than 10%, or in relative terms, a 56% reduction in error rate. PMID- 25523042 TI - Growth and characterization of a new organic single crystal: 1-(4-Nitrophenyl) pyrrolidine (4NPY). AB - A new 1-(4-Nitrophenyl) pyrrolidine single crystal has grown by slow evaporation solution growth technique. The grown crystal have characterized by single crystal X-ray analysis, and it shows that 1-(4-Nitrophenyl) pyrrolidine crystallizes in the orthorhombic space group Pbca, with cell parameters a=10.3270 (5)A, b=9.9458 (6)A, c=18.6934 (12)A, and Z=8. Powder XRD pattern confirmed that grown crystal posses highly crystalline nature. The functional groups have identified by using FTIR spectral analysis. The absorbance and the luminescence spectra of the title compound have analyzed using UV-Visible and PL spectra. The thermo analytical properties of the crystal have studied using TG/DTA spectrum. The mechanical property of the grown crystal has determined using Vickers micro hardness measurement. The grown features of the crystal have analyzed using etching technique. PMID- 25523043 TI - Online spectrophotometric determination of Fe(II) and Fe(III) by flow injection combined with low pressure ion chromatography. AB - A simple and new low pressure ion chromatography combined with flow injection spectrophotometric procedure for determining Fe(II) and Fe(III) was established. It is based on the selective adsorption of low pressure ion chromatography column to Fe(II) and Fe(III), the online reduction reaction of Fe(III) and the reaction of Fe(II) in sodium acetate with phenanthroline, resulting in an intense orange complex with a suitable absorption at 515nm. Various chemical (such as the concentration of colour reagent, eluant and reductive agent) and instrumental parameters (reaction coil length, reductive coil length and wavelength) were studied and were optimized. Under the optimum conditions calibration graph of Fe(II)/Fe(III) was linear in the Fe(II)/Fe(III) range of 0.040-1.0mg/L. The detection limit of Fe(III) and Fe(II) was respectively 3.09 and 1.55MUg/L, the relative standard deviation (n=10) of Fe(II) and Fe(III) 1.89% and 1.90% for 0.5mg/L of Fe(II) and Fe(III) respectively. About 2.5 samples in 1h can be analyzed. The interfering effects of various chemical species were studied. The method was successfully applied in the determination of water samples. PMID- 25523044 TI - Temperature-controlled ionic liquid-based ultrasound-assisted microextraction for preconcentration of trace quantity of cadmium and nickel by using organic ligand in artificial saliva extract of smokeless tobacco products. AB - A new approach was developed for the preconcentration of cadmium (Cd) and nickel (Ni) in artificial saliva extract of dry snuff (brown and black) products using temperature-controlled ionic liquid-based ultrasound-assisted dispersive liquid liquid microextraction (TIL-UDLLMUE) followed by electrothermal atomic absorption spectrometry (ETAAS). The Cd and Ni were complexed with ammonium pyrrolidinedithiocarbamate (APDC), extracted in ionic liquid drops, 1-butyl-3 methylimidazolium hexafluorophosphate [C4MIM][PF6]. The multivariate strategy was applied to estimate the optimum values of experimental variables influence the % recovery of analytes by TIL-UDLLMUE method. At optimum experimental conditions, the limit of detection (3s) were 0.05 and 0.14MUgL(-1) while relative standard deviations (% RSD) were 3.97 and 3.55 for Cd and Ni respectively. After extraction, the enhancement factors (EF) were 87 and 79 for Cd and Ni, respectively. The RSD for six replicates of 10MUgL(-1) Cd and Ni were 3.97% and 3.55% respectively. To validate the proposed method, certified reference material (CRM) of Virginia tobacco leaves was analyzed, and the determined values of Cd and Ni were in good agreement with the certified values. The concentration of Cd and Ni in artificial saliva extracts corresponds to 39-52% and 21-32%, respectively, of the total contents of both elements in dry brown and black snuff products. PMID- 25523045 TI - Five different spectrophotometric methods for determination of Amprolium hydrochloride and Ethopabate binary mixture. AB - Five simple, specific, accurate and precise UV-spectrophotometric methods are adopted for the simultaneous determination of Amprolium hydrochloride (AMP) and Ethopabate (ETH), a binary mixture with overlapping spectra, without preliminary separation. The first method is first derivative of the ratio spectra ((1)DD) for determination of AMP and ETH at 234.7nm and 306.8nm respectively with mean percentage recoveries 99.76+/-0.907 and 100.29+/-0.842 respectively. The second method is the mean centering of the ratio spectra for determination of AMP and ETH at 238.8nm and 313nm respectively with mean percentage recoveries 100.26+/ 1.018 and 99.94+/-1.286 respectively. The third method is based on dual wavelength selection for determination of AMP and ETH at 235.3nm & 308nm and 244nm & 268.4nm respectively with mean percentage recoveries 99.30+/-1.097 and 100.03+/-1.065 respectively. The fourth method is ratio difference method for determination of AMP and ETH at 239nm & 310nm and 239nm & 313nm respectively with mean percentage recoveries 99.27+/-0.892 and 100.40+/-1.814 respectively. The fifth one is area under the curve (AUC) method where the areas between 235.6 243nm and 268.3-275nm are selected for determination of AMP and ETH with mean percentage recoveries 100.35+/-1.031 and 100.39+/-0.956 respectively. These methods are tested by analyzing synthetic mixtures of the two drugs and they are applied to their pharmaceutical veterinary preparation. Methods are validated according to the ICH guidelines and accuracy, precision and repeatability are found to be within the acceptable limit. PMID- 25523046 TI - Synthesis, characterization, optical and antimicrobial studies of polyvinyl alcohol-silver nanocomposites. AB - Silver nanoparticles (Ag NPs) were synthesized by chemical reduction of silver salt (AgNO3) through sodium borohydride. The characteristic surface plasmon resonance band located at around 400nm in the UV-Visible absorption spectrum confirmed the formation of Ag nanoparticles. Polyvinyl alcohol-silver (PVA-Ag) nanocomposite films were prepared by the casting technique. The morphology and interaction of PVA with Ag NPs were examined by transmission electron microscopy and FTIR spectroscopy. Optical studies show that PVA exhibited indirect allowed optical transition with optical energy gap of 4.8eV, which reduced to 4.45eV under addition of Ag NPs. Optical parameters such as refractive index, complex dielectric constant and their dispersions have been analyzed using Wemple and DiDomenco model. Color properties of the nanocomposites are discussed in the framework of CIE L(*)u(*)v(*) color space. The antimicrobial activity of the nanocomposite samples was tested against Gram positive bacteria (Staphylococcus aureus NCTC 7447 &Bacillus subtillis NCIB 3610), Gram negative bacteria (Escherichia coli, NTC10416 &Pseudomonas aeruginosa NCIB 9016) and fungi (Aspergillus niger Ferm - BAM C-21) using the agar diffusion technique. The antimicrobial study showed that PVA has moderate antibacterial activity against B. subtillis and the 0.04wt% Ag NPs composite sample effect was strong against S. aureus. PMID- 25523047 TI - A new multi-addressable molecular switch based on a photochromic diarylethene with a 6-aryl[1,2-c]quinazoline unit. AB - A novel diarylethene with a 6-aryl[1,2-c]quinazoline unit has been synthesized via a nucleophilic reaction. Its photochromism and fluorescence exhibited multi addressable behaviors by the stimulation of both light irradiation and acid/base. Addition of trifluoroacetic acid to the solution of the diarylethene resulted in notable absorption spectral change, and the protonated form also possessed excellent photochromic properties. Meanwhile, its emission intensity was enhanced remarkably and the emission peak redshifted with a notable color change from dark blue to bright green. The changes could be recovered to the initial state by neutralizing with triethylamine. Consequently, a logic circuit was constructed with the diarylethene by using the fluorescence intensity at 482nm as output and acid/base as inputs. PMID- 25523048 TI - Vibrational spectra (FT-IR, FT-Raman), frontier molecular orbital, first hyperpolarizability, NBO analysis and thermodynamics properties of Piroxicam by HF and DFT methods. AB - The solid phase FT-IR and FT-Raman spectra of 4-Hydroxy-2-methyl-N-(2-pyridinyl) 2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (Piroxicam) have been recorded in the region 4000-400 and 4000-100cm(-1) respectively. The molecular geometry, harmonic vibrational frequencies and bonding features of piroxicam in the ground state have been calculated by Hartree-Fock (HF) and density functional theory (DFT) methods using 6-311++G(d,p) basis set. The calculated harmonic vibrational frequencies are scaled and they are compared with experimental obtained by FT-IR and FT-Raman spectra. A detailed interpretation of the vibrational spectra of the title compound has been made on the basis of the calculated potential energy distribution (PED). The electronic properties, such as HOMO and LUMO energies, molecular electrostatic potential (MESP) are also performed. The linear polarizability (alpha) and the first order hyper polarizability (beta) values of the title compound have been computed. The molecular stability arising from hyper conjugative interaction, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. PMID- 25523049 TI - Simple computational technique to quantify nuclear shape asymmetry. AB - The nucleus of an eukaryotic cell is a membrane-bound organelle containing a major part of the cellular genome. Nuclear shape is controlled by forces generated in the cytoskeleton, nuclear envelope and matrix of the nucleus and may change when the balance of these forces is disturbed. In certain cases, such changes may be indicative of cell pathology. Nuclear shape feature is being commonly addressed in both experimental research and diagnostics; nevertheless its symmetry-related aspects receive little attention. This article introduces a technique allowing to estimate nuclear shape asymmetry in digital images captured from cyto- or histological preparations. Implemented in a software package, this technique quantifies the asymmetry using two scenarios. The first one presumes the identification of nuclear pixels laying outside the largest inscribed circle. According to the second scenario, the algorithm searches for nuclear pixels lacking pixel-partners symmetric with respect to the nuclear area's centroid. In both cases, the proportion of "asymmetric" pixels is used to estimate the feature of interest. The technique was validated on images of cell nuclei having distinctive shape phenotypes. A conclusion was made that shape asymmetry feature may be useful accessory to the toolbox of nuclear morphometry. PMID- 25523050 TI - Use of follow-up imaging in isolated perimesencephalic subarachnoid hemorrhage: a meta-analysis. AB - BACKGROUND AND PURPOSE: Multiple studies have shown that negative computed tomographic angiograms (CTAs) are reliable in excluding aneurysms in patients with isolated perimesencephalic subarachnoid hemorrhage (pSAH). We evaluate the use of digital subtraction angiography versus CTA for initial diagnosis and of angiographic follow-ups in patients with pSAH by performing an institutional analysis and a meta-analysis of literature. METHODS: Retrospective institutional analysis of patients with pSAH was performed from 2008 to 2014. The number and types of follow-up imaging studies were tabulated. Initial and follow-up studies were evaluated by an experienced neuroradiologist for intracranial aneurysm. Meta analysis of literature was performed to assess the use of initial digital subtraction angiography and of follow-up imaging. RESULTS: Our institutional review revealed no additional use of initial digital subtraction angiography or of any angiographic follow-up after initial negative CTA in patients with pSAH on noncontrast CT. Meta-analysis of 40 studies yielded a total of 1031 patients. Only 8 aneurysms were first diagnosed on follow-ups (0.78%). Careful review showed that some of these aneurysms reported on follow-up are of questionable validity. Initial digital subtraction angiography and follow-up imaging after a negative initial CTA showed no statistically significant benefits. CONCLUSIONS: In patients meeting the strict imaging criteria of pSAH, initial negative CTA is reliable in excluding aneurysms. A critical review of the literature through meta analysis shows no foundation for multiple follow-up studies in patients with pSAH. PMID- 25523051 TI - Association of postural instability with asymptomatic cerebrovascular damage and cognitive decline: the Japan Shimanami health promoting program study. AB - BACKGROUND AND PURPOSE: Asymptomatic cerebral small-vessel disease (cSVD) in elderly individuals are potent risk factors for stroke. In addition to common clinical risk factors, postural instability has been postulated to be associated with cSVD in older frail patients. Here, we conducted a cross-sectional study to understand the possible link between postural instability and asymptomatic cSVD further, namely periventricular hyperintensity, lacunar infarction, and microbleeds, as well as cognitive function, in a middle-aged to elderly general population (n=1387). METHODS: Postural instability was assessed based on one-leg standing time (OLST) and posturography findings. cSVD was evaluated by brain MRI. Mild cognitive impairment was assessed using a computer-based questionnaire, and carotid intima-media thickness as an index of atherosclerosis was measured via ultrasonography. RESULTS: Frequency of short OLST, in particular <20 s, increased linearly with severity of cSVD (lacunar infarction lesion: none, 9.7%; 1, 16.0%; >2, 34.5%; microbleeds lesion: none, 10.1%; 1, 15.3%; >2, 30.0%; periventricular hyperintensity grade: 0, 5.7%; 1, 11.5%; >2, 23.7%). The association of short OLST with lacunar infarction and microbleeds but not periventricular hyperintensity remained significant even after adjustment for possible covariates (lacunar infarction, P=0.009; microbleeds, P=0.003; periventricular hyperintensity, P=0.601). In contrast, no significant association was found between posturographic parameters and cSVD, whereas these parameters were linearly associated with OLST. Short OLST was also significantly associated with reduced cognitive function independent of covariates, including cSVD (P=0.002). CONCLUSIONS: Postural instability was found to be associated with early pathological changes in the brain and functional decline, even in apparently healthy subjects. PMID- 25523052 TI - 17beta-Estradiol attenuates hematoma expansion through estrogen receptor alpha/silent information regulator 1/nuclear factor-kappa b pathway in hyperglycemic intracerebral hemorrhage mice. AB - BACKGROUND AND PURPOSE: 17beta-estradiol (E2) has been reported to reduce bleeding and brain injury in experimental intracerebral hemorrhage (ICH) model. However, it is not clear if E2 can prevent early hematoma expansion (HE) induced by hyperglycemia in acute ICH. The aim of this study is to evaluate the effects of E2 on HE and its potential mechanisms in hyperglycemic ICH mice. METHODS: Two hundred, 8-week-old male CD1 mice were used. ICH was performed by collagenase injection. 50% dextrose (8 mL/kg) was injected intraperitoneally 3 hours after ICH to induce acute HE (normal saline was used as control). The time course of HE was measured 6, 24, and 72 hours after ICH. Two dosages (100 and 300 MUg/kg) of E2 were administrated 1 hour after ICH intraperitoneally. Neurobehavioral deficits, hemorrhage volume, blood glucose level, and blood-brain barrier disruption were measured. To study the mechanisms of E2, estrogen receptor alpha (ERalpha) inhibitor methyl-piperidino-pyrazole, silent information regulator 1 (Sirt1) siRNA was administered, respectively. Protein expression of ERalpha, Sirt1, and acetylated nuclear factor-kappa B, and activity of matrix metalloproteinases-9 were detected. RESULTS: Hyperglycemia enhanced HE and deteriorated neurological deficits after ICH from 6 hours after ICH. E2 treatment prevented blood-brain barrier disruption and improved neurological deficits 24 and 72 hours after ICH. E2 reduced HE by activating its receptor ERalpha, decreasing the expression of Sirt1, deacelylation of nuclear factor-kappa B, and inhibiting the activity of matrix metalloproteinases-9. ERalpha inhibitor methyl piperidino-pyrazole and Sirt1 siRNA removed these effects of E2. CONCLUSIONS: E2 treatment prevented hyperglycemia-enhanced HE and improved neurological deficits in ICH mice mediated by ERalpha/Sirt1/nuclear factor-kappa B pathway. E2 may serve as an alternative treatment to decrease early HE after ICH. PMID- 25523053 TI - White matter ischemic changes in hyperacute ischemic stroke: voxel-based analysis using diffusion tensor imaging and MR perfusion. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate changes in fractional anisotropy (FA), as measured by diffusion tensor imaging, of white matter (WM) infarction and hypoperfusion in patients with acute ischemic stroke using a quantitative voxel-based analysis. METHODS: In this prospective study, diffusion tensor imaging and dynamic susceptibility contrast perfusion sequences were acquired in 21 patients with acute ischemic stroke who presented within 6 hours of symptom onset. The coregistered FA, apparent diffusion coefficient, and dynamic susceptibility contrast time to maximum (Tmax) maps were used for voxel based quantification using a region of interest approach in the ipsilateral affected side and in the homologous contralateral WM. The regions of WM infarction versus hypoperfusion were segmented using a threshold method. Data were analyzed by regression and ANOVA. RESULTS: There was an overall significant mean difference (P<0.001) for the apparent diffusion coefficient, Tmax, and FA values between the normal, hypoperfused, and infarcted WM. The mean+/-SD of FA was significantly higher (P<0.001) in hypoperfused WM (0.397+/-0.019) and lower (P<0.001) in infarcted WM (0.313+/-0.037) when compared with normal WM (0.360+/ 0.020). Regression tree analysis of hypoperfused WM showed the largest mean FA difference at Tmax above versus below 5.4 s with a mean difference of 0.033 (P=0.0096). CONCLUSIONS: Diffusion tensor imaging-FA was decreased in regions of WM infarction and increased in hypoperfused WM in patients with hyperacute acute ischemic stroke. The significantly increased FA values in the hypoperfused WM with Tmax>=5.4 s are suggestive of early ischemic microstructural changes. PMID- 25523054 TI - Recombinant tissue-type plasminogen activator plus eptifibatide versus recombinant tissue-type plasminogen activator alone in acute ischemic stroke: propensity score-matched post hoc analysis. AB - BACKGROUND AND PURPOSE: The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke-Enhanced Regimen (CLEAR-ER) trial demonstrated safety of recombinant tissue-type plasminogen activator (r-tPA) plus eptifibatide in acute ischemic stroke (AIS). CLEAR-ER randomized AIS patients (5:1) to 0.6 mg/kg r-tPA plus eptifibatide versus standard r-tPA (0.9 mg/kg). Interventional Management of Stroke III randomized AIS patients to r-tPA plus endovascular therapy versus standard r-tPA. Albumin in Acute Stroke Part 2 randomized patients to albumin+/-r-tPA versus saline+/-r-tPA. Our aim was to compare outcomes in CLEAR-ER combination arm patients to propensity score-matched r-tPA only subjects in Albumin in Acute Stroke Part 2 and Interventional Management of Stroke III. METHODS: The primary outcome was 90-day severity-adjusted modified Rankin score (mRS) dichotomization based on baseline National Institutes of Health Stroke Scale. Secondary outcomes were 90-day mRS dichotomization as excellent (mRS, 0 1); mRS dichotomization as favorable (mRS, 0-2); and nonparametric analysis of the ordinal mRS. RESULTS: Eighty-five combination arm CLEAR-ER subjects were matched with 169 Albumin in Acute Stroke Part 2 and Interventional Management of Stroke III trials' r-tPA only patients (controls). Median age in CLEAR-ER and control subjects was 68years; median National Institutes of Health Stroke Scale in the CLEAR-ER subjects was 11 and in control subjects 12. At 90 days, CLEAR-ER subjects had a nonsignificantly greater proportion of patients with favorable outcomes (45% versus 36%; unadjusted relative risks, 1.24; 95% confidence intervals, 0.91-1.69; P=0.18). Secondary outcomes were 52% versus 34% excellent outcomes (relative risks, 1.51; 95% confidence intervals, 1.13-2.02; P=0.007); 60% versus 53% favorable outcome (relative risks, 1.13; 95% confidence intervals, 0.90-1.41; P=0.31); and ordinal Cochran-Mantel-Haenszel P=0.10. CONCLUSION: r-tPA plus eptifibatide showed a favorable direction of effect that was consistent across multiple approaches for AIS outcome evaluation. A phase III trial to establish the efficacy of r-tPA plus eptifibatide for improving AIS outcomes is warranted. PMID- 25523055 TI - MicroRNA-424 protects against focal cerebral ischemia and reperfusion injury in mice by suppressing oxidative stress. AB - BACKGROUND AND PURPOSE: We previously showed that the microRNA miR-424 protects against permanent cerebral ischemic injury in mice by suppressing microglia activation. This study investigated the role of miR-424 in transient cerebral ischemia in mice with a focus on oxidative stress-induced neuronal injury. METHODS: Transient cerebral ischemia was induced in C57/BL6 mice by middle cerebral artery occlusion for 1 hour followed by reperfusion (ischemia/reperfusion). The miR-424 level in the peri-infarct cortex was quantified. Mice were also administered miR-424 angomir by intracerebroventricular injection. Cerebral infarct volume, neuronal apoptosis, and levels of oxidative stress markers and antioxidants were evaluated. In an in vitro experiment, primary cortical neurons were exposed to H2O2 and treated with miR-424 angomir, nuclear factor erythroid 2-related factor 2 siRNA, and superoxide dismutase (SOD) inhibitor; cell activity, lactate dehydrogenase release, malondialdehyde level, and manganese (Mn)SOD activity were then evaluated. RESULTS: MiR-424 levels in the peri-infarct cortex increased at 1 and 4 hours then decreased 24 hours after reperfusion. Treatment with miR-424 decreased infarct volume and inhibited neuronal apoptosis after ischemia/reperfusion, reduced reactive oxygen species and malondialdehyde levels in the cortex, and increased the expression and activation of MnSOD as well as the expression of extracellular SOD and the redox-sensitive transcription factor nuclear factor erythroid 2-related factor. In neuronal cultures, miR-424 treatment abrogated H2O2-induced injury, as evidenced by decreased lactate dehydrogenase leakage and malondialdehyde level and increased cell viability and MnSOD activity; the protective effects of miR-424 against oxidative stress were reversed by nuclear factor erythroid 2-related factor knockdown and SOD inhibitor treatment. CONCLUSIONS: MiR-424 protects against transient cerebral ischemia/reperfusion injury by inhibiting oxidative stress. PMID- 25523056 TI - Persistent cerebrovascular damage after stroke in type two diabetic rats measured by magnetic resonance imaging. AB - BACKGROUND AND PURPOSE: Diabetes mellitus is a disease with vascular components. Consequently, the blood-brain barrier disruption after stroke may differ between diabetic and nondiabetic animals. However, few studies have documented the longitudinal blood-brain barrier disruption afte stroke in diabetic animals. In this study, using MRI, we noninvasively evaluated the blood-brain barrier damage after middle cerebral artery occlusion in diabetic and nondiabetic rats. METHODS: Type 2 diabetes mellitus (T2DM) was induced in adult male Wistar rats by administration of a high-fat diet in combination with a single intraperitoneal injection (35 mg/kg) of streptozotocin. T2DM rats (n=9) and nondiabetic wild-type (WT) rats (n=9) were subjected to middle cerebral artery occlusion for 2 hours using the filament model. MRI was performed 1 day and then weekly for 5 weeks after middle cerebral artery occlusion for all rats. RESULTS: The ischemic lesion volumes after stroke as measured using T2 maps were not significantly different between the T2DM and WT rats. Compared with the WT rats, the volumes of blood brain barrier disruption evaluated using contrast-enhanced T1-weighted imaging with gadolinium-diethylenetriamine penta-acetic acid and the cerebral hemorrhagic volumes measured with susceptibility-weighted imaging were significantly (P<0.05) larger in the T2DM rats from 1 to 5 weeks after stroke; values of diffusion fractional anisotropy were significantly lower in T2DM rats (P<0.03) than in WT rats after stroke. These MRI measurements were consistent with histological data. CONCLUSIONS: Using MRI, T2-weighted imaging did not detect significant differences of the ischemic lesion volumes between T2DM and WT rats. In contrast to the WT rats, however, contrast-enhanced T1-weighted imaging and susceptibility weighted imaging identified much more severe ischemic vascular damage, whereas fractional anisotropy demonstrated lower axonal density in the T2DM rats after stroke. PMID- 25523057 TI - Bright vessel appearance on arterial spin labeling MRI for localizing arterial occlusion in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate whether bright vessel appearance on arterial spin labeling (ASL) MRI can help localize arterial occlusion sites in patients with acute ischemic stroke. METHODS: Patients who underwent MRI for suspected acute ischemic stroke, as identified by an area of restricted diffusion, were included. All images were visually analyzed for the presence or absence of (1) arterial occlusion on time-of-flight MR angiography, (2) bright vessel appearance on ASL images, and (3) susceptibility vessel sign. McNemar 2-tailed test was used to compare the sensitivities of ASL and susceptibility-weighted imaging for the detection of arterial occlusion, using MR angiography as the reference standard. RESULTS: ASL bright vessel appearance was significantly more common in the group with occlusion than in the group without occlusion (94% [33 of 35] versus 21% [17 of 82], respectively; P<0.001). The bright vessel appearance, when present, was seen proximal or distal to the occlusion site. The bright vessel appearance had a significantly higher sensitivity for the detection of occlusion than the susceptibility vessel sign (94% [33 of 35] versus 66% [23 of 35], respectively; P=0.002). In cases with negative MR angiography, the bright vessel appearance helped identify more additional arterial occlusions than the susceptibility vessel sign (21% [17 of 82] versus 10% [8 of 82], respectively; P=0.012). CONCLUSIONS: The bright vessel appearance on ASL imaging can provide an important diagnostic clue for the detection and localization of arterial occlusion sites in patients with acute ischemic stroke. PMID- 25523058 TI - Challenge of identifying the cause of intracranial artery stenosis in patients with ischemic stroke. PMID- 25523059 TI - Effects of stroke education of junior high school students on stroke knowledge of their parents: Tochigi project. AB - BACKGROUND AND PURPOSE: Educating the youth about stroke is a promising approach for spreading stroke knowledge. The aim of this study was to verify communication of stroke knowledge to parents by educating junior high school students about stroke. METHODS: We enrolled 1127 junior high school students (age, 13-15 years) and their parents in the Tochigi prefecture, Japan. All students received a stroke lesson, watched an animated cartoon, and read the related Manga comic as educational aids. The students took back home the Manga and discussed what they learned with their parents. Questionnaires on stroke knowledge were given to all at baseline and immediately after the lesson. RESULTS: A total of 1125 students and 915 parents answered the questionnaires. In the students, the frequency of correct answers increased significantly for all questions on stroke symptoms except for headache, and for all questions on risk factors after the lesson. In the parents, the correct answer rates increased for stroke symptoms except for headache and numbness in one side of the body, and for all questions on risk factors except for hypertension. Ninety-one percent of students and 92.7% of parents correctly understood the Face, Arm, Speech, and Time (FAST) mnemonic after the lesson. CONCLUSIONS: Improvement of stroke knowledge immediately after the stroke lesson was observed in parents as well as their children, which indicated that our teaching materials using the Manga was effective in delivering the stroke knowledge to parents through their children. PMID- 25523061 TI - N-Phosphonyl/phosphinyl imines and group-assisted purification (GAP) chemistry/technology. AB - The development of environmentally benign, operationally simple, and economically viable synthetic methodologies has been a great challenge in organic synthesis. Group-assisted purification (GAP) chemistry was established to enable the synthesis of organic compounds without using traditional purification technologies, such as column chromatography and recrystallization. This concept/technology should encourage the synthetic community to make more efforts on searching for environmentally benign reagents and reactions to reduce the waste generated from silica and solvents, particularly toxic solvents; also, to reduce production/synthesis expenses, manpower, and energy. This review will discuss the GAP concept/technology and related reactions that were mainly conducted in the PI's laboratories after 2010. PMID- 25523060 TI - Individual dietetic consultations in first episode psychosis: a novel intervention to reduce cardiometabolic risk. AB - Individual dietetic consultations were trialled in a community-based first episode psychosis program. Participants received eight individualised dietetic consultations, plus weekly shopping tours and cooking groups. The outcome measure was waist circumference (WC). In total, 30 patients commenced the program. An intention-to-treat analysis revealed, a statistically significant reduction in WC (mean=2.1+/-5.4 cm, t=2.1, df=29, p=0.04). Similar results were found for the 14 participants who attended all eight sessions (mean WC reduction=2.9+/-4.7 cm, t=2.3, df=13, p=0.04). Dietetic consultations were feasible and effective in reducing WC, and could enhance programs to reduce cardiometabolic risk in youth with psychosis using lifestyle interventions. PMID- 25523062 TI - Quantification of the energy expenditure during training exercises in Standardbred trotters. AB - An appropriate energy feeding management that ensures the optimal dietary energy supply according to the energy expenditure (EE) is a crucial component for the horse's performance. The main purpose of this study was to determine the EE during four specific exercises used in the training of Standardbred trotters (promenade, jogging, parcours and interval work-outs). A total of six Standardbred geldings performed four different testing situations on a track. The intensity (expressed in percentage of the maximal velocity over 500 m, i.e. v500) and volume (distance and duration) of the testing situations were determined according to practices reported by French trainers. Promenade and jogging included only an exercise phase, whereas parcours and interval situations also included a warm-up and a recovery phase. Oxygen uptake (VO2), carbon dioxide production (VCO2) and heart rate (HR) were continuously recorded from 2 min before the beginning through to the end of the testing situations, using a portable respiratory gas analyser. Blood lactate levels and rectal temperature were determined before and immediately after the exercise phase of each testing situations. EE of the different phases (warm-up, exercise and recovery) and EE of the entire testing situations (EETOTAL) were calculated from VO2 measurements and the O2 caloric equivalent. Interval and parcours situations induced higher physiological responses than promenade and jogging situations, particularly in terms of VO2peak, VCO2peak and HRpeak. The highest blood lactate concentration (6 mmol/l) was measured after the interval exercise, and respiratory exchange ratios ?1 were observed only for the parcours situation. The EE of exercise phase varied from 0.49 to 1.79 kJ/min per kg for promenade and parcours situations. The EE of warm-up and recovery phases did not differ between parcours and interval situations, and was estimated at 1.04 and 0.57 kJ/min per kg BW, respectively. On average, the warm-up and the recovery phases contributed to 38% and 19% of the EETOTAL. For promenade, jogging, parcours and interval situations, EETOTAL was evaluated at 12 618, 11 119, 13 698 and 18 119 kJ, respectively. PMID- 25523063 TI - Additional US or DBT after digital mammography: which one is the best combination? AB - BACKGROUND: Digital mammography (DM) is widespread used for the detection of breast cancer, but its sensitivity drops in dense breasts. It is well known that additional breast ultrasound (US) and digital breast tomosynthesis (DBT) increase the sensitivity of DM. However, to our knowledge, there are no articles comparing the role of both additional techniques. PURPOSE: To assess the diagnostic performance of DM and the different combinations of DM + additional DBT and DM + additional US in an enriched sample of patients. MATERIAL AND METHODS: Retrospective study in an enriched sample of 1042 patients. Out of them, 84 patients had histologically proven malignant lesions and 258 patients had benign lesions. Finally 700 patients with normal explorations or benign lesions without biopsy confirmation (but stable for at least 12 months) were included. All of them underwent DM, US, and DBT examinations that were retrospectively reviewed by one expert radiologist, blinded to the final diagnoses. The DBT examinations were performed using one single view with wide angle (50 degrees ). The reader categorized the cases as benign (BI-RADS 1 or 2) or malignant (BI-RADS 3-5) for DM and the different combination of techniques. The sensitivity (SE) and specificity (SP) were calculated with the PEPI software and the ROC curves of the different techniques and combinations were calculated by using the SPSS 15.0 software. RESULTS: The SE and SP of DM were 69.05% and 88.20%, respectively. Additional DBT significantly increased the AUC of DM as well as additional US or the combination DM + DBT + US (P < 0.05). However there were no significant differences between the AUC of DM + US and DM + DBT (P = 0.7). CONCLUSION: Additional US, DBT, or both, in combination with DM, significantly increased the AUC of DM. However, there were no significant differences between DM + DBT and DM + US. PMID- 25523064 TI - Presurgical functional magnetic resonance imaging in patients with brain tumors. AB - BACKGROUND: Clinical functional magnetic resonance imaging (fMRI) is still an upcoming diagnostic tool because it is time-consuming to perform the post-scan calculations and interpretations. A standardized and easily used method for the clinical assessment of fMRI scans could decrease the workload and make fMRI more attractive for clinical use. PURPOSE: To evaluate a standardized clinical approach for distance measurement between benign brain tumors and eloquent cortex in terms of the ability to predict pre- and postoperative neurological deficits after intraoperative neuronavigation-assisted surgery. MATERIAL AND METHODS: A retrospective study of 34 patients. The fMRI data were reanalyzed using a standardized distance measurement procedure combining data from both fMRI and three-dimensional T1 MRI scans. The pre- and postoperative neurological status of each patient was obtained from hospital records. Data analysis was performed using logistic regression analysis to determine whether the distance measured between the tumor margin and fMRI activity could serve as a predictor for neurological deficits. RESULTS: An odds ratio of 0.89 mm(-1) (P = 0.03) was found between the risk of preoperative neurological motor deficits and the tumor-fMRI distance. An odds ratio of 0.82 mm(-1) (P = 0.04) was found between the risk of additional postoperative neurological motor deficits and the tumor-fMRI distance. The tumor was radically removed in 10 cases; five patients experienced additional postoperative motor deficits (tumor-fMRI distance <18 mm) and five did not (tumor fMRI distance >18 mm) (P = 0.008). CONCLUSION: This study indicates that the distance measured between the tumor margin and fMRI activation could serve as a valuable predictor of neurological motor deficits. PMID- 25523066 TI - Prevalence of mental illness, intellectual disability, and developmental disability among homeless people in Nagoya, Japan: A case series study. AB - AIM: While it has been reported that the prevalence of mental illness is higher in homeless people than in the national population, few studies have investigated the prevalence of intellectual and developmental disability among the homeless. In this study, we conducted a survey to comprehensively assess these mental problems among homeless people in Nagoya, Japan. METHODS: The subjects were 18 homeless men. Mental illness was diagnosed with semi-structured interviews conducted by psychiatrists. We used the Wechsler Adult Intelligence Scale III to diagnose intellectual disability. Discrepancies between Wechsler Adult Intelligence Scale III subtest scores were used as criteria for developmental disability. RESULTS: Eleven of the 18 participants were diagnosed with mental illness: six with mood disorder, two with psychotic disorder, and six with alcohol problems. The mean IQ of all subjects was 83.4 +/- 27.4. The 95% confidence interval (CI) was 96.2-69.1. Seven participants were found to have intellectual disability. Three men showed discrepancies of more than 10 between subtest scores, and all of them were diagnosed with a mental illness. We divided the participants into four groups: those with mental illness only; those with intellectual disability only; those with both problems; and those without diagnosis. The men with intellectual disability only were significantly younger and had been homeless since a younger age than the other groups. Participants diagnosed with a mental illness had been homeless for longer than those without mental health problems. CONCLUSION: Although the sample size was limited, this study revealed the high prevalence of mental illness and intellectual disability, 61% (95%CI, 35-83%) and 39% (95%CI, 17-64%), respectively, in homeless people in Nagoya, Japan. PMID- 25523065 TI - Manganese-enhanced MRI detection of impaired calcium regulation in a mouse model of cardiac hypertrophy. AB - The aim of this study was to use manganese (Mn)-enhanced MRI (MEMRI) to detect changes in calcium handling associated with cardiac hypertrophy in a mouse model, and to determine whether the impact of creatine kinase ablation is detectable using this method. Male C57BL/6 (C57, n = 11) and male creatine kinase double knockout (CK-M/Mito(-/-) , DBKO, n = 12) mice were imaged using the saturation recovery Look-Locker T1 mapping sequence before and after the development of cardiac hypertrophy. Hypertrophy was induced via subcutaneous continuous 3-day infusion of isoproterenol, and sham mice not subjected to cardiac hypertrophy were also imaged. During each scan, the contrast agent Mn was administered and the resulting change in R1 (=1/T1) was calculated. Two anatomical regions of interest (ROIs) were considered, the left-ventricular free wall (LVFW) and the septum, and one ROI in an Mn-containing standard placed next to the mouse. We found statistically significant (p < 0.05) decreases in the uptake of Mn in both the LVFW and septum following the induction of cardiac hypertrophy. No statistically significant decreases were detected in the standard, and no statistically significant differences were found among the sham mice. Using a murine model, we successfully demonstrated that changes in Mn uptake as a result of cardiac hypertrophy are detectable using the functional contrast agent and calcium mimetic Mn. Our measurements showed a decrease in the relaxivity (R1) of the myocardium following cardiac hypertrophy compared with normal control mice. PMID- 25523067 TI - Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia. AB - Activating germ-line and somatic mutations in AKT3 (OMIM 611223) are associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH; OMIM # 615937) and megalencephaly-capillary malformation (MCAP; OMIM # 602501). Here we report an individual with megalencephaly, polymicrogyria, refractory epilepsy, hypoglycemia and a germline AKT3 mutation. At birth, head circumference was 43 cm (5 standard deviations above the mean). No organomegaly was present, but there was generalized hypotonia, joint and skin laxity, developmental delay and failure to thrive. At 6 months of age the patient developed infantile spasms that were resistant to antiepileptic polytherapy. Recurrent hypoglycemia was noted during treatment with adrenocorticotropic hormone but stabilized upon introduction of continuous, enriched feeding. The infantile spasms responded to the introduction of a ketogenic diet, but the hypoglycemia recurred until the diet was adjusted for increased resting energy expenditure. A novel, de novo AKT3 missense variant (exon 5; c.548T>A, p.(V183D)) was identified and shown to activate AKT3 by in vitro functional testing. We hypothesize that the sustained hypoglycemia in this patient is caused by increased glucose utilization due to activation of AKT3 signaling. This might explain the efficacy of the ketogenic diet in this individual. PMID- 25523068 TI - The methodological quality of health economic evaluations for the management of hip fractures: A systematic review of the literature. AB - BACKGROUND AND OBJECTIVES: Approximately 76,000 people a year sustain a hip fracture in the UK and the estimated cost to the NHS is L1.4 billion a year. Health economic evaluations (HEEs) are one of the methods employed by decision makers to deliver healthcare policy supported by clinical and economic evidence. The objective of this study was to (1) identify and characterize HEEs for the management of patients with hip fractures, and (2) examine their methodological quality. METHODS: A literature search was performed in MEDLINE, EMBASE and the NHS Economic Evaluation Database. Studies that met the specified definition for a HEE and evaluated hip fracture management were included. Methodological quality was assessed using the Consensus on Health Economic Criteria (CHEC). RESULTS: Twenty-seven publications met the inclusion criteria of this study and were included in our descriptive and methodological analysis. Domains of methodology that performed poorly included use of an appropriate time horizon (66.7% of studies), incremental analysis of costs and outcomes (63%), future discounting (44.4%), sensitivity analysis (40.7%), declaration of conflicts of interest (37%) and discussion of ethical considerations (29.6%). CONCLUSIONS: HEEs for patients with hip fractures are increasing in publication in recent years. Most of these studies fail to adopt a societal perspective and key aspects of their methodology are poor. The development of future HEEs in this field must adhere to established principles of methodology, so that better quality research can be used to inform health policy on the management of patients with a hip fracture. PMID- 25523069 TI - The relevance of hyponatraemia to perioperative care of surgical patients. AB - BACKGROUND: Hyponatraemia is the most common electrolyte disturbance in hospitalized patients. There is an increasing awareness of the impact of hyponatraemia on the perioperative management of surgical patients. METHODS: We performed a literature review. We have included relevant data from different surgical disciplines for analysis. In this review we discuss the differential diagnosis of hyponatraemia, and explain the specific relevance of hyponatraemia to pre-, peri- and post-operative care. RESULTS: Hyponatraemia is common during the preoperative period and is associated with an increase in subsequent peri operative complications, such as wound infection, pneumonia, higher mortality rate and higher direct and indirect costs. Furthermore, data shows poorer surgical outcomes when plasma sodium concentration drops. Careful preoperative evaluation of the hyponatraemic patient enables assessment of surgical risk and individualization of the management of hyponatraemia. CONCLUSIONS: We outline a practical guide to the assessment of the cause of hyponatraemia, which dictates the correct management of hyponatraemia and the correct selection of perioperative fluids. Finally, for the therapeutic role of the new vasopressin antagonist drugs in the treatment of surgical hyponatraemia is discussed in two illustrative surgical clinical cases. PMID- 25523070 TI - Elective repeat caesarean section versus induction of labour for women with a previous caesarean birth. AB - BACKGROUND: When a woman has had a previous caesarean birth and requires induction of labour in a subsequent pregnancy there are two options for her care, an elective repeat caesarean or planned induction of labour. While there are risks and benefits for both elective repeat caesarean birth and planned induction of labour, current sources of information are limited to non-randomised cohort studies. Studies designed in this way have significant potential for bias and consequently any conclusions based on these results are limited in their reliability and should be interpreted with caution. OBJECTIVES: To assess, using the best available evidence, the benefits and harms of elective repeat caesarean section and planned induction of labour for women with a previous caesarean birth, who require induction of labour in a subsequent pregnancy. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (31 October 2014). SELECTION CRITERIA: Randomised controlled trials with reported data that compared outcomes in mothers and babies for women who planned an elective repeat caesarean section with outcomes in women who planned induction of labour, where a previous birth had been by caesarean. DATA COLLECTION AND ANALYSIS: There was no data extraction performed. MAIN RESULTS: There were no randomised controlled trials identified. AUTHORS' CONCLUSIONS: Both planned elective repeat caesarean section and planned induction of labour for women with a prior caesarean birth are associated with benefits and harms. Evidence for these care practices is drawn from non-randomised studies that are associated with potential bias. Any results and conclusions must therefore be interpreted with caution. Randomised controlled trials are required to provide the most reliable evidence regarding the benefits and harms of both planned elective repeat caesarean section and planned induction of labour for women with a previous caesarean birth. PMID- 25523071 TI - Chiral separation of four stereoisomers of ketoconazole drugs using capillary electrophoresis. AB - This work aimed to develop a chiral separation method of ketoconazole enantiomers using electrokinetic chromatography. The separation was achieved using heptakis (2, 3, 6-tri-O-methyl)-beta-cyclodextrin (TMbetaCD), a commonly used chiral selector (CS), as it is relatively inexpensive and has a low UV absorbance in addition to an anionic surfactant, sodium dodecyl sulfate (SDS). The influence of TMbetaCD concentration, phosphate buffer concentration, SDS concentration, buffer pH, and applied voltage were investigated. The optimum conditions for chiral separation of ketoconazole was achieved using 10 mM phosphate buffer at pH 2.5 containing 20 mM TMbetaCD, 5 mM SDS, and 1.0% (v/v) methanol with an applied voltage of 25 kV at 25 degrees C with a 5-s injection time (hydrodynamic injection). The four ketoconazole stereoisomers were successfully resolved for the first time within 17 min (total analysis time was 28 min including capillary conditioning). The migration time precision of this method was examined to give repeatability and reproducibility with RSDs <=5.80% (n =3) and RSDs <=8.88% (n =9), respectively. PMID- 25523072 TI - Molecular diagnosis of cryptococcal meningitis in cerebrospinal fluid: comparison of primer sets for Cryptococcus neoformans and Cryptococcus gattii species complex. AB - AIM: This study evaluated the use of polymerase chain reaction for cryptococcal meningitis diagnosis in clinical samples. MATERIALS AND METHODS: The sensitivity and specificity of the methodology were evaluated using eight Cryptococcus neoformans/C. gattii species complex reference strains and 165 cerebrospinal fluid samples from patients with neurological diseases divided into two groups: 96 patients with cryptococcal meningitis and AIDS; and 69 patients with other neurological opportunistic diseases (CRL/AIDS). Two primer sets were tested (CN4 CN5 and the multiplex CNa70S-CNa70A/CNb49S-CNb-49A that amplify a specific product for C. neoformans and another for C. gattii). RESULTS: CN4-CN5 primer set was positive in all Cryptococcus standard strains and in 94.8% in DNA samples from cryptococcal meningitis and AIDS group. With the multiplex, no 448-bp product of C. gattii was observed in the clinical samples of either group. The 695bp products of C. neoformans were observed only in 64.6% of the cryptococcal meningitis and AIDS group. This primer set was negative for two standard strains. The specificity based on the negative samples from the CTL/AIDS group was 98.5% in both primer sets. CONCLUSIONS: These data suggest that the CN4/CN5 primer set was highly sensitive for the identification of C. neoformans/C. gattii species complex in cerebrospinal fluid samples from patients with clinical suspicion of cryptococcal meningitis. PMID- 25523073 TI - Late onset sepsis in newborn babies: epidemiology and effect of a bundle to prevent central line associated bloodstream infections in the neonatal intensive care unit. AB - AIM: We assessed late onset sepsis (LOS) rates of neonates in a neonatal intensive care unit (NICU) before and after implementing an evidence-based bundle to prevent these infections in a country with poor resources. METHODS: We evaluate trends of LOS between October 2010 and August 2012 in a large tertiary hospital in Brazil. We designed a protocol based of CDC guidelines for insertion of maintenance of central venous catheter targeted to reduction of bloodstream infections. During this period two major events occurred: a great increase of LOS rates in January months and relocation of the unit to a provisory place. Additionally we evaluated the risk factors and etiology of these infections. RESULTS: A total of 112 (20.3%) cases defined as LOS were found. The overall incidence rate of LOS in the study was 16.1/1000 patient/days and 23.0/1000 CVC days. Our monthly rates data of LOS/1000 patient-day reveal fluctuations over the studied period, with incidence rates of these infections in staff vacation period (January 2011 and 2012) significantly higher (59.6/1000 patients-days) than compared with the other months rates (16.6/1000 patients-days) (IRR=3.59; p<0.001). As opposite, the incidence rates of LOS during relocation period was lower (10.3/1000 patients-days) when compared with baseline period 26.7/1000 patients-days (IRR=2.59; p=0.007). After the intervention period, these rates decreased in the post intervention period, when compared with preintervention 14.7/1000 patients-days and 23.4/1000 patients-days, respectively (IRR=1.59; p=0.04). CONCLUSION: Through simple infection control measures, LOS can be successfully controlled especially in NICUs of limited resources countries such as ours. PMID- 25523074 TI - Norovirus and Rotavirus infection in children aged less than five years in a paediatric hospital, Havana, Cuba. PMID- 25523075 TI - Staphylococcus aureus nasal carriage among outpatients attending primary health care centers: a comparative study of two cities in Saudi Arabia and Egypt. AB - Epidemiological and molecular data on community acquired methicillin resistant Staphylococcus aureus (CA-MRSA) are still scarce in both Egypt and Saudi Arabia. There is almost no data regarding methicillin resistant Staphylococcus aureus (MRSA) prevalence in both countries. This study was conducted to investigate the prevalence and molecular epidemiology of S. aureus and MRSA nasal carriage among outpatients attending primary health care centers in two big cities in both countries. A total of 206 nasal swabs were obtained, 103 swabs from each country. S. aureus isolates were characterized by antibiotic susceptibility, presence of mecA and PVL genes, SCCmec-typing and spa typing, the corresponding Multi locus sequence typing clonal complex was assigned for each spa type based on Ridom StaphType database. MRSA was detected in 32% of the Egyptian outpatients while it was found in 25% of the Saudi Arabian outpatients. All MRSA isolates belonged to SCCmec type V and IVa, where some isolates in Saudi Arabia remained nontypeable. Surprisingly PVL(+) isolates were low in frequency: 15% of MRSA Egyptian isolates and 12% of MRSA isolates in Saudi Arabia. Two novel spa types were detected t11839 in Egypt, and t11841 in Saudi Arabia. We found 8 spa types among 20 isolates from Egypt, and 12 spa types out of 15 isolates from Saudi Arabia. Only two spa types t008 and t223 coexisted in both countries. Four clonal complexes (CC5, CC8, CC22, and CC80) were identified in both Egypt and Saudi Arabia. However, the data collected lacked a representation of isolates from different parts of each country as only one health center from each country was included, it still partially illustrates the CA-MRSA situation in both countries. In conclusion a set of control measures is required to prevent further increase in MRSA prevalence. PMID- 25523076 TI - Sao Paulo urban heat islands have a higher incidence of dengue than other urban areas. AB - Urban heat islands are characterized by high land surface temperature, low humidity, and poor vegetation, and considered to favor the transmission of the mosquito-borne dengue fever that is transmitted by the Aedes aegypti mosquito. We analyzed the recorded dengue incidence in Sao Paulo city, Brazil, in 2010-2011, in terms of multiple environmental and socioeconomic variables. Geographical information systems, thermal remote sensing images, and census data were used to classify city areas according to land surface temperature, vegetation cover, population density, socioeconomic status, and housing standards. Of the 7415 dengue cases, a majority (93.1%) mapped to areas with land surface temperature >28 degrees C. The dengue incidence rate (cases per 100,000 inhabitants) was low (3.2 cases) in high vegetation cover areas, but high (72.3 cases) in low vegetation cover areas where the land surface temperature was 29+/-2 degrees C. Interestingly, a multiple cluster analysis phenogram showed more dengue cases clustered in areas of land surface temperature >32 degrees C, than in areas characterized as low socioeconomic zones, high population density areas, or slum like areas. In laboratory experiments, A. aegypti mosquito larval development, blood feeding, and oviposition associated positively with temperatures of 28-32 degrees C, indicating these temperatures to be favorable for dengue transmission. Thus, among all the variables studied, dengue incidence was most affected by the temperature. PMID- 25523077 TI - Endocarditis by Kocuria rosea in an immunocompetent child. AB - Kocuria rosea belongs to genus Kocuria (Micrococcaceae family, suborder Micrococcineae, order Actinomycetales) that includes about 11 species of bacteria. Usually, Kocuria sp are commensal organisms that colonize oropharynx, skin and mucous membrane; Kocuria sp infections have been described in the last decade commonly affecting immunocompromised patients, using intravenous catheter or peritoneal dialysis. These patients had mainly bacteremia/recurrent sepsis. We hereby describe the case of a 10-year-old girl, immunocompetent, who had endocarditis/sepsis by K. rosea which was identified in five different blood cultures by Vitek 2 ID-GPC card (BioMerieux, France). Negative HIV serology, blood count within normal range of leukocytes/neutrophils and lymphocytes, normal fractions of the complement, normal level of immunoglobulins for the age; lymphocyte immunophenotyping was also within the expected values. Thymus image was normal at chest MRI. No catheters were required. Identification of K. rosea was essential to this case, allowing the differentiation of coagulase-negative staphylococci and use of an effective antibiotic treatment. Careful laboratory analysis of Gram-positive blood-born infections may reveal more cases of Kocuria sp infections in immunocompetent patients, which may collaborate for a better understanding, prevention and early treatment of these infections in pediatrics. PMID- 25523078 TI - High HPV prevalence and need for ancillary care. PMID- 25523079 TI - Clinical relevance of rhinovirus infections among adult hospitalized patients. AB - Human rhinovirus (HRV) is an emerging viral pathogen. AIM: To characterize a group of patients admitted due to infection by this agent in a general hospital in Chile. METHODS: Cases were identified by RT-PCR for 1 year through active surveillance of patients admitted with severe respiratory illness. Diagnosis was not available during hospitalization. Thirty-two cases were identified, 90% were >=60 years old or had co-morbid conditions. Human rhinovirus-related admissions represented 23.7% of hospitalization due to severe acute respiratory infections among adults and ranked second to influenza (37.8%). Patients presented with pneumonia (68.8%), decompensated chronic lung conditions (21.9%), heart failure or influenza-like illness (6.3% each). Admission to intensive or intermediate care units was required by 31.2% and in-hospital mortality reached 12.5%. A CURB 65 score >=3 was significantly associated to in-hospital mortality (p<0.05). Most patients received antibiotics (90%). CONCLUSIONS: Human rhinovirus infections in elderly patients with co-morbid conditions are associated with hospitalizations, requiring critical or semi-critical antibiotics use. A high CURB-65 score was associated to in-hospital mortality. PMID- 25523080 TI - Lack of evidence of viral reactivation in HBsAg-negative HBcAb-positive and HCV patients undergoing immunosuppressive therapy for psoriasis. AB - BACKGROUND: HBV and HCV reactivation have been widely reported in patients undergoing immunosuppressive therapy (IT); however, few data are available on the risk of reactivation in patients with psoriasis receiving IT. The aim of our study was to assess the prevalence of HBV and HCV infection in patients with psoriasis and to evaluate the effects of IT during the course of the infection. METHODS: The study included psoriatic patients who attended an Italian tertiary referral hospital from 2009 to 2012. A total of 224 patients were enrolled. We evaluated: HBV and HCV markers, type of IT and the occurrence of viral reactivation. The observational period ranged from the beginning of IT to the last visit, with a mean follow-up period of 54 months. RESULTS: Two hundred and twenty patients (135 males and 89 females; mean age 59 years; range 18-86 years) with psoriasis, with or without psoriatic arthritis, receiving conventional IT and/or biological drugs were tested for markers of infection. We identified 23/224 patients (10.2%) with isolated positivity for HBcAb positivity, 36/224 (16%) with positivity for HBsAb/HBcAb, and 15/224 (6.6%) with positivity for HCV Ab. No patient was HBsAg positive, none of them underwent pre-emptive therapy with lamivudine or other antiviral drugs and no one showed episodes of viral reactivation. CONCLUSIONS: The prevalence of HBsAg in patients with psoriasis is lower than that observed in the general population. The prevalence of isolated positivity for HBcAb and of combined positivity for HBcAb and HBsAb is 10.2% and 16%, respectively. The prevalence of HCV infection (HCV-RNA+) is 4%. In patients with psoriasis and HCV-Ab or HBcAb positivity, the IT seems to be safe, regardless of the type of drugs. PMID- 25523081 TI - Interleukin-17 inhibits adult hippocampal neurogenesis. AB - Interleukin 17(A) (IL-17) is a potent pro-inflammatory cytokine that acts as a central regulator of inflammatory response within the brain, but its physiological roles under non-inflammatory conditions remain elusive. Here we report that endogenous IL-17 ablates neurogenesis in the adult dentate gyrus (DG) of hippocampus. Genetic deletion of IL-17 increased the number of adult-born neurons in the DG. Further, we found that IL-17 deletion altered cytokine network, facilitated basal excitatory synaptic transmission, enhanced intrinsic neuronal excitability, and increased expression of proneuronal genes in neuronal progenitor cells (NPCs). Our findings suggest a profound role of IL-17 in the negative regulation of adult hippocampal neurogenesis under physiology conditions. PMID- 25523083 TI - LexA protein of cyanobacterium Anabaena sp. strain PCC7120 exhibits in vitro pH dependent and RecA-independent autoproteolytic activity. AB - The LexA protein of the nitrogen-fixing cyanobacterium, Anabaena sp. strain PCC7120 exhibits a RecA-independent and alkaline pH-dependent autoproteolytic cleavage. The autoproteolytic cleavage of Anabaena LexA occurs at pH 8.5 and above, stimulated by the addition of Ca(2+) and in the temperature range of 30-57 degrees C. Mutational analysis of Anabaena LexA protein indicated that the cleavage occurred at the peptide bond between Ala-84 and Gly-85, and optimal cleavage required the presence of Ser-118 and Lys-159, as also observed for LexA protein of Escherichia coli. Cleavage of Anabaena LexA was affected upon deletion of three amino acids, (86)GLI. These three amino acids are unique to all cyanobacterial LexA proteins predicted to be cleavable. The absence of RecA dependent cleavage at physiological pH, which has not been reported for other bacterial LexA proteins, is possibly due to the absence of RecA interacting sites on Anabaena LexA protein, corresponding to the residues identified in E. coli LexA, and low cellular levels of RecA in Anabaena. Exposure to SOS-response inducing stresses, such as UV-B and mitomycin C neither affected the expression of LexA in Anabaena nor induced cleavage of LexA in either Anabaena 7120 or E. coli overexpressing Anabaena LexA protein. Though the LexA may be acting as a repressor by binding to the LexA box in the vicinity of the promoter region of specific gene, their derepression may not be via proteolytic cleavage during SOS inducing stresses, unless the stress induces increase in cytoplasmic pH. This could account for the regulation of several carbon metabolism genes rather than DNA-repair genes under the regulation of LexA in cyanobacteria especially during high light induced oxidative stress. PMID- 25523082 TI - The song of the old mother: reproductive senescence in female drosophila. AB - Among animals with multiple reproductive episodes, changes in adult condition over time can have profound effects on lifetime reproductive fitness and offspring performance. The changes in condition associated with senescence can be particularly acute for females who support reproductive processes from oogenesis through fertilization. The pomace fly Drosophila melanogaster is a well established model system for exploring the physiology of reproduction and senescence. In this review, we describe how increasing maternal age in Drosophila affects reproductive fitness and offspring performance as well as the genetic foundation of these effects. Describing the processes underlying female reproductive senescence helps us understand diverse phenomena including population demographics, condition-dependent selection, sexual conflict, and transgenerational effects of maternal condition on offspring fitness. Understanding the genetic basis of reproductive senescence clarifies the nature of life-history trade-offs as well as potential ways to augment and/or limit female fertility in a variety of organisms. PMID- 25523084 TI - The pharmacotherapy of male hypogonadism besides androgens. AB - INTRODUCTION: Adulthood male hypogonadism (HG) is the most common form of HG. Although testosterone (T) replacement therapy (TRT) is the most common way of treating HG, other options are available depending on patient's needs and expectations. AREAS COVERED: We analyze alternative options to TRT as a medical intervention in treating HG. Gonadotropin (Gn) therapy is the treatment of choice in men with secondary HG (sHG), who require fertility. Gonadotropin-releasing hormone therapy represents an alternative to Gn for inducing spermatogenesis in patients with sHG, however, its use is limited by the poor patient compliance and high cost. In obese HG men, lifestyle modifications and, in particular, weight loss should be the first step. Recent data suggest that antiestrogens represent a successful treatment for sHG. Other potential therapeutic options include the stimulation of hypothalamic activity (i.e., kisspeptin and neurokinin-B agonists). Conversely, the possibility of increasing Leydig cell steroid production, independently from Gn stimulation, seems unreliable. EXPERT OPINION: Understanding the nature of male HG and patient's needs are mandatory before choosing among treatment options. For primary HG only TRT is advisable, whereas for the secondary form several alternative possibilities can be offered. PMID- 25523085 TI - Cloning and functional characterization of MusaVND1 using transgenic banana plants. AB - Vascular related NAC (NAM, ATAF and CUC) domain-containing genes regulate secondary wall deposition and differentiation of xylem vessel elements. MusaVND1 is an ortholog of Arabidopsis VND1 and contains the highly conserved NAC domain. The expression of MusaVND1 is highest in developing corm and during lignification conditions, the increase in expression of MusaVND1 coincides with the expression of PAL, COMT and C4H genes. MusaVND1 encodes a nuclear localized protein as MusaVND1-GFP fusion protein gets localized to nucleus. Transient overexpression of MusaVND1 converts banana embryogenic cells to xylem vessel elements, with a final differentiation frequency of 33.54% at the end of tenth day. Transgenic banana plants overexpressing MusaVND1 showed stunted growth and were characterized by PCR and Southern blot analysis. Transgenic banana plants showed transdifferentiation of various types of cells into xylem vessel elements and ectopic deposition of lignin in cells of various plant organs such as leaf and corm. Tracheary element formation was seen in the cortical region of transgenic corm as well as in epidermal cells of leaves. Biochemical analysis indicates significantly higher levels of lignin and cellulose content in transgenic banana lines than control plants. MusaVND1 overexpressing transgenic banana plants showed elevated expression levels of genes involved in lignin and cellulose biosynthesis pathway. Further expression of different MYB transcription factors positively regulating secondary wall deposition was also up regulated in MusaVND1 transgenic lines. PMID- 25523086 TI - Age- and sex-related differences in pituitary height and its effect on the optic chiasm height. PMID- 25523087 TI - Burns in Nepal: A population based national assessment. AB - BACKGROUND: Burns are ranked in the top 15 leading causes of the burden of disease globally, with an estimated 265,000 deaths annually and a significant morbidity from non-fatal burns, the majority located in low and middle-income countries. Given that previous estimates are based on hospital data, the purpose of this study was to explore the prevalence of burns at a population level in Nepal, a low income South Asian country. METHODS: A cluster randomized, cross sectional countrywide survey was administered in Nepal using the Surgeons OverSeas Assessment of Surgical Need (SOSAS) from May 25th to June 12th, 2014. Fifteen of the 75 districts of Nepal were randomly chosen proportional to population. In each district, three clusters, two rural and one urban, were randomly selected. The SOSAS survey has two portions: the first collects demographic data about the household's access to healthcare and recent deaths in the household; the second is structured anatomically and designed around a representative spectrum of surgical conditions, including burns. RESULTS: In total, 1350 households were surveyed with 2695 individuals with a response rate of 97%. Fifty-five burns were present in 54 individuals (2.0%, 95% CI 1.5-2.6%), mean age 30.6. The largest proportion of burns was in the age group 25-54 (2.22%), with those aged 0-14 having the second largest proportion (2.08%). The upper extremity was the most common anatomic location affected with 36.4% of burns. Causes of burns included 60.4% due to hot liquid and/or hot objects, and 39.6% due to an open fire or explosion. Eleven individuals with a burn had an unmet surgical need (20%, 95% CI 10.43-32.97%). Barriers to care included facility/personnel not available (8), fear/no trust (1) and no money for healthcare (2). CONCLUSION: Burns in Nepal appear to be primarily a disease of adults due to scalds, rather than the previously held belief that burns occur mainly in children (0-14) and women and are due to open flames. This data suggest that the demographics and etiology of burns at a population level vary significantly from hospital level data. To tackle the burden of burns, interventions from all the public health domains including education, prevention, healthcare capacity and access to care, need to be addressed, particularly at a community level. Increased efforts in all spheres would likely lead to a significant reduction of burn-related death and disability. PMID- 25523088 TI - Novel mechanisms of surfactants against Candida albicans growth and morphogenesis. AB - Candida albicans is a common opportunistic fungal pathogen, causing not only superficial mucosal infections but also life-threatening systemic candidiasis in immune-compromised individuals. Surfactants are a kind of amphiphilic compounds implemented in a wide range of applications. Although their antimicrobial activity has been characterized, their effect on C. albicans physiology remains to be elucidated. In this study, we investigated the inhibitory effect of two representative surfactants, cetyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS), on C. albicans growth and morphogenesis. Both surfactants exhibited inhibitory effect on C. albicans growth. This effect was not attributed to plasma membrane (PM) damage, but was associated with mitochondrial dysfunction. Excitingly, the surfactants, especially CTAB, showed strong inhibitory effect on hyphal development (IC50=0.183 ppm for CTAB and 6.312 ppm for SDS) and biofilms (0.888 ppm for CTAB and 76.092 ppm for SDS). Actin staining and Hwp1-GFP localization further revealed that this inhibition is related to abnormal organization of actin skeleton and subsequent defect in polarized transport of hyphae-related factors. This study sheds a novel light on the antimicrobial mechanisms of surfactants, and suggests these agents as potential drugs against C. albicans hyphae-related infections in clinical practice. PMID- 25523089 TI - Identification of potential clinically significant drug interactions in HIV infected patients: a comprehensive therapeutic approach. AB - OBJECTIVES: The aim of the study was to determine the prevalence of potential clinically significant drug interactions (CSDIs) in HIV-positive individuals and to identify associated risk factors. METHODS: A cross-sectional study was conducted including all HIV-infected out-patients attending the Pharmacy Service of a regional reference hospital in Murcia, south-eastern Spain. The complete treatment was screened for possible CSDIs using the Spanish College of Pharmacists' online software resource, bot. Additionally, the severity level of the CSDIs involving antiretroviral (ARV) drugs was compared with that established in the specific antiretroviral database InteraccionesHIV.com. Multivariate logistic regression was used to identify associated risk factors. RESULTS: Two hundred and sixty-eight patients were included in the study. A total of 292 potential drug interactions were identified, of which 102 (34.9%) were CSDIs, of which 52.9% involved ARV drugs. Seven therapeutic drug classes were involved in 75% of CSDIs (protease inhibitors, benzodiazepines, nonsteroidal anti inflammatory drugs, nonnucleoside reverse transcriptase inhibitors, corticosteroids, antithrombotics and proton pump inhibitors). Factors independently associated with CSDIs were treatment with more than five drugs [odds ratio (OR) 15.1; 95% confidence interval (CI) 6.3-36.2], and treatment with a protease inhibitor (OR 5.3; 95% CI 2.4-11.74). CONCLUSIONS: The findings of this study suggest that the prevalence of clinically relevant drug-drug interactions is high in HIV-infected patients, and could represent a major health problem. Awareness, recognition and management of drug interactions are important in optimizing the pharmaceutical care of HIV-infected patients and helping to prevent adverse events and/or loss of efficacy of the drugs administered. PMID- 25523090 TI - Cloning and expression of a transcription factor activator protein-1 (AP-1) member identified from manila clam Venerupis philippinarum. AB - The transcription factor activator protein-1 (AP-1) proteins are implicated to play a major role in the regulation of numerous genes involved in the function and development of the immune system, cell differentiation, proliferation, apoptosis, etc. It can bind to promoter of its target genes in a sequence specific manner to transactivate or repress them. In this study, the full-length cDNA of an AP-1 was identified from Venerupis philippinarum (denoted as VpAP-1) by EST analysis and RACE approaches. Phylogenetic analysis indicated that VpAP-1 had higher evolutional conservation to invertebrate than vertebrate counterparts and should be a new member of the AP-1 protein family. Spatial expression analysis found that VpAP-1 transcript was most abundantly expressed in the hemocytes and hepatopancreas, weakly expressed in the tissues of the gills, mantle and muscle. After Vibrio anguillarum challenge, the expression of VpAP-1 transcript in overall hemocyte population was up-regulated in the first 6h, and then decreased to 1.5-fold of the control group at 12h. As time progressed, a second peak of VpAP-1 expression was detected at 24h post-infection, which was 5 fold compared with that of the control group (P<0.01). After that, the expression level was sharply decreased and dropped to 0.5-fold of the control at 96h. The above results indicated that VpAP-1 was perhaps involved in the immune responses against microbe infection and might be contributed to the clearance of bacterial pathogens. PMID- 25523091 TI - The mitochondrial genome of Dastarcus helophoroides (Coleoptera: Bothrideridae) and related phylogenetic analyses. AB - The complete mitochondrial genome of Dastarcus helophoroides (Coleoptera: Bothrideridae) which consists of 13 PCGs, 22 tRNA genes, two rRNA genes and a non coding region (D-loop), is sequenced for its nucleotide sequence of 15,878 bp (GenBank: KF811054.1). The genome has a typical gene order which is identical to other Coleoptera species. Except for COI gene generally starts with non-canonical initial codon, all protein-coding genes start with ATN codon and terminate with the stop codon TA(A) or TAG. The secondary structure of rrnL and rrnS consists of 48 helices (contains four newly proposed helices) and 35 helices (contains two newly proposed helices) respectively. All 22 tRNAs in D. helophoroides are predicted to fold into typical cloverleaf secondary structure, except trnS1 (AGN), in which the dihydrouracil arm (DHU arm) could not form stable stem-loop structure. Thirteen protein-coding genes (nucleotide dataset and nucleic acid dataset) of the available species (29 taxa) have been used to infer the phylogenetic relationships among these orders. Tenebrionoidea and Cucujoidea form a sister group, and D. helophoroides is classified into Cucujoidea (Bothrideridae). The study first research on the phylogenetic analyses involving to the D. helophoroides mitogenome, and the results strongly bolster the current morphology-based hypothesis. PMID- 25523092 TI - Segregation of a novel homozygous 6 nucleotide deletion in GLUT2 gene in a Fanconi-Bickel syndrome family. AB - Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, impaired utilization of glucose and galactose, rickets, and severe short stature. It has been shown to be caused by mutations in GLUT2 gene, a member of the facilitative glucose transporter family. Here, we report an Iranian family with 2 affected siblings. The clinical findings in the patients include developmental delay, failure to thrive, hepatomegaly, enlarged kidneys and rickets. A novel 6 nucleotide deletion (c.1061_1066del6, p.V355_S356del2) is shown to be segregated with the disease in this family. PMID- 25523093 TI - Enhanced seed oil content by overexpressing genes related to triacylglyceride synthesis. AB - Oilseed rape (Brassica napus) is one of the most important oilseed crops globally. To meet increasing demand for oil-based products, the ability to enhance desirable oil content in the seed is required. This study assessed the capability of five genes in the triacylglyceride (TAG) synthesis pathway to enhance oil content. The genes BnGPDH, BnGPAT, BnDGAT, ScGPDH and ScLPAAT were overexpressed separately in a tobacco (Nicotiana benthamiana) model system, and simultaneously by pyramiding in B. napus, under the control of a seed specific Napin promoter. ScLPAAT transgenic plants showed a significant increase of 6.84% to 8.55% in oil content in tobacco seeds, while a ~4% increase was noted for BnGPDH and BnGPAT transgenic seeds. Seed-specific overexpression of all four genes in B. napus resulted in as high a 12.57% to 14.46% increased in seed oil content when compared to WT, equaling close to the sum of the single-gene overexpression increases in tobacco. Taken together, our study demonstrates that BnGPDH, BnGPAT and ScLPAAT may effectively increase seed oil content, and that simultaneous overexpression of these in transgenic B. napus may further enhance the desirable oil content relative to single-gene overexpressors. PMID- 25523095 TI - Molecular cloning and characterization of a novel bovine IFN-epsilon. AB - A bovine IFN-epsilon (BoIFN-epsilon) gene was amplified from bovine liver genomic DNA consisting of a 463bp partial 5'UTR, 582bp complete ORF and 171bp partial 3'UTR, which encodes a protein of 193 amino acids with a 21-amino acid signal peptide and shares 61 to 87% identity with other species IFN-epsilon. Then BoIFN epsilon gene was characterized, and it can be transcribed in EBK cells at a high level after being infected by VSV. Recombinant proteins were expressed in Escherichia coli and the antiviral activity was determined in vitro, which revealed that bovine IFN-epsilon has less antiviral activity than bovine IFN alpha. In addition, an immunofluorescence assay indicated that BoIFN-epsilon expressed in MDBK cells could be detected by polyclonal antibody against BoIFN epsilon. Furthermore, the BoIFN-epsilon gene can be constitutively expressed in the liver, thymus, kidney, small intestine and testis, but not in the heart. This study revealed that BoIFN-epsilon has the typical characteristics of type I interferon and can be expressed constitutively in certain tissue, which not only can be a likely candidate for a novel, effective therapeutic agent, but also facilitate further research on the role of bovine IFN system. PMID- 25523094 TI - Associations between polymorphisms of interleukin-6 and related cytokine genes and serum liver damage markers: a cross-sectional study in the Japan Multi Institutional Collaborative Cohort (J-MICC) Study. AB - Cytokines, including interleukin-6 (IL-6), play an important role in the liver. The aim of this study was to investigate associations between common polymorphisms in potential functional promoters of cytokine genes and liver damage markers among enrollees of a large Japanese cohort study. Subjects included 3257 Japanese individuals (1608 men and 1649 women, aged 35-69 years). Six single nucleotide polymorphisms (SNPs) in the promoter regions of five cytokine genes, IL1B (T-31C), IL6 (C-634G), IL8 (T-251A), IL10 (T-819C), tumor necrosis factor-A (TNFA) (T-1031C), and TNFA (C-857T), were genotyped by polymerase chain reaction. Information regarding alcohol intake, smoking habits, height, and weight was collected by a self-administered questionnaire. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured during a routine health check-up. Of the six SNPs genotyped, an IL6 polymorphism (rs1800796, C-634G) was most strongly associated with a liver damage marker, AST. Mean serum AST was significantly different among the three genotypes (mean +/- SD, 22.7 +/- 7.3 IU/L for CC, 22.8 +/- 7.7 IU/L for CG, and 24.3 +/- 8.6 IU/L for GG, p=0.011 by analysis of variance). The differences remained significant after adjustment for potential confounders by general linear models. The variations in mean serum AST and ALT levels were marked especially among men. Thus, the functional polymorphism IL6 C-634G may affect serum AST and ALT levels, possibly through different IL-6 production. PMID- 25523096 TI - Comprehensive expression analysis of miRNA in breast cancer at the miRNA and isomiR levels. AB - Breast cancer (BC) is the main factor that leads cause of cancer death in women worldwide. A class of small non-coding RNAs, microRNAs (miRNAs), has been widely studied in human cancers as crucial regulatory molecule. Recent studies indicate that a series of isomiRs can be yielded from a miRNA locus, and these physiological miRNA isoforms have versatile roles in miRNA biogenesis. Herein, we performed a comprehensive analysis of miRNAs at the miRNA and isomiR levels in BC using next-generation sequencing data from The Cancer Genome Atlas (TCGA). Abnormally expressed miRNA (miR-21, miR-221, miR-155, miR-30e and miR-25) and isomiR profiles could be obtained at the miRNA and isomiR levels, and similar biological roles could be detected. IsomiR expression profiles should be further concerned, and especially isomiRs are actual regulatory molecules in the miRNA mRNA regulatory networks. The study provides a comprehensive expression analysis at the miRNA and isomiR levels in BC, which indicates biological roles of isomiRs. PMID- 25523097 TI - Molecular cloning, characterisation and expression analysis of melanoma differentiation associated gene 5 (MDA5) of green chromide, Etroplus suratensis. AB - Innate immune system recognises pathogen-associated molecular patterns (PAMPs) by limited number of germline encoded and non-clonally developed pathogen recognition receptors (PRRs). Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are important cytosolic PRRs for sensing viral RNAs. The receptor encoded by melanoma differentiation associated gene 5 (MDA5), an RLR, recognises viral RNA and enhances antiviral response in host cells. The full length MDA5 cDNA in Etroplus suratensis was cloned and found to have 3673 nucleotides encoding a polypeptide of 978 amino acids. The deduced amino acid sequence contains four main structural domains: two CARD domains in the N terminal region, a DExDc (DEAH/DEAD box helicase domain), HELICc (C-terminal helicase) domain and a C-terminal regulatory domain (RD). Phylogenetic analysis revealed a close relationship of E. suratensis MDA5 (EsMDA5) with MDA5 of Neolamprologus brichardi and Oreochromis niloticus, both belonging to Cichlidae family. EsMDA5 transcripts were ubiquitously expressed in all the 12 tissues tested in healthy fish. Although, transcript level was found to be the highest in muscle, high expression was also detected in the spleen, head kidney and hindgut. In poly I:C-injected fish, EsMDA5 transcripts showed peak expression in the spleen, intestine and heart at 12h post-injection (hpi). However, in gill and kidney tissues, maximum up-regulation of EsMDA5 was observed at 6 and 48 hpi, respectively. Further, liver tissue showed an increasing trend in expression profile from 6 to 48 hpi. Interferon promoter stimulator-1 (IPS-1) gene, an adaptor triggering RIG-I- and MDA5-mediated type I interferon induction, also showed up-regulated expression at initial time-points in poly I:C-injected E. suratensis. The constitutive expression and up-regulation of EsMDA5 and the IPS-1 genes in different tissues indicate that EsMDA5 may play an important role in sensing viral PAMPs in conjunction with IPS-1. PMID- 25523098 TI - Phospholipase D activates HIF-1-VEGF pathway via phosphatidic acid. AB - Growth factor-stimulated phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine (PC), generating phosphatidic acid (PA) which may act as a second messenger during cell proliferation and survival. Therefore, PLD is believed to play an important role in tumorigenesis. In this study, a potential mechanism for PLD-mediated tumorigenesis was explored. Ectopic expression of PLD1 or PLD2 in human glioma U87 cells increased the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) protein. PLD-induced HIF-1 activation led to the secretion of vascular endothelial growth factor (VEGF), a HIF-1 target gene involved in tumorigenesis. PLD induction of HIF-1alpha was significantly attenuated by 1-butanol which blocks PA production by PLD, and PA per se was able to elevate HIF-1alpha protein level. Inhibition of mTOR, a PA-responsive kinase, reduced the levels of HIF-1alpha and VEGF in PLD-overexpressed cells. Epidermal growth factor activated PLD and increased the levels of HIF-1alpha and VEGF in U87 cells. A specific PLD inhibitor abolished expression of HIF-1alpha and secretion of VEGF. PLD may utilize HIF-1-VEGF pathway for PLD-mediated tumor cell proliferation and survival. PMID- 25523100 TI - Prospective surveillance of D- recipients of D+ apheresis platelets: alloimmunization against D is not detected. AB - BACKGROUND: Recent retrospective studies indicate that D- recipients of D+ apheresis platelets (PLTs) are not alloimmunized to D. Our hospital policy is to offer RhIG to D- women of childbearing age who received D+ apheresis PLTs but not to other D- recipients of D+ apheresis PLTs. We instituted prospective surveillance of the D- recipients who were not given RhIG. STUDY DESIGN AND METHODS: All apheresis PLT recipients were prospectively entered into a database that recorded the patient's age, sex, diagnosis, D status, apheresis PLT transfusions, and antibody screen results from before and after PLT transfusions. Data are reported for PLTs transfused between October 16, 2012, and April 16, 2014, and antibody screens obtained through June 16, 2014. The analysis excludes neonates; women not more than 50 years of age; and patients who also received D+ red blood cells, received only D- PLTs, received RhIG, were previously alloimmunized to D, and did not have a follow-up antibody screen after the first D-incompatible apheresis PLT transfusion. RESULTS: A total of 158 of 1107 apheresis PLT recipients were D-. Seventy-nine were eligible for analysis based on the exclusion criteria listed above. None became alloimmunized to D during the observation interval. In 45 (57%) cases the last follow-up antibody screen was obtained at least 4 weeks after the first D-incompatible apheresis PLT transfusion. CONCLUSION: Prospective surveillance confirms prior retrospective observations that D- patients do not appear to risk D alloimmunization after receiving D+ apheresis PLTs. PMID- 25523099 TI - Omega-3 polyunsaturated fatty acid and ursodeoxycholic acid have an additive effect in attenuating diet-induced nonalcoholic steatohepatitis in mice. AB - Nonalcoholic steatohepatitis (NASH) can progress into liver cirrhosis; however, no definite treatment is available. Omega-3 polyunsaturated fatty acid (omega-3) has been reported to alleviate experimental NASH, although its beneficial effect was not evident when tested clinically. Thus, this study aimed to investigate the additive effect of omega-3 and ursodeoxycholic acid (UDCA) on diet-induced NASH in mice. C57BL/6 mice were given a high-fat diet (HFD) for 24 weeks, at which point the mice were divided into three groups and fed HFD alone, HFD with omega-3 or HFD with omega-3 in combination with UDCA for another 24 weeks. Feeding mice an HFD and administering omega-3 improved histologically assessed liver fibrosis, and UDCA in combination with omega-3 further attenuated this disease. The assessment of collagen alpha1(I) expression agreed with the histological evaluation. Omega-3 in combination with UDCA resulted in a significant attenuation of inflammation whereas administering omega-3 alone failed to improve histologically assessed liver inflammation. Quantitative analysis of tumor necrosis factor alpha showed an additive effect of omega-3 and UDCA on liver inflammation. HFD-induced hepatic triglyceride accumulation was attenuated by omega-3 and adding UDCA accentuated this effect. In accordance with this result, the expression of sterol regulatory binding protein-1c decreased after omega-3 administration and adding UDCA further diminished SREBP-1c expression. The expression of inducible nitric oxide synthase (iNOS), which may reflect oxidative stress-induced tissue damage, was suppressed by omega-3 administration and adding UDCA further attenuated iNOS expression. These results demonstrated an additive effect of omega-3 and UDCA for alleviating fibrosis, inflammation and steatosis in diet-induced NASH. PMID- 25523101 TI - Computational extraction of a neural molecular network through alternative splicing. AB - BACKGROUND: Generally, the results of high throughput analyses contain information about gene expressions, and about exon expressions. Approximately 90% of primary protein-coding transcripts undergo alternative splicing in mammals. However, changes induced by alternative exons have not been properly analyzed for their impact on important molecular networks or their biological events. Even when alternative exons are identified, they are usually subjected to bioinformatics analysis in the same way as the gene ignoring the possibility of functionality change because of the alteration of domain caused by alternative exon. Here, we reveal an effective computational approach to explore an important molecular network based on potential changes of functionality induced by alternative exons obtained from our comprehensive analysis of neuronal cell differentiation. RESULTS: From our previously identified 262 differentially alternatively spliced exons during neuronal cell differentiations, we extracted 241 sets that changed the amino acid sequences between the alternatively spliced sequences. Conserved domain searches indicated that annotated domain(s) were changed in 128 sets. We obtained 49 genes whose terms overlapped between domain description and gene annotation. Thus, these 49 genes have alternatively differentially spliced in exons that affect their main functions. We performed pathway analysis using these 49 genes and identified the EGFR (epidermal growth factor receptor) and mTOR (mammalian target of rapamycin) signaling pathway as being involved frequently. Recent studies reported that the mTOR pathway is associated with neuronal cell differentiation, vindicating that our approach extracted an important molecular network successfully. CONCLUSIONS: Effective informatics approaches for exons should be more complex than those for genes, because changes in alternative exons affect protein functions via alterations of amino acid sequences and functional domains. Our method extracted alterations of functional domains and identified key alternative splicing events. We identified the EGFR and mTOR signaling pathway as the most affected pathway. The mTOR pathway is important for neuronal differentiation, suggesting that this in silico extraction of alternative splicing networks is useful. This preliminary analysis indicated that automated analysis of the effects of alternative splicing would provide a rich source of biologically relevant information. PMID- 25523102 TI - Photonic quasi-crystal terahertz lasers. AB - Quasi-crystal structures do not present a full spatial periodicity but are nevertheless constructed starting from deterministic generation rules. When made of different dielectric materials, they often possess fascinating optical properties, which lie between those of periodic photonic crystals and those of a random arrangement of scatterers. Indeed, they can support extended band-like states with pseudogaps in the energy spectrum, but lacking translational invariance, they also intrinsically feature a pattern of 'defects', which can give rise to critically localized modes confined in space, similar to Anderson modes in random structures. If used as laser resonators, photonic quasi-crystals open up design possibilities that are simply not possible in a conventional periodic photonic crystal. In this letter, we exploit the concept of a 2D photonic quasi crystal in an electrically injected laser; specifically, we pattern the top surface of a terahertz quantum-cascade laser with a Penrose tiling of pentagonal rotational symmetry, reaching 0.1-0.2% wall-plug efficiencies and 65 mW peak output powers with characteristic surface-emitting conical beam profiles, result of the rich quasi-crystal Fourier spectrum. PMID- 25523103 TI - Pharmacokinetics of intravenous ketorolac in cats undergoing gonadectomy. AB - AIM: To determine the pharmacokinetics of ketorolac tromethamine (0.5 mg/kg) when administered I/V to cats undergoing gonadectomy. METHODS: Ketorolac was administered to nine female and three male shorthair domestic cats as an I/V bolus of 0.5 mg/kg after intubation, and 20 minutes prior to ovariectomy or orchiectomy. Intra-operative cardiorespiratory variables were monitored and blood samples were collected over 24 hours. Concentrations of ketorolac in serum were determined by high-performance liquid chromatography to establish pharmacokinetic parameters. RESULTS: During surgery, mean end tidal isoflurane concentration was 1.63 (SD 0.24)% and normocapnia and spontaneous ventilation were maintained in all animals. The kinetics of ketorolac was described by a two-compartment model. The distribution and elimination half-lives were 0.09 (SD 0.06) and 4.14 (SD 1.18) hours, respectively. The body clearance was 56.8 (SD 33.1) mL/h/kg. The volume of distribution at steady-state and the mean residence time were 323.9 (SD 115.7) mL/kg and 6.47 (SD 2.86) hours, respectively. CONCLUSION AND CLINICAL RELEVANCE: On the basis of the results, concentrations of ketorolac in serum in cats were above the human effective concentrations for 5-6 hours postoperatively. However, other studies including a control group are advocated to further investigate the ketorolac kinetics and the analgesic efficacy in this species. PMID- 25523104 TI - Asynaptic feature and heterogeneous distribution of the cholinergic innervation of the globus pallidus in primates. AB - The internal (GPi) and external (GPe) segments of the primate globus pallidus receive a significant cholinergic (ACh) innervation from the brainstem pedunculopontine tegmental nucleus. The present immunohistochemical study describes this innervation in the squirrel monkey (Saimiri sciureus), as visualized with an antibody raised against choline acetyltransferase (ChAT). At the light microscopic level, unbiased stereological quantification of ChAT positive (+) axon varicosities reveals a significantly lower density of innervation in GPi (0.26 +/- 0.03 * 10(6)) than in GPe (0.47 +/- 0.07 * 10(6) varicosities/mm(3) of tissue), with the anterior half of both segments more densely innervated than the posterior half. Neuronal density of GPi (3.00 +/- 0.13 * 10(3) neurons/mm(3)) and GPe (3.62 +/- 0.22 * 10(3) neurons/mm(3)) yields a mean ratio of ChAT+ axon varicosities per pallidal neuron of 74 +/- 10 in the GPi and 128 +/- 28 in the GPe. At the electron microscopic level, the pallidal ChAT+ axon varicosities are significantly smaller than their unlabeled counterparts, but are comparable in size and shape in the two pallidal segments. Only a minority of ChAT+ varicosities displays a synaptic specialization (12 % in the GPi and 17 % in the GPe); these scarce synaptic contacts are mostly of the symmetrical type and occur exclusively on pallidal dendrites. No ChAT+ axo-axonic synaptic contacts are observed, suggesting that ACh exerts its modulatory action on pallidal afferents through diffuse transmission, whereas pallidal neurons may be influenced by both volumic and synaptic delivery of ACh. PMID- 25523105 TI - The subpopulation of microglia expressing functional muscarinic acetylcholine receptors expands in stroke and Alzheimer's disease. AB - Microglia undergo a process of activation in pathology which is controlled by many factors including neurotransmitters. We found that a subpopulation (11 %) of freshly isolated adult microglia respond to the muscarinic acetylcholine receptor agonist carbachol with a Ca(2+) increase and a subpopulation of similar size (16 %) was observed by FACS analysis using an antibody against the M3 receptor subtype. The carbachol-sensitive population increased in microglia/brain macrophages isolated from tissue of mouse models for stroke (60 %) and Alzheimer's disease (25 %), but not for glioma and multiple sclerosis. Microglia cultured from adult and neonatal brain contained a carbachol-sensitive subpopulation (8 and 9 %), which was increased by treatment with interferon-gamma to around 60 %. This increase was sensitive to blockers of protein synthesis and correlated with an upregulation of the M3 receptor subtype and with an increased expression of MHC-I and MHC-II. Carbachol was a chemoattractant for microglia and decreased their phagocytic activity. PMID- 25523106 TI - Amyloid-beta disrupts ongoing spontaneous activity in sensory cortex. AB - The effect of Alzheimer's disease pathology on activity of individual neocortical neurons in the intact neural network remains obscure. Ongoing spontaneous activity, which constitutes most of neocortical activity, is the background template on which further evoked-activity is superimposed. We compared in vivo intracellular recordings and local field potentials (LFP) of ongoing activity in the barrel cortex of APP/PS1 transgenic mice and age-matched littermate CONTROLS, following significant amyloid-beta (Abeta) accumulation and aggregation. We found that membrane potential dynamics of neurons in Abeta-burdened cortex significantly differed from those of nontransgenic CONTROLS: durations of the depolarized state were considerably shorter, and transitions to that state frequently failed. The spiking properties of APP/PS1 neurons showed alterations from those of CONTROLS: both firing patterns and spike shape were changed in the APP/PS1 group. At the population level, LFP recordings indicated reduced coherence within neuronal assemblies of APP/PS1 mice. In addition to the physiological effects, we show that morphology of neurites within the barrel cortex of the APP/PS1 model is altered compared to CONTROLS. These results are consistent with a process where the effect of Abeta on spontaneous activity of individual neurons amplifies into a network effect, reducing network integrity and leading to a wide cortical dysfunction. PMID- 25523107 TI - In favor of general probability distributions: lateral prefrontal and insular cortices respond to stimulus inherent, but irrelevant differences. AB - A key aspect of optimal behavior is the ability to predict what will come next. To achieve this, we must have a fairly good idea of the probability of occurrence of possible outcomes. This is based both on prior knowledge about a particular or similar situation and on immediately relevant new information. One question that arises is: when considering converging prior probability and external evidence, is the most probable outcome selected or does the brain represent degrees of uncertainty, even highly improbable ones? Using functional magnetic resonance imaging, the current study explored these possibilities by contrasting words that differ in their probability of occurrence, namely, unbalanced ambiguous words and unambiguous words. Unbalanced ambiguous words have a strong frequency-based bias towards one meaning, while unambiguous words have only one meaning. The current results reveal larger activation in lateral prefrontal and insular cortices in response to dominant ambiguous compared to unambiguous words even when prior and contextual information biases one interpretation only. These results suggest a probability distribution, whereby all outcomes and their associated probabilities of occurrence--even if very low--are represented and maintained. PMID- 25523108 TI - Pharmacological trials in migraine: it's time to reappraise where the headache is and what the pain is like. AB - Most pharmacological trials deal with migraine as if it were a clinically homogeneous disease, and when detailing its characteristics, they usually report only the presence, or absence, of aura and attack frequency but provide no information on pain location, a non-trivial clinical detail. The past decade has witnessed growing emerging evidence suggesting that individuals with unilateral pain, especially those with associated unilateral cranial autonomic symptoms, are more responsive than others to trigeminal-targeted symptomatic and preventive therapy with drugs such as triptans or botulinum toxin. A simple way for migraine research treatment to take a step forward might be to step back, reappraise, and critically evaluate easily obtainable patient-reported clinical findings along with current knowledge on pain features. PMID- 25523109 TI - The effect of corn trypsin inhibitor and inhibiting antibodies for FXIa and FXIIa on coagulation of plasma and whole blood: comment. PMID- 25523110 TI - Investigation of protein secretion and secretion stress in Ashbya gossypii. AB - BACKGROUND: Ashbya gossypii is a filamentous Saccharomycete used for the industrial production of riboflavin that has been recently explored as a host system for recombinant protein production. To gain insight into the protein secretory pathway of this biotechnologically relevant fungus, we undertook genome wide analyses to explore its secretome and its transcriptional responses to protein secretion stress. RESULTS: A computational pipeline was used to predict the inventory of proteins putatively secreted by A. gossypii via the general secretory pathway. The proteins actually secreted by this fungus into the supernatants of submerged cultures in minimal and rich medium were mapped by two dimensional gel electrophoresis, revealing that most of the A. gossypii secreted proteins have an isoelectric point between 4 and 6, and a molecular mass above 25 kDa. These analyses together indicated that 1-4% of A. gossypii proteins are likely to be secreted, of which less than 33% are putative hydrolases. Furthermore, transcriptomic analyses carried out in A. gossypii cells under recombinant protein secretion conditions and dithiothreitol-induced secretion stress unexpectedly revealed that a conventional unfolded protein response (UPR) was not activated in any of the conditions, as the expression levels of several well-known UPR target genes (e.g. IRE1, KAR2, HAC1 and PDI1 homologs) remained unaffected. However, several other genes involved in protein unfolding, endoplasmatic reticulum-associated degradation, proteolysis, vesicle trafficking, vacuolar protein sorting, secretion and mRNA degradation were up-regulated by dithiothreitol-induced secretion stress. Conversely, the transcription of several genes encoding secretory proteins, such as components of the glycosylation pathway, was severely repressed by dithiothreitol CONCLUSIONS: This study provides the first insights into the secretion stress response of A. gossypii, as well as a basic understanding of its protein secretion potential, which is more similar to that of yeast than to that of other filamentous fungi. Contrary to what has been widely described for yeast and fungi, a conventional UPR was not observed in A. gossypii, but alternative protein quality control mechanisms enabled it to cope with secretion stress. These data will help provide strategies for improving heterologous protein secretion in A. gossypii. PMID- 25523112 TI - Erratum to: Nonradiographic axial spondyloarthritis. What brings the new concept? PMID- 25523111 TI - Genetic counselors' (GC) knowledge, awareness, understanding of clinical next generation sequencing (NGS) genomic testing. AB - Genomic tests are increasingly complex, less expensive, and more widely available with the advent of next-generation sequencing (NGS). We assessed knowledge and perceptions among genetic counselors pertaining to NGS genomic testing via an online survey. Associations between selected characteristics and perceptions were examined. Recent education on NGS testing was common, but practical experience limited. Perceived understanding of clinical NGS was modest, specifically concerning tumor testing. Greater perceived understanding of clinical NGS testing correlated with more time spent in cancer-related counseling, exposure to NGS testing, and NGS-focused education. Substantial disagreement about the role of counseling for tumor-based testing was seen. Finally, a majority of counselors agreed with the need for more education about clinical NGS testing, supporting this approach to optimizing implementation. PMID- 25523113 TI - Conceptual and practical challenges in the assessment of physician competencies. AB - Abstract The shift to using outcomes-based competency frameworks in medical education in many countries around the world requires educators to find ways to assess multiple competencies. Contemporary medical educators recognize that a competent trainee not only needs sound biomedical knowledge and technical skills, they also need to be able to communicate, collaborate and behave in a professional manner. This paper discusses methodological challenges of assessment with a particular focus on the CanMEDS Roles. The paper argues that the psychometric measures that have been the mainstay of assessment practices for the past half-century, while still valuable and necessary, are not sufficient for a competency-oriented assessment environment. New assessment approaches, particularly ones from the social sciences, are required to be able to assess non Medical Expert (Intrinsic) roles that are situated and context-bound. Realist and ethnographic methods in particular afford ways to address the challenges of this new assessment. The paper considers the theoretical and practical bases for tools that can more effectively assess non-Medical Expert (Intrinsic) roles. PMID- 25523114 TI - Specialty resident perceptions of the impact of a distributed education model on practice location intentions. AB - OBJECTIVES: There is an increased focus internationally on the social mandate of postgraduate training programs. This study explores specialty residents' perceptions of the impact of the University of Calgary's (UC) distributed education rotations on their self-perceived likelihood of practice location, and if this effect is influenced by resident specialty or stage of program. METHODS: Residents participating in the UC Distributed Royal College Initiative (DistRCI) between July 2010 and June 2013 completed an online survey following their rotation. Descriptive statistics and student's t-test were employed to analyze quantitative survey data, and a constant comparative approach was used to analyze free text qualitative responses. RESULTS: Residents indicated they were satisfied with the program (92%), and that the distributed rotations significantly increased their self-reported likelihood of practicing in smaller centers (p < 0.05). The findings suggest that the shift in attitude is independent of discipline, program year, and logistical experiences of living at the distributed sites, and is consistent across multiple cohorts over several academic years. CONCLUSION: The findings highlight the value of a distributed education program in contributing to future practice and career development, and its relevance in the social accountability of postgraduate programs. PMID- 25523115 TI - "Everyone wants his son to be a doctor": external motives in choosing medicine as a career among an ethnic minority. PMID- 25523116 TI - Standardized Patient Training: Using ANGER to quickly evoke anger in standardized patients. PMID- 25523117 TI - A teaching intervention for medical undergraduates to practice skills and attitudes necessary for providing sexual health care. PMID- 25523118 TI - Gradation of the stress response in rainbow trout exposed to stressors of different severity: the role of brain serotonergic and dopaminergic systems. AB - After an intense acute stressor, fish develop a metabolic and behavioural response that usually lasts for several hours. Brain monoaminergic systems, particularly the serotonergic system, appear to play a key role in the central regulation of the stress response. However, the influence of stressor severity on brain monoaminergic systems and on the induced stress responses is yet poorly understood. We hypothesise that serotonergic system could have a direct role in the integration of sensory information during stressor exposure and in the organisation of the subsequent integrated stress response. According to our hypothesis, a low stressor intensity would induce a low response of brain serotonergic system and therefore stress responses of low magnitude and duration. To test this hypothesis, we exposed fish to handling disturbance for 5 s, 15 s or 3 min. We sampled fish at 0 (controls), 3, 15, 45 and 240 min after the start of the stress protocol. Brain levels of serotonin, dopamine and their respective main oxidative metabolites were quantified, along with plasma levels of stress markers (catecholamines, cortisol, glucose and lactate). Regarding stress markers, the 5-s and 15-s stress protocols induced similar and relatively low elevations in all parameters assessed. As expected, the 3-min protocol induced responses of a higher intensity and duration in all plasma parameters. Interestingly, the alterations of brain monoaminergic systems did not follow the same trend. The three stress protocols induced increases in the serotonergic activity in all brain regions analysed (hypothalamus, telencephalon and medulla oblongata), independently of the duration of the handling disturbance, whereas the effects on the dopaminergic system were minor and brain region-dependent. These data suggest that the brain serotonergic system, although likely involved in the recognition of the stressor stimuli, is not the only actor determining the magnitude and duration of the acute stress response in trout. PMID- 25523119 TI - Regulatory T cells protect against hypoxia-induced pulmonary arterial hypertension in mice. AB - Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the complex proliferation of the pulmonary vascular endothelium and progressive pulmonary vascular remodeling. CD4+CD25+ regulatory T cells (Tregs) have been the focus of numerous studies into PAH. The present study aimed to investigate the role and mechanisms of Tregs in hypoxia-induced PAH. A total of 60 male mice were divided at random into three groups: Normoxia group, hypoxia control group and Tregs group. Measurements were obtained of the right ventricle systolic pressure (RVSP) and the Fulton's index; in addition, the mRNA and protein expression of pro-inflammatory cytokines including monocyte chemotactic protein 1 (MCP-1), interleukin (IL)-1beta and IL-6, as well as the anti inflammatory cytokine IL-10 in the lungs were determined by reverse transcription quantitative polymerase chain reaction and western blot analysis in vivo. Human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic condition with or without Tregs for 48 h, and the proliferation rate and cell cycle of HPASMCs were determined. In addition, the protein levels of phosphorylated (p)-Akt and p-extracellular signal-regulated kinase (ERK) were measured in HPASMCs in vitro. The results showed that Treg treatment significantly reduced the increased the hypoxia-induced RVSP and Fulton's index, decreased pro-inflammatory cytokine expression as well as enhanced IL-10 levels in vivo. Furthermore, Treg treatment significantly reduced HPASMCs proliferation and the expression of cyclin D1, cyclin-dependent kinase (CDK)4, p-Akt and p-ERK, as well as increased p27 expression in vitro. In conclusion, the results of the present study indicated that Tregs protected against hypoxia-induced PAH in mice; the mechanisms of which may proceed via the suppression of the inflammatory response, as Tregs were found to enhance anti-inflammatory cytokine levels, inhibit HPASMCs proliferation and regulate the cell cycle. These results therefore indicated that Tregs may be a potential novel target for the treatment of PAH. PMID- 25523121 TI - [Tobacco smoking and psychiatric intensive care unit: Impact of the strict smoking ban on the risk of violence]. AB - BACKGROUND: Tobacco smoking is the main cause of death among mentally ill persons. Since February 2007, smoking has been strictly forbidden in French covered and closed psychiatric wards. The fear of an increased violence risk induced by tobacco withdrawal is one of the most frequent arguments invoked against this tobacco ban. According to the literature, it seems that the implementation of this ban does not imply such a risk. All these studies compared inpatients' violence risk before and after the tobacco ban in a same psychiatric ward. AIM: We aimed to analyse the strict tobacco withdrawal consequences on the violence risk in a retrospective study including patients hospitalised in a psychiatric intensive care unit of the university hospital of Caen during the same period. METHODS: We compared clinical and demographic data and the violence risk between the smoker group (strict tobacco withdrawal with proposed tobacco substitution) and the non-smoker group (control group). In order to evaluate the violence risk, we used three indicators: a standardised scale (the Broset Violence Checklist) and two assessments specific to the psychiatric intensive care setting ("the preventing risk protocol" and the "seclusion time"). The clinical and demographic data were compared using the Khi2 test, Fisher test and Mann-Whitney test, and the three violence risk indicators were compared with the Mann-Whitney test. Firstly, comparisons were conducted in the total population, and secondly (in order to eliminate a bias of tobacco substitution) in the subgroup directly hospitalised in the psychiatric intensive care setting. Finally, we analysed in the smoker group the statistical correlation between tobacco smoking intensity and violence risk intensity using a regression test. RESULTS: A population of 72 patients (50 male) was included; 45 were smokers (62.5%) and 27 non-smokers. No statistically significant differences were found in clinical and demographic data between smoker and non-smoker groups in the whole population, as well as in the subgroup directly hospitalised in the psychiatric intensive care setting. Whatever the violence risk indicators, no statistically significant difference was found between the smoker group and the non-smoker group in the total population, as well as the subgroup directly hospitalised in the psychiatric intensive care setting. Moreover, no correlation was found between the tobacco smoking intensity and the violence risk intensity in the smoker group. CONCLUSION: Strict tobacco withdrawal does not appear to constitute a violence risk factor in psychiatric intensive care unit inpatients. However, further studies are needed to confirm these results. They should be prospective and they should take into account larger samples including patients hospitalised in non-intensive care psychiatric wards. PMID- 25523120 TI - Curcumin inhibits proliferation of gastric cancer cells by impairing ATP sensitive potassium channel opening. AB - BACKGROUND: This study was aimed to investigate whether ATP-sensitive potassium channel (KATP) is involved in curcumin's anti-proliferative effects against gastric cancer. METHODS: In an in vitro study, gastric cancer cell line SGC-7901 was treated with curcumin at serial concentrations and co-administrated with the KATP opener, diazoxide. The effect of curcumin and diazoxide on proliferation were assessed by MTT assay. Mitochondrial membrane potential (MMP) was studied by flow cytometry detection of rhodamine 123 staining. Apoptosis was evaluated by flow cytometry detection of Annexin V propidium iodide double staining. In an in vivo study, SGC-7901 cells were planted into nude mice as xenografts. Animals were treated with curcumin co-administered with diazoxide. Tumor volume and tumor weight were observed. RESULTS: Curcumin incubation significantly induced loss of MMP in SGC-7901 cells in a dose- dependent manner (P < 0.05); the cell apoptotic rate also dramatically increased after curcumin incubation in a dose-dependent manner (P < 0.05). After co-administration with diazoxide, however, we found that both the MMP-loss-inducing and the apoptosis-inducing effects of curcumin in SGC 7901 cells were significantly impaired (all P < 0.05). As a result, the proliferation of SGC-7901 cells was maintained by diazoxide treatment. CONCLUSIONS: Impaired mitoKATP opening causes MMP loss, and is involved in curcumin-induced apoptosis in gastric cancer. PMID- 25523122 TI - [Path causal analysis of a model of a functional organization between defense mechanisms and coping strategies]. AB - BACKGROUND: In the psychological literature, two concepts are often used to approach psychological and social adaptation: defense mechanisms and coping strategies. Many empirical studies deal with these strategies independently of each other. However, the nature of their relationship is still debated, making empirical studies necessary jointly evaluating these two types of strategies to better reflect the adaptive process. OBJECTIVE: To test Chabrol and Callahan's theoretical model of the relationship between defence mechanisms and coping strategies. According to theses authors, defence mechanisms and coping strategies are distinct mechanisms, functionally organized: defenses appear first and modulate the emergence of coping strategy defenses through threat representation. METHOD: Ninety-four young adult volunteers completed the Coping Inventory for Stressful Situations (CISS), the Defense Style Questionnaire (DSQ-40) and the Perceived Stress Scale (PSS14). The data were treated according to the structural equation modeling method. RESULTS: Overall, the results support the theoretical model proposed by Chabrol and Callahan. The statistical model provides a good fit to the data (chi(2)/df=18.62/22=.85, P=.67, RMSEA=.00 (90% CI: .00-.07), CFI=1, TLI=1.04). It explains from 7 to 24% of coping variability scores (Avoidant Coping: R(2)=.07, P<.01; emotional coping and problem-focused coping: R(2)=24, P<.01). Results also show that the relationships between defence mechanisms and copings strategies are mediated by perceived distress and perceived controllability. Defence impact on coping strategies is not the same whether one considers problem-focused coping or emotional and avoidant coping. Immature and mature defences' impact on problem-focused coping is underpinned by a simple mediation: perceived controllability. Defences' impact on emotional coping and avoidant coping is more complex and underpinned by a double mediation: first by the perceived controllability and then, in a second time, the perceived distress. Finally, the results show the existence of a feedback loop from emotional copings to immature defences. CONCLUSION: It is now clearly relevant for the therapist to simultaneously work on defence mechanisms and coping strategies without assimilating these two categories of processes. Such work involves being able to identify them in their specificities. One of the crucial therapeutic targets is to understand the role of defences on the mental construction of reality in order to maximize adaptive reactions, critical in stress management. PMID- 25523123 TI - [Neurocognitive and psychiatric management of the 22q11.2 deletion syndrome]. AB - INTRODUCTION: The 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22. 22q11.2DS has several presentations including Di George's syndrome, velo-cardio-facial syndrome or Shprintzen's syndrome and it is the most frequent microdeletion syndrome in the general population (prevalence estimated at 1/4000 births, de novo: 90%). The inheritance of the syndrome (10%) is autosomal dominant. Most people with 22q11.2DS are missing a sequence of about 3 million DNA building blocks (base pairs) on one copy of chromosome 22 in each cell. A small percentage of affected individuals have shorter deletions in the same region (contiguous gene deletion syndrome). The general features of 22q11.2DS vary widely (more than 180 phenotypic presentations) and the syndrome is under diagnosed. Characteristic symptoms may include congenital heart disease, defects in the palate, neuromuscular problems, velo-pharyngeal insufficiency, hypoparathyroidism, craniofacial features and problems with the immune system T cell mediated response (caused by hypoplasia of the thymus). COGNITIVE PHENOTYPE: The neurocognitive phenotype of the 22q11.2DS is complex. Cognitive deficits are seen in the majority (80-100%) of individuals with 22q11DS with impairments in sustained attention, executive function, memory and visual-spatial perception. Borderline intellectual function (IQ: 70-75) is most common, mild intellectual disability (IQ: 55-75) is slightly less frequent and a small percentage of children fall into the low average intelligence range. Most children with 22q11.2DS achieve higher scores in verbal tasks than in non-verbal tasks, although this pattern of dysfunction being not universal. Brain MRI studies have shown volumetric changes in multiple cortical and subcortical regions in individuals with 22q11DS that could be related to both cognition and psychoses. PSYCHIATRIC PHENOTYPE: General psychiatric features included anxiety disorders, attention deficit disorder and poor social skills (40-50%). An elevated risk of bipolar disorder and major depression occurs in adolescence and young adulthood. A strong and specific relationship exists between the presence of the 22q11.2 microdeletion and schizophrenia (30-40%). This risk is not associated with any other neurogenetic syndrome. Social cognition is impaired in 22q11.2 DS and this observation is correlated with psychotic features. So, long-term medical care is increasingly being directed towards the treatment and recognition of these symptoms. TREATMENT: Required pharmacological treatment strategies have to be adapted to the syndrome. Moreover, cognitive remediation is a promising tool for treating neuro- and social cognitive deficits in 22q11.2DS. However, these new therapeutic strategies have to be developed to improve quality of life. PMID- 25523124 TI - [Pharmacists' interventions conducted by hospital pharmacists on psychotropic drugs pharmacotherapy]. AB - INTRODUCTION: The French Society of Clinical Pharmacy (SFPC) through the special interest group "standardization and optimization of clinical pharmacy activities" stated that the study of pharmacists' interventions (PIs) conducted during prescription analysis was a priority. The SFPC developed an internet website named Act-IP((r)) (http://www.sfpc.eu/fr/) where French speaking pharmacists were able to document PIs using a normalized codification. The objective of this study was to analyze medication-related problems linked to psychotropic drugs in hospital and to investigate PIs performed during prescription analysis. MATERIALS AND METHODS: This is a multicenter, retrospective, observational study using PIs involving psychotropic medications recorded between September 2006 and February 2009 on the Act-IP((r)) website. RESULTS: Four thousand six hundred and twenty PIs recorded by 165 pharmacists in 57 hospitals were related to psychotropic drugs. Patients concerned by these drug-related problems were 64 years old on average. Seven categories of medication-related problems represented more than 69% of PIs (1.1-Non Conformity of the drug choice compared to the formulary; 4.1 Supratherapeutic dose; 5.3 Therapeutic redundancy; 6.2 Drug interaction (all levels of severity); 7.0 Adverse drug reaction; 8.3 Inappropriate drug form; 8.5 Inappropriate timing of administration). The PIs related to 9.2 Patient's non compliance, 2.0 Untreated indication and 3.2 Length of the treatment too short were infrequent (less than 1%). The most common type of intervention was the dose adjustment. Almost 45% of these PIs involved Zopiclone or Zolpidem prescription in elderly patients. Seven hundred and nine drug interactions were identified by pharmacists. The most common type of drug interaction considered the risk of cardiac arrhythmias due to antipsychotic medications. One hundred and thirty three PIs concerned adverse drug reaction. The most frequent adverse drug reactions were a fall (36 PIs), hemorrhage/bleeding (32 PIs), drowsiness (12 PIs) and extrapyramidal syndrome (12 PIs). Antidepressant drugs were the greatest pharmacological class concerning adverse drug reaction. The overall acceptance rate was 57%. Eight hundred and seventy-four PIs (19%) were refused and 1111 (24%) were non-assessable. DISCUSSION: PIs avoids drug-related problems, such as the polyprescription of benzodiazepine or supratherapeutic dose. However, few PIs concern compliance to therapy or polyprescription of antipsychotic drugs. These two categories of medication-related problems are known to be an issue in mental health therapy. The lack of guidelines describing mental health pathology (such as the HAS guideline) is an obstacle for performing evidence-based PIs. The lack of information describing the context of the prescription is a limitation of this study. In order to improve their practice, pharmacists have to focus more on the context in which patients are evolving, and to take into account its entire situation based on Anglo-Saxon approaches. A second way is to identify clinical settings where PIs are useful and to describe PIs needed. Doctors and pharmacists should get together and talk about these clinical situations and PIs, because some may be misunderstood or disapproved by prescribers. This collaboration could take the form of a thesaurus combining clinical situation and PIs. CONCLUSION: It appears important for pharmacists to show their daily involvement in the quality of medical care. This feedback on medication problems encountered and PIs proposed should help prescribers to identify clinical situations at risk. Nevertheless, this study also suggests that progress is possible. Dialogue must allow pharmacists and physicians to delete misunderstandings about their practices. PMID- 25523126 TI - Open-door versus French-door laminoplasty for the treatment of cervical multilevel compressive myelopathy. AB - Open-door laminoplasty (ODL) and French-door laminoplasty (FDL) are used to treat cervical multilevel compressive myelopathy. However, differences in outcome between the approaches remain unknown. To investigate treatment differences, we performed a systematic review and meta-analysis. Four comparative trials were identified and analyzed in the review. The results showed that ODL had a higher postoperative Japanese Orthopaedic Association (JOA) score than FDL (weighted mean difference [WMD]=0.83; 95% confidence interval [CI]: 0.47 to 1.19; p<0.01). There were no significant differences between the two methods in terms of operative time (WMD=-6.76; 95% CI: -21.70 to 8.18; p=0.38), intraoperative blood loss (WMD=41.70; 95% CI: -61.43 to 144.82; p=0.43), total complication rate (OR=2.43, 95% CI: 0.22 to 27.04; p=0.47), postoperative C5 palsy (OR=1.97, 95% CI: 0.46 to 8.39; p=0.36), postoperative cervical lordosis (WMD=-0.60; 95% CI: 0.37 to 1.86; p=0.63) or range of motion (WMD=-4.62; 95% CI: -13.06 to 3.82; p=0.28). These results suggest that neither cervical laminoplasty approach is superior to the other based on the postoperative radiological data and complication rate, although ODL had higher postoperative JOA score than FDL. PMID- 25523125 TI - Treatment of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome with intravenous immunoglobulin in a patient with multiple sclerosis treated with fingolimod after discontinuation of natalizumab. AB - We report a case of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome in a multiple sclerosis (MS) patient 3.5 months after fingolimod commencement and 4.5 months after natalizumab (NTZ) cessation. Three cerebrospinal fluid analyses were required before a definitive diagnosis of progressive multifocal leukoencephalopathy was reached. Intravenous immunoglobulin (IVIG) was subsequently given as the sole MS treatment along with mirtazapine and mefloquine. There has been improvement and subsequent clinical stabilization. The notable features are the difficult timing of fingolimod commencement in the context of previous NTZ therapy, the role of repeated cerebrospinal fluid John Cunningham virus analyses in progressive multifocal leukoencephalopathy diagnosis, and the role of IVIG. PMID- 25523127 TI - Val66Met polymorphism of brain-derived neurotrophic factor is associated with idiopathic dystonia. AB - The Val66Met (G196A; rs6265) single nucleotide polymorphism of brain-derived neurotrophic factor (BDNF) affects morphology and neuronal activity, and is expected to be associated with central nervous system disorders. However, it remains controversial whether Val66Met polymorphism is a risk factor for idiopathic dystonia. We aimed to clarify the impact of BDNF polymorphism on idiopathic dystonia. A literature search of PubMed was carried out. A random effects model was employed for the meta-analysis. A pooled odds ratio (OR) was calculated along with 95% confidence intervals (CI) to reflect the risk of idiopathic dystonia in each genotype (GG, AG, AA) or minor allele. The proportion of variation due to heterogeneity was computed and expressed as I(2). Five case control studies, comprising a total sample size of 1804 subjects (784 idiopathic dystonia patients, 1020 normal controls), were included in this meta-analysis. AA genotype was significantly more frequent in patients with idiopathic dystonia (OR=1.47, 95% CI 1.09-1.99, p=0.01, four studies, n=1716). This finding was derived from homogeneous studies (p=0.97, I(2)=0%). Our meta-analysis has revealed a significant overall effect of the AA genotype on the development of idiopathic dystonia. PMID- 25523128 TI - In situ DNA-hybridization chain reaction (HCR): a facilitated in situ HCR system for the detection of environmental microorganisms. AB - In situ detection of microorganisms by fluorescence in situ hybridization (FISH) is a powerful tool for environmental microbiology, but analyses can be hampered by low rRNA content in target organisms, especially in oligotrophic environments. Here, we present a non-enzymatic, hybridization chain reaction (HCR)-based signal amplified in situ whole-cell detection technique (in situ DNA-HCR). The components of the amplification buffer were optimized to polymerize DNA amplifier probes for in situ DNA-HCR. In situ hybridization of initiator probes followed by signal amplification via HCR produced bright signals with high specificity and probe permeation into cells. The detection rates for Bacteria in a seawater sample and Archaea in anaerobic sludge samples were comparable with or greater than those obtained by catalyzed reporter deposition (CARD)-FISH or standard FISH. Detection of multiple organisms (Bacteria, Archaea and Methanosaetaceae) in an anaerobic sludge sample was achieved by simultaneous in situ DNA-HCR. In summary, in situ DNA-HCR is a simple and easy technique for detecting single microbial cells and enhancing understanding of the ecology and behaviour of environmental microorganisms in situ. PMID- 25523130 TI - Single-dose, open-label study of the differences in pharmacokinetics of colchicine in subjects with renal impairment, including end-stage renal disease. PMID- 25523129 TI - Investigating the "Rule of W," a mnemonic for teaching on postoperative complications. AB - OBJECTIVE: To identify the timing and relative frequency of common postoperative complications in a contemporary, diverse surgical population and develop a mnemonic for teaching and clinical decision support. PATIENTS AND METHODS: We enrolled a cohort of general and vascular surgical patients undergoing elective, inpatient surgery in the American College of Surgeons National Surgical Quality Improvement Program database between 2005 and 2011. Index complications were noted by postoperative day (POD). Timing and incidence were compared within each day. RESULTS: Among 614,525 patients, 51,173 (9.88%) experienced the following index complications over 30 days: pneumonia (n = 5947), urinary tract infection (n = 9459), superficial surgical site infection (sSSI) (n = 20,460), deep/organ space surgical site infection (dSSI) infection (n = 11,847), venous thromboembolism (n = 4478), kidney injury (n = 2620), and myocardial infarction (n = 1813). Median time to complication differed significantly for index complications (p < 0.0001). On POD 0, the most common complication was myocardial infarction (incidence 4.26/10,000 patient days; 95% CI: 3.75-4.78). On POD 1 and 2, pneumonia was the most common complication, with peak incidence on POD 2 (20.36; 95% CI: 19.22-21.51). On POD 3, pneumonia (16.3; 95% CI: 15.27-17.33) and urinary tract infection (15.5; 95% CI: 14.49-16.51) were significantly more common than other complications. On POD 4, the most common complication was sSSI (16.24; 95% CI: 15.20-17.28). From POD 5 to POD 30, sSSI and dSSI were the 2 most common complications. Risk of venous thromboembolism declined only slightly through POD 30. CONCLUSION: We propose a mnemonic for postoperative complication timing and frequency, independent of fever, as follows: Waves (myocardial infarction), Wind (pneumonia), Water (urinary tract), Wound (sSSI and dSSI), and Walking (venous thromboembolism) in the order of likelihood. PMID- 25523131 TI - Tooth loss associated with physical and cognitive decline in older adults. AB - OBJECTIVES: To examine the effect of total tooth loss (edentulousness) on decline in physical and cognitive functioning over 10 years in older adults in England. DESIGN: Secondary data analysis. SETTING: English Longitudinal Study of Ageing, a national prospective cohort study of community-dwelling people aged 50 and older. PARTICIPANTS: Individuals aged 60 and older (N = 3,166). MEASUREMENTS: Cognitive function (memory) was measured using a 10-word recall test. Physical function was assessed using gait speed (m/s). Generalized estimating equations were used to model associations between baseline edentulousness and six repeated measurements of gait speed and memory from 2002-03 to 2012-13. Models were sequentially adjusted for time, demographic characteristics, socioeconomic status, comorbidities, health behaviors, depressive symptoms, and anthropometric measurements and mutually adjusted for gait speed or memory. RESULTS: Edentulous participants recalled 0.88 fewer words and were 0.09 m/s slower than dentate participants after adjusting for time and demographics. Only the latter association remained significant after full adjustment, with edentulous participants being 0.02 m/s slower than dentate participants. In age-stratified analyses, baseline edentulousness was associated with both outcomes in fully adjusted models in participants aged 60 to 74 but not in those aged 75 and older. Supplementary analysis indicated significant associations between baseline edentulousness and 4-year change in gait speed and memory in participants aged 60 to 74; the former was fully explained in the fully adjusted model and the latter after adjusting for socioeconomic status. CONCLUSION: Total tooth loss was independently associated with physical and cognitive decline in older adults in England. Tooth loss is a potential early marker of decline in older age. PMID- 25523132 TI - Trop2: from development to disease. AB - BACKGROUND: Trop2 was first discovered as a biomarker of invasive trophoblast cells. Since then most research has focused on its role in tumourigenesis because it is highly expressed in the vast majority of human tumours and animal models of cancer. It is also highly expressed in stem cells and in many organs during development. RESULTS: We review the multifaceted role of Trop2 during development and tumourigenesis, including its role in regulating cell proliferation and migration, self-renewal, and maintenance of basement membrane integrity. We discuss the evolution of Trop2 and its related protein Epcam (Trop1), including their distinct roles. Mutation of Trop2 leads to gelatinous drop-like corneal dystrophy, whereas over-expression of Trop2 in human tumours promotes tumour aggressiveness and increases mortality. Although Trop2 expression is sufficient to promote tumour growth, the surprising discovery that Trop2-null mice have an increased risk of tumour development has highlighted the complexity of Trop2 signaling. Recently, studies have begun to identify the mechanisms underlying TROP2's functions, including regulated intramembrane proteolysis or specific interactions with integrin b1 and claudin proteins. CONCLUSIONS: Understanding the mechanisms underlying TROP2 signaling will clarify its role during development, aid in the development of better cancer treatments and unlock a promising new direction in regenerative medicine. PMID- 25523133 TI - Primary carcinoid tumor of medulla spinalis: case report and review of the literature. AB - BACKGROUND: Carcinoid tumors are slow growing neuroendocrine tumors which can originate from various sites within the body. A carcinoid tumor originating in the medulla spinalis has not previously been reported in the literature. CASE REPORT: We report a case of a 33-year-old man, presenting with a five-month history of bilateral lower extremity pain, as well as paresthesia, and mild weakness in one lateral lower extremity. A lumbar laminectomy of L3 to L5 and en bloc resection of the tumor was performed. Postoperative histopathology and immunohistochemical analysis of the tumor were consistent with that of a carcinoid tumor. There were no clinical or radiological signs of tumor recurrence or metastasis at the patient's two year postoperative follow-up. CONCLUSIONS: During the differential diagnosis of medulla spinalis tumors, the possibility of a primary carcinoid tumor originating within the medulla spinalis should be considered. An accurate tumor classification is imperative to ensure that the most effective course of treatment is pursued. PMID- 25523135 TI - Revisiting [(RSn(IV))6Sn(III)2S12]: directed synthesis, crystal transformation, and luminescence properties. AB - We report the synthesis of the mixed-valence cluster [(R(5)Sn(IV))6Sn(III)2S12] [1; R(5) = CMe2CH2C(O)Me] under optimization of the reaction conditions. A new crystalline form of 1 in the orthorhombic space group Pbca was found at 250 K, which undergoes crystal transformation into the known monoclinic one at lower temperature. Further, we have studied the luminescence properties of 1. Time resolved photoluminescence measurements confirm the lability of the tin chalcogenide bonds to UV irradiation, while the organic ligands are much less affected by it. PMID- 25523136 TI - Explicit calculation of the excited electronic states of the photosystem II reaction centre. AB - The excited states of sets of the cofactors found in the photosystem II reaction centre have been calculated directly as a multi-monomer supermolecule for the first time. Time-dependent density functional theory was used with the CAM-B3LYP functional. Multiple excited states for each cofactor were found at lower energies than the lowest energy state corresponding to charge transfer states (in which an electron is shifted from one cofactor to another). The electrostatic environment was found to have a dramatic impact on the excited state energies, with the effect of a surrounding dielectric medium being less significant. PMID- 25523137 TI - Examining the significance of urban-rural context in tobacco quitline use: does rurality matter? AB - OBJECTIVES: The purpose of this study was to examine the importance of urban rural context as a determinant of call rates to smoking cessation lines. METHODS: This study used individual level New Zealand Quitline call data from 2005 to 2009, and 2006 New Zealand Census data on smoking to calculate Quitline call rates for smokers. Negative binomial regression examined the relationship between call rates and a sevenfold urban-rural classification, controlling for age, sex, ethnicity and deprivation. RESULTS: We found a significant urban-rural gradient in the rate of smokers calling Quitline. Rates were highest among smokers in main urban areas [0.09 (95 % confidence interval (CI) = 0.089, 0.091)] decreasing with successive urban-rural classifications to the lowest rate in rural/remote areas [0.036 (95 % CI = 0.03, 0.04)]. This association was not confounded by age, sex, ethnicity or deprivation. CONCLUSIONS: Smokers in rural areas are less likely to use the New Zealand Quitline, even after controlling for confounding factors. This suggests that the national quitline is less effective in reaching rural smokers and more attention to the promotion of smoking cessation in rural communities is needed. PMID- 25523138 TI - Fluidic dielectrophoresis: The polarization and displacement of electrical liquid interfaces. AB - Traditional particle-based dielectrophoresis has been exploited to manipulate bubbles, particles, biomolecules, and cells. In this work, we investigate analytically and experimentally how to utilize Maxwell-Wagner polarization to initiate fluidic dielectrophoresis (fDEP) at electrically polarizable aqueous liquid-liquid interfaces. In fDEP, an AC electric field is applied across a liquid electrical interface created between two coflowing fluid streams with different electrical properties. When potentials as low as 2 volts are applied, we observe a frequency-dependent interfacial displacement that is dependent on the relative differences in the electrical conductivity (Deltasigma) and dielectric constant (DeltaE) between the two liquids. At low frequency this deflection is independent of dielectric constant, while at high frequency it is independent of electrical conductivity. At intermediate frequencies, we observe an fDEP cross-over frequency that is independent of applied voltage, sensitive to both fluid electrical properties, and where no displacement is observed. An analytical fDEP polarization model is presented that accurately predicts the liquid interfacial cross-over frequency, the dependence of interfacial displacement on liquid electrical conductivity and dielectric constant, and accurately scales the measured fDEP displacement data. The results show that miscible aqueous liquid interfaces are capable of polarizing under AC electric fields, and being precisely deflected in a direction and magnitude that is dependent on the applied electric field frequency. PMID- 25523139 TI - ANKHD1 silencing inhibits Stathmin 1 activity, cell proliferation and migration of leukemia cells. AB - ANKHD1 is highly expressed in human acute leukemia cells and potentially regulates multiple cellular functions through its ankyrin-repeat domains. In order to identify interaction partners of the ANKHD1 protein and its role in leukemia cells, we performed a yeast two-hybrid system screen and identified SIVA, a cellular protein known to be involved in proapoptotic signaling pathways. The interaction between ANKHD1 and SIVA was confirmed by co-imunoprecipitation assays. Using human leukemia cell models and lentivirus-mediated shRNA approaches, we showed that ANKHD1 and SIVA proteins have opposing effects. While it is known that SIVA silencing promotes Stathmin 1 activation, increased cell migration and xenograft tumor growth, we showed that ANKHD1 silencing leads to Stathmin 1 inactivation, reduced cell migration and xenograft tumor growth, likely through the inhibition of SIVA/Stathmin 1 association. In addition, we observed that ANKHD1 knockdown decreases cell proliferation, without modulating apoptosis of leukemia cells, while SIVA has a proapoptotic function in U937 cells, but does not modulate proliferation in vitro. Results indicate that ANKHD1 binds to SIVA and has an important role in inducing leukemia cell proliferation and migration via the Stathmin 1 pathway. ANKHD1 may be an oncogene and participate in the leukemia cell phenotype. PMID- 25523141 TI - Mitochondrial function contributes to oxysterol-induced osteogenic differentiation in mouse embryonic stem cells. AB - Oxysterols, oxidized derivatives of cholesterol, are biologically active molecules. Specific oxysterols have potent osteogenic properties that act on osteoprogenitor cells. However, the molecular mechanisms underlying these osteoinductive effects on embryonic stem cells (ESCs) are unknown. This study investigated the effect of an oxysterol combination of 22(S)-hydroxycholesterol and 20(S)-hydroxycholesterol (SS) on osteogenic differentiation of ESCs and the alterations to mitochondrial activity during differentiation. Osteogenic differentiation was assessed by alkaline phosphatase (ALP) activity, matrix mineralization, mRNA expression of osteogenic factors, runt-related transcription factor 2, osterix, and osteocalcin, and protein levels of collagen type IA (COLIA) and osteopontin (OPN). Treatment of cells with SS increased osteoinductive activity compared to the control group. Intracellular reactive oxygen species production, intracellular ATP content, mitochondrial membrane potential, mitochondrial mass, mitochondrial DNA copy number, and mRNA expression of peroxisome proliferator-activated receptor-gamma coactivators 1alpha and beta, transcription factors involved in mitochondrial biogenesis, were significantly increased during osteogenesis, indicating upregulation of mitochondrial activity. Oxysterol combinations also increased protein levels of mitochondrial respiratory complexes I-V. We also found that SS treatment increased hedgehog signaling target genes, Smo and Gli1 expression. Inhibition of Hh signaling by cyclopamine suppressed mitochondrial biogenesis and ESC osteogenesis. Subsequently, oxysterol induced Wnt/beta-catenin pathways were inhibited by repression of Hh signaling and mitochondrial biogenesis. Transfection of beta-catenin specific siRNA decreased the protein levels of COLIA and OPN, as well as ALP activity. Collectively, these data suggest that lipid-based oxysterols enhance differentiation of ESCs toward the osteogenic lineage by regulating mitochondrial activity, canonical Hh/Gli, and Wnt/beta-catenin signaling. PMID- 25523140 TI - MAPK signaling triggers transcriptional induction of cFOS during amino acid limitation of HepG2 cells. AB - Amino acid (AA) deprivation in mammalian cells activates a collection of signaling cascades known as the AA response (AAR), which is characterized by transcriptional induction of stress-related genes, including FBJ murine osteosarcoma viral oncogene homolog (cFOS). The present study established that the signaling mechanism underlying the AA-dependent transcriptional regulation of the cFOS gene in HepG2 human hepatocellular carcinoma cells is independent of the classic GCN2-eIF2-ATF4 pathway. Instead, a RAS-RAF-MEK-ERK cascade mediates AAR signaling to the cFOS gene. Increased cFOS transcription is observed from 4-24 h after AAR-activation, exhibiting little or no overlap with the rapid and transient increase triggered by the well-known serum response. Furthermore, serum is not required for the AA-responsiveness of the cFOS gene and no phosphorylation of promoter-bound serum response factor (SRF) is observed. The ERK-phosphorylated transcription factor E-twenty six-like (p-ELK1) is increased in its association with the cFOS promoter after activation of the AAR. This research identified cFOS as a target of the AAR and further highlights the importance of AA-responsive MAPK signaling in HepG2 cells. PMID- 25523142 TI - Glucocorticoids enhance prolonged clearance of apoptotic cells by upregulating liver X receptor, peroxisome proliferator-activated receptor-delta and UCP2. AB - Efficient phagocytic clearance of apoptotic cells (efferocytosis) is essential to prevent the development of chronic inflammation and autoimmunity. Glucocorticoids are widely used in the therapy of chronic inflammatory diseases, and increasing evidence suggests that they act partly via enhancing efferocytosis by macrophages. Glucocorticoids were previously shown to promote both protein S- and MFG-E8-dependent efferocytosis. Since previous studies in our laboratory have demonstrated that glucocorticoids induce the expression of retinaldehyde dehydrogenases in macrophages, in the present experiments the possible involvement of retinoids in the glucocorticoid-induced efferocytosis was studied in mouse bone marrow derived macrophages. Here we show that glucocorticoids promote not only short-term, but also long-term clearance of apoptotic cells. Glucocorticoids seem to directly induce the expression of the phagocytosis related genes MERTK, C1q, UCP2, and the transcription factor C/EBPbeta. C/EBPbeta contributes to the further induction of the phagocytosis-related genes, and is required for the induction of lipid sensing receptors LXRs, PPARdelta, RARalpha, RXRalpha and RALDH1, the latter one in an LXR- and RARalpha-dependent manner. Glucocorticoid-induced enhancement in long-term efferocytosis was dependent on the induction of lipid sensing receptors known to be triggered by the lipid content of the engulfed cells to enhance phagocytic capacity. Retinoids did not affect the glucocorticoid-induced short term phagocytosis of apoptotic cells, but were required for the glucocorticoid-induced enhancement of efferocytosis during prolonged clearance of apoptotic cells by promoting efficient LXR and PPARdelta upregulation. Our data indicate that retinoids could be considered as potential promoters of the efficacy of glucocorticoid treatment in inflammatory diseases. PMID- 25523143 TI - Evaluation of Prosopis africana Seed Gum as an Extended Release Polymer for Tablet Formulation. AB - In the present work, an attempt has been made to screen Prosopis africana seed gum (PG), anionic polymer for extended release tablet formulation. Different categories of drugs (charge basis) like diclofenac sodium (DS), chlorpheniramine maleate (CPM), and ibuprofen (IB) were compacted with PG and compared with different polymers (charge basis) like xanthan gum (XG), hydroxypropyl methyl cellulose (HPMC-K100M), and chitosan (CP). For each drug, 12 batches of tablets were prepared by wet granulation technique, and granules were evaluated for flow properties, compressibility, and compactibility by Heckel and Leuenberger analysis, swelling index, in vitro dissolution studies, etc. It has been observed that granules of all batches showed acceptable flowability. According to Heckel and Leuenberger analysis, granules of PG-containing compacts showed similar and satisfactory compressibility and compactibility compared to granules of other polymers. PG showed significant swelling (P < 0.05) compared to HPMC, and better than CP and XG. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared (FTIR) study showed no interaction between drugs and polymers. From all PG-containing compacts of aforesaid drugs, drug release was sustained for 12 h following anomalous transport. Especially, polyelectrolyte complex formation retarded the release of oppositely charged drug (CPM-PG). However, extended release was noted in both anionic (DS) and nonionic (IB) drugs, maybe due to swollen gel. All compacts were found to be stable for 3-month period during stability study. This concludes that swelling and release retardation of PG has close resemblance to HPMC, so it can be used as extended release polymer for all types of drugs. PMID- 25523144 TI - Cost-effectiveness of trastuzumab in metastatic breast cancer: mainly a matter of price in the EU? AB - Trastuzumab (TR), a monoclonal antibody approved by EMA in 2000 and one of the first examples of "targeted therapy", is indicated to treat human epidermal growth factor receptor 2 (HER2) positive breast cancer. TR, whose patent will expire in 2015 in Europe, has been judged positively for reimbursement by most public authorities in the EU. Here we critically review the existing evidence on TR in metastatic breast cancer (MBC), in line with the multidisciplinary health technology assessment (HTA) approach, to assess whether the existing evidence supports TR positive reimbursement decisions taken in MBC by EU health authorities. We did a literature search for the main HTA topics (efficacy, quality of life and ethics) on the PubMed international database (2000-2013). Then, we did a specific literature search to select the full economic evaluations (FEEs) conducted in EU countries focused on TR as first-line innovative therapy in MBC. We retrieved scant evidence in the literature to support TR reimbursement in MBC. We found only two clinical trials and their results were unclear because of the large proportion of patients who crossed over. Moreover, the quality of methods was poor in all four European FEEs selected. This example of HTA exercise on a mature monoclonal antibody in a specific indication casts doubts on how often the reimbursement decisions taken by EU health authorities in emotional pathologies like cancer are rational. These decisions should at least be reconsidered periodically on the basis of the latest evidence. PMID- 25523145 TI - Doctor and two nurses charged with manslaughter over death of boy at Leicester Royal Infirmary. PMID- 25523146 TI - Expression of syntaxin 8 in visceral adipose tissue is increased in obese patients with type 2 diabetes and related to markers of insulin resistance and inflammation. AB - BACKGROUND AND AIMS: Obesity is associated with increased adipose tissue inflammation as well as with the development of type 2 diabetes (T2D). Syntaxin 8 (STX8) is a protein required for the transport of endosomes. In this study we analyzed the relationship of STX8 with the presence of T2D in the context of obesity. METHODS: With this purpose, 21 subjects (seven lean [LN], eight obese normoglycemic [OB-NG] and six obese with type 2 diabetes [OB-T2D]) were included in the study. Gene and protein expression levels of STX8 and GLUT4 were analyzed in visceral adipose tissue (VAT). RESULTS: mRNA (p = 0.008) and protein (p <0.001) expression levels of STX8 were significantly increased in VAT of OB-T2D patients. Moreover, gene expression levels of SLC2A4 (GLUT4) were downregulated (p = 0.002) in VAT of obese patients. We found that STX8 was positively correlated (p <0.05) with fasting glucose concentrations, plasma glucose 2 h after an OGTT and C-reactive protein. Interestingly, the expression of STX8 was negatively correlated (p <0.05) with the expression of SLC2A4 in VAT. CONCLUSIONS: Increased STX8 expression in VAT appears to be associated with the presence of T2D in obese patients through a mechanism that may involve GLUT4. PMID- 25523147 TI - In vitro evaluation of synergistic inhibitory effects of neuraminidase inhibitors and methylglyoxal against influenza virus infection. AB - BACKGROUND AND AIMS: Influenza virus infections are serious public health concerns worldwide that cause considerable mortality and morbidity. Moreover, the emergence of resistance to anti-influenza viral agents underscores the need to develop new anti-influenza viral agents and novel treatment strategies. Recently, we identified anti-influenza viral activity of manuka honey. Therefore, we hypothesized that methylglyoxal (MGO), a key component of manuka honey, may impart anti-influenza viral activity. The aim of this study was to evaluate the anti-influenza viral activity of MGO and its potential in combination treatments with neuraminidase (NA) inhibitors. METHODS: MDCK cells were used to evaluate anti-influenza viral activity. To evaluate the mechanism of MGO, plaque inhibition assays were performed. The synergistic effects of MGO and viral NA inhibitors were tested. RESULTS: MGO inhibited influenza virus A/WSN/33 replication 50% inhibitory concentration = 240 +/- 190 MUM; 50% cytotoxic concentration = 1.4 +/- 0.4 mM; selective index (SI) = 5.8, which is related to its virucidal effects. Moreover, we found that MGO showed promising activity against various influenza strains. A synergistic effect was observed by a marked increase in SI of NA inhibitors at ~1/100(th) of their single usage. A synergistic effect of MGO and oseltamivir was also observed against oseltamivir resistant virus. CONCLUSIONS: Our results showed that MGO has potent inhibitory activity against influenza viruses and also enhanced the effect of NA inhibitors. Thus, the co-administration of MGO and NA inhibitors should be considered for treatment of influenza virus infections. PMID- 25523148 TI - Normal laser-evoked cortical responses in patients with chronic hemibody pain. AB - BACKGROUND: Patients with widespread unilateral chronic pain associated with recurrent herpes simplex virus (HSV) infections show functional and/or structural changes in the insula, anterior cingulate cortex, frontal and prefrontal cortices, as well as the thalamus, suggesting central dysfunction of the pain system in these patients. Central pain has been associated with attenuated laser evoked cortical responses. We aimed to clarify whether the observed deficient activation of these areas to acute nociceptive stimuli is due to a lesion at a lower level of pain processing pathways. METHODS: We explored the functional integrity of the ascending nociceptive pathways by recording the cortical-evoked responses to noxious laser stimulation using magnetoencephalography and electroencephalography in eight patients (age 41-51 years, mean 46) with recurrent HSV infections and a history of chronic, spontaneous, widespread unilateral pain, and in nine age-matched healthy control subjects. RESULTS: The cortical-evoked fields of the HSV patients originating from the secondary somatosensory and posterior parietal cortices, as well as the evoked potentials recorded from the midline, did not differ from those of the control subjects, indicating functionally intact ascending nociceptive pathways. CONCLUSIONS: The present results show that our patients with chronic hemibody pain do not show signs of spinothalamic tract lesion. This indicates normal processing of sensory aspects of painful stimuli, while higher pain processing areas show altered activation. We conclude that normal laser-evoked magnetic fields (LEF) or laser evoked potentials (LEP) may not exclude central pain condition. PMID- 25523149 TI - Tuning CO2 uptake and reversible iodine adsorption in two isoreticular MOFs through ligand functionalization. AB - The synthesis and characterization of two isoreticular metal-organic frameworks (MOFs), {[Cd(bdc)(4-bpmh)]}n?2 n(H2O) (1) and {[Cd(2-NH2bdc)(4-bpmh)]}n?2 n(H2O) (2) [bdc = benzene dicarboxylic acid; 2-NH2bdc = 2-amino benzene dicarboxylic acid; 4-bpmh = N,N-bis-pyridin-4-ylmethylene-hydrazine], are reported. Both compounds possess similar two-fold interpenetrated 3D frameworks bridged by dicarboxylates and a 4-bpmh linker. The 2D Cd-dicarboxylate layers are extended along the a-axis to form distorted square grids which are further pillared by 4 bpmh linkers to result in a 3D pillared-bilayer interpenetrated framework. Gas adsorption studies demonstrate that the amino-functionalized MOF 2 shows high selectivity for CO2 (8.4 wt % 273 K and 7.0 wt % 298 K) over CH4 , and the uptake amounts are almost double that of non-functional MOF 1. Iodine (I2 ) adsorption studies reveal that amino-functionalized MOF 2 exhibits a faster I2 adsorption rate and controlled delivery of I2 over the non-functionalized homolog 1. PMID- 25523150 TI - Contorted polycyclic aromatics. AB - CONSPECTUS: This Account describes a body of research in the design, synthesis, and assembly of molecular materials made from strained polycyclic aromatic molecules. The strain in the molecular subunits severely distorts the aromatic molecules away from planarity. We coined the term "contorted aromatics" to describe this class of molecules. Using these molecules, we demonstrate that the curved pi-surfaces are useful as subunits to make self-assembled electronic materials. We have created and continue to study two broad classes of these "contorted aromatics": discs and ribbons. The figure that accompanies this conspectus displays the three-dimensional surfaces of a selection of these "contorted aromatics". The disc-shaped contorted molecules have well-defined conformations that create concave pi-surfaces. When these disc-shaped molecules are substituted with hydrocarbon side chains, they self-assemble into columnar superstructures. Depending on the hydrocarbon substitution, they form either liquid crystalline films or macroscopic cables. In both cases, the columnar structures are photoconductive and form p-type, hole- transporting materials in field effect transistor devices. This columnar motif is robust, allowing us to form monolayers of these columns attached to the surface of dielectrics such as silicon oxide. We use ultrathin point contacts made from individual single-walled carbon nanotubes that are separated by a few nanometers to probe the electronic properties of short stacks of a few contorted discs. We find that these materials have high mobility and can sense electron-deficient aromatic molecules. The concave surfaces of these disc-shaped contorted molecules form ideal receptors for the molecular recognition and assembly with spherical molecules such as fullerenes. These interfaces resemble ball-and-socket joints, where the fullerene nests itself in the concave surface of the contorted disc. The tightness of the binding between the two partners can be increased by creating more hemispherically shaped contorted molecules. Given the electronic structure of these contorted discs and the fullerenes, this junction is a molecular version of a p-n junction. These ball-and-socket interfaces are ideal for photoinduced charge separation. Photovoltaic devices containing these molecular recognition elements demonstrate approximately two orders of magnitude increase in charge separation. The ribbon-shaped, contorted molecules can be conceptualized as ultranarrow pieces of graphene. The contortion causes them to wind into helical ribbons. These ribbons can be formed into the active layer of field effect transistors. We substitute the ribbons with di-imides and therefore are able to transport electrons. Furthermore, these materials absorb light strongly and have ideal energetic alignment of their orbitals with conventional p-type electronic polymers. In solar cells, these contorted ribbons with commercial donor polymers have record efficiencies for non-fullerene-based solar cells. An area of interest for future exploration is the merger of these highly efficient contorted ribbons with the well-defined interfaces of the ball-and-socket materials. PMID- 25523151 TI - Phase I study of the novel Cdc2/CDK1 and AKT inhibitor terameprocol in patients with advanced leukemias. AB - PURPOSE: Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial. PATIENTS AND METHODS: Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days. RESULTS: Patients had AML (n = 11), chronic myelogeneous leukemia in blast phase (CML-BP, n = 2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3*/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression. CONCLUSION: Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed. PMID- 25523152 TI - Development and reproducibility of a computed tomography-based measurement for upper body subcutaneous neck fat. AB - BACKGROUND: Upper body subcutaneous neck fat (UBSF) is a unique fat depot anatomically separate from visceral abdominal fat that appears to be associated with cardiometabolic risk above and beyond generalized adiposity. We sought to develop a protocol to quantify UBSF using multidetector computed tomography measurements. METHODS AND RESULTS: Protocol development was performed in participants from the Framingham Heart Study who had participated in the multidetector computed tomography scanning substudy, consisting of chest scans. Volumetric assessment of UBSF was defined by 40 contiguous 0.625-mm slices superior to the body of the sternum. The reader manually traced the chest to identify total neck fat. Breast tissue exterior to the chest wall was excluded. Subcutaneous and visceral fat volumes were obtained using standard protocols. Age and sex-adjusted Pearson correlation coefficients were used to assess the association among UBSF, traditional adiposity measures, and cardiometabolic risk factors. Inter- and intrareader reproducibility was assessed using intraclass correlation coefficients. Volumetric assessments were obtained in 92 participants because 8 scans were not readable (51% women; mean age: 59 years [women], 58 years [men]). The mean volume of UBSF was 310 cm3 for women and 345 cm3 for men. Intra- and interreader class correlation coefficients were 0.99 and 0.99, respectively. UBSF was correlated with waist circumference (r=0.90), neck circumference (r=0.75), body mass index (r=0.89), subcutaneous adipose tissue (r=0.87), and visceral adipose tissue (r=0.86). CONCLUSIONS: UBSF can be quantified reproducibly using computed tomography in a community-dwelling sample from the Framingham Heart Study. PMID- 25523153 TI - Longitudinal and circumferential strain of the proximal aorta. AB - BACKGROUND: Accurate assessment of mechanical properties of the proximal aorta is a requisite first step for elucidating the pathophysiology of isolated systolic hypertension. During systole, substantial proximal aortic axial displacement produces longitudinal strain, which we hypothesize causes variable underestimation of ascending aortic circumferential strain compared to values in the longitudinally constrained descending aorta. METHODS AND RESULTS: To assess effects of longitudinal strain, we performed magnetic resonance imaging in 375 participants (72 to 94 years old, 204 women) in the Age, Gene/Environment Susceptibility-Reykjavik Study and measured aortic circumferential and longitudinal strain. Circumferential ascending aortic area strain uncorrected for longitudinal strain was comparable in women and men (mean [95% CI], 8.3 [7.8, 8.9] versus 7.9 [7.4, 8.5]%, respectively, P=0.3). However, longitudinal strain was greater in women (8.5+/-2.5 versus 7.0+/-2.5%, P<0.001), resulting in greater longitudinally corrected circumferential ascending aortic strain (14.4 [13.6, 15.2] versus 13.0 [12.4, 13.7]%, P=0.010). Observed circumferential descending aortic strain, which did not require correction (women: 14.0 [13.2, 14.8], men: 12.4 [11.6, 13.2]%, P=0.005), was larger than uncorrected (P<0.001), but comparable to longitudinally corrected (P=0.12) circumferential ascending aortic strain. Carotid-femoral pulse wave velocity did not correlate with uncorrected ascending aortic strain (R=-0.04, P=0.5), but was inversely related to longitudinally corrected ascending and observed descending aortic strain (R= 0.15, P=0.004; R=-0.36, P<0.001, respectively). Longitudinal strain was also inversely related to carotid-femoral pulse wave velocity and other risk factors for higher aortic stiffness including treated hypertension. CONCLUSIONS: Longitudinal strain creates substantial and variable errors in circumferential ascending aortic area strain measurements, particularly in women, and should be considered to avoid misclassification of ascending aortic stiffness. PMID- 25523154 TI - Consumption of sucrose, but not high fructose corn syrup, leads to increased adiposity and dyslipidaemia in the pregnant and lactating rat. AB - Excess consumption of added sugars, including sucrose and high fructose corn syrup (HFCS-55), have been implicated in the global epidemics of obesity and type 2 diabetes. This study aimed to investigate and compare the impact of maternal consumption of sucrose or HFCS-55 during pregnancy and lactation on the metabolic health of the dam and her offspring at birth. Female Albino Wistar rats were given access to chow and water, in addition to a sucrose or HFCS-55 beverage (10% w/v) before, and during pregnancy and lactation. Maternal glucose tolerance was determined throughout the study, and a postmortem was conducted on dams following lactation, and on offspring within 24 h of birth. Sucrose and HFCS-55 consumption resulted in increased total energy intake compared with controls, however the increase from sucrose consumption was accompanied by a compensatory decrease in chow consumption. There was no effect of sucrose or HFCS-55 consumption on body weight, however sucrose consumption resulted in increased adiposity and elevated total plasma cholesterol in the dam, while HFCS-55 consumption resulted in increased plasma insulin and decreased plasma non-esterified fatty acids (NEFA). Maternal HFCS-55 consumption was associated with decreased relative liver weight and plasma NEFA in the offspring at birth. There was no effect of either treatment on pup weight at birth. These findings suggest that both sucrose and HFCS-55 consumption during pregnancy and lactation have the potential to impact negatively on maternal metabolic health, which may have adverse consequences for the long-term health of the offspring. PMID- 25523155 TI - Distinctive outcome in patients with non-uterine and uterine leiomyosarcoma. AB - BACKGROUND: Leiomyosarcomas represent the largest subtype of soft tissue sarcomas. Two subgroups can be distinguished, non-uterine (NULMS) and uterine leiomyosarcomas (ULMS). The aim of this retrospective study was to evaluate differences in clinical features and outcome between these two subgroups. METHODS: Outcome and clinical-pathological parameters between 50 patients with NULMS and 45 patients with ULMS were assessed, and compared between both groups. Univariate and multivariable survival analyses were performed. RESULTS: Patients with ULMS presented with larger tumors when compared to patients with NULMS (p < 0.001). More patients with ULMS initially presented with metastatic disease (67% vs. 36%, p = 0.007). Most common metastatic site was lung for both subtypes (28% and 38%). Five-year overall survival (OS) rates of 82.6% and 41.2% and median OS times of 92.6 (range: 79.7-105.4) and 50.4 (range: 34.8-66.0) months were observed in patients with NULMS and ULMS, respectively (p = 0.006). In multivariate analysis, initial metastatic disease remained an independent prognostic factor in terms of OS (p < 0.0001). CONCLUSION: At time of diagnosis ULMS were larger and more often metastasized. Therefore patients with ULMS showed unfavorable outcome when compared to NULMS. Later diagnosis might be caused by differences in symptoms and clinical presentation or a more aggressive biological tumor behavior. PMID- 25523157 TI - Antifungal activity of various essential oils against Rhizoctonia solani and Macrophomina phaseolina as major bean pathogens. AB - AIMS: The main objective of this study was to investigate the effect of various essential oils (EOs) to decrease the activity of cell wall degrading enzymes (CWDEs) produced by fungal phytopathogens, which are associated with disease progress. Also, effect of seed treatment and foliar application of peppermint EO and its main constituent, menthol, on diseases caused by two necrotrophic pathogens on bean was investigated. METHODS AND RESULTS: Antifungal activity of EOs on Rhizoctonia solani and Macrophomina phaseolina, as bean pathogens, was evaluated. The EOs of Mentha piperita, Bunium persicum and Thymus vulgaris revealed the highest antifungal activity against fungi. The EO of M. piperita had the lowest minimum inhibitory concentration (MIC) for R. solani among the three EOs tested. This pathogen did not grow in the presence of M. piperita, B. persicum and T. vulgaris EOs at 850, 1200 and 1100 ppm concentrations, respectively. The B. persicum EO had the lowest MIC for M. phaseolina as this fungus did not grow in the presence of M. piperita, B. persicum and T. vulgaris EOs at concentrations of 975, 950 and 1150 ppm, respectively. Hyphae exposed to EOs showed structural changes. Activities of cellulase and pectinase, as main CWDEs of pathogens, decreased by EOs at low concentration without effect on fungal growth. Seed treatment and foliar application of peppermint EO and/or menthol significantly reduced the development of bean diseases caused by both fungi. Higher capability of menthol than peppermint EO in decreasing diseases on bean was observed. CONCLUSIONS: Reducing CDWEs activity is a mechanism of EOs' effect on fungi. Higher antifungal activity of menthol compared to peppermint EO was observed not only in vitro but also in vivo. SIGNIFICANCE AND IMPACT OF THE STUDY: Effect of EOs on CWDEs involved in pathogenesis is described in this study for the first time. Menthol can be used as a botanical fungicide to control destructive fungal diseases on bean. PMID- 25523158 TI - Shape-controlled orientation and assembly of colloids with sharp edges in nematic liquid crystals. AB - The assembly of colloids in nematic liquid crystals via topological defects has been extensively studied for spherical particles, and investigations of other colloid shapes have revealed a wide array of new assembly behaviors. We show, using Landau-de Gennes numerical modeling, that nematic defect configurations and colloidal assembly can be strongly influenced by fine details of colloid shape, in particular the presence of sharp edges. For cylinder, microbullet, and cube colloid geometries, we obtain the particles' equilibrium alignment directions and effective pair interaction potentials as a function of simple shape parameters. We find that defects pin at sharp edges, and that the colloid consequently orients at an oblique angle relative to the far-field nematic director that depends on the colloid's shape. This shape-dependent alignment, which we confirm in experimental measurements, raises the possibility of selecting self-assembly outcomes for colloids in liquid crystals by tuning particle geometry. PMID- 25523156 TI - Time-domain microfluidic fluorescence lifetime flow cytometry for high-throughput Forster resonance energy transfer screening. AB - Sensing ion or ligand concentrations, physico-chemical conditions, and molecular dimerization or conformation change is possible by assays involving fluorescent lifetime imaging. The inherent low throughput of imaging impedes rigorous statistical data analysis on large cell numbers. We address this limitation by developing a fluorescence lifetime-measuring flow cytometer for fast fluorescence lifetime quantification in living or fixed cell populations. The instrument combines a time-correlated single photon counting epifluorescent microscope with microfluidics cell-handling system. The associated computer software performs burst integrated fluorescence lifetime analysis to assign fluorescence lifetime, intensity, and burst duration to each passing cell. The maximum safe throughput of the instrument reaches 3,000 particles per minute. Living cells expressing spectroscopic rulers of varying peptide lengths were distinguishable by Forster resonant energy transfer measured by donor fluorescence lifetime. An epidermal growth factor (EGF)-stimulation assay demonstrated the technique's capacity to selectively quantify EGF receptor phosphorylation in cells, which was impossible by measuring sensitized emission on a standard flow cytometer. Dual-color fluorescence lifetime detection and cell-specific chemical environment sensing were exemplified using di-4-ANEPPDHQ, a lipophilic environmentally sensitive dye that exhibits changes in its fluorescence lifetime as a function of membrane lipid order. To our knowledge, this instrument opens new applications in flow cytometry which were unavailable due to technological limitations of previously reported fluorescent lifetime flow cytometers. The presented technique is sensitive to lifetimes of most popular fluorophores in the 0.5-5 ns range including fluorescent proteins and is capable of detecting multi-exponential fluorescence lifetime decays. This instrument vastly enhances the throughput of experiments involving fluorescence lifetime measurements, thereby providing statistically significant quantitative data for analysis of large cell populations. (c) 2014 International Society for Advancement of Cytometry. PMID- 25523159 TI - A fluorescence-quenching platform based on biomineralized hydroxyapatite from natural seashell and applied to cancer cell detection. AB - As a typical biomineral, hydroxyapatite (HAp) is widely applied in bone implants and other related fields. However, the inherent nature of HAp can potentially be altered through restricting its fabrication conditions. Here, HAp fabricated by a hydrothermal treatment of pieces of natural seashell is demonstrated to have the capability of fluorescence quenching. To the best of the author's knowledge, this is the first time that this new property of HAp has been reported. Consequently, we assembled a fluorescence-quenching platform based on the biomineralized HAp substrate following a hydrothermal treatment and associated with a DNA molecular beacon and applied to cancer cell detection by the transformation from "OFF state" (fluorescence quenching) to "ON state" (fluorescence recovery). Herein, we found that the outer surface of HAp material after hydrothermal biomineralization for 5 days has considerable capability for both fluorescence quenching and recovery. These results may also have implications in the further detection of various targets such as cancer cells with other special surface antigens, significant biological small molecules or disease related microRNA, just by changing the sequence of the nucleic acid beacon according to the corresponding aptamer. PMID- 25523160 TI - [Health education through a pediatric mobile phone application]. PMID- 25523161 TI - [To be or not to be a reviewer of Revista de Calidad Asistencial]. PMID- 25523162 TI - [Primary care for diabetic patients: a quality improvement cycle]. AB - OBJECTIVE: The aim of this study was to evaluate and improve the quality of medical care provided to diabetic patients following the standards proposed by the American Diabetes Association. MATERIAL AND METHODS: The study was conducted in three phases by analyzing data from the computerized clinical history of a sample of 340 patients. First phase (2010): cross-sectional, descriptive study which assessed the proportion of patients who met the standards related to the screening of diabetes, and goals of control and treatment. Subsequently, health professionals reviewed the results in order to promote the implementation of corrective action. Finally (2012), a new assessment with the same standards was performed. RESULTS: An increase in the number of patients treated with insulin (12.7% in 2010 and 20.2% in 2012) was observed (P < .01). There were also percentage increases in the number of patients who met the screening standards as regards analytical determinations: glycosylated hemoglobin (from 44.4% to 68.2%), lipid profile (47.6%-73.8%), creatinine (32.5% - 73.5%), and albumin-creatinine ratio (9.2%-24.4%) (P < .001). Only 6.4% (CI: 3.2- 9.8) of diabetic patients attained the composite target of glycosylated hemoglobin < 7%, blood pressure < 130/80 mmHg and low-density lipoprotein cholesterol < 100 mg/dl in 2012. CONCLUSIONS: This study shows that medical care has improved the goals related to analytical determinations and the number of insulin-treated diabetic type 2 patients. An optimal level was also maintained in metabolic control of diabetes, but there was still poor control of risk factors for cardiovascular disease. PMID- 25523163 TI - [Caregiver burden and social support perceived by patients with chronic obstructive pulmonary disease]. AB - OBJECTIVES: To analyse the psycho-emotional state of the primary caregiver, the burden of the usual care in patients with exacerbations of COPD and perceived social support on the part of the patient. MATERIAL AND METHODS: The study included patients and caregivers who came for a specific visit to the COPD clinic of the Chest Diseases Department the Regional Hospital of Malaga. A total of 151 patients with severe/very severe COPD according to the functional classification of severity by Global Initiative for Chronic Obstructive Lung Disease (GOLD) and 96 caregivers were followed-up over a year. The Zarit burden scale (caregiver burden interview) was used, as well as the Duke-UNC questionnaire, validated in Spanish to determine the burden of the caregiver and the social support as perceived by the patient, respectively. The demographic variables recorded were, sex, age, population, cohabitation, relationship and work activity. RESULTS: The mean age of patients was 66.1 +/- 9 years versus their caregivers 60.2 +/- 11.5 years. All of the patients, of whom 88.1% were males, were occupationally inactive. The large majority (76.8%) were living with a caregiver, generally a wife or daughter. The social support was perceived as normal by 79.5%, and 19% perceived the social support as low. No burden or mild burden was reported by 79.2% with the Zarit questionnaire. CONCLUSIONS: The mean age of the patients, as well as their primary caregivers, was over 60 years of age. The score on perceived social support showed normal values, except for patients who live alone in rural areas. The Zarit questionnaire gave results of mild or no burden. There was no statistically significant correlation between the Zarit questionnaire and the patient health status, rural or urban area, relationship, or age of the caregiver. PMID- 25523164 TI - Sexual homicide in the USA committed by juveniles and adults, 1976-2007: Age of arrest and incidence trends over 32 years. AB - BACKGROUND: Reliable epidemiological data on sexual homicide are sparse, especially on trends in its incidence over time and age at arrest. AIMS: Our main aims were to study age at arrest and incidence trends for sexual homicide in the USA over about three decades (1976-2007). METHODS: We conducted longitudinal analyses of data from the largest USA homicide database available for the years 1976-2007. RESULTS: The mean age at arrest for a sexual homicide was 26.3 years (range 7-76; modal 21 years). Three quarters of these offenders were young adults aged 18-35. Age at probable first arrest for a sexual homicide rose significantly from a mean of 25 to a mean of 29 years over the study period. The last decade of the three studied accounted for just one quarter of the homicides as charged in the whole period, but the proportion of sexual homicides specifically fell with each decade, so that the first period accounted for 56% of those in the whole period, the second for 33% and the final decade for just 11%. This was reflected in a reduction in the proportion of all homicides that were sexual, from 1.4% in the first decade to 0.8% in the second and 0.4% in the third, declining by a factor of five for adults and seven for juveniles. CONCLUSIONS: Use of official national criminal statistics has limitations in studying the epidemiology of any particular behaviour. Nonetheless, our findings of falling sexual homicide rates and of changes in at least one important demographic of these killers indicate a need for a considered reappraisal of such crimes. Establishment of accurate epidemiology and a study of associated factors may assist in the improvement of investigative and preventive strategies. PMID- 25523165 TI - Role of T lymphocytes in hypertension. AB - Accumulating evidence indicates that the immune system plays a critical role in the pathogenesis of cardiovascular diseases including hypertension. Mice lacking T lymphocytes are resistant to blood pressure elevation, suggesting a key contribution of T lymphocytes to hypertension. However, the individual T cell subsets, including CD8(+), Th1, Th17, and T regulatory T cells have shown widely discrepant effects on blood pressure and target organ damage in this disorder. Moreover, the activation state of a T lymphocyte population exerts considerable influence over its role in hypertension. In turn, activated T cells regulate blood pressure through the elaboration of reactive oxygen species and vasoactive cytokines, altering the inflammatory milieu in the vascular wall and the kidney. Recent GWAS studies similarly point to a role for T lymphocytes in human hypertension. PMID- 25523166 TI - Intermittent self-dilatation for urethral stricture disease in males. AB - BACKGROUND: Intermittent urethral self-dilatation is sometimes recommended to reduce the risk of recurrent urethral stricture. There is no consensus as to whether it is a clinically effective or cost-effective intervention in the management of this disease. OBJECTIVES: The purpose of this review is to evaluate the clinical effectiveness and cost-effectiveness of intermittent self-dilatation after urethral stricture surgery in males compared to no intervention. We also compared different programmes of, and devices for, intermittent self-dilatation. . SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Register (searched 7 May 2014), CENTRAL (2014, Issue 4), MEDLINE (1 January 1946 to Week 3 April 2014), PREMEDLINE (covering 29 April 2014), EMBASE (1 January 1947 to Week 17 2014), CINAHL (31 December 1981 to 30 April 2014) OpenGrey (searched 6 May 2014), ClinicalTrials.gov (6 May 2014), WHO International Clinical Trials Registry Platform (6 May 2014), Current Controlled Trials (6 May 2014) and the reference lists of relevant articles. SELECTION CRITERIA: Randomised and quasi-randomised trials where one arm was a programme of intermittent self-dilatation for urethral stricture were identified. Studies were excluded if they were not randomised or quasi-randomised trials, or if they pertained to clean intermittent self-catheterisation for bladder emptying. DATA COLLECTION AND ANALYSIS: Two authors screened the records for relevance and methodological quality. Data extraction was performed according to predetermined criteria using data extraction forms. Analyses were carried out in Cochrane Review Manager (RevMan 5). The primary outcomes were patient-reported symptoms and health-related quality of life, and risk of recurrence; secondary outcomes were adverse events, acceptability of the intervention to patients and cost effectiveness. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Eleven trials were selected for inclusion in the review, including a total of 776 men. They were generally small; all were of poor quality and all were deemed to have high risk of bias. Performing intermittent self-dilatation versus not performing intermittent self-dilatation The data from six trials were heterogeneous, imprecise and had a high risk of bias, but indicated that recurrent urethral stricture was less likely in men who performed intermittent self-dilatation than men who did not perform intermittent self-dilatation (RR 0.70, 95% CI 0.48 to 1.00; very low quality evidence). Adverse events were generally poorly reported: two trials did not report adverse events and two trials reported adverse events only for the intervention group. Meta-analysis of the remaining two trials found no evidence of a difference between performing intermittent self-dilatation and not performing it (RR 0.60, 95% CI 0.11 to 3.26). No trials formally assessed acceptability, and no trials reported on patient-reported lower urinary tract symptoms, patient-reported health-related quality of life, or cost-effectiveness. One programme of intermittent self dilatation versus another We identified two trials that compared different durations of intermittent self-dilatation, but data were not combined. One study could not draw robust conclusions owing to cross-over, protocol deviation, administrative error, post-hoc analysis and incomplete outcome reporting. The other study found no evidence of a difference between intermittent self dilatation for six months versus for 12 months after optical urethrotomy (RR 0.67, 95% CI 0.12 to 3.64), although again the evidence is limited by the small sample size and risk of bias in the included study. Adverse events were reported narratively and were not stratified by group. No trials formally assessed acceptability, and no trials reported on patient-reported lower urinary tract symptoms, patient-reported health-related quality of life, or cost-effectiveness. One device for performing intermittent self-dilatation versus another Three trials compared one device for performing intermittent self-dilatation with another. Results from one trial at a high risk of bias were too uncertain to determine the effects of a low friction hydrophilic catheter and a standard polyvinyl chloride catheter on the risk of recurrent urethral stricture (RR 0.32, 95% CI 0.07 to 1.40). Similarly one study did not find evidence of a difference between one percent triamcinolone gel for lubricating the intermittent self dilatation catheter versus water-based gel on risk of recurrent urethral stricture (RR 0.68, 95% CI 0.35 to 1.32). Two trials reported adverse events, but one did not provide sufficient detail for analysis. The other small study reported fewer instances of prostatitis, urethral bleeding or bacteriuria with a low friction hydrophilic catheter compared with a standard polyvinyl chloride catheter (RR 0.13, 95% CI 0.02 to 0.98). 'Happiness with the intervention' was assessed using a non-validated scale in one study, but no trials formally assessed patient-reported health-related quality of life or acceptability. No trials reported on patient-reported lower urinary tract symptoms or cost effectiveness. GRADE quality assessment The evidence that intermittent self dilatation reduces the risk of recurrent urethral stricture after surgical intervention was downgraded to 'very low' on the basis that the studies comprising the meta-analysis were deemed to have high risk of bias, and the data was imprecise and inconsistent. Insufficient evidence No trials provided cost effectiveness data or used a validated patient-reported outcome measure, and adverse events were not reported rigorously. Acceptability of the intervention to patients has not been assessed quantitatively or qualitatively. AUTHORS' CONCLUSIONS: Performing intermittent self-dilatation may confer a reduced risk of recurrent urethral stricture after endoscopic treatment. We have very little confidence in the estimate of the effect owing to the very low quality of the evidence. Evidence for other comparisons and outcomes is limited. Further research is required to determine whether the apparent benefit is sufficient to make the intervention worthwhile, and in whom. PMID- 25523167 TI - Glabellar ecchymosis and headache: Variations of pain-associated ecchymosis. PMID- 25523169 TI - The story behind Bt cotton: where does Sudan stand? PMID- 25523170 TI - Marsh v Baxter: coexistence in Australia. PMID- 25523171 TI - Transgene flow: facts, speculations and possible countermeasures. AB - Convincing evidence has accumulated that unintended transgene escape occurs in oilseed rape, maize, cotton and creeping bentgrass. The escaped transgenes are found in variant cultivars, in wild type plants as well as in hybrids of sexually compatible species. The fact that in some cases stacked events are present that have not been planted commercially, implies unintended recombination of transgenic traits. As the consequences of this continuous transgene escape for the ecosystem cannot be reliably predicted, I propose to use more sophisticated approaches of gene technology in future. If possible GM plants should be constructed using either site-directed mutagenesis or cisgenic strategies to avoid the problem of transgene escape. In cases where a transgenic trait is needed, efficient containment should be the standard approach. Various strategies available or in development are discussed. Such a cautious approach in developing novel types of GM crops will enhance the sustainable potential of GM crops and thus increase the public trust in green gene technology. PMID- 25523172 TI - Research advances in major cereal crops for adaptation to abiotic stresses. AB - With devastating increase in population there is a great necessity to increase crop productivity of staple crops but the productivity is greatly affected by various abiotic stress factors such as drought, salinity. An attempt has been made a brief account on abiotic stress resistance of major cereal crops viz. In spite of good successes obtained on physiological and use molecular biology, the benefits of this high cost technology are beyond the reach of developing countries. This review discusses several morphological, anatomical, physiological, biochemical and molecular mechanisms of major cereal crops related to the adaptation of these crop to abiotic stress factors. It discusses the effect of abiotic stresses on physiological processes such as flowering, grain filling and maturation and plant metabolisms viz. photosynthesis, enzyme activity, mineral nutrition, and respiration. Though significant progress has been attained on the physiological, biochemical basis of resistance to abiotic stress factors, very little progress has been achieved to increase productivity under sustainable agriculture. Therefore, there is a great necessity of inter disciplinary research to address this issue and to evolve efficient technology and its transfer to the farmers' fields. PMID- 25523173 TI - Analysis of resistance to Cry1Ac in field-collected pink bollworm, Pectinophora gossypiella (Lepidoptera:Gelechiidae), populations. AB - High survivorship of pink bollworrm, Pectinophora gossypiella in bolls of Bollgard(r) cotton hybrids and resistance to Cry1Ac protein, expressed in Bollgard cotton were reported in field-populations collected from the state of Gujarat (western India) in 2010. We have found Cry1Ac-resistance in pink bollworm populations sourced from Bollgard and non-Bt cotton fields in the adjoining states of Maharashtra and Madhya Pradesh in Central India. Further, we observed reduced binding of labeled Cry1Ac protein to receptors localized on the brush border membrane of pink bollworm larval strains with high tolerance to Cry1Ac. These strains were sourced from Bollgard and conventional cotton fields. A pooled Cry1Ac-resistant strain, further selected on Cry1Ac diet also showed significantly reduced binding to Cry1Ac protein. The reduced binding of Cry1Ac to receptors could be an underlying mechanism for the observed resistance in pink bollworm populations feeding on Bollgard hybrids. PMID- 25523174 TI - The effect of flowering time and distance between pollen source and recipient on maize. AB - Field experiments were conducted in Central Taiwan for 2 crop seasons to examine the effect of non-coincidence flowering on the cross-pollination (CP) rate of maize at various distances. Four local maize hybrid varieties with different flowering dates and one local maize variety were sown as the pollen sources and recipient, respectively. All varieties were sown on the same day to simulate the real situation of coexistence in which adjacent fields are sown with different genetically modified (GM) and non-GM varieties of maize. The CP rate was <0.2% at a distance of 3 m for the first crop season when the flowering time for the recipient was 5 d later than that of the pollen source variety. The CP rate was <0.02% at all distances for the second season when the flowering time for the recipient was 7 d later than that of the pollen source variety. The CP rate was <1% at a distance of 0.75 m when the flowering time was 3 d later. However, varieties with closer synchrony may result in a CP rate of >1% at a distance of 1.5 m and <1% at 2.25 m. Temporal separation and isolation distances can work together in Taiwan with fragmented landscapes to minimize the adventitious presence of one crop with another. PMID- 25523168 TI - Body fluid biomarkers in multiple sclerosis: how far we have come and how they could affect the clinic now and in the future. AB - Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system, which affects over 2.5 million people worldwide. Although MS has been extensively studied, many challenges still remain in regards to treatment, diagnosis and prognosis. Typically, prognosis and individual responses to treatment are evaluated by clinical tests such as the expanded disability status scale, MRI and presence of oligoclonal bands in the cerebrospinal fluid. However, none of these measures correlates strongly with treatment efficacy or disease progression across heterogeneous patient populations and subtypes of MS. Numerous studies over the past decades have attempted to identify sensitive and specific biomarkers for diagnosis, prognosis and treatment efficacy of MS. The objective of this article is to review and discuss the current literature on body fluid biomarkers in MS, including research on potential biomarker candidates in the areas of miRNA, mRNA, lipids and proteins. PMID- 25523175 TI - High concentrations of protein test substances may have non-toxic effects on Daphnia magna: implications for regulatory study designs and ecological risk assessments for GM crops. AB - Laboratory testing for possible adverse effects of insecticidal proteins on non target organisms (NTOs) is an important part of many ecological risk assessments for regulatory decision-making about the cultivation of insect-resistant genetically modified (IRGM) crops. To increase confidence in the risk assessments, regulatory guidelines for effects testing specify that representative surrogate species for NTOs are exposed to concentrations of insecticidal proteins that are in excess of worst-case predicted exposures in the field. High concentrations in effects tests are achieved by using protein test substances produced in microbes, such as Escherichia coli. In a study that exposed Daphnia magna to a single high concentration of a microbial test substance containing Vip3Aa20, the insecticidal protein in MIR162 maize, small reductions in growth were observed. These effects were surprising as many other studies strongly suggest that the activity of Vip3Aa20 is limited to Lepidoptera. A plausible explanation for the effect on growth is that high concentrations of test substance have a non-toxic effect on Daphnia, perhaps by reducing its feeding rate. A follow-up study tested that hypothesis by exposing D. magna to several concentrations of Vip3Aa20, and a high concentration of a non-toxic protein, bovine serum albumin (BSA). Vip3Aa20 and BSA had sporadic effects on the reproduction and growth of D. magna. The pattern of the effects suggests that they result from non-toxic effects of high concentrations of protein, and not from toxicity. The implications of these results for regulatory NTO effects testing and ERA of IRGM crops are discussed. PMID- 25523177 TI - Weed control changes and genetically modified herbicide tolerant crops in the USA 1996-2012. AB - Crops that have been genetically modified (GM) to be tolerant to herbicides have been widely grown in the USA since 1996. The rapid and widespread adoption of this technology reflects the important economic and environmental benefits that farmers have derived from its use (equal to $21.7 billion additional farm income and a 225 million kg reduction in herbicide active ingredient use 1996-2012). During this time, weed control practices in these crops relative to the 'conventional alternative' have evolved to reflect experience of using the technology, the challenges that have arisen and the increasing focus in recent years on developing sustainable production systems. This paper examines the evidence on the changing nature of herbicides used with these crops and in particular how farmers addressed the challenge of weed resistance. The evidence shows that use of the technology has resulted in a net reduction in both the amount of herbicide used and the associated environmental impact, as measured by the EIQ indicator when compared to what can reasonably be expected if the area planted to GM HT crops reverted to conventional production methods. It also facilitated many farmers being able to derive the economic and environmental benefits associated with switching from a plough-based to a no tillage or conservation tillage production system. In terms of herbicide use, the technology has also contributed to a change the profile of herbicides used. A broad range of, mostly selective herbicides has been replaced by one or 2 broad-spectrum herbicides (mostly glyphosate) used in conjunction with one or 2 other (complementary) herbicides. Since the mid-2000s, the average amount of herbicide applied and the associated environmental load, as measured by the EIQ indicator, have increased on both GM HT and conventional crops. A primary reason for these changes has been increasing incidence of weed species developing populations resistant to herbicides and increased awareness of the consequences of relying on a single or very limited number of herbicides for weed control. As a result, growers of GM HT crops have become much more proactive and diversified in their weed management programs in line with weed scientist recommendations and now include other herbicides (with different and complementary modes of action) in combination with glyphosate, even where instances of weed resistance to glyphosate have not been found. The willingness to proactively diversity weed management systems in the GM HT crops is also influenced by a desire to maintain effective weed control and hence continue to enjoy the benefits of no tillage and conservation tillage. Nevertheless, despite the increase in herbicide use in recent years, the use of GM HT technology continues to deliver significant economic and environmental gains to US farmers. PMID- 25523178 TI - Statement of removal. PMID- 25523176 TI - A comprehensive transcriptome analysis of silique development and dehiscence in Arabidopsis and Brassica integrating genotypic, interspecies and developmental comparisons. AB - Asynchronous flowering of Brassica napus (canola) leads to seeds and siliques at varying stages of maturity as harvest approaches. This range of maturation can result in premature silique dehiscence (pod shattering), resulting in yield losses, which may be worsened by environmental stresses. Therefore, a goal for canola crop improvement is to reduce shattering in order to maximize yield. We performed a comprehensive transcriptome analysis on the dehiscence zone (DZ) and valve of Arabidopsis and Brassica siliques in shatter resistant and sensitive genotypes at several developmental stages. Among known Arabidopsis dehiscence genes, we confirmed that homologs of SHP1/2, FUL, ADPG1, NST1/3 and IND were associated with shattering in B. juncea and B. napus. We noted a correlation between reduced pectin degradation genes and shatter-resistance. Tension between lignified and non-lignified cells in the silique DZ plays a major role in dehiscence. Light microscopy revealed a smaller non-lignified separation layer in relatively shatter-resistant B. juncea relative to B. napus and this corresponded to increased expression of peroxidases involved in monolignol polymerization. Sustained repression of auxin biosynthesis, transport and signaling in B. juncea relative to B. napus may cause differences in dehiscence zone structure and cell wall constituents. Tension on the dehiscence zone is a consequence of shrinkage and loss of flexibility in the valves, which is caused by senescence and desiccation. Reduced shattering was generally associated with upregulation of ABA signaling and down-regulation of ethylene and jasmonate signaling, corresponding to more pronounced stress responses and reduced senescence and photosynthesis. Overall, we identified 124 cell wall related genes and 103 transcription factors potentially involved in silique dehiscence. PMID- 25523179 TI - A novel, layered phase in Ti-rich SrTiO3 epitaxial thin films. AB - Sr2Ti7O14, a new phase, is synthesized by leveraging the innate chemical and thermo-dynamic instabilities in the SrTiO3-TiO2 system and non-equilibrium growth techniques. The chemical composition, epitaxial relationships, and orientation play roles in the formation of this novel layered phase, which, in turn, possesses unusual charge ordering, anti-ferromagnetic ordering, and low, glass like thermal conductivity. PMID- 25523180 TI - Rat submandibular glands secrete nanovesicles with NTPDase and 5'-nucleotidase activities. AB - Extracellular nucleotides modulate a wide number of biological processes such as neurotransmission, platelet aggregation, muscle contraction, and epithelial secretion acting by the purinergic pathway. Nucleotidases as NTPDases and ecto-5' nucleotidase are membrane-anchored proteins that regulate extracellular nucleotide concentrations. In a previous work, we have partially characterized an NTPDase-like activity expressed by rat submandibular gland microsomes, giving rise to the hypothesis that membrane NTPDases could be released into salivary ducts to regulate luminal nucleotide concentrations as was previously proposed for ovarian, prostatic, and pancreatic secretions. Present results show that rat submandibular glands incubated in vitro release membrane-associated NTPDase and ecto-5'-nucleotidase activities. Electron microscopy images show that released membranes presenting nucleotidase activity correspond to exosome-like vesicles which are also present at microsomal fraction. Both exosome release and nucleotidase activities are raised by adrenergic stimulation. Nucleotidase activities present the same kinetic characteristics than microsomal nucleotidase activity, corresponding mainly to the action of NTPDase2 and NTPDase3 isoforms as well as 5'-nucleotidase. This is consistent with Western blot analysis revealing the presence of these enzymes in the microsomal fraction. PMID- 25523181 TI - Evaluation of the International Association of the Diabetes In Pregnancy Study Group new criteria: gestational diabetes project. AB - OBJECTIVE: To examine the diagnostic rates of gestational diabetes (GDM) and maternal/fetal outcomes before and after replacement of the Carpenter and Coustan (C&C) criteria with the International Association Diabetes Pregnancy Study Group (IADPSG) criteria. METHODS: A retrospective analysis of all pregnancies in 2 separate 6-month cohorts in the province of British Columbia. The first C&C cohort was defined as a 6-month period prior to the introduction of the IADPSG 75 g glucose tolerance test on October 1, 2010. The IADPSG cohort was studied during a 6-month period after the change. RESULTS: There was a significant increase in rates of GDM when using the IADPSG 75 g criteria, from 7.9% (1838 of 23 211) to 9.4% (2104 of 22 397). There were no significant changes in maternal outcomes when using the IADPSG criteria (caesarean section, induction of labour, perineal laceration, pregnancy-induced hypertension, antepartum hemorrhage >20 weeks or postpartum hospital length of stay). The caesarean section rate was not increased according to multivariate analysis (30.9% vs. 29.7%; p=0.073). There were no significant changes in most fetal outcomes when using the IADPSG criteria (mean gestational age at birth, premature birth, meconium, birth trauma, mean birth weight, large for gestational age, small for gestational age, intrauterine growth restriction), but neonatal hypoglycemia was significantly higher (1.6 % vs. 1.3 %; p=0.007). CONCLUSIONS: The rates of GDM were higher when using the new IADPSG criteria. Overall, all of the maternal and most of the fetal outcomes were similar. PMID- 25523182 TI - Effectiveness of angiotensin II receptor antagonists in a cohort of Dutch patients with type 2 diabetes mellitus (ZODIAC-14). AB - OBJECTIVE: There is limited evidence with respect to the between-group effects of various angiotensin receptor blockers (ARBs) on blood pressure and albuminuria in patients with type 2 diabetes mellitus. Therefore, we aimed to investigate the effects of differing ARBs on systolic blood pressure (SBP) and the albumin creatinine ratio after 1 year in a large cohort of patients with type 2 diabetes mellitus. METHODS: In 2007, 24 940 primary care patients with type 2 diabetes mellitus participated in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study, a prospective observational cohort study. Patients were included in the current study if they were prescribed an ARB in 2007 and if 1-year follow-up data were available. The final study population comprised 3610 patients. Multivariate mixed-model analyses were performed to estimate effects of the various ARBs on SBP and albuminuria. Stratified subgroup analyses were performed according to baseline hypertension and albuminuria. RESULTS: SBP decreased in all groups, the largest decrease being observed in the group receiving telmisartan. No significant or relevant changes over time were observed among groups for SBP and albuminuria. In the subgroup (n=1225) of normotensive patients, telmisartan was associated with a larger decrease in SBP after 1 year compared to other ARBs, without different effects on the albumin-creatinine ratio. CONCLUSIONS: We observed no differences in effects on SBP and the albumin creatinine ratio among differing ARBs in patients with type 2 diabetes mellitus. PMID- 25523183 TI - Donor cell-derived acute promyelocytic leukemia after allogeneic hematopoietic stem cell transplant. PMID- 25523184 TI - SARA: a "new" low-frequency MNS antigen (MNS47) provides further evidence of the extreme diversity of the MNS blood group system. AB - BACKGROUND: Until recently, SARAH (SARA) was a low-frequency antigen within the 700 series (700.052). SARA was discovered in Australia and subsequently described in Canada where anti-SARA was implicated in severe hemolytic disease of the fetus and newborn (HDFN). This study investigated whether SARA could be recategorized into an existing, or novel, blood group system. STUDY DESIGN AND METHODS: Serologically typed Australian SARA family members (n = 9) were exome sequenced followed by bioinformatics analysis. Sanger sequencing of Exon 3 of GYPA of Australian (n = 9) and Canadian (n = 9) family members was then performed, as were peptide inhibition studies. RESULTS: Exome sequencing identified 499,329 single-nucleotide variants (SNVs) within the nine individuals. Filtering excluded SNVs with an NCBI dbSNP ID (n = 482,177) and non-protein coding SNVs (n = 14,008); for the remaining 3144 SNVs, only one, c.240G>T of GYPA encoding p.Arg80Ser, was present in all six SARA-positive individuals. Sanger sequencing confirmed the presence of c.240G>T in the Australian SARA-positive individuals and demonstrated the same genetic basis in the Canadian SARA family. For a peptide representing the SARA sequence, inhibition of anti-SARA against SARA positive cells was 84.6% at a concentration of 1.0 mg/mL. CONCLUSION: We provide evidence that the SARA antigen is encoded by a SNV on GYPA and SARA has been reassigned to the MNS blood group system, now MNS47. This discovery provides a basis for application of genetic approaches in SARA typing when clinically indicated, for example, in HDFN. PMID- 25523185 TI - HBV DNA level could predict significant liver fibrosis in HBeAg negative chronic hepatitis B patients with biopsy indication. AB - BACKGROUND: Non-invasive models and methods to substitute liver biopsy in chronic hepatitis B (CHB) patients were investigated but their roles as predictors of significant liver histology for diagnosis of HBeAg-negative CHB patients who had indication for liver biopsy according to The American Association for the Study of Liver Diseases (AASLD) and The Asian Pacific Association for the Study of the Liver (APASL) guidelines are still unknown. This study was designed to identify predictors of significant liver necroinflammation as defined by a Histology Activity Index of necroinflammatory score >= 4 or Metavir necroinflammatory activity score >= 2 and significant liver fibrosis as defined by a Metavir fibrosis score >= 2 in HBeAg-negative CHB patients that had a hepatitis B virus (HBV) DNA level >= 2,000 IU/ml and age >= 40 years or elevated alanine aminotransferase level between 1-2 times the upper limit of normal. METHODS: Twenty-two patients were prospectively included and performed liver biopsies. Clinical and laboratory parameters including age, gender, underlying disease, family history of cirrhosis or hepatocellular carcinoma, body mass index (BMI), HBV DNA level, HBsAg level, liver function test, complete blood count, aspartate aminotransferase-to-platelet ratio index and transient elastography were collected and analyzed with liver histology profiles. RESULTS: Five patients (23%) had significant liver inflammation and 7 patients (32%) had significant liver fibrosis. Factors associated with significant liver inflammation were a lower BMI and higher alkaline phosphatase level while a factor associated with significant liver fibrosis was lower age. On multivariate analysis, only HBV DNA level > 5.5 log IU/ml could predict significant liver fibrosis (odds ratio 28.012, 95% CI, 1.631-481.240, p = 0.022) and its sensitivity, specificity, positive predictive value and negative predictive value were 71.4%, 93.3%, 83.3% and 87.5% respectively. CONCLUSIONS: An HBV DNA level of > 5.5 log IU/ml was able to predict significant liver fibrosis for treatment of HBeAg-negative CHB patients that had indication for liver biopsy as recommended by AASLD and APASL guidelines. PMID- 25523186 TI - Changes in Caco-2 cells transcriptome profiles upon exposure to gold nanoparticles. AB - Higher efficacy and safety of nano gold therapeutics require examination of cellular responses to gold nanoparticles (AuNPs). In this work we compared cellular uptake, cytotoxicity and RNA expression patterns induced in Caco-2 cells exposed to AuNP (5 and 30nm). Cellular internalization was dose and time dependent for both AuNPs. The toxicity was observed by colony forming efficiency (CFE) and not by Trypan blue assay, and exclusively for 5nm AuNPs, starting at the concentration of 200MUM (24 and 72h of exposure). The most pronounced changes in gene expression (Agilent microarrays) were detected at 72h (300MUM) of exposure to AuNPs (5nm). The biological processes affected by smaller AuNPs were: RNA/zinc ion/transition metal ion binding (decreased), cadmium/copper ion binding and glutathione metabolism (increased). Some Nrf2 responsive genes (several metallothioneins, HMOX, G6PD, OSGIN1 and GPX2) were highly up regulated. Members of the selenoproteins were also differentially expressed. Our findings indicate that exposure to high concentration of AuNPs (5nm) induces metal exposure, oxidative stress signaling pathways, and might influence selenium homeostasis. Some of detected cellular responses might be explored as potential enhancers of anti-cancer properties of AuNPs based nanomedicines. PMID- 25523187 TI - Review article: breath analysis in inflammatory bowel diseases. AB - BACKGROUND: There is an urgent need for cheap, reproducible, easy to perform and specific biomarkers for diagnosis, differentiation and stratification of inflammatory bowel disease (IBD) patients. Technical advances allow for the determination of volatile organic compounds in the human breath to differentiate between health and disease. AIM: Review and discuss medical literature on volatile organic compounds in exhaled human breath in GI disorders, focusing on diagnosis and differentiation of IBD. METHODS: A systematic search in PubMed, Ovid Medline and Scopus was completed using appropriate keywords. In addition, a bibliography search of each article was performed. RESULTS: Mean breath pentane, ethane, propane, 1-octene, 3-methylhexane, 1-decene and NO levels were elevated (P < 0.05 to P < 10(-7)) and mean breath 1-nonene, (E)-2-nonene, hydrogen sulphide and methane were decreased in IBD compared to healthy controls (P = 0.003 to P < 0.001). A combined panel of 3 volatile organic compounds (octene, (E)-2-nonene and decene) showed the best discrimination between paediatric IBD and controls (AUC 0.96). Breath condensate cytokines were higher in IBD compared to healthy individuals (P < 0.008). Breath pentane, ethane, propane, isoprene and NO levels correlated with disease activity in IBD patients. Breath condensate interleukin-1beta showed an inverse relation with clinical disease activity. CONCLUSIONS: Breath analysis in IBD is a promising approach that is not yet ready for routine clinical use, but data from other gastrointestinal diseases suggest the feasibility for use of this technology in clinical practice. Well-designed future trials, incorporating the latest breath detection techniques, need to determine the exact breath metabolome pattern linked to diagnosis and phenotype of IBD. PMID- 25523188 TI - How many times should we screen a chemical library to discover an anticancer drug? PMID- 25523189 TI - Intraspecific variability in associative learning in the parasitic wasp Nasonia vitripennis. AB - The ability to learn is key to behavioral adaptation to changing environments. Yet, learning rate and memory retention can vary greatly across or even within species. While interspecific differences have been attributed to ecological context or life history constraints, intraspecific variability in learning behavior is rarely studied and more often, ignored: inferences of the cognitive abilities of a species are most of the time made from experiments using individuals of a single population. Here, we show that learning of host associated cues in the parasitic wasp Nasonia vitripennis (Walker) (Hymenoptera: Pteromalidae) shows considerable interpopulation variability, which is at least partly, genetically determined. The strengths of the learning response differed predictably between populations and also varied with the rewarding stimulus. We tested memory retention in a genetically diverse strain and in an iso-female line, bearing a low genetic variability. In addition, we compared our findings with published studies on a third strain using a meta-analytical approach. Our findings suggest that all three strains differ in memory formation from each other. We conclude that, even though the associative learning of host cues is most likely under strong natural selection in parasitoid wasps, considerable genetic variability is maintained at the population as well as at the species level in N. vitripennis. PMID- 25523190 TI - Randomised controlled trial of daily versus stoss vitamin D therapy in Aboriginal children. AB - AIM: The prevalence of vitamin D deficiency has risen in countries with a high ultraviolet index and sunny environment such as Australia. There is lack of information on vitamin D status and best possible therapy in Australian Aboriginal children. We aim to (i) describe the vitamin D status in an opportunistic sample of Aboriginal children in Western Australia and (ii) compare the efficacy of oral daily vitamin D with oral stoss vitamin D therapy in this sample. METHOD: Participants were recruited from a metropolitan area (31' S) and a rural area (17' S). Those with a 25(OH)D level less than 78 nmol/L were randomised to receive daily or stoss vitamin D therapy with follow-up at 4-6 months and 9-12 months. Biochemical and clinical parameters such as 25(OH)D, alkaline phosphatase, calcium and sun exposure were collected. RESULTS: Seventy three participants were enrolled (61 from a metropolitan and 12 from a rural area). 25(OH)D levels were greater than 78 nmol/L in 9/12 (75%) participants in the rural group and 21/61 (34%) in the metropolitan group. 25(OH)D levels were less than 78 nmol/L in 43/73 (59%) participants. Of these, 34/43 (79%) were insufficient (50-78 nmol/L), 8/43 (19%) mildly deficient (27.5-50 nmol/L) and 1/43 (2%) deficient (<27.5 nmol/L). Daily vitamin D therapy had a higher average increase in 25(OH)D levels from baseline than stoss therapy; however, this was not significant. CONCLUSION: Vitamin D insufficiency is common in Aboriginal children of Western Australia and stoss therapy is a safe alternative to daily vitamin D therapy but requires further evaluation of timing and doses. PMID- 25523191 TI - The abnormal reaction data-detecting function of the automated biochemical analyzer was useful to prevent erroneous total-bilirubin measurement and to identify monoclonal proteins. AB - BACKGROUND: Recently, to detect abnormal reactions and failures of the device in biological analysis, a reaction data monitoring system has been provided for automated biochemical analyzers. We investigated the usefulness of this function for total-bilirubin (T-Bil) measurement in routine testing. METHODS: Abnormal reactions of T-Bil were detected in the reaction data over time based on the following items: whether the absorbance variance after mixing of the first reagent and sample exceeds the cut-off value. RESULTS: In the cases in which the abnormal reaction was observed, the absorbance rapidly rose because of turbidity after mixing the sample with Reagent-1. The measured value was higher than the actual T-Bil level, for which the analyzer showed a warning mark with the output data. When this particular serum sample was subjected to immunofixation electrophoresis, the presence of a monoclonal protein was confirmed. We encountered seven similar cases out of 30,731 samples. CONCLUSIONS: The reaction data monitoring system of the automated biochemical analyzers was useful to prevent false reports (misdiagnosis) due to unpredictable problems during T-Bil measurement. It was also suggested that detection of false reaction with a reagent may be a clue to find a new pathology, such as monoclonal gammopathy. PMID- 25523192 TI - Novel LC-MS/MS method for plasma vancomycin: comparison with immunoassays and clinical impact. AB - BACKGROUND: Accurate quantification of vancomycin in plasma is important for adequate dose-adjustment. As literature suggests between-method differences, our first objective was to develop a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for total vancomycin in human plasma and to compare frequently used immunoassays with this method. Secondly, we investigated the clinical impact of between-method quantification differences. METHODS: For LC MS/MS, lithium heparin plasma was extracted by adding a precipitation reagent containing the internal standard (vancomycin-des-leucine). Analysis was performed on an Acquity TQD mass spectrometer equipped with an Acquity UPLC 2795 separations module. Our method was analytically validated and compared with four frequently used immunoassays from four different manufacturers. Vancomycin concentrations were clinically classified as toxic, therapeutic and sub therapeutic. Clinical discordance was calculated using LC-MS/MS as a reference. RESULTS: A novel LC-MS/MS method using protein precipitation as sole pretreatment and an analysis time of 5.0 min was developed. The assay had a total imprecision of 2.6-8.5%, a limit of quantification of 0.3 mg/L and an accuracy ranging from 101.4 to 111.2%. Using LC-MS/MS as reference, three immunoassays showed a mean proportional difference within 10% and one showed a substantial mean proportional difference of >20%. Clinical discordant interpretation of the obtained concentrations ranged from 6.1 to 22.2%. CONCLUSIONS: We developed a novel LC MS/MS method for rapid analysis of total vancomycin concentrations in human plasma. Correlation of the method with immunoassays showed a mean proportional difference >20% for one of the assays, causing discordant clinical interpretation in more than 1 out of 5 samples. PMID- 25523193 TI - A validation study: assessing the reliability of the hand held StatStripXPress lactate meter to test lactate in amniotic fluid. AB - BACKGROUND: The level of lactate in amniotic fluid may provide useful clinical information when assessing whether a woman in labour is experiencing labour dystocia. If so, a rapid, reliable method to assess the concentration of amniotic fluid lactate at the bedside will be required in order to be clinically relevant. To assess efficacy, we compared the hand held StatStripXPreass lactate meter (Nova Biomedical) to the reference laboratory analyser ABX Pentra 400 (Horiba) in a controlled environment. Baseline biological lactate concentration was measured in triplicate and samples of a known quantity of thawed amniotic fluid spiked with lactate substrate (62 mmol/L) from the LDH12 kit (Roche, SUI) to yield a predetermined lactate concentration above baseline then measured in triplicate. Deming Regression was used to determine the linear agreement and a Bland Altman plot used to determine the paired agreement across the range of values. FINDINGS: The mean difference with Bland-Altman plot between hand held meter and lab instrument was -1.0 mmol/L (SD 3.0 mmol/L) with 95% CI limits of agreement between -6.9 mmol/L to 4.9 mmol/L. The Deming regression co-efficient or slope of agreement was 0.91 (SD of 0.21). CONCLUSION: The measurement of amniotic fluid lactate using the StatStripXPress hand held meter was reliable compared to reference laboratory methods for measuring lactate levels in amniotic fluid. PMID- 25523194 TI - The role of hepatic immune regulation in systemic immunity to viral infection. AB - The liver has particular immune functions attributed by its unique microenvironment and its liver-resident cell populations. During autoimmunity and viral hepatitis, the liver serves as target for effector responses of immune cells. However, skewing of effector T cell functions through tolerogenic liver resident antigen-presenting cells and through the immune regulatory hepatic microenvironment. Importantly, the liver also participates in shaping systemic antigen-specific immunity. Local antigen-presenting cell populations, in particular liver sinusoidal endothelial cells (LSECs), cross-present soluble, circulating or hepatocyte-derived antigens to naive CD8 T cells. Upon priming by cross-presenting LSECs, naive CD8 T cells develop into a unique population of antigen-experienced memory-like T cell population that can be reactivated in an inflammatory context to protect against infection with viruses or bacteria. Furthermore, upon prolonged inflammatory TNF-dependent signaling, the induction of intrahepatic myeloid cell aggregates for T cell population expansion (iMATEs) is observed in liver tissue. iMATEs are formed by inflammatory monocytes developing into dendritic cells and function to attract recently activated CD8 T cells. Those CD8 T cells located within the cocoon-like iMATE structure show strong proliferation initiated by co-stimulatory signaling. Locally expanded CD8 T cells are key to control acute and chronic viral infections. The mechanistic understanding of local hepatic T cell priming and local expansion of effector CD8 T cells will help to develop novel therapeutic vaccination strategies. PMID- 25523196 TI - Old and new adjuvants for hepatitis B vaccines. AB - The safety and immunogenicity profiles of currently available recombinant hepatitis B vaccines are excellent. However, it remains a real challenge to induce protective immunity in the target groups that respond poorly or not at all to conventional vaccines. Ideally, a hepatitis B vaccine can be developed that conveys lifelong protection against infection rapidly after the injection of a single dose. Although this goal is far from being reached, important improvements have been made. Novel vaccine adjuvants have been developed that enhance the immunogenicity of recombinant hepatitis B vaccines while maintaining a good safety profile. The different adjuvants and adjuvant systems that are discussed herein have all been thoroughly evaluated in clinical trials and some have reached or are close to reach the market. PMID- 25523197 TI - Mouse models for therapeutic vaccination against hepatitis B virus. AB - A mouse model for persistent HBV infection is essential for the development of a therapeutic vaccine against HBV. Because HBV cannot infect mouse hepatocytes, even if the HBV receptor is introduced, surrogate models are used. A suitable model needs to establish persistent HBV replication and must allow the establishment of HBV-specific adaptive cellular and humoral immune responses. Therefore, an immunocompetent mouse model is needed in which one can break HBV specific tolerance and ideally eliminate the HBV transcription template. The most widely used model for chronic HBV infection is the HBV transgenic mouse. Although HBV replicates from an integrated transgene, HBV-specific immune tolerance can be broken upon adequate immune stimulation because antigen expression only starts shortly before birth. Alternative mouse models of chronic HBV infection are generated by introducing HBV genomes either using viral vectors or using hydrodynamic injection. In these alternative models, the HBV transcription template is introduced into a proportion of hepatocytes and stays extra chromosomal. It thus mimics the natural HBV transcription template, the HBV cccDNA in humans. Unlike an HBV transgene, however, it can be cleared upon appropriate treatment or immune stimulation. Human hepatocyte chimeric mice in which murine hepatocytes are widely replaced by human hepatocytes represent another important mouse model for persistent HBV infection. These mice are susceptible for HBV infection, but need to be severely immune deficient to accept human hepatocytes. In conclusion, a variety of mouse models for persistent HBV infection are available suitable for preclinical efficacy evaluations of therapeutic vaccination strategies against HBV. PMID- 25523198 TI - Median arcuate ligament syndrome. PMID- 25523195 TI - Prophylactic vaccination against hepatitis B: achievements, challenges and perspectives. AB - Large-scale vaccination against hepatitis B virus (HBV) infection started in 1984 with first-generation vaccines made from plasma of chronic carriers containing HBV surface antigen (HBsAg). Thereafter, it was replaced in most countries by second-generation vaccines manufactured in yeast cells transformed with gene S encoding HBsAg. Both generations of vaccines have been applied for universal neonate and early childhood vaccination worldwide and have led to a 70-90 % decrease in chronic HBV carrier rates. However, 10-30% of newborns from HBsAg/HBeAg-positive mothers cannot be protected by passive/active vaccination alone and become chronic HBV carriers themselves. Asymptomatic occult HBV infections are frequent even in those who have protective levels of anti-HBs. Suboptimal protection may be due to heterologous HBsAg subtypes that are present in 99% of HBV carriers worldwide. Second-generation vaccines contain partially misfolded HBsAg and lack preS1 antigen that carries the major HBV attachment site and neutralizing epitopes. Third-generation vaccines produced in mammalian cells contain correctly folded HBsAg and neutralizing epitopes of the preS antigens, induce more rapid protection, overcome nonresponse to second-generation vaccines and, most importantly, may provide better protection for newborns of HBV-positive mothers. PreS/S vaccines expressed in mammalian cells are more expensive to manufacture, but introduction of more potent HBV vaccines should be considered in regions with a high rate of vertical transmission pending assessment of health economics and healthcare priorities. With optimal vaccines and vaccination coverage, eradication of HBV would be possible. PMID- 25523199 TI - Differential factors associated with challenge-proven food allergy phenotypes in a population cohort of infants: a latent class analysis. AB - BACKGROUND: Food allergy, eczema and wheeze are early manifestations of allergic disease and commonly co-occur in infancy although their interrelationship is not well understood. Data from population studies are essential to determine whether there are differential drivers of multi-allergy phenotypes. We aimed to define phenotypes and risk factors of allergic disease using latent class analysis (LCA). METHODS: The HealthNuts study is a prospective, population-based cohort of 5276 12-month-old infants in Melbourne, Australia. LCA was performed using the following baseline data collected at age 12 months: food sensitization (skin prick test >= 2 mm) and allergy (oral food challenge) to egg, peanut and sesame; early (< 4 months) and late-onset eczema; and wheeze in the first year of life. Risk factors were modelled using multinomial logistic regression. RESULTS: Five distinct phenotypes were identified: no allergic disease (70%), non-food sensitized eczema (16%), single egg allergy (9%), multiple food allergies (predominantly peanut) (3%) and multiple food allergies (predominantly egg) (2%). Compared to the baseline group of no allergic disease, shared risk factors for all allergic phenotypes were parents born overseas (particularly Asia), delayed introduction of egg, male gender (except for single egg allergy) and family history of allergic disease, whilst exposure to pet dogs was protective for all phenotypes. Other factors including filaggrin mutations, vitamin D and the presence of older siblings differed by phenotype. CONCLUSIONS AND CLINICAL RELEVANCE: Multiple outcomes in infancy can be used to determine five distinct allergy phenotypes at the population level, which have both shared and separate risk factors suggesting differential mechanisms of disease. PMID- 25523200 TI - MPV may reflect subcinical platelet activation in diabetic patients with and without diabetic retinopathy. AB - PURPOSE: To search subclinical platelet activation via detecting three important platelet activation parameters; mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) in diabetic retinopathy (DR) in comparison with those in healthy adults as controls. METHODS: This prospective study included 140 patients who were followed-up at the Ankara Ulucanlar Eye Education and Research Hospital, and 40 normal subjects. All patients and control subjects underwent complete ophthalmologic evaluation. Of patients with type 2 diabetes, 43 cases with diabetes mellitus (DM) have no DR (Group 1), 45 cases with DM have nonproliferative DR (NPDR) (Group 2), and 52 cases with DM have proliferative DR (PDR) (Group 3). In addition, 40 age- and sex-matched healthy controls (Group 4) were included into the study. MPV, PDW, and PCT were measured in the studied groups. RESULTS: The MPV levels were significantly altered in Group 1, Group 2, and Group 3 patients when compared with those in the controls (P<0.05), whereas PDW and PCT levels were not significantly changed among groups (P>0.05). CONCLUSION: The data provided a significant association between MPV levels and DM. Diabetic patients have increased MPV values compared with healthy subjects, but MPV levels were not altered together with the DR stage. Diabetic and DR patients have no different PDW and PCT values compared with healthy subjects. MPV may be a clue for the reflection of subclinical platelet activation in DM regardless of the DR stage. PMID- 25523201 TI - Effects of intravitreal injection of bevacizumab on nitric oxide levels. AB - PURPOSE: This study aimed to determine the possible effects of single-dose intravitreal bevacizumab on nitric oxide (NO) levels in serum and remote organs and to reveal one of the possible mechanisms in the pathophysiology of hypertension. METHODS: Thirty-eight adult New Zealand albino rabbits were divided into a control group (no injection was performed, killed on day 28 of the study), group 1 (killed on day 1 of the study), group 2 (killed on day 7 of the study), group 3 (killed on day 14 of the study), and group 4 (killed on day 28 of the study). The right eyes of the animals in groups 1-4 received an intravitreal single injection of 1.25 mg (0.05 ml) bevacizumab (Avastin), and their brain, heart, liver, kidney, and blood samples were collected. NO levels were evaluated in the serum and organ homogenates. Kidney tissues were assessed by electron microscopy. RESULTS: Serum, brain, kidney, and liver NO levels significantly decreased in groups 2, 3, and 4 as compared with the control group (P<0.05). In addition, heart NO levels significantly decreased in groups 3 and 4 compared with the control group (P<0.05). There were no electron microscopic changes in the kidneys of either group. CONCLUSIONS: This study demonstrated that single intravitreal injection of bevacizumab decreased NO levels in serum, brain, heart, liver, and kidneys. In addition, there were no electron microscopic changes in the kidneys. PMID- 25523202 TI - A different approach for manual foldable IOL injection for keeping wound size and integrity. PMID- 25523203 TI - Response to: 'A different approach for manual foldable IOL injection for keeping wound size and integrity'. PMID- 25523204 TI - Management of strabismus in thyroid eye disease. AB - Thyroid eye disease is an auto-immune condition characterised by an acute inflammatory phase followed by a fibrotic phase, which sometimes leads to restricted eye movements and diplopia. Medical treatment with systemic steroids with or without orbital radiotherapy and immunosuppression can control the inflammatory response. Strabismus surgery should be carried out only after the inflammation is no longer active and after any decompression surgery. Surgery comprises recession of tight muscles using adjustable sutures so as to maximise the area of binocular single vision. There is debate as to whether adjustable sutures should be used for the inferior rectus muscle. Patients should be encouraged to have realistic expectations, as binocular single vision may not be achievable in all directions of gaze and lid retraction may be made worse by surgery. PMID- 25523205 TI - In vivo biocompatibility of a new cyanine dye for ILM peeling. AB - PURPOSE: To investigate the biocompatibility of the new cyanine dye: 3,3'-Di-(4 sulfobutyl)-1,1,1',1'-tetramethyl-di-1H-benz[e]indocarbocyanine (DSS) as a vital dye for intraocular application in an in vivo rat model and to evaluate the effects of this dye on retinal structure and function. METHODS: DSS at a concentration of 0.5% was applied via intravitreal injections to adult Brown Norway rats with BSS serving as a control. Retinal toxicity was assessed 7 days later by means of retinal ganglion cell (RGC) counts, light microscopy, optical coherence tomography (OCT), and electroretinography (ERG). RESULTS: No significant decrease in RGC numbers was observed. No structural changes of the central retina were observed either in vivo (OCT) or under light microscopy. ERGs detected a temporary reduction of retinal function 7 days after injection; this was no longer evident 14 days after injection. CONCLUSIONS: DSS showed good biocompatibility in a well-established experimental in vivo setting and may be usable for intraocular surgery as an alternative to other cyanine dyes. In contrast to indocyanine green, it additionally offers fluorescence in the visual spectrum. Further studies with other animal models are needed before translation into clinical application. PMID- 25523206 TI - Viable influenza A virus in airborne particles from human coughs. AB - Patients with influenza release aerosol particles containing the virus into their environment. However, the importance of airborne transmission in the spread of influenza is unclear, in part because of a lack of information about the infectivity of the airborne virus. The purpose of this study was to determine the amount of viable influenza A virus that was expelled by patients in aerosol particles while coughing. Sixty-four symptomatic adult volunteer outpatients were asked to cough 6 times into a cough aerosol collection system. Seventeen of these participants tested positive for influenza A virus by viral plaque assay (VPA) with confirmation by viral replication assay (VRA). Viable influenza A virus was detected in the cough aerosol particles from 7 of these 17 test subjects (41%). Viable influenza A virus was found in the smallest particle size fraction (0.3 MUm to 8 MUm), with a mean of 142 plaque-forming units (SD 215) expelled during the 6 coughs in particles of this size. These results suggest that a significant proportion of patients with influenza A release small airborne particles containing viable virus into the environment. Although the amounts of influenza A detected in cough aerosol particles during our experiments were relatively low, larger quantities could be expelled by influenza patients during a pandemic when illnesses would be more severe. Our findings support the idea that airborne infectious particles could play an important role in the spread of influenza. PMID- 25523207 TI - The structure and ultrastructure of the egg capsule of Brachyptera risi (Plecoptera, Nemouroidea, Taeniopterygidae) with some remarks concerning choriogenesis. AB - The organization of the egg capsule of the euholognathan stonefly, which represents the family Taeniopterygidae (Nemuroidea) was investigated using light and electron microscopy techniques. The presence of a complex, multilayered egg capsule, composed of a vitelline envelope, multilayered chorion, and extrachorion is described. The morphology of the eggshell of Brachyptera risi was compared with that of euholognthan and systellognathan egg coverings and the ground plan of the egg capsule in Plecoptera was discussed. PMID- 25523209 TI - Diabetes mellitus and cognitive functioning in a Serbian sample. AB - INTRODUCTION: Diabetes is associated with cognitive impairments, particularly in executive functioning and memory. AIM: The aim was to describe cognitive functioning in Type 1 (T1DM) and Type 2 (T2DM) diabetes compared to healthy controls in a Serbian sample. METHOD: We studied 15 patients with adult onset T1DM (age range 19-60 years), 37 patients with T2DM (age range 50-77 years), and 32 healthy controls (28-78 years). All participants underwent comprehensive neuropsychological assessment. RESULTS: T2DM subjects exhibited poorer performance than healthy controls in global cognitive performance, as well as verbal learning and memory. After correcting for multiple comparisons, follow-up examination of individual tests showed significantly poorer performance only on Trail Making Test Part B (TMT-B). Effect sizes for T2DM versus healthy controls ranged from medium to large for several cognitive variables, while comparisons between T1DM and the other two groups tended to yield much smaller effects. CONCLUSION: T2DM is associated with poorer cognition, particularly in executive functions, learning/memory, and global cognition. Lack of group differences may be due to use of an adult onset T1DM sample, relatively young age of our T2DM sample, or characteristics of healthy control subjects in our Serbian sample. PMID- 25523208 TI - A gene-by-gene population genomics platform: de novo assembly, annotation and genealogical analysis of 108 representative Neisseria meningitidis genomes. AB - BACKGROUND: Highly parallel, 'second generation' sequencing technologies have rapidly expanded the number of bacterial whole genome sequences available for study, permitting the emergence of the discipline of population genomics. Most of these data are publically available as unassembled short-read sequence files that require extensive processing before they can be used for analysis. The provision of data in a uniform format, which can be easily assessed for quality, linked to provenance and phenotype and used for analysis, is therefore necessary. RESULTS: The performance of de novo short-read assembly followed by automatic annotation using the pubMLST.org Neisseria database was assessed and evaluated for 108 diverse, representative, and well-characterised Neisseria meningitidis isolates. High-quality sequences were obtained for >99% of known meningococcal genes among the de novo assembled genomes and four resequenced genomes and less than 1% of reassembled genes had sequence discrepancies or misassembled sequences. A core genome of 1600 loci, present in at least 95% of the population, was determined using the Genome Comparator tool. Genealogical relationships compatible with, but at a higher resolution than, those identified by multilocus sequence typing were obtained with core genome comparisons and ribosomal protein gene analysis which revealed a genomic structure for a number of previously described phenotypes. This unified system for cataloguing Neisseria genetic variation in the genome was implemented and used for multiple analyses and the data are publically available in the PubMLST Neisseria database. CONCLUSIONS: The de novo assembly, combined with automated gene-by-gene annotation, generates high quality draft genomes in which the majority of protein-encoding genes are present with high accuracy. The approach catalogues diversity efficiently, permits analyses of a single genome or multiple genome comparisons, and is a practical approach to interpreting WGS data for large bacterial population samples. The method generates novel insights into the biology of the meningococcus and improves our understanding of the whole population structure, not just disease causing lineages. PMID- 25523210 TI - Comparison of systematic transrectal biopsy to transperineal magnetic resonance imaging/ultrasound-fusion biopsy for the diagnosis of prostate cancer. AB - OBJECTIVES: To compare targeted, transperineal magnetic resonance imaging (MRI)/ultrasound (US)-fusion biopsy to systematic transrectal biopsy in patients with previous negative or first prostate biopsy and to evaluate the gain in diagnostic information with systematic biopsies in addition to targeted MRI/US fusion biopsies. PATIENTS AND METHODS: In all, 263 consecutive patients with suspicion of prostate cancer were investigated. All patients were evaluated by 3 T multiparametric MRI (mpMRI) applying the European Society of Urogenital Radiology criteria. All patients underwent MRI/US-fusion biopsy transperineally (mean nine cores) and additionally a systematic transrectal biopsy (mean 12 cores). RESULTS: In all, 195 patients underwent repeat biopsy and 68 patients underwent first biopsy. The median age was 66 years, median PSA level was 8.3 ng/mL and median prostate volume was 50 mL. Overall, the prostate cancer detection rate was 52% (137/263). MRI/US-fusion biopsy detected significantly more cancer than systematic prostate biopsy (44% [116/263] vs 35% [91/263]; P = 0.002). In repeat biopsy, the detection rate was 44% (85/195) in targeted and 32% (62/195) in systematic biopsy (P = 0.002). In first biopsy, the detection rate was 46% (31/68) in targeted and 43% (29/68) in systematic biopsy (P = 0.527). In all, 80% (110/137) of biopsy confirmed prostate cancers were clinically significant. For the upgrading of Gleason score, 44% (32/72) more clinically significant prostate cancer was detected by using additional targeted biopsy than by systematic biopsy alone. Conversely, 12% (10/94) more clinically significant cancer was found by systematic biopsy additionally to targeted biopsy. CONCLUSIONS: MRI/US-fusion biopsy was associated with a higher detection rate of clinically significant prostate cancer while taking fewer cores, especially in patients with prior negative biopsy. Due to a high portion of additional tumours with Gleason score >=7 detected in addition to targeted biopsy, systematic biopsy should still be performed additionally to targeted biopsy. PMID- 25523211 TI - Identification of potent orally active factor Xa inhibitors based on conjugation strategy and application of predictable fragment recommender system. AB - Anticoagulant agents have emerged as a promising class of therapeutic drugs for the treatment and prevention of arterial and venous thrombosis. We investigated a series of novel orally active factor Xa inhibitors designed using our previously reported conjugation strategy to boost oral anticoagulant effect. Structural optimization of anthranilamide derivative 3 as a lead compound with installation of phenolic hydroxyl group and extensive exploration of the P1 binding element led to the identification of 5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[4-(4 methyl-1,4-diazepan-1-yl)benzoyl]amino}benzamide (33, AS1468240) as a potent factor Xa inhibitor with significant oral anticoagulant activity. We also reported a newly developed Free-Wilson-like fragment recommender system based on the integration of R-group decomposition with collaborative filtering for the structural optimization process. PMID- 25523212 TI - Do we need a replacement medication for influenza with good efficacy? PMID- 25523213 TI - The Escherichia coli effector EspJ blocks Src kinase activity via amidation and ADP ribosylation. AB - The hallmark of enteropathogenic Escherichia coli (EPEC) infection is the formation of actin-rich pedestal-like structures, which are generated following phosphorylation of the bacterial effector Tir by cellular Src and Abl family tyrosine kinases. This leads to recruitment of the Nck-WIP-N-WASP complex that triggers Arp2/3-dependent actin polymerization in the host cell. The same phosphorylation-mediated signalling network is also assembled downstream of the Vaccinia virus protein A36 and the phagocytic Fc-gamma receptor FcgammaRIIa. Here we report that the EPEC type-III secretion system effector EspJ inhibits autophosphorylation of Src and phosphorylation of the Src substrates Tir and FcgammaRIIa. Consistent with this, EspJ inhibits actin polymerization downstream of EPEC, Vaccinia virus and opsonized red blood cells. We identify EspJ as a unique adenosine diphosphate (ADP) ribosyltransferase that directly inhibits Src kinase by simultaneous amidation and ADP ribosylation of the conserved kinase domain residue, Src E310, resulting in glutamine-ADP ribose. PMID- 25523214 TI - Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV. AB - BACKGROUND AND OBJECTIVES: Antiretrovirals are currently used for the treatment and prevention of HIV infection. However, poor adherence and low tolerability of some existing oral formulations can hinder their efficacy. Long-acting (LA) injectable nanoformulations could help address these complications by simplifying antiretroviral administration. The aim of this study is to inform the optimisation of intramuscular LA formulations for eight antiretrovirals through physiologically based pharmacokinetic (PBPK) modelling. METHODS: A whole-body PBPK model was constructed using mathematical descriptions of molecular, physiological and anatomical processes defining pharmacokinetics. These models were validated against available clinical data and subsequently used to predict the pharmacokinetics of injectable LA formulations RESULTS: The predictions suggest that monthly intramuscular injections are possible for dolutegravir, efavirenz, emtricitabine, raltegravir, rilpivirine and tenofovir provided that technological challenges to control their release rate can be addressed. CONCLUSIONS: These data may help inform the target product profiles for LA antiretroviral reformulation strategies. PMID- 25523216 TI - [Prevalence study of nosocomial infections in university hospitals in the Czech Republic]. AB - OBJECTIVE: In 2005-2010, a nosocomial infection prevalence study was conducted in 12 university hospitals, namely at the departments of surgery, urology, neurology, cardiology, neurosurgery, otorhinolaryngology, and traumatology. The primary objective was to evaluate the overall epidemiological situation of nosocomial infections (NI) at the highest risk departments of selected healthcare facilities in the Czech Republic and to characterize the NI detected. METHODS: To collect data, a questionnaire survey method was used, as it suited the routine operation conditions in healthcare facilities and was inexpensive, easy to understand, reproducible, and repeatable if needed. The questionnaire was designed according to the protocol recommended by the working group HELICS (Hospital in Europe Link for Infection Control through Surveillance). In each of the participating hospitals, the medical records of all patients hospitalized at the respective departments were analyzed. The patient data, hospitalization data, potential risk factors, and occurrence of hospital infection, if any, were derived from the medical records and entered in the questionnaire. RESULTS: Overall, data on 1889 hospitalized patients were analyzed. Eighty-one confirmed NI cases were found, i.e. the prevalence rate in this study was 4.3% (the percentage of HI per the number of hospitalized patients), which is in agreement with the recent data reported in the European Union. The most common causative agents were Pseudomonas spp. (16%), Staphylococcus aureus (15%), Escherichia coli (12%), Proteus spp. (10%), and Klebsiella spp. (4%), with the urinary tract (41%) and respiratory tract (23%) being affected most often. PMID- 25523215 TI - Identifying Possible False Matches in Anonymized Hospital Administrative Data without Patient Identifiers. AB - OBJECTIVE: To identify data linkage errors in the form of possible false matches, where two patients appear to share the same unique identification number. DATA SOURCE: Hospital Episode Statistics (HES) in England, United Kingdom. STUDY DESIGN: Data on births and re-admissions for infants (April 1, 2011 to March 31, 2012; age 0-1 year) and adolescents (April 1, 2004 to March 31, 2011; age 10-19 years). DATA COLLECTION/EXTRACTION METHODS: Hospital records pseudo-anonymized using an algorithm designed to link multiple records belonging to the same person. Six implausible clinical scenarios were considered possible false matches: multiple births sharing HESID, re-admission after death, two birth episodes sharing HESID, simultaneous admission at different hospitals, infant episodes coded as deliveries, and adolescent episodes coded as births. PRINCIPAL FINDINGS: Among 507,778 infants, possible false matches were relatively rare (n = 433, 0.1 percent). The most common scenario (simultaneous admission at two hospitals, n = 324) was more likely for infants with missing data, those born preterm, and for Asian infants. Among adolescents, this scenario (n = 320) was more common for males, younger patients, the Mixed ethnic group, and those re admitted more frequently. CONCLUSIONS: Researchers can identify clinically implausible scenarios and patients affected, at the data cleaning stage, to mitigate the impact of possible linkage errors. PMID- 25523217 TI - [Outbreak of viral hepatitis B and C in hospitalized cancer patients]. AB - The Regional Public Health Office recorded 47 cases of hepatitis B and C in 39 patients hospitalized in the regional hospital between September 2009 and July 2010. The outbreak cases included in the study met the previously set standard definition. Based on the epidemiological investigations a hypothesis was formulated on the route of infection transmission through the administration of parenteral solutions using a peripheral venous cannula during hospitalization. A retrospective cohort study revealed a statistically significant association between parenteral therapy administered using a peripheral venous cannula and disease (for viral hepatitis B: X2=49.53, p<0.001 and viral hepatitis C: X2=22.42, p<0.001). The results were in accordance with the failures to comply with the sanitary-epidemiological standards revealed by audits at the respective departments. PMID- 25523218 TI - Hepatitis C treatment uptake and adherence among injecting drug users in the Czech Republic. AB - BACKGROUND: Injecting drug users (IDUs) represent a major subpopulation of hepatitis C virus (HCV)-infected people in developed countries. Yet their uptake to treatment is generally low despite well-documented effectiveness of HCV treatment among former and active IDUs. The present study represents the first attempt to describe the HCV treatment coverage among IDUs and identify factors that affect treatment uptake in the Czech Republic. METHODS: From January to March 2011, a questionnaire survey was conducted among viral hepatitis treatment centres in the Czech Republic. RESULTS: From a total of 76 identified hepatitis treatment centres existing in the country, 39 provided HCV treatment to (mainly former or abstaining) IDUs in 2010. Most clinicians reported being cautious in initiating HCV treatment in IDUs. Abstinence, a screening phase before treatment initiation, opioid substitution treatment and an external evaluation by a specialist were often prerequisites for skrting treatment. However, HCV treatment centres rarely provided drug-use specific services. Financial constraints were also reported, further limiting the inclusion of IDUs into treatment, as non users are widely preferred to active drug users. Clinicians reported no difference in treatment uptake and adherence between drug users and non-users, nor between opioid and methamphetamine users. CONCLUSION: A number of system- and provider-related factors limit HCV treatment in IDUs in the Czech Republic, despite permissive national clinical guidelines. Targeting these factors is crucial to reduce HCV prevalence at population level. PMID- 25523219 TI - [Pertussis trend in children under one year of age in the Czech Republic in 1997 2013]. AB - STUDY OBJECTIVE: To characterize the epidemiological situation of pertussis in children under one year of age in the Czech Republic in 1997-2013. MATERIAL AND METHODS: The study cohort consisted of children under one year of age with laboratory confirmed pertussis reported to the communicable disease system from 1997 to 2013. A total of 265 pertussis cases were reported in children under one year of age over the study period. Selected demographic data, need for hospitalization, and vaccination history were evaluated in the study cohort. RESULTS: Children under one year of age have shown a steady upward trend in reported cases of pertussis since the 1990s. The reported incidence of pertussis in this age group was the lowest in 1998 (1.1/100,000 population) and the highest in 2013 (31.3/100,000). In 1997-2013, 265 pertussis cases were reported in children under one year of age, 128 females and 137 males, to the communicable disease system in the Czech Republic. Most of these children, nearly 77%, developed pertussis within the first four months of life. Of the 265 children, 79% were not vaccinated before the onset of the disease and 21% were immunized with at least one dose of pertussis vaccine before developing the disease. As many as 75% of the children with pertussis needed hospitalization. Most of them, nearly 81%, were hospitalized with pertussis in the first four months of life and 90% of them in the first six months of life. CONCLUSIONS: In 1997-2013, an upward trend was observed in pertussis cases in children under one year of age. Most children developed the disease within the first four months of life while not vaccinated against pertussis. This fact unambiguously supports the "cocoon" strategy, i.e. vaccination of the closest contacts of the child, and a booster dose at 25 years of age. At the same time, a question arises whether to provide vaccination to pregnant women. PMID- 25523220 TI - [Current situation in clinical trials with vaccines in the Czech Republic]. AB - Clinical trials are an important part of clinical research. The conduction of clinical trials is strictly regulated and has to comply with an approved protocol. Local regulatory authorities, independent ethic committees, sponsors of clinical trials as well as the investigators are involved from the submission until the very end of the trial. All clinical trials performed in the Czech Republic have to be approved by the State Institute for Drug Control and by the Ethics Committee. The regulatory bodies and independent ethics committees evaluate and continuously supervise the justification and protocol of the clinical trial, quality of the investigational medicinal products and, primarily, the safety of the participants (patients and/or healthy volunteers) in clinical trials. In the Czech Republic there are many advanced clinical research centres, either located in private practices or within hospitals. The investigators are able to conduct a wide variety of clinical trials and recruit a high number of subjects for the trials, as well as to comply with the Good Clinical Practice guidelines and other regulatory requirements. The aim of this article is to summarise the current situation of clinical trials in the Czech Republic as well as the opportunities for getting involved in clinical trials and obligations arising for health professionals from such an involvement. PMID- 25523221 TI - [Epidemiology and risk factors in legionellosis]. AB - Legionella was discovered in the first half of the 20th century. The main representative of the genus is the bacterial species Legionella pneumophila. Legionella can cause a mild disease with fever but also severe to fatal pneumonia. At highest risk are individuals with an underlying disease, immunosuppressed patients or individuals exposed to other risk factors (e.g. users of addictive substances). Information on the etiology and epidemiology of legionellosis is presented. Selected risk factors are described as well as preventive measures to be taken in water supply and cooling systems. In conclusion, emphasis is placed on the prevention. PMID- 25523222 TI - [Infections caused by non-typhi serovars of Salmonella at the Infectious Diseases Clinic of the University Hospital Brno in 2011-2013]. AB - INTRODUCTION: The aim of the study is to describe the basic clinical, laboratory, and microbiological characteristics in adult patients with salmonellosis hospitalized at the Infectious Diseases Clinic of the University Hospital Brno in 2011-2013. MATERIALS AND METHODS: A retrospective analysis of clinical and laboratory parameters of 161 patients hospitalized at the Infectious Diseases Clinic of the University Hospital Brno from 1 January 2011 to 31 December 2013. RESULTS: Invasive salmonellosis was seen in 22.4% of the study group. The overall lethality rate reached 3.1%. Treatment with antibiotics was used in 93.8% of patients. Transient mild to moderate leukocytopenia was reported in 4.3% of patients and thrombocytopenia in 9.3% of patients. Transient changes in white blood cells as well as in the thrombocyte count were not clinically important. Long-term treatment with proton pump inhibitors is a risk factor for salmonellosis (p=0.128), but not for invasive salmonellosis. Long-term use of opioids (p=0.003) and/or acetylsalicylic acid (p=0.015) is a risk factor for invasive salmonellosis. Other risk factors for invasive disease are: age over 70 years (p=0.011), arterial hypertension (p=0.004), disease duration of less than three days (p=0.006), serum creatinine level above 250 MUmol/l (p=0.01), peripheral leucocyte count above 12x10(9)/l (p=0.001), and body temperature above 38 degrees C (p=0.001). Hypokalemia does not represent a risk factor for invasive salmonellosis. CONCLUSIONS: Aged patients on long-term opioids or acetylsalicylic acid, with disease duration of less than three days, and meeting the criteria for systemic inflammatory response syndrome are at the highest risk for invasive salmonellosis. Empirical antibiotics are prescribed too often and the treatment is not properly de-escalated. PMID- 25523223 TI - [Seroprevalence of Anaplasma phagocytophilum in patients with suspected Lyme borreliosis]. AB - Human granulocytic anaplasmosis (HGA) is an emerging tick-borne zoonotic disease caused by an obligate intracellular bacterium, Anaplasma phagocytophilum. In Europe, A. phagocytophilum is transmitted by Ixodes ricinus ticks. After Lyme borreliosis and European tick-borne encephalitis, HGA is the third most common tick-borne infection in the USA and Europe. The clinical symptoms of anaplasmosis are non-specific and include malaise, fever, headache, myalgia, and arthralgia. In more severe cases, the gastrointestinal or respiratory tract may be affected. However, most infections are asymptomatic. The aim of our study was to determine the seroprevalence of A. phagocytophilum in patients with suspected Lyme borreliosis. A total of 314 sera from patients with suspected Lyme borreliosis were screened for IgG and IgM antibodies against A. phagocytophilum. The immunoblot assay was used to detect the antibodies. Anti-A. phagocytophilum antibodies were detected in 34 patients, i.e. in 10.82%. IgM antibodies were positive in 19 cases and IgG antibodies in 10 cases. Positivity to both IgM and IgG antibodies was revealed in five patients. Antibodies against Borrelia burgdorferi sensu lato were detected in 181 patients (57.64%). Co-seroprevalence of Borrelia burgdorferi s. l. and A. phagocytophilum was found in 26 patients (8.3%). Positivity for anti-A. phagocytophilum antibodies was most often seen in samples from the age group 60-69 years. Our results show that A. phagocytophilum infection is not uncommon in the Czech Republic and should be considered in patients with a history of a tick bite. PMID- 25523224 TI - [An uncommon detection of Mycobacterium tuberculosis in pericardial effusion]. AB - Pericardial tuberculosis is a specific pericarditis which is rarely reported in the absence of pulmonary tuberculosis. A case history is presented of a 74-year old patient, immunocompromised as a result of kidney and liver cancer therapy. Mycobacterium tuberculosis was repeatedly recovered from pericardial effusion but not from other clinical specimens. Despite the early treatment of specific pericarditis, the patient died. PMID- 25523225 TI - [Surveillance of West Nile fever in horses in the Czech Republic from 2011 to 2013]. AB - STUDY AIM: The West Nile virus (WNV) is an important mosquito-borne flavivirus occurring around the world. Occasionally found in Central Europe, the virus spread massively through whole Hungary between 2008 and 2009. The aim of our study was to determine the recent prevalence of the WNV infection in horses in the Czech Republic. MATERIAL AND METHODS: Overall, 2349 serum samples, collected from healthy unvaccinated adult horses in the Czech Republic between 2011 and 2013, were tested. A commercially available competitive ELISA kit (cELISA) was used for this purpose and positive samples were confirmed by virus neutralisation tests using WNV and tick-borne encephalitis virus (TBEV). RESULTS: Altogether 271 of 2348 samples (11.5%) were positive by cELISA. Confirmatory VNT revealed 16 WNV positive samples, 11 of which had titres from 8 to 1024; VNTs with TBEV were negative. Three samples had antibodies against both viruses and the WNV antibody titres were less than or equal to the TBEV antibody titres. A cross reactivity of flaviviruses might have had an impact on the results, but in samples with similar WNV and TBEV titres, co-infection with both pathogens cannot be ruled out either. VNT antibody titres in two horses were inconclusive (cut-off titre 4). The place of birth and transfers (if any) were checked for each WNV seropositive horse. Five WNV positive/TBEV negative samples (0.2%) came from five administrative regions (South Bohemian, Karlovy Vary, Central Bohemian, South Moravian, and Moravian-Silesian) and the respective animals were never moved to a foreign country. Four of these horses never left the farm. Other six WNV positive/TBEV negative horses were imported to the Czech Republic from North America or Central and West Europe and therefore, it is not possible to tell unambiguously whether their infection is autochthonous or imported. CONCLUSION: The results of the present study confirm that WNV antibodies occur sporadically in horses in the Czech Republic. WNV was found to circulate in different parts of the Czech Republic and not only in the South of Moravia. PMID- 25523226 TI - Terpenoid biosynthesis in prokaryotes. AB - Prokaryotic organisms (archaea and eubacteria) are found in all habitats where life exists on our planet. This would not be possible without the astounding biochemical plasticity developed by such organisms. Part of the metabolic diversity of prokaryotes was transferred to eukaryotic cells when endosymbiotic prokaryotes became mitochondria and plastids but also in a large number of horizontal gene transfer episodes. A group of metabolites produced by all free living organisms is terpenoids (also known as isoprenoids). In prokaryotes, terpenoids play an indispensable role in cell-wall and membrane biosynthesis (bactoprenol, hopanoids), electron transport (ubiquinone, menaquinone), or conversion of light into chemical energy (chlorophylls, bacteriochlorophylls, rhodopsins, carotenoids), among other processes. But despite their remarkable structural and functional diversity, they all derive from the same metabolic precursors. Here we describe the metabolic pathways producing these universal terpenoid units and provide a complete picture of the main terpenoid compounds found in prokaryotic organisms. PMID- 25523227 TI - Autophagic responses to hypoxia and anticancer therapy in head and neck cancer. AB - Autophagy is a major intracellular pathway involving in the degradation and recycling of cytosolic material, including organelles, proteins, and ribosomes. Autophagy is commonly active in tumor cells and could be induced by stress conditions such as hypoxia, nutrient depletion and anticancer therapy. Increasing evidence supports the role of autophagy in modulating cancer behavior in head and neck squamous cell carcinoma (HNSCC). Despite recent advances in surgery combined with chemotherapy and radiotherapy, the survival rate of patients with HNSCC has not been improved substantially. To adapt to the hostile microenvironment induced by stress condition including hypoxia and anticancer therapy, more biological changes such as autophagy are induced in tumor cells contributing to their malignant and aggressive behavior. In the present review, we summarized recent findings on the molecules involved in the autophagy induced by hypoxia and anticancer therapy and basic mechanisms of autophagy, and focused on elucidating the role of autophagy in tumor progression of HNSCC. Some novel studies on the relationships between mircoRNA and autophagy were also discussed in this review. A better understanding of this knowledge may provide new ideas and targets for effective prevention and treatment in HNSCC. PMID- 25523229 TI - Cellular microbiology editorial letter. PMID- 25523228 TI - Association of lymphocytic colitis and lactase deficiency in pediatric population. AB - Characterized by colonic mucosa intraepithelial lymphocytosis, lymphocytic colitis is primarily an entity presented in the middle-aged to elderly patient population. Very few large series of lymphocytic colitis of childhood occurrence are available in the medical literature. Ten cases each of lymphocytic colitis and of colonic lymphocytosis of other diagnosis, all with duodenal disaccharidases analysis data, were collected from the files of our institution. The electronic medical records were reviewed and multiple variables were analyzed. The ten patients with lymphocytic colitis presented with diarrhea. Of these, three had abdominal pain. The age range was 2-18 years. Nearly all patients were Caucasian (90%) and 70% were female. Endoscopically, most had normal appearing colonic mucosa. Significant past medical history, family medical history and associated comorbidities included celiac disease, Down syndrome, juvenile arthritis and other autoimmune diseases. Interestingly, the most revealing observation was that the majority of cases (80%) were associated with lactase deficiency and, for the most part, gastrointestinal symptoms improved simply by treatment with Lactaid or avoidance of dairy products. This association is statistically significant. Our clinicopathological study indicates that the typical pediatric patient is a female Caucasian. A large of portion of the patients had associated lactase deficiency and improved on Lactaid supplement alone. PMID- 25523230 TI - mtDNA mutations variously impact mtDNA maintenance throughout the human embryofetal development. AB - Mitochondria are the largest generator of ATP in the cell. It is therefore expected that energy-requiring processes such as oocyte maturation, early embryonic or fetal development, would be adversely impacted in case of mitochondrial deficiency. Human mitochondrial DNA (mtDNA) mutations constitute a spontaneous model of mitochondrial failure and offer the opportunity to study the consequences of energetic defects over fertility and embryofetal development. This review provides an update on the mtDNA metabolism in the early preimplantation embryo, and compiles data showing the impact of mtDNA mutations over mtDNA segregation. Despite convincing evidences about the essential role of mitochondria in oogenesis and preimplantation development, no correlation between the presence of a mtDNA mutation and fertilization failure, impaired oocyte quality, or embryofetal development arrest was found. In some cases, mutant cells might upregulate their mitochondrial content to overcome the bioenergetic defects induced by mtDNA mutations, and might escape negative selection. Finally we discuss some of the clinical consequences of these observations. PMID- 25523231 TI - Pick-off annihilation of positronium in matter using full correlation single particle potentials: solid He. AB - We investigate the modeling of positronium (Ps) states and their pick-off annihilation trapped at open volumes pockets in condensed molecular matter. Our starting point is the interacting many-body system of Ps and a He atom because it is the smallest entity that can mimic the energy gap between the highest occupied and lowest unoccupied molecular orbitals of molecules, and yet the many-body structure of the HePs system can be calculated accurately enough. The exact diagonalization solution of the HePs system enables us to construct a pairwise full-correlation single-particle potential for the Ps-He interaction, and the total potential in solids is obtained as a superposition of the pairwise potentials. We study in detail Ps states and their pick-off annihilation rates in voids inside solid He and analyze experimental results for Ps-induced voids in liquid He obtaining the radii of the voids. More importantly, we generalize our conclusions by testing the validity of the Tao-Eldrup model, widely used to analyze ortho-Ps annihilation measurements for voids in molecular matter, against our theoretical results for the solid He. Moreover, we discuss the influence of the partial charges of polar molecules and the strength of the van der Waals interaction on the pick-off annihilation rate. PMID- 25523232 TI - Ventricular septal defect. AB - BACKGROUND: Ventricular septal defects are the commonest congenital cardiac malformations. They can exist in isolation, but are also found as integral components of other cardiac anomalies, such as tetralogy of Fallot, double outlet right ventricle, or common arterial trunk. As yet, there is no agreement on how best to classify such defects, nor even on the curved surface that is taken to represent the defect. METHODS: Based on our previous pathological and clinical experiences, we have reviewed the history of classification of holes between the ventricles. We proposed that the defects are best defined as representing the area of deficient ventricular septation. This then permits the recognition of clinically significant variants according to the anatomic borders, and the way the curved surface representing the area of deficient septation opens into the morphologically right ventricle. RESULTS: Clinical manifestation depends on the size of the defect, and on the relationship between systemic and pulmonary vascular resistances. Symptoms include failure to thrive, along with the manifestations of the increase in flow of blood to the lungs. Diagnosis can be made by physical examination, but is confirmed by echocardiographic interrogation, which delineates the precise anatomy, and also provides the physiologic information required for optimal clinical decision-making. Cardiac catheterization offers additional information regarding hemodynamics, particularly if there is a concern regarding an increase in pulmonary vascular resistance. Hemodynamic assessment is rarely necessary to make decisions regarding management, although it can be helpful if assessing symptomatic adults with hemodynamically restrictive defects. In infants with defects producing large shunts, surgical closure is now recommended in most instances as soon as symptoms manifest. Only in rare cases is palliative banding of the pulmonary trunk now recommended. Closure with devices inserted on catheters is now the preferred approach for many patients with muscular defects, often using a hybrid procedure. Therapeutic closure should now be anticipated with virtually zero mortality, and with excellent anticipated long-term survival. CONCLUSION: Ventricular septal defects are best defined as representing the borders of the area of deficient ventricular septation. An approach on this basis permits recognition of the clinically significant phenotypic variants. PMID- 25523233 TI - A comparative approach of four different image registration techniques for quantitative assessment of coronary artery calcium lesions using intravascular ultrasound. AB - In IVUS imaging, constant linear velocity and a constant angular velocity of 1800 rev/min causes displacement of the calcium in subsequent image frames. To overcome this error in intravascular ultrasound video, IVUS image frames must be registered prior to the lesion quantification. This paper presents a comprehensive comparison of four registration methods, namely: Rigid, Affine, B Splines and Demons on five set of calcium lesion quantification parameters namely: (i) the mean lesion area, (ii) mean lesion arc, (iii) mean lesion span, (iv) mean lesion length, and (v) mean lesion distance from catheter. Using our IRB approved data of 100 patient volumes, our results shows that all four registrations showed a decrease in five calcium lesion parameters as follows: for Rigid registration, the values were: 4.92%, 5.84%, 5.89%, 5.27%, and 4.57%, respectively, for Affine registration the values were: 6.06%, 6.51%, 7.28%, 6.50%, and 5.94%, respectively, for B-Splines registration the values were: 7.35%, 8.03%, 9.54%, 8.18%, and 7.62%, respectively, and for Demons registration the five parameters were 7.32%, 8.02%, 10.11%, 7.94%, and 8.92% respectively. The relative overlap of identified lesions decreased by 5.91% in case of Rigid registration, 6.23% in case of Affine registration, 4.48% for Demons registration, whereas it increased by 3.05% in case of B-Splines registration. Rigid and Affine transformation-based registration took only 0.1936 and 0.2893 s per frame, respectively. Demons and B-Splines framework took only 0.5705 and 0.9405 s per frame, respectively, which were significantly slower than Rigid and Affine transformation based image registration. PMID- 25523235 TI - Ab initio multiple cloning simulations of pyrrole photodissociation: TKER spectra and velocity map imaging. AB - We report a detailed computational simulation of the photodissociation of pyrrole using the ab initio Multiple Cloning (AIMC) method implemented within MOLPRO. The efficiency of the AIMC implementation, employing train basis sets, linear approximation for matrix elements, and Ehrenfest configuration cloning, allows us to accumulate significant statistics. We calculate and analyze the total kinetic energy release (TKER) spectrum and Velocity Map Imaging (VMI) of pyrrole and compare the results directly with experimental measurements. Both the TKER spectrum and the structure of the velocity map image (VMI) are well reproduced. Previously, it has been assumed that the isotropic component of the VMI arises from long time statistical dissociation. Instead, our simulations suggest that ultrafast dynamics contributes significantly to both low and high energy portions of the TKER spectrum. PMID- 25523236 TI - Real-world variability in dabigatran levels in patients with atrial fibrillation. AB - BACKGROUND: In clinical practice, physicians are given the choice of selecting one of two dabigatran doses based on patient characteristics, with the lower dose typically used in patients at a higher risk of bleeding. OBJECTIVES: The objectives of the study were to (i) estimate the inter- and intra-patient variability in dabigatran levels with 110 mg (DE110) and 150 mg (DE150) doses, (ii) examine the effect of physicians' dose selection on levels in DE110 and DE150 subgroups, and (iii) explore whether a single trough measurement identifies patients with extreme levels on subsequent visits. METHODS: In this prospective observational study of 100 patients with atrial fibrillation (AF), peak and trough levels of dabigatran were measured with the Hemoclot((r)) assay at baseline and every 2 months thereafter (maximum four visits). RESULTS: Inter patient variability in dabigatran levels (geometric coefficient of variation [gCV], 51-64%) was greater than intra-patient variability (gCV, 32-40%). Similar medians and distributions of levels were observed in DE110 and DE150 subgroups. Patients receiving DE110 were older, had lower renal function and weighed less than those receiving DE150. Up to 40% of patients whose trough levels were in the upper extremes, and up to 80% of patients whose trough levels were in the lower extremes at baseline, showed subsequent levels that fell in the middle quartiles. CONCLUSIONS: Our data support the practice of selecting the dabigatran dose based upon clinical characteristics because it results in similar levels of drug exposure in patients given DE110 or DE150. They do not support the concept that a single Hemoclot((r)) measurement reliably identifies patients with consistently high or low values. PMID- 25523237 TI - An incremental isoconversional method for kinetic analysis based on the orthogonal distance regression. AB - The parameters obtained from a kinetic analysis of thermoanalytical data often exhibit a conversion-dependent behavior. A novel incremental isoconversional method able to deal with this phenomenon is proposed. The kinetic model is directly fitted to the experimental data using nonlinear orthogonal least squares procedure. The data are processed without transformations, so their error distribution is preserved. As the objective function is based on a maximum likelihood approach, reliable uncertainties of the parameters can be estimated. In contrast to other methods, the activation energy and the pre-exponential factor are treated as equally important kinetic parameters and are estimated simultaneously. Validity of the method is verified on simulated data, including a dataset with local nonlinearity in the temperature variation. A practical application on the nonisothermal cold crystallization of polyethylene terephthalate is presented. PMID- 25523238 TI - Dealloying of mesoporous PtCu alloy film for the synthesis of mesoporous Pt films with high electrocatalytic activity. AB - Mesoporous Pt film with highly electrocatalytic activity is successfully synthesized by dealloying of mesoporous PtCu alloy film prepared through electrochemical micelle assembly. The resulting mesoporous electrode exhibits high current density and superior stability toward the methanol oxidation reaction. PMID- 25523239 TI - MicroRNA-146a and -21 cooperate to regulate vascular smooth muscle cell proliferation via modulation of the Notch signaling pathway. AB - A number of microRNAs (miRs) have been shown to participate in the regulation of vascular smooth muscle cell (VSMC) proliferation, a key step in the formation of atherosclerotic plaque, by targeting certain genes. The aim of the present study was to investigate the roles of miR-146a and miR-21 in VSMC growth and to study the underlying mechanisms. The expression levels of four previously reported, differentially expressed microRNAs in atherosclerotic plaque (miR-146a/b, miR-21, miR-34a and miR-210) were measured in two groups: An atherosclerotic plaque group (n=10) and a normal control group (n=10). Polymerase chain reaction (PCR) analysis revealed that the relative expression levels of miR-146a and miR-21 in atherosclerotic plaque samples were significantly upregulated to ~260 and 250%, respectively, compared with those in normal controls. Notch2 and Jag1 were confirmed to be target genes of miR-146a and miR-21 through the use of a luciferase assay, PCR and western blot analysis. Additionally, VSMCs transfected with miR-146a expressed significantly lower levels of Notch2 protein and presented an accelerated cell proliferation, which could be attributed to a reduction in the levels of cell cycle arrest. Cotransfection of miR-146a and miR 21 further promoted cell cycle progression in addition to VSMC proliferation. In conclusion, the present study revealed that miR-146a and miR-21 were significantly upregulated in atherosclerotic plaque, and cooperated to accelerate VSMC growth and cell cycle progression by targeting Notch2 and Jag1. PMID- 25523234 TI - Pivotal role of pervasive neoplastic and stromal cells reprogramming in circulating tumor cells dissemination and metastatic colonization. AB - Reciprocal interactions between neoplastic cells and their microenvironment are crucial events in carcinogenesis and tumor progression. Pervasive stromal reprogramming and remodeling that transform a normal to a tumorigenic microenvironment modify numerous stromal cells functions, status redox, oxidative stress, pH, ECM stiffness and energy metabolism. These environmental factors allow selection of more aggressive cancer cells that develop important adaptive strategies. Subpopulations of cancer cells acquire new properties associating plasticity, stem-like phenotype, unfolded protein response, metabolic reprogramming and autophagy, production of exosomes, survival to anoikis, invasion, immunosuppression and therapeutic resistance. Moreover, by inducing vascular transdifferentiation of cancer cells and recruiting endothelial cells and pericytes, the tumorigenic microenvironment induces development of tumor associated vessels that allow invasive cells to gain access to the tumor vessels and to intravasate. Circulating cancer cells can survive in the blood stream by interacting with the intravascular microenvironment, extravasate through the microvasculature and interact with the metastatic microenvironment of target organs. In this review, we will focus on many recent paradigms involved in the field of tumor progression. PMID- 25523240 TI - Attention bias modification and its impact on experimental pain outcomes: Comparison of training with words versus faces in pain. AB - BACKGROUND: The aim of this study was to compare the effectiveness of training participants' attention towards or away from painful faces versus pain-related words on pain outcomes on an acute experimental pain paradigm. METHODS: Participants were randomized to receive either training towards or away from painful faces or words. Following training, participants completed the cold pressor task. RESULTS: The results confirm that attention bias modification produced the predicted changes in attentional biases. Clear training effects were observed for words and faces, such that attentional biases changed in the predicted direction on the stimuli presented during the training. However, for those trained on words, training effects also generalized to face stimuli. As predicted, those who received training away from painful stimuli took longer to report pain (higher pain threshold) during the cold pressor task, and this effect was more pronounced for those trained on words. Contrary to expectations, those trained on faces (regardless of training direction) reported less pain than those trained on words. There were no differences between the groups for pain tolerance (length of time participants were able to keep their arms in the cold pressor). CONCLUSIONS: These findings confirm that attentional biases are modifiable, and impact (in the expected manner) how quickly participants perceive pain. Further, exposure to painful faces resulted in additional benefits to the level of pain reported. However, we were unable to confirm that change in attentional biases was the mechanism of change. PMID- 25523241 TI - A qualitative description of telemedicine for acute stroke care in Norway: technology is not the issue. AB - BACKGROUND: To assist small hospitals in providing advanced stroke treatment, the Norwegian Directorate of Health has recommended telemedicine services. Telestroke enables specialists to examine patients via videoconferencing supplemented by teleradiology and to provide decision support to local health care personnel. There is evidence that telestroke increases thrombolysis rates. In Norway, telemedicine has mainly been used in non-critical situations. The first telestroke trials took place in 2008. The aim of this paper is to present an overview of telestroke trials and today's status with telestroke in Norway. Based on the divergent experience from two health regions in Norway, the paper discusses crucial factors for the integration of telestroke in clinical practice. METHODS: This is a descriptive study based on multiple methods to obtain an overview of the practice and experience with telestroke in Norway. A Web and literature search for 'telestroke in Norway' was performed and compared with a survey of telemedicine services at the country's largest hospitals. These findings were supplemented by interviews with key personnel involved in telestroke in two of four health regions, as well as hospital field observations and log data of telestroke transmissions from five of the hospitals involved. RESULTS: In Norway, experience in telemedicine for acute stroke care is limited. At the beginning of 2014, three of four regional health authorities were working with telestroke projects and services. Integration of the service in practice is challenging, with varying experience. The problems are not attributed to the technology in itself, but to organization (availability of staff on duty 24/7 and surveillance of the systems), motivation of staff, logistics (patient delay), and characteristics of the buildings (lack of space). CONCLUSIONS: Prerequisites for successful integration of telestroke in clinical practice include realization of the collaboration potential in the technology with consistent procedures for training and triage, availability of the equipment, and providing advice beyond questions concerning thrombolysis. PMID- 25523242 TI - The role of central sensitization in shoulder pain: A systematic literature review. AB - INTRODUCTION: Hyperexcitability of the central nervous system has been suggested to play an important role in pain experienced by patients with unilateral shoulder pain. A systematic literature review following the PRISMA guidelines was performed to evaluate the existing evidence related to the presence of central sensitization in patients with unilateral shoulder pain of different etiologies including those with chronic subacromial impingement syndrome. Studies addressing neuropathic pain (e.g., post-stroke shoulder pain) were not considered. METHODS: Electronic databases PubMed, EBSCO, and Web of Science were searched to identify relevant articles using predefined keywords regarding central sensitization and shoulder pain. Articles were included till September 2013. Full-text clinical reports addressing studies of central sensitization in human adults with unilateral shoulder complaints including those diagnosed with subacromial impingement syndrome were included and screened for methodological quality by two independent reviewers. RESULTS: A total of 10 articles were retrieved for quality assessment and data extraction. All studies were cross-sectional (case-control) or longitudinal in nature. Different subjective and objective parameters, considered manifestations of central sensitization, were established in subjects with unilateral shoulder pain of different etiologies, including those receiving a diagnosis of subacromial impingement syndrome. Overall results suggest that, although peripheral mechanisms are involved, hypersensitivity of the central nervous system plays a role in a subgroup within the shoulder pain population. CONCLUSIONS: Although the majority of the literature reviewed provides emerging evidence for the presence of central sensitization in unilateral shoulder pain (including those diagnosed with subacromial impingement syndrome), our understanding of the role central sensitization plays in the shoulder pain population is still in its infancy. Future studies with high methodical quality are therefore required to investigate this further. PMID- 25523243 TI - A new pyrosequencing assay for rapid detection and genotyping of Shiga toxin, intimin and O157-specific rfbE genes of Escherichia coli. AB - Shiga toxin (stx)-producing Escherichia coli (STEC) contamination in food and water is one of the most recognized concerns and a major financial burden in human hygiene control worldwide. Rapid and highly reliable methods of detecting and identifying STEC causing gastroenteric illnesses are crucial to prevent foodborne outbreaks. A number of tests have been developed and commercialized to detect STEC using molecular microbiology techniques. Most of these are designed to identify virulence factors such as Shiga toxin and intimin as well as E. coli O and H antigen serotype specific genes. In order to screen pathogenic STEC without relying on O:H serotyping, we developed a rapid detection and genotyping assay for STEC virulence genes using a PCR-pyrosequencing application. We adapted the PyroMark Q24 Pyrosequencing platform for subtyping 4 major virulence genes, Shiga toxin 1 and 2 (stx1 and stx2), intimin (eae) and O157-antigen gene cluster target rfbE, using Single Nucleotide Polymorphism (SNP) analysis. A total of 224 E. coli strains including isolates from Canadian environment, food and clinical cases were examined. Based on the multiple alignment analysis of 30-80 base nucleotide pyrogram reads, three alleles of the Shiga toxin 1a gene (stx1a) (stx1a-I, stx1a-II, stx1a-III) were identified. Results of the stx1, stx2, eae and rfbE genotyping revealed that each group of O:H serotype shares distinctive characteristics that could be associated with the virulence of each genotype. O157:H7/NM carries stx1a-II (94%), stx2a (82%), lambda/gamma1-eae (100%) and rfbE type-H7/NM (100%). Whereas isolates of the "Top-6" serotypes (O26, O45, O103, O111, O121, O145) had a high incidence of stx1a-I (90%) and stx2a (100%). stx1a III (60%) was only observed in non Top-7 (Top-6 plus O157) STEC and Shigella spp. The entire assay, from extracting DNA from colonies on a plate to the generation of sequence information, can be completed in 5h. The method of profiling these 4 STEC pathogenic genotypes as demonstrated in this paper is rapid, easily performed, informative and cost-effective, and thus has a potential to be deployed in the food industry for the routine screening of potentially pathogenic STEC isolates. PMID- 25523244 TI - Reply: HPV in focal cortical dysplasia. PMID- 25523245 TI - The quest for excellence (part 2): reviewing a clinical trial for the British Journal of Dermatology. PMID- 25523246 TI - One hundred and twenty-five years and counting: into an era of systems dermatology. PMID- 25523247 TI - Rosacea, the face of innate immunity. PMID- 25523248 TI - Screening for infections prior to initiating immunosuppressive treatment for patients with autoimmune blistering diseases. PMID- 25523249 TI - Which HOME for atopic dermatitis? PMID- 25523250 TI - Third time coming HOME: not just EASI. PMID- 25523251 TI - Human sebocytes: the new leptin connection? PMID- 25523252 TI - Update: advanced methods in three-dimensional organotypic tissue engineering for congenital ichthyosis and other rare keratinization disorders. PMID- 25523253 TI - Ultraviolet involvement in melanocyte transformation to melanoma. PMID- 25523254 TI - Melanoma excision: how deep must we go? PMID- 25523255 TI - A peptide from a gastric pathogen for the treatment of acne. PMID- 25523256 TI - Hand eczema-a chronic condition with far-reaching consequences. PMID- 25523257 TI - Hidradenitis suppurativa outcome measures and treatment goals. PMID- 25523258 TI - Essential inputs for studies of cost-effectiveness analysis in melanoma. PMID- 25523259 TI - Alcoholic drinks and skin cancer-boozing on the beach and beyond. PMID- 25523260 TI - A telephone-based motivational interviewing intervention has positive effects on psoriasis severity and self-management: a randomized controlled trial. PMID- 25523261 TI - Vitamin D and photodermatoses. PMID- 25523262 TI - Photodynamic therapy: increasing acceptance through reduction of adverse reactions. PMID- 25523263 TI - Penicillin to prevent recurrent leg cellulitis: a critical appraisal. PMID- 25523264 TI - Author response to van Zuuren et al., Penicillin to prevent recurrent cellulitis: a critical appraisal. PMID- 25523265 TI - Preventing cellulitis: where next? PMID- 25523269 TI - Measuring attachment and parental bonding in psychosis and its clinical implications. AB - BACKGROUND: Attachment theory proposes that psychological functioning and affect regulations are influenced by the attachment we form with others. Early relationships with parents or caregivers lay the foundations for attachment styles. These styles are proposed to influence how we relate to others during our life can be modified by the relationships and events we experience in our lifespan. A secure attachment style is associated with a capacity to manage distress, comfort with autonomy and the ability to form relationships with others, whereas insecure attachment can lead to dysfunctional relationships, emotional and behaviour avoidance. Attachment theory provides a useful framework to inform our understanding of relationship difficulties in people with psychosis. This paper aims to complement recent systematic reviews by providing an overview of attachment theory, its application to psychosis, including an understanding of measurement issues and the clinical implications offered. METHOD: A narrative review was completed of the measures of attachment and parental bonding in psychosis. Its clinical implications are also discussed. The paper also explores the link between insecure attachment styles and illness course, social functioning and symptomatology. The following questions are addressed: What are the key attachment measures that have been used within the attachment and psychosis literature? What are the results of studies that have measured attachment or parental bonding in psychosis and what clinical implications can we derive from it? What are some of the key questions for future research from these findings in relation to the onset of psychosis research field? RESULTS: The most commonly used measures of attachment in psychosis research are reviewed. Self-report questionnaires and semi-structured interviews have mainly been used to examine attachment styles in adult samples and in recent years comprise a measure specifically developed for a psychosis group. The review suggests that insecure attachment styles are common in psychosis samples. Key relationships were observed between insecure, avoidant and anxious attachment styles and psychosis development, expression and long-term outcome. CONCLUSIONS: Attachment theory can provide a useful framework to facilitate our understanding of interpersonal difficulties in psychosis that may predate its onset and impact on observed variability in outcomes, including treatment engagement. Greater attention should be given to the assessment of attachment needs and to the development of interventions that seek to compensate for these difficulties. However, further investigations are required on specifying the exact mechanisms by which specific attachment styles impact on the development of psychosis and its course. PMID- 25523270 TI - alpha-Synuclein insertion into supported lipid bilayers as seen by in situ X-ray reflectivity. AB - Large aggregates of misfolded alpha-synuclein inside neuronal cells are the hallmarks of Parkinson's disease. The protein's natural function and its supposed toxicity, however, are believed to be closely related to its interaction with cell and vesicle membranes. Upon this interaction, the protein folds into an alpha-helical structure and intercalates into the membrane. In this study, we focus on the changes in the lipid bilayer caused by this intrusion. In situ X-ray reflectivity was applied to determine the vertical density structure of the bilayer before and after exposure to alpha-synuclein. It was found that the alpha synuclein insertion, wild type and E57K variant, caused a reduction in bilayer thickness. This effect may be one factor in the membrane pore formation ability of alpha-synuclein. PMID- 25523271 TI - Toxicity in semiarid sediments influenced by tailings of an abandoned gold mine. AB - The mining district of El Triunfo (ET-MD) has an estimated 800,000 t of mine wastes scattered in the environment, contaminating the sediment with potentially toxic elements such as As, Cd, Pb, and Zn. In order to estimate the toxicity of the sediment to the adjacent biota, the aims of our study are to calculate the mortality and inhibition through bioassays, using sediment, and test organisms such as Daphnia magna and Selenastrum capricornutum (Pseudokirchneriella subcapitata), respectively. The D. magna mortality was 31 +/- 12% and the S. capricornutum growth inhibition was 53 +/- 24%. The contamination of the sediment determines the high mortality of D. magna and the high inhibition of S. capricornutum in the system, indicating risk for the biota in the contaminated system. PMID- 25523273 TI - The secret lives of the Bastion Bakers. PMID- 25523272 TI - Intratumoral heterogeneity in a minority of ovarian low-grade serous carcinomas. AB - BACKGROUND: Ovarian low-grade serous carcinoma (LGSC) has fewer mutations than ovarian high-grade serous carcinoma (HGSC) and a less aggressive clinical course. However, an overwhelming majority of LGSC patients do not respond to conventional chemotherapy resulting in a poor long-term prognosis comparable to women diagnosed with HGSC. KRAS and BRAF mutations are common in LGSC, leading to clinical trials targeting the MAPK pathway. We assessed the stability of targetable somatic mutations over space and/or time in LGSC, with a view to inform stratified treatment strategies and clinical trial design. METHODS: Eleven LGSC cases with primary and recurrent paired samples were identified (stage IIB IV). Tumor DNA was isolated from 1-4 formalin-fixed paraffin-embedded tumor blocks from both the primary and recurrence (n = 37 tumor and n = 7 normal samples). Mutational analysis was performed using the Ion Torrent AmpliSeqTM Cancer Panel, with targeted validation using Fluidigm-MiSeq, Sanger sequencing and/or Raindance Raindrop digital PCR. RESULTS: KRAS (3/11), BRAF (2/11) and/or NRAS (1/11) mutations were identified in five unique cases. A novel, non synonymous mutation in SMAD4 was observed in one case. No somatic mutations were detected in the remaining six cases. In two cases with a single matched primary and recurrent sample, two KRAS hotspot mutations (G12V, G12R) were both stable over time. In three cases with multiple samplings from both the primary and recurrent surgery some mutations (NRAS Q61R, BRAF V600E, SMAD4 R361G) were stable across all samples, while others (KRAS G12V, BRAF G469V) were unstable. CONCLUSIONS: Overall, the majority of cases with detectable somatic mutations showed mutational stability over space and time while one of five cases showed both temporal and spatial mutational instability in presumed drivers of disease. Investigation of additional cases is required to confirm whether mutational heterogeneity in a minority of LGSC is a general phenomenon that should be factored into the design of clinical trials and stratified treatment for this patient population. PMID- 25523274 TI - Learning from those without: identifying barriers and creating solutions to establishing hospital palliative care services. PMID- 25523275 TI - Rings in random environments: sensing disorder through topology. AB - In this paper we study the role of topology in DNA gel electrophoresis experiments via molecular dynamics simulations. The gel is modelled as a 3D array of obstacles from which half edges are removed at random with probability p, thereby generating a disordered environment. Changes in the microscopic structure of the gel are captured by measuring the electrophoretic mobility of ring polymers moving through the medium, while their linear counterparts provide a control system as we show they are insensitive to these changes. We show that ring polymers provide a novel, non-invasive way of exploiting topology to sense microscopic disorder. Finally, we compare the results from the simulations with an analytical model for the non-equilibrium differential mobility, and find a striking agreement between simulation and theory. PMID- 25523276 TI - Micelle-template synthesis of nitrogen-doped mesoporous graphene as an efficient metal-free electrocatalyst for hydrogen production. AB - Synthesis of mesoporous graphene materials by soft-template methods remains a great challenge, owing to the poor self-assembly capability of precursors and the severe agglomeration of graphene nanosheets. Herein, a micelle-template strategy to prepare porous graphene materials with controllable mesopores, high specific surface areas and large pore volumes is reported. By fine-tuning the synthesis parameters, the pore sizes of mesoporous graphene can be rationally controlled. Nitrogen heteroatom doping is found to remarkably render electrocatalytic properties towards hydrogen evolution reactions as a highly efficient metal-free catalyst. The synthesis strategy and the demonstration of highly efficient catalytic effect provide benchmarks for preparing well-defined mesoporous graphene materials for energy production applications. PMID- 25523277 TI - [Liver ultrasound: focal lesions and diffuse diseases]. AB - Liver ultrasound is frequently used as a first-line technique for the detection and characterization of the most common liver lesions, especially those incidentally found focal liver lesions, and for monitoring of chronic liver diseases. Ultrasound is not only used in the Bmode, but also with Doppler and, more recently, contrast-enhanced ultrasound. It is mainly used in the diagnosis of diffuse liver diseases, such as steatosis or cirrhosis. This article presents a practical approach for diagnosis workup, in which the different characteristics of the main focal liver lesions and diffuse liver diseases are reviewed. PMID- 25523278 TI - Enhanced biosynthesis of O-desmethylangolensin from daidzein by a novel oxygen tolerant cock intestinal bacterium in the presence of atmospheric oxygen. AB - AIMS: To improve the oxygen-tolerant capability of a newly isolated anaerobic bacterium and to biosynthesize O-desmethylangolensin (O-Dma) from daidzein aerobically. METHODS AND RESULTS: After a long-term domestication process, an oxygen-tolerant bacterium, which we named Aeroto-AUH-JLC108, was derived from the newly isolated obligate anaerobic bacterium Clostridium sp. AUH-JLC108. Strain Aeroto-AUH-JLC108 differed from the natively anaerobic wild-type strain AUH JLC108 by various characteristics, including a change in bacterial shape, biochemical characteristics and 16S rRNA gene sequences. Both the growth speed and the maximal optical density (OD) value of strain Aeroto-AUH-JLC108 grown aerobically were significantly increased compared to that of the wild-type strain grown anaerobically. The maximal concentration of the substrate daidzein that the oxygen-tolerant strain Aeroto-AUH-JLC108 grown aerobically was able to convert efficiently was 2.0 mmol l(-1) and 0.6 mmol l(-1) for strain AUH-JLC108 that was grown anaerobically. CONCLUSIONS: Strain Aeroto-AUH-JLC108 is a conditional oxygen-tolerant bacterium. The growth speed, bacterial growth mass and bioconversion capability of strain Aeroto-AUH-JLC108 grown aerobically was significantly increased compared to that of the wild-type strain AUH-JLC108 grown anaerobically. SIGNIFICANCE AND IMPACT OF THE STUDY: Strain Aeroto-AUH-JLC108 is the first reported pure culture responsible for the formation of O-Dma from daidzein in the presence of atmospheric oxygen. PMID- 25523279 TI - Creatine for women in pregnancy for neuroprotection of the fetus. AB - BACKGROUND: Creatine is an amino acid derivative and, when phosphorylated (phosphocreatine), is involved in replenishing adenosine triphosphate (ATP) via the creatine kinase reaction. Cells obtain creatine from a diet rich in fish, meat, or dairy and by endogenous synthesis from the amino acids arginine, glycine, and methionine in an approximate 50:50 ratio. Animal studies have shown that creatine may provide fetal neuroprotection when given to the mother through her diet in pregnancy. It is important to assess whether maternally administered creatine in human pregnancy (at times of known, suspected, or potential fetal compromise) may offer neuroprotection to the fetus and may accordingly reduce the risk of adverse neurodevelopmental outcomes, such as cerebral palsy and associated impairments and disabilities arising from fetal brain injury. OBJECTIVES: To assess the effects of creatine when used for neuroprotection of the fetus. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 November 2014). SELECTION CRITERIA: We planned to include all published, unpublished, and ongoing randomised trials and quasi randomised trials. We planned to include studies reported as abstracts only as well as full-text manuscripts. Trials using a cross-over or cluster-randomised design were not eligible for inclusion.We planned to include trials comparing creatine given to women in pregnancy for fetal neuroprotection (regardless of the route, timing, dose, or duration of administration) with placebo, no treatment, or with an alternative agent aimed at providing fetal neuroprotection. We also planned to include comparisons of different regimens for administration of creatine. DATA COLLECTION AND ANALYSIS: We identified no completed or ongoing randomised controlled trials. MAIN RESULTS: We found no randomised controlled trials for inclusion in this review. AUTHORS' CONCLUSIONS: As we did not identify any randomised controlled trials for inclusion in this review, we are unable to comment on implications for practice. Although evidence from animal studies has supported a fetal neuroprotective role for creatine when administered to the mother during pregnancy, no trials assessing creatine in pregnant women for fetal neuroprotection have been published to date. If creatine is established as safe for the mother and her fetus, research efforts should first be directed towards randomised trials comparing creatine with either no intervention (ideally using a placebo), or with alternative agents aimed at providing fetal neuroprotection (including magnesium sulphate for the very preterm infant). If appropriate, these trials should then be followed by studies comparing different creatine regimens (dosage and duration of exposure). Such trials should be high quality and adequately powered to evaluate maternal and infant short and longer-term outcomes (including neurodevelopmental disabilities such as cerebral palsy), and should consider utilisation/costs of health care. PMID- 25523280 TI - Barriers to mental health care in Japan: Results from the World Mental Health Japan Survey. AB - AIMS: The reasons for accessing and maintaining access to mental health services in Japan may be different to those in other countries. Using the World Health Organization World Mental Health Japan survey data, this study investigated the prevalence of sociodemographic correlates of barriers for the use of, reasons for delayed access to, and reasons for dropping out from mental health care in a Japanese community-based sample. METHODS: An interview survey was conducted with a random sample of residents living in 11 communities across Japan during the years 2002-2006. Data from 4130 participants were analyzed. RESULTS: The most frequently reported reason for not seeking mental health care was a low perceived need (63.9%). The most common reason for delaying access to help was the wish to handle the problem on one's own (68.8%), while the most common reason for dropping out of care was also a low perceived need (54.2%). Being a woman and of younger age were key sociodemographic barriers to the use of mental health services. CONCLUSIONS: Low perceived need was a major reason for not seeking, delay in using, and dropout from mental health services in Japan. In addition, low perceived need and structural barriers were more frequently reported than attitudinal barriers, with the exception of a desire to handle the problem on one's own. These findings suggest that improving therapist-patient communication and quality of mental health care, as well as mental health literacy education in the community, might improve access to care in Japan. PMID- 25523281 TI - Salvage microbiology: opportunities and challenges in the detection of bacterial pathogens following initiation of antimicrobial treatment. AB - Broad-range 16S ribosomal RNA gene PCR coupled with Sanger sequencing was originally employed by soil scientists and was subsequently adapted for clinical applications. PCR coupled with electrospray ionization mass spectrometry has also progressed from initial applications in the detection of organisms from environmental samples into the clinical realm and has demonstrated promise in detection of pathogens in clinical specimens obtained from patients with suspected infection but negative cultures. We review studies of multiplex PCR, 16S ribosomal RNA gene PCR and sequencing and PCR coupled with electrospray ionization mass spectrometry for detection of bacteria in specimens that were obtained from patients during or after administration of antibiotic treatment, and examine the role of each for assisting in antimicrobial treatment and stewardship efforts. Following an exploration of the available data in this field, we discuss the opportunities that the preliminary investigations reveal, as well as the challenges faced with the implementation of these strategies in clinical practice. PMID- 25523282 TI - Five birds, one stone: neutralization of alpha-hemolysin and 4 bi-component leukocidins of Staphylococcus aureus with a single human monoclonal antibody. AB - Staphylococcus aureus is a major human pathogen associated with high mortality. The emergence of antibiotic resistance and the inability of antibiotics to counteract bacterial cytotoxins involved in the pathogenesis of S. aureus call for novel therapeutic approaches, such as passive immunization with monoclonal antibodies (mAbs). The complexity of staphylococcal pathogenesis and past failures with single mAb products represent considerable barriers for antibody based therapeutics. Over the past few years, efforts have focused on neutralizing alpha-hemolysin. Recent findings suggest that the concerted actions of several cytotoxins, including the bi-component leukocidins play important roles in staphylococcal pathogenesis. Therefore, we aimed to isolate mAbs that bind to multiple cytolysins by employing high diversity human IgG1 libraries presented on the surface of yeast cells. Here we describe cross-reactive antibodies with picomolar affinity for alpha-hemolysin and 4 different bi-component leukocidins that share only ~26% overall amino acid sequence identity. The molecular basis of cross-reactivity is the recognition of a conformational epitope shared by alpha hemolysin and F-components of gamma-hemolysin (HlgAB and HlgCB), LukED and LukSF (Panton-Valentine Leukocidin). The amino acids predicted to form the epitope are conserved and known to be important for cytotoxic activity. We found that a single cross-reactive antibody prevented lysis of human phagocytes, epithelial and red blood cells induced by alpha-hemolysin and leukocidins in vitro, and therefore had superior effectiveness compared to alpha-hemolysin specific antibodies to protect from the combined cytolytic effect of secreted S. aureus toxins. Such mAb afforded high levels of protection in murine models of pneumonia and sepsis. PMID- 25523283 TI - Greater fruit intake was associated with better bone mineral status among Chinese elderly men and women: results of Hong Kong Mr. Os and Ms. Os studies. AB - OBJECTIVES: Although studies in white populations have reported the beneficial effects of intakes of fruit and vegetables (F&V) on bone mass, limited data are available in Asians, especially among the elderly population. We examined the association of F&V intakes and bone mineral status in Chinese elderly adults and explored the potential mechanisms. DESIGN, SETTING, AND PARTICIPANTS: The study was a population-based cross-sectional study among 4000 Hong Kong Chinese men and women aged 65 years and older. MEASUREMENTS: Habitual F&V intakes were ascertained from a validated food frequency questionnaire. Bone mineral measurements of the whole body, hip, lumber spine, and femoral neck were made by dual-energy X-ray absorptiometry. Information on demographic, health, and lifestyles factors was obtained by standardized questionnaire. Relations between F&V intakes and bone mass at various sites were assessed by regression models. RESULTS: Whole-body and femoral neck bone mineral density and content were significantly and positively associated with fruit intake in both men and women, even when adjustment for a range of potential confounders was made. A daily increase of 100 g/kcal total fruit intake was associated with 4.5% and 6.4% increase of BMD at whole body, and 3.9% and 4.8% increase at the femoral neck in men and women, respectively. No significant association was found between vegetable intake and bone mass. The adjustment for vitamin C intake, but not dietary acid load, attenuated the association between fruit intake and bone mass. CONCLUSIONS: Greater fruit intake was independently associated with better bone mineral status among Chinese elderly men and women. The association is probably modified by dietary vitamin C. PMID- 25523284 TI - Impact of dual sensory impairment on onset of behavioral symptoms in European nursing homes: results from the Services and Health for Elderly in Long-Term Care study. AB - OBJECTIVES: To investigate if dual sensory impairment (DSI) in the form of a combined visual and hearing impairment is associated with the onset of behavioral symptoms in nursing homes. METHODS: A total of 1524 nursing home residents without behavioral symptoms at baseline followed for 12 months in 59 nursing homes from the Czech Republic, England, Finland, France, Germany, Israel, Italy, and The Netherlands. The interRAI instrument for long-term care facilities was assessed by trained staff at baseline and 12 months later. RESULTS: Altogether, 11% of residents had a new onset of behavioral symptoms (wandering, verbal abuse, physical abuse, socially inappropriate behavior, public disrobing, and resisting care) at 12-month follow-up. In multivariate analyses adjusted for potential confounders, DSI residents had significantly higher incidence of new behavioral symptoms at 12-month follow-up, irrespective of the severity of vision and hearing impairments [odds ratio (OR) = 2.1, 95% confidence interval (CI) = 1.3:3.4 for mild DSI, OR = 2.5, 95% CI = 1.6:4.0 for moderate DSI, and OR = 2.1, 95% CI = 1.2:3.7 for severe DSI] compared with residents without sensory impairment. Among the different types of symptoms, only abusive behaviors were less likely to be associated with DSI. CONCLUSIONS: This study provides evidence that DSI could play a significant role in the development of behavioral symptoms in nursing home residents. More attention should be paid to DSI even when each of vision and hearing function is only minimally impaired. PMID- 25523285 TI - A double-blind randomized placebo-controlled withdrawal trial comparing memantine and antipsychotics for the long-term treatment of function and neuropsychiatric symptoms in people with Alzheimer's disease (MAIN-AD). AB - BACKGROUND: Neuropsychiatric symptoms in Alzheimer disease (AD) cause significant distress and present a complex clinical challenge for treatment. Pharmacological treatment options are limited to antipsychotics, which carry extensive safety issues. There is emerging evidence to support the potential benefits of memantine, currently licensed for moderate to severe AD, in the prophylaxis of neuropsychiatric symptoms. METHODS: The MAIN-AD study is a double-blind randomized placebo-controlled withdrawal trial comparing memantine with antipsychotics for the treatment of neuropsychiatric symptoms over 24 weeks. A total of 199 people with probable AD living in care homes already receiving an antipsychotic were randomized to receive either memantine or to continue an antipsychotic. The primary outcomes were function (Bristol Activities of Daily Living Scale [BADLS]) and agitation (Cohen-Mansfield Agitation Inventory [CMAI]). Secondary outcomes were Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), and mortality. RESULTS: There was no significant difference between groups on the BADLS or CMAI. At 24 weeks, there was a nonsignificant adjusted difference in favor of memantine on the BADLS of 0.23 (95% CI -1.80 2.27; P = .82) and in favor of antipsychotic on the CMAI of 0.09 (95% CI -0.35 8.53; P = .07). Although there were no significant differences in total NPI, there were 5.01 (95% CI -1.68-11.70; P = .05) and 3.63 (95% CI -1.40-8.67; P = .16) point advantages favoring antipsychotics at weeks 12 and 24, respectively. In addition, in an exploratory analysis, individuals allocated to antipsychotics were significantly less likely to experience relapse of neuropsychiatric symptoms at all time points. The group receiving memantine had a nonsignificant 1.3-point advantage on the MMSE at 24 weeks. DISCUSSION: This study indicates no benefits for memantine in the long-term treatment and prophylaxis of clinically significant neuropsychiatric symptoms. The results did indicate some benefits for antipsychotic medications in reducing the relapse of neuropsychiatric symptoms, but this must be balanced against increased mortality risk. PMID- 25523286 TI - Self-reported walking speed: a useful marker of physical performance among community-dwelling older people? AB - BACKGROUND: Walking speed is central to emerging consensus definitions of sarcopenia and frailty as well as being a major predictor of future health outcomes in its own right. However, measurement is not always feasible in clinical settings. We hypothesized that self-reported walking speed might be a good marker of objectively measured walking speed for use in this context. METHODS: We investigated the relationship between self-reported and measured walking speed and their associations with clinical characteristics and mortality using data from 730 men and 999 women, aged 61 to 73 years, who participated in the Hertfordshire Cohort Study. Walking speed was measured over 3 meters. Participants rated their walking speed as "unable to walk," "very slow," "stroll at an easy pace," "normal speed," "fairly brisk," or "fast." RESULTS: Self reported walking speed was strongly associated with measured walking speed among men and women (P < .001). Average walking speeds ranged from 0.78 m/s (95% CI 0.73-0.83) among men with "very slow" self-reported walking speed to 0.98 m/s (95% CI 0.93-1.03) among "fast" walkers (corresponding figures for women were 0.72 m/s [95% CI 0.68-0.75] and 1.01 m/s [95% CI 0.98-1.05]). Self-reported and measured walking speeds were similarly associated with clinical characteristics and mortality; among men and women, slower self-reported and measured walking speeds were associated (P < .05) with increased likelihood of poor physical function, having more systems medicated and with increased mortality risk, with and without adjustment for sociodemographic and lifestyle factors (hazard ratios for mortality per slower band of self-reported walking speed, adjusted for sociodemographic and lifestyle characteristics: men 1.44 [95% CI 1.11-1.87]; women 1.35 [95% CI 1.02-1.81]). CONCLUSION AND IMPLICATIONS: Self-reported walking speed is a good marker of measured walking speed and could serve as a useful marker of physical performance in consensus definitions of sarcopenia and frailty when direct measurement of walking speed is not feasible. PMID- 25523287 TI - Pharmacokinetic/pharmacodynamic-based decision making in the development of MK 0888, a VEGFR-2/FLT-3 kinase inhibitor. AB - PURPOSE: MK-0888 is an investigational VEGFR-2 inhibitor with demonstrated potent in vitro enzyme activity. Clinical investigation in healthy volunteers and cancer patients was undertaken to evaluate its pharmacokinetic properties and early safety profile. Early data were used to guide whether further clinical development was warranted. METHODS: Five phase I studies were conducted. Studies 1-4 were conducted in healthy male volunteers and examined safety and pharmacokinetics across a dose range of 0.5-100 mg. Single-dose and limited multiple-dose escalations were performed. Three formulations and food effect were assessed. Study 5 was a dose escalation study in cancer patients, evaluating pharmacokinetics and safety at doses of 6-100 mg administered up to twice daily. RESULTS: Safety: MK-0888 was generally well tolerated in healthy volunteers at single doses up to 100 mg and in cancer patients at doses up to 100 mg twice daily. Pharmacokinetics: After single-dose administration, MK-0888 was readily absorbed with a T(max) of 4-5 h and a half-life of 11.3-22.7 h. AUC, C(max), and C(24h) increased in a slightly less than dose proportional manner. With longer duration multiple-dose administration (2 weeks), trough concentrations decreased from Day 2 at doses of 50 mg twice daily and higher, suggestive of autoinduction of metabolism. The efficacious trough pharmacokinetic target was not attained at steady state. CONCLUSIONS: The pharmacokinetic behavior of MK-0888 does not support continued development. The early pharmacokinetic profile of the compound provides important information as to the probability of success of MK-0888 achieving efficacious exposures. PMID- 25523288 TI - Impaired fasting pyloric compliance in gastroparesis and the therapeutic response to pyloric dilatation. AB - BACKGROUND: Pyloric pressure and compliance have never been investigated in health nor gastroparesis. AIM: We hypothesised that pyloric pressure and/or compliance may be altered in gastroparesis. METHODS: Fasting pyloric pressure and compliance were investigated in 21 healthy volunteers (HV), 27 gastroparetic patients (GP) and 5 patients who had undergone oesophagectomy without pyloroplasty as positive controls. Under videofluoroscopic control, pyloric compliance and pressure were measured by the EndoFLIP technique. Gastric emptying half time (T1/2 ) using (13) C-octanoic acid breath test, as well as symptoms and quality of life (GIQLI score) were also monitored. RESULTS: Mean fasting pyloric compliance was measured at 25.2 +/- 2.4 mm2/mmHg in HV, and was lower both in GP (16.9 +/- 2.1 mm2/mmHg; P < 0.05) and patients with oesophagectomy (10.9 +/- 2.9 mm2/mmHg; P < 0.05). By contrast, fasting pyloric pressure was not different among groups. Fasting pyloric compliance and pressure correlated with T1/2 in GP (R = -0.43; P = 0.04). Fasting pyloric compliance, but not pressure, correlated with symptoms and GIQLI score. Pyloric dilation in 10 GP with low fasting pyloric compliance (<10 mm2/mmHg) increased compliance from 7.4 +/- 0.4 to 20.1 +/- 4.9 mm2/mmHg (P < 0.01) and improved the GIQLI score from 72.5 +/- 5.5 to 89.3 +/- 6.1 (P = 0.04). CONCLUSION: This prospective study assessed pyloric compliance for the first time, and showed that fasting pyloric compliance is decreased in gastroparetic patients and is associated with T1/2 , symptoms and quality of life. This suggests that pyloric compliance may be a new relevant metric in gastroparetic patients, and may be useful to target patients for pyloric dilation or botulinum toxin injection. PMID- 25523289 TI - Effect of confertifolin from Polygonum hydropiper L. against dengue vector mosquitoes Aedes aegypti L. AB - The essential oil from the leaves of Polygonum hydropiper L. (Polygonaceae) was tested against Aedes aegypti L. The LC50 values were 190.72 and 234.37 ppm against second and fourth instar larvae of A. aegypti, respectively. Confertifolin (6,6,9a-trimethy l-4,5,5a,6,7,8,9,9a-octahydronaphtho [1,2-c] furan 3 (1H)-one) was isolated from the essential oil of P. hydropiper leaves using silica gel column chromatography. The LC50 values were 2.90 and 2.96 ppm for second and fourth instar larvae of A. aegypti, respectively. At 10 ppm, the concentration of confertifolin showed ovicidal activity of 100, 100, and 77.6 % on 0-6, 6-12, and 12-18 h old eggs; the repellent activity was 323.2 min; and oviposition deterrent activity was 97.52 % and adulticidal activity was 100 % against A. aegypti. The results were statistically significant at P < 0.05 level. The results suggested that confertifolin as an effective major constituent against A. aegypti and might be considered as a potent source for the production of superior natural mosquitocides. PMID- 25523291 TI - Prediction and quantifying parameter importance in simultaneous anaerobic sulfide and nitrate removal process using artificial neural network. AB - The present investigation deals with the prediction of the performance of simultaneous anaerobic sulfide and nitrate removal in an upflow anaerobic sludge bed (UASB) reactor through an artificial neural network (ANN). Influent sulfide concentration, influent nitrate concentration, S/N mole ratio, pH, and hydraulic retention time (HRT) for 144 days' steady-state condition were the inputs of the model; whereas output parameters were sulfide removal percentage, nitrate removal percentage, sulfate production percentage, and nitrogen production percentage. The prediction performance was evaluated by calculating root mean square error (RMSE), mean absolute error (MAE), mean absolute relative error (MARE), and determination coefficient (R (2)) values. Generally, the ANN model exhibited good prediction of the simultaneous sulfide and nitrate removal process. The effect of five input parameters to the performance of the reactor was quantified and compared using the connection weights method, Garson's algorithm method, and partial derivatives (PaD) method. The results showed that HRT markedly affects the performance of the reactor. PMID- 25523290 TI - Transcriptional response of stress-regulated genes to cadmium exposure in the cockle Cerastoderma glaucum from the gulf of Gabes area (Tunisia). AB - This study investigates cadmium effects on key messenger RNA (mRNA) expression (MT, MnSOD, CuZnSOD, CAT, ABCB1, HSP70, and CO1) by qPCR in the cockle Cerastoderma glaucum after chronic exposure to two high but environmentally relevant concentrations of CdCl2 (50 MUg/L and 5 mg/L) for 12 h to 18 days. Cd accumulation measured in cockles' tissues is significantly higher in both treatment conditions compared to controls and in a dose-dependent manner. Stress on stress tests performed at different times of the experiment clearly demonstrated that exposure to both concentrations of Cd significantly affects cockle survival time in air. Important changes in gene transcription were also highlighted. In particular, MT, HSP70, CAT, and CuZnSOD seem to be relevant biomarkers of Cd exposure because (1) their mRNA levels increase upon exposure and (2) they are highly correlated to Cd accumulation in tissues. Results may be useful for control strategies and for the use of cockles as sentinel organisms. PMID- 25523292 TI - The efficacy of artemisinin, artemether, and lumefantrine against Babesia gibsoni in vitro. AB - Artemisinin has many derivatives, and it is effective against Plasmodium spp. However, only a limited number of reports have confirmed the efficacy of artemisinin derivatives against Babesia spp. In this study, whether artemisinin and artemether could inhibit the growth of Babesia gibsoni was evaluated in vitro. In addition, the interaction between artemether and lumefantrine was evaluated. These drugs inhibited the growth of B. gibsoni, but artemisinin and artemether showed lower sensitivity against atovaquone-resistant B. gibsoni than against wild-type B. gibsoni. The interaction between artemether and lumefantrine showed synergism against B. gibsoni. Although further study is needed, the combination of artemisinin derivatives could be useful for babesiosis. PMID- 25523293 TI - Purification and characterization of Taenia crassiceps cysticerci thioredoxin: insight into thioredoxin-glutathione-reductase (TGR) substrate recognition. AB - Thioredoxin (Trx) is an oxidoreductase central to redox homeostasis in cells and is involved in the regulation of protein activity through thiol/disulfide exchanges. Based on these facts, our goal was to purify and characterize cytosolic thioredoxin from Taenia crassiceps cysticerci, as well as to study its behavior as a substrate of thioredoxin-glutathione reductase (TGR). The enzyme was purified >133-fold with a total yield of 9.7%. A molecular mass of 11.7kDa and a pI of 4.84 were measured. Native electrophoresis was used to identify the oxidized and reduced forms of the monomer as well as the presence of a homodimer. In addition to the catalytic site cysteines, cysticerci thioredoxin contains Cys28 and Cys65 residues conserved in previously sequenced cestode thioredoxins. The following kinetic parameters were obtained for the substrate of TGR: a Km of 3.1MUM, a kcat of 10s(-1) and a catalytic efficiency of 3.2*10(6)M(-1)s(-1). The negative patch around the alpha3-helix of Trx is involved in the interaction with TGR and suggests variable specificity and catalytic efficiency of the reductase toward thioredoxins of different origins. PMID- 25523294 TI - Extensive fibrous dysplasia of skull base: case report. PMID- 25523295 TI - Genetic Predisposition to Dyslipidemia and Risk of Preeclampsia. AB - BACKGROUND: Large epidemiologic studies support the role of dyslipidemia in preeclampsia; however, the etiology of preeclampsia or whether dyslipidemia plays a causal role remains unclear. We examined the association between the genetic predisposition to dyslipidemia and risk of preeclampsia using validated genetic markers of dyslipidemia. METHODS: Preeclampsia cases (n = 164) and normotensive controls (n = 110) were selected from live birth certificates to nulliparous Iowa women during the period August 2002 to May 2005. Disease status was verified by medical chart review. Genetic predisposition to dyslipidemia was estimated by 4 genetic risk scores (GRS) (total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglycerides) on the basis of established loci for blood lipids. Logistic regression analyses were used to evaluate the relationships between each of the 4 genotype scores and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry. RESULTS: The GRS related to higher levels of TC, LDL-C, and triglycerides demonstrated no association with the risk of preeclampsia in either the Iowa or replication population. The GRS related to lower HDL-C was marginally associated with an increased risk for preeclampsia (odds ratio (OR) = 1.03, 95% confidence interval (CI) = 0.99-1.07; P = 0.10). In the independent replication population, the association with the HDL C GRS was also marginally significant (OR = 1.03, 95% CI: 1.00-1.06; P = 0.04). CONCLUSIONS: Our data suggest a potential effect between the genetic predisposition to dyslipidemic levels of HDL-C and an increased risk of preeclampsia, and, as such, suggest that dyslipidemia may be a component along the causal pathway to preeclampsia. PMID- 25523296 TI - Association Between Arterial Stiffness and Skin Microvascular Function: The SUVIMAX2 Study and The Maastricht Study. AB - BACKGROUND: It has been hypothesized that arterial stiffness leads to generalized microvascular dysfunction and that individuals with type 2 diabetes mellitus (T2DM) are particularly prone to the detrimental effects of arterial stiffness. However, evidence for an association between stiffness and markers of generalized microvascular dysfunction is lacking. We therefore investigated the association between arterial stiffness and skin microvascular function in individuals without and with T2DM. METHODS: Cross-sectional data were used of The Supplementation en Vitamines et Mineraux Antioxydants 2 (SUVIMAX2) Study (n = 284/62.2 years/48.6% women/0% T2DM (by design)) and The Maastricht Study (n = 737/59.7 years/45.2% women/28.8% T2DM (by design)). Arterial stiffness was determined by carotid femoral pulse wave velocity (cfPWV). Skin capillaroscopy was used to determine capillary density at baseline, and during reactive hyperemia and venous congestion. Laser Doppler flowmetry was used to assess acetylcholine- and local heating-induced vasoreactivity, and skin flowmotion. RESULTS: In The SUVIMAX2 Study, cfPWV (per +1 SD) was not associated with baseline capillary density (regression coefficient: -0.48 (95% confidence interval: 2.37; 1.41)) or capillary recruitment during venous congestion (0.54% (-0.74; 1.81%)). In addition, cfPWV was not associated with acetylcholine (-0.02% (-0.14; 0.10%)) or local heating-induced vasoreactivity (0.03% (-0.07; 0.12%)). In The Maastricht Study, in individuals without T2DM, cfPWV was not associated with baseline capillary density (-1.20 (-3.17; 0.77)), and capillary recruitment during reactive hyperemia (1.22% (-0.41; 2.84%)) or venous congestion (1.50% (-0.25; 3.25%)). In addition, cfPWV was not associated with flowmotion (-0.01 (-0.07; 0.06)). Results were adjusted for age and sex. Additional adjustments for confounders did not materially change these results. Results were qualitatively similar in individuals with T2DM. CONCLUSIONS: Arterial stiffness is not associated with skin microvascular function, irrespective of the presence of T2DM. PMID- 25523297 TI - Seroepidemiology and clinical features of hepatitis delta among HBsAg carriers: a study from Hepatitis Clinic of Iranian Blood Transfusion Organization. AB - BACKGROUND: Hepatitis B is a significant health problem and more than 350 million individuals are infected with hepatitis B virus (HBV) globally. About 5% of these individuals are coinfected with hepatitis D virus (HDV). HBV-HDV coinfection increases the rate of fulminant hepatitis, chronic hepatitis and cirrhosis. This study aimed to evaluate the epidemiology of HDV in individuals positive for hepatitis B surface antigen (HBsAg) who were referred to Tehran Blood Transfusion Hepatitis Clinic from 2011 to 2012. MATERIALS AND METHODS: HBsAg-positive individuals attending this clinic were tested for anti-HDAg antibodies (anti HDAbs). All samples positive for anti-HDAb were also tested for detection of HDV RNA by reverse transcription-polymerase chain reaction (RT-PCR). A questionnaire consisting of demographic characteristics and potential risk factors for acquisition of HDV was filled for each individual. RESULTS: Among 1038 individuals, HBsAg was detected in 660 (63.6%) cases following blood donation and in 378 (36.4%) cases following blood testing. In this study, 23 [2.2%, 95% confidence interval (CI) = 1.3-3.2%] patients were HDV-seropositive. In HDV seropositive patients, 14 (60.9%, 95% CI = 39.1-78.3%) were positive for HDV RNA. HDV-seropositive cases were more likely to have evidence of severe forms of hepatitis than the group of individuals without anti-HDAb (P < 0.01). Familial history of hepatitis D infection was more observed in HDV-seropositive patients than in individuals negative for anti-HDAb (P < 0.01). CONCLUSION: The seroprevalence of HDV in HBsAg-positive individuals in this study was about 2% which seems to be lower than the global prevalence of HDV. PMID- 25523298 TI - A screening instrument to identify ulcerative colitis patients with the high possibility of current non-adherence to aminosalicylate medication based on the Health Belief Model: a cross-sectional study. AB - BACKGROUND: Non-adherence to aminosalicylates is observed among 30% to 45% of patients with ulcerative colitis and increases the risk of relapse. The Health Belief Model is a theoretical model that could offer a broader perspective to improve patients' self-medication adherence. This study aimed to develop a screening instrument based on the Health Belief Model to screen patients with ulcerative colitis who had a high possibility of current non-adherence to aminosalicylates. The study was also designed to allow examination of factors of non-adherence. METHODS: A multicenter, cross-sectional study was conducted in outpatients diagnosed with ulcerative colitis and prescribed aminosalicylates. Non-adherence was defined as taking less than 80% of the prescribed dose. We hypothesized that there was a significant relationship between current aminosalicylate non-adherence and five components of the HBM: beliefs about taking aminosalicylates, disease characteristics, medication characteristics, abdominal symptoms, and sociodemographic characteristics. A logistic regression model was applied and the coefficients converted to a numeric scores in order to develop a screening instrument which could reliably discriminate non-adherent and adherent subjects. RESULTS: Non-adherence was observed in 127 (29.6%) of the 429 enrolled subjects. Lower perceptions of belief in taking aminosalicylates, absence of visible bleeding, eight daily tablets or less taken, and no concomitant use of thiopurines were related to non-adherence. We then developed a screening instrument comprising 22 items. When the cut-off point was set at 60, the instrument showed 85.0% sensitivity and 69.2% specificity with an area under the curve of 0.84 (95% confidence interval = 0.79-0.91). CONCLUSIONS: The instrument appeared to be reliable for identifying patients with a high possibility of current non-adherence to aminosalicylates. Further, the instrument may provide useful information for detecting patients with a high possibility of current non-adherence and for assessing factors of non-adherence. On the other hand, we need to evaluate disease activity more strictly and examine whether it is included in the screening instrument in the future. PMID- 25523299 TI - Plasma and intracellular pharmacokinetic-pharmacodynamic analysis of mycophenolic acid in de novo kidney transplant patients. AB - OBJECTIVES: Little is known about the correlation between the inosine monophosphate dehydrogenase (IMPDH) activity and mycophenolic acid (MPA) concentrations in peripheral-blood-mononuclear cells (PBMCs), where the drug is acting. The aim of this study was to analyze the relationship between plasma or PBMC MPA levels, as pharmacokinetic (PK) markers, and the intracellular IMPDH enzyme activity, as a pharmacodynamic (PD) biomarker, in kidney transplantation. DESIGN AND METHODS: Forty de novo renal transplant patients were enrolled in this prospective study. The sampling was performed on the day before transplantation and at T0, T1.5 and T3.5 following the morning dose, on days 2, 4 and 10 post transplantation. All subjects were treated with a fixed MMF dose (500 mg twice-a day). IMPDH activities were determined by HPLC, and MPA plasma or PBMC concentrations were obtained by LC-MSMS. RESULTS: Important inter-patient variability was observed both for the PK and PD biomakers. Pre-dose IMPDH activity, surprisingly, increased during the 10 days post-transplantation. As expected, a significant inverse relationship was found between IMPDH activities and MPA concentrations in both plasma and PBMCs. A significant correlation was found between plasma and PBMC MPA values. Maximum IMPDH inhibition was found mostly at T1.5, before returning to its pre-dose levels at T3.5. IMPDH inhibition at T1.5 better correlated with plasma MPA AUC(0-3.5) (p=0.027) than with PBMC AUC(0-3.5) (p=0.323). Mean MPA plasma concentrations paralleled the enzyme inhibition profiles and decreased strongly at T3.5, whereas the decreasing slope of MPA concentrations in PBMCs appeared slower. CONCLUSIONS: These findings suggest that PBMC MPA concentrations do not provide any better correlation with the IMPDH activity than plasma MPA values, most likely due to the correlation between plasma and PBMC MPA levels and to the important interpatient variability both in MPA levels and enzyme activities. PMID- 25523300 TI - Detection of BRAF-V600E and V600K in melanoma circulating tumour cells by droplet digital PCR. AB - OBJECTIVES: Defining the BRAF mutation status in metastatic melanoma patients is critical to selecting patients for therapeutic treatment with targeted therapies. Circulating tumour cells (CTCs) can provide an alternative source of contemporaneous tumour genetic material. However methodologies to analyse the presence of rare mutations in a background of wild-type DNA requires a detailed assessment. Here we evaluate the sensitivity of two technologies for cancer mutation detection and the suitability of whole genome amplified DNA as a template for the detection of BRAF-V600 mutations. DESIGN AND METHODS: Serial dilutions of mutant BRAF-V600E DNA in wild-type DNA were tested using both competitive allele-specific PCR (castPCR) and droplet digital PCR (ddPCR), with and without previous whole genome amplification (WGA). Using immunomagnetic beads, we partially enriched CTCs from blood obtained from metastatic melanoma patients with confirmed BRAF mutation positive tumours and extracted RNA and DNA from the CTCs. We used RT-PCR of RNA to confirm the presence of melanoma cells in the CTC fraction then the DNAs of CTC positive fractions were WGA and tested for BRAF V600E or V600K mutations by ddPCRs. RESULTS: WGA DNA produced lower than expected fractional abundances by castPCR analysis but not by ddPCR. Moreover, ddPCR was found to be 200 times more sensitive than castPCR and in combination with WGA produced the most concordant results, with a limit of detection of 0.0005%. BRAF-V600E or V600K mutated DNA was detected in 77% and 44%, respectively, of enriched CTC fractions from metastatic melanoma patients carrying the corresponding mutations. CONCLUSIONS: Our results demonstrate that using ddPCR in combination with WGA DNA allows the detection with high sensitivity of cancer mutations in partially enriched CTC fractions. PMID- 25523301 TI - Stability of selected serum hormones and lipids after long-term storage in the Janus Serum Bank. AB - BACKGROUND: The potential value of a biobank depends on the quality of the samples, i.e. how well they reflect the biological or biochemical state of the donors at the time of sampling. Documentation of sample quality has become a particularly important issue for researchers and users of biobank studies. OBJECTIVE: The aim of this study was to investigate the long-term stability of selected components: cholesterol, high density cholesterol (HDLC), low density cholesterol (LDLC), apolipoprotein A1 (apo-A1), apolipoprotein B (apo B), follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), thyroid stimulating hormone (TSH) and free thyroxin (FT4). DESIGN AND METHODS: Samples, stored at -25 degrees C, from 520 men aged 40-49 years at blood sampling distributed in equally sized groups (n=130) according to length of storage, 0, 4, 17 and 29 years, respectively, were used in a cross sectional design. The freshly collected serum samples were used as a reference group to calculate storage related changes. RESULTS: The differences between fresh samples and samples stored for 29 years were substantial for apo-A1 (+12%), apo-B (+22.3%), HDLC ( 69.2%), LDLC (+31.3%), and PRL (-33.5%), while total cholesterol, FSH, LH, TSH and FT4 did not show any significant difference. CONCLUSIONS: The study showed large differences in serum level of the selected components. The lipids and apolipoproteins were all changed except for total cholesterol. Most hormones investigated (FSH, LH, TSH and FT4) proved to be stable after 29 years of storage while PRL showed sign of degradation. The observed differences are probably due to long-term storage effects and/or external factors (i.e. diet and smoking). PMID- 25523302 TI - Diffusion Tensor Imaging in Radiation-Induced Myelopathy. AB - Radiation myelopathy (RM) is a rare complication of spinal cord irradiation. Diagnosis is based on the history of radiotherapy, laboratory tests, and magnetic resonance imaging of the spinal cord. The MRI findings may nevertheless be quite unspecific. In this paper, we describe the findings of diffusion tensor imaging in a case of the delayed form of RM. We observed areas of restricted diffusion within the spinal cord which probably corresponded to the ischemic changes. This would concur with the currently accepted pathogenetic theory concerning RM. PMID- 25523303 TI - Effects of Mood Induction on the Pain Responses in Patients with Migraine and the Role of Pain Catastrophizing. AB - Migraine has close associations with depression and anxiety. Catastrophizing, an alarmist reaction to pain, has been proposed as one of the mediators in the relationship between headache and emotional distress. However, much experimental evidence is needed to make such a view more validated. The aims of this study are to examine the effects of mood induction on the pain responses and to investigate the role of pain catastrophizing in the relationship between pain and mood amongst a sample of patients with migraine. For this purpose, 60 patients with migraine were recruited from a headache clinic in Tehran-Iran and were randomly assigned into one of three groups: negative mood induced group, positive mood induced group and control group. The following instruments and measures were used in this study: mood induction by presenting different types of films (positive, negative), a computerized cognitive task to elicit pain, Beck Depression Inventory and Pain Catastrophizing Scale. The results showed that while the induction of depressed mood increased the pain intensity, the induction of positive mood reduced it significantly (p < 0.05). Further analyses revealed that catastrophizing is as a confounding factor in the relationship between pain and mood. Once catastrophizing scores were entered into the analyses as a covariate, the significant effect of mood on the pain intensity reduced. In conclusion, both mood and catastrophizing are important factors in understanding the migraine pain. Clinical implications of these findings are discussed in the paper. Copyright (c) 2014 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Pain-related catastrophizing and mood induction are important factors in understanding pain intensity amongst patients with migraine pain. Catastrophizing as a confounding factor in the relationship between pain and mood may partially mediate the relationship between mood and pain. Therapeutic interventions should focus on the reduction of depression and catastrophizing. PMID- 25523304 TI - Identification and characterization of the CONSTANS-like gene family in the short day plant Chrysanthemum lavandulifolium. AB - The CONSTANS (CO) and CONSTANS-like (COL) genes play key roles in the photoperiodic flowering pathways, and studying their functions can elucidate the molecular mechanisms underlying flowering control in photoperiod-regulated plants. We identified eleven COL genes (ClCOL1-ClCOL11) in Chrysanthemum lavandulifolium and divided them into three groups that are conserved among the flowering plants based on phylogenetic analysis. Most of the ClCOL genes are primarily expressed in the leaf and shoot apices, except for ClCOL6-ClCOL9, which belong to Group II. The expression levels of ClCOL4-ClCOL5 and ClCOL7-ClCOL8 are up-regulated under inductive short-day (SD) conditions, whereas ClCOL6 is down regulated under inductive SD conditions. The ClCOL genes exhibit four different diurnal rhythm expressions (Type I-Type IV). The Type I genes (ClCOL4-ClCOL5) are highly transcribed under light. The Type II genes (ClCOL1-ClCOL2, ClCOL10) display increased expression in darkness and are rapidly suppressed under light. Transcripts of ClCOL6-ClCOL9 and ClCOL11, belonging to Type III, are abundant in the late light period or at the beginning of the dark period. ClCOL3 belongs to Type IV, with high expression in the early light period and dark period. The peak expression levels of ClCOL4-ClCOL6 are decreased and postponed in the non inductive night break (NB) and under long-day (LD) conditions, indicating that those genes may play an essential role in the flowering regulation of C. lavandulifolium. The overexpression of ClCOL5 promotes the flowering of Arabidopsis grown under LD conditions, suggesting that ClCOL5 may function as a flowering enhancer in C. lavandulifolium. This study will be useful not only for the study of the C. lavandulifolium photoperiod-dependent flowering process but also for the genetic manipulation of flowering time-related genes to change the flowering time in the chrysanthemum. PMID- 25523307 TI - CT features of pulmonary arterial hypertension and its major subtypes: a systematic CT evaluation of 292 patients from the ASPIRE Registry. AB - We evaluated the prevalence and prognostic value of CT-pulmonary angiographic (CTPA) measures in 292 treatment naive patients with pulmonary arterial hypertension (PAH). Pulmonary artery calcification (13%) and thrombus (10%) were exclusively seen in PAH-congenital heart disease. Oesophageal dilation (46%) was most frequent in PAH-systemic sclerosis. Ground glass opacification (GGO) (41%), pericardial effusion (38%), lymphadenopathy (19%) and pleural effusion (11%) were common. On multivariate analysis, inferior vena caval area, the presence of pleural effusion and septal lines predicted outcome. In PAH, CTPA provides diagnostic and prognostic information. In addition, the presence of GGO on a CT performed for unexplained breathlessness should alert the physician to the possibility of PAH. PMID- 25523308 TI - The mechanism of rapamycin in the intervention of paraquat-induced acute lung injury in rats. AB - 1. Paraquat (PQ) is an organic nitrogen heterocyclic herbicide that is widely used in agriculture throughout the world. Numerous studies have reported PQ intoxication on humans. 2. In this study, we established a rat lung injury model induced by PQ and evaluated the intervention effect of rapamycin on the model, exploring the pathogenesis of PQ on lung injury as well as therapeutic effects of rapamycin on PQ-induced lung injury. 3. A rat lung injury model was established by gavage of PQ, and rapamycin was used to treat the model animals with PQ induced lung injury. Different physiological indices were measured through Western blot and real-time polymerase chain reaction to evaluate the effect of rapamycin on the PQ-induced lung injury. 4. The analyses showed that application of rapamycin could significantly reduce the lung injury damage caused by PQ, with lung tissue wet-dry weight ratio, pathological features, compositions in serum, protein in bronchoalveolar lavage fluid and other indices being significantly improved after the injection of rapamycin. 5. It was inferred that the use of rapamycin could improve the PQ-induced lung injury through inhibiting the activity of mTOR. And we expected the use of rapamycin to be a potential treatment method for the PQ intoxication in future. PMID- 25523309 TI - Co-option of alternate sperm activation programs in the evolution of self-fertile nematodes. AB - Self-fertility evolved independently in three species of Caenorhabditis, yet the underlying genetic changes remain unclear. This transition required that XX animals acquire the ability to produce sperm and then signal those sperm to activate and fertilise oocytes. Here, we show that all genes that regulate sperm activation in C. elegans are conserved throughout the genus, even in male/female species. By using gene editing, we show that C. elegans and C. briggsae hermaphrodites use the SPE-8 tyrosine kinase pathway to activate sperm, whereas C. tropicalis hermaphrodites use a TRY-5 serine protease pathway. Finally, our analysis of double mutants shows that these pathways were redundant in ancestral males. Thus, newly evolving hermaphrodites became self-fertile by co-opting either of the two redundant male programs. The existence of these alternatives helps explain the frequent origin of self-fertility in nematode lineages. This work also demonstrates that the new genome-editing techniques allow unprecedented power and precision in evolutionary studies. PMID- 25523310 TI - Internal dosimetry of nuclear medicine workers through the analysis of (131)I in aerosols. AB - (131)I is widely used in nuclear medicine for diagnostic and therapy of thyroid diseases. Depending of workplace safety conditions, routine handling of this radionuclide may result in a significant risk of exposure of the workers subject to chronic intake by inhalation of aerosols. A previous study including in vivo and in vitro measurements performed recently among nuclear medicine personnel in Brazil showed the occurrence of (131)I incorporation by workers involved in the handling of solutions used for radioiodine therapy. The present work describes the development, optimization and application of a methodology to collect and analyze aerosol samples aiming to assess internal doses based on the activity of (131)I present in a radiopharmacy laboratory. Portable samplers were positioned at one meter distant from the place where non-sealed liquid sources of (131)I are handled. Samples were collected over 1h using high-efficiency filters containing activated carbon and analyzed by gamma spectrometry with a high-purity germanium detection system. Results have shown that, although a fume hood is available in the laboratory, (131)I in the form of vapor was detected in the workplace. The average activity concentration was found to be of 7.4Bq/m(3). This value is about three orders of magnitude below the Derived Air Concentration (DAC) of 8.4kBq/m(3). Assuming that the worker is exposed by inhalation of iodine vapor during 1h, (131)I concentration detected corresponds to an intake of 3.6Bq which results in a committed effective dose of 7.13*10(-5)mSv. These results show that the radiopharmacy laboratory evaluated is safe in terms of internal exposure of the workers. However it is recommended that the presence of (131)I should be periodically re-assessed since it may increase individual effective doses. It should also be pointed out that the results obtained so far reflect a survey carried out in a specific workplace. Thus, it is suggested to apply the methodology developed in this work to other nuclear medicine services where significant activities of (131)I are routinely handled as an effective means to optimize individual exposures and improve occupational radiation protection safety. PMID- 25523311 TI - Thermal effect on thermoluminescence response of hydroxyapatite. AB - This paper presents the experimental results of the thermoluminescence (TL) induced by gamma radiation in synthetic hydroxyapatite (HAp) obtained by the precipitation method, using Ca(NO3)2.4H2O and (NH4)2HPO4 and calcined at different temperatures. The structural and morphological characterization was carried out by X-ray diffraction (XRD) and scanning electron microscopy (SEM) techniques. TL response as a function of gamma radiation dose was in a wide range, where intensity was enhanced in the sample annealed at 900 degrees C, which tricalcium diphosphate (TCP) phase appear. Fading of the TL was also studied. PMID- 25523312 TI - A genome-guided analysis of energy conservation in the thermophilic, cytochrome free acetogenic bacterium Thermoanaerobacter kivui. AB - BACKGROUND: Acetogenic bacteria are able to use CO2 as terminal electron acceptor of an anaerobic respiration, thereby producing acetate with electrons coming from H2. Due to this feature, acetogens came into focus as platforms to produce biocommodities from waste gases such as H2+CO2 and/or CO. A prerequisite for metabolic engineering is a detailed understanding of the mechanisms of ATP synthesis and electron-transfer reactions to ensure redox homeostasis. Acetogenesis involves the reduction of CO2 to acetate via soluble enzymes and is coupled to energy conservation by a chemiosmotic mechanism. The membrane-bound module, acting as an ion pump, was of special interest for decades and recently, an Rnf complex was shown to couple electron flow from reduced ferredoxin to NAD+ with the export of Na+ in Acetobacterium woodii. However, not all acetogens have rnf genes in their genome. In order to gain further insights into energy conservation of non-Rnf-containing, thermophilic acetogens, we sequenced the genome of Thermoanaerobacter kivui. RESULTS: The genome of Thermoanaerobacter kivui comprises 2.9 Mbp with a G+C content of 35% and 2,378 protein encoding orfs. Neither autotrophic growth nor acetate formation from H2+CO2 was dependent on Na+ and acetate formation was inhibited by a protonophore, indicating that H+ is used as coupling ion for primary bioenergetics. This is consistent with the finding that the c subunit of the F1FO ATP synthase does not have the conserved Na+ binding motif. A search for potential H+-translocating, membrane-bound protein complexes revealed genes potentially encoding two different proton reducing, energy-conserving hydrogenases (Ech). CONCLUSIONS: The thermophilic acetogen T. kivui does not use Na+ but H+ for chemiosmotic ATP synthesis. It does not contain cytochromes and the electrochemical proton gradient is most likely established by an energy-conserving hydrogenase (Ech). Its thermophilic nature and the efficient conversion of H2+CO2 make T. kivui an interesting acetogen to be used for the production of biocommodities in industrial micobiology. Furthermore, our experimental data as well as the increasing number of sequenced genomes of acetogenic bacteria supported the new classification of acetogens into two groups: Rnf- and Ech-containing acetogens. PMID- 25523313 TI - Posterior brain white matter abnormalities in older adults with probable mild cognitive impairment. AB - OBJECTIVE: Much of the mild cognitive impairment (MCI) neuroimaging literature has exclusively focused on regions associated with Alzheimer's disease. Little research has examined white matter abnormalities of other brain regions, including those associated with visual processing, despite evidence that other brain abnormalities appear in these regions in early disease stages. METHOD: Diffusion tensor imaging (DTI) was utilized to examine participants (n = 44) that completed baseline imaging as part of a longitudinal healthy aging study. Participants were divided into two groups based on scores from the Montreal Cognitive Assessment (MoCA), a brief screening tool for MCI. Participants who scored <26 were defined as "probable MCI" while those who scored >=26 were labeled cognitively healthy. Two DTI indices were analyzed including fractional anisotropy (FA) and mean diffusivity (MD). DTI values for white matter in the lingual gyrus, cuneus, pericalcarine, fusiform gyrus, and all four lobes were compared using multivariate analysis of variance (MANOVA). Regression analyses examined the relationship between DTI indices and total MoCA score. RESULTS: RESULTS revealed significantly lower FA in the probable MCI group in the cuneus, fusiform, pericalcarine, and occipital lobe, and significantly higher MD in the temporal lobe. Fusiform FA and temporal lobe MD were significantly related to total MoCA score after accounting for age and education. CONCLUSIONS: RESULTS indicate that there are posterior white matter microstructural changes in individuals with probable MCI. These differences demonstrate that white matter abnormalities are evident among individuals with probable MCI in regions beyond those commonly associated with Alzheimer's disease and anterior brain aging patterns. PMID- 25523314 TI - Transperineal template-guided prostate biopsy: 10 years of experience. AB - OBJECTIVE: To assess the efficacy and safety of transperineal template-guided prostate biopsy. MATERIALS AND METHODS: From December 2003 to December 2013, a total of 3 007 patients (30-91 years old, mean age 69.1) who met the inclusion criteria underwent 11-region transrectal ultrasound-guided transperineal template prostate biopsy. The inclusion criteria included a prostate-specific antigen (PSA) level of 4.0 ng/mL or greater and abnormal prostate gland findings on digital rectal examination, ultrasound, CT or MRI. The median PSA level was 11.0 ng/mL (range 0.2-100 ng/mL). The prostate cancer detection rate and prostate biopsy adverse effects, as well as prostate cancer spatial distribution were analyzed. RESULTS: A mean of 19.3 cores (range 11-44) were obtained for each biopsy, and more cores were obtained in larger prostates than in smaller ones. One to four cores were collected from each region. Prostate cancer was detected in 1 067 of the 3 007 patients (35.5%). The prostate cancer detection rates in groups with PSA levels of 0-4.0 ng/mL, 4.1-10.0 ng/mL, 10.1-20.0 ng/mL, 20.1-50.0 ng/mL, and 50.1-100.0 ng/mL were 15.3% (27/176), 21.0% (248/1 179), 32.6% (318/975), 56.0% (232/414), and 92.0% (241/262), respectively. The mean positives for cancer in regions 1-10 and region 11 (the apical region) were 46.7% vs 52.0% (P = 0.014). Regarding adverse effects, 47.0% of the patients reported hematuria, 6.1% developed hemospermia, 1.9% required short-term catheterization after biopsy because of acute urinary retention, and 0.03% (one patient) developed urosepsis. CONCLUSIONS: Transrectal ultrasound-guided transperineal template prostate biopsy is safe and accurate. The current study suggests that prostate carcinoma foci are more frequently localized in the apical region. PMID- 25523315 TI - Using Grounded Theory Method to Capture and Analyze Health Care Experiences. AB - OBJECTIVE: Grounded theory (GT) is an established qualitative research method, but few papers have encapsulated the benefits, limits, and basic tenets of doing GT research on user and provider experiences of health care services. GT can be used to guide the entire study method, or it can be applied at the data analysis stage only. METHODS: We summarize key components of GT and common GT procedures used by qualitative researchers in health care research. We draw on our experience of conducting a GT study on amyotrophic lateral sclerosis patients' experiences of health care services. FINDINGS: We discuss why some approaches in GT research may work better than others, particularly when the focus of study is hard-to-reach population groups. We highlight the flexibility of procedures in GT to build theory about how people engage with health care services. CONCLUSION: GT enables researchers to capture and understand health care experiences. GT methods are particularly valuable when the topic of interest has not previously been studied. GT can be applied to bring structure and rigor to the analysis of qualitative data. PMID- 25523316 TI - Caregiver preferences for emerging duchenne muscular dystrophy treatments: a comparison of best-worst scaling and conjoint analysis. AB - BACKGROUND: Through Patient-Focused Drug Development, the US Food and Drug Administration (FDA) documents the perspective of patients and caregivers and are currently conducting 20 public meetings on a limited number of disease areas. Parent Project Muscular Dystrophy (PPMD), an advocacy organization for Duchenne muscular dystrophy (DMD), has demonstrated a community-engaged program of preference research that would complement the FDA's approach. OBJECTIVE: Our objective was to compare two stated-preference methods, best-worst scaling (BWS) and conjoint analysis, within a study measuring caregivers' DMD-treatment preferences. METHODS: Within one survey, two preference-elicitation methods were applied to 18 potential treatments incorporating six attributes and three levels. For each treatment profile, caregivers identified the best and worst feature and intention to use the treatment. We conducted three analyses to compare the elicitation methods using parameter estimates, conditional attribute importance and policy simulations focused on the 18 treatment profiles. For each, concordance between the results was compared using Spearman's rho. RESULTS: BWS and conjoint analysis produced similar parameter estimates (p < 0.01); conditional attribute importance (p < 0.01); and policy simulations (p < 0.01). Greatest concordance was observed for the benefit and risk parameters, with differences observed for nausea and knowledge about the drug-where a lack of monotonicity was observed when using conjoint analysis. CONCLUSIONS: The observed concordance between approaches demonstrates the reliability of the stated preference methods. Given the simplicity of combining BWS and conjoint analysis on single profiles, a combination approach is easily adopted. Minor irregularities for the conjoint-analysis results could not be explained by additional analyses and needs to be the focus of future research. PMID- 25523317 TI - A case of delayed oxaliplatin-induced pseudo-obstruction: an atypical presentation of oxaliplatin neurotoxicity. AB - Chemotherapy-induced neurotoxicity is a serious complication of cancer treatment. Oxaliplatin, a third-generation platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer. Peripheral neuropathy is a common complication of platinum-based chemotherapy. Most commonly a sensory neuropathy occurs with cold-triggered symptoms in the acute phase and numbness and painful paresthesias as a late presentation. Autonomic neurotoxicity and late presentation, months after cessation of the therapy, has rarely been described. We report a patient who clinically presented with a pseudo-obstruction months after treatment with oxaliplatin for metastatic colorectal cancer. Intestinal adhesions and relapsing malignancy were carefully excluded. By exclusion the pseudo-obstruction was attributed to a toxic oxaliplatin-induced autonomic neuropathy which slowly improved during months of follow-up. PMID- 25523318 TI - Staphylococcus saprophyticus bacteremia after ESWL in an immunocompetent woman. AB - Staphylococcus saprophyticus is a well-known cause of uncomplicated urinary tract infections, especially in young and sexually active women. Presence in blood cultures is rare and often attributed to contamination. When bacteremia is significant, it occurs mostly in patients with hematologic malignancies and is predominantly catheter-related. However, we describe a case of significant bacteremia with S. saprophyticus associated with urinary tract infection after extracorporeal shock wave lithotripsy of an ureterolithiasis in an otherwise healthy patient. PMID- 25523319 TI - [Pediatric emergencies in the emergency medical service]. AB - Out-of-hospital pediatric emergencies occur rarely but are feared among medical personnel. The particular characteristics of pediatric cases, especially the unaccustomed anatomy of the child as well as the necessity to adapt the drug doses to the little patient's body weight, produce high cognitive and emotional pressure. In an emergency standardized algorithms can facilitate a structured diagnostic and therapeutic approach. The aim of this article is to provide standardized procedures for the most common pediatric emergencies. In Germany, respiratory problems, seizures and analgesia due to trauma represent the most common emergency responses. This article provides a practical approach concerning the diagnostics and therapy of emergencies involving children. PMID- 25523320 TI - [Tapia's syndrome : Rare complication of securing airways]. AB - Nerve injuries are a rare complication of airway management. Two cases of Tapia's syndrome following orotracheal intubation are reported. Case 1: a 23-year-old male patient underwent an otorhinolaryngology (ENT) surgical procedure with orotracheal intubation. A left-sided Tapia's syndrome was verified 3 days later. Case 2: a 67-year-old patient developed a right-sided Tapia's syndrome following an arthroscopic intervention of the left shoulder in the beach-chair position. In both cases there was permanent damage of both nerves. On the basis of a comprehensive literature survey the reasons for an intubation-induced Tapia's syndrome are discussed. In order to avoid a glottis or immediate subglottic position it is recommended to check and to document the position of the cuff (depth of intubation) and the measured cuff pressure immediately after intubation. It also seems to be advisable to document an overstretched head position if required for the operation. PMID- 25523321 TI - [Ultrasound-guided infraclavicular venipuncture at the junction of the axillary and subclavian veins]. AB - BACKGROUND: Compared to other access routes a central venous catheter inserted via the subclavian vein (VS) is advantageous in terms of patient comfort, care of the puncture site and the infection rate. Puncture of the VS admittedly has a higher risk of mechanical complications but ultrasound guidance can reduce this risk; however, it is technically demanding due to anatomical peculiarities and this access route is therefore used comparatively less frequently. AIM: The aim of the study was to clarify to what extent a modified puncture technique guided by sonography can reduce the risk potential. MATERIAL UND METHODS: A technique is presented in which the infraclavicular insertion site is laterally shifted in the direction of the axillary vein (VA). RESULTS: When the vein is visualized by sonography in the long axis the accompanying artery and the pleura remain outside the ultrasound plane. By doing so, a needle that is strictly guided in the imaging plane can barely damage these structures even if accidentally inserted too deep as they lie outside of the needle trajectory. CONCLUSION: This presented technique can provide benefits for operators experienced in in-plane puncture. PMID- 25523322 TI - [Hot topics in neuroanesthesiology : Three important publications in 2013 and 2014]. PMID- 25523323 TI - Sialolithiasis: use tomosynthesis! PMID- 25523324 TI - Superficial brachioradial artery: multidetector-row computed tomography angiography findings in one case. PMID- 25523325 TI - Treatment of pelvic venous insufficiency with amplatzer vascular plugs. PMID- 25523326 TI - Continuous exposure to dizocilpine facilitates the acquisition and escalation of cocaine consumption in male Sprague-Dawley rats. AB - BACKGROUND: Blocking N-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) prevents cocaine locomotor sensitization, but facilitates escalation of cocaine self-administration and produces ambiguous effects on acquisition of cocaine self administration. This study used a recently described model of acquisition and escalation to test the hypothesis that continuous NMDAR antagonism functionally increases the effects of a given dose of cocaine. METHODS: We assessed acquisition of cocaine self-administration (0.6 mg/kg/infusion) in rats treated continuously with either vehicle or the NMDAR antagonist dizocilpine (0.4 mg/kg/day) for 14 consecutive 2h fixed ratio 1 (FR1) sessions. In a separate experiment that assessed the effect of dizocilpine treatment on escalation of cocaine self-administration, rats acquired cocaine self-administration (0.6 mg/kg/infusion) prior to vehicle or dizocilpine treatment. Then, immediately post acquisition, rats were treated continuously with either vehicle or dizocilpine and allowed to self-administer either 0.6 or 1.2mg/kg/infusion cocaine for an additional seven consecutive 2h FR1 sessions. RESULTS: Relative to vehicle treated rats, a significantly greater percentage of dizocilpine-treated rats acquired cocaine self-administration. During the escalation experiment, both vehicle- and dizocilpine-treated rats escalated intake of 1.2mg/kg/infusion cocaine. Whereas vehicle-treated rats exhibited stable intake of 0.6 mg/kg/infusion cocaine, dizocilpine-treated rats escalated intake of this moderate cocaine dose to levels indistinguishable from intake levels produced by self-administration of the high cocaine dose (i.e., 1.2mg/kg/infusion). CONCLUSIONS: These findings suggest that chronic NMDAR blockade potentiates, rather than attenuates, cocaine's effects and argue for reconsideration of the role of NMDARs in cocaine "addiction-like" behavior. PMID- 25523327 TI - EPMLR: sequence-based linear B-cell epitope prediction method using multiple linear regression. AB - BACKGROUND: B-cell epitopes have been studied extensively due to their immunological applications, such as peptide-based vaccine development, antibody production, and disease diagnosis and therapy. Despite several decades of research, the accurate prediction of linear B-cell epitopes has remained a challenging task. RESULTS: In this work, based on the antigen's primary sequence information, a novel linear B-cell epitope prediction model was developed using the multiple linear regression (MLR). A 10-fold cross-validation test on a large non-redundant dataset was performed to evaluate the performance of our model. To alleviate the problem caused by the noise of negative dataset, 300 experiments utilizing 300 sub-datasets were performed. We achieved overall sensitivity of 81.8%, precision of 64.1% and area under the receiver operating characteristic curve (AUC) of 0.728. CONCLUSIONS: We have presented a reliable method for the identification of linear B cell epitope using antigen's primary sequence information. Moreover, a web server EPMLR has been developed for linear B-cell epitope prediction: http://www.bioinfo.tsinghua.edu.cn/epitope/EPMLR/ . PMID- 25523328 TI - Intervertebral disc disease in Dachshunds radiographically screened for intervertebral disc calcifications. AB - BACKGROUND: Intervertebral disc disease (IDD) is a very common neurological disease, Dachshunds being the breed most often affected. In this breed, IDD has a hereditary background and is associated with intervertebral disc calcification (IDC), an indicator of severe intervertebral disc degeneration. In Finland, spinal radiography is used, when screening for IDC before breeding Dachshunds. We evaluated the association between IDC and IDD in Finnish Dachshunds radiographically screened for IDC. A questionnaire was sent to owners of 193 radiographically screened Dachshunds aged at least ten years. Clinical signs indicative of IDD were compared with IDC grade (grade 0 = no calcifications, grade 1 = 1 - 2 calcifications, grade 2 = 3 - 4 calcifications and grade 3 = 5 or more calcifications) and with age at the time of the radiographic examination. The diagnosis of IDD was confirmed by a veterinarian. RESULTS: IDD was common in the study population with 31% of dogs being affected. IDD and IDC were clearly connected (P < 0.001); IDD was rare in dogs with no calcifications (grade 0) and common in dogs with severe IDC (grade 3). The IDC grade was strongly positively associated with frequency of back pain periods (P < 0.001), and dogs with IDC grade 3 had frequent periods of pain. Reluctance to jump onto a sofa had a strong positive association with back pain. No association existed between age of the dog at the time of the radiographic examination and clinical signs indicative of IDD. CONCLUSIONS: Radiographically detected IDC and IDD are common in Finnish Dachshunds and are strongly associated with one another. Spinal radiography is an appropriate screening tool for breeders attempting to diminish IDC and IDD in Dachshunds. A breeding program that screens dogs and selects against IDC can be expected to reduce the occurrence of IDD in future. Twenty-four to 48 months of age is a suitable age for screening. PMID- 25523329 TI - Necrotic ulcerations after splenectomy. PMID- 25523330 TI - Solvation of an excess electron in pyrrolidinium dicyanamide based ionic liquids. AB - In a recent article [J. Am. Chem. Soc. 2011, 133, 20186], we described the nature of the "dry" excess electron in a variety of different ionic liquids. We found that this could delocalize over cations or anions depending on the nature of the ions involved. A second article [J. Am. Chem. Soc. 2013, 135, 17528] explored the nature of the "dry to trapped" excess electron transition, the early localization dynamics, and associated spectroscopic signatures in alkylamonium and pyrrolidinium bis(trifluoromethylsulfonyl)amide based ionic liquids. In this study we predicted that the trapped electron localizes on an anion, resulting in fragmentation that is undesirable for photochemical, electrochemical, and radiation chemistry applications. The current work focuses instead on an ionic liquid based on the dicyanamide anion that on a time scale relevant to electron transfer and solvation dynamics does not appear to undergo facile fragmentation. Although electrochemical cathodic and anodic limits were correctly predicted by our recent study, it is unclear whether the reaction channels explored are necessarily those responsible for the observed near-infrared (NIR) band typical of excess electrons at long time. Could it be possible that the electrochemically relevant reaction channel is not necessarily the one giving rise to the NIR signal? This work attempts to approach such structural and dynamical aspects relevant to photodegradation, radiation chemistry, and electrochemistry in the case of pyrrolidinium dicyanamide based ionic liquids. PMID- 25523331 TI - [Anterior polar pyramidal cataract]. PMID- 25523332 TI - [Pseudotumor cerebri in children with sickle cell disease]. PMID- 25523333 TI - Acute renal failure is prevalent in patients with thrombotic thrombocytopenic purpura associated with low plasma ADAMTS13 activity. AB - BACKGROUND: Among patients with thrombotic microangiopathies, acute kidney injury (AKI) is the hallmark of hemolytic uremic syndrome (HUS) and is largely underestimated in patients with thrombotic thrombocytopenic purpura (TTP). OBJECTIVE: We sought to report AKI features and outcomes in patients with TTP. METHODS: We conducted a retrospective study of 92 patients with TTP assessed by low ADAMTS13 activity (< 10%) between 2001 and 2013. A logistic regression identified variables independently associated with AKI. RESULTS: Among the 92 patients, 54 (58.7%) presented with AKI, including 25 (46.3%) with stage 3 AKI. Fourteen (27.4%) patients had a nephrotic-range proteinuria and 21 (45.6%) had hemoglobinuria. Hematuria and leucocyturia were detected in 19 (41.3%) and 16 patients (36.4%), respectively. Renal replacement therapy (RRT) was required in 14 patients (25.9%). Six months after TTP remission, RRT-free patients had median (IQR) MDRD (Modification of Diet in Renal Disease formula estimating the glomerular filtration rate) of 93 mL min(-1) per 1.73 m(2) (68.8-110) and three patients required long-term dialysis. Mild or moderate chronic renal disease occurred in 23/54 (42.6%) AKI patients. By multivariate analysis, serum level of complement component 3 at admission was the only factor independently associated with AKI (OR per 0.25 unit decrease of C3, 0.85; CI, 1.82-8.33; P = 0.001). CONCLUSIONS: In patients with TTP, AKI is present in more than half the patients, and half of those will have lasting renal effects. Further studies to better understand the pathophysiology of renal involvement in patients with TTP and to identify a subset of patients with TTP syndrome overlapping HUS are warranted. PMID- 25523334 TI - Perfect light trapping in nanoscale thickness semiconductor films with a resonant back reflector and spectrum-splitting structures. AB - The optical absorption of nanoscale thickness semiconductor films on top of light trapping structures based on optical interference effects combined with spectrum splitting structures is theoretically investigated. Nearly perfect absorption over a broad spectrum range can be achieved in <100 nm thick films on top of a one-dimensional photonic crystal or metal films. This phenomenon can be attributed to interference induced photonic localization, which enhances the absorption and reduces the reflection of the films. Perfect solar absorption and low carrier thermalization loss can be achieved when the light-trapping structures with a wedge-shaped spacer layer or semiconductor films are combined with spectrum-splitting structures. PMID- 25523335 TI - Enantioselective addition of dialkylzinc to aromatic aldimines mediated by camphor-derived chiral beta-amino alcohols. AB - The enantioselective addition of diethylzinc or dimethylzinc to N (diphenylphosphinoyl)imines mediated by 1 or 2 could be achieved in high yields (70-97 %) and enantioselectivities (85-98 % ee). The catalytic loading of 1 or 2 a could be reduced to 10 mol % for methylation or ethylation of imines in high yields and enantioselectivities (79-96 %) when the reaction was conducted in the presence of 1.8 equiv of methanol. N-Monosubstituted amino alcohols induced higher enantioselectivity than their N,N-disubstituted congener in our catalytic system. PMID- 25523336 TI - RPL13A as a reference gene for normalizing mRNA transcription of ovarian cancer cells with paclitaxel and 10-hydroxycamptothecin treatments. AB - Gene transcription analysis is important in cancer research, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) has been demonstrated to be an effective method to evaluate gene transcription in cancer. RT-qPCR requires an internal reference gene with a consistent level of mRNA transcription across various experimental conditions. However, it has been suggested that different treatments, including anticancer therapy, may influence the transcriptional stability of internal reference genes. Paclitaxel (PTX) and 10-hydroxycamptothecin (HCPT) are widely used to treat various types of cancer, and a suitable internal reference gene is required in order to analyze the transcription profiles of the cells following treatment. In the current study, the transcriptional stability of 30 candidate reference genes was investigated in cancer cells following treatment with PTX and HCPT. The two ovarian cancer cell lines, UACC-1598 and SKOV3, were treated with PTX and HCPT for 24 and 48 h, and the transcriptional levels of the candidate reference genes were subsequently evaluated by RT-qPCR analysis. The transcriptional stability of the selected genes was then analyzed using qbase+ and NormFinder software. A total of 9 genes were demonstrated to exhibit high transcriptional stability and one of these genes, ribosomal protein L13a (RPL13A), was identified to exhibit high transcriptional stability in every group. The current study identified various reference genes suitable under different circumstances, while RPL13A was indicated to be the most suitable reference gene for analyzing the transcription profile of ovarian cancer cells following treatment with PTX and HCPT. PMID- 25523341 TI - Morphological and functional changes in regenerated primary afferent fibres following mental and inferior alveolar nerve transection. AB - BACKGROUND: It is important to know the mechanisms underlying pain abnormalities associated with inferior alveolar nerve (IAN) regeneration in order to develop the appropriate treatment for orofacial neuropathic pain patients. However, peripheral mechanisms underlying orofacial pain abnormalities following IAN regeneration are not fully understood. METHODS: Head withdrawal threshold (HWT), jaw opening reflex (JOR) thresholds, single-fibre recordings of the regenerated mental nerve (MN) fibres, calcitonin gene-related peptide (CGRP), isolectin B4 (IB4), peripherin, neurofilament-200 (NF-200) and transient receptor potential vanilloid 1 (TRPV1) expression in trigeminal ganglion (TG) cells, and electron microscopic (EM) observations of the regenerated MN fibres were studied in MN- and IAN-transected (M-IANX) rats. RESULTS: HWT to mechanical or heat stimulation of the mental skin was significantly lower in M-IANX rats compared with sham rats. Mean conduction velocity of action potentials recorded from MN fibres (n = 124) was significantly slower in M-IANX rats compared with sham rats. The percentage of Fluoro-Gold (FG)-labelled CGRP-, peripherin- or TRPV1 immunoreactive (IR) cells was significantly larger in M-IANX rats compared with that of sham rats, whereas that of FG-labelled IB4- and NF-200-IR cells was significantly smaller in M-IANX rats compared with sham rats. Large-sized myelinated nerve fibres were rarely observed in M-IANX rats, whereas large-sized unmyelinated nerve fibres were frequently observed and were aggregated in the bundles at the distal portion of regenerated axons. CONCLUSIONS: These findings suggest that the demyelination of MN fibres following regeneration may be involved in peripheral sensitization, resulting in the orofacial neuropathic pain associated with trigeminal nerve injury. PMID- 25523342 TI - Persistent homology for the quantitative prediction of fullerene stability. AB - Persistent homology is a relatively new tool often used for qualitative analysis of intrinsic topological features in images and data originated from scientific and engineering applications. In this article, we report novel quantitative predictions of the energy and stability of fullerene molecules, the very first attempt in using persistent homology in this context. The ground-state structures of a series of small fullerene molecules are first investigated with the standard Vietoris-Rips complex. We decipher all the barcodes, including both short-lived local bars and long-lived global bars arising from topological invariants, and associate them with fullerene structural details. Using accumulated bar lengths, we build quantitative models to correlate local and global Betti-2 bars, respectively with the heat of formation and total curvature energies of fullerenes. It is found that the heat of formation energy is related to the local hexagonal cavities of small fullerenes, while the total curvature energies of fullerene isomers are associated with their sphericities, which are measured by the lengths of their long-lived Betti-2 bars. Excellent correlation coefficients (>0.94) between persistent homology predictions and those of quantum or curvature analysis have been observed. A correlation matrix based filtration is introduced to further verify our findings. PMID- 25523343 TI - Profiling the quality characteristics of the butter of Pentadesma butyracea with reference to shea butter. AB - BACKGROUND: Pentadesma butyracea is a tropical plant species. Its kernels are rich in edible butter similar to shea butter. This study evaluated the quality characteristics of the Pentadesma butter produced by cottage enterprises in Benin, using a quantitative survey approach and physicochemical and sensorial analysis methods. RESULTS: The butter of Pentadesma is mostly used for food preparation, cosmetic and therapeutic applications. It is characterized by a yellow colour, a hard texture, a relatively sweet taste and a bright appearance. Consumers preferred Pentadesma butter to shea butter for colour, taste, texture and appearance. Instrumental analysis showed that the average water content (6.5 g kg(-1) ) and peroxide value (0.74 mEq O2 kg(-1) ) of Pentadesma butter were lower than those of shea butter, for which average water content and peroxide values were 20.7g kg(-1) and 2.09 mEq O2 kg(-1) respectively. The fatty acid profile of Pentadesma butter is similar to that of shea butter. CONCLUSION: This study showed that the Pentadesma butyracea butter produced by cottage enterprises in Benin exhibited quality characteristics which are better than that of shea butter. The data generated can be used for a better exploitation of the butter in food and cosmetic industries. PMID- 25523344 TI - Retrograde lung perfusion in the treatment of massive pulmonary embolism. A randomised porcine study. AB - INTRODUCTION: The treatment of massive pulmonary embolisms with an associated cardiac arrest is controversial; however, surgical thrombectomy with extracorporeal circulation (ECC) is an option for treatment. It is difficult to remove all thromboembolic material. Theoretically, retrograde blood perfusion through the lungs may be beneficial. OBJECTIVES: To investigate whether retrograde blood perfusion through the lungs during a thrombectomy is beneficial. METHODS: Twelve pigs were prepared for ECC. Repetitive injections of preformed blood thrombi into the right atrium resulted in cardiac arrests. ECC was established after 10 minutes of cardiac arrest, and after a sternotomy, the main pulmonary artery was incised and as much thrombotic material as possible was removed from the pulmonary arteries. The pigs were randomised to ECC for one hour either with or without retrograde perfusion in the pulmonary circulation. After one hour, the released material was removed from the pulmonary arteries, and the incision was sutured. The pigs were weaned from the ECC. After sacrificing the pigs, they were autopsied with special attention to the amount of remaining thrombi. Additional histological analyses were performed with special attention to microembolisms, atelectases, and signs of tissue damage. RESULTS: All of the pigs were weaned from the ECC. The amount of the embolic material removed varied considerably, as did the amount removed after the retrograde or antegrade perfusion, and there was no significant difference between the two treatment modalities. There were no signs of tissue damage in the lungs. CONCLUSIONS: Retrograde lung perfusion was not generally beneficial in the treatment of massive pulmonary embolism in this setup; however, it may be an option if only a modest amount of material is accessible in the pulmonary artery. PMID- 25523345 TI - Elevated circulating VE-cadherin+CD144+endothelial microparticles in ischemic cerebrovascular disease. AB - OBJECTIVES: Circulating endothelial microparticles act as biological markers of endothelial function that reflect vascular injury. Here, we examined the hypothesis that the quantity of endothelial microparticles in the circulation is increased in patients with ischemic cerebrovascular diseases, and investigated the potential utility of various phenotypes of endothelial microparticles as specific biomarkers of endothelial cell dysfunction. We additionally focused on identifying endothelial microparticles that may be effectively utilized as biomarkers of stroke severity in acute ischemic stroke patients. METHODS: In total, 129 subjects, including 68 consecutive patients with acute ischemic stroke and 61 age- and sex-matched healthy controls, were included in the study. Levels of circulating endothelial microparticles (CD144+/CD41a-, CD31+CD41a-, CD62E+, Annexin V+CD62E+) and platelet-derived microparticles (CD41a+/CD144-) in platelet free plasma of patients and controls were measured using flow cytometry. RESULTS: Levels of circulating endothelial CD144+/CD41a-, CD31+CD41a-, CD62E+, and Annexin V+CD62E+microparticles, but not platelet microparticles, were significantly increased in acute ischemic stroke patients, compared with control subjects (p<0.05). Notably, levels of CD144+/CD41a- microparticles were significantly correlated with stroke severity. A mild degree of correlation was evident between Annexin V+CD62E+microparticles and stroke subtype. No association with stroke was observed for other microparticle phenotypes. CONCLUSIONS: Circulating endothelial microparticle amounts are increased in acute ischemic stroke patients, compared with healthy subjects. Levels of CD144+/CD41a- microparticle, but not the other phenotypes examined, may be effectively utilized as a biomarker of ischemic severity in the clinic. PMID- 25523346 TI - From pre-attentive processes to durable representation: an ERP index of visual distraction. AB - Visual search and oddball paradigms were combined to investigate memory for to-be ignored color changes in a group of 12 healthy participants. The onset of unexpected color change of an irrelevant stimulus evoked two reliable ERP effects: a component of the event-related potential (ERP), similar to the visual mismatch negativity response (vMMN), with a latency of 120-160 ms and a posterior distribution over the left hemisphere and Late Fronto-Central Negativity (LFCN) with a latency of 320-400 ms, apparent at fronto-central electrodes and some posterior sites. Color change of that irrelevant stimulus also slowed identification of a visual target, indicating distraction. The amplitude of this color-change vMMN, but not LFCN, indexed this distraction effect. That is, electrophysiological and behavioral measures were correlated. The interval between visual scenes approximated 1s (611-1629 ms), indicating that the brain's sensory memory for the color of the preceding visual scenes must persist for at least 600 ms. Therefore, in the case of the neural code for color, durable memory representations are formed in an obligatory manner. PMID- 25523347 TI - Oscillatory correlates of autobiographical memory. AB - Recollection of events from one's own life is referred to as autobiographical memory. Autobiographical memory is an important part of our self. Neuroimaging findings link self-referential processes with the default mode network (DMN). Much evidence coming primarily from functional magnetic resonance imaging studies shows that autobiographical memory and DMN have a common neural base. In this study, electroencephalographic data collected in 47 participants during recollection of autobiographical episodes were analyzed using temporal and spatial independent component analyses in combination with source localization. Autobiographical remembering was associated with an increase of spectral power in alpha and beta and a decrease in delta band. The increase of alpha power, as estimated by sLORETA, was most prominent in the posterior DMN, but was also observed in visual and motor cortices, prompting an assumption that it is associated with activation of DMN and inhibition of irrelevant sensory and motor areas. In line with data linking delta oscillations with aversive states, decrease of delta power was more pronounced in episodes associated with positive emotions, whereas episodes associated with negative emotions were accompanied by an increase of delta power. Vividness of recollection correlated positively with theta oscillations. These results highlight the leading role of alpha oscillations and the DMN in the processes accompanying autobiographical remembering. PMID- 25523348 TI - Cyclical konzo epidemics and climate variability. AB - Konzo epidemics have occurred during droughts in the Democratic Republic of Congo (DR Congo) for >70 years, but also in Mozambique, Tanzania, and the Central African Republic. The illness is attributed to exposure to cyanide from cassava foods, on which the population depends almost exclusively during droughts. Production of cassava, a drought-resistant crop, has been shown to correlate with cyclical changes in precipitation in konzo-affected countries. Here we review the epidemiology of konzo as well as models of its pathogenesis. A spectral analysis of precipitation and konzo is performed to determine whether konzo epidemics are cyclical and whether there is spectral coherence. Time series of environmental temperature, precipitation, and konzo show cyclical changes. Periodicities of dominant frequencies in the spectra of precipitation and konzo range from 3 to 6 years in DR Congo. There is coherence of the spectra of precipitation and konzo. The magnitude squared coherence of 0.9 indicates a strong relationship between variability of climate and konzo epidemics. Thus, it appears that low precipitation phases of climate variability reduce the yield of food crops except cassava, upon which the population depends for supply of calories during droughts. Presence of very high concentrations of thiocyanate (SCN(-) ), the major metabolite of cyanide, in the bodily fluids of konzo subjects is a consequence of dietary exposure to cyanide, which follows intake of poorly processed cassava roots. Because cyanogens and minor metabolites of cyanide have not induced konzo-like illnesses, SCN(-) remains the most likely neurotoxicant of konzo. Public health control of konzo will require food and water programs during droughts. [Correction added on 26 February 2015, after first online publication: abstract reformatted per journal style] PMID- 25523349 TI - Health facility barriers to HIV linkage and retention in Western Kenya. AB - BACKGROUND: HIV linkage and retention rates in sub-Saharan Africa remain low. The objective of this study was to explore perceived health facility barriers to linkage and retention in an HIV care program in western Kenya. METHODS: This qualitative study was conducted July 2012-August 2013. A total of 150 participants including; 59 patients diagnosed with HIV, TB, or hypertension; 16 caregivers; 10 community leaders; and 65 healthcare workers, were purposively sampled from three Academic Model Providing Access to Healthcare (AMPATH) sites. We conducted 16 in-depth interviews and 17 focus group discussions (FGDs) in either, English, Swahili, Kalenjin, Teso, or Luo. All data were audio recorded, transcribed, translated to English, and a content analysis performed. Demographic data was only available for those who participated in the FGDs. RESULTS: The mean age of participants in the FGDs was 36 years (SD = 9.24). The majority (87%) were married, (62.7%) had secondary education level and above, and (77.6%) had a source of income. Salient barriers identified reflected on patients' satisfaction with HIV care. Barriers unique to linkage were reported as quality of post-test counseling and coordination between HIV testing and care. Those unique to retention were frequency of clinic appointments, different appointments for mother and child, lack of HIV care for institutionalized populations including students and prisoners, lack of food support, and inconsistent linkage data. Barriers common to both linkage and retention included access to health facilities, stigma associated with health facilities, service efficiency, poor provider-patient interactions, and lack of patient incentives. CONCLUSION: Our findings revealed that there were similarities and differences between perceived barriers to linkage and retention. The cited barriers reflected on the need for a more patient-centered approach to HIV care. Addressing health facility barriers may ultimately be more efficient and effective than addressing patient related barriers. PMID- 25523350 TI - Associations between physical activity and cardiometabolic risk factors assessed in a Southern California health care system, 2010-2012. AB - INTRODUCTION: Risk factors associated with many chronic diseases can be improved through regular physical activity. This study investigated whether cross sectional associations between physical activity, assessed by the Exercise Vital Sign (EVS), and cardiometabolic risk factors can be detected in clinical settings. METHODS: We used electronic records from Kaiser Permanente Southern California members (N = 622,897) to examine the association of EVS category with blood pressure, fasting glucose, random glucose, and glycosylated hemoglobin. Adults aged 18 years or older with at least 3 EVS measures between April 2010 and December 2012, without comorbid conditions, and not taking antihypertension or glucose-lowering medications were included. We compared consistently inactive (EVS = 0 min/wk for every measure) with consistently active (EVS >=150 min/wk) and irregularly active (EVS 1-149 min/wk or not meeting the consistently active or inactive criteria) patients. Separate linear regression analyses were conducted controlling for age, sex, race/ethnicity, body mass index, and smoking status. RESULTS: Consistently active women had lower systolic (-4.60 mm Hg; 95% confidence interval [CI], -4.70 to -4.44) and diastolic (-3.28 mm Hg; 95% CI, 3.40 to -3.17) blood pressure than inactive women. Active men had lower diastolic blood pressure than inactive men. Consistently active patients (women, -5.27 mg/dL [95% CI, -5.56 to -4.97]; men, -1.45 mg/dL [95% CI, -1.75 to -1.16] and irregularly active patients (women, -4.57 mg/dL [95% CI, -4.80 to -4.34]; men, 0.42 mg/dL [95% CI, -0.66 to -0.19]) had lower fasting glucose than consistently inactive patients. Consistently active and irregularly active men and women also had favorable random glucose and HbA1c compared with consistently inactive patients. CONCLUSION: Routine clinical physical activity assessment may give health care providers additional information about their patients' cardiometabolic risk factors. PMID- 25523351 TI - NSAID-avoidance education in community pharmacies for patients at high risk for acute kidney injury, upstate New York, 2011. AB - INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently associated with community-acquired acute kidney injury (AKI), a strong risk factor for development and progression of chronic kidney disease. Using access to prescription medication profiles, pharmacists can identify patients at high risk for NSAID-induced AKI. The primary objective of this analysis was to evaluate the effectiveness of a community pharmacy-based patient education program on patient knowledge of NSAID-associated renal safety concerns. METHODS: Patients receiving prescription medications for hypertension or diabetes mellitus were invited to participate in an educational program on the risks of NSAID use. A patient knowledge questionnaire (PKQ) consisting of 5 questions scored from 1 to 5 was completed before and after the intervention. Information was collected on age, race, sex, and frequency of NSAID use. RESULTS: A total of 152 participants (60% women) completed both the pre- and post-intervention questionnaire; average age was 54.6 (standard deviation [SD], 17.5). Mean pre-intervention PKQ score was 3.3 (SD, 1.4), and post-intervention score was 4.6 (SD, 0.9) (P = .002). Participants rated program usefulness (1 = not useful to 5 = extremely useful) as 4.2 (SD, 1.0). In addition, 48% reported current NSAID use and 67% reported that the program encouraged them to limit their use. CONCLUSION: NSAID use was common among patients at high risk for AKI. A brief educational intervention in a community pharmacy improved patient knowledge on NSAID-associated risks. Pharmacists practicing in the community can partner with primary care providers in the medical home model to educate patients at risk for AKI. PMID- 25523352 TI - Cancer disparities among Alaska native people, 1970-2011. AB - INTRODUCTION: Cancer is the leading cause of death among Alaska Native people. The objective of this study was to examine cancer incidence data for 2007-2011, age-specific rates for a 15-year period, incidence trends for 1970-2011, and mortality trends for 1990-2011. METHODS: US data were from the Surveillance, Epidemiology, and End Results (SEER) Program SEER*Stat database and from the SEER Alaska Native Tumor Registry. Age-adjusted cancer incidence rates among Alaska Native people and US whites were compared using rate ratios. Trend analyses were performed using the Joinpoint Regression Program. Mortality data were from National Center for Health Statistics. RESULTS: During 2007-2011 the cancer incidence rate among Alaska Native women was 16% higher than the rate among US white women and was similar among Alaska Native men and US white men. Incidence rates among Alaska Native people exceeded rates among US whites for nasopharyngeal, stomach, colorectal, lung, and kidney cancer. A downward trend in colorectal cancer incidence among Alaska Native people occurred from 1999 to 2011. Significant declines in rates were not observed for other frequently diagnosed cancers or for all sites combined. Cancer mortality rates among Alaska Native people during 2 periods, 1990-2000 and 2001-2011, did not decline. Cancer mortality rates among Alaska Native people exceeded rates among US whites for all cancers combined; for cancers of the lung, stomach, pancreas, kidney, and cervix; and for colorectal cancer. CONCLUSION: Increases in colorectal screening among Alaska Native people may be responsible for current declines in colorectal cancer incidence; however; improvements in treatment of colon and rectal cancers may also be contributing factors. PMID- 25523353 TI - Prevalence of and risk factors for adolescent obesity in Southern Appalachia, 2012. AB - The objective of this study was to examine weight status among southern Appalachian adolescents and to identify risk factors for obesity. We analyzed baseline data from the Team Up for Healthy Living study in 2012. Overall, 19.8% of the sample was overweight, and 26.6% was obese. Boys had higher rates of overweight/obesity than girls (50.5% vs 42.3%). Being male (odds ratio [OR] = 1.79; 95% confidence interval [CI], 1.39-2.29), having a mother with a high school education or less (OR = 1.39; 95% CI, 1.05-1.83), or having a father with a high school education or less (OR = 1.57; 95% CI, 1.17-2.09) was associated with a higher prevalence of obesity and a higher body mass index z score (beta = 0.131, 0.160, and 0.043, respectively, P < .05). Parental education could be used to identify adolescents with a higher likelihood of obesity. PMID- 25523354 TI - Parental age and Neurofibromatosis Type 1: a report from the NF1 Patient Registry Initiative. AB - One of the potential etiologies for non-familial Neurofibromatosis Type 1 (NF1) is increasing parental age. We sought to evaluate recent evidence for parental age effects in NF1 in a large study. Individuals with NF1 and a comparison group from the U.S. general population born between 1994 and 2012 were ascertained from the NF1 Patient Registry Initiative (NPRI) and the National Center for Vital Statistics, respectively. Multiple linear regression analysis was employed to identify differences between familial NF1, non-familial NF1, and U.S. population subjects in the mean parental ages at the time of the birth of offspring in each group. In addition, we also evaluated the effect of parental age on NF1 offspring with and without a pediatric brain tumor history. A total of 313 subjects from the NPRI (including 99 brain tumor cases) matched by birth year at a 1:3 ratio to U.S. general population births (n = 939) were included. Compared to the U.S. general population and familial NF1 cases, the mean paternal age for non-familial NF1 cases was 4.34 years (95% CI 3.23-5.46, p <= 0.0001) and 3.39 years (95% CI 1.57-5.20, p <= 0.0001) older, respectively, after adjusting for birth year. A similar pattern was observed for maternal age. There were no statistically significant differences in the mean maternal or paternal ages between NF1 offspring with and without a pediatric brain tumor. In conclusion, these data support a parental age effect for non-familial NF1 cases, but not for pediatric brain tumors in NF1. PMID- 25523355 TI - From Lyme disease emergence to endemicity: a cross sectional comparative study of risk perceptions in different populations. AB - BACKGROUND: Lyme disease (LD) is a tick-borne emerging disease in Canada that has been endemic in many temperate countries for decades. Currently, one of the main approaches for LD prevention is the promotion of individual-level preventive behaviors against ticks. Health behaviors are influenced by individual and social factors, one important of which is risk perception. This study aims to describe and compare risk perception of LD, within and between general populations and experts living in two different regions: the Neuchatel canton in Switzerland, where LD is endemic, and the Monteregie region in Quebec (Canada), where LD is emerging. METHOD: A web-based survey was conducted in both study regions (814 respondents) in 2012, and a questionnaire was administered to 16 experts. Comparative analyses of knowledge, risk exposure and different components of LD risk perception were performed. Multivariate analyses were used to calculate a global risk perception score and to identify determinants of risk perception in both regions. RESULTS: In Monteregie, only 15% of the survey respondents had a good level of knowledge of LD compared to Neuchatel where 51% of survey respondents had good levels of knowledge. In Monteregie, 24% of respondents perceived themselves as being at high or very high risk of contracting LD vs 54% in Neuchatel; however, a higher percentage of respondents from this region believed that personal protection was simple to carry out (73% vs 58% in Monteregie). Based on the population surveys, almost all of the identified determinants of risk perception were different between both populations except for gender. A good level of knowledge, living in the risk zone and knowing someone who has had LD increased risk perception, while a high level of education and being 18-34 years of age decreased this perception. The majority of the studied components of risk perception were different between populations and their regional experts. CONCLUSION: This study suggests that risk perception of LD differs between populations and regional experts living in different epidemiological situations. Monitoring of knowledge and risk perception in local populations may help to better target LD communication efforts in accordance with population specific attributes thereby enhancing prevention efficacy. PMID- 25523356 TI - The study of psychiatric disease genes and drugs in zebrafish. AB - Mutations associated with psychiatric disease are being identified, but it remains unclear how the affected genes contribute to disease. Zebrafish is an emerging model to study psychiatric disease genes with a rich repertoire of phenotyping tools. Recent zebrafish research has uncovered potential developmental phenotypes for genes associated with psychiatric disorders, while drug screens have behaviorally characterized small molecules and identified new classes of drugs. Behavioral studies have led to promising models for endophenotypes of psychiatric diseases. While further research is needed to firmly link these models to psychiatric disorders, they are valuable tools for phenotyping genetic mutations and drugs. Recently developed tools in genome editing and in vivo imaging promise additional insights into the processes disrupted by mutations in psychiatric disease genes. PMID- 25523357 TI - Entropy, complexity, and Markov diagrams for random walk cancer models. AB - The notion of entropy is used to compare the complexity associated with 12 common cancers based on metastatic tumor distribution autopsy data. We characterize power-law distributions, entropy, and Kullback-Liebler divergence associated with each primary cancer as compared with data for all cancer types aggregated. We then correlate entropy values with other measures of complexity associated with Markov chain dynamical systems models of progression. The Markov transition matrix associated with each cancer is associated with a directed graph model where nodes are anatomical locations where a metastatic tumor could develop, and edge weightings are transition probabilities of progression from site to site. The steady-state distribution corresponds to the autopsy data distribution. Entropy correlates well with the overall complexity of the reduced directed graph structure for each cancer and with a measure of systemic interconnectedness of the graph, called graph conductance. The models suggest that grouping cancers according to their entropy values, with skin, breast, kidney, and lung cancers being prototypical high entropy cancers, stomach, uterine, pancreatic and ovarian being mid-level entropy cancers, and colorectal, cervical, bladder, and prostate cancers being prototypical low entropy cancers, provides a potentially useful framework for viewing metastatic cancer in terms of predictability, complexity, and metastatic potential. PMID- 25523358 TI - The effect of hospitalist discontinuity on adverse events. AB - BACKGROUND: Patient-physician continuity is difficult to achieve in hospital settings because of the need to provide care continuously. The impact of hospital physician discontinuity on patient safety is unknown. OBJECTIVE: To determine the association between hospital physician continuity and the incidence of adverse events (AEs). DESIGN: Retrospective observational study using multivariable models to adjust for patient characteristics. PARTICIPANTS: Patients admitted to a nonteaching hospitalist service in a large academic hospital between March 1, 2009 and December 31, 2011. MAIN MEASURE(S): Two measures of continuity were used. The Number of Physicians Index (NPI) was the total number of unique hospitalists caring for a patient. The Usual Provider of Care (UPC) Index was the proportion of encounters with the most frequently encountered hospitalist. Outcome measures were AEs detected by automated queries of information systems and confirmed by 2 physician researchers. KEY RESULTS: Our analysis included data from 474 hospitalizations. In unadjusted models, each 1-unit increase in the NPI (ie, less continuity) was significantly associated with the incidence of 1 or more AEs (odds ratio = 1.75; P < 0.001). However, UPC was not associated with incidence of AEs. Across all adjusted models, neither NPI nor UPC was significantly associated with the incidence of AEs. The direction of the effect of discontinuity on AEs was also inconsistent across models. CONCLUSIONS: Hospitalist physician continuity does not appear to be associated with the incidence of AEs. Because hospital care is provided by teams of clinicians, future research should evaluate the impact of team complexity and dynamics on patient outcomes. PMID- 25523359 TI - New insights on glucose homoeostasis during Ramadan. PMID- 25523360 TI - Self-assembly of "Mickey Mouse" shaped colloids into tube-like structures: experiments and simulations. AB - The self-assembly of anisotropic patchy particles with a triangular shape was studied by experiments and computer simulations. The colloidal particles were synthesized in a two-step seeded emulsion polymerization process, and consist of a central smooth lobe connected to two rough lobes at an angle of ~90 degrees , resembling the shape of a "Mickey Mouse" head. Due to the difference in overlap volume, adding an appropriate depletant induces an attractive interaction between the smooth lobes of the colloids only, while the two rough lobes act as steric constraints. The essentially planar geometry of the Mickey Mouse particles is a first geometric deviation of dumbbell shaped patchy particles. This new geometry enables the formation of one-dimensional tube-like structures rather than spherical, essentially zero-dimensional micelles. At sufficiently strong attractions, we indeed find tube-like structures with the sticky lobes at the core and the non-sticky lobes pointing out as steric constraints that limit the growth to one direction, providing the tubes with a well-defined diameter but variable length both in experiments and simulations. In the simulations, we found that the internal structure of the tubular fragments could either be straight or twisted into so-called Bernal spirals. PMID- 25523361 TI - Does sharing the electronic health record in the consultation enhance patient involvement? A mixed-methods study using multichannel video recording and in depth interviews in primary care. AB - BACKGROUND: Sharing the electronic health-care record (EHR) during consultations has the potential to facilitate patient involvement in their health care, but research about this practice is limited. METHODS: We used multichannel video recordings to identify examples and examine the practice of screen-sharing within 114 primary care consultations. A subset of 16 consultations was viewed by the general practitioner and/or patient in 26 reflexive interviews. Screen-sharing emerged as a significant theme and was explored further in seven additional patient interviews. Final analysis involved refining themes from interviews and observation of videos to understand how screen-sharing occurred, and its significance to patients and professionals. RESULTS: Eighteen (16%) of 114 videoed consultations involved instances of screen-sharing. Screen-sharing occurred in six of the subset of 16 consultations with interviews and was a significant theme in 19 of 26 interviews. The screen was shared in three ways: 'convincing' the patient of a diagnosis or treatment; 'translating' between medical and lay understandings of disease/medication; and by patients 'verifying' the accuracy of the EHR. However, patients and most GPs perceived the screen as the doctor's domain, not to be routinely viewed by the patient. CONCLUSIONS: Screen-sharing can facilitate patient involvement in the consultation, depending on the way in which sharing comes about, but the perception that the record belongs to the doctor is a barrier. To exploit the potential of sharing the screen to promote patient involvement, there is a need to reconceptualise and redesign the EHR. PMID- 25523362 TI - Afterload-induced left ventricular diastolic dysfunction during myocardial ischaemia and reperfusion. AB - NEW FINDINGS: What is the central question of this study? While the load dependence of the diastolic function is established for the normal heart, little is known about the response of the acutely ischaemic and reperfused myocardium to alterations in afterload. What is the main finding and its importance? Using a model that simulates the clinical scenario of acute ischaemia-reperfusion, we show that increased afterload aggravates diastolic dysfunction during both acute ischaemia and reperfusion. In addition, increased afterload induces diastolic dyssynchrony, which might be the underlying mechanism of the diastolic dysfunction of the ischaemic myocardium. These findings provide us with new information regarding how better to manage patients who undergo revascularization therapy after acute myocardial infarction. The effects of changes in left ventricular (LV) afterload on diastolic function of acutely ischaemic and reperfused myocardium have not been studied in depth. We examined the following factors: (i) the consequences of increasing the LV afterload on LV diastolic function during acute ischaemia and reperfusion; (ii) whether the myocardial response to afterload elevation is stable throughout a 2 h reperfusion period; and (iii) the role of LV wall synchrony in the development of afterload-induced diastolic dysfunction. We instrumented 12 anaesthetized, open-chest pigs with Millar pressure catheters and piezoelectric crystals before ligating mid-left anterior descending coronary artery for 1 h, followed by reperfusion for 2 h. Six of the animals survived throughout the 2 h of reperfusion, and their data were used for comparisons across the different experimental phases. Left ventricular afterload was increased by inflating an intra-aortic balloon. Data were recorded at baseline, after 20 min of coronary occlusion and at 30 and 90 min of myocardial reperfusion. The increased afterload for 2 min lengthened the isovolumic relaxation during ischaemia and during early and late reperfusion but had no significant effect on isovolumic relaxation before coronary artery occlusion. Increasing the afterload aggravated LV diastolic dyssynchrony during coronary artery occlusion, but not during reperfusion. The afterload-induced prolongation of isovolumic relaxation was positively correlated with afterload induced diastolic dyssynchrony. These observations indicate that, during myocardial ischaemia and throughout reperfusion, LV diastolic function is afterload dependent. Afterload-induced diastolic dyssynchrony might be an underlying mechanism of diastolic dysfunction during acute ischaemia. PMID- 25523363 TI - Portopulmonary hypertension: an update. AB - Portopulmonary hypertension represents a serious lung vascular disorder, defined as the presence of pulmonary arterial hypertension that is associated with portal hypertension, with or without the presence of significant liver disease. Transthoracic echocardiography represents the single best initial tool for the diagnostic evaluation in portopulmonary hypertension, and right heart catheterization remains the gold standard for definitive diagnosis. Despite the lack of randomized controlled trials in portopulmonary hypertension, some therapies have demonstrated improvements in cardiopulmonary haemodynamics and right ventricular function as described in case reports and case series. Specialists should be able to recognize indications and contraindications for liver transplantation in the setting of portopulmonary hypertension, and this review focuses on the appropriate diagnostic approach and current advances in medical therapies. Recognition of patients eligible for liver transplantation is needed to improve quality of life and survival. PMID- 25523364 TI - English as she is mis-spoke, misread, and miswrote--or, why you should read before you sign. PMID- 25523365 TI - Pyrazine derivatives: a patent review (June 2012 - present). AB - INTRODUCTION: Pyrazine is a member of 1,4-diazines, which constitute an important class of heterocycles. Various pyrazine derivatives have been synthesized and successfully evaluated as agents with diverse pharmacological effects (including but not limited to antiproliferative, anti-infective, and effects on cardiovascular or nervous system) and some of them have become clinically used drugs worldwide. AREA COVERED: This review is a survey of important patents on pyrazine derivatives with pharmacological activity published in the period June 2012 - July 2014. The patent databases SciFinder and esp@cenet were used to locate patent applications. EXPERT OPINION: Pyrazine derivatives possess numerous noteworthy pharmacological effects, including antimycobacterial, antibacterial, antifungal, antidiabetic, diuretic, anticancer, antiviral, hypnotic, and analgesic. The class of pyrazine-based candidate drugs has experienced a rapid growth both in absolute numbers of investigated compounds and in the spectrum of diverse biological activities. We expect that several of these compounds will add to existing pharmaceuticals in the very near future. According to the number of compounds and filed patents, the most promising areas are: i) inhibitors of protein kinases (applicable as antiproliferatives); and ii) inhibitors of beta secretase (applicable for the treatment of Alzheimer's disease). PMID- 25523367 TI - Therapeutic monoclonal antibodies and the need for targeted pharmacovigilance in India. AB - A growing number of innovative mAb therapeutics are on the global market, and biosimilar versions have now also been approved, including in India. Although efficacy and safety is demonstrated prior to approval, targeted pharmacovigilance is essential for the identification and assessment of risk for any mAb products. We analyzed the ADR data related to mAbs reported to the NCC-PvPI through the spontaneous reporting system Vigiflow during April 2011 to February 2014 to identify mAbs with the highest number of ADR including fatal/serious ADR. Only 0.72% reports were related to mAbs. Although 15 mAbs are approved in the country, only 6 mAbs were reported through Vigiflow. Rituximab was highly reported, and no fatal/serious ADR related to any mAbs were reported during the study period. Our study shows that PvPI is effective and robust system in the detection and assessment of risks associated with the use of mAbs. PMID- 25523368 TI - Self-assembly of functional molecules into 1D crystalline nanostructures. AB - Self-assembled functional nanoarchitectures are employed as important nanoscale building blocks for advanced materials and smart miniature devices to fulfill the increasing needs of high materials usage efficiency, low energy consumption, and high-performance devices. One-dimensional (1D) crystalline nanostructures, especially molecule-composed crystalline nanostructures, attract significant attention due to their fascinating infusion structure and functionality which enables the easy tailoring of organic molecules with excellent carrier mobility and crystal stability. In this review, we discuss the recent progress of 1D crystalline self-assembled nanostructures of functional molecules, which include both a small molecule-derived and a polymer-based crystalline nanostructure. The basic principles of the molecular structure design and the process engineering of 1D crystalline nanostructures are also discussed. The molecular building blocks, self-assembly structures, and their applications in optical, electrical, and photoelectrical devices are overviewed and we give a brief outlook on crucial issues that need to be addressed in future research endeavors. PMID- 25523369 TI - Effects of plant stress signal molecules on the production of wilforgine in an endophytic actinomycete isolated from Tripterygium wilfordii Hook.f. AB - The endophytic actinomycete F4-20 was isolated from Tripterygium wilfordii Hook.f. and was confirmed to produce wilforgine, a secondary metabolite discovered in its host. F4-20 showed a close phylogenetic relationship to Streptomyces species. To seek elicitors that may enhance the production of wilforgine in F4-20, four plant stress molecules were applied to the in vitro liquid cultures. Results showed that methyl jasmonate (MeJA), salicylic acid (SA), and hydrogen peroxide (H2O2) inhibited bacterial growth, whereas glutathione (GSH) treatment significantly increased bacterial growth. The wilforgine contents in the mycelia of F4-20 were reduced by MeJA and GSH but were induced by SA and H2O2. When added in the end of the culture period (7 day), 1 mM SA and 5 mM H2O2 resulted in 69.35 +/- 1.71 and 71.80 +/- 3.35 ug/g DW of wilforgine production, 1.55 and 1.60 fold to that of control (44.83 +/- 1.35 ug/g DW), respectively. Though this improved production was about 6.5 times lower than that of the natural root (454.00 ug/g dry root bark), it provided an alternative method for the production of valuable plant secondary metabolites. PMID- 25523370 TI - Inhibitory effect of black tea and its combination with acarbose on small intestinal alpha-glucosidase activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: It is said that black tea is effective against type 2 diabetes mellitus because it can help modulate postprandial hyperglycemia. However, the mechanism underlying its therapeutic and preventive effects on type 2 diabetes mellitus is unclear. In this study, we focused on the effect of black tea on the carbohydrate digestion and absorption process in the gastrointestinal tract. We examined whether black tea can modulate postprandial hyperglycemia. MATERIALS AND METHODS: The freeze-dried powder of the aqueous extract of black tea leaves (JAT) was used for in vitro studies of alpha-amylase activity, alpha glucosidase activity, and glucose uptake by glucose transporters in Caco-2 cells; ex vivo studies of small intestinal alpha-glucosidase activity; and in vivo studies of oral sugar tolerance in GK rats, an animal model of nonobese type 2 diabetes mellitus. RESULTS: Half maximal inhibitory concentration values indicated that JAT significantly reduced alpha-glucosidase activity, but weakly reduced alpha-amylase activity. Kinetic studies of rat small intestinal alpha glucosidase activity revealed that the combination of JAT and the alpha glucosidase inhibitor, acarbose, showed a mixed-type inhibition. JAT had no effect on the uptake of 2'-deoxy-d-glucose by glucose transporter 2 (GLUT2) and the uptake of alpha-methyl-d-glucose by sodium-dependent glucose transporter 1 (SGLT1). In the oral sucrose tolerance test in GK rats, JAT reduced plasma glucose levels in a dose-dependent manner compared with the control group. The hypoglycemic action of JAT was also confirmed: JAT, in combination with acarbose, produced a synergistic inhibitory effect on plasma glucose levels in vivo. In contrast to the oral sucrose tolerance test, JAT showed no effect in the oral glucose tolerance test. CONCLUSIONS: JAT was demonstrated to inhibit the degradation of disaccharides into monosaccharides by alpha-glucosidase in the small intestine. Thereby indirectly preventing the absorption of the dietary source of glucose mediated by SGLT1 and GLUT2 transporters localized at the apical side of enterocytes in the small intestine. The results indicate that black tea could be useful as a functional food in the dietary therapy for borderline type 2 diabetes mellitus that could modulate postprandial hyperglycemia. PMID- 25523371 TI - Prevalence and pattern of traditional medical therapy utilisation in Kumasi Metropolis and Sekyere South District, Ghana. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Whilst over three-quarters of the world's population continues to use traditional medicine (TRM) with an increasing trend globally, limited data exist in the Ashanti Region regarding TRM utilisation. This study espoused a retrospective cross-sectional quantitative approach to examine the prevalence and pattern of TRM use among the general population in the Kumasi Metropolis and Sekyere South District, Ghana. MATERIALS AND METHODS: A sample of 324, drawn through systematic random sampling was used. The main instrument for data collection was formal face-to-face interviewer-administered questionnaire. Data were analysed using Chi-square and Fisher's exact tests from the PASW (V.17.0) with p <= 0.05 as significant. RESULTS: The survey found that TRM use alongside conventional medicines was pervasive with prevalence of 86.1%. Biologically-based therapies (88.5%) and distant prayer interventions (58.4%) were commonly used modalities through the influence of families (50.3%), friends (19.4%) and the mass media (18.0%). Whilst self-administration and purchases from pharmacy shops remained important sources of TRM, TMPs' consultation was less credible (p<0.005). The disclosure rate of TRM use to health care professionals remained low (12.2%; p<0.001). CONCLUSION: Concomitant TRM use with conventional therapies without disclosure may interfere with the potency of treatment regimen and result in drug interactions. Inclusion of alternative medicines on the National Health Insurance Scheme's drug plan will fortify monitoring and professional administration of TRM. Information as regards TRM use needs to be incorporated into clinical and medical practice, hence the need to prioritise patient-physician communication. PMID- 25523372 TI - Comparison on hypoglycemic and antioxidant activities of the fresh and dried Portulaca oleracea L. in insulin-resistant HepG2 cells and streptozotocin-induced C57BL/6J diabetic mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Fresh Portulaca oleracea L. (family: Portulacaceae; POL) has been used as a folk medicine for the treatment of diabetes mellitus for a long time. More bioactive components with higher activity could be retained in fresh medicinal herbs compared to the dried ones. The present study was conducted to compare different antidiabetic activity between fresh and dried POL, including hypoglycemic and antioxidant activities both in vivo and in vitro. Furthermore, in order to explore which components were responsible for the antidiabetic activity, the difference on chemical components between fresh and dried POL was analyzed and compared. MATERIALS AND METHODS: Insulin-resistant HepG2 cells induced by insulin were used to evaluate the promoting effect of the fresh and dried POL on glucose utilization in vitro. Streptozotocin (STZ)-induced C57BL/6J diabetic mice were used to compare the differences on hypoglycemic and antioxidant activities of fresh and dried POL, including the fasting blood glucose, glucose tolerance, serum insulin level, malondialdehyde (MDA) level and superoxide dismutase (SOD) activity in vivo. UPLC/Q-TOF-MS method was performed to analyze the difference of antidiabetic components between fresh and dried POL. RESULTS: Compared with the dried POL extract, the fresh POL extract significantly increased the consumption of extracellular glucose in insulin-resistant HepG2 cells (P<0.05). In STZ-induced C57BL/6J diabetic mice, both fresh and dried extracts decreased markedly the fasting blood glucose (FBG) levels, and improved significantly oral glucose tolerance test (OGTT), as well as enhanced significantly insulin secretion and antioxidative activities (P<0.05; P<0.01). Furthermore, the fresh extract showed stronger antidiabetic activity (P<0.05). The UPLC/Q-TOF-MS analysis results also revealed that the relative contents of polyphenols and alkaloids in the fresh herbs were more abundant than those in the dried POL. CONCLUSION: Our results indicated that both fresh and dried POL possessed antidiabetic activities, besides stronger activity was observed in the fresh herb. These findings provided evidence for the application and development of fresh POL in the treatment of diabetes mellitus. PMID- 25523373 TI - Comparative analysis of imaging and pathology features of mucinous carcinoma of the breast. AB - BACKGROUND: The purpose of the study was to explore the relationship between the mammographic features, MR features, and pathological manifestations of PMBCs and MMBCs. PATIENTS AND METHODS: Twenty-seven cases of mucinous breast carcinoma confirmed in surgical biopsy, including 18 cases of PMBC and 9 cases of MMBC, were included (mean age, 51.2 and 53.3 years, respectively). All patients underwent preoperative mammography, and 13 of 27 patients underwent preoperative MR imaging (MRI), 4 of whom underwent diffusion-weighted imaging. All mammographic and MRI information, such as the size, shape, borders of the mass, and evidence of calcification were classified according to the American Collage of Radiology (ACR) Breast Imaging-Reporting And Data System (BI-RADS) mammography/MR lexicon. The signal intensity of the mass was visually classified as low, iso, high, strongly high, or mixed in accordance with surrounding mammary gland tissues. The pattern of internal enhancement of the mass included homogeneity, rim enhancement, central enhancement, dark internal septation, and enhancing internal septation. The kinetic curve pattern was categorized into 3 types: persistent, plateau, or washout. RESULTS: There was no significant difference PMBC and MMBC in the shape of tumor, calcifications, T2 signal intensity, internal mass enhancement, kinetic curve assessment, and positivity for estrogen receptor (ER), progesterone receptor (PR), and human epidermalgrowth factor receptor-2 (HER-2). The PMBC tumors were larger than MMBC tumors (P < .001), and MMBC tended to present as an ill-circumscribed mass (P = .043). The ADC values of the 5 lesions of 4 mucinous breast carcinoma (MBCs) ranged from 0.771 to 2.252 * 10(3) mm(2)/s, markedly greater than that of conventional infiltrating ductal carcinoma (IDC). The ADC values of MMBC were visibly less than those of PMBC for the former mixed with massive tumor cells of IDC. CONCLUSION: MBC commonly presented as masses with well circumscribed, round, or lobular shapes. The remaining cases presented with focal symmetry. The rate of regional nodal involvement of MBC was less than that of IDC. The MR features of PMBC included benign (homogenous intensity on T1-weighted imaging [WI] and T2-WI, persistent enhancement pattern) and malignant characteristics (rim or heterogeneous enhancement). The ADC values of MBC were greater than those of benign lesions and other malignant tumors. We believe that the combination of mammography and Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may help to improve the diagnostic accuracy of MBC. PMID- 25523374 TI - Cochrane Airways Group reviews were prioritized for updating using a pragmatic approach. AB - OBJECTIVES: Cochrane Reviews should address the most important questions for guideline writers, clinicians, and the public. It is not possible to keep all reviews up-to-date, so the Cochrane Airways Group (CAG) decided to prioritize updates and new reviews without requesting additional resources. The aim of the objective was to develop pragmatic and transparent prioritization techniques to identify 25 to 35 high-priority updates from a total of 270 CAG Reviews and become more selective over which new reviews we publish. STUDY DESIGN AND SETTING: We used elements from existing prioritization processes, including existing health care uncertainties, expert opinion, and a decision tool. We did not conduct a full face-to-face workshop or an iterative group decision-making process. RESULTS: We prioritized 30 reviews in need of updating and aimed to update these within 2 years. Within the first 18 months, nine of these have been published. CONCLUSION: A pragmatic approach to prioritization can indicate priority reviews without an excessive drain on time and resources. The steps provide us with better control over the reviews in our scope and can be built on in the future. PMID- 25523375 TI - Reporting and methodological quality of sample size calculations in cluster randomized trials could be improved: a review. AB - OBJECTIVES: To assess the quality of reporting and accuracy of a priori estimates used in sample size calculations for cluster randomized trials (CRTs). STUDY DESIGN AND SETTING: We reviewed 300 CRTs published between 2000 and 2008. The prevalence of reporting sample size elements from the 2004 CONSORT recommendations was evaluated and a priori estimates compared with those observed in the trial. RESULTS: Of the 300 trials, 166 (55%) reported a sample size calculation. Only 36 of 166 (22%) reported all recommended descriptive elements. Elements specific to CRTs were the worst reported: a measure of within-cluster correlation was specified in only 58 of 166 (35%). Only 18 of 166 articles (11%) reported both a priori and observed within-cluster correlation values. Except in two cases, observed within-cluster correlation values were either close to or less than a priori values. CONCLUSION: Even with the CONSORT extension for cluster randomization, the reporting of sample size elements specific to these trials remains below that necessary for transparent reporting. Journal editors and peer reviewers should implement stricter requirements for authors to follow CONSORT recommendations. Authors should report observed and a priori within cluster correlation values to enable comparisons between these over a wider range of trials. PMID- 25523376 TI - The impact of generalized joint laxity on the clinical and radiological outcomes of single-level posterior lumbar interbody fusion. AB - BACKGROUND CONTEXT: Recent reports have suggested that excessive motion of the lumbar spine might be associated with low back pain and accelerated disc degeneration and may negatively influence the outcome of posterior lumbar interbody fusion (PLIF) surgery. These findings suggest that generalized joint laxity (GJL) might be a negative factor affecting PLIF outcome, although this relationship has not been well studied. In addition, the impact of GJL on adjacent segment pathology (ASP) after PLIF has not been reported. PURPOSE: To explore the relationship between GJL and the outcome of single-level PLIF, we compared fusion rates, clinical outcomes, and ASP in PLIF patients with and without GJL. STUDY DESIGN: Retrospective comparative study. PATIENT SAMPLE: A total of 256 patients who underwent PLIF and were followed for at least 2 years after surgery were classified into two groups: Group A (37 patients with GJL) and Group B (219 patients without GJL). OUTCOME MEASURES: The primary outcome measure was the fusion rate on dynamic radiographs and computed tomography scans. The secondary outcome measures were pain intensity in the low back based on a visual analog scale, functional outcome based on the Oswestry Disability Index, and prevalence and severity of ASP on lumbar spine magnetic resonance imaging 2 years postoperatively compared with preoperative images. METHODS: We compared baseline data for the two groups studied. To evaluate the effects of GJL on the outcome of PLIF, we also compared outcome measures between the two groups. No funds were received in support of this work. RESULTS: Successful fusion 2 years after surgery was achieved in 91.9% of patients in Group A and 91.8% of patients in Group B according to dynamic radiographs (p=.85) and in 86.5% of patients in Group A and 90% of patients in Group B according to computed tomography scans (p=.14). Secondary endpoints including pain intensity (visual analog scale) and Oswestry Disability Index scores were not significantly different between the two groups (p=.71 and .86, respectively). Adjacent segment pathology was present in both the superior and inferior adjacent segments in both groups and was not significantly different (p=.07 and .06, respectively), although severe degeneration that was greater than Grade III on modified Pfirrmann classification was more frequently observed in Group A (15 of 37, 40.5%, at the superior segment and 11 of 20, 55%, at the inferior segment) than in Group B (60 of 219, 27.4%, at the superior segment and 30 of 111, 27%, at the inferior segment), which was statistically significant (p=.02 and .01, respectively). Moreover, ASP was more prominent at the superior adjacent segment compared with the inferior adjacent segment and was most commonly observed at the inferior adjacent segment (L5-S1) after L4-L5 PLIF and the superior adjacent segment (L4-L5) after L5-S1 PLIF (p=.02 and .03, respectively). CONCLUSIONS: Generalized joint laxity at baseline does not impact fusion rate or clinical outcome with respect to pain intensity or functional status but could negatively impact ASP compared with that in patients without GJL. Consequently, GJL should be evaluated preoperatively, and patients with GJL undergoing PLIF should be informed of the potential risks of surgery. PMID- 25523377 TI - Assessment of pedicle screw placement accuracy in thoracolumbosacral spine using freehand technique aided by lateral fluoroscopy: results of postoperative computed tomography in 114 patients. AB - BACKGROUND CONTEXT: Pedicle screw fixation is currently widely used in spine surgery for various pathologies. Increasing screw placement accuracy would improve the outcomes. PURPOSE: To determine the accuracy rate of screw placement in a group of patients who underwent pedicle screw fixation with conventional techniques. STUDY DESIGN: A case series. PATIENT SAMPLE: It includes patients undergoing posterior spinal fixation with pedicle screw insertion. Outcome measures include the accuracy of screw placement in pedicles defined by postoperative computed tomography (CT). METHODS: After surgery, an axial thin-cut CT scan was performed in all patients. Screw position was classified as correct when the screw was completely surrounded by the pedicle cortex and incorrect when any part of the screw was outside the pedicle boundaries. RESULTS: Seven hundred seventy screws were inserted at vertebral levels T7-S1 of 114 patients between March 2012 and December 2012. There were three wound infections and one death. Eighteen screws were diagnosed as having an incorrect position (2.3%). The highest accuracy was observed in levels L4 and L5 (0.8% inaccuracy rate for each), whereas the highest inaccuracy rate was observed in T9. The mean inaccuracy rate was 10.5% for levels T7-T9, 3.5% for levels T10-L2, and 0.9% for levels L3-S1. The differences were statistically significant. Only one screw (5%) needed revision. CONCLUSIONS: The results of our study show that conventional methods for pedicle screw placement remain safe and accurate, with best results obtained in the lumbosacral spine, followed by the thoracolumbar junction. Nonetheless, results are less accurate in the midthoracic spine. PMID- 25523378 TI - Anterior retropharyngeal approach to C1 for percutaneous vertebroplasty under C arm fluoroscopy. AB - BACKGROUND CONTEXT: Percutaneous vertebroplasty (PVP) has proven to be a valuable palliative treatment option for patients with medically refractory painful osteolytic metastases of the spine. Percutaneous vertebroplasty of the atlas has been reported in only seven articles and has been performed with different techniques and approaches. PURPOSE: To describe the technique we used to perform PVP of a lytic lesion of the lateral mass of C1 via anterior retropharyngeal approach guided by C-arm fluoroscopy. STUDY DESIGN: A technical report. PATIENT SAMPLE: It included a 75-year-old man with known metastatic lung carcinoma and incapacitating right suboccipital and neck pain refractory to conventional medical treatment. Radiologic evaluation showed revealed osteolytic destruction of C1 and C2, mainly invading the right lateral mass of C1 and the vertebral body of C2. OUTCOME MEASURES: The right suboccipital and neck pain was measured using the visual analog scale (VAS). METHODS: Under C-arm fluoroscopy, a novel anterior retropharyngeal approach, through the vertebral body of C2 into the metastatic osteolytic vertebral lesion of C1, was performed to achieve the PVP in C1 followed by a PVP in C2. RESULTS: Immediately after the operation, the patient reported substantial pain relief (from VAS 9/10 preoperatively to 3/10). At 12 hours postoperatively, the range of motion was also improved. There were no surgery-related complications. The immediately postoperative cervical plain film and computed tomography scan showed adequate filling of the osteolytic lesion without the obvious leakage of bone cement. Clinical follow-up at 3 months revealed that this pain condition was improved and maintained (VAS 1/10). CONCLUSIONS: When the transoral approach is unsuitable or contraindicated, the anterior retropharyngeal approach could be an efficacious alternative in selected patients with C1 metastasis, providing adequate filling of bone cement and significant pain relief. Based on our preliminary exploration, only assisted by C arm fluoroscopy, this approach is feasible to achieve PVP in C1 under local anesthesia and intravenous analgesia. Nevertheless, when considering the substantial potential risks, this technically challenging procedure should be performed by experienced operators. PMID- 25523379 TI - Extensive ossification of the ligamentum flavum treated with triple stage decompression: a case report. AB - BACKGROUND CONTEXT: Concurrent ossification of the ligamentum flavum (OLF) in the cervical, thoracic, and lumbar spine is a rare occurrence often associated with rheumatologic abnormalities. Although the pathology may be asymptomatic and discovered incidentally on routine imaging, compression of the cord and surrounding nerve roots can produce myelopathic or radiculopathic symptoms that are best treated with surgical decompression. There is limited evidence to support the use of single versus multistage decompression for tandem ossification at multiple levels, although several factors including duration of symptoms have been associated with a worse prognosis. PURPOSE: To describe the presence of extensive symptomatic tandem OLF with concurrent ossification of the posterior longitudinal ligament (PLL) and its treatment using multistage decompression. STUDY DESIGN: Case report and literature review. METHODS: The authors describe a case of a 35-year-old woman with OLF extending from the cervical to lumbar spine and tandem ossification of the cervical PLL. Her initial presentation was significant for symptoms consistent with thoracic myelopathy in the absence of radiculopathic findings, and initial imaging also demonstrated disc herniation at L4-L5 and L5-S1. RESULTS: The patient was first treated with a thoracic laminectomy and fusion from T7 to T11, given her back pain and thoracic myelopathy. Persistence of myelopathic symptoms necessitated further surgical intervention with a posterior cervical decompression and fusion from C3 to T1. Finally, after the appearance of radiculopathic findings, she underwent a microscopic L4-L5 laminectomy with improvements in her symptoms and ambulation. CONCLUSIONS: Symptomatic OLF in non-East Asian population is a rare occurrence. Its etiology is likely multifactorial, involving both biomechanical and genetic factors. Although early detection and management are necessary, multistage decompression can be an effective intervention for extensive multilevel ossification. PMID- 25523380 TI - Use of bone morphogenetic protein among patients undergoing fusion for degenerative diagnoses in the United States, 2002 to 2012. AB - BACKGROUND CONTEXT: Use of bone morphogenetic protein (BMP) as an adjunct to spinal fusion surgery proliferated after Food and Drug Administration (FDA) approval in 2002. Major safety concerns emerged in 2008. PURPOSE: The purpose of this study was to examine whether published concerns about the safety of BMP altered clinical practice. STUDY DESIGN/SETTING: The study design involved the analysis of the National Inpatient Sample from 2002 through 2012. PATIENT SAMPLE: Adults (older than 20 years) undergoing an elective fusion operation for common degenerative diagnoses were identified using codes from the International Classification of Diseases, ninth revision, Clinical Modification. OUTCOME MEASURES: Outcome measures were proportion of cervical and lumbar fusion operations, over time, that involved BMP. METHODS: We aggregated the data into a monthly time series and reported the proportion of cervical and lumbar fusion operations, over time, that involved BMP. Autoregressive Integrated Moving Average, a regression model for time series data, was used to test whether there was a statistically significant change in the overall rate of BMP use after an FDA Public Health Notification in 2008. RESULTS: Use of BMP in spinal fusion procedures increased rapidly until 2008, involving up to 45.2% of lumbar and 13.5% of cervical fusions. Bone morphogenetic protein use significantly decreased after the 2008 FDA Public Health Notification and revelations of financial payments to surgeons involved in the pivotal FDA-approved trials. For lumbar fusion, the average annual increase was 7.9 percentage points per year from 2002 to 2008, followed by an average annual decrease of 11.7 percentage points thereafter (p<=.001). Use of BMP in cervical fusion increased 2.0% per year until the FDA Public Health Notification, followed by a 2.8% per year decrease (p=.035). CONCLUSIONS: Use of BMP in spinal fusion surgery declined subsequent to published safety concerns and revelations of financial conflicts of interest for investigators involved in the pivotal clinical trials. PMID- 25523381 TI - Proton pump inhibitor treatment is associated with the severity of liver disease and increased mortality in patients with cirrhosis. AB - BACKGROUND: Proton pump inhibitors (PPI) are widely used in patients with liver diseases. Within the last years, there have been concerns about the PPI use as they may promote infections in patients with cirrhosis. AIM: As there are sparse data of the prognostic relevance of PPI treatment, to perform a prospective study investigating the relation of PPI treatment and overall survival (OS) in cirrhotic individuals. METHODS: Patients with cirrhosis were enrolled and followed prospectively. The primary end point was OS. PPI treatment and additional clinical and laboratory data were assessed at the day of the study inclusion. The time until the end point death was assessed and the individual risks were calculated with Cox regression analyses. RESULTS: A total of 272 patients were included and 213 individuals (78.3%) were on PPI treatment. In multivariate logistic regression analysis, PPI treatment was associated with higher MELD scores (P = 0.027) and ascites (P = 0.039). In a multivariate Cox regression model, PPI use was an independent predictor of mortality (hazard ratio 2.330, 95% confidence interval 1.264-4.296, P = 0.007) in addition to the model of end-stage liver disease (MELD) score, hepatocellular carcinoma and hepatic decompensation. CONCLUSIONS: PPI use is an independent risk factor for mortality in patients with cirrhosis. Although a causative role for increased mortality in patients taking PPI is still missing, the prescription of PPI in cirrhotics should be considered carefully taking into account its potential adverse effects. PMID- 25523382 TI - A 3.0-kb deletion including an erythroid cell-specific regulatory element in intron 1 of the ABO blood group gene in an individual with the Bm phenotype. AB - We developed a sequence-specific primer PCR (SSP-PCR) for detection of a 5.8-kb deletion (B(m) 5.8) involving an erythroid cell-specific regulatory element in intron 1 of the ABO blood group gene. Using this SSP-PCR, we performed genetic analysis of 382 individuals with Bm or ABm. The 5.8-kb deletion was found in 380 individuals, and disruption of the GATA motif in the regulatory element was found in one individual. Furthermore, a novel 3.0-kb deletion involving the element (B(m) 3.0) was demonstrated in the remaining individual. Comparisons of single nucleotide polymorphisms and microsatellites in intron 1 between B(m) 5.8 and B(m) 3.0 suggested that these deletions occurred independently. PMID- 25523383 TI - Medical Care Services in Community Mental Health Centers: a National Survey of Psychiatrists. PMID- 25523384 TI - Expression of a cyclophilin OsCyp2-P isolated from a salt-tolerant landrace of rice in tobacco alleviates stress via ion homeostasis and limiting ROS accumulation. AB - Cyclophilins are a set of ubiquitous proteins present in all subcellular compartments, involved in a wide variety of cellular processes. Comparative bioinformatics analysis of the rice and Arabidopsis genomes led us to identify novel putative cyclophilin gene family members in both the genomes not reported previously. We grouped cyclophilin members with similar molecular weight and subtypes together in the phylogenetic tree which indicated their co-evolution in rice and Arabidopsis. We also characterized a rice cyclophilin gene, OsCyp2-P (Os02g0121300), isolated from a salinity-tolerant landrace, Pokkali. Publicly available massively parallel signature sequencing (MPSS) and microarray data, besides our quantitative real time PCR (qRT-PCR) data suggest that transcript abundance of OsCyp2-P is regulated under different stress conditions in a developmental and organ specific manner. Ectopic expression of OsCyp2-P imparted multiple abiotic stress tolerance to transgenic tobacco plants as evidenced by higher root length, shoot length, chlorophyll content, and K(+)/Na(+) ratio under stress conditions. Transgenic plants also showed reduced lipid peroxidase content, electrolyte leakage, and superoxide content under stress conditions suggesting better ion homeostasis than WT plants. Localization studies confirmed that OsCyp2-P is localized in both cytosol and nucleus, indicating its possible interaction with several other proteins. The overall results suggest the explicit role of OsCyp2-P in bestowing multiple abiotic stress tolerance at the whole plant level. OsCyp2-P operates via reactive oxygen species (ROS) scavenging and ion homeostasis and thus is a promising candidate gene for enhancing multiple abiotic stress tolerance in crop plants. PMID- 25523385 TI - Outcomes of second-line combination antiretroviral therapy for HIV-infected patients: a cohort study from Rio de Janeiro, Brazil. AB - BACKGROUND: World-wide, the notable expansion of HIV/AIDS treatment programs in resource-limited settings has lead to an increasing number of patients in need of second-line cART. To adequately address and prepare for this scenario, critical assessments of the outcomes of second-line cART are particularly relevant in settings where monitoring strategies may be inadequate. We evaluated virologic outcomes of second-line combination antiretroviral therapy (cART) among HIV infected individuals from Brazil. METHODS: This study was conducted at the Instituto Nacional de Infectologia Evandro Chagas, Fundacao Oswaldo Cruz, at Rio de Janeiro, Brazio. For this study we included all patients who started first line and second-line cART between 2000 and 2013. Second-line cART required a switch in the anchor drug of first-line cART. We evaluated time from second-line start to virologic failure and factors associated with increased risk of failure using multivariable Cox proportional hazards regression models. RESULTS: Among the 1,311 patients who started first-line cART a total of 386 patients (29.5%) initiated second-line cART, out of which 35.0% and 60.6% switched from their first-line to their second-line cART when their HIV RNA was undetectable and after documented virologic failure, respectively. At second line cART initiation, median age was 38 years [interquartile range (IQR): 31-45years]. Median CD4 count was significantly different for patients starting second-line cART undetectable [412 cells/mm3 (IQR: 240-617)] compared to those starting second-line cART after documented virologic failure [230 cells/mm3 (IQR: 118-322.5)] (p < 0.01). Median time from second-line cART initiation to failure was also significantly different for patients starting second-line cART undetectable compared to those who with documented virologic failure (log-rank test p < 0.01). Multivariable Cox models showed that younger age, lower education, and HIV RNA level were independently associated with an increased hazard of second-line failure among those with documented virologic failure at start of second-line cART. CONCLUSIONS: We have shown that in a middle-income country with universal access to cART, having a detectable HIV RNA at the start of second-line cART as well as younger age and lower education negatively impact second-line outcomes. Our findings could guide HIV treatment efforts as to which strategies would help maximize the durability of these regimens. PMID- 25523386 TI - 'Getting back to normal' or 'a new type of normal'? A qualitative study of patients' responses to the existential threat of cancer. AB - Existential concerns about cancer have been studied extensively in palliative care but less so in curative settings. The present report aims to describe ways in which patients viewed the continuity or discontinuity of their identity in the face of the mortal threat of cancer. Twenty-eight patients with breast, prostate or lung cancer attending pre-treatment, treatment or follow-up appointments were interviewed about their emotional experiences following diagnosis. Qualitative analysis followed an inductive, constant comparative approach. Patients spoke of 'getting back to normal', but presented two distinct accounts of 'normality'. Some, particularly those only recently diagnosed, maintained continuity to past identity by upholding previous routines, emphasising resilience and minimising the impact of cancer. Others talked of a new 'normality' discontinuous with their past. Most accounts, however, evidenced elements of continuity and discontinuity, often in ostensibly contradictory ways. We suggest that holding contradictory perspectives simultaneously characterises an intermediate stage of adjustment for some patients: between reliance on continuity with the past in the aftermath of diagnosis and, later, a sense of being a new person, changed by cancer. Practitioners should appreciate that patients' wishes for 'normality' can signify very different responses to cancer, and that holding such contradictory orientations is functional, not aberrant. PMID- 25523387 TI - Identification of physicians with unusual performance in screening colonoscopy databases: a Bayesian approach. AB - BACKGROUND: The adenoma detection rate (ADR) is an important surrogate measure of performance quality for screening colonoscopies. OBJECTIVE: To demonstrate how physicians with unusual performance concerning the adenoma detection rate may be identified in screening colonoscopy databases. DESIGN: Bayesian random-effects modeling and Winsorization of potential outliers were applied to develop a robust model for the majority of providers. Divergence was assessed with adjustment for multiple testing. The steps in the analysis were visualized by using funnel plots. Additionally, minimum requirements for the number of colonoscopies with 1 or more detected adenomas were derived. SETTING: Data from 422 physicians offering screening colonoscopy and participating in a quality assurance program in Bavaria, Germany, were used. PATIENTS: A total of 69,738 asymptomatic individuals 55 to 79 years of age. INTERVENTION: Screening colonoscopy. MAIN OUTCOME MEASUREMENTS: Physician-specific ADRs. RESULTS: The overall ADR in the sample was 26%. From an initial model, 62 physicians (15%) were identified as potential outliers. A model with normally distributed random effects was then chosen as the robust null model. Of the potential outliers, 10 (16%) were confirmed as physicians with unusual performance at a false discovery rate of 5%. For all of them, the observed ADR was lower than expected, and together they accounted for 1.4% of all included colonoscopies. LIMITATIONS: Analysis of routine data. CONCLUSION: The applied statistical approach appears suitable to identify unusual performance in screening colonoscopy databases. Its application may help to evaluate and improve the quality of colonoscopy in population-based colorectal cancer screening programs. PMID- 25523388 TI - Convexity Subarachnoid Hemorrhage with PiB Positive Pet Scans: Clinical Features and Prognosis. AB - BACKGROUND: Cerebral amyloid angiopathy (CAA) has been reported to present as convexity subarachnoid hemorrhage (cSAH). Lesser known is that cSAH can herald intracerebral hemorrhage (ICH) and ischemic lesions. We present seven new cases with (11) C-Pittsburgh compound B (PiB) positive positron emission tomography (PET) scans including two with biopsy, review the literature and comment on clinical and radiological findings. METHODS: Patients with cSAH identified on CT, underwent MR imaging and MR angiography to exclude intracranial aneurysm. Nonaneurysmal cSAH were further prospectively evaluated for amyloid angiopathy using PiB. Clinical and radiological features of cSAH, subsequent ICH and ischemic lesions were characterized. RESULTS: Seven patients with nonaneurysmal cSAH fulfilled the Boston criteria for probable CAA. All had PiB PET scans consistent with CAA. Of the 4 patients who had contrast MR Imaging all had enhancement overlying the cSAH, followed by ICH in three cases. All patients presented with transient sensory symptoms. All patients had small punctate subcortical and cortical infarcts on diffusion-weighted MR imaging. Literature review revealed subsequent ICH in approximately 11/79 patients. CONCLUSION: The finding of cSAH and PiB binding in our patients suggest underlying CAA. cSAH may be associated with ischemic lesion as well as future ICH occurrence. PMID- 25523389 TI - Whole-tree dynamics of non-structural carbohydrate and nitrogen pools across different seasons and in response to girdling in two temperate trees. AB - Despite extensive research on the seasonal dynamics of non-structural carbohydrate (NSC) and nitrogen (N) concentrations, the size and relative contributions of NSC and N pools across different tree organs are not well understood. We have measured the changes in NSC and N concentrations in leaves, branches, stems and all root branch orders at monthly intervals in control and girdled trees of larch (Larix gmelinii) and ash (Fraxinus mandshurica). The biomass of each plant compartment was also determined to calculate the size of the NSC and N pools. In both species, 13-37% of the NSC and N pools were mobilized at the beginning of the growing season. Among the mobilized pools, stems and non-absorptive roots (branch orders 4-9) acted as the largest NSC sources in larch and ash, respectively, while branches served as the largest N source in both species. After stem girdling, 22 and 50% of the root NSC stores in larch and ash, respectively, were mobilized to maintain root activities during the growing season. Tree mortality was observed 1 year after girdling, at which time there was still an abundant NSC pool in the roots. We conclude that (1) different storage organs differ in their contribution to new tissue growth at the beginning of the growing season and that those storage organs holding higher fractions of the NSC or N pool are not necessarily those which mobilize more NSC or N; (2) tree growth may not be limited by carbon (C) availability; (3) C storage in non-absorptive roots plays an important role in maintaining tree survival after the termination of photosynthate flow from aboveground sources. PMID- 25523390 TI - Expression patterns of transcription factor PPARgamma and C/EBP family members during in vitro adipogenesis of human bone marrow mesenchymal stem cells. AB - In the past decades increasing lines of evidence have demonstrated that adipose tissue, as an endocrine organ plays a central role in metabolic homeostasis and its related maladies. CCAAT/enhancer-binding protein (C/EBP) family members and the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) were known to be the vital transcription factors in the regulation of adipogenesis. However, the exact mechanism for increased marrow fat in patients with bone metabolic diseases, such as osteoporosis, is still poorly understood. Herein, we studied the expression pattern of PPARgamma and C/EBPs in human bone marrow mesenchymal stem cell (hBMSC) adipogenesis and evaluated the effects of individual components of an adipogenic cocktail on the differentiation and transcription factor expression. We furthermore examined whether the ERK signaling pathway was involved in mediating these effects. These findings showed that C/EBPbeta and C/EBPdelta were detected in undifferentiated hBMSC and maintained during the whole process of adipogenesis, and could initiate the expression of PPARgamma1 under the treatment of dexamethasone and IBMX. Subsequently, the activation of PPARgamma1 by indomethacin, its exogenous ligand, activated C/EBPalpha, which, together with IBMX, up-regulated PPARgamma2 expression and therefore the fullest adipogenesis. Insulin and its downstream signal pathway extracellular signal-regulated kinases (ERK), however, were found not necessary for hBMSC adipogenesis. Our results revealed some unique characteristics of human adipocyte formation, which may help to understand the molecular mechanisms of bone marrow adipogenesis and give insights into the treatment of osteoporosis. PMID- 25523391 TI - p120 Catenin is required for normal tubulogenesis but not epithelial integrity in developing mouse pancreas. AB - The intracellular protein p120 catenin aids in maintenance of cell-cell adhesion by regulating E-cadherin stability in epithelial cells. In an effort to understand the biology of p120 catenin in pancreas development, we ablated p120 catenin in mouse pancreatic progenitor cells, which resulted in deletion of p120 catenin in all epithelial lineages of the developing mouse pancreas: islet, acinar, centroacinar, and ductal. Loss of p120 catenin resulted in formation of dilated epithelial tubules, expansion of ductal epithelia, loss of acinar cells, and the induction of pancreatic inflammation. Aberrant branching morphogenesis and tubulogenesis were also observed. Throughout development, the phenotype became more severe, ultimately resulting in an abnormal pancreas comprised primarily of duct-like epithelium expressing early progenitor markers. In pancreatic tissue lacking p120 catenin, overall epithelial architecture remained intact; however, actin cytoskeleton organization was disrupted, an observation associated with increased cytoplasmic PKCzeta. Although we observed reduced expression of adherens junction proteins E-cadherin, beta-catenin, and alpha catenin, p120 catenin family members p0071, ARVCF, and delta-catenin remained present at cell membranes in homozygous p120(f/f) pancreases, potentially providing stability for maintenance of epithelial integrity during development. Adult mice homozygous for deletion of p120 catenin displayed dilated main pancreatic ducts, chronic pancreatitis, acinar to ductal metaplasia (ADM), and mucinous metaplasia that resembles PanIN1a. Taken together, our data demonstrate an essential role for p120 catenin in pancreas development. PMID- 25523392 TI - C. elegans NIMA-related kinases NEKL-2 and NEKL-3 are required for the completion of molting. AB - Caenorhabditis elegans molting is a process during which the apical extracellular matrix of the epidermis, the cuticle, is remodeled through a process of degradation and re-synthesis. Using a genetic approach, we identified nekl-3 as essential for the completion of molting. NEKL-3 is highly similar to the mammalian NEK kinase family members NEK6 and NEK7. Animals homozygous for a hypomorphic mutation in nekl-3, sv3, had a novel molting defect in which the central body region, but not the head or tail, was unable to shed the old cuticle. In contrast, a null mutation in nekl-3, gk506, led to complete enclosure within the old cuticle. nekl-2, which is most similar to mammalian NEK8, was also essential for molting. Mosaic analyses demonstrated that NEKL-2 and NEKL-3 were specifically required within the large epidermal syncytium, hyp7, to facilitate molting. Consistent with this, NEKL-2 and NEKL-3 were expressed at the apical surface of hyp7 where they localized to small spheres or tubular structures. Inhibition of nekl-2, but not nekl-3, led to the mislocalization of LRP 1/megalin, a cell surface receptor for low-density lipoprotein (LDL)-binding proteins. In addition, nekl-2 inhibition led to the mislocalization of several other endosome-associated proteins. Notably, LRP-1 acts within hyp7 to facilitate completion of molting, suggesting at least one mechanism by which NEKL-2 may influence molting. Notably, our studies failed to reveal a requirement for NEKL-2 or NEKL-3 in cell division, a function reported for several mammalian NEKs including NEK6 and NEK7. Our findings provide the first genetic and in vivo evidence for a role of NEK family members in endocytosis, which may be evolutionarily conserved. PMID- 25523393 TI - E3 ubiquitin ligases promote progression of differentiation during C. elegans embryogenesis. AB - Regulated choice between cell fate maintenance and differentiation provides decision points in development to progress toward more restricted cell fates or to maintain the current one. Caenorhabditis elegans embryogenesis follows an invariant cell lineage where cell fate is generally more restricted upon each cell division. EMS is a progenitor cell in the four-cell embryo that gives rise to the endomesoderm. We recently found that when ubiquitin-mediated protein degradation is compromised, the anterior daughter of EMS, namely MS, reiterates the EMS fate. This observation demonstrates an essential function of ubiquitin mediated protein degradation in driving the progression of EMS-to-MS differentiation. Here we report a genome-wide screen of the ubiquitin pathway and extensive lineage analyses. The results suggest a broad role of E3 ligases in driving differentiation progression. First, we identified three substrate-binding proteins for two Cullin-RING ubiquitin ligase (CRL) E3 complexes that promote the progression from the EMS fate to MS, namely LIN-23/beta-TrCP and FBXB-3 for the CRL1/SCF complex and ZYG-11/ZYG-11B for the CRL2 complex. Genetic analyses suggest these E3 ligases function through a multifunctional protein OMA-1 and the endomesoderm lineage specifier SKN-1 to drive differentiation. Second, we found that depletion of components of the CRL1/SCF complex induces fate reiteration in all major founder cell lineages. These data suggest that regulated choice between self-renewal and differentiation is widespread during C. elegans embryogenesis as in organisms with regulative development, and ubiquitin-mediated protein degradation drives the choice towards differentiation. Finally, bioinformatic analysis of time series gene expression data showed that expression of E3 genes is transiently enriched during time windows of developmental stage transitions. Transcription factors show similar enrichment, but not other classes of regulatory genes. Based on these findings we propose that ubiquitin-mediated protein degradation, like many transcription factors, function broadly as regulators driving developmental progression during embryogenesis in C. elegans. PMID- 25523395 TI - A microscopic steam engine implemented in an optical tweezer. AB - The introduction of improved steam engines at the end of the 18th century marked the start of the industrial revolution and the birth of classical thermodynamics. Currently, there is great interest in miniaturizing heat engines, but so far traditional heat engines operating with the expansion and compression of gas have not reached length scales shorter than one millimeter. Here, a micrometer-sized piston steam engine is implemented in an optical tweezer. The piston is a single colloidal microparticle that is driven by explosive vapourization of the surrounding liquid (cavitation bubbles) and by optical forces at a rate between a few tens of Hertz and one kilo-Hertz. The operation of the engine allows to exert impulsive forces with optical tweezers and induce streaming in the liquid, similar to the effect of transducers when driven at acoustic and ultrasound frequencies. PMID- 25523394 TI - Tak1, Smad4 and Trim33 redundantly mediate TGF-beta3 signaling during palate development. AB - Transforming growth factor-beta3 (TGF-beta3) plays a critical role in palatal epithelial cells by inducing palatal epithelial fusion, failure of which results in cleft palate, one of the most common birth defects in humans. Recent studies have shown that Smad-dependent and Smad-independent pathways work redundantly to transduce TGF-beta3 signaling in palatal epithelial cells. However, detailed mechanisms by which this signaling is mediated still remain to be elucidated. Here we show that TGF-beta activated kinase-1 (Tak1) and Smad4 interact genetically in palatal epithelial fusion. While simultaneous abrogation of both Tak1 and Smad4 in palatal epithelial cells resulted in characteristic defects in the anterior and posterior secondary palate, these phenotypes were less severe than those seen in the corresponding Tgfb3 mutants. Moreover, our results demonstrate that Trim33, a novel chromatin reader and regulator of TGF-beta signaling, cooperates with Smad4 during palatogenesis. Unlike the epithelium specific Smad4 mutants, epithelium-specific Tak1:Smad4- and Trim33:Smad4-double mutants display reduced expression of Mmp13 in palatal medial edge epithelial cells, suggesting that both of these redundant mechanisms are required for appropriate TGF-beta signal transduction. Moreover, we show that inactivation of Tak1 in Trim33:Smad4 double conditional knockouts leads to the palatal phenotypes which are identical to those seen in epithelium-specific Tgfb3 mutants. To conclude, our data reveal added complexity in TGF-beta signaling during palatogenesis and demonstrate that functionally redundant pathways involving Smad4, Tak1 and Trim33 regulate palatal epithelial fusion. PMID- 25523396 TI - A new scoring function for top-down spectral deconvolution. AB - BACKGROUND: Top-down mass spectrometry plays an important role in intact protein identification and characterization. Top-down mass spectra are more complex than bottom-up mass spectra because they often contain many isotopomer envelopes from highly charged ions, which may overlap with one another. As a result, spectral deconvolution, which converts a complex top-down mass spectrum into a monoisotopic mass list, is a key step in top-down spectral interpretation. RESULTS: In this paper, we propose a new scoring function, L-score, for evaluating isotopomer envelopes. By combining L-score with MS-Deconv, a new software tool, MS-Deconv+, was developed for top-down spectral deconvolution. Experimental results showed that MS-Deconv+ outperformed existing software tools in top-down spectral deconvolution. CONCLUSIONS: L-score shows high discriminative ability in identification of isotopomer envelopes. Using L-score, MS-Deconv+ reports many correct monoisotopic masses missed by other software tools, which are valuable for proteoform identification and characterization. PMID- 25523397 TI - Hyperbaric oxygen therapy as a prevention modality for radiation damage in the mandibles of mice. AB - BACKGROUND: Radiation therapy (RT) as part head and neck cancer treatment often leads to irradiation of surrounding normal tissue, such as mandibular bone. A reduced reparative capacity of the bone can lead to osteoradionecrosis (ORN). Hyperbaric oxygen therapy (HBOT) is used to treat ORN, based on its potential to raise the oxygen tension in tissues. However, prevention of radiation-induced damage is of great interest. Our purpose was to investigate whether HBOT could prevent radiation-induced damage to murine mandibles. METHODS: Twenty-eight mice were irradiated in the head and neck region with a single dose (15 Gy) and half of them were subsequently subjected to HBOT. Another 14 mice did not receive any treatment and served as controls. Ten and 24 weeks after RT, mandibles were harvested and analysed histologically and by microcomputed tomography (micro-CT). RESULTS: Micro-CT analysis showed a reduction in relative bone volume by RT, which was partly recovered by HBOT. Trabecular thickness and separation were also positively influenced by HBOT. Morphologically, HBOT suppressed the osteoclast number, indicating decreased resorption, and decreased the amount of lacunae devoid of osteocytes, indicating increased bone viability. CONCLUSIONS: HBOT was able to partly reduce radiation-induced effects on microarchitectural parameters, resorption, and bone viability in mouse mandibles. HBOT could therefore potentially play a role in the prevention of radiation-induced damage to human mandibular bone. PMID- 25523398 TI - The value of early intraoral incisions in patients with perimandibular odontogenic maxillofacial abscesses. AB - Perimandibular abscesses require drainage and removal of the underlying cause of infection. Traditionally drainage was established extraorally, but this can be associated with delay to treatment, because this is done under general anaesthesia. Between July 2008 and June 2013, 205 patients were initially either treated by immediate intraoral incision under local anaesthesia or extraoral incisions under general anaesthesia and prospectively evaluated. Predictors of treatment outcomes and complications were analysed. Fewer secondary procedures were needed for patients with primary treatment under general anaesthesia (p < 0.0001), but the overall stay in hospital was shorter after initial treatment under local anaesthesia (p < 0.0001, Odds Ratio (OR) 0.72, 95% CI 0.62-0.85). Postoperative complications occurred significantly more often under general anaesthesia (p < 0.0001, OR = 16.63, 95% CI 5.59-49.5). Significant prognostic variable was the administration of amoxicillin combined with clavulanic acid (p = 0.016, OR = 1.24, 95% CI 1.09-1.41) and adverse prognostic factors were infections with Human Immunodeficiency Virus (HIV) (p = 0.048, OR 17.45, 95% CI 1.02-298) or diabetes mellitus (p = 0.003, OR 10.39, 95% CI 2.23-48.41). Amoxicillin combined with clavulanic acid showed a significant impact on the treatment course of patients with perimandibular abscesses. PMID- 25523399 TI - Ethics of pharmacological research involving adolescents. AB - Pharmacological research in the adolescent population is not meeting adolescents' needs. Medication is still frequently prescribed off label, and studies especially in sensitive areas of adolescent health care are underrepresented. Adolescents did not benefit from the new knowledge gained in cancer research, and their outcome has essentially not improved during the last two decades in comparison to younger children and adults. There are many obstacles that make it challenging to enroll adolescents in pharmacological research. Access can be difficult. Confidentiality plays an essential role for minors and may be a hindrance, notably to studying sexual and mental health matters. Pharmaceutical companies may exclude the adolescent patient because of a lack of profit and in fear of a complex study design. Research concepts should be explained to the adolescent in a comprehensive manner, and assent and consent forms should be clear and understandable. New laws and incentives have been developed to encourage pharmaceutical companies to engage adolescents in their research projects. Centralization and collaboration of all parties involved may make the whole approach to adolescent research more efficient and uniform. The mature minor doctrine has facilitated the enrollment process. Parental consent may be waived for low-risk medical trials to promote recruitment. Ethics committees therefore play a major role in protecting the adolescent from harm from participating in research. In conclusion, pharmacological research in adolescents has to be encouraged. This will increase the safety of current medical treatment regimens and will allow this population to benefit from therapeutic advancements. PMID- 25523400 TI - A Simple Method for Evaluating Within Sample Prognostic Balance Achieved by Published Comorbidity Summary Measures. AB - OBJECTIVE: To demonstrate how a researcher can investigate the appropriateness of a published comorbidity summary measure for use with a given sample. DATA SOURCE: Surveillance, Epidemiology, and End Results linked to Medicare claims data. STUDY DESIGN: We examined Kaplan-Meier estimated survival curves for four diseases within strata of a comorbidity summary measure, the Charlson Comorbidity Index. DATA COLLECTION: We identified individuals with early-stage kidney cancer diagnosed from 1995 to 2009. We recorded comorbidities present in the year before diagnosis. PRINCIPAL FINDINGS: The use of many comorbidity summary measures is valid under appropriate conditions. One condition is that the relationships of the comorbidities with the outcome of interest in a researcher's own population are comparable to the relationships in a published algorithm's population. The original comorbidity weights from the Charlson Comorbidity Index seemed adequate for three of the diseases in our sample. We found evidence that the Charlson Comorbidity Index might underestimate the impact of one disease in our sample. CONCLUSION: Examination of survival curves within strata defined by a comorbidity summary measure can be a useful tool for determining whether a published method appropriately accounts for comorbidities. A comorbidity score is only as good as those variables included. PMID- 25523401 TI - Patient experience and satisfaction with Onabotulinumtoxin A for refractory overactive bladder. AB - OBJECTIVE: To evaluate the patient experience of our dedicated botulinum toxin A (BTX-A) service using a validated patient-reported experience measure (PREM) and assess patient-reported satisfaction with treatment. MATERIALS AND METHODS: The first 100 patients who underwent BTX-A treatment for refractory idiopathic detrusor overactivity (IDO) in our institution were contacted for telephone interview. They had all been assessed, injected and followed up in a dedicated BTX-A clinic. Patients were asked to complete a validated PREM - the Client Satisfaction Questionnaire (CSQ-8) - as well as a questionnaire developed in our department to assess satisfaction with the results of the treatment. Most patients received 200 U OnabotulinumtoxinA (Botox((r)) ) via an outpatient local anaesthetic flexible cystoscopy technique. RESULTS: Complete data was available for 72 patients. In all, 49 patients were continuing to receive BTX-A treatment while 23 had opted for no further injections. The overall mean (sd) CSQ-8 satisfaction score was 38.3 (3.3), indicating a high level of patient satisfaction with the service offered in our institution. There was a significant difference in total satisfaction scores between those still receiving BTX-A (mean score 29.8) and those who have discontinued treatment (mean score 25.1) (P < 0.01). Overall patient satisfaction with the result of the treatment was high with an overall mean (sd) score of 8.6 (2.0) on a visual analogue scale. Of those who had discontinued BTX-A, most were either using conservative measures only (44%) or had recommenced anticholinergic medications. CONCLUSION: Overall patient satisfaction with the dedicated BTX-A service offered in our institution is high and can result in a positive patient experience. The use of PREMs are advocated in order to fully capture the patient's views of the quality of services and treatments they receive. PMID- 25523402 TI - How meta-analytic evidence impacts clinical decision making in oral implantology: a Delphi opinion poll. AB - OBJECTIVES: To investigate the impact of meta-analytic evidence in scientific literature on clinical decision making in the field of oral implantology. METHODS: A Delphi opinion poll was performed at the meeting of the "Next Generation" Committees of the Austrian, German and Swiss Societies for Implantology (OGI, DGI and SGI). First, the experts gave their opinion on 20 questions regarding routine implant treatment (uninformed decisions), then they were confronted with up-to-date Level I evidence from scientific literature on these topics and again asked to give their opinion (informed decisions) as well as to rate the available evidence as satisfactory or insufficient. Topics involved surgical issues, such as immediate implant placement, flapless surgery, tilted and short implants and bone substitute materials, as well as opinions on prosthodontic paradigms, such as immediate loading, abutment materials and platform switching. RESULTS: Compared to their uninformed decisions prior to confrontation with recent scientific literature, on average, 37% of experts (range: 15-50%) changed their opinion on the topic. When originally favoring one treatment alternative, less than half were still convinced after review of meta analytic evidence. Discrepancy between uninformed and informed decisions was significantly associated with insufficient evidence (P = 0.014, 49% change of opinion vs. 26% on topics rated as sufficiently backed with evidence). Agreement regarding strength of evidence could be reached for eight topics (40%), in three issues toward sufficiency and in five issues toward lack of evidence. CONCLUSION: Confrontation with literature results significantly changes clinical decisions of implantologists, particularly in cases of ambiguous or lacking meta-analytic evidence. PMID- 25523403 TI - Genetic characterization of near full length SIVdrl genomes from four captive drills (Mandrillus leucophaeus). AB - We sequenced near full length SIVdrl genomes from four captive drills (Mandrillus leucophaeus). All four animals were born in captivity in German zoos. Although serologically SIV negative before acquisition in zoo A in 2008 and 2009, during a routine analysis all four animals were determined to be SIV antibody positive in 2011. Comparisons of the four new SIVdrl sequences showed high identity among each other (90.7-97.7% in env) and to the only published full length sequence SIVdrl FAO (90.5-92.8% in env), which is also derived from a captive drill. SIVdrl infections seem to be highly prevalent in captive drills, probably resulting from frequent animal transfers between the zoos in an effort to maintain this highly endangered species and its genetic diversity. This should be kept in mind as SIVdrl may be transmitted to uninfected animals in open groups and potentially also to animal keepers having contact with these nonhuman primates. PMID- 25523404 TI - [Diagnosis and therapy of genitoanal ulcers of infectious etiology]. AB - BACKGROUND/OBJECTIVES: In this review article the diagnostic and therapeutic principles of genital ulcers of infectious etiology are highlighted. Besides frequent causative infections rare but relevant diseases in the differential diagnosis are discussed in detail. MATERIAL AND METHODS: A Pubmed literature search was carried out, guidelines from different task groups and clinical experiences are presented. RESULTS: Infections with herpes simplex virus (first) and syphilis (second) are still the most common causes of infectious genital ulcers. An endemic occurrence, previously rare in Europe, has been observed in recent years. Particular risk groups, such as men who have sex with men (MSM), sex workers or sex tourists are affected. Even less common locations, such as the mouth or the rectum, lymphogranuloma venereum (LGV) and atypical clinical symptoms (e.g. pelvic pain in pelvic lymphadenopathy with LGV) must be considered in the differential diagnosis. CONCLUSION: In recent years sexually transmitted infections (STI) have shown a significant increase in western industrialized nations. In all cases with unclear findings in the genital and anal areas (and also in the oral cavity) STI diseases must be reconsidered in the differential diagnosis. PMID- 25523405 TI - [Genital dermatology: an important part of dermatology]. PMID- 25523406 TI - The parasympathetic system: a renewed role in goal-directed therapy. PMID- 25523408 TI - Patients waking up to the benefits of interrupted sedation. PMID- 25523407 TI - Individualised oxygen delivery targeted haemodynamic therapy in high-risk surgical patients: a multicentre, randomised, double-blind, controlled, mechanistic trial. AB - BACKGROUND: Morbidity after major surgery is associated with low oxygen delivery. Haemodynamic therapy aimed at increasing oxygen delivery in an effort to reduce oxygen debt, tissue injury, and morbidity, is controversial. The most appropriate target for this strategy is unclear and might have several off-target effects, including loss of neural (parasympathetic)-mediated cellular protection. We hypothesised that individualised oxygen delivery targeted haemodynamic therapy (goal-directed therapy) in high-risk surgical patients would reduce postoperative morbidity, while secondarily addressing whether goal-directed therapy affected parasympathetic function. METHODS: In this multicentre, randomised, double-blind, controlled trial, adult patients undergoing major elective surgery were allocated by computer-generated randomisation to a postoperative protocol (fluid, with and without dobutamine) targeted to achieve their individual preoperative oxygen delivery value (goal-directed therapy) or standardised care (control). Patients and staff were masked to the intervention. The primary outcome was absolute risk reduction (ARR) in morbidity (defined by Clavien-Dindo grade II or more) on postoperative day 2. We also assessed a secondary outcome focused on parasympathetic function, using time-domain heart rate variability measures. Analyses were done on an intention-to-treat basis. The trial was registered with Controlled Clinical Trials (number ISRCTN76894700). FINDINGS: We enrolled 204 patients between May 20, 2010, and Feb 12, 2014. Intention-to-treat analysis of the 187 (92%) patients who completed the trial intervention period showed that early morbidity was similar between goal-directed therapy (44 [46%] of 95 patients) and control groups (49 [53%] of 92 patients) (ARR -7%, 95% CI -22 to 7; p=0.30). Prespecified secondary analysis showed that 123 (66%) of 187 patients achieved preoperative oxygen delivery (irrespective of intervention). These patients sustained less morbidity (ARR 19%, 95% CI 3-34; p=0.016), including less infectious complications. Goal-directed therapy reduced parasympathetic activity postoperatively (relative risk 1.33, 95% CI 1.01-1.74). INTERPRETATION: Achievement of preoperative oxygen delivery values in the postoperative phase was associated with less morbidity, but this was not affected by the use of an oxygen delivery targeted strategy. Reduced parasympathetic activity after goal-directed therapy was associated with the failure of this intervention to reduce postoperative morbidity. FUNDING: Academy of Medical Sciences and Health Foundation Clinician Scientist Award. PMID- 25523409 TI - Interactive visual exploration of overlapping similar structures for three dimensional microscope images. AB - BACKGROUND: Recent advances in microscopy enable the acquisition of large numbers of tomographic images from living tissues. Three-dimensional microscope images are often displayed with volume rendering by adjusting the transfer functions. However, because the emissions from fluorescent materials and the optical properties based on point spread functions affect the imaging results, the intensity value can differ locally, even in the same structure. Further, images obtained from brain tissues contain a variety of neural structures such as dendrites and axons with complex crossings and overlapping linear structures. In these cases, the transfer functions previously used fail to optimize image generation, making it difficult to explore the connectivity of these tissues. RESULTS: This paper proposes an interactive visual exploration method by which the transfer functions are modified locally and interactively based on multidimensional features in the images. A direct editing interface is also provided to specify both the target region and structures with characteristic features, where all manual operations can be performed on the rendered image. This method is demonstrated using two-photon microscope images acquired from living mice, and is shown to be an effective method for interactive visual exploration of overlapping similar structures. CONCLUSIONS: An interactive visualization method was introduced for local improvement of visualization by volume rendering in two-photon microscope images containing regions in which linear nerve structures crisscross in a complex manner. The proposed method is characterized by the localized multidimensional transfer function and interface where the parameters can be determined by the user to suit their particular visualization requirements. PMID- 25523410 TI - Exercise interventions improve postural control in children with cerebral palsy: a systematic review. AB - AIM: The aim of this study was to evaluate the efficacy and effectiveness of exercise interventions that may improve postural control in children with cerebral palsy (CP). METHOD: A systematic review was performed using American Academy of Cerebral Palsy and Developmental Medicine (AACPDM) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. Six databases were searched using the following keywords: ('cerebral palsy' OR 'brain injury'); AND ('postur*' OR 'balance' OR 'postural balance' [MeSH]); AND ('intervention' OR 'therapy' OR 'exercise' OR 'treatment'). Articles were evaluated based on their level of evidence and conduct. RESULTS: Searches yielded 45 studies reporting 13 exercise interventions with postural control outcomes for children with CP. Five interventions were supported by a moderate level of evidence: gross motor task training, hippotherapy, treadmill training with no body weight support (no-BWS), trunk-targeted training, and reactive balance training. Six of the interventions had weak or conflicting evidence: functional electrical stimulation (FES), hippotherapy simulators, neurodevelopmental therapy (NDT), treadmill training with body weight support, virtual reality, and visual biofeedback. Progressive resistance exercise was an ineffective intervention, and upper limb interventions lacked high-level evidence. INTERPRETATION: The use of exercise-based treatments to improve postural control in children with CP has increased significantly in the last decade. Improved study design provides more clarity regarding broad treatment efficacy. Research is required to establish links between postural control impairments, treatment options, and outcome measures. Low-burden, low-cost, child-engaging, and mainstream interventions also need to be explored. PMID- 25523411 TI - Poisoning in the United States: 2012 emergency medicine report of the National Poison Data System. AB - Deaths from drug overdose have become the leading cause of injury death in the United States, where the poison center system is available to provide real-time advice and collect data about a variety of poisonings. In 2012, emergency medical providers were confronted with new poisonings, such as bath salts (substituted cathinones) and Spice (synthetic cannabinoid drugs), as well as continued trends in established poisonings such as from prescription opioids. This article addresses current trends in opioid poisonings; new substances implicated in poisoning cases, including unit-dose laundry detergents, bath salts, Spice, and energy drinks; and the role of poison centers in public health emergencies such as the Fukushima radiation incident. PMID- 25523412 TI - IL5RA polymorphisms, smoking and eczema in Japanese women: the Kyushu Okinawa Maternal and Child Health Study. AB - The present case-control study examined the relationship between IL5RA SNPs and eczema in young adult Japanese women. Cases and control subjects were selected from pregnant women who participated in the baseline survey of the Kyushu Okinawa Maternal and Child Health Study, which is an ongoing prebirth cohort study. Cases comprised 188 women with eczema in the previous 12 months as defined according to the criteria of the International Study of Asthma and Allergies in Childhood (ISAAC), regardless of the presence of a doctor's diagnosis of atopic eczema. Control subjects comprised 1130 women without eczema as defined according to the ISAAC criteria who also had not been diagnosed with atopic eczema by a doctor. Compared with the AA genotype of IL5RA SNP rs17881144, the AT genotype, but not the TT genotype, was significantly associated with a decreased risk of eczema. The ATTAGA haplotype and the GTAGCA haplotype of rs17882210, rs3804797, rs334809, rs9831572, rs6771148 and rs17881144 were significantly associated with an increased risk of eczema. In contrast, the GCTGCA haplotype was significantly related to a decreased risk of eczema. Multiplicative interactions between IL5RA SNPs rs334809 and rs17881144 and smoking with respect to eczema were marginally significant (P = 0.07 and 0.07, respectively). This is the first study to show significant associations between IL5RA SNP rs17881144, the ATTAGA haplotype, the GTAGCA haplotype, and the GCTGCA haplotype and eczema. Smoking may modify the relationships between SNPs rs334809 and rs17881144 and eczema. PMID- 25523413 TI - Switching to a reversible proton motion in a charge-transferred dye. AB - We report on the steady-state, pico- and femtosecond time-resolved emission studies of 6-amino-2-(2-methoxyphenyl)benzoxazole (6A-MBO) and 6-amino-2-(2 hydroxyphenyl)benzoxazole (6A-HBO) in different solvents. We observed an intramolecular charge transfer (ICT) reaction following by slow (relatively) solvent relaxation, which happened in the same time domain for both molecules. The ultrafast ICT reaction happens in 80-140 fs whereas the solvent relaxation occurs in 0.5-1.1 ps. In 6A-MBO the excited CT species has a lifetime of ~2.5 ns. However, in 6A-HBO and after the ICT reaction, a reversible excited-state intramolecular proton transfer (ESIPT) reaction takes place in the formed enol charge transfer (ECT*) species producing a keto (K*) type tautomer. Depending on the solvent, the forward ESIPT reaction (ECT* -> K*) happens in 40-175 ps while that of the reverse one (ECT* <- K*) occurs in 240-990 ps. Kinetic isotopic effect (OH/OD exchange) study in acetone shows that the reversible ESIPT reaction occurs via tunneling, while we suggest that in acetonitrile solution it evolves along the IHB and solvent coordinates. Our results show a reversible proton motion coupled to charge-transfer reactions opening the way to new explorations of charge- and proton-transfer dynamics and spectroscopy. PMID- 25523414 TI - Molecular dynamics simulation of planar elongational flow in a nematic liquid crystal based on the Gay-Berne potential. AB - Molecular dynamics simulations of planar elongational flow in a nematic liquid crystal model system based on the Gay-Berne fluid were undertaken by applying the SLLOD equations of motion with an elongational velocity field or strain rate. In order to facilitate the simulation, Kraynik-Reinelt periodic boundary conditions allowing arbitrarily long simulations were used. A Lagrangian constraint algorithm was utilized to fix the director at different angles relative to the elongation direction, so that the various pressure tensor elements could be calculated as a function of this angle. This made it possible to obtain accurate values of the shear viscosities which were found to agree with results previously obtained by shear flow simulations. The torque needed to fix the director at various angles relative to the elongation direction was evaluated in order to determine the stable orientation of the director, where this torque is equal to zero. This orientation was found to be parallel to the elongation direction. It was also noted that the irreversible entropy production was minimal when the director attained this orientation. Since the simulated system was rather large and fairly long simulation runs were undertaken it was also possible to study the cross coupling between the strain rate and the order tensor. It turned out to be very weak at low strain rates but at higher strain rates it could lead to break down of the liquid crystalline order. PMID- 25523416 TI - Review of cardiovascular imaging in The Journal of Nuclear Cardiology in 2014: Part 1 of 2: Positron emission tomography, computed tomography, and neuronal imaging. AB - The year 2014 has been an exciting year for the cardiovascular imaging community with significant advances in the realm of nuclear and multimodality cardiac imaging. In this new feature of the Journal of Nuclear Cardiology, we will summarize some of the breakthroughs that were published in the Journal in 2014 in 2 sister articles. This first article will concentrate on publications dealing with cardiac positron emission tomography (PET), computed tomography (CT), and neuronal imaging. PMID- 25523417 TI - Allicin induces apoptosis of the MGC-803 human gastric carcinoma cell line through the p38 mitogen-activated protein kinase/caspase-3 signaling pathway. AB - Gastric cancer is one of the most common forms of malignant tumor, and the development of anti-gastric cancer drugs with minimal toxicity is of clinical importance. Allicin is extracted from Allium sativum (garlic). Recent research, including clinical experiments, has shown that garlic has anticancer and tumor suppressive effects. The present study aimed to investigate the effects of allicin on the MGC-803 human gastric carcinoma cell line, and to further explore the possible mechanisms of its tumor suppressor effects. The effects of allicin on the MGC-803 cells were initially examined using an 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide assay. Hoechst staining was also used, in order to demonstrate the impact of allicin on MGC-803 cell apoptosis. In addition, western blot analysis was performed to determine the abnormal expression levels of apoptosis-associated proteins, following the treatment of MGC-803 cells with allicin. Western blotting was also used to investigate the specific mechanisms underlying allicin-induced apoptosis of MGC-803 cells. The rate of MGC-803 apoptosis was significantly increased, when the concentration and treatment time of allicin were increased. Hoechst staining detected an enhanced rate of apoptosis, and enhanced expression levels of cleaved caspase 3 were determined by western blotting. Notably, the protein expression levels of p38 were increased when the MGC-803 cells were treated with allicin. The results of the present study suggest that allicin may inhibit the proliferation and induce the apoptosis of MGC-803 human gastric carcinoma cells, and this may partially be achieved through the enhanced expression of p38 and cleaved caspase 3. PMID- 25523415 TI - 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. Developed in collaboration with the American College of Surgeons, American Society of Anesthesiologists, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Anesthesiologists, and Society of Vascular Medicine Endorsed by the Society of Hospital Medicine. PMID- 25523418 TI - Vitreous humor in the pathologic scope: insights from proteomic approaches. AB - The vitreous humor (VH) is the largest component of the eye. It is a colorless, gelatinous, highly hydrated matrix that fills the posterior segment of the eye between the lens and retina in vertebrates. In VH, a diversity of proteins that can influence retinal physiology is present, including growth factors, hormones, proteins with transporter activity, and enzymes. More importantly, the protein composition of VH has been described as being altered in a number of disease states. Therefore, attempts aiming at establishing a map of VH proteins and detecting putative biomarkers for ocular illness or protein fluctuations with putative physiologic significance were conducted over the last two decades, using proteomic approaches. Proteomic strategies often involve gel-based or LC techniques as sample fractioning approaches, subsequently coupled with MS procedures. This set of studies resulted in the proteomic characterization of a range of ocular disease samples, with particular incidence on diabetic retinopathy. However, practical therapeutic applications arising from these studies are scarce at the moment. A pertinent example of therapeutic targets arising from VH proteomics has emerged concerning vasoproliferative factors present in the vitreous, which should be involved in neovascularization and subsequent fibrovascular proliferation of the retina, in ocular disease context. Therefore, this review attempts to sum up the information acquired from the proteomic approaches to ocular disease conducted in VH samples, highlighting its clinical potential for disclosing ocular disease mechanisms and engendering pharmacological therapeutic treatments. PMID- 25523419 TI - Rapid monitoring of grape withering using visible near-infrared spectroscopy. AB - BACKGROUND: Wineries need new practical and quick instruments, non-destructive and able to quantitatively evaluate during withering the parameters that impact product quality. The aim of the work was to test an optical portable system (visible near-infrared (NIR) spectrophotometer) in a wavelength range of 400-1000 nm for the prediction of quality parameters of grape berries during withering. RESULTS: A total of 300 red grape samples (Vitis vinifera L., Corvina cultivar) harvested in vintage year 2012 from the Valpolicella area (Verona, Italy) were analyzed. Qualitative (principal component analysis, PCA) and quantitative (partial least squares regression algorithm, PLS) evaluations were performed on grape spectra. PCA showed a clear sample grouping for the different withering stages. PLS models gave encouraging predictive capabilities for soluble solids content (R(2) val = 0.62 and ratio performance deviation, RPD = 1.87) and firmness (R(2) val = 0.56 and RPD = 1.79). CONCLUSION: The work demonstrated the applicability of visible NIR spectroscopy as a rapid technique for the analysis of grape quality directly in barns, during withering. The sector could be provided with simple and inexpensive optical systems that could be used to monitor the withering degree of grape for better management of the wine production process. PMID- 25523420 TI - NF-kappaB is required for dengue virus NS5-induced RANTES expression. AB - Dengue virus (DENV) infection associates with renal disorders. Patients with dengue hemorrhagic fever and acute kidney injury have a high mortality rate. Increased levels of cytokines may contribute to the pathogenesis of DENV-induced kidney injury. Currently, molecular mechanisms how DENV induces kidney cell injury has not been thoroughly investigated. Excessive cytokine production may be involved in this process. Using human cytokine RT(2) Profiler PCR array, 14 genes including IP-10, RANTES, IL-8, CXCL-9 and MIP-1beta were up-regulated more than 2 folds in DENV-infected HEK 293 cells compared to that of mock-infected HEK 293 cells. In the present study, RANTES was suppressed by the NF-kappaB inhibitor, compound A (CpdA), in DENV-infected HEK 293 cells implying the role of NF-kappaB in RANTES expression. Chromatin immunoprecipitation (ChIP) assay showed that NF kappaB binds more efficiently to its binding sites on the RANTES promoter in NS5 transfected HEK 293 cells than in HEK 293 cells expressing the vector lacking NS5 gene. To further examine whether the NS5-activated RANTES promoter is mediated through NF-kappaB, the two NF-kappaB binding sites on the RANTES promoter were mutated and this promoter was coupled to the luciferase cDNA. The result showed that when both binding sites of NF-kappaB in the RANTES promoter were mutated, the ability of NS5 to induce the luciferase activity was significantly decreased. Therefore, DENV NS5 activates RANTES production by increasing NF-kappaB binding to its binding sites on the RANTES promoter. PMID- 25523421 TI - Associations between Alzheimer's disease and blood homocysteine, vitamin B12, and folate: a case-control study. AB - BACKGROUND: There is a growing focus on nutritional therapy for Alzheimer's disease (AD), and controversy exists regarding the association between AD and homocysteine (Hcy), vitamin B12, and folate levels. OBJECTIVE: The present study evaluated the association between AD and the combined levels of Hcy, vitamin B12, and folate. METHODS: This case-control study consisted of 115 patients with AD and 115 matched controls. Serum folate and vitamin B12 were measured using an automated immunoassay analyzer. Plasma Hcy was measured using high-performance liquid chromatography. The association between AD and Hcy, vitamin B12, and folate was analyzed using binary logistic regression, adjusted for age and sex. RESULTS: With the combination of normal blood Hcy, vitamin B12, and folate levels as the reference category, low vitamin B12 in subjects with normal Hcy and folate was associated with AD (adjusted odds ratio [OR], 4.6; 95% confidence interval [CI]: 1.6-13.2). The combination of low vitamin B12 and folate in subjects with normal Hcy was associated with AD (adjusted OR, 4.3; 95% CI: 1.3-14.6). The combination of high Hcy and low folate levels in patients with normal vitamin B12 was associated with AD (adjusted OR, 17.0; 95% CI: 5.4- 53.4). The combination of high Hcy, low vitamin B12, and any folate level was associated with AD (adjusted OR, 30.5; 95% CI: 9.7-95.9). CONCLUSION: Vitamin B12 was directly associated with AD. The combination of high Hcy, low vitamin B12, and any folate level represented the poorest association with AD. PMID- 25523422 TI - Examination of hippocampal differences between Alzheimer disease, amnestic mild cognitive impairment and normal aging: diffusion kurtosis. AB - PURPOSE: To examine hippocampal differences between Alzheimer disease (AD), amnestic mild cognitive impairment (aMCI) and normal aging. MATERIALS AND METHODS: This study was approved by the local ethics review board, and informed consent was obtained from volunteers/guardians. The study comprised 60 subjects: 20 aMCI patients, 20 AD patients and 20 normal controls (NC group). Magnetic resonance imaging and diffusion kurtosis imaging of the hippocampus were performed. Nonlinear fitting routines and equations were used to calculate mean diffusion (MD) and mean kurtosis (MK). Analysis of variance was used to compare the bilateral MK/MD values/volumes of the hippocampus for the three groups using the Fisher least significant difference test (a two-sample t-test comparison). Pearson correlation coefficients were calculated for the correlations between mini-mental state examination (MMSE) scores and MK/MD values/volumes. RESULTS: There were significant differences between the AD and NC groups and between the AD and aMCI groups in terms of normalized bilateral hippocampal volume. There were significant differences between the NC, aMCI and AD groups in terms of both right and left hippocampus MK values. For the right hippocampus MD values, there was a significant difference between the NC and AD groups. For the left hippocampus MD values, there were significant differences between the AD and NC groups and between the AD and aMCI groups. Pearson correlation coefficients for all correlations between MMSE scores and hippocampus MK/MD values/volumes were significant. CONCLUSION: The bilateral hippocampal MK/MD values may be more sensitive than volumes in the diagnosis of aMCI and AD patients. PMID- 25523423 TI - Acute oral Bryostatin-1 administration improves learning deficits in the APP/PS1 transgenic mouse model of Alzheimer's disease. AB - BACKGROUND: Previous studies showed that Bryostatin-1, a potent PKC modulator and alphasecretase activator, can improve cognition in models of Alzheimer's disease (AD) with chronic (>10 weeks), intraperitoneal (i.p.) administration of the drug. We compared learning and spatial memory in the APPswe, PSEN1dE985Dbo (APP/PS1) mouse model of AD and studied the ability of acute intraperitoneal and oral Bryostatin-1 to reverse cognitive deficits in this model. Compared to wild-type (WT) mice, APP/PS1 mice showed significant delays in learning the location of a submerged platform in the Morris water maze. Bryostatin-1 was administered over a 2-week course prior to and during water maze testing. RESULTS: Acute i.p. Bryostatin-1 administration did not improve latency to escape but oral Bryostatin 1 significantly improved memory (measured by a reduction in latency to escape). This benefit of oral Bryostatin-1 administration was most apparent during the first 3 days of testing. These findings show that: 1) Bryostatin-1 is orally active in models of learning and memory, 2) this effect can be produced in less than 2 weeks and 3) this effect is not seen with i.p. administration. We conclude that oral Bryostatin-1 represents a novel, potent and long-acting memory enhancer with future clinical applications in the treatment of human AD. PMID- 25523426 TI - Expanded temporal binding windows in people with mild cognitive impairment. AB - Previous studies investigating mild cognitive impairment (MCI) have focused primarily on cognitive, memory, attention, and executive function deficits. There has been relatively little research on the perceptual deficits people with MCI may exhibit. This is surprising given that it has been suggested that sensory and cognitive functions share a common cortical framework [1]. In the following study, we presented the sound-induced flash illusion (SiFi) to a group of participants with mild cognitive impairment (MCI) and healthy controls (HC). The SiFi is an audio-visual illusion whereby two-beeps and one-flash are presented. Participants tend to perceive two flashes when the time-interval between the auditory beeps is small [2, 3]. Participants with MCI perceived significantly more illusions compared to HC over longer auditory time-intervals. This suggests that MCIs integrate more (arguably irrelevant) audiovisual information compared to HCs. By incorporating perceptual tasks into a clinical diagnosis it may be possible to gain a more comprehensive understanding into the disease, as well as provide a more accurate diagnose to those who may have a language impairment. PMID- 25523425 TI - Beneficial effects of the beta-secretase inhibitor GRL-8234 in 5XFAD Alzheimer's transgenic mice lessen during disease progression. AB - The beta-secretase enzyme BACE1, which initiates the cleavage of amyloid precursor protein (APP) into the amyloid-beta (Abeta) peptide, is a prime therapeutic target for Alzheimer's disease (AD). However, recent investigations using genetic animal models raise concern that therapeutic BACE1 inhibition may encounter the dramatic reduction of efficacy in ameliorating AD-like pathology and memory deficits during disease progression. Here, we compared the effects of the potent and selective small-molecule BACE1 inhibitor GRL-8234 in different pathological stages of AD mouse model. Specifically, we administered GRL-8234 (33.4 mg/kg, i.p.) once daily for 2 months to 5XFAD transgenic mice, which showed modest (4 months) and massive (10 months of age) Abeta plaque deposition at starting points. Chronic treatments with GRL-8234 reversed memory impairments, as tested by the spontaneous alternation Y-maze task, in the younger 5XFAD group concomitant with significant reductions in cerebral Abeta42 levels. In contrast, only marginal reductions of Abeta42 were observed in 12-month-old 5XFAD mice treated with GRL-8234 and their memory function remained impaired. We found that not only BACE1 but also full-length APP expression was significantly elevated with progressive Abeta accumulation in 5XFAD mice, while GRL-8234 failed to affect these detrimental mechanisms that further accelerate plaque growth in brains of older 5XFAD mice. Therefore, our results provide important insights into the mechanisms by which Abeta accumulation and related memory impairments become less responsive to rescue by BACE1 inhibition during the course of AD development. PMID- 25523424 TI - Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer's disease. AB - Amyloid-beta proteins (Abeta) of 42 (Abeta42) and 40 aa (Abeta40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Abeta precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the epsilon4 allele of Apolipoprotein E (ApoE epsilon4) foster the accumulation of Abeta and also induce the entire spectrum of pathology associated with the disease. Abeta accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by beta-site APP cleaving enzyme (BACE1) and gamma secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Abeta. Although Abeta accumulates in all forms of AD, the only pathways known to be affected in FAD increase Abeta production by APP gene duplication or via base substitutions on APP and gamma-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Abeta42 or both Abeta40 and Abeta42. However, the vast majority of AD patients accumulate Abeta without these known mutations. This led to proposals that impairment of Abeta degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of gamma-secretase inhibitors to paradoxically increase the yield of Abeta and we have recently established that the mechanism is by skirting Abeta degradation. This review outlines major cellular pathways of Abeta degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Abeta turnover. PMID- 25523427 TI - No significant effect of 7,8-dihydroxyflavone on APP processing and Alzheimer associated phenotypes. AB - It is reported that 7,8-dihydroxyflavone (DHF), a TrkB agonist, has beneficial effects on neuronal excitotoxicity, stroke, and Parkinson disease in animal models by enhancing axon regeneration, muscle reinnervation and neuromuscular transmission. The effect of DHF on AD neuropathology remains not well defined. In this study we examined whether DHF affects APP processing and cognitive functions in vitro and in vivo. We found that DHF had no significant effect on amyloid beta precursor protein (APP), BACE1 and amyloid beta protein (Abeta). DHF had little effect on APP processing in cell cultures. DHF treatment did not reduce the deposition of Abeta to form neuritic plaques in the brain of AD model mice APP23/PS45. Furthermore, DHF did not alleviate learning and memory impairments in the AD model mice. Our study suggest that further extensive and careful studies are warranted for considering DHF as a new therapeutic agent for reducing amyloid pathology and alleviating cognitive deficits for AD treatment. PMID- 25523428 TI - Predicting progression from cognitive impairment to Alzheimer's disease with the Disease State Index. AB - We evaluated the performance of the Disease State Index (DSI) method when predicting progression to Alzheimer's disease (AD) in patients with subjective cognitive impairment (SCI), amnestic or non-amnestic mild cognitive impairment (aMCI, naMCI). The DSI model measures patients' similarity to diagnosed cases based on available data, such as cognitive tests, the APOE genotype, CSF biomarkers and MRI. We applied the DSI model to data from the DESCRIPA cohort, where non-demented patients (N=775) with different subtypes of cognitive impairment were followed for 1 to 5 years. Classification accuracies for the subgroups were calculated with the DSI using leave-one-out crossvalidation. The DSI's classification accuracy in predicting progression to AD was 0.75 (AUC=0.83) in the total population, 0.70 (AUC=0.77) for aMCI and 0.71 (AUC=0.76) for naMCI. For a subset of approximately half of the patients with high or low DSI values, accuracy reached 0.86 (all), 0.78 (aMCI), and 0.85 (naMCI). For patients with MRI or CSF biomarker data available, theywere 0.78 (all), 0.76 (aMCI) and 0.76 (naMCI), while for clear cases the accuracies rose to 0.90 (all), 0.83 (aMCI) and 0.91 (naMCI). The results show that the DSI model can distinguish between clear and ambiguous cases, assess the severity of the disease and also provide information on the effectiveness of different biomarkers. While a specific test or biomarker may confound analysis for an individual patient, combining several different types of tests and biomarkers could be able to reveal the trajectory of the disease and improve the prediction of AD progression. PMID- 25523429 TI - The contribution of proteinase-activated receptors to intracellular signaling, transcellular transport and autophagy in Alzheimer's disease. AB - The etiopathogenesis of Alzheimer's disease is characterized by beta amyloid Abeta(1-42) toxic fragment aggregation and its association with impaired autophagy. In mitochondria, chronic damage due to transport and enzymatic processes together with the production of reactive oxygen species (ROS) are followed by the subsequent accumulation of Abeta in the form of senile plaques and the accumulation of hyperphosphorylated tau protein in intracellular deposits called tangles. Proteinase-activated receptors (PARs), members of the G protein coupled receptor (GPCR) family, facilitate and modulate the transcellular transport and distribution of a variety of subcellular molecular components to the lysosomal system and, thus, influence their degradation. A review of the data shows that the activation or inhibition of PARs leads to changes in the process of autophagy, which may influence ROS production and Abeta (1-42) degradation in lysosomes and result in AD pathogenesis. PMID- 25523430 TI - Evaluating high-dose rivastigmine patch in severe Alzheimer's disease: analyses with concomitant memantine usage as a factor. AB - BACKGROUND: ACTION, a 24-week, prospective, randomized, parallel-group, double blind study in patients with severe Alzheimer's disease (AD), demonstrated significant efficacy of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch on the Severe Impairment Battery (SIB) and Alzheimer's Disease Cooperative Study Activities of Daily Living scale-Severe Impairment Version (ADCS-ADL-SIV). Overall, 61% of the study population received at least 1 dose of concomitant memantine, regardless of dose or duration. This retrospective analysis investigated the effects of concomitant memantine on the efficacy, safety and tolerability of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch. METHODS: Patients were stratified according to whether or not they received at least one dose of concomitant memantine during the double-blind phase. Changes from baseline on the SIB and ADCS-ADL-SIV were compared using analysis of covariance (ANCOVA) with treatment, pooled center, memantine usage and treatment-by memantine as factors, and baseline as a covariate. Safety and tolerability were assessed. RESULTS: Memantine-treated patients were younger than those not receiving memantine (mean 75.9 and 78.8 years, respectively), with a lower screening Mini-Mental State Examination (8.6 and 9.2, respectively). ANCOVA confirmed there was no significant interaction (p>0.1) between study treatment and memantine use on the SIB or ADCS-ADL-SIV. The incidence of adverse events was: 71.4%, 13.3 mg/24 h patch with memantine; 79.7%, 13.3 mg/24 h patch alone; 74.7%, 4.6 mg/24 h patch with memantine; and 71.1%, 4.6 mg/24 h patch alone. CONCLUSION: These data suggest benefit of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch, regardless of concomitant memantine use. The incidence of adverse events with highdose patch was similar in memantine-treated patients and those not receiving memantine. PMID- 25523431 TI - Design, synthesis, and biological evaluation of novel 2H-pyran-2-one derivatives as potential HIV-1 reverse transcriptase inhibitors. AB - In search for more effective drugs against HIV infection acting as non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of new molecules with hybrid structures based on the natural product (+)-calanolide A and the synthetic molecule alpha-APA, known as potent and selective inhibitors of this enzyme, were selected by docking calculations. A convergent synthetic strategy gave 21 compounds with a 2H-pyran-2-one structural unit and bearing isosteric modifications, which were tested against HIV-infected CEM cell cultures. Only compound 6 (4-((2-(1H-indol-3-yl)ethyl)amino)-6-methyl-2H-pyran-2-one) displayed inhibitory activity (EC50 : 25-50 uM). However, it was associated with a relatively high cytostatic effect on human T lymphocyte (CEM) cell cultures, not easily predictable, neither by the chemical structure nor by the computational approach. Although this drug design has failed in selecting a novel scaffold for NNRTIs, the results have driven the interest towards new potential antitumor molecules showing activity against L1210 murine leukemia and HeLa cervix carcinoma cells, among which compound 21 (6-methyl-4-((2-(naphthalen-1 yl)ethyl)sulfonyl)-2H-pyran-2-one) was the most effective (IC50 : 0.95 and 2.9 uM, respectively). PMID- 25523432 TI - Influenza vaccination in patients with end-stage renal disease: systematic review and assessment of quality of evidence related to vaccine efficacy, effectiveness, and safety. AB - BACKGROUND: Vaccination against influenza is recommended in patients with end stage renal disease (ESRD). However, so far, no systematic review has summarized the available evidence on the effectiveness and safety of influenza vaccination in this patient group. METHODS: We conducted a systematic review and meta analysis and assessed the quality of evidence using the GRADE methodology. We searched MEDLINE, EMBASE, Cochrane Library databases, ClinicalTrials.gov, and reference lists for studies on efficacy, effectiveness, and/or safety of seasonal influenza vaccination in patients with ESRD receiving dialysis. All reported clinical outcomes were considered, including all-cause mortality, cardiac death, infectious death, all-cause hospitalization, hospitalization due to influenza or pneumonia, hospitalization due to bacteremia, viremia, or septicemia, hospitalization due to respiratory infection, ICU admission, and influenza-like illness. RESULTS: Five observational studies and no randomized-controlled trial were identified. In four studies, risk of bias was high regarding all reported outcomes. Strong residual confounding was likely to be present in one study reporting on three outcomes, as indicated by significant protective effects of vaccination outside influenza seasons. Therefore, the statistically significant protective effects on all-cause mortality (vaccine effectiveness (VE), 32%; 95% CI, 24-39%), cardiac death (VE, 16%; 95% CI, 1-29%), hospitalization due to influenza or pneumonia (VE, 14%; 95% CI, 7-20%), ICU admission (VE, 81%; 95% CI, 63-86%), and influenza-like illness (VE, 12%; 95% CI, 10-14%) have to be taken with caution. According to GRADE, the quality of the body of evidence was considered very low for all outcomes. No study reported on laboratory-confirmed influenza virus infections or on safety endpoints. CONCLUSIONS: Evidence on the protective effects of influenza vaccination in patients with ESRD is limited and of very low quality. Since VE estimates in the available literature are prone to unmeasured confounding, studies using randomization or quasi-experimental designs are needed to determine the extent by which vaccination prevents influenza and related clinical outcomes in this at-risk population. However, given the high rates of health-endangering events in these patients, even a low VE can be considered as sufficient to recommend annual influenza vaccination. PMID- 25523433 TI - Presence of autoimmune regulator and absence of desmoglein 1 in a thymoma in a patient with pemphigus foliaceus. PMID- 25523434 TI - Prevalence and risk factors for diabetes and diabetic retinopathy: results from the Nigeria national blindness and visual impairment survey. AB - BACKGROUND: In Nigeria, urbanisation and increasing life expectancy are likely to increase the incidence of non-communicable diseases. As the epidemic of diabetes matures, visual loss from diabetic retinopathy (DR) will increase unless mechanisms for early detection and treatment improve, and health systems respond to the growing burden of non-communicable diseases. METHODS: A nationally representative population-based sample of 13,591 participants aged >=40 years selected by multistage-stratified-cluster-random-sampling with probability proportional-to-size procedures were examined in 305 clusters in Nigeria between January 2005 to June 2007. All were asked about history of diabetes and underwent basic eye examination. Visual acuity (VA) was measured using logMAR E-chart. Participants with VA<6/12 and/or DR detected underwent detailed eye examination including dilated retinal examination and retinal photography. Systematic sampling of 1-in-7 gave a subsample (n=1759) examined in detail regardless of VA; and had random blood glucose (RBG) testing. Images were graded by Moorfields Eye Hospital Reading Centre. Participants were defined as having diabetes if they were previously diagnosed or RBG>11.1mmol/l or had DR. Data in the subsample were used to estimate the prevalence and to analyse risk factors for diabetes and DR using multivariable logistic regression. Additional information on the types of DR was obtained from participants not in the subsample. RESULTS: In the subsample, 164 participants were excluded due to missing data; and 1,595 analysed. 52/1,595 had diabetes, a prevalence of 3.3% (95%CI 2.5-4.3%); and 25/52(48%) did not know. Media opacity in 8/52 precluded retinal examination. 9/44(20.5%) had DR. Higher prevalence of diabetes was associated with urban residence (Odds ratio [OR]1.87) and overweight/obesity (OR3.02/4.43 respectively). Although not statistically significant, DR was associated with hypertension (OR3.49) and RBG>15.0mmol/L (OR8.10). Persons with diabetes had 3 times greater odds of blindness. Of 11,832 other participants in the study sample, 175(1.5%) had history of diabetes; 28 had DR. Types of DR (total=37) included 10.8% proliferative, 51.4% macular oedema. CONCLUSION: The age-adjusted prevalence of diabetes in Nigeria was 3.25% (95%CI 2.50-4.30) and over 10% of people with diabetes aged >=40 years had sight-threatening-DR. These data will enable the development of better public health strategies for the control of diabetes and planning services for DR to prevent vision loss. PMID- 25523435 TI - National Lipid Association Annual Summary of Clinical Lipidology 2015. AB - The National Lipid Association (NLA) Annual Summary of Clinical Lipidology 2015 is a summary of principles important to the patient-centered evaluation, management, and care of patients with dyslipidemia. This summary is intended to be a "living document," with future annual updates based on emerging science, clinical considerations, and new NLA Position and Consensus Statements. The goal is to provide clinicians an ongoing resource that translates the latest advances in medical science toward the evaluation and treatment of patients with dyslipidemia. The 2015 NLA Annual Summary of Clinical Lipidology was founded on the principles of evidence-based medicine and is generally consistent with established national and international lipid guidelines. Topics include a general discussion of the 2014 NLA Recommendations for Patient-Centered Management of Dyslipidemia, genetics, secondary causes of dyslipidemia, biomarkers and "advanced lipid testing," medical nutrition, physical activity, obesity, pharmacotherapy, statin safety, lipid-altering drug interactions, lipoprotein apheresis, dyslipidemia in children and adolescence, dyslipidemia in older individuals, race/ethnicity, and women, health information technology and electronic medical records, as well as investigational lipid-altering drugs in development. PMID- 25523436 TI - Alternating current driven organic light emitting diodes using lithium fluoride insulating layers. AB - We demonstrate an alternating current (AC)-driven organic light emitting diodes (OLED) with lithium fluoride (LiF) insulating layers fabricated using simple thermal evaporation. Thermal evaporated LiF provides high stability and excellent capacitance for insulating layers in AC devices. The device requires a relatively low turn-on voltage of 7.1 V with maximum luminance of 87 cd/m(2) obtained at 10 kHz and 15 Vrms. Ultraviolet photoemission spectroscopy and inverse photoemission spectroscopy are employed simultaneously to examine the electronic band structure of the materials in AC-driven OLED and to elucidate the operating mechanism, optical properties and electrical characteristics. The time-resolved luminance is also used to verify the device performance when driven by AC voltage. PMID- 25523437 TI - Estrogen and glucocorticoid receptor agonists and antagonists in oocytes modulate the pattern of expression of genes that encode nuclear receptor proteins in very early stage rainbow trout (Oncorhynchus mykiss) embryos. AB - Previous studies show that changes in estrogen (ER) and glucocorticoid receptor (GR) function in rainbow trout (Oncorhynchus mykiss) oocytes modulate the growth performance phenotype of embryo and juvenile progeny; the present study was undertaken to determine whether this altered growth performance is associated with changes in the expression of several growth-related genes in early-stage embryos. Unfertilized oocytes were incubated in the presence of various combinations of GR and ER agonists and antagonists; the oocytes were then fertilized and the expression of genes that encode for six nuclear receptor superfamily (NRS) proteins (GR1, GR2, ERalpha, ERbeta, TRalpha, and TRbeta) and the two IGF peptides (IGF1 and IGF2) were measured in the 7-, 13-, and 26-dpf embryos. By day 26 of embryogenesis, the expression of the six NRS-related genes of interest and that of igf2 were significantly enhanced in embryos reared from ER agonist- or ER antagonist-treated oocytes, regardless of whether the GR agonist, cortisol, was also included in the initial oocyte incubation medium. Conversely, the igf1 expression pattern among treatment groups was significantly enhanced in the cortisol-only treatment group and in the ER antagonist and GR antagonist groups that were co-incubated with cortisol. Additionally, in the ER agonist treatment groups igf1 expression was significantly inhibited when cortisol was included in the oocyte incubation medium. The findings show that a single in ovo exposure to the receptor agonists/antagonists markedly changed the programming of the expression of NRS-related and IGF-related genes of the early stage trout embryos. PMID- 25523438 TI - Molecular simulations of metal-coupled protein folding. AB - Many proteins require help from metal cofactors to function properly. Due to the involvement of metal binding, folding of these metalloproteins can be much more complicated. In recent years, several computational methods have been developed to reveal the essential features of metal-coupled protein folding, ranging from quantum mechanics (QM) to atomistic and coarse-grained (CG) simulations. These theoretical tools have achieved great successes in solving the multiscale difficulties arising from metal binding, and provided new insights into the mechanisms of metalloprotein folding. In this review, we first discuss the interaction features of metal-coordination and then introduce several computational models and their applications in metal-coupled folding. Finally we discuss the effects of metal-binding on the protein energy landscape, which is followed by some perspectives. PMID- 25523439 TI - Smectic layer instabilities in liquid crystals. AB - Scientists aspire to understand the underlying physics behind the formation of instabilities in soft matter and how to manipulate them for diverse investigations, while engineers aim to design materials that inhibit or impede the nucleation and growth of these instabilities in critical applications. The present paper reviews the field-induced rotational instabilities which may occur in chiral smectic liquid-crystalline layers when subjected to an asymmetric electric field. Such instabilities destroy the so-named bookshelf geometry (in which the smectic layers are normal to the cell surfaces) and have a detrimental effect on all applications of ferroelectric liquid crystals as optical materials. The transformation of the bookshelf geometry into horizontal chevron structures (in which each layer is in a V-shaped structure), and the reorientation dynamics of these chevrons, are discussed in details with respect to the electric field conditions, the material properties and the boundary conditions. Particular attention is given to the polymer-stabilisation of smectic phases as a way to forbid the occurrence of instabilities and the decline of related electro-optical performances. It is also shown which benefit may be gained from layer instabilities to enhance the alignment of the liquid-crystalline geometry in practical devices, such as optical recording by ferroelectric liquid crystals. Finally, the theoretical background of layer instabilities is given and discussed in relation to the experimental data. PMID- 25523440 TI - Inflammation and oxidative stress during intermittent hypoxia: the impact on chemoreception. AB - NEW FINDINGS: What is the topic of this review? This article describes the contribution of oxidative stress and pro-inflammatory cytokines to the enhanced carotid body chemosensory responsiveness to the hypoxia and systemic hypertension induced by chronic intermittent hypoxia. What advances does it highlight? Chronic intermittent hypoxia enhances the carotid body chemosensory discharge during normoxia and hypoxia, leading to sympathetic overactivity and hypertension. New evidence suggests that chronic intermittent hypoxia increases pro-inflammatory cytokines. Here, we discuss the role of inflammation in the alterations of the carotid chemoreceptor function as well as the cardiorespiratory alterations following chronic intermittent hypoxia. Chronic intermittent hypoxia (CIH), the main characteristic of obstructive sleep apnoea, enhances carotid body (CB) chemosensory discharges during normoxia and hypoxia and elicits hypertension. These alterations are attributed to oxidative stress, because antioxidants prevent the enhanced CB chemosensory discharges and the hypertension. In this report, we discuss new evidence supporting the suggestion that oxidative stress induced upregulation of pro-inflammatory cytokines (i.e. tumour necrosis factor alpha and interleukin-1beta) in the CB is involved in the chemosensory potentiation and the hypertension following CIH. Anti-inflammatory treatment with ibuprofen prevents the increased tumour necrosis factor-alpha and interleukin 1beta levels in the CB and the hypertension, but does not reduce the enhanced chemosensory hypoxic response and the local oxidative stress in the CB. In contrast, antioxidant treatment with ascorbic acid prevents the increase in cytokine concentrations and CB oxidative stress, the chemosensory potentiation and the hypertension. Thus, the enhanced CB chemosensory responses to hypoxia depend critically on the oxidative stress, but not on the increased tumour necrosis factor-alpha and interleukin-1beta in the CB. We discuss a possible role for pro-inflammatory cytokines in development of the hypertension produced by CIH, acting on cardiorespiratory centres located in the CNS. PMID- 25523441 TI - Epigenetics and lupus. AB - Systemic lupus erythematosus (SLE) is among the systemic autoimmune diseases whose complex pathogenesis involves both genetic and environmental factors. Epigenetic dysregulation resulting in overexpression of certain genes in some of the key immune cells, such as T cells, has been incriminated in the pathophysiology of SLE. Epigenetics is defined as transmissible and reversible modifications in gene expression without alterations in the nucleotide sequences. Epigenetic information is carried chiefly by DNA itself, histones, and noncoding RNAs. Several epigenetic mechanisms may play a role in SLE pathogenesis. This review discusses the various epigenetic mechanisms that regulate gene expression and provides examples relevant to SLE. PMID- 25523442 TI - 'And then you can decide'--antenatal foetal diagnosis decision making in South Africa. AB - BACKGROUND: Decision making is integral to genetic counselling and the premise is that autonomous decisions emerge if patients are provided with information in a non-directive manner. The pivotal activity in antenatal diagnosis counselling with at-risk pregnant women is decision making regarding invasive procedures. This process is not well understood in multicultural settings. OBJECTIVE: This study examined multicultural genetic counselling interactions with women of advanced maternal age (AMA). It aimed to investigate the participants' orientation towards the amniocentesis decision. DESIGN: Data were collected during 14 video-recorded consultations between six genetic counsellors and 14 women of AMA in a genetic counselling clinic in South Africa. The design was qualitative and conversation analysis was used for analysis. RESULTS: Analysis revealed that counsellors used several strategies to facilitate discussions and decision making. However, the invitation to make a decision regarding amniocentesis was not perceived as being neutral. Both the counsellors and the women appeared to treat the offer as one which should be accepted. This resulted in a paradox, as strategies intended to allow neutral discussion seem to achieve the opposite. It is suggested that these results may be linked to the local health-care setting. CONCLUSION: The results suggest that the understanding of decision-making processes and enhancing autonomy may require a more detailed investigation into psychosocial, political and historical factors in the local health-care setting. Models of practice as well as the training of genetic counsellors need to be sensitive to these influences. A closer examination of interactional variables may yield new and relevant insights for the profession. PMID- 25523443 TI - Non-convulsive seizures in children with infection-related altered mental status. AB - BACKGROUND: In the intensive care unit, the use of continuous electroencephalography (cEEG) in children with altered mental status often results in the detection of non-convulsive seizures (NCS). Children with influenza can occasionally display altered mental status, but the prevalence of NCS in children with influenza with altered mental status is yet to be determined. This study determined the prevalence of NCS in pediatric patients with altered mental status associated with influenza A(H1N1)pdm09 infection. METHODS: We retrospectively reviewed admissions to the pediatric intensive care unit between September 2009 and February 2010 and confirmed the presence of NCS on cEEG in children with influenza A(H1N1)pdm09 and with altered mental status. RESULTS: Of the 15 patients (aged 41-159 months old), NCS was identified on cEEG in five children (33%). CONCLUSIONS: Approximately one-third of the children infected with influenza A(H1N1)pdm09 with altered mental status had NCS. Further research is needed to determine if the detection and management of NCS improve outcome in these children. PMID- 25523444 TI - Angular momentum and arboreal stability in common marmosets (Callithrix jacchus). AB - Despite the importance that concepts of arboreal stability have in theories of primate locomotor evolution, we currently lack measures of balance performance during primate locomotion. We provide the first quantitative data on locomotor stability in an arboreal primate, the common marmoset (Callithrix jacchus), predicting that primates should maximize arboreal stability by minimizing side-to side angular momentum about the support (i.e., Lsup ). If net Lsup becomes excessive, the animal will be unable to arrest its angular movement and will fall. Using a novel, highly integrative experimental procedure we directly measured whole-body Lsup in two adult marmosets moving along narrow (2.5 cm diameter) and broad (5 cm diameter) poles. Marmosets showed a strong preference for asymmetrical gaits (e.g., gallops and bounds) over symmetrical gaits (e.g., walks and runs), with asymmetrical gaits representing >90% of all strides. Movement on the narrow support was associated with an increase in more "grounded" gaits (i.e., lacking an aerial phase) and a more even distribution of torque production between the fore- and hind limbs. These adjustments in gait dynamics significantly reduced net Lsup on the narrow support relative to the broad support. Despite their lack of a well-developed grasping apparatus, marmosets proved adept at producing muscular "grasping" torques about the support, particularly with the hind limbs. We contend that asymmetrical gaits permit small bodied arboreal mammals, including primates, to expand "effective grasp" by gripping the substrate between left and right limbs of a girdle. This model of arboreal stability may hold important implications for understanding primate locomotor evolution. PMID- 25523445 TI - An inhibitory role of NEK6 in TGFbeta/Smad signaling pathway. AB - The NEK6 (NIMA-related kinases 6) is reported to play potential roles in tumorigenesis. Although it is suggested to function in several cellular pathways, the underlying mechanism in tumorigenesis is still largely unknown. In the present study, we discovered interaction of NEK6 with Smad4, a key member of transforming growth factor beta (TGFbeta) pathway. Over-expression of NEK6 in hepatocellular carcinoma (HCC) cell lines suppresses TGFbeta-mediated transcription activity in a kinase activity-dependent manner. In addition, NEK6 suppresses the cell growth arrest induced by TGFbeta. Mechanically, NEK6 blocks nuclear translocation of Smad4, which is essential for TGFbeta function. Moreover, we identified that NEK6 could be regulated by TGFbeta and hypoxia. Our study sheds new light on the roles of NEK6 in canonical TGFbeta/Smad pathway and tumorigenesis. PMID- 25523446 TI - A new steroidal saponin from dragon's blood of Dracaena cambodiana. AB - Phytochemical study on dragon's blood of Dracaena cambodiana led to a new steroidal saponin, cambodianoside G(1), and six known ones (2-7). The structure of the new compound was elucidated on the basis of detailed spectroscopic analysis. Evaluation of antibacterial activities showed that compound 7 exhibited antibacterial activity against Staphylococcus aureus. PMID- 25523447 TI - Activation of endothelium, coagulation and fibrinolysis is enhanced and associates with renal anti-neutrophil cytoplasmic antibody-associated vasculitis. AB - BACKGROUND: While the incidence of thromboembolism in anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) is high, the coagulation and fibrinolysis profile in AAV patients remains poorly characterized. We aimed at studying this profile in association with vasculitis activity and renal function. METHODS: This prospective study included 21 AAV patients with renal disease and 40 controls with other chronic kidney disease. Platelet count, antithrombin, FVIII : C, von Willebrand factor (VWF) activities (VWF : RCo) and antigen (VWF : Ag), fibrinogen, prothrombin fragments (F1 + 2), fibrin degradation product d-dimer and the presence of antiphospholipid antibodies were measured during the active and remission states of the AAV and at the baseline in controls. Occurrence of thromboembolic events was recorded. RESULTS: F1 + 2 was 2.6-fold and D-dimer was 5-fold higher during the active AAV than its remission (median 563 versus 212 pM and 3.0 versus 0.6 mg/L, P = 0.001 for both). FVIII : C (median 228%), VWF : RCo (198%) and VWF : Ag (222%) were the highest among the patients with active AAV and remained elevated also under remission. In active AAV, both F1 + 2 and d dimer clearly associated with impaired renal function (r = -0.67, P = 0.001 and r = -0.66, P = 0.001). In AAV patients, two thromboembolic events occurred during the follow-up. CONCLUSIONS: In active renal AAV, thrombin formation and especially fibrin turnover prevail compared both with remission and other kidney diseases. Overall, AAV is characterized by an enhanced coagulation, especially FVIII activity, which continues partly in remission. PMID- 25523448 TI - Evidence-based choice of dialysis technique in diabetics with end-stage kidney disease: half a loaf is better than no bread. PMID- 25523449 TI - Genetic aspects of anti-neutrophil cytoplasmic antibody-associated vasculitis. AB - The genetics of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a complex area of investigation because of the low frequency of AAVs, the rarity of familial cases and the complexity of disease phenotypes. However, recent studies have been able to gather significant numbers of patients, and multicentre collaborative efforts have allowed the performance of two genome-wide association studies (GWASs). Genetic association studies based on candidate gene approaches and the two GWASs have greatly contributed to our current understanding of the genetic basis of AAV. The central role of autoimmunity has been confirmed by the significant association with HLA polymorphisms; interestingly, the three main AAV subtypes are associated with distinct HLA variants, i.e. granulomatosis with polyangiitis (Wegener's GPA) with HLA-DP1, microscopic polyangiitis with HLA-DQ and eosinophilic GPA (Churg-Strauss) with HLA-DRB4. GWASs also revealed that polymorphic variants of genes encoding proteinase 3 (PR3), the predominant antigenic target of ANCA in GPA, and its main inhibitor, alpha-1 antitrypsin, are highly associated with GPA and, even more significantly, with PR3-ANCA positivity (regardless of the clinical diagnosis); this emphasizes the central pathogenic role of PR3 and humoral autoimmunity in PR3-ANCA positive vasculitis. Finally, candidate gene approach studies have shown associations with other variants involved in autoimmunity, such as those belonging to the CTLA-4 and PTPN22 genes, although these findings warrant replication in larger studies. Additional studies are underway to better characterize disease associations within the AAV spectrum, which could provide new pathogenetic clues and possibly new treatment targets. PMID- 25523450 TI - Impaired expression of key molecules of ammoniagenesis underlies renal acidosis in a rat model of chronic kidney disease. AB - BACKGROUND: Advanced chronic kidney disease (CKD) is associated with the development of renal metabolic acidosis. Metabolic acidosis per se may represent a trigger for progression of CKD. Renal acidosis of CKD is characterized by low urinary ammonium excretion with preserved urinary acidification indicating a defect in renal ammoniagenesis, ammonia excretion or both. The underlying molecular mechanisms, however, have not been addressed to date. METHODS: We examined the Han:SPRD rat model and used a combination of metabolic studies, mRNA and protein analysis of renal molecules involved in acid-base handling. RESULTS: We demonstrate that rats with reduced kidney function as evident from lower creatinine clearance, lower haematocrit, higher plasma blood urea nitrogen, creatinine, phosphate and potassium had metabolic acidosis that could be aggravated by HCl acid loading. Urinary ammonium excretion was highly reduced whereas urinary pH was more acidic in CKD compared with control animals. The abundance of key enzymes and transporters of proximal tubular ammoniagenesis (phosphate-dependent glutaminase, PEPCK and SNAT3) and bicarbonate transport (NBCe1) was reduced in CKD compared with control animals. In the collecting duct, normal expression of the B1 H(+)-ATPase subunit is in agreement with low urinary pH. In contrast, the RhCG ammonia transporter, critical for the final secretion of ammonia into urine was strongly down-regulated in CKD animals. CONCLUSION: In the Han:SPRD rat model for CKD, key molecules required for renal ammoniagenesis and ammonia excretion are highly down-regulated providing a possible molecular explanation for the development and maintenance of renal acidosis in CKD patients. PMID- 25523451 TI - Diagnostic validation and prognostic significance of the Malnutrition Inflammation Score in nondialyzed chronic kidney disease patients. AB - BACKGROUND: Malnutrition and inflammation are highly prevalent and intimately linked conditions in chronic kidney disease (CKD) patients that lead to a state of protein-energy wasting (PEW), the severity of which can be assessed by the Malnutrition-Inflammation Score (MIS). Here, we applied MIS and validated, for the first time, its ability to grade PEW and predict mortality in nondialyzed CKD patients. METHODS: We cross-sectionally evaluated 300 CKD stages 3-5 patients [median age 61 (53-68) years; estimated glomerular filtration rate 18 (12-27) mL/min/1.73 m(2); 63% men] referred for the first time to our center. Patients were followed during a median 30 (18-37) months for all-cause mortality. RESULTS: A worsening in MIS scale was associated with inflammatory biomarkers increase (i.e. alpha-1 acid glycoprotein, fibrinogen, ferritin and C-reactive protein) as well as a progressive deterioration in various MIS-independent indicators of nutritional status based on anthropometrics, dynamometry, urea kinetics and bioelectric impedance analysis. A structural equation model with two latent variables (assessing simultaneously malnutrition and inflammation factors) demonstrated good fit to the observed data. During a follow-up, 71 deaths were recorded; patients with higher MIS were at increased mortality risk in both crude and adjusted Cox models. CONCLUSIONS: MIS appears to be a useful tool to assess PEW in nondialyzed CKD patients. In addition, MIS identified patients at increased mortality risk. PMID- 25523452 TI - Perspectives on pregnancy in women with chronic kidney disease: systematic review of qualitative studies. AB - BACKGROUND: Achieving parenthood in women with chronic kidney disease (CKD) is challenging due to reduced fertility and the risk of adverse outcomes. We aimed to describe women's perspectives of pregnancy in CKD. METHODS: Electronic databases were searched to April 2014. Studies were synthesized thematically. RESULTS: From 15 studies (n = 257) we identified seven themes. 'Pursuing motherhood' was fulfilling an innate or social desire to have a child. 'Failure to fulfill social norms' of being unable to conceive diminished their self-worth. 'Fear of birth defects' was attributed to the potential side effects of immunosuppression. 'Decisional insecurity and conflict' encompassed uncertainties of prioritizing pregnancy as sacrifices had to be made in family life and work to minimize their risk of complications. Transplant recipients were concerned about the increased likelihood of graft loss. The possibility of genetic transmission of kidney disease influenced decisions about childbearing. 'Withholding emotional investment' was a way of protecting against the devastation of inability to conceive, miscarriage or stillbirth. 'Control and determination' reflected their capacity to choose to accept the risks of pregnancy. Some felt traumatized when their physician unduly warned against pregnancy. 'Exacerbating disease' due to pregnancy was also of concern to women. CONCLUSIONS: For women with CKD, pregnancy decisions can be emotionally complicated by health risks, family burden and the perceived risk of fetal malformation. Proactive counseling, shared decision-making about family planning and managing pregnancy in CKD that addresses patient preferences, and multidisciplinary care involving nephrologists, reproductive and obstetrics specialists, and psychological support may improve management of pregnancy issues in CKD. PMID- 25523454 TI - Generation of potent mouse monoclonal antibodies to self-proteins using T-cell epitope "tags". AB - Immunization of mice or rats with a "non-self" protein is a commonly used method to obtain monoclonal antibodies, and relies on the immune system's ability to recognize the immunogen as foreign. Immunization of an antigen with 100% identity to the endogenous protein, however, will not elicit a robust immune response. To develop antibodies to mouse proteins, we focused on the potential for breaking such immune tolerance by genetically fusing two independent T-cell epitope containing sequences (from tetanus toxin (TT) and diphtheria toxin fragment A (DTA)) to a mouse protein, mouse ST2 (mST2). Wild-type CD1 mice were immunized with three mST2 tagged proteins (Fc, TT and DTA) and the specific serum response was determined. Only in mice immunized with the T-cell epitope-containing antigens were specific mST2 serum responses detected; hybridomas generated from these mice secreted highly sequence-diverse IgGs that were capable of binding mST2 and inhibiting the interaction of mST2 with its ligand, mouse interleukin (IL)-33 (mIL-33). Of the hundreds of antibodies profiled, we identified five potent antibodies that were able to inhibit IL-33 induced IL-6 release in a mast cell assay; notably one such antibody was sufficiently potent to suppress IL-5 release and eosinophilia infiltration in an Alternaria alternata challenge mouse model of asthma. This study demonstrated, for the first time, that T-cell epitope containing tags have the ability to break tolerance in wild-type mice to 100% conserved proteins, and it provides a compelling argument for the broader use of this approach to generate antibodies against any mouse protein or conserved ortholog. PMID- 25523455 TI - Assessing liver function in patients with HBV-related HCC: a comparison of T1 mapping on Gd-EOB-DTPA-enhanced MR imaging with DWI. AB - OBJECTIVES: To compare the potential of T1 mapping on gadoxetic acid (Gd-EOB DTPA)-enhanced magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) for assessing liver function in patients with hepatitis B virus (HBV) related hepatocellular carcinoma (HCC). METHODS: One hundred consecutive patients with known HBV-related HCCs were included. T1 relaxation time and apparent diffusion coefficient (ADC) of the liver were measured, and the reduction rate of T1 relaxation time (?%) was calculated. T1 relaxation time measurements were compared with ADC values according to the Model for End-Stage Liver Disease (MELD) score. RESULTS: Hepatobiliary phase (HBP) and ?% of T1 relaxation time measurements showed significant correlations with MELD score (rho = 0.571, p < 0.0001; rho = -0.573, p < 0.0001, respectively). HBP and ?% of T1 relaxation time were significantly different between good (MELD <=8) and poor liver function (MELD >=9) (p < 0.0001 for both). Areas under the receiver operating characteristic curves (AUCs) of T1 relaxation time for HBP (AUC 0.84) and ?% (AUC 0.82) were significantly better than for ADC (AUC 0.53; p < 0.0001). CONCLUSIONS: T1 mapping on Gd-EOB-DTPA-enhanced MRI showed promise for evaluating liver function in patients with HBV-related HCC, while DWI was not reliable. HBP T1 relaxation time measurement was equally accurate as ?% measurement. KEY POINTS: * T 1 mapping on Gd-EOB-DTPA MRI was accurate for assessing liver function. * HBP T 1 relaxation time measurement was as accurate as ?% T 1 * T 1 mapping on Gd-EOB DTPA MRI was more accurate than DWI-ADC measurement. PMID- 25523456 TI - Erratum to: comparison of diagnostic performance between single- and multiphasic contrast-enhanced abdominopelvic computed tomography in patients admitted to the emergency department with abdominal pain: potential radiation dose reduction. PMID- 25523453 TI - Prevalence and cardiovascular risk profile of chronic kidney disease in Italy: results of the 2008-12 National Health Examination Survey. AB - BACKGROUND: National surveys in countries outside Europe have reported a high prevalence (11-13%) of chronic kidney disease (CKD). Studies in Europe have provided a variable prevalence likely due to differences in study design, including age and extent of geographic areas, equation used to evaluate estimated glomerular filtration rate (eGFR) and CKD stages examined. METHODS: The 2008-12 National Health Examination Survey in Italy randomly extracted samples from the general population aged 35-79 years, stratified by age and gender, from the resident list of each Italian region (440 persons/1.5 million of residents). We estimated the prevalence of CKD by means of urinary albumin : creatinine ratio and eGFR (CKD-EPI equation-enzymatic assay of serum creatinine). Cardiovascular (CV) risk profile was also evaluated. RESULTS: Three thousand eight hundred and forty-eight men and 3704 women were examined. In the whole population, mean age was 57 +/- 12 and 56 +/- 12 years in men and women, respectively; hypertension was prevalent in men and women, respectively (56 and 43%) and the same held true for overweight (48 and 33%), obesity (26 and 27%), diabetes (14 and 9%) and smoking (21 and 18%), whereas CV disease was less frequent (9 and 6%). Overall, the prevalence of CKD (95% confidence interval) was 7.05% (6.48-7.65). Early stages constituted 59% of the CKD population [Stage G1-2 A2-3: 4.16% (3.71-4.61) and Stage G3-5: 2.89% (2.51-3.26)]. At multivariate regression analysis, age, obesity, hypertension, diabetes, CV disease and smoking were all independent correlates of CKD. CONCLUSIONS: CKD has a relatively lower prevalence in Italy, in particular for advanced stages, when compared with similar national surveys outside Europe. This occurs despite older age and unfavourable CV risk profile of the whole population. PMID- 25523457 TI - Radiation dose reduction in fluoroscopic procedures: left varicocele embolization as a model. AB - OBJECTIVES: To investigate the effect of a radiation reduction program on total dose, fluoroscopy dose per second corrected for body habitus and degree of collimation in left varicocele embolizations (LVE). METHODS: A radiation reduction program for LVE was implemented, consisting of a technique minimizing fluoroscopy time, using low-dose presets, virtual collimation, and virtual patient positioning. Height, weight, fluoroscopy time, kerma area product (KAP) and reference air kerma (Ka,r) were recorded for 100 consecutive cases satisfying the inclusion criteria. For each patient, a device specific dose correction factor, determined using a phantom, was used to standardize the KAP to that of the cylindrical diameter of the standard man and a collimation index was derived from the KAP and Ka,r. RESULTS: Median fluoroscopy time was 3 minutes (mean 4.5, range 1-23.8). Median KAP was 0.54 Gy/cm(2) (mean 0.82, range 0.12-6.52). There was a significant decrease in KAP/second corrected for cylindrical diameter (p < 0.001) and the collimation index (p < 0.001) over time. CONCLUSIONS: This study shows that a dedicated dose reduction program can achieve very low total radiation dose rates for LVE. The significant decrease in collimation index and standardized KAP per second during this study suggest a learning curve for collimation. KEY POINTS: * Left varicocele embolization can be performed with very low radiation doses. * The most effective real time radiation reduction measure is collimation. * There is a learning curve to achieving optimal collimation. PMID- 25523458 TI - Seamless stitching of graphene domains on polished copper (111) foil. AB - Seamless stitching of graphene domains on polished copper (111) is proved clearly not only at atomic scale by scanning tunnelling microscopy (STM) and transmission electron micoscopy (TEM), but also at the macroscale by optical microscopy after UV-treatment. Using this concept of seamless stitching, synthesis of 6 cm * 3 cm monocrystalline graphene without grain boundaries on polished copper (111) foil is possible, which is only limited by the chamber size. PMID- 25523459 TI - Foot placement of the equine forelimb: Relationship between foot conformation, foot placement and movement asymmetry. AB - REASONS FOR PERFORMING STUDY: Hoof conformation, foot placement and movement asymmetry are routinely assessed as part of the lameness examination. However, to date, few studies have described these parameters, or the interplay between them, in the general horse population. OBJECTIVES: To assess foot conformation and foot placement in the forelimbs of a group of general purpose horses and investigate the relationships between foot placement, foot conformation and movement asymmetry. STUDY DESIGN: Observational cross-sectional study. METHODS: Forty three horses were included in the study. Measurements were taken from photographs of each forelimb to assess foot conformation. Video footage was recorded simultaneously from perpendicular cameras at both walk and trot and used to categorise foot placement. Inertial sensor data were used to assess head movement asymmetry in trot. RESULTS: There was a high degree of variation in foot placement between and within horses, but a 'lateral heel' placement was most common in walk and a 'lateral' placement most common in trot. Foot placement was associated with dorsal and palmar hoof angles but there was no relationship between foot placement and the other conformation parameters, nor with movement asymmetry. Moderate negative correlations were found between several of the conformation parameters and movement asymmetry. CONCLUSIONS: A relationship exists between foot conformation and movement asymmetry with decreasing hoof width and hoof length related to increasing amount of movement asymmetry. In the population of horses studied here--deemed to be 'well functioning' by their owners/riders--foot placement was found to be independent of movement asymmetry and, to a large extent, independent of foot conformation. PMID- 25523460 TI - Suppression of nuclear factor-kappa B and mitogen-activated protein kinase signalling pathways by goshonoside-F5 extracted from Rubi Fructus. AB - Rubi Fructus, a traditional Chinese medicine, was considered as an anti inflammatory agent in folk medicine. In the present study, we investigated the signalling pathways involved in the anti-inflammatory effects of goshonoside-F5 (GF5), isolated from Rubi Fructus, in peritoneal macrophages and examined its therapeutic effect in a mouse endotoxic shock model. GF5 decreased NO and PGE2 production in LPS-stimulated macrophages (IC50=3.84 and 3.16MUM). This effect involved the suppression of NOS-2 and COX-2 gene expression at the transcriptional level. Examination of the effects of GF5 on NF-kappaB signalling demonstrated that it inhibits the phosphorylation of IkappaB-alpha and IkappaB beta, blocking their degradation and the nuclear translocation of the NF-kappaB p65 subunit. Moreover, inhibition of MAPK signalling was also observed, and phosphorylation of p38 and JNK was suppressed in the presence of GF5. Inflammatory cytokines, including IL-6 and TNF-alpha, were down-regulated by this compound after activation with LPS (IC50=17.04 and 4.09MUM). Additionally, GF5 (30 and 90mg/kg, i.p.) significantly reduced the circulating cytokine levels (IL 6 and TNF-alpha) and increased survival in a mouse model of endotoxemia. These results show that GF5 significantly inhibits the pro-inflammatory response induced by LPS, both in vitro and in vivo. Our results provide a strong pharmacological basis for further understanding the potential therapeutic role of GF5 in inflammatory disease and shed new light on the bioactivity of ent-labdane diterpene glucoside. PMID- 25523461 TI - Asiatic acid ameliorates dextran sulfate sodium-induced murine experimental colitis via suppressing mitochondria-mediated NLRP3 inflammasome activation. AB - In the present study, the effect of asiatic acid, a natural triterpenoid compound, on murine experimental colitis induced by dextran sulfate sodium (DSS) and its possible mechanism were examined in vivo and vitro. Oral administration of asiatic acid dose-dependently attenuated the loss of body weight and shortening of colon length induced by DSS. The disease activity index, histopathologic scores of musco and myeloperoxidase activity were also significantly reduced by asiatic acid treatment. Protein and mRNA levels of DSS induced pro-inflammatory cytokines in colon, including TNF-alpha, IL-1beta, IL-6 and IFN-gamma, were markedly suppressed by asiatic acid. At the same time, decreased activation of caspase-1 in peritoneal macrophages was detected in asiatic acid-treated mice, which suggested that the NLRP3 inflammasome activation was suppressed. In addition, we also found that asiatic acid dose-dependently inhibited IL-1beta secretion, caspase-1 activation as well as inflammasome assembling in vitro. Furthermore, the mechanism of asiatic acid was related to the inhibition of mitochondrial reactive oxygen species generation and prevention of mitochondrial membrane potential collapse. Taken together, our results demonstrate the ability of asiatic acid to inhibit NLRP3 inflammasome activation and its potential usage in the treatment of inflammatory bowel diseases. PMID- 25523462 TI - Calorie restriction and methionine restriction in control of endogenous hydrogen sulfide production by the transsulfuration pathway. AB - H2S is a gas easily identified by its distinctive odor. Although environmental exposure to H2S has been viewed alternately as therapeutic or toxic through the centuries, H2S has recently regained recognition for its numerous beneficial biological effects. Most experiments documenting such benefits, including improved glucose tolerance, increased stress resistance, and even lifespan extension, are based on exposure of experimental organisms to exogenous sources of H2S. However, appreciation is growing for the importance of H2S produced endogenously by the evolutionary conserved transsulfuration pathway (TSP) in health and longevity. Recent data implicate H2S produced by the TSP in pleiotropic benefits of dietary restriction (DR), or reduced nutrient/energy intake without malnutrition. DR, best known as the most reliable way to extend lifespan in a wide range of experimental organisms, includes various regimens aimed at either reducing overall calorie intake (calorie restriction, intermittent/every-other-day fasting) or reducing particular nutrients such as protein or the essential amino acid, methionine (methionine restriction), with overlapping functional benefits on stress resistance, metabolic fitness and lifespan. Here we will review the small but growing body of literature linking the TSP to the functional benefits of DR in part through the production of endogenous H2S, with an emphasis on regulation of the TSP and H2S production by diet and mechanisms of beneficial H2S action. PMID- 25523463 TI - Surrogate light chain expression beyond the pre-B cell stage promotes tolerance in a dose-dependent fashion. AB - While surrogate light chain (SLC) expression is normally terminated in differentiating pre-B cells, co-expression of SLC and conventional light chains has been reported in a small population of autoreactive peripheral human B cells that accumulate in arthritic joints. Despite this association with autoimmunity the contribution of SLC expressing mature B cells to disease development is still unknown. We studied the pathogenicity of SLC(+) B cells in a panel of mice that transgenically express the SLC components VpreB and lambda5 throughout B cell development. Here we report that although VpreB or lambda5 expression mildly activated mature B cells, only moderate VpreB expression levels - in the absence of lambda5 - enhanced IgG plasma cell formation. However, no autoantibody production was detectable in VpreB or lambda5 transgenic mice and VpreB expression could not accelerate autoimmunity. Instead, moderate VpreB expression partially protected mice from induced autoimmune arthritis. In support of a tolerogenic role of SLC-transgenic B cells, we observed that in a dose-dependent manner SLC expression beyond the pre-B cell stage enhanced clonal deletion among immature and transitional B cells and rendered mature B cells anergic. These findings suggest that SLC expression does not propagate autoimmunity, but instead may impose tolerance. PMID- 25523464 TI - LC-APCI-MS/MS Quantification and Topical Bioavailability of Chloroacetamide in Rats. AB - Chloroacetamide (CAA) is a preservative used in various cosmetic, personal care and household products. Due to the hazard potential for allergic reaction and reproductive toxicity, CAA is being considered a high priority for screening assessment and toxicological re-evaluation. This study describes the development of a highly specific and sensitive atmospheric pressure chemical ionization tandem mass spectrometry method for the determination of CAA in rat plasma and its application to a topical bioavailability study. Chromatographic separations were achieved on a C8 column using a highly aqueous mobile phase with a binary gradient elution. The assay was linear in the concentration range of 5-2,500 ng/mL (r >= 0.995) using a small sample volume (100 uL). Applicability of the assay was demonstrated in a bioavailability study in rats after i.v. injection (0.5 or 2 mg/kg) and topical application (7.02 mg/kg). Average elimination half life and clearance ranged from 26.6 to 30.5 min and 53.9 to 57.3 mL/min/kg, respectively. Upon topical application, CAA was slowly but steadily absorbed for a prolonged time period (12 h). The topical bioavailability was 53.5 and 48.3% for emulsion and lotion, respectively. The developed assay may be useful to examine the relationship between exposure and toxic potential of CAA in risk assessment. PMID- 25523465 TI - Simultaneous Quantification of Gymnemic Acid as Gymnemagenin and Charantin as beta-Sitosterol Using Validated HPTLC Densitometric Method. AB - Gymnemic acid and charantin are well-established antidiabetic phytosterols found in Gymnema sylvestre and Momordica charantia, respectively. The fact that these plants are often used together in antidiabetic poly-herbal formulations lured us to develop an HPTLC densitometric method for the simultaneous quantification of their bioactive compounds. Indirect estimation of gymnemic acid as gymnemagenin and charantin as beta-sitosterol after hydrolysis has been proposed. Aluminum backed silica gel 60 F254 plates (20 * 10 cm) were used as stationary phase and toluene-ethyl acetate-methanol-formic acid (60 : 20 : 15 : 5, v/v) as mobile phase. Developed chromatogram was scanned at 550 nm after derivatization with modified vanillin-sulfuric acid reagent. Regression analysis of the calibration data showed an excellent linear relationship between peak area versus concentration of the analytes. Linearity was found to be in the range of 500 2,500 and 100-500 ng/band for gymnemagenin and beta-sitosterol, respectively. The suitability of the developed HPTLC method for simultaneous estimation of analytes was established by validating it as per the ICH guidelines. The limits of detection and quantification for gymnemagenin were found to be ~60 and ~190 ng/band, and those for beta-sitosterol ~30 and ~90 ng/band, respectively. The developed method was found to be linear (r(2) = 0.9987 and 0.9943), precise (relative standard deviation <1.5 and <2% for intra- and interday precision) and accurate (mean recovery ranged between 98.43-101.44 and 98.68-100.20%) for gymnemagenin and beta-sitosterol, respectively. The proposed method was also found specific and robust for quantification of both the analytes and was successfully applied to herbal drugs and in-house herbal formulation without any interference. PMID- 25523466 TI - Evaluating semantic similarity and relatedness over the semantic grouping of clinical term pairs. AB - INTRODUCTION: This article explores how measures of semantic similarity and relatedness are impacted by the semantic groups to which the concepts they are measuring belong. Our goal is to determine if there are distinctions between homogeneous comparisons (where both concepts belong to the same group) and heterogeneous ones (where the concepts are in different groups). Our hypothesis is that the similarity measures will be significantly affected since they rely on hierarchical is-a relations, whereas relatedness measures should be less impacted since they utilize a wider range of relations. In addition, we also evaluate the effect of combining different measures of similarity and relatedness. Our hypothesis is that these combined measures will more closely correlate with human judgment, since they better reflect the rich variety of information humans use when assessing similarity and relatedness. METHOD: We evaluate our method on four reference standards. Three of the reference standards were annotated by human judges for relatedness and one was annotated for similarity. RESULTS: We found significant differences in the correlation of semantic similarity and relatedness measures with human judgment, depending on which semantic groups were involved. We also found that combining a definition based relatedness measure with an information content similarity measure resulted in significant improvements in correlation over individual measures. AVAILABILITY: The semantic similarity and relatedness package is an open source program available from http://umls similarity.sourceforge.net/. The reference standards are available at http://www.people.vcu.edu/~{}btmcinnes/downloads.html. PMID- 25523467 TI - Three-year experience with access to nationally funded growth hormone (GH) replacement for GH-deficient adults. AB - OBJECTIVE: Treatment of growth hormone (GH)-deficient adults with GH has been shown to improve a range of metabolic abnormalities and enhance quality of life. However, the results of access to nationally funded treatment have not been reported. DESIGN: Retrospective case series auditing nationally funded treatment of defined GH-deficient adults in New Zealand, with carefully designed entry and exit criteria overseen by a panel of endocrinologists. PATIENTS: Applications for 201 patients were assessed and 191 approved for funded treatment over the initial 3 years since inception. The majority had GH deficiency following treatment of pituitary adenomas or tumours adjacent to the pituitary. RESULTS: After an initial 9-month treatment period using serum IGF-I measurements to adjust GH dosing, all patients reported a significant improvement in quality of life (QoL) score on the QoL-AGHDA((r)) instrument (baseline (95%CI) 19 (18-21), 9 months 6 (5-7.5)), and mean serum IGF-I SD scores rose from -3 to zero. Mean waist circumference decreased significantly by 2.8 +/- 0.6 cm. The mean maintenance GH dose after 9 months of treatment was 0.39 mg/day. After 3 years, 17% of patients had stopped treatment, and all of the remaining patients maintained the improvements seen at 9 months of treatment. CONCLUSION: Carefully designed access to nationally funded GH replacement in GH-deficient adults was associated with a significant improvement in quality of life over a 3-year period with mean daily GH doses lower than in the majority of previously reported studies. PMID- 25523468 TI - Quebec proposes to ban women over 42 from having IVF. PMID- 25523469 TI - The use of rituximab to prevent severe delayed haemolytic transfusion reaction in immunized patients with sickle cell disease. AB - BACKGROUND: Delayed haemolytic transfusion reaction (DHTR) is mainly caused by an immune response to transfused red blood cells (RBCs). Immunized patients have a high risk of producing antibodies in response to further transfusion. Controlling the immune response to RBCs is therefore a major goal in sickle cell disease (SCD). STUDY DESIGN: We report an observational study of eight alloimmunized SCD patients with history of severe DHTR who were treated with rituximab before a new transfusion to prevent further immunization and DHTR. RESULTS: Five patients showed a good clinical outcome following transfusion preceded by preemptive treatment with rituximab. The remaining patients presented mild DHTR. In all patients, the results of post-transfusion screening tests were identical to those of pretransfusion tests; no newly formed antibodies were detected. CONCLUSION: These cases suggest that rituximab prevents at least occurrence of newly formed antibodies in high responders and minimizes the risk of severe DHTR. This study confirms that DHTR is complex in SCD and does not rely only on the classical antigens/antibodies conflict. Considering potentially serious adverse effect of rituximab, this treatment should be considered cautiously, and only when transfusion is absolutely necessary in patients with history of severe DHTR linked to immunization. PMID- 25523470 TI - Hospital strategy uptake and reductions in unplanned readmission rates for patients with heart failure: a prospective study. AB - BACKGROUND: Despite recent reductions in national unplanned readmission rates, we have relatively little understanding of which hospital strategies are most associated with changes in risk-standardized readmission rates (RSRR). OBJECTIVE: We examined associations between the change in hospital 30-day RSRR for patients with heart failure and the uptake of strategies over 12-18 months in a national sample of hospitals. DESIGN: We conducted a prospective study of hospitals using a Web-based survey at baseline (November 2010-May 2011, n = 599, 91.0% response rate) and 12-18 months later (November 2011-October 2012, n = 501, 83.6% response rate), with RSRR measured at the same time points. The final analytic sample included 478 hospitals. PARTICIPANTS: The study included hospitals participating in the Hospital-to-Home (H2H) and State Action on Avoidable Rehospitalizations (STAAR) initiatives. MAIN MEASURES: We examined associations between change in hospital 30-day RSRR for patients with heart failure and the uptake of strategies previously demonstrated to have increased between baseline and follow-up, using unadjusted and adjusted linear regression. KEY RESULTS: The average number of strategies taken up from baseline to follow-up was 1.6 (SE = 0.06); approximately one-quarter (25.3%) of hospitals took up at least three new strategies. Hospitals that adopted the strategy of routinely discharging patients with a follow-up appointment already scheduled experienced significant reductions in RSRR (reduction of 0.63 percentage point, p value < 0.05). Hospitals that took up three or more strategies had significantly greater reductions in RSRR compared to hospitals that took up only zero to two strategies (reduction of 1.29 versus 0.57 percentage point, p value < 0.05). Among the 117 hospitals that took up three or more strategies, 93 unique combinations of strategies were used. CONCLUSIONS: Although most individual strategies were not associated with RSRR reduction, hospitals that took up any three or more strategies showed significantly greater reduction in RSRR compared to hospitals that took up fewer than three strategies. PMID- 25523471 TI - The need for higher standards in correctional healthcare to improve public health. PMID- 25523473 TI - Relationship between inpatient pressure ulcer prevalence and patient satisfaction levels based on US Medicare's Hospital Compare data. PMID- 25523472 TI - The Mycobacterium tuberculosis Uganda II family and resistance to first-line anti tuberculosis drugs in Uganda. AB - BACKGROUND: The global increase in the burden of multidrug-resistant tuberculosis (MDR-TB) underscores an urgent need for data on factors involved in generation and spread of TB drug resistance. We performed molecular analyses on a representative sample of Mycobacterium tuberculosis (MTB) isolates. Basing on findings of the molecular epidemiological study in Kampala, we hypothesized that the predominant MTB strain lineage in Uganda is negatively associated with anti TB drug resistance and we set out to test this hypothesis. METHODS: We extracted DNA from mycobacterial isolates collected from smear-positive TB patients in the national TB drug resistance survey and carried out IS6110-PCR. To identify MTB lineages/sub lineages RT-PCR SNP was performed using specific primers and hybridization probes and the 'melting curve' analysis was done to distinguish the Uganda II family from other MTB families. The primary outcome was the distribution of the Uganda II family and its associations with anti-TB drug resistance and HIV infection. RESULTS: Out of the 1537 patients enrolled, MTB isolates for 1001 patients were available for SNP analysis for identification of Uganda II family, of which 973 (97%) had conclusive RT-PCR results. Of these 422 (43.4%) were of the Uganda II family, mostly distributed in the south west zone (55.0%; OR = 4.6 for comparison with other zones; 95% CI 2.83-7.57; p < 0.001) but occurred in each of the other seven geographic zones at varying levels. Compared to the Uganda II family, other genotypes as a group were more likely to be resistant to any anti-TB drug (OR(adj) =2.9; 95% CI 1.63-5.06; p = 0.001) or MDR (OR(adj) 4.9; 95% CI, 1.15-20.60; p = 0.032), even after adjusting for geographic zone, patient category, sex, residence and HIV status. It was commonest in the 25-34 year age group 159/330 (48.2%). No association was observed between Uganda II family and HIV infection. CONCLUSION: The Uganda II family is a major cause of morbidity due to TB in all NTLP zones in Uganda. It is less likely to be resistant to anti-TB drugs than other MTB strain lineages. PMID- 25523474 TI - Clinical and Neuroimaging Profile of Children with Lesions in the Corpus Callosum. AB - PURPOSE: T2-hyperintense signal changes in corpus callosum (CC) have been described in epilepsy and encephalitis/encephalopathy. Little is known about their pathophysiology. The aim of this study was to examine the clinical presentation and evolution of CC lesions and relationship to seizures. METHODS: We identified 12 children among 29,634 patients from Radiology Database. We evaluated following characteristics: seizures and accompanying medical history, antiepileptic drug usage, presenting symptoms, and radiological evolution of lesions. RESULTS: CC lesions were seen in patients with prior diagnosis of epilepsy (n = 5) or in those with new onset seizures (n = 3), or with encephalitis/encephalopathy without history of seizures (n = 4). Seizure clustering or disturbances of consciousness were the main presenting symptoms. No relationship was observed between CC lesion and AEDs. On imaging, ovoid lesions at presentation resolved on follow up imaging and linear lesions persisted. DTI showed that the fibers passing through splenial lesions originated from the posterior parietal cortex and occipital cortex bilaterally. CONCLUSION: In patients with seizures, no clear relationship was demonstrated between seizure characteristics or AED use with CC lesions. Ovoid lesions resolved and may have different pathophysiologic mechanism when compared to linear lesions that persisted. PMID- 25523475 TI - A comprehensive approach to psychometric assessment of instruments used in dementia educational interventions for health professionals: a cross-sectional study. AB - BACKGROUND: Suboptimal care for people with dementia in hospital settings has been reported and is attributed to the lack of knowledge and inadequate attitudes in dementia care among health professionals. Educational interventions have been widely used to improve care outcomes; however, Chinese-language instruments used in dementia educational interventions for health professionals are lacking. OBJECTIVES: The aims of this study were to select, translate and evaluate instruments used in dementia educational interventions for Chinese health professionals in acute-care hospitals. DESIGN: A cross-sectional study design was used. PARTICIPANTS AND SETTING: A modified stratified random sampling was used to recruit 442 participants from different levels of hospitals in Changsha, China. METHODS: Dementia care competence was used as a framework for the selection and evaluation of Alzheimer's Disease Knowledge Scale and Dementia Care Attitudes Scale for health professionals in the study. These two scales were translated into Chinese using forward and back translation method. Content validity, test retest reliability and internal consistency were assessed. Construct validity was tested using exploratory factor analysis. Known-group validity was established by comparing scores of Alzheimer's Disease Knowledge Scale and Dementia Care Attitudes Scale in two sub-groups. A person-centred care scale was utilised as a gold standard to establish concurrent validity of these two scales. RESULTS: Results demonstrated acceptable content validity, internal consistency, test retest reliability and concurrent validity. Exploratory factor analysis presented a single-factor structure of the Chinese Alzheimer's Disease Knowledge Scale and a two-factor structure of the Chinese Dementia Care Attitudes Scale, supporting the conceptual dimensions of the original scales. The Chinese Alzheimer's Disease Knowledge Scale and Chinese Dementia Care Attitudes Scale demonstrated known group validity evidenced by significantly higher scores identified from the sub group with a longer work experience compared to those in the sub-group with less work experience. CONCLUSIONS: The use of dementia care competence as a framework to inform the selection and evaluation of instruments used in dementia educational interventions for health professionals has wide applicability in other areas. The results support that Chinese Alzheimer's Disease Knowledge Scale and Chinese Dementia Care Attitudes Scale are reliable and valid instruments for health professionals to use in acute-care settings. PMID- 25523476 TI - Evaluation of an infant with hypercalcemia. PMID- 25523477 TI - Changes in urinary angiotensinogen posttreatment in pediatric IgA nephropathy patients. AB - BACKGROUND: Recently, we demonstrated that urinary angiotensinogen (AGT) levels are increased and reflect intrarenal renin-angiotensin system (RAS) status in pediatric patients with chronic glomerulonephritis. Therefore, this study was performed to test the hypothesis that urinary AGT (UAGT) levels provide a specific index of intrarenal RAS status associated with RAS blockade treatment in pediatric IgA nephropathy (IgAN) patients. METHODS: We measured plasma and UAGT levels and urinary transforming growth factor beta (TGF-beta) levels, after which we performed immunohistochemical analysis of AGT, angiotensin II (Ang II), and TGF-beta in 24 pediatric IgAN patients treated with RAS blockades for 2 years. Paired tests were used to analyze the changes from baseline to study end. RESULTS: Although there was no change in plasma AGT levels, UAGT and TGF-beta levels were significantly decreased after RAS blockade, which was accompanied by the expression levels of AGT, Ang II, and TGF-beta, as well as the magnitude of glomerular injury. Baseline UAGT levels positively correlated with diastolic blood pressure, urinary protein levels, scores for mesangial hypercellularity, and the expression levels of AGT, Ang II, and TGF-beta in renal tissues. CONCLUSIONS: These data indicate that UAGT is a useful biomarker of intrarenal RAS activation, which is associated with glomerular injury during RAS blockade in pediatric IgAN patients. PMID- 25523478 TI - Intensified home haemodialysis for managing severe cardiac failure. AB - BACKGROUND: Conventional thrice weekly haemodialysis (HD) provides adequate dialysis to prevent mortality, but morbidity is prevalent in both the paediatric and adult population. There has been growing interest in the potential of intensive dialysis regimes entering the realm of optimal dialysis, with superior health and quality of life outcomes. CASE DIAGNOSIS/TREATMENT: We present the case of a 13-year-old girl who had bilateral nephrectomies as a result of bilateral Wilms tumors. In the third year of treatment with conventional HD, she presented with symptomatic progressive cardiac failure, presumably secondary to anthracycline-induced cardiomyopathy. Consequently, she was taken off the renal transplant list and became increasingly dependent on frequent in-centre dialysis sessions to manage her symptoms. Five months after switching to a frequent and extended home HD regime, we observed a tremendous improvement in her health and well-being, with complete reversal of her cardiac dysfunction. CONCLUSIONS: Home HD is a practically viable option in children with severe cardiac dysfunction. Gentler, more intensive dialysis will draw out and improve the ureamic component of heart disease. This may translate into improved cardiac function. PMID- 25523479 TI - Clinorotation impacts root apex respiration and the ultrostructure of mitochondria. AB - Mitochondrial respiration in plants provides energy for biosynthesis, and its balance with photosynthesis determines the rate of plant biomass accumulation. However, there are very limited data on the influence of altered gravity on the functional status of plant mitochondria. In the given paper, we presented the results of our investigations of root respiration, the mitochondrion ultrastructure, and AOX expression of pea 1-, 3- and 5-day old seedlings grown under slow horizontal clinorotation by using an inhibitor analysis, electron microscopy, and quantitative real-time RT-PCR. It was in the first time shown that enhancement of the respiration rate in root apices of pea etiolated seedlings at the 5th day of clinorotation does not connected with increasing of both alternative oxidize capacity and AOX expression. We assumed this phenomenon is provided by more intensive oxidation of respiratory substrates. At the structural level, mitochondria in cells of the distal elongation zone were the most sensitive to clinorotation that confirms the special physiological status of this zone. The performed investigation revealed an enough resistance of plant mitochondria to the influence of altered gravity that, on our opinion, is one of components providing plant adaptation to microgravity in space flight. PMID- 25523480 TI - Neuroprotective effect of 3-morpholinosydnonimine against Zn2+-induced PC12 cell death. AB - Excessive intracellular accumulation of zinc (Zn(2+)) is neurotoxic and contributes to a number of neuropathological conditions. Here, we investigated the protective effect of 3-morpholinosydnonimine (SIN-1) against Zn(2+)-induced neuronal cell death in differentiated PC12 cells. We found that Zn(2+)-induced PC12 cell death was reduced in a concentration-dependent manner by pretreatment with SIN-1. The intracellular accumulation of Zn(2+) was not affected by pretreatment with SIN-1, indicating that SIN-1-induced neuroprotection was not attributable to reduced influx of Zn(2+) into cells. SIN-1C, the stable decomposition product of SIN-1, failed to prevent Zn(2+)-induced cell death. Furthermore, the protective effect of SIN-1 against Zn(2+)-induced PC12 cell death was almost completely abolished by uric acid, a free radical scavenger, suggesting that reactive oxygen and nitrogen species generated by SIN-1 may contribute to the protective effect. SIN-1 prevented the inactivation of glutathione reductase (GR) and the increase in the ratio of oxidized glutathione/total glutathione (GSSG/total GSH) induced by Zn(2+). Addition of membrane permeable GSH ethyl ester (GSH-EE) to PC12 cells prior to Zn(2+) treatment significantly increased cell viability. We therefore conclude that SIN 1 may exert neuroprotective effect against Zn(2+)-induced cell death in differentiated PC12 cells by preventing inhibition of GR and increase in GSSG/total GSH ratio. PMID- 25523481 TI - Ang-(1-7) exerts protective role in blood-brain barrier damage by the balance of TIMP-1/MMP-9. AB - Cerebrovascular disease (CVD) ranks as the top three health risks, specially cerebral ischemia characterized with the damage of blood-brain barrier (BBB). The angiotensin Ang-(1-7) was proven to have a protective effect on cerebrovascular diseases. However, its role on blood-brain barrier and the underlying molecular mechanism remains unclear. In this study, Ang-(1-7) significantly relieved damage of ischemia reperfusion injury on blood-brain barrier in cerebral ischemia reperfusion injury (IRI) rats. Furthermore, its treatment attenuated BBB permeability and brain edema. Similarly, Ang-(1-7) also decreased the barrier permeability of brain endothelial cell line RBE4. Further analysis showed that Ang-(1-7) could effectively restore tight junction protein (claudin-5 and zonula occludens ZO-1) expression levels both in IRI-rats and hypoxia-induced RBE4 cells. Furthermore, Ang-(1-7) stimulation down-regulated hypoxia-induced matrix metalloproteinase-9 (MMP-9) levels, whose silencing with (matrix metalloproteinase-9 hemopexin domain) MMP9-PEX inhibitor significantly increased the expression of claudin-5 and ZO-1. Further mechanism analysis demonstrated that Ang-(1-7) might junction protein levels by tissue inhibitor of metalloproteinase 1 (TIMP1)-MMP9 pathway, because Ang-(1-7) enhanced TIMP1 expression, whose silencing obviously attenuated the inhibitor effect of Ang-(1 7) on MMP-9 levels and decreased Ang-(1-7)-triggered increase in claudin-5 and ZO 1. Together, this study demonstrated a protective role of Ang-(1-7) in IRI induced blood-brain barrier damage by TIMP1-MMP9-regulated tight junction protein expression. Accordingly, Ang-(1-7) may become a promising therapeutic agent against IRI and its complications. PMID- 25523482 TI - Effects of bleomycin, etoposide and cisplatin treatment on Leydig cell structure and transcription of steroidogenic enzymes in rat testis. AB - Cytotoxic anticancer chemotherapy affects pituitary-testicular hormonal axis in humans and in animals. This study investigated the effects on Leydig cells of three cycles of bleomycin, etoposide and cisplatin (0.75, 7.5, and 1.5mg/kg, respectively; BEP) chemotherapy in rat testis. The chemotherapy has induced hyperplasia of and degenerative changes in Leydig cells at the end of BEP exposure, which remained so even after a recovery time of 63 days. The increased testicular oxidative stress at the end of the chemotherapy returned to normal level after the recovery time. The chemotherapy has stimulated the transcription of scavenger receptor class type-B1 (SCARB1), steroidogenic acute-regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), CYP17A1, and inhibited that of 17beta-hydroxysteroid dehydrogenase (HSD17B6) and CYP19A1 in association with increased cholesterol and decreased testosterone levels. Even after the recovery time, the chemotherapy still had inhibitory effects on the transcription of all of the above genes in addition to luteinizing hormone receptor and HSD3B1, but not on the StAR gene. The cholesterol and testosterone levels also did not show any significant differences with the control group. The decreased testosterone level at the end of chemotherapy was probably due to inhibition of HSD3B1 and HSD17B6 genes. In conclusion, clinically relevant dose-levels and treatment protocols of BEP chemotherapy adversely affect Leydig cell function. The BEP chemotherapy inhibits the transcription of steroidogenic enzymes and that these effects sustain over an extended period of time without returning to normal levels. PMID- 25523485 TI - Novel membrane-based targets - Therapeutic potential in gynecological cancers. AB - Recent advances have been made in the molecular profiling of gynecological tumors. These discoveries have led to the development of targeted therapies that have the potential to disrupt molecular pathways involved in the oncogenesis or tumor progression. In this review, we highlight areas of recent progress in the field of membrane receptor inhibitors in gynecological malignancies and describe the biological rationale underlying the inhibition of these receptors. We will introduce drug immuno-conjugates, and give an update on the biological rationale and the clinical studies involving agents directed against EGFR, HER3, IGFR, MET, FGFR, NOTCH, and TRAIL. We also discuss the challenge facing these new therapies. PMID- 25523484 TI - Decelerated genome evolution in modern vertebrates revealed by analysis of multiple lancelet genomes. AB - Vertebrates diverged from other chordates ~500 Myr ago and experienced successful innovations and adaptations, but the genomic basis underlying vertebrate origins are not fully understood. Here we suggest, through comparison with multiple lancelet (amphioxus) genomes, that ancient vertebrates experienced high rates of protein evolution, genome rearrangement and domain shuffling and that these rates greatly slowed down after the divergence of jawed and jawless vertebrates. Compared with lancelets, modern vertebrates retain, at least relatively, less protein diversity, fewer nucleotide polymorphisms, domain combinations and conserved non-coding elements (CNE). Modern vertebrates also lost substantial transposable element (TE) diversity, whereas lancelets preserve high TE diversity that includes even the long-sought RAG transposon. Lancelets also exhibit rapid gene turnover, pervasive transcription, fastest exon shuffling in metazoans and substantial TE methylation not observed in other invertebrates. These new lancelet genome sequences provide new insights into the chordate ancestral state and the vertebrate evolution. PMID- 25523483 TI - Tissue-specific transcriptomics, chromosomal localization, and phylogeny of chemosensory and odorant binding proteins from the red flour beetle Tribolium castaneum reveal subgroup specificities for olfaction or more general functions. AB - BACKGROUND: Chemoreception is based on the senses of smell and taste that are crucial for animals to find new food sources, shelter, and mates. The initial step in olfaction involves the translocation of odorants from the periphery through the aqueous lymph of the olfactory sensilla to the odorant receptors most likely by chemosensory proteins (CSPs) or odorant binding proteins (OBPs). RESULTS: To better understand the roles of CSPs and OBPs in a coleopteran pest species, the red flour beetle Tribolium castaneum (Coleoptera, Tenebrionidae), we performed transcriptome analyses of male and female antennae, heads, mouthparts, legs, and bodies, which revealed that all 20 CSPs and 49 of the 50 previously annotated OBPs are transcribed. Only six of the 20 CSP are significantly transcriptionally enriched in the main chemosensory tissues (antenna and/or mouthparts), whereas of the OBPs all eight members of the antenna binding proteins II (ABPII) subgroup, 18 of the 20 classic OBP subgroup, the C + OBP, and only five of the 21 C-OBPs show increased chemosensory tissue expression. By MALDI-TOF-TOF MS protein fingerprinting, we confirmed three CSPs, four ABPIIs, three classic OBPs, and four C-OBPs in the antennae. CONCLUSIONS: Most of the classic OBPs and all ABPIIs are likely involved in chemoreception. A few are also present in other tissues such as odoriferous glands and testes and may be involved in release or transfer of chemical signals. The majority of the CSPs as well as the C-OBPs are not enriched in antennae or mouthparts, suggesting a more general role in the transport of hydrophobic molecules. PMID- 25523486 TI - Hepatotoxicity with vascular endothelial growth factor receptor tyrosine kinase inhibitors: A meta-analysis of randomized clinical trials. AB - A meta-analysis of randomized controlled trials (RCT) was conducted to determine the relative risk (RR) of hepatotoxicity with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI). Citations from PubMed/Medline, abstracts from major conferences, clinicaltrials.gov and package inserts were reviewed to include RCTs comparing arms with or without a VEGFR TKI. The RRs of all-grade ALT, AST, ALP and bilirubin elevation in 18,282 patients from 52 trials were 1.57 (95% CI 1.38-1.79, p<0.001), 1.57 (95% CI 1.36-1.81, p<0.001), 1.20 (95% CI 1.09-1.83, p<0.001) and 1.55 (95% CI 1.21-1.97, p<0.001) respectively, and high-grade elevations were 1.66 (95% CI 1.25-2.20, p=0.001), 1.61 (95% CI 1.21-2.14, p=0.001), 1.02 (95% CI 0.70-1.47, p=0.932) and 1.34 (95% CI 1.0-1.81, p=0.054) respectively compared to those in the non-TKI group. The incidence of hepatic failure with VEGFR TKIs was 0.8%. PMID- 25523487 TI - Is there evidence for different effects among EGFR-TKIs? Systematic review and meta-analysis of EGFR tyrosine kinase inhibitors (TKIs) versus chemotherapy as first-line treatment for patients harboring EGFR mutations. AB - Three EGFR tyrosine kinase inhibitors have been compared to standard chemotherapy as up-front treatment in patients with advanced EGFR-positive NSCLC. We performed a systematic review and meta-analysis using indirect comparisons to estimate the risk/benefit associated with each drug. EGFR-TKIs fared better than chemotherapy in terms of PFS. The relative probability of overall response was gefitinib versus erlotinib 0.96 (95% CI 0.69-1.34), gefitinib versus afatinib 0.91 (95% CI 0.67-1.23), erlotinib versus afatinib 0.94 (95% CI 0.65-1.35). Indirect comparisons for safety showed the RR for diarrhea gefitinib versus erlotinib 0.80 (95% CI 0.63-1.01), gefitinib versus afatinib 0.29 (95% CI 0.20-0.41), erlotinib versus afatinib 0.36 (95% CI 0.25-0.54); for rash gefitinib versus erlotinib 1.00 (95% CI 0.82-1.22), gefitinib versus afatinib 0.41(95% CI 0.25-0.65), erlotinib versus afatinib 0.41 (95% CI 0.25-0.66); for hypertransaminasemia gefitinib versus erlotinib 2.29 (95% CI 1.63-3.23). Our analysis showed that all treatments had similar efficacy but they differ for toxicities. PMID- 25523488 TI - Journal of Hepatology: the home of liver research. PMID- 25523489 TI - 50 years of EASL--from a European to a global perspective. PMID- 25523490 TI - From the editor's desk ... PMID- 25523491 TI - A new inducible transgenic mouse model for C9orf72-associated GGGGCC repeat expansion supports a gain-of-function mechanism in C9orf72-associated ALS and FTD. PMID- 25523492 TI - Comparison of the effects of cognitive behavioural therapy and inhalation sedation on child dental anxiety. AB - AIM: To compare the effectiveness of inhalation sedation with nitrous oxide/oxygen (N2O/O2) and cognitive behavioural therapy (CBT) in reducing dental anxiety in preschool children. STUDY DESIGN: Randomised controlled clinical trial. METHODS: This study was conducted on 45 preschoolers with moderate to severe dental anxiety (determined by the Children's Fear Survey Schedule Dental Subscale), who required pulp treatment of at least one primary mandibular molar. Baseline anxiety and cooperation levels were determined using Venham Clinical Anxiety and Cooperation Scales (VCAS and VCCS) and Venham Picture Test (VPT) at the first dental visit (dental prophylaxis and fluoride treatment). Before the second dental visit (pulp treatment), the children were randomly assigned to one of three groups--1: control, 2: N(2)O/O(2) and 3: CBT. In group 1, the usual behaviour management techniques were used, in group 2, nitrous oxide/oxygen gas was used and in group 3, unrelated play, Benson's breathing and positive self talk and modelling were used. Anxiety and cooperation levels were determined at three periods: injection, rubber dam placement and the application of a high speed handpiece with VCAS and VCCS and VPT. Finally, anxiety and cooperation differences between the two dental visits were compared within the three groups. STATISTICS: Chi square, ANOVA and Kruskal-Wallis and Mann-Whitney U tests were used. RESULTS: N(2)O/O(2) and CBT significantly resulted in lower anxiety and higher cooperation in the second visit (at all three periods) compared to the control, although there was no significant difference between these two treatment methods. CONCLUSION: Both test methods were effective in reducing dental anxiety in preschoolers. Considering the adverse effects and necessity of equipment and trained personnel when using nitrous oxide and oxygen inhalation sedation, cognitive behavioural therapy is preferable because of its better applicability. PMID- 25523493 TI - Non-steroidal antiandrogen monotherapy compared with luteinizing hormone releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer: a Cochrane systematic review. AB - To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for treating advanced hormone-sensitive stages of prostate cancer. We searched the Cochrane Prostatic Diseases and Urologic Cancers Group Specialized Register (PROSTATE), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science with Conference Proceedings, three trial registries and abstracts from three major conferences to 23 December 2013, together with reference lists, and contacted selected experts in the field and manufacturers. We included randomized controlled trials comparing non-steroidal antiandrogen monotherapy with medical or surgical castration monotherapy for men in advanced hormone-sensitive stages of prostate cancer. Two review authors independently examined full-text reports, identified relevant studies, assessed the eligibility of studies for inclusion, extracted data and assessed risk of bias as well as quality of evidence according to the GRADE working group guidelines. We used Review Manager 5.2 for data synthesis and the fixed-effect model as primary analysis (when heterogeneity was low with I(2) < 50%); we used a random-effects model when confronted with substantial or considerable heterogeneity (when I(2) >=50%). A total of 11 studies involving 3060 randomly assigned participants were included in the present review. Use of non-steroidal antiandrogens resulted in lower overall survival times (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.05-1.48, six studies, 2712 participants) and greater clinical progression (1 year: risk ratio [RR] 1.25, 95% CI 1.08-1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08-1.45, six studies, 2373 participants; 2 years: RR 1.14, 95% CI 1.04-1.25, three studies, 1336 participants), as well as treatment failure (1 year: RR 1.19, 95% CI 1.02 1.38, four studies, 1539 participants; 70 weeks: RR 1.27, 95% CI 1.05-1.52, five studies, 1845 participants; 2 years: RR 1.14, 95% CI 1.05-1.24, two studies, 808 participants), compared with medical or surgical castration. The quality of evidence for overall survival, clinical progression and treatment failure was rated as moderate according to GRADE. Use of non-steroidal antiandrogens increased the risk for treatment discontinuation as a result of adverse events (RR 1.82, 95% CI 1.13-2.94, eight studies, 1559 participants), including events such as breast pain (RR 22.97, 95% CI 14.79- 35.67, eight studies, 2670 participants) and gynaecomastia (RR 8.43, 95% CI 3.19-22.28, nine studies, 2774 participants) The risk of other adverse events, such as hot flushes (RR 0.23, 95% CI 0.19-0.27, nine studies, 2774 participants) was decreased when non-steroidal antiandrogens were used. The quality of evidence for breast pain, gynaecomastia and hot flushes was rated as moderate according to GRADE. The effects of non steroidal antiandrogens on cancer-specific survival and biochemical progression remained unclear. Non-steroidal antiandrogen monotherapy compared with medical or surgical castration monotherapy for advanced prostate cancer is less effective in terms of overall survival, clinical progression, treatment failure and treatment discontinuation resulting from adverse events. Evidence quality was rated as moderate according to GRADE; therefore, further research is likely to have an important impact on results for patients with advanced but non-metastatic prostate cancer treated with non-steroidal antiandrogen monotherapy. PMID- 25523494 TI - Assessing Diabetes Care Disparities with Ambulatory Care Quality Measures. AB - OBJECTIVE: To identify and describe racial/ethnic disparities in overall diabetes management. DATA SOURCE/STUDY SETTING: Electronic health record data from calendar year 2010 were obtained from all primary care clinics at one large health system in Minnesota (n = 22,633). STUDY DESIGN: We used multivariate logistic regression to estimate the odds of achieving the following diabetes management goals: A1C <8 percent, LDL cholesterol <100 mg/dl, blood pressure <140/90 mmHg, tobacco-free, and daily aspirin. PRINCIPAL FINDINGS: Blacks and American Indians have higher odds of not achieving all goals compared to whites. Disparities in specific goals were also found. CONCLUSIONS: Although this health system has above-average diabetes care quality, significant disparities by race/ethnicity were identified. This underscores the importance of stratifying quality measures to improve care and outcomes for all. PMID- 25523495 TI - C-terminal unfolding of an amyloidogenic beta2-microglobulin fragment: DeltaN6beta2-microglobulin. AB - OBJECTIVES: A beta2-microglobulin (beta2m) fragment that lacks the first six amino acids, i.e., DeltaN6beta2-microglobulin (DeltaN6beta2m), is an endogenous, proteolytically derived, amyloidogenic fragment of beta2m, the precursor protein in Abeta2M amyloidosis (dialysis-related amyloidosis). As reports suggest the importance of C-terminal unfolding for the amyloidogenicity of beta2m, in this study we aimed to investigate conformational characteristics of DeltaN6beta2m related to amyloidogenicity. We also measured the concentration of an amyloidogenic intermediate of beta2m with C-terminal unfolding (beta2m92-99) in serum samples from 10 patients undergoing hemodialysis (HD). METHODS: We utilized capillary electrophoretic analysis, surface plasmon resonance and enzyme-linked immunosorbent assay. RESULTS AND CONCLUSIONS: We confirmed the normal core structure of DeltaN6beta2m with a commercial monoclonal anti-beta2m antibody. In addition, using the specific monoclonal antibody for the C-terminal peptide, i.e. mAb 92-99, we confirmed unfolding in the C-terminal region of DeltaN6beta2m. On the basis of these findings, we established an ELISA to measure beta2m92-99 using DeltaN6beta2m as a standard molecule in circulation. However, we did not detect beta2m92-99 in serum from 10 HD patients, despite the absence of uremic inhibitors in the serum. PMID- 25523496 TI - Screening colonoscopy in Australia. AB - Colorectal cancer (CRC) is a global epidemic predominantly affecting Western countries. It is the second leading cause of cancer-related deaths in Australia with one in 12 Australians affected by this condition by the age of 85 years. Appropriate preventive measures by screening followed by colonoscopy can detect cancer and precancerous lesions, which are potentially curable. The National Bowel Cancer Screening Program (NBCSP) is a national screening program implemented by the Australian Government aimed at reducing morbidity and mortality from bowel cancer by actively recruiting and screening the target population. The long-term goal of the program is to include the at-risk population (50-74 years of age) in a biennial screening program. Newer technologies could have a potential role in screening programs by enhancing adenoma detection rates. However, until more evidence is available, improving screening uptake and bowel preparation strategies are the prime focus in reducing CRC-related morbidity and mortality. PMID- 25523497 TI - A survey of stakeholder perspectives on exoskeleton technology. AB - BACKGROUND: Exoskeleton technology has potential benefits for wheelchair users' health and mobility. However, there are practical barriers to their everyday use as a mobility device. To further understand potential exoskeleton use, and facilitate the development of new technologies, a study was undertaken to explore perspectives of wheelchair users and healthcare professionals on reasons for use of exoskeleton technology, and the importance of a variety of device characteristics. METHODS: An online survey with quantitative and qualitative components was conducted with wheelchair users and healthcare professionals working directly with individuals with mobility impairments. Respondents rated whether they would use or recommend an exoskeleton for four potential reasons. Seventeen design features were rated and compared in terms of their importance. An exploratory factor analysis was conducted to categorize the 17 design features into meaningful groupings. Content analysis was used to identify themes for the open ended questions regarding reasons for use of an exoskeleton. RESULTS: 481 survey responses were analyzed, 354 from wheelchair users and 127 from healthcare professionals. The most highly rated reason for potential use or recommendation of an exoskeleton was health benefits. Of the design features, 4 had a median rating of very important: minimization of falls risk, comfort, putting on/taking off the device, and purchase cost. Factor analysis identified two main categories of design features: Functional Activities and Technology Characteristics. Qualitative findings indicated that health and physical benefits, use for activity and access reasons, and psychosocial benefits were important considerations in whether to use or recommend an exoskeleton. CONCLUSIONS: This study emphasizes the importance of developing future exoskeletons that are comfortable, affordable, minimize fall risk, and enable functional activities. Findings from this study can be utilized to inform the priorities for future development of this technology. PMID- 25523498 TI - Possible adverse effects of SGLT2 inhibitors on bone. PMID- 25523500 TI - Fighting pertussis re-emergence: promise from vaccination in pregnancy. PMID- 25523501 TI - Identification and mapping of Sr46 from Aegilops tauschii accession CIae 25 conferring resistance to race TTKSK (Ug99) of wheat stem rust pathogen. AB - KEY MESSAGE: Mapping studies confirm that resistance to Ug99 race of stem rust pathogen in Aegilops tauschii accession Clae 25 is conditioned by Sr46 and markers linked to the gene were developed for marker-assisted selection. The race TTKSK (Ug99) of Puccinia graminis f. sp. tritici, the causal pathogen for wheat stem rust, is considered as a major threat to global wheat production. To address this threat, researchers across the world have been devoted to identifying TTKSK resistant genes. Here, we report the identification and mapping of a stem rust resistance gene in Aegilops tauschii accession CIae 25 that confers resistance to TTKSK and the development of molecular markers for the gene. An F2 population of 710 plants from an Ae. tauschii cross CIae 25 * AL8/78 were first evaluated against race TPMKC. A set of 14 resistant and 116 susceptible F2:3 families from the F2 plants were then evaluated for their reactions to TTKSK. Based on the tests, 179 homozygous susceptible F2 plants were selected as the mapping population to identify the simple sequence repeat (SSR) and sequence tagged site (STS) markers linked to the gene by bulk segregant analysis. A dominant stem rust resistance gene was identified and mapped with 16 SSR and five new STS markers to the deletion bin 2DS5-0.47-1.00 of chromosome arm 2DS in which Sr46 was located. Molecular marker and stem rust tests on CIae 25 and two Ae. tauschii accessions carrying Sr46 confirmed that the gene in CIae 25 is Sr46. This study also demonstrated that Sr46 is temperature-sensitive being less effective at low temperatures. The marker validation indicated that two closely linked markers Xgwm210 and Xwmc111 can be used for marker-assisted selection of Sr46 in wheat breeding programs. PMID- 25523502 TI - Unique features of apicoplast DNA gyrases from Toxoplasma gondii and Plasmodium falciparum. AB - BACKGROUND: DNA gyrase, an enzyme once thought to be unique to bacteria, is also found in some eukaryotic plastids including the apicoplast of Apicomplexa such as Plasmodium falciparum and Toxoplasma gondii which are important disease-causing organisms. DNA gyrase is an excellent target for antibacterial drugs, yet such antibacterials seem ineffective against Apicomplexa. Characterisation of the apicoplast gyrases would be a useful step towards understanding why this should be so. While purification of active apicoplast gyrase has proved impossible to date, in silico analyses have allowed us to discover differences in the apicoplast proteins. The resulting predicted structural and functional differences will be a first step towards development of apicoplast-gyrase specific inhibitors. RESULTS: We have carried out sequence analysis and structural predictions of the enzymes from the two species and find that P. falciparum gyrase lacks a GyrA box, but T. gondii may retain one. All proteins contained signal/transport peptides for localization to the apicoplast but T. gondii Gyrase B protein lacks the expected hydrophobic region. The most significant difference is in the GyrA C-terminal domain: While the cores of the proteins, including DNA binding and cleavage regions are essentially unchanged, both apicoplast gyrase A proteins have C-terminal domains that are significantly larger than bacterial counterparts and are predicted to have different structures. CONCLUSION: The apicoplast gyrases differ significantly from bacterial gyrases while retaining similar core domains. T. gondii Gyrase B may have an unusual or inefficient mechanism of localisation to the apicoplast. P.falciparum gyrase, lacks a GyrA box and is therefore likely to be inefficient in DNA supercoiling. The C-terminal domains of both apicoplast Gyrase A proteins diverge significantly from the bacterial proteins. We predict that an additional structural element is present in the C-terminal domain of both apicoplast Gyrase A proteins, including the possibility of a beta-pinwheel with a non-canonical number of blades. These differences undoubtedly will affect the DNA supercoiling mechanism and have perhaps evolved to compensate for the lack of Topoisomerase IV in the apicoplast. These data will be useful first step towards further characterisation and development of inhibitors for apicoplast gyrases. PMID- 25523503 TI - Catalytic, asymmetric, and stereodivergent synthesis of non-symmetric beta,beta diaryl-alpha-amino acids. AB - We report a concise, enantio- and diastereoselective route to novel nonsymmetrically substituted N-protected beta,beta-diaryl-alpha-amino acids and esters, through the asymmetric hydrogenation of tetrasubstituted olefins, some of the most challenging examples in the field. Stereoselective generation of an E- or Z-enol tosylate, when combined with stereoretentive Suzuki-Miyaura cross coupling and enantioselective hydrogenation catalyzed by (NBD)2RhBF4 and a Josiphos ligand, allows for full control over the two vicinal stereogenic centers. High yields and excellent enantioselectivities (up to 99% ee) were obtained for a variety of N-acetyl, N-methoxycarbonyl, and N-Boc beta,beta diaryldehydroamino acids, containing a diverse and previously unreported series of heterocyclic and aryl substituted groups (24 examples) and allowing access to all four stereoisomers of these valuable building blocks. PMID- 25523504 TI - The feline oral microbiome: a provisional 16S rRNA gene based taxonomy with full length reference sequences. AB - The human oral microbiome is known to play a significant role in human health and disease. While less well studied, the feline oral microbiome is thought to play a similarly important role. To determine roles oral bacteria play in health and disease, one first has to be able to accurately identify bacterial species present. 16S rRNA gene sequence information is widely used for molecular identification of bacteria and is also useful for establishing the taxonomy of novel species. The objective of this research was to obtain full 16S rRNA gene reference sequences for feline oral bacteria, place the sequences in species level phylotypes, and create a curated 16S rRNA based taxonomy for common feline oral bacteria. Clone libraries were produced using "universal" and phylum selective PCR primers and DNA from pooled subgingival plaque from healthy and periodontally diseased cats. Bacteria in subgingival samples were also cultivated to obtain isolates. Full-length 16S rDNA sequences were determined for clones and isolates that represent 171 feline oral taxa. A provisional curated taxonomy was developed based on the position of each taxon in 16S rRNA phylogenetic trees. The feline oral microbiome curated taxonomy and 16S rRNA gene reference set will allow investigators to refer to precisely defined bacterial taxa. A provisional name such as "Propionibacterium sp. feline oral taxon FOT-327" is an anchor to which clone, strain or GenBank names or accession numbers can point. Future next generation-sequencing studies of feline oral bacteria will be able to map reads to taxonomically curated full-length 16S rRNA gene sequences. PMID- 25523505 TI - Positron emission tomography in Warthin's tumor mimicking malignancy impacts the evaluation of head and neck patients. AB - PURPOSE: 1) To determine SUVs and PET/CT characteristics of Warthin's tumors in patients presenting to a head and neck cancer clinic. 2) To analyze the impact of PET/CT on the clinical course of these patients. MATERIALS AND METHODS: This is a single-institution retrospective analysis of patients with proven Warthin's tumors who underwent PET/CT done at or near the time of diagnosis and presented to a head and neck cancer practice. Data were obtained from the electronic medical records of these patients and the imaging and pathology databases. RESULTS: Six patients with Warthin's tumor met the criteria for and form the study cohort. Three patients had bilateral tumors. The SUVs for Warthin's varied from 3.4 to 16.1 in these patients, with an average of 7.8 and these SUVs were higher for Warthin's than for the cancers. These findings on PET/CT in this group required additional workup of all patients and required FNA, surgery or SPECT-CT to confirm the diagnosis. CONCLUSION: Although it is known that Warthin's tumor may be hypermetabolic on PET, this finding in the parotid or neck on PET/CT alters the evaluation and treatment of head and neck cancer patients and patients with cancers outside the head and neck by raising the concern about metastatic disease or multiple primary cancers. In other patients, PET/CT obtained for other reasons may prompt concern about incidental malignancy. This series specifically characterizes clinical features, SPECT-CT and FNA findings that can help reinforce the diagnosis of Warthin's and facilitate management. PMID- 25523506 TI - A prospective cohort study investigating gross motor function, pain, and health related quality of life 17 years after selective dorsal rhizotomy in cerebral palsy. AB - AIM: The aim of this study is to evaluate the long-term effects of selective dorsal rhizotomy (SDR), 15 to 20 years after surgery in patients with cerebral palsy. METHOD: Eighteen children (four females, 14 males; mean age at SDR 4y 7mo, SD 1y 7mo) with bilateral spastic cerebral palsy (CP), were prospectively assessed after SDR. This study focuses on the outcome 15 to 20 years after the procedure. The assessments include the Modified Ashworth Scale for spasticity, the Gross Motor Function Measure (GMFM-88), the Wilson Mobility Scale, The Health Related Quality of Life Health Survey, SF-36v2, and the Brief Pain Inventory. RESULTS: The effect of normalized muscle tone in lower extremities after SDR was sustained after a median of 17 years. The best gross motor function capacity, according to the GMFM score, was seen at the 3-year follow-up, thereafter a gradual decline followed. Half of the individuals reported low intensity pain and interference. Compared to a norm sample the physical health component of SF-36v2 was slightly lower and the mental health component slightly higher. INTERPRETATION: The spasticity-reducing effect of SDR does not improve long-term functioning, nor prevent contractures, but it can possibly reduce the pain often experienced by individuals with CP. PMID- 25523507 TI - High IDH1 expression is associated with a poor prognosis in cytogenetically normal acute myeloid leukemia. AB - The prognostic value of IDH1 mutations has been systematically evaluated in acute myeloid leukemia (AML) patients recently. However, the role of IDH1 expression in AML is still under exploration. To investigate the clinical significance, we analyzed the IDH1/2 expression in 320 patients with cytogenetically normal AML (CN-AML) by quantitative real-time reverse-transcription polymerase chain reaction. High expression of IDH1 was predominant in patients with FLT3-ITD and DNMT3A mutations and less prevalent in cases with CEBPA double allele mutations. Strong association was observed between high IDH1 expression and low expression of microRNA 181 family. Prognosis was adversely affected by high IDH1 expression, with shorter overall survival and event-free survival in the context of clinical characteristics, including age, WBC count, and gene mutations of NPM1, FLT3-ITD, CEBPA, IDH1, IDH2 and DNMT3A in CN-AML. Moreover, the clinical outcome of IDH1 expression in terms of overall survival, event-free survival and complete remission rate still remained in multivariate models in CN-AML. Importantly, the prognostic value was validated using the published microarray data from 79 adult patients treated according to the German AMLCG-1999 protocol. Our results demonstrated that high IDH1 expression is associated with a poor prognosis of CN AML. PMID- 25523508 TI - A near field optical image of a gold surface: a luminescence study. AB - This paper addresses recent experimental findings about luminescence of a gold tip in near-field interaction with a gold surface. Our electrochemically etched gold tips show a typical, intrinsic luminescence that we exploit to track the plasmon resonance modeled by a Lorentzian oscillator. Our experimental device is based on a spectrometer optically coupled to an atomic force microscope used in tuning fork mode. Our measurements provide evidence of a strong optical coupling between the tip and the surface. We demonstrate that this coupling strongly affects the luminescence (intensity, wavelength and FHWM) as a function of the tip position in 2D maps. The fluctuation of these parameters is directly related to the plasmonic properties of the gold surface and is used to qualify the optical near field enhancement (which subsequently plays the predominant role in surface enhanced spectroscopies) with a very high spatial resolution (typically around 20 nm). We compare these findings to the independently recorded near-field scattered elastic Rayleigh signal. PMID- 25523509 TI - An overview of regular dialysis treatment in Japan (as of 31 December 2012). AB - A nationwide statistical survey of 4279 dialysis facilities was conducted at the end of 2012, among which 4238 responded (99.0%). The number of new dialysis patients was 38055 in 2012. Since 2008, the number of new dialysis patients has remained almost the same without any marked increase or decrease. The number of dialysis patients who died in 2012 was 30710; a slight decrease from 2011 (30743). The dialysis patient population has been growing every year in Japan; it was 310007 at the end of 2012, which exceeded 310000 for the first time. The number of dialysis patients per million at the end of 2012 was 2431.2. The crude death rate of dialysis patients in 2012 was 10.0%, a slight decrease from that in 2011 (10.2%). The mean age of new dialysis patients was 68.5 years and the mean age of the entire dialysis patient population was 66.9 years. The most common primary cause of renal failure among new dialysis patients was diabetic nephropathy (44.2%). The actual number of new dialysis patients with diabetic nephropathy has been approximately 16000 for the last few years. Diabetic nephropathy was also the most common primary disease among the entire dialysis patient population (37.1%), followed by chronic glomerulonephritis (33.6%). The percentage of dialysis patients with diabetic nephropathy has been continuously increasing, whereas not only the percentage but also the actual number of dialysis patients with chronic glomerulonephritis has decreased. The number of patients who underwent hemodiafiltration (HDF) at the end of 2012 was 21725, a marked increase from that in 2011 (14115). In particular, the number of patients who underwent on-line HDF increased threefold from 4890 in 2011 to 14069 in 2012. From the results of the facility survey, the number of patients who underwent peritoneal dialysis (PD) was 9514 and that of patients who did not undergo PD despite having a PD catheter in the abdominal cavity was 347. From the results of the patient survey, among the PD patients, 1932 also underwent another dialysis method using extracorporeal circulation, such as hemodialysis (HD) and HDF. The number of patients who underwent HD at home in 2012 was 393, a marked increase from that in 2011 (327). PMID- 25523511 TI - High pressure Raman scattering and synchrotron X-ray diffraction studies of benzyl azide. AB - Benzyl azide was investigated by high-pressure Raman scattering spectroscopy and X-ray diffraction technologies. A complete vibrational analysis of benzyl azide was performed by combining the experimental measurements and theoretical calculations using DFT-based scaled quantum chemical approach. The high-pressure Raman spectra and calculation results indicate that benzyl azide underwent a conformational change at 0.67 GPa accompanied by rotation of methylene group and azide group. The frequency of the CH2 bending mode decreases with increasing pressure due to the increase of the C-H...pi interactions, which is similar to the role of the hydrogen bond. A liquid to solid phase transition occurred at 2.7 GPa, which was confirmed by the X-ray diffraction measurements. As the pressure reached 25.6 GPa, all the azide group vibrations vanished, indicating that the decomposition pressure of the molecular azide groups in organic azides is lower than that of the azide ions in inorganic azides. PMID- 25523512 TI - Asymptomatic diabetes: screening by routine imaging beneficial? PMID- 25523513 TI - Biomarkers for cardiovascular risk assessment in autoimmune diseases. AB - Autoimmune diseases, such as antiphospholipid syndrome, systemic lupus erythematosus, and rheumatoid arthritis, are characterized by a high prevalence of cardiovascular (CV) disease (CVD), which constitutes the leading causes of morbidity and mortality among such patients. Although such effects are partly explained by a higher prevalence of traditional CV risk factors, many studies indicate that such factors do not fully explain the enhanced CV risk in these patients. In addition, risk stratification algorithms based upon traditional CV risk factors are not as predictive in autoimmune diseases as in the general population. For these reasons, the timely and accurate assessment of CV risk in these high-risk populations still remains an unmet clinical need. An enhanced contribution of different inflammatory components of the immune response, as well as autoimmune elements (e.g. autoantibodies, autoantigens, and cellular response), has been proposed to underlie the incremental CV risk observed in these populations. Recent advances in proteomic tools have contributed to the discovery of proteins involved in CVDs, including some that may be suitable to be used as biological markers. In this review we summarize the main markers in the field of CVDs associated with autoimmunity, as well as the recent advances in proteomic technology and their application for biomarker discovery in autoimmune disease. PMID- 25523514 TI - Histopathological assessment of inflammation and expression of inflammatory markers in patients with ketamine-induced cystitis. AB - The aim of the current study was to evaluate the histopathological features of inflammation and the expression levels of inflammatory markers in tissue samples from patients with ketamine-induced cystitis. Bladder biopsy samples for histological analysis were obtained from 23 patients (18 men and 5 women) with a self-reported history of ketamine use and who were treated for cystitis at the Tri-Service General Hospital of Taipei, Taiwan. Immunohistochemical staining for cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), matrix metallopeptidase-9 (MMP-9), mammalian target of rapamycin (mTOR), and phosphorylated 40S ribosomal protein S6 (Phos-S6) was performed. The results revealed urothelial atypia in all patients, and intravascular eosinophil accumulation in 22 patients. Histopathological features included denuded urothelial mucosa, ulceration, collagen deposition, smooth muscle degeneration and vessel proliferation. Tissue samples were immunopositive for all of the inflammation markers, including the urothelium, vessel walls, and smooth muscle. COX-2 staining revealed a significant difference between the inflammatory levels in the urothelium and smooth muscle, and iNOS staining differed significantly between inflammatory levels in smooth muscle (p=0.029). A positive correlation was observed between the percentage of Phos-S6-positive cells and the levels of inflammation in the urothelium. These results add to the descriptive literature on the histopathological aspects of ketamine-induced cystitis, emphasizing the inflammatory nature and a possible role for proteins such as COX-2, iNOS and Phos S6 in the degree of inflammation. PMID- 25523515 TI - Seasonal weather patterns drive population vital rates and persistence in a stream fish. AB - Climate change affects seasonal weather patterns, but little is known about the relative importance of seasonal weather patterns on animal population vital rates. Even when such information exists, data are typically only available from intensive fieldwork (e.g., mark-recapture studies) at a limited spatial extent. Here, we investigated effects of seasonal air temperature and precipitation (fall, winter, and spring) on survival and recruitment of brook trout (Salvelinus fontinalis) at a broad spatial scale using a novel stage-structured population model. The data were a 15-year record of brook trout abundance from 72 sites distributed across a 170-km-long mountain range in Shenandoah National Park, Virginia, USA. Population vital rates responded differently to weather and site specific conditions. Specifically, young-of-year survival was most strongly affected by spring temperature, adult survival by elevation and per-capita recruitment by winter precipitation. Low fall precipitation and high winter precipitation, the latter of which is predicted to increase under climate change for the study region, had the strongest negative effects on trout populations. Simulations show that trout abundance could be greatly reduced under constant high winter precipitation, consistent with the expected effects of gravel scouring flows on eggs and newly hatched individuals. However, high-elevation sites would be less vulnerable to local extinction because they supported higher adult survival. Furthermore, the majority of brook trout populations are projected to persist if high winter precipitation occurs only intermittently (<=3 of 5 years) due to density-dependent recruitment. Variable drivers of vital rates should be commonly found in animal populations characterized by ontogenetic changes in habitat, and such stage-structured effects may increase population persistence to changing climate by not affecting all life stages simultaneously. Yet, our results also demonstrate that weather patterns during seemingly less consequential seasons (e.g., winter precipitation) can have major impacts on animal population dynamics. PMID- 25523516 TI - Salicornia herbacea prevents weight gain and hepatic lipid accumulation in obese ICR mice fed a high-fat diet. AB - BACKGROUND: Foods that are rich in fat and or sodium chloride promote obesity and associated diseases, whereas intake of dietary fiber averts obesity development. Salicornia herbacea (SH) is a rich source of dietary fiber and high in sodium chloride; therefore, we investigated whether replacing common salt with SH in a high-fat diet could prevent obesity development. RESULTS: Mice were divided into five groups: group ND was fed a normal diet, group HD was fed a high-fat diet, group HD-NaCl was fed a high fat diet with sodium chloride 10 g kg(-1) , group HD CL was fed a high-fat diet with cellulose 30 g kg(-1) and group HD-SH was fed a high-fat diet with SH powder 50 g kg(-1) . The amount of sodium chloride and cellulose added in the respective diet was equivalent to their amount in SH. Data from our study showed that, SH supplementation significantly decreased body weight gain, liver weight, hepatic triglyceride, serum leptin and insulin, along with the mRNA level of key lipid anabolic genes such as SREBP-1c, PPARgamma and FAS compared to the HD group. CONCLUSION: The results of this study demonstrated that SH is a potential natural anti-obesity agent that can be used in place of sodium chloride. PMID- 25523517 TI - Infantile hemangiomas, retinopathy of prematurity and cancer: a common pathogenetic role of the beta-adrenergic system. AB - The serendipitous demonstration that the nonselective beta-adrenergic receptor (beta-AR) antagonist propranolol promotes the regression of infantile hemangiomas (IHs) aroused interest around the involvement of the beta-adrenergic system in angiogenic processes. The efficacy of propranolol was related to the beta2-AR blockade and the consequent inhibition of the production of vascular endothelial growth factor (VEGF), suggesting the hypothesis that propranolol could also be effective in treating retinopathy of prematurity (ROP), a retinal pathology characterized by VEGF-induced neoangiogenesis. Consequent to the encouraging animal studies, a pilot clinical trial showed that oral propranolol protects newborns from ROP progression, even though this treatment is not sufficiently safe. Further, animal studies clarified the role of beta3-ARs in the development of ROP and, together with several preclinical studies demonstrating the key role of the beta-adrenergic system in tumor progression, vascularization, and metastasis, prompted us to also investigate the participation of beta3-ARs in tumor growth. The aim of this review is to gather the recent findings on the role of the beta-adrenergic system in IHs, ROP, and cancer, highlighting the fact that these different pathologies, triggered by different pathogenic noxae, share common pathogenic mechanisms characterized by the presence of hypoxia-induced angiogenesis, which may be contrasted by targeting the beta-adrenergic system. The mechanisms characterizing the pathogenesis of IHs, ROP, and cancer may also be active during the fetal-neonatal development, and a great contribution to the knowledge on the role of beta-ARs in diseases characterized by chronic hypoxia may come from research focusing on the fetal and neonatal period. PMID- 25523518 TI - Tear-mediated delivery of nanoparticles through transcytosis of the lacrimal gland. AB - Rapid clearance from the tears presents a formidable obstacle to the delivery of peptide drugs to the eye surface. This impedes therapies for ocular infections, wound healing, and dry-eye disease that affect the vision of millions worldwide. To overcome this challenge, this manuscript explores a novel strategy to reach the ocular surface via receptor-mediated transcytosis across the lacrimal gland (LG), which produces the bulk of human tears. The LG abundantly expresses the coxsackievirus and adenovirus receptor (CAR); furthermore, we recently reported a peptide-based nanoparticle (KSI) that targets CAR on liver cells. This manuscript reports the unexpected finding that KSI both targets and transcytoses into the LG acinar lumen, which drains to tear ducts. When followed using ex vivo live cell imaging KSI rapidly accumulates in lumen formed by LG acinar cells. LG transduction with a myosin Vb tail, which is dominant negative towards transcytosis, inhibits lumenal accumulation. Transcytosis of KSI was confirmed in vivo by confocal and TEM imaging of LG tissue following administration of KSI nanoparticles. These findings suggest that it is possible to target nanomaterials to the tears by targeting certain receptors on the LG. This design strategy represents a new opportunity to overcome barriers to ocular delivery. PMID- 25523520 TI - Construction of three-dimensional vascularized cardiac tissue with cell sheet engineering. AB - Construction of three-dimensional (3D) tissues with pre-isolated cells is a promising achievement for novel medicine and drug-discovery research. Our laboratory constructs 3D tissues with an innovative and unique method for layering multiple cell sheets. Cell sheets maintain a high-efficiently regenerating function, because of the higher cell density and higher transplantation efficiency, compared to other cell-delivery methods. Cell sheets have already been applied in clinical applications for regenerative medicine in treating patients with various diseases. Therefore, in our search to develop a more efficient treatment with cell sheets, we are constructing 3D tissues by layering cell sheets. Native animal tissues and organs have an abundance of capillaries to supply oxygen and nutrients, and to remove waste molecules. In our investigation of vascularized cardiac cell sheets, we have found that endothelial cells within cell sheets spontaneously form blood vessel networks as in vivo capillaries. To construct even thicker 3D tissues by layering multiple cell sheets, it is critical to have a medium or blood flow within the vascular networks of the cell sheets. Therefore, to perfuse medium or blood in the cell sheet vascular network to maintain the viability of all cells, we developed two types of vascular beds; (1) a femoral muscle-based vascular bed, and (2) a synthetic collagen gel-based vascular bed. Both vascular beds successfully provide the critical flow of culture medium, which allows 12-layer cell sheets to survive. Such bioreactor systems, when combined with cell sheet engineering techniques, have produced functional vascularized 3D tissues. Here we explain and discuss the various processes to obtain vascular networks by properly connecting cell sheets and the engineering of 3D tissues. PMID- 25523519 TI - Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. AB - The use of exosomes as a drug delivery vehicle has gained considerable interest. To establish if exosomes could be utilized effectively for drug delivery, a better understanding of their in vivo fate must be established. Through comparisons to liposomal formulations, which have been studied extensively for the last thirty years, we were able to make some comprehensive conclusions about the fate of unmodified tumor-derived exosomes in vivo. We observed a comparable rapid clearance and minimal tumor accumulation of intravenously-injected exosomes, PC:Chol liposomes, and liposomes formulated with the lipid extract of exosomes, suggesting that the unique protein and lipid composition of exosomes does not appreciably impact exosomes' rate of clearance and biodistribution. This rapid clearance along with minimal tumor accumulation of unmodified exosomes limits their use as an anti-cancer drug delivery vehicle; however, when delivered intratumorally, exosomes remained associated with tumor tissue to a significantly greater extent than PC:Chol liposomes. Furthermore, experiments utilizing mice with impaired adaptive or innate immune systems, revealed the significance of the innate immune system along with the complement protein C5 on exosomes' rate of clearance. PMID- 25523521 TI - Acute toxicity of arsenic and oxidative stress responses in the embryonic development of the common South American toad Rhinella arenarum. AB - Arsenic (As), a natural element of ecological relevance, is found in natural water sources throughout Argentina in concentrations between 0.01 mg/L and 15 mg/L. The autochthonous toad Rhinella arenarum was selected to study the acute toxicity of As and the biochemical responses elicited by the exposure to As in water during its embryonic development. The median lethal concentration (LC50) value averaged 24.3 mg/L As and remained constant along the embryonic development. However, As toxicity drastically decreased when embryos were exposed from heartbeat-stage on day 4 of development, suggesting the onset of detoxification mechanisms. Given the environmental concentrations of As in Argentina, there is a probability of exceeding lethal levels at 1% of sites. Arsenic at sublethal concentrations caused a significant decrease in the total antioxidant potential but generated an increase in endogenous glutathione (GSH) content and glutathione S-transferase (GST) activity. This protective response might prevent a deeper decline in the antioxidant system and further oxidative damage. Alternatively, it might be linked to As conjugation with GSH for its excretion. The authors conclude that toad embryos are more sensitive to As during early developmental stages and that relatively high concentrations of this toxic element are required to elicit mortality, but oxidative stress may be an adverse effect at sublethal concentrations. PMID- 25523523 TI - 'What is it about your skin cancer that bothers you the most?': 700 patients respond. PMID- 25523522 TI - Treatment with embryonic stem-like cells into osteochondral defects in sheep femoral condyles. AB - BACKGROUND: Articular cartilage has poor intrinsic capacity for regeneration because of its avascularity and very slow cellular turnover. Defects deriving from trauma or joint disease tend to be repaired with fibrocartilage rather than hyaline cartilage. Consequent degenerative processes are related to the width and depth of the defect. Since mesenchymal stem cells (MSCs) deriving from patients affected by osteoarthritis have a lower proliferative and chondrogenic activity, the systemic or local delivery of heterologous cells may enhance regeneration or inhibit the progressive loss of joint tissue. Embryonic stem cells (ESCs) are very promising, since they can self-renew for prolonged periods without differentiation and can differentiate into tissues from all the 3 germ layers. To date only a few experiments have used ESCs for the study of the cartilage regeneration in animal models and most of them used laboratory animals. Sheep, due to their anatomical, physiological and immunological similarity to humans, represent a valid model for translational studies. This experiment aimed to evaluate if the local delivery of male sheep embryonic stem-like (ES-like) cells into osteochondral defects in the femoral condyles of adult sheep can enhance the regeneration of articular cartilage. Twenty-two ewes were divided into 5 groups (1, 2, 6, 12 and 24 months after surgery). Newly formed tissue was evaluated by macroscopic, histological, immunohistochemical (collagen type II) and fluorescent in situ hybridization (FISH) assays. RESULTS: Regenerated tissue was ultimately evaluated on 17 sheep. Samples engrafted with ES-like cells had significantly better histologic evidence of regeneration with respect to empty defects, used as controls, at all time periods. CONCLUSIONS: Histological assessments demonstrated that the local delivery of ES-like cells into osteochondral defects in sheep femoral condyles enhances the regeneration of the articular hyaline cartilage, without signs of immune rejection or teratoma for 24 months after engraftment. PMID- 25523524 TI - Detection of co-colonization with Streptococcus pneumoniae by algorithmic use of conventional and molecular methods. AB - Detection of pneumococcal carriage by multiple co-colonizing serotypes is important in assessing the benefits of pneumococcal conjugate vaccine (PCV). Various methods differing in sensitivity, cost and technical complexity have been employed to detect multiple serotypes of pneumococcus in respiratory specimens. We have developed an algorithmic method to detect all known serotypes that preserves the relative abundance of specific serotypes by using Quellung-guided molecular techniques. The method involves culturing respiratory swabs followed by serotyping of 100 colonies by either capsular (10 colonies) or PCR (90 colonies) reactions on 96-well plates. The method was evaluated using 102 nasal swabs from children carrying pneumococcus. Multiple serotypes were detected in 22% of carriers, compared to 3% by World Health Organization (WHO)-recommended morphology-based selection of 1 to 3 colonies. Our method, with a processing cost of $87, could detect subdominant strains making up as low as 1% of the population. The method is affordable, practical, and capable of detecting all known serotypes without false positive reactions or change in the native distribution of multiple serotypes. PMID- 25523525 TI - Using a school-based approach to deliver immunization-global update. AB - Vaccines, such as HPV vaccine, are increasingly administered to school-age children, and school-based immunization is an approach that can be used to reach these children. Limited information has thus far been published that provides an overview of the school-based approach worldwide. This article, based on self reported data from countries, summarizes the extent to which a school-based immunization approach is used around the world, and what antigens are most frequently being administered. Of the 174 countries for which data on school based immunization were available, ninety five countries reported using a school based approach for immunization. Children in grades 1 and 6 (or at an age corresponding with these grades) are most often targeted, and tetanus and diphtheria toxoids are the most frequently administered antigens. The impact of the school-based approach may be reduced in areas with low school attendance, unless specific measures are taken to target out-of-school children. Methods to monitor coverage need to be standardized and data on coverage and on the reach of the approach need to be more systematically analyzed and reported. PMID- 25523526 TI - Evaluation of invalid vaccine doses in 31 countries of the WHO African Region. AB - We examined (a) the fraction of and extent to which vaccinations were administered earlier than recommended (age-invalid) or with too short intervals between vaccine doses (interval-invalid) in countries of the World Health Organisation (WHO) African Region and (b) individual- and community-level factors associated with invalid vaccinations using multilevel techniques. Data from the Demographic and Health Surveys conducted in the last 10 years in 31 countries were used. Information about childhood vaccinations was based on vaccination records (n=134,442). Invalid vaccinations (diphtheria, tetanus, pertussis [DTP1, DTP3] and measles-containing vaccine (MCV)) were defined using the WHO criteria. The median percentages of invalid DTP1, DTP3 and MCV vaccinations across all countries were 12.1% (interquartile range, 9.4-15.2%), 5.7% (5.0-7.6%), and 15.5% (10.0-18.1%), respectively. Of the invalid DTP1 vaccinations, 7.4% and 5.5% were administered at child's age of less than one and two weeks, respectively. In 12 countries, the proportion of invalid DTP3 vaccinations administered with an interval of less than two weeks before the preceding dose varied between 30% and 50%. In 13 countries, the proportion of MCV doses administered at child's age of less than six months varied between 20% and 45%. Community-level variables explained part of the variation in invalid vaccinations. Invalid vaccinations are common in African countries. Timing of childhood vaccinations should be improved to ensure an optimal protection against vaccine-preventable infections and to avoid unnecessary wastage in these economically deprived countries. PMID- 25523527 TI - Stability and variability in income position over time: exploring their role in self-rated health in Swedish survey data. AB - BACKGROUND: The adverse relationship between income and health is well documented, but less is known of how income trajectories, i.e. downward or upward trends in income, determine health. We therefore link longitudinal income information to cross-sectional data on self-rated health and conduct logistic regression models in order to investigate income trends over time and their relationship with health. METHODS: The data, with the exception of income information, are derived from the Swedish Level-of-Living Survey 2000. The information on income was drawn from the income register covering the period 1995 to 2000. We used an age-restricted sample of those 30-64 years of age, and generated a series of models accounting for average income position, lagged income position, income decrease and increase, and annual periods in specific income positions. The analysis was conducted for men and women separately. RESULTS: Apart from the overall association between income and health, we found a similar pattern when including average and lagged income in the model. The analysis of length of time in a specific income position showed substantial sex differences in poor health. Income decrease was more strongly associated with men's poor health, whereas income increase revealed only weak associations with self-rated health. CONCLUSIONS: It was shown that income changes and the time dimension of income are important for self-rated health. Self-rated health responds to decreases in absolute income and lowered rank position in the income distribution to a greater extent than to income gains over time. Lagged lower income position and its associations with health suggest that socio-economic disadvantages accumulate over time. PMID- 25523528 TI - Novel insight into the role of heterotrophic dinoflagellates in the fate of crude oil in the sea. AB - Although planktonic protozoans are likely to interact with dispersed crude oil after a spill, protozoan-mediated processes affecting crude oil pollution in the sea are still not well known. Here, we present the first evidence of ingestion and defecation of physically or chemically dispersed crude oil droplets (1-86 MUm in diameter) by heterotrophic dinoflagellates, major components of marine planktonic food webs. At a crude oil concentration commonly found after an oil spill (1 MUL L(-1)), the heterotrophic dinoflagellates Noctiluca scintillans and Gyrodinium spirale grew and ingested ~0.37 MUg-oil MUg-C(dino)(-1) d(-1), which could represent ~17% to 100% of dispersed oil in surface waters when heterotrophic dinoflagellates are abundant or bloom. Egestion of faecal pellets containing crude oil by heterotrophic dinoflagellates could contribute to the sinking and flux of toxic petroleum hydrocarbons in coastal waters. Our study indicates that crude oil ingestion by heterotrophic dinoflagellates is a noteworthy route by which petroleum enters marine food webs and a previously overlooked biological process influencing the fate of crude oil in the sea after spills. PMID- 25523529 TI - Direct oral anticoagulants: new drugs and new concepts. AB - Direct oral anticoagulants (DOACs) are approved for multiple thromboembolic disorders and provide advantages over existing agents. As with all anticoagulants, management protocols for the eventuality of bleeding are important. Randomized phase III studies generally show that DOACs have a similar risk of clinically relevant bleeding compared with standard anticoagulants, with reductions in major bleeding in some cases. This may be particularly important in patients with atrial fibrillation, for whom the rate of intracranial hemorrhage was approximately halved with DOACs compared with warfarin. Conversely, the risk of gastrointestinal bleeding may be increased. Specific patient characteristics, such as renal impairment, comedications, and particular aspects of each drug, including the proportion eliminated by the kidneys, must be taken into account when assessing the risk of bleeding. Although routine coagulation monitoring of DOACs is not required, it may be useful under some circumstances. Of the traditional clotting assays, a sensitive and calibrated prothrombin time may be useful for detecting the presence or absence of clinically relevant factor Xa inhibitor concentrations (rivaroxaban or apixaban), but specific anti-factor Xa assays can measure drug levels quantitatively. For dabigatran, the results of an activated partial thromboplastin time test may exclude a clinically relevant pharmacodynamic effect, but a calibrated dilute thrombin time assay can be used for quantification of drug levels. In the event of mild or moderate bleeding, normal hemostatic support measures are recommended. For life-threatening bleeding, use of nonspecific prohemostatic agents may be considered, although clinical evidence is scarce. Specific antidotes are in development. PMID- 25523530 TI - Shedding light on scaffold vascular response. PMID- 25523531 TI - Outcomes in patients with cardiogenic shock following percutaneous coronary intervention in the contemporary era: an analysis from the BCIS database (British Cardiovascular Intervention Society). AB - OBJECTIVES: This study sought to determine mortality rates among cardiogenic shock (CGS) patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome in the contemporary treatment era and to determine predictors of mortality. BACKGROUND: It is unclear whether recent advances in pharmacological and interventional strategies have resulted in further improvements in short- and long-term mortality and which factors are associated with adverse outcomes in patients presenting with CGS and undergoing PCI in the setting of acute coronary syndrome. METHODS: This study analyzed prospectively collected data for patients undergoing PCI in the setting of CGS as recorded in the BCIS (British Cardiovascular Intervention Society) PCI database. RESULTS: In England and Wales, 6,489 patients underwent PCI for acute coronary syndrome in the setting of CGS. The mortality rates at 30 days, 90 days, and 1 year were 37.3%, 40.0%, and 44.3%, respectively. On multiple logistic regression analysis, age (for each 10-year increment of age: odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.51 to 1.68; p < 0.0001), diabetes mellitus (OR: 1.47, 95% CI: 1.28 to 1.70; p < 0.0001), history of renal disease (OR: 2.03, 95% CI: 1.63 to 2.53; p < 0.0001), need for artificial mechanical ventilation (OR: 2.56, 95% CI: 2.23 to 2.94; p < 0.0001), intra-aortic balloon pump use (OR: 1.57, 95% CI: 1.40 to 1.76; p < 0.0001), and need for left main stem PCI (OR: 1.90, 95% CI: 1.62 to 2.23; p < 0.0001) were associated with higher mortality at 1 year. CONCLUSIONS: In this large U.K. cohort of patients undergoing PCI in the context of CGS, mortality remains high in spite of the use of contemporary PCI strategies. The highest mortality occurs early, and this time period may be a particular target of therapeutic intervention. PMID- 25523532 TI - Incidence and imaging outcomes of acute scaffold disruption and late structural discontinuity after implantation of the absorb Everolimus-Eluting fully bioresorbable vascular scaffold: optical coherence tomography assessment in the ABSORB cohort B Trial (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions). AB - OBJECTIVES: This study sought to describe the frequency and clinical impact of acute scaffold disruption and late strut discontinuity of the second-generation Absorb bioresorbable polymeric vascular scaffolds (Absorb BVS, Abbott Vascular, Santa Clara, California) in the ABSORB (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) cohort B study by optical coherence tomography (OCT) post-procedure and at 6, 12, 24, and 36 months. BACKGROUND: Fully bioresorbable scaffolds are a novel approach to treatment for coronary narrowing that provides transient vessel support with drug delivery capability without the long-term limitations of metallic drug-eluting stents. However, a potential drawback of the bioresorbable scaffold is the potential for disruption of the strut network when overexpanded. Conversely, the structural discontinuity of the polymeric struts at a late stage is a biologically programmed fate of the scaffold during the course of bioresorption. METHODS: The ABSORB cohort B trial is a multicenter single-arm trial assessing the safety and performance of the Absorb BVS in the treatment of 101 patients with de novo native coronary artery lesions. The current analysis included 51 patients with 143 OCT pullbacks who underwent OCT at baseline and follow-up. The presence of acute disruption or late discontinuities was diagnosed by the presence on OCT of stacked, overhung struts or isolated intraluminal struts disconnected from the expected circularity of the device. RESULTS: Of 51 patients with OCT imaging post procedure, acute scaffold disruption was observed in 2 patients (3.9%), which could be related to overexpansion of the scaffold at the time of implantation. One patient had a target lesion revascularization that was presumably related to the disruption. Of 49 patients without acute disruption, late discontinuities were observed in 21 patients. There were no major adverse cardiac events associated with this finding except for 1 patient who had a non-ischemia-driven target lesion revascularization. CONCLUSIONS: Acute scaffold disruption is a rare iatrogenic phenomenon that has been anecdotally associated with anginal symptoms, whereas late strut discontinuity is observed in approximately 40% of patients and could be viewed as a serendipitous OCT finding of a normal bioresorption process without clinical implications. (ABSORB Clinical Investigation, Cohort B [ABSORB B]; NCT00856856). PMID- 25523533 TI - Relationship between inflammation and benefits of early high-dose rosuvastatin on contrast-induced nephropathy in patients with acute coronary syndrome: the pathophysiological link in the PRATO-ACS study (Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Nephropathy and Myocardial Damage in Patients With Acute Coronary Syndrome Undergoing Coronary Intervention). AB - OBJECTIVES: This study sought to investigate whether the beneficial impact of high-dose rosuvastatin against contrast-induced acute kidney injury (CI-AKI) in acute coronary syndrome (ACS) patients varied in relation to baseline high sensitivity C-reactive protein (hs-CRP) levels. BACKGROUND: High-dose rosuvastatin administered on admission has been shown to prevent CI-AKI and improve short- and mid-term clinical outcome in ACS patients. METHODS: All 504 statin-naive ACS patients enrolled in the PRATO-ACS (Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Acute Kidney Injury and Myocardial Damage in ACS Patients) study were stratified into baseline hs-CRP tertiles: <2.7 mg/l, >=2.7 to <7.5 mg/l, and >=7.5 mg/l. The primary endpoint was CI-AKI occurrence (creatinine >=0.5 mg/dl or >=25% above baseline within 72 h). Logistic regression models were used to evaluate the relationship between hs-CRP levels and effects of rosuvastatin. RESULTS: Patients with higher baseline hs-CRP values presented a significantly higher incidence of CI-AKI (5.4%, 8.7%, and 18.3% in the first, second, and third tertiles, respectively; p = 0.0001). The beneficial effect of rosuvastatin was markedly significant in the third hs-CRP tertile (odds ratio: 0.20; 95% confidence interval: 0.07 to 0.54; p = 0.002). Statin-treated patients in the third tertile presented a significantly lower rate of adverse events at 30 days (7.2% vs. 17.4%, p = 0.043) with a trend toward better outcome at 6 months (6.02% vs. 13.04%, p = 0.12). CONCLUSIONS: High-dose rosuvastatin administered on admission appears to exert more effective kidney protection in ACS subjects with higher baseline hs-CRP levels resulting in better short- and mid-term clinical outcome. (Protective Effect of Rosuvastatin and Antiplatelet Therapy on Contrast-Induced Nephropathy and Myocardial Damage in Patients With Acute Coronary Syndrome Undergoing Coronary Intervention [PRATO ACS]; NCT01185938). PMID- 25523534 TI - Results of the combined U.S. Multicenter Pivotal Study and the Continuing Access Study of the Nit-Occlud PDA device for percutaneous closure of patent ductus arteriosus. AB - OBJECTIVES: This study aimed to compare the efficacy and safety of the Nit-Occlud PDA device (PFM Medical, Cologne, Germany) to benchmarks designed as objective performance criteria (OPC). BACKGROUND: The Nit-Occlud PDA is a nitinol coil-type patent ductus arteriosus (PDA) occluder with a reverse cone configuration, which is implanted using a controlled delivery system. METHODS: Patients with <4-mm minimum diameter PDA were prospectively enrolled in the Pivotal and the Continuing Access Studies from 15 sites in the United States and were followed up for 12 months post-procedure. Investigator-reported outcomes were compared to OPC including a composite success criterion, efficacy criteria of successful closure (clinical and echocardiographic), and safety criteria incidence of adverse events (serious and of total). RESULTS: The Pivotal Study enrolled patients between November 1, 2002 and October 31, 2005, and the Continuing Access Study enrolled additional patients between September 1, 2006 and October 31, 2007. A total of 357 patients were enrolled, and 347 had successful device implantations. After 12 months, 96.8% had complete echocardiographic closure (OPC = 85%) and 98.1% had clinical closure (OPC = 95%). There were no deaths or serious adverse events (OPC = 1%). The total adverse event rate was 4.7% (OPC = 6%). Composite success was 95.1% in the study patients (OPC = 80%). CONCLUSIONS: Closure of small- and medium-sized PDA with the Nit-Occlud PDA is effective and safe when compared with OPC. PMID- 25523535 TI - Cardiac catheterization in the early post-operative period after congenital cardiac surgery. AB - OBJECTIVES: This study sought to demonstrate that early cardiac catheterization, whether used solely as a diagnostic modality or for the use of transcatheter interventional techniques, can be used effectively and with an acceptable risk in the post-operative period. BACKGROUND: Cardiac catheterization offers important treatment for patients with congenital heart disease. Early post-operative cardiac catheterization is often necessary to diagnose and treat residual anatomic defects. Experience with interventional catheterization to address post operative concerns is limited. METHODS: This was a retrospective cohort study. The medical and catheterization data of pediatric patients who underwent a cardiac catheterization <=30 days after congenital heart surgery between November 2004 and July 2013 were reviewed. Patients who underwent right heart catheterization and endomyocardial biopsy after heart transplantation were excluded. RESULTS: A total of 219 catheterizations (91 interventional procedures, 128 noninterventional catheterizations) were performed on 193 patients. Sixty five interventions (71.43%) were dilations, either balloon angioplasty or stent implantation. There was no difference in survival to hospital discharge between those who underwent an interventional versus noninterventional catheterization (p = 0.93). One-year post-operative survival was comparable between those who underwent an intervention (66%) versus diagnostic (71%) catheterization (p = 0.58). There was no difference in the incidence of major or minor complications between the interventional and diagnostic catheterization cohorts (p = 0.21). CONCLUSIONS: Cardiac catheterization, including transcatheter interventions, can be performed safely in the immediate post-operative period after congenital heart surgery. PMID- 25523536 TI - Two-year life expectancy in patients with critical limb ischemia. AB - OBJECTIVES: This study sought to estimate the 2-year life expectancy (2YLE) (estimated survival rate >50% at 2 years) in patients with critical limb ischemia (CLI) using the risk score based on predictors of all-cause mortality within 2 years. BACKGROUND: It has been reported that 2YLE is one of the important factors in the decision making of the revascularization strategy. However, little is known about the probability and the prognostic factors of a 2YLE. METHOD: This study was performed as a multicenter retrospective analysis. Between March 2004 and December 2011, 995 CLI patients with follow-up period >730 days undergoing endovascular therapy (EVT) were identified and analyzed. RESULTS: Within 2 years, 412 patients (41%) died, and a cardiovascular cause accounted for 47% of deaths. On multivariate analysis, the independent prognostic factors were age 65 to 79 years (odds ratio [OR]: 1.9), 80 years of age or older (OR: 3.7), body mass index (BMI) 18.0 to 19.9 kg/m(2) (OR: 1.5), BMI <18.0 kg/m(2) (OR: 2.9), nonambulatory status (OR: 2.4), hemodialysis (OR: 2.1), cerebrovascular disease (OR: 1.6), left ventricular ejection fraction (LVEF) of 40% to 49% (OR: 1.8), LVEF <40% (OR: 2.6), Rutherford class 5 (OR: 1.9), and Rutherford class 6 (OR: 3.4). The 2-year survival rate in each risk score was calculated based on each OR (full score: 15 points). After that, 2YLE was estimated based on the survival rate in each risk score, the probability of a 2YLE of >=8 points indicated a <50% probability of 2 year survival. CONCLUSIONS: The independent prognostic factors for the 2YLE were age, BMI, nonambulatory status, hemodialysis, cerebrovascular disease, LVEF, and tissue loss. A 2YLE score of >=8 points indicated a <50% probability of 2-year survival. This score seemed to be helpful for identifying CLI patients with a poor prognosis. PMID- 25523537 TI - Critical limb ischemia and intermediate-term survival. PMID- 25523538 TI - Reply: organized thrombus mimicking spontaneous coronary artery dissection. PMID- 25523539 TI - Research in China: from imitation to innovation. PMID- 25523540 TI - An unexpected finding: stuck leaflet after transapical mitral valve-in-valve implantation. PMID- 25523541 TI - Chronic total coronary occlusion with bronchocoronary collateral circulation failed to visualize by conventional angiography. PMID- 25523542 TI - Coarse-grained simulation of dynamin-mediated fission. AB - Fission is a process in which a region of a lipid bilayer is deformed and separated from its host membrane, so that an additional, topologically independent compartment surrounded by a continuous lipid bilayer is formed. It is a fundamental process in the organization of the compartmentalization of living organisms and carefully regulated by a number of membrane-shaping proteins. An important group within these is the dynamin family of proteins that are involved in the final severance of the hourglass-shaped neck, via which the growing compartment remains connected to the main volume until the completion of fission. We present computer simulations testing different hypotheses of how dynamin proteins facilitate fission by constriction and curvature. Our results on constraint-induced fission of cylindrical membrane tubes emphasize the importance of the local creation of positive curvature and reveal a complex picture of fission, in which the topological transformation can become arrested in an intermediate stage if the proteins constituting the fission machinery are not adaptive. PMID- 25523543 TI - Evidences of local adaptation in quantitative traits in Prosopis alba (Leguminosae). AB - Signals of selection on quantitative traits can be detected by the comparison between the genetic differentiation of molecular (neutral) markers and quantitative traits, by multivariate extensions of the same model and by the observation of the additive covariance among relatives. We studied, by three different tests, signals of occurrence of selection in Prosopis alba populations over 15 quantitative traits: three economically important life history traits: height, basal diameter and biomass, 11 leaf morphology traits that may be related with heat-tolerance and physiological responses and spine length that is very important from silvicultural purposes. We analyzed 172 G1-generation trees growing in a common garden belonging to 32 open pollinated families from eight sampling sites in Argentina. The multivariate phenotypes differ significantly among origins, and the highest differentiation corresponded to foliar traits. Molecular genetic markers (SSR) exhibited significant differentiation and allowed us to provide convincing evidence that natural selection is responsible for the patterns of morphological differentiation. The heterogeneous selection over phenotypic traits observed suggested different optima in each population and has important implications for gene resource management. The results suggest that the adaptive significance of traits should be considered together with population provenance in breeding program as a crucial point prior to any selecting program, especially in Prosopis where the first steps are under development. PMID- 25523544 TI - Genetic control of the seed coat colour of Middle American and Andean bean seeds. AB - Seed coat colour of bean seeds is decisive for acceptance of a cultivar. The objectives of this research were to determine whether there is maternal effect for "L", a* and b* colour parameters in Middle American and Andean bean seeds; to obtain estimates of heritability and gain with selection for "L", a* and b* values; and select recombinants with the seed coat colour required by the market demand. Thus, controlled crossings were carried out between the Middle American lines CNFP 10104 and CHC 01-175, and between the Andean lines Cal 96 and Hooter, for obtaining F1, F1 reciprocal, F2 and F2 reciprocal generations for each hybrid combination. Parents and generations were evaluated in two field experiments (2012 normal rainy and 2013 dry seasons) in the state of Rio Grande do Sul, Brazil. Seed coat colour was quantified with a portable colorimeter. Genetic variability for "L" (luminosity), chromaticity a* (green to red shade), and chromaticity b* (blue to yellow shade) values was observed in seeds with F2 seed coat of Middle American and Andean beans. "L", a* and b* values in bean seeds presented maternal effects. High broad-sense heritability are observed for luminosity (h(2)b: 76.66-95.07%), chromaticity a* (h(2)b: 73.08-89.31%), and chromaticity b* (h(2)b: 88.63-92.50%) values in bean seeds. From the crossings, it was possible to select bean seeds in early generation for the black group, and for carioca and cranberry types (dark or clear background) which present the colour required by the market demand. PMID- 25523545 TI - [Pressurized intraperitoneal aerosol chemotherapy (PIPAC): a new way of administration in peritoneal carcinomatosis of ovarian cancer]. PMID- 25523546 TI - [G. Moullec and I. Boucoiran in reply to the article by G. Filhol et al. International recommendations on physical exercise for pregnant women. Gynecol Obstet Fertil 2014;42:856-60]. PMID- 25523547 TI - Relationship between electrocardiographic signs and shunt volume in atrial septal defect. AB - BACKGROUND: The aim of this study was to determine whether electrocardiographic signs correlate with hemodynamics and the magnitude of the intracardiac shunt in children with ostium secundum atrial septal defects (ASD). METHODS: A total of 100 ASD patients (median age, 6 years 4 months; 54 girls) underwent cardiac catheterization between August 1980 and April 2010. We retrospectively investigated the relationship between electrocardiographic signs and the pulmonary/systemic blood flow ratio (Qp/Qs) in these patients. We also compared 63 postoperative electrocardiograms with those recorded before surgery. RESULTS: The mean Qp/Qs ratio of the 100 patients was 2.46 +/- 0.81 (range, 1.1-5.0). The Qp/Qs ratio in patients with and without right bundle branch block (RBBB) was 2.57 +/- 0.82 (n = 73) and 2.15 +/- 0.72 (n = 27), respectively (P = 0.016). The Qp/Qs ratio in patients with and without isolated negative T-wave was 2.85 +/- 0.87 (n = 38) and 2.22 +/- 0.68 (n = 62), respectively (P = 0.0003). None of the patients with low Qp/Qs ratio (Qp/Qs ratio <= 1.5) had both RBBB and isolated negative T-wave. The prevalence of these two signs decreased from 73.0% (n = 46) and 36.5% (n = 23) to 15.9% (n = 10) and 15.9% (n = 10) after surgical repair, respectively. CONCLUSIONS: RBBB and isolated negative T-wave in the precordial leads are well correlated with high Qp/Qs ratio in ASD patients. PMID- 25523548 TI - The Holy Grail of Polymer Therapeutics for Cancer Therapy: An Overview on the Pharmacokinetics and Bio Distribution. AB - In recent years, multifaceted clinical benefits of polymeric therapeutics have been reported. Over the past decades, cancer has been one of the leading causes of mortality in the world. Many clinically approved chemotherapeutics encounter potential challenges against deadly cancer. Moreover, safety and efficacy of anticancer agents have been limited by undesirable pharmacokinetics and biodistribution. To address these limitations, various polymer drug conjugates are being studied and developed to improve the antitumor efficacy. Among other therapeutics, polymer therapeutics are well established platforms that circumvent anticancer therapeutics from enzymatic metabolism via direct conjugation to therapeutic molecules. Interestingly, polymer therapeutics meets an unmet need of small molecules. Further clinical study showed that polymer-drug conjugation can achieve desired pharmacokinetics and biodistribution properties of several anticancer drugs. The present retrospective review mainly enlightens the most recent preclinical and clinical studies include safety, stability, pharmacokinetic behavior and distribution of polymer therapeutics. PMID- 25523549 TI - Chemical synthesis of gamma-secretase activating protein using pseudoglutamines as ligation sites. AB - The chemical synthesis of analogue of a novel gamma-secretase activating protein, which may play a pivotal role in the formation of amyloid peptides, the precursor to Alzheimer's disease, is described. The linear polypeptide sequence, consisting of 121 amino acids was assembled from four unprotected peptide building blocks using a convergent ligation-based synthesis. A strategic mutation of three glutamine residues to cysteine enabled the ligations, and the cysteines were subsequently converted to pseudoglutamines, to mimic the native glutamine. The full length unfolded protein was obtained in milligram amounts and was demonstrated to be homogeneous by liquid chromatography and mass spectrometry. PMID- 25523550 TI - Achievements and challenges in the management of inflammatory bowel disease. PMID- 25523551 TI - Intestinal barrier homeostasis in inflammatory bowel disease. AB - The single-cell thick intestinal epithelial cell (IEC) lining with its protective layer of mucus is the primary barrier protecting the organism from the harsh environment of the intestinal lumen. Today it is clear that the balancing act necessary to maintain intestinal homeostasis is dependent on the coordinated action of all cell types of the IEC, and that there are no passive bystanders to gut immunity solely acting as absorptive or regenerative cells: Mucin and antimicrobial peptides on the epithelial surface are continually being replenished by goblet and Paneth's cells. Luminal antigens are being sensed by pattern recognition receptors on the enterocytes. The enteroendocrine cells sense the environment and coordinate the intestinal function by releasing neuropeptides acting both on IEC and inflammatory cells. All this while cells are continuously and rapidly being regenerated from a limited number of stem cells close to the intestinal crypt base. This review seeks to describe the cell types and structures of the intestinal epithelial barrier supporting intestinal homeostasis, and how disturbance in these systems might relate to inflammatory bowel disease. PMID- 25523552 TI - The genetics of Crohn's disease and ulcerative colitis--status quo and beyond. AB - The two major subtypes of inflammatory bowel disease (IBD), ulcerative colitis (UC, MIM#191390) and Crohn's disease (CD, MIM#266600), are chronic relapsing remitting inflammatory disorders affecting primarily the gastrointestinal tract. Prevalence rates in North America and Europe range from 21 to 246 per 100,000 for UC and 8 to 214 per 100,000 for CD. Although CD and UC share some clinical and pathological features, they can be distinguished by localization, endoscopic appearance, histology and behavior, which suggest differences in the underlying pathophysiology. The importance of genetic risk factors in disease etiology is high and has been documented more clearly for CD than for UC (relative sibling risks lambda(s): 15-35 for CD, 6-9 for UC). The most recent and largest genetic association study for IBD, which employed genome-wide association data for over 75,000 patients and controls, established the association of 163 susceptibility loci with IBD. Although the disease variance explained by the 163 loci only amounts to 13.6% for CD and 7.5% for UC, the identified loci and the candidate genes within yielded valuable insights into the pathogenesis of IBD and the relevant disease pathways. We here review the current research on the genetics of IBD and provide insights into on current efforts as well as suggest topics for future research. PMID- 25523553 TI - The innate immune system and inflammatory bowel disease. AB - The innate immune system is a key factor in understanding the pathogenesis of inflammatory bowel disease (IBD) and in the hopes of improving its treatment. NOD2, a pattern recognition receptor, was one of the first major susceptibility genes identified in Crohn's disease (CD). This discovery has been followed by genome-wide association studies that have identified other genes involved in innate immune responses. Most notably, polymorphisms in the interleukin (IL)-23 receptor have also been linked to IBD - both CD and ulcerative colitis. At the core of the innate immune defects associated with IBD is a lack of generating a robust response to control invasive commensal or pathogenic bacteria. The defect sometimes lies in a failure of the epithelium to express antimicrobial peptides or in defective control of intracellular bacteria by phagocytic cells such as dendritic cells, macrophages, or neutrophils. The recent identification of innate lymphoid cells that express the IL-23 receptor and generate both proinflammatory and protective or regulatory responses to commensal or pathogenic bacteria provides another layer of complexity to the interplay of host protection and dysregulated inflammation. Although inhibition of tumor necrosis factor has been highly successful as a strategy in treating IBD, we must better understand the nuanced role of other innate cytokines before we may incorporate these in the treatment of IBD. PMID- 25523554 TI - Contentious host-microbiota relationship in inflammatory bowel disease--can foes become friends again? AB - Inflammatory bowel diseases (IBDs) are chronic debilitating disorders of unknown etiology, consisting of two main conditions, ulcerative colitis and Crohn's disease. Major advances have recently taken place in human genetic studies of IBD and over 160 risk loci for these two diseases have been uncovered. These genetic data highlight a key role for genes that code for immunological and epithelial barrier functions. Environmental factors also make substantial contributions to the pathogenesis of IBD and account for the growing incidence of the diseases around the world. Intestinal microbiota creates resistance to infection, provides nutrients, and educates the immune system and in many ways has a significant impact on human health. Aberrant microbiota composition and decreased diversity (dysbiotic microbiota) are key etiopathological events in IBD. Dysbiotic microbiota can lead to loss of normal, regulatory immune effects in the gut mucosa. This may play a central role in the development and perpetuation of chronic inflammation. Further, the expression of specific innate immune receptors that recognize microbes is altered in the IBD epithelium. Therefore, the combination of host side epithelial barrier functions and the presence of dysbiotic microbiota in the gut together promote inflammation. New therapeutic options targeting microbiota are currently considered for IBD and they may, in the future, provide means to reverse the pathogenic host-microbiota relationship into a symbiotic one. In this review, the focus is on the intestinal microbiota and host-microbe interactions in IBD. PMID- 25523555 TI - Mucosal healing in the era of biologic agents in treatment of inflammatory bowel disease. AB - Mucosal healing has been a central issue in inflammatory bowel disease (IBD) for the last years, and has been proposed to be included as the new treatment goal in IBD. The molecular understanding of both the disruption and the healing of the intestinal epithelial cell lining and the mucosal barrier in IBD is complex and only partly understood. There is no general agreement on how to define healed mucosa, but there is a general acceptance that clinicians should use endoscopy and imaging technique in their assessments. Mucosal healing is an old concept that has been actualized in the present era of the highly effective biological agents. Randomized clinical studies with mucosal healing as end-point parameters have been reported, and early mucosal healing has been associated with low complication rates. We are waiting for documentation of whether treatment to healed mucosa can change the natural course of IBD. The concept of immunological remission has recently been introduced and can be the new treatment goal and one of several criteria for discontinuation of biological treatment in IBD. In conclusion, mucosal healing is a fairly novel concept and goal for biological treatment of IBD. There is a need for a standardization of its assessment and validation of the prognostic value. PMID- 25523556 TI - Mechanisms of initiation and progression of intestinal fibrosis in IBD. AB - Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs). It becomes clinically apparent in >30% of patients with Crohn's disease (CD) and in about 5% with ulcerative colitis (UC). Fibrosis is a consequence of local chronic inflammation and is characterized by excessive extracellular matrix (ECM) protein deposition. ECM is produced by activated myofibroblasts, which are modulated by both, profibrotic and antifibrotic factors. Fibrosis depends on the balance between the production and degradation of ECM proteins. This equilibrium can be impacted by a complex and dynamic interaction between profibrotic and antifibrotic mediators. Despite the major therapeutic advances in the treatment of active inflammation in IBD over the past two decades, the incidence of intestinal strictures in CD has not significantly changed as the current anti inflammatory therapies neither prevent nor reverse the established fibrosis and strictures. This implies that control of intestinal inflammation does not necessarily affect the associated fibrotic process. The conventional view that intestinal fibrosis is an inevitable and irreversible process in patients with IBD is also gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the mechanisms of intestinal fibrosis is thus vital and may pave the way for the developments of antifibrotic agents and new therapeutic approaches in IBD. PMID- 25523557 TI - Magnetic resonance enterography in Crohn's disease: optimal use in clinical practice and clinical trials. AB - The purpose of this review is to provide a practical appraisal of the usefulness of magnetic resonance enterography in the management of Crohn's disease and the potential utilities that this imaging modality may have in clinical research. Also, we review some basic technical considerations that clinicians should know to understand the value and limitations of the technique. Lastly, we outline the future trends and potential contributions of new technological advances in the field of magnetic resonance imaging that can improve the classic magnetic resonance enterography technique. PMID- 25523558 TI - Fecal calprotectin in diagnosis and clinical assessment of inflammatory bowel disease. AB - The fecal neutrophil-derived biomarker calprotectin has several features of an ideal noninvasive test for detecting intestinal inflammation: it is simple, reliable, and low in cost. Its utility in differentiating inflammatory bowel diseases (IBDs) from functional conditions such as irritable bowel syndrome is well documented. Fecal calprotectin (FC) correlates closely with endoscopic activity of IBD. Emerging evidence suggest its usefulness in serial monitoring of disease activity and of therapy success in IBD. A low FC concentration predicts persistence of clinical remission especially in non-symptomatic ulcerative colitis and Crohn's colitis. Here, an overview is given to the current role of FC in diagnosis and clinical assessment of IBD. PMID- 25523559 TI - Malignancies in inflammatory bowel disease. AB - Patients with inflammatory bowel diseases (IBDs) are at increased risk of colorectal cancer (CRC), but the risk varies between different studies and seems to be decreasing. The cumulative risk of CRC has been reported to be 1%, 2%, and 5% after 10, 20, and over 20 years of disease duration, respectively, in recent meta-analysis. Disease duration and grade of inflammation are the main driving forces of dysplasia and CRC development. Also, the risk of extraintestinal cancers is increased in IBD, where the degree of immunosuppression and its duration are the most important risk factors. Most important extraintestinal malignancies are lymphomas and non-melanoma skin cancers, both of which are increased in patients receiving thiopurines. Also, extraintestinal manifestations or concomitant diseases such as primary sclerosing cholangitis predispose IBD patients to malignancies such as cholangiocarcinoma. History of previous cancer increases the risk of developing either new or recurrent cancers and should be taken into account when choosing therapy and planning surveillance. Dysplasia and cancer screening and surveillance must be individualized according to patients' risk factors. Malignancies are the second most common cause of death after cardiovascular diseases in both genders in patients with IBD. PMID- 25523560 TI - Conventional drug therapy for inflammatory bowel disease. AB - Most patients with inflammatory bowel diseases (IBD) are offered conventional medical therapy, because emerging therapies for IBD are regulated by health-care jurisdiction and often limited to academic centres. This review distils current evidence to provide a pragmatic approach to conventional IBD therapy, including aminosalicylates, corticosteroids, thiopurines, methotrexate, calcineurin inhibitors, infliximab and adalimumab. It addresses drug efficacy, safety and salient practice points for optimal and appropriate practice. PMID- 25523561 TI - New targeted therapies such as anti-adhesion molecules, anti-IL-12/23 and anti Janus kinases are looking toward a more effective treatment of inflammatory bowel disease. AB - Antitumor necrosis factor alpha agents have dramatically changed the management of inflammatory bowel disease (IBD). However, a significant proportion of patients does not respond or lose response over time. Hence, there is an urgent need for new molecules, with different mechanisms of action, and with a targeted and more effective approach. These new drugs include either small molecules or biological agents. We describe the three most promising classes of molecules in the field of IBD: anti-adhesion, anti-interleukin 12/23 and anti-Janus Kinases therapies. PMID- 25523562 TI - Surgery in the age of biological treatment. AB - Surgery for IBD is in constant evolution; it does not appear that the introduction of biologicals has had a major effect on the chance of a patient being operated on or not. Pouch surgery had its heydays in the 80s and 90s and has since then become less frequent, but the number of patients undergoing surgery still seem about the same from one year to the other. Likewise, there is no substantial evidence that surgery for Crohn's disease is diminishing. There have been fears that patients on biological treatment have an increased risk of postoperative complications. The issue is not completely settled but it is likely that patients on biological treatment who come to surgery are those who do not benefit from biologicals. Thus, they are compromised in that they have an ongoing inflammation, are in bad nutritional state, and might have several other known risk factors for a complicated postoperative course. These factors and perhaps not the biologicals per se is what surgeons should consider. During the recent years, we have seen several new developments in IBD surgery; the ileorectal anastomosis is being used for ulcerative colitis and laparoscopic surgery usually resulting in a shorter hospital stay, less pain, and better cosmetics. We have also seen the introduction of robotic surgery, single incision minimal invasive surgery, transanal minimal invasive surgery, and other approaches to minimize surgical trauma. Time will show which of these innovations patients will benefit from. PMID- 25523563 TI - [Effect of hypothermia therapy on serum GFAP and UCH-L1 levels in neonates with hypoxic-ischemic encephalopathy]. AB - OBJECTIVE: To evaluate the effect of hypothermia therapy on serum glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) levels in neonates with hypoxic-ischemic encephalopathy (HIE). METHODS: Sixty-four HIE neonates were enrolled in this study. Thirty-three neonates with mild HIE were given conventional treatment and 31 neonates with moderate or severe HIE received conventional treatment and hypothermia therapy. Serum levels of GFAP and UCH-L1 were measured using ELISA before treatment and 6-12 hours after treatment. RESULTS: Serum levels of IL-6, IL-8, GFAP and UCH-L1 in the moderate/severe HIE group were significantly higher than in the mild HIE group (P<0.05) before treatment. Serum GFAP level was positively correlated with serum IL-6 (r=0.54; P<0.05) and IL-8 levels (r=0.63; P<0.05), while negatively correlated with Apgar score (r=-0.47, P<0.05). After treatment, serum levels of IL-6, IL-8 and UCH-L1 in the moderate/severe HIE group were significantly reduced (P<0.05), while serum GFAP levels increased significantly (P<0.05). The patients with abnormal neurological development showed higher serum GFAP levels than those with favourable prognosis (P<0.05). Receiver operating characteristic (ROC) curves analysis demonstrated that the area under curve (AUC) of GFAP and UCH-L1 were 0.714 and 0.703 respectively. At a cut-off value of 0.07 ng/mL, the sensitivity and specificity of GFAP for the diagnosis of HIE were 77% and 78% respectively. CONCLUSIONS: Hypothermia therapy can decrease serum UCH-L1 levels and increase serum GFAP levels in neonates with HIE. Based on their diagnostic value of brain injury, GFAP and UCH-L1 are promising to be novel biomarkers for HIE. PMID- 25523564 TI - [Results of 779 cases of neonatal fundus screening and risk factors for neonatal fundus diseases]. AB - OBJECTIVE: To determine the prevalence and risk factors of retinal diseases of preterm infants and full term for newborns small gestational age born (SGA) by using wide-angle digital retinal imaging system (RetCam3). METHODS: Clinical data of 779 preterm and SGA infants whose eyes were detected by RetCam3 between January and December 2013 before discharge were studied retrospectively. RESULTS: Among the 779 infants, there were 69 cases of retinal hemorrhage (8.9%), 10 cases (1.3%) of retinopathy of prematurity (ROP), 9 cases of retinal exudative changes, 4 cases of retinal myelinated nerve fibers, 2 cases of congenita cataract, 3 cases of retinal chromatosis, 2 cases of retinal crystalline changes and 1 case of retinoblastoma. Logistic regression analysis indicated that low birth weight and gestational age and the history of oxygen inhalation were risk factors for the development of ROP and that vaginal delivery and mechanical ventilation increased the risk of retinal hemorrhage. CONCLUSIONS: Neonatal fundus diseases may be so various and harmful that early fundus screening should be carried out on high-risk infants, such as preterm and SAG infants. Preventive measures should be taken against the risk factors for fundus diseases. PMID- 25523565 TI - [Comparative analysis of risk factors for preterm and small-for-gestational-age births]. AB - OBJECTIVE: To compare the risk factors between preterm and small-for-gestational age (SGA) births. METHODS: A total of 1 270 newborns who had no obstetric risk factors or maternal diseases were enrolled in this study. Their mothers' stature, body weight, passive smoking, and history of abnormal pregnancy were investigated using the self-designed questionnaire. The infants were divided into four groups: preterm, appropriate-for-gestational-age (AGA), SGA, and term infants. Multivariate logistic regression analysis was performed to compare the risk factors between preterm and SGA births. RESULTS: A weight gain less than 9 kg during pregnancy increased the risks of preterm (OR=1.63, 95% CI: 1.12-2.07) and SGA (OR=1.92, 95% CI: 1.56-2.58). The histories of abortion (OR=1.46, 95% CI: 1.09-1.93) and preterm birth (OR=2.63, 95% CI: 1.81-3.92) were independent risk factors for preterm births, while low pre-pregnancy body mass index (<18.5) (OR=2.16, 95% CI: 1.53-3.16), short stature (<1.55 m) (OR=2.46, 95% CI: 1.78 3.48), and passive smoking (OR=2.24, 95% CI: 1.65-2.98) were independent risk factors for SGA births. CONCLUSIONS: Due to different risk factors between preterm and SGA births, specific preventive measures should be taken pertinently to reduce the incidence of the two bad pregnancy outcomes. PMID- 25523566 TI - [Effects of sublingual immunotherapy on serum IL-17 and IL-35 levels in children with allergic rhinitis or asthma]. AB - OBJECTIVE: To study the clinical effect and mechanisms of specific sublingual immunotherapy (SLIT) for the treatment of allergic rhinitis or asthma in children. METHODS: Thirty children suffering from Dermatophagoides farinae allergic rhinitis or asthma (case group) and 30 healthy children (control group) were enrolled in this study. The case group accepted SLIT between January and December 2011. The ratio of forced expiratory volume in one second (FEV1) and its expected value, the ratio of airway resistance and its expected value, peripheral blood eosinophil (Eos) count and serum levels of IL-17 and IL-35 were measured before treatment and one and two years after treatment. The rhinitis or asthma symptom scores were rated and the level of asthma control was monitored. RESULTS: Serum IL-17 level in the case group was significantly higher than in the control group before treatment and one year after treatment (P<0.01). Furthermore, serum IL-17 level in the case group gradually decreased from before treatment to 1 year to 2 years after treatment (P<0.01). By two years of treatment, there was no significant difference in serum IL-17 level between the case and control groups (P>0.05). The changes of serum IL-35 level after treatment were opposite to serum IL-17 in the case group. The ratio of FEV1 and its expected value gradually increased from before treatment to 1 year to 2 years after treatment (P<0.01) in the case group. In contrast, the change of the ratio of airway resistance and its expected value and Eos count gradually decreased from before treatment to 1 year to 2 years after treatment (P<0.01) in the case group. More patients achieved improved rhinitis or asthma symptom scores two years after treatment than one year after treatment in the case group (P<0.01). SLIT was effective in 85% of children with allergic rhinitis one after treatment vs 100% two years after treatment. Asthma control was observed in 76% of the asthmatic patients one after treatment vs 92% two years after treatment. CONCLUSIONS: SLIT is effective for allergic rhinitis and asthma in children, and the treatment period of two years seems to be superior to one year. The mechanism of action of SLIT for the treatment of allergic rhinitis and asthma may be associated with inhibition of IL 17 expression and promotion of IL-35 expression. PMID- 25523567 TI - [Roles of CD4+CD25+Foxp3+ regulatory T cells and IL-33 in the pathogenesis of asthma in children]. AB - OBJECTIVE: To study the roles of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) and IL-33 in the pathogenesis of asthma in children. METHODS: Flow cytometry was used to detect peripheral blood CD4(+)CD25(+)Foxp3(+)Treg proportion in CD4(+)T lymphocytes in.45 children with asthma, 50 children with wheezing caused by respiratory syncytial virus infection and 40 healthy children. Serum levels of IFN-gamma, IL-4, IL-5 and IL-33 were measured using ELISA. RESULTS: The level of peripheral blood CD4(+)CD25(+)Foxp3(+)Treg in the asthma group was significantly lower than in the wheezing and control groups (P<0.05). In contrast, serum levels of IL-33 in the asthma group was significantly higher than in the wheezing and control groups (P<0.05). Peripheral blood CD4(+)CD25(+)Foxp3(+)Treg level was negatively correlated with serum IL-33 level in the asthma group(r=-0.156, P<0.01). CONCLUSIONS: CD4(+)CD25(+)Foxp3(+)Treg may interact with IL-33 in the pathogenesis of childhood asthma. PMID- 25523568 TI - [Alterations of CD4+CXCR5+Tfh cells and its transcription regulatory factors in children with asthma]. AB - OBJECTIVE: To study the alterations of follicular T helper cells (CD4(+)CXCR5(+)Tfh cells, Tfh) on circulating T lymphocytes in children with asthma, and to study the expression of transcription regulatory factors BCL-6 and BLIMP-1 mRNA. METHODS: Sixty-four children with asthma and 25 healthy controls were enrolled in this study. On the basis of the disease, the children with asthma were classified into acute phase group (n=36) and remission phase group (n=28). The flow cytometry was used to detect the proportion of CD4(+)CXCR5(+)Tfh cells on CD4(+)T lymphocytes. Real-time PCR was performed to detect the levels of BCL-6 mRNA and BLIMP-1 mRNA. The double -antibody Sandwich ELISA was used to detect plasma concentrations of total IgE, IL-2, IL-6 and IL-21. RESULTS: The proportion of CD4(+)CXCR5(+)Tfh cells was significantly higher in the acute group than in the control group and the remission group (P<0.05). Transcription levels of BCL-6 mRNA were significantly higher, while the inhibitory factors BLIMP-1 mRNA was significantly lower in the acute group than in the remission group and control group (P<0.05). The plasma concentration of IL-6 in the acute group increased significantly compared with the control group (P<0.05). Plasma concentrations of total IgE and IL-21 increased significantly, in contrast, plasma IL-2 concentration decreased significantly in the acute group, compared with the control group and the remission group (P<0.05). Correlation analysis showed that both IL-21 and IL-6 concentrations were positively correlated with the proportion of CD4(+)CXCR5(+)Tfh cells (r=0.76, r=0.46 respectively; P<0.05), while IL-2 level was negatively correlated with the proportion of Tfh cells (r= 0.68, P<0.05). CONCLUSIONS: The abnormal proportion of CD4(+)CXCR5(+)Tfh cells might be involved in the immunological pathogenesis of acute asthma in children. The increased expression of BCL-6 mRNA and decreased expression of BLIMP-1 mRNA as well as the alterations of plasma total IgE, cytokines IL-2, IL-6 and IL-21 in microenvironment might be account for the increased proportion of CD4(+)CXCR5(+)Tfh cells in children with acute asthma. PMID- 25523569 TI - [Epidemiological survey and risk factor analysis of asthma in children in urban districts of Zhengzhou, China]. AB - OBJECTIVE: To study the epidemiological features, treatment status, and risk factors for asthma in children in Zhengzhou, China. METHODS: Questionnaires for primary screening were issued using the method of multi-stage stratified sampling. Suspected asthmatic children were given a second questionnaire, physical examination, medical history review, and auxiliary examination to confirm the diagnosis. Age- and sex-matched non-asthmatic children were randomly recruited to the control group. RESULTS: The number of valid questionnaires was 10 616 (5 444 males and 5 172 females). There were 308 confirmed asthma cases and the overall prevalence was 2.90%. The prevalence in boys was higher than that in girls (3.4% vs 2.4%). The prevalence in children under 3 years of age was 10.2%, which was higher than that in other age groups. The top three triggers for asthma attack in children were respiratory infection (94.2%), weather changes (89.0%), and exercise (35.1%). The most common asthma attack was moderate (71.8%), followed by mild (22.7%). Inhaled corticosteroids, systemic corticosteroids, and antibiotics were applied to 94.8% (292 cases), 74.7% (230 cases), and 90.9% (280 cases) of all patients, respectively. Multivariate logistic regression analysis indicated the following major risk factors for asthma: history of allergic rhinitis (OR=150.285, 95% CI: 31.934-707.264), history of eczema (OR=10.600, 95% CI: 1.054-106.624), history of atopic dermatitis (OR=31.368, 95% CI: 3.339 294.683), food allergies (OR=27.373, 95% CI: 2.670-280.621), method of birth (OR=2.853, 95% CI: 1.311-6.208), age of first antibiotic use (OR=0.384, 95% CI: 0.172-0.857), frequency of antibiotic use within 1 year of age (OR=9.940, 95% CI: 6.246-15.820), use of wall decorating materials (OR=2.108, 95% CI: 1.464-3.036), and use of heat supply in winter (OR=6.046, 95% CI: 1.034-35.362). CONCLUSIONS: The prevalence of childhood asthma is associated with age and gender in Zhengzhou. Most asthma attacks are moderate, often triggered by respiratory infection. Treatment of asthma has been standardized, but still needs further improvement. History of allergic rhinitis, eczema, atopic dermatitis and food allergies, cesarean delivery, frequent use of antibiotics within 1 year of age, use of decorating materials on the wall, and use of heating in winter may increase risk for asthma, and use of antibiotics in older age is a protective factor against asthma in children. PMID- 25523570 TI - [Pathologic bacterial distribution and antibiotic resistance in induced sputum of infants aged from 1 to 3 months with lower respiratory tract infection]. AB - OBJECTIVE: To investigate the pathologic bacterial distribution and their antibiotic resistance in infants aged from 1 to 3 months with lower respiratory tract infection, so as to provide instructions for clinical application of antibiotics. METHODS: Induced sputum was extracted from 622 cases of hospitalized infants aged from 1 to 3 months with lower respiratory tract infection between January 2013 and December 2013, and microbial sensitivity test was performed with agar diffusion sensitivity test. RESULTS: A total of 379 (60.9%) strains of bacteria were isolated from induced sputum in the 622 infants. The Gram-negative strains were detected in 325 strains (85.8%), and the Gram-positive strains were found in 50 strains (13.2%) in the 379 strains. The others were Fungal strains (4 strains, 1.1%). The Gram-negative bacteria included Escherichia coli (31.1%) and Klebsiella pneumoniae (18.2%), with extended-spectrum beta-lactamases (ESBLs) production of 48.3% and 52.2% respectively. The average rate of antibiotic resistance for ESBLs-producing bacteria was 53%. ESBLs-producing bacteria were highly resistant (100%) to ampicillin and cefotaxime, but sensitive to carbapenems. Staphylococcus aureus (10.0%) was the dominant bacteria in Gram positive bacteria. A lower proportion of methicillin-resistant Staphylococcus aureus (1.8%) was observed, however the resistance rate of methicillin-resistant Staphylococcus aureus to beta-lactam antibiotics were 100%. CONCLUSIONS: Escherichia coli and Klebsiella pneumoniae are the main pathogenic bacteria causing lower respiratory tract infection in infants aged from 1 to 3 months. ESBLs-producing bacteria accounted for over 48%, and the antibiotic resistance rate were more than 53% in these infants. These results provide a basis for the first empirical clinical use of antimicrobial in infants with lower respiratory tract infection. PMID- 25523571 TI - [Clinical analysis of childhood Henoch-Schonlein purpura on the Tibetan Plateau, China]. AB - OBJECTIVE: To study the clinical characteristics of childhood Henoch-Schonlein purpura (HSP) on the Tibetan Plateau, China. METHODS: One hundred and twenty-five HSP children admitted to Shannan People's Hospital, Tibet, were assigned to the observation group, and 96 HSP children admitted to Wuhan Children's Hospital were assigned to the control group. The disease characteristics, clinical manifestations, treatment, and prognosis in both groups were retrospectively analyzed and compared. RESULTS: The mean age of HSP onset and the female-to-male ratio in the observation group were both significantly higher than in the control group (P<0.05). There was a significant difference in seasonal onset between two groups. Significant differences in the etiological factors were observed between the two groups (P<0.05). The gastrointestinal manifestation was more prominent in the observation group compared with that in the control group (P<0.05). Laboratory findings showed that the mean erythrocyte sedimentation rate, counts of white blood cells and platelets, and percentage of neutrophil leucocytes were significantly lower, while the hemoglobin level was significantly higher in the observation group than in the control group (P<0.05). A total of 124 HSP patients (99.2%) in the observation group had a full recovery or improvement, and the overall cure rate and improvement rate showed no significant differences between two groups (P>0.05). Only 2.4% of the patients (3 cases) in the observation group had recurrent attack during follow-up, which was significantly lower than that in the control group (16.7%; P<0.05). CONCLUSIONS: Childhood HSP on the Tibetan Plateau shows partial differences in disease characteristics, clinical manifestations, and laboratory measurements compared with that in the plain area. The overall prognosis is better and the recurrent rate is lower among HSP children on the Tibetan Plateau. PMID- 25523572 TI - [Effects of r-hGH replacement therapy on glucose and lipid metabolism and thyroid function in children with idiopathic short stature]. AB - OBJECTIVE: To study the effects of recombinant human growth hormone (r-hGH) replacement therapy on glucose and lipid metabolism and thyroid function in children with idiopathic short stature (ISS). METHODS: Forty-seven ISS children with a mean age of 10+/-3 years treated between January 2009 and January 2013 were enrolled. All children underwent r-hGH replacement therapy for 3-24 months and were followed up once every 3 months. Fasting blood glucose (FBG), insulin (INS), blood lipids and thyroid function were measured before treatment and after 0-1 and 1-2 years of treatment. RESULTS: After treatment with r-hGH, there were no significant changes in FBG, INS, insulin sensitivity index (ISI), and FBG/INS ratio (FGIR), but the FGIR showed a declining trend. The percentage of patients with FGIR<7 (a marker of insulin resistance) was 13% before treatment compared to 18% 1-2 years after treatment. The atherosclerosis index decreased after r-hGH treatment, but there were no significant changes in total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and BMI. Furthermore, no significant change in thyroid function was observed after r-hGH therapy. CONCLUSIONS: r-hGH therapy can improve lipid metabolism, without significant impacts on thyroid function, FBG and INS. It seems to be a safe and reliable therapy for children with ISS. However, this therapy possibly reduces insulin sensitivity. PMID- 25523573 TI - [Serum cytokine levels in children with newly diagnosed active systemic juvenile idiopathic arthritis]. AB - OBJECTIVE: To study the changes in serum cytokines levels in children with newly diagnosed active systemic juvenile idiopathic arthritis (SJIA) and to explore the role of cytokines in the development and progression of SJIA. METHODS: Seventy four pediatric patients with active SJIA between January 2010 and December 2013 were included in the study. Serum levels of interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukine-10 (IL-10), tumor necrosis factor (TNF), and interferon gamma (IFN-gamma) were measured by flow cytometry in these patients. The levels of cytokines were also determined in 202 healthy children as the control group. Routine laboratory parameters including white blood cell (WBC) count, percentage of neutrophils, hemoglobin level, platelet count, hypersensitive C-reactive protein (hs-CRP), and erythrocyte sedimentation rate (ESR) were monitored in the patient group. RESULTS: The WBC count, percentage of neutrophils, hs-CRP, and ESR in 74 cases of SJIA were significantly above the normal range, their platelet counts were within the normal range, whereas hemoglobin levels were below the normal range. Compared with the control group, the patient group showed a significantly increased level of IL-6 (P<0.01) and significantly reduced levels of IL-4, IL-10, and TNF (P<0.01). However, there were no significant changes in serum levels of IL-2 and IFN-gamma in the patient group (P>0.05). In SJIA children, IL-6 level, which was significantly elevated, was negatively correlated with hemoglobin level, which was significantly reduced (r=-0.244, P<0.05). CONCLUSIONS: Serum level of IL-6 is significantly increased in children with SJIA, and it has a negative correlation with anemia. PMID- 25523574 TI - [Clinical value of minimal residual disease detection by flow cytometry in childhood B-cell acute lymphoblastic leukemia]. AB - OBJECTIVE: To elevate the prognostic value of minimal residual disease (MRD) detection by four-color flow cytometry with the antibody panel in childhood B cell acute lymphoblastic leukemia (B-ALL). METHODS: The clinical data of 183 children with newly-diagnosed acute B-ALL and who accepted MRD detection between October 2010 and March 2012 was retrospectively reviewed. According to the detection time and result of MRD, the 183 children were classified into four groups: MRD negative (n=37) and positive (n=18) in the induction chemotherapy and MRD negative (n=113) and positive (n=15) in the maintenance chemotherapy. RESULTS: During both induction and maintenance chemotherapy, the percentage of patients at high and median risk in the MRD positive group was higher than in the MRD positive group (P<0.05). In the maintenance chemotherapy group, the 3- year cumulative incidence of relapse in MRD positive patients was higher than negative patients (P=0.04). The Cox's proportional hazards regression analysis showed that insensitive reaction for prednisone (RR=1.005, 95%CI: 0.864-1.170, P=0.032), bone marrow morphology that did not meet M1 on the 15th day (RR=6.454, 95%CI: 2.191 19.01, P=0.002) and MRD>=0.01% (RR=1.923, 95%CI: 0.750-4.933, P=0.043) were risk factors for relapse in children with B-ALL. CONCLUSIONS: The four-color flow cytometry with the antibody panel can distinguish from MRD positive patients from negative patients with B-ALL. The result of MRD detection, as prednisone sensitivity and bone marrow morphology on the 15th day, is also a independent prognostic factor in children with B-ALL. PMID- 25523575 TI - [Short-term prognostic factors in children with acute liver failure]. AB - OBJECTIVE: To investigate the factors that influence the short-term (6 months) prognosis in children with acute liver failure. METHODS: The clinical information of 53 children with acute liver failure treated between June 2008 and September 2013 was retrospectively analyzed. The patients were divided into survival group (n=21) and death group (n=32) according to their outcomes. The liver function parameters and incidence of complications were compared between the two groups, and multivariate logistic regression analysis was used to identify major factors affecting the short-term prognosis in these patients. RESULTS: There were significant differences between the death and survival groups in the indices of international normalized ratio (INR), blood ammonia and serum albumin (Alb), and complications such as hepatic encephalopathy, gastrointestinal hemorrhage, and multiple organ failure (P<0.05). Multivariate logistic regression analysis demonstrated that serum Alb, INR, and hepatic encephalopathy were the major factors affecting the short-term prognosis of acute liver failure (OR=0.616, 75.493 and 1210.727 respectively; P<0.05). CONCLUSIONS: INR, hepatic encephalopathy and serum Alb are the major factors that influence the short-term prognosis in children with acute liver failure. PMID- 25523576 TI - [Incidence of accident proneness and its influencing factors in rural children]. AB - OBJECTIVE: To investigate the incidence of accident proneness and its influencing factors in rural children. METHODS: By random cluster sampling, 1 560 children were enrolled from one rural area in Hunan Province, China, and were surveyed with self-designed general and injury questionnaires. Unconditional multivariate logistic regression analysis was used to explore the major risk factors for accident-prone children. RESULTS: One hundred and forty-seven accident-prone children were screened out and the incidence of accident proneness was 9.42%. Univariate analysis showed that gender (P<0.01), academic record (P<0.01), left behind status (P<0.05), family type (P<0.05), family economic status (P<0.01), guardian's gender (P<0.05), guardian's marital status (P<0.05), guardian's occupation (P<0.05), and family educational mode (P<0.05) were influencing factors for accident proneness in rural children. Multivariate logistic regression analysis further revealed that low grade (OR=3.683, 95%CI: 1.028 4.283) and very low grade (OR=2.099, 95% CI: 1.587-8.546) in academic record, poverty in family economic status (OR=2.353, 95% CI: 1.222-4.533), and indulgence or indifference (OR=1.914, 95% CI: 1.029-3.559) and fickleness (OR=4.153, 95% CI: 1.847-9.338) in guardian's educational mode were risk factors for accident proneness in rural children, while female gender (OR=0.539, 95% CI: 0.369-0.788) was a protective factor. CONCLUSIONS: Low academic record, poor family economy, and incorrect family education mode (indulgence or indifference and fickleness) would increase the incidence of accident proneness in rural children, but girls have less accident proneness than boys. PMID- 25523577 TI - [Effect of perinatal recurrent infection on the brain development in immature mice]. AB - OBJECTIVE: To study the effects of perinatal recurrent infection on the brain development in immature mice. METHODS: Six pregnant C57BL6 mice were randomly assigned to three groups: intrauterine infection, perinatal recurrent infection and control. The intrauterine infection group was intraperitoneally injected with LPS (0.5 mg/kg) on the 18th day of pregnancy. The perinatal recurrent infection group was injected with LPS (0.5 mg/kg) on the 18th day of pregnancy and their offsprings were intraperitoneally injected with the same dose of LPS daily from postnatal day 3 to 12. The control group was administered with normal saline at the same time points as the recurrent infection group. The short-time neurobehaviors were assessed on postnatal day 13. The mice were then sacrificed to measure brain weights and neuropathological changes using cresyl violet staining. Western blot was used to evaluate the expression of TNF-alpha, Caspase 3 and myelin basic protein (MBP). RESULTS: The brain weights of the recurrent infection group were significantly lower than the control and intrauterine infection groups (P<0.05) and the recurrent infection group displayed significant neuropathological changes. Perinatal recurrent infection resulted in increased expression levels of TNF-alpha and Caspase-3, and decreased expression level of MBP compared with the intrauterine infection and control groups (P<0.01). The neurobehavior test showed that the recurrent infection group used longer time in gait reflex, right reflex and geotaxis reflex compared with the control and intrauterine infection groups on postnatal day 13 (P<0.05). CONCLUSIONS: Perinatal recurrent infection may exacerbate inflammatory response and cell death in the immature brain, which may be one of the important factors for perinatal brain injury. PMID- 25523578 TI - [Effect of dexamethasone on osteopontin expression in the lung tissue of asthmatic mice]. AB - OBJECTIVE: To study the correlation between airway inflammation and osteopontin (OPN) level in the lung tissue, and to study the effect of dexamethasone (DXM) on OPN expression. METHODS: Fifty mice were randomly divided into 5 groups: normal control, ovalbumin (OVA)-challenged asthma groups (OVA inhalation for 1 week or 2 weeks) and DXM-treated asthma groups (DXM treatment for 1 week or 2 weeks). The mice were sensitized and challenged with OVA to prepare mouse model of acute asthma. Alterations of airway inflammation were observed by haematoxylin-eosin staining. Serum level of OVA-sIgE was evaluated using ELISA. OPN expression in the lung tissue was located and measured by immunohistochemistry and Western blot respectively. OPN mRNA level in the lung tissue was detected by real-time PCR. RESULTS: The asthma groups showed more pathological changes in the airway than the normal control and the DXM-treated groups. Compared with the OVA-challenged 1 week group, the pathological alterations increased in the OVA-challenged 2 weeks group. The level of OVA-sIgE in serum increased in the asthma groups compared with the control and the DXM groups (P<0.01). Serum OVA-sIgE sevel increased more significantly in the OVA-challenged 2 weeks group compared with the OVA challenged 1 week group (P<0.01). OPN protein and mRNA levels were significantly raised in the asthma groups compared with the normal control and the DXM groups (P<0.01), and both levels increased more significantly in the OVA-challenged 2 weeks group compared with the OVA-challenged 1 week group (P<0.01). CONCLUSIONS: The increased OPN expression in the lung tissue is associated with more severe airway inflammation in asthmatic mice, suggesting that OPN may play an important role in the pathogenesis of asthma. DXM can alleviate airway inflammation possibly by inhibiting OPN production. PMID- 25523579 TI - [A modified culture method for astrocytes from rat cortical tissue in vitro]. AB - OBJECTIVE: To evaluate the efficiency of a modified culture method for rat cerebral cortical astrocytes in vitro. METHODS: The astrocytes derived from the cerebral cortex of 3-day-old Sprague-Dawley rats were first purified as described previously, then the cells were replanted at a low density. The culture flask was changed after 1 hour and substratum was replaced after 24 hours. Cells were syncretized to a monolayer, followed by cell passage. After three passages the cells were cultured in DMEM medium containing 10% fetal serum for a long period. The derivation of the cells was identified by immunofluorescent staining with anti-GFAP polyclonal antibodies. RESULTS: A variety of morphologically distinct astrocytes with many long processes and small cell bodies were obtained. Finally an astrocytic network occurred through cellular process connections. The immunofluorescent staining demonstrated the percentage of GFAP-positive cells was above 98%. CONCLUSIONS: The modified culture method for astrocytes from rat cerebral tissue is reliable, with a high purity. The cultured astrocytes have a similar morphological development to those in vivo. PMID- 25523580 TI - [Clinical features of onychomadesis following hand-foot-mouth disease in children]. PMID- 25523581 TI - [Diagnosis of Wolf-Hirschhorn syndrome by array-comparative genomic hybridization in an infant]. PMID- 25523582 TI - [A case report of congenital esophageal stenosis owing to ectopic tracheobronchial remnants]. PMID- 25523583 TI - [A case report of giardia lamblia and EB virus associated hemophagocytic syndrome]. PMID- 25523584 TI - [Diagnosis and treatment of myocarditis]. AB - Myocarditis is a focal or diffuse inflammatory process of the myocardium. Along with the deepening of research, there are new technological advances which are useful to the diagnosis and treatment of myocarditis. Cardiovascular magnetic resonance imaging has become a useful noninvasive imaging tool for diagnosis of myocarditis, but does not replace endomyocardial biopsy. The supportive treatment has remained the mainstay of therapy for patients with myocarditis, especially with fulminant myocarditis, including the comprehensive treatment of shock, heart failure, and arrhythmia. Due to the lack of large clinical data, diagnosis and treatment for myocarditis remains to be further explored. PMID- 25523585 TI - [Research advances in immunological dysfunction in children with autism spectrum disorders]. AB - Autism spectrum disorders (ASD) are a group of neuro-developmental disorders in early childhood which are defined by social difficulties, communication deficits and repetitive or restrictive interests and behaviours. The etiology of ASD remains poorly understood. Much research has shown that children with ASD suffer from immunological dysfunction. This article reviews the current research progress on immunological dysfunction in children with ASD, including abnormalities in immune cells, antibodies, complements, cytokines, major histocompatibility complex and their potential association with ASD, and explores the impacts of maternal immunological activation on the immune dysfunction of children with ASD. PMID- 25523586 TI - Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies. AB - Targeted therapies of malignancies currently consist of therapeutic monoclonal antibodies and small molecule kinase inhibitors. The combination of these novel agents raises the issue of potential antagonisms. We evaluated the potential effect of 4 kinase inhibitors, including the Bruton tyrosine kinase inhibitor ibrutinib, and 3 PI3K inhibitors idelalisib, NVP-BEZ235 and LY294002, on the effects of the 3 monoclonal antibodies, rituximab and obinutuzumab (directed against CD20) and trastuzumab (directed against HER2). We found that ibrutinib potently inhibits antibody-dependent cell-mediated cytotoxicity exerted by all antibodies, with a 50% inhibitory concentration of 0.2 microM for trastuzumab, 0.5 microM for rituximab and 2 microM for obinutuzumab, suggesting a lesser effect in combination with obinutuzumab than with rituximab. The 4 kinase inhibitors were found to inhibit phagocytosis by fresh human neutrophils, as well as antibody-dependent cellular phagocytosis induced by the 3 antibodies. Conversely co-administration of ibrutinib with rituximab, obinutuzumab or trastuzumab did not demonstrate any inhibitory effect of ibrutinib in vivo in murine xenograft models. In conclusion, some kinase inhibitors, in particular, ibrutinib, are likely to exert inhibitory effects on innate immune cells. However, these effects do not compromise the antitumor activity of monoclonal antibodies in vivo in the models that were evaluated. PMID- 25523587 TI - Characterizing the location of spinal and vertebral levels in the human cervical spinal cord. AB - BACKGROUND AND PURPOSE: Advanced MR imaging techniques are critical to understanding the pathophysiology of conditions involving the spinal cord. We provide a novel, quantitative solution to map vertebral and spinal cord levels accounting for anatomic variability within the human spinal cord. For the first time, we report a population distribution of the segmental anatomy of the cervical spinal cord that has direct implications for the interpretation of advanced imaging studies most often conducted across groups of subjects. MATERIALS AND METHODS: Twenty healthy volunteers underwent a T2-weighted, 3T MRI of the cervical spinal cord. Two experts marked the C3-C8 cervical nerve rootlets, C3-C7 vertebral bodies, and pontomedullary junction. A semiautomated algorithm was used to locate the centerline of the spinal cord and measure rostral-caudal distances from a fixed point in the brain stem, the pontomedullary junction, to each of the spinal rootlets and vertebral bodies. Distances to each location were compared across subjects. Six volunteers had 2 additional scans in neck flexion and extension to measure the effects of patient positioning in the scanner. RESULTS: We demonstrated that substantial variation exists in the rostral-caudal position of spinal cord segments among individuals and that prior methods of predicting spinal segments are imprecise. We also show that neck flexion or extension has little effect on the relative location of vertebral versus-spinal levels. CONCLUSIONS: Accounting for spinal level variation is lacking in existing imaging studies. Future studies should account for this variation for accurate interpretation of the neuroanatomic origin of acquired MR signals. PMID- 25523588 TI - Assessing Blood Flow in an Intracranial Stent: A Feasibility Study of MR Angiography Using a Silent Scan after Stent-Assisted Coil Embolization for Anterior Circulation Aneurysms. AB - BACKGROUND AND PURPOSE: Blood flow in an intracranial stent cannot be visualized with 3D time-of-flight MR angiography owing to magnetic susceptibility and radiofrequency shielding. As a novel follow-up tool after stent-assisted coil embolization, we applied MRA by using a Silent Scan algorithm that contains an ultrashort TE combined with an arterial spin-labeling technique (Silent MRA). The purpose of this study was to determine whether Silent MRA could visualize flow in an intracranial stent placed in the anterior circulation. MATERIALS AND METHODS: Nine patients treated with stent-assisted coil embolization for anterior circulation aneurysms underwent MRAs (Silent MRA and TOF MRA) and x-ray digital subtraction angiography. MRAs were performed in the same session on a 3T unit. Two neuroradiologists independently reviewed the MRA images and subjectively scored flow in a stent as 1 (not visible) to 4 (excellent) by referring to the latest x-ray digital subtraction angiography image as a criterion standard. RESULTS: Both observers gave MRA higher scores than TOF MRA for flow in a stent in all cases. The mean score for Silent MRA was 3.44 +/- 0.53, and for TOF MRA, it was 1.44 +/- 0.46 (P < .001). CONCLUSIONS: Silent MRA was able to visualize flow in an intracranial stent more effectively than TOF MRA. Silent MRA might be useful for follow-up imaging after stent-assisted coil embolization, though these study results may be only preliminary due to some limitations. PMID- 25523589 TI - Strategies of collateral blood flow assessment in ischemic stroke: prediction of the follow-up infarct volume in conventional and dynamic CTA. AB - BACKGROUND AND PURPOSE: Collateral blood flow is an important prognostic marker in the acute stroke situation but approaches for assessment vary widely. Our aim was to compare strategies of collateral blood flow assessment in dynamic and conventional CTA in their ability to predict the follow-up infarction volume. MATERIALS AND METHODS: We retrospectively included all patients with an M1 occlusion from an existing cohort of 1912 consecutive patients who underwent initial multimodal stroke CT and follow-up MR imaging or nonenhanced CT. Collateralization was assessed in both conventional CT angiography and dynamic CT angiography by using 3 different collateral grading scores and segmentation of the volume of hypoattenuation. Arterial, arteriovenous, and venous phases were reconstructed for dynamic CT angiography, and all collateral scores and the volume of hypoattenuation were individually assessed for all phases. Different grading systems were compared by using the Bayesian information criterion calculated for multivariate regression analyses (Bayesian information criterion difference = 2-6, "positive"; Bayesian information criterion difference = 6-10, "strong"; Bayesian information criterion difference = >10, "very strong"). RESULTS: One hundred thirty-six patients (mean age, 70.4 years; male sex, 41.2%) were included. In the multivariate analysis, models containing the volume of hypoattenuation showed a significantly better model fit than models containing any of the 3 collateral grading scores in conventional CT angiography (Bayesian information criterion difference = >10) and dynamic CT angiography (Bayesian information criterion difference = >10). All grading systems showed the best model fit in the arteriovenous phase. For the volume of hypoattenuation, model fit was significantly higher for models containing the volume of hypoattenuation as assessed in the arteriovenous phase of dynamic CT angiography compared with the venous phase (Bayesian information criterion difference = 6.2) and the arterial phase of dynamic CT angiography (Bayesian information criterion difference = >10) and in comparison with conventional CT angiography (Bayesian information criterion difference = >10). CONCLUSIONS: The use of dynamic CT angiography within the arteriovenous phase by using quantification of the volume of hypoattenuation is the superior technique for assessment of collateralization among the tested approaches. PMID- 25523590 TI - Cerebral microbleeds: different prevalence, topography, and risk factors depending on dementia diagnosis-the Karolinska Imaging Dementia Study. AB - BACKGROUND AND PURPOSE: Cerebral microbleeds are thought to represent cerebral amyloid angiopathy when in lobar regions of the brain and hypertensive arteriopathy when in deep and infratentorial locations. By studying cerebral microbleeds, their topography, and risk factors, we aimed to gain an insight into the vascular and amyloid pathology of dementia diagnoses and increase the understanding of cerebral microbleeds in dementia. MATERIALS AND METHODS: We analyzed 1504 patients (53% women; mean age, 63 +/- 10 years; 10 different dementia diagnoses) in this study. All patients underwent MR imaging as part of the dementia investigation, and all their clinical parameters were recorded. RESULTS: Among the 1504 patients with dementia, 22% had cerebral microbleeds. Cerebral microbleed topography was predominantly lobar (P = .01) and occipital (P = .007) in Alzheimer disease. Patients with cerebral microbleeds were significantly older (P < .001), were more frequently male (P < .001), had lower cognitive scores (P = .006), and more often had hypertension (P < .001). Risk factors for cerebral microbleeds varied depending on the dementia diagnosis. Odds ratios for having cerebral microbleeds increased with the number of risk factors (hypertension, hyperlipidemia, diabetes, male sex, and age 65 and older) in the whole patient group and increased differently in the separate dementia diagnoses. CONCLUSIONS: Prevalence, topography, and risk factors of cerebral microbleeds vary depending on the dementia diagnosis and reflect the inherent pathology of different dementia diagnoses. Because cerebral microbleeds are seen as possible predictors of intracerebral hemorrhage, their increasing prevalence with an increasing number of risk factors, as shown in our study, may require taking the number of risk factors into account when deciding on anticoagulant therapy in dementia. PMID- 25523591 TI - Ultra-High-Field MR Neuroimaging. AB - At ultra-high magnetic fields, such as 7T, MR imaging can noninvasively visualize the brain in unprecedented detail and through enhanced contrast mechanisms. The increased SNR and enhanced contrast available at 7T enable higher resolution anatomic and vascular imaging. Greater spectral separation improves detection and characterization of metabolites in spectroscopic imaging. Enhanced blood oxygen level-dependent contrast affords higher resolution functional MR imaging. Ultra high-field MR imaging also facilitates imaging of nonproton nuclei such as sodium and phosphorus. These improved imaging methods may be applied to detect subtle anatomic, functional, and metabolic abnormalities associated with a wide range of neurologic disorders, including epilepsy, brain tumors, multiple sclerosis, Alzheimer disease, and psychiatric conditions. At 7T, however, physical and hardware limitations cause conventional MR imaging pulse sequences to generate artifacts, requiring specialized pulse sequences and new hardware solutions to maximize the high-field gain in signal and contrast. Practical considerations for ultra-high-field MR imaging include cost, siting, and patient experience. PMID- 25523592 TI - Extra-aneurysmal flow modification following pipeline embolization device implantation: focus on regional branches, perforators, and the parent vessel. AB - BACKGROUND AND PURPOSE: Flow-diverter technology has proved to be a safe and effective treatment for intracranial aneurysm based on the concept of flow diversion allowing parent artery and collateral preservation and aneurysm healing. We investigated the patency of covered side branches and flow modification within the parent artery following placement of the Pipeline Embolization Device in the treatment of intracranial aneurysms. MATERIALS AND METHODS: Sixty-six aneurysms in 59 patients were treated with 96 Pipeline Embolization Devices. We retrospectively reviewed imaging and clinical results during the postoperative period at 6 and 12 months to assess flow modification through the parent artery and side branches. Reperfusion syndrome was assessed by MR imaging and clinical evaluation. RESULTS: Slow flow was observed in 13 of 68 (19.1%) side branches covered by the Pipeline Embolization Device. It was reported in all cases of anterior cerebral artery coverage, in 3/5 cases of M2 MCA coverage, and in 5/34 (14.7%) cases of ophthalmic artery coverage. One territorial infarction was observed in a case of M2-MCA coverage, without arterial occlusion. One case of deep Sylvian infarct was reported in a case of coverage of MCA perforators. Two ophthalmic arteries (5.9%) were occluded, and 11 side branches (16.2%) were narrowed at 12 months' follow-up; patients remained asymptomatic. Parent vessel flow modification was responsible for 2 cases (3.4%) of reperfusion syndrome. Overall permanent morbidity and mortality rates were 5.2% and 6.9%, respectively. We did not report any permanent deficit or death in case of slow flow observed within side branches. CONCLUSIONS: After Pipeline Embolization Device placement, reperfusion syndrome was observed in 3.4%, and territorial infarction, in 3.4%. Delayed occlusion of ophthalmic arteries and delayed narrowing of arteries covered by the Pipeline Embolization Device were observed in 5.9% and 16.2%, respectively. No permanent morbidity or death was related to side branch coverage at midterm follow-up. PMID- 25523593 TI - Detection of calcifications in retinoblastoma using gradient-echo MR imaging sequences: comparative study between in vivo MR imaging and ex vivo high resolution CT. AB - BACKGROUND AND PURPOSE: Intratumoral calcifications are very important in the diagnosis of retinoblastoma. Although CT is considered superior in detecting calcification, its ionizing radiation, especially in patients with hereditary retinoblastoma, should be avoided. The purpose of our study was to validate T2*WI for the detection of calcification in retinoblastoma with ex vivo CT as the criterion standard. MATERIALS AND METHODS: Twenty-two consecutive patients with retinoblastoma (mean age, 21 months; range, 1-71 months) with enucleation as primary treatment were imaged at 1.5T by using a dedicated surface coil. Signal intensity voids indicating calcification on T2*WI were compared with ex vivo high resolution CT, and correlation was scored by 2 independent observers as poor, good, or excellent. Other parameters included the shape and location of the signal-intensity voids. In 5 tumors, susceptibility-weighted images were evaluated. RESULTS: All calcifications visible on high-resolution CT could be matched with signal-intensity voids on T2*WI, and correlation was scored as excellent in 17 (77%) and good in 5 (23%) eyes. In total, 93% (25/27) of the signal-intensity voids inside the tumor correlated with calcifications compared with none (0/8) of the signal-intensity voids outside the tumor. Areas of nodular signal-intensity voids correlated with calcifications in 92% (24/26), and linear signal-intensity voids correlated with hemorrhage in 67% (6/9) of cases. The correlation of signal-intensity voids on SWI was better in 4 of 5 tumors compared with T2*WI. CONCLUSIONS: Signal-intensity voids on in vivo T2*WI correlate well with calcifications on ex vivo high-resolution CT in retinoblastoma. Gradient echo sequences may be helpful in the differential diagnosis of retinoblastoma. The combination of funduscopy, sonography, and high-resolution MR imaging with gradient-echo sequences should become the standard diagnostic approach for retinoblastoma. PMID- 25523594 TI - Microglia in the tumor microenvironment: taking their TOLL on glioma biology. PMID- 25523595 TI - Influence of pedal cadence on the respiratory compensation point and its relation to critical power. AB - It is not known if the respiratory compensation point (RCP) is a distinct work rate (Watts (W)) or metabolic rate V(O2) and if the RCP is mechanistically related to critical power (CP). To examine these relationships, 10 collegiate men athletes performed cycling incremental and constant-power tests at 60 and 100 rpm to determine RCP and CP. RCP work rate was significantly (p<=0.05) lower for 100 than 60 rpm (197+/-24 W vs. 222+/-24 W), while RCP V(O2) was not significantly different (3.00+/-0.33 l min(-1) vs. 3.12+/-0.41 l min(-1)). CP at 60 rpm (214+/ 51 W; V(O2): 3.01+/-0.69 l min(-1)) and 100 rpm (196+/-46 W; V(O2): 2.95+/-0.54 l min(-1)) were not significantly different from RCP. However, RCP and CP were not significantly correlated. These findings demonstrate that RCP represents a distinct metabolic rate, which can be achieved at different power outputs, but that RCP and CP are not equivalent parameters and should not, therefore, be used synonymously. PMID- 25523596 TI - Should aldosterone suppression tests be conducted during a particular phase of the menstrual cycle, and, if so, which phase? Results of a preliminary study. AB - BACKGROUND: As renin and aldosterone levels vary during the menstrual cycle, and are critical criteria for interpretation of aldosterone suppression tests to confirm or exclude primary aldosteronism, outcome of testing may vary depending on the menstrual cycle phase. We assessed the effect of timing within the menstrual cycle on levels of renin, aldosterone and female sex steroids during fludrocortisone suppression testing (FST). METHODS: In 22 women undergoing FST who experienced regular menstrual cycles, renin (measured as both plasma renin activity and direct renin concentration), aldosterone (mass spectrometry) and cortisol, progesterone, oestradiol, LH and FSH (immunoassay) levels were compared, relative to phase of cycle. Aldosterone levels were compared to those in age-matched males undergoing FST. RESULTS: Progesterone (P < 0.0001) and aldosterone (P = 0.006) levels were higher in nine women (after one of 10 was excluded with anovulatory cycle) studied during the luteal phase than in the 12 studied during the follicular phase. All studied during the luteal phase had positive FST, and all three with negative FST were studied during the follicular phase. There were no significant differences in other parameters measured except FSH, which was higher (P = 0.02) during the follicular phase. Aldosterone was higher (P = 0.01) in women studied in the luteal (but not follicular) phase compared to men. CONCLUSION: The menstrual cycle may affect the outcome of FST and other suppression testing used to diagnose primary aldosteronism. Larger patient numbers and preferably restudy of the same patient in both phases should clarify this and determine the optimum time in the cycle for testing. PMID- 25523597 TI - Evaluating the efficiency of humic acid to remove micro-organisms from denture base material. AB - OBJECTIVE: To evaluate the efficiency of humic acid substances on removing micro organisms from denture base materials. BACKGROUND: Old denture wearer needs effective, easy-use and safe denture-cleaning material. MATERIAL AND METHODS: Square-shaped, heat-polymerised acrylic resin specimens (n = 550) were prepared and divided into five groups (n = 110 for each) corresponding to the microbial contamination (Candida albicans, Staphylococcus aureus, Bacillus cereus, Enterococcus faecalis, Pseudomonas aeruginosa). Contaminated specimens were randomly assigned to the application of five different denture-cleaning agents as follows (n = 20 for each): Kloroben, Corsodyl, Steradent, Corega, experimental solution with humic acid. Ten specimens were assessed as an experimental control carried out simultaneously for the treatment groups for each micro-organism. It was divided into two groups: negative control and positive control (n = 5 for each). All acrylic specimens were incubated 37 degrees C for 24 h (for bacterial strains) and 37 degrees C for 48 h (for yeast strains). After incubation period, all brain-heart infusion broths (BHI) which contain disinfectant acrylic specimens were cultured on 5% sheep blood agar (for bacteria) and Sabouraud dextrose agar (SDA) for yeast using loop. The numbers of colony-forming units per millilitre (CFU/ml) were calculated. The results were analysed by Mann-Whitney U test and Kruskal-Wallis tests (p = 0.05). RESULTS: Corsodyl and Kloroben completely eliminated the adherence of all investigated micro-organisms (100%) and showed the highest removal activity compared with other cleaning agents (p < 0.05). There was no statistically significant difference between Corsodyl and Kloroben (p >= 0.05), and there was no statistically significant difference between Corega, Steradent and experimental solution (p >= 0.05). CONCLUSION: Humic acid could be used as an alternative 'natural' solution for denture cleaning agent. PMID- 25523598 TI - Effect of panax notoginseng saponins injection on the p38MAPK pathway in lung tissue in a rat model of hypoxic pulmonary hypertension. AB - OBJECTIVE: To investigate the effect of panax notoginseng saponins (PNS) injection on pulmonary artery pressure and the expression of p38MAPK in lung tissue of rats subjected to chronic hypoxia. METHODS: Thirty adult male Sprague Dawley rats were randomly divided into three groups (ten in each group): rats in control group were exposed to normoxic condition and the rats in hypoxia group and PNS group were subjected to 4-week hypoxia, and PNS injection (50 mg . kg(-1) . d(-1)) was administrated intraperitoneally at 30 min in the PNS group daily before the rats were kept in the hypoxic chamber, while rats in the other two groups received equal dose of normal saline instead. After chronic hypoxia, mean pulmonary artery pressure (mPAP) and mean carotid artery pressure (mCAP) were measured. The heart and lung tissues were harvested, and right ventricle (RV) and left ventricle plus ventricular septum (LV+S) were weighed to calculate the ratio of RV/(LV+S). The expression of p38MAPK mRNA was determined by reverse transcription-polymerase chain reaction, the quantity of phosphorylated p38MAPK (p-p38MAPK) in rat lung tissues and pulmonary arterioles was determined by Western blot and immunohistochemistry. RESULTS: Compared with the control group, mPAP and the ratio of RV/(LV+S) in the hypoxia group were increased, the expression of p-p38MAPK in pulmonary arterioles and p38MAPK mRNA in the lung were higher (P<0.05). The changes of these parameters in the hypoxia group were significantly attenuated by PNS treatment (P<0.05). CONCLUSION: PNS injection was shown to prevent hypoxic pulmonary hypertension at least partly by regulating p38MAPK pathway. PMID- 25523599 TI - Circulating levels of inflammatory cytokines in patients with psoriasis vulgaris of different Chinese medicine syndromes. AB - OBJECTIVE: To investigate whether the serum levels of inflammation-related cytokines might be different between the healthy individuals and the psoriatic patients diagnosed of three varied Chinese medicine (CM) syndromes [blood-stasis syndrome (BSS), blood-dryness syndrome (BDS) and wind-heat syndrome (WHS)]. METHODS: A total of 62 psoriatic patients were recruited and assigned to 3 groups according to their CM syndromes, including 27 patients of BSS, 21 of BDS and 14 of WHS. Another 20 sex- and age-matched healthy subjects were enrolled into the control group. Serum concentrations of multiple cytokines, including monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1alpha (MIP 1alpha), soluble CD4O ligand (SCD40L), tumor necrosis factor-alpha (TNF-alpha), epidermal growth factor (EGF), interleukin-8 (IL-8), interleukin-17 (IL-17), interferon gamma inducible protein-10 (IP-10) and vascular endothelial growth factor (VEGF), were measured by a multiplexed flow cytometric assay. RESULTS: The circulating levels of MIP-1alpha, TNF-alpha, IL-8, and IP-10 were significantly increased in the psoriatic patients compared with the healthy controls (P<0.01). Male and female patients tended to have higher serum levels of MCP-1 and IP-10, respectively (P<0.05). Interestingly, compared with the control group, 6 out of the 9 cytokines (MCP-1, MIP-1alpha, TNF-alpha, EGF, IL-8 and IP-10) were substantially increased in the BSS group (P<0.05 or P<0.01), whereas only MIP 1alpha and IL-8 levels were elevated in the BDS group (P<0.05 or P<0.01) concurrent with lowered concentrations of SCD40L and IL-17 (P<0.05). In the WHS group, MIP-1alpha was the only cytokine whose level was evidently increased (P<0.01), in contrast to IL-17 which was decreased as compared with the control (P<0.05). The psoriatic patients overall owned higher levels of MIP-1alpha and IL 8 in the circulation which were comparable among the 3 groups of CM syndromes (P<0.01). In contrast, TNF-alpha level of the BSS group was the highest among the three (P<0.01), followed by the BDS and the WHS groups. CONCLUSIONS: The expression profiles of cytokines in the circulation might not be necessarily identical for psoriatic patients with different CM syndromes. Accordingly, the serum concentrations of certain cytokines could potentially be used as the ancillary indices for the clinical classification of psoriatic CM syndromes. PMID- 25523600 TI - Understanding interactions between Chinese medicines and pharmaceutical drugs in integrative healthcare. AB - In the 21st century, the public are more informed, mainly via the Internet, about health and medical products and have become more knowledgeable about matters relating to their health conditions and well-being in curing and preventing illnesses. They often self-medicate themselves with various health products and over-the-counter (OTC) medicines apart from prescribed pharmaceutical drugs (PD). Some of those non-prescribed products may have doubtful quality control and contain harmful additives or unchecked ingredients; thus their usefulness is in doubt. The increasing popularity world-wide of using Chinese medicines (CM) and related OTC functional products has raised concerns over their concomitant use with PD and the consequential adverse effects. In most cases the alleged causes of adverse effects are linked with herbal sources, although the authorised information on the interactions between CM-PD is not plentiful in the literature. There is an urgent need for such a data base. The future professionals in health and medical care should be knowledgeable or aware of what their patients have been taking or given. In actual practice the patients may receive both treatments intentionally or unintentionally, with or without the awareness of the practitioner. In these situations a reliable database for interactions between CM PD will be extremely useful for consultation when treatment problems appear or during emergency situations. Their combining of medications may be involved with possible outcomes of adverse reactions or beneficial effects. Such a database will be welcomed by both practitioners of herbal medicines and orthodox medicine practitioners in the emerging trend of integrative medicine. The author has been involved in various research projects of basic and clinical aspects in mainly CM among other herbal and PD. Examples will be given largely on those related to these disciplines as illustrations in this overview. PMID- 25523601 TI - Effect of Yanggyuksanhwa-tang on non-insulin-dependent diabetes mellitus unresponsive to oral hypoglycemic agents: a case report. PMID- 25523602 TI - Incidence rates of tuberculosis in chronic hepatitis C infected patients with or without interferon based therapy: a population-based cohort study in Taiwan. AB - BACKGROUND: It is debated whether interferon-based therapy (IBT) would affect the incidence of active tuberculosis (TB) among hepatitis C virus (HCV) infected patients. Although some case reports have demonstrated a possible association, the results are currently inconclusive. Therefore, we conducted a nation-wide population study to investigate the incidence of active TB in HCV infected patients receiving IBT in Taiwan. METHODS: This 9-year cohort study was based on the Longitudinal Health Insurance Database 2000 (LHID 2000) consisting of 1,000,000 beneficiaries randomly selected from all Taiwan National Health Insurance enrollees in 2000 ( >23.7 million). This insurance program covers all citizens in Taiwan. We conducted a retrospective cohort study that identified subjects with HCV infection. IBTs were defined as regimens that included interferon alpha, peginterferon alpha2a and peginterferon alpha2b for at least 2 months. Among them, 621 subjects received IBT, and 2,460 age- and gender-matched subjects were enrolled for analysis. The Cox proportional hazards models were used to estimate the hazard ratio (HR) for active TB, and associated confidence intervals (CIs), comparing IBT cohort and untreated cohort. The endpoint in this study was whether an enrolled subject had a new diagnosis of active TB. RESULTS: During the 9-year enrollment period, the treated and untreated cohorts were followed for a mean (+/- SD) duration of 6.97 +/- 0.02 years and 8.21 +/- 0.01 years, respectively. The cumulative incidence rate of active TB during this study period was 0.150 and 0.151 per 100 person-years in the IBT treated and untreated cohorts, respectively. There was no significant difference in the incidence of active TB in either cohort during a 1-year follow-up (Adjusted Hazard Ratio (AHR): 2.81, 95% Confidence Interval (95% CI): 0.61-12.98) or the long-term follow-up (AHR: 1.02, 95% CI: 0.28-3.78). The Cox proportional hazards model demonstrated that IBT was not a risk factor for active TB . The only risk factor for active TB was the occurrence of hepatic encephalopathy. CONCLUSION: Our results showed that IBT is associated with increased hazard of active TB in HCV infected patients in 1-year follow-up; however, the effect sizes were not statistically significant. PMID- 25523603 TI - Orderly packed anodes for high-power lithium-ion batteries with super-long cycle life: rational design of MnCO3/large-area graphene composites. AB - MnCO3 particles uniformly distributed on large-area graphene form 2D composites whose large-area character enables them to self-assemble face-to-face into orderly packed electrodes. Such regular structures form continuous and efficient transport networks, leading to outstanding lithium storage with high capacity, ultralong cycle life, and excellent rate capability--all characteristics that are required for high-power lithium-ion batteries. PMID- 25523605 TI - US Senate confirms Obama's choice for surgeon general. PMID- 25523604 TI - Clinical effect of locally delivered gel containing green tea extract as an adjunct to non-surgical periodontal treatment. AB - Green tea catechins had an in vitro antibacterial effect against periodontopathic bacteria and were able to inhibit destruction of the periodontal tissue. In this study, we aimed to evaluate the effect of locally delivered gel containing green tea extract as an adjunct to non-surgical periodontal treatment. Forty-eight subjects who had teeth with probing pocket depth of 5-10 mm were randomly allocated into the test or control group. Probing pocket depth, clinical attachment level, gingival index (GI), bleeding on probing (BOP) and full mouth plaque score were measured at baseline. Subjects received oral hygiene instruction, single episode of scaling and root planing and subgingival application of the green tea gel (test group) or the placebo gel (control group). The gel was repeatedly applied at 1 and 2 weeks later. The parameters were recorded again at the 1st, 3rd and 6th month after the last gel application. The results showed that all parameters were improved in both groups compared to baseline. The test group exhibited significantly higher reduction in BOP at the 3rd month (p = 0.003) and significantly lower GI at the 1st month (p < 0.001) and 3rd month (p < 0.001) when compared with the control group. Thus, green tea gel could provide a superior benefit in reducing bleeding on probing and gingival inflammation when used as an adjunct to non-surgical periodontal treatment. ( TRIAL REGISTRATION: MU-IRB 2008/153.0511, ClinicalTrials.gov NCT00918060). PMID- 25523606 TI - Blood group B gene is barely expressed in in vitro erythroid culture of Bm derived CD34+ cells without an erythroid cell-specific regulatory element. AB - BACKGROUND AND OBJECTIVES: Previously, a weak phenotype Am or Bm was assumed to be caused by a reduction of A or B gene expression in bone marrow cells, but not in mucus-secreting cells. However, ABO expression has not been examined in erythroid progenitor cells of Am or Bm individuals. MATERIALS AND METHODS: We carried out in vitro erythroid differentiation of CD34(+) cells from peripheral blood of a Bm individual harbouring a 3.0-kb deletion including an erythroid cell specific regulatory element, named the +5.8-kb site, in intron 1 of the human ABO blood group gene. RESULTS: During the in vitro differentiation of CD34(+) cells from this Bm individual into erythroid cells, B-antigens were not detectable on the cultured cells by flow cytometric analysis, and allele-specific RT-PCR consistently detected the transcripts from the O allele, but not from the B allele. Moreover, chromatin immunoprecipitation assay demonstrated that both RUNX1 and GATA-2 or GATA-1 were bound to the +5.8-kb site in cultured erythroid cells expressing ABO. CONCLUSION: It is likely that the +5.8-kb site enhances transcription from the ABO promoter in erythroid cells through binding of RUNX1 and GATA-2 or GATA-1. PMID- 25523607 TI - Inductively coupled wireless RF coil arrays. AB - As the number of coils increases in multi-channel MRI receiver-coil arrays, RF cables and connectors become increasingly bulky and heavy, degrading patient comfort and slowing workflow. Inductive coupling of signals provides an attractive "wireless" approach, with the potential to reduce coil weight and cost while simplifying patient setup. In this work, multi-channel inductively coupled anterior arrays were developed and characterized for 1.5T imaging. These comprised MR receiver coils inductively (or "wirelessly") linked to secondary or "sniffer" coils whose outputs were transmitted via preamps to the MR system cabinet. The induced currents in the imaging coils were blocked by passive diode circuits during RF transmit. The imaging arrays were totally passive, obviating the need to deliver power to the coils, and providing lightweight, untethered signal reception with easily positioned coils. Single-shot fast spin echo images were acquired from 5 volunteers using a 7-element inductively coupled coil array and a conventionally cabled 7-element coil array of identical geometry, with the inductively-coupled array showing a relative signal-to-noise ratio of 0.86 +/- 0.07. The concept was extended to a larger 9-element coil array to demonstrate the effect of coil element size on signal transfer and RF-transmit blocking. PMID- 25523608 TI - Undetected intraocular metallic foreign body causing hyphema in a patient undergoing MRI: a rare occurrence demonstrating the limitations of pre-MRI safety screening. AB - The case reported is of a 47-year-old man with an undetected ferromagnetic metallic intraocular foreign body in the right eye who underwent elective MR examinations for chronic neck and low back pain. The patient underwent the MR scans and subsequently developed blurred vision in his right eye caused by a hyphema associated with an anterior chamber metallic foreign body. Case reports of orbital injuries in patients with intraocular metallic foreign bodies undergoing MRI are rare, with only one prior report in the radiology literature. While the incidence of intraocular foreign bodies causing injury in patients undergoing MRI is likely rare even among patients with foreign bodies, this case demonstrates that complications from an IMFB can potentially have a subtle presentation. Our case also illustrates potential limitations of pre-MRI safety questionnaires, particularly pertaining to a patient's understanding of the thoroughness of foreign body removal. PMID- 25523609 TI - A new technique with high reproducibility to estimate renal oxygenation using BOLD-MRI in chronic kidney disease. AB - OBJECTIVES: To assess inter-observer variability of renal blood oxygenation level dependent MRI (BOLD-MRI) using a new method of analysis, called the concentric objects (CO) technique, in comparison with the classical ROI (region of interest) based technique. METHODS: MR imaging (3T) was performed before and after furosemide in 10 chronic kidney disease (CKD) patients (mean eGFR 43+/ 24ml/min/1.73m(2)) and 10 healthy volunteers (eGFR 101+/-28ml/min1.73m(2)), and R2* maps were determined on four coronal slices. In the CO-technique, R2* values were based on a semi-automatic procedure that divided each kidney in six equal layers, whereas in the ROI-technique, all circles (ROIs) were placed manually in the cortex and medulla. The mean R2*values as assessed by two independent investigators were compared. RESULTS: With the CO-technique, inter-observer variability was 0.7%-1.9% across all layers in non-CKD, versus 1.6%-3.8% in CKD. With the ROI-technique, median variability for cortical and medullary R2* values was 3.6 and 6.8% in non-CKD, versus 4.7 and 12.5% in CKD; similar results were observed after furosemide. CONCLUSION: The CO-technique offers a new, investigator-independent, highly reproducible alternative to the ROI-based technique to estimate renal tissue oxygenation in CKD. PMID- 25523610 TI - In-situ visual observation for the formation and dissociation of methane hydrates in porous media by magnetic resonance imaging. AB - In this work, magnetic resonance imaging (MRI) was employed to observe the in situ formation and dissociation of methane hydrates in porous media. Methane hydrate was formed in a high-pressure cell with controlled temperature, and then the hydrate was dissociated by thermal injection. The process was photographed by the MRI, and the pressure was recorded. The images confirmed that the direct visual observation was achieved; these were then employed to provide detailed information of the nucleation, growth, and decomposition of the hydrate. Moreover, the saturation of methane hydrate during the dissociation was obtained from the MRI intensity data. Our results showed that the hydrate saturation initially decreased rapidly, and then slowed down; this finding is in line with predictions based only on pressure. The study clearly showed that MRI is a useful technique to investigate the process of methane hydrate formation and dissociation in porous media. PMID- 25523611 TI - [Change of therapy from ranibizumab to aflibercept for recurrent or persistent exudative age-related macular degeneration]. AB - BACKGROUND: Even during consistent anti-vascular endothelial growth factor (VEGF) therapy a reactivation of exudative age-related macular degeneration (AMD) lesions can be observed in many patients. The present case series examined whether a switch from ranibizumab to aflibercept is safe and whether differences in potency can be observed. PATIENTS AND METHODS: In 56 consecutive patients with recurrent activity of AMD according to the morphological criteria of the spectral domain optical coherence tomography (SD-OCT) examination, a change to aflibercept was made after 6-41 (mean 18.9, SD 6.3) injections with ranibizumab. In all controls and before each injection logMAR visual acuity was measured and a SD-OCT (volume scan) was performed in addition to the clinical examination. RESULTS: The mean visual acuity was stable under both therapies. The analysis of the morphological parameters showed a greater reduction of the retinal thickness after the change in therapy (mean retinal thickness within 1000 MUm and central foveal thickness) compared to the initial treatment. The changes in the subretinal fluid as well as the height of an associated pigment epithelial detachment (PED) did not show any significant differences. The analysis of the morphological parameters at the level of the photoreceptors showed a decrease in discontinuity in the ellipsoid layer and also in the external limiting membrane (ELM). CONCLUSION: In patients with recurrent or high SD-OCT-based activity of exudative AMD lesions, a switch of the treatment strategy from ranibizumab to aflibercept can achieve a new functional stability in spite of multiple pretreatment. We found morphological indications of a regression of intraretinal edema and improvement in the photoreceptor area. In the context of a well-defined treatment strategy, a switch from anti-VEGF therapy to a similar active substance is safe. Before a definitive evaluation can be made, prospective controlled conditions are required to verify the clinical benefits of the switch. PMID- 25523613 TI - The relationship between housing and heat wave resilience in older people. AB - Older people have justifiably been highlighted as a high-risk group with respect to heat wave mortality and morbidity. However, there are older people living within the community who have developed adaptive and resilient environments around their home that provide some protection during periods of extreme heat. This study investigated the housing stock and self-reported thermal comfort of a group of older people living in a regional town in Australia during the summer of 2012. The results indicated that daily maximum living room temperature was not significantly correlated with outdoor temperature, and daily minimum living room temperature was very weakly correlated with outdoor temperature. Residents reported feeling comfortable when indoor temperature approximated 26 degrees C. As living room temperature increased, indoor thermal comfort decreased. Significant differences between indoor temperatures were noted for homes that were related to house characteristics such as the age of the house, the number of air-conditioning units, the pitch of the roof, home insulation and the number of heat-mitigation modifications made to the home. Brick veneer homes showed smaller diurnal changes in temperature than other building materials. With population ageing and the increasing focus on older people living in the community, the quality of the housing stock available to them will influence their risk of heat exposure during extreme weather. PMID- 25523612 TI - The protective effect of p16(INK4a) in oral cavity carcinomas: p16(Ink4A) dampens tumor invasion-integrated analysis of expression and kinomics pathways. AB - A large body of evidence shows that p16(INK4a) overexpression predicts improved survival and increased radiosensitivity in HPV-mediated oropharyngeal squamous cell carcinomas.(OPSCC). Here we demonstrate that the presence of transcriptionally active HPV16 in oral cavity squamous cell carcinomas does not correlate with p16(INK4a) overexpression, enhanced local tumor immunity, or improved outcome. It is interesting that HPV-mediated oropharyngeal squamous cell carcinomas can be categorized as having a 'nonaggressive' invasion phenotype, whereas aggressive invasion phenotypes are more common in HPV-negative squamous cell carcinomas. We have developed primary cancer cell lines from resections with known pattern of invasion as determined by our validated risk model. Given that cell lines derived from HPV-mediated oropharyngeal squamous cell carcinomas are less invasive than their HPV-negative counterparts, we tested the hypothesis that viral oncoproteins E6, E7, and p16(INK4a) can affect tumor invasion. Here we demonstrate that p16(INK4a) overexpression in two cancer cell lines (UAB-3 and UAB-4), derived from oral cavity squamous cell carcinomas with the most aggressive invasive phenotype (worst pattern of invasion type 5 (WPOI-5)), dramatically decreases tumor invasiveness by altering expression of extracellular matrix remodeling genes. Pathway analysis integrating changes in RNA expression and kinase activities reveals different potential p16(INK4a)-sensitive pathways. Overexpressing p16(INK4a) in UAB-3 increases EGFR activity and increases MMP1 and MMP3 expression, possibly through STAT3 activation. Overexpressing p16(INK4a) in UAB-4 decreases PDGFR gene expression and reduces MMP1 and MMP3, possibly through STAT3 inactivation. Alternatively, ZAP70/Syk might increase MUC1 phosphorylation, leading to the observed decreased MMP1 expression. PMID- 25523614 TI - A strain-absorbing design for tissue-machine interfaces using a tunable adhesive gel. AB - To measure electrophysiological signals from the human body, it is essential to establish stable, gentle and nonallergic contacts between the targeted biological tissue and the electrical probes. However, it is difficult to form a stable interface between the two for long periods, especially when the surface of the biological tissue is wet and/or the tissue exhibits motion. Here we resolve this difficulty by designing and fabricating smart, stress-absorbing electronic devices that can adhere to wet and complex tissue surfaces and allow for reliable, long-term measurements of vital signals. We demonstrate a multielectrode array, which can be attached to the surface of a rat heart, resulting in good conformal contact for more than 3 h. Furthermore, we demonstrate arrays of highly sensitive, stretchable strain sensors using a similar design. Ultra-flexible electronics with enhanced adhesion to tissue could enable future applications in chronic in vivo monitoring of biological signals. PMID- 25523615 TI - Peri-conception parental obesity, reproductive health, and transgenerational impacts. AB - Maternal over-nutrition during pregnancy is a risk factor for pregnancy complications and is increasingly associated with adverse childhood outcomes such as increased propensity for obesity and metabolic disease. However, there is emerging evidence that parental lifestyle factors prior to and at conception have a powerful impact on the health of the offspring for more than one generation. Maternal and paternal obesity prior to conception alters the molecular composition of both oocytes and sperm, which can partly escape epigenetic reprogramming at fertilization, altering the developmental trajectory of the resultant embryo, ultimately increasing the incidence of obesity and metabolic disorders in offspring. Understanding the molecular underpinning of these changes may help create interventions to reduce the risk of disease in future generations. PMID- 25523617 TI - Sex differences in normal age trajectories of functional brain networks. AB - Resting-state functional magnetic resonance image (rs-fMRI) is increasingly used to study functional brain networks. Nevertheless, variability in these networks due to factors such as sex and aging is not fully understood. This study explored sex differences in normal age trajectories of resting-state networks (RSNs) using a novel voxel-wise measure of functional connectivity, the intrinsic connectivity distribution (ICD). Males and females showed differential patterns of changing connectivity in large-scale RSNs during normal aging from early adulthood to late middle-age. In some networks, such as the default-mode network, males and females both showed decreases in connectivity with age, albeit at different rates. In other networks, such as the fronto-parietal network, males and females showed divergent connectivity trajectories with age. Main effects of sex and age were found in many of the same regions showing sex-related differences in aging. Finally, these sex differences in aging trajectories were robust to choice of preprocessing strategy, such as global signal regression. Our findings resolve some discrepancies in the literature, especially with respect to the trajectory of connectivity in the default mode, which can be explained by our observed interactions between sex and aging. Overall, results indicate that RSNs show different aging trajectories for males and females. Characterizing effects of sex and age on RSNs are critical first steps in understanding the functional organization of the human brain. PMID- 25523616 TI - Quantification of global cerebral atrophy in multiple sclerosis from 3T MRI using SPM: the role of misclassification errors. AB - PURPOSE: We tested the validity of a freely available segmentation pipeline to measure compartmental brain volumes from 3T MRI in patients with multiple sclerosis (MS). Our primary focus was methodological to explore the effect of segmentation corrections on the clinical relevance of the output metrics. METHODS: Three-dimensional T1-weighted images were acquired to compare 61 MS patients to 30 age- and gender-matched normal controls (NC). We also tested the within patient MRI relationship to disability (eg, expanded disability status scale [EDSS] score) and cognition. Statistical parametric mapping v. 8 (SPM8) derived gray matter (GMF), white matter (WMF), and total brain parenchyma fractions (BPF) were derived before and after correcting errors from T1 hypointense MS lesions and/or ineffective deep GM contouring. RESULTS: MS patients had lower GMF and BPF as compared to NC (P<.05). Cognitively impaired patients had lower BPF than cognitively preserved patients (P<.05). BPF was related to EDSS; BPF and GMF were related to disease duration (all P<.05). Errors caused bias in GMFs and WMFs but had no discernable influence on BPFs or any MRI clinical associations. CONCLUSIONS: We report the validity of a segmentation pipeline for the detection of MS-related brain atrophy with 3T MRI. Longitudinal studies are warranted to extend these results. PMID- 25523618 TI - Human mesenchymal stem cells/multipotent stromal cells consume accumulated autophagosomes early in differentiation. AB - INTRODUCTION: Bone marrow mesenchymal stem cells/multipotent stromal cells (MSCs) are recruited to sites of injury and subsequently support regeneration through differentiation or paracrine activity. During periods of stress such as wound site implant or differentiation, MSCs are subjected to a variety of stressors that might activate pathways to improve cell survival and generate energy. In this study, we monitored MSC autophagy in response to the process of differentiation. METHODS: MSC autophagosome structures were observed by using transmission electron microscopy and a tandem green fluorescent protein-red fluorescent protein autophagic flux reporter to monitor the mammalian microtubule associated protein-1 light chain 3 (LC3) turnover in real time. MSCs were differentiated by using standard osteogenic and adipogenic media, and autophagy was examined during short-term and long-term differentiation via immunoblots for LC3I and II. Autophagy was modulated during differentiation by using rapamycin and bafilomycin treatments to disrupt the autophagosome balance during the early stages of the differentiation process, and differentiation was monitored in the long term by using Von Kossa and Oil Red O staining as well as quantitative polymerase chain reaction analysis of typical differentiation markers. RESULTS: We found that undifferentiated MSCs showed an accumulation of a large number of undegraded autophagic vacuoles, with little autophagic turnover. Stimulation of autophagy with rapamycin led to rapid degradation of these autophagosomes and greatly increased rough endoplasmic reticulum size. Upon induction of osteogenic differentiation, MSC expression of LC3II, a common autophagosome marker, was lost within 12 hours, consistent with increased turnover. However, during adipogenic differentiation, drug treatment to alter the autophagosome balance during early differentiation led to changes in differentiation efficiency, with inhibited adipocyte formation following rapamycin treatment and accelerated fat accumulation following autophagosome blockade by bafilomycin. CONCLUSIONS: Our findings suggest that MSCs exist in a state of arrested autophagy with high autophagosome accumulation and are poised to rapidly undergo autophagic degradation. This phenotype is highly sensitive, and a balance of autophagy appears to be key in efficient MSC differentiation and function, as evidenced by our results implicating autophagic flux in early osteogenesis and adipogenesis. PMID- 25523619 TI - Special AT-rich sequence-binding protein 2 suppresses invadopodia formation in HCT116 cells via palladin inhibition. AB - Invadopodia are specialized actin-based microdomains of the plasma membrane that combine adhesive properties with matrix degrading activities. Proper functioning of the bone, immune, and vascular systems depend on these organelles, and their relevance in cancer cells is linked to tumor metastasis. The elucidation of the mechanisms driving invadopodia formation is a prerequisite to understanding their role and ultimately to controlling their functions. Special AT-rich sequence binding protein 2 (SATB2) was reported to suppress tumor cell migration and metastasis. However, the mechanism of action of SATB2 is unknown. Here, we show that SATB2 inhibits invadopodia formation in HCT116 cells and that the molecular scaffold palladin is inhibited by exogenous expression of SATB2. To confirm this association, we elucidated the function of palladin in HCT116 using a knock down strategy. Palladin knock down reduced cell migration and invasion and inhibited invadopodia formation. This phenotype was confirmed by a rescue experiment. We then demonstrated that palladin expression in SATB2-expressing cells restored invasion and invadopodia formation. Our results showed that SATB2 action is mediated by palladin inhibition and the SATB2/palladin pathway is associated with invadopodia formation in colorectal cancer cells. PMID- 25523620 TI - Characterization of the sebocyte lipid droplet proteome reveals novel potential regulators of sebaceous lipogenesis. AB - Lipid metabolism depends on lipid droplets (LD), cytoplasmic structures surrounded by a protein-rich phospholipid monolayer. Although lipid synthesis is the hallmark of sebaceous gland cell differentiation, the LD-associated proteins of sebocytes have not been evaluated systematically. The LD fraction of SZ95 sebocytes was collected by density gradient centrifugation and associated proteins were analyzed by nanoliquid chromatography/tandem mass spectrometry. 54 proteins were significantly enriched in LD fractions, and 6 of them have not been detected previously in LDs. LD fractions contained high levels of typical LD associated proteins as PLIN2/PLIN3, and most proteins belonged to functional categories characteristic for LD-associated proteins, indicating a reliable dataset. After confirming expression of transcripts encoding the six previously unidentified proteins by qRT-PCR in SZ95 sebocytes and in another sebocyte line (SebE6E7), we focused on two of these proteins, ALDH1A3 and EPHX4. While EPHX4 was localized almost exclusively on the surface of LDs, ALDH1A3 showed a more widespread localization that included additional cytoplasmic structures. siRNA mediated downregulation revealed that depletion of EPHX4 increases LD size and sebaceous lipogenesis. Further studies on the roles of these proteins in sebocyte physiology and sebaceous lipogenesis may indicate novel strategies for the therapy of sebaceous gland-associated diseases such as acne. PMID- 25523621 TI - Using qualitative methods in developing an instrument to identify barriers to self-care among persons with type 2 diabetes mellitus. AB - AIMS AND OBJECTIVES: To develop a questionnaire to address barriers and self-care behaviour among persons with type 2 diabetes mellitus. BACKGROUND: Several instruments are available in the literature to measure barriers to self-care in this population, but many of them present limitations in its psychometric validation process, and lack of theoretical background. DESIGN: Content validation study using multiple qualitative methods. METHODS: A systematic review was conducted, and two focus groups with fifteen participants (n = 15) were analysed to identify key topics and categories concerning barriers and self-care behaviour. These categories were used to generate items that were subjected to expert scrutiny, using the Delphi technique. The resulting list of items was tested for readability and comprehension by nine diabetic patients (n = 9), through cognitive interviews. The whole process was conducted in accordance with the Theory of Planned Behaviour. RESULTS: The mean age (standard deviation) of participants in the focus groups and cognitive interviews was 66.05 (8.47) and 63.11 (6.13) years, respectively. 46.7% of the members of the focus groups and 44.4% of those interviewed were female, and the mean duration (standard deviation) of their diabetes was 6.53 (3.17) and 4.89 (3.84) years, respectively. After the qualitative analysis, 27 codes were obtained. Thereafter, items were generated in accordance with the dimensions of this theory: attitudes towards the behaviour (n = 23), social norms (n = 13), perceived behavioural control (n = 17) and behavioural intention (n = 15). CONCLUSIONS: A rigorous process of content validation with multiple methods was implemented to obtain an instrument aimed at addressing barriers and self-care behaviour of patients with type 2 Diabetes Mellitus. RELEVANCE TO CLINICAL PRACTICE: An instrument theoretically rooted and supported on professional and patients' views is available to assess self-care behaviours in patients with type 2 Diabetes Mellitus. The evaluation of its reliability and construct validity will determine the instrument's value and practical application in the clinical context. PMID- 25523622 TI - Automated genomic context analysis and experimental validation platform for discovery of prokaryote transcriptional regulator functions. AB - BACKGROUND: The clustering of genes in a pathway and the co-location of functionally related genes is widely recognized in prokaryotes. We used these characteristics to predict the metabolic involvement for a Transcriptional Regulator (TR) of unknown function, identified and confirmed its biological activity. RESULTS: A software tool that identifies the genes encoded within a defined genomic neighborhood for the subject TR and its homologs was developed. The output lists of genes in the genetic neighborhoods, their annotated functions, the reactants/products, and identifies the metabolic pathway in which the encoded-proteins function. When a set of TRs of known function was analyzed, we observed that their homologs frequently had conserved genomic neighborhoods that co-located the metabolically related genes regulated by the subject TR. We postulate that TR effectors are metabolites in the identified pathways; indeed the known effectors were present. We analyzed Bxe_B3018 from Burkholderia xenovorans, a TR of unknown function and predicted that this TR was related to the glycine, threonine and serine degradation. We tested the binding of metabolites in these pathways and for those that bound, their ability to modulate TR binding to its specific DNA operator sequence. Using rtPCR, we confirmed that methylglyoxal was an effector of Bxe_3018. CONCLUSION: These studies provide the proof of concept and validation of a systematic approach to the discovery of the biological activity for proteins of unknown function, in this case a TR. Bxe_B3018 is a methylglyoxal responsive TR that controls the expression of an operon composed of a putative efflux system. PMID- 25523623 TI - Autophagy in the posterior interosseous nerve of patients with type 1 and type 2 diabetes mellitus: an ultrastructural study. AB - AIMS/HYPOTHESIS: We addressed the question of whether the autophagy pathway occurs in human peripheral nerves and whether this pathway is associated with peripheral neuropathy in diabetes mellitus. METHODS: By using electron microscopy, we evaluated the presence of autophagy-related structures and neuropathy in the posterior interosseous nerve of patients who had undergone carpal tunnel release and had type 1 or type 2 diabetes mellitus, and in patients with no diabetes (controls). RESULTS: Autophagy-related ultrastructures were observed in the samples taken from all patients of the three groups. The number of autophagy-associated structures was significantly higher (p < 0.05) in the nerves of patients with type 1 than type 2 diabetes. Qualitative and quantitative evaluations of fascicle area, diameter of myelinated and unmyelinated nerve fibres, the density of myelinated and unmyelinated fibres and the g-ratio of myelinated fibres were performed. We found degeneration and regeneration of a few myelinated axons in controls, and a well-developed neuropathy with the loss of large myelinated axons and the presence of many small ones in patients with diabetes. The pathology in type 1 diabetes was more extensive than in type 2 diabetes. CONCLUSIONS/INTERPRETATION: The results of this study show that the human peripheral nerves have access to the autophagy machinery, and this pathway may be regulated differently in type 1 and type 2 diabetes; insulin, presence of extensive neuropathy, and/or other factors such as duration of diabetes and HbA1c level may underlie this differential regulation. PMID- 25523624 TI - Temperature impacts on deep-sea biodiversity. AB - Temperature is considered to be a fundamental factor controlling biodiversity in marine ecosystems, but precisely what role temperature plays in modulating diversity is still not clear. The deep ocean, lacking light and in situ photosynthetic primary production, is an ideal model system to test the effects of temperature changes on biodiversity. Here we synthesize current knowledge on temperature-diversity relationships in the deep sea. Our results from both present and past deep-sea assemblages suggest that, when a wide range of deep-sea bottom-water temperatures is considered, a unimodal relationship exists between temperature and diversity (that may be right skewed). It is possible that temperature is important only when at relatively high and low levels but does not play a major role in the intermediate temperature range. Possible mechanisms explaining the temperature-biodiversity relationship include the physiological tolerance hypothesis, the metabolic hypothesis, island biogeography theory, or some combination of these. The possible unimodal relationship discussed here may allow us to identify tipping points at which on-going global change and deep water warming may increase or decrease deep-sea biodiversity. Predicted changes in deep-sea temperatures due to human-induced climate change may have more adverse consequences than expected considering the sensitivity of deep-sea ecosystems to temperature changes. PMID- 25523625 TI - Distribution and feeding habitat characterization of whale sharks Rhincodon typus in a protected area in the north Caribbean Sea. AB - The relationship between the distribution of the whale shark Rhincodon typus and hydrobiological variables in the Caribbean Sea during 2005-2009 was analysed. Monthly trips were made to the R. typus aggregation area during the months when this species is present in the region (May to September) to record sightings and hydrological data and to collect samples to determine nutrients, chlorophyll a (Chl a) and zooplankton biomass. A total of 2104 R. typus were counted and three zones of high abundance were identified: Cabo-Catoche, Contoy (both within the Whale Shark Biosphere Reserve, WSBR) and the zone knows as Afuera. The zones of greatest R. typus density within the WSBR were characterized by high Chl a concentrations (median: 1.1 mg m-3 , interpercentile range: 0.5-1.8 mg m-3 ) and high nutrient concentrations, such as ammonium (median: 2.5 umol l-1 , interpercentile range: 0.5-6.4 umol l-1 ), due to the influence of local upwelling. A generalized additive model (GAM) was used to explore the relationship between R. typus distribution and the environmental variables inside WSBR. Zooplankton biomass was the most influential environmental variable, supporting the close relationship between R. typus distribution and biological productivity. Copepods were the dominant zooplankton group within the WSBR. In the Afuera zone, there were large R. typus aggregations (>80 individuals) associated with zooplankton dominated by fish eggs and significantly higher mean +/- s.d. biomass (3356.1 +/- 1960.8 mg m-3 ) compared with that recorded inside the WSBR (103.5 +/- 57.2 mg m-3 ). The differences among zones generated changes in R. typus distribution patterns and provided opportunities to develop local management strategies for this species. PMID- 25523626 TI - Relative risk of lung obstruction in relation to PM10 concentration as assessed by pulmonary function tests. AB - Epidemiological studies show that long-term exposure to air pollution may increase the relative risk of obstructive lung diseases such as COPD or asthma. The risk of increased obstruction is higher among residents living in close proximity to high traffic routes where there are high concentrations of PM(10). The present study consists of two parts: the measurement of the concentration of air pollutants and of pulmonary function in selected groups of people. The study was conducted in Warsaw, Poland, in seven localizations with typical urban canyon characteristics and roads with high traffic. The control group consisted of people living in other regions of Poland with a significantly lower (p < 0.05) concentration of air pollutants. The study was performed in the years 2008-2012. The incidence of obstructive lung disease was determined according to the GOLD guidelines. The study subjects were all non-smokers. The relative risk of disease took into account different exposure times to air pollutants. The findings indicate that an increase in PM(10) concentration by each 10 MUg/m(3) caused an increase in the relative risk of lung obstruction by a factor of 1.27, 1.24, and 1.19 for the residence period in the vicinity to heavy traffic city roads for 20, 30, and 40 years, respectively as compared with the residence of rural unpolluted areas. A decrease in the number of people with lung obstruction with the length of residence actually indicates that people exposed to high concentrations of PM(10) become affected by lung obstruction at a lower age. The study shows a positive relative risk of lung obstruction due to an exposure to high PM(10) emission. PMID- 25523627 TI - Diagnostic performance of different pleural fluid biomarkers in tuberculous pleurisy. AB - Due to the paucibacillary nature of tuberculous pleural effusion the diagnosis of pleural tuberculosis is challenging. This prospective study was undertaken to evaluate the diagnostic performance of ten different pleural fluid biomarkers in the differentiation between tuberculous and non-tuberculous pleural effusions. Two hundred and three patients with pleural effusion (117 men and 86 women, median age 65 years) were enrolled. Routine diagnostic work-up, including thoracentesis and pleural fluid analysis, was performed to determine the cause of pleural effusion. The following biomarkers were measured in pleural fluid: adenosine deaminase (ADA), interferon gamma (IFN-gamma), interleukin 2 soluble receptor (IL-2sRalpha), sub-unit p40 of interleukin 12b (IL-12p40), interleukin 18 (IL-18), interleukin 23 (IL-23), IFN-gamma induced protein 10 kDa (IP-10), Fas ligand, human macrophage-derived chemokine (MDC) and tumor necrosis factor alfa (TNF-alpha). There were 44 (21.7%) patients with tuberculous pleural effusion, 88 (43.3%) patients with malignant pleural effusion, 35 (17.2%) with parapneumonic effusion/pleural empyema, 30 (14.8%) with pleural transudates, and 6 (3%) with miscellaneous underlying diseases. Pleural fluid IFN-gamma was found the most accurate marker differentiating tuberculous from non-tuberculous pleural effusion, with sensitivity, specificity, PPV, NPV, and AUC 97%, 98%, 95.5%, 99.4%, and 0.99, respectively. Two other biomarkers (IP-10 and Fas ligand) also showed very high diagnostic accuracy with AUC>=0.95. AUC for ADA was 0.92. We conclude that IFN-gamma, IP-10, and Fas-ligand in pleural fluid are highly accurate biomarkers differentiating tuberculous from non-tuberculous pleural effusion. PMID- 25523628 TI - Recall and recognition hypermnesia for Socratic stimuli. AB - In two experiments, we investigate hypermnesia, net memory improvements with repeated testing of the same material after a single study trial. In the first experiment, we found hypermnesia across three trials for the recall of word solutions to Socratic stimuli (dictionary-like definitions of concepts) replicating Erdelyi, Buschke, and Finkelstein and, for the first time using these materials, for their recognition. In the second experiment, we had two "yes/no" recognition groups, a Socratic stimuli group presented with concrete and abstract verbal materials and a word-only control group. Using signal detection measures, we found hypermnesia for concrete Socratic stimuli-and stable performance for abstract stimuli across three recognition tests. The control group showed memory decrements across tests. We interpret these findings with the alternative retrieval pathways (ARP) hypothesis, contrasting it with alternative theories of hypermnesia, such as depth of processing, generation and retrieve-recognise. We conclude that recognition hypermnesia for concrete Socratic stimuli is a reliable phenomenon, which we found in two experiments involving both forced-choice and yes/no recognition procedures. PMID- 25523629 TI - A reply to: The transferability of diatoms to clothing and the methods appropriate for their collection and analysis in forensic geoscience, Forensic Sci. Int. 241 (2014) 127-137. PMID- 25523630 TI - Divergent evolutionary rates in vertebrate and mammalian specific conserved non coding elements (CNEs) in echolocating mammals. AB - BACKGROUND: The majority of DNA contained within vertebrate genomes is non coding, with a certain proportion of this thought to play regulatory roles during development. Conserved Non-coding Elements (CNEs) are an abundant group of putative regulatory sequences that are highly conserved across divergent groups and thus assumed to be under strong selective constraint. Many CNEs may contain regulatory factor binding sites, and their frequent spatial association with key developmental genes - such as those regulating sensory system development - suggests crucial roles in regulating gene expression and cellular patterning. Yet surprisingly little is known about the molecular evolution of CNEs across diverse mammalian taxa or their role in specific phenotypic adaptations. We examined 3,110 vertebrate-specific and ~82,000 mammalian-specific CNEs across 19 and 9 mammalian orders respectively, and tested for changes in the rate of evolution of CNEs located in the proximity of genes underlying the development or functioning of auditory systems. As we focused on CNEs putatively associated with genes underlying the development/functioning of auditory systems, we incorporated echolocating taxa in our dataset because of their highly specialised and derived auditory systems. RESULTS: Phylogenetic reconstructions of concatenated CNEs broadly recovered accepted mammal relationships despite high levels of sequence conservation. We found that CNE substitution rates were highest in rodents and lowest in primates, consistent with previous findings. Comparisons of CNE substitution rates from several genomic regions containing genes linked to auditory system development and hearing revealed differences between echolocating and non-echolocating taxa. Wider taxonomic sampling of four CNEs associated with the homeobox genes Hmx2 and Hmx3 - which are required for inner ear development - revealed family-wise variation across diverse bat species. Specifically within one family of echolocating bats that utilise frequency-modulated echolocation calls varying widely in frequency and intensity high levels of sequence divergence were found. CONCLUSIONS: Levels of selective constraint acting on CNEs differed both across genomic locations and taxa, with observed variation in substitution rates of CNEs among bat species. More work is needed to determine whether this variation can be linked to echolocation, and wider taxonomic sampling is necessary to fully document levels of conservation in CNEs across diverse taxa. PMID- 25523631 TI - MicroRNA-196a promotes an oncogenic effect in head and neck cancer cells by suppressing annexin A1 and enhancing radioresistance. AB - Radiotherapy is a major treatment modality for head and neck squamous cell carcinoma (HNSCC). Up to 50% of patients with locally advanced disease relapse after radical treatment and there is therefore a need to develop predictive bomarkers for clinical use that allow the selection of patients who are likely to respond. MicroRNA (miRNA) expression profiling of a panel of HNSCC tumours with and without recurrent disease after surgery and radiotherapy detected miR-196a as one of the highest upregulated miRNAs in the poor prognostic group. To further study the role of miR-196a, its expression was determined in eight head and neck cancer cell lines. Overexpression of miR-196a in HNSCC cells, with low endogenous miR-196a expression, significantly increased cell proliferation, migration and invasion, and induced epithelial to mesenchymal transition. Conversely, miR-196a knockdown in cells with high endogenous expression levels significantly reduced oncogenic behaviour. Importantly, overexpression of miR-196a increased radioresistance of cells as measured by gamma H2AX staining and MTT survival assay. Annexin A1 (ANXA1), a known target of miR-196a, was found to be directly modulated by miR-196a as measured by luciferase assay and confirmed by Western blot analysis. ANXA1 knockdown in HNSCC exhibited similar phenotypic effects to miR-196a overexpression, suggesting the oncogenic effect of miR-196a may at least be partly regulated through suppression of ANXA1. In conclusion, this study identifies miR-196a as a potential important biomarker of prognosis and response of HNSCC to radiotherapy. Furthermore, our data suggest that miR-196a and/or its target gene ANXA1 could represent important therapeutic targets in HNSCC. PMID- 25523632 TI - Extension of the CD4+Foxp3+CD25(-/low) regulatory T-cell subpopulation in type 1 diabetes mellitus. AB - Regulatory T-cells (Treg) have a crucial role in limiting physiologic autoreactivity. Foxp3 is a master regulator transcription factor of Treg differentiation and active Treg cells express high levels of IL-2 receptor alpha chain (CD25). The aim of our study was to assess the key markers of Treg cell function in type 1 diabetic (T1DM) and control subjects by flow cytometry. The proportion of CD25(-/low) cells among CD4(+)Foxp3(+) Treg cells was higher in T1DM patients that might suggest a shifted proportion of the incomplete/reserve and the fully active (CD4(+)Foxp3(+)CD25(+)) Treg cell subpopulations in T1DM, similarly to other Th1-mediated autoimmune diseases. In addition to the decreased expression of CD25 and CTLA-4 in T1DM patients, a positive correlation was observed between the CD25 expression on CD4(+) and the CTLA-4 expression in CD8( ) T-lymphocytes both in the T1DM and in the healthy control group. Our results suggest an impaired balance of CD25(+) and CD25(-/low) Treg cells in T1DM which might reflect a decreased late phase peripheral Treg activation even in patients with a mean disease duration of more than a decade. PMID- 25523633 TI - Anagliptin and sitagliptin as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, active-controlled, phase III clinical trial with a 28-week extension. AB - We conducted a 24-week, multicentre, double-blind, randomized study with a 28 week extension to compare the efficacy and safety of anagliptin and sitagliptin as an add-on to metformin in patients with type 2 diabetes. Patients inadequately controlled on metformin were randomized to either anagliptin (100 mg twice daily, n = 92) or sitagliptin (100 mg once daily, n = 88). The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. The mean changes in HbA1c were -0.85 +/- 0.70% (p < 0.0001) for anagliptin and -0.83 +/- 0.61% (p < 0.0001) for sitagliptin, with a mean difference of -0.02% (95% confidence interval of difference, -0.22 to 0.18%). In both groups, the fasting proinsulin : insulin ratio significantly decreased from baseline, with improved insulin secretion. Safety profiles were similar in each group. In conclusion, the non inferiority of the efficacy of anagliptin to sitagliptin as an add-on therapy was established with regard to efficacy and safety. PMID- 25523634 TI - Weekly low-dose methotrexate for reduction of Global Initiative for Asthma Step 5 treatment in severe refractory asthma: study protocol for a randomized controlled trial. AB - BACKGROUND: Patients with chronic severe asthma (CSA) have a crippling disease and current available treatments are not satisfactory. Thus, management of CSA remains a major unmet need. Although the evidence from existing randomized controlled trials fails to support a definite role for immunomodulatory drugs in these patients due to major methodologic drawbacks, findings with low-dose methotrexate (MTX) are encouraging. However, larger and well-designed clinical trials are required to establish the beneficial role of MTX in CSA, and for the detection of the key characteristics of those who are going to respond to this drug. METHODS/DESIGN: Patients will be recruited from the accessible asthmatic patients lists of tertiary referral centers. All patients will meet the stringent diagnostic criteria for CSA, including the requirement for the regular use of Global Initiative for Asthma (GINA) Global Strategy for Asthma Management and Prevention Step 5 medications (oral prednisone and/or omalizumab). The experimental design of the proposed study will take the form of a double-blind parallel-randomized placebo-controlled trial consisting of a total of eight visits, including run-in and run-out periods. Patients will be randomly allocated to receive either MTX or a matched placebo once a week as an add-on therapy to their existing medication after run-in. Physiological, laboratory and clinical assessments will be measured regularly throughout the study and compared with baseline assessments. DISCUSSION: We expect that MTX will reduce Step 5 medications dosage in patients with CSA without compromising the overall disease control. Improvement in several indicators of asthma severity and control will be also investigated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02124226 (assigned 25 April 2014). PMID- 25523636 TI - Mutation analysis of MATR3 in Australian familial amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that arises from the progressive degeneration of the motor neurons. Recently, mutations in the matrin 3 (MATR3) gene were described in both ALS and autosomal dominant distal myopathy with vocal cord and pharyngeal weakness. We sought to determine the prevalence of MATR3 mutations in Australian familial ALS (n = 106) using whole exome sequencing. No mutations were identified, indicating that MATR3 mutations are not a common cause of ALS in Australian familial cases with predominately European ancestry. PMID- 25523637 TI - Phosphate-water interplay tunes amorphous calcium carbonate metastability: spontaneous phase separation and crystallization vs stabilization viewed by solid state NMR. AB - Organisms tune the metastability of amorphous calcium carbonates (ACC), often by incorporation of additives such as phosphate ions and water molecules, to serve diverse functions, such as modulating the availability of calcium reserves or constructing complex skeletal scaffolds. Although the effect of additive distribution on ACC was noted for several biogenic and synthetic systems, the molecular mechanisms by which additives govern ACC stability are not well understood. By precipitating ACC in the presence of different PO4(3-) concentrations and regulating the initial water content, we identify conditions yielding either kinetically locked or spontaneously transforming coprecipitates. Solid state NMR, supported by FTIR, XRD, and electron microscopy, define the interactions of phosphate and water within the initial amorphous matrix, showing that initially the coprecipitates are homogeneous molecular dispersions of structural water and phosphate in ACC, and a small fraction of P-rich phases. Monitoring the transformations of the homogeneous phase shows that PO4(3-) and waters are extracted first, and they phase separate, leading to solid-solid transformation of ACC to calcite; small part of ACC forms vaterite that subsequently converts to calcite. The simultaneous water-PO4(3-) extraction is the key for the subsequent water-mediated accumulation and crystallization of hydroxyapatite (HAp) and carbonated hydroxyapatite. The thermodynamic driving force for the transformations is calcite crystallization, yet it is gated by specific combinations of water-phosphate levels in the initial amorphous coprecipitates. The molecular details of the spontaneously transforming ACC and of the stabilized ACC modulated by phosphate and water at ambient conditions, provide insight into biogenic and biomimetic pathways. PMID- 25523638 TI - Juvenile neuronal ceroid lipofuscinoses (CLN3 Batten disease): what kind of epilepsy? PMID- 25523639 TI - Preparation of water-dispersible porous g-C3N4 with improved photocatalytic activity by chemical oxidation. AB - Hydrophilic treatment of bulk graphene-like carbon nitride (g-C3N4) for future applications has aroused extensive interest, due to its enhanced specific surface area and unusual electronic properties. Herein, water-dispersible g-C3N4 with a porous structure can be obtained by chemical oxidation of bulk g-C3N4 with K2Cr2O7-H2SO4. Acid oxidation results in the production of hydroxyl and carboxyl groups on its basal plane and the formation of a porous structure of g-C3N4 at the same time. The porous g-C3N4 appears as networks with tens of micrometers in width and possesses a high specific surface area of 235.2 m(2) g(-1). The final concentration of porous g-C3N4 can be up to 3 mg mL(-1). Compared with bulk g C3N4, the as-obtained porous g-C3N4 exhibits excellent water dispersion stability and shows great superiority in photoinduced charge carrier separation and transfer. The photocatalytic activities of porous g-C3N4 towards degradation of organic pollutants are much higher than those of the bulk due to the larger band gap (by 0.2 eV) and specific surface areas. PMID- 25523635 TI - Heritability and genetic association analysis of neuroimaging measures in the Diabetes Heart Study. AB - Patients with type 2 diabetes are at increased risk of age-related cognitive decline and dementia. Neuroimaging measures such as white matter lesion volume, brain volume, and fractional anisotropy may reflect the pathogenesis of these cognitive declines, and genetic factors may contribute to variability in these measures. This study examined multiple neuroimaging measures in 465 participants from 238 families with extensive genotype data in the type 2 diabetes enriched Diabetes Heart Study-Mind cohort. Heritability of these phenotypes and their association with candidate single-nucleotide polymorphisms (SNPs), and SNP data from genome- and exome-wide arrays were explored. All neuroimaging measures analyzed were significantly heritable (h(2) = 0.55-0.99 in unadjusted models). Seventeen candidate SNPs (from 16 genes/regions) associated with neuroimaging phenotypes in prior studies showed no significant evidence of association. A missense variant (rs150706952, A432V) in PLEKHG4B from the exome-wide array was significantly associated with white matter mean diffusivity (p = 3.66 * 10(-7)) and gray matter mean diffusivity (p = 2.14 * 10(-7)). This analysis suggests genetic factors contribute to variation in neuroimaging measures in a population enriched for metabolic disease and other associated comorbidities. PMID- 25523640 TI - Effects of focal mild hypothermia on thrombin-induced brain edema formation and the expression of protease activated receptor-1, matrix metalloproteinase-9 and aquaporin 4 in rats. AB - Hypothermia is an effective neuroprotective treatment for brain injury caused by intracerebral hemorrhage (ICH). It is reported to reduce brain edema and neuronal cell death. Thrombin, a coagulation protease released from blood clots, is critical in brain edema formation following ICH. Protease activated receptor-1 (PAR-1), matrix metalloproteinase-9 (MMP-9) and aquaporin 4 (AQP4) are edema associated mediators that have been implicated in ICH pathology. In the present study, thrombin was used to induce brain edema in adult male Sprague-Dawley rats. Differences between a focal mild hypothermic group (33+/-0.5C) and a normothermic group (37C) were investigated. Following hypothermia, brain water content and blood-brain barrier (BBB) disruption was assessed at 6, 24 and 48 h and subsequently at 3, 5 and 7 days. At the same time, the mRNA and protein expression of PAR-1, MMP-9 and AQP4 were also determined. It was identified that brain water content and BBB disruption increased at 6 h and reached a maximal level at 24 h in the normothermic group. The mRNA and protein expression levels of PAR-1, MMP-9 and AQP4 started to increase at 24 h and reached a maximal level at 48 h. Focal mild hypothermia tended to significantly reduce brain water content, BBB disruption and PAR-1, MMP-9 and AQP expression at 24 and 48 h. The present data suggest that focal mild hypothermia is an effective treatment for edema formation through moderation of the mRNA and protein expression of PAR-1, MMP-9 and AQP4. PMID- 25523641 TI - Coupling enrichment methods with proteomics for understanding and treating disease. AB - Owing to recent advances in proteomics analytical methods and bioinformatics capabilities there is a growing trend toward using these capabilities for the development of drugs to treat human disease, including target and drug evaluation, understanding mechanisms of drug action, and biomarker discovery. Currently, the genetic sequences of many major organisms are available, which have helped greatly in characterizing proteomes in model animal systems and humans. Through proteomics, global profiles of different disease states can be characterized (e.g. changes in types and relative levels as well as changes in PTMs such as glycosylation or phosphorylation). Although intracellular proteomics can provide a broad overview of physiology of cells and tissues, it has been difficult to quantify the low abundance proteins which can be important for understanding the diseased states and treatment progression. For this reason, there is increasing interest in coupling comparative proteomics methods with subcellular fractionation and enrichment techniques for membranes, nucleus, phosphoproteome, glycoproteome as well as low abundance serum proteins. In this review, we will provide examples of where the utilization of different proteomics coupled enrichment techniques has aided target and biomarker discovery, understanding the drug targeting mechanism, and mAb discovery. Taken together, these improvements will help to provide a better understanding of the pathophysiology of various diseases including cancer, autoimmunity, inflammation, cardiovascular disease, and neurological conditions, and in the design and development of better medicines for treating these afflictions. PMID- 25523642 TI - Effect of sustainability information on consumers' liking of freshwater prawn (Macrobrachium rosenbergii). AB - BACKGROUND: This research aimed to investigate whether consumer acceptance is affected by information on sustainable practices on the product label. Hedonic evaluations of freshwater prawns were performed by 80 consumers under three aspects: the blind condition - consumers taste samples without information; expected - without tasting samples, consumers evaluated the message 'Freshwater prawns were grown using sustainable practices, reducing environmental impacts caused by traditional breeding'; informed - in which prawns were tasted and the card evaluated. RESULTS: For the entire consumer group, it was observed that the message about sustainability on packaging increased freshwater prawn acceptability (8.25, expected condition (E) versus 6.75, blind condition (B)). High scores were observed under all three test conditions, ranging from 6 (like slightly) to 9 (like extremely), on a 9-point scale. CONCLUSION: It can be concluded that the use of sustainable information can influence consumers' perception and increase their preference toward freshwater prawns, and even increase the sensory attributes of the product. PMID- 25523643 TI - Lithium ion solvation and diffusion in bulk organic electrolytes from first principles and classical reactive molecular dynamics. AB - Lithium-ion battery performance is strongly influenced by the ionic conductivity of the electrolyte, which depends on the speed at which Li ions migrate across the cell and relates to their solvation structure. The choice of solvent can greatly impact both the solvation and diffusivity of Li ions. In this work, we used first-principles molecular dynamics to examine the solvation and diffusion of Li ions in the bulk organic solvents ethylene carbonate (EC), ethyl methyl carbonate (EMC), and a mixture of EC and EMC. We found that Li ions are solvated by either carbonyl or ether oxygen atoms of the solvents and sometimes by the PF6(-) anion. Li(+) prefers a tetrahedrally coordinated first solvation shell regardless of which species are involved, with the specific preferred solvation structure dependent on the organic solvent. In addition, we calculated Li diffusion coefficients in each electrolyte, finding slightly larger diffusivities in the linear carbonate EMC compared to the cyclic carbonate EC. The magnitude of the diffusion coefficient correlates with the strength of Li(+) solvation. Corresponding analysis for the PF6(-) anion shows greater diffusivity associated with a weakly bound, poorly defined first solvation shell. These results can be used to aid in the design of new electrolytes to improve Li-ion battery performance. PMID- 25523645 TI - Visualizing copper assisted graphene growth in nanoscale. AB - Control synthesis of high quality large-area graphene on transition metals (TMs) by chemical vapor deposition (CVD) is the most fascinating approach for practical device applications. Interaction of carbon atoms and TMs is quite critical to obtain graphene with precise layer number, crystal size and structure. Here, we reveal a solid phase reaction process to achieve Cu assisted graphene growth in nanoscale by in-situ transmission electron microscope (TEM). Significant structural transformation of amorphous carbon nanofiber (CNF) coated with Cu is observed with an applied potential in a two probe system. The coated Cu particle recrystallize and agglomerate toward the cathode with applied potential due to joule heating and large thermal gradient. Consequently, the amorphous carbon start crystallizing and forming sp(2) hybridized carbon to form graphene sheet from the tip of Cu surface. We observed structural deformation and breaking of the graphene nanoribbon with a higher applied potential, attributing to saturated current flow and induced Joule heating. The observed graphene formation in nanoscale by the in-situ TEM process can be significant to understand carbon atoms and Cu interaction. PMID- 25523644 TI - Relation of the multilocus genetic composite reflecting high dopamine signaling capacity to future increases in BMI. AB - Because food intake exerts its rewarding effect by increasing dopamine (DA) signaling in reward circuitry, it theoretically follows that individuals with a greater number of genotypes putatively associated with high DA signaling capacity are at increased risk for overeating and subsequent weight gain. We tested the association between the multilocus genetic composite risk score, defined by the total number of genotypes putatively associated with greater DA signaling capacity (i.e. TaqIA A2 allele, DRD2-141C Ins/Del and Del/Del genotypes, DRD4-S allele, DAT1-S allele, and COMT Val/Val genotype), and future increases in Body Mass Index (BMI) in three prospective studies. Participants in Study 1 (N = 30; M age = 15.2; M baseline BMI = 26.9), Study 2 (N = 34; M age = 20.9; M baseline BMI = 28.2), and Study 3 (N = 162; M age = 15.3, M baseline BMI = 20.8) provided saliva samples from which epithelial cells were collected, permitting DNA extraction. The multilocus genetic composite risk score was associated with future increases in BMI in all three studies (Study 1, r = 0.37; Study 2, r = 0.22; Study 3, r = 0.14) and the overall sample (r = 0.19). DRD4-S was associated with increases in BMI in Study 1 (r = 0.42), Study 2 (r = 0.27), and in the overall sample (r = 0.17). DAT1-S was associated with increases in BMI in Study 3 (r = 0.17) and in the overall sample (r = 0.12). There were no associations between the other genotypes (TaqIA, COMT, and DRD2-141C) and change in BMI over 2 year follow-up. Data suggest that individuals with a genetic propensity for greater DA signaling capacity are at risk for future weight gain and that combining alleles that theoretically have a similar function may provide a more reliable method of modeling genetic risk associated with future weight gain than individual genotypes. PMID- 25523646 TI - Statistical modeling of the hormetic dose zone and the toxic potency completes the quantitative description of hormetic dose responses. AB - Quantifying the characteristics of hormesis provides valuable insights into this low-dose phenomenon and helps to display and capture its variability. A prerequisite to do so is a statistical procedure allowing quantification of general hormetic features, namely the maximum stimulatory response, the dose range of hormesis, and the distance from the maximum stimulation to the dose where hormesis disappears. Applying extensions of a hormetic dose-response model that is well-established in plant biology provides a direct estimation of several quantities, except the hormetic dose range. Another dose range that is difficult to model directly is the distance between the dose where hormesis disappears and the dose giving 50% inhibition, known as toxic potency. The present study presents 2 further model extensions allowing for a direct quantification of the hormetic dose range and the toxic potency. Based on this, a 4-step mathematical modeling approach is demonstrated to quantify various dose-response quantities, to compare these quantities among treatments, and to interrelate hormesis features. Practical challenges are exemplified, and possible remedies are identified. The software code to perform the analysis is provided as Supplemental Data to simplify adoption of the modeling procedure. Because numerous patterns of hormesis are observed in various sciences, it is clear that the proposed approach cannot cope with all patterns; however, it should be possible to analyze a great range of hormesis patterns. PMID- 25523648 TI - Hair loss and Hedgehog inhibitors: a class effect? PMID- 25523647 TI - Genome engineering for improved recombinant protein expression in Escherichia coli. AB - A metabolic engineering perspective which views recombinant protein expression as a multistep pathway allows us to move beyond vector design and identify the downstream rate limiting steps in expression. In E.coli these are typically at the translational level and the supply of precursors in the form of energy, amino acids and nucleotides. Further recombinant protein production triggers a global cellular stress response which feedback inhibits both growth and product formation. Countering this requires a system level analysis followed by a rational host cell engineering to sustain expression for longer time periods. Another strategy to increase protein yields could be to divert the metabolic flux away from biomass formation and towards recombinant protein production. This would require a growth stoppage mechanism which does not affect the metabolic activity of the cell or the transcriptional or translational efficiencies. Finally cells have to be designed for efficient export to prevent buildup of proteins inside the cytoplasm and also simplify downstream processing. The rational and the high throughput strategies that can be used for the construction of such improved host cell platforms for recombinant protein expression is the focus of this review. PMID- 25523649 TI - Behaviour-modifying compounds for management of the red palm weevil (Rhynchophorus ferrugineus Oliver). AB - BACKGROUND: Populations of red palm weevil (RPW), a severe pest of palms in Mediterranean countries, might be limited by semiochemical-based behaviour disrupting methods. We evaluated the effects of electroantennogram (EAG)-active plant volatiles on the behaviour of RPWs from Italy and Israel. In field experiments, alpha-pinene, citronellol, geraniol, citral and 1-octen-3-ol were tested for their ability to disrupt attraction to pheromone-kairomone and molasses baited traps. Those that were found to be disruptive in the field were evaluated in a laboratory choice bioassay in individual cages for their effect on RPW female feeding and oviposition. RESULTS: Field experiments showed reduced captures in traps loaded with geraniol (-57%), 1-octen-3-ol (-50%) or alpha pinene (-45% to -60%); captures in citronellol- or citral-loaded traps did not differ from control. In laboratory experiments, 1-octen-3-ol was the most potent behaviour-modifying compound, eliciting a significant/marginally significant reduction in both feeding and oviposition at the lowest dose tested in both populations. Geraniol generally caused a strong reduction in feeding and oviposition at each dose tested (Israel), or at the highest dose (Italy). alpha Pinene caused some reduction in feeding activity at the highest dose tested (Italy), but no consistent repellency (Israel). CONCLUSION: Field and laboratory data suggest the potential for the use of 1-octen-3-ol, geraniol and alpha-pinene for RPW population management. PMID- 25523650 TI - Characterization of aluminum resistant Anoxybacillus sp. SK 3-4 isolated from a hot spring. AB - The Anoxybacillus sp. SK 3-4, previously isolated from a hot spring, was screened for its heavy metals resistance (Al(3+), Mn(2+), Cu(2+), Co(2+), Zn(2+), and Ni(2+)) and the strain was found to be most resistant to aluminum. Significant growth of the strain was observed when it was grown in medium containing aluminum (200 mg L(-1)-800 mg L(-1)) with relative growth rates ranging between 77% and 100%. A gene encoding the aluminum resistance protein (accession number: WP_021095658.1) was found in genome of strain SK 3-4, which revealed high sequence identity (>95%) to its homologues from Anoxybacillus species. Sequence comparisons with two functionally characterized aluminum resistance proteins, namely G2alt and ALU1-P, showed 97% and 81% of sequence identity, respectively. Four putative metal binding sites were detected in SK 3-4 aluminum resistance protein and G2alt at same amino acid residue positions of 186, 195, 198, and 201. Strain SK 3-4 was found to be able to remove aluminum from aqueous solution. This study demonstrated that Anoxybacillus sp. SK 3-4 could be applied in the treatment of aluminum contaminated wastewater. PMID- 25523651 TI - Re: ClearCode34: a prognostic risk predictor for localized clear cell renal cell carcinoma. PMID- 25523652 TI - Re: Hereditary-like urothelial carcinomas of the upper urinary tract benefit more from adjuvant cisplatin-based chemotherapy after radical nephroureterectomy than do sporadic tumours. PMID- 25523653 TI - Re: Multiparametric MRI of the bladder: ready for clinical routine? PMID- 25523654 TI - Re: Prospective evaluation of a preoperative biomarker panel for prediction of upstaging at radical cystectomy. PMID- 25523656 TI - Re: Contemporary nationwide patterns of self-reported prostate-specific antigen screening. PMID- 25523657 TI - Re: The added value of percentage of free to total prostate-specific antigen, PCA3, and a kallikrein panel to the ERSPC risk calculator for prostate cancer in prescreened men. PMID- 25523658 TI - Re: Vasectomy and risk of aggressive prostate cancer: a 24-year follow-up study. PMID- 25523659 TI - Re: Contemporary use of initial active surveillance among men in Michigan with low-risk prostate cancer. PMID- 25523660 TI - Re: Testicular cancer incidence to rise by 25% in Europe? Model-based predictions in 40 countries using population-based registry data. PMID- 25523661 TI - Re: Lateral temperature spread of monopolar, bipolar and ultrasonic instruments for robot-assisted laparoscopic surgery. PMID- 25523662 TI - Re: The humoral pattern recognition molecule PTX3 is a key component of innate immunity against urinary tract infection. PMID- 25523663 TI - Re: The influence of urinary pH on antibiotic efficacy against bacterial uropathogens. PMID- 25523664 TI - Re: Effectiveness of cranberry capsules to prevent urinary tract infections in vulnerable older persons: a double-blind randomized placebo-controlled trial in long-term care facilities. PMID- 25523665 TI - Re: Cost-effectiveness of cranberry capsules to prevent urinary tract infection in long-term care facilities: economic evaluation with a randomized controlled trial. PMID- 25523666 TI - Re: Adverse events resulting from lasers used in urology. PMID- 25523667 TI - Re: Predicting urinary stone composition based on single-energy noncontrast computed tomography: the challenge of cystine. PMID- 25523668 TI - Re: Safety, minimization, and awareness radiation training reduces fluoroscopy time during unilateral ureteroscopy. PMID- 25523669 TI - Re: One- vs 4-week stent placement after laparoscopic and robot-assisted pyeloplasty: results of a prospective randomised single-centre study. PMID- 25523670 TI - Re: Reducing postoperative venous thromboembolism complications with a standardized risk-stratified prophylaxis protocol and mobilization program. PMID- 25523671 TI - Re: Detrusor underactivity in men following radical retropubic prostatectomy- prevalence, importance and evaluation. PMID- 25523672 TI - Re: The Pharmacological rationale for combining muscarinic receptor antagonists and beta-adrenoceptor agonists in the treatment of airway and bladder disease. PMID- 25523673 TI - Re: Urodynamic studies for management of urinary incontinence in children and adults. PMID- 25523674 TI - Re: Biomarkers in lower urinary tract symptoms/overactive bladder: a critical overview. PMID- 25523675 TI - Re: Pre-operative urodynamics in women with stress urinary incontinence increases physician confidence, but does not improve outcomes. PMID- 25523676 TI - Re: Surgical intervention for symptomatic benign prostatic hyperplasia is correlated with expression of the AP-1 transcription factor network. PMID- 25523677 TI - Re: Promising molecular targets and biomarkers for male BPH and LUTS. PMID- 25523678 TI - Re: Does this man with lower urinary tract symptoms have bladder outlet obstruction? The rational clinical examination: a systematic review. PMID- 25523679 TI - Re: Extended outcomes in the treatment of male stress urinary incontinence with a transobturator sling. PMID- 25523680 TI - Re: Prostate volume correlates with diabetes in elderly benign prostatic hyperplasia patients. PMID- 25523681 TI - Re: Transplantation between monozygotic twins: how identical are they? PMID- 25523682 TI - Re: Endocrine biomarkers and symptom clusters during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study. PMID- 25523683 TI - Re: Five-year potency preservation after iodine-125 prostate brachytherapy. PMID- 25523684 TI - Re: Sexual function in the late postmenopause: a decade of follow-up in a population-based cohort of Australian women. PMID- 25523685 TI - Re: Male sexual function and pelvic floor surgery of their female partner: a one year follow-up study. PMID- 25523686 TI - Re: A guide for inflatable penile prosthesis reservoir placement: pertinent anatomical measurements of the retropubic space. PMID- 25523687 TI - Re: Women's expectations and experiences of hormone treatment for sexual dysfunction. PMID- 25523688 TI - Re: Prevention of recurrent ischemic priapism with ketoconazole: evolution of a treatment protocol and patient outcomes. PMID- 25523689 TI - Re: Outcomes of abdominal wall reservoir placement in inflatable penile prosthesis implantation: a safe and efficacious alternative to the space of Retzius. PMID- 25523690 TI - Re: Determinants of sexual activity in four birth cohorts of Swedish 70-year-olds examined 1971-2001. PMID- 25523691 TI - Re: Clinical outcomes and patient satisfaction rates among elderly male aged >= 75 years with inflatable penile prosthesis implant for medically refractory erectile dysfunction. PMID- 25523692 TI - Re: Is ex vivo microdissection testicular sperm extraction indicated for infertile men undergoing radical orchiectomy for testicular cancer? Case report and literature review. PMID- 25523693 TI - Re: Age does not adversely affect sperm retrieval in men undergoing microdissection testicular sperm extraction. PMID- 25523694 TI - Re: Eliminating acute lymphoblastic leukemia cells from human testicular cell cultures: a pilot study. PMID- 25523695 TI - Re: Analysis of international practice patterns regarding postvasectomy fertility options. PMID- 25523696 TI - Re: Clinical outcome of microsurgical varicocelectomy in infertile men with severe oligozoospermia. PMID- 25523697 TI - Re: Vertical integration: hospital ownership of physician practices is associated with higher prices and spending. PMID- 25523698 TI - Re: Effect of insurance expansion on utilization of inpatient surgery. PMID- 25523699 TI - Re: Procedures take less time at ambulatory surgery centers, keeping costs down and ability to meet demand up. PMID- 25523700 TI - Re: Attention to surgeons and surgical care is largely missing from early medicare accountable care organizations. PMID- 25523701 TI - Re: First national survey of ACOs finds that physicians are playing strong leadership and ownership roles. PMID- 25523702 TI - Re: Measuring low-value care in medicare. PMID- 25523703 TI - Re: Postpubertal examination after hypospadias repair is necessary to evaluate the success of the primary reconstruction. PMID- 25523704 TI - Re: Analysis of 3,776 pediatric inguinal hernia and hydrocele cases in a tertiary center. PMID- 25523705 TI - Re: Ultrasound as a screening test for genitourinary anomalies in children with UTI. PMID- 25523706 TI - Re: Age at orchidopexy as an indicator of the quality of regional child health services. PMID- 25523707 TI - Re: Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer. PMID- 25523708 TI - Re: Neurosensory perception of environmental cues modulates sperm motility critical for fertilization. PMID- 25523709 TI - Re: Lack of testicular seipin causes teratozoospermia syndrome in men. PMID- 25523713 TI - Synthesis, characterization, and tuning of the liquid crystal properties of ionic materials based on the cyclic polyoxothiometalate [{Mo4O4S4(H2O)3(OH)2}2(P8W48O184)](36-). AB - A series of compounds resulting from the ionic association of a nanoscopic inorganic cluster of formula [K2NaxLiy{Mo4O4S4(OH)2(H2O)3}2(HzP8W48O184)]((34-x-y z)-), 1, with several organic cations such as dimethyldioctadecylammonium DODA(+), trimethylhexadecylammonium TMAC16(+), alkylmethylimidazoliums mimCn(+) (n = 12-20) and alkyl-dimethylimidazoliums dmimCn(+) (n = 12 and 16) was prepared and characterized in the solid state by FT-IR, EDX, Elemental analysis, TGA and solid state NMR. The solid state NMR experiments performed on (1)H, (13)C and (31)P nuclei evidenced the interactions between the cations and 1 as well as the organization of the alkyl chains of the cations within the solid. Polarized optical microscopy, DSC and SA-XRD experiments implicated mesomorphic phases for DODA(+) and mimCn(+) salts of 1. The crystallographic parameters were determined and demonstrated that the inter-lamellar spacing could be controlled upon changing the length of the alkyl chain, a very interesting result if we consider the huge size of the inorganic cluster 1 and the simple nature of the cations. PMID- 25523712 TI - Participation levels of physical activity programs for community-dwelling older adults: a systematic review. AB - BACKGROUND: Although many physical activity (PA) programs have been implemented and tested for effectiveness, high participation levels are needed in order to achieve public health impact. This study aimed to determine participation levels of PA programs aimed to improve PA among community-dwelling older adults. METHODS: We searched five databases up until March 2013 (PubMed, PubMed publisher, Cochrane Library, EMBASE, and Web of Science) to identify English written studies investigating the effect of PA programs on at least one component of PA (e.g. frequency, duration) among community-dwelling populations (i.e. not in a primary care setting and/or assisted living or nursing home) of persons aged 55 years and older. Proportions of participants starting and completing the PA programs (initial and sustained participation, respectively) were determined. RESULTS: The search strategy yielded 11,994 records of which 16 studies were included reporting on 17 PA programs. The number of participants enrolled in the PA programs ranged between 24 and 582 persons. For 12 PA programs it was not possible to calculate initial participation because the number of older adults invited to participate was unknown due to convenience sampling. Of the five remaining programs, mean initial participation level was 9.2% (+/-5.7%). Mean sustained participation level of all 17 programs was 79.8% (+/-13.2%). CONCLUSIONS: Understanding how to optimize initial participation of older adults in PA programs deserves more attention in order to improve the population impact of PA programs for community-dwelling older adults. PMID- 25523714 TI - Solar-photocatalytic disinfection of Vibrio cholerae by using Ag@ZnO core-shell structure nanocomposites. AB - Disinfection of Gram-negative bacterium Vibrio cholerae 569B in aqueous matrix by solar-photocatalysis mediated by Ag@ZnO core-shell structure nanocomposite particles was investigated. Silver nanoparticles are synthesized by the reduction of silver perchlorate followed by precipitation of zinc oxide shell and are employed in the photocatalytic disinfection of the model pathogen. Effect of photocatalyst loading and reaction temperature on the disinfection kinetics was studied. Disinfection efficiency in laboratory as well as real water samples was compared with that of pure-ZnO and TiO2 (Degussa P25). Nanocomposite system has shown optimum disinfection (~98%) at 40-60min of sun-light exposure with a catalyst loading of 0.5mg/L of the reaction solution. The reduction of aquatic bacterial densities by photocatalytically active Ag@ZnO core-shell nanocomposite in presence of natural sun-light may have potential ex situ application in water decontamination at ambient conditions. PMID- 25523715 TI - Expression of HMGB1 in the periodontal tissue subjected to orthodontic force application by Waldo's method in mice. AB - Recent studies indicate that high mobility group box protein 1 (HMGB1) originating from periodontal ligament (PDL) cells can be a potential regulator in the process of orthodontic tooth movement and periodontal tissue remodeling. The aim of this study is to investigate HMGB1 expression in periodontal tissue during orthodontic tooth movement in mice according to Waldo's method. Six 7-week-old C57BL6 mice were used in these experiments. The elastic band was inserted into the teeth space between the right first and second maxillary molars. After 3 days of mechanical loading, mice were fixed with transcardial perfusion of 4 % paraformaldehyde in 0.1 M phosphate buffer (pH 7.4), and the maxillary was extracted for histochemical analyses. The histological examination revealed local PDL tear at the tension side and the formation of extensive cell-free hyaline zones at the compression side. The immunolocalization of HMGB1 was significantly presented at tension side of PDL, apical area and dental pulp, whereas at the compression side of PDL, the labeling of HMGB1 was almost undetectable as the presence of hyaline zone. Taken together, we concluded that the orthodontic tooth movement by Waldo's method leads to histological changes and HMGB1 expression pattern that differ from those of coil spring method, including PDL tear and extensive hyaline zone which may severely destroy periodontal tissue and in turn impede tooth movement. PMID- 25523717 TI - Metal oxide semiconductors for dye- and quantum-dot-sensitized solar cells. AB - This Review provides a brief summary of the most recent research developments in the synthesis and application of nanostructured metal oxide semiconductors for dye sensitized and quantum dot sensitized solar cells. In these devices, the wide bandgap semiconducting oxide acts as the photoanode, which provides the scaffold for light harvesters (either dye molecules or quantum dots) and electron collection. For this reason, proper tailoring of the optical and electronic properties of the photoanode can significantly boost the functionalities of the operating device. Optimization of the functional properties relies with modulation of the shape and structure of the photoanode, as well as on application of different materials (TiO2, ZnO, SnO2) and/or composite systems, which allow fine tuning of electronic band structure. This aspect is critical because it determines exciton and charge dynamics in the photoelectrochemical system and is strictly connected to the photoconversion efficiency of the solar cell. The different strategies for increasing light harvesting and charge collection, inhibiting charge losses due to recombination phenomena, are reviewed thoroughly, highlighting the benefits of proper photoanode preparation, and its crucial role in the development of high efficiency dye sensitized and quantum dot sensitized solar cells. PMID- 25523716 TI - Post-marketing safety and effectiveness evaluation of the intravenous anti influenza neuraminidase inhibitor peramivir. II: a pediatric drug use investigation. AB - Peramivir is the only intravenous formulation among anti-influenza neuraminidase inhibitors currently available. Peramivir was approved for manufacturing and marketing in Japan in January 2010. In October 2010, an additional indication for pediatric use was approved. We conducted a pediatric drug use investigation of peramivir from October 2010 to February 2012 and evaluated its real-world safety and effectiveness in pediatric patients. We collected the data of 1254 peramivir treated pediatric patients from 161 facilities across Japan and examined the safety in 1199 patients and effectiveness in 1188 patients. In total, 245 adverse events were observed with an incidence rate of 14.01% (168/1199). Of these, 115 events were adverse drug reactions (ADRs) with an incidence rate of 7.67% (92/1199). Common ADRs were diarrhea and abnormal behavior, with incidence rates of 2.50% (30/1199) and 2.25% (27/1199), respectively. Fourteen serious ADRs were observed in 12 patients (1.00%), including 5 cases each of abnormal behavior and neutrophil count decreased. While 87.0% (100 events) of ADRs occurred within 3 days after the initiation of peramivir administration, 87.8% (101 events) resolved or improved within 7 days after onset. Multivariate analyses indicated that the presence or absence of underlying diseases/complications was significantly related to ADR incidence. With regard to effectiveness, the median time to alleviation of both influenza symptoms and fever was 3 days, including the first day of administration. Thus, this study confirms the pediatric safety of peramivir without any concerns about effectiveness under routine clinical settings. PMID- 25523718 TI - Randomized, double-blind comparison of standard-dose vs. high-dose trivalent inactivated influenza vaccine in pediatric solid organ transplant patients. AB - Children who have undergone SOT mount a lower immune response after vaccination with TIV compared to healthy controls. HD or SD TIV in pediatric SOT was given to subjects 3-17 yr and at least six months post-transplant. Subjects were randomized 2:1 to receive either the HD (60 MUg) or the SD (15 MUg) TIV. Local and systemic reactions were solicited after each vaccination, and immune responses were measured before and after each vaccination. Thirty-eight subjects were enrolled. Mean age was 11.25 yr; 68% male, 45% renal, 26% heart, 21% liver, 5% lung, and 5% intestinal. Twenty-three subjects were given HD and 15 SD TIV. The median time since transplant receipt was 2.2 yr. No severe AEs or rejection was attributed to vaccination. The HD group reported more tenderness and local reactions, fatigue, and body ache when compared to the SD cohort, but these were considered mild and resolved within three days. Subjects in the HD group demonstrated a higher percentage of four-fold titer rise to H3N2 compared to the SD group. HD influenza vaccine was well tolerated and may have increased immunogenicity. A phase 2 trial is needed to confirm. PMID- 25523719 TI - Effect of probiotic bacteria-fermented medicinal plants (Gynura procumbens, Rehmannia glutinosa, Scutellaria baicalensis) as performance enhancers in growing pigs. AB - This study was conducted to investigate the effect of dietary supplementation of mixed fermented medicinal plants (FMP) obtained from exudates of Gynura procumbens, Rehmannia glutinosa and Scutellaria baicalensis fermented with Lactobacillus plantarum, Saccharomyces cerevisiae and Bacillus licheniformis, respectively, on growth performance in growing pigs in order to assess the feasibility of using FMP as an alternative to antibiotic growth promoters (AGP), such as tiamulin. A total of 150 growing pigs (body wieght 25.50 +/- 2.50 kg) were used in a 6 weeks experiment and randomly divided into five groups with six replicates of five growing pigs each. The treatments were NC (basal diet), basal diet with 33 ppm tiamulin (PC), basal diet with FMP 0.05% (FMP 0.05), basal diet with FMP 0.1% (FMP 0.1) and basal diet with FMP 0.2% (FMP 0.2). Overall, body weight gain, feed conversion rate, the digestibility of dry matter and gross energy, noxious gas emission all improved with FMP supplementation as compared to NC. Taken together, these results suggest the feasibility of using FMP as an alternative to AGP for enhancing the growth performance, nutrient digestibility and excreta noxious gas emission of growing pigs. PMID- 25523720 TI - Hepatitis C treatment gets into a new gear. PMID- 25523721 TI - Vaccine effectiveness and risk factors associated with measles among children presenting to the hospitals of Karachi, Pakistan. AB - OBJECTIVE: To determine the risk factors regarding guardian's practices associated with development of Measles and also find out effectiveness of Measles vaccine among children less than 12 years of age presenting to the hospitals of Karachi. STUDY DESIGN: Matched case control study. PLACE AND DURATION OF STUDY: Multicenter surveillance was conducted in 11 public and private sector hospitals of Karachi from January 2011 to September 2012 in consultation with World Health Organization Measles Surveillance Cell. METHODOLOGY: Cases were children aged less than 12 years with Measles presenting to the hospitals. Controls for cases were enrolled from the same hospitals without Measles, matched for age and gender. Studied variables were analyzed by multivariate conditional logistic regression analysis adjusted for age and gender. RESULTS: Measles cases were more likely to have mothers with 'lower education' [adjusted matched Odds Ratio or mOR: 3.2 (95% CI: 1.2 - 7.6), for < 5 years of schooling adjusted mOR: 2.2 (95% CI: 1.0 - 5.7) for 6 - 10 years of schooling]. Children with Measles were also more likely to be not given breast milk in initial 2 years of life [adjusted mOR: 2.6, 95% CI 1.0 - 7.0]. Cases were also more likely to have never received vaccination [adjusted mOR: 10.1, 95% CI 4.5 - 22.5] and having no other children vaccinated at home [adjusted mOR: 3, 95% CI 1.5 - 5.3]. Vaccine effectiveness for single dose was found to be 87.4 (95% CI: 76.1 - 93.4), while for two doses it was approximately 93% (95% CI: 86.2 - 96.6). CONCLUSION: For Measles elimination, mother's education on breast feeding and appropriate weaning practices is required. PMID- 25523722 TI - Comparison between Greulich-Pyle and Girdany-Golden methods for estimating skeletal age of children in Pakistan. AB - OBJECTIVE: To compare Greulich-Pyle (GP) and Girdany-Golden (GG) methods for estimation of Skeletal Age (SA) in children referred to a tertiary care hospital in Karachi, Pakistan. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Department of Radiology, The Aga Khan University Hospital, Karachi, Pakistan, from July 2010 to June 2012. METHODOLOGY: Children up to the age of 18 years, who had undergone X-ray for the evaluation of trauma were included. Each X ray was interpreted using both methods by two consultant paediatric radiologists having at least 10 years experience, who were blinded to the actual Chronologic Age (CA) of children. RESULTS: A total of 283 children were included. No significant difference was noted in mean SA estimated by GP method and mean CA for female children (p=0.695). However, a significant difference was noted between mean CA and mean SA by GG method for females (p=0.011). For males, there was a significant difference between mean CA and mean SA estimated by both GP and GG methods. A stronger correlation was found between CA and SA estimated by GP method (r=0.943 for girls, r=0.915 for boys) as compared to GG method (r=0.909 for girls, r=0.865 for boys) respectively. Bland- Altman analysis also revealed that the two methods cannot be used interchangeably. Excellent correlation was seen between the two readers for both GP and GG methods. CONCLUSION: There was no additional benefit of using GP and GG methods simultaneously over using GP method alone. Moreover, although GP was reliable in estimating SA in girls, it was unable to accurately assess SA in boys. Therefore, it would be ideal to develop indigenous standards of bone age estimation based on a representative sample of healthy native children. PMID- 25523723 TI - RIPASA score: a new diagnostic score for diagnosis of acute appendicitis. AB - OBJECTIVE: To determine the usefulness of RIPASA score for the diagnosis of acute appendicitis using histopathology as a gold standard. STUDY DESIGN: Cross sectional study. PLACE AND DURATION OF STUDY: Department of General Surgery, Combined Military Hospital, Kohat, from September 2011 to March 2012. METHODOLOGY: A total of 267 patients were included in this study. RIPASA score was assessed. The diagnosis of appendicitis was made clinically aided by routine sonography of abdomen. After appendicectomies, resected appendices were sent for histopathological examination. The 15 parameters and the scores generated were age (less than 40 years = 1 point; greater than 40 years = 0.5 point), gender (male = 1 point; female = 0.5 point), Right Iliac Fossa (RIF) pain (0.5 point), migration of pain to RIF (0.5 point), nausea and vomiting (1 point), anorexia (1 point), duration of symptoms (less than 48 hours = 1 point; more than 48 hours = 0.5 point), RIF tenderness (1 point), guarding (2 points), rebound tenderness (1 point), Rovsing's sign (2 points), fever (1 point), raised white cell count (1 point), negative urinalysis (1 point) and foreign national registration identity card (1 point). The optimal cut-off threshold score from the ROC was 7.5. Sensitivity analysis was done. RESULTS: Out of 267 patients, 156 (58.4%) were male while remaining 111 patients (41.6%) were female with mean age of 23.5 +/- 9.1 years. Sensitivity of RIPASA score was 96.7%, specificity 93.0%, diagnostic accuracy was 95.1%, positive predictive value was 94.8% and negative predictive value was 95.54%. CONCLUSION: RIPASA score at a cut-off total score of 7.5 was a useful tool to diagnose appendicitis, in equivocal cases of pain. PMID- 25523724 TI - Chondroblastoma: a clinico-pathological analysis. AB - OBJECTIVE: To determine the clinico-pathological and histological features of Chondroblastoma (CB). STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital, Karachi, from 2000 to 2013. METHODOLOGY: The histological slides of all reported cases of CB were retrieved and reviewed for morphological features. Clinical features were noted from surgical pathology reports. Frequency of features was noted. RESULTS: Sixty one cases of CB were identified. Pain was the most common presenting symptom. The age ranged from 10 to 38 years (mean 20 +/- 1.98 years; M: F 2.5:1) with 61% patients in the second decade of life. Forty six cases occurred in long tubular bones; distal femur being most common site. Metaphysis, clavicle, temporal bone and metacarpal were also involved. Histologically, all CBs were composed of round to polygonal cells and scattered osteoclast-type multinucleated giant cells and majority had hemosiderin pigment. Chicken-wire calcifications and coarse calcifications were seen in 85% and 26% of cases respectively. A spindle cell component was seen in 54% of cases. ABC-like areas were seen in 10 cases. Mitosis ranged from 1 to 6/10 HPFs. Recurrence was seen in 2 cases. Recurrent tumor showed similar morphology when compared with the initial tumor. CONCLUSION: CB is a benign tumor but has potential for recurrence. Males are more affected, second decade is more common and distal femur is most common site. Metaphysis, clavicle, temporal bone and metacarpal were the rare sites of CB. Histological features predictive of recurrence were not separately identified. PMID- 25523725 TI - Developing professionalism: dental students' perspective. AB - OBJECTIVE: To explore the undergraduate dental students' insight of their professionalism development through Focus Group Discussions (FGD). STUDY DESIGN: Constructivist approach using qualitative phenomenological design. PLACE AND DURATION OF STUDY: Fatima Memorial Hospital, College of Dentistry, Lahore, from April to June 2011. METHODOLOGY: Four FGDs of 1st year (8 students), 2nd year (6 students), 3rd year (6 students) and 4th year (6 students) enrolled in Bachelor of Dental Surgery (BDS) program were conducted to explore how they have developed various elements of professionalism namely altruism, accountability, excellence, duty and service, honor and integrity, and respect for all; and how professionalism can be further developed in them. The FGDs were audio taped, transcribed and analyzed through thematic analysis. Triangulation of themes and trends were done through content analysis by relating to their respective frequency of quotes. Data verification was done through audit by second author. RESULTS: Role models and social responsibility were the main reasons in the students' professionalism development thus far with personal virtues and reasons; religion; and punishment and reward contributing to a lesser degree. Training contributed least but was deemed most in furthering professionalism. Excessive workload (quota) and uncongenial educational environment were considered detrimental to the cause. CONCLUSION: Formal planning and implementation of professionalism curriculum; selection of students with appropriate attributes; control of hidden curriculum, including effective role models, good educational and working environments will foster professionalism among dental students maximally. PMID- 25523726 TI - Perceptions of doctors on being treated by a doctor just completing the house job. AB - OBJECTIVE: To determine the percentage of medical teachers and fresh doctors who feel that graduating doctors are competent or incompetent to handle common ailments and to evaluate the reasons for their perceptions. STUDY DESIGN: Sequential mixed method. PLACE AND DURATION OF STUDY: First phase extending from December 2010 to December 2011 and second phase was conducted in March 2014. METHODOLOGY: First phase comprised electronic distribution of questionnaire to 100 medical teachers and fresh doctors working in hospitals attached with 5 private and 5 public sector medical colleges of Lahore and Karachi to rate an average house officer on a frequency scale of 1 - 6 and do self-assessment, in case of a fresh doctor. The second phase included interviews of 20 medical teachers to explore justification for their rating in the survey questionnaire and for triangulation of data. Quantitative data was analyzed through SPSS version 15 to calculate frequencies and percentages and interviews were analyzed through quasi-statistical approach. RESULTS: In survey, 38.36% out of 73 medical teachers and 30% out of 20 medical teachers in interviews confirmed their confidence on consulting fresh doctors for common ailments as opposed to 61.64% and 70% respectively, expressing their dissatisfaction. Self-assessment of fresh doctors indicated that 40% are confident in handling common medical conditions as opposed to 33.3% out of 75 respondents, who are not confident about their clinical skills. CONCLUSION: Faculty and self-assessment of fresh doctors has a fair overlap, indicating room for further improvement in the house job training program. PMID- 25523727 TI - In vitro activity of fosfomycin tromethamine against extended spectrum beta lactamase producing urinary tract bacteria. AB - OBJECTIVE: To determine the in vitro activity of Fosfomycin tromethamine against extended spectrum beta-lactamase producing uropathogens. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Department of Microbiology, Armed Forces Institute of Pathology, Rawalpindi, from October 2011 to October 2012. METHODOLOGY: A total of 381 culture positive ESBL producing isolates from 2400 urine samples submitted over a period of one year were included in this study. Identification of isolates was done by standard biochemical profile of the organisms. The antimicrobial susceptibility of culture positive isolates was performed by disk diffusion method as recommended by Clinical Laboratory Standard Institute guidelines (CLSI). RESULTS: The antimicrobial activity of Fosfomycin to various isolates revealed that 93% of E. coli, 64% Klebsiella spp. 50% Proteus spp. 75% Enterobacter cloacae, 100% Citrobacter freundii, 100% Burkholderia spp. 100% Serratia spp. and 50% Stenotrophomonas maltophilia were susceptible to this chemical compound. CONCLUSION: Fosfomycin showed excellent effectiveness to most of the common ESBL producing bacteria such as E. coli, Klebsiella and Proteus spp. PMID- 25523728 TI - Axial length variability in cataract surgery. AB - OBJECTIVE: To determine the mean axial length and biometric measures in patients undergoing cataract surgery and further compare the variability of axial length between the gender and with age. STUDY DESIGN: Cross-sectional observational study. PLACE AND DURATION OF STUDY: Eye Unit I, Department of Ophthalmology, Liaquat University of Medical and Health Sciences, Hyderabad, Pakistan from January 2010 to December 2012. METHODOLOGY: All patients referred for cataract surgery were assessed. The study included 886 eyes which were straightforward cataract cases with no other ocular problem. The data was collected for axial length, keratometric values and Intra-Ocular Lens (IOL) power prior to cataract surgery. The collected data was then analyzed using SPSS version 19 for windows software. RESULTS: Gender based comparison showed significant difference in age, axial length, keratometric values and IOL power between the two groups (p=0.000). 86% of the eyes had an axial length between 21.00 mm and 23.99 mm. In univariate analysis there was significant (p=0.000) relation between overall age and axial length. The keratometric values ranged between 36.75 D and 52.50 D. Majority of the IOL powers ranged between 20.00 D and 23.00 D. CONCLUSION: The mean axial length of patients undergoing cataract surgery was 22.96 +/- 1.04 mm, was comparable to Indian and Chinese population but shorter than the Western population. Females had shorter axial lengths, similar to other studies. Axial length was positively associated with age among the females, the cause of which is yet to be determined. PMID- 25523729 TI - Visual acuity after trans-scleral sutured posterior chamber intraocular lens. AB - OBJECTIVE: To determine the changes in visual acuity in patients undergoing Trans Scleral Sutured Posterior Chamber Intra-Ocular Lens (TSSPCIOL) implantation at a tertiary care hospital in Karachi, Pakistan. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: LRBT Tertiary Eye Hospital, Karachi, from January 2006 to December 2010. METHODOLOGY: Records of all patients undergoing implantation of TSSPCIOL were reviewed. Patients with diagnosed glaucoma, diabetic retinopathy, macular degeneration, history of recurrent uveitis, corneal haze or central corneal scars were excluded. For the final analysis, 70 eyes out of a total of 75 were selected. Main outcomes of interest were pre and postoperative visual acuities and surgical complications. SPSS 21 was used for data analysis. RESULTS: Pre-operatively, the average Best Spectacle-Corrected Visual Acuity (BSCVA) was 6/36 on the Snellen chart. This improved to 6/12 postoperatively. The mean improvement seen was 2.4 lines on the Snellen chart (p < 0.05). Complications include transient intraocular pressure elevation in 25 eyes (36%), IOL tilt in 4 eyes (7.1%), Cystoid Macular Edema (CME) in 4 eyes (5.7%), vitreous haemorrhage in 2 eyes (2.9%), hyphema in 2 eyes (2.9%), uveitis in 1 eye (1.4%), and retinal detachment 1 eye (1.4%). No IOL subluxation, suture erosion, iris capture, choroidal effusion or endophthalmitis was encountered and no re-operations were needed. CONCLUSION: TSSPCIOLs are a good management option for patients with aphakia in whom PC IOLs cannot be placed. PMID- 25523730 TI - Atorvastatin in the management of tinnitus with hyperlipidemias. AB - OBJECTIVE: To determine the role of atorvastatin in management of tinnitus in patients with hyperlipidemia. STUDY DESIGN: Quasi-experimental study. PLACE AND DURATION OF STUDY: ENT Department, Combined Military Hospital, Rawalpindi, from July 2011 to August 2012. METHODOLOGY: Ninety eight patients of tinnitus with sensorineural hearing loss having hyperlipidemia were included in the study. Their pre-therapy serum cholesterols were measured, and tinnitus scores were recorded on a 'Tinnitus handicap questionnaire'. They were administered tablet atorvastatin 40 mg once daily with low fat diet for 8 months. After 8 months of therapy, patients were purposefully divided into responsive and unresponsive group depending on serum cholesterol levels. Post therapy serum cholesterol levels and tinnitus scores were also recorded after 8 months and compared with pre-therapy records. RESULTS: Serum cholesterol came to within normal limits in 51 (52%) patients (responsive group), while it remained high in 47 (48%) patients (unresponsive group). Improvement in tinnitus score in the responsive group was seen in 36 (70.5%) patients and in 2 (4.2%) patients of the unresponsive group. Improvement in tinnitus scores was compared in the two groups using Fisher's exact test and were found to be statistically better in the responsive group (p < 0.001). CONCLUSION: Tinnitus, in patients having hyperlipidemia, can be successfully dealt with by treating hyperlipidemia with lipid lowering agent atorvastatin. PMID- 25523731 TI - The mean visible labial length of maxillary and mandibular anterior teeth at rest. AB - OBJECTIVE: To determine the mean visible labial length of maxillary and mandibular anterior teeth at rest. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Department of Prosthodontics, Dr. Ishrat-ul-Ebad Khan Institute of Oral Health Sciences, Karachi, from October 2012 to March 2013. METHODOLOGY: A total of 200 subjects were included. Measurements were carried out using digital caliper from the border of the lip to the incisal edges of incisor and to the cusp tip for the canines. The length of the upper lip was measured from subnasale to stomion. Statistical analyses were performed by Mann Whitney-U test and Kruskal Walli's test. RESULTS: The age of the participant ranged between 20 and 65 years. At rest, females significantly displayed more of the maxillary central incisor (2.93 +/- 1.57 mm; p=0.003), lateral incisor (1.87 +/- 1.12 mm; p=0.005) and canine (0.59 +/- 0.62 mm; p=0.031). With increasing age, the amount of maxillary anterior teeth visible at rest significantly decreased (p < 0.001), and increased for the mandibular teeth (p < 0.001). Subjects with shorter upper lips significantly displayed more maxillary anterior incisor structure than subjects with longer upper lip (p < 0.001). CONCLUSION: Females displayed significantly more labial length of the maxillary anterior teeth. The mean visible labial length of maxillary anterior teeth significantly decreased with increasing age and increased for the mandibular teeth. As the upper lip length increased, the mean visible labial length of maxillary anterior teeth significantly decreased. PMID- 25523732 TI - Treatment updates regarding anaplastic oligodendroglioma and anaplastic oligoastrocytoma. AB - Anaplastic Oligodendroglioma / Anaplastic Oligoastrocytoma (AO/AOA) is a WHO Grade-III primary brain tumor. These tumors comprise about 5 - 10% of all gliomas, which make them the third most common primary brain tumors after glioblastoma multiforme and astrocytomas. For many years standard of treatment remained Maximum Safe Resection (MSR) followed by Radiotherapy (RT). These tumors have also been known to be sensitive to alkylator-based chemotherapy particularly the subset having 1p/19q co-deletion signature. There is robust data showing that these tumors are responsive to chemotherapy in recurrent or progressive setting. Recently, up front chemotherapy has been added to standard post-surgery RT. It has been found that subset of AO/AOA having 1p/19q co-deletion responded very well to the addition of chemotherapy. This substantial benefit in terms of median Overall Survival (OS) and median Progression Free Survival (PFS) have intrigued the personalized treatment of AO/AOA on the basis of molecular signature markers. PMID- 25523733 TI - The ringing bells: perspective of Karachiites regarding noise pollution. AB - OBJECTIVE: To identify the awareness regarding noise pollution and its adverse effects on human health in the people of urban areas of Karachi. STUDY DESIGN: Cross-sectional survey. PLACE AND DURATION OF STUDY: Urban areas of Karachi, from September to October 2012. METHODOLOGY: A survey was conducted with 50 selected subjects of urban areas of Karachi with their informed consent. The questionnaire covered aspects of noise pollution. Descriptive analysis was done with percent responses. RESULTS: All (100%, n=50) subjects admitted to be suffering from noise pollution. The source of noise pollution was vehicles in 64% (n=32). There was 90% (n=45) agreement for laws and regulations regarding noise pollution to be in place. CONCLUSION: Awareness sessions need to be conducted for the public regarding the effects of noise pollution on health with formulation of laws and regulations. PMID- 25523734 TI - Rectus abdominis muscle endometriosis. AB - Endometriosis is characterized by an abnormal existence of functional endometrial tissue outside the uterine cavity, typically occuring within the pelvis of women in reproductive age. We report two cases with endometriosis of the abdominal wall; the first one in the rectus abdominis muscle and the second one in the surgical scar of previous caesarean incision along with the rectus abdominis muscle. Pre-operative evaluation included magnetic resonance imaging. The masses were dissected free from the surrounding tissue and excised with clear margins. Diagnosis of the excised lesions were verified by histopathology. PMID- 25523735 TI - Adrenocortical oncocytoma. AB - Adrenocortical oncocytoma is an exceedingly rare pathological variant of an adrenal neoplasm. The pathogenesis of oncocytic neoplasms is poorly understood. Females have been reported to be affected 2.5 times more frequently than males, and left-sided lesions are more common than those on right side. This case describes a 20 years old female with right lumbar pain. She found to have a right adrenal gland mass measuring about 6 x 5 cm. A computed tomogram showed hypodense mass lesion 6 x 4.2 cm involving right adrenal gland. Differential diagnosis of non-functional adrenal adenoma was made. A laparoscopic right adrenalectomy was performed using the 3-ports lateral transperitoneal approach. Histopathology showed adrenocortical oncocytoma of adrenal gland. PMID- 25523736 TI - Intralobar bronchopulmonary sequestration with large aberrant vessel presenting as recurrent pneumonias. AB - Bronchopulmonary sequestration is a rare congenital malformation of the lower respiratory tract comprising of a nonfunctioning lung tissue mass that lacks normal communication with the tracheobronchial tree. The diagnosis may be easily missed as many of the symptoms of bronchopulmonary sequestration overlap with that of other pulmonary diseases. Bronchopulmonary sequestration can be complicated by recurrent infections, hemorrhage and malignant transformation and, therefore, needs to be timely diagnosed and resected to decrease both morbidity and mortality. A high degree of suspicion in the differential diagnosis helps diagnose the positive cases. The parenchymal abnormalities associated with bronchopulmonary sequestration are best visualized using computed tomography, although their appearance is variable. We report the case of a 14 years old boy with intralobar bronchopulmonary sequestration with the sole manifestation of recurrent pneumonias. PMID- 25523737 TI - Better physician-patient communication; an important milestone in control of hypertension, a multicenter study from Karachi, Pakistan. AB - Control of hypertension is an important cornerstone in prevention of cardiovascular morbidity and mortality. This study was designed to compare physician encounter score in patients with controlled and uncontrolled hypertension. It was conducted at three tertiary care hospitals in Karachi. Patients were categorized into controlled and uncontrolled hypertension based on their initial blood pressure readings on presentation. Primary outcome variable was control of hypertension and physician encounter score (a composite score of 12 item question) was the main candidate variable. Higher scores reflected favorable encounter with physician. Mean age of participants was 57.7 +/- 12 years; 224 (50.1%) were men. Controlled hypertension was present in 72.3% (323) and uncontrolled hypertension was present in 27.4% (124). Mean physician encounter score in uncontrolled hypertensive was 7.25 +/- 2.64 versus 7.83 +/- 2.22 (p=0.02) in controlled hypertensive. Patient-physician encounter is an important milestone in control of hypertension in hypertensive patients and directly translates into better adherence to antihypertensives in these patients. PMID- 25523738 TI - Dentist-nephrologist symbiosis in the dental management of chronic kidney disease patient. PMID- 25523739 TI - Gossypiboma: an unrecognized and under-reported problem in Pakistan. PMID- 25523740 TI - Middle East respiratory syndrome and Pakistan. PMID- 25523741 TI - Research in emergency medicine in Pakistan: a local perspective. PMID- 25523745 TI - Factor structure and psychometric properties of the Body Appreciation Scale among adults in Hong Kong. AB - Previous research has suggested that the factor structure of Body Appreciation Scale (BAS), a widely-used measure of positive body image, may not be cross culturally equivalent. Here, we used confirmatory factor analysis to evaluate the conceptual equivalence of a Chinese (Cantonese) translation of the BAS among women (n=1319) and men (n=1084) in Hong Kong. Results showed that neither the one dimensional nor proposed two-dimensional factor structures had adequate fit. Instead, a modified two-dimensional structure, which retained 9 of the 13 BAS items in two factors, had the best fit. However, only one of these factors, reflective of General Body Appreciation, had adequate internal consistency. This factor also had good patterns of construct validity, as indicated through significant correlations with participant body mass index, self-esteem, and (among women) actual-ideal weight discrepancy. The present results suggest that there may be cultural differences in the concept and experience of body appreciation. PMID- 25523747 TI - Comparison of residual alpha- and beta-structures between two intrinsically disordered proteins by using NMR. AB - Intrinsically disordered proteins contain some residual structures, which may fold further upon binding to the partner protein for function. The residual structures observed in two intrinsically disordered proteins, including the C terminal segment of peripherin-2 (63 residues) and measles virus nucleocapsid protein Ntail (125 residues), were compared using NMR. Differences in the chemical shifts of alpha-, beta- and carbonyl carbons between the observed structure and calculated random coil revealed the existence of a helix and some possible beta-structures in both proteins. The intensity of signals in the C terminal segment of peripherin-2 in NMR spectra was informative and locally low, particularly in the middle and N-terminal parts: this suggested the broadening of the signals caused by the formation of residual structures in those areas. Furthermore, the protection of exchange of amide protons was significantly observed at the N-terminus. Conversely, the intensities of signals for Ntail were random beyond the overall areas of protein, and indicated no characteristic pattern. Only a faint protection of amide-proton exchange in Ntail was observed in the C-terminus. It was concluded that Ntail was more intrinsically disordered than the C-terminal segment of peripherin-2. The combination of chemical shifts with the amide-proton exchanges and signal intensities was useful for the analyses of the remaining secondary structures. The beta-structure might be more detectable by the protection of amide-proton exchange than the helical structure, although the changes in chemical shifts were sensitive for the detection of elements of both secondary structures. PMID- 25523746 TI - Nanocell targeting using engineered bispecific antibodies. AB - There are many design formats for bispecific antibodies (BsAbs), and the best design choice is highly dependent on the final application. Our aim was to engineer BsAbs to target a novel nanocell (EnGeneIC Delivery Vehicle or EDV(TM)nanocell) to the epidermal growth factor receptor (EGFR). EDV(TM)nanocells are coated with lipopolysaccharide (LPS), and BsAb designs incorporated single chain Fv (scFv) fragments derived from an anti-LPS antibody (1H10) and an anti EGFR antibody, ABX-EGF. We engineered various BsAb formats with monovalent or bivalent binding arms and linked scFv fragments via either glycine-serine (G4S) or Fc-linkers. Binding analyses utilizing ELISA, surface plasmon resonance, bio layer interferometry, flow cytometry and fluorescence microscopy showed that binding to LPS and to either soluble recombinant EGFR or MDA-MB-468 cells expressing EGFR, was conserved for all construct designs. However, the Fc-linked BsAbs led to nanocell clumping upon binding to EDV(TM)nanocells. Clumping was eliminated when additional disulfide bonds were incorporated into the scFv components of the BsAbs, but this resulted in lower BsAb expression. The G4S linked tandem scFv BsAb format was the optimal design with respect to EDV binding and expression yield. Doxorubicin-loaded EDV(TM)nanocells actively targeted with tandem scFv BsAb in vivo to MDA-MB-468-derived tumors in mouse xenograft models enhanced tumor regression by 40% compared to passively targeted EDV(TM)nanocells. BsAbs therefore provide a functional means to deliver EDV(TM)nanocells to target cells. PMID- 25523748 TI - Physical and cardiovascular performance in cases with acromegaly after regular short-term exercise. AB - OBJECTIVE: Impaired physical performance is a disturbing complication of acromegaly. We aimed to evaluate the role of regular exercise in amelioration of the impaired physical performance in acromegaly. METHODS: Patients with acromegaly were divided into two groups according to their participation in a prescheduled programme of exercise. Participants in the study group were exercised 3 days a week for 3 consecutive months. Exercise tolerance was evaluated by maximal oxygen consumption (VO2 max) and time (T) taken to complete the Bruce protocol, muscle flexibility by the sit and reach test (SRT) and muscle strength by the hand grip strength test (HGST). Concomitantly, anthropometric assessment was performed using body mass index (BMI), waist-to-hip ratio (WHR), skinfold measurements from 8 points, percentage body fat (PBF), fat mass (FM) and lean body mass (LBM). RESULTS: After 3 months of exercise, VO2 max and T were higher in cases that exercised than in cases that did not (P = 0.004 and P = 0.001). Over 3 months, within the exercise group, VO2 max and T of the Bruce protocol increased (P = 0.003 and P = 0.004) and heart rate during warming decreased (P = 0.04). SRT increased within the exercise group after 3 months (P = 0.004). HGSRT did not change significantly (right P = 0.06 and left P = 0.2). The sum of skinfolds, BMI, WHR and LBM remained stable over the study period (P = 0.1, P = 0.08, P = 0.3 and P = 0.09). PBF decreased slightly and FM decreased significantly over 3 months (P = 0.05 and P = 0.03). CONCLUSION: Even short-term exercise may improve impaired physical performance, muscle activity and disturbed body fat composition in acromegaly. PMID- 25523749 TI - Comparative evaluation of antifungal action of tea tree oil, chlorhexidine gluconate and fluconazole on heat polymerized acrylic denture base resin - an in vitro study. AB - OBJECTIVE: Candida albicans-associated denture stomatitis is the most common type of denture stomatitis seen in denture wearers. This study evaluates and compares the antifungal action of fluconazole, chlorhexidine gluconate and tea tree oil on heat-polymerised denture base resin, which has been previously contaminated with C. albicans grown in BHI broth. MATERIAL AND METHODS: Seventy-five specimens were immersed in BHI broth previously inoculated with C. albicans and stored for 3 h at 37 degrees C. They were divided into five groups (n = 15): G1: 2% chlorhexidine solution; G2: 100% pure pharmaceutical grade tea tree oil; G3: 65 MUg/ml fluconazole solution; C1: specimens not disinfected; C2: specimens not contaminated with Candida. Each specimen was then transferred to individual tubes containing BHI broth and incubated for 24 h. Culture media turbidity was evaluated for absorbance over a period of 14 days using a microplate reader. It was observed that the lower the absorbance, the stronger the antimicrobial action. Statistical analysis was performed (two-way anova and Bonferroni test, p < 0.001). RESULTS: Chlorhexidine and tea tree oil inhibited Candida up to the 14th day, whereas antifungal effect of fluconazole was not significant after the 7th day. CONCLUSION: Tea tree oil and chlorhexidine gluconate are more effective than fluconazole in inhibiting C. albicans growth on heat-polymerised acrylic resin. PMID- 25523750 TI - Reproductive toxicity study with a novel deoxyguanosine analogue (Metacavir) in pregnant SD rats. AB - Our preliminary studies demonstrated that Metacavir has potential to become a new anti-HBV agent. The main targets of the toxic effects of Metacavir, in rhesus monkeys, were gastrointestinal tracts, liver, blood, and kidneys, which were not related to mitochondrial effects. In this study, the maternal toxicity, embryo fetal developmental toxicity and teratogenicity were studied in pregnant Sprague Dawley rats after intragastric administration of Metacavir (200, 100, 50, 0 mg/kg body weight) during the first 6-15 days of pregnancy. Slower weight gain was observed in 5 out of 21 rats subjected to a 200 mg/kg dose, as well as 2 out of 20 subjected to a 100 mg/kg dose. Compared with the solvent control group, the calibration weight gain in the 200 mg/kg and 100 mg/kg dosage groups respectively, during first 6-20 pregnant days were significantly different (P < 0.01, P < 0.05). Significant dose related adverse effects to other reproductive parameters were not seen in F0 and F1, but the number of stillbirths in high dose group showed notably difference compared with the control group (P < 0.05), while the litter incidence showed no difference. No Metacavir-associated pathological changes were observed. The present research indicated that at a dose of 200 mg/(kg.d) (i.e., 40 times the effective dose in rats), Metacavir shows some maternal toxicity to SD rats. The embryotoxicity in the 200 mg/kg group encompass decreased fetal body weight, and higher fetal mortality rates, compared with the control group. However, the litter incidence showed no statistical difference. All the treated rats displayed normal bone development, no teratogenicity and without adverse effects on fetal development, thus indicating that below a dose of 200 mg/(kg.d) there is no teratogenic side effects. PMID- 25523751 TI - Assessing sub-clinical psychosis phenotypes in the general population--a multidimensional approach. AB - Several studies have demonstrated that expression of a psychosis phenotype can be observed below the threshold of its clinical detection. To date, however, no conceptual certainty has been reported for the validity and reliability of sub clinical psychosis. Our main objectives were to assess the prevalence rates and severity of various psychosis symptoms in a representative community sample. Furthermore, we wanted to analyze which latent factors are depicted by several currently used psychosis questionnaires. We also examined how those latent factors for sub-clinical psychosis are linked to psychosocial factors, normal personality traits, and coping abilities related to chronic stress. Most of the eight subscales from the Paranoia Checklist and the Structured Interview for Assessing Perceptual Anomalies had a very similar type of distribution, i.e., an inverse Gaussian (Wald) distribution. This supported the notion of a continuity of psychotic symptoms, which we would expect to find for continuously distributed symptoms within the general population. Sub-clinical psychosis can be reduced to two different factors - one representing odd beliefs about the world and odd behavior, and the other one representing anomalous perceptions (such as hallucinations). Persons with odd beliefs and behavior are under greater burden and more susceptible to psychosocial risks than are persons with anomalous perceptions. These sub-clinical psychosis syndromes are also related to stable personality traits. In conclusion, we obtained strong support for the notion that there is no natural cut-off separating psychotic illness from good health. Sub clinical psychosis of any kind is not trivial because it is associated with various types of social disability. PMID- 25523752 TI - Wearable magnetic field sensors for flexible electronics. AB - Highly flexible bismuth Hall sensors on polymeric foils are fabricated, and the key optimization steps that are required to boost their sensitivity to the bulk value are identified. The sensor can be bent around the wrist or positioned on the finger to realize an interactive pointing device for wearable electronics. Furthermore, this technology is of great interest for the rapidly developing market of -eMobility, for optimization of eMotors and magnetic bearings. PMID- 25523753 TI - HIV treatment outcomes among people who inject drugs in Victoria, Australia. AB - BACKGROUND: People who inject drugs (PWID) are a key population affected by HIV. We assessed the effectiveness of HIV treatment among a clinical cohort of people living with HIV (PLHIV) diagnosed and referred for community-based antiretroviral therapy (ART) in Victoria, Australia. METHODS: HIV notification data from a central statewide registry were matched with HIV clinical data from two large HIV treatment centers in Melbourne. We used survival analysis and Cox proportional hazard models to estimate time to AIDS and death for PWID in HIV treatment, compared with non-injectors, in the period 1996-2008. RESULTS: Of the 871 individuals, 93 (10.8%) had injecting as an exposure category and 671 (86%) had ever commenced ART. Adjusted analysis showed younger age, high initial CD4 cell count (>500 cells/mm(3)) or ever having a CD4 cell count >500/mm(3), and more recent calendar year of ART commencement were all associated with reduced hazards for AIDS and death, while older age, low initial CD4 cell count (<200/mm(3)), ever having a CD4 count <200/mm(3) (before or during treatment) and high initial viral load (>5 log10) were associated with increased risk of AIDS and death. PWID were no more likely to experience AIDS (HR 0.98 [0.54-1.80]) or death (HR 0.78 [0.18-3.42]) than non-injectors. CONCLUSION: Survival of HIV-infected PWID on HIV treatment was equivalent to non-injectors. CD4 cell count, initial viral load, calendar year of commencing ART and age are more important determinants of AIDS and mortality than injecting status for in-treatment PLHIV in Victoria, Australia. PMID- 25523755 TI - Craniocerebral gunshot wound in a baby chimpanzee--an uncommon experience of neurosurgical treatment conducted in the Guinean forest. AB - An orphan female chimpanzee was wounded by a left craniocerebral gunshot complicated with a right hemiparesis. Local treatment and long-term antibiotherapy failed to lead to healing. A neurosurgical procedure was planned and achieved. She fully recovered, and 2 years after the procedure, there is no evidence of infection. PMID- 25523754 TI - Chronic changes in the articular cartilage and meniscus following traumatic impact to the lapine knee. AB - The objective of this study was to induce anterior cruciate ligament (ACL) and meniscal damage, via a single tibiofemoral compressive impact, in order to document articular cartilage and meniscal changes post-impact. Tibiofemoral joints of Flemish Giant rabbits were subjected to a single blunt impact that ruptured the ACL and produced acute meniscal damage. Animals were allowed unrestricted cage activity for 12 weeks before euthanasia. India ink analysis of the articular cartilage revealed higher degrees of surface damage on the impacted tibias (p=0.018) and femurs (p<0.0001) compared to controls. Chronic meniscal damage was most prevalent in the medial central and medial posterior regions. Mechanical tests revealed an overall 19.4% increase in tibial plateau cartilage thickness (p=0.026), 34.8% increase in tibial plateau permeability (p=0.054), 40.8% increase in femoral condyle permeability (p=0.029), and 20.1% decrease in femoral condyle matrix modulus (p=0.012) in impacted joints compared to controls. Both instantaneous and equilibrium moduli of the lateral and medial menisci were decreased compared to control (p<0.02). Histological analyses revealed significantly increased presence of fissures in the medial femur (p=0.036). In both meniscus and cartilage there was a significant decrease in GAG coverage for the impacted limbs. Based on these results it is clear that an unattended combined meniscal and ACL injury results in significant changes to the soft tissues in this experimental joint 12 weeks post-injury. Such changes are consistent with a clinical description of mid to late stage PTOA of the knee. PMID- 25523756 TI - Oxygen-dependent heat tolerance and developmental plasticity in turtle embryos. AB - Oxygen and temperature have previously been treated as different environmental stresses and studied separately in most cases. Although the oxygen-temperature interaction may provide new insight into proximate and evolutionary constraints on embryonic development and offspring fitness, it has rarely been studied in oviparous amniotes. We used a two-factor experiment [three oxygen concentrations (12, 22 and 30%) * two temperatures (26.5 and 34 degrees C)] to identify the effect of the oxygen-temperature interaction on embryonic development and hatchling traits in the Chinese soft-shelled turtle, Pelodiscus sinensis. When eggs were incubated at the critically high temperature, hatching success of turtle eggs was enhanced by hyperoxia but reduced by hypoxia; this result was not observed in eggs incubated at the benign temperature. Hypoxia retarded embryonic development, and reduced body size, locomotor performance and survival rate of hatchings at the critically high temperature. However, the effects of hypoxia were greatly reduced at the benign temperature. Our study demonstrates that oxygen and temperature interact to affect not only the heat tolerance and developmental rate of embryos but also the fitness-related traits of hatchlings, suggesting that interactions among environmental factors impose significant ecological constraints on embryonic development in oviparous amniotes. PMID- 25523757 TI - Modulator-free quadrature amplitude modulation signal synthesis. AB - The ability to generate high-speed on-off-keyed telecommunication signals by directly modulating a semiconductor laser's drive current was one of the most exciting prospective applications of the nascent field of laser technology throughout the 1960s. Three decades of progress led to the commercialization of 2.5 Gbit s(-1)-per-channel submarine fibre optic systems that drove the growth of the internet as a global phenomenon. However, the detrimental frequency chirp associated with direct modulation forced industry to use external electro-optic modulators to deliver the next generation of on-off-keyed 10 Gbit s(-1) systems and is absolutely prohibitive for today's (>)100 Gbit s(-1) coherent systems, which use complex modulation formats (for example, quadrature amplitude modulation). Here we use optical injection locking of directly modulated semiconductor lasers to generate complex modulation format signals showing distinct advantages over current and other currently researched solutions. PMID- 25523758 TI - Acute nasal injury. PMID- 25523759 TI - Perforin gene transfer into hematopoietic stem cells improves immune dysregulation in murine models of perforin deficiency. AB - Defects in perforin lead to the failure of T and NK cell cytotoxicity, hypercytokinemia, and the immune dysregulatory condition known as familial hemophagocytic lymphohistiocytosis (FHL). The only curative treatment is allogeneic hematopoietic stem cell transplantation which carries substantial risks. We used lentiviral vectors (LV) expressing the human perforin gene, under the transcriptional control of the ubiquitous phosphoglycerate kinase promoter or a lineage-specific perforin promoter, to correct the defect in different murine models. Following LV-mediated gene transfer into progenitor cells from perforin deficient mice, we observed perforin expression in mature T and NK cells, and there was no evidence of progenitor cell toxicity when transplanted into irradiated recipients. The resulting perforin-reconstituted NK cells showed partial recovery of cytotoxicity, and we observed full recovery of cytotoxicity in polyclonal CD8(+) T cells. Furthermore, reconstituted T cells with defined antigen specificity displayed normal cytotoxic function against peptide-loaded targets. Reconstituted CD8(+) lymphoblasts had reduced interferon-gamma secretion following stimulation in vitro, suggesting restoration of normal immune regulation. Finally, upon viral challenge, mice with >30% engraftment of gene modified cells exhibited reduction of cytokine hypersecretion and cytopenias. This study demonstrates the potential of hematopoietic stem cell gene therapy as a curative treatment for perforin-deficient FHL. PMID- 25523760 TI - Cell cycle status of CD34(+) hemopoietic stem cells determines lentiviral integration in actively transcribed and development-related genes. AB - Gene therapy utilizing lentiviral-vectors (LVs) is postulated as a dynamic therapeutic alternative for monogenic diseases. However, retroviral gene transfer may cause insertional mutagenesis. Although, such risks had been originally estimated as extremely low, several reports of leukemias or clonal dominance, have led to a re-evaluation of the mechanisms operating in insertional mutagenesis. Therefore, unraveling the mechanism of retroviral integration is mandatory toward safer gene therapy applications. In the present study, we undertook an experimental approach which enabled direct correlation of the cell cycle stage of the target cell with the integration profile of LVs. CD34(+) cells arrested at different stages of cell cycle, were transduced with a GFP-LV. LAM PCR was employed for integration site detection, followed by microarray analysis to correlate transcribed genes with integration sites. The results indicate that ~10% of integration events occurred in actively transcribed genes and that the cell cycle stage of target cells affects integration pattern. Specifically, use of thymine promoted a safer profile, since it significantly reduced integration within cell cycle-related genes, while we observed increased possibility for integration into genes related to development, and decreased possibility for integration within cell cycle and cancer-related genes, when transduction occurs during mitosis. PMID- 25523761 TI - Biological ablation of sentinel lymph node metastasis in submucosally invaded early gastrointestinal cancer. AB - Currently, early gastrointestinal cancers are treated endoscopically, as long as there are no lymph node metastases. However, once a gastrointestinal cancer invades the submucosal layer, the lymph node metastatic rate rises to higher than 10%. Therefore, surgery is still the gold standard to remove regional lymph nodes containing possible metastases. Here, to avoid prophylactic surgery, we propose a less-invasive biological ablation of lymph node metastasis in submucosally invaded gastrointestinal cancer patients. We have established an orthotopic early rectal cancer xenograft model with spontaneous lymph node metastasis by implantation of green fluorescent protein (GFP)-labeled human colon cancer cells into the submucosal layer of the murine rectum. A solution containing telomerase specific oncolytic adenovirus was injected into the peritumoral submucosal space, followed by excision of the primary rectal tumors mimicking the endoscopic submucosal dissection (ESD) technique. Seven days after treatment, GFP signals had completely disappeared indicating that sentinel lymph node metastasis was selectively eradicated. Moreover, biologically treated mice were confirmed to be relapse-free even 4 weeks after treatment. These results indicate that virus mediated biological ablation selectively targets lymph node metastasis and provides a potential alternative to surgery for submucosal invasive gastrointestinal cancer patients. PMID- 25523762 TI - Comparative Genome Analysis of Two Isolates of the Fish Pathogen Piscirickettsia salmonis from Different Hosts Reveals Major Differences in Virulence-Associated Secretion Systems. AB - Outbreaks caused by Piscirickettsia salmonis are one of the major threats to the sustainability of the Chilean salmon industry. We report here the annotated draft genomes of two P. salmonis isolates recovered from different salmonid species. A comparative analysis showed that the number of virulence-associated secretion systems constitutes a main genomic difference. PMID- 25523763 TI - Complete Genome Sequence of the Larval Shellfish Pathogen Vibrio tubiashii Type Strain ATCC 19109. AB - Vibrio tubiashii is a larval shellfish pathogen. Here, we report the first closed genome sequence for this species (ATCC type strain 19109), which consists of two chromosomes (3,294,490 and 1,766,582 bp), two megaplasmids (251,408 and 122,808 bp), and two plasmids (57,076 and 47,973 bp). PMID- 25523764 TI - Complete Genome Sequence for the Shellfish Pathogen Vibrio coralliilyticus RE98 Isolated from a Shellfish Hatchery. AB - Vibrio coralliilyticus is a pathogen of corals and larval shellfish. Publications on strain RE98 list it as a Vibrio tubiashii; however, whole genome sequencing confirms RE98 as V. coralliilyticus containing a total of 6,037,824 bp consisting of two chromosomes (3,420,228 and 1,917,482 bp) and two megaplasmids (380,714 and 319,400 bp). PMID- 25523765 TI - Draft Whole-Genome Sequences of 10 Serogroup O6 Enterotoxigenic Escherichia coli Strains. AB - Entertotoxigenic Escherichia coli (ETEC) is a major cause of global diarrhea, resulting in approximately 200 million occurrences and 300,000 to 400,000 deaths annually, primarily in children under the age of five. Here, we announce the release of the draft genomes of 10 ETEC isolates belonging to serogroup O6. PMID- 25523766 TI - Draft Genome Sequences of Escherichia coli Strains Isolated from Septic Patients. AB - We present the draft genome sequences of six strains of Escherichia coli isolated from blood cultures collected from patients with sepsis. The strains were collected from two patient sets, those with a high severity of illness, and those with a low severity of illness. Each genome was sequenced by both Illumina and PacBio for comparison. PMID- 25523767 TI - Genome sequence of torovirus identified from a pig with porcine epidemic diarrhea virus from the United States. AB - Porcine torovirus (PToV) strain PToV-NPL/2013 was identified from a pig that tested positive for porcine epidemic diarrhea virus (PEDV). The spike protein encoding gene from PToV-NPL/2013 had 92% identity with PToV-SH1, suggesting that PToV circulating in the United States is slightly different from the isolates circulating in China. To our knowledge, this is the first report of PToV in the United States. PMID- 25523768 TI - Draft Genome Sequence of New Bacillus cereus Strain tsu1. AB - This paper reports the draft genome sequence of new Bacillus cereus strain tsu1, isolated on an agar-cellulose plate. The draft genome sequence is 5.81 Mb, revealing 5,673 coding sequences. It contains genes for cellulose-degradation and biosynthesis pathways of polyhydroxybutyrate (PHB) and 8 rRNA genes (5S, 16S, and 23S). PMID- 25523769 TI - Complete Genome Sequence of Solvent-Tolerant Clostridium beijerinckii Strain SA 1. AB - We report the complete genome sequence of Clostridium beijerinckii SA-1, derived by directed evolution from C. beijerinckii NCIMB 8052, selecting for enhanced solvent tolerance. This sequence allows for accurate placement of SA-1 as C. beijerinckii, permits functional analyses of mutant phenotypes, and suggests methods for distinguishing SA-1 from its parent. PMID- 25523770 TI - Complete Genome Sequence of Bifidobacterium longum 105-A, a Strain with High Transformation Efficiency. AB - Bifidobacterium longum 105-A shows high transformation efficiency and allows for the generation of gene knockout mutants through homologous recombination. Here, we report the complete genome sequence of strain 105-A. Genes encoding at least four putative restriction-modification systems were found in this genome, which might contribute to its transformation efficiency. PMID- 25523771 TI - Complete Genome Sequence of a Betanodavirus Isolated from Half-Smooth Tongue Sole (Cynoglossus semilaevis). AB - Betanodavirus, commonly called nervous necrosis virus (NNV) of fish, has emerged as a major constraint on marine aquaculture worldwide. Here, we report the complete genome sequence of a betanodavirus (strain CsCN128) isolated from diseased half-smooth tongue sole (Cynoglossus semilaevis) in China. The genome sequence of strain CsCN128 shares >=98.7% similarity with seven-band grouper nervous necrosis virus from Japan. Phylogenetic analysis indicates that strain CsCN128 belongs to the red-spotted grouper nervous necrosis virus (RGNNV) genotype of betanodavirus. The genome of the strain CsCN128 will facilitate further study on the molecular epidemiology and natural susceptible host range of betanodaviruses. PMID- 25523772 TI - Genome Sequence of the Deep-Sea Denitrifier Pseudomonas sp. Strain MT-1, Isolated from the Mariana Trench. AB - Pseudomonas sp. strain MT-1 was the first deep-sea denitrifier isolated and characterized from mud recovered from a depth of 11,000 m in the Mariana Trench. We report here the genome sequence of this bacterium, which contributes to our understanding of denitrification and bioenergetics in the deep sea. PMID- 25523773 TI - Draft Genome Sequence of Bradyrhizobium japonicum Is-34, Which Is Incompatible with Rj4 Genotype Soybeans. AB - We report here the draft genome sequence of Bradyrhizobium japonicum Is-34, which is incompatible with Rj4 genotype soybeans. A candidate gene involved in this incompatibility was found to be present in this genome. PMID- 25523774 TI - Complete Genome Sequence of Vibrio coralliilyticus Strain OCN014, Isolated from a Diseased Coral at Palmyra Atoll. AB - Vibrio coralliilyticus is a marine gammaproteobacterium that has been implicated as an etiological agent of disease for multiple coral genera on reefs worldwide. We report the complete genome of V. coralliilyticus strain OCN014, isolated from a diseased Acropora cytherea colony off the western reef terrace of Palmyra Atoll. PMID- 25523775 TI - Full-Genome Sequence of a Reassortant H1N2 Influenza A Virus Isolated from Pigs in Brazil. AB - In this study, the full-genome sequence of a reassortant H1N2 swine influenza virus is reported. The isolate has the hemagglutinin (HA) and neuraminidase (NA) genes from human lineage (H1-delta cluster and N2), and the internal genes (polymerase basic 1 [PB1], polymerase basic 2 [PB2], polymerase acidic [PA], nucleoprotein [NP], matrix [M], and nonstructural [NS]) are derived from human 2009 pandemic H1N1 (H1N1pdm09) virus. PMID- 25523776 TI - Characterization of human papillomavirus subtype 72b. AB - We report the characterization of human papillomavirus (HPV) subtype 72b of the genus Alphapapillomavirus isolated from an oral rinse sample of a healthy woman. The HPV72b L1 open reading frame (ORF) was 90.2% identical to that of HPV72, indicating a subtype close to the border of a novel HPV type. PMID- 25523777 TI - Draft Genome Sequence of Chelonobacter oris Strain 1662T, Associated with Respiratory Disease in Hermann's Tortoises. AB - Chelonobacter oris 1662(T) is a type strain of the recently described species of the Pasteurellaceae family. The strain was isolated from the choanae of a captive tortoise with signs of respiratory tract infection. The genome reported here is approximately 2.6 Mb in size and has a G+C content of 47.1%. PMID- 25523778 TI - Draft Genome Sequence of the Organophosphorus Compound-Degrading Burkholderia zhejiangensis Strain CEIB S4-3. AB - Burkholderia species are widely distributed in the environment. A Burkholderia zhejiangensis strain was isolated from pesticide-contaminated soil from an agricultural field in Mexico and identified as an organophosphorus compound degrading bacterium. In this study, we report the draft genome sequence of Burkholderia zhejiangensis strain CEIB S4-3. PMID- 25523779 TI - Draft Genome Sequence of Pseudomonas aeruginosa Strain WS394, a Multidrug Resistant and Highly Cytotoxic Wound Isolate from Chronic Ulcus Cruris. AB - Pseudomonas aeruginosa is a frequent human pathogen that increasingly causes chronic infections of nonhealing wounds. Here we present the 6.8 Mb draft genome of strain WS394, a multidrug-resistant chronic ulcer isolate that exhibited outstanding high cell cytotoxicity despite defective secretion of exotoxin U, suggesting a habitat-dependent adaptation process. PMID- 25523780 TI - Draft Genome Sequence of Acetobacter tropicalis Type Strain NBRC16470, a Producer of Optically Pure d-Glyceric Acid. AB - Here we report the 3.7-Mb draft genome sequence of Acetobacter tropicalis NBRC16470(T), which can produce optically pure d-glyceric acid (d-GA; 99% enantiomeric excess) from raw glycerol feedstock derived from biodiesel fuel production processes. PMID- 25523781 TI - Complete genome sequences of three ebola virus isolates from the 2014 outbreak in west Africa. AB - Here, we report the complete genome sequences, including the genome termini, of three Ebola virus isolates (species Zaire ebolavirus) originating from Guinea that are now being widely used in laboratories in North America for research regarding West African Ebola viruses. PMID- 25523782 TI - Complete Genome Sequence of Cedecea neteri Strain SSMD04, a Bacterium Isolated from Pickled Mackerel Sashimi. AB - We report here the complete genome sequence of C. neteri SSMD04, a strain isolated from pickled mackerel sashimi, sequenced by third-generation sequencing technology. To the best of our knowledge, this is the first documentation that reports the complete genome of Cedecea neteri. PMID- 25523783 TI - Draft Genome Sequence of the Principal Etiological Agent of Farmer's Lung Disease, Saccharopolyspora rectivirgula. AB - Saccharopolyspora rectivirgula is the main cause of farmer's lung disease. The development of recombinant antigens to standardize the serodiagnosis of the disease requires knowledge of the S. rectivirgula genome. We sequenced the genome of an environmental strain, S. rectivirgula DSM 43113. A total of 3,221 proteins were found to be encoded in a short 3.9-Mb genome. PMID- 25523784 TI - Draft Genome Sequence of the Probiotic Yeast Saccharomyces cerevisiae var. boulardii Strain ATCC MYA-796. AB - Saccharomyces boulardii is the only yeast approved as a probiotic for human consumption. Here, we report the draft genome sequence of the strain ATCC MYA 796, derived from the French Ultra Levure probiotic drug. The genome has a size of 11.6 Mb with 5,305 putative open reading frames predicted. PMID- 25523785 TI - Complete Genome Sequence of Bifidobacterium longum GT15: Unique Genes for Russian Strains. AB - In this study, we report the first completely annotated genome sequence of the Russian-origin Bifidobacterium longum subsp. longum strain GT15. We discovered 35 unique genes (UGs) which were detected from only the B. longum GT15 genome and were absent from other B. longum strain genomes (not of Russian origin). PMID- 25523786 TI - Characterization of the cell growth analysis for detection of immortal cellular impurities in human mesenchymal stem cells. AB - The analysis of in vitro cell senescence/growth after serial passaging can be one of ways to show the absence of immortalized cells, which are frequently tumorigenic, in human cell-processed therapeutic products (hCTPs). However, the performance of the cell growth analysis for detection of the immortalized cellular impurities has never been evaluated. In the present study, we examined the growth rates of human mesenchymal stem cells (hMSCs, passage 5 (P = 5)) contaminated with various doses of HeLa cells, and compared with that of hMSCs alone. The growth rates of the contaminated hMSCs were comparable to that of hMSCs alone at P = 5, but significantly increased at P = 6 (0.1% and 0.01% HeLa) or P = 7 (0.001% HeLa) within 30 days. These findings suggest that the cell growth analysis is a simple and sensitive method to detect immortalized cellular impurities in hCTPs derived from human somatic cells. PMID- 25523787 TI - A research roadmap of future endovascular stroke trials. PMID- 25523788 TI - Endovascular therapy for acute ischemic stroke is indicated and evidence based: a position statement. PMID- 25523789 TI - A mixed methods study of the work patterns of full-time nurse practitioners in nursing homes. AB - AIMS AND OBJECTIVES: The aim of this study was to explore the integration of the nurse practitioner role in Canadian nursing homes to enable its full potential to be realised for resident and family care. The objective was to determine nurse practitioners' patterns of work activities. BACKGROUND: Nurse practitioners were introduced in Canadian nursing homes a decade ago on a pilot basis. In recent years, government and nursing home sector interest in the role has grown along with the need for data to inform planning efforts. DESIGN: The study used a sequential mixed methods design using a national survey followed by case studies. METHODS: A national survey of nurse practitioners included demographic items and the EverCare Nurse Practitioner Role and Activity Scale. Following the survey, case studies were conducted in four nursing homes. Data were collected using individual and focus group interviews, document reviews and field notes. RESULTS: Twenty-three of a target population of 26 nurse practitioners responded to the survey, two-thirds of whom provided services in nursing homes with one site and the remainder in nursing homes with as many as four sites. On average, nurse practitioners performed activities in communicator, clinician, care manager/coordinator and coach/educator subscales at least three to four times per week and activities in the collaborator subscale once a week. Of the 43 activities, nurse practitioners performed daily, most were in the clinician and communicator subscales. Case study interviews involved 150 participants. Findings complemented those of the survey and identified additional leadership activities. CONCLUSION: Nurse practitioners undertake a range of primary health care and advanced practice activities which they adapt to meet the unique needs of nursing homes. RELEVANCE TO CLINICAL PRACTICE: Knowledge of work patterns enables nursing homes to implement the full range of nurse practitioner roles and activities to enhance resident and family care. PMID- 25523790 TI - PACAP38/PAC1 signaling induces bone marrow-derived cells homing to ischemic brain. AB - Understanding stem cell homing, which is governed by environmental signals from the surrounding niche, is important for developing effective stem cell-based repair strategies. The molecular mechanism by which the brain under ischemic stress recruits bone marrow-derived cells (BMDCs) to the vascular niche remains poorly characterized. Here we report that hypoxia-inducible factor-1alpha (HIF 1alpha) activation upregulates pituitary adenylate cyclase-activating peptide 38 (PACAP38), which in turn activates PACAP type 1 receptor (PAC1) under hypoxia in vitro and cerebral ischemia in vivo. BMDCs homing to endothelial cells in the ischemic brain are mediated by HIF-1alpha activation of the PACAP38-PAC1 signaling cascade followed by upregulation of cellular prion protein and alpha6 integrin to enhance the ability of BMDCs to bind laminin in the vascular niche. Exogenous PACAP38 confers a similar effect in facilitating BMDCs homing into the ischemic brain, resulting in reduction of ischemic brain injury. These findings suggest a novel HIF-1alpha-activated PACAP38-PAC1 signaling process in initiating BMDCs homing into the ischemic brain for reducing brain injury and enhancing functional recovery after ischemic stroke. PMID- 25523791 TI - [Hindfoot fusion for Charcot osteoarthropathy with a curved retrograde nail]. AB - BACKGROUND: Charcot osteoarthropathy of the hindfoot with considerable dislocation and instability represents a therapeutic dilemma. The treatment goal is a plantigrade, stable foot that is free of infection and ulceration with the ability to ambulate in special footwear. MATERIALS AND METHODS: Over a period of 6 years, we performed 23 hindfoot fusions in 21 patients with manifest Charcot arthropathy with the help of a curved retrograde nail (HAN). All patients suffered from insulin-dependent diabetes mellitus with polyneuropathy; 12 patients had additional peripheral vasculopathy. An average of 3.5 previous surgeries had been performed prior to hindfoot fusion. RESULTS: Complete tibiotalocalcaneal fusion was obtained in 16 of 21 patients (76 %). Of these 21 patients, 18 (86 %) were followed clinically and radiologically for an average of 2 years. Overall, 16 patients (89 %) reported a substantial subjective improvement compared to the preoperative state. Hardware failure occurred in 7 cases (30 %) that could be brought to consolidation with exchange of the locking bolts or the complete nail. In 5 cases (22 %), a postoperative hematoma had to be removed and in 8 cases (35 %) wound edge necrosis was treated with local wound care. In 2 cases (9 %), a secondary or reactivated osteitis occurred that finally required below knee amputation. CONCLUSION: Tibiotalocalcaneal fusion with a curved retrograde intramedullary nail (HAN) is an effective treatment option in highly unstable and deforming Charcot osteoarthropathy of the hindfoot. It is an alternative to external or other internal fixation methods and helps to avoid below knee amputation in more than 90 % of cases. PMID- 25523792 TI - Human adipose-derived stromal/stem cells demonstrate short-lived persistence after implantation in both an immunocompetent and an immunocompromised murine model. AB - INTRODUCTION: Mesenchymal cells are emerging as a promising cell platform for regenerative therapies. However, the fate of cells after transplantation in many different disease settings and tissue beds remains unclear. METHODS: In this study, human adipose-derived stromal/stem (ASCs) cells were fluorescently labeled with a membrane dye and injected into both immunocompetent and immunocompromised mouse strains. Cells were injected either as single cell suspensions, or as self assembling spheroids. In parallel, cells were purposefully devitalized prior to injection and then implanted in the opposite side in a randomized fashion. These 'control' groups were included to determine whether the fluorescent membrane dye would remain localized at the injection site despite the use of nonviable cells. Cell implants and the surrounding tissues were harvested on days 3, 10 and 21 after in vivo delivery and evaluated in a blinded manner. Injection sites were analyzed by fluorescent microscopy, and human cell numbers were quantified using PCR detection of a human-specific endogenous retrovirus (ERV-3). Host response was evaluated by immunofluorescent staining of macrophages. RESULTS: ERV-3 quantification showed that 95% of the human cells that were viable when they were injected were undetectable at the three-week time-point. Although fluorescent signal persisted for the entire study period, further analysis revealed that much of this signal was located within host macrophages. CONCLUSIONS: These results suggest that human ASCs survive for less than three weeks after injection into even immunocompromised mice, and call into question the notion that human ASCs are immuno-privileged and capable of surviving for extended periods in xenogeneic and/or allogeneic models. PMID- 25523793 TI - Changes in Oral Health-Related Quality of Life in Elderly Edentulous Patients after Complete Denture Therapy and Possible Role of their Initial Expectation: A Follow-Up Study. AB - PURPOSE: An edentulous patient's psychosocial attributes that may have influence on the oral health-related quality of life (OHRQoL) are given little consideration in therapeutic care. The aim of this study was to assess the impact of complete denture therapy on overall OHRQoL in elderly edentulous patients. The possible role of the patient's initial expectation toward OHRQoL was also evaluated. METHODS AND MATERIALS: OHRQoL was assessed using the OHIP-EDENT psychometric instrument, and 56 patients participated in the study. The assessment was done at three time points including pretreatment, after 1 month, and after 6 months. Significant differences in the OHIP-EDENT scores between pretreatment to after 1 month and pretreatment to after 6 months were calculated using Wilcoxon Signed Rank test (p < 0.05). Mann-Whitney test was used to analyze the association of patient expectations with OHIP-EDENT scores. RESULT: Statistically significant improvement in OHRQoL after complete denture therapy at both 1 and 6 months postinsertion was evident. Statistically significant difference in the mean scores between the genders was observed after 6 months. There was no statistically significant difference in the levels of dysfunction, discomfort, and disability associated with oral problems between moderate and high expectation group at any time point. CONCLUSION: Elderly edentulous patients had an improved overall OHRQoL after complete denture therapy, and female patients had appreciably better OHRQoL than their male counterparts. A patient's initial expectation did not have significant influence on overall OHRQoL. PMID- 25523795 TI - Automated system for characterization and classification of malaria-infected stages using light microscopic images of thin blood smears. AB - In this paper, we propose a comprehensive image characterization cum classification framework for malaria-infected stage detection using microscopic images of thin blood smears. The methodology mainly includes microscopic imaging of Leishman stained blood slides, noise reduction and illumination correction, erythrocyte segmentation, feature selection followed by machine classification. Amongst three-image segmentation algorithms (namely, rule-based, Chan-Vese-based and marker-controlled watershed methods), marker-controlled watershed technique provides better boundary detection of erythrocytes specially in overlapping situations. Microscopic features at intensity, texture and morphology levels are extracted to discriminate infected and noninfected erythrocytes. In order to achieve subgroup of potential features, feature selection techniques, namely, F statistic and information gain criteria are considered here for ranking. Finally, five different classifiers, namely, Naive Bayes, multilayer perceptron neural network, logistic regression, classification and regression tree (CART), RBF neural network have been trained and tested by 888 erythrocytes (infected and noninfected) for each features' subset. Performance evaluation of the proposed methodology shows that multilayer perceptron network provides higher accuracy for malaria-infected erythrocytes recognition and infected stage classification. Results show that top 90 features ranked by F-statistic (specificity: 98.64%, sensitivity: 100%, PPV: 99.73% and overall accuracy: 96.84%) and top 60 features ranked by information gain provides better results (specificity: 97.29%, sensitivity: 100%, PPV: 99.46% and overall accuracy: 96.73%) for malaria-infected stage classification. PMID- 25523794 TI - Biochemical composition of haemagglutinin-based influenza virus-like particle vaccine produced by transient expression in tobacco plants. AB - Influenza virus-like particles (VLPs) are noninfectious particles resembling the influenza virus representing a promising vaccine alternative to inactivated influenza virions as antigens. Medicago inc. has developed a plant-based VLP manufacturing platform allowing the large-scale production of GMP-grade influenza VLPs. In this article, we report on the biochemical compositions of these plant based influenza candidate vaccines, more particularly the characterization of the N-glycan profiles of the viral haemagglutinins H1 and H5 proteins as well as the tobacco-derived lipid content and residual impurities. Mass spectrometry analyses showed that all N-glycosylation sites of the extracellular domain of the recombinant haemagglutinins carry plant-specific complex-type N-glycans having core alpha(1,3)-fucose, core beta(1,2)-xylose epitopes and Lewis(a) extensions. Previous phases I and II clinical studies have demonstrated that no hypersensibility nor induction of IgG or IgE directed against these glycans was observed. In addition, this article showed that the plant-made influenza vaccines are highly pure VLPs preparations while detecting no protein contaminants coming either from Agrobacterium or from the enzymes used for the enzyme-assisted extraction process. In contrast, VLPs contain few host cell proteins and glucosylceramides associated with plant lipid rafts. Identification of such raft markers, together with the type of host cell impurity identified, confirmed that the mechanism of VLP formation in planta is similar to the natural process of influenza virus assembly in mammals. PMID- 25523796 TI - Ecological validity of the Dysexecutive Questionnaire: Results from the PariS-TBI study. AB - The Dysexecutive Questionnaire (DEX; Wilson, Pettigrew, & Teasdale, 1998 ) has been designed to assess executive dysfunctions in daily life. However, its relationships with cognitive testing, mood, and the ability to fulfil daily life demands, have not yet been systematically addressed. The objective of this study was to address these issues in a prospective four-year follow-up study of patients with severe traumatic brain injury (TBI) (PariS-TBI study). One hundred and forty seven patients were included. The DEX (self-version) showed a good internal consistency. The total DEX score was significantly inversely correlated with years of education, but did not significantly correlate with any initial injury severity measure. The DEX was significantly and positively related to cognitive deficits, as assessed with the Neurobehavioral Rating Scale-Revised (NRS-R); with mood disorders, as assessed with the Hospital Anxiety and Depression Scale (HADS); with dependency in elementary and extended activities of daily living; and with non-return to work. In multivariate analyses, cognitive and mood impairments were significantly and independently related to the total DEX score. These results suggest that the DEX is a multidetermined sensitive questionnaire to detect everyday life difficulties in patients with severe TBI at a chronic stage. PMID- 25523797 TI - Finding CKD studies--automated searching and screening. PMID- 25523798 TI - Multidrug-resistant organisms within the dialysis population: a potentially preventable perfect storm. PMID- 25523799 TI - Daily home hemodialysis: balancing cardiovascular benefits with infectious harms. PMID- 25523800 TI - Impact of ESRD on infections of implantable cardiac rhythm devices. PMID- 25523801 TI - In reply to 'impact of ESRD on infections of implantable cardiac rhythm devices'. PMID- 25523802 TI - In reply to 'increased cardiovascular risk in women with kidney stones: urinary tract infection should be considered'. PMID- 25523803 TI - Increased cardiovascular risk in women with kidney stones: urinary tract infection should be considered. PMID- 25523804 TI - Reduced kidney function in rheumatoid arthritis: rheumatologists have a role. PMID- 25523805 TI - In reply to 'reduced kidney function in rheumatoid arthritis: rheumatologists have a role'. PMID- 25523806 TI - Making music. PMID- 25523807 TI - Quiz Page January 2015: acute kidney injury in a patient with well-controlled HIV infection. PMID- 25523809 TI - Using the quantum cell expansion system for the automated expansion of clinical grade bone marrow-derived human mesenchymal stromal cells. AB - Bone marrow-derived human mesenchymal stromal cells (hMSCs) constitute a promising therapeutic approach. However, the extremely low frequency of hMSCs in bone marrow makes the translation of these regulatory cells to clinical therapies difficult for large patient populations. Here, we describe a good manufacturing practices-compliant procedure for the expansion of hMSCs using the Quantum Cell Expansion System. This closed and automated system allows the large-scale expansion of hMSCs while maintaining their multipotency, immunophenotype, morphology, and karyotype. PMID- 25523808 TI - Evolutionarily emerged G tracts between the polypyrimidine tract and 3' AG are splicing silencers enriched in genes involved in cancer. AB - BACKGROUND: The 3' splice site (SS) at the end of pre-mRNA introns has a consensus sequence (Y)nNYAG for constitutive splicing of mammalian genes. Deviation from this consensus could change or interrupt the usage of the splice site leading to alternative or aberrant splicing, which could affect normal cell function or even the development of diseases. We have shown that the position "N" can be replaced by a CA-rich RNA element called CaRRE1 to regulate the alternative splicing of a group of genes. RESULTS: Taking it a step further, we searched the human genome for purine-rich elements between the -3 and -10 positions of the 3' splice sites of annotated introns. This identified several thousand such 3'SS; more than a thousand of them contain at least one copy of G tract. These sites deviate significantly from the consensus of constitutive splice sites and are highly associated with alterative splicing events, particularly alternative 3' splice and intron retention. We show by mutagenesis analysis and RNA interference that the G tracts are splicing silencers and a group of the associated exons are controlled by the G tract binding proteins hnRNP H/F. Species comparison of a group of the 3'SS among vertebrates suggests that most (~87%) of the G tracts emerged in ancestors of mammals during evolution. Moreover, the host genes are most significantly associated with cancer. CONCLUSION: We call these elements together with CaRRE1 regulatory RNA elements between the Py and 3'AG (REPA). The emergence of REPA in this highly constrained region indicates that this location has been remarkably permissive for the emergence of de novo regulatory RNA elements, even purine-rich motifs, in a large group of mammalian genes during evolution. This evolutionary change controls alternative splicing, likely to diversify proteomes for particular cellular functions. PMID- 25523810 TI - Generation of Patient-Specific induced Pluripotent Stem Cell from Peripheral Blood Mononuclear Cells by Sendai Reprogramming Vectors. AB - Induced pluripotent stem cells (iPSC) technology has changed preclinical research since their generation was described by Shinya Yamanaka in 2006. iPSCs are derived from somatic cells after being reprogrammed back to an embryonic state by specific combination of reprogramming factors. These reprogrammed cells resemble all the characteristic of embryonic stem cells (ESC). The reprogramming technology is even more valuable to research diseases biology and treatment by opening gene and cell therapies in own patient's iPSC. Patient-specific iPSC can be generated from a large variety of patient cells by any of the myriad of reprogramming platforms described. Here, we describe the generation of patient specific iPSC from patient peripheral blood mononuclear cells by Sendai Reprogramming vectors. PMID- 25523811 TI - Generation of Cardiomyocytes from Pluripotent Stem Cells. AB - The advent of pluripotent stem cells (PSCs) enabled a multitude of studies for modeling the development of diseases and testing pharmaceutical therapeutic potential in vitro. These PSCs have been differentiated to multiple cell types to demonstrate its pluripotent potential, including cardiomyocytes (CMs). However, the efficiency and efficacy of differentiation vary greatly between different cell lines and methods. Here, we describe two different methods for acquiring CMs from human pluripotent lines. One method involves the generation of embryoid bodies, which emulates the natural developmental process, while the other method chemically activates the canonical Wnt signaling pathway to induce a monolayer of cardiac differentiation. PMID- 25523812 TI - Human glial progenitor engraftment and gene expression is independent of the ALS environment. AB - Although Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease, basic research studies have highlighted that astrocytes contribute to the disease process. Therefore, strategies which replace the diseased astrocyte population with healthy astrocytes may protect against motor neuron degeneration. Our studies have sought to evaluate astrocyte replacement using glial-restricted progenitors (GRPs), which are lineage-restricted precursors capable of differentiating into astrocytes after transplantation. The goal of our current study was to evaluate how transplantation to the diseased ALS spinal cord versus a healthy, wild-type spinal cord may affect human GRP engraftment and selected gene expression. Human GRPs were transplanted into the spinal cord of either an ALS mouse model or wild-type littermate mice. Mice were sacrificed for analysis at either the onset of disease course or at the endstage of disease. The transplanted GRPs were analyzed by immunohistochemistry and NanoString gene profiling which showed no gross differences in the engraftment or gene expression of the cells. Our data indicate that human glial progenitor engraftment and gene expression is independent of the neurodegenerative ALS spinal cord environment. These findings are of interest given that human GRPs are currently in clinical development for spinal cord transplantation into ALS patients. PMID- 25523813 TI - Optimized methods for epilepsy therapy development using an etiologically realistic model of focal epilepsy in the rat. AB - Conventionally developed antiseizure drugs fail to control epileptic seizures in about 30% of patients, and no treatment prevents epilepsy. New etiologically realistic, syndrome-specific epilepsy models are expected to identify better treatments by capturing currently unknown ictogenic and epileptogenic mechanisms that operate in the corresponding patient populations. Additionally, the use of electrocorticography permits better monitoring of epileptogenesis and the full spectrum of acquired seizures, including focal nonconvulsive seizures that are typically difficult to treat in humans. Thus, the combined use of etiologically realistic models and electrocorticography may improve our understanding of the genesis and progression of epilepsy, and facilitate discovery and translation of novel treatments. However, this approach is labor intensive and must be optimized. To this end, we used an etiologically realistic rat model of posttraumatic epilepsy, in which the initiating fluid percussion injury closely replicates contusive closed-head injury in humans, and has been adapted to maximize epileptogenesis and focal non-convulsive seizures. We obtained week-long 5-electrode electrocorticography 1 month post-injury, and used a Monte-Carlo based non-parametric bootstrap strategy to test the impact of electrode montage design, duration-based seizure definitions, group size and duration of recordings on the assessment of posttraumatic epilepsy, and on statistical power to detect antiseizure and antiepileptogenic treatment effects. We found that use of seizure definition based on clinical criteria rather than event duration, and of recording montages closely sampling the activity of epileptic foci, maximize the power to detect treatment effects. Detection of treatment effects was marginally improved by prolonged recording, and 24h recording epochs were sufficient to provide 80% power to detect clinically interesting seizure control or prevention of seizures with small groups of animals. We conclude that appropriate electrode montage and clinically relevant seizure definition permit convenient deployment of fluid percussion injury and electrocorticography for epilepsy therapy development. PMID- 25523814 TI - Clock model makes a large difference to age estimates of long-stemmed clades with no internal calibration: a test using Australian grasstrees. AB - BACKGROUND: Estimating divergence times in phylogenies using a molecular clock depends on accurate modeling of nucleotide substitution rates in DNA sequences. Rate heterogeneity among lineages is likely to affect estimates, especially in lineages with long stems and short crowns ("broom" clades) and no internal calibration. We evaluate the performance of the random local clocks model (RLC) and the more routinely employed uncorrelated lognormal relaxed clock model (UCLN) in situations in which a significant rate shift occurs on the stem branch of a broom clade. We compare the results of simulations to empirical results from analyses of a real rate-heterogeneous taxon - Australian grass trees (Xanthorrhoea) - whose substitution rate is slower than in its sister groups, as determined by relative rate tests. RESULTS: In the simulated datasets, the RLC model performed much better than UCLN: RLC correctly estimated the age of the crown node of slow-rate broom clades, whereas UCLN estimates were consistently too young. Similarly, in the Xanthorrhoea dataset, UCLN returned significantly younger crown ages than RLC (mean estimates respectively 3-6 Ma versus 25-35 Ma). In both real and simulated datasets, Bayes Factor tests strongly favored the RLC model over the UCLN model. CONCLUSIONS: The choice of an unsuitable molecular clock model can strongly bias divergence time estimates. In particular, for data predicted to have more rate variation among than within clades, dating with RLC is much more likely to be accurate than with UCLN. The choice of clocks should be informed by the biology of the study group (e.g., life-form) or assessed with relative rate tests and post-hoc model comparisons. PMID- 25523815 TI - Effectiveness of lifestyle-based weight loss interventions for adults with type 2 diabetes: a systematic review and meta-analysis. AB - AIMS: To provide a systematic review and meta-analysis of recent evidence on the effectiveness of lifestyle-based weight loss interventions for adults with type 2 diabetes. METHODS: A search of the literature from January 2003 to July 2013 was conducted (PubMed, Embase, CINAHL and Web of Science). The studies considered eligible were randomized controlled trials evaluating weight loss interventions (diet and physical activity, with or without behavioural strategies) of >=12 weeks duration, compared with usual care or another comparison intervention. Ten studies were included for review. Some heterogeneity was present in the sample, therefore, random-effects models were used to calculate pooled effects. RESULTS: Intervention duration ranged from 16 weeks to 9 years, with all but one delivered via individual or group face-to-face sessions. From six studies comparing lifestyle intervention with usual care the pooled effect on weight (n = 5795) was -3.33 kg [95% confidence interval (CI) -5.06, -1.60 kg], and on glycated haemoglobin (HbA1c; n = 5784) was -0.29% (95% CI -0.61, 0.03%), with both attenuated in sensitivity analyses. The pooled within-group effect on weight (n = 3063) from all 10 lifestyle intervention groups was -5.33 kg (95% CI -7.33, -3.34 kg), also attenuated in sensitivity analyses. None of the participant or intervention characteristics examined explained the heterogeneity. Only one study assessed whether intervention effects were maintained after the end of the intervention. CONCLUSIONS: Lifestyle-based weight loss intervention trials in type 2 diabetes achieve, on average, modest reductions in weight and HbA1c levels, but results were heavily influenced by one trial. Evidence-based approaches for improving the effectiveness of lifestyle-based interventions in type 2 diabetes are needed, along with future studies reporting on maintenance and cost-effectiveness. PMID- 25523817 TI - A bridge over troubled waters. PMID- 25523816 TI - Single (19)F probe for simultaneous detection of multiple metal ions using miCEST MRI. AB - The local presence and concentration of metal ions in biological systems has been extensively studied ex vivo using fluorescent dyes. However, the detection of multiple metal ions in vivo remains a major challenge. We present a magnetic resonance imaging (MRI)-based method for noninvasive detection of specific ions that may be coexisting, using the tetrafluorinated derivative of the BAPTA (TF BAPTA) chelate as a (19)F chelate analogue of existing optical dyes. Taking advantage of the difference in the ion-specific (19)F nuclear magnetic resonance (NMR) chemical shift offset (Deltaomega) values between the ion-bound and free TF BAPTA, we exploited the dynamic exchange between ion-bound and free TF-BAPTA to obtain MRI contrast with multi-ion chemical exchange saturation transfer (miCEST). We demonstrate that TF-BAPTA as a prototype single (19)F probe can be used to separately visualize mixed Zn(2+) and Fe(2+) ions in a specific and simultaneous fashion, without interference from potential competitive ions. PMID- 25523818 TI - Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke. AB - Although exposure to environmental pollutants is one of the risk factors for renal cell carcinoma (RCC), its relationship with carcinogenesis and the progression of RCC remains unknown. The present study was designed to elucidate the role of the aryl hydrocarbon receptor (AhR), a major mediator of carcinogenesis caused by environmental pollutants, in the progression of RCC. The expression of AhR was investigated in 120 patients with RCC using immunohistochemistry, and its relationship with clinicopathological parameters and prognoses was statistically analyzed. RCC cell lines were exposed to indirubin or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), AhR ligands, to activate the AhR pathway, or were transfected with small interfering RNA (siRNA) for AhR. The expression of the AhR target genes CYP1A1 and CYP1B1, matrix metalloproteinases (MMPs), and invasion through Matrigel(TM) were then examined. AhR was predominantly expressed in the nuclei of high-grade clear cell RCC (ccRCC) and tumor-infiltrating lymphocytes (TILs), and its expression levels in cancer cells and TILs correlated with the pathological tumor stage and histological grade. A multivariate Cox analysis revealed that the strong expression of AhR in cancer cells was a significant and independent predictor of disease-specific survival. AhR ligands up-regulated the expression of AhR and CYPs and promoted invasion by up-regulating MMPs. Furthermore, siRNA for AhR down regulated CYPs, and inhibited cancer cell invasion together with the down regulation of MMPs. These results suggest that AhR regulates the invasion of ccRCC and may be involved in tumor immunity. Therefore, inhibiting the activation of AhR may represent a potentially attractive therapeutic target for ccRCC patients. PMID- 25523819 TI - Knock-in mouse model of alternating hemiplegia of childhood: behavioral and electrophysiologic characterization. AB - OBJECTIVES: Mutations in the ATP1alpha3 subunit of the neuronal Na+/K+-ATPase are thought to be responsible for seizures, hemiplegias, and other symptoms of alternating hemiplegia of childhood (AHC). However, the mechanisms through which ATP1A3 mutations mediate their pathophysiologic consequences are not yet understood. The following hypotheses were investigated: (1) Our novel knock-in mouse carrying the most common heterozygous mutation causing AHC (D801N) will exhibit the manifestations of the human condition and display predisposition to seizures; and (2) the underlying pathophysiology in this mouse model involves increased excitability in response to electrical stimulation of Schaffer collaterals and abnormal predisposition to spreading depression (SD). METHODS: We generated the D801N mutant mouse (Mashlool, Mashl+/-) and compared mutant and wild-type (WT) littermates. Behavioral tests, amygdala kindling, flurothyl induced seizure threshold, spontaneous recurrent seizures (SRS), and other paroxysmal activities were compared between groups. In vitro electrophysiologic slice experiments on hippocampus were performed to assess predisposition to hyperexcitability and SD. RESULTS: Mutant mice manifested a distinctive phenotype similar to that of humans with AHC. They had abnormal impulsivity, memory, gait, motor coordination, tremor, motor control, endogenous nociceptive response, paroxysmal hemiplegias, diplegias, dystonias, and SRS, as well as predisposition to kindling, to flurothyl-induced seizures, and to sudden unexpected death. Hippocampal slices of mutants, in contrast to WT animals, showed hyperexcitable responses to 1 Hz pulse-trains of electrical stimuli delivered to the Schaffer collaterals and had significantly longer duration of K+-induced SD responses. SIGNIFICANCE: Our model reproduces the major characteristics of human AHC, and indicates that ATP1alpha3 dysfunction results in abnormal short-term plasticity with increased excitability (potential mechanism for seizures) and a predisposition to more severe SD responses (potential mechanism for hemiplegias). This model of the human condition should help in understanding the molecular pathways underlying these phenotypes and may lead to identification of novel therapeutic strategies of ATP1alpha3 related disorders and seizures. PMID- 25523820 TI - [A challenge that is worth it]. PMID- 25523821 TI - Cognition and brain abnormalities on MRI in pituitary patients. AB - PURPOSE: The extent to which cognitive dysfunction is related to specific brain abnormalities in patients treated for pituitary macroadenoma is unclear. Therefore, we compared brain abnormalities seen on Magnetic Resonance Imaging (MRI) in patients treated for nonfunctioning pituitary macroadenoma (NFA) with or without impairments in cognitive functioning. METHODS: In this cross-sectional design, a cohort of 43 NFA patients was studied at the University Medical Center Groningen. White matter lesions (WMLs), cerebral atrophy, (silent) brain infarcts and abnormalities of the temporal lobes and hippocampi were assessed on pre treatment and post-treatment MRI scans. Post-treatment cognitive examinations were performed using a verbal memory and executive functioning test. We compared our patient cohort with large reference populations representative of the Dutch population. RESULTS: One or more impairments on both cognitive tests were frequently observed in treated NFA patients. No treatment effects were found with regard to the comparison between patients with and without impairments in executive functioning. Interestingly, in patients with one or more impairments on verbal memory function, treatment with radiotherapy had been given more frequently (74% in the impaired group versus 40% in the unimpaired group, P=0.025). Patients with or without any brain abnormality on MRI did not differ in verbal memory or executive functioning. CONCLUSIONS: Brain abnormalities on MRI are not observed more frequently in treated NFA patients with impairments compared to NFA patients without impairments in verbal memory or executive functioning. Conversely, the absence of brain abnormalities on MRI does not exclude impairments in cognition. PMID- 25523822 TI - Quantitative T2(*) assessment of knee joint cartilage after running a marathon. AB - OBJECTIVE: To study the effect of repetitive joint loading on the T2(*) assessment of knee joint cartilage. MATERIALS AND METHODS: T2(*) mapping was performed in 10 non-professional marathon runners (mean age: 28.7+/-3.97 years) with no morphologically evident cartilage damage within 48h prior to and following the marathon and after a period of approximately four weeks. Bulk and zonal T2(*) values at the medial and lateral tibiofemoral compartment and the patellofemoral compartment were assessed by means of region of interest analysis. Pre- and post-marathon values were compared. RESULTS: There was a small increase in the T2(*) after running the marathon (30.47+/-5.16ms versus 29.84+/-4.97ms, P<0.05) while the T2(*) values before the marathon and those after the period of convalescence were similar (29.84+/-4.97ms versus 29.81+/-5.17ms, P=0.855). Regional analyses revealed lower T2(*) values in the medial tibial plateau (P<0.001). CONCLUSIONS: It appears that repetitive joint loading has a transient influence on the T2(*) values. However, this effect is small and probably not clinically relevant. The low T2(*) values in the medial tibial plateau may be related to functional demand or early cartilage degeneration. PMID- 25523823 TI - Percutaneous cannulated screw fixation of sacral fractures and sacroiliac joint disruptions with CT-controlled guidewires performed by interventionalists: single center experience in treating posterior pelvic instability. AB - OBJECTIVE: The purpose of our study was to evaluate minimally invasive sacroiliac screw fixation for treatment of posterior pelvic instability with the help of CT controlled guidewires, assess its accuracy, safety and effectiveness, and discuss potential pitfalls. METHODS: 100 guidewires and hollow titan screws were inserted in 38 patients (49.6+/-19.5 years) suffering from 35 sacral fractures and/or 16 sacroiliac joint disruptions due to 33 (poly-)traumatic, 2 osteoporotic and 1 post-infectious conditions. The guidewire and screw positions were analyzed in multiplanar reconstructions. RESULTS: The mean minimal distance between guidewire and adjacent neural foramina was 4.5+/-2.01mm, with a distinctly higher precision in S1 than S2. Eight guidewires showed cortical contacts, resulting in a total of 2% mismatched screws with subsequent wall violation. The fracture gaps were reduced from 3.6+/-0.53mm to 1.2+/-0.54mm. During follow-up 3 cases of minor iatrogenic sacral impaction (<5mm) due to the bolting and 2 cases of screw loosening were observed. Interventional time was 84.0min with a mean of 2.63 screws per patient whilst acquiring a mean of 93.7 interventional CT-images (DLP 336.7mGycm). CONCLUSIONS: The treatment of posterior pelvic instability with a guidewire-based screw insertion technique under CT-imaging results in a very high accuracy and efficacy with a low complication rate. Careful attention should be drawn to radiation levels. PMID- 25523824 TI - Phosphine and phosphine oxide groups in metal-organic frameworks detected by P K edge XAS. AB - Phosphine metal-organic frameworks (P-MOFs) are crystalline porous coordination polymers that contain phosphorus functional groups within their pores. We present the use of X-ray absorption spectroscopy (XAS) at the P K-edge to determine the phosphine to phosphine oxide ratio in two P-MOFs with MIL-101 topology. The phosphorus oxidation state is of particular interest as it strongly influences the coordination affinity of these materials for transition metals. This method can determine the oxidation state of phosphorus even when the material contains paramagnetic nuclei, differently from NMR spectroscopy. We observed that phosphine in LSK-15 accounts for 72 +/- 4% of the total phosphorus groups and that LSK-12 contains only phosphine oxide. PMID- 25523825 TI - Intratumoral anti-HuD immunotoxin therapy for small cell lung cancer and neuroblastoma. AB - BACKGROUND: Most patients with small cell lung cancer (SCLC) or neuroblastoma (NB) already show clinically detectable metastases at diagnosis and have an extremely poor prognosis even when treated with combined modalities. The HuD antigen is a neuronal RNA-binding protein that is expressed in 100% of SCLC tumor cells and over 50% of neuroblastoma cells. The correlation between high titers of circulating anti-HuD antibodies in patients and spontaneous tumor remission suggests that the HuD-antigen might be a potential molecular target for immunotherapy. METHODS: We have constructed a new antibody-toxin compound (called BW-2) by assembling a mouse anti-human-HuD monoclonal antibody onto streptavidin/saporin complexes. RESULTS: We found that the immunotoxin BW-2 specifically killed HuD-positive human SCLC and NB cancer cells at very low concentrations in vitro. Moreover, intratumoral immunotoxin therapy in a nude mouse model of human SCLC (n = 6) significantly reduced local tumor progression without causing toxicity. When the same intratumoral immunotoxin protocol was applied to an immunocompetent A/J mouse model of NB, significant inhibition of local tumor growth was also observed. In neuroblastoma allografted A/J mice (n = 5) treated twice with intratumoral immunotoxin, significant tumor regression occurred in over 80% of the animals and their duration of tumor response was significantly prolonged. CONCLUSIONS: Our study suggests that anti-HuD based immunotoxin therapy may prove to be an effective alternative treatment for patients with SCLC and NB. PMID- 25523826 TI - Clinical characteristics and outcome of the capsular warning syndrome: a multicenter study. AB - BACKGROUND: The capsular warning syndrome is defined as recurrent transient lacunar syndromes that usually precede a capsular infarction. Several aspects regarding the clinical management are controversial. We report the clinical and radiological characteristics of a multicenter series of patients with capsular warning syndrome, as well as their functional outcome during the follow-up. AIMS: We sought to describe the clinico-radiological spectrum of the capsular warning syndrome and to report the functional outcomes and recurrences of these patients during the follow-up. METHODS: We conducted a multicenter study that collected clinical and radiological data from patients with capsular warning syndrome during 2003-2013. Capsular warning syndrome was defined as the succession of three or more motor or sensory-motor lacunar syndromes within a period of 72 h, with complete recovery between them. We recorded the functional outcome (favorable when Rankin scale score <=2) and recurrences during follow-up. RESULTS: Our study included 42 patients whose mean age was 66.4 +/- 10 years; 71.4% of them were men. The mean number of episodes before a permanent neurological impairment occurred or before a complete recovery of symptoms was 5.1 +/- 2.3. Up to 30 patients (71.2%) had an acute infarct visible on the neuroimaging (computed tomography/magnetic resonance imaging). The internal capsule was the most frequent infarct location (50%), but other locations were noted. Twelve patients (28.6%) received thrombolysis in the acute phase. A favorable outcome was observed in 39 patients (92.9%). After a mean follow-up of 35 +/- 29 months, only one patient suffered a recurrent ischemic stroke. CONCLUSIONS: Capsular warning syndrome preceded an ischemic infarction in 71.2% of patients. In addition to the internal capsule, other locations were noted. The most effective treatment remains unclear. The functional prognosis is favorable in most patients and recurrences are rare. PMID- 25523828 TI - Identification of oxidative stress-induced gene expression profiles in cavernosal endothelial cells. AB - The aim of the present study was to explore the regulation status of genes in oxidative stress (OS)-induced endothelial dysfunction and to elucidate the mechanism of action of OS-associated genes, which induce cavernosal endothelial dysfunction in erectile dysfunction (ED). OS was established in purified cavernosal endothelial cells (CECs) using xanthine/xanthine oxidase and the differentially expressed OS-associated genes were analyzed using gene microarrays. In addition, an ED rat model was established through bilateral internal iliac artery ligation with hyperlipidemia and was verified by an intracavernosal pressure test. The selected OS-associated genes were validated in the CECs and ED rat model using reverse transcription-quantitative polymerase chain reaction. Student's t-test and one-way analysis of variance were performed using SBC analysis system. Gene microarray analysis revealed that 13090 (31.92%) genes were expressed in the control group, whereas 12039 (29.35%) genes were expressed in the treated group. The cut-off value for differential expression was set at 2.0 fold-change and 2480 genes were found to be differentially expressed compared with the control group. Of these cells, 1454 were upregulated and 1026 were downregulated. Cluster analysis identified relevant cell signaling pathways that were hypothesized to be significant in OS-associated endothelial dysfunction, including the cytokine-cytokine receptor interactions, nitrogen metabolism, coagulation cascades and cell adherens. Cxcl12, Tgfbr1, Asns, Bdkrb1 and Cdh3 genes showed a corresponding variation in the CECs and ED rat model compared with the results of the gene microarray analysis. In conclusion, in the present study, the network of differentially expressed genes and OS-associated signaling pathways identified using gene microarray analysis were validated in the CECs and ED rat model. The results indicated that OS may lead to endothelial dysfunction through certain cell signaling pathways, inducing ED. However, further functional verification is required in order to elucidate the underlying mechanisms of OS-associated cell signaling pathways in ED. PMID- 25523829 TI - Discovering cancer biomarkers from clinical samples by protein microarrays. AB - Cancer biomarkers are of potential use in early cancer diagnosis, anticancer therapy development, and monitoring the responses to treatments. Protein-based cancer biomarkers are major forms in use, as they are much easier to be monitored in body fluids or tissues. For cancer biomarker discovery, high-throughput techniques such as protein microarrays hold great promises, because they are capable of global unbiased monitoring but with a miniaturized format. In doing so, novel and cancer type specific biomarkers can be systematically discovered at an affordable cost. In this review, we give a relatively complete picture on protein microarrays applied to clinical samples for cancer biomarker discovery, and conclude this review with the future perspectives. PMID- 25523827 TI - Associations between brain microstructures, metabolites, and cognitive deficits during chronic HIV-1 infection of humanized mice. AB - BACKGROUND: Host-species specificity of the human immunodeficiency virus (HIV) limits pathobiologic, diagnostic and therapeutic research investigations to humans and non-human primates. The emergence of humanized mice as a model for viral infection of the nervous system has overcome such restrictions enabling research for HIV-associated end organ disease including behavioral, cognitive and neuropathologic deficits reflective of neuroAIDS. Chronic HIV-1 infection of NOD/scid-IL-2Rgcnull mice transplanted with human CD34+ hematopoietic stem cells (CD34-NSG) leads to persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges and perivascular spaces. Murine cells are not infected with virus. METHODS: Changes in mouse behavior were measured, starting at 8 weeks after viral infection. These were recorded coordinate with magnetic resonance spectroscopy metabolites including N acetylaspartate (NAA), creatine and choline. Diffusion tensor magnetic resonance imaging (DTI) was recorded against multispectral immunohistochemical staining for neuronal markers that included microtubule associated protein-2 (MAP2), neurofilament (NF) and synaptophysin (SYN); for astrocyte glial fibrillary acidic protein (GFAP); and for microglial ionized calcium binding adaptor molecule 1 (Iba-1). Oligodendrocyte numbers and integrity were measured for myelin associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG) antigens. RESULTS: Behavioral abnormalities were readily observed in HIV-1 infected mice. Longitudinal open field activity tests demonstrated lack of habituation indicating potential for memory loss and persistent anxiety in HIV-1 infected mice compared to uninfected controls. End-point NAA and creatine in the cerebral cortex increased with decreased MAG. NAA and glutamate decreased with decreased SYN and MAG. Robust inflammation reflected GFAP and Iba-1 staining intensities. DTI metrics were coordinate with deregulation of NF, Iba-1, MOG and MAG levels in the whisker barrel and MAP2, NF, MAG, MOG and SYN in the corpus callosum. CONCLUSIONS: The findings are consistent with some of the clinical, biochemical and pathobiologic features of human HIV-1 nervous system infections. This model will prove useful towards investigating the mechanisms of HIV-1 induced neuropathology and in developing novel biomarkers and therapeutic strategies for disease. PMID- 25523830 TI - Fenugreek (Trigonella foenum graecum) seed protein isolate: extraction optimization, amino acid composition, thermo and functional properties. AB - BACKGROUND: With increasing demand for new protein sources, research on plant protein extraction and evaluation of the functional properties of protein isolates is necessary. In this study, pH and NaCl concentration, as two parameters affecting protein extraction of fenugreek seed, was investigated and the condition of fenugreek protein isolate (FPI) extraction was optimized using response surface methodology. RESULTS: FPI had significantly (P< 0.05) higher protein and essential amino acid content (891.00 and 387.41 g kg(-1) , respectively) compared with soy protein isolate (SPI). FPI was rich in Asp and Glu, confirming the presence of bands in the acidic region (30-39 kDa) of its electrophoretic pattern. Differential scanning calorimeter thermography of both FPI and SPI showed two peaks with high denaturation temperature, confirming the presence of high protein content and hydrophobic amino acids. Protein solubility, foaming capacity, foam stability and emulsion stability of FPI were higher than SPI; moreover, both FPI and SPI showed pH-dependent protein functionalities. CONCLUSION: Fenugreek seed protein extraction was optimized by control of pH and NaCl concentration. FPI could be used as a protein source with remarkable functional properties. PMID- 25523831 TI - The dimethylarginine (ADMA)/nitric oxide pathway in the brain and periphery of rats with thioacetamide-induced acute liver failure: Modulation by histidine. AB - Hepatic encephalopathy (HE) is related to variations in the nitric oxide (NO) synthesis and oxidative/nitrosative stress (ONS), and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases (NOSs). In the present study we compared the effects of acute liver failure (ALF) in the rat TAA model on ADMA concentration in plasma and cerebral cortex, and on the activity and expression of the ADMA degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH), in brain and liver. ALF increased blood and brain ADMA, and the increase was correlated with decreased DDAH activity in both brain and liver. An i.p. administration of histidine (His), an amino acid reported to alleviate oxidative stress associated with HE (100 mg/kg b.w.), reversed the increase of brain ADMA, which was accompanied by the recovery of brain DDAH activity (determined ex vivo), and with an increase of the total NOS activity. His also activated DDAH ex vivo in brain homogenates derived from control and TAA rats. ALF in this model was also accompanied by increases of blood cyclooxygenase activity and blood and brain TNF-alpha content, markers of the inflammatory response in the periphery, but these changes were not affected by His, except for the reduction of TNF-alpha mRNA transcript in the brain. His increased the total antioxidant capacity of the brain cortex, but not of the blood, further documenting its direct neuroprotective power. PMID- 25523832 TI - Photoexcited Energy Transfer in a Weakly Coupled Dimer. AB - Nonadiabatic excited-state molecular dynamics (NA-ESMD) simulations have been performed in order to study the time-dependent exciton localization during energy transfer between two chromophore units of the weakly coupled anthracene dimer dithia-anthracenophane (DTA). Simulations are done at both low temperature (10 K) and room temperature (300 K). The initial photoexcitation creates an exciton which is primarily localized on a single monomer unit. Subsequently, the exciton experiences an ultrafast energy transfer becoming localized on either one monomer unit or the other, whereas delocalization between both monomers never occurs. In half of the trajectories, the electronic transition density becomes completely localized on the same monomer as the initial excitation, while in the other half, it becomes completely localized on the opposite monomer. In this article, we present an analysis of the energy transfer dynamics and the effect of thermally induced geometry distortions on the exciton localization. Finally, simulated fluorescence anisotropy decay curves for both DTA and the monomer unit dimethyl anthracene (DMA) are compared. Our analysis reveals that changes in the transition density localization caused by energy transfer between two monomers in DTA is not the only source of depolarization and exciton relaxation within a single DTA monomer unit can also cause reorientation of the transition dipole. PMID- 25523833 TI - Perspectives and reflections on the public reaction to recent Fukushima-related radionuclide studies and a call for enhanced training in environmental radioactivity. PMID- 25523834 TI - Intraovarian factors associated with switching of a future dominant follicle to a subordinate follicle during induced luteolysis in heifers. AB - The factors involved in the switching of a future dominant follicle (DF) to subordinate status were studied (n = 42) by induction of luteolysis with PGF2alpha (hour 0) when the largest follicle (F1) in follicular wave 2 was 7.0 or 8.5 mm. Combined for 7.0- and 8.5-mm groups, the frequency of switching was greater (P < 0.01) when F1 and CL were ipsilateral (10 of 28, 36%) than when contralateral (0 of 14). The frequency of switching in the ipsilateral relationship was greater (P < 0.002) when F1 and CL were adjacent (<3 mm apart; 10 of 17) than when separated (0 of 11). The difference in diameter between F1 and F2 was less (P < 0.005) when switching occurred (0.4 +/- 0.1 mm) than when switching did not occur (ipsilateral, 1.3 +/- 0.2 mm; contralateral, 1.1 +/- 0.2 mm). Treatment at hour 0 when F1 was 7.0 mm and ipsilateral to the CL resulted in smaller diameter (P < 0.001) of F1 at hour 12 (7.6 +/- 0.2 mm) than when treatment was not given (8.3 +/- 0.1 mm). The hypotheses were supported that (1) switching from a future DF to a future subordinate is functionally related to luteolysis, and (2) factors involved in switching include an ipsilateral relationship between the largest follicle and CL and close intraovarian proximity of the follicle to the regressing CL. It is proposed that switching of the future DF to subordinate status during spontaneous luteolysis accounts for the reported greater frequency of the contralateral than ipsilateral relationships between the preovulatory follicle and CL in three-wave interovulatory intervals. PMID- 25523835 TI - Oxytocin induction of pulses of a prostaglandin metabolite and luteolysis in mares. AB - A procedure for oxytocin (OT) administration on Day 13 postovulation was developed in mares for stimulation of a pulse of PGFM (a PGF2alpha metabolite) that mimics a natural PGFM pulse during luteolysis. Bolus treatment with each of five OT doses (1-10 IU/mare, n = 3) stimulated a burst of PGFM that was maximum in 4 minutes and was unlike a natural pulse. A 2-hour OT infusion of 1.25, 2.5, or 5 IU/100 kg (n = 4) induced a PGFM pulse similar to reported pulses; lower doses did not. The peak of an induced pulse (approximately 260-380 pg/mL) seemed similar to reported natural peaks (approximately 200-300 pg/mL), using the same assay system. The interval from nadir to nadir was 6.6 +/- 0.2 hours. Percentage decrease in progesterone (P4) within 8 hours was greater (P < 0.05) for doses of 1.25, 2.5, or 5 IU/100 kg (43%-50%) than that for a vehicle group (11%). Treatment with flunixin meglumine (1.0 mg/kg), a cyclooxygenase inhibitor, decreased (P < 0.008) P4 concentration, but treatment 2 hours before the beginning of OT infusion (2.5 IU/100 kg) did not prevent the OT-induced PGFM pulses and the decrease in P4. In conclusion, a PGFM pulse was simulated by infusion of OT during 2 hours but not by a single OT bolus, and an OT-simulated PGFM pulse stimulated a decrease in P4 that was not prevented by a cyclooxygenase inhibitor. These are the first firm demonstrations that OT in mares as in other species has a role in luteolysis. PMID- 25523836 TI - Dimensionality-dependent charge transport in close-packed nanoparticle arrays: from 2D to 3D. AB - Charge transport properties in close-packed nanoparticle arrays with thickness crossing over from two dimensions to three dimensions have been studied. The dimensionality transition of nanoparticle arrays was realized by continually printing spatially well-defined nanoparticle monolayers on top of the device in situ. The evolution of charge transport properties depending on the dimensionality has been investigated in both the Efros-Shaklovskii variable-range hopping (ES-VRH) (low temperature) regime and the sequential hopping (SH) (medium temperature) regime. We find that the energy barriers to transport decrease when the thickness of nanoparticle arrays increases from monolayer to multilayers, but start to level off at the thickness of 4-5 monolayers. The energy barriers are characterized by the coefficient betaD at ES-VRH regime and the activation energy Ea at SH regime. Moreover, a turning point for the temperature coefficient of conductance was observed in multilayer nanoparticle arrays at high temperature, which is attributed to the increasing mobility with decreasing temperature of hopping transport in three dimensions. PMID- 25523838 TI - The quest for an evidence-based approach to surveillance for methotrexate-related hepatotoxicity: promise and perils. PMID- 25523837 TI - Efficacy of a single dose of dexmedetomidine for cough suppression during anesthetic emergence: a randomized controlled trial. AB - PURPOSE: Maintenance of a remifentanil infusion during anesthetic emergence has been reported to decrease the incidence of coughing and thereby help to ensure a smooth emergence. It may, however, cause respiratory depression and possibly delay emergence. The purpose of this study was to investigate the effect of a single dose of dexmedetomidine combined with a low-dose remifentanil infusion on cough suppression during emergence from general anesthesia. METHODS: American Society of Anesthesiologists physical status I-II adults undergoing elective thyroidectomy under sevoflurane anesthesia were recruited and randomly allocated to receive either dexmedetomidine 0.5 MUg.kg(-1) iv (Group D, n = 70) or saline (Group S, n = 71), each combined with a low-dose remifentanil infusion ten minutes before the end of surgery. Coughing was assessed using a four-point scale. The respiratory rate (RR), heart rate (HR), and mean arterial pressure were also recorded. RESULTS: The incidence of coughing was lower in Group D than in Group S (64% vs 91%, respectively; mean difference 27%; 95% confidence interval [CI] 13 to 41; P < 0.001). The median cough grade at extubation was also lower in Group D. Mean arterial pressure and HR were elevated in Group S during tracheal extubation but were similar to baseline values in Group D. There was no difference in RR between the two groups throughout the study. A small delay in extubation was observed in Group D (3 minutes longer than Group S; 95% CI 2 to 4; P < 0.001). CONCLUSION: Compared with an infusion of low-dose remifentanil alone, the addition of a single dose (0.5 MUg.kg(-1)) of dexmedetomidine during emergence from sevoflurane-remifentanil anesthesia was effective in attenuating coughing and hemodynamic changes and did not exacerbate respiratory depression after thyroid surgery. This trial was registered at Clinicaltrial.gov, identifier: NCT01774305. PMID- 25523839 TI - Stopped in its tracks: how lambda-cyhalothrin can break the aphid transmission of a potato potyvirus. AB - BACKGROUND: Pyrethroids are one of the most widespread and commonly used classes of insecticide and are used in multiple roles, including protecting potato crops from virus vector aphids. Resistance in some genotypes of a few species is now widespread, but most species remain susceptible. The rate of virus transmission by two genotypes of the peach potato aphid, Myzus persicae, fed on potato virus Y (PVY)-infected leaves of potato treated with the pyrethroid lambda-cyhalothrin was evaluated. RESULTS: The susceptible genotype, type J, was significantly inhibited from transmitting virus to uninfected seedlings. A genotype containing the M918L super knockdown resistance mutation conferring resistance to pyrethroids, type O, showed no inhibition of transmission. However, when survival of the aphids after exposure was compared, the pyrethroid had not killed the type J aphids. CONCLUSIONS: lambda-Cyhalothrin in a commercial formulation disrupts PVY transmission by disorienting aphid vectors for a sufficient time for the virus to lose its transmissibility. However, M. persicae genotypes carrying the M918L mutation are not prevented from transmitting. PMID- 25523840 TI - Combined exposure to lead, inorganic mercury and methylmercury shows deviation from additivity for cardiovascular toxicity in rats. AB - Environmental exposure to metal mixtures in the human population is common. Mixture risk assessments are often challenging because of a lack of suitable data on the relevant mixture. A growing number of studies show an association between lead or mercury exposure and cardiovascular effects. We investigated the cardiovascular effects of single metal exposure or co-exposure to methylmercury [MeHg(I)], inorganic mercury [Hg(II)] and lead [Pb(II)]. Male Wistar rats received four different metal mixtures for 28 days through the drinking water. The ratios of the metals were based on reference and environmental exposure values. Blood and pulse pressure, cardiac output and electrical activity of the heart were selected as end-points. While exposure to only MeHg(I) increased the systolic blood pressure and decreased cardiac output, the effects were reversed with combined exposures (antagonism). In contrast to these effects, combined exposures negatively affected the electrical activity of the heart (synergism). Thus, it appears that estimates of blood total Hg levels need to be paired with estimates of what species of mercury dominate exposure as well as whether lead co exposure is present to link total blood Hg levels to cardiovascular effects. Based on current human exposure data and our results, there may be an increased risk of cardiac events as a result of combined exposures to Hg(II), MeHg(I) and Pb(II). This increased risk needs to be clarified by analyzing lead and Hg exposure data in relation to cardiac electrical activity in epidemiological studies. PMID- 25523841 TI - A focus group study of enteric disease case investigation: successful techniques utilized and barriers experienced from the perspective of expert disease investigators. AB - BACKGROUND: In Ontario, Canada, enteric case investigators perform a number of functions when conducting telephone interviews including providing health education, collecting data for regulatory purposes ultimately to prevent further illness, enforcement, illness source attribution and outbreak detection. Information collected must be of high quality as it may be used to inform decisions about public health actions that could have significant consequences such as excluding a person from work, recalling a food item that is deemed to be a health hazard, and/or litigations. The purpose of this study was to describe, from the perspectives of expert investigators, barriers experienced and the techniques used to overcome these barriers during investigation of enteric disease cases. METHODS: Twenty eight expert enteric investigators participated in one of four focus groups via teleconference. Expert investigators were identified based on their ability to 1) consistently obtain high quality data from cases 2) achieve a high rate of completion of case investigation questionnaires, 3) identify the most likely source of the disease-causing agent, and 4) identify any possible links between cases. Qualitative data analysis was used to identify themes pertaining to successful techniques used and barriers experienced in interviewing enteric cases. RESULTS: Numerous barriers and strategies were identified under the following categories: case investigation preparation and case communication, establishing rapport, source identification, education to prevent disease transmission, exclusion, and linking cases. Unique challenges experienced by interviewers were how to collect accurate exposure data and educate cases in the face of misconceptions about enteric illness, as well as how to address tensions created by their enforcement role. Various strategies were used by interviewers to build rapport and to enhance the quality of data collected. CONCLUSIONS: To our knowledge, this is the first study to examine the perspectives of expert enteric disease case investigators on successful interview techniques and barriers experienced during enteric case investigation. A number of recommendations could improve the process of enteric case investigation in the Ontario context which include formal training and development of resource materials pertaining to interviewing, standardized interviewing tools, strategies to address cultural and language barriers, and the implementation of the single interviewer approach. PMID- 25523842 TI - [Quality medicine needs quality research: are we prepared?]. PMID- 25523843 TI - [Points of view: the role of quality measurement from the Federal Joint Committee's perspective]. AB - The Federal Joint Committee (G-BA) is a central decision-making body that issues binding directives to ensure the quality of both inpatient and outpatient health care services within the German Statutory Health Insurance system. Quality measurement on the basis of quality indicators has proceeded furthest in the field of external quality assurance (QA) of inpatient services. Originally designed for quality development in a "protected environment" through learning from better practices, it has been faced with new expectations since competitive elements have been introduced into the health care system. The economisation of medicine is de facto the driving force of the development of QA measures. In terms of health policy, the 2013 coalition agreement includes "a renaissance of the concept of quality competition". In particular, this is meant to strengthen the decision-making options of insured persons by creating more transparency into the quality of not only inpatient but also outpatient care and, if necessary, to support the possibility of selective agreements with individual health insurance funds. The campaign planned to improve the quality of hospitals also provides for a quality-oriented advancement of hospital planning and funding; and the Federal Joint Committee, supported by the new Institute for Quality Assurance and Transparency in the Healthcare System in accordance with Section 137a of Book V of the Social Code (SGB V) in the GKV-FQWG version will be assigned new tasks within this context, too. On the whole, the measures already agreed upon in the Act to Improve the Financial Structure and Quality of the Statutory Health Insurance System (GKV-FQWG) and-as far as can now be anticipated-the proceedings of the working group set up between the German government and the German federal states indicate that there is a high need to improve the methods and tools of external quality assurance available, starting with questions about the validity of the quality indicators used and their relevance to patient care. Special issues and tasks require the development of new methods and tools. The need for paying more attention to the patient perspective will pose a particular challenge to future quality measurement. Additional information about the QA documentation of health care providers and the basis of social data that should be used preferentially can be gained from patient surveys. Despite the high political expectations (for example, concerning the development of online charts comparing the quality of inpatient care delivery), the Federal Joint Committee should not overlook the necessity of embedding quality measurement and public reporting into a comprehensive quality framework which can be used to promote continuous quality improvement through a structured feedback of the results to health care providers. In addition, we need a consistent patient orientation and a systematic evaluation of the QA measures employed. By networking more closely with evidence based medicine and health services research, quality assurance may give rise to a systematic quality research from which genuine quality and care objectives can be derived and which, as an integral part of a "learning care", supports a patient oriented advancement of care structures. PMID- 25523844 TI - [Quality measurement using administrative data in mandatory quality assurance]. AB - For several years, the use of administrative data in mandatory quality measurement has been requested by several stakeholders in Germany. Main advantages of using administrative data include the reduction of documentary expenditures and the possibility to perform longitudinal quality analyses across different healthcare units. After a short introduction, a brief overview of the current use of administrative data for mandatory quality assurance as well as current developments is given, which will then be further exemplified by decubital ulcer prophylaxis. By using administrative data coding expenditures in this clinical area could be reduced by nine million data fields. At the same time the population analysed was expanded resulting in a more than tenfold increase in potentially quality-relevant events. Finally, perspectives, further developments, possibilities as well as limits of quality measurement with administrative data are discussed. PMID- 25523845 TI - [Measuring quality in the German Guideline Programme in Oncology (GGPO) methodology and implementation]. AB - The German Guideline Programme in Oncology (GGPO) is a joint initiative between the German Cancer Society, the Association of the Scientific Medical Societies in Germany and German Cancer Aid. In accordance with the aims of the German National Cancer Plan, the GGPO supports the systematic development of high-quality guidelines. To enhance implementation and evaluation, the suggestion of performance measures (PMs) derived from guideline recommendations following a standardised methodology is obligatory within the GGPO. For this purpose, PM teams are convened representing the multidisciplinary guideline development groups including clinical experts, methodologists and patient representatives as well as those organisations that take an active part in and share responsibility for documentation and quality improvement, i.e., clinical cancer registries, certified cancer centres and, if appropriate, the institution responsible for external quality assurance according to the German Social Code (SGB). The primary selection criteria for PMs include strength of the underlying recommendation (strong, grade A), existing potential for improvement of care and measurability. The premises of data economy and standardised documentation are taken into account. Between May 2008 and July 2014, 12 guidelines with suggestions for 100 PMs have been published. The majority of the suggested performance measures is captured by the specific documentation requirements of the clinical cancer registries and certified cancer centres. This creates a solid basis for an active quality management and re-evaluation of the suggested PMs. In addition, the suspension of measures should be considered if improvement has been achieved on a broad scale and for a longer period in order to concentrate on a quality oriented, economic documentation. PMID- 25523846 TI - The NICE process for developing quality standards and indicators. AB - This paper describes the core principles and processes used by the National Institute for Health and Care Excellence (NICE) to develop quality standards and quality indicators from evidence based guidelines. PMID- 25523847 TI - [Hospital quality measurement-what matters?]. AB - In Germany, the aims of hospital quality measurement have evolved from intra professional quality assurance via organisational quality improvement to public reporting. Recently, quality-based purchasing is also discussed as a political option. These developments lead to new requirements for quality measurement which have gained little attention so far. Quality indicators have to become more comprehensive, more outcome-related, and more tamper-resistant. Furthermore statistical limitations of quality measurement related to low case numbers may impair quality assessment and therefore have to be considered in political discussions. In many cases the use of administrative data allows for the measurement of meaningful endpoints and is less prone to manipulation than separate data collections. Also, it allows for the extension of quality measurements to other medical conditions without causing additional effort. Bearing costs and benefits in mind, the use of administrative data might be the only way to establish nationwide long-term outcome measurements. Using administrative data also enables the advancement of provider-independent quality measurement. This may cause political controversies. Irrespective of future political regulations, new outcome-related quality measurements already have been shown to contribute to improving hospital care, if used in internal quality management systems. PMID- 25523848 TI - [Measurement and assessment of study quality and reporting quality]. AB - Clinical trials are undertaken to evaluate the effectiveness and safety of clinical interventions or to investigate other unclarified (e.g. diagnostic) research questions. But not every clinical study is optimally planned, conducted and analysed and is therefore exposed to risk of systematic errors which can distort (bias) the study results. Clinical studies should be conducted in accordance with specific quality criteria in order to reduce these risks. To estimate the methodological quality of studies instruments such as the Cochrane Risk of Bias tool were developed. But it can only be appraised what is reported. Often important information on the conduct and analysis of a study is missing in research articles, and in most cases detailed study protocols are not freely available. Reporting guidelines available for different study types can help improve the transparency and completeness of reports of clinical studies and thus the reporting quality. PMID- 25523849 TI - [Practice report: the process-based indicator dashboard. Visualising quality assurance results in standardised processes]. AB - Process management (PM) is a valuable method for the systematic analysis and structural optimisation of the quality and safety of clinical treatment. PM requires a high motivation and willingness to implement changes of both employees and management. Definition of quality indicators is required to systematically measure the quality of the specified processes. One way to represent comparable quality results is the use of quality indicators of the external quality assurance in accordance with Sect. 137 SGB V-a method which the Federal Joint Committee (GBA) and the institutions commissioned by the GBA have employed and consistently enhanced for more than ten years. Information on the quality of inpatient treatment is available for 30 defined subjects throughout Germany. The combination of specified processes with quality indicators is beneficial for the information of employees. A process-based indicator dashboard provides essential information about the treatment process. These can be used for process analysis. In a continuous consideration of these indicator results values can be determined and errors will be remedied quickly. If due consideration is given to these indicators, they can be used for benchmarking to identify potential process improvements. PMID- 25523850 TI - [STandardized Reporting Of Secondary data Analyses (STROSA)-a recommendation]. AB - Secondary data analyses will play an increasingly important role in health services research. But to date, there is no guideline for the systematic, transparent and complete reporting of secondary data. We investigated whether the STROBE statement, i.e., the recommendations for reporting observational studies, satisfies the specific characteristics of secondary data analyses and whether any specifications/modifications and extensions are necessary. For the majority of the 22 STROBE criteria, specifications and extensions are needed to meet the requirements of systematic, transparent and complete reporting of secondary data analysis. Seven aspects of secondary data analysis not covered by STROBE (legal aspects, data flow, protocol, unit of analysis, internal validations/definitions, advantages of secondary data utilisation, role of data owners) should be considered as a specific complement to STROBE. The so called STROSA (STandardized Reporting Of Secondary data Analyses) checklist therefore includes 29 items that relate to the title/abstract, introduction, methods, results and discussion sections of articles. The STROSA checklist is intended to support authors and readers in the critical appraisal of secondary data analyses. This proposal will now be subject to continued scientific discussions. PMID- 25523851 TI - [Quality assurance in an epidemiological cohort study: on-site monitoring in gynaecological practices]. AB - Quality assurance is required for all relevant instruments and procedures in epidemiological studies just like for clinical trials. The structure and complexity of the monitoring was developed based on the monitoring in clinical trials and applied to an epidemiological cohort study on early detection of cervical cancer (MARZY Study). Analyses of the on-site monitoring in participating gynaecological practices during the baseline investigation of the MARZY cohort were presented. The baseline investigation of the MARZY study was conducted between 2005 and 2007 in the city of Mainz, the rural district of Mainz Bingen and surrounding areas. Women, who were randomly selected via population registries, were invited to attend cervical cancer screening at a gynaecologist's office of their choice. All study participants received a study swab in addition to their routine Pap smear. The on-site monitoring included equipment and support of all participating gynaecological practices during study recruitment. Each participant and physician signed an informed consent form. In addition, the participant completed an epidemiological questionnaire. The gynaecologist took the study swab and completed the study documentation form. Prior to recruitment, standardised processes and documentation forms were developed for the monitoring process. The monitoring visits were carried out every six to eight weeks. During the baseline investigation, participants were included in the study among 121 gynaecological practices. In total, 2,892 monitoring documentation forms from 390 on-site monitoring visits in 96 gynaecological practices from the study region and surrounding areas were analysed. On-site monitoring visits were more frequently conducted during the first year of the study. The average time needed for an on-site visit was 107 minutes (minimum 73 minutes, maximum 200 minutes). Problems such as incomplete study documentation forms or erroneous inclusion into the study occurred among 975 study participants (33.7%). 664 study participants (68.1%) did not fully complete the study forms, and 89 (9.1%) were included in the study despite the fact that they met the exclusion criteria such as hysterectomy or pregnancy. Most of these problems could be sufficiently corrected during the on-site monitoring. Monitoring in epidemiological studies performed at physicians' offices should be carried out in accordance with the monitoring in clinical trials. On-site monitoring helped to avoid missing data and to ensure adherence to exclusion criteria. On-site monitoring considerably contributed to the correct and complete study inclusion of all eligible participants and a high quality of study data. PMID- 25523852 TI - [Patient-relevant outcomes and surrogates in the early benefit assessment of drugs: first experiences]. AB - The Act on the Reform of the Market for Medicinal Products (AMNOG) became effective in Germany on January 1, 2011. Since then, the assessment of the added benefit of new drugs versus a therapeutic standard on the basis of dossiers submitted by pharmaceutical companies has been required by law. The Federal Joint Committee (G-BA) generally commissions the Institute for Quality and Efficiency in Health Care (IQWiG) with this task. The added benefit is primarily to be demonstrated on the basis of patient-relevant outcomes. The aim of this paper is to describe the feasibility of the early benefit assessment on the basis of patient-relevant outcomes by systematically characterising the outcomes available in company dossiers and comparing the companies' and IQWiG's evaluations regarding patient relevance and surrogate validity. Dossier assessments published between October 2011 and June 2012 were used for this purpose. The outcomes available and the respective evaluations were extracted and compared. 12 out of 22 submitted dossiers contained sufficient data to assess outcomes; all 12 assessable dossiers provided data on patient-relevant outcomes. Data on mortality and adverse events were available in all dossiers, except that one dossier did not contain adverse event data on the relevant subpopulation. In contrast, data on morbidity and health-related quality of life were available in 8 and 7 dossiers, respectively. Of a total of 214 outcomes extracted by IQWiG, 124 patient-relevant and 3 surrogate outcomes were included in IQWiG's assessment (companies: a total of 183 outcomes included, of which 172 were patient-relevant and 11 were surrogates). The first experiences with AMNOG have shown that in principle an early benefit assessment of drugs based on patient-relevant outcomes is feasible. The companies' and IQWiG's evaluations regarding patient relevance and surrogate validity of outcomes partly deviated from each other. By increasingly considering patient-relevant outcomes in approval studies, pharmaceutical companies can create the necessary data basis for the early benefit assessment. PMID- 25523853 TI - A reproductive, developmental and neurobehavioral study following oral exposure of tetrabromobisphenol A on Sprague-Dawley rats. AB - The objectives of these GLP US EPA OPPTS 970.3800 and 970.3700 studies were to examine the effects of tetrabromobisphenol A (TBBPA) at oral doses of 10, 100 or 1000 mg/kg BW/day over the course of 2 generations on growth as well as behavioral, neurological and neuropathologic functions in offspring. In a separate study the influence of oral TBBPA (0, 100, 300 or 1000 mg/kg BW/d) was examined on embryonic/fetal development from gestation days (GDs) 0-19. In the reproductive study, exposure to >= 100-mg/kg BW/d TBBPA resulted in a decrease in circulating, peripheral thyroxine (T4) levels in rats that were not accompanied by any marked alterations in triiodothyronine (T3) and thyroid stimulating hormone (TSH). These findings are explainable on the basis of induction of rat liver catabolism, a phenomenon that may be species-specific and not relevant for humans. TBBPA at up to 1000 mg/kg BW/d was not associated with any significant non-neurological effects on reproduction, growth and development. A subtle reduction, of unknown biological relevance, in the thickness of the parietal cortices of 11-day-old F2 pups in the 1000 mg/kg BW/d group was noted. This change was not accompanied by evidence of micro-anatomic changes. No estrogenic effects sufficient to affect macro and micro anatomy, fertility, reproduction, development, survival or behavior were detected in the embryofetal development study or in the multigenerational study. No other TBBPA-related effects on developmental neurotoxicity/neuropathology were detected. In the developmental study no TBBPA related change in mortality rate was observed in any of the dams. No other significant test article-related effects were noted. The no observed effect level (NOEL) for maternal and developmental toxicity was 1000 mg/kg BW/d, the highest dose evaluated. PMID- 25523854 TI - Unprofessional doctors--are they really born this way? PMID- 25523855 TI - High glycaemic index (GI) of Asian diet--what are the clinical implications? PMID- 25523856 TI - Antibiotic therapy and clinical outcomes of Pseudomonas aeruginosa (PA) bacteraemia. AB - INTRODUCTION: Pseudomonas aeruginosa (PA) bacteraemia is associated with high morbidity and mortality. We assessed clinical outcomes in patients with PA bacteraemia treated with piperacillin-tazobactam (TZP) versus other antibiotics, and monotherapy versus combination, all with proven activity by disc testing without minimum inhibitory concentration (MIC) data. MATERIALS AND METHODS: All patients with PA bacteraemia in 2007 to 2008 were reviewed for demographic, comorbidity, clinical, laboratory, treatment and outcome data. Primary outcome was 30-day mortality. Secondary outcomes included microbiological clearance, clinical response and length of stay (LOS). RESULTS: Median age for 91 patients was 65 years. Median Simplified Acute Physiology Score (SAPS) II score was 30. Monotherapy was used in 77 cases: 42 on ceftazidime, 17 on TZP, 10 on carbapenems, and 8 on other antipseudomonal antibiotics. The 30-day mortality was 20.9%, and similar between ceftazidime and TZP versus other antibiotics respectively. More patients in combination versus monotherapy group had cardiovascular diseases, diabetes mellitus and vascular access as source of bacteraemia. Patients on monotherapy had higher 30-day mortality (24.7% vs 0%, P = 0.037). Multivariate analysis identified SAPS II score (OR = 1.097, 95% CI, 1.032 to 1.166, P = 0.003) and cancer (OR = 4.873, 95% CI, 1.235 to 19.223, P = 0.024) as independent predictors of 30-day mortality. CONCLUSION: TZP appeared to be an effective culture-guided antibiotic for PA bacteraemia. High 30-day mortality in monotherapy might be confounded by comorbidity, illness severity and sample size. Cancer patients and a high SAPS II score were independent predictors of 30-day mortality. PMID- 25523857 TI - Hoarding in an Asian population: prevalence, correlates, disability and quality of life. AB - INTRODUCTION: Hoarding is defined as the acquisition of, and inability to discard items even though they appear to others to have no value. The objectives of the study were to establish the prevalence of hoarding behaviour among the general population and among individuals with obsessive-compulsive disorder (OCD) in a cross-sectional study conducted in Singapore. MATERIALS AND METHODS: The Singapore Mental Health Study was a cross-sectional epidemiological survey of a nationally representative sample of residents aged 18 years or older, living in households. The diagnoses of mental disorders were established using Version 3.0 of Composite International Diagnostic Interview (CIDI 3.0). Differences between 3 groups i.e. those diagnosed with lifetime/12-month Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) OCD with hoarding, those diagnosed with lifetime/12-month DSM-IV OCD without hoarding and those with lifetime hoarding behaviour without diagnosis of DSM-IV OCD were determined. RESULTS: The weighted prevalence of lifetime hoarding behaviour was 2% and that of hoarding among those with OCD was 22.6%. Those who met the criteria for hoarding behaviour alone were associated with lower odds of having obsessions of contamination, harming, ordering as well as compulsions of ordering and other compulsions than those who met criteria for both OCD and hoarding. CONCLUSION: Hoarders without OCD were less impaired, in terms of comorbid psychopathology, than those with OCD with and without hoarding, and had a higher quality of life versus those with both OCD and hoarding, though still lower than that of the general population. PMID- 25523858 TI - When traditional model meets competencies in Singapore: beyond conflict resolution. AB - INTRODUCTION: The implementation of competency-based internal medicine (IM) residency programme that focused on the assurance of a set of 6 Accreditation Council for Graduate Medical Education (ACGME) core competencies in Singapore marked a dramatic departure from the traditional process-based curriculum. The transition ignited debates within the local IM community about the relative merits of the traditional versus competency-based models of medical education, as well as the feasibility of locally implementing a training structure that originated from a very different healthcare landscape. At the same time, it provided a setting for a natural experiment on how a rapid integration of 2 different training models could be achieved. MATERIALS AND METHODS: Our department reconciled the conflicts by systematically examining the existing training structure and critically evaluating the 2 educational models to develop a new training curriculum aligned with institutional mission values, national healthcare priorities and ACGME-International (ACGME-I) requirements. RESULTS: Graduate outcomes were conceptualised as competencies that were grouped into 3 broad areas: personal attributes, interaction with practice environment, and integration. These became the blueprint to guide curricular design and achieve alignment between outcomes, learning activities and assessments. The result was a novel competency-based IM residency programme that retained the strengths of the traditional training model and integrated the competencies with institutional values and the unique local practice environment. CONCLUSION: We had learned from this unique experience that when 2 very different models of medical education clashed, the outcome may not be mere conflict resolution but also effective consolidation and transformation. PMID- 25523859 TI - Magnetic resonance-guided focused ultrasound surgery (MRgFUS) of uterine fibroids in Singapore. AB - INTRODUCTION: Uterine fibroids are the most common type of gynaecologic benign tumours, occurring in 25% to 50% of women during their reproductive lives. About half of the affected women have clinically significant symptoms, including abnormal bleeding, menstrual pain, frequent urination, constipation and abdominal distension. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) has been used to treat patients with benign lesions and a variety of malignancies. The objective of this study is to evaluate symptom relief before and after MR guided ultrasound ablation of fibroids. MATERIALS AND METHODS: A total of 37 patients with symptomatic uterine fibroids were treated in this study. RESULTS: MRgFUS treatment led to a significant, time-dependent decrease in not only Symptom Severity Scores (SSS), but also the mean fibroid volume. The average reductions in volume were 41.6% and 52.6% at 6 months and 12 months respectively (P <0.05). The mean SSS of the 37 patients was 41.7 +/- 2.8 before treatment whereas the average SSS was 26.9 +/- 3.6, 20.7 +/- 3.4, 18.5 +/- 3.6, 16.5 +/- 7.1, 9.8 +/- 3.6 at 3 months, 6 months, 1 year, 2 years, and 3 to 4 years respectively. The decrease in scores was significant at all time points up to 3 to 4 years (P <0.05 and P <0.001). CONCLUSION: MRgFUS is a safe and effective non invasive treatment for patients with symptomatic fibroids. PMID- 25523860 TI - Aorto-oesophageal fistula from miliary tuberculosis: a rare cause of massive haematemesis. PMID- 25523861 TI - Transient ischaemic attack as first presentation of polycythaemia vera. PMID- 25523862 TI - Graphene quantums dots combined with endonuclease cleavage and bidentate chelation for highly sensitive electrochemiluminescent DNA biosensing. AB - A novel strategy for highly sensitive electrochemiluminescence (ECL) detection of DNA was proposed based on site-specific cleavage of BamHI endonuclease combined with the excellent ECL activity of graphene quantum dots (GQDs) and bidentate chelation of the dithiocarbamate DNA (DTC-DNA) probe assembly. The difference between photoluminescence and ECL spectral peaks suggested that a negligible defect existed on the GQDs surface for generation of an ECL signal. The formed DTC-DNA was directly attached to the gold surface by bidentate anchoring (S-Au-S bonds), which conferred a strong affinity between the ligands and the gold surface, increasing the robustness of DNA immobilization on the gold surface. BamHI endonuclease site-specifically recognized and cleaved the duplex symmetrical sequence, which made the double-stranded DNA fragments and GQDs break off from the electrode surface, inducing a decrease of the ECL signal. Using hepatitis C virus-1b genotype complementary DNA (HCV-1b cDNA) as a model, a novel signal-off ECL DNA biosensor was developed based on variation of the ECL intensity before and after digestion of the DNA hybrid. Electrochemical impedance spectroscopy confirmed the successful fabrication of the ECL DNA biosensor. This ECL biosensor for HCV-1b cDNA determination exhibited a linear range from 5 fM to 100 pM with a detection limit of 0.45 fM at a signal-to-noise ratio of 3 and showed satisfactory selectivity and good stability, which validated the feasibility of the designed strategy. The proposed strategy may be conveniently combined with other specific biological recognition events for expansion of the biosensing application, especially in clinical diagnoses. PMID- 25523863 TI - Posterior scleritis with retinal pigment epithelium rip: an unusual presentation. AB - Posterior scleritis is a great mimicker and can cause irreversible visual loss because of late or misdiagnosis. We report a case of retinal pigment epithelial rip in the event of nodular posterior scleritis that is hardly reported in the literature. The authors hypothesize the rip to be a result of inflammation, exudation and continuing pressure by the fluid or granuloma on the pigment epithelium. PMID- 25523864 TI - Management of intrastromal glass foreign body based on anterior segment optical coherence tomography and Pentacam analysis. PMID- 25523865 TI - Permeability study of cancellous bone and its idealised structures. AB - Artificial bone is a suitable alternative to autografts and allografts, however their use is still limited. Though there were numerous reports on their structural properties, permeability studies of artificial bones were comparably scarce. This study focused on the development of idealised, structured models of artificial cancellous bone and compared their permeability values with bone surface area and porosity. Cancellous bones from fresh bovine femur were extracted and cleaned following an established protocol. The samples were scanned using micro-computed tomography (MUCT) and three-dimensional models of the cancellous bones were reconstructed for morphology study. Seven idealised and structured cancellous bone models were then developed and fabricated via rapid prototyping technique. A test-rig was developed and permeability tests were performed on the artificial and real cancellous bones. The results showed a linear correlation between the permeability and the porosity as well as the bone surface area. The plate-like idealised structure showed a similar value of permeability to the real cancellous bones. PMID- 25523866 TI - Prediction of small-for-gestational-age neonates: screening by fetal biometry at 30-34 weeks. AB - OBJECTIVE: To investigate the value of fetal biometry at 30-34 weeks' gestation in the prediction of delivery of small-for-gestational-age (SGA) neonates, in the absence of pre-eclampsia (PE). METHODS: This was a screening study in 30 849 singleton pregnancies at 30-34 weeks' gestation, comprising 1727 that delivered SGA neonates with a birth weight < 5(th) percentile and 29 122 cases unaffected by SGA, PE or gestational hypertension. Multivariable logistic regression analysis was used to determine if screening by a combination of maternal factors and Z-scores of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) or estimated fetal weight (EFW) had a significant contribution to the prediction of SGA neonates. RESULTS: Combined screening by maternal characteristics and obstetric history, with Z-scores of EFW at 30-34 weeks, predicted 79%, 87% and 92% of the SGA neonates that delivered < 5 weeks following assessment, with a birth weight < 10(th) , < 5(th) and < 3(rd) percentiles, respectively, at a 10% false-positive rate. The respective detection rates for the prediction of SGA neonates delivering >= 5 weeks from the time of assessment were 53%, 58% and 61%. The performance of screening by a combination of Z-scores of fetal HC, AC and FL was similar to that achieved by the EFW Z-score alone. CONCLUSION: Combined testing by maternal characteristics and fetal biometry at 30 34 weeks could identify a high proportion of pregnancies that will deliver SGA neonates. PMID- 25523867 TI - Reduced-intensity conditioning umbilical cord blood transplantation in Nijmegen breakage syndrome. AB - NBS is a rare autosomal recessive congenital disorder associated with chromosome instability caused by a mutation in the NBN gene (8q21). Clinical manifestations include microcephaly, growth retardation, combined immunodeficiency, and a strong predisposition to develop (mainly lymphatic) malignancies. There is no specific treatment for patients with NBS, and the prognosis is generally poor. The therapeutic option for some patients with NBS may be HSCT. We present a case of safe and successful non-myeloablative UCB transplantation in the 19th month of the life of a female child with NBS concomitant with SCID. PMID- 25523868 TI - Is there a correlation between bronchial artery hypertrophy and coronary artery disease? PMID- 25523869 TI - Bronchial arteries enlargement can be correlated to coronary artery disease. PMID- 25523870 TI - Identification of nondeletional alpha-thalassemia in a prenatal screening program by reverse dot-blot in southern China. AB - The aim of this study was to demonstrate the performance of nondeletional alpha thalassemia (alpha-thal) prevention using a reverse dot-blot method at a Mainland Chinese hospital. A prenatal control program for nondeletional Hb H disease was performed between January 2009 and December 2013. All couples were screened for alpha-thal trait, and for couples in which one partner tested positive for alpha(0)-thal, the other was subjected to screening for Hb Constant Spring (Hb CS, HBA2: c.427T > C) and Hb Quong Sze (Hb QS, HBA2: c.377T > C) mutations by reverse dot-blot assay. Prenatal diagnoses were offered in at-risk pregnancies. During the study period, 51,105 couples were found to be carrying alpha-thal; among these, 35 (0.07%) couples were found to be at-risk of conceiving an offspring with nondeletional Hb H disease, including 25 couples for Hb H-CS and 10 cases for Hb H-QS. Nine fetuses were diagnosed with nondeletional Hb H disease, and eight of the affected pregnancies were terminated. Detection of nondeletional alpha-thal is necessary for any prenatal diagnosis (PND) programs in Southeast Asian countries. Reverse dot-blot is a relatively simple method for simultaneous typing of common nondeletional alpha-thal mutations. PMID- 25523871 TI - beta-globin genes: mutation hot-spots in the global thalassemia belt. AB - The concurrence of malaria and hemoglobinopathies, observed in malaria endemic regions, reflects the phenomenon of natural selection. Since the life cycle of the malaria parasite has an erythrocytic stage, abnormalities in the red blood cells (RBCs) hinder the parasite's survival in the human host. Hemoglobin (Hb) variants affect the life span of RBCs and thus lower the chance of infection by the parasite. While a change in just one of the Hb genes offers some protection against malaria, change in both alleles results in beta-thalassemia major (beta TM). A striking geographical heterogeneity of beta-thalassemia (beta-thal) has been observed. Moving from Mexico in the west to China towards the east, the spectrum of mutations in the beta-globin gene has been seen to vary. In the western end of the thalassemia belt, defects in the first intervening sequence (IVS-I) and exon 2 of the beta-globin gene are more common, while on the eastern coast, IVS-II and exon 1 are also vulnerable to mutations. The worldwide increase in the incidence of beta-TM mandates the need for efficient measures to reduce beta-thal births, and the geographical heterogeneity of beta-thal alleles reduces the burden of genetic testing of fetuses suspected of carrying a mutant allele. In the present review, the common mutations in the global thalassemia belt have been illustrated, and the possible factors that affect the mutagenicity of sites have been discussed. A biogeographic analysis that may provide insight into the non biological factors influencing different loci in the beta-globin gene in different geographical regions is suggested. PMID- 25523872 TI - Dynamic interactions of neutrophils and biofilms. AB - BACKGROUND: The majority of microbial infections in humans are biofilm-associated and difficult to treat, as biofilms are highly resistant to antimicrobial agents and protect themselves from external threats in various ways. Biofilms are tenaciously attached to surfaces and impede the ability of host defense molecules and cells to penetrate them. On the other hand, some biofilms are beneficial for the host and contain protective microorganisms. Microbes in biofilms express pathogen-associated molecular patterns and epitopes that can be recognized by innate immune cells and opsonins, leading to activation of neutrophils and other leukocytes. Neutrophils are part of the first line of defense and have multiple antimicrobial strategies allowing them to attack pathogenic biofilms. OBJECTIVE/DESIGN: In this paper, interaction modes of neutrophils with biofilms are reviewed. Antimicrobial strategies of neutrophils and the counteractions of the biofilm communities, with special attention to oral biofilms, are presented. Moreover, possible adverse effects of neutrophil activity and their biofilm promoting side effects are discussed. RESULTS/CONCLUSION: Biofilms are partially, but not entirely, protected against neutrophil assault, which include the processes of phagocytosis, degranulation, and formation of neutrophil extracellular traps. However, virulence factors of microorganisms, microbial composition, and properties of the extracellular matrix determine whether a biofilm and subsequent microbial spread can be controlled by neutrophils and other host defense factors. Besides, neutrophils may inadvertently contribute to the physical and ecological stability of biofilms by promoting selection of more resistant strains. Moreover, neutrophil enzymes can degrade collagen and other proteins and, as a result, cause harm to the host tissues. These parameters could be crucial factors in the onset of periodontal inflammation and the subsequent tissue breakdown. PMID- 25523874 TI - A thermoresponsive, micro-roughened cell culture surface. AB - Surface topography has been shown to play a major role in cell behavior, but has yet to be seriously exploited in the field of cell surface engineering. In the present work, surface roughness has been used in combination with the thermoresponsive polymer polyisopropylacrylamide (PIPAAm) to generate cell sheets with tailored biochemical properties. Micro-roughened polystyrene (PS) with 1.5 5.5 MUm features was derivatized with PIPAAm to form a cell culture surface for the growth of human fibroblast cell sheets that exhibit a modified cytoskeleton and extracellular matrix. Fibroblasts cell sheets cultured on the rough surfaces had fewer actin stress fibers and twice the average fibronectin (FN) fibril formation when compared to cell sheets on flat substrates. The cell sheets harvested from the roughened PS were collected after only 2 days of culture and detached from the PIPAAm grafted surface in <1h after cooling the culture system. The simple and rapid method for generating cell sheets with increased FN fibril formation has applications in tissue grafts or wound repair and has demonstrated that the thermoresponsive surface can be used for reliable cell sheet formation. PMID- 25523873 TI - Structural insights and biomedical potential of IgNAR scaffolds from sharks. AB - In addition to antibodies with the classical composition of heavy and light chains, the adaptive immune repertoire of sharks also includes a heavy-chain only isotype, where antigen binding is mediated exclusively by a small and highly stable domain, referred to as vNAR. In recent years, due to their high affinity and specificity combined with their small size, high physicochemical stability and low-cost of production, vNAR fragments have evolved as promising target binding scaffolds that can be tailor-made for applications in medicine and biotechnology. This review highlights the structural features of vNAR molecules, addresses aspects of their generation using immunization or in vitro high throughput screening methods and provides examples of therapeutic, diagnostic and other biotechnological applications. PMID- 25523875 TI - Adding MgO nanoparticles to hydroxyapatite-PLLA nanocomposites for improved bone tissue engineering applications. AB - Magnesium plays an important role in the body, mediating cell-extracellular matrix interactions and bone apatite structure and density. This study investigated, for the first time, the effects of adding magnesium oxide (MgO) nanoparticles to poly (l-lactic acid) (PLLA) and to hydroxyapatite (HA) nanoparticle-PLLA composites for orthopedic tissue engineering applications. Results showed that MgO nanoparticles significantly enhanced osteoblast adhesion and proliferation on HA-PLLA nanocomposites while maintaining mechanical properties (Young's modulus ~1,000 MPa) suitable for cancellous bone applications. Additionally, osteoblasts (or bone-forming cells) cultured in the supernatant of degrading nanocomposites showed improved proliferation in the presence of magnesium, indicating that the increased alkalinity of solutions containing MgO nanocomposites had no toxic effects towards cells. These results together indicated the promise of further studying MgO nanoparticles as additive materials to polymers to enhance the integration of implanted biomaterials with bone. PMID- 25523876 TI - Poly(ethylene glycol) diacrylate/hyaluronic acid semi-interpenetrating network compositions for 3-D cell spreading and migration. AB - To serve as artificial matrices for therapeutic cell transplantation, synthetic hydrogels must incorporate mechanisms enabling localized, cell-mediated degradation that allows cell spreading and migration. Previously, we have shown that hybrid semi-interpenetrating polymer networks (semi-IPNs) composed of hydrolytically degradable poly(ethylene glycol) diacrylates (PEGdA), acrylate-PEG GRGDS and native hyaluronic acid (HA) support increased cell spreading relative to fully synthetic networks that is dependent on cellular hyaluronidase activity. This study systematically investigated the effects of PEGdA/HA semi-IPN network composition on 3-D spreading of encapsulated fibroblasts, the underlying changes in gel structure responsible for this activity, and the ability of optimized gel formulations to support long-term cell survival and migration. Fibroblast spreading exhibited a biphasic response to HA concentration, required a minimum HA molecular weight, decreased with increasing PEGdA concentration and was independent of hydrolytic degradation at early time points. Increased gel turbidity was observed in semi-IPNs, but not in copolymerized hydrogels containing methacrylated HA, which did not support cell spreading. This suggests that there is an underlying mechanism of polymerization-induced phase separation that results in HA-enriched defects within the network structure. PEGdA/HA semi IPNs were also able to support cell spreading at relatively high levels of mechanical properties (~10kPa elastic modulus) compared to alternative hybrid hydrogels. In order to support long-term cellular remodeling, the degradation rate of the PEGdA component was optimized by preparing blends of three different PEGdA macromers with varying susceptibility to hydrolytic degradation. Optimized semi-IPN formulations supported long-term survival of encapsulated fibroblasts and sustained migration in a gel-within-gel encapsulation model. These results demonstrate that PEGdA/HA semi-IPNs provide dynamic microenvironments that can support 3-D cell survival, spreading and migration for a variety of cell therapy applications. PMID- 25523878 TI - Geographic differences in the associations between impaired glucose regulation and cardiovascular risk factors among young adults. AB - AIMS: To assess geographic differences in the association between BMI, blood pressure and lipid levels with impaired glucose regulation among young adults from various geographical regions. METHODS: This was a cross-sectional study including data from 6987 participants aged <= 30 years from India, Singapore, Australia, Greenland, Kenya and Tanzania. Impaired glucose regulation was determined by the 75-g oral glucose tolerance test. For each geographical region, BMI, blood pressure and lipids were examined and compared between participants with normal glucose tolerance and those with impaired glucose regulation. Multiple logistic regression models were used to assess the association between risk factors and impaired glucose regulation. RESULTS: Indian and East African people had a higher prevalence of impaired glucose regulation compared with participants from other regions, despite their lower BMI. Compared with the other regions, blood pressure was lower among Indian and Singaporean people but higher in those from Greenland. Greenlanders had the highest, while Indian and East African people, had the lowest level of HDL cholesterol. BMI was positively associated with impaired glucose regulation in all regions, and there were no statistically significant geographic differences. In the Indian, Singaporean and Australian participants, there was a positive association between blood pressure and impaired glucose regulation. Triglycerides were positively associated with and HDL cholesterol had no association with impaired glucose regulation in all geographical regions. CONCLUSIONS: Higher BMI and triglyceride levels were positively associated with prevalent impaired glucose regulation in all geographical regions. There were geographic differences in the association between impaired glucose regulation and blood pressure and lipids, probably reflecting environmental and genetic factors. PMID- 25523877 TI - Revealing cytokine-induced changes in the extracellular matrix with secondary ion mass spectrometry. AB - Cell-secreted matrices (CSMs), where extracellular matrix (ECM) deposited by monolayer cell cultures is decellularized, have been increasingly used to produce surfaces that may be reseeded with cells. Such surfaces are useful to help us understand cell-ECM interactions in a microenvironment closer to the in vivo situation than synthetic substrates with adsorbed proteins. We describe the production of CSMs from mouse primary osteoblasts (mPObs) exposed to cytokine challenge during matrix secretion, mimicking in vivo inflammatory environments. Time-of-flight secondary ion mass spectrometry data revealed that CSMs with cytokine challenge at day 7 or 12 of culture can be chemically distinguished from one another and from untreated CSM using multivariate analysis. Comparison of the differences with reference spectra from adsorbed protein mixtures points towards cytokine challenge resulting in a decrease in collagen content. This is supported by immunocytochemical and histological staining, demonstrating a 44% loss of collagen mass and a 32% loss in collagen I coverage. CSM surfaces demonstrate greater cell adhesion than adsorbed ECM proteins. When mPObs were reseeded onto cytokine-challenged CSMs they exhibited reduced adhesion and elongated morphology compared to untreated CSMs. Such changes may direct subsequent cell fate and function, and provide insights into pathological responses at sites of inflammation. PMID- 25523879 TI - Are anti-inflammatory agents effective in treating gingivitis as solo or adjunct therapies? A systematic review. AB - OBJECTIVE: Systematically review the scientific evidence for efficiency of anti inflammatory agents against gingivitis, either as solo treatments or adjunctive therapies. METHODS: A protocol was developed aimed to answer the following focused question: "Are anti-inflammatory agents effective in treating gingivitis as solo or adjunct therapies?" RCTs and cohort studies on anti-inflammatory agents against gingivitis studies were searched electronically. Screening, data extraction and quality assessment were conducted. The primary outcome measures were indices of gingival inflammation. A sub-analysis was performed dividing the active agents into anti-inflammatory and other drugs. RESULTS: The search identified 3188 studies, of which 14 RCTs met the inclusion criteria. The use of anti-inflammatory or other agents, in general showed a higher reduction in the test than in the control in terms of gingival indexes and bleeding scores. Only two RCTs on inflammatory drugs could be meta-analysed, showing a statistically significant reduction in the GI in the experimental group [WMD = -0.090; 95% CI ( 0.105; -0.074); p = 0.000]. However, the contribution of both studies to the global result was unbalanced (% weight: 99.88 and 0.12 respectively). CONCLUSIONS: Most of the tested material showed beneficial effect as anti inflammatory agents against gingivitis, either as a single treatment modality or as an adjunctive therapy. PMID- 25523880 TI - Erratum to: Thoracic and cardiovascular surgery in Japan during 2012: Annual report by The Japanese Association for Thoracic Surgery. PMID- 25523882 TI - Antipsychotics-induced metabolic alterations: focus on adipose tissue and molecular mechanisms. AB - The use of antipsychotic drugs for the treatment of mood disorders and psychosis has increased dramatically over the last decade. Despite its consumption being associated with beneficial neuropsychiatric effects in patients, atypical antipsychotics (which are the most frequently prescribed antipsychotics) use is accompanied by some secondary adverse metabolic effects such as weight gain, dyslipidemia and glucose intolerance. The molecular mechanisms underlying these adverse effects are not fully understood but have been suggested to involve a dysregulation of adipose tissue homeostasis. As such, the aim of this paper is to review and discuss the role of adipose tissue in the development of secondary adverse metabolic effects induced by atypical antipsychotics. Data analyzed in this article suggest that atypical antipsychotics may increase adipose tissue (particularly visceral adipose tissue) lipogenesis, differentiation/hyperplasia, pro-inflammatory mediator secretion and insulin resistance and decrease adipose tissue lipolysis. Consequently, patients receiving antipsychotic medication could be at risk of developing obesity, type 2 diabetes and cardiovascular disease. A better knowledge of the impact of these drugs on adipose tissue homeostasis may unveil strategies to develop novel antipsychotic drugs with less adverse metabolic effects and to develop adjuvant therapies (e.g. behavioral and nutritional therapies) to neuropsychiatric patients receiving antipsychotic medication. PMID- 25523881 TI - Coronary artery bypass grafting in a patient with hemophilia B: continuous recombinant factor IX infusion as per the Japanese guidelines for replacement therapy. AB - We herein report our experience of successfully managing the hemostatic system by controlling serum factor IX levels throughout the perioperative period in a patient with hemophilia B. Coronary artery bypass grafting with cardiopulmonary bypass was planned for a 52-year-old man with moderate severity of hemophilia B. During surgery, recombinant factor IX (rFIX; BeneFIX((r)) Pfizer Japan inc., Tokyo, Japan) was administered by bolus infusion followed by continuous infusion as per the guidelines of the Japanese Society on Thrombosis and Hemostasis. The operative course was uneventful without any considerable bleeding or complications. PMID- 25523883 TI - Curcumin and major depression: a randomised, double-blind, placebo-controlled trial investigating the potential of peripheral biomarkers to predict treatment response and antidepressant mechanisms of change. AB - A recent randomised, double-blind, placebo controlled study conducted by our research group, provided partial support for the efficacy of supplementation with a patented curcumin extract (500 mg, twice daily) for 8 weeks in reducing depressive symptoms in people with major depressive disorder. In the present paper, a secondary, exploratory analysis of salivary, urinary and blood biomarkers collected during this study was conducted to identify potential antidepressant mechanisms of action of curcumin. Pre and post-intervention samples were provided by 50 participants diagnosed with major depressive disorder, and the Inventory of Depressive Symptomatology self-rated version (IDS SR30) was used as the primary depression outcome measure. Compared to placebo, 8 weeks of curcumin supplementation was associated with elevations in urinary thromboxane B2 (p<0.05), and substance P (p<0.001); while placebo supplementation was associated with reductions in aldosterone (p<0.05) and cortisol (p<0.05). Higher baseline plasma endothelin-1 (rs=-0.587; p<0.01) and leptin (rs=-0.470; p<0.05) in curcumin-treated individuals was associated with greater reductions in IDS-SR30 score after 8 weeks of treatment. Our findings demonstrate that curcumin supplementation influences several biomarkers that may be associated with its antidepressant mechanisms of action. Plasma concentrations of leptin and endothelin-1 seem to have particular relevance to treatment outcome. Further investigations using larger samples sizes are required to elucidate these findings, as the multiple statistical comparisons completed in this study increased the risk of type I errors. PMID- 25523884 TI - Human papillomavirus prevalence and type-distribution among women in Zhejiang Province, Southeast China: a cross-sectional study. AB - BACKGROUND: Human papillomavirus (HPV) infection is the main etiological factor for cervical cancer and premalignant lesions of the cervix. The purposes of the present study were to determine the prevalence of type-specific HPV infections and the association of different HPV types with cervical dysplasia among women in Zhejiang province, Southeast China. METHODS: A total of 15,267 women presenting to a gynaecological outpatient clinic were enrolled in this study. Women were screened for HPV in addition to routine cervical cytology testing. Microarray hybridization and liquid-based cytology tests were used to detect HPV genotypes and cervical cytology, respectively. RESULTS: Based on the population attending a gynaecological outpatient clinic, overall prevalence of any 23 HPV type was 22.8% and multiple HPV infection was found in 4.0% of all the outpatients. HPV prevalence showed bimodal age distribution, with a peak (55.7%) at the <=20 age group and a second one (35.5%) at >60 age group. In total samples, the five most frequent types were HPV 16 (4.4%), 58 (2.9%), 52 (2.7%), 33 (2.2%) and 11 (1.9%). Overall HPV prevalence increased with the severity of the cytologic result. Analysis through crude odds ratios (ORs) revealed that the cervical lesion risk of HPV-infected women increased to about 26-fold of uninfected women (OR 26.1, 95% CI 22.4 to 30.3). The five most risky HPV types associated with abnormal cytology were HPV 73, 16, 82, 45 and 51. CONCLUSIONS: This study provided baseline data on HPV prevalence in women attending a gynecological outpatient clinic in Zhejiang province. Our data will supply guidance for the primary screening and vaccination program for cervical cancer in this area. PMID- 25523885 TI - Simultaneous and sensitive analysis of aliphatic carboxylic acids by ion chromatography using on-line complexation with copper(II) ion. AB - A new approach to ion chromatography is proposed to improve the UV detection of aliphatic carboxylic acids separated by anion-exchange chromatography. When copper(II) ion added to the mobile phase, it forms complexes with carboxylic acids that can be detected at 240 nm. The absorbance was found to increase with increasing copper(II) ion concentration. The retention times of alpha-hydroxy acids were also found to depend on the copper(II) ion concentration. Addition of acetonitrile to the mobile phase improved the separation of aliphatic carboxylic acids. The detection limits of the examined carboxylic acids (formate, glycolate, acetate, lactate, propionate, 3-hydroxypropionate, n-butyrate, isobutyrate, n valerate, isovalerate, n-caproate) calculated at S/N=3 ranged from 0.06 to 3 MUM. The detector signal was linear over three orders of magnitude of carboxylic acid concentration. The proposed method was successfully applied to analyze aliphatic carboxylic acids in rainwater and bread. PMID- 25523886 TI - Diagnostic performance and reproducibility of circumpapillary retinal nerve fiber layer thickness measurement in 10-degree sectors in early stage glaucoma. AB - PURPOSE: To study the circumpapillary retinal nerve fiber layer thickness (cpRNFLT) in a 10 degrees -wide sector using spectral-domain optical coherence tomography for diagnostic ability in early stage open-angle glaucoma (OAG). METHODS: cpRNFLT measurements (3.4-mm diameter centered on the disc) were obtained from 89 eyes with early stage OAG (mean deviation, -2.5 +/- 1.8 decibels) and 89 age-matched normal eyes. The ability of 180 degrees -, 90 degrees -, 30 degrees -, and 10 degrees -wide cpRNFLT sectors in discriminating early stage OAG eyes was evaluated by calculating the area under the receiver operating characteristic curves (AUCs) and sensitivity/specificity per diagnostic criteria with varying sector widths, normative data-based cpRNFLT cutoff levels and numbers of abnormal sectors. The intra- and inter-visit reproducibilities of the cpRNFLT 10 degrees -sector measurements were studied in a separate group of eyes with normal and early stage OAG. RESULTS: The greatest AUC obtained using the cpRNFLT 10 degrees sector, 0.924 (confidence interval, 0.875-0.958), did not differ significantly from those obtained with the 180 degrees , 90 degrees , and 30 degrees sectors. Only calculations using the 10 degrees sectors had sensitivities and specificities of 0.90 or higher with the best performance of the sensitivity/specificity of 0.92/0.94. These values tended to be better (P = 0.070) than with the 30 degrees sectors, 0.85/0.94, which were also selected with several combinations of various cutoff levels and the number of abnormal sectors. The coefficients of variation for the intra- and inter-visit reproducibility of the 10 degrees -sector measurements were 10 % or less in 32 and 24 of the 36 sectors. CONCLUSION: The cpRNFLT 10 degrees -sector measurements showed reasonable reproducibility and identified eyes with early stage OAG with a sensitivity and specificity of 0.92/0.94. PMID- 25523887 TI - Single bouts of exercise selectively sustain attentional processes. AB - This study examined how single bouts of exercise may differentially modulate neuroelectric correlates of attentional orienting and processing. Using a within participants design, ERPs and task performance were assessed in response to a perceptually challenging three-stimulus oddball task prior to and following a bout of exercise or seated rest during two separate, counterbalanced sessions. Findings revealed that, following a single bout of exercise, attentional processing was sustained relative to pretest whereas prolonged sitting resulted in attentional decrements. Focal attention resulting from attentional orienting, in contrast, does not appear to be sensitive to the influences of single bouts of physical activity. These findings suggest that acute exercise-induced changes in cognition do not originate from an overall modulation of attention but instead are specific to aspects of attentional processing. PMID- 25523888 TI - Validation of a fentanyl transdermal adhesion scoring tool for use in clinical practice. AB - CONTEXT: The therapeutic efficacy of a transdermal system (TDS) is directly related to the adhesion of TDS, with partial adhesion resulting in lower plasma concentration. Currently there is no TDS adhesion scoring tool available for use in the clinical setting. OBJECTIVES: To validate a U.S. Food and Drug Administration (FDA) scoring system for the adhesion of the fentanyl TDS in cancer patients. METHODS: A library of images was created from photographs of fentanyl/placebo TDS placed on patients/volunteers. Thirty photographs, reflecting varying degrees of adhesion, were selected for each of series A and B, with 10 photographs common to both series. Each series was shown to 30 health professionals asked to score the photographs using the FDA scoring system. Validity was assessed using Spearman's rank correlation and reliability by Cohen's kappa (k). Photo editing software was used to assign control scores to each photograph. RESULTS: Validity was high for both series (>= 0.954). Inter reliability (k) ranged from 0.327 to 0.858 (average, 0.547) and 0.433-0.910 (average, 0.620) in series A and B, respectively. The combined agreement across both series was 0.585. Intra-rater agreement (k) of the 10 common images was 0.605. No significant difference was observed between the scoring patterns for those with more than 10 years of working experience. CONCLUSION: Overall, the TDS adhesion score determined by the participants visually in this study corresponded well to those generated by photo editing software, thus rendering the scoring system highly valid. The FDA scoring system is an adequate tool for assessing fentanyl TDS adhesion in clinical practice. PMID- 25523889 TI - Toward safe accessibility of opioid pain medicines in Vietnam and other developing countries: a balanced policy method. AB - Moderate or severe pain is common among people with advanced cancer and other life-threatening illnesses. Yet despite agreement that pain relief is a human right, the poorest 80% of the world's population rarely have access to strong opioid analgesics. Excessively restrictive opioid policies, especially in developing countries, both stem from and propagate misguided fears about opioids, so-called opiophobia. Because opiophobia, like any norm, is historically, socially, and culturally situated, efforts to change opiophobic policies will be most effective if guided by awareness of their historical, social, and cultural determinants. We describe some of these determinants in Vietnam and report on results of an ongoing project there to allay opiophobia and improve safe access to opioids for medical uses. We used a method that entails working with committed local partners, including a high-level official from the Ministry of Health, to review all Vietnamese policies governing opioid accessibility to identify the barriers; devising an action plan to safely reduce or circumnavigate the barriers; obtaining buy-in for the plan from all stakeholders, including drug regulators and the police; and assisting the Ministry of Health to implement the plan. Since the start of the project, morphine consumption has increased each year and as of 2010 was ninefold greater than in 2003, and the number of hospitals offering palliative care has increased from three to 15. We conclude that this balanced policy method appears to be helping to reduce barriers to opioid access in Vietnam and should be used in other developing countries. PMID- 25523890 TI - Modified Edmonton Symptom Assessment System including constipation and sleep: validation in outpatients with cancer. AB - CONTEXT: The Edmonton Symptom Assessment System (ESAS) measures the severity of nine symptoms. Constipation and sleep disturbance are common in patients with cancer, but are not currently included in the ESAS. OBJECTIVES: To validate the numerical rating scale (NRS) versions of ESAS and its revised version (ESAS-r), with the additional symptoms of constipation and sleep (CS), and to assess patient preference for either version. METHODS: Outpatients with advanced cancer (N = 202) completed three assessments during a single clinic visit: ESAS-CS, and an added time window of "past 24 hours"; ESAS-r-CS, with a time window of "now" and symptom definitions; and the Memorial Symptom Assessment Scale (MSAS). Internal consistency was calculated using Cronbach's alpha. Paired t-tests compared ESAS-CS and ESAS-r-CS scores; these were correlated with MSAS using Spearman correlation coefficients. Test-retest reliability at 24 hours was assessed in 26 patients. RESULTS: ESAS-CS and ESAS-r-CS total scores correlated well with total MSAS (Spearman's rho 0.62 and 0.64, respectively). Correlation of individual symptoms with MSAS symptoms ranged from 0.54-0.80 for ESAS-CS and 0.52 0.74 for ESAS-r-CS. Although participants preferred the ESAS-r-CS format (42.8% vs. 18.6%) because of greater clarity and understandability, the "past 24 hours" time window (52.8%) was favored over "now" (21.3%). Shortness of breath and nausea correlated better for the "past 24 hours" time window (0.8 and 0.72 vs. 0.74 and 0.64 in ESAS-r-CS, respectively). The 24-hour test-retest of the ESAS-CS demonstrated acceptable reliability (intraclass correlation coefficient = 0.69). CONCLUSION: The ESAS-CS and ESAS-r-CS NRS versions are valid and reliable for measuring symptoms in this population of outpatients with advanced cancer. Although the ESAS-r-CS was preferred, patients favored the 24-hour time window of the ESAS-CS, which also may best characterize fluctuating symptoms. PMID- 25523891 TI - Influence of hemodialysis duration on mid-term clinical outcomes in hemodialysis patients with coronary artery disease after drug-eluting stent implantation. AB - Accelerated atherosclerosis in prolonged maintenance hemodialysis (HD) has been recognized; however, whether HD duration is associated with poor clinical outcome in HD patients with coronary artery disease (CAD) after drug-eluting stent (DES) implantation is unknown. We evaluated the impact of HD duration on clinical outcomes in HD patients with CAD after DES implantation. Between April 2007 and December 2012, 168 angina pectoris patients (320 de novo lesions) on HD were treated with DES. Major adverse cardiovascular events (MACE) and target lesion revascularization (TLR) were investigated at 3 years according to the HD duration (<= 3 years, 83 patients; >3 years, 85 patients). The incidence of MACE was significantly higher in the long HD duration group (25.3 vs. 50.6 %; P = 0.001). Especially, sudden cardiac death (SCD) was significantly higher in the long HD duration group (3.6 vs. 16.5 %; P = 0.006). On the other hand, the rates of TLR were similar between the two groups (12.0 vs. 14.1 %; P = 0.69). Cox's proportional hazard analysis revealed that HD duration (HR 1.08 per year, 95 % CI 1.03-1.13, P = 0.002), beta-blocker use (0.28, 0.17-0.46, P < 0.001), and diabetes mellitus (2.10, 1.23-3.56, P = 0.007) were independent predictors of MACE. Longer HD duration did not affect TLR; however, SCD was significantly higher in the long HD duration group. PMID- 25523892 TI - Clinical characteristics and intravascular ultrasound findings of culprit lesions in elderly patients with acute coronary syndrome. AB - Acute coronary syndrome (ACS) is one of the main causes of cardiovascular death. According to rapid aging of society, the peak age of ACS onset has grown older globally. Despite growing recognition of the necessity to build the ACS prevention strategy in the elderly, patients background and culprit lesion morphology of these elderly ACS patients have not been well studied. We sought to assess the clinical characteristics and intravascular ultrasound (IVUS) findings of the culprit lesions in elderly ACS patients. One-hundred and fifty-eight consecutive ACS patients whose culprit lesions imaged by pre-intervention IVUS were divided into two groups based on the age of onset: elderly [E] group (>=75 years, n = 65) and non-elderly [NE] group (<75 years, n = 93). As compared with NE group, hemoglobin (12.7 +/- 2.0 g/dL vs. 13.7 +/- 1.6 g/dL, p = 0.001), estimated glomerular filtration rate (62.5 +/- 22.5 mL/min/1.73 m(2) vs. 75.5 +/- 20.5 mL/min/1.73 m(2), p = 0.0001), and body mass index (22.9 +/- 3.4 kg/m(2) vs. 24.5 +/- 3.4 kg/m(2), p = 0.003) were significantly lower, and comorbid malignancy was more common (20.0 vs 6.5 %, p = 0.01) in E group. Although whole culprit segment was not positively remodeled (mean vessel area was 15.2 +/- 5.6 mm(3)/mm vs. 16.2 +/- 5.1 mm(3)/mm, p = 0.16) in E group, at maximum external elastic membrane site of the culprit lesion, lumen area was smaller (5.5 +/- 3.2 mm(2) vs. 6.7 +/- 3.5 mm(2), p = 0.04), and plaque burden tended to be more abundant (70 +/- 13 vs. 66 +/- 13 %, p = 0.08). Interestingly, echo attenuation arc of culprit attenuated plaque was significantly greater in E group than in NE group (157 +/- 83 degrees vs. 118 +/- 60 degrees , p = 0.01). In conclusion, extracardiac comorbidity was more common in elderly ACS patients, and their culprit coronary lesions were still rupture prone, and "vulnerable." PMID- 25523894 TI - Interstitial modification of palladium nanoparticles with boron atoms as a green catalyst for selective hydrogenation. AB - Lindlar catalysts comprising of palladium/calcium carbonate modified with lead acetate and quinoline are widely employed industrially for the partial hydrogenation of alkynes. However, their use is restricted, particularly for food, cosmetic and drug manufacture, due to the extremely toxic nature of lead, and the risk of its leaching from catalyst surface. In addition, the catalysts also exhibit poor selectivities in a number of cases. Here we report that a non surface modification of palladium gives rise to the formation of an ultra selective nanocatalyst. Boron atoms are found to take residence in palladium interstitial lattice sites with good chemical and thermal stability. This is favoured due to a strong host-guest electronic interaction when supported palladium nanoparticles are treated with a borane tetrahydrofuran solution. The adsorptive properties of palladium are modified by the subsurface boron atoms and display ultra-selectivity in a number of challenging alkyne hydrogenation reactions, which outclass the performance of Lindlar catalysts. PMID- 25523893 TI - Perinatal vs genetic programming of serotonin states associated with anxiety. AB - Large numbers of women undergo antidepressant treatment during pregnancy; however, long-term consequences for their offspring remain largely unknown. Rodents exposed to serotonin transporter (SERT)-inhibiting antidepressants during development show changes in adult emotion-like behavior. These changes have been equated with behavioral alterations arising from genetic reductions in SERT. Both models are highly relevant to humans yet they vary in their time frames of SERT disruption. We find that anxiety-related behavior and, importantly, underlying serotonin neurotransmission diverge between the two models. In mice, constitutive loss of SERT causes life-long increases in anxiety-related behavior and hyperserotonemia. Conversely, early exposure to the antidepressant escitalopram (ESC; Lexapro) results in decreased anxiety-related behavior beginning in adolescence, which is associated with adult serotonin system hypofunction in the ventral hippocampus. Adult behavioral changes resulting from early fluoxetine (Prozac) exposure were different from those of ESC and, although somewhat similar to SERT deficiency, were not associated with changes in hippocampal serotonin transmission in late adulthood. These findings reveal dissimilarities in adult behavior and neurotransmission arising from developmental exposure to different widely prescribed antidepressants that are not recapitulated by genetic SERT insufficiency. Moreover, they support a pivotal role for serotonergic modulation of anxiety-related behavior. PMID- 25523895 TI - The cancer burden attributable to biologic agents. AB - PURPOSE: A review of cohort and case-control studies that attempt to quantify the proportion of cancer cases diagnosed in the United States and throughout the world that may be attributed to biologic or infectious agents. METHODS: Epidemiologic studies published primarily since the year 2000 are summarized that estimate population attributable fractions based on consensus estimates of relative risk and of the exposure prevalence to putative oncogenic infectious agents in representative populations. RESULTS: The proportion of incident cancers attributable to infectious agents diagnosed in low- and middle-income countries, comprising more than 80% of the world's population, has been estimated to vary from 20% to 30%, in contrast to a range of 5% or less to 10% in the United States and other highly industrialized populations. More than 90% of the global cancer cases attributed to infectious agents have been caused by hepatitis B virus, hepatitis C virus, human papillomaviruses, and the gram-negative bacterium, Helicobacter pylori. CONCLUSIONS: Epidemiologic and pathologic studies that use molecular diagnostic probes and immunologic and biochemical assays have described the substantial impact of infectious agents on global cancer incidence. These compelling observations have stimulated the development of effective hepatitis B virus and human papillomavirus vaccines and the rationale for eradication of Helicobacter pylori. PMID- 25523896 TI - Neighborhood deprivation and preterm birth: an application of propensity score matching. AB - PURPOSE: On the basis of a neighborhood deprivation index (NDI), this study aims to examine the association between neighborhood deprivation and preterm birth (PTB) by applying propensity score matching (PSM) methods. METHODS: NDI was calculated for all census tracts in South Carolina based on the US Census data. Live births in South Carolina during 2008 to 2009 (n = 98,456) were assigned to an NDI quartile group based on residential addresses. PSM was used to create matched pairs by NDI quartiles to avoid any potential inference on imbalanced data. The differences of prevalence of PTB were calculated for exposed and reference deprivation groups. RESULTS: Neighborhood deprivation was higher among blacks than whites. The overall prevalence of PTB was 8.5% for whites and 12.6% for blacks. Living in neighborhoods with higher deprivation was associated with increased risk of PTB among blacks compared with living in neighborhoods with lower deprivation among blacks. However, random-effect regression models showed that the most deprived whites experienced 1.13 times the odds of having PTB than the least deprived whites. CONCLUSIONS: The racial disparities in adverse birth outcomes might be partially explained by neighborhood deprivation in South Carolina. PSM may be an appropriate approach to avoid imbalanced data inferences. PMID- 25523898 TI - Anti-IgE therapy with omalizumab for severe asthma: current concepts and potential developments. AB - The humanized monoclonal anti-IgE antibody omalizumab is currently the only biologic drug approved for asthma treatment. Omalizumab inhibits allergic responses by binding to serum immunoglobulins E (IgE), thus preventing their interactions with cellular IgE receptors. Omalizumab is also capable of down regulating the expression of high affinity IgE receptors on inflammatory cells, as well as the numbers of eosinophils in both peripheral blood and induced sputum. The clinical effects of omalizumab include relevant improvements in respiratory symptoms and quality of life, paralleled by a marked reduction of asthma exacerbations, emergency room visits, and use of systemic corticosteroids and rescue bronchodilators. Moreover, some recent studies suggest potential benefits of omalizumab also in non allergic phenotypes of severe asthma. Very interesting are also further recent reports referring to the potential inhibitory effect of omalizumab with regard to bronchial structural changes, especially occurring in severe asthma and globally defined as airway remodeling. Omalizumab is relatively well tolerated, and only very rarely induces anaphylactic reactions. Therefore, this drug represents a valid option as add-on therapy for patients with severe persistent asthma, inadequately controlled by high doses of standard inhaled treatments. PMID- 25523899 TI - Intracellular Ca2+ Signals to Reconstruct A Broken Heart: Still A Theoretical Approach? AB - The infusion of autologous stem cells has recently been put forward as an alternative strategy to regenerate infarcted myocardium and restore the contractile functions of diseased hearts. A growing number of cell types have been probed to induce cardiac repair in several animal models of ischemic myocardium, including human cardiac progenitor cells (hCPCs), human embryonic stem cells (hESCs), human mesenchymal stem cells (hMSCs) and human endothelial progenitor cells (hEPCs). The enthusiasm raised by pre-clinical studies has been dampened by clinical practice, according to which the extent of cardiac repair by cell based therapy is inadequate with respect to animal models. There is no doubt that regenerative medicine of acute myocardial infarction (AMI) will greatly benefit from the full comprehension of the signal transduction pathways which guide stem cell towards the injury site and their subsequent acquisition of a therapeutically relevant phenotype. The present review will focus on the role that oscillations in intracellular Ca(2+) concentration might play to promote the stem cells-dependent regrowth of ischemic myocardium. We will describe how intracellular Ca(2+) spikes may be manipulated to redirect stem cell fate to the most suitable lineage to restore cardiac vascularisation and contractility. PMID- 25523897 TI - Atrial fibrillation incidence and risk factors in relation to race-ethnicity and the population attributable fraction of atrial fibrillation risk factors: the Multi-Ethnic Study of Atherosclerosis. AB - PURPOSE: We studied incident atrial fibrillation (AF) in the prospective community-based Multi-Ethnic Study of Atherosclerosis (MESA). Reportedly, non Hispanic blacks (NHBs) have a lower AF burden compared with their non-Hispanic white (NHW) counterparts. Information on the epidemiology of AF in Hispanic and Asian populations is much more limited. METHODS: We excluded participants with a history of AF at enrollment. A total of 6721 MESA participants were monitored for the first AF event ascertained according to hospital discharge International Classification of Diseases, Ninth Revision, codes. Age- and sex-adjusted incidence rates (IRs) of AF were calculated per 1000 person-years of observation. IR ratios were calculated using NHWs as the reference group. Age- and sex adjusted population attributable fractions (PAFs) of established modifiable AF risk factors were ascertained. RESULTS: In the MESA cohort, 47.2% was male; at baseline, 25.7% had hypertension; 12.5% had diabetes. Three hundred five incident hospitalized AF events occurred over a mean follow-up of 7.3 years. Age- and sex adjusted IRs and IR ratios showed that overall AF incidence was significantly lower among Hispanics, NHBs and Chinese compared with NHWs (all P < .001). Among participants 65 years of age or greater, Hispanics, Chinese, and blacks had significantly lower AF incidence than NHWs (all P <= .01), but IRs were similar among participants under age 65 years. The PAF for smoking was 27% among NHBs but lower among other race-ethnic groups. Among NHWs, the PAF for hypertension was 22.2%, but this was higher among NHBs (33.1%), Chinese (46.3%), and Hispanics (43.9%). CONCLUSIONS: Overall, the incidence of hospitalized AF was significantly lower in Hispanics, NHBs, and Chinese than in NHWs. A larger proportion of AF events appear to be attributable to hypertension among nonwhite populations compared with NHWs. PMID- 25523900 TI - PDZ Structure and Implication in Selective Drug Design against Cystic Fibrosis. AB - PDZ domains play an essential role in a number of cellular processes by facilitating protein scaffolding and assembly of protein complexes. These domains consist of 80 to 90 amino acids and are found to recognize short C-terminal sequences of target proteins. Protein complex formation between PDZ target molecules can lead to a number of signaling and regulatory cascades that may either promote or inhibit the activation of certain proteins. It has been shown that the interaction of the PDZ domains of NHERF2 with LPA2 plays an inhibitory role on the cystic fibrosis transmembrane conductance regulator (CFTR) by promoting the assembly of a CFTR-NHERF2-LPA2 complex. CFTR regulates chloride ion transport across the epithelial plasma membrane, and individuals possessing CFTR mutations show decreased protein function and consequently, viscous mucus accumulation due to improper fluid transport. This type of ailment is termed cystic fibrosis. Thus, insight to the structure of PDZ domains and how they function to form macromolecular complexes could be therapeutically important in augmenting CFTR channel activity in cystic fibrosis patients. Here we review the PDZ domain family while dissecting their structure, function and implications in CFTR regulation and cystic fibrosis. PMID- 25523901 TI - Aquaporin-1 and sodium-hydrogen exchangers as pharmacological targets in diabetic atherosclerosis. AB - Sodium-hydrogen exchangers (NHEs) and aquaporins (AQPs) are key regulators of cell volume and intracellular ions both in physiological and pathological conditions. By directly affecting water and ion exchanges across the plasma membrane, NHEs and AQPs, particularly isoforms 1, can also influence vascular tone and the cytoskeleton, respectively, in response to several types of stimuli, such as hypertonic stress. NHE-1 and AQP1 are mainly expressed in tissues of the cardiovascular system. Their excessive activation in response to elevated extracellular osmolarity, as occurring in diabetic hyperglycemia, can be deleterious both for micro- and macrovascular endothelial cells. Although NHE-1 and AQP1 regulate the intracellular volume and ions, they also influence the activation of hypertonicity-responsive genes and cell functions involved in glucotoxicity and vascular injury. Because of the involvement of NHEs and AQPs in micro- and macrovascular disease, including arterial hypertension and atherosclerotic plaque destabilization, research has focused on developing inhibitors of these transporters. We here review current knowledge of NHEs and AQPs investigating biological aspects and mechanisms of their regulation, including their potential as target for developing new drugs that could target diabetic atherosclerosis. PMID- 25523902 TI - Should arm span or height be used in calculating the BMI for the older people? Preliminary results. AB - AIMS AND OBJECTIVES: To consider using arm span rather than height for calculating the body mass index, as a parameter that offers greater long-term stability, for the nutritional assessment of persons aged over 65 years. BACKGROUND: The body mass index presents certain drawbacks for the nutritional screening of older people suffering malnutrition or at risk of malnutrition, due to the anthropometric changes that occur with increasing age, especially the progressive loss of height. DESIGN: Observational, cross-sectional study, using nonprobabilistic convenience sampling, with anthropometric measurements and nutritional screening in older men and women, divided into two groups: (1) aged 65-75 years and (2) aged over 75 years. METHODOLOGY: Height and arm span were measured to calculate two separate indices of body mass: body mass index (weight/height) and body mass index.1 (weight/arm span). Nutritional screening was conducted using the Mini Nutritional Assessment Short-Form, which includes the body mass index as an anthropometric measure. RESULTS: Our results reveal statistically significant differences between the two indices, for the sample analysed. Body mass index.1 classifies a larger number of older people as suffering malnutrition and fewer as being at nutritional risk. When this new index is used, there is a displacement of the subjects at risk, thus increasing the number considered at risk of malnutrition and in need of appropriate therapeutic intervention. Therefore, the use of body mass index.1 would enable more people suffering malnutrition, who would otherwise remain untreated, to be attended. CONCLUSIONS: As arm span, as an anthropometric measure, remains unchanged over time, it could be used instead of height, as an alternative index (body mass index.1) to the conventional body mass index. Further research is needed to determine the association between body mass index.1 and clinical status parameters to determine optimum cut-off points. RELEVANCE TO CLINICAL PRACTICE: This study describes the greater stability of body mass index.1 with respect to body mass index for nutritional screening, and the resulting benefits for nutritional monitoring and intervention for older people. PMID- 25523903 TI - Antenatal and postnatal mental health: summary of updated NICE guidance. PMID- 25523904 TI - Genome-wide patterns of genetic polymorphism and signatures of selection in Plasmodium vivax. AB - Plasmodium vivax is the most prevalent human malaria parasite outside of Africa. Yet, studies aimed to identify genes with signatures consistent with natural selection are rare. Here, we present a comparative analysis of the pattern of genetic variation of five sequenced isolates of P. vivax and its divergence with two closely related species, Plasmodium cynomolgi and Plasmodium knowlesi, using a set of orthologous genes. In contrast to Plasmodium falciparum, the parasite that causes the most lethal form of human malaria, we did not find significant constraints on the evolution of synonymous sites genome wide in P. vivax. The comparative analysis of polymorphism and divergence across loci allowed us to identify 87 genes with patterns consistent with positive selection, including genes involved in the "exportome" of P. vivax, which are potentially involved in evasion of the host immune system. Nevertheless, we have found a pattern of polymorphism genome wide that is consistent with a significant amount of constraint on the replacement changes and prevalent negative selection. Our analyses also show that silent polymorphism tends to be larger toward the ends of the chromosomes, where many genes involved in antigenicity are located, suggesting that natural selection acts not only by shaping the patterns of variation within the genes but it also affects genome organization. PMID- 25523905 TI - Chemical Response of the Toxic Dinoflagellate Karenia mikimotoi Against Grazing by Three Species of Zooplankton. AB - We investigated the toxicity of Karenia mikimotoi toward three model grazers, the cladoceran Moina mongolica, the copepod Pseudodiaptomus annandalei, and the crustacean Artemia salina, and explored its chemical response upon zooplankton grazing. An induction experiment, where K. mikimotoi was exposed to grazers or waterborne cues from the mixed cultures revealed that K. mikimotoi might be toxic or nutritionally inadequate toward the three grazers. In general, direct exposure to the three grazers induced the production of hemolytic toxins and the synthesis of eicosapentaenoic acid (EPA). Both EPA and the hemolytic toxins from K. mikimotoi decreased the survival rate of the three grazers. In addition, the survival rates of M. mongolica, P. annandalei, and A. salina in the presence of induced K. mikimotoi that had previously been exposed to a certain grazer were lower than their counterparts caused by fresh K. mikimotoi, suggesting that exposure to some grazers might increase the toxicity of K. mikimotoi. The chemical response and associated increased resistance to further grazing suggested that K. mikimotoi could produce deterrents to protect against grazing by zooplankton and that the substances responsible might be hemolytic toxins and EPA. PMID- 25523906 TI - Variation in the practice of laparoscopic sacrohysteropexy and laparoscopic sacrocolpopexy for the treatment of pelvic organ prolapse: a Dutch survey. AB - INTRODUCTION AND HYPOTHESIS: Laparoscopic techniques for pelvic organ prolapse surgery using mesh are gaining interest. A standard approach or published guideline for the laparoscopic sacrohysteropexy (LSH) or laparoscopic sacrocolpopexy (LSC) is lacking. The purpose of this study is to assess the variation between Dutch gynecologists in executing LSH and LSC. METHODS: A questionnaire was developed to evaluate the technique of LSH and LSC. All members of the Dutch Society for Gynecological Endoscopy and Minimally Invasive Surgery and the Dutch Society for Urogynecology were invited by email to participate in a web-based survey. RESULTS: With 357 respondents, the response rate was 71%. Of the respondents, a total of 49 gynecologists (13.7%) perform LSH and/or LSC. Gynecologists who perform both procedures use the same surgical technique for LSH and LSC. There are variations among gynecologists on several key points such as the level of dissection along the anterior and posterior walls of the vagina, the type of mesh used, the type of sutures used, the tension of the implanted mesh and reperitonealization of the mesh. CONCLUSIONS: There is a high practice variation in LSH and LSC performed by a selected group of Dutch gynecologists. Different methods have been described in the literature and there is no consensus on how to perform these procedures. A well-designed prospective study or randomized controlled trial with regard to the specific parts of these procedures is needed to provide evidence for the best surgical technique. The outcomes of these studies will help to establish evidence-based guidelines. PMID- 25523907 TI - Human white and brite adipogenesis is supported by MSCA1 and is impaired by immune cells. AB - Obesity-associated inflammation contributes to the development of metabolic diseases. Although brite adipocytes have been shown to ameliorate metabolic parameters in rodents, their origin and differentiation remain to be characterized in humans. Native CD45-/CD34+/CD31- cells have been previously described as human adipocyte progenitors. Using two additional cell surface markers, MSCA1 (tissue nonspecific alkaline phosphatase) and CD271 (nerve growth factor receptor), we are able to partition the CD45-/CD34+/CD31- cell population into three subsets. We establish serum-free culture conditions without cell expansion to promote either white/brite adipogenesis using rosiglitazone, or bone morphogenetic protein 7 (BMP7), or specifically brite adipogenesis using 3 isobuthyl-1-methylxanthine. We demonstrate that adipogenesis leads to an increase of MSCA1 activity, expression of white/brite adipocyte-related genes, and mitochondriogenesis. Using pharmacological inhibition and gene silencing approaches, we show that MSCA1 activity is required for triglyceride accumulation and for the expression of white/brite-related genes in human cells. Moreover, native immunoselected MSCA1+ cells exhibit brite precursor characteristics and the highest adipogenic potential of the three progenitor subsets. Finally, we provided evidence that MSCA1+ white/brite precursors accumulate with obesity in subcutaneous adipose tissue (sAT), and that local BMP7 and inflammation regulate brite adipogenesis by modulating MSCA1 in human sAT. The accumulation of MSCA1+ white/brite precursors in sAT with obesity may reveal a blockade of their differentiation by immune cells, suggesting that local inflammation contributes to metabolic disorders through impairment of white/brite adipogenesis. Stem Cells 2015;33:1277-1291. PMID- 25523908 TI - Predicting the potential invasion suitability of regions to cassava lacebug pests (Heteroptera: Tingidae: Vatiga spp.). AB - Cassava (Manihot esculenta Crantz) is one of the most important staple crops for small farmers in the tropics, feeding about 800 million people worldwide. It is currently cultivated in South and Central America, Africa and Asia. The genus Vatiga is widespread throughout the Neotropical region. Its species are sympatric and feed exclusively on cassava. The main objectives of this paper are: (1) to assess the potential distribution of Vatiga, one of the most relevant pests of cassava; (2) to project the resulting models onto the world; (3) to recognize areas with suitable and optimal climates (and thus, high probability) for future colonization, and (4) to compare this model with the harvested area of cassava analyzing the climatic variables required by both the host and the pest species. Species distribution models were built using Maxent (v3.3.3k) with bioclimatic variables from the WorldClim database in 2.5 arc min resolution across the globe. Our model shows that Vatiga has the potential to expand its current distribution into other suitable areas, and could invade other regions where cassava is already cultivated, e.g., Central Africa and Asia. Considering the results and the high host specificity of Vatiga, its recent appearance in Reunion Island (Africa) poses a serious threat, as nearby areas are potentially suitable for invasion and could serve as dispersal routes enabling Vatiga to reach the continent. The present work may help prevention or early detection of Vatiga spp. in areas where cassava is grown. PMID- 25523909 TI - Acute eccentric resistance exercise decreases matrix metalloproteinase activity in obese elderly women. AB - The association of ageing with obesity commits elderly women and has been correlated with multiple degenerative processes, which could be occasioned by an enhancing in levels of matrix metalloproteinase-2 and metalloproteinase-9 (MMPs) as well by an cytokine unbalance that included an enhancing on interleukin-6 (IL 6). Furthermore, other factors could be also related to degenerative process, as they could be reduced by eccentric resistance exercise (ERE), which seems particularly important to initiate resistance training in obese older adults. In this view, this study aims to determinate the effects of an acute ERE session on serum MMP-2, MMP-9 and IL-6 in elderly obese women. Ten elderly obese women participated in this study and completed a 10 repetitions maximum test (10 RM) utilizing leg extension exercise. Subjects then completed an acute ERE session consisting of seven sets of 10 repetitions at 110% of 10 RM with a rest of 3 min between sets. Blood samples were collected before, immediately after, 3, 24 and 48 h following the ERE session. Zymograms were utilized to measure the MMP-2 and MMP-9 enzymes from all individuals. Moreover, IL-6 concentration was also determinated. After ERE session, MMP-2 and MMP-9 decreased, remaining significantly below baseline values after 48 h (P<0.05). Although not statistically significant, there was a tendency for IL-6 to decrease 48 h after the ERE when compared with 3 h (P = 0.06). An acute ERE session decreases MMP-9, MMP-2 and IL-6 in elderly obese women, possibly indicating a transient protection against the low grade inflammation present in this specific population. PMID- 25523910 TI - Techniques for RNA in vivo imaging in plants. AB - Since the discovery of small RNAs and RNA silencing, RNA biology has taken a centre stage in cell and developmental biology. Small RNAs, but also mRNAs and other types of cellular and viral RNAs are processed at specific subcellular localizations. To fully understand cellular RNA metabolism and the various processes influenced by it, techniques are required that permit the sequence specific tracking of RNAs in living cells. A variety of methods for RNA visualization have been developed since the 1990s, but plant cells pose particular challenges and not all approaches are applicable to them. On the other hand, plant RNA metabolism is particularly diverse and RNAs are even transported between cells, so RNA imaging can potentially provide many valuable insights into plant function at the cellular and tissue level. This Short Review briefly introduces the currently available techniques for plant RNA in vivo imaging and discusses their suitability for different biological questions. PMID- 25523912 TI - [Current developments in psychotherapy research in childhood and adolescence]. PMID- 25523913 TI - [Psychotherapy of personality disorders in adolescence]. AB - By the current state of knowledge adolescent personality disorders should be taken seriously due to their high prevalence and severe symptomatology. Personality disorders are characterized by a stable pattern of deviation concerning cognition, affectivity, impulse control, and interpersonal relationships and have negative repercussions in psychosocial functioning and subsequent development. There is emerging evidence that personality disorder diagnosis is reliable and valid during adolescence. It is essential to detect youth with personality pathology in order to refer them to specific psychotherapeutic interventions and consequently avoid further chronification and life-long functional impairment. This selective review will give an overview over personality disorders in adolescents as well as according psychotherapeutic interventions. PMID- 25523914 TI - [Maternal reflective functioning as a predictor of therapeutic success of psychoanalytic short-term therapy for children aged 4 to 10 years]. AB - Recent work implicates the capacity to mentalize as a predictor of therapeutic success of psychodynamically oriented psychotherapy for adults. However, little, if any, research focuses on similar associations in childhood. In the current study, we investigated the role of maternal reflective functioning (RF) in the treatment of 25 children with clinically diagnosed anxiety disorders and a high level of externalizing comorbidity in an outpatient setting. Before and after treatment of their children with short-term Psychoanalytic Child Therapy (PaCT), we assessed maternal RF using the Parent Development Interview and requested parents to report on symptoms of their 4-10-year-old children using the Child Behavior Checklist (CBCL). RF proved highly stable and showed no significant change from pre- to post-treatment over an average treatment interval of 41 weeks. While remission in internalizing symptoms was unrelated to pretreatment maternal RF, children with high-RF mothers showed significant remission of externalizing comorbidity in comparison to children with low-RF mothers both immediately after treatment as well as at six-month follow-up. These preliminary results support parental RF as a valuable prognostic criterion for successful treatment of externalizing symptoms with PaCT. These findings call for replication in large-scale follow-up studies with children diagnosed with externalizing disorders. PMID- 25523915 TI - [Multiprofessional intermittent psychiatric treatment of children in preschool age and their parents in a family day clinic]. AB - Psychiatric treatment of children in preschool age (0-6 years) and their parents is an expanding field of research due to its high clinical significance. Specific family psychiatric treatment programs have been developed to meet the demands of this young age group, but are little known. A multiprofessional intermittent treatment approach sensitive to developmental and family context has been established in the Preschool Family Day Hospital for Infants, Toddlers and Preschoolers and their Families at Munster University Hospital, Germany. Group and individual therapeutic interventions for both children and parents, video based parent-child-interaction therapy, psychiatric and psychotherapeutic treatments of parents and family therapeutic interventions integrating siblings are supporting and enhancing each other in an innovative and integrated family psychiatric program. First results of evaluation studies are reported that show that this treatment is effective. PMID- 25523916 TI - [Operationalized psychodynamic diagnostics in childhood and adolescence (OPD-CA): the axis during psychoanalytic child- and adolescent psychotherapy]. AB - There is evidence for the effectiveness of psychodynamic therapies in terms of symptom reduction. Up to now, there is little evidence to what extend therapy translates to the improvement of core analytical concepts, like psychic structure, interpersonal relatedness, and intrapsychic conflicts. The current study focuses on these concepts over the course of therapy as well as in connection with outcome. The concepts are assessed with the Operationalized Psychodynamic Diagnostics in Childhood and Adolescence (OPD-CA). Additionally, the OPD-CA axis prerequisites of treatment is tested as a predictor of outcome. 16 therapists rated 146 participating patients at the beginning and the end of therapy within the framework of a study on the effectiveness of psychoanalytical psychotherapy. Therapists rated the OPD-CA as well as the level of psychosocial impairment. Psychic structure, interpersonal relatedness, and intrapsychic conflicts improved significantly over the course of therapy. Positive outcome was predicted by communicative abilities, positive self-relatedness and an undistinctive intrapsychic conflict at the beginning of therapy as well as the improvement of these during therapy. Among the prerequisites of treatment only the subjective level of mental impairment and the intrapsychic resources were predictive of outcome. Psychoanalytic psychotherapy for children and adolescents improved central psychodynamic concepts like psychic structure, interpersonal relatedness, and intrapsychic conflicts. PMID- 25523921 TI - ERRATUM: Transactivation of Large Ribozymes. PMID- 25523922 TI - Mitogen-activated protein kinase Hog1 is activated in response to curcumin exposure in the budding yeast Saccharomyces cerevisiae. AB - BACKGROUND: Curcumin (CUR), an active polyphenol derived from the spice turmeric, has been traditionally used for centuries in ancient Indian medicine to treat a number of diseases. The physiological effects of CUR have been shown to be diverse; however, the target molecules and pathways that CUR affects have yet to be fully described. RESULTS: Here, we demonstrate for the first time that the budding yeast mitogen-activated protein kinase (MAPK) Hog1 is essential for the response to CUR. Moreover, CUR-induced Hog1 phosphorylation was rescued by supplementation of iron to the growth medium. Hog1 was rapidly phosphorylated upon CUR treatment, but unlike the response to hyperosmotic shock (0.8 M NaCl), it remains activated for an extended period of time. A detailed analysis of HOG pathway mutants revealed that Pbs2p, Ptc2p, and Ssk2p are required for optimal CUR-induced Hog1 phosphorylation. We also observed a Hog1 dependent transcriptional response to CUR treatment that involved the up-regulation of glycerol-3-phosphate dehydrogenase 1 (GPD1), a factor that is essential for the hyperosmotic stress response. CONCLUSIONS: Our present finding revealed the role of Hog1 MAPK in regulation of CUR-induced transcriptional response. We anticipate that our finding will enhance the understanding on the molecular mode of action of CUR on S. cerevisiae. PMID- 25523923 TI - Qualification of a whole blood intracellular cytokine staining assay to measure mycobacteria-specific CD4 and CD8 T cell immunity by flow cytometry. AB - BACKGROUND: Qualified or validated assays are essential in clinical trials. Short term stimulation of whole blood and intracellular cytokine staining assay is commonly used to measure immunogenicity in tuberculosis vaccine clinical trials. Previously, the short-term stimulation process of whole blood with BCG was optimized. We aimed to qualify the intracellular cytokine staining process and assess the effects of long-term cryopreservation. Our hypotheses were that the assay is robust in the measurement of the mycobacteria-specific T cells, and long term cryopreservation of fixed cells from stimulated whole blood would not compromise reliable measurement of mycobacteria induced CD4 T cell immunity. METHODS: Whole blood from healthy adults was collected in sodium heparinized tubes. The blood was left unstimulated or stimulated with mycobacterial antigens or mitogens for 12h. Cells were harvested, fixed and multiple aliquots from each participant cryopreserved. Later, mycobacteria-specific CD4 and CD8 T cells expressing IFN-gamma, TNF-alpha, IL-2 and IL-17 were quantitated by flow cytometry. Assay performance characteristics evaluated included limit of quantification and detection, reproducibility, precision, robustness, specificity and sensitivity. To assess the effects of long-term cryopreservation, fixed cells from the stimulated bloods were analysed one week post-cryopreservation and at 3 month intervals over a 3-year period. RESULTS: The limit of quantification for the different cytokines was variable: 0.04% for frequencies of IFN-gamma- and IL 2-expressing T cells and less than 0.01% for TNF-alpha- and IL-17-expressing T cells. When measurement of the mycobacteria-specific T cells was assessed at levels above the detection limit, the whole blood intracellular cytokine assay showed high precision that was operator-independent. The assay was also robust: variation in staining conditions including temperature (4 degrees C or 20-23 degrees C) and time (45, 60 or 90 min) did not markedly affect quantification of specific T cells. Finally, prolonged periods of cryopreservation also did not significantly influence quantification of mycobacteria-specific CD4 T cells. CONCLUSIONS: The whole blood intracellular cytokine assay is robust and reliable in quantification of the mycobacteria-specific T cells and is not significantly affected by cryopreservation of fixed cells. PMID- 25523924 TI - ELISpot and ELISA analyses of human IL-21-secreting cells: Impact of blocking IL 21 interaction with cellular receptors. AB - Interleukin (IL)-21 is crucial for the regulation of lymphocytes and is implicated in autoimmune and other diseases. The relevance of being able to measure human IL-21 prompted us to develop ELISA and ELISpot assays for analysis of IL-21 levels and IL-21-producing cells, respectively. Monoclonal antibodies (mAbs) to IL-21 were made and ELISA and ELISpot assays were developed. The selected detection mAb also neutralized IL-21-mediated activation of human cells. Peripheral blood mononuclear cells (PBMCs) from healthy donors (n=24) were stimulated polyclonally (phytohemagglutinin; PHA) or with antigen (Candida albicans extract and tetanus toxoid). Using ELISpot, high numbers of IL-21 producing cells were detected after PHA activation; lower but positive responses to antigen were seen in approximately 50% of the donors. In contrast, the ELISA detected IL-21 in supernatants from PHA-activated cells but not from antigen stimulated cells. When analyzing IL-17A in parallel, PHA and antigens induced detectable responses in ELISpot as well as in ELISA. Hypothesizing that the lack of detectable IL-21 levels after antigenic stimulation was due to a combination of low frequencies of IL-21-secreting cells and consumption of IL-21 by cellular receptors during cell culture, PBMCs (n=18) were stimulated in the presence of the neutralizing detection mAb. When preventing IL-21 from interacting with its receptor, increased IL-21 levels were found by ELISA after PHA activation and IL 21 could also be measured after antigen stimulation. ELISpot results were unaffected by the addition of the neutralizing mAb. In conclusion, IL-21 secreted by low frequencies of antigen-specific ex vivo-stimulated PBMC can be difficult to detect by ELISA but prevention of IL-21 interaction with its receptor leads to detectable IL-21 levels. In ELISpot, where the cytokine is captured by mAbs on a solid phase immediately upon secretion, blocking the receptor interaction does not affect the detection of IL-21-secreting cells. PMID- 25523925 TI - A method for high-throughput, sensitive analysis of IgG Fc and Fab glycosylation by capillary electrophoresis. AB - The N-glycan of the IgG constant region (Fc) plays a central role in tuning and directing multiple antibody functions in vivo, including antibody-dependent cellular cytotoxicity, complement deposition, and the regulation of inflammation, among others. However, traditional methods of N-glycan analysis, including HPLC and mass spectrometry, are technically challenging and ill suited to handle the large numbers of low concentration samples analyzed in clinical or animal studies of the N-glycosylation of polyclonal IgG. Here we describe a capillary electrophoresis-based technique to analyze plasma-derived polyclonal IgG glycosylation quickly and accurately in a cost-effective, sensitive manner that is well suited for high-throughput analyses. Additionally, because a significant fraction of polyclonal IgG is glycosylated on both Fc and Fab domains, we developed an approach to separate and analyze domain-specific glycosylation in polyclonal human, rhesus and mouse IgGs. Overall, this protocol allows for the rapid, accurate, and sensitive analysis of Fc-specific IgG glycosylation, which is critical for population-level studies of how antibody glycosylation may vary in response to vaccination or infection, and across disease states ranging from autoimmunity to cancer in both clinical and animal studies. PMID- 25523927 TI - Laparoscopic repair of postoperative perineal hernia using a two-mesh technique. AB - AIM: Perineal herniation following abdomino-perineal excision of the rectum (APER) can be debilitating. Repair options include a transabdominal (laparoscopic or open), perineal or a combined approach, but there is no consensus on the optimal technique. We describe a novel laparoscopic two-mesh technique and short- to medium-term outcomes. METHOD: Six patients underwent this operation between 2008 and 2014. Patients were positioned in a modified Lloyd-Davies position, allowing perineal access, and steep Trendelenburg to aid displacement of small bowel from the pelvis. A polypropylene mesh was shaped, placed over the hernial defect, tacked postero-laterally and sutured antero-laterally to reconstitute the pelvic diaphragm. A second larger mesh (composite) was placed over the first supporting mesh and secured with tacks and sutures, overlapping the hernial defect, preventing small bowel contact with the mesh. RESULTS: The median time from the index operation to presentation of the hernia was 5 months. One patient with dense small bowel adhesions from the primary repair had a combined laparoscopic and perineal approach. The median operating time was 141 min and median length of stay was 3 days. There were no intra-operative complications and no recurrences over a follow-up of 1-76 months. CONCLUSION: We describe a novel laparoscopic technique for perineal hernia repair following APER with a low recurrence rate in the intermediate term. PMID- 25523926 TI - In vivo elimination of parental clones in general and site-directed mutagenesis. AB - The Eco29k I restriction endonuclease is a Sac II isoschizomer that recognizes the sequence 5'-CCGCGG-3' and is encoded, along with the Eco29k I methylase, in the Escherichia coli strain 29k. We have expressed the Eco29k I restriction methylation system (RM2) in E. coli strain TG1 to produce the strain AXE688. We have developed a directed molecular evolution (DME) mutagenesis method that uses Eco29k I to restrict incoming parental DNA in transformed cells. Using our DME method, we have demonstrated that our AXE688 strain results in mutated directed molecular evolution libraries with diversity greater than 10(7) from a single transformation and with greater than 90% recombinant clones. PMID- 25523928 TI - [Oral bisphosphonates, denosumab and osteonecrosis of the jaws]. PMID- 25523929 TI - Postencephalitic epilepsy: clinical characteristics and predictors. AB - OBJECTIVE: To describe the etiologies, clinical presentations, outcomes, and predictors of postencephalitic epilepsy (PE) in a large series of adult patients with acute encephalitis. METHODS: We conducted a retrospective review of patients diagnosed with acute encephalitis at Mayo Clinic, Rochester, between January 2000 and December 2012. The patients were categorized into two groups based on the presence or absence of PE at last follow-up. Multivariate logistic regression analysis was used to analyze factors associated with PE. RESULTS: We identified 198 consecutive patients (100 [50.5%] male and 98 [49.5%] female) with a median age of 58 years (range 41.8-69). Etiologies included viral infection (n=95, 48%), autoimmune (n=44, 22%), and unknown/others (n=59, 30%). During hospitalization, seizures were seen in patients with autoimmune encephalitis (n=24, 54.5%), unknown/others (n=20, 33.9%), and viral encephalitis (n=23, 24.2%). Interictal epileptiform discharges on electroencephalography (EEG) were present in 34 (54%), whereas periodic lateralized epileptiform discharges (PLEDs) and generalized periodic discharges (GPDs) were seen in 14 (41.2%) and 2 (5.9%) patients. Forty six patients with seizures (70.8%) had fluid-attenuated inversion recovery (FLAIR)/T2 abnormalities, 20 (31.3%) diffusion abnormalities, and 43 (66.2%) cortical involvement. Good outcome at discharge among patients with seizures was seen in 8/23 patients with viral etiology (34.8%), 10/24 patients with autoimmune encephalitis (45.5%), and 12/20 patients with unknown cause (60%). PE was present in 43 patients (29.9%). On multivariate regression analysis, the factors associated with PE were generalized seizures during hospitalization (p=0.03), focal seizures (p<=0.001), and the presence of FLAIR/T2 abnormalities on brain magnetic resonance imaging (MRI) (p=0.003). SIGNIFICANCE: The presence of seizures during hospitalization and an abnormal brain MRI are the strongest predictors of the development of PE. The etiology of encephalitis, presence of focal neurologic deficits, and interictal EEG abnormalities did not influence the development of PE. PMID- 25523930 TI - Use of SWATH mass spectrometry for quantitative proteomic investigation of Shewanella oneidensis MR-1 biofilms grown on graphite cloth electrodes. AB - Quantitative proteomics from low biomass, biofilm samples is not well documented. In this study we show successful use of SWATH-MS for quantitative proteomic analysis of a microbial electrochemically active biofilm. Shewanella oneidensis MR-1 was grown on carbon cloth electrodes under continuous anodic electrochemical polarizations in a bioelectrochemical system (BES). Using lactate as the electron donor, anodes serving as terminal microbial electron acceptors were operated at three different electrode potentials (+0.71 V, +0.21 V & -0.19 V vs. SHE) and the development of catalytic activity was monitored by measuring the current traces over time. Once maximum current was reached (usually within 21-29 h) the electrochemical systems were shut off and biofilm proteins were extracted from the electrodes for proteomic assessment. SWATH-MS analysis identified 704 proteins, and quantitative comparison was made of those associated with tricarboxcylic acid (TCA) cycle. Metabolic differences detected between the biofilms suggested a branching of the S. oneidensis TCA cycle when grown at the different electrode potentials. In addition, the higher abundance of enzymes involved in the TCA cycle at higher potential indicates an increase in metabolic activity, which is expected given the assumed higher energy gains. This study demonstrates high numbers of identifications on BES biofilm samples can be achieved in comparison to what is currently reported. This is most likely due to the minimal preparation steps required for SWATH-MS. PMID- 25523931 TI - Syntheses, structures, and optical properties of Ba4Ga4SnSe12 and Ba6Ga2SnSe11. AB - Two new quaternary selenides, namely Ba4Ga4SnSe12 and Ba6Ga2SnSe11, have been synthesized for the first time, representing the first two members in the A/M/Sn/Q (A = alkaline-earth metal; M = Al, Ga, In; Q = S, Se, Te) system. Ba4Ga4SnSe12 crystallizes in the non-centrosymmetric space group P4[combining macron]21/c of the tetragonal system and has a three-dimensional structure. Its three-dimensional framework is built up from corner-sharing GaSe4 and SnSe4 tetrahedra with eight-coordinated Ba(2+) cations residing in the cavities. Ba6Ga2SnSe11 crystallizes in a new structure type in the monoclinic centrosymmetric space group P21/c. The structure of Ba6Ga2SnSe11 features a zero dimensional structure containing totally isolated distorted SnSe4 tetrahedra and a discrete Ga2Se7 unit with Ba(2+) cations located between them. On the basis of the diffuse-reflectance spectra, the band gaps are 2.16 (2) eV and 1.99 (2) eV for Ba4Ga4SnSe12 and Ba6Ga2SnSe11 respectively. In addition, the electronic structure calculation of Ba4Ga4SnSe12 indicates that it is a direct-gap semiconductor with the band gap mainly determined by the [Ga4SnSe12](8-) anionic framework. PMID- 25523932 TI - Histone acetyltransferase inhibitor II induces apoptosis in glioma cell lines via the p53 signaling pathway. AB - BACKGROUND: Histone acetyltransferase (HAT) inhibitors can inhibit proliferation and induce apoptosis in cancer cell lines. The novel cell-permeable p300/CREB binding protein (CBP)-selective HAT inhibitor HATi II can reduce histone H3 acetylation and induce chromatin condensation in HeLa cells. Here, we examined the effects and mechanism of action of HATi II in glioma cell lines. METHODS: Cell viability was assessed using the CCK-8 assay. Cell cycle analysis was performed using flow cytometry. Apoptosis was evaluated using Annexin V staining and flow cytometry, Hoechst 33342 staining and the TUNEL assay. Expression and cleavage of caspase-3, caspase-9 and poly ADP-ribose polymerase (PARP) were assessed by Western blotting. Statistical analysis was performed using two-tailed Student's t-tests. The gene expression profiles of U251 glioma cells treated with HATi II or DMSO were analyzed using the Arraystar Human 8 x 60 K LncRNA/mRNA expression array; data was analyzed using MEV (Multi Experiment View) cluster software. Datasets representing genes with altered expression profiles (>=2-fold) derived from the cluster analyses were subjected to gene ontology and pathway analysis. RESULTS: HATi II inhibited the proliferation of U251, U87, HS683 and SHG44 cells in a dose-dependent manner. HATi II induced cell cycle arrest at the G2/M phase, and induced significant levels of apoptosis, apoptotic body formation and DNA fragmentation in HATi II-treated U251 and SHG44 cells. HATi II induced cleavage of caspase-3, caspase-9 and PARP in U251 and SHG44 cells. In HATi II treated U251 cells, 965 genes were upregulated, 984 genes were downregulated and 3492/33327 lncRNAs were differentially expressed. GO analysis showed the differentially expressed genes with known functions are involved in a variety of processes; alcoholism, p53 signaling pathway, cytokine-cytokine receptor interaction and transcriptional mis-regulation in cancer were the four most significant pathways. Upregulation of p53 signaling pathway-related genes in HATi II-treated cells was confirmed by quantitative RT-PCR and Western blotting. CONCLUSIONS: HATi II inhibits proliferation and induces apoptosis via the caspase dependent pathway in human glioma cell lines, possibly by activating the p53 signaling pathway. HATi II deserves further investigation as a novel treatment for glioma. PMID- 25523934 TI - Pioglitazone inhibits high glucose-induced expression of receptor for advanced glycation end products in coronary artery smooth muscle cells. AB - Receptor for advanced glycation end products (RAGE) is critical in inflammatory diseases, including diabetes and atherosclerosis. The mechanism underlying the effect of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist pioglitazone (PIO) on RAGE expression in coronary artery smooth muscle cells (SMCs) stimulated by high glucose concentrations remains to be elucidated. In the present study, the effect and mechanism of action of PIO on RAGE expression in SMCs was investigated following treatment with high glucose concentrations. Rat coronary artery SMCs were pretreated with PIO alone, PIO and GW9662 (a PPARgamma antagonist), diphenyleneiodonium (DPI; a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor) or the antioxidant pyrrolidine dithiocarbamate (PDTC; a nuclear factor-kappaB (NF-kappaB) inhibitor), followed by treatment with high glucose. RAGE mRNA and protein expression, reactive oxygen species (ROS) production and NF-kappaB nuclear translocation were investigated. Glucose induced RAGE expression in a dose-dependent manner, with maximal effect at a concentration of 25 mmol/l following treatment for 48 h. PIO, DPI and PDTC reduced high glucose-induced increases in RAGE protein and mRNA expression. PIO prominently downregulated RAGE expression and inhibited high glucose-induced increases in ROS production and NF-kappaB activation (P<0.05). Pretreatment with PIO and GW9662 did not exhibit this inhibitory effect. High glucose may stimulate RAGE expression in coronary artery SMCs through NADPH oxidase-mediated ROS generation and NF-kappaB activation. PIO downregulated RAGE expression and inhibited ROS production and NF-kappaB activation via PPARgamma activation, which may prevent the inflammatory effect of AGE/RAGE system in diabetes. PMID- 25523933 TI - Structural biology of presenilin 1 complexes. AB - The presenilin genes were first identified as the site of missense mutations causing early onset autosomal dominant familial Alzheimer's disease. Subsequent work has shown that the presenilin proteins are the catalytic subunits of a hetero-tetrameric complex containing APH1, nicastrin and PEN-2. This complex (variously termed presenilin complex or gamma-secretase complex) performs an unusual type of proteolysis in which the transmembrane domains of Type I proteins are cleaved within the hydrophobic compartment of the membrane. This review describes some of the molecular and structural biology of this unusual enzyme complex. The presenilin complex is a bilobed structure. The head domain contains the ectodomain of nicastrin. The base domain contains a central cavity with a lateral cleft that likely provides the route for access of the substrate to the catalytic cavity within the centre of the base domain. There are reciprocal allosteric interactions between various sites in the complex that affect its function. For instance, binding of Compound E, a peptidomimetic inhibitor to the PS1 N-terminus, induces significant conformational changes that reduces substrate binding at the initial substrate docking site, and thus inhibits substrate cleavage. However, there is a reciprocal allosteric interaction between these sites such that prior binding of the substrate to the initial docking site paradoxically increases the binding of the Compound E peptidomimetic inhibitor. Such reciprocal interactions are likely to form the basis of a gating mechanism that underlies access of substrate to the catalytic site. An increasingly detailed understanding of the structural biology of the presenilin complex is an essential step towards rational design of substrate- and/or cleavage site specific modulators of presenilin complex function. PMID- 25523936 TI - Sensory impairments, problems of balance and accidental injury at work: a case control study. AB - OBJECTIVES: Sensory impairments are becoming increasingly common in the workforces of Western countries. To assess their role in occupational injury, and that of disorders of balance, we undertook a case-control study. METHODS: Using the Clinical Practice Research Datalink, which documents all medical consultations, referrals and diagnoses in primary care for 6% of the British population, we identified 1348 working-aged patients who had consulted medical services over a 22-year period for workplace injury (cases) and 6652 age-matched, sex-matched and practice-matched controls. Risks were assessed by conditional logistic regression, for earlier recorded diagnoses of visual impairment, common eye diseases, hearing loss, perforated ear drum, non-acute otitis media and disorders of balance. RESULTS: In all, 173 (2.2%) participants had an earlier eye problem, 792 (9.9%) an ear problem (including 336 with impaired hearing and 482 with non-acute otitis media) and 266 (3.3%) a disorder of balance. No associations were found with glaucoma, cataract, retinal disorders or perforation of the ear drum specifically, but adjusted ORs were moderately elevated for eye and ear problems more generally, and higher where there was a record of blindness or partial sight (OR 1.90, 95% CI 1.05 to 3.44) or non-acute otitis media (OR 2.04, 95% CI 1.64 to 2.54). Risks for non-acute otitis media and for disorders of balance were particularly elevated for consultations in the 12 months preceding injury consultation (OR 2.70, 95% CI 1.58 to 4.62 and 1.77, 95% CI 1.01 to 3.11, respectively). CONCLUSIONS: Problems of vision, impairments of hearing and disorders of balance all may carry moderately increased risks of occupational injury. PMID- 25523935 TI - Proteomics in the investigation of HIV-1 interactions with host proteins. AB - Productive HIV-1 infection depends on host machinery, including a broad array of cellular proteins. Proteomics has played a significant role in the discovery of HIV-1 host proteins. In this review, after a brief survey of the HIV-1 host proteins that were discovered by proteomic analyses, I focus on analyzing the interactions between the virion and host proteins, as well as the technologies and strategies used in those proteomic studies. With the help of proteomics, the identification and characterization of HIV-1 host proteins can be translated into novel antiretroviral therapeutics. PMID- 25523937 TI - The association between job strain and atrial fibrillation in Swedish men. AB - OBJECTIVES: The purpose of this study was to investigate whether psychosocial stress defined as high strain based on the job demand-control model increases risk for atrial fibrillation. METHODS: The present study comprised 6035 men born between 1915 and 1925 and free from previous coronary heart disease, atrial fibrillation and stroke at baseline (1974-1977). Work-related psychosocial stress was measured using a job-exposure matrix for the job demand-control model based on occupation at baseline. The participants were followed from baseline examination until death, hospital discharge or 75 years of age, using the Swedish national register on cause of death and the Swedish hospital discharge register for any registration for atrial fibrillation, resulting in the identification of 436 cases. Data were analysed with Cox regression models with atrial fibrillation as the outcome using high strain as the explanatory variable adjusted for age, smoking, body mass index, hypertension, diabetes and socioeconomic status. RESULTS: There was an increased risk for atrial fibrillation in relation to high strain (HR 1.32, 95% CI 1.003 to 1.75). When the four categories of the job strain model were included and low strain was used as reference, the risk for high strain decreased (HR 1.23, 95% CI 0.84 to 1.82). CONCLUSIONS: Exposure to occupational psychosocial stress defined as high strain may be associated with increased risk for atrial fibrillation. The observed increase in risk is small and residual confounding may also be present. PMID- 25523938 TI - What is the role of the adenoid in pediatric chronic rhinosinusitis? PMID- 25523939 TI - Our evolving journal. PMID- 25523940 TI - Mirabel: an integrated project for risk and cost/benefit analysis of peanut allergy. AB - Food allergy is a major public health issue. However, no regulatory measures exist when allergens are present at trace levels and the different risk components are poorly described. Thus, knowledge on exposure components such as the allergens present in foods and the consumption behaviour of allergic consumers and models to estimate the related risk need to be enriched. Mirabel proposes for the first time studying each risk component using an integrated approach in order to improve the quality of life of the allergic population. Field surveys were conducted in order to fill in the current gaps in unintentional allergen traces in food, allergic consumers' food behaviour, threshold doses of allergic reaction, allergy symptoms and severity. The aim is also to propose methodological and operational tools to quantify allergic risk, to test management scenarios and to produce a cost/benefit analysis. Medical data on the peanut allergies of 785 patients were collected in the MIRABEL survey and 443 patients answered the food consumption questionnaire. The population surveyed was mostly paediatric - 86% were children under 16 years of age, with a high percentage of males (60%). This project will generate tangible results on peanut allergen exposure and risk which could be used in future risk assessment work and particularly to provide science-based guidance to set up concentration limits for peanut traces on packages. PMID- 25523941 TI - Aqueous Photogeneration of H2 with CdSe Nanocrystals and Nickel Catalysts: Electron Transfer Dynamics. AB - CdSe quantum dots (QDs) and simple aqueous Ni(2+) salts in the presence of a sacrificial electron donor form a highly efficient, active, and robust system for photochemical reduction of protons to molecular hydrogen in water. Using ultrafast transient absorption (TA) spectroscopy, the electron transfer (ET) processes from the QDs to the Ni catalysts have been characterized. CdSe QDs transfer photoexcited electrons to a Ni-dihydrolipoic acid (Ni-DHLA) catalyst complex extremely fast and with high efficiency: the amplitude-weighted average ET lifetime is 69 +/- 2 ps, and ~90% of the ultrafast TA signal is assigned to ET processes. The impacts of Auger recombination, QD size and shelling on ET are also reported. These results help clarify the reasons for the exceptional photocatalytic H2 activity of the CdSe QD/Ni-DHLA system and suggest direction for further improvements of the system. PMID- 25523942 TI - Assessment of interactive effects of elevated salinity and three pesticides on life history and behavior of southern toad (Anaxyrus terrestris) tadpoles. AB - Because habitats are increasingly exposed to multiple stressors simultaneously, assessing the interactive effects of stressors is crucial for understanding how populations respond to human-altered habitats. Salinization of freshwater habitats is increasing and has the potential to interact with other stressors. Chemical pollutants also contribute to habitat degradation in freshwater environments, and both salinity and various pesticides can harm amphibians. The present study used a factorial experiment to investigate the effect of elevated salinity alone and in combination with each of 3 pesticides-atrazine, carbaryl, and glyphosate-on life history and behavior of southern toad larvae (Anaxyrus terrestris). Tadpoles were negatively affected by elevated salinity and by exposure to the insecticide carbaryl, with the most deleterious outcomes associated with both stressors combined. Carbaryl exposure led to reduced survival as well as sublethal effects on growth, activity and feeding behavior, escape response swimming, and time to metamorphosis. Tadpoles reared at elevated salinity were also smaller and less active, and ultimately metamorphosed later and at smaller size. Together, carbaryl and elevated salinity had a synergistic effect, resulting in particularly poor growth, depressed activity and feeding, and sluggish escape swimming among tadpoles exposed to both stressors simultaneously. These results suggest that both elevated salinity and carbaryl represent threats for amphibian populations and that pesticide exposure in salinized habitats may pose a particularly high risk. PMID- 25523943 TI - Dynamic mechanical thermal properties of the dental light-cured nanohybrid composite Kalore, GC: effect of various food/oral simulating liquids. AB - OBJECTIVE: The aim of this work is the study of the dynamic mechanical thermal properties (viscoelastic properties) of a current dental commercial light-cured nanohybrid resin composite, Kalore, GC (GC Corporation, Tokyo, Japan) along with the study of the effect of some food/oral simulating liquids (FSLs) on these properties. METHODS: Dynamic mechanical thermal analysis (DMTA) tests were performed on a Diamond Dynamic Mechanical Thermal Analyzer in bending mode. A frequency of 1Hz and a temperature range of 25-185 degrees C were applied, while the heating rate of 2 degrees C/min was selected to cover mouth temperature and the material's likely Tg. The properties were determined after storage in air, distilled water, heptane, ethanol/water solution (75% v/v) or absolute ethanol at 37 degrees C for up to 1h, 1, 7 or 30 days. RESULTS: Storage modulus, loss modulus and tangent delta (tandelta) were plotted against temperature. The glass transition temperatures are taken from the peak of the tangent tandelta versus temperature curves. Moreover, some factors indicating the heterogeneity of the polymer matrix, such as the width (DeltaT) at the half of tandelta peak and the "zeta" parameter were determined. All samples analyzed after storage for 1h or 1 day in the aging media showed two Tg values. All samples analyzed after storage for 7 or 30 days in the ageing media showed a unique Tg value. SIGNIFICANCE: Storage of Kalore GC in dry air, water or heptane at 37 degrees C for 7 days caused post-curing reactions. Storage in air or water for 30 days did not seem to cause further effects. Storage in heptane for 30 days may cause plasticization and probably some degradation of the filler-silane bond and polymer matrix. Storage in ethanol/water solution (75% v/v) or ethanol for 7 days seems to cause post-curing reactions and degradation reactions of the matrix-filler bonds. Storage in ethanol for 30 days caused a strong change of the sample morphology and the DMTA results were not reliable. PMID- 25523944 TI - Preparation of three-dimensional entanglement for distant atoms in coupled cavities via atomic spontaneous emission and cavity decay. AB - We propose a dissipative scheme to prepare a three-dimensional entangled state for two atoms trapped in separate coupled cavities. Our work shows that both atomic spontaneous emission and cavity decay, which are two typical obstacles in unitary-dynamics-based schemes, are no longer detrimental, but necessary for three-dimensional entangled state preparation without specifying initial state and controlling the evolution time precisely. Final numerical simulation with one group of experimental parameters indicates that the performance of our scheme could be better than the unitary-dynamics-based scheme. PMID- 25523946 TI - The relationship between bilateral oophorectomy and plasma hormone levels in postmenopausal women. AB - Oophorectomy prior to natural menopause reduces breast cancer risk. We evaluated whether timing of oophorectomy (during premenopause vs. postmenopause) or hysterectomy was associated with hormone levels, specifically estradiol, estrone, estrone sulfate, testosterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and prolactin, using data from the Nurses' Health Study. We included 2,251 postmenopausal women not using hormones who provided blood samples in 1989-1990 and/or 2000-2002, and who were controls in various nested case-control studies. We used multivariate linear mixed-effects models to assess geometric mean hormone levels by surgery status. Bilateral oophorectomy was associated with 25% lower testosterone levels versus women with natural menopause (20.8 vs. 15.5 ng/dL) (P < 0.0001) with no effect of timing of surgery (P = 0.80). SHBG levels were lower among women with a premenopausal oophorectomy (52.2 nmol/L) versus those with natural menopause (58.1 nmol/L) or a postmenopausal oophorectomy (62.0 nmol/L) (P = 0.02). There was no significant association of oophorectomy with estradiol, estrone, estrone sulfate, DHEAS, or prolactin levels (P >= 0.23). A simple hysterectomy was associated with a significant 8% lower testosterone (P = 0.03) and 14 % lower DHEAS (P = 0.02) levels compared with women with natural menopause but not with other hormone levels. Although limited by small numbers, our findings suggest no differential influence of timing of surgery on sex hormone levels. The reduction of testosterone levels in women with oophorectomy or hysterectomy suggests a possible role of this hormone in postmenopausal breast cancer development. PMID- 25523945 TI - Left atrial transcriptional changes associated with atrial fibrillation susceptibility and persistence. AB - BACKGROUND: Prior transcriptional studies of atrial fibrillation (AF) have been limited to specific transcripts, animal models, chronic AF, right atria, or small samples. We sought to characterize the left atrial transcriptome in human AF to distinguish changes related to AF susceptibility and persistence. METHODS AND RESULTS: Left atrial appendages from 239 patients stratified by coronary artery disease, valve disease, and AF history (no history of AF, AF history in sinus rhythm at surgery, and AF history in AF at surgery) were selected for genome-wide mRNA microarray profiling. Transcripts were examined for differential expression with AF phenotype group. Enrichment in differentially expressed genes was examined in 3 gene set collections: a transcription factor collection, defined by shared conserved cis-regulatory motifs, a miRNA collection, defined by shared 3' untranslated region motifs, and a molecular function collection, defined by shared Gene Ontology molecular function. AF susceptibility was associated with decreased expression of the targets of CREB/ATF family, heat-shock factor 1, ATF6, SRF, and E2F1 transcription factors. Persistent AF activity was associated with decreased expression in genes and gene sets related to ion channel function consistent with reported functional changes. CONCLUSIONS: AF susceptibility was associated with decreased expression of targets of several transcription factors related to inflammation, oxidation, and cellular stress responses. In contrast, changes in ion channel expression were associated with AF activity but were limited in AF susceptibility. Our results suggest that significant transcriptional remodeling marks susceptibility to AF, whereas remodeling of ion channel expression occurs later in the progression or as a consequence of AF. PMID- 25523947 TI - Elevations in T-helper-2-initiating cytokines (interleukin-33, interleukin-25 and thymic stromal lymphopoietin) in lesional skin from chronic spontaneous ('idiopathic') urticaria. AB - BACKGROUND: The mechanism of wealing in chronic spontaneous urticaria (CSU) is largely unknown. We previously demonstrated increased expression of T-helper 2 [interleukin (IL)-4 and IL-5] cytokines in skin biopsies from CSU. This suggested that Th2-initiating cytokines [IL-33, IL-25 and thymic stromal lymphopoietin (TSLP)], released through innate immune mechanisms, may play a role in pathogenesis. OBJECTIVES: To identify Th2-initiating cytokines in lesional and nonlesional skin from patients with CSU and to compare the results with a control group. METHODS: Paired biopsies (one from a 4-8 h spontaneous weal and one from uninvolved skin) were taken from eight patients with CSU and nine control subjects, and studied by immunohistochemistry and confocal microscopy. RESULTS: There were increases in IL-4(+) and IL-5(+) cells in lesional skin vs. controls (P = 0.03 and P < 0.001, respectively) and marked elevations in the numbers of IL 33(+), IL-25(+) and TSLP(+) cells in the dermis of lesional skin vs. both nonlesional skin (P = 0.002, P = 0.01 and P = 0.04, respectively) and controls (P = 0.001, P < 0.001 and P = 0.005, respectively). There was also a correlation between the numbers of IL-33(+) and IL-25(+) cells (r = 0.808, P = 0.015). IL-33 localized to CD31(+) endothelial cells, CD90(+) fibroblasts, CD68(+) macrophages and tryptase(+) mast cells, whereas IL-25 was expressed by epithelial cells, mast cells and major basic protein-positive eosinophils. IL-33 and IL-25 were constitutively expressed in the epidermis of both controls and patients with CSU. CONCLUSIONS: Increased expression of Th2-initiating cytokines in lesional skin in CSU suggests that innate pathways might play a role in the mechanism of wealing. As Th2-initiating cytokines play a role in mast cell activation, inflammation and vascular leakage in CSU, these findings may also have therapeutic implications. PMID- 25523949 TI - Ginsenoside Re protects methamphetamine-induced mitochondrial burdens and proapoptosis via genetic inhibition of protein kinase C delta in human neuroblastoma dopaminergic SH-SY5Y cell lines. AB - Recently, we have demonstrated that ginsenoside Re protects methamphetamine (MA) induced dopaminergic toxicity in mice via genetic inhibition of PKCdelta and attenuation of mitochondrial stress. In addition, we have reported that induction of mitochondrial glutathione peroxidase (GPx) is also important for neuroprotection mediated by ginsenoside Re. To extend our knowledge, we examined the effects of ginsenoside Re against MA toxicity in vitro condition using SH SY5Y neuroblastoma cells. Treatment with ginsenoside Re resulted in significant attenuations against a decrease in the activity of GPx and an increase in the activity of superoxide dismutase (SOD) in the cytosolic and mitochondrial fraction. The changes in glutathione (GSH) paralleled those in GPx in the same experimental condition. Consistently, ginsenoside Re treatment exhibited significant protections against cytosolic and mitochondrial oxidative damage (i.e. lipid peroxidation and protein oxidation), mitochondrial translocation of PKCdelta, mitochondrial dysfunction (mitochondrial transmembrane potential and intra-mitochondrial Ca(2+)), apoptotic events [i.e., cytochrome c release from mitochondria, cleavage of caspase-3 and poly(ADP-ribose)polymerase-1, nuclear condensation, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive apoptotic cells], and a reduction in the tyrosine hydroxylase (TH) expression and TH activity induced by MA in SH-SY5Y neuroblastoma cells. These protective effects of ginsenoside Re were comparable to those of PKCdelta antisense oligonucleotide (ASO). However, ginsenoside Re did not significantly provide additional protective effects mediated by genetic inhibition of PKCdelta. Our results suggest that PKCdelta is a specific target for ginsenoside Re-mediated protective activity against MA toxicity in SH-SY5Y neuroblastoma cells. PMID- 25523950 TI - Multidimensional poverty and health: evidence from a nationwide survey in Japan. AB - INTRODUCTION: It is well known that lower income is associated with poorer health, but poverty has several dimensions other than income. In the current study, we investigated the associations between multidimensional poverty and health variables. METHODS: Using micro data obtained from a nationwide population survey in Japan (N = 24,905), we focused on four dimensions of poverty (income, education, social protection, and housing conditions) and three health variables (self-rated health (SRH), psychological distress, and current smoking). We examined how health variables were associated with multidimensional poverty measures, based on descriptive and multivariable logistic regression analyses. RESULTS: Unions as composite measures of multiple poverty dimensions were more useful for identifying individuals in poor SRH or psychological distress than a single dimension such as income. In comparison, intersections of poverty dimensions reduced the coverage of individuals considered to be in poverty and tend to be difficult to justify without any explicit policy objective. Meanwhile, education as a unidimensional poverty indicator could be useful for predicting current smoking. CONCLUSIONS: Results obtained from the current study confirmed the practical relevance of multidimensional poverty for health. PMID- 25523951 TI - Work stress and alcohol consumption among adolescents: moderation by family and peer influences. AB - BACKGROUND: Excessive alcohol use in adolescence can be detrimental to health and academic performance. Few studies consider the moderating effects of parental and peer influence within the context of adolescent work outside of the school environment. This study aims to examine work stress among adolescents and the association with alcohol use and drunkenness, in the context of parental and peer influences. METHODS: Grade 12 students who participated in Monitoring the Future surveys between 2005 and 2009 (n = 12,341) were included in this study. Independent variables included work stress (job satisfaction, perceived safety, and perceived safety of possessions), self-reported perceptions towards academics and influence from parents and peers. Frequency of alcohol use and drunkenness were measured for lifetime, last 30 days and 12 months. The moderating effects of academic aspiration, parental, and peer influence were assessed on the relationship between work stress and alcohol use. RESULTS: Any work stress was positively associated with alcohol use over the past 12 months (odds ratio = 1.12, 95% confidence interval (CI) 1.02-1.23). Stratified analysis found that peer influence significantly moderated the relationship between work stress and alcohol use over the lifetime and past 12 months. Among adolescents with work stress, odds ratios of alcohol use over the lifetime was 0.83 (95% CI 0.71-0.97) for those with low negative peer influence and 1.09 (95% CI 0.97-1.22) for those with high negative peer influence. CONCLUSIONS: Problematic drinking patterns were more apparent among high school students who experienced stress at work. Positive peer influence, however, may buffer the adverse effect of work stress on alcohol use. PMID- 25523953 TI - Output, pressure and shunt: misrepresentation of pulmonary haemodynamics. PMID- 25523952 TI - Relation between N-terminal pro-brain natriuretic peptide and cardiac remodeling and function assessed by cardiovascular magnetic resonance imaging in patients with arrhythmogenic right ventricular cardiomyopathy. AB - Although N-terminal pro-brain natriuretic peptide (NT-proBNP) is a useful screening test of impaired right ventricular (RV) function in conditions affecting the right-sided cardiac muscle, the role of NT-proBNP remains unclear in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). This study was designed to clarify the relation between the plasma NT-proBNP level and the RV function evaluated by cardiovascular magnetic resonance (CMR) imaging. We selected 56 patients with confirmed ARVC only when their blood specimens for NT proBNP measurements were collected within 48 hours of a CMR scan. The NT-proBNP level was significantly higher in patients with RV dysfunction than in patients without RV dysfunction (median of 655.3 [interquartile range 556.4 to 870.0] vs 347.0 [interquartile range 308.0 to 456.2] pmol/L, p <0.001). The NT-proBNP levels were positively correlated with RV end-diastolic and end-systolic volume indices (r = 0.49 and 0.70, respectively) and negatively correlated with RV ejection fraction (r = -0.76, all p <0.001), which remained significant after adjustment for age, gender, and body mass index. The area under the receiver operating characteristic curve for NT-proBNP was 0.91 (95% confidence interval 0.80 to 0.97, p <0.001). The cut-off value of NT-proBNP (458 pmol/L) was associated with sensitivity, specificity, and positive and negative predictive values of 91%, 89%, 67%, and 98%, respectively. In conclusion, NT-proBNP is a useful marker for the detection of RV dysfunction and associated with extent of RV dilatation and dysfunction determined by CMR in patients with ARVC. PMID- 25523954 TI - The influence of mandibular ridge anatomy on treatment outcome with conventional complete dentures. AB - Since prognostic indicators are likely to take on increasing importance as a diagnostic tool for selection of patients for implant provision, this study investigated the influence of the shape and resiliency of the mandibular alveolar ridge on the retention and stability of conventional complete dentures. Ninety- three edentulous patients wearing both maxillary and mandibular conventional complete dentures composed the sample. Data were collected regarding shape and resiliencyof the mandibular residual ridge. Dentures were assessed for retention and stability using an objective and reproducible tool.The associations between the clinical characteristics of the mandibular alveolar ridge and denture retention and stability were analyzed using chi-square and Fisher exact tests (a = 0.05). A significant association between ridge shape and denture stability (p < 0.05) was found, while ridge resiliency was significantly associated to denture retention (p < 0.001). Based on the results, mandibular ridge shape and resiliency influenced the retention and stability of conventional complete dentures. PMID- 25523955 TI - Variations in the vestibular cortical bone of permanent canine teeth in orthodontic patients. a comparative study: linear tomography vs. cbct (3d accuitomo). AB - The aim of this study was to compare the results of measuring the height of the vestibular cortical bone of canine teeth by linear tomography (LT) and 3-D Accuitomo cone beam computed tomography (CBCT) before and after aligning dental arches by orthodontic treatment. LT and CBCT were performed before and after orthodontic alignment on 12 canines in three patients undergoing orthodontic treatment, and the height of the canine vestibular cortical bones measured in mm. Measurements were taken by double-blinded operators. The mean variation in height of the vestibular cortical bone with orthodontic treatment was - 0,33 mm?} 0.233 standard error using CBCT and -0,08mm ?} 0.55 standard error using LT. Analysis of variance (ANOVA) was performed to compare the techniques, the patients and upper and lower canines. No significant difference was found for any of the cases. Using LT to evaluate vestibular crest cortical bone in canines is comparable in efficiency to using CBCT. Height in millimeters is less in LT because image resolution is lower and when it is very thin it is not appreciable by this method. PMID- 25523956 TI - Evaluation of photodynamic therapy using a diode laser and different photosensitizers against enterococcus faecalis. AB - Photodynamic therapy (PDT) has been proven to be effective in disinfecting root canals. The aim of this present study was to evaluate the effects of PDT on the viability of Enterococcus faecalis using methylene blue (MB) and malachite green (MG) as photosensitizers. Solutions containing E. faecalis (ATCC 29212) were prepared and harvested by centrifugation to obtain cell suspensions, which were mixed with MB and MG. Samples were individually irradiated by the diode laser at a distance of 1mm for 30, 60, or 120 seconds. Colonyforming units (CFU) were determined for each treatment. PDT for 60 and 120 seconds with MG reduced E. faecalis viability significantly. Similar results were obtained when MB was used as photosensitizer. PDT using MB and MG have antibacterial effect against E. faecalis, showing potential to be used as an adjunctive antimicrobial procedure in endodontic therapy. PMID- 25523957 TI - Effect of two mouthwashes on salivary ph. AB - To analyze the effect of two mouthwashes on salivary pH and correlate it with age, buffer capacity and saliva flow rate in healthy volunteers, a crossover phase IV clinical study involving three age-based groups was designed. Two commercial mouthwashes (MW), Cool Mint ListerineR (MWa) and Periobacter R (MWb) were used. The unstimulated saliva of each individual was first characterized by measuring flow rate, pH, and buffer capacity. Salivary pH was evaluated before rinsing with a given MW, immediately after rinsing, 5 minutes later, and then every 10 min (at 15, 25, 35 min) until the baseline pH was recovered. Paired t test, ANOVA with a randomized block design, and Pearson correlation tests were used. Averages were 0.63 mL/min, 7.06, and 0.87 for flow rate, pH, and buffer capacity, respectively. An immediate significant increase in salivary pH was observed after rinsing, reaching average values of 7.24 (MWb) and 7.30 (MWa), which declined to an almost stable value 15 minutes. The great increase in salivary pH, after MW use shows that saliva is a dynamic system, and that the organism is capable of responding to a stimulus with changes in its composition. It is thus evident that pH of the external agent alone is not a good indicator for its erosive potential because biological systems tend to neutralize it. The results of this study enhance the importance of in vivo measurements and reinforce the concept of the protective action of saliva. PMID- 25523958 TI - Effect of post-curing treatment on mechanical properties of composite resins. AB - The aim of this study is to assess the effect of additional curing procedures on the flexural strength and modulus of elasticity of indirect and direct composite materials. Twenty-four rectangular prism-shaped 2 mm x 2 mm x 25 mm samples of Belleglass, Premisa (Kerr), Adoro and Heliomolar (Ivoclar Vivadent) were prepared. Each composite was packed in an ad-hoc stainless steel device with a TeflonR instrument. A mylar strip and a glass slab were placed on top to obtain a flat surface. Polymerization was activated for 20 seconds with a halogen unit (Astralis 10, Ivoclar - Vivadent) with soft start regime and an output with a 350 to 1200 mw/cm2 range at four different points according to the diameter of the end of the guide. The specimens obtained were then randomly divided into two different groups: with and without additional treatment. In the group with additional treatment, the samples adorro were submitted to 25 minutes in Lumamat 100 (Ivoclar Vivadent) and the rest to 20 minutes in BelleGlass HP (Kerr). After the curing procedures, all samples were treated with sandpapers of decreasing grain size under water flow, and stored in distilled water for 24 h. Flexural strength was measured according to the ISO 404920 recommendations and elastic modulus was determined following the procedures of ANSI/ADA standard No. 27. Statistical differences were found among the different materials and curing procedures employed (P<0.01). The elastic modulus was significantly higher after the additional curing treatment for all materials except Premisa. Further work is needed to determine the association between the actual monomers present in the matrix and the effect of additional curing processes on the mechanical properties of both direct and indirect composites, and its clinical relevance. PMID- 25523959 TI - Evaluation of apical foramen deformation produced by manual and mechanized patency maneuvers. AB - Achieving apical foramen patency through surgical maneuvers during the biomechanical preparation of root canals is a goal sought by several schools. The aim of this study was to evaluate the deformation of the foramen as a result of using stainless steel hand files and nickeltitanium rotary instruments for achieving patency. Forty recently extracted dental roots with single canals were calibrated to a length of 18 mm and mounted on acrylic blocks to enable study maneuvers. Each foramen was observed and mapped using SEM (Phillips high vacuum) at x 100, using Golden Ratio software (Softonic). Endodontic surgical preparation was subsequently performed on all samples to 1 mm from the foramen using the Protaper rotary system up to instrument F3. The samples were then divided into two groups of twenty for apical patency maneuvers: Group A (manual patency) on which stainless steel Flexofile (MailleferSuiza) hand files gauge .10 were used, and Group B (rotary patency) on which NiTi Pathfile (DentsplyMailleferSuiza) rotary instruments gauge .13 at 150 rpm, were used. The foramina were examined again using SEM, measured, mapped and compared with the previous images. A scale was established to evaluate the observations. Results were analyzed using the Mann Whitney test, which showed no significant difference between groups (p=0.110). It is concluded that under the conditions of this study, surgical apical patency maneuvers using stainless steel manual files or nickel titanium rotary instruments produced different degrees of foramen deformation, with no significant difference between methods. PMID- 25523960 TI - Human papilloma virus in oral mucosa and its association with periodontal status of gynecologically infected women. AB - The aim of this study was to determine whether Human Papillomavirus was present in tongue and periodontium of periodontally healthy and diseased women who had genital lesions caused by the virus. Thirty non-menopausal women, systemically healthy and diagnosed with gynecological HPV lesions, were referred by the Gynecology Service Department of the University Maternal Neonatal Hospital of the City of Cordoba. Anamnesis, oral mucosa examination and periodontal clinical assessment were performed. Three brush samples were taken per patient: two from the same periodontal location (external epithelium of the gum and internal epithelium of the periodontal sulcus/pocket), and the third from the tongue. The 90 samples were submitted to Pap cytology and Polymerase Chain Reaction. The data were statistically analyzed by "Chi Square Test" (chi2) and "Kappa Index" (kappa). High prevalence of HPV was found in the tongue (30%) and periodontal tissues (15%). High risk (HR) genotype -16 was detected with the highest percentage (67%), and genotypes -52 and -6 were also detected. Whenever HPV was present in periodontal location, it was also identified in the tongue of the same patients, of whom 88.89% reported that they practiced oral sex. Is worth noting the clinical finding of stomatologic lesions compatible with foliate papillitis in patients with positive intraoral HPV. High prevalence of HPV was found in the female population in Cordoba, with genotype -16 being detected at the highest percentage. No positive correlation was found between HPV and higher incidence and severity of periodontal lesions. PMID- 25523961 TI - Microbiological effects of periodontal therapy plus azithromycin in patients with diabetes: results from a randomized clinical trial. AB - Current evidence suggests that periodontal infection may aggravate diabetes control. The aim of this study was to determine the changes in the frequency with which Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola and Aggregatibacter actinomycetemcomitans were detected in patients with diabetes with the use of non-surgical therapy plus azithromycin in a randomized clinical trial. One hundred and five (105) patients with diabetes and chronic periodontitis were randomly assigned to three treatment groups: subgingival mechanical therapy with azithromycin, subgingival mechanical therapy with placebo and supragingival prophylaxis with azithromycin. Complete periodontal clinical examinations and detection of periodontal pathogens using polymerase chain reaction were carried out at baseline, 3, 6 and 9 months after periodontal therapy. The frequency with which Porphyromonas gingivalis, Treponemadenticola and Aggregatibacter actinomycetemcomitans were detected decreased at 3 months in all groups. Tannerella forsythia increased after3 months in all groups. All organisms had similar frequencies at 9 months in all groups. Subgingival mechanical therapy with adjunctive azithromycin had no additional effect on the frequency with which the periodontal pathogens investigated were detected in patients with diabetes. PMID- 25523962 TI - Duration of the peak of adolescent growth spurt in class i and ii malocclusion subjects using a cervical vertebrae maturation analysis. AB - The aim of the present work was to determine the duration of the adolescent peak growth spurt using cervical vertebral maturation analysis in class I and II malocclusion subjects. The study was conducted on a sample which consisted of 154 lateral cephalograms of children and adolescents aged 9-15 years (84 females and 70 males). The evaluation of skeletal maturation stage was performed using a visual morphological analysis of CS3 and CS4 cervical vertebrae. The sagittal skeletal relation was evaluated according to Steiner analysis. Descriptive statistics were used to summarize chronological age in each malocclusion group and for each CS3 and CS4 skeletal maturation stage. Due to a lack of normal distribution, comparisons of CS3 and CS4 age intervals on class I and II subjects were compared using the Mann-Whitney U test for independent samples. The results show that the mean duration of the adolescent peak growth spurt was 10 months between CS3 and CS4 stages in class I malocclusion subjects, whereas in class II malocclusion patients the duration was 6 months. This difference of 4 months was statistically significant (p<0.001). Finally, a clinically significant difference of 4 months in the duration of the adolescent peak growth spurt for class I and II malocclusion subjects was identified. PMID- 25523963 TI - Factor analysis of the Hamilton Depression Rating Scale in Parkinson's disease. AB - INTRODUCTION: Several studies have validated the Hamilton Depression Rating Scale (HAMD) in patients with Parkinson's disease (PD), and reported adequate reliability and construct validity. However, the factorial validity of the HAMD has not yet been investigated. The aim of our analysis was to explore the factor structure of the HAMD in a large sample of PD patients. METHODS: A principal component analysis of the 17-item HAMD was performed on data of 341 PD patients, available from a previous cross sectional study on anxiety. An eigenvalue >=1 was used to determine the number of factors. Factor loadings >=0.4 in combination with oblique rotations were used to identify which variables made up the factors. Kaiser-Meyer-Olkin measure (KMO), Cronbach's alpha, Bartlett's test, communality, percentage of non-redundant residuals and the component correlation matrix were computed to assess factor validity. RESULTS: KMO verified the sample's adequacy for factor analysis and Cronbach's alpha indicated a good internal consistency of the total scale. Six factors had eigenvalues >=1 and together explained 59.19% of the variance. The number of items per factor varied from 1 to 6. Inter-item correlations within each component were low. There was a high percentage of non redundant residuals and low communality. CONCLUSION: This analysis demonstrates that the factorial validity of the HAMD in PD is unsatisfactory. This implies that the scale is not appropriate for studying specific symptom domains of depression based on factorial structure in a PD population. PMID- 25523964 TI - Medication non-adherence in essential tremor. AB - BACKGROUND: There are numerous studies of medication adherence in a variety of chronic diseases including Parkinson's disease; however, there are no such studies in patients with essential tremor (ET). This study aimed to (1) present self-report data on medication adherence in ET cases, (2) examine the demographic and clinical factors that might be associated with lower medication adherence. METHODS: 151 ET cases were enrolled in a clinical-epidemiological study at Columbia University. An 11-item medication adherence questionnaire, modeled after the Morisky medication adherence questionnaire, was administered. RESULTS: Seventy-three (48.3%) of 151 cases were taking daily medication for ET. One-third (24/73; 32.9%) of cases reported that they sometimes forgot to take their medication, and 1 in 5 (15/73; 20.5%) reported missed doses within the past week. Most striking was that nearly 1 in 4 (17/73; 23.3%) reported that there were whole days in the past two weeks in which they had not taken their medication. A factor analysis revealed four factors that captured different aspects of non adherence. Higher non-adherence was associated with more depressive symptoms, younger age, and less severe tremor but was not associated with type or number of ET medications. CONCLUSIONS: Approximately one in four ET patients reported whole days in the past two weeks in which they had not taken their medication. It is possible that this relatively high rate of non-adherence could be a function of the poor therapeutic efficacy of the medications currently available to treat ET. PMID- 25523965 TI - Lithium response viewed as a biomarker to predict developmental psychopathology in offspring with bipolar disorder: a commentary. PMID- 25523966 TI - Determination of optimal timing of serial in-utero transfusions in red-cell alloimmunization. AB - OBJECTIVES: To assess the performance of middle cerebral artery peak systolic velocity (MCA-PSV) and of the expected daily decrease in fetal hemoglobin in determining the timing of serial in-utero transfusions (IUT) in red-cell alloimmunization. METHODS: This was a retrospective study of a continuous series of suspected anemic fetuses undergoing IUT between June 2003 and December 2012. Doppler measurement of MCA-PSV and pre- and post-transfusion hemoglobin levels were recorded at the time of the first, second and third IUT. Receiver-operating characteristics (ROC) curves and negative and positive predictive values of MCA PSV in the prediction of severe fetal anemia were calculated. The daily decrease of fetal hemoglobin (Hb) between IUTs was calculated. Regression analysis was used to assess the correlation between pretransfusion fetal hemoglobin and MCA PSV, and between observed and expected (by projection of daily decreases) pretransfusion fetal hemoglobin levels. RESULTS: One hundred and eleven fetuses required an IUT, of which 96 and 67 received a second and third IUT, respectively. The area under the ROC curve for MCA-PSV in the prediction of severe fetal anemia was not different for each rank of transfusion. The positive predictive value of MCA-PSV decreased from 75.3% at the first IUT, to 46.7% and 48.8% at the second and third IUTs, respectively, while the negative predictive value for a 1.5-MoM threshold remained high (88.9% at the second and 91.7% at the third IUT). The mean daily decrease in hemoglobin following each transfusion was 0.45, 0.35 and 0.32 g/dL, respectively. There was a persistent linear correlation between fetal hemoglobin and MCA-PSV and between observed and expected fetal hemoglobin levels. CONCLUSIONS: Both MCA-PSV and projection of daily decrease in hemoglobin are reliable means of diagnosing fetal anemia following previous IUTs. The high negative predictive value of MCA-PSV could allow subsequent IUTs to be postponed in selected cases. PMID- 25523967 TI - Cylindrical agar gel with fluid flow subjected to an alternating magnetic field during hyperthermia. AB - PURPOSE: In magnetic fluid hyperthermia (MFH), nanoparticles are injected into diseased tissue and subjected to an alternating high frequency magnetic field. The process triggers sufficient heat to destroy the cancerous cells. One of the challenging problems during MFH is blood flow in tissue. In real conditions the heat which is transferred by blood flow should be considered in the analysis of MFH. METHODS: In this study, heat transfer was investigated in an agar gel phantom containing fluid flow. Fe3O4 as a nano-fluid was injected into the centre of a gel cylinder which was filled with another gel cylinder and subjected to an alternating magnetic field of 7.3 kA/m and a frequency of 50 kHz for 3600 s. The temperature was measured at three points in the gel. Temperature distributions regarding the time at these three points were experimentally measured. Moreover, the specific absorption rate (SAR) function was calculated with a temperature function. RESULTS: The SAR function was a key asset in the hyperthermia and was obtained on the condition that the fluid flowed through the gel. Finally, a finite element analysis (FEA) was performed to verify the SAR function. The results revealed that there was good agreement between the measured temperature and the one obtained from FEA. In addition, the effects of fluid flow and accuracy of function obtained for heat production in the gel were presented. CONCLUSION: It is believed that the proposed model has the potential ability to get close to reality in this type of investigation. The proposed function has implications for use in further modelling studies as a heat generation source. PMID- 25523968 TI - Management of pregnant women infected with Ebola virus in a treatment centre in Guinea, June 2014. AB - We report two cases of confirmed Ebola virus disease in pregnant women, who presented at the Medecins Sans Frontieres Ebola treatment centre in Gueckedou. Despite the very high risk of death, both pregnant women survived. In both cases the critical decision was made to induce vaginal delivery. We raise a number of considerations regarding the management of Ebola virus-infected pregnant women, including the place of amniocentesis and induced delivery, and whether certain invasive medical acts are justified. PMID- 25523969 TI - Emergence of clonally related multidrug resistant Haemophilus influenzae with penicillin-binding protein 3-mediated resistance to extended-spectrum cephalosporins, Norway, 2006 to 2013. AB - Resistance to cephalosporins in Haemophilus influenzae is usually caused by characteristic alterations in penicillin-binding protein 3 (PBP3), encoded by the ftsI gene. Resistance to extended-spectrum cephalosporins is associated with high level PBP3-mediated resistance (high-rPBP3), defined by the second stage S385T substitution in addition to a first stage substitution (R517H or N526K). The third stage L389F substitution is present in some high-rPBP3 strains. High-rPBP3 H. influenzae are considered rare outside Japan and Korea. In this study, 30 high rPBP3 isolates from Norway, collected between 2006 and 2013, were examined by serotyping, multilocus sequence typing (MLST), ftsI sequencing, detection of beta lactamase genes and minimum inhibitory concentration (MIC) determination. MICs were interpreted according to clinical breakpoints from the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Respiratory isolates predominated (proportion: 24/30). The 30 isolates included one serotype f isolate, while the remaining 29 lacked polysaccharide capsule genes. Resistance to extended-spectrum cephalosporins (cefixime, 29 isolates/30 isolates; cefepime, 28/30; cefotaxime, 26 /30; ceftaroline, 26/30; ceftriaxone, 14/30), beta-lactamase production (11/30) and co-resistance to non-beta-lactams (trimethoprim-sulfamethoxazole, 13/30; tetracycline, 4/30; chloramphenicol, 4/30; ciprofloxacin, 3/30) was frequent. The N526K substitution in PBP3 was present in 23 of 30 isolates; these included a blood isolate which represents the first invasive S385T + N526K isolate reported from Europe. The L389F substitution, present in 16 of 30 isolates, coincided with higher beta-lactam MICs. Non-susceptibility to meropenem was frequent in S385T + L389F + N526K isolates (8/12). All 11 beta-lactamase positive isolates were TEM-1. Five clonal groups of two to 10 isolates with identical MLST-ftsI allelic profiles were observed, including the first reported high-rPBP3 clone with TEM-1 beta-lactamase and co-resistance to ciprofloxacin, tetracycline, chloramphenicol and trimethoprim-sulfamethoxazole. Prior to this study, no multidrug resistant high-rPBP3 H. influenzae had been reported in Norway. Intensified surveillance of antimicrobial resistance is needed to guide empiric therapy. PMID- 25523970 TI - Measles outbreak in Greater Manchester, England, October 2012 to September 2013: epidemiology and control. AB - This paper describes the epidemiology and management of a prolonged outbreak of measles across the 2.7 million conurbation of Greater Manchester in the United Kingdom. Over a period of one year (from October 2012 to September 2013), over a thousand suspected measles cases (n = 1,073) were notified across Greater Manchester; of these, 395 (37%) were laboratory-confirmed, 91 (8%) were classed as probable, 312 (29%) were classed as possible and 275 (26%) excluded. Most confirmed and probable cases occurred in children within two age groups-infants (too young to be eligible for measles-mumps-rubella (MMR) vaccination according to the national immunisation programme) and children aged 10-19 years (low vaccine uptake in this cohort because of unfounded alleged links between the MMR vaccine and autism). During this one year period, there were a series of local outbreaks and many of these occurred within the secondary school setting. A series of public health measures were taken to control this prolonged outbreak: setting up incident management teams to control local outbreaks, a concerted immunisation catch-up campaign (initially local then national) to reduce the pool of children partially or totally unprotected against measles, and the exclusion of close contacts from nurseries and school settings for a period of 10 days following the last exposure to a case of measles. PMID- 25523971 TI - Clinical severity of human infections with avian influenza A(H7N9) virus, China, 2013/14. AB - Assessing the severity of emerging infections is challenging because of potential biases in case ascertainment. The first human case of infection with influenza A(H7N9) virus was identified in China in March 2013; since then, the virus has caused two epidemic waves in the country. There were 134 laboratory-confirmed cases detected in the first epidemic wave from January to September 2013. In the second epidemic wave of human infections with avian influenza A(H7N9) virus in China from October 2013 to October 2014, we estimated that the risk of death among hospitalised cases of infection with influenza A(H7N9) virus was 48% (95% credibility interval: 42-54%), slightly higher than the corresponding risk in the first wave. Age-specific risks of death among hospitalised cases were also significantly higher in the second wave. Using data on symptomatic cases identified through national sentinel influenza-like illness surveillance, we estimated that the risk of death among symptomatic cases of infection with influenza A(H7N9) virus was 0.10% (95% credibility interval: 0.029-3.6%), which was similar to previous estimates for the first epidemic wave of human infections with influenza A(H7N9) virus in 2013. An increase in the risk of death among hospitalised cases in the second wave could be real because of changes in the virus, because of seasonal changes in host susceptibility to severe infection, or because of variation in treatment practices between hospitals, while the increase could be artefactual because of changes in ascertainment of cases in different areas at different times. PMID- 25523972 TI - The dynamic changes of dominant clones of Staphylococcus aureus causing bloodstream infections in the European region: results of a second structured survey. AB - Staphylococcus aureus is one of the most important human pathogens and meticillin resistant S. aureus (MRSA) presents a major cause of healthcare- and community acquired infections. This study investigated the spatial and temporal changes of S. aureus causing bacteraemia in Europe over a five-year interval and explored the possibility of integrating pathogen-based typing data with epidemiological and clinical information at a European level. Between January 2011 and July 2011, 350 laboratories serving 453 hospitals in 25 countries collected 3,753 isolates (meticillin-sensitive S. aureus (MSSA) and MRSA) from patients with S. aureus bloodstream infections. All isolates were sent to the national staphylococcal reference laboratories and characterised by quality-controlled spa typing. Data were uploaded to an interactive web-based mapping tool. A wide geographical distribution of spa types was found, with some prevalent in all European countries. MSSA was more diverse than MRSA. MRSA differed considerably between countries with major international clones expanding or receding when compared to a 2006 survey. We provide evidence that a network approach of decentralised typing and visualisation of aggregated data using an interactive mapping tool can provide important information on the dynamics of S. aureus populations such as early signalling of emerging strains, cross-border spread and importation by travel. PMID- 25523973 TI - Training infection control and hospital hygiene professionals in Europe, 2010: agreed core competencies among 33 European countries. AB - The harmonisation of training programmes for infection control and hospital hygiene (IC/HH) professionals in Europe is a requirement of the Council recommendation on patient safety. The European Centre for Disease Prevention and Control commissioned the 'Training Infection Control in Europe' project to develop a consensus on core competencies for IC/HH professionals in the European Union (EU). Core competencies were drafted on the basis of the Improving Patient Safety in Europe (IPSE) project's core curriculum (CC), evaluated by questionnaire and approved by National Representatives (NRs) for IC/HH training. NRs also re-assessed the status of IC/HH training in European countries in 2010 in comparison with the situation before the IPSE CC in 2006. The IPSE CC had been used to develop or update 28 of 51 IC/HH courses. Only 10 of 33 countries offered training and qualification for IC/HH doctors and nurses. The proposed core competencies are structured in four areas and 16 professional tasks at junior and senior level. They form a reference for standardisation of IC/HH professional competencies and support recognition of training initiatives. PMID- 25523974 TI - Enhancing infectious disease mapping with open access resources. PMID- 25523975 TI - A generic approach to engineer antibody pH-switches using combinatorial histidine scanning libraries and yeast display. AB - There is growing interest in the fast and robust engineering of protein pH sensitivity that aims to reduce binding at acidic pH, compared to neutral pH. Here, we describe a novel strategy for the incorporation of pH-sensitive antigen binding functions into antibody variable domains using combinatorial histidine scanning libraries and yeast surface display. The strategy allows simultaneous screening for both, high affinity binding at pH 7.4 and pH-sensitivity, and excludes conventional negative selection steps. As proof of concept, we applied this strategy to incorporate pH-dependent antigen binding into the complementary determining regions of adalimumab. After 3 consecutive rounds of separate heavy and light chain library screening, pH-sensitive variants could be isolated. Heavy and light chain mutations were combined, resulting in 3 full-length antibody variants that revealed sharp, reversible pH-dependent binding profiles. Dissociation rate constants at pH 6.0 increased 230- to 780-fold, while high affinity binding at pH 7.4 in the sub-nanomolar range was retained. Furthermore, binding to huFcRn and thermal stability were not affected by histidine substitutions. Overall, this study emphasizes a generalizable strategy for engineering pH-switch functions potentially applicable to a variety of antibodies and further proteins-based therapeutics. PMID- 25523976 TI - The combined abdominal and perineal approach for dissection of the lower rectum. The development of new indications. AB - AIMS: Dissection of the lower rectum in some low rectal and pararectal pathologies can be technically difficult that it ends up in abandoning the procedure or raising a permanent stoma. The recently described combined abdomino perineal approach allows completion of rectal dissection from the perineal route and preservation of the anal sphincters. Patients requiring the combined approach are not seen frequently and reports on this new technique are scarce. The purpose of this study is to analyze our results of using the combined abdomino-perineal approach in different benign and malignant low rectal pathologies, and to describe two new indications for the technique. PATIENTS AND METHODS: This is a retrospective analysis of prospectively collected data of 10 patients (8 males, age range 22-75 years), including 7 cancer patients who required the combined abdomino-perineal approach for completion of their procedures. Previously unreported indications for the technique included iatrogenic rectovaginal fistula and presacral tumor. The study was conducted in a tertiary referral colorectal unit in a university hospital. RESULTS: The procedure was completed and the sphincters preserved in all patients. All cancer patients had adequate resection with good quality mesorectum. Continence was preserved in 4 patients. Three patients are living with permanent stoma. Anastomotic perineal fistula requiring dismantling the anastomosis and raising a permanent stoma occurred in one patient. CONCLUSIONS: The combined abdomino-perineal approach is useful to complete rectal resection in a highly selected group of patients with technically difficult low rectal pathologies. The technique is probably safe in cancer patients and new indications are evolving. Expectations for preservation of continence are disappointing. PMID- 25523977 TI - Mechanical properties and cytocompatibility of carbon fibre reinforced nano hydroxyapatite/polyamide66 ternary biocomposite. AB - BACKGROUND AND METHODS: Fibre-reinforced composites with good strength and ductility as bone repair biomaterials have been attracting increasing attention in biomedical applications. In the present study, a novel ternary composite was prepared using carbon fibre (CF) to reinforce a nano-hydroxyapatite/polyamide66 composite (HA/PA). The interface and mechanical strength of the ternary composite (CF/HA/PA) were characterised. In addition, to assess the cytocompatibility, the composite was co-cultured with MG-63 cells, and the cell morphology, MTT, and ALP were tested. RESULTS: The results indicated that CFs were uniformly distributed in the HA/PA matrix with random orientation and that the CFs bonded well to the HA/PA matrix. The reinforced ternary composite exhibited a compressive strength of 116-212 MPa, a bending strength of 89-138 MPa, a tensile strength of 109-181 MPa, with the breaking elongation ratio of 6.2-9.1%, and a tensile modulus of 2.9 5.8 GPa, with the values varying with increasing CF content from 5 to 20 (mass fraction). The MG-63 cells of normal phenotype were well extended and spread onto the ternary composite surface. In addition, its proliferation and differentiation on the composite surface were significantly increased with time, indicating that the incorporation of CFs into HA/PA had little negative effects on MG-63 cells. CONCLUSIONS: The incorporation of CFs into a HA/PA66 composite improved the strength and ductility and introduced no negative effects on the cytocompatibility. Hence, the CF/HA/PA ternary composite has potential to be used as a bone repair materials and in fixation devices. PMID- 25523978 TI - Redesign of Indonesian-made osteosynthesis plates to enhance their mechanical behavior. AB - Mechanical properties determined by fatigue strength, ductility, and toughness are important measures for osteosynthesis plates in order to tolerate some load bearing situations caused by muscle contractions and weight-bearing effects. Previous study indicated that Indonesian-made plates showed lower mechanical strength compared to the European AO standard plate. High stress under load bearing situations often starts from surface of the plate; we therefore refined the grain size of the surface by using shot peening and surface mechanical attrition treatment (SMAT). Single cycle bending tests showed that shot-peened and SMAT-treated plates had significantly higher load limit and bending stress compared to the original plates (p<0.05). Weibull analysis confirmed the improvement of proportional load limit of SMAT-treated plates. Fatigue limit also increased upon shot-peening and SMAT treatment (improvement ratio 18% and 27%, respectively). Significant improvement ratio of fatigue tests can be observed in SMAT-treated plates compared to the untreated and shot-peened plates. Fatigue performance demonstrated equivalent results between SMAT-treated and standard plate. These designated that mechanical properties of Indonesian-made plates can be improved upon SMAT treatment leading to significant enhancement of mechanical strength thus is comparable to the standard plate. Our findings highlight the benefits of SMAT treatment to improve mechanical strength of Indonesian-made osteosynthesis plates. PMID- 25523979 TI - Autoantibody-defined risk for Type 1 diabetes mellitus in a general population of schoolchildren: results of the Karlsburg Type 1 Diabetes Risk Study after 18 years. AB - AIMS: To investigate the occurrence of diabetes-associated autoantibodies and cumulative Type 1 diabetes risk over 18 years in a general population of schoolchildren. METHODS: In the Karlsburg Type 1 Diabetes Risk Study, 11 986 schoolchildren from north-eastern Germany without a family history of diabetes were screened for glutamic acid decarboxylase antibodies, insulinoma-associated antigen-2 antibodies and insulin autoantibodies by radioligand binding assay. Those children found to be autoantibody-positive were invited to follow-up examinations and HLA-DQB1 genotyping, and were followed for progression to Type 1 diabetes. RESULTS: At first follow-up, 119 children had single and 36 children had multiple autoantibodies. Of the multiple autoantibody-positive children, 33 had at least one diabetes-associated HLA-DQB1 allele (*02 and/or *0302). A total of 26 children progressed to Type 1 diabetes, of whom 22 had multiple autoantibodies. The male-to-female ratio of those who progressed to Type 1 diabetes was 1.6. The positive predictive value of multiple autoantibodies was 61.1% compared with only 23.7% for diabetes-associated HLA-DQB1 genotypes among all those who were autoantibody-positive. The cumulative risk was 59.7% after 10 years and 75.1% after 18 years for children with multiple autoantibodies compared with 1.2 and 22.6%, respectively, for children with single autoantibodies (P<0.001). Among the three examined autoantibodies, insulinoma-associated antigen 2 antibodies conferred the highest risk. CONCLUSIONS: The diabetes risk in schoolchildren with multiple autoantibodies was similar to the risk reported in other studies for genetically preselected probands; thus, a combined autoantibody based screening could effectively identify at-risk individuals from the general population for future intervention trials. PMID- 25523980 TI - TMD pain is partly heritable. A systematic review of family studies and genetic association studies. AB - The aim of this study was to describe the current knowledge on the role of heritability in TMD pain through a systematic review of the literature, including familiar aggregation studies and genetic association studies. For the systematic search of the literature, the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines were followed. In total, 21 studies were included in the review, including five familiar aggregation studies and 16 genetic association studies. From both familiar aggregation studies and genetic association studies, modest evidence for the role of heritability in TMD pain was found. The literature mainly suggests genetic contributions from candidate genes that encode proteins involved in the processing of painful stimuli from the serotonergic and catecholaminergic system. This systematic review shows that the evidence for the role of heritability in the development of TMD pain is cumulating. PMID- 25523981 TI - The myth of the distinction between classification and diagnostic criteria. PMID- 25523982 TI - Inflammatory back pain in a 44 year old male. PMID- 25523983 TI - Takayasu's arteritis in the newborn: a diagnosis to suspect. AB - Takayasu Arteritis is a vasculitis that affects the aorta, and its large branches, including renal, coronary and pulmonary arteries. This is a case report of a newborn who had early onset sepsis, vascular imaging reported aneurysms in the thoracic and abdominal aorta, with decreased distal pulses, a blood pressure difference >10 mmHg and angiographic changes, integrating the diagnose of Takayasu's Arteritis. PMID- 25523984 TI - Factors associated with sustained remission in patients with rheumatoid arthritis. AB - OBJECTIVE: To find out the factors that are associated with sustained remission measured by DAS28 and boolean ACR EULAR 2011 criteria at the time of diagnosis of rheumatoid arthritis. MATERIALS AND METHODS: Medical records of patients with rheumatoid arthritis in sustained remission according to DAS28 were reviewed. They were compared with patients who did not achieved values of DAS28<2.6 in any visit during the first 3 years after diagnosis. We also evaluated if patients achieved the boolean ACR/EULAR criteria. Variables analyzed: sex, age, smoking, comorbidities, rheumatoid factor, anti-CCP, ESR, CRP, erosions, HAQ, DAS28, extra articular manifestations, time to initiation of treatment, involvement of large joints, number of tender joints, number of swollen joints, pharmacological treatment. RESULTS: Forty five patients that achieved sustained remission were compared with 44 controls. The variables present at diagnosis that significantly were associated with remission by DAS28 were: lower values of DAS28, HAQ, ESR, NTJ, NSJ, negative CRP, absence of erosions, male sex and absence of involvement of large joints. Only 24.71% achieved the boolean criteria. The variables associated with sustained remission by these criteria were: lower values of DAS28, HAQ, ESR, number of tender joints and number of swollen joints, negative CRP and absence of erosions. CONCLUSION: The factors associated with sustained remission were the lower baseline disease activity, the low degree of functional disability and lower joint involvement. We consider it important to recognize these factors to optimize treatment. PMID- 25523987 TI - Solvent-free one-step photochemical hydroxylation of benzene derivatives by the singlet excited state of 2,3-Dichloro-5,6-dicyano-p-benzoquinone acting as a super oxidant. AB - Photoinduced hydroxylation of neat deaerated benzene to phenol occurred under visible-light irradiation of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), which acts as a super photooxidant in the presence of water. Photocatalytic solvent free hydroxylation of benzene derivatives with electron-withdrawing substituents such as benzonitrile, nitrobenzene, and trifluoromethylbenzene used as neat solvents has been achieved for the first time by using DDQ as a super photooxidant to yield the corresponding phenol derivatives and 2,3-dichloro-5,6 dicyanohydroquinone (DDQH2 ) in the presence of water under deaerated conditions. In the presence of dioxygen and tert-butyl nitrite, the photocatalytic hydroxylation of neat benzene occurred with DDQ as a photocatalyst to produce phenol. The photocatalytic reactions are initiated by oxidation of benzene derivatives with the singlet and triplet excited states of DDQ to form the corresponding radical cations, which associate with benzene derivatives to produce the dimer radical cations, which were detected by the femto- and nanosecond laser flash photolysis measurements to clarify the photocatalytic reaction mechanisms. Radical cations of benzene derivatives react with water to yield the OH-adduct radicals. On the other hand, DDQ(.) (-) produced by the photoinduced electron transfer from benzene derivatives reacts with the OH-adduct radicals to yield the corresponding phenol derivatives and DDQH2 . DDQ is recovered by the reaction of DDQH2 with tert-butyl nitrite when DDQ acts as a photocatalyst for the hydroxylation of benzene derivatives by dioxygen. PMID- 25523986 TI - Rituximab in the treatment of eosinophilic granulomatosis with polyangiitis. AB - BACKGROUND: The general consensus is that for patients with EGPA with poor prognosis, intensive therapy with both GC and CF is indicated. The maintenance of remission is made with GC and AZA. A considerable number of patients with EGPA are refractory to first line therapy, experience dose-limiting side effects or relapse. In clinical trials, RTX was effective for the treatment of ANCA associated vasculitis. However, patients with a diagnosis of EGPA were not included. OBJECTIVE: to review and analyze the published literature regarding the use of RTX in the treatment of EGPA. METHODS: The literature search was performed in MEDLINE and LILACS from 1965 and 1986 respectively until february 2014. RESULTS: 27 patients were included. RTX treatment was due to refractory disease (n=20), relapse (n=5) and with newly diagnosed (n=2). The affected organs were the lungs, peripheral nervous system, kidney and the eyes. Sixteen patients had clinical remission and 8 patients had clinical response. CONCLUSIONS: RTX was effective and well tolerated for the treatment of EGPA. PMID- 25523985 TI - Performance of an objective structured clinical examination in a national certification process of trainees in rheumatology. AB - OBJECTIVE: To assess reliability and validity of the objectively-structured clinical examination (OSCE) applied in postgraduate certification processes by the Mexican Board of Rheumatology. METHOD: Thirty-two (2013) and 38 (2014) Rheumatology trainees (RTs) underwent an OSCE consisting of 12 and 15 stations respectively, scored according to a validated check-list, as well as 300-multiple choice 300 question examination (MCQ). Previously, 3 certified rheumatologists underwent a pilot-OSCE. A composite OSCE score was obtained for each participant and its performance examined. RESULTS: In 2013, OSCE mean score was 7.1+/-0.6 with none RT receiving a failing score while the MCQ score was 6.5+/-0.6 and 7 (21.9%) RTs receiving a failing (< 6) score. In 2014, the OSCE score was 6.7+/ 0.6, with 3 (7.9%) RTs receiving a failing score (2 of them also failed MCQ) while the MCQ score was 6.4+/-0.5 and 7 (18.5%) RTs were disqualified (2 of them also failed OSCE). A significant correlation between the MCQ and the OSCE scores was observed in the 2013 (r=0.44; P=0.006). Certified rheumatologists performed better than RTs at both OSCE. Overall, 86% of RTs obtaining an OSCE passing score also obtained a MCQ passing score, while this was only 67% (P=.02) among those who obtained an OSCE failing score. Nine stations were applied at both consecutive years. Their performance was similar in both certification processes, with correlation coefficients ranging from 0.81 to 0.95 (P<=0.01). CONCLUSION: The OSCE is a valid and reliable tool to assess the Rheumatology clinical skills in RTs. PMID- 25523988 TI - Helpline strengthened by mental health and wellbeing initiative. PMID- 25523989 TI - Avian influenza: restrictions eased. PMID- 25523990 TI - UK pets 'heading for animal welfare disaster'. PMID- 25523991 TI - High jumps and science at London festival. PMID- 25523992 TI - Tighter controls on dog breeding in Wales. PMID- 25523993 TI - Feeding the world: the role of vets in food sustainability. PMID- 25523994 TI - Wildlife--an integral part of One Health. PMID- 25523995 TI - Linking theory and practice in emergency critical care. PMID- 25523996 TI - Canine and feline obesity: a One Health perspective. PMID- 25523997 TI - Klebsiella pneumoniae infection causes mastitis in pigs. PMID- 25523998 TI - Opioids for field procedures in equine practice. PMID- 25524000 TI - RCVS guide to student behaviour. PMID- 25524001 TI - RCVS guide to student behaviour. PMID- 25524002 TI - Switched on to business. PMID- 25524003 TI - Diary of a poultry intern. PMID- 25524004 TI - Trajectories of fear of recurrence in women with breast cancer. AB - PURPOSE: Although fear of recurrence (FCR) is common among cancer survivors, it remains unclear what factors predict initial levels (e.g., prior to surgery) or changes in FCR in the post-treatment period. Among women treated for breast cancer, this study evaluated the effects of demographic, clinical, symptom, and psychosocial adjustment characteristics on the initial (preoperative) levels of FCR and trajectories of FCR over 6 months following surgery. METHODS: Prior to and for 6 months following breast cancer surgery, 396 women were assessed for demographic and clinical (disease and treatment) characteristics, symptoms, psychological adjustment characteristics, and quality of life (QOL). FCR was assessed using a four-item subscale from the QOL instrument. Hierarchical linear modeling was used to examine changes in FCR scores and to identify predictors of inter-individual differences in preoperative FCR levels and trajectories over 6 months. RESULTS: From before surgery to 6 months post-operatively, women with breast cancer showed a high degree of inter-individual variability in FCR. Preoperatively, women who lived with someone, experienced greater changes in spiritual life, had higher state anxiety, had more difficulty coping, or experienced more distress due to diagnosis or distress to family members reported higher FCR scores. Patients who reported better overall physical health and higher FCR scores at enrollment demonstrated a steeper decrease in FCR scores over time. CONCLUSIONS: These findings highlight inter-individual heterogeneity in initial levels and changes in FCR over time among women undergoing breast cancer surgery. Further work is needed to identify and provide interventions for women experiencing FCR during and after breast cancer treatment. PMID- 25524005 TI - Comparison of filgrastim and pegfilgrastim to prevent neutropenia and maintain dose intensity of adjuvant chemotherapy in patients with breast cancer. AB - PURPOSE: The aim of this study was to compare the effectiveness of prophylactic single fixed dose of pegfilgrastim and daily administration of filgrastim on febrile neutropenia (FN), severe neutropenia, treatment delay, and dose reduction in patients with breast cancer receiving dose-dense adjuvant chemotherapy. METHODS: A retrospective cohort study with 1058 breast cancer patients matched by age and chemotherapy was conducted. The primary endpoints were FN, severe (grade 3, 4) neutropenia, dose reduction (>10 % reduction of the dose planned), and treatment delay (dose given more than 2 days later). RESULTS: Eighteen episodes of FN (3.4%) in the filgrastim group and 23 (4.3%) in the pegfilgrastim group (p = 0.500) were recorded. More than half of the total episodes (27/41) occurred during the first 4 cycles of treatment. Patients who received filgrastim were almost three times more likely to experience a severe neutropenia episode and were significantly more likely to experience a dose reduction (18.5%) compared to those who received pegfilgrastim (10.8%) (p < 0.001). The percentage of patients, who received their planned dose on time, was significantly lower in patients receiving filgrastim (58%) compared to those receiving pegfilgrastim (72.4%, p < 0.001). CONCLUSIONS: No significant difference was detected on FN rate between daily administration of filgrastim and single administration of pegfilgrastim. However, patients receiving pegfilgrastim had a significantly lower rate of severe neutropenia, as well as dose reduction and treatment delay, thus, achieving a higher dose density. PMID- 25524007 TI - Statistical contact angle analyses; "slow moving" drops on a horizontal silicon oxide surface. AB - Sessile drop experiments on horizontal surfaces are commonly used to characterise surface properties in science and in industry. The advancing angle and the receding angle are measurable on every solid. Specially on horizontal surfaces even the notions themselves are critically questioned by some authors. Building a standard, reproducible and valid method of measuring and defining specific (advancing/receding) contact angles is an important challenge of surface science. Recently we have developed two/three approaches, by sigmoid fitting, by independent and by dependent statistical analyses, which are practicable for the determination of specific angles/slopes if inclining the sample surface. These approaches lead to contact angle data which are independent on "user-skills" and subjectivity of the operator which is also of urgent need to evaluate dynamic measurements of contact angles. We will show in this contribution that the slightly modified procedures are also applicable to find specific angles for experiments on horizontal surfaces. As an example droplets on a flat freshly cleaned silicon-oxide surface (wafer) are dynamically measured by sessile drop technique while the volume of the liquid is increased/decreased. The triple points, the time, the contact angles during the advancing and the receding of the drop obtained by high-precision drop shape analysis are statistically analysed. As stated in the previous contribution the procedure is called "slow movement" analysis due to the small covered distance and the dominance of data points with low velocity. Even smallest variations in velocity such as the minimal advancing motion during the withdrawing of the liquid are identifiable which confirms the flatness and the chemical homogeneity of the sample surface and the high sensitivity of the presented approaches. PMID- 25524006 TI - The first CD73-instructed supramolecular hydrogel. AB - Enzymatic supramolecular hydrogelation is a simple, controllable, and novel strategy for preparation of soft colloidal materials, which allows the integration of self-assembly with enzyme associated biological processes. The development of more enzymes involve in hydrogelation is a subject of developing useful soft colloids. In this work, an ectoenzyme, CD73, was found to trigger the formation of nanofibers as matrices of hydrogels. CD73 is an important cell surface enzyme which converts extracellular adenosine monophosphate (AMP) to adenosine. It is broadly expressed in many cancer cells and participates in tumor growth. The successful application of CD73 in self-assembly and hydrogelation may provide new strategies for CD73-guided materials and therapies. PMID- 25524008 TI - Effect of water absorption on pollen adhesion. AB - Pollens possess a thin liquid coating, pollenkitt, which plays a major role in adhesion by forming capillary menisci at interfaces. Unfortunately, the influence of humidity on pollenkitt properties and capillary adhesion is unknown. Because humidity varies widely in the environment, the answers have important implications for better understanding plant reproduction, allergy and asthma, and pollen as atmospheric condensation nuclei. Here, pollenkitt-mediated adhesion of sunflower pollen to hydrophilic and hydrophobic surfaces was measured as a function of humidity. The results quantify for the first time the significant water absorption of pollenkitt and the resulting complex dependence of adhesion on humidity. On hydrophilic Si, adhesion increased with increasing RH for pollens with or without pollenkitt, up to 200nN at 70% RH. In contrast, on hydrophobic PS, adhesion of pollenkitt-free pollen is independent of RH. Surprisingly, when pollenkitt was present adhesion forces on hydrophobic PS first increased with RH up to a maximum value at 35% RH (~160nN), and then decreased with further increases in RH. Independent measurement of pollenkitt properties is used with models of capillary adhesion to show that humidity-dependent changes in pollenkitt wetting and viscosity are responsible for this complex adhesion behavior. PMID- 25524010 TI - A novel therapeutic combination sequentially targeting aurora B and Bcl-xL in hepatocellular carcinoma. AB - BACKGROUND: Effective therapeutic combinations targeting the oncogenic pathway still are unknown in human hepatocellular carcinoma (HCC). The authors previously identified aberrant expression of aurora B kinase as the independent predictor for the lethal recurrence of HCC, showing that AZD1152 induced in vitro and in vivo apoptosis with polyploidy in human HCC cells. In this preclinical study, the combined effects of molecular-targeted therapies were evaluated based on the cellular response of aurora B inhibition. METHODS: This study analyzed the expression of Bcl-2 family proteins in polyploidization induced by AZD1152 and the in vitro synergistic effects of AZD1152 with control of the Bcl-2 family pathway in human HCC cells. The in vivo effects of the combination therapy targeting the specific molecules were evaluated using subcutaneous tumor xenograft models. RESULTS: The findings showed that Bcl-xL was specifically overexpressed in AZD1152-induced polyploid HCC cells. The combination of AZD1152 followed by Bcl-xL/2 inhibitor ABT263 induced synergistically cellular apoptosis (p < 0.001) and growth inhibition (p < 0.0001). Interestingly, the reverse sequential administration of AZD1152 combined with pretreatment of ABT263 was less effective than the original one. In vivo studies using tumor xenografts of human HCC cells showed that combination therapy of ABT263 after AZD1152 pretreatment induced significant intratumoral apoptosis (p < 0.05) and remarkable anti-tumor effects (p < 0.05) without a severe adverse effect compared with the monotherapy. CONCLUSION: Based on Bcl-xL overexpression in polyploidy induced by aurora B inhibition, the rationale for therapeutic combinations targeting aurora B and Bcl-xL was demonstrated in the authors' preclinical studies, leading to a promising novel approach for the mechanism-based treatment of human HCC. PMID- 25524009 TI - Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies. AB - BACKGROUND: DAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated. METHODS: We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were examined for endocrine developmental anomalies. RESULTS: Mutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NFKappaB2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC). CONCLUSIONS: We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function. PMID- 25524011 TI - Prognostic Significance of (18)F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET)-Positive Lymph Nodes Following Neoadjuvant Chemotherapy and Surgery for Resectable Thoracic Esophageal Squamous Cell Carcinoma. AB - PURPOSE: Patients with resectable thoracic esophageal squamous cell cancer (TESCC) and positron emission tomography (PET)-positive lymph nodes (PET-N positive) are likely to have >=3 pathological lymph node metastases (pLNMs) and show a higher rate of postoperative recurrence despite curative resection than PET-N-negative TESCC patients. We examined the prognostic significance of (18)F fluorodeoxyglucose uptake into lymph node metastases after neoadjuvant chemotherapy (NAC) for PET-N positive TESCC and aimed to propose the optimal NAC response criteria for these patients. METHODS: Fifty-one patients with PET-N positive TESCC underwent two courses of NAC followed by surgery. Metabolic responses of primary tumors and LNs were prospectively evaluated and associations with clinicopathological data and patient survival assessed by univariate and multivariate analyses. RESULTS: After NAC, 21 patients were post-treatment (post ) PET-N positive and 30 post-PET-N negative. A significantly (p < 0.001) high proportion of the post-PET-N-negative group had <=2 pLNMs than the post-PET-N positive group (86.7 vs. 28.6 %). The PET-N negative group also had a significantly lower distant metastasis rate (23.3 vs. 75.0 %) and higher 5-year relapse-free survival (RFS) rate (69.0 vs. 20.0 %). Univariate and multivariate Cox's proportional hazard regression analyses identified post-PET-N negative status as the only significant favorable predictive factor for low postoperative recurrence (p = 0.015) independent of the primary tumor response. CONCLUSIONS: PET-N negative status predicts <=2 pLNMs and longer RFS in resectable TESCC patients even after NAC. Therefore, post-PET-N status, not the effects on the primary tumor, is a critical NAC treatment response criterion for evaluating prognosis and guiding subsequent treatment. PMID- 25524012 TI - Emotion, sighing, and respiratory variability. AB - How dimensions of emotion affect respiratory regulation assessed by respiratory variability and sighing is unknown. The present studies aimed to investigate the effects of emotional valence and arousal on respiratory variability and sigh rate. Within subjects, emotions were induced by picture viewing in a first experiment, and script-driven mental imagery in a second experiment. Respiration was measured throughout the experiment, while valence, arousal, and dominance ratings were assessed after each trial. Negative and/or high-arousal emotions increased sigh rates and respiratory variability during picture viewing and imagery. Only depression imagery, however, decreased correlated variability (and only in minute ventilation). Fear imagery particularly increased variability in end-tidal carbon dioxide and expiratory time. These findings show that dimensions of emotion importantly influence respiratory regulation. PMID- 25524013 TI - Distinct gene expression responses of two anticonvulsant drugs in a novel human embryonic stem cell based neural differentiation assay protocol. AB - Hazard assessment of chemicals and pharmaceuticals is increasingly gaining from knowledge about molecular mechanisms of toxic action acquired in dedicated in vitro assays. We have developed an efficient human embryonic stem cell neural differentiation test (hESTn) that allows the study of the molecular interaction of compounds with the neural differentiation process. Within the 11-day differentiation protocol of the assay, embryonic stem cells lost their pluripotency, evidenced by the reduced expression of stem cell markers Pou5F1 and Nanog. Moreover, stem cells differentiated into neural cells, with morphologically visible neural structures together with increased expression of neural differentiation-related genes such as betaIII-tubulin, Map2, Neurogin1, Mapt and Reelin. Valproic acid (VPA) and carbamazepine (CBZ) exposure during hESTn differentiation led to concentration-dependent reduced expression of betaIII-tubulin, Neurogin1 and Reelin. In parallel VPA caused an increased gene expression of Map2 and Mapt which is possibly related to the neural protective effect of VPA. These findings illustrate the added value of gene expression analysis for detecting compound specific effects in hESTn. Our findings were in line with and could explain effects observed in animal studies. This study demonstrates the potential of this assay protocol for mechanistic analysis of specific compound-induced inhibition of human neural cell differentiation. PMID- 25524015 TI - Association of plasma brain natriuretic peptide levels in acute ischemic stroke subtypes and outcome. AB - BACKGROUND: Brain natriuretic peptide (BNP) is believed to be a diagnostic marker for cardiovascular diseases, including atrial fibrillation (AF). Recent studies have incriminated BNP as a marker of cardioembolic stroke. We aimed at investigating association of plasma BNP levels in acute ischemic stroke subtypes and their outcome in Indian patients. METHODS: We recruited 270 acute ischemic stroke patients within 48 hours of symptom onset and compared with 110 age- and sex-matched control subjects. This study was carried out at Yashoda Hospital, Hyderabad, India between April 2011 and March 2013. Serum BNP levels were estimated in stroke patients and control subjects. Good functional outcome at 3 months was defined as modified Rankin score (mRS) 2 or less. RESULTS: Elevated BNP levels was significantly more in patients with acute ischemic stroke patients 119 (44%) compared with controls 4 (3.6%; P < .0001). Among stroke subtypes, elevated BNP levels were observed in 75% of cardioembolic strokes, 45.8% of small artery disease, 43.1% of larger artery atherosclerosis, and 34.5% of stroke of undetermined etiology. On multiple logistic regression analysis, elevated BNP levels were significantly associated with acute ischemic stroke (odds ratio [OR], 13.0; 95% confidence interval [CI], 8.1-15.4). Among stroke subtypes, significant association was seen with cardioembolic stroke (OR, 3.5; 95% CI, 2.2-7.2). Elevated BNP levels were independently associated with poor outcome (OR, 3.4; 95% CI, 1.2-13.7; P < .0001) and higher mortality (OR, 3.4; 95% CI, 1.2-13.7; P < .0001). CONCLUSIONS: Elevated BNP level is an independent marker for cardioembolic stroke and poor outcome at 90 days follow-up. No significant association was seen with other stroke subtypes. PMID- 25524014 TI - Prestroke living situation and depression contribute to initial stroke severity and stroke recovery. AB - Substantial evidence from both experimental and clinical studies has demonstrated that social isolation can increase stroke incidence and impair recovery. Social isolation leads to higher rates of recurrent stroke but is often not reported as a risk factor. We examined prospectively collected stroke center database variables, which included prestroke living situation, to determine if social isolation could be determined from existing data using living arrangement as a proxy. Patients were categorized into 4 groups hypothesized to represent increasing levels of social isolation: living with spouse, living with family, living alone with visiting services, and living alone. Initial stroke severity and recovery were measured using the National Institutes of Health Stroke Scale and Barthel Index, respectively. A multivariate model was used to determine the relationship among prestroke living situation, stroke severity, and functional outcome. Patients living alone had less severe strokes on admission and better recovery at 3 months compared with the other cohorts. Patients living alone or those who lived with a spouse had less severe strokes on presentation and better recovery at both 3 and 12 months after stroke compared with the other cohorts. However, on detailed examination, it was found that these patients also had significantly higher prestroke function. Pre-existing depression was significantly higher in women, and depressed patients had poorer outcomes 3 months after stroke. Information regarding isolation is notably absent from most large stroke databases. A more comprehensive evaluation of social interaction should be obtained to more accurately measure social isolation. PMID- 25524016 TI - A systemized stroke code significantly reduced time intervals for using intravenous tissue plasminogen activator under magnetic resonance imaging screening. AB - BACKGROUND: A stroke code can shorten time intervals until intravenous tissue plasminogen activator (IV t-PA) treatment in acute ischemic stroke (AIS). Recently, several reports demonstrated that magnetic resonance imaging (MRI) based thrombolysis had reduced complications and improved outcomes in AIS despite longer processing compared with computed tomography (CT)-based thrombolysis. METHODS: In January 2009, we implemented CODE RED, a computerized stroke code, at our hospital with the aim of achieving rapid stroke assessment and treatment. We included patients with thrombolysis from January 2007 to December 2008 (prestroke code period) and from January 2009 to May 2013 (poststroke code period). The IV t PA time intervals and 90-day modified Rankin Scale (mRS) scores were collected. RESULTS: During the observation period, 252 patients used IV t-PA under the CODE RED (MRI based: 208; CT based: 44). The remaining 71 patients (MRI based: 53; CT based: 18) received it before the implementation of our stroke code. After implementation of CODE RED, door-to-image time, door-to-needle time, and the onset-to-needle time were significantly reduced by 11, 18, and 22 minutes in MRI based thrombolysis. Particularly, the proportion of favorable outcome (mRS score 0-2) was significantly increased (from 41.5% to 60.1%, P = .02) in poststroke than in prestroke code period in MRI-based thrombolysis. However, in ordinal regression, the presence of stroke code showed just a trend for favorable outcome (odds ratio, .99-2.87; P = .059) at 90 days of using IV t-PA after correction of age, sex, and National Institutes of Health Stroke Scale. CONCLUSIONS: In this study, we demonstrated that a systemized stroke code shortened time intervals for using IV t-PA under MRI screening. Also, our results showed a possibility that a systemized stroke code might enhance the efficacy of MRI-based thrombolysis. In the future, we need to carry out a more detailed prospective study about this notion. PMID- 25524017 TI - Risk factors for pediatric intussusception complicated by loss of intestine viability in China from June 2009 to May 2014: a retrospective study. AB - PURPOSE: Intussusception is one of the most common causes of acute abdominal emergencies in infants and preschool children. Loss of intestine viability is the most serious complication of intussusception. This study aimed to investigate the risk factors for loss of intestine viability in pediatric intussusception cases among children. METHODS: Data were collected for operative pediatric intussusception cases (N = 316) from medical records of 5,537 hospitalized children due to intussusception between June 2009 and May 2014 in a pediatric surgery department of an academic teaching hospital in China. Seventy-six patients (24.1 %) of the operated intussusception cases had complication of loss intestine viability. RESULTS: Pediatric intussusception cases with loss of intestine viability and without loss of intestine viability were similar in terms of their age, malformation and season of admission. The median time of the duration from onset of symptoms to operative treatment was 23 h (range 3-90 h). The loss of intestine viability group of the intussusception cases was significantly associated with longer length of history (P = 0.000). Receiver operating characteristic curve analysis for length of history showed that the optimal ratio of sensitivity (0.70) and specificity (0.73) was calculated for the length of history longer than 27.5 h regarding loss of intestine viability of intussusception. In addition, the risk of loss of intestine viability was higher for female (31 %) than for male (20.8 %) (P = 0.049). The loss of intestine viability rate was also significantly higher in ileo-ileal intussusception cases than that of the other types (P = 0.033). However, there is no difference among the other groups. CONCLUSION: The result of our risk factor analysis for loss of intestine viability in pediatric intussusception cases may help develop a predictability index to prevent the complication to happen. Further prospective studies are required to confirm our findings. PMID- 25524018 TI - European regulatory experience with drugs for central nervous system disorders. PMID- 25524019 TI - Women's self-management of chronic illnesses in the context of caregiving: a grounded theory study. AB - AIMS AND OBJECTIVES: Uncover how women self-manage their own chronic illness while taking care of a dependent relative. BACKGROUND: International policies place special emphasis in promoting interventions addressed to control, prevent and care for people with chronic health conditions. Self-management is a crucial part of this care. Caregivers are more prone to have chronic illness than non caregivers. They are confronted with dilemmas about taking care of themselves while taking care of their dependent relative and the rest of their families. Caregivers articulate strategies to enable them to focus their energy on caring. DESIGN: Qualitative study using constructivist grounded theory. METHODS: Thirty nine women caregivers with a chronic illness participated in the study. Twenty three semi-structured interviews and two focus groups were carried out between April 2010-December 2011. Data were analysed using grounded theory procedures. FINDINGS: Self-management helps women caregivers with a chronic illness to balance the demands of their own illness and those of the dependent relative. They self-manage their illness by self-regulating the treatment, by regulating their strength and by controlling their emotions. CONCLUSIONS: Women caregivers integrate effectively and creatively the management of their chronic illnesses within the complexities of family care. This renders their health needs invisible and reaffirms them as capable caregivers. RELEVANCE TO CLINICAL PRACTICE: Identifying self-management strategies of women caregivers allow health professionals to acknowledge and reinforce effective self-care measures and to deter those that are ineffective and lessen their quality of life. PMID- 25524021 TI - Undercarboxylated osteocalcin may be an attractive marker of teriparatide treatment in RA patients: response to Mokuda. PMID- 25524022 TI - Increased risk of bone fracture among patients with urinary calculi: a nationwide longitudinal population-based study. AB - Urinary calculi were associated with higher risk of vertebral and upper limb fracture. Therefore, patients with urinary calculi should be evaluated carefully because they may have a higher risk of subsequent fracture later in life. INTRODUCTION: The contribution of urinary calculi to reduced bone mineral density has been recognized. However, the association of urinary calculi with the risk of fracture remains inconclusive. The aim of the study was to determine the risk of overall fracture and fractures at different anatomic sites in patients with urinary calculi. METHODS: The records of inpatients and outpatients with urinary calculi were retrieved from the Taiwan National Health Insurance Database from 2000 to 2010. Among patients with urinary calculi at the cohort entry, controls were matched using propensity scores on a 1:1 ratio. All subjects were followed up from the date of enrollment until fracture occurrence, death, or December 31, 2010. There were 46,243 Medicare beneficiaries with a diagnosis of urinary calculi and 46,243 controls without calculi enrolled. RESULTS: Among these patients, 6005 patients with a diagnosis of urinary calculi and 5339 controls developed fractures during a median follow-up period of 5.3 years. Patients with urinary calculi had a higher incidence of fracture compared with controls (23.9 versus 22.1 per 1000 person-years) and a greater risk of overall fractures (adjusted hazard ratio [aHR] 1.08, 95 % confidence interval [CI], 1.04-1.12), mainly located at the vertebrae (aHR 1.15, 95 % CI, 1.06-1.25) and upper limb (aHR 1.07, 95 % CI, 1.01-1.14), but the risk for hip fracture was not increased (aHR 1.09, 95 % CI, 0.96-1.22). CONCLUSIONS: Urinary calculus is independently associated with higher risk of subsequent fracture. Patients with urinary calculi should pay attention to the future vertebral and upper limb fractures. PMID- 25524020 TI - Family resemblance of bone turnover rate in mothers and daughters--the MODAM study. AB - We studied bone turnover markers (BTM) and bone microarchitecture (using high resolution peripheral quantitative computed tomography (HR-pQCT)) in 171 postmenopausal women and their 210 premenopausal daughters. BTM levels correlated positively between mothers and daughters. The mother-daughter pairs with high BTM levels had lower cortical density than those with low BTM levels. INTRODUCTION: We assessed the correlation of serum bone turnover markers (BTM) between postmenopausal mothers and their premenopausal daughters as well as possible determinants of this association and its impact on resemblance of bone microarchitecture between mothers and their daughters. METHODS: Cross-sectional analysis was performed in 171 untreated postmenopausal mothers (54 sustained fragility fractures) and their 210 premenopausal daughters. Intact N-terminal propeptide of type I collagen (PINP) and beta-isomerized C-terminal crosslinking telopeptide of type I collagen (CTX-I) were measured in the fasting status. Bone microarchitecture was assessed using HR-pQCT. RESULTS: After adjustment for age, weight, lifestyle factors, hormones, and mother's fracture status, BTM levels correlated positively between mothers and daughters (Intraclass Correlation Coefficient = 0.22-0.27, p <0.005). Average BTM levels were ~ 0.6 SD higher among daughters of mothers in the highest BTM quartile vs. the ones in the lowest BTM quartile. The variability of BTM levels explained <= 10 and <= 14% of variability of bone microarchitecture in the daughters and mothers, respectively. Cortical density was lower by 2.3-2.9% (0.6 SD, p <0.05 to <0.005) in the daughters from the mother-daughter pairs with high BTM levels (defined by generation-specific quartiles) than in the daughters from the pairs with low BTM levels. Corresponding differences for the mothers were 4.5-4.8% (0.5 SD, p <0.05 to <0.01). CONCLUSION: BTM levels correlated between postmenopausal mothers and their premenopausal daughters after adjustment for age, weight, mother's fracture status, lifestyle, and hormonal factors. Family resemblance of BTM levels may contribute to family resemblance of some bone microarchitectural parameters, especially of cortical density. PMID- 25524024 TI - Doctors: caring extroverts or self deluded chocoholics? PMID- 25524023 TI - Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism. AB - No data on the pharmacological treatment of normocalcemic hyperparathyroidism (NPHPT) are available. We treated 30 NPHPT postmenopausal women with alendronate/cholecalciferol (treated group) or vitamin D alone (control group). Over 1 year, bone mineral density (BMD) increased significantly in treated group, but not in control group. Both treatments did not affect serum or urinary calcium. INTRODUCTION: Normocalcemic primary hyperparathyroidism (NPHPT) is defined by normal serum calcium and consistently elevated PTH levels after ruling out the causes of secondary hyperparathyroidism. It is likely that subjects with NPHPT may develop kidney and bone disease. As no data on the pharmacological treatment of NPHPT are available, we aimed to investigate the effects of alendronate and cholecalciferol on both BMD and bone biochemical markers in postmenopausal women with NPHPT. Safety of vitamin D was evaluated as secondary endpoint. METHODS: The study was a prospective open label randomized trial comparing 15 postmenopausal women with NPHPT (PMW-NPHPT), treated with oral alendronate plus cholecalciferol (treated group) and 15 PMW-NPHPT treated only with cholecalciferol (control group). Blood samples were obtained at baseline and after 3, 6, and 12 months. Bone turnover markers (BTM) were measured at baseline, 3, and 6 months, respectively. BMD was assessed at baseline and after 12 months. RESULTS: After 1 year of treatment, BMD increased significantly at the lumbar, femoral neck, and hip level in the treated group, but not in the control group (p = 0.001). No differences were found between or within groups in serum calcium, PTH, and urinary calcium levels. BTM significantly decreased in the treated group but not in the control group, at 3 and 6 months (p < 0.001), respectively. No cases of hypercalcemia or hypercalciuria were detected during the study. CONCLUSION: The results of this study indicate that alendronate/cholecalciferol increases BMD in postmenopausal women with NPHPT. Alendronate/cholecalciferol or vitamin D alone does not affect serum or urinary calcium. PMID- 25524025 TI - Genome-wide analysis of the human p53 transcriptional network unveils a lncRNA tumour suppressor signature. AB - Despite the inarguable relevance of p53 in cancer, genome-wide studies relating endogenous p53 activity to the expression of lncRNAs in human cells are still missing. Here, by integrating RNA-seq with p53 ChIP-seq analyses of a human cancer cell line under DNA damage, we define a high-confidence set of 18 lncRNAs that are p53 transcriptional targets. We demonstrate that two of the p53 regulated lncRNAs are required for the efficient binding of p53 to some of its target genes, modulating the p53 transcriptional network and contributing to apoptosis induction by DNA damage. We also show that the expression of p53 lncRNAs is lowered in colorectal cancer samples, constituting a tumour suppressor signature with high diagnostic power. Thus, p53-regulated lncRNAs establish a positive regulatory feedback loop that enhances p53 tumour suppressor activity. Furthermore, the signature defined by p53-regulated lncRNAs supports their potential use in the clinic as biomarkers and therapeutic targets. PMID- 25524027 TI - Therapeutic efficacy of autologous platelet-rich plasma and polydeoxyribonucleotide on female pattern hair loss. AB - Autologous platelet-rich plasma (PRP) exerts positive therapeutic effects on hair thickness and density in patients with pattern hair loss. The aim of our study was to evaluate the efficacy of intra-perifollicular autologous PRP and polydeoxyribonucleotide (PDRN) injections in treating female pattern hair loss (FPHL). Twenty FPHL patients were treated with a single session of PRP injection, followed by 12 sessions of PDRN intra-perifollicular injection, along the scalp at weekly intervals. Additionally, another 20 FPHL patients were treated with 12 sessions of PDRN injection only. Meanwhile, one half of the backs of two rabbits was injected with the PRP preparation, while the other half was injected with phosphate buffered saline as a control. Tissue samples from the rabbits were analyzed by real-time polymerase chain reaction and Western blotting. Compared with baseline values, patients treated with PRP and PDRN injections exhibited clinical improvement in mean hair counts (23.2 +/- 15.5%; p < 0.001) and mean hair thickness (16.8 +/- 10.8%; p < 0.001). In addition, patients treated with the 12 sessions of intra-perifollicular PDRN injection alone also showed clinical improvement in mean hair counts (17.9 +/- 13.2%; p < 0.001) and mean hair thickness (13.5 +/- 10.7%; p < 0.001). Comparison analyses between the two groups revealed that combined therapy with PRP and PDRN induces greater improvement in hair thickness than treatment with PDRN therapy alone (p = 0.031), but not in hair counts (p > 0.05). The pilot animal study revealed significant up-regulation of WNT, platelet-derived growth factor, and fibroblast growth factor expression in rabbit skin treated with the PRP preparation, compared with control skin. In conclusion, intra-perifollicular injections of autologous PRP and/or PDRN generate improvements in hair thickness and density in FPHL patients. PMID- 25524028 TI - Occurrence of sexuals of African weaver ant (Oecophylla longinoda Latreille) (Hymenoptera: Formicidae) under a bimodal rainfall pattern in eastern Tanzania. AB - The African weaver ant, Oecophylla longinoda, is being utilized as a biocontrol agent and may also be targeted for future protein production. Rearing of mated queens in nurseries for colony production is needed to cater for such demands. Thus, newly mated queens must be collected for use as seed stocks in the nurseries. To collect mated queens efficiently it is important to identify when sexuals occur in mature colonies. We studied the occurrence of sexuals in O. longinoda colonies for 2 years in Tanga, Tanzania, a region characterized by a bimodal rainfall pattern. We found that O. longinoda sexuals occurred almost throughout the year with abundance peaks from January to April. Production of sexuals appeared to be triggered by rainfall, suggesting that populations in areas with long rainy periods may show prolonged mating periods compared to populations experiencing extended dry periods. The bimodal rain pattern may thus cause a low production over a long period. The average yearly production of queens per tree and per colony was estimated to be 449 and 2753, respectively. The average number of queens per nest was 17. Worker abundance declined from January to March with minimum by the end of this period, being inversely proportional to the production of sexuals. In conclusion, mated queens may be collected almost throughout the year, but most efficiently by the onset of the long rainy season when the majority disperse. PMID- 25524026 TI - RBFOX and PTBP1 proteins regulate the alternative splicing of micro-exons in human brain transcripts. AB - Ninety-four percent of mammalian protein-coding exons exceed 51 nucleotides (nt) in length. The paucity of micro-exons (<= 51 nt) suggests that their recognition and correct processing by the splicing machinery present greater challenges than for longer exons. Yet, because thousands of human genes harbor processed micro exons, specialized mechanisms may be in place to promote their splicing. Here, we survey deep genomic data sets to define 13,085 micro-exons and to study their splicing mechanisms and molecular functions. More than 60% of annotated human micro-exons exhibit a high level of sequence conservation, an indicator of functionality. While most human micro-exons require splicing-enhancing genomic features to be processed, the splicing of hundreds of micro-exons is enhanced by the adjacent binding of splice factors in the introns of pre-messenger RNAs. Notably, splicing of a significant number of micro-exons was found to be facilitated by the binding of RBFOX proteins, which promote their inclusion in the brain, muscle, and heart. Our analyses suggest that accurate regulation of micro-exon inclusion by RBFOX proteins and PTBP1 plays an important role in the maintenance of tissue-specific protein-protein interactions. PMID- 25524029 TI - Safety and efficacy of a tCD25 preselective combination anti-HIV lentiviral vector in human hematopoietic stem and progenitor cells. AB - The successful suppression of human immunodeficiency virus (HIV) in the "Berlin Patient" has highlighted the ability of HIV-resistant hematopoietic stem cells to offer a potential functional cure for HIV-infected patients. HIV stem cell gene therapy can mimic this result by genetically modifying a patient's own cells with anti-HIV genes. Previous attempts of HIV gene therapy have been hampered by a low percentage of transplanted HIV-resistant cells which has led to minimal clinical efficacy. In our current study, we have evaluated the in vitro and in vivo safety and efficacy of a truncated/mutated form of human CD25 preselective anti-HIV lentiviral vector in human hematopoietic stem cells. This preselective vector allows us to purify vector-transduced cells prior to transplantation so an increased percentage of gene-modified cells can be delivered. Here, we demonstrate the safety of this strategy with successful engraftment and multilineage hematopoiesis of transduced cells in a humanized NOD-RAG1-/-IL 2rgamma-/- knockout mouse model. Efficacy was also demonstrated with significant protection from HIV-1 infection including maintenance of human CD4+ cell levels and a decrease in HIV-1 plasma viremia. Collectively, these results establish the utility of this HIV stem cell gene therapy strategy and bring it closer to providing a functional cure for HIV-infected patients. PMID- 25524030 TI - Myocardial uptake of bone scintigraphic agents associated with increased pulmonary uptake. AB - OBJECTIVE: Due to delivery problems with the most commonly used bone scintigraphic agent medronate-(99m)Tc-methylene diphosphonate (MDP) (medronate), several regional institutions changed, at various time points, to (99m)Tc dicarboxypropane diphosphonate (DPD) (Teceos) from 2010. Extraosseous uptake, in particular, myocardial uptake, was observed in a number of patient examined with DPD, with reduced quality of the bone scans. Additionally, an increase in pulmonary uptake was apparent in many of these patients. The aim of this quality control was to assess pulmonary soft tissue uptake in the patients with high myocardial uptake. METHODS: A retrospective analysis of the 2435 bone scintigraphies performed during a 3-year period revealed relatively intense myocardial uptake in 10 of the 1195 patients examined with DPD (Teceos). A comparison of pulmonary uptake in a control group of age- and gender-matched subjects and a control group of patients examined with the same preparation of DPD were assessed. RESULTS: In patients with cardiac uptake of DPD, it could also be shown a relatively intense background uptake in the lungs with significantly higher uptake ratio over intercostals regions versus the abdomen, compared to the control groups. Furthermore, we found, as already well documented, a significantly lower bone to soft tissue uptake in these patients, as quantified by a femur to surrounding soft tissue ratio. CONCLUSION: Cardiac uptake of bone scintigraphic agents is associated with high pulmonary uptake. This may be a sign of pulmonary involvement which may give extraosseous bone tracer uptake its own importance and DPD a new role. PMID- 25524031 TI - Transcription factors Sox10 and Sox2 functionally interact with positive transcription elongation factor b in Schwann cells. AB - Sox proteins are mechanistically versatile regulators with established relevance to different developmental processes and crucial impact on chromatin structure, DNA conformation, and transcriptional initiation. Here, we show that Sox2 and Sox10, two Sox proteins important for Schwann cell development, also have the capability to activate transcriptional elongation in a Schwann cell line by recruiting the positive transcription elongation factor b. Recruitment is mediated by physical interaction between the carboxyterminal transactivation domains of the two Sox proteins and the Cyclin T1 subunit of positive transcription elongation factor b, with interaction interfaces for the two Sox proteins being mapped to adjacent regions of the central part of Cyclin T1. Supporting the relevance of this interaction to Schwann cell development, transcription of myelin genes appears regulated at the level of elongation. Our results thus add a new facet to the activity of Sox proteins and expand the functional repertoire of this important group of developmental regulators. Sox transcription factors are important regulators of nervous system development. While they are known to regulate transcription by recruiting and stabilizing the RNA polymerase II preinitiation complex directly or with help of the Mediator complex, this study provides evidence that Sox10 and Sox2 additionally influence transcription in glial cells at the elongation stage by recruiting P-TEFb. Cdk9, cyclin-dependent kinase 9; P-TEFb, positive transcription elongation factor b; Pol II, RNA polymerase II; Sox, Sox2 or Sox10 protein. PMID- 25524032 TI - Transcriptome analysis of carbohydrate metabolism during bulblet formation and development in Lilium davidii var. unicolor. AB - BACKGROUND: The formation and development of bulblets are crucial to the Lilium genus since these processes are closely related to carbohydrate metabolism, especially to starch and sucrose metabolism. However, little is known about the transcriptional regulation of both processes. To gain insight into carbohydrate related genes involved in bulblet formation and development, we conducted comparative transcriptome profiling of Lilium davidii var. unicolor bulblets at 0 d, 15 d (bulblets emerged) and 35 d (bulblets formed a basic shape with three or four scales) after scale propagation. RESULTS: Analysis of the transcriptome revealed that a total of 52,901 unigenes with an average sequence size of 630 bp were generated. Based on Clusters of Orthologous Groups (COG) analysis, 8% of the sequences were attributed to carbohydrate transport and metabolism. The results of KEGG pathway enrichment analysis showed that starch and sucrose metabolism constituted the predominant pathway among the three library pairs. The starch content in mother scales and bulblets decreased and increased, respectively, with almost the same trend as sucrose content. Gene expression analysis of the key enzymes in starch and sucrose metabolism suggested that sucrose synthase (SuSy) and invertase (INV), mainly hydrolyzing sucrose, presented higher gene expression in mother scales and bulblets at stages of bulblet appearance and enlargement, while sucrose phosphate synthase (SPS) showed higher expression in bulblets at morphogenesis. The enzymes involved in the starch synthetic direction such as ADPG pyrophosphorylase (AGPase), soluble starch synthase (SSS), starch branching enzyme (SBE) and granule-bound starch synthase (GBSS) showed a decreasing trend in mother scales and higher gene expression in bulblets at bulblet appearance and enlargement stages while the enzyme in the cleavage direction, starch de branching enzyme (SDBE), showed higher gene expression in mother scales than in bulblets. CONCLUSIONS: An extensive transcriptome analysis of three bulblet development stages contributes considerable novel information to our understanding of carbohydrate metabolism-related genes in Lilium at the transcriptional level, and demonstrates the fundamentality of carbohydrate metabolism in bulblet emergence and development at the molecular level. This could facilitate further investigation into the molecular mechanisms underlying these processes in lily and other related species. PMID- 25524034 TI - [Effects of Ward Interventions on Repeated Critical Incidents in Child and Adolescent Psychiatric Inpatient Care]. AB - Effects of Ward Interventions on Repeated Critical Incidents in Child and Adolescent Psychiatric Inpatient Care. The aim of this study was to evaluate the effects of several ward interventions (transition to an open ward concept, individualized treatment plans, tiered crisis-management, staff training, quality control) on repeated critical incidents, non-restrictive and restrictive measures. The outcome variables were compared in two time periods, 2007 and 2011. The study included 74 critical incident reports of 51 child and adolescent inpatients that had at least one hospital stay and one critical incident in the selected time periods. Aggressive, self-harming, and absconding incidents were included. The quantitative results suggest that ward interventions can contribute to a reduction of repeated critical incidents and restrictive measures. The qualitative evaluation suggests a cultural change of crisis management. PMID- 25524035 TI - [How do Affected Children and Adolescents Experience their Short Stature, and what is the Point of View of their Parents?]. AB - How do Affected Children and Adolescents Experience their Short Stature, and what is the Point of View of their Parents? Despite a large number of publications on the psychosocial situation of short statured children and their parents only a few qualitative studies focus on the perspective of the affected families. Within the European QoLISSY study ("Quality of Life in Short Stature Youth") an instrument to assess the health related quality of life of short statured children was developed. The aim of this project was to examine the self-perceived quality of life of the children themselves in comparison to their parents' perspective. During the development of the QoLISSY instrument, focus groups were conducted as a first step of this study. A total of 23 short statured children and 31 parents participated and discussed their experiences in separate groups with trained moderators. The discussions were analyzed qualitatively und results were used to generate a first list of items for the questionnaire to be developed. While parents focused on socio-emotional problems, children talked much more about their growth hormone treatment and problems in their social environment. In comparison to other studies children rated their quality of life worse than their parents. Not only medical treatment but also a psychological and socio-emotional intervention seems to be indicated. PMID- 25524036 TI - [Caregiver Stress in Foster and Adoptive Parents of Children with Fetal Alcohol Spectrum Disorders]. AB - Caregiver Stress in Foster and Adoptive Parents of Children with Fetal Alcohol Spectrum Disorders. Foster and adoptive parents of 71 children with fetal alcohol syndrome (FAS) report on developmental and behavioral characteristics, family stress, coping resources and their satisfaction with support. The data reveal an elevated rate of social and emotional problems in the children. In spite positive individual and social resources, the foster and adoptive parents feel a high level of caregiver stress. 30 % of them rate the support they receive from pediatric, therapeutic or educational services as lower than expected. Specifically, they miss early information on the diagnosis, professional knowledge and support for the special challenges of education and managing behavioral problems in their collaboration with social support agencies. PMID- 25524037 TI - [The German Competence Analysis Questionnaire (KANN): Autism-spectrum-disorders and/or ADHD Compared]. AB - The German Competence Analysis Questionnaire (KANN): Autism-spectrum-disorders and/or ADHD Compared. Due to the frequent comorbidity of autism spectrum disorders (ASD) and attention-deficit hyperactivity disorders (ADHD) the investigation of similarities and differences between these two syndromes has been the focus of research in recent years. The main objective of the present paper is to compare the three clinical groups "ASD", "ADHD" and "ASD+ADHD" as well as a control group on the basis of competencies relevant to everyday and social life by using the German Competence Analysis Questionnaire (Kompetenzanalyseverfahren, KANN). The KANN is an external assessment tool used to determine observable personal resources (competencies) in children and adolescents. A total of n = 205 children and adolescents under the care of child and youth welfare services are analyzed. The results show that the clinical group "ADHD" is superior to the groups "ASD" (in this case statistically significant) and "ASD+ADHD" at the KANN-scale "Leisure Behavior & Peer Groups" and "Independence in Everyday Life". The similar KANN-profiles of the two autistic groups do not support - contrary to the additionally collected data of behavior disorders (CBCL/4-18) - the hypothesis of an additive symptom effect within the meaning of the loss of competencies for the combined diagnoses group "ASD+ADHD". Furthermore, the ability of the KANN scales to differentiate between a clinical and a non-clinical child and youth welfare group underlines the validity of the KANN. PMID- 25524041 TI - Haploinsufficiency MYBPC3 mutations: another stress induced cardiomyopathy? Let's take a look! PMID- 25524042 TI - Analysis of cerebrovascular mortality trends in Spain from 1980 to 2011. AB - INTRODUCTION: In recent decades, mortality rates for cerebrovascular diseases (CVD) have declined significantly in many countries. This study analyses changes in CVD mortality rates in Spain (1980-2011) to determine if previously observed trends remain. PATIENTS AND METHODS: Data on CVD mortality rates and the population data needed for the analysis were provided by Spain's National Statistics Institute. We calculated age-specific mortality rate, age-standardised overall mortality, and age-truncated mortality (35-64 years) using the direct method and standard European population structure. Joinpoint analysis was used to estimate the percentage of annual change in rates and identify significant changes in trends. RESULTS: CVD mortality rate decreased considerably and continuously over the last 32 years in all age groups and in both sexes in Spain. For both sexes, joinpoint analysis identifies a final period with more marked decline: 2005-2011 in women (-6.3%) and 2007-2011 in men (-7.2%). CONCLUSIONS: CVD mortality rates displayed a marked and continuous decline in Spain between 1980 and 2011. Due to the ageing of the population, doctors expect an increase in CVD prevalence and therefore its magnitude in terms of disability and healthcare costs, which poses a challenge to our health system. PMID- 25524043 TI - Demographic and social profile of epilepsy in a vulnerable low-income population in Bogota, Colombia. AB - INTRODUCTION: Very few studies describe the demographic and social profile of epilepsy in vulnerable low-income populations. METHODS: Observational, descriptive, cross-sectional study prospectively recording data from all patients diagnosed with epilepsy who attended a specialist neurology consultation between January and March 2014. Data were analysed using descriptive epidemiology tools. RESULTS: A total of 107 patients were evaluated, of whom 24.2% were illiterate and only 10.2% had completed a higher education programme. Most of the patients (86.8%) had a low socioeconomic status; 73.8% were single and 76.7% were unemployed. The main risk factors for epilepsy in this population were recorded as follows: delayed psychomotor development (n=24, 22.4%), head trauma (n=16, 14.9%), and central nervous system infection (n=13, 12.1%). Most patients (70.1%) responded to antiepileptic drugs (controlled cases) and 15.4% (n=15) had drug resistant epilepsy (refractory cases). CONCLUSION: The demographic and clinical profiles of the patients included in this study resemble those published for high income populations; differences are mostly limited to aetiological classification and risk factors. The social profile of the patients evaluated in this study shows high rates of unemployment, illiteracy, and single marital status. These findings seem to be more frequent and prevalent in this group than in high income populations. PMID- 25524044 TI - Motor impairments induced by microinjection of linamarin in the dorsal hippocampus of Wistar rats. AB - INTRODUCTION: Cassava, also known as yuca or manioc (Manihot esculenta Crantz), is a staple food in tropical and subtropical regions since it is an important source of carbohydrates. Nevertheless, it contains cyanogenic compounds including lotaustralin and linamarin, which have been shown by experimental models to affect brain structures such as the thalamus, the piriform cortex, the hippocampus, and others. These findings may explain the presence of such neurological diseases as konzo and tropical ataxic neuropathy. However, hippocampal involvement in the neurological alterations associated with the chemical compounds in cassava has yet to be explored. METHOD: Male Wistar rats (3 months old), were assigned to 4 groups (n = 8 per group) as follows: a vehicle control group (receiving injectable solution 1MUl) and three groups receiving linamarin (10, 15, and 20mM). The substances were microinjected intrahippocampally (CA1) every 24hours for 7 consecutive days, and their effects on locomotor activity, rotarod, and swim tests were assessed daily. RESULTS: Linamarin microinjected into the dorsal hippocampus produced hyperactivity and loss of motor coordination which became more evident as treatment time increased. In the swim test, rats treated with linamarin displayed lateral rotation beginning on the fourth day of microinjection. CONCLUSIONS: Microinjection of linamarin into the dorsal hippocampus of the rat is associated with impaired motor coordination, suggesting that the dorsal hippocampus, among other brain structures, may be affected by the neurological changes associated with inappropriate consumption of cassava in humans. PMID- 25524045 TI - Defining the histopathological changes induced by nonablative radiofrequency treatment of faecal incontinence--a blinded assessment in an animal model. AB - AIM: Nonablative radiofrequency (RF) sphincter remodelling has been used to treat gastro-oesophageal reflux disease (GERD) and faecal incontinence (FI). Its mechanism of action is unclear. We aimed to investigate the histomorphological and pathophysiological changes to the internal and external anal sphincter (IAS and EAS) following RF remodelling. METHOD: An experimental FI model was created in 12 female pigs: eight underwent RF 6 weeks following induction of FI (FI+RF) and four were untreated (UFI). Four animals served as controls (CG). Two blinded pathologists examined all haematoxylin and eosin and trichrome stained slides. RESULTS: Compared with the UFI group, histological examination of the IAS in the FI+RF group demonstrated an increased smooth muscle (SM)/connective tissue ratio (77.2 vs 68.1%, P < 0.05) and increased collagen I compared with collagen III content (67.2 vs 54.9%, P < 0.001). The RF+FI group exhibited greater SM bundle thickness compared with the UFI group (SM width 486.93 vs 338.59 MUm, P < 0.01; height 4384.4 vs 3321.0 MUm, P < 0.05). The EAS of the FI+RF animals showed a significantly higher type I/II fibre ratio (33.5 vs 25.2%, P = 0.023) and fibre type I diameter (67.2 vs 59.7 MUm, P < 0.001) compared with the UFI group. Post RF manometry showed higher basal (18.8 vs 0 mmHg, P < 0.001) and squeeze (76.8 vs 12.4 mmHg, P < 0.05) anal pressures. After RF treatment, the number of interstitial cells of Cajal was significantly reduced compared with the UFI and CG groups [0.9 (FI+RF) vs 6.7 (UFI) vs 0.7 (CG) per mm(2) , P < 0.001]. CONCLUSION: In an animal model nonablative RF appeared to induce morphological changes in the IAS and EAS leading to an anatomical state reminiscent of normal sphincter structure. PMID- 25524047 TI - Overcoming crystallographically imposed geometrical restrictions on the valence state of Eu in CaGdAlO4: realization of white light emission from singly-doped Eu phosphors. AB - We demonstrate a strategy to manipulate the valence state of Eu in CaGdAlO4 based on breaking down geometrical restrictions on the activators. This strategy could promote the search for novel phosphors for white light emission diodes (WLEDs). PMID- 25524046 TI - In vivo imaging of epileptic foci in rats using a miniature probe integrating diffuse optical tomography and electroencephalographic source localization. AB - OBJECTIVE: The goal of this work is to establish a new dual-modal brain-mapping technique based on diffuse optical tomography (DOT) and electroencephalographic source localization (ESL) that can chronically/intracranially record optical/electroencephalography (EEG) data to precisely map seizures and localize the seizure-onset zone and associated epileptic brain network. METHODS: The dual modal imaging system was employed to image seizures in an experimental acute bicuculline methiodide rat model of focal epilepsy. Depth information derived from DOT was used as constraint in ESL to enhance the image reconstruction. Groups of animals were compared based on localization of seizure foci, either at different positions or at different depths. RESULTS: This novel imaging technique successfully localized the seizure-onset zone in rat induced by bicuculline methiodide injected at a depth of 1, 2, and 3 mm, respectively. The results demonstrated that the incorporation of the depth information from DOT into the ESL image reconstruction resulted in more accurate and reliable ESL images. Although the ESL images showed a horizontal shift of the source localization, the DOT identified the seizure focus accurately. In one case, when the bicuculline methiodide (BMI) was injected at a site outside the field of view (FOV) of the DOT/ESL interface, ESL gave false-positive detection of the focus, while DOT showed negative detection. SIGNIFICANCE: This study represents the first to identify seizure-onset zone using implantable DOT. In addition, the combination of DOT/ESL has never been documented in neuroscience and epilepsy imaging. This technology will enable us to precisely measure the neural activity and hemodynamic response at exactly the same tissue site and at both cortical and subcortical levels. PMID- 25524048 TI - Photodamage in deep tissue two-photon optical biopsy of human skin. AB - Photodamage, induced by femtosecond laser radiation, was studied in thick samples of human skin tissue (healthy skin and neoplastic lesions). Photobleaching, photoionization, and thermomechanical damage effects were characterized comparatively. The laser power dependence of the damage rates allowed to connect macroscopic effects to underlying molecular processes. Optical effects were correlated to histopathological changes. Tissue alterations were found only from thermomechanical cavitation and limited to superficial layers of the epidermis. From the depth-dependencies of all damage thresholds a depth-dependent power compensation scheme was defined allowing for damage-free deep tissue optical biopsy. Damage-induced luminescence pattern for different excitation powers and a corresponding threshold analysis. PMID- 25524050 TI - Antibodies against influenza A (H7N9) virus among veterinarians in China before 2013. PMID- 25524049 TI - Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer's disease early phenotypes. AB - BACKGROUND: It is suspected that excess of brain cholesterol plays a role in Alzheimer's disease (AD). Membrane-associated cholesterol was shown to be increased in the brain of individuals with sporadic AD and to correlate with the severity of the disease. We hypothesized that an increase of membrane cholesterol could trigger sporadic AD early phenotypes. RESULTS: We thus acutely loaded the plasma membrane of cultured neurons with cholesterol to reach the 30% increase observed in AD brains. We found changes in gene expression profiles that are reminiscent of early AD stages. We also observed early AD cellular phenotypes. Indeed we found enlarged and aggregated early endosomes using confocal and electron microscopy after immunocytochemistry. In addition amyloid precursor protein vesicular transport was inhibited in neuronal processes, as seen by live imaging. Finally transient membrane cholesterol loading lead to significantly increased amyloid-beta42 secretion. CONCLUSIONS: Membrane cholesterol increase in cultured neurons reproduces most early AD changes and could thus be a relevant model for deciphering AD mechanisms and identifying new therapeutic targets. PMID- 25524051 TI - Contribution of influenza to acute exacerbations of chronic obstructive pulmonary disease in Kashmir, India, 2010-2012. AB - We estimate the contribution of influenza to hospitalizations for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in Kashmir, India. Prospective surveillance for influenza among patients hospitalized with AECOPD was conducted at a tertiary care hospital. Patients had clinical data collected and nasal/throat swabs tested for influenza viruses. Outcomes among patients with and without influenza were compared with logistic regression adjusting for age and underlying conditions. During October 2010-September 2012, 498 patients hospitalized with AECOPD were enrolled, of whom 40 (8%) had received influenza vaccine. Forty (8%) had influenza; influenza virus detection peaked in winter (January-March). Patients with influenza were more likely to die during hospitalization (adjusted OR 3.4, CI 1.0-11.4) than those without. PMID- 25524052 TI - Safety, pharmacokinetics, and pharmacodynamics of TV-1380, a novel mutated butyrylcholinesterase treatment for cocaine addiction, after single and multiple intramuscular injections in healthy subjects. AB - Human plasma butyrylcholinesterase (BChE) contributes to cocaine metabolism and has been considered for use in treating cocaine addiction and cocaine overdose. TV-1380 is a recombinant protein composed of the mature form of human serum albumin fused at its amino terminus to the carboxy-terminus of a truncated and mutated BChE. In preclinical studies, TV-1380 has been shown to rapidly eliminate cocaine in the plasma thus forestalling entry of cocaine into the brain and heart. Two randomized, blinded phase I studies were conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of TV-1380, following single and multiple administration in healthy subjects. TV-1380 was found to be safe and well tolerated with a long half-life (43-77 hours) and showed a dose-proportional increase in systemic exposure. Consistent with preclinical results, the ex vivo cocaine hydrolysis, TV-1380 activity clearly increased upon treatment in a dose dependent manner. In addition, there was a direct relationship between ex vivo cocaine hydrolysis (kel ) and TV-1380 serum concentrations. There was no evidence that TV-1380 affected heart rate, the uncorrected QT interval, or the heart-rate corrected QTcF interval. TV-1380, therefore, offers a safe once-weekly therapy to increase cocaine hydrolysis. PMID- 25524053 TI - Serum Golgi protein 73 levels and liver pathological grading in cases of chronic hepatitis B. AB - The present study was designed to assess the correlation between serum Golgi protein 73 (GP73) and liver pathological grading and staging in patients with chronic hepatitis B (CHB). Two hundred and fifty-three patients with chronic hepatitis B virus (HBV) infections were enrolled in the present study. All patients received a serum GP73 test, and 91 CHB patients underwent liver biopsy. GP73 expression in liver tissue was assessed by immunohistochemical analysis. The results indicated that serum GP73 levels were positively correlated with disease progression in patients with chronic HBV infection (r=0.677). There was no significant difference in serum GP73 levels between hepatitis B e antigen positive and -negative patients (P>0.05). There were also no significant differences in serum GP73 levels among specimens with varying HBV DNA contents (P>0.05). Serum GP73 levels were positively correlated with increased liver pathological grading (r=0.737) and staging (r=0.692), and immunohistochemical analysis indicated that GP73 protein expression increased concurrently with liver pathological grading and staging. In conclusion, serum GP73 was found to be correlated with liver pathological grading and staging in patients with CHB, and may be an effective indicator for the evaluation of disease progression. However, serum GP73 levels were not associated with HBV replication. PMID- 25524054 TI - Application of a generalized linear mixed model to analyze mixture toxicity: survival of brown trout affected by copper and zinc. AB - Increased concerns about the toxicity of chemical mixtures have led to greater emphasis on analyzing the interactions among the mixture components based on observed effects. The authors applied a generalized linear mixed model (GLMM) to analyze survival of brown trout (Salmo trutta) acutely exposed to metal mixtures that contained copper and zinc. Compared with dominant conventional approaches based on an assumption of concentration addition and the concentration of a chemical that causes x% effect (ECx), the GLMM approach has 2 major advantages. First, binary response variables such as survival can be modeled without any transformations, and thus sample size can be taken into consideration. Second, the importance of the chemical interaction can be tested in a simple statistical manner. Through this application, the authors investigated whether the estimated concentration of the 2 metals binding to humic acid, which is assumed to be a proxy of nonspecific biotic ligand sites, provided a better prediction of survival effects than dissolved and free-ion concentrations of metals. The results suggest that the estimated concentration of metals binding to humic acid is a better predictor of survival effects, and thus the metal competition at the ligands could be an important mechanism responsible for effects of metal mixtures. Application of the GLMM (and the generalized linear model) presents an alternative or complementary approach to analyzing mixture toxicity. PMID- 25524055 TI - Trapeziometacarpal arthrodesis: is bone union necessary for a good outcome? AB - We present a retrospective study of 107 cases of thumb carpometacarpl joint arthrodesis. The aim of our study was to analyse our population and to compare the outcomes of patients who obtained bone union with the patients who did not. There were no statistical differences in most of the clinical outcomes (DASH score, visual analogue scale, Kapandji test, grip, and key pinch) between the two groups of patients; there were fewer cases of scaphotrapeziotrapezoid arthritis in the group that did not obtain bone union. We conclude that the bone union is not necessary for a good outcome. Level IV of evidence. PMID- 25524056 TI - Effects of DNA damage in smooth muscle cells in atherosclerosis. AB - RATIONALE: DNA damage and the DNA damage response have been identified in human atherosclerosis, including in vascular smooth muscle cells (VSMCs). However, although double-stranded breaks (DSBs) are hypothesized to promote plaque progression and instability, in part, by promoting cell senescence, apoptosis, and inflammation, the direct effects of DSBs in VSMCs seen in atherogenesis are unknown. OBJECTIVE: To determine the presence and effect of endogenous levels of DSBs in VSMCs on atherosclerosis. METHODS AND RESULTS: Human atherosclerotic plaque VSMCs showed increased expression of multiple DNA damage response proteins in vitro and in vivo, particularly the MRE11/RAD50/NBS1 complex that senses DSB repair. Oxidative stress-induced DSBs were increased in plaque VSMCs, but DSB repair was maintained. To determine the effect of DSBs on atherosclerosis, we generated 2 novel transgenic mice lines expressing NBS1 or C-terminal deleted NBS1 only in VSMCs, and crossed them with apolipoprotein E(-/-) mice. SM22alpha NBS1/apolipoprotein E(-/-) VSMCs showed enhanced DSB repair and decreased growth arrest and apoptosis, whereas SM22alpha-(DeltaC)NBS1/apolipoprotein E(-/-) VSMCs showed reduced DSB repair and increased growth arrest and apoptosis. Accelerating or retarding DSB repair did not affect atherosclerosis extent or composition. However, VSMC DNA damage reduced relative fibrous cap areas, whereas accelerating DSB repair increased cap area and VSMC content. CONCLUSIONS: Human atherosclerotic plaque VSMCs show increased DNA damage, including DSBs and DNA damage response activation. VSMC DNA damage has minimal effects on atherogenesis, but alters plaque phenotype inhibiting fibrous cap areas in advanced lesions. Inhibiting DNA damage in atherosclerosis may be a novel target to promote plaque stability. PMID- 25524057 TI - Effect of the multimodal acting antidepressant vortioxetine on rat hippocampal plasticity and recognition memory. AB - Depression is frequently associated with cognitive disturbances. Vortioxetine is a multimodal acting antidepressant that functions as a 5-HT3 and 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter. Given its pharmacological profile, the present study was undertaken to determine whether vortioxetine could modulate several preclinical parameters known to be involved in cognitive processing. In the dorsal hippocampus of anaesthetized rats, the high-frequency stimulation of the Schaffer collaterals provoked a stable long-term potentiation (LTP) of ~25%. Interestingly, vortioxetine (10mg/kg, i.p.) counteracted the suppressant effect of elevated platform stress on hippocampal LTP induction. In the novel object recognition test, vortioxetine (10mg/kg, i.p.) increased the time spent exploring the novel object during the retention test and this pro-cognitive effect was prevented by the partial 5-HT3 receptor agonist SR57227 (1mg/kg, i.p.). Finally, compared to fluoxetine, sustained administration of vortioxetine (5mg/kg/day, s.c.) induced a rapid increase of cell proliferation in the hippocampal dentate gyrus. In summary, vortioxetine prevented the effect of stress on hippocampal LTP, increased rapidly hippocampal cell proliferation and enhanced short-term episodic memory, via, at least in part, its 5-HT3 receptor antagonism. Taken together, these preclinical data suggest that the antidepressant vortioxetine may have a beneficial effect on human cognitive processes. PMID- 25524058 TI - The assessment of the in vivo to in vitro cellular transition of human umbilical cord multipotent stromal cells. AB - INTRODUCTION: Human umbilical cord stroma is a rich source of primitive multipotent stromal cells (hUC-MSCs). However, the methods for hUC-MSC isolation and propagation remain controversial and vary among laboratories. Our group previously demonstrated that two cell types emerge upon enzymatic isolation of hUC-MSCs, which subsequently undergo a transition towards a fibroblastoid phenotype in later passages. The aim of this study was to further analyse cultured hUC-MSCs by evaluating the cytoskeletal and cell adhesion proteins and by comparing the remodelling of those proteins in umbilical cord sections to determine the cell alterations due to enzymatic and explant methods. METHODS: Tissue sections and cultured cells isolated by enzymatic or explant methods were analysed morphologically and by labelling cytokeratin, vimentin, alpha-smooth muscle actin, E-cadherin and N-cadherin profiles. RESULTS: The present observations confirmed that wide, flat cells (type-1) share myofibroblastic features, appear exclusively in enzymatically isolated early cultures; gradually diminish or are replaced by fibroblastoid cells (type-2) in later passages. In contrast, the explant method does not result in the existence of type-1 cells in vitro. Among the tested CK subtypes, CK18 expression is upregulated, whereas CK19 expression is downregulated upon culturing after both protocols. Vimentin and alpha-SMA, as the major intermediate filaments of hUC-MSCs were found unaltered throughout the culturing period regardless of the cell isolation technique used. DISCUSSION: The data presented confirm and further elucidate the previously observed phenotypic change in hUC-MSCs as illustrated by alterations in structural proteins during enzymatic isolation and subsequent culturing of cells compared with in situ equivalents. PMID- 25524059 TI - Review: Endocrine regulation of placental phenotype. AB - Hormones have an important role in regulating fetal development. They act as environmental signals and integrate tissue growth and differentiation with relation to nutrient availability. While hormones control the developmental fate of resources available to the fetus, the actual supply of nutrients and oxygen to the fetus depends on the placenta. However, much less is known about the role of hormones in regulating placental development, even though the placenta has a wide range of hormone receptors and produces hormones itself from early in gestation. The placenta is, therefore, exposed to hormones by autocrine, paracrine and endocrine mechanisms throughout its lifespan. It is known to adapt its phenotype in response to environmental cues and fetal demand signals, particularly when there is a disparity between the fetal genetic drive for growth and the nutrient supply. These adaptive responses help to maintain fetal growth during adverse conditions and are likely to depend, at least in part, on the hormonal milieu. This review examines the endocrine regulation of placental phenotype with particular emphasis on the glucocorticoid hormones. It focuses on the availability of placental hormone receptors and on the effects of hormones on the morphology, transport capacity and endocrine function of the placenta. PMID- 25524061 TI - First-principles study of point defects at a semicoherent interface. AB - Most of the atomistic modeling of semicoherent metal-metal interfaces has so far been based on the use of semiempirical interatomic potentials. We show that key conclusions drawn from previous studies are in contradiction with more precise ab initio calculations. In particular we find that single point defects do not delocalize, but remain compact near the interfacial plane in Cu-Nb multilayers. We give a simple qualitative explanation for this difference on the basis of the well known limited transferability of empirical potentials. PMID- 25524060 TI - A systematic review of placental pathology in maternal diabetes mellitus. AB - INTRODUCTION: During a pregnancy complicated by diabetes, the human placenta undergoes a number of functional and structural pathologic changes, such as increased placental weight and increased incidence of placental lesions including villous maturational defects and fibrinoid necrosis. The pathologic findings reported have differed among studies, potentially reflecting differences in type of diabetes, study methodology, or glycemic control of study participants. Alternatively, these discrepancies may represent different biologic adaptations to distinct metabolic diseases. METHODS: We conducted a comprehensive review of English language citations in Pubmed and Embase using the keywords "diabetes", "placenta", AND "pathology". Abstracts were reviewed for relevance then full-text articles were reviewed in order to extract a comprehensive summary of current pathological findings associated with pregestational and gestational diabetes mellitus, as well as an understanding of the impact of glycemic control on placental pathology. RESULTS: Placental abnormalities most consistently associated with maternal diabetes are an increased incidence of villous immaturity, increased measures of angiogenesis, and increased placental weight. CONCLUSIONS: The literature suggests that, despite similarities in placental abnormalities, differences in placental pathology may reflect differences in pathophysiology among different types of diabetes. Consequently, standardization of terminology used to define placental lesions is warranted. Moreover, further research is needed to investigate the impact of pathophysiology, glycemic control and clinical factors, such as infant sex, weight and race, on placental structure and function. PMID- 25524062 TI - Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration. AB - The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates various cellular activities, including redox balance, detoxification, metabolism, autophagy, proliferation, and apoptosis. Several studies have demonstrated that Nrf2 regulates hepatocyte proliferation during liver regeneration. The aim of this study was to investigate how Nrf2 modulates the cell cycle of replicating hepatocytes in regenerating livers. Wild-type and Nrf2 null mice were subjected to 2/3 partial hepatectomy (PH) and killed at multiple time points for various analyses. Nrf2 null mice exhibited delayed liver regrowth, although the lost liver mass was eventually restored 7 days after PH. Nrf2 deficiency did not affect the number of hepatocytes entering the cell cycle but did delay hepatocyte mitosis. Mechanistically, the lack of Nrf2 resulted in increased mRNA and protein levels of hepatic cyclin A2 when the remaining hepatocytes were replicating in response to PH. Moreover, Nrf2 deficiency in regenerating livers caused dysregulation of Wee1, Cdc2, and cyclin B1 mRNA and protein expression, leading to decreased Cdc2 activity. Thus, Nrf2 is required for timely M phase entry of replicating hepatocytes by ensuring proper regulation of cyclin A2 and the Wee1/Cdc2/cyclin B1 pathway during liver regeneration. PMID- 25524063 TI - Role of Fn14 in acute alcoholic steatohepatitis in mice. AB - TNF-like weak inducer of apoptosis (TWEAK) is a growth factor for bipotent liver progenitors that express its receptor, fibroblast growth factor-inducible 14 (Fn14), a TNF receptor superfamily member. Accumulation of Fn14(+) progenitors occurs in severe acute alcoholic steatohepatitis (ASH) and correlates with acute mortality. In patients with severe ASH, inhibition of TNF-alpha increases acute mortality. The aim of this study was to determine whether deletion of Fn14 improves the outcome of liver injury in alcohol-consuming mice. Wild-type (WT) and Fn14 knockout (KO) mice were fed control high-fat Lieber deCarli diet or high fat Lieber deCarli diet with 2% alcohol (ETOH) and injected intraperitoneally with CCl4 for 2 wk to induce liver injury. Mice were euthanized 3 or 10 days after CCl4 treatment. Survival was assessed. Liver tissues were analyzed for cell death, inflammation, proliferation, progenitor accumulation, and fibrosis by quantitative RT-PCR, immunoblot, hydroxyproline content, and quantitative immunohistochemistry. During liver injury, Fn14 expression, apoptosis, inflammation, hepatocyte replication, progenitor and myofibroblast accumulation, and fibrosis increased in WT mice fed either diet. Mice fed either diet expressed similar TWEAK/Fn14 levels, but ETOH-fed mice had higher TNF-alpha expression. The ETOH-fed group developed more apoptosis, inflammation, fibrosis, and regenerative responses. Fn14 deletion did not reduce hepatic TNF-alpha expression but improved all injury parameters in mice fed the control diet. In ETOH-fed mice, Fn14 deletion inhibited TNF-alpha induction and increased acute mortality, despite improvement in liver injury. Fn14 mediates wound-healing responses that are necessary to survive acute liver injury during alcohol exposure. PMID- 25524064 TI - K114 (trans, trans)-bromo-2,5-bis(4-hydroxystyryl)benzene is an efficient detector of cationic amyloid fibrils. AB - Cationic amyloid fibrils found in human semen enhance the transmission of the human immunodeficiency virus (HIV) and thus, are named semen-derived enhancer of virus infection (SEVI). The mechanism for the enhancement of transmission is not completely understood but it has been proposed that SEVI neutralizes the repulsion that exists between the negatively charged viral envelope and host cell membrane. Consistent with this view, here we show that the fluorescence of cationic thioflavin T (ThT) in the presence of SEVI is weak, and thus ThT is not an efficient detector of SEVI. On the other hand, K114 ((trans, trans)-bromo-2,5 bis(4-hydroxystyryl)benzene) forms a highly fluorescent, phenolate-like species on the cationic surface of SEVI. This species does not form in the presence of amyloid fibrils from insulin and amyloid-beta protein, both of which are efficiently detected by ThT fluorescence. Together, our results show that K114 is an efficient detector of SEVI. PMID- 25524065 TI - Radiation-induced malignant gliomas: a current review. AB - OBJECTIVE: Radiation-induced malignant gliomas (RIMGs) are known uncommon risks of brain irradiation. We describe 4 cases of RIMG that occurred at our institution and conduct the largest comprehensive review of the literature to characterize RIMGs better. METHODS: Patients were identified through the PubMed database. Pearson R linear correlation test was used to evaluate the correlation between radiotherapy (RT) dose and age and latency period. Student t test was used to evaluate differences between latency periods for original tumor lesions. A normalized biologic equivalent dose analysis was performed to indicate the minimum and maximum radiation threshold for neoplasia. A Kaplan-Meier analysis was used to illustrate the overall survival curves. RESULTS: The analysis included 172 cases from the PubMed database and 4 cases occurring at our institution. The median RT dose administered was 35.6 Gy, with the most common dosage ranges being 21-30 Gy (31%) and 41-50 Gy (21.5%). Median latency period was 9 years until diagnosis of RIMG, and RIMG occurred within 15 years in 82% of the patients. There was no correlation between the age of the patient at the time RT was administered (R(2) = 0.00081) or amount of RT (R(2) = 0.00005) and latency period for RIMG. The mean biologic equivalent dose for neoplasia of a RIMG was 63.3 Gy. The median survival of patients with RIMG improved over time (P = 0.004), with median survival of 9 months before 2007 and 11.5 months after 2007. CONCLUSIONS: The risk of RIMG appears to be the same for all age groups, histologies, and RT dosages. Although the risk is low, patients should be aware of RIMG as a possible complication of brain irradiation. PMID- 25524066 TI - The cognitive and technical skills impact of the Congress of Neurological Surgeons simulation curriculum on neurosurgical trainees at the 2013 Neurological Society of India meeting. AB - OBJECTIVE: To assess the impact of a simulation-based educational curriculum of 4 modules on neurosurgical trainees at the Neurological Societies of India annual meeting, which was held in Mumbai, India, in December 2013. METHODS: We developed a microanastomosis, anterior cervical discectomy and fusion (ACDF), posterior cervical fusion (PCF), and durotomy repair and their corresponding objective assessment scales. Each module was divided into 3 components: 1) a before didactic cognitive knowledge and technical skills testing, 2) a didactic lecture, and 3) an after didactic cognitive knowledge and technical skills testing. We compared the trainees' cognitive and technical scores from the before and after testing phases. Wilcoxon sum rank test was used to test statistical significance. The incorporation of a simulation-based educational program into neurosurgical education curriculum has faced a number of barriers. It is essential to develop and assess the success and feasibility of simulation-based modules on neurosurgical residents. RESULTS: The knowledge test median scores increased from 60%, 69% to 72%, and 60% to 80%, 85%, 90%, and 75% on the microanastomosis, ACDF, PCF, and durotomy modules, respectively (P < 0.05). The practical hands-on scores increased from 45%, 45% to 60%, and 65% to 62%, 68%, 81%, and 70% on the microanastomosis, ACDF, PCF, and durotomy modules, respectively (P < 0.05). CONCLUSIONS: Our course suggests that a simulation-based neurosurgery curriculum has the potential to enhance resident knowledge and technical proficiency. PMID- 25524067 TI - Impact of consanguinity on cardio-metabolic health and other diseases: findings from an Afro-Indian tribal community. AB - Numerous anthropological reports have indicated consanguineous marriage in populous Asian countries, but the overall impact of first cousin marriage on survival and health of specific communities has rarely been reported. The aim of the study was to estimate risks for various complex diseases in the progeny of consanguineous parents. A cross-sectional study was conducted among 222 women among Siddis, a particularly vulnerable tribal group in the state of Gujarat, India, who are Sunni Muslims by faith. The Siddis are not part of the original Negrito element of India. They are descendants of Africans from Northeast and East Africa who were brought to India as slaves, soldiers, or servants. The degree of consanguinity between each female and her spouse and the degree of consanguinity between their parents and proband's grandparents were recorded with the help of pedigrees. The results showed that the rate of consanguinity in the present generation was 49 % (N = 109), higher than preceding generations. A significant association was observed between women's age, educational level, occupational status, consanguineous parents, and consanguinity. Socioeconomic status and consanguinity showed U-shaped associations. Nearly three times odds for cardio-metabolic risks (2.65 odds ratio (OR) for heart diseases, 2.44 OR for diabetes mellitus, and 2.62 OR for hypertension) have been contracted in the progeny of consanguineous marriage in the parental generation. The risk of cardio metabolic diseases is higher in offspring of consanguineous couples, and there is a significant increase in the prevalence of common adult diseases. PMID- 25524068 TI - Functional inhibition of beta-catenin-mediated Wnt signaling by intracellular VHH antibodies. AB - The Wnt signaling pathway is of central importance in embryogenesis, development and adult tissue homeostasis, and dysregulation of this pathway is associated with cancer and other diseases. Despite the developmental and potential therapeutic significance of this pathway, many aspects of Wnt signaling, including the control of the master transcriptional co-activator beta-catenin, remain poorly understood. In order to explore this aspect, a diverse immune llama VHH phagemid library was constructed and panned against beta-catenin. VHH antibody fragments from the library were expressed intracellularly, and a number of antibodies were shown to possess function-modifying intracellular activity in a luciferase-based Wnt signaling HEK293 reporter bioassay. Further characterization of one such VHH (named LL3) confirmed that it bound endogenous beta-catenin, and that it inhibited the Wnt signaling pathway downstream of the destruction complex, while production of a control Ala-substituted complementarity-determining region (CDR)3 mutant demonstrated that the inhibition of beta-catenin activity by the parent intracellular antibody was dependent on the specific CDR sequence of the antibody. PMID- 25524069 TI - Physiological and transcriptional responses to high temperature in Arthrospira (Spirulina) platensis C1. AB - Arthrospira (Spirulina) platensis is a well-known commercial cyanobacterium that is used as a food and in feed supplements. In this study, we examined the physiological changes and whole-genome expression in A. platensis C1 exposed to high temperature. We found that photosynthetic activity was significantly decreased after the temperature was shifted from 35 degrees C to 42 degrees C for 2 h. A reduction in biomass production and protein content, concomitant with the accumulation of carbohydrate content, was observed after prolonged exposure to high temperatures for 24 h. Moreover, the results of the expression profiling in response to high temperature at the designated time points (8 h) revealed two distinct phases of the responses. The first was the immediate response phase, in which the transcript levels of genes involved in different mechanisms, including genes for heat shock proteins; genes involved in signal transduction and carbon and nitrogen metabolism; and genes encoding inorganic ion transporters for magnesium, nitrite and nitrate, were either transiently induced or repressed by the high temperature. In the second phase, the long-term response phase, both the induction and repression of the expression of genes with important roles in translation and photosynthesis were observed. Taken together, the results of our physiological and transcriptional studies suggest that dynamic changes in the transcriptional profiles of these thermal-responsive genes might play a role in maintaining cell homeostasis under high temperatures, as reflected in the growth and biochemical composition, particularly the protein and carbohydrate content, of A. platensis C1. PMID- 25524070 TI - Transcriptomic analysis highlights reciprocal interactions of urea and nitrate for nitrogen acquisition by maize roots. AB - Even though urea and nitrate are the two major nitrogen (N) forms applied as fertilizers in agriculture and occur concomitantly in soils, the reciprocal influence of these two N sources on the mechanisms of their acquisition are poorly understood. Therefore, molecular and physiological aspects of urea and nitrate uptake were investigated in maize (Zea mays), a crop plant consuming high amounts of N. In roots, urea uptake was stimulated by the presence of urea in the external solution, indicating the presence of an inducible transport system. On the other hand, the presence of nitrate depressed the induction of urea uptake and, at the same time, the induction of nitrate uptake was depressed by the presence of urea. The expression of about 60,000 transcripts of maize in roots was monitored by microarray analyses and the transcriptional patterns of those genes involved in nitrogen acquisition were analyzed by real-time reverse transcription-PCR (RT-PCR). In comparison with the treatment without added N, the exposure of maize roots to urea modulated the expression of only very few genes, such as asparagine synthase. On the other hand, the concomitant presence of urea and nitrate enhanced the overexpression of genes involved in nitrate transport (NRT2) and assimilation (nitrate and nitrite reductase, glutamine synthetase 2), and a specific response of 41 transcripts was determined, including glutamine synthetase 1-5, glutamine oxoglutarate aminotransferase, shikimate kinase and arogenate dehydrogenase. Also based on the real-time RT-PCR analysis, the transcriptional modulation induced by both sources might determine an increase in N metabolism promoting a more efficient assimilation of the N that is taken up. PMID- 25524071 TI - Axonal morphological changes following impulse activity in mouse peripheral nerve in vivo: the return pathway for sodium ions. AB - KEY POINTS: Conduction in myelinated axons involves substantial ion movements that must be reversed to restore homeostasis. The pathway taken by sodium ions returning to their original location and the potential osmotic consequences are currently unknown. We report striking morphological changes in axons following sustained impulse conduction that appear to result from osmosis and to indicate accumulation of ions in the periaxonal space followed by their release at the paranode. We conclude that the morphological changes illustrate a hitherto unrecognized part of normal axonal physiology that may also indicate the return pathway for the sodium ions involved in impulse formation. ABSTRACT: Myelinated axons can conduct sustained trains of impulses at high frequency, but this involves substantial ion movements that must be reversed to restore homeostasis. Little attention has been paid to the potential osmotic consequences of the ion movements or to the pathway taken by sodium ions returning to their original endoneurial location, given that the axolemmal Na(+)-K(+)-ATPase extrudes these ions into the periaxonal space beneath the myelin rather than into the endoneurium. Serial confocal imaging of fluorescent axons conducting at sustained physiological frequencies in vivo has revealed surprising morphological changes that may illuminate these problems. Saphenous nerves and spinal roots of anaesthetized transgenic mice expressing axoplasmic yellow fluorescent protein were stimulated electrically or pharmacologically (veratridine). Within 2 h, the axon herniated on one or both sides of the nodal membrane, displacing the paranodal myelin and widening the nodal gap. The herniated axoplasm became directed back towards the internode, forming a 'cap' up to 30 MUm long. Concurrently, the fluid in the expanded periaxonal space accumulated into droplets that appeared to travel to the paranode, where they escaped. No such alterations occurred in axons treated with sodium channel or Na(+)-K(+)-ATPase inhibitors. Remarkably, impulse conduction continued throughout, and all these changes reversed spontaneously over hours or days. The morphological changes were verified ultrastructurally, and occurred in virtually all myelinated axons. The findings appear to reveal an overlooked part of the physiological repertoire of nerve fibres, and here they are interpreted in terms of osmotic changes that may illuminate the pathway by which sodium ions return to the endoneurial space after they have entered the axon during impulse conduction. PMID- 25524073 TI - Burden of celiac disease in Europe: a review of its childhood and adulthood prevalence and incidence as of September 2014. AB - BACKGROUND: Recent epidemiological studies have demonstrated that coeliac disease (CD) prevalence is still underestimated both in Europe and in Mediterranean regions. Here we review the latest data on CD prevalence and incidence in the European Union (EU) as of September 2014. METHODS: The current epidemiological scenario of CD prevalence and incidence was investigated by searching PubMed for papers in English using the following key words: "celiac disease", "celiac disease plus prevalence" (limits: 1990-2014), "incidence" (limits: 1970-2014), and "frequency", plus "in Europe". Another search was performed with the same key words plus the name of each European country. Only prevalence data obtained by serology using anti-gliadin antibodies (AGA), EMA test, tTG test, and/or duodenal biopsy were included. The study designs considered were retrospective and prospective studies: population-based (PB), cross-sectional, case-control and cohort studies. RESULTS: Extensive research based on serological screening has demonstrated that 0.5-1% of the EU population suffers from undiagnosed CD, whereas the highest estimate reported in PB studies is approximately 1%. Considering data from different periods, incidence seems to range from 0.1 to 3.7/1000 live births in the child population and from 1.3 to 39/100,000/year in the adult population. CONCLUSIONS: The present data disclose marked geographical variation in CD incidence and prevalence in different European countries. Here we document rising CD occurrence in recent decades in European countries due partly to the advent of improved serological testing (tTG + EMA) and partly to increased awareness of its clinical presentation. PMID- 25524072 TI - Culture conditions profoundly impact phenotype in BEAS-2B, a human pulmonary epithelial model. AB - BEAS-2B, an immortalized, human lung epithelial cell line, has been used to model pulmonary epithelial function for over 30 years. The BEAS-2B phenotype can be modulated by culture conditions that include the presence or absence of fetal bovine serum (FBS). The popularity of BEAS-2B as a model of arsenic toxicology, and the common use of BEAS-2B cultured both with and without FBS, led us to investigate the impact of FBS on BEAS-2B in the context of arsenic toxicology. Comparison of genome-wide gene expression in BEAS-2B cultured with or without FBS revealed altered expression in several biological pathways, including those related to carcinogenesis and energy metabolism. Real-time measurements of oxygen consumption and glycolysis in BEAS-2B demonstrated that FBS culture conditions were associated with a 1.4-fold increase in total glycolytic capacity, a 1.9-fold increase in basal respiration, a 2.0-fold increase in oxygen consumed for ATP production and a 2.8-fold increase in maximal respiration, compared with BEAS-2B cultured without FBS. Comparisons of the transcriptome changes in BEAS-2B resulting from FBS exposure to the transcriptome changes resulting from exposure to 1 MUM sodium arsenite revealed that mRNA levels of 43% of the arsenite modulated genes were also modulated by FBS. Cytotoxicity studies revealed that BEAS-2B cells exposed to 5% FBS for 8 weeks were almost 5 times more sensitive to arsenite cytotoxicity than non-FBS-exposed BEAS-2B cells. Phenotype changes induced in BEAS-2B by FBS suggest that culture conditions should be carefully considered when using BEAS-2B as an experimental model of arsenic toxicity. PMID- 25524074 TI - Comparison of self-reported and observed prevalence of safety belt and helmet use in Florence. AB - METHODS: Safety belt and helmet use was estimated from PASSI data and measured through Ulisse observations. Between 2008 and 2012 a total of 2,081 cars and motorcycle users were interviewed in the LHU of Florence and a total of 59,787 drivers (11,870 front passengers, 1,129 rear passengers and 16,816 motorcyclists) were observed. The comparison between self-reported and observed prevalences was performed by calculating the over-reporting factor (ORF), defined as the ratio of the self-reported to the observed prevalence of seat belt or helmet use. The time trend of the prevalence (both from self-reported and observed data) and of the ORF was assessed by using linear regression and Poisson's regression, respectively. RESULTS: The correlation between self-reported and observed prevalence is high, with a Pearson's correlation coefficient of 0.95 (p <0.05). Regarding front seat belt use rates, the difference between self-reported and observed data increases over time and the ORF range varies from 1.12 to 1.32. Rear seat belt data show a great variability, and the ORF varies from 0.67 to 1.37. In 2011 and 2012, the observed prevalence was higher than the self-reported one (ORF <1). Helmet use rates are very high, close to 100% with both methods; ORF has very small oscillations and ranges from 0.98 to 1, showing a good correlation between self-reported and observational data. There are no significant temporal variations both for the prevalences of use and for the ORF. CONCLUSIONS: The reasonable accuracy of self-reported data makes this method fit in the routinary assessment of safety belts and helmet usage, in order to limit the observations of the Ulisse system at predetermined time intervals. However, self-reported estimates need to be adjusted using an appropriate over-reporting factor. PMID- 25524075 TI - Antibiotic prescriptions in the paediatric population in the Lazio Region of Italy: association with children's and physician's characteristics. AB - BACKGROUND: Estimating prevalence rates for antibacterial use in 0-14 year old children in 2009 in Lazio (Italy). METHODS: Antibiotic prescriptions has been selected as drugs belonging to the J01 main therapeutic of the Anatomical Therapeutic Chemical system. Prevalence data by sex and age were calculated. The proportion of children who underwent 1, 2 or >= 3 treatments was calculated. Relation between use of antibiotics and incidence of influenza cases was evaluated. The association of children's and physician's characteristics with prescription was assessed by multi-level Poisson regression model. RESULTS: 45% of children received one antibiotic with a peak in the 1-2 age. Penicillins combinations and beta-lactamase inhibitors were the most frequently prescribed group. Multilevel model highlighted prescription rate decreases with doctor's increasing age, if the doctor is a paediatrician and female. Contrarily, doctors with >900 patients present higher probability to prescribe antibiotics. CONCLUSIONS AND DISCUSSION: The study highlights the variability in antibiotic use and the fact that several children's and primary care doctors' characteristics are associated with antibiotic prescription. Paper findings appear to be coherent with other Italian studies but prevalence rate is definitively higher comparing to other countries. PMID- 25524076 TI - Study of socio-economic characteristics, diagnosis and outcome of women participating or not participating in mammogram screening. AB - BACKGROUND: Breast cancer is the most common cancer and the leading cause of cancer death in women. Early detection is essential to reduce cancer mortality. Studying participation in an organised breast cancer screening program is important in order to evaluate the program effectiveness. Breast screening both enables minimally invasive breast surgery and reduces cause-specific mortality. METHODS: The main objective of this study was to evaluate, through the use of a questionnaire, the influence of socio-economic characteristics (age, education, occupational status, participation in other screening programs etc.) on participation in a mammography screening program organized by the local health units (LHU) of Novara and Verbano-Cusio-Ossola, located in the Italian region of Piedmont. A sample of 500 women was identified. Eligible participants included women aged 50-69 years, resident in the area of the LHUs of Novara and Verbano Cusio-Ossola who had been invited to participate in the screening program 2006 2007. Twenty six women were excluded, leaving 474 women in the final analysis: 23 women were unable to be contacted due to incorrect contact details and 3 women were unable to complete the questionnaire due to neurodegenerative diseases. A postal questionnaire was sent by post during 2008-2009. Two postal reminders were sent to non-responders, followed by a phone call. One group of women received an additional copy of the questionnaire with the first postal reminder and another group received only the reminder letter. The socio-personal profiles and their influence in women's participation in the screening program were evaluated. RESULTS: Among the responders, 93% of the women (348/374) received a mammogram at least once following LHU invitation for check-up. 74.1% of women got a mammogram at least once using the organized screening program, an additional 17.8% got a mammogram in a private clinic, and the type of prevention was unknown for 8.1% of the women. 25.3% began having mammogram for prevention before the age of 45. CONCLUSIONS: A screening program is a sanitary intervention of secondary prevention and the identification of the attitude towards this kind of prevention is quite complex. Some causes of non-participation in this screening program were the belief that mammogram is not necessary, fear of pain, and presence of family problems. This study obtained a higher response than expected and the data also allowed an assessment of the degree of participation of women in the prevention services, identifying that most of them carried out a mammogram using an organized screening program. PMID- 25524077 TI - Clinical risk in rehabilitation: an exploratory investigation in Campania region. AB - BACKGROUND: Clinical risk management is a comprehensive programme that encompasses all the measures implemented to improve the quality of the healthcare service and ensure patient safety, which is based on learning through error. This process is intended to bring about ongoing improvements in clinical practice, starting with risk identification, before moving on to risk assessment and analysis, in order to reduce risks where possible. When clinical risk management is applied in rehabilitation, the first step involves identifying errors by assessing adverse events, which are considered to indicate the existing risk. Our work aims to explore the characteristics of the clinical risk in rehabilitation so as to learn more about its extent, its components, and its implications for the user. METHODS: Our study involved numerous workers operating in four different branches of rehabilitation - speech therapy, physiotherapy, psychomotor education and occupational therapy - at forty-nine private rehabilitation centres in the province of Naples, an area that has not been studied before. A questionnaire was drafted regarding the main errors committed in the rehabilitation sector. It was then distributed and collected in again, after which the results were analysed and outcomes measured. Out of a total of 556 questionnaires distributed, 493 were returned (88.6% response rate.). RESULTS: The study revealed that for all the rehabilitation branches considered, the macro category of errors linked to technical and professional aspects accounted for the highest percentage of the total errors (39%). In this study, the most frequent errors linked to technical and professional aspects were: wrong dose errors, treatment planning errors and functional assessment errors. CONCLUSIONS: There is an evident need to take action in order to manage the clinical risk in rehabilitation: to promote a concept of errors as opportunities for learning and improvement; to maintain the focus on both individual responsibility and on any systemic failings; to share fundamental values such as transparency, collaboration between workers, communication with patients, and a commitment to ongoing improvements in healthcare quality. PMID- 25524078 TI - Occupational exposure to urban stressors and effects on atrial natriuretic peptide: preliminary results. AB - PURPOSE: The aim of this pilot study is to evaluate whether occupational exposure to low doses of pollutants present in the air of the city selected for the study could cause alterations in the concentration of atrial natriuretic peptide (ANP) in workers from the Municipal Police with outdoor tasks, compared to those with indoor tasks. METHODS: A total of 208 non-smoking male and female subjects were enrolled and divided on the basis of whether their tasks were mainly outdoors or indoors. The dosage of plasma ANP was carried out on all workers included in the study. Differences between means and frequencies were compared using student's t test for unpaired data and chi-square test with Yates' correction, and they were considered significant when the p value was <0.05. RESULTS: Even after the subdivision of the total sample on the basis of sex, mean plasma levels of ANP were higher but not statistically significant in traffic police compared with controls. CONCLUSIONS: The preliminary results suggest that further studies should be conducted before the influence of urban pollution on ANP could be confirmed or rejected. PMID- 25524079 TI - Health-related quality of life in Kazakh heart failure patients evaluated by the Minnesota living with heart failure questionnaire and comparison with a published large international sample. AB - BACKGROUND: To assess health-related quality of life (HRQL) in Kazakh patients (n=285) treated in Cardiology Department of the Emergency Hospital of Semey during 2012 with acute myocardial infarction and to compare results with HRQL measured in 21 countries (n=3,847). METHODS: Telephone interviews survey was conducted in February 2014 with the Russian translation of Minnesota Living with Heart Failure Questionnaire (MLHFQ). Descriptive statistics were used to characterize the sample according to each single item of MLHFQ and grouping them in three subset concerning physical, emotional, and social environment dimensions of patients' life. The distribution of scores was evaluated in terms of floor and ceiling effects; Cronbach's alpha coefficient was calculated for the different dimensions to assess internal consistency. RESULTS: Mean age of sample is 60.8 years, most of patients are male (71.6%) and retired (43.5%). The total MLHFQ score was generally low at a moderate degree (mean 34.7, range 0-105). Physical dimension score (mean 14.92) shows mild to moderate impairment in HRQL and a better perception than the average of the control countries (14.9 vs 16.6); emotional status (mean 4.8) is moderately adequate and better than the controls (4.8 vs 7.2); social environment (9.82) showed significant impairment of HRQL and a worse evaluation (9.82 vs 7.8). CONCLUSIONS: Kazakh patients reported better emotional and physical HRQL as consequence of the social structure where family environment promotes emotional support and improves self-care, social environment affects the total MLHFQ score that is low and related to the requested availability of free medicines. PMID- 25524080 TI - [Exceptions to hygienic requirements of dwellings in building restoration and indemnity for abuses in Italy]. AB - Building restoration represents a fundamental tool to combine the population needs for housing with soil saving. Old buildings offer great possibilities, if we consider that 20% of residential buildings in Italy have been constructed before the beginning of XX century. In order to understand the public health impact of exemptions from hygienic requirements of dwellings, as well as indemnity for abuses, the authors analyse the national legislation on this topic. There is a strong need to update health standards and to rationalize and simplify the regulations, as a fundamental tool for the protection of public health in indoor environment. PMID- 25524081 TI - Stakeholders in nursing education: their role and involvement. AB - INTRODUCTION: In literature, there is evidence that all stakeholders need to be involved in the curricula building process to make sure that health professionals are "educated" to meet the stakeholders' "demands". In Italy, the involvement of stakeholders in the definition of university curricula is ratified by various regulations. AIMS: To describe the major experiences of stakeholder involvement in nursing education, identify the main stakeholders for nursing education, and the processes in which they are involved. METHODS: The search strategy included an electronic exploration of the relevant databases. The search terms were: Stakeholders, Curriculum, Nursing Education combined with Boolean operators. The references of the retrieved articles were hand searched for additional related studies. RESULTS: Most of the studies identified were from the United Kingdom, Australia, and the USA. In Italy, no relevant studies were found. The most frequently identified stakeholders were: students, clinicians, educators, nurse managers. They were mainly involved during profound changes in the curricula and the implementation of new educational approaches. DISCUSSION AND CONCLUSIONS: Stakeholders are mostly involved in countries with a private funding system for universities. Such funding systems have probably developed in the academia a greater propensity to involve stakeholders, to provide recognition of success when starting new programs, and are perceived more as marketing research. This seems contrary to the spirit of the Italian and European regulatory interventions, which instead, provide a structured commitment to consolidating and expanding the collaboration among universities, users, and the world of labor. This latter collaboration should facilitate internship activities, lifelong learning, and employability of the newly-graduated professionals. PMID- 25524082 TI - The students' reasons to choose a nursing degree program: an Italian exploratory study. AB - BACKGROUND: From the international literature very interesting cues emerge about students' motivations to choose a Nursing Degree Program. Unfortunately, this phenomenon is largely unexplored in Italy. An observational study was conducted at the University of Pavia, with the aim to investigate the reasons underpinning the students' choice to enter a Nursing Degree Program. METHODS: A semi structured, self-administrated questionnaire was used for this single-center cross-sectional study. The questionnaire was aimed to investigate the reasons underpinning the students' choice to enter a Nursing Degree Program, using both open-ended and close-ended multiple choice questions. Descriptive statistics have been used to describe collected data. Open-ended response analysis was conducted through an exploratory and qualitative analysis of language. RESULTS: Response rate was 71% (196/275). Our study results highlighted a variety of reasons that encourage students to begin a Nursing Degree Program: the feeling of usefulness (80%), the desire to help and to care people (78%), the interest in the sciences (71%), the compassion to the suffering people (66%). We also identified 4 categories that describe which characteristics a nurse should have according to the students' point of view: expertise; personal characteristics; to experience the professional life as a social function and to have interest in the health field. CONCLUSIONS: Students' answers indicate that often the choice to enter a Nursing Degree Program is not supported by clear ideas and strong motivations. We consider it crucial to provide a realistic image of the nursing role and opportunities for career development, so that students can have the right elements to make a conscious choice. There is a need for more qualitative research to explore the reasons why students choose the Nursing Degree Program; moreover, to identify, from the beginning of the course, those students who are in crisis of motivation, in order to adopt support strategies that could enable them to successfully achieve academic career. PMID- 25524083 TI - Serum gastrin-releasing peptide levels correlate with disease severity and pruritus in patients with atopic dermatitis. PMID- 25524084 TI - Treatment of glaucoma with high intensity focused ultrasound. AB - Glaucoma is a common disease mainly due to an increase in pressure inside the eye, leading to a progressive destruction of the optic nerve, potentially to blindness. Intraocular pressure (IOP) is the result of a balance between production of liquid that fills the eye--aqueous humour--and its resorption. All treatments for glaucoma aim to reduce IOP and can therefore have two mechanisms of action: reducing aqueous humour production by the partial destruction or medical inhibition of the ciliary body--the anatomical structure responsible for production of aqueous humour--or facilitating the evacuation of aqueous humour from the eye. Several physical methods can be used to destroy the ciliary body, e.g. laser, cryotherapy, microwave. All these methods have two major drawbacks: they are non-selective for the organ to be treated and they have an unpredictable dose-effect relationship. High intensity focused ultrasound (HIFU) can be used to coagulate the ciliary body and avoid these drawbacks. A commercially available device was marketed in the 1980s, but later abandoned, essentially for technical reasons. A smaller circular device using miniaturised transducers was recently developed and proposed for clinical practice. Experimental studies have shown selective coagulation necrosis of the treated ciliary body. The first three clinical trials in humans have shown that this device was well tolerated and allowed a significant, predictable and sustained reduction of IOP. The aim of this contribution is to present a summary of the work concerning the use of HIFU to treat glaucoma. PMID- 25524086 TI - Photoinduced electron transfer reactions of ruthenium(II) phenanthroline complexes with dimethylaniline in aqueous and micellar media. AB - Four [Ru(NN)(3)](2+) complexes (NN = polypyridine) with ligands of varying hydrophobicity with different charges +2, 0 and -4 were synthesized. The photophysics and photoinduced electron transfer reactions of these Ru(II) complexes with dimethylaniline (DMA) as the quencher have been studied in aqueous medium and ionic and non-ionic micellar medium. The extent of binding of the complexes with the surfactant interface is evident from the calculated binding constant values (K). Dimethylaniline (DMA) being a neutral quencher, the hydrophobic and electrostatic interactions competing with one another and their combined effect with the surfactants were reported by observing the quenching rate constant (k(q)) values. The formation of anilinium cation radical in transient absorption spectrum confirms the excited state electron transfer reactions of ruthenium(II) complexes with dimethylaniline. The calculated rate constant values (k(q)) are in good agreement with the experimental k(q) values giving quantitative evidence for the bimolecular reductive quenching rate constant for the complexes with DMA. Pseudophase ion exchange model is successfully applied to analyse the quenching data. PMID- 25524085 TI - The longitudinal course of sleep timing and circadian preferences in adults with bipolar disorder. AB - OBJECTIVES: To study the longitudinal course of sleep timing and circadian preferences in individuals with bipolar disorder (BP) compared to individuals with non-BP psychopathology and healthy controls. METHODS: Individuals with bipolar I and bipolar II disorder (n = 257), non-BP psychopathology (n = 105), and healthy controls (n = 55) (mean age 40.2 years, 21.3% male, 85.1% Caucasian) were followed on average every 27 months for a mean of four years. Sleep timing parameters and circadian preference were reported using the Sleep Timing Questionnaire and The Composite Scale for Morningness. Group comparisons were adjusted for multiple comparisons and between-group differences in demographic variables and psychopharmacological treatment. RESULTS: Regardless of their current mood state, individuals with BP showed more sleep onset latency (SOL), wakening after sleep onset (WASO), and evening preference in comparison to both individuals with non-BP psychopathology and healthy controls. Individuals with BP also showed less stability of bed and awakening times in comparison to the other two groups, though these results were dependent on mood state. Non-BP individuals only showed more WASO and less stability in bed and awakening times before work/school days than healthy controls. Adjusting for comorbid disorders yielded similar results. Within-group analyses found little to no effect of time and BP subtype on sleep timing and circadian preference. CONCLUSIONS: Disturbances of sleep timing are prominent in individuals with BP. These disturbances are worse during mood episodes, but still apparent during euthymic periods. Evening preference was not associated with polarity type, or mood state in BP, suggesting that this characteristic may be a trait marker. PMID- 25524087 TI - Pharmacogenomics of interferon-beta in multiple sclerosis: what has been accomplished and how can we ensure future progress? AB - Multiple sclerosis (MS) is a progressive disorder of the central nervous system, often resulting in significant disability in early adulthood. The field of pharmacogenomics holds promise in distinguishing responders from non-responders to drug treatment. Most studies on genetic polymorphisms in MS have addressed treatment with interferon-beta, yet few findings have been replicated. This review outlines the barriers that currently hinder the validity, reproducibility, and inter-study comparison of pharmacogenomics research as it relates to the use of interferon-beta. Notably, statistical power, varying definitions of responder status, varying assay and genotyping methodologies, and anti-interferon-beta neutralizing antibodies significantly confound existing data. Future work should focus on addressing these factors in order to optimize interferon-beta treatment outcomes in MS. PMID- 25524088 TI - Mildly pruritic violaceous papules on the dorsum of the left hand. PMID- 25524089 TI - Stable pi-extended p-quinodimethanes: synthesis and tunable ground states. AB - p-Quinodimethane (p-QDM) is a highly reactive hydrocarbon showing large biradical character in the ground state. It has been demonstrated that incorporation of the p-QDM moiety into an aromatic hydrocarbon framework could lead to new pi conjugated systems with significant biradical character and unique optical, electronic and magnetic properties. On the other hand, the extension of p-QDM is expected to result in molecules with even larger biradical character and higher reactivity. Therefore, the synthesis of stable pi-extended p-QDMs is very challenging. In this Personal Account we will briefly discuss different stabilizing strategies and synthetic methods towards stable pi-extended p-QDMs with tunable ground states and physical properties, including two types of polycyclic hydrocarbons: (1) tetrabenzo-Tschitschibabin's hydrocarbons, and (2) tetracyano-rylenequinodimethanes. We will discuss how the aromaticity, substituents and steric hindrance play important roles in determining their ground states and properties. PMID- 25524093 TI - The rise of mammals. AB - Mammalian synthetic biology represents a vibrant and growing technical discipline. As this nascent field matures, technologies for engineering sophisticated mammalian cell functions are enabling the development of novel therapies that address unmet medical needs. These transformative capabilities are likely to impact clinical practice in ways that have yet to be identified. PMID- 25524091 TI - Synthetic biology of multicellular systems: new platforms and applications for animal cells and organisms. PMID- 25524094 TI - Book review of synthetic biology: a lab manual. PMID- 25524095 TI - Natural LacI from E. coli yields faster response and higher level of expression than the LVA-tagged LacI. AB - The lac promoter is one of the most commonly used promoters for expression control of recombinant genes in E. coli. In the absence of galactosides, the lac promoter is repressed by its repressor protein LacI. Since the lac promoter is regulated by a repressor, overexpression of LacI is necessary for regulation when the promoter is introduced on a high-copy plasmid. For that purpose, a modified variant of LacI, a LVA-tagged LacI, was submitted to the Registry of Standard Biological Parts and has been used for more than 500 constructs since then. We have found, however, that natural LacI is superior to the LVA-tagged LacI as controller of expression. PMID- 25524096 TI - A multiplexed transcription activator-like effector system for detecting specific DNA sequences. AB - Transcription activator-like effectors (TALEs), originating from the Xanthomonas genus of bacteria, bind to specific DNA sequences based on amino acid sequence in the repeat-variable diresidue (RVD) positions of the protein. By altering these RVDs, it has been shown that a TALE protein can be engineered to bind virtually any DNA sequence of interest. The possibility of multiplexing TALEs for the purposes of identifying specific DNA sequences has yet to be explored. Here, we demonstrate a system in which a TALE protein bound to a nitrocellulose strip has been utilized to capture purified DNA, which is then detected using the binding of a second distinct TALE protein conjugated to a protein tag that is then detected by a dot blot. This system provides a signal only when both TALEs bind to their respective sequences, further demonstrating the specificity of the TALE binding. PMID- 25524097 TI - One primer to rule them all: universal primer that adds BBa_B0034 ribosomal binding site to any coding standard 10 BioBrick. AB - Here, we present a universal, simple, efficient, and reliable way to add small BioBrick parts to any BioBrick via PCR that is compatible with BioBrick assembly standard 10. As a proof of principle, we have designed a universal primer, rbs_B0034, that contains a ribosomal binding site (RBS; BBa_B0034) and that can be used in PCR to amplify any coding BioBrick that starts with ATG. We performed test PCRs with rbs_B0034 on 31 different targets and found it to be 93.6% efficient. Moreover, when supplemented with a complementary primer, addition of RBS can be accomplished via whole plasmid site-directed mutagenesis, thus reducing the time required for further assembly of composite parts. The described method brings simplicity to the addition of small parts, such as regulatory elements to existing BioBricks. The final product of the PCR assembly is indistinguishable from the standard or 3A BioBrick assembly. PMID- 25524098 TI - Standardization of functional reporter and antibiotic resistance cassettes to facilitate the genetic engineering of filamentous fungi. AB - The unique physiological properties of fungi are useful for a myriad of applications, which could greatly benefit from increased control of native pathways and introduction of recombinant genes. However, fungal genetic engineering is still limited in scope and accessibility, largely due to lack of standardization. To help standardize the genetic engineering of filamentous fungi, we created BioBricks of commonly used antibiotic resistance genes, neomycin phosphotransferase (nptII) and hygromycin phosphotransferase (hph), which confer resistance to G418 (Geneticin) and hygromycin B, respectively. Additionally, we created a BioBrick of the constitutive trpC promoter, from the tryptophan biosynthesis pathway of Aspergillus nidulans, and used it to create a composite part including the GFP gene. The functionality of these parts was demonstrated in the model fungal organism Cochliobolus heterostrophus, and as these tools are in modular BioBrick format, they can be easily used to facilitate genetic engineering of other fungal species. PMID- 25524099 TI - Detection of thrombin with an aptamer-based macromolecule biosensor using bacterial ghost system. AB - A rapid on-site detection of exogenous proteins without the need for equipped laboratories or skilled personnel would benefit many areas. We built a rapid protein detection platform based on aptamer-induced inner-membrane scaffolds dimerization by virtue of bacterial ghost system. When the detection platform was coincubated with two kinds of aptamers targeting two different sites of thrombin, green fluorescence or beta-lactamase activity were yielded with two different designs. The latter was detected by commercially available testing strips. PMID- 25524100 TI - Owl: electronic datasheet generator. AB - Owl ( www.owlcad.org ) is a biodesign automation tool that generates electronic datasheets for synthetic biological parts using common formatting. Data can be retrieved automatically from existing repositories and modified in the Owl user interface (UI). Owl uses the data to generate an HTML page with standard typesetting that can be saved as a PDF file. Here we present the Owl software tool in its alpha version, its current UI, its description of input data for generating a datasheet, its example datasheets, and the vision of the tool's role in biodesign automation. PMID- 25524101 TI - Engineered calcium-precipitable restriction enzyme. AB - We have developed a simple system for tagging and purifying proteins. Recent experiments have demonstrated that RTX (Repeat in Toxin) motifs from the adenylate cyclase toxin gene (CyaA) of B. pertussis undergo a conformational change upon binding calcium, resulting in precipitation of fused proteins and making this method a viable alternative for bioseparation. We have designed an iGEM Biobrick comprised of an RTX tag that can be easily fused to any protein of interest. In this paper, we detail the process of creating an RTX tagged version of the restriction enzyme EcoRI and describe a method for expression and purification of the functional enzyme. PMID- 25524102 TI - Solving a four-destination traveling salesman problem using Escherichia coli cells as biocomputers. AB - The Traveling Salesman Problem involves finding the shortest possible route visiting all destinations on a map only once before returning to the point of origin. The present study demonstrates a strategy for solving Traveling Salesman Problems using modified E. coli cells as processors for massively parallel computing. Sequential, combinatorial DNA assembly was used to generate routes, in the form of plasmids made up of marker genes, each representing a path between destinations, and short connecting linkers, each representing a given destination. Upon growth of the population of modified E. coli, phenotypic selection was used to eliminate invalid routes, and statistical analysis was performed to successfully identify the optimal solution. The strategy was successfully employed to solve a four-destination test problem. PMID- 25524103 TI - Fusion of pyruvate decarboxylase and alcohol dehydrogenase increases ethanol production in Escherichia coli. AB - Ethanol is an important biofuel. Heterologous expression of Zymomonas mobilis pyruvate decarboxylase (Pdc) and alcohol dehydrogenase (AdhB) increases ethanol production in Escherichia coli. A fusion of PDC and ADH was generated and expressed in E. coli. The fusion enzyme was demonstrated to possess both activities. AdhB activity was significantly lower when fused to PDC than when the two enzymes were expressed separately. However, cells expressing the fusion protein generated ethanol more rapidly and to higher levels than cells coexpressing Pdc and AdhB, suggesting a specific rate enhancement due to the fusion of the two enzymes. PMID- 25524104 TI - Quantitatively relating gene expression to light intensity via the serial connection of blue light sensor and CRISPRi. AB - The ability to regulate endogenous gene expression is critical in biological research. Existing technologies, such as RNA interference, zinc-finger regulators, transcription-activator-like effectors, and CRISPR-mediated regulation, though proved to be competent in significantly altering expression levels, do not provide a quantitative adjustment of regulation effect. As a solution to this problem, we place CRISPR-mediated interference under the control of blue light: while dCas9 protein is constitutively expressed, guide RNA transcription is regulated by YF1-FixJ-PFixK2, a blue light responding system. With a computer-controlled luminous device, the quantitative relationship between target gene expression and light intensity has been determined. As the light intensifies, the expression level of target gene gradually ascends. This remarkable property enables sensor-CRISPRi to accurately interrogate cellular activities. PMID- 25524105 TI - Designing safety policies to meet evolving needs: iGEM as a testbed for proactive and adaptive risk management. AB - iGEM has spent the past decade encouraging teams to push their projects to the frontiers of synthetic biology. However, as project complexity increases, so too does the level of assumed risk. In the absence of a coherent international framework for evaluating these risks in synthetic biology, iGEM has recently engaged with the MIT Program on Emerging Technologies to develop a progressive approach for handling questions of safety and security. These two groups have worked together to create a rigorous screening program, acknowledging that a strengthened set of iGEM safety policies ultimately serves to expand, not contract, the universe of acceptable projects. This paper reports on the policy process evolution thus far, screening findings from the 2013 competition, and expectations for future policy evolution. PMID- 25524106 TI - Modularized CRISPR/dCas9 effector toolkit for target-specific gene regulation. AB - The ability to control mammalian genes in a synergistic mode using synthetic transcription factors is highly desirable in fields of tissue engineering, stem cell reprogramming and fundamental research. In this study, we developed a standardized toolkit utilizing an engineered CRISPR/Cas9 system that enables customizable gene regulation in mammalian cells. The RNA-guided dCas9 protein was implemented as a programmable transcriptional activator or repressor device, including targeting of endogenous loci. For facile assembly of single or multiple CRISPR RNAs, our toolkit comprises a modular RNAimer plasmid, which encodes the required noncoding RNA components. PMID- 25524107 TI - Design and characterization of a modular membrane protein anchor to functionalize the moss Physcomitrella patens with extracellular catalytic and/or binding activities. AB - Heterologous enzymes and binding proteins were secreted by the moss Physcomitrella patens or anchored extracellularly on its cell membrane in order to functionalize the apoplast as a biochemical reaction compartment. This modular membrane anchoring system utilizes the signal peptide and the transmembrane segment of the somatic embryogenesis receptor-like kinase (SERK), which were identified in a comprehensive bioinformatic analysis of the P. patens genome. By fusing the soluble enzyme NanoLuc luciferase to the signal peptide, its secretion capability was confirmed in vivo. The membrane localization of hybrid proteins comprising the SERK signal peptide, NanoLuc or other functional modules, the SERK transmembrane anchor, and a C-terminal GFP reporter was demonstrated using fluorescence microscopy as well as site-specific proteolytic release of the extracellular enzyme domain. Our membrane anchoring system enables the expression of various functional proteins in the apoplast of P. patens, empowering this photoautotrophic organism for biotechnological applications. PMID- 25524108 TI - Toolkit for visualization of the cellular structure and organelles in Aspergillus niger. AB - Aspergillus niger is a filamentous fungus that is extensively used in industrial fermentations for protein expression and the production of organic acids. Inherent biosynthetic capabilities, such as the capacity to secrete these biomolecules in high amounts, make A. niger an attractive production host. Although A. niger is renowned for this ability, the knowledge of the molecular components that underlie its production capacity, intercellular trafficking processes and secretion mechanisms is far from complete. Here, we introduce a standardized set of tools, consisting of an N-terminal GFP-actin fusion and codon optimized eforRed chromoprotein. Expression of the GFP-actin construct facilitates visualization of the actin filaments of the cytoskeleton, whereas expression of the chromoprotein construct results in a clearly distinguishable red phenotype. These experimentally validated constructs constitute the first set of standardized A. niger biomarkers, which can be used to study morphology, intercellular trafficking, and secretion phenomena. PMID- 25524109 TI - Bacillus subtilis biosensor engineered to assess meat spoilage. AB - Here, we developed a cell-based biosensor that can assess meat freshness using the Gram-positive model bacterium Bacillus subtilis as a chassis. Using transcriptome analysis, we identified promoters that are specifically activated by volatiles released from spoiled meat. The most strongly activated promoter was PsboA, which drives expression of the genes required for the bacteriocin subtilosin. Next, we created a novel BioBrick compatible integration plasmid for B. subtilis and cloned PsboA as a BioBrick in front of the gene encoding the chromoprotein amilGFP inside this vector. We show that the newly identified promoter could efficiently drive fluorescent protein production in B. subtilis in response to spoiled meat and thus can be used as a biosensor to detect meat spoilage. PMID- 25524110 TI - Silencing of antibiotic resistance in E. coli with engineered phage bearing small regulatory RNAs. AB - In response to emergent antibiotic resistance, new strategies are needed to enhance the effectiveness of existing antibiotics. Here, we describe a phagemid delivered, RNA-mediated system capable of directly knocking down antibiotic resistance phenotypes. Small regulatory RNAs (sRNAs) were designed to specifically inhibit translation of chloramphenicol acetyltransferase and kanamycin phosphotransferase. Nonlytic phagemids coding for sRNA expression were able to infect and restore chloramphenicol and kanamycin sensitivity to populations of otherwise resistant E. coli. This modular system could easily be extended to other bacteria with resistance profiles that depend on specific transcripts. PMID- 25524111 TI - Multistage regulator based on tandem promoters and CRISPR/Cas. AB - Accurately controlling expression of target genes between several designed levels is essential for low-noise gene network and dynamic range of gene expression. However, such manipulations have been hard to achieve due to technical limitations. Based on tandem promoters and CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR-associated) system, we constructed a multistage regulator that could stably regulate the expression of the reporter gene on three levels, with more than 2-fold difference between each of them. Our findings provide novel insights into constructing a more powerful gene regulation system. PMID- 25524113 TI - Sensory neurons: the sense in reprogramming. PMID- 25524112 TI - Design, construction, and characterization of a set of biosensors for aromatic compounds. AB - Aromatic pollutants in the environments pose significant threat to human health due to their persistence and toxicity. Here, we report the design and comprehensive characterization of a set of aromatic biosensors constructed using green fluorescence protein as the reporter and aromatics-responsive transcriptional regulators, namely, NahR, XylS, HbpR, and DmpR, as the detectors. The genetic connections between the detectors and the reporter were carefully adjusted to achieve fold inductions far exceeding those reported in previous studies. For each biosensor, the functional characteristics including the dose responses, dynamic range, and the detection spectrum of aromatic species were thoroughly measured. In particular, the interferences that nontypical inducers exert on each biosensor's response to its strongest inducer were evaluated. These well-characterized biosensors might serve as potent tools for environmental monitoring as well as quantitative gene regulation. PMID- 25524118 TI - Visual processing: taking an in-depth look at motion. PMID- 25524119 TI - The mechanisms and functions of spontaneous neurotransmitter release. AB - Fast synaptic communication in the brain requires synchronous vesicle fusion that is evoked by action potential-induced Ca(2+) influx. However, synaptic terminals also release neurotransmitters by spontaneous vesicle fusion, which is independent of presynaptic action potentials. A functional role for spontaneous neurotransmitter release events in the regulation of synaptic plasticity and homeostasis, as well as the regulation of certain behaviours, has been reported. In addition, there is evidence that the presynaptic mechanisms underlying spontaneous release of neurotransmitters and their postsynaptic targets are segregated from those of evoked neurotransmission. These findings challenge current assumptions about neuronal signalling and neurotransmission, as they indicate that spontaneous neurotransmission has an autonomous role in interneuronal communication that is distinct from that of evoked release. PMID- 25524122 TI - A case of allergic contact dermatitis caused by propolis-enriched honey. PMID- 25524123 TI - Allergic contact dermatitis caused by an antiseptic containing cetrimide. PMID- 25524124 TI - Occupational systemic allergic dermatitis caused by sevoflurane. PMID- 25524120 TI - Endocannabinoid signalling and the deteriorating brain. AB - Ageing is characterized by the progressive impairment of physiological functions and increased risk of developing debilitating disorders, including chronic inflammation and neurodegenerative diseases. These disorders have common molecular mechanisms that can be targeted therapeutically. In the wake of the approval of the first cannabinoid-based drug for the symptomatic treatment of multiple sclerosis, we examine how endocannabinoid (eCB) signalling controls--and is affected by--normal ageing and neuroinflammatory and neurodegenerative disorders. We propose a conceptual framework linking eCB signalling to the control of the cellular and molecular hallmarks of these processes, and categorize the key components of endocannabinoid signalling that may serve as targets for novel therapeutics. PMID- 25524125 TI - Randomized clinical trial of the effect of gum chewing on postoperative ileus and inflammation in colorectal surgery. AB - BACKGROUND: Postoperative ileus (POI) is a common complication following colorectal surgery that delays recovery and increases length of hospital stay. Gum chewing may reduce POI and therefore enhance recovery after surgery. The aim of the study was to evaluate the effect of gum chewing on POI, length of hospital stay and inflammatory parameters. METHODS: Patients undergoing elective colorectal surgery in one of two centres were randomized to either chewing gum or a dermal patch (control). Chewing gum was started before surgery and stopped when oral intake was resumed. Primary endpoints were POI and length of stay. Secondary endpoints were systemic and local inflammation, and surgical complications. Gastric emptying was measured by ultrasonography. Soluble tumour necrosis factor receptor 1 (TNFRSF1A) and interleukin (IL) 8 levels were measured by enzyme linked immunosorbent assay. RESULTS: Between May 2009 and September 2012, 120 patients were randomized to chewing gum (58) or dermal patch (control group; 62). Mean(s.d.) length of hospital stay was shorter in the chewing gum group than in controls, but this difference was not significant: 9.5(4.9) versus 14.0(14.5) days respectively. Some 14 (27 per cent) of 52 analysed patients allocated to chewing gum developed POI compared with 29 (48 per cent) of 60 patients in the control group (P = 0.020). More patients in the chewing gum group first defaecated within 4 days of surgery (85 versus 57 per cent; P = 0.006) and passed first flatus within 48 h (65 versus 50 per cent; P = 0.044). The decrease in antral area measured by ultrasonography following a standard meal was significantly greater among patients who chewed gum: median 25 (range -36 to 54) per cent compared with 10 (range -152 to 54) per cent in controls (P = 0.004). Levels of IL-8 (133 versus 288 pg/ml; P = 0.045) and TNFRSF1A (0.74 versus 0.92 ng/ml; P = 0.043) were lower among patients in the chewing gum group. Fewer patients in this group developed a grade IIIb complication (2 of 58 versus 10 of 62; P = 0.031). CONCLUSION: Gum chewing is a safe and simple treatment to reduce POI, and is associated with a reduction in systemic inflammatory markers and complications. REGISTRATION NUMBER: NTR2867 (http://www.trialregister.nl). PMID- 25524127 TI - Predominant expression of N-acetylglucosaminyltransferase V (GnT-V) in neural stem/progenitor cells. AB - Neural stem/progenitor cells (NPCs) express a variety of asparagine-linked oligosaccharide chains, called N-glycans, on the cell surface, and mainly produce hybrid-type and complex-type N-glycans. However, the expression profiles and roles of N-acetylglucosaminyltransferase-V (GnT-V), an enzyme that forms beta1,6 branched N-glycans, in NPCs remain unknown. In this study, cultured NPCs were prepared from adult or embryo cortex, and were maintained as either proliferating NPCs or differentiated cells in vitro. Analysis using reverse-transcriptase polymerase chain reaction, Western blot and lectin blot revealed that GnT-V and its reaction products were distinctly expressed in proliferating NPCs; moreover expression of GnT-V and its reaction products were markedly diminished in differentiated cells. In brain slices, many GnT-V-positive neurogenic cells were detected throughout the cerebral cortex on embryonic day 13, while only a few doublecortin (Dcx)- and GnT-V-double positive NPCs were detected around the subventricular zone of the lateral ventricle in the adult brain. However, in the mice in which motor function was spontaneously recovered after cryoinjury to the motor cortex, many Dcx- and GnT-V-double positive NPCs were found to have accumulated around the brain lesion of the adult cerebral cortex compared with the mice in which the function did not recover. These results indicate that GnT-V expression is under rigorous control during NPC differentiation. Furthermore, expression of GnT-V and its reaction products in NPCs may be necessary for the functional recovery after brain injury, and could be used as a marker for visualization of NPCs. PMID- 25524126 TI - First report on prevalence and risk factors of severe atypical pneumonia in Vietnamese children aged 1-15 years. AB - BACKGROUND: Atypical pathogens such as Mycoplasma pneumoniae, Chlamydophila pneumoniae, and Legionella pneumophila are increasingly recognized as important causes of community acquired pneumonia (CAP) worldwide. Such etiological data for Vietnam is scarce and clinical doctors lack accurate information on which to base their diagnosis and treatment of pneumonia. This study identifies the prevalence and risk factors of severe community acquired pneumonia due to these atypical pathogens (severe-ApCAP) in children aged 1-15 years with CAP in a pediatric hospital in Hanoi, Vietnam. METHODS: 722 hospitalized children with CAP were recruited for detecting those atypical pathogens, using multiplex PCR and ELISA. Clinical and epidemiological data were collected. Multivariate logistic regression analyses were performed to evaluate the associations of potential risk factors with severe-ApCAP. RESULTS: Among 215 atypical pathogen-positive CAP cases, 45.12% (97/215) were severe-ApCAP. Among the severe-ApCAP group, 55.67% (54/97) cases were caused by pure atypical pathogens and 44.33% (43/97) resulted from a co-infection with typical respiratory pathogens. M. pneumoniae was the most common, with 86.6% cases (84/97) in the severe-ApCAP group, whereas C. pneumoniae and L. pneumophila were less frequent (6.19% and 7.22%, respectively). The highest rate of severe-ApCAP was in children younger than two years (65.98%). The differences related to age are statistically significant (P = 0.008).The factors significantly associated with severe-ApCAP were age (OR = 0.84, 95% CI = 0.75-0.93, P = 0.001), co-infection with typical bacteria (OR = 4.86, 95% CI = 2.17-10.9, P < 0.0001), co-infection with respiratory viruses (OR = 4.36, 95% CI = 1.46-13.0, P = 0.008), respiratory/cardiac system malformation (OR = 14.8, 95% CI = 1.12-196, P = 0.041) and neonatal pneumonia (OR = 11.1, 95% CI = 1.06-116, P = 0.044). CONCLUSIONS: Severe-ApCAP presented at a significant rate in Vietnamese children. More than 50% of severe-ApCAP cases were associated with pure atypical pathogen infection. M. pneumoniae appeared most frequently. The highest rate of severe-ApCAP was in children younger than two years. Younger age and co-infection with typical bacteria or viruses were the most significant risk factors, while respiratory/cardiac system malformation and neonatal pneumonia were additional potential risk factors, associated with severe-ApCAP in Vietnamese children. PMID- 25524128 TI - Ionic Pathways in Li13Si4 investigated by (6)Li and (7)Li solid state NMR experiments. AB - Local environments and dynamics of lithium ions in the binary lithium silicide Li13Si4 have been studied by (6)Li MAS-NMR, (7)Li spin-lattice relaxation time and site-resolved (7)Li 2D exchange NMR measurements as a function of mixing time. Variable temperature experiments result in distinct differences in activation energies characterizing the transfer rates between the different lithium sites. Based on this information, a comprehensive picture of the preferred ionic transfer pathways in this silicide has been developed. With respect to local mobility, the results of the present study suggests the ordering Li6/Li7>Li5>Li1>Li4 >Li2/Li3. Mobility within the z=0.5 plane is distinctly higher than within the z=0 plane, and the ionic transfer between the planes is most facile via Li1/Li5 exchange. The lithium ionic mobility can be rationalized on the basis of the type of the coordinating silicide anions and the lithium lithium distances within the structure. Lithium ions strongly interacting with the isolated Si(4-) anions have distinctly lower mobility than those the coordination of which is dominated by Si2(6-) dumbbells. PMID- 25524129 TI - Noninvasive diagnostic methods for Helicobacter pylori infection. PMID- 25524131 TI - Sickness behavior is delayed in hypothyroid mice. AB - Sickness behavior is an expression of a motivational state triggered by activation of the peripheral innate immune system, whereby an organism reprioritizes its functions to fight infection. The relationship between thyroid hormone and immune cells is complex, and additional insights are needed about the involvement of the cross-talk between thyroid hormone, the central nervous system and immune function, as demonstrated by the consequences to sickness behavior. The aim of this work was to evaluate sickness behavior in hypothyroid mice. Control mice and mice treated with propylthiouracil (PTU) for 30days (0.05%; added to drinking water) received a single dose of LPS (200MUg/kg; i.p.) or saline, and the behavioral response was assessed for 24h. We provide evidence that thyroid status acts a modulator for the development of depressive-like and exploratory behaviors in mice that are subjected to an immunological challenge because the PTU pretreatment delayed the LPS-induced behavioral changes observed in an open field test and in a forced swimming test. This response was observed concomitantly with a lower thermal index until 4h after the LPS administration. This result demonstrates that thyroid status modifies behavioral responses to immune challenge and suggests that thyroid hormones are essential for the manifestation of sickness behavior during endotoxemia. PMID- 25524132 TI - Repositioning of the humeral tuberosities can be guided by pectoralis major insertion. AB - In complex proximal humerus fractures, positioning of the tuberosities can be a challenge. This study demonstrates the constant angle between the pectoralis major (PM) and the medial lip of the bicipital groove (BG) on the horizontal axial plane. This angle can be used to determine the rotation, as well as the positioning of the tuberosities, when planning a hemiarthroplasty or a reconstruction. Thirty-one shoulder MRIs were reviewed by three independent observers. The measurements were taken by superposing the axial cut of the proximal humerus, at the level of the distal bicipital groove, and the cut at the top of the PM insertion. By aligning the centers of rotation, we could determine the arcs of rotation between the insertion of the PM and the lips of the medial and lateral bicipital groove (MBG and LBG). Both angles were compared in terms of reliability, reproducibility, and precision. The mean PM-MBG angle was 3.7 degrees [standard deviation (SD) 14.7 degrees ] and 27.4 degrees (SD 14.4 degrees ) for the PM-LBG angle. We obtained good and very good intra-class correlation coefficient (ICC) results for inter- (0.675) and intra-observer (0.793) reliabilities on the medial angle, plus excellent results for the lateral angle (inter-observers 0.962 and intra-observer 0.895). This study demonstrates that the repositioning of humeral tuberosities can be guided by pectoralis major insertion. This will help achieve proper positioning of the metaphysis in relation to the diaphysis during surgery for complex proximal humerus fractures. PMID- 25524133 TI - Cobalt catalyst with a proton-responsive ligand for water oxidation. AB - Herein, we report the synthesis, the thermochemical data, and the catalytic reactivity of a new mononuclear cobalt complex, which has four NH protons in the ligand sphere. The combination of the redox-active metal ion and NH units enabled the coupling of proton and electron-transfer steps, which we exploited in the electrocatalytic water oxidation. PMID- 25524134 TI - Distribution on contingency of alignment of two literal sequences under constrains. AB - The case of ungapped alignment of two literal sequences under constrains is considered. The analysis lead to general formulas for probability mass function and cumulative distribution function for the general case of using an alphabet with a chosen number of letters (e.g. 4 for deoxyribonucleic acid sequences) in the expression of the literal sequences. Formulas for three statistics including mean, mode, and standard deviation were obtained. Distributions are depicted for three important particular cases: alignment on binary sequences, alignment of trinomial series (such as coming from generalized Kronecker delta), and alignment of genetic sequences (with four literals in the alphabet). A particular case when sequences contain each letter of the alphabet at least once in both sequences has also been analyzed and some statistics for this restricted case are given. PMID- 25524130 TI - Capsaicin-sensitive sensory nerves exert complex regulatory functions in the serum-transfer mouse model of autoimmune arthritis. AB - OBJECTIVE: The K/BxN serum-transfer arthritis is a widely-used translational mouse model of rheumatoid arthritis, in which the immunological components have thoroughly been investigated. In contrast, little is known about the role of sensory neural factors and the complexity of neuro-immune interactions. Therefore, we analyzed the involvement of capsaicin-sensitive peptidergic sensory nerves in autoantibody-induced arthritis with integrative methodology. METHODS: Arthritogenic K/BxN or control serum was injected to non-pretreated mice or resiniferatoxin (RTX)-pretreated animals where capsaicin-sensitive nerves were inactivated. Edema, touch sensitivity, noxious heat threshold, joint function, body weight and clinical arthritis severity scores were determined repeatedly throughout two weeks. Micro-CT and in vivo optical imaging to determine matrix metalloproteinase (MMP) and neutrophil-derived myeloperoxidase (MPO) activities, semiquantitative histopathological scoring and radioimmunoassay to measure somatostatin in the joint homogenates were also performed. RESULTS: In RTX pretreated mice, the autoantibody-induced joint swelling, arthritis severity score, MMP and MPO activities, as well as histopathological alterations were significantly greater compared to non-pretreated animals. Self-control quantification of the bone mass revealed decreased values in intact female mice, but significantly greater arthritis-induced pathological bone formation after RTX pretreatment. In contrast, mechanical hyperalgesia from day 10 was smaller after inactivating capsaicin-sensitive afferents. Although thermal hyperalgesia did not develop, noxious heat threshold was significantly higher following RTX pretreatment. Somatostatin-like immunoreactivity elevated in the tibiotarsal joints in non-pretreated, which was significantly less in RTX-pretreated mice. CONCLUSIONS: Although capsaicin-sensitive sensory nerves mediate mechanical hyperalgesia in the later phase of autoantibody-induced chronic arthritis, they play important anti-inflammatory roles at least partially through somatostatin release. PMID- 25524136 TI - The role of family phenomena in children and adolescents with attention deficit hyperactivity disorder. AB - TOPIC: Previous research suggests that families are integral to the understanding of children and adolescents with attention deficit hyperactivity disorder (ADHD). PURPOSE: The purpose of this article is to identify family phenomena related to children and adolescents with ADHD and highlight research findings that intersect family phenomena with the care and treatment of ADHD in youth. SOURCES: A literature review was conducted at the University of Pennsylvania in spring of 2014 using an online library system. The four major databases utilized are Cumulative Index to Nursing and Allied Health Literature (CINAHL), Ovid Medline, Scopus, and Psyc-INFO. CONCLUSIONS: A wide array of family-related concepts are identified in the literature and represent a multifaceted and dynamic range of family phenomena related to ADHD youth. Four major themes emerged in the literature, including family stress and strain, parenting practices and caregiver health, family relationships, and family processes related to ADHD management. Different cultural and ethnic groups are reflected in the studies, but the majority of participants are self-identified Caucasian. As a collective, the research findings suggest family-related phenomena are essential and relevant to the investigation of children and adolescents with ADHD and worthwhile to explore in future research endeavors, especially in diverse populations. PMID- 25524135 TI - Why older nurses leave the workforce and the implications of them staying. AB - AIMS AND OBJECTIVES: To identify factors that motivate older nurses to leave the workforce. BACKGROUND: As many older nurses are now reaching retirement age and will be eligible for government-funded pensions, governments are concerned about the impending financial burden. To prepare for this scenario, many are looking at increasing the age of retirement to 67 or 70 years. Little is known about how this will affect the continuing employment of older nurses and the consequences for employers and the nurses themselves if they remain longer in the workforce. DESIGN: Prospective randomised quantitative survey study. METHODS: The Mature Age Workers Questionnaire, Job Descriptive Index and Job in General Scale were used to measure job satisfaction, intention to retire and factors encouraging retirement in registered nurses aged 45 years and over (n = 352) in Australia (July-August 2007). RESULTS: There were 319 respondents. The mean age proposed for leaving the workforce was 61.7 years. Key motivators were: financial considerations (40.1%), primarily financial security; nurse health (17.4%) and retirement age of partner (13.3%). CONCLUSIONS: Older nurses are leaving the workforce prior to retirement or pension age, primarily for financial, social and health reasons, taking with them significant experience and knowledge. As financial considerations are important in older nurses decisions to continue to work, increasing the age of retirement may retain them. However, consideration will need to be given to ensure that they continue to experience job satisfaction and are physically and mentally able to undertake demanding work. RELEVANCE TO CLINICAL PRACTICE: Increasing retirement age may retain older nurses in the workforce, however, the impact on the health of older nurses is not known, nor is the impact for employers of older nurses continuing to work known. Employers must facilitate workplace changes to accommodate older nurses. PMID- 25524137 TI - Launch of JA Clinical Reports. Anesthesia research crisis in Japan. PMID- 25524138 TI - Equivalence of wave-particle duality to entropic uncertainty. AB - Interferometers capture a basic mystery of quantum mechanics: a single particle can exhibit wave behaviour, yet that wave behaviour disappears when one tries to determine the particle's path inside the interferometer. This idea has been formulated quantitatively as an inequality, for example, by Englert and Jaeger, Shimony and Vaidman, which upper bounds the sum of the interference visibility and the path distinguishability. Such wave-particle duality relations (WPDRs) are often thought to be conceptually inequivalent to Heisenberg's uncertainty principle, although this has been debated. Here we show that WPDRs correspond precisely to a modern formulation of the uncertainty principle in terms of entropies, namely, the min- and max-entropies. This observation unifies two fundamental concepts in quantum mechanics. Furthermore, it leads to a robust framework for deriving novel WPDRs by applying entropic uncertainty relations to interferometric models. As an illustration, we derive a novel relation that captures the coherence in a quantum beam splitter. PMID- 25524139 TI - Changes in serotonin transporter (5-HTT) gene expression in peripheral blood cells after MDMA intake. AB - RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is an amphetamine derivative abused worldwide. Although data report that relatively high doses of MDMA deplete serotonin (5-HT) content and decrease the availability of serotonin transporters (5-HTT), there is no available evidence as to the adaptive mechanisms taking place in 5-HTT gene expression following MDMA intake in humans. OBJECTIVE: To evaluate the pharmacological effects of MDMA on 5-HTT gene expression, using peripheral mononuclear cells as a biomarker of the central nervous system, and study whether an association exists between 5-HTT gene expression and psychobiological scores. METHODS: A randomized, double-blind, controlled trial was conducted in 18 (nine women) healthy recreational MDMA users. Subjects were genotyped for 5-HTT linked polymorphism region (5-HTTLPR). MDMA 75 mg or placebo was administered; Profile of Mood States (POMS) and 5-HTT gene expression measures were performed at baseline, 90, and 165 min post administration. POMS scores were correlated with changes in gene expression. RESULTS: The administration of 75 mg MDMA induced a significant twofold increase in 5-HTT gene expression after 165 min of drug administration. Significant associations were found between gene expression and POMS scores after MDMA administration. Results for each gender and 5-HTTLPR genotype are also reported. CONCLUSIONS: Preliminary results show that MDMA causes substantial regulatory changes in the expression of serotonergic markers, likely being modulated by the 5-HTTLPR polymorphism. Changes in 5-HTT gene expression may play an important role in the regulation of mood state. PMID- 25524140 TI - Investigating interactions between phentermine, dexfenfluramine, and 5-HT2C agonists, on food intake in the rat. AB - RATIONALE: Synergistic or supra-additive interactions between the anorectics (dex)fenfluramine and phentermine have been reported previously in the rat and in the clinic. Studies with 5-HT2C antagonists and 5-HT2C knockouts have demonstrated dexfenfluramine hypophagia in the rodent to be mediated by actions at the 5-HT2C receptor. Given the recent FDA approval of the selective 5-HT2C agonist lorcaserin (BELVIQ(r)) for weight management, we investigated the interaction between phentermine and 5-HT2C agonists on food intake. OBJECTIVES: This study aims to confirm dexfenfluramine-phentermine (dex-phen) synergy in a rat food intake assay, to extend these findings to other 5-HT2C agonists, and to determine whether pharmacokinetic interactions could explain synergistic findings with particular drug combinations. METHODS: Isobolographic analyses were performed in which phentermine was paired with either dexfenfluramine, the 5-HT2C agonist AR630, or the 5-HT2C agonist lorcaserin, and inhibition of food intake measured in the rat. Subsequent studies assessed these same phentermine-drug pair combinations spanning both the full effect range and a range of fixed ratio drug combinations. Satellite groups received single doses of each drug either alone or in combination with phentermine, and free brain concentrations were measured. RESULTS: Dex-phen synergy was confirmed in the rat and extended to the 5-HT2C agonist AR630. In contrast, although some synergistic interactions between lorcaserin and phentermine were observed, these combinations were largely additive. Synergistic interactions between phentermine and dexfenfluramine or AR630 were accompanied by combination-induced increases in brain levels of phentermine. CONCLUSIONS: Dex-phen synergy in the rat is caused by a pharmacokinetic interaction, resulting in increased central concentrations of phentermine. PMID- 25524141 TI - [Tablet computers and their benefits for nursing home residents with dementia: Results of a qualitative pilot study]. AB - BACKGROUND: Initial sporadic experiences in a Berlin nursing home showed that residents with dementia responded well to activating therapy with tablet computers. This innovative technology seemed to provide a differentiated and individual therapeutic access. These observations encouraged the nursing home management to contact the Institute of Medical Sociology and Rehabilitation Science at the Charite Universitatsmedizin Berlin with the aim to examine the practical experiences. The Centre for Quality in Care (ZQP) sponsored the 1 year pilot study. OBJECTIVE: An examination of the feasibility and usability of tablet computers in the daily care of nursing home residents with dementia was carried out. MATERIALS AND METHODS: In this study 14 residents (12 women and 2 men) of a special care unit for dementia patients were included in a 3-month intervention of tablet activation 3 times a week. Qualitative and quantitative methods were used to analyze data (e.g. observation protocols and videos, staff interviews, document analysis of nursing records and standardized resident interviews/proxy interviews). RESULTS: Nursing home residents suffering from dementia showed a high degree of acceptance of tablet computers. Most notable benefits were easy handling and the variety of multifunctional applications. Sustainable therapeutic effects resulted in stimulation of communication and interaction, improvement of well-being, memory training and reduction of neuropsychiatric symptoms. Furthermore, contact to family members of several residents was improved. CONCLUSIONS: The use of tablet computers was convincing as an activation therapy for nursing home residents with dementia. Further research and development of specially adapted software are required. PMID- 25524143 TI - Two-day-old newborn infants recognise their mother by her axillary odour. AB - AIM: The aim of this study was to verify the influence of mother to child skin-to skin contact and the ability of 2-day-old infants to recognise their own mother's axillary odour. METHODS: We tested the responses of 19 vaginally delivered, breastfeeding newborns to their mothers' axillary odours using a paired-choice test. The eight males and 11 females were exposed to their own mother's axillary odour and the odour of another unfamiliar new mother taking part in the study, and their responses to each woman were taped for 60 sec. We did this by assessing how long their heads were orientated towards pads carrying the scents of their mothers and the unfamiliar women. RESULTS: The average time that the infants' heads were orientated towards the olfactory stimulus of their own mothers was 20.53 sec, which was significantly longer than the 11.13 sec recorded for the unfamiliar women (p < 0.05). In addition, this orientation increased significantly with the newborn infants' age in hours (Spearman's Rho = 0.58, p < 0.01) and their recognition time significantly decreased (Spearman's Rho = -0.52, p < 0.05). CONCLUSION: Two-day-old breastfeeding newborn infants who experienced skin-to-skin contact with their mothers were able to recognise their axillary odour. PMID- 25524142 TI - Determining eligibility for lung transplantation: A nationwide assessment of the cutoff glomerular filtration rate. AB - BACKGROUND: Historical concerns about lung transplantation in patients with a glomerular filtration rate (GFR) <= 50 ml/min/1.73 m(2) have not been validated. We hypothesize that a pre-transplant GFR <= 50 ml/min/1.73 m(2) represents a high mortality risk, especially in the setting of acute GFR decline. In addition, we explore the potential for improved risk stratification using a statistically derivable alternative cutoff. METHODS: Adult, primary, lung recipients in the United Network for Organ Sharing database were analyzed (October 1987 to December 2011). Recursive partitioning identified the GFR value that provides maximal separation in 1-year mortality. Survival over/under the cutoffs was compared using stratified log-rank, Cox, and Kaplan-Meier methods, before and after 1:2 propensity score matching. RESULTS: Median GFR at time of transplant for 19,425 study patients was 94.2 ml/min/1.73 m(2) (quartile 1-quartile, 2 76.9-105.9 ml/min/1.73 m(2)). Recursive partitioning identified a GFR of 40.2 ml/min/1.73 m(2) as the ideal inflection point for predicting 1-year survival. Cutoffs demonstrated statistically significant effects on survival after 840 patients with a GFR <= 50 ml/min/1.73 m(2) (hazard ratio, 1.28; 95% confidence interval, 1.15-1.43) and 401 patients with a GFR <= 40.2 ml/min/1.73 m(2) (hazard ratio, 1.57; 95% confidence interval, 1.36-1.83) were matched with high GFR controls (p < 0.001). In 13,509 patients with available GFR at the time of listing and transplant, a pre-transplant GFR decline of >= 50% from baseline was associated with worse survival (p < 0.001). CONCLUSIONS: A pre-transplant GFR <= 50 ml/min/1.73 m(2) is associated with decreased survival. However, patients with GFR between 40 and 50 ml/min/1.73 m(2) do not suffer excessive post-transplant mortality and should not be automatically excluded from listing. Notably, outcomes are worse in patients with poor renal function and concomitant pre transplant GFR decline. Strategies should be devised to detect and manage interval renal deterioration before lung transplantation. PMID- 25524144 TI - Immunohistochemical expression of fibrillin-1 and fibrillin-2 during tooth development. AB - BACKGROUND AND OBJECTIVE: Oxytalan fibers are categorized as a microfibril assembly without elastin deposition, and are unique components in the periodontal ligament (PDL). However, little is known about their formation during PDL development. To clarify the mechanisms of oxytalan fiber formation in developing PDL, we performed immunohistochemical analysis to detect the direct expression of fibrillin-1 and fibrillin-2, which are major components of microfibrils. MATERIAL AND METHODS: Frozen sections of lower molars from mice at several stages of growth were prepared without chemical fixation and decalcification using the film transfer method. Immunostaining was performed with anti-fibrillin-1 and -2, and anticytokeratin antibodies. RESULTS: Fibrillin-1 was not expressed in the dental follicle during the crown forming stage. At postneonatal day 9, fibrillin-1 expression started with meshwork appearance between the epithelial cells from Hertwig's epithelial root sheath at the root dentin surface. Fibirillin-2 was detected much earlier than fibrillin-1 expression. Fibrillin-2 was expressed with a liner appearance, running parallel to the root axis in PDL, and was partially co-expressed with cytokeratin 14 expression in Hertwig's epithelial root sheath. Furthermore, we detected both fibrillin-1 and fibrillin-2 expression in human PDL. Fibrillin-1 was detected in fibers with a vertically oriented root axis in PDL. Fibrillin-2 was widely expressed in PDL, including around the epithelial cell rests of Malassez. Fibrillin-1 and fibrillin-2 were clearly co-expressed in thick fiber structures in human PDL. CONCLUSION: Our results suggest that both fibrillin-1 and fibrillin-2 expression is required to form thick oxytalan fibers in PDL. Based on the expression patterns for fibrillin-1 and fibrillin-2, they have different functions during tooth root and PDL development. Early expression of fibrillin-2 may regulate dental epithelial cell behavior during root and PDL development. PMID- 25524145 TI - Independent association between symptom onset time and infarct size in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - Recent studies have reported on circadian variation in infarct size in ST elevation myocardial infarction (STEMI) patients. Controversy remains as to whether this finding indicates circadian dependence of myocardial tolerance to ischemia/reperfusion injury or that it can simply be explained by confounding factors such as baseline profile and ischemic time. We assessed the clinical impact and independent association between symptom onset time and infarct size, accounting for possible subgroup differences. From a multicenter registry, 6799 consecutive STEMI patients undergoing primary percutaneous coronary intervention (PCI) between 2004 and 2010 were included. Infarct size was measured using peak creatine kinase (CK). Infarct size exhibited circadian variation with largest infarct size in patients with symptom onset around 03:00 at night (estimated peak CK 1322 U/l; 95% confidence interval (CI): 1217-1436) and smallest infarct size around 11:00 in the morning (estimated peak CK 1071 U/l; 95% CI: 1001-1146; relative reduction 19%; p = 0.001). Circadian variation in infarct size followed an inverse pattern in patients with prior myocardial infarction (p-interaction <0.001) and prior PCI (p-interaction = 0.006), although the later did not persist in multivariable analysis. Symptom onset time remained associated with infarct size after accounting for these interactions and adjusting for baseline characteristics and ischemic time. Symptom onset time did not predict one-year mortality (p = 0.081). In conclusion, there is substantial circadian variation in infarct size, which cannot be fully explained by variations in baseline profile or ischemic time. Our results lend support to the hypothesis of circadian myocardial ischemic tolerance and suggest a different mechanism in patients with prior myocardial infarction. PMID- 25524146 TI - Concise review: cell therapies for hereditary metabolic liver diseases-concepts, clinical results, and future developments. AB - The concept of cell-based therapies for inherited metabolic liver diseases has been introduced for now more than 40 years in animal experiments, but controlled clinical data in humans are still not available. In the era of dynamic developments in stem cell science, the "right" cell for transplantation is considered as an important key for successful treatment. Do we aim to transplant mature hepatocytes or do we consider the liver as a stem/progenitor-driven organ and replenish the diseased liver with genetically normal stem/progenitor cells? Although conflicting results from cell tracing and transplantation experiments have recently emerged about the existence and role of stem/progenitor cells in the liver, their overall contribution to parenchymal cell homeostasis and tissue repair is limited. Accordingly, engraftment and repopulation efficacies of extrahepatic and liver-derived stem/progenitor cell types are considered to be lower compared to mature hepatocytes. On the basis of these results, we will discuss the current clinical cell transplantation programs for inherited metabolic liver diseases and future developments in liver cell therapy. PMID- 25524148 TI - Attraction of Callosobruchus maculatus (F.) (Coleoptera: Bruchidae) to four varieties of Lathyrus sativus L. seed volatiles. AB - Callosobruchus maculatus (F.) (Coleoptera: Bruchidae) is an important stored grain pest of Lathyrus sativus L. (Leguminosae), commonly known as khesari, in India, Bangladesh and Ethiopia. Volatiles were collected from four varieties, i.e., Bio L 212 Ratan, Nirmal B-1, WBK-14-7 and WBK-13-1 of uninfested khesari seeds, and subsequently identified and quantified by gas chromatography mass spectrometry and gas chromatography flame ionization detector analyses, respectively. A total of 23 volatiles were identified in the four varieties of khesari seeds. In Bio L 212 Ratan and WBK-13-1 seeds, nonanal was the most abundant followed by farnesyl acetone; whereas farnesyl acetone was predominant followed by nonanal in Nirmal B-1 and WBK-14-7 khesari seeds. The olfactory responses of female C. maculatus toward volatile blends from four varieties of khesari seeds, and individual synthetic compounds and their combinations were examined through Y-shaped glass tube olfactometer bioassays. Callosobruchus maculatus showed significant preference for the whole volatile blends from Bio L 212 Ratan seeds compared to whole volatile blends from other three varieties. The insect exhibited attraction to five individual synthetic compounds, 3-octanone, 3 octanol, linalool oxide, 1-octanol and nonanal. A synthetic blend of 448, 390, 1182, 659 and 8114 ng/20 MUl methylene chloride of 3-octanone, 3-octanol, linalool oxide, 1-octanol and nonanal, respectively, was most attractive to C. maculatus, and this combination might be used for insect pest management program such as baited traps. PMID- 25524147 TI - Left ventricular filling pressure assessed by exercise TDI was correlated with early HFNEF in patients with non-obstructive hypertrophic cardiomyopathy. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) patients are more susceptible to suffer from heart failure with normal ejection fraction (HFNEF). Therefore, it is critical to evaluate the relationship between left ventricular filling pressure (LVFP) and HFNEF, even if a large proportion of HCM patients have normal LVFP at rest. The objective was to assess the correlation between exercise tissue Doppler imaging (TDI) and early HFNEF in HCM patients by treadmill exercise echocardiography combined with cardiopulmonary exercise test (CPET). METHOD: Twenty-seven non-obstructive HCM patients and 31 age- and gender-matched healthy volunteers were enrolled in this study. All subjects underwent treadmill exercise echocardiography combined with CPET. N-terminal pro-brain natriuretic peptide (NT proBNP) levels were analyzed before and after exercise. RESULT: Five HCM patients had normal LVFP at rest and increased after exercise. For this subgroup, the relationship between minute ventilation and carbon dioxide production (VE/VCO2 slope) and NT-proBNP levels were higher compared with controls and the subgroup with normal resting and stress LVFP, but was similar to the subgroup with elevated LVFP both at rest and after exercise. CONCLUSION: Elevated LVFP after exercise suggested the occurrence of early HFNEF in patients with non-obstructive HCM. PMID- 25524149 TI - Impaired coronary artery distensibility is an endothelium-dependent process and is associated with vulnerable plaque composition. AB - Coronary endothelial-dependent microvascular dysfunction, an early reversible stage of coronary artery disease (CAD), is associated with poor clinical outcome. The current study investigated whether coronary artery distensibility index (CDI) is associated with: (i) coronary endothelial-dependent microvascular dysfunction and (ii) vulnerable plaque composition among subjects with non-obstructive CAD. Seventy-four subjects with non-obstructive CAD (luminal stenosis <30%) were studied. In 20 subjects with and without coronary endothelial-dependent microvascular dysfunction, coronary flow reserve (CFR) of target segment during intracoronary (IC) infusion of acetylcholine (Ach) and bolus injection of adenosine as well as CDI at rest of corresponding target segment were measured. In 54 subjects, plaque compositions and CDI at rest of 154 non-obstructive coronary segments as well as proximal segment without disease were measured by intravascular ultrasound (IVUS). CDI was defined as: [(Early-diastolic cross sectional-area (CSA) - End-diastolic CSA of target segment)/(end-diastolic CSA of target segment * coronary-pulse-pressure) * 10(3) ]. There is a direct association between endothelial dysfunction and impaired CDI of a coronary segment both in the given coronary segment and corresponding microvessels in which a strong agreement between CDI and CFR Ach (r(2) = 0.85, P = 0.0001) was observed. Multivariable regression-analysis showed that CDI was an independent predictor of the vulnerable plaque characteristics. The risk of impaired CDI was 125% higher in segments with necrotic core and 60% higher in segments with fibrofatty components as compared to normal segments (P = 0.001). In conclusions, the current study reveals that impaired CDI is an endothelial-dependent process of both given coronary segment and corresponding microvessels and is associated with vulnerable plaque composition. PMID- 25524150 TI - Deletion of the low-molecular-weight glutenin subunit allele Glu-A3a of wheat (Triticum aestivum L.) significantly reduces dough strength and breadmaking quality. AB - BACKGROUND: Low-molecular-weight glutenin subunits (LMW-GS), encoded by Glu-3 complex loci in hexaploid wheat, play important roles in the processing quality of wheat flour. To date, the molecular characteristics and effects on dough quality of individual Glu-3 alleles and their encoding proteins have been poorly studied. We used a Glu-A3 deletion line of the Chinese Spring (CS-n) wheat variety to conduct the first comprehensive study on the molecular characteristics and functional properties of the LMW-GS allele Glu-A3a. RESULTS: The Glu-A3a allele at the Glu-A3 locus in CS and its deletion in CS-n were identified and characterized by proteome and molecular marker methods. The deletion of Glu-A3a had no significant influence on plant morphological and yield traits, but significantly reduced the dough strength and breadmaking quality compared to CS. The complete sequence of the Glu-A3a allele was cloned and characterized, which was found to encode a B-subunit with longer repetitive domains and an increased number of alpha-helices. The Glu-A3a-encoded B-subunit showed a higher expression level and accumulation rate during grain development. These characteristics of the Glu-A3a allele could contribute to achieving superior gluten quality and demonstrate its potential application to wheat quality improvement. Furthermore, an allele-specific polymerase chain reaction (AS-PCR) marker for the Glu-A3a allele was developed and validated using different bread wheat cultivars, including near-isogenic lines (NILs) and recombinant inbred lines (RILs), which could be used as an effective molecular marker for gluten quality improvement through marker-assisted selection. CONCLUSIONS: This work demonstrated that the LMW-GS allele Glu-A3a encodes a specific LMW-i type B-subunit that significantly affects wheat dough strength and breadmaking quality. The Glu-A3a-encoded B subunit has a long repetitive domain and more alpha-helix structures as well as a higher expression level and accumulation rate during grain development, which could facilitate the formation of wheat with a stronger dough structure and superior breadmaking quality. PMID- 25524151 TI - Global epidemic invasion thresholds in directed cattle subpopulation networks having source, sink, and transit nodes. AB - Through the characterization of a metapopulation cattle disease model on a directed network having source, transit, and sink nodes, we derive two global epidemic invasion thresholds. The first threshold defines the conditions necessary for an epidemic to successfully spread at the global scale. The second threshold defines the criteria that permit an epidemic to move out of the giant strongly connected component and to invade the populations of the sink nodes. As each sink node represents a final waypoint for cattle before slaughter, the existence of an epidemic among the sink nodes is a serious threat to food security. We find that the relationship between these two thresholds depends on the relative proportions of transit and sink nodes in the system and the distributions of the in-degrees of both node types. These analytic results are verified through numerical realizations of the metapopulation cattle model. PMID- 25524152 TI - Commentary: Thailand: sexual and reproductive health before and after universal health coverage in 2002. PMID- 25524153 TI - [Prevalence and clinical characteristics of subclinical hypothyroidism in an opportunistic sample in the population of Castile-Leon (Spain)]. AB - OBJECTIVE: To describe the distribution of thyroid-stimulating hormone (TSH) values and to estimate the prevalence of subclinical hypothyroidism in the adult population of Castile and Leon (Spain). METHOD: An observational study was conducted in an opportunistic sample of 45 primary care centers in Castile and Leon. TSH was determined in people aged >=35 years that attended a primary care physician and had a blood test for any reason. Confirmatory analysis included free thyroxine and anti-thyroid peroxidase antibody determination. RESULTS: A total of 3957 analyses were carried out, 63% in women. The mean age was 61.5 years. The median TSH value was 2.3 MUIU/mL (2.5 MUIU/mL in women and 2.1 MUIU/mL in men), with a rising trend with age. TSH values were higher in undiagnosed or untreated subclinical hypothyroidism than in patients under treatment. The lowest levels were found in euthyroidism. The prevalence of subclinical hypothyroidism was 9.2% (95%CI: 8.3-10.2), and hypothyroidism was three times higher in women than in men (12.4% versus 3.7%). Hypothyroidism increased with age, reaching a peak of 16.9% in women aged 45 to 64 years. CONCLUSIONS: The prevalence of subclinical hypothyroidism in our sample was high and in the upper limits of values found in previous studies. Proper diagnosis and treatment are important because of the risk of progression to hypothyroidism and the association with multiple diseases and other risk factors. PMID- 25524154 TI - Righteous Among the Nations: doctors and medical students. PMID- 25524155 TI - Plant genetic archaeology: whole-genome sequencing reveals the pedigree of a classical trisomic line. AB - The circadian oscillator is astonishingly robust to changes in the environment but also to genomic changes that alter the copy number of its components through genome duplication, gene duplication, and homeologous gene loss. While studying the potential effect of aneuploidy on the Arabidopsis thaliana circadian clock, we discovered that a line thought to be trisomic for chromosome 3 also bears the gi-1 mutation, resulting in a short period and late flowering. With the help of whole-genome sequencing, we uncovered the unexpected complexity of this trisomic stock's history, as its genome shows evidence of past outcrossing with another A. thaliana accession. Our study indicates that although historical aneuploidy lines exist and are available, it might be safer to generate new individuals and confirm their genomes and karyotypes by sequencing. PMID- 25524156 TI - Fermentative conditions modulating sweetness in dry wines: genetics and environmental factors influencing the expression level of the Saccharomyces cerevisiae HSP12 gene. AB - Yeast lees influence the organoleptic properties of wines by increasing their sweet taste. This effect is in part due to the protein Hsp12p, which is regulated by different stress response pathways in Saccharomyces cerevisiae. This work investigated the genetics and environmental factors influencing the expression level of the HSP12 gene in an enological context. RT-qPCR confirmed that the HSP12 expression level is regulated by temperature change and ethanol content during the alcoholic fermentation but not by the sugar content. Moreover, this gene shows an important variation according to the yeast strain used. For the first time yeast strain is demonstrated to play an important role in the perception of sweetness in red wine due to post-fermentation lees autolysis. Interestingly, a correlation between the expression level of HSP12 and the sweetness perception was found using yeast strains of different origins. All of the findings provide new insights on the contribution of yeast to wine taste. PMID- 25524157 TI - A meta-analysis to determine the oncological implications of conversion in laparoscopic colorectal cancer surgery. AB - AIM: Laparoscopic colon and rectal cancer surgery is oncologically equivalent to open resection, but the impact of conversion is undetermined. The aim of this study was to assess the oncological outcome and predictive factors associated with conversion. METHOD: A comprehensive search for published studies examining the associated factors and outcome of conversion from laparoscopic to open colorectal cancer resection was performed adhering to PRISMA (Preferred Reporting Items in Systematic Reviews and Meta-analyses) guidelines. Only randomized control trials and prospective studies were included. Each study was reviewed and the data extracted. Random effects methods were used to combine data. RESULTS: Fifteen studies, including 5293 patients, met the inclusion criteria. Of these 4391 patients had a completed laparoscopic resection and 902 were converted to an open resection. The average conversion rate of the studies was 17.9 +/- 10.1%. Meta-analysis showed completed laparoscopic surgery favoured lower 30-day mortality (OR 0.134, 95% CI 0.047-0.385, P < 0.0001), lower long-term disease recurrence (OR 0.634, 95% CI 0.421-0.701, P < 0.023) and lower overall mortality (OR 0.512, 95% CI 0.417-0.629, P < 0.0001). Factors negatively associated with completion of laparoscopic surgery were male gender (P = 0.011), rectal tumour (P = 0.017), T3/T4 tumour (P = 0.009) and node-positive disease (P = 0.009). Completed laparoscopic surgery was also associated with a lower body mass index (BMI; mean difference -0.93 kg/m(2) , P = 0.004). CONCLUSION: The results suggest that conversion from laparoscopic to open colorectal cancer resection is influenced by patient and tumour characteristics and is associated with an adverse perioperative outcome. Although confounding factors such as advanced tumour stage and elevated BMI are present, unsuccessful laparoscopic surgery appears to be associated with an adverse long-term oncological outcome. PMID- 25524158 TI - Frequency of fungal agents identified in sinus samples from patients with clinically suspected rhinosinusitis. AB - Fungal rhinosinusitis (FRS) is one of the most important rhinosinusoidal disorders, which involves a variety of etiological agents. We carried out a study to determine the frequency of fungal agents in sinus samples from patients with clinically suspected rhinosinusitis (RS). A total of 205 clinical samples were assessed from 174 patients with clinically suspected RS, of which 48 were positive for microscopic examination and culture, 47 were positive for direct examination but negative by culture, 4 were negative for direct examination but positive by culture, and 106 were negative for both methodologies. The main fungal agents isolated were Aspergillus spp. (32.7%), followed by Schizophyllum commune (28.8%). Sensitivity and specificity of the direct examination were 92.3% and 69.3%, respectively, and concordance between the direct examination and culture was 48.4%. This study indicated that both Aspergillus and S. commune appear to be the most important agents involved in the development of FRS. PMID- 25524159 TI - [2014 ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment andmanagement]. PMID- 25524160 TI - Depression and anxiety in women with epilepsy during pregnancy and after delivery: a prospective population-based cohort study on frequency, risk factors, medication, and prognosis. AB - OBJECTIVE: To assess incidence, prevalence, risk factors, and prognosis of peripartum depression and anxiety in a prospective study of women with epilepsy. METHOD: Pregnancies in women with epilepsy (n=706) were compared to pregnancies in all women without epilepsy (n=106,511) including women with specified nonepileptic chronic diseases (n=8,372) in the Norwegian Mother and Child Cohort Study. The database was linked to the Medical Birth Registry of Norway. Depression and anxiety were assessed with validated questionnaires five times from the second trimester to 36 months after delivery. Blood was drawn for analysis of antiepileptic drug (AED) concentrations. RESULTS: Women with epilepsy more often had peripartum depression (26.7%) or anxiety (22.4%) than women without epilepsy (18.9% and 14.8%, respectively, p<0.001 for both comparisons) and women with other chronic diseases (23.1% and 18.4%, respectively, p=0.03 and 0.01). Women using AEDs during pregnancy were especially at risk regardless of AED type. The risk further increased with the use of multiple AEDs and with high doses and/or plasma levels. Risk factors associated with peripartum depression and/or anxiety in the epilepsy cohort were high seizure frequency, a history of physical and/or sexual abuse, adverse socioeconomic factors, previous loss of a child, AED use, unplanned pregnancy, and prepregnancy depression and/or anxiety. The recovery rate 3 years after delivery was lower for women with epilepsy with a history of depression/anxiety or physical/sexual abuse than for women without epilepsy. Depressed women with epilepsy were less frequently treated with antidepressive drugs during pregnancy than women without epilepsy. SIGNIFICANCE: Women with epilepsy frequently have depression and anxiety during and after pregnancy. Patients at risk should be identified before delivery as depressive symptoms could be undertreated in this group. PMID- 25524161 TI - Transbuccal sonographic evaluation of the local extent of tumors of the tongue with pathological correlation. AB - PURPOSE: The object of this study was to evaluate the usefulness of preoperative transbuccal ultrasound (US) for the evaluation of tongue tumors. Thus, we evaluated the correlation between preoperative US measurements and postoperative pathologic measurements of tongue tumor size. METHODS: From January 2003 to March 2011, 29 patients with tongue tumors were evaluated. All patients underwent preoperative transbuccal US at 1 day before surgery. Preoperative US was compared with pathology findings, including specimen size. The maximum anterior-posterior (AP) diameter of the long axis of the tumor, the maximum width (WD), and the maximum thickness (TH) of the tumor were measured with US along with a pathologic evaluation of the specimens. RESULTS: The mean AP was 22 +/- 1 mm; WD was 13 +/- 6 mm, and TH was 10 +/- 5 mm using US. The pathologic mean AP was 21 +/- 12 mm; WD was 12 +/- 6 mm, and TH was 9 +/- 4 mm. The Spearman's correlation coefficients of the AP, WD, and TH were 0.905 (p < 0.001), 0.918 (p < 0.001), and 0.971 (p < 0.001), respectively. CONCLUSIONS: Transbuccal US is a useful tool for predicting tongue tumor extent. PMID- 25524162 TI - A visible-light harvesting system for CO2 reduction using a Ru(II) -Re(I) photocatalyst adsorbed in mesoporous organosilica. AB - A photocatalytic system for CO2 reduction exhibiting visible-light harvesting was developed by preparing a hybrid consisting of a supramolecular metal complex as photocatalyst and periodic mesoporous organosilica (PMO) as light harvester. A Ru(II) ?Re(I) binuclear complex (Ru?Re) with methylphosphonic acid anchor groups was adsorbed on acridone or methylacridone embedded in the walls of PMO mesochannels to yield the hybrid structure. The embedded organic groups absorbed visible light, and the excitation energy was funneled to the Ru units. The energy accumulation was followed by electron transfer and catalytic reduction of CO2 to CO on the Re unit. The light harvesting of these hybrids enhanced the photocatalytic CO evolution rate by a factor of up to ten compared with that of Ru?Re adsorbed on mesoporous silica without a light harvester. PMID- 25524163 TI - Seborrhoeic keratosis removal in a multicentre phase I/II clinical trial using a novel topical formulation (BL-5010). PMID- 25524164 TI - African swine fever virus CD2v and C-type lectin gene loci mediate serological specificity. AB - African swine fever (ASF) is an emerging disease threat for the swine industry worldwide. No ASF vaccine is available and progress is hindered by lack of knowledge concerning the extent of ASF virus (ASFV) strain diversity and the viral antigens responsible for protection in the pig. Available data from vaccination/challenge experiments in pigs indicate ASF protective immunity is haemadsorption inhibition (HAI) serotype-specific. A better understanding of ASFV HAI serological groups and their diversity in nature, as well as improved methods to serotype ASFV isolates, is needed. Here, we demonstrated that the genetic locus encoding ASFV CD2v and C-type lectin proteins mediates HAI serological specificity and that CD2v/C-type lectin genotyping provides a simple method to group ASFVs by serotype, thus facilitating study of ASFV strain diversity in nature, and providing information necessary for eventual vaccine design, development and efficacious use. PMID- 25524165 TI - Identification of DNA sequences that imply a novel gammaherpesvirus in seals. AB - Various herpesviruses have been discovered in marine mammals and are associated with a wide spectrum of disease. In the present study we describe the detection and phylogenetic analysis of a novel gammaherpesvirus, tentatively called phocine herpesvirus 7 (PhHV-7), which was detected in samples collected during an outbreak of ulcerative gingivitis and glossitis from juvenile harbour seals (Phoca vitulina) at the Seal Rehabilitation and Research Centre, the Netherlands. The presence of this novel gammaherpesvirus was confirmed by viral metagenomics, while no other viruses other than four novel anelloviruses were detected. However, PhHV-7 DNA was also detected in harbour and grey seals (Halichoerus grypus) without gingivitis or glossitis. Genetic analysis of the partial polymerase gene of PhHV-7 detected in both species revealed limited sequence variation. Additional studies are needed to elucidate whether the viruses discovered played a role in the disease observed. PMID- 25524166 TI - Isolation of an Adoxophyes orana granulovirus (AdorGV) occlusion body morphology mutant: biological activity, genome sequence and relationship to other isolates of AdorGV. AB - A granulovirus (GV) producing occlusion bodies (OBs) with an unusual appearance was isolated from Adoxophyes spp. larvae in the field. Ultrastructural observations revealed that its OBs were significantly larger and cuboidal in shape, rather than the standard ovo-cylindrical shape typical of GVs. N-terminal amino acid sequence analysis of the OB matrix protein from this virus suggested that this new isolate was a variant of Adoxophyes orana granulovirus (AdorGV). Bioassays of this GV (termed AdorGV-M) and an English isolate of AdorGV (termed AdorGV-E) indicated that the two isolates were equally pathogenic against larvae of Adoxophyes honmai. However, AdorGV-M retained more infectivity towards larvae after irradiation with UV light than did AdorGV-E. Sequencing and analysis of the AdorGV-M genome revealed little sequence divergence between this isolate and AdorGV-E. Comparison of selected genes among the two AdorGV isolates and other Japanese AdorGV isolates revealed differences that may account for the unusual OB morphology of AdorGV-M. PMID- 25524167 TI - Effects of developmental perfluorooctane sulfonate exposure on spatial learning and memory ability of rats and mechanism associated with synaptic plasticity. AB - The present study aims to explore the effects of perfluorooctane sulfonate (PFOS) on cognitive function in developing rats and the underlying mechanism associated with synaptic plasticity. Pregnant Wistar rats were fed with 0, 5, and 15 mg/L of PFOS via drinking water during gestation and lactation. Offspring were exposed to PFOS on prenatal and/or postnatal days by cross-fostering. Spatial learning and memory abilities were tested from postnatal day (PND) 35. We also analyzed the expression pattern of the synaptic plasticity-related genes and proteins in the hippocampus on PND7 and PND35. Results revealed that PFOS exposure reduced the spatial learning and memory abilities of the offspring, particularly of those with prenatal exposure. Meanwhile, protein levels of growth-associated protein 43, neural cell adhesion molecule 1, nerve growth factor, and brain-derived neurotrophic factor decreased on PND35, which are involved in the formation of synaptic plasticity. In contrast, significant increase in gap-43, ncam1, and bdnf genes on the mRNA level was observed on PND7, possibly due to the post transcriptional mechanism. Results of both behavioral effects and molecular endpoints suggested the high risk of prenatal PFOS exposure. The decline of spatial learning and memory abilities induced by developmental PFOS exposure was closely related to synaptic plasticity. PMID- 25524168 TI - The structural basis for specificity in lipoxygenase catalysis. AB - Many intriguing facets of lipoxygenase (LOX) catalysis are open to a detailed structural analysis. Polyunsaturated fatty acids with two to six double bonds are oxygenated precisely on a particular carbon, typically forming a single chiral fatty acid hydroperoxide product. Molecular oxygen is not bound or liganded during catalysis, yet it is directed precisely to one position and one stereo configuration on the reacting fatty acid. The transformations proceed upon exposure of substrate to enzyme in the presence of O2 (RH + O2 -> ROOH), so it has proved challenging to capture the precise mode of substrate binding in the LOX active site. Beginning with crystal structures with bound inhibitors or surrogate substrates, and most recently arachidonic acid bound under anaerobic conditions, a picture is consolidating of catalysis in a U-shaped fatty acid binding channel in which individual LOX enzymes use distinct amino acids to control the head-to-tail orientation of the fatty acid and register of the selected pentadiene opposite the non-heme iron, suitably positioned for the initial stereoselective hydrogen abstraction and subsequent reaction with O2 . Drawing on the crystal structures available currently, this review features the roles of the N-terminal beta-barrel (C2-like, or PLAT domain) in substrate acquisition and sensitivity to cellular calcium, and the alpha-helical catalytic domain in fatty acid binding and reactions with O2 that produce hydroperoxide products with regio and stereospecificity. LOX structures combine to explain how similar enzymes with conserved catalytic machinery differ in product, but not substrate, specificities. PMID- 25524169 TI - In vivo heat-stimulus-triggered osteogenesis. AB - Several studies have reported that heat stress stimulates the activity of osteoblastic cells in vitro. However, few have addressed the effects of heat stress on osteogenesis in vivo, nor have the optimal temperatures for bone formation been determined. The aim of the present study was to investigate the effects of hyperthermia treatment on osteogenesis in a rat tibial defect model. Forty-four Sprague Dawley rats were divided into two groups with or without hyperthermia treatment. A 3-mm circular defect in the proximal tibia filled with magnetite cationic liposomes embedded in alginate beads was subjected to hyperthermia treatment (43-46 degrees C). Radiological assessment at 2 weeks after the treatment showed that significantly stimulated osteogenesis was observed in the hyperthermia group as compared to the control group (p = 0.003). Histomorphometrical analysis at 2 weeks revealed a significant increase of newly formed bone in the hyperthermia group, compared with the control group (p < 0.001). Area of newly formed bone in each hyperthermia group was significantly increased as compared with the control group (43 degrees C; p = 0.005, 44 degrees C; p = 0.019, 45 degrees C; p = 0.003, and 46 degrees C; p = 0.003, respectively). Alkaline phosphatase was overexpressed at the surfaces of newly formed bone adjacent to magnetite cationic liposome implantation. Our results demonstrate for the first time that heat stimulus accelerates osteogenesis in vivo, and may thus be of interest as a novel and promising tool to induce osteogenesis clinically as well. PMID- 25524170 TI - Solution studies on DNA interactions of substitution-inert platinum complexes mediated via the phosphate clamp. AB - The phosphate clamp is a distinct mode of ligand-DNA binding where the molecular recognition is manifested through ("non-covalent") hydrogen-bonding from am(m)ines of polynuclear platinum complexes to the phosphate oxygens on the oligonucleotide backbone. This third mode of DNA binding is unique to the "classical" DNA intercalators and minor groove binding agents and even the closely related covalently binding mononuclear and polynuclear drugs. 2D (1)H NMR studies on the Dickerson-Drew dodecamer (DDD, d(CGCGAATTCGCG)2) showed significant A-T contacts mainly on nucleotides A6, T7 and T8 implying a selective bridging from C9G10 in the 3' direction to C9G10 of the opposite strand. {(1)H, (15)N} HSQC NMR spectroscopy using the fully (15)N-labelled compound [{trans Pt(NH2)3(H2N(CH2)6NH3}2MU-(H2N(CH2)6NH2)2(Pt(NH3)2](8+) (TriplatinNC) showed at pH 6 significant chemical shifts and (1)J((195)Pt-(15)N) coupling constants for the free drug and DDD-TriplatinNC at pH 7 indicative of formation of the phosphate clamp. (31)P NMR results are also reported for the hexamer d(CGTACG)2 showing changes in (31)P NMR chemical shifts indicative of changes around the phosphorus center. The studies confirm the DNA binding modes by substitution inert (non-covalent) polynuclear platinum complexes and help in further establishing the chemotype as a new class of potential anti-tumour agents in their own right with a distinct profile of biological activity. PMID- 25524171 TI - Carbohydrate functionalization of silver nanoparticles modulates cytotoxicity and cellular uptake. AB - BACKGROUND: Increasing use of silver nanoparticles (Ag-NPs) in various products is resulting in a greater likelihood of human exposure to these materials. Nevertheless, little is still known about the influence of carbohydrates on the toxicity and cellular uptake of nanoparticles. METHODS: Ag-NPs functionalized with three different monosaccharides and ethylene glycol were synthesized and characterised. Oxidative stress and toxicity was evaluated by protein carbonylation and MTT assay, respectively. Cellular uptake was evaluated by confocal microscopy and ICP-MS. RESULTS: Ag-NPs coated with galactose and mannose were considerably less toxic to neuronal-like cells and hepatocytes compared to particles functionalized by glucose, ethylene glycol or citrate. Toxicity correlated to oxidative stress but not to cellular uptake. CONCLUSIONS: Carbohydrate coating on silver nanoparticles modulates both oxidative stress and cellular uptake, but mainly the first has an impact on toxicity. These findings provide new perspectives on modulating the bioactivity of Ag-NPs by using carbohydrates. PMID- 25524172 TI - A simplified memory network model based on pattern formations. AB - Many experiments have evidenced the transition with different time scales from short-term memory (STM) to long-term memory (LTM) in mammalian brains, while its theoretical understanding is still under debate. To understand its underlying mechanism, it has recently been shown that it is possible to have a long-period rhythmic synchronous firing in a scale-free network, provided the existence of both the high-degree hubs and the loops formed by low-degree nodes. We here present a simplified memory network model to show that the self-sustained synchronous firing can be observed even without these two necessary conditions. This simplified network consists of two loops of coupled excitable neurons with different synaptic conductance and with one node being the sensory neuron to receive an external stimulus signal. This model can be further used to show how the diversity of firing patterns can be selectively formed by varying the signal frequency, duration of the stimulus and network topology, which corresponds to the patterns of STM and LTM with different time scales. A theoretical analysis is presented to explain the underlying mechanism of firing patterns. PMID- 25524173 TI - Andrographolide reduces cognitive impairment in young and mature AbetaPPswe/PS-1 mice. AB - Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid beta (Abeta) oligomers are a key factor in synaptic impairment and in spatial memory decline associated with neuronal dysfunction. This impairment includes synaptic failure associated with the loss of synaptic proteins that contribute to AD progression. Interestingly, the use of natural compounds is an emergent conceptual strategy in the search for drugs with therapeutic potentials for treating neurodegenerative disorders. In the present study, we report that andrographolide (ANDRO), which is a labdane diterpene extracted from Andrographis paniculata, increases slope of field excitatory postsynaptic potentials (fEPSP) in the CA1 region of hippocampal slices and inhibits long-term depression (LTD), protecting the long-term potentiation (LTP) against the damage induced by Abeta oligomers in vitro, most likely by inhibiting glycogen synthase kinase-3beta (GSK 3beta). Additionally, ANDRO prevents changes in neuropathology in two different age groups (7- and 12-month-old mice) of an AbetaPPswe/PS-1 Alzheimer's model. ANDRO reduces the Abeta levels, changing the ontogeny of amyloid plaques in hippocampi and cortices in 7-month-old mice, and reduces tau phosphorylation around the Abeta oligomeric species in both age groups. Additionally, we observed that ANDRO recovers spatial memory functions that correlate with protecting synaptic plasticity and synaptic proteins in two different age groups. Our results suggest that ANDRO could be used in a potential preventive therapy during AD progression. PMID- 25524174 TI - Suppressive effects of induced pluripotent stem cell-conditioned medium on in vitro hypertrophic scarring fibroblast activation. AB - Hypertrophic scarring (HS) is a type of fibrosis that occurs in the skin, and is characterized by fibroblast activation and excessive collagen production. However, at present, therapeutic strategies for this condition are ineffective. Previous studies have identified that the mutual regulation of chronic inflammation, mechanical force and fibroblast activation leads to the formation of HS. Induced pluripotent stem cells (iPSCs) are novel bioengineered embryonic like stem cells, initially created from mouse adult fibroblasts. The current study demonstrated that iPSC-conditioned medium (iPSC-CM) may significantly suppress hypertrophic scar fibroblast activation. It was observed that in the presence of iPSC-CM, the level of collagen I was markedly reduced and alpha smooth muscle actin, a marker for myofibroblasts (activated fibroblasts that mediate mechanical force-induced HS formation), exhibited a significantly lower level of expression in human dermal fibroblasts (HDFs) activated with transforming growth factor-beta1. Additionally, iPSC-CM attenuated the local inflammatory cell response by blocking the adhesion of human acute monocytic leukemia cell monocytes and fibroblasts in vitro. In addition, the contractile ability of HDFs may be reduced by iPSC-CM. These observations suggest that iPSC CM may protect against processes leading to hypertrophic scarring by attenuating fibroblast activation, blocking inflammatory cell recruitment and adhesion and reducing the contractile ability of fibroblasts. PMID- 25524175 TI - A novel cause of community-acquired pneumonia in a young immunocompetent host. AB - Diffuse pulmonary infiltrates represent a common problem encountered by pulmonologists. The differential diagnosis is extensive and includes infectious, inflammatory, environmental and malignant conditions. Appropriate evaluation, aside from a thorough history and physical examination, includes serologic, radiographic and procedural elements. We describe a case of a healthy male with diffuse pulmonary infiltrates. Work up revealed a novel infectious etiology. Although this particular microorganism has been described to cause native valve endocarditis, recurrent breast abscesses, osteomyelitis and bacteremia, it has to date not been described as a cause for community acquired pneumonia in immunocompetent hosts. PMID- 25524176 TI - Hepatitis C infection is associated with hepatic toxicity but does not compromise the survival of patients with diffuse large B cell lymphoma treated with rituximab-based chemotherapy. AB - The influence of hepatitis C virus (HCV) infection on the outcome of patients with diffuse large B cell lymphoma (DLBCL) treated with rituximab-based chemotherapy is controversial. We retrospectively analyzed the characteristics and clinical outcomes of 168 patients with DLBCL diagnosed between January 2005 and December 2011. Twenty-nine patients who were HCV-positive before lymphoma treatment were compared with 139 patients who did not have HCV infection. The median follow-up duration was 3.0 (0.07-8.02) years. HCV infection resulted in more hepatic toxicity in both univariate (p=0.001) and multivariate (p=0.003) analyses. In addition, HCV-positive DLBCL patients were more likely to have treatment delay (20.1% vs. 0.7%, p<0.001). For patients who developed hepatic toxicity during immunochemotherapy, HCV-positive patients had significantly higher folds of aspartate aminotransferase elevation (p=0.042) and total bilirubin elevation (p=0.012) compared with those who were HCV negative. However, HCV did not influence the 5-year progression-free survival rate (p=0.412) or 5 year overall survival rate (p=0.410). In conclusion, HCV infection is associated with increased hepatic toxicity and delayed chemotherapy without compromised survival in DLBCL patients treated with rituximab-based chemotherapy. PMID- 25524177 TI - Azacitidine for the treatment of relapsed and refractory AML in older patients. AB - The prognosis of patients older than 50 with relapsed or refractory AML is dismal. Azacitidine has been investigated in older AML patients. Here we report the outcome of 130 patients older than 50 years included in a multicenter patient named program of azacitidine after relapse (n=67) or induction failure (n=63) of intensive chemotherapy. Median age was 67 years, cytogenetic risk was high in 28% and performance status >=2 in 15% of cases. Most (72%) patients received azacitidine at the standard schedule (75mg/m(2)/d, 7 days/month) for a median of 4 courses. The overall response rate was 17% (CR: 10%, CRi: 7%). Median overall survival was 8.4 months. Achievement of CR/CRi was associated with prolonged survival (P=0.0001), whereas hematological improvement according to MDS criteria, achieved in 36% of patients with resistant disease, did not improve survival. In multivariate analysis, high risk cytogenetics (P=0.022) and peripheral blasts >10% (P<0.0001) at onset of azacitidine were independently predictive of poor prognosis. Combining these two factors, we identified a subgroup of 48% of patients with intermediate risk cytogenetics and peripheral blasts <=10% and a median OS of 11.3 months. These results warrant further investigation of azacitidine-based regimens in this subgroup of patients. PMID- 25524178 TI - Orchidectomy-induced alterations in volumetric bone density, cortical porosity and strength of femur are attenuated by dietary conjugated linoleic acid in aged guinea pigs. AB - Age-related osteoporosis and sarcopenia are ascribed in part to reductions in anabolic hormones. Dietary conjugated linoleic acid (CLA) improves lean and bone mass, but its impact during androgen deficiency is not known. This study tested if CLA would attenuate the effects of orchidectomy (ORX)-induced losses of bone and lean tissue. Male guinea pigs (n=40; 70-72 weeks), were randomized into four groups: (1) SHAM+Control diet, (2) SHAM+CLA diet, (3) ORX+Control diet, (4) ORX+CLA diet. Baseline blood sampling and dual-energy X-ray absorptiometry (DXA) scans were conducted, followed by surgery 4 days later with the test diets started 7 days after baseline sampling. Serial blood sampling and DXA scans were repeated 2, 4, 8 and 16 weeks on the test diets. Body composition and areal BMD (aBMD) of whole body, lumbar spine, femur and tibia were measured using DXA. At week 16, muscle protein fractional synthesis rate (FSR), volumetric BMD (vBMD), microarchitecture and bone strength were assessed. Body weight declined after SHAM and ORX surgery, with slower recovery in the ORX group. Dietary CLA did not affect weight or lean mass, but attenuated gains in fat mass. Lean mass was stable in SHAM and reduced in ORX by 2 weeks with whole body and femur bone mineral content (BMC) reduced by 4 weeks; CLA did not alter BMC. By week 16 ORX groups had lower free testosterone and myofibrillar FSR, yet higher cortisol, osteocalcin and ionized calcium with no alterations due to CLA. ORX+Control had higher prostaglandin E2 (PGE2) and total alkaline phosphatase compared to SHAM+Control whereas ORX+CLA were not different from SHAM groups. Femur metaphyseal vBMD was reduced in ORX+CTRL with the reduction attenuated by CLA. Femur cortical thickness (Ct.Th.) and biomechanical strength were reduced and cortical porosity (Ct.Po.) elevated by ORX and attenuated by CLA. This androgen deficient model with a sarcopenic-osteoporotic phenotype similar to aging men responded to dietary CLA with significant benefits to femur density and strength. PMID- 25524180 TI - A 14-year paraneoplastic rash: urticarial vasculitis and dermal binding bullous pemphigoid secondary to chronic lymphocytic leukaemia. AB - A 72-year-old woman with a 14-year history of urticarial vasculitis (UV) and a 13 year history of bullous pemphigoid (BP) presented with associated progressive chronic lymphocytic leukaemia (CLL). Both skin conditions responded poorly to treatment, until chemotherapy for CLL was commenced. The skin features showed a clear paraneoplastic course, resolving with chemotherapy and recurring when the CLL relapsed and the lymphocyte count rose above 5 * 10(9)/L. No case of UV secondary to CLL, and very few cases of BP related to CLL have been reported, and no paraneoplastic rash of any type lasting 14 years has been reported previously. PMID- 25524179 TI - Postsynaptic P2X3-containing receptors in gustatory nerve fibres mediate responses to all taste qualities in mice. AB - Taste buds release ATP to activate ionotropic purinoceptors composed of P2X2 and P2X3 subunits, present on the taste nerves. Mice with genetic deletion of P2X2 and P2X3 receptors (double knockout mice) lack responses to all taste stimuli presumably due to the absence of ATP-gated receptors on the afferent nerves. Recent experiments on the double knockout mice showed, however, that their taste buds fail to release ATP, suggesting the possibility of pleiotropic deficits in these global knockouts. To test further the role of postsynaptic P2X receptors in afferent signalling, we used AF-353, a selective antagonist of P2X3-containing receptors to inhibit the receptors acutely during taste nerve recording and behaviour. The specificity of AF-353 for P2X3-containing receptors was tested by recording Ca(2+) transients to exogenously applied ATP in fura-2 loaded isolated geniculate ganglion neurons from wild-type and P2X3 knockout mice. ATP responses were completely inhibited by 10 MUm or 100 MUm AF-353, but neither concentration blocked responses in P2X3 single knockout mice wherein the ganglion cells express only P2X2-containing receptors. Furthermore, AF-353 had no effect on taste-evoked ATP release from taste buds. In wild-type mice, i.p. injection of AF-353 or simple application of the drug directly to the tongue, inhibited taste nerve responses to all taste qualities in a dose-dependent fashion. A brief access behavioural assay confirmed the electrophysiological results and showed that preference for a synthetic sweetener, SC-45647, was abolished following i.p. injection of AF-353. These data indicate that activation of P2X3-containing receptors is required for transmission of all taste qualities. PMID- 25524181 TI - Bioaccumulation kinetics of the conventional energetics TNT and RDX relative to insensitive munitions constituents DNAN and NTO in Rana pipiens tadpoles. AB - The manufacturing of explosives and their loading, assembling, and packing into munitions for use in testing on training sites or battlefields has resulted in contamination of terrestrial and aquatic sites that may pose risk to populations of sensitive species. The bioaccumulative potential of the conventional explosives 2,4,6-trinitrotoluene (TNT) and hexahydro-1,3,5-trinitro-1,3,5 triazine (RDX) and of the insensitive munitions (i.e., less shock sensitive) compound 2,4-dinitroanisole (DNAN) were assessed using the Northern leopard frog, Rana pipiens. Trinitrotoluene entering the organism was readily biotransformed to aminodinitrotoluenes, whereas no transformation products were measured for RDX or DNAN. Uptake clearance rates were relatively slow and similar among compounds (1.32-2.19 L kg(-1) h(-1) ). Upon transfer to uncontaminated water, elimination rate was very fast, resulting in the prediction of fast time to approach steady state (5 h or less) and short elimination half-lives (1.2 h or less). A preliminary bioconcentration factor of 0.25 L kg(-1) was determined for the insensitive munitions compound 3-nitro-1,2,4-trizole-5-one (NTO) indicating negligible bioaccumulative potential. Because of the rapid elimination rate for explosives, tadpoles inhabiting contaminated areas are expected to experience harmful effects only if under constant exposure conditions given that body burdens can rapidly depurate preventing tissue concentrations from persisting at levels that may cause detrimental biological effects. PMID- 25524182 TI - Transport and retention mechanisms govern lipid droplet inheritance in Saccharomyces cerevisiae. AB - Lipid droplets are ubiquitous cellular structures involved in energy homeostasis and metabolism that have long been considered as simple inert deposits of lipid. Here, we show that lipid droplets are bona fide organelles that are actively partitioned between mother cell and daughter cell in Saccharomyces cerevisiae. Video microscopy revealed that a subset of lipid droplets moves from mother cell to bud in an ordered, vectorial process, while the remaining lipid droplets are retained by the mother cell. Bud-directed movement of lipid droplets is mediated by the molecular motor Myo2p, while retention of lipid droplets occurs at the perinuclear endoplasmic reticulum. Lipid droplets are thus apportioned between mother cell and daughter cell at cell division rather than being made anew. PMID- 25524183 TI - Validation Study of the Malay version of the Neuropsychiatric Inventory. AB - OBJECTIVES: There is a lack of local instruments to assess behavioural and psychological symptoms of dementia (BPSD). This 2-stage cross-sectional study was aimed at validating a Malay translated version of the Neuropsychiaric Inventory (MvNPI). MATERIALS AND METHODS: It was conducted on a selected group of 138 elderly outpatients with dementia and their caregivers in Hospital Pulau Pinang. Severity of dementia was assessed using the Malay-translated version of Mini Mental State Examination (MMSE). The original NPI was translated and then back translated before it was pilot-tested. The MvNPI was administered twice, a week apart on the same caregiver by the same investigator. RESULTS: The individual items and total scale score of MvNPI had high internal consistency, with Corrected Item-Total Correlation ranging from satisfactory to good (0.41 to 0.77). The Cronbach's alpha for all the NPI domains showed high internal consistency (0.83), and subtotal for severity and distress scores were perfect (0.998 to 1.00). There was no significant difference between test-retest mean scores (p>0.05) and their correlations were perfect (0.996 to 1.00). Content validity indicated mild and inverse relationship between MMSE scores and severity, and distress score (-0.281 and -0.268, respectively, with p<0.001). Discriminant validity calculated using Mann-Whitney U test was found to be significant (p<0.001) in differentiating severity of cognitive impairment. Factor analysis revealed four possible components existed in MvNPI. CONCLUSIONS: The MvNPI is a valid and reliable tool for assessing BPSD among Malay speaking populations of Malaysia and its neighbouring South East Asian countries. PMID- 25524185 TI - Successful pregnancy with the use of vaginal pessary in a patient with a very short cervix. A case report. AB - Preterm birth is one of the causes of perinatal morbidity and mortality. The traditional treatment for a short cervix has been the cerclage in addition with the progesterone administration. Recently, the idea of using vaginal pessaries as a new less invasive method of treatment for the same indication is under discussion. The case of a 29-year-old pregnant woman with an extremely short cervix and the treatment, she underwent during her second pregnancy, is presented. In order to avoid a preterm delivery the patient was treated with the use of a vaginal pessary. After the placement of the pessary and its removal after 37 weeks of gestation, a full term delivery was performed. The pessary was symptom free throughout. In conclusion, the cervical pessary may offer a safe and easy alternative to cerclage for the treatment of cervical insufficiency and prevention of preterm birth. PMID- 25524184 TI - Transarterial angioembolization versus surgery after failed endoscopic therapy for non-variceal upper gastrointestinal bleeding. AB - BACKGROUND AND OBJECTIVE: To compare the outcome of transarterial angioembolization (TAE) and surgery with endoscopically unmanageable non-variceal hemorrhage of the upper gastrointestinal tract. MATERIALS AND METHODS: A case note review of all patients treated for non-variceal upper gastrointestinal bleeding from January 2006 till January 2012 was performed. RESULTS: Fifty-four of 667 patients with non-variceal bleeding did not respond to endoscopic treatment. Nine of the 54 patients had incomplete data, leaving 45 patients in the study; 24 had angiography and another 21 had surgery. The two groups were broadly similar in terms of relevant clinical variables. Nineteen of 24 having angiography had embolisation. Re-bleeding recurred in 8 patients (33%) in the TAE group and 6 patients (28.6%) in the surgery group (p = 0.28). There was no statistically significant difference in post procedural complications (81% vs 62.5%, p = 0.17), 30-day mortality (33% vs 29.1%, p = 0.17 ) units of blood transfused (12.24 vs 8.92, p = 0.177) and mean hospital stay (30.7 vs 22.9 days, p = 0.281) observed in patients undergoing surgery as compared to TAE. CONCLUSIONS: TAE and surgery have similar outcomes in patients with endoscopically unmanageable non-variceal upper gastrointestinal haemorrhage. PMID- 25524186 TI - Breast core biopsy of a rare case of unknown primary large cell neuroendocrine carcinoma metastatic to the breast. AB - Metastases to the breast from extramammary neoplasms are very rare. Correct diagnosis of breast malignancy is important for establishing appropriate management. Here we report a 57-year old male patient with breast metastasis from large cell neuroendocrine carcinoma (LCNEC) which was diagnosed with ultrasonography-guided-core-biopsy. PMID- 25524187 TI - [Long-term survival metastatic ovarian cancer elderly patient]. AB - Ovarian cancer is the sixth diagnosed cancer among women worldwide, it has a high mortality and in most cases it's diagnosed in advanced stage (stage III-IV). Combination platinum-paclitaxel chemotherapy administered every 3 weeks is considered the gold standard for first-line treatment of patients with advanced ovarian cancer. Elderly patients with ovarian cancer represents a subgroup with poor prognosis because they are often treated less radically for comorbidities and age. In the present article, we report a case of a 85 year old woman who was diagnosed with stage IV ovarian carcinoma for the presence of peritoneal carcinomatosis ab initio, not radically debulked and then treated with weekly schedule platinum-based and paclitaxel. Despite not being able to complete the chemotherapy, the patient achieved excellent results and represents a case of long survival. PMID- 25524188 TI - Adenocarcinomas of appendix: a rare tumor. Two case reports. AB - Primary Adenocarcinomas of the appendix are rare tumor. Most commonly diagnosis was made after surgical pocedure of appendicectomy for suspect acute appendicitis and the pathology report confirms appendiceal neoplasm. Laboratory exams and imaging show low sensibility and specificity for preoperative diagnosis. We report two cases of primary mucinous adenocarcinoma in caucasian men misdiagnosed as having acute appendicitis. Appendicectomy was done and excised appendix was sent for histopathological examination. Mucinous Adenocarcinoma of the appendix was confirmed after histopathological examination. Right hemicolectomy, peritonectomy and Intraoperative Hyperthermic Chemotherapy were done as a second stage procedure. The surgical treatment of these neoplasms depends from the histological stage and local presentation. Cytoreductive surgery associated with Intraoperative Hyperthermic Chemotherapy show best results in advanced cases. PMID- 25524189 TI - Biopsy-triggered gastric signet ring cell adenocarcinoma proliferation. PMID- 25524190 TI - [The evolution of the Italian Code of Medical Deontology: a historical epistemological perspective]. AB - The Italian Code of Medical Deontology is a set of self-discipline rules prefixed by the medical profession, that are mandatory for the members of the medical registers, who must conform to these rules. The history of the Italian Code of Medical Deontology dates back to the beginning of the twentieth century. In 1903 it appeared in the form of a "Code of Ethics and Deontology" and was prepared by the Board of the Medical Register of Sassari (Sardinia). This Board inserted the principles inspiring the correct practice of the medical profession in an articulated and self-normative system, also foreseeing disciplinary measures. About ten years later, in 1912, the Medical Register of Turin (Piedmont) elaborated a Code which constituted the basis for a subsequent elaboration leading to a Unified Code of Medical Ethics (1924). After World War II the idea prevailed in Italy that the codes of medical deontology should undergo periodical review, updating and dissemination, and the new 1947 text (Turin) was for the first time amply diffused among Italian physicians. The next national code dates back to 1958, and twenty years later a revision was published. In the 1989 Code new topics appeared, including organ transplantation, artificial in vitro insemination and the role of police doctors; these and other issues were later developed in the 1995, 1998 and 2006 versions of the Code. The last available edition of the Italian Code of Medical Deontology is that of May 2014. PMID- 25524191 TI - Anhedonia among patients with Major Depressive Disorder: A comparison between patients on escitalopram and healthy controls. AB - BACKGROUND AND AIMS: Escitalopram has widely been recognized as one of the most frequently used antidepressants, with superior tolerability and great efficacy in preventing major depressive disorder (MDD) relapse and recurrence. However, anhedonia, which is a core symptom of MDD, remains difficult to treat. This study investigates the hedonic levels of MDD patients treated with Escitalopram. MATERIALS AND METHODS: A total of 108 participants, 26 of whom with MDD on Escitalopram, were recruited in this cross sectional study. They were evaluated using the Snaith-Hamilton Pleasure Scale (SHAPS) and Beck Depression Inventory (BDI) questionnaires to assess their hedonic state, general mental health condition and level of depression. RESULTS: Our study shows that most items in the SHAPS scores are significantly different between MDD patients on Escitalopram and the controls. CONCLUSIONS: The hedonic capacity remains different between the two groups despite patients with MDD are put on Escitalopram treatment. Escitalopram fails to alleviate the hedonic state of MDD patients. Antidepressants that improve both depressive symptoms and hedonic states should be considered when treating MDD patients in clinical settings. PMID- 25524192 TI - Endoscopic laser-assisted dacryocistorhinostomy DCR with the placement of a customised silicone and Teflon bicanalicular stent Endoscopic laser-assisted dacryocystorhinostomy (DCR). AB - INTRODUCTION: We present our experience in endoscopic laser assisted dacryocystorhinostomy (DCR) analyzing the results obtained with a new technique that involves placing bicanalicolar silicone stent more Teflon tube, in combination with paraseptal silastic sheet. MATERIALS AND METHODS: In our study 49 of 57 patients (85%) at a mean follow up of at least 12 months have not reported epiphora or more episodes of acute dacryocystitis. RESULTS: 49 out of the 57 patients (85%) in our group reported no additional epiphora or episodes of acute dacryocystitis. CONCLUSIONS: Endoscopic DCR is currently the gold standard for sac and post-sac stenosis given the minimal invasiveness of the procedure and the long-term results that appear comparable to those obtained with extrinsic DCR. The principal problem is cicatricial stenosis that can occlude the stoma over time. PMID- 25524193 TI - Safety and prolonged efficacy of Botulin Toxin A in primary hyperhidrosis. AB - BACKGROUND: Hyperhidrosis is a condition characterized by generalized or localized hyperfunction of the eccrine sweat glands with a deep negative impact on patient's quality of life. OBJECTIVES: To evaluate the efficacy and the safety of Botulin Toxin A (BTX-A) intradermal injection in the treatment of primary axillary and palmar hyperhidrosis, investigating symptoms-free period, and the subjective improving of quality life. MATERIALS AND METHODS: 50 consecutive patients with primary hyperhidrosis were evaluated detecting age, gender, hyperhidrosis onset period, disease duration and years of treatment with BTX-A, Minor's iodine test, Hyperhidrosis Disease Severity Scale (HDSS), Dermatology Life Quality Index (DLQI). RESULTS: The treatment is significantly effective both for axillae and palms: the majority of the patients improved their HDSS and Minor's scores from a value of 4 in the two tests, to values of 1 (HDSS) and 0 (Minor test). Patients reported a duration of symptoms relief from 4 to 12 months, with a mean of 5.68 months; specifically, we have observed that the axillary group experienced a longer symptoms-free period (mean RFS 7.2 months) than the palmar group (mean: RFS 4.27 months). CONCLUSIONS: Authors suggest that BTX-A is a safe, easy, and fast procedure for the treatment of primary axillary and palmar hyperhidrosis. PMID- 25524194 TI - Reliability study of biometrics "do not contact" in myopia. AB - PURPOSE: The aim of the study is a comparison between the actually achieved after surgery condition versus the expected refractive condition of the eye as calculated via a biometer. MATERIALS AND METHODS: The study was conducted in a random group of 38 eyes of patients undergoing surgery by phacoemulsification. RESULTS: The mean absolute error was calculated between the predicted values from the measurements with the optical biometer and those obtained in the post operative error which was at around 0.47% CONCLUSIONS: Our study shows results not far from those reported in the literature, and in relation, to the mean absolute error is among the lowest values at 0.47 +/- 0.11 SEM. PMID- 25524195 TI - [The cardiological evaluation in patients undergoing to Day Surgery: when is indicated]. AB - AIM: Guidelines established preoperative cardiac management of the patient undergoing non-cardiac surgery in hospitalization. Regarding the patients undergoing the surgery in DS, the management is not defined. Aim of this study was to evaluate the appropriateness of the cardiological consultation requested by the patients undergoing surgery with this method. MATERIALS AND METHODS: We examined the request of cardiological evaluation for patient admitted to DS of Sant'Andrea Hospital in Rome. We have considered: age, sex, clinic history, simpthomatology, electrocardiogram, cardiovascular objectivity, hemodynamic stability, comorbidity, therapy, type of the surgery, the motivation of the request. RESULTS: Of 2350 patients, 495 patients (21%) have been undergone the preoperative cardiologic consultation. The request was resulted as unnecessary for 432 (87.2%) patients, appropriate for 63 (12.7%): 4 that had the ischemic heart disease without knowing this, 6 with severe hypertension; 2 with mitral valve prolapse and valvular regurgitation; 34 with congestive heart failure; 6 with the alterations in EKG : 3 with "Brugada pattern"; 1 with Pace Maker (PMK) that had to be reprogrammed before the operation; 3 under dual antiplatelet therapy; 7 that were taking the oral anticoagulant therapy. Cardiac complications occurred just in one case with patient suffering dilated cardiomyopathy, diabetes and hypertension; during the cataract surgery was presented the abrupt increase of blood pressure and left ventricular failure. CONCLUSIONS: Preoperative cardiologic evaluation results as useless in most patients. However, in some particular situations had allowed the diagnosis of heart disease for the patients who did not know to have it. PMID- 25524196 TI - Metachronous elastofibromas. AB - Elastofibroma Dorsi (EFD) is a rare pseudo-tumor characterized by the overgrowth of elastic fibers mixed to adipose and connective tissues typically growing in the subscapular region. This can be bilateral but only rarely synchronous affecting different anatomical sites at the same time. Hereby we present a case of a 42-year-old male patient found with three different metachronous elastofibromas: bilateral EFD and a further third localization by the right elbow. The two EFs in the subscapular region were resected. After surgery pain reoccurred on the right side. This required the implantation of a spinal electro stimulator. The elbow lesion was not excised as it was asymptomatic. PMID- 25524197 TI - A rare case of myocardial infarction by myocardial bridging of circumflex artery. AB - Myocardial Bridging (MB) is a benign condition that may be considered as a possible cause of ischaemic cardiopathy up to myocardial infarction. The authors describe the autopsy case of an MB of circumflex artery in a person with a myocardial infarction of the posterior wall of the left ventricle. In this case, the chronic ischemic heart disease can be explained by the congenital anomaly and in the literature there is scientific evidence to support the thesis. The MB is a benign condition that in combination with other risk factors can cause ischemic heart disease. PMID- 25524198 TI - Coronary artery disease in thrombotic aneurysm of the abdominal aorta. AB - Even if the rupture is the most common cause of death of patients with Abdominal Aortic Aneurysm (AAA) and the risk increases with the presence and the size of IntraLuminal Thrombosis (ILT), there are cases in which death occurs for other causes. The Authors present an autoptic report of considerable size AAA with ILT in a patient who died by heart failure due to CAD thrombotic and ischemic heart disease. A protective role of approved in the literature and the role of products resulting from the thrombotic formation could explain the death event. PMID- 25524199 TI - Multiple painful papulo-nodular lesions: clinical pitfall. AB - A 43-year-old male presented with multiple (>10) painful, papulo-nodular lesions, associated with paresthesia, over the face, neck and trunk, appeared 15 years prior and increased with time. The patient's brother has cutaneous leiomyomas and testicle cancer, his mother underwent hysterectomy for symptomatic leiomyomas while his maternal grandfather died from aggressive renal cell carcinoma at age 57 years. The patient reported that he had removed a kidney cancer 5 years prior. Dermoscopy, histologic evaluation and genetical analysis were done and Hereditary leiomyomatosis and renal cell carcinoma was diagnosed. PMID- 25524200 TI - The human papillomavirus vaccination: a review of the cost-effectiveness studies. AB - BACKGROUND: The Human Papillomavirus (HPV) is one of the most common sexually transmitted viruses, its infection with certain subtypes is the primary cause of cervical cancer. Several countries conducted specific cost-effectiveness evaluations toward HPV vaccination. The constant growth of healthcare demand, in an economic context characterized by limited resources, requires that the decision-making process be based on the comparison of alternative choices. This study offers an overview of the published cost-effectiveness studies about HPV vaccination. BIBLIOGRAPHIC RETRIEVAL METHOD: The research was performed on the scientific databases MEDLINE and SCOPUS in order to find out journal articles focused on cost-effectiveness of the HPV vaccination. The rational for any exclusion criteria of data in the search is mainly due to lack of relevance to cost-effectiveness information. RESULTS: The literature results were presented according to different groups of countries worldwide. A total of 24 articles were finally retrieved. In spite of the different models and assumptions, most studies showed the cost-effectiveness of vaccination; only two studies considered the vaccination as not cost effective. CONCLUSIONS: HPV vaccination may determine a cost reduction for country-specific National Health Systems. However, the cost effectiveness of universal HPV vaccination still remains an open debate. It is important that economic analysis of universal HPV vaccination adopts large perspectives than is the case with the existing literature, focusing on the critical issues that still exist in many areas. Reducing cost, increasing duration of efficacy, and integrating vaccines into existing screening and treatment procedures in a cost-effective manner are of crucial importance even as they are a major challenge. PMID- 25524201 TI - [Measuring the instant]. AB - The instant is the infinitesimal fraction of time nearest to zero. Its computational measurement is not feasable in that it should be an infinitesimal commensurable portion of infinite time, which is incommensurabile by principle. The philosophical implication is that the instant has to be intended as an abstract entity belonging to metaphysical, transcendent, supranormal, suprasensitive, infinite time. In other words, the instant does not represent an experential deduction of our intellect, but an aprioristic innate idea letting us to be aware of physical, immanent, natural, sensible, finite temporality. PMID- 25524202 TI - The Th1 chemokine IP-10 in Systemic sclerosis. AB - Many studies have suggested that IP-10/CXCR3 axis plays a critical role in the autoimmune process and in fibrosis in patients with systemic sclerosis (SSc). A longitudinal study demonstrated high serum levels of IP-10 [T-helper (Th)1] and MCP-1 (Th2) chemokines in newly diagnosed SSc. High values of IP-10 were associated with a more severe clinical phenotype (lung and kidney involvement). IP-10 declined during the follow-up, while MCP-1 remained unmodified, suggesting that the disease progresses from the early Th1 inflammatory condition to the advanced Th2-like stage. Other studies have shown that IP-10 is a marker of a more aggressive autoimmune process involving organs such as thyroid or lung. SSc fibroblasts show in vitro various types of dysregulated production of IP-10, when stimulated with cytokines, such as interferons (IFNs). Furthermore, it has been suggested that the IFN-inducible chemokine IP-10 is a stable serologic marker of a more severe form of SSc and may be useful for risk stratification of patients, regardless of disease type (limited or diffuse). PMID- 25524203 TI - Interferon gamma -induced chemokines in psoriatic arthritis. AB - Interferon gamma-inducible protein (IP-10) chemokine is implicated in the pathogenesis of psoriatic arthritis (PsA). It was shown that chemokine (C-X-C motif) receptor (CXCR) 3 and CXCR4 were expressed by both blood-derived plasmacytoid dendritic cells (pDCs) and pDCs isolated from rheumatoid arthritis (RA) and PsA synovial fluid (SF) and that IP-10, chemokine (C-X-C motif) ligand (CXCL)-11, and CXCL-12 present in RA and PA SF stimulated chemotaxis of blood derived pDCs. High circulating levels of IP-10 and chemokine (C-C motif) ligand (CCL) 2 have been found in PsA patients, with a T helper cells (Th) 1 immune predominance in the early phase of the disease. Moreover a decline of IP-10 levels has been observed in long lasting PsA, with a significant increase of the CCL2/IP-10 ratio, suggesting a shift from Th1 to Th2 immune response in long duration PsA. IP-10 levels in PsA patients are significantly higher in presence of autoimmune thyroiditis. IP-10 has been suggested to be a good marker to monitor the activity or progression of PsA. Attempts have been made to modulate or inhibit the production of IP-10 in PsA in order to modify the course of the disease. PMID- 25524204 TI - Rheumatoid arthritis and the alpha-chemokine IP-10. AB - Interferon(IFN)-gamma-induced protein 10 (IP-10) and its receptor, CXCR3, appear to contribute to the pathogenesis of rheumatoid arthritis (RA). IP-10 has been detected in sera, synovial fluid (SF), and synovial tissue in RA patients. IP-10 is mainly expressed by infiltrating macrophage-like cells and fibroblast-like synoviocytes in RA synovium. The elevated expression of CXCR3 on T cells from SF has been associated with high levels of IFN-gamma, which suggest a preferential Th1 phenotype. A human phase II clinical trial using an anti-IP-10 monoclonal antibody (MDX-1100) for RA patients who had an inadequate response to methotrexate treatment has shown that blocking IP-10 significantly increased response rate compared to the placebo group, suggesting a possible therapeutic use in humans. PMID- 25524205 TI - [Tyrosine kinase inhibitors for the treatment of papillary thyroid cancer]. AB - Since 2005, different types of multitargeted tyrosine kinase inhibitors were used in clinical trials for the treatment of patients with advanced thyroid cancers. Experimental studies have demonstrated that tyrosine kinase inhibitors has both anti-proliferative and anti-angiogenic properties in vitro and in vivo, against thyroid cancer cells. Furthermore, several completed (or ongoing) studies have evaluated the long-term efficacy and tolerability of tyrosine kinase inhibitors in patients with papillary, follicular and medullary aggressive thyroid cancer. The results of the different studies showed good clinical responses and stabilization of the disease and suggested that tyrosine kinase inhibitors are a promising therapeutic option in patients with advanced thyroid cancer that is not responsive to traditional therapeutic strategies (such as radioiodine). PMID- 25524206 TI - Sjogren's syndrome and chemokines. AB - Interferon (IFN)-gamma-induced protein 10 (IP-10) and its receptor, chemokine (C X-C motif) receptor (CXCR)3, appear to contribute to the pathogenesis of Sjogren's syndrome (SS). The expression of IP-10 and CXCR3 is increased, in salivary glands from SS patients, both in the ductal epithelium adjacent to lymphoid infiltrates and in lymphocytes. IFN-gamma induces the production of high levels of IP-10 and monokine induced by IFN-gamma (MIG) proteins from cultured SS salivary epithelial cells. Under the influence of IFN-gamma, IP-10 secreted by salivary cells, recruits T helper (Th)1 lymphocytes that may be responsible for enhanced IFN-gamma, which in turn stimulates a further IP-10 secretion from epithelial cells creating an amplification feedback loop and perpetuating the autoimmune process. Determination of high level of IP-10 in tears and saliva is therefore a marker of a Th1 orientated immune response. In experimental settings IP-10 antagonists can ameliorate the progression of autoimmune sialadenitis, providing a new therapeutic approach to SS. Further studies are needed to investigate whether IP-10 is a novel therapeutic target in SS in humans. PMID- 25524207 TI - Non-antigen-contacting region of an asymmetric bispecific antibody to factors IXa/X significantly affects factor VIII-mimetic activity. AB - While antibody engineering improves the properties of therapeutic antibodies, optimization of regions that do not contact antigens has been mainly focused on modifying the effector functions and pharmacokinetics of antibodies. We recently reported an asymmetric anti-FIXa/FX bispecific IgG4 antibody, ACE910, which mimics the cofactor function of FVIII by placing the two factors into spatial proximity for the treatment of hemophilia A. During the optimization process, we found that the activity was significantly affected by IgG subclass and by modifications to the inter-chain disulfide bonds, upper hinge region, elbow hinge region, and Fc glycan, even though these regions were unlikely to come into direct contact with the antigens. Of these non-antigen-contacting regions, the tertiary structure determined by the inter-chain disulfide bonds was found to strongly affect the FVIII-mimetic activity. Interestingly, IgG4-like disulfide bonds between Cys131 in the heavy chain and Cys114 in the light chain, and disulfide bonds between the two heavy chains at the hinge region were indispensable for the high FVIII-mimetic activity. Moreover, proline mutations in the upper hinge region and removal of the Fc glycan enhanced the FVIII-mimetic activity, suggesting that flexibility of the upper hinge region and the Fc portion structure are important for the FVIII-mimetic activity. This study suggests that these non-antigen-contacting regions can be engineered to improve the biological activity of IgG antibodies with functions similar to ACE910, such as placing two antigens into spatial proximity, retargeting effector cells to target cells, or co-ligating two identical or different antigens on the same cell. PMID- 25524208 TI - Xenotransplantation exposes the etiology of azoospermia factor (AZF) induced male sterility. AB - Ramathal et al. have employed an elegant xenotransplantation technique to study the fate of human induced pluripotent stem cells (hiPSCs) from fertile males and from males carrying Y chromosome deletions of the azoospermia factor (AZF) region. When placed in a mouse testis niche, hiPSCs from fertile males differentiate into germ cell-like cells (GCLCs). Highlighting the crucial role of cell autonomous factors in male sterility, hiPSCs derived from azoospermic males prove to be less successful under similar circumstances. Their studies argue that the agametic "Sertoli cell only" phenotype of two of the AZF deletions likely arises from a defect in the maintenance of germline stem cells (GSCs) rather than from a defect in their specification. These observations underscore the importance of the dialogue between the somatic niche and its inhabitant stem cells, and open up interesting questions concerning the functioning of the somatic niche and how it communicates to the GSCs. PMID- 25524209 TI - The analysis of incontinence episodes and other count data in patients with overactive bladder by Poisson and negative binomial regression. AB - Clinical studies in overactive bladder have traditionally used analysis of covariance or nonparametric methods to analyse the number of incontinence episodes and other count data. It is known that if the underlying distributional assumptions of a particular parametric method do not hold, an alternative parametric method may be more efficient than a nonparametric one, which makes no assumptions regarding the underlying distribution of the data. Therefore, there are advantages in using methods based on the Poisson distribution or extensions of that method, which incorporate specific features that provide a modelling framework for count data. One challenge with count data is overdispersion, but methods are available that can account for this through the introduction of random effect terms in the modelling, and it is this modelling framework that leads to the negative binomial distribution. These models can also provide clinicians with a clearer and more appropriate interpretation of treatment effects in terms of rate ratios. In this paper, the previously used parametric and non-parametric approaches are contrasted with those based on Poisson regression and various extensions in trials evaluating solifenacin and mirabegron in patients with overactive bladder. In these applications, negative binomial models are seen to fit the data well. PMID- 25524210 TI - HIV Diagnoses, Prevalence and Outcomes in Nine Southern States. AB - A group of nine states in the Southern United States, hereafter referred to as the targeted states, has experienced particularly high HIV diagnosis and case fatality rates. To provide additional information about the HIV burden in this region, we used CDC HIV surveillance data to examine characteristics of individuals diagnosed with HIV in the targeted states (2011), 5-year HIV and AIDS survival, and deaths among persons living with HIV (2010). We used multivariable analyses to explore the influence of residing in the targeted states at diagnosis on deaths among persons living with HIV after adjustment for demographics and transmission risk. In 2011, the targeted states had a higher HIV diagnosis rate (24.5/100,000 population) than the US overall (18.0/100,000) and higher proportions than other regions of individuals diagnosed with HIV who were black, female, younger, and living in suburban and rural areas. Furthermore, the targeted states had lower HIV and AIDS survival proportions (0.85, 0.73, respectively) than the US overall (0.86, 0.77, respectively) and the highest death rate among persons living with HIV of any US region. Regional differences in demographics and transmission risk did not explain the higher death rate among persons living with HIV in the targeted states indicating that other factors contribute to this disparity. Differences in characteristics and outcomes of individuals with HIV in the targeted states are critical to consider when creating strategies to address HIV in the region, as are other factors identified in previous research to be prominent in the region including poverty and stigma. PMID- 25524211 TI - Sustainability of Public Health Interventions to Reduce the Risk of Dioxin Exposure at Severe Dioxin Hot Spots in Vietnam. AB - Severe dioxin contamination at Bien Hoa and Da Nang airbases, Vietnam is of international concern. Public Health risk reduction programs were implemented in Bien Hoa in 2007-2009 and in Da Nang in 2009-2011. In 2009 and 2011 we reported the encouraging results of these interventions in improving the knowledge, attitude and practices (KAP) of local residents in reducing the dioxin exposure risk through foods. In 2013 we revisited these dioxin hot spots, aimed to evaluate whether the results of the intervention were maintained and to identify factors affecting the sustainability of the programs. To assess this, 16 in-depth interviews, six focus group discussions, and pre and post intervention KAP surveys were undertaken. 800 respondents from six intervention wards and 200 respondents from Buu Long Ward (the control site) were randomly selected to participate in the surveys. The results showed that as of 2013, the programs were rated as "moderately sustained" with a score of 3.3 out of 5.0 (cut off points 2.5 to <3.5) for Bien Hoa, and "well sustained" with a score of 3.8 out of 5.0 (cut off points 3.5 to <4.5) for Da Nang. Most formal intervention program activities had ceased and dioxin risk communication activities were no longer integrated into local routine health education programs. However, the main outcomes were maintained and were better than that in the control ward. Migration, lack of official guidance from City People's Committees and local authorities as well as the politically sensitive nature of dioxin issues were the main challenges for the sustainability of the programs. PMID- 25524212 TI - Expression of human leukocyte antigen class I in endocrine and exocrine pancreatic tissue at onset of type 1 diabetes. AB - The cause of type 1 diabetes remains unknown. To dissect the link between hyperexpression of human leukocyte antigen (HLA) class I on the islet cells, we examined its expression in subjects with recent-onset type 1 diabetes. IHC showed seemingly pronounced hyperexpression in subjects with recent-onset type 1 diabetes, as well as in some nondiabetic subjects. In all subjects, HLA class I expression on exocrine tissue was low. However, no difference in the level of HLA class I expression was found between islet and exocrine tissue using Western blot, flow cytometry, real-time quantitative PCR, or RNA sequencing analyses. Also, the level of HLA class I expression on the messenger level was not increased in islets from subjects with recent-onset type 1 diabetes compared with that in nondiabetic subjects. Consistently, the HLA class I specific enhanceosome (NLRC5) and related transcription factors, as well as interferons, were not enhanced in islets from recent-onset type 1 diabetic subjects. In conclusion, a discrepancy in HLA class I expression in islets assessed by IHC was observed compared with that using quantitative techniques showing similar expression of HLA class I in islets and exocrine tissue in subjects with recent-onset type 1 diabetes, nor could any differences be found between type 1 diabetic and nondiabetic subjects. Results presented provide important clues for a better understanding on how this complex disease develops. PMID- 25524213 TI - Physiological phenotyping of plants for crop improvement. AB - Future progress in crop breeding requires a new emphasis in plant physiological phenotyping for specific, well-defined traits. Success in physiological phenotyping to identify parents for use in breeding efforts for improved cultivars has been achieved by employing a multi-tier screening approach with different levels of sophistication and trait resolution. Subsequently, cultivar development required an integrated mix of classical breeding approaches and one or more tiers of phenotyping to identify genotypes expressing the desired trait. The role of high throughput systems can be useful; here, we emphasize that this approach is likely to offer useful results at an initial tier of phenotyping and will need to be complemented with more directed tiers of phenotyping. PMID- 25524214 TI - The effect of different doses and different routes of acetylsalicylic acid administration on platelet aggregation in healthy volunteers and ischemic stroke patients. AB - The purpose was to assess the effect of different doses and different routes of acetylsalicylic acid (ASA) administration on platelet aggregation and the comparison between platelet aggregation after the single and the repetitive administration of ASA in healthy individuals and in patients after ischemic stroke. The study group consists of 22 healthy individuals and 30 patients with documented ischemic stroke. Platelet aggregation was measured in healthy individuals: (a) twice before ASA and (b) 2 h after different single doses and different routes of ASA administration-(b1) 500 mg orally, (b2) 500 mg intravenously, and (b3) 100 mg orally. We measured aggregability in healthy individuals after five consecutive days of 100 mg of ASA q.d. and in patients on chronic ASA 100 mg q.d. The VerifyNow was used with results expressed in aspirin reaction units (ARU). In healthy individuals, the dose-(b1) 500 mg orally-reduced the aggregability to mean (SD) 392 (36) ARU (p < 0.001), (b2) 500 mg intravenously to 428 (46) (p < 0.001) and (b3) 100 mg orally to 460 (76) (p < 0.001). The suppression of aggregation after 500 mg was (p = 0.029) higher after the oral compared to intravenous administration, and the same is true for the suppression after single dose of 500 mg orally and 100 mg orally (p = 0.011). Oral dose 100 mg for 5 days in healthy individuals reduced aggregation to 405 (37) and in post-stroke patients to 433 (54). All doses of ASA, both orally and intravenously, have produced a significant reduction of platelet aggregation. Preference of the parenteral to oral application has not been established. PMID- 25524215 TI - Contact allergy caused by Tinosorb(r) M: let us not forget about xanthan gum. PMID- 25524216 TI - Model for risk adjustment of postoperative mortality in patients with colorectal cancer. AB - BACKGROUND: A model was developed for risk adjustment of postoperative mortality in patients with colorectal cancer in order to make fair comparisons between healthcare providers. Previous models were derived in relatively small studies with the use of suboptimal modelling techniques. METHODS: Data from adults included in a national study of major surgery for colorectal cancer were used to develop and validate a logistic regression model for 90-day mortality. The main risk factors were identified from a review of the literature. The association with age was modelled as a curved continuous relationship. Bootstrap resampling was used to select interactions between risk factors. RESULTS: A model based on data from 62 314 adults was developed that was well calibrated (absolute differences between observed and predicted mortality always smaller than 0.75 per cent in deciles of predicted risk). It discriminated well between low- and high risk patients (C-index 0.800, 95 per cent c.i. 0.793 to 0.807). An interaction between age and metastatic disease was included as metastatic disease was found to increase postoperative risk in young patients aged 50 years (odds ratio 3.53, 95 per cent c.i. 2.66 to 4.67) far more than in elderly patients aged 80 years (odds ratio 1.48, 1.32 to 1.66). CONCLUSION: Use of this model, estimated in the largest number of patients with colorectal cancer to date, is recommended when comparing postoperative mortality of major colorectal cancer surgery between hospitals, clinical teams or individual surgeons. PMID- 25524218 TI - Loss of intramolecular electrostatic interactions and limited conformational ensemble may promote self-association of cis-tau peptide. AB - Self-association of proteins can be triggered by a change in the distribution of the conformational ensemble. Posttranslational modification, such as phosphorylation, can induce a shift in the ensemble of conformations. In the brain of Alzheimer's disease patients, the formation of intra-cellular neurofibrillary tangles deposition is a result of self-aggregation of hyper phosphorylated tau protein. Biochemical and NMR studies suggest that the cis peptidyl prolyl conformation of a phosphorylated threonine-proline motif in the tau protein renders tau more prone to aggregation than the trans isomer. However, little is known about the role of peptidyl prolyl cis/trans isomerization in tau aggregation. Here, we show that intra-molecular electrostatic interactions are better formed in the trans isomer. We explore the conformational landscape of the tau segment containing the phosphorylated-Thr(231)-Pro(232) motif using accelerated molecular dynamics and show that intra-molecular electrostatic interactions are coupled to the isomeric state of the peptidyl prolyl bond. Our results suggest that the loss of intra-molecular interactions and the more restricted conformational ensemble of the cis isomer could favor self aggregation. The results are consistent with experiments, providing valuable complementary atomistic insights and a hypothetical model for isomer specific aggregation of the tau protein. PMID- 25524217 TI - Media actors' perceptions of their roles in reporting food incidents. AB - BACKGROUND: Previous research has shown that the media can play a role in shaping consumer perceptions during a public health crisis. In order for public health professionals to communicate well-informed health information to the media, it is important that they understand how media view their role in transmitting public health information to consumers and decide what information to present. This paper reports the perceptions of media actors from three countries about their role in reporting information during a food incident. This information is used to present ideas and suggestions for public health professionals working with media during food incidents. METHODS: Thirty three semi-structured interviews with media actors from Australia, New Zealand and the United Kingdom were conducted and analysed thematically. Media actors were recruited via purposive sampling using a sampling strategy, from a variety of formats including newspaper, television, radio and online. RESULTS: Media actors said that during a food incident, they play two roles. First, they play a role in communicating information to consumers by acting as a conduit for information between the public and the relevant authorities. Second, they play a role as investigators by acting as a public watchdog. CONCLUSION: Media actors are an important source of consumer information during food incidents. Public health professionals can work with media by actively approaching them with information about food incidents; promoting to media that as public health professionals, they are best placed to provide the facts about food incidents; and by providing angles for further investigation and directing media to relevant and correct information to inform such investigations. Public health professionals who adapt how they work with media are more likely to influence media to portray messages that fit what they would like the public to know and that are in line with public health recommendations and enable consumers to engage in safe and health promoting behaviours in response to food incidents. PMID- 25524219 TI - Behavioral disorders as unusual presentation of pediatric extraventricular neurocytoma: report on two cases and review of the literature. AB - BACKGROUND: Extraventricular neurocytomas (EVNs) are rare parenchymal brain tumors, distinct from central neurocytomas that are typically located within the supratentorial ventricular system. Seizures and headache represent the most common symptoms of extraventricular neurocytomas in the cerebral hemisphere both in adult and pediatric population. CASE PRESENTATION: We describe two cases of pediatric EVN with clinical onset characterized by behavioral and attention deficit/ hyperactivity disorders. The association between behavioral/attention disorders in childhood and the presence of a frontal neurocytoma has never been described before. Furthermore, inappropriate levels of inattention, hyperactivity and impulsivity are common among the neurobehavioral and developmental disorders in childhood. We reviewed 43 pediatric cases of extraventricular neurocytoma included in the PubMed database and their clinical presentation, and we never found this unusual relationship. CONCLUSION: In childhood, the attention/hyperactivity disorders seem to be often over-diagnosed. When these deficits are more subtle and do not well-fit in a specific neurocognitive disorder, the clinicians should have a suspicion that they might mask the clinical features of a frontal lesion. This paper is focused on the clinical presentation of the extraventricular neurocytoma and the possible organic etiology of an attention and hyperactivity deficit. PMID- 25524220 TI - Gel-embedded niosomes: preparation, characterization and release studies of a new system for topical drug delivery. AB - In the present paper physical gels, prepared with two polysaccharides, Xanthan and Locust Bean Gum, and loaded with non-ionic surfactant vesicles, are described. The vesicles, composed by Tween20 and cholesterol or by Tween85 and Span20, were loaded with Monoammonium glycyrrhizinate for release experiments. Size and zeta (zeta)-potential of the vesicles were evaluated and the new systems were characterized by rheological and dynamo-mechanical measurements. For an appropriate comparison, a Carbopol gel and a commercial gel for topical applications were also tested. The new formulations showed mechanical properties comparable with those of the commercial product indicating their suitability for topical applications. In vitro release experiments showed that the polysaccharide network protects the integrity of the vesicles and leads to their slow release without disruption of the aggregated structures. Furthermore, being the vesicles composed of molecules possessing enhancing properties, the permeation of the loaded drugs topically delivered can be improved. Thus, the new systems combine the advantages of matrices for a modified release (polymeric component) and those of an easier permeability across the skin (vesicle components). Finally, shelf live experiments indicated that the tested gel/vesicle formulations were stable over 1 year with no need of preservatives. PMID- 25524221 TI - Mesenchymal stromal cells loading curcumin-INVITE-micelles: a drug delivery system for neurodegenerative diseases. AB - This work reports on the formation of a carrier-in-carrier device for the systemic delivery and targeting of hydrophobic drugs mediated by micelle-loaded mesenchymal stromal cells (MSCs) (carrier-in-carrier) to be administered by intravenous injection. The innate ability of MSCs to reach injured tissues such as the central nervous system or other damaged tissues, is the key for the second order delivery and first order targeting. Inulin-D-alfa-tocopherol succinate micelles (INVITE M) are able to incorporate highly hydrophobic drugs and, due to their dimensions (~7 nm diameter), to penetrate the cell membrane easily and quickly. This study demonstrates that the curcumin loaded micelles (INVITE MC), sterilized by filtration, reached the maximum loading in MSCs in few minutes and that the loading was concentration-dependent. When "naked" curcumin was used, an evident cytotoxicity on MSCs was detected, while INVITE micelles protected them from this effect. Moreover, MSCs loaded with INVITE MC are able to release the entrapped drug. This study strongly supports the feasibility of the carrier-in carrier approach for the therapy of selected diseases, i.e., this innovative drug delivery system will be proposed for the treatment of the amyotrophic lateral sclerosis (ALS). PMID- 25524222 TI - Effect of polymer molecular weight on chitosan-protein interaction. AB - We present a comprehensive study of the interactions between chitosan nanoparticles (15, 100 and 200 kDa with the same degree of deacetylation 90%) and two model proteins, i.e., bovine (BSA) and human serum albumins (HSA), with the aim of correlating chitosan molecular weight (Mw) and the binding affinity of these naturally occurring polymers to protein. The effect of chitosan on the protein secondary structure and the influence of protein complexation on the shape of chitosan nanoparticles are discussed. A combination of multiple spectroscopic methods, transmission electron microscopy (TEM) and thermodynamic analysis were used to assess the polymer-protein complex formation. Results revealed that the three chitosan nanoparticles interact with BSA to form chitosan BSA complexes, mainly through hydrophobic contacts with the affinity order: 200>100>15 kDa. However, HSA-chitosan complexation is mainly via electrostatic interactions with the stability order: 100>200>15 kDa. Furthermore, the association between polymer and protein causes a partial protein conformational change by a major reduction of alpha-helix from 63% (free BSA) to 57% (chitosan BSA) and 57% (free HSA) to 51% (chitosan-HSA). Finally, TEM micrographs clearly revealed that the binding of serum albumins with chitosan nanoparticles induces a significant change in protein morphology and the shape of the polymer. PMID- 25524223 TI - PDLIM5 mediates PKCepsilon translocation in PMA-induced growth cone collapse. AB - Growth cone collapse is a critical repulsive response to various guidance cues for axon guidance. Protein kinase C epsilon (PKCepsilon) plays important regulation roles in such responses. Translocation of PKCepsilon from cytoplasm to membrane is crucial to archive its regulatory roles in this process. We previously reported that PDLIM5 could selectively recruit PKCepsilon to its specific substrate in neurons. However, the molecular mechanism of PKCepsilon translocation in the neuronal growth cone collapse remains elusive. Here, we demonstrated that PDLIM5 and PKCepsilon co-existed in the nerve growth cones. By interacting with alpha-actinin, but not beta-actin or beta-tubulin, PDLIM5 might contribute to regulation of remodeling of the microfilaments in neurons. Meanwhile, PDLIM5 could also bind to PKCepsilon to form PDLIM5-PKCepsilon complexes in growth cones. In the primary cultured neurons, activation of PKCepsilon by PMA resulted in translocation of both PKCepsilon and PDLIM5 from cytoplasm to the membrane. Knockdown of either PDLIM5 or PKCepsilon rescued the neuron from PMA-induced growth cone collapse. Furthermore, in neurons, application of PDLIM5 shRNA or over-expression of PDLIM5 LIM1-3 mutants reduced the amount of PKCepsilon in the membrane. Together, these results suggest that PDLIM5 acts as a scaffold protein by mediated PKCepsilon translocated to the membrane in PMA-induced growth cone collapse. PMID- 25524224 TI - The mediating effect of context variation in mixed practice for transfer of basic science. AB - Applying a previously learned concept to a novel problem is an important but difficult process called transfer. Practicing multiple concepts together (mixed practice mode) has been shown superior to practicing concepts separately (blocked practice mode) for transfer. This study examined the effect of single and multiple practice contexts for both mixed and blocked practice modalities on transfer performance. We looked at performance on near transfer (familiar contexts) cases and far transfer (unfamiliar contexts) cases. First year psychology students (n = 42) learned three physiological concepts in a 2 * 2 factorial study (one or two practice contexts and blocked or mixed practice). Each concept was practiced with two clinical cases; practice context was defined as the number of organ systems used (one system per concept vs. two systems). In blocked practice, two practice cases followed each concept; in mixed practice, students learned all concepts before seeing six practice cases. Transfer testing consisted of correctly classifying and explaining 15 clinical cases involving near and far transfer. The outcome was ratings of quality of explanations on a 0 3 scale. The repeated measures analysis showed a significant near versus far by organ system interaction [F(1,38) = 3.4, p < 0.002] with practice with a single context showing lower far transfer scores than near transfer [0.58 (0.37)-0.83 (0.37)] compared to the two contexts which had similar far and near transfer scores [1.19 (0.50)-1.01 (0.38)]. Practicing with two organ contexts had a significant benefit for far transfer regardless of mixed or blocked practice; the single context mixed practice group had the lowest far transfer performance; this was a large effect size (Cohen's d = 0.81). Using only one practice context during practice significantly lowers performance even with the usually superior mixed practice mode. Novices should be exposed to multiple contexts and mixed practice to facilitate transfer. PMID- 25524225 TI - Simple access to highly functional bicyclic gamma- and delta-lactams: origins of chirality transfer to contiguous tertiary/quaternary stereocenters assessed by DFT. AB - This paper describes the synthesis of both polysubstituted oxazolo-pyrrolidinones and -piperidinones by a domino process. The methodology is based on the reaction between hydroxyl halogenoamides and Michael acceptors, which leads efficiently to bicyclic lactams. The process is compatible with unsymmetrical electron withdrawing groups on the Michael acceptor, which allows the formation of two contiguous and fully controlled tertiary and quaternary stereocenters. In the case of tetrasubstituted Michael acceptors, two adjacent quaternary stereocenters are formed in good yield. Starting from (R)-phenylglycinol derived amides results in the formation of enantioenriched bicyclic lactams in low to good yields and with high levels of stereoselectivity, thus greatly increasing the scope and interest of this strategy. The origins of chirality transfer and diastereoselectivity were studied by DFT calculations and have been attributed to a kinetic control in one of the last two steps of the reaction sequence. This selectivity is dependent upon both the substituents on the Michael acceptor and the sodium cation chelation. PMID- 25524226 TI - Editorial: Money, money, money: not so funny in the research world. PMID- 25524228 TI - Observation of decoherence in a carbon nanotube mechanical resonator. AB - In physical systems, decoherence can arise from both dissipative and dephasing processes. In mechanical resonators, the driven frequency response measures a combination of both, whereas time-domain techniques such as ringdown measurements can separate the two. Here we report the first observation of the mechanical ringdown of a carbon nanotube mechanical resonator. Comparing the mechanical quality factor obtained from frequency- and time-domain measurements, we find a spectral quality factor four times smaller than that measured in ringdown, demonstrating dephasing-induced decoherence of the nanomechanical motion. This decoherence is seen to arise at high driving amplitudes, pointing to a nonlinear dephasing mechanism. Our results highlight the importance of time-domain techniques for understanding dissipation in nanomechanical resonators, and the relevance of decoherence mechanisms in nanotube mechanics. PMID- 25524227 TI - Influence of cervical bone mineral density on cage subsidence in patients following stand-alone anterior cervical discectomy and fusion. AB - PURPOSE: Anterior cervical discectomy and fusion (ACDF) is a common procedure for the treatment of cervical degenerative diseases. However, cage subsidence remains a frequent problem. We therefore investigated if cage design and site-specific bone mineral density (BMD) contribute to the rate and direction of subsidence following ACDF. METHODS: Patients were prospectively included and received two different cages (groups 1 and 2) using minimization randomization. The degree and direction of cage subsidence were determined using plain radiographs. Neck pain intensity on the visual analogue scale (VAS), the neck disability index (NDI), and the patient satisfaction index were recorded up to 12 months after surgery. RESULTS: 88 patients were analysed with a mean age of 53.7 +/- 11.8 years. BMD values decreased in craniocaudal direction from 302.0 +/- 62.2 to 235.5 +/- 38.9 mg/cm(3). Both groups showed significant height gain after the operation (both p < 0.001), followed by height loss at 3 months (both p < 0.05) and at 3-12 months after the operation (both p > 0.05). Both groups showed improvement of VAS neck pain intensity (both p < 0.05) and NDI (both p < 0.05). The direction of cage subsidence was similar, no correlations were found between cage subsidence and BMD or various clinical parameters. CONCLUSIONS: Implant geometry of both cages and variations of the operative procedure promoted a relatively high degree of cage subsidence. Further studies are necessary to identify a relation of BMD and subsidence using optimized implant geometry and by controlling additional intraoperative variables. PMID- 25524229 TI - [Remission maintenance with methotrexate, azathioprine or mycophenolate-mofetil after induction therapy with rituximab for granulomatosis with polyangiitis]. PMID- 25524231 TI - Mass spectrometric identification, sequence evolution, and intraspecific variability of dimeric peptides encoded by cockroach akh genes. AB - Neuropeptides are structurally the most diverse group of messenger molecules of the nervous system. Regarding neuropeptide identification, distribution, function, and evolution, insects are among the best studied invertebrates. Indeed, more than 100 neuropeptides are known from single species. Most of these peptides can easily be identified by direct tissue or cell profiling using MALDI TOF MS. In these experiments, protein hormones with extensive post-translational modifications such as inter- and intramolecular disulfides are usually missed. It is evident that an exclusion of these bioactive molecules hinders the utilization of direct profiling methods in comprehensive peptidomic analyses. In the current study, we focus on the detection and structural elucidation of homo- and heterodimeric adipokinetic hormone precursor-related peptides (APRPs) of cockroaches. The physiological relevance of these molecules with highly conserved sequences in insects is still uncertain. Sequence similarities with vertebrate growth hormone-releasing factors have been reported, but remarkably, few data regarding APRP processing exist and these data are restricted to locusts. Here, we elucidated sequences of carbamidomethylated APRP monomers of different cockroaches by means of MALDI-TOF MS(2), and we were able to identify a surprisingly large number of APRP sequences, resulting either from intraspecific amino acid substitutions within the APRP sequences or C-terminal truncated APRPs. PMID- 25524230 TI - Biomarkers probed in saliva by surface plasmon resonance imaging coupled to matrix-assisted laser desorption/ionization mass spectrometry in array format. AB - Detection of protein biomarkers is of major interest in proteomics. This work reports the analysis of protein biomarkers directly from a biological fluid, human saliva, by surface plasmon resonance imaging coupled to mass spectrometry (SPRi-MS), using a functionalized biochip in an array format enabling multiplex SPR-MS analysis. The SPR biochip presented a gold surface functionalized by a self-assembled monolayer of short poly(ethylene oxide) chains carrying an N hydroxysuccinimide end-group for the immobilization of antibodies. The experiments were accomplished without any sample pre-purification or spiking with the targeted biomarkers. SPRi monitoring of the interactions, immune capture from the biochip surface, and finally on-chip matrix-assisted laser desorption/ionization-MS structural identification of two protein biomarkers, salivary alpha-amylase and lysozyme, were successively achieved directly from saliva at the femtomole level. For lysozyme, the on-chip MS identification was completed by a proteomic analysis based on an on-chip proteolysis procedure and a peptide mass fingerprint. PMID- 25524232 TI - Anticodeine aptamer immobilized on a Whatman cellulose paper for thin-film microextraction of codeine from urine followed by electrospray ionization ion mobility spectrometry. AB - A combination of thin-film microextaction based on an aptamer immobilized on modified Whatman cellulose paper followed by electrospray ionization ion mobility spectrometry has been developed for the analysis of codeine in urine samples. The immobilization is based on the covalent linking of an amino-modified anticodeine aptamer to aldehyde groups of the oxidized cellulose paper. The covalent bonds were examined by infrared spectroscopy and elemental analysis. The effect of the extraction parameters, including the elution conditions (solvent type and volume), extraction time, and extraction temperature, on the extraction efficiency were investigated. Under the optimized conditions, the linear dynamic range was found to be 10-300 ng/mL with a detection limit of 3.4 ng/mL for codeine in urine. The relative standard deviation was 6.8% for three replicate measurements of codeine at 100 ng/mL in urine. Furthermore, the samples were analyzed with a standard method for the analysis of codeine using high performance liquid chromatography with ultraviolet detection. The comparison of the results validates the accuracy of the proposed method as an alternative method for the analysis of codeine in urine samples. PMID- 25524234 TI - Ectomycorrhizal fungi - potential organic matter decomposers, yet not saprotrophs. AB - Although hypothesized for many years, the involvement of ectomycorrhizal fungi in decomposition of soil organic matter remains controversial and has not yet been fully acknowledged as an important factor in the regulation of soil carbon (C) storage. Here, we review recent findings, which support the view that some ectomycorrhizal fungi have the capacity to oxidize organic matter, either by 'brown-rot' Fenton chemistry or using 'white-rot' peroxidases. We propose that ectomycorrhizal fungi benefit from organic matter decomposition primarily through increased nitrogen mobilization rather than through release of metabolic C and question the view that ectomycorrhizal fungi may act as facultative saprotrophs. Finally, we discuss how mycorrhizal decomposition may influence organic matter storage in soils and mediate responses of ecosystem C sequestration to environmental changes. PMID- 25524236 TI - Regulation of Zn and Fe transporters by the GPC1 gene during early wheat monocarpic senescence. AB - BACKGROUND: During wheat senescence, leaf components are degraded in a coordinated manner, releasing amino acids and micronutrients which are subsequently transported to the developing grain. We have previously shown that the simultaneous downregulation of Grain Protein Content (GPC) transcription factors, GPC1 and GPC2, greatly delays senescence and disrupts nutrient remobilization, and therefore provide a valuable entry point to identify genes involved in micronutrient transport to the wheat grain. RESULTS: We generated loss-of-function mutations for GPC1 and GPC2 in tetraploid wheat and showed in field trials that gpc1 mutants exhibit significant delays in senescence and reductions in grain Zn and Fe content, but that mutations in GPC2 had no significant effect on these traits. An RNA-seq study of these mutants at different time points showed a larger proportion of senescence-regulated genes among the GPC1 (64%) than among the GPC2 (37%) regulated genes. Combined, the two GPC genes regulate a subset (21.2%) of the senescence-regulated genes, 76.1% of which are upregulated at 12 days after anthesis, before the appearance of any visible signs of senescence. Taken together, these results demonstrate that GPC1 is a key regulator of nutrient remobilization which acts predominantly during the early stages of senescence. Genes upregulated at this stage include transporters from the ZIP and YSL gene families, which facilitate Zn and Fe export from the cytoplasm to the phloem, and genes involved in the biosynthesis of chelators that facilitate the phloem-based transport of these nutrients to the grains. CONCLUSIONS: This study provides an overview of the transport mechanisms activated in the wheat flag leaf during monocarpic senescence. It also identifies promising targets to improve nutrient remobilization to the wheat grain, which can help mitigate Zn and Fe deficiencies that afflict many regions of the developing world. PMID- 25524237 TI - Acute blood pressure changes are related to chronic effects of resistance exercise in medicated hypertensives elderly women. AB - BACKGROUND: A previous study observed that the chronic effects of aerobic training on blood pressure (BP) are related to acute BP responses after a single bout of aerobic exercise. However, whether similar responses are observed with resistance exercise (RE) remains obscure. Thus, this study analysed the relationship between the acute BP responses to a single bout of RE and chronic changes in resting BP after a RE training in medicated hypertensive elderly women. METHODS AND RESULTS: Twenty medicated hypertensive women participated in the study. They underwent an acute RE bout where BP and heart rate (HR) were obtained at rest and for 60 min after the RE. Subsequently, the participants underwent a progressive RE training for 12 weeks at 60-80% of maximal strength test. Resting BP and HR were also obtained after the RE training. The chronic decreases in systolic and diastolic BP were significantly greater in the participants who experienced acutely decreased systolic and diastolic BP, respectively (P<0.05). The changes in systolic BP after acute RE were correlated with the chronic changes in resting systolic BP after RE training (r = 0.47; P = 0.03). Similar correlations between acute and chronic responses were also observed for diastolic BP (r = 0.70; P = 0.01), mean BP (r = 0.58; P = 0.01), HR (r = 0.73; P<0.01) and RPP (r = 0.52; P = 0.01). CONCLUSION: Similar to previously work involving aerobic exercise, BP responses to a single bout of RE are strongly related to chronic effects of RE training on BP in medicated hypertensive elderly women. PMID- 25524238 TI - Isolation and characterization of embryonic stem cell-derived cardiac Purkinje cells. AB - The cardiac Purkinje fiber network is composed of highly specialized cardiomyocytes responsible for the synchronous excitation and contraction of the ventricles. Computational modeling, experimental animal studies, and intracardiac electrical recordings from patients with heritable and acquired forms of heart disease suggest that Purkinje cells (PCs) may also serve as critical triggers of life-threatening arrhythmias. Nonetheless, owing to the difficulty in isolating and studying this rare population of cells, the precise role of PC in arrhythmogenesis and the underlying molecular mechanisms responsible for their proarrhythmic behavior are not fully characterized. Conceptually, a stem cell based model system might facilitate studies of PC-dependent arrhythmia mechanisms and serve as a platform to test novel therapeutics. Here, we describe the generation of murine embryonic stem cells (ESC) harboring pan-cardiomyocyte and PC-specific reporter genes. We demonstrate that the dual reporter gene strategy may be used to identify and isolate the rare ESC-derived PC (ESC-PC) from a mixed population of cardiogenic cells. ESC-PC display transcriptional signatures and functional properties, including action potentials, intracellular calcium cycling, and chronotropic behavior comparable to endogenous PC. Our results suggest that stem-cell derived PC are a feasible new platform for studies of developmental biology, disease pathogenesis, and screening for novel antiarrhythmic therapies. PMID- 25524239 TI - Secondhand smoke exposure toxicity accelerates age-related cardiac disease in old hamsters. AB - BACKGROUND: Aging is associated with physiological or pathological left ventricular hypertrophy (LVH) cardiac changes. Secondhand smoke (SHS) exposure is associated with pathological LVH. The action mechanism in cardiac concentric hypertrophy from SHS exposure is understood, but the transition contributed from SHS exposure is not. To determine whether exposure to SHS has an impact on age induced LVH we examined young and old hamsters that underwent SHS exposure in a chamber for 30 mins. METHODS: Morphological and histological studies were then conducted using hematoxylin and eosin (H&E) and Masson's trichrome staining. Echocardiographic analysis was used to determine left ventricular wall thickness and function. LVH related protein expression levels were detected by western blot analysis. RESULTS: The results showed that both young and aged hamsters exposed to SHS exhibited increased heart weights and left ventricular weights, left ventricular posterior wall thickness and intraventricular septum systolic and diastolic pressure also increased. However, left ventricular function systolic and diastolic pressure deteriorated. H&E and Masson's trichrome staining results showed LV papillary muscles were ruptured, resulting in lower cardiac function at the myocardial level. LV muscle fiber arrangement was disordered and collagen accumulation occurred. Concentric LVH related protein molecular markers increased only in young hamsters exposed to SHS. However, this declined with hamster age. By contrast, eccentric LVH related proteins increased in aging hamsters exposed the SHS. Pro-inflammatory proteins, IL-6, TNF-alpha, JAK1, STAT3, and SIRTI expression increased in aging hamsters exposed to SHS. CONCLUSIONS: We suggest that SHS exposure induces a pro-inflammatory response that results in concentric transition to aging eccentric LVH. PMID- 25524240 TI - Impact of renal anatomy on shock wave lithotripsy outcomes for lower pole kidney stones: results of a prospective multifactorial analysis controlled by computerized tomography. AB - PURPOSE: We evaluated which variables impact fragmentation and clearance of lower pole calculi after shock wave lithotripsy. MATERIALS AND METHODS: We prospectively evaluated patients undergoing shock wave lithotripsy for a solitary 5 to 20 mm lower pole kidney stone between June 2012 and August 2014. Patient body mass index and abdominal waist circumference were recorded. One radiologist blinded to shock wave lithotripsy outcomes measured stone size, area and density, stone-to-skin distance, infundibular length, width and height, and infundibulopelvic angle based on baseline noncontrast computerized tomography. Fragmentation, success (defined as residual fragments less than 4 mm in asymptomatic patients) and the stone-free rate were evaluated by noncontrast computerized tomography 12 weeks postoperatively. Univariate and multivariate analysis was performed. RESULTS: A total of 100 patients were enrolled in the study. Mean stone size was 9.1 mm. Overall fragmentation, success and stone-free rates were 76%, 54% and 37%, respectively. On logistic regression body mass index (OR 1.27, 95% CI 1.11-1.49, p = 0.004) and stone density (OR 1.0026, 95% CI 1.0008-1.0046, p = 0.005) significantly impacted fragmentation. Stone size (OR 1.24, 95% CI 1.07-1.48, p = 0.039) and stone density (OR 1.0021, 95% CI 1.0007 1.0037, p = 0.012) impacted the success rate while stone size (OR 1.24, 95% CI 1.04-1.50, p = 0.029), stone density (OR 1.0015, 95% CI 1.0001-1.0032, p = 0.046) and infundibular length (OR 1.1035, 95% CI 1.015-1.217, p = 0.015) impacted the stone-free rate. The best outcomes were found in patients with a body mass index of 30 kg/m(2) or less, stones 10 mm or less and 900 HU or less, and an infundibular length of 25 mm or less. The coexistence of significant unfavorable variables led to a stone-free rate of less than 20%. CONCLUSIONS: Obese patients with higher than 10 mm density stones (greater than 900 HU) in the lower pole of the kidney with an infundibular length of greater than 25 mm should be discouraged from undergoing shock wave lithotripsy. PMID- 25524242 TI - Expression and Function of LPA1 in Bladder Cancer. AB - PURPOSE: LPA is one of several physiologically active lipid mediators that promote cell proliferation and invasion, and are present in serum, ascites and urine. LPA receptor is a G-protein coupled receptor that is considered a potential therapeutic target for some malignant cancers. We evaluated the expression of LPA receptors in bladder cancer and the effect of LPA in bladder cancer invasion. MATERIALS AND METHODS: Using real-time polymerase chain reaction and immunohistochemical staining we determined LPA receptor expression in bladder cancer specimens from patients with bladder cancer, including 12 with Ta or T1 and 15 with T2-T4 disease. ROCK expression, myosin light chain phosphorylation and MatrigelTM invasion assays were done and morphological observations were made to assess LPA effects in T24 cells, which were derived from bladder cancer. RESULTS: Notably LPA1 mRNA expression was significantly higher in muscle invasive bladder cancer specimens than in nonmuscle invasive specimens. Strong LPA1 expression was evident on cell membranes in muscle invasive specimens. T24 cell invasion was increased by LPA treatment and invasiveness was decreased by LPA1 siRNA or LPA1 inhibitor. LPA treatment increased ROCK1 expression and myosin light chain phosphorylation, and induced morphological changes, including lamellipodia formation and cell rounding. CONCLUSIONS: Results indicate that LPA signaling via LPA1 activation promoted bladder cancer invasion. LPA1 might be useful to detect bladder cancer with highly invasive potential and become a new therapeutic target for invasive bladder cancer treatment. PMID- 25524241 TI - Genetic contributions to urgency urinary incontinence in women. AB - PURPOSE: We identify genetic variants associated with urgency urinary incontinence in postmenopausal women. MATERIALS AND METHODS: A 2-stage genome wide association analysis was conducted to identify variants associated with urgency urinary incontinence. The WHI GARNET substudy with 4,894 genotyped post reproductive white women was randomly split into independent discovery and replication cohorts. Genome-wide imputation was performed using IMPUTE2 with the 1000 Genomes ALL Phase I integrated variant set as a reference. Controls reported no urgency urinary incontinence at enrollment or followup. Cases reported monthly or greater urgency urinary incontinence and leaked sufficiently to wet/soak underpants/clothes. Logistic regression models were used to predict urgency urinary incontinence case vs control status based on genotype, assuming additive inheritance. Age, obesity, diabetes and depression were included in the models as covariates. RESULTS: Following quality control, 975,508 single nucleotide polymorphisms in 2,241 cases (discovery 1,102; replication 1,133) and 776 controls (discovery 405, replication 371) remained. Genotype imputation resulted in 9,077,347 single nucleotide polymorphisms and insertions/deletions with minor allele frequency greater than 0.01 available for analysis. Meta-analysis of the discovery and replication samples identified 6 loci on chromosomes 5, 10, 11, 12 and 18 associated with urgency urinary incontinence at p <10(-6). Of the loci 3 were within genes, the zinc finger protein 521 (ZFP521) gene on chromosome 18q11, the ADAMTS16 gene on chromosome 5p15 and the CIT gene on chromosome 12q24. The other 3 loci were intergenic. CONCLUSIONS: Although environmental factors also likely contribute, this first exploratory genome-wide association study for urgency urinary incontinence suggests that genetic variants in the ZFP521, CIT and ADAMTS16 genes might account for some of the observed heritability of the condition. PMID- 25524243 TI - Risk of diabetes among patients receiving primary androgen deprivation therapy for clinically localized prostate cancer. AB - PURPOSE: Androgen deprivation therapy may increase diabetes risk. As the benefits of primary androgen deprivation therapy for localized prostate cancer are controversial, and most prostate cancer survivors are of advanced age with comorbidities, it is important to determine if primary androgen deprivation therapy increases the risk of diabetes and to determine the susceptibility factors. MATERIALS AND METHODS: We conducted a retrospective cohort study of 12,191 men diagnosed with incident localized prostate cancer during 1995 to 2008, age 35 to 100 years, and without diabetes or receipt of prostatectomy or radiation 1 year after diagnosis. Patients were enrolled in 1 of 3 managed health plans and followed through 2010. Primary androgen deprivation therapy was defined as androgen deprivation therapy within 1 year after diagnosis. Incident diabetes was ascertained using inpatient and outpatient diagnosis codes, diabetes medications and hemoglobin A1c values. We estimated primary androgen deprivation therapy associated diabetes risk using Cox proportional hazard models in conventional and propensity score analyses. RESULTS: Diabetes developed in 1,203 (9.9%) patients during followup (median 4.8 years) with incidence rates of 2.5 and 1.6 events per 100 person-years in the primary androgen deprivation therapy and nonprimary androgen deprivation therapy groups, respectively. Primary androgen deprivation therapy was associated with a 1.61-fold increased diabetes risk (95% CI 1.38-1.88). The number needed to harm was 29. The association was stronger in men age 70 or younger than in older men (HR 2.25 vs 1.40, p value for interaction=0.008). CONCLUSIONS: Primary androgen deprivation therapy may increase diabetes risk by 60% and should be used with caution when managing localized prostate cancer. Because of the consistent association between androgen deprivation therapy and greater diabetes risk across disease states, we recommend routine screening and lifestyle interventions to reduce the risk of diabetes in men receiving androgen deprivation therapy. PMID- 25524245 TI - Establishing smoke-free hospitals in Vietnam: a pilot project. AB - In Vietnam, a pilot 'smoke-free hospital' model was implemented in nine hospitals in 2009-2010 to supply lessons learned that would facilitate a replication of this model elsewhere. This study aimed to assess smoking patterns among health professionals and to detect levels of second-hand smoke (SHS) exposure within hospital premises before and after the 'smoke-free hospital' model implementation. A pre- and post-intervention cross-sectional study was conducted in nine purposively selected hospitals. Air nicotine levels were measured using passive nicotine monitors; smoking evidence was collected through on-site observations; and smoking patterns were assessed through interviews with health workers. Despite the 'smoke-free hospital' intervention, smoking continued among health-care workers who were former smokers. Specifically, self-reported smoking prevalence significantly decreased post-intervention, but the number of daily cigarettes smoked at workplaces among male health workers remained unchanged. Post-intervention, smoking was more likely to take place outside buildings and cafeterias. However, air nicotine levels in the doctors' lounges and in emergency departments did not change post-intervention. Air nicotine levels at other sites decreased minimally. Tailored tobacco cessation programmes, targeting current smokers and mechanisms to enforce non-smoking, should be established to meet requirements of Vietnam's comprehensive National Tobacco Control Law effective in May 2013. PMID- 25524244 TI - Long-term survival rates after resection for locally advanced kidney cancer: Memorial Sloan Kettering Cancer Center 1989 to 2012 experience. AB - PURPOSE: We analyzed the 23-year Memorial Sloan Kettering Cancer Center experience with surgical resection, and concurrent adrenalectomy and lymphadenectomy for locally advanced nonmetastatic renal cell carcinoma. MATERIALS AND METHODS: We retrospectively reviewed the records of 802 patients who underwent nephrectomy with or without concurrent adrenalectomy or lymphadenectomy for locally advanced renal cell carcinoma, defined as stage T3 or greater and M0. Patients who received adjuvant treatment within 3 months of surgery or had fewer than 3 months of followup or bilateral renal masses at presentation were excluded from analysis. Five and 10-year progression-free and overall survival was estimated by the Kaplan-Meier method. Differences between groups were analyzed by the log rank test. RESULTS: A total of 596 (74%) and 206 patients (26%) underwent radical and partial nephrectomy, respectively. Renal cell carcinoma progressed in 189 patients and 104 died of the disease. Median followup in patients without progression was 4.6 years. Symptoms at presentation, ASA((r)) classification, tumor stage, histological subtype, grade and lymph node status were significantly associated with progression-free and overall survival. On multivariate analysis adrenalectomy use decreased with time but lymphadenectomy use increased (OR 0.82 vs 1.16 per year). Larger tumors were associated with a higher likelihood of concurrent adrenalectomy and lymphadenectomy. CONCLUSIONS: In our series of patients with locally advanced nonmetastatic renal cell carcinoma survival was favorable in those in good health who were asymptomatic at presentation with T3 tumors and negative lymph nodes. Further, there has been a trend toward more selective use of adrenalectomy and increased use of lymphadenectomy. PMID- 25524246 TI - Water stress proteins from Nostoc commune Vauch. exhibit anti-colon cancer activities in vitro and in vivo. AB - Nostoc commune has been traditionally used in China as a health food and medicine. The water stress proteins (WSP) of Nostoc commune are the major component of the extracellular matrix. This study purified and identified the water stress proteins (WSP1) from Nostoc commune Vauch., which could inhibit the proliferation of human colon cancer cell lines. The IC50 values of WSP1 against DLD1, HCT116, HT29, and SW480 cells were 0.19 +/- 0.02, 0.21 +/- 0.03, 0.39 +/- 0.05, and 0.41 +/- 0.01 MUg/MUL, respectively. Notably, it displayed very little effect on the normal human intestinal epithelial FHC cell line. The IC50 value of WSP1 against FHC cells was 0.67 +/- 0.05 MUg/MUL. Moreover, the growth of DLD1 xenografted tumors in nude mice were significantly suppressed in the WSP1 treated group. Mechanistically, the cell-cycle analysis revealed that WSP1 induced growth inhibition by G1/S arrest. Meanwhile, Western blotting and immunohistochemistry assays showed WSP1 could activate caspase-8, -9, and -3, along with subsequent PARP cleavage. Furthermore, the pan-caspase inhibitor, z-VAD-FMK, partly reversed the effect caused by WSP1, confirming that WSP1 induced cell apoptosis through caspase-dependent pathway. Collectively, WSP1 has targeted inhibition for colon cancer proliferation both in vitro and in vivo and it is valuable for future exploitation and utilization as an antitumor agent. PMID- 25524247 TI - Treatment of rectovaginal fistula after colorectal resection with endoscopic stenting: long-term results. AB - AIM: To treat patients with rectovaginal fistula after anterior resection for cancer using self-expanding metal stents. METHOD: Ten patients of mean age of 56.3 years with rectovaginal fistula after colorectal resection for cancer were treated with endoscopic placement of a self-expanding metal stent. In three patients a diverting proximal stoma had been performed elsewhere. The rectal opening of the fistula was located from 3 to 10 cm from the anal verge (mean 6 cm). All patients had preoperative radiotherapy. In seven patients the stent was placed as the initial treatment while three referred patients had had multiple failed operations. RESULTS: There were no complications after the procedure. At a mean follow-up of 24 months the rectovaginal fistula has healed without major faecal incontinence in eight patients. In the remaining two the fistula has reduced significantly in size to allow a successful flap transposition. CONCLUSION: Endoscopic placement of a self-expanding metal stent is a valid adjunct to treat patients with rectovaginal fistula after colorectal resection for cancer. PMID- 25524248 TI - In response: Nonadherence to treatment causing acute hospitalizations in people with epilepsy: An observational, prospective study. PMID- 25524249 TI - Prevention Across the Spectrum: a randomized controlled trial of three programs to reduce risk factors for both eating disorders and obesity. AB - BACKGROUND: A randomized controlled trial of three school-based programs and a no intervention control group was conducted to evaluate their efficacy in reducing eating disorder and obesity risk factors. METHOD: A total of 1316 grade 7 and 8 girls and boys (mean age = 13.21 years) across three Australian states were randomly allocated to: Media Smart; Life Smart; the Helping, Encouraging, Listening and Protecting Peers (HELPP) initiative; or control (usual school class). Risk factors were measured at baseline, post-program (5 weeks later), and at the 6- and 12-month follow-ups. RESULTS: Media Smart girls had half the rate of onset of clinically significant concerns about shape and weight than control girls at the 12-month follow-up. Media Smart and HELPP girls reported significantly lower weight and shape concern than Life Smart girls at the 12 month follow-up. Media Smart and control girls scored significantly lower than HELPP girls on eating concerns and perceived pressure at the 6-month follow-up. Media Smart and HELPP boys experienced significant benefit on media internalization compared with control boys and these were sustained at the 12 month follow-up in Media Smart boys. A group * time effect found that Media Smart participants reported more physical activity than control and HELPP participants at the 6-month follow-up, while a main effect for group found Media Smart participants reported less screen time than controls. CONCLUSIONS: Media Smart was the only program to show benefit on both disordered eating and obesity risk factors. Whilst further investigations are indicated, this study suggests that this program is a promising approach to reducing risk factors for both problems. PMID- 25524250 TI - Surface modification of titanium with hydroxyapatite-heparin-BMP-2 enhances the efficacy of bone formation and osseointegration in vitro and in vivo. AB - Surface-modified titanium (Ti) samples with hydroxyapatite (HAp) and heparin (Hep)-bone morphogenetic protein-2 (BMP-2) complex (Ti/HAp/Hep/BMP-2) were prepared, and their efficacies on the enhancements of bone formation and osseointegration in vitro and in vivo were examined as compared to Ti/HAp and Ti/Hep/BMP-2. The modified surfaces were characterized by X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and contact angle goniometry. In vitro studies revealed that MG-63 human osteosarcoma cell lines grown on Ti/HAp/Hep/BMP-2 increased the amounts of alkaline phosphatase (ALP) activity, calcium deposition and the levels of OCN mRNA gene expression as compared to those grown on Ti/HAp, Ti/Hep/BMP-2 or pristine Ti. Moreover, Ti/HAp/Hep/BMP-2 exhibited higher bone volume (BV), bone volume/tissue volume (BV/TV), removal torque value and bone-implant contact (BIC) than Ti/HAp, Ti/Hep/BMP-2 or pristine Ti in vivo. Histological evaluations showed that many desirable features of bone remodelling existed at the interface between Ti/HAp/Hep/BMP-2 and the host bone. Consequently, Ti/HAp/Hep/BMP-2 may have potential for clinical use as dental or orthopaedic implants. PMID- 25524251 TI - Medicinal chemistry of P2X receptors: allosteric modulators. AB - P2X receptors are trimeric ligand-gated ion channels whose potential as novel drug targets for a number of diseases has been recognized. They are mainly involved in inflammatory processes, including neuroinflammation, and pain sensation. The orthosteric binding site is lined by basic amino acid residues that bind the negatively charged agonist ATP. Therefore it is not easy to develop orthosteric ligands that possess drug-like properties for such a highly polar binding site. However, ligand-gated ion channels offer multiple additional binding sites for allosteric ligands, positive or negative allosteric modulators enhancing or blocking receptor function. So far, the P2X3 (and P2X2/3), as well as the P2X7 receptor subtype have been the main focus of drug development efforts. A number of potent and selective allosteric antagonists have been developed to block these receptors. We start to see the development of novel allosteric ligands also for the other P2X receptor subtypes, P2X1, P2X2 and especially P2X4. The times when only poor, non-selective, non-drug-like tools for studying P2X receptor function were available have been overcome. The first clinical studies with allosteric P2X3 and P2X7 antagonists suggest that P2X therapeutics may soon become a reality. PMID- 25524252 TI - P2X receptors and inflammation. AB - Until recently, P2X receptors have not received much attention in the context of immunology and inflammation. While this is justified to a certain extent for P2X1, P2X2, P2X3, P2X5 and P2X6, which still await identification of a convincing role in the pathophysiology of immune cells, it is clearly not any more the case for P2X4 and even more so for P2X7, a molecule that has achieved the status of an essential, nonredundant, immunomodulatory receptor. In this review I will highlight the most important inflammatory responses participated by P2X receptors. PMID- 25524253 TI - Christmas dinner for doctors on duty: it's grimmer up north. PMID- 25524254 TI - Severe postherpetic neuralgia and other neuropathic pain syndromes alleviated by topical gabapentin. PMID- 25524255 TI - Experimental and modeling study of pure terephthalic acid (PTA) wastewater transport in the vadose zone. AB - PTA wastewater discharged from a factory was selected as the research object in this project and CODcr was selected as the characteristic pollution factor. Static adsorption and soil column leaching experiments of silty clay and clayey soil were carried out to study the adsorption, bio-degradation and dispersion coefficient of CODcr in PTA wastewater. Hydrus-1D was used to build the convection-diffusion model to demonstrate the migration of PTA wastewater in the vadose zone. The results indicate that silty clay and clayey soil in the vadose zone can adsorb, degrade and impede the contaminants in PTA wastewater; however, the coefficient of adsorption and degradation were very low, they were down to 0.0002 L g(-1), 0.0003 L g(-1) and 0.0097 d(-1), 0.0077 d(-1) for silty clay and clayey soil, respectively. Under the virtual condition that, wastewater in the sewage pool is 5 m deep, CODcr concentration is 4000 mg L(-1), vadose zone is 21 m, PTA wastewater will reach the phreatic surface after 20.87 years. When wastewater in the sewage pool is 7 m with other conditions unchanged, after 17.18 years PTA wastewater will reach groundwater. The results show that there is a higher pollution risk for groundwater if we do not take any anti-seepage measures. PMID- 25524256 TI - Analysis of sentinel node biopsy combined with other diagnostic tools in staging cN0 head and neck cancer: A diagnostic meta-analysis. AB - BACKGROUND: The purpose of this was to find a staging strategy sensitive enough to reduce the risk of occult metastases in cN0 head and neck cancer to below 15% to 20%. METHODS: A total of 73 articles were selected for analysis of the diagnostic performance in staging cN0 head and neck cancer. Hypothetical estimation of negative predictive value (NPV) was calculated based on the Bayesian theory. RESULTS: The pooled estimates for sensitivity were 56.4% and 84.9% for ultrasound-guided fine-needle aspiration (FNA) and sentinel node biopsy (SNB). The pooled estimates for sensitivity were 47.0%, 56.6%, 48.3%, and 63.3% for CT, MRI, positron emission tomography (PET), and ultrasound, respectively. The pooled estimates for specificity were 88.9%, 82.5%, 86.2%, and 79.1% for CT, MRI, PET, and ultrasound. In estimation, the CT or MRI with SNB strategies had NPV higher than 85% even when the pretest metastatic rate was 60%. CONCLUSION: The SNB procedure has the best performance. A combination of CT/MRI and SNB for cN0 head and neck cancer is preferred. PMID- 25524257 TI - Stimulus similarity determines the prevalence of behavioral laterality in a visual discrimination task for mice. AB - Animal choices depend on direct sensory information, but also on the dynamic changes in the magnitude of reward. In visual discrimination tasks, the emergence of lateral biases in the choice record from animals is often described as a behavioral artifact, because these are highly correlated with error rates affecting psychophysical measurements. Here, we hypothesized that biased choices could constitute a robust behavioral strategy to solve discrimination tasks of graded difficulty. We trained mice to swim in a two-alterative visual discrimination task with escape from water as the reward. Their prevalence of making lateral choices increased with stimulus similarity and was present in conditions of high discriminability. While lateralization occurred at the individual level, it was absent, on average, at the population level. Biased choice sequences obeyed the generalized matching law and increased task efficiency when stimulus similarity was high. A mathematical analysis revealed that strongly-biased mice used information from past rewards but not past choices to make their current choices. We also found that the amount of lateralized choices made during the first day of training predicted individual differences in the average learning behavior. This framework provides useful analysis tools to study individualized visual-learning trajectories in mice. PMID- 25524258 TI - Aminaphtone therapy in patients with type 1 diabetes and albuminuria: a case report. AB - INTRODUCTION: Microalbuminuria in type 1 diabetes is the earliest manifestation of diabetic microangiopathy (nephropathy). To date, the pharmacological approach to microangiopathy has not been shown to be useful. By using aminaphtone to control nephrologic complications of insulin-dependent diabetes mellitus we first obtained a significant improvement in microalbuminuria confirming this new pharmacological approach for insulin-dependent diabetes mellitus organospecific complications control. CASE PRESENTATION: After being treated with standard therapy for insulin-dependent diabetes mellitus (insulin) for more than 20 years, a 49-year-old white man affected by insulin-dependent diabetes mellitus adopted the standard therapy aminaphtone for a period of 2 months.This therapy allowed a significant reduction of proteinuria from baseline evaluation that immediately increased after he stopped aminaphtone therapy. CONCLUSIONS: Aminaphtone therapy, used globally in the treatment and prevention of endothelial dysfunctions, could be an interesting option for patients with insulin-dependent diabetes mellitus with the express purpose of preventing diabetic nephropathy. PMID- 25524259 TI - Graphic representation of the burden of suffering in dizziness patients. AB - BACKGROUND: Dizziness adversely affects an individual's well-being. However, its impact is not only influenced by its physical manifestations, but also by its subjective importance to the patient. Appropriately assessing the subjective burden of dizziness is difficult. The Pictorial-Representation of Illness- and Self-Measure (PRISM), on which patients illustrate the distance between their 'self' and their illness, has been documented to indicate the perception of suffering in several different illnesses. Our study objectives were (1) to assess how useful the PRISM is in patients with dizziness; and (2) to determine which clinical, emotional and sociodemographic factors contribute to their burden of suffering. METHODS: A total of 177 outpatients with dizziness completed this cross-sectional study, in which the following measures were assessed of suffering rated using the PRISM tool; dizziness-related variables, like emotional distress (Hospital Anxiety and Depression-Scale, HADS); self-perceived severity of dizziness (Dizziness Handicap Inventory, DHI); and sociodemographic variables. RESULTS: Regression analyses identified the strongest association between PRISM rated suffering and DHI (p < 0.001), explaining 34% of the variance in PRISM rated suffering. The HADS score and having continuous dizziness versus transient attacks each explained roughly 2% of the variance in suffering. No significant associations with PRISM-rated suffering were found for sociodemographic variables or other dizziness characteristics. CONCLUSIONS: The PRISM is applicable to patients suffering from dizziness, demonstrating a significant association with the severity of dizziness and reliably distinguishing between those with low and high intensities of dizziness. The PRISM also reflects the multi-factorial aspects of suffering. Due to its immediate, timesaving and economical use, the PRISM could enable clinicians to identify vulnerable patients at risk for chronic symptoms and distress. Whether the PRISM can detect improvements and worsening of symptoms during treatment warrants further research. PMID- 25524260 TI - Role of inflammation in the initiation and maintenance of atrial fibrillation and the protective effect of atorvastatin in a goat model of aseptic pericarditis. AB - The present study was designed to determine the association between atrial fibrillation (AF) and inflammation in a goat sterile pericarditis model and to assess the effect of atorvastatin, a cholesterol-reducing drug, on AF. A total of 15 adult male goats were randomly divided into control, untreated pericarditis and atorvastatin-treated pericarditis groups. Pericarditis was induced via thoracotomy and atorvastatin was administered orally (60 mg/day) to the goats in the latter group for the duration of the study, commencing 1 week prior to surgery. The levels of high-sensitivity C-reactive protein (hs-CRP), interleukin(IL)-6 and tumor necrosis factor-alpha (TNF-alpha) were significantly elevated following surgery in the untreated pericarditis and atorvastatin groups compared with the control group (P<0.05). However, lower levels of hs-CRP, IL-6 and TNF-alpha were observed in the atorvastatin group compared with the untreated pericarditis group (P<0.05). Additionally, the animals in the atorvastatin treated pericarditis group had a longer effective refractory period (ERP) and a higher rate adaptation of the ERP compared with those in the untreated pericarditis group (P<0.05). There was a significant negative correlation between the levels of ERP and hs-CRP in the untreated pericarditis group. The inducibility of AF in the left atrium and the duration of AF in the untreated pericarditis and atorvastatin-treated groups increased significantly following surgery (P<0.05). The pericarditis group, however, had a longer duration of AF compared with the atorvastatin group (P<0.05). Thus, inflammation may promote AF by shortening atrial ERP and by reducing the rate adaptation of ERP. These results suggested that atorvastatin can attenuate AF by inhibiting inflammation and may assist in preventing the occurrence and recurrence of AF following cardiac surgery. PMID- 25524261 TI - Comparison of colonoscopic performance between medical and nurse endoscopists: a non-inferiority randomised controlled study in Asia. AB - OBJECTIVE: To test the hypothesis that trained nurse endoscopists are not inferior to medical endoscopists in finding adenomas during colonoscopy. DESIGN: This is a prospective, randomised, single-blind, non-inferiority study comparing nurses with medical endoscopists in performing screening colonoscopy. The nurse endoscopists had been trained according to the British Joint Advisory Group on GI Endoscopy curriculum and had completed at least 140 colonoscopic procedures prior to the study. The primary endpoint was the adenoma detection rate. Secondary endpoints included the caecal intubation rate, intubation time, complication rate, patient pain and satisfaction scores. RESULTS: We enrolled and analysed a total of 731 patients over a 15-month period. At least one adenoma was found in 159 (43.8%) of 363 patients by nurse endoscopists and 120 (32.7%) of 367 patients by medical endoscopists and a proportion difference of +11.1% compared with the medical endoscopists (95% CI 4.1% to 18.1%). The withdrawal time was, however, significantly longer among nurses (998 vs 575 s, p<0.001). After adjusting for differences in a regression analysis, colonoscopy by nurses was associated with a lower adenoma detection rate (OR 0.475: 95% CI 0.311 to 0.725). Nurse endoscopists had a lower caecal intubation rate (97.3% vs 100%), received better pain and satisfaction scores and had a high rate of patient acceptance. CONCLUSIONS: In this pragmatic trial, nurses can perform screening colonoscopy but require a longer procedural time to achieve a comparable adenoma detection rate as medical endoscopists. TRIAL REGISTRATION NUMBER: NCT01923155. PMID- 25524262 TI - Additive antitumour response to the rabbit VX2 hepatoma by combined radio frequency ablation and toll like receptor 9 stimulation. AB - INTRODUCTION: Radiofrequency ablation (RFA), a palliative therapeutic option for solid hepatic tumours, stimulates localised and systemic antitumour cytotoxic T cells. We studied how far addition of CpG B oligonucleotides, toll like receptor (TLR) 9 agonists, would increase the antitumoural T cell response of RFA in the highly aggressive VX2 hepatoma. METHODS: Rabbits were randomised to receive RFA, CpG B, their combination or no therapy. The antitumour efficacy of RFA alone or in combination with CpG B was further tested by rechallenging a separate group with intravenously injected VX2 tumour cells after 120 days. Animals were assessed for survival, tumour size and spread, and tumour and immune related histological markers after 120 days. Peripheral blood mononuclear cells were tested for tumour-specific T cell activation and cytotoxicity. Immune modulatory cytokines tumour necrosis factor alpha, interleukin (IL)-2/IL-8/IL-10/IL-12 and interferon gamma, and vascular endothelial growth factor were measured in serum. RESULTS: Mean survival of untreated animals was 36 days, as compared with 97, 78 and 114 days for RFA, CpG and combination therapy, respectively. Compared with untreated controls, antitumour T cell stimulation/cytotoxicity increased 26/16 fold, 32/17-fold and 50/38-fold 2 weeks after RFA, CpG and combination treatments, respectively. The combination inhibited tumour spread to lungs and peritoneum significantly and prohibited new tumour growth in animals receiving a secondary systemic tumour cell injection. RFA alone induced a Th1 cytokine pattern, while IL-8 and IL-10 were only upregulated in CpG treated animals and controls. CONCLUSIONS: The combination of TLR9 stimulation with RFA resulted in a potentiated antitumour T cell response and cytotoxicity in the VX2 tumour model. Only this combination prevented subsequent tumour spread and resulted in a significantly improved survival, justifying the need for further exploration of the combination of ablative therapies and TLR9 agonists in liver cancer. PMID- 25524263 TI - It Is Not About the Influence Religiosity Ought to Have, But the Influence It Does Have: A Response. AB - In my response to the article "Both Islam and Christianity Invite to Tolerance" I adress the different criticisms that are raised by the authors. Some of the criticisms can be agreed with, while others can be refuted. In general I do not share the author's perspective that every religion promotes peaceful coexistence. Instead claiming theoretically that religiosity has such an effect, the relationship between religiosity and violence should be analyzed empirically. PMID- 25524264 TI - Both Islam and Christianity Invite to Tolerance: A Commentary on Dirk Baier. AB - Baier recently published an interesting original article in the Journal of Interpersonal Violence. He compared violent behavior (VB) between Christians and Muslims and concluded that religiosity was not a protecting factor against violence and that Muslim religiosity associated positively with increased VB. We appreciate the author's enormous efforts on researching such an issue of relevance to today's world. However, in our view, the article has methodological weaknesses in terms of participants, instruments, and statistical analyses, which we examine in detail. Therefore, Baier's results should be interpreted more cautiously. Although interpersonal violence may sometimes be observable among Muslims, we do not attribute these to Islam's teachings. In our opinion, both Islam and Christianity invite to tolerance, peace, and friendship. So, the comparison of such differences and the drawing of conclusions that may reflect negatively on specific religious groups need better defined research, taking into consideration other basic variables in different communities. PMID- 25524265 TI - The Effect of Gender and Perpetrator-Victim Role on Mental Health Outcomes and Risk Behaviors Associated With Intimate Partner Violence. AB - Intimate partner violence (IPV) is a major public health concern. Previous studies have consistently shown that IPV is tied by to a variety of detrimental consequences for affected individuals, including negative mental health outcomes. However, the differential impact of gender and perpetrator-victim role (i.e., whether an individual is the perpetrator or victim of violence or both) remains largely understudied in the academic literature. Thus, the purpose of the present study was to describe a variety of mental health outcomes and risk behaviors among men and women experiencing no violence, perpetration-only, victimization only, and bidirectional violence. Data from Waves 3 and 4 of the National Longitudinal Study of Adolescent Health (N = 7,187) were used. Participants provided information on their perpetrator-victim role and on a variety of factors related to mental health (depression, suicidality, alcohol use, illegal drug use, and relationship satisfaction). For all outcomes, prevalence and severity generally tended to be highest among individuals affected by bidirectional IPV and lowest among individuals not affected by any violence (independent of gender). The present findings highlight that IPV and negative mental health outcomes and risk behaviors should be addressed as co-occurring problems in research, prevention, and treatment. In addition, all gender-role combinations should be addressed to better understand and address all potential effects of IPV. According to the present findings, couples affected by bidirectional violence are at particularly high risk of developing mental health disorders. Thus, policy makers and clinicians should predominantly target couples as well as individuals who are not only the victims but also the perpetrators of IPV and pay particular attention to potential signs of mental health distress these individuals might exhibit. PMID- 25524266 TI - Sexual Assault Victimization Among Female Undergraduates During Study Abroad: A Single Campus Survey Study. AB - Almost all research on sexual assault victimization among undergraduate university students pertains to incidents that occur on domestic college and university campuses. The purpose of the present study was to investigate the prevalence of sexual assault victimization and related factors among undergraduates in the context of study-abroad programs. Two hundred eight female students (52% response rate) from a small university in the northeastern United States who had recently studied abroad responded to an online survey containing measures of sexual assault, posttraumatic stress responses (PSR), and alcohol consumption. Almost 19% of the respondents indicated one or more types of sexual assault victimization. Approximately 17% reported non-consensual sexual touching, 7% attempted rape, 4% rape, with 9% reporting attempted rape or rape. As in domestic studies, victimization in this sample was related positively to alcohol consumption and PSR. Use of force was the most frequently reported perpetrator tactic. In sum, the high rates of sexual assault victimization reported by this sample during study abroad replicate previous findings. This context requires further attention from sexual assault researchers, especially given the increasing numbers of university students engaging in study abroad, and from campus support personnel who may be unaware of the likelihood of assault in this context. PMID- 25524267 TI - Social Information Processing in Dating Conflicts: Reciprocal Relationships With Dating Aggression in a One-Year Prospective Study. AB - The aim of this study was to assess the reciprocal associations among social information processing (SIP) in dating conflicts and the perpetration of dating aggression. A first step involved the development of a measure (The Social Information Processing Questionnaire in Dating Conflicts, SIPQ-DC) to assess social information in scenarios of conflict with dating partners. A sample of 1,272 adolescents (653 girls, 619 boys; Mage = 14.74 years, SD = 1.21) completed measures of SIP and dating aggression perpetration in two different times, which were spaced 1 year apart. Confirmatory factor analyses provided support for a model with five correlated factors for the SIPQ-DC, namely, hostile attribution, anger, aggressive response access, anticipation of positive consequences for oneself, and anticipation of negative consequences for partners. Although the perpetration of dating aggression at T1 was cross-sectionally associated with all the SIP components, anger was the only component that predicted the residual increase in dating aggression behavior over time. The perpetration of dating aggression predicted a worsening of cognitive-emotional processes involved in dating conflicts. Some longitudinal paths were significant only in male adolescents. In conclusion, relationships among SIP and aggression are reciprocal. Gender differences in longitudinal paths can contribute to explaining men's higher perpetration of violence in adulthood. PMID- 25524268 TI - Correlations between changes in conformational dynamics and physical stability in a mutant IgG1 mAb engineered for extended serum half-life. AB - This study compares the local conformational dynamics and physical stability of an IgG1 mAb (mAb-A) with its corresponding YTE (M255Y/S257T/T259E) mutant (mAb E), which was engineered for extended half-life in vivo. Structural dynamics was measured using hydrogen/deuterium (H/D) exchange mass spectrometry while protein stability was measured with differential scanning calorimetry (DSC) and size exclusion chromatography (SEC). The YTE mutation induced differences in H/D exchange kinetics at both pH 6.0 and 7.4. Segments covering the YTE mutation sites and the FcRn binding epitopes showed either subtle or no observable differences in local flexibility. Surprisingly, several adjacent segments in the CH2 and distant segments in the VH, CH1, and VL domains had significantly increased flexibility in the YTE mutant. Most notable among the observed differences is increased flexibility of the 244-254 segment of the CH2 domain, where increased flexibility has been shown previously to correlate with decreased conformational stability and increased aggregation propensity in other IgG1 mAbs (e.g., presence of destabilizing additives as well as upon de-glycosylation or methionine oxidation). DSC analysis showed decreases in both thermal onset (Tonset) and unfolding (Tm1) temperatures of 7 degrees C and 6.7 degrees C, respectively, for the CH2 domain of the YTE mutant. In addition, mAb-E aggregated faster than mAb-A under accelerated stability conditions as measured by SEC analysis. Hence, the relatively lower physical stability of the YTE mutant correlates with increased local flexibility of the 244-254 segment, providing a site-directed mutant example that this segment of the CH2 domain is an aggregation hot spot in IgG1 mAbs. PMID- 25524269 TI - The diagnosis of benign prostatic obstruction: Development of a clinical nomogram. AB - AIMS: To develop a nomogram predicting benign prostatic obstruction (BPO). METHODS: We included in this study 600 men with lower urinary tract symptoms (LUTS) and benign prostatic enlargement (BPE) who underwent standardized pressure flow studies (PFS) between 1996 and 2000. Complete clinical and urodynamic data were available for all patients. Variables assessed in univariate and multivariate logistic regression models consisted of IPSS, PSA, prostate size, maximal urinary flow rate (Qmax) at free flow, residual urine (RU), and bladder wall thickness (BWT). These were used to predict significant BPO (defined as a Schafer grade >= 3 in PFS). RESULTS: A preliminary multivariate model, including IPSS, Qmax at free flow and RU, suggested that only Qmax at free flow was a statistically significant predictor of BPO (P = 0.00) with a predictive accuracy (PA) of 82%. Further development of the multivariate model showed how the inclusion of BWT did not increase PA. Only transitional zone volume (TZV) proved to be an additional statistically significant predictor for BPO (P = 0.00). The combination of Qmax at free flow and TZV demonstrated a PA of 83.2% and were included in the final nomogram format. CONCLUSIONS: We developed a clinical nomogram, which is both accurate and well calibrated, which can be helpful in the management of patients with LUTS and BPE. External validation is warranted to confirm our findings. PMID- 25524270 TI - Community characteristics, conservative ideology, and child abuse rates. AB - Authoritarian ideology, including religious conservativism, endorses obedience to authority and physical punishment of children. Although this association has been studied at the level of the family, little research has been conducted on whether conservativism in the broader community context correlates with the mistreatment of children. The purpose of this study was to determine whether this relation between conservativism and physical punishment of children extends to child abuse rates at the community level. Predictors included county-level religious and political conservativism and demographic variables. Political and religious conservativism covaried, and both were inversely related to child abuse rates. Population density was strongly related to rates of maltreatment and with demographic factors controlled, religious conservativism but not political conservativism continued to predict rates of child abuse. The results suggest that community factors related to social disorganization may be more important than religious or political affiliation in putting children at risk for maltreatment. PMID- 25524271 TI - Section 5(4) (nurse's holding power) of the Mental Health Act 1983: a literature review. AB - Section 5(4) (nurse's holding power) of the Mental Health Act 1983 permits nurses of the 'prescribed class' to detain an informal inpatient. The patient must already be receiving treatment for mental disorder. The section lasts for up to 6 h. Section 5(4) is over 30 years old; however, there is relatively little literature exploring its use. Existing literature has limited itself to surveys and audits investigating: nurses' opinions of Section 5(4); nurses' knowledge of Section 5(4); and trends associated with the implementation of Section 5(4). The literature review suggests that what is known about the implementation of Section 5(4) is incomplete. For example, there are no accounts of how and why the holding power is implemented from both a nursing and patient perspective. Section 5(4) (nurse's holding power) of the Mental Health Act 1983 in England and Wales accounts for 10% (n = 1714) of all detentions after admission to hospital. It is followed by further detention in 66% of cases and may require nurses to restrain, seclude or closely observe the patient to prevent them harming themselves and/or others. To conduct a literature review of empirical articles concerning the implementation of Section 5(4), a literature search was undertaken in ASSIA, British Nursing Index, Medline, PsycINFO and Lawtel, using a combination of the keywords 'Section 5(4)', 'nurse's holding powers', 'holding powers', 'Mental Health Act 1983', 'MHA', 'compulsory detention', 'formal detention', 'emergency psychiatric interventions', 'containment interventions' and 'involuntary commitment'. Twenty-five articles were included in the review. Existing literature has focused on surveys and audits investigating: nurses' opinions of Section 5(4); nurses' knowledge of Section 5(4); and trends associated with the implementation of Section 5(4). While this literature has provided some insights into the implementation of Section 5(4), it is clear that what is known about its use is incomplete. Further research is required to examine a number of areas, for example, how and why the section is implemented. PMID- 25524272 TI - Investigation of oxidative stress in patients with alopecia areata and its relationship with disease severity, duration, recurrence and pattern. AB - BACKGROUND: Alopecia areata (AA) is an inflammatory autoimmune disease that causes hair loss on the scalp or trunk without scarring. Although the precise aetiopathogenesis of alopecia areata remains unknown, oxidative stress is thought to play a role. AIM: To investigate the relationship between severity and the role of oxidative stress in AA, by measuring plasma oxidant levels and antioxidant enzyme activities in erythrocytes. METHODS: In total, 62 patients with AA (24 males and 38 females), and 62 sex- and age-matched healthy controls (HCs) were enrolled in the study. We investigated the levels of plasma malondialdehyde (MDA) and the activities of erythrocyte catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). The relationship between oxidative stress and AA was also investigated with regard to disease pattern, severity, duration and recurrence. RESULTS: The mean erythrocyte GSH-Px and SOD activities were significantly reduced (P < 0.001 and P < 0.001 respectively) compared with the control group. Plasma MDA levels were increased but statistically insignificant (P = 0.08) in patients with AA compared with controls. No significant difference between erythrocyte CAT activities was observed between patients and controls (P = 0.2). In addition, we observed no statistically significant difference in patient plasma MDA levels or erythrocyte CAT, GSH-Px or SOD activities with regard to AA severity, duration, recurrence or pattern (P > 0.05). CONCLUSIONS: Patients with AA displayed reduced erythrocyte SOD and GSH-Px activities and enhanced plasma MDA levels. These findings support the possible role of oxidative stress in the pathogenesis of AA. PMID- 25524273 TI - Changing bodies changes minds: owning another body affects social cognition. AB - Research on stereotypes demonstrates how existing prejudice affects the way we process outgroups. Recent studies have considered whether it is possible to change our implicit social bias by experimentally changing the relationship between the self and outgroups. In a number of experimental studies, participants have been exposed to bodily illusions that induced ownership over a body different to their own with respect to gender, age, or race. Ownership of an outgroup body has been found to be associated with a significant reduction in implicit biases against that outgroup. We propose that these changes occur via a process of self association that first takes place in the physical, bodily domain as an increase in perceived physical similarity between self and outgroup member. This self association then extends to the conceptual domain, leading to a generalization of positive self-like associations to the outgroup. PMID- 25524275 TI - Hepatocytes maintain greater fluorescent bile acid accumulation and greater sensitivity to drug-induced cell death in three-dimensional matrix culture. AB - Primary hepatocytes undergo phenotypic dedifferentiation upon isolation from liver that typically includes down regulation of uptake transporters and up regulation of efflux transporters. Culturing cells between layers of collagen in a three-dimensional (3D) "sandwich" is reported to restore hepatic phenotype. This report examines how 3D culturing affects accumulation of fluorophores, the cytotoxic response to bile acids and drugs, and whether cell to cell differences in fluorescent anion accumulation correlate with differences in cytotoxicity. Hepatocytes were found to accumulate fluorescent bile acid (FBA) at significantly higher levels than the related fluorophores, carboxyfluorescein diacetate, (4.4 fold), carboxyfluorescein succinimidyl ester (4.8-fold), and fluorescein (30 fold). In 2D culture, FBA accumulation decreased to background levels by 32 h, Hoechst nuclear accumulation strongly decreased, and nuclear diameter increased, indicative of an efflux phenotype. In 3D culture, FBA accumulation was maintained through 168 h but at 1/3 the original intensity. Cell to cell differences in accumulated FBA did not correlate with levels of liver zonal markers L-FBAP (zone 1) or glutamine synthetase (zone 3). Cytotoxic response to hydrophobic bile acids, acetaminophen, and phalloidin was maintained in 3D culture, and cells with higher FBA accumulation showed 12-18% higher toxicity than the total population toward hydrophobic bile acids (P < 0.05). Long-term imaging showed oscillations in the accumulation of FBA over periods of hours. Overall, the studies suggest that high accumulation of FBA can indicate the sensitivity of cultured hepatocytes to hydrophobic bile acids and other toxins. PMID- 25524276 TI - A method for longitudinal, transcranial imaging of blood flow and remodeling of the cerebral vasculature in postnatal mice. AB - In the weeks following birth, both the brain and the vascular network that supplies it undergo dramatic alteration. While studies of the postnatal evolution of the pial vasculature and blood flow through its vessels have been previously done histologically or acutely, here we describe a neonatal reinforced thin-skull preparation for longitudinally imaging the development of the pial vasculature in mice using two-photon laser scanning microscopy. Starting with mice as young as postnatal day 2 (P2), we are able to chronically image cortical areas >1 mm(2), repeatedly for several consecutive days, allowing us to observe the remodeling of the pial arterial and venous networks. We used this method to measure blood velocity in individual vessels over multiple days, and show that blood flow through individual pial venules was correlated with subsequent diameter changes. This preparation allows the longitudinal imaging of the developing mammalian cerebral vascular network and its physiology. PMID- 25524277 TI - Chronically endurance-trained individuals preserve skeletal muscle mitochondrial gene expression with age but differences within age groups remain. AB - Maintenance of musculoskeletal function in older adults is critically important for preserving cardiorespiratory function and health span. Aerobic endurance training (ET) improves skeletal muscle metabolic function including age-related declines in muscle mitochondrial function. To further understand the underlying mechanism of enhanced muscle function with ET, we profiled the gene transcription (mRNA levels) patterns by gene array and determined the canonical pathways associated with skeletal muscle aging in a cross-sectional study involving vastus lateralis muscle biopsy samples of four subgroups (young and old, trained, and untrained). We first analyzed the sedentary individuals and then sought to identify the pathways impacted by long-term ET (>4 years) and determined the age effect. We found that skeletal muscle aging in older sedentary adults decreased mitochondrial genes and pathways involved in oxidative phosphorylation while elevating pathways in redox homeostasis. In older adults compared to their younger counterparts who chronically perform ET however, those differences were absent. ET did, however, impact nearly twice as many genes in younger compared to older participants including downregulation of gene transcripts involved in protein ubiquitination and the ERK/MAPK pathways. This study demonstrates that in individuals who are chronically endurance trained, the transcriptional profile is normalized for mitochondrial genes but aging impacts the number of genes that respond to ET including many involved in protein homeostasis and cellular stress. PMID- 25524278 TI - Endothelin inhibits renin release from juxtaglomerular cells via endothelin receptors A and B via a transient receptor potential canonical-mediated pathway. AB - Renin is the rate-limiting step in the production of angiotensin II: a critical element in the regulation of blood pressure and in the pathogenesis of hypertension. Renin release from the juxtaglomerular (JG) cell is stimulated by the second messenger cAMP and inhibited by increases in calcium (Ca). Endothelins (ETs) inhibit renin release in a Ca-dependent manner. JG cells contain multiple isoforms of canonical transient receptor potential (TRPC) Ca-permeable channels. The proposed hypothesis is that endothelin inhibits renin release by activating TRPC store-operated Ca channels. RT-PCR and immunofluorescence revealed expression of both ETA and ETB receptors in mouse JG cells. Incubation of primary cultures of JG cells with ET-1 (10 nmol/L) decreased renin release by 28%. Addition of either an ETA or an ETB receptor blocker completely prevented the ET inhibition of renin release. Incubation with the TRPC blocker (SKF 96365, 50 MUmol/L) completely reversed the Ca-mediated inhibition of renin release by ETs. These results suggest that endothelin inhibits renin release from JG cells via both ETA and ETB receptors, which leads to the activation of TRPC store-operated Ca channels. PMID- 25524279 TI - Developmental regulation of key gluconeogenic molecules in nonhuman primates. AB - Aberrant glucose regulation is common in preterm and full-term neonates leading to short and long-term morbidity/mortality; however, glucose metabolism in this population is understudied. The aim of this study was to investigate developmental differences in hepatic gluconeogenic pathways in fetal/newborn baboons. Fifteen fetal baboons were delivered at 125 day (d) gestational age (GA), 140d GA, and 175d GA (term = 185d GA) via cesarean section and sacrificed at birth. Term and healthy adult baboons were used as controls. Protein content and gene expression of key hepatic gluconeogenic molecules were measured: cytosolic and mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-C and PEPCK M), glucose-6-phosphatase-alpha (G6Pase-alpha), G6Pase-beta, fructose-1,6 bisphosphatase (FBPase), and forkhead box-O1 (FOXO1). Protein content of PEPCK-M increased with advancing gestation in fetal baboons (9.6 fold increase from 125d GA to 175d GA, P < 0.001). PEPCK-C gene expression was consistent with these developmental differences. Phosphorylation of FOXO1 was significantly lower in preterm fetal baboons compared to adults, and gene expression of FOXO1 was lower in all neonates when compared to adults (10% and 62% of adults respectively, P < 0.05). The FOXO1 target gene G6Pase expression was higher in preterm animals compared to term animals. No significant differences were found in G6Pase-alpha, G6Pase-beta, FOXO1, and FBPase during fetal development. In conclusion, significant developmental differences are found in hepatic gluconeogenic molecules in fetal and neonatal baboons, which may impact the responses to insulin during the neonatal period. Further studies under insulin-stimulated conditions are required to understand the physiologic impact of these maturational differences. PMID- 25524280 TI - Noninvasive assessment for acute allograft rejection in a rat lung transplantation model. AB - After lung transplantation, early detection of acute allograft rejection is important not only for timely and optimal treatment, but also for the prediction of chronic rejection which is a major cause of late death. Many biological and immunological approaches have been developed to detect acute rejection; however, it is not well known whether lung mechanics correlate with disease severity, especially with pathological rejection grade. In this study, we examined the relationship between lung mechanics and rejection grade development in a rat acute rejection model using the forced oscillation technique, which provides noninvasive assessment of lung function. To this end, we assessed lung resistance and elastance (RL and EL) from implanted left lung of these animals. The perivascular/interstitial component of rejection severity grade (A-grade) was also quantified from histological images using tissue fraction (TF; tissue + cell infiltration area/total area). We found that TF, RL, and EL increased according to A-grade. There was a strong positive correlation between EL at the lowest frequency (Elow; EL at 0.5 Hz) and TF (r(2) = 0.930). Furthermore, the absolute difference between maximum value of EL (Emax) and Elow (Ehet; Emax - Elow) showed the strong relationship with standard deviation of TF (r(2) = 0.709), and A-grade (Spearman's correlation coefficients; rs = 0.964, P < 0.0001). Our results suggest that the dynamic elastance as well as its frequency dependence have the ability to predict A-grade. These indexes should prove useful for noninvasive detection and monitoring the progression of disease in acute rejection. PMID- 25524283 TI - Could abnormal neutrophil-platelet interactions and complex formation contribute to oxidative stress and organ failure in cirrhosis? PMID- 25524282 TI - Independent purinergic mechanisms of central and peripheral chemoreception in the rostral ventrolateral medulla. AB - The rostral ventrolateral medulla oblongata (RVLM) contains two functionally distinct types of neurons that control and orchestrate cardiovascular and respiratory responses to hypoxia and hypercapnia. One group is composed of the central chemoreceptor neurons of the retrotrapezoid nucleus, which provides a CO2/H(+) -dependent drive to breathe and serves as an integration centre and a point of convergence of chemosensory information from other central and peripheral sites, including the carotid bodies. The second cluster of RVLM cells forms a population of neurons belonging to the C1 catecholaminergic group that controls sympathetic vasomotor tone in resting conditions and in conditions of hypoxia and hypercapnia. Recent evidence suggests that ATP-mediated purinergic signalling at the level of the RVLM co-ordinates cardiovascular and respiratory responses triggered by hypoxia and hypercapnia by activating retrotrapezoid nucleus and C1 neurons, respectively. The role of ATP-mediated signalling in the RVLM mechanisms of cardiovascular and respiratory activities is the main subject of this short review. PMID- 25524284 TI - Pelvic exenterations for specific extraluminal recurrences in the era of total mesorectal excision: is there still a chance for cure?: a single-center review of patients with extraluminal pelvic recurrence for rectal cancer from March 2004 to November 2010. AB - BACKGROUND: The benefits in terms of curative resection and survival of pelvic exenterations for specific extraluminal pelvic recurrences from rectal cancer in the era of total mesorectal excision were assessed. METHODS: We conducted a single-center review of patients with extraluminal pelvic recurrence from colorectal cancer between March 2004 and November 2010. Twenty-seven pelvic exenterations (13 posterior and 14 total) were performed. Independent predicative factors such as age, sex, local control on first surgery, pelvic sidewall excision, initial International Union Against Cancer (UICC) staging, sphincter preserving resection at first surgery, tumor presentation on computed tomography and magnetic resonance imaging (pelvis sidewall involvement, number of fixation sites, ureteral involvement), local disease-free interval, previous symptoms, and postoperative treatment were analyzed. RESULTS: No operative mortality was noted in this series. Overall morbidity rate was 74%; 22% of the patients developed severe complications. Complete surgical clearance (R0) was obtained in 63% of the patients. The rate of R0 resections was lower in total pelvic exenteration (57%) than in posterior pelvic exenteration (69%). Three years overall survival and disease-free survival were 76% and 59%, respectively. Curative resection (R0) was the only independent prognostic factor for overall survival (P = .0016) and disease-free survival (P < .0001). CONCLUSION: Pelvic exenterations for extraluminal pelvic recurrences from rectal cancer afford a high R0 resection rate with acceptable morbidity. PMID- 25524285 TI - Involvement of c-Myc in the proliferation of MCF-7 human breast cancer cells induced by bHLH transcription factor DEC2. AB - Differentiated embryonic chondrocyte expressed gene 1 (DEC1; BHLHE40/Stra13/Sharp2) and differentiated embryonic chondrocyte expressed gene 2 (DEC2; BHLHE41/Sharp1) are basic helix-loop-helix (bHLH) transcriptional factors that are involved in the regulation of cell differentiation, circadian rhythms, response to hypoxia and carcinogenesis. Previous studies have demonstrated that the expression of DECs is induced under hypoxic conditions in various normal and cancer cell lines. In the present study, using RT-qPCR and western blot analysis, we demonstrated that hypoxia induced the expression of DEC1 and DEC2 in MCF-7 human breast cancer cells; their expression levels reached a peak at different time points. In particular, we found that the expression pattern of the hypoxia inducible factor (HIF)-1alpha protein was similar to DEC1, and that of the HIF 2alpha protein was identical to that of DEC2. The knockdown of HIF-2alpha using siRNA suppressed the phosphorylation of Akt, as well as the expression of DEC2 and c-Myc. Hypoxia failed to affect the expression of DEC2 and c-Myc when the PI3K/Akt signaling pathway was blocked. In addition, the overexpression of DEC1 and DEC2 was induced by transfecting the cells with a pcDNA vector. The overexpression of DEC2, but not that of DEC1, increased the proliferation of the MCF-7 cells under both normoxic and hypoxic conditions. Concomitantly, the expression of c-Myc was upregulated by exposure to hypoxia and by the overexpression of DEC2. In conclusion, DEC2 participates in hypoxia-induced cell proliferation by functioning as a target gene of the PI3K/Akt signaling pathway and regulating the expression of c-Myc. PMID- 25524288 TI - [Propranolol and lactatemia during hypovolemic shock: a case report]. AB - Lactate production results from anaerobic glycolysis. This pathway is recruited physiologically during intense and sustained muscular contractions. Hyperlactatemia may develop when tissue oxygenation is jeopardized such as in shock, its absence having been, however, sometimes reported in sepsis in which interactions between infectious agents and the organism's cells might blunt or disrupt hyperlactatemia development. During the course of acute rotavirus gastroenteritis, a 9-month-old girl developed severe dehydration (capillary refill time, 5 s) leading to hypovolemic shock without signs of sepsis and with hypotension at 62/21 mmHg Surprisingly, the child failed to develop hyperlactatemia during shock. An etiologic search to understand why hyperlactatemia did not occur revealed that this patient had been receiving propranolol since the age of four months for the treatment of a Cyrano hemangioma. Via its inhibitory action on beta-adrenergic receptors, propranolol antagonizes the stimulation of glycolysis by catecholamines, which may be rationally proposed to have contributed to preventing hyperlactatemia during hypovolemic shock in this patient. Mechanisms by which propranolol can mediate this antihyperlactatemia action are further illustrated and discussed. PMID- 25524289 TI - [Gradenigo syndrome and petrositis in a child]. AB - Gradenigo syndrome is caused by petrous inflammation, also called petrositis. It includes acute otitis media, diplopia, and homolateral retroorbital pain due to trigeminal and abducens nerve injury. We describe a child with petrositis secondary to acute otitis media. The lack of otoscopic abnormality and the presence of bilateral headache made the diagnostic difficult. After complementary investigations searching for an intracranial process, the diagnosis was made based on brain and skull base dimensional computed tomography. PMID- 25524286 TI - Ventilatory function and cardiovascular disease risk factors: a cross-sectional study in young adults. AB - BACKGROUND: The association between impaired lung function and cardiovascular disease (CVD) risk factors has been shown in adults. However, there is little evidence of such an association in young adults, particularly from South America, where the burden of CVD and chronic obstructive pulmonary disease (COPD) is as high as that observed in more developed countries. We therefore investigated the relation between CVD risk factors including metabolic syndrome (MS), and lung function status in young adults from Chile. METHODS: 970 subjects from a sample of 998 adults born between 1974 and 1978 in Limache, Chile, were studied. A Spanish translation of the European Community Respiratory Health Survey (ECRHS) questionnaire was used. Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured. Weight, height, waist circumference (WC), blood pressure, Homeostatic model assessment (HOMA-IR), triglycerides, high density lipoprotein (HDL), glycaemia, and metabolic syndrome (MS) were also assessed. RESULTS: The prevalence of MS was 11.8%. A lower FEV1 and lower FVC were associated with having MS (beta-coefficient -0.13; 95% Confidence Interval [CI] -0.21 to -0.05, and beta-coefficient -0.18; 95% CI -0.27 to -0.09, respectively). Both spirometric measures were also negatively associated with having an elevated HOMA-IR (beta-coefficient for FEV1 -0.08; 95% CI -0.13 to 0.03, and beta-coefficient for FVC -0.11; 95% CI -0.17 to -0.05). In males only, a lower FEV1 and FVC were associated with having elevated triglycerides (beta coefficient highest vs. lowest tertile -0.13, 95% CI -0.24 to -0.03, and beta coefficient -0.13, 95% CI -0.25 to -0.01, respectively). In women, a higher FEV1 and FVC were statistically significantly related to having higher levels of HDL. Ventilatory function was unrelated to hypertension or WC in this population. CONCLUSION: In this population-based study of young adults, a poorer ventilatory function was associated with many CVD risk factors. Endeavours to understand better causality issues of such associations are warranted. PMID- 25524290 TI - [Congenital foot abnormalities]. AB - The foot may be the site of birth defects. These abnormalities are sometimes suspected prenatally. Final diagnosis depends on clinical examination at birth. These deformations can be simple malpositions: metatarsus adductus, talipes calcaneovalgus and pes supinatus. The prognosis is excellent spontaneously or with a simple orthopedic treatment. Surgery remains outstanding. The use of a pediatric orthopedist will be considered if malposition does not relax after several weeks. Malformations (clubfoot, vertical talus and skew foot) require specialized care early. Clubfoot is characterized by an equine and varus hindfoot, an adducted and supine forefoot, not reducible. Vertical talus combines equine hindfoot and dorsiflexion of the forefoot, which is performed in the midfoot instead of the ankle. Skew foot is suspected when a metatarsus adductus is resistant to conservative treatment. Early treatment is primarily orthopedic at birth. Surgical treatment begins to be considered after walking age. Keep in mind that an abnormality of the foot may be associated with other conditions: malposition with congenital hip, malformations with syndromes, neurological and genetic abnormalities. PMID- 25524291 TI - [Xanthogranulomatous pyelonephritis with pyonephrosis in a 4-year-old child]. AB - Xanthogranulomatous pyelonephritis is a rare form of chronic pyelonephritis observed in only a few cases in children. Symptoms are mild, which explains the delay in diagnosis. Diagnosis is based on histology but can be suspected on CT. The treatment is medical and often surgical, with an uncertain renal prognosis. It is therefore imperative to diagnose early. We report the case of a 4-year-old child who presented with xanthogranulomatous pyelonephritis caused by Pseudomonas aeruginosa, which evolved into pyonephrosis, due to inadequate antibiotic therapy. This highlights the importance of understanding this disease and not treating urinary tract infections blindly. PMID- 25524292 TI - Neuronal and immune synapses on the move at traffic. PMID- 25524293 TI - The National Mastitis Council: A Global Organization for Mastitis Control and Milk Quality, 50 Years and Beyond. AB - The National Mastitis Council was founded in 1961 based on the desire of a forward-thinking group of individuals to bring together "all forces of organized agriculture in the United States to combat, through every practical device, the mastitis threat to the Nation's health and food safety". What started as a small organization focused on mastitis of dairy cattle in the United States has grown into a global organization for mastitis and milk quality. Over the last 50-plus years the concerted efforts of the membership have led to the synthesis and dissemination of a considerable body of knowledge regarding udder health, milk quality, and food safety which has improved dairy cattle health and well-being and farm productivity. PMID- 25524294 TI - Allergic contact dermatitis resulting from a poly(carbonate urethane) chronic haemodialysis central venous catheter. PMID- 25524295 TI - Sinistral portal hypertension after pancreaticoduodenectomy with splenic vein ligation. AB - BACKGROUND: Splenic vein ligation may result in sinistral (left-sided) portal hypertension and gastrointestinal haemorrhage. The aim of this study was to analyse the pathogenesis of sinistral portal hypertension following splenic vein ligation in pancreaticoduodenectomy. METHODS: Patients who underwent pancreaticoduodenectomy for pancreatic cancer between January 2005 and December 2012 were included in this retrospective study. The venous flow pattern from the spleen and splenic hypertrophy were examined after surgery. RESULTS: Of 103 patients who underwent pancreaticoduodenectomy with portal vein resection, 43 had splenic vein ligation. There were two predominant venous flow patterns from the spleen. In the varicose route (27 patients), flow from the spleen passed to colonic varices and/or other varicose veins. In the non-varicose route, flow from the spleen passed through a splenocolonic collateral (14 patients) or a spontaneous splenorenal shunt (2 patients). The varicose route was associated with significantly greater splenic hypertrophy than the non-varicose route (median splenic hypertrophy ratio 1.52 versus 0.94; P < 0.001). All patients with the varicose route had colonic varices, and none had a right colic marginal vein at the hepatic flexure. CONCLUSION: Pancreaticoduodenectomy with splenic vein ligation may lead to sinistral portal hypertension. To avoid the development of varices, it is important to preserve the right colic marginal vein. Reconstruction of the splenic vein should be considered if the right colic marginal vein is divided. PMID- 25524296 TI - Aminocatalytic cross-coupling approach via iminium ions to different C - C Bonds. AB - Given the attractive ability of iminium ions to functionalize molecules directly at ostensibly unreactive positions, the reactivity of iminium ions, in which an alpha CH2 group is replaced by C?O was explored. Background studies on the ability of such iminium cations to promote reactions via an iminium-catalyzed or iminium-equivalent pathway are apparently unavailable. Previously, tandem cross coupling reactions were reported, in which an iminium ion undergoes nucleophilic 1,2-addition to give a putative three-component intermediate that abstracts a proton in situ and undergoes self-deamination followed by unprecedented DMSO/aerobic oxidation to generate alpha-ketoamides. However, later it was observed that iminium ions can generate valuable alpha-ketoamides through simple aerobic oxidation. In all reactions, iminium ions were generated in situ by reaction of 2-oxoaldehydes with secondary amines. PMID- 25524297 TI - Regulation of histone H3 phosphorylation at serine 10 in PTTH-stimulated prothoracic glands of the silkworm, Bombyx mori. AB - A complex signaling network appears to be involved in prothoracicotropic hormone (PTTH)-stimulated ecdysteroidogenesis in insect prothoracic glands (PGs). In the present study, we investigated the localization of phosphorylated extracellular signal-regulated kinase (ERK) in PTTH-stimulated PGs in Bombyx mori. The nuclear effect of PTTH was further studied by examining phosphorylation of histone H3 at serine 10. Results showed that in PTTH-stimulated PGs, higher phosphorylated ERK was detected in nuclear fraction compared to that in cytosolic fraction. PTTH treatment in vitro appears to rapidly enhance the transcriptional activation associated histone H3 phosphorylation at serine 10. PTTH stimulated histone H3 phosphorylation in a time-dependent manner. Injection of PTTH into day-6 last instar larvae greatly increased histone H3 phosphorylation, verifying the in vitro effect. The stimulation of histone H3 phosphorylation by PTTH appears to be developmentally regulated. PTTH-stimulated histone H3 phosphorylation was greatly reduced in Ca(2+)-free saline or by pretreatment with a potent and specific inhibitor of phospholipase C (PLC), U73122. When PGs were treated with agents that directly elevate the intracellular Ca(2+) concentration (either A23187 or thapsigargin), a greatly increase in histone H3 phosphorylation at serine 10 was observed, indicating Ca(2+)-dependency of histone H3 phosphorylation stimulated by PTTH. In addition, PTTH-stimulated histone H3 phosphorylation was partially reduced by U0126, a specific mitogen-activated protein kinase (MAPK)/ERK kinase (MEK) inhibitor, indicating the involvement of ERK. However, pretreatment with LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, did not inhibit PTTH stimulated histone H3 phosphorylation, implying that PI3K signaling is not related to PTTH-stimulated histone H3 phosphorylation. Taken together, these results suggest that PTTH-stimulated histone H3 phosphorylation at serine 10 is mediated by Ca(2+)/ERK signaling in B. mori PGs. PMID- 25524298 TI - Analysis of chitin-binding proteins from Manduca sexta provides new insights into evolution of peritrophin A-type chitin-binding domains in insects. AB - In insects, chitin is a major structural component of the cuticle and the peritrophic membrane (PM). In nature, chitin is always associated with proteins among which chitin-binding proteins (CBPs) are the most important for forming, maintaining and regulating the functions of these extracellular structures. In this study, a genome-wide search for genes encoding proteins with ChtBD2-type (peritrophin A-type) chitin-binding domains (CBDs) was conducted. A total of 53 genes encoding 56 CBPs were identified, including 15 CPAP1s (cuticular proteins analogous to peritrophins with 1 CBD), 11 CPAP3s (CPAPs with 3 CBDs) and 17 PMPs (PM proteins) with a variable number of CBDs, which are structural components of cuticle or of the PM. CBDs were also identified in enzymes of chitin metabolism including 6 chitinases and 7 chitin deacetylases encoded by 6 and 5 genes, respectively. RNA-seq analysis confirmed that PMP and CPAP genes have differential spatial expression patterns. The expression of PMP genes is midgut specific, while CPAP genes are widely expressed in different cuticle forming tissues. Phylogenetic analysis of CBDs of proteins in insects belonging to different orders revealed that CPAP1s from different species constitute a separate family with 16 different groups, including 6 new groups identified in this study. The CPAP3s are clustered into a separate family of 7 groups present in all insect orders. Altogether, they reveal that duplication events of CBDs in CPAP1s and CPAP3s occurred prior to the evolutionary radiation of insect species. In contrast to the CPAPs, all CBDs from individual PMPs are generally clustered and distinct from other PMPs in the same species in phylogenetic analyses, indicating that the duplication of CBDs in each of these PMPs occurred after divergence of insect species. Phylogenetic analysis of these three CBP families showed that the CBDs in CPAP1s form a clearly separate family, while those found in PMPs and CPAP3s were clustered together in the phylogenetic tree. For chitinases and chitin deacetylases, most of phylogenetic analysis performed with the CBD sequences resulted in similar clustering to the one obtained by using catalytic domain sequences alone, suggesting that CBDs were incorporated into these enzymes and evolved in tandem with the catalytic domains before the diversification of different insect orders. Based on these results, the evolution of CBDs in insect CBPs is discussed to provide a new insight into the CBD sequence structure and diversity, and their evolution and expression in insects. PMID- 25524299 TI - Movement disorders due to bilirubin toxicity. AB - Advances in the care of neonatal hyperbilirubinemia have led to a decreased incidence of kernicterus. However, neonatal exposure to high levels of bilirubin continues to cause severe motor symptoms and cerebral palsy (CP). Exposure to moderate levels of unconjugated bilirubin may also cause damage to the developing central nervous system, specifically the basal ganglia and cerebellum. Brain lesions identified using magnetic resonance imaging following extreme hyperbilirubinemia have been linked to dyskinetic CP. Newer imaging techniques, such as diffusion tensor imaging or single-photon emission computed tomography, allow quantification of more subtle white matter injury following presumed exposure to unbound bilirubin, and may explain more subtle movement disorders. New categories of bilirubin-induced neurologic dysfunction, characterized by subtle bilirubin encephalopathy following moderate hyperbilirubinemia, have been implicated in long-term motor function. Further research is needed to identify subtle impairments resulting from moderate-severe neonatal hyperbilirubinemia, to understand the influence of perinatal risk factors on bilirubin toxicity, and to develop neuroprotective treatment strategies to prevent movement disorders due to bilirubin toxicity. PMID- 25524300 TI - Long-term survival with a stentless free-hand Batista pericardial aortic valve prosthesis: A case report. AB - INTRODUCTION: Stented bovine pericardial prosthetic valves are a good option for older patients, except when there is a fragile small aortic annulus, when, if there is no contraindication to anticoagulation, a mechanical prosthesis may be indicated. PRESENTATION OF CASE: We report a 72 year-old man who underwent coronary bypass grafting and aortic valve replacement with a stentless valve fashioned from bovine pericardium using the Batista technique. Despite early sternal infection and dehiscence, and renal and respiratory failure during 15 years follow-up, he remains alive and self-sufficient. Echocardiography demonstrates a well-functioning aortic valve. DISCUSSION: When Batista reported his first 60 patients, concerns were raised about the surgical feasibility of constructing the valve and its long-term durability. Our case perhaps addresses both concerns. CONCLUSION: Replacement of the aortic valve with a free-hand Batista pericardial valve is a feasible option in a suitable and carefully selected patient. PMID- 25524301 TI - Myxolipoma of the renal capsule: A case report. AB - INTRODUCTION: Although lipomas are the most common mesenchymal tumors of the human body, primary intrarenal lipomas are quite rare. In this report we present a case of benign mesenchymal tumor with lipomatous and myxoid components. PRESENTATION OF CASE: A sixty one years old male patient was admitted to our outpatient clinic for a general control since he had a right radical nephrectomy operation due to renal cell carcinoma (RCC) eight years ago and he did not have any urological control for last 3 years. However the urinary ultrasound revealed a mass lesion on left kidney and then on axial contrast-enhanced computed tomography (CT) scan, there were two masses on the left kidney. In the magnetic resonance imaging (MRI), the tumor on cortex was depicted as a homogeneous low signal intensity on the T1-weighted pulse sequence and as a heterogeneous high signal intensity on the T2-weighted pulse sequence. In pathological evaluation, the biopsy material of the cortical mass was a tumoral lesion containing lipomatous and mixoid areas without atypia, mitosis or necrosis which was diagnosed as myxolipoma. DISCUSSION: Myxolipoma, an uncommon type of lipoma, is a benign tumor composed mainly of fat cells with myxoid (mucus-like) components. In our case, the tumor was composed of mature adipocytes together with areas rich in mucoid substances and there were no malignant features including lipoblasts, mitosis or abundant capillary network. CONCLUSION: Herein we present a case of a fatty tumor originating from the renal capsule with the histologic diagnosis of myxolipoma. To the best of our knowledge, myxolipoma, a very rare form of lipoma, is not reported in kidney, in the literature before. PMID- 25524302 TI - Upper extremity deep vein thrombosis with tourniquet use. AB - INTRODUCTION: Upper extremity deep vein thrombosis is an increasingly important clinical finding with significant morbidity and mortality. The condition may be under-diagnosed in trauma and surgery settings. PRESENTATION OF CASE: We present a case of upper extremity thrombosis with venous congestive symptoms secondary to the use of an operative tourniquet. A literature review and discussion of the causes of upper extremity deep vein thrombosis and the pathophysiological disturbances seen with tourniquet use are presented. DISCUSSION: Upper extremity deep venous thrombosis is uncommon. In this case the likely cause was operative tourniquet use. CONCLUSION: Operative tourniquet may be a risk factor in upper extremity deep vein thrombosis. PMID- 25524303 TI - Peritonitis secondary to spontaneous perforation of a primary gastrointestinal stromal tumour of the small intestine: A case report and a literature review. AB - INTRODUCTION: A few cases of acute abdomen caused by perforation of small intestinal gastrointestinal stromal tumours (GISTs) have been reported in the literature. PRESENTATION OF CASE: Together with a review of the published cases, here we report a case of an elderly patient with peritonitis due to spontaneous perforation of a GIST of the jejunum. An 82-year-old man was admitted to the emergency unit of our hospital with fever and severe abdominal pain. An abdominal enhanced computed tomography scan detected a 6cm solid mass in the left upper quadrant adherent to a jejunal loop and surrounded by free fluid and free air. Due to the radiological features of the mass, the diagnosis of a perforation of a GIST arising from the jejunum wall was suspected. The patient underwent emergency laparotomy. Intraoperative findings confirmed diffuse peritonitis secondary to jejunal tumour perforation. A segmental resection of the jejunum containing the mass was performed followed by a mechanical end-to-side anastomosis. The histopathologic examination of the mass confirmed the diagnosis of a perforated GIST of the small intestine (high-risk category). The post-operative course was uneventful and the patient was treated with adjuvant imatinib therapy. DISCUSSION: Twenty-one other cases of spontaneous perforation of small intestine GISTs are reported in the literature and are summarized in the present review. CONCLUSION: The described case is the tip of the iceberg and spontaneous rupture or perforation of GISTs are a far more frequent first presentation of this rare tumour. PMID- 25524304 TI - Global health and orthopaedic surgery-A call for international morbidity and mortality conferences. AB - INTRODUCTION: There is a large discrepancy between supply and demand of surgical services in developing countries. This inequality holds true in orthopaedic surgery and the delivery of musculoskeletal care. Intertwined amongst the decision to perform surgical procedures in the developing world are the ethics of doing so - just because one is capable of performing a procedure, should it be done? PRESENTATION OF CASE: A 31 year-old female with end-stage joint destruction underwent a left total hip replacement by a foreign orthopaedic team in Tanzania. She had a favorable outcome for 8 months, but is now diagnosed with tuberculosis and a deep space infection in her prosthetic left hip - an unsolvable problem in the developing world. DISCUSSION: This case demonstrates the ethical challenges that can be created from performing surgical procedures in the developing world without concomitant access to appropriate patient follow-up or resources for treating post-operative complications. While the current system is inadequate to manage the burden of disease, these inadequacies may be exacerbated at times by post-operative complications resulting from well-intentioned surgical missions. CONCLUSION: This case illustrates many difficulties in caring for individuals in the developing world, raising several questions: (1) How can complications be prevented in the future? (2) What are possible ways of managing complications with resources at hand once it occurs? (3) What resources are needed to minimize patient? Ideally an international forum can help provide descriptions of issues and problems that are encountered so as to increase awareness and identify potential solutions. PMID- 25524305 TI - Electroencephalographic biomarkers of psychosis: present and future. PMID- 25524306 TI - Using biomarker batteries. PMID- 25524307 TI - MicroRNAs in copy number variants in schizophrenia: misregulation of genome-wide gene expression programs. PMID- 25524308 TI - Foreign-Born Persons Diagnosed with HIV: Where are They From and Where Were They Infected? AB - We sought to calculate rates of HIV diagnoses by area of birth among foreign-born persons in a high-incidence US city with many immigrants, and determine probable place of HIV acquisition. Data from the New York City HIV surveillance registry and American Community Survey were used to calculate HIV diagnosis rates by area of birth and determine probable place of HIV acquisition among foreign-born diagnosed in 2006-2012. HIV diagnosis rates varied by area of birth and were highest among African-born persons; absolute numbers were highest among Caribbean born persons. Probable place of acquisition was a foreign country for 23 % (from 9 % among Middle Easterners to 43 % among Africans), US for 61 % (from 34 % among Africans to 76 % among South Americans), and not possible to estimate for 16 %. HIV prevention and testing initiatives should take into account variability by foreign area of birth in HIV diagnosis rates and place of acquisition. PMID- 25524310 TI - Translational impact of nanoparticle-drug conjugate CRLX101 with or without bevacizumab in advanced ovarian cancer. AB - PURPOSE: Increased tumor hypoxia and hence elevated hypoxia-inducible factor 1alpha (HIF1alpha) is thought to limit the efficacy of vascular endothelial growth factor (VEGF) pathway-targeting drugs by upregulating adaptive resistance genes. One strategy to counteract this is to combine antiangiogenic drugs with agents able to suppress HIF1alpha. One such possibility is the investigational drug CRLX101, a nanoparticle-drug conjugate (NDC) containing the payload camptothecin, a known topoisomerase-I poison. EXPERIMENTAL DESIGN: CRLX101 was evaluated both as a monotherapy and combination with bevacizumab in a preclinical mouse model of advanced metastatic ovarian cancer. These preclinical studies contributed to the rationale for undertaking a phase II clinical study to evaluate CRLX101 monotherapy in patients with advanced platinum-resistant ovarian cancer. RESULTS: Preclinically, CRLX101 is highly efficacious as a monotherapy when administered at maximum-tolerated doses. Furthermore, chronic low-dose CRLX101 with bevacizumab reduced bevacizumab-induced HIF1alpha upregulation and resulted in synergistic efficacy, with minimal toxicity in mice. In parallel, initial data reported here from an ongoing phase II clinical study of CRLX101 monotherapy shows measurable tumor reductions in 74% of patients and a 16% RECIST response rate to date. CONCLUSIONS: Given these preclinical and initial clinical results, further clinical studies are currently evaluating CRLX101 in combination with bevacizumab in ovarian cancer and warrant the evaluation of this therapy combination in other cancer types where HIF1alpha is implicated in pathogenesis, as it may potentially be able to improve the efficacy of antiangiogenic drugs. PMID- 25524311 TI - Circulating tumor cell analysis in metastatic triple-negative breast cancers. AB - PURPOSE: Recent developments in rare-cell technology have led to improved blood based assays that allow for the reliable detection, enumeration, and more recently, genomic profiling of circulating tumor cells (CTC). We evaluated two different approaches for enumeration of CTCs in a prospective therapeutic study of patients with metastatic triple-negative breast cancer (TNBC). EXPERIMENTAL DESIGN: The CellSearch system, a commercially available and U.S. Food and Drug Administration (FDA)-cleared assay for CTC enumeration, and IE/FC, an alternative method using EPCAM-based immunomagnetic enrichment and flow cytometry that maintains cell viability, were used to enumerate CTCs in the blood of patients with metastatic TNBC. CTC numbers were assessed at baseline and 7 to 14 days after initiation of therapy with cetuximab +/- carboplatin in a phase II multicenter clinical trial (TBCRC 001). RESULTS: CTC numbers from two methods were significantly correlated at baseline (r = 0.62) and at 7 to 14 days (r = 0.53). Baseline CTCs showed no association with time-to-progression (TTP), whereas CTCs at 7 to 14 days were significantly correlated with TTP (CellSearch P = 0.02; IE/FC P = 0.03). CTCs at both time points were significantly associated with overall survival (OS) [CellSearch: baseline (P = 0.0001) and 7 to 14 days (P < 0.0001); IE/FC: baseline (P = 0.0009) and 7 to 14 days (P = 0.0086)]. CONCLUSIONS: Our findings demonstrate that CTC enumeration by two different assays was highly concordant. In addition, results of both assays were significantly correlated with TTP and OS in patients with TNBC. The IE/FC method is also easily adapted to isolation of pure populations of CTCs for genomic profiling. PMID- 25524309 TI - We can't all be supermodels: the value of comparative transcriptomics to the study of non-model insects. AB - Insects are the most diverse group of organisms on the planet. Variation in gene expression lies at the heart of this biodiversity and recent advances in sequencing technology have spawned a revolution in researchers' ability to survey tissue-specific transcriptional complexity across a wide range of insect taxa. Increasingly, studies are using a comparative approach (across species, sexes and life stages) that examines the transcriptional basis of phenotypic diversity within an evolutionary context. In the present review, we summarize much of this research, focusing in particular on three critical aspects of insect biology: morphological development and plasticity; physiological response to the environment; and sexual dimorphism. A common feature that is emerging from these investigations concerns the dynamic nature of transcriptome evolution as indicated by rapid changes in the overall pattern of gene expression, the differential expression of numerous genes with unknown function, and the incorporation of novel, lineage-specific genes into the transcriptional profile. PMID- 25524313 TI - Non-interacting surface solvation and dynamics in protein-protein interactions. AB - Protein-protein interactions control a plethora of cellular processes, including cell proliferation, differentiation, apoptosis, and signal transduction. Understanding how and why proteins interact will inevitably lead to novel structure-based drug design methods, as well as design of de novo binders with preferred interaction properties. At a structural and molecular level, interface and rim regions are not enough to fully account for the energetics of protein protein binding, even for simple lock-and-key rigid binders. As we have recently shown, properties of the global surface might also play a role in protein-protein interactions. Here, we report on molecular dynamics simulations performed to understand solvent effects on protein-protein surfaces. We compare properties of the interface, rim, and non-interacting surface regions for five different complexes and their free components. Interface and rim residues become, as expected, less mobile upon complexation. However, non-interacting surface appears more flexible in the complex. Fluctuations of polar residues are always lower compared with charged ones, independent of the protein state. Further, stable water molecules are often observed around polar residues, in contrast to charged ones. Our analysis reveals that (a) upon complexation, the non-interacting surface can have a direct entropic compensation for the lower interface and rim entropy and (b) the mobility of the first hydration layer, which is linked to the stability of the protein-protein complex, is influenced by the local chemical properties of the surface. These findings corroborate previous hypotheses on the role of the hydration layer in shielding protein-protein complexes from unintended protein-protein interactions. PMID- 25524312 TI - Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. AB - PURPOSE: The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. EXPERIMENTAL DESIGN: HLA-A*0201 positive patients with HMB-45, NY-ESO 1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. RESULTS: Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4(+)/CD4(+), CD25(+)Treg/CD4(+), and tetramer specific CD8(+) T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25(+)Treg/CD4(+) populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. CONCLUSIONS: Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study. PMID- 25524314 TI - Optimal periods of exclusive breastfeeding associated with any breastfeeding duration through one year. AB - OBJECTIVE: To quantify optimal minimum durations of exclusive breastfeeding associated with maintenance of any breastfeeding at 15 time points during the first year of life. STUDY DESIGN: Mothers (n = 1189) from the prospective Infant Feeding Practices Study II cohort who initiated exclusive breastfeeding with healthy term infants were included. In a 80:20 split-sample validation study, receiver operating characteristic curves estimated optimal minimum durations of exclusive breastfeeding needed to predict maintenance of any breastfeeding at 15 time points during the first year (n = 951). Logistic regression estimated the predictive performance of the identified thresholds adjusted for maternal age, race, education, parity, support system, and return-to-work status. Results were validated in the remaining 20% (n = 238). RESULTS: Optimal minimum durations ranged from 4.0-17.1 weeks of exclusive breastfeeding associated with maintenance of any breastfeeding at 15 time points. All estimated threshold durations were statistically significant after adjustment. CONCLUSIONS: Using a methodological approach unique to breastfeeding duration research, the authors report optimal durations of exclusive breastfeeding associated with duration of any breastfeeding at time points throughout the first year. Perinatal clinicians, pediatricians, lactation professionals, policymakers, researchers, and families might apply these findings to achieve desirable collective breastfeeding duration outcomes. PMID- 25524315 TI - A population-based study of acute care revisits following tonsillectomy. AB - OBJECTIVES: To describe the clinical spectrum and frequency of acute care revisits after tonsillectomy in a population-based sample from a single state in the US. STUDY DESIGN: We used California state discharge databases from 2009 to 2011 to retrospectively identify retrospectively routine tonsillectomy discharges in residents <25 years of age and to establish record linkage to revisits within 30 days at ambulatory surgery, inpatient, and emergency department facilities statewide. Percentages and descriptive statistics were sample-weighted, and revisit rates were adjusted for demographic factors, expected payer, chronic conditions, surgical indication, facility type, and clustering. RESULTS: Records were available for 35 085 index tonsillectomies, most of which were performed at hospital-owned ambulatory and inpatient facilities. There were 4944 associated revisits: 3761 (75.9%) treat-and-release emergency room visits, 816 (17.1%) inpatient admissions, and 367 (7.0%) ambulatory surgery visits. Most revisits (3225 [67.7%]) were unrelated to bleeding; these typically occurred early (mode, day 2) and were commonly associated with diagnosis codes indicating pain, nausea/vomiting, or dehydration. Crude all-cause revisit and readmission rates were 10.5% and 2.1%, respectively. Adjusted all-cause revisit rates (range, 8.6% 24.5%) were lowest in young children, increased in adolescents, and peaked in young adults. Adjusted bleeding-related revisit rates increased abruptly in adolescents and reached 13.9% in males (6.8% in females, P < .001) ages 20-24 years. CONCLUSIONS: Acute care revisits after tonsillectomy performed at predominantly hospital-owned facilities in California are common and strongly age related. Most revisits are early treat-and-release outpatient encounters, and these are usually associated with potentially preventable problems such as pain, nausea and vomiting, and dehydration. PMID- 25524316 TI - The stability of sleep patterns in children 3 to 7 years of age. AB - OBJECTIVE: To determine the reliability and stability of sleep (duration and quality) over time in young children using repeated accelerometer estimates of sleep. STUDY DESIGN: One hundred ninety-four children wore Actical accelerometers for 5-day periods (24-hour monitoring) at 3, 4, 5, 5.5, 6.5, and 7 years of age. Sleep variables of interest (duration, onset, offset, latency, efficiency, and wake after sleep onset) were estimated using the Sadeh algorithm within a commercial data reduction program (ActiLife). Children were divided into various groups according to sleep stability, and demographic and behavioral differences were compared across groups by ANOVA. RESULTS: All measures of sleep quantity and quality required 4-7 days of accelerometry to obtain acceptable reliability estimates, except morning wake time (2-4 days), and sleep latency (11-21 days). Average year-to-year correlations were only moderate for most measures (r = 0.41 0.51), but considerably higher than those observed for sleep latency, efficiency, and wake after onset (r = 0.15-0.24). Only 29 children were classified as sleep stable over the 4 years. These children were less likely to be from ethnic minority groups (P = .017) and had higher levels of day-time physical activity (P = .032). CONCLUSIONS: Sleep patterns in children are not particularly stable, showing considerable variation both within a week and across the years. Few children exhibit stable sleep patterns over time, yet characterization of these children might provide further information regarding how sleep benefits health. PMID- 25524317 TI - Prenatal exposure to polybrominated diphenyl ethers and polyfluoroalkyl chemicals and infant neurobehavior. AB - OBJECTIVE: To assess the impact of prenatal exposure to polybrominated diphenyl ethers (PBDEs) and polyfluoroalkyl chemicals (PFCs) on early infant neurobehavior. STUDY DESIGN: In a cohort of 349 mother/infant pairs, we measured maternal serum concentrations during pregnancy of PBDEs, including BDE-47 and other related congeners, as well as 2 common PFCs, perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid. When the infants were 5 weeks of age, we measured their neurobehavior by using the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS). RESULTS: Neither PBDE nor PFC exposures during gestation were associated with the 11 individual NNNS outcomes included in our study; however, when we used latent profile analysis to categorize infants into neurobehavioral profiles based on performance on the NNNS (social/easygoing, high arousal/difficult, or hypotonic), a 10-fold increase in prenatal PFOA concentrations significantly increased the odds of being categorized as hypotonic compared with social/easygoing (aOR 3.79; 95% CI 1.1-12.8). CONCLUSIONS: Infants of mothers with greater serum concentrations of PFOA during pregnancy were more likely to be categorized as hypotonic. No association between PBDE concentrations and hypotonia was found. Additional studies should further investigate possible associations of prenatal PFC exposure and muscle tone in infants and children. PMID- 25524318 TI - Cemented metal-on-metal total hip replacement with 28-mm head: prospective, long term, clinical, radiological and metal ions data. AB - PURPOSE: The aim of this study was to evaluate the long-term clinical, radiological and metal ion blood concentration results following 28-mm metal-on metal cemented total hip replacement using Metasul((r)) acetabular component and polished, cannulated Allopro CF-30 (Sulzer-Medica, subsequently Centerpulse Zimmer, Winterthur, Switzerland) femoral component. METHODS: Prospective follow up of patients operated between 1997 and 2000 at a district general hospital. RESULTS: Seventy-nine patients (89 implants) with female predominance and median age of 66 years (IQR 45-87 years) were prospectively followed up for mean 13 years (11-14 years). There was significant improvement in Harris hip score (paired Student's t test p = 0.0001). The mean plasma cobalt and chromium levels were 1.3 ug/L (IQR 0.5-23.9) and 3.6 ug/L (IQR 1.0-22), respectively. Elevated plasma metal ions >7 ug/L were noted in four asymptomatic patients with negative ultrasound examination. Radiolucent lines were present in various zones but majority were stable. One femoral component was revised due to aseptic femoral loosening. Three acetabular and one femoral component have radiologically failed but not revised yet. The Kaplan-Meier survival at 14 years was 92 % for failure as endpoint. CONCLUSION: The long-term survival of Metasul((r)) cemented total hip replacements using 28-mm metal-on-metal head is comparable with metal on polyethylene bearing devices. PMID- 25524319 TI - Treatment of unusual proximal humeral fractures using unilateral external fixator: a case series. AB - OBJECTIVE: To report the functional and radiological results of unusual comminuted fractures of the proximal humerus, treated with 'closed reduction and external fixation' (CREF) using hybrid-type unilateral external fixators (EFs). PATIENTS AND METHODS: Between January 2012 and June 2013, eight patients (mean age 62.6; range 48-84 years) with comminuted proximal humeral fractures extending to the humeral head and one-third proximal diaphysis were treated with CREF using hybrid-type EFs. Functional results were evaluated in terms of shoulder ranges of movement, Constant, DASH, and VAS scores, and radiological results were evaluated using antero-posterior and lateral radiograms of the treated humerus. RESULTS: The mean follow-up was 16.6 (range 12-28) months. The mean fixator time was 84 (range 63-118) days. The mean range of forward flexion, internal rotation, external rotation, and abduction were 145 degrees , 61.2 degrees , 65 degrees , and 115 degrees , respectively. The mean Constant, DASH, and VAS scores were 79.8, 10, and 1.75, respectively. Seven of the eight patients (87.5 %) healed radiologically. Two complications were observed in two patients: non-union and superficial pin site infection. CONCLUSIONS: In the treatment of unusual, comminuted proximal diaphyseal humeral fractures, CREF using a hybrid-type EF is a minimally invasive, advantageous procedure with acceptable rates of healing, low risk of surgical site infection, and early range of motion. LEVEL OF EVIDENCE: Level IV, case series. PMID- 25524320 TI - High electron mobility in thin films formed via supersonic impact deposition of nanocrystals synthesized in nonthermal plasmas. AB - Thin films comprising semiconductor nanocrystals are emerging for applications in electronic and optoelectronic devices including light emitting diodes and solar cells. Achieving high charge carrier mobility in these films requires the identification and elimination of electronic traps on the nanocrystal surfaces. Herein, we show that in films comprising ZnO nanocrystals, an electron acceptor trap related to the presence of OH on the surface limits the conductivity. ZnO nanocrystal films were synthesized using a nonthermal plasma from diethyl zinc and oxygen and deposited by inertial impaction onto a variety of substrates. Surprisingly, coating the ZnO nanocrystals with a few nanometres of Al2O3 using atomic layer deposition decreased the film resistivity by seven orders of magnitude to values as low as 0.12 Omega cm. Electron mobility as high as 3 cm(2) V(-1) s(-1) was observed in films comprising annealed ZnO nanocrystals coated with Al2O3. PMID- 25524321 TI - Variations in Scientific Data Production: What Can We Learn from #Overlyhonestmethods? AB - In recent months months the hashtag #overlyhonestmethods has steadily been gaining popularity. Posts under this hashtag--presumably by scientists--detail aspects of daily scientific research that differ considerably from the idealized interpretation of scientific experimentation as standardized, objective and reproducible. Over and above its entertainment value, the popularity of this hashtag raises two important points for those who study both science and scientists. Firstly, the posts highlight that the generation of data through experimentation is often far less standardized than is commonly assumed. Secondly, the popularity of the hashtag together with its relatively blase reception by the scientific community reveal that the actions reported in the tweets are far from shocking and indeed may be considered just "part of scientific research". Such observations give considerable pause for thought, and suggest that current conceptions of data might be limited by failing to recognize this "inherent variability" within the actions of generation--and thus within data themselves. Is it possible, we must ask, that epistemic virtues such as standardization, consistency, reportability and reproducibility need to be reevaluated? Such considerations are, of course, of particular importance to data sharing discussions and the Open Data movement. This paper suggests that the notion of a "moral professionalism" for data generation and sharing needs to be considered in more detail if the inherent variability of data are to be addressed in any meaningful manner. PMID- 25524322 TI - Ethical Guidelines for Structural Interventions to Small-Scale Historic Stone Masonry Buildings. AB - Structural interventions to historic stone masonry buildings require that both structural and heritage values be considered simultaneously. The absence of one of these value systems in implementation can be regarded as an unethical professional action. The research objective of this article is to prepare a guideline for ensuring ethical structural interventions to small-scale stone historic masonry buildings in the conservation areas of Northern Cyprus. The methodology covers an analysis of internationally accepted conservation documents and national laws related to the conservation of historic buildings, an analysis of building codes, especially Turkish building codes, which have been used in Northern Cyprus, and an analysis of the structural interventions introduced to a significant historic building in a semi-intact state in the walled city of Famagusta. This guideline covers issues related to whether buildings are intact or ruined, the presence of earthquake risk, the types of structural decisions in an architectural conservation project, and the values to consider during the decision making phase. PMID- 25524323 TI - Platelet-Rich Plasma in the Treatment of Patellar Tendinopathy: A Systematic Review. AB - BACKGROUND: Patellar tendinopathy (PT) is a major cause of morbidity in both high level and recreational athletes. While there is good evidence for the effectiveness of eccentric exercise regimens in its treatment, a large proportion of patients have disease that is refractory to such treatments. This has led to the development of novel techniques, including platelet-rich plasma (PRP) injection, which aims to stimulate a normal healing response within the abnormal patellar tendon. However, little evidence exists at present to support its use. PURPOSE: To determine the safety and effectiveness of PRP in the treatment of PT and to quantify its effectiveness relative to other therapies for PT. STUDY DESIGN: Systematic review. METHODS: A systematic review was conducted in accordance with the preferred reporting items for systematic reviews and meta analyses (PRISMA) guidelines. A literature review was conducted of the Medline, EMBASE, and Cochrane databases as well as trial registries. Both single-arm and comparative studies were included. The outcomes of interest were pain (as measured by visual analog or other, comparable scoring systems), functional scores, and return to sport. Study quality and risk of bias were assessed using the methodological index for nonrandomized studies (MINORS) score and the Cochrane risk of bias tool. RESULTS: Eleven studies fit the inclusion criteria. Of these, 2 were randomized, controlled trials (RCTs), and 1 was a prospective, nonrandomized cohort study. The remainder were single-arm case series. All noncomparative studies demonstrated a significant improvement in pain and function after PRP injection. Complications and adverse outcomes were rare. The results of the comparative studies were inconsistent, and superiority of PRP over control treatments could not be conclusively demonstrated. CONCLUSION: Platelet rich plasma is a safe and promising therapy in the treatment of recalcitrant PT. However, its superiority over other treatments such as physical therapy remains unproven. Further RCTs are required to determine the relative effectiveness of the many available treatments for PT and to determine the subgroups of patients who stand to gain the most from the use of these therapies. PMID- 25524324 TI - Germline mutations in NKX2-5, GATA4, and CRELD1 are rare in a Mexican sample of Down syndrome patients with endocardial cushion and septal heart defects. AB - Congenital heart defects (CHD) are found in ~50 % of Down syndrome (DS) patients. Genetic variants have been implicated, including CRELD1 mutations, but no previous study has examined the candidate genes, NKX2-5 and GATA4, in DS patients with secundum atrial defects (ASDII) and ventricular septal defects (VSD). Furthermore, CRELD1 mutations have not yet been studied in Mexican DS patients with atrioventricular septal defects (AVSD). Mexican DS patients (n = 148) with standard trisomy 21 were classified as follows: group I, normal heart; group II, VSD, ASDII, or both; and group III, AVSD. Mexican healthy controls (n = 113) were also included. Sequence analysis was performed on NKX2-5 and GATA4 in all three groups, and on CRELD1 in only group III. Statistical differences in the percentages of functional variants were analyzed by Fisher's exact test. Three non-synonymous variants in NKX2-5 were identified in the heterozygous state: a novel p.Pro5Ser was found in one DS patient without CHD; the p.Glu21Gln was found in one ASDII patient; and the p.Arg25Cys (R25C) was found in three patients (one from each DS study group). The p.Glu21Gln and R25C were also documented in 0.88 % of the controls. No significant difference was observed between the DS groups and healthy controls. Germline mutations in the NKX2-5, GATA4, and CRELD1 genes do not appear to be associated with CHD in Mexican DS patients. Our findings also support the notion that the R25C variant of NKX2-5 is a polymorphism, as it was not significantly different between our DS patients and controls. PMID- 25524326 TI - Testing non-inferiority of a new treatment in three-arm clinical trials with binary endpoints. AB - BACKGROUND: A two-arm non-inferiority trial without a placebo is usually adopted to demonstrate that an experimental treatment is not worse than a reference treatment by a small pre-specified non-inferiority margin due to ethical concerns. Selection of the non-inferiority margin and establishment of assay sensitivity are two major issues in the design, analysis and interpretation for two-arm non-inferiority trials. Alternatively, a three-arm non-inferiority clinical trial including a placebo is usually conducted to assess the assay sensitivity and internal validity of a trial. Recently, some large-sample approaches have been developed to assess the non-inferiority of a new treatment based on the three-arm trial design. However, these methods behave badly with small sample sizes in the three arms. This manuscript aims to develop some reliable small-sample methods to test three-arm non-inferiority. METHODS: Saddlepoint approximation, exact and approximate unconditional, and bootstrap resampling methods are developed to calculate p-values of the Wald-type, score and likelihood ratio tests. Simulation studies are conducted to evaluate their performance in terms of type I error rate and power. RESULTS: Our empirical results show that the saddlepoint approximation method generally behaves better than the asymptotic method based on the Wald-type test statistic. For small sample sizes, approximate unconditional and bootstrap-resampling methods based on the score test statistic perform better in the sense that their corresponding type I error rates are generally closer to the prespecified nominal level than those of other test procedures. CONCLUSIONS: Both approximate unconditional and bootstrap-resampling test procedures based on the score test statistic are generally recommended for three-arm non-inferiority trials with binary outcomes. PMID- 25524325 TI - Concise review: custodians of the transcriptome: how microRNAs guard stemness in squamous epithelia. AB - At the core of every dynamic epithelium resides a population of carefully regulated stem cells ensuring its maintenance and balance. The complex mammalian epidermis is no exception to this rule. The last decade has delivered a wealth of knowledge regarding the biology of adult stem cells, but questions still remain regarding the intricate details of their function and maintenance. To help address these gaps, we turn to the small, single-stranded RNA molecules known as microRNAs. Since their discovery, microRNAs have provided us with novel insights and ground-breaking impulses to enhance our understanding of the biological sciences. Due to their unique role in post-transcriptional regulation, microRNAs are essential to cutaneous biology as well as the epidermal stem cell. By serving as buffers to balance between epithelial stemness, proliferation, and differentiation, microRNAs play essential roles in the maintenance of cutaneous stem cells and their transition out of the stem cell compartment. Following an updated overview of microRNA biology, we summarize the current knowledge of the role of microRNAs in cutaneous stem cells, focusing on three major players that have dominated the recent literature: miR-205, miR-203, and miR-125b. We then review clinical applications, discussing the potential of microRNAs as therapeutic targets in regenerative and oncological stem cell-based medicine. PMID- 25524327 TI - Effect of low-dose selenium on thyroid autoimmunity and thyroid function in UK pregnant women with mild-to-moderate iodine deficiency. AB - PURPOSE: Selenium is an essential trace mineral and a component of selenoproteins that are involved in the production of thyroid hormones and in regulating the immune response. We aimed to explore the effect of low-dose selenium supplementation on thyroid peroxidase antibody (TPO-Ab) concentration and thyroid function in pregnant women from a mild-to-moderate iodine-deficient population. METHODS: Samples and data were from a secondary analysis of Selenium in PRegnancy INTervention (SPRINT), a double-blind, randomized, placebo-controlled study that recruited 230 women with singleton pregnancies from a UK antenatal clinic at 12 weeks of gestation. Women were randomized to receive 60 ug/day selenium or placebo until delivery. Serum thyroid peroxidase antibodies (TPO-Ab), thyrotropin (TSH) and free thyroxine (FT4) were measured at 12, 20 and 35 weeks and thyroglobulin antibodies (Tg-Ab) at 12 weeks. RESULTS: 93.5% of participants completed the study. Se supplementation had no more effect than placebo in decreasing TPO-Ab concentration or the prevalence of TPO-Ab positivity during the course of pregnancy. In women who were either TPO-Ab or Tg-Ab negative at baseline (Thy-Ab(-ve)), TSH increased and FT4 decreased significantly throughout gestation (P < 0.001), with no difference between treatment groups. In women who were Thy-Ab(+ve) at baseline, TSH tended to decrease and was lower than placebo at 35 weeks (P = 0.050). FT4 fell more on Se than placebo supplementation and was significantly lower at 35 weeks (P = 0.029). CONCLUSIONS: Low-dose selenium supplementation in pregnant women with mild-to-moderate deficiency had no effect on TPO-Ab concentration, but tended to change thyroid function in Thy-Ab(+ve) women. PMID- 25524328 TI - Response to Letter to the editor from Dr. Kawada regarding the article Dietary glycaemic load and cognitive performance in elderly subjects. AB - In his offered opinion piece, (Dietary glycaemic load and cognitive performance in elderly subjects) Dr. Kawada comments upon the statistical analysis and suggests that the conclusions of the study should be interpreted with caution. Having closely examined these comments, we believe that they are over-stated and we draw different conclusions. At first viewing, the statistical arguments put forward by Dr. Kawada look complicated, but one may summarize that he believes the analysis lacked statistical power. This argument is directed towards two sets of regression analyses, a Poisson analysis on which one of the messages of the paper hinges, and a second logistic analysis that was acknowledged as statistically underpowered in our publication. No statistical argument is provided as to why the Poisson regression model is underpowered; the critique contains no new scientific content but relies on a technical re-iteration of the limitations of the study (that were highlighted in the original manuscript) combined with quasi philosophical arguments on data set size and the need for biochemical markers in observational dietary studies. PMID- 25524330 TI - Inhibition of GPR137 suppresses proliferation of medulloblastoma cells in vitro. AB - Medulloblastoma is the most common malignant pediatric brain tumor in children. GPR137 is a ubiquitously expressed gene in the central nervous system. It has been reported that GPR137 modulates malignant proliferation of glioma cells. However, the relationship between GPR137 and medulloblastoma is still unknown. In this study, we knocked down GPR137 in the medulloblastoma cell line Daoy via a lentivirus-based RNA interference system to explore its role in medulloblastoma. Functional analyses showed that cell proliferation and colony formation were obviously restrained in Daoy cells after GPR137 knockdown. Furthermore, knockdown of GPR137 in Daoy cells led to a significant increase in cell percentage in the G0/G1 phase but a decrease in the S phase. Additionally, the cell population in the sub-G1 phase, which represents apoptotic cells, was remarkably increased in GPR137 knockdown cells. GPR137 inhibition induced a strong proapoptotic effect in Daoy cells, as confirmed by annexin V-APC/7-AAD double staining. In conclusion, GPR137 knockdown inhibited growth of Daoy medulloblastoma cells via disturbing cell cycle progression and inducing apoptosis. Our investigation suggested that GPR137 could be a potential oncogene in medulloblastoma cells and might serve as a target for the treatment of medulloblastoma. PMID- 25524329 TI - Transcriptomic analysis of the late stages of grapevine (Vitis vinifera cv. Cabernet Sauvignon) berry ripening reveals significant induction of ethylene signaling and flavor pathways in the skin. AB - BACKGROUND: Grapevine berry, a nonclimacteric fruit, has three developmental stages; the last one is when berry color and sugar increase. Flavors derived from terpenoid and fatty acid metabolism develop at the very end of this ripening stage. The transcriptomic response of pulp and skin of Cabernet Sauvignon berries in the late stages of ripening between 22 and 37 degrees Brix was assessed using whole-genome micorarrays. RESULTS: The transcript abundance of approximately 18,000 genes changed with degrees Brix and tissue type. There were a large number of changes in many gene ontology (GO) categories involving metabolism, signaling and abiotic stress. GO categories reflecting tissue differences were overrepresented in photosynthesis, isoprenoid metabolism and pigment biosynthesis. Detailed analysis of the interaction of the skin and pulp with degrees Brix revealed that there were statistically significantly higher abundances of transcripts changing with degrees Brix in the skin that were involved in ethylene signaling, isoprenoid and fatty acid metabolism. Many transcripts were peaking around known optimal fruit stages for flavor production. The transcript abundance of approximately two-thirds of the AP2/ERF superfamily of transcription factors changed during these developmental stages. The transcript abundance of a unique clade of ERF6-type transcription factors had the largest changes in the skin and clustered with genes involved in ethylene, senescence, and fruit flavor production including ACC oxidase, terpene synthases, and lipoxygenases. The transcript abundance of important transcription factors involved in fruit ripening was also higher in the skin. CONCLUSIONS: A detailed analysis of the transcriptome dynamics during late stages of ripening of grapevine berries revealed that these berries went through massive transcriptional changes in gene ontology categories involving chemical signaling and metabolism in both the pulp and skin, particularly in the skin. Changes in the transcript abundance of genes involved in the ethylene signaling pathway of this nonclimacteric fruit were statistically significant in the late stages of ripening when the production of transcripts for important flavor and aroma compounds were at their highest. Ethylene transcription factors known to play a role in leaf senescence also appear to play a role in fruit senescence. Ethylene may play a bigger role than previously thought in this non-climacteric fruit. PMID- 25524331 TI - Body composition changes were related to nutrient intakes in elderly men but elderly women had a higher prevalence of sarcopenic obesity in a population of Korean adults. AB - In this study, we examined the relationship between sarcopenic obesity (SO) and nutrition status, according to sex in Korean adults who were 60 years or older. Body composition was categorized as SO, sarcopenic nonobesity, nonsarcopenic obesity, and nonsarcopenic nonobesity. Obesity was defined by body mass index. Sarcopenia was defined as an appendicular skeletal muscle mass divided by weight (Wt) of less than 1 SD below the sex-specific mean for young adults. Subjects included 1433 subjects (658 men and 775 women) who were 60 years or older and who participated in the fifth Korea National Health and Nutritional Examination Survey 2010. Sarcopenic obesity was more prevalent in women (31.3%) than in men (19.6%). Individuals with SO had significantly higher fasting insulin, homeostasis model assessment of insulin resistance (male: 3.2 +/- 1.4, female: 3.4 +/- 2.1), and triglycerides (male: 167.3 +/- 90.6 mg/dL, female: 160.7 +/- 85.0 mg/dL). High-density lipoprotein was under the normal criteria (50 mg/dL) in women. Intake of nutrients associated with muscle loss (protein, vitamin D, calcium, and vitamin C) was significantly different among the male but not the female groups. Although protein intake was normal, calcium and vitamin D intakes were insufficient in all groups. In conclusion, body composition changes were related to nutrient intakes in elderly (60 years or older) men but not elderly women. Women had a higher prevalence of SO than did men, suggesting that early nutritional intervention in elderly women may help them address age-associated body composition changes. PMID- 25524332 TI - Acute and training effects of resistance exercise on heart rate variability. AB - Heart rate variability (HRV) has been used as a non-invasive method to evaluate heart rate (HR) regulation by the parasympathetic and sympathetic divisions of the autonomic nervous system. In this review, we discuss the effect of resistance exercise both acutely and after training on HRV in healthy individuals and in those with diseases characterized by autonomic dysfunction, such as hypertension and fibromyalgia. HR recovery after exercise is influenced by parasympathetic reactivation and sympathetic recovery to resting levels. Therefore, examination of HRV in response to acute exercise yields valuable insight into autonomic cardiovascular modulation and possible underlying risk for disease. Acute resistance exercise has shown to decrease cardiac parasympathetic modulation more than aerobic exercise in young healthy adults suggesting an increased risk for cardiovascular dysfunction after resistance exercise. Resistance exercise training appears to have no effect on resting HRV in healthy young adults, while it may improve parasympathetic modulation in middle-aged adults with autonomic dysfunction. Acute resistance exercise appears to decrease parasympathetic activity regardless of age. This review examines the acute and chronic effects of resistance exercise on HRV in young and older adults. PMID- 25524334 TI - Prasugrel in NSTEMI: loading after seeing. PMID- 25524333 TI - Effect of prasugrel pre-treatment strategy in patients undergoing percutaneous coronary intervention for NSTEMI: the ACCOAST-PCI study. AB - BACKGROUND: After percutaneous coronary intervention (PCI) for non-ST-segment elevation myocardial infarction (NSTEMI), treatment with a P2Y12 antagonist with aspirin is recommended for 1 year. OBJECTIVES: The oral P2Y12 antagonists ticagrelor and prasugrel have higher recommendations than clopidogrel, but it is unknown if administration before the start of PCI is beneficial. METHODS: In the randomized, double-blind ACCOAST (A Comparison of prasugrel at the time of percutaneous Coronary intervention Or as pre-treatment At the time of diagnosis in patients with non-ST-segment elevation myocardial infarction) trial, 4,033 patients were diagnosed with NSTEMI and 68.7% underwent PCI; 1,394 received pre treatment with prasugrel (30-mg loading dose), and 1,376 received placebo. At the time of PCI, patients who received pre-treatment with prasugrel received an additional 30-mg dose of prasugrel, and those who received placebo received a 60 mg loading dose of prasugrel. Primary efficacy was a composite of cardiovascular death, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa bailout through 7 days from randomization. Investigators captured the presence of thrombus on initial angiography and during PCI. RESULTS: The incidence of the primary endpoint through 7 days from randomization in the pre treatment group versus the no pre-treatment group was 13.1% versus 13.1% (p = 0.93). Pre-treatment with prasugrel was not associated with decreases in any ischemic event, including total mortality. Patients with thrombus on angiography had a 3-fold higher incidence of the primary endpoint than patients without thrombus. There was no impact of pre-treatment with prasugrel on the presence of thrombus before PCI or on occurrence of stent thrombosis after PCI. There was a 3 fold increase in all non-coronary artery bypass graft Thrombolysis In Myocardial Infarction (TIMI) major bleeding and a 6-fold increase in non-coronary artery bypass graft life-threatening bleeding with pre-treatment with prasugrel; the same trends persisted in patients who had radial or femoral access even with use of a closure device. CONCLUSIONS: These findings support deferring treatment with prasugrel until a decision is made about revascularization in patients with NSTEMI undergoing angiography within 48 h of admission. (A Comparison of prasugrel at the time of percutaneous Coronary intervention Or as pre-treatment At the time of diagnosis in patients with non-ST-segment elevation myocardial infarction [ACCOAST]; NCT01015287). PMID- 25524335 TI - Engineered electrical conduction tract restores conduction in complete heart block: from in vitro to in vivo proof of concept. AB - BACKGROUND: Cardiac electrical conduction delays and blocks cause rhythm disturbances such as complete heart block, which can be fatal. Standard of care relies on electronic devices to artificially restore synchrony. We sought to create a new modality for treating these disorders by engineering electrical conduction tracts designed to propagate electrical impulses. OBJECTIVES: This study sought to create a new approach for treating cardiac conduction disorders by using engineered electrical conduction tracts (EECTs). METHODS: Paramagnetic beads were conjugated with an antibody to gamma-sarcoglycan, a cardiomyocyte cell surface antigen, and mixed with freshly isolated neonatal rat ventricular cardiomyocytes. A magnetic field was used to pattern a linear EECT. RESULTS: In an in vitro model of conduction block, the EECT was patterned so that it connected 2 independently beating neonatal rat ventricular cardiomyocyte monolayers; it achieved coordinated electrical activity, with action potentials propagating from 1 region to the other via EECT. Spiking the EECT with heart derived stromal cells yielded stable structures with highly reproducible conduction velocities. Transplantation of EECTs in vivo restored atrioventricular conduction in a rat model of complete heart block. CONCLUSIONS: An EECT can re establish electrical conduction in the heart. This novel approach could, in principle, be used not only to treat cardiac arrhythmias but also to repair other organs. PMID- 25524336 TI - Structural and functional recoupling of atrial and ventricular myocardium: new conduits for electrical flow. PMID- 25524337 TI - Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations. AB - BACKGROUND: Mild hypertrophy but increased arrhythmic risk characterizes the stereotypic phenotype proposed for hypertrophic cardiomyopathy (HCM) caused by thin-filament mutations. However, whether such clinical profile is different from more prevalent thick-filament-associated disease is unresolved. OBJECTIVES: This study aimed to assess clinical features and outcomes in a large cohort of patients with HCM associated with thin-filament mutations compared with thick filament HCM. METHODS: Adult HCM patients (age >18 years), 80 with thin-filament and 150 with thick-filament mutations, were followed for an average of 4.5 years. RESULTS: Compared with thick-filament HCM, patients with thin-filament mutations showed: 1) milder and atypically distributed left ventricular (LV) hypertrophy (maximal wall thickness 18 +/- 5 mm vs. 24 +/- 6 mm; p < 0.001) and less prevalent outflow tract obstruction (19% vs. 34%; p = 0.015); 2) higher rate of progression to New York Heart Association functional class III or IV (15% vs. 5%; p = 0.013); 3) higher prevalence of systolic dysfunction or restrictive LV filling at last evaluation (20% vs. 9%; p = 0.038); 4) 2.4-fold increase in prevalence of triphasic LV filling pattern (26% vs. 11%; p = 0.002); and 5) similar rates of malignant ventricular arrhythmias and sudden cardiac death (p = 0.593). CONCLUSIONS: In adult HCM patients, thin-filament mutations are associated with increased likelihood of advanced LV dysfunction and heart failure compared with thick-filament disease, whereas arrhythmic risk in both subsets is comparable. Triphasic LV filling is particularly common in thin-filament HCM, reflecting profound diastolic dysfunction. PMID- 25524338 TI - Thin-filament mutations, hypertrophic cardiomyopathy, and risk. PMID- 25524339 TI - Incidence, predictors, and prognostic impact of late bleeding complications after transcatheter aortic valve replacement. AB - BACKGROUND: The incidence and prognostic impact of late bleeding complications after transcatheter aortic valve replacement (TAVR) are unknown. OBJECTIVES: The aim of this study was to identify the incidence, predictors, and prognostic impact of major late bleeding complications (MLBCs) (>=30 days) after TAVR. METHODS: Clinical and echocardiographic outcomes of patients who underwent TAVR within the randomized cohorts and continued access registries in the PARTNER (Placement of Aortic Transcatheter Valves) trial were analyzed after stratifying by the occurrence of MLBCs. Predictors of MLBCs and their association with 30-day to 1-year mortality were assessed. RESULTS: Among 2,401 patients who underwent TAVR and survived to 30 days, MLBCs occurred in 142 (5.9%) at a median time of 132 days (interquartile range: 71 to 230 days) after the index procedure. Gastrointestinal complications (n = 58 [40.8%]), neurological complications (n = 22 [15.5%]), and traumatic falls (n = 11 [7.8%]) were identified as the most frequent types of MLBCs. Independent predictors of MLBCs were the presence of low hemoglobin at baseline, atrial fibrillation or flutter at baseline or 30 days, the presence of moderate or severe paravalvular leak at 30 days, and greater left ventricular mass at 30 days. MLBCs were identified as a strong independent predictor of mortality between 30 days and 1 year (adjusted hazard ratio: 3.91; 95% confidence interval: 2.67 to 5.71; p < 0.001). CONCLUSIONS: MLBCs after TAVR were frequent and associated with increased mortality. Better individualized and risk-adjusted antithrombotic therapy after TAVR is urgently needed in this high risk population. (THE PARTNER TRIAL: Placement of AoRTic TraNscathetER Valve Trial; NCT00530894). PMID- 25524340 TI - From innovation to implementation: optimizing long-term outcomes after TAVR. PMID- 25524342 TI - The proximal thoracic aorta: keystone or Achilles' heel? PMID- 25524341 TI - Proximal aortic distensibility is an independent predictor of all-cause mortality and incident CV events: the MESA study. AB - BACKGROUND: The predictive value of ascending aortic distensibility (AAD) for mortality and hard cardiovascular disease (CVD) events has not been fully established. OBJECTIVES: This study sought to assess the utility of AAD to predict mortality and incident CVD events beyond conventional risk factors in MESA (Multi-Ethnic Study of Atherosclerosis). METHODS: AAD was measured with magnetic resonance imaging at baseline in 3,675 MESA participants free of overt CVD. Cox proportional hazards regression was used to evaluate risk of death, heart failure (HF), and incident CVD in relation to AAD, CVD risk factors, indexes of subclinical atherosclerosis, and Framingham risk score. RESULTS: There were 246 deaths, 171 hard CVD events (myocardial infarction, resuscitated cardiac arrest, stroke and CV death), and 88 HF events over a median 8.5-year follow-up. Decreased AAD was associated with increased all-cause mortality with a hazard ratio (HR) for the first versus fifth quintile of AAD of 2.7 (p = 0.008) independent of age, sex, ethnicity, other CVD risk factors, and indexes of subclinical atherosclerosis. Overall, patients with the lowest AAD had an independent 2-fold higher risk of hard CVD events. Decreased AAD was associated with CV events in low to intermediate- CVD risk individuals with an HR for the first quintile of AAD of 5.3 (p = 0.03) as well as with incident HF but not after full adjustment. CONCLUSIONS: Decreased proximal aorta distensibility significantly predicted all-cause mortality and hard CV events among individuals without overt CVD. AAD may help refine risk stratification, especially among asymptomatic, low- to intermediate-risk individuals. PMID- 25524344 TI - Tricuspid regurgitation after left heart surgery: does it matter? PMID- 25524343 TI - Right ventricular dysfunction, but not tricuspid regurgitation, is associated with outcome late after left heart valve procedure. AB - BACKGROUND: Significant tricuspid regurgitation (TR) late after left heart valve procedure is frequent and associated with increased morbidity. Surgical correction carries a significant mortality risk, whereas the impact of TR on survival in these patients is unclear. OBJECTIVES: This study sought to assess the impact of significant TR late after left heart valve procedure. METHODS: A total of 539 consecutive patients with previous left heart valve procedure (time interval from valve procedure to enrollment 50 +/- 30 months) were prospectively followed for 53 +/- 15 months. RESULTS: Significant TR (defined as moderate or greater severity by echocardiography) was present in 91 (17%) patients (65% female). Patients with TR presented with more symptoms (New York Heart Association functional class >=II 55% vs. 31%), lower glomerular filtration rates (61 +/- 19 ml/min vs. 68 +/- 18 ml/min), and a higher likelihood of atrial fibrillation (41% vs. 20%), all statistically significant. Right ventricular (RV) systolic function was worse in patients with significant TR (RV fractional area change 43 +/- 11% vs. 47 +/- 9%, p < 0.001). A total of 117 (22%) patients died during follow-up. By Kaplan-Meier analysis, overall survival was significantly worse in patients with significant TR (log-rank p < 0.001). However, by multivariable Cox analysis, only RV fractional area change, age, left atrial size, diabetes, and previous coronary artery bypass graft procedure were significantly associated with mortality, but not tricuspid regurgitation. CONCLUSIONS: RV dysfunction, but not significant TR, is independently associated with survival late after left heart valve procedure. PMID- 25524345 TI - The evolution of percutaneous mitral valve repair therapy: lessons learned and implications for patient selection. AB - Mitral regurgitation (MR) is the most common valve disease in the United States. However, a significant number of patients are denied surgery due to increased age, poor ventricular function, or associated comorbidities, putting them at high risk for adverse events. Moreover, the benefit of surgery for MR is unclear in patients with functional (secondary) MR. Recently, percutaneous repair of the mitral valve with a particular device (MitraClip, Abbott, Menlo Park, California) has emerged as a novel therapeutic option for patients with secondary MR or those deemed to be high risk for surgery. We review data from its initial concept through clinical trials and current data available from several registries. We focused on lessons learned regarding adequate patient selection, along with current and future perspectives on the use of device therapy for the treatment of MR. PMID- 25524346 TI - Tobacco kills: a call to industry. PMID- 25524347 TI - Text messaging versus paging: new technology for the next generation. PMID- 25524348 TI - Initial results of a cardiac e-consult pilot program. PMID- 25524349 TI - Long-term follow-up of elective chronic total coronary occlusion angioplasty: analysis from the U.K. Central Cardiac Audit Database. PMID- 25524350 TI - Comparing failed and successful revascularization. PMID- 25524351 TI - Long-term follow-up of elective chronic total coronary occlusion angioplasty. PMID- 25524352 TI - Reply: Long-term follow-up of elective chronic total coronary occlusion angioplasty. PMID- 25524353 TI - Beta-blockers for angina: time to reassess the specific impact of drug therapy in coronary heart disease patients. PMID- 25524355 TI - Commentary: Sexual and reproductive health services in Tamil Nadu: progress and way forward. PMID- 25524354 TI - Reply: Beta-blockers for angina: time to reassess the specific impact of drug therapy in coronary heart disease patients. PMID- 25524356 TI - Prognostic impact of hyponatraemia in patients with colorectal cancer. AB - AIM: Hyponatraemia is a common in surgical practice, but its clinical impact in patients with colorectal cancer has not been evaluated. METHOD: We retrospectively assessed 2944 patients who had been admitted to Chonnam National University Hwasun Hospital, Korea with a diagnosis of colorectal cancer. In order to determine the relationship between the serum sodium level and 3-year mortality, we categorized the patients as having normonatraemia (135-147 mEq/l), or mild (130-134 mEq/l), moderate (125-129 mEq/l) or severe hyponatraemia (< 125 mEq/l). RESULTS: Hyponatraemia, defined as a serum sodium level of < 135 mEq/l, was evident in 27.6% of patients during hospitalization. Declining serum sodium levels were associated with increasing age, a higher number of comorbidities, a more advanced TNM stage and worsening biochemical parameters. In a multivariate Cox-proportional regression analysis, the mortality risk was correlated with the severity of hyponatraemia [hazard ratio (HR) 1.65, 95% CI 1.38-1.96; HR 2.24, 95% CI 1.69-2.98; HR 2.20, 95% CI 1.25-3.90, for patients with mild, moderate, and severe hyponatraemia, respectively, compared with patients with normonatraemia]. An independent association between hyponatraemia and long-term mortality was sustained among various subpopulations and patients with persistent hyponatraemia had a worse prognosis than those with hyponatraemia that resolved. CONCLUSION: A substantial proportion of patients developed hyponatraemia during hospitalization, and the long-term mortality risk increased even in mild cases of hyponatraemia. Hyponatraemia should be considered as an important prognostic factor in colorectal cancer. PMID- 25524357 TI - Reproducibility in urine peptidome profiling using MALDI-TOF. AB - MALDI-TOF profiling of low molecular weight peptides (peptidome) usage is limited due to the lack of reproducibility from the confounding inferences of sample preparation, data acquisition, and processing. We applied MALDI-TOF analysis to profile urine peptidome with the aims to: (i) compare centrifugal ultrafiltration and dialysis pretreatments, (ii) determine whether using signal LOD (sLOD), together with data normalization, may reduce MALDI-TOF variability. We also investigated the influence of peaks detection on reproducibility. Dialysis allowed to obtain better MALDI-TOF spectra than ultrafiltration. Within the 1000 4000 m/z range, we identified 120 and 129 peaks in intra- and interassay studies, respectively. To estimate the sLOD, serial dilution of pooled urines up to 1/256 were analyzed in triplicate. Six data normalization strategies were investigated the mean, median, internal standard, relative intensity, TIC, and linear rescaling normalization. Normalization methods alone performed poorly in reducing features variability while when combined to sLOD adjustment showed an overall reduction in features CVs. Applying a feedback signal processing approach, after median normalization and sLOD adjustment, CVs were reduced from 103 to 26% and 113 to 25% for the intra- and interassay, respectively, and spectra became more comparable in terms of data dispersion. PMID- 25524358 TI - Effects of tail suspension on serum testosterone and molecular targets regulating muscle mass. AB - INTRODUCTION: The contribution of reduced testosterone levels to tail suspension (TS)-induced muscle atrophy remains equivocal. The molecular mechanism by which testosterone regulates muscle mass during TS has not been investigated. METHODS: Effects of TS on serum testosterone levels, muscle mass, and expression of muscle atrophy- and hypertrophy-inducing targets were measured in soleus (SOL) and extensor digitorum longus (EDL) muscles after testosterone administration during 1, 5, and 14 days of TS in male mice. RESULTS: TS produced an increase followed by a transient drop in testosterone levels. Muscle atrophy was associated with downregulation of Igf1 and upregulation of Mstn, Redd1, Atrogin-1, and MuRF1 mRNA with clear differences in Igf1, Mstn, and MAFbx/Atrogin-1 gene expression between SOL and EDL. Testosterone supplementation did not affect muscle mass or protein expression levels during TS. Conclusions The known anabolic effects of testosterone are not sufficient to ameliorate loss of muscle mass during TS. PMID- 25524359 TI - Chilaiditi sign: why are clinical findings more important in ED? PMID- 25524360 TI - Severe recurrent coagulopathy following crotaline envenomation refractory to maintenance dosing of antivenom. PMID- 25524361 TI - International variation in policies and practices related to informed consent in acute cardiovascular research: Results from a 44 country survey. AB - BACKGROUND: Research in an emergency setting such as that with an acute cardiovascular event is challenging because the window of opportunity to treat may be short and may preclude time to obtain informed consent from the patient or their representative. Some perceive that requiring informed consent in emergency situations has limited improvements in care. Vulnerable populations including minorities or residents of low-income countries are at greatest risk of need for resuscitation. Lack of enrollment of such patients would increase uncertainties in treatment benefit or harm in those at greater risk of need for resuscitation. We sought to assess international variation in policies and procedures related to exception from informed consent (EFIC) or deferred consent for emergency research. METHODS: A brief survey instrument was developed and modified by consensus among the investigators. Included were multiple choice and open-ended responses. The survey included an illustrative example of a hypothetical randomized study. Elicited information included the possibility of conducting such a study in the respondent's country, as well as approvals required to conduct the study. The population of interest was emergency physicians or other practitioners of acute cardiovascular event research. RESULTS: Usable responses were obtained from 44 countries (76% of surveyed). Community opposition to EFIC was noted in 6 (14%) countries. Emergency Medical Services (EMS) providers in 8 (20%) countries were judged unable or unwilling to participate. A majority of countries (36, 82%) required approval by a Research Ethics Committee or similar. Government approval was required in 25 (57%) countries. CONCLUSION: There is international variation in practices and policies related to consent for emergency research. There is an ongoing need to converge regulations based on the usefulness of multinational emergency research to benefit both affluent and disadvantaged populations. PMID- 25524362 TI - Reliability and accuracy of the thoracic impedance signal for measuring cardiopulmonary resuscitation quality metrics. AB - AIM: To determine the accuracy and reliability of the thoracic impedance (TI) signal to assess cardiopulmonary resuscitation (CPR) quality metrics. METHODS: A dataset of 63 out-of-hospital cardiac arrest episodes containing the compression depth (CD), capnography and TI signals was used. We developed a chest compression (CC) and ventilation detector based on the TI signal. TI shows fluctuations due to CCs and ventilations. A decision algorithm classified the local maxima as CCs or ventilations. Seven CPR quality metrics were computed: mean CC-rate, fraction of minutes with inadequate CC-rate, chest compression fraction, mean ventilation rate, fraction of minutes with hyperventilation, instantaneous CC-rate and instantaneous ventilation rate. The CD and capnography signals were accepted as the gold standard for CC and ventilation detection respectively. The accuracy of the detector was evaluated in terms of sensitivity and positive predictive value (PPV). Distributions for each metric computed from the TI and from the gold standard were calculated and tested for normality using one sample Kolmogorov Smirnov test. For normal and not normal distributions, two sample t-test and Mann Whitney U test respectively were applied to test for equal means and medians respectively. Bland-Altman plots were represented for each metric to analyze the level of agreement between values obtained from the TI and gold standard. RESULTS: The CC/ventilation detector had a median sensitivity/PPV of 97.2%/97.7% for CCs and 92.2%/81.0% for ventilations respectively. Distributions for all the metrics showed equal means or medians, and agreements >95% between metrics and gold standard was achieved for most of the episodes in the test set, except for the instantaneous ventilation rate. CONCLUSION: With our data, the TI can be reliably used to measure all the CPR quality metrics proposed in this study, except for the instantaneous ventilation rate. PMID- 25524363 TI - Preventable deaths following emergency medical dispatch--an audit study. AB - BACKGROUND: Call taker triage of calls to the 112 emergency number, can be error prone because rapid decisions must be made based on limited information. Here we investigated the preventability and common characteristics of same-day deaths among patients who called 112 and were not assigned an ambulance with lights and sirens by the Emergency Medical Communication Centre (EMCC). METHODS: An audit was performed by an external panel of experienced prehospital consultant anaesthesiologists. The panel focused exclusively on the role of the EMCC, assessing whether same-day deaths among 112 callers could have been prevented if the EMCC had assessed the situations as highly urgent. The panels' assessments were based on review of patient charts and voice-log recordings of 112 calls. All patient related material was reviewed by the audit panel and all cases where then scored as preventable, potentially preventable or non-preventable during a two day meeting. The study setting was three of five regions in Denmark with a combined population of 4,182,613 inhabitants, which equals 75% of the Danish population. The study period was 18 months, from mid-2011 to the end of 2012. RESULTS: Linkage of prospectively collected EMCC data with population-based registries resulted in the identification of 94,488 non-high-acuity 112 callers. Among these callers, 152 (0.16% of all) died on the same day as the corresponding 112 call, and were included in this study. The mean age of included patients was 74.4 years (range, 31-100 years) and 45.4% were female. The audit panel found no definitively preventable deaths; however, 18 (11.8%) of the analysed same-day deaths (0.02% of all non-high-acuity callers) were found to be potentially preventable. In 13 of these 18 cases, the dispatch protocol was either not used or not used correctly. CONCLUSION: Same-day death rarely occurred among 112 callers whose situations were assessed as not highly urgent. No same-day deaths were found to be definitively preventable by a different EMCC call assessment, but a minority of same-day deaths could potentially have been prevented with more accurate triage. Better adherence with dispatch protocol could improve the safety of the dispatch process. PMID- 25524365 TI - Maternal depression symptoms, unhealthy diet and child emotional-behavioural dysregulation. AB - BACKGROUND: Maternal depression and unhealthy diet are well-known risk factors for adverse child emotional-behavioural outcomes, but their developmental relationships during the prenatal and postnatal periods are largely uncharted. This study sought to examine the inter-relationships between maternal depression symptoms and unhealthy diet (assessed during pregnancy and postnatal periods) in relation to child emotional-behavioural dysregulation (assessed at the ages of 2, 4 and 7 years). METHOD: In a large prospective birth cohort of 7814 mother-child pairs, path analysis was used to examine the independent and inter-related associations of maternal depression symptoms and unhealthy diet with child dysregulation. RESULTS: Higher prenatal maternal depression symptoms were prospectively associated with higher unhealthy diet, both during pregnancy and the postnatal period, which, in turn, was associated with higher child dysregulation up to the age of 7 years. In addition, during pregnancy, higher maternal depression symptoms and unhealthy diet were each independently associated with higher child dysregulation up to the age of 7 years. These results were robust to other prenatal, perinatal and postnatal confounders (such as parity and birth complications, poverty, maternal education, etc.). CONCLUSIONS: Maternal depression symptoms and unhealthy diet show important developmental associations, but are also independent risk factors for abnormal child development. PMID- 25524366 TI - Extra money for NHS will bring underfunded areas closer to target level, NHS England announces. PMID- 25524364 TI - Task dependent lexicality effects support interactive models of reading: a meta analytic neuroimaging review. AB - Models of reading must explain how orthographic input activates a phonological representation, and elicits the retrieval of word meaning from semantic memory. Comparisons between tasks that theoretically differ with respect to the degree to which they rely on connections between orthographic, phonological and semantic systems during reading can thus provide valuable insight into models of reading, but such direct comparisons are not well-represented in the literature. An ALE meta-analysis explored lexicality effects directly contrasting words and pseudowords using the lexical decision task and overt or covert naming, which we assume rely most on the semantic and phonological systems, respectively. Interactions between task and lexicality effects demonstrate that different demands of the lexical decision and naming tasks lead to different manifestations of lexicality effects. PMID- 25524367 TI - One species in eight: DNA barcodes from type specimens resolve a taxonomic quagmire. AB - Each holotype specimen provides the only objective link to a particular Linnean binomen. Sequence information from them is increasingly valuable due to the growing usage of DNA barcodes in taxonomy. As type specimens are often old, it may only be possible to recover fragmentary sequence information from them. We tested the efficacy of short sequences from type specimens in the resolution of a challenging taxonomic puzzle: the Elachista dispunctella complex which includes 64 described species with minuscule morphological differences. We applied a multistep procedure to resolve the taxonomy of this species complex. First, we sequenced a large number of newly collected specimens and as many holotypes as possible. Second, we used all >400 bp examine species boundaries. We employed three unsupervised methods (BIN, ABGD, GMYC) with specified criteria on how to handle discordant results and examined diagnostic bases from each delineated putative species (operational taxonomic units, OTUs). Third, we evaluated the morphological characters of each OTU. Finally, we associated short barcodes from types with the delineated OTUs. In this step, we employed various supervised methods, including distance-based, tree-based and character-based. We recovered 658 bp barcode sequences from 194 of 215 fresh specimens and recovered an average of 141 bp from 33 of 42 holotypes. We observed strong congruence among all methods and good correspondence with morphology. We demonstrate potential pitfalls with tree-, distance- and character-based approaches when associating sequences of varied length. Our results suggest that sequences as short as 56 bp can often provide valuable taxonomic information. The results support significant taxonomic oversplitting of species in the Elachista dispunctella complex. PMID- 25524368 TI - Highly sensitive colorimetric detection of 17beta-estradiol using split DNA aptamers immobilized on unmodified gold nanoparticles. AB - Gold nanoparticle (AuNP) based colorimetric aptasensor have been developed for many analytes recently largely because of the ease of detection, high sensitivity, and potential for high-throughput analysis. Most of the target aptamers for detection have short sequences. However, the approach shows poor performance in terms of detection sensitivity for most of the long-sequence aptamers. To address this problem, for the first time, we split the 76 mer aptamer of 17beta-estradiol into two short pieces to improve the AuNP based colorimetric sensitivity. Our results showed that the split P1 + P2 still retained the original 76 mer aptamer's affinity and specificity but increased the detection limit by 10-fold, demonstrating that as low as 0.1 ng/mL 17beta estradiol could be detected. The increased sensitivity may be caused by lower aptamer adsorption concentration and a lower affinity to the AuNPs of a short single-strand DNA (ssDNA) sequence. Our study provided a new way to use long sequence aptamers to develop a highly sensitive AuNP-based colorimetric aptasensor. PMID- 25524369 TI - Gentio-oligosaccharides from Leuconostoc mesenteroides NRRL B-1426 dextransucrase as prebiotics and as a supplement for functional foods with anti-cancer properties. AB - Gentio-oligosaccharides (GnOS) were synthesized by the acceptor reaction of dextransucrase from Leuconostoc mesenteroides NRRL B-1426 with gentiobiose and sucrose. GnOS were purified by gel permeation chromatography using a Bio-Gel P-2 column and identified by mass spectrometry. The purified GnOS (degree of polymerization >=3) were investigated for their in vitro prebiotic and cytotoxic activity. GnOS exhibited a significantly lower degree of digestibility of 18.1% by simulated human gastric juice (pH 1.0) and 7.1% by human alpha-amylase (pH 7.0) after 6 h, whereas inulin, a standard prebiotic, showed 39.7% and 12.8% of digestibility, respectively. The prebiotic score showed that GnOS significantly supported the growth of probiotics such as Bifidobacterium infantis and Lactobacillus acidophilus and was comparable to that of inulin. The selective inhibitory effect of GnOS on human colon carcinoma (HT-29) cells revealed its potential as an anti-cancer agent that can serve as a functional food additive for the benefit of human health. PMID- 25524370 TI - Post-surgical surveillance of locally advanced ileal carcinoids found by routine ileal intubation during screening colonoscopy: a case series. AB - INTRODUCTION: Carcinoid tumors are the most common type of small bowel tumor, and the incidence is rising. The majority of small bowel carcinoid tumors arise within 60 cm of the ileocecal valve. The addition of ileoscopy to screening colonoscopy can detect asymptomatic small bowel carcinoid tumors and improve long term prognosis through early surgical resection. Ileoscopy is a brief procedure with a high success rate and minimal complications beyond those of colonoscopy. The use of ileoscopy during screening colonoscopy has led to an increase in the early-stage detection of locoregional small bowel carcinoid tumors that can be completely treated with surgery alone, and as such has improved long-term prognosis in these patients. CASE PRESENTATIONS: Five asymptomatic Caucasian patients, 3 males and 2 females, from 53 to 70 years old (mean age, 60 years old), were diagnosed with locoregional ileal carcinoids during routine colonoscopy with ileoscopy. Since having an ileocolectomy and without adjuvant treatment, no patient has developed tumor recurrence over a follow-up period of one and half to 12 and a half years. CONCLUSION: The early detection of carcinoid tumors by ileoscopy during screening colonoscopy can lead to increased long-term survival in patients with locally invasive disease. The high success rate and brief duration of the procedure, in addition to the lack of associated morbidity and mortality suggest that with further studies, routine ileoscopy during colonoscopy may be promising in the diagnosis of small bowel carcinoid tumors. PMID- 25524371 TI - Influence of bariatric surgery on the expression of nesfatin-1 in rats with type 2 diabetes mellitus. AB - OBJECTIVE: Bariatric surgery has been reported to be very effective in the remission of type 2 diabetes mellitus (T2DM). However, the mechanism is still under debate. Nesfatin-1, a recently discovered anorexigenic neuropeptide, was reported to be very important in glucose metabolism and regulating food intake. In this study, the effects of bariatric surgery on the expression and regulation of nesfatin-1 were discussed. METHODS: T2DM was induced in SD rats by a diet high in sugar and fat plus a low dose of streptozotocin (STZ) (25 mg/kg) injection. Bariatric surgeries, including Roux-En-Y Gastric Bypass (RYGB) and sleeve gastrectomy (SG), were performed on these rats. Two months after the surgery, the plasma nesfatin-1 level and the expression of nesfatin-1 in different organs of the rats were tested. Next, in vivo administration of nesfatin-1 after surgery was performed to investigate the role of nesfatin-1 in bariatric surgery. RESULTS: Both RYGB and SG could reduce the weight of the rats. However, only RYGB had significant effects on the blood glucose level. Neither surgeries seemed to affect the blood concentration of insulin. However, RYGB significantly improved insulin sensitivity. Expression of nesfatin-1 in the plasma and relative organs decreased in T2DM rats and rose again after RYGB; however, this pattern did not occur in SG. Injection of nesfatin-1 after SG significantly improved insulin resistance and reduced blood glucose levels. CONCLUSIONS: Nesfatin-1 may improve insulin sensitivity in T2DM rats and thus plays a very important role in the remission of T2DM after RYGB. This neuropeptide could be a new target for directing future improvements in the bariatric surgical process. PMID- 25524372 TI - Replication of risk variants for psoriasis in a Southern European case-control study: correlation with clinical subphenotypes. PMID- 25524373 TI - A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability. AB - Mutations in the KCNQ2 gene encoding for voltage-gated potassium channel subunits have been found in patients affected with early onset epilepsies with wide phenotypic heterogeneity, ranging from benign familial neonatal seizures (BFNS) to epileptic encephalopathy with cognitive impairment, drug resistance, and characteristic electroencephalography (EEG) and neuroradiologic features. By contrast, only few KCNQ3 mutations have been rarely described, mostly in patients with typical BFNS. We report clinical, genetic, and functional data from a family in which early onset epilepsy and neurocognitive deficits segregated with a novel mutation in KCNQ3 (c.989G>T; p.R330L). Electrophysiological studies in mammalian cells revealed that incorporation of KCNQ3 R330L mutant subunits impaired channel function, suggesting a pathogenetic role for such mutation. The degree of functional impairment of channels incorporating KCNQ3 R330L subunits was larger than that of channels carrying another KCNQ3 mutation affecting the same codon but leading to a different amino acid substitution (p.R330C), previously identified in two families with typical BFNS. These data suggest that mutations in KCNQ3, similarly to KCNQ2, can be found in patients with more severe phenotypes including intellectual disability, and that the degree of the functional impairment caused by mutations at position 330 in KCNQ3 may contribute to clinical disease severity. PMID- 25524374 TI - Protecting the airway and the physician: Aspects of litigation arising from tracheotomy. AB - BACKGROUND: In recent decades, medical malpractice costs have increased and have led to a change in the way physicians practice medicine. Tracheotomies are cases in which complications have a high risk of morbidity and mortality and the potential for litigation. METHODS: The Westlaw legal database was used to gather data on 43 jury verdicts and settlements from 1987 to 2013. Various factors included outcome, defendant specialty, and the reason for litigation. RESULTS: Median settlements were $500,000 and median verdict awards were $2,000,000. Postoperative negligence was alleged most often (81%) followed by intraoperative negligence (27.9%) and permanent injury (18.6%). Otolaryngologists were named as defendants most often (25.6%), with nurses named second most often. Pediatric cases had significantly higher awards and were more often named in favor of the plaintiff. CONCLUSION: An awareness of tracheotomy malpractice litigation has the potential to both help physicians avoid future litigation and improve patient safety. PMID- 25524375 TI - [2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism]. PMID- 25524376 TI - [2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy]. PMID- 25524377 TI - Clinical-instrumental and morphological evaluation of the effect of autologous dermal fibroblasts administration. AB - Basic molecular mechanisms, associated with the main cell population of the dermis - fibroblasts - are the basis of skin aging. The number of functionally active fibroblasts in the skin and their biosynthetic activity decreases with age, thus enhancement of their cell density with synthetically active cells is accepted as a one of the most effective methods. The objective of the present study was to evaluate the safety and effectiveness of intradermal administration of autologous dermal fibroblasts in a year after treatment of 17 patients, aged 45-65 years. Results obtained with modern instrumental skin diagnostic methods (vacuum cutometry, optical profilometry, VISIA photometric analysis, etc.) demonstrate the safety and clinical effectiveness of dermal autofibroblast therapy: after transplantation, cultured autofibroblasts keep their biosynthetic activity and produce extracellular matrix for at least 12 months. As a result, remodelling of the dermis microstructures is observed, accompanied by a progressive increase of collagen content and thickness of the dermis (up to 62.5 +/-6.7% in 12 months). This is clinically expressed by increase of skin elasticity (24.0 +/-4.3% in periorbital area) and thickness of the skin, and by decrease in the number and depth of wrinkles (46 +/-7% by the end of observation period). Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 25524378 TI - NRSF/REST regulates the mTOR signaling pathway in oral cancer cells. AB - The neuron-restrictive silencer factor/repressor element 1-silencing transcription factor (NRSF/REST) was originally discovered as a transcriptional repressor of neuronal genes in non-neuronal cells. However, it was recently reported to be abundantly expressed in several types of aggressive cancer cells, as well as in mature neurons. In the present study, the role of NRSF/REST in the human oral squamous cell carcinoma (SCC) KB cell line was evaluated. NRSF/REST was expressed at a higher level in KB cells when compared with that in normal human oral keratinocytes (NHOKs). Knockdown of NRSF/REST by siRNA reduced cell viability only in KB cells in a time-dependent manner, and this effect was due to the activation of apoptosis components and DNA fragmentation. In addition, knockdown of NRSF/REST disrupted the mTOR signaling pathway which is a key survival factor in many types of cancer cells. For example, the phosphorylation of elF4G, elF4E and 4E-BP1 was significantly reduced in the KBeta cells upon NRSF/REST knockdown. These results imply that NRSF/REST plays an important role in the survival of oral cancer cells by regulating the mTOR signaling pathway. PMID- 25524380 TI - Targeting innate immunity for treatment of type 1 diabetes. PMID- 25524379 TI - Large scale production of phage antibody libraries using a bioreactor. AB - One of the limitations of the use of phage antibody libraries in high throughput selections is the production of sufficient phage antibody library at the appropriate quality. Here, we successfully adapt a bioreactor-based protocol for the production of phage peptide libraries to the production of phage antibody libraries. The titers obtained in the stirred-tank bioreactor are 4 to 5 times higher than in a standard shake flask procedure, and the quality of the phage antibody library produced is indistinguishable to that produced using standard procedures as assessed by Western blotting and functional selections. Availability of this protocol will facilitate the use of phage antibody libraries in high-throughput scale selections. PMID- 25524381 TI - Potential role of rilotumumab in the treatment of gastric cancer. AB - In 2014, outcomes for patients with advanced gastric cancer remain extremely poor with a high level of unmet need regarding effective therapeutic options. However, recent years have seen increasing interest in the role of the MET signaling pathway in this disease subtype, leading to the development and evaluation of MET targeted therapeutics. Rilotumumab is a monoclonal antibody directed against hepatocyte growth factor, the only known ligand for the MET receptor. It is an unlicensed product which is currently undergoing evaluation in a randomized Phase III trial in 'MET-positive' gastric cancer. Here we discuss the background to the treatment of gastric cancer as well as the characteristics of rilotumumab and reported results with this agent in the trials performed to date. PMID- 25524382 TI - Candidin and trichophytin stimulate the production of Th1 and regulatory cytokines by peripheral blood mononuclear cells: implication for their use as adjuvants in immunotherapy. AB - AIM: This study's objective was to investigate whether candidin or trichophytin elicit recall immune responses that could potentially inhibit a Th2 response. MATERIALS & METHODS: Peripheral blood mononuclear cells from nine allergic and seven nonallergic individuals were cultivated in vitro in the presence or absence of these fungal extracts. RESULTS: Trichophytin or candidin, or both, stimulated the production of regulatory cytokines (TGF-beta and/or IL-10), accompanied or not by stimulation of production of cytokines associated with the Th1 response (TNF-alpha, IL-12 and IFN-gamma), but without stimulation of Th2 cytokines (IL-5 and IL-13) and IL-17, by peripheral blood mononuclear cells of most allergic and nonallergic individuals. CONCLUSION: These results indicate that these fungal extracts could be used as adjuvants in personalized therapeutic vaccines in a fair proportion of individuals. In addition, they justify the carrying out of investigations aimed at identifying molecules in these extracts that might exclusively induce Treg and/or Th1 immune responses. PMID- 25524383 TI - Current advances in T-cell-based cancer immunotherapy. AB - Cancer is a leading cause of death worldwide; due to the lack of ideal cancer biomarkers for early detection or diagnosis, most patients present with late stage disease at the time of diagnosis, thus limiting the potential for successful treatment. Traditional cancer treatments, including surgery, chemotherapy and radiation therapy, have demonstrated very limited efficacy for patients with late-stage disease. Therefore, innovative and effective cancer treatments are urgently needed for cancer patients with late-stage and refractory disease. Cancer immunotherapy, particularly adoptive cell transfer, has shown great promise in the treatment of patients with late-stage disease, including those who are refractory to standard therapies. In this review, we will highlight recent advances and discuss future directions in adoptive cell transfer based cancer immunotherapy. PMID- 25524386 TI - Evidence supporting pre-radiation elimination of oral foci of infection in head and neck cancer patients to prevent oral sequelae. A systematic review. AB - Pre-radiation dental screening of head-neck cancer patients aims to identify and eliminate oral foci of infection to prevent post-radiation oral problems. The evidence for the efficacy of dental screening is unclear. In this systematic review, we analyzed available evidence on the efficacy of pre-radiation elimination of oral foci of infection in preventing oral sequelae. A search was conducted (MEDLINE/EMBASE) for papers published up to May 2014. Papers on head neck cancer patients subjected to pre-radiation dental screening, (chemo)radiation and oral follow-up were included. Of the 1770 identified papers, 20 studies fulfilled the inclusion criteria of which 17 were retrospective. A great heterogeneity in patient groups, dental screening techniques, definitions of oral foci of infection and techniques for eliminating foci was found. Most papers lacked essential details on how dental screening was performed and a clear definition of an oral focus of infection. The evidence for efficacy of elimination of oral foci of infection to prevent post-radiotherapy oral sequelae was inconclusive. Consequently, the efficacy of pre-radiation elimination of oral foci of infection remains unclear. No conclusions can be drawn about a definition of an oral focus of infection and whether pre-radiation elimination of these foci should be mandatory. We therefore suggest prospective studies with well-defined criteria for oral foci of infection, a clear description of which foci were eliminated and how, a detailed description of pre-radiation dental screening, clearly described patient and tumor characteristics, and a detailed dental history and dental status. Subsequently, oral problems that occur post-radiation should be systematically recorded. PMID- 25524384 TI - Past, present and future targets for immunotherapy in ovarian cancer. AB - Ovarian cancer is the leading cause of death from gynecologic malignancy in the US. Treatments have improved with conventional cytotoxic chemotherapy and advanced surgical techniques but disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. Ovarian cancer immunotherapy is targeting tumors through active, passive and adoptive approaches. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the different immunotherapies available for ovarian cancer as well as current ongoing studies and potential future directions. PMID- 25524387 TI - Evaluation of the use of freehand SPECT for sentinel node biopsy in early stage oral carcinoma. AB - RATIONALE: Inadequate intraoperative visualization of the sentinel node can hamper its harvest. Freehand SPECT is a 3D tomographic imaging modality based on the concepts of SPECT, which can be used for intraoperative visualization and navigation towards the sentinel node in order to improve its localization and removal during surgery. PATIENTS AND METHODS: The use of freehand SPECT was evaluated during 66 sentinel node biopsy procedures in early stage oral cancer patients. Intraoperative detection of sentinel nodes was compared with preoperative identified sentinel nodes on lymphoscinitigraphic examination. Additional value of freehand SPECT was subjectively scored by the surgeon directly following the biopsy procedure. RESULTS: Freehand SPECT was able to detect 94% of sentinel nodes intraoperatively. Most sentinel nodes not detected (7 out of 9) were located in level I of the neck. Freehand SPECT appeared to be of additional value for facilitating the intraoperative detection of the sentinel node in 24% of procedures. CONCLUSION: The use of the freehand SPECT system is feasible in the intraoperative detection of sentinel nodes in early stage oral cancer. Freehand SPECT provides helpful information facilitating the SN biopsy procedure in a quarter of cases. However, freehand SPECT cannot detect all SNs which are located in the vicinity of the injection site. PMID- 25524385 TI - mTOR signaling, Tregs and immune modulation. AB - Foxp3(+) Tregs are central regulators of immune tolerance. As dysregulated Treg responses contribute to disease pathogenesis, novel approaches to target the immunomodulatory functions of Tregs are currently under investigation. mTORC1 and mTORC2 are therapeutic targets of interest. Recent studies revealed that mTOR signaling impacts conventional T-cell homeostasis, activation and differentiation. Moreover, mTOR controls the differentiation and functions of Tregs, suggesting that its activity could be targeted to modulate Treg responses. Here, we summarize how Tregs suppress immune responses, their roles in disease development and methods used to alter their functions therapeutically. We also discuss the diverse effects exerted by mTOR inhibition on the development, homeostasis, and functions of conventional T cells and Tregs. We conclude with a discussion of how modulation of mTOR activity in Tregs may be therapeutically beneficial or detrimental in different disease settings. PMID- 25524388 TI - Charcot arthropathy of the spine in spinal cord injured individuals with sacral deafferentation and anterior root stimulator implantation. AB - AIMS: To investigate the occurrence of Charcot spinal arthropathy (CSA) after sacral deafferentation (SDAF) and sacral anterior root stimulation (SARS) of the bladder in patients suffering from neurogenic lower urinary tract dysfunction (NLUTD) as a result of spinal cord injury (SCI). METHODS: Retrospective evaluation of patients who had undergone SDAF/SARS at a single SCI rehabilitation centre. The occurrence rate of stimulation dysfunction was determined, and the medical records and radiological images of the included patients were examined for CSA. The diagnosis of CSA was based on radiological criteria. The occurrence rate of CSA was estimated for all SARS patients and for those with SARS dysfunction, and the odds ratios (OR) for the occurrence of CSA were calculated. RESULTS: In 11/130 SARS patients (8%), CSA was observed a median 8 years (95% CI 5-16 years) after SDAF/SARS or a median 21 years (95% CI 9-41 years) after SCI had occurred. The median follow-up time was 14 years (range 6-25 years). The proportion of patients with CSA was significantly (P = 0.036) greater in patients with SARS dysfunction (7/41) than in patients without SARS dysfunction (4/89). The odds of CSA were four times greater (OR 4.3, 95% CI 1.0-21.5) in patients with SARS dysfunction compared to those without. Furthermore, the odds of CSA were 20 times greater (OR 20.2, 95% CI 8.4-47.0) in patients with SARS compared to those without. CONCLUSIONS: Charcot spinal arthropathy should be considered a potential long-term complication of SDAF/SARS, and spinal instability is a possible reason for SARS dysfunction. PMID- 25524389 TI - Inpatient resource use and cost burden of deep vein thrombosis and pulmonary embolism in the United States. AB - PURPOSE: Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is associated with significant morbidity and mortality. VTE frequently leads to hospitalization and represents a considerable economic burden to the US health care system. However, little information exists on the duration of hospitalization and associated charges among patients with an admitting or primary diagnosis of DVT or PE. This study assessed the charges associated with hospitalization length of stay in patients with DVT or PE discharged from US hospitals in 2011. METHODS: Using data from the Nationwide Inpatient Sample of the Healthcare Utilization Project database, this analysis examined hospital length of stay and associated charges in patients with DVT or PE discharged from US hospitals in 2011. Both initial and subsequent hospitalizations were analyzed. FINDINGS: DVT was responsible for fewer hospitalizations than PE. In 2011, among 330,044 patients with VTE discharged from US hospitals, 143,417 had DVT and 186,627 had PE. Mean length of stay for patients with DVT was 4.7 days (median, 3.9 days) compared with 5.1 days (median, 4.5 days) for patients with PE. For initial hospitalizations, the mean (SE) charge amounted to $30,051 ($246) for DVT compared with $37,006 ($214) for PE. Older patients with PE incurred greater hospital charges than younger ones, and for both DVT and PE patients, women incurred greater charges than men. Of 31,463 patients admitted to the hospital with PE, 4.0% had a subsequent admission, which was more costly than the initial admission. Many patients with both DVT and PE were discharged to specialist nursing facilities, indicating continuing posthospitalization charges. IMPLICATIONS: Hospital stays for DVT and PE represent a substantial cost burden to the US health care system. Health care systems have the potential to reduce the clinical and economic burden of VTE by ensuring that evidence-based, guideline-recommended anticoagulation therapy is adhered to by patients with an initial VTE. Appropriate anticoagulant therapy and continuity of care in these patients may reduce the incidence and frequency of hospital readmissions and VTE-related morbidity and mortality and have a potential effect on health care resources. PMID- 25524390 TI - Utilization patterns of antihypertensive drugs among the chronic kidney disease population in the United States: a cross-sectional analysis of the national health and nutrition examination survey. AB - PURPOSE: Antihypertensive drugs are prescribed to patients with chronic kidney disease (CKD) for their cardioprotective and renoprotective effects. Nationally representative information on the use of antihypertensive drugs among CKD patients is limited. The purpose of this study was to assess the utilization patterns of antihypertensive drugs among the CKD population (stages I-IV) in the United States. METHODS: We conducted a retrospective cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) panels from 2005 2006, 2007-2008, and 2009-2010. The estimated glomerular filtration rate was calculated and kidney damage was assessed to identify participants with CKD. The demographic and clinical characteristics of the participants with CKD were reported, as were the antihypertensive drugs they used. FINDINGS: A total weighted sample of 116,231,361 participants representative of the CKD population in the United States (stages I-IV) was identified. Less than one half of the participants with CKD in the NHANES were using antihypertensive drugs. beta blockers were the most commonly used and angiotensin II receptor blockers were the least used antihypertensive agents among participants with CKD. Age (>=70 years), awareness of hypertension or diabetes, and higher stage of CKD were associated with an increased likelihood of antihypertensive drug use among participants with CKD. IMPLICATIONS: The results of our analyses suggest that antihypertensive drugs are underused in the CKD population, and the use of preferred agents (ie, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers) is low. Efforts should be directed toward emphasizing the importance of using antihypertensive drugs in the CKD population. PMID- 25524392 TI - Site of botulinum toxin type A administration in craniofacial hyperhidrosis. PMID- 25524391 TI - Follow-up Care Education and Information: Identifying Cancer Survivors in Need of More Guidance. AB - Cancer survivors engage in cancer screenings and protective health behaviors at suboptimal rates despite their increased risk for future illness. Survivorship care plans and other educational strategies to prepare cancer survivors to adopt engaged roles in managing long-term follow-up care and health risks are needed. In a sample of cancer survivors, we identified patient characteristics and psychosocial predictors associated with increased follow-up care informational needs. Cross-sectional surveys were administered to early-stage breast and prostate survivors (N = 278; 68 % breast) at least 2 years post treatment from four community hospital programs in New Jersey between May 2012 and July 2013. Patient demographics, medical history, psychosocial characteristics (i.e., worries about the future, fear of disease recurrence, and patient activation), and perceptions of oncology and primary care were assessed. African-American survivors (AOR = 2.69, 95 % confidence interval [CI] 1.27-5.68) and survivors with higher comorbidity (AOR =1.16, CI 1.01-1.33) were more likely to want additional information to guide follow-up care. Adjusting for race and comorbidities, survivors who wanted more information to guide their follow-up care reported greater worries about the future (p < 0.05) and fears about disease recurrence (p < 0.05) compared to those who did not want additional information. Results emphasize the need to develop cancer survivorship educational strategies that are both responsive to the needs of specific populations (e.g., African American survivors and patients with multiple comorbidities) and the psychosocial profiles that motivate requests for more extensive follow-up guidance. PMID- 25524393 TI - Metabolic abnormalities among people diagnosed with schizophrenia: a literature review and implications for mental health nurses. AB - Metabolic abnormalities such as diabetes, obesity and dyslipidaemia are found in much higher rates in people with a diagnosis of schizophrenia when compared with the general population. This review discusses the most prevalent metabolic abnormalities associated with schizophrenia, their frequency and implications for mental health nurses (MHN). This review illuminates the need for MHN to acquire added awareness, knowledge and practical strategies in managing people at high risk of developing metabolic abnormalities associated with MetS. By doing this, it contributes to the literature by highlighting practical strategies for MHN in assessment and ongoing monitoring of metabolic abnormalities in clinical practice. This review highlights the need for MHN to be vigilant in monitoring a person's physical state on commencement and throughout treatment with antipsychotics. There is a need for an early detection monitoring system for people who are potentially at risk of developing metabolic abnormalities. The literature review aimed to investigate metabolic abnormalities associated with metabolic syndrome (MetS) in people diagnosed with schizophrenia; they are almost twice as likely to have metabolic risk factors and die approximately 20 years younger than the general population. MetS has become an issue of growing concern in mental health nursing. A comprehensive literature review was conducted utilizing various databases to address the reviews aim. Databases such as CINAHL Plus with full text (via EBSCO), MEDLINE(R) (OVID), PsycINFO and the COCHRANE library were accessed. The main metabolic abnormalities that emerged were: diabetes, obesity and dyslipidaemia. Antipsychotic medication also plays a vital role in a person's susceptibility to the development of MetS. It is critical that MHN has access to training and education in managing people at high risk of developing metabolic abnormalities associated with MetS. This review contributes to the literature by highlighting practical strategies for MHN in assessment and ongoing monitoring of metabolic abnormalities in clinical practice. PMID- 25524394 TI - Going back to class I: MHC and immunotherapies for childhood cancer. AB - After decades of unfulfilled promise, immunotherapies for cancer have reached a tipping point, with several FDA approved products now on the market and many more showing promise in both adult and pediatric clinical trials. Tumor cell expression of MHC class I has emerged as a potential determinant of the therapeutic success of many immunotherapy approaches. Here we review current knowledge regarding MHC class I expression in pediatric cancers including a discussion of prognostic significance, the opposing influence of MHC on T-cell versus NK-mediated therapies, and strategies to reverse or circumvent MHC down regulation. PMID- 25524395 TI - The effects of the framing of time on delay discounting. AB - We examined the effects of the framing of time on delay discounting. Delay discounting is the process by which delayed outcomes are devalued as a function of time. Time in a titrating delay discounting task is often framed in calendar units (e.g., as 1 week, 1 month, etc.). When time is framed as a specific date, delayed outcomes are discounted less compared to the calendar format. Other forms of framing time; however, have not been explored. All participants completed a titrating calendar unit delay-discounting task for money. Participants were also assigned to one of two delay discounting tasks: time as dates (e.g., June 1st, 2015) or time in units of days (e.g., 5000 days), using the same delay distribution as the calendar delay-discounting task. Time framed as dates resulted in less discounting compared to the calendar method, whereas time framed as days resulted in greater discounting compared to the calendar method. The hyperboloid model fit best compared to the hyperbola and exponential models. How time is framed may alter how participants attend to the delays as well as how the delayed outcome is valued. Altering how time is framed may serve to improve adherence to goals with delayed outcomes. PMID- 25524396 TI - Effect of combined treatment with rosuvastatin and protein kinase Cbeta2 inhibitor on angiogenesis following myocardial infarction in diabetic rats. AB - The aim of the present study was to investigate the effects of combined treatment with rosuvastatin and LY333531, a selective protein kinase C (PKC)beta2 inhibitor, on angiogenesis under hyperglycemic conditions. Human umbilical vein endothelial cells (HUVECs) cultured in medium containing a normal or high concentration of glucose (33.3 mmol/l) were treated with rosuvastatin (0.1 umol/l) alone or in combination with LY333531 (10 nmol/l). HUVEC migration and tube formation were assessed. Furthermore, rats with streptozotocin-induced diabetes were randomly divided into groups and treated with either rosuvastatin alone (5 mg/kg/day) or in combination with LY333531 (10 mg/kg/day) for 4 weeks following the induction of myocardial infarction (MI). Echocardiographic patterns, the extent of myocardial fibrosis, capillary density in myocardial tissue, the phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), as well as the expression levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1alpha) were assessed. The results from the in vitro experiment revealed that the tube-forming and migration ability of the HUVECs exposed to high-glucose medium was significantly improved in the group treated with the combination of rosuvastatin and LY333531. In vivo, the combination of rosuvastatin and LY333531 significantly improved left ventricular function, reduced the extent of myocardial fibrosis and increased myocardial capillary density compared to treatment with rosuvastatin alone. In addition, the expression levels of VEGF, and Akt and eNOS phosphorylation were significantly higher in the group exposed to the combination treatment than in the group treated with rosuvastatin alone. The results of the present study indicate that, compared to treatment with rosuvastatin alone, combined treatment with rosuvastatin and LY333531 promotes a greater level of angiogenesis in diabetic rats with MI. This effect is likely mediated through the upregulation of the VEGF dependent Akt/eNOS signaling pathway. PMID- 25524397 TI - Injectable microsphere gel progressively improves global ventricular function, regional contractile strain, and mitral regurgitation after myocardial infarction. AB - BACKGROUND: There is continued need for therapies which reverse or abate the remodeling process after myocardial infarction (MI). In this study, we evaluate the longitudinal effects of calcium hydroxyapatite microsphere gel on regional strain, global ventricular function, and mitral regurgitation (MR) in a porcine MI model. METHODS: Twenty-five Yorkshire swine were enrolled. Five were dedicated weight-matched controls. Twenty underwent posterolateral infarction by direct ligation of the circumflex artery and its branches. Infarcted animals were randomly divided into the following 4 groups: 1-week treatment; 1-week control; 4 week treatment; and 4-week control. After infarction, animals received either twenty 150 MUL calcium hydroxyapatite gel or saline injections within the infarct. At their respective time points, echocardiograms, cardiac magnetic resonance imaging, and tissue were collected for evaluation of MR, regional and global left ventricular function, wall thickness, and collagen content. RESULTS: Global and regional left ventricular functions were depressed in all infarcted subjects at 1 week compared with healthy controls. By 4-weeks post-infarction, global function had significantly improved in the calcium hydroxyapatite group compared with infarcted controls (ejection fraction 0.485 +/- 0.019 vs 0.38 +/- 0.017, p < 0.01). Similarly, regional borderzone radial contractile strain (16.3% +/- 1.5% vs 11.2% +/- 1.5%, p = 0.04), MR grade (0.4 +/- 0.2 vs 1.2 +/- 0.2, p = 0.04), and infarct thickness (7.8 +/- 0.5 mm vs 4.5 +/- 0.2 mm, p < 0.01) were improved at this time point in the treatment group compared with infarct controls. CONCLUSIONS: Calcium hydroxyapatite injection after MI progressively improves global left ventricular function, borderzone function, and mitral regurgitation. Using novel biomaterials to augment infarct material properties is a viable alternative in the current management of heart failure. PMID- 25524399 TI - Fostering autonomous motivation, physical activity and cardiorespiratory fitness in rheumatoid arthritis: protocol and rationale for a randomised control trial. AB - BACKGROUND: People with rheumatoid arthritis are at greater risk of morbidity and mortality from cardiovascular disease than the general population. Sustained physical activity increases cardio-respiratory fitness and reduces cardiovascular disease risk factors. However, little is known about how we can effectively promote long-term participation in physical activity in patients with rheumatoid arthritis. The literature consistently calls for physical activity interventions, and their implementation, to be theoretically-grounded. METHODS/DESIGN: This paper documents the protocol of a randomised control trial that investigates whether a Self-determination Theory-based intervention fosters the adoption and maintenance of physical activity (3, 6 and 12 months) sufficient to provide sustained cardiovascular and personal well-being benefits in patients with rheumatoid arthritis. The cost effectiveness of the intervention will also be determined. The trial is registered as Current Controlled Trials ISRCTN04121489. DISCUSSION: Results from this trial will provide guidance regarding key social environmental factors that can be manipulated to support motivational processes conducive to positive health behaviour change and optimal functioning in patients with Rheumatoid Arthritis. PMID- 25524398 TI - Colonization of the upper genital tract by vaginal bacterial species in nonpregnant women. AB - OBJECTIVE: The objective of the study was to evaluate the upper genital tract (UGT) presence of vaginal bacterial species using sensitive molecular methods capable of detecting fastidious bacterial vaginosis (BV)-associated bacteria. STUDY DESIGN: Vaginal swabs were collected prior to hysterectomy. The excised uterus was sterilely opened and swabs collected from the endometrium and upper endocervix. DNA was tested in 11 quantitative polymerase chain reaction (PCR) assays for 12 bacterial species: Lactobacillus iners, L crispatus, L jensenii, Gardnerella vaginalis, Atopobium vaginae, Megasphaera spp, Prevotella spp, Leptotrichia/Sneathia, BVAB1, BVAB2, BVAB3, and a broad-range16S ribosomal ribonucleic acid gene assay. Endometrial fluid was tested with Luminex and an enzyme-linked immunosorbent assay for cytokines and defensins and tissue for gene expression of defensins and cathelicidin. RESULTS: We enrolled 58 women: mean aged 43+/-7 years, mostly white (n=46; 79%) and BV negative (n=43; 74%). By species-specific quantitative PCR, 55 (95%) had UGT colonization with at least 1 species (n=52) or were positive by 16S PCR (n=3). The most common species were L iners (45% UGT, 61% vagina), Prevotella spp (33% UGT, 76% vagina) and L crispatus (33% UGT, 56% vagina). Median quantities of bacteria in the UGT were lower than vaginal levels by 2-4 log10 ribosomal ribonucleic acid gene copies per swab. There were no differences in the endometrial inflammatory markers between women with no bacteria, Lactobacillus only, or any BV-associated species in the UGT. CONCLUSION: Our data suggest that the endometrial cavity is not sterile in most women undergoing hysterectomy and that the presence of low levels of bacteria in the uterus is not associated with significant inflammation. PMID- 25524400 TI - Poor linkages in maternal health care services-evidence on antenatal care and institutional delivery from a community-based longitudinal study in Tigray region, Ethiopia. AB - BACKGROUND: Progress towards attaining the maternal mortality and maternal health targets set by Millennium Development Goal 5 has been slow in most African countries. Assessing antenatal care and institutional delivery service utilization and their determinants is an important step towards improving maternal health care services. METHODS: Data were drawn from the longitudinal database of Kilite-Awlaelo Health and Demographic Surveillance System. A total of 2361 mothers who were pregnant and who gave birth between September 2009 and August 2013 were included in the analysis. Potential variables to explain antenatal care and institutional delivery service utilization were extracted, and descriptive statistics and logistic regression were used to determine the magnitude of maternal health care service utilization and associated factors, respectively. RESULTS: More than three-quarters, 76% [95% CI: 74.8%-78.2%] (n = 1806), of mothers had undergone at least one antenatal care visit during their previous pregnancy. However, only 27% [95% CI: 25.3%-28.9%] (n = 639) of mothers gave birth at a health institution. Older mothers, urban residents, mothers with higher education attainment, and farmer mothers were more likely to use antenatal care. Institutional delivery services were more likely to be used among older mothers, urban residents, women with secondary education, mothers who visited antenatal care, and mothers with lower parity. CONCLUSIONS: Despite a relatively high proportion of mothers attending antenatal care services at least once, we found low levels of institutional delivery service utilization. Health service providers in Kilite-Awlaelo should be particularly vigilant regarding the additional maternal health needs of rural and less educated women with high parity. PMID- 25524401 TI - The impact of phlebotomy in nonalcoholic fatty liver disease: A prospective, randomized, controlled trial. AB - Iron is implicated in the pathogenesis of liver injury and insulin resistance (IR) and thus phlebotomy has been proposed as a treatment for nonalcoholic fatty liver disease (NAFLD). We performed a prospective 6-month randomized, controlled trial examining the impact of phlebotomy on the background of lifestyle advice in patients with NAFLD. Primary endpoints were hepatic steatosis (HS; quantified by magnetic resonance imaging) and liver injury (determined by alanine aminotransaminase [ALT] and cytokeratin-18 [CK-18]). Secondary endpoints included insulin resistance measured by the insulin sensitivity index (ISI) and homeostasis model of assessment (HOMA), and systemic lipid peroxidation determined by plasma F2-isoprostane levels. A total of 74 subjects were randomized (33 phlebotomy and 41 control). The phlebotomy group underwent a median (range) of 7 (1-19) venesection sessions and had a significantly greater reduction in ferritin levels over 6 months, compared to controls (-148 +/- 114 vs. -38 +/- 89 ng/mL; P < 0.001). At 6 months, there was no difference between phlebotomy and control groups in HS (17.7% vs. 15.5%; P = 0.4), serum ALT (36 vs. 46 IU/L; P = 0.4), or CK-18 levels (175 vs. 196 U/L; P = 0.9). Similarly, there was no difference in end-of-study ISI (2.5 vs. 2.7; P = 0.9), HOMA (3.2 vs. 3.2; P = 0.6), or F2-isoprostane levels (1,332 vs. 1,190 pmmol/L; P = 0.6) between phlebotomy and control groups. No differences in any endpoint were noted in patients with hyperferritinemia at baseline. Among patients undergoing phlebotomy, there was no correlation between number of phlebotomy sessions and change in HS, liver injury, or IR from baseline to end of study. CONCLUSION: Reduction in ferritin by phlebotomy does not improve liver enzymes, hepatic fat, or IR in subjects with NAFLD. PMID- 25524403 TI - Selenite-stress selected mutant strains of probiotic bacteria for Se source production. AB - Selenium deficiency is a major health problem worldwide for about 1 billion people. Bacterial cells usually possess low tolerance to selenite stress and also low ability to reduce high concentrations of toxic selenite. Here, high tolerance to selenite and selenium bioaccumulation capability were developed in mutated clones of probiotic and starter bacteria including Enterococcus faecium, Bifidobacterium animalis ssp. lactis, Lactobacillus casei and Lactococcus lactis ssp. lactis by food-level strain development process and clone selection. All mutant clones possessed increased glutathione concentration and glutathione reductase activity. The selenite treatment increased further these values in L. casei mutant strain pointing at a different selenite reduction pathway and/or stress response in this organism. Considerable conversion of selenite to cell bound selenium forms with a concomitant high biomass production was detected in E. faecium and B. animalis ssp. lactis cultures. Possible application of these strains as food and feed supplements is under investigation. PMID- 25524402 TI - Association between plasma selenium level and NRF2 target genes expression in humans. AB - Animal studies in rodent and in vitro studies indicate compensatory role of nuclear factor (erythroid-derived 2)-like (Nrf2) and Nrf2-regulated antioxidant and phase II biotransformation enzymes for the dietary selenium (Se) deficiency or for the loss of selenoproteins. To explore associations between plasma Se level and NRF2-regulated cytoprotective genes expression, an observational study was conducted in a population of 96 healthy non-smoking men living in Central Poland aged 18-83 years with relatively low plasma Se level. NRF2, KEAP2, CAT, EPHX1, GCLC, GCLM, GPX2, GSR, GSTA1, GSTM1, GSTP1, GSTT1, HMOX1, NQO1, PRDX1, SOD1, SOD2, TXNRD1 transcript levels in peripheral blood leukocytes and polymorphism of NRF2-617C/A (rs6721961) in blood genomic DNA were determined by means of quantitative real-time PCR. Mean plasma Se level was found to be 51.10+/ 15.25MUg/L (range 23.86-96.18MUg/L). NRF2 mRNA level was positively correlated with expression of investigated NRF2-target genes. The multivariate linear regression adjusting for selenium status showed that plasma Se level was significantly inversely associated only with expression of GSTP1 (beta-coef.= 0.270, p=0.009), PRDXR1 (beta-coef.=-0.245, p=0.017) and SOD2 with an inverse trend toward significance (beta-coef.=-0.186, p=0.074), but without an effect of NRF2 gene variants. NRF2 expression was inversely associated with age (r=-0.23, p=0.03) and body mass index (r=-0.29, p<0.001). The findings may suggest a possible link between plasma Se level and cytoprotective response at gene level in humans. PMID- 25524404 TI - Effects of vitamin D repletion on glycemic control and inflammatory cytokines in adolescents with type 1 diabetes. AB - OBJECTIVE: Little is known about the relationship between vitamin D deficiency and adolescents with type 1 diabetes. On the basis of adult studies showing that vitamin D improves insulin sensitivity and decreases inflammatory cytokines linked to microvascular complications, we hypothesized that treating vitamin D deficiency in adolescents with type 1 diabetes would improve glycemia and reduce inflammatory markers. RESEARCH DESIGN AND METHODS: This was a randomized, prospective, crossover study of 25 adolescents with type 1 diabetes for at least a year (aged: 13-21 yr; 62% female; 62% Hispanic) and vitamin D deficiency (25-OH vitamin D <=30 ng/mL). Subjects received vitamin D3 (20 000 IU/week) for 6 months, either immediately or after 6 months of observation. RESULTS: At baseline, 63% of subjects screened were vitamin D deficient and randomized. Interleukin-6 (IL-6) was significantly higher in the vitamin D deficient group compared with the sufficient group (medians: 0.36 vs. 0.18) (p = 0.026), whereas neither C-reactive protein (CRP) nor tumor necrosis factor-alpha (TNF-alpha) differed. Vitamin D treatment increased serum levels of 25-OH vitamin D from 22 +/- 5.3 to 34.3 +/- 12.1 ng/mL (p < 0.01). However, treatment did not affect glycated hemoglobin (HbA1c), insulin dosage, CRP, interleukin-6 (IL-6), or TNF alpha. CONCLUSIONS: Vitamin D deficiency is prevalent in the adolescent type 1 diabetes population, and could be associated with changes in inflammatory markers. However, vitamin D repletion over 6 months did not affect glycemia or markers of inflammation in our study, highlighting the need for additional research to validate these findings. PMID- 25524405 TI - Dorsal hippocampal microinjection of chlorpheniramine reverses the anxiolytic like effects of l-histidine and impairs emotional memory in mice. AB - Several findings have pointed to the role of histaminergic neurotransmission in the modulation of anxiety-like behaviors and emotional memory. The elevated plus maze (EPM) test has been widely used to investigate the process of anxiety and also has been used to investigate the process of learning and memory. Visual cues are relevant to the formation of spatial maps, and as the hippocampus is involved in this task, experiment 1 explored this issue. Experiment 2 investigated the effects of intraperitoneal (i.p.) injections of l-histidine (LH, a precursor of histamine) and of intra-dorsal hippocampus (intra-DH) injections of chlorpheniramine (CPA, an H1 receptor antagonist) on anxiety and emotional memory in mice re-exposed to the EPM. Mice received saline (SAL) or LH i.p. and SAL or CPA (0.016, 0.052, and 0.16 nmol/0.1 MUl) intra-DH prior to Trial 1 (T1) and Trial 2 (T2). No significant changes were observed in the number of enclosed-arm entries (EAE) in T1, an EPM index of general exploratory activity. LH had an anxiolytic-like effect that was reversed by intra-DH injections of CPA. T2 versus T1 analysis revealed that only the lower dose of CPA resulted in impaired emotional memory. Combined injections of LH and CPA revealed that higher doses of CPA impair emotional memory. Taken together, these results suggest that LH and H1 receptors present in the dorsal hippocampus are involved in anxiety-related behaviors and emotional memory in mice submitted to EPM. PMID- 25524406 TI - Level of plasma neuregulin-1 SMDF is reduced in patients with idiopathic Parkinson's disease. AB - Parkinson's disease (PD) is characterised by the progressive loss of dopaminergic neurons, neurons that are regulated by the development, protection and function of neuregulin-1 (NRG1)-ErbB4 signals, in the substantia nigra (SN). NRG1 is a neurotrophic differentiation factor and one of its isoforms is a sensory and motor neuron-derived factor (SMDF), mostly expressed in neurons. To examine the relationship between NRG1 SMDF and PD, we tested whether NRG1 SMDF can be detected and measured in plasma and whether their level in plasma correlates with the clinical severity of PD. We detected NRG1 SMDF to be immunoreactive in plasma. Using an ELISA method specific for NRG1 SMDF, we found that NRG1 SMDF levels were significantly reduced in sporadic PD as compared to controls. However, levels of plasma NRG1 SMDF showed no correlation with the clinical severity of PD. Additionally, we found that there was a correlation of NRG1 SMDF levels in CSF with that in plasma where levels in plasma were significantly higher, at approximately ten times that in CSF. Finally, we also examined the expression of NRG1 SMDF in the post-mortem brain using immunohistochemistry and showed that Lewy bodies in the SN of patients with PD were immunoreactive for NRG1 SMDF. In summary, we found that the reduction of plasma NRG1 SMDF is specifically associated with PD, but has no correlation with the clinical severity of PD. These findings of NRG1 SMDF may provide important complementary information for diagnosing the onset of PD. PMID- 25524407 TI - Microglial P2X7 receptor in the hypothalamic paraventricular nuclei contributes to sympathoexcitatory responses in acute myocardial infarction rat. AB - Several pieces of evidence indicate that the microglial P2X7 receptor (P2X7R) regulate cardiovascular activities. We explored the possible roles of microglial P2X7R in the PVN mediated sympathoexcitatory responses in acute myocardial infarction (AMI) rat. Sprague-Dawley rats underwent coronary artery ligation to induce AMI. The rats received intraperitoneal administration of the P2X7R antagonist Brilliant Blue-G (BBG, 25 or 50 mg kg(-1), once a day for 5 days) prior to myocardial ischemia. Other rats received bilateral microinjection of P2X7R-siRNA (0.015 or 0.03 nmol 0.1MUl per side, once a day for 2 days) targeting P2X7R mRNA into the PVN prior to myocardial ischemia. First, we examined the ATP levels and protein expression P2X7R in the PVN in different ischemia time groups, and we found that the change of P2X7R was positive correlated with the ATP levels in a time-dependent manner. The double-immunofluorescence evidence showed that P2X7R was mainly co-localizated with the microglial marker Iba-1 in the PVN. Second, gene knockdown of P2X7R with P2X7-siRNA or inhibition of P2X7R with BBG reduce the mRNA and protein expression of IL-1beta and TNF-alpha in the PVN of AMI rat. Third, microinjected P2X7-siRNA also suppressed the up-regulation of P2X7R, oxytocin and vasopressin in the PVN of AMI rats. Fourth, P2X7-siRNA and BBG also attenuated the renal sympathetic nerve activity (RSNA) in the AMI rats. Our results indicate that microglial P2X7R activation in PVN mediating the production of proinflammatory cytokines that activate oxytocinergic and vasopressinergic neuron, which augmented the RSNA in the AMI rat. PMID- 25524408 TI - Effects of rizatriptan on the expression of calcitonin gene-related peptide and cholecystokinin in the periaqueductal gray of a rat migraine model. AB - Triptans are serotonin 5-hydroxytryptamine receptor 1B/D agonists that are highly effective in the treatment of migraine. We previously found that rizatriptan can reduce the expression of proenkephalin and P substance in the rat midbrain, suggesting that rizatriptan may exert its analgesic effects by influencing the endogenous pain modulatory system. Calcitonin gene-related peptide (CGRP) and cholecystokinin (CCK) are mainly responsible for antagonizing the analgesic effects of opioid peptides in the endogenous pain modulatory system. In this study, we investigated the effects of rizatriptan on the expression of CGRP and CCK in the periaqueductal gray (PAG), a key structure of the endogenous pain modulatory system, in a rat migraine model induced by nitroglycerin. We found that the mRNA and protein levels of CGRP and CCK in the PAG of migraine rats were significantly increased compared to those in control rats, and these levels were significantly reduced upon treatment with rizatriptan in migraine rats (P<0.05). Our results suggest that the expression of CGRP and CCK in the endogenous pain modulatory system may be increased during migraine attacks, which further antagonizes the analgesic effects of endogenous opioid peptides and induces sustained migraine. Rizatriptan, however, significantly reduces the levels of CGRP and CCK to enhance the inhibition of pain signals via the endogenous pain modulatory system, resulting in effective treatment of migraine. PMID- 25524409 TI - Acute effects of muscle vibration on sensorimotor integration. AB - Projections from the somesthetic cortex are believed to be involved in the modulation of motor cortical excitability by muscle vibration. The aim of the present pilot study was to analyse the effects of a vibration intervention on short-latency afferent inhibition (SAI), long-latency afferent inhibition (LAI), and afferent facilitation (AF), three intracortical mechanisms reflecting sensorimotor integration. Abductor pollicis brevis (APB) SAI, AF and LAI were investigated on 10 subjects by conditioning test transcranial magnetic stimulation pulses with median nerve electrical stimulation at inter-stimuli intervals in the range 15-25 ms, 25-60 ms, and 100-200 ms, respectively. Test motor evoked potentials (MEPs) were compared to unconditioned MEPs. Measurements were performed before and just after 15 min of vibration applied to the muscle belly of APB at a frequency of 80 Hz. SAI and LAI responses were significantly reduced compared to unconditioned test MEPs (P=0.039 and P<0.001, respectively). AF MEP amplitude was greater than SAI and LAI one (P=0.009 and P=0.004, respectively), but not different from test MEP (P=0.511). There was no significant main effect of vibration (P=0.905). However, 4 subjects were clearly identified as responders. Their mean vibration-induced increase was 324 +/- 195% in APB SAI MEP amplitude, and 158 +/- 53% and 319 +/- 80% in AF and LAI, respectively. Significant differences in SAI, AF and LAI vibration-induced changes were found for responders when compared to non-responders (P=0.019, P=0.038, and P=0.01, respectively). A single session of APB vibration may increase sensorimotor integration, via decreased inhibition and increased facilitation. However, such results were not observed for all subjects, suggesting that other factors (such as attention to the sensory inputs) may have played a role. PMID- 25524410 TI - Isoflurane anesthesia results in reversible ultrastructure and occludin tight junction protein expression changes in hippocampal blood-brain barrier in aged rats. AB - The underlying mechanism of isoflurane-induced cognitive dysfunction in older individuals is unknown. In this study, the effects of isoflurane exposure on the hippocampal blood-brain barrier (BBB) in aged rats were investigated because it was previously shown that BBB disruption involves in cognitive dysfunction. Twenty-month-old rats randomly received 1.5% isoflurane or vehicle gas as control. Hippocampal BBB ultrastructure was analyzed by transmission electron microscopy and expression of tight junction proteins was measured by western blot analysis. BBB permeability was detected with sodium fluorescein extravasation and further confirmed by immunoglobulin G immunohistochemistry. Spatial learning and memory were assessed by the Morris water maze test. Isoflurane anesthesia resulted in reversible time-dependent BBB ultrastructure morphological damage and significant decreases in expression of the tight junction proteins occludin, which contributed to sodium fluorescein and IgG leakage. Rats with isoflurane exposure also showed significant cognitive deficits in the Morris water maze test. This in vivo data indicate that occludin down-regulation may be one of the mediators of isoflurane-induced hippocampus BBB disruption, and may contribute to hippocampus-dependent cognitive impairment after isoflurane exposure in aged rats. PMID- 25524411 TI - Migraine is associated with altered levels of neurotrophins. AB - Neurotrophic factors have been implicated in hyperalgesia and peripheral levels of these molecules were altered in behavioral and neurological disorders. The objectives of this study were to assess neurotrophic factors levels in migraine patients in comparison with controls, and to investigate whether there was any association between them and clinical parameters. This was a cross-sectional study. We measured serum levels of neurotrophin family members - nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 and 4/5 (NT3 and NT4/5) - and glial cell line-derived factor (GDNF) in patients suffering from migraine and matched controls. One hundred forty-one people were enrolled in this study, seventy-one were migraine patients and seventy were controls. Migraine patients showed more depressive and anxiety symptoms than control individuals as assessed, respectively, by the Beck Depression Inventory (BDI) and the Beck Anxiety Inventory. Chronic and episodic migraine patients showed higher NT4/5 levels than control individuals (P=0.001). Patients with chronic migraine had lower levels of BDNF that were not influenced by the presence of depressive symptoms (P=0.02). This is the first report to evaluate NT3 and NT-4/5 levels in migraine patients. Our findings suggest a possible role of neurotrophic factors in migraine pathophysiology. PMID- 25524412 TI - Cerebellar vermis H2 receptors mediate fear memory consolidation in mice. AB - Histaminergic fibers are present in the molecular and granular layers of the cerebellum and have a high density in the vermis and flocullus. Evidence supports that the cerebellar histaminergic system is involved in memory consolidation. Our recent study showed that histamine injections facilitate the retention of an inhibitory avoidance task, which was abolished by pretreatment with an H2 receptor antagonist. In the present study, we investigated the effects of intracerebellar post training injections of H1 and H2 receptor antagonists as well as the selective H2 receptor agonist on fear memory consolidation. The cerebellar vermi of male mice were implanted with guide cannulae, and after three days of recovery, the inhibitory avoidance test was performed. Immediately after a training session, animals received a microinjection of the following histaminergic drugs: experiment 1, saline or chlorpheniramine (0.016, 0.052 or 0.16 nmol); experiment 2, saline or ranitidine (0.57, 2.85 or 5.07 nmol); and experiment 3, saline or dimaprit (1, 2 or 4 nmol). Twenty-four hours later, a retention test was performed. The data were analyzed using one-way analysis of variance (ANOVA) and Duncan's tests. Animals microinjected with chlorpheniramine did not show any behavioral effects at the doses that we used. Intra-cerebellar injection of the H2 receptor antagonist ranitidine inhibited, while the selective H2 receptor agonist dimaprit facilitated, memory consolidation, suggesting that H2 receptors mediate memory consolidation in the inhibitory avoidance task in mice. PMID- 25524413 TI - How Organ Donors are Different from Non-donors: Responsibility, Barriers, and Religious Involvement. AB - To see if religious involvement, previously linked to various health behaviors, was linked to organ donation, 143 ethnically diverse undergraduates stated whether they were registered donors (53% were), and completed measures of organ donation attitudes and religious involvement. Compared with non-donors, donors reported fewer barriers, more family responsibility, and more willingness to receive donor organs, but were not different in religious involvement. Even in 2014, when being a "good Samaritan" by agreeing to organ donation is as easy as checking one box on a driver's license application, religious involvement does not seem to be a factor in checking this box. PMID- 25524414 TI - The Role of Meaning in Life Within the Relations of Religious Coping and Psychological Well-Being. AB - The purpose of this study was to examine whether meaning in life understood in terms of presence, search, and personal meaning is a mediator in the relationships between religious coping and psychological well-being. Associations of religiousness and psychological well-being are complex and suggest the existence of meaning and purpose in their internal structures. Two studies were conducted. In Study 1, presence of meaning in life was a mediator between negative coping and psychological well-being in the scope of a total score and all its dimensions. Search for meaning in life did not mediate the above relations. In Study 2, personal meaning turned out to be a partial mediator between negative coping and psychological well-being. These findings suggest that meaning in life is a crucial element of religious coping and psychological well being that is used by people as a part of their meaning system to cope with life's difficulties and challenges. PMID- 25524415 TI - Becoming incapacitated? Long-term sickness benefit recipients and the construction of stigma and identity narratives. AB - The transition to becoming 'incapacitated' and receiving sickness benefits represents a significant shift in an individual's narrative. Drawing on in-depth interviews with 25 long-term sickness benefits recipients in North-East England, this article focuses upon how individuals perceived and managed becoming 'incapacitated', particularly in relation to stigma and identity. The findings show that participants negotiated changes to their identity in varying ways - constructing new dimensions of self, validating their illness and pursuing aspirations. Importantly, the transition onto sickness benefits does not inevitably result in a shift to a negative identity. The term incapacity can include many realities, challenging the notion of sickness benefit recipients as being passively dependent. Instead, an active, sometimes very functional sense of self can be accompanied by a positive identity for recipients, which is especially important, in a context of the rhetoric surrounding ongoing welfare reform and sickness benefits recipients in the UK. PMID- 25524417 TI - Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer. AB - BACKGROUND: Locally advanced pancreatic cancer (LAPC) is associated with a very poor prognosis. Current palliative (radio)chemotherapy provides only a marginal survival benefit of 2-3 months. Several innovative local ablative therapies have been explored as new treatment options. This systematic review aims to provide an overview of the clinical outcomes of these ablative therapies. METHODS: A systematic search in PubMed, Embase and the Cochrane Library was performed to identify clinical studies, published before 1 June 2014, involving ablative therapies in LAPC. Outcomes of interest were safety, survival, quality of life and pain. RESULTS: After screening 1037 articles, 38 clinical studies involving 1164 patients with LAPC, treated with ablative therapies, were included. These studies concerned radiofrequency ablation (RFA) (7 studies), irreversible electroporation (IRE) (4), stereotactic body radiation therapy (SBRT) (16), high intensity focused ultrasound (HIFU) (5), iodine-125 (2), iodine-125-cryosurgery (2), photodynamic therapy (1) and microwave ablation (1). All strategies appeared to be feasible and safe. Outcomes for postoperative, procedure-related morbidity and mortality were reported only for RFA (4-22 and 0-11 per cent respectively), IRE (9-15 and 0-4 per cent) and SBRT (0-25 and 0 per cent). Median survival of up to 25.6, 20.2, 24.0 and 12.6 months was reported for RFA, IRE, SBRT and HIFU respectively. Pain relief was demonstrated for RFA, IRE, SBRT and HIFU. Quality of-life outcomes were reported only for SBRT, and showed promising results. CONCLUSION: Ablative therapies in patients with LAPC appear to be feasible and safe. PMID- 25524418 TI - What controls the magnetic exchange interaction in mixed- and homo-valent Mn7 disc-like clusters? A theoretical perspective. AB - Density functional theory (DFT) studies have been undertaken to compute the magnetic exchange and to probe the origin of the magnetic interactions in two hetero- and two homo-valent heptanuclear manganese disc-like clusters, of formula [Mn(II) 4 Mn(IV) 3 (tea)(teaH2 )3 (peolH)4 ] (1), [Mn(II) 4 Mn(III) 3 F3 (tea)(teaH)(teaH2 )2 (piv)4 (Hpiv)(chp)3 ] (2), [Mn(II) 7 (pppd)6 (tea)(OH)3 ] (3) and [Mn(II) 7 (paa)6 (OMe)6 ] (4) (teaH3 =triethanolamine, peolH4 =pentaerythritol, Hpiv=pivalic acid, Hchp=6-chloro-2-hydroxypyridine, pppd=1 phenyl-3-(2-pyridyl) propane-1,3-dione; paaH=N-(2-pyridinyl)acetoacetamide). DFT calculations yield J values, which reproduce the magnetic susceptibility data very well for all four complexes; these studies are also highlighting the likely ageing/stability problems in two of the complexes. It is found that the spin ground states, S, for complexes 1-4 are drastically different, varying from S=29/2 to S=1/2. These values are found to be controlled by the nature of the oxidation state of the metal ions and minor differences present in the structures. Extensive magneto-structural correlations are developed for the seven building unit dimers present in the complexes, with the correlations unlocking the reasons behind the differences in the magnetic properties observed. Independent of the oxidation state of the metal ions, the Mn-O-Mn/Mn-F-Mn angles are found to be the key parameters, which significantly influence the sign as well as the magnitude of the J values. The magneto-structural correlations developed here, have broad applicability and can be utilised to understand the magnetic properties of other Mn clusters. PMID- 25524416 TI - Modulation properties of factors released by bone marrow stromal cells on activated microglia: an in vitro study. AB - In the present paper we develop a new non-cell based (cell-free) therapeutic approach applied to BV2 microglial cells and spinal cord derived primary microglia (PM) using conditioned media from rat bone marrow stromal cells (BMSCs CM). First we collected conditioned media (CM) from either naive or injured rat spinal cord tissue (SCI-CM, inflammatory stimulation agent) and from rat bone marrow stromal cells (BMSCs-CM, therapeutic immunomodulation agent). They were both subsequently checked for the presence of chemokines and growth, neurotrophic and neural migration factors using proteomics analysis. The data clearly showed that rat BMSCs-CM contain in vitro growth factors, neural migration factors, osteogenic factors, differentiating factors and immunomodulators, whereas SCI-CM contain chemokines, chemoattractant factors and neurotrophic factors. Afterwards we determined whether the BMSCs-CM affect chemotactic activity, NO production, morphological and pro-apoptotic changes of either BV2 or PM cells once activated with SCI-CM. Our results confirm the anti-migratory and NO-inhibitory effects of BMSCs-CM on SCI-CM-activated microglia with higher impact on primary microglia. The cytotoxic effect of BMSCs-CM occurred only on SCI-CM-stimulated BV2 cells and PM, not on naive BV2 cells, nor on PM. Taken together, the molecular cocktail found in BMSCs-CM is favorable for immunomodulatory properties. PMID- 25524419 TI - An integrative analysis of regional gene expression profiles in the human brain. AB - Studies of the brain's transcriptome have become prominent in recent years, resulting in an accumulation of datasets with somewhat distinct attributes. These datasets, which are often analyzed only in isolation, also are often collected with divergent goals, which are reflected in their sampling properties. While many researchers have been interested in sampling gene expression in one or a few brain areas in a large number of subjects, recent efforts from the Allen Institute for Brain Sciences and others have focused instead on dense neuroanatomical sampling, necessarily limiting the number of individual donor brains studied. The purpose of the present work is to develop methods that draw on the complementary strengths of these two types of datasets for study of the human brain, and to characterize the anatomical specificity of gene expression profiles and gene co-expression networks derived from human brains using different specific technologies. The approach is applied using two publicly accessible datasets: (1) the high anatomical resolution Allen Human Brain Atlas (AHBA, Hawrylycz et al., 2012) and (2) a relatively large sample size, but comparatively coarse neuroanatomical dataset described previously by Gibbs et al. (2010). We found a relatively high degree of correspondence in differentially expressed genes and regional gene expression profiles across the two datasets. Gene co-expression networks defined in individual brain regions were less congruent, but also showed modest anatomical specificity. Using gene modules derived from the Gibbs dataset and from curated gene lists, we demonstrated varying degrees of anatomical specificity based on two classes of methods, one focused on network modularity and the other focused on enrichment of expression levels. Two approaches to assessing the statistical significance of a gene set's modularity in a given brain region were studied, which provide complementary information about the anatomical specificity of a gene network of interest. Overall, the present work demonstrates the feasibility of cross-dataset analysis of human brain microarray studies, and offers a new approach to annotating gene lists in a neuroanatomical context. PMID- 25524420 TI - High-precision, automated integration of multiple isothermal titration calorimetric thermograms: new features of NITPIC. AB - Isothermal titration calorimetry (ITC) has become a standard and widely available tool to measure the thermodynamic parameters of macromolecular associations. Modern applications of the method, including global analysis and drug screening, require the acquisition of multiple sets of data; sometimes these data sets number in the hundreds. Therefore, there is a need for quick, precise, and automated means to process the data, particularly at the first step of data analysis, which is commonly the integration of the raw data to yield an interpretable isotherm. Herein, we describe enhancements to an algorithm that previously has been shown to provide an automated, unbiased, and high-precision means to integrate ITC data. These improvements allow for the speedy and precise serial integration of an unlimited number of ITC data sets, and they have been implemented in the freeware program NITPIC, version 1.1.0. We present a comprehensive comparison of the performance of this software against an older version of NITPIC and a current version of Origin, which is commonly used for integration. The new methods recapitulate the excellent performance of the previous versions of NITPIC while speeding it up substantially, and their precision is significantly better than that of Origin. This new version of NITPIC is therefore well suited to the serial integration of many ITC data sets. PMID- 25524421 TI - Palleronia abyssalis sp. nov., isolated from the deep Mediterranean Sea and the emended description of the genus Palleronia and of the species Palleronia marisminoris. AB - Three strains designated 221-F1(T), 221-F2 and 3030-F1 were isolated from the Matapan Vavilov Deep canyon, also known as Calypso Deep in the Eastern Mediterranean Sea, at a depth of 4,908 m. Based on 16S rRNA gene sequence analysis these strains were found to be most closely related to Palleronia marisminoris and Hwanghaeicola aestuarii, with 16S rRNA gene pairwise sequence similarity of 95.3 and 94.7 % respectively, belonging to the family Rhodobacteraceae. The strains were observed to be red-pigmented and to form non motile cocci or pleomorphic cells. The cells were found to stain Gram-negative, to be strictly aerobic, oxidase and catalase positive. Strains 221-F1(T), 221-F2 and 3030-F1 were found to be mesophilic and to grow in medium containing up to 13 % NaCl. The major polar lipids of the three strains were identified as diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, an unidentified glycolipid and an unidentified aminolipid. Ubiquinone 10 (U-10) was found to be the major respiratory quinone. The DNA G+C content of strain 221 F1(T) was determined to be 64.7 mol%. Based on phylogenetic, physiological and biochemical characteristics we describe a new species represented by strain 221 F1(T) (=CECT 8504(T) = LMG 27977(T)) for which we propose the name Palleronia abyssalis sp. nov. We also propose to emend the description of the genus Palleronia and the species P. marisminoris to reflect new results obtained in this study. PMID- 25524422 TI - Effects comparison between low glycemic index diets and high glycemic index diets on HbA1c and fructosamine for patients with diabetes: A systematic review and meta-analysis. AB - AIMS: The purpose of this study is to evaluate the effect of low glycemic index (GI) through the comparison of low-GI foods group and high-GI foods group on glycemic control (the measurements were HbA1c and fructosamine) for patients with diabetes. METHODS: The studies were retrieved from databases including PubMed, MEDLINE, Springer, Elsevier Science Direct, Cochrane Library and Google scholar from their inception to August 2014. Review Manager 5.1 and STATA package v.11.0 software were applied for the meta-analysis. Standard mean difference (SWD) and its corresponding 95% confidence interval (CI) for HbA1c and fructosamine of patients with diabetes were collected and calculated in a fixed or random effects model when appropriate. Subgroup analysis stratified by study design, geographic area of participants and types of diabetes were also conducted. RESULTS: There were significant differences of overall effects on HbA1c between low-GI foods group and high-GI foods group (SWD=-0.42, 95%CI=-0.69 to -0.16, P<0.01) in patients with diabetes, and the subgroup analysis indicated that significant differences of HbA1c were also found between the two groups in crossover study, in Australian population and American population, as well as in type 2 diabetes. The overall fructosamine was also significantly different in patients with diabetes between low-GI foods and high-GI foods group (SMD=-0.44, 95%CI=-0.82 to 0.06, P=0.02). CONCLUSIONS: Our results suggest that low-GI diets achieve a more beneficial effect on glycemic control than that of high-GI foods diets. PMID- 25524425 TI - Controversial tumors in pediatric surgical oncology. PMID- 25524426 TI - Anomalous low-temperature Coulomb drag in graphene-GaAs heterostructures. AB - Vertical heterostructures combining different layered materials offer novel opportunities for applications and fundamental studies. Here we report a new class of heterostructures comprising a single-layer (or bilayer) graphene in close proximity to a quantum well created in GaAs and supporting a high-mobility two-dimensional electron gas. In our devices, graphene is naturally hole-doped, thereby allowing for the investigation of electron-hole interactions. We focus on the Coulomb drag transport measurements, which are sensitive to many-body effects, and find that the Coulomb drag resistivity significantly increases for temperatures <5-10 K. The low-temperature data follow a logarithmic law, therefore displaying a notable departure from the ordinary quadratic temperature dependence expected in a weakly correlated Fermi-liquid. This anomalous behaviour is consistent with the onset of strong interlayer correlations. Our heterostructures represent a new platform for the creation of coherent circuits and topologically protected quantum bits. PMID- 25524427 TI - Room temperature crystal structure of the fast switching M159T mutant of the fluorescent protein dronpa. AB - The fluorescent protein Dronpa undergoes reversible photoswitching reactions between the bright "on" and dark "off" states via photoisomerization and proton transfer reactions. We report the room temperature crystal structure of the fast switching Met159Thr mutant of Dronpa at 2.0-A resolution in the bright on state. Structural differences with the wild type include shifted backbone positions of strand beta8 containing Thr159 as well as an altered A-C dimer interface involving strands beta7, beta8, beta10, and beta11. The Met159Thr mutation increases the cavity volume for the p-hydroxybenzylidene-imidazolinone chromophore as a result of both the side chain difference and the backbone positional differences. PMID- 25524428 TI - How are dysplastic hips different? A three-dimensional CT study. AB - BACKGROUND: Surgical correction of acetabular dysplasia can postpone or prevent joint degeneration. The specific abnormalities that make up the dysplastic hip are controversial. QUESTIONS/PURPOSES: (1) What are the relative size, shape, and orientations of the typical nondysplastic hip? (2) How do these variables differ in the developmentally dysplastic hip? (3) Are there version differences between the acetabuli of dysplastic and nondysplastic hips? (4) Are there pairs of variables in which the change in one is always accompanied by a change in the other for both nondysplastic and dysplastic acetabuli? METHODS: Of 117 consecutive three-dimensional (3-D) CT scans performed for hip dysplasia between March 1988 and October 1995, 48 met criteria of developmentally dysplastic hips by plain radiography. These were retrospectively compared with 55 pelvic 3-D CT scans culled from 81 consecutive scans performed for reasons other than hip dysplasia (ie, hip pain, trauma, infection) that did not affect the hip or pelvic landmarks. The 3-D reconstructions were orientated anatomically for standardization of the measurements to be compared. Representative 3-D volumes of the acetabular space were constructed from which we could measure anatomic positions and dimensional information. One author performed all image orientation and measurements. RESULTS: Nondysplastic acetabuli are essentially hemispheric with height equal to width and twice the depth. The dysplastic acetabuli were elongated in females (52.4 +/- 6.2 mm for dysplastic versus 46.5 +/- 4.6 mm for nondysplastic (mean difference, 5.0; 95% confidence interval [CI], 1.9-8.0; p = 0.002) and shallower in both females (18.7 +/- 4.9 mm for dysplastic versus 23.6 +/- 4.0 mm for nondysplastic; mean difference, 6.5; 95% CI, 4.4-8.5; p < 0.0001) and males (21.1 +/- 4.8 mm for dysplastic versus 25.0 +/- 4.3 mm for nondysplastic, mean difference, 5.3; 95% CI, 2.6-8.1; p = 0.0002); width was similar to that of nondysplastic hips. Acetabular openings were slightly more vertical than nondysplastic hips in females (5 degrees ; 95% CI, 1.9-8.1; p = 0.002) but not in male subjects. The dysplastic acetabuli were smaller in volume (18% in females, p = 0.002, and 19% in males, p = 0.0012) and had less space occupied by the femoral head compared with nondysplastic hips (p < 0.0001 for females, p < 0.0001 for males). Dysplastic hip midacetabulum was 4 degrees more anteverted in females (95% CI, 0.5-6.8; p = 0.022) but not for males (p = 0.538). The upper dysplastic acetabulum was more retroverted in females and males (10.2 degrees ; 95% CI, 5.5-15; p < 0.0001, and 7.0 degrees ; 95% CI, 0.6-13.4; p = 0.032, respectively). Acetabular volumes in nondysplastic and dysplastic hips were related to acetabular width but not to length. CONCLUSIONS: Developmentally dysplastic acetabuli are not deficient in merely a single dimension but are globally deficient. The subluxated femoral head lies in the elongated and retroverted superior acetabulum, which becomes progressively shallower as the acetabulum increases in length. Focally deficient anterior or posterior femoral head coverage is uncommon. Current procedures that redirect the acetabulum, no matter how technically successful, cannot fully compensate for the incongruence of a spherical femoral head within a shallow and elongated acetabulum unless corrected at an early age when acetabular remodeling is possible. Early detection and treatment of acetabular dysplasia should be emphasized. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 25524430 TI - Spectroscopic and chromatographic quantification of an antioxidant-stabilized ultrahigh-molecular-weight polyethylene. AB - BACKGROUND: The oxidative stability of various antioxidant-containing ultrahigh molecular-weight polyethylene (UHMWPE) formulations has been widely reported. Depending on which specific antioxidant is used, the process by which it is incorporated into UHMWPE, and the amount of the antioxidant incorporated, there could be substantial differences in the material and toxicological properties of the UHMWPE formulation. Pentaerythritol tetrakis (3-[3,5-di tertiary butyl-4 hydroxyphenyl] propionate) (PBHP) has been extensively used as an efficient antioxidant in various applications. However, it has not thus far been used to stabilize UHMWPE in orthopaedic implants. It is therefore important to characterize and verify the concentration and homogeneity of distribution of PBHP in the composition, the chemical consequence of exposure of the antioxidant to gamma irradiation, and to assess the toxicological risk of use by the identification and quantification of leachables before the use of PBHP-containing UHMWPE in implantable devices. QUESTIONS/PURPOSES: (1) Can the concentration and uniformity of distribution of the antioxidant PBHP in UHMWPE powder and in the consolidated, preirradiated formulation be verified? (2) Can the leachable compounds in the gamma radiation crosslinked PBHP/UHMWPE formulation be identified and quantified? METHODS: PBHP in GUR 1020 UHMWPE was quantified by Fourier transform infrared (FTIR) and ultraviolet-visible (UV-Vis) spectroscopy. The chemical byproducts generated by gamma irradiation of PBHP were identified using gas chromatography in conjunction with mass spectrometry followed by a second-stage mass spectrometry (GC-MS/MS). When GC-MS/MS was coupled with Stir Bar Sorptive extraction, leachable components in the UHMWPE formulation were identified and quantified. RESULTS: The percent concentration of PBHP in UHMWPE powder was confirmed by UV-Vis spectroscopy and the concentration and uniform distribution of PBHP in UHMWPE after consolidation and before radiation crosslinking was verified through FTIR spectroscopy. GC-MS/MS analysis enabled the identification and quantification of 16 gamma irradiation byproducts of PBHP. These 16 compounds were verified as potentially leachable compounds in PBHP stabilized UHMWPE and were found to be well below the safety threshold concern of 150 ng/device in orthopaedic knee inserts made from PBHP-stabilized UHMWPE. CONCLUSIONS: Spectroscopic analysis has been successfully used to demonstrate the ability to reliably quantify the amount as well as the distribution of PBHP in UHMWPE in orthopaedic bearings. State-of-the-art chemical extraction and analytical techniques have enabled the identification of the gamma radiation induced byproducts of PBHP and the quantification of these components as leachables from the PBHP-stabilized UHMWPE formulation. CLINICAL RELEVANCE: Antioxidant-stabilized UHMWPE materials being considered for orthopaedic bearings must be fully characterized for composition before use because it is apparent that exposure to high doses of gamma radiation would cause the formation of new chemical entities. It is important to verify the identities and quantities of chemical species that could leach out of implanted devices in the long term to enable their toxicological risk assessment. PMID- 25524429 TI - What Are Risk Factors for 30-day Morbidity and Transfusion in Total Shoulder Arthroplasty? A Review of 1922 Cases. AB - BACKGROUND: Total shoulder arthroplasty (TSA) is an effective treatment for end stage glenohumeral joint pathology with good long-term results. Previous descriptions of morbidity and blood transfusion in TSA are limited by preoperative risk factors and postoperative complications considered and single center studies. QUESTIONS/PURPOSES: The purpose of this study was to define in a group of patients undergoing TSA (1) the type and incidence of complications; (2) the frequency of and risk factors for both minor and major complications; and (3) the risk factors for bleeding resulting in transfusion. METHODS: We retrospectively queried the National Surgical Quality Improvement Program database using Current Procedural Terminology billing codes and identified 1922 cases of TSA performed between 2006 and 2011. Postoperative outcomes were divided into one of four categories: any complication, major morbidity (systemic life threatening event or a substantial threat to a vital organ) or mortality, minor morbidity (localized to the operative upper extremity or not posing a major systemic threat to the patient), or bleeding resulting in transfusion. Univariate and multivariate analyses were then used to identify risk factors for complications. RESULTS: There were a total of 155 complications (8% of the 1922 patients identified). The most common complication was bleeding resulting in transfusion (82 patients [4.26%]) followed by urinary tract infections (27 patients [1.40%]), return to the operating room (14 patients [0.73%]), pneumonia (10 patients [0.52%]), and peripheral nerve injury (nine patients [0.47%]). The incidence of major morbidity was 2% (44 patients), which included five patients (0.26%) who died; the incidence of any minor morbidity was 7% (136 patients). After controlling for likely confounding variables, we found steroid use (odds ratio [OR], 3; 95% confidence interval [CI], 2-6), hematocrit < 38% (OR, 2; 95% CI, 1-3), American Society of Anesthesiologists (ASA) Class 4 (OR, 3; 95% CI, 1 7), and operating time > 2 hours (OR, 2; 95% CI, 1-3) as independent predictors of complication and congestive heart failure (OR, 12; 95% CI, 1-106) as an independent risk factor for major morbidity or mortality. Hematocrit < 38% (OR, 3; 95% CI, 2-6), resident involvement (OR, 3; 95% CI, 2-5), steroid use (OR, 3; 95% CI, 1-6), and ASA Class 3 versus 1 or 2 (OR, 2; 95% CI, 1-5) were independent risk factors for bleeding resulting in transfusion. CONCLUSIONS: Short-term morbidity after TSA is higher than previously reported. The prevalence of complications within 30 days of surgery and our outlined risk factors should guide surgeon-driven preoperative patient evaluation, management, and counseling. Surgeons who perform TSA should be aware operative time > 2 hours is associated with increased complications. Patients with preoperative hematocrit < 38%, history of steroid use, ASA Class > 2, and patients with congestive heart failure should receive medical optimization before TSA. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 25524431 TI - RNA-seq reveals regional differences in transcriptome response to heat stress in the marine snail Chlorostoma funebralis. AB - To investigate the role of gene expression in adaptation of marine ectotherms to different temperatures, we examined the transcriptome-wide thermal stress response in geographically separated populations of the intertidal snail Chlorostoma funebralis. Snails from two southern (heat tolerant) and two northern (heat sensitive) populations were acclimated to a common thermal environment, exposed to an environmentally relevant thermal stress and analysed using RNA-seq. Pooling across all populations revealed 306 genes with differential expression between control and heat-stressed samples, including 163 significantly upregulated and 143 significantly downregulated genes. When considered separately, regional differences in response were widely apparent. Heat shock proteins (Hsps) were upregulated in both regions, but the magnitude of response was significantly greater in northern populations for most Hsp70s, while the southern populations showed greater upregulation for approximately half of the Hsp40s. Of 177 stress-responsive genes in northern populations, 55 responded to heat stress only in northern populations. Several molecular chaperones and antioxidant genes that were not differentially expressed in southern populations showed higher expression under control conditions compared with northern populations. This suggests that evolution of elevated expression of these genes under benign conditions preadapts the southern populations to frequent heat stress and contributes to their higher thermal tolerance. These results indicate that evolution has resulted in different transcriptome responses across populations, including upregulation of genes in response to stress and preadaptation of genes in anticipation of stress (based on evolutionary history of frequent heat exposure). The relative importance of the two mechanisms differs among gene families and among populations. PMID- 25524432 TI - Cancer and bone fractures in observational follow-up of the RECORD study. AB - AIMS: The RECORD study evaluated the effects of rosiglitazone on cardiovascular outcomes. A 4-year observational follow-up was added to the study to monitor the occurrence of cancer and bone fractures. We present the cancer and bone fracture data aggregated across the main study and its observational follow-up. METHODS: RECORD was a multicentre, open-label trial in people with type 2 diabetes on metformin or sulfonylurea monotherapy randomly assigned to addition of rosiglitazone (n = 2,220) or to a combination of metformin and sulfonylurea (n = 2,227). At the end of the main study, patients stopped study drug and were invited to enter the observational follow-up during which glucose-lowering treatment was selected by the patient's physician. Serious adverse events of cancer and serious and non-serious events of bone fracture were recorded. The study is registered with ClinicalTrials.gov, number NCT00379769. RESULTS: Of the 4,447 patients comprising the intent-to-treat population, 2,546 entered the observational follow-up (1,288 rosiglitazone, 1,258 metformin/sulfonylurea) and added 9,336 patient-years experience to the main RECORD study, making an aggregate of 33,744 patient-years. Based on the totality of follow-up, malignancies were reported in 179 of 2,220 patients (8.1 %) in the group originally randomised to rosiglitazone and in 195 of 2,227 patients (8.8 %) in the group allocated metformin/sulfonylurea [relative risk, RR, 0.92 (95 % CI 0.76 1.12)]. More patients reported bone fractures in the rosiglitazone group (238, 10.7 %) than in the metformin/sulfonylurea control [151, 6.8 %; RR 1.58 (1.30 1.92)]. For women, the corresponding figures were rosiglitazone 156 (14.5 %), metformin/sulfonylurea 91 (8.5 %), RR 1.71 (1.34-2.18), and for men, the corresponding figures were rosiglitazone 82 (7.2 %), metformin/sulfonylurea 60 (5.2 %), RR 1.37 (0.99-1.90). Potentially high-morbidity fractures (hip, pelvis, femur, and spine) occurred in the same number of patients (31, 1.4 %) in the two treatment groups. CONCLUSIONS: We conclude that data from a 4-year observational follow-up, combined with the main RECORD study data, do not suggest an increased risk of cancer in patients randomised to rosiglitazone combination use compared with those randomised to metformin/sulfonylurea. Consistent with the main study, rosiglitazone is associated with an increased risk of peripheral bone fracture in women, and probably in men, but the combined data do not suggest an increase in potentially high-morbidity (hip, pelvis, femur, and spine) fractures. PMID- 25524433 TI - Persistence and adherence to oral antidiabetics: a population-based cohort study. AB - AIMS: A population-based cohort study design was used to estimate persistence rate, re-initiation rate after discontinuation, and adherence level among incident users of oral antidiabetics (OADs), and to investigate predictors of non persistence and non-adherence. METHODS: Incident OAD users were identified using healthcare databases of residents covered by the public drug insurance plan of the Province of Quebec, Canada. Patients initiated OAD therapy between January 2000 and October 2009 and were aged 45-85 years at cohort entry. Persistence rate, re-initiation after discontinuation, and adherence level were assessed over 2 years. Predictors of non-persistence and non-adherence were analyzed using Cox and logistic regression models, respectively. RESULTS: The cohort included 160,231 incident OAD users at entry. One year after OAD initiation, persistence rate was 51 % and adherence level 67 %. Among those deemed non-persistent, 80.6 % re-initiated OAD therapy within 12 months of discontinuation; a proportion increasing with primary persistence duration. The 1-year persistence rate varied according to OAD classes; being the highest for thiazolidinediones (62 %) and the lowest for alpha-glucosidase inhibitors (30 %). The likelihood for non persistence was 39-54 % higher when drug copayments were required. Conversely, OAD discontinuation was least likely for patients with schizophrenia [hazard ratio 0.70 (95 % CI 0.67-0.73)], dyslipidemia [0.85 (0.84-0.87)], anticoagulation [0.86 (0.83-0.88)], hypertension [0.87 (0.85-0.88)], and >=7 medications [0.90 (0.88-0.91)]. Predictors of non-adherence were similar. CONCLUSIONS: Non persistence and non-adherence to OAD therapy were common, although re-initiation rate was high. OAD classes, drug copayments, comorbidities and co-medications may help identifying those who were more likely to benefit from counseling. PMID- 25524434 TI - Open Axial and True Vertical Ankle Dislocation Without Malleolar Fractures: A Case Report. AB - Tibiotalar dislocation is rare and usually associated with a high-velocity, high energy impact or extreme sporting injuries. I describe complete tibiotalar dislocation from an unusual mechanism. A 22-year-old mechanic was sitting under a hydraulic lift when it began to leak, lowering the engine on which he was working onto his right lower thigh. This heavy load, without rotational force or high velocity impact, was transmitted down his foreleg. Because his foot was fixed to the ground, the talus was proximally and vertically displaced, and the distal tibia was forced to the ground, beside his foot, and was contaminated with sand and grease. The circumferential ligament complexes and capsule were completely transected, but, despite a severely disrupted dorsal and capsular blood supply, talar vasculature remained adequate. In the emergency department, gentle traction restored impaired circulation. No malleolar fractures were seen. The wound was meticulously irrigated with saline and povidone-iodine and debrided. Cefepime, 2 g, was given twice daily. In surgery, the unstable joint was transfixed with two thick Kirschner wires, passed retrograde. Interrupted sutures were placed in the anterior capsule and anterior third of the lateral ligament without additional incisions. The wound healed aseptically. The Kirschner wires were removed at 6 weeks. The joint space was only minimally reduced. He returned to work after 4 months. His ankle-hindfoot score was 90/100 at 18 months, he could jog at 24 months, and he was still asymptomatic at 36 months. The case illustrates the importance of preserving talar circulation and treatment within the "golden hour." PMID- 25524435 TI - Predictors of maternal and paternal depressive symptoms at postpartum. AB - OBJECTIVES: Postnatal depression has emerged as a major public health concern, which has deleterious effects on the well-being of the entire family. The aim of this study was to examine the predictive role of prenatal family sense of coherence, stress, social support and family, and marital functioning; the effect that any changes in these factors from pregnancy to postpartum; and partner's depressive symptoms on depressive symptoms at 6 months postpartum. METHODS: This study used a longitudinal design. A convenience sample of 200 childbearing couples in Hong Kong completed assessments of family sense of coherence, stress, social support, family, and marital functioning and depressive symptoms during pregnancy and at 6 months postpartum. Multiple regression analyses were employed. RESULTS: The results showed that a low level of family sense of coherence and a high level of depressive symptoms during pregnancy and partner's depressive symptoms were significantly associated with an increase in depressive symptoms for both mothers and fathers at 6 months postpartum. A lack of social support was significantly associated with increased risk of depressive symptoms for mothers, but not for fathers. CONCLUSION: The results suggest that couple-based interventions that foster a sense of family coherence may be helpful in promoting parental well-being. Well-designed trials to test the effects of such interventions are recommended for future research. PMID- 25524436 TI - Differential associations of specific depressive and anxiety disorders with somatic symptoms. AB - OBJECTIVE: Previous studies have shown that depressive and anxiety disorders are strongly related to somatic symptoms, but much is unclear about the specificity of this association. This study examines the associations of specific depressive and anxiety disorders with somatic symptoms, and whether these associations are independent of comorbid depressive and anxiety disorders. METHODS: Cross sectional data were derived from The Netherlands Study of Depression and Anxiety (NESDA). A total of 2008 persons (mean age: 41.6 years, 64.9% women) were included, consisting of 1367 patients with a past-month DSM-diagnosis (established with the Composite International Diagnostic Interview [CIDI]) of depressive disorder (major depressive disorder, dysthymic disorder) and/or anxiety disorder (generalized anxiety disorder, social phobia, panic disorder, agoraphobia), and 641 controls. Somatic symptoms were assessed with the somatization scale of the Four-Dimensional Symptom Questionnaire (4DSQ), and included cardiopulmonary, musculoskeletal, gastrointestinal, and general symptoms. Analyses were adjusted for covariates such as chronic somatic diseases, sociodemographics, and lifestyle factors. RESULTS: All clusters of somatic symptoms were more prevalent in patients with depressive and/or anxiety disorders than in controls (all p<.001). Multivariable logistic regression analyses showed that all types of depressive and anxiety disorders were independently related to somatic symptoms, except for dysthymic disorder. Major depressive disorder showed the strongest associations. Associations remained similar after adjustment for covariates. CONCLUSION: This study demonstrated that depressive and anxiety disorders show strong and partly differential associations with somatic symptoms. Future research should investigate whether an adequate consideration and treatment of somatic symptoms in depressed and/or anxious patients improve treatment outcomes. PMID- 25524437 TI - The role of ultrasound in the follow-up of children with differentiated thyroid cancer. AB - BACKGROUND: Thyroid cancer is the most common endocrine malignancy with relatively good prognosis in children. However, unlike adults, children usually present with more advanced disease and have a higher local recurrence and distant metastases. Thus surveillance for recurrence is a major goal of long-term follow up. OBJECTIVE: This retrospective study evaluates the diagnostic value of ultrasound (US) imaging in the post-therapy surveillance of children with differentiated thyroid cancer. MATERIALS AND METHODS: We reviewed the charts of 54 children (40 girls; mean age 14.3 +/- 3.6 years) with differentiated thyroid cancer treated with total or near-total thyroidectomy. Forty children (29 girls and 11 boys) who had routine follow-up US examinations (112 studies) were included for the evaluation of US accuracy in the follow-up of pediatric differentiated thyroid cancer. Histopathology, stimulated thyroglobulin determination, post-therapy whole-body iodine scan and clinical follow-up were used as the standards of reference. RESULTS: Mean period of follow-up was 34 months. The frequency of recurrence was 42% (17/40). Seventeen percent of the children had lung metastases either at presentation or on follow-up. In all cases of lung metastases, stimulated thyroglobulin level was greater than 10 ng/ml. The sensitivity was 85.7%, specificity 89.4%, negative predictive value 94.4% and positive predictive value 75% for US in detecting loco-regional recurrence in follow-up studies of pediatric differentiated thyroid cancer. In 17.3% (18/104) of studies, the results of stimulated thyroglobulin and US were discordant. CONCLUSION: US showed very good sensitivity and specificity and a high negative predictive value for evaluation of loco-regional involvement in follow-up of pediatric differentiated thyroid cancer. Diagnostic whole-body iodine scan is indicated when serum anti-thyroglobulin Ab is high, or in cases of discordant findings between US and stimulated thyroglobulin levels, or when stimulated thyroglobulin levels are >10 ng/ml (to evaluate for lung metastasis). PMID- 25524438 TI - Untargeted metabolic profiling identifies altered serum metabolites of type 2 diabetes mellitus in a prospective, nested case control study. AB - BACKGROUND: Application of metabolite profiling could expand the etiological knowledge of type 2 diabetes mellitus (T2D). However, few prospective studies apply broad untargeted metabolite profiling to reveal the comprehensive metabolic alterations preceding the onset of T2D. METHODS: We applied untargeted metabolite profiling in serum samples obtained from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort comprising 300 individuals who developed T2D after a median follow-up time of 6 years and 300 matched controls. For that purpose, we used ultraperformance LC-MS with a protocol specifically designed for large-scale metabolomics studies with regard to robustness and repeatability. After multivariate classification to select metabolites with the strongest contribution to disease classification, we applied multivariable adjusted conditional logistic regression to assess the association of these metabolites with T2D. RESULTS: Among several alterations in lipid metabolism, there was an inverse association with T2D for metabolites chemically annotated as lysophosphatidylcholine(dm16:0) and phosphatidylcholine(O-20:0/O-20:0). Hexose sugars were positively associated with T2D, whereas higher concentrations of a sugar alcohol and a deoxyhexose sugar reduced the odds of diabetes by approximately 60% and 70%, respectively. Furthermore, there was suggestive evidence for a positive association of the circulating purine nucleotide isopentenyladenosine-5'-monophosphate with incident T2D. CONCLUSIONS: This study constitutes one of the largest metabolite profiling approaches of T2D biomarkers in a prospective study population. The findings might help generate new hypotheses about diabetes etiology and develop further targeted studies of a smaller number of potentially important metabolites. PMID- 25524439 TI - Direct nkx2-5 transcriptional repression of isl1 controls cardiomyocyte subtype identity. AB - During cardiogenesis, most myocytes arise from cardiac progenitors expressing the transcription factors Isl1 and Nkx2-5. Here, we show that a direct repression of Isl1 by Nkx2-5 is necessary for proper development of the ventricular myocardial lineage. Overexpression of Nkx2-5 in mouse embryonic stem cells (ESCs) delayed specification of cardiac progenitors and inhibited expression of Isl1 and its downstream targets in Isl1(+) precursors. Embryos deficient for Nkx2-5 in the Isl1(+) lineage failed to downregulate Isl1 protein in cardiomyocytes of the heart tube. We demonstrated that Nkx2-5 directly binds to an Isl1 enhancer and represses Isl1 transcriptional activity. Furthermore, we showed that overexpression of Isl1 does not prevent cardiac differentiation of ESCs and in Xenopus laevis embryos. Instead, it leads to enhanced specification of cardiac progenitors, earlier cardiac differentiation, and increased cardiomyocyte number. Functional and molecular characterization of Isl1-overexpressing cardiomyocytes revealed higher beating frequencies in both ESC-derived contracting areas and Xenopus Isl1-gain-of-function hearts, which associated with upregulation of nodal specific genes and downregulation of transcripts of working myocardium. Immunocytochemistry of cardiomyocyte lineage-specific markers demonstrated a reduction of ventricular cells and an increase of cells expressing the pacemaker channel Hcn4. Finally, optical action potential imaging of single cardiomyocytes combined with pharmacological approaches proved that Isl1 overexpression in ESCs resulted in normally electrophysiologically functional cells, highly enriched in the nodal subtype at the expense of the ventricular lineage. Our findings provide an Isl1/Nkx2-5-mediated mechanism that coordinately regulates the specification of cardiac progenitors toward the different myocardial lineages and ensures proper acquisition of myocyte subtype identity. PMID- 25524440 TI - Review: typically-developing students' views and experiences of inclusive education. AB - PURPOSE: The present review aimed to summarize and critique existing qualitative studies that have examined typically-developing students' views of inclusive education (i.e. the policy of teaching students with special educational needs in mainstream settings). METHODS: Guidelines from the Centre for Reviews and Dissemination were followed, outlining the criteria by which journal articles were identified and critically appraised. Narrative Synthesis was used to summarize findings across studies. RESULTS: Fourteen studies met the review's inclusion criteria and were subjected to quality assessment. Analysis revealed that studies were of variable quality: three were of "good" methodological quality, seven of "medium" quality, and four of "poor" quality. With respect to findings, three overarching themes emerged: students expressed mostly negative attitudes towards peers with disabilities; were confused by the principles and practices of inclusive education; and made a number of recommendations for improving its future provision. CONCLUSIONS: A vital determinant of the success of inclusive education is the extent to which it is embraced by typically developing students. Of concern, this review highlights that students tend not to understand inclusive education, and that this can breed hostility towards it. More qualitative research of high methodological quality is needed in this area. Implications for Rehabilitation Typically-developing students are key to the successful implementation of inclusive education. This review shows that most tend not to understand it, and can react by engaging in avoidance and/or targeted bullying of peers who receive additional support. Schools urgently need to provide teaching about inclusive education, and increase opportunities for contact between students who do and do not receive support (e.g. cooperative learning). PMID- 25524443 TI - Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. AB - BACKGROUND: In systematic reviews and meta-analysis, researchers often pool the results of the sample mean and standard deviation from a set of similar clinical trials. A number of the trials, however, reported the study using the median, the minimum and maximum values, and/or the first and third quartiles. Hence, in order to combine results, one may have to estimate the sample mean and standard deviation for such trials. METHODS: In this paper, we propose to improve the existing literature in several directions. First, we show that the sample standard deviation estimation in Hozo et al.'s method (BMC Med Res Methodol 5:13, 2005) has some serious limitations and is always less satisfactory in practice. Inspired by this, we propose a new estimation method by incorporating the sample size. Second, we systematically study the sample mean and standard deviation estimation problem under several other interesting settings where the interquartile range is also available for the trials. RESULTS: We demonstrate the performance of the proposed methods through simulation studies for the three frequently encountered scenarios, respectively. For the first two scenarios, our method greatly improves existing methods and provides a nearly unbiased estimate of the true sample standard deviation for normal data and a slightly biased estimate for skewed data. For the third scenario, our method still performs very well for both normal data and skewed data. Furthermore, we compare the estimators of the sample mean and standard deviation under all three scenarios and present some suggestions on which scenario is preferred in real-world applications. CONCLUSIONS: In this paper, we discuss different approximation methods in the estimation of the sample mean and standard deviation and propose some new estimation methods to improve the existing literature. We conclude our work with a summary table (an Excel spread sheet including all formulas) that serves as a comprehensive guidance for performing meta-analysis in different situations. PMID- 25524441 TI - Transcriptional, posttranscriptional, and posttranslational regulation of SHOOT MERISTEMLESS gene expression in Arabidopsis determines gene function in the shoot apex. AB - The activity of SHOOT MERISTEMLESS (STM) is required for the functioning of the shoot apical meristem (SAM). STM is expressed in the SAM but is down-regulated at the site of leaf initiation. STM is also required for the formation of compound leaves. However, how the activity of STM is regulated at the transcriptional, posttranscriptional, and posttranslational levels is poorly understood. We previously found two conserved noncoding sequences in the promoters of STM-like genes across angiosperms, the K-box and the RB-box. Here, we characterize the function of the RB-box in Arabidopsis (Arabidopsis thaliana). The RB-box, along with the K-box, regulates the expression of STM in leaf sinuses, which are areas on the leaf blade with meristematic potential. The RB-box also contributes to restrict STM expression to the SAM. We identified FAR1-RELATED SEQUENCES-RELATED FACTOR1 (FRF1) as a binding factor to the RB-box region. FRF1 is an uncharacterized member of a subfamily of four truncated proteins related to the FAR1-RELATED SEQUENCES factors. Internal deletion analysis of the STM promoter identified a region required to repress the expression of STM in hypocotyls. Expression of STM in leaf primordia under the control of the JAGGED promoter produced plants with partially undifferentiated leaves. We further found that the ELK domain has a role in the posttranslational regulation of STM by affecting the nuclear localization of STM. PMID- 25524445 TI - Interaction of crown ether-annelated styryl dyes with double-stranded DNA. AB - DNA-binding properties of 15-crown-5-derived mono- and bis-styryl dyes were investigated in the presence of calf thymus DNA. To access the factors that influence the DNA association in the series of these ligands, the structure of the molecules was varied by either changing size of the heterocyclic moiety or altering the position of the styryl substituents. The major binding mode for the monostyryl dyes is intercalation. Notably, binding of the dyes to the nucleic acids leads to a fluorescence enhancement by a factor of up to 54. Therefore, these cationic styryl derivatives may be applied as fluorescent "light-up" probes for DNA detection. PMID- 25524442 TI - PECTIN METHYLESTERASE48 is involved in Arabidopsis pollen grain germination. AB - Germination of pollen grains is a crucial step in plant reproduction. However, the molecular mechanisms involved remain unclear. We investigated the role of PECTIN METHYLESTERASE48 (PME48), an enzyme implicated in the remodeling of pectins in Arabidopsis (Arabidopsis thaliana) pollen. A combination of functional genomics, gene expression, in vivo and in vitro pollen germination, immunolabeling, and biochemical analyses was used on wild-type and Atpme48 mutant plants. We showed that AtPME48 is specifically expressed in the male gametophyte and is the second most expressed PME in dry and imbibed pollen grains. Pollen grains from homozygous mutant lines displayed a significant delay in imbibition and germination in vitro and in vivo. Moreover, numerous pollen grains showed two tips emerging instead of one in the wild type. Immunolabeling and Fourier transform infrared analyses showed that the degree of methylesterification of the homogalacturonan was higher in pme48-/- pollen grains. In contrast, the PME activity was lower in pme48-/-, partly due to a reduction of PME48 activity revealed by zymogram. Interestingly, the wild-type phenotype was restored in pme48-/- with the optimum germination medium supplemented with 2.5 mm calcium chloride, suggesting that in the wild-type pollen, the weakly methylesterified homogalacturonan is a source of Ca(2+) necessary for pollen germination. Although pollen-specific PMEs are traditionally associated with pollen tube elongation, this study provides strong evidence that PME48 impacts the mechanical properties of the intine wall during maturation of the pollen grain, which, in turn, influences pollen grain germination. PMID- 25524444 TI - Characterization of a panel of Vietnamese rice varieties using DArT and SNP markers for association mapping purposes. AB - BACKGROUND: The development of genome-wide association studies (GWAS) in crops has made it possible to mine interesting alleles hidden in gene bank resources. However, only a small fraction of the rice genetic diversity of any given country has been exploited in the studies with worldwide sampling conducted to date. This study presents the development of a panel of rice varieties from Vietnam for GWAS purposes. RESULTS: The panel, initially composed of 270 accessions, was characterized for simple agronomic traits (maturity class, grain shape and endosperm type) commonly used to classify rice varieties. We first genotyped the panel using Diversity Array Technology (DArT) markers. We analyzed the panel structure, identified two subpanels corresponding to the indica and japonica sub species and selected 182 non-redundant accessions. However, the number of usable DArT markers (241 for an initial library of 6444 clones) was too small for GWAS purposes. Therefore, we characterized the panel of 182 accessions with 25,971 markers using genotyping by sequencing. The same indica and japonica subpanels were identified. The indica subpanel was further divided into six populations (I1 to I6) using a model-based approach. The japonica subpanel, which was more highly differentiated, was divided into 4 populations (J1 to J4), including a temperate type (J2). Passport data and phenotypic traits were used to characterize these populations. Some populations were exclusively composed of glutinous types (I3 and J2). Some of the upland rice varieties appeared to belong to indica populations, which is uncommon in this region of the world. Linkage disequilibrium decayed faster in the indica subpanel (r2 below 0.2 at 101 kb) than in the japonica subpanel (r2 below 0.2 at 425 kb), likely because of the strongest differentiation of the japonica subpanel. A matrix adapted for GWAS was built by eliminating the markers with a minor allele frequency below 5% and imputing the missing data. This matrix contained 21,814 markers. A GWAS was conducted on time to flowering to prove the utility of this panel. CONCLUSIONS: This publicly available panel constitutes an important resource giving access to original allelic diversity. It will be used for GWAS on root and panicle traits. PMID- 25524446 TI - Heterogeneous neuromuscular activation within human rectus femoris muscle during pedaling. AB - INTRODUCTION: We investigated the effect of workload and the use of pedal straps on the spatial distribution of neuromuscular activation within the rectus femoris (RF) muscle during pedaling movements. METHODS: Eleven healthy men performed submaximal pedaling exercises on an electrically braked ergometer at different workloads and with or without pedal straps. During these tasks, surface electromyograms (SEMGs) were recorded from the RF using 36 electrode pairs, and central locus activation (CLA) was calculated along the longitudinal line of the muscle. RESULTS: CLA moved markedly, indicating changes in spatial distribution of SEMG within the muscle, during a crank cycle under all conditions (P < 0.05). There were significant differences in CLA among different workloads and between those with and without pedal straps (P < 0.05). CONCLUSION: These results suggest that neuromuscular activation within the RF is regulated regionally by changes in workload and the use of pedal straps during pedaling. PMID- 25524447 TI - Enhanced detection of in-gel released N-glycans by MALDI-TOF-MS. AB - Many biologically relevant glycoproteins need to be separated on 1D- or 2D-gels prior to analysis and are available in picomole amounts. Therefore, it is important to have optimized methods to unravel the glycome that combine in-gel digestions with MALDI-TOF-MS. In this technical report, we investigated how the detection of in-gel released N-glycans could be improved by MALDI-TOF-MS. First, an AnchorChip target was tested and compared to ground steel target using several reference oligosaccharides. The highest signals were obtained with an AnchorChip target and D-arabinosazone as the matrix; a LOD of 1.3 to 10 fmol was attained. Then, the effect of octyl-beta-glucopyranoside, a nonionic detergent, was studied during in-gel peptide-N(4) -(acetyl-beta-glucosaminyl) asparagine amidase F digestion of standard glycoproteins and during glycan extraction. Octyl-beta glucopyranoside increased the intensity and the amount of detected neutral as well as acidic N-glycans. A LOD of under 7 pmol glycoprotein could be achieved. PMID- 25524448 TI - [Orbital congenital nevi: Principles of treatment about 51 cases]. AB - INTRODUCTION: The incidence of congenital nevi is one over 20,000 newborns per year, 14 % of them are located in the head and neck area. Nevi of the orbital region are particularly difficult to handle on the aesthetic and functional side. The objectives of this study were to conduct an analysis of different clinical presentations of congenital nevi of the eyelid orbital region in children to establish a treatment algorithm. MATERIEL AND METHODS: We realised a bi-centric retrospective study including 51 children with orbito-palpebral congenital nevi. We analysed the different clinical presentations, their treatments and their results. RESULTS: Nineteen underwent direct suture excision; three a total skin graft; 15 a combination of treatments, among them four underwent tissular expansion and 14 patients were not operated and clinically followed-up. The average follow-up time was 6.6 years. In 33 cases residual nevic area was still present. The postoperative sequelae were: dyschromia (n=17), anatomical deformation of the eye (n=10), nevi outbreaks (n=8), internal canthus deformation (n=5) and ectropion (n=1). CONCLUSION: The results of our study show that therapeutic abstention is preferred when the aesthetic wrong is accepted by the patient and when there is not a higher risk of malignant degeneration. In order to minimise the risk of postoperative sequelae, we propose a therapeutic algorithm for the management of congenital orbital nevi. PMID- 25524449 TI - Stereotactic radiation therapy for treatment of canine intracranial meningiomas. AB - The objective of this study is to determine the rate of toxicity, median survival time (MST) and prognostic factors in dogs with presumed intracranial meningiomas that were treated with stereotactic radiation therapy (SRT). Patient demographics, neurological history, details of SRT plans and response to treatment (including toxicity and survival times) were examined for potential prognostic factors. Overall MST (MST) due to death for any cause was 561 days. There was a mild to moderate exacerbation of neurological symptoms 3-16 weeks following SRT treatments in 11/30 (36.7%) of dogs. This presumed adverse event was treated with corticosteroids, and improvement was seen in most of these dogs. Death within 6 months of treatment as a result of worsening neurologic signs was seen in 4/30 (13.3%) of dogs. Volume of normal brain that received full dose at a prescription of 8Gy * 3 fractions was predictive of death due to neurological problems within this 6-month period. PMID- 25524451 TI - Yersinia enterocolitica type III secretion injectisomes form regularly spaced clusters, which incorporate new machines upon activation. AB - Bacterial type III secretion systems or injectisomes are multiprotein complexes directly transporting bacterial effector proteins into eukaryotic host cells. To investigate the distribution of injectisomes in the bacterium and the influence of activation of the system on that distribution, we combined in vivo fluorescent imaging and high-resolution in situ visualization of Yersinia enterocolitica injectisomes by cryo-electron tomography. Fluorescence microscopy showed the injectisomes as regularly distributed spots around the bacterial cell. Under secreting conditions (absence of Ca(2+) ), the intensity of single spots significantly increased compared with non-secreting conditions (presence of Ca(2+) ), in line with an overall up-regulation of expression levels of all components. Single injectisomes observed by cryo-electron tomography tended to cluster at distances less than 100 nm, suggesting that the observed fluorescent spots correspond to evenly distributed clusters of injectisomes, rather than single injectisomes. The up-regulation of injectisome components led to an increase in the number of injectisomes per cluster rather than the formation of new clusters. We suggest that injectisome clustering may allow more effective secretion into the host cells. PMID- 25524450 TI - Pathological response of locally advanced rectal cancer to preoperative chemotherapy without pelvic irradiation. AB - AIM: Pathological response to chemotherapy without pelvic irradiation is not well defined in rectal cancer. This study aimed to evaluate the objective pathological response to preoperative chemotherapy without pelvic irradiation in middle or low locally advanced rectal cancer (LARC). METHODS: Between 2008 and 2013, 22 patients with middle or low LARC (T3/4 and/or N+ and circumferential resection margin < 2 mm) and synchronous metastatic disease or a contraindication to pelvic irradiation underwent rectal resection after preoperative chemotherapy. The pathological response of rectal tumour was analysed according to the Rodel tumour regression grading (TRG) system. Predictive factors of objective pathological response (TRG 2-4) were analysed. RESULTS: All patients underwent rectal surgery after a median of six cycles of preoperative chemotherapy. Of these, 20 (91%) had sphincter saving surgery and an R0 resection. Twelve (55%) patients had an objective pathological response (TRG 2-4), including one complete response. Poor response (TRG 0-1) to chemotherapy was noted in 10 (45%) patients. In univariate analyses, none of the factors examined was found to be predictive of an objective pathological response to chemotherapy. At a median follow-up of 37.2 months, none of the 22 patients experienced local recurrence. Of the 19 patients with Stage IV rectal cancer, 15 (79%) had liver surgery with curative intent. CONCLUSION: Preoperative chemotherapy without pelvic irradiation is associated with objective pathological response and adequate local control in selected patients with LARC. Further prospective controlled studies will address the question of whether it can be used as a valuable alternative to radiochemotherapy in LARC. PMID- 25524452 TI - Teucrium polium phenylethanol and iridoid glycoside characterization and flavonoid inhibition of biofilm-forming Staphylococcus aureus. AB - The chemical composition and biofilm regulation of 15 metabolites from Teucrium polium are reported. Compounds were isolated from a CH2Cl2-MeOH extract of the aerial parts of the plant and included iridoid and phenylethanol glycosides and a monoterpenoid, together with nine known compounds. The structures were elucidated based on standard spectroscopic (UV, (1)H and (13)C NMR), 2D NMR ((1)H-(1)H COSY, HMQC, HMBC, and NOESY), and/or LC-ESIMS/MS data analyses. Inhibition of the biofilm-forming strain Staphylococcus aureus was observed with exposure to compounds 7 and 8. PMID- 25524453 TI - Evaluation of urinary tissue inhibitor of metalloproteinase-2 in acute kidney injury: a prospective observational study. AB - INTRODUCTION: Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an emerging acute kidney injury (AKI) biomarker. We evaluated the performance of urinary TIMP 2 in an adult mixed ICU by comparison with other biomarkers that reflect several different pathways of AKI. METHODS: In this study, we prospectively enrolled 98 adult critically ill patients who had been admitted to the adult mixed ICU. Urinary TIMP-2 and N-acetyl-beta-D-glucosaminidase (NAG) and plasma neutrophil gelatinase-associated lipocalin (NGAL), interleukin-6 (IL-6) and erythropoietin (EPO) were measured on ICU admission. We evaluated these biomarkers' capability of detecting AKI and its severity as determined by using the Kidney Disease Improving Global Outcomes serum creatinine criteria, as well as its capacity to predict in-hospital mortality. The impact of sepsis, the leading cause of AKI in ICUs, was also evaluated. RESULTS: We found AKI in 42 patients (42.9%). All biomarkers were significantly higher in AKI than in non-AKI. In total, 27 patients (27.6%) developed severe AKI. Urinary TIMP-2 was able to distinguish severe AKI from non-severe AKI with an area under the receiver operating characteristic curve (AUC-ROC) of 0.80 (95% confidence interval, 0.66 to 0.90). A total of 41 cases (41.8%) were complicated with sepsis. Although plasma NGAL and IL-6 were increased by sepsis, urinary TIMP-2 and NAG were increased not by sepsis, but by the presence of severe AKI. Plasma EPO was increased only by septic AKI. In-hospital mortality was 15.3% in this cohort. Urinary TIMP-2 and NAG, and plasma NGAL, were significantly higher in non-survivors than in survivors, although plasma IL-6 and EPO were not. Among the biomarkers, only urinary TIMP-2 was able to predict in-hospital mortality significantly better than serum creatinine. CONCLUSION: Urinary TIMP-2 can detect severe AKI with performance equivalent to plasma NGAL and urinary NAG, with an AUC-ROC value higher than 0.80. Furthermore, urinary TIMP-2 was associated with mortality. Sepsis appeared to have only a limited impact on urinary TIMP-2, in contrast to plasma NGAL. PMID- 25524454 TI - Epidemiology of pertussis in adolescents and adults in Turkey. AB - Two hundred and fourteen patients who had a cough illness lasting at least 2 weeks were studied to investigate Bordetella pertussis as a cause of prolonged cough in adolescents and adults. Medical history and nasopharyngeal swab specimens for culture and polymerase chain reaction (PCR) were obtained at presentation. Three (1.4%) patients were B. pertussis culture-positive; 15 (7%) were B. pertussis PCR-positive (including the culture-positive patients) and 11 (5.1%) were Bordetella spp. PCR-positive. Symptom combinations were significantly high both in patients with pertussis and patients with indeterminate results (P < 0.05). We conclude that B. pertussis should be considered among differential diagnoses of prolonged cough in adolescents and adults and PCR and culture should be used to detect these cases and facilitate public health response. PMID- 25524455 TI - Lateral canthotomy and cantholysis: emergency management of orbital compartment syndrome. AB - BACKGROUND: Orbital compartment syndrome is a sight-threatening emergency. Vision may be preserved when timely intervention is performed. OBJECTIVE: To present a case of orbital compartment syndrome caused by traumatic retrobulbar hemorrhage and the procedure of lateral canthotomy and cantholysis, reviewed with photographic illustration. DISCUSSION: Lateral canthotomy and cantholysis are readily performed at the bedside with simple instruments. The procedure may prevent irreversible blindness in cases of acute orbital compartment syndrome. CONCLUSIONS: Emergency physicians should be familiar with lateral canthotomy and cantholysis in the management of orbital compartment syndrome to minimize the chance of irreversible visual loss. PMID- 25524456 TI - Residue 146 regulates prolactin receptor folding, basal activity and ligand responsiveness: potential implications in breast tumorigenesis. AB - PRLR(I146L) is the first identified gain-of-function variant of the prolactin receptor (PRLR) that was proposed to be associated with benign breast tumorigenesis. Structural investigations suggested this hydrophobic core position in the extracellular D2 domain to be linked to receptor dimerization. Here, we used a mutational approach to address how the conservative I-to-L substitution induced constitutive activity. Using cell-based assays of different I146-PRLR variants in combination with spectroscopic/nuclear magnetic resonance analyses we found that chemical manipulation of position 146 profoundly altered folding, PRL responsiveness, and ligand-independent activity of the receptor in a mutation specific manner. Together, these data further add to the critical role of position 146, showing it to also be crucial to structural integrity thereby imposing on the biological PRLR properties. When stably introduced in MCF-7 (luminal) and MDA-MB231 (mesenchymal) breast cancer cells, the most potent of the PRL-insensitive mutants (PRLR(I146D)) had minimal impact on cell proliferation and cell differentiation status. PMID- 25524457 TI - Inactivation and identification of three genes encoding glycosyltransferase required for biosynthesis of nogalamycin. AB - Nogalamycin is an anthracycline antitumor antibiotic, consisting of the aromatic aglycone attached with a nogalose and a nogalamine. At present, the biosynthesis pathway of nogalamycin, especially the glycosylation mechanism of the two deoxysugar moieties, had still not been extensively investigated in vivo. In this study, we inactivated the three glycotransferase genes in the nogalamycin produced strain, and investigated the function of these genes by analyzing the metabolites profiles in the fermentation broth. The in-frame deletion of snogD and disruption of snogE abolished the production of nogalamycin completely, indicating that the gene products of snogD and snogE are essential to the biosynthesis of nogalamycin. On the other hand, in-frame deletion of snogZ does not abolish the production of nogalamycin, but production yield was reduced to 28% of the wild type, implying that snogZ gene may involved in the activation of other glycotransferases in nogalamycin biosynthesis. This study laid the foundation of modification of nogalamycin biosynthesis/production by genetic engineering methods. PMID- 25524458 TI - Survival outcomes for patients with stage IVB vulvar cancer with grossly positive pelvic lymph nodes: time to reconsider the FIGO staging system? AB - OBJECTIVE: To evaluate treatment outcomes for patients with vulvar cancer with grossly positive pelvic lymph nodes (PLNs). METHODS: From a database of 516 patients with vulvar cancer, we identified patients with grossly positive PLNs without distant metastasis at initial diagnosis. We identified 20 patients with grossly positive PLNs; inclusion criteria included PLN 1.5cm or larger in short axis dimension on CT/MRI (n=11), FDG-avid PLN on PET/CT (n=3), or biopsy-proven PLN disease (n=6). Ten patients were treated with chemoradiation therapy (CRT), 4 with RT alone, and 6 with various combinations of surgery, RT or CRT. Median follow-up time for patients who had not died of cancer was 47months (range, 4 228months). RESULTS: Mean primary vulvar tumor size was 6.4cm; 12 patients presented with 2009 AJCC T2 and 8 with T3 disease. All patients had grossly positive inguinal nodes, and the mean inguinal nodal diameter was 2.8cm. The 5 year overall survival and disease specific survival rates were 43% and 48%, respectively. Eleven patients had recurrences, some at multiple sites. There were 9 recurrences in the vulva, but no isolated nodal recurrences. Four patients developed distant metastasis within 6months of starting radiation therapy. CONCLUSIONS: Aggressive locoregional treatment can lead to favorable outcomes for many patients with grossly involved PLNs that is comparable to that of grossly involved inguinal nodes only. We recommend modification of the FIGO stage IVB classification to more accurately reflect the relatively favorable prognosis of patients with PLN involvement. PMID- 25524459 TI - Can malignant potential of endometrial polyps be determined by incorporating the endometrial intraepithelial neoplasia (EIN) classification? AB - OBJECTIVE: The reported frequency of malignant or premalignant changes confined to endometrial polyps (EP) is 0.5-6%. The management of atypical endometrial hyperplasia (AEH) confined to EP is not yet established. Recently, an alternative pathological nomenclature has emerged using the term endometrial intraepithelial neoplasia (EIN) instead of atypia. The objective of this study was to evaluate the safety of conservative hysteroscopic resection of endometrial polyps with AEH or EIN. METHODS: Retrospective cohort study of all cases of hysteroscopic resections of EP was performed at a single center between the years 2000-2011. All patients with a pathologic diagnosis of AEH in EP were included. A post-hoc revision of the pathologic specimens was made according to the EIN classification. RESULTS: Of the 32 patients with AEH in EP, 25 had normal endometrial curetting. Even with AEH confined to EP, 12 cases (48%) showed AEH (11 cases) or carcinoma (1 case) in the hysterectomy specimens. EIN in EP (14 cases) was correlated with 57% of diagnosis of EIN or carcinoma in the uterus; whereas in the absence of EIN in EP only 1 of 9 cases showed EIN in the final pathologic specimen (p=0.002), and none with carcinoma, which yields a PPV of 14% and a NPV of 100%. CONCLUSION: The diagnosis of EIN in EP may be a better predictor than AEH for endometrial involvement with malignant or pre-malignant neoplasms. The safety of conservative hysteroscopic resection of EP with AEH/EIN is questioned. PMID- 25524461 TI - Microfluidic vapor-diffusion barrier for pressure reduction in fully closed PCR modules. AB - Microfluidic systems for polymerase chain reaction (PCR) should be fully closed to avoid vapor loss and to exclude the risk of contaminating the laboratory environment. In closed systems however, the high temperatures of up to 95 degrees C associated with PCR cause high overpressures up to 100 kPa, dominated by the increase of vapor partial pressure upon evaporation. Such high overpressures pose challenges to the mechanical stability of microfluidic chips as well as to the liquid handling in integrated sample-to-answer systems. In this work, we drastically reduce the pressure increase in fully closed PCR systems by integrating a microchannel that serves as a vapor-diffusion barrier (VDB), separating the liquid-filled PCR chamber from an auxiliary air chamber. In such configurations, propagation of vapor from the PCR chamber into the auxiliary air chamber and as a consequence the increase of pressure is limited by the slow diffusion process of vapor through the VDB. At temperature increase from 23 degrees C to 95 degrees C, we demonstrate the reduction of overpressure from more than 80 kPa without the VDB to only 35 kPa with the VDB. We further demonstrate proper function of VDB and its easy integration with downstream processes for PCR based nucleic acid amplification within centrifugal microfluidics. Without integration of the VDB, malfunction due to pressure induced delamination of the microfluidic chip occurred. PMID- 25524460 TI - Fluorination of metal phthalocyanines: single-crystal growth, efficient N-channel organic field-effect transistors, and structure-property relationships. AB - The fluorination of p-type metal phthalocyanines produces n-type semiconductors, allowing the design of organic electronic circuits that contain inexpensive heterojunctions made from chemically and thermally stable p- and n-type organic semiconductors. For the evaluation of close to intrinsic transport properties, high-quality centimeter-sized single crystals of F16CuPc, F16CoPc and F16ZnPc have been grown. New crystal structures of F16CuPc, F16CoPc and F16ZnPc have been determined. Organic single-crystal field-effect transistors have been fabricated to study the effects of the central metal atom on their charge transport properties. The F16ZnPc has the highest electron mobility (~1.1 cm(2) V(-1) s( 1)). Theoretical calculations indicate that the crystal structure and electronic structure of the central metal atom determine the transport properties of fluorinated metal phthalocyanines. PMID- 25524462 TI - Genetic background of mice strongly influences treatment resistance in the 6 Hz seizure model. AB - OBJECTIVE: The 6 Hz model of focal seizures has been increasingly used to identify anticonvulsant compounds with potential activity against therapy resistant epilepsy, but the protective response to anticonvulsants in this model could be dependent on experimental conditions and selection of mouse strains. METHODS: Seizure thresholds in the 6 Hz model were compared in CF-1, NMRI, and C57Bl/6J male mice with two different electrical stimulators (Ugo Basile 5780 and Grass S48). Dose-response curves for phenytoin and levetiracetam were generated in the three strains at 32 and 44 mA current intensities using both devices. Plasma and brain exposure to the two drugs were measured in all three strains. RESULTS: CF-1 mice had the lowest seizure threshold and responded to phenytoin at 32 mA stimulation intensity, but not at 44 mA. NMRI and C57Bl/6J mice had nearly identical threshold values, but NMRI mice responded well to phenytoin at 32 mA and showed limited responsiveness to this drug at 44 mA, whereas C57Bl/6J mice were nearly completely resistant to phenytoin. Furthermore, levetiracetam showed limited efficacy and low potency in CF-1 and C57Bl/6J mice, particularly at 44 mA, whereas in NMRI mice the drug showed much higher potency in all experimental conditions. No obvious difference in the pharmacokinetics of both phenytoin and levetiracetam was detected between the mouse strains that would have explained these unexpected variations in potency. We have also found that the protective effects of both drugs may be influenced by the device type. SIGNIFICANCE: Collectively these observations clearly indicate that treatment resistance of 6 Hz seizures should be interpreted with strain and experimental conditions in mind. Furthermore, it is important to note that strain differences, much like human genetic differences, may explain why some mice and patients respond to a given treatment and others do not. PMID- 25524463 TI - Skin cancer risk in BRCA1/2 mutation carriers. AB - Women with BRCA1/2 mutations have an elevated risk of breast and ovarian cancer. These patients and their clinicians are often concerned about their risk for other cancers, including skin cancer. Research evaluating the association between BRCA1/2 mutations and skin cancer is limited and has produced inconsistent results. Herein, we review the current literature on the risk of melanoma and nonmelanoma skin cancers in BRCA1/2 mutation carriers. No studies have shown a statistically significant risk of melanoma in BRCA1 families. BRCA2 mutations have been linked to melanoma in large breast and ovarian cancer families, though a statistically significant elevated risk was reported in only one study. Five additional studies have shown some association between BRCA2 mutations and melanoma, while four studies did not find any association. With respect to nonmelanoma skin cancers, studies have produced conflicting results. Given the current state of medical knowledge, there is insufficient evidence to warrant increased skin cancer surveillance of patients with a confirmed BRCA1/2 mutation or a family history of a BRCA1/2 mutation, in the absence of standard risk factors. Nonetheless, suspected BRCA1/2 mutation carriers should be counselled about skin cancer risks and may benefit from yearly full skin examinations. PMID- 25524465 TI - Pituitary stalk interruption syndrome presenting as short stature: a case report. AB - INTRODUCTION: Pituitary stalk interruption syndrome is a rare congenital abnormality of the pituitary that is responsible for anterior pituitary deficiency. It is characterized by a classic triad of interrupted pituitary stalk, absent or ectopic posterior pituitary, and anterior pituitary hypoplasia or aplasia. Clinical presentation varies according to age. In adults it presents as short stature and anterior pituitary deficiency. Without early diagnosis and treatment, mortality and morbidity in these patients is high. Early diagnosis and treatment of this rare disease can prevent permanent short statue of the patient. We report the first case of pituitary stalk interruption syndrome from Pakistan. CASE PRESENTATION: A 17-year-old Pakistani young man presented with short stature and underdeveloped secondary sexual characters. His siblings and parents were healthy, with normal height. An examination showed his blood pressure was 90/60 mmHg, and his height, weight, and body mass index were 142 cm, 34.5 kg, and 17.10 kg/m2, respectively. He had no hair growth on his face, axilla, or pubis. His testes were between 1 and 2 mL in size, with a 4 cm-at-stretch micropenis. His lab investigations showed that his thyroid stimulating hormone (TSH) was 8.58 uIU/mL (0.4 to 4.2), his free thyroid hormone level FT4 was 0.46 ng/dL (0.89 to 1.76), his prolactin was 21.1 ng/mL (3.0 to 14.7), and his baseline cortisol was 0.30 ug/dL (4.3 to 22.4). His cortisol level after 60 minutes of cosyntropin injection was 3.5 ug/dL (4.3 to 22.4), his insulin like growth factor IGF-1 was 31.56 ng/mL (247.3 to 481.7), his testosterone level was under 2.5 ng/dL (2 to 800), his follicle stimulating hormone FSH was 0.41 uIU/mL (0.0 to 10.0), and his leutinizing hormone LH was under 0.1 uIU/mL (1.2 to 7.8). His bone age was 10 years according to the Greulich and Pyle method, as shown by X-rays. The results from his pituitary magnetic resonance imaging scan were consistent with pituitary stalk interruption syndrome. CONCLUSIONS: We describe a young man who presented with short stature and was found to have pituitary stalk interruption syndrome. Despite the fact that this is a rare disorder, it should always be kept in the differential diagnosis of a patient presenting with short stature. Patients with this disease have an excellent opportunity to reach normal height if they present before the joining of epiphyses. PMID- 25524464 TI - Response of recurrent BRAFV600E mutated ganglioglioma to Vemurafenib as single agent. AB - BACKGROUND: Ganglioglioma (GG) and pilocytic astrocytoma (PA) represent the most frequent low-grade gliomas (LGG) occurring in paediatric age. LGGs not amenable of complete resection (CR) represent a challenging subgroup where traditional treatments often fail. Activation of the MAP Kinase (MAPK) pathway caused by the BRAFV600E mutation or the KIAA1549-BRAF fusion has been reported in pediatric GG and PA, respectively. CASE PRESENTATION: We report on a case of BRAFV600E mutated cervicomedullary GG treated with standard chemotherapy and surgery. After multiple relapse, BRAF status was analyzed by immunohistochemistry and sequencing showing a BRAFV600E mutation. Treatment with Vemurafenib as single agent was started. For the first time, a radiological and clinical response was obtained after 3 months of treatment and sustained after 6 months. CONCLUSION: Our experience underline the importance of understanding the driver molecular alterations of LGG and suggests a role for Vemurafenib in the treatment of pediatric GG not amenable of complete surgical resection. PMID- 25524466 TI - Pretreatment maximum standardized uptake value of (18)F-fluorodeoxyglucose positron emission tomography as a predictor of distant metastasis in adenoid cystic carcinoma of the head and neck. AB - BACKGROUND: The purpose of this study was to determine whether the maximum standardized uptake value (SUVmax) of the primary tumor on pretreatment (18)F fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) has prognostic significance in patients with adenoid cystic carcinoma (ACC) of the head and neck. METHODS: A retrospective review was carried out on 34 patients with ACC of the head and neck who underwent pretreatment (18)F-FDG PET imaging from June 2005 through July 2009. All patients underwent surgery with curative intent, and 26 of them received adjuvant radiotherapy (RT). RESULTS: When subjects were stratified into 2 groups according to a cutoff value for SUVmax of 4.15, the risk of distant metastasis was significantly high in patients with high SUVmax (p = .014). Multivariate analysis showed that high SUVmax and histologic grade 3 were independent poor prognostic factors for distant metastasis-free and disease-free survival. CONCLUSION: Pretreatment SUVmax of the primary tumor is an independent prognostic factor in patients with ACC of the head and neck. PMID- 25524467 TI - First Polish experience in follow-up care of a patient with a subcutaneous cardioverter-defibrillator (S-ICD). PMID- 25524469 TI - Biospecimen repositories and cytopathology. AB - Biospecimen repositories are important for the advancement of biomedical research. Literature on the potential for biobanking of fine-needle aspiration, gynecologic, and nongynecologic cytology specimens is very limited. The potential for biobanking of these specimens as valuable additional resources to surgically excised tissues appears to be excellent. The cervicovaginal specimens that can be used for biobanking include Papanicolaou-stained monolayer preparations and residual material from liquid-based cytology preparations. Different types of specimen preparations of fine-needle aspiration and nongynecologic specimens, including Papanicolaou-stained and Diff-Quik-stained smears, cell blocks. and dedicated passes/residual material from fine-needle aspiration stored frozen in a variety of solutions, can be used for biobanking. Because of several gaps in knowledge regarding the standard of operative procedures for the procurement, storage, and quality assessment of cytology specimens, further studies as well as national conferences and workshops are needed not only to create awareness but also to facilitate the use of cytopathology specimens for biobanking. PMID- 25524470 TI - Deferoxamine inhibits TRAIL-mediated apoptosis via regulation of autophagy in human colon cancer cells. AB - Deferoxamine (DFO), an iron chelator, has numerous clinical applications for patients presenting with iron overload in regards to the improvement in the quality of life and overall survival. In addition, experimental iron chelators have demonstrated potent anticancer properties. The present study investigated the effects of DFO on TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in colon cancer cells and and the mechanism involved. The experimental results showed that DFO treatment inhibited TRAIL-mediated cancer cell apoptosis by increasing Akt activation and decreasing caspase activation in human colon cancer cells. Furthermore, DFO treatment induced autophagy flux, and chloroquine, an autophagy inhibitor, blocked DFO-mediated inhibition of TRAIL-induced apoptosis. The present study demonstrated that DFO inhibited TRAIL-mediated tumor cell death via the autophagy pathway, and the results suggest that potent anticancer agent, DFO, can be an inhibitor against antitumor therapy including TRAIL protein. PMID- 25524471 TI - Yoga, as a transitional platform to more active lifestyle: a 6-month pilot study in the USA. AB - A 6-month pilot study explored the effects of a yoga program on the physical activity (PA) level of overweight or obese sedentary adults. Fourteen community dwelling overweight or obese sedentary adults participated in a 6-month program (2-month yoga program and 4-month follow-up) delivered by two types of instruction [the direct guidance of an instructor (face-to-face group) vs. the self-learning method of using a DVD (DVD group)]. Measurements included program adherence (class attendance and home practice; min/week) and level of PA [metabolic equivalent (MET)-hour/week] at baseline, 2, 4 and 6 months. Descriptive statistics and nonparametric tests were used to describe the sample and examine differences by group and time. There were no significant differences in demographic variables by group assigned. Participants showed significant PA changes from baseline to each measurement point. The direct guidance of an instructor was preferred over the self-learning method. At each time interval, the DVD group showed higher levels of PA than the face-to-face group; the only difference that achieved statistical significance occurred at 4 months. The PA level significantly changed over 6 months in the DVD group, but not in the face to-face group. The results indicate that a yoga program may be utilized as a 'stepping-stone' toward regular exercise among overweight sedentary adults. Research with a larger sample is needed to further evaluate the effects of the program on the level of PA among this population. PMID- 25524468 TI - Comparison of methods for the analysis of therapeutic immunoglobulin G Fc glycosylation profiles--part 1: separation-based methods. AB - Immunoglobulin G (IgG) crystallizable fragment (Fc) glycosylation is crucial for antibody effector functions, such as antibody-dependent cell-mediated cytotoxicity, and for their pharmacokinetic and pharmacodynamics behavior. To monitor the Fc-glycosylation in bioprocess development, as well as product characterization and release analytics, reliable techniques for glycosylation analysis are needed. A wide range of analytical methods has found its way into these applications. In this study, a comprehensive comparison was performed of separation-based methods for Fc-glycosylation profiling of an IgG biopharmaceutical. A therapeutic antibody reference material was analyzed 6-fold on 2 different days, and the methods were compared for precision, accuracy, throughput and other features; special emphasis was placed on the detection of sialic acid-containing glycans. Seven, non-mass spectrometric methods were compared; the methods utilized liquid chromatography-based separation of fluorescent-labeled glycans, capillary electrophoresis-based separation of fluorescent-labeled glycans, or high-performance anion exchange chromatography with pulsed amperometric detection. Hydrophilic interaction liquid chromatography ultra high performance liquid chromatography of 2-aminobenzamide (2-AB)-labeled glycans was used as a reference method. All of the methods showed excellent precision and accuracy; some differences were observed, particularly with regard to the detection and quantitation of minor glycan species, such as sialylated glycans. PMID- 25524472 TI - Perceived vulnerability and HIV testing among youth in Cape Town, South Africa. AB - The importance of perceived vulnerability to risk-reducing behaviors, including HIV testing, is fairly established, especially among youth in sub-Saharan Africa. Yet, the majority of studies that examined this important relationship used cross sectional data that inherently assume that perceived vulnerability does not change. While these studies have been useful, the assumption of perceived vulnerability as time invariant is a major flaw and has largely limited the practical usefulness of this variable in AIDS prevention and programing. Using longitudinal data and applying random-effects logit models, this study makes a major contribution to scholarship by examining if changes in perceived vulnerability associate with a change to test for HIV among 857 young people in Cape Town, South Africa. Results show that female youth who changed their risk perceptions were more likely to also change to test for HIV, but the effects were completely attenuated after controlling for theoretically relevant variables. No significant relationships were observed for males. Also, females who were virgins at wave 2 but had sex between waves were significantly more likely to have changed to test for HIV. Of most importance was that sexual behavior eliminated the effects of change in risk perceptions suggesting that a change in perception may have occurred as a result of changes in sexual behavior. AIDS prevention programs must pay particular attention to helping youth become aware of their vulnerability to HIV risks, especially as these have implications for risk reducing behaviors, especially for females who are burdened. PMID- 25524473 TI - Participatory photography gives voice to young non-drivers in New Zealand. AB - Youth have the highest crash injury risk in New Zealand. Maori and Pacific youth have an even higher risk. Highlighting and promoting benefits of modal shift from cars to active and public transport may increase health and safety. We aimed to create a discussion surrounding transport issues to gain a better understanding of attitudes and behaviours of non-driving youth, to empower our participants and to promote health and social change by making participants' opinions and experiences known to the broader community through a public exhibition. We engaged nine non-drivers aged 16-24 years in photovoice. Through sharing their photos and stories, participants used the power of the visual image to communicate their experiences. This method is an internationally recognized tool that reduces inequalities by giving those who have minimal decision-making power an opportunity to share their voice. By the end of the project, it was clear that the participants were comfortable with their non-driving status, noting that public and active transport was more cost-effective, easy and convenient. This attitude reflects recent studies showing a marked decrease in licensure among young people in developed countries. This project uniquely prioritized young Maori, Pacific and Asian non-drivers. PMID- 25524474 TI - Permissiveness toward tobacco sponsorship undermines tobacco control support in Africa. AB - School personnel, who are respected members of the community, may exert significant influence on policy adoption. This study assessed the impact of school personnel's permissiveness toward tobacco industry sponsorship activities on their support for complete bans on tobacco advertisements, comprehensive smoke free laws and increased tobacco prices. Representative data were obtained from the Global School Personnel Survey for 29 African countries (n = 17 929). Adjusted prevalence ratios (aPR) were calculated using multi-variable Poisson regression models to assess the impact of permissiveness toward tobacco sponsorship activities on support for tobacco control policies (p < 0.05). The median of prevalence of support for different tobacco control policies among all countries was as follows: complete ban on tobacco advertisements (84.9%); comprehensive smoke-free laws (92.4%) and tobacco price increases (80.8%). School personnel who believed that the tobacco industry should be allowed to sponsor school events were significantly less likely to support complete bans on tobacco advertisements [aPR = 0.89; 95% confidence interval (CI) 0.84-0.95] and comprehensive smoke-free laws (aPR = 0.95; 95% CI 0.92-0.98). In contrast, support for complete tobacco advertisement bans was more likely among those who believed that the tobacco industry encourages youths to smoke (aPR = 1.27; 95% CI 1.17-1.37), and among those who taught about health sometimes (aPR = 1.06; 95% CI 1.01-1.11) or a lot (aPR = 1.05; 95% CI 1.01-1.10) compared with those who did not teach about health at all. These findings underscore the need to educate school personnel on tobacco industry's strategies to undermine tobacco control policies. This may help to build school personnel support for laws intended to reduce youth susceptibility, experimentation and established use of tobacco products. PMID- 25524475 TI - Quality assessment of modeled protein structure using physicochemical properties. AB - Physicochemical properties of proteins always guide to determine the quality of the protein structure, therefore it has been rigorously used to distinguish native or native-like structure from other predicted structures. In this work, we explore nine machine learning methods with six physicochemical properties to predict the Root Mean Square Deviation (RMSD), Template Modeling (TM-score), and Global Distance Test (GDT_TS-score) of modeled protein structure in the absence of its true native state. Physicochemical properties namely total surface area, euclidean distance (ED), total empirical energy, secondary structure penalty (SS), sequence length (SL), and pair number (PN) are used. There are a total of 95,091 modeled structures of 4896 native targets. A real coded Self-adaptive Differential Evolution algorithm (SaDE) is used to determine the feature importance. The K-fold cross validation is used to measure the robustness of the best predictive method. Through the intensive experiments, it is found that Random Forest method outperforms over other machine learning methods. This work makes the prediction faster and inexpensive. The performance result shows the prediction of RMSD, TM-score, and GDT_TS-score on Root Mean Square Error (RMSE) as 1.20, 0.06, and 0.06 respectively; correlation scores are 0.96, 0.92, and 0.91 respectively; R(2) are 0.92, 0.85, and 0.84 respectively; and accuracy are 78.82% (with +/- 0.1 err), 86.56% (with +/- 0.1 err), and 87.37% (with +/- 0.1 err) respectively on the testing data set. The data set used in the study is available as supplement at http://bit.ly/RF-PCP-DataSets. PMID- 25524476 TI - An "enigmatic" L-carnosine (beta-alanyl-L-histidine)? Cell proliferative activity as a fundamental property of a natural dipeptide inherent to traditional antioxidant, anti-aging biological activities: balancing and a hormonally correct agent, novel patented oral therapy dosage formulation for mobility, skeletal muscle power and functional performance, hypothalamic-pituitary- brain relationship in health, aging and stress studies. AB - Hypothalamic releasing and inhibiting hormones are major neuroendocrine regulators of human body metabolism being driven directly to the anterior pituitary gland via hypothalamic-hypophyseal portal veins. The alternative physiological or therapeutic interventions utilizing the pharmaco-nutritional boost of imidazole-containing dipeptides (non-hydrolized oral form of carnosine, carcinine, N-acetylcarnosine lubricant eye drops) can maintain health, enhance physical exercise performance and prevent ageing. Carnosine (beta-alanyl-L histidine) is synthesized in mammalian skeletal muscle. There is an evidence that the release of carnosine from the skeletal muscle sarcomeres moieties during physical exercise affects autonomic neurotransmission and physiological functions. Carnosine released from skeletal muscle during exercise acts as a powerful afferent physiological signaling stimulus for hypothalamus, may be transported into the hypothalamic tuberomammillary nucleus (TMN), specifically to TMN-histamine neurons and hydrolyzed herewith via activities of carnosine degrading enzyme (carnosinase 2) localized in situ. Through the colocalized enzymatic activity of Histidine decarboxylase in the histaminergic neurons, the resulting L-histidine may subsequently be converted into histamine, which could be responsible for the effects of carnosine on neurotransmission and physiological function. Carnosine and its imidazole-containing dipeptide derivatives are renowned for their anti-aging, antioxidant, membrane protective, metal ion chelating, buffering, anti-glycation/ transglycating activities used to prevent and treat a spectrum of age-related and metabolic diseases, such as neurodegenerative disease, sight threatening eye diseases, Diabetes mellitus and its complications, cancers and other disorders due to their wide spectrum biological activities. The precursor of carnosine (and related imidazole containing compounds) synthesis in skeletal muscles beta-alanine is used as the oral supplement by athletes to achieve the fine sporting art results due to the buffering activities of carnosine and its related imidazole- containing compounds which contribute to the maintenance of the acid-base balance in the acting muscles. This work originally emphasizes that overall data indicate the signaling activities of carnosine in skeletal and cardiac muscles switching on the mechanisms of exercise-induced telomere protection and point to the stress response and growth/cellular proliferation pathways as high-priority candidates for the ongoing studies and therapeutic concepts. The therapeutic interventions utilizing the specific oral formulation (Can-C Plus), timing dosing and pharmaco nutritional boost of imidazolecontaining dipeptides can maintain health, enhance physical exercise performance and prevent aging. The patented therapeutic concept protects the existence of the interesting physiological major activities, better controls and therapeutic treatments for aging/age-related disorders (including age-related loss of muscle mass and muscle function) using carnosine dipeptide for cellular rejuvenation and manipulating telomeres and enzyme telomerase activity that may reduce some of the physiological declines that accompany aging. PMID- 25524477 TI - A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival. AB - BACKGROUND: Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib. PATIENTS AND METHODS: This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib. RESULTS: A total of 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum lactate dehydrogenase (LDH; <= versus >upper normal limit; P = 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall performance status (OPS) (0 versus >= 1; P = 0.00089), and BRAF mutation subtype (V600E versus V600K; P = 0.016). Multivariate analysis identified ECOG OPS >= 1 [hazard ratio (HR) = 1.88; P = 0.00005], immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012), ECOG OPS >= 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P = 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014), immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95% confidence interval 0.50-0.98; P = 0.039) were found as predictors. CONCLUSION: Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patient's OPS, serum LDH, age, and gender independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients. PMID- 25524479 TI - The failure of figitumumab: the danger of taking shortcuts in drug development. PMID- 25524478 TI - A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer. AB - BACKGROUND: The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan isoform inhibitor of PI3K. A phase I trial demonstrated tolerability of this combination. This randomized phase II study evaluated PX-866 combined with cetuximab in patients with advanced, refractory HNSCC. METHODS: Patients with recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1 : 1) to cetuximab with or without PX-866 (8 mg p.o. daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS), toxicity, and correlation of key biomarkers with efficacy outcomes. RESULTS: Eighty-three patients were enrolled. There was a similar response rate between arms (10% versus 7%). Of patients for whom tissue was assessable, 57% were human papillomavirus (HPV) positive. Median PFS was 80 days in both arms and there was no difference in OS between the two arms (211 versus 256 days). Overall toxicity was higher in arm A compared with arm B, especially in terms of nausea (53% versus 23%), vomiting (45% versus 15%), fatigue (43% versus 23%), diarrhea (40% versus 21%), and hypokalemia (25% versus 10%). Grade 3 or higher adverse events were infrequent, but more common in the combination arm although without a specific pattern. PIK3CA mutations were observed in 17% of the cases assessed, and PTEN loss was infrequently observed. CONCLUSION: The addition of PX-866 to cetuximab did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC enrolled without molecular preselection. In this contemporary cohort, HPV-positive patients comprised the majority, and neither HPV-positive nor HPV-negative patients derived clinical benefit for the addition of cetuximab plus PX-866. PMID- 25524480 TI - Functional outcome of supratrigonal cystectomy and augmentation ileocystoplasty in adult patients with refractory neurogenic lower urinary tract dysfunction. AB - AIMS: To investigate the functional outcome after supratrigonal cystectomy and augmentation ileocystoplasty in adult patients with refractory neurogenic lower urinary tract dysfunction (NLUTD). METHODS: Retrospective follow-up investigation in a single spinal cord injury rehabilitation center. In 29 patients, urodynamic data before and after supratrigonal cystectomy and augmentation ileocystoplasty, clinical outcome and post-operative complications were evaluated. RESULTS: The median age of the 29 patients at the time of surgery was 31 years, a median 14 years after NLUTD had occurred. At the last follow-up visit (median 2.4, range 0.4-9.0 years post-operatively), 20/29 patients (69%) were continent compared to 2/29 pre-operatively (P = 0.001). Furthermore, 16 patients required no or less detrusor relaxation therapy after augmentation ileocystoplasty. Augmentation cystoplasty resulted in a significant (P = 0.001) increase in the median bladder capacity (from 240 ml to 500 ml) and compliance (from 13 ml/cm H2 O to 50 ml/cm H2 O). The median maximum detrusor pressure had decreased significantly (P = 0.001) from 38 cm H2 O to 15 cm H2 O. Significantly (P = 0.001) fewer patients presented with a risk for renal damage (1 vs. 15 with maximum detrusor pressure >40 cm H2 O and 1 vs. 12 with detrusor compliance <20 ml/cm H2 O) at the last follow-up. The following complications were observed in 11/29 (38%) patients: paralytic and obstructive ileus, impaired bowel function, bladder stones, dehiscence, metabolic acidosis and autonomic dysreflexia. CONCLUSIONS: Protection of renal function, adequate bladder capacity and low detrusor pressure can be achieved using supratrigonal cystectomy and augmentation ileocystoplasty in patients suffering from refractory NLUTD. PMID- 25524481 TI - A comparison of high viscosity bone cement and low viscosity bone cement vertebroplasty for severe osteoporotic vertebral compression fractures. AB - OBJECTIVE: To compare the clinical outcome and complications of high viscosity and low viscosity poly-methyl methacrylate bone cement PVP for severe OVCFs. METHODS: From December 2010 to December 2012, 32 patients with severe OVCFs were randomly assigned to either group H using high viscosity cement (n=14) or group L using low viscosity cement (n=18). The clinical outcomes were assessed by the Visual Analog Scale (VAS), Oswestry Disability Index (ODI), Short Form-36 General Health Survey (SF-36), kyphosis Cobb's angle, vertebral height, and complications. RESULTS: Significant improvement in the VAS, ODI, SF-36 scores, kyphosis Cobb's angle, and vertebral height were noted in both the groups, and there were no significant differences between the two groups. Cement leakage was seen less in group H. Postoperative assessment using computed tomography identified cement leakage in 5 of 17 (29.4%) vertebrae in group H and in 15 of 22 (68.2%) vertebrae in group L (P=0.025). CONCLUSIONS: The PVP using high viscosity bone cement can provide the same clinical outcome and fewer complications compared with PVP using low viscosity bone cement. PMID- 25524482 TI - Preoperative MRI in neurovascular compression syndromes and its role for microsurgical considerations. AB - BACKGROUND: Neurovascular compression (NVC) in the posterior fossa is characterized by complex, three-dimensional (3D) neurovascular relationships at the root entry zones (REZ) and other parts of cranial nerves, resulting in syndromes such as trigeminal neuralgia (TN), hemifacial spasm, vertigo and glossopharyngeal neuralgia. Microvascular decompression (MVD) requires microsurgical experience and 3D orientation within the cisternal spaces to achieve adequate clinical results. The vascular structures in anatomical relation to the trigeminal nerve root at the lateral pontine aspect of the brainstem should be examined and maximally decompressed to minimize the risk of recurrent TN. Indication was traditionally based on clinical decisions, only. New MR techniques have become available, and their chances and potential impact should be evaluated in this study. METHODS: In our study we examined 7 consecutive patients with TN and one patient with vertigo analyzing the details of NVC with high resolution magnetic resonance (MR) imaging in correlation to the intraoperative findings. All 8 patients underwent 1.5 T MRI with T2 fast spin echo. The MRI data were retrospectively analyzed and compared to the intraoperative findings with the focus on the length of the corresponding cranial nerve and topography of the NVC site, the distance of the location of the NVC from the surface of the brainstem. RESULTS: The superior cerebellar artery (SCA) was the most common causative vessel in 5 of 8 cases (62.5%), the anterior inferior cerebellar artery (AICA) in 2 of 8 cases (25%) and veins in 1 of 8 cases (12.5%). The cisternal length of the examined trigeminal nerve on the high resolution MR images at the affected side ranged from 8.1mm to 10.8mm and on the unaffected contralateral sides from 9.4mm to 11.4mm. The vestibular nerve in one vertigo patient had an equal cisternal length of 18.0mm on either side, whereas the distance of the neurovascular conflict site was 8.0mm from the surface of the flocculus. The distance of the neurovascular conflict location site to the brainstem ranged from 1.4mm to 8.5mm on the reviewed MR image slices. One patient with vertigo showed an AICA loop in the MR images, which was confirmed intraoperatively. All causative vessels on the trigeminal nerve performed loops from cranially to caudally. All 7 patients (100%) with TN and one vertigo patient were symptom-free since discharge. CONCLUSION: We show that high resolution MR images provide reliable and detailed information on corresponding intraoperative anatomy. Especially in unusual cases, the application of such MR techniques and preoperative evaluation may contribute to indication, planning, and also for teaching purposes. PMID- 25524483 TI - Vestibular schwannoma between 1 and 3 cm: importance of the tumor size in surgical and functional outcome. AB - OBJECTIVE: The aim of the study was to compare the surgical and functional outcomes of the microsurgical osteoplastic retro-sigmoid approach in a semi sitting position in two groups of patients with vestibular schwannomas (VSs) ranging from 1 to 3 cm in size. METHOD: A 5-year retrospective evaluation was made of these two groups of patients with VS: Patients with VS sizes 1-<2 cm in maximal intra/extrameatal diameter (n=292) were assigned to group "A" and a matched group of patients with VS between 2 and 3 cm in size (n=154) were assigned to group "B". RESULTS: Significant differences in postoperative outcomes (p<0.05) were found for facial nerve function of House-Brackmann grade I (94% group A vs. 78% group B) and preservation of preoperative hearing (51% group B vs. 34% group A). Patients with tumors sizes ranging between 1 and <2 cm exhibited total tumor removal with significantly higher facial nerve preservation and hearing function preservation rates compared with patients with tumors 2-3 cm in size. CONCLUSION: Even a small increase in tumor size correlated with a significant reduction in good hearing and facial preservation postoperatively, which implies that tumor removal should be performed at the earliest stage possible. Furthermore, these results contradict recommending the wait-and-see approach for intra/extrameatal tumors. PMID- 25524484 TI - Influence of cachexia and sarcopenia on survival in pancreatic ductal adenocarcinoma: a systematic review. AB - BACKGROUND/OBJECTIVES: Cachexia affects ~ 80% of pancreatic cancer patients. An international consensus defines cachexia as an ongoing loss of skeletal muscle mass (sarcopenia) with or without loss of fat, which impairs body functioning and cannot be reversed by conventional nutritional measures. Weight loss percentage and elevated inflammation markers have been employed to define this condition earlier. This review aimed to assess the prevalence and consequences of cachexia and sarcopenia on survival in patients with pancreatic ductal adenocarcinoma. METHODS: The systematic review was performed by searching the articles with preset terms published in PubMed and Cochrane Database until December 2013. After identifying relevant titles, abstracts were read and eligible articles data retrieved on preformatted sheets. The prevalence and impact of sarcopenia/cachexia on survival was evaluated. RESULTS: In total 1145 articles were retrieved, only 10 were eligible. Definitions of cachexia and sarcopenia were heterogeneous. In patients with normal weight (BMI 18.5-24.9 kg/m(2)) the prevalence of sarcopenia ranged from 29.7 to 65%. In overweight or obese patients (BMI >25 kg/m(2)) were 16.2%-67%. Sarcopenia alone was not demonstrated to be an independent factor of decreased survival, although obese sarcopenic patients were shown to have significantly worse survival in two studies. CONCLUSIONS: Impact of cachexia and sarcopenia on survival in pancreatic ductal adenocarcinoma is currently understudied in the available literature. Definitive association between cachexia and survival cannot be drawn from available studies, although weight loss and sarcopenic obesity might be considered as poor prognostic factors. Further prospective trials utilizing the consensus definition of cachexia and including other confounding factors are needed to investigate the impact of cachexia and sarcopenia on survival in pancreatic adenocarcinoma. PMID- 25524485 TI - Type 1 autoimmune pancreatitis with histologically proven granulocytic epithelial lesions. AB - There are two distinct subtypes of autoimmune pancreatitis (AIP): type 1 and type 2. Type 1 AIP is the pancreatic manifestation of systemic fibroinflammatory disease, which is named as IgG4-related disease. On the other hand, type 2 AIP is a pancreatic disorder that is not associated with IgG4. Type 1 and type 2 AIP have different clinical profiles and histologic findings. We present a 22-year old man who has been diagnosed as type 1 AIP with histologically proven granulocytic epithelial lesion after surgical resection for pancreatic head mass. Since the patient had no pancreatic duct narrowing, elevation of serum IgG4, and other organ involvement, it was very difficult to diagnose preoperatively. This is a rare and interesting case in which histologic features of type 1 and type 2 AIP coexist. PMID- 25524486 TI - An approach to diagnostic radiology dosimetry. PMID- 25524487 TI - Magnetic resonance imaging measures of decreased aortic strain and distensibility are proportionate to insulin resistance in adolescents with type 1 diabetes mellitus. AB - OBJECTIVES: To determine whether children with type 1 diabetes mellitus (T1DM) have evidence of increased aortic stiffness or early atherosclerosis as measured by magnetic resonance imaging (MRI). BACKGROUND: T1DM increases risk for cardiovascular disease in adults but whether this process starts in childhood is unknown. SUBJECTS: A total of 54 T1DM patients (15.4 +/- 2.6 yr) and 30 age matched controls (14.8 +/- 2.7 yr) participated. METHODS: MRI was performed to assess aortic arch pulse wave velocity (PWV), strain, and distensibility of the ascending and descending thoracic aorta and measures of atherosclerosis. RESULTS: Groups were well-matched for age, pulse pressure, and gender. Low-density lipoprotein-cholesterol (LDL-C) was higher in T1DM (119.3 +/- 50 vs. 76.1 +/- 13.5 mg/dL, p < 0.0001). There was a trend toward decreased strain and distensibility in T1DM vs. controls in the ascending (distensibility: T1DM 62.2 +/- 19.9 kPa-1 * 10-3, control 71.6 +/- 26.4 kPa-1 * 10-3, p = 0.08) and descending aorta (strain: T1DM 25.8 +/- 6.2% vs. control 28.3 +/- 6.8%, p = 0.09). There was no difference in arch PWV. Advancing age and male gender was negatively associated with aortic stiffness. Hemoglobin A1c (HbA1c) was inversely related to descending aorta strain and distensibility (p < 0.05). Children with diabetes in the lowest two tertiles of insulin sensitivity demonstrated thoracic descending aortas with significantly lower strain (p = 0.027) and distensibility (p = 0.039) and increased measures of wall irregularity (p = 0.005). There were no differences in measurements of atherosclerosis between the two groups. CONCLUSIONS: Adolescents with T1DM, especially those with lower insulin sensitivity, demonstrated a trend toward stiffer, less compliant thoracic aortas, which was inversely associated with diabetes control. These data suggest large vessel aortopathy starts early in T1DM. PMID- 25524488 TI - Technology in MicroRNA Profiling: Circulating MicroRNAs as Noninvasive Cancer Biomarkers in Breast Cancer. AB - This report describes technologies to identify and quantify microRNAs (miRNAs) as potential cancer biomarkers, using breast cancer as an example. Most breast cancer patients are not diagnosed until the disease has advanced to later stages, which decreases overall survival rates. Specific miRNAs are up- or downregulated in breast cancer patients at various stages, can be detected in plasma and serum, and have shown promising preliminary clinical sensitivity and specificity for early cancer diagnosis or staging. Nucleic acid testing methods to determine relative concentrations of selected miRNAs include reverse transcription, followed by quantitative PCR (RT-qPCR), microarrays, and next-generation sequencing (NGS). Of these methods, NGS is the most powerful approach for miRNA biomarker discovery, whereas RT-qPCR shows the most promise for eventual clinical diagnostic applications. PMID- 25524489 TI - Efficient production of a gene mutant cell line through integrating TALENs and high-throughput cell cloning. AB - Transcription activator-like effectors (TALEs) are becoming powerful DNA targeting tools in a variety of mammalian cells and model organisms. However, generating a stable cell line with specific gene mutations in a simple and rapid manner remains a challenging task. Here, we report a new method to efficiently produce monoclonal cells using integrated TALE nuclease technology and a series of high-throughput cell cloning approaches. Following this method, we obtained three mTOR mutant 293T cell lines within 2 months, which included one homozygous mutant line. PMID- 25524490 TI - Biomimetic cardiac microsystems for pathophysiological studies and drug screens. AB - Microfabricated organs-on-chips consist of tissue-engineered 3D in vitro models, which rely on engineering design and provide the physiological context of human organs. Recently, significant effort has been devoted to the creation of a biomimetic cardiac system by using microfabrication techniques. By applying allometric scaling laws, microengineered cardiac systems simulating arterial flow, pulse properties, and architectural environments have been implemented, allowing high-throughput pathophysiological experiments and drug screens. In this review, we illustrate the recent trends in cardiac microsystems with emphasis on cardiac pumping and valving functions. We report problems and solutions brought to light by existing organs-on-chip models and discuss future directions of the field. We also describe the needs and desired design features that will enable the control of mechanical, electrical, and chemical environments to generate functional in vitro cardiac disease models. PMID- 25524491 TI - 96-well format-based microfluidic platform for parallel interconnection of multiple multicellular spheroids. AB - In this article, we present a microfluidic platform, compatible with conventional 96-well formats, that enables facile and parallelized culturing and testing of spherical microtissues in a standard incubator. The platform can accommodate multiple microtissues (up to 66) of different cell types, formed externally by using the hanging-drop method, and enables microtissue interconnection through microfluidic channels for continuous media perfusion or dosage of substances. The platform contains 11 separate channels, and each channel has six tissue compartments. Primary rat liver tissues were cultured over 8 days, and multiple tumor tissues (HCT116) were exposed to various concentrations of 5-fluorouracil for platform characterization. PMID- 25524492 TI - Cell dispensing in low-volume range with the immediate drop-on-demand technology (I-DOT). AB - Handling and dosing of cells comprise the most critical step in the microfabrication of cell-based assay systems for screening and toxicity testing. Therefore, the immediate drop-on-demand technology (I-DOT) was developed to provide a flexible noncontact liquid handling system enabling dispensing of cells and liquid without the risk of cross-contamination down to a precise volume in the nanoliter range. Liquid is dispensed from a source plate within nozzles at the bottom by a short compressed air pulse that is given through a quick release valve into the well, thus exceeding the capillary pressure in the nozzle. Droplets of a defined volume can be spotted directly onto microplates or other cell culture devices. We present a study on the performance and biological impact of this technology by applying the cell line MCF-7, human fibroblasts, and human mesenchymal stem cells (hMSCs). For all cell types tested, viability after dispensing is comparable to the control and exhibits similar proliferation rates in the absence of apoptotic cells, and the differentiation potential of hMSCs is not impaired. The immediate drop-on-demand technology enables accurate cell dosage and offers promising potential for single-cell applications. PMID- 25524493 TI - ICECAP: an integrated, general-purpose, automation-assisted IC50/EC50 assay platform. AB - BACKGROUND: IC50 and EC50 values are commonly used to evaluate drug potency. Mass spectrometry (MS)-centric bioanalytical and biomarker labs are now conducting IC50/EC50 assays, which, if done manually, are tedious and error-prone. Existing bioanalytical sample preparation automation systems cannot meet IC50/EC50 assay throughput demand. RESULT: A general-purpose, automation-assisted IC50/EC50 assay platform was developed to automate the calculations of spiking solutions and the matrix solutions preparation scheme, the actual spiking and matrix solutions preparations, as well as the flexible sample extraction procedures after incubation. In addition, the platform also automates the data extraction, nonlinear regression curve fitting, computation of IC50/EC50 values, graphing, and reporting. CONCLUSION: The automation-assisted IC50/EC50 assay platform can process the whole class of assays of varying assay conditions. In each run, the system can handle up to 32 compounds and up to 10 concentration levels per compound, and it greatly improves IC50/EC50 assay experimental productivity and data processing efficiency. PMID- 25524494 TI - Accuracy of the refractive prediction determined by multiple currently available intraocular lens power calculation formulas in small eyes. AB - PURPOSE: To observe the refractive outcomes of cataract surgery in small adult eyes, and to investigate the accuracy of different intraocular lens (IOL) power prediction formulas. DESIGN: Retrospective interventional case series. METHODS: We included consecutive small eyes undergoing uneventful phacoemulsification cataract surgery with a single highly powerful IOL (Acrysof SA60AT) implanted in the capsular bag (range of powers +35.0 to +40.0 diopters [D]), at the Cataract Centre for Moorfields Eye Hospital. Exclusion criteria were combined or previous intraocular surgical procedures, and any type of intraoperative complications. Main outcome measures were mean prediction errors with Hoffer Q, Holladay 1, Holladay 2, Haigis, SRK-T, and SRK-II IOL power prediction formulas and proportions of eyes achieving absolute errors within the dioptric ranges of 0.5, 1.0, and 2.0 D of target and emmetropia, respectively. The ANOVA test was used to compare the refractive results among various formulas. RESULTS: Twenty-eight eyes were studied; the mean numerical error was 0.22 +/- 1.22 D and the mean absolute error was 0.95 +/- 0.78 D with the adopted Hoffer Q formula; 39%, 61%, and 89% of the eyes had a final refraction within 0.5 D, 1.0 D, and 2.0 D of target, respectively. None of the latest-generation formulas significantly outperformed the others (P = .245). CONCLUSIONS: The Hoffer Q formula led to good or fair refractive outcomes in less than two thirds of the cases. With Holladay 1 and 2 and Haigis formulas, outcomes would have not been significantly different. The SRK formulas yielded less accurate predictions. Possible reasons are discussed. PMID- 25524495 TI - Not just black and white: peer victimization and the intersectionality of school diversity and race. AB - Although bullying is a prevalent issue in the United States, limited research has explored the impact of school diversity on types of bullying behavior. This study explores the relationship between school diversity, student race, and bullying within the school context. The participants were African American and Caucasian middle school students (n = 4,581; 53.4% female). Among the participants, 89.4% were Caucasian and 10.6% were African American. The research questions examined the relationship between school diversity, student race and bullying behaviors, specifically race-based victimization. The findings suggested that Caucasian middle school students experience more bullying than African American students generally, and specifically when minorities in school settings. Caucasian students also experienced almost three times the amount of race-based victimization than African American students when school diversity was held constant. Interestingly, African American students experienced twice the amount of race-based victimization than Caucasian students when in settings with more students of color. The present study provides insight into bullying behaviors across different contexts for different races and highlights the need to further investigate interactions between personal and environmental factors on the bulling experiences of youth. PMID- 25524496 TI - Multiplex detection of functional G protein-coupled receptors harboring site specifically modified unnatural amino acids. AB - We developed a strategy for identifying positions in G protein-coupled receptors that are amenable to bioorthogonal modification with a peptide epitope tag under cell culturing conditions. We introduced the unnatural amino acid p-azido-l phenylalanine (azF) into human CC chemokine receptor 5 (CCR5) at site-specific amber codon mutations. We then used strain-promoted azide-alkyne [3+2] cycloaddition to label the azF-CCR5 variants with a FLAG peptide epitope conjugated aza-dibenzocyclooctyne (DBCO) reagent. A microtiter plate-based sandwich fluorophore-linked immunosorbent assay was used to probe simultaneously the FLAG epitope and the receptor using infrared dye-conjugated antibodies so that the extent of DBCO incorporation, corresponding nominally to labeling efficiency, could be quantified ratiometrically. The extent of incorporation of DBCO at the various sites was evaluated in the context of a recent crystal structure of maraviroc-bound CCR5. We observed that labeling efficiency varied dramatically depending on the topological location of the azF in CCR5. Interestingly, position 109 in transmembrane helix 3, located in a hydrophobic cavity on the extracellular side of the receptor, was labeled most efficiently. Because the bioorthogonal labeling and detection strategy described might be used to introduce a variety of different peptide epitopes or fluorophores into engineered expressed receptors, it might prove to be useful for a wide range of applications, including single-molecule detection studies of receptor trafficking and signaling mechanism. PMID- 25524497 TI - Higher antiviral response of RIG-I through enhancing RIG-I/MAVS-mediated signaling by its long insertion variant in zebrafish. AB - As an intracellular pattern recognition receptor (PRR), the retinoic acid inducible gene-I (RIG-I) is responsible for the recognition of cytosolic viral nucleic acids and the production of type I interferons (IFNs). In the present study, an insertion variant of RIG-I with 38 amino acids inserted in the N terminal CARD2 domain, as well as the typical type, named as RIG-Ia and RIG-Ib respectively were identified in zebrafish. RIG-Ia and RIG-Ib were all up regulated following the infection of a negative ssRNA virus, the Spring Viremia of Carp Virus (SVCV), and an intracellular Gram-negative bacterial pathogen Edwardsiella tarda, indicating the RLR may have a role in the recognition of both viruses and bacteria. The over-expression of RIG-Ib in cultured fish cells resulted in significant increase in type I IFN promoter activity, and in protection against SVCV infection, whereas the over-expression of RIG-Ia had no direct effect on IFN activation nor antiviral response. Furthermore, it was revealed that both RIG-Ia and RIG-Ib were associated with the downstream molecular mitochondrial antiviral signaling protein, MAVS, and interestingly RIG Ia when co-transfected with RIG-Ib or MAVS, induced a significantly higher level of type I IFN promoter activity and the expression level of Mx and IRF7, implying that the RIG-Ia may function as an enhancer in the RIG-Ib/MAVS-mediated signaling pathway. PMID- 25524498 TI - Unsafe abortion in rural Tanzania - the use of traditional medicine from a patient and a provider perspective. AB - BACKGROUND: The circumstances under which women obtain unsafe abortion vary and depend on the traditional methods known and the type of providers present. In rural Tanzania women often resort to traditional providers who use plant species as abortion remedies. Little is known about how these plants are used and their potential effect. METHODS: Data were obtained among women admitted with incomplete abortion at Kagera Regional Hospital during the period January - June, 2006. The women underwent an empathetic interview to determine if they had experienced an unsafe abortion prior to their admission. In all 125/187 women revealed having had an unsafe abortion. The women identified as having had an unsafe abortion underwent a questionnaire interview where information about abortion provider and abortion method used was obtained through open-ended questions. To get more detailed information about the traditional methods used to induce abortion, in-depths interviews and focus group discussions were performed among traditional providers and nurses. Finally, the plant specimen's effectiveness as abortion remedies was assessed through pharmacological analyses. RESULTS: Among women admitted with incomplete abortions, 67% had had an unsafe abortion. Almost half of the women who had experienced an unsafe abortion had resorted to traditional providers and plant species were in these cases often used as abortion remedies. In all 21 plant species were identified as potential abortion remedies and analysed, 16 of the species were found to have a uterine contractive effect; they significantly increased the force of contraction, increased the frequency of contractions or did both. CONCLUSION: Unsafe abortion is common in rural Tanzania where many women use plant species to terminate an unwanted pregnancy. The plants have a remarkable strong uterine contractive effect. To further understand the consequences of unsafe abortion there is a need for further analyses of the plants' potential toxicity and mutagenicity. PMID- 25524500 TI - Costly choices for treating Wilson's disease. PMID- 25524499 TI - X chromosome inactivation in human parthenogenetic embryonic stem cells following prolonged passaging. AB - The present study aimed to investigate the X chromosome inactivation (XCI) status in long-term cultured human parthenogenetic embryonic stem cells. One human embryonic stem (hES) cell line and 2 human parthenogenetic embryonic stem (hPES) cell lines were subjected to long-term culture in vitro (>50 passages). Karyotyping, array-based comparative genomic hybridization (aCGH), X-inactive specific transcript (XIST) RNA, immunofluorescence staining and real-time PCR were used to assess the chromosome karyotypes of these cells and the XCI status. X chromosome microdeletion was observed in the hPES-2 cells following culture for 50 passages. As early as 20 passages, XIST RNA expression was detected in the hPES-2 cells and was followed by low X-linked gene expression. The XIST RNA expression level was higher in the differentiated hPES-2 cells. The hPES-2' cells that were subclones of hPES-2 retained the XCI status, and had low XIST and X linked gene expression. XIST RNA expression remained at a low level in the differentiated hPES-2' cells. The human biparental embryonic stem (hBES)-1 and hPES-1 cells did not exhibit XCI, and the differentiated hPES-1 cells had high expression levels of XIST RNA. In conclusion, the chromosome karyotypes of some hPES cell lines revealed instabilities. Similar to the hES cells, the hPES cells exhibited 3 XCI statuses. The unstable XCI status of the hPES-2 line may have been related to chromosome instability. These unstable chromosomes renedered these cells susceptible to environmental conditions and freezing processes, which may be the result of environmental adaptations. PMID- 25524501 TI - Nurses' experiences of restraint and seclusion use in short-stay acute old age psychiatry inpatient units: a qualitative study. AB - Restraint and seclusion are often ineffective and can affect patients adversely. In this study, we explored nurses' experiences of restraint and seclusion in short-stay acute old age psychiatry inpatient units and how these experiences underpin resistance to eliminating these practices. Qualitative interviews were conducted with nurses in three old age psychiatry units in Melbourne, Australia. The results provide one overarching theme, lack of accessible alternatives to restraint and seclusion, indicating that nurses believe there are no effective, accessible alternatives to these practices. Three related themes contribute to this perception. First, an adverse interpersonal environment contributes to restraint and seclusion, which relates to undesirable consequences of poor staff to-patient relationships. Second, an unfavourable physical environment contributes to aggression and restraint and seclusion use. Third, the practice environment influences the adoption of restraint and seclusion. The findings contribute to the limited evidence about nurses' experiences of these practices in short-stay old age psychiatry, and how account needs to be taken of these experiences and contextual influences when introducing measures to address these practices. Policies addressing these measures need to be accompanied by wide ranging initiatives to deal with aggression, including providing appropriate education and support and addressing ethical and workplace cultural issues surrounding these practices. PMID- 25524502 TI - Low enhancing papillary renal cell carcinoma diagnosed by using dual energy computerized tomography: a case report and review of literature. AB - BACKGROUND: Papillary renal cell carcinoma (pRCC) is a mixed group of tumors that constitutes about 15-20% of all renal cortical cancers. Strong enhancement on computerized tomography (CT) is a feature of clear cell, but not of pRCC making the differentiation of papillary tumors from benign cysts a diagnostic problem in some cases. CASE PRESENTATION: We report here a case of a female patient with pRCC that was initially diagnosed as a benign renal cyst. The patient is a 66 year old Caucasian female who initially presented with an ultrasound showing a 2.6 cm hypo-echoic lesion within the inferior pole of her left kidney. This was followed by a contrast enhanced computerized tomography that suggested the hypo echoic lesion to be a hyper-attenuating benign renal cyst. Follow-up CT scan 4 months later demonstrated an increase in the size of the lesion to 3.2 cm with equivocal enhancement. A dual energy computerized tomography (DECT) showed the lesion to be a solid mass suspicious for renal cell carcinoma. A robotic partial nephrectomy revealed a papillary renal cell carcinoma with negative margins. CONCLUSION: In this case report, we reviewed the literature on variations in enhancement of renal tumors and the possible role of dual energy contract enhanced CT in differentiating papillary tumors with low enhancement from benign kidney cystic lesions. PMID- 25524503 TI - Amphiphilic polyoxometalates for the controlled synthesis of hybrid polystyrene particles with surface reactivity. AB - Amphiphilic organo-polyoxometalates (POMs) used in the radical emulsion polymerization of styrene allowed the preparation in aqueous medium of stable 50 100 nm polystyrene-POM composite latexes. Thanks to the presence of a trithiocarbonate group in the POM amphiphile, POMs could be covalently linked to the polymer particle surface. The chemical and catalytic integrity of the POMs was confirmed, and the POM-mediated surface photoactivity of the latexes was demonstrated by the spatially controlled nucleation of silver nanoparticles at the periphery of the composites. PMID- 25524505 TI - Inside 'bed management': ethnographic insights from the vantage point of UK hospital nurses. AB - In the face of unprecedented financial and demographic challenges, optimising acute bed utilisation by the proactive management of patient flows is a pressing policy concern in high-income countries. Despite the growing literature on this topic, bed management has received scant sociological attention. Drawing on practice-based approaches, this article deploys ethnographic data to examine bed management from the perspective of UK hospital nurses. While the nursing contribution to bed management is recognised formally in their widespread employment in patient access and discharge liaison roles, nurses at all levels in the study site were enrolled in this organisational priority. Rather than the rational, centrally controlled processes promulgated by policymakers, bed management emerges as a predominantly distributed activity, described here as match-making. An example of micro-level rationing, for the most part, match making was not informed by explicit criteria nor did it hinge on clearly identifiable decisions to grant or deny access. Rather it was embedded in the everyday practices and situated rationalities through which nurses accomplished the accommodations necessary to balance demand with resources. PMID- 25524504 TI - Safety and diagnostic accuracy of tumor biopsies in children with cancer. AB - BACKGROUND: Tumor biopsies are central to the diagnosis and management of cancer and are critical to efforts in personalized medicine and targeted therapeutics. In the current study, the authors sought to evaluate the safety and accuracy of biopsies in children with cancer. METHODS: All biopsies performed in children at the study institution with a suspected or established diagnosis of cancer from 2003 through 2012 were reviewed retrospectively. Patient characteristics and disease-related and procedure-related factors were correlated with procedure related complications and diagnostic accuracy using logistic regression analysis. RESULTS: A total of 1073 biopsies were performed in 808 patients. Of 1025 biopsies with adequate follow-up, 79 (7.7%) were associated with an adverse event, 35 (3.4%) of which were minor (grade 1-2) and 32 (3.1%) of which were major (grade 3-4) (grading was performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). The most common major adverse events were blood transfusion (>10 mL/kg; 24 cases) and infection requiring intravenous antibiotics (6 cases). Eleven deaths (1.4%) occurred within 30 days after the procedure, but the procedure may have contributed to the outcome in only 2 cases. A total of 926 biopsies (90.3%) provided definitive histologic diagnoses. Using multivariable analysis, biopsy site, preprocedure hematocrit level, and body mass index were found to be associated with the risk of postprocedural complications (P<.0001, P<.0001, and P =.0029, respectively). Excisional biopsy and biopsy site were found to be independently associated with obtaining a diagnostic result (P =.0002 and P =.0008, respectively). CONCLUSIONS: Tumor biopsies in children with cancer are associated with a low incidence of complications and a high rate of diagnostic accuracy. The predictive factors identified for adverse outcomes may aid in risk assessment and preprocedural counseling. PMID- 25524507 TI - Fluticasone furoate/vilanterol 200/25 mcg in Asian asthma patients: a randomized trial. AB - BACKGROUND: This study investigated the efficacy and safety of the inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) combination fluticasone furoate (FF)/vilanterol (VI) in Asian asthma patients. METHODS: A 12-week, double blind, double-dummy, active-comparator, parallel-group, multicenter study. 309 Asian asthma patients (>=12 years, uncontrolled with high-strength ICS or mid dose ICS/LABA) were randomized (1:1) and included in the intent-to-treat population; 155 received once-daily FF/VI 200/25 mcg and 154 received twice-daily fluticasone propionate (FP) 500 mcg. The primary endpoint was change from baseline in daily evening peak expiratory flow (PEF) averaged over 12 weeks. Secondary endpoints were mean change from baseline in % rescue-free 24-h periods, daily morning PEF, % symptom-free 24-h periods, and overall Asthma Quality of Life Questionnaire score. Safety assessments were performed. RESULTS: For change from baseline in daily evening PEF, the adjusted mean treatment difference for FF/VI versus FP of 28.5 L/min (95% confidence interval [CI]: 20.1, 36.9) was clinically and statistically significant (p < 0.001). For change from baseline in % rescue-free 24-h periods, the adjusted mean treatment difference (1.0%; 95% CI: -7.3, 9.2) was not statistically significant (p = 0.821). Statistical significance could not be inferred for the remaining endpoints due to the statistical hierarchy employed. Incidence of on-treatment adverse events was similar with FF/VI (26%; 3% treatment-related; n = 1 serious) and FP (27%; 3% treatment-related; n = 2 serious); none were fatal. No further safety concerns were identified. CONCLUSIONS: FF/VI improved evening PEF over 12 weeks versus FP in Asian patients, with a similar safety profile. The results are generally consistent with a global study comparing the same treatments. PMID- 25524508 TI - Airway wall thickness of allergic asthma caused by weed pollen or house dust mite assessed by computed tomography. AB - PURPOSE: Little was known about Airway wall thickness of asthma patients with different allergen allergy. So we explored the possible difference of Airway wall thickness of asthma patients mono-sensitized to weed pollen or HDM using high resolution computed tomography. MATERIALS AND METHODS: 85 severe asthma patients were divided into weed pollen group and HDM group according to relevant allergen. 20 healthy donors served as controls. Airway wall area, percentage wall area and luminal area at the trunk of the apical bronchus of the right upper lobe were quantified using HRCT and compared. The values of pulmonary function were assessed as well. RESULTS: There were differences between HDM group and weed pollen group in WA/BSA,WA% and FEF25-75% pred, and no significant difference in FEV1%pred, FEV1/FVC and LA/BSA. In weed pollen group, WA/BSA was observed to correlate with the duration of rhinitis, whereas in HDM group, WA/BSA and LA/BSA was observed to correlate with the duration of asthma. In weed pollen group, FEV1/FVC showed a weak but significant negative correlation with WA%, but in HDM group FEV1/FVC showed a significant positive correlation with WA% and a statistical negative correlation with LA/BSA. FEV1/FVC and FEF25-75% pred were higher and WA/BSA and LA/BSA were lower in healthy control group than asthma group. FEV1%pred and WA% was no significant difference between asthma patients and healthy subjects. CONCLUSION: There are differences between HDM mono sensitized subjects and weed pollen mono-sensitized subjects, not only in airway wall thickness, but also small airway obstruction. PMID- 25524510 TI - Purification of vitellin and dynamics of vitellogenesis in the parthenogenetic tick Haemaphysalis longicornis (Acari: Ixodidae). AB - Vitellin (Vt) was purified from eggs of parthenogenetic bush tick Haemaphysalis longicornis by gel filtration and ion exchange chromatography. Our results revealed that only one single Vt existed in parthenogenetic bush tick, and the purified Vt was proved to be a hemoglycolipoprotein consisting of nine polypeptides with molecular weights of 203, 147, 126, 82, 74, 70, 61, 47 and 31 kDa, respectively. Polyclonal antibody and monoclonal antibody against Vt were produced using the purified Vt. The change in vitellogenin (Vg) and Vt levels over time of the parthenogenetic H. longicornis was established, and the Vg content in haemolymph and Vt in ovary at different feeding or engorgement statuses was also determined using a double antibody sandwich enzyme-linked immunosorbent assay. The Vg level in haemolymph was distinctly increased on the day of engorgement (1.785 mg/mL) and continued to increase until 2nd day post engorgement (5.611 mg/mL). There was a slight decrease in Vg level after 4 days of engorgement, and a second peak was observed on day 2 post-oviposition (10.774 mg/mL). Subsequently, Vg content continuously decreased and reached a low level on the 10th day post-oviposition. The Vt content in ovary continuously increased once the female reached its critical weight (0.024 mg per female), and reached the maximum level on day 2 post-oviposition (1.942 mg per female). Afterwards, Vt content rapidly decreased. PMID- 25524511 TI - Amblyseius swirskii: what made this predatory mite such a successful biocontrol agent? AB - The predatory mite Amblyseius swirskii quickly became one of the most successful biocontrol agents in protected cultivation after its introduction into the market in 2005 and is now released in more than 50 countries. There are several key factors contributing to this success: (1) it can control several major pests including the western flower thrips, Frankliniella occidentalis, the whiteflies Bemisia tabaci and Trialeurodes vaporariorum and the broad mite, Polyphagotarsonemus latus, simultaneously in vegetables and ornamental crops; (2) it can develop and reproduce feeding on non-prey food sources such as pollen, which allows populations of the predator to build up on plants before the pests are present and to persist in the crop during periods when prey is scarce or absent; and (3) it can be easily reared on factitious prey, which allows economic mass production. However, despite the fact that A. swirskii provides growers with a robust control method, external demands were initially a key factor in promoting the use of this predator, particularly in Spain. In 2006, when exports of fresh vegetables from Spain were stopped due to the presence of pesticide residues, growers were forced to look for alternatives to chemical control. This resulted in the massive adoption of biological control-based integrated pest management programmes based on the use of A. swirskii in sweet pepper. Biological control increased from 5 % in 2005, 1 year before A. swirskii was commercially released, to almost 100 % of a total 6,000 ha of protected sweet pepper in Spain within 3 years. Later, it was demonstrated that A. swirskii was equally effective in other crops and countries, resulting in extensive worldwide use of A. swirskii in greenhouses. PMID- 25524512 TI - Interspecific interactions involving Neoseiulus californicus (Acari: Phytoseiidae) and Agistemus brasiliensis (Acari: Stigmaeidae) as predators of Brevipalpus phoenicis (Acari: Tenuipalpidae). AB - Brevipalpus phoenicis (Geijskes) is associated with the transmission of Citrus leprosis which is considered the main viral disease for the Brazilian citrus production. Mites of the families Stigmaeidae and Phytoseiidae coexist in various agricultural crops, often promoting the biological control of pest mites. The aim of this work was to study the interactions of Neoseiulus californicus (McGregor) (Phytoseiidae) and Agistemus brasiliensis Matioli, Ueckermann & Oliveira (Stigmaeidae), in the presence or absence of B. phoenicis. Two experiments were carried out. In the first, a N. californicus female was placed in each leaf disc arena, with eggs of B. phoenicis and A. brasiliensis as food sources. In the second, an A. brasiliensis female was placed in each arena, with eggs of B. phoenicis and N. californicus as food sources. Adults of both predators were able to consume both types of eggs available as food sources, but they fed on considerably higher proportions of B. phoenicis than on eggs of the predator. Eggs of A. brasiliensis were not a suitable food source for N. californicus, which produced only 0.1 egg per female per day when only eggs of that species were present in the experimental unit. The results suggest that eggs of N. californicus were a suitable food source for A. brasiliensis, which oviposited 1.12 eggs per day, when only eggs of N. californicus were provided to the stigmaeid mite. The possible interactions among N. californicus, A. brasiliensis and B. phoenicis in citrus orchards are discussed. PMID- 25524515 TI - Current trends in preoperative, intraoperative, and postoperative care of the adult cardiac surgery patient. PMID- 25524516 TI - The challenges of psychiatry. PMID- 25524518 TI - Suicide prevention: let's start at the very beginning. PMID- 25524517 TI - Why academic psychiatry is endangered. PMID- 25524519 TI - In vitro function of platelets treated with ultraviolet C light for pathogen inactivation: a comparative study with nonirradiated and gamma-irradiated platelets. AB - BACKGROUND: During storage of platelet concentrates (PCs) replication of contaminating pathogens might occur, which can be prevented by various pathogen inactivation (PI) methods using photoactive substances in combination with ultraviolet (UV) light. A new method uses only UVC light for PI without photoactive substances. This study evaluates the in vitro function, including hemostatic properties (clot formation and elasticity), of platelets (PLTs) treated with UVC light. STUDY DESIGN AND METHODS: A PC with 35% plasma and 65% PLT additive solution (SSP+) was prepared from five buffy coats. Three PCs were pooled and divided into 3 units. One unit was used as a nonirradiated control, the second was a gamma-irradiated control, and the third unit was treated with UVC light. In vitro variables including analysis of coagulation by free oscillation rheometry were analyzed on Days 1, 5, and 7 of storage. Ten units in each group were investigated. RESULTS: Swirling was well preserved, and the pH level was higher than the reference limit (6.4) during storage of PLTs in all groups. Glycolysis and PLT activation were higher for UVC-treated PLTs but the clot-forming capacity was unaffected. However, immediately after UVC treatment, the clot elastic properties were slightly affected. Hypotonic shock response decreased immediately after UVC treatment but recovered partly during the storage period. CONCLUSION: UVC treatment affected the in vitro properties, but PLT quality and storage stability were well preserved for up to 7 days, and the in vitro hemostatic capacity of UVC-treated PLTs was only minimally altered. The clinical relevance of these changes needs to be evaluated in controlled trials. PMID- 25524520 TI - Complex relationship of body mass index with mortality in patients with critical limb ischemia undergoing endovascular treatment. AB - OBJECTIVE: To investigate the relationship between body mass index (BMI) and long term outcomes of patients with CLI after endovascular treatment (EVT). DESIGN: Retrospective multicenter study. SUBJECTS: 1088 consecutive patients (1306 limbs, mean age 72 +/- 10 years) with CLI who underwent EVT for isolated infrapopliteal artery lesions were evaluated. These subjects were identified in the J-BEAT III registry. METHODS: The patients were divided into groups based on BMI <18.5 kg/m2 (underweight, n = 188; 219 limbs), 18.5 to 24.9 kg/m2 (normal weight, n = 718; 868 limbs), and >25.0 kg/m2 (overweight/obese, n = 182; 219 limbs). The endpoints were overall survival and freedom from major adverse limb events (MALE). RESULTS: The median follow up period was 1.5 years (range: 1 month-8.7 years). The 3 year overall survival rates were 33.3%, 61.2%, and 69.8% in underweight, normal, and overweight/obese patients, respectively. The survival rate was significantly lower in underweight patients and significantly higher in overweight/obese patients compared with patients of normal weight (both p < .0001). The 3 year rates of freedom from MALE did not differ significantly among the three groups (36.4%, 45.4%, and 52.3%, respectively, p = .32). Age, BMI <18.5 kg/m2, heart failure, aortic valve stenosis, renal failure, triglyceride levels, serum albumin <3.0 g/dL, anticoagulant treatment, non-ambulatory status, and Rutherford 6 classification all were significantly associated with overall survival. CONCLUSIONS: BMI has a complex correlation with mortality in patients with CLI after EVT for isolated infrapopliteal artery lesions. Underweight patients with CLI have an extremely poor prognosis. Such patients have many other factors associated with mortality, but low BMI was identified as an independent predictor of a poor prognosis in patients with CLI. Similarly, normal weight patients had a small but significant increase in mortality compared with overweight/obese patients. PMID- 25524521 TI - Salidroside ameliorates Cd-induced calcium overload and gap junction dysfunction in BRL 3A rat liver cells. AB - It is known that cadmium (Cd) induces cytotoxicity via Ca(2+) signaling, although the underlying mechanism is unclear. Here, we studied the molecular mechanisms of Cd-induced cytotoxicity in BRL 3A cells, a rat liver cell line. We observed that Cd treatment was associated with a time-dependent decrease in cell index (CI) in BRL 3A cells. Mechanistically, we observed that Cd exposure was associated with decreased expression of Cx43, P-Cx43, and Cx32. Specifically, Cx43 was decreased at the site of cell-cell junctions at the cell membrane, corresponding to a decrease in gap junctional intercellular connections (GJICs). We also found that Cd triggered a rise in the intracellular free Ca(2+) concentration ([Ca(2+)]i), and the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N' tetraacetic acid tetrakis, acetoxymethyl ester (BAPTA-AM), prevented the Cd induced decrease in CI. On the other hand, the gap junction blocker 18-beta glycyrrhetinic acid (GA) and the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin exacerbated cytotoxic injury induced by Cd via further elevating [Ca(2+)]i, The extracellular calcium chelator ethylene glycol tetraacetic acid could partly attenuate Cd-induced calcium elevation but had little effect on GA combined Cd. Furthermore, salidroside as a protective agent prevented Cd-induced GJIC inhibition and calcium overload. Our findings suggest that Cd triggers elevation of [Ca(2+)]i via mainly stimulating Ca(2+) release from intracellular Ca(2+) storage organelles and inhibiting GJIC, causing cytotoxic injury, and salidroside could be used to prevent Cd-induced cytotoxicity. PMID- 25524522 TI - Neutron activation analysis of scalp hair from ALS patients and residents in the Kii Peninsula, Japan. AB - The aim of this study was to evaluate the accumulation of transition metals in the scalp hair of amyotrophic lateral sclerosis (ALS) patients in the Koza/Kozagawa/Kushimoto (K) area (K-ALS) in the Kii Peninsula, Japan. Metal contents were measured in the unpermed, undyed hair samples of 88 K-residents, 20 controls, 7 K-ALS patients, and 10 sporadic ALS patients using neutron activation analysis at the Research Reactor Institute, Kyoto University. A human hair standard and elemental standards were used as comparative standards. The contents of Zn, Mn, and V were higher, while that of S was lower in K-ALS patients than in the controls. The content of Mn in K-ALS patients negatively correlated with clinical durations. The content of Al was significantly higher in K-residents than in the controls, with 15.9 % of K-residents having high Mn contents over the 75th percentile of the controls. The contents of Zn, Mn, and V were high in the scalp hair of K-ALS patients and correlated with the content of Al. The accumulation of these transition metals may chronically increase metal-induced oxidative stress, which may, in turn, trigger the neuronal degeneration associated with K-ALS. PMID- 25524523 TI - Analysis of six elements (Ca, Mg, Fe, Zn, Cu, and Mn) in several wild vegetables and evaluation of their intakes based on Korea National Health and Nutrition Examination Survey 2010-2011. AB - Wild vegetables, those edible among naturally grown vegetables, have been reported to contain many bioactive substances, dietary fibers, vitamins, and minerals. The purpose of this study is to examine the six elements of the wild vegetables frequently consumed by Koreans and assess the element intakes through them. Contents of six kinds of elements (Ca, Mg, Fe, Zn, Cu, and Mn) in 11 wild vegetables were analyzed by inductively coupled plasma optical emission spectroscopy. Using these analysis data, the 6-element intakes from the wild vegetables were evaluated in healthy Korean adults aged 19-64 years from the Korea National Health and Nutrition Examination Survey (2010-2011). Sedum and shepherd's purse contained over 100 mg of Ca in 100 g of their edible portion. The Mg content per 100 g of the 11 wild vegetables ranged from 12.1 mg to 43.4 mg. The wild vegetable with the highest mineral content per 100 g was sedum for Ca, spinach for Mg, shepherd's purse for Fe, spinach for Zn, bracken for Cu, and fragrant edible wild aster for Mn. The element intakes from the 11 wild vegetables compared with dietary reference intakes in the healthy Koreans were 1.0 % for Ca, 2.1 % for Mg, 5.3 % for Fe, 1.4 % for Zn, 0.3 % for Cu, and 1.8 % for Mn. Considering the low intake ratio (1.2 %) of the wild vegetable to total food intake, wild vegetables may contribute to some element intakes. Our results show the nutritional value of the wild vegetables in the aspect of mineral nutrition; however, further research is needed to evaluate the bioavailability of various elements in wild vegetables. PMID- 25524524 TI - Editorial. PMID- 25524525 TI - Structures of citrate synthase and malate dehydrogenase of Mycobacterium tuberculosis. AB - The tricarboxylic acid (TCA) cycle is a central metabolic pathway of all aerobic organisms and is responsible for the synthesis of many important precursors and molecules. TCA cycle plays a key role in the metabolism of Mycobacterium tuberculosis and is involved in the adaptation process of the bacteria to the host immune response. We present here the first crystal structures of M. tuberculosis malate dehydrogenase and citrate synthase, two consecutive enzymes of the TCA, at 2.6 A and 1.5 A resolution, respectively. General analogies and local differences with the previously reported homologous protein structures are described. PMID- 25524526 TI - Role of diffusion tensor imaging or magnetic resonance spectroscopy in the diagnosis and disability assessment of amyotrophic lateral sclerosis. AB - OBJECTIVE: To compare the results of magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) in amyotrophic lateral sclerosis (ALS) patients. METHODS: Nineteen ALS patients and thirteen age-matched healthy controls underwent MRS and DTI between October 2013 and July 2014. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) were collected as the quantitative results of the imaging study. The ALS functional rating scale-revised (ALSFRS-R) and disease progression rate were evaluated to assess patients' disability. The imaging study results were compared between ALS patients and healthy controls. The relationship between disability assessment and imaging study results was analyzed. RESULTS: NAA/Cr in the motor cortex and FA in the corticospinal tract (CST) of both sides were significantly lower in patients than controls. There was no significant difference between the two groups in Cho/Cr, tract length, tract volume, ADC or NAA. No relationship was found between ALSFRS-R and FA (r=0.243, p=0.316) in the right CST; NAA (r=0.095, p=0.699) or NAA/Cr (r=0.172, p=0.481) in the left motor cortex; or NAA (r=0.320, p=0.182) or NAA/Cr (r=0.193, p=0.492) in the right motor cortex. There was no relationship between the disease progression rate and FA, NAA, or NAA/Cr on either side. CONCLUSION: NAA/Cr and FA can help diagnose ALS. Regional brain NAA/Cr and FA values could not assess the ALSFRS-R or disease progression rate. PMID- 25524527 TI - Association between MTHFD1 polymorphisms and neural tube defect susceptibility. AB - OBJECTIVES: Neural tube defect (NTD) is a common disease among neonates with multiplex symptom and complex origins, and the exact mechanism of NTD has not been definitely elucidated. Nevertheless, it is hypothesized that NTD risk can be prevented by periconceptional folic acid in folate metabolism. The methylenetetrahydrofolate dehydrogenase (MTHFD1) gene has been proved to play an important role in folate metabolism, which was strongly associated with the high risk for NTD. We focused on three folate metabolism-related single-nucleotide polymorphisms (SNPs) on the MTHFD1 gene to evaluate the associations between MTHFD1 polymorphisms and NTD susceptibility. METHODS: We genotyped blood samples from 222 specimens (including 122 NTD-affected infants and 100 healthy controls) in a case-control study. We investigated the association between NTD and three selected tag-SNPs on MTHFD1 gene: 401A>G (rs1950902), 2305C>T (rs17857382) and 1958G>A (rs2236225) by the SNapShot method. These SNPs were identified by Haploview 4.2 software with HapMap databases, and then these associations were evaluated by the Mann-Whitney test, one-way analysis of variance (ANOVA) and chi square test. Furthermore, a meta-analysis of the association between MTHFD1 1958G>A and NTD risk was also performed. RESULTS: In our study, an increased risk of NTD was observed for 1958G>A of MTHFD1 (AA vs. GG: OR=2.63, 95% CI=2.61-5.70; AA vs. GG+GA: OR=2.10, 95% CI=1.07-4.14; A vs. G: OR=1.62, 95% CI=1.11-2.36). However, the other two SNPs (401A>G and 2305C>T) displayed no statistically significant association with NTD risk. The overall result of the meta-analysis indicated that the 1958G>A variant might not be a genetic susceptible factor for the Caucasian population. CONCLUSIONS: Our analysis implicated that MTHFD1 1958G>A was significantly associated with the susceptibility of NTD in a Chinese population. In addition, the AA homozygote carriers were more likely to suffer NTD, compared with the others with GA or GG genotypes. Validation of the risk effect and functional impact of this polymorphism is needed in future investigations. PMID- 25524528 TI - Scalp-EEG fast activity synchronization precedes nosewiping in sleep-arousal in temporal lobe epilepsy. PMID- 25524529 TI - Sleep characteristics as predictor variables of stress systems markers in insomnia disorder. AB - This study investigates the extent to which sleep characteristics serve as predictor variables for inflammatory, hypothalamic-pituitary-adrenal and autonomic systems markers. Twenty-nine participants with a diagnosis of insomnia disorder based on the Diagnostic Statistical Manual of Mental Disorders, Fifth Edition (age 25.3 +/- 1.6 years, insomnia duration 6.6 +/- 0.8 years) and 19 healthy control sleepers (age 25.4 +/- 1.4 years) underwent a 2-week at-home evaluation keeping a sleep diary and wearing an actigraph, followed by a visit to the Research Center to measure blood pressure, and collect blood and urine samples. The actigraphy- and diary-based variables of sleep duration, sleep-onset latency, wake after sleep onset and sleep fragmentation/number of night-time awakenings were averaged and entered as dependent variables in regression analyses. Composite scores were calculated for the autonomic (blood pressure, norepinephrine), inflammatory (monocyte counts, interleukin-6, C-reactive protein) and hypothalamic-pituitary-adrenal systems (cortisol), and used as predictor variables in regression models. Compared with controls, individuals with insomnia had a shorter sleep duration (P < 0.05), and a higher hypothalamic pituitary-adrenal and inflammatory composite score (P < 0.05). The higher inflammatory score was mainly due to higher circulating monocytes (P < 0.05), rather than differences in interleukin-6 or C-reactive protein. In persistent insomnia disorder, cortisol is upregulated and associated with actigraphy- and diary-based wake after sleep onset, suggesting that wake after sleep onset may serve as a marker to identify individuals at increased risks for disorders associated with a hyperactive hypothalamic-pituitary-adrenal system. The absence of autonomic and pro-inflammatory changes (interleukin-6, C-reactive protein), despite a substantial decrease in actigraphic sleep duration, may relate to a higher resilience to the adverse biological consequences of insomnia in this young age group. PMID- 25524530 TI - Arabidopsis ERF109 mediates cross-talk between jasmonic acid and auxin biosynthesis during lateral root formation. AB - Jasmonic acid (JA) is well known to promote lateral root formation but the mechanisms by which JA signalling is integrated into the pathways responsible for lateral root formation, and how it interacts with auxin in this process remains poorly understood. Here, we report that the highly JA-responsive ethylene response factor 109 (ERF109) mediates cross-talk between JA signalling and auxin biosynthesis to regulate lateral root formation in Arabidopsis. erf109 mutants have fewer lateral roots under MeJA treatments compared with wild type whereas ERF109 overexpression causes a root phenotype that resembles those of auxin overproduction mutants. ERF109 binds directly to GCC-boxes in the promoters of ASA1 and YUC2, which encode two key enzymes in auxin biosynthesis. Thus, our study reveals a molecular mechanism for JA and auxin cross-talk during JA-induced lateral root formation. PMID- 25524531 TI - Viscoelasticity of smart fluids based on wormlike surfactant micelles and oppositely charged magnetic particles. AB - Novel viscoelastic smart suspensions based on cationic wormlike micelles (WLMs) of erucylbis(hydroxyethyl)methylammonium chloride and oppositely charged submicron magnetite particles in the presence of added low molecular weight salt were prepared and investigated. The suspensions demonstrate remarkable stability against sedimentation, which can be due to the incorporation of particles into the network of entangled WLMs by linking to energetically unfavorable micellar end-caps. Added particles enhance significantly the viscosity, the plateau modulus, and the relaxation time of the system, acting as additional multifunctional physical cross-links in the micellar network. The increase of plateau modulus stops when the concentration of particles reaches ca. 1.5 wt %, indicating that all micellar end-caps available in the system are linked to the particles. Further addition of particles may lead just to the redistribution of micellar ends between the particles without creation of new elastically active chains. The increase of rheological characteristics by added particles is more pronounced in suspensions with a smaller content of low molecular weight salt KCl when the WLMs are shorter in length and therefore contain a larger amount of end caps responsible for the interaction with the particles. Magnetite particles not only enhance the rheological characteristics but also impart magnetoresponsive properties to the suspension. Upon application of magnetic field, the liquidlike system transforms into a solidlike one, demonstrating a constant value of storage modulus in all frequency range and the appearance of yield stress, which is due to the formation of field-aligned chainlike aggregates of particles opposing the flow. A combination of responsive properties inherent to both the matrix and the particles makes these smart fluids very competitive with other magnetic soft matter materials for various applications. PMID- 25524532 TI - Model development including interactions with multiple imputed data. AB - BACKGROUND: Multiple imputation is a reliable tool to deal with missing data and is becoming increasingly popular in biostatistics. However, building a model with interactions that are not specified a priori, in the presence of missing data, presents a challenge. On the one hand, the interactions are needed to impute the data, while on the other hand, the data is needed to identify the interactions. The objective of this study was to present a way in which this challenge can be addressed. METHODS: This paper investigates two strategies in which model development with interactions is achieved using a single data set generated from the Expectation Maximization (EM) algorithm. Imputation using both the fully conditional specification approach and the multivariate normal approach is carried out and results are compared. The strategies are illustrated with data from a study of ambient pollution and childhood asthma in Durban, South Africa. RESULTS: The different approaches to model building and imputation yielded similar results despite the data being mainly categorical. Both strategies investigated for building the model using the multivariate normal imputed data resulted in the identical set of variables and interactions being identified; while models built using data imputed by fully conditional specification were marginally different for the two strategies. It was found that, for both imputation approaches, model building with backward elimination applied to the initial EM data set was easier to implement, and produced good results, compared to those from a complete case analysis. CONCLUSIONS: Developing a predictive model including interactions with data that suffers from missingness is easily done by identifying significant interactions and then applying backward elimination to a single data set imputed from the EM algorithm. It is hoped that this idea can be further developed and, by addressing this practical dilemma, there will be increased adoption of multiple imputation in medical research when data suffers from missingness. PMID- 25524533 TI - Antenatal diagnosis of idiopathic arterial calcification: a systematic review with a report of two cases. AB - INTRODUCTION: Idiopathic antenatal calcification is a rare, generally lethal, condition with unclear etiology. MATERIALS AND METHODS: Around 200 cases, most of them undergoing postnatal diagnosis, are reported in literature. The majority of the affected infants die before the age of 6 months, and very few have survived for more than 1 year. Five cases of spontaneous resolution of the disease are described. DISCUSSION: An autosomal recessive pattern of inheritance has been suggested for this condition, with some gene mutations which have been recently discovered. Therapy with bisphosphonates has been suggested, with conflicting evidence regarding the utility in the regression of the disease. CONCLUSION: The main purpose of the present report is to provide the available knowledge on this subject through a systematic review of the literature. In addition, we describe two cases of antenatal idiopathic arterial calcification in which antenatal diagnosis was achieved. PMID- 25524534 TI - Total laparoscopic hysterectomy, vaginal hysterectomy and total abdominal hysterectomy using electrosurgical bipolar vessel sealing technique: a randomized controlled trial. AB - PURPOSE: To compare total laparoscopic hysterectomy (TLH), total abdominal hysterectomy (TAH) and vaginal hysterectomy (VH) using electrosurgical bipolar vessel sealing (EBVS) technique regarding operative time, intra and postoperative complications. METHODS: The current prospective randomized controlled clinical trial was conducted at Ain-shams University maternity Hospital, Cairo, Egypt. Ninety patients who were admitted from gynecologic outpatient clinic to undergo hysterectomy were enrolled. The study population was randomized according to type of hysterectomy done into 3 groups: group 1: VH; group 2: AH and group 3: TLH. EBVS was used in all groups. Three staff members' surgeons were also randomized to operate on the patients and they were all equally competent in all the procedures. Main outcome measures were operative time, operative blood loss, operative complications, postoperative pain assessment using the visual analogue scale (0-10), and the need for analgesics as well as the postoperative hospital stay. RESULTS: Ninety patients were randomized to undergo VH, TAH or TLH for benign pathology using EBVS. Postoperative pain score and the need for analgesia were least in TLH compared to the other two groups, (p < 0.001). The hospital stay in TLH group was shorter than the other two groups, but there was no significant difference between VH group and TAH group with regard to hospital stay, (p < 0.001). The total operative time was shortest in the VH group (100.4 +/- 35.8 min) compared to TLH (126 +/- 42.7 min) and TAH (123.6 +/- 44.5 min) (p = 0.033). The operative complications were more with VH and TAH groups. The blood loss was more with VH (p = 0.039). CONCLUSION: TLH had a longer operation time, yet, less blood loss, shorter hospital stay, less postoperative pain and fewer complications, compared to TAH and VH using EBVS. PMID- 25524536 TI - Hysteroscopy in women with abnormal uterine bleeding: a meta-analysis on four major endometrial pathologies. AB - PURPOSE: To determine the accuracy of hysteroscopy in diagnosing endometrial cancer, hyperplasia, polyps and submucous myomas. METHODS: Relevant articles were retrieved from the MEDLINE and the Cochrane Library (1986-2011). Studies were selected blindly. Results for diagnostic accuracy were extracted to form separate 2 * 2 tables (for endometrial cancer, hyperplasia, polyps and submucous myomas). A summary sensitivity and specificity point reflected the average accuracy observed. Summary ROCs (SROCs) were also calculated according to the HSROC model. RESULTS: For endometrial cancer, the estimated sensitivity was 82.6% (95% CR 66.9 91.8%) and the specificity was 99.7% (95% CR 98.1-99.9%). For endometrial hyperplasia, sensitivity was 75.2% (95% CR 55.4-88.1 %), while specificity was 91.5% (95% CR 85.7-95.0%). For endometrial polyps, sensitivity was 95.4% (95% CR 87.4-98.4%) and specificity was 96.4% (95% CR 93.7-98.0%). Finally, for submucous myomas, sensitivity was estimated to 97.0% (95% CR 89.8-99.2%) and specificity to 98.9% (95% CR 93.3-99.8%). CONCLUSIONS: Diagnostic accuracy for hysteroscopy is high for endometrial cancer, polyps and submucous myomas, but only moderate for endometrial hyperplasia. PMID- 25524535 TI - Phosphorylated IGFBP-1 in predicting successful vaginal delivery in post-term pregnancy. AB - PURPOSE: To estimate whether phosphorylated IGFBP-1 (phIGFBP-1) in cervical secretion in term and post-term pregnancies can predict spontaneous onset of labor or vaginal delivery. METHODS: A prospective cohort study of 167 women in singleton term and post-term pregnancies, was conducted at 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, between 2013 and 2014. phIGFBP-1 test (Actim Partus Medix Biochemica), ultrasound cervix assessment and Bishop score were analyzed in the study group. Spontaneous onset of labor was the primary and vaginal delivery was the secondary outcome. RESULTS: In 32.5 % of patients, spontaneous uterine contractions appeared. 67.5 % of women delivered vaginally, 32.5 % had cesarean section. phIGFBP-1 test predicted spontaneous onset of labor (sensitivity 0.69, specificity of 0.42) and successful vaginal delivery (0.67, 0.48). In the prediction of spontaneous delivery onset ultrasound cervical assessment and phIBFBP-1 had comparable sensitivity and in the prediction of successful vaginal birth all three tests had comparable sensitivity. The time from preinduction to spontaneous onset of delivery was significantly shorter in women with positive phIGFBP-1 test (13.65 +/- 6.7 vs 20.75 +/- 2.6 h; p = 0.006). CONCLUSION: A test for phIGFBP1 presence might be an additional tool for predicting both spontaneous onset of labor and successful vaginal delivery in post-term pregnancies. PMID- 25524537 TI - Could surgeon's expertise resolve the debate about surgery effectiveness in treatment of endometriosis-related infertility? AB - PURPOSE: Restoring the anatomical relationship and preserving the function of pelvic organs represent the ideal outcome of surgical intervention in patients suffering from endometriosis-related infertility. The aim of the study was to compare two large cohorts (Group A and Group B) of infertile patients in terms of postsurgical spontaneous/assisted fertility and perioperative surgical outcomes. The surgical treatment was performed by a skilled surgeon (Group A) and a surgeon dedicated to endometriosis-related infertility (Group B). METHODS: An observational cohort study on women affected by pelvic endometriosis who underwent laparoscopic treatment (to restore/improve their fertility) was conducted. A comparison, between Group A and Group B, in terms of perioperative surgical outcomes, clinical/ongoing pregnancy and live birth rates, spontaneous pregnancy rate and obstetrical outcome was performed. RESULTS: A significantly higher spontaneous fertility rate (particularly in the first year after surgery) and lower ectopic pregnancy rate were found in Group B. ART success rates were not affected by different surgical approaches. Perioperative and obstetrical outcomes were similar in both groups. CONCLUSION: In patients affected by endometriosis, the choice between expectant management versus intervention should be personalized: when the estimated probability of natural conception is low, surgery may be considered as a second-line treatment. Conversely, in all other cases surgery should be offered early (as a first-line approach) as it improves the chance of spontaneous conception. The laparoscopic treatment of infertility due to endometriosis must be performed by a skilled specialized surgeon to ensure a complete "pelvic cleanout" while respecting the anatomical structures and reducing the risk of fertility impairment due to surgical procedures. PMID- 25524538 TI - Very late recurrence (after more than 20 years) of epithelial ovarian carcinoma: case report and literature review. AB - PURPOSE: To present a case of very late (more than 20 years) recurrence of epithelial ovarian carcinoma and to review the pertinent literature. We encountered a 50-year-old patient who, at the age of 22, underwent cytoreductive surgery and adjuvant chemotherapy for stage III serous ovarian carcinoma. She recurred after 28 years and underwent secondary surgery and chemotherapy. METHOD: A PubMed search of the English literature containing the following key words: ovarian cancer, late recurrence, late relapse, late metastasis was performed. RESULTS: Only five cases (including the present one) with recurrence after more than 20 years are so far on record. Of these, four patients were 33 years old or younger and had advanced stage at diagnosis. Time to recurrence ranged from 21 to 28 years. All patients had serous carcinoma and three had recurrence in lymph nodes. CONCLUSIONS: Very late recurrence is an extremely rare event and may result from either regrowth of dormant tumor cells or from development of a new cancer. Lifelong follow-up is critically important for ovarian cancer patients. PMID- 25524540 TI - PPARalpha regulates endothelial progenitor cell maturation and myeloid lineage differentiation through a NADPH oxidase-dependent mechanism in mice. AB - Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a key modulator of lipid metabolism. Here, we propose that PPARalpha regulates the maturation and function of bone marrow (BM) progenitor cells. Although PPARalpha deletion increased the number of BM-resident cells and the differentiation of endothelial progenitor cells (EPCs) and monocytic progenitor cells, it impaired re endothelialization of injured carotid artery that was associated with reduced circulating EPCs. Also, PPARalpha deletion diminished the in vivo proangiogenic effect of PPARalpha agonist without affecting EPC differentiation markers. Macrophage colony-stimulating factor treatment increased the population of monocytic progenitor cells as well as secretome of BM-derived cells in PPARalpha wild-type but not in knockout mice. In addition, PPARalpha-null mice displayed reduced lymphocytes and increased monocytes and neutrophils in the blood. Furthermore, PPARalpha-null mice exhibited increments in the number of total cells (as well as of phenotypically distinct subpopulations of lymph node cells) but also a significant alteration in the number of various subpopulations of splenocytes and thymocytes. Finally, PPARalpha negatively regulated reactive oxygen species derived by NADPH oxidase in BM-resident progenitor cells. Taken together, our data provide evidence that PPARalpha is a critical regulator of recruitment, homing, and maturation of BM-derived progenitor cells. PMID- 25524541 TI - The translation of preschoolers' physical activity guidelines into a daily step count target. AB - This study aimed at translating the physical activity (PA) guideline (180 min of total PA per day) into a step count target in preschoolers. 535 Flemish preschoolers (mean age: 4.41 +/- 0.58) wore an ActiGraph accelerometer (GT1M, GT3X and GT3X+) - with activated step count function - for four consecutive days. The step count target was calculated from the accelerometer output using a regression equation, applying four different cut-points for light-to-vigorous PA: Pate, Evenson, Reilly, and Van Cauwenberghe. The present analysis showed that 180 min of total PA per day is equivalent to the following step count targets: 5,274 steps/day using the Pate cut-point, 4,653 steps/day using the Evenson cut-point, 11,379 steps/day using the Reilly cut-point and 13,326 steps/day using the Van Cauwenberghe cut-point. Future studies should focus on achieving consensus on which cut-points to use in preschoolers before a definite step count target in preschoolers can be proposed. Until then, we propose to use a provisional step count target of 11,500 steps/day as this step count target is attainable, realistic and helpful in promoting preschoolers' PA. PMID- 25524539 TI - Melatonin causes regression of endometriotic implants in rats by modulating angiogenesis, tissue levels of antioxidants and matrix metalloproteinases. AB - PURPOSE: The aim of this study was to test if melatonin causes regression of endometriotic implants and whether it influences implant levels of superoxide dismutase (SOD), malondialdehyde (MDA), vascular endothelial growth factor (VEGF), tissue inhibitor of metalloproteinase (TIMP)-2 and matrix metalloproteinase (MMP)-9 in rats. METHODS: Endometriotic implants were introduced surgically to 20 female Wistar albino rats, which were either treated with melatonin via intraperitoneal injection for four weeks (melatonin group, n = 10) or with saline (control group, n = 10) after a second-look laparotomies. The main outcome measures included volume (mm(3)) and weight (mg) of explants and tissue levels of SOD, MDA, VEGF, TIMP-2 and MMP-9. RESULTS: Before and after treatment implant volumes of the melatonin group were decreased significantly (P < 0.01) while there was no significant difference between the pretreatment and posttreatment implant volumes of the control group. Moreover, weight (P < 0.05) and histologic score (P < 0.05) of implants of the melatonin-treated rats were significantly lower than controls. Activity of SOD and TIMP-2 staining in melatonin group was significantly higher (both P < 0.01) while there were significant reductions in implant levels of VEGF and MMP-9 in melatonin group (both P < 0.01) than controls. CONCLUSIONS: Melatonin induces the regression of endometriotic implants in rats by modulating implant levels of SOD, MDA, VEGF, MMP-9 and TIMP-2. PMID- 25524542 TI - Impact of Australia's introduction of tobacco plain packs on adult smokers' pack related perceptions and responses: results from a continuous tracking survey. AB - OBJECTIVES: To investigate the impact of Australia's plain tobacco packaging policy on two stated purposes of the legislation--increasing the impact of health warnings and decreasing the promotional appeal of packaging--among adult smokers. DESIGN: Serial cross-sectional study with weekly telephone surveys (April 2006 May 2013). Interrupted time-series analyses using ARIMA modelling and linear regression models were used to investigate intervention effects. PARTICIPANTS: 15,745 adult smokers (aged 18 years and above) in New South Wales (NSW), Australia. Random selection of participants involved recruiting households using random digit dialling and selecting the nth oldest smoker for interview. INTERVENTION: The introduction of the legislation on 1 October 2012. OUTCOMES: Salience of tobacco pack health warnings, cognitive and emotional responses to warnings, avoidance of warnings, perceptions regarding one's cigarette pack. RESULTS: Adjusting for background trends, seasonality, antismoking advertising activity and cigarette costliness, results from ARIMA modelling showed that, 2-3 months after the introduction of the new packs, there was a significant increase in the absolute proportion of smokers having strong cognitive (9.8% increase, p=0.005), emotional (8.6% increase, p=0.01) and avoidant (9.8% increase, p=0.0005) responses to on-pack health warnings. Similarly, there was a significant increase in the proportion of smokers strongly disagreeing that the look of their cigarette pack is attractive (57.5% increase, p<0.0001), says something good about them (54.5% increase, p<0.0001), influences the brand they buy (40.6% increase, p<0.0001), makes their pack stand out (55.6% increase, p<0.0001), is fashionable (44.7% increase, p<0.0001) and matches their style (48.1% increase, p<0.0001). Changes in these outcomes were maintained 6 months postintervention. CONCLUSIONS: The introductory effects of the plain packaging legislation among adult smokers are consistent with the specific objectives of the legislation in regard to reducing promotional appeal and increasing effectiveness of health warnings. PMID- 25524543 TI - Discontinuation of infliximab therapy in patients with Crohn's disease in sustained complete remission (the STOP IT study): protocol for a double-blind, randomised, placebo-controlled, multicentre trial. AB - INTRODUCTION: Infliximab (IFX), a monoclonal chimeric antibody against tumour necrosis factor (TNF) alpha, is effective for induction and maintenance of remission in moderate to severe Crohn's disease. Discontinuation of IFX maintenance therapy in patients in remission should be considered in order to reduce the potential long-term side effects and lower costs. METHODS AND ANALYSIS: This is a prospective, double-blind, randomised, placebo-controlled, multicentre study of patients with luminal Crohn's disease who have been treated with IFX for at least 1 year and are in sustained complete clinical, biochemical and endoscopic remission (ie, Crohn's Disease Activity Index (CDAI) score <150, complete mucosal healing and biochemical markers of inflammation within the normal range). These patients are randomised to receive placebo infusions or continue IFX maintenance therapy. The primary end point is the proportion of patients in maintained remission after 48 weeks (def. CDAI <150). ETHICS AND DISSEMINATION: It is estimated that the knowledge gained about how to optimally handle patients with Crohn's disease in complete long-term sustained remission on IFX is proportionate to the risks and inconveniences related to participation in this study. Prolonged exposure to IFX may cause severe side effects and increased risk of malignancies. Conversely, IFX discontinuation should not unnecessarily create a high risk of relapse. Thus, empirical evidence is needed concerning the safety of discontinuing IFX once a patient exhibits sustained remission. Study results will be published in an English language scientific medical journal. The study is approved by the Danish Medicines Agency (EudraCT-number: 2012-002702-51) and the Regional Ethics Committee of Region Hovedstaden Denmark (Approval-number: H-4-2012-099). The project is reported to the Danish Data Protection Agency (ID number: 2007-58-0015/HEH.750.89-27), registered at Clinicaltrials.gov, and monitored by independent GCP units for the University of Copenhagen, Odense and Aarhus. The current approved protocol is V.3.2, dated 1 June 2014. TRIAL REGISTRATION NUMBER: http://clinicaltrials.gov/show/NCT01817426. PMID- 25524544 TI - Prescribing of antipsychotics in UK primary care: a cohort study. AB - OBJECTIVE: To examine the recorded indication for antipsychotic prescriptions in UK primary care. DESIGN: Cohort study. SETTING: Primary care. PARTICIPANTS: Individuals prescribed antipsychotics between 2007 and 2011. MEASURES: The proportion of individuals prescribed antipsychotics with a diagnosis of (1) psychosis and bipolar disorder, (2) other diagnoses including depression, anxiety and dementia and (3) none of these diagnoses. RESULTS: We identified 47,724 individuals prescribed antipsychotic agents. 13,941 received first-generation agents and 27,966 received second-generation agents. The rates of prescribing were higher in females (incidence rate ratio (IRR) 1.092 (95% CI 1.088 to 1.095), older people (80+ vs 40-49; IRR 2.234 (2.222 to 2.246)) and in those from the most deprived areas (most deprived vs least deprived IRR 3.487 (3.567 to 3.606). Of those receiving first-generation antipsychotics, less than 50% had a diagnosis of psychosis/bipolar disorder. For the second-generation agents, the numbers ranged from 4824 (36%) for quetiapine to 7094 (62%) for olanzapine. In patients without psychosis/bipolar disorder, common diagnoses included anxiety, depression, dementia, sleep and personality disorders. For example, in risperidone users, 14% had an anxiety code, 22% depression, 12% dementia, 11% sleep disorder and 4% personality disorder. The median daily doses and duration of treatment were greater in those with schizophrenia (eg, risperidone median daily dose 4 mg; IQR 2-6: median duration 1.2 years) than in those with non psychotic/bipolar disorders such as depression or anxiety (eg, risperidone 1 mg; IQR 1-2: 0.6 years). A relatively large proportion (between 6% and 17%) of people receiving individual antipsychotics had none of the diagnoses stated above. CONCLUSIONS: In UK primary care, a large proportion of people prescribed antipsychotics have no record of psychotic or bipolar disorder. They are often older people with conditions including dementia, non-psychotic depression, anxiety and sleep disorders. PMID- 25524545 TI - Risk factors for acute exacerbations of COPD in a primary care population: a retrospective observational cohort study. AB - OBJECTIVES: To evaluate risk factors associated with exacerbation frequency in primary care. Information on exacerbations of chronic obstructive pulmonary disease (COPD) has mainly been generated by secondary care-based clinical cohorts. DESIGN: Retrospective observational cohort study. SETTING: Electronic medical records database (England and Wales). PARTICIPANTS: 58,589 patients with COPD aged >=40 years with COPD diagnosis recorded between 1 April 2009 and 30 September 2012, and with at least 365 days of follow-up before and after the COPD diagnosis, were identified in the Clinical Practice Research Datalink. Mean age: 69 years; 47% female; mean forced expiratory volume in 1s 60% predicted. OUTCOME MEASURES: Data on moderate or severe exacerbation episodes defined by diagnosis and/or medication codes 12 months following cohort entry were retrieved, together with demographic and clinical characteristics. Associations between patient characteristics and odds of having none versus one, none versus frequent (>=2) and one versus frequent exacerbations over 12 months follow-up were evaluated using multivariate logistic regression models. RESULTS: During follow-up, 23% of patients had evidence of frequent moderate-to-severe COPD exacerbations (24% one; 53% none). Independent predictors of increased odds of having exacerbations during the follow-up, either frequent episodes or one episode, included prior exacerbations, increasing dyspnoea score, increasing grade of airflow limitation, females and prior or current history of several comorbidities (eg, asthma, depression, anxiety, heart failure and cancer). CONCLUSIONS: Primary care-managed patients with COPD at the highest risk of exacerbations can be identified by exploring medical history for the presence of prior exacerbations, greater COPD disease severity and co-occurrence of other medical conditions. PMID- 25524547 TI - Antiproliferative Effect of Novel Aminoacridine-based Compounds. AB - We tested the antiproliferative activity and mechanism of the action of several novel aminoacridine derivatives. Six different cancer cell lines were used to evaluate the potential cytotoxic effect of eleven aminoacridine-based molecules. A standard MTT assay was used for cell bioavailability analysis. Additionally, the potential cytotoxic effect of the tested compounds on non-cancer cells was investigated in rat skeletal muscle myotubes (L6) and in bovine aortic smooth muscle cells. In order to investigate whether the DNA binding activity of tested compounds correlated with their cytotoxic effect, circular dichroism (CD) measurement and DNA T4 ligase assay were performed. Finally, the potential mutagenic activity of the lead compound 5 was investigated. The cytotoxic effect of compound 5 in cancer cells was obtained in lower concentrations than the well known: 9- aminoacridine based drug, amsacrine. The lead compound binds to DNA, but in a different mode than the parent molecules. Additionally, compound 5 was not cytotoxic in the effective range of concentrations in non-cancer cells. In identical concentrations, the parent compound (9-aminoacridine) and amsacrine were extremely toxic for both types of these normal cells. Finally, based on CD measurement and T4 ligase assay, it was confirmed that 5 binds to DNA but in different from the parent compounds manner. Important to mention, that compound 5 might have increased mutagenic activity which must be verified in vivo. Based on these in vitro results, we conclude that 5 is a more potent and more selective antiprolifirative compound than amsacrine. Compound 5 was also more effective in HepG2 and P-12 cells. Thus, 5 is suitable for future in vivo biological evaluation and its structure might be used as a basis for developing novel anticancer drugs. PMID- 25524546 TI - Access to medicines by child refugees in the East Midlands region of England: a cross-sectional study. AB - OBJECTIVES: To explore access to primary healthcare and drug therapy by refugee children in the East Midlands region of England. DESIGN: Interviews with refugees with children and a control group of British parents with children. SETTING: East Midlands region of England. PARTICIPANTS: 50 refugees with children and a control group of 50 parents with children. MAIN OUTCOME MEASURES: Number of medicines used by children in the last month and the past 6 months. Health of parents and children. Registration with a general practitioner (GP). RESULTS: All families in both groups were registered with a GP. There was no difference in the number of children in the two groups experiencing illnesses .In the last month, 30 refugee children received 60 medicines and 31 control children 63 medicines. In the past 6 months, 48 refugee children received 108 medicines and 43 control children 96 medicines. There was no difference between the two groups of children in relation to the likelihood of receiving any medicines in either the last month (P=0.839) or the past 6 months (p=0.81). Children in the refugee group were more likely to receive prescribed medicines for the last month (p=0.008) and the past 6 months (p<0.001). They were also less likely to receive over the counter (OTC) medicines in the past 6 months (p=0.009). CONCLUSIONS: The refugee children in this study in the East Midlands had access to primary healthcare, medicines and a family doctor. They were more likely to receive prescribed medicines and less likely to receive OTC medicines, especially paracetamol. PMID- 25524548 TI - Sex chromosome drive. AB - Sex chromosome drivers are selfish elements that subvert Mendel's first law of segregation and therefore are overrepresented among the products of meiosis. The sex-biased progeny produced then fuels an extended genetic conflict between the driver and the rest of the genome. Many examples of sex chromosome drive are known, but the occurrence of this phenomenon is probably largely underestimated because of the difficulty to detect it. Remarkably, nearly all sex chromosome drivers are found in two clades, Rodentia and Diptera. Although very little is known about the molecular and cellular mechanisms of drive, epigenetic processes such as chromatin regulation could be involved in many instances. Yet, its evolutionary consequences are far-reaching, from the evolution of mating systems and sex determination to the emergence of new species. PMID- 25524550 TI - Association of a polymorphism of the interleukin 6 receptor gene with chronic kidney disease in Japanese individuals. AB - AIM: Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified in Caucasian populations by genome-wide association studies (GWASs). The aim of the present study was to examine a possible association of chronic kidney disease (CKD) with 29 polymorphisms previously identified as susceptibility loci for CAD by meta-analyses of GWASs. METHODS: The study population comprised 2247 Japanese individuals, including 1588 subjects with CKD [estimated glomerular filtration rate (eGFR) of <60 mL min(-1) 1.73 m( 2) ] and 659 controls (eGFR of >=90 mL min(-1) 1.73 m(-2) ). The genotypes for 29 polymorphisms of 28 candidate genes were determined. RESULTS: The chi(2) test revealed that rs4845625 (T->C) of IL6R, rs4773144 (A->G) of COL4A1, rs9319428 (G >A) of FLT1, and rs46522 (T->C) of UBE2Z were significantly (P < 0.05) related to CKD. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidaemia revealed that rs4845625 of IL6R (P = 0.0008; dominant model; odds ratio, 1.49), rs4773144 of COL4A1 (P = 0.0252; dominant model; odds ratio, 1.28), and rs9319428 of FLT1 (P = 0.0260: additive model; odds ratio, 0.77) were significantly associated with CKD. The serum concentration of creatinine was significantly (P = 0.0065) greater and eGFR was significantly (P = 0.0009) lower in individuals with the TC or CC genotype of IL6R than in those with the TT genotype. CONCLUSION: The rs4845625 of IL6R may be a susceptibility locus for CKD in Japanese individuals. PMID- 25524551 TI - Polo-like kinase 1 inhibitor BI2536 causes mitotic catastrophe following activation of the spindle assembly checkpoint in non-small cell lung cancer cells. AB - Polo-like kinase 1 (PLK1), a critical kinase that regulates multiple steps in mitosis, is overexpressed in diverse human cancers; thus many PLK1 inhibitors have been developed as potential cancer therapeutic agents. One of these compounds, the PLK1-specific inhibitor BI2536, has been investigated as a cytotoxic drug in several cancers, including lung cancer; however, the detailed mechanism by which BI2536 induces defects in cell proliferation of non-small cell lung cancer (NSCLC) has not yet been determined. We found that BI2536 treatment resulted in mitotic arrest due to improper formation of the mitotic spindles and mitotic centrosomes. The unattached kinetochores in BI2536-treated NSCLC cells activated the spindle assembly checkpoint (SAC). The prolonged activation of the SAC led to a type of apoptotic cell death referred to as mitotic catastrophe. Finally, BI2536-treated NSCLC cells show a defect in cell proliferation. Overall, these data indicate that PLK1 inhibition via mitotic disruption represents a potential approach for the treatment of NSCLC. PMID- 25524552 TI - A novel temozolomide analog, NEO212, with enhanced activity against MGMT-positive melanoma in vitro and in vivo. AB - The alkylating agent temozolomide (TMZ) represents an important component of current melanoma therapy, but overexpression of O6-methyl-guanine DNA methyltransferase (MGMT) in tumor cells confers resistance to TMZ and impairs therapeutic outcome. We investigated a novel perillyl alcohol (POH)-conjugated analog of TMZ, NEO212, for its ability to exert anticancer activity against MGMT positive melanoma cells. Human melanoma cells with variable MGMT expression levels were treated with NEO212, TMZ, or perillyl alcohol in vitro and in vivo, and markers of DNA damage and apoptosis, and tumor cell growth were investigated. NEO212 displayed substantially greater anticancer activity than any of the other treatments. It reduced colony formation of MGMT-positive cells up to eight times more effectively than TMZ, and much more potently induced DNA damage and cell death. In a nude mouse tumor model, NEO212 showed significant activity against MGMT-positive melanoma, whereas TMZ, or a mix of TMZ plus POH, was ineffective. At the same time, NEO212 was well tolerated. NEO212 may have potential as a more effective therapy for advanced melanoma, and should become particularly suitable for the treatment of patients with MGMT-positive tumors. PMID- 25524549 TI - Tumor necrosis factor superfamily in innate immunity and inflammation. AB - The tumor necrosis factor superfamily (TNFSF) and its corresponding receptor superfamily (TNFRSF) form communication pathways required for developmental, homeostatic, and stimulus-responsive processes in vivo. Although this receptor ligand system operates between many different cell types and organ systems, many of these proteins play specific roles in immune system function. The TNFSF and TNFRSF proteins lymphotoxins, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator [HVEM], a receptor expressed by T lymphocytes), lymphotoxin-beta receptor (LT-betaR), and HVEM are used by embryonic and adult innate lymphocytes to promote the development and homeostasis of lymphoid organs. Lymphotoxin expressing innate-acting B cells construct microenvironments in lymphoid organs that restrict pathogen spread and initiate interferon defenses. Recent results illustrate how the communication networks formed among these cytokines and the coreceptors B and T lymphocyte attenuator (BTLA) and CD160 both inhibit and activate innate lymphoid cells (ILCs), innate gammadelta T cells, and natural killer (NK) cells. Understanding the role of TNFSF/TNFRSF and interacting proteins in innate cells will likely reveal avenues for future therapeutics for human disease. PMID- 25524553 TI - MicroRNAs in colorectal cancer: small molecules with big functions. AB - Colorectal cancer (CRC) is the third most lethal malignancy, with pathogenesis intricately dependent upon microRNAs (miRNAs). miRNAs are short, non-protein coding RNAs, targeting the 3'-untranslated regions (3'-UTR) of certain mRNAs. They usually serve as tumor suppressors or oncogenes, and participate in tumor phenotype maintenance. Therefore, miRNAs consequently regulate CRC carcinogenesis and other biological functions, including apoptosis, development, angiogenesis, migration, and proliferation. Due to its differential expression and distinct stability, miRNAs are regarded as molecular biomarkers (for diagnosis/prognosis) and therapeutic targets for CRC. Recently, a remarkable number of miRNAs have been discovered with implications via incompletely understood mechanisms in CRC. As further study of relevant miRNAs continues, it is hopeful that novel miRNA based therapeutic strategies may be available for CRC patients in the future. PMID- 25524554 TI - Estrogen receptors beta1 and beta2 are associated with distinct responses of estrogen receptor alpha-positive breast carcinoma to adjuvant endocrine therapy. AB - Our purpose was to assess whether and how ERbeta1 and/or ERbeta2 expression status could predict response of early stage ERalpha-positive breast carcinoma to adjuvant endocrine therapy (AET). ERbeta1 and ERbeta2 expression were determined using immunohistochemistry. ERbeta1- and ERbeta2-positivity were derived from receiver operating characteristic analysis and the median percentage of immunostained tumor cells, respectively. Patients with recurrent disease were grouped according to whether they relapsed within 4 years or after 4 years from surgery. The predictive significance of ERbeta1 and ERbeta2 was determined using Kaplan-Meier survival analysis and Cox proportional hazards regression analysis. ERbeta1-positivity in the first-4-year relapse patient group was lower and ERbeta2-positivity in the post-4-year relapse group was higher compared with no relapse group. ERbeta1-positivity was associated with lower tumor size and longer first-4-year disease-free survival, while ERbeta2-positivity was associated with shorter post-4-year disease-free survival. Cox multivariate analysis including ERbeta1, ERbeta2 and established clinico-pathological variables showed that ERbeta1-positivity was an independent predictor of lower first-4-year risk of relapse. Thus, low ERbeta1 expression and high ERbeta2 expression are markers for identification of AET-treated ERalpha-positive breast carcinoma patients at risk of early and late relapse, respectively. PMID- 25524555 TI - Oxamate-mediated inhibition of lactate dehydrogenase induces protective autophagy in gastric cancer cells: involvement of the Akt-mTOR signaling pathway. AB - Cancer cells produce a substantial amount of energy through aerobic glycolysis even in the presence of adequate oxygen. Lactate dehydrogenase (LDH), a key regulator of glycolysis, reversibly catalyzes the conversion of pyruvate to lactate. Recently, oxamate, an inhibitor of LDH, has been shown to be a promising anticancer agent. However, the detailed mechanism remains largely unclear. In this study, we demonstrate that oxamate inhibits the viability of human gastric cancer cells in a dose- and time-dependent manner. In addition, treatment with oxamate induces protective autophagy in gastric cancer cells. Moreover, autophagy inhibited by chloroquine or Beclin 1 small interfering RNA (siRNA) enhances oxamate-induced apoptosis and proliferation inhibition. Further study has shown that oxamate treatment significantly augments reactive oxygen species (ROS) production. Furthermore, cells pretreated with N-acetyl cysteine (NAC), a ROS inhibitor, display significantly reduced ROS production and attenuated oxamate induced autophagy. Finally, functional studies reveal that the Akt-mTOR signaling pathway, a major negative regulator of autophagy, is inhibited by oxamate. Together, our results provide new insights regarding the biological and anti proliferative activities of oxamate against gastric cancer, and may offer a promising therapeutic strategy for gastric cancer. PMID- 25524556 TI - Antiphospholipid syndrome: 30 years and our contribution. AB - In 1983, Graham Hughes first described the concept of antiphospholipid syndrome (APS). In 1984, we described the enzyme-linked immunosorbent assay (ELISA) system which directly detected circulating aCL in patients with systemic lupus erythematosus (SLE) who revealed biological false positive serological test for syphilis. In 1990, three groups, including our group, independently reported the necessity of a cofactor for the binding of autoimmune anticardiolipin antibodies (aCL) to the solid phase phospholipids. beta2-glycoprotein I (beta2GPI) was identified as this cofactor. In 1994,the epitope for aCL was shown to develop when beta2GPI is adsorbed on polyoxygenated polystyrene plates. In 2000, we described antiprothrombin antibodies bind to prothrombin exposed to immobilized phosphatidylserine and established a phosphatidylserine dependent monoclonal antiprothrombin antibody. In 2004, a novel role of nicked beta2GPI was identified in the negative feedback pathway of extrinsic fibrinolysis. Nicked beta2GPI was found to bind angiostatin 4.5 and to attenuate its antiangiogenic property. In 2004, we demonstrated that the p38 MAPK pathway mediates induction of the TF gene in stimulated with human monoclonal anti- beta2GPI antibodies. Very recently, beta2GPI was identified as a complement regulator. The cross-link between complement activation and prothrombotic status in patients with APS has been drawn much attention. Genetic factors are hypothesized to play a role in the susceptibility to APS based on several family studies in patients with antiphospholipid antibodies (aPL) and/or clinical manifestations of APS. The genetics of beta2GPI has been extensively studied. 247 Val/Leu polymorphism can affect the conformational change of beta2-GPI and the exposure of the epitopes for aCL. We found that 247 Val was correlated with anti-beta2-GPI production in patients with primary APS, and 247 Val may be important for beta2-GPI antigenicity. STAT4 SNP in Japanese patients with SLE and/or APS. T allele frequencies in SLE and APS were significantly elevated compared with that in healthy controls. When analyzed only in primary APS patients, T allele frequency was further higher. BANK1, BLK and SNP in 1q25.1 region were associated with not only SLE but also APS in Japanese population. These results suggest that APS and SLE, in part, share a common genetic background. PMID- 25524557 TI - Closing the gap: training for healthcare workers and people with disabilities on the interrelationship of HIV and disability. AB - BACKGROUND: HIV and disability are interrelated providing a double burden to HIV endemic countries in East and Southern Africa and their already fragile health systems. Although literature reveals that people with disabilities are particularly vulnerable to HIV and that HIV, its opportunistic infections and treatments can cause disability, only few interventions target this issue and none have been evaluated in this region. METHODS: Formative evaluation was undertaken with regard to the effectiveness of a workshop-based intervention for healthcare workers and people with disabilities on the intersection of disability and HIV in order to inform the further development of this intervention. The formative evaluation assessed participants' perception of the inclusion of disability in HIV services and of opportunities to initiate change after the workshops. It also captured their experiences in utilising knowledge and skills after the workshops using quantitative (short checklist and ranking exercise) and qualitative (semi-structured interviews) methods of inquiry. Frequencies and conventional content analysis were used in the analysis of the data. This study presents an example of applied research conducted under real-world conditions. RESULTS: 60 healthcare workers and people with disabilities took part in this pilot workshop training and participated in the formative evaluation. Healthcare workers and people with disabilities alike identified various barriers to access health services. Reasonable accommodation was perceived as being mainly absent by most participants, while some participants indicated a lack of physical accessibility in the form of universal design. Participants also identified a lack of integration of services and disability-related skills within the healthcare staff. Participants reported a number of enablers, success and challenges while implementing the knowledge from the workshops related to structural issues, service provision and integration. While participants worked on health workers' attitudes and accessibility of services, screening and referrals practice was not improved through the workshops. CONCLUSIONS: Formative evaluation indicates that the workshops can be effective not only in sensitising healthcare workers and people with disabilities to opportunities to improve services for people with disabilities but also to provide knowledge and skills to initiate improvements. Skills that need more practical training (e.g. screening for disability) need to be trained in more detail, and this will inform the adaptation of the workshops. However, the workshop evaluation also revealed that without policy implementation and budget allocations this change would only be limited. Implications for Rehabilitation HIV, its co-morbidities and treatments cause health conditions and impairments that have the potential to develop into disability. People with disabilities are at increased risk of exposure to HIV. Rehabilitation professionals, healthcare workers and people with disabilities can be sensitised in a three-day workshop on the relationship of disability and HIV. However, the trained participants can only implement no or low-cost elements of interventions, while high-cost interventions need budget allocations at provincial and national level. PMID- 25524558 TI - Controlling networks of nonlinearly-coupled nodes using response surfaces. AB - Control of complex processes is a major goal of network analyses. Most approaches to control nonlinearly coupled systems require the network topology and/or network dynamics. Unfortunately, neither the full set of participating nodes nor the network topology is known for many important systems. On the other hand, system responses to perturbations are often easily measured. We show how the collection of such responses -a response surface- can be used for network control. Analyses of model systems show that response surfaces are smooth and hence can be approximated using low order polynomials. Importantly, these approximations are largely insensitive to stochastic fluctuations in data or measurement errors. They can be used to compute how a small set of nodes need to be altered in order to direct the network close to a pre-specified target state. These ideas, illustrated on a nonlinear electrical circuit, can prove useful in many contexts including in reprogramming cellular states. PMID- 25524559 TI - Improving recognition and referral of patients with an increased familial risk of colorectal cancer: results from a randomized controlled trial. AB - AIM: Only 12-49% of colorectal cancer (CRC) patients and their first-degree relatives with an increased familial CRC risk are referred for cancer prevention measures (surveillance colonoscopies or genetic counselling). The study was performed to evaluate the effectiveness and feasibility of a novel strategy to improve the uptake of genetic counselling for high risk individuals and surveillance colonoscopy for moderate risk groups. METHOD: Eighteen hospitals participated in a clustered randomized controlled trial. Patients in nine hospitals received usual care (group A). Nine other hospitals received the novel strategy (group B) including access to a website for patients and clinicians, patient-targeted brochures and clinician-targeted education and pocket referral cards. Data before and after dissemination of the strategy were collected from questionnaires and medical records. RESULTS: Data were complete for 358 (44%) of 820 CRC patients and 50 (36%) of 137 clinicians before dissemination of the strategy and 392/862 patients (45%) and 47/137 clinicians (34%) after. Referral for cancer prevention measures was assessed at a median of 8 (2-12) months after CRC diagnosis in groups A and B before the dissemination of the strategy and in group A after. In group B referral was assessed at a median of 9 (4-11) months after the dissemination of the strategy. Uptake of genetic counselling by high risk patients was equal in groups A and B, being 33% before and 15% after (P = 0.003). Uptake of surveillance colonoscopy by moderate risk relatives did not change significantly (group A, 36% before vs 41% after; group B, 33% before vs 19% after). In group B 94/140 patients (67%) and 25/72 clinicians (35%) visited the website and 34/140 (24%) patients read the brochure. Patients valued clinicians' information as most useful, followed by the patient brochure. Clinicians preferred pocket cards and education. CONCLUSION: Our strategy did not improve referral for cancer prevention measures. Although the newly offered strategy elements were appreciated, patients preferred clinicians' advice regarding referral for cancer prevention measures. It may be useful to aim future interventions at healthcare professionals rather than patients to improve the prevention of familial cancer. PMID- 25524560 TI - Kinetic variations between reverse transcriptases of viral protein X coding and noncoding lentiviruses. AB - BACKGROUND: Host SAM domain and HD domain-containing protein 1 (SAMHD1) suppresses reverse transcription kinetics of HIV-1 in nondividing cells such as macrophages by hydrolyzing and nearly depleting cellular dNTPs, which are the substrates of viral reverse transcriptase (RT). However, unlike HIV-1, HIV-2 and SIVsm encode viral protein X (Vpx), which counteracts the dNTPase activity of SAMHD1 and elevates dNTP concentration, allowing the viruses to replicate under abundant dNTP conditions even in nondividing cells. FINDINGS: Here we tested whether RTs of these Vpx coding and noncoding lentiviruses display different enzyme kinetic profiles in response to dNTP concentrations. For this test, we characterized an extensive collection of RTs from 7 HIV-1 strains, 4 HIV-2 strains and 7 SIV strains, and determined their steady-state kinetic parameters. The K m values of all HIV-1 RTs were consistently low and close to the low dNTP concentrations found in macrophages. However, the K m values of SIV and HIV-2 RTs were not only higher than those of HIV-1 RTs but also varied significantly, indicating that HIV-2/SIV RTs require higher dNTP concentrations for efficient DNA synthesis, compared to HIV-1 RT. However, the k cat values of all eighteen lentiviral RTs were very similar. CONCLUSIONS: Our biochemical analysis supports the hypothesis that the enzymological properties, particularly, K m values, of lentivirus RTs, are mechanistically tied with the cellular dNTP availability in nondividing target cells, which is controlled by SAMHD1 and Vpx. PMID- 25524561 TI - Risk factors for initial surgery in patients with Crohn's disease in Central China. AB - PURPOSES: To establish the risk factors for initial surgery in patients with Crohn's disease (CD) in Central China. METHODS: The subjects of this study were patients with CD treated at Zhongnan Hospital of Wuhan University, an IBD center in Wuhan City, Central China, between January, 1992 and June, 2012. We conducted uni- and multivariate analyses of the risk factors for initial surgery for CD in these patients. RESULTS: A total of 197 patients with CD were included in this study. The cumulative incidence of initial surgery was 21.8, 28.9, and 32.5%, at 1, 5, and 10 years, respectively, after the onset of symptoms. Analysis using multivariate Cox models showed that the relative risk for initial surgery was lower in patients who were younger than 16 years at diagnosis (HR = 0.57, 95% CI 0.34-0.96, P = 0.034). The risk increased in patients with stricturing (HR = 4.75, 95% CI 2.48-9.11), those with CD showing penetrating behavior at diagnosis (HR = 5.14, 95% CI 2.54-10.39), and those with a history of appendectomy (HR = 1.87, 95% CI 1.03-3.40). Azathioprine (AZA) treatment appeared to decrease the risk for initial surgery in patients with non-penetrating and non-stricturing CD (HR = 0.14, 95% CI 0.13-3.10). CONCLUSION: Age at diagnosis, disease behavior, and a history of appendectomy appeared to have an impact on the risk for initial surgery. AZA treatment might be helpful for decreasing the risk of needing initial surgery for patients in whom stricturing or fistulizing disease has not yet developed. PMID- 25524564 TI - Safety and efficacy of same-day discharge following elective percutaneous coronary intervention, including evaluation of next day troponin T levels. AB - BACKGROUND: As patients are increasingly undergoing elective percutaneous coronary intervention (PCI) with same-day discharge (SDD), and as post-PCI troponin T (TnT) elevations are associated with increased rates of death/myocardial infarction (MI) following elective PCI, we examined late outcomes with respect to post-PCI TnT elevations in patients undergoing SDD. METHODS AND RESULTS: We studied 303 patients (mean age 62+/-9years, 89% male) who underwent elective-PCI between October 2007 and September 2012, of whom 149 had SDD and 154 stayed overnight (ON) who were age-and sex-matched. Eligibility for SDD excluded patients with: multi-vessel PCI, proximal LAD lesions, chronic total occlusions, side branch occlusions, or access site complications. Femoral access rates were 72% and 96% among SDD and ON patients respectively. Post-PCI, SDD patients left at 4.40[4.13-5.30]hours, and ON patients left at 23.44[21.50 25.41]hours (p<0.001). Overall 8.45% met the 2012 universal MI definition. No patients were re-hospitalised within 48hours. At 30-days, unplanned cardiac re hospitalisation rates were 3.4% and 0.7% among SDD and ON patients (p=0.118); the only event was MI in an SDD patient. At 16[9-32] months, rates of death, MI, target vessel revascularisation, stroke, were 1.3%,1.3%,2.7% and 1% respectively; the composite rate was 6%(6.1% SDD; 6% ON; p=0.965). Late death/MI rates among patients with, and without, post-PCI TnT levels>=5xURL were 3.4% and 2.8% respectively (p=0.588). CONCLUSION: SDD following elective PCI among low risk patients appears to be safe and >=5 fold post-PCI TnT elevations did not appear to confer incremental short and long term risk. A larger cohort is required to confirm this observation. PMID- 25524563 TI - The spliceosomal PRP19 complex of trypanosomes. AB - In trypanosomes, mRNAs are processed by spliced leader (SL) trans splicing, in which a capped SL, derived from SL RNA, is spliced onto the 5' end of each mRNA. This process is mediated by the spliceosome, a large and dynamic RNA-protein machinery consisting of small nuclear ribonucleoproteins (snRNPs) and non-snRNP proteins. Due to early evolutionary divergence, the amino acid sequences of trypanosome splicing factors exhibit limited similarity to those of their eukaryotic orthologs making their bioinformatic identification challenging. Most of the ~ 60 protein components that have been characterized thus far are snRNP proteins because, in contrast to individual snRNPs, purification of intact spliceosomes has not been achieved yet. Here, we characterize the non-snRNP PRP19 complex of Trypanosoma brucei. We identified a complex that contained the core subunits PRP19, CDC5, PRL1, and SPF27, as well as PRP17, SKIP and PPIL1. Three of these proteins were newly annotated. The PRP19 complex was associated primarily with the activated spliceosome and, accordingly, SPF27 silencing blocked the first splicing step. Interestingly, SPF27 silencing caused an accumulation of SL RNA with a hypomethylated cap that closely resembled the defect observed previously upon depletion of the cyclin-dependent kinase CRK9, indicating that both proteins may function in spliceosome activation. PMID- 25524565 TI - Marital status and head and neck cancer outcomes. AB - BACKGROUND: The objective of this study was to examine the effects of marital status on stage at presentation, receipt of treatment, and survival in patients with head and neck cancer (HNC). METHODS: The Surveillance, Epidemiology, and End Results database was used to analyze 51,272 patients who were diagnosed with HNC from 2007 to 2010. The impact of marital status on cancer stage at presentation, receipt of definitive treatment, and HNC-specific mortality (HNCSM) was determined using multivariable logistic and Fine and Gray competing-risks regression models, as appropriate. RESULTS: Marriage had a protective effect against metastatic presentation of oral and laryngeal cancers (oral cancer: adjusted odds ratio [AOR], 0.72; 95% confidence interval [CI], 0.60-0.87; P < .001; laryngeal cancer: AOR, 0.53; 95% CI, 0.42-0.67; P < .001) but not against oropharyngeal, hypopharyngeal, or nasopharyngeal cancers. Among patients with nonmetastatic disease, married patients were more likely to receive definitive treatment (overall AOR, 1.77; 95% CI, 1.60-1.95; P < .001) and had a lower risk of HNCSM (overall adjusted hazard ratio, 0.72; 95% CI, 0.68-0.77; P < .001); these associations remained significant across all HNC sites. CONCLUSIONS: Among patients with oral and laryngeal cancers, those who are married are less likely to present with metastatic disease. In addition, married patients are more likely to receive definitive treatment and less likely to die from HNC across all HNC sites. This suggests that spousal support may have a role in the surveillance of visual and symptomatic HNC types and leads to higher rates of treatment and better survival across all HNC sites. PMID- 25524567 TI - A severe collodion phenotype in the newborn period associated with a homozygous missense mutation in ALOX12B. PMID- 25524568 TI - Diagnosis and molecular aspects of solid-pseudopapillary neoplasms of the pancreas. AB - Solid-pseudopapillary neoplasm of the pancreas (SPN) is an uncommon low-grade malignant neoplasm occurring mostly in young women. In addition to its distinctive pathological appearance of pseudopapillae with poorly cohesive neoplastic cells, rare variants exist raising the differential diagnosis especially with neuroendocrine neoplasms. The overall prognosis for patients with SPNs is excellent after surgical resection. Nevertheless, 10% of cases may have malignant behavior characterized by tumor recurrence and/or metastasis. Despite numerous studies, the histogenesis of this neoplasm remains unclear. Distinctive molecular alterations such as the presence of CTNNB1 mutations are observed in nearly all cases, while mutations classically observed in ductal adenocarcinoma, such as KRAS, TP53, and SMAD4, are not observed in SPNs, reinforcing its distinct nature compared to all other pancreatic neoplasms. Recent transcriptional studies have shown that activation of the Wnt/beta-catenin pathway in these tumors is associated with the upregulation of genes belonging to Notch, Hedgehog, and androgen receptor signaling pathways. PMID- 25524569 TI - Metagenomic-based study of the phylogenetic and functional gene diversity in Galapagos land and marine iguanas. AB - In this study, a metagenome-based analysis of the fecal samples from the macrophytic algae-consuming marine iguana (MI; Amblyrhynchus cristatus) and terrestrial biomass-consuming land iguanas (LI; Conolophus spp.) was conducted. Phylogenetic affiliations of the fecal microbiome were more similar between both iguanas than to other mammalian herbivorous hosts. However, functional gene diversities in both MI and LI iguana hosts differed in relation to the diet, where the MI fecal microbiota had a functional diversity that clustered apart from the other terrestrial-biomass consuming reptilian and mammalian hosts. A further examination of the carbohydrate-degrading genes revealed that several of the prevalent glycosyl hydrolases (GH), glycosyl transferases (GT), carbohydrate binding modules (CBM), and carbohydrate esterases (CE) gene classes were conserved among all examined herbivorous hosts, reiterating the important roles these genes play in the breakdown and metabolism of herbivorous diets. Genes encoding some classes of carbohydrate-degrading families, including GH2, GH13, GT2, GT4, CBM50, CBM48, CE4, and CE11, as well as genes associated with sulfur metabolism and dehalogenation, were highly enriched or unique to the MI. In contrast, gene sequences that relate to archaeal methanogenesis were detected only in LI fecal microbiome, and genes coding for GH13, GH66, GT2, GT4, CBM50, CBM13, CE4, and CE8 carbohydrate active enzymes were highly abundant in the LI. Bacterial populations were enriched on various carbohydrates substrates (e.g., glucose, arabinose, xylose). The majority of the enriched bacterial populations belong to genera Clostridium spp. and Enterococcus spp. that likely accounted for the high prevalence of GH13 and GH2, as well as the GT families (e.g., GT2, GT4, GT28, GT35, and GT51) that were ubiquitously present in the fecal microbiota of all herbivorous hosts. PMID- 25524572 TI - Surgical treatment of scoliosis in Treacher Collins syndrome: a case report. AB - INTRODUCTION: Treacher Collins syndrome is an autosomal dominant disorder resulting in congenital craniofacial deformities. Scoliosis has not been previously reported as one of the extracranial manifestations of this syndromic condition. CASE PRESENTATION: We present a 15-year-old British Caucasian girl with Treacher Collins syndrome who developed a severe double thoracic scoliosis measuring 102 degrees and 63 degrees respectively. The deformity was noted at age 14 years by the local general practitioner and gradually progressed until she was referred to our service and subsequently was scheduled for surgical correction. There were no congenital vertebral anomalies. As part of the condition, she had bilateral conductive hearing impairment. She also had reduced respiratory reserves and a restrictive lung disease. Both curves were rigid on supine maximum traction radiographs. She underwent a single-stage anterior and posterior spinal arthrodesis with pedicle hook/sublaminar wire/screw and rod instrumentation and autologous rib graft, supplemented by allograft bone and made a good postoperative recovery. Her scoliosis was corrected to 25 degrees and 24 degrees and a balanced spine in the coronal and sagittal planes was achieved. At latest follow-up beyond skeletal maturity (3 years post-surgery) she had an excellent cosmetic outcome with no loss of deformity correction, no detected pseudarthrosis and a normal level of activities. CONCLUSIONS: Scoliosis can occur in patients with Treacher Collins syndrome with the deformity demonstrating significant deterioration around the adolescent growth spurt. A high index of awareness will allow for an early diagnosis and scoliosis correction at a stage when this can be safer and performed through a single-stage posterior procedure. If the deformity is detected at a later age and stage of growth as occurred in our patient, more complex surgery is required and this increases the risk for major morbidity and potential mortality. Surgical treatment can correct the deformity, balance the spine and restore cosmesis, as well as prevent mechanical back pain and respiratory complications if the scoliosis progressed to cause severe thoracic distortion. A thorough preoperative assessment can diagnose associated comorbidities and reduce the risk for postoperative complications. PMID- 25524571 TI - The relationship between stress and social functioning in adults with autism spectrum disorder and without intellectual disability. AB - Adults with autism spectrum disorder (ASD) face substantial challenges accomplishing basic tasks associated with daily living, which are exacerbated by their broad and pervasive difficulties with social interactions. These challenges put people with ASD at increased risk for psychophysiological distress, which likely factors heavily into social functioning for adults with ASD, as suggested by a growing literature on stress in children that indicates that children with ASD have differential responses to stress than healthy children. We hypothesized that adults with ASD and without intellectual disability (n = 38) would experience more stress than healthy volunteers (n = 37) and that there would be an inverse relationship between stress and social functioning in individuals with ASD. Baseline, semi-structured interview data from a randomized controlled trial of two treatments for adults with ASD were used to assess differences in stress between adults with ASD and healthy volunteers and to assess the relationship between stress response and social functioning in adults with ASD. Findings indicate that adults with ASD experience greater perceived and interviewer observed stress than healthy volunteers and that stress is significantly related to social functioning in adults with ASD. These findings highlight the role of stress in adult functioning and outcomes and suggest the need to develop and assess treatments designed to target stress and coping in adults with ASD. PMID- 25524570 TI - The gut microbiota appears to compensate for seasonal diet variation in the wild black howler monkey (Alouatta pigra). AB - For most mammals, including nonhuman primates, diet composition varies temporally in response to differences in food availability. Because diet influences gut microbiota composition, it is likely that the gut microbiota of wild mammals varies in response to seasonal changes in feeding patterns. Such variation may affect host digestive efficiency and, ultimately, host nutrition. In this study, we investigate the temporal variation in diet and gut microbiota composition and function in two groups (N = 13 individuals) of wild Mexican black howler monkeys (Alouatta pigra) over a 10-month period in Palenque National Park, Mexico. Temporal changes in the relative abundances of individual bacterial taxa were strongly correlated with changes in host diet. For example, the relative abundance of Ruminococcaceae was highest during periods when energy intake was lowest, and the relative abundance of Butyricicoccus was highest when young leaves and unripe fruit accounted for 68 % of the diet. Additionally, the howlers exhibited increased microbial production of energy during periods of reduced energy intake from food sources. Because we observed few changes in howler activity and ranging patterns during the course of our study, we propose that shifts in the composition and activity of the gut microbiota provided additional energy and nutrients to compensate for changes in diet. Energy and nutrient production by the gut microbiota appears to provide an effective buffer against seasonal fluctuations in energy and nutrient intake for these primates and is likely to have a similar function in other mammal species. PMID- 25524573 TI - Thyroid thyrothymic extension: An anatomic study in a surgical series. AB - BACKGROUND: The thyrothymic extension (TTE) is a variable projection from the inferior thyroid pole along the course of the thyrothymic ligament. Awareness of the TTE is critical to ensure complete total thyroidectomy. However, there is little mention of the TTE in the literature. The purpose of the present study was to investigate the frequency of the TTE in our surgical series. METHODS: We conducted a prospective cohort study of 284 thyroid and parathyroid surgeries performed by a single surgeon. RESULTS: A TTE was present in 138 of 414 evaluable thyroid lobes (33.3%), with no predilection for left or right. The TTE was bilateral in 57% of cases. In 5 cases, there was significant nodular enlargement of the TTE. The inferior parathyroid gland was closely associated with 8% of TTEs. CONCLUSION: The TTE is a commonly encountered projection from the inferior thyroid pole. Awareness of the TTE is important to ensure complete total thyroidectomy. PMID- 25524574 TI - An accurate prognostic staging system for hepatocellular carcinoma patients after curative hepatectomy. AB - The aim of this study was to develop an accurate predictive system for prognosis of hepatocellular carcinoma (HCC) patients after hepatectomy. We pooled data of clinicopathological features of 234 HCC patients who underwent curative hepatectomy. On the basis of the pooled data, we established a simple predictive staging system (PS score) scored by the mathematical product of tumor number and size, and degree of liver function. We compared the prognostic abilities of the PS score (score 0-3) with those of six well-known clinical staging systems. Then, we found that there were significant differences (P<0.05) in both disease-free survival (DFS) and overall survival (OS) between patients with different PS scores (PS score 0 vs. 1; PS score 1 vs. 2), and there was a significant difference in DFS, but not OS, between patients with PS score 2 and those with PS score 3. Moreover, the PS score had smaller values of the Akaike information criterion for both DFS and OS than any of the six well-known clinical staging systems. These results suggest that the PS score serves as a simple, accurate predictor for the prognosis of HCC patients after hepatectomy. PMID- 25524575 TI - Interleukin-11 receptor alpha is overexpressed in human osteosarcoma, and near infrared-labeled IL-11Ralpha imaging agent could detect osteosarcoma in mouse tumor xenografts. AB - IL-11Ralpha is an important cytokine receptor that links oxidative stress and compensatory proliferation. Mounting evidence has demonstrated that IL-11Ralpha regulates autoimmune demyelination and the invasion and proliferation of cancer cells, making it an important therapeutic target for molecular targeted therapy. Moreover, overexpression of IL-11Ralpha indicates a poor long-term prognosis in cancer patients. However, the expression status and its potential as a biomarker for diagnosis, tumor imaging, and prognosis in osteosarcoma remain to be determined. We report here that IL-11Ralpha is highly expressed in osteosarcoma and near-infrared (NIR)-labeled IL-11Ralpha imaging agent could detect osteosarcoma in mouse tumor xenografts. In a panel of human osteosarcoma specimens, IL-11Ralpha protein was positively stained in most cases by immunohistochemistry. Western blot analysis and flow cytometry showed that IL 11Ralpha was overexpressed in osteosarcoma SOSP-9607 cells. Cell-binding assay demonstrated specific binding of the IL-11Ralpha targeted imaging agent to osteosarcoma SOSP-9607 cells in vitro. In addition, administration of an IL 11Ralpha targeted imaging agent in a nude mice orthotopic model resulted in selective accumulation of NIR fluorescent signals in the bone tumor as well as several metabolic organs. These results indicate that IL-11Ralpha is a potential target for the development of molecular targeted therapy and noninvasive tumor imaging in human osteosarcoma. Furthermore, NIR-labeled IL-11Ralpha imaging agent is a promising lead for the development of a tumor in vivo imaging method at the molecular level in the management of human osteosarcoma. PMID- 25524576 TI - Leishmanial sphingolipid induces apoptosis in Sarcoma 180 cancer cells through regulation of tumour growth via angiogenic switchover. AB - Sphingolipids are membrane and intracellular lipids that typically modulate cellular processes to cause cell death. Exogenous administration of sphingolipids may cause restriction of tumour growth and several alternative strategies are being used to control the cell growth. The microbes, their cellular component(s) or metabolites like DHA, EPA and also FTY720 have been employed as new therapeutic entities to regulate the disease condition. The therapeutic efficacy of lipids from Leishmania donovani in rheumatoid arthritis and also in sepsis condition associated with inflammatory diseases is well established. In this study, we explored the apoptotic effect of LSPL-1 (leishmanial sphingolipid-1) in Sarcoma 180 cells towards the regulation of tumour growth. The study using a panel of cancer cell lines revealed that LSPL-1 induces cell death in Sarcoma 180. The apoptotic changes were assessed by annexin exposure and DNA content analysis using flow cytometry. LSPL-1 appears to activate several pro- and anti apoptotic molecules through reactive oxygen species (ROS) generation and also caspase activation, as determined by Western blot and ELISA analyses. Simultaneously, it may improve the survival rate of mice bearing tumour induced by Sarcoma 180 cells, with pathological changes. LSPL-1 may also suppress the cancer-associated inflammatory responses with the expression of matrix metalloproteinase having inhibitory role. It may regulate several angiogenic factors including VEGF, Ang-2 and CD34 in angiogenic events generated in Sarcoma 180 cell-induced tumour. These studies underline the significance of anti neoplastic potential of LSPL-1 through apoptosis induction and abrogation of angiogenic responses in Sarcoma 180 cell-associated tumour. PMID- 25524577 TI - LYTAK1, a novel TAK1 inhibitor, suppresses KRAS mutant colorectal cancer cell growth in vitro and in vivo. AB - KRAS mutation in colorectal cancer (CRC) activates transforming growth factor beta (TGF-beta)-activated kinase 1 (TAK1) to promote tumor progression. In the current study, we explored the potential effect of LYTAK1, a novel TAK1 inhibitor, against KRAS mutant CRC cells in vitro and in vivo. We found that LYTAK1 dose-dependently inhibited KRAS mutant CRC cell (HT-29 and SW-620 lines) growth, and induced cell cycle G1-S arrest. Further, LYTAK1 activated apoptosis in HT-29 cells and SW-620 cells, and apoptosis inhibitors almost reversed LYTAK1 mediated growth inhibition. While in KRAS wild-type (WT) CRC cell lines (DLD-1 and HCT-116), LYTAK1 had almost no effect on cell growth, cell cycle progression, or cell apoptosis. In KRAS mutant HT-29 cells and SW-260 cells, LYTAK1 blocked TAK1 activation or phosphorylation at Thr-184/187. Activation of nuclear factor kappaB (NF-kappaB) in these cells, detected by phosphorylations of p65 and IkappaB kinase alpha (IKKalpha) as well as expression of NF-kappaB-regulated gene cyclin D1, was significantly inhibited by LYTAK1. Further, LYTAK1 treatment resulted in downregulation of beta-catenin and Wnt response gene Axin 2, indicating Wnt inactivation. In vivo, oral LYTAK1 significantly inhibited HT-29 xenograft growth in nude mice. Together, these results show that LYTAK1 inhibits KRAS mutant CRC cell growth both in vitro and in vivo. LYTAK1 might be investigated as a novel agent against CRC with KRAS mutation. PMID- 25524578 TI - Decorin is responsible for progression of non-small-cell lung cancer by promoting cell proliferation and metastasis. AB - Decorin, a member of the small leucine-rich proteoglycans family, exists and plays multifunctional roles in stromal and epithelial cells. Emerging evidences showed that decorin is dysregulated expression in a wide variety of human tumors and affects a broad biology process of cancer cells, including growth, metastasis, and angiogenesis. Recent studies demonstrated that decorin could affect A549 proliferation though decreasing TGF-beta1, cycling D1 expression and increasing P53 and P21 expression. However, limited data are available on the effect of decorin on metastasis of non-small-cell lung cancer (NSCLC) cell lines and how decorin impacts metastasis is still unknown. In this study, we identified decorin mRNA expression through Oncomine database and verified the expression of decorin mRNA and protein in 50 patients who underwent primary surgical resection of a NSCLC in the Department of Thoracic Surgery, Jinling Hospital, Nanjing University School of Medicine, China, between September 2013 and March 2014 by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blot. Also, the correlationship between decorin and the NSCLC patients' clinical characteristics or survival ( www.kmplot.com ) was analyzed. Via ectopic expression analyses and Western blot, the roles of decorin in proliferation, metastasis, and the underline mechanism for decorin expression were further explored. We found that decorin was downregulated in NSCLC tissues compared with the adjacent normal lung tissues or normal tissues. Additionally, the expression of decorin was correlated with tumor size, lymph node metastasis, tumor stage, and prognosis. We also showed that overexpression of decorin could inhibit NSCLC cell lines proliferation and metastasis. Through Western blot analysis, we identified that E-cadherin and vascular endothelial growth factor (VEGF) are two key factors responsible for the growth arrest and metastasis inhibition induced by decorin in NSCLC. Our results indicated that decorin plays crucial roles in NSCLC against carcinogenesis and progression. Decorin might be a predictive factor and an attractive therapeutic target for NSCLC patients. PMID- 25524579 TI - MicroRNA-181 functions as a tumor suppressor in non-small cell lung cancer (NSCLC) by targeting Bcl-2. AB - MicroRNAs (miRNAs) are small non-coding RNAs frequently dysregulated in human malignancies. In this study, we analyzed the global expression profile of miR-181 in non-small cell lung cancer (NSCLC), as its participation in some other types of cancer has been suggested by previous reports. We found that miR-181 was downregulated both in NSCLC tissues and cell lines. Overexpression of miR-181 evidently inhibited A549 cell proliferation, migration, and invasion and promotes cell apoptosis. Moreover, we also found miR-181 reduction was associated with increased Bcl-2 levels and miR-181 was further suggested to exert its pro apoptotic function mainly through targeting Bcl-2 expression. Taken together, our study implicates important roles of miR-181 in lung cancer pathogenesis and implicates its potential application in cancer therapy. PMID- 25524580 TI - Plasmacytoid dendritic cells, a role in neoplastic prevention and progression. AB - BACKGROUND: Plasmacytoid dendritic cells (pDCs) are multifunctional bone-marrow derived immune cells that are key players in bridging the innate and adaptive immune systems. Activation of pDCs through toll-like receptor agonists has proven to be an effective treatment for some neoplastic disorders. MATERIALS AND METHODS: In this mini-review, we will explore the fascinating contribution of pDCs to neoplastic pathology and discuss their potential utilization in cancer immunotherapy. RESULTS: Current research suggests that pDCs have cytotoxic potential and can effectively induce apoptosis of tumour-derived cells lines. They are also reported to display tolerogenic function with the ability to suppress T-cell proliferation, analogous to regulatory T cells. In this capacity, they are critical in the suppression of autoimmunity but can be exploited by tumour cells to circumvent the expansion of tumour-specific T cells, thereby allowing tumours to persist. CONCLUSION: Several forms of skin cancer are successfully treated with the topical drug Imiquimod, which activates pDCs through toll-like receptor 7 engagement. Additionally, pDC-based anticancer vaccines have shown encouraging results for the treatment of melanoma in early trials. Future studies regarding the contributions of pDCs to malignancy will likely afford many opportunities for immunotherapy strategies. PMID- 25524581 TI - The deep end of the metabolite pool: influences on epigenetic regulatory mechanisms in cancer. AB - BACKGROUND: Epigenetic control of gene expression is mediated by cytosine methylation/demethylation and histone modifications including methylation, acetylation and glycosylation. The epigenetic programme is corrupted in cancer cells to maintain a pattern of gene expression that leads to their de differentiated, rapidly proliferating phenotype. Enzymes responsible for modifying histones and cytosine are sensitive to the cellular metabolite pool and can be activated by an increase in their substrates or inhibited by an increase in their products or competitors for substrate binding. METHODS: This review is based on publications identified on PubMed using a literature search of cytosine methylation, histone methylation, acetylation and glycosylation. RESULTS: In cancer, changes in glycolytic enzymes lead to increased production of serine, increasing the pool of S-adenosylmethionine (the major methyl donor for methylation reactions) and UDP-N-acetylglucosamine (a substrate for O-linked glycosylation of histones and cytosine methyltransferases). Mutations in tricarboxylic acid cycle enzymes lead to accumulation of fumarate, succinate and hydroxyglutarate, all of which inhibit demethylation of cytosine and histones. In contrast, proline catabolism produces alpha-ketoglutarate and reactive oxygen, both of which promote the activity of enzymes that remove methyl groups from cytosine and histones, and the key enzyme in proline catabolism acts as a tumour suppressor. CONCLUSIONS: Our emerging understanding of how the epigenetic profiles are metabolically reprogrammed in cancer cells will lead to novel diagnostic and therapeutic targets for treatment of patients. PMID- 25524582 TI - New insights on chromatin modifiers and histone post-translational modifications in renal cell tumours. AB - Renal cell tumours (RCTs) are the most common neoplasms affecting the kidney. They are clinically, pathologically and genetically heterogeneous, comprises four major histological subtypes [clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC) and chromophobe renal cell carcinoma (chRCC), which are malignant tumours, and oncocytoma, a benign tumour], as well as an increasing number of less common entities. Epigenetics has emerged as an important field in oncology due to the critical role it plays in neoplastic transformation and progression. Among epigenetic mechanisms, the modulation of chromatin packaging through covalent modifications is fundamental for gene transcription regulation and its deregulation is involved in carcinogenesis. Recently, deregulation of chromatin machinery in RCTs has increasingly acknowledged as an important mechanism for renal neoplastic transformation. The aim of this review is to summarize the most relevant alterations in histone post-translational modifications and chromatin modifiers, which have been implicated in renal tumorigenesis. The recognition of those modifications might provide new biomarkers for diagnosis and prognostication as well as novel targets for personalized therapeutic intervention. PMID- 25524583 TI - The interplay between p66Shc, reactive oxygen species and cancer cell metabolism. AB - The adaptor protein p66Shc links membrane receptors to intracellular signalling pathways and has the potential to respond to energy status changes and regulate mitogenic signalling. Initially reported to mediate growth signals in normal and cancer cells, p66Shc has also been recognized as a pro-apoptotic protein involved in the cellular response to oxidative stress. Moreover, it is a key element in processes such as cancer cell proliferation, tumor progression, metastasis and metabolic reprogramming. Recent findings on the role of p66Shc in the above mentioned processes have been obtained through the use of various tumor cell types, including prostate, breast, ovarian, lung, colon, skin and thyroid cancer cells. Interestingly, the impact of p66Shc on the proliferation rate was mainly observed in prostate tumors, while its impact on metastasis was mainly found in breast cancers. In this review, we summarize the current knowledge about the possible roles of p66Shc in different cancers. PMID- 25524584 TI - Bisphenol A as epigenetic modulator: setting the stage for carcinogenesis? AB - BACKGROUND: Bisphenol A (BPA) is one of the most widely produced chemicals worldwide and is often used in the production of food and beverage containers. As a result of BPA contact with food, drink and toiletries, its ingestion and absorption by humans has been growing. The industrialization and modern lifestyles brought a constant exposure to several health-disturbing compounds and ushered a new era of chronic diseases. The endocrine disruptor potential of BPA is well known, but the research around its epigenotoxic effects raised further concerns whether chronic exposure to BPA can contribute to chronic human illness, including cancer in hormone-sensitive organs. MATERIALS AND METHODS: Focusing on computerized databases, we reviewed original and review articles which elucidate and link some of the information already available about BPA and related epigenetic alterations. RESULTS: A number of studies indicate that short-term administration of low or high-doses of BPA may be associated with an increased risk of epigenetic modifications, increasing the risk for carcinogenesis. However, it is clear that more studies considering real daily exposures are essential to define a real tolerable daily intake and to tighten up manufactory regulations. CONCLUSION: In this review, we highlight some evidences suggesting a relationship between BPA exposure, genotoxic activity and epigenetic modifications, which may prime for carcinogenesis. PMID- 25524585 TI - Metabolic evaluations of cancer metabolism by NMR-based stable isotope tracer methodologies. AB - BACKGROUND: Cancer cells are widely recognized for being able to adapt their metabolism towards converting available nutrients into biomass to increase proliferation rates. MATERIALS AND METHODS: We will review a series of nuclear magnetic resonance (NMR)-based stable isotope tracer methodologies for probing cancer metabolism. RESULTS: The monitoring of such adaptations is of the utmost importance to unravel cancer metabolism and tumour growth. Several major metabolic targets have been recognized as promising foci and have been addressed by multiple studies in recent years. In this work are presented strategies to quantify glycolysis, pentose phosphate pathway, Krebs cycle turnover and de novo lipogenesis by NMR isotopomer analysis. CONCLUSIONS: Being able to adequately define the interplay between metabolic pathways allows the monitoring of their prevalence in tissues and such information is critical for an accurate knowledge of the metabolic distinctive nature of tumours towards devising more efficient antitumorigenic strategies. Discussed methodologies are currently available in the literature, but to date, no single review has compiled all their possible uses, particularly in an interdependent perspective. PMID- 25524586 TI - Role of mtDNA-related mitoepigenetic phenomena in cancer. AB - BACKGROUND: Abnormal mitochondrial function has long been associated with the development and the progression of cancer. Multiple defects in the mitochondrial genome have been reported for various cancers, however the often disregarded mitochondrial epigenetic landscape provides an additional source of deregulation that may contribute to carcinogenesis. DESIGN: This article reviews the current understanding of mitochondrial epigenetics and how it may relate to cancer progression and development. Relevant studies were found through electronic databases (Web of Science and PubMed). RESULTS AND CONCLUSIONS: The remarkably unexplored field of mitochondrial epigenetics has the potential to shed light on several cancer-related mitochondrial abnormalities. More studies using innovative, genome-wide sequencing technologies are highly warranted to assess whether and how altered mtDNA methylation patterns affect cancer initiation and progression. PMID- 25524588 TI - Unusual tandem expansion and positive selection in subgroups of the plant GRAS transcription factor superfamily. AB - BACKGROUND: GRAS proteins belong to a plant transcription factor family that is involved with multifarious roles in plants. Although previous studies of this protein family have been reported for Arabidopsis, rice, Chinese cabbage and other species, investigation of expansion patterns and evolutionary rate on the basis of comparative genomics in different species remains inadequate. RESULTS: A total of 289 GRAS genes were identified in Arabidopsis, B. distachyon, rice, soybean, S. moellendorffii, and P. patens and were grouped into seven subfamilies, supported by the similarity of their exon-intron patterns and structural motifs. All of tandem duplicated genes were found in group II except one cluster of rice, indicating that tandem duplication greatly promoted the expansion of group II. Furthermore, segment duplications were mainly found in the soybean genome, whereas no single expansion pattern dominated in other plant species indicating that GRAS genes from these five species might be subject to a more complex evolutionary mechanism. Interestingly, branch-site model analyses of positive selection showed that a number of sites were positively selected under foreground branches I and V. These results strongly indicated that these groups were experiencing higher positive selection pressure. Meanwhile, the site specific model revealed that the GRAS genes were under strong positive selection in P. patens. DIVERGE v2.0 was used to detect critical amino acid sites, and the results showed that the shifted evolutionary rate was mainly attributed to the functional divergence between the GRAS genes in the two groups. In addition, the results also demonstrated the expression divergence of the GRAS duplicated genes in the evolution. In short, the results above provide a solid foundation for further functional dissection of the GRAS gene superfamily. CONCLUSIONS: In this work, differential expression, evolutionary rate, and expansion patterns of the GRAS gene family in the six species were predicted. Especially, tandem duplication events played an important role in expansion of group II. Together, these results contribute to further functional analysis and the molecular evolution of the GRAS gene superfamily. PMID- 25524589 TI - Stirring rate regulates the proliferation and metabolism of microencapsulated recombinant CHO cells. AB - Stirred tank bioreactors are the most widely used method for the large-scale culture of mammalian cells. However, the scale of stirred tank bioreactors is limited by insufficient oxygen/nutrient mixing and the accumulation of waste products in high cell density cultures. The most effective method to solve these problems is to increase the stirring rate; this usually leads to increased cell proliferation, but can decrease the utilization of nutrients for recombinant protein synthesis. To investigate the effects of stirring rate on the proliferation, metabolism, and recombinant protein yield of microencapsulated recombinant Chinese hamster ovary (rCHO) cells, the cells were cultured under different stirring rates, and cell viability, metabolic activity, and protein yield were measured. Microencapsulation promoted Desmodus rotundus salivary plasminogen activator expression, and higher stirring rates promoted increases in microencapsulated cell density and metabolic activity. However, the maximum yield of recombinant protein was obtained at a moderate stirring rate, whereas protein yield was decreased at the highest tested stirring rate. The stirring rate had a significant impact on the growth and protein expression of microencapsulated rCHO cells, and a specific stirring rate was identified to maximize the yield of recombinant protein. PMID- 25524591 TI - The addition of nitriles to tetramesityldisilene: a comparison of the reactivity between surface and molecular disilenes. AB - The addition of acetonitrile, propionitrile, and phenylacetonitrile to tetramesityldisilene (Mes2 Si=SiMes2 ) was examined. In general, 1,2,3 azadisiletines and the tautomeric enamines were formed, although a ketenimine was formed as the major product in the addition of phenylacetonitrile to the disilene. In the presence of LiCl, the mode of addition changed for both acetonitrile and propionitrile: insertion into the alpha-CH bond of acetonitrile and/or formation of the formal HCN adduct was observed. Preliminary investigations of the reactivity of the nitrile adducts are also reported. A comparison between the reactivity of nitriles with Mes2 Si=SiMes2 and the Si(100) 2*1 surface was made both in terms of the types of adducts formed and their reactivity. Some insights into the surface chemistry are offered. PMID- 25524590 TI - Bioactive sesquiterpene aryl esters from the culture broth of Armillaria sp. AB - Two new compounds, 10-dehydroxymelleolide D (1) and 13-hydroxymelleolide K (2), along with seven known compounds, 5'-O-methylmelledonal (3), melleolide D (4), 13 hydroxydihydromelleolide (5), melleolide (6), armillarinin (7), armillaridin (8), and armillarikin (9), were isolated from the culture broth of Armillaria sp. Their structures were determined by spectroscopic data analysis. All the compounds inhibited plant growth of lettuce. Melleolide (6) and armillarikin (9) inhibited mycelial growth of Coprinopsis cinerea and/or Flammulina velutipes. PMID- 25524592 TI - The arterial blood pressure associated with terminal cardiovascular collapse in critically ill patients: a retrospective cohort study. AB - INTRODUCTION: Liberal and overaggressive use of vasopressors during the initial period of shock resuscitation may compromise organ perfusion and worsen outcome. When transiently applying the concept of permissive hypotension, it would be helpful to know at which arterial blood pressure terminal cardiovascular collapse occurs. METHODS: In this retrospective cohort study, we aimed to identify the arterial blood pressure associated with terminal cardiovascular collapse in 140 patients who died in the intensive care unit while being invasively monitored. Demographic data, co-morbid conditions and clinical data at admission and during the 24 hours before and at the time of terminal cardiovascular collapse were collected. The systolic, mean and diastolic arterial blood pressures immediately before terminal cardiovascular collapse were documented. Terminal cardiovascular collapse was defined as an abrupt (<5 minutes) and exponential decrease in heart rate (> 50% compared to preceding values) followed by cardiac arrest. RESULTS: The mean +/- standard deviation (SD) values of the systolic, mean and diastolic arterial blood pressures associated with terminal cardiovascular collapse were 47 +/- 12 mmHg, 35 +/- 11 mmHg and 29 +/- 9 mmHg, respectively. Patients with congestive heart failure (39 +/- 13 mmHg versus 34 +/- 10 mmHg; P = 0.04), left main stem stenosis (39 +/- 11 mmHg versus 34 +/- 11 mmHg; P = 0.03) or acute right heart failure (39 +/- 13 mmHg versus 34 +/- 10 mmHg; P = 0.03) had higher arterial blood pressures than patients without these risk factors. Patients with severe valvular aortic stenosis had the highest arterial blood pressures associated with terminal cardiovascular collapse (systolic, 60 +/- 20 mmHg; mean, 46 +/- 12 mmHg; diastolic, 36 +/- 10 mmHg), but this difference was not significant. Patients with sepsis and patients exposed to sedatives or opioids during the terminal phase exhibited lower arterial blood pressures than patients without sepsis or administration of such drugs. CONCLUSIONS: The arterial blood pressure associated with terminal cardiovascular collapse in critically ill patients was very low and varied with individual co-morbid conditions (for example, congestive heart failure, left main stem stenosis, severe valvular aortic stenosis, acute right heart failure), drug exposure (for example, sedatives or opioids) and the type of acute illness (for example, sepsis). PMID- 25524594 TI - Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs?. AB - Sixty-four dogs were treated with single-agent doxorubicin (DOX) for presumptive cardiac hemangiosarcoma (cHSA). The objective response rate (CR + PR) was 41%, and the biologic response rate (CR + PR + SD), or clinical benefit, was 68%. The median progression-free survival (PFS) for treated dogs was 66 days. The median survival time (MST) for this group was 116 days and was significantly improved compared to a MST of 12 days for untreated control dogs (P = 0.0001). Biologic response was significantly associated with improved PFS (P < 0.0001) and OS (P < 0.0001). Univariate analysis identified larger tumour size as a variable negatively associated with PFS. The high rate of clinical benefit and improved MST suggest that DOX has activity in canine cHSA. PMID- 25524593 TI - Improving accuracy of protein contact prediction using balanced network deconvolution. AB - Residue contact map is essential for protein three-dimensional structure determination. But most of the current contact prediction methods based on residue co-evolution suffer from high false-positives as introduced by indirect and transitive contacts (i.e., residues A-B and B-C are in contact, but A-C are not). Built on the work by Feizi et al. (Nat Biotechnol 2013; 31:726-733), which demonstrated a general network model to distinguish direct dependencies by network deconvolution, this study presents a new balanced network deconvolution (BND) algorithm to identify optimized dependency matrix without limit on the eigenvalue range in the applied network systems. The algorithm was used to filter contact predictions of five widely used co-evolution methods. On the test of proteins from three benchmark datasets of the 9th critical assessment of protein structure prediction (CASP9), CASP10, and PSICOV (precise structural contact prediction using sparse inverse covariance estimation) database experiments, the BND can improve the medium- and long-range contact predictions at the L/5 cutoff by 55.59% and 47.68%, respectively, without additional central processing unit cost. The improvement is statistically significant, with a P-value < 5.93 * 10( 3) in the Student's t-test. A further comparison with the ab initio structure predictions in CASPs showed that the usefulness of the current co-evolution-based contact prediction to the three-dimensional structure modeling relies on the number of homologous sequences existing in the sequence databases. BND can be used as a general contact refinement method, which is freely available at: http://www.csbio.sjtu.edu.cn/bioinf/BND/. PMID- 25524596 TI - Teachers' and parents' views on the Internet and social media usage by pupils with intellectual disabilities. AB - This article reports experiences from a Swedish study, discussing teachers' and parents' views on how young people with intellectual disabilities use the Internet and social media. Five semi-structured focus group interviews were conducted with teachers (n = 8) in special programmes in upper secondary schools for pupils with intellectual disabilities and parents (n = 5) of pupils in the same form of schooling, and they were analysed with thematic analysis. Teachers more strongly emphasize a pupil's use of the Internet for interactive purposes. Parents had expectations that the Internet could be a tool for gaining more awareness of one's own disability and a way to meet other peer group pupils. Teachers' and parents' perspectives on the Internet and social media usage are important since it is imperative to show how support can be provided for young people with intellectual disabilities. PMID- 25524595 TI - Tobacco brief intervention training for chiropractic, acupuncture, and massage practitioners: protocol for the CAM reach study. AB - BACKGROUND: Tobacco use remains the leading cause of morbidity and mortality in the US. Effective tobacco cessation aids are widely available, yet underutilized. Tobacco cessation brief interventions (BIs) increase quit rates. However, BI training has focused on conventional medical providers, overlooking other health practitioners with regular contact with tobacco users. The 2007 National Health Interview Survey found that approximately 20% of those who use provider-based complementary and alternative medicine (CAM) are tobacco users. Thus, CAM practitioners potentially represent a large, untapped community resource for promoting tobacco cessation and use of effective cessation aids. Existing BI training is not well suited for CAM practitioners' background and practice patterns, because it assumes a conventional biomedical foundation of knowledge and philosophical approaches to health, healing and the patient-practitioner relationship. There is a pressing need to develop and test the effectiveness of BI training that is both grounded in Public Health Service (PHS) Guidelines for tobacco dependence treatment and that is relevant and appropriate for CAM practitioners. METHODS/DESIGN: The CAM Reach (CAMR) intervention is a tobacco cessation BI training and office system intervention tailored specifically for chiropractors, acupuncturists and massage therapists. The CAMR study utilizes a single group one-way crossover design to examine the CAMR intervention's impact on CAM practitioners' tobacco-related practice behaviors. Primary outcomes included CAM practitioners' self-reported conduct of tobacco use screening and BIs. Secondary outcomes include tobacco using patients' readiness to quit, quit attempts, use of guideline-based treatments, and quit rates and also non-tobacco using patients' actions to help someone else quit. DISCUSSION: CAM practitioners provide care to significant numbers of tobacco users. Their practice patterns and philosophical approaches to health and healing are well suited for providing BIs. The CAMR study is examining the impact of the CAMR intervention on practitioners' tobacco-related practice behaviors, CAM patient behaviors, and documenting factors important to the conduct of practice-based research in real-world CAM practices. PMID- 25524597 TI - Food choice by people with intellectual disabilities at day centres: A qualitative study. AB - People with intellectual disabilities experience a range of health inequalities. It is important to investigate possible contributory factors that may lead to these inequalities. This qualitative study identified some difficulties for healthy eating in day centres. (1) Service users and their family carers were aware of healthy food choices but framed these as diets for weight loss rather than as everyday eating. (2) Paid carers and managers regarded the principle of service user autonomy and choice as paramount, which meant that they felt limited in their capacity to influence food choices, which they attributed to the home environment. (3) Carers used food as a treat, a reward and for social bonding with service users. (4) Service users' food choices modelled other service users' and carers' choices at the time. It is suggested that healthy eating should be made more of a priority in day care, with a view to promoting exemplarily behaviour that might influence food choice at home. PMID- 25524598 TI - Electrospun biomaterial scaffolds with varied topographies for neuronal differentiation of human-induced pluripotent stem cells. AB - In this study, we investigated the effect of micro and nanoscale scaffold topography on promoting neuronal differentiation of human induced pluripotent stem cells (iPSCs) and directing the resulting neuronal outgrowth in an organized manner. We used melt electrospinning to fabricate poly (epsilon-caprolactone) (PCL) scaffolds with loop mesh and biaxial aligned microscale topographies. Biaxial aligned microscale scaffolds were further functionalized with retinoic acid releasing PCL nanofibers using solution electrospinning. These scaffolds were then seeded with neural progenitors derived from human iPSCs. We found that smaller diameter loop mesh scaffolds (43.7 +/- 3.9 um) induced higher expression of the neural markers Nestin and Pax6 compared to thicker diameter loop mesh scaffolds (85 +/- 4 um). The loop mesh and biaxial aligned scaffolds guided the neurite outgrowth of human iPSCs along the topographical features with the maximum neurite length of these cells being longer on the biaxial aligned scaffolds. Finally, our novel bimodal scaffolds also supported the neuronal differentiation of human iPSCs as they presented both physical and chemical cues to these cells, encouraging their differentiation. These results give insight into how physical and chemical cues can be used to engineer neural tissue. PMID- 25524599 TI - Auxin and physical constraint exerted by the perianth promote androgynophore bending in Passiflora mucronata L. (Passifloraceae). AB - The androgynophore column, a distinctive floral feature in passion flowers, is strongly crooked or bent in many Passiflora species pollinated by bats. This is a floral feature that facilitates the adaptation to bat pollination. Crooking or bending of plant organs are generally caused by environmental stimulus (e.g. mechanical barriers) and might involve the differential distribution of auxin. Our aim was to study the role of the perianth organs and the effect of auxin in bending of the androgynophore of the bat-pollinated species Passiflora mucronata. Morpho-anatomical characterisation of the androgynophore, including measurements of curvature angles and cell sizes both at the dorsal (convex) and ventral (concave) sides of the androgynophore, was performed on control flowers, flowers from which perianth organs were partially removed and flowers treated either with auxin (2,4-dichlorophenoxyacetic acid; 2,4-D) or with an inhibitor of auxin polar transport (naphthylphthalamic acid; NPA). Asymmetric growth of the androgynophore column, leading to bending, occurs at a late stage of flower development. Removing the physical constraint exerted by perianth organs or treatment with NPA significantly reduced androgynophore bending. Additionally, the androgynophores of plants treated with 2,4-D were more curved when compared to controls. There was a larger cellular expansion at the dorsal side of the androgynophores of plants treated with 2,4-D and in both sides of the androgynophores of plants treated with NPA. This study suggests that the physical constraint exerted by perianth and auxin redistribution promotes androgynophore bending in P. mucronata and might be related to the evolution of chiropterophily in the genus Passiflora. PMID- 25524600 TI - Mitochondrial estrogen receptor beta inhibits cell apoptosis via interaction with Bad in a ligand-independent manner. AB - Previous studies reported that estrogen receptor beta (ERbeta) is localized to mitochondria, whereas little is known about the physiological functions of mitochondrial ERbeta. In the present study, we explored the role of mitochondrial ERbeta in regulating apoptosis using stable ERbeta-expressing and ERbeta knockdown cells lines. We found that exogenous ERbeta was mainly expressed in mitochondrial but not in nuclear after ERbeta overexpression and protected cells from apoptosis induced by hydrogen peroxide (H2O2), ultraviolet (UV), and staurosporine (STS). Moreover, overexpression of ERbeta prevented Bax activation, cytochrome c release, caspase-3 activation, and PARP cleavage during apoptosis. Furthermore, knockdown of ERbeta significantly suppressed the expression of ERbeta in mitochondrial and promoted cell apoptosis induced by H2O2, UV, and STS. Downregulation of ERbeta also enhanced Bax activation, cytochrome c release, caspase-3 activation and PARP cleavage. In addition, our study discovered that mitochondrial ERbeta interacted with proapoptotic protein Bad in a ligand independent manner, which suggests that mitochondrial ERbeta inhibits Bad, and prevents Bax activation and cytochrome c release. Collectively, the results of this study support that mitochondrial ERbeta prevents cell apoptosis via the mitochondrial apoptotic pathway in a ligand-independent manner. PMID- 25524601 TI - Diminished nitric oxide generation from neutrophils suppresses platelet activation in chronic renal failure. AB - Chronic renal failure (CRF) is a complex clinical condition associated with accelerated atherosclerosis and thrombosis leading to cardiovascular events. The aim of this study was to investigate in detail the NO pathway in neutrophils obtained from hemodialysis patients and its association with platelet function and oxidative status. Fifteen CRF patients on hemodialysis and fifteen controls were included in this study. Laboratory and experimental evaluations were performed after hemodialysis in CRF patients. We evaluated L-[3H] arginine transport, NO synthase (NOS) activity, amino acid concentration in neutrophils, and expressions of NOS isoforms and p47(phox) by western blotting. Platelet aggregation was analyzed in the presence or absence of neutrophils. Oxidative status was measured through glutathione peroxidase, catalase activities, protein oxidation, lipid peroxidation, and DNA/RNA oxidation in serum. Basal NOS activity (pmol/106 cells/min) was impaired in CRF patients on hemodialysis (0.33 +/- 0.17) compared to controls (0.65 +/- 0.12), whereas the expression of NOS isoforms remained unaltered. L-Arginine transport into neutrophils was similar in CRF patients on hemodialysis and controls. In addition, intracellular concentration of L-arginine was increased fourfold in the patient group. Systemic oxidative stress markers were not affected by CRF. On the other hand, NADPH oxidase subunit p47(phox) in neutrophils was overexpressed in CRF. In the presence of neutrophils, there was a reduction time-dependent in platelet aggregation in both groups with no difference between them. This data suggest that reduced basal generation of NO by neutrophils in CRF patients on hemodialysis occurs independently of L-arginine bioavailability and is able to suppress platelet activation. PMID- 25524602 TI - Paradoxical (REM) sleep deprivation in mice using the small-platforms-over-water method: polysomnographic analyses and melanin-concentrating hormone and hypocretin/orexin neuronal activation before, during and after deprivation. AB - Studying paradoxical sleep homeostasis requires the specific and efficient deprivation of paradoxical sleep and the evaluation of the subsequent recovery period. With this aim, the small-platforms-over-water technique has been used extensively in rats, but only rare studies were conducted in mice, with no sleep data reported during deprivation. Mice are used increasingly with the emergence of transgenic mice and technologies such as optogenetics, raising the need for a reliable method to manipulate paradoxical sleep. To fulfil this need, we refined this deprivation method and analysed vigilance states thoroughly during the entire protocol. We also studied activation of hypocretin/orexin and melanin concentrating hormone neurones using Fos immunohistochemistry to verify whether mechanisms regulating paradoxical sleep in mice are similar to those in rats. We showed that 48 h of deprivation was highly efficient, with a residual amount of paradoxical sleep of only 2.2%. Slow wave sleep and wake quantities were similar to baseline, except during the first 4 h of deprivation, where slow wave sleep was strongly reduced. After deprivation, we observed a 124% increase in paradoxical sleep quantities during the first hour of rebound. In addition, 34% of hypocretin/orexin neurones were activated during deprivation, whereas melanin concentrated hormone neurones were activated only during paradoxical sleep rebound. Corticosterone level showed a twofold increase after deprivation and returned to baseline level after 4 h of recovery. In summary, a fairly selective deprivation and a significant rebound of paradoxical sleep can be obtained in mice using the small-platforms-over-water method. As in rats, rebound is accompanied by a selective activation of melanin-concentrating hormone neurones. PMID- 25524603 TI - Sporadic late-onset nemaline myopathy in a woman with multiple myeloma successfully treated with lenalidomide/dexamethasone. PMID- 25524604 TI - [2014 ESC Guidelines on the diagnosis and treatment of aortic diseases]. PMID- 25524606 TI - The use of an automated external defibrillator in a victim of car accident. PMID- 25524605 TI - [2014 ESC/EACTS Guidelines on myocardial revascularization]. PMID- 25524607 TI - Dual guiding catheter approach for the treatment of massive coronary artery perforation. PMID- 25524608 TI - Statistics regarding interventional cardiology in Poland in 2013. Summary report of the Association of Cardiovascular Interventions of the Polish Cardiac Society (AISN PTK). PMID- 25524609 TI - The DEK oncoprotein is upregulated by multiple leukemia-associated fusion genes. PMID- 25524610 TI - Barriers to healthcare seeking, beliefs about cancer and the role of socio economic position. A Danish population-based study. AB - BACKGROUND: Cancer-related health behaviours may be affected by barriers to healthcare seeking and beliefs about cancer. The aim was to assess anticipated barriers to healthcare seeking and beliefs about cancer in a sample of the Danish population and to assess the association with socio-economic position. METHODS: A population-based telephone interview with 3000 randomly sampled persons aged 30 years or older was performed using the Awareness and Beliefs about Cancer measure from 31 May to 4 July 2011. The Awareness and Beliefs about Cancer measure includes statements about four anticipated barriers to healthcare seeking and three positively and three negatively framed beliefs about cancer. For all persons, register-based information on socio-economic position was obtained through Statistics Denmark. RESULTS: Two anticipated barriers, worry about what the doctor might find and worry about wasting the doctor's time, were present among 27% and 15% of the respondents, respectively. Overall, a high proportion of respondents concurred with positive beliefs about cancer; fewer concurred with negative beliefs. Having a low educational level and a low household income were strongly associated with having negative beliefs about cancer. CONCLUSION: The fact that worry about what the doctor might find and worry about wasting the doctor's time were commonly reported barriers call for initiatives in general practice. The association between low educational level and low household income and negative beliefs about cancer might to some degree explain the negative socio economic gradient in cancer outcome. PMID- 25524611 TI - The impact of computer use in myopia progression: a cohort study in Spain. AB - OBJECTIVE: Many subjects, especially highly educated subjects, are increasingly exposed to computer use. This exposure might represent an explanation for the growing rates of myopia. METHODS: We assessed 17,217 Spanish university graduates from the SUN project, an open-recruitment cohort. Their mean age was 38.5 years (SD 12.1), and their mean time of exposure to computers was 14.3h/week (SD 14.6). We estimated multivariable-adjusted odds ratios (OR) for the risk of myopia development and/or progression (>=0.5 diopters) according to baseline exposure to computer and to changes in exposure. RESULTS: The age and sex-adjusted OR comparing >40 h/week of exposure versus<10h/week was 1.34 (95% confidence interval (CI): 1.12-1.60). This association remained essentially unchanged after additional adjustments. Comparing participants who increased their exposure to computers, versus those with no change, the age and sex-adjusted OR was 1.49 (1.34-1.66). This result was unchanged after additional adjustments. CONCLUSIONS: To our knowledge this is the first large longitudinal assessment in young adults, showing that exposure to computer use is associated with myopia development or progression in a cohort of Spanish university graduates. Further studies are needed to confirm these epidemiological findings. PMID- 25524612 TI - Can skin cancer prevention and early detection be improved via mobile phone text messaging? A randomised, attention control trial. AB - OBJECTIVE: To test the impact of a theory-based, SMS (text message)-delivered behavioural intervention (Healthy Text) targeting sun protection or skin self examination behaviours compared to attention control. METHOD: Overall, 546 participants aged 18-42 years were randomised using a computer-generated number list to the skin self-examination (N=176), sun protection (N=187), or attention control (N=183) text messages group. Each group received 21 text messages about their assigned topic over 12 months (12 weekly messages for 3 months, then monthly messages for the next 9 months). Data were collected via telephone survey at baseline, 3, and 12 months across Queensland from January 2012 to August 2013. RESULTS: One year after baseline, the sun protection (mean change 0.12; P=0.030) and skin self-examination groups (mean change 0.12; P=0.035) had significantly greater improvement in their sun protection habits (SPH) index compared to the attention control group (reference mean change 0.02). The increase in the proportion of participants who reported any skin self-examination from baseline to 12 months was significantly greater in the skin self-examination intervention group (103/163; 63%; P<0.001) than the sun protection (83/173; 48%) or attention control (65/165; 36%) groups. There was no significant effect of the intervention for participants' self-reported whole-body skin self-examination, sun tanning, or sunburn behaviours. CONCLUSION: The Healthy Text intervention was effective in inducing significant improvements in sun protection and any type of skin self examination behaviours. TRIAL REGISTRATION: The Australian and New Zealand Clinical Trials register (ACTRN12612000577819). FUNDING: Cancer Australia 1011999. PMID- 25524613 TI - Effectiveness of interventions applicable to primary health care settings to promote Mediterranean diet or healthy eating adherence in adults: A systematic review. AB - OBJECTIVE: To evaluate the effects on healthy eating or the Mediterranean diet adherence achieved by interventions suitable for implementation in primary care settings. METHODS: Medline (PubMed) and The Cochrane Library bibliographic searches retrieved randomized controlled trials published in English or Spanish, January 1990-January 2013. The inclusion criteria were adult population, >3 months follow-up, and interventions suitable for primary care settings. Exclusion resulted if studies focused exclusively on weight loss or did not analyze food intake (fats, fruits and vegetables--F&V, fiber) or Mediterranean diet adherence. Validity (risk of bias) was independently evaluated by two researchers; discrepancies were reviewed until a consensus was reached. RESULTS: Of the 15 included articles (14 studies), only 3 studies surpassed 12-months follow-up. Ten interventions emphasized healthy nutrition (n = 9948); 4 added activity levels (n = 3816). Six trials included participants with cardiovascular risk; 7 were community-based; 1 focused on women with cancer. Eleven studies showed 9.7% to 59.3% increased F&V intake with counseling interventions, compared to baseline ( 13.3% to 27.8% in controls). Seven studies reported significant differences between intervention and control groups. CONCLUSION: Nutritional counseling moderately improves nutrition, increases intake of fiber, F&V, reduces dietary saturated fats, and increases physical activity. Studies with longer follow-up are needed to determine long-term effects, cardiovascular morbidity, and mortality. PMID- 25524615 TI - Pregnancy resolutions among pregnant teens: termination, parenting or adoption? AB - BACKGROUND: Teenagers are unprepared to face or to deal with an unexpected pregnancy. Adolescents do not necessarily possess the cognitive ability needed to clearly evaluate such a situation or to determine how to resolve their pregnancy. This study seeks to shed light on what pregnant adolescents consider when coming to a decision about what to do about their pregnancy. METHODS: In-depth interviews were conducted among a purposive sample of Hong Kong Chinese women recruited from a Maternal and Child Health Centre, who had a history of being pregnant in their teens and out of wedlock. Interviews were conducted to explore the considerations surrounding their decision on how to resolve their pregnancy. RESULTS: A total of nine women were interviewed. An analysis of the interview transcripts revealed that to arrive at a decision on what to do about their pregnancy, pregnant teens took into consideration their relationship with their boyfriend, their family's advice or support, practical considerations, their personal values in life, and views on adoption. CONCLUSIONS: The results of this study results highlighted that during this life-altering event for adolescents, an open discussion should take place among all of the parties concerned. A better understanding of each party's perspective would allow for better decision making on the resolution of the pregnancy. Health professionals or social workers are there to help pregnant adolescents, romantic partners, and family members make informed choices on how to resolve the pregnancy. PMID- 25524614 TI - Social engagement and chronic disease risk behaviors: the Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVE: Although engagement in social networks is important to health, multiple different dimensions exist. This study identifies which dimensions are associated with chronic disease risk behaviors. METHODS: Cross-sectional data on social support, loneliness, and neighborhood social cohesion from 5381 participants, aged 45-84 from the Multi-Ethnic Study of Atherosclerosis was used. RESULTS: After adjusting for individual characteristics and all social engagement variables, social support was associated with lower smoking prevalence (PR=0.88, 95% CI: 0.82, 0.94), higher probability of having quit (PR=1.03, 95% CI: 1.01, 1.06) and a slightly higher probability of achieving physical activity recommendations (PR=1.03, 95% CI: 1.01, 1.06). Neighborhood social cohesion was associated with very slightly higher probability of achieving recommended (PR=1.03, 95% CI: 1.01, 1.05) or any regular (PR=1.0, 95% CI: 1.01, 1.04) physical activity, and a higher probability of consuming at least five daily fruit and vegetable servings (PR=1.05, 95% CI: 1.01, 1.09). CONCLUSIONS: Both social support and neighborhood social cohesion, a less commonly considered aspect of social engagement, appear to be important for chronic disease prevention interventions and likely act via separate pathways. PMID- 25524616 TI - Development of an ultrasensitive immunoassay using affinity maturated antibodies for the measurement of rodent insulin. AB - The measurement of plasma insulin is important for clinical diagnosis of diabetes and for preclinical research of metabolic diseases, especially in rodent models used in drug discovery research for type 2 diabetes. Fasting immunoreactive insulin (F-IRI) concentrations are used to calculate the homeostasis model assessment ratio (HOMA-R), an index of insulin sensitivity. However, even the most sensitive commercially available enzyme-linked immunosorbent assay (ELISA) kits cannot measure the very low F-IRI concentrations in normal rats and mice. Therefore, we sought to develop a new rodent insulin ELISA with greater sensitivity for low F-IRI concentrations. Despite repeated efforts, high-affinity antibodies could not be generated by immunizing mice with mouse insulin (self antigen). Therefore, we generated two weak monoclonal antibodies (13G4 and 26B2) that were affinity maturated and used to develop a highly sensitive ELISA. The measurement range of the sandwich ELISA with the affinity maturated antibodies (13G4m1 and 26B2m1) was 1.5 to 30,000 pg/ml, and its detection limit was at least 10 times lower than those of commercially available kits. In conclusion, we describe the development of a new ultrasensitive ELISA suitable for measuring very low plasma insulin concentrations in rodents. This ELISA might be very useful in drug discovery research in diabetes. PMID- 25524617 TI - An enzyme-linked immunosorbent assay for detection of pyrene and related polycyclic aromatic hydrocarbons. AB - Polycyclic aromatic hydrocarbons (PAHs) can form DNA-binding compounds that show genotoxicity and carcinogenicity. Pyrene, as a PAH, was covalently linked to carrier protein bovine serum albumin and ovalbumin. A monoclonal antibody (McAb) was produced that showed high cross-reactivity values with chrysene (169.73%), benzo[a]pyrene (693.34%), benzo[a]anthracene (16.36%), and indeno[1,2,3-cd]pyrene (40.96%) and showed no significant cross-reactivity values with other homologues (<0.1%). A competitive enzyme-linked immunosorbent assay (ELISA) was developed for detection of pyrene and some homologues in water samples. The detection limit of the assay was 65.08 pg ml(-1). The average recoveries of PAHs from tap water, lake water, and mineral water were 99.13, 99.74, and 99.19%, respectively, indicating that matrices of water samples do not interfere with the assay. The results demonstrated that the developed ELISA seems to be a potential method for monitoring of pyrene and some homologous PAHs in water samples. PMID- 25524618 TI - DNA biosensor based on hybridization refractory mutation system approach for single mismatch detection. AB - We report on a simple approach to enhance solid-phase hybridization-based single base mismatch discrimination at high ionic strength based on the deliberate insertion of a natural DNA base mismatch in the surface-tethered probe. A large drop in hybridization signal of single base mismatched alleles using the designed probe as compared with the conventional probe, from 80% to less than 25% of the signal obtained with the fully complementary, non-mutation-containing sequence, when using colorimetric detection was further improved to 20% when using electrochemical detection, attributable to a difference of spacing of immobilized probes. Finally, the designed probe was used for the electrochemical detection of the DQA1*05:05 allele amplified from real human blood samples. PMID- 25524619 TI - Tris(3-hydroxypropyl)phosphine is superior to dithiothreitol for in vitro assessment of vitamin K 2,3-epoxide reductase activity. AB - Use of the reductant dithiothreitol (DTT) as a substrate for measuring vitamin K 2,3-epoxide reductase (VKOR) activity in vitro has been reported to be problematic because it enables side reactions involving the vitamin K1 2,3 epoxide (K1>O) substrate. Here we characterize specific problems when using DTT and show that tris(3-hydroxypropyl)phosphine (THPP) is a reliable alternative to DTT for in vitro assessment of VKOR enzymatic activity. In addition, the pH buffering compound imidazole was found to be problematic in enhancing DTT dependent non-enzymatic side reactions. Using THPP and phosphate-based pH buffering, we measured apparent Michaelis-Menten constants of 1.20 MUM for K1>O and 260 MUM for the active neutral form of THPP. The Km value for K1>O is in agreement with the value that we previously obtained using DTT (1.24 MUM). Using THPP, we successfully eliminated non-enzymatic production of 3-hydroxyvitamin K1 and its previously reported base-catalyzed conversion to K1, both of which were shown to occur when DTT and imidazole are used as the reductant and pH buffer, respectively, in the in vitro VKOR assay. Accordingly, substitution of THPP for DTT in the in vitro VKOR assay will ensure more accurate enzymatic measurements and assessment of warfarin and other 4-hydroxycoumarin inhibition constants. PMID- 25524620 TI - Dielectrophoretically controlled Fresnel zone plate. AB - Switchability is a highly sought after feature for planar optical systems. Suspensions of nanomaterials can be used for generating controllable changes in such systems. We report a planar diffractive microfluidic lens which integrates controlled dielectrophoresis (DEP) for trapping suspended nanomaterials. Silicon and tungsten oxide nanoparticle suspensions are used. These nanomaterials are trapped in such a way as to form alternating opaque and transparent rings using the DEP forces on demand. These rings form a planar diffractive Fresnel zone plate to focus the incident light. The Fresnel zone plate is tuned for the visible light region and the lens can be turned on (DEP applied) or off (DEP removed) in a controlled manner. This proof of concept demonstration can be further expanded for a variety of switchable optical devices and can be integrated with lab-on-a-chip and optofluidic devices. PMID- 25524621 TI - Acai berry extract attenuates glycerol-induced acute renal failure in rats. AB - Acute renal failure (ARF) is one of the most common problems encountered in hospitalized critically ill patients. In recent years great effort has been focused on the introduction of herbal medicine as a novel therapeutic agent for prevention of ARF. Hence, the current study was designed to investigate the effect of Acai berry extract (ABE) on glycerol-induced ARF in rats. Results of the present study showed that rat groups that received oral ABE in a dose of 100 and 200 mg/kg/day for 7 days before or 7 days after induction of ARF by a single intramuscular glycerol injection reported a significant improvement in kidney functions tests [decrease in serum urea, serum creatinine, and blood urea nitrogen (BUN)] when compared to the ARF model groups. Moreover, there was significant amelioration in renal oxidative stress markers [renal catalase (CAT), renal reduced glutathione (GSH)] and renal histopathological changes in the ABE treated groups when compared to ARF model groups. The most significant improvement was reported in the groups where ABE was administered in a dose 200 mg/kg/day. These results indicate that ABE has a potential role in ameliorating renal damage involved in ARF. PMID- 25524622 TI - Renoprotective effect of aliskiren on renal ischemia/reperfusion injury in rats: electron microscopy and molecular study. AB - PURPOSE: To determine the protective effect of aliskiren on ischemia-reperfusion (I/R) injury in a rat renal (I/R) model. METHODS: Rats were randomly divided into five groups: sham control group; sham control with aliskiren pretreatment; I/R group and I/R with two doses of aliskiren pretreatment. Rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h reperfusion. Aliskiren (50 and 100 mg/kg) was administered orally by gavage 24 and 1 h prior to ischemia. After 24 h reperfusion, kidney samples were taken for the determination of malondialdehyde (MDA) level, superoxide dismutase (SOD), glutathione (GSH) activity and histological evaluation. The level of serum creatinine (SCR) and blood urea nitrogen (BUN), renin and angiotensin II (AT-2) was measured in serum samples. RESULTS: Kidneys from I/R groups showed significant increase in MDA level and significant decrease in GSH, and SOD activity. IL-1beta, iNOS and NFkB gene expression significantly increased in the I/R groups in the rat kidney tissue. Aliskiren treatment showed a significant down-regulatory effect on IL-1beta, iNOS and NFkB mRNA expression. Compared with the sham group, SCR and BUN, renin and AT-2 were significantly increased in the I/R rats, accompanied by histopathological damage to the kidney. CONCLUSION: Pretreatment with aliskiren ameliorated I/R-induced renal injury through decreasing nitric oxide and AT-2 levels and by the reduction of injury induced by I/R injury and ameliorated renal histopathological molecular and biochemical changes. PMID- 25524623 TI - Mechanism and experimental study on the photocatalytic performance of Ag/AgCl @ chiral TiO2 nanofibers photocatalyst: the impact of wastewater components. AB - The effect of the water matrix components of a secondary effluent of a urban wastewater treatment plant on the photocatalytic activity of Ag/AgCl @ chiral TiO2 nanofibers and the undergoing reaction mechanisms were investigated. These effects were evaluated through the water components-induced changes on the net rate of hydroxyl radical (OH) generation and modeled using a relative rate technique. Dissolved organic matter DOM (k=-2.8*10(8) M(-1) s(-1)) scavenged reactive oxygen species, Cl(-) (k=-5.3*10(8) M(-1) s(-1)) accelerated the transformation from Ag to AgCl (which is not photocatalytically active under visible-light irradiation), while Ca(2+) at concentrations higher than 50 mM (k= 1.3*10(9) M(-1) s(-1)) induced aggregation of Ag/AgCl and thus all of them revealed inhibitory effects. In contrast, NO3(-) (k=6.9*10(8) M(-1) s(-1)) and CO3(2-) (k=3.7*10(8) M(-1) s(-1)) improved the photocatalytic activity of Ag/AgCl slightly by improving the rate of HO generation. Other ubiquitous secondary effluent components including SO4(2-) (k=3.9*10(5) M(-1) s(-1)), NH3(+) (k=3.5*10(5) M(-1) s(-1)) and Na(+) (k=2.6*10(4) M(-1) s(-1)) had negligible effects. 90% of 17-alpha-ethynylestradiol (EE2) spiked in the secondary effluent was removed within 12 min, while the structure and size of Ag/AgCl @ chiral TiO2 nanofibers remained stable. This work may be helpful not only to uncover the photocatalytic mechanism of Ag/AgCl based photocatalyst but also to elucidate the transformation and transportation of Ag and AgCl in natural water. PMID- 25524627 TI - Synthetic lethality of combined glutaminase and Hsp90 inhibition in mTORC1-driven tumor cells. AB - The mammalian target of rapamycin complex 1 (mTORC1) integrates multiple signals from growth factors, nutrients, and cellular energy status to control a wide range of metabolic processes, including mRNA biogenesis; protein, nucleotide, and lipid synthesis; and autophagy. Deregulation of the mTORC1 pathway is found in cancer as well as genetic disorders such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. Recent studies have shown that the mTORC1 inhibitor rapamycin and its analogs generally suppress proliferation rather than induce apoptosis. Therefore, it is critical to use alternative strategies to induce death of cells with activated mTORC1. In this study, a small-molecule screen has revealed that the combination of glutaminase (GLS) and heat shock protein 90 (Hsp90) inhibitors selectively triggers death of TSC2-deficient cells. At a mechanistic level, high mTORC1-driven translation rates in TSC1/2-deficient cells, unlike wild-type cells, sensitizes these cells to endoplasmic reticulum (ER) stress. Thus, Hsp90 inhibition drives accumulation of unfolded protein and ER stress. When combining proteotoxic stress with oxidative stress by depletion of the intracellular antioxidant glutathione by GLS inhibition, acute cell death is observed in cells with activated mTORC1 signaling. This study suggests that this combination strategy may have the potential to be developed into a therapeutic use for the treatment of mTORC1-driven tumors. PMID- 25524628 TI - Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. AB - A key aspect of cancer metastases is the tendency for specific cancer cells to home to defined subsets of secondary organs. Despite these known tendencies, the underlying mechanisms remain poorly understood. Here we develop a microfluidic 3D in vitro model to analyze organ-specific human breast cancer cell extravasation into bone- and muscle-mimicking microenvironments through a microvascular network concentrically wrapped with mural cells. Extravasation rates and microvasculature permeabilities were significantly different in the bone-mimicking microenvironment compared with unconditioned or myoblast containing matrices. Blocking breast cancer cell A3 adenosine receptors resulted in higher extravasation rates of cancer cells into the myoblast-containing matrices compared with untreated cells, suggesting a role for adenosine in reducing extravasation. These results demonstrate the efficacy of our model as a drug screening platform and a promising tool to investigate specific molecular pathways involved in cancer biology, with potential applications to personalized medicine. PMID- 25524629 TI - Dietary lipids and adipocytes: potential therapeutic targets in cancers. AB - Lipids play an important role to support the rapid growth of cancer cells, which can be derived from both the endogenous synthesis and exogenous supplies. Enhanced de novo fatty acid synthesis and mobilization of stored lipids in cancer cells promote tumorigenesis. Besides, lipids and fatty acids derived from diet or transferred from neighboring adipocytes also influence the proliferation and metastasis of cancer cells. Indeed, the pathogenic roles of adipocytes in the tumor microenvironment have been recognized recently. The adipocyte-derived mediators or the cross talk between adipocytes and cancer cells in the microenvironment is gaining attention. This review will focus on the impacts of lipids on cancers and the pathogenic roles of adipocytes in tumorigenesis and discuss the possible anticancer therapeutic strategies targeting lipids in the cancer cells. PMID- 25524630 TI - Oral exposure to the anti-pyridoxine compound 1-amino D-proline further perturbs homocysteine metabolism through the transsulfuration pathway in moderately vitamin B6 deficient rats. AB - Pyridoxal 5'-phosphate (PLP; a B6 vitamer) serves as an important cofactor in a myriad of metabolic reactions, including the transsulfuration (TS) pathway, which converts homocysteine (Hcy) to cysteine. While overt vitamin B6 deficiency is rare, moderate deficiency is common and may be exacerbated by anti-pyridoxine factors in the food supply. To this end, we developed a model of moderate B6 deficiency and a study was conducted to examine the in vivo effect of 1-amino D proline (1ADP), an anti-pyridoxine factor found in flaxseed, on indices of Hcy metabolism through the TS pathway in moderately B6 deficient rats. Male weaning rats received a semi-purified diet containing either 7 mg/kg (control; CD) or 0.7 mg/kg (moderately deficient; MD) diet of pyridoxine.hydrochloride (PN?HCl), each with 1 of 4 levels of 1ADP, viz. 0, 0.1, 1 and 10 mg/kg diet for 5 weeks. Perturbations in vitamin B6 biomarkers were more pronounced in the MD group. Plasma PLP was significantly reduced, while plasma Hcy (8-fold) and cystathionine (11-fold) were increased in rats consuming the highest amount of 1ADP in the MD group. The activities of hepatic cystathionine beta-synthase and cystathionine gamma-lyase enzymes were significantly reduced in rats consuming the highest 1ADP compared to the lowest, for both levels of PN?HCl. Dilation of hepatic central veins and sinusoids, mild steatosis and increased liver triglycerides were present in MD rats consuming the highest 1ADP level. The current data provide evidence that the consumption of an anti-pyridoxine factor linked to flaxseed may pose a risk for subjects who are moderate/severe vitamin B6 deficient. PMID- 25524632 TI - Two decades of voluntary nonremunerated blood donation in Shenzhen, China. AB - BACKGROUND: As an emerging metropolis with population expansion from 2 million to 10 million from 1993 to 2012, the clinical demand for blood in Shenzhen has increased 20 times. To deal with this big challenge, Shenzhen utilized voluntary nonremunerated blood donation (VNRBD) in 1993 for the first time in China. After two decades of efforts, Shenzhen has achieved self-sufficiency in its blood supply and guaranteed its blood security by nonpaid blood donation. STUDY DESIGN AND METHODS: We summarized the strategies to achieve self-sufficiency and security in the blood supply in Shenzhen during two decades, including the legal construction of VNRBDs and the continuously improving strategies to recruit and retain nonpaid donors. The collection data of whole blood (WB) and apheresis platelet (PLT) donations were retrieved, and donor demographic and donation characteristics were analyzed. RESULTS: From 1993 to 1998, paid and nonpaid blood donations coexisted in Shenzhen. From the year 1999, all WB for clinical use came from VNRBDs. From 1999 to 2012, the donors who chose to donate 400 mL each time and repeat and regular donors increased sharply to meet the fast growth of clinical demand. From the year 2005, the clinical demand for PLTs was entirely satisfied by nonpaid donations. CONCLUSIONS: After two decades of practice, we believe that the legal regime of VNRBD is fundamental guarantee for long-term self-sufficiency and security in the blood supply. In addition, strengthening the publicity to improve the public's awareness and improving donation services and measures to recruit more nonpaid donors and retain repeat and regular donors are very important. PMID- 25524631 TI - Membranoproliferative glomerulonephritis and C3 glomerulonephritis: frequency, clinical features, and outcome in children. AB - AIM: C3 glomerulonephritis (C3GN) is a recently described disease that is related to membranoproliferative glomerulonephritis (MPGN). We retrospectively compared the frequencies, clinical characteristics, treatment modalities, and outcomes of C3GN and MPGN in a cohort of Japanese children. METHODS: Children who were pathologically diagnosed with MPGN (type I or III) in our hospital were divided into two groups based on immunofluorescence imaging of renal biopsies: children with MPGN induced by classical complement pathway activation (classical MPGN) and children with C3GN. RESULTS: Of 14 children with MPGN (five boys), four had classical MPGN, eight had C3GN, and two had unclassifiable glomerulonephritis. Four children with classical MPGN and seven with C3GN received methylprednisolone pulse therapy followed by oral prednisolone for 2 years (MPT+PSL therapy). Subsequently, six of seven children with C3GN received combined therapy (prednisolone, azathioprine, and anticoagulants) for 2 years because they responded poorly to MPT+PSL therapy. At the last follow-up visit, two children with classical MPGN and seven with C3GN had not achieved remission. One child with classical MPGN and five with C3GN had hypocomplementaemia at the last follow up. None of the children had renal impairment. CONCLUSION: More than half of the patients previously diagnosed with MPGN fulfilled the criteria for C3GN in children. C3GN may be more refractory than classical MPGN to immunosuppressant therapy. PMID- 25524633 TI - A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder. AB - Sulfatases are key enzymatic regulators of sulfate homeostasis with several biological functions including degradation of glycosaminoglycans (GAGs) and other macromolecules in lysosomes. In a severe lysosomal storage disorder, multiple sulfatase deficiency (MSD), global sulfatase activity is deficient due to mutations in the sulfatase-modifying factor 1 (SUMF1) gene, encoding the essential activator of all sulfatases. We identify a novel regulatory layer of sulfate metabolism mediated by a microRNA. miR-95 depletes SUMF1 protein levels and suppresses sulfatase activity, causing the disruption of proteoglycan catabolism and lysosomal function. This blocks autophagy-mediated degradation, causing cytoplasmic accumulation of autophagosomes and autophagic substrates. By targeting miR-95 in cells from MSD patients, we can effectively increase residual SUMF1 expression, allowing for reactivation of sulfatase activity and increased clearance of sulfated GAGs. The identification of this regulatory mechanism opens the opportunity for a unique therapeutic approach in MSD patients where the need for exogenous enzyme replacement is circumvented. PMID- 25524634 TI - A critical analysis of the trampoline test for diagnosis of SUI. Re: Rimstad L, Larsen ES, Schiotz HA, Kulseng-Hansen S, Pad tests with increasing load for the diagnosis of stress incontinence, Neurourology and Urodynamics, 2014: 33:1135 1139. PMID- 25524635 TI - Population genetics for 23 Y-STR loci in Tibetan in China and confirmation of DYS448 null allele. AB - Tibetan is one of 56 ethnic groups in China, where a level of genetic sub structure might be expected. Although a global analysis of Y-chromosomal haplotype diversity for 23 STR loci and Y-STR databases with PPY23 kit were created with collaborative effort, there was a lack of data for Tibetan population. In this study we evaluated 248 unrelated male individuals of Chinese Tibetan living in the Tibet Autonomous Region to explore the underlying genetic structure of Tibetan populations. These samples were typed for 23 short-tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, GATAH4, DYS481, DYS533, DYS549, DYS570, DYS576, and DYS643) by using PPY23 kit. A total of 224 different haplotypes were found. Haplotype diversity was 0.9990. Both Rst pairwise analyses and multidimensional scaling plot showed the genetic structure of Tibetan population was significantly different from some of Chinese ethnic groups and neighboring populations. There were few interesting null features at DYS448 observed by PPY23 that deserved some comment. It revealed that PPY23 marker set provided substantially stronger discriminatory power in Tibetan population. PMID- 25524636 TI - Kurarinone Synergizes TRAIL-Induced Apoptosis in Gastric Cancer Cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been identified as a promising anti-tumor agent against in a variety of cancers. However, gastric cancer cells are less sensitive than other cancer cells to TRAIL induced apoptosis. Here, we combined TRAIL with kurarinone, a natural compound, to induce apoptosis in gastric cancer cell lines SGC7901. After the cells were treated with TRAIL and/or kurarinone, the cell viability and apoptosis were examined by MTT and flow cytometry, respectively. The expression of apoptosis associated proteins was determined by western blot and q-RT-PCR. Kurarinone at low concentration significantly potentiated the cytotoxic effect of TRAIL by enhancing apoptosis as well as cell cycle arrest at G2/Mphase. The enhancement of apoptosis TRAIL induced by kurarinone involved downregulation of anti-apoptotic proteins Mcl-1 and c-FLIP as well as inhibition of STAT3 signaling. Moreover, we found that STAT3 inhibitor could synergistically enhanced TRAIL-induced apoptosis, similar to kurarinone. Kurarinone synergizes TRAIL-induced apoptosis in human gastric cancer cells. The synergistic effect between these two drugs is associated with downregulation of Mcl-1 and c-FLIP via inhibiting STAT3 signaling. The combination of TRAIL and kurarinone might be an effective regimen for the treatment of advanced gastric cancer. PMID- 25524637 TI - Overview of recent trends in diagnosis and management of leptomeningeal multiple myeloma. AB - Neurological complications related to multiple myeloma (MM) are not uncommon; however, direct involvement of the central nervous system (CNS) is extremely rare and represents a diagnostic and therapeutic challenge. Significant survival difference has been noted with the introduction of novel therapy in patients with MM, but their effect on the incidence and their use for management of leptomeningeal myeloma (LMM) is uncertain. Analysis of published data demonstrates its recent increased incidence, median time to CNS presentation, and slight improvement in median survival after diagnosis of LMM. Less common MM isotypes have been overrepresented in LMM. CNS relapse occurred mostly in patients with Durie-Salmon stage III MM. Despite treatments, standard or experimental, the survival rates of LMM remain dismal. Monitoring high risk patients closely, even after achieving complete remission, may be useful in early detection of LMM. As we gain better understanding of LMM, we recommend that future research and clinical care focus on earlier diagnosis and development of more efficient CNS-directed therapy to improve survival in this patient population. PMID- 25524639 TI - Exploring the critiques of the social model of disability: the transformative possibility of Arendt's notion of power. AB - The social model of disability has demonstrated political success for disabled people in society. At the same time, it has been labelled an outdated ideology in need of further development. While the social model of disability has been used successfully for political activism, it has simultaneously created conflict and tensions in disability studies, sociology and the sociology of the body. This article sheds light on the confusion surrounding the social model of disability by discussing the historical emergence of its different forms. It then proceeds to analyse and evaluate key criticisms of the social model of disability. The article then goes on to explore the relevance of different forms of power to the current discourse on disability before proceeding to explore in depth what might be gained from the approach of one particular theorist on power; Hannah Arendt. It suggests that there may be merit in drawing on Arendt and illustrates some of the benefits of a more nuanced idea of a pluralistic body and experiences. PMID- 25524638 TI - p53 loss increases the osteogenic differentiation of bone marrow stromal cells. AB - The tumor suppressor, p53, plays a critical role in suppressing osteosarcoma. Bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) have been suggested to give rise to osteosarcomas. However, the role of p53 in BMSCs has not been extensively explored. Here, we report that p53 regulates the lineage choice of mouse BMSCs (mBMSCs). Compared to mBMSCs with wild-type p53, mBMSCs deficient in p53 have enhanced osteogenic differentiation, but with similar adipogenic and chondrogenic differentiation. The role of p53 in inhibiting osteogenic lineage differentiation is mainly through the action of Runx2, a master transcription factor required for the osteogenic differentiation of mBMSCs. We find that p53 indirectly represses the expression of Runx2 by activating the microRNA-34 family, which suppresses the translation of Runx2. Since osteosarcoma may derive from BMSCs, we examined whether p53 has a role in the osteogenic differentiation of osteosarcoma cells and found that osteosarcoma cells with p53 deletion have higher levels of Runx2 and faster osteogenic differentiation than those with wild-type p53. A systems biology approach reveals that p53-deficient mBMSCs are more closely related to human osteosarcoma while mBMSCs with wild-type p53 are similar to normal human BMSCs. In summary, our results indicate that p53 activity can influence cell fate specification of mBMSCs, and provide molecular and cellular insights into the observation that p53 loss is associated with increased osteosarcoma incidence. PMID- 25524640 TI - The effects of CA1 5HT4 receptors in MK801-induced amnesia and hyperlocomotion. AB - In this study, the effects of 5-HT4 receptors of the CA1 on MK801-induced amnesia and hyperlocomotion were examined. One-trial step-down method was used to assess memory retention and then, the hole-board method to assess exploratory behaviors. The results showed that post-training intra-CA1 administration of RS67333 (62.5 and 625 ng/mouse) and RS23597 (1 and 10 ng/mouse) decreased memory consolidation, but it did not alter head-dip counts, head-dip latency and locomotor activity. Similarly, MK801 (0.5 and 1 MUg/mouse) decreased memory consolidation, but had no effect on head-dip counts and head-dip latency. Interestingly, it increased locomotor activity. The results also showed that post-training intra-CA1 injection of a sub-threshold dose of RS67333 (6.25 ng/mouse) or RS23597 (0.1 ng/mouse) could heighten MK801 induced amnesia and decrease locomotor activity, but it did not alter head-dip counts and head-dip latency. In conclusion, our findings suggest that the CA1 5-HT4 receptors are involved in MK801-induced amnesia and hyperlocomotion. PMID- 25524641 TI - Post-transcriptional regulation of transcript abundance by a conserved member of the tristetraprolin family in Candida albicans. AB - Members of the tristetraprolin (TTP) family of CCCH tandem zinc finger proteins bind to AU-rich regions in target mRNAs, leading to their deadenylation and decay. Family members in Saccharomyces cerevisiae influence iron metabolism, whereas the single protein expressed in Schizosaccharomyces pombe, Zfs1, regulates cell-cell interactions. In the human pathogen Candida albicans, deep sequencing of mutants lacking the orthologous protein, Zfs1, revealed significant increases (> 1.5-fold) in 156 transcripts. Of these, 113 (72%) contained at least one predicted TTP family member binding site in their 3'UTR, compared with only 3 of 56 (5%) down-regulated transcripts. The zfs1Delta/Delta mutant was resistant to 3-amino-1,2,4-triazole, perhaps because of increased expression of the potential target transcript encoded by HIS3. Sequences of the proteins encoded by the putative Zfs1 targets were highly conserved among other species within the fungal CTG clade, while the predicted Zfs1 binding sites in these mRNAs often 'disappeared' with increasing evolutionary distance from the parental species. C. albicans Zfs1 bound to the ideal mammalian TTP binding site with high affinity, and Zfs1 was associated with target transcripts after co-immunoprecipitation. Thus, the biochemical activities of these proteins in fungi are highly conserved, but Zfs1-like proteins may target different transcripts in each species. PMID- 25524642 TI - The efficacy of honey for ameliorating pain after tonsillectomy: a meta-analysis. AB - Postoperative pain and wound healing following tonsillectomy can result in dissatisfaction for the patient. However, there is no consensus on whether postoperatively administered honey effectively reduces morbidity after tonsillectomy. Therefore, a systematic review with a meta-analysis of the efficacy of honey as a treatment for postoperative pain and wound healing was performed. Two authors independently searched the database records (MEDLINE, SCOPUS, and Cochrane databases) dating from inception to June 2014. Studies comparing postoperative oral administration of honey with administration of placebo where the outcomes of interest were pain and wound healing on postoperative days were included. Baseline study characteristics, study quality, numbers of patients in steroid-treated and control groups, and treatment outcomes were extracted. Sufficient data for meta-analysis were retrieved from 4 trials with a total of 264 patients. We analyzed patient-reported pain scores and quantities of administered analgesics during the first 5 postoperative days. The pain score was significantly decreased in the honey-treated patients in comparison with the placebo-treated patients on postoperative day 1 only, but the analgesic intake of the honey-treated patients on the first 5 postoperative days was significantly less than that of the placebo-treated patients. In addition, honey significantly increased tonsillectomy bed wound healing in comparison with placebo during the first 2 weeks after surgery. This meta-analysis shows that postoperative administration of honey after tonsillectomy significantly reduces pain and promotes wound healing. Further trials comparing honey with good research methodology should be conducted to confirm these results. PMID- 25524643 TI - Endonasal dilatation of the Eustachian tube (EET) in children: feasibility and the role of tubomanometry (Esteve) in outcomes measurement. AB - Studies on endonasal dilatation of the Eustachian tube (EET) utilizing a balloon catheter have shown encouraging results over the last years. This retrospective analysis presents our outcomes with EET in children with chronic obstructive dysfunction of the Eustachian tube, as well as the role of tubomanometry (TMM, Esteve) as a diagnostic tool in the pre- and postoperative assessment of the Eustachian tube (ET) dysfunction. The data of 33 children, having undergone EET between September 2010 and March 2014, were retrospectively evaluated. They were assessed using tubomanometry before and after the EET. The R-data as the rate of Eustachian tube function in tubomanometry (TMM) were pre- and postoperatively matched with the clinical outcomes. Moreover, the patients' complaints before and after the procedure were analyzed. We did not see any EET-related complications in children. Most patients noticed a relief of their complaints. In the same time, tubomanometry was not able to show improved tube function or favorable postoperative changes in the R-data. Ear-related symptoms (e.g. otorrhea, otalgia, hearing loss) have been improved. EET is a feasible method in adults as well as in children to treat chronic tube dysfunction. However, tubomanometry does not seem to be the adequate tool to evaluate the tube function and thus the success rate of EET in children with chronic dysfunction of the Eustachian tube. PMID- 25524644 TI - Template-guided implantation of the Bonebridge: clinical experience. AB - The surgical procedure for Bonebridge implantation cannot be done in some cases without exposing the dura mater or sigmoid sinus. Surgical simulation technology can help to identify such difficulties prior to surgery and be used to clarify the optimal location and orientation of the device to be implanted. However, there has not been a simple strategy to drill the temporal bone at exactly the same location as that simulated on the computer. Based on our previous development of the surface template-assisted marker positioning (STAMP) method for performing image-guided otologic surgery, we recently developed a noninvasive guiding method, the BB-STAMP method, for performing image-guided Bonebridge implantation. Three patients underwent Bonebridge implantation at our surgical center during the years of 2013-2014. The authors in the simulation center supported the surgery using the BB-STAMP method. The time and effort required to prepare for the surgery were evaluated. In addition, a postoperative analysis was performed to assess the accuracy of placing the device in the planned location. The BB-STAMP method enabled the surgeon to precisely replicate the computer simulation in the real patient with submillimetric accuracy without complexity. Thus, the use of experienced and elaborative simulation coupled with the creation of a tailor-made three-dimensional template (BB-STAMP) enables surgeons to perform quick, precise and safe surgical procedures at distant institutions. PMID- 25524645 TI - Re-visiting the functional Relevance of the highly conserved Serine 40 Residue within HIV-1 p6(Gag). AB - BACKGROUND: HIV-1 formation is driven by the viral structural polyprotein Gag, which assembles at the plasma membrane into a hexagonal lattice. The C-terminal p6(Gag) domain harbors short peptide motifs, called late domains, which recruit the cellular endosomal sorting complex required for transport and promote HIV-1 abscission from the plasma membrane. Similar to late domain containing proteins of other viruses, HIV-1 p6 is phosphorylated at multiple residues, including a highly conserved serine at position 40. Previously published studies showed that an S40F exchange in p6(Gag) severely affected virus infectivity, while we had reported that mutation of all phosphorylatable residues in p6(Gag) had only minor effects. FINDINGS: We introduced mutations into p6(Gag) without affecting the overlapping pol reading frame by using an HIV-1 derivative where gag and pol are genetically uncoupled. HIV-1 derivatives with a conservative S40N or a non conservative S40F exchange were produced. The S40F substitution severely affected virus maturation and infectivity as reported before, while the S40N exchange caused no functional defects and the variant was fully infectious in T-cell lines and primary T-cells. CONCLUSIONS: An HIV-1 variant carrying a conservative S40N exchange in p6(Gag) is fully functional in tissue culture demonstrating that neither S40 nor its phosphorylation are required for HIV-1 release and maturation. The phenotype of the S40F mutation appears to be caused by the bulky hydrophobic residue introduced into a flexible region. PMID- 25524646 TI - Efficient generation of twin photons at telecom wavelengths with 2.5 GHz repetition-rate-tunable comb laser. AB - Efficient generation and detection of indistinguishable twin photons are at the core of quantum information and communications technology (Q-ICT). These photons are conventionally generated by spontaneous parametric down conversion (SPDC), which is a probabilistic process, and hence occurs at a limited rate, which restricts wider applications of Q-ICT. To increase the rate, one had to excite SPDC by higher pump power, while it inevitably produced more unwanted multi photon components, harmfully degrading quantum interference visibility. Here we solve this problem by using recently developed 10 GHz repetition-rate-tunable comb laser, combined with a group-velocity-matched nonlinear crystal, and superconducting nanowire single photon detectors. They operate at telecom wavelengths more efficiently with less noises than conventional schemes, those typically operate at visible and near infrared wavelengths generated by a 76 MHz Ti Sapphire laser and detected by Si detectors. We could show high interference visibilities, which are free from the pump-power induced degradation. Our laser, nonlinear crystal, and detectors constitute a powerful tool box, which will pave a way to implementing quantum photonics circuits with variety of good and low cost telecom components, and will eventually realize scalable Q-ICT in optical infra-structures. PMID- 25524647 TI - Robust enzyme design: bioinformatic tools for improved protein stability. AB - The ability of proteins and enzymes to maintain a functionally active conformation under adverse environmental conditions is an important feature of biocatalysts, vaccines, and biopharmaceutical proteins. From an evolutionary perspective, robust stability of proteins improves their biological fitness and allows for further optimization. Viewed from an industrial perspective, enzyme stability is crucial for the practical application of enzymes under the required reaction conditions. In this review, we analyze bioinformatic-driven strategies that are used to predict structural changes that can be applied to wild type proteins in order to produce more stable variants. The most commonly employed techniques can be classified into stochastic approaches, empirical or systematic rational design strategies, and design of chimeric proteins. We conclude that bioinformatic analysis can be efficiently used to study large protein superfamilies systematically as well as to predict particular structural changes which increase enzyme stability. Evolution has created a diversity of protein properties that are encoded in genomic sequences and structural data. Bioinformatics has the power to uncover this evolutionary code and provide a reproducible selection of hotspots - key residues to be mutated in order to produce more stable and functionally diverse proteins and enzymes. Further development of systematic bioinformatic procedures is needed to organize and analyze sequences and structures of proteins within large superfamilies and to link them to function, as well as to provide knowledge-based predictions for experimental evaluation. PMID- 25524649 TI - Behavioral, metabolic and functional brain changes in a rat model of chronic neuropathic pain: a longitudinal MRI study. AB - Peripheral neuropathy often manifests clinically with symptoms of mechanical and cold allodynia. However, the neuroplastic changes associated with peripheral neuropathic pain and the onset and progression of allodynic symptoms remain unclear. Here, we used a chronic neuropathic pain model (spared nerve injury; SNI) to examine functional and metabolic brain changes associated with the development and maintenance of mechanical and cold hypersensitivity, the latter which we assessed both behaviorally and during a novel acetone application paradigm using functional MRI (fMRI). Female Sprague-Dawley rats underwent SNI (n=7) or sham (n=5) surgery to the left hindpaw. Rats were anesthetized and scanned using a 7 T MRI scanner 1 week prior to (pre-injury) and 4 (early/subchronic) and 20 weeks (late/chronic) post-injury. Functional scans were acquired during acetone application to the left hindpaw. (1)H magnetic resonance spectroscopy was also performed to assess SNI-induced metabolic changes in the anterior cingulate cortex (ACC) pre- and 4 weeks post-injury. Mechanical and cold sensitivity, as well as anxiety-like behaviors, were assessed 2 weeks pre-injury, and 2, 5, 9, 14, and 19 weeks post-injury. Stimulus-evoked brain responses (acetone application to the left hindpaw) were analyzed across the pre- and post injury time points. In response to acetone application during fMRI, SNI rats showed widespread and functionally diverse changes within pain-related brain regions including somatosensory and cingulate cortices and subcortically within the thalamus and the periaqueductal gray. These functional brain changes temporally coincided with early and sustained increases in both mechanical and cold sensitivity. SNI rats also showed increased glutamate within the ACC that correlated with behavioral measures of cold hypersensitivity. Together, our findings suggest that extensive functional reorganization within pain-related brain regions may underlie the development and chronification of allodynic-like behaviors. PMID- 25524650 TI - Spatiotemporal changes in neural response patterns to faces varying in visual familiarity. AB - Increasing experience with a previously unfamiliar face improves human ability to recognize it in challenging and novel viewing conditions. Differential neural responses to familiar versus unfamiliar faces in multiple regions of the ventral temporal and parietal cortex have been reported in previous work, but with limited attention to how behavioral and neural measures change with increasing familiarity. We examined changes in the spatial and temporal characteristics of neural response patterns elicited by faces that vary in their degree of visual familiarity. First, we developed a behavioral paradigm to familiarize participants to low-, medium-, and high-levels of familiarity with faces. Recognition of novel, naturalistic images of the learned individuals improved with increasing familiarity with faces. Next, a new set of participants learned faces using the behavioral paradigm, outside the fMRI scanner, and subsequently viewed blocks of whole-body images of the learned and novel people, inside the scanner. We found that the face-selective FFA and OFA, and a combination of the ventral-temporal areas (e.g., fusiform gyrus) and parietal areas (e.g., precuneus) contained patterns useful for classifying highly familiar versus unfamiliar faces. Classification along the temporal-sequence of the face blocks revealed an early separation of neural patterns elicited in response to highly familiar versus unfamiliar faces in the FFA and OFA, but not in other regions of interest. This indicates the potential for a rapid assessment of the "known versus unknown" status of faces in core face-selective regions of the brain. The present study provides a first look at the perceptual and neural correlates underlying experience gains with faces as they become familiar. PMID- 25524648 TI - The neural signature of information regularity in temporally extended event sequences. AB - Statistical regularities exist at different timescales in temporally unfolding event sequences. Recent studies have identified brain regions that are sensitive to the levels of regularity in sensory inputs, enabling the brain to construct a representation of environmental structure and adaptively generate actions or predictions. However, the temporal specificity of the statistical regularity to which the brain responds remains largely unknown. This uncertainty applies to the regularities of sensory inputs as well as instrumental actions. Here, we used fMRI to investigate the neural correlates of regularity in sequences of task events and action selections in a visuomotor choice task. We quantified timescale dependent regularity measures by calculating Shannon's entropy and surprise from a sliding-window of consecutive task events and actions. Activity in the frontopolar cortex negatively correlated with the entropy in action selection, while activity in the temporoparietal junction, the striatum, and the cerebellum negatively correlated with the entropy in stimulus events at longer timescales. In contrast, activity in the supplementary motor area, the superior frontal gyrus, and the superior parietal lobule was positively correlated with the surprise of each stimulus across different timescales. The results suggest a spatial distribution of regions sensitive to various information regularities according to a temporal hierarchy, which may play a central role in concurrently monitoring the regularity in previous and current events over different timescales to optimize behavioral control in a dynamic environment. PMID- 25524652 TI - Survey of an Australian general emergency department: estimated prevalence of mental health disorders. AB - ACCESSIBLE SUMMARY: Compared to the general population, people with mental health disorders have an increased risk of morbidity and mortality, and are associated with higher health-care costs and lost societal productivity. Evidence indicates that more people are presenting to emergency departments with mental health disorders and that this group represents a disproportionately large number of emergency department attendees. The study results indicate that around a third of people who attended the emergency department may have had a mental health disorder, which is more than that found in the general adult Australian population. The results also suggest that the majority of emergency department attendees that have a mental health disorder are not identified at this opportunistic point of contact. The emergency department is an ideal point of contact to screen people for mental health problems. If problems are identified early, and treatment is started early, then it is likely that more people would be helped before their mental health problem became severe. However, increased identification of mental health problems may have implications for mental health services in terms of workload and delivery. The aim of this study was to estimate the prevalence of mental health disorders in an Australian general emergency department. A cross-sectional survey was used to screen a sample of 708 patients, using the Kessler Psychological Distress Scale (K10). The mean age of participants was 50.2 years, and their mean K10 score was 19.96 (SD 7.83), with 24% categorized as having high or very high psychological distress. Seventeen per cent self-reported having a mental health issue. Post-probability calculations based on observed K10 scores estimated that 37% of participants had an actual mental health disorder. The results suggest the prevalence of mental health disorder is significantly higher in emergency department attendees than Australian population norms, supporting the contention that a substantial proportion of ED attendees has a mental health disorder that, in the majority of cases, is not investigated at this point of contact. There is potential to screen all emergency department attendees for the presence of mental health disorder; early identification of mental illness would enable early referral for treatment. However, if all patients are screened, then it is likely that more mental health conditions will be picked up. The implications for mental health nursing are that this may increase workload. PMID- 25524653 TI - Perioperative management and outcomes of aortic surgery during pregnancy. AB - OBJECTIVE: Pathology of the aortic valve and ascending thoracic aorta is an uncommon but life-threatening complication of pregnancy. Cardiac surgery during pregnancy is known to carry a high risk of mortality to both the mother and fetus. We present our experience of performing aortic surgery during the patients' pregnancy. METHODS: All patients undergoing aortic surgery during pregnancy at St George's Hospital, from January 2004 until October 2013, were identified. Surgery was performed using cardiopulmonary bypass at 36 degrees C, with pulsatile perfusion at 70 mm Hg. Fetal blood flow parameters were serially monitored during surgery, via transabdominal and/or transvaginal Doppler ultrasonography. Surgery was performed in the second trimester when possible to allow completion of organogenesis and minimize hemodynamic compromise. RESULTS: Eleven patients underwent aortic surgery. The median age was 28 years (range, 26 31 years), with gestational age 19 weeks (range, 16-21 weeks). Six patients had aortic root dilatation with aortic regurgitation, and 5 had aortic stenosis, one of whom presented with acute type A dissection. Four patients had Marfan syndrome, and 2 had undergone previous cardiac surgery. The operative procedures were aortic root replacement (tissue valve, n = 5; homograft, n = 1), aortic valve replacement (n = 3), valve-sparing root replacement (n = 1), and aortic and mitral valve replacements (n = 1). Mean cardiopulmonary bypass and cross-clamp times were 105 and 89 minutes, respectively. There were no maternal deaths; 8 healthy babies were born at term, and 3 pregnancies resulted in intrauterine demise within 1 week of surgery. CONCLUSIONS: Major aortic surgery during pregnancy carries a high risk to both mother and baby. With appropriate maternal and fetal monitoring, attention to cardiopulmonary bypass, pulsatile perfusion, near-normothermia, and avoidance of vasoconstrictors, these risks may be minimized. PMID- 25524654 TI - Differential effects of chlorinated and oxidized phospholipids in vascular tissue: implications for neointima formation. AB - The presence of inflammatory cells and MPO (myeloperoxidase) in the arterial wall after vascular injury could increase neointima formation by modification of phospholipids. The present study investigates how these phospholipids, in particular oxidized and chlorinated species, are altered within injured vessels and how they affect VSMC (vascular smooth muscle cell) remodelling processes. Vascular injury was induced in C57BL/6 mice and high fat-fed ApoE-/- (apolipoprotein E) mice by wire denudation and ligation of the left carotid artery (LCA). Neointimal and medial composition was assessed using immunohistochemistry and ESI-MS. Primary rabbit aortic SMCs (smooth muscle cells) were utilized to examine the effects of modified lipids on VSMC proliferation, viability and migration at a cellular level. Neointimal area, measured as intima to-media ratio, was significantly larger in wire-injured ApoE-/- mice (3.62+/ 0.49 compared with 0.83+/-0.25 in C57BL/6 mice, n=3) and there was increased oxidized low-density lipoprotein (oxLDL) infiltration and elevated plasma MPO levels. Relative increases in lysophosphatidylcholines and unsaturated phosphatidylcholines (PCs) were also observed in wire-injured ApoE-/- carotid arteries. Chlorinated lipids had no effect on VSMC proliferation, viability or migration whereas chronic incubation with oxidized phospholipids stimulated proliferation in the presence of fetal calf serum [154.8+/-14.2% of viable cells at 1 MUM PGPC (1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine) compared with control, n=6]. In conclusion, ApoE-/- mice with an inflammatory phenotype develop more neointima in wire-injured arteries and accumulation of oxidized lipids in the vessel wall may propagate this effect. PMID- 25524651 TI - Practice adaptive reserve and colorectal cancer screening best practices at community health center clinics in 7 states. AB - BACKGROUND: Enhancing the capability of community health centers to implement best practices (BPs) may mitigate health disparities. This study investigated the association of practice adaptive reserve (PAR) with the implementation of patient centered medical home (PCMH) colorectal cancer (CRC) screening BPs at community health center clinics in 7 states. METHODS: A convenience sample of clinic staff participated in a self-administered, online survey. Eight PCMH CRC screening BPs were scored as a composite ranging from 0 to 32. The PAR composite score was scaled from 0 to 1 and then categorized into 3 levels. Multilevel analyses examined the relation between PAR and self-reported implementation of PCMH BPs. RESULTS: There were 296 respondents, and 59% reported 6 or more PCMH BPs at their clinics. The mean PAR score was 0.66 (standard deviation, 0.18), and the PCMH BP mean scores were significantly higher for respondents who reported higher clinic PAR categories. In comparison with the lowest PAR level, adjusted PCMH BP means were 25.0% higher at the middle PAR level (difference, 3.2; standard error, 1.3; t = 2.44; P = .015) and 63.2% higher at the highest PAR level (difference, 8.0; standard error, 1.9; t = 4.86; P < .0001). CONCLUSIONS: A higher adaptive reserve, as measured by the PAR score, was positively associated with self reported implementation of PCMH CRC screening BPs by clinic staff. Future research is needed to determine the PAR levels most conducive to implementing CRC screening and to develop interventions that enhance PAR in primary care settings. PMID- 25524655 TI - Most functional outcomes are similar for men and women after hip fracture: a secondary analysis of the enhancing mobility after hip fracture trial. AB - BACKGROUND: The impact of gender on functional outcomes after hip fracture is not known. We aimed to determine the extent to which gender influenced functional outcome and response to exercise in older people after hip fracture, and to determine if any differences persisted after adjusting for cognition, weight and age. METHOD: Secondary analysis of data from the Enhancing Mobility After Hip Fracture trial in which older people after hip fracture received either a lower or higher intensity exercise program. Functional outcomes included physical performance and self-reported measures. Regression models were used to compare genders at baseline, week 4 and week 16, with adjustment for baseline values, cognition, weight and age. Interaction terms were used to assess a differential impact of the intervention by gender. RESULTS: Outcome data were available for 160 participants, 30 men (19%) and 130 women (81%) at baseline, with the withdrawal of 4 men (13%) and 6 women (5%) at week 16. There were no gender differences for any baseline measures or for most of the 19 functional outcome measures at weeks 4 and 16. At week 4 men performed better in knee extensor strength (2.1 kg, 95% CI 0.6 to 3.7, p < 0.01). This difference did not persist after adjustment for body weight, however persisted after adjusting for baseline, cognition, and age (p = 0.038). At week 4, men performed better in coordinated stability (-10.0 error score, 95% CI -17.6 to -2.4, p=0.010) and this persisted after adjusting for baseline values only but not for cognition and age (p = 0.073). At week 16, men performed better in coordinated stability (-10.2 error score, 95% CI -18.4 to -1.9, p=0.016) and this persisted after adjusting only for cognitive impairment (p = 0.029) but not for age and baseline (p = 0.135). There was no indication of a differential impact of intervention type on the basis of gender. CONCLUSIONS: A few between gender differences were observed in strength and balance, however these appeared to be confounded by body weight, age and/or cognition. PMID- 25524656 TI - Assessment of clinical manifestations, disease activity and organ damage in 996 Korean patients with systemic lupus erythematosus: comparison with other Asian populations. AB - AIM: To describe the clinical manifestations, disease activity and organ damage in Korean patients with systemic lupus erythematosus (SLE). METHOD: American College of Rheumatology (ACR) criteria, SLE Disease Activity Index (SLEDAI), and Systemic Lupus International Collaborating Clinics/ACR damage index (SDI) were assessed in patients with SLE from 1998 to 2012. RESULTS: A total of 996 SLE patients were analyzed. The common accrual of ACR criteria included: immunologic (93%), hematologic (93%), arthritic (66%) and nephritic (50%). In the inception cohort over 10 years of follow-up (n = 120), the number of ACR criteria increased significantly (5.0 +/- 1.2 to 5.7 +/- 1.3), and nephritis, serositis and neuropsychiatric symptoms tended to increase continuously over time. SLEDAI-2K decreased significantly (5.6 +/- 3.4 to 4.1 +/- 1.2), but the percentage of patients with SLEDAI scores >= 12 did not decrease over time. The common organ damages were musculoskeletal (14.9%) and renal (11.1%). The mean SDI score increased significantly (0.4 +/- 0.8 to 1.1 +/- 1.6) and renal damage had two peaks in 1 and 6-10 years, musculoskeletal and neuropsychiatric damage were predominant from 1 to 5 years, and ophthalmic damage increased sharply over 10 years. CONCLUSION: Compared to other Asian cohorts, disease activity was lower and organ damage was less in our Korean cohort. Nephritis, serositis and neuropsychiatric symptoms increased continuously over time. Overall disease activity decreased significantly, but a small portion of severe disease activity continued during the disease course. The most common organ damage was musculoskeletal. The time in organ damage development varied, which reflects the possible causality, such as disease itself and/or treatment. PMID- 25524658 TI - Persistent communicating hydrocephalus in adult tuberous sclerosis patients: a possible therapeutic role for everolimus. AB - Subependymal giant cell tumor (SGCT) is a benign intraventricular tumor, usually located near the foramen of Monro. It is almost always associated with tuberous sclerosis complex (TSC). SGCTs may obstruct cerebrospinal fluid (CSF) pathways. Rarely, they may secrete a protein-rich exudate, causing communicating hydrocephalus. Surgery is indicated for symptomatic lesions or growing asymptomatic lesions. The operative approach to SGCT has shifted from simple shunt placement to a more aggressive approach, leading to early attempts at gross total resection. Recently, the mTOR inhibitor everolimus has been approved for treating SGCT. In this article, we present two cases of recurrent shunt malfunctions in adult TSC patients with protein-secreting SGCTs. We describe the complexity of treating such patients with an emphasis on the role mTOR inhibitors may have in their management. We also review the literature on surgical management of SGCT-related hydrocephalus. PMID- 25524657 TI - Associations between catecholaminergic, GABAergic, and serotonergic genes and self-reported attentional function in oncology patients and their family caregivers. AB - PURPOSE OF THE RESEARCH: Evaluate for associations between variations in genes involved in catecholaminergic, gamma-aminobutyric acid (GABA)-ergic, and serotonergic mechanisms of neurotransmission and attentional function latent classes. PATIENTS AND METHODS: This descriptive, longitudinal study was conducted at two radiation therapy departments. The sample included three latent classes of individuals with distinct trajectories of self-reported attentional function during radiation therapy, who were previously identified using growth mixture modeling among 167 oncology patients and 85 of their family caregivers. Multivariable models were used to evaluate for genotypic associations of neurotransmission genes with attentional function latent class membership, after controlling for covariates. RESULTS: Variations in catecholaminergic (i.e., ADRA1D rs4815675, SLC6A3 rs37022), GABAergic (i.e., SLC6A1 rs2697138), and serotonergic (i.e., HTR2A rs2296972, rs9534496) neurotransmission genes were significant predictors of latent class membership in multivariable models. CONCLUSIONS: Findings suggest that variations in genes that encode for three distinct but related neurotransmission systems are involved in alterations in attentional function. Knowledge of both phenotypic and genetic markers associated with alterations in attentional function can be used by clinicians to identify patients and family caregivers who are at higher risk for this symptom. Increased understanding of the genetic markers associated with alterations in attentional function may provide insights into the underlying mechanisms for this significant clinical problem. PMID- 25524659 TI - Upregulation of AIOLOS induces apoptosis and enhances etoposide chemosensitivity in Jurkat leukemia cells. AB - T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder of immature hematopoietic precursors committed to T-cell lineage. T-ALL accounts for ~15% of pediatric ALL cases and is prone to early relapse. With new and improved treatment protocols, the prognosis of T-ALL has improved particularly in children; however, the outcome of relapsed T-ALL cases remains poor. The AIOLOS gene is necessary to control lymphocyte differentiation and may be a potential target of T-ALL therapy. In the present study, Jurkat cells were divided into three groups: untransfected (UT) control, lentiviral vector control (Lenti-Mock) and AIOLOS-overexpressing (Lenti-AIOLOS) groups. Lenti-AIOLOS Jurkat cells were constructed by lentiviral transduction; cell cycle analysis, apoptosis and cytotoxicity assays were then performed to evaluate the effects of AIOLOS on cell cycle distribution, apoptosis and cell chemosensitivity to etoposide of Jurkat cells in vitro. Moreover, the expression levels of genes associated with apoptosis and cell cycle were investigated by quantitative reverse transcription polymerase chain reaction. Results showed that the percentage of Jurkat cells in the G0/G1 phase increased from 71.5 (UT) to 85.4% (Lenti-AIOLOS; P<0.05), yet the percentage of cells in the S-phase decreased from 15.1 (UT) to 11.6% (Lenti AIOLOS; P<0.05). The percentage of total apoptotic cells was significantly increased in the AIOLOS-transfected Jurkat cells (21.93%) compared with this percentage in the Lenti-Mock (13.35%) or the UT group (13.30%; P<0.05). Consistent with these results, AIOLOS overexpression induced P21 and P27 upregulation and CCND3 and SKP2 downregulation. Furthermore, AIOLOS overexpression synergistically increased the cytotoxic effects of etoposide and downregulated NF-kappaB expression. Our findings revealed that lentivirus mediated AIOLOS overexpression in Jurkat cells induced cell apoptosis, arrested the cell cycle at the G0/G1 phase, and synergistically increased the sensitivity of Jurkat cells to etoposide by inhibiting NF-kappaB activity. PMID- 25524660 TI - Is group pelvic floor retraining as effective as individual treatment? AB - AIM: Traditionally, pelvic floor retraining for faecal incontinence or obstructed defaecation has been delivered to patients through individual sessions with a specialist pelvic floor nurse, a resource-intensive practice. This study aimed to assess whether a similar outcome can be achieved by delivering retraining to patients in small groups, allowing considerable savings in the use of resources. METHOD: Data were collected prospectively in a pelvic floor database. Patients received pelvic floor retraining either individually or in a small group setting and completed baseline and follow-up questionnaires. Two hundred and fifteen patients were treated, 119 individually and 96 in a small group setting. Scores before and after treatment for the two settings were compared for the Gastrointestinal Quality of Life Index, the Fecal Incontinence Severity Index and the Patient Assessment of Constipation Symptoms. Additionally patients receiving group treatment completed a short questionnaire on their experience. RESULTS: The median change in Gastrointestinal Quality of Life Index score was 5 (range -62 to 73) for individual treatment and 4 (range -41 to 47) for group treatment, both showing statistically significant improvement. However, there was no significant difference between the settings. Similar results were obtained with the Fecal Incontinence Severity Index and Patient Assessment of Constipation Symptoms scores for the faecal incontinence and obstructed defaecation subgroups respectively. CONCLUSION: The majority of patients experienced symptomatic improvement following pelvic floor retraining and there was no significant difference in the resulting improvement according to treatment setting. As treatment costs are considerably less in a group setting, group pelvic floor retraining is more cost-effective than individual treatment. PMID- 25524661 TI - "When I was no longer able to see and walk, that is when I was affected most": experiences of disability in people living with HIV in South Africa. AB - PURPOSE: HIV-related disability is an emerging issue in countries where HIV is endemic. This study aimed to understand experiences of disability in patients living with HIV in South Africa using the International Classification of Functioning, Disability and Health (ICF) as a guiding framework. METHODS: In depth interviews were conducted with 19 HIV-positive people receiving ART through a public hospital in KwaZulu-Natal. Data were analyzed using collaborative qualitative content analysis. RESULTS: Participants described a variety of impairments related to mental, sensory, neuromusculoskeletal, skin, cardiovascular, digestive or reproductive systems. A tenuous relationship was evident between HIV and mental health impairments and the experience of other disabilities. Impairments affected participants' activity levels, especially mobility, domestic life, self-care and ability to work. Activity limitations affecting livelihood were often of more concern to participants than the impairments. Furthermore, women and men appeared to experience disability related to activities relevant to gendered norms in their cultural context. CONCLUSIONS: More understanding of the intersections among HIV, disability, gender and livelihood is needed. To respond to the increased need to manage disability within HIV care in Africa, HIV programs should include rehabilitative approaches, address concerns related to livelihoods in households with disability and consider gender differences in the experience of disability. IMPLICATIONS FOR REHABILITATION: HIV, its opportunistic infections and the treatments associated to them are related to health conditions and impairments that have the potential to develop into disability. Rehabilitation professionals in HIV endemic countries have therefore a larger and changing number of people living with HIV and need to consider the impact of the disease on the rehabilitation process. Mental health issues and disability might be interrelated and affect antiretroviral treatment (ART) adherence. Hence, rehabilitation has to use a holistic approach and integrate different therapy approaches (e.g. physiotherapy and mental health). The experience of living with HIV and developing disability has unreflected gender dynamics that need to be considered in rehabilitative care. Hence, the rehabilitation process has to consider the cultural realities and gendered experience of the condition. The study highlights the interrelationship between disability levels, the influence of environmental and social factors, and the changing experience related to gender. Hence, rehabilitation professionals in resource-poor settings have to go beyond the clinical response and therapy approaches in order to improve the activity and participation of people with disabilities and those living with HIV in their homes and communities. Community or home-based care might be avenues to further explore. PMID- 25524662 TI - Reversible switching of magnetic states by electric fields in nitrogenized divacancies graphene decorated by tungsten atoms. AB - Magnetic graphene-based materials have shown great potential for developing high performance electronic devices at sub-nanometer such as spintronic data storage units. However, a significant reduction of power consumption and great improvement of structural stability are needed before they can be used for actual applications. Based on the first-principles calculations, here we demonstrate that the interaction between tungsten atoms and nitrogenized-divacancies (NDVs) in the hybrid W@NDV-graphene can lead to high stability and large magnetic anisotropy energy (MAE). More importantly, reversible switching between different magnetic states can be implemented by tuning the MAE under different electric fields, and very low energy is consumed during the switching. Such controllable switching of magnetic states is ascribed to the competition between the tensile stain and orbital magnetic anisotropy, which originates from the change in the occupation number of W-5d orbitals under the electric fields. Our results provide a promising avenue for developing high-density magnetic storage units or multi state logical switching devices with ultralow power at sub-nanometer. PMID- 25524663 TI - Unusual location of a blue nevus: development on the lacrimal punctum. PMID- 25524664 TI - CD68 expression is a discriminative feature of indolent cutaneous CD8-positive lymphoid proliferation and distinguishes this lymphoma subtype from other CD8 positive cutaneous lymphomas. AB - BACKGROUND: Indolent cutaneous CD8+ lymphoid proliferation is a recently described rare entity among cutaneous T-cell lymphomas that typically presents with solitary skin lesions at acral sites. Separation from otherwise aggressive T cell lymphomas bearing a cytotoxic CD8+ phenotype is fundamental to avoid unnecessary harmful treatment. However, up to now, no reliable discriminative marker has been identified. OBJECTIVES: Motivated by these diagnostic quandaries, we have analyzed a large series of archived formalin-fixed paraffin-embedded (FFPE) specimens of atypical CD8+ cutaneous infiltrates with clear-cut diagnosis and clinical follow-up (n = 44) including five cases of indolent CD8+ lymphoid proliferation by using immunohistochemistry with the aim of obtaining markers predictive of subtype assignment. RESULTS: We identified exclusive expression of CD68 by lymphoma cells within the subgroup of indolent CD8+ lymphoid proliferation (5/5 cases). Specific CD68 expression in this entity was confirmed by the application of several monoclonal antibodies (KP1, PG-M1, KiM1P) against the CD68 molecule available for FFPE tissue. In contrast, none of the infiltrates of the other CD8+ cutaneous lymphoma entities stained positive for CD68 (0/39). CONCLUSIONS: Based on these observations, we suggest CD68 as a new discriminative marker which is helpful in distinguishing indolent CD8+ lymphoid proliferation from other CD8+ cutaneous lymphomas in ambiguous cases. PMID- 25524665 TI - Where have all the clinical trials gone? PMID- 25524666 TI - W(h)ither the hybrid? Up the "Slope of Enlightenment". PMID- 25524667 TI - Aortic valve repair and aortic valve-sparing operations. PMID- 25524668 TI - Discussion. PMID- 25524669 TI - Practice improves performance on a coronary anastomosis simulator, attending surgeon supervision does not. PMID- 25524670 TI - Characteristics and outcomes of secondary nodules identified on initial computed tomography scan for patients undergoing resection for primary non-small cell lung cancer. AB - OBJECTIVE: We sought to define the prevalence, malignancy rate, and outcome of secondary nodules (SNs) detected on computed tomography (CT) scan for patients undergoing resection for primary non-small cell lung cancer (NSCLC). METHODS: In consecutive patients with NSCLC, we reviewed all CT scan reports obtained at diagnosis of the dominant tumor for description of SNs. When resected, pathology was reviewed. Serial CT reports for 2 years postoperatively were evaluated to follow SNs not resected. RESULTS: Among 155 patients, 88 (57%) were found to have SNs. A total of 137 SNs were evaluated (median size, 0.5 cm). Thirty-two nodules were resected at primary resection. Nineteen (61%) resected nodules were benign, whereas 13 (39%) were malignant (8 synchronous primary tumors and 5 lobar metastases). A total of 105 unresected nodules were followed by CT. Of these, 32 (30%) resolved completely, 20 (19%) shrunk, and 28 (27%) were stable, whereas 11 (11%) were lost to follow-up. Fourteen SNs (13%) grew, of which 5 were found to be malignant, each a new primary. Overall 5-year survival was not different between patients with or without SNs (67% vs 64%; P = .88). DISCUSSION: The prevalence of SNs on CT scan in patients undergoing resection for primary NSCLC is high. Only a low proportion of SNs are ever found to be malignant, predominantly those on the ipsilateral side as the dominant tumor. The presence of SNs has no effect on survival. Patients with SNs, if otherwise appropriately staged, should not be denied surgical therapy. PMID- 25524671 TI - The prevalence and fate of secondary nodules found in patients undergoing resection for lung cancer. PMID- 25524672 TI - Discussion. PMID- 25524673 TI - Discussion. PMID- 25524674 TI - Are we looking at a surgical black box in the future? PMID- 25524675 TI - Discussion. PMID- 25524676 TI - Discussion. PMID- 25524677 TI - A French connection. PMID- 25524678 TI - Thymic carcinoma outcomes and prognosis: results of an international analysis. AB - OBJECTIVES: The objectives of this collaborative study were to characterize patients with thymic carcinoma, their treatment patterns, and association with overall survival (OS) and recurrence-free survival (RFS). METHODS: Clinical, pathologic, treatment, and follow-up information were analyzed. OS and RFS were the primary outcome measures. RESULTS: In 1042 cases of thymic carcinoma, 42 (5%) patients had pathologic Masaoka stage I, 138 (17%) had stage II, 370 (45%) had stage III, and 274 (33%) had stage IV disease. Overall, 166 patients (22%) underwent induction chemotherapy and 48 (6%) had preoperative radiation therapy. An R0 resection was performed in 447 cases (61%), R1 in 102 cases (14%), and R2 in 184 cases (25%). Squamous cell carcinoma was the predominant histologic subtype (n = 560; 79%). Adjuvant chemotherapy was administered to 237 (31%) patients, and 449 (60%) received adjuvant radiation therapy. The median OS was 6.6 years (95% confidence interval [CI], 5.8-8.3) and the cumulative incidence of recurrence at 5 years was 35% (95% CI, 30%-40%). In univariate analysis, early Masaoka stage, R0 resection, chemotherapy, and radiation therapy were associated with OS. Early Masaoka stage and R0 resection were also associated with RFS. On multivariable analysis, R0 resection and radiation therapy were associated with prolonged OS. Radiation therapy and male gender were associated with prolonged RFS. CONCLUSIONS: R0 resection and radiation therapy are associated with improved OS, whereas radiation therapy and male gender are associated with longer RFS. PMID- 25524679 TI - Discussion. PMID- 25524680 TI - Rarest of a rare disease: challenges in advancing our knowledge of thymic carcinoma. PMID- 25524681 TI - What comes out of Pandora's box? PMID- 25524682 TI - Valve-sparing aortic root replacement: too many cooks? PMID- 25524683 TI - Stage 1 hybrid palliation for hypoplastic left heart syndrome--assessment of contemporary patterns of use: an analysis of The Society of Thoracic Surgeons Congenital Heart Surgery Database. PMID- 25524684 TI - Extracorporeal membrane oxygenation as a bridge to lung transplantation in the United States: an evolving strategy in the management of rapidly advancing pulmonary disease. AB - OBJECTIVE: Improvements in technology have led to a resurgence in the use of extracorporeal membrane oxygenation as a bridge to lung transplantation. By using a national registry, we sought to evaluate how short-term survival has evolved using this strategy. METHODS: With the use of the United Network for Organ Sharing database, we analyzed data from 12,458 adults who underwent lung transplantation between 2000 and 2011. Patients were categorized into 2 cohorts: 119 patients who were bridged to transplantation using extracorporeal membrane oxygenation and 12,339 patients who were not. The study period was divided into four 3-year intervals: 2000 to 2002, 2003 to 2005, 2006 to 2008, and 2009 to 2011. With Kaplan-Meier analysis, 1-year survival was compared for the 2 cohorts of patients in each of the time periods. A propensity score-adjusted Cox regression model was used to estimate the risk of 1-year mortality. RESULTS: Of the total number of recipients, 4 (3.4%) were bridged between 2000 and 2002, 17 (14.3%) were bridged between 2003 and 2005, 31 (26.1%) were bridged between 2006 and 2008, and 67 were bridged (56.3%) between 2009 and 2011. Recipients bridged using extracorporeal membrane oxygenation were more likely to be younger and diabetic and to have higher serum creatinine and bilirubin levels. The 1-year survival for those bridged with extracorporeal membrane oxygenation was significantly lower in subsequent periods: 25.0% versus 81.0% (2000-2002), 47.1% versus 84.2% (2006-2008), and 74.4% versus 85.7% (2009-2011). However, this survival progressively increased with each period, as did the number of patients bridged using extracorporeal membrane oxygenation. CONCLUSIONS: Short-term survival with the use of extracorporeal membrane oxygenation as a bridge to lung transplantation has significantly improved over the past few years. PMID- 25524685 TI - Discussion. PMID- 25524687 TI - Physical exercise reduces transplant arteriosclerosis in a mouse aorta transplantation model. AB - BACKGROUND: Transplant arteriosclerosis limits long-term outcome after heart transplantation. The underlying mechanism of transplant arteriosclerosis remains alloreactivity, but it is also influenced by nonimmunologic cofactors. Physical exercise has well-established effects on the prevention of native arteriosclerosis. We hypothesized that physical exercise would reduce the development of transplant arteriosclerosis in an allogeneic transplantation setting. METHODS: Segments of the thoracic aorta from C57.Bl6 (H2b) or C3H.HeJ (H2k) mice were transplanted into the abdominal aortas of CBA.Ca mice (H2k), representing a major or minor alloantigen mismatch, respectively. Three days after surgery, recipient mice were assigned to either the control or physical exercise (consisting of 2 * 45 minutes of treadmill training per day) groups. Transplant arteriosclerosis was assessed and quantified by histology on day 28 after vessel transplantation. Endothelial cell integrity and function in histology sections and peripheral blood was assessed. RESULTS: All animals developed transplant arteriosclerosis with more severe luminal occlusion in the major alloantigen mismatch setting. Animals undergoing physical exercise developed significantly less severe transplant arteriosclerosis in both the major (P < .0001) and minor (P < .0001) antigen mismatches than their respective control groups without physical exercise. CD31(+) endothelial cells were present in significantly higher numbers in the grafts and circulating in peripheral blood in the exercise groups compared with their respective control. Above that, we found enhanced endothelial nitric oxide synthase-positive cells in both exercise groups compared with the untreated groups (P = .01 and P = .02, respectively). CONCLUSIONS: Physical exercise has a protective effect against the development of transplant arteriosclerosis. This could be due to enhanced endothelial cell regeneration and function in the graft. PMID- 25524688 TI - Of mice and men ... does exercise decrease progression of transplant coronary vasculopathy? PMID- 25524686 TI - Presurgical levels of circulating cell-derived microparticles discriminate between patients with and without transfusion in coronary artery bypass graft surgery. AB - OBJECTIVES: Improved understanding of presurgical risk factors for transfusions will lead to reduction in their number and related complications. The goal of this study is to identify these factors in coronary artery bypass graft (CABG) surgery. METHODS: Presented herein are results of analyses of data from an ongoing study of transfusion in CABG surgery. Of 122 patients, 81 received transfusion (Tx) and 41 did not (NoTx). In addition to routine tests, presurgical levels of microparticles from platelets (PMPs), red cells (RMPs), and other lineages were assayed. RESULTS: The Tx and NoTx groups were similar with respect to most presurgical variables but differed in distribution of gender, blood type, diabetes prevalence, activated partial thromboplastin time (aPTT), hemoglobin (HGB), and microparticle levels. Stepwise multiple logistic regression was used to evaluate presurgical variables and to develop a model to assess risk factors for transfusion. CD41(+) PMP and CD235(+) RMP levels were found to be the main risk factors for transfusion. The Model's discriminating ability was assessed using receiver operating characteristic curve analysis, which showed that the area under the model curve (+/- standard error) was 0.86 +/- 0.04 (95% confidence interval, 0.77-0.94). According to the model, patients with higher presurgical levels of circulating CD41(+) PMP, CD235a(+) RMP, and HGB, as well as a shorter aPTT, are less likely to receive transfusion(s). CONCLUSIONS: Presurgical levels of CD41(+) PMPs and CD235a(+) RMPs are the main risk factors for transfusion in CABG, followed by HGB and aPTT. PMID- 25524689 TI - Directly measuring spinal cord blood flow and spinal cord perfusion pressure via the collateral network: correlations with changes in systemic blood pressure. AB - OBJECTIVE: During thoracoabdominal surgery in which segmental arteries are sacrificed over a large area, blood supply routes from collateral networks have received attention as a means of avoiding spinal cord injury. The aim of this study was to investigate spinal cord blood supply through a collateral network by directly measuring spinal cord blood flow and spinal cord perfusion pressure experimentally. METHODS: In beagle dogs (n = 8), the thoracoabdominal aorta and segmental arteries L1-L7 were exposed, and a temporary bypass was created for distal perfusion. Next, a laser blood flow meter was placed on the spinal dura mater in the L5 region to measure the spinal cord blood flow. The following were measured simultaneously when the direct blood supply from segmental arteries L2 L7 to the spinal cord was stopped: mean systemic blood pressure, spinal cord perfusion pressure (blood pressure within the aortic clamp site), and spinal cord blood flow supplied via the collateral network. These variables were then investigated for evidence of correlations. RESULTS: Positive correlations were observed between mean systemic blood pressure and spinal cord blood flow during interruption of segmental artery flow both with (r = 0.844, P < .01) and without (r = 0.834, P < .01) distal aortic perfusion. In addition, we observed significant correlations between spinal cord perfusion pressure and spinal cord blood flow with and without distal perfusion (r = 0.803, P < .001 and r = 0.832, P < .01, respectively), and between mean systemic blood pressure and spinal cord perfusion pressure with and without distal perfusion (r = 0.898, P < .001 and r = 0.837, P < .001, respectively). The spinal cord was perfused from the collateral network from outside the interrupted segmental arteries, and high systemic blood pressure (~1.33-fold higher) was needed to obtain the preclamping spinal cord blood flow, whereas 1.68-fold higher systemic blood pressure was needed when distal perfusion was halted. CONCLUSIONS: Spinal cord blood flow is positively correlated with mean systemic blood pressure and spinal cord perfusion pressure under spinal cord ischemia caused by clamping a wide range of segmental arteries. In open and endovascular thoracic and thoracoabdominal surgery, elevating mean systemic blood pressure is a simple and effective means of increasing spinal cord blood flow, and measuring spinal cord perfusion pressure seems to be useful for monitoring perioperative spinal cord blood flow. PMID- 25524690 TI - Preventing spinal cord injury during thoracic aortic surgery: simpler than we thought? PMID- 25524691 TI - What the Human Genome Project hasn't told us: the epigenetics of development of esophageal squamous cell cancer. PMID- 25524692 TI - Benefits of sutureless aortic valves may not be limited to reduced crossclamp time. PMID- 25524693 TI - What is the reality? The surgeon versus the cardiologist deployment insufficinecies in TAVI procedures: paravalvular leak, annular rupture, and pacemaker need. PMID- 25524694 TI - Is pleurodesis for the treatment of primary spontaneous pneumothorax a misnomer- and if it works, does it matter? PMID- 25524695 TI - We have to be pioneers: we owe it to the future generations. PMID- 25524696 TI - Acoustic parameters of speech: Lack of correlation with perceptual and questionnaire-based speech evaluation in patients with oral and oropharyngeal cancer treated with primary surgery. AB - BACKGROUND: Acoustic evaluation of speech is the least explored method of speech evaluation in patients with oral cavity and oropharyngeal cancer. The purpose of this study was to explore acoustic parameters of speech and their correlation with questionnaire evaluation and perceptual evaluation in patients with oral cavity and oropharyngeal cancer. METHODS: One hundred seventeen subjects (65 consecutive patients with oral cavity and oropharyngeal cancer and 52 controls) participated in this study. Formant frequencies (by Linear Predictive Coding), Speech Handicap Index, and London Speech Evaluation scale were used for acoustic evaluation, questionnaire evaluation, and perceptual evaluation, respectively. RESULTS: Men showed significant elevation in second formant (F2) values for patients with oral cavity cancer and those who underwent surgery alone. Female patients with early T classification cancers and those who underwent surgery and chemoradiation showed significant reduction in the mean F2 values. Importantly, however, acoustic evaluation parameters did not correlate with either perceptual evaluation or questionnaire evaluation parameters, although there was moderate correlation between questionnaire evaluation and perceptual evaluation speech parameters. CONCLUSION: Acoustic evaluation modalities have no clear role in the management of patients with oral cavity and oropharyngeal cancer. PMID- 25524697 TI - Regulation of acetate metabolism in Escherichia coli BL21 by protein N(epsilon) lysine acetylation. AB - Acetate production is one of the most striking differences between Escherichia coli K12 and BL21 strains. Transcription of acetate metabolism genes is regulated. Additionally, acetyl-CoA synthetase, which activates acetate to acetyl CoA, is regulated by post-translational acetylation. The aim of this study was to understand the contribution of reversible protein lysine acetylation to the regulation of acetate metabolism in E. coli BL21. The phenotypic differences between both strains were especially important in the presence of acetate. The high expression of acetyl-CoA synthetase (acs) in glucose exponential phase in BL21 allows the simultaneous consumption of acetate and glucose. Lack of catabolite repression also affected its post-translational regulator, the protein acetyltransferase (patZ). The effect of the deletion of cobB (encoding a sirtuin like protein deacetylase) and patZ genes depended on the genetic background. The deletion of cobB in both strains increased acetate production and decreased growth rate in acetate cultures. The deletion of patZ in BL21 suppressed acetate overflow in glucose medium and increased the growth rate in acetate cultures. Differences on acetate overflow between BL21 and K12 strains are caused by many overlapping factors. Two major contributing effects were identified: (1) the expression of acs during exponential growth is not repressed in the BL21 strain due to concomitant cAMP production and (2) the acetyl-CoA synthetase activity is more tightly regulated by protein acetylation in BL21 than in the K12. Altogether these differences contribute to the lower acetate overflow and the improved ability of E. coli BL21 to consume this metabolite in the presence of glucose. PMID- 25524698 TI - Impact of salinity on the aerobic metabolism of phosphate-accumulating organisms. AB - The use of saline water in urban areas for non-potable purposes to cope with fresh water scarcity, intrusion of saline water, and disposal of industrial saline wastewater into the sewerage lead to elevated salinity levels in wastewaters. Consequently, saline wastewater is generated, which needs to be treated before its discharge into surface water bodies. The objective of this research was to study the effects of salinity on the aerobic metabolism of phosphate-accumulating organisms (PAO), which belong to the microbial populations responsible for enhanced biological phosphorus removal (EBPR) in activated sludge systems. In this study, the short-term impact (hours) of salinity (as NaCl) was assessed on the aerobic metabolism of a PAO culture, enriched in a sequencing batch reactor (SBR). All aerobic PAO metabolic processes were drastically affected by elevated salinity concentrations. The aerobic maintenance energy requirement increased, when the salinity concentration rose up to a threshold concentration of 2 % salinity (on a W/V basis as NaCl), while above this concentration, the maintenance energy requirements seemed to decrease. All initial rates were affected by salinity, with the NH4- and PO4-uptake rates being the most sensitive. A salinity increase from 0 to 0.18 % caused a 25, 46, and 63 % inhibition of the O2, PO4, and NH4-uptake rates. The stoichiometric ratios of the aerobic conversions confirmed that growth was the process with the highest inhibition, followed by poly-P and glycogen formation. The study indicates that shock loads of 0.18 % salt, which corresponds to the use or intrusion of about 5 % seawater may severely affect the EBPR process already in wastewater treatment plants not exposed regularly to high salinity concentrations. PMID- 25524699 TI - Development of a novel uric-acid-responsive regulatory system in Escherichia coli. AB - A novel uric-acid-responsive regulatory system was developed in Escherichia coli by adapting the HucR-related regulatory elements from Deinococcus radiodurans into E. coli. The induction performance of this system was compared to the performance of both the pBAD and pET systems. Our novel regulatory system was induced in a dose-dependent manner in the presence of uric acid and exhibited low basal expression in its absence. The system was characterized by a wide dynamic range of induction, being compatible with various E. coli strains and not requiring genomic modifications of the bacterial host. E. coli DH5alpha and DH10B were the most suitable host strains for optimal performance of this system. In conclusion, we developed a regulatory system with potential for applications in both recombinant protein expression and metabolic optimization. PMID- 25524700 TI - Effect of 1,3-propanediol, organic acids, and ethanol on growth and metabolism of Clostridium butyricum DSP1. AB - Knowledge of tolerance of bacteria to toxic stress is important, especially for processes targeted at high final titers of product. Information on environmental limits and stress responses may help during selection of strains or design and control of processes. The influence of the main product and its co-products on the process of 1,3-propanediol (PD) synthesis was determined. Adaptation to toxic compounds was noticed as Clostridium butyricum DSP1 was less sensitive to the addition of these factors during its exponential growth on glycerol than when the factor was present in the medium before inoculation. It was also shown that the response of the tested strain to the toxicity of 1,3-propanediol (1,3-PD) has different proteomic profiles depending on the stage of culture when this substance is introduced. Relatively satisfactory activity of the analyzed strain was sustained up to a concentration of 1,3-PD of 40 g/L while 80 g/L of this metabolite was lethal to the bacterium. As for the by-products, acetic acid was determined to be the most toxic among the acids excreted during the process. PMID- 25524701 TI - Isolation and characterization of a gamma-aminobutyric acid producing strain Lactobacillus buchneri WPZ001 that could efficiently utilize xylose and corncob hydrolysate. AB - Lactobacillus buchneri strain WPZ001 that could efficiently produce gamma aminobutyric acid was isolated from Chinese fermented sausages. Optimal cultivation conditions for gamma-aminobutyric acid production in L. buchneri WPZ001 were determined, and xylose was found to be the best carbon source. Using xylose as the sole carbon source, 70 g/L gamma-aminobutyric acid was produced by flask fermentation of L. buchneri WPZ001 for 48 h, and the harvested cells could continue to convert monosodium glutamate to gamma-aminobutyric acid in buffer and produce 59 g gamma-aminobutyric acid after eight runs of biotransformation; the total yield of gamma-aminobutyric acid reached 129 g/L. This combination strategy also worked well when the low-cost corncob hydrolysate was used as the sole carbon source, and the yield of gamma-aminobutyric acid reached 117 g/L. The results indicate that L. buchneri WPZ001 has great potential for industrial production of gamma-aminobutyric acid. PMID- 25524702 TI - Metastasis in lymph nodes on the anterior pancreatic surface of the body and tail: an extremely rare finding during bursectomy in extended surgery for gastric cancer. PMID- 25524703 TI - Targeting the effector domain of the myristoylated alanine rich C-kinase substrate enhances lung cancer radiation sensitivity. AB - Lung cancer is the leading cause of cancer related deaths. Common molecular drivers of lung cancer are mutations in receptor tyrosine kinases (RTKs) leading to activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pro-growth, pro survival signaling pathways. Myristoylated alanine rich C-kinase substrate (MARCKS) is a protein that has the ability to mitigate this signaling cascade by sequestering the target of PI3K, phosphatidylinositol (4,5)-bisphosphate (PIP2). As such, MARCKS has been implicated as a tumor suppressor, though there is some evidence that MARCKS may be tumor promoting in certain cancer types. Since the MARCKS function depends on its phosphorylation status, which impacts its subcellular location, MARCKS role in cancer may depend highly on the signaling context. Currently, the importance of MARCKS in lung cancer biology is limited. Thus, we investigated MARCKS in both clinical specimens and cell culture models. Immunohistochemistry scoring of MARCKS protein expression in a diverse lung tumor tissue array revealed that the majority of squamous cell carcinomas stained positive for MARCKS while other histologies, such as adenocarcinomas, had lower levels. To study the importance of MARCKS in lung cancer biology, we used inducible overexpression of wild-type (WT) and non-phosphorylatable (NP)-MARCKS in A549 lung cancer cells that had a low level of endogenous MARCKS. We found that NP-MARCKS expression, but not WT-MARCKS, enhanced the radiosensitivity of A549 cells in part by inhibiting DNA repair as evidenced by prolonged radiation induced DNA double strand breaks. We confirmed the importance of MARCKS phosphorylation status by treating several lung cancer cell lines with a peptide mimetic of the phosphorylation domain, the effector domain (ED), which effectively attenuated cell growth as measured by cell index. Thus, the MARCKS ED appears to be an important target for lung cancer therapeutic development. PMID- 25524704 TI - Biochemical, histological and functional correction of mucopolysaccharidosis type IIIB by intra-cerebrospinal fluid gene therapy. AB - Gene therapy is an attractive tool for the treatment of monogenic disorders, in particular for lysosomal storage diseases (LSD) caused by deficiencies in secretable lysosomal enzymes in which neither full restoration of normal enzymatic activity nor transduction of all affected cells are necessary. However, some LSD such as Mucopolysaccharidosis Type IIIB (MPSIIIB) are challenging because the disease's main target organ is the brain and enzymes do not efficiently cross the blood-brain barrier even if present at very high concentration in circulation. To overcome these limitations, we delivered AAV9 vectors encoding for alpha-N-acetylglucosaminidase (NAGLU) to the Cerebrospinal Fluid (CSF) of MPSIIIB mice with the disease already detectable at biochemical, histological and functional level. Restoration of enzymatic activity in Central Nervous System (CNS) resulted in normalization of glycosaminoglycan content and lysosomal physiology, resolved neuroinflammation and restored the pattern of gene expression in brain similar to that of healthy animals. Additionally, transduction of the liver due to passage of vectors to the circulation led to whole-body disease correction. Treated animals also showed reversal of behavioural deficits and extended lifespan. Importantly, when the levels of enzymatic activity were monitored in the CSF of dogs following administration of canine NAGLU-coding vectors to animals that were either naive or had pre-existing immunity against AAV9, similar levels of activity were achieved, suggesting that CNS efficacy would not be compromised in patients seropositive for AAV9. Our studies provide a strong rationale for the clinical development of this novel therapeutic approach as the treatment for MPSIIIB. PMID- 25524705 TI - The p.R482W substitution in A-type lamins deregulates SREBP1 activity in Dunnigan type familial partial lipodystrophy. AB - Nuclear lamins are involved in many cellular functions due to their ability to bind numerous partners including chromatin and transcription factors, and affect their properties. Dunnigan type familial partial lipodystrophy (FPLD2; OMIM#151660) is caused in most cases by the A-type lamin R482W mutation. We report here that the R482W mutation affects the regulatory activity of sterol response element binding protein 1 (SREBP1), a transcription factor that regulates hundreds of genes involved in lipid metabolism and adipocyte differentiation. Using in situ proximity ligation assays (PLA), reporter assays and biochemical and transcriptomic approaches, we show that interactions of SREBP1 with lamin A and lamin C occur at the nuclear periphery and in the nucleoplasm. These interactions involve the Ig-fold of A-type lamins and are favored upon SREBP1 binding to its DNA target sequences. We show that SREBP1, LMNA and sterol response DNA elements form ternary complexes in vitro. In addition, overexpression of A-type lamins reduces transcriptional activity of SREBP1. In contrast, both overexpression of LMNA R482W in primary human preadipocytes and endogenous expression of A-type lamins R482W in FPLD2 patient fibroblasts, reduce A-type lamins-SREBP1 in situ interactions and upregulate a large number of SREBP1 target genes. As this LMNA mutant was previously shown to inhibit adipogenic differentiation, we propose that deregulation of SREBP1 by mutated A-type lamins constitutes one underlying mechanism of the physiopathology of FPLD2. Our data suggest that SREBP1 targeting molecules could be considered in a therapeutic context. PMID- 25524707 TI - Transgenic replacement of Cx32 in gap junction-deficient oligodendrocytes rescues the phenotype of a hypomyelinating leukodystrophy model. AB - Oligodendrocytes are coupled by gap junctions (GJs) formed mainly by connexin47 (Cx47) and Cx32. Recessive GJC2/Cx47 mutations cause Pelizaeus-Merzbacher-like disease, a hypomyelinating leukodystrophy, while GJB1/Cx32 mutations cause neuropathy and chronic or acute-transient encephalopathy syndromes. Cx32/Cx47 double knockout (Cx32/Cx47dKO) mice develop severe CNS demyelination beginning at 1 month of age leading to death within weeks, offering a relevant model to study disease mechanisms. In order to clarify whether the loss of oligodendrocyte connexins has cell autonomous effects, we generated transgenic mice expressing the wild-type human Cx32 under the control of the mouse proteolipid protein promoter, obtaining exogenous hCx32 expression in oligodendrocytes. By crossing these mice with Cx32KO mice, we obtained expression of hCx32 on Cx32KO background. Immunohistochemical and immunoblot analysis confirmed strong CNS expression of hCx32 specifically in oligodendrocytes and correct localization forming GJs at cell bodies and along the myelin sheath. TG(+)Cx32/Cx47dKO mice generated by further crossing with Cx47KO mice showed that transgenic expression of hCx32 rescued the severe early phenotype of CNS demyelination in Cx32/Cx47dKO mice, resulting in marked improvement of behavioral abnormalities at 1 month of age, and preventing the early mortality. Furthermore, TG(+)Cx32/Cx47dKO mice showed significant improvement of myelination compared with Cx32/Cx47dKO CNS at 1 month of age, while the inflammatory and astrogliotic changes were fully reversed. Our study confirms that loss of oligodendrocyte GJs has cell autonomous effects and that re-establishment of GJ connectivity by replacement of least one GJ protein provides correction of the leukodystrophy phenotype. PMID- 25524708 TI - Temporally distinct phosphorylations differentiate Tau-dependent learning deficits and premature mortality in Drosophila. AB - Abnormally phosphorylated Tau protein, the major component of neurofibrillary tangles, is critical in the pathogenesis of Alzheimer's disease and related Tauopathies. We used Drosophila to examine the role of key disease-associated phosphorylation sites on Tau-mediated neurotoxicity. We present evidence that the late-appearing phosphorylation on Ser(238) rather than hyperphosphorylation per se is essential for Tau toxicity underlying premature mortality in adult flies. This site is also occupied at the time of neurodegeneration onset in a mouse Tauopathy model and in damaged brain areas of confirmed Tauopathy patients, suggesting a similar critical role on Tau toxicity in humans. In contrast, occupation of Ser(262) is necessary for Tau-dependent learning deficits in adult Drosophila. Significantly, occupation of Ser(262) precedes and is required for Ser(238) phosphorylation, and these temporally distinct phosphorylations likely reflect conformational changes. Because sequential occupation of Ser(262) and Ser(238) is required for the progression from Tau-mediated learning deficits to premature mortality in Drosophila, they may also play similar roles in the escalating symptom severity in Tauopathy patients, congruent with their presence in damaged regions of their brains. PMID- 25524706 TI - Structural basis for misfolding in myocilin-associated glaucoma. AB - Olfactomedin (OLF) domain-containing proteins play roles in fundamental cellular processes and have been implicated in disorders ranging from glaucoma, cancers and inflammatory bowel disorder, to attention deficit disorder and childhood obesity. We solved crystal structures of the OLF domain of myocilin (myoc-OLF), the best studied such domain to date. Mutations in myoc-OLF are causative in the autosomal dominant inherited form of the prevalent ocular disorder glaucoma. The structures reveal a new addition to the small family of five-bladed beta propellers. Propellers are most well known for their ability to act as hubs for protein-protein interactions, a function that seems most likely for myoc-OLF, but they can also act as enzymes. A calcium ion, sodium ion and glycerol molecule were identified within a central hydrophilic cavity that is accessible via movements of surface loop residues. By mapping familial glaucoma-associated lesions onto the myoc-OLF structure, three regions sensitive to aggregation have been identified, with direct applicability to differentiating between neutral and disease-causing non-synonymous mutations documented in the human population worldwide. Evolutionary analysis mapped onto the myoc-OLF structure reveals conserved and divergent regions for possible overlapping and distinctive functional protein-protein or protein-ligand interactions across the broader OLF domain family. While deciphering the specific normal biological functions, ligands and binding partners for OLF domains will likely continue to be a challenging long-term experimental pursuit, atomic detail structural knowledge of myoc-OLF is a valuable guide for understanding the implications of glaucoma associated mutations and will help focus future studies of this biomedically important domain family. PMID- 25524709 TI - Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage. AB - Affinity maturation, the process in which somatic hypermutation and positive selection generate antibodies with increasing affinity for an antigen, is pivotal in acquired humoral immunity. We have studied the mechanism of affinity gain in a human B-cell lineage in which two main maturation pathways, diverging from a common ancestor, lead to three mature antibodies that neutralize a broad range of H1 influenza viruses. Previous work showed that increased affinity in the mature antibodies derives primarily from stabilization of the CDR H3 loop in the antigen binding conformation. We have now used molecular dynamics simulations and existing crystal structures to identify potentially key maturation mutations, and we have characterized their effects on the CDR H3 loop and on antigen binding using further simulations and experimental affinity measurements, respectively. In the two maturation pathways, different contacts between light and heavy chains stabilize the CDR H3 loop. As few as two single-site mutations in each pathway can confer substantial loop stability, but none of them confers experimentally detectable stability on its own. Our results support models of the germinal center reaction in which two or more mutations can occur without concomitant selection and show how divergent pathways have yielded functionally equivalent antibodies. PMID- 25524711 TI - Pivotal role of choline metabolites in remyelination. AB - Neuroprotective approaches for central nervous system regeneration have not been successful in clinical practice so far and compounds that enhance remyelination are still not available for patients with multiple sclerosis. The objective of this study was to determine potential regenerative effects of the substance cytidine-5'-diphospho (CDP)-choline in two different murine animal models of multiple sclerosis. The effects of exogenously applied CDP-choline were tested in murine myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. In addition, the cuprizone-induced mouse model of de- and remyelination was used to specifically test the hypothesis that CDP-choline directly increases remyelination. We found that CDP-choline ameliorated the disease course of experimental autoimmune encephalomyelitis and exerted beneficial effects on myelin, oligodendrocytes and axons. After cuprizone-induced demyelination, CDP-choline effectively enhanced myelin regeneration and reversed motor coordination deficits. The increased remyelination arose from an increase in the numbers of proliferating oligodendrocyte precursor cells and oligodendrocytes. Further in vitro studies suggest that this process is regulated by protein kinase C. We thus identified a new mechanism to enhance central nervous system remyelination via the choline pathway. Due to its regenerative action combined with an excellent safety profile, CDP-choline could become a promising substance for patients with multiple sclerosis as an add-on therapy. PMID- 25524710 TI - Evidence for inhibitory deficits in the prefrontal cortex in schizophrenia. AB - Abnormal gamma-aminobutyric acid inhibitory neurotransmission is a key pathophysiological mechanism underlying schizophrenia. Transcranial magnetic stimulation can be combined with electroencephalography to index long-interval cortical inhibition, a measure of GABAergic receptor-mediated inhibitory neurotransmission from the frontal and motor cortex. In previous studies we have reported that schizophrenia is associated with inhibitory deficits in the dorsolateral prefrontal cortex compared to healthy subjects and patients with bipolar disorder. The main objective of the current study was to replicate and extend these initial findings by evaluating long-interval cortical inhibition from the dorsolateral prefrontal cortex in patients with schizophrenia compared to patients with obsessive-compulsive disorder. A total of 111 participants were assessed: 38 patients with schizophrenia (average age: 35.71 years, 25 males, 13 females), 27 patients with obsessive-compulsive disorder (average age: 36.15 years, 11 males, 16 females) and 46 healthy subjects (average age: 33.63 years, 23 females, 23 males). Long-interval cortical inhibition was measured from the dorsolateral prefrontal cortex and motor cortex through combined transcranial magnetic stimulation and electroencephalography. In the dorsolateral prefrontal cortex, long-interval cortical inhibition was significantly reduced in patients with schizophrenia compared to healthy subjects (P = 0.004) and not significantly different between patients with obsessive-compulsive disorder and healthy subjects (P = 0.5445). Long-interval cortical inhibition deficits in the dorsolateral prefrontal cortex were also significantly greater in patients with schizophrenia compared to patients with obsessive-compulsive disorder (P = 0.0465). There were no significant differences in long-interval cortical inhibition across all three groups in the motor cortex. These results demonstrate that long-interval cortical inhibition deficits in the dorsolateral prefrontal cortex are specific to patients with schizophrenia and are not a generalized deficit that is shared by disorders of severe psychopathology. PMID- 25524712 TI - Lead exposure and increased food allergic sensitization in U.S. children and adults. AB - BACKGROUND: Whether blood lead levels are associated with sensitization to food allergens in adults and children is unclear. Prior studies have shown that exposure to lead is associated with atopic sensitization and modulation of several cytokines (eg, interleukin [IL]-12, IL-10, interferon [IFN]-gamma, and IL 4 production) and with T-cell dysregulation and bias toward T helper 2 (Th2) activity. The objective of this work was to assess whether exposure to lead is independently associated with allergic symptoms and sensitizations in a large nationally representative sample of children and adults. METHODS: We studied 2712 children and 4333 adults enrolled in the 2005-2006 cycle of the National Health and Nutritional Examination Surveys (NHANES). Participants were tested for serum specific immunoglobulin E (IgE) levels to food allergens as well as blood lead levels. Food allergens tested included shrimp, egg, peanut, and milk. Logistic regression models adjusted for demographic factors, body mass index, history of asthma, smoking, housing characteristics, and current exposure to animals in the home, to assess the association of blood lead levels with sensitization to food allergens. RESULTS: Median (interquartile range [IQR]) for serum blood was 0.87 MUg/L (0.61 to 1.31) in children and 1.48 MUg/L (0.92 to 2.34) in adults. At baseline, 672 (24.7%) of children participants and 719 (16.6%) of adult participants tested positive for increased sensitization to food allergens. A 2 fold increase in blood lead levels in adult participants was associated with increased sensitization to food allergens (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.02 to 1.22). Blood lead was not associated with sensitization to food allergens among pediatric participants (OR, 0.95; 95% CI, 0.82 to 1.10). CONCLUSION: Exposure to lead was associated with increased odds of sensitization to food allergens in adult but not children participants. PMID- 25524713 TI - TWEAK and NT-proBNP levels predict exercise capacity in hypertrophic cardiomyopathy. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by inappropriate hypertrophy, myocyte disarray and increased interstitial fibrosis. The tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is a cell surface cytokine with biological activities including stimulation of cell growth, induction of inflammatory cytokines and stimulation of apoptosis. There are controversial data about the potential role of TWEAK in different cardiovascular pathologies. NT proBNP is an established biomarker of myocardial wall stress, associated with poor functional class in HCM. We hypothesized that effort capacity in patients with HCM could be related to serum levels of these biomarkers. MATERIALS AND METHODS: We included 40 haemodynamic stable HCM patients and 53 healthy controls with similar sex and age. We studied exercise capacity by maximal oxygen consumption in a limited treadmill exercise test. TWEAK and NT-proBNP were assayed by ELISA method and automated Elecsys(r) platform, respectively. We obtained 46 samples of myocardial tissues by septal myectomy in patients with HCM and evaluated myocardial fibrosis, immunoreaction with TWEAK antibody and apoptosis with TUNEL assay. RESULTS: We found raised TWEAK and NT-proBNP serum levels in patients when compared with control levels (both P < 0.001). In a multivariate analysis, TWEAK and NT-proBNP levels, as well as sex, remained independently associated with the effort capacity (all P < 0.05). We found an association between immunoreaction degree and the degree of myocardial fibrosis (P = 0.021), as well as apoptosis (P = 0.002) in the tissue samples from patients undergoing septal myectomy. CONCLUSIONS: TWEAK and NT-proBNP levels are biomarkers of disease severity independently associated with the effort capacity in patients with HCM. PMID- 25524714 TI - Unusual c-KIT+ squamous cell carcinoma of the uterine cervix showing paradoxical hypermethylation of the c-KIT proto-oncogene. PMID- 25524715 TI - Emerging evidence regarding statins use as novel endometriosis targeted treatment: real "magic pills" or "trendy" drugs? Some considerations. PMID- 25524716 TI - Total synthesis and structure elucidation of JBIR-39: a linear hexapeptide possessing piperazic acid and gamma-hydroxypiperazic acid residues. AB - The total synthesis and stereochemical structural elucidation of JBIR-39, containing four nonproteinogenic piperazic acid (Piz) residues, is reported. The synthesis includes Sc(OTf)3 -catalyzed acylation of a Piz(gamma-OTBS) derivative with piperazic acid chloride, providing the desired Piz-Piz(gamma-OTBS) dipeptide in high yield without epimerization. After assembling two additional Piz moieties and (S)-isoleucic acid at the N-terminus, amidation with the (R)-alpha methylserine ester at the C-terminus, and deprotection afforded the desired (2R,8S)-hexapeptide, which is the assumed structure of JBIR-39. Although the spectral data of the (2R,8S)-hexapeptide was not identical to JBIR-39, further synthesis of three stereoisomers confirmed the stereochemical structure of JBIR 39 to be (2S,6S,8S,11R,16S,21R,26S,27S). PMID- 25524717 TI - Purification and characterization of an intracellular levansucrase derived from Bacillus methylotrophicus SK 21.002. AB - An intracellular levansucrase from Bacillus methylotrophicus SK 21.002 was isolated, purified, and characterized. The final specific levansucrase activity was 135.40 U/mg protein with an 11.78-fold enrichment and a 9.28% recovery rate. The molecular weight of the enzyme was approximately 60,000 Da as evaluated by gel filtration and SDS-PAGE. Both the maximum transfructosylation and hydrolytic activities were observed at pH 6.5. The enzyme exhibited optimum transfructosylation activity at 40 degrees C, whereas the optimum temperature of hydrolytic activity was 45 degrees C. Cu(2+), Fe(2+), Zn(2+), and Ni(2+) inhibited both the transfructosylation and hydrolytic activities up to 100%, whereas Mn(2+) inhibited only hydrolytic activity. Ca(2+) and Mg(2+) stimulated both transfructosylation and hydrolytic activities. The chemical modifiers (n bromosuccinimide and phenylmethanesulfonyl fluoride) strongly inhibited hydrolytic and transfructosylation activity of the levansucrase. The Km and Vmax values of the purified levansucrase were 117.2 mM and 33.23 MUmol/mg.Min, respectively. When the fructose concentration was below 0.2 M, higher fructose concentrations promoted the transfructosylation and inhibited the hydrolytic activity. PMID- 25524719 TI - PCNA and grade in 13 canine oral squamous cell carcinomas: association with prognosis. AB - This study evaluated the prognosis factors of age, tumour size, anatomic location, histological grade and proliferating cell nuclear antigen (PCNA) expression in 13 dogs with oral squamous cell carcinoma (OSCC) with bone invasion and without signs of lymph node or distant metastasis. All animals were treated with radical excision performed with at least 1 cm margin, based on computed tomography images. In the 2-year follow-up, median disease-free survival was 138 days for dogs with grade 3 tumours and was not reached for those with grade 2 tumours. Grade 3 tumours and PCNA labelling index >=65% were related with a shorter disease-free survival time and consequently poor prognosis (p = 0.003 and p = 0.034, respectively). Mean PCNA labelling index was significantly higher in recurrent cases (p = 0.011). Histological grade and PCNA expression may be important prognosis factors in canine OSCC. PMID- 25524718 TI - Herbal medicine for the management of polycystic ovary syndrome (PCOS) and associated oligo/amenorrhoea and hyperandrogenism; a review of the laboratory evidence for effects with corroborative clinical findings. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a prevalent, complex endocrine disorder characterised by polycystic ovaries, chronic anovulation and hyperandrogenism leading to symptoms of irregular menstrual cycles, hirsutism, acne and infertility. Evidence based medical management emphasises a multidisciplinary approach for PCOS, as conventional pharmaceutical treatment addresses single symptoms, may be contra-indicated, is often associated with side effects and not effective in some cases. In addition women with PCOS have expressed a strong desire for alternative treatments. This review examines the reproductive endocrine effects in PCOS for an alternative treatment, herbal medicine. The aim of this review was to identify consistent evidence from both pre-clinical and clinical research, to add to the evidence base for herbal medicine in PCOS (and associated oligo/amenorrhoea and hyperandrogenism) and to inform herbal selection in the provision clinical care for these common conditions. METHODS: We undertook two searches of the scientific literature. The first search sought pre-clinical studies which explained the reproductive endocrine effects of whole herbal extracts in oligo/amenorrhoea, hyperandrogenism and PCOS. Herbal medicines from the first search informed key words for the second search. The second search sought clinical studies, which corroborated laboratory findings. Subjects included women with PCOS, menstrual irregularities and hyperandrogenism. RESULTS: A total of 33 studies were included in this review. Eighteen pre-clinical studies reported mechanisms of effect and fifteen clinical studies corroborated pre-clinical findings, including eight randomised controlled trials, and 762 women with menstrual irregularities, hyperandrogenism and/or PCOS. Interventions included herbal extracts of Vitex agnus-castus, Cimicifuga racemosa, Tribulus terrestris, Glycyrrhiza spp., Paeonia lactiflora and Cinnamomum cassia. Endocrine outcomes included reduced luteinising hormone (LH), prolactin, fasting insulin and testosterone. There was evidence for the regulation of ovulation, improved metabolic hormone profile and improved fertility outcomes in PCOS. There was evidence for an equivalent effect of two herbal medicines and the pharmaceutical agents bromocriptine (and Vitex agnus castus) and clomiphene citrate (and Cimicifuga racemosa). There was less robust evidence for the complementary combination of spirinolactone and Glycyrrhiza spp. for hyperandrogenism. CONCLUSIONS: Preclinical and clinical studies provide evidence that six herbal medicines may have beneficial effects for women with oligo/amenorrhea, hyperandrogenism and PCOS. However the quantity of pre-clinical data was limited, and the quality of clinical evidence was variable. Further pre clinical studies are needed to explain the effects of herbal medicines not included in this review with current clinical evidence but an absence of pre clinical data. PMID- 25524720 TI - Animal models of tuberculosis: Guinea pigs. AB - The progression of the disease that follows infection of guinea pigs with Mycobacterium tuberculosis displays many features of human tuberculosis (TB), and the guinea pig model of TB has been used for more than 100 years as a research tool to understand and describe disease mechanisms. Changes in the bacterial burden and pathology following infection can be readily monitored and used to evaluate the impact of TB interventions. Demonstration of the protective efficacy of vaccines in the low-dose aerosol guinea pig model is an important component of the preclinical data package for novel vaccines in development, and there is a continual need to improve the model to facilitate progression of vaccines to the clinic. Development of better tools with which to dissect the immune responses of guinea pigs is a focus of current research. PMID- 25524721 TI - Gene Therapies for Neovascular Age-Related Macular Degeneration. AB - Pathological neovascularization is a key component of the neovascular form (also known as the wet form) of age-related macular degeneration (AMD) and proliferative diabetic retinopathy. Several preclinical studies have shown that antiangiogenesis strategies are effective for treating neovascular AMD in animal models. Vascular endothelial growth factor (VEGF) is one of the main inducers of ocular neovascularization, and several clinical trials have shown the benefits of neutralizing VEGF in patients with neovascular AMD or diabetic macular edema. In this review, we summarize several preclinical and early-stage clinical trials with intraocular gene therapies, which have the potential to reduce or eliminate the repeated intravitreal injections that are currently required for the treatment of neovascular AMD. PMID- 25524722 TI - Baseball bats and chocolate chip cookies: the judicial treatment of DNA in the myriad genetics litigation. AB - In June 2013, the U.S. Supreme Court rendered a controversial ruling that naturally occurring DNA segments are "products of nature" and therefore not patentable subject matter. At this intersection between science and law, in litigation of crucial importance to patients, science, and multibillion-dollar biotech enterprises, the appellate judges sidestepped genetics and engaged in a war of metaphors from diamonds to chocolate chip cookies. This case is not an outlier. Apprehensive judges and juries in both Canada and the United States find many convenient excuses to avoid coming to grips with the underlying science in patent cases. But this is simply not acceptable. Legal rulings must be, and must seem to be, well grounded, as a matter of both law and science. The legitimacy of court decisions in the eyes of the stakeholders and the broader public depends on it. PMID- 25524723 TI - Persistent and fluctuating anxiety levels in the 18 months following acute myocardial infarction: the role of personality. AB - OBJECTIVE: To identify the varying courses of anxiety symptoms in the first 18 months after a myocardial infarction (MI) and to examine the importance of personality in determining elevated anxiety. METHODS: Four hundred eighty-six MI patients completed the State-Trait Anxiety Inventory during hospitalization and at 2-, 12- and 18-months post-MI. At baseline, patients also completed the DS14 Type D personality scale, Anxiety Sensitivity Index and Beck Depression Inventory, and clinical and sociodemographic information was collected. RESULTS: Growth mixture modeling analysis identified four anxiety trajectories. The majority of patients reported stable anxiety scores over time, indicative of either persistent high (17%) or low (71%) anxiety. Patients in the other two smaller groups initially reported moderate levels of anxiety that fluctuated during follow-up. Type D personality [odds ratio (OR)=5.34; 95% confidence interval (CI): 2.26-12.63], negative affectivity (OR=3.24; 95% CI: 1.29-8.14) and anxiety sensitivity (OR=3.35; 95% CI: 1.69-6.62) were the most prominent determinants of persistent high anxiety, independent of depression, sociodemographic and clinical factors. CONCLUSIONS: The course of anxiety in the first 18 months after MI is relatively stable for the majority of patients. Patients with Type D personality, negative affectivity and anxiety sensitivity are at an increased risk for persisting elevated anxiety and should be identified and offered appropriate treatment. PMID- 25524724 TI - Ernest W. Johnson, MD. PMID- 25524725 TI - Cryptococcus neoformans prosthetic joint infection: case report and review of the literature. AB - A 77-year-old woman with diabetes mellitus, myasthenia gravis and bilateral total hip arthroplasties underwent a two-stage procedure followed by treatment with vancomycin for a coagulase-negative staphylococcal prosthetic hip infection. This was complicated by a spontaneous left hip dislocation with a hematoma that was evacuated; all intraoperative cultures grew out Cryptococcus neoformans. Treatment with intravenous liposomal amphotericin B was started. Her prosthetic device was retained, and she was treated for 12 weeks, after which she was transitioned to fluconazole for long-term therapy. The hip remained stable 1 year out from her admission, and she retained mobility with the assistance of a walker. Fungi are an uncommon but potentially devastating cause of prosthetic joint infections, and most are due to Candida species. Cryptococcus neoformans is an ubiquitous yeast with worldwide distribution that generally causes infections in patients with major T cell immune deficiencies (e.g., HIV, transplantation and receipt of corticosteroids). Cryptococcal infections of native osteoarticular structures are uncommon, but have been well described in the literature. Data regarding cryptococcal prosthetic joint infections, however, are sparse. PMID- 25524726 TI - 3D Bioprinting of complex channels-Effects of material, orientation, geometry, and cell embedding. AB - Creating filled or hollow channels within 3D tissues has become increasingly important in tissue engineering. Channels can serve as vasculature enhancing medium perfusion or as conduits for nerve regeneration. The 3D biofabrication seems to be a promising method to generate these structures within 3D constructs layer-by-layer. In this study, geometry and interface of bioprinted channels were investigated with micro-computed tomography and fluorescent imaging. In filament printing, size and shape of printed channels are influenced by their orientation, which was analyzed by printing horizontally and vertically aligned channels, and by the ink, which was evaluated by comparing channels printed with an alginate gelatin hydrogel or with an emulsion. The influence of geometry and cell embedding in the hydrogel on feature size and shape was investigated by printing more complex channels. The generation of hollow channels, induced through leaching of a support phase, was monitored over time. Horizontally aligned channels provided 16* smaller cross-sectional areas than channels in vertical orientation. The smallest feature size of hydrogel filaments was twice as large compared to emulsion filaments. Feature size and shape depended on the geometry but did not alter when living cells were embedded. With that knowledge, channels can be consciously tailored to the particular needs. PMID- 25524727 TI - Mistress Joyce Jeffreys and her physician, Dr Bridstock Harford (1607-1695). AB - The notebooks of Joyce Jeffreys, a wealthy Hereford businesswoman in the mid-17th century, provide information about the medicines she purchased and the fees she paid to her medical advisors. Her physician, Dr Bridstock Harford, was a successful doctor but a troublesome neighbour, who was often the subject of litigation. As an ardent parliamentarian, he held public offices during the Commonwealth. Later his opinions mellowed and he ended his days as a loyal subject of the king and a benefactor to his city. PMID- 25524728 TI - Syncope. PMID- 25524729 TI - Pacing for neurally-mediated syncope: How to decide? AB - Neurally-mediated syncope has a broad clinical spectrum which ranges from typical vasovagal syncope on one hand, to those situations in which reflex syncope occurs with uncertain, or even apparently absent, triggers or prodromes, on the other hand. Overlap of clinical features is frequent in clinical practice and makes any classification difficult to apply when selecting patients for cardiac pacing. Typically, the reflex is both hypotensive and cardio-inhibitory. The rationale for efficacy of cardiac pacing is that the cardio-inhibitory reflex is dominant, since there is no role for pacing in preventing vasodilatation and hypotension. Establishing a relationship between symptoms and cardio-inhibitory reflex should be the goal of the clinical evaluation before embarking on permanent pacing. Similar efficacy has been observed in patients affected by dominant cardio inhibitory reflex irrespective of the clinical form. In general, cardiac pacing should be considered last choice applied only in highly selected patients, i.e. those >= 40 years of age, affected by severe forms of reflex syncope with recurrences associated with frequent injury, often due to the lack of prodromes. Recurrence of syncope may still occur despite cardiac pacing in a minority of patients. PMID- 25524730 TI - Does non-pharmacological treatment affect outcomes in dysautonomic syndromes? AB - Dysautonomic syndromes are very common clinical conditions with different presentations and a wide spectrum of mechanisms. Many non-pharmacological and pharmacological interventions have been recommended to treat dysautonomic patients along these years, but the majority of them were not supported by multicenter controlled trials. General measures, like water drinking and salt intake, avoiding triggers and recognizing prodromal symptoms, as well as performing orthostatic training and physical conditioning are commonly able to improve symptoms and avoid syncope and falls. In this article, we will explore why and how such measures are applied to treat patients with dysautonomic syndromes, based on the physiopathology of these disorders. PMID- 25524731 TI - Does any therapy really work for neurocardiogenic syncope? AB - Effectiveness of a treatment for neurocardiogenic syncope can be defined in terms of symptom response, quality-of-life, healthcare utilization, treatment side effects and cost-effectiveness. Most trials have focused on syncope recurrence or burden, without assessing quality-of-life formally. Drug and device interventions are characterized by a dearth of randomized controlled trials, with those few of robust design demonstrating little impact on recurrence of syncope. General advice includes hydration, trigger recognition and counter pressure maneuvers to attenuate episodes. Lifestyle recommendations have limited comparative effectiveness evidence, but are favored due to lack of side effects and low cost. The frequency of syncope improves in many patients regardless of the intervention, although ultimate recurrence of syncope remains high. In the minority of patients seeking treatment due to recurrence, midodrine has reasonable supporting evidence for effectiveness with some evidence for beta blockers in older age patients. Emerging evidence favors pacing in patients with asystole during spontaneous (as opposed to provoked) syncope. Combining long-term implantable cardiac monitoring, tilt and adenosine triphosphate testing may yet accurately define the optimal minority who benefit from pacing. In the remaining majority, pharmacologic and device interventions should be used sparingly until clear benefits are established. Better understanding of patient fears, beliefs and behaviors may help develop cognitive therapies and improve quality-of-life alongside the focus on physical symptoms. PMID- 25524732 TI - New monitoring techniques to diagnose the cause of syncope. AB - Syncope is a very common clinical problem. Given the extensive differential diagnosis, we have developed a structured approach for the evaluation and management of patients with unexplained syncope. Patients with overt cardiac, neurologic, or metabolic disturbances are identified and treated accordingly. However, the remaining patients with high-risk characteristics are hospitalized for risk stratification. After excluding patients who can benefit from pacemaker or implantable cardioverter-defibrillator implantation, an implantable loop recorder (ILR) appears to be a very effective diagnostic tool. The recent availability of a small ILR that can be implanted within minutes and provides daily data wirelessly for over 3 years appears to have elevated the ILR over short-term external electrocardiography (ECG) monitoring techniques in patients with unexplained syncope. Herein, using specific case examples, we review how we use a structural pathway at our institution to guide the evaluation and management of patients presenting with unexplained syncope, identify the types of patients who benefit from long-term ECG monitoring, and show how this strategy has positively affected clinical care in these patients. PMID- 25524733 TI - Clinical improvement of vasovagal syncope in the absence of specific therapies: The Seinfeld effect. AB - Vasovagal syncope can persist for decades and recur sporadically but many patients appear to improve after being seen in specialty clinics. The absence of specific and proven effective therapy raises the possibility that this might be due to regression to the mean or to a placebo effect. However, analysis using the Poisson distribution indicates the extreme unlikeliness that regression to the mean is the explanation. A main cause of the placebo effect is expectancy. Subject expectancy is the influence of the subject's anticipation of benefit on outcomes, and observer expectancy is the influence of investigator or physician attitudes and behavior on subject response. Ample data support the role of expectancy in outcomes of syncope patients. Moreover, expectancy can vary depending on the type of ineffective intervention. Interestingly, studies in which patients are blinded but the investigator is not show similar patient benefits compared with completely open label studies consistent with a strong observer expectancy effect due to physician-subject interaction. These results suggest the paramount importance of properly conducted randomized clinical trials in assessing biomedical interventions, and also illuminate the powerful potential of studies aimed at enhancing the expectancy effect on patient outcome. PMID- 25524734 TI - Clinical history in management of suspected syncope: A powerful diagnostic tool. AB - In this paper, the role of history taking as a diagnostic tool in patients with transient loss of consciousness (TLOC) is addressed. From a literature review it can be demonstrated that, if properly performed, the history is a powerful diagnostic tool, which in the majority of cases proves to be the only 'test' necessary to establish a diagnosis other than physical examination and electrocardiogram in patients with TLOC. In order to substantiate this conclusion, we examine the different levels of history taking according to the skills and training of the physician involved, the diagnostic yield of each level, the methodology, and the influence of the venue and urgency of the case. PMID- 25524735 TI - Managing the patient with episodic sinus tachycardia and orthostatic intolerance. AB - Patients with episodic sinus tachycardia and associated orthostatic intolerance present a diagnostic and management dilemma to the clinician. We define this group of disorders to include sinus node reentrant tachycardia (SNRT), inappropriate sinus tachycardia (IAST), and postural orthostatic tachycardia syndrome (POTS). After a brief review of the current understanding of the pathophysiology and epidemiology of this group of disorders, we focus on the diagnosis and management of IAST and POTS. Our approach attempts to recognize the considerable overlap in pathophysiology and clinical presentation between these two heterogeneous conditions. Thus, we focus on a mechanism-based workup and therapeutic approach. Sinus tachycardia related to identifiable causes should first be ruled out in these patients. Next, a basic cardiovascular and autonomic workup is suggested to exclude structural heart disease, identify a putative diagnosis, and guide therapy. We review both nonpharmacologic and pharmacologic therapy, with a focus on recent advances. Larger randomized control trials and further mechanistic studies will help refine management in the future. PMID- 25524736 TI - History of syncope predicts loss of consciousness after head trauma: Retrospective study. AB - BACKGROUND: Head trauma may present as transient loss of consciousness (TLOC) currently classified as traumatic in origin, in contrast to non-traumatic forms, such as syncope. Whether past history of syncope predisposes to loss of consciousness after head injury has been poorly studied. METHODS: A retrospective analysis of data obtained from 818 consecutive patients admitted to Emergency Departments was conducted. Face-to-face semi-structured interviews were performed, where patients' past history of syncope and head injury were explored. Head injury events were stratified as high- or low-energy trauma. Data regarding past syncopal events were explored in regard to number, age at the first occurrence, and syncope circumstances. Multivariate logistic regression model was applied to assess the relationship between loss of consciousness during head injury and past history of syncope. RESULTS: Both past history of non-traumatic TLOC (odds ratio [OR] 3.78; 95% confidence interval [CI] 2.13-6.68, p < 0.001) and high-energy mechanism (OR 3.84; 95% CI 2.35-6.28, p < 0.001) predicted TLOC after head trauma. This relationship was even stronger when past episodes of TLOC were limited to those typical for reflex syncope (OR 4.34; 95% CI 2.34-7.89, p < 0.001). Further, the number of non-traumatic TLOC episodes in the patient's history was also predictive of TLOC after head injury (OR per 1 episode: 1.24; 95% CI 1.04-1.48, p = 0.015). CONCLUSIONS: Syncope in a patient's history predicts loss of consciousness after head injury. The clinical importance of this finding merits further investigation. PMID- 25524737 TI - PI3K/AKT and Mdm2 activation are associated with inhibitory effect of cAMP increasing agents on DNA damage-induced cell death in human pre-B NALM-6 cells. AB - DNA damage response (DDR) consists of both proapoptotic and prosurvival signaling branches. Superiority of each signaling branch determines the outcome of DNA damage: death or allowing the repair. The present authors have previously shown that an increased intracellular level of cAMP disrupts p53-mediated apoptosis in human pre-B NALM-6 cells and inhibition of NF-kappaB prevents prosurvival effect of cAMP during DNA damage. AKT/PKB (protein kinase B) is a general mediator of survival signaling. AKT signaling inhibits p53-mediated transcription and apoptosis. The results of present study showed that cAMP disrupted DNA damage/p53 mediated apoptosis through AKT and subsequent NF-kappaB activation. These results suggested that AKT may be found as part of a complex with scaffolding proteins, beta-arrestins and PDE4D. cAMP disarticulated the complex through binding to PDE4D compartment. It seems that release of AKT protein potentiated DDR activated pro-survival AKT in NALM-6 cells. Taken together, the present data indicated that regulation of AKT signaling may determine the fate of cells exposed to genotoxic stress. PMID- 25524738 TI - The shikimate dehydrogenase family: functional diversity within a conserved structural and mechanistic framework. AB - Shikimate dehydrogenase (SDH) catalyzes the NADPH-dependent reduction of 3 deydroshikimate to shikimate, an essential reaction in the biosynthesis of the aromatic amino acids and a large number of other secondary metabolites in plants and microbes. The indispensible nature of this enzyme makes it a potential target for herbicides and antimicrobials. SDH is the archetypal member of a large protein family, which contains at least four additional functional classes with diverse metabolic roles. The different members of the SDH family share a highly similar three-dimensional structure and utilize a conserved catalytic mechanism, but exhibit distinct substrate preferences, making the family a particularly interesting system for studying modes of substrate recognition used by enzymes. Here, we review our current understanding of the biochemical and structural properties of each of the five previously identified SDH family functional classes. PMID- 25524741 TI - An update to the cost-effectiveness of posaconazole vs fluconazole or itraconazole in the prevention of invasive fungal disease among neutropenic patients in the United States. AB - OBJECTIVES: Posaconazole has shown superior clinical efficacy in the prevention of invasive fungal disease (IFD) among neutropenic patients as well as cost effectiveness in the US healthcare setting vs fluconazole or itraconazole (FLU/ITRA) based on oral suspension formulations of each therapy. This study aims to provide an update on the cost-effectiveness of posaconazole in the current US healthcare setting to reflect bioequivalent tablet formulations of posaconazole and fluconazole, as well as changes in healthcare and drug costs. METHODS: An existing model was used to assess the cost-effectiveness of posaconazole vs FLU/ITRA in the prevention of IFD among patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) and chemotherapy-induced neutropenia. Drug efficacy, mortality related to IFD, and death from other causes were estimated for tablet formulations using data from a randomized clinical trial of oral suspensions based on bioequivalence. IFD treatment costs were updated using the average inflation rate over 8 years (2006-2014) and drug costs were based on 2014 Analysource data. RESULTS: Trial data show a lower IFD probability over 100 days of follow-up with posaconazole compared to standard azole therapy (0.05 vs 0.11). The treatment duration on posaconazole is 29 days compared to 24 days for FLU and 29 days for ITRA. The average cost of prophylaxis is higher in the posaconazole group compared to FLU/ITRA ($4673 vs $353); however, the costs associated with treating the IFD are lower in the posaconazole group compared to FLU/ITRA ($2205 vs $5303). The incremental cost effectiveness ratio of IFD avoided for posaconazole is $18,898 vs FLU/ITRA. CONCLUSIONS: In the current healthcare cost environment where both drug costs and overall IFD treatment costs have increased since 2007, posaconazole tablets are a cost-effective alternative to fluconazole or itraconazole in the prevention of IFD among neutropenic patients with AML and MDS in the US. PMID- 25524740 TI - Aromaticity and amyloid formation: effect of pi-electron distribution and aryl substituent geometry on the self-assembly of peptides derived from hIAPP(22-29). AB - A comprehensive investigation of peptides derived from the 22-29 region of human islet amyloid polypeptide (hIAPP) that contain phenylalanine analogs at position 23 with a variety of electron donating and withdrawing groups, along with heteroaromatic surrogates, has been employed to interrogate how pi-electron distribution effects amyloid formation. Kinetic aggregation studies using turbidity measurements indicate that electron rich aromatic ring systems consistently abolish the amyloidogenic propensity of hIAPP(22-29). Electron poor systems modulate the rate of aggregation. Raman and Fourier transform infrared spectroscopy confirm the parallel beta-sheet secondary structure of aggregates derived from peptides containing electron poor phenylalanine analogs and provide direct evidence of ring stacking. Transmission electron microscopy confirms the presence of amyloid fibrils. The effect of aryl substituent geometry on peptide self-assembly reveals that the electronic nature of substituents and not their steric profile is responsible for failure of the electron donating group peptides to aggregate. Non-aggregating hIAPP(22-29) peptides were found to inhibit the self-assembly of full-length hIAPP(1-37). The most potent inhibitory peptides contain phenylalanine with the p-amino and p-formamido functionalities. These novel peptides may serve as leads for the development of future aggregation inhibitors. A potential mechanism for inhibition of amylin self-assembly by electron rich (-29) peptides is proposed. PMID- 25524739 TI - Regulation of myofibroblast differentiation by miR-424 during epithelial-to mesenchymal transition. AB - Idiopathic pulmonary fibrosis (IPF) is one of the most common and severe interstitial lung diseases. Epithelial-to-mesenchymal transition (EMT) is a process whereby epithelial cells undergo transition to a mesenchymal phenotype. This process has been shown to contribute to IPF. MicroRNAs (miRNAs) are small non-coding RNAs of 18-24 nucleotides in length which regulate gene expression. Several studies have implicated miRNAs in EMT; however, specific miRNAs that regulate EMT in IPF have not yet been identified. In this study, we identified 6 up-regulated and 3 down-regulated miRNAs in a human lung epithelial cell EMT model using miRNA microarray and real-time PCR. Overexpression of one of these up regulated miRNAs, miR-424, increased the expression of alpha-smooth muscle actin, an indicator of myofibroblast differentiation, but had no effects on the epithelial or mesenchymal cell markers. miR-424 enhanced the activity of the TGF beta signaling pathway, as demonstrated by a luciferase reporter assay. Further experiments showed that miR-424 decreased the protein expression of Smurf2, a negative regulator of TGF-beta signaling, indicating that miR-424 exerts a forward regulatory loop in the TGF-beta signaling pathway. Our results suggest that miR-424 regulates the myofibroblast differentiation during EMT by potentiating the TGF-beta signaling pathway, likely through Smurf2. PMID- 25524742 TI - beta-D-Glucan nanoparticle pre-treatment induce resistance against Pythium aphanidermatum infection in turmeric. AB - In vitro experiments were carried out to test the efficacy of GNP (beta-D-glucan nanoparticle prepared from mycelium of Pythium aphanidermatum) against rhizome rot disease of turmeric (Curcuma longa L.) caused by P. aphanidermatum. GNP (0.1%, w/v) was applied to rhizome prior to inoculation with P. aphanidermatum (0 h, 24 h). Cell death, activities of defense enzymes such as peroxidase, polyphenol oxidase, protease inhibitor and beta-1,3 glucanase were monitored. Prior application of GNP (24 h) to turmeric rhizome effectively controls P. aphanidermatum infection. The increase in defense enzyme activities occurred more rapidly and was enhanced in P. aphanidermatum infected rhizomes that were pre treated with GNP. Pre-treatment also induced new isoforms of defense enzymes. Increased activities of defense enzymes suggest that they play a key role in restricting the development of disease symptoms in the rhizomes as evidenced by a reduction in cell death. The results demonstrated that GNP can be used as a potential agent for control of rhizome rot disease. PMID- 25524743 TI - Synthesis and characterization of antibacterial carboxymethyl cellulose/ZnO nanocomposite hydrogels. AB - In this study, carboxymethyl cellulose/ZnO nanocomposite hydrogels have been synthesized through the in situ formation of ZnO nanoparticles within swollen carboxymethyl cellulose hydrogels. The formation of ZnO nanoparticles in the hydrogels was confirmed using X-ray diffraction, UV-vis spectroscopy and scanning electron microscopy (SEM) studies. SEM micrographs revealed the formation of ZnO nanoparticles with size range of 10-20 nm within the hydrogel matrix. The prepared nanocomposite hydrogels showed a pH and salt sensitive swelling behavior. The ZnO nanocomposite hydrogels have rather higher swelling in different aqueous solutions in comparison with neat hydrogel. The nanocomposite hydrogels demonstrated antibacterial effects against Escherichia coli and Staphylococcus aureus bacteria. The developed carboxymethyl cellulose/ZnO nanocomposite hydrogels can be used effectively for biomedical application. PMID- 25524744 TI - How mothers and fathers perceive childhood food allergies: comparing apples to oranges? PMID- 25524745 TI - Idiopathic angioedema with F12 mutation: is it a new entity? PMID- 25524746 TI - Body mass index correlates with pollutant-induced interleukin-1beta in sputum and blood. PMID- 25524747 TI - Peer training to improve parenting and childhood asthma management skills: a pilot study. PMID- 25524749 TI - Life cycle costing of waste management systems: overview, calculation principles and case studies. AB - This paper provides a detailed and comprehensive cost model for the economic assessment of solid waste management systems. The model was based on the principles of Life Cycle Costing (LCC) and followed a bottom-up calculation approach providing detailed cost items for all key technologies within modern waste systems. All technologies were defined per tonne of waste input, and each cost item within a technology was characterised by both a technical and an economic parameter (for example amount and cost of fuel related to waste collection), to ensure transparency, applicability and reproducibility. Cost items were classified as: (1) budget costs, (2) transfers (for example taxes, subsidies and fees) and (3) externality costs (for example damage or abatement costs related to emissions and disamenities). Technology costs were obtained as the sum of all cost items (of the same type) within a specific technology, while scenario costs were the sum of all technologies involved in a scenario. The cost model allows for the completion of three types of LCC: a Conventional LCC, for the assessment of financial costs, an Environmental LCC, for the assessment of financial costs whose results are complemented by a Life Cycle Assessment (LCA) for the same system, and a Societal LCC, for socio-economic assessments. Conventional and Environmental LCCs includes budget costs and transfers, while Societal LCCs includes budget and externality costs. Critical aspects were found in the existing literature regarding the cost assessment of waste management, namely system boundary equivalency, accounting for temporally distributed emissions and impacts, inclusions of transfers, the internalisation of environmental impacts and the coverage of shadow prices, and there was also significant confusion regarding terminology. The presented cost model was implemented in two case study scenarios assessing the costs involved in the source segregation of organic waste from 100,000 Danish households and the subsequent co-digestion of organic waste with animal manure. Overall, source segregation resulted in higher financial costs than the alternative of incinerating the organic waste with the residual waste: 1.6 M?/year, of which 0.9 M?/year was costs for extra bins and bags used by the households, 1.0 M?/year for extra collections and -0.3 M?/year saved on incineration. PMID- 25524748 TI - Association between Western diet pattern and adult asthma: a focused review. AB - OBJECTIVE: Radical changes in diet have paralleled the increase in asthma with shifts toward a "Western" diet pattern, characterized by the high intake of processed meats and refined grains, high-fat dairy products, and sugary desserts and drinks. Because diet represents a modifiable risk factor in numerous chronic diseases, the authors examined the association between consumption of a Western diet pattern and asthma incidence, prevalence, and morbidity in adults. DATA SOURCES: PubMed, Cochrane, Web of Science, and Scopus were searched for peer reviewed publications published from January 1980 to April 2014. STUDY SELECTION: Studies retrieved for inclusion assessed dietary patterns representative of a Western diet and asthma incidence, prevalence, respiratory symptoms, and lung function. RESULTS: Ten observational studies conducted in North American, European, and Asian countries, ranging from 153 to more than 70,000 individuals, did not provide evidence to support an association between a Western dietary pattern and asthma incidence and prevalence. Five of these studies also investigated asthma morbidity, with variable findings. CONCLUSION: Current evidence does not support an association between a Western diet and incident or prevalent adult asthma but does suggest a possible link between a Western diet pattern and adult asthma morbidity. PMID- 25524750 TI - Flows of engineered nanomaterials through the recycling process in Switzerland. AB - The use of engineered nanomaterials (ENMs) in diverse applications has increased during the last years and this will likely continue in the near future. As the number of applications increase, more and more waste with nanomaterials will be generated. A portion of this waste will enter the recycling system, for example, in electronic products, textiles and construction materials. The fate of these materials during and after the waste management and recycling operations is poorly understood. The aim of this work is to model the flows of nano-TiO2, nano ZnO, nano-Ag and CNT in the recycling system in Switzerland. The basis for this study is published information on the ENMs flows on the Swiss system. We developed a method to assess their flow after recycling. To incorporate the uncertainties inherent to the limited information available, we applied a probabilistic material flow analysis approach. The results show that the recycling processes does not result in significant further propagation of nanomaterials into new products. Instead, the largest proportion will flow as waste that can subsequently be properly handled in incineration plants or landfills. Smaller fractions of ENMs will be eliminated or end up in materials that are sent abroad to undergo further recovery processes. Only a reduced amount of ENMs will flow back to the productive process of the economy in a limited number of sectors. Overall, the results suggest that risk assessment during recycling should focus on occupational exposure, release of ENMs in landfills and incineration plants, and toxicity assessment in a small number of recycled inputs. PMID- 25524752 TI - Microwave gain medium with negative refractive index. AB - Artificial effective media are attractive because of the fantastic applications they may enable, such as super lensing and electromagnetic invisibility. However, the inevitable loss due to their strongly dispersive nature is one of the fundamental challenges preventing such applications from becoming a reality. In this study, we demonstrate an effective gain medium based on negative resistance, to overcompensate the loss of a conventional passive metamaterial, meanwhile keeping its original negative-index property. Energy conservation-based theory, full-wave simulation and experimental measurement show that a fabricated sample consisting of conventional sub-wavelength building blocks with embedded microwave tunnel diodes exhibits a band-limited Lorentzian dispersion simultaneously with a negative refractive index and a net gain. Our work provides experimental evidence to the assertion that a stable net gain in negative-index gain medium is achievable, proposing a potential solution for the critical challenge current metamateiral technology faces in practical applications. PMID- 25524751 TI - The prescription of addiction medications after implementation of chronic care management for substance dependence in primary care. AB - People with addictive disorders commonly do not receive efficacious medications. Chronic care management (CCM) is designed to facilitate delivery of effective therapies. Using data from the CCM group in a trial testing its effectiveness for addiction (N=282), we examined factors associated with the prescription of addiction medications. Among participants with alcohol dependence, 17% (95% CI 12.0-22.1%) were prescribed alcohol dependence medications. Among those with drug dependence, 9% (95% CI 5.5-12.6%) were prescribed drug dependence medications. Among those with opioids as a substance of choice, 15% (95% CI 9.3-20.9%) were prescribed opioid agonist therapy. In contrast, psychiatric medications were prescribed to 64% (95% CI 58.2-69.4%). Absence of co-morbid drug dependence was associated with prescription of alcohol dependence medications. Lower alcohol addiction severity and recent opioid use were associated with prescription of drug dependence medications. Better understanding of infrequent prescription of addiction medications, despite a supportive clinical setting, might inform optimal approaches to delivering addiction medications. PMID- 25524753 TI - Circumferential urinary sphincter surface electromyography: A novel diagnostic method for intrinsic sphincter deficiency. AB - AIMS: The diagnosis of intrinsic sphincter deficiency (ISD) in patients with stress urinary incontinence (SUI) is not well established. We explored the possibility of applying a new tool: minimally invasive circumferential sphincter surface electromyography (CSS-EMG) to assess the muscular integrity of the urethral sphincter in patients with SUI/ISD. METHODS: CSS-EMG of the urethral sphincter and urodynamic studies were performed in 44 women with SUI. A urethral pressure profile (UPP) was measured in four directions. Maximal urethral closure pressure (MUCP) <40 cm/H2 O or the presence of SUI without urethral hypermobility was used to define ISD. RESULTS: Twenty-one patients had urodynamic SUI, 23 had no SUI and 12 patients had ISD. The mean average rectified value (ARV) of the motor unit action potential (MUAP), an indicator of the strength of urethral rhabdosphincter, was estimated. ARV measured in the 12 o'clock quadrant during maximal contraction was the only CSS-EMG parameter that had significant predictive value for ISD. With an increase in the 12 o'clock ARV value, the likelihood of ISD decreases (Odds Ratio 0.36 95% confidence interval 0.67-0.92). In the ROC curve with ARV measured in the 12 o'clock quadrant during maximal contraction, the explained area was 0.794 (P = 0.02); implying that ARV measured at the 12 o'clock quadrant during maximal contraction was able to predict ISD significantly. CONCLUSIONS: Myogenic changes of the urethral sphincter that contribute to ISD can be assessed with CSS-EMG. This new concept for assessing the functionality of the female urethral sphincter may assist with better understanding of the pathophysiology, the diagnosis and the treatment of SUI. PMID- 25524754 TI - Discrete alterations of brain network structural covariance in individuals at ultra-high risk for psychosis. AB - BACKGROUND: Investigation of aberrant large-scale brain networks offers novel insight into the role these networks play in diverse psychiatric disorders such as schizophrenia. Although studies report altered functional brain connectivity in participants at ultra-high risk (UHR) for psychosis, it is unclear whether these alterations extend to structural brain networks. METHODS: Whole-brain structural covariance patterns of 133 participants at UHR for psychosis (51 of whom subsequently developed psychosis) and 65 healthy control (HC) subjects were studied. Following data preprocessing (using VBM8 toolbox), the mean signal in seed regions relating to specific networks (visual, auditory, motor, speech, semantic, executive control, salience, and default-mode) were extracted, and voxel-wise analyses of covariance were conducted to compare the association between whole-brain signal and each seed region for UHR and HC individuals. The UHR participants who transitioned to psychosis were compared with the UHR participants who did not. RESULTS: Significantly reduced structural covariance was observed in the UHR sample compared with the HC sample for the default-mode network, and increased covariance was observed for the motor and executive control networks. When the UHR participants who transitioned to psychosis were compared with the UHR participants who did not, aberrant structural covariance was observed in the salience, executive control, auditory, and motor networks. CONCLUSIONS: Whole-brain structural covariance analyses revealed subtle changes of connectivity of the default-mode, executive control, salience, motor, and auditory networks in UHR individuals for psychosis. Although we found significant differences, these are small changes and tend to reflect largely intact structural networks. PMID- 25524756 TI - Two-stage estimation for multivariate recurrent event data with a dependent terminal event. AB - Recurrent event data arise in longitudinal follow-up studies, where each subject may experience the same type of events repeatedly. The work in this article is motivated by the data from a study of repeated peritonitis for patients on peritoneal dialysis. Due to the aspects of medicine and cost, the peritonitis cases were classified into two types: Gram-positive and non-Gram-positive peritonitis. Further, since the death and hemodialysis therapy preclude the occurrence of recurrent events, we face multivariate recurrent event data with a dependent terminal event. We propose a flexible marginal model, which has three characteristics: first, we assume marginal proportional hazard and proportional rates models for terminal event time and recurrent event processes, respectively; second, the inter-recurrences dependence and the correlation between the multivariate recurrent event processes and terminal event time are modeled through three multiplicative frailties corresponding to the specified marginal models; third, the rate model with frailties for recurrent events is specified only on the time before the terminal event. We propose a two-stage estimation procedure for estimating unknown parameters. We also establish the consistency of the two-stage estimator. Simulation studies show that the proposed approach is appropriate for practical use. The methodology is applied to the peritonitis cohort data that motivated this study. PMID- 25524755 TI - Converging Medial Frontal Resting State and Diffusion-Based Abnormalities in Borderline Personality Disorder. AB - BACKGROUND: The psychological profile of patients with borderline personality disorder (BPD), with impulsivity and emotional dysregulation as core symptoms, has guided the search for abnormalities in specific brain areas such as the hippocampal-amygdala complex and the frontomedial cortex. However, whole-brain imaging studies so far have delivered highly heterogeneous results involving different brain locations. METHODS: Functional resting-state and diffusion magnetic resonance imaging data were acquired in patients with BPD and in an equal number of matched control subjects (n = 60 for resting and n = 43 for diffusion). While mean diffusivity and fractional anisotropy brain images were generated from diffusion data, amplitude of low-frequency fluctuations and global brain connectivity images were used for the first time to evaluate BPD-related brain abnormalities from resting functional acquisitions. RESULTS: Whole-brain analyses using a p = .05 corrected threshold showed a convergence of alterations in BPD patients in genual and perigenual structures, with frontal white matter fractional anisotropy abnormalities partially encircling areas of increased mean diffusivity and global brain connectivity. Additionally, a cluster of enlarged amplitude of low-frequency fluctuations (high resting activity) was found involving part of the left hippocampus and amygdala. In turn, this cluster showed increased resting functional connectivity with the anterior cingulate. CONCLUSIONS: With a multimodal approach and without using a priori selected regions, we prove that structural and functional abnormality in BPD involves both temporolimbic and frontomedial structures as well as their connectivity. These structures have been previously related to behavioral and clinical symptoms in patients with BPD. PMID- 25524757 TI - Volumetric analysis of hippocampal sub-regions in late onset depression: a 3 tesla magnetic resonance imaging study. AB - BACKGROUND: While many studies have reported reduced volume of hippocampus in late onset depression (LOD), the status of hippocampus sub-regions (anterior/posterior) is yet to be explored. Evaluating hippocampal sub-regions might facilitate better elucidation of the neurobiological basis of LOD. METHODS: Twenty five elderly subjects with LOD (mean age=65.28yr, SD=5.73, 15 females) and 20 healthy controls (mean age=65.35yr, SD=5.67, 7 females) were examined using 3 tesla magnetic resonance imaging (MRI). They were also evaluated with Montgomery Asberg Depression Rating Scale (MADRS) and Hindi Mental State Examination (HMSE). We examined the difference in volume of Hippocampal sub-regions between the LOD group and control group controlling for the age, sex and intracranial volume. RESULTS: Left posterior hippocampus volume was significantly smaller in LOD group than the control group (1.01+/-0.19ml vs 1.16+/-0.25ml, F=7.50, p=0.009). There was a similar trend for the right posterior hippocampus (1.08+/-0.19ml vs 1.18+/ 0.27ml, F=3.18, p=0.082). Depression severity (mean MADRS score=20.64+/-8.99) had a significant negative correlation with volumes of right posterior hippocampus (r=-0.37, p=0.012) and left posterior hippocampus (r=-0.46, p=0.001) in the LOD group. CONCLUSIONS: Specific reduction of posterior hippocampus volume and its relationship with depression severity indicates sub region specific hippocampal volumetric abnormalities in LOD. Future studies need to evaluate sub region specific hippocampal volume in LOD longitudinally for better understanding of the pathogenesis of LOD in view of the functional differences between anterior and posterior hippocampus. PMID- 25524758 TI - Comparative distribution and validity of DSM-IV and DSM-5 diagnoses of eating disorders in adolescents from the community. AB - OBJECTIVES: DSM-5 changes for eating disorders (EDs) aimed to reduce preponderance of non-specified cases and increase validity of specific diagnoses. The objectives were to estimate the combined effect of changes on prevalence of EDs in adolescents and examine validity of diagnostic groupings. METHOD: A total of 3043 adolescents (1254 boys and 1789 girls, Mage = 14.19 years, SD = 1.61) completed self-report questionnaires including the Eating Disorder Diagnostic Scale. RESULTS: Prevalence of full-threshold EDs increased from 1.8% (DSM-IV) to 3.7% (DSM-5), with a higher prevalence of bulimia nervosa (1.6%) and the addition of the diagnosis of purging disorder (1.4%); prevalence of binge eating disorder was unchanged (0.5%), and non-specified cases decreased from 5.1% (DSM-IV) to 3.4% (DSM-5). Validation analyses demonstrated that DSM-5 ED subgroups better captured variance in psychopathology than DSM-IV subgroups. DISCUSSION: Findings extend results from previous prevalence and validation studies into the adolescent age range. Improved diagnostic categories should facilitate identification of EDs and indicate targeted treatments. PMID- 25524759 TI - Thermodynamic signatures of fragment binding: Validation of direct versus displacement ITC titrations. AB - BACKGROUND: Detailed characterization of the thermodynamic signature of weak binding fragments to proteins is essential to support the decision making process which fragments to take further for the hit-to-lead optimization. METHOD: Isothermal titration calorimetry (ITC) is the method of choice to record thermodynamic data, however, weak binding ligands such as fragments require the development of meaningful and reliable measuring protocols as usually sigmoidal titration curves are hardly possible to record due to limited solubility. RESULTS: Fragments can be titrated either directly under low c-value conditions (no sigmoidal curve) or indirectly by use of a strong binding ligand displacing the pre-incubated weak fragment from the protein. The determination of Gibbs free energy is reliable and rather independent of the applied titration protocol. CONCLUSION: Even though the displacement method achieves higher accuracy, the obtained enthalpy-entropy profile depends on the properties of the used displacement ligand. The relative enthalpy differences across different displacement experiments reveal a constant signature and can serve as a thermodynamic fingerprint for fragments. Low c-value titrations are only reliable if the final concentration of the fragment in the sample cell exceeds 2-10 fold its K(D) value. Limited solubility often prevents this strategy. GENERAL SIGNIFICANCE: The present study suggests an applicable protocol to characterize the thermodynamic signature of protein-fragment binding. It shows however, that such measurements are limited by protein and fragment solubility. Deviating profiles obtained by use of different displacement ligands indicate that changes in the solvation pattern and protein dynamics most likely take influence on the resulting overall binding signature. PMID- 25524760 TI - Erratum to: Genetic and toxicologic investigation of Sudden Cardiac Death in a patient with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) under cocaine and alcohol effects. PMID- 25524761 TI - Ventilated post-mortem computed tomography through the use of a definitive airway. AB - Ventilated post-mortem computed tomography (VPMCT) has been shown to achieve lung expansion in cadavers and has been proposed to enhance the diagnosis of lung pathology. Two key problems of the method of ventilation have been identified: firstly, the presence of head and neck rigor making airway insertion challenging and, secondly, air leak, if there is not a good seal around the airway, which diminishes lung expansion and causes inflation of the stomach. Simple procedures to insert a 'definitive' cuffed airway, which has a balloon inflated within the trachea, are therefore desirable. This study aims to test different procedures for inserting cuffed airways in cadavers and compare their ventilation efficacy and to propose a decision algorithm to select the most appropriate method. We prospectively tested variations on two ways of inserting a cuffed airway into the trachea: firstly, using an endotracheal tube (ET) approach, either blind or by direct visualisation, and, secondly, using a tracheostomy incision, either using a standard tracheostomy tube or shortened ET tube. We compare these approaches with a retrospective analysis of a previously reported series using supraglottic airways. All techniques, except 'blind' insertion of ET tubes, were possible with adequate placement of the airway in most cases. However, achieving both adequate insertion and a complete tracheal seal was better for definitive airways with 56 successful cases from 59 (95 %), compared with 9 cases from 18 (50 %) using supraglottic airways (p < 0.0001). Good lung expansion was achieved using all techniques if the airway was adequately positioned and achieved a good seal, and there was no significant chest pathology. We prefer inserting a shortened ET tube via a tracheostomy incision, as we find this the easiest technique to perform and train. Based on our experience, we have developed a decision algorithm to select the most appropriate method for VPMCT. PMID- 25524762 TI - Abortion after deliberate Arthrotec(r) addition to food. Mass spectrometric detection of diclofenac, misoprostol acid, and their urinary metabolites. AB - Arthrotec((r)) (AT) is a combination of diclofenac, a nonsteroidal anti inflammatory drug (NSAID), and misoprostol (MP), a synthetic analogue of prostaglandin E1 (PGE1). MP is a lipophilic methyl ester prodrug. It is readily metabolized to the biologically active misoprostol acid (MPA). During the last few years, medical studies exhibited MP to be an excellent abortive. In this paper, we describe a rare criminal case of MP abortion, initiated by the expectant father. After the abortion, samples of vomit and urine were collected. Systemic exposure to MP is difficult to prove, because both MP and the active metabolite MPA are hardly excreted in urine. Therefore, in addition to routine toxicological analysis, we used slightly modified, well-established liquid and gas chromatographic/tandem mass spectrometric (LC/MS/MS and GC/MS/MS) methods, for the direct and the indirect detection of MPA and its metabolites. In this case, we were able to demonstrate the presence of the major MP metabolites 2,3 dinor-MPA and 2,3,4,5-tetranor-MPA in the urine of the victim. We also detected paracetamol, 3-methoxyparacetamol and diclofenac-glucuronide in the urine. In the vomit of the victim, we detected diclofenac and MPA. These results, combined with the criminal investigations, showed that the accused had mixed MP into the food of his pregnant girlfriend. Finally, these investigations contributed to a confession of the accused. PMID- 25524764 TI - Photo quiz: risk in travelers after barefoot sand walking in tropical countries. Tunga penetrans. PMID- 25524763 TI - Greater temporal changes of sediment microbial community than its waterborne counterpart in Tengchong hot springs, Yunnan Province, China. AB - Temporal variation in geochemistry can cause changes in microbial community structure and diversity. Here we studied temporal changes of microbial communities in Tengchong hot springs of Yunnan Province, China in response to geochemical variations by using microbial and geochemical data collected in January, June and August of 2011. Greater temporal variations were observed in individual taxa than at the whole community structure level. Water and sediment communities exhibited different temporal variation patterns. Water communities were largely stable across three sampling times and dominated by similar microbial lineages: Hydrogenobaculum in moderate-temperature acidic springs, Sulfolobus in high-temperature acidic springs, and Hydrogenobacter in high temperature circumneutral to alkaline springs. Sediment communities were more diverse and responsive to changing physicochemical conditions. Most of the sediment communities in January and June were similar to those in waters. However, the August sediment community was more diverse and contained more anaerobic heterotrophs than the January and June: Desulfurella and Acidicaldus in moderate-temperature acidic springs, Ignisphaera and Desulfurococcus in high temperature acidic springs, the candidate division OP1 and Fervidobacterium in alkaline springs, and Thermus and GAL35 in neutral springs. Temporal variations in physicochemical parameters including temperature, pH, and dissolved organic carbon may have triggered the observed microbial community shifts. PMID- 25524765 TI - Use of alternative reference standards and exempted species to evaluate the performance of the Vitek 2 GP67 cefoxitin/oxacillin screen for coagulase-negative staphylococci. PMID- 25524766 TI - Reply to "use of alternative reference standards and exempted species to evaluate the performance of the Vitek 2 GP67 cefoxitin/oxacillin screen for coagulase negative staphylococci". PMID- 25524770 TI - Associations of plasma kynurenines with risk of acute myocardial infarction in patients with stable angina pectoris. AB - OBJECTIVE: Enhanced tryptophan degradation, induced by the proinflammatory cytokine interferon-gamma, has been related to cardiovascular disease progression and insulin resistance. We assessed downstream tryptophan metabolites of the kynurenine pathway as predictors of acute myocardial infarction in patients with suspected stable angina pectoris. Furthermore, we evaluated potential effect modifications according to diagnoses of pre-diabetes mellitus or diabetes mellitus. APPROACH AND RESULTS: Blood samples were obtained from 4122 patients (median age, 62 years; 72% men) who underwent elective coronary angiography. During median follow-up of 56 months, 8.3% had acute myocardial infarction. Comparing the highest quartile to the lowest, for the total cohort, multivariable adjusted hazard ratios (95% confidence intervals) were 1.68 (1.21-2.34), 1.81 (1.33-2.48), 1.68 (1.21-2.32), and 1.48 (1.10-1.99) for kynurenic acid, hydroxykynurenine, anthranilic acid, and hydroxyanthranilic acid, respectively. The kynurenines correlated with phenotypes of the metabolic syndrome, and risk associations were generally stronger in subgroups classified with pre-diabetes mellitus or diabetes mellitus at inclusion (Pint<=0.05). Evaluated in the total population, hydroxykynurenine and anthranilic acid provided statistically significant net reclassification improvements (0.21 [0.08-0.35] and 0.21 [0.07 0.35], respectively). CONCLUSIONS: In patients with suspected stable angina pectoris, elevated levels of plasma kynurenines predicted increased risk of acute myocardial infarction, and risk estimates were generally stronger in subgroups with evidence of impaired glucose homeostasis. Future studies should aim to clarify roles of the kynurenine pathway in atherosclerosis and glucose metabolism. PMID- 25524771 TI - MicroRNA 302a is a novel modulator of cholesterol homeostasis and atherosclerosis. AB - OBJECTIVE: Macrophage foam cell formation is a key feature of atherosclerosis. Recent studies have shown that specific microRNAs (miRs) are regulated in modified low-density lipoprotein-treated macrophages, which can affect the cellular cholesterol homeostasis. Undertaking a genome-wide screen of miRs regulated in primary macrophages by modified low-density lipoprotein, miR-302a emerged as a potential candidate that may play a key role in macrophage cholesterol homeostasis. APPROACH AND RESULTS: The objective of this study was to assess the involvement of miR-302a in macrophage lipid homeostasis and if it can influence circulating lipid levels and atherosclerotic development when it is inhibited in a murine atherosclerosis model. We found that transfection of primary macrophages with either miR-302a or anti-miR-302a regulated the expression of ATP-binding cassette (ABC) transporter ABCA1 mRNA and protein. Luciferase reporter assays showed that miR-302a repressed the 3' untranslated regions (UTR) activity of mouse Abca1 by 48% and human ABCA1 by 45%. In addition, transfection of murine macrophages with miR-302a attenuated cholesterol efflux to apolipoprotein A-1 (apoA-1) by 38%. Long-term in vivo administration of anti-miR 302a to mice with low-density lipoprotein receptor deficiency (Ldlr(-/-)) fed an atherogenic diet led to an increase in ABCA1 in the liver and aorta as well as an increase in circulating plasma high-density lipoprotein levels by 35% compared with that of control mice. The anti-miR-302a-treated mice also displayed reduced atherosclerotic plaque size by ~25% and a more stable plaque morphology with reduced signs of inflammation. CONCLUSIONS: These studies identify miR-302a as a novel modulator of cholesterol efflux and a potential therapeutic target for suppressing atherosclerosis. PMID- 25524772 TI - A peptide antagonist of thrombospondin-1 promotes abdominal aortic aneurysm progression in the angiotensin II-infused apolipoprotein-E-deficient mouse. AB - OBJECTIVE: Interaction of the activating sequence in thrombospondin-1 (TSP-1) with the conserved sequence (leucine-serine-lysine-leucine [LSKL]) in the latency associated peptide region of latent transforming growth factor (TGF)-beta complex is important in regulating TGF-beta1 activity. We aimed to assess the effect of blocking peptide LSKL on the progression of pre-established abdominal aortic aneurysm in angiotensin II-infused apolipoprotein E-deficient (ApoE(-/-)) mice. APPROACH AND RESULTS: Abdominal aortic aneurysm was established in 3-month-old male ApoE(-/-) mice with subcutaneous infusion of angiotensin II for 28 days. After this, mice received LSKL peptide or control SLLK (serine-leucine-leucine lysine) peptide (4 mg/kg) via daily intraperitoneal injection for an additional 2 weeks. Administration of LSKL peptide promoted larger suprarenal aortic diameter, as determined by ultrasound and morphometric analysis, and stimulated more severe atherosclerosis within the aortic arch. In addition, mice receiving LSKL peptide exhibited elevated circulating proinflammatory cytokine levels and greater inflammatory cells within the suprarenal aorta compared with controls. Mice receiving LSKL peptide showed low plasma TGF-beta1 activity and low levels of aortic tissue phosphorylated to total Smad2/3. Aortic gene expression of TGF-beta receptor 1 (TGFBRI) and receptor 2 (TGFBRII), but not TGF-beta1 and thrombospondin-1, were lower in mice receiving LSKL peptide than controls. LSKL peptide administration was associated with greater aortic elastin fragmentation and lower expression and activity of the TGF-beta1-target gene lysyl oxidase like 1 (LOXL1). CONCLUSIONS: Attenuation of thrombospondin-1-directed activation of TGF-beta1 promotes abdominal aortic aneurysm and atherosclerosis progression in the angiotensin II-infused ApoE(-/-) mouse model. PMID- 25524773 TI - BubR1 insufficiency inhibits neointimal hyperplasia through impaired vascular smooth muscle cell proliferation in mice. AB - OBJECTIVE: BubR1, a cell cycle-related protein, is an essential component of the spindle checkpoint that regulates cell division. Mice with BubR1 expression reduced to 10% of the normal level display a phenotype characterized by progeria; however, the involvement of BubR1 in vascular diseases is still unknown. We generated mice in which BubR1 expression was reduced to 20% (BubR1(L/L) mice) of that in wild-type mice (BubR1(+/+)) to investigate the effects of BubR1 on arterial intimal hyperplasia. APPROACH AND RESULTS: Ten-week-old male BubR1(L/L) and age-matched wild-type littermates (BubR1(+/+)) were used in this study. The left common carotid artery was ligated, and histopathologic examinations were conducted 4 weeks later. Bone marrow transplantation was also performed. Vascular smooth muscle cells (VSMCs) were isolated from the thoracic aorta to examine cell proliferation, migration, and cell cycle progression. Severe neointimal hyperplasia was observed after artery ligation in BubR1(+/+) mice, whereas BubR1(L/L) mice displayed nearly complete inhibition of neointimal hyperplasia. Bone marrow transplantation from all donors did not affect the reconstitution of 3 hematopoietic lineages, and neointimal hyperplasia was still suppressed after bone marrow transplantation from BubR1(+/+) mice to BubR1(L/L) mice. VSMC proliferation was impaired in BubR1(L/L) mice because of delayed entry into the S phase. VSMC migration was unaffected in these BubR1(L/L) mice. p38 mitogen activated protein kinase-inhibited VSMCs showed low expression of BubR1, and BubR1-inhibited VSMCs showed low expression of p38. CONCLUSIONS: BubR1 may represent a new target molecule for treating pathological states of vascular remodeling, such as restenosis after angioplasty. PMID- 25524774 TI - Cluster of differentiation 43 deficiency in leukocytes leads to reduced atherosclerosis--brief report. AB - OBJECTIVE: The aim of this study was to investigate the role of cluster of differentiation 43 (CD43), an integral membrane glycoprotein with both proadhesive and antiadhesive activities, in atherosclerosis. APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice were lethally irradiated and reconstituted with either bone marrow from CD43(-/-) mice or from wild-type controls. We found that mice lacking the CD43 on their leukocytes had significantly less severe atherosclerosis and that, contrary to our expectation, macrophage infiltration into the vessel wall was not affected by the lack of CD43 in the leukocytes. However, we found that CD43 mediates cholesterol homeostasis in macrophages by facilitating cholesterol efflux. This resulted in a significant reduction in storage of cholesterol in the aorta of mice lacking CD43 in the leukocytes. CONCLUSIONS: CD43 may be an important mediator of macrophage lipid homeostasis, thereby affecting macrophage foam cell formation and ultimately atherosclerotic plaque development. PMID- 25524775 TI - Molecular controls of lymphatic VEGFR3 signaling. AB - OBJECTIVES: Vascular endothelial growth factor receptor 3 (VEGFR3) plays important roles both in lymphangiogenesis and angiogenesis. On stimulation by its ligand VEGF-C, VEGFR3 is able to form both homodimers as well as heterodimers with VEGFR2 and activates several downstream signal pathways, including extracellular signal-regulated kinases (ERK)1/2 and protein kinase B (AKT). Despite certain similarities with VEGFR2, molecular features of VEGFR3 signaling are still largely unknown. APPROACH AND RESULTS: Human dermal lymphatic endothelial cells were used to examine VEGF-C-driven activation of signaling. Compared with VEGF-A activation of VEGFR2, VEGF-C-induced VEGFR3 activation led to a more extensive AKT activation, whereas activation of ERK1/2 displayed a distinctly different kinetics. Furthermore, VEGF-C, but not VEGF-A, induced formation of VEGFR3/VEGFR2 complexes. Silencing VEGFR2 or its partner neuropilin 1 specifically abolished VEGF-C-induced AKT but not ERK activation, whereas silencing of neuropilin 2 had little effect on either signaling pathway. Finally, suppression of vascular endothelial phosphotyrosine phosphatase but not other phosphotyrosine phosphatases enhanced VEGF-C-induced activation of both ERK and AKT pathways. Functionally, both ERK and AKT pathways are important for lymphatic endothelial cells migration. CONCLUSIONS: VEGF-C activates AKT signaling via formation of VEGFR3/VEGFR2 complex, whereas ERK is activated by VEGFR3 homodimer. Neuropilin 1 and vascular endothelial phosphotyrosine phosphatase are involved in regulation of VEGFR3 signaling. PMID- 25524776 TI - Angiotensin II mobilizes spleen monocytes to promote the development of abdominal aortic aneurysm in Apoe-/- mice. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) is widespread among elderly people and results in progressive expansion and rupture of the aorta with high mortality. Macrophages, which are the main population observed within the site of aneurysm, are thought to derive from circulating monocytes although no direct evidence has been provided to date. In this study, we were particularly interested in understanding the trafficking behavior of monocyte subsets in AAA and their role in disease pathogenesis. APPROACH AND RESULTS: Using bone marrow transplantation in Apoe(-/-) mice, we showed that circulating monocytes give rise to abdominal aortic macrophages in hypercholesterolemic mice submitted to angiotensin II (AngII). Detailed monitoring of monocyte compartmentalization revealed that lymphocyte antigen 6C(high) and lymphocyte antigen 6C(low) monocytes transiently increase in blood early after AngII infusion and differentially infiltrate the abdominal aorta. The splenic reservoir accounted for the mobilization of the 2 monocyte subsets after 3 days of AngII infusion. Spleen removal or lymphocyte deficiency in Apoe(-/-) Rag2(-/-) mice similarly impaired early monocyte increase in blood in response to AngII and protected against AAA development, independently of blood pressure. Reconstitution of Apoe(-/-) Rag2(-/-) mice with total splenocytes but not with B-cell-depleted splenocytes restored monocyte mobilization in response to AngII and enhanced susceptibility to AAA. CONCLUSIONS: Taken together, the data show that lymphocyte antigen 6C(high) and lymphocyte antigen 6C(low) monocytes are mobilized from the spleen in response to AngII. Intriguingly, the process is dependent on the presence of B cells and significantly contributes to the development of AAA and the occurrence of aortic rupture. PMID- 25524777 TI - Photosynthesis-dependent formation of convoluted plasma membrane domains in Chara internodal cells is independent of chloroplast position. AB - The characean green alga Chara australis forms complex plasma membrane convolutions called charasomes when exposed to light. Charasomes are involved in local acidification of the surrounding medium which facilitates carbon uptake required for photosynthesis. They have hitherto been only described in the internodal cells and in close contact with the stationary chloroplasts. Here, we show that charasomes are not only present in the internodal cells of the main axis, side branches, and branchlets but that the plasma membranes of chloroplast containing nodal cells, protonemata, and rhizoids are also able to invaginate into complex domains. Removal of chloroplasts by local irradiation with intense light revealed that charasomes can develop at chloroplast-free "windows" and that the resulting pH banding pattern is independent of chloroplast or window position. Charasomes were not detected along cell walls containing functional plasmodesmata. However, charasomes formed next to a smooth wound wall which was deposited onto the plasmodesmata-containing wall when the neighboring cell was damaged. In contrast, charasomes were rarely found at uneven, bulged wound walls which protrude into the streaming endoplasm and which were induced by ligation or puncturing. The results of this study show that charasome formation, although dependent on photosynthesis, does not require intimate contact with chloroplasts. Our data suggest further that the presence of plasmodesmata inhibits charasome formation and/or that exposure to the outer medium is a prerequisite for charasome formation. Finally, we hypothesize that the absence of charasomes at bulged wound walls is due to the disturbance of uniform laminar mass streaming. PMID- 25524778 TI - Expression profile of long noncoding RNAs in cartilage from knee osteoarthritis patients. AB - OBJECTIVES: Long noncoding RNAs (lncRNAs) have emerged as a novel class of regulatory molecules involved in various biological processes, but their role in osteoarthritis (OA) remains unknown. Therefore, we aimed to reveal lncRNAs expression profile in human osteoarthritic cartilage and explore the potential functions of lncRNAs in OA. METHODS: The expression profiles of lncRNAs and mRNAs in OA cartilage were obtained using microarray and verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Bioinformatics analyses including lncRNA classification and subgroup analysis, gene ontology (GO) analysis, pathway analysis, network analysis and target prediction were performed. RESULTS: There were 3007 upregulated lncRNAs and 1707 downregulated lncRNAs in OA cartilage compared with normal samples (Fold change >= 2.0). In addition, 2136 mRNAs were upregulated and 2,241 mRNAs were downregulated in OA cartilage (Fold change >= 2.0). The qRT-PCR results of six dysregulated lncRNAs were consistent with the microarray data. 106 lncRNAs and 291 mRNAs composed the coding-non-coding gene co-expression network (CNC network). In the 600 top differentially expressed lncRNAs, 48 lncRNAs were predicted to have more than five cis-regulated target genes and up to 530 lncRNAs might regulate their trans target genes through collaboration with transcriptional factor (TF) SP1. The positive correlation between lncRNA uc.343 and predicted target homeobox gene C8 (HOXC8) expression in SW1353 cells treating with interleukin-1 beta confirmed the target prediction to some extent. CONCLUSIONS: This study revealed the expression pattern of lncRNAs in OA cartilage and predicted the potential function and targets, which indicated that lncRNAs may be new biomarkers for diagnosis or novel therapeutic targets of OA. PMID- 25524779 TI - Scandinavian clinical practice guideline on mechanical ventilation in adults with the acute respiratory distress syndrome. AB - BACKGROUND: The objective of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI) task force on mechanical ventilation in adults with the acute respiratory distress syndrome (ARDS) is to formulate treatment recommendations based on available evidence from systematic reviews and randomised trials. METHODS: This guideline was developed according to standards for trustworthy guidelines through a systematic review of the literature and the use of the Grading of Recommendations Assessment, Development and Evaluation system for assessment of the quality of evidence and for moving from evidence to recommendations in a systematic and transparent process. RESULTS: We found evidence of moderately high quality to support a strong recommendation for pressure limitation and small tidal volumes in patients with ARDS. Also, we suggest positive end-expiratory pressure (PEEP) > 5 cm H2O in moderate to severe ARDS and prone ventilation 16/24 h for the first week in moderate to severe ARDS (weak recommendation, low quality evidence). Volume controlled ventilation or pressure control may be equally beneficial or harmful and partial modes of ventilatory support may be used if clinically feasible (weak recommendation, very low quality evidence). We suggest utilising recruitment manoeuvres as a rescue measure in catastrophic hypoxaemia only (weak recommendation, low quality evidence). Based on high-quality evidence, we strongly recommend not to use high frequency oscillatory ventilation. We could find no relevant data from randomised trials to guide decisions on choice of FiO2 or utilisation of non-invasive ventilation. CONCLUSION: We strongly recommend pressure- and volume limitation and suggest using higher PEEP and prone ventilation in patients with severe respiratory failure. PMID- 25524781 TI - Nursing students' post-traumatic growth, emotional intelligence and psychological resilience. AB - Nursing students in the present sample who have experienced childhood adversity have a certain level of post-traumatic growth. If introduced into nursing curricula, emotional intelligence interventions may increase emotional coping resources and enhance social skills for nurses, which may benefit their long-term occupational health. As researchers consider personal resilience a strategy for responding to workplace adversity in nurses, resilience building should be incorporated into nursing education. This is a preliminary study that may guide future investigations of the curvilinear relationship rather than linear relationship between post-traumatic growth and positive factors in the special sample of nursing students. Resilience, emotional intelligence and post-traumatic growth may benefit nursing students' careers and personal well-being in clinical work. Developing both their emotional intelligence and resilience may assist their individual post-traumatic growth and enhance their ability to cope with clinical stress. To investigate the relationships among post-traumatic growth, emotional intelligence and psychological resilience in vocational school nursing students who have experienced childhood adversities, a cross-sectional research design with anonymous questionnaires was conducted and self-report data were analysed. The Childhood Adversities Checklist (Chinese version), Posttraumatic Growth Inventory, Emotional Intelligence Scale and the 10-item Connor-Davidson Resilience Scale were used. Survey data were collected from 202 Chinese vocational school nursing students during 2011. Post-traumatic growth was associated with emotional intelligence and psychological resilience. Results indicated a curvilinear relationship between emotional intelligence and post traumatic growth, and between psychological resilience and post-traumatic growth. Moderate-level emotional intelligence and psychological resilience were most associated with the greatest levels of growth. The results imply that moderate resilience and emotional intelligence can help nursing students cope with adversity in their future clinical work. This study first provided preliminary data suggesting the curvilinear relationship rather than linear relationship between post-traumatic growth and positive factors in the sample of nursing students. PMID- 25524782 TI - Here/In this issue and there/abstract thinking: milestones. PMID- 25524780 TI - Human pluripotent stem cell-derived products: advances towards robust, scalable and cost-effective manufacturing strategies. AB - The ability to develop cost-effective, scalable and robust bioprocesses for human pluripotent stem cells (hPSCs) will be key to their commercial success as cell therapies and tools for use in drug screening and disease modelling studies. This review outlines key process economic drivers for hPSCs and progress made on improving the economic and operational feasibility of hPSC bioprocesses. Factors influencing key cost metrics, namely capital investment and cost of goods, for hPSCs are discussed. Step efficiencies particularly for differentiation, media requirements and technology choice are amongst the key process economic drivers identified for hPSCs. Progress made to address these cost drivers in hPSC bioprocessing strategies is discussed. These include improving expansion and differentiation yields in planar and bioreactor technologies, the development of xeno-free media and microcarrier coatings, identification of optimal bioprocess operating conditions to control cell fate and the development of directed differentiation protocols that reduce reliance on expensive morphogens such as growth factors and small molecules. These approaches offer methods to further optimise hPSC bioprocessing in terms of its commercial feasibility. PMID- 25524783 TI - The medical and psychiatric evaluation of the nonverbal child. PMID- 25524784 TI - Tourette's syndrome and translational clinical science. PMID- 25524785 TI - Corrected QT interval changes with atypical antipsychotics. PMID- 25524787 TI - Corrected QT changes during antipsychotic treatment of children and adolescents: a systematic review and meta-analysis of clinical trials. AB - OBJECTIVE: To evaluate the effect of antipsychotics on the corrected QT (QTc) interval in youth. METHOD: We searched PubMed (http://www.ncbi.nlm.nih.gov/pubmed) for randomized or open clinical trials of antipsychotics in youth <18 years with QTc data, meta-analyzing the results. Meta regression analyses evaluated the effect of age, sex, dose, and study duration on QTc. Incidences of study-defined QTc prolongation (>440-470 milliseconds), QTc >500 milliseconds, and QTc change >60 milliseconds were also evaluated. RESULTS: A total of 55 studies were meta-analyzed, evaluating 108 treatment arms covering 9 antipsychotics and including 5,423 patients with QTc data (mean age = 12.8 +/- 3.6 years, female = 32.1%). Treatments included aripiprazole: studies = 14; n = 814; haloperidol: studies = 1; n = 15; molindone: studies = 3; n = 125; olanzapine: studies = 5; n = 212; paliperidone: studies = 3; n = 177; pimozide: studies = 1; n = 25; quetiapine: studies = 5; n = 336; risperidone: studies = 23; n = 2,234; ziprasidone: studies = 10, n = 523; and placebo: studies = 19, n = 962. Within group, from baseline to endpoint, aripiprazole significantly decreased the QTc interval (-1.44 milliseconds, CI = -2.63 to -0.26, p = .017), whereas risperidone (+1.68, CI = +0.67 to +2.70, p = .001) and especially ziprasidone (+8.74, CI = +5.19 to +12.30, p < .001) significantly increased QTc. Compared to pooled placebo arms, aripiprazole decreased QTc (p = .007), whereas ziprasidone increased QTc (p < .001). Compared to placebo, none of the investigated antipsychotics caused a significant increase in the incidence of the 3 studied QTc prolongation measures, but there was significant reporting bias. CONCLUSION: Based on these data, the risk of pathological QTc prolongation seems low during treatment with the 9 studied antipsychotics in otherwise healthy youth. Nevertheless, because individual risk factors interact with medication related QTc effects, both medication and patient factors need to be considered when choosing antipsychotic treatment. PMID- 25524786 TI - Sex/gender differences and autism: setting the scene for future research. AB - OBJECTIVE: The relationship between sex/gender differences and autism has attracted a variety of research ranging from clinical and neurobiological to etiological, stimulated by the male bias in autism prevalence. Findings are complex and do not always relate to each other in a straightforward manner. Distinct but interlinked questions on the relationship between sex/gender differences and autism remain underaddressed. To better understand the implications from existing research and to help design future studies, we propose a 4-level conceptual framework to clarify the embedded themes. METHOD: We searched PubMed for publications before September 2014 using search terms "'sex OR gender OR females' AND autism." A total of 1,906 articles were screened for relevance, along with publications identified via additional literature reviews, resulting in 329 articles that were reviewed. RESULTS: Level 1, "Nosological and diagnostic challenges," concerns the question, "How should autism be defined and diagnosed in males and females?" Level 2, "Sex/gender-independent and sex/gender dependent characteristics," addresses the question, "What are the similarities and differences between males and females with autism?" Level 3, "General models of etiology: liability and threshold," asks the question, "How is the liability for developing autism linked to sex/gender?" Level 4, "Specific etiological developmental mechanisms," focuses on the question, "What etiological developmental mechanisms of autism are implicated by sex/gender and/or sexual/gender differentiation?" CONCLUSIONS: Using this conceptual framework, findings can be more clearly summarized, and the implications of the links between findings from different levels can become clearer. Based on this 4-level framework, we suggest future research directions, methodology, and specific topics in sex/gender differences and autism. PMID- 25524788 TI - Major depression in the national comorbidity survey-adolescent supplement: prevalence, correlates, and treatment. AB - OBJECTIVE: To present the 12-month prevalence of DSM-IV major depressive disorder (MDD) and severe MDD; to examine sociodemographic correlates and comorbidity; and to describe impairment and service use. METHOD: Data are from the National Comorbidity Survey-Adolescent Supplement (NCS-A), a nationally representative survey of 10,123 adolescents aged 13 to 18 years that assesses DSM-IV disorders using the Composite International Diagnostic Interview (CIDI) Version 3.0. One parent or surrogate of each participating adolescent was also asked to complete a self-administered questionnaire. RESULTS: Lifetime and 12-month prevalence of MDD were 11.0% and 7.5%, respectively. The corresponding rates of severe MDD were 3.0% and 2.3%. The prevalence of MDD increased significantly across adolescence, with markedly greater increases among females than among males. Most cases of MDD were associated with psychiatric comorbidity and severe role impairment, and a substantial minority reported suicidality. The prevalence of severe MDD was about one-fourth of that of all MDD cases; estimates of impairment and clinical correlates were of 2- to 5-fold greater magnitude for severe versus mild/moderate depression, with markedly higher rates for suicidal thoughts and behaviors. Treatment in any form was received by the majority of adolescents with 12-month DSM-IV MDD (60.4%), but only a minority received treatment that was disorder specific or from the mental health sector. CONCLUSION: Findings underscore the important public health significance of depression among US adolescents and the urgent need to improve screening and treatment access in this population. PMID- 25524789 TI - The space of common psychiatric disorders in adolescents: comorbidity structure and individual latent liabilities. AB - OBJECTIVE: To construct a virtual space of common adolescent psychiatric disorders, spanned by factors reflecting major psychopathological dimensions; and to locate psychiatric disorders in that space, examine whether the major psychopathological dimensions can be hierarchically organized, and determine the distribution of the latent scores of individuals in the space spanned by those dimensions. METHOD: Exploratory factor analyses of data from the National Comorbidity Survey Adolescent Supplement (NCS-A) using the psychiatric diagnoses as indicators were used to identify the latent major psychopathological dimensions. The loadings of the disorders on those dimensions were used as coordinates to calculate the distance among disorders. The distribution of individuals in the space was based on the latent scores on the factors reflecting the major psychopathological conditions. RESULTS: A model with 3 correlated factors provided an excellent fit (Comparative Fit Index [CFI] = 0.97, Tucker Lewis Index [TLI] = 0.95, the root mean squared error of approximation [RMSEA] = 0.008) for the structure of disorders and a 4-factor model could be hierarchically organized, ultimately yielding a general psychopathology factor. Distances between disorders ranged from 0.079 (between social phobia and generalized anxiety disorder [GAD]) and 1.173 (between specific phobia and conduct disorder [CD]). At the individual level, there were 546 distinct liabilities observed (22% of all 2,455 potential liabilities). CONCLUSION: A novel way of understanding psychiatric disorders in adolescents is as existing in a space with a limited number of dimensions with no disorder aligning along 1 single dimension. These dimensions are hierarchically organized, allowing analyses at different levels of organization. Furthermore, individuals with psychiatric disorders present with a broad range of liabilities, reflecting the diversity of their clinical presentations. PMID- 25524790 TI - The impact of case definition on attention-deficit/hyperactivity disorder prevalence estimates in community-based samples of school-aged children. AB - OBJECTIVE: To determine the impact of varying attention-deficit/hyperactivity disorder (ADHD) diagnostic criteria, including new DSM-5 criteria, on prevalence estimates. METHOD: Parent and teacher reports identified high- and low-screen children with ADHD from elementary schools in 2 states that produced a diverse overall sample. The parent interview stage included the Diagnostic Interview Schedule for Children-IV (DISC-IV), and up to 4 additional follow-up interviews. Weighted prevalence estimates, accounting for complex sampling, quantified the impact of varying ADHD criteria using baseline and the final follow-up interview data. RESULTS: At baseline 1,060 caregivers were interviewed; 656 had at least 1 follow-up interview. Teachers and parents reported 6 or more ADHD symptoms for 20.5% (95% CI = 18.1%-23.2%) and 29.8% (CI = 24.5%-35.6%) of children respectively, with criteria for impairment and onset by age 7 years (DSM-IV) reducing these proportions to 16.3% (CI = 14.7%-18.0%) and 17.5% (CI = 13.3% 22.8%); requiring at least 4 teacher-reported symptoms reduced the parent reported prevalence to 8.9% (CI = 7.4%-10.6%). Revising age of onset to 12 years per DSM-5 increased the 8.9% estimate to 11.3% (CI = 9.5%-13.3%), with a similar increase seen at follow-up: 8.2% with age 7 onset (CI = 5.9%-11.2%) versus 13.0% (CI = 7.6%-21.4%) with onset by age 12. Reducing the number of symptoms required for those aged 17 and older increased the overall estimate to 13.1% (CI = 7.7% 21.5%). CONCLUSION: These findings quantify the impact on prevalence estimates of varying case definition criteria for ADHD. Further research of impairment ratings and data from multiple informants is required to better inform clinicians conducting diagnostic assessments. DSM-5 changes in age of onset and number of symptoms required for older adolescents appear to increase prevalence estimates, although the full impact is uncertain due to the age of our sample. PMID- 25524793 TI - Dynamics of semiflexible recursive small-world polymer networks. AB - One of the fundamental issues in polymer physics is to reveal the relation between the structures of macromolecules and their various properties. In this report, we study the dynamical properties of a family of deterministically growing semiflexible treelike polymer networks, which are built in an iterative method. From the analysis of the corresponding dynamical matrix we derive the solution for its eigenvalues and their multiplicities, making use of a combined numerical and analytical approach. The eigenvalue spectra allow us to investigate the mechanical relaxation forms in depth for different values of the stiffness parameter. We observe that the dynamics of semiflexible networks is sensitive to the stiffness parameter. Our work paves a way to explore the structures of the highly symmetric polymers and provides a comprehensive understanding of the role of semiflexibility for the regular treelike networks which possess a small-world feature. PMID- 25524791 TI - Treatment of children with attention-deficit/hyperactivity disorder (ADHD) and irritability: results from the multimodal treatment study of children with ADHD (MTA). AB - OBJECTIVE: Clinically impairing irritability affects 25% to 45% of children with attention-deficit/hyperactivity disorder (ADHD); yet, we know little about what interventions are effective in treating children with ADHD and co-occurring irritability. We used data from the Multimodal Treatment Study of Children With ADHD (MTA) to address 3 aims: to establish whether irritability in children with ADHD can be distinguished from other symptoms of oppositional defiant disorder (ODD); to examine whether ADHD treatment is effective in treating irritability; and to examine how irritability influences ADHD treatment outcomes. METHOD: Secondary analyses of data from the MTA included multivariate analyses, and intent-to-treat random-effects regression models were used. RESULTS: Irritability was separable from other ODD symptoms. For treating irritability, systematic stimulant treatment was superior to behavioral management but not to routine community care; a combination of stimulants and behavioral treatment was superior to community care and to behavioral treatment alone, but not to medication alone. Irritability did not moderate the impact of treatment on parent- and teacher reported ADHD symptoms in any of the 4 treatment groups. CONCLUSION: Treatments targeting ADHD symptoms are helpful for improving irritability in children with ADHD. Moreover, irritability does not appear to influence the response to treatment of ADHD. CLINICAL TRIAL REGISTRATION INFORMATION: Multimodal Treatment Study of Children With Attention Deficit and Hyperactivity Disorder (MTA); http://www.clinicaltrials.gov; NCT00000388. PMID- 25524794 TI - Hormonal and metabolic responses to endurance exercise in children with Prader Willi syndrome and non-syndromic obesity. AB - OBJECTIVE: Excess adiposity affects endocrine and metabolic function at rest and during exercise. This study evaluated the endocrine and metabolic responses to exercise in syndromic (Prader-Willi syndrome) and non-syndromic pediatric obesity. MATERIALS/METHODS: Eleven PWS (10.9+/-1.6 y, 45.4+/-9.5% body fat), 12 lean (9.4+/-1.2 y, 17.5+/-4.6% body fat), and 12 obese (9.2+/-1.2 y, 39.9+/-6.8% body fat) children completed ten two-minute cycling exercise bouts, separated by one-minute rest. Blood samples were obtained at rest pre-exercise (PRE), immediately post-exercise (IP), and 15, 30 and 60 minutes into recovery. Samples were analyzed for hormones and metabolites. RESULTS: Growth hormone increased in response to exercise in lean and obese but not PWS (IP>PRE; IP: lean>obese). Epinephrine increased with exercise in lean (IP>PRE), while norepinephrine increased in lean and obese (IP>PRE) but not PWS; no differences were observed between lean and obese groups at IP. No other significant hormonal group interactions existed. Glucose, lactate, free fatty acid, glycerol and ketone responses were similar among groups. CONCLUSION: PWS children exhibited altered stress hormone responses to exercise. However, glucose-regulating hormones and metabolic responses to exercise appeared normal. PMID- 25524796 TI - POT1: a genetic link for familial glioma. PMID- 25524795 TI - Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials. AB - BACKGROUND: Cancer anorexia-cachexia syndrome is associated with increased morbidity and mortality. Anamorelin is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity. We assessed the effects of anamorelin on body composition, strength, quality of life, biochemical markers, and safety in patients with cancer anorexia-cachexia. METHODS: Data were pooled, a priori, from two completed phase 2, multicentre, placebo-controlled, double-blind trials in patients with advanced or incurable cancer and weight loss of 5% or more. Patients were stratified by weight loss severity (5-15%, >15%) and randomly allocated (1:1) with a computer-generated randomisation schedule to anamorelin hydrochloride 50 mg or placebo once-daily for 12 weeks. Primary outcome was lean body mass by dual-energy x-ray absorptiometry over the 12 week treatment period in eligible patients who had at least one dose of study drug and post-treatment efficacy assessment. We assessed safety in all patients who received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT00219817 and NCT00267358. FINDINGS: Between June 29, 2005, and Oct 26, 2006, we enrolled 44 patients in the anamorelin group and 38 patients in the placebo group. 74 patients were eligible for the efficacy analyses. Over 12 weeks, lean body mass increased in 38 patients in the anamorelin group by a least-squares mean of 1.89 kg (95% CI 0.84 to 2.95) compared with a decrease of a least-squares mean of -0.20 kg (-1.23 to 0.83) for 36 patients in the placebo group (difference 2.09 kg [0.94-3.25]; p=0.0006). 42 (95%) of 44 patients treated with anamorelin and 33 (87%) of 38 patients treated with placebo had adverse events. The most common grade 3-4 adverse events (treatment-related or not) in the anamorelin group were fatigue, asthenia, atrial fibrillation, and dyspnoea (two [5%] each); in the placebo group, such events were pneumonia (three [8%]) and anaemia, thrombocytopenia, abdominal pain, anxiety, and dyspnoea (two [5%] each). INTERPRETATION: Anamorelin treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome. These findings support further investigation in this setting. FUNDING: Helsinn Therapeutics (US), Helsinn Healthcare SA. PMID- 25524797 TI - Smoking and mosaic Y chromosome loss. PMID- 25524799 TI - Blinatumomab: a new era of treatment for adult ALL? PMID- 25524798 TI - The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. AB - BACKGROUND: Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced, oestrogen receptor-positive, HER2-negative breast cancer. METHODS: In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1, patients were enrolled on the basis of their oestrogen receptor positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1:1 via an interactive web-based randomisation system, stratified by disease site and disease-free interval, to receive continuous oral letrozole 2.5 mg daily or continuous oral letrozole 2.5 mg daily plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual; these are the results of the final analysis of progression-free survival. The study is registered with the ClinicalTrials.gov, number NCT00721409. FINDINGS: Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival (median follow-up 29.6 months [95% CI 27.9-36.0] for the palbociclib plus letrozole group and 27.9 months [25.5-31.1] for the letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 10.2 months (95% CI 5.7-12.6) for the letrozole group and 20.2 months (13.8-27.5) for the palbociclib plus letrozole group (HR 0.488, 95% CI 0.319-0.748; one-sided p=0.0004). In cohort 1 (n=66), median progression-free survival was 5.7 months (2.6-10.5) for the letrozole group and 26.1 months (11.2-not estimable) for the palbociclib plus letrozole group (HR 0.299, 0.156-0.572; one-sided p<0.0001); in cohort 2 (n=99), median progression-free survival was 11.1 months (7.1-16.4) for the letrozole group and 18.1 months (13.1-27.5) for the palbociclib plus letrozole group (HR 0.508, 0.303-0.853; one-sided p=0.0046). Grade 3-4 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib plus letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 (19%) versus none, and fatigue in four (4%) versus one (1%). Serious adverse events that occurred in more than one patient in the palbociclib plus letrozole group were pulmonary embolism (three [4%] patients), back pain (two [2%]), and diarrhoea (two [2%]). No cases of febrile neutropenia or neutropenia related infections were reported during the study. 11 (13%) patients in the palbociclib plus letrozole group and two (2%) in the letrozole group discontinued the study because of adverse events. INTERPRETATION: The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is currently underway. FUNDING: Pfizer. PMID- 25524801 TI - CDK4/6 inhibitors in luminal breast cancer. PMID- 25524800 TI - Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. AB - BACKGROUND: Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. METHODS: In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 MUg/day for the first 7 days and 28 MUg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. FINDINGS: Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment related by the investigators. INTERPRETATION: Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted. FUNDING: Amgen. PMID- 25524802 TI - 56th American Society of Hematology Annual Meeting. PMID- 25524803 TI - Skeletal muscle anabolism in patients with advanced cancer. PMID- 25524805 TI - Combined treatment of XIAP-targeting shRNA and celecoxib synergistically inhibits the tumor growth of non-small cell lung cancer cells in vitro and in vivo. AB - X-linked inhibitor of apoptosis protein (XIAP) has been shown to be highly expressed in lung cancer, but not in normal lung tissue, which makes it an attractive target for lung cancer treatment. Celecoxib (CXB), a cyclooxygenase-2 inhibitor, is in wide clinical use for the treatment and prevention of non-small cell lung cancer (NSCLC). Therefore, in our study, we combined short hairpin RNA (shRNA) targeted to XIAP (XIAP-shRNA) with CXB and tested the effects of this combination on lung cancer cells to identify more effective therapeutics against lung cancer. An XIAP-shRNA plasmid was constructed and transfected into the A549 NSCLC cell line. The cells were then treated with CXB and XIAP-shRNA alone or in combination for indicated time periods, and the treatments were assessed for their effects on cell proliferation, apoptosis, migration, invasion and receptor signaling using the MTT, TUNEL, wound healing and Matrigel invasion assays and western blotting, respectively. In addition, an NSCLC xenograft model was prepared to observe tumor growth. It was found that both CXB and XIAP-shRNA significantly inhibited cell proliferation, migration and invasion, and induced cell apoptosis in vitro, as well as suppressed tumor growth in vivo. Moreover, the combination of the agents significantly enhanced these effects compared to the single agent treatments. We also found that the combination treatment significantly suppressed constitutive phosphorylation of PI3K and AKT, which may contribute to the inhibition of tumor growth. These findings suggest that the combination of XIAP-shRNA and CXB is a promising drug candidate for the treatment of NSCLC. PMID- 25524806 TI - Factor structure of the Spanish version of the Patient Health Questionnaire-9 in Mexican women. AB - Structure of the Spanish version of the nine-item Patient Health Questionnaire (PHQ-9) has been inconclusive. We report the factor structure of the PHQ-9 in 55,555 women from the Mexican Teachers' Cohort (MTC). Factor structure of the PHQ 9 was assessed by exploratory and confirmatory factor analyses in two sub-samples (n = 27,778 and 27,777 respectively). A one-factor model of the PHQ-9 was the solution with the best fit to the data, exhibiting strong factor loadings (0.71 to 0.90) and high internal consistency (Cronbach's alpha = 0.89). A prevalence rate of moderate to high severity of depressive symptoms of 12.6% was identified. Results suggest that a global score is an appropriate measure of depressive symptoms and commend the use of the Spanish PHQ-9 as a measure of depression for research and clinical purposes. PMID- 25524807 TI - The role of IGFBP-5 in mediating the anti-proliferation effect of tetrandrine in human colon cancer cells. AB - Colon cancer is one of the most common malignancies, causes considerable morbidity and mortality. The current treatment for colon cancer is more modest than had been hoped. There is an urgent clinical need to explore new agents or adjuvants for colon cancer treatment. Natural products and their derivates act as one of the major source for anticancer agent. In the present study, we investigated the anti-proliferation and chemoprevention effects of tetrandrine (Tet) on colon cancer cells to uncover the possible molecular basis of this effect. We found that Tet can inhibit proliferation and induce apoptosis in LoVo cells. With dimethylhydrazine (DMH) and dextran sodium sulfate (DSS) induced colon cancer model, we found that Tet can prevent or inhibit DMH plus DSS induced aberrant crypt foci (ACF) and colon cancer formation, as well as suppress tumor growth in the xenograft colon cancer model. Tet can downregulate the expression of IGFBP-5 in LoVo cells. Exogenous expression of IGFBP-5 can attenuate the anti cancer activity of Tet, while IGFBP-5 knockdown potentiates this effect of Tet on LoVo cells. Tet can inhibit Wnt/beta-catenin signaling transduction, which can be partly reversed by exogenous expression of IGFBP-5, but is enhanced by IGFBP-5 knockdown. Our results demonstrated that the anticancer activity of Tet in colon cancer cells may be mediated partly by downregulating the expression of IGFBP-5, thus inactivating Wnt/beta-catenin signaling transduction. PMID- 25524808 TI - Fimbriae-mediated outer membrane vesicle production and invasion of Porphyromonas gingivalis. AB - Porphyromonas gingivalis is a keystone periopathogen that plays an essential role in the progress of periodontitis. Like other gram-negative bacteria, the ability of P. gingivalis to produce outer membrane vesicles is a strategy used to interact with, and survive within its biological niches. Here we compared the protein components associated with vesicles derived from a fimbriated strain (33277) and an afimbriated strain (W83) of P. gingivalis using proteomic analyses. Some well-known virulence factors were identified in vesicles from both strains, such as gingipains and hemagglutinin. In contrast, FimC, FimD, and FimE, minor components of long fimbriae were found exclusively in 33277 vesicles, while proteins with a tetratricopeptide repeat (TPR) domain were unique to W83 vesicles. We found that significantly more 33277 than W83 vesicles were internalized into human oral keratinocytes and gingival fibroblasts. Interestingly, FimA, a well-known adhesin responsible for the attachment and invasion of P. gingivalis into host cells, was not essential for the invasive capabilities of P. gingivalis vesicles. Rather minor components of long fimbriae were required for an efficient invasive activity of vesicles. The most striking finding was that P. gingivalis strains lacking or having a reduced FimA expression showed a significant reduction in vesiculation. These results suggest that production and pathogenicity of P. gingivalis vesicles may largely depend on expression of the fim locus, and that the integration of vesicle production and pathogenicity with fimbrial expression may allow P. gingivalis to confer upon itself certain functional advantages. PMID- 25524809 TI - TiO2 nanoparticles induce DNA double strand breaks and cell cycle arrest in human alveolar cells. AB - TiO2 nanoparticles (NPs) have the second highest global annual production (~3000 tons) among the metal-containing NPs. These NPs are used as photocatalysts for bacterial disinfection, and in various other consumer products including sunscreen, food packaging, therapeutics, biosensors, surface cleaning agents, and others. Humans are exposed to these NPs during synthesis (laboratory), manufacture (industry), and use (consumer products, devices, medicines, etc.), as well as through environmental exposures (disposal). Hence, there is great concern regarding the health effects caused by exposure to NPs and, in particular, to TiO2 NPs. In the present study, the genotoxic potential of TiO2 NPs in A549 cells was examined, focusing on their potential to induce ROS, different types of DNA damage, and cell cycle arrest. We show that TiO2 NPs can induce DNA damage and a corresponding increase in micronucleus frequency, as evident from the comet and cytokinesis-block micronucleus assays. We demonstrate that DNA damage may be attributed to increased oxidative stress and ROS generation. Furthermore, genomic and proteomic analyses showed increased expression of ATM, P53, and CdC-2 and decreased expression of ATR, H2AX, and Cyclin B1 in A549 cells, suggesting induction of DNA double strand breaks. The occurrence of double strand breaks was correlated with cell cycle arrest in G2/M phase. Overall, the results indicate the potential for genotoxicity following exposure to these TiO2 NPs, suggesting that use should be carefully monitored. PMID- 25524811 TI - Highly efficient and chemoselective zinc-catalyzed hydrosilylation of esters under mild conditions. AB - A mild and highly efficient catalytic hydrosilylation protocol for room temperature ester reductions has been developed using diethylzinc as the catalyst. The methodology is operationally simple, displays high functional group tolerance and provides for a facile access to a broad range of different alcohols in excellent yields. PMID- 25524810 TI - Characterizing the impact of lymph node metastases on the survival outcome for metastatic renal cell carcinoma patients treated with targeted therapies. AB - BACKGROUND: It is unknown whether lymph node metastases (LNM) and their localization negatively affect clinical outcome in metastatic renal cell carcinoma (mRCC) patients. OBJECTIVE: To evaluate the clinicopathological features, survival outcome, and treatment response in mRCC patients with LNM versus those without LNM after treatment with targeted therapies (TT). DESIGN, SETTING, AND PARTICIPANTS: Patients (n=2996) were first analyzed without consideration of lymph node (LN) localization or histologic subtype. Additional analyses (n=1536) were performed in subgroups of patients with supradiaphragmatic (SPD) LNM, subdiaphragmatic (SBD) LNM, and patients with LNM in both locations (SPD+/SBD+) without histologic considerations, and then separately in clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC) patients, respectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was overall survival (OS) and the secondary outcome was progression-free survival (PFS). RESULTS AND LIMITATIONS: All patients with LNM had worse PFS (p=0.001) and OS (p<0.001) compared to those without LNM. Compared to patients without LNM (PFS 8.8 mo; OS 25.1 mo), any SBD LNM involvement was associated with worse PFS (SBD, 6.8 mo; p=0.003; SPD+/SBD+, 5.5 mo; p<0.001) and OS (SBD, 16.2 mo; p<0.001; SPD+/SBD+, 11.5 mo; p<0.001). Both SBD and SPD+/SBD+ LNM were retained as independent prognostic factors in multivariate analyses (MVA) for PFS (p=0.006 and p=0.022, respectively) and OS (both p<0.001), while SPD LNM was not an independent risk factor. Likewise, in ccRCC, SBD LNM (19.8 mo) and SPD+/SBD+ LNM (12.85 mo) patients had the worst OS. SPD+/SBD+ LNM (p=0.006) and SBD LNM (p=0.028) were independent prognostic factors for OS in MVA, while SPD LNM was not significant (p=0.301). The study is limited by its retrospective design and the lack of pathologic evaluation of LNM in all cases. CONCLUSIONS: The metastatic spread of RCC to SBD lymph nodes is associated with poor prognosis in mRCC patients treated with TT. PATIENT SUMMARY: The presence of lymph node metastases below the diaphragm is associated with shorter survival outcome when metastatic renal cell carcinoma (mRCC) patients are treated with targeted therapies. Clinical trials should evaluate whether surgical removal of regional lymph nodes at the time of nephrectomy may improve outcomes in high-risk RCC patients. PMID- 25524812 TI - Application of hepatocellular carcinoma surveillance in a European setting. What can we learn from clinical practice? AB - BACKGROUND & AIMS: Surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is recommended in clinical guidelines. In real-life management, surveillance rates below 20% have been reported from the United States. We aimed to determine the use of HCC-surveillance in patients diagnosed with HCC in a European setting, and to identify the reasons for surveillance failures. METHODS: Age, gender, tumour characteristics, BCLC classification, Child-Pugh stage, pre existing liver disease, treatment, survival, frequency of HCC surveillance and reasons for surveillance failures were retrospectively determined in 616 patients diagnosed with HCC at Karolinska University Hospital 2005-2012. RESULTS: Hepatitis C, alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD) were the most common diagnoses. The proportion of HCC patients diagnosed through surveillance was 22%. In 35% of cases, surveillance was missed due to doctor's failure to order surveillance or to diagnose the underlying liver disease. Diagnosis of NAFLD or alcoholic liver disease increased the risk of not receiving surveillance more than two-fold. Undiagnosed liver disease was most common in NAFLD patients. Patients who underwent surveillance had smaller tumours, more frequently received curative treatment, and had better survival compared to those in whom surveillance was indicated but missed. CONCLUSION: In a European setting, only 22% of HCCs were diagnosed by surveillance, and in more than one-third of cases, surveillance was indicated but missed. NAFLD and alcoholic liver disease were associated with deficient surveillance. Survival was significantly better in patients who underwent surveillance compared with those in whom surveillance was missed although indicated. PMID- 25524813 TI - Parents with serious mental illness: differences in internalised and externalised mental illness stigma and gender stigma between mothers and fathers. AB - Research demonstrates that people living with serious mental illness (SMI) contend with widespread public stigma; however, little is known about the specific experiences of stigma that mothers, and in particular fathers, with SMI encounter as parents. This study aimed to explore and compare the experiences of stigma for mothers and fathers with SMI inferred not only by living with a mental illness but also potential compounding gender effects, and the associated impact of stigma on parenting. Telephone surveys were conducted with 93 participants with SMI who previously identified as parents in the Second Australian National Survey of Psychosis. Results indicated that mothers were more likely than fathers to perceive and internalise stigma associated with their mental illness. Conversely, fathers were more inclined to perceive stigma relating to their gender and to hold stigmatising attitudes towards others. Mental illness and gender stigma predicted poorer self-reported parenting experiences for both mothers and fathers. These findings may assist in tailoring interventions for mothers and fathers with SMI. PMID- 25524814 TI - Reply: To PMID 25524879. PMID- 25524815 TI - Olanzapine inhibits proliferation, migration and anchorage-independent growth in human glioblastoma cell lines and enhances temozolomide's antiproliferative effect. AB - The poor prognosis of patients with glioblastoma fuels the search for more effective therapeutic compounds. We previously hypothesised that the neuroleptic olanzapine may enhance antineoplastic effects of temozolomide the standard chemotherapeutic agent used in this disease. This study tested this hypothesis. The anti-proliferative effect of olanzapine was examined by MTT assays and cell count analysis. Soft-agar assays were performed to examine colony-forming ability. In addition, the inhibitory effect of olanzapine on the migratory capacity of U87MG and A172 cells was analyzed by Transwell((r)) assays. Moreover, staining for annexin V/propidium iodide or carboxyfluorescein succinimidyl ester was performed prior to flow cytometric analysis in order to better understand the subjacent cellular mechanism. Our initial hypothesis that olanzapine may enhance temozolomide's anti-tumor activity could be confirmed in U87MG and A172 glioblastoma cell lines. Moreover, treatment with olanzapine alone resulted in a marked anti-proliferative effect on U87MG, A172 and two glioma stem-like cells with IC50 values ranging from 25 to 79.9 uM. In U87MG cells, anchorage independent growth was dose-dependently inhibited. In A172 cells, migration was also shown to be inhibited in a dose-dependent manner. In addition, olanzapine was shown to exert a cell line-dependent pleomorphism with respect to the induction of apoptosis, necrosis and/or cytostasis. Our data show that the neuroleptic olanzapine enhances the anti-tumor activity of temozolomide against glioblastoma cell lines. Moreover, this is the first study to show that olanzapine provides on its own anti-cancer activity in glioblastoma and thus may have potential for repurposing. PMID- 25524816 TI - Phosphodiesterase type 5 inhibitor Tadalafil increases Rituximab treatment efficacy in a mouse brain lymphoma model. AB - The treatment efficacy of Rituximab on lymphoma as an immunotherapeutic approach is confirmed, but this treatment has limited penetration through the brain micro vessels. Such limitation significantly attenuates the efficacy of systemic administration of this antibody on brain lymphomas. We aimed to confirm that Tadalafil, a long-acting phosphodiesterase type 5 inhibitor, could increase microvascular permeability and Rituximab treatment efficacy in brain lymphomas. We established a mouse brain lymphoma model by planting human-derived lymphoma cell line Raji into brain parenchyma of mice using stereotaxic techniques. After 16 days, 7.0 T magnetic resonance imaging was performed to confirm the presence of the mass. The mice were observed under near-infrared fluorescence after intravenous injection of fluorescence-labeled Rituximab. Evans Blue was used as probe to detect the microvascular permeability of brain lymphomas after Tadalafil administration. Starting from 4 days after implantation, the mice were administered different treatments. Survival analysis of brain lymphoma-loaded mice was performed. Evans Blue detection showed that Tadalafil administration could increase brain vascular permeability in the tumor-bearing group compared with control mice. Rituximab treatment prolonged the survival time of mice compared with the untreated control group (mean 25.75 vs. 20.8 days, p < 0.05). Tadalafil with Rituximab treatment resulted in the longest survival time (29 days, p < 0.05). Rituximab may be a promising therapeutic agent for the treatment of brain lymphoma. Tadalafil can enhance Rituximab treatment efficacy by improving the microvascular permeability in mice brain lymphoma. PMID- 25524817 TI - Phase II trial of hypofractionated intensity-modulated radiation therapy combined with temozolomide and bevacizumab for patients with newly diagnosed glioblastoma. AB - Bevacizumab blocks the effects of VEGF and may allow for more aggressive radiotherapy schedules. We evaluated the efficacy and toxicity of hypofractionated intensity-modulated radiation therapy with concurrent and adjuvant temozolomide and bevacizumab in patients with newly diagnosed glioblastoma. Patients with newly diagnosed glioblastoma were treated with hypofractionated intensity modulated radiation therapy to the surgical cavity and residual tumor with a 1 cm margin (PTV1) to 60 Gy and to the T2 abnormality with a 1 cm margin (PTV2) to 30 Gy in 10 daily fractions over 2 weeks. Concurrent temozolomide (75 mg/m(2) daily) and bevacizumab (10 mg/kg) was administered followed by adjuvant temozolomide (200 mg/m(2)) on a standard 5/28 day cycle and bevacizumab (10 mg/kg) every 2 weeks for 6 months. Thirty newly diagnosed patients were treated on study. Median PTV1 volume was 131.1 cm(3) and the median PTV2 volume was 342.6 cm(3). Six-month progression-free survival (PFS) was 90 %, with median follow-up of 15.9 months. The median PFS was 14.3 months, with a median overall survival (OS) of 16.3 months. Grade 4 hematologic toxicity included neutropenia (10 %) and thrombocytopenia (17 %). Grades 3/4 non hematologic toxicity included fatigue (13 %), wound dehiscence (7 %) and stroke, pulmonary embolism and nausea each in 1 patient. Presumed radiation necrosis with clinical decline was seen in 50 % of patients, two with autopsy documentation. The study was closed early to accrual due to this finding. This study demonstrated 90 % 6-month PFS and OS comparable to historic data in patients receiving standard treatment. Bevacizumab did not prevent radiation necrosis associated with this hypofractionated radiation regimen and large PTV volumes may have contributed to high rates of presumed radiation necrosis. PMID- 25524818 TI - Biocompatibility and biodegradation of protein microparticle and film scaffolds made from kafirin (sorghum prolamin protein) subcutaneously implanted in rodent models. AB - Kafirin, the sorghum prolamin protein, like its maize homologue zein, can be made into microparticles and films and potentially used as a biomaterial. Zein has good bio- and cyto-compatibility. Kafirin could be advantageous as it is more hydrophobic, more crosslinked, more slowly digested by mammalian proteases than zein and is non-allergenic. The safety and biocompatibility of kafirin implants in two forms was determined in rodent models. One week post subcutaneous injection of kafirin microparticles (size 5-um diameter) in mice, chronic inflammation, abnormal red blood cells, and gross fibrin formation were observed. This chronic inflammatory response was possibly caused by the release of hydrolysis products such as glutamate during the degradation of the kafirin microparticles. In contrast, films made from kafirin microparticles (50-um thick, folded into 1 cm(3) ) implanted in rats showed no abnormal inflammatory reactions and were only partially degraded by day 28. The slower degradation of the kafirin films was probably due to their far smaller surface area when compared to kafirin microparticles. Thus, kafirin films appear to have potential as a biomaterial. This study also raises awareness that the form of prolamin based biomaterials, (kafirin and zein) should be considered when assessing the safety of such materials. PMID- 25524820 TI - Limiting immunopathology: Interaction between carotenoids and enzymatic antioxidant defences. AB - The release of reactive oxygen and nitrogen species (ROS and RNS) during the inflammatory response generates damages to host tissues, referred to as immunopathology, and is an important factor in ecological immunology. The integrated antioxidant system, comprising endogenous antioxidant enzymes (e.g. superoxide dismutase SOD, and catalase CAT) and dietary antioxidants (e.g. carotenoids), helps to cope with immune-mediated oxidative stress. Crustaceans store large amounts of dietary carotenoids for yet unclear reasons. While being immunostimulants and antioxidants, the interaction of these pigments with antioxidant enzymes remains unclear. Here, we tested the interaction between dietary supplementation with carotenoids and immune challenge on immune defences and the activity of the antioxidant enzymes SOD and CAT, in the amphipod crustacean Gammarus pulex. Dietary supplementation increased the concentrations of circulating carotenoids and haemocytes in the haemolymph, while the immune response induced the consumption of circulating carotenoids and a drop of haemocyte density. Interestingly, supplemented gammarids exhibited down-regulated SOD activity but high CAT activity compared to control ones. Our study reveals specific interactions of dietary carotenoids with endogenous antioxidant enzymes, and further underlines the potential importance of carotenoids in the evolution of immunity and/or of antioxidant mechanisms in crustaceans. PMID- 25524819 TI - Monte Carlo simulations of excitation and electron transfer in grana membranes. AB - Time-resolved fluorescence measurements on grana membranes with instrumental response function of 3 ps reveal faster excitation dynamics (120 ps) than those reported previously. A possible reason for the faster decay may be a relatively low amount of "extra" LHCII trimers per reaction center of Photosystem II. Monte Carlo modeling of excitation dynamics in C2S2M2 form of PSII-LHCII supercomplexes has been performed using a coarse grained model of this complex, constituting a large majority of proteins in grana membranes. The main factor responsible for the fast fluorescence decay reported in this work was the deep trap constituted by the primary charge separated state in the reaction center (950-1090 cm(-1)). This value is critical for a good fit, whereas typical hopping times between antenna polypeptides (from ~4.5 to ~10.5 ps) and reversible primary charge separation times (from ~4 to ~1.5 ps, respectively) are less critical. Consequently, respective mean migration times of excitation from anywhere in the PSII-LHCII supercomplexes to reaction center range from ~30 to ~80 ps. Thus 1/4 2/3 of the ~120-ps average excitation lifetime is necessary for the diffusion of excitation to reaction center, whereas the remaining time is due to the bottle neck effect of the trap. Removal of 27% of the Lhcb6 apoprotein pool by mutagenesis of DEG5 gene caused the acceleration of the excitation decay from ~120 to ~100 ps. This effect may be due to the detachment of LHCII-M trimers from PSII-LHCII supercomplexes, accompanied by deepening of the reaction center trap. PMID- 25524821 TI - Ipsilateral kidney sparing in treatment of pancreatic malignancies using volumetric-modulated arc therapy avoidance sectors. AB - Recent research has shown treating pancreatic cancer with volumetric-modulated arc therapy (VMAT) to be superior to either intensity-modulated radiation therapy or 3-dimensional conformal radiotherapy (3D-CRT), with respect to reducing normal tissue toxicity, monitor units, and treatment time. Furthermore, using avoidance sectors with RapidArc planning can further reduce normal tissue dose while maintaining target conformity. This study looks at the methods in reducing dose to the ipsilateral kidney, in pancreatic head cases, while observing dose received by other critical organs using avoidance sectors. Overall, 10 patients were retrospectively analyzed. Each patient had preoperative/unresectable pancreatic tumor and were selected based on the location of the right kidney being situated within the traditional 3D-CRT treatment field. The target planning target volume (286.97 +/- 85.17 cm(3)) was prescribed to 50.4 Gy using avoidance sectors of 30 degrees , 40 degrees , and 50 degrees and then compared with VMAT as well as 3D-CRT. Analysis of the data shows that the mean dose to the right kidney was reduced by 11.6%, 15.5%, and 21.9% for avoidance angles of 30 degrees , 40 degrees , and 50 degrees , respectively, over VMAT. The mean dose to the total kidney also decreased by 6.5%, 8.5%, and 11.0% for the same increasing angles. Spinal cord maximum dose, however, increased as a function of angle by 3.7%, 4.8%, and 6.1% compared with VMAT. Employing avoidance sector angles as a complement to VMAT planning can significantly reduce high dose to the ipsilateral kidney while not greatly overdosing other critical organs. PMID- 25524822 TI - Dietary resveratrol supplementation improves meat quality of finishing pigs through changing muscle fiber characteristics and antioxidative status. AB - This study investigated the effects of resveratrol (0, 300, 600 mg/kg) on meat quality, muscle fiber characteristics and antioxidative capacity of finishing pigs. The results showed that resveratrol not only increased m. longissimus dorsi (LM) pH(24 h), a*, crude protein and myoglobin content but also decreased L*(24 h), shear force, drip loss, glycolytic potential, as well as backfat depth, LM lactate dehydrogenase activity and mRNA level. Meanwhile, LM total antioxidative capacity, glutathione peroxidase activity and its mRNA level were increased by resveratrol, while malonaldehyde content was decreased. In addition, resveratrol increased myosin heavy chain (MyHC)IIa mRNA level and decreased MyHCIIb mRNA level, along with decreased myofiber cross-sectional area. In conclusion, these results suggest that resveratrol is an effective feed additive to improve pork quality, and the underlying mechanism may be partly due to the changed muscle fiber characteristics and antioxidative capacity induced by resveratrol. PMID- 25524823 TI - The efficacy of short and repeated high-pressure processing treatments on the reduction of non-O157:H7 Shiga-toxin producing Escherichia coli in ground beef patties. AB - High pressure processing (HPP) has previously been shown to be effective at reducing Escherichia coli O157:H7 in meat products. However, few studies have determined whether HPP may be effective at reducing non-O157:H7 Shiga toxin producing E. coli (STEC) in ground beef. This study investigated the efficacy of short and repeated HPP treatments to reduce non-O157:H7 STEC inoculated into ground beef. Irradiated ground beef patties (80:20, 90:10 [lean:fat]) were inoculated with pairs of E. coli serogroups O103, O111, O26, O145, O121, O45, O157:H7, and DH5alpha, vacuum-packaged and high-pressure processed (four, 60 s cycles, 400 MPa, 17 degrees C). Surviving E. coli populations were enumerated on Rainbow Agar O157 and Tryptic Soy Agar. HPP treatments produced >2.0 log10 CFU/g reductions of each E. coli serogroup, and reductions ranged from 2.35-3.88 and 2.26-4.31 log10 CFU/g in 80:20 and 90:10 samples, respectively. These results suggest that HPP could be an effective, post-processing intervention to reduce the risk of non-O157:H7 STEC contamination in ground beef. PMID- 25524824 TI - Catheter-directed interventions for acute pulmonary embolism. AB - Acute pulmonary embolism (PE) is a leading cause of cardiovascular mortality. Systemic anticoagulation is the standard of care, and treatment can be escalated in the setting of massive or submassive PE, given the high mortality risk. A secondary consideration for intervention is the prevention of late-onset chronic thromboembolic pulmonary hypertension. Treatment options include systemic thrombolysis, catheter-directed interventions, and surgical thromboembolectomy. Whereas systemic thrombolysis seems to be beneficial in the setting of massive PE, it appears to be associated with a higher rate of major complications compared with catheter-directed thrombolysis as shown in recent randomized trials for submassive PE. The hemodynamic and clinical outcomes continue to be defined to determine the indications for and benefits of intervention. The current review summarizes contemporary evidence on the role and outcomes of catheter-directed therapies in the treatment of acute massive and submassive PE. PMID- 25524825 TI - Bottom-up formation of endohedral mono-metallofullerenes is directed by charge transfer. AB - An understanding of chemical formation mechanisms is essential to achieve effective yields and targeted products. One of the most challenging endeavors is synthesis of molecular nanocarbon. Endohedral metallofullerenes are of particular interest because of their unique properties that offer promise in a variety of applications. Nevertheless, the mechanism of formation from metal-doped graphite has largely eluded experimental study, because harsh synthetic methods are required to obtain them. Here we report bottom-up formation of mono metallofullerenes under core synthesis conditions. Charge transfer is a principal factor that guides formation, discovered by study of metallofullerene formation with virtually all available elements of the periodic table. These results could enable production strategies that overcome long-standing problems that hinder current and future applications of metallofullerenes. PMID- 25524826 TI - Preliminary results of botulinum toxin A switch after first detrusor injection failure as a treatment of neurogenic detrusor overactivity. AB - AIMS: To assess the results of onabotulinum toxin detrusor injections when abobotulinum toxin detrusor injection failed. METHODS: Twenty-six patients, 15 women and 11 men, mean age 40.8 +/- 12.7 years old, in whom a first injection of 750 U abobotulinum toxin in 20 sites failed in treating neurogenic detrusor overactivity, received onabotulinum toxin 300 U detrusor injections in 30 sites. Neurologic conditions were spinal cord injury in 14 cases, multiple sclerosis in nine, myelomeningocele in two and myelitis in one. Mean time between the two injections was 5.6 +/- 1.4 months. Before and 6 weeks after each injection, patients carried out a 3-day bladder diary and had urodynamics. The success was defined as the combination of a clean intermittent self-catheterization number under 8 per 24 hr, urgency, urinary incontinence and detrusor overactivity relief. RESULTS: Out of 26 patients, the second injection was successful in 15 (57.7%). While the first injection of 750 U abobotulinum toxin had no impact at all, after 300 U onabotulinum toxin injection, the number of clean intermittent self-catheterization decreased significantly (11.3 +/- 2.1 vs. 6.4 +/- 1.9, P = 0.01), 17/26 (65.4%) patients achieved continence, urgency was relieved in 18/26 (69.2%) and detrusor overactivity in 15/26 (57.7%). CONCLUSIONS: In case of failure after a first detrusor injection of abobotulinum toxin, switching for onabotulinum toxin is efficient. Further investigations should be performed to assess whether the replacement of onabotulinum toxin by abobotulinum toxin provides the same results. PMID- 25524827 TI - Different protective and reparative effects of olmesartan in stroke according to time of administration and withdrawal. AB - Angiotensin type 1 receptor blockers (ARBs) have induced improved functional recovery and reduced infarct volume in experimental animal models of stroke. Clinical data have indicated a positive correlation between prestroke treatment with ARBs and reduced stroke severity and better outcomes; however, the mechanisms of these beneficial effects are not yet well understood. This study compares the protective and possible reparative effects of continuous oral treatment with olmesartan (OLM) with OLM pretreatment and withdrawal after permanent middle cerebral artery occlusion (pMCAO) in rats. Fifty-two Sprague Dawley rats were randomly assigned to five groups: MCAO(-/OLM) (OLM 10 mg/kg/day for 14 days after infarct), MCAO(OLM/OLM) (OLM 10 mg/kg/day for 7 days before and 14 days after infarct), MCAO(OLM/-) (OLM 10 mg/kg/day for 7 days before infarct), sham, and control. We analyzed functional recovery; lesion size; cell death; expression of the pro-oxidant enzyme NADPH oxidase 4 (NOX-4); isolectin-B4; and repair markers such as glial fibrillary acidic protein, vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF). All of the OLM-treated groups showed significantly better functional scores and reduced infarct sizes and cell death compared with the control group 14 days after pMCAO. Levels of NOX-4, VEGF, and BDNF were significantly lower in the brains of the MCAO(OLM/OLM) and sham groups compared with the other groups. OLM treatment improved functional recovery and reduced lesion size and cell death after cerebral ischemia. Only the continuous administration of OLM before and after stroke reduced oxidative stress levels, with better tissue preservation, without triggering brain repair marker activation. PMID- 25524829 TI - Peptide internalization enabled by folding: triple helical cell-penetrating peptides. AB - Cell-penetrating peptides (CPPs) are known as efficient transporters of molecular cargo across cellular membranes. Their properties make them ideal candidates for in vivo applications. However, challenges in the development of effective CPPs still exist: CPPs are often fast degraded by proteases and large concentration of CPPs required for cargo transporting can cause cytotoxicity. It was previously shown that restricting peptide flexibility can improve peptide stability against enzymatic degradation and limiting length of CPP peptide can lower cytotoxic effects. Here, we present peptides (30-mers) that efficiently penetrate cellular membranes by combining very short CPP sequences and collagen-like folding domains. The CPP domains are hexa-arginine (R6) or arginine/glycine (RRGRRG). Folding is achieved through multiple proline-hydroxyproline-glycine (POG [proline hydroxyproline-glycine])n repeats that form a collagen-like triple helical conformation. The folded peptides with CPP domains are efficiently internalized, show stability against enzymatic degradation in human serum and have minimal toxicity. Peptides lacking correct folding (random coil) or CPP domains are unable to cross cellular membranes. These features make triple helical cell penetrating peptides promising candidates for efficient transporters of molecular cargo across cellular membranes. PMID- 25524830 TI - Broadband and wide field-of-view plasmonic metasurface-enabled waveplates. AB - Quasi two-dimensional metasurfaces composed of subwavelength nanoresonator arrays can dramatically alter the properties of light in an ultra-thin planar geometry, enabling new optical functions such as anomalous reflection and refraction, polarization filtering, and wavefront modulation. However, previous metasurface based nanostructures suffer from low efficiency, narrow bandwidth and/or limited field-of-view due to their operation near the plasmonic resonance. Here we demonstrate plasmonic metasurface-based nanostructures for high-efficiency, angle insensitive polarization transformation over a broad octave-spanning bandwidth. The structures are realized by optimizing the anisotropic response of an array of strongly coupled nanorod resonators to tailor the interference of light at the subwavelength scale. Nanofabricated reflective half-wave and quarter-wave plates designed using this approach have measured polarization conversion ratios and reflection magnitudes greater than 92% over a broad wavelength range from 640 to 1290 nm and a wide field-of-view up to +/- 40 degrees . This work outlines a versatile strategy to create metasurface-based photonics with diverse optical functionalities. PMID- 25524828 TI - Neural processing of reward in adolescent rodents. AB - Immaturities in adolescent reward processing are thought to contribute to poor decision making and increased susceptibility to develop addictive and psychiatric disorders. Very little is known; however, about how the adolescent brain processes reward. The current mechanistic theories of reward processing are derived from adult models. Here we review recent research focused on understanding of how the adolescent brain responds to rewards and reward associated events. A critical aspect of this work is that age-related differences are evident in neuronal processing of reward-related events across multiple brain regions even when adolescent rats demonstrate behavior similar to adults. These include differences in reward processing between adolescent and adult rats in orbitofrontal cortex and dorsal striatum. Surprisingly, minimal age related differences are observed in ventral striatum, which has been a focal point of developmental studies. We go on to discuss the implications of these differences for behavioral traits affected in adolescence, such as impulsivity, risk-taking, and behavioral flexibility. Collectively, this work suggests that reward-evoked neural activity differs as a function of age and that regions such as the dorsal striatum that are not traditionally associated with affective processing in adults may be critical for reward processing and psychiatric vulnerability in adolescents. PMID- 25524831 TI - Acute kidney injury with hydroxyethyl starch 130/0.42 in severe sepsis. AB - BACKGROUND: We aimed to detail the effects of hydroxyethyl starch (HES) vs. Ringer's on kidney function including the interaction with mortality in post-hoc analyses as resuscitation with HES 130/0.42 increased mortality in the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) trial. METHODS: In all 798 randomised patients, we assessed the incidence and effect on mortality of acute kidney injury (AKI) in the HES vs. Ringer's acetate groups using the Kidney Disease: Improving Global Outcome criteria. We also assessed the intervention effect on time to and duration of renal replacement therapy (RRT). RESULTS: At baseline, the intervention groups were similar. The maximal AKI stage was higher in the HES vs. Ringer's group within the first 5 days after randomisation (P = 0.03), the average difference being 0.2 points (P < 0.01). An increase in AKI stage was associated with mortality (hazard ratio (HR) 1.35; 95% CI 1.22 to 1.49; P < 0.01). Significantly, more patients in the HES group received RRT within the first 5 days (P = 0.01), and the time to initiation of RRT was also shorter compared with the Ringer's group (HR 1.40; 95% CI 1.01-1.93; P = 0.04). The intervention effect of HES on mortality was reduced when adjusting for AKI stage as a time-dependent covariate (P = 0.15). CONCLUSION: In patients with severe sepsis, HES appeared to increase the rate of severe AKI and use of RRT within the first 5 days. The increased mortality observed with HES may have been partly mediated through acute kidney impairment. PMID- 25524832 TI - Hydrogen sulfide improves glucose metabolism and prevents hypertrophy in cardiomyocytes. AB - INTRODUCTION: Hydrogen sulfide (H2S) has been reported to inhibit myocardial hypertrophy in a cell model of cardiomyocyte hypertrophy. Our previous study also shows an H2S-induced increase in glucose metabolism in insulin-targeting cells. The present study aims to examine the hypothesis that H2S attenuates myocardial hypertrophy and promotes glucose utilization in cardiomyocytes. METHODS: The cell model of cardiomyocyte hypertrophy was induced by application of phenylephrine and cardiomyocyte hypertrophy was examined using leucine incorporation assay. Protein levels were measured using Western blot analysis. The activity of related enzymes was measured with enzyme-linked immunosorbent assay (ELISA). RESULTS: NaHS (an H2S donor) treatment increased the activity of cultured cardiomyocytes and reduced hypertrophy in cultured cardiomyocytes at concentrations ranging from 25 to 200 umol/L. NaHS treatment increased glucose uptake and the efficiency of glycolysis and the citric acid cycle. The key enzymes in these reactions, including lactate dehydrogenase and pyruvate kinase and succinate dehydrogenase, were activated by NaHS treatment (100 umol/L). Some intermediates of glycolysis and the citric acid cycle, including lactic acid, cyclohexylammonium, oxaloacetic acid, succinate, L-dimalate, sodium citrate, cis-aconitic acid, ketoglutarate and DL-isocitric acid trisodium also showed anti-hypertrophic effects in cardiomyocytes. CONCLUSIONS: H2S improves glucose utilization and inhibits cardiomyocyte hypertrophy. PMID- 25524833 TI - Inducible nitric oxide regulates intestinal glutamine assimilation during chronic intestinal inflammation. AB - To facilitate assimilation of glutamine, different Na-dependent glutamine absorptive pathways are present in the rabbit small intestine, specifically B0AT1 in villus and SN2 in crypt cell brush border membrane. Further, both are uniquely regulated in the chronically inflamed intestine. B0AT1 is inhibited secondary to reduced number of brush border membrane (BBM) co-transporters while SN2 is stimulated secondary to an increased affinity for glutamine. These unique changes are reversible by treatment with a broad spectrum immune modulator such as glucocorticoids. However, whether inducible nitric oxide (iNO), known to be elevated in the mucosa of the chronically inflamed intestine, may be responsible for these co-transporter alterations is not known. In the present study, treatment of chronically inflamed rabbits with L-NIL, a selective inhibitor of iNO synthase, reversed the inhibition of B0AT1 in villus and the stimulation of SN2 in crypt cells. At the level of the co-transporter in the brush border membrane, inhibition of iNO production reversed the inhibition of villus B0AT1 by restoring the co-transporter numbers while the stimulation of crypt SN2 was reversed back to normal by restoring its affinity for glutamine. Western blot analyses of BBM proteins also confirmed the kinetic studies. Thus, L-NIL treatment restores the uniquely altered Na-glutamine co-transporters in the enterocytes of chronically inflamed intestine. All these data indicate that iNO functions as an upstream immune modulator directly regulating glutamine assimilation during chronic intestinal inflammation. PMID- 25524835 TI - Bidirectional selection between two classes in complex social networks. AB - The bidirectional selection between two classes widely emerges in various social lives, such as commercial trading and mate choosing. Until now, the discussions on bidirectional selection in structured human society are quite limited. We demonstrated theoretically that the rate of successfully matching is affected greatly by individuals' neighborhoods in social networks, regardless of the type of networks. Furthermore, it is found that the high average degree of networks contributes to increasing rates of successful matches. The matching performance in different types of networks has been quantitatively investigated, revealing that the small-world networks reinforces the matching rate more than scale-free networks at given average degree. In addition, our analysis is consistent with the modeling result, which provides the theoretical understanding of underlying mechanisms of matching in complex networks. PMID- 25524834 TI - Virologic response and haematologic toxicity of boceprevir- and telaprevir containing regimens in actual clinical settings. AB - Effectiveness, safety and tolerability of boceprevir (BOC) and telaprevir (TPV) in actual clinical settings remain unknown. We determined rates of sustained virologic response (SVR) and haematologic adverse effects among persons treated with BOC- or TPV-containing regimens, compared with pegylated interferon/ribavirin (PEG/RBV). Using an established cohort of hepatitis C virus (HCV)-infected persons, Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES), we identified those treated with a BOC- or TPV-containing regimen and HCV genotype 1-infected controls treated with PEG/RBV. We excluded those with HIV coinfection and missing HCV RNA values to determine SVR. Primary endpoints were SVR (undetectable HCV RNA >=12 weeks after treatment completion) and haematologic toxicity (grade 3/4 anaemia, neutropenia and thrombocytopenia). We evaluated 2288 persons on BOC-, 409 on TPV-containing regimen and 6308 on PEG/RBV. Among these groups, respectively, 31%, 43% and 9% were treatment-experienced; 17%, 37% and 14% had baseline cirrhosis; 63%, 54% and 48% were genotype 1a. SVR rates among noncirrhotics were as follows: treatment naive: 65% (BOC), 67% (TPV) and 31% (PEG/RBV); treatment experienced: 57% (BOC), 54% (TPV) and 13% (PEG/RBV); (P value not significant for BOC vs TPV; P < 0.0001 for BOC or TPV vs PEG/RBV). Haematologic toxicities among BOC-, TPV- and PEG/RBV-treated groups were as follows: grade 3/4 anaemia 7%, 11% and 3%; grade 4 thrombocytopenia 2.2%, 5.4% and 1.7%; grade 4 neutropenia 8.2%, 5.6% and 3.4%. SVR rates are higher and closer to those reported in pivotal clinical trials among BOC- and TPV-treated persons compared with PEG/RBV-treated persons. Haematologic adverse events are frequent, but severe toxicity is uncommon. PMID- 25524836 TI - Epilepsy associated with Leukoaraiosis mainly affects temporal lobe: a casual or causal relationship? AB - OBJECTIVE: To compare anatomo-electro-clinical findings between patients with epilepsy associated with leukoaraiosis only (EAL) and patients with a well defined vascular lesion, i.e. post-stroke epilepsy (PSE). METHODS: Two hundred eighty-three subjects with epilepsy and cerebrovascular disease, consecutively seen in our epilepsy centres from January 2000 to March 2014, were retrospectively considered. Inclusion criteria were: history of one or more unprovoked seizures and MRI evidence of one or more vascular lesions. Exclusion criteria were: inadequate neuroimaging data, coexistence of nonvascular lesions, and psychogenic seizures. Subjects were divided in two groups: PSE and EAL, based onclinical and MRI findings. Epileptogenic focus was identified according to ictal semiology and EEG findings. In PSE group, coherence between the vascular lesion(s) and epileptogenic focus was scored as likely or unlikely. RESULTS: One hundred seventeen subjects were included: 58 had PSE, 59 EAL. Coherence was identified as likely in 38 (95%) and unlikely in 2 (5%). At univariate analysis, abnormal EEG and frontal localization were associated with a lower EAL probability [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.15-0.87, p=0.02 and OR 0.12, 95% CI 0.04-0.37, p<0.001, respectively], while temporal localization was associated with a higher EAL probability (OR 4.0, 95% CI 1.8 9.0, p<0.001). Multivariate confirmed these associations. CONCLUSIONS: While in PSE epileptogenic focus is coherent with the vascular lesions, in EAL temporal lobe epilepsy predominates. In EAL, causal relationship between vascular lesions and epilepsy is not straightforward, and the role of adjunctive factors needs to be elucidated. PMID- 25524837 TI - How long is long enough? The utility of prolonged inpatient video EEG monitoring. AB - Video EEG monitoring (VEM) is a valuable tool for the diagnosis of epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES). We sought to determine the benefits of prolonged length of stay (LOS). We retrospectively reviewed the records of patients admitted for VEM. We analyzed LOS for ES and PNES patients to determine if there was reduced utility, as evidenced by a significantly higher inconclusive outcome, beyond a certain duration. We calculated receiver operating characteristic (ROC) curves to determine optimal cut off points for LOS based on futility. Patients admitted with presumed PNES were significantly more likely to have an inconclusive admission (31/150, 20.7%) versus all others (58/446, 13%, p=0.033). There was no significant difference in the likelihood of having an inconclusive admission if monitoring was continued for any duration in patients with ES (area under curve, AUC, 0.46). For patients with PNES, a LOS >=5 days was associated with an increased risk of the stay being inconclusive (28% versus 12.5%, p=0.026). Although the ROC curve suggested a cut off of 5.5 days, it did not predict outcomes well (AUC 0.52, sensitivity 0.55, specificity 0.5). Based on our data, prolonging VEM appears useful for the proper classification and localization of ES. PMID- 25524839 TI - Detection of global DNA hypomethylation of peripheral blood lymphocytes in patients with infantile spasms. AB - The pathogenesis of infantile spasms remains unclear. DNA methylation may play a pivotal role in the development of some types of neurological diseases, such as epilepsy. In this study, we aimed to investigate the relationship between global DNA methylation of peripheral blood leukocytes and cryptogenic infantile spasms. DNA from peripheral blood leukocytes was extracted from 20 patients with cryptogenic infantile spasms and 20 gender and age matched healthy controls. Global DNA methylation percentage of peripheral blood leukocytes was measured using a global DNA methylation quantification kit. Global DNA methylation levels of peripheral blood lymphocytes in patients with cryptogenic infantile spasms (23.4 +/- 20.0%) were significantly lower than those in healthy controls (46.8 +/ 8.4%). Furthermore, we did not find any association between the levels of DNA methylation and effectiveness of Adrenocorticotropic hormone treatment. Our study demonstrates that global DNA hypomethylation of peripheral blood lymphocytes is correlated with infantile spasms. This finding provides information for better understanding of the pathogenesis of infantile spasms. PMID- 25524838 TI - Chronic stress shifts the GABA reversal potential in the hippocampus and increases seizure susceptibility. AB - The most commonly reported precipitating factor for seizures is stress. However, the underlying mechanisms whereby stress triggers seizures are not yet fully understood. Here we demonstrate a potential mechanism underlying changes in neuronal excitability in the hippocampus following chronic stress, involving a shift in the reversal potential for GABA (EGABA) associated with a dephosphorylation of the potassium chloride co-transporter, KCC2. Mice subjected to chronic restraint stress (30min/day for 14 consecutive days) exhibit an increase in serum corticosterone levels which is associated with increased susceptibility to seizures induced with kainic acid (20mg/kg). Following chronic stress, but not acute stress, we observe a dephosphorylation of KCC2 residue S940, which regulates KCC2 cell surface expression and function, in the hippocampus. To determine the impact of alterations in KCC2 expression following chronic stress, we performed gramicidin perforated patch recordings to measure changes in EGABA and neuronal excitability of principal hippocampal neurons. We observe a depolarizing shift in EGABA in hippocampal CA1 pyramidal neurons after chronic stress. In addition, there is an increase in the intrinsic excitability of CA1 pyramidal neurons, evident by a shift in the input-output curve which could be reversed with the NKCC1 inhibitor, bumetanide. These data uncover a potential mechanism involving chronic stress-induced plasticity in chloride homeostasis which may contribute to stress-induced seizure susceptibility. PMID- 25524840 TI - Epilepsy phenotype associated with a chromosome 2q24.3 deletion involving SCN1A: Migrating partial seizures of infancy or atypical Dravet syndrome? AB - The deletion of a sodium channel gene cluster located on chromosome 2q24.3 is associated with variable epilepsy phenotypes, including Dravet syndrome and migrating partial seizures of infancy. Although SCN1A is considered as the major contributor to the epilepsy phenotype, the role of other sodium channel genes that map within this cluster has not been delineated. We presented five new cases with a chromosome 2q24.3 deletion involving SCN1A and investigated their epilepsy phenotype in relation to the extent of the deletion. Three cases with deletion of the whole sodium channel gene cluster (SCN3A, SCN2A, SCN1A, SCN9A, and SCN7A) exhibited a complex epilepsy phenotype that was atypical for Dravet syndrome and suggestive of migrating partial seizures of infancy: early seizure onset (before 2 months of age), severe developmental delay from seizure onset, multifocal interictal spikes, polymorphous focal seizures, and acquired microcephaly. Two cases with partial deletion of SCN1A and SCN9A and whole SCN1A deletion had an epilepsy phenotype of Dravet syndrome. A literature review of cases with chromosome 2q24.3 deletion revealed that, in most Dravet syndrome cases, it does not involve SCN2A and SCN3A, whereas a complex epilepsy phenotype that is shared with migrating partial seizures of infancy was associated with cases of deletion of the whole sodium channel gene cluster. PMID- 25524841 TI - Quantitative assessment of corpus callosum morphology in periventricular nodular heterotopia. AB - We investigated systematic differences in corpus callosum morphology in periventricular nodular heterotopia (PVNH). Differences in corpus callosum mid sagittal area and subregional area changes were measured using an automated software-based method. Heterotopic gray matter deposits were automatically labeled and compared with corpus callosum changes. The spatial pattern of corpus callosum changes were interpreted in the context of the characteristic anterior posterior development of the corpus callosum in healthy individuals. Individuals with periventricular nodular heterotopia were imaged at the Melbourne Brain Center or as part of the multi-site Epilepsy Phenome Genome project. Whole brain T1 weighted MRI was acquired in cases (n=48) and controls (n=663). The corpus callosum was segmented on the mid-sagittal plane using the software "yuki". Heterotopic gray matter and intracranial brain volume was measured using Freesurfer. Differences in corpus callosum area and subregional areas were assessed, as well as the relationship between corpus callosum area and heterotopic GM volume. The anterior-posterior distribution of corpus callosum changes and heterotopic GM nodules were quantified using a novel metric and compared with each other. Corpus callosum area was reduced by 14% in PVNH (p=1.59*10(-9)). The magnitude of the effect was least in the genu (7% reduction) and greatest in the isthmus and splenium (26% reduction). Individuals with higher heterotopic GM volume had a smaller corpus callosum. Heterotopic GM volume was highest in posterior brain regions, however there was no linear relationship between the anterior-posterior position of corpus callosum changes and PVNH nodules. Reduced corpus callosum area is strongly associated with PVNH, and is probably associated with abnormal brain development in this neurological disorder. The primarily posterior corpus callosum changes may inform our understanding of the etiology of PVNH. Our results suggest that interhemispheric pathways are affected in PVNH. PMID- 25524842 TI - Non-expert use of quantitative EEG displays for seizure identification in the adult neuro-intensive care unit. AB - Video-EEG monitoring is the ultimate way to diagnose non-convulsive status epilepticus (NCSE) in intensive care units (ICU). Usually EEG recordings are evaluated once a day by an electrophysiologist, which may lead to delay in diagnosis. Digital EEG trend analysis methods like amplitude integrated EEG (aEEG) and density spectral array (DSA) have been developed to facilitate recognition of seizures. In this study, we aimed to investigate the diagnostic utility of these methods by non-expert physicians and ICU nurses for NCSE identification in an adult neurological ICU. Ten patients with NCSE and ten control patients without seizures were included in the study. The raw EEG recordings of all subjects were converted to both aEEG and DSA and displayed simultaneously without conventional EEG. After training for seizure recognition with both methods, two physicians and two nurses analyzed the visual displays individually, and marked seizure timings. Their results were compared with those of a study epileptologist. Participants analyzed 615h of EEG data with 700 seizures. Overall, 63% of the seizures were recognized by all, 15.6% by three, 11.6% by two, 8.3% by one rater and only 1.5% were missed by all of them (sensitivity was 88-99%, and specificity was 89-95% when the ratings were assessed as 1-h epochs). False positive rates were 1 per 2h in the study and 1 per 6h in the control groups. Interrater agreement was high (kappa=0.79-0.81). Bilateral independent seizures and ictal recordings with lower amplitude and shorter duration were more likely to be missed. There was no difference in performance between the rating of physicians and nurses. Our study demonstrates that bedside nurses, ICU fellows and residents can achieve acceptable level of accuracy for seizure identification using the digital EEG trend analysis methods following brief training. This may help earlier notification of the electrophysiologist who is not always available in ICUs. PMID- 25524843 TI - A prospective longitudinal study on visuo-cognitive development in Dravet syndrome: Is there a "dorsal stream vulnerability"? AB - A group of five DS patients whose first development was already reported were longitudinally followed up till the scholar age. Beside the general and epileptic clinical evolution, visual and cognitive functions were investigated in order to define their trajectory and possibly provide information about mechanisms of cognitive decline as well as to improve prognosis and tertiary prevention. Neuropsychological assessment was performed with a test battery investigating the development of visual function that progressively integrates into extrastriate components and higher cognitive skills (global form and motion coherence, stereopsis, crowding cards, ABCDEFV battery, general intelligence and specific cognitive tests). Main results showed a fall in visuo-motor items including global motion coherence and specific cognitive skills, presenting a continuity of the visual function deterioration extended from basic abilities to visuo-motor dorsal pathway skills. Moreover, a case whose previous visual and cognitive functions had been in the normal range began showing a visual deterioration with increasing age, followed by the cognitive decline; that prevents from excluding in early ages a poor development in presence of a normal visual function. A dorsal stream vulnerability seems thus shown in this sample of DS patients, like in other genetic syndromes (Williams, Prader Willi. fragile-X), providing new information about mechanisms underlying cognitive decline and suggesting a possible strategy to improve their neuropsychological outcome. Larger cohorts may confirm whether these findings are part of a specific pattern of DS neuropsychological phenotype. PMID- 25524844 TI - Dexmedetomidine anesthesia enhances spike generation during intra-operative electrocorticography: A promising adjunct for epilepsy surgery. AB - BACKGROUND: Anesthetic-induced suppression of cortical electrical activity is a major concern during epilepsy surgery. Dexmedetomidine (Dex) has been recently evaluated in a few small series for its effect on the electrocorticographic spikes intra-operatively. METHODS: In this prospective study, electrocorticogram (ECoG) was monitored during dexmedetomidine infusion in 34 patients (M:F=23:11, age=29.2 +/- 10.9 years; duration of epilepsy=15.3 +/- 8.9 years) undergoing anterior temporal lobe resection with amygdalo-hippocampectomy for drug-resistant mesial temporal lobe epilepsy (Right: 18, Left: 16). Anesthesia was induced with thiopental/propofol and maintained with oxygen-N2O-isoflurane. ECoG was recorded for 5 min after the end tidal MAC of N2O and isoflurane were decreased to zero; anesthesia was maintained with O2:Air=50:50, vecuronium and fentanyl. ECoG was recorded using a 4-contact strip electrode for: (a) 5 min prior to dexmedetomidine (PreDEX), (b) 5 min during dexmedetomidine infusion (DEX; 1 MUg/kg) and (c) 5 min after stopping dexmedetomidine (PostDEX). RESULTS: The ECoG spikes were manually counted in all the channels. The mean spike rate in the 2 channels with maximum spikes (MAX CH A and MAX CH B) was normalized to a 3-min duration. RM-ANOVA and post hoc comparison of three phases were used to compare the spike rates. The mean spike rate during Dex phase was higher compared to preDEX (MAX CH B: p=0.007 and MAX CH A: p=0.079) and PostDEX (MAX CH B: p=0.17, MAX CH A: p=0.79) phases. The spike rate increased in 67.6% patients, while 11.8% patients showed <= 25% reduction and 20.6% patients showed >25% reduction in spike frequency. CONCLUSION: Dexmedetomidine is useful during intra-operative ECoG recording in epilepsy surgery as it enhances or does not alter spike rate in most of the cases, without any major adverse effects. PMID- 25524845 TI - Memory, executive function and language function are similarly impaired in both temporal and extra temporal refractory epilepsy-A prospective study. AB - INTRODUCTION: Cognitive impairment has long been recognized as a co-morbidity or sequel to refractory epilepsy. This study was conducted to evaluate the degree and selectivity of involvement of memory, language and executive functions performance among patients with temporal (TLE) versus extratemporal epilepsy (ETLE). METHODS: We prospectively enrolled adolescent and adult patients with medically refractory focal epilepsy, who had undergone pre-surgical evaluation. Language, memory and executive function assessment was done using Western Aphasia Battery, PGI memory scale and battery of four executive function tests (trail making test A & B, digit symbol test, Stroop Task and verbal fluency test), respectively. RESULTS: Among102 patients enrolled (TLE-59, ETLE-43), mean age of patients 23.0 4+/- 8.3 years, 83 (82%) had impairment of more than one cognitive domain and 21 (21%) had all three domains involved. Severely impaired memory scores were found in 8.6% patients with MTLE-HS, 8% of the rest of the patients with TLE and 7% patients with ETLE. The differences in the mean scores were also not found statistically significant (p=0.669). Naming impairment was the most common language abnormality, although all aphasia subscores were similar for the ETLE and TLE groups. Executive function impairment was the most common cognitive domain affected. Overall performance on executive function tests was found impaired in almost all patients of both groups without any significant inter group difference, except on Trail-A test, which revealed better results in patients with mTLE-HS as compared to all other sub-groups. CONCLUSION: Our study shows that impairment of memory, language and executive function is common among patients with drug refractory epilepsy. The most prevalent impairment is in executive function. There is no significant difference in the degree, prevalence or selectivity of impairment in either of the three domains, between the TLE versus ETLE groups. PMID- 25524846 TI - Efficacy and tolerability of the ketogenic diet in Dravet syndrome - Comparison with various standard antiepileptic drug regimen. AB - There is strong evidence for the use of the ketogenic diet (KD) in Dravet syndrome (DS). The purpose of this study was to evaluate both effectiveness and tolerability in comparison with various antiepileptic drugs (AEDs). METHODS: 32 children (19 males) with genetically confirmed DS treated at our center since 1999 were analyzed retrospectively. Data collected from patients' files included type of mutation, age at treatment initiation and treatment lag, overall seizure frequency and frequency of different seizure types, especially prolonged seizures and status epilepticus (SE). Efficacy and safety of the KD were evaluated. In addition, the effect on seizure count was compared with that of various AED regimen and the vagus nerve stimulation (VNS). RESULTS: Overall response to the KD was 70% at 3 months and 60% at 12 months. No SE occurred while patients were on the diet, and the frequencies of prolonged generalized and myoclonic seizures were reduced. No severe side effects requiring withdrawal of the KD were observed. Although the effect of the KD was independent of age at initiation, it had to be withdrawn due to noncompliance more frequently in solid fed older children compared with infants treated with the liquid ketogenic formula. The KD was not significantly inferior to the current gold standard AED triple combination of Stiripentol+Valproate+Clobazam (89%), Bromides (78%), Valproate alone (48%), Topiramate (35%) and VNS (37%) and significantly more effective than Levetiracetam (30%; p=0.037, Pearson's Chi-square). SIGNIFICANCE: These data suggest that the KD ranks among currently used AEDs as an effective treatment for seizures in DS. According to our results (good effect on SE and prolonged seizures, good tolerability, less compliance problems due to formula treatment) the KD should be considered as an early treatment option in infants with DS. PMID- 25524847 TI - Sleep-potentiated epileptiform activity in early thalamic injuries: Study in a large series (60 cases). AB - OBJECTIVE: The study aims at a better definition of continuous spike-waves during sleep (CSWS) with an early thalamic lesion, focusing on various grades of sleep potentiated epileptiform activity (SPEA). Their possible relationship with different clinical features was studied to try to define prognostic factors of the epileptic disorder, especially relating to behavior/cognitive outcome, in order to improve prevention and treatment strategies. METHODS: Sixty patients with early thalamic injury were followed since the first registration of SPEA with serial neurological, long term EEG monitoring and neuropsychological examinations, as well as neuroimaging and a detailed clinical history. They were classified in three different groups according to the sleep spike-waves (SW) quantification: electrical status epilepticus during sleep (ESES), more than 85% of slow sleep; overactivation between 50% and 85% and simple activation between 10 and 50%). Results were then examined also with a statistical analysis. RESULTS: In our series of CSWS occurring in early brain injured children with unilateral thalamic involvement there is a common neuropathologic origin but with various grades of SPEA severity. Statistical analysis showed that patients evolving toward ESES presented more commonly the involvement of the mediodorsal part of thalamus nuclei and a bilateral cortico-subcortical brain injury, epilepsy was more severe with a delayed onset; moreover, in the acute stage .ESES patients presented the worst behavior/cognitive performances. As to cognitive and behavior outcome, longer SPEA duration as well as bilateral brain injury and cognitive/behavior impairment in acute phase appear linked to a poor outcome; some particular neuropathology (ischemic stroke and haemorrhagic infarction) as well as hydrocephalus shunting are associated with behavior disorders. CONCLUSIONS: Discrete features seem to support different underlying mechanisms in ESES patients in comparison with less severe SPEA; they represent negative prognostic factors. Longer SPEA duration as well as bilateral brain injury and cognitive/behavior impairment in acute phase seem predictive of a worse cognitive/behavior outcome. PMID- 25524848 TI - IDH1/2 mutation is associated with seizure as an initial symptom in low-grade glioma: A report of 311 Chinese adult glioma patients. AB - BACKGROUND: Seizure commonly presents as an initial symptom and plays an important role in the clinical presentation and quality of life of patients with low-grade glioma (LGG). To date, the mechanism and genetic alterations underlying tumor-related seizures in LGG remain to be fully elucidated. Both isocitrate dehydrogenase 1/2 (IDH1/2) mutation and seizure frequently occur in patients with LGG. We set out to investigate the potential relationship between IDH1/2 mutation and presentation of seizure preoperatively, and observe whether or not IDH1/2 mutation influences seizure control postoperatively. METHODS: A total of 311 adult patients with LGG were enrolled in our study with both clinical data and IDH1/2 mutation data available. IDH1/2 mutation was detected directly by pyro sequencing. The chi-squared test was performed to determine whether the IDH1/2 mutation has any relevance to seizure onset and to evaluate the potential impact that IDH1/2 mutation may exert on seizure control postoperatively. RESULTS: Seizure presented as an initial symptom in 71.4% (222/311) of patients with LGG, among which 189 patients were detected to bear IDH1/2 mutation in their tumors (P=0.035, chi-squared test). However, IDH1/2 mutation does not seem to contribute to the seizure control postoperatively (P=0.350 and 0.577 for the 6- and 12-month follow-up, respectively, chi-squared test). CONCLUSIONS: IDH1/2 mutation occurs more frequently in LGG patients with seizure as an initial symptom, suggesting a potential relationship between this genetic phenotype and clinical seizure presentation. IDH1/2 mutation shows no prognostic value for postoperative seizure control. PMID- 25524849 TI - An antagonist of calcium permeable AMPA receptors, IEM1460: Anticonvulsant action in immature rats? AB - AMPA receptors lacking GluA2 subunit are widely distributed in developing brain. IEM1460 as a specific antagonist of these receptors might be a potential age specific anticonvulsant. Possible anticonvulsant action was assessed in two models of epileptic seizures: pentylenetetrazol (PTZ) - induced convulsions and cortical afterdischarges elicited in 12-, 18- and 25-day-old rats. IEM1460 was administered intraperitoneally in doses of 3, 10 and 20mg/kg. Pretreatment with IEM1460 at the dose of 20mg/kg resulted in delayed onset of PTZ-induced minimal clonic seizures in all age groups. PTZ-induced generalized tonic-clonic seizures were suppressed in 18- and 25-day-old rats by 10 and 20mg/kg doses of IEM1460. Duration of cortical afterdischarges progressively increased with repeated stimulations in control 12-day-old rats. The IEM1460 dose of 10mg/kg fully blocked this prolongation and the 20-mg/kg dose partly suppressed it. Administration of IEM1460 had moderate proconvulsant effect on 18- and 25-day-old animals - afterdischarges were prolonged with repeated stimulations. The duration of cortical epileptic afterdischarges in adult (80-day-old) animals was not affected by IEM1460. Effects of IEM1460 are dependent on the model of seizures used, their ictogenic structures and developmental changes in subunit composition of AMPA receptors. PMID- 25524851 TI - Electric stimulation of the tuberomamillary nucleus affects epileptic activity and sleep-wake cycle in a genetic absence epilepsy model. AB - Deep brain stimulation (DBS) is a promising approach for epilepsy treatment, but the optimal targets and parameters of stimulation are yet to be investigated. Tuberomamillary nucleus (TMN) is involved in EEG desynchronization-one of the proposed mechanisms for DBS action. We studied whether TMN stimulation could interfere with epileptic spike-wave discharges (SWDs) in WAG/Rij rats with inherited absence epilepsy and whether such stimulation would affect sleep-wake cycle. EEG and video registration were used to determine SWD occurrence and stages of sleep and wake during three-hours recording sessions. Stimulation (100Hz) was applied in two modes: closed-loop (with previously determined interruption threshold intensity) or open-loop mode (with 50% or 70% threshold intensity). Closed-loop stimulation successfully interrupted SWDs but elevated their number by 148 +/- 54% compared to baseline. It was accompanied by increase in number of episodes but not total duration of both active and passive wakefulness. Open-loop stimulation with amplitude 50% threshold did not change measured parameters, though 70% threshold stimulation reduced SWDs number by 40 +/- 9%, significantly raised the amount of active wakefulness and decreased the amount of both slow-wave and rapid eye movement sleep. These results suggest that the TMN is unfavorable as a target for DBS as its stimulation may cause alterations in sleep-wake cycle. A careful choosing of parameters and control of sleep-wake activity is necessary when applying DBS in epilepsy. PMID- 25524850 TI - Optimization of pilocarpine-mediated seizure induction in immunodeficient NodScid mice. AB - Temporal lobe epilepsy (TLE) has been modeled in mice using pilocarpine induction, with variable results depending on specific strains. To allow efficient xenotransplantation for the purpose of optimizing potential cell-based therapy of human TLE, we have determined the optimal dosing strategy to produce spontaneous recurring seizures in immunodeficient NodScid mice. Multiple 100mg/kg injections of pilocarpine have been shown to be more effective than single 300 400mg/kg injections for inducing spontaneous seizures in NodScid mice. Under our optimal conditions, 88.1 +/- 2.9% of the mice experienced status epilepticus (SE) with a survival rate of 61.8 +/- 5.9%. Surviving SE mice displayed spontaneous recurrent seizures at a frequency of 2.8 +/- 0.9 seizures/day for a duration of 41.1 +/- 3.5s. The widely used method of a single injection of pilocarpine was significantly less efficient in inducing seizures in NodScid mice. Therefore, we have determined that a multiple injection "ramping up" of 100mg/kg of pilocarpine is optimal for inducing TLE-like spontaneous seizures in NodScid mice. Using this method, mice with SE efficiently developed SRS and expressed mossy fiber sprouting, a signature histopathological feature of TLE. PMID- 25524852 TI - The role of the corpus callosum in seizure spread: MRI lesion mapping in oligodendrogliomas. AB - BACKGROUND: Some patients with oligodendrogliomas have generalized tonic-clonic seizures (GTCS) while others have only partial seizures (PS). We investigated the relationship between tumour localization and seizure generalization using quantitative lesion mapping on magnetic resonance images. METHODS: Twenty one patients with histologically proven oligodendrogliomas and GTCS (n=11) or PS (n=10) were studied. Data were acquired on a 3 Tesla MRI System. We performed lesion mapping techniques to compare the spatial distribution of oligodendrogliomas between patient groups, and quantitatively determined the extent to which lesions intersected each probabilistic regions-of-interest, including the cerebral lobes, thalamus, striatum, and genu of the corpus callosum. RESULTS: In patients experiencing GTCS, the greatest lesion load was observed in mesial frontal regions, including cortex connected to the genu. In contrast, the greatest lesion load in patients experiencing PS was observed more caudo-laterally in orbitofrontal and temporal lobes, but typically sparing cortex connected to the genu. The number of lesion intersections with genu region of interest was significantly greater in patients experiencing GTCS relative to patients with PS (p=0.03). There were no significant differences between patient groups with respect to lesion intersection with the individual cerebral lobes, thalamus and striatum, or with respect to overall oligodendroglioma size. CONCLUSION: Our data suggest that the genu of the corpus callosum may be a major pathway for seizure generalization in patients with oligodendrogliomas. PMID- 25524853 TI - Changes in the behavior and oscillatory activity in cortical and subcortical brain structures induced by repeated l-glutamate injections to the medial septal area in guinea pigs. AB - Although the presence and importance of oscillations in cortical structures is well-documented, little is known about this rhythmic activity in subcortical areas. In waking guinea pigs, during their inattentive rest, local field potentials (LFPs) were recorded simultaneously in eight brain structures. In the cortical areas (prefrontal and entorhinal fields, hippocampus, dentate gyrus) and subcortical ones (medial and lateral septal nuclei, central nucleus of amygdala, and supramammillary nucleus), different types of oscillations were observed: delta (0.5-4Hz), theta (4-8), alpha (10-12), gamma (40-80), and high-frequency, presumable ripples (100-200Hz). In all structures, low-frequency oscillations (delta and theta) were more powerful than high-frequency ones. Structural communications in different bands of rhythmic activity were expressed differently. On the whole they were the more intensive, the stronger were the oscillations, however, this was not the absolute rule. A long-term (about a month) daily injection of l-glutamate into the medial septal region induced significant changes in theta, gamma, and high-frequency oscillations in most regions examined. The correlations of some structures also changed; they significantly decreased between the entorhinal cortex and hippocampus in the theta band and between the medial septum and central amygdala in the gamma band. During permanent septal glutamate infusion, distinct signs of epileptogenesis were revealed (epileptiform activity, seizure behavior of animals, and formation of aberrant fibers in the hippocampus). Thus, we believe that the glutamatergic system of medial septum can participate in the development of epilepsy. The earliest sign of pathology in electrical activity was alterations in high frequency oscillations in the dentate gyrus and medial septum, but the strongest changes were in theta and especially gamma rhythms in many structures. The data obtained help to advance our understanding of the basic mechanisms of brain functioning and its disturbances in seizure pathology. PMID- 25524854 TI - Clinical characteristics of seizures associated with viral gastroenteritis in children. AB - OBJECTIVE: We analyzed the clinical features of seizures during gastroenteritis in children by comparing the norovirus and rotavirus pathogen, and the impact of fever, if present, during the seizure episodes. METHODS: Retrospective analysis was performed on 293 consecutive pediatric patients admitted with viral gastroenteritis to Osaka General Hospital between November 2007 and May 2009. Eighteen patients developed seizures, 12 of whom were positive for norovirus and six for rotavirus, as revealed by antigen detection. Of these 18 seizure patients, eight presented without fever (the aFS group) and 10 presented with febrile episodes (FS group). RESULTS: Seizure patients in the rotavirus group (83%) were more likely to be febrile than those in the norovirus group (58%). Compared with the aFS group, 90% of patients in the FS group presented seizures at an early stage of gastroenteritis. The frequency of clustered seizures in the FS group was considerably higher than that of febrile seizures in general and was also as high as that of "convulsions with mild gastroenteritis (CwG)". All seizure patients, whether febrile or afebrile, presented with generalized tonic clonic seizures (GTCS), complex partial seizures (CPS), or both. Diazepam (DZP) was less effective and carbamazepine (CBZ) was completely effective for the cessation of seizures in the FS group, similar to the drug response observed in CwG. CONCLUSIONS: The causative pathogen (norovirus or rotavirus) affected the frequency of febrile episodes during gastroenteritis, but fever had little effect on the clinical features of seizures. However, seizures occurred earlier during gastroenteritis in the FS group. On the whole, the clinical features of febrile seizures during viral gastroenteritis may closely resemble those of "convulsions with mild gastroenteritis" (CwG) than those of febrile seizures in general with respect to the frequency of clustered seizures and the antiepileptic drug responses and may have a pathogenic mechanism distinct from those of febrile seizures due to other causes. PMID- 25524855 TI - Neurodevelopmental outcome of infantile spasms: A systematic review and meta analysis. AB - BACKGROUND: The aims of this systematic review and meta-analysis were to assess (i) estimates of good neurodevelopmental outcome in infantile spasms (IS), (ii) if neurodevelopmental outcome has changed since the publication of the first guideline on medical treatment of IS in 2004 and (iii) effect of lead time to treatment (LTTT). METHODS: The Medline, Embase, Cochrane, PsycINFO, Web of Science and Scopus databases, and reference lists of retrieved articles were searched. Studies inclusion criteria were: (i) >5 patients with IS, (ii) mean/median follow-up of >6 months, (iii) neurodevelopmental outcome, and (iv) randomized and observational studies. The data extracted included proportion of good neurodevelopmental outcome, year of publication, cryptogenic or symptomatic IS and LTTT. RESULTS: Of the 1436 citations screened, 55 articles were included in final analysis, with a total of 2967 patients. The pooled estimate for good neurodevelopmental outcome was 0.236 (95% CI: 0.193-0.286). There was no difference between the proportions of good neurodevelopmental outcome for the 21 studies published after 2004 [0.264 (95% CI: 0.197-0.344)] compared to the 34 studies published before 2004 [0.220 (95% CI: 0.168-0.283)] (Q value=0.862, p=0.353). The pooled estimate of good neurodevelopmental outcome for cryptogenic IS [0.543 (95% CI: 0.458-0.625)] was higher than symptomatic IS [0.125 (95% CI: 0.09-0.171)] (Q value=69.724, p<0.001). Risk ratio of LTTT <4weeks relative to >4weeks for good neurodevelopmental outcome of 8 studies was 1.519 (95% CI: 1.064 2.169). CONCLUSION: Neurodevelopmental outcome was overall poor in patients with IS and has not changed since the publication of first guideline on IS. Although cryptogenic IS has better prognosis than symptomatic IS, the outcome for cryptogenic IS remained poor. There was heterogeneity in neurodevelopmental outcome ascertainment methods, highlighting the need for a more standardized and comprehensive assessment of cognitive, behavioural, emotional and functional outcomes. PMID- 25524856 TI - Focal seizures without awareness. AB - OBJECTIVE: To characterize patients with seizures that only occur without their awareness (SWA). METHODS: Twenty-four patients with SWA were retrospectively identified by chart review and subsequently underwent video-EEG monitoring (VEM). Eleven patients met selection criteria for SWA and were never aware of any seizures. A case-matched control group of patients who were always aware (SA) was used for comparison. Statistical analysis included Pearson's Chi-square, Fisher's Exact, and Mann-Whitney. RESULTS: Patients with SWA were older at seizure diagnosis than those with SA (p=0.04), were less often referred for evaluation of seizures or epilepsy (p=0.04), and were referred faster for VEM, despite SWA were significantly less likely to include motor manifestations (p=0.0004). SWA more often had temporal lobe onsets (p<0.0001) with left lateralization on ictal EEG (p<0.0001). At final follow up, patients with SWA had tried fewer antiseizure drugs (p=0.03), but reported seizure freedom as often as patients with SA (p=0.4). SIGNIFICANCE: We suggest that patients with SWA have a unique epilepsy syndrome. Patients with absent recall were older, referred later, had fewer motor signs, and dominant hemisphere limbic localization than patients with SA, but fewer antiseizure drugs are used in treatment. Patients with SWA can be detected from the clinical history, though serial VEM is needed to validate effective management. PMID- 25524857 TI - Quantitative peri-ictal electrocorticography and long-term seizure outcomes in temporal lobe epilepsy. AB - We analyzed peri-ictal electrocorticography below 70 Hz by a semiautomatic quantitative method. Thirty-four patients with medically intractable temporal lobe epilepsy underwent chronic electrocorticography using subdural electrodes. The resection extent of cortices with maximum amplitude activities were compared between seizure outcome groups. In detected activity significantly related to seizure outcome, we analyzed waveforms with automated waveform amplitude analysis. Mann-Whitney U tests were used. Mean follow-up duration was 49.7 +/- 18.2 months. The resection extents of maximum amplitude activities in theta bands during the period between -10 and -5s from the ictal onset were significantly different between seizure outcome groups (adjusted p=0.01, the Benjamini-Hochberg correction). Delta, alpha and beta bands were related to seizure outcome only without multiple comparison corrections (unadjusted p=0.02, 0.03 and 0.04). Waveform peak amplitudes greater than 200 MUV tended to be more common in the seizure free group than in the non-seizure-free group (unadjusted p=0.06). Waveform peak amplitudes greater than 350 MUV were significantly more common in the cortical dysplasia type I group than in the hippocampal sclerosis group (unadjusted p=0.03). The resection of theta band activities during the preictal period was most important for good seizure outcome in temporal lobe epilepsy. PMID- 25524859 TI - Seizure semiology identifies patients with bilateral temporal lobe epilepsy. AB - OBJECTIVE: Laterality in temporal lobe epilepsy is usually defined by EEG and imaging results. We investigated whether the analysis of seizure semiology including lateralizing seizure phenomena identifies bilateral independent temporal lobe seizure onset. METHODS: We investigated the seizure semiology in 17 patients in whom invasive EEG-video-monitoring documented bilateral temporal seizure onset. The results were compared to 20 left and 20 right consecutive temporal lobe epilepsy (TLE) patients who were seizure free after anterior temporal lobe resection. The seizure semiology was analyzed using the semiological seizure classification with particular emphasis on the sequence of seizure phenomena over time and lateralizing seizure phenomena. Statistical analysis included chi-square test or Fisher's exact test. RESULTS: Bitemporal lobe epilepsy patients had more frequently different seizure semiology (100% vs. 40%; p<0.001) and significantly more often lateralizing seizure phenomena pointing to bilateral seizure onset compared to patients with unilateral TLE (67% vs. 11%; p<0.001). The sensitivity of identical vs. different seizure semiology for the identification of bilateral TLE was high (100%) with a specificity of 60%. Lateralizing seizure phenomena had a low sensitivity (59%) but a high specificity (89%). The combination of lateralizing seizure phenomena and different seizure semiology showed a high specificity (94%) but a low sensitivity (59%). SIGNIFICANCE: The analysis of seizure semiology including lateralizing seizure phenomena adds important clinical information to identify patients with bilateral TLE. PMID- 25524858 TI - Spatiotemporal differences in the c-fos pathway between C57BL/6J and DBA/2J mice following flurothyl-induced seizures: A dissociation of hippocampal Fos from seizure activity. AB - Significant differences in seizure characteristics between inbred mouse strains highlight the importance of genetic predisposition to epilepsy. Here, we examined the genetic differences between the seizure-resistant C57BL/6J (B6) mouse strain and the seizure-susceptible DBA/2J (D2) strain in the phospho-Erk and Fos pathways to examine seizure-induced neuronal activity to uncover potential mechanistic correlates to these disparate seizure responsivities. Expression of neural activity markers was examined following 1, 5, or 8 seizures, or after 8 seizures, a 28 day rest period, and a final flurothyl rechallenge. Two brain regions, the hippocampus and ventromedial nucleus of the hypothalamus (VMH), had significantly different Fos expression profiles following seizures. Fos expression was highly robust in B6 hippocampus following one seizure and remained elevated following multiple seizures. Conversely, there was an absence of Fos (and phospho-Erk) expression in D2 hippocampus following one generalized seizure that increased with multiple seizures. This lack of Fos expression occurred despite intracranial electroencephalographic recordings indicating that the D2 hippocampus propagated ictal discharge during the first flurothyl seizure suggesting a dissociation of seizure discharge from Fos and phospho-Erk expression. Global transcriptional analysis confirmed a dysregulation of the c fos pathway in D2 mice following 1 seizure. Moreover, global analysis of RNA expression differences between B6 and D2 hippocampus revealed a unique pattern of transcripts that were co-regulated with Fos in D2 hippocampus following 1 seizure. These expression differences could, in part, account for D2's seizure susceptibility phenotype. Following 8 seizures, a 28 day rest period, and a final flurothyl rechallenge, ~85% of B6 mice develop a more complex seizure phenotype consisting of a clonic-forebrain seizure that uninterruptedly progresses into a brainstem seizure. This seizure phenotype in B6 mice is highly correlated with bilateral Fos expression in the VMH and was not observed in D2 mice, which always express clonic-forebrain seizures upon flurothyl retest. Overall, these results illustrate specific differences in protein and RNA expression in different inbred strains following seizures that precede the reorganizational events that affect seizure susceptibility and changes in seizure semiology over time. PMID- 25524860 TI - Focal seizures versus epileptic spasms in children with focal cortical dysplasia and epilepsy onset in the first year. AB - PURPOSE: Focal cortical dysplasia (FCD) has been recognized as one of the most frequent causes of drug resistant epilepsy, especially in children. In infancy, onset of FCD-related epilepsy is substantially characterized by epileptic spasms (ES) or focal seizures. Which elements pertaining to the FCD are responsible for the onset of one type of seizure over the other is still unclear. Purpose of our study was to compare the characteristics of FCDs in terms of lateralization and site in patients with epileptic spasms versus patients with focal seizures. METHODS: We retrospectively reviewed data from 41 patients with FCD related epilepsy with onset during the first 14 months of life. Seizure semeiology and drug resistance were analyzed, as were age at onset and FCD site and lateralization. RESULTS: Twenty-one children had focal seizures, 11 had ES and nine had focal seizures followed by ES. Mean age at onset was respectively 8.2, 5.1 and 1.8 months. Drug resistance was present in respectively 38.5%, 34.6% and 26.9% of children. Among patients with only ES, 90.9% had an exclusively frontal FCD localization, versus 42.9% of patients with focal seizures and 11.1% of patients with focal seizures followed by ES. FCD lateralization was right sided respectively in 47.6%, 81.8% and 66.7% of patients. CONCLUSIONS: Frontal lobe localization of FCDs was closely associated with ES (p=0.001). Moreover we also found that patients with focal seizures followed by ES had a significantly earlier age at onset compared to patients with focal seizures only (p<0.001). The association between ES and right-sided FCD lateralization, even if numerically suggestive, did not reach statistical significance (p=0.16). There was no significant association between seizure type and drug resistance (p=0.08). PMID- 25524861 TI - Cognitive rehabilitation in epilepsy: An evidence-based review. AB - AIM OF THE STUDY: To review the modalities of cognitive rehabilitation (CR), outcome endpoints, and the levels of evidence of efficacy of different interventions. METHODS: A systematic research in Pubmed, Psychinfo, and SCOPUS was performed assessing the articles written in the entire period covered by these databases till December 2013. Articles in English, Spanish or French were evaluated. A manual research evaluated the references of all of the articles. The experimental studies were classified according to the level of evidence of efficacy, using a standardized Italian method (SPREAD, 2007), adopting the criteria reported by Cicerone et al. (2000, 2011). RESULTS: Eighteen papers were classified into two reviews, four papers dealing with the principles and efficacy of CR in epilepsy, a methodological paper, a single-case report, a multiple-case report, and nine experimental papers. Most studies involved patients with temporal lobe epilepsy. Different types of CR were used to treat patients with epilepsy. A holistic rehabilitation approach was more useful than selective interventions to treat memory and attention disturbances. CONCLUSIONS: CR may be a useful tool to treat cognitive impairment in patients with epilepsy. However, the modalities of treatment and outcome endpoints are important concerns of clinical care and research. Controlled studies are needed to determine the efficacy of rehabilitation in well-defined groups of patients with epilepsy. PMID- 25524862 TI - Modeling the World Health Organization Disability Assessment Schedule II using non-parametric item response models. AB - The World Health Organization Disability Assessment Schedule II (WHO-DAS II) is a multidimensional instrument developed for measuring disability. It comprises six domains (getting around, self-care, getting along with others, life activities and participation in society). The main purpose of this paper is the evaluation of the psychometric properties for each domain of the WHO-DAS II with parametric and non-parametric Item Response Theory (IRT) models. A secondary objective is to assess whether the WHO-DAS II items within each domain form a hierarchy of invariantly ordered severity indicators of disability. A sample of 352 patients with a schizophrenia spectrum disorder is used in this study. The 36 items WHO DAS II was administered during the consultation. Partial Credit and Mokken scale models are used to study the psychometric properties of the questionnaire. The psychometric properties of the WHO-DAS II scale are satisfactory for all the domains. However, we identify a few items that do not discriminate satisfactorily between different levels of disability and cannot be invariantly ordered in the scale. In conclusion the WHO-DAS II can be used to assess overall disability in patients with schizophrenia, but some domains are too general to assess functionality in these patients because they contain items that are not applicable to this pathology. PMID- 25524863 TI - Impact of probiotic Lactobacillus plantarum TENSIA in different dairy products on anthropometric and blood biochemical indices of healthy adults. AB - The blood pressure-lowering effect of dairy products holds the potential to decrease the risk of cardiovascular disease (CVD). An open question is if the successful expression of functional properties of the probiotic strain depends on host biomarkers and/or food matrix properties. The probiotic Lactobacillus plantarum strain TENSIA(r) (DSM 21380) is a novel microorganism with antimicrobial and antihypertensive functional properties. The aim of this study was to characterise the functional properties of the probiotic L. plantarum TENSIA and compare its effects on host anthropometric, clinical, and blood biomarkers when consumed with cheese or yoghurt. This study involved two double blinded randomised placebo-controlled exploratory trials (ISRCTN15061552 and ISRCTN79645828) of healthy adults over a three-week period. The three-week consumption of probiotic L. plantarum TENSIA in a daily dose of 1*1010 cfu in probiotic cheese or a daily dose of 6*109 cfu in yoghurt with different content of carbohydrates, proteins, and lipids did not significantly change the body mass index (BMI), plasma glucose and lipid levels, or inflammatory markers in the blood. Reduced lowered systolic and diastolic blood pressure values were detected, regardless of food matrix or baseline values for blood pressure and BMI. In conclusion, our study showed that three-week consumption of the probiotic L. plantarum TENSIA either in cheese or yoghurt lowered diastolic and systolic blood pressure regardless of food matrix and baseline values of blood pressure and BMI, confirming the impact of the functional properties of the probiotic strain in decreasing CVD risk. PMID- 25524864 TI - LncTar: a tool for predicting the RNA targets of long noncoding RNAs. AB - Long noncoding RNAs (lncRNAs) represent a big category of noncoding RNA molecules, and increasing studies have shown that they play important roles in various critical biological processes. They show a diversity of functions through diverse mechanisms, among which regulating RNA molecules is one of the most popular ones. Given the big number of lncRNAs, it becomes urgent and important to predict the RNA targets of lncRNAs in a large scale for the comprehensive understanding of lncRNA functions and action mechanisms. Although several methods have been developed to predict RNA-RNA interactions, none of them can be used to predict the RNA targets of lncRNAs in a large scale. Here we presented a tool, LncTar, which shows the ability to efficiently predict the RNA targets of lncRNAs in a large scale. To test the accuracy of LncTar, we applied it to 10 experimentally supported lncRNA-mRNA interactions. As a result, LncTar successfully predicted 8 (80%) of the 10 lncRNA-mRNA pairs, suggesting that LncTar has a reliable accuracy. Finally, we believe that LncTar could be an efficient tool for the fast identification of the RNA targets of lncRNAs. LncTar is freely available at http://www.cuilab.cn/lnctar. PMID- 25524865 TI - The financial burden of medical spending: estimates and implications for evaluating the impact of ACA reforms. AB - This article uses the 2013 Current Population Survey Annual Social and Economic Supplement to estimate the financial burden of medical out-of-pocket costs by comparing medical out-of-pocket expenditures to income. This measure is important for evaluating the magnitude of burden, better understanding who bears it, and establishing a baseline to assess the impact of the Patient Protection and Affordable Care Act. We examine the distribution of burden and the incidence of high burden across all families and by individuals' health insurance status and demographic and socioeconomic characteristics. We look more closely at one group vulnerable to having high burden: those younger than age 65 with incomes between 138% and 200% of the federal poverty line. We find that 18.5% of these individuals have incomes below the threshold of expansion Medicaid eligibility after accounting for non-over-the-counter medical expenses and examine the characteristics associated with being classified below this threshold. PMID- 25524866 TI - Health insurers' financial performance and quality improvement expenditures in the Affordable Care Act's second year. AB - The Affordable Care Act requires health insurers to rebate any amounts less than 80%-85% of their premiums that they fail to spend on medical claims or quality improvement. This study uses the new comprehensive reporting under this law to examine changes in insurers' financial performance and differences in their quality improvement expenditures. In the ACA's second year (2012), insurers' median medical loss ratios continued to increase and their median administrative cost ratios dropped, producing moderate operating margins in the group markets but a small operating loss in the individual market, at the median. For-profit insurers showed larger changes, in general, than did nonprofits. For quality improvement, insurers reported spending a significantly greater amount per member in their government plans than they did on their self-insured members, with spending on commercial insurance being in between these two extremes. The magnitude and source of these differences varied by corporate ownership. PMID- 25524869 TI - Power and promise of narrative for advancing physical therapist education and practice. AB - This perspective article provides a justification for and an overview of the use of narrative as a pedagogical tool for educators to help physical therapist students, residents, and clinicians develop skills of reflection and reflexivity in clinical practice. The use of narratives is a pedagogical approach that provides a reflective and interpretive framework for analyzing and making sense of texts, stories, and other experiences within learning environments. This article describes reflection as a well-established method to support critical analysis of clinical experiences; to assist in uncovering different perspectives of patients, families, and health care professionals involved in patient care; and to broaden the epistemological basis (ie, sources of knowledge) for clinical practice. The article begins by examining how phronetic (ie, practical and contextual) knowledge and ethical knowledge are used in physical therapy to contribute to evidence-based practice. Narrative is explored as a source of phronetic and ethical knowledge that is complementary but irreducible to traditional objective and empirical knowledge-the type of clinical knowledge that forms the basis of scientific training. The central premise is that writing narratives is a cognitive skill that should be learned and practiced to develop critical reflection for expert practice. The article weaves theory with practical application and strategies to foster narrative in education and practice. The final section of the article describes the authors' experiences with examples of integrating the tools of narrative into an educational program, into physical therapist residency programs, and into a clinical practice. PMID- 25524867 TI - HLA-DRB1-associated rheumatoid arthritis risk at multiple levels in African Americans: hierarchical classification systems, amino acid positions, and residues. AB - OBJECTIVE: To evaluate HLA-DRB1 genetic risk of rheumatoid arthritis (RA) in African Americans by 3 validated allele classification systems and by amino acid position and residue, and to compare genetic risk between African American and European ancestries. METHODS: Four-digit HLA-DRB1 genotyping was performed on 561 autoantibody-positive African American cases and 776 African American controls. Association analysis was performed on Tezenas du Montcel (TdM), de Vries (DV), and Mattey classification system alleles and separately by amino acid position and individual residues. RESULTS: TdM S2 and S3P alleles were associated with RA (odds ratio [95% confidence interval] 2.8 [2.0-3.9] and 2.1 [1.7-2.7], respectively). The DV (P = 3.2 * 10(-12)) and Mattey (P = 6.5 * 10(-13)) system alleles were both protective in African Americans. Amino acid position 11 (permutation P < 0.00001) accounted for nearly all variability explained by HLA DRB1, although conditional analysis demonstrated that position 57 was also significant (0.01 <= permutation P <= 0.05). The valine and aspartic acid residues at position 11 conferred the highest risk of RA in African Americans. CONCLUSION: With some exceptions, the genetic risk conferred by HLA-DRB1 in African Americans is similar to that in individuals of European ancestry at multiple levels: classification system (e.g., TdM), amino acid position (e.g., 11), and residue (Val11). Unlike that reported for individuals of European ancestry, amino acid position 57 was associated with RA in African Americans, but positions 71 and 74 were not. Asp11 (odds ratio 1 in European ancestry) corresponds to the 4-digit classical allele *09:01, which is also a risk allele for RA in Koreans. PMID- 25524871 TI - Predicting 6-minute walking distance in recipients of lung transplantation: longitudinal study of 108 patients. AB - BACKGROUND: Exercise capacity, muscle function, and physical activity levels remain reduced in recipients of lung transplantation. Factors associated with this deficiency in functional exercise capacity have not been studied longitudinally. OBJECTIVE: The study aims were to analyze the longitudinal change in 6-minute walking distance and to identify factors contributing to this change. DESIGN: This was a longitudinal historical cohort study. METHODS: Data from patients who received a lung transplantation between March 2003 and March 2013 were analyzed for the change in 6-minute walking distance and contributing factors at screening, discharge, and 6 and 12 months after transplantation. Linear mixed-model and logistic regression analyses were performed with data on characteristics of patients, diagnosis, waiting list time, length of hospital stay, rejection, lung function, and peripheral muscle strength. RESULTS: Data from 108 recipients were included. Factors predicting 6-minute walking distance were measurement moment, diagnosis, sex, quadriceps muscle and grip strength, forced expiratory volume in 1 second (percentage of predicted), and length of hospital stay. After transplantation, 6-minute walking distance increased considerably. This initial increase was not continued between 6 and 12 months. At 12 months after lung transplantation, 58.3% of recipients did not reach the cutoff point of 82% of the predicted 6-minute walking distance. Logistic regression demonstrated that discharge values for forced expiratory volume in 1 second and quadriceps or grip strength were predictive for reaching this criterion. LIMITATIONS: Study limitations included lack of knowledge on the course of disease during the waiting list period, type and frequency of physical therapy after transplantation, and number of missing data points. CONCLUSIONS: Peripheral muscle strength predicted 6-minute walking distance; this finding suggests that quadriceps strength training should be included in physical training to increase functional exercise capacity. Attention should be paid to further increasing 6-minute walking distance between 6 and 12 months after transplantation. PMID- 25524870 TI - Investigating the validity of the environmental framework underlying the original and modified Dynamic Gait Index. AB - BACKGROUND: The modified Dynamic Gait Index (mDGI), developed from a person environment model of mobility disability, measures mobility function relative to specific environmental demands. The framework for interpreting mDGI scores relative to specific environmental dimensions has not been investigated. OBJECTIVE: The aim of this study was to examine the person-environmental model underlying the development and interpretation of mDGI scores. DESIGN: This was a cross-sectional, descriptive study. METHODS: There were 794 participants in the study, including 140 controls. Out of the total study population, 239 had sustained a stroke, 140 had vestibular dysfunction, 100 had sustained a traumatic brain injury, 91 had gait abnormality, and 84 had Parkinson disease. Exploratory factor analysis was used to investigate whether mDGI scores supported the 4 environmental dimensions. RESULTS: Factor analysis showed that, with some exceptions, tasks loaded on 4 underlying factors, partially supporting the underlying environmental model. LIMITATIONS: Limitations of this study included the uneven sample sizes in the 6 groups. CONCLUSIONS: Support for the environmental framework underlying the mDGI extends its usefulness as a clinical measure of functional mobility by providing a rationale for interpretation of scores that can be used to direct treatment and infer change in mobility function. PMID- 25524872 TI - Construct validity of the canadian occupational performance measure in participants with tendon injury and Dupuytren disease. AB - BACKGROUND: In patient-centered practice, instruments need to assess outcomes that are meaningful to patients with hand conditions. It is unclear which assessment tools address these subjective perspectives best. OBJECTIVE: The aim of this study was to establish the construct validity of the Canadian Occupational Performance Measure (COPM) in relation to the Disabilities of Arm, Shoulder, and Hand (DASH) questionnaire and the Michigan Hand Outcomes Questionnaire (MHQ) in people with hand conditions. It was hypothesized that COPM scores would correlate with DASH and MHQ total scores only to a moderate degree and that the COPM, DASH questionnaire, and MHQ would all correlate weakly with measures of hand impairments. DESIGN: This was a validation study. METHODS: The COPM, DASH questionnaire, and MHQ were scored, and then hand impairments were measured (pain [numerical rating scale], active range of motion [goniometer], grip strength [dynamometer], and pinch grip strength [pinch meter]). People who had received postsurgery rehabilitation for flexor tendon injuries, extensor tendon injuries, or Dupuytren disease were eligible. RESULTS: Seventy-two participants were included. For all diagnosis groups, the Pearson coefficient of correlation between the DASH questionnaire and the MHQ was higher than .60, whereas the correlation between the performance scale of the COPM and either the DASH questionnaire or the MHQ was lower than .51. Correlations of these assessment tools with measures of hand impairments were lower than .46. LIMITATIONS: The small sample sizes may limit the generalization of the results. CONCLUSIONS: The results supported the hypotheses and, thus, the construct validity of the COPM after surgery in people with hand conditions. PMID- 25524873 TI - Does perturbation-based balance training prevent falls? Systematic review and meta-analysis of preliminary randomized controlled trials. AB - BACKGROUND: Older adults and individuals with neurological conditions are at an increased risk for falls. Although physical exercise can prevent falls, certain types of exercise may be more effective. Perturbation-based balance training is a novel intervention involving repeated postural perturbations aiming to improve control of rapid balance reactions. PURPOSE: The purpose of this study was to estimate the effect of perturbation-based balance training on falls in daily life. DATA SOURCES: MEDLINE (1946-July 2014), EMBASE (1974-July 2014), PEDro (all dates), CENTRAL (1991-July 2014), and Google Scholar (all dates) were the data sources used in this study. STUDY SELECTION: Randomized controlled trials written in English were included if they focused on perturbation-based balance training among older adults or individuals with neurological conditions and collected falls data posttraining. DATA EXTRACTION: Two investigators extracted data independently. Study authors were contacted to obtain missing information. A PEDro score was obtained for each study. Primary outcomes were proportion of participants who reported one or more falls (ie, number of "fallers") and the total number of falls. The risk ratio (proportion of fallers) and rate ratio (number of falls) were entered into the analysis. DATA SYNTHESIS: Eight studies involving 404 participants were included. Participants who completed perturbation based balance training were less likely to report a fall (overall risk ratio=0.71; 95% confidence interval=0.52, 0.96; P=.02) and reported fewer falls than those in the control groups (overall rate ratio=0.54; 95% confidence interval=0.34, 0.85; P=.007). LIMITATIONS: Study authors do not always identify that they have included perturbation training in their intervention; therefore, it is possible that some appropriate studies were not included. Study designs were heterogeneous, preventing subanalyses. CONCLUSIONS: Perturbation-based balance training appears to reduce fall risk among older adults and individuals with Parkinson disease. PMID- 25524874 TI - Walking dynamics in preadolescents with and without Down syndrome. AB - BACKGROUND: A force-driven harmonic oscillator (FDHO) model reveals the elastic property of general muscular activity during walking. OBJECTIVE: This study aimed to investigate whether children with Down syndrome (DS) have a lower K/G ratio, a primary variable derived from the FDHO model, compared with children with typical development during overground and treadmill walking and whether children with DS can adapt the K/G ratio to walking speeds, external ankle load, and a treadmill setting. DESIGN: A cross-sectional study design was used that included 26 children with and without DS, aged 7 to 10 years, for overground walking and 20 of them for treadmill walking in a laboratory setting. METHODS: During overground walking, participants walked at 2 speeds: normal and fastest speed. During treadmill walking, participants walked at 75% and 100% of their preferred overground speed. Two load conditions were manipulated for both overground and treadmill walking: no load and an ankle load that was equal to 2% of body mass on each side. RESULTS: Children with DS showed a K/G ratio similar to that of their healthy peers and increased this ratio with walking speed regardless of ankle load during overground walking. Children with DS produced a lower K/G ratio at the fast speed of treadmill walking without ankle load, but ankle load helped them produce a K/G ratio similar to that of their healthy peers. LIMITATIONS: The FDHO model cannot specify what muscles are used or how muscles are coordinated for a given motor task. CONCLUSIONS: Children with DS show elastic property of general muscular activity similar to their healthy peers during overground walking. External ankle load helps children with DS increase general muscular activity and match their healthy peers while walking fast on a treadmill. PMID- 25524875 TI - Further Development and Validation of the Affordances in the Home Environment for Motor Development-Infant Scale (AHEMD-IS). AB - BACKGROUND: Affordances in the home environment may play a significant role in infant motor development. OBJECTIVE: The purpose of this study was to further develop and validate the Affordances in the Home Environment for Motor Development-Infant Scale (AHEMD-IS), an inventory that measures the quantity and quality of motor affordances in the home. DESIGN: A cross-sectional study was conducted to evaluate criteria for content validity, reliability, internal consistency, floor and ceiling effects, and interpretability of the instrument. METHODS: A pilot version of the inventory with 5 dimensions was used for expert panel analysis and administered to parents of infants (N=419). Data were analyzed with Cronbach alpha, intraclass correlation coefficients (ICCs), ceiling and floor effects, and item and dimension interpretability analyses for creation of a scoring system with descriptive categories for each dimension and total score. RESULTS: Average agreement among the expert panel was 95% across all evaluation criteria. Cronbach alpha values with the 41-item scale ranged between .639 and .824 for the separate dimensions, with a total value of .824 (95% confidence interval [95% CI]=.781, .862). The ICC values were .990 for interrater reliability and .949 for intrarater reliability. There was a ceiling effect on 3 questions for the Inside Space dimension and on 3 questions for the Variety of Stimulation dimension. These results demonstrated the need for reduction in total items (from 41 to 35) and the combination of space dimensions. After removal of questions, internal consistency was .766 (95% CI=.729, .800) for total score. Overall assessment categories were created as: less than adequate, moderately adequate, adequate, and excellent. LIMITATIONS: The inventory does not determine specific use (time, frequency) of affordances in the home, and it does not account for infants' out-of-home activities. CONCLUSIONS: The AHEMD-IS is a reliable and valid instrument to assess affordances in the home environment that promote infant motor development. PMID- 25524876 TI - Blood-brain barrier impairment in dementia: current and future in vivo assessments. AB - Increasing evidence indicates that blood-brain barrier (BBB) impairment may play a role in the pathophysiology of cognitive decline and dementia. In vivo imaging studies are needed to quantify and localize the BBB defects during life, contemplating the circulatory properties. We reviewed the literature for imaging studies investigating BBB impairment in patients suffering from dementia. After selection, 11 imaging studies were included, of which 6 used contrast-enhanced magnetic resonance imaging (MRI), 2 used contrast-enhanced computed tomography (CT), and 3 positron emission tomography (PET). Primarily the MRI studies hint at a subtle increasing permeability of the BBB, particularly in patients already exhibiting cerebrovascular pathology. More elaborate studies are required to provide convincing evidence on BBB impairment in patients with various stages of dementia with and without obvious cerebrovascular pathology. In the future, dynamic contrast enhanced MRI techniques and transport specific imaging using PET may further detail the research on the molecular nature of BBB defects. PMID- 25524879 TI - The value of ultrasonography versus clinical examination in differentiating acute inflammatory demyelinating polyneuropathy from acute-onset chronic inflammatory demyelinating polyneuropathy: The importance of timing. PMID- 25524878 TI - Evidence supporting product standards for carcinogens in smokeless tobacco products. AB - Smokeless tobacco products sold in the United States vary significantly in yields of nicotine and tobacco-specific nitrosamines (TSNA). With the passage of the Family Smoking Prevention and Tobacco Control Act, the Food and Drug Administration now has the authority to establish product standards. However, limited data exist determining the relative roles of pattern of smokeless tobacco use versus constituent levels in the smokeless tobacco product in exposure of users to carcinogens. In this study, smokeless tobacco users of brands varying in nicotine and TSNA content were recruited from three different regions in the U.S. Participants underwent two assessment sessions. During these sessions, demographic and smokeless tobacco use history information along with urine samples to assess biomarkers of exposure and effect were collected. During the time between data collection, smokeless tobacco users recorded the amount and duration of smokeless tobacco use on a daily basis using their diary cards. Results showed that independent of pattern of smokeless tobacco use and nicotine yields, levels of TSNA in smokeless tobacco products played a significant role in carcinogen exposure levels. Product standards for reducing levels of TSNA in smokeless tobacco products are necessary to decrease exposure to these toxicants and potentially to reduce risk for cancer. PMID- 25524880 TI - Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma. AB - Despite the introduction of 13-cis-retinoic acid (13-cis-RA) into the current chemotherapy, more than half of high-risk neuroblastoma patients have experienced tumor relapses driven by chemoresistant cancer stem cells (CSCs) that can be isolated by their ability to grow as spheres. Although aldehyde dehydrogenase (ALDH) has been used to characterize CSCs in certain cancers, ALDH remains elusive in neuroblastoma. In the present study, we determined ALDH activity and expression of its 19 isoforms in spheres and parental cells of neuroblastoma. ALDH activity and several ALDH isoforms were consistently induced in spheres of different neuroblastoma cells. While ALDH1A2, ALDH1L1 and ALDH3B2 expression was consistently induced in spheres and associated with the sphere and colony formation, only ALDH1A2 expression was significantly correlated with the poor prognosis of neuroblastoma patients. ALDH1A2 expression was further associated with the growth and undifferentiation of neuroblastoma xenografts and the resistance of neuroblastoma cells to 13-cis-RA. These results suggest that ALDH1A2 is involved in the regulation of CSC properties in neuroblastoma. PMID- 25524881 TI - Transport of massless Dirac fermions in non-topological type edge states. AB - There are two types of intrinsic surface states in solids. The first type is formed on the surface of topological insulators. Recently, transport of massless Dirac fermions in the band of "topological" states has been demonstrated. States of the second type were predicted by Tamm and Shockley long ago. They do not have a topological background and are therefore strongly dependent on the properties of the surface. We study the problem of the conductivity of Tamm-Shockley edge states through direct transport experiments. Aharonov-Bohm magneto-oscillations of resistance are found on graphene samples that contain a single nanohole. The effect is explained by the conductivity of the massless Dirac fermions in the edge states cycling around the nanohole. The results demonstrate the deep connection between topological and non-topological edge states in 2D systems of massless Dirac fermions. PMID- 25524882 TI - Malnutrition-induced Wernicke's encephalopathy following a water-only fasting diet. AB - BACKGROUND: Wernicke's encephalopathy is a critical condition of neurological dysfunction resulting from a deficiency in thiamine. Chronic alcoholism is recognized as the most common cause of Wernicke's encephalopathy, but other causes, including fasting/starvation and malnutrition, have been documented within the scientific literature. These causes may not be readily recognized by healthcare professionals and may lead to Wernicke's encephalopathy being overlooked as a diagnosis when a nonalcoholic patient presents with classic signs and symptoms of the disorder. MATERIALS AND METHODS: A narrative review of thiamine and its relationship to the development, diagnosis, and treatment of Wernicke's encephalopathy is presented based on a review of evidence-based guidelines and published research. To heighten awareness of the development of Wernicke's encephalopathy in fasted/starved and malnourished patients and to contribute to the scientific body of knowledge for the identification and management of Wernicke's encephalopathy in these patients, the clinical course and treatment of an adult woman who developed Wernicke's encephalopathy following a 40-day water-only fasting diet is outlined. RESULTS: Clinical suspicion was required to identify the patient's condition and initiate immediate intervention through parenteral thiamine administration. Oral thiamine supplementation of 100 to 800 mg per day for 6 months was required to aid recovery. OUTCOMES: The patient's clinical course and response to treatment illustrate the necessity for clinical awareness and suspicion of Wernicke's encephalopathy among healthcare professionals, timely and adequate parenteral thiamine administration, and oral thiamine supplementation at therapeutic doses to correct the nutrient deficiency, halt the progression of Wernicke's encephalopathy, and promote recovery. PMID- 25524883 TI - Pharmaconutrition with selenium in critically ill patients: what do we know? AB - Selenium is a component of selenoproteins with antioxidant, anti-inflammatory, and immunomodulatory properties. Systemic inflammatory response syndrome (SIRS), multiorgan dysfunction (MOD), and multiorgan failure (MOF) are associated with an early reduction in plasma selenium and glutathione peroxidase activity (GPx), and both parameters correlate inversely with the severity of illness and outcomes. Several randomized clinical trials (RCTs) evaluated selenium therapy as monotherapy or in antioxidant cocktails in intensive care unit (ICU) patient populations, and more recently several meta-analyses suggested benefits with selenium therapy in the most seriously ill patients. However, the largest RCT on pharmaconutrition with glutamine and antioxidants, the REducing Deaths due to Oxidative Stress (REDOXS) Study, was unable to find any improvement in clinical outcomes with antioxidants provided by the enteral and parenteral route and suggested harm in patients with renal dysfunction. Subsequently, the MetaPlus study demonstrated increased mortality in medical patients when provided extra glutamine and selenium enterally. The treatment effect of selenium may be dependent on the dose, the route of administration, and whether administered with other nutrients and the patient population studied. Currently, there are few small studies evaluating the pharmacokinetic profile of intravenous (IV) selenium in SIRS, and therefore more data are necessary, particularly in patients with MOD, including those with renal dysfunction. According to current knowledge, high dose pentahydrate sodium selenite could be given as an IV bolus injection (1000 2000 ug), which causes transient pro-oxidant, cytotoxic, and anti-inflammatory effects, and then followed by a continuous infusion of 1000-1600 ug/d for up to 10-14 days. Nonetheless, the optimum dose and efficacy still remain controversial and need to be definitively established. PMID- 25524884 TI - Gastric residual volume in critically ill patients: a dead marker or still alive? AB - Early enteral nutrition (EN) is consistently recommended as first-line nutrition therapy in critically ill patients since it favorably alters outcome, providing both nutrition and nonnutrition benefits. However, critically ill patients receiving mechanical ventilation are at risk for regurgitation, pulmonary aspiration, and eventually ventilator-associated pneumonia (VAP). EN may increase these risks when gastrointestinal (GI) dysfunction is present. Gastric residual volume (GRV) is considered a surrogate parameter of GI dysfunction during the progression of enteral feeding in the early phase of critical illness and beyond. By monitoring GRV, clinicians may detect patients with delayed gastric emptying earlier and intervene with strategies that minimize or prevent VAP as one of the major risks of EN. The value of periodic GRV measurements with regard to risk reduction of VAP incidence has frequently been questioned in the past years. Increasing the GRV threshold before interrupting gastric feeding results in marginal increases in EN delivery. More recently, a large randomized clinical trial revealed that abandoning GRV monitoring did not negatively affect clinical outcomes (including VAP) in mechanically ventilated patients. The results have revived the discussion on the role of GRV monitoring in critically ill, mechanically ventilated patients receiving early EN. This review summarizes the most recent clinical evidence on the use of GRV monitoring in critically ill patients. Based on the clinical evidence, it discusses the pros and cons and further addresses whether GRV is a dead marker or still alive for the nutrition management of critically ill patients. PMID- 25524877 TI - Diet, behavior and immunity across the lifespan. AB - It is increasingly appreciated that perinatal events can set an organism on a life-long trajectory for either health or disease, resilience or risk. One early life variable that has proven critical for optimal development is the nutritional environment in which the organism develops. Extensive research has documented the effects of both undernutrition and overnutrition, with strong links evident for an increased risk for obesity and metabolic disorders, as well as adverse mental health outcomes. Recent work has highlighted a critical role of the immune system, in linking diet with long term health and behavioral outcomes. The present review will summarize the recent literature regarding the interactions of diet, immunity, and behavior. PMID- 25524886 TI - Inguinal lymphadenectomy for stage III melanoma: a comparative study of two surgical approaches at the onset of lymphoedema. AB - INTRODUCTION: When sentinel lymph node is positive for metastasis (exclusion for micro-metastasis) and in cases of palpable adenopathy, a lymphadenectomy should be performed. Many incisional surgical approach have been described in literature. We perform two type of incision (vertical with skin excision and transversal) for inguinal lymphadenectomy. The aim of this study was to compare post-operative morbidity between these two approach in cases of Stage III Melanoma. We analysed chronic lymphoedeme, skin necrosis, wound dehiscence, wound infection and seroma rates between the two techniques. METHODS: From April 2000 to February 2012 fifty-three patients underwent to inguinal lymphadenectomy for Stage III melanoma at CHU of Rennes. Patients were stratified in 2 groups according to the surgical approach, group 1 with a vertical incision with skin excision and group 2 with a transverse incision. RESULTS: Chronic lymphoedema rate for group 1 was 37.04% and for group 2 rate was 26.92%, this complication was lower un group 2 but no significant difference was observed (p = 0.558). Skin necrosis (p = 0.235), wound dehiscence (p = 1.000), wound infection (p = 0.236) and seroma (p = 0.757) were not significantly different. Two cases of skin necrosis were observed in group 2 (7.69%) and none in group 1. CONCLUSION: We do not found significant difference for chronic lymphoedema between these two approach. However, we had less lymphoedema with the transversal technique which has the advantage to reduce the skin suffering when external iliac lymphadenectomy dissection is necessary in addition to the inguinal lymphadenectomy. PMID- 25524885 TI - Small molecule-mediated stabilization of vesicle-associated helical alpha synuclein inhibits pathogenic misfolding and aggregation. AB - alpha-synuclein is an abundant presynaptic protein that is important for regulation of synaptic vesicle trafficking, and whose misfolding plays a key role in Parkinson's disease. While alpha-synuclein is disordered in solution, it folds into a helical conformation when bound to synaptic vesicles. Stabilization of helical, folded alpha-synuclein might therefore interfere with alpha-synuclein induced neurotoxicity. Here we show that several small molecules, which delay aggregation of alpha-synuclein in solution, including the Parkinson's disease drug selegiline, fail to interfere with misfolding of vesicle-bound alpha synuclein. In contrast, the porphyrin phtalocyanine tetrasulfonate directly binds to vesicle-bound alpha-synuclein, stabilizes its helical conformation and thereby delays pathogenic misfolding and aggregation. Our study suggests that small molecule-mediated stabilization of helical vesicle-bound alpha-synuclein opens new possibilities to target Parkinson's disease and related synucleinopathies. PMID- 25524887 TI - Paget's disease of the bone mimicking lymphomatous bone marrow involvement at FDG PET. PMID- 25524888 TI - A single-cell correlative nanoelectromechanosensing approach to detect cancerous transformation: monitoring the function of F-actin microfilaments in the modulation of the ion channel activity. AB - Cancerous transformation may be dependent on correlation between electrical disruptions in the cell membrane and mechanical disruptions of cytoskeleton structures. Silicon nanotube (SiNT)-based electrical probes, as ultra-accurate signal recorders with subcellular resolution, may create many opportunities for fundamental biological research and biomedical applications. Here, we used this technology to electrically monitor cellular mechanosensing. The SiNT probe was combined with an electrically activated glass micropipette aspiration system to achieve a new cancer diagnostic technique that is based on real-time correlation between mechanical and electrical behaviour of single cells. Our studies demonstrated marked changes in the electrical response following increases in the mechanical aspiration force in healthy cells. In contrast, such responses were extremely weak for malignant cells. Confocal microscopy results showed the impact of actin microfilament remodelling on the reduction of the electrical response for aspirated cancer cells due to the significant role of actin in modulating the ion channel activity in the cell membrane. PMID- 25524889 TI - Biopotency of serine protease inhibitors from cowpea (Vigna unguiculata) seeds on digestive proteases and the development of Spodoptera littoralis (Boisduval). AB - Serine protease inhibitors (PIs) have been described in many plant species and are universal throughout the plant kingdom, where trypsin inhibitors is the most common type. In the present study, trypsin and chymotrypsin inhibitory activity was detected in the seed flour extracts of 13 selected cultivars/accessions of cowpea. Two cowpea cultivars, Cream7 and Buff, were found to have higher trypsin and chymotrypsin inhibitory potential compared to other tested cultivars for which they have been selected for further purification studies using ammonium sulfate fractionation and DEAE-Sephadex A-25 column. Cream7-purified proteins showed two bands on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) corresponding to molecular mass of 17.10 and 14.90 kDa, while the purified protein from Buff cultivar showed a single band corresponding mass of 16.50 kDa. The purified inhibitors were stable at temperature below 60 degrees C and were active at wide range of pH from 2 to 12. The kinetic analysis revealed noncompetitive type of inhibition for both inhibitors against both enzymes. The inhibitor constant (Ki ) values suggested high affinity between inhibitors and enzymes. Purified inhibitors were found to have deep and negative effects on the mean larval weight, larval mortality, pupation, and mean pupal weight of Spodoptera littoralis, where Buff PI was more effective than Cream7 PI. It may be concluded that cowpea PI gene(s) could be potential insect control protein for future studies in developing insect-resistant transgenic plants. PMID- 25524890 TI - Probing o-diphenylphosphanyl benzoate (o-DPPB)-directed C-C bond formation: total synthesis of dictyostatin. AB - Herein, we report a robust total synthesis of dictyostatin. This polyketide natural product has attracted much attention because of its impressive antiproliferative activity against several human cancer-cell lines. We accomplished its synthesis in a highly convergent manner from three fragments of equal complexity, which were prepared on multigram scale. The southern and northwestern subunits were constructed through application of our o-DPPB-directed hydroformylation and allylic substitution methodology, respectively. These methods generated the C6 and C14 stereocenters of dictyostatin with good diastereoselectivities and simultaneously allowed further elaboration of the fragments by Wittig olefination and Sharpless asymmetric epoxidation, respectively. The compelling performance of the hydroformylation and allylic substitution with regard to practicability, selectivity, and scale underline their value for the construction of propionate motifs. PMID- 25524892 TI - "Real-world" practical evaluation strategies: a review of telehealth evaluation. AB - BACKGROUND: Currently, the increasing interest in telehealth and significant technological breakthroughs of the past decade create favorable conditions for the widespread adoption of telehealth services. Therefore, expectations are high that telehealth can help alleviate prevailing challenges in health care delivery. However, in order to translate current research to policy and facilitate adoption by patients and health care providers, there is need for compelling evidence of the effectiveness of telehealth interventions. Such evidence is gathered from rigorously designed research studies, which may not always be practical in many real-world settings. OBJECTIVE: Our aim was to summarize current telehealth evaluation strategies and challenges and to outline practical approaches to conduct evaluation in real-world settings using one of our previously reported telehealth initiatives, the Diabetes Connect program, as a case study. METHODS: We reviewed commonly used current evaluation frameworks and strategies, as well as best practices based on successful evaluative efforts to date to address commonly encountered challenges in telehealth evaluation. These challenges in telehealth evaluation and commonly used frameworks are described relevant to the evaluation of Diabetes Connect, a 12-month Web-based blood glucose monitoring program. RESULTS: Designers of telehealth evaluation frameworks must give careful consideration to the elements of planning, implementation, and impact assessment of interventions. Evaluating performance at each of these phases is critical to the overall success of an intervention. Although impact assessment occurs at the end of a program, our review shows that it should begin at the point of problem definition. Critical to the success of an evaluative strategy is early planning that involves all stakeholders to identify the overall goals of the program and key measures of success at each phase of the program life cycle. This strategy should enable selection of an appropriate evaluation strategy and measures to aid in the ongoing development and implementation of telehealth and provide better evidence of program impact. CONCLUSIONS: We recommend a pragmatic, multi-method, multi-phase approach to telehealth evaluation that is flexible and can be adapted to the characteristics and challenges unique to each telehealth program. PMID- 25524893 TI - Anterior cruciate ligament tear in Hong Kong Chinese patients. AB - OBJECTIVE: To investigate the associations between patient sex, age, cause of injury, and frequency of meniscus and articular cartilage lesions seen at the time of the anterior cruciate ligament reconstruction. SETTING: University affiliated hospital, Hong Kong. PATIENTS: Medical notes and operating records of 672 Chinese patients who had received anterior cruciate ligament reconstruction between January 1997 and December 2010 were reviewed. Data concerning all knee cartilage and meniscus injuries documented at the time of surgery were analysed. RESULTS: Of the 593 patients, meniscus injuries were identified in 315 (53.1%). Patients older than 30 years were more likely to suffer from meniscal injury compared with those younger than 30 years (60% vs 51%, P=0.043). Longer surgical delay was observed in patients with meniscal lesions compared with those without (median, 12.3 months vs 9.1 months, P=0.021). Overall, 139 cartilage lesions were identified in 109 (18.4%) patients. Patients with cartilage lesions were significantly older than those without the lesions (mean, 27.6 years vs 25.1 years, P=0.034). Male patients were more likely to have chondral injuries than female patients (20.1% vs 10.9%, P=0.028). The risk of cartilage lesions was increased by nearly 3 times in the presence of meniscal tear (P<0.0001; odds ratio=2.7; 95% confidence interval, 1.7-4.2). CONCLUSIONS: Increased age and surgical delay increased the risk of meniscal tears in patients with anterior cruciate ligament tear. Increased age, male sex, and presence of meniscal tear were associated with an increased frequency of articular lesions after an anterior cruciate ligament tear. PMID- 25524891 TI - The organization of AMPA receptor subunits at the postsynaptic membrane. AB - AMPA receptors are the principal mediators of excitatory synaptic transmission in the mammalian central nervous system. The subunit composition of these tetrameric receptors helps to define their functional properties, and may also influence the synaptic trafficking implicated in long-term synaptic plasticity. However, the organization of AMPAR subunits within the synapse remains unclear. Here, we use postembedding immunogold electron microscopy to study the synaptic organization of AMPAR subunits in stratum radiatum of CA1 hippocampus in the adult rat. We find that GluA1 concentrates away from the center of the synapse, extending at least 25 nm beyond the synaptic specialization; in contrast, GluA3 is uniformly distributed along the synapse, and seldom extends beyond its lateral border. The fraction of extrasynaptic GluA1 is markedly higher in small than in large synapses; no such effect is seen for GluA3. These observations imply that different kinds of AMPARs are differently trafficked to and/or anchored at the synapse. PMID- 25524894 TI - Performance assessment of bio-inspired systems: flow sensing MEMS hairs. AB - Despite vigorous growth in biomimetic design, the performance of man-made devices relative to their natural templates is still seldom quantified, a procedure which would however significantly increase the rigour of the biomimetic approach. We applied the ubiquitous engineering concept of a figure of merit (FoM) to MEMS flow sensors inspired by cricket filiform hairs. A well known mechanical model of a hair is refined and tailored to this task. Five criteria of varying importance in the biological and engineering fields are computed: responsivity, power transfer, power efficiency, response time and detection threshold. We selected the metrics response time and detection threshold for building the FoM to capture the performance in a single number. Crickets outperform actual MEMS on all criteria for a large range of flow frequencies. Our approach enables us to propose several improvements for MEMS hair-sensor design. PMID- 25524895 TI - VarSim: a high-fidelity simulation and validation framework for high-throughput genome sequencing with cancer applications. AB - SUMMARY: VarSim is a framework for assessing alignment and variant calling accuracy in high-throughput genome sequencing through simulation or real data. In contrast to simulating a random mutation spectrum, it synthesizes diploid genomes with germline and somatic mutations based on a realistic model. This model leverages information such as previously reported mutations to make the synthetic genomes biologically relevant. VarSim simulates and validates a wide range of variants, including single nucleotide variants, small indels and large structural variants. It is an automated, comprehensive compute framework supporting parallel computation and multiple read simulators. Furthermore, we developed a novel map data structure to validate read alignments, a strategy to compare variants binned in size ranges and a lightweight, interactive, graphical report to visualize validation results with detailed statistics. Thus far, it is the most comprehensive validation tool for secondary analysis in next generation sequencing. AVAILABILITY AND IMPLEMENTATION: Code in Java and Python along with instructions to download the reads and variants is at http://bioinform.github.io/varsim. CONTACT: rd@bina.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25524896 TI - PrimerDesign-M: a multiple-alignment based multiple-primer design tool for walking across variable genomes. AB - SUMMARY: Analyses of entire viral genomes or mtDNA requires comprehensive design of many primers across their genomes. Furthermore, simultaneous optimization of several DNA primer design criteria may improve overall experimental efficiency and downstream bioinformatic processing. To achieve these goals, we developed PrimerDesign-M. It includes several options for multiple-primer design, allowing researchers to efficiently design walking primers that cover long DNA targets, such as entire HIV-1 genomes, and that optimizes primers simultaneously informed by genetic diversity in multiple alignments and experimental design constraints given by the user. PrimerDesign-M can also design primers that include DNA barcodes and minimize primer dimerization. PrimerDesign-M finds optimal primers for highly variable DNA targets and facilitates design flexibility by suggesting alternative designs to adapt to experimental conditions. AVAILABILITY AND IMPLEMENTATION: PrimerDesign-M is available as a webtool at http://www.hiv.lanl.gov/content/sequence/PRIMER_DESIGN/primer_design.html CONTACT: tkl@lanl.gov or seq-info@lanl.gov. PMID- 25524897 TI - The uncertain fate of otolaryngology in sleep medicine. AB - Since 2011, otolaryngologists have been required to complete a 1-year fellowship in sleep medicine in order to be eligible for the ABOto Sleep Medicine Certification Examination (ASMCE). Resultantly, the number of sleep medicine board-certified otolaryngologists has plunged since that time. This push toward extinction comes at a time when otolaryngologists have been cast into the spotlight for the diagnosis and treatment of obstructive sleep apnea, the prevailing disorder in sleep medicine. To reverse the trajectory of this subspecialty, 2 changes need to occur: increase the exposure to sleep medicine/surgery during residency and improve access to sleep medicine fellowships featuring a strong otolaryngology presence. PMID- 25524898 TI - First branchial cleft anomalies: otologic manifestations and treatment outcomes. AB - OBJECTIVE: This study describes the presentation of first branchial cleft anomalies and compares outcomes of first branchial cleft with other branchial cleft anomalies with attention to otologic findings. STUDY DESIGN: Case series with chart review. SETTING: Pediatric tertiary care facility. METHODS: Surgical databases were queried to identify children with branchial cleft anomalies. Descriptive analysis defined sample characteristics. Risk estimates were calculated using Fisher's exact test. RESULTS: Queries identified 126 subjects: 27 (21.4%) had first branchial cleft anomalies, 80 (63.4%) had second, and 19 (15.1%) had third or fourth. Children with first anomalies often presented with otologic complications, including otorrhea (22.2%), otitis media (25.9%), and cholesteatoma (14.8%). Of 80 children with second branchial cleft anomalies, only 3 (3.8%) had otitis. Compared with children with second anomalies, children with first anomalies had a greater risk of requiring primary incision and drainage: 16 (59.3%) vs 2 (2.5%) (relative risk [RR], 3.5; 95% confidence interval [CI], 2.4 5; P<.0001). They were more likely to have persistent disease after primary excision: 7 (25.9%) vs 2 (2.5%) (RR, 3; 95% CI, 1.9-5; P=.0025). They were more likely to undergo additional surgery: 8 (29.6%) vs 3 (11.1%) (RR, 2.9; 95% CI, 1.8-4.7; P=.0025). Of 7 persistent first anomalies, 6 (85.7%) were medial to the facial nerve, and 4 (57.1%) required ear-specific surgery for management. CONCLUSIONS: Children with first branchial cleft anomalies often present with otologic complaints. They are at increased risk of persistent disease, particularly if anomalies lie medial to the facial nerve. They may require ear specific surgery such as tympanoplasty. PMID- 25524899 TI - Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. AB - Cancer immunotherapy has proven to be challenging as it depends on overcoming multiple mechanisms that mediate immune tolerance to self-antigens. A growing understanding of immune tolerance has been the foundation for new approaches to cancer immunotherapy. Adoptive transfer of immune effectors such as antitumor mAb and chimeric antigen receptor T cells bypasses many of the mechanisms involved in immune tolerance by allowing for expansion of tumor-specific effectors ex vivo. Vaccination with whole tumor cells, protein, peptide, or dendritic cells has proven challenging, yet may be more useful when combined with other cancer immunotherapeutic strategies. Immunomodulatory approaches to cancer immunotherapy include treatment with agents that enhance and maintain T-cell activation. Recent advances in the use of checkpoint blockade to block negative signals and to maintain the antitumor response are particularly exciting. With our growing knowledge of immune tolerance and ways to overcome it, combination treatments are being developed, tested, and have particular promise. One example is in situ immunization that is designed to break tolerance within the tumor microenvironment. Progress in all these areas is continuing based on clear evidence that cancer immunotherapy designed to overcome immune tolerance can be useful for a growing number of patients with cancer. PMID- 25524900 TI - Regulation of epithelial-mesenchymal transition through SUMOylation of transcription factors. AB - Carcinoma cells can transition from an epithelial-to-mesenchymal differentiation state through a process known as epithelial-mesenchymal transition (EMT). The process of EMT is characterized by alterations in the pattern of gene expression and is associated with a loss of cell polarity, an increase in invasiveness, and an increase in cells expressing cancer stem cell (CSC) markers. The reverse process of mesenchymal-to-epithelial transition (MET) can also occur, though the transitions characterizing EMT and MET can be incomplete. A growing number of transcription factors have been identified that influence the EMT/MET processes. Interestingly, SUMOylation regulates the functional activity of many of the transcription factors governing transitions between epithelial and mesenchymal states. In some cases, the transcription factor is a small ubiquitin-like modifier conjugated directly, thus altering its transcriptional activity or cell trafficking. In other cases, SUMOylation alters transcriptional mechanisms through secondary effects. This review explores the role of SUMOylation in controlling transcriptional mechanisms that regulate EMT/MET in cancer. Developing new drugs that specifically target SUMOylation offers a novel therapeutic approach to block tumor growth and metastasis. PMID- 25524902 TI - The effects of screening length in the non-local screened-exchange functional. AB - The screened exchange (sX) hybrid functional can give good band structures for simple sp bonded semiconductors and insulators, charge transfer insulators, Mott Hubbard insulators, two dimensional systems and defect systems. This is particularly attributed to the sX hybrid scheme fixing the self-interaction problem associated with local functionals. We investigate the effect of varying the screening parameter of the exchange potential on various material properties such as the band gap. The Thomas Fermi screening scheme in which the screening parameter varies with an average valence electron density leads to a weak dependence of the band gap on valence electron density, so that a fixed screening parameter could be applied to heterogeneous systems like surfaces, interfaces and defects. PMID- 25524901 TI - eIF4E threshold levels differ in governing normal and neoplastic expansion of mammary stem and luminal progenitor cells. AB - Translation initiation factor eIF4E mediates normal cell proliferation, yet induces tumorigenesis when overexpressed. The mechanisms by which eIF4E directs such distinct biologic outputs remain unknown. We found that mouse mammary morphogenesis during pregnancy and lactation is accompanied by increased cap binding capability of eIF4E and activation of the eIF4E-dependent translational apparatus, but only subtle oscillations in eIF4E abundance. Using a transgenic mouse model engineered so that lactogenic hormones stimulate a sustained increase in eIF4E abundance in stem/progenitor cells of lactogenic mammary epithelium during successive pregnancy/lactation cycles, eIF4E overexpression increased self renewal, triggered DNA replication stress, and induced formation of premalignant and malignant lesions. Using complementary in vivo and ex vivo approaches, we found that increasing eIF4E levels rescued cells harboring oncogenic c-Myc or H RasV12 from DNA replication stress and oncogene-induced replication catastrophe. Our findings indicate that distinct threshold levels of eIF4E govern its biologic output in lactating mammary glands and that eIF4E overexpression in the context of stem/progenitor cell population expansion can initiate malignant transformation by enabling cells to evade DNA damage checkpoints activated by oncogenic stimuli. Maintaining eIF4E levels below its proneoplastic threshold is an important anticancer defense in normal cells, with important implications for understanding pregnancy-associated breast cancer. PMID- 25524903 TI - Effect of compression stockings on cutaneous microcirculation: Evaluation based on measurements of the skin thermal conductivity. AB - OBJECTIVE: To study of the microcirculatory effects of elastic compression stockings. MATERIALS AND METHODS: In phlebology, laser Doppler techniques (flux or imaging) are widely used to investigate cutaneous microcirculation. It is a method used to explore microcirculation by detecting blood flow in skin capillaries. Flux and imaging instruments evaluate, non-invasively in real-time, the perfusion of cutaneous micro vessels. Such tools, well known by the vascular community, are not really suitable to our protocol which requires evaluation through the elastic compression stockings fabric. Therefore, we involve another instrument, called the Hematron (developed by Insa-Lyon, Biomedical Sensor Group, Nanotechnologies Institute of Lyon), to investigate the relationship between skin microcirculatory activities and external compression provided by elastic compression stockings. The Hematron measurement principle is based on the monitoring of the skin's thermal conductivity. This clinical study examined a group of 30 female subjects, aged 42 years +/-2 years, who suffer from minor symptoms of chronic venous disease, classified as C0s, and C1s (CEAP). RESULTS: The resulting figures show, subsequent to the pressure exerted by elastic compression stockings, an improvement of microcirculatory activities observed in 83% of the subjects, and a decreased effect was detected in the remaining 17%. Among the total population, the global average increase of the skin's microcirculatory activities is evaluated at 7.63% +/- 1.80% (p < 0.0001). CONCLUSION: The results from this study show that the pressure effects of elastic compression stockings has a direct influence on the skin's microcirculation within this female sample group having minor chronic venous insufficiency signs. Further investigations are required for a deeper understanding of the elastic compression stockings effects on the microcirculatory activity in venous diseases at other stages of pathology. PMID- 25524904 TI - Cardiac amyloidosis presenting with paroxysmal atrial fibrillation. PMID- 25524905 TI - Herpetic epithelial keratitis. PMID- 25524906 TI - A London experience 1995-2012: demographic, dietary and biochemical characteristics of a large adult cohort of patients with renal stone disease. AB - BACKGROUND: Kidney stone disease has an estimated prevalence of around 10%. Genetic as well as environmental factors are thought to play an important role in the pathogenesis of renal stones. AIM: The aim of our study was to analyse and report the main characteristics of patients with kidney stones attending a large UK metabolic stone clinic in London between 1995 and 2012. DESIGN: A cross sectional study. METHODS: Analysis of data from stone formers attending the University College and Royal Free Hospitals' metabolic stone clinic from 1995 to 2012. Demographic, clinical, dietary and biochemical characteristics have been summarized and analysed for men and women separately; trends over time have also been analysed. RESULTS: Of the 2861 patients included in the analysis, 2016 (70%) were men with an average age of 47 years (range 18-87 years) and median duration of disease of 6 years (range 0-60 years). The prevalence of low urine volume, hypercalciuria, hyperoxaluria, hyperuricosuria and hypocitraturia was 5.6%, 38%, 7.9%, 18% and 23%, respectively. The prevalence of several risk factors for stones increased over time. The majority of stones were mixed, with around 90% composed of calcium salts in varying proportion. CONCLUSION: Our findings in a large cohort of patients attending a London-based stone clinic over the past 20 years show differences in distributions of risk factors for stones for men and women, as well as metabolic profiles and stone composition. The impact of most risk factors for stones appeared to change over time. PMID- 25524907 TI - Hypercalcaemic hyperparathyroid crisis. PMID- 25524908 TI - Secondary hemorrhage in traumatic hyphema. PMID- 25524909 TI - Attributes of primary care in community health centres in China and implications for equitable care: a cross-sectional measurement of patients' experiences. AB - BACKGROUND: China has been undergoing a health-care reform, and community health centres (CHCs) are being established as primary care provider across urban areas. AIM: To evaluate primary care attributes in CHCs by measuring patients' experiences. DESIGN: Cross-sectional surveys of 3360 adult service users with multistage cluster sampling. METHODS: We developed a short assessment tool consisting of 33 items derived from the short version of the original Primary Care Assessment Tool-Adult Edition (PCAT-AE). The reliability and validity of the instrument were evaluated. Score distributions were assessed using descriptive statistics with 95% confidence interval (CI). The overall PCAT scores were categorized into three quantile groups (lower score, medium score and optimal score). Ordinal logistic regression analysis was performed to explore patient characteristics associated with optimal score after controlling for demographic, socio-economic, health conditions and health-care utilization characteristics. RESULTS: One-third (33.4%, 95% CI: 31.0-35.9%) of subjects had optimal overall PCAT scores, while the majority (83.4%) reported medium-to-lower score in the community orientation scale. Patients' characteristics with respect to health care utilization had major effects on PCAT scores. Subjects with the presence of social medical insurance had higher odds of having greater experience in most primary care attributes and tended to report optimal primary care experience (aOR 2.30, 95% CI: 1.92-2.75) compared with those without social medical insurance. CONCLUSIONS: Equitable primary care is yet to be strengthened with regard to the community orientation attribute, and particularly among patients without social medical insurance, as they tend to have inferior experiences in the primary care sector. PMID- 25524910 TI - Restoration of Glucose Counterregulation by Islet Transplantation in Long standing Type 1 Diabetes. AB - Patients with long-standing type 1 diabetes (T1D) may exhibit defective glucose counterregulation and impaired hypoglycemia symptom recognition that substantially increase their risk for experiencing severe hypoglycemia. The purpose of this study was to determine whether intrahepatic islet transplantation improves endogenous glucose production (EGP) in response to hypoglycemia in T1D patients experiencing severe hypoglycemia. We studied longitudinally subjects (n = 12) with ~30 years, disease duration before and 6 months after intrahepatic islet transplantation using stepped hyperinsulinemic-hypoglycemic and paired hyperinsulinemic-euglycemic clamps with infusion of 6,6-(2)H2-glucose and compared the results with those from a nondiabetic control group (n = 8). After islet transplantation, HbA1c was normalized, and time spent while hypoglycemic (<70 mg/dL) was nearly abolished as indicated by continuous glucose monitoring. In response to insulin-induced hypoglycemia, C-peptide (absent before transplant) was appropriately suppressed, glucagon secretion was recovered, and epinephrine secretion was improved after transplantation. Corresponding to these hormonal changes, the EGP response to insulin-induced hypoglycemia, which was previously absent, was normalized after transplantation, with a similar effect seen for autonomic symptoms. Because the ability to increase EGP is ultimately required to circumvent the development of hypoglycemia, these results provide evidence that intrahepatic islet transplantation can restore glucose counterregulation in long standing T1D and support its consideration as treatment for patients with hypoglycemia unawareness experiencing severe hypoglycemia. PMID- 25524913 TI - Lipid-induced insulin resistance is associated with an impaired skeletal muscle protein synthetic response to amino acid ingestion in healthy young men. AB - The ability to maintain skeletal muscle mass appears to be impaired in insulin resistant conditions, such as type 2 diabetes, that are characterized by muscle lipid accumulation. The current study investigated the effect of acutely increasing lipid availability on muscle protein synthesis. Seven healthy young male volunteers underwent a 7-h intravenous infusion of l-[ring (2)H5]phenylalanine on two randomized occasions combined with 0.9% saline or 10% Intralipid at 100 mL/h. After a 4-h "basal" period, a 21-g bolus of amino acids was administered and a 3-h hyperinsulinemic-euglycemic clamp was commenced ("fed" period). Muscle biopsy specimens were obtained from the vastus lateralis at 1.5, 4, and 7 h. Lipid infusion reduced fed whole-body glucose disposal by 20%. Furthermore, whereas the mixed muscle fractional synthetic rate increased from the basal to the fed period during saline infusion by 2.2-fold, no change occurred during lipid infusion, despite similar circulating insulin and leucine concentrations. This "anabolic resistance" to insulin and amino acids with lipid infusion was associated with a complete suppression of muscle 4E-BP1 phosphorylation. We propose that increased muscle lipid availability may contribute to anabolic resistance in insulin-resistant conditions by impairing translation initiation. PMID- 25524912 TI - HbA1c Predicts Time to Diagnosis of Type 1 Diabetes in Children at Risk. AB - Prediction of type 1 diabetes is based on the detection of multiple islet autoantibodies in subjects who are at increased genetic risk. Prediction of the timing of diagnosis is challenging, however. We assessed the utility of HbA1c levels in predicting the clinical disease in genetically predisposed children with multiple autoantibodies. Cord blood samples from 168,055 newborn infants were screened for class II HLA genotypes in Finland, and 14,876 children with increased genetic risk for type 1 diabetes were invited to participate in regular follow-ups, including screening for diabetes-associated autoantibodies. When two or more autoantibodies were detected, HbA1c levels were analyzed at each visit. During follow-up, multiple (two or more) autoantibodies developed in 466 children; type 1 diabetes was diagnosed in 201 of these children (43%, progressors), while 265 children remained disease free (nonprogressors) by December 2011. A 10% increase in HbA1c levels in samples obtained 3-12 months apart predicted the diagnosis of clinical disease (hazard ratio [HR] 5.7 [95% CI 4.1-7.9]) after a median time of 1.1 years (interquartile range [IQR] 0.6-3.1 years) from the observed rise of HbA1c. If the HbA1c level was >=5.9% (41 mmol/mol) in two consecutive samples, the median time to diagnosis was 0.9 years (IQR 0.3-1.5, HR 11.9 [95% CI 8.8-16.0]). In conclusion, HbA1c is a useful biochemical marker when predicting the time to diagnosis of type 1 diabetes in children with multiple autoantibodies. PMID- 25524911 TI - Metformin treatment in the period after stroke prevents nitrative stress and restores angiogenic signaling in the brain in diabetes. AB - Diabetes impedes vascular repair and causes vasoregression in the brain after stroke, but mechanisms underlying this response are still unclear. We hypothesized that excess peroxynitrite formation in diabetic ischemia/reperfusion (I/R) injury inactivates the p85 subunit of phosphoinositide 3-kinase (PI3K) by nitration and diverts the PI3K-Akt survival signal to the p38-mitogen-activated protein kinase apoptosis pathway. Nitrotyrosine (NY), Akt and p38 activity, p85 nitration, and caspase-3 cleavage were measured in brains from control, diabetic (GK), or metformin-treated GK rats subjected to sham or stroke surgery and in brain microvascular endothelial cells (BMVECs) from Wistar and GK rats subjected to hypoxia/reoxygenation injury. GK rat brains showed increased NY, caspase-3 cleavage, and p38 activation and decreased Akt activation. Metformin attenuated stroke-induced nitrative signaling in GK rats. GK rat BMVECs showed increased basal nitrative stress compared with controls. A second hit by hypoxia/reoxygenation injury dramatically increased the nitration of p85 and activation of p38 but decreased Akt. These effects were associated with impairment of angiogenic response and were restored by treatment with the peroxynitrite scavenger 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride or the nitration inhibitor epicatechin. Our results provide evidence that I/R-induced peroxynitrite inhibits survival, induces apoptosis, and promotes peroxynitrite as a novel therapeutic target for the improvement of reparative angiogenesis after stroke in diabetes. PMID- 25524914 TI - Transthyretin Antisense Oligonucleotides Lower Circulating RBP4 Levels and Improve Insulin Sensitivity in Obese Mice. AB - Circulating transthyretin (TTR) is a critical determinant of plasma retinol binding protein 4 (RBP4) levels. Elevated RBP4 levels cause insulin resistance, and the lowering of RBP4 levels improves glucose homeostasis. Since lowering TTR levels increases renal clearance of RBP4, we determined whether decreasing TTR levels with antisense oligonucleotides (ASOs) improves glucose metabolism and insulin sensitivity in obesity. TTR-ASO treatment of mice with genetic or diet induced obesity resulted in an 80-95% decrease in circulating levels of TTR and RBP4. Treatment with TTR-ASOs, but not control ASOs, decreased insulin levels by 30-60% and improved insulin sensitivity in ob/ob mice and high-fat diet-fed mice as early as after 2 weeks of treatment. The reduced insulin levels were sustained for up to 9 weeks of treatment and were associated with reduced adipose tissue inflammation. Body weight was not changed. TTR-ASO treatment decreased LDL cholesterol in high-fat diet-fed mice. The glucose infusion rate during a hyperinsulinemic-euglycemic clamp was increased by 50% in high-fat diet-fed mice treated with TTR-ASOs, demonstrating improved insulin sensitivity. This was also demonstrated by 20% greater inhibition of hepatic glucose production, a 45-60% increase of glucose uptake into skeletal and cardiac muscle, and a twofold increase in insulin signaling in muscle. These data show that decreasing circulating TTR levels or altering TTR-RBP4 binding could be a potential therapeutic approach for the treatment of type 2 diabetes. PMID- 25524915 TI - Loss of anergic B cells in prediabetic and new-onset type 1 diabetic patients. AB - Although dogma predicts that under normal circumstances, potentially offensive autoreactive cells are silenced by mechanisms of immune tolerance, islet antigen reactive B lymphocytes are known to play a crucial role in the development of autoimmunity in type 1 diabetes (T1D). Thus, participation of these cells in T1D may reflect escape from silencing mechanisms. Consistent with this concept, we found that in healthy subjects, high-affinity insulin-binding B cells occur exclusively in the anergic naive IgD(+), IgM(-) B-cell (BND) compartment. Antigen receptors expressed by these cells are polyreactive and have N-region additions, Vh usage, and charged complementarity-determining region 3 consistent with autoreactivity. Consistent with a potential early role in autoimmunity, these high-affinity insulin-binding B cells are absent from the anergic compartment of some first-degree relatives and all prediabetic and new-onset (<1 year) T1D patients tested, but return to normal levels in individuals diabetic for >1 year. Interestingly, these changes were correlated by transient loss of the entire BND compartment. These findings suggest that environmental events such as infection or injury may, by disrupting B-cell anergy, dispose individuals toward autoimmunity, the precise nature of which is specified by genetic risk factors, such as HLA alleles. PMID- 25524917 TI - Lowering body weight in obese mice with diastolic heart failure improves cardiac insulin sensitivity and function: implications for the obesity paradox. AB - Recent studies suggest improved outcomes and survival in obese heart failure patients (i.e., the obesity paradox), although obesity and heart failure unfavorably alter cardiac function and metabolism. We investigated the effects of weight loss on cardiac function and metabolism in obese heart failure mice. Obesity and heart failure were induced by feeding mice a high-fat (HF) diet (60% kcal from fat) for 4 weeks, following which an abdominal aortic constriction (AAC) was produced. Four weeks post-AAC, mice were switched to a low-fat (LF) diet (12% kcal from fat; HF AAC LF) or maintained on an HF (HF AAC HF) for a further 10 weeks. After 18 weeks, HF AAC LF mice weighed less than HF AAC HF mice. Diastolic function was improved in HF AAC LF mice, while cardiac hypertrophy was decreased and accompanied by decreased SIRT1 expression, increased FOXO1 acetylation, and increased atrogin-1 expression compared with HF AAC HF mice. Insulin-stimulated glucose oxidation was increased in hearts from HF AAC LF mice, compared with HF AAC HF mice. Thus lowering body weight by switching to LF diet in obese mice with heart failure is associated with decreased cardiac hypertrophy and improvements in both cardiac insulin sensitivity and diastolic function, suggesting that weight loss does not negatively impact heart function in the setting of obesity. PMID- 25524918 TI - Luteolin attenuates hepatic steatosis and insulin resistance through the interplay between the liver and adipose tissue in mice with diet-induced obesity. AB - The flavonoid luteolin has various pharmacological activities. However, few studies exist on the in vivo mechanism underlying the actions of luteolin in hepatic steatosis and obesity. The aim of the current study was to elucidate the action of luteolin on obesity and its comorbidity by analyzing its transcriptional and metabolic responses, in particular the luteolin-mediated cross-talk between liver and adipose tissue in diet-induced obese mice. C57BL/6J mice were fed a normal, high-fat, and high-fat + 0.005% (weight for weight) luteolin diet for 16 weeks. In high fat-fed mice, luteolin improved hepatic steatosis by suppressing hepatic lipogenesis and lipid absorption. In adipose tissue, luteolin increased PPARgamma protein expression to attenuate hepatic lipotoxicity, which may be linked to the improvement in circulating fatty acid (FA) levels by enhancing FA uptake genes and lipogenic genes and proteins in adipose tissue. Interestingly, luteolin also upregulated the expression of genes controlling lipolysis and the tricarboxylic acid (TCA) cycle prior to lipid droplet formation, thereby reducing adiposity. Moreover, luteolin improved hepatic insulin sensitivity by suppressing SREBP1 expression that modulates Irs2 expression through its negative feedback and gluconeogenesis. Luteolin ameliorates the deleterious effects of diet-induced obesity and its comorbidity via the interplay between liver and adipose tissue. PMID- 25524919 TI - Fermi level tuning and weak localization/weak antilocalization competition of bulk single crystalline Bi(2-x)Sb(x)Se2Te compounds. AB - From the investigation of the electrical transport properties of single crystalline Bi(2-x)Sb(x)Se2Te (x = 0.0, 0.6, 0.8, 1.0, 1.2 and 1.4) compounds, we observed a systematic change of the Fermi level from n-type metallic (x = 0.0 and 0.6) or small-gap semiconducting (x = 0.8) to p-type semiconducting (x = 1.0) and metallic (x = 1.2 and 1.4), respectively, with increasing Sb-substitution concentration based on temperature-dependent electrical resistivity rho(T) and Hall resistivity rhoxy(H) measurements, respectively. The parent compound Bi2Se2Te exhibits linear negative magnetoresistance at low magnetic fields (H ? 1 T) by weak localization. The intermediate doped compounds of x = 0.8 and 1.0 showed weak antilocalization (WAL) and weak localization (WL) crossover behavior from the field-dependent magnetoresistance measurements at low temperatures. From the Hikami-Larkin-Nagaoka analysis of the compounds (x = 0.8 and 1.0), we found that there is a competing behavior between WL and WAL in terms of Sb-doping and magnetic field strength. PMID- 25524920 TI - Orbital ordering to orbital glass transition in spinel FeCr(2-x)Al(x)S4 (0 ? x ? 0.2). AB - The polycrystalline (PC) sample of FeCr2S4 displays orbital ordering around TOO ~ 9 K, while single crystal sample shows orbital glass. In this paper, with the substitution of Al for Cr, a step by step transition from the orbital ordering to the orbital glass is reported in FeCr(2-x)Al(x)S4 (0 ? x ? 0.2). For PC FeCr2S4, the onset of long-range orbital order at TOO is evidenced by the appearance of a step-like transition in the temperature dependence of the magnetization (M(T)), a small kink at about 5.5 T below 9 K in the isotherms' magnetic field dependence of the magnetization (M(H)) curves as well as a lambda-type anomaly in specific heat. With increasing Al content, the TOO decreases gradually. For the samples with x ? 0.1, the orbital ordering is replaced by orbital glass, where the specific heat obeys a T(2)-dependence. The calculated residual orbital entropy consistently increases with x, implying the progressive freezing of the orbital moments and the coexistence of orbital ordering and orbital glass in the middle doping level. PMID- 25524916 TI - Genetic Variants Associated With Quantitative Glucose Homeostasis Traits Translate to Type 2 Diabetes in Mexican Americans: The GUARDIAN (Genetics Underlying Diabetes in Hispanics) Consortium. AB - Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components, although few studies have examined their genetic architecture or influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multicohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently sampled intravenous glucose tolerance test (four cohorts) or euglycemic clamp (three cohorts), and random effects models were used to test the association between loci and quantitative traits, adjusting for age, sex, and admixture proportions (Discovery). Analysis revealed a significant (P < 5.00 * 10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P < 0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D case and 9,232 control subjects of Mexican ancestry (Translation). Nonparametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive the risk for T2D. PMID- 25524921 TI - Androgens in post-menopausal patients with systemic sclerosis. PMID- 25524922 TI - Anti-signal recognition particle autoantibody ELISA validation and clinical associations. AB - OBJECTIVE: The aim of this study was to develop and validate a quantitative anti signal recognition particle (SRP) autoantibody serum ELISA in patients with myositis and longitudinal association with myositis disease activity. METHODS: We developed a serum ELISA using recombinant purified full-length human SRP coated on ELISA plates and a secondary antibody that bound human IgG to detect anti-SRP binding. Protein immunoprecipitation was used as the gold standard for the presence of anti-SRP. Serum samples from three groups were analysed: SRP(+) myositis subjects by immunoprecipitation, SRP(-) myositis subjects by immunoprecipitation and non-myositis controls. The ELISA's sensitivity, specificity, positive predictive value and negative predictive value were evaluated. Percentage agreement and test-retest reliability were assessed. Serial samples from seven SRP immunoprecipitation-positive subjects were also tested, along with serum muscle enzymes and manual muscle testing. RESULTS: Using immunoprecipitation, we identified 26 SRP(+) myositis patients and 77 SRP(-) controls (including 38 patients with necrotizing myopathy). Non-myositis control patients included SLE (n = 4) and SSc (n = 7) patients. Anti-SRP positivity by ELISA showed strong agreement (97.1%) with immunoprecipitation (kappa = 0.94). The sensitivity, specificity, positive predictive value, and negative predictive value of the anti-SRP ELISA were 88, 100, 100 and 96, respectively. The area under the curve was 0.94, and test-retest reliability was strong (r = 0.91, P < 0.001). Serial samples showed that anti-SRP levels paralleled changes in muscle enzymes and manual muscle testing. CONCLUSION: We developed a quantitative ELISA for detecting serum anti-SRP autoantibodies and validated the assay in myositis. Longitudinal assessment of SRP levels by ELISA may be a useful biomarker for disease activity. PMID- 25524924 TI - Prognostic significance of pretreatment serum levels of albumin, LDH and total bilirubin in patients with non-metastatic breast cancer. AB - Liver function tests (LFTs) have been reported as independent predictors of non liver disease-related morbidity and mortality in general population and cancer patients. In this study, we evaluated the relationship between pretreatment serum LFTs and overall survival (OS) in non-metastatic Caucasian breast cancer patients. Seven LFTs, including albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase (LDH), total bilirubin and total protein, were measured in pretreatment serum from 2425 female Caucasian patients with newly diagnosed, histologically confirmed non-metastatic invasive breast cancer. Multivariate Cox model was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for the association of individual LFTs with 5-year OS while adjusting for age, smoking status, pathological characteristics and treatment regimen. We found that serum albumin, LDH and total bilirubin were significantly associated with 5-year OS in multivariate Cox analyses. Patients with higher albumin level exhibited 45% reduced risk of death (HR = 0.55, 95% CI: 0.40-0.75) compared with those with lower albumin level. Patients with higher total bilirubin level had a nearly 40% reduction in the risk of death (HR = 0.62, 95% CI: 0.45-0.85) and patients with higher LDH levels had a 1.42-fold increased risk of death (HR = 1.42, 95% CI: 1.08-1.88). Furthermore, cumulative analysis showed a significant dose-response trend of significantly increasing risk of death with increasing number of unfavorable LFT levels. Our result highlighted the potential of using pretreatment serum levels of albumin, LDH and total bilirubin as prognostic factors for OS in patients with non-metastatic breast cancer. PMID- 25524926 TI - Evolution of atomic structure in Al75Cu25 liquid from experimental and ab initio molecular dynamics simulation studies. AB - X-ray diffraction and electrostatic levitation measurements, together with the ab initio molecular dynamics simulation of liquid Al(75)Cu(25) alloy have been performed from 800 to 1600 K. Experimental and ab initio molecular dynamics simulation results match well with each other. No abnormal changes were experimentally detected in the specific heat capacity over total hemispheric emissivity and density curves in the studied temperature range for a bulk liquid Al(75)Cu(25) alloy measured by the electrostatic levitation technique. The structure factors gained by the ab initio molecular dynamics simulation precisely coincide with the experimental data. The atomic structure analyzed by the Honeycutt-Andersen index and Voronoi tessellation methods shows that icosahedral like atomic clusters prevail in the liquid Al(75)Cu(25) alloy and the atomic clusters evolve continuously. All results obtained here suggest that no liquid liquid transition appears in the bulk liquid Al(75)Cu(25) alloy in the studied temperature range. PMID- 25524925 TI - Mitochondrial DNA copy number in peripheral blood leukocytes and the risk of clear cell renal cell carcinoma. AB - Variation of mitochondrial DNA copy number (mtDNAcn) in peripheral blood leukocytes has been associated with the risk of various cancers, including renal cell carcinoma (RCC). We assessed the association between mtDNAcn and clear cell RCC (ccRCC) risk in 608 cases and 629 controls frequency-matched on age and gender. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, gender, body mass index, smoking status, history of hypertension, total energy intake and physical activity. Our results suggest an association between low mtDNAcn and ccRCC risk (OR = 1.28, 95% CI: 0.97-1.68, P = 0.09). Lower mtDNAcn was associated with increased ccRCC risk in younger individuals (age <60, OR = 1.68, 95% CI: 1.13 2.49, P = 0.01), women (OR = 1.66, 95% CI: 1.03-2.73, P = 0.04), individuals without history of hypertension (OR = 1.62, 95% CI: 1.09-2.41, P = 0.02) and individuals with low physical activity levels (OR = 1.55, 95% CI: 1.02-2.37, P = 0.05). We observed significant and marginally significant interactions between both age and history of hypertension and mtDNAcn in elevating ccRCC risk (P for interaction = 0.04 and 0.07, respectively). Additionally, low mtDNAcn was associated with ccRCC risk in younger individuals with low levels of physical activity [ORs and 95% CI for medium and low physical activity levels, respectively, 2.31 (1.18-4.52) and 2.09 (1.17-3.75), P interaction = 0.04]. To our knowledge, this is the first report to investigate the role of mtDNAcn in the ccRCC subtype and the first to suggest that this association may be modified by risk factors including age, gender, history of hypertension and physical activity. PMID- 25524928 TI - Integrating electronic health records in the delivery of optimized anticoagulation therapy. AB - Integration of accepted practice standards into electronic health record systems can facilitate standardization of anticoagulation care delivery and result in improved anticoagulation safety. However, the majority of commonly used electronic health record systems are lacking the specialized features necessary for optimal anticoagulation management. The Task Force on Electronic Health Records of the New York State Anticoagulation Coalition provides such a Consensus Statement in this issue of the journal. The Anticoagulation Forum endorses these recommendations and advises the electronic health record industry and health information technology programmers at the institutional level to adopt these recommendations in a comprehensive and timely manner. PMID- 25524923 TI - Genetic polymorphisms of ADH1B, ADH1C and ALDH2, alcohol consumption, and the risk of gastric cancer: the Japan Public Health Center-based prospective study. AB - The association between alcohol consumption, genetic polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) and gastric cancer risk is not completely understood. We investigated the association between ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms, alcohol consumption and the risk of gastric cancer among Japanese subjects in a population-based, nested, case-control study (1990-2004). Among 36 745 subjects who answered the baseline questionnaire and provided blood samples, 457 new gastric cancer cases matched to 457 controls were used in the analysis. The odds ratios (OR) and corresponding 95% confidence intervals (CI) were calculated using logistic regression models. No association was observed between alcohol consumption, ADH1B (rs1229984), ADH1C (rs698) and ALDH2 (rs671) polymorphisms and gastric cancer risk. However, considering gene-environmental interaction, ADH1C G allele carriers who drink >=150 g/week of ethanol had a 2.5-fold increased risk of gastric cancer (OR = 2.54, 95% CI = 1.05-6.17) relative to AA genotype carriers who drink 0 to <150 g/week (P for interaction = 0.02). ALDH2 A allele carriers who drink >=150 g/week also had an increased risk (OR = 2.08, 95% CI = 1.05-4.12) relative to GG genotype carriers who drink 0 to < 150 g/week (P for interaction = 0.08). To find the relation between alcohol consumption and gastric cancer risk, it is important to consider both alcohol consumption level and ADH1C and ALDH2 polymorphisms. PMID- 25524927 TI - Independent roles of the priming and the triggering of the NLRP3 inflammasome in the heart. AB - AIMS: The NLRP3 inflammasome is activated in the ischaemic heart promoting caspase-1 activation, inflammation, and cell death. Ischaemic injury establishes both a priming signal (transcription of inflammasome components) and a trigger (NLRP3 activation). Whether NLRP3 activation, without priming, induces cardiac dysfunction and/or failure is unknown. The aim of this study was to assess the independent and complementary roles of the priming and the triggering signals in the heart, in the absence of ischaemia or myocardial injury. METHODS AND RESULTS: We used mice with mutant NLRP3 (constitutively active), NLRP3-A350V, under the control of tamoxifen-driven expression of the Cre recombinase (Nlrp3-A350V/CreT mice). The mice were treated for 10 days with tamoxifen before measuring the activity of caspase-1, the effector enzyme in the inflammasome. Tamoxifen treatment induced the inflammasome in the spleen but not in the heart, despite expression of the mutant NLRP3-A350V. The components of the inflammasome were significantly less expressed in the heart compared with the spleen. Subclinical low-dose lipopolysaccharide (LPS; 2 mg/kg) in Nlrp3-A350V/CreT mice induced the expression of the components of the inflammasome (priming), measured using real time PCR and western blot, leading to the formation of an active inflammasome (caspase-1 activation) in the heart and LV systolic dysfunction while low-dose LPS was insufficient to induce LV systolic dysfunction in wild-type mice (all P < 0.01 for mutant vs. wild-type mice). CONCLUSION: The signalling pathway governing the inflammasome formation in the heart requires a priming signal in order for an active NLRP3 to induce caspase-1 activation and LV dysfunction. PMID- 25524929 TI - The "doctors" will see you now: a pharmacist's take on the "Truth in Advertising" campaign. AB - In response to this growing movement of allied health "doctors," the American Medical Association (AMA) launched its "Truth in Advertising" campaign in 2011, which aims to pass legislation regarding use of the "doctor" title. As a result of this initiative, several states have enacted laws that require any nonphysician practitioners who evoke the "doctor" salutation with patients to immediately identify their profession. Although designed to prevent confusion among patients, this initiative is misguided, and we as pharmacists need to use our professional organizations to open a dialog with the AMA and address this issue. PMID- 25524930 TI - Evaluation of aspirin use for primary prevention in diabetic patients. PMID- 25524931 TI - Abiraterone acetate-induced life-threatening torsade de pointes. PMID- 25524932 TI - Criteria for prescribing dabigatrin extexilate and rivaroxaban really appropriate? Comment. PMID- 25524933 TI - Criteria for prescribing dabigatrin extexilate and rivaroxaban really appropriate? Authors' reply. PMID- 25524935 TI - Atomic scale study of corrugating and anticorrugating states on the bare Si(1 0 0) surface. AB - In this article, we study the origin of the corrugating and anticorrugating states through the electronic properties of the Si(1 0 0) surface via a low temperature (9 K) scanning tunneling microscope (STM). Our study is based on the analysis of the STM topographies corrugation variations when related to the shift of the local density of states (LDOS) maximum in the [Formula: see text] direction. Our experimental results are correlated with numerical simulations using the density-functional theory with hybrid Heyd-Scuseria-Ernzerhof (HSE06) functional to simulate the STM topographies, the projected density of states variations at different depths in the silicon surface as well as the three dimensional partial charge density distributions in real-space. This work reveals that the Si(1 0 0) surface exhibits two anticorrugating states at +0.8 and +2.8 V that are associated with a phase shift of the LDOS maximum in the unoccupied states STM topographies. By comparing the calculated data with our experimental results, we have been able to identify the link between the variations of the STM topographies corrugation and the shift of the LDOS maximum observed experimentally. Each surface voltage at which the STM topographies corrugation drops is defined as anticorrugating states. In addition, we have evidenced a sharp jump in the tunnel current when the second LDOS maximum shift is probed, whose origin is discussed and associated with the presence of Van Hove singularities. PMID- 25524936 TI - Combining conventional and stroma-derived tumour markers in pancreatic ductal adenocarcinoma. AB - BACKGROUND: A lack of disease-specific symptoms and good tumour markers makes early detection and diagnosis of pancreatic ductal adenocarcinoma (PDAC) challenging. OBJECTIVE: To analyse the tissue expression and circulating levels of four stroma-derived substances (type IV collagen, endostatin/type XVIII collagen, osteopontin and tenascin C) and four conventional tumour markers (CA 19 9, TPS, CEA and Ca 125) in a PDAC cohort. METHODS: Tissue expression of markers in normal pancreas and PDAC tissue was analysed with immunofluorescence. Plasma concentrations of markers were measured before and after surgery. Patients with non-malignant disorders served as controls. RESULTS: The conventional and stromal substances were expressed in the cancer cell compartment and the stroma, respectively. Although most patients had increased levels of many markers before surgery, 2/12 (17%) of patients had normal levels of Ca 19-9 at this stage. High preoperative endostatin/type XVIII collagen, and postoperative type IV collagen was associated with short survival. Neither the pre- nor postoperative levels of TPS, Ca 125 or CA 19-9 were associated to survival. CONCLUSIONS: PDAC is characterized by an abundant stroma. These initial observations indicate that the stroma can be a source of PDAC tumour markers that are found in different compartments of the cancer, thus reflecting different aspects of tumour biology. PMID- 25524937 TI - Expression and epigenetic regulation of DACT1 and DACT2 in oral squamous cell carcinoma. AB - BACKGROUND: DACT genes regulates Wnt as well TGF-beta pathway, and were already associated with hepatocellular and lung cancer. Alterations on Wnt/beta-catenin were associated with head and neck cancer through beta-catenin cytoplasmatic accumulation. OBJECTIVE: The aim of the study was to evaluate DACT1 and DACT2 expression and methylation on oral squamous cell cancer (OSCC). METHODS: 47 samples of salivary rinse and tissue were collected from 29 OSCC and 18 control patients. qMSP and RT-PCR reactions were performed in order to detect hypermethylation and expression of DACT1 and DACT2 genes. Statistical analysis was conducted to evaluate these genes as possible biomarkers for OSCC. RESULTS: As expected man over 60 years old with tobacco and alcohol consumption history were associated with OSCC. There was no statistical difference between groups concerning DACT1 and DACT2 either in promoter hypermethylation or transcript levels. Age was associated with DACT2 promoter hypermethylation, especially over 56 years old. CONCLUSION: Patients older than 56 years old were about 5 times more likely to have DACT2 promoter hypermethylation. These findings could partially explain why older subjects are more prone to carcinogenesis. Wnt/beta catenin pathway plays an important role in carcinogenesis, and the study of their regulators may help understand malignant transformation. PMID- 25524938 TI - p21{Waf1/CIP1} is a poor diagnostic and prognostic marker for OSCC although its expression increases in patients with N1 regional metastasis. AB - OBJECTIVES: Downregulation of p21{Waf1/CIP1} (a cyclin-dependent kinase inhibitor) has been reported for mouth cancer. The goal of this article is to quantitatively report expression of p21{Waf1/CIP1} and evaluate its relationship with the clinical and prognostic factors. MATERIALS AND METHODS: this is a retrospective study of 68 patients diagnosed with OSCC. We constructed a tissue microarray to develop an immunohistochemical assessment of p21{Waf1/CIP1} expression. A multivariate analysis using a forward-selection stepwise regression model (Cox, 1972) for predicting survival was performed. RESULTS: The quantitative expression of p21{Waf1/CIP1} showed a statistically significant relationship with the risk of lymph node metastasis, showing a higher expression in patients with homolateral single nodes of less than 3 cm (N1) (X{2}=6.58; p< 0.05). We found no statistically significant relationship with any other clinical or pathological parameters. The Cox univariate regression analysis verifies that the effect of the value of p21{Waf1/CIP1} on survival was not statistically significant (p=0.6). The best predictive multivariate Cox analysis included the covariates: recurrence, p21{Waf1/CIP1}, gender, stage, and dysplasia in the adjacent margin. All these variables showed a statistically significant relationship with survival, except p21{Waf1/CIP1}. CONCLUSION: quantitative determination of p21{Waf1/CIP1} standardizes and facilitates its analysis. Although its expression increases in patients with N1 regional metastasis, the loss of p21{WAF1/CIP1} does not seem to have any relationship with the clinical and pathological variables of the tumors. PMID- 25524939 TI - Genetic variants at 6p21.1 are associated with head and neck cancer in Chinese Han population. AB - BACKGROUND: A recent study synthesized several published genome-wide association studies (GWAS) on three types of cancers and identified variants at 6p21.1 and 7p15.3 as candidate susceptibility loci for multiple types of human cancers. However, the role of these loci in the development of head and neck cancer (HNC) is still unclear. METHODS: To evaluate the relationships between genetic variants in these regions and HNC risk, we genotyped two common SNPs rs2494938 at 6p21.1 and rs2285947 at 7p15.3 in a case-control study with a total of 503 HNC cases and 900 controls in Han Chinese. RESULTS: We found that rs2494938 at 6p21.1 was associated with a significantly increased risk of HNC in our population [AA vs. GG: adjusted odds ratio (OR)=1.84, 95% confidence interval (CI)=1.13-3.00, P=0.014; AAvs. GA/GG: adjusted OR=1.78, 95% CI=1.10-2.87, P=0.018]. However, no significant association was observed between rs2285947 at 7p15.3 and HNC risk. CONCLUSION: Our results suggest that genetic variants at 6p21.1 may play an important role in HNC development in Han Chinese, and rs2494938 may be a candidate marker for HNC susceptibility. PMID- 25524940 TI - Associations of miR-146a and miR-146b expression and clinical characteristics in papillary thyroid carcinoma. AB - BACKGROUND: Human miRNAs have emerged as potentially useful diagnostic and prognostic markers in cancer within the past decade. Abnormal expression of microRNA-146 (miR-146) has been found in several classes of cancers. OBJECTIVE: To explore expression and clinical associations of miR-146a and miR-146b in papillary thyroid carcinoma. METHODS: We investigated expressions of miR-146a and miR-146b in tissues and peripheral blood among 128 patients with primary PTC, 120 patients with nodular goiter and 120 healthy controls by RT-PCR. Furthermore, the associations between the miR-146a and miR-146b expression and clinical parameters of PTC were analyzed. RESULTS: Levels of miR-146a and miR-146b expression in PTC tissues were higher compared to the nodular goiter tissues (P=0.014 and 0.001) and perineoplastic thyroid tissues (P=0.023 and 0.002). Positive associations were found between levels of miR-146a expression in PTC tissues and gender (female), cervical lymph node metastasis, multifocality, extra tyroidal invasion and advanced clinical TNM stages (III and IV). For miR-146b, there were positive association between levels of miR-146b expression and female, extra tyroidal invasion and advanced clinical TNM stages. CONCLUSIONS: Up-regulation of miR-146a and miR-146b expression in tissues was related to carcinogenesis and deterioration of PTC. MicroRNA-146a and miR-146b expressed in thyroid tissue may act as potential biomarkers for PTC patients. PMID- 25524941 TI - HIF1A expression in localized prostate cancer treated with dose escalation radiation therapy. AB - PURPOSE: To analyze the expression of hypoxia inducible factor 1 alpha (HIF1A) and its correlation with clinical outcome in men with localized prostate cancer (PC) treated with dose escalation radiotherapy (RT) and androgen deprivation (AD). METHODS: Between 1996 and 2004, 129 PC patients who had diagnostic biopsies pre-treatment and 24-36 months following RT were enrolled in this study. Median follow-up was 129 months. Suitable archival diagnostic tissue was obtained from 86 patients. Correlation analysis was done to assess association between HIF1A expression and clinical outcome. RESULTS: HIF1A expression was observed in 25/86 (29%) of diagnostic biopsies, and in 5/14 (36%) of post-RT biopsies. No significant association was noted between HIF1A expression and clinical and treatment parameters. We also failed to show a significant correlation between HIF1A overexpression and outcome. A borderline significant relationship was observed between expression of HIF1A and overall survival (OS) (HR 0.03, p=0.08). CONCLUSION: To our knowledge this is the first study assessing the pattern of change of HIF1A staining in biopsies of patients prior and following treatment. While we did not find significant variations in the expression of HIF1A following radio-hormone therapy, a high HIF1A expression was unexpectedly associated with a borderline improved OS. PMID- 25524942 TI - Diagnostic value of circulating miR-21 for colorectal cancer: a meta-analysis. AB - BACKGROUND: MicroRNA-21 (miR-21) is highly expressed in the plasma of colorectal cancer (CRC) patients. Thus, miR-21 may be a useful novel diagnostic biomarker for CRC. This meta-analysis aims to verify the diagnostic value of circulating miR-21 in CRC patients. METHODS: A literature search was conducted for publications that evaluated the diagnostic value of miR-21 for CRC. The quality of each study was scored with the Quality Assessment of Diagnostic Accuracy Studies. The bivariate meta-analysis model was employed to summarize the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). Receiver operating characteristic curves were used to check the overall test performance. RESULTS: Five publications with six studies involving 579 patients and 266 controls were included in this meta-analysis. The pooled sensitivity was 77.4% [95% confidence interval (CI): 67.2%-85.1%], specificity was 84.6% (95% CI: 79.7%-88.5%), PLR was 5.02 (95% CI: 3.73-6.75), NLR was 0.27 (95% CI: 0.18-0.40), and DOR was 18.77 (95% CI: 10.41-33.83). The area under the summary ROC curve was 0.86. In addition, the results became prominent in the CRC group when a study that explored the advanced adenoma was excluded. CONCLUSION: Circulating miR-21 may be a suitable diagnostic biomarker for CRC with moderate sensitivity and specificity. Further studies should evaluate the diagnostic value of miR-21 for CRC in the future. PMID- 25524943 TI - The associations of nucleotide polymorphisms in mir-196a2, mir-146a, mir-149 with lung cancer risk. AB - BACKGROUND: Many studies have explored the associations between microRNAs (miRNAs) polymorphisms and lung cancer susceptibility. However, due to their limited statistical sizes, some discrepancies were discovered in these studies. This article summarized eligible studies to identify the roles of miRNAs polymorphisms in lung cancer, and analyzed the associations of polymorphisms in mir-196a2, mir-146a and mir-149 with lung cancer risk respectively. METHODS: The PubMed, Web of Science, ScienceDirect and CNKI databases were searched updated to May 30, 2014. The complete data of three miRNAs polymorphisms for lung cancer were analyzed by odd ratios (ORs) and 95% confidence intervals (CIs). Finally, four studies about mir-196a2 single nucleotide polymorphism (SNP), two studies about mir-146a SNP, three studies about mir-149 SNP were investigated in this analysis. RESULTS: The mir-196a2 polymorphism was revealed to be associated with lung cancer susceptibility (additive model: OR=1.120, 95%CI 1.030 ~ 1.217, P=0.008; dominant model: OR=1.118, 95%CI 1.039 ~ 1.357, P=0.011; recessive model: OR=1.133, 95%CI 0.987 ~ 1.300, P=0.077). However, no relationships were discovered between mir-146a or mir-149 polymorphism and lung cancer risk. CONCLUSIONS: This meta-analysis demonstrates that mir-196a2 SNP influences the susceptibility of lung cancer. Mir-146a and mir-149 SNP do not play a role in lung cancer risk. These findings need more validation by larger studies. PMID- 25524944 TI - Prognostic and predictive significance of thymidylate synthase protein expression in non-small cell lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: It remains controversial whether thymidylate synthase (TS) protein expression is associated with survival for patients with non-small cell lung cancer (NSCLC). OBJECTIVE: To evaluate prognostic and predictive significance of tumor TS protein level in NSCLC. METHODS: Electronic searches were performed for relevant studies in PubMed, EMBASE, Web of Science, and Chinese Biomedical Literature Database. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled for meta-analysis. Subgroup and sensitivity analyses were performed. Publication bias was evaluated by funnel plot and Begg's test. RESULTS: Twenty-four studies, including 2280 patients, were eligible. This analysis showed that patients with low TS expression had statistically significantly longer OS and PFS than those with high TS (HR=0.51 and HR=0.49, respectively). Based on TS-targeted drug use status, TS expression was significantly associated with OS in pemetrexed (HR=0.42) and 5-Fluorouracil subgroups (HR=0.34), but not in no TS-targeted drug subgroup. There were similar results for PFS analyses. Sensitivity analysis indicated that the results were robust. Begg's test did not reveal any publication bias. CONCLUSION: Low TS protein expression is a favorable predictive factor for better OS/PFS in NSCLC patients treated with TS-targeted drugs. Prognostic value of TS protein expression needs further validation. PMID- 25524945 TI - The identification and characterization of a STAT5 gene signature in hematologic malignancies. AB - BACKGROUND: The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. Dysregulated JAK-STAT signaling has been implicated in the pathogenesis of multiple human malignancies. OBJECTIVE: Given this pivotal role of JAK-STAT dysregulation, it is important to identify patients with an overactive JAK-STAT pathway for possible treatment with JAK inhibitors. METHODS: We developed a gene signature assay to detect overactive JAK-STAT signaling. The cancer cell line encyclopedia and associated gene expression data were used to correlate the activation status of STAT5 with the induction of a set of STAT5 target genes. RESULTS: Four target genes were identified (PIM1, CISH, SOCS2, and ID1), the expression of which correlated significantly with pSTAT5 status in 40 hematologic tumor cell lines. In pSTAT5 positive models, the expression of the gene signature genes decreased following ruxolitinib treatment, which corresponded to pSTAT5 downmodulation. In pSTAT5 negative cell lines, neither pSTAT5 modulation nor a change in signature gene expression was observed following ruxolitinib treatment. CONCLUSIONS: The gene signature can potentially be used to stratify or enrich for patient populations with activated JAK-STAT5 signaling that might benefit from treatments targeting JAK-STAT signaling. Furthermore, the 4-gene signature is a predictor of the pharmacodynamic effects of ruxolitinib. PMID- 25524946 TI - No association of single nucleotide polymorphisms involved in GHRL and GHSR with cancer risk: a meta-analysis. AB - BACKGROUND: Ghrelin was associated with several of cancers. The conflict results of SNPs with GHRL and GHSR gene were demonstrated in different studies. Thus, this meta-analysis is to evaluate the associations. METHODS: Systematic literature search was done on PubMed database up to October 2013. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association by a fixed-effect model and a random-effect model. RESULTS: A total of 7 studies, which included 3 studies for breast cancer, 2 for colorectal cancer, 1 for hepatocellular carcinoma, 1 for esophageal cancer and 1 for Non Hodgkin lymphoma. When analyzed all the GHRL SNPs with all kinds of cancers, there was significantly difference with cancer patients compared with controls (Recessive model: OR 0.938, 95% CI 0.890-0.989, p=0.017), while no significant difference was existed in the additive model (OR 0.9903, 95% CI 0.957-1.024, p=0.558) and dominant model (OR 1.014, 95% CI 0.970-1.061, p=0.536). When analyzed all the GHSR SNPs with all kinds of cancers, no significant difference was observed. CONCLUSION: Our results suggest that the SNP with GHRL and GHSR might be weaker association with cancer risk, especially with breast cancer risk. PMID- 25524947 TI - Antipapain activity in the serum of patients with breast cancer. AB - BACKGROUND: Complement information about the share the role of antipapain activity in serum people with breast cancer. OBJECTIVE: We measured the activity of cysteine peptidase inhibitors in the sera of 150 patients with breast cancer. Patients were divided into four groups depending on the cancer type and treatment method. We also analysed the control group. The activity of cysteine peptidase inhibitors was defined as a 'defensiveness' marker. METHODS: The activity of cysteine peptidase inhibitors was measured against papain using the colorimetric method and the BANA substrate. RESULTS: The highest activity of enzymes was found in the group of patients with BC and hereditary predisposition to it, and the lowest activity was found in patients after surgical treatment. CONCLUSION: The activity of cysteine peptidase inhibitors in serum was measured against papain. We found that the activity levels were correlated with the cancer stage and treatment method. The lowest activity was found in patients after surgical treatment; the highest in women with active cancer and a hereditary predisposition to it. PMID- 25524948 TI - Progression of diabetes retinal status within community screening programs and potential implications for screening intervals. AB - OBJECTIVE: This study aimed to follow the natural progression of retinal changes in patients with diabetes. Such information should inform decisions with regard to the screening intervals for such patients. RESEARCH DESIGN AND METHODS: An observational study was undertaken linking the data from seven diabetes retinal screening programs across the U.K. for retinal grading results between 2005 and 2012. Patients with absent or background retinopathy were followed up for progression to the end points referable retinopathy and treatable retinopathy (proliferative retinopathy). RESULTS: In total, 354,549 patients were observed for up to 4 years during which 16,196 patients progressed to referable retinopathy. Of patients with no retinopathy in either eye for two successive screening episodes at least 12 months apart, the conditions of between 0.3% (95% CI 0.3-0.8%) and 1.3% (1.0-1.6%) of patients progressed to referable retinopathy, and rates of treatable eye disease were <0.3% at 2 years. The corresponding progression rates for patients with bilateral background retinopathy in successive screening episodes were 13-29% and up to 4%, respectively, in the different programs. CONCLUSIONS: It may be possible to stratify patients for risk, according to baseline retinal criteria, into groups with low and high risk of their conditions progressing to proliferative retinopathy. Screening intervals for such diverse groups of patients could safely be modified according to their risk. PMID- 25524949 TI - comparative study of glucose homeostasis, lipids and lipoproteins, HDL functionality, and cardiometabolic parameters in modestly severely obese African Americans and White Americans with prediabetes: implications for the metabolic paradoxes. AB - OBJECTIVE: To determine whether modestly severe obesity modifies glucose homeostasis, levels of cardiometabolic markers, and HDL function in African Americans (AAs) and white Americans (WAs) with prediabetes. RESEARCH DESIGN AND METHODS: We studied 145 subjects with prediabetes (N = 61 WAs, N = 84 AAs, mean age 46.5 +/- 11.2 years, mean BMI 37.8 +/- 6.3 kg/m(2)). We measured fasting levels of lipids, lipoproteins, and an inflammatory marker (C-reactive protein [CRP]); HDL functionality (i.e., levels of paraoxonase 1 [PON1]); and levels of oxidized LDL, adiponectin, and interleukin-6 (IL-6). We measured serum levels of glucose, insulin, and C-peptide during an oral glucose tolerance test. Values for insulin sensitivity index (Si), glucose effectiveness index (Sg), glucose effectiveness at zero insulin (GEZI), and acute insulin response to glucose (AIRg) were derived using a frequently sampled intravenous glucose tolerance test (using MINMOD software). RESULTS: Mean levels of fasting and incremental serum glucose, insulin, and C-peptide tended to be higher in WAs versus AAs. The mean Si was not different in WAs versus AAs (2.6 +/- 2.3 vs. 2.9 +/- 3.0 * 10(-4) * min(-1) [MUU/mL](-1)). Mean values for AIRg and disposition index as well as Sg and GEZI were lower in WAs than AAs. WAs had higher serum triglyceride levels than AAs (116.1 +/- 55.5 vs. 82.7 +/- 44.2 mg/dL, P = 0.0002). Mean levels of apolipoprotein (apo) A1, HDL cholesterol, PON1, oxidized LDL, CRP, adiponectin, and IL-6 were not significantly different in obese AAs versus WAs with prediabetes. CONCLUSIONS: Modestly severe obesity attenuated the ethnic differences in Si, but not in Sg and triglyceride levels in WAs and AAs with prediabetes. Despite the lower Si and PON1 values, AAs preserved paradoxical relationships between the Si and HDL/apoA1/triglyceride ratios. We conclude that modestly severe obesity has differential effects on the pathogenic mechanisms underlying glucose homeostasis and atherogenesis in obese AAs and WAs with prediabetes. PMID- 25524950 TI - Pharmacokinetics and pharmacodynamics of insulin glargine given in the evening as compared with in the morning in type 2 diabetes. AB - OBJECTIVE: To compare pharmacokinetics (PK) and pharmacodynamics (PD) of insulin glargine in type 2 diabetes mellitus (T2DM) after evening versus morning administration. RESEARCH DESIGN AND METHODS: Ten T2DM insulin-treated persons were studied during 24-h euglycemic glucose clamp, after glargine injection (0.4 units/kg s.c.), either in the evening (2200 h) or the morning (1000 h). RESULTS: The 24-h glucose infusion rate area under the curve (AUC0-24h) was similar in the evening and morning studies (1,058 +/- 571 and 995 +/- 691 mg/kg * 24 h, P = 0.503), but the first 12 h (AUC0-12h) was lower with evening versus morning glargine (357 +/- 244 vs. 593 +/- 374 mg/kg * 12 h, P = 0.004), whereas the opposite occurred for the second 12 h (AUC12-24h 700 +/- 396 vs. 403 +/- 343 mg/kg * 24 h, P = 0.002). The glucose infusion rate differences were totally accounted for by different rates of endogenous glucose production, not utilization. Plasma insulin and C-peptide levels did not differ in evening versus morning studies. Plasma glucagon levels (AUC0-24h 1,533 +/- 656 vs. 1,120 +/- 344 ng/L/h, P = 0.027) and lipolysis (free fatty acid AUC0-24h 7.5 +/- 1.6 vs. 8.9 +/ 1.9 mmol/L/h, P = 0.005; beta-OH-butyrate AUC0-24h 6.8 +/- 4.7 vs. 17.0 +/- 11.9 mmol/L/h, P = 0.005; glycerol, P < 0.020) were overall more suppressed after evening versus morning glargine administration. CONCLUSIONS: The PD of insulin glargine differs depending on time of administration. With morning administration insulin activity is greater in the first 0-12 h, while with evening administration the activity is greater in the 12-24 h period following dosing. However, glargine PK and plasma C-peptide levels were similar, as well as glargine PD when analyzed by 24-h clock time independent of the time of administration. Thus, the results reflect the impact of circadian changes in insulin sensitivity in T2DM (lower in the night-early morning vs. afternoon hours) rather than glargine per se. PMID- 25524952 TI - Prevalence and determinants of overweight, obesity, and type 2 diabetes mellitus in adults in Malaysia. AB - This systematic review aimed to examine trends in overweight, obesity, and type 2 diabetes mellitus (T2DM) among Malaysian adults, and to identify its underlying determinants. A review of studies published between 2000 and 2012 on overweight, obesity, and T2DM was conducted. The Cochrane library of systematic reviews, MEDLINE, EMBASE, Biosis, Scopus, and MyJurnal digital database were searched. According to national studies, the prevalence of overweight increased from 26.7% in 2003 to 29.4% in 2011; obesity prevalence increased from 12.2% in 2003 to 15.1% in 2011, and T2DM prevalence was reported as 11.6% in 2006 and 15.2% in 2011. Distal determinants of increased risk of overweight, obesity, and T2DM were as follows: female, Malay/Indian ethnicity, and low educational level. The limited number of studies on proximal determinants of these noncommunicable diseases (NCDs) indicated that an unhealthy diet was associated with increased risk, whereas smoking was associated with decreased risk. However, more studies on the proximal determinants of overweight, obesity, and T2DM within the Malaysian context are needed. Overall, our findings provide insights for designing both future investigative studies and strategies to control and prevent these NCDs in Malaysia. PMID- 25524951 TI - Serum 25-hydroxyvitamin D: a predictor of macrovascular and microvascular complications in patients with type 2 diabetes. AB - OBJECTIVE: People with diabetes frequently develop vascular disease. We investigated the relationship between blood 25-hydroxyvitamin D (25OH-D) concentration and vascular disease risk in type 2 diabetes. RESEARCH DESIGN AND METHODS: The relationships between blood 25OH-D concentration at baseline and the incidence of macrovascular (including myocardial infarction and stroke) and microvascular (retinopathy, nephropathy, neuropathy, and amputation) disease were analyzed with Cox proportional hazards models and logistic regression in an observational study of patients in the 5-year Fenofibrate Intervention and Event Lowering in Diabetes trial. RESULTS: A total of 50% of the patients had low vitamin D concentrations, as indicated by median blood 25OH-D concentration of 49 nmol/L. These patients with a blood 25OH-D concentration <50 nmol/L had a higher cumulative incidence of macrovascular and microvascular events than those with levels >=50 nmol/L. Multivariate analysis, stratified by treatment and adjusted for relevant confounders, identified blood 25OH-D concentration as an independent predictor of macrovascular events. A 50 nmol/L difference in blood 25OH-D concentration was associated with a 23% (P = 0.007) change in risk of macrovascular complications during the study, and further adjustments for seasonality, hs-CRP, and physical activity level had little impact. The unadjusted risk of microvascular complications was 18% (P = 0.006) higher during the study, though the excess risk declined to 11-14% and lost significance with adjustment for HbA1c, seasonality, or physical activity. CONCLUSIONS: Low blood 25OH-D concentrations are associated with an increased risk of macrovascular and microvascular disease events in type 2 diabetes. However, a causal link remains to be demonstrated. PMID- 25524953 TI - hSOD1 promotes tau phosphorylation and toxicity in the Drosophila model. AB - Tau hyperphosphorylation has been found in several neurodegenerative diseases such as Alzheimer's disease (AD), Down syndrome, and amyotrophic lateral sclerosis (ALS). However, factors affecting tau hyperphosphorylation are not yet clearly understood. SOD1, a Cu/Zn superoxide dismutase whose mutations can cause adult-onset ALS, is believed to be involved in the pathology of Down syndrome. In this work, the model organism Drosophila was used to study the possible link between hSOD1 and tau. Our results show that hSOD1, and to a higher degree hSOD1(A4V), can increase tau toxicity in Drosophila and exacerbate the corresponding neurodegeneration phenotype. The increased tau toxicity appears to be explainable by elevated tau phosphorylation. Tau(S2A), a tau mutant with impaired phosphorylation capabilities, does not respond to expression of hSOD1 and hSOD1(A4V). We suggest that increased SOD1 expression can lead to tau hyperphosphorylation, which might serve as an important contributing factor to the etiology of Down syndrome and SOD1-related ALS disease. PMID- 25524954 TI - Elevated HbA1c is associated with increased risk of incident dementia in primary care patients. AB - Type 2 diabetes mellitus (T2DM) is a risk factor of dementia. The effect of T2DM treatment quality on dementia risk, however, is unclear. 1,342 elderly individuals recruited via general practitioner registries (AgeCoDe cohort) were analyzed. This study analyzed the association between HbA1c level and the incidence of all-cause dementia (ACD) and of Alzheimer's disease dementia (referred to here as AD). HbA1c levels >=6.5% were associated with 2.8-fold increased risk of incident ACD (p = 0.027) and for AD (p = 0.047). HbA1c levels >=7% were associated with a five-fold increased risk of incident ACD (p = 0.001) and 4.7-fold increased risk of incident AD (p = 0.004). The T2DM diagnosis per se did not increase the risk of either ACD or AD. Higher levels of HbA1c are associated with increased risk of ACD and AD in an elderly population. T2DM diagnosis was not associated with increased risk if HbA1c levels were below 7%. PMID- 25524955 TI - Cognition, brain atrophy, and cerebrospinal fluid biomarkers changes from preclinical to dementia stage of Alzheimer's disease and the influence of apolipoprotein e. AB - BACKGROUND: Knowledge of Alzheimer's disease (AD) manifestation in the pre dementia stage facilitates the selection of appropriate measures for early detection and disease progression. OBJECTIVE: To examine the trajectories of cognitive performance, gray matter volume (GMV), and cerebrospinal fluid (CSF) biomarkers, together with the influence of apolipoprotein E (APOE) in subjects with amyloid-beta (Abeta) deposits across the pre-clinical to dementia stages of AD. METHODS: 356 subjects were dichotomized into Abeta+ and Abeta- groups based on their CSF Abeta1-42 level. We derived AD-related atrophic regions (AD-ROIs) using the voxel-based morphometry approach. We characterized the trajectories of cognitive scores, GMV at AD-ROIs, and CSF biomarkers from preclinical to disease stages in Abeta+ subjects. The effect of APOE epsilon4 genotype on these trajectories was examined. RESULTS: Impairments in executive functioning/processing speed (EF/PS) and atrophy at the right supramarginal/inferior parietal gyrus were detected in cognitively normal Abeta+ subjects. Together with the APOE epsilon4 carrier status, these measures showed potential to identify cognitively normal elderly with abnormal CSF Abeta1-42 level in another independent cohort. Subsequently, impairment in memory, visuospatial, language, and attention as well as atrophy in the temporal lobe, thalamus, and mid-cingulate cortex were detectable in Abeta+ mild cognitive impairment (MCI) subjects. In MCI and dementia Abeta+ subjects, epsilon4 carriers had more severe atrophy of the medial temporal lobe and memory impairment but higher EF/PS compared to non-carriers. CONCLUSIONS: EF/PS decline and right parietal atrophy might act as non-invasive screening tests for abnormal amyloid deposition in cognitively normal elderly. APOE modulation on subsequent trajectories in cognition and atrophy should be taken into account when analyzing disease progression. PMID- 25524956 TI - A combination of supplements may reduce the risk of Alzheimer's disease in elderly Japanese with normal cognition. AB - A number of studies have examined the effect of a single supplement against Alzheimer's disease (AD) with conflicting results. Taking into account the complex and multifactorial nature of AD pathogenesis, multiple supplements may be more effective. Physical activity is another prospect against AD. An open-label intervention study was conducted to explore a potential protective effect of multiple supplements and physical activity. Their interaction was also examined. Participants were community-dwelling volunteers aged 65 or older as of May 2001 in a rural area of Japan. Among 918 cognitively normal participants included in the analyses, 171 took capsules daily for three years that contained n-3 polyunsaturated fatty acid, Ginkgo biloba leaf dry extracts, and lycopene. Two hundred and forty one participants joined the two-year exercise intervention that included a community center-based and a home-based exercise program. One-hundred and forty eight participated in both interventions. A standardized neuropsychological battery was administered at baseline in 2001, the first follow up in 2004-2005, and the second in 2008-2009. The primary outcome was AD diagnosis at follow-ups. A complementary log-log model was used for survival analysis. A total of 76 participants were diagnosed with AD during follow-up periods. Higher adherence to supplementation intervention was associated with lower AD incidence in both unadjusted and adjusted models. Exercise intervention was also associated with lower AD incidence in the unadjusted model, but not in the adjusted model. We hypothesized that the combination of supplements acted in a complementary and synergistic fashion to bring significant effects against AD occurrence. PMID- 25524957 TI - Low noise in autism: cause or consequence? PMID- 25524958 TI - Adapting to domiciliary non-invasive ventilation in chronic obstructive pulmonary disease: a qualitative interview study. AB - BACKGROUND: Domiciliary non-invasive ventilation may be used in palliative care of patients with chronic obstructive pulmonary disease, although there is uncertainty regarding effect on quality of life. AIM: Explore experiences of domiciliary non-invasive ventilation in chronic obstructive pulmonary disease, to understand decision-making processes and improve future palliative care. DESIGN: Qualitative interview study, based on constructivist grounded theory, and using the framework method for data management and analysis. PARTICIPANTS: 20 chronic obstructive pulmonary disease patients, 4 carers and 15 healthcare professionals. RESULTS: Most patients had very severe chronic obstructive pulmonary disease. Data were categorised into four domains - clinical, technical, socio-economic and experiential. Healthcare professionals felt uncertain regarding clinical evidence, emphasising social support and tolerance as deciding factors in non invasive ventilation use. Conversely, patients reported symptomatic benefit, which generally outweighed negative experiences and led to continued use. Healthcare professionals felt that patients chose to be on non-invasive ventilation; however, most patients felt that they had no choice as healthcare professionals recommended non-invasive ventilation or their poor health mandated it. CONCLUSIONS: Our study identifies 'adapting to non-invasive ventilation' as the central process enabling long-term use in palliative care, although the way in which this is approached by healthcare professionals and patients does not always converge. We present ideas emerging from the data on potential interventions to improve patient experience and adaptation. PMID- 25524959 TI - Implementation of a Hospital-Based Home Palliative Care at regional level: a quantitative study of the Ospedalizzazione Domiciliare Cure Palliative Oncologiche program in Lombardy. AB - BACKGROUND: Home Palliative Care services can overcome trends of institutionalized dying and support higher rates of death at home. Home Palliative Care services rarely scale-up into regional health planning. This generates unwarranted variability in service provision and outcomes across patients. Lombardy Region sponsored a Hospital-Based Home Palliative Care program, which implemented a common service to oncological patients in the territory, with the purpose to align hospitals toward a target of 65% deaths at home. AIM: Our work assesses service characteristics and outcomes achieved by the regional program from 2009 to 2011. DESIGN AND SETTING: Descriptive analysis from an institutional database of service characteristics, regional expenditure, and outcomes (temporary hospitalization and patient discharge) representing 11,841 patients served by 24 providers in the period 2009-2011. RESULTS: Targets of 65% deaths at home were achieved across the Region, with temporary re-hospitalization below 4.4%. The average pathway length stood above 1 month; intensity of care stood above ministerial and regional standards, with most home visits performed by nurses and physicians. CONCLUSIONS: The implementation of the regional program revealed three strengths (prompt identification and enrollment of eligible patients, and quantity of home visits) and two weaknesses (limited enrollment from general practitioners and multi-disciplinarity). This highlights opportunities for policy-makers to invest on regional protocols of Hospital-Based Home Palliative Care to reduce trends of institutionalized dying and align providers to homogeneous results. PMID- 25524960 TI - Preparing palliative home care nurses to act as facilitators for physicians' learning: Evaluation of a training programme. AB - BACKGROUND: Palliative care requires a multidisciplinary care team. General practitioners often ask specialised palliative home care teams for support. Working with specialised nurses offers learning opportunities, also called workplace learning. This can be enhanced by the presence of a learning facilitator. OBJECTIVES: To describe the development and evaluation of a training programme for nurses in primary care. The programme aimed to prepare palliative home care team nurses to act as facilitators for general practitioners' workplace learning. DESIGN: A one-group post-test only design (quantitative) and semi structured interviews (qualitative) were used. METHODS: A multifaceted train-the trainer programme was designed. Evaluation was done through assignments with individual feedback, summative assessment through videotaped encounters with simulation-physicians and individual interviews after a period of practice implementation. RESULTS: A total of 35 nurses followed the programme. The overall satisfaction was high. Homework assignments interfered with the practice workload but showed to be fundamental in translating theory into practice. Median score on the summative assessment was 7 out of 14 with range 1-13. Interviews revealed some aspects of the training (e.g. incident analysis) to be too difficult for implementation or to be in conflict with personal preferences (focus on patient care instead of facilitating general practitioners' learning). CONCLUSION: Training palliative home care team nurses as facilitator of general practitioners' workplace learning is a feasible but complex intervention. Personal characteristics, interpersonal relationships and contextual variables have to be taken into account. Training expert palliative care nurses to facilitate general practitioners' workplace learning requires careful and individualised mentoring. PMID- 25524961 TI - Integration of palliative care into the routine care of cystic fibrosis patients. PMID- 25524962 TI - Is the use of negative pressure wound therapy for a malignant wound legitimate in a palliative context? "The concept of NPWT ad vitam": A case series. AB - BACKGROUND: The management of malignant wounds remains particularly difficult. They are often malodorous, highly exuding, and painful. In this context, the use of negative pressure wound therapy is usually not recommended. It is, however, an effective procedure for maintaining a good quality of life in certain palliative situations. CASE PRESENTATION: Five patients underwent negative pressure wound therapy for a malignant wound in our unit. Three had sarcomas, one patient had a parietal recurrence of breast carcinoma, and one patient had melanoma. They were in a metastatic palliative situation and were no longer receiving specific treatment. CASE MANAGEMENT AND OUTCOMES: The patients reported a decrease in odor and exudates with negative pressure wound therapy, compared with conventional dressings. No patients complained of pain associated with the suction system itself. Fewer dressing changes reduced the pain and encouraged the resumption of social interactions. The average duration of negative pressure wound therapy before the death of the patients was 49 days. No complications or bleeding were observed. The duration of the patients' stay was shortened by implementing negative pressure wound therapy at home. CONCLUSION: We report on our experiences with five patients for whom manufacturers and health authorities contraindicated the use of negative pressure wound therapy because of its potential to encourage tumor growth, although it was considered to be beneficial for all of these patients. This procedure may offer an alternative to conventional wound dressings at the end of life and improve the quality of life of patients by controlling the three most disabling elements: the odor, exudate, and pain associated with changing the dressings. Miniaturization and lower costs could promote the systematic use of negative pressure wound therapy. PMID- 25524963 TI - Discrepancy between symptom scoring and self-reported palliative care needs in a survey of interstitial lung disease patients. PMID- 25524964 TI - Change in physiological variables in the last 2 weeks of life: an observational study of hospital in-patients with cancer. AB - BACKGROUND: Recognising dying remains a difficult clinical skill which has gained increasing importance in the United Kingdom since the Neuberger review. Clinical and research methods exist to aid recognition of dying but do not exhibit the level of accuracy required for such an important decision. AIM: To explore change in key clinical parameters as cancer patients near the end of life. DESIGN: This is a retrospective cohort study of terminally ill patients. Data were collected from hospital case-notes. Case-note data were analysed using multilevel modelling to explore absolute values and rates of change of given variables. SETTING/PARTICIPANTS: Hospital in-patients who died from solid-tumour malignancies within a 3-month period in 2009 formed the cohort. The setting was an acute hospital trust in the North of England. RESULTS: A total of 15,337 data points from the case-notes of 102 patients were analysed. There was a clinically and statistically significant deterioration in respiratory function and renal function over the last 2 weeks of life. Heart rate and serum sodium also changed but did not vary greatly from normal limits. White cell parameters, haemoglobin and albumin showed evidence for change over longer periods. CONCLUSION: Results demonstrate statistically and clinically significant change in routinely measured respiratory and renal function variables during the final 2 weeks of life in people dying with cancer. Although useful in acute early warning scores, in a terminally ill patient, relative haemodynamic stability should not be interpreted as reassuring. Further work is needed to understand how these findings apply to the individual or inform other prognostic work. PMID- 25524965 TI - Peripheral quantitative computed tomography-derived muscle density and peripheral magnetic resonance imaging-derived muscle adiposity: precision and associations with fragility fractures in women. AB - PURPOSE: To determine the degree to which muscle density and fractures are explained by inter and intramuscular fat (IMF). METHODS: Women ?50 years of age (Hamilton, ON, Canada) had peripheral magnetic resonance imaging and peripheral quantitative computed tomography scans at 66% of the tibial length. Muscle on computed tomography images was segmented from subcutaneous fat and bone using fixed thresholds, computing muscle density. IMF was segmented from muscle within magnetic resonance images using a region-growing algorithm, computing IMF volume. Fracture history over the last 14 years was obtained. Odds ratios for fractures were determined for muscle density, adjusting for IMF volume, total hip BMD, age and body mass index. RESULTS: Women with a history of fractures were older (N=32, age:75.6+/-8.3 years) than those without (N=39, age: 67.0+/-5.2 years) (<0.01). IMF volume explained 49.3% of variance in muscle density (p<0.001). Odds for fractures were associated with lower muscle density even after adjusting for IMF volume but were attenuated after adjusting for age. CONCLUSIONS: Muscle adiposity represents only 50% of the muscle density measurement. Properties of muscle beyond its adiposity may be related to fractures, but larger and prospective studies are needed to confirm these associations. PMID- 25524966 TI - Associations between pQCT-based fat and muscle area and density and DXA-based total and leg soft tissue mass in healthy women and men. AB - Peripheral Quantitative Computed Tomography (pQCT) can be used for muscle and fat area and density assessments. These may independently influence muscle and fat mass measurements from Dual Energy X-ray Absorptiometry (DXA). OBJECTIVE: To determine associations between pQCT-derived soft tissue density and area measures and DXA-derived soft tissue mass. METHODS: Linear regression models were developed based on BMI and calf fat and muscle cross-sectional area (FCSA and MCSA) and density measured by pQCT in healthy women (n=76) and men (n=82) aged 20 59 years. Independent variables for these models were leg and total bone-free lean mass (BFLM) and fat mass (FM) measured by DXA. RESULTS: Sex differences (p<0.01) were found in both muscle (Mean+/-SE: Women: 78.6+/-0.4; Men: 79.9+/-0.2 mg/cm(3)) and fat (Women: 0.8+/-0.4 Men: 9.1+/-0.6 mg/cm(3)) density. BMI, fat density, and age (R(2)=0.86, p<0.01) best accounted for the variability in total FM. FCSA, BMI, and fat density explained the variance in leg FM (R(2)=0.87, p<0.01). MCSA and muscle density explained the variance in total (R(2)=0.65, p<0.01) and leg BFLM (R(2)=0.70, p<0.01). CONCLUSION: Calf muscle and fat area and density independently predict lean and fat tissue mass. PMID- 25524967 TI - Relationship between lower limb neuromuscular performance and bone strength in postmenopausal women with mild knee osteoarthritis. AB - OBJECTIVES: To investigate whether neuromuscular performance predicts lower limb bone strength in different lower limb sites in postmenopausal women with mild knee osteoarthritis (OA). METHODS: Neuromuscular performance of 139 volunteer women aged 50-68 with mild knee OA was measured using maximal counter movement jump test, isometric knee flexion and extension force and figure-of-eight-running test. Femoral neck section modulus (Z, mm(3)) was determined by data obtained from dual-energy X-ray absorptiometry. Data obtained using peripheral quantitative computed tomography was used to asses distal tibia compressive (BSId, g(2)/cm(4)) and tibial mid-shaft bending (SSImax(mid), mm(3)) strength indices. RESULTS: After adjustment for height, weight and age, counter movement jump peak power production was the strongest independent predictor for Z (beta=0.44; p<0.001) and for BSId (beta=0.32; p=0.003). This was also true in concentric net impulse for Z (beta=0.37; p=0.001) and for BSId (beta=0.40; p<0.001). Additionally, knee extension force (beta=0.30; p<0.001) and figure-of eight-running test (beta= -0.32; p<0.001) were among strongest independent predictors for BSId after adjustments. For SSImax(mid), concentric net impulse (beta=0.33; p=0.002) remained as the strongest independent predictor after adjustments. CONCLUSIONS: Neuromuscular performance in postmenopausal women with mild knee OA predicted lower limb bone strength in every measured skeletal site. PMID- 25524968 TI - Prevalence of sarcopenia: the impact of different diagnostic cut-off limits. AB - INTRODUCTION: In the definition of the European Working Group on Sarcopenia in Older People (EWGSOP), different cut-off limits are proposed for appendicular lean mass, muscle strength and gait speed. Therefore we aimed to examine the variation in prevalence of sarcopenia obtained with these cut-off limits. MATERIALS AND METHODS: Subjects aged 65 years and older were recruited in an outpatient clinic in Belgium and screened for sarcopenia using the EWGSOP definition. Appendicular lean mass was measured by Dual Energy X-Ray Absorptiometry, muscle strength by a hydraulic handgrip dynamometer and gait speed was measured on a 4-meter distance. Two different cut-off points proposed by the EWGSOP were examined for each variable and 8 diagnostic methods were thereby established. RESULTS: 400 subjects were recruited for this study. Prevalence of sarcopenia varied from 9.25% to 18% depending on the cut-offs applied. When stratified by sex, it seems that the variation in prevalence of sarcopenia was mainly attributable to women. This prevalence ranged from 6.58% to 20.2% for women and only from 13.4% to 14.7% for men. CONCLUSION: Prevalence of sarcopenia varies widely depending on the EWGSOP cut-off points applied for women. This may limit clinical researches and development of therapeutic strategies in the field of sarcopenia. PMID- 25524969 TI - Whey protein plus bicarbonate supplement has little effects on structural atrophy and proteolysis marker immunopatterns in skeletal muscle disuse during 21 days of bed rest. AB - OBJECTIVES: To investigate the effect of whey protein plus potassium bicarbonate supplement on disused skeletal muscle structure and proteolysis after bed rest (BR). METHODS: Soleus (SOL) and vastus lateralis (VL) biopsies were sampled from ten (n=10) healthy male subjects (aged 31+/-6 years) who did BR once with and once without protein supplement as a dietary countermeasure (cross-over study design). The structural changes (myofibre size and type distribution) were analysed by histological sections, and muscle protein breakdown indirectly via the proteolysis markers, calpain 1 and 3, calpastatin, MuRF1 and 2, both in muscle homogenates and by immunohistochemistry. RESULTS: BR caused size-changes in myofiber cross-sectional area (FCSA, SOL, p=0,004; VL, p=0.03), and myofiber slow-to-fast type transition with increased hybrids (SOL, p=0.043; VL, p=0.037) however with campaign differences in SOL (p<0.033). No significant effect of BR and supplement was found by any of the key proteolysis markers. CONCLUSIONS: Campaign differences in structural muscle adaptation may be an issue in cross over design BR studies. The whey protein plus potassium bicarbonate supplement did not attenuate atrophy and fibre type transition during medium term bed rest. Alkaline whey protein supplements may however be beneficial as adjuncts to exercise countermeasures in disuse. PMID- 25524970 TI - A specialized rehabilitation approach improves mobility in children with osteogenesis imperfecta. AB - OBJECTIVE: Osteogenesis imperfecta (OI) is a rare disease leading to recurrent fractures, hyperlaxicity of ligaments, short stature and muscular weakness. Physiotherapy is one important treatment approach. The objective of our analysis was to evaluate the effect of a new physiotherapy approach including side alternating whole body vibration on motor function in children with OI. METHODS: In a retrospective analysis data of 53 children were analyzed. The 12 months approach included 6 months of side alternating whole body vibration training, concomitant physiotherapy, resistance training, treadmill training and 6 months follow up. Primary outcome parameter was the Gross Motor Function Measure after 12 months (M12). RESULTS: 53 children (male: 32; age (mean+/-SEM): 9.1+/-0.61, range 2.54-24.81 years) participated in the treatment approach. A significant increase of motor function (GMFM-66 score 55.47+/-2.45 to 58.67+/-2.83; p=0.001) and walking distance (47.04 m+/-6.52 to 63.36+/-8.25 m (p<0.01) between M0 and M12 was seen. Total body without head bone mineral density increased significantly at M12 (p=0.0189). CONCLUSIONS: In the cohort of OI children which participated in the specialized treatment approach improvements of motor function were observed. Therefore this program should be considered as additional therapeutic approach for children with severe OI. PMID- 25524971 TI - Sharpin is a key regulator of skeletal homeostasis in a TNF-dependent manner. AB - OBJECTIVES: SHARPIN is a subunit of LUBAC and regulates activation of NF-kappaB, a pivotal transcription factor in skeletal homeostasis. Mutated SHARPIN gene (cpdm) mice develop chronic proliferative dermatitis and systemic inflammation. Cpdm mice have an osteopaenic phenotype characterised by decreased cortical and trabecular bone volume, but whether this is a consequence of the hyper inflammatory phenotype is unknown. The inflammatory phenotype of cpdm mice is prevented by Tnf deficiency so we examined cpdm.Tnf (-/-) mice to examine the role of SHARPIN in skeletal development. METHODS: This research determined the extent to which SHARPIN and TNF interact within the skeleton through analyses of gene expression, MUCT and biomechanical properties of bones of control (CTRL), cpdm, Tnf (-/-) (TNF KO) and cpdm.Tnf (-/-) (cpdm/TNF KO) mice. RESULTS: Gene expression of IL-1beta, TNF and caspase-3 increased in cpdm mice but was comparable to control values in cpdm/TNF KO mice. Decreased cortical and trabecular bone in cpdm mice translated to a loss in bone strength (ultimate stress and peak force). Cpdm/TNF KO mice developed bones similar to, or stronger than, control bones. CONCLUSIONS: Our results suggest that SHARPIN plays a significant role in skeletal homeostasis and that this role is strongly regulated through TNF pathways. PMID- 25524972 TI - Promotion of apoptosis and cytochrome c depletion by a low-temperature environment in hindlimb-unloading rats. AB - OBJECTIVE: This study aimed to clarify the influence of a low-temperature environment on muscle atrophy and apoptosis. METHODS: Wistar rats were divided into four groups: two groups of hindlimb-unloading rats maintained in a normal (25 degrees C, HU) or low-temperature (10 degrees C, HU+LT) environment for 3 weeks and two corresponding control groups (CON; normal temperature, CON+LT; low temperature). RESULTS: The soleus muscle wet weight and muscle-to-body mass ratio were lower in the experimental groups than in the control groups. The cross sectional areas of myofibers in the HU+LT and HU groups were significantly decreased than those in the CON and CON+LT groups. Ubiquitin ladder levels from soleus muscle lysates were significantly increased in the HU+LT group. Caspase-3 activated myofibers were observed only in the HU+LT group. Decreased cytochrome c levels were present in these caspase-3-activated myofibers. Meanwhile, cytochrome c levels were increased significantly in CON+LT rats but unchanged in HU+LT rats. CONCLUSION: Our results suggest that apoptosis caused by hindlimb unloading at low temperatures is associated with a lack of cytochrome c in myofibers. This indicates that long-term hindlimb unloading at low temperatures did not suppress muscle atrophy. We conclude that low-temperature stimulation should not be used as a long-term treatment for preventing disuse atrophy. PMID- 25524973 TI - Growth hormone mitigates loss of periosteal bone formation and muscle mass in disuse osteopenic rats. AB - Growth hormone (GH) is a potent anabolic agent capable of increasing both bone and muscle mass. The aim was to investigate whether GH could counteract disuse induced loss of bone and muscle mass in a rat model. Paralysis was induced by injecting 4 IU Botox (BTX) into the muscles of the right hind limb. Sixty female Wistar rats, 14 weeks old, were divided into the following groups: baseline, controls, BTX, BTX+GH, and GH. GH was given at a dosage of 5 mg/kg/d for 4 weeks. Compared with controls, BTX resulted in lower periosteal bone formation rate (BFR/BS,-79%, P<0.001), bone mineral density (aBMD, -13%, P<0.001), trabecular bone volume (BV/TV, -26%, P<0.05), and mid-femoral bone strength (-12%, P<0.05). In addition, BTX reduced rectus femoris muscle mass (-69%, P<0.001) and muscle cell cross sectional area (CSA) (-73%, P<0.001) compared with controls. GH counteracted disuse-induced losses of periosteal BFR/BS (2-fold increase vs. BTX, P<0.001), whereas no effect on aBMD, trabecular BV/TV, or bone strength was found. In addition, GH partly prevented loss of muscle mass (+29% vs. BTX, P<0.001), and tended to prevent loss of muscle CSA (+11%, P=0.064). In conclusion, GH mitigates disuse-induced loss of periosteal BFR/BS at the mid femur and rectus femoris muscle mass. PMID- 25524974 TI - Conservative treatment of humeral fracture in a patient with Paget's disease of bone. PMID- 25524975 TI - Effect of the abrasive properties of sedges on the intestinal absorptive surface and resting metabolic rate of root voles. AB - Recent studies on grasses and sedges suggest that the induction of a mechanism reducing digestibility of plant tissues in response to herbivore damage may drive rodent population cycles. This defence mechanism seems to rely on the abrasive properties of ingested plants. However, the underlying mechanism has not been demonstrated in small wild herbivores. Therefore, we carried out an experiment in which we determined the joint effect of abrasive sedge components on the histological structure of small intestine as well as resting metabolic rate (RMR) of the root vole (Microtus oeconomus). Histological examination revealed that voles fed with a sedge-dominated diet had shorter villi composed from narrower enterocytes in duodenum, jejunum and ileum. Reduction in the height of villi decreased along the small intestine. Activity of the mucus secretion increased along the small intestine and was significantly higher in the ileum. The intestinal abrasion exceeded the compensatory capabilities of voles, which responded to a sedge-dominated diet by a reduction of body mass and a concomitant decrease in whole body RMR. These results explain the inverse association between body mass and the probability of winter survival observed in voles inhabiting homogenous sedge wetlands. PMID- 25524976 TI - Comparative structural and functional analysis of the larval and adult dorsal vessel and its role in hemolymph circulation in the mosquito Anopheles gambiae. AB - Hemolymph circulation in insects is driven primarily by the contractile action of a dorsal vessel, which is divided into an abdominal heart and a thoracic aorta. As holometabolous insects, mosquitoes undergo striking morphological and physiological changes during metamorphosis. This study presents a comprehensive structural and functional analysis of the larval and adult dorsal vessel in the malaria mosquito Anopheles gambiae. Using intravital video imaging we show that, unlike the adult heart, the larval heart contracts exclusively in the anterograde direction and does not undergo heartbeat directional reversals. The larval heart contracts 24% slower than the adult heart, and hemolymph travels across the larval dorsal vessel at a velocity that is 68% slower than what is seen in adults. By fluorescently labeling muscle tissue we show that although the general structure of the heart and its ostia are similar across life stages, the heart associated alary muscles are significantly less robust in larvae. Furthermore, unlike the adult ostia, which are the entry points for hemolymph into the heart, the larval ostia are almost entirely lacking in incurrent function. Instead, hemolymph enters the larval heart through incurrent openings located at the posterior terminus of the heart. These posterior openings are structurally similar across life stages, but in adults have an opposite, excurrent function. Finally, the larval aorta and heart differ significantly in the arrangement of their cardiomyocytes. In summary, this study provides an in-depth developmental comparison of the circulatory system of larval and adult mosquitoes. PMID- 25524978 TI - Preparing the leg for ground contact in running: the contribution of feed-forward and visual feedback. AB - While running on uneven ground, humans are able to negotiate visible but also camouflaged changes in ground level. Previous studies have shown that the leg kinematics before touch down change with ground level. The present study experimentally investigated the contributions of visual perception (visual feedback), proprioceptive feedback and feed-forward patterns to the muscle activity responsible for these adaptations. The activity of three bilateral lower limb muscles (m. gastrocnemius medialis, m. tibialis anterior and m. vastus medialis) of nine healthy subjects was recorded during running across visible (drop of 0, -5 and -10 cm) and camouflaged changes in ground level (drop of 0 and -10 cm). The results reveal that at touchdown with longer flight time, m. tibialis anterior activation decreases and m. vastus medialis activation increases purely by feed-forward driven (flight time-dependent) muscle activation patterns, while m. gastrocnemius medialis activation increase is additionally influenced by visual feedback. Thus, feed-forward driven muscle activation patterns are sufficient to explain the experimentally observed adjustments of the leg at touchdown. PMID- 25524979 TI - Nutritional physiology of life-history trade-offs: how food protein-carbohydrate content influences life-history traits in the wing-polymorphic cricket Gryllus firmus. AB - Although life-history trade-offs result from the differential acquisition and allocation of nutritional resources to competing physiological functions, many aspects of this topic remain poorly understood. Wing-polymorphic insects, which possess alternative morphs that trade off allocation to flight capability versus early reproduction, provide a good model system for exploring this topic. In this study, we used the wing-polymorphic cricket Gryllus firmus to test how expression of the flight capability versus reproduction trade-off was modified across a heterogeneous protein-carbohydrate nutritional landscape. Newly molted adult female long- and short-winged crickets were given one of 13 diets with different concentrations and ratios of protein and digestible carbohydrate; for each cricket, we measured consumption patterns, growth and allocation to reproduction (ovary mass) versus flight muscle maintenance (flight muscle mass and somatic lipid stores). Feeding responses in both morphs were influenced more by total macronutrient concentration than by protein-carbohydrate ratio, except at high macronutrient concentration, where protein-carbohydrate balance was important. Mass gain tended to be greatest on protein-biased diets for both morphs, but was consistently lower across all diets for long-winged females. When long-winged females were fed high-carbohydrate foods, they accumulated greater somatic lipid stores; on high-protein foods, they accumulated greater somatic protein stores. Food protein-carbohydrate content also affected short-winged females (selected for early reproductive onset), which showed dramatic increases in ovary size, including ovarian stores of lipid and protein, on protein-biased foods. This is the first study to show how the concentration and ratio of dietary protein and carbohydrate affects consumption and allocation to key physiological features associated with the reproduction-dispersal life-history trade-off. PMID- 25524977 TI - Cortisol modulates vasotocinergic and isotocinergic pathways in the gilthead sea bream. AB - In the present study, we assessed the responses of the vasotocinergic and isotocinergic systems to chronic stress induced by cortisol administration in the gilthead sea bream (Sparus aurata). Pituitary and plasma arginine vasotocin (AVT) and isotocin (IT) levels, as well as hypothalamic pro-vasotocin (pro-VT) and pro isotocin (pro-IT) mRNA expression levels, were analysed. In addition, the mRNA levels of three receptors, AVTR type V1a2, AVTR type V2 and ITR, were analysed in several target organs associated with the following physiological processes: (i) integration and control (hypothalamus), (ii) metabolism and its control (liver and hypothalamus), (iii) osmoregulation (gills) and (iv) stress response (head kidney). Specimens were injected intraperitoneally with slow-release implants (5 MUL g(-1) body mass) containing coconut oil alone (control group) or with cortisol (50 MUg g(-1) body mass; cortisol group). Both AVT and IT synthesis and release were correlated with plasma cortisol values, suggesting a potential interaction between both hormonal systems and cortisol administration. Our results suggest that the activation of hepatic metabolism as well as the hypothalamic control of metabolic processes provide the energy necessary to overcome stress, which could be partly mediated by AVTRs and ITR. Upregulation of branchial AVT and IT receptor expression following cortisol treatment suggests an involvement of the vasotocinergic and isotocinergic systems in the regulation of ion channels/transporters during stressful situations. Finally, changes in AVT and IT receptor mRNA expression in the head kidney suggest these nonapeptides participate in feedback mechanisms that regulate the synthesis/release of cortisol. Our results indicate a relationship between cortisol and both the vasotocinergic and isotocinergic systems during simulated chronic stress in S. aurata. PMID- 25524980 TI - A genetic reduction in antioxidant function causes elevated aggression in mice. AB - Male-male aggression can have a large influence on access to mates, particularly in highly territorial animals such as mice. It has been suggested that males with impaired antioxidant defence and a consequential increased susceptibility to oxidative stress may have a reduced ability to invest in aggressive behaviours, which could limit their mating opportunities and reproductive success. Oxidative stress occurs as a result of an uncontrolled over-production of reactive oxygen species (ROS) in relation to defence mechanisms (such as antioxidants), and can cause damage to a variety of different cellular components. Impairments in specific aspects of antioxidant defence, leading to oxidative stress, can limit investment in some reproductive traits in males, such as sperm quality and the production of sexual signals to attract mates. However, a direct effect of impaired antioxidant defence on aggressive behaviour has not, to our knowledge, been reported. In this study, we demonstrate that mice with experimentally elevated sensitivity to oxidative stress (through inhibition of copper-zinc superoxide dismutase, Sod1) actually show the opposite response to previous predictions. Males completely deficient in SOD1 are more aggressive than both wild-type males and males that express 50% of this antioxidant enzyme. They are also faster to attack another male. The cause of this increased aggression is unknown, but this result highlights that aggressive behaviour in mice is not highly constrained by inhibited Sod1 expression, in contrast to other reproductive traits known to be impaired in this mouse model. PMID- 25524981 TI - Evidence for a carotid body homolog in the lizard Tupinambis merianae. AB - The homolog to the mammalian carotid body has not yet been identified in lizards. Observational studies and evolutionary history provide indirect evidence for the existence of a chemoreceptor population at the first major bifurcation of the common carotid artery in lizards, but a chemoreceptive role for this area has not yet been definitively demonstrated. We explored this possibility by measuring changes in cardiorespiratory variables in response to focal arterial injections of the hypoxia mimic sodium cyanide (NaCN) into the carotid artery of 12 unanesthetized specimens of Tupinambis merianae. These injections elicited increases in heart rate (f(H); 101+/-35% increase) and respiratory rate (f(R); 620+/-119% increase), but not mean arterial blood pressure (MAP). These responses were eliminated by vagal denervation. Similar responses were elicited by injections of the neurotransmitters acetylcholine (ACh) and serotonin (5-HT) but not norepinephrine. Heart rate and respiratory rate increases in response to NaCN could be blocked or reduced by antagonists to ACh (atropine) and/or 5-HT (methysergide). Finally, using immunohistochemistry, we demonstrate the presence of putative chemoreceptive cells immunopositive for the cholinergic cell marker vesicular ACh transporter (VAChT) and 5-HT on internal lattice-like structures at the carotid bifurcation. These results provide evidence in lizards for the existence of dispersed chemoreceptor cells at the first carotid bifurcation in the central cardiovascular area that have similar properties to known carotid body homologs, adding to the picture of chemoreceptor evolution in vertebrates. PMID- 25524982 TI - Behavioral correction to prevent overhydration and increase survival by larvae of the net-spinning caddisflies in relation to water flow. AB - We report behavioral regulation of body water content in caddisfly larvae, Hydropsyche morosa and Cheumatopsyche pettiti, by selecting microhabitats with different water flow rates. The purpose of our study was to examine features necessary for survival in the same apparent habitat, because the two species co exist in riffle areas of freshwater streams. Both species are highly sensitive to water loss as a result of high water loss rates and depend on immersion in fresh water (hypo-osmotic) to maintain water stores. In contrast to C. pettiti, H. morosa is larger, retains water more effectively, and features reduced water loss rates with suppressed activation energies. When H. morosa was confined to areas of low or no water flow, overhydration led to rapid mortality, whereas the same conditions favored water balance maintenance and survival in C. pettiti. In attraction bioassays, H. morosa moved and remained within areas of high water flow and C. pettiti preferred areas with low water flow. Because water flow rates are unlikely to directly impact water gain, the mechanism responsible for increased survival and water balance maintenance is likely related to the impact of water flow on oxygen availability, differences in feeding ecology, or other underlying factors. PMID- 25524983 TI - Locomotor benefits of being a slender and slick sand swimmer. AB - Squamates classified as 'subarenaceous' possess the ability to move long distances within dry sand; body elongation among sand and soil burrowers has been hypothesized to enhance subsurface performance. Using X-ray imaging, we performed the first kinematic investigation of the subsurface locomotion of the long, slender shovel-nosed snake (Chionactis occipitalis) and compared its biomechanics with those of the shorter, limbed sandfish lizard (Scincus scincus). The sandfish was previously shown to maximize swimming speed and minimize the mechanical cost of transport during burial. Our measurements revealed that the snake also swims through sand by propagating traveling waves down the body, head to tail. Unlike the sandfish, the snake nearly followed its own tracks, thus swimming in an approximate tube of self-fluidized granular media. We measured deviations from tube movement by introducing a parameter, the local slip angle, betas, which measures the angle between the direction of movement of each segment and body orientation. The average betas was smaller for the snake than for the sandfish; granular resistive force theory (RFT) revealed that the curvature utilized by each animal optimized its performance. The snake benefits from its slender body shape (and increased vertebral number), which allows propagation of a higher number of optimal curvature body undulations. The snake's low skin friction also increases performance. The agreement between experiment and RFT combined with the relatively simple properties of the granular 'frictional fluid' make subarenaceous swimming an attractive system to study functional morphology and bauplan evolution. PMID- 25524984 TI - Comparative whole-body kinematics of closely related insect species with different body morphology. AB - Legged locomotion through natural environments is very complex and variable. For example, leg kinematics may differ strongly between species, but even within the same species it is adaptive and context-dependent. Inter-species differences in locomotion are often difficult to interpret, because both morphological and ecological differences among species may be strong and, as a consequence, confound each other's effects. In order to understand better how body morphology affects legged locomotion, we compare unrestrained whole-body kinematics of three stick insect species with different body proportions, but similar feeding ecology: Carausius morosus, Aretaon asperrimus and Medauroidea extradentata (=Cuniculina impigra). In order to co-vary locomotory context, we introduced a gradually increasing demand for climbing by varying the height of stairs in the setup. The species were similar in many aspects, for example in using distinct classes of steps, with minor differences concerning the spread of corrective short steps. Major differences were related to antenna length, segment lengths of thorax and head, and the ratio of leg length to body length. Whereas all species continuously moved their antennae, only Medauroidea executed high swing movements with its front legs to search for obstacles in the near-range environment. Although all species adjusted their body inclination, the range in which body segments moved differed considerably, with longer thorax segments tending to be moved more. Finally, leg posture, time courses of leg joint angles and intra-leg coordination differed most strongly in long-legged Medauroidea. PMID- 25524985 TI - Immediate and delayed effects of growth conditions on ageing parameters in nestling zebra finches. AB - Conditions experienced during development and growth are of crucial importance as they can have a significant influence on the optimisation of life histories. Indeed, the ability of an organism to grow fast and achieve a large body size often confers short- and long-term fitness benefits. However, there is good evidence that organisms do not grow at their maximal rates as growth rates seem to have potential costs on subsequent lifespan. There are several potential proximate causes of such a reduced lifespan. Among them, one emerging hypothesis is that growth impacts adult survival and/or longevity through a shared, end point, ageing mechanism: telomere erosion. In this study, we manipulated brood size in order to investigate whether rapid growth (chicks in reduced broods) is effectively done at the cost of a short- (end of growth) and long-term (at adulthood) increase of oxidative damage and telomere loss. Contrary to what we expected, chicks from the enlarged broods displayed more oxidative damage and had shorter telomeres at the end of the growth period and at adulthood. Our study extends the understanding of the proximate mechanisms involved in the trade-off between growth and ageing. It highlights that adverse environmental conditions during growth can come at a cost via transient increased oxidative stress and pervasive eroded telomeres. Indeed, it suggests that telomeres are not only controlled by intrinsic growth rates per se but also may be under the control of some extrinsic environmental factors, which could complicate our understanding of the growth-ageing interaction. PMID- 25524986 TI - The Yerkes-Dodson law and appropriate stimuli for conditioned taste aversion in Lymnaea. AB - The pond snail Lymnaea stagnalis can learn conditioned taste aversion and then consolidate it into long-term memory (LTM). A high-voltage electric shock was used as the unconditioned stimulus, where we have previously used KCl. We varied the strength of both the conditioned and unconditioned stimuli to determine whether the so-called Yerkes-Dodson law prevailed. This is an empirical relationship between the state of arousal and LTM formation, showing that there is an optimal level of arousal leading to memory formation. However, too little or too much arousal results in poorer LTM. We found here that the most appropriate stimuli to use in taste aversion training in Lymnaea were a 10 mmol l(-1) sucrose solution as the conditioned stimulus and a 3 s electric shock as the unconditioned stimulus. PMID- 25524987 TI - The colony environment modulates sleep in honey bee workers. AB - One of the most important and evolutionarily conserved roles of sleep is the processing and consolidation of information acquired during wakefulness. In both insects and mammals, environmental and social stimuli can modify sleep physiology and behavior, yet relatively little is known about the specifics of the wake experiences and their relative contribution to experience-dependent modulation of sleep. Honey bees provide an excellent model system in this regard because their behavioral repertoire is well characterized and the environment they experience during the day can be manipulated while keeping an ecologically and sociobiologically relevant context. We examined whether social experience modulates sleep in honey bees, and evaluated the relative contribution of different social signals. We exposed newly emerged bees to different components of their natural social environment and then monitored their sleep behavior in individual cages in a constant lab environment. We found that rich waking experience modulates subsequent sleep. Bees that experienced the colony environment for 1 or 2 days slept more than same-age sister bees that were caged individually or in small groups in the lab. Furthermore, bees placed in mesh enclosures in the colony, that prevented direct contact with nestmates, slept similarly to bees freely moving in the colony. These results suggest that social signals that do not require direct or close distance interactions between bees are sufficiently rich to encompass almost the entire effect of the colony on sleep. Our findings provide a remarkable example of social experience-dependent modulation of an essential biological process. PMID- 25524989 TI - Parallel ionoregulatory adjustments underlie phenotypic plasticity and evolution of Drosophila cold tolerance. AB - Low temperature tolerance is the main predictor of variation in the global distribution and performance of insects, yet the molecular mechanisms underlying cold tolerance variation are poorly known, and it is unclear whether the mechanisms that improve cold tolerance within the lifetime of an individual insect are similar to those that underlie evolved differences among species. The accumulation of cold-induced injuries by hemimetabolous insects is associated with loss of Na(+) and K(+) homeostasis. Here we show that this model holds true for Drosophila; cold exposure increases haemolymph [K(+)] in D. melanogaster, and cold-acclimated flies maintain low haemolymph [Na(+)] and [K(+)], both at rest and during a cold exposure. This pattern holds across 24 species of the Drosophila phylogeny, where improvements in cold tolerance have been consistently paired with reductions in haemolymph [Na(+)] and [K(+)]. Cold-acclimated D. melanogaster have low activity of Na(+)/K(+)-ATPase, which may contribute to the maintenance of low haemolymph [Na(+)] and underlie improvements in cold tolerance. Modifications to ion balance are associated with both phenotypic plasticity within D. melanogaster and evolutionary differences in cold tolerance across the Drosophila phylogeny, which suggests that adaptation and acclimation of cold tolerance in insects may occur through similar mechanisms. Cold-tolerant flies maintain haemolymph osmolality despite low haemolymph [Na(+)] and [K(+)], possibly through modest accumulations of organic osmolytes. We propose that this could have served as an evolutionary route by which chill-susceptible insects developed more extreme cold tolerance strategies. PMID- 25524988 TI - Opsins in Limulus eyes: characterization of three visible light-sensitive opsins unique to and co-expressed in median eye photoreceptors and a peropsin/RGR that is expressed in all eyes. AB - The eyes of the horseshoe crab Limulus polyphemus have long been used for studies of basic mechanisms of vision, and the structure and physiology of Limulus photoreceptors have been examined in detail. Less is known about the opsins Limulus photoreceptors express. We previously characterized a UV opsin (LpUVOps1) that is expressed in all three types of Limulus eyes (lateral compound eyes, median ocelli and larval eyes) and three visible light-sensitive rhabdomeric opsins (LpOps1, -2 and -5) that are expressed in Limulus lateral compound and larval eyes. Physiological studies showed that visible light-sensitive photoreceptors are also present in median ocelli, but the visible light-sensitive opsins they express were unknown. In the current study we characterize three newly identified, visible light-sensitive rhabdomeric opsins (LpOps6, -7 and -8) that are expressed in median ocelli. We show that they are ocellar specific and that all three are co-expressed in photoreceptors distinct from those expressing LpUVOps1. Our current findings show that the pattern of opsin expression in Limulus eyes is much more complex than previously thought and extend our previous observations of opsin co-expression in visible light-sensitive Limulus photoreceptors. We also characterize a Limulus peropsin/RGR (LpPerOps1). We examine the phylogenetic relationship of LpPerOps1 with other peropsins and RGRs, demonstrate that LpPerOps1 transcripts are expressed in each of the three types of Limulus eyes and show that the encoded protein is expressed in membranes of cells closely associated with photoreceptors in each eye type. These finding suggest that peropsin was in the opsin repertoire of euchelicerates. PMID- 25524990 TI - The importance of ultraviolet and near-infrared sensitivity for visual discrimination in two species of lacertid lizards. AB - Male and female Lacertid lizards often display conspicuous coloration that is involved in intraspecific communication. However, visual systems of Lacertidae have rarely been studied and the spectral sensitivity of their retinal photoreceptors remains unknown. Here, we characterise the spectral sensitivity of two Lacertid species from contrasting habitats: the wall lizard Podarcis muralis and the common lizard Zootoca vivipara. Both species possess a pure-cone retina with one spectral class of double cones and four spectral classes of single cones. The two species differ in the spectral sensitivity of the LWS cones, the relative abundance of UVS single cones (potentially more abundant in Z. vivipara) and the coloration of oil droplets. Wall lizards have pure vitamin A1-based photopigments, whereas common lizards possess mixed vitamin A1 and A2 photopigments, extending spectral sensitivity into the near infrared, which is a rare feature in terrestrial vertebrates. We found that spectral sensitivity in the UV and near infrared improves discrimination of small variations in throat coloration among Z. vivipara. Thus, retinal specialisations optimise chromatic resolution in common lizards, indicating that the visual system and visual signals might co-evolve. PMID- 25524991 TI - Serum and vitreous levels of visfatin in patients with diabetic retinopathy. AB - BACKGROUND: Angiogenesis plays an important role in the mechanism of diabetic retinopathy (DR). Visfatin, a recently identified adipokine, is thought to possess an angiogenic effect. The aim of our study was to investigate serum and vitreous levels of visfatin in patients with proliferative diabetic retinopathy (PDR) and non-PDR (NPDR). MATERIAL AND METHODS: A total of 280 diabetic patients (124 without DR, 56 with NPDR, and 100 with PDR) and 78 control subjects were enrolled in this study. Serum and vitreous levels of visfatin were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum and vitreous visfatin levels in PDR patients were significantly elevated compared with those in the other 3 groups. NPDR patients showed elevated vitreous visfatin levels compared with patients without DR. However, no significant differences in serum visfatin levels were found between NPDR patients and patients without DR. In addition, control subjects had significantly lower levels of serum and vitreous visfatin compared with diabetic patients without DR, NPDR patients, and PDR patients. CONCLUSIONS: Serum and vitreous visfatin levels are associated with the presence and severity of DR. PMID- 25524992 TI - Survival on biventricular mechanical support with the Centrimag(r) as a bridge to decision: a single-center risk stratification. AB - OBJECTIVE: Temporary mechanical assist devices are increasingly being used as a lifesaving bridge to decision in patients requiring cardiopulmonary resuscitation. We report our single-center experience with biventricular Centrimag(r) pumps over a five-year period. METHOD: Data was retrospectively collected in consecutive patients who required biventricular support from 2008 to 2013. Patients who were supported with central cannulation using the Centrimag(r) system were analyzed. In addition to demographic information, data pertaining to indications, outcomes and mortality were collected. RESULTS: The cohort consisted of 48 patients (19 women and 29 men, mean age of 56 years). The median duration of support was 14 days. The median duration to patient expiration while still on the Centrimag(r) was 12 days. Thirty-day survival was 56% (27/48). Nine patients were explanted to recovery, while fourteen patients were converted to a durable LVAD, two of whom were then transplanted. We stratified patients into two groups. Group I comprised patients who were either explanted to recovery, converted to durable LVAD or transplanted (23/48) and Group II consisted of patients who either died on the Centrimag(r) or were explanted for withdrawal of care (25/48). Statistical analysis did not reveal any clinically significant differences between the two groups in terms of age, sex, etiology, hemodynamic, co morbidities or laboratory parameters. CONCLUSION: The biventricular Centrimag(r) can be used as a bridge to decision in patients with thirty-day survival of >50%. Parameters to predict 30-day survival in this high-risk cohort continue to remain elusive. PMID- 25524993 TI - In search of memory tests equivalent for experiments on animals and humans. AB - Older people often exhibit memory impairments. Contemporary demographic trends cause aging of the society. In this situation, it is important to conduct clinical trials of drugs and use training methods to improve memory capacity. Development of new memory tests requires experiments on animals and then clinical trials in humans. Therefore, we decided to review the assessment methods and search for tests that evaluate analogous cognitive processes in animals and humans. This review has enabled us to propose 2 pairs of tests of the efficiency of working memory capacity in animals and humans. We propose a basic set of methods for complex clinical trials of drugs and training methods to improve memory, consisting of 2 pairs of tests: 1) the Novel Object Recognition Test - Sternberg Item Recognition Test and 2) the Object-Location Test - Visuospatial Memory Test. We postulate that further investigations of methods that are equivalent in animals experiments and observations performed on humans are necessary. PMID- 25524995 TI - Still taking care. PMID- 25524996 TI - Oral medicine: off-label cream use. PMID- 25524994 TI - Heterozygote advantage: the effect of artificial selection in livestock and pets. AB - There are a number of mutants in livestock and pets that have a heterozygote advantage because of artificial selection for these mutants in heterozygotes and strong detrimental effects from natural selection in homozygotes. In livestock, these mutants include ones that influence milk yield in dairy cattle, fecundity in sheep, litter size in pigs, muscling in beef cattle, color in horses, lean meat content in pigs, and comb morphology in chickens. In pets, these mutants include ones that influence tail length in cats and hairlessness, muscling, color, or ridgeback hair in dogs. A large variety of mutants are responsible, including small or large deletions or insertions and single base-pair nonsynonymous changes. Many of the mutants cause loss of function for the genes involved, a change that results in the pleiotropic effects of a desired phenotype in heterozygotes and low fitness or an undesirable phenotype in mutant homozygotes. I examine how selection changes the frequency of these mutants and provide an approach to estimate the amount of artificial selection that is necessary to maintain these mutants at the high frequencies often observed. The amount of artificial selection ranges from low selection favoring heterozygotes for double muscling in whippet dogs to very strong selection favoring the "flash" (part white, part solid) heterozygote in boxer dogs and the rose comb in chickens. In several examples (rose comb in Wyandotte chickens and the hair ridge in Rhodesian ridgeback dogs), there is actually stronger selection for the mutant than against it, making the frequency of the mutant greater than 50%. PMID- 25524997 TI - Dental patients: tossing for it. PMID- 25524998 TI - Periodontology: antibiotics protocol. PMID- 25524999 TI - Mass in a crypt. PMID- 25525000 TI - Infection control: Ebola aware; Ebola beware; Ebola healthcare. PMID- 25525001 TI - Cover series: tending to Tommys' teeth in World War I. PMID- 25525005 TI - A dental educator's life: I will fondly remember the smell of burning shellac. PMID- 25525010 TI - The management of traumatic tooth loss with dental implants: part 2. Severe trauma. AB - In part 2 of this series, we look at the clinician's role in replacing multiple missing teeth and the associated soft tissues and bone, following severe forms of trauma. These patients usually wish to have fixed prostheses to help restore their appearance and function. In order to fulfil the patient's request, the multidisciplinary team can be faced with significant challenges, often requiring extensive reconstructive surgery and complex implant oral rehabilitation. The aim of this paper is to highlight to the general dental practitioner some of the challenges faced in rehabilitating severe trauma patients with implant retained prosthesis. By understanding the challenges it is hoped that the general dental practitioner will be able to make an assessment of the clinical situation and seek appropriate specialist advice to ensure optimal results for their patients. In the longer term, the management of these patients requires a shared care approach between the general dental practitioner and relevant specialists. PMID- 25525011 TI - An audit of implant practice websites: content and regulatory compliance. AB - AIMS AND OBJECTIVES: To audit the content of dental practice websites offering dental implant services against a framework based on the GDC 2012 Guidelines for Ethical Advertising and other relevant advertising standards. METHODS: An audit framework was constructed and applied to the top fifty websites resulting from a Google UK search using the search term 'dental implant specialist'. RESULTS: Compliance with many elements of the GDC Guidance remains poor. Sixty-eight percent of websites claimed that the practitioner providing the service was a GDC registered specialist, though examples were found where this claim was unfounded. Fourteen percent of practice websites claimed that the service was being carried out by an 'implant specialist' and 16% claimed the practitioner was an 'implantologist'; the majority of sites using these terms (10%) involved practitioners that had no specialist status. The display of potentially misleading memberships and fellowships of a range of dental associations, academies, societies and foundations remains common (52%), as does the adoption of the title 'Dr' (60%). CONCLUSION: Comparison with earlier studies indicates that compliance with recent GDC standards is generally improving, though whether the pace of improvement is seen as acceptable or not is something that policymakers and regulatory authorities may need to consider further. PMID- 25525016 TI - Summary of: managing patients on bisphosphonates: the practice of primary care dentists before and after the publication of national guidance. AB - BACKGROUND: In April 2011 the Scottish Dental Clinical Effectiveness Programme published the Oral health management of patients prescribed bisphosphonates guidance document. The aims of this study were to examine whether dentists' practice and beliefs changed after guidance publication to determine whether a knowledge translation intervention was required, and to inform its development. METHODS: Three postal surveys sent to three independent, random samples of dentists throughout Scotland pre- and post-guidance publication. The questionnaire, framed using the theoretical domains framework (TDF), assessed current practice and beliefs relating to recommended management of patients on bisphosphonates. RESULTS: The results (N = 420) suggest that any significant impact the guidance may have had on the recommended management of patients on bisphosphonates by primary care dentists, had reached its peak ten months post publication. A more positive attitude, greater perceived ability, and greater motivation were all associated with significantly more performing of all recommended behaviours at every time point. CONCLUSIONS: Prior to this study, there was little available information about how patients on bisphosphonates were being managed in primary dental care, or what beliefs may be influencing management decisions. This study was able to identify levels of compliance pre- and post-guidance publication and determine that further intervention was necessary to enable sustained uptake of recommendations. Using the TDF to identify beliefs associated with best practice made it possible to suggest theoretically informed strategies for service improvement. The next step is to test the intervention(s) in a randomised controlled trial. PMID- 25525012 TI - Guidelines for management of sodium hypochlorite extrusion injuries. AB - Sodium hypochlorite (NaOCl) is the most common irrigant used in modern endodontics. It is highly effective at dissolving organic debris and disinfecting the root canal system due to the high pH. Extravasation of NaOCl into intra-oral and extra-oral tissues can lead to devastating outcomes leading to long-term functional and aesthetic deficits. Currently no clear guidelines are available which has caused confusion among the dental and oral and maxillofacial (OMFS) surgical community how best to manage these patients. Following a literature review and considering our own experience we have formulated clear and precise guidelines to manage patients with NaOCl injury. PMID- 25525017 TI - Summary of: school bullying and traumatic dental injuries in East London adolescents. AB - AIM: To explore the association between school bullying and traumatic dental injuries (TDI) among 15-16-year-old school children from East London. DESIGN: Data from phase III of the Research with East London Adolescents Community Health Survey (RELACHS), a school-based prospective study of a representative sample of adolescents, were analysed. Adolescents provided information on demographic characteristics, socioeconomic measures and frequency of bullying in school through self-administered questionnaires and were clinically examined for overjet, lip coverage and TDI. The association between school bullying and TDI was assessed using binary logistic regression models. RESULTS: The prevalence of TDI was 17%, while lifetime and current prevalence of bullying was 32% and 11%, respectively. The prevalence of TDI increased with a growing frequency of bullying; from 16% among adolescents who had never been bullied at school, to 21% among those who were bullied in the past but not this school term, to 22% for those who were bullied this school term. However, this association was not statistically significant either in crude or adjusted regression models. CONCLUSION: There was no evidence of an association between frequency of school bullying and TDI in this sample of 15-16-year-old adolescents in East London. PMID- 25525018 TI - 'Dentists' and the establishment of the Anglo-American profession in the 18th century. Part 4. North America. AB - This series of papers examines how the Anglo-American dental profession was established in the eighteenth century, examining its need for a name and identity, public recognition and official status. This final paper describes the presence of the new dentists in North America before and after the revolution. PMID- 25525031 TI - Managing patients on bisphosphonates: the practice of primary care dentists before and after the publication of national guidance. AB - BACKGROUND: In April 2011 the Scottish Dental Clinical Effectiveness Programme published the Oral health management of patients prescribed bisphosphonates guidance document. The aims of this study were to examine whether dentists' practice and beliefs changed after guidance publication to determine whether a knowledge translation intervention was required, and to inform its development. METHODS: Three postal surveys sent to three independent, random samples of dentists throughout Scotland pre- and post-guidance publication. The questionnaire, framed using the theoretical domains framework (TDF), assessed current practice and beliefs relating to recommended management of patients on bisphosphonates. RESULTS: The results (N = 420) suggest that any significant impact the guidance may have had on the recommended management of patients on bisphosphonates by primary care dentists, had reached its peak ten months post publication. A more positive attitude, greater perceived ability, and greater motivation were all associated with significantly more performing of all recommended behaviours at every time point. CONCLUSIONS: Prior to this study, there was little available information about how patients on bisphosphonates were being managed in primary dental care, or what beliefs may be influencing management decisions. This study was able to identify levels of compliance pre- and post-guidance publication and determine that further intervention was necessary to enable sustained uptake of recommendations. Using the TDF to identify beliefs associated with best practice made it possible to suggest theoretically informed strategies for service improvement. The next step is to test the intervention(s) in a randomised controlled trial. PMID- 25525032 TI - School bullying and traumatic dental injuries in East London adolescents. AB - AIM: To explore the association between school bullying and traumatic dental injuries (TDI) among 15-16-year-old school children from East London. DESIGN: Data from phase III of the Research with East London Adolescents Community Health Survey (RELACHS), a school-based prospective study of a representative sample of adolescents, were analysed. Adolescents provided information on demographic characteristics, socioeconomic measures and frequency of bullying in school through self-administered questionnaires and were clinically examined for overjet, lip coverage and TDI. The association between school bullying and TDI was assessed using binary logistic regression models. RESULTS: The prevalence of TDI was 17%, while lifetime and current prevalence of bullying was 32% and 11%, respectively. The prevalence of TDI increased with a growing frequency of bullying; from 16% among adolescents who had never been bullied at school, to 21% among those who were bullied in the past but not this school term, to 22% for those who were bullied this school term. However, this association was not statistically significant either in crude or adjusted regression models. CONCLUSION: There was no evidence of an association between frequency of school bullying and TDI in this sample of 15-16-year-old adolescents in East London. PMID- 25525033 TI - Analysis of glioblastoma tumor coverage by oncolytic virus-loaded neural stem cells using MRI-based tracking and histological reconstruction. AB - In preclinical studies, neural stem cell (NSC)-based delivery of oncolytic virus has shown great promise in the treatment of malignant glioma. Ensuring the success of this therapy will require critical evaluation of the spatial distribution of virus after NSC transplantation. In this study, the patient derived GBM43 human glioma line was established in the brain of athymic nude mice, followed by the administration of NSCs loaded with conditionally replicating oncolytic adenovirus (NSC-CRAd-S-pk7). We determined the tumor coverage potential of oncolytic adenovirus by examining NSC distribution using magnetic resonance (MR) imaging and by three-dimensional reconstruction from ex vivo tissue specimens. We demonstrate that unmodified NSCs and NSC-CRAd-S-pk7 exhibit a similar distribution pattern with most prominent localization occurring at the tumor margins. We were further able to visualize the accumulation of these cells at tumor sites via T2-weighted MR imaging as well as the spread of viral particles using immunofluorescence. Our analyses reveal that a single administration of oncolytic virus-loaded NSCs allows for up to 31% coverage of intracranial tumors. Such results provide valuable insights into the therapeutic potential of this novel viral delivery platform. PMID- 25525034 TI - Antitumor effects of TRAIL-expressing mesenchymal stromal cells in a mouse xenograft model of human mesothelioma. AB - Malignant mesothelioma (MM) remains a highly deadly malignancy with poor treatment option. The MM cells further promote a highly inflammatory microenvironment, which contributes to tumor initiation, development, severity and propagation. We reasoned that the anti-inflammatory actions of mesenchymal stromal cells (MSCs) and further antitumor effects of MSCs engineered to overexpress tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein (MSC-TRAIL) would effectively inhibit mesothelioma growth. Using a mouse xenograft model of intraperitoneal human mesothelioma, native mouse (mMSCs) or human (hMSC) MSCs were administered either systemically (intravenously or intraperitoneally) at various times following tumor inoculation. Both mMSCs and hMSCs localized at the sites of MM tumor growth in vivo and decreased local inflammation. Further, a trend towards decrease in tumor burden was observed. Parallel studies of in vitro exposure of nine primary human mesothelioma cell lines to mMSCs or hMSCs demonstrated reduced tumor cell migration. MSC-TRAIL exposure induced apoptosis of TRAIL-sensitive MM cells in vitro, and both mouse and human MSC-TRAIL significantly reduced the inflammatory tumor environment in vivo. Moreover, human MSC-TRAIL administration significantly reduced peritoneal tumor burden in vivo and increased tumor cell apoptosis. These proof-of-concept studies suggest that TRAIL-expressing MSCs may be useful against malignant mesothelioma. PMID- 25525035 TI - A novel immunocompetent murine model for replicating oncolytic adenoviral therapy. AB - Oncolytic adenoviruses are under investigation as a promising novel strategy for cancer immunotherapeutics. Unfortunately, there is no immunocompetent mouse cancer model to test oncolytic adenovirus because murine cancer cells are generally unable to produce infectious viral progeny from human adenoviruses. We find that the murine K-ras-induced lung adenocarcinoma cell line ADS-12 supports adenoviral infection and generates infectious viral progeny. ADS-12 cells express the coxsackie and adenovirus receptor and infected ADS-12 cells express the viral protein E1A. We find that our previously described oncolytic virus, adenovirus TAV-255 (AdTAV-255), kills ADS-12 cells in a dose- and time-dependent manner. We investigated ADS-12 cells as an in-vivo model system for replicating oncolytic adenoviruses. Subcutaneous injection of ADS-12 cells into immunocompetent 129 mice led to tumor formation in all injected mice. Intratumoral injection of AdTAV 255 in established tumors causes a significant reduction in tumor growth. This model system represents the first fully immunocompetent mouse model for cancer treatment with replicating oncolytic adenoviruses, and therefore will be useful to study the therapeutic effect of oncolytic adenoviruses in general and particularly immunostimulatory viruses designed to evoke an antitumor immune response. PMID- 25525037 TI - Are weight-related attitudes and behaviours associated with the accuracy of BMI derived from self-reported weight and height among 13-year-olds? AB - AIMS: The aim was to explore the association between weight-related attitudes and behaviours and the accuracy of body mass index (BMI) derived from self-reported weight and height. METHODS: A total of 828 adolescents from the Health In Adolescents study were included. Self-reported and objective weight and height data were collected, and BMI was computed. Information about weight-related attitudes and behaviours was obtained. The association between weight-related attitudes and behaviours and the difference between BMI computed from self reported and objective measures was assessed using generalized linear mixed model analyses. RESULTS: BMI was under-reported by overweight girls (p<0.001) and boys (p<0.001) compared to their normal weight counterparts. Underweight girls on the other hand over-reported their BMI (p=0.002). Girls who reported trying to lose weight under-reported their BMI compared to girls who had not tried to do anything about their weight (p=0.02). Girls who perceived their weight as being too much under-reported their BMI compared to girls who thought their weight was ok, the association was however borderline significant (p=0.06); this association was also found among boys (p=0.03). Self-weighing and the reported importance of weight for how adolescents perceive themselves were not associated with the accuracy of BMI. CONCLUSIONS: weight perception and weight control behaviour among girls only were related to the accuracy of self-reported BMI; no association was found with self-weighing behaviour and the perceived importance of weight for how adolescents perceive themselves. Knowledge of such factors will allow for a better interpretation and possibly adjustment/correction of results of surveys based on self-reported weight and height data. PMID- 25525036 TI - Isolation and characterization of progenitor mesenchymal cells in human pituitary tumors. AB - The Cancer Stem Cells (CSCs) theory suggests that genetic alterations in stem cells are the direct cause for cancer. The evidence for a CSC population that results in pituitary tumors is poor. Some studies report the isolation of CSCs, but a deep characterization of the stemness of these cells is lacking. Here, we report the isolation and detailed characterization of progenitor mesenchymal cells (PMCs) from both growth hormone-secreting (GH(+)) and non-secreting (NS) pituitary adenomas, determining the immunophenotype, the expression of genes related to stemness or to pituitary hormone cell types, and the differentiative potential towards osteo-, chondro- and adipogenic lineages. Finally, the expression of CD133, known as a marker for CSCs in other tumors, was analyzed. Isolated cells, both from GH(+) and NS tumors, satisfy all the criteria for the identification of PMCs and express known stem cell markers (OCT4, SOX2, KLF4, NANOG), but do not express markers of pituitary hormone cell types (PITX2, PROP1, PIT1). Finally, PMCs express CD133. We demonstrated that pituitary tumors contain a stem cell population that can generate cell types characteristic of mesenchymal stem cells, and express CD133, which is associated with CSCs in other tumors. PMID- 25525038 TI - Gender differences in co-occurrence of depressive and anger symptoms among adolescents in five Nordic countries. AB - AIMS: The aim of this study was to carry out a comparative examination on gender differences in depressive and anger symptoms and their co-occurrence, using comparative self-report survey data from 16-19-year-old students in five Nordic countries. METHODS: In total, 8038 adolescents participated in the study, 4183 females (52%) and 3855 males (48%) with an average age of 17.1 years. Analysis of Covariance (ANCOVA) was used to test for gender differences in symptoms for the sample as a whole and also for each country. Furthermore, partial bivariate correlation was carried out and followed up by ANCOVA to test for gender differences in the co-occurrence of depressive and anger symptoms in the five countries. RESULTS: The results indicated that, on average, adolescent females reported higher levels of depressive symptoms than males in all the countries under study and higher levels of anger symptoms in four out of five countries. The relationship between depressive and anger symptoms turned out to be stronger for females than males for all the countries under study, demonstrating higher co occurrence of depressive and anger symptoms on average among females than males. CONCLUSIONS: The findings underline the need for attending to both depressive and anger symptoms among adolescents when designing mental health interventions and treatments as co-occurrence of both types of symptoms is common, particularly among females. PMID- 25525039 TI - Initial choice of medication has little effect on short-term or long-term outcome for most patients with Parkinson's disease. PMID- 25525040 TI - Gum chewing is associated with early recovery of bowel motility and shorter length of hospital stay for women after caesarean section. PMID- 25525041 TI - Potential confounding still clouds the possible association of maternal caffeine intake and low birth weight. PMID- 25525042 TI - The unprecedented scale of the West African Ebola virus disease outbreak is due to environmental and sociological factors, not special attributes of the currently circulating strain of the virus. PMID- 25525043 TI - Collaborative care improves clinical outcomes for adolescents with depression treated in primary care. PMID- 25525044 TI - Management of coexistent multi-valvular prosthetic dysfunction: a unique approach. PMID- 25525045 TI - Thromboembolic Events in Malignant Pleural Mesothelioma. AB - AIM: Malignant pleural mesothelioma (MPM) increases the risk of thromboembolic events (TEEs). In this retrospective study, we aimed to determine the rate of TEEs in MPM and investigate its relationship with the presence of thrombocytosis, the disease stage, and the tumor histopathology. METHODS: The study included 178 patients who were histopathologically diagnosed as MPM between the years January 2008 and June 2014. RESULTS: The mean age was 58.7 +/- 11.8 years, and the median follow-up time was 8 months. Seventy-one patients (39.9%) had thrombocytosis (>350 * 10(3)/mL). In total, 14 (7.9%) TEEs were identified: 6 (3.4%) pulmonary thromboembolism, 6 (3.4%) deep venous thrombosis, and 2 (1.1%) myocardial infarctions. Although 5 (2.8%) of the TEEs preceded the diagnosis of MPM, 1 (0.6%) occurred simultaneously with the diagnosis of MPM and 8 (4.5%) followed the diagnosis of MPM. Thromboembolic event rates were not statistically different based on the presence of thrombocytosis (P = .51), disease stage (P = .14), and histopathology (P = .38). CONCLUSION: The rate of TEEs was 7.9%. Presence of thrombocytosis, disease stage, and histopathology did not affect the incidence of TEEs. PMID- 25525046 TI - Thromboelastometric Monitoring of the Hemostatic Effect of Platelet Concentrates Transfusion in Thrombocytopenic Children Undergoing Chemotherapy. AB - Prophylactic platelet concentrates transfusion represents a therapeutic choice in patients with chemotherapy-induced thrombocytopenia. This prospective, non interventional study evaluated the effects of platelet concentrates transfusion on thromboelastometric parameters of platelet function in 36 transfusion occasions for 11 thrombocytopenic children undergoing chemotherapy. Pre- and posttransfusion (1-2 hours) blood samples were analyzed using standard coagulation tests and thromboelastometry (ROTEM) measurements (EXTEM and FIBTEM tests). Platelet component of the clot was calculated based on the EXTEM and FIBTEM maximum clot elasticity (MCE) results. After transfusion, mean platelet count increased from 16.5 * 10(9)/L to 43.0 * 10(9)/L (P < .001) and platelet component increased from 34.1 to 73.0 (P < .001). Statistically significant increases for posttransfusion EXTEM parameters A10, A20, and maximum clot firmness (MCF) were observed compared to pretransfusion values (P < .001). The EXTEM alpha-angle values increased posttransfusion (P < .05). The FIBTEM measurements were comparable pre- and posttransfusion. The study showed that platelet concentrates transfusion in thrombocytopenic children undergoing chemotherapy improves platelet-related coagulation pattern. PMID- 25525047 TI - Efficacy of Change to New P2Y12 Receptor Antagonists in Patients High on Treatment Platelet Reactivity Undergoing Percutaneous Coronary Intervention. AB - Selective intensification of platelet inhibition may improve high on treatment platelet reactivity (HPR). We evaluated the efficacy of dual-antiplatelet therapy, including clopidogrel (CPG), compared to new P2Y12-receptor antagonists in patients with HPR undergoing percutaneous coronary intervention, regarding the outcome of composite major adverse cardiac events (MACEs, including death, acute coronary syndrome [ACS], and stent restenosis). The presence of HPR (71 of 181 patients) almost doubled the risk of MACEs. The new antiplatelet agent reduced MACEs (45.8%, 26%, and 16.7% for CPG, prasugrel, and ticagrelor [TGL]; RR 0.36; 0.13-0.98, P = .03, TGL), specifically in patients with ACS. Failure to reduce HPR after the antiplatelet change and diabetes were independent predictors for MACEs. The HPR was early and effectively reduced after changing the antiplatelet therapy, but the intensity of this reduction did not significantly decrease the risk of MACEs. These findings support the benefit of HPR-guided intensification of platelet inhibition. Whether the intensity of this reduction improves the patient's clinical outcomes deserves further investigation. PMID- 25525048 TI - Laboratory assessment of the anticoagulant activity of dabigatran. AB - BACKGROUND: Our aim was to identify laboratory assays in order to assess the anticoagulant effects of dabigatran etexilate (DE). METHODS: Twenty patients with nonvalvular atrial fibrillation treated on DE (110 mg per os twice daily) and 20 on acenocoumarol were studied. Conventional coagulation tests, endogenous thrombin potential (ETP), thromboelastometry (ROTEM), epinephrine-induced light transmission aggregometry (LTA), and Hemoclot Thrombin Inhibitors (HTI) were performed in all patients. RESULTS: In ROTEM analysis, the lysis index at 60 minutes was significantly lower in patients receiving DE (P = .011). In LTA, patients on DE showed decreased aggregation compared to those on acenocoumarol, marginally insignificant (P = .068). Regarding ETP, acenocoumarol affected thrombin generation more than dabigatran (area under the curve [AUC], P < .001), while statistically significant associations were detected between dabigatran levels, as determined by the HTI assay, and almost all parameters of ETP assay (AUC, P < .001). CONCLUSION: The role of ETP in estimating anticoagulant activity of dabigatran possibly requires further research. PMID- 25525049 TI - Evaluation of Immunostimulatory Potential of Branded and US-Generic Enoxaparins in an In Vitro Human Immune System Model. AB - Low-molecular-weight heparins (LMWHs) have several positive therapeutic effects and can also form immunostimulatory complexes with plasma proteins, such as platelet factor 4 (PF4). We compared the innate response and functional profiles of branded and US-generic enoxaparins from 2 manufacturers in either native or PF4-bound forms in an in vitro model of human immunity. In an analysis of 2 product lots from each manufacturer and multiple separate batches of protein heparin complexes, branded enoxaparin was shown to be consistently nonstimulatory for innate responses, whereas US-generic enoxaparins generated variable immunostimulatory profiles depending on the enoxaparin lot used to prepare the PF4-LMWH complexes. Production of tissue factor pathway inhibitor (TFPI), a physiologic heparin-induced inhibitor of tissue factor-induced coagulation that was used as a functional readout of biological activity of enoxaparins in these assays, was heightened in the presence of branded enoxaparin complexes, but its levels were variable in cultures treated with complexes containing US-generic enoxaparins. Analytical analyses suggest that the heightened immunostimulatory potential of some of the US-generic enoxaparin product lots could be tied to their capacity to form ultra-large and/or more stable complexes with PF4 than the other LMWHs included in this study. Although these distinct biological and analytical profiles might be related to the composition and/or consistency of branded and US-generic enoxaparins included in our data set, further studies are warranted to elucidate the pathophysiological relevance of these in vitro findings. PMID- 25525050 TI - Host-pathogen Interaction at the Intestinal Mucosa Correlates With Zoonotic Potential of Streptococcus suis. AB - BACKGROUND: Streptococcus suis has emerged as an important cause of bacterial meningitis in adults. The ingestion of undercooked pork is a risk factor for human S. suis serotype 2 (SS2) infection. Here we provide experimental evidence indicating that the gastrointestinal tract is an entry site of SS2 infection. METHODS: We developed a noninvasive in vivo model to study oral SS2 infection in piglets. We compared in vitro interaction of S. suis with human and porcine intestinal epithelial cells (IEC). RESULTS: Two out of 15 piglets showed clinical symptoms compatible with S. suis infection 24-48 hours after ingestion of SS2. SS2 was detected in mesenteric lymph nodes of 40% of challenged piglets. SS2 strains isolated from patients showed significantly higher adhesion to human IEC compared to invasive strains isolated from pigs. In contrast, invasive SS9 strains showed significantly higher adhesion to porcine IEC. Translocation across human IEC, which occurred predominately via a paracellular route, was significantly associated with clonal complex 1, the predominant zoonotic genotype. Adhesion and translocation were dependent on capsular polysaccharide production. CONCLUSIONS: SS2 should be considered a food-borne pathogen. S. suis interaction with human and pig IEC correlates with S. suis serotype and genotype, which can explain the zoonotic potential of SS2. PMID- 25525051 TI - Randomized, controlled trial of high-dose influenza vaccine among frail residents of long-term care facilities. AB - BACKGROUND: Despite vaccination, residents of long-term-care facilities (LTCFs) remain at high risk of influenza-related morbidity and mortality. More-effective vaccine options for this population are needed. METHODS: We conducted a single blinded, randomized, controlled trial comparing high-dose (HD) to standard-dose (SD) inactivated influenza vaccine (IIV) in 205 frail, elderly residents of LTCFs during the 2011-2012 and 2012-2013 influenza seasons. Hemagglutination inhibition (HI) antibody titers were measured at baseline and 30 and 180 days following vaccination. RESULTS: A total of 187 subjects (91%) completed the study. The mean age was 86.7 years. Geometric mean titers (GMTs) were significantly higher (P < .05) at day 30 for HD recipients, compared with SD recipients, for all comparisons except influenza A(H1N1) during 2012-2013 (the HD formulation was noninferior to the SD formulation for influenza A[H1N1] during 2012-2013). GMTs for HD and SD recipients during 2011-2012 were as follows: influenza A(H1N1), 78 (95% confidence interval [CI], 45-136) and 27 (95% CI, 17-44), respectively; influenza A(H3N2), 26 (95% CI, 17-40) and 10 (95% CI, 7-15), respectively; and influenza B, 26 (95% CI, 19-35) and 14 (95% CI, 11-18), respectively. During 2012 2013, GMTs for HD and SD recipients were as follows: influenza A(H1N1), 46 (95% CI, 33-63) and 50 (95% CI, 37-67); influenza A(H3N2), 23 (95% CI, 18-31) and 14 (95% CI, 11-18), respectively; and influenza B, 26 (95% CI, 21-32) and 17 (95% CI, 14-22), respectively. GMTs were significantly higher at day 180 for HD recipients, compared with SD recipients, for influenza A(H3N2) in both years (P < .001). CONCLUSIONS: Among frail, elderly residents of LTCFs, HD influenza vaccine produced superior responses for all strains except influenza A(H1N1) in 2012 2013. CLINICAL TRIALS REGISTRATION: NCT01654224. PMID- 25525052 TI - Multifaceted Strategies Needed for Influenza Prevention in Long-term Care. PMID- 25525054 TI - Bacterial loads of Ureaplasma parvum contribute to the development of inflammatory responses in the male urethra. AB - Ureaplasma parvum, which has been recognised as a coloniser in the male urethra, is detected in some men with non-gonococcal urethritis. In this study, we quantified the 16 S rRNA genes of U. parvum by a real-time polymerase chain reaction-based assay in first-voided urine from 15 symptomatic and 38 asymptomatic men who were positive only for U. parvum. We also determined the leukocyte counts by automated quantitative urine particle analysis in their first voided urine. Positive correlations were observed between copies of the 16 S rRNA genes of U. parvum/ml and the leukocyte counts/ul in first-voided urine (p = 0.0019). The loads of >=10(4) copies of the 16 S rRNA gene/ml, corresponding to >=5 * 10(3) cells of U. parvum/ml, were significantly associated with the presence of >=12.5 leukocytes/ul in first-voided urine that might document the presence of inflammatory responses in the urethra. However, a large portion of the subjects (83.0%) had bacterial loads of <5 * 10(3) cells of U. parvum/ml, and 79.5% of them showed <12.5 leukocytes/ul. The ambiguity of the pathogenic role of U. parvum in non-gonococcal urethritis could, in part, be due to its low bacterial loads, which might not give rise to inflammatory responses in the male urethra. PMID- 25525056 TI - Chest Pain in an Adolescent Male With a Leg Abscess. PMID- 25525053 TI - Effectiveness of antidepressants and predictors of treatment response for depressed HIV patients in Uganda. AB - Antidepressant medication is well established for the treatment of depression but little is known about its effectiveness for HIV populations in sub-Saharan Africa. This study examined the effectiveness of antidepressant treatment and predictors of treatment response among depressed HIV patients in Uganda. Data were obtained from two open-label trials in which 184 HIV patients were diagnosed with depression and started on antidepressants. Data at treatment baseline and month 6 were compared to assess treatment response, and baseline predictors of response were assessed. A total of 154 completed month 6, of whom 122 (79%) had responded to treatment and were no longer depressed (Patient Health Questionnaire 9, score < 5). Bivariate analysis found that education, CD4 count, general health functioning, physical health, pain, quality of life and social support variables were associated with antidepressant treatment response; however, only secondary education and social support independently predicted treatment response in logistic multiple regression analysis. Baseline depression severity was not associated with treatment response. In conclusion, antidepressants are effective in treating both moderate and more severe depression among persons living with HIV in Uganda, and education [OR (95% CI) = 4.33 (1.33-14.11)] and social support [OR (95% CI) = 1.54 (1.03-2.30)] were most predictive of treatment response. PMID- 25525055 TI - Rapid progression to gummatous syphilitic hepatitis and neurosyphilis in a patient with newly-diagnosed HIV. AB - We review the literature on hepatic involvement in patients with HIV and syphilis co-infection and describe a case of rapid progression to neurosyphilis and presumed gummatous syphilitic hepatitis in a patient newly diagnosed with HIV. To our knowledge, this is the first case of syphilitic hepatitis with gummas described in the HIV population. PMID- 25525057 TI - The occurrence of ochratoxin A in rice in six provinces of Iran. AB - Three hundred and eight samples of rice purchased from retail markets in six different provinces in Iran from March 2012 to January 2013 were surveyed for the presence of ochratoxin A (OTA) using enzyme-linked immunosorbent assay. The recovery percentages of OTA from spiked rice samples at concentrations of 5 and 10 ng/g were found to be 85.3% and 86.7%, respectively. Analytical results showed a 9.4% frequency of contamination from total analyzed rice samples with a mean OTA level of 3.60 +/- 2.66 ng/g. Concentrations of OTA in positive samples ranged from 0.84 ng/g to 11.37 ng/g, and in 17.3% of contaminated rice samples the concentrations exceeded the maximum tolerance limit set by European regulations for OTA in cereals (5 ng/g). Based on the results of this study, the estimated daily intake of OTA in rice was 0.62 ng/kg body weight/day for Iranian consumers. PMID- 25525059 TI - Mindfulness of the kindness of others: The contemplative practice of Naikan in cultural context. AB - Mindfulness in the Buddhist tradition involves a variety of practices, and contemporary secular forms of mindfulness practices, therapies, and interventions can similarly be broadened to include more of these forms. The Japanese practice of Naikan takes one mindfulness practice from the Buddhist tradition--that of recollecting the kindness of others--and asks clients to engage in this practice for 1 solid week, 15 hours per day. Difficult interpersonal relationships and a perceived lack of social support are chief sources of stress, and Japanese selfhood in particular has been described as interdependent and highly social in nature. It is unsurprising therefore that Japanese would be drawn to relational forms of practice like Naikan, and that they would find particular benefit from such practices. Recent ethnographic and survey work I have conducted at 2 Naikan centers suggests that Naikan significantly improves positive mental health, perceived connection with others, and perceived meaning in life, even up to 6 months later, thereby potentially undercutting factors contributing to depression and suicide. Naikan practice is not entirely limited to Japan, however, and its use in Europe and North America prompts us to ask about the culturally specific and universal aspects of mindfulness practices, and how we may construct mindfulness interventions that are best suited for addressing the mental health problems that face our communities. PMID- 25525058 TI - Cardiac rehabilitation improves coronary endothelial function in patients with heart failure due to dilated cardiomyopathy: A positron emission tomography study. AB - BACKGROUND: Endothelial dysfunction is common in patients with heart failure and is associated with poor clinical outcome. Cardiac rehabilitation is able to enhance peripheral endothelial function but its impact on coronary vasomotion remains unknown. We aimed to evaluate the effect of cardiac rehabilitation on coronary vasomotion in patients with heart failure. METHOD: We prospectively enrolled 29 clinically stable heart failure patients from non-ischaemic dilated cardiomyopathy and without coronary risk factors. Myocardial blood flow was quantified using (15)-O water positron emission tomography at rest and during a cold pressor test, before and after 12 weeks of cardiac rehabilitation and optimization of medical therapy. RESULTS: Rest myocardial blood flow was significantly improved after the completion of rehabilitation compared to baseline (1.31 +/- 0.38 mL/min/g vs. 1.16 +/- 0.41 mL/min/g, p = 0.04). The endothelium-related change in myocardial blood flow from rest to cold pressor test and the percentage of myocardial blood flow increase during the cold pressor test were both significantly improved after cardiac rehabilitation (respectively from -0.03 +/- 0.22 mL/min/g to 0.19 +/- 0.22 mL/min/g, p < 0.001 and from 101.5 +/- 16.5% to 118.3 +/- 24.4%, p < 0.001). Left ventricular ejection fraction, plasma levels of brain natriuretic peptide, maximal oxygen consumption and the Minnesota Living with Heart Failure Questionnaire score were also significantly improved. The improvement was not related to uptitration of medical therapy. CONCLUSIONS: Coronary endothelial function is altered in patients with heart failure due to non-ischaemic dilated cardiomyopathy. In these patients, cardiac rehabilitation significantly improves coronary vasomotion. PMID- 25525060 TI - Pulmonary vein stenosis after radiofrequency ablation: in vivo optical coherence tomography insights. PMID- 25525061 TI - Extremely high Agatston calcium score without significant coronary artery stenoses. PMID- 25525062 TI - First experience with single-source, dual-energy CCTA for monochromatic stent imaging. AB - AIMS: Single-source, dual-energy coronary computed tomography angiography (CCTA) with monochromatic image reconstruction allows significant noise reduction. The aim of the study was to evaluate the impact of monochromatic CCTA image reconstruction on coronary stent imaging, as the latter is known to be affected by artefacts from highly attenuating strut material resulting in artificial luminal narrowing. METHODS AND RESULTS: Twenty-one patients with 62 stents underwent invasive coronary angiography and single-source, dual-energy CCTA after stent implantation. Standard polychromatic images as well as eight monochromatic series (50, 60, 70, 80, 90, 100, 120, and 140 keV) were reconstructed for each CCTA. Signal and noise were measured within the stent lumen and in the aortic root. Mean in-stent luminal diameter was assessed in all CCTA reconstructions and compared with quantitative invasive coronary angiography (QCA). Luminal attenuation was higher in the stent than in the aortic root throughout all monochromatic reconstructions (P < 0.001). An increase in monochromatic energy was associated with a decrease in luminal attenuation values (P < 0.001). The mean in-stent luminal diameter underestimation by monochromatic CCTA compared with QCA was 90% at low monochromatic energy (50 keV) and improved to 37% at high monochromatic (140 keV) reconstruction while stent diameter was underestimated by 39% with standard CCTA. CONCLUSION: Monochromatic CCTA can be used reliably in patients with coronary stents. However, reconstructions with energies below 80 keV are not recommended as the blooming artefacts are most pronounced at such low energies, resulting in up to 90% stent diameter underestimation. PMID- 25525063 TI - Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. AB - Recognizing the critical need for standardization in strain imaging, in 2010, the European Association of Echocardiography (now the European Association of Cardiovascular Imaging, EACVI) and the American Society of Echocardiography (ASE) invited technical representatives from all interested vendors to participate in a concerted effort to reduce intervendor variability of strain measurement. As an initial product of the work of the EACVI/ASE/Industry initiative to standardize deformation imaging, we prepared this technical document which is intended to provide definitions, names, abbreviations, formulas, and procedures for calculation of physical quantities derived from speckle tracking echocardiography and thus create a common standard. PMID- 25525064 TI - Clinical significance of dynamic pulmonary vascular resistance in two populations at risk of pulmonary arterial hypertension. AB - AIMS: Patients at risk of pulmonary arterial hypertension (PAH) may present with abnormal dynamic pulmonary vascular resistance (PVR) during exercise. However, its clinical significance remains unclear. The present study aimed at analysing the meaning of dynamic PVR in two populations at risk of PAH: secundum atrial septal defect (ASD) and systemic sclerosis (SSc). METHODS AND RESULTS: Adult patients with corrected ASD were consecutively selected from the database of Pediatric and Congenital Heart Disease of the University Hospitals Leuven. Patients with SSc were consecutively selected from the rheumatology database of the University Hospital Liege. At inclusion, all underwent a rest and bicycle stress echocardiography to obtain baseline right heart characteristics and dynamic PVR. Routine follow-up echocardiography was performed. Twenty-eight patients with corrected ASD (mean age 41 +/- 17 years, 79% female) were followed for a median time of 3.7 [inter-quartile range (IQR) 2.9-4.1] years. No patient developed PAH. Dynamic PVR was significantly associated with right atrial dilatation at latest follow-up (Spearman's rho 0.51, P = 0.013). Forty-five SSc patients (mean age 54 +/- 13 years, 76% female) were followed for a median time of 2.4 (IQR 0.8-2.9) years. Thirteen patients (30%) developed PAH. Dynamic PVR was the only independent predictor of PAH (hazards ratio 1.22, 95% confidence interval 1.01-1.47). No significant right heart morphometric changes occurred. CONCLUSION: Dynamic PVR predicted PAH development in patients with SSc, whereas dynamic PVR was associated with right heart morphometric changes after ASD closure. The predictive role of dynamic PVR might depend on the underlying disease type. Larger studies are needed to confirm this hypothesis. PMID- 25525065 TI - Effects of exercise training with traditional dancing on functional capacity and quality of life in patients with schizophrenia: a randomized controlled study. AB - OBJECTIVE: To examine the effects of an eight-month exercise training programme with Greek traditional dancing on functional capacity and quality of life in patients with schizophrenia. DESIGN: Randomized controlled trial. SETTING: Sports Medicine Laboratory. SUBJECTS: A total of 31 patients, aged 59.9 +/- 14.1 years. INTERVENTIONS: They were randomly assigned either to a Greek traditional dancing programme (Group A) or to a sedentary control group (Group B). MAIN MEASURES: A functional capacity assessment was performed at baseline and the end of the study. Global Assessment of Functioning Scale and Positive and Negative Syndrome Scale were also used. Quality of life was examined using the Quality of Life and Satisfaction questionnaire. RESULTS: After the eight months, Group A increased walking distance in the 6-minute walk test (328.4 +/- 35.9 vs. 238.0 +/- 47.6 m), sit-to-stand test (19.1 +/- 1.8 vs. 25.1 +/- 1.4 seconds), Berg Balance Scale score (53.1 +/- 2.1 vs. 43.2 +/- 6.7), lower limbs maximal isometric force (77.7 +/- 25.7 vs. 51.0 +/- 29.8 lb), Positive and Negative Syndrome Scale total score (77.0 +/- 23.1 vs. 82.0 +/- 24.4), Global Assessment of Functioning Scale total score (51.3 +/- 15.5 vs. 47.7 +/- 13.3) and Quality of Life total score (34.9 +/- 5.2 vs. 28 +/- 4.5), compared with Group B. CONCLUSIONS: Our results demonstrate that Greek traditional dances improve functional capacity and quality of life in patients with schizophrenia. PMID- 25525066 TI - Effects of whole body vibration on pain, stiffness and physical functions in patients with knee osteoarthritis: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the effects of whole body vibration for pain, stiffness and physical functions in patients with knee osteoarthritis. DATA SOURCES: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Physiotherapy Evidence Database (PEDro) and EMBASE (up to October 2014) to identify relevant randomized controlled trials. The outcome measures were pain, stiffness and physical functions. REVIEW METHODS: Two investigators identified eligible studies and extracted data independently. The PEDro score was used to evaluate the methodological quality of the selected studies. Standard mean differences (SMDs) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed using the I(2) test. RESULTS: A total of five randomized controlled trials involving 170 patients with knee osteoarthritis met the inclusion criteria. Only four studies involving 144 patients were deemed to be good quality trials (PEDro score = 6-7). Meta-analysis revealed that whole body vibration has a significant treatment effect in Western Ontario and McMaster Universities index physical function score (SMD = -0.72 points, 95% CI = -1.14 to -0.30, P = 0.0008), 12 weeks whole body vibration improved the 6-minute walk test (SMD 1.15 m, 95% CI 0.50 to 1.80, P = 0.0006) and balance (SMD = -0.78 points, 95% CI -1.40 to -0.16, P = 0.01). Whole body vibration was not associated with a significant reduction in Western Ontario and McMaster Universities index pain and stiffness score. CONCLUSION: Eight-week and 12-week whole body vibration is beneficial for improving physical functions in patients with knee osteoarthritis and could be included in rehabilitation programs. PMID- 25525068 TI - Should we consider nickel allergy a potential factor associated with peripheral stent patency? PMID- 25525067 TI - Late onset acute occlusion of the subclavian artery after clavicle fracture. AB - Vascular injuries after a clavicle fracture are rare. The treatment remains, if possible, conservative. In case of life-threatening bleeding or limb ischemia, endovascular treatment is the treatment of choice. In this case report, we describe a patient who suffered a clavicle fracture five years before and now presented with acute invalidating claudication caused by an acute occlusion superimposed on a brachial artery stenosis. After unsuccessful thrombolytic therapy a surgical exploration of the brachial artery was performed. PMID- 25525069 TI - Victims' voices and victims' choices in three IPV courts. AB - Critics of mandatory interventions for intimate partner violence (IPV) propose that the justice system disempowers victims by denying them voice and choice in legal proceedings. This exploratory study examines this claim through observations of three criminal courts. Findings show that victims are offered voice and a degree of choice in only one of the three courts. Court procedures that enhance victim voice and choice include a specialized IPV court, victim advocates trained in victims' rights issues, and a lead judge who models respectful treatment of victims. The author proposes that voice and choice are distinct aspects of victim empowerment and that the provision of voice may have benefits to IPV victims that are distinct from the benefits of choice. PMID- 25525070 TI - Living too long: the current focus of medical research on increasing the quantity, rather than the quality, of life is damaging our health and harming the economy. PMID- 25525072 TI - Commentary: confidentiality of interim trial data-the emerging crisis. PMID- 25525073 TI - Commentary: data monitoring confidentiality and FDA transparency. PMID- 25525071 TI - The composition of the gut microbiota shapes the colon mucus barrier. AB - Two C57BL/6 mice colonies maintained in two rooms of the same specific pathogen free (SPF) facility were found to have different gut microbiota and a mucus phenotype that was specific for each colony. The thickness and growth of the colon mucus were similar in the two colonies. However, one colony had mucus that was impenetrable to bacteria or beads the size of bacteria-which is comparable to what we observed in free-living wild mice-whereas the other colony had an inner mucus layer penetrable to bacteria and beads. The different properties of the mucus depended on the microbiota, as they were transmissible by transfer of caecal microbiota to germ-free mice. Mice with an impenetrable mucus layer had increased amounts of Erysipelotrichi, whereas mice with a penetrable mucus layer had higher levels of Proteobacteria and TM7 bacteria in the distal colon mucus. Thus, our study shows that bacteria and their community structure affect mucus barrier properties in ways that can have implications for health and disease. It also highlights that genetically identical animals housed in the same facility can have rather distinct microbiotas and barrier structures. PMID- 25525074 TI - Burden of care, social support, and sense of coherence in elderly caregivers living with individuals with symptoms of dementia. AB - Family members are often the care providers of individuals with dementia, and it is assumed that the need for this will increase. There has been little research into the association between the burden of care and the caregiver's sense of coherence or receipt of social support. This study examined the relationship between the social support subdimensions and sense of coherence and the burden of care among older people giving care to a partner with dementia. The study was a cross-sectional observation study of 97 individuals, >=65 years old and living with a partner who had symptoms of dementia. We used the Informant Questionnaire on Cognitive Decline in the Elderly, the Relative Stress Scale, the Social Provisions Scale, the Sense of Coherence Scale, and a questionnaire on sociodemographic variables. We used multiple regression analysis in a general linear model procedure. We defined statistical significance as p < 0.05. With adjustments for sociodemographic variables, the association with burden of care was statistically significant for the subdimension attachment (p < 0.01) and for sense of coherence (p < 0.001). The burden of care was associated with attachment and with sense of coherence. Community nurses and other health professionals should take necessary action to strengthen attachment and sense of coherence among the caregivers of people with dementia. Qualitative studies could provide deeper understanding of the variation informal caregivers experience when living together with their partner with dementia. PMID- 25525075 TI - Citizenship as practice: Handling communication problems in encounters between persons with dementia and social workers. AB - The overall aim of the study was to investigate if and how persons with dementia were able to take part in negotiations for formal support, as cases of citizenship as practice The transcripts used for analysis were from 11 assessment meetings conducted in Sweden, in which the formal applicant was a person with dementia. The findings suggest that the actual participation of persons with dementia in assessment meetings varies. Communication problems were found in the meetings to different degrees and were dealt with differently and with various consequences. For those persons with dementia contributing at the same levels as the other participants, there was an attempt at mutual understanding. For those making fewer contributions, the other interlocutors took over the initiative and thus affected the practice of citizenship by persons with dementia in a negative way. The practice of citizenship is situation based and varies depending on all participants. When the person with dementia is able to participate in the conversation, social workers can facilitate for them to overcome communication problems by giving them more time and signaling acceptance. If the person with dementia has great problems in participating, the other participants can find different strategies to at least involve her or him in the conversation. PMID- 25525076 TI - Pulse pressure does not predict the response of diabetic nephropathy to glucose lowering therapy. AB - We aimed to study whether pulse pressure (PP) predicts the response of diabetic nephropathy to glucose-lowering treatment. Patients with uncontrolled type 2 diabetes were followed for decrease in albuminuria after insulin/oral hypoglycemic treatment. A total of 143 patients were followed for a median time of 10.5 months in a cohort study. Fasting blood sugar and HbA1C significantly decreased, while systolic, diastolic and pulse pressures remained constant during intervention. Median albuminuria decreased from 18.4 mg/day [10-40] to 16.4 mg/day [9-28] at the end of study (p-value < 0.005). The number of patients with normo/micro/macro-albuminuria changed from 98/36/9 to 108/31/4 (p-value < 0.001). No significant difference in baseline PP (47.5 +/- 1.61 vs. 45.9 +/- 1.81 mmHg; p value = 0.51) or final PP (47.0 +/- 2.41 vs. 49.4 +/- 2.38 mmHg; p-value = 0.47) existed between those with decreased and increased albuminuria. PP was not a significant predictor of albuminuria changes in receiver operating characteristic curve (p-value = 0.77) and regression (p-value = 0.98) analyses. Benefits of glycemic control in diabetic nephropathy are independent of PP. PMID- 25525077 TI - Elevated serum glucose levels and survival after acute heart failure: a population-based perspective. AB - BACKGROUND: Limited data are available about the characteristics, treatment and survival in patients without diabetes mellitus (DM), previously diagnosed DM and patients with hyperglycaemia who present with acute decompensated heart failure (ADHF). Our objectives were to examine differences in these endpoints in patients hospitalized with ADHF. METHODS: Patients hospitalized with ADHF during 1995, 2000, 2002 and 2004 comprised the study population. RESULTS: A total of 5428 non diabetic patients were hospitalized with ADHF, 3807 with diagnosed DM and 513 with admission hyperglycaemia. Patients with admission hyperglycaemia experienced the highest in-hospital death rates (9.9%) compared to those with diagnosed DM (6.5%) and non-diabetics (7.5%). Patients with diagnosed DM had the greatest risk of dying after hospital discharge. CONCLUSIONS: Patients with elevated blood glucose levels at hospital admission are more likely to die acutely. After resolution of the acute illness, patients with previously diagnosed DM need careful monitoring and enhanced treatment. PMID- 25525078 TI - Transplant for CLL: still an option? PMID- 25525079 TI - GlycoPEGylated factor IX: a new step forward. PMID- 25525080 TI - HMGB1 takes a "Toll" in sickle cell disease. PMID- 25525081 TI - HLA allotype expressivity in transplantation. PMID- 25525083 TI - eComment. How trainees perform and develop their skills on the simulator. PMID- 25525084 TI - eComment. Routine preoperative platelet function assessment in paediatric surgery: is it safer? PMID- 25525085 TI - eComment. Is video-assisted thoracoscopic surgery resection really superior to the thoracotomic approach in mediastinal neurogenic tumours? PMID- 25525086 TI - eComment. The supraclavicular approach for removal of neurogenic tumours at the thoracic apex. PMID- 25525087 TI - eComment. Muscle sparing thoracotomy for the apical posterior mediastinal lesions. PMID- 25525088 TI - eComment. Postoperative rise in serum creatinine following coronary artery bypass grafting: how is this best measured and what is its significance? PMID- 25525089 TI - eReply. Postoperative rise in serum creatinine following coronary artery bypass grafting: how is this best measured and what is its significance? PMID- 25525090 TI - eComment. Preoperative atrial fibrillation and outcome in patients undergoing on pump or off-pump coronary bypass surgery. PMID- 25525091 TI - eComment. The importance of nutritional assessement and support in patients undergoing oesophagectomy for oesophageal malignancies. PMID- 25525092 TI - eComment. In postoperative oesophagectomy patients, does a change in albumin predict better postoperative outcomes? PMID- 25525093 TI - eComment. Tricuspid valve surgery in left-sided valve surgery: good outcome depends on the preoperative right ventricular function. PMID- 25525094 TI - eComment. Hemiarch or total arch replacement for type A aortic dissection? PMID- 25525095 TI - eComment. Persistent type 2 endoleaks after endovascular aneurysm repair: why and when to intervene? PMID- 25525096 TI - Reference values of within-district intraclass correlations of academic achievement by district characteristics: results from a meta-analysis of district specific values. AB - BACKGROUND: Randomized experiments are often considered the strongest designs to study the impact of educational interventions. Perhaps the most prevalent class of designs used in large-scale education experiments is the cluster randomized design in which entire schools are assigned to treatments. In cluster randomized trials that assign schools to treatments within a set of school districts, the statistical power of the test for treatment effects depends on the within district school-level intraclass correlation (ICC). Hedges and Hedberg (2014) recently computed within-district ICC values in 11 states using three-level models (students in schools in districts) that pooled results across all the districts within each state. Although values from these analyses are useful when working with a representative sample of districts, they may be misleading for other samples of districts because the magnitude of ICCs appears to be related to district size. To plan studies with small or nonrepresentative samples of districts, better information are needed about the relation of within-district school-level ICCs to district size. OBJECTIVE: Our objective is to explore the relation between district size and within-district ICCs to provide reference values for math and reading achievement for Grades 3-8 by district size, poverty level, and urbanicity level. These values are not derived from pooling across all districts within a state as in previous work but are based on the direct calculation of within-district school-level ICCs for each school district. RESEARCH DESIGN: We use mixed models to estimate over 7,000 district-specific ICCs for math and reading achievement in 11 states and for Grades 3-8. We then perform a random effects meta-analysis on the estimated within-district ICCs. Our analysis is performed by grade and subject for different strata designated by district size (number of schools), urbanicity, and poverty rates. PMID- 25525097 TI - Foraging activity rhythms of Dinoponera quadriceps (Hymenoptera: Formicidae) in its natural environment. AB - This study characterizes the foraging activity of the queenless ant Dinoponera quadriceps (Kempf) (Hymenoptera: Formicidae) in its natural environment by testing the hypotheses that foraging activity presents both daily and seasonal rhythmic variations, and that these rhythms are related to environmental variables. Four colonies of D. quadriceps were observed in an area of secondary Atlantic forest in northeastern Brazil. Data collection was performed over 72 h every three months during an annual cycle. Both daily and seasonal foraging activity rhythms of D. quadriceps colonies were related to environmental factors, but colony differences also explained part of foraging variations. Foraging activity of D. quadriceps colonies was predominantly diurnal independently of season. In the early dry season, the colonies had two activity peaks, one in the morning and another in the afternoon, with a decrease in foraging at midday; however, during the rest of the year, foraging activity was distributed more evenly throughout the daylight hours. The daily rhythm of foraging activity was likely determined by an endogenous circadian rhythm year-round, but in the dry season, temperature and relative humidity also influenced daily foraging activity, with a negative effect of temperature and a positive effect of relative humidity. On a seasonal scale, foraging activity peaked in the early dry season and suddenly declined at the end of this season, increasing again at the late rainy season. The seasonal rhythm of foraging was negatively related to relative humidity and positively related to prey availability. PMID- 25525098 TI - Fruit flies of the genus Anastrepha (Diptera: Tephritidae) from some localities of Paraguay: new records, checklist, and illustrated key. AB - This study deals with fruit flies of the genus Anastrepha Schiner (Diptera: Tephritidae) collected in McPhail traps in the municipalities of Concepcion, Belen, Horqueta, Loreto (state of Concepcion) and Santa Rosa (state of Misiones), Paraguay. In total, 17 species were captured, 9 of which are new records for Paraguay. All morphological characters used for species identification are illustrated. PMID- 25525100 TI - Mechanism of entomotoxicity of the Concanavalin A in Rhopalosiphum padi (Hemiptera: Aphididae). AB - The toxicity effect of Concanavalin A (Canavalia ensiformis lectin, ConA) to bird cherry-oat aphid, Rhopalosiphum padi L. (Hemiptera: Aphididae), was investigated in the laboratory by using artificial diets containing ConA concentrations. Bird cherry-oat aphid performance was affected by the presence of Con A in artificial diets. The lectin added into the liquid diet increased the prereproductive period, mortality, and the average time of generation development (T) and decreased fecundity and the intrinsic rate of natural increase (rm). In attempt to unravel the mode of action of ConA, the interaction of the lectin with insect gut and the effect of ConA on feeding behavior were investigated. Extract of gut of treated grain aphid demonstrated DNA fragmentation, and this was accompanied with an increase in caspase 3 activity. Moreover, addition of ConA to the sucrose agarose gels reduced salivation and passive ingestion of fluids from the gel. The results indicate that the insecticidal activity of ConA on R. padi may involve effects on death of the gut epithelial cells and effects on feeding behavior. This can be employed to create plants that are resistant to aphids. PMID- 25525099 TI - Microarray analysis of tomato plants exposed to the nonviruliferous or viruliferous whitefly vector harboring Pepper golden mosaic virus. AB - Plants are routinely exposed to biotic and abiotic stresses to which they have evolved by synthesizing constitutive and induced defense compounds. Induced defense compounds are usually made, initially, at low levels; however, following further stimulation by specific kinds of biotic and abiotic stresses, they can be synthesized in relatively large amounts to abate the particular stress. cDNA microarray hybridization was used to identify an array of genes that were differentially expressed in tomato plants 15 d after they were exposed to feeding by nonviruliferous whiteflies or by viruliferous whiteflies carrying Pepper golden mosaic virus (PepGMV) (Begomovirus, Geminiviridae). Tomato plants inoculated by viruliferous whiteflies developed symptoms characteristic of PepGMV, whereas plants exposed to nonviruliferous whitefly feeding or nonwounded (negative) control plants exhibited no disease symptoms. The microarray analysis yielded over 290 spotted probes, with significantly altered expression of 161 putative annotated gene targets, and 129 spotted probes of unknown identities. The majority of the differentially regulated "known" genes were associated with the plants exposed to viruliferous compared with nonviruliferous whitefly feeding. Overall, significant differences in gene expression were represented by major physiological functions including defense-, pathogen-, photosynthesis-, and signaling-related responses and were similar to genes identified for other insect plant systems. Viruliferous whitefly-stimulated gene expression was validated by real-time quantitative polymerase chain reaction of selected, representative candidate genes (messenger RNA): arginase, dehydrin, pathogenesis-related proteins 1 and -4, polyphenol oxidase, and several protease inhibitors. This is the first comparative profiling of the expression of tomato plants portraying different responses to biotic stress induced by viruliferous whitefly feeding (with resultant virus infection) compared with whitefly feeding only and negative control nonwounded plants exposed to neither. These results may be applicable to many other plant-insect-pathogen system interactions. PMID- 25525101 TI - Genetic diversity of Sogatella furcifera (Hemiptera: Delphacidae) in China detected by inter-simple sequence repeats. AB - The white-backed planthopper (WBPH), Sogatella furcifera (Horvath) is a serious pest causing grievous damage to rice plants. In the present study, inter-simple sequence repeats were employed to investigate the genetic diversity of 108 samples from 27 WBPH geographic populations in China. Ten primers were screened out with 147 amplified bands, average percentage of polymorphic bands, polymorphic information content, and marker index were 78.9, 0.456, and 6.753% respectively. The results indicated that genetic diversity was different among populations, but genetic variation was as low as 0.2% among the populations and as high as 99.8% within the same geographic population. Among the examined WBPH populations, genetic distances were weakly correlated to geographic distance, and there was no correlation between genetic identity and elevation. Cluster analysis showed that the 27 WBPH populations studied could be lumped into four clusters, with which the results of principal coordinate analysis (were almost consistent. In conclusion, the molecular genetic data demonstrated that the region consisting of Yunnan, Guizhou, Guangdong, and Guangxi was the first landing area of WBPH in its migrating process from overwintering sites to China. PMID- 25525102 TI - Performance of the species-typical alarm response in young workers of the ant Myrmica sabuleti (Hymenoptera: Formicidae) is induced by interactions with mature workers. AB - Young workers of the ant Myrmica sabuleti (Hymenoptera: Formicidae) Meinert 1861 perceived nestmate alarm pheromone but did not display normal alarm behavior (orientation toward the source of emission, increased running speed). They changed their initial behavior when in the presence of older nestmates exhibiting normal alarm behavior. Four days later, the young ants exhibited an imperfect version of normal alarm behavior. This change of behavior did not occur in young ants, which were not exposed to older ants reacting to alarm pheromone. Queen ants perceived the alarm pheromone and, after a few seconds, moved toward its source. Thus, the ants' ability to sense the alarm pheromone and to identify it as an alarm signal is native, while the adult alarm reaction is acquired over time (= age based polyethism) by young ants. It is possible that the change in behavior observed in young ants could be initiated and/or enhanced (via experience-induced developmental plasticity, learning, and/or other mechanisms) by older ants exhibiting alarm behavior. PMID- 25525104 TI - Unusual occurrence of cocoons in population of Haplodiplosis marginata (Diptera: Cecidomyiidae) in Belgium. AB - The saddle gall midge, Haplodiplosis marginata (von Roser) (Diptera: Cecidomyiidae), is a phytophagous species that develops in saddle-shaped galls on stems of wheat Triticum vulgare, barley Hordeum sativum, rye Secale cereale, and some other species of Poaceae. Only one generation develops per year. Full-grown larvae leave galls and drop onto the soil where they remain up to the springtime of the following year. Larvae do not usually spin cocoons. However, formation of cocoons by larvae was observed in populations developing in western Europe: in England in 1954, in the Netherlands in the 1960s, and in Belgium in 2011. On the basis of our analysis, a part of the larval population forms cocoons as protection against unfavorable weather conditions, especially drought. PMID- 25525103 TI - Immature stages of Spodoptera eridania (Lepidoptera: Noctuidae): developmental parameters and host plants. AB - This study aimed to detail the temporal and morphological parameters of the immature stages of southern armyworm Spodoptera eridania (Stoll, 1782) with larvae feed on artificial diet, under controlled conditions (25 +/- 1 degrees C, 70 +/- 10% relative humidity and 14-h photophase) and gather information about their larval host plants. The viability of the egg, larval, pupal, and prepupal stages was 97.82, 93.62, 96.42, and 97.03%, respectively. The average duration of the egg, larval, pupal, and pre-pupal stages was 4.00, 16.18, 1.58, and 9.17 d, respectively. During the larval stage, 43.44% of females passed through seven instars, observing that the female's development was significant slower than males. The female larvae that developed through six and seven instars exhibited a mean growth rate of 1.52 and 1.44, respectively. Female pupae were significantly larger, exhibiting faster development than males. The rearing method proved to be adequate, providing more detailed observations of the biological cycle, especially at the larval stage, and resulting in an overall survival of almost 85%. Two hundred two plant species belonging to 58 families are listed as natural hosts for S. eridania, mainly including Asteraceae, Fabaceae, Solanaceae, Poaceae, Amaranthaceae, and Malvaceae. PMID- 25525105 TI - Body size and nutrition intake effects on fecundity and overwintering success in Anchomenus dorsalis (Coleoptera: Carabidae). AB - Structural body size and adult feeding conditions seem to be important determinants of fitness in income breeding species. However, little is known about the relative importance of structural body size and nutritional state on fecundity and winter survival in carabids. In this study, two separate experiments were performed. The effects of the structural body size of females (expressed as the length of the elytra and the width of the pronotum) and the effect of starvation on the fecundity of the ground beetle Anchomenus dorsalis (Pontoppidan, 1763) were investigated in the "fecundity experiment." The influence of structural body size, feeding conditions (full, partial, or no feeding) before the winter, and behavior during the winter (burrowing into the substrate) on winter survival in A. dorsalis females were studied in the "overwintering experiment." Egg production was positively influenced by both the structural body size of females and adult feeding. The effect of structural body size on the number of eggs laid outweighed the effect of feeding. However, the total fecundity (the number of eggs laid plus the number of mature eggs in ovaries) were more strongly affected by feeding in comparison to the structural body size of females. Interestingly, there was no significant effect of structural body size, feeding before winter, or behavior during winter on the survival of A. dorsalis females during the winter. However, our overwintering results could be affected by extreme weather conditions throughout experimental season and by the experimental design, which is discussed in detail. PMID- 25525106 TI - Insecticidal, fumigant, and repellent activities of sweet wormwood oil and its individual components against red imported fire ant workers (Hymenoptera: Formicidae). AB - In total, 29 compounds from sweet wormwood (Artemisia annua L.) oil were identified using gas chromatography-mass spectrometry. The five active components were D-camphor, linalool, cineole, alpha-terpineol, and L(-)-borneol. The effectiveness of A. annua oil, as well as d-camphor, linalool, cineole, alpha terpineol, and L(-)-borneol, as fumigants, contact insecticides, and repellents, were tested on the red imported fire ant Solenopsis invicta Buren. The results indicated that A. annua oil has no significant topical toxicity; however, the spray contact test revealed that it has strong insecticidal activity and the inhibitory effect is stronger during closed exposure than during open exposure. In the fumigant test, cineole and D-camphor exhibited strong fumigant toxicity on minor and major S. invicta workers. They also caused 100% mortality at 5, 3, 2, and 1 mg/centrifuge tube but not at 0.5 mg/centrifuge tube. The mortality rates of linalool, alpha-terpineol, and L(-)-borneol exceeded 80% at 5, 3, and 2 mg/centrifuge tube. In the repellent test, cineole and d-camphor showed significant repellency at 100, 10, and 1 mg/kg. However, linalool, alpha terpineol, and L(-)-borneol significantly facilitated digging at 10 and 1 mg/kg. PMID- 25525107 TI - Oviposition deterrent activities of Pachyrhizus erosus seed extract and other natural products on Plutella xylostella (Lepidoptera: Plutellidae). AB - An extract of a rotenone-containing plant yam bean, Pachyrhizus erosus (L.) Urban, seeds was tested against the diamondback moth, Plutella xylostella (L.) in a greenhouse to determine its potential as an oviposition deterrent and compared with coumarin and rutin, known as diamondback moth oviposition deterrent compounds, rotenone, and an extract of Peruvian cube root, at a concentration of 0.5% (w/v). Oviposition deterrent index (ODI) was used to determine effects of extracts or compounds in inhibiting oviposition of diamondback moth. Coumarin showed a stronger deterrent effect than the yam bean seed extract with a higher ODI value. On the contrary, rotenone, rutin, and the cube root extract, containing 6.7% (w/w) of rotenone, showed no significant deterrent effects having low or negative ODI values, suggesting that the deterrent effect of the yam bean seed extract is not due to rotenone content of the yam bean seeds. The extract of yam bean seed and coumarin partially deterred the moth from laying eggs on treated leaves in a concentration-dependent manner. The effective concentration for 50% deterrency of coumarin and the yam bean seed extract were 0.11 and 0.83% (w/v), respectively. However, the yam bean seed extract showed a residual deterrent effect on the moth even at 3 d after the treatment and is probably because of its low volatile nature. A long-term deterrency of the yam bean seed extract is an advantage over coumarins. Both the yam bean seed extract and coumarin deterred diamondback moth from laying eggs in total darkness, indicating their nonvisual deterrent effect. This made the extract an effective deterrence to diamondback moth in light and in darkness. To conclude, this study revealed the potential of the crude extract of the yam bean seed to prevent diamondback moth from ovipositing on its plant host. PMID- 25525108 TI - Adaptation of the egg of the desert beetle, Microdera punctipennis (Coleoptera: Tenebrionidae), to arid environment. AB - Microdera punctipennis Kaszab (Coleoptera: Tenebrionidae) is an endemic species in Guerbantonggut desert in China. To explore the ways that M. punctipennis egg adapts to dry desert environment, morphological characteristics of the egg was investigated along with the egg of the nondesert beetle Tenebrio molitor (Coleoptera: Tenebrionidae). Water loss rate and survival rate of these eggs under different dry treatments (relative humidity0, 10, and 20%) were measured to evaluate the desiccation resistance of the eggs at different developmental stages (day 0, 2, and 5 eggs). Our results showed that the 50-egg weight in T. molitor was heavier than M. punctipennis, while the 50-first-instar larva weight in T. molitor was almost the same as in M. punctipennis. The water loss rate of M. punctipennis egg under dry conditions was significantly lower than T. molitor, and the egg survival rate was significantly higher than T. molitor. The estimated developmental threshold temperature of M. punctipennis egg was 18.30 degrees C, and the critical thermal maximum of M. punctipennis egg is above 39 degrees C. These features partly account for the adaptability of M. punctipennis to desert environment in egg stage. PMID- 25525109 TI - Polyommatus ripartii: the biological basis for the conservation and the morphology of the developmental stages of a critically endangered, relict population in central Europe. AB - Ripart's Anomalous Blue Polyommatus ripartii (Freyer, 1830) is one of the most seriously endangered butterfly species in central Europe, a small, relict population of which has survived in two localities in Poland. This isolated population is undoubtedly the last and northernmost remnant of a once much wider range in central Europe. P. ripartii is associated with highly xerophilous vegetation on gypsum and calcareous soils. Only active conservation measures can ensure its survival. For these to be successful, however, precise information on the butterfly's biology, behavior and also its morphology is crucial. The first to do so, this article describes the butterfly's egg-laying preferences, and specifies the numbers of eggs on a single shoot and their placement on it. A unique behavioral trait of the female--the secretion of oviposition-deterring pheromones--is reported. The preferred plant associations and nectar sources have been investigated, and information on overnight roosts is given. In addition, an exhaustive description of the morphologies of the egg, final instar and pupa, as well as new details of adult behavior are provided. The main conclusion of the this study is that the existence of a stable population in the Nida Region is determined by the presence of large patches of sainfoin, which is both the larval host plant and a source of nectar for the imago. Moreover, stress is laid on the importance of Inula ensifolia L. as the secondary nectaring plant, which may facilitate dispersion among patches of suitable habitat. Finally, the study shows that searching for the easily detected eggs may be the best method for proving the existence of the species in a given locality. PMID- 25525110 TI - Patterns of species richness and diversity of insects associated with cucurbit fruits in the southern part of Cameroon. AB - Patterns of species diversity and community structure of insects associated with fruits of domesticated cucurbits were investigated from January 2009 to 2011 in three localities from two agroecological zones in the southern part of Cameroon. Rarefaction curves combined with nonparametric estimators of species richness were used to extrapolate species richness beyond our own data. Sampling efforts of over 92% were reached in each of the three study localities. Data collected revealed a total of 66 insect morphospecies belonging to 37 families and five orders, identified from a set of 57,510 insects. The orders Diptera (especially Tephritidae and Lonchaeidae) and Hymenoptera (mainly Braconidae and Eulophidae) were the most important, in terms of both abundance and species richness on the one hand, and effects on agronomic performance on the other. Values for both the species diversity (Shannon and Simpson) and the species richness indices (Margalef and Berger-Parker) calculated showed that the insect communities were species-rich but dominated, all to a similar extent, by five main species (including four fruit fly species and one parasitoid). Species abundance distributions in these communities ranged from the Zipf-Mandelbrot to Mandelbrot models. The communities are structured as tritrophic networks, including cucurbit fruits, fruit-feeding species (fruit flies) and carnivorous species (parasitoids). Within the guild of the parasitoids, about 30% of species, despite their low abundance, may potentially be of use in biological control of important pests. Our field data contribute in important ways to basic knowledge of biodiversity patterns in agrosystems and constitute baseline data for the planned implementation of biological control in Integrated Pest Management. PMID- 25525111 TI - The survivorship and water loss of Liometopum luctuosum (Hymenoptera: Formicidae) and Liometopum occidentale (Hymenoptera: Formicidae) exposed to different temperatures and relative humidity. AB - Two species of velvety tree ants, Liometopum luctuosum Wheeler, and Liometopum occidentale Emery (Hymenoptera: Formicidae), are commonly found in the western Unites States from Washington to southern California. L. luctuosum is restricted to coniferous forests in the mountains in the southern range, whereas L. occidentale is found in the lowlands. The survivorship of workers of both species exposed to several temperatures and relative humidity (RH) was determined. As temperature increased, survival of both species decreased. As the RH increased, survival of both species increased. However, L. luctuosum had higher overall survival in all treatment groups. The cuticular permeability (CP) and the rates of body water loss for each species were determined. Both species had similar CPs. Increased physiological tolerances of L. luctuosum may be an explanation for its broader distribution. PMID- 25525112 TI - Annual activity density of groundbeetles (Coleoptera: Carabidae) of a Celtis ehrenbergiana (Rosales: Celtidaceae) forest of Buenos Aires province, Argentina. AB - The aim of this study was to describe the annual activity cycle, the sex ratio, and the relationship between the weather variables and activity density of the 16 most abundant carabid species of a typical southeastern region of Pampasia, Argentina. The study focused on the southernmost Celtis ehrenbergiana (Klotzsch) Liebmann ( = C. tala Guillies ex Planch) native forest of the region, from March 2008 to March 2009, a period during which there was a marked draught associated with the La Nina phenomenon. Forty-five pitfall traps were emptied once every 2 wk, and the occurrence of larvae, tenerals, and subtenerals was recorded. Photoperiod, temperature, and precipitations explained 35% of the total variation in the catch. Total carabid activity was high in early autumn and late spring. Eight species reached their maximum activity in spring, five in winter, two in summer, and one in autumn. Possible reproductive strategies, the influence of different variables involved in the life cycles of the species, and the sex ratio and their limitations are discussed. PMID- 25525113 TI - Repellence produced by monoterpenes on Rhodnius prolixus (Hemiptera: Reduviidae) decreases after continuous exposure to these compounds. AB - Botanical monoterpenes are secondary metabolites present in essential oils produced by plants. Some of them are insect repellents. The bloodsucking bug Rhodnius prolixus Stahl (Hemiptera: Reduviidae) is one of the main vectors of Chagas disease in the north of South America and some countries in Central America. In this study, we studied the repellence produced by two monoterpenes, menthyl acetate and geraniol, on fifth instar nymphs of R. prolixus. In the absence of other stimuli, both menthyl acetate and geraniol produced a repellent effect from 740 MUg/cm(2) and 74 MUg/cm(2), respectively. Pre-exposure to each monoterpene reduced the repellent activity produced by the same substance. Additionally, pre-exposure to one monoterpene decreased the behavioral response of the nymphs to the other one. The repellent effect of both monoterpenes also decreased when nymphs' antennae were previously treated with the nitric oxide donor S-nitroso-N-acetyl-cysteine. PMID- 25525114 TI - Purification, characterization, and sensitivity to pesticides of carboxylesterase from Dendrolimus superans (Lepidoptera: Lasiocampidae). AB - Through a combination of steps including centrifugation, ammonium sulfate gradient precipitation, sephadex G-25 gel chromatography, diethylaminoethyl cellulose 52 ion-exchange chromatography and hydroxyapatite affinity chromatography, carboxylesterase (CarE, EC3.1.1.1) from sixth instar larch caterpillar moth, Dendrolimus superans (Lepidoptera: Lasiocampidae) larvae was purified and its biochemical properties were compared between crude homogenate and purified CarE. The final purified CarE after hydroxyapatite chromatography had a specific activity of 52.019 MUmol/(min.mg protein), 138.348-fold of crude homogenate, and the yield of 2.782%. The molecular weight of the purified CarE was approximately 84.78 kDa by SDS-PAGE. Three pesticides (dichlorvos, lambda cyhalothrin, and avermectins) showed different inhibition to crude CarE and purified CarE, respectively. In vitro median inhibitory concentration indicated that the sensitivity of CarE (both crude homogenate and final purified CarE) to pesticides was in decreasing order of dichlorvos > avermectins > lambda cyhalothrin. By the kinetic analysis, the substrates alpha-naphthyl acetate (alpha-NA) and beta-naphthyl acetate (beta-NA) showed lesser affinity to crude extract than purified CarE. The results also indicated that both crude homogenate and purified CarE had more affinity to alpha-NA than to beta-NA, and the Kcat and Vmax values of crude extract were lower than purified CarE using alpha-NA or beta NA as substrate. PMID- 25525115 TI - The signaling symphony: T cell receptor tunes cytokine-mediated T cell differentiation. AB - T cell development, differentiation, and maintenance are orchestrated by 2 key signaling axes: the antigen-specific TCR and cytokine-mediated signals. The TCR signals the recognition of self- and foreign antigens to control T cell homeostasis for immune tolerance and immunity, which is regulated by a variety of cytokines to determine T cell subset homeostasis and differentiation. TCR signaling can synergize with or antagonize cytokine-mediated signaling to fine tune T cell fate; however, the latter is less investigated. Murine models with attenuated TCR signaling strength have revealed that TCR signaling can function as regulatory feedback machinery for T cell homeostasis and differentiation in differential cytokine milieus, such as IL-2-mediated Treg development; IL-7 mediated, naive CD8(+) T cell homeostasis; and IL-4-induced innate memory CD8(+) T cell development. In this review, we discuss the symphonic cross-talk between TCR and cytokine-mediated responses that differentially control T cell behavior, with a focus on the negative tuning by TCR activation on the cytokine effects. PMID- 25525116 TI - Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies. AB - Oxidation-specific epitopes (OSEs) present on apoptotic cells and oxidized low density lipoprotein (OxLDL) represent danger-associated molecular patterns that are recognized by different arcs of innate immunity, including natural IgM antibodies. Here, we investigated whether circulating microparticles (MPs), which are small membrane vesicles released by apoptotic or activated cells, are physiological carriers of OSEs. OSEs on circulating MPs isolated from healthy donors and patients with ST-segment elevation myocardial infarction (STE-MI) were characterized by flow cytometry using a panel of OSE-specific monoclonal antibodies. We found that a subset of MPs carry OSEs on their surface, predominantly malondialdehyde (MDA) epitopes. Consistent with this, a majority of IgM antibodies bound on the surface of circulating MPs were found to have specificity for MDA-modified LDL. Moreover, we show that MPs can stimulate THP-1 (human acute monocytic leukemia cell line) and human primary monocytes to produce interleukin 8, which can be inhibited by a monoclonal IgM with specificity for MDA epitopes. Finally, we show that MDA(+) MPs are elevated at the culprit lesion site of patients with STE-MI. Our results identify a subset of OSE(+) MPs that are bound by OxLDL-specific IgM. These findings demonstrate a novel mechanism by which anti-OxLDL IgM antibodies could mediate protective functions in CVD. PMID- 25525117 TI - A novel immunoregulatory role for NK-cell cytotoxicity in protection from HLH like immunopathology in mice. AB - The impairment of cytotoxic activity of lymphocytes disturbs immune surveillance and leads to the development of hemophagocytic lymphohistiocytic syndrome (HLH). Although cytotoxic T lymphocyte (CTL) control of HLH development is well documented, the role for natural killer (NK)-cell effector functions in the pathogenesis of this immune disorder remains unclear. In this study, we specifically targeted a defect in cytotoxicity to either CTL or NK cells in mice so as to dissect the contribution of these lymphocyte subsets to HLH-like disease severity after lymphocytic choriomeningitis virus (LCMV) infection. We found that NK-cell cytotoxicity was sufficient to protect mice from the fatal outcome that characterizes HLH-like disease and was also sufficient to reduce HLH-like manifestations. Mechanistically, NK-cell cytotoxicity reduced tissue infiltration by inflammatory macrophages and downmodulated LCMV-specific T-cell responses by limiting hyperactivation of CTL. Interestingly, the critical protective effect of NK cells on HLH was independent of interferon-gamma secretion and changes in viral load. Therefore our findings identify a crucial role of NK-cell cytotoxicity in limiting HLH-like immunopathology, highlighting the important role of NK cytotoxic activity in immune homeostasis. PMID- 25525119 TI - Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. AB - Vascular safety is an emerging issue in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Whereas imatinib exhibits a well-documented and favorable long-term safety profile without obvious accumulation of vascular events, several types of vascular adverse events (VAEs) have been described in patients receiving second- or third-generation BCR/ABL1 TKIs. Such VAEs include pulmonary hypertension in patients treated with dasatinib, peripheral arterial occlusive disease and other arterial disorders in patients receiving nilotinib, and venous and arterial vascular occlusive events during ponatinib. Although each TKI interacts with a unique profile of molecular targets and has been associated with a unique pattern of adverse events, the mechanisms of drug-induced vasculopathy are not well understood. Here, recent data and concepts around VAEs in TKI-treated patients with CML are discussed, with special reference to potential mechanisms, event management, and strategies aimed at avoiding occurrence of such events in long-term treated patients. PMID- 25525118 TI - Prognostic factors for remission of and survival in acquired hemophilia A (AHA): results from the GTH-AH 01/2010 study. AB - Acquired hemophilia A (AHA) is caused by autoantibodies against factor VIII (FVIII). Immunosuppressive treatment (IST) results in remission of disease in 60% to 80% of patients over a period of days to months. IST is associated with frequent adverse events, including infections as a leading cause of death. Predictors of time to remission could help guide IST intensity but have not been established. We analyzed prognostic factors in 102 prospectively enrolled patients treated with a uniform IST protocol. Partial remission (PR; defined as no active bleeding, FVIII restored >50 IU/dL, hemostatic treatment stopped >24 hours) was achieved by 83% of patients after a median of 31 days (range 7-362). Patients with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days) than patients with >=1 IU/dL (89%, 24 days). After adjustment for other baseline characteristics, low FVIII remained associated with a lower rate of PR (hazard ratio 0.52, 95% confidence interval 0.33-0.81, P < .01). In contrast, PR achieved on steroids alone within <=21 days was more common in patients with FVIII >=1 IU/dL and inhibitor concentration <20 BU/mL (odds ratio 11.2, P < .0001). Low FVIII was also associated with a lower rate of complete remission and decreased survival. In conclusion, presenting FVIII and inhibitor concentration are potentially useful to tailor IST in AHA. PMID- 25525121 TI - Connectome of the fly visual circuitry. AB - Recent powerful tools for reconstructing connectomes using electron microscopy (EM) have made outstanding contributions to the field of neuroscience. As a prime example, the detection of visual motion is a classic problem of neural computation, yet our understanding of the exact mechanism has been frustrated by our incomplete knowledge of the relevant neurons and synapses. Recent connectomic studies have successfully identified the concrete neuronal circuit in the fly's visual system that computes the motion signals. This identification was greatly aided by the comprehensiveness of the EM reconstruction. Compared with light microscopy, which gives estimated connections from arbor overlap, EM gives unequivocal connections with precise synaptic counts. This paper reviews the recent study of connectomics in a brain of the fruit fly Drosophila and highlights how connectomes can provide a foundation for understanding the mechanism of neuronal functions by identifying the underlying neural circuits. PMID- 25525120 TI - Yaws. AB - INTRODUCTION: Yaws, caused by Treponema pallidum ssp. pertenue, is endemic in parts of West Africa, Southeast Asia and the Pacific. The WHO has launched a campaign based on mass treatment with azithromycin, to eradicate yaws by 2020. SOURCES OF DATA: We reviewed published data, surveillance data and data presented at yaws eradication meetings. AREAS OF AGREEMENT: Azithromycin is now the preferred agent for treating yaws. Point-of-care tests have demonstrated their value in yaws. AREAS OF CONTROVERSY: There is limited data from 76 countries, which previously reported yaws. Different doses of azithromycin are used in community mass treatment for yaws and trachoma. GROWING POINTS: Yaws eradication appears an achievable goal. The programme will require considerable support from partners across health and development sectors. AREAS TIMELY FOR DEVELOPING RESEARCH: Studies to complete baseline mapping, integrate diagnostic tests into surveillance and assess the impact of community mass treatment with azithromycin are ongoing. PMID- 25525122 TI - Arthrobacter liuii sp. nov., resuscitated from Xinjiang desert soil. AB - A Gram-stain positive, aerobic, non-motile actinobacterium, designated DSXY973(T), was isolated from soil samples collected from Xinjiang desert using medium supplemented with resuscitation-promoting factor, and subjected to a polyphasic taxonomic investigation. Phylogenetic analysis based on 16S rRNA gene sequences revealed that DSXY973(T) belonged to the genus Arthrobacter and was most closely related to Arthrobacter oryzae JCM 15922(T) with 97.1 % similarity. The DNA G+C content was 67.6 %. Cells of strain DSXY973(T) mainly contained MK 9(H2), and the cell wall contained l-lysine as the primary diamino acid. The major cellular fatty acids were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C15 : 0. Strain DSXY973(T) was positive for catalase and negative for oxidase activity. On the basis of its phylogenetic position and phenotypic properties, strain DSXY973(T) represents a novel species of the genus Arthrobacter, for which the name Arthrobacter liuii sp. nov. is proposed. The type strain is DSXY973(T) ( = CGMCC1.12778(T) = JCM 19864(T)). PMID- 25525123 TI - Dyadobacter sediminis sp. nov., isolated from a subterranean sediment sample. AB - A Gram-reaction-negative, flexirubin-type-pigmented, rod-shaped, aerobic, non motile bacterium, designated strain Z12(T), was isolated from a subsurface sediment sample. In a phylogenetic tree based on 16S rRNA gene sequences, strain Z12(T) formed a distinct clade with the members of the genus Dyadobacter (<96.7 % sequence similarity). The G+C content of genomic DNA was 45.4 %. The major fatty acids of strain Z12(T) were iso-C15 : 0, C16 : 1omega6c and/or C16 : 1omega7c (summed feature 3) and anteiso-C17 : 1 B and/or iso-C17 : 1 I (summed feature 4). The major respiratory quinone was MK-7 and the major polar lipid was phosphatidylethanolamine. On the basis of phenotypic, phylogenetic and genotypic features, strain Z12(T) is considered to represent a novel species, for which the name Dyadobacter sediminis sp. nov., is proposed. The type strain is Z12(T) ( = JCM 30073(T) = CGMCC 1.12895(T)). PMID- 25525124 TI - Pseudomonas matsuisoli sp. nov., isolated from a soil sample. AB - An aerobic, Gram-stain-negative, rod-shaped and polar-flagellated bacterium, designated strain CC-MHH0089(T), was isolated from a soil sample taken on Matsu Island (Taiwan). Strain CC-MHH0089(T) grew at 15-30 degrees C and pH 5.0-10.0 and tolerated <=8 % (w/v) NaCl. 16S rRNA gene sequence analysis showed high pairwise sequence similarity to Pseudomonas azotifigens 6H33b(T) (97.3 %) and Pseudomonas balearica SP1402(T) (96.7 %) and lower sequence similarity to other strains (<96.0 %). In DNA-DNA reassociation experiments, the relatedness of strain CC-MHH0089(T) to P. azotifigens JCM 12708(T) was 38.3 % (reciprocal value 19.5 %). Evolutionary trees reconstructed on the basis of 16S rRNA, gyrB and rpoB gene sequences revealed a varying phylogenetic neighbourhood of strain CC MHH0089(T) with regard to the most closely related type strains. The predominant quinone system was ubiquinone 9 (Q-9) and the DNA G+C content was 63.6 mol%. The major fatty acids were C12 : 0, C16 : 0, C17 : 0, C19 : 0 cyclo omega8c and summed features 2 (C14 : 0 3-OH/iso-C16 : 1 I), 3 (C16 : 1omega7c/C16 : 1omega6c) and 8 (C18 : 1omega7c/C18 : 1omega6c). The major polar lipids were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine and diphosphatidylglycerol. According to its distinct phylogenetic, phenotypic and chemotaxonomic features, strain CC-MHH0089(T) is proposed to represent a novel species within the genus Pseudomonas, for which the name Pseudomonas matsuisoli sp. nov. is proposed. The type strain is CC-MHH0089(T) ( = BCRC 80771(T) = JCM 30078(T)). PMID- 25525125 TI - Actinomadura rayongensis sp. nov., isolated from peat swamp forest soil. AB - A novel actinomycete strain RY35-68(T), isolated from a peat swamp forest soil sample in Rayong Province, Thailand, was characterized using a polyphasic approach. The strain belonged to the genus Actinomadura based on morphological and chemotaxonomic characteristics. Cell-wall analysis revealed the presence of meso-diaminopimelic acid and N-acetylmuramic acid in the peptidoglycan layer. The diagnostic sugar in whole-cell hydrolysates was identified as madurose. The predominant menaquinones were MK-9(H6), MK-9(H8) and MK-9(H4). The major cellular fatty acids were C16 : 0 and iso-C16 : 0. The major polar lipids were diphosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannoside. The genomic DNA G+C content was 73.7 mol%. On the basis of 16S rRNA gene sequence similarity analysis, strain RY35-68(T) was closely related to the species Actinomadura atramentaria JCM 6250(T) (97.5 %). The value of DNA-DNA relatedness between strain RY35-68(T) and A. atramentaria JCM 6250(T) was 37.6-42.6 %. On the basis of its phenotypic characteristics and these results mentioned, this strain could be distinguished from the closely related type strain and represents a novel species of the genus Actinomadura, for which the name Actinomadura rayongensis sp. nov. (type strain RY35-68(T) = JCM 19830(T) = TISTR 2211(T) = PCU 332(T)) is proposed. PMID- 25525126 TI - Chelatococcus caeni sp. nov., isolated from a biofilm reactor sludge sample. AB - A polyphasic taxonomic study was carried out on strain EBR-4-1(T), which was isolated from a biofilm reactor in the Republic of Korea. The cells of the strain were Gram-stain-negative, non-spore-forming, motile and rod-shaped. Comparative 16S rRNA gene sequence studies showed a clear affiliation of this strain to the Alphaproteobacteria, and it was most closely related to Chelatococcus daeguensis CCUG 54519(T), Chelatococcus sambhunathii HT4(T), and Chelatococcus asaccharovorans DSM 6462(T) with 16S rRNA gene sequence similarities to the type strains of these species of 98.8 %, 98.7 %, and 96.3 %, respectively. The G+C content of the genomic DNA of strain EBR-4-1(T) was 68.7 mol%. Phenotypic and chemotaxonomic data [Q-10 as the major ubiquinone; C19 : 0cycloomega8c, C18 : 1 2 OH, and summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) as the major fatty acids] supported the affiliation of strain EBR-4-1(T) to the genus Chelatococcus. On the basis of the polyphasic evidence, it is proposed that strain EBR-4-1(T) should be assigned to a new species, Chelatococcus caeni sp. nov. The type strain is EBR-4-1(T) ( = KCTC 32487(T) = JCM 30181(T)). PMID- 25525127 TI - Most people use adrenaline autoinjectors and asthma inhalers incorrectly, study warns. PMID- 25525129 TI - Acquired haemophilia A in a patient with systemic sclerosis treated with autologous haematopoietic stem cell transplantation. PMID- 25525130 TI - Type, size and age of vehicles driven by teenage drivers killed in crashes during 2008-2012. AB - Given teenagers' elevated crash rates, it is especially important that their vehicles have key safety features and good crash protection. A profile of vehicles driven by teenagers killed in crashes was developed. Data on vehicles of drivers ages 15-17 and ages 35-50 who died in crashes during 2008-2012 were obtained from the Fatality Analysis Reporting System. Using vehicle identification numbers, the vehicle make, model and model year were identified. 29% of fatally injured teenagers were driving mini or small cars, 82% were driving vehicles at least 6 years old, and 48% were driving vehicles at least 11 years old. Compared with middle-aged drivers, teenagers' vehicles more often were small or mini cars or older vehicles. Few teenagers' vehicles had electronic stability control or side airbags as standard features. Parents should consider safety when choosing vehicles for their teenagers. PMID- 25525131 TI - Low glycaemic index diet fails to reduce cardiovascular risk factors, study shows. PMID- 25525133 TI - The 2014 E. P. Pope memorial award to Dr. Tim Baszler. PMID- 25525132 TI - Determining the utility and durability of medical equipment donated to a rural clinic in a low-income country. AB - BACKGROUND: Health centers in low-income countries often depend on donations to provide appropriate diagnostic equipment. However, donations are sometimes made without an understanding of the recipient's needs, practical constraints or sustainability of supplies. METHODS: We donated a set of physical diagnostic equipment, non-invasive instrument tests and laboratory supplies to a rural health center in the Democratic Republic of Congo. We collected information on the usage and durability of equipment and supplies for each patient encounter over a 1-year period. RESULTS: We recorded 913 patient encounters. The most commonly used physical diagnostic equipment were the stethoscope (98.9%; 903/913), thermometer (81.7%; 746/913), adult scale (81.4%; 744/913), stop watch (62.6%; 572/913), adult sphygmomanometer (55.8%; 510/913), infant scale (24.9%; 228/913), measuring tape (24.3%; 222/913) and fetoscope (23.8%; 218/913). The most commonly used laboratory tests were the blood smear for malaria (53.7%; 491/913), hematocrit (23.5%; 215/913), urinalysis (20.1%; 184/913) and sputum stain for TB (13.3%; 122/913). With the exception of a penlight and solar lantern, all equipment remained functional. CONCLUSIONS: This study adds valuable information about the utility and durability of equipment supplied to a health center in the Democratic Republic of Congo. Our results might aid in determining the appropriateness of donated medical equipment in similar settings. The selection of donated goods should be made with knowledge of the context in which it will be used, and utilization should be monitored. PMID- 25525135 TI - Inflammatory, immunological, and intestinal disease biomarkers in Chinese Shar Pei dogs with marked hypocobalaminemia. AB - Chinese Shar-Pei dogs have a high prevalence of hypocobalaminemia and are commonly presented with clinical signs suggestive of severe and long-standing gastrointestinal disease such as diarrhea, vomiting, and/or weight loss. The aim of the current study was to evaluate serum concentrations of inflammatory markers, markers for intestinal disease, and immunological markers in Shar-Peis with hypocobalaminemia or normocobalaminemia (serum cobalamin concentrations within the reference interval). Serum samples from Shar-Peis were collected from various parts of the United States. Serum concentrations of inflammatory markers (i.e., C-reactive protein [CRP], calprotectin [CP], and S100A12), hyaluronic acid (HA, a marker for cutaneous mucinosis), and analytes commonly altered in chronic intestinal diseases (i.e., albumin, zinc, alpha1-proteinease inhibitor [alpha1PI], immunoglobulin [Ig]A, and IgM) were compared between Shar-Peis with hypocobalaminemia and Shar-Peis with normocobalaminemia. Serum concentrations of CRP, CP, S100A12, HA, zinc, and calpha1-PI concentrations did not differ between hypocobalaminemic and normocobalaminemic Shar-Peis (P > 0.05). Serum concentrations of albumin were significantly lower in hypocobalaminemic Shar-Peis (median: 2.5 g/dl) than in normocobalaminemic Shar-Peis (median: 2.9 g/dl; P < 0.0001). Higher serum IgA concentrations and lower serum IgM concentrations were observed in hypocobalaminemic Shar-Peis (median: 1.7 g/l and 0.8 g/l, respectively) than in normocobalaminemic Shar-Peis (median: 0.7 g/l and 1.9 g/l, respectively; both P < 0.0001). In conclusion, no difference was found in serum concentrations of CRP, CP, S100A12, and HA between hypocobalaminemic and normocobalaminemic Shar-Peis whereas some differences were observed in analytes (e.g., albumin, IgA, and IgM) that may be altered in patients with chronic enteropathies. PMID- 25525134 TI - Estimation of nasal shedding and seroprevalence of organisms known to be associated with bovine respiratory disease in Australian live export cattle. AB - The prevalence of organisms known to be associated with bovine respiratory disease (BRD) was investigated in cattle prior to export. A quantitative reverse transcription polymerase chain reaction assay was used to detect nucleic acids from the following viruses and bacteria in nasal swab samples: Bovine coronavirus (BoCV; Betacoronavirus 1), Bovine herpesvirus 1 (BoHV-1), Bovine viral diarrhea virus 1 (BVDV-1), Bovine respiratory syncytial virus (BRSV), Bovine parainfluenza virus 3 (BPIV-3), Histophilus somni, Mycoplasma bovis, Mannheimia haemolytica, and Pasteurella multocida. Between 2010 and 2012, nasal swabs were collected from 1,484 apparently healthy cattle destined for export to the Middle East and Russian Federation. In addition, whole blood samples from 334 animals were tested for antibodies to BoHV-1, BRSV, BVDV-1, and BPIV-3 using enzyme-linked immunosorbent assay. The nasal prevalence of BoCV at the individual animal level was 40.1%. The nasal and seroprevalence of BoHV-1, BRSV, BVDV-1, and BPIV-3 was 1.0% and 39%, 1.2% and 46%, 3.0% and 56%, and 1.4% and 87%, respectively. The nasal prevalence of H. somni, M. bovis, M. haemolytica, and P. multocida was 42%, 4.8%, 13.4%, and 26%, respectively. Significant differences in nasal and seroprevalence were detected between groups of animals from different geographical locations. The results of the current study provide baseline data on the prevalence of organisms associated with BRD in Australian live export cattle in the preassembly period. This data could be used to develop strategies for BRD prevention and control prior to loading. PMID- 25525136 TI - Comparison of culture, polymerase chain reaction, and fluorescent in situ hybridization for detection of Brachyspira hyodysenteriae and "Brachyspira hampsonii" in pig feces. AB - Swine dysentery is characterized by mucohemorrhagic diarrhea and can occur following infection by Brachyspira hyodysenteriae or "Brachyspira hampsonii ". A definitive diagnosis is often based on the isolation of strongly beta-hemolytic spirochetes from selective culture or by the application of species-specific polymerase chain reaction (PCR) assays directly to feces. While culture is highly sensitive, it typically requires 6 or more days to complete, and PCR, although rapid, can be limited by fecal inhibition. Fluorescent in situ hybridization (FISH) has been described in formalin-fixed tissues; however, completion requires approximately 2 days. Because of the time constraints of available assays, a same day FISH assay was developed to detect B. hyodysenteriae and "B. hampsonii " in pig feces using previously described oligonucleotide probes Hyo1210 and Hamp1210 for B. hyodysenteriae and "B. hampsonii", respectively. In situ hybridization was simultaneously compared with culture and PCR on feces spiked with progressive dilutions of spirochetes to determine the threshold of detection for each assay at 0 and 48 hr. The PCR assay on fresh feces and FISH on formalin-fixed feces had similar levels of detection. Culture was the most sensitive method, detecting the target spirochetes at least 2 log-dilutions less when compared to other assays 48 hr after sample preparation. Fluorescent in situ hybridization also effectively detected both target species in formalin-fixed feces from inoculated pigs as part of a previous experiment. Accordingly, FISH on formalin-fixed feces from clinically affected pigs can provide same-day identification and preliminary speciation of spirochetes associated with swine dysentery in North America. PMID- 25525137 TI - Diagnosis of the Lelystad strain of Porcine reproductive and respiratory syndrome virus infection in individually housed pigs: comparison between serum and oral fluid samples for viral nucleic acid and antibody detection. AB - There has been a developing interest in the use of oral fluid for the diagnosis of different pathogens such as Porcine reproductive and respiratory syndrome virus (PRRSV). PRRSV and PRRSV-specific antibodies have been shown to be present in oral fluid samples, but the correlation between diagnostic results in oral fluid and serum samples has been insufficiently addressed. Studies investigating this correlation focused on boars older than 6 months and type 2 strains, but it is known that the outcome of a PRRSV infection is age and strain dependent. To address this gap, the current study reports on the detection of PRRSV and PRRSV specific antibodies in serum and oral fluid samples collected over a 6-week period after an experimental infection of 8-week-old individually housed pigs with Lelystad virus, the type 1 prototype strain. Quantitative reverse transcription polymerase chain reaction analysis showed that significantly more serum samples were PRRSV RNA-positive than oral fluid until 5 days postinfection (dpi). Between 7 and 21 dpi, PRRSV RNA detection was similar in both samples but higher detection rates in oral fluid were found from 28 dpi. Compared with existing literature, this highlights that detection rates at particular time points postinfection might vary in function of strain virulence and animal age and provides useful information for the interpretation of pen-based oral fluid results. An excellent agreement between the oral fluid and serum enzyme-linked immunosorbent assay results was observed at every time point, further supporting the usefulness of oral fluid as a diagnostic sample for antibody detection. PMID- 25525138 TI - The effect of anatomic site and age on detection of Staphylococcus aureus in pigs. AB - Despite active research into methicillin-resistant Staphylococcus aureus (MRSA) in pigs since 2004, the ecology of the susceptible ancestral organism has been neglected. A longitudinal study of pigs in 2 intensive production systems was conducted to investigate the effects of age and anatomical site on detection of S. aureus. Sampling was replicated in 2 cohorts per farm, with swabs collected from the nares, tonsils, skin (axilla), and rectum in lactating sows, suckling, weaned, and market-age pigs, plus the vagina of sows. No MRSA were isolated, but S. aureus was detected in a least 1 site in 175 (91.1%) out of 192 pigs. Pig level prevalence did not differ among the age groups, but the proportion of positive samples (all sites) was higher in market-age pigs (75.2%) and nursery age pigs (63.2%) than in sows (40.7%) and suckling piglets (38%). Prevalence did not differ among nasal (67.9%), skin (62.3%), and tonsil (61.7%) swabs, but was lower in rectal (42%) and vaginal swabs (39.6%). Multiple multilocus sequence typing (MLST) and spa types were found in both production systems, but all isolates were of ST398, ST9, or ST5. These MLST lineages have been variably predominant among reports of MRSA in pigs on 3 continents, and the presence of methicillin-sensitive variants in several countries raises the likelihood that MRSA in pigs has likely resulted from independent acquisition of the mecA gene by multiple S. aureus lineages that have been adapted to swine over the long term, rather than recent introduction of novel clones into swine populations. PMID- 25525139 TI - Analytical validation of a second-generation immunoassay for the quantification of N-terminal pro-B-type natriuretic peptide in canine blood. AB - N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been shown to have clinical utility as a biomarker in dogs with heart disease. There were several limitations associated with early diagnostic assay formats including a limited dynamic range and the need for protease inhibitors to maintain sample stability. A second-generation Cardiopet(r) proBNP enzyme-linked immunosorbent assay (IDEXX Laboratories Inc., Westbrook, Maine) was developed to address these limitations, and the present study reports the results of the analytical method validation for the second-generation assay. Coefficients of variation for intra-assay, interassay, and total precision based on 8 samples ranged from 3.9% to 8.9%, 2.0% to 5.0%, and 5.5% to 10.6%, respectively. Analytical sensitivity was established at 102 pmol/l. Accuracy averaged 102.0% based on the serial dilutions of 5 high dose canine samples. Bilirubin, lipids, and hemoglobin had no effect on results. Reproducibility across 3 unique assay lots was excellent with an average coefficient of determination (r (2)) of 0.99 and slope of 1.03. Both ethylenediamine tetra-acetic acid plasma and serum gave equivalent results at time of blood draw (slope = 1.02, r (2) = 0.89; n = 51) but NT-proBNP was more stable in plasma at 25 degrees C with median half-life measured at 244 hr and 136 hr for plasma and serum, respectively. Plasma is the preferred sample type and is considered stable up to 48 hr at room temperature whereas serum should be frozen or refrigerated when submitted for testing. Results of this study validate the second-generation canine Cardiopet proBNP assay for accurate and precise measurement of NT-proBNP in routine sample types from canine patients. PMID- 25525140 TI - Hematological values for adult eastern Hermann's tortoise (Testudo hermanni boettgeri) in semi-natural conditions. AB - Hermann's tortoise (Testudo hermanni) is considered near threatened in the wild but, by contrast, it is one of the most popular pet tortoises in Europe. Scant data is reported in the veterinary literature on hematological values for T. hermanni and, to our knowledge, none focused on the subspecies boettgeri (eastern Hermann's tortoise). Published reports are based on small sample populations, and confusion arises when comparing the sampling sites, the anticoagulants, and the counting methods used. The purpose of the current study was to establish the normal mean values and reference intervals for the main hematological parameters for captive adult T. hermanni boettgeri and to evaluate the reliability of a semiautomated blood analyzer for red blood cell count and hematocrit determination. Blood values were determined in 23 adult tortoises using a Neubauer chamber with Natt and Herrick solution; red blood cells and hematocrit were also measured using a semiautomated blood analyzer. Statistical analysis included descriptive statistics, differences between sexes, and agreement between the counting methods. Reference intervals were calculated with the robust method. Wilcoxon signed rank test with continuity correction was used to investigate differences between sexes, and Bland-Altman analysis was performed to compare manual versus semiautomated values. Red blood cells, hematocrit, and hemoglobin determinations were significantly higher in males than in females. White blood cell counts did not show any sex variability. The agreement of manual versus semiautomated determination was considered acceptable for clinical use. PMID- 25525141 TI - Pathology and diagnosis of proliferative and ulcerative dermatitis associated with Tunga penetrans infestation in cattle. AB - Tunga penetrans is the smallest biting flea known. In cattle, infestation by T. penetrans (tungiasis) typically affects the skin of the distal legs, udder, prepuce, and perianal area. A detailed clinical and pathologic description of bovine tungiasis, together with electron microscopy and molecular diagnostics to establish the identity of the parasite are described. Ninety percent of the cows and heifers and 80% of the bulls in a herd in northwest Argentina had proliferative and ulcerative skin lesions affecting the coronary band, interdigital space, heels, and rudimentary toes of the fore and/or rear limbs, teats, and/or prepuce. These proliferative lesions had multiple large cavities filled with hemorrhagic fluid, necrotic debris, and Tunga spp. parasites. Histologically, the skin showed diffuse papillary epithelial hyperplasia with severe orthokeratotic hyperkeratosis, and it was multifocally ulcerated and inflamed. Multifocally, sections of arthropod parasites were observed embedded in the epidermis and dermis with the posterior end toward the surface. Images of wet mounts and scanning electron microscopy of the parasite showed morphologic characteristics compatible with Tunga spp. Polymerase chain reaction followed by sequencing of the cytochrome c oxidase subunit II and the internal transcribed spacer region indicated 99% homology to published T. penetrans sequences. Tungiasis should be considered as a differential diagnosis for proliferative lesions in skin of cattle. PMID- 25525142 TI - Classification and clinical features in 88 cases of equine cutaneous lymphoma. AB - Equine cutaneous lymphoma is an uncommon disease that can present with variable clinical signs, immunosuppression, and rapid systemic disease progression. Various subtypes of equine lymphoma have been described and classified according to a veterinary adaptation of the World Health Organization classification system, but little data is available regarding the association between lymphoma subtypes and epidemiological criteria and/or clinical outcome. The objective of the current study was to classify previously diagnosed cases of equine cutaneous lymphoma and correlate subtypes with clinical data to investigate epidemiological trends and prognostic implications. Results from the study confirm T-cell-rich, large B-cell lymphoma (TCRLBCL) as the predominant subtype in equine cutaneous lymphoma. Cutaneous T-cell lymphoma (CTCL) was the second most common phenotype in the current study. To the authors' knowledge, a description of the morphological and immunohistochemical features of CTCL in horses, an epitheliotropic neoplasm similar to the cutaneous epitheliotropic lymphoma variant (mycosis fungoides) observed in human beings and canids, has not been previously described. Less common lymphoma subtypes identified in the study include diffuse large B-cell lymphoma and anaplastic large T-cell lymphoma. Quarter Horses almost exclusively developed TCRLBCL, while the frequency of CTCL was increased significantly in Thoroughbreds compared with other breeds. TCRLBCLs more frequently presented as multiple masses while CTCLs were more often solitary nodules. When multiple regions of the body were affected, 100% of cases were TCRBCL. Finally, there was an observable trend for longer survival in cases of TCRLBCL without local recurrence, suggesting adequate surgical excision may be an effective treatment modality. PMID- 25525143 TI - Equine pancreatic disease: a review and characterization of the lesions of four cases (2005-2014). AB - Equine pancreatic disease is considered rare, and successful treatment is limited. Additionally, antemortem diagnosis of equine pancreatitis is difficult because of the lack of definitive diagnostic tests. Although a paucity of information exists on this entity in the horse, pancreatic disease has typically been shown to be secondary to other gastrointestinal, hepatic, and endocrine conditions. No predisposition based on age, sex, or breed appears to exist, but several conditions predispose a horse to pancreatitis, including grain overload, endocrine disease, and parasite migration. A retrospective search of cases within the archive of the University of Tennessee necropsy database revealed only 4 cases during a 9-year period (2005-2014). In only 1 case was pancreatic disease considered primary, and in the other 3, pathologies often seen concurrently with pancreatic lesions were identified. These included cecal rupture, colonic displacement, neoplasia (lymphocytic leukemia), and pituitary adenoma. A review of available historical data and associated laboratory results are included with the gross and histologic characteristics of pancreatic lesions, in these 4 newly reported cases. PMID- 25525144 TI - Genotyping of Canine parvovirus in western Mexico. AB - Canine parvovirus (CPV) is one of the most common infectious agents related to high morbidity rates in dogs. In addition, the virus is associated with severe gastroenteritis, diarrhea, and vomiting, resulting in high death rates, especially in puppies and nonvaccinated dogs. To date, there are 3 variants of the virus (CPV-2a, CPV-2b, and CPV-2c) circulating worldwide. In Mexico, reports describing the viral variants circulating in dog populations are lacking. In response to this deficiency, a total of 41 fecal samples of suspected dogs were collected from October 2013 through April 2014 in the Veterinary Hospital of the University of Guadalajara in western Mexico. From these, 24 samples resulted positive by polymerase chain reaction, and the viral variant was determined by restriction fragment length polymorphism. Five positive diagnosed samples were selected for partial sequencing of the vp2 gene and codon analysis. The results demonstrated that the current dominant viral variant in Mexico is CPV-2c. The current study describes the genotyping of CPV strains, providing valuable evidence of the dominant frequency of this virus in a dog population from western Mexico. PMID- 25525145 TI - Cluster of cases of massive hemorrhage associated with anticoagulant detection in race horses. AB - Five horses originating from 4 different California race tracks were submitted to the California Animal Health and Food Safety Laboratory for necropsy and diagnostic workup. The 5 horses had a history of sudden collapse and death during exercise. In all of them, massive hemoperitoneum and hemorrhages in other cavities or organs were observed. The liver from these 5 animals and from 27 horses that had been euthanized due to catastrophic leg injuries (controls) were subjected to a rodenticide anticoagulant screen. Traces of brodifacoum, diphacinone, or bromadiolone were detected in the 5 horses with massive bleeding (5/5), and no traces of rodenticides were detected in control horses (0/27). Other frequent causes of massive hemorrhages in horses were ruled out in 4 of the cases; one of the horses had a pelvic fracture. Although only traces of anticoagulants were found in the livers of these horses and the role of these substances in the massive bleeding remains uncertain, it is speculated that exercise-related increases in blood pressure may have reduced the threshold for toxicity of these anticoagulants. PMID- 25525146 TI - Identification of Parabodo caudatus (class Kinetoplastea) in urine voided from a dog with hematuria. AB - A voided urine sample, obtained from a 13-year-old intact male dog residing in a laboratory animal research facility, was observed to contain biflagellate protozoa 5 days following an episode of gross hematuria. The protozoa were identified as belonging to the class Kinetoplastea on the basis of light microscopic observation of Wright-Giemsa-stained urine sediment in which the kinetoplast was observed basal to 2 anterior flagella. A polymerase chain reaction (PCR) assay using primers corresponding with conserved regions within the 18S ribosomal RNA gene of representative kinetoplastid species identified nucleotide sequences with 100% identity to Parabodo caudatus. Parabodo caudatus organisms were unable to be demonstrated cytologically or by means of PCR in samples collected from the dog's environment. The dog had a history of 50 complete urinalyses performed over the 12-year period preceding detection of P. caudatus, and none of these were noted to contain protozoa. Moreover, the gross hematuria that was documented 5 days prior to detection of P. caudatus had never before been observed in this dog. Over the ensuing 2.5 years of the dog's life, 16 additional complete urinalyses were performed, none of which revealed the presence of protozoa. Bodonids are commonly found in soil as well as in freshwater and marine environments. However, P. caudatus, in particular, has a 150-year-long, interesting, and largely unresolved history in people as either an inhabitant or contaminant of urine. This historical conundrum is revisited in the current description of P. caudatus as recovered from the urine of a dog. PMID- 25525147 TI - Countries agree to spell out plans on climate change after fraught talks in Peru. PMID- 25525148 TI - Improving the identification and management of chronic kidney disease in primary care: lessons from a staged improvement collaborative. AB - QUALITY PROBLEM: Undiagnosed chronic kidney disease (CKD) contributes to a high cost and care burden in secondary care. Uptake of evidence-based guidelines in primary care is inconsistent, resulting in variation in the detection and management of CKD. INITIAL ASSESSMENT: Routinely collected general practice data in one UK region suggested a CKD prevalence of 4.1%, compared with an estimated national prevalence of 8.5%. Of patients on CKD registers, ~ 30% were estimated to have suboptimal management according to Public Health Observatory analyses. CHOICE OF SOLUTION: An evidence-based framework for implementation was developed. This informed the design of an improvement collaborative to work with a sample of 30 general practices. IMPLEMENTATION: A two-phase collaborative was implemented between September 2009 and March 2012. Key elements of the intervention included learning events, improvement targets, Plan-Do-Study-Act cycles, benchmarking of audit data, facilitator support and staff time reimbursement. EVALUATION: Outcomes were evaluated against two indicators: number of patients with CKD on practice registers; percentage of patients achieving evidence-based blood pressure (BP) targets, as a marker for CKD care. In Phase 1, recorded prevalence of CKD in collaborative practices increased ~ 2-fold more than that in comparator local practices; in Phase 2, this increased to 4-fold, indicating improved case identification. Management of BP according to guideline recommendations also improved. LESSONS LEARNED: An improvement collaborative with tailored facilitation support appears to promote the uptake of evidence-based guidance on the identification and management of CKD in primary care. A controlled evaluation study is needed to rigorously evaluate the impact of this promising improvement intervention. PMID- 25525149 TI - Cystic nephroma/mixed epithelial stromal tumor: a benign neoplasm with potential for recurrence. AB - Cystic nephroma (CN) is a rare, benign, renal neoplasm composed of epithelial and stromal elements. Only about 200 cases have been reported since 1892 and recurrence has rarely been observed. We report a 32-year-old Hispanic woman, with a history of a right, complex cystic, renal mass treated by robotic decortication 2 years ago, who presented with flank pain, hematuria, and recurrent urinary tract infection. A magnetic resonance imaging study showed a 3.4-cm multicystic lesion with thickened septa and enhancement at the right kidney. The partial nephrectomy specimen revealed a well-circumscribed, multicystic tumor abutting the renal pelvis, with thick septa and smooth walls, filled with clear fluid. Microscopic examination showed variably sized cysts lined by cuboidal epithelium with focal hobnailing, without significant cytologic atypia and mitosis. The epithelial lining was positive for CK19, high molecular weight cytokeratin, and alpha-methylacyl-CoA racemase suggesting a primitive tubular epithelial phenotype. Primitive glomeruli-like structures were also present. The ovarian like stroma was condensed around the cysts and was variably cellular with areas of muscle differentiation and thick-walled vessels. The stroma was positive for desmin, estrogen receptor, progesterone receptor, and CD10. We suggest that CN represents a variable mixture of epithelial and stromal elements, immature glomerular, tubular, muscle, and vascular elements, which may be present in variable proportions creating a spectrum of lesions previously described as CN and mixed epithelial and stromal tumors (MEST). This case emphasizes that CN/MEST clinically/radiologically mimics other cystic renal neoplasms, especially cystic renal cell carcinoma and tubulocystic carcinoma, necessitating histopathological examination and immunohistochemial studies for definitive diagnosis. Additionally, CN has the tendency to recur when not completely excised initially. PMID- 25525150 TI - Diaphragm disease of the small intestine: an interesting case report. AB - Diaphragm disease of small intestine usually presents with nonspecific clinical features. Radiological investigations often fail to differentiate it from small intestinal tumors and inflammatory bowel disease. It is therefore diagnosed on final histology after surgical resection. We hereby report an interesting case of a suspected small bowel tumor later diagnosed as diaphragm disease on histology. PMID- 25525151 TI - Identification, expression, and molecular evolution of microRNAs in the "living fossil" Triops cancriformis (tadpole shrimp). AB - MicroRNAs have been identified and analyzed in various model species, but an investigation of miRNAs in nonmodel species is required for a more complete understanding of miRNA evolution. In this study, we investigated the miRNAs of the nonmodel species Triops cancriformis (tadpole shrimp), a "living fossil," whose morphological form has not changed in almost 200 million years. Dramatic ontogenetic changes occur during its development. To clarify the evolution of miRNAs, we comparatively analyzed its miRNAs and the components of its RNAi machinery. We used deep sequencing to analyze small RNA libraries from the six different developmental stages of T. cancriformis (egg, first-fourth instars, and adult), and also analyzed its genomic DNA with deep sequencing. We identified 180 miRNAs (87 conserved miRNAs and 93 novel candidate miRNAs), and deduced the components of its RNAi machinery: the DICER1, AGO1-3, PIWI, and AUB proteins. A comparative miRNA analysis of T. cancriformis and Drosophila melanogaster showed inconsistencies in the expression patterns of four conserved miRNAs. This suggests that although the miRNA sequences of the two species are very similar, their roles differ across the species. An miRNA conservation analysis revealed that most of the conserved T. cancriformis miRNAs share sequence similarities with those of arthropods, although T. cancriformis is called a "living fossil." However, we found that let-7 and DICER1 of T. cancriformis are more similar to those of the vertebrates than to those of the arthropods. These results suggest that miRNA systems of T. cancriformis have evolved in a unique fashion. PMID- 25525152 TI - p38MAPK/MK2-mediated phosphorylation of RBM7 regulates the human nuclear exosome targeting complex. AB - The nuclear exosome targeting complex (NEXT) directs a major 3'-5' exonuclease, the RNA exosome, for degradation of nuclear noncoding (nc) RNAs. We identified the RNA-binding component of the NEXT complex, RBM7, as a substrate of p38(MAPK)/MK2-mediated phosphorylation at residue S136. As a result of this phosphorylation, RBM7 displays a strongly decreased RNA-binding capacity, while inhibition of p38(MAPK) or mutation of S136A in RBM7 increases its RNA association. Interestingly, promoter-upstream transcripts (PROMPTs), such as proRBM39, proEXT1, proDNAJB4, accumulated upon stress stimulation in a p38(MAPK)/MK2-dependent manner, a process inhibited by overexpression of RBM7(S136A). While there are no stress-dependent changes in RNA-polymerase II (RNAPII) occupation of PROMPT regions representing unchanged transcription, stability of PROMPTs is increased. Hence, we propose that phosphorylation of RBM7 by the p38(MAPK)/MK2 axis increases nuclear ncRNA stability by blocking their RBM7-binding and subsequent RNA exosome targeting to allow stress-dependent modulations of the noncoding transcriptome. PMID- 25525154 TI - A simple real-time assay for in vitro translation. AB - A high-throughput assay for real-time measurement of translation rates in cell free protein synthesis (SNAP assay) is described. The SNAP assay enables quantitative, real-time measurement of overall translation rates in vitro via the synthesis of O(6)-alkylguanine DNA O(6)-alkyltransferase (SNAP). SNAP production is continuously detected by fluorescence produced by the reaction of SNAP with a range of quenched fluorogenic substrates. The capabilities of the assay are exemplified by measurements of the activities of Escherichia coli MRE600 ribosomes and fluorescently labeled E. coli mutant ribosomes in the PURExpress translation system and by determination of the 50% inhibitory concentrations (IC50) of three common macrolide antibiotics. PMID- 25525153 TI - WBSCR22/Merm1 is required for late nuclear pre-ribosomal RNA processing and mediates N7-methylation of G1639 in human 18S rRNA. AB - Ribosomal (r)RNAs are extensively modified during ribosome synthesis and their modification is required for the fidelity and efficiency of translation. Besides numerous small nucleolar RNA-guided 2'-O methylations and pseudouridinylations, a number of individual RNA methyltransferases are involved in rRNA modification. WBSCR22/Merm1, which is affected in Williams-Beuren syndrome and has been implicated in tumorigenesis and metastasis formation, was recently shown to be involved in ribosome synthesis, but its molecular functions have remained elusive. Here we show that depletion of WBSCR22 leads to nuclear accumulation of 3'-extended 18SE pre-rRNA intermediates resulting in impaired 18S rRNA maturation. We map the 3' ends of the 18SE pre-rRNA intermediates accumulating after depletion of WBSCR22 and in control cells using 3'-RACE and deep sequencing. Furthermore, we demonstrate that WBSCR22 is required for N(7) methylation of G1639 in human 18S rRNA in vivo. Interestingly, the catalytic activity of WBSCR22 is not required for 18S pre-rRNA processing, suggesting that the key role of WBSCR22 in 40S subunit biogenesis is independent of its function as an RNA methyltransferase. PMID- 25525156 TI - Prevalence of Anxiety Disorders in Hong Kong Chinese Children With ADHD. AB - OBJECTIVE: This study examined the prevalence and correlates of anxiety disorders in Chinese children with ADHD. METHOD: Overall, 120 children with ADHD aged 6 to 12 years were recruited, and the parent version of computerized Diagnostic Interview Schedule for Children-Version 4 was administrated to their primary caretakers. RESULTS: The prevalence rate of anxiety disorders was 27.5%, which is consistent with the reports of previous Asian and Western studies. Among the children with ADHD and anxiety disorders, more than 50% of them also had comorbid oppositional defiant disorder or conduct disorder (ODD/CD), which yielded an adjusted odds ratio of 3.0 in multivariable analysis for anxiety disorder, with comorbid ODD/CD. In addition, anxiety disorders were positively associated with inattention symptoms in children with both disorders. CONCLUSION: Clinicians should perform screening and careful assessment for anxiety symptoms in children with ADHD, particularly those suffering from comorbid ODD/CD. PMID- 25525157 TI - Comparisons of Intelligence and Behavior in Children With Fetal Alcohol Spectrum Disorder and ADHD. AB - OBJECTIVE: Children with fetal alcohol spectrum disorder (FASD) can easily be misdiagnosed as having ADHD. METHOD: A total of 164 children were compared on cognitive and behavioral measures for four groups of children: FASD, ADHD, FASD + ADHD, and other neuropsychological disorders. RESULTS: The ADHD group was not significantly different from the "other diagnosis" group on any of the measurements. The children with FASD were found to perform significantly worse than ADHD on externalizing problems, Full-Scale IQ, and indices of Verbal Comprehension, Perceptual Reasoning, and Working Memory. The comorbid FASD + ADHD group was significantly weaker than ADHD on verbal comprehension measures. The FASD children demonstrated significantly higher levels of atypicality and aggression relative to ADHD, and the FASD + ADHD group demonstrated significantly higher levels of hyperactivity and withdrawal relative to ADHD. CONCLUSION: These results indicate that children with FASD display a differential behavioral and cognitive profile that is significantly poorer than children with ADHD and other types of neuropsychological disorders. PMID- 25525155 TI - Maternal ADHD Symptoms, Personality, and Parenting Stress: Differences Between Mothers of Children With ADHD and Mothers of Comparison Children. AB - OBJECTIVE: Mothers raising a child with ADHD can experience high parenting stress. We evaluated if mothers' personality traits and own ADHD symptoms could also affect parenting stress. METHOD: 430 biological mothers from the Multimodal Treatment Study of Children with ADHD (MTA mothers) and 237 of a local normative comparison group (LNCG mothers) were evaluated at baseline. Interactions were tested between mothers' group and maternal personality/ADHD symptoms related to parenting stress. RESULTS: Compared to LNCG, MTA mothers had higher parenting stress, self-reported ADHD, neuroticism, and lower conscientiousness and agreeableness. When personality and ADHD were evaluated together, ADHD symptoms interacted with mothers' group: high maternal ADHD was positively associated with parenting stress for LNCG but not MTA mothers. CONCLUSION: Personality traits or ADHD characteristics do not appear operative for the high parenting stress of mothers of a child with ADHD. However, high maternal ADHD or low conscientiousness are associated with stress levels similar to raising a child with ADHD. PMID- 25525158 TI - Transition to Adult Mental Health Services for Young People With ADHD. AB - OBJECTIVE: To investigate the care management and continuity from child to adult mental health service for young adults with ADHD. METHOD: A questionnaire survey from 18 Regional ADHD Pediatric Centers (RAPC) in Lombardy, Italy, was used to collect data on transition protocols and population served, and to track the pathway of care of ADHD patients once they reached adulthood. RESULTS: Twenty eight percent of RAPC had transition protocols and 3% of the population annually served were potential referrals to adult service. Of 52 patients who turned 18 years, just over 70% were monitored by the general practitioner, of those 5 with RAPC support. One fifth of patients continued to use mental health services, the majority was still monitored by the RAPC, and only three by services for adult. CONCLUSION: Managing the process of transition to adult services in mental health care remains a need to be prioritized and better defined for ADHD patients. PMID- 25525160 TI - An Aharonov-Bohm interferometer for determining Bloch band topology. AB - The geometric structure of a single-particle energy band in a solid is fundamental for a wide range of many-body phenomena and is uniquely characterized by the distribution of Berry curvature over the Brillouin zone. We realize an atomic interferometer to measure Berry flux in momentum space, in analogy to an Aharonov-Bohm interferometer that measures magnetic flux in real space. We demonstrate the interferometer for a graphene-type hexagonal optical lattice loaded with bosonic atoms. By detecting the singular pi Berry flux localized at each Dirac point, we establish the high momentum resolution of this interferometric technique. Our work forms the basis for a general framework to fully characterize topological band structures. PMID- 25525161 TI - Quantum optics. Quantum harmonic oscillator state synthesis by reservoir engineering. AB - The robust generation of quantum states in the presence of decoherence is a primary challenge for explorations of quantum mechanics at larger scales. Using the mechanical motion of a single trapped ion, we utilize reservoir engineering to generate squeezed, coherent, and displaced-squeezed states as steady states in the presence of noise. We verify the created state by generating two-state correlated spin-motion Rabi oscillations, resulting in high-contrast measurements. For both cooling and measurement, we use spin-oscillator couplings that provide transitions between oscillator states in an engineered Fock state basis. Our approach should facilitate studies of entanglement, quantum computation, and open-system quantum simulations in a wide range of physical systems. PMID- 25525159 TI - RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. AB - To facilitate precision medicine and whole-genome annotation, we developed a machine-learning technique that scores how strongly genetic variants affect RNA splicing, whose alteration contributes to many diseases. Analysis of more than 650,000 intronic and exonic variants revealed widespread patterns of mutation driven aberrant splicing. Intronic disease mutations that are more than 30 nucleotides from any splice site alter splicing nine times as often as common variants, and missense exonic disease mutations that have the least impact on protein function are five times as likely as others to alter splicing. We detected tens of thousands of disease-causing mutations, including those involved in cancers and spinal muscular atrophy. Examination of intronic and exonic variants found using whole-genome sequencing of individuals with autism revealed misspliced genes with neurodevelopmental phenotypes. Our approach provides evidence for causal variants and should enable new discoveries in precision medicine. PMID- 25525162 TI - Understanding Service Utilization in Cases of Elder Abuse to Inform Best Practices. AB - Elder abuse (EA) case resolution is contingent upon victims accepting and pursuing protective service interventions. Refusal/underutilization of services is a major problem. This study explored factors associated with extent of EA victim service utilization (SU). Data were collected from a random sample of EA cases (n = 250) at a protective service program in New York City. In cases involving financial abuse, higher SU was associated with females, poor health, perceived danger, previous help-seeking, and self or family referral. In physical abuse cases, higher SU was associated with family referral and previous help seeking; lower SU was related to Hispanic race/ethnicity, being married, and child/grandchild perpetrator. In emotional abuse cases, higher SU was associated with self or family referral, victim-perpetrator gender differential, perceived danger, and previous help-seeking; lower SU was related to child/grandchild perpetrator. Findings carry implications for best practices to retain and promote service use among elder victims of abuse. PMID- 25525163 TI - Antioxidative capacity of a dietary supplement on retinal hemodynamic function in a human lipopolysaccharide (LPS) model. AB - PURPOSE: Beneficial effects of dietary supplements in age-related macular degeneration (AMD) are related to antioxidative properties. In the Age-Related Eye Disease Study 1 (AREDS 1), a reduced progression to late stage AMD was found using vitamin C, E, zinc, and beta-carotene. We showed previously that the AREDS 1 formulation restores the O2-induced retinal vasoconstrictor response of retinal vessels in a human endotoxin (lipopolysaccharide [LPS]) model. METHODS: We hypothesized that the abnormal O2-induced retinal red blood cell (RBC) flow response can be modulated by a different formulation (vitamin C, E, and zinc, lutein/zeaxanthin, selenium, taurine, Aronia extract, and omega-3 free fatty acids). A total of 43 healthy subjects was included in this randomized, double masked, placebo-controlled parallel group study. The reactivity of retinal arterial and venous diameter, RBC velocity, and flow to 100% O2 breathing was investigated in the absence and presence of 2 ng/kg LPS. Between the two study days was a 14-day period of daily dietary supplement intake. RESULTS: The decrease in retinal arterial diameter, RBC velocity, and flow during 100% O2 breathing was diminished significantly after LPS infusion. Dietary supplement intake for 14 days almost restored the response of retinal hemodynamic parameters to 100% O2 after LPS administration. This effect was significant for retinal arterial diameter (P = 0.03 between groups), and RBC velocity and flow (each P < 0.01 between groups). CONCLUSIONS: The present data indicate restoring of the RBC flow response to 100% O2 after LPS administration. This is likely due to an amelioration of endothelial dysfunction resulting from oxidative stress, a factor involved in AMD pathophysiology. (ClinicalTrials.gov number, NCT00914576.). PMID- 25525165 TI - A nationwide population-based study of low vision and blindness in South Korea. AB - PURPOSE: To investigate the prevalence and associated risk factors of low vision and blindness in the Korean population. METHODS: This cross-sectional, population based study examined the ophthalmologic data of 22,135 Koreans aged >=5 years from the fifth Korea National Health and Nutrition Examination Survey (KNHANES V, 2010-2012). According to the World Health Organization criteria, blindness was defined as visual acuity (VA) less than 20/400 in the better-seeing eye, and low vision as VA of 20/60 or worse but 20/400 or better in the better-seeing eye. The prevalence rates were calculated from either presenting VA (PVA) or best corrected VA (BCVA). Multivariate regression analysis was conducted for adults aged >=20 years. RESULTS: The overall prevalence rates of PVA-defined low vision and blindness were 4.98% and 0.26%, respectively, and those of BCVA-defined low vision and blindness were 0.46% and 0.05%, respectively. Prevalence increased rapidly above the age of 70 years. For subjects aged >=70 years, the population weighted prevalence rates of low vision, based on PVA and BCVA, were 12.85% and 3.87%, respectively, and the corresponding rates of blindness were 0.49% and 0.42%, respectively. The presenting vision problems were significantly associated with age (younger adults or elderly subjects), female sex, low educational level, and lowest household income, whereas the best-corrected vision problems were associated with age >= 70 years, a low educational level, and rural residence. CONCLUSIONS: This population-based study provides useful information for planning optimal public eye health care services in South Korea. PMID- 25525164 TI - Exome array analysis identifies CAV1/CAV2 as a susceptibility locus for intraocular pressure. AB - PURPOSE: Intraocular pressure (IOP) is an important clinical parameter in the evaluation of ocular health. Elevated IOP is a major risk factor for primary open angle glaucoma (POAG). The goal of this study was to identify rare and less common variants that influence IOP. METHODS: We performed an exome array analysis in a subset of 1660 individuals from a population-based cohort, the Beaver Dam Eye Study. Associations with IOP were tested on 45,849 single nucleotide variants and 12,390 autosomal genes across the genome. RESULTS: Intraocular pressure was suggestively associated with novel variants located in FAR2 at 12p11.22 (rs4931170, P = 1.2 * 10(-5)), in GGA3 at 17q25.1 (rs52809447, P = 6.7 * 10(-5)), and in PKDREJ at 22q13.31 (rs7291444, P = 7.4 * 10(-5)). Gene-based analysis found suggestive associations between IOP and the genes HAP1, MTBP, FREM3, and PHF12. We successfully replicated the associations with GAS7 (P = 7.4 * 10(-3)) for IOP, and also identified a previously reported POAG locus in the CAV1/CAV2 region to be associated with IOP (P = 3.3 * 10(-3)). This association was confirmed in a meta-analysis with three published genome-wide association studies (Pcombined = 4.0 * 10(-11)). CONCLUSIONS: Our results suggest that novel genetic variants and genes with multiple, less common variants may play a role in the control of IOP. The implication of the caveolin genes, CAV1/CAV2, as a common genetic factor influencing both IOP variations and POAG may provide new insights of the underlying mechanism leading to glaucoma and glaucomatous visual field loss. PMID- 25525166 TI - Henle fiber layer phase retardation changes associated with age-related macular degeneration. AB - PURPOSE: To quantify and compare phase retardation amplitude and regularity associated with the Henle fiber layer (HFL) between nonexudative AMD patients and age-matched controls using scanning laser polarimetry (SLP) imaging. METHODS: A scanning laser polarimeter was used to collect 15 * 15 degrees macular-centered images in 25 patients with nonexudative AMD and 25 age-matched controls. Raw image data were used to compute macular phase retardation maps associated with the HFL. Consecutive, annular regions of interest from 0.5 to 3.0 degrees eccentricity, centered on the fovea, were used to generate intensity profiles from phase retardation data and analyzed with two complementary techniques: a normalized second harmonic frequency (2f) of the fast Fourier Transform (FFT) analysis and a curve fitting analysis using a 2f sine function. Paired t-tests were used to compare the normalized 2f FFT magnitude at each eccentricity between the two groups, the eccentricity that yielded the maximum normalized 2f FFT between paired individuals across the two groups, and curve fitting RMS error at each eccentricity between the two groups. RESULTS: Normalized 2f FFT components were lower in the AMD group at each eccentricity, with no difference between the two groups in the maximum normalized 2f FFT component eccentricity. The root-mean square (RMS) error from curve fitting was significantly higher in the AMD group. CONCLUSIONS: Phase retardation changes in the central macula indicate loss and/or structural alterations to central cone photoreceptors in nonexudative AMD patients. Scanning laser polarimetry imaging is a noninvasive method for quantifying cone photoreceptor changes associated with central macular disease. PMID- 25525167 TI - Regulation of fibroblast growth factor 2 expression in oxygen-induced retinopathy. AB - PURPOSE: Fibroblast growth factor (FGF) 2 is a potent endothelial cell mitogen and survival factor that is postulated to participate in the pathogenesis of retinopathy of prematurity (ROP). The purpose of the current study was to determine the transcriptional and translational regulation of FGF2 expression in oxygen-induced retinopathy (OIR), the animal model of ROP. METHODS: We examined FGF2 protein and mRNA expression and optokinetic visual responses in transgenic mice possessing a dual-luciferase bicistronic transgene containing a 5'-internal ribosome entry site (IRES) of FGF2. RESULTS: We found that retinal FGF2 protein isoform expression varies with age but not in response to OIR. Analysis of luciferase, protein, and mRNA data indicate that FGF2 protein expression is translationally repressed during the vaso-obliterative phase of OIR, possibly by inhibiting elongation. At the transition from vaso-obliteration to neovascularization, heightened FGF2 protein expression corresponds to maintenance of IRES activity and diminished cap-dependent translational activity. During neovascularization, FGF2 expression is primarily regulated by transcription. Mice recovering from OIR display alterations in visual optokinetic responses and increased FGF2 protein expression at 6 weeks of age. CONCLUSIONS: In total, these findings illustrate the complexity of translational and transcriptional regulation of FGF2 protein expression in OIR. The augmentation of FGF2 expression and reduced optokinetic responses during the resolution of surface vasculopathy may indicate a role for FGF2 in the maintenance of neuroretinal function in OIR/ROP. PMID- 25525168 TI - Detection of mutations in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 in 298 families with early-onset high myopia by exome sequencing. AB - PURPOSE: To evaluate variants in the LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 genes in 298 unrelated patients with early-onset high myopia (eoHM). METHODS: Genomic DNA from 298 patients with eoHM was analyzed by whole exome sequencing. Variants in LRPAP1, CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2 genes were selected and analyzed with bioinformatics. Potential candidate variants were confirmed by Sanger sequencing and then validated in available family members and 192 healthy controls. RESULTS: A total of nine variants predicted to affect the functional residues were detected. The LRPAP1 gene showed a homozygous frameshift mutation (c.199delC, p.Q67Sfs*8) in a consanguineous family. The ZNF644 gene showed five heterozygous missense mutations (c.1106A>T, p.K369M; c.1648G>A, p.A550T; c.2014A>G, p.S672G; c.2048G>C, p.R683T, and c.2551G>C, p.D851H) in five families, but the c.1106A>T, (p.K369M) and c.1648G>A, (p.A550T) in ZNF644 did not co-segregated with high myopia in the families and should be excluded as causative mutations. The SLC39A5 gene showed a heterozygous missense variant (c.1238G>C, p.G413A) in a sporadic individual. The SCO2 gene showed two heterozygous missense variants (c.334C>T, p.R112W and c.358C>T, p.R120W) in two families. None of the variants was detected in 192 healthy controls and all were predicted to be damaging by both Polyphen-2 and SIFT, except for the previously reported p.S672G mutation in ZNF644, which was predicted to be damaging by SIFT but benign by Polyphen-2. No homozygous or compound heterozygous variants were found in CTSH and LEPREL1. CONCLUSIONS: Our results provide additional evidence to support the idea that mutation in LRPAP1 is associated with high myopia. Further studies are expected to evaluate the pathogenicity of the variants in CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2. PMID- 25525169 TI - RGS6: a novel gene associated with congenital cataract, mental retardation, and microcephaly in a Tunisian family. AB - PURPOSE: The object of this study is to identify the underlying genetic defect in a consanguineous Tunisian family affected with autosomal recessive congenital cataract associated with mental retardation and microcephaly. METHODS: A whole genome scan was performed with polymorphic microsatellites in the axiom data for the screened members. Homozygous regions were analyzed with integrated Systems Tool for Eye gene Discovery (iSyTE), to identify candidate genes with lens enriched expression that were potentially associated with cataract. Then we screened for mutations by direct sequencing. Structure and function of the mutant gene were analyzed by bioinformatics analysis. RESULTS: Using whole-genome scanning, we identified six runs of homozygosity shared among affected members of the studied family. Analysis of these regions by iSyTE allowed us to select 3 genes (RGS6, PCNX, and P4HA1) according to their expression in 3 critical stages of lens development. Upon screening for mutations by sequencing analysis, we found a novel mutation in RGS6, the splice-acceptor variant c.1369-1G>C that was not previously reported in congenital cataract phenotypes. CONCLUSIONS: Our study identified a new gene to be included in the large spectrum of cataract-associated genes. Importantly, the study demonstrated that, in addition to lens-enriched genes that exhibit high expression levels, genes identified by iSyTE that are highly lens-enriched but have lower absolute expression may also represent candidates for potential function in the lens. PMID- 25525170 TI - Retinal vascular caliber, iris color, and age-related macular degeneration in the Irish Nun Eye Study. AB - PURPOSE: To evaluate the relationship between retinal vascular caliber (RVC), iris color, and age-related macular degeneration (AMD) in elderly Irish nuns. METHODS: Data from 1233 participants in the cross-sectional observational Irish Nun Eye Study were assessed from digital photographs with a standardized protocol using computer-assisted software. Macular images were graded according to the modified Wisconsin Age-related Maculopathy Grading System. Regression models were used to assess associations, adjusting for age, mean arterial blood pressure, body mass index, refraction, and fellow RVC. RESULTS: In total, 1122 (91%) participants had gradable retinal images of sufficient quality for vessel assessment (mean age: 76.3 years [range, 56-100 years]). In an unadjusted analysis, we found some support for a previous finding that individuals with blue iris color had narrower retinal venules compared to those with brown iris color (P < 0.05), but this was no longer significant after adjustment. Age-related macular degeneration status was categorized as no AMD, any AMD, and late AMD only. Individuals with any AMD (early or late AMD) had significantly narrower arterioles and venules compared to those with no AMD in an unadjusted analysis, but this was no longer significant after adjustment. A nonsignificant reduced risk of any AMD or late AMD only was observed in association with brown compared to blue iris color, in both unadjusted and adjusted analyses. CONCLUSIONS: Retinal vascular caliber was not significantly associated with iris color or early/late AMD after adjustment for confounders. A lower but nonsignificant AMD risk was observed in those with brown compared to blue iris color. PMID- 25525171 TI - Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial. AB - PURPOSE: To investigate the safety and effects of intravitreal sirolimus for the potential treatment of geographic atrophy (GA). METHODS: The study was a single center, open-label, phase I/II trial enrolling six participants with bilateral GA treated with intravitreal sirolimus in only one randomly assigned eye, with the fellow eye as control. The primary efficacy outcome measure was the change in total GA area from baseline on color fundus photography (CFP); secondary outcomes included changes in GA area on fundus autofluorescence (FAF), visual acuity, central retinal thickness (CRT), and macular sensitivity from baseline. RESULTS: Although no systemic adverse events were attributed to treatment, two of six participants had ocular adverse events that were possibly associated. The treated eye of one participant developed abnormal paralesional changes on FAF that were associated with accelerated retinal thinning. This accelerated retinal thinning was also seen in the treated eye of a second participant. Because of concern that these events were associated with treatment, treatment was suspended. Comparisons of treated and fellow eyes for change in visual acuity, change in GA area, and change in CRT showed no evidence of treatment benefit and generally favored the untreated fellow eye. CONCLUSIONS: While paralesional FAF changes and rapid retinal thinning observed are potentially part of the natural course of GA, they may possibly be related to treatment. No general evidence of anatomical or functional benefit was detected in treated eyes. Further data on intravitreal sirolimus for GA treatment will be available from a larger phase II trial. (ClinicalTrials.gov number, NCT01445548.). PMID- 25525173 TI - Factors associated with persistent subfoveal fluid and complete macular hole closure in the PIONEER study. AB - PURPOSE: To investigate preoperative and intraoperative factors associated with persistent subfoveal fluid in surgically closed macular holes (MHs). METHODS: This was a prospective consecutive case series of eyes undergoing surgical repair for full-thickness MH in the PIONEER study, a prospective intraoperative optical coherence tomography (OCT) multisurgeon single-center study. Thirty-seven eyes (36 patients) with surgically closed MH were studied. Quantitative OCT analysis was performed including intraoperative MH area, volume, ellipsoid zone to retinal pigment epithelium (EZ-RPE) height, extent of subretinal hyporeflectivity (SRHR), and the amount of postoperative subfoveal fluid. RESULTS: Persistent subfoveal fluid was identified in 58% of eyes at 2 weeks following surgery. The mean time to two-line improvement in visual acuity was greater in eyes with persistent subfoveal fluid (P = 0.03). Final visual acuity did not correlate with the initial presence of fluid. Two intraoperative factors following internal limiting membrane (ILM) peeling were associated with the formation of persistent subfoveal fluid: EZ-RPE height and SRHR width (P < 0.01). These were both negatively correlated with amount of postoperative subfoveal fluid (P = 0.028 and 0.04, respectively). CONCLUSIONS: Persistent subfoveal fluid following MH surgery is a common finding that appears to delay visual recovery but not effect final visual outcome. The incidence of persistent subfoveal fluid appears to be related to intraoperative alterations after ILM peeling in the outer retinal architecture (e.g., increased EZ-RPE height and SRHR width). This finding suggests a novel mechanism for facilitating MH closure through ILM peeling (e.g., altering photoreceptor/RPE adherence and increasing retinal mobility that allows for complete hole closure). PMID- 25525172 TI - Radiation pretreatment does not protect the rat optic nerve from elevated intraocular pressure-induced injury. AB - PURPOSE: Optic nerve injury has been found to be dramatically reduced in a genetic mouse glaucoma model following exposure to sublethal, head-only irradiation. In this study, the same radiation treatment was used prior to experimental induction of elevated intraocular pressure (IOP) to determine if radiation is neuroprotective in another glaucoma model. METHODS: Episcleral vein injection of hypertonic saline was used to elevate IOP unilaterally in two groups of rats: (1) otherwise untreated and (2) radiation pretreated, n > 25/group. Intraocular pressure histories were collected for 5 weeks, when optic nerves were prepared and graded for injury. Statistical analyses were used to compare IOP history and nerve injury. The density of microglia and macrophages in two nerve head regions was determined by Iba1 immunolabeling. RESULTS: Mean and peak IOP elevations were not different between the two glaucoma model groups. Mean optic nerve injury grades were not different in glaucoma model optic nerves and were equivalent to approximately 35% of axons degenerating. Nerves selected for lower mean or peak IOP elevations did not differ in optic nerve injury. Similarly, nerves selected for lower injury grade did not differ in IOP exposure. By multiple regression modeling, nerve injury grade was most significantly associated with mean IOP (P < 0.002). There was no significant effect of radiation treatment. Iba1+ cell density was not altered by radiation treatment. CONCLUSIONS: In contrast to previous observations in a mouse genetic glaucoma model, head-only irradiation offers the adult rat optic nerve no protection from optic nerve degeneration due to chronic, experimentally induced IOP elevation. PMID- 25525174 TI - Pioglitazone restores IGFBP-3 levels through DNA PK in retinal endothelial cells cultured in hyperglycemic conditions. AB - PURPOSE: Previously, we reported that pioglitazone prevented insulin resistance and cell death in type 2 diabetic retina by reducing TNFalpha and suppressor of cytokine signaling 3 (SOCS3) levels. Numerous reports suggest prominent vasoprotective effects of insulin growth factor binding protein-3 (IGFBP-3) in diabetic retinopathy. We hypothesized that pioglitazone protects against retinal cell apoptosis by regulating IGFBP-3 levels, in addition to reducing TNFalpha. The current study explored potential IGFBP-3 regulatory pathways by pioglitazone in retinal endothelial cells cultured in high glucose. METHODS: Primary human retinal endothelial cells (REC) were grown in normal (5 mM) and high glucose (25 mM) and treated with pioglitazone for 24 hours. Cell lysates were processed for Western blotting and ELISA analysis to evaluate IGFBP-3, TNFalpha, and cleaved caspase 3 protein levels. RESULTS: Our results show that treatment with pioglitazone restored the high glucose-induced decrease in IGFBP-3 levels. This regulation was independent of TNFalpha actions, as reducing TNFalpha levels with siRNA did not prevent pioglitazone from increasing IGFBP-3 levels. Pioglitazone required protein kinase A (PKA) and DNA-dependent protein kinase (DNA PK) activity to regulate IGFBP-3, as specific inhibitors for each protein prevented pioglitazone-mediated normalization of IGFBP-3 in high glucose. Insulin growth factor binding protein-3 activity was increased and apoptosis decreased by pioglitazone, which was eliminated when serine site 156 of IGFBP-3 was mutated suggesting a key role of this phosphorylation site in pioglitazone actions. CONCLUSIONS: Our findings suggest that pioglitazone mediates regulation of IGFBP 3 via activation of PKA/DNA PK pathway in hyperglycemic retinal endothelial cells. PMID- 25525176 TI - Altered amplitude of low-frequency fluctuation in primary open-angle glaucoma: a resting-state FMRI study. AB - PURPOSE: To analyze the altered amplitude of low-frequency fluctuation (ALFF) of the brain using resting-state functional magnetic resonance imaging (fMRI) in patients with primary open-angle glaucoma (POAG). METHODS: Resting-state fMRI was conducted in 21 POAG patients and 22 age-matched healthy control subjects. After the ALFF and fractional amplitude of low-frequency fluctuation (fALFF) for slow 4 and slow 5 bands were calculated, the results between POAG patients and healthy controls were compared. Then the correlations between ALFF/fALFF values and the disease stage of POAG were analyzed. RESULTS: Compared with controls, POAG patients showed significantly decreased ALFF/fALFF values in the visual cortices, posterior regions of the default-mode network (DMN), and motor and sensory cortices. Meanwhile, ALFF/fALFF values in the prefrontal cortex, left superior temporal gyrus (STG), right middle cingulate cortex (MCC), and left inferior parietal lobule (IPL) significantly increased in POAG patients. Hodapp-Anderson Parrish (HAP) score for POAG was positively correlated with ALFF values of the right superior frontal gyrus (SFG) and negatively correlated with that of the left cuneus. For the slow 5 band, the fALFF values of the bilateral middle temporal gyri (MTG) of POAG patients were negatively correlated with HAP score. CONCLUSIONS: Primary open-angle glaucoma is a neurodegenerative disease involving multiple brain regions, including the visual cortices, DMN, limbic system, and motor and sensory networks. Moreover, the alterations in some of these networks are correlated with the progression of POAG; for the abnormal spontaneous neural activities in the left cuneus, bilateral MTG and right prefrontal cortex are correlated with glaucoma severity. PMID- 25525175 TI - The use of time-lapse optical coherence tomography to image the effects of microapplied toxins on the retina. AB - PURPOSE: We developed a novel technique for accelerated drug screening and retinotoxin characterization using time-lapse optical coherence tomography (OCT) and a drug microapplication device. METHODS: Using an ex vivo rabbit eyecup preparation, we studied retinotoxin effects in real-time by microperfusing small retinal areas under a transparent fluoropolymer tube. Known retinotoxic agents were applied to the retina for 5-minute periods, while changes in retinal structure, thickness, and reflectance were monitored with OCT. The OCT images of two agents with dissimilar mechanisms, cyanide and kainic acid, were compared to their structural changes seen histologically. RESULTS: We found the actions of retinotoxic agents tested could be classified broadly into two distinct types: (1) agents that induce neuronal depolarization, such as kainic acid, causing increases in OCT reflectivity or thickness of the inner plexiform and nuclear layers, and decreased reflectivity of the outer retina; and (2) agents that disrupt mitochondrial function, such as cyanide, causing outer retinal structural changes as evidenced by a reduction in the OCT reflectivity of the photoreceptor outer segment and pigment epithelium layers. CONCLUSIONS: Retinotoxin-induced changes in retinal layer reflectivity and thickness under the microperfusion tube in OCT images closely matched the histological evidence of retinal injury. Time lapse OCT imaging of the microperfused local retina has the potential to accelerate drug retinotoxicological screening and expand the use of OCT as an evaluation tool for preclinical animal testing. PMID- 25525177 TI - Mechanisms for discomfort glare in central vision. AB - PURPOSE: The presence of a bright light source in the visual field can generate visual discomfort. Based on empirical observations we can predict to a reasonable degree of accuracy how uncomfortable a given lighting installation is likely to be; yet very little is known about the mechanism or physiological underpinnings that lead to visual discomfort. This study attempts to elucidate some of the underlying mechanisms by controlling the amount of light reaching the retina and by varying photometric properties of the glare source. METHODS: The participants were required to view a source of light presented against a simulated residential street background in the form of uniform flashes of light of varying intensity. Discomfort-glare thresholds were estimated using a staircase procedure; the dependent variable was retinal illuminance. The size of the glare source and the luminance of the surrounding background were varied systematically. RESULTS: Across glare-source sizes or background luminances the discomfort-glare threshold varied less in terms of retinal illuminance than it did in terms of pupil-plane illuminance or light flux. A two-stage model based on saturation of photoreceptors followed by summation of an edge response signal that defines the edges of the glare-source accurately predicted the data. CONCLUSIONS: Discomfort glare in central vision is more closely associated with the spatial properties of the glare source, such as contrast-defined edges, than the overall amount of light entering the eye. The results suggest that discomfort glare in lighting installations could be reduced while maintaining adequate illuminance levels by an appropriate choice of illuminant source size. PMID- 25525178 TI - The association of predonation hypertension with glomerular function and number in older living kidney donors. AB - The effect of preexisting hypertension on living donor nephron number has not been established. In this study, we determined the association between preexisting donor hypertension and glomerular number and volume and assessed the effect of predonation hypertension on postdonation BP, adaptive hyperfiltration, and compensatory glomerular hypertrophy. We enrolled 51 living donors to undergo physiologic, morphometric, and radiologic evaluations before and after kidney donation. To estimate the number of functioning glomeruli (NFG), we divided the whole-kidney ultrafiltration coefficient (Kf) by the single-nephron ultrafiltration coefficient (SNKf). Ten donors were hypertensive before donation. We found that, in donors ages >50 years old, preexisting hypertension was associated with a reduction in NFG. In a comparison of 10 age- and sex-matched hypertensive and normotensive donors, we observed more marked glomerulopenia in hypertensive donors (NFG per kidney, 359,499+/-128,929 versus 558,239+/-205,152; P=0.02). Glomerulopenia was associated with a nonsignificant reduction in GFR in the hypertensive group (89+/-12 versus 95+/-16 ml/min per 1.73 m(2)). We observed no difference in the corresponding magnitude of postdonation BP, hyperfiltration capacity, or compensatory renocortical hypertrophy between hypertensive and normotensive donors. Nevertheless, we propose that the greater magnitude of glomerulopenia in living kidney donors with preexisting hypertension justifies the need for long-term follow-up studies. PMID- 25525180 TI - Quantitative PET/CT scanner performance characterization based upon the society of nuclear medicine and molecular imaging clinical trials network oncology clinical simulator phantom. AB - The Clinical Trials Network (CTN) of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) operates a PET/CT phantom imaging program using the CTN's oncology clinical simulator phantom, designed to validate scanners at sites that wish to participate in oncology clinical trials. Since its inception in 2008, the CTN has collected 406 well-characterized phantom datasets from 237 scanners at 170 imaging sites covering the spectrum of commercially available PET/CT systems. The combined and collated phantom data describe a global profile of quantitative performance and variability of PET/CT data used in both clinical practice and clinical trials. METHODS: Individual sites filled and imaged the CTN oncology PET phantom according to detailed instructions. Standard clinical reconstructions were requested and submitted. The phantom itself contains uniform regions suitable for scanner calibration assessment, lung fields, and 6 hot spheric lesions with diameters ranging from 7 to 20 mm at a 4:1 contrast ratio with primary background. The CTN Phantom Imaging Core evaluated the quality of the phantom fill and imaging and measured background standardized uptake values to assess scanner calibration and maximum standardized uptake values of all 6 lesions to review quantitative performance. Scanner make-and-model-specific measurements were pooled and then subdivided by reconstruction to create scanner specific quantitative profiles. RESULTS: Different makes and models of scanners predictably demonstrated different quantitative performance profiles including, in some cases, small calibration bias. Differences in site-specific reconstruction parameters increased the quantitative variability among similar scanners, with postreconstruction smoothing filters being the most influential parameter. Quantitative assessment of this intrascanner variability over this large collection of phantom data gives, for the first time, estimates of reconstruction variance introduced into trials from allowing trial sites to use their preferred reconstruction methodologies. Predictably, time-of-flight-enabled scanners exhibited less size-based partial-volume bias than non-time-of-flight scanners. CONCLUSION: The CTN scanner validation experience over the past 5 y has generated a rich, well-curated phantom dataset from which PET/CT make-and-model and reconstruction-dependent quantitative behaviors were characterized for the purposes of understanding and estimating scanner-based variances in clinical trials. These results should make it possible to identify and recommend make-and model-specific reconstruction strategies to minimize measurement variability in cancer clinical trials. PMID- 25525179 TI - Alteration of the Intestinal Environment by Lubiprostone Is Associated with Amelioration of Adenine-Induced CKD. AB - The accumulation of uremic toxins is involved in the progression of CKD. Various uremic toxins are derived from gut microbiota, and an imbalance of gut microbiota or dysbiosis is related to renal failure. However, the pathophysiologic mechanisms underlying the relationship between the gut microbiota and renal failure are still obscure. Using an adenine-induced renal failure mouse model, we evaluated the effects of the ClC-2 chloride channel activator lubiprostone (commonly used for the treatment of constipation) on CKD. Oral administration of lubiprostone (500 ug/kg per day) changed the fecal and intestinal properties in mice with renal failure. Additionally, lubiprostone treatment reduced the elevated BUN and protected against tubulointerstitial damage, renal fibrosis, and inflammation. Gut microbiome analysis of 16S rRNA genes in the renal failure mice showed that lubiprostone treatment altered their microbial composition, especially the recovery of the levels of the Lactobacillaceae family and Prevotella genus, which were significantly reduced in the renal failure mice. Furthermore, capillary electrophoresis-mass spectrometry-based metabolome analysis showed that lubiprostone treatment decreased the plasma level of uremic toxins, such as indoxyl sulfate and hippurate, which are derived from gut microbiota, and a more recently discovered uremic toxin, trans-aconitate. These results suggest that lubiprostone ameliorates the progression of CKD and the accumulation of uremic toxins by improving the gut microbiota and intestinal environment. PMID- 25525181 TI - Update on time-of-flight PET imaging. AB - Time-of-flight (TOF) PET was initially introduced in the early days of PET. The TOF PET scanners developed in the 1980s had limited sensitivity and spatial resolution, were operated in 2-dimensional mode with septa, and used analytic image reconstruction methods. The current generation of TOF PET scanners has the highest sensitivity and spatial resolution ever achieved in commercial whole-body PET, is operated in fully-3-dimensional mode, and uses iterative reconstruction with full system modeling. Previously, it was shown that TOF provides a gain in image signal-to-noise ratio that is proportional to the square root of the object size divided by the system timing resolution. With oncologic studies being the primary application of PET, more recent work has shown that in modern TOF PET scanners there is an improved tradeoff between lesion contrast, image noise, and total imaging time, leading to a combination of improved lesion detectability, reduced scan time or injected dose, and more accurate and precise lesion uptake measurement. Because the benefit of TOF PET is also higher for heavier patients, clinical performance is more uniform over all patient sizes. PMID- 25525183 TI - The usefulness of dynamic O-(2-18F-fluoroethyl)-L-tyrosine PET in the clinical evaluation of brain tumors in children and adolescents. AB - Experience regarding O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET in children and adolescents with brain tumors is limited. METHODS: Sixty-nine (18)F FET PET scans of 48 children and adolescents (median age, 13 y; range, 1-18 y) were analyzed retrospectively. Twenty-six scans to assess newly diagnosed cerebral lesions, 24 scans for diagnosing tumor progression or recurrence, 8 scans for monitoring of chemotherapy effects, and 11 scans for the detection of residual tumor after resection were obtained. Maximum and mean tumor-to-brain ratios (TBRs) were determined at 20-40 min after injection, and time-activity curves of (18)F-FET uptake were assigned to 3 different patterns: constant increase; peak at greater than 20-40 min after injection, followed by a plateau; and early peak (<= 20 min), followed by a constant descent. The diagnostic accuracy of (18)F-FET PET was assessed by receiver-operating-characteristic curve analyses using histology or clinical course as a reference. RESULTS: In patients with newly diagnosed cerebral lesions, the highest accuracy (77%) to detect neoplastic tissue (19/26 patients) was obtained when the maximum TBR was 1.7 or greater (area under the curve, 0.80 +/- 0.09; sensitivity, 79%; specificity, 71%; positive predictive value, 88%; P = 0.02). For diagnosing tumor progression or recurrence, the highest accuracy (82%) was obtained when curve patterns 2 or 3 were present (area under the curve, 0.80 +/- 0.11; sensitivity, 75%; specificity, 90%; positive predictive value, 90%; P = 0.02). During chemotherapy, a decrease of TBRs was associated with a stable clinical course, and in 2 patients PET detected residual tumor after presumably complete tumor resection. CONCLUSION: Our findings suggest that (18)F-FET PET can add valuable information for clinical decision making in pediatric brain tumor patients. PMID- 25525182 TI - Imaging pulmonary inducible nitric oxide synthase expression with PET. AB - Inducible nitric oxide synthase (iNOS) activity increases in acute and chronic inflammatory lung diseases. Imaging iNOS expression may be useful as an inflammation biomarker for monitoring lung disease activity. We developed a novel tracer for PET that binds to iNOS in vivo, (18)F-NOS. In this study, we tested whether (18)F-NOS could quantify iNOS expression from endotoxin-induced lung inflammation in healthy volunteers. METHODS: Healthy volunteers were screened to exclude cardiopulmonary disease. Qualifying volunteers underwent a baseline, 1-h dynamic (18)F-NOS PET/CT scan. Endotoxin (4 ng/kg) was then instilled bronchoscopically in the right middle lobe. (18)F-NOS imaging was performed again approximately 16 h after endotoxin instillation. Radiolabeled metabolites were determined from blood samples. Cells recovered by bronchoalveolar lavage (BAL) after imaging were stained immunohistochemically for iNOS. (18)F-NOS uptake was quantified as the distribution volume ratio (DVR) determined by Logan plot graphical analysis in volumes of interest placed over the area of endotoxin instillation and in an equivalent lung region on the left. The mean Hounsfield units (HUs) were also computed using the same volumes of interest to measure density changes. RESULTS: Seven healthy volunteers with normal pulmonary function completed the study with evaluable data. The DVR increased by approximately 30%, from a baseline mean of 0.42 +/- 0.07 to 0.54 +/- 0.12, and the mean HUs by 11% after endotoxin in 6 volunteers who had positive iNOS staining in BAL cells. The DVR did not change in the left lung after endotoxin. In 1 volunteer with low level iNOS staining in BAL cells, the mean HUs increased by 7% without an increase in DVR. Metabolism was rapid, with approximately 50% of the parent compound at 5 min and 17% at 60 min after injection. CONCLUSION: (18)F-NOS can be used to image iNOS activity in acute lung inflammation in humans and may be a useful PET tracer for imaging iNOS expression in inflammatory lung disease. PMID- 25525184 TI - Whole-body PET/CT evaluation of tumor perfusion using generator-based 62Cu ethylglyoxal bis(thiosemicarbazonato)copper(II): validation by direct comparison to 15O-water in metastatic renal cell carcinoma. AB - This study was undertaken to demonstrate the feasibility of whole-body (62)Cu ethylglyoxal bis(thiosemicarbazonato)copper(II) ((62)Cu-ETS) PET/CT tumor perfusion imaging in patients with metastatic renal carcinoma and to validate (62)Cu-ETS as a quantitative marker of tumor perfusion by direct comparison with (15)O-water perfusion imaging. METHODS: PET/CT imaging of 10 subjects with stage IV renal cell cancer was performed after intravenous administration of (15)O water (10-min dynamic list-mode study) with the heart and at least 1 tumor in the PET field of view, followed 10 min later by intravenous (62)Cu-ETS (6-min list mode study). Whole-body (62)Cu imaging was then performed from 6 to 20 min at 2-3 min/bed position. Blood flow (K1) was quantified with both agents for normal and malignant tissues in the 21.7-cm dynamic field of view. The required arterial input functions were derived from the left atrium and, in the case of (62)Cu-ETS, corrected for partial decomposition of the agent by blood with data from an in vitro analysis using a sample of each patient's blood. This imaging protocol was repeated at an interval of 3-4 wk after initiation of a standard clinical treatment course of the antiangiogenic agent sunitinib. RESULTS: All subjects received the scheduled (62)Cu-ETS doses for the dynamic and subsequent whole-body PET/CT scans, but technical issues resulted in no baseline (15)O-water data for 2 subjects. Direct comparisons of the perfusion estimates for normal tissues and tumor metastases were made in 18 paired baseline and treatment studies (10 subjects; 8 baseline studies, 10 repeated studies during treatment). There was an excellent correlation between the blood flow estimates made with (62)Cu-ETS and (15)O-water for normal tissues (muscle, thyroid, myocardium) and malignant lesions (pulmonary nodules, bone lesions); the regression line was y = 0.85x + 0.15, R(2) = 0.83, for the 88 regions analyzed. CONCLUSION: (62)Cu-ETS provided high-quality whole-body PET/CT images, and (62)Cu-ETS measures of blood flow were highly and linearly correlated with (15)O-water-derived K1 values (mL(-1) ? min( 1) ? g). This tracer is suitable for use as a PET tracer of tumor perfusion in patients with metastatic renal cell carcinoma. PMID- 25525185 TI - Prognostic value of total lesion glycolysis by 18F-FDG PET/CT in surgically resected stage IA non-small cell lung cancer. AB - Despite the favorable prognosis of stage IA non-small cell lung cancer (NSCLC), the disease recurs after complete surgical resection in 20%-30% of patients. This study determined the prognostic value of various metabolic parameters of (18)F FDG PET/CT in surgically resected stage IA NSCLC. METHODS: We retrospectively reviewed 248 patients with stage IA NSCLC who underwent lobectomy and complete lymph node dissection after PET/CT. A region of interest was drawn on the primary lesion, and metabolic indices such as metabolic tumor volume, maximum standardized uptake value (SUV(max)), and total lesion glycolysis (TLG) were measured using an SUV cutoff of 2.5. RESULTS: The patients included 134 men and 114 women, and the mean age was 63.03 +/- 10.01 y; 129 were stage T1a (<= 2 cm) and 119 were T1b (>2 cm). The median follow-up period was 36.6 mo. Recurrence took place in 15 patients. The mean (+/- SD) SUV(max), metabolic tumor volume, and TLG were 4.55 +/- 3.75, 5.92 +/- 5.57, and 14.42 +/- 17.35, respectively. The cutoffs of SUV(max) and TLG were 3.7 and 13.76, respectively. The 5-y overall survival (OS) was 95.1% in low-SUV(max) patients and 82.2% in high-SUV(max) patients (P = 0.02). The 5-y OS was 93.7% in low-TLG patients and 78.3% in high TLG patients (P = 0.01). On multivariate analysis, TLG was a risk factor for OS (hazard ratio, 3.159; P = 0.040), but SUV(max) showed marginal significance (P = 0.064). The concordance index of the TLG model was 0.676 (95% CI, 0.541-0.812). CONCLUSION: TLG was a significant prognostic factor for OS in patients with stage IA NSCLC. PMID- 25525186 TI - Positive clinical impact of an additional PET/CT scan before adjuvant radiotherapy or concurrent chemoradiotherapy in patients with advanced oral cavity squamous cell carcinoma. AB - The aim of this single-center study was to investigate whether obtaining an additional PET/CT scan before adjuvant radiotherapy or concurrent chemoradiotherapy (CCRT) could meaningfully improve 2-y disease-free survival (DFS) and disease-specific survival (DSS) rates. METHODS: Six hundred seventy four patients with oral cavity squamous cell carcinoma who received adjuvant therapy after radical surgery were included. Of these, 152 patients were initially scheduled to receive an additional preradiotherapy/CCRT PET/CT scan within 1 wk of starting adjuvant therapy. However, 16 patients were excluded because of either medical problems or refusal. Therefore, 136 patients underwent a preradiotherapy/CCRT PET/CT scan (PET group), and 522 did not (NO-PET group). All of the participants were followed up for at least 2 y or censored at the last follow-up. The impact of preradiotherapy/CCRT PET/CT imaging was examined using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Two-year DFS (80% vs. 70%, P = 0.033) and DSS (84% vs. 75%, P = 0.010) rates were significantly higher in the PET than in the NO-PET group. In the PET group, both DFS and DSS were higher in patients with negative findings than in those without (88% vs. 22% and 91% vs. 36%, respectively; both P < 0.001). A prognostic scoring system based on the presence of the 2 independent risk factors in the PET group (extracapsular spread and lymphatic invasion) predicted both DFS (P = 0.001 and P < 0.001, respectively) and DSS (P = 0.001 and P < 0.001, respectively). Nineteen patients (14%) had their treatment modified by preradiotherapy/CCRT PET/CT findings. Of these, 15 were treated with curative intent due to the presence of locoregional disease, and 4 received palliative care due to distant metastases. Seven of the 15 patients are currently alive without disease. CONCLUSION: An additional preradiotherapy/CCRT PET/CT scan improves both DFS and DSS in patients with advanced oral cavity squamous cell carcinoma. PMID- 25525188 TI - Role of ITGAE in the development of autoimmune diabetes in non-obese diabetic mice. AB - There is compelling evidence that autoreactive CD8(+)T cells play a central role in precipitating the development of autoimmune diabetes in non-obese diabetic (NOD) mice, but the underlying mechanisms remain unclear. Given that ITGAE (CD103) recognizes an islet-restricted ligand (E-cadherin), we postulated that its expression is required for initiation of disease. We herein use a mouse model of autoimmune diabetes (NOD/ShiLt mice) to test this hypothesis. We demonstrate that ITGAE is expressed by a discrete subset of CD8(+)T cells that infiltrate pancreatic islets before the development of diabetes. Moreover, we demonstrate that development of diabetes in Itgae-deficient NOD mice is significantly delayed at early but not late time points, indicating that ITGAE is preferentially involved in early diabetes development. To rule out a potential contribution by closely linked loci to this delay, we treated WT NOD mice beginning at 2 weeks of age through 5 weeks of age with a depleting anti-ITGAE mAb and found a decreased incidence of diabetes following anti-ITGAE mAb treatment compared with mice that received isotype control mAbs or non-depleting mAbs to ITGAE. Moreover, a histological examination of the pancreas of treated mice revealed that NOD mice treated with a depleting mAb were resistant to immune destruction. These results indicate that ITGAE(+) cells play a key role in the development of autoimmune diabetes and are consistent with the hypothesis that ITGAE(+)CD8(+)T effectors initiate the disease process. PMID- 25525187 TI - 18F-FDG PET/CT monitoring of beta3 agonist-stimulated brown adipocyte recruitment in white adipose tissue. AB - There is rising interest in recruitment of brown adipocytes into white adipose tissue (WAT) as a means to augment energy expenditure for weight reduction. We thus investigated the potential of (18)F-FDG uptake as an imaging biomarker that can monitor the process of WAT browning. METHODS: C57BL/6 mice were treated daily with the beta3 agonist CL316,243 (5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2 hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylic acid disodium salt), whereas controls received saline. (18)F-FDG small-animal PET/CT was serially performed at 1 h after CL316,243 injection. After sacrifice, interscapular brown adipose tissue (BAT) and WAT depots were extracted, weighed, and measured for (18)F-FDG uptake. Tissues underwent immunostaining, and UCP1 content was quantified by Western blotting. RESULTS: PET/CT showed low (18)F-FDG uptake in both BAT and inguinal WAT at baseline. BAT uptake was substantially increased by a single stimulation with CL316,243. Uptake in inguinal WAT was only modestly elevated by the first stimulation uptake but gradually increased to BAT level by prolonged stimulation. Ex vivo measurements recapitulated the PET findings, and measured (18)F-FDG uptake in other WAT depots was similar to inguinal WAT. WAT browning by prolonged stimulation was confirmed by a substantial increase in uncoupling protein 1 (UCP1), cytochrome-c oxidase 4 (COX4), and PR domain containing 16 (PRDM16) staining as markers of brown adipocytes. UCP1 content, which served as a measure for extent of browning, was low in baseline inguinal WAT but linearly increased over 10 d of CL316,243 injection. Finally, image-based and ex vivo-measured (18)F-FDG uptake in inguinal WAT correlated well with UCP1 content. CONCLUSION: (18)F-FDG PET/CT has the capacity to monitor brown adipocyte recruitment into WAT depots in vivo and may thus be useful for screening the efficacy of strategies to promote WAT browning. PMID- 25525189 TI - Delayed vision loss and therapeutic intervention after blast injury. PMID- 25525190 TI - In vivo pharmacological characterization of TAK-063, a potent and selective phosphodiesterase 10A inhibitor with antipsychotic-like activity in rodents. AB - Phosphodiesterase 10A (PDE10A) is a cAMP/cGMP phosphodiesterase highly expressed in medium spiny neurons (MSNs) in the striatum. We evaluated the in vivo pharmacological profile of a potent and selective PDE10A inhibitor, TAK-063 (1-[2 fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl) pyridazin-4(1H)-one). TAK-063 at 0.3 and 1 mg/kg p.o., increased cAMP and cGMP levels in the rodent striatum and upregulated phosphorylation levels of key substrates of cAMP- and cGMP-dependent protein kinases. TAK-063 at 0.3 and 1 mg/kg p.o., strongly suppressed MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H dibenzo[a,d]cyclohepten-5,10-imine]-induced hyperlocomotion, which is often used as a predictive model for antipsychotic-like activity in rodents. Upregulation of striatal cAMP/cGMP levels and the antipsychotic-like effect of TAK-063 were not attenuated after 15 days of pretreatment with TAK-063 in mice. The potential side effect profile of TAK-063 was assessed in rats using the clinical antipsychotics haloperidol, olanzapine, and aripiprazole as controls. TAK-063 did not affect plasma prolactin or glucose levels at doses up to 3 mg/kg p.o. At 3 mg/kg p.o., TAK-063 elicited a weak cataleptic response compared with haloperidol and olanzapine. Evaluation of pathway-specific markers (substance P mRNA for the direct pathway and enkephalin mRNA for the indirect pathway) revealed that TAK 063 activated both the direct and indirect pathways of MSNs. These findings suggest that TAK-063 represents a promising drug for the treatment of schizophrenia with potential for superior safety and tolerability profiles. PMID- 25525191 TI - Effect of memantine on cough reflex sensitivity: translational studies in guinea pigs and humans. AB - Cough is the most common complaint for which outpatients in the United States seek medical attention, and yet available therapeutic options for cough lack proven efficacy and are further limited by safety and abuse liabilities. Thus, safe and effective cough suppressants are needed. Recent preclinical studies described the antitussive effects of memantine, an N-methyl-d-aspartate receptor channel blocker used in the treatment of Alzheimer's disease. The goals of the present study were to compare the antitussive effects of memantine, dextromethorphan, and codeine in guinea pigs; to relate the dose-dependent actions of memantine in these studies to peak plasma concentrations achieved following oral administration; and to provide the first ever evaluation of the antitussive effect of memantine in humans. In guinea pigs, memantine and codeine were comparable in efficacy and potency but both were superior to dextromethorphan in the citric acid cough challenge model. The pharmacokinetic analyses suggest that memantine was active in guinea pigs at micromolar plasma concentrations. Subsequently, 14 healthy volunteers as well as 14 otherwise healthy adults with acute viral upper respiratory tract infection (URI) underwent capsaicin cough challenges 6 hours after ingestion of 20 mg memantine and matched placebo in a randomized, double-blind, crossover fashion. In healthy volunteers, memantine significantly inhibited cough reflex sensitivity (P = 0.034). In subjects with URI, responsiveness to capsaicin was markedly increased, and in these patients, the inhibition of cough reflex sensitivity by memantine relative to placebo did not reach statistical significance (P = 0.088). These data support further research to investigate the potential of memantine as a clinically useful antitussive. PMID- 25525192 TI - Descriptive normative beliefs and the self-regulation in alcohol use among Slovak university students. AB - AIM: This study aims (i) to understand how descriptive normative beliefs (DNB) about typical students' alcohol use and self-regulation (SRG) are related to alcohol use (AU) by exploring the indirect effect of SRG on AU through DNB and (ii) to explore gender differences and the differences between universities in DNB, SRG and AU. SUBJECT AND METHODS: The cross-sectional data were collected online from 817 Slovak university students from four universities (75.22% females; Mage = 19.61; SD = 1.42), who filled in the AUDIT-C items, items measuring the DNB about typical students' AU and SRG. T-tests, one-way Anova and structural equation modelling were used for data analysis. RESULTS: Gender differences in AU and DNB were found with males having higher levels of both AU and DNB. The tested model of AU fits the data well. A significant association was found between DNB and (i) AU (positive) and (ii) SRG (negative). The analysis confirmed the existence of an indirect effect of SRG on AU through DNB. CONCLUSION: The study contributes to research concerning AU by the way in which DNB and SRG are linked to AU among Slovak university students. The research findings can also be used in developing prevention and intervention programs. PMID- 25525193 TI - Well-being in 15-year-old adolescents: a matter of relationship with school. AB - BACKGROUND: Psychosomatic health complaints are significant indicators of adolescent well-being. The aim of this study is to describe the full set of interactions between health complaints and the presence of subjective resources, represented by the quality of relationships with parents and peers and by a positive school perception, in a population of 15-year-old adolescents. Smoking and alcohol consumption were also included in the analyses. METHODS: Bayesian networks were built for males and females separately, in order to understand the interactions among all considered variables in a representative sample of 16 018 Italian adolescents participating in the Health Behaviour in School-Aged Children survey 2009-10. RESULTS: The resulting networks show that school is the crucial node linking adolescents' well-being with parents and peer relationships, as well as with smoking and alcohol consumption. CONCLUSIONS: Adolescents' well-being, as well as the prevalence of typical risk behaviours, such as smoking and alcohol consumption, is mediated by the adolescents' academic stress. Therefore, public health interventions, to be effective, should consider addressing the school environment by making it a more inclusive environment promoting critical thinking and sense of belonging rather than just focusing on personal behaviours. PMID- 25525194 TI - Interprofessional collaboration in primary health care: a review of facilitators and barriers perceived by involved actors. AB - BACKGROUND: The epidemiological transition calls for redefining the roles of the various professionals involved in primary health care towards greater collaboration. We aimed to identify facilitators of, and barriers to, interprofessional collaboration in primary health care as perceived by the actors involved, other than nurses. METHODS: Systematic review using synthetic thematic analysis of qualitative research. Articles were retrieved from Medline, Web of science, Psychinfo and The Cochrane library up to July 2013. Quality and relevance of the studies were assessed according to the Dixon-Woods criteria. The following stakeholders were targeted: general practitioners, pharmacists, mental health workers, midwives, physiotherapists, social workers and receptionists. RESULTS: Forty-four articles were included. The principal facilitator of interprofessional collaboration in primary care was the different actors' common interest in collaboration, perceiving opportunities to improve quality of care and to develop new professional fields. The main barriers were the challenges of definition and awareness of one another's roles and competences, shared information, confidentiality and responsibility, team building and interprofessional training, long-term funding and joint monitoring. CONCLUSIONS: Interprofessional organization and training based on appropriate models should support collaboration development. The active participation of the patient is required to go beyond professional boundaries and hierarchies. Multidisciplinary research projects are recommended. PMID- 25525195 TI - Reduced darunavir dose is as effective in maintaining HIV suppression as the standard dose in virologically suppressed HIV-infected patients: a randomized clinical trial. AB - OBJECTIVES: Maximizing ART efficiency is of growing interest. This study assessed the efficacy, safety, pharmacokinetics and economics of a darunavir dose reduction strategy. METHODS: This was a multicentre, randomized, open-label clinical trial in HIV-infected patients with plasma HIV-1 RNA <50 copies/mL while receiving triple ART including 800 mg of darunavir once daily. Participants were randomized to continue 800 mg of darunavir (DRV800) or to 600 mg of darunavir (DRV600), both once daily. Treatment failure was defined as two consecutive HIV-1 RNA determinations >50 copies/mL or discontinuation of study treatment by week 48. The study was registered at https://www.clinicaltrialsregister.eu (trial number 2011-006272-39). RESULTS: Fifty participants were allocated to each arm. The mean (SD) CD4+ T cell count at baseline was 562 (303) cells/mm(3) and HIV-1 RNA had been <50 copies/mL for a median (IQR) of 106.9 (43.4-227.9) weeks before enrolment. At week 48 no treatment failure had occurred in 45/50 (90%) DRV600 patients and in 47/50 (94%) DRV800 patients (difference -4%; 95% CI lower limit, 12.9%). When only patients with virological data were considered, that endpoint was met by 45/48 (94%) in the DRV600 arm and 47/49 (96%) in the DRV800 arm (difference -2.2%; 95% CI lower limit, -9.6%). Darunavir exposure was similar in the two arms. The average reduction in annual cost per successfully treated DRV600-arm patient was US$7273. CONCLUSIONS: The efficacy of a darunavir daily dose of 600 mg seemed to be similar to the efficacy of the standard 800 mg dose in virologically suppressed HIV-infected patients on triple ART. This strategy can potentially translate to substantial savings in the cost of care of HIV infected patients. PMID- 25525196 TI - Monotherapy with boosted PIs as an ART simplification strategy in clinical practice. AB - BACKGROUND: Data on the efficacy of simplifying therapy using darunavir/ritonavir and lopinavir/ritonavir monotherapy in clinical practice remain limited. METHODS: A retrospective single-centre study including patients initiating darunavir/ritonavir or lopinavir/ritonavir monotherapy with a plasma HIV-1 viral load (pVL) <50 copies/mL and at least one subsequent follow-up visit. The primary endpoint was the percentage of patients remaining free of virological failure (VF; defined as a confirmed pVL >50 copies/mL or as any change in the regimen after a single determination with a pVL >50 copies/mL) during the follow-up. We also evaluated the percentage of patients remaining free of treatment failure (TF; defined as VF or the early discontinuation of monotherapy for any reason) and compared the effectiveness of the two regimens. Effectiveness was evaluated using cumulative survival analysis (at Weeks 48 and 96). Factors associated with VF and TF were analysed using Cox regression. RESULTS: A total of 522 patients were included (309 receiving lopinavir/ritonavir and 213 receiving darunavir/ritonavir). The median follow-up was 64.3 (30.5-143.0) weeks. The percentage of patients free of VF and TF was 94% (95% CI 91%-96%) and 79% (95% CI 75%-82%) at 48 weeks, respectively, and 86% (95% CI 81%-89%) and 62% (95% CI 57% 67%) at 96 weeks, respectively. The risk of VF was similar for the two regimens (HR=1.0, 95% CI 0.6-1.8; P=0.962). Lopinavir/ritonavir monotherapy was associated with a 1.5-fold greater risk of TF (95% CI 1.1-2.1; P=0.012) and a 2.3-fold greater risk of discontinuation of therapy due to adverse events (95% CI 1.3-3.9; P=0.003). CONCLUSIONS: The virological efficacy of darunavir/ritonavir and lopinavir/ritonavir monotherapy is high in clinical practice. Treatment discontinuation due to safety issues is more frequent with lopinavir/ritonavir. PMID- 25525197 TI - Bone and kidney toxicity induced by nucleotide analogues in patients affected by HBV-related chronic hepatitis: a longitudinal study. AB - OBJECTIVES: Nucleotide analogues may promote renal and bone toxicity. The aim of the present study was to evaluate markers of osteorenal toxicity in patients affected by hepatitis B virus-related chronic hepatitis treated with lamivudine plus adefovir who were switched to tenofovir. PATIENTS AND METHODS: We evaluated 60 consecutive patients at the time of the switch of treatment and after 1, 3, 6, 9 and 12 months. The mean baseline estimated glomerular filtration rate (eGFR) was 89.3 +/- 19.0 mL/min/1.73 m(2). RESULTS: During the study period we observed a reduction in mean eGFR up to 6 months after switching to tenofovir, and this remained stable for the last two timepoints. At the end of study, the mean eGFR was 82.6 +/- 21.5 mL/min/1.73 m(2), a reduction of 7.5%. The mean baseline proteinuria was 202.6 +/- 237.6 mg/24 h. Microhaematuria was observed in 22.6% of patients and hypophosphataemia in 18.6%. After 1 month of tenofovir, we observed a worsening of serum phosphate and parathyroid hormone levels, haemoglobinuria and 24 h proteinuria. After 3 and 12 months of tenofovir, these data tended to recover to baseline levels. A total of 92.6% of patients at baseline had hypovitaminosis D. After supplementation with cholecalciferol, this percentage decreased significantly. We observed a reduced bone mineral density (BMD) in 52.7% of patients at baseline; this increased to 77.8% after 6 months of tenofovir, but at the last timepoint the percentage of patients with a reduced BMD had fallen to a level above the baseline. CONCLUSIONS: In conclusion, patients exposed to lamivudine plus adefovir showed relevant osteorenal damage. The switch to tenofovir provoked a slight reduction in eGFR that stabilized after 6 months. The reduced BMD at baseline did not worsen under tenofovir treatment. PMID- 25525198 TI - Exploring the epidemiology of carbapenem-resistant Gram-negative bacteria in west London and the utility of routinely collected hospital microbiology data. AB - OBJECTIVES: The objective of this study was to identify carbapenem-resistant organisms using routinely collected local microbiology data and describe the epidemiology of carbapenem resistance in two London teaching hospitals. METHODS: Data on inpatients infected or colonized with Gram-negative organisms between March 2009 and February 2012 were extracted. A computer algorithm was developed incorporating internationally recognized criteria to distinguish carbapenem resistant organisms. Multivariable analysis was conducted to identify factors associated with infection or colonization with carbapenem-resistant organisms. Binomial regression was performed to detect changes in resistance trends over time. RESULTS: Yearly incidence of carbapenem resistance was observed to be increasing, with significant increasing trends in Acinetobacter baumannii (47.1% in 2009-10 to 77.2% in 2011-12; P<0.001) and Enterobacter spp. (2.2% in 2009-10 to 11.5% in 2011-12; P<0.001). Single-variable and multivariable analysis demonstrated differences in the proportion of carbapenem-resistant isolates across all variables investigated, including age, sex and clinical specialty; in the latter organism-specific niches were identified. Patients in the youngest age group (16-24 years old) had the highest odds of being infected or colonized with carbapenem-resistant isolates of Escherichia coli, Klebsiella spp. or Pseudomonas aeruginosa. Furthermore, proportions of carbapenem-resistant organisms differed between the hospitals. CONCLUSIONS: Carbapenem resistance is an emerging problem within the UK inpatient healthcare setting. This is not an issue confined to the Enterobacteriaceae and fine-resolution surveillance is needed to identify at-risk groups. Regular analysis of routinely collected data can provide insight into the evolving carbapenem-resistance threat, with the ability to inform efforts to prevent the spread of resistance. PMID- 25525199 TI - Transmitted HIV drug resistance at the Thai Red Cross anonymous clinic in Bangkok: results from three consecutive years of annual surveillance. AB - OBJECTIVES: The aim of this study was to prospectively survey transmitted drug resistance (TDR) among recently infected individuals (mostly MSM). METHODS: TDR was determined in prospective annual cohorts of recently HIV-1-infected individuals consecutively recruited from 2008 to 2010. Resistance interpretation was carried out using Stanford Database tools and the WHO surveillance drug resistance mutation list. Kruskal-Wallis and Fisher's exact tests were used to compare demographic and laboratory outcomes. RESULTS: A total of 299 subjects were enrolled, with 89% MSM. Median viral load was significantly higher in 2010 than in 2008 (P=0.004). Of the 284 analysable reverse transcriptase/protease sequences, TDR to any drug was found in 14/284 (4.9%); 4.0% in 2008, 5.9% in 2009 and 5.3% in 2010, with an increasing trend of TDR to NRTIs and NNRTIs from 2008 to 2010 (P=0.07). Good correlation was found between our data and the WHO threshold surveillance method. Only rilpivirine had significantly higher (P<0.05) predicted resistance in 2010 than in 2008 and 2009. CONCLUSIONS: A trend towards an increase in TDR in Thailand where the major epidemic is among MSM was observed, but did not reach the WHO-defined high-level threshold (>15%). Attention to prevent the development and spread of drug resistance is needed. PMID- 25525200 TI - Association between oral fluoroquinolone use and the development of retinal detachment: a systematic review and meta-analysis of observational studies. AB - OBJECTIVES: Several observational studies have been published investigating the association between oral fluoroquinolone use and the development of retinal detachment; however, the findings are not concordant. This study is a meta analysis of the existing literature and estimates the overall absolute risk of such an event. METHODS: Electronic databases were searched for observational studies on the association between oral fluoroquinolone and retinal detachment up to August 2014. Studies that did not meet the criteria for meta-analysis were narratively reviewed. Cases of retinal detachment during current fluoroquinolone use were also extracted for absolute risk calculation. RESULTS: Seven observational studies were included. Three (case-control and self-controlled case series studies) were eligible for meta-analysis and four (cohort studies) were narratively reviewed. The rate ratio of the case-control studies was 1.82 (95% CI 0.67-4.93), I(2) =96% and the incidence rate ratio of the self-controlled case series was 1.03 (95% CI 0.84-1.27), I(2) =36%. Three of the four cohort studies found no significant association between oral fluoroquinolone use and the development of retinal detachment. The pooled absolute risk of retinal detachment whilst on current oral fluoroquinolone treatment is estimated to be 4.85 per 1000000 prescriptions (95% CI 0.78-8.91). CONCLUSIONS: The findings of this systematic review and meta-analysis do not support an association between oral fluoroquinolone use and the development of retinal detachment. Given the low absolute risk, such an event would be rare if there were an association. The current prescribing practice for fluoroquinolones should not be altered because of a previously suggested potential risk of retinal detachment. PMID- 25525202 TI - PTSD, stigma and barriers to help-seeking within the UK Armed Forces. AB - Among the general public, much is known about the longer-term consequences of not seeking support for mental health difficulties. However, within military populations, and in particular, the UK Armed Forces, less is known. Understanding the factors that present barriers for UK service personnel with mental health difficulties accessing support is important because this may provide a means for support personnel to seek help sooner. This paper explores the literature relating to the impact of untreated post-traumatic stress disorder (PTSD) among military personnel, attempts to draw conclusions about the barriers that may prevent personnel seeking help and the efficacy of previous interventions to address these. Stigma has been highlighted as the key barrier to help-seeking behaviours, in particular, internal stigma, which can be classified as negative beliefs about the self that an individual may hold as a result of experiencing symptoms of PTSD. PMID- 25525201 TI - beta-Lactamase inhibition by avibactam in Mycobacterium abscessus. AB - OBJECTIVES: Two beta-lactams, cefoxitin and imipenem, are part of the reference treatment for pulmonary infections with Mycobacterium abscessus. M. abscessus has recently been shown to produce a broad-spectrum beta-lactamase, BlaMab, indicating that the combination of beta-lactams with a BlaMab inhibitor may improve treatment efficacy. The objectives of this study were to evaluate the impact of BlaMab production on the efficacy of beta-lactams in vitro and to assess the benefit of BlaMab inhibition on the activity of beta-lactams intracellularly and in an animal model. METHODS: We analysed the mechanism and kinetics of BlaMab inactivation by avibactam, a non-beta-lactam beta-lactamase inhibitor currently in Phase III of development, in combination with ceftazidime for the treatment of serious infections due to Gram-negative bacteria. We then deleted the gene encoding BlaMab to assess the extent of BlaMab inhibition by avibactam based on a comparison of the impact of chemical and genetic inactivation. Finally, the efficacy of amoxicillin in combination with avibactam was evaluated in cultured human macrophages and in a zebrafish model of M. abscessus infection. RESULTS: We showed that avibactam efficiently inactivated BlaMab via the reversible formation of a covalent adduct. An inhibition of BlaMab by avibactam was observed in both infected macrophages and zebrafish. CONCLUSIONS: Our data identify avibactam as the first efficient inhibitor of BlaMab and strongly suggest that beta-lactamase inhibition should be evaluated to provide improved therapeutic options for M. abscessus infections. PMID- 25525203 TI - Medical aspects of the Battle of Waterloo: the battle. AB - The Duke of Wellington's polyglot army assembled for the Waterloo campaign was hastily aggregated and the Army Medical Department was somewhat short of staff and not entirely of the calibre of the department serving latterly in the Peninsular campaigns. The casualty rates during the battles of this campaign were high and the regimental and hospital staff struggled with the large number of casualties. Lack of stretcher bearers and transport were significant problems, which were compounded by the high density of the casualties. Three quarters of the surviving wounded rejoined their units. PMID- 25525204 TI - Macular injury resulting from a high-powered tank laser telemetry device. AB - A high-powered laser is an essential part of a modern military rangefinder; however, this paper presents three cases with macular injury resulting from a high-powered tank laser telemetry device. All injuries occurred when another user deliberately pointed the telemetry target unit at the patient's eyes. The devastating effect of this high-powered laser resulted in a permanent foveal scar in the second patient and a macular hole formation in the third patient. This report emphasises that education plays a primary role in preventing accidental laser injuries. Using general guidelines and safety regulations will prevent accidental macular injuries. PMID- 25525206 TI - Probiotics or antibiotics: future challenges in medicine. AB - Genetic and environmental factors can affect the intestinal microbiome and microbial metabolome. Among these environmental factors, the consumption of antibiotics can significantly change the intestinal microbiome of individuals and consequently affect the corresponding metagenome. The term 'probiotics' is related to preventive medicine rather than therapeutic procedures and is, thus, considered the opposite of antibiotics. This review discusses the challenges between these opposing treatments in terms of the following points: (i) antibiotic resistance, the relationship between antibiotic consumption and microbiome diversity reduction, antibiotic effect on the metagenome, and disease associated with antibiotics; and (ii) probiotics as living drugs, probiotic effect on epigenetic alterations, and gut microbiome relevance to hygiene indulgence. The intestinal microbiome is more specific for individuals and may be affected by environmental alterations and the occurrence of diseases. PMID- 25525205 TI - Semi-quantitative measurement of a specific glycoform using a DNA-tagged antibody and lectin affinity chromatography for glyco-biomarker development. AB - Aberrant glycosylation-targeted disease biomarker development is based on cumulative evidence that certain glycoforms are mass-produced in a disease specific manner. However, the development process has been hampered by the absence of an efficient validation method based on a sensitive and multiplexed platform. In particular, ELISA-based analytical tools are not adequate for this purpose, mainly because of the presence of a pair of N-glycans of IgG-type antibodies. To overcome the associated hurdles in this study, antibodies were tagged with oligonucleotides with T7 promoter and then allowed to form a complex with corresponding antigens. An antibody-bound specific glycoform was isolated by lectin chromatography and quantitatively measured on a DNA microarray chip following production of fluorescent RNA by T7-trascription. This tool ensured measurement of targeted glycoforms of multiple biomarkers with high sensitivity and multiplexity. This analytical method was applied to an in vitro diagnostic multivariate index assay where a panel of hepatocellular carcinoma (HCC) biomarkers comprising alpha-fetoprotein, hemopexin, and alpha-2-macroglobulin (A2M) was examined in terms of the serum level and their fuco-fractions. The results indicated that the tests using the multiplexed fuco-biomarkers provided improved discriminatory power between non- hepatocellular carcinoma and hepatocellular carcinoma subjects compared with the alpha-fetoprotein level or fuco-alpha-fetoprotein test alone. The developed method is expected to facilitate the validation of disease-specific glycan biomarker candidates. PMID- 25525208 TI - Fatigue-related firing of muscle nociceptors reduces voluntary activation of ipsilateral but not contralateral lower limb muscles. AB - During fatiguing upper limb exercise, maintained firing of group III/IV muscle afferents can limit voluntary drive to muscles within the same limb. It is not known if this effect occurs in the lower limb. We investigated the effects of group III/IV muscle afferent firing from fatigued ipsilateral and contralateral extensor muscles and ipsilateral flexor muscles of the knee on voluntary activation of the knee extensors. In three experiments, we examined voluntary activation of the knee extensors by measuring changes in superimposed twitches evoked by femoral nerve stimulation. Subjects attended on 2 days for each experiment. On one day a sphygmomanometer cuff occluded blood flow of the fatigued muscles to maintain firing of group III/IV muscle afferents. After a 2 min extensor contraction (experiment 1; n = 9), mean voluntary activation was lower with than without maintained ischemia (47 +/- 19% vs. 87 +/- 8%, respectively; P < 0.001). After a 2-min knee flexor maximal voluntary contraction (MVC) (experiment 2; n = 8), mean voluntary activation was also lower with than without ischemia (59 +/- 21% vs. 79 +/- 9%; P < 0.01). After the contralateral (left) MVC (experiment 3; n = 8), mean voluntary activation of the right leg was similar with or without ischemia (92 +/- 6% vs. 93 +/- 4%; P = 0.65). After fatiguing exercise, activity in group III/IV muscle afferents reduces voluntary activation of the fatigued muscle and nonfatigued antagonist muscles in the same leg. However, group III/IV muscle afferents from the fatigued left leg had no effect on the unfatigued right leg. This suggests that any "crossover" of central fatigue in the lower limbs is not mediated by group III/IV muscle afferents. PMID- 25525207 TI - Novel regulatory roles of cAMP receptor proteins in fast-growing environmental mycobacteria. AB - Mycobacterium smegmatis is a fast-growing, saprophytic, mycobacterial species that contains two cAMP-receptor protein (CRP) homologues designated herein as Crp1 and Crp2. Phylogenetic analysis suggests that Crp1 (Msmeg_0539) is uniquely present in fast-growing environmental mycobacteria, whereas Crp2 (Msmeg_6189) occurs in both fast- and slow-growing species. A crp1 mutant of M. smegmatis was readily obtained, but crp2 could not be deleted, suggesting it was essential for growth. A total of 239 genes were differentially regulated in response to crp1 deletion (loss of function), including genes coding for mycobacterial energy generation, solute transport and catabolism of carbon sources. To assess the role of Crp2 in M. smegmatis, the crp2 gene was overexpressed (gain of function) and transcriptional profiling studies revealed that 58 genes were differentially regulated. Identification of the CRP promoter consensus in M. smegmatis showed that both Crp1 and Crp2 recognized the same consensus sequence (TGTGN8CACA). Comparison of the Crp1- and Crp2-regulated genes revealed distinct but overlapping regulons with 11 genes in common, including those of the succinate dehydrogenase operon (MSMEG_0417-0420, sdh1). Expression of the sdh1 operon was negatively regulated by Crp1 and positively regulated by Crp2. Electrophoretic mobility shift assays with purified Crp1 and Crp2 demonstrated that Crp1 binding to the sdh1 promoter was cAMP-independent whereas Crp2 binding was cAMP dependent. These data suggest that Crp1 and Crp2 respond to distinct signalling pathways in M. smegmatis to coordinate gene expression in response to carbon and energy supply. PMID- 25525209 TI - Effect of inhaled carbon dioxide on laryngeal abduction. AB - Hypercapnia produces a profound effect on respiratory drive and upper airway function to maintain airway patency. Previous work has evaluated the effects of hypercapnia on the sole arytenoid abductor, the posterior cricoarytenoid (PCA), using indirect measures of function, such as electromyography and direct nerve recording. Here we describe a novel method to evaluate PCA function in anesthetized animals and use this method to determine the effects of hypercapnia on PCA function. Eight dogs were anesthetized, and a laryngeal mask airway was used, in combination with high-speed videoendoscopy, to evaluate laryngeal function. A stepwise increase in inspired partial pressure of CO2 produced marked arytenoid abduction above 70-mmHg end-tidal CO2 (ETCO2 ) (P < 0.001). Glottic length increased above 80-mmHg ETCO2 (P < 0.02), and this lead to underrepresentation of changes in glottic area, if standard measures of glottic area (normalized glottic gap area) were used. Use of a known scale to determine absolute glottic area demonstrated no plateau with increasing ETCO2 up to 120 mmHg. Ventilatory parameters also continued to increase with no evidence of a maximal response. In a second anesthetic episode, repeated bursts of transient hypercapnia for 60 s with an ETCO2 of 90 mmHg produced a 43-55% increase in glottic area (P < 0.001) at or shortly after the end of the hypercapnic burst. A laryngeal mask airway can be used in combination with videoendoscopy to precisely determine changes in laryngeal dimensions with high temporal resolution. Absolute glottic area more precisely represents PCA function than normalized glottic gap area at moderate levels of hypercapnia. PMID- 25525210 TI - Baroreceptor unloading does not limit forearm sweat rate during severe passive heat stress. AB - This study tested the hypothesis that sweat rate during passive heat stress is limited by baroreceptor unloading associated with heat stress. Two protocols were performed in which healthy subjects underwent passive heat stress that elicited an increase in intestinal temperature of ~1.8 degrees C. Upon attaining this level of hyperthermia, in protocol 1 (n = 10, 3 females) a bolus (19 ml/kg) of warm (~38 degrees C) isotonic saline was rapidly (5-10 min) infused intravenously to elevate central venous pressure (CVP), while in protocol 2 (n = 11, 5 females) phenylephrine was infused intravenously (60-120 MUg/min) to return mean arterial pressure (MAP) to normothermic levels. In protocol 1, heat stress reduced CVP from 3.9 +/- 1.9 mmHg (normothermia) to -0.6 +/- 1.4 mmHg (P < 0.001), while saline infusion returned CVP to normothermic levels (5.1 +/- 1.7 mmHg; P > 0.999). Sweat rate was elevated by heat stress (1.21 +/- 0.44 mg.cm(-2).min(-1)) but remained unchanged during rapid saline infusion (1.26 +/- 0.47 mg.cm(-2).min( 1), P = 0.5), whereas cutaneous vascular conductance increased from 77 +/- 10 to 101 +/- 20% of local heating max (P = 0.029). In protocol 2, MAP was reduced with heat stress from 85 +/- 7 mmHg to 76 +/- 8 mmHg (P = 0.048). Although phenylephrine infusion returned MAP to normothermic levels (88 +/- 7 mmHg; P > 0.999), sweat rate remained unchanged during phenylephrine infusion (1.39 +/- 0.22 vs. 1.41 +/- 0.24 mg.cm(-2).min(-1); P > 0.999). These data indicate that both cardiopulmonary and arterial baroreceptor unloading do not limit increases in sweat rate during passive heat stress. PMID- 25525211 TI - The two-hour marathon: What's the equivalent for women? PMID- 25525212 TI - Increased hepcidin levels in high-altitude pulmonary edema. AB - Low iron availability enhances hypoxic pulmonary vasoconstriction (HPV). Considering that reduced serum iron is caused by increased erythropoiesis, insufficient reabsorption, or elevated hepcidin levels, one might speculate that exaggerated HPV in high-altitude pulmonary edema (HAPE) is related to low serum iron. To test this notion we measured serum iron and hepcidin in blood samples obtained in previously published studies at low altitude and during 2 days at 4,559 m (HA1, HA2) from controls, individuals with HAPE, and HAPE-susceptible individuals where prophylactic dexamethasone and tadalafil prevented HAPE. As reported, at 4,559 m pulmonary arterial pressure was increased in healthy volunteers but reached higher levels in HAPE. Serum iron levels were reduced in all groups at HA2. Hepcidin levels were reduced in all groups at HA1 and HA2 except in HAPE, where hepcidin was decreased at HA1 but unexpectedly high at HA2. Elevated hepcidin in HAPE correlated with increased IL-6 at HA2, suggesting that an inflammatory response related to HAPE contributes to increased hepcidin. Likewise, platelet-derived growth factor, a regulator of hepcidin, was increased at HA1 and HA2 in controls but not in HAPE, suggesting that hypoxia-controlled factors that regulate serum iron are inappropriately expressed in HAPE. In summary, we found that HAPE is associated with inappropriate expression of hepcidin without inducing expected changes in serum iron within 2 days at HA, likely due to too short time. Although hepcidin expression is uncoupled from serum iron availability and hypoxia in individuals developing HAPE, our findings indicate that serum iron is not related with exaggerated HPV. PMID- 25525213 TI - Altering blood flow does not reveal differences between nitrogen and helium kinetics in brain or in skeletal miracle in sheep. AB - In underwater diving, decompression schedules are based on compartmental models of nitrogen and helium tissue kinetics. However, these models are not based on direct measurements of nitrogen and helium kinetics. In isoflurane-anesthetized sheep, nitrogen and helium kinetics in the hind limb (n = 5) and brain (n = 5) were determined during helium-oxygen breathing and after return to nitrogen oxygen breathing. Nitrogen and helium concentrations in arterial, femoral vein, and sagittal sinus blood samples were determined using headspace gas chromatography, and venous blood flows were monitored continuously using ultrasonic Doppler. The experiment was repeated at different states of hind limb blood flow and cerebral blood flow. Using arterial blood gas concentrations and blood flows as input, parameters and model selection criteria of various compartmental models of hind limb and brain were estimated by fitting to the observed venous gas concentrations. In both the hind limb and brain, nitrogen and helium kinetics were best fit by models with multiexponential kinetics. In the brain, there were no differences in nitrogen and helium kinetics. Hind limb models fit separately to the two gases indicated that nitrogen kinetics were slightly faster than helium, but models with the same kinetics for both gases fit the data well. In the hind limb and brain, the blood:tissue exchange of nitrogen is similar to that of helium. On the basis of these results, it is inappropriate to assign substantially different time constants for nitrogen and helium in all compartments in decompression algorithms. PMID- 25525214 TI - Trans-splicing and operons in metazoans: translational control in maternally regulated development and recovery from growth arrest. AB - Polycistronic mRNAs transcribed from operons are resolved via the trans-splicing of a spliced-leader (SL) RNA. Trans-splicing also occurs at monocistronic transcripts. The phlyogenetically sporadic appearance of trans-splicing and operons has made the driving force(s) for their evolution in metazoans unclear. Previous work has proposed that germline expression drives operon organization in Caenorhabditis elegans, and a recent hypothesis proposes that operons provide an evolutionary advantage via the conservation of transcriptional machinery during recovery from growth arrested states. Using a modified cap analysis of gene expression protocol we mapped sites of SL trans-splicing genome-wide in the marine chordate Oikopleura dioica. Tiled microarrays revealed the expression dynamics of trans-spliced genes across development and during recovery from growth arrest. Operons did not facilitate recovery from growth arrest in O. dioica. Instead, we found that trans-spliced transcripts were predominantly maternal. We then analyzed data from C. elegans and Ciona intestinalis and found that an enrichment of trans-splicing and operon gene expression in maternal mRNA is shared between all three species, suggesting that this may be a driving force for operon evolution in metazoans. Furthermore, we found that the majority of known terminal oligopyrimidine (TOP) mRNAs are trans-spliced in O. dioica and that the SL contains a TOP-like motif. This suggests that the SL in O. dioica confers nutrient-dependent translational control to trans-spliced mRNAs via the TOR-signaling pathway. We hypothesize that SL-trans-splicing provides an evolutionary advantage in species that depend on translational control for regulating early embryogenesis, growth and oocyte production in response to nutrient levels. PMID- 25525218 TI - Energy Research. U.S. fusion effort melts down. PMID- 25525216 TI - Breakthrough to our origins. PMID- 25525219 TI - Research Funding. Science agencies make gains despite tight U.S. budget. PMID- 25525221 TI - Costa Rica. Celebrated biodiversity institute faces financial crisis. PMID- 25525215 TI - The eukaryotic ancestor had a complex ubiquitin signaling system of archaeal origin. AB - The origin of the eukaryotic cell is one of the most important transitions in the history of life. However, the emergence and early evolution of eukaryotes remains poorly understood. Recent data have shown that the last eukaryotic common ancestor (LECA) was much more complex than previously thought. The LECA already had the genetic machinery encoding the endomembrane apparatus, spliceosome, nuclear pore, and myosin and kinesin cytoskeletal motors. It is unclear, however, when the functional regulation of these cellular components evolved. Here, we address this question by analyzing the origin and evolution of the ubiquitin (Ub) signaling system, one of the most important regulatory layers in eukaryotes. We delineated the evolution of the whole Ub, Small-Ub-related MOdifier (SUMO), and Ub-fold modifier 1 (Ufm1) signaling networks by analyzing representatives from all major eukaryotic, bacterial, and archaeal lineages. We found that the Ub toolkit had a pre-eukaryotic origin and is present in three extant archaeal groups. The pre-eukaryotic Ub toolkit greatly expanded during eukaryogenesis, through massive gene innovation and diversification of protein domain architectures. This resulted in a LECA with essentially all of the Ub-related genes, including the SUMO and Ufm1 Ub-like systems. Ub and SUMO signaling further expanded during eukaryotic evolution, especially labeling and delabeling enzymes responsible for substrate selection. Additionally, we analyzed protein domain architecture evolution and found that multicellular lineages have the most complex Ub systems in terms of domain architectures. Together, we demonstrate that the Ub system predates the origin of eukaryotes and that a burst of innovation during eukaryogenesis led to a LECA with complex posttranslational regulation. PMID- 25525220 TI - Ancient DNA. The thoroughly bred horse. PMID- 25525222 TI - Biomedical Research. Ambitious children's study meets disappointing end. PMID- 25525223 TI - Comet Breakthrough of the Year + People's choice. PMID- 25525224 TI - Runners-up. PMID- 25525225 TI - Scorecard for 2014. PMID- 25525226 TI - Areas to watch in 2015. PMID- 25525227 TI - Breakdown + Breakdown runners-up. PMID- 25525228 TI - Cell Biology. Fixing problems with cell lines. PMID- 25525229 TI - Immunology. Retroviral help for B cells. PMID- 25525230 TI - Protein Design. What I cannot create, I do not understand. PMID- 25525231 TI - Biochemistry. More than fine tuning. PMID- 25525232 TI - Cancer. For pediatric glioma, leave no histone unturned. PMID- 25525233 TI - Cancer. Malicious exosomes. PMID- 25525234 TI - Climate. Projecting regional change. PMID- 25525235 TI - Retraction. Polymerase exchange during Okazaki fragment synthesis observed in living cells. PMID- 25525236 TI - On the origin of feathers. PMID- 25525237 TI - On the origin of feathers--response. PMID- 25525238 TI - Comment on "A 12-million-year temperature history of the tropical Pacific Ocean". AB - Zhang et al. (Reports, 4 April 2014, p. 84) interpret TEX86 and U(37)(K') paleotemperature data as providing a fundamentally new view of tropical Pacific climate during the warm Pliocene period. We argue that, within error, their Pliocene data actually support previously published data indicating average western warm-pool temperature similar to today and a reduced zonal gradient, referred to as a permanent El Nino-like state. PMID- 25525239 TI - Response to Comment on "A 12-million-year temperature history of the tropical Pacific Ocean". AB - Contrary to our conclusions, Ravelo et al. argue that our TEX86-based sea surface temperature (SST) records do not conflict with the supposition of "permanent El Nino-like" conditions during the early Pliocene. We show that the way Ravelo et al. treat the existing temperature data perpetuates an inaccurate impression of cooler Pacific warm-pool SSTs and low equatorial temperature gradients in the past. PMID- 25525241 TI - Toward control of electron transfer in donor-acceptor molecules by bond-specific infrared excitation. AB - Electron transfer (ET) from donor to acceptor is often mediated by nuclear electronic (vibronic) interactions in molecular bridges. Using an ultrafast electronic-vibrational-vibrational pulse-sequence, we demonstrate how the outcome of light-induced ET can be radically altered by mode-specific infrared (IR) excitation of vibrations that are coupled to the ET pathway. Picosecond narrow band IR excitation of high-frequency bridge vibrations in an electronically excited covalent trans-acetylide platinum(II) donor-bridge-acceptor system in solution alters both the dynamics and the yields of competing ET pathways, completely switching a charge separation pathway off. These results offer a step toward quantum control of chemical reactivity by IR excitation. PMID- 25525242 TI - One-pot room-temperature conversion of cyclohexane to adipic acid by ozone and UV light. AB - Nitric acid oxidation of cyclohexane accounts for ~95% of the worldwide adipic acid production and is also responsible for ~5 to 8% of the annual worldwide anthropogenic emission of the ozone-depleting greenhouse gas nitrous oxide (N2O). Here we report a N2O-free process for adipic acid synthesis. Treatment of neat cyclohexane, cyclohexanol, or cyclohexanone with ozone at room temperature and 1 atmosphere of pressure affords adipic acid as a solid precipitate. Addition of acidic water or exposure to ultraviolet (UV) light irradiation (or a combination of both) dramatically enhances the oxidative conversion of cyclohexane to adipic acid. PMID- 25525240 TI - MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses. AB - Multivalent molecules with repetitive structures including bacterial capsular polysaccharides and viral capsids elicit antibody responses through B cell receptor (BCR) crosslinking in the absence of T cell help. We report that immunization with these T cell-independent type 2 (TI-2) antigens causes up regulation of endogenous retrovirus (ERV) RNAs in antigen-specific mouse B cells. These RNAs are detected via a mitochondrial antiviral signaling protein (MAVS) dependent RNA sensing pathway or reverse-transcribed and detected via the cGAS cGAMP-STING pathway, triggering a second, sustained wave of signaling that promotes specific immunoglobulin M production. Deficiency of both MAVS and cGAS, or treatment of MAVS-deficient mice with reverse transcriptase inhibitors, dramatically inhibits TI-2 antibody responses. These findings suggest that ERV and two innate sensing pathways that detect them are integral components of the TI-2 B cell signaling apparatus. PMID- 25525243 TI - Element-specific anisotropic growth of shaped platinum alloy nanocrystals. AB - Morphological shape in chemistry and biology owes its existence to anisotropic growth and is closely coupled to distinct functionality. Although much is known about the principal growth mechanisms of monometallic shaped nanocrystals, the anisotropic growth of shaped alloy nanocrystals is still poorly understood. Using aberration-corrected scanning transmission electron microscopy, we reveal an element-specific anisotropic growth mechanism of platinum (Pt) bimetallic nano octahedra where compositional anisotropy couples to geometric anisotropy. A Pt rich phase evolves into precursor nanohexapods, followed by a slower step-induced deposition of an M-rich (M = Ni, Co, etc.) phase at the concave hexapod surface forming the octahedral facets. Our finding explains earlier reports on unusual compositional segregations and chemical degradation pathways of bimetallic polyhedral catalysts and may aid rational synthesis of shaped alloy catalysts with desired compositional patterns and properties. PMID- 25525244 TI - Direct observation of closed magnetic flux trapped in the high-latitude magnetosphere. AB - The structure of Earth's magnetosphere is poorly understood when the interplanetary magnetic field is northward. Under this condition, uncharacteristically energetic plasma is observed in the magnetotail lobes, which is not expected in the textbook model of the magnetosphere. Using satellite observations, we show that these lobe plasma signatures occur on high-latitude magnetic field lines that have been closed by the fundamental plasma process of magnetic reconnection. Previously, it has been suggested that closed flux can become trapped in the lobe and that this plasma-trapping process could explain another poorly understood phenomenon: the presence of auroras at extremely high latitudes, called transpolar arcs. Observations of the aurora at the same time as the lobe plasma signatures reveal the presence of a transpolar arc. The excellent correspondence between the transpolar arc and the trapped closed flux at high altitudes provides very strong evidence of the trapping mechanism as the cause of transpolar arcs. PMID- 25525245 TI - Extreme electric fields power catalysis in the active site of ketosteroid isomerase. AB - Enzymes use protein architecture to impose specific electrostatic fields onto their bound substrates, but the magnitude and catalytic effect of these electric fields have proven difficult to quantify with standard experimental approaches. Using vibrational Stark effect spectroscopy, we found that the active site of the enzyme ketosteroid isomerase (KSI) exerts an extremely large electric field onto the C=O chemical bond that undergoes a charge rearrangement in KSI's rate determining step. Moreover, we found that the magnitude of the electric field exerted by the active site strongly correlates with the enzyme's catalytic rate enhancement, enabling us to quantify the fraction of the catalytic effect that is electrostatic in origin. The measurements described here may help explain the role of electrostatics in many other enzymes and biomolecular systems. PMID- 25525246 TI - A stagnation event in the deep South Atlantic during the last interglacial period. AB - During the last interglacial period, global temperatures were ~2 degrees C warmer than at present and sea level was 6 to 8 meters higher. Southern Ocean sediments reveal a spike in authigenic uranium 127,000 years ago, within the last interglacial, reflecting decreased oxygenation of deep water by Antarctic Bottom Water (AABW). Unlike ice age reductions in AABW, the interglacial stagnation event appears decoupled from open ocean conditions and may have resulted from coastal freshening due to mass loss from the Antarctic ice sheet. AABW reduction coincided with increased North Atlantic Deep Water (NADW) formation, and the subsequent reinvigoration in AABW coincided with reduced NADW formation. Thus, alternation of deep water formation between the Antarctic and the North Atlantic, believed to characterize ice ages, apparently also occurs in warm climates. PMID- 25525248 TI - De novo design of a transmembrane Zn2+-transporting four-helix bundle. AB - The design of functional membrane proteins from first principles represents a grand challenge in chemistry and structural biology. Here, we report the design of a membrane-spanning, four-helical bundle that transports first-row transition metal ions Zn(2+) and Co(2+), but not Ca(2+), across membranes. The conduction path was designed to contain two di-metal binding sites that bind with negative cooperativity. X-ray crystallography and solid-state and solution nuclear magnetic resonance indicate that the overall helical bundle is formed from two tightly interacting pairs of helices, which form individual domains that interact weakly along a more dynamic interface. Vesicle flux experiments show that as Zn(2+) ions diffuse down their concentration gradients, protons are antiported. These experiments illustrate the feasibility of designing membrane proteins with predefined structural and dynamic properties. PMID- 25525247 TI - Recovery of large carnivores in Europe's modern human-dominated landscapes. AB - The conservation of large carnivores is a formidable challenge for biodiversity conservation. Using a data set on the past and current status of brown bears (Ursus arctos), Eurasian lynx (Lynx lynx), gray wolves (Canis lupus), and wolverines (Gulo gulo) in European countries, we show that roughly one-third of mainland Europe hosts at least one large carnivore species, with stable or increasing abundance in most cases in 21st-century records. The reasons for this overall conservation success include protective legislation, supportive public opinion, and a variety of practices making coexistence between large carnivores and people possible. The European situation reveals that large carnivores and people can share the same landscape. PMID- 25525249 TI - A designed supramolecular protein assembly with in vivo enzymatic activity. AB - The generation of new enzymatic activities has mainly relied on repurposing the interiors of preexisting protein folds because of the challenge in designing functional, three-dimensional protein structures from first principles. Here we report an artificial metallo-beta-lactamase, constructed via the self-assembly of a structurally and functionally unrelated, monomeric redox protein into a tetrameric assembly that possesses catalytic zinc sites in its interfaces. The designed metallo-beta-lactamase is functional in the Escherichia coli periplasm and enables the bacteria to survive treatment with ampicillin. In vivo screening of libraries has yielded a variant that displays a catalytic proficiency [(k(cat)/K(m))/k(uncat)] for ampicillin hydrolysis of 2.3 * 10(6) and features the emergence of a highly mobile loop near the active site, a key component of natural beta-lactamases to enable substrate interactions. PMID- 25525250 TI - Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation. AB - Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3. The role of the H3.3K27M mutation in tumorigenesis is not fully understood. Here, we use a human embryonic stem cell system to model this tumor. We show that H3.3K27M expression synergizes with p53 loss and PDGFRA activation in neural progenitor cells derived from human embryonic stem cells, resulting in neoplastic transformation. Genome wide analyses indicate a resetting of the transformed precursors to a developmentally more primitive stem cell state, with evidence of major modifications of histone marks at several master regulator genes. Drug screening assays identified a compound targeting the protein menin as an inhibitor of tumor cell growth in vitro and in mice. PMID- 25525251 TI - Promoter architecture dictates cell-to-cell variability in gene expression. AB - Variability in gene expression among genetically identical cells has emerged as a central preoccupation in the study of gene regulation; however, a divide exists between the predictions of molecular models of prokaryotic transcriptional regulation and genome-wide experimental studies suggesting that this variability is indifferent to the underlying regulatory architecture. We constructed a set of promoters in Escherichia coli in which promoter strength, transcription factor binding strength, and transcription factor copy numbers are systematically varied, and used messenger RNA (mRNA) fluorescence in situ hybridization to observe how these changes affected variability in gene expression. Our parameter free models predicted the observed variability; hence, the molecular details of transcription dictate variability in mRNA expression, and transcriptional noise is specifically tunable and thus represents an evolutionarily accessible phenotypic parameter. PMID- 25525252 TI - Detection of self-reactive CD8+ T cells with an anergic phenotype in healthy individuals. AB - Immunological tolerance to self requires naturally occurring regulatory T (Treg) cells. Yet how they stably control autoimmune T cells remains obscure. Here, we show that Treg cells can render self-reactive human CD8(+) T cells anergic (i.e., hypoproliferative and cytokine hypoproducing upon antigen restimulation) in vitro, likely by controlling the costimulatory function of antigen-presenting cells. Anergic T cells were naive in phenotype, lower than activated T cells in T cell receptor affinity for cognate antigen, and expressed several coinhibitory molecules, including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Using these criteria, we detected in healthy individuals anergic T cells reactive with a skin antigen targeted in the autoimmune disease vitiligo. Collectively, our results suggest that Treg cell-mediated induction of anergy in autoimmune T cells is important for maintaining self-tolerance. PMID- 25525253 TI - For the love of ferns. PMID- 25525256 TI - Evaluation of bilirubin displacement effect by acetaminophen in vitro. AB - BACKGROUND: The use of acetaminophen as a drug for pain control is expected to increase in the neonatal field. The displacement factor of acetaminophen in the reaction in the glucose oxidase peroxidase method is very high, but is also considered to be inaccurate based on physicochemical properties. METHOD: Unbound bilirubin was measured using the erythrocyte-bound bilirubin measurement method and glucose oxidase peroxidase method by the addition of acetaminophen or sulfisoxazole. The displacement factor was measured using glucose oxidase peroxidase method with the addition of tert-butyl-p-hydroxyanisole. RESULTS: Acetaminophen did not increase erythrocyte-bound bilirubin, and the addition of tert-butyl-p-hydroxyanisole lowered its displacement factor. On the other hand, sulfisoxazole increased erythrocyte-bound bilirubin, while tert-butyl-p hydroxyanisole did not change its displacement factor. CONCLUSION: Acetaminophen is an accelerator of the reaction in the glucose oxidase peroxidase method and does not displace bilirubin from human serum albumin. PMID- 25525255 TI - Evolution of oligomeric state through allosteric pathways that mimic ligand binding. AB - Evolution and design of protein complexes are almost always viewed through the lens of amino acid mutations at protein interfaces. We showed previously that residues not involved in the physical interaction between proteins make important contributions to oligomerization by acting indirectly or allosterically. In this work, we sought to investigate the mechanism by which allosteric mutations act, using the example of the PyrR family of pyrimidine operon attenuators. In this family, a perfectly sequence-conserved helix that forms a tetrameric interface is exposed as solvent-accessible surface in dimeric orthologs. This means that mutations must be acting from a distance to destabilize the interface. We identified 11 key mutations controlling oligomeric state, all distant from the interfaces and outside ligand-binding pockets. Finally, we show that the key mutations introduce conformational changes equivalent to the conformational shift between the free versus nucleotide-bound conformations of the proteins. PMID- 25525259 TI - Dimeric Structure of the Bacterial Extracellular Foldase PrsA. AB - Secretion of proteins into the membrane-cell wall space is essential for cell wall biosynthesis and pathogenicity in Gram-positive bacteria. Folding and maturation of many secreted proteins depend on a single extracellular foldase, the PrsA protein. PrsA is a 30-kDa protein, lipid anchored to the outer leaflet of the cell membrane. The crystal structure of Bacillus subtilis PrsA reveals a central catalytic parvulin-type prolyl isomerase domain, which is inserted into a larger composite NC domain formed by the N- and C-terminal regions. This domain architecture resembles, despite a lack of sequence conservation, both trigger factor, a ribosome-binding bacterial chaperone, and SurA, a periplasmic chaperone in Gram-negative bacteria. Two main structural differences are observed in that the N-terminal arm of PrsA is substantially shortened relative to the trigger factor and SurA and in that PrsA is found to dimerize in a unique fashion via its NC domain. Dimerization leads to a large, bowl-shaped crevice, which might be involved in vivo in protecting substrate proteins from aggregation. NMR experiments reveal a direct, dynamic interaction of both the parvulin and the NC domain with secretion propeptides, which have been implicated in substrate targeting to PrsA. PMID- 25525260 TI - Structural and inhibitory effects of hinge loop mutagenesis in serpin-2 from the malaria vector Anopheles gambiae. AB - Serpin-2 (SRPN2) is a key negative regulator of the melanization response in the malaria vector Anopheles gambiae. SRPN2 irreversibly inhibits clip domain serine proteinase 9 (CLIPB9), which functions in a serine proteinase cascade culminating in the activation of prophenoloxidase and melanization. Silencing of SRPN2 in A. gambiae results in spontaneous melanization and decreased life span and is therefore a promising target for vector control. The previously determined structure of SRPN2 revealed a partial insertion of the hinge region of the reactive center loop (RCL) into beta sheet A. This partial hinge insertion participates in heparin-linked activation in other serpins, notably antithrombin III. SRPN2 does not contain a heparin binding site, and any possible mechanistic function of the hinge insertion was previously unknown. To investigate the function of the SRPN2 hinge insertion, we developed three SRPN2 variants in which the hinge regions are either constitutively expelled or inserted and analyzed their structure, thermostability, and inhibitory activity. We determined that constitutive hinge expulsion resulted in a 2.7-fold increase in the rate of CLIPB9Xa inhibition, which is significantly lower than previous observations of allosteric serpin activation. Furthermore, we determined that stable insertion of the hinge region did not appreciably decrease the accessibility of the RCL to CLIPB9. Together, these results indicate that the partial hinge insertion in SRPN2 does not participate in the allosteric activation observed in other serpins and instead represents a molecular trade-off between RCL accessibility and efficient formation of an inhibitory complex with the cognate proteinase. PMID- 25525261 TI - The olfactomedin domain from gliomedin is a beta-propeller with unique structural properties. AB - All members of the olfactomedin (OLF) family have a conserved extracellular OLF domain, for which a structure has not been available. We present here the crystal structure of the OLF domain from gliomedin. Gliomedin is a protein expressed by Schwann cells in peripheral nerves, important for the formation of the nodes of Ranvier. Gliomedin interacts with neuronal cell adhesion molecules, such as neurofascin, but the structural details of the interaction are not known. The structure of the OLF domain presents a five-bladed beta-propeller fold with unusual geometric properties. The symmetry of the structure is not 5-fold, but rather reveals a twisted arrangement. The conserved top face of the gliomedin OLF domain is likely to be important for binding to neuronal ligands. Our results provide a structural basis for the functions of gliomedin in Schwann cells, enable the understanding of the role of the gliomedin OLF domain in autoimmune neuropathies, and unravel the locations of human disease-causing mutations in other OLF family members, including myocilin. PMID- 25525262 TI - Reduced sialylation impacts ventricular repolarization by modulating specific K+ channel isoforms distinctly. AB - Voltage-gated K(+) channels (Kv) are responsible for repolarizing excitable cells and can be heavily glycosylated. Cardiac Kv activity is indispensable where even minimal reductions in function can extend action potential duration, prolong QT intervals, and ultimately contribute to life-threatening arrhythmias. Diseases such as congenital disorders of glycosylation often cause significant cardiac phenotypes that can include arrhythmias. Here we investigated the impact of reduced sialylation on ventricular repolarization through gene deletion of the sialyltransferase ST3Gal4. ST3Gal4-deficient mice (ST3Gal4(-/-)) had prolonged QT intervals with a concomitant increase in ventricular action potential duration. Ventricular apex myocytes isolated from ST3Gal4(-/-) mice demonstrated depolarizing shifts in activation gating of the transient outward (Ito) and delayed rectifier (IKslow) components of K(+) current with no change in maximum current densities. Consistently, similar protein expression levels of the three Kv isoforms responsible for Ito and IKslow were measured for ST3Gal4(-/-) versus controls. However, novel non-enzymatic sialic acid labeling indicated a reduction in sialylation of ST3Gal4(-/-) ventricular Kv4.2 and Kv1.5, which contribute to Ito and IKslow, respectively. Thus, we describe here a novel form of regulating cardiac function through the activities of a specific glycogene product. Namely, reduced ST3Gal4 activity leads to a loss of isoform-specific Kv sialylation and function, thereby limiting Kv activity during the action potential and decreasing repolarization rate, which likely contributes to prolonged ventricular repolarization. These studies elucidate a novel role for individual glycogene products in contributing to a complex network of cardiac regulation under normal and pathologic conditions. PMID- 25525263 TI - New insights on the mechanism of quinoline-based DNA Methyltransferase inhibitors. AB - Among the epigenetic marks, DNA methylation is one of the most studied. It is highly deregulated in numerous diseases, including cancer. Indeed, it has been shown that hypermethylation of tumor suppressor genes promoters is a common feature of cancer cells. Because DNA methylation is reversible, the DNA methyltransferases (DNMTs), responsible for this epigenetic mark, are considered promising therapeutic targets. Several molecules have been identified as DNMT inhibitors and, among the non-nucleoside inhibitors, 4-aminoquinoline-based inhibitors, such as SGI-1027 and its analogs, showed potent inhibitory activity. Here we characterized the in vitro mechanism of action of SGI-1027 and two analogs. Enzymatic competition studies with the DNA substrate and the methyl donor cofactor, S-adenosyl-l-methionine (AdoMet), displayed AdoMet non competitive and DNA competitive behavior. In addition, deviations from the Michaelis-Menten model in DNA competition experiments suggested an interaction with DNA. Thus their ability to interact with DNA was established; although SGI 1027 was a weak DNA ligand, analog 5, the most potent inhibitor, strongly interacted with DNA. Finally, as 5 interacted with DNMT only when the DNA duplex was present, we hypothesize that this class of chemical compounds inhibit DNMTs by interacting with the DNA substrate. PMID- 25525264 TI - Matrix confinement plays a pivotal role in regulating neutrophil-generated tractions, speed, and integrin utilization. AB - Neutrophils are capable of switching from integrin-dependent motility on two dimensional substrata to integrin-independent motion following entry into the confined three-dimensional matrix of an afflicted tissue. However, whether integrins still maintain a regulatory role for cell traction generation and cell locomotion under the physical confinement of the three-dimensional matrix is unknown, and this is challenging to deduce from motility studies alone. Using three-dimensional traction force microscopy and a double hydrogel sandwich system, we determined the three-dimensional spatiotemporal traction forces of motile neutrophils at unprecedented resolution and show, for the first time, that entry into a highly confined space (2.5D) is a sufficient trigger to convert to integrin-independent migration. We find that integrins exert a significant regulatory role in determining the magnitude and spatial distribution of tractions and cell speed on confined cells. We also find that 90% of neutrophil tractions are in the out-of-plane axis, and this may be a fundamental element of neutrophil traction force generation. PMID- 25525265 TI - Positioning of cysteine residues within the N-terminal portion of the BST 2/tetherin ectodomain is important for functional dimerization of BST-2. AB - BST-2/tetherin is a cellular host factor capable of restricting the release of a variety of enveloped viruses, including HIV-1. Structurally, BST-2 consists of an N-terminal cytoplasmic domain, a transmembrane domain, an ectodomain, and a C terminal membrane anchor. The BST-2 ectodomain encodes three cysteine residues in its N-terminal half, each of which can contribute to the formation of cysteine linked dimers. We previously reported that any one of the three cysteine residues is sufficient to produce functional BST-2 dimers. Here we investigated the importance of cysteine positioning on the ectodomain for functional dimerization of BST-2. Starting with a cysteine-free monomeric form of BST-2, individual cysteine residues were reintroduced at various locations throughout the ectodomain. The resulting BST-2 variants were tested for expression, dimerization, surface presentation, and inhibition of HIV-1 virus release. We found significant flexibility in the positioning of cysteine residues, although the propensity to form cysteine-linked dimers generally decreased with increasing distance from the N terminus. Interestingly, all BST-2 variants, including the one lacking all three ectodomain cysteines, retained the ability to form non covalent dimers, and all of the BST-2 variants were efficiently expressed at the cell surface. Importantly, not all BST-2 variants capable of forming cysteine linked dimers were functional, suggesting that cysteine-linked dimerization of BST-2 is necessary but not sufficient for inhibiting virus release. Our results expose new structural constraints governing the functional dimerization of BST-2, a property essential to its role as a restriction factor tethering viruses to the host cell. PMID- 25525266 TI - Bivalent ligation of the collagen-binding modules of fibronectin by SFS, a non anchored bacterial protein of Streptococcus equi. AB - SFS is a non-anchored protein of Streptococcus equi subspecies equi that causes upper respiratory infection in horses. SFS has been shown to bind to fibronectin (FN) and block interaction of FN with type I collagen. We have characterized interactions of a recombinant 60-mer polypeptide, R1R2, with FN. R1R2 contains two copies of collagen-like 19-residue repeats. Experiments utilizing various FN fragments and epitope-mapped anti-FN monoclonal antibodies located the binding site to (8-9)FNI modules of the gelatin-binding domain. Fluorescence polarization and competitive enzyme-linked assays demonstrated that R1R2 binds preferentially to compact dimeric FN rather than monomeric constructs containing (8-9)FNI or a large dimeric FN construct that is constitutively in an extended conformation. In contrast to bacterial peptides that bind (2-5)FNI in addition to (8-9)FNI, R1R2 did not cause conformational extension of FN as assessed by a conformationally sensitive antibody. Equilibrium and stopped-flow binding assays and size exclusion chromatography were compatible with a two-step binding reaction in which each of the repeats of R1R2 interacts with one of the subunits of dimeric FN, resulting in a stable complex with a slow koff. In addition to not binding to type I collagen, the R1R2.FN complex incorporated less efficiently into extracellular matrix than free FN. Thus, R1R2 binds to FN utilizing features of compact soluble FN and in doing so interferes with the organization of the extracellular matrix. A similar bivalent binding strategy may underlie the collagen-FN interaction. PMID- 25525267 TI - Deletion of the collagen-specific molecular chaperone Hsp47 causes endoplasmic reticulum stress-mediated apoptosis of hepatic stellate cells. AB - Chronic liver injury, often caused by alcoholism and viral hepatitis, causes liver fibrosis via the induction of collagen production. In liver fibrosis, hepatic stellate cells (HSCs) are activated and transform into myofibroblasts, which actively produce and secrete collagen into the extracellular matrix. Hsp47 (heat shock protein 47) is a collagen-specific molecular chaperone that is essential for the maturation and secretion of collagen. Here, we used the Cre LoxP system to disrupt the Hsp47 gene in isolated HSCs from Hsp47 floxed mice. Immature type I procollagen accumulated and partially aggregated in Hsp47-KO HSCs. This accumulation was augmented when autophagy was inhibited, which induced expression of the endoplasmic reticulum (ER) stress-inducible proteins BiP (immunoglobulin heavy chain-binding protein) and Grp94 (94-kDa glucose-regulated protein). The inhibition of autophagy in Hsp47-KO HSCs also induced CHOP (CCAAT/enhancer-binding protein homologous protein), which is an ER stress induced transcription factor responsible for apoptosis. These data suggest that apoptosis is induced through ER stress by procollagen accumulation in Hsp47-KO HSCs when autophagy is inhibited. Thus, Hsp47 could be a promising therapeutic target in liver fibrosis. PMID- 25525268 TI - Bacteriophage SPP1 tail tube protein self-assembles into beta-structure-rich tubes. AB - The majority of known bacteriophages have long tails that serve for bacterial target recognition and viral DNA delivery into the host. These structures form a tube from the viral capsid to the bacterial cell. The tube is formed primarily by a helical array of tail tube protein (TTP) subunits. In phages with a contractile tail, the TTP tube is surrounded by a sheath structure. Here, we report the first evidence that a phage TTP, gp17.1 of siphophage SPP1, self-assembles into long tubes in the absence of other viral proteins. gp17.1 does not exhibit a stable globular structure when monomeric in solution, even if it was confidently predicted to adopt the beta-sandwich fold of phage lambda TTP. However, Fourier transform infrared and nuclear magnetic resonance spectroscopy analyses showed that its beta-sheet content increases significantly during tube assembly, suggesting that gp17.1 acquires a stable beta-sandwich fold only after self assembly. EM analyses revealed that the tube is formed by hexameric rings stacked helicoidally with the same organization and helical parameters found for the tail of SPP1 virions. These parameters were used to build a pseudo-atomic model of the TTP tube. The large loop spanning residues 40-56 is located on the inner surface of the tube, at the interface between adjacent monomers and hexamers. In line with our structural predictions, deletion of this loop hinders gp17.1 tube assembly in vitro and interferes with SPP1 tail assembly during phage particle morphogenesis in bacteria. PMID- 25525269 TI - Identification of significant amino acids in multiple transmembrane domains of human transient receptor potential ankyrin 1 (TRPA1) for activation by eudesmol, an oxygenized sesquiterpene in hop essential oil. AB - Transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable non selective cation channel that is activated by various noxious or irritant substances in nature, including spicy compounds. Many TRPA1 chemical activators have been reported; however, only limited information is available regarding the amino acid residues that contribute to the activation by non-electrophilic activators, whereas activation mechanisms by electrophilic ligands have been well characterized. We used intracellular Ca(2+) measurements and whole-cell patch clamp recordings to show that eudesmol, an oxygenated sesquiterpene present at high concentrations in the essential oil of hop cultivar Hallertau Hersbrucker, could activate human TRPA1. Gradual activation of inward currents with outward rectification by eudesmol was observed in human embryonic kidney-derived 293 cells expressing human TRPA1. This activation was completely blocked by a TRPA1 specific inhibitor, HC03-0031. We identified three critical amino acid residues in human TRPA1 in putative transmembrane domains 3, 4, and 5, namely threonine at 813, tyrosine at 840, and serine at 873, for activation by beta-eudesmol in a systematic mutational study. Our results revealed a new TRPA1 activator in hop essential oil and provide a novel insight into mechanisms of human TRPA1 activation by non-electrophilic chemicals. PMID- 25525270 TI - Toxicity of an alpha-pore-forming toxin depends on the assembly mechanism on the target membrane as revealed by single molecule imaging. AB - alpha-Pore-forming toxins (alpha-PFTs) are ubiquitous defense tools that kill cells by opening pores in the target cell membrane. Despite their relevance in host/pathogen interactions, very little is known about the pore stoichiometry and assembly pathway leading to membrane permeabilization. Equinatoxin II (EqtII) is a model alpha-PFT from sea anemone that oligomerizes and forms pores in sphingomyelin-containing membranes. Here, we determined the spatiotemporal organization of EqtII in living cells by single molecule imaging. Surprisingly, we found that on the cell surface EqtII did not organize into a unique oligomeric form. Instead, it existed as a mixture of oligomeric species mostly including monomers, dimers, tetramers, and hexamers. Mathematical modeling based on our data supported a new model in which toxin clustering happened in seconds and proceeded via condensation of EqtII dimer units formed upon monomer association. Furthermore, altering the pathway of EqtII assembly strongly affected its toxic activity, which highlights the relevance of the assembly mechanism on toxicity. PMID- 25525271 TI - Epidermal growth factor activates the Rho GTPase-activating protein (GAP) Deleted in Liver Cancer 1 via focal adhesion kinase and protein phosphatase 2A. AB - Deleted in Liver Cancer 1 (DLC1) is a RHO GTPase-activating protein (GAP) that negatively regulates RHO. Through its GAP activity, it modulates the actin cytoskeleton network and focal adhesion dynamics, ultimately leading to suppression of cell invasion and metastasis. Despite its presence in various structural and signaling components, little is known about how the activity of DLC1 is regulated at focal adhesions. Here we show that EGF stimulation activates the GAP activity of DLC1 through a concerted mechanism involving DLC1 phosphorylation by MEK/ERK and its subsequent dephosphorylation by protein phosphatase 2A (PP2A) and inhibition of focal adhesion kinase by MEK/ERK to allow the binding between DLC1 and PP2A. Phosphoproteomics and mutation studies revealed that threonine 301 and serine 308 on DLC1, known previously to be mutated in certain cancers, are required for DLC1-PP2A interaction and the subsequent activation of DLC1 upon their dephosphorylation. The intricate interplay of this "MEK/ERK-focal adhesion kinase-DLC1-PP2A" quartet provides a novel checkpoint in the spatiotemporal control of cell spreading and cell motility. PMID- 25525272 TI - Cytosolic Hsp60 can modulate proteasome activity in yeast. AB - Hsp60, an essential oligomeric molecular mitochondrial chaperone, has been subject to rigorous basic and clinical research. With yeast as a model system, we provide evidence for the ability of cytosolic yHsp60 to inhibit the yeast proteasome. (i) Following biological turnover of murine Bax (a proteasome substrate), we show that co-expression of cytosolic yHsp60 stabilizes Bax, enhances its association with mitochondria, and enhances its killing capacity. (ii) Expression of yHsp60 in the yeast cytosol (yHsp60c) inhibits degradation of a cytosolic protein DeltaMTS-Aco1 tagged with the degron SL17 (a ubiquitin proteasome substrate). (iii) Conditions under which Hsp60 accumulates in the cytosol (elevated Hsp60c or growth at 37 degrees C) correlate with reduced 20 S peptidase activity in proteasomes purified from cell extracts. (iv) Elevated yHsp60 in the cytosol correlate with accumulation of polyubiquitinated proteins. (v) According to 20 S proteasome pulldown experiments, Hsp60 is physically associated with proteasomes in extracts of cells expressing Hsp60c or grown at 37 degrees C. Even mutant Hsp60 proteins, lacking chaperone activity, were still capable of proteasome inhibition. The results support the hypothesis that localization of Hsp60 to the cytosol may modulate proteasome activity according to cell need. PMID- 25525273 TI - Structural basis for the disruption of the cerebral cavernous malformations 2 (CCM2) interaction with Krev interaction trapped 1 (KRIT1) by disease-associated mutations. AB - Familial cerebral cavernous malformations (CCMs) are predominantly neurovascular lesions and are associated with mutations within the KRIT1, CCM2, and PDCD10 genes. The protein products of KRIT1 and CCM2 (Krev interaction trapped 1 (KRIT1) and cerebral cavernous malformations 2 (CCM2), respectively) directly interact with each other. Disease-associated mutations in KRIT1 and CCM2 mostly result in loss of their protein products, although rare missense point mutations can also occur. From gene sequencing of patients known or suspected to have one or more CCMs, we discover a series of missense point mutations in KRIT1 and CCM2 that result in missense mutations in the CCM2 and KRIT1 proteins. To place these mutations in the context of the molecular level interactions of CCM2 and KRIT1, we map the interaction of KRIT1 and CCM2 and find that the CCM2 phosphotyrosine binding (PTB) domain displays a preference toward the third of the three KRIT1 NPX(Y/F) motifs. We determine the 2.75 A co-crystal structure of the CCM2 PTB domain with a peptide corresponding to KRIT1(NPX(Y/F)3), revealing a Dab-like PTB fold for CCM2 and its interaction with KRIT1(NPX(Y/F)3). We find that several disease-associated missense mutations in CCM2 have the potential to interrupt the KRIT1-CCM2 interaction by destabilizing the CCM2 PTB domain and that a KRIT1 mutation also disrupts this interaction. We therefore provide new insights into the architecture of CCM2 and how the CCM complex is disrupted in CCM disease. PMID- 25525275 TI - An atypical psbA gene encodes a sentinel D1 protein to form a physiologically relevant inactive photosystem II complex in cyanobacteria. AB - Photosystem II, a large membrane-bound enzyme complex in cyanobacteria and chloroplasts, mediates light-induced oxidation of water to molecular oxygen. The D1 protein of PSII, encoded by the psbA gene, provides multiple ligands for cofactors crucial to this enzymatic reaction. Cyanobacteria contain multiple psbA genes that respond to various physiological cues and environmental factors. Certain unicellular cyanobacterial cells, such as Cyanothece sp. ATCC 51142, are capable of nitrogen fixation, a highly oxygen-sensitive process, by separating oxygen evolution from nitrogen fixation using a day-night cycle. We have shown that c-psbA4, one of the five psbA orthologs in this cyanobacterium, is exclusively expressed during nighttime. Remarkably, the corresponding D1 isoform has replacements of a number of amino acids that are essential ligands for the catalytic Mn4CaO5 metal center for water oxidation by PSII. At least 30 cyanobacterial strains, most of which are known to have nitrogen fixing abilities, have similar psbA orthologs. We expressed the c-psbA4 gene from Cyanothece 51142 in a 4E-3 mutant strain of the model non-nitrogen-fixing cyanobacterium Synechocystis sp. PCC 6803, which lacks any psbA gene. The resultant strain could not grow photoautotrophically. Moreover, these Synechocystis 6803 cells were incapable of PSII-mediated oxygen evolution. Based on our findings, we have named this physiologically relevant, unusual D1 isoform sentinel D1. Sentinel D1 represents a new class of D1 protein that, when incorporated in a PSII complex, ensures that PSII cannot mediate water oxidation, thus allowing oxygen-sensitive processes such as nitrogen fixation to occur in cyanobacterial cells. PMID- 25525274 TI - Gonadotrope-specific deletion of Dicer results in severely suppressed gonadotropins and fertility defects. AB - Pituitary gonadotropins follicle-stimulating hormone and luteinizing hormone are heterodimeric glycoproteins expressed in gonadotropes. They act on gonads and promote their development and functions including steroidogenesis and gametogenesis. Although transcriptional regulation of gonadotropin subunits has been well studied, the post-transcriptional regulation of gonadotropin subunits is not well understood. To test if microRNAs regulate the hormone-specific gonadotropin beta subunits in vivo, we deleted Dicer in gonadotropes by a Cre-lox genetic approach. We found that many of the DICER-dependent microRNAs, predicted in silico to bind gonadotropin beta subunit mRNAs, were suppressed in purified gonadotropes of mutant mice. Loss of DICER-dependent microRNAs in gonadotropes resulted in profound suppression of gonadotropin-beta subunit proteins and, consequently, the heterodimeric hormone secretion. In addition to suppression of basal levels, interestingly, the post-gonadectomy-induced rise in pituitary gonadotropin synthesis and secretion were both abolished in mutants, indicating a defective gonadal negative feedback control. Furthermore, mutants lacking Dicer in gonadotropes displayed severely reduced fertility and were rescued with exogenous hormones confirming that the fertility defects were secondary to suppressed gonadotropins. Our studies reveal that DICER-dependent microRNAs are essential for gonadotropin homeostasis and fertility in mice. Our studies also implicate microRNAs in gonadal feedback control of gonadotropin synthesis and secretion. Thus, DICER-dependent microRNAs confer a new layer of transcriptional and post-transcriptional regulation in gonadotropes to orchestrate the hypothalamus-pituitary-gonadal axis physiology. PMID- 25525279 TI - How Johnson Fought the War on Poverty: The Economics and Politics of Funding at the Office of Economic Opportunity. AB - This article presents a quantitative analysis of the geographic distribution of spending through the 1964 Economic Opportunity Act (EOA). Using newly assembled state- and county-level data, the results show that the Johnson administration directed funding in ways consistent with the War on Poverty's rhetoric of fighting poverty and racial discrimination: poorer areas and those with a greater share of nonwhite residents received systematically more funding. In contrast to New Deal spending, political variables explain very little of the variation in EOA funding. The smaller role of politics may help explain the strong backlash against the War on Poverty's programs. PMID- 25525276 TI - SorLA complement-type repeat domains protect the amyloid precursor protein against processing. AB - SorLA is a neuronal sorting receptor that is genetically associated with Alzheimer disease. SorLA interacts directly with the amyloid precursor protein (APP) and affects the processing of the precursor, leading to a decreased generation of the amyloid-beta peptide. The SorLA complement-type repeat (CR) domains associate in vitro with APP, but the precise molecular determinants of SorLA.APP complex formation and the mechanisms responsible for the effect of binding on APP processing have not yet been elucidated. Here, we have generated protein expression constructs for SorLA devoid of the 11 CR-domains and for two SorLA mutants harboring substitutions of the fingerprint residues in the central CR-domains. We generated SH-SY5Y cell lines that stably express these SorLA variants to study the binding and processing of APP using co-immunoprecipitation and Western blotting/ELISAs, respectively. We found that the SorLA CR-cluster is essential for interaction with APP and that deletion of the CR-cluster abolishes the protection against APP processing. Mutation of identified fingerprint residues in the SorLA CR-domains leads to changes in the O-linked glycosylation of APP when expressed in SH-SY5Y cells. Our results provide novel information on the mechanisms behind the influence of SorLA activity on APP metabolism by controlling post-translational glycosylation in the Golgi, suggesting new strategies against amyloidogenesis in Alzheimer disease. PMID- 25525278 TI - The effectiveness of psychoeducation and systematic desensitization to reduce test anxiety among first-year pharmacy students. AB - OBJECTIVE: To analyze the effect of psychological intervention on reducing performance anxiety and the consequences of the intervention on first-year pharmacy students. METHODS: In this experimental study, 236 first-year undergraduate pharmacy students from a private university in Malaysia were approached between weeks 5 and 7 of their first semester to participate in the study. The completed responses for the Westside Test Anxiety Scale (WTAS), the Kessler Perceived Distress Scale (PDS), and the Academic Motivation Scale (AMS) were received from 225 students. Out of 225 students, 42 exhibited moderate to high test anxiety according to the WTAS (score ranging from 30 to 39) and were randomly placed into either an experiment group (n=21) or a waiting list control group (n=21). RESULTS: The prevalence of test anxiety among pharmacy students in this study was lower compared to other university students in previous studies. The present study's anxiety management of psychoeducation and systematic education for test anxiety reduced lack of motivation and psychological distress and improved grade point average (GPA). CONCLUSION: Psychological intervention helped significantly reduce scores of test anxiety, psychological distress, and lack of motivation, and it helped improve students' GPA. PMID- 25525280 TI - Valuing Diversity. AB - This paper explores the economics of diversity-enhancing policies. A model is proposed in which heterogeneous agents, distinguished by skill level and social identity, purchase productive opportunities in a competitive market. We analyze policies designed to raise the status of a disadvantaged identity group. When agent identity is contractible, efficient policy grants preferred access to slots but offers no direct assistance for acquiring skills. When identity is not contractible, efficient policy provides universal subsidies to skill development when the fraction of the disadvantaged group at the skill development margin is larger than their share at the slot assignment margin. PMID- 25525277 TI - Pigment interactions in light-harvesting complex II in different molecular environments. AB - Extraction of plant light-harvesting complex II (LHCII) from the native thylakoid membrane or from aggregates by the use of surfactants brings about significant changes in the excitonic circular dichroism (CD) spectrum and fluorescence quantum yield. To elucidate the cause of these changes, e.g. trimer-trimer contacts or surfactant-induced structural perturbations, we compared the CD spectra and fluorescence kinetics of LHCII aggregates, artificial and native LHCII-lipid membranes, and LHCII solubilized in different detergents or trapped in polymer gel. By this means we were able to identify CD spectral changes specific to LHCII-LHCII interactions, at (-)-437 and (+)-484 nm, and changes specific to the interaction with the detergent n-dodecyl-beta-maltoside (beta-DM) or membrane lipids, at (+)-447 and (-)-494 nm. The latter change is attributed to the conformational change of the LHCII-bound carotenoid neoxanthin, by analyzing the CD spectra of neoxanthin-deficient plant thylakoid membranes. The neoxanthin specific band at (-)-494 nm was not pronounced in LHCII in detergent-free gels or solubilized in the alpha isomer of DM but was present when LHCII was reconstituted in membranes composed of phosphatidylcholine or plant thylakoid lipids, indicating that the conformation of neoxanthin is sensitive to the molecular environment. Neither the aggregation-specific CD bands, nor the surfactant-specific bands were positively associated with the onset of fluorescence quenching, which could be triggered without invoking such spectral changes. Significant quenching was not active in reconstituted LHCII proteoliposomes, whereas a high degree of energetic connectivity, depending on the lipid:protein ratio, in these membranes allows for efficient light harvesting. PMID- 25525281 TI - When Do Laws Matter? National Minimum-Age-of-Marriage Laws, Child Rights, and Adolescent Fertility, 1989-2007. AB - Using the case of adolescent fertility, we ask the questions of whether and when national laws have an effect on outcomes above and beyond the effects of international law and global organizing. To answer these questions, we utilize a fixed-effect time-series regression model to analyze the impact of minimum-age-of marriage laws in 115 poor- and middle-income countries from 1989 to 2007. We find that countries with strict laws setting the minimum age of marriage at 18 experienced the most dramatic decline in rates of adolescent fertility. Trends in countries that set this age at 18 but allowed exceptions (for example, marriage with parental consent) were indistinguishable from countries that had no such minimum-age-of-marriage law. Thus, policies that adhere strictly to global norms are more likely to elicit desired outcomes. The article concludes with a discussion of what national law means in a diffuse global system where multiple actors and institutions make the independent effect of law difficult to identify. PMID- 25525282 TI - Poor Families Striving to Save in Matched Children's Savings Accounts: Findings from a Randomized Experimental Design in Uganda. AB - This study examines participants' savings in children's savings accounts (CSAs) set up for AIDS-orphaned children ages 10-15 in Uganda. Using a cluster randomized experimental design, we examine the extent to which families participating in a CSA program report more savings than their counterparts not participating in the program, explore the extent to which families who participate in the CSA program report using formal financial institutions compared with families who do not have a CSA, and consider whether families participating in the CSA program bring new money into the CSA or whether they reshuffle existing household assets. We find that participating in a CSA increased families' likelihood to report having saved money. However, our results show no intervention effect either on the amount of self-reported savings or on the likelihood of using formal financial institutions. Further research is needed to understand whether use of a CSA helps families generate new wealth. PMID- 25525283 TI - The Effect of Fertility Reduction on Economic Growth. AB - We assess quantitatively the effect of exogenous reductions in fertility on output per capita. Our simulation model allows for effects that run through schooling, the size and age structure of the population, capital accumulation, parental time input into child-rearing, and crowding of fixed natural resources. The model is parameterized using a combination of microeconomic estimates, data on demographics and natural resource income in developing countries, and standard components of quantitative macroeconomic theory. We apply the model to examine the effect of a change in fertility from the UN medium-variant to the UN low variant projection, using Nigerian vital rates as a baseline. For a base case set of parameters, we find that such a change would raise output per capita by 5.6 percent at a horizon of 20 years, and by 11.9 percent at a horizon of 50 years. PMID- 25525284 TI - Matching With Doses in an Observational Study of a Media Campaign Against Drug Abuse. AB - Multivariate matching with doses of treatment differs from the treatment-control matching in three ways. First, pairs must not only balance covariates, but also must differ markedly in dose. Second, any two subjects may be paired, so that the matching is nonbipartite, and different algorithms are required. Finally, a propensity score with doses must be used in place of the conventional propensity score. We illustrate multivariate matching with doses using pilot data from a media campaign against drug abuse. The media campaign is intended to change attitudes and intentions related to illegal drugs, and the evaluation compares stated intentions among ostensibly comparable teens who reported markedly different exposures to the media campaign. PMID- 25525285 TI - Can We Measure Immigrants' Legal Status? Lessons from Two U.S. Surveys. AB - This research note examines response and allocation rates for legal status questions asked in publicly available U.S. surveys to address worries that the legal status of immigrants cannot be reliably measured. Contrary to such notions, we find that immigrants' response rates to questions about legal status are typically not higher than response rates to other immigration-related questions, such as country of birth and year of immigration. Further exploration of two particular surveys - the Los Angeles Family and Neighborhood Survey (LAFANS) and the Survey of Income and Program Participation (SIPP) - reveals that these data sources produce profiles of the unauthorized immigrant population that compare favorably to independently estimated profiles. We also find in the case of the SIPP that the introduction of legal status questions does not appear to have an appreciable "chilling effect" on the subsequent survey participation of unauthorized immigrant respondents. Based on the results, we conclude that future data collection efforts should include questions about legal status in order to (a) improve models of immigrant incorporation and (b) better position assimilation research to inform policy discussions. PMID- 25525288 TI - Social-Ecological Changes in a Quilombola Community in the Atlantic Forest of Southeastern Brazil. AB - Through a combined adaptive cycle and political ecology approach, this article explores how the Afro-Brazilian Quilombolas of Bombas, living inside the protected area of PETAR, respond to and shape social-ecological changes in the Atlantic Forest. Field data reveal that both environmental restrictions and social policies of state transfer payments and food packages have contributed to decreased engagement in agricultural practices, loss of traditional knowledge, and reduced agro-biodiversity. The claim to land rights based on a Quilombola identity and recent negotiations with forest authorities insinuate a shift of this trend. Contrary to dominant conservation narratives, the findings indicate that small-scale shifting cultivation practices by the Quilombolas have the potential to increase structural ecological complexity of the Atlantic Forest. The article therefore argues that legalization of settlement and subsistence activities is important not only for livelihood security and social cohesion of Bombas inhabitants, but also possibly for biodiversity conservation. PMID- 25525286 TI - High SHIP2 expression indicates poor survival in colorectal cancer. AB - SH2-containing inositol 5'-phosphatase 2 (SHIP2), which generally regulates insulin signaling, cytoskeleton remodeling, and receptor endocytosis, has been suggested to play a significant role in tumor development and progression. However, the associations between SHIP2 expression and the clinical features to evaluate its clinicopathologic significance in colorectal cancer (CRC) have not been determined yet. In the present study, one-step quantitative real-time polymerase chain reaction (qPCR) test and immunohistochemistry (IHC) analysis with CRC tissue microarrays (TMA) were employed to evaluate the mRNA and protein expression of SHIP2 in CRC. The results showed that SHIP2 expression in the mRNA and protein levels was significantly higher in CRC tissues than that in corresponding noncancerous tissues (both P < 0.05). The expression of SHIP2 protein in CRC was related to lymph node metastasis (P = 0.036), distant metastasis (P = 0.001), and overall survival (P = 0.009). Kaplan-Meier method and Cox multifactor analysis suggested that high SHIP2 protein level (P = 0.040) and positive distant metastasis (P = 0.048) were critically associated with the unfavorable survival of CRC patients. The findings suggested that SHIP2 may be identified as a useful prognostic marker in CRC and targeting CRC may provide novel strategy for CRC treatment. PMID- 25525289 TI - Ecological restoration in a cultural landscape: conservationist and Chagossian approaches to controlling the 'coconut chaos' on the Chagos Archipelago. PMID- 25525287 TI - Haptoglobin duplicon, hemoglobin, and vitamin C: analyses in the british women's heart and health study and Caerphilly prospective study. AB - BACKGROUND: Haptoglobin acts as an antioxidant by limiting peroxidative tissue damage by free hemoglobin. The haptoglobin gene allele Hp2 comprises a 1.7 kb partial duplication. Relative to allele Hp1, Hp2 carriers form protein multimers, suboptimal for hemoglobin scavenging. OBJECTIVE: To examine the association of haptoglobin genotype with a range of phenotypes, with emphasis on vitamin C and hemoglobin levels. METHODS: We applied a quantitative PCR assay for the duplication junction to two population cohorts including 2747 British women and 1198 British men. We examined the association of haptoglobin duplicon copy number with hemoglobin and vitamin C and used the copy number to complete a phenome scan. RESULTS: Hemoglobin concentrations were greater in those with Hp2,2 genotype, in women only (Hp1,1 13.45 g/dL, Hp1,2 13.49 g/dL, Hp2,2 13.61 g/dL; P = 0.002), though statistically there was no evidence of a difference between the sexes (z value = 1.2, P = 0.24). Haptoglobin genotype was not associated with vitamin C or any other phenotype in either cohort. CONCLUSIONS: Our results do not support association of haptoglobin genotype with vitamin C or with other phenotypes measured in two population cohorts. The apparent association between haptoglobin genotype and hemoglobin in the women's cohort merits further investigation. PMID- 25525290 TI - UV resonance Raman study of TrpZip2 and related peptides: pi-pi interactions of tryptophan. AB - Aromatic interactions are important stabilizing forces in proteins but are difficult to detect in the absence of high-resolution structures. Ultraviolet resonance Raman spectroscopy is used to probe the vibrational signatures of aromatic interactions in TrpZip2, a synthetic beta-hairpin peptide that is stabilized by edge-to-face and face-to-face tryptophan pi-pi interactions. The vibrational markers of isolated edge-to-face pi-pi interactions are investigated in the related beta-hairpin peptide W2W11. The bands that comprise the Fermi doublet exhibit systematic shifts in position and intensity for TrpZip2 and W2W11 relative to the model peptide, W2W9, which does not form aromatic interactions. Additionally, hypochromism of the Bb absorption band of tryptophan in TrpZip2 leads to a decrease in the relative Raman cross-sections of Bb-coupled Raman bands. These results reveal spectral markers for stabilizing tryptophan pi-pi interactions and indicate that ultraviolet resonance Raman may be an important tool for the characterization of these biological forces. PMID- 25525291 TI - Daily Spiritual Experiences and Adolescent Treatment Response. AB - The purpose of this study is to explore changes in belief orientation during treatment and the impact of increased daily spiritual experiences (DSE) on adolescent treatment response. One-hundred ninety-five adolescents court-referred to a 2-month residential treatment program were assessed at intake and discharge. Forty percent of youth who entered treatment as agnostic or atheist identified themselves as spiritual or religious at discharge. Increased DSE was associated with greater likelihood of abstinence, increased prosocial behaviors, and reduced narcissistic behaviors. Results indicate a shift in DSE that improves youth self care and care for others that may inform intervention approaches for adolescents with addiction. PMID- 25525292 TI - Text Messaging as an Adjunct to CBT in Low-Income Populations: A Usability and Feasibility Pilot Study. AB - This article outlines the development and usability-feasibility testing of an automated text-messaging adjunct to cognitive- behavioral therapy (CBT) for depression in a public sector clinic serving low-income patients. The text messaging adjunct is aimed at increasing homework adherence, improving self awareness, and helping track patient progress. Daily text messages were sent to patients, inquiring about their mood. Additional daily messages corresponded to themes of a manualized group CBT intervention. These included (1) thought tracking (both positive and negative), (2) tracking of pleasant activities, (3) tracking of positive and negative contacts, and (4) tracking of physical well being. We tested the adjunct in 2 CBT groups (1 English & 1 Spanish) consisting of 12 patients total during and after treatment. Participants responded at a rate of 65% to text messages, and they reported overall positive experiences. We propose that text messaging has the potential to improve mental health care broadly, and among low-income populations specifically, with cost-effective means. PMID- 25525293 TI - "A safe way to explore": Reframing risk on the Internet amidst young gay men's search for identity. AB - Internet use provides a vital opportunity for sexual minority youth to learn about sexual desires and pursue partnerships otherwise publically stigmatized. Researchers, however, have portrayed the Internet as an inherently risky venue for HIV/STI transmission among young gay men (YGM). We therefore investigated how YGM use the Internet during adolescence and emerging adulthood. In the course of 34 in-depth, semi-structured interviews with a sample of self-identified YGM, 18 24 years of age, we inquired about initial experiences of online dating. We found that YGM benefit online through exploration of their sexual identities, while simultaneously encountering and negotiating sources of risk. In examining YGM's perceptions of risk, we hope to reach a greater understanding of the opportunities for HIV prevention and health promotion among YGM. PMID- 25525294 TI - Assessing small non-zero perceptions of chance: The case of H1N1 (swine) flu risks. AB - Feelings of unwarranted invulnerability, seen in judgments of 0% risk, can reflect misunderstandings of risk and risk behaviors, suggesting increased need for risk communication. However, judgments of 0% risk may be given by individuals who feel invulnerable, and by individuals who are rounding from small non-zero probabilities. We examined the effect of allowing participants to give more precise responses in the 0-1% range on the validity of reported probability judgments. Participants assessed probabilities for getting H1N1 influenza and dying from it conditional on infection, using a 0-100% visual linear scale. Those responding in the 0-1% range received a follow-up question with more options in that range. This two-step procedure reduced the use of 0% and increased the resolution of responses in the 0-1% range. Moreover, revised probability responses improved predictions of attitudes and self-reported behaviors. Hence, our two-step procedure allows for more precise and more valid measurement of perceived invulnerability. PMID- 25525295 TI - Parent-Child Conversations About Letters and Pictures. AB - Learning about letters, and how they differ from pictures, is one important aspect of a young child's print awareness. To test the hypothesis that parent speech provides children with information about these differences, we studied parent-child conversations in CHILDES (MacWhinney, 2000). We found that parents talk to their young children about letters, differentiating them from pictures, by 1-2 years of age and that some of these conversational patterns change across the preschool years in ways that emphasize important features of letters, such as their shape. We also found that children talk about letters and pictures in distinct ways, suggesting an implicit understanding of some of the differences between letters and pictures at an early age. Some differences in parent-child conversations about letters were found as a function of socioeconomic status: Lower SES families appeared to focus more on alphabetic order than higher SES families. The general letter knowledge expressed in these conversations suggests that everyday interactions are an important component of the home literacy environment and that they differ, in some respects, as a function of child age and family background. PMID- 25525296 TI - Counterfactual thinking in Tourette's syndrome: a study using three measures. AB - Pathophysiological evidence suggests an involvement of frontostriatal circuits in Tourette syndrome (TS) and cognitive abnormalities have been detected in tasks sensitive to cognitive deficits associated with prefrontal damage (verbal fluency, planning, attention shifting, working memory, cognitive flexibility, and social reasoning). A disorder in counterfactual thinking (CFT), a behavioural executive process linked to the prefrontal cortex functioning, has not been investigated in TS. CFT refers to the generation of a mental simulation of alternatives to past factual events, actions, and outcomes. It is a pervasive cognitive feature in everyday life and it is closely related to decision-making, planning, problem-solving, and experience-driven learning-cognitive processes that involve wide neuronal networks in which prefrontal lobes play a fundamental role. Clinical observations in patients with focal prefrontal lobe damage or with neurological and psychiatric diseases related to frontal lobe dysfunction (e.g., Parkinson's disease, Huntington's disease, and schizophrenia) show counterfactual thinking impairments. In this work, we evaluate the performance of CFT in a group of patients with Tourette's syndrome compared with a group of healthy participants. Overall results showed no statistical differences in counterfactual thinking between TS patients and controls in the three counterfactual measures proposed. The possible explanations of this unexpected result are discussed below. PMID- 25525297 TI - Anabolic properties of high mobility group box protein-1 in human periodontal ligament cells in vitro. AB - High mobility group box protein-1 (HMGB1) is mainly recognized as a chemoattractant for macrophages in the initial phase of host response to pathogenic stimuli. However, recent findings provide evidence for anabolic properties in terms of enhanced proliferation, migration, and support of wound healing capacity of mesenchymal cells suggesting a dual role of the cytokine in the regulation of immune response and subsequent regenerative processes. Here, we examined potential anabolic effects of HMGB1 on human periodontal ligament (PDL) cells in the regulation of periodontal remodelling, for example, during orthodontic tooth movement. Preconfluent human PDL cells (hPDL) were exposed to HMGB1 protein and the influence on proliferation, migration, osteogenic differentiation, and biomineralization was determined by MTS assay, real time PCR, immunofluorescence cytochemistry, ELISA, and von Kossa staining. HMGB1 protein increased hPDL cell proliferation, migration, osteoblastic marker gene expression, and protein production as well as mineralized nodule formation significantly. The present findings support the dual character of HMGB1 with anabolic therapeutic potential that might support the reestablishment of the structural and functional integrity of the periodontium following periodontal trauma such as orthodontic tooth movement. PMID- 25525299 TI - Control and resolution mechanisms of the inflammatory response. PMID- 25525298 TI - Osteopontin expression in the brain triggers localized inflammation and cell death when immune cells are activated by pertussis toxin. AB - Upregulation of osteopontin (OPN) is a characteristic of central nervous system pathologies. However, the role of OPN in inflammation is still controversial, since it can both prevent cell death and induce the migration of potentially damaging inflammatory cells. To understand the role of OPN in inflammation and cell survival, we expressed OPN, utilizing an adenoviral vector, in the caudoputamen of mice deficient in OPN, using beta-galactosidase- (beta-gal-) expressing vector as control. The tissue pathology and the expression of proinflammatory genes were compared in both treatments. Interestingly, inflammatory infiltrate was only found when the OPN-vector was combined with a peripheral treatment with pertussis toxin (Ptx), which activated peripheral cells to express the OPN receptor CD44v6. Relative to beta-gal, OPN increased the levels of inflammatory markers, including IL13Ralpha1, CXCR3, and CD40L. In Ptx treated OPN KOs, apoptotic TUNEL+ cells surrounding the OPN expression site increased, compared to beta-gal. Together, these results show that local OPN expression combined with a peripheral inflammatory stimulus, such as Ptx, may be implicated in the development of brain inflammation and induction of cell death, by driving a molecular pattern characteristic of cytotoxicity. These are characteristics of inflammatory pathologies of the CNS in which OPN upregulation is a hallmark. PMID- 25525302 TI - Clinical significance of IL-23 regulating IL-17A and/or IL-17F positive Th17 cells in chronic periodontitis. AB - OBJECTIVE: To investigate the expression level and clinical significance of (IL 17A(+) and/or IL-17F(+)) Th17 cells under IL-23 regulation in patients of chronic periodontitis (CP) and healthy controls (HC). MATERIALS AND METHODS: The whole peripheral blood samples were collected from 30 CP patients and 25 healthy controls. Flow cytometry was used to test the (IL-17A(+) and/or IL-17F(+)) Th17 expression level. Recombinant human IL-23 (rhIL-23) was used to detect Th17 differentiation and expansion. Correlation coefficient analysis between Th17 expression level and clinical parameters was analyzed by SPSS software. RESULTS: Flow cytometry results showed that IL-17A(+)IL-17F(-) and IL-17A(-)IL-17F(+) Th17 were both increased in CP group than in HC group (P < 0.01), while, under recombinant human IL-23 (rhIL-23) stimulation, the number of IL-17A(+)IL-17F(-) Th17 cells was significantly increased in both CP and HC groups (P < 0.01). Interestingly, IL-17A(-)IL-17F(+) Th17 cells were only increased in CP group after rhIL-23 stimulation. Additionally, correlation coefficient analysis showed significant correlation between IL-17A(+)IL-17F(-) Th17 cell and attachment loss or probing depth (P < 0.05). CONCLUSIONS: This study indicates that both the IL 17A(+)IL-17F(-) and IL-17A(-)IL-17F(+) Th17 cells may be involved in pathogenesis of periodontitis. The role of these Th17 cells in the disease pathogenesis needs to be further investigated. PMID- 25525303 TI - GSK-3beta inhibition attenuates CLP-induced liver injury by reducing inflammation and hepatic cell apoptosis. AB - Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK ) 3beta is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3beta inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3beta in C57BL/6 mice. GSK-3beta was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3beta also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3beta inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF kappaB) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3beta inhibition reduced inflammatory cytokine production via modulation of NF-kappaB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3beta blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-kappaB and CREB activity and suppression of hepatic apoptosis. PMID- 25525300 TI - Collaborative action of Toll-like and NOD-like receptors as modulators of the inflammatory response to pathogenic bacteria. AB - Early sensing of pathogenic bacteria by the host immune system is important to develop effective mechanisms to kill the invader. Microbial recognition, activation of signaling pathways, and effector mechanisms are sequential events that must be highly controlled to successfully eliminate the pathogen. Host recognizes pathogens through pattern-recognition receptors (PRRs) that sense pathogen-associated molecular patterns (PAMPs). Some of these PRRs include Toll like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors (NLRs), retinoic acid-inducible gene-I- (RIG-I-) like receptors (RLRs), and C type lectin receptors (CLRs). TLRs and NLRs are PRRs that play a key role in recognition of extracellular and intracellular bacteria and control the inflammatory response. The activation of TLRs and NLRs by their respective ligands activates downstream signaling pathways that converge on activation of transcription factors, such as nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1) or interferon regulatory factors (IRFs), leading to expression of inflammatory cytokines and antimicrobial molecules. The goal of this review is to discuss how the TLRs and NRLs signaling pathways collaborate in a cooperative or synergistic manner to counteract the infectious agents. A deep knowledge of the biochemical events initiated by each of these receptors will undoubtedly have a high impact in the design of more effective strategies to control inflammation. PMID- 25525301 TI - Control of the inflammatory response mechanisms mediated by natural and induced regulatory T-cells in HCV-, HTLV-1-, and EBV-associated cancers. AB - Virus infections are involved in chronic inflammation and, in some cases, cancer development. Although a viral infection activates the immune system's response that eradicates the pathogen mainly through inflammatory mechanisms, it is now recognized that this inflammatory condition is also favorable to the development of tumors. Indeed, it is well described that viruses, such as hepatitis C virus (HCV), Epstein Barr virus (EBV), human papillomavirus (HPV) or human T-cell lymphotropic virus type-1 (HTLV-1), are important risk factors for tumor malignancies. The inflammatory response is a fundamental immune mechanism which involves several molecular and cellular components consisting of cytokines and chemokines that are released by various proinflammatory cells. In parallel to this process, some endogenous recruited components release anti-inflammatory mediators to restore homeostasis. The development of tools and strategies using viruses to hijack the immune response is mostly linked to the presence of regulatory T-cells (Treg) that can inhibit inflammation and antiviral responses of other effector cells. In this review, we will focus on current understanding of the role of natural and induced Treg in the control and the resolution of inflammatory response in HCV-, HTLV-1-, and EBV-associated cancers. PMID- 25525304 TI - Immunomodulatory effects of polysaccharide from marine fungus Phoma herbarum YS4108 on T cells and dendritic cells. AB - YCP, as a kind of natural polysaccharides from the mycelium of marine filamentous fungus Phoma herbarum YS4108, has great antitumor potential via enhancement of host immune response, but little is known about the molecular mechanisms. In the present study, we mainly focused on the effects and mechanisms of YCP on the specific immunity mediated by dendritic cells (DCs) and T cells. T cell /DC activation-related factors including interferon- (IFN-) gamma, interleukin-12 (IL 12), and IL-4 were examined with ELISA. Receptor knock-out mice and fluorescence activated cell sorting are used to analyze the YCP-binding receptor of T cells and DCs. RT-PCR is utilized to measure MAGE-A3 for analyzing the tumor-specific killing effect. In our study, we demonstrated YCP can provide the second signal for T cell activation, proliferation, and IFN-gamma production through binding to toll-like receptor- (TLR-) 2 and TLR-4. YCP could effectively promote IL-12 secretion and expression of markers (CD80, CD86, and MHC II) via TLR-4 on DCs. Antigen-specific immunity against mouse melanoma cells was strengthened through the activation of T cells and the enhancement of capacity of DCs by YCP. The data supported that YCP can exhibit specific immunomodulatory capacity mediated by T cells and DCs. PMID- 25525305 TI - Serum amyloid A as a marker of persistent inflammation and an indicator of cardiovascular and renal involvement in patients with rheumatoid arthritis. AB - OBJECTIVES: Rheumatoid arthritis (RA) is a systemic, inflammatory disease. Serum amyloid A (SAA) is an acute-phase protein, involved in pathogenesis of atherosclerosis. The aim of the study was to assess serum concentration of SAA in RA patients, with reference to other inflammatory parameters and markers of extra articular involvement. METHODS: The study population consisted of 140 RA patients, low/moderate disease activity (L/MDA) in 98 (70%) patients and high disease activity (HDA) in 42 (30%). Comprehensive clinical and laboratory assessment was performed with evaluation of electrocardiogram and carotid intima media thickness. RESULTS: The mean SAA concentration [327.0 (263.4) mg/L] was increased highly above the normal value, even in patients with L/MDA. Simultaneously, SAA was significantly higher in patients with HDA versus L/MDA. The mean SAA concentration was significantly higher in patients treated with glucocorticoids, was inversely associated with QTc duration, and was markedly higher in patients with atherosclerotic plaques, emphasizing increased CV risk. SAA was significantly higher in patients with increased cystatin-C level. CONCLUSIONS: In RA patients, high serum SAA concentration was strongly associated with activity of the disease and risk of CV and renal involvement. Recurrent assessment of SAA may facilitate searching patients with persistent inflammation and risk of extra-articular complications. PMID- 25525306 TI - Incident reporting and learning in radiation oncology: Need of the hour. PMID- 25525307 TI - Acceptance criteria for flattening filter-free photon beam from standard medical electron linear accelerator: AERB task group recommendations. AB - Medical electron linear accelerators with the capability of generating unflat photon (flattening filter-free, FFF) beams are also available commercially for clinical applications in radiotherapy. However, the beam characteristics evaluation criteria and parameters are not yet available for such photon beams. Atomic Energy Regulatory Board (AERB) of India constituted a Task Group comprising experts from regulatory agency, advisory body/research and technical institutions, and clinical radiotherapy centers in the country to evolve and recommend the acceptance criteria for the flattening filter-free (FFF) photon beams. The Task Group thoroughly reviewed the literature and inputs of the manufactures/suppliers of the FFF linac and recommended a set of dosimetry parameters for evaluating the characteristics of the unflat photon beam. The recommendations included the evaluation of quality index, degree of unflatness, difference in percentage surface dose between flat and unflat photon beams, percentage depth dose at 10 cm depth, off-axis-ratios and radiation beam penumbra. The recommended parameters were evaluated for FFF photon beams generated by three different models of the linac, and it was observed that recommended evaluation methods are simple and easy to be implemented with the existing dosimetry and quality assurance infrastructure of the linac facilities of the radiotherapy departments. Recommendations were also made for periodic quality control check of the unflat photon beams and constancy evaluation in the beam characteristics. PMID- 25525308 TI - Dosimetric impact of number of treatment fields in uniform scanning proton therapy planning of lung cancer. AB - The main purpose of this study was to perform a treatment planning study for lung cancer comparing 2-field (2F) versus 3-field (3F) techniques in uniform scanning proton therapy (USPT). Ten clinically approved lung cancer treatment plans delivered using USPT at our proton center were included in this retrospective study. All 10 lung cases included 4D computed tomography (CT) simulation. The delineation of target volumes was done based on the maximum intensity projection (MIP) images. Both the 3F and 2F treatment plans were generated for the total dose of 74 cobalt-gray-equivalent (CGE) with a daily dose of 2 CGE. 3F plan was generated by adding an extra beam in the 2F plan. Various dosimetric parameters between 2F and 3F plans were evaluated. 3F plans produced better target coverage and conformality as well as lower mean dose to the lung, with absolute difference between 3F and 2F plans within 2%. In contrast, the addition of third beam led to increase of low-dose regions (V20 and V5) in the lung in 3F plans compared to the ones in 2F plans with absolute difference within 2%. Maximum dose to the spinal cord was lower in 2F plans. Mean dose to the heart and esophagus were comparable in both 3F and 2F plans. In conclusion, the 3F technique in USPT produced better target coverage and conformality, but increased the low-dose regions in the lung when compared to 2F technique. PMID- 25525309 TI - Results of 1 year of clinical experience with independent dose calculation software for VMAT fields. AB - It is widely accepted that a redundant independent dose calculation (RIDC) must be included in any treatment planning verification procedure. Specifically, volumetric modulated arc therapy (VMAT) technique implies a comprehensive quality assurance (QA) program in which RIDC should be included. In this paper, the results obtained in 1 year of clinical experience are presented. Eclipse from Varian is the treatment planning system (TPS), here in use. RIDC were performed with the commercial software; Diamond((r)) (PTW) which is capable of calculating VMAT fields. Once the plan is clinically accepted, it is exported via Digital Imaging and Communications in Medicine (DICOM) to RIDC, together with the body contour, and then a point dose calculation is performed, usually at the isocenter. A total of 459 plans were evaluated. The total average deviation was 0.3 +/- 1.8% (one standard deviation (1SD)). For higher clearance the plans were grouped by location in: Prostate, pelvis, abdomen, chest, head and neck, brain, stereotactic radiosurgery, lung stereotactic body radiation therapy, and miscellaneous. The highest absolute deviation was -0.8 +/- 1.5% corresponding to the prostate. A linear fit between doses calculated by RIDC and by TPS produced a correlation coefficient of 0.9991 and a slope of 1.0023. These results are very close to those obtained in the validation process. This agreement led us to consider this RIDC software as a valuable tool for QA in VMAT plans. PMID- 25525310 TI - Neutron dose estimation via LET spectrometry using CR-39 detector for the reaction (9)Be (p, n). AB - CR-39 detectors, widely used for neutron dosimetry in accelerator radiation environment, have also been applied in tissue microdosimetry by generating the linear energy transfer (LET) spectrum. In this work, the neutron dose has been estimated via LET spectrometry for (9)Be (p, n) reaction which is useful for personnel monitoring around particle accelerators and accelerator based therapy facilities. Neutrons were generated by the interaction of protons of 6 different energies from 4-24 MeV with a thick Be target. The LET spectra were obtained from the major and minor radii of each track and the thickness of removed surface. From the LET spectra, the absorbed dose (D LET) and the dose equivalent (H LET) were estimated using Q-L relationship as given by International Commission on Radiological Protection (ICRP) 60. The track density in CR-39 detector and hence the neutron yield was found to be increasing with the increase in projectile (proton) energy. Similar observations were also obtained for absorbed dose (D LET) and dose equivalents (H LET). PMID- 25525311 TI - Influence of increment of gantry angle and number of arcs on esophageal volumetric modulated arc therapy planning in Monaco planning system: A planning study. AB - The objective of this study was to analyze the influence of the increment of gantry angle and the number of arcs on esophageal volumetric modulated arc therapy plan. All plans were done in Monaco planning system for Elekta Synergy linear accelerator with 80 multileaf collimator (MLC). Volumetric modulated arc therapy (VMAT) plans were done with different increment of gantry angle like 15 degrees , 20 degrees , 30 degrees and 40 degrees . The remaining parameters were similar for all the plans. The results were compared. To compare the plan quality with number of arcs, VMAT plans were done with single and dual arc with increment of gantry angle of 20 degrees . The dose to gross tumor volume (GTV) for 60 Gy and planning target volume (PTV) for 48 Gy was compared. The dosimetric parameters D98%, D95%, D50% and Dmax of GTV were analyzed. The homogeneity index (HI) and conformity index (CI) of GTV were studied and the dose to 98% and 95% of PTV was analyzed. Maximum dose to spinal cord and planning risk volume of cord (PRV cord) was compared. The Volume of lung receiving 10 Gy, 20 Gy and mean dose was analyzed. The volume of heart receiving 30 Gy and 45 Gy was compared. The volume of normal tissue receiving greater than 2 Gy and 5 Gy was compared. The number of monitor units (MU) required to deliver the plans were compared. The plan with larger increment of gantry angle proved to be superior to smaller increment of gantry angle plans in terms of dose coverage, HI, CI and normal tissue sparing. The number of arcs did not make any difference in the quality of the plan. PMID- 25525312 TI - Effects of shielding the radiosensitive superficial organs of ORNL pediatric phantoms on dose reduction in computed tomography. AB - In computed tomography (CT), some superficial organs which have increased sensitivity to radiation, receive doses that are significant enough to be matter of concern. Therefore, in this study, the effects of using shields on the amount of dose reduction and image quality was investigated for pediatric imaging. Absorbed doses of breasts, eyes, thyroid and testes of a series of pediatric phantoms without and with different thickness of bismuth and lead were calculated by Monte Carlo simulation. Appropriate thicknesses of shields were chosen based on their weights, X-ray spectrum, and the amount of dose reduction. In addition, the effect of lead shield on image quality of a simple phantom was assessed quantitatively using region of interest (ROI) measurements. Considering the maximum reduction in absorbed doses and X-ray spectrum, using a lead shield with a maximum thickness of 0.4 mm would be appropriate for testes and thyroid and two other organs (which are exposed directly) should be protected with thinner shields. Moreover, the image quality assessment showed that lead was associated with significant increases in both noise and CT attenuation values, especially in the anterior of the phantom. Overall, the results suggested that shielding is a useful optimization tool in CT. PMID- 25525313 TI - Dose verification in carcinoma of uterine cervix patients undergoing 3D conformal radiotherapy with Farmer type ion chamber. AB - External beam radiotherapy (EBRT) for carcinoma of uterine cervix is a basic line of treatment with three dimensional conformal radiotherapy (3DCRT) in large number of patients. There is need for an established method for verification dosimetry. We tried to document absorbed doses in a group of carcinoma cervix patients by inserting a 0.6 cc Farmer type ion chamber in the vaginal cavity. A special long perspex sleeve cap is designed to cover the chamber for using in the patient's body. Response of ionization chamber is checked earlier in water phantom with and without cap. Treatment planning was carried out with X-ray computed tomography (CT) scan and with the chamber along with cap in inserted position, and with the images Xio treatment planning system. Three measurements on 3 days at 5-6 fraction intervals were recorded in 12 patients. Electrometer measured charges are converted to absorbed dose at the chamber center, in vivo. Our results show good agreement with planned dose within 3% against prescribed dose. This study, is a refinement over our previous studies with transmission dosimetry and chemicals in ampules. This preliminary work shows promise that this can be followed as a routine dose check with special relevance to new protocols in the treatment of carcinoma cervix with EBRT. PMID- 25525314 TI - A simple planning technique of craniospinal irradiation in the eclipse treatment planning system. AB - A new planning method for Craniospinal Irradiation by Eclipse treatment planning system using Field alignment, Field-in-Field technique was developed. Advantage of this planning method was also studied retrospectively for previously treated five patients of medulloblastoma with variable spine length. Plan consists of half beam blocked parallel opposed cranium, and a single posterior cervicospine field was created by sharing the same isocenter, which obviates divergence matching. Further, a single symmetrical field was created to treat remaining Lumbosacral spine. Matching between a inferior diverging edge of cervicospine field and superior diverging edge of a Lumbosacral field was done using the field alignment option. 'Field alignment' is specific option in the Eclipse Treatment Planning System, which automatically matches the field edge divergence as per field alignment rule. Multiple segments were applied in both the spine field to manage with hot and cold spots created by varying depth of spinal cord. Plan becomes fully computerized using this field alignment option and multiple segments. Plan evaluation and calculated mean modified Homogeneity Index (1.04 and 0.1) ensured that dose to target volume is homogeneous and critical organ doses were within tolerance. Dose variation at the spinal field junction was verified using ionization chamber array (I'MatriXX) for matched, overlapped and gap junction spine fields; the delivered dose distribution confirmed the ideal clinical match, over exposure and under exposure at the junction, respectively. This method is simple to plan, executable in Record and Verify mode and can be adopted for various length of spinal cord with only two isocenter in shorter treatment time. PMID- 25525315 TI - Letter to the Editor concerning Bhandari et al. "Impact of repeat computerized tomography replans in the radiation therapy of head and neck cancers". PMID- 25525316 TI - SEQUENTIAL TESTING OF MEASUREMENT ERRORS IN INTER-RATER RELIABILITY STUDIES. AB - Inter-rater reliability is usually assessed by means of the intraclass correlation coefficient. Using two-way analysis of variance to model raters and subjects as random effects, we derive group sequential testing procedures for the design and analysis of reliability studies in which multiple raters evaluate multiple subjects. Compared with the conventional fixed sample procedures, the group sequential test has smaller average sample number. The performance of the proposed technique is examined using simulation studies and critical values are tabulated for a range of two-stage design parameters. The methods are exemplified using data from the Physician Reliability Study for diagnosis of endometriosis. PMID- 25525317 TI - Using Theory to Design Evaluations of Communication Campaigns: The Case of the National Youth Anti-Drug Media Campaign. AB - We present a general theory about how campaigns can have effects and suggest that the evaluation of communication campaigns must be driven by a theory of effects. The National Youth Anti-Drug Media Campaign illustrates both the theory of campaign effects and implications that theory has for the evaluation design. Often models of effect assume that individual exposure affects cognitions that continue to affect behavior over a short term. Contrarily, effects may operate through social or institutional paths as well as through individual learning, require substantial levels of exposure achieved through multiple channels over time, take time to accumulate detectable change, and affect some members of the audience but not others. Responsive evaluations will choose appropriate units of analysis and comparison groups, data collection schedules sensitive to lagged effects, samples able to detect subgroup effects, and analytic strategies consistent with the theory of effects that guides the campaign. PMID- 25525318 TI - The Influence of Compensatory Strategies on Ethical Decision Making. AB - Ethical decision making is of concern to researchers across all fields. However, researchers typically focus on the biases that may act to undermine ethical decision making. Taking a new approach, this study focused on identifying the most common compensatory strategies that counteract those biases. These strategies were identified using a series of interviews with university researchers in a variety of areas, including biological, physical, social, and health as well as scholarship and the performing arts. Interview transcripts were assessed with two scoring procedures, an expert rating system and computer assisted qualitative analysis. Although the expert rating system identified Understanding Guidelines, Recognition of Insufficient Information, and Recognizing Boundaries as the most frequently used compensatory strategies across fields, other strategies, Striving for Transparency, Value/Norm Assessment, and Following Appropriate Role Models, were identified as most common by the computer assisted qualitative analyses. Potential reasons for these findings and implications for training and practice are identified and discussed. PMID- 25525319 TI - Reducing Alcohol Risk in Adjudicated Male College Students: Further Validation of a Group Motivational Enhancement Intervention. AB - This study examined the effectiveness of a single-session group motivational enhancement alcohol intervention on adjudicated male college students. Over two sequential academic years, 230 students sanctioned by the university for alcohol related infractions attended a 60- to 75-minute group intervention. The intervention consisted of a timeline followback, social norms education, decisional balance for behavioral change, blood alcohol content (BAC) information, expectancy challenge, and generation of behavioral goals. Participants were followed weekly for three months and showed reductions in drinking (29%) and alcohol-related consequences (32%) at three-month follow-up. The intervention was successful in reducing drinking for both first-year students and upperclassmen, with reductions appearing to be a function of the intervention and not the citation itself. Furthermore, a post hoc control condition revealed that those participants randomly assigned to the intervention group condition reduced drinking (19%) and alcohol-related consequences (44%) more than participants in the control condition over one month. These results provide continued evidence of the effectiveness of group motivational enhancement interventions with adjudicated male college students. PMID- 25525321 TI - Toward a Bioecological Model of School Engagement: A Biometric Analysis of Gene and Environmental Factors. AB - School disengagement is associated with poor academic achievement, dropout, and risk behaviors such as truancy, delinquency, and substance use. Despite empirical research identifying risk correlates of school disengagement across the ecology, it is unclear from which domain these correlates arise. To redress this issue, the current study used intraclass correlation and DeFries-Fulker analyses to longitudinally decompose variance in three domains of engagement (academic, behavioral, and emotional) using data from the National Longitudinal Study of Adolescent Health. Findings suggest that nonshared environmental factors (that is, environmental contexts and experiences that are unique to each sibling) account for approximately half of the variance in indicators of school disengagement when controlling for genetic influences, and that this variance increases as adolescents grow older and rely less on their immediate family. The present study contributes new evidence on the biosocial underpinnings of school engagement and highlights the importance of interventions targeting factors in the nonshared environment. PMID- 25525320 TI - Using DNA-Stable Isotope Probing to Identify MTBE- and TBA-Degrading Microorganisms in Contaminated Groundwater. AB - Although the anaerobic biodegradation of methyl tert-butyl ether (MTBE) and tert butyl alcohol (TBA) has been documented in the laboratory and the field, knowledge of the microorganisms and mechanisms involved is still lacking. In this study, DNA-stable isotope probing (SIP) was used to identify microorganisms involved in anaerobic fuel oxygenate biodegradation in a sulfate-reducing MTBE and TBA plume. Microorganisms were collected in the field using Bio-Sep(r) beads amended with 13C5-MTBE, 13C1-MTBE (only methoxy carbon labeled), or13C4-TBA. 13C DNA and 12C-DNA extracted from the Bio-Sep beads were cloned and 16S rRNA gene sequences were used to identify the indigenous microorganisms involved in degrading the methoxy group of MTBE and the tert-butyl group of MTBE and TBA. Results indicated that microorganisms were actively degrading 13C-labeled MTBE and TBA in situ and the 13C was incorporated into their DNA. Several sequences related to known MTBE- and TBA-degraders in the Burkholderiales and the Sphingomonadales orders were detected in all three13C clone libraries and were likely to be primary degraders at the site. Sequences related to sulfate-reducing bacteria and iron-reducers, such as Geobacter and Geothrix, were only detected in the clone libraries where MTBE and TBA were fully labeled with 13C, suggesting that they were involved in processing carbon from the tert-butyl group. Sequences similar to the Pseudomonas genus predominated in the clone library where only the methoxy carbon of MTBE was labeled with 13C. It is likely that members of this genus were secondary degraders cross-feeding on 13C-labeled metabolites such as acetate. PMID- 25525322 TI - A Novel Binocular Vision System for Wearable Devices. AB - We present a novel binocular imaging system for wearable devices incorporating the biology knowledge of the human eyes. Unlike the camera system in smartphones, two fish-eye lenses with a larger angle of view are used, the visual field of the new system is larger, and the central resolution of output images is higher. This design leads to more effective image acquisition, facilitating computer vision tasks such as target recognition, navigation and object tracking. PMID- 25525323 TI - SWAMP: Sliding Window Alignment Masker for PAML. AB - With the greater availability of genetic data, large genome-wide scans for positive selection increasingly incorporate data from a range of sources. These data sets may be derived from different sequencing methods, each of which has potential sources of error. Sequencing errors, compounded by alignment errors, greatly increase the number of false positives in tests for adaptive evolution. Genome-wide analyses often fail to fully address these issues or to provide sufficient detail on postalignment masking/filtering. Here, we introduce a Sliding Window Alignment Masker for Phylogenetic Analysis by Maximum Likelihood (SWAMP) that scans multiple-sequence alignments for short regions enriched with unreasonably high rates of nonsynonymous substitutions caused, for example, by sequence or alignment errors. SWAMP prevents their inclusion in downstream evolutionary analyses and therefore increases the reliability of downstream analyses. It is able to effectively mask short stretches of erroneous sequence, particularly prevalent in low-coverage genomes, which may not be detected by existing methods based on filtering by sitewise conservation or alignment confidence. SWAMP offers a flexible masking approach, and the user can apply different masking regimens to specific branches or sequences in the phylogeny allowing the stringency of masking to vary according to branch length, expected divergence levels, or assembly quality. We exemplify SWAMPs effectiveness on a dataset of 6,379 protein-coding genes from primate species, including data of variable quality. Full reporting of the software parameters will further improve the reproducibility of genome-wide analyses, as well as reduce false-positive rates. PMID- 25525324 TI - Prognostic phenotypic and genotypic factors associated with photodynamic therapy response in patients with age-related macular degeneration. AB - BACKGROUND: This study aimed to demonstrate the phenotypic and genotypic factors associated with photodynamic therapy (PDT) for age-related macular degeneration (AMD). METHODS: The study included 149 patients with exudative AMD treated by PDT. Eight phenotypic factors and ten genotypic factors for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the complement factor H (CFH) gene, rs 11200638-SNP in the high temperature requirement A-1 (HTRA1) gene, two SNPs (rs699947, rs2010963) in the vascular endothelial growth factor (VEGF) gene, and four SNPs (rs12948385, rs12150053, rs9913583, rs1136287) in the pigment epithelium-derived factor (PEDF) gene were evaluated. RESULTS: A significant association with best-corrected visual acuity change was demonstrated in the greatest linear dimension, presence or absence of pigment epithelial detachment, and HTRA1-rs11200638 genotype statistically (P=3.67*10(-4), 1.95*10( 2), 1.24*10(-3), respectively). Best-corrected visual acuity in patients with AA genotype of HTRA1-rs11200638 significantly decreased compared with that in patients with GG genotype (P=1.33*10(-3)). Logistic regression analyses demonstrated HTRA1-rs11200638 genotype was most strongly associated with best corrected visual acuity outcome from baseline at 12 months after photodynamic therapy (P=4.60*10(-3); odds ratio 2.363; 95% confidence interval 1.303-4.285). CONCLUSION: The HTRA1-rs11200638 variant showed the most significant association. Therefore, this variant may be used as a prognostic factor to estimate the PDT response with significant predictive power. PMID- 25525325 TI - Nasolacrimal duct obstruction following radioactive iodine 131 therapy in differentiated thyroid cancers: review of 19 cases. AB - BACKGROUND: Radioactive iodine 131 ((131)I) therapy has long been used in the treatment of differentiated thyroid cancers (DTC). While salivary and lacrimal glandular complications secondary to (131)I therapy are well documented, there is little in the literature addressing nasolacrimal duct obstruction (NLDO). We aimed to evaluate the frequency of (131)I therapy-acquired NLDO, its correlation to (131)I therapy doses, and the surgical treatment outcome of this rare side effect. METHODS: From 2000-2012, a retrospective review of 864 among 1,192 patients with confirmed DTC who were treated with (131)I therapy was performed to examine the frequency of NLDO, its causative factors, as well as imaging, surgical intervention, and outcomes. RESULTS: Nineteen (2.2%) patients were identified with NLDO. The mean age was 51.9+/-10.5 years (range: 39-72 years). Fifteen (78.9%) were female and four were male (21.1%). The mean individual (131)I doses were 311.1+/-169.3 millicurie (mCi) (range: 150-600 mCi). The mean duration between the date of (131)I therapy and the occurrence of NLDO was 11.6+/ 4.1 months (range: 6.5-20). Fourteen (73.7%) patients had bilateral epiphora. Computed tomography dacryography allowed for the detection of all NLDO. Eighteen (94.7%) patients underwent dacryocystorhinostomy. Complete recovery was obtained in 14 (73.7%) patients. Age >45 years and (131)I therapy doses >150 mCi were significantly correlated with NLDO (P=0.02 and P=0.03, respectively). CONCLUSION: NLDO is an underestimated complication of (131)I therapy in DTC patients. Clinicians should be aware of this rare complication for prompt intervention. PMID- 25525326 TI - First experience with the new high-frequency femtosecond laser system (LDV Z8) for cataract surgery. AB - BACKGROUND: The purpose of this work is to report our experience using the new Z8 laser system for femtosecond laser-assisted cataract surgery (FLACS) and to provide a sample of the performance and safety results using this new technology. METHODS: This prospective observational study was performed at the Swiss Eye Research Foundation, Eye Clinic ORASIS, Reinach, Switzerland. Fourteen patients were subjected to unilateral FLACS. Capsulotomy and lens fragmentation were performed with the aid of the LDV Z8 femtosecond laser system. Ease of phacoemulsification (on a 4-point scale), completeness of capsulotomy (on a 10 point scale), time for preparation of femtosecond laser (minutes), effective phacoemulsification time (seconds), total duration of surgery (minutes), and safety of the procedure were evaluated. RESULTS: Ease of fragmentation and completeness of capsulotomy were estimated at 3.9 and 9.9, respectively. The preparation time for femtosecond was 3.6+/-0.7 minutes, effective phacoemulsification time was 2.5+/-3.1 seconds, and total duration of the FLACS procedure was 16.3+/-4.5 minutes. No major complications were observed. Approximately 42% of all patients (6/14) showed Descemet's folds directly postoperatively. CONCLUSION: FLACS with the LDV Z8 system was characterized by complete capsulotomy and highly effective and reproducible lens fragmentation. The safety of the procedure was very good as perceived by the surgeon operating in this observational case series. The cost to benefit ratio should be further debated by assessing the results of a major prospective study, which is required for valid evaluation of the efficiency and safety of the LDV Z8 laser system and of FLACS in general. PMID- 25525327 TI - Dacryocystorhinostomy ostium: parameters to evaluate and DCR ostium scoring. AB - AIM: This study aims to provide a systematic protocol for the evaluation of a dacryocystorhinostomy (DCR) ostium and to propose a scoring system to standardize the assessment. METHODS: Retrospective evaluation of 125 consecutive lacrimal ostia post-DCR was performed. Medical records were screened, and photographs and videos were assessed to note the details of various ostial parameters. The major time points in evaluation were 4 weeks, 6 weeks, 3 months, and 6 months post-DCR. The ostia were defined and parameters like shape, size, location, and evolution of ostium were noted. Evaluation parameters were defined for internal common opening (ICO), ostium stents, and ostium granulomas. Ostium cicatrix and synechiae were graded based on their significance. Surgical success rates were computed and ostium characteristics in failed cases were studied. RESULTS: A total of 125 ostia were evaluated on the aforementioned ostium parameters. Because five ostia showed a complete cicatricial closure with no recognizable features, the remaining 120 ostia were studied. The ostium location was anterior to the axilla of middle turbinate in 85.8% (103/120) of the cases. Moreover, 76.6% (92/120) of the ostia were circular to oval in shape, with a shallow base. The ostium size was >8*5 mm in 78.3% (94/120) of the cases. The ICO was found to be located in the central or paracentral basal area in 75.8% (91/120). The anatomical and functional success rates achieved were 96% and 93.6%, respectively. All the five cases with anatomical failures showed a complete cicatrization and the ICO movements were poor in all the three cases of functional failure. CONCLUSION: The article attempts to standardize the postoperative evaluation of a DCR ostium and provides a systematic protocol and scoring system for possible use by surgeons and researchers alike. PMID- 25525328 TI - Endoilluminator phototoxic maculopathy associated with combined ICG-assisted epiretinal membrane and internal limiting membrane peeling. AB - Phototoxic maculopathy caused by endoillumination during macular surgery is uncommon. Previously identified risk factors have included intensity of the light source, proximity to the retinal surface, and length of exposure. In the era of indocyanine green (ICG)-assisted internal limiting membrane (ILM) peeling, the use of ICG, and the technique of ILM peeling may both contribute to subsequent phototoxic maculopathy. We present cases of routine chromovitrectomy who developed phototoxic maculopathy in the precise discrete distribution of the ILM rhexes, and discuss potential mechanisms and implications. PMID- 25525330 TI - Retrospective study of recession of four horizontal rectus muscle in periodic alternating nystagmus. AB - PURPOSE: Periodic alternating nystagmus (PAN) is a spontaneous horizontal nystagmus observed in disorders of the central nervous system. Patients with congenital PAN complain of oscillating vision at high rates. Medication is the first-choice treatment for PAN; however, clinicians still seek better therapy. The aim of this study was to evaluate outcomes of recession of four horizontal rectus muscle (R-FHR) in patients with congenital PAN. PATIENTS AND METHODS: This study reports a retrospective case series of ten patients (seven males and three females; mean age 24.4+/-10.9) with congenital PAN who underwent R-FHR between 2007 and 2012, which was performed by the same surgeon at the Hyogo College of Medicine. Patients were evaluated for complications, recession amount, deviation angle, eye movements including a nystagmus amplitude, and visual acuity during pre- and post-operative periods. RESULTS: Pre-operatively, patients complained of oscillating vision, abnormal head posture, esotropia, and congenital superior oblique palsy. Post-operatively, changes from the previous observations of nystagmus amplitudes and abnormal head posture demonstrated a complete reversal in all patients. In addition, visual acuity determined with a Snellen chart improved in two patients. However, esotropia occurred in three patients who underwent additional strabismus surgery 2 days after R-FHR. R-FHR was particularly effective in eight patients who pre-operatively had periodic oscillating vision with a regular pattern of periodic nystagmus. CONCLUSION: We demonstrated that ten patients with congenital PAN had improved vision following R-FHR, indicating that R-FHR was an effective procedure, especially in patients suffering PAN with periodic oscillating vision. PMID- 25525329 TI - Photoreceptor inner segment ellipsoid band integrity on spectral domain optical coherence tomography. AB - Spectral domain optical coherence tomography cross-sectional imaging of the macula has conventionally been resolved into four bands. However, some doubts were raised regarding authentication of the existence of these bands. Recently, a number of studies have suggested that the second band appeared to originate from the inner segment ellipsoids of the foveal cone photoreceptors, and therefore the previously called inner segment-outer segment junction is now referred to as inner segment ellipsoidband. Photoreceptor dysfunction may be a significant predictor of visual acuity in a spectrum of surgical and medical retinal diseases. This review aims to provide an overview and summarizes the role of the photoreceptor inner segment ellipsoid band in the management and prognostication of various vitreoretinal diseases. PMID- 25525331 TI - Pilot Phase II study of mazindol in children with attention deficit/hyperactivity disorder. AB - OBJECTIVE: Mazindol has been proposed as a potential treatment of children with attention deficit/hyperactivity disorder (ADHD). The purpose of this pilot study was to assess its pharmacokinetics, short-term efficacy, and safety. SUBJECTS AND METHODS: A total of 24 children (aged 9-12 years) with ADHD (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text revision criteria) received a daily dose of 1 mg for 7 days and were followed for 3 additional weeks. Pharmacokinetic samples were collected after the first administration. ADHD symptoms were assessed using the ADHD Rating Scale (RS)-IV, Conners' Parent Rating Scale - Revised: Long (CPRS-R:L) at screening, baseline, and the end of the study. The Clinical Global Impression - Severity (CGI-S) scale was assessed at baseline, and the CGI - Improvement (CGI-I) scale was assessed at subsequent visits. RESULTS: Twenty-one subjects (aged 10+/-1 years) were analyzed. Pharmacokinetic data were described by a one-compartment model with first-order absorption, elimination, and lag time. The typical apparent clearance and apparent volume of distribution were 27.9 L/h and 234 L, and increased with fat-free mass and age, respectively. The mean change in score in ADHD RS-IV after 1 week of mazindol was -24.1 (P<0.0001), greater than a 90% improvement from baseline. Reduction of CPRS-R:L and CGI-S scores were -52.1 (P<0.0001) and -2.5 (P<0.01), respectively. Adverse events were mild to moderate, decreased appetite and upper abdominal pain being the most common. CONCLUSION: This preliminary study shows that mazindol might be an effective, well-tolerated, and long-acting (more than 8 hours) agent for the treatment of ADHD in children. PMID- 25525332 TI - Clinicopathological significance and potential drug target of RUNX3 in breast cancer. AB - BACKGROUND: Previous reports indicate that RUNX3 is a tumor suppressor in several types of human tumors, including breast cancer (BC). However, the correlation between RUNX3 hypermethylation and the incidence of BC remains unclear. In this study, we conducted a systematic review and meta-analysis aiming to comprehensively assess the potential role of RUNX3 hypermethylation in the pathogenesis of BC. METHODS: A detailed literature search was made to identify studies for related research publications. Methodological quality of the studies was evaluated. Analysis of pooled data was performed. Odds ratio (OR) was calculated and summarized respectively. RESULTS: Final analysis of 565 BC patients from eleven eligible studies was performed. The results showed that RUNX3 hypermethylation was significantly higher in BC than in normal breast tissue, the pooled OR from nine studies including 339 BC and 248 normal breast tissue (OR =24.12, 95% confidence interval [CI] =13.50-43.11, Z=10.75, P<0.00001). Further analysis also showed significantly increased OR of RUNX3 hypermethylation in estrogen receptor (ER)-positive than in ER-negative BC patients (OR =5.67, 95% CI =2.69-11.95, Z=4.57, P<0.00001). In addition, RUNX3 messenger RNA (mRNA) high expression was found to be correlated to better overall survival in 3,455 cases of BC patients that were followed up for 20 years (hazard ratio [HR] 0.79, P=8.8*10(-5)). Interestingly, RUNX3 mRNA overexpression was found to be correlated to better overall survival in only 668 cases of ER negative patients (HR 0.72, P=0.01), but not in 1,767 cases of ER-positive patients (HR 0.87, P=0.13). CONCLUSION: The results of this meta-analysis suggest that RUNX3 hypermethylation may be implicated in the pathogenesis of BC. Detection of RUNX3 mRNA may be a helpful and valuable biomarker for diagnosis of BC, especially in ER-negative BC. We also discussed the significance of RUNX3 as a potential drug target. PMID- 25525333 TI - Design real-time reversal of tumor multidrug resistance cleverly with shortened carbon nanotubes. AB - Multidrug resistance (MDR) in tumors renders many currently available chemotherapeutic drugs ineffective. Research in nanobiotechnology-based therapeutic alternatives has provided innovative and promising strategies to overcome MDR. The aim of this study was to investigate whether the new strategy of a co-loaded reversal agent and chemotherapeutic drug with shortened carbon nanotubes (CNTs) would show useful effects on the real-time reversal of tumor MDR. CNTs were cut and purified via ultrasonication and oxidative acid treatment to optimize their length for drug-delivery vehicles, then verapamil (Ver) and doxorubicin (Dox) were co-loaded on shortened CNTs (denoted as Ver/Dox/shortened CNTs), which acted as a drug delivery system. The multidrug resistant leukemia K562/A02 cells were treated with the denoted Ver/Dox/shortened CNTs. The real time reversal of tumor MDR were evaluated by flow cytometer, 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, acridine orange/ethidium bromide staining, and Western blot analysis. In the same MDR tumor cells the new strategy of a co-loaded reversal agent and chemotherapeutic drug with CNTs could inhibit the function of P-glycoprotein in real-time by Ver as reversal agent, significantly increase the uptake of Dox, enhance the sensitivity of the MDR cancer cells to the chemotherapeutic agent, and induce apoptosis. It was therefore concluded that a co-loaded reversal agent and chemotherapeutic drug with shortened CNTs could have real-time reversal ability of MDR in tumors, which could represent a promising approach in cancer therapy. PMID- 25525334 TI - Matrix-induced autologous chondrocyte implantation for the treatment of chondral defects of the knees in Chinese patients. AB - Articular cartilage injury is the most common type of damage seen in clinical orthopedic practice. The matrix-induced autologous chondrocyte implant (MACI) was developed to repair articular cartilage with an advance on the autologous chondrocyte implant procedure. This study aimed to evaluate whether MACI is a safe and efficacious cartilage repair treatment for patients with knee cartilage lesions. The primary outcomes were the Knee Injury and Osteoarthritis Outcome Score (KOOS) domains and magnetic resonance imaging (MRI) results, compared between baseline and postoperative months 3, 6, 12, and 24. A total of 15 patients (20 knees), with an average age of 33.9 years, had a mean defect size of 4.01 cm(2). By 6-month follow-up, KOOS results demonstrated significant improvements in symptoms and knee-related quality of life. MRI showed significant improvements in four individual graft scoring parameters at 24 months postoperatively. At 24 months, 90% of MACI grafts had filled completely and 10% had good-to-excellent filling of the chondral defect. Most (95%) of the MACI grafts were isointense and 5% were slightly hyperintense. Histologic evaluation at 15 and 24 months showed predominantly hyaline cartilage in newly generated tissue. There were no postoperative complications in any patients and no adverse events related to the MACI operation. This 2-year study has confirmed that MACI is safe and effective with the advantages of a simple technique and significant clinical improvements. Further functional and mechanistic studies with longer follow-up are needed to validate the efficacy and safety of MACI in patients with articular cartilage injuries. PMID- 25525336 TI - Scientometrics of anesthetic drugs and their techniques of administration, 1984 2013. AB - The aim of this study was to assess progress in the field of anesthetic drugs over the past 30 years using scientometric indices: popularity indices (general and specific), representing the proportion of articles on a drug relative to all articles in the field of anesthetics (general index) or the subfield of a specific class of anesthetics (specific index); index of change, representing the degree of growth in publications on a topic from one period to the next; index of expectations, representing the ratio of the number of articles on a topic in the top 20 journals relative to the number of articles in all (>5,000) biomedical journals covered by PubMed; and index of ultimate success, representing a publication outcome when a new drug takes the place of a common drug previously used for the same purpose. Publications on 58 topics were assessed during six 5 year periods from 1984 to 2013. Our analysis showed that during 2009-2013, out of seven anesthetics with a high general popularity index (>=2.0), only two were introduced after 1980, ie, the inhaled anesthetic sevoflurane and the local anesthetic ropivacaine; however, only sevoflurane had a high index of expectations (12.1). Among anesthetic adjuncts, in 2009-2013, only one agent, sugammadex, had both an extremely high index of change (>100) and a high index of expectations (25.0), reflecting the novelty of its mechanism of action. The index of ultimate success was positive with three anesthetics, ie, lidocaine, isoflurane, and propofol, all of which were introduced much longer than 30 years ago. For the past 30 years, there were no new anesthetics that have produced changes in scientometric indices indicating real progress. PMID- 25525335 TI - Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts. AB - Mesenchymal stem cells (MSCs) have been recognized as promising delivery vehicles for gene therapy of tumors. Gastric cancer is the third leading cause of worldwide cancer mortality, and novel treatment modalities are urgently needed. NK4 is an antagonist of hepatocyte growth factor receptors (Met) which are often aberrantly activated in gastric cancer and thus represent a useful candidate for targeted therapies. This study investigated MSC-delivered NK4 gene therapy in nude mice bearing gastric cancer xenografts. MSCs were transduced with lentiviral vectors carrying NK4 complementary DNA or enhanced green fluorescent protein (GFP). Such transduction did not change the phenotype of MSCs. Gastric cancer xenografts were established in BALB/C nude mice, and the mice were treated with phosphate-buffered saline (PBS), MSCs-GFP, Lenti-NK4, or MSCs-NK4. The tropism of MSCs toward gastric cancer cells was determined by an in vitro migration assay using MKN45 cells, GES-1 cells and human fibroblasts and their presence in tumor xenografts. Tumor growth, tumor cell apoptosis and intratumoral microvessel density of tumor tissue were measured in nude mice bearing gastric cancer xenografts treated with PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4 via tail vein injection. The results showed that MSCs migrated preferably to gastric cancer cells in vitro. Systemic MSCs-NK4 injection significantly suppressed the growth of gastric cancer xenografts. MSCs-NK4 migrated and accumulated in tumor tissues after systemic injection. The microvessel density of tumor xenografts was decreased, and tumor cellular apoptosis was significantly induced in the mice treated with MSCs-NK4 compared to control mice. These findings demonstrate that MSC-based NK4 gene therapy can obviously inhibit the growth of gastric cancer xenografts, and MSCs are a better vehicle for NK4 gene therapy than lentiviral vectors. Further studies are warranted to explore the efficacy and safety of the MSC-based NK4 gene therapy in animals and cancer patients. PMID- 25525337 TI - Optimizing iron delivery in the management of anemia: patient considerations and the role of ferric carboxymaltose. AB - With the challenge of optimizing iron delivery, new intravenous (iv) iron carbohydrate complexes have been developed in the last few years. A good example of these new compounds is ferric carboxymaltose (FCM), which has recently been approved by the US Food and Drug Administration for the treatment of iron deficiency anemia in adult patients who are intolerant to oral iron or present an unsatisfactory response to oral iron, and in adult patients with non-dialysis dependent chronic kidney disease (NDD-CKD). FCM is a robust and stable complex similar to ferritin, which minimizes the release of labile iron during administration, allowing higher doses to be administered in a single application and with a favorable cost-effective rate. Cumulative information from randomized, controlled, multicenter trials on a diverse range of indications, including patients with chronic heart failure, postpartum anemia/abnormal uterine bleeding, inflammatory bowel disease, NDD-CKD, and those undergoing hemodialysis, supports the efficacy of FCM for iron replacement in patients with iron deficiency and iron-deficiency anemia. Furthermore, as FCM is a dextran-free iron-carbohydrate complex (which has a very low risk for hypersensitivity reactions) with a small proportion of the reported adverse effects in a large number of subjects who received FCM, it may be considered a safe drug. Therefore, FCM appears as an interesting option to apply high doses of iron as a single infusion in a few minutes in order to obtain the quick replacement of iron stores. The present review on FCM summarizes diverse aspects such as pharmacology characteristics and analyzes trials on the efficacy/safety of FCM versus oral iron and different iv iron compounds in multiple clinical scenarios. Additionally, the information on cost effectiveness and data on change in quality of life are also discussed. PMID- 25525340 TI - Perceived need to take medication is associated with medication non-adherence in patients with rheumatoid arthritis. AB - BACKGROUND: This is the first cross-sectional study that aims to examine associations between beliefs about medication and non-adherence in patients with rheumatoid arthritis (RA) using disease-modifying antirheumatic drugs, taking potential psychological confounders into account. METHODS: Eligible patients (diagnosed with RA for >=1 year or >=18 years, using greater than or equal to one disease-modifying antirheumatic drug) were included by their rheumatologist during regular outpatient visits between September 2009 and September 2010. Included patients received questionnaires. The Beliefs about Medicines Questionnaire was used to measure the perceived need to take medication (necessity beliefs), the concerns about taking medication (concern beliefs), general medication beliefs, and attitudes toward taking medication. Medication non-adherence (no/yes) was measured using the Compliance Questionnaire Rheumatology (CQR). Associations between beliefs and non-adherence, and the influence of demographical, clinical, and psychological factors (symptoms of anxiety/depression, illness cognitions, self-efficacy) were assessed using logistic regression. RESULTS: A total of 580 of the 820 eligible patients willing to participate were included in the analyses (68% female, mean age 63 years, 30% non-adherent to their medication). Weaker necessity beliefs (OR [odds ratio]: 0.8, 95% CI [confidence interval]: 0.8-0.9) and an unfavorable balance between necessity and concern beliefs (OR: 0.9, 95% CI: 0.9-1.0) were associated with CQR non-adherence. Also, having an indifferent attitude toward medication (no/yes) was associated with CQR non-adherence (OR: 5.3, 95% CI: 1.1-25.8), but the prevalence of patients with an indifferent attitude toward medication was low. The associations were barely confounded by demographical, clinical, and psychological factors. CONCLUSION: Increasing necessity beliefs about medication in clinical practice might be worthwhile in improving medication adherence in RA patients. PMID- 25525339 TI - Alitretinoin for the treatment of severe chronic hand eczema. AB - Chronic hand eczema is a common and often debilitating condition. Alitretinoin, a 9-cis-retinoic acid and pan-retinoic acid agonist, is a new and effective systemic treatment for chronic hand eczema, which provides another treatment option. A "clear" or "almost clear" response can be achieved in up to half of patients within a 24-week course of treatment. Even higher rates of remission can be obtained with a longer duration of treatment. Alitretinoin has a favorable overall profile of adverse effects; however, female patients who are at risk of becoming pregnant should follow a strict pregnancy-prevention program due to the teratogenic effects of this drug. PMID- 25525338 TI - Dapagliflozin for the treatment of type 2 diabetes: a review of the literature. AB - OBJECTIVE: Dapagliflozin was the first drug in a class of therapies that took a new approach to glycemic control in adults with type 2 diabetes (T2D). It is an inhibitor of the sodium glucose cotransporter, resident in the proximal nephron, which is responsible for the recovery of filtered glucose back into circulation. Inhibiting this cotransporter reduces glucose recovery, increases glucose excretion, and reduces hyperglycemia. Here, we review some of the literature relating to the action, efficacy, and clinical use of dapagliflozin. MATERIALS AND METHODS: A Medline search was conducted within date, animal, and language limits, and relevant papers were selected for review. Conference proceedings were reviewed to obtain up-to-date literature on this drug. Clinical trial websites were reviewed for ongoing studies. RESULTS: On average, treatment with dapagliflozin results in improvement in glycated hemoglobin by 0.50%, fasting plasma glucose by 1 mmol/L, weight by 2 kg, body mass index by 1.1%, and systolic/diastolic blood pressure by 4/2 mmHg over 24-52 weeks. The weight benefit is greater when used in association with sulfonylureas. It is generally well tolerated, but comes with an increased risk of genitourinary and urinary tract infections. In addition, it is associated with reversible changes to renal function that need to be explored. Early reports of an association with cancer also need to be carefully monitored. CONCLUSION: Dapagliflozin is a useful therapy for adult patients with T2D. It also holds potential for a broader range of patients with T2D (such as the elderly and pediatric populations), as well as those with other forms of diabetes, such as type 1 diabetes. While longer-term outcome studies of safety and efficacy are awaited, dapagliflozin forms a very useful and welcome addition to our armamentarium for managing patients with T2D. PMID- 25525342 TI - The interference in the suicide ideation of patients with malignant tumors by mental clinical nursing pathway. AB - BACKGROUND: The purpose of this study was to examine the effect of mental clinical nursing pathways on suicidal ideation and life quality of patients with malignant tumors. METHODS: Two hundred patients with malignant tumors were randomly divided into a study group and a control group, with 100 patients in each group. During the treatment, patients in the study group received mental clinical nursing pathway care, while those in the control group were given the usual nursing care, such as timely inspection, nurse's reactions to patient's behavior, and execution of medical orders. Thereafter, the "self-rating idea of suicide scale" and Karnofsky Performance Status (KPS) were used to compare the differences in the suicidal ideation of patients with malignant tumors between the two groups before and after the treatment. RESULTS: There were no statistical differences in the scores of despair factor, optimistic factor, sleep factor, and cover factor between the two groups before the treatment (P>0.05). After different styles of nursing, the former four factors of patients in the study group were significantly lower than those in the control group (P<0.01), while there were no significant differences in the score of cover factor between the two groups (P>0.05). The KPS of patients receiving mental clinical nursing pathway care was higher than those receiving usual nursing care, and there was a statistical significant difference between the two groups (P<0.01). Interestingly, the patients' suicidal ideation scale was negatively correlated with KPS (r =-0.29, P<0.05). CONCLUSION: For individuals diagnosed with a malignant tumor, using a mental health clinical nursing pathway can effectively decrease the degree of suicidal ideation and positively impact the quality of life. PMID- 25525341 TI - Treatment adherence and other patient-reported outcomes as cost determinants in multiple sclerosis: a review of the literature. AB - BACKGROUND: Treatment adherence is one of the key factors for achieving optimal clinical outcomes. In order to assess costs related to adherence to, and persistence and compliance with, disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS), a narrative review of the literature was performed. Satisfaction with and preference for DMTs and their delivery devices were also assessed, as both can have an influence on patients' adherence and persistence. METHODS: Electronic databases (MEDLINE, PubMed, Google Scholar, congress proceedings) were searched to identify publications analyzing MS costs related to adherence, persistence, satisfaction, and preferences for MS treatments. Bibliographic references were hand searched. English or Spanish studies published between January 2007 and January 2013 were selected. RESULTS: A total of 398 titles were identified, of which 12 met the inclusion criteria. Six studies evaluated the impact of adherence, persistence, and compliance on treatment costs; four publications analyzed satisfaction with DMTs; and two assessed treatment preferences based on attributes of the delivery device. Increased adherence and persistence were associated with better clinical outcomes, leading to lower relapse risk (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.59 0.85) and a decrease in health care resource use, such as MS-related hospitalizations (OR: 0.63; 95% CI: 0.47-0.83) and emergency department visits (OR: 0.80; 95% CI: 0.60-1.07). This reduction in resource use led to a patient/year total cost reduction (excluding DMT costs) of up to 22%. CONCLUSION: This review highlights the importance of ensuring adequate adherence in MS patients through treatments and devices better tailored to patients' needs that could enhance clinical outcomes and reduce MS costs. Understanding the factors underlying satisfaction and compliance with treatment and patients' preference for certain therapies could help in the development of strategies that can improve adherence. PMID- 25525343 TI - Measuring patients' satisfaction with their anti-TNF treatment in severe Crohn's disease: scoring and psychometric validation of the Satisfaction for PAtients in Crohn's diseasE Questionnaire (SPACE-Q((c))). AB - BACKGROUND: Severe Crohn's disease management includes anti-tumor necrosis factor (anti-TNF) drugs that differ from early-stage treatments regarding efficacy, safety, and convenience. This study aimed to finalize and psychometrically validate the Satisfaction for PAtients in Crohn's diseasE Questionnaire (SPACE Q((c))), developed to measure satisfaction with anti-TNF treatment in patients with severe Crohn's disease. METHODS: A total of 279 patients with severe Crohn's disease receiving anti-TNF therapy completed the SPACE-Q 62-item pilot version at inclusion and 12 and 13 weeks after first anti-TNF injection. The final SPACE-Q scoring was defined using multitrait and regression analyses and clinical relevance considerations. Psychometric validation included clinical validity against Harvey-Bradshaw score, concurrent validity against Treatment Satisfaction Questionnaire for Medication (TSQM), internal consistency reliability, test retest reliability, and responsiveness against the patient global impression of change (PGIC). RESULTS: Quality of completion was good (55%-67% of patients completed all items). Four items were removed from the questionnaire. Eleven scores were defined within the final 58-item SPACE-Q: disease control; symptoms, anal symptoms, and quality of life transition scales; tolerability; convenience; expectation confirmation toward efficacy, side effects, and convenience; satisfaction with treatment; and motivation. Scores met standards for concurrent validity (correlation between SPACE-Q satisfaction with treatment and TSQM satisfaction scores =0.59), internal consistency reliability (Cronbach's alpha=0.67-0.93), test-retest reliability (intraclass correlations =0.62-0.91), and responsiveness (improvement in treatment experience assessed by the SPACE-Q for patients reporting improvement on the PGIC). Significantly different mean scores were observed between groups of patients with different Harvey-Bradshaw disease severity scores. CONCLUSION: The SPACE-Q is a valid, reliable, and responsive instrument to measure satisfaction with anti-TNF treatment in patients with severe Crohn's disease and for use in future studies. PMID- 25525345 TI - Lung vital capacity and oxygen saturation in adults with cerebral palsy. AB - BACKGROUND: Individuals with infantile cerebral palsy have multiple disabilities. The most conspicuous syndrome being investigated from many aspects is motor movement disorder with a spastic gait pattern. The lung function of adults with spasticity attracts less attention in the literature. This is surprising because decreased thoracic mobility and longstanding scoliosis should have an impact on lung function. With increasing age and the level of disability, individuals become susceptible to lung infections and reflux illness, and these are accompanied by increased aspiration risk. This study examined, with different methods, to what extent adults with congenital cerebral palsy and acquired spastic paresis - following traumatic brain injury - showed restriction of lung function. It also assessed the contribution of disability level on this restriction. METHODS: The oxygen saturation of 46 adults with a diagnosis of cerebral palsy was measured with an oximeter. Lung vital capacity was measured with a mobile spirometer and excursion of the thorax was clinically registered. The gross motor function levels and the presence or absence of scoliosis were determined. RESULTS: A significantly positive correlation between lung vital capacity and chest expansion was established. Both the lung vital capacity and the thorax excursion decreased with increases in gross motor function level. Oxygen saturation remained within the normal range in all persons, in spite of reduced values of the measured lung parameters. No statistically significant dependency between lung vital capacity and oxygen saturation, and between chest expansion and oxygen saturation was found. The scoliotic deformities of the spine were associated with an additional decrease in the vital capacity, but this did not affect blood oxygen supply. CONCLUSION: Despite the decreased chest expansion and the significantly reduced lung volume in adults with cerebral palsy, sufficient oxygen supply was registered. PMID- 25525344 TI - Efficacy of a brief multifactorial adherence-based intervention in reducing blood pressure: a randomized clinical trial. AB - BACKGROUND: Lowering blood pressure (BP) by antihypertensive (AHT) drugs reduces the risks of cardiovascular events, stroke, and total mortality. However, poor adherence to AHT medications reduces their effectiveness and increases the risk of adverse events. OBJECTIVE: To evaluate the effectiveness of a multifactorial adherence-based intervention in a primary care setting in lowering BP. METHODS/DESIGN: Multicenter parallel randomized controlled trial. Thirty two nurses in 28 primary care centers of three Spanish regions. Patients aged 18-80 years, taking AHT drugs with uncontrolled BP (n=221) were randomized to a control group (usual care) or a multifactorial adherence-based intervention including nurse-led motivational interviews, pill reminders, family support, BP self recording, and simplification of the dosing regimen by a pharmacist. MAIN OUTCOME MEASURES: The primary outcome was 12-month blinded measure of systolic BP (mean of three measurements). The secondary outcomes were 12-month diastolic BP and proportion of patients with adequately controlled BP. RESULTS: One hundred and fourteen patients were allocated to the intervention group and 109 to the control group. At 12 months, 212 (89%) participants completed the study. The systolic BP in the intervention group was 151.3 versus 153.7 in the control group (P=0.294). The diastolic BP did not differ between groups (83.4 versus 83.6). Of the patients in the control group, 9.2% achieved BP control versus a 15.8% in the intervention group. The relative risk for achieving BP control was 1.72 (95% confidence interval: 0.83-3.56). CONCLUSION: A multifactorial intervention based on improving adherence in patients with uncontrolled hypertension failed to find evidence of effectiveness in lowering systolic BP. TRIAL REGISTRATION: ISRCTN21229328. PMID- 25525346 TI - Experience of insomnia, symptom attribution and treatment preferences in individuals with moderate to severe COPD: a qualitative study. AB - Persons with chronic obstructive pulmonary disease (COPD) are known to have poor sleep quality. Acceptance of and adherence to therapies for sleep problems may depend on how the person with COPD regards the source of his sleep problem, yet little is known about their attribution as to the cause of these sleep symptoms. The objective of this study was to describe the subjective sleep complaints of individuals with COPD along with their attributions as to the cause of these symptoms, and their treatment preferences for insomnia. Three focus groups were conducted (N=18) with participants who have moderate to severe COPD. Focus group data were transcribed, compared and contrasted to identify themes of attribution. Participants reported difficulty falling asleep, staying asleep, and daytime sleepiness. They attributed their sleep problems primarily to their pulmonary symptoms, but also poor air quality (thick humid air) and death anxiety when awake during the night. There was no clear preference for type of treatment to remedy this problem (medication, cognitive therapy), although they indicated that traveling to the clinic was difficult and should be avoided as much as possible. These data suggest that environmental manipulation to improve air quality (eg, air conditioning) and modifications to reduce death anxiety could be beneficial to persons with COPD. In-person multi-session therapy may not be acceptable to persons with moderate to severe COPD, however internet-based therapy might make treatment more accessible. PMID- 25525347 TI - Patient involvement in selection of immunosuppressive regimen following transplantation. AB - Transplantation has made a considerable difference to the lives of many patients. However, feedback from patients indicates that although having a transplant is a hugely positive experience, having to take medications indefinitely is one of the biggest challenges. An ideal scenario would be no medications following a transplant. A compromise would be a minimal number of medications, with minimal restrictions and as simple a regimen as possible. Although there is considerable research going into fine-tuning the management of the immune response to a transplant, to date there is no universal regimen that enables patients to remain free of immunosuppressant medications, making adherence paramount to maintain long-term allograft survival. This paper reviews the available immunosuppressant regimens and factors influencing choice from both the clinician's and the patient's perspective. Factors influencing the decision-making process, such as quality of life for patients, their satisfaction, acceptability, and adherence uptake are reviewed. We conclude with a further assessment of patient choice as a factor in regimen selection, its impact on adherence, and its implications. PMID- 25525348 TI - Patient preference and ease of use for different coagulation factor VIII reconstitution device scenarios: a cross-sectional survey in five European countries. AB - INTRODUCTION: Hemophilia A treatment involves replacing the deficient coagulation factor VIII. This process may involve multiple steps that might create a barrier to adherence. A new dual-chamber syringe (DCS; FuseNGo((r))) was recently introduced with the aim of simplifying reconstitution. AIM: This study aimed to identify factors associated with adult patients' preferences for different coagulation factor VIII reconstitution systems and to test ease of use and patient preference for the DCS. METHODS: A cross-sectional survey of adults with hemophilia A in five European countries was conducted; a subset of subjects also participated in a practical testing session of the DCS. RESULTS: Among the 299 survey participants, the device scenario requiring the least equipment and reconstitution steps (the DCS) received a median preference rating of 71 out of 100 (0 being "the least desirable" and 100 "the most desirable" rating). This was significantly higher than the other scenarios (the next highest achieved a median of 50 points; P<0.001). Participants would be more likely to use this device prophylactically (P<0.001). Among the 98 participants who tested the DCS, 57% preferred this device over their current device, 26% preferred their current device, and 17% had no preference. The DCS was rated as easier to use than current treatment devices (median score 9/10 versus 7/10 for current treatment, P=0.001). CONCLUSION: The survey indicates that the prefilled DCS, FuseNGo((r)), requiring the least equipment and fewest reconstitution steps, was preferred by patients and was the device most likely to be used prophylactically; the practical device testing supports these results. PMID- 25525349 TI - Effectiveness of weekly cognitive stimulation therapy for people with dementia and the additional impact of enhancing cognitive stimulation therapy with a carer training program. AB - PURPOSE OF THE STUDY: Cognitive stimulation therapy (CST) is a widely used, evidence-based intervention for people with dementia (PwD). Although designed as a 14 session, twice weekly intervention, many services in the UK deliver CST once a week for 14 weeks. However, this method of delivery has yet to be evaluated. In addition, CST does not include any formal carer training. This study aimed to evaluate the effectiveness of once weekly CST and determine any additional impact when enhanced with a carer training program. DESIGN AND METHODS: A single blind, randomized controlled trial was conducted. Sixty eight PwD and their carers were recruited through three community Memory Assessment Services. PwD and their carers were randomized to one of three conditions: CST plus carer training, CST only, or a wait list control. PwD were administered standardized measures of cognition, quality of life, and quality of relationship with carer at baseline and the 15 week follow-up. RESULTS: There were no baseline differences across the three groups. At follow-up, there were no significant differences between PwD in the three groups on any outcomes. IMPLICATIONS: Weekly CST with or without carer training may not be an effective form of delivery. Several possible explanations for the outcomes are proposed. Weekly CST may not offer the necessary "dose" required to combat decline, and equally the carer training may have been too brief to have made a difference. Services currently offering weekly CST should collect routine outcome data to support its use and provide practice-based evidence. PMID- 25525350 TI - Systematic review comparing LABA, olodaterol, and indacaterol: limitations. PMID- 25525351 TI - Paradoxical association between body mass index and in-hospital mortality in elderly patients with chronic obstructive pulmonary disease in Japan. AB - BACKGROUND AND OBJECTIVE: The prevalence and mortality of chronic obstructive pulmonary disease (COPD) in elderly patients are increasing worldwide. Low body mass index (BMI) is a well-known prognostic factor for COPD. However, the obesity paradox in elderly patients with COPD has not been well elucidated. We investigated the association between BMI and in-hospital mortality in elderly COPD patients. METHODS: Using the Diagnosis Procedure Combination database in Japan, we retrospectively collected data for elderly patients (>65 years) with COPD who were hospitalized between July 2010 and March 2013. We performed multivariable logistic regression analysis to compare all-cause in-hospital mortality between patients with BMI of <18.5 kg/m2 (underweight), 18.5-22.9 kg/m2 (low-normal weight), 23.0-24.9 kg/m2 (high-normal weight), 25.0-29.9 kg/m2 (overweight), and >=30.0 kg/m2 (obesity) with adjustment for patient backgrounds. RESULTS: In all, 263,940 eligible patients were identified. In-hospital mortality was 14.3%, 7.3%, 4.9%, 4.3%, and 4.4%, respectively, in underweight, low-normal weight, high-normal weight, overweight, and obese patients. Underweight patients had a significantly higher mortality than low-normal weight patients (odds ratio [OR]: 1.55, 95% confidence interval [CI]: 1.48-1.63), whereas lower mortality was associated with high-normal weight (OR: 0.76, CI: 0.70-0.82), overweight (OR: 0.73, CI: 0.66-0.80), and obesity (OR: 0.67, CI: 0.52-0.86). Higher mortality was significantly associated with older age, male sex, more severe dyspnea, lower level of consciousness, and lower activities of daily living. CONCLUSION: Overweight and obese patients had a lower mortality than low-normal weight patients, which supports the obesity paradox. PMID- 25525352 TI - Lobar analysis of collapsibility indices to assess functional lung volumes in COPD patients. AB - BACKGROUND: We investigated correlations between lung volume collapsibility indices and pulmonary function test (PFT) results and assessed lobar differences in chronic obstructive pulmonary disease (COPD) patients, using paired inspiratory and expiratory three dimensional (3D) computed tomography (CT) images. METHODS: We retrospectively assessed 28 COPD patients who underwent paired inspiratory and expiratory CT and PFT exams on the same day. A computer aided diagnostic system calculated total lobar volume and emphysematous lobar volume (ELV). Normal lobar volume (NLV) was determined by subtracting ELV from total lobar volume, both for inspiratory phase (NLVI) and for expiratory phase (NLVE). We also determined lobar collapsibility indices: NLV collapsibility ratio (NLVCR) (%)=(1-NLVE/NLVI)*100%. Associations between lobar volumes and PFT results, and collapsibility indices and PFT results were determined by Pearson correlation analysis. RESULTS: NLVCR values were significantly correlated with PFT results. Forced expiratory volume in 1 second, measured as percent of predicted results (FEV1%P) was significantly correlated with NLVCR values for the lower lobes (P<0.01), whereas this correlation was not significant for the upper lobes (P=0.05). FEV1%P results were also moderately correlated with inspiratory, expiratory ELV (ELVI,E) for the lower lobes (P<0.05). In contrast, the ratio of the diffusion capacity for carbon monoxide to alveolar gas volume, measured as percent of predicted (DLCO/VA%P) results were strongly correlated with ELVI for the upper lobes (P<0.001), whereas this correlation with NLVCR values was weaker for upper lobes (P<0.01) and was not significant for the lower lobes (P=0.26). CONCLUSION: FEV1%P results were correlated with NLV collapsibility indices for lower lobes, whereas DLCO/VA%P results were correlated with NLV collapsibility indices and ELV for upper lobes. Thus, evaluating lobar NLV collapsibility might be useful for estimating pulmonary function in COPD patients. PMID- 25525353 TI - The relationship between the COPD Assessment Test score and airflow limitation in Japan in patients aged over 40 years with a smoking history. AB - BACKGROUND: A large number of chronic obstructive pulmonary disease (COPD) patients in Japan remain undiagnosed, primarily due to the underuse of spirometry. Two studies were conducted to see whether the COPD Assessment Test (CAT) in primary care has the potential to identify those patients who need spirometry for a diagnosis of COPD and to determine whether patients with cardiovascular disease had airflow limitation, which could be detected by CAT. MATERIALS AND METHODS: Two multicenter, noninterventional, prospective studies (studies 1 and 2) were conducted across Japan. Patients in both studies were >=40 years old with a smoking history. Those in study 1 were seen in primary care and had experienced repeated respiratory tract infections, but had no diagnosis of COPD. Patients in study 2 were identified in cardiovascular disease clinics when routinely visiting for their cardiovascular disease. All patients completed the CAT prior to lung-function testing by hand-held spirometry. The presence of airflow limitation was defined as a forced expiratory volume in 1 second (FEV1)/FEV6 ratio<0.73. RESULTS: A total of 3,062 subjects completed the CAT (2,067 in study 1, 995 in study 2); 88.8% were male, and the mean age (+/ standard deviation) was 61.5+/-11.6 years. Airflow limitation was found in 400 (19.4%) patients in study 1, and 269 (27.0%) in study 2. The CAT score in patients with airflow limitation was significantly higher than in patients without airflow limitation in both studies: 8.6 (95% confidence interval [CI] 7.9 9.2) versus 7.4 (95% CI 7.1-7.6) in study 1, and 8.3 (95% CI 7.5-9.2) versus 6.4 (95% CI 6.0-6.8) in study 2 (both P<0.001). CONCLUSION: These findings suggest that the CAT has the potential to identify patients with cardiovascular disease or a history of frequent chest infections who need spirometry to diagnose COPD. PMID- 25525354 TI - Ease-of-use preference for the ELLIPTA(r) dry powder inhaler over a commonly used single-dose capsule dry powder inhaler by inhalation device-naive Japanese volunteers aged 40 years or older. AB - BACKGROUND: In patients receiving inhaled medication, dissatisfaction with and difficulty in using the inhaler can affect treatment adherence. The incidence of handling errors is typically higher in the elderly than in younger people. The aim of the study was to assess inhaler preference for and handling errors with the ELLIPTA(r) dry powder inhaler (DPI), (GSK), compared with the established BREEZHALERTM, a single-dose capsule DPI (Novartis), in inhalation device-naive Japanese volunteers aged >=40 years. METHODS: In this open-label, nondrug interventional, crossover DPI preference study comparing the ELLIPTA DPI and BREEZHALER, 150 subjects were randomized to handle the ELLIPTA or BREEZHALER DPIs until the point of inhalation, without receiving verbal or demonstrative instruction (first attempt). Subjects then crossed over to the other inhaler. Preference was assessed using a self-completed questionnaire. Inhaler handling was assessed by a trained assessor using a checklist. Subjects did not inhale any medication in the study, so efficacy and safety were not measured. RESULTS: The ELLIPTA DPI was preferred to the BREEZHALER by 89% of subjects (odds ratio [OR] 70.14, 95% confidence interval [CI] 33.69-146.01; P-value not applicable for this inhaler) for ease of use, by 63% of subjects (OR 2.98, CI 1.87-4.77; P<0.0001) for ease of determining the number of doses remaining in the inhaler, by 91% for number of steps required, and by 93% for time needed for handling the inhaler. The BREEZHALER was preferred to the ELLIPTA DPI for comfort of the mouthpiece by 64% of subjects (OR 3.16, CI 1.97-5.06; P<0.0001). The incidence of handling errors (first attempt) was 11% with ELLIPTA and 68% with BREEZHALER; differences in incidence were generally similar when analyzed by age (< or >=65 years) or sex. CONCLUSION: These data, obtained in an inhalation device-naive population, suggest that the ELLIPTA DPI is preferred to an established alternative based on its ease-of-use features and is associated with fewer handling errors. PMID- 25525355 TI - Preparation and characterization of self-assembled nanoparticles based on low molecular-weight heparin and stearylamine conjugates for controlled delivery of docetaxel. AB - Low-molecular-weight heparin (LMWH)-stearylamine (SA) conjugates (LHSA)-based self-assembled nanoparticles were prepared for intravenous delivery of docetaxel (DCT). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide were used as coupling agents for synthesis of LHSA conjugates. The physicochemical properties, in vitro antitumor efficacy, in vitro cellular uptake efficiency, in vivo antitumor efficacy, and in vivo pharmacokinetics of LHSA nanoparticles were investigated. The LHSA nanoparticles exhibited a spherical shape with a mean diameter of 140-180 nm and a negative surface charge. According to in vitro release and in vivo pharmacokinetic test results, the docetaxel loaded LHSA5 (LMWH:SA =1:5) nanoparticles exhibited sustained drug release profiles. The blank LHSA nanoparticles demonstrated only an insignificant cytotoxicity in MCF-7 and MDAMB 231 human breast cancer cells; additionally, higher cellular uptake of coumarin 6 (C6) in MCF-7 and MDAMB 231 cells was observed in the LHSA5 nanoparticles group than that in the C6 solution group. The in vivo tumor growth inhibition efficacy of docetaxel-loaded LHSA5 nanoparticles was also significantly higher than the Taxotere-treated group in the MDAMB 231 tumor-xenografted mouse model. These results indicated that the LHSA5-based nanoparticles could be a promising anticancer drug delivery system. PMID- 25525356 TI - Closing the gap: accelerating the translational process in nanomedicine by proposing standardized characterization techniques. AB - On the cusp of widespread permeation of nanomedicine, academia, industry, and government have invested substantial financial resources in developing new ways to better treat diseases. Materials have unique physical and chemical properties at the nanoscale compared with their bulk or small-molecule analogs. These unique properties have been greatly advantageous in providing innovative solutions for medical treatments at the bench level. However, nanomedicine research has not yet fully permeated the clinical setting because of several limitations. Among these limitations are the lack of universal standards for characterizing nanomaterials and the limited knowledge that we possess regarding the interactions between nanomaterials and biological entities such as proteins. In this review, we report on recent developments in the characterization of nanomaterials as well as the newest information about the interactions between nanomaterials and proteins in the human body. We propose a standard set of techniques for universal characterization of nanomaterials. We also address relevant regulatory issues involved in the translational process for the development of drug molecules and drug delivery systems. Adherence and refinement of a universal standard in nanomaterial characterization as well as the acquisition of a deeper understanding of nanomaterials and proteins will likely accelerate the use of nanomedicine in common practice to a great extent. PMID- 25525357 TI - Selective inhibition of liver cancer growth realized by the intrinsic toxicity of a quantum dot-lipid complex. AB - Using the intrinsic toxicity of nanomaterials for anticancer therapy is an emerging concept. In this work, we discovered that CdTe/CdS quantum dots, when coated with lipids (QD-LC) instead of popular liposomes, polymers, or dendrimers, demonstrated extraordinarily high specificity for cancer cells, which was due to the difference in the macropinocytosis uptake pathways of QD-LC between the cancer cells and the normal cells. QD-LC-induced HepG2 cell apoptosis was concomitant with the activation of the JNK/caspase-3 signaling pathway. Moreover, QD-LC treatment resulted in a delay in the latent period for microtumor formation of mouse hepatocarcinoma H22 cells and inhibited tumor growth, with a reduction of 53.2% in tumor volume without toxicity in major organs after intratumoral administrations to tumor-bearing mice. Our results demonstrate that QD-LC could be a very promising theranostic agent against liver cancer. PMID- 25525358 TI - Quantum dots immunofluorescence histochemical detection of EGFR gene mutations in the non-small cell lung cancers using mutation-specific antibodies. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) mutation status plays an important role in therapeutic decision making for non-small cell lung cancer (NSCLC) patients. Since EGFR mutation-specific antibodies (E746-A750del and L858R) have been developed, EGFR mutation detection by immunohistochemistry (IHC) is a suitable screening test. On this basis, we want to establish a new screening test, quantum dots immunofluorescence histochemistry (QDs-IHC), to assess EGFR gene mutation in NSCLC tissues, and we compared it to traditional IHC and amplification refractory mutation system (ARMS). MATERIALS AND METHODS: EGFR gene mutations were detected by QDs-IHC, IHC, and ADx-ARMS in 65 cases of NSCLC composed of 55 formalin-fixed, paraffin-embedded specimens and ten pleural effusion cell blocks, including 13 squamous cell carcinomas, two adenosquamous carcinomas, and 50 adenocarcinomas. RESULTS: Positive rates of EGFR gene mutations detected by QDs-IHC, IHC, and ADx-ARMS were 40.0%, 36.9%, and 46.2%, respectively, in 65 cases of NSCLC patients. The sensitivity of QDs-IHC when detecting EGFR mutations, as compared to ADx-ARMS, was 86.7% (26/30); the specificity for both antibodies was 100.0% (26/26). IHC sensitivity was 80.0% (24/30) and the specificity was 92.31% (24/26). When detecting EGFR mutations, QDs-IHC and ADx-ARMS had perfect consistency (kappa =0.882; P<0.01). Excellent agreement was observed between IHC and ADx-ARMS when detecting EGFR mutations (kappa =0.826; P<0.01). CONCLUSION: QDs-IHC is a simple and standardized method to detect EGFR mutations with its high sensitivity and specificity, as compared with real-time polymerase chain reaction. In addition, the development of specific antibodies against EGFR mutation proteins might be useful for the diagnosis and treatment of lung cancer. PMID- 25525359 TI - Influence of nanoparticles on color stability, microhardness, and flexural strength of acrylic resins specific for ocular prosthesis. AB - The aim of this study was to assess the effect of adding nanoparticles to N1 acrylic resin intended for artificial sclera, in terms of the color stability, microhardness, and flexural strength of the resin. Three hundred samples of N1 acrylic resin were used: 100 samples for color stability and microhardness tests (each test was performed on the opposite side of each sample), and 200 samples for flexural strength testing (100 samples before and after 1,008 hours of accelerated aging). Samples for each test were separated into ten groups (n=10), ie, without nanoparticles (control group) or with nanoparticles of zinc oxide, titanium dioxide (TiO2), and barium sulfate at weight concentrations of 1%, 2%, and 2.5% (nanoparticle groups). Data were subjected to statistical analysis with nested analysis of variance and Tukey's test (P<0.05 significance level). Among the nanoparticle groups, the TiO2 groups showed better color stability at all concentrations. Microhardness values increased after artificial aging, except for the control and zinc oxide groups. After aging, the 1%-2% TiO2 groups had significantly higher microhardness values compared with the other nanoparticle groups. Before aging, there was a significant difference in flexural strength between the control and nanoparticle groups. After aging, the control and TiO2 groups, regardless of concentration, showed the lowest flexural strength values. Incorporation of nanoparticles directly influenced the acrylic resin properties, with TiO2 being the most influential nanoparticle in terms of the evaluated properties. PMID- 25525360 TI - Drug and bioactive molecule screening based on a bioelectrical impedance cell culture platform. AB - This review will present a brief discussion on the recent advancements of bioelectrical impedance cell-based biosensors, especially the electric cell substrate impedance sensing (ECIS) system for screening of various bioactive molecules. The different technical integrations of various chip types, working principles, measurement systems, and applications for drug targeting of molecules in cells are highlighted in this paper. Screening of bioactive molecules based on electric cell-substrate impedance sensing is a trial-and-error process toward the development of therapeutically active agents for drug discovery and therapeutics. In general, bioactive molecule screening can be used to identify active molecular targets for various diseases and toxicity at the cellular level with nanoscale resolution. In the innovation and screening of new drugs or bioactive molecules, the activeness, the efficacy of the compound, and safety in biological systems are the main concerns on which determination of drug candidates is based. Further, drug discovery and screening of compounds are often performed in cell based test systems in order to reduce costs and save time. Moreover, this system can provide more relevant results in in vivo studies, as well as high-throughput drug screening for various diseases during the early stages of drug discovery. Recently, MEMS technologies and integration with image detection techniques have been employed successfully. These new technologies and their possible ongoing transformations are addressed. Select reports are outlined, and not all the work that has been performed in the field of drug screening and development is covered. PMID- 25525361 TI - Association of Per3 length polymorphism with bipolar I disorder and schizophrenia. AB - BACKGROUND: Sleep-wake disturbances have frequently been reported in bipolar disorder and schizophrenia, and are considered to be caused by an underlying circadian rhythm disorder. The study presented here was designed to investigate the existence of Per3 polymorphism in bipolar disorder type I (BD-I) and schizophrenic patients in South India. METHODS: Blood samples were collected from 311 BD-I patients, 293 schizophrenia patients, and 346 age- and sex-matched normal controls. Per3 genotyping was performed on DNA by polymerase chain reaction using specific primers. RESULTS: An increased prevalence of five repeat homozygotes was seen in BD-I patients as compared with healthy controls (odds ratio =1.72 [95% confidence interval: 1.08-2.76, P=0.02]). In BD-I patients, the frequency of the five repeat allele was higher (allele frequency =0.41), and that of the four repeat allele lower (allele frequency =0.36) (chi (2)=4.634; P<0.03) than in the control group. No significant association was observed in the allele frequencies of four and five repeat alleles in schizophrenia patients when compared with controls. CONCLUSION: The occurrence of the five repeat allele of Per3 may be a risk factor for BD-I onset in this ethnic group. PMID- 25525363 TI - Iminodibenzyl class antipsychotics for schizophrenia: a systematic review and meta-analysis of carpipramine, clocapramine, and mosapramine. AB - BACKGROUND: We conducted a meta-analysis of the iminodibenzyl antipsychotics carpipramine, clocapramine, and mosapramine, which are classified as second generation antipsychotics (SGAs) for schizophrenia treatment. METHODS: We searched data that had been published in PubMed, the Cochrane Library databases, PsycINFO, CiNii, and the Japan Medical Abstracts Society up to August 29, 2014. Randomized controlled trials that compared iminodibenzyl antipsychotics with other antipsychotics in patients with schizophrenia were included. Odds ratios and standardized mean differences were evaluated. RESULTS: We included four randomized controlled trials on carpipramine (number of patients [n]=290), six on clocapramine (n=1,048), and five on mosapramine (n=986) in the meta-analysis. There were no significant differences in the response rates or in the discontinuation rates either between carpipramine and the other pooled antipsychotics or between clocapramine and the other pooled antipsychotics. On the Positive and Negative Syndrome Scale, mosapramine's positive subscale scores were superior to those of the other pooled antipsychotics (standard mean of difference =-0.22); however, on that same scale, there were no significant differences in total scores, negative scores, general subscale scores, response rates, or the discontinuation rates between mosapramine and the other pooled antipsychotics. Furthermore, the incidences of extrapyramidal symptoms and of hyperprolactinemia were significantly greater with mosapramine than with the other pooled antipsychotics. CONCLUSION: The pharmacological profiles of carpipramine and clocapramine, which are classified as SGAs, were similar to those of first-generation antipsychotics because there were no significant differences in efficacy and safety outcomes. However, mosapramine was associated with a greater risk of extrapyramidal symptoms and hyperprolactinemia than the other SGAs were, although it may be beneficial for the improvement of positive symptoms. PMID- 25525362 TI - Parkinson's disease-associated melanin steal. AB - Urinary dopamine fluctuations in the competitive inhibition state were first documented in 2009. At that time, it was noted that progressively higher daily dosing values of L-tyrosine decreased the magnitude of these fluctuations. While extensive statistical analysis has been performed by the authors since 2004, it was not until 2012 that a plausible explanation was formulated. In the process, correlations with L-tyrosine administration and the on/off effect of Parkinson's disease were defined. This paper documents the current knowledge with regard to the management of retrograde phase 1 dopamine fluctuations and investigates the hypothesis that they are caused by a melanin steal phenomenon. PMID- 25525364 TI - Single event-related changes in cerebral oxygenated hemoglobin using word game in schizophrenia. AB - Neuroimaging studies have been conducted using word generation tasks and have shown greater hypofrontality in patients with schizophrenia compared with healthy subjects. In this study, we compared the characteristics of oxygenated hemoglobin changes involved in both phonological and categorical verbal fluency between 35 outpatients with schizophrenia and 35 healthy subjects during a Japanese "shiritori" task using single-event-related near-infrared spectroscopy. During this task, the schizophrenic patients showed significantly smaller activation in the prefrontal cortex area than the controls. In addition, a significant positive correlation was obtained between oxygenated hemoglobin changes (prefrontal cortex area, inferior parietal area) and the severity of positive psychiatric symptoms. It is possible that hypofrontality of patients may be a diagnostic assistance tool for schizophrenia, and that the relationship between activation and positive syndrome scores may be of help in predicting functional outcome in patients. PMID- 25525365 TI - Prospective study of incidence and predictors of peripheral intravenous catheter induced complications. AB - BACKGROUND: Although intravenous therapy is one of the most commonly performed procedures in hospitalized patients, it remains susceptible to infectious and noninfectious complications. Previous studies investigated peripheral intravenous catheter (PIVC) complications mainly in pediatrics, but apparently none were investigated among Saudi adult populations. The aim of this study was to assess the pattern and complications of PIVCs at King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia. METHODS: An observational prospective cohort study investigated PIVCs pattern and complications among adults with PIVCs, admitted to various wards at KAMC. PIVCs-related clinical outcomes (pain, phlebitis, leaking, and others) were recorded in 12-hour intervals, using the Visual Inspection Phlebitis scale. Density incidence (DI) and cumulative incidence (CI) of complications and their relative risks (RRs) were calculated. Regression analyses were applied and significance limits were set at P<0.05. RESULTS: During the study period, 359 adults were included, mounting to 842 PIVCs and 2,505 catheter days. The majority of patients, 276 (76.9%), had medical, chief admission complaints, whereas 83 (23.1%) were trauma/surgical and infectious cases. Complicated catheters were found in 141 (39.3%) patients, with 273 complications (32.4/100 catheters), in 190 complicated catheters (CI =22.56/100 catheters and DI =75.84/1,000 catheter days). Phlebitis ranked first among complications, 148 (CI =17.6%), followed by pain 64 (CI =7.6%), leaking 33 (CI =3.9%), dislodgement 20 (CI =2.4%), and extravasations and occlusion 4 (CI =0.5% each). Phlebitis was predicted with female sex (P<0.001), insertion in fore/upper arm (P=0.024), and infusion of medication (P=0.02). Removal time for PIVCs insertion was not a significant predictor of phlebitis (RR =1.46, P=0.08). CONCLUSION: Incidence of complications in this study was significantly higher than rates in previous studies. Better insertion techniques may be sought to lower the incidences of PIVC complications, thus extending their onset beyond day 3. Changing catheters is recommended when clinically indicated rather than routinely post-72 hours. PMID- 25525366 TI - Prevalence of risk factors at presentation and early mortality in patients aged 80 years or older with ST-segment elevation myocardial infarction. AB - BACKGROUND: Elderly patients with ST-segment elevation myocardial infarction (STEMI) are at high risk for complications and early mortality; still, they are underrepresented in clinical trials and observational studies. We studied the risk profiles at presentation and early mortality in elderly (>=80 years) versus younger (<80 years) STEMI patients. DESIGN: This was a prospective cohort study. METHODS: The study population comprised 4,092 consecutive STEMI patients admitted to Oslo University Hospital, Ulleval from 2006 to 2010. Baseline characteristics at admission were recorded, as well as in-hospital mortality. Etiologic strategy was used in the analyses. RESULTS: Patients >=80 years of age (n=536) were more likely to be women and have prior myocardial infarction, angina, and stroke, but were less likely to be current smokers. The crude in-hospital mortality was 16.2% in patients aged 80 years and older versus 3.5% in those younger than 80 years. The adjusted odds ratio for mortality in patients aged 80 years and older versus those younger than 80 years increased with increasing levels of serum creatinine and total cholesterol. In patients with low levels of serum creatinine and total cholesterol, the odds ratio was 3.01 (95% confidence interval, 1.86-4.93; P=0.0001); increasing to 11.72 (95% confidence interval, 5.26-26.3; P=0.001) in patients with high levels. CONCLUSION: High levels of serum cholesterol and creatinine were important risk factors for early mortality in elderly patients. Depending on the levels of cholesterol and creatinine, in-hospital mortality in patients aged 80 years and older varied from a threefold to an almost twelvefold risk compared with younger patients. PMID- 25525367 TI - Web-based collaboration in individual care planning challenges the user and the provider roles - toward a power transition in caring relationships. AB - BACKGROUND AND OBJECTIVE: The Individual Care Plan (ICP) was introduced in Norway to meet new statutory requirements for user participation in health care planning, incorporating multidisciplinary and cross-sector collaboration. A web based solution (electronic ICP [e-ICP]) was used to support the planning and documentation. The aim of this study was to investigate how web-based collaboration challenged user and professional roles. METHODS: Data were obtained from 15 semistructured interviews with users and eight with care professionals, and from two focus-group interviews with eight care professionals in total. The data were analyzed using systematic text condensation in a stepwise analysis model. RESULTS: Users and care professionals took either a proactive or a reluctant role in e-ICP collaboration. Where both user and care professionals were proactive, the pairing helped to ensure that the planning worked well; so did pairings of proactive care professionals and reluctant users. Proactive users paired with reluctant care professionals also made care planning work, thanks to the availability of information and the users' own capacity or willingness to conduct the planning. Where both parties were reluctant, no planning activities occurred. CONCLUSION: Use of the e-ICP challenged the user-professional relationship. In some cases, a power transition took place in the care process, which led to patient empowerment. This knowledge might be used to develop a new understanding of how role function can be challenged when users and care professionals have equal access to health care documentation and planning tools. PMID- 25525368 TI - Subdural porous and notched mini-grid electrodes for wireless intracranial electroencephalographic recordings. AB - BACKGROUND: Intracranial electroencephalography (EEG) studies are widely used in the presurgical evaluation of drug-refractory patients with partial epilepsy. Because chronic implantation of intracranial electrodes carries a risk of infection, hemorrhage, and edema, it is best to limit the number of electrodes used without compromising the ability to localize the epileptogenic zone (EZ). There is always a risk that an intracranial study may fail to identify the EZ because of suboptimal coverage. We present a new subdural electrode design that will allow better sampling of suspected areas of epileptogenicity with lower risk to patients. METHOD: Impedance of the proposed electrodes was characterized in vitro using electrochemical impedance spectroscopy. The appearance of the novel electrodes on magnetic resonance imaging (MRI) was tested by placing the electrodes into a gel solution (0.9% NaCl with 14 g gelatin). In vivo neural recordings were performed in male Sprague Dawley rats. Performance comparisons were made using microelectrode recordings from rat cortex and subdural/depth recordings from epileptic patients. Histological examinations of rat brain after 3-week icEEG intracerebral electroencephalography (icEEG) recordings were performed. RESULTS: The in vitro results showed minimum impedances for optimum choice of pure gold materials for electrode contacts and wire. Different attributes of the new electrodes were identified on MRI. The results of in vivo recordings demonstrated signal stability, 50% noise reduction, and up to 6 dB signal-to-noise ratio (SNR) improvement as compared to commercial electrodes. The wireless icEEG recording system demonstrated on average a 2% normalized root-mean square (RMS) deviation. Following the long-term icEEG recording, brain histological results showed no abnormal tissue reaction in the underlying cortex. CONCLUSION: The proposed subdural electrode system features attributes that could potentially translate into better icEEG recordings and allow sampling of large of areas of epileptogenicity at lower risk to patients. Further validation for use in humans is required. PMID- 25525369 TI - Magnetic resonance imaging of graded skeletal muscle injury in live rats. AB - INTRODUCTION: Increasing number of stretch-shortening contractions (SSCs) results in increased muscle injury. METHODS: Fischer Hybrid rats were acutely exposed to an increasing number of SSCs in vivo using a custom-designed dynamometer. Magnetic resonance imaging (MRI) imaging was conducted 72 hours after exposure when rats were infused with Prohance and imaged using a 7T rodent MRI system (GE Epic 12.0). Images were acquired in the transverse plane with typically 60 total slices acquired covering the entire length of the hind legs. Rats were euthanized after MRI, the lower limbs removed, and tibialis anterior muscles were prepared for histology and quantified stereology. RESULTS: Stereological analyses showed myofiber degeneration, and cellular infiltrates significantly increased following 70 and 150 SSC exposure compared to controls. MRI images revealed that the percent affected area significantly increased with exposure in all SSC groups in a graded fashion. Signal intensity also significantly increased with increasing SSC repetitions. DISCUSSION: These results suggest that contrast-enhanced MRI has the sensitivity to differentiate specific degrees of skeletal muscle strain injury, and imaging data are specifically representative of cellular histopathology quantified via stereological analyses. PMID- 25525370 TI - Potential Contribution of Work-Related Psychosocial Stress to the Development of Cardiovascular Disease and Type II Diabetes: A Brief Review. AB - Two of the major causes of death worldwide are cardiovascular disease and Type II diabetes. Although death due to these diseases is assessed separately, the physiological process that is attributed to the development of cardiovascular disease can be linked to the development of Type II diabetes and the impact that this disease has on the cardiovascular system. Physiological, genetic, and personal factors contribute to the development of both these disorders. It has also been hypothesized that work-related stress may contribute to the development of Type II diabetes and cardiovascular disease. This review summarizes some of the studies examining the role of work-related stress on the development of these chronic disorders. Because women may be more susceptible to the physiological effects of work-related stress, the papers cited in this review focus on studies that examined the difference in responses of men or women to work-related stress or on studies that focused on the effects of stress on women alone. Based on the papers summarized, it is concluded that (1) work-related stress may directly contribute to the development of cardiovascular disease by inducing increases in blood pressure and changes in heart rate that have negative consequences on functioning of the cardiovascular system; (2) workers reporting increased levels of stress may display an increased risk of Type II diabetes because they adopt poor health habits (ie, increased level of smoking, inactivity etc), which in turn contribute to the development of cardiovascular problems; and (3) women in high demand and low-control occupations report an increased level of stress at work, and thus may be at a greater risk of negative health consequences. PMID- 25525371 TI - Multidrug resistance protein 1 localization in lipid raft domains and prostasomes in prostate cancer cell lines. AB - BACKGROUND: One of the problems in prostate cancer (CaP) treatment is the appearance of the multidrug resistance phenotype, in which ATP-binding cassette transporters such as multidrug resistance protein 1 (MRP1) play a role. Different localizations of the transporter have been reported, some of them related to the chemoresistant phenotype. AIM: This study aimed to compare the localization of MRP1 in three prostate cell lines (normal, androgen-sensitive, and androgen independent) in order to understand its possible role in CaP chemoresistance. METHODS: MRP1 and caveolae protein markers were detected using confocal microscopy, performing colocalization techniques. Lipid raft isolation made it possible to detect these proteins by Western blot analysis. Caveolae and prostasomes were identified by electron microscopy. RESULTS: We show that MRP1 is found in lipid raft fractions of tumor cells and that the number of caveolae increases with malignancy acquisition. MRP1 is found not only in the plasma membrane associated with lipid rafts but also in cytoplasmic accumulations colocalizing with the prostasome markers Caveolin-1 and CD59, suggesting that in CaP cells, MRP1 is localized in prostasomes. CONCLUSION: We hypothesize that the presence of MRP1 in prostasomes could serve as a reservoir of MRP1; thus, taking advantage of the release of their content, MRP1 could be translocated to the plasma membrane contributing to the chemoresistant phenotype. The presence of MRP1 in prostasomes could serve as a predictor of malignancy in CaP. PMID- 25525372 TI - The effect of a unique propolis compound (PropoelixTM) on clinical outcomes in patients with dengue hemorrhagic fever. AB - BACKGROUND: Dengue fever is a mosquito-borne virus belonging to the family Flaviviridae. It is an old virus that has re-emerged globally over the past 20 years and now causes a global burden of 50 million infections per year across approximately 100 countries. Despite this, there is no safe vaccine available, and therapy is largely supportive. Its pathogenesis is multifaceted and currently still poorly understood, leading to a lack of disease-specific therapy. Propolis is a natural antiviral and anti-inflammatory product derived from the saps of plants and mixed with the saliva of honeybees. PropoelixTM is a uniquely potent and water-soluble extract of propolis containing high concentrations of anti inflammatory compounds like caffeic acid phenethyl ester. OBJECTIVE: The primary objective is to determine the effectiveness of a unique propolis extract (PropoelixTM) on the clinical course of patients with dengue hemorrhagic fever (DHF). The secondary objective is to examine the effect of PropoelixTM on tumor necrosis factor-alpha (TNF-alpha) levels in patients with DHF. METHODS: A double blind, randomized, placebo-controlled trial was conducted at the Department of Internal Medicine, Gatot Soebroto Central Army Hospital in Jakarta, Indonesia, from May 2012 to July 2013. Sixty-three patients who met the inclusion criteria were enrolled in the trial. Patients were randomized to receive either two capsules of PropoelixTM 200 mg three times a day or placebo daily for 7 days. Clinical and laboratory variables of both groups, including the anti-inflammatory marker TNF-alpha, were investigated. Patients were deemed technically fit for discharge if their platelet counts had recovered and exceeded 100,000/MUL but were all observed as inpatients for 7 days. RESULTS: There were 31 patients in the PropoelixTM treatment group and 32 patients in the placebo group. Platelet counts in the PropoelixTM-treated group showed a trend toward a faster recovery by day 3 of admission and became statistically significant by day 6 (101.42+/ 48.79 vs 80.78+/-43.35 [10(3)/mL], P=0.042) and day 7 (146.67+/-64.68 vs 107.84+/ 57.22 [10(3)/mL], P=0.006). Patients treated with PropoelixTM had a significantly greater decline in TNF-alpha levels on day 7 of therapy compared with patients in the placebo group (P=0.018). They also had a significantly shorter length of hospitalization compared with those in the placebo group (4.69+/-0.78 days vs 5.46+/-1.16 days, P=0.012). CONCLUSION: PropoelixTM appears to hasten the improvement in platelet counts and TNF-alpha levels and shortens the duration of hospitalization in patients with DHF. PMID- 25525373 TI - Does antimicrobial use density at the ward level influence monthly central line associated bloodstream infection rates? AB - The aim of this study was to elucidate risk factors, including ward antimicrobial use density (AUD), for central line-associated bloodstream infection (CLABSI) as defined by the Centers for Disease Control and Prevention in a 430-bed community hospital using central venous lines with closed-hub systems. We calculated AUD as (total dose)/(defined daily dose * patient days) *1,000 for a total of 20 drugs, nine wards, and 24 months. Into each line day data, we inputed AUD and device utilization ratios, number of central line days, and CLABSI. The ratio of susceptible strains in isolates were subjected to correlation analysis with AUD. Of a total of 9,997 line days over 24 months, CLABSI was present in 33 cases (3.3 0/00), 14 (42.4%) of which were on surgical wards out of nine wards. Of a total of 43 strains isolated, eight (18.6%) were methicillin-resistant Staphylococcus aureus (MRSA); none of the MRSA-positive patients had received cefotiam before the onset of infection. Receiver-operating characteristic analysis showed that central line day 7 had the highest accuracy. Logistic regression analysis showed the central line day showed an odds ratio of 5.511 with a 95% confidence interval of 1.936-15.690 as did AUD of cefotiam showing an odds ratio of 0.220 with 95% confidence interval of 0.00527-0.922 (P=0.038). Susceptible strains ratio and AUD showed a negative correlation (R (2)=0.1897). Thus, CLABSI could be prevented by making the number of central line days as short as possible. The preventative role of AUD remains to be investigated. PMID- 25525375 TI - Effect of occasional epoetin use in combination with a stable darbepoetin dosage on anemia management in hemodialysis patients. AB - AIM: Taking advantage of the characteristics of both darbepoetin (DA) and epoetin (EPO) might be a reasonable option for stabilizing hemoglobin (Hb) control in hemodialysis (HD) patients. The effect of DA assisted by EPO (DA/EPO) on Hb control was evaluated retrospectively in comparison with that of EPO monotherapy. METHODS: Twenty-six HD patients whose annual mean Hb values were available for both an EPO monotherapy period and a DA/EPO period were selected for analysis. During the DA/EPO period, DA was given on the second HD day of a week, and EPO was given if needed on the first and third HD days. Under stable DA dosage, when Hb rose >12 g/dL, EPO was eliminated. When Hb decreased <10 g/dL, EPO was added again. The variability of annual mean Hb values from the 26 HD patients during the DA/EPO period was compared with that during the EPO period. Additionally, the distance in Hb (d-Hb; absolute value of difference) between the annual mean Hb values and the target Hb (11 g/dL) during the DA/EPO period was compared with that during the EPO period. RESULTS: The variability of annual mean Hb values during the DA/EPO period was significantly smaller than that during the EPO period (11.2+/-0.25 g/dL versus [vs] 11.0+/-0.50 g/dL; the F-test for equality of variance, P<0.001). Additionally, the d-Hb during the DA/EPO period was significantly smaller than that during the EPO period (0.22+/-0.21 g/dL vs 0.38+/ 0.31 g/dL, P<0.03). The total doses (as EPO equivalents) of DA with EPO were reduced to 82.2% of the baseline EPO dose during the EPO monotherapy period. The expenditure for the DA/EPO period was significantly reduced to 80.9% of that for the EPO monotherapy. Also, the annual total amount of intravenous iron supplementation during the DA/EPO period was significantly reduced compared with that during the EPO period (546+/-304 mg/year vs 684+/-314 mg/year, P<0.05). CONCLUSION: The occasional use of EPO in combination with a stable DA dosage may be useful for Hb control within a narrow range of the target level. PMID- 25525374 TI - Current perspectives on the spread of dengue in India. AB - Dengue fever (DF) and dengue hemorrhagic fever (DHF) are important arthropod borne viral diseases. Each year, there are ~50 million dengue infections and ~500,000 individuals are hospitalized with DHF, mainly in Southeast Asia. Dengue in India has dramatically expanded over the last few decades, with rapidly changing epidemiology. The first major DHF outbreak in the entire nation occurred in 1996 by dengue virus serotype 2, and after a gap of almost a decade, the country faced yet another DF outbreak in the year 2003 by dengue virus serotype 3. A dramatic increase in the number and frequency of outbreaks followed, and, at present, in most of the states of India, dengue is almost endemic. At present, all the four serotypes are seen in circulation, but the predominant serotype keeps changing. Despite this trend, surveillance, reporting, and diagnosis of dengue remain largely passive in India. More active community-based epidemiological studies with intensive vector control and initiatives for dengue vaccine development should be geared up to control the spread of dengue in India. We review here the factors that may have contributed to the changing epidemiology of dengue in India. PMID- 25525376 TI - Severity and impact of acne vulgaris on the quality of life of adolescents in Nigeria. AB - BACKGROUND: Acne vulgaris is a common skin condition, which affects most adolescents at some point in their lives. It has been found to have a significant impact on their psychological well-being and has been associated with depression and suicide ideation. Many studies have assessed the impact of acne vulgaris on the quality of life (QoL) in different population subgroups around the world, but there is a dearth of reports from the African subcontinent. This study thus seeks to assess the severity of acne vulgaris and determine its effect on the QoL of adolescents in Lagos, Nigeria. METHODS: In a cross-sectional survey employing a two-stage sampling method, the severity of acne vulgaris and its impact on the QoL of adolescents attending a senior secondary school in Lagos, Nigeria was assessed using the Global Acne Grading Scale (GAGS) and the Cardiff Acne Disability Index (CADI), respectively. The correlation between the results of the GAGS and CADI was also determined. RESULTS: One hundred and sixty adolescent students with acne were recruited, with males accounting for 51.9% and females 48.1%. The mean and standard deviation of the GAGS severity scores were 11.3+/ 5.4 for males and 11.9+/-5.4 for females. Only one student had severe acne vulgaris (GAGS, 31-38), 10% moderate (GAGS, 19-30), and 89.4% mild (GAGS, 1-18). The overall CADI score was 3.4+/-3.0, which suggests mild impairment in QoL; however, the solitary student with severe acne had severe QoL impairment. There was a weak positive correlation between the GAGS and the CADI score. CONCLUSION: Most adolescents in our study had mild acne vulgaris, and the overall impact on their QoL was mild. However, the correlation between the psychosocial impact and acne severity was weak. There is a need for similar studies in other parts of the country and for further studies to determine the adequacy of the existing instruments in assessing the impact of acne vulgaris in Nigerian adolescents. PMID- 25525377 TI - Radiofrequency ablation using BarRx for the endoscopic treatment of radiation proctopathy: a series of three cases. AB - Radiation proctopathy is a complication of pelvic radiotherapy, which occurs in patients treated for carcinoma of the prostate, rectum, urinary bladder, cervix, uterus, and testes. If it presents within 6 weeks to 9 months after therapy, it is called acute radiation proctitis/proctopathy (ARP), and if it occurs 9 months to a year after treatment, it is classified as chronic radiation proctitis/proctopathy (CRP). CRP occurs in 5%-20% of patients receiving pelvic radiation, depending on the radiation dose and the presence or absence of chemotherapy. In many cases, CRP resolves spontaneously, but in some, it can lead to persistent rectal bleeding. Other symptoms of CRP include diarrhea, mucoid discharge, urgency, tenesmus, rectal pain, and fecal incontinence. Despite the availability of several therapies, many patients fail to respond, and continue to suffer in their quality of life. Radiofrequency ablation (RFA) is a newer endoscopic technique that uses radiofrequency energy to ablate tissue. This is an emerging way to treat radiation proctopathy and other mucosal telangiectasia. We present three cases of radiation proctopathy treated with RFA at our institute and review the literature on treatment modalities for CRP. We were also able to find 16 other cases of CRP that used RFA, and review their literature as well as literature on other treatment modalities. PMID- 25525378 TI - Pharmacokinetics and safety of dexlansoprazole MR in pediatric patients with symptomatic gastroesophageal reflux disease. AB - OBJECTIVE: To evaluate the safety and pharmacokinetic profile of dexlansoprazole modified-release (MR) capsules in pediatric patients with symptomatic gastroesophageal reflux disease (GERD). METHODS: This Phase I, open-label study enrolled male and female patients (1 to 11 years of age) with GERD. Patients received dexlansoprazole MR 15 mg, 30 mg, or 60 mg (according to weight) once daily for 7 days. Blood samples for the measurement of plasma dexlansoprazole concentrations were collected for 24 hours after the day 7 dose. Dexlansoprazole plasma concentrations and pharmacokinetic parameters were summarized by dose group. Safety assessments included adverse events (AEs), clinical laboratory evaluations, fasting gastrin concentrations, physical examinations, electrocardiograms, and vital signs. RESULTS: Thirty-six patients received study drug (12 per dose group), and 31 had evaluable pharmacokinetic data. There was a significant effect of weight on dose-normalized area under the curve (AUC, P=0.003) and dose-normalized maximum plasma concentration (Cmax) (P=0.013), indicating that for a given dose, dexlansoprazole exposure decreases as body weight increases. After adjusting for body weight, both dexlansoprazole Cmax and AUC increased in an approximately dose-proportional manner with increasing dexlansoprazole dose. A total of ten of 36 patients reported at least one treatment-emergent AE, with most events considered mild in intensity. The most common AEs were vomiting, abdominal pain, diarrhea, and nausea. CONCLUSION: In 1- to 11-year-old patients with symptomatic GERD, weight-adjusted dexlansoprazole AUC and Cmax increased approximately dose-proportionally. However, for a given dose, dexlansoprazole exposure decreased with increasing body weight. Dexlansoprazole MR was well tolerated, and the incidence of AEs did not increase with increasing dose. PMID- 25525380 TI - Targeted therapy of short-bowel syndrome with teduglutide: the new kid on the block. AB - Extensive intestinal resection impairs the absorptive capacity and results in short-bowel syndrome-associated intestinal failure (SBS-IF), when fluid, electrolyte, acid-base, micro-, and macronutrient homeostasis cannot be maintained on a conventional oral diet. Several factors, including the length and site of the resected intestine, anatomical conformation of the remnant bowel, and the degree of postresection intestinal adaptation determine the disease severity. While mild SBS patients achieve nutritional autonomy with dietary modification (eg, hyperphagia, small frequent meals, and oral rehydration fluids), those with moderate-to-severe disease may develop SBS-IF and become dependent on parenteral support (PS) in the form of intravenous fluids and/or nutrition for sustenance of life. SBS-IF is a chronic debilitating disease associated with a poor quality of life, and carries significant morbidity and health care costs. Medical management of SBS-IF is primarily focused on individually tailored symptomatic treatment strategies, such as antisecretory and antidiarrheal agents to mitigate fluid losses, and PS. However, PS administration is associated with potentially life threatening complications, such as central venous thromboses, bloodstream infections, and liver disease. In pursuit of a targeted therapy to augment intestinal adaptation, research over the past 2 decades has identified glucagon like peptide, an intestinotrophic gut peptide that has been shown to enhance intestinal absorptive capacity by causing an increase in the villus length, crypt depth, and mesenteric blood flow and by decreasing gastrointestinal motility and secretions. Teduglutide, a recombinant analog of glucagon-like peptide-2, is the first targeted therapeutic agent to gain approval for use in adult SBS-IF. Teduglutide was shown to result in significant (20%-100%) reduction in PS-volume requirement and have a satisfactory safety profile in three randomized control trials. Further research is warranted to see if reduction in PS dependency translates to improved quality of life and reduced PS-associated complications. PMID- 25525379 TI - Systematic review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory bowel disease. AB - BACKGROUND: Probiotics are microorganisms that are ingested either in combination or as a single organism in an effort to normalize intestinal microbiota and potentially improve intestinal barrier function. Recent evidence has suggested that inflammatory bowel disease (IBD) may result from an inappropriate immunologic response to intestinal bacteria and a disruption in the balance of the gastrointestinal microbiota in genetically susceptible individuals. Prebiotics, synbiotics, and probiotics have all been studied with growing interest as adjuncts to standard therapies for IBD. In general, probiotics have been shown to be well-tolerated with few side effects, making them a potential attractive treatment option in the management of IBD. AIM: To perform a systematic review of randomized controlled trials on the use of probiotics, prebiotics, and synbiotics in IBD. RESULTS: In our systematic review we found 14 studies in patients with Crohn's disease (CD), 21 studies in patients with ulcerative colitis (UC), and five studies in patients with pouchitis. These were randomized controlled trials using probiotics, prebiotics, and/or synbiotics. In patients with CD, multiple studies comparing probiotics and placebo showed no significant difference in clinical outcomes. Adding a probiotic to conventional treatment improved the overall induction of remission rates among patients with UC. There was also a similar benefit in maintaining remission in UC. Probiotics have also shown some efficacy in the treatment of pouchitis after antibiotic induced remission. CONCLUSIONS: To date, there is insufficient data to recommend probiotics for use in CD. There is evidence to support the use of probiotics for induction and maintenance of remission in UC and pouchitis. Future quality studies are needed to confirm whether probiotics, prebiotics, and synbiotics have a definite role in induction or maintenance of remission in CD, UC, and pouchitis. Similar to probiotics, fecal microbiota transplantation provides an alternate modality of therapy to treat IBD by influencing the intestinal flora. PMID- 25525381 TI - Molecular analysis of beta-globin gene mutations among Thai beta-thalassemia children: results from a single center study. AB - BACKGROUND: Beta-thalassemia is one of the most common genetic disorders in Thailand. Clinical phenotype ranges from silent carrier to clinically manifested conditions including severe beta-thalassemia major and mild beta-thalassemia intermedia. OBJECTIVE: This study aimed to characterize the spectrum of beta globin gene mutations in pediatric patients who were followed-up in Phramongkutklao Hospital. PATIENTS AND METHODS: Eighty unrelated beta-thalassemia patients were enrolled in this study including 57 with beta thalassemia/hemoglobin E, eight with homozygous beta-thalassemia, and 15 with heterozygous beta-thalassemia. Mutation analysis was performed by multiplex amplification refractory mutation system (M-ARMS), direct DNA sequencing of beta globin gene, and gap polymerase chain reaction for 3.4 kb deletion detection, respectively. RESULTS: A total of 13 different beta-thalassemia mutations were identified among 88 alleles. The most common mutation was codon 41/42 (-TCTT) (37.5%), followed by codon 17 (A>T) (26.1%), IVS-I-5 (G>C) (8%), IVS-II-654 (C>T) (6.8%), IVS-I-1 (G>T) (4.5%), and codon 71/72 (+A) (2.3%), and all these six common mutations (85.2%) were detected by M-ARMS. Six uncommon mutations (10.2%) were identified by DNA sequencing including 4.5% for codon 35 (C>A) and 1.1% initiation codon mutation (ATG>AGG), codon 15 (G>A), codon 19 (A>G), codon 27/28 (+C), and codon 123/124/125 (-ACCCCACC), respectively. The 3.4 kb deletion was detected at 4.5%. The most common genotype of beta-thalassemia major patients was codon 41/42 (-TCTT)/codon 26 (G>A) or beta(E) accounting for 40%. CONCLUSION: All of the beta-thalassemia alleles have been characterized by a combination of techniques including M-ARMS, DNA sequencing, and gap polymerase chain reaction for 3.4 kb deletion detection. Thirteen mutations account for 100% of the beta thalassemia genes among the pediatric patients in our study. PMID- 25525382 TI - The spectral analysis of photoplethysmography to evaluate an independent cardiovascular risk factor. AB - BACKGROUND: In this study, we evaluate homeostatic markers correlated to autonomic nervous and endothelial functions in a population of coronary artery disease (CAD) patients versus a control group. Since CAD is the highest risk marker for sudden cardiac death, the study objective is to determine whether an independent cardiovascular risk score based on these markers can be used alongside known conventional cardiovascular risk markers to strengthen the understanding of a patient's vascular state. MATERIALS AND METHODS: Sixty-five subjects (13 women) with a mean age of 62.9 years (range 40-80 years) who were diagnosed with CAD using coronary angiography (group 1) and seventy-two subjects (29 women) with a mean age of 45.1 years (range 18-85 years) who claimed they were healthy (group 2) were included in the study. These subjects underwent examination with the TM-Oxi and SudoPath systems at IPC Heart Care Centers in Mumbai, India. The TM-Oxi system takes measurements from a blood pressure device and a pulse oximeter. The SudoPath measures galvanic skin response to assess the sudomotor pathway function. Spectral analysis of the photoplethysmograph (PTG) waveform and electrochemical galvanic skin response allow the TM-Oxi and SudoPath systems to calculate several homeostatic markers, such as the PTG index (PTGi), PTG very low frequency index (PTGVLFi), and PTG ratio (PTGr). The focus of this study was to evaluate these markers (PTGi, PTGVLFi, and PTGr) in CAD patients against a control group, and to calculate an independent cardiovascular risk factor score: the PTG cardiovascular disease risk score (PTG CVD), calculated solely from these markers. We compared PTGi, PTGVLFi, PTGr, and PTG CVD scores between the CAD patient group and the healthy control group. Statistical analyses were performed using receiver operating characteristic curves to determine the specificity and sensitivity of the markers to detect CAD at optimal cutoff values for PTGi, PTGVLFi, PTGr, and PTG CVD. In addition, correlation analyses between these markers and conventional autonomic nervous system and endothelial function markers were performed to understand the possible underlying physiological sources of the differences observed in marker values between CAD patients and healthy control patients. Additionally, t-tests were performed between two subgroups of the CAD patient group to determine whether diabetic or coronary artery bypass grafting (CABG) patients have significantly different PTGi marker values. RESULTS: Each spectral analysis PTG marker yielded a high specificity and sensitivity to detect CAD. Most notably, the PTG CVD score had a sensitivity of 82.5% and specificity of 96.8%, at a cutoff of 2, when used to detect CAD (P=0.0001; area under the receiver operating characteristic curve =0.967). The PTG spectral analysis markers were well-correlated to other autonomic nervous system and endothelial function markers. CAD diabetic patients (n=27) had a lower PTGi value compared with the CAD non-diabetic patients (n=38): and patients that underwent CABG (n=18) had a higher PTGi value compared with the CAD without CABG surgery patients (n=47). CONCLUSION: The spectral analysis of the photoplethysmography method is noninvasive, fast, operator-independent, and cost effective, as only an oximeter and galvanic skin response device are required in order to assess in a single testing the autonomic nervous system and endothelial function. The spectral analysis techniques used on the photoplethysmogram, as outlined in this study, could be useful when used alongside conventional known cardiovascular disease risk markers. PMID- 25525383 TI - Antihypertensive combination therapy in primary care offices: results of a cross sectional survey in Switzerland. AB - BACKGROUND: Most hypertensive patients need more than one substance to reach their target blood pressure (BP). Several clinical studies indicate the high efficacy of antihypertensive combinations, and recent guidelines recommend them in some situations even as initial therapies. In general practice they seem widespread, but only limited data are available on their effectiveness under the conditions of everyday life. The objectives of this survey among Swiss primary care physicians treating hypertensive patients were: to know the frequency of application of different treatment modalities (monotherapies, free individual combinations, single-pill combinations); to see whether there are relationships between prescribed treatment modalities and patient characteristics, especially age, treatment duration, and comorbidities; and to determine the response rate (percentage of patients reaching target BP) of different treatment modalities under the conditions of daily practice. METHODS: This cross-sectional, observational survey among 228 randomly chosen Swiss primary care physicians analyzed data for 3,888 consecutive hypertensive patients collected at one single consultation. RESULTS: In this survey, 31.9% of patients received monotherapy, 41.2% two substances, 20.9% three substances, and 4.7% more than three substances. By combination mode, 34.9% took free individual combinations and 30.0% took fixed-dose single-pill combinations. Combinations were more frequently given to older patients with a long history of hypertension and/or comorbidities. In total, 67.8% of patients achieved their BP target according to their physician's judgment. When compared, single-pill combinations were associated with a higher percentage of patients achieving target BP than free individual combinations and monotherapies for the total sample and for patients with comorbidity. CONCLUSION: Antihypertensive combination therapy was widely used in Swiss primary care practices. The number of prescribed substances depended on age, treatment duration, and type and number of comorbidities. Although the response rate was generally modest under the conditions of daily practice, it was higher for single-pill combinations than for monotherapies and free individual combinations. Further studies are needed to confirm these observations. PMID- 25525384 TI - Sensitivity of quantitative sensory models to morphine analgesia in humans. AB - INTRODUCTION: Opioid analgesia can be explored with quantitative sensory testing, but most investigations have used models of phasic pain, and such brief stimuli may be limited in the ability to faithfully simulate natural and clinical painful experiences. Therefore, identification of appropriate experimental pain models is critical for our understanding of opioid effects with the potential to improve treatment. OBJECTIVES: The aim was to explore and compare various pain models to morphine analgesia in healthy volunteers. METHODS: The study was a double-blind, randomized, two-way crossover study. Thirty-nine healthy participants were included and received morphine 30 mg (2 mg/mL) as oral solution or placebo. To cover both tonic and phasic stimulations, a comprehensive multi-modal, multi tissue pain-testing program was performed. RESULTS: Tonic experimental pain models were sensitive to morphine analgesia compared to placebo: muscle pressure (F=4.87, P=0.03), bone pressure (F=3.98, P=0.05), rectal pressure (F=4.25, P=0.04), and the cold pressor test (F=25.3, P<0.001). Compared to placebo, morphine increased tolerance to muscle stimulation by 14.07%; bone stimulation by 9.72%; rectal mechanical stimulation by 20.40%, and reduced pain reported during the cold pressor test by 9.14%. In contrast, the more phasic experimental pain models were not sensitive to morphine analgesia: skin heat, rectal electrical stimulation, or rectal heat stimulation (all P>0.05). CONCLUSION: Pain models with deep tonic stimulation including C fiber activation and and/or endogenous pain modulation were more sensitive to morphine analgesia. To avoid false negative results in future studies, we recommend inclusion of reproducible tonic pain models in deep tissues, mimicking clinical pain to a higher degree. PMID- 25525385 TI - A randomized clinical study of the heated lidocaine/tetracaine patch versus subacromial corticosteroid injection for the treatment of pain associated with shoulder impingement syndrome. AB - BACKGROUND: Treatment for pain due to shoulder impingement syndrome (SIS) typically begins conservatively with nonsteroidal anti-inflammatory drugs and physical therapy and can include subacromial injection of corticosteroids, particularly in patients unresponsive to conservative measures. The heated lidocaine/tetracaine (HLT) patch has been reported to reduce SIS pain in a small case series. METHODS: This was a prospective, randomized, open-label clinical trial in which adult patients with SIS pain lasting at least 14 days, with an average intensity of >=4 on a 0-10 scale (0= no pain, 10= worst pain) were randomized to treatment with the HLT patch or a single subacromial injection of triamcinolone acetonide (10 mg). Patients in the HLT patch group applied a single HLT patch to the shoulder for 4 hours twice daily, with a 12-hour interval between treatments during the first 14 days, and could continue to use the patch on an as-needed basis (up to twice daily) during the second 14-day period. No treatment was allowed in the final 14-day period. At baseline and at days 14, 28, and 42, patients rated their pain and pain interference with specific activities (0-10 scale). RESULTS: Sixty patients enrolled in the study (average age =51 years, range 18-75, n=21 female). Average pain scores declined from 6.0+/-1.6 at baseline to 3.5+/-2.4 at day 42 in the HLT patch group (n=29, P<0.001) and from 5.6+/-1.2 to 3.2+/-2.6 in the injection group (n=31, P<0.001). Similar improvements were seen in each group for worst pain; pain interference with general activity, work, or sleep; and range of motion. No significant between group differences were seen for any pain or pain interference scores at any time point. CONCLUSION: These results suggest that short-term, noninvasive treatment with the HLT patch has similar efficacy to subacromial corticosteroid injections for the treatment of pain associated with SIS. PMID- 25525387 TI - Oseltamivir phosphate monotherapy ablates tumor neovascularization, growth, and metastasis in mouse model of human triple-negative breast adenocarcinoma. AB - BACKGROUND: Triple-negative breast cancers (TNBCs) lack the estrogen, progesterone, and epidermal growth factor (EGF) receptor-2 (HER2/neu) receptors. Patients with TNBC have typical high grading, more frequent relapses, and exhibit poorer outcomes or prognosis compared with the other subtypes of breast cancers. Currently, there are no targeted therapies that are effective for TNBC. Preclinical antitumor activity of oseltamivir phosphate (OP) therapy was investigated to identify its role in tumor neovascularization, growth, invasiveness, and long-term survival in a mouse model of human TNBC. METHODS: Live cell sialidase, water soluble tetrazolium, WST-1 cell viability, and immunohistochemistry assays were used to evaluate sialidase activity, cell survival, and the expression levels of tumor E-cadherin, N-cadherin, and host endothelial CD31+/PECAM-1 cells in archived paraffin-embedded TNBC MDA-MB-231 tumors grown in RAGxCgamma double mutant mice. RESULTS: OP, anti-Neu1 antibodies, and matrix metalloproteinase-9-specific inhibitor blocked Neu1 activity associated with EGF-stimulated TNBC MDA-MB-231 cells. OP treatment of MDA-MB-231 and MCF-7 cells and their long-term tamoxifen-resistant clones reproducibly and dose-dependently reduced the sialidase activity associated with EGF-stimulated live cells and the cell viability after 72 hours of incubation. Combination of 1 MUM cisplatin, 5-FU, paclitaxel, gemcitabine, or tamoxifen with OP dosages >=300 MUg/mL significantly reduced cell viability at 24, 48, and 72 hours when compared to the chemodrug alone. Heterotopic xenografts of MDA-MB-231 tumors developed robust and bloody tumor vascularization in RAG2xCgamma double mutant mice. OP treatment at 30 mg/kg daily intraperitoneally reduced tumor vascularization and growth rate as well as significantly reduced tumor weight and spread to the lungs compared with the untreated cohorts. OP treatment at 50 mg/kg completely ablated tumor vascularization, tumor growth and spread to the lungs, with significant long-term survival at day 180 postimplantation, tumor shrinking, and no relapses after 56 days off-drug. OP 30 mg/kg cohort tumors expressed significantly reduced levels of human N-cadherins and host CD31+ endothelial cells with concomitant significant expression of E-cadherins compared to the untreated cohorts. CONCLUSION: OP monotherapy may be the effective treatment therapy for TNBC. PMID- 25525388 TI - Malignant phyllodes tumor of the breast presenting with hypoglycemia: a case report and literature review. AB - Phyllodes tumors are rare fibroepithelial neoplasms that account for less than 1% of all breast tumors and are typically found in middle-aged women. Phyllodes tumors that present with hypoglycemia are even rarer. No one morphologic finding is reliable in predicting the clinical behavior of this tumor. Surgery has been the primary mode of treatment to date. However, the extent of resection and the role of adjuvant radiotherapy or chemotherapy are still controversial. Here, we present a challenging case of malignant phyllodes tumor of the breast associated with hypoglycemia, and review the literature regarding clinical findings, pathologic risk factors for recurrence, and treatment recommendations. PMID- 25525389 TI - Biliary stenting in advanced malignancy: an analysis of predictive factors for survival. AB - PURPOSE: Stenting of the biliary tree is a common palliative procedure to relieve obstructive jaundice in advanced malignancy. Although effective in relief of biliary obstruction and palliation of symptoms, little information is available on predictive factors for survival post-procedure. This retrospective study sought to assess factors influencing post-procedure survival in cancer patients after biliary stenting. METHODS: Case notes of all patients from a regional academic cancer center, who underwent biliary stenting for obstructive jaundice related to malignancy during 2008 and 2009 were reviewed. We collected epidemiological, biochemical, treatment and survival data on all patients. We used Kaplan-Meyer analysis to assess survival from day of first biliary stenting (adjusted for cancer types), and the Cox proportional hazards model for univariate and multivariate analysis. RESULTS: One hundred and ninety-four patients were included in the final analysis. Most cases were related to pancreatic cancer or cholangiocarcinoma (89 and 46 cases respectively). Median survival for all patients was 143 days. In multivariate analysis serum albumin >=34 g/L at the time of procedure (hazard ratio 0.573; 95% confidence interval 0.424-0.773, P<0.001) and chemotherapy post-stent (hazard ratio 0.636; 95% confidence interval 0.455-0.889, P=0.008) were two independent prognostic factors predicting a better survival post-stenting. The 30 day mortality post-procedure in the 194 patients was 12%. CONCLUSION: This study suggests that stenting of the biliary tree in cases of malignant obstruction allows durable palliation of symptoms even in cases where further active chemotherapy treatment is not possible. However, the better outcome observed in patients with albumin >=34 g/L and those receiving chemotherapy post-stent requires further validation. PMID- 25525386 TI - Potential of garlic (Allium sativum) in lowering high blood pressure: mechanisms of action and clinical relevance. AB - Garlic supplements have shown promise in the treatment of uncontrolled hypertension, lowering blood pressure (BP) by about 10 mmHg systolic and 8 mmHg diastolic, similar to standard BP medication. Aged garlic extract, which contains S-allylcysteine as the bioactive sulfur compound, in particular is standardizable and highly tolerable, with little or no known harmful interaction when taken with other BP-reducing or blood-thinning medication. Here we describe biologically plausible mechanisms of garlic's BP-lowering effect. Garlic-derived polysulfides stimulate the production of the vascular gasotransmitter hydrogen sulfide (H2S) and enhance the regulation of endothelial nitric oxide (NO), which induce smooth muscle cell relaxation, vasodilation, and BP reduction. Several dietary and genetic factors influence the efficiency of the H2S and NO signaling pathways and may contribute to the development of hypertension. Sulfur deficiency might play a part in the etiology of hypertension, and could be alleviated with supplementation of organosulfur compounds derived from garlic. PMID- 25525390 TI - Sepsis in Canadian children: a national analysis using administrative data. AB - BACKGROUND: Severe infection resulting in sepsis is recognized as a leading cause of morbidity and mortality worldwide. The purpose of this study is to use longitudinal, population-based data to report national-level hospital metrics, providing a current assessment of the status of sepsis hospitalizations in Canadian children. METHODS: We performed an analysis of previously abstracted data from the Canadian Institute for Health Information (CIHI) Discharge Abstract Database (DAD). Children aged 0-17 years at the time of hospital admission were identified from a cohort of patients with sepsis or severe sepsis using the International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10-CA) and the Canadian Classification of Health Interventions (CCI). Descriptive population-based statistics are reported. RESULTS: Hospitalization data for 20,130 children admitted over 5 years were reviewed. The majority of children were young, with neonates (56.3%) and infants under 2 months (18.8%) representing the majority of cases. A decline in age-adjusted hospitalization rates was demonstrated in both overall and non-severe sepsis across the study period; however, no change was demonstrated for severe sepsis. While overall in-hospital crude mortality rates did not change significantly across the study period (range 5.1%-5.4%), a significant decrease was found in children aged 3-23 months and adolescents. Multi-organ failure was reported in more than one-quarter of children with severe sepsis. Odds of mortality increased significantly with number of organs failed. CONCLUSION: Sepsis remains an important cause of morbidity and mortality in Canadian children, posing a significant burden on health care resources. Age continues to be associated with the incidence and severity of illness. Overall hospitalization rates have declined over time, as has mortality in severe sepsis. This report provides baseline metrics for future outcome-based research in Canada targeting prevention strategies and early diagnosis, as well as therapies preventing and managing organ failure. PMID- 25525391 TI - Frequency of medication errors in an emergency department of a large teaching hospital in southern Iran. AB - This study was conducted with the purpose of determining the frequency of medication errors (MEs) occurring in tertiary care emergency department (ED) of a large academic hospital in Iran. The incidence of MEs was determined through the disguised direct observation method conducted by a trained observer. A total of 1,031 medication doses administered to 202 patients admitted to the tertiary care ED were observed over a course of 54 6-hour shifts. Following collection of the data and analysis of the errors with the assistance of a clinical pharmacist, frequency of errors in the different stages was reported and analyzed in SPSS-21 software. For the 202 patients and the 1,031 medication doses evaluated in the present study, 707 (68.5%) MEs were recorded in total. In other words, 3.5 errors per patient and almost 0.69 errors per medication are reported to have occurred, with the highest frequency of errors pertaining to cardiovascular (27.2%) and antimicrobial (23.6%) medications. The highest rate of errors occurred during the administration phase of the medication use process with a share of 37.6%, followed by errors of prescription and transcription with a share of 21.1% and 10% of errors, respectively. Omission (7.6%) and wrong time error (4.4%) were the most frequent administration errors. The less-experienced nurses (P=0.04), higher patient-to-nurse ratio (P=0.017), and the morning shifts (P=0.035) were positively related to administration errors. Administration errors marked the highest share of MEs occurring in the different medication use processes. Increasing the number of nurses and employing the more experienced of them in EDs can help reduce nursing errors. Addressing the shortcomings with further research should result in reduction of MEs in EDs. PMID- 25525392 TI - Pre-pregnancy high-risk factors at first antenatal visit: how predictive are these of pregnancy outcomes? AB - OBJECTIVE: To determine relationships between pre-pregnancy risk factors at first antenatal visit booking and pregnancy outcomes. STUDY DESIGN: This was a multicenter, cross-sectional study involving women admitted for singleton delivery from July 1 until October 31 (3 months), 2013, at nine major maternity clinics in Kinshasa, Democratic Republic of Congo. All women were checked for hereditary, community, and personal medical/surgical risk situations and mother/infant problems in previous pregnancies. Maternal and perinatal complications related to current/just-terminated pregnancy were analyzed according to pre-pregnancy risk factors in order to establish their prediction concerning maternal and perinatal complications related to current/just terminated pregnancy (odds ratios). Results are given with 95% confidence intervals, and P<0.05 was considered significant. RESULTS: The study sample comprised 2,086 women. Primiparity (36.5%), single relationship status (26.4%), and maternal age >=35 years (18.3%) were the most important non-pathologic risk factors, while arterial hypertension in family (34.3%), previous miscarriage (33.2%), overweight/obesity (21.9%), diabetes in family (21.1%), previous cesarean section (15.7%), previous postpartum hemorrhage (13.1%), low birth weight (10%), previous macrosomia (10%), and previous premature rupture of membranes (6.2%) predominated among pathologic risk factors. Major adverse outcomes recurred in some women, with recurrence rates of 21/37 (57%), 111/208 (53%), 74/208 (36%), 191/598 (32%), 132/466 (28%), 24/130 (18%), and 4/65 (6%) for prematurity, low birth weight, macrosomia, preeclampsia/eclampsia, cesarean section, premature rupture of membranes, and stillbirth, respectively. Outcomes that were significantly influenced by non-pathologic risk factors were also significantly influenced by pathologic risk factors. CONCLUSION: Pregnancy adverse outcomes are strongly influenced by either non-pathologic or pathologic pre-pregnancy risk factors at first antenatal visit booking. The recurrence potential of complications is one reason to establish the predictability and preventability of morbidity such that the most appropriate referrals and best options throughout the pregnancy can be determined. PMID- 25525393 TI - The effect of pycnogenol on patients with dysmenorrhea using low-dose oral contraceptives. AB - OBJECTIVE: Menstrual symptoms such as dysmenorrhea usually occur during the hormone-free interval in oral contraceptive users. Progestin withdrawal activates NF-kappaB transcription factor, which upregulates both vascular endothelial growth factor (VEGF) and Cox-2 expression in the endometrium. The use of natural NF-kappaB inhibitors such as pycnogenol may block this response, improving dysmenorrhea. PATIENTS AND METHODS: Twenty-four patients with severe dysmenorrhea were allocated to one of two treatment groups. In Group A (n=13), women were treated with an oral contraceptive containing 15 MUg of ethinyl estradiol and 60 mg of gestodene (Adoless((r))) in a 24/4 regimen for three consecutive cycles. Women in Group B (n=11) used the same contraceptive regimen together with 100 mg of pycnogenol (Flebon((r))) continuously for 3 months. Pain scores were graded using a visual analog scale (VAS) before and during the hormone-free interval at the end of the third treatment cycle. RESULTS: Before treatment, VAS pain scores for dysmenorrhea were 8 and 9 in Groups A and B, respectively. However, by the end of the third treatment cycle, pain scores had decreased significantly (P<0.05) both in groups A and B. The final pain scores were 6 in Group A and 2 in Group B, a difference that was statistically significant (P<0.0001). In Group B, 27% of the patients became pain-free, while in Group A, none of the women reported complete disappearance of this symptom. The number of bleeding days was also lower in Group B. DISCUSSION: Pycnogenol effectively decreased pain scores and the number of bleeding days when administered concomitantly with a low-dose 24/4 oral contraceptive containing gestodene. PMID- 25525395 TI - A qualitative study of the experience of obstetric fistula survivors in Addis Ababa, Ethiopia. AB - Research on obstetric fistula has paid limited attention to the lived experiences of survivors. This qualitative study explored the evolution of survivors' perceptions of their social relationships and health since developing this obstetric complication. In-depth interviews were conducted with eight survivors who were selected based on purposive and snowball sampling techniques. Thematic categorization and content analysis was used to analyze the data. The resultant themes included participants' understanding of factors predisposing to fistula, challenges they encounter, their coping responses, and the meaning of their experiences. First, the participants had a common understanding of the factors that predisposed them to obstetric fistula. They mentioned poor knowledge about pregnancy, early marriage, cultural practices, and a delay in or lack of access to emergency obstetric care. Second, the participants suffered from powerlessness experienced during their childhood and married lives. They also faced prolonged obstructed labor, physical injury, emotional breakdown, depression, erosion of social capital, and loss of healthy years. Third, to control their negative emotions, participants reported isolating themselves, having suicidal thoughts, positive interpretation about the future, and avoidance. To obtain relief from their disease, the women used their family support, sold their properties, and oriented to reality. Fourth, the participants were struggling to keep going, to accept their changed reality, and to change their perspectives on life. In conclusion, obstetric fistula has significant physical, psychosocial, and emotional consequences. The study participants were not passive victims but rather active survivors of these challenges. Adequate support was not provided by their formal or informal support systems. To prevent and manage obstetric fistula successfully, there should be family-based interventions that improve access to and provision of emergency obstetric care. These initiatives should also ensure men's participation, women's empowerment, and the utilization of community-based institutions. PMID- 25525394 TI - New molecular targets against cervical cancer. AB - Cervical cancer is the third most commonly diagnosed cancer worldwide and the fourth leading cause of cancer death in women. Major advances but still insufficient achievements in the treatment of locally advanced and high-risk early stage patients have occurred in the last decade with the incorporation of concurrent cisplatin with radiation and, lately, gemcitabine added to cisplatin chemoradiation. Despite a number of clinical studies incorporating molecular targeted therapy as radiosensitizers being in progress, so far, only antiangiogenic therapy with bevacizumab added to cisplatin chemoradiation has demonstrated safety and shown encouraging results in a Phase II study. In advanced disease, cisplatin doublets do not have a great impact on the natural history of the disease with median survival rates not exceeding 13 months. The first Phase III study of bevacizumab, added to cisplatin or a non-cisplatin containing doublet, showed significant increase in both overall survival and progression-free survival. Further studies are needed before bevacizumab plus chemotherapy can be considered the standard of care for advanced disease. Characterization of the mutational landscape of cervical cancer has already been initiated, indicating that, for now, few of these targetable alterations match with available agents. Progress in both the mutational landscape knowledge and developments of novel targeted therapies may result in more effective and individualized treatments for cervical cancer. The potential efficacy of knocking down the key alterations in cervical cancer - E6 and E7 human papillomavirus oncoproteins - must not be overlooked. PMID- 25525396 TI - Biomechanical evaluation of three fixation modalities for preperitoneal inguinal hernia repair: a 24-hour postoperative study in pigs. AB - PURPOSE: Tacks and sutures ensure a strong fixation of meshes, but they can be associated with pain and discomfort. Less invasive methods are now available. Three fixation modalities were compared: the ProGripTM laparoscopic self-fixating mesh; the fibrin glue TisseelTM with BardTM Soft Mesh; and the SorbaFixTM absorbable fixation system with BardTM Soft Mesh. MATERIALS AND METHODS: Meshes (6 cm *6 cm) were implanted in the preperitoneal space of swine. Samples were explanted 24 hours after surgery. Centered defects were created, and samples (either ten or eleven per fixation type) were loaded in a pressure chamber. For each sample, the pressure, the mesh displacement through the defect, and the measurements of the contact area were recorded. RESULTS: At all pressures tested, the ProGripTM laparoscopic self-fixating mesh both exhibited a significantly lower displacement through the defect and retained a significantly higher percentage of its initial contact area than either the BardTM Soft Mesh with TisseelTM system or the BardTM Soft Mesh with SorbaFixTM absorbable fixation system. Dislocations occurred with the BardTM Soft Mesh with TisseelTM system and with the BardTM Soft Mesh with SorbaFixTM absorbable fixation system at physiological pressure (,225 mmHg). No dislocation was recorded for the ProGripTM laparoscopic self-fixating mesh. CONCLUSION: At 24 hours after implantation, the mechanical fixation of the ProGripTM laparoscopic self-fixating mesh was found to be significantly better than the fixation of the TisseelTM system or the SorbaFixTM absorbable fixation system. PMID- 25525398 TI - Post-marathon wearing of Masai Barefoot Technology shoes facilitates recovery from race-induced fatigue: an evaluation utilizing a visual analog scale. AB - PURPOSE: To investigate the potential benefit of post-race wearing of unstable shoes (Masai Barefoot Technology [MBT]) on recovery from marathon race-induced fatigue. PATIENTS AND METHODS: Forty-five runners who participated in a full marathon race were divided into three groups: 1) MBT shoes, 2) trail running shoes, and 3) control (CON). Participants ran a full marathon with their own running shoes, and then put on the assigned shoes immediately after the race. They continued to wear the assigned shoes for the ensuing 3 days. The CON group wore their usual shoes. Estimates of post-race fatigue were made by the participants on questionnaires that utilized a visual analog scale. Estimates were made just after the race, as well as for the next 3 days. RESULTS: The subjective fatigue of the MBT group was lower than that of the CON (P<0.05) or trail running shoe groups (P<0.05) on day 3. CONCLUSION: MBT shoe intervention can promote recovery from the fatigue induced by running a full marathon. PMID- 25525397 TI - Non-invasive imaging of microcirculation: a technology review. AB - Microcirculation plays a crucial role in physiological processes of tissue oxygenation and nutritional exchange. Measurement of microcirculation can be applied on many organs in various pathologies. In this paper we aim to review the technique of non-invasive methods for imaging of the microcirculation. Methods covered are: videomicroscopy techniques, laser Doppler perfusion imaging, and laser speckle contrast imaging. Videomicroscopy techniques, such as orthogonal polarization spectral imaging and sidestream dark-field imaging, provide a plentitude of information and offer direct visualization of the microcirculation but have the major drawback that they may give pressure artifacts. Both laser Doppler perfusion imaging and laser speckle contrast imaging allow non-contact measurements but have the disadvantage of their sensitivity to motion artifacts and that they are confined to relative measurement comparisons. Ideal would be a non-contact videomicroscopy method with fully automatic analysis software. PMID- 25525399 TI - PPARalpha gene variants as predicted performance-enhancing polymorphisms in professional Italian soccer players. AB - BACKGROUND: The PPARalpha gene encodes the peroxisome proliferator-activator receptor alpha, a central regulator of expression of other genes involved in fatty acid metabolism. The purpose of this study was to determine the prevalence of G allele of the PPARalpha intron 7 G/C polymorphism (rs4253778) in professional Italian soccer players. METHODS: Sixty professional soccer players and 30 sedentary volunteers were enrolled in the study. Samples of venous blood were obtained at rest, in the morning, by conventional clinical procedures; blood serum was collected and total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured. An aliquot of anticoagulant-treated blood was used to prepare genomic DNA from whole blood. The G/C polymorphic site in PPARalpha intron 7 was scanned by using the PCR-RFLP (polymerase chain reaction restriction fragment length polymorphism) protocol with TaqI enzyme. RESULTS: We found variations in genotype distribution of PPARalpha polymorphism between professional soccer players and sedentary volunteers. Particularly, G alleles and the GG genotype were significantly more frequent in soccer players compared with healthy controls (64% versus 48%). No significant correlations were found between lipid profile and genotype background. CONCLUSION: Previous results demonstrated an association of intron 7 G allele as well as the GG genotype in endurance athletes. Our result suggests that this is the case also in professional soccer players. PMID- 25525400 TI - Misperceptions of weight status among adolescents: sociodemographic and behavioral correlates. AB - OBJECTIVE: Accurate perceptions of weight status are important motivational triggers for weight loss among overweight or obese individuals, yet weight misperception is prevalent. To identify and characterize individuals holding misperceptions around their weight status, it may be informative for clinicians to assess self-reported body mass index (BMI) classification (ie, underweight, normal, overweight, obese) in addition to clinical weight measurement. METHODS: Self-reported weight classification data from the 2007 Current Visit Information Child and Adolescent Survey collected at Mayo Clinic in Rochester, MN, were compared with measured clinical height and weight for 2,993 adolescents. RESULTS: While, overall, 74.2% of adolescents accurately reported their weight status, females, younger adolescents, and proxy (vs self) reporters were more accurate. Controlling for demographic and behavioral characteristics, the higher an individual's BMI percentile, the less likely there was agreement between self report and measured BMI percentile. Those with high BMI who misperceive their weight status were less likely than accurate perceivers to attempt weight loss. CONCLUSION: Adolescents' and proxies' misperception of weight status increases with BMI percentile. Obtaining an adolescent's self-perceived weight status in addition to measured height and weight offers clinicians valuable baseline information to discuss motivation for weight loss. PMID- 25525401 TI - Native T1 mapping of the heart - a pictorial review. AB - T1 mapping is now a clinically feasible method, providing pixel-wise quantification of the cardiac structure's T1 values. Beyond focal lesions, well depicted by late gadolinium enhancement sequences, it has become possible to discriminate diffuse myocardial alterations, previously not assessable by noninvasive means. The strength of this method includes the high reproducibility and immediate clinical applicability, even without the use of contrast media injection (native or pre-contrast T1). The two most important determinants of native T1 augmentation are (1) edema related to tissue water increase (recent infarction or inflammation) and (2) interstitial space increase related to fibrosis (infarction scar, cardiomyopathy) or to amyloidosis. Conversely, lipid (Anderson-Fabry) or iron overload diseases are responsible for T1 reduction. In this pictorial review, the main features provided by native T1 mapping are discussed and illustrated, with a special focus on the awaited clinical purpose of this unique, promising new method. PMID- 25525402 TI - A case of fallopian tube adenofibroma: difficulties associated with differentiation from ectopic pregnancy. AB - Benign solid tumors of the fallopian tubes are extremely rare and often difficult to differentiate from tumors associated with adjacent organs or from various inflammatory diseases. Here, we present a patient who was diagnosed with ectopic pregnancy, based on preoperative tests and intraoperative macroscopic findings, but was later diagnosed with a fallopian tube adenofibroma, based on histopathological evidence, and intrauterine pregnancy. Although initial pregnancy test results were positive, no gestational sac (GS) was seen in the uterus and the patient was diagnosed with an ectopic pregnancy and underwent emergency laparoscopic surgery. A 20-mm, fetus-like solid mass was noted inside the GS-like cystic tumor of the left fallopian tube. From histopathological findings, the lesion was identified as a serous fallopian tube adenofibroma. The baby was born healthy with no problems. This case report suggests that fallopian tube adenofibroma should be considered in the differential diagnosis of suspected ectopic pregnancies. PMID- 25525403 TI - Stiff man syndrome: a diagnostic dilemma in a young female with diabetes mellitus and thyroiditis. AB - Stiff Person Syndrome (SPS), is a very rare neuroimmunologic disorder characterized by progressive muscle pain, rigidity, stiffness, and spasms. It can be very debilitating if misdiagnosed or not recognized in time. Herein we discuss a case of a female in her 20s who presented with an unsteady gait, lower extremity weakness, persistent leg pain, and stiffness few weeks after uncomplicated childbirth. She has type 1 diabetes mellitus (DM) and was diagnosed with thyroiditis in the course of her illness. The triad of thyroiditis, DM, and stiffness with normal neuroimaging in a young female patient is an unusual occurrence. PMID- 25525404 TI - Competency-based medical education in two Sub-Saharan African medical schools. AB - BACKGROUND: Relatively little has been written on Medical Education in Sub Saharan Africa, although there are over 170 medical schools in the region. A number of initiatives have been started to support medical education in the region to improve quality and quantity of medical graduates. These initiatives have led to curricular changes in the region, one of which is the introduction of Competency-Based Medical Education (CBME). INSTITUTIONAL REVIEWS: This paper presents two medical schools, Makerere University College of Health Sciences and College of Medicine, University of Ibadan, which successfully implemented CBME. The processes of curriculum revision are described and common themes are highlighted. Both schools used similar processes in developing their CBME curricula, with early and significant stakeholder involvement. Competencies were determined taking into consideration each country's health and education systems. Final competency domains were similar between the two schools. Both schools established medical education departments to support their new curricula. New teaching methodologies and assessment methods were needed to support CBME, requiring investments in faculty training. Both schools received external funding to support CBME development and implementation. CONCLUSION: CBME has emerged as an important change in medical education in Sub-Saharan Africa with schools adopting it as an approach to transformative medical education. Makerere University and the University of Ibadan have successfully adopted CBME and show that CBME can be implemented even for the low-resourced countries in Africa, supported by external investments to address the human resources gap. PMID- 25525405 TI - Effects of different doses of testosterone on gonadotropins, 25-hydroxyvitamin D3, and blood lipids in healthy men. AB - AIMS: To study the effect and time profile of different doses of testosterone enanthate on the blood lipid profile and gonadotropins. EXPERIMENTAL DESIGN: Twenty-five healthy male volunteers aged 27-43 years were given 500 mg, 250 mg, and 125 mg of testosterone enanthate as single intramuscular doses of Testoviron((r)) Depot. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), blood lipid profile (total cholesterol, plasma [p-] low-density lipoprotein, p-high-density lipoprotein [HDL], p-apolipoprotein A1 [ApoA1], p apolipoprotein B, p-triglycerides, p-lipoprotein(a), serum [s-] testosterone, and 25-hydroxyvitamin D3) were analyzed prior to, and 4 and 14 days after dosing. Testosterone and epitestosterone in urine (testosterone/epitestosterone ratio) were analyzed prior to each dose after a washout period of 6-8 weeks. RESULTS AND DISCUSSION: All doses investigated suppressed the LH and FSH concentrations in serum. LH remained suppressed 6 weeks after the 500 mg dose. These results indicate that testosterone has a more profound endocrine effect on the hypothalamic-pituitary-gonadal axis than was previously thought. There was no alteration in 25-hydroxyvitamin D3 levels after testosterone administration compared to baseline levels. The 250 and 500 mg doses induced decreased concentrations of ApoA1 and HDL, whereas the lowest dose (125 mg) did not have any effect on the lipid profile. CONCLUSION: The single doses of testosterone produced a dose-dependent increase in serum testosterone concentrations together with suppression of s-LH and s-FSH. Alterations in ApoA1 and HDL were observed after the two highest single doses. It is possible that long-time abuse of anabolic androgenic steroids will lead to alteration in vitamin D status. Knowledge and understanding of the side effects of anabolic androgenic steroids are important to the treatment and care of abusers of testosterone. PMID- 25525406 TI - Intra-urban spatial variability of PM2.5-bound carbonaceous components. AB - The Denver Aerosol Sources and Health (DASH) study was designed to evaluate associations between PM2.5 species and sources and adverse human health effects. The DASH study generated a five-year (2003-2007) time series of daily speciated PM2.5 concentration measurements from a single, special-purpose monitoring site in Denver, CO. To evaluate the ability of this site to adequately represent the short term temporal variability of PM2.5 concentrations in the five county Denver metropolitan area, a one year supplemental set of PM2.5 samples was collected every sixth day at the original DASH monitoring site and concurrently at three additional sites. Two of the four sites, including the original DASH site, were located in residential areas at least 1.9 km from interstate highways. The other two sites were located within 0.3 km of interstate highways. Concentrations of elemental carbon (EC), organic carbon (OC), and 58 organic molecular markers were measured at each site. To assess spatial variability, site pairs were compared using the Pearson correlation coefficient (r) and coefficient of divergence (COD), a statistic that provides information on the degree of uniformity between monitoring sites. Biweekly co-located samples collected from July 2004 to September 2005 were also analyzed and used to estimate the uncertainty associated with sampling and analytical measurement for each species. In general, the two near-highway sites exhibited higher concentrations of EC, OC, polycyclic aromatic hydrocarbons (PAHs), and steranes than did the more residential sites. Lower spatial heterogeneity based on r and COD was inferred for all carbonaceous species after considering their divergence and lack of perfect correlations in co located samples. Ratio-ratio plots combined with available gasoline- and diesel powered motor vehicle emissions profiles for the region suggested a greater impact to high molecular weight (HMW) PAHs from diesel-powered vehicles at the near-highway sites and a more uniformly distributed impact to ambient hopanes from gasoline-powered motor vehicles at all four sites. PMID- 25525407 TI - Developmental psychiatry and intellectual disabilities: an American perspective. AB - The Natalie Cobbing Travelling Fellowship gives the opportunity to medical professionals trained in the Psychiatry of Intellectual Disabilities to gain experience in their field from centres overseas. This article concentrates on specialist work settings and the practice in developmental disabilities in Boston, USA. The authors conclude that such training opportunities not only are important educational milestones but also help in creating a network of professionals who can work together to improve standards of research and clinical practice across different cultural and ethnic divides. PMID- 25525408 TI - Imparting the unique properties of DNA into complex material architectures and functions. AB - While the remarkable chemical and biological properties of DNA have been known for decades, these properties have only been imparted into materials with unprecedented function much more recently. The inimitable ability of DNA to form programmable, complex assemblies through stable, specific, and reversible molecular recognition has allowed the creation of new materials through DNA's ability to control a material's architecture and properties. In this review we discuss recent progress in how DNA has brought unmatched function to materials, focusing specifically on new advances in delivery agents, devices, and sensors. PMID- 25525409 TI - Diversity and distribution of archaea community along a stratigraphic permafrost profile from Qinghai-Tibetan Plateau, China. AB - Accompanying the thawing permafrost expected to result from the climate change, microbial decomposition of the massive amounts of frozen organic carbon stored in permafrost is a potential emission source of greenhouse gases, possibly leading to positive feedbacks to the greenhouse effect. In this study, the community composition of archaea in stratigraphic soils from an alpine permafrost of Qinghai-Tibetan Plateau was investigated. Phylogenic analysis of 16S rRNA sequences revealed that the community was predominantly constituted by Crenarchaeota and Euryarchaeota. The active layer contained a proportion of Crenarchaeota at 51.2%, with the proportion of Euryarchaeota at 48.8%, whereas the permafrost contained 41.2% Crenarchaeota and 58.8% Euryarchaeota, based on 16S rRNA gene sequence analysis. OTU1 and OTU11, affiliated to Group 1.3b/MCG-A within Crenarchaeota and the unclassified group within Euryarchaeota, respectively, were widely distributed in all sediment layers. However, OTU5 affiliated to Group 1.3b/MCG-A was primarily distributed in the active layers. Sequence analysis of the DGGE bands from the 16S rRNAs of methanogenic archaea showed that the majority of methanogens belonged to Methanosarcinales and Methanomicrobiales affiliated to Euryarchaeota and the uncultured ZC-I cluster affiliated to Methanosarcinales distributed in all the depths along the permafrost profile, which indicated a dominant group of methanogens occurring in the cold ecosystems. PMID- 25525410 TI - Prognostic value of the MicroRNA regulators Dicer and Drosha in non-small-cell lung cancer: co-expression of Drosha and miR-126 predicts poor survival. AB - BACKGROUND: Dicer and Drosha are important enzymes for processing microRNAs. Recent studies have exhibited possible links between expression of different miRNAs, levels of miRNA processing enzymes, and cancer prognosis. We have investigated the prognostic impact of Dicer and Drosha and their correlation with miR-126 expression in a large cohort of non-small cell lung cancer (NSCLC) patients. We aimed to find patient groups within the cohort that might have an advantage of receiving adjunctive therapies. METHODS: Dicer expression in the cytoplasm and Drosha expression in the nucleus were evaluated by manual immunohistochemistry of tissue microarrays (TMAs), including tumor tissue samples from 335 patients with resected stages I to IIIA NSCLC. In addition, in situ hybridizations of TMAs for visualization of miR-126 were performed. Kaplan-Meier analysis was performed, and the log-rank test via SPSS v.22 was used for estimating significance levels. RESULTS: In patients with normal performance status (ECOG = 0, n = 197), high Dicer expression entailed a significantly better prognosis than low Dicer expression (P = 0.024). Dicer had no significant prognostic value in patients with reduced performance status (ECOG = 1-2, n = 138). High Drosha expression was significantly correlated with high levels of the microRNA 126 (miR-126) (P = 0.004). Drosha/miR-126 co-expression had a significant negative impact on the disease-specific survival (DSS) rate (P < 0.001). Multivariate analyses revealed that the interaction Dicer*Histology (P = 0.049) and Drosha/miR-126 co-expression (P = 0.033) were independent prognostic factors. CONCLUSIONS: In NSCLC patients with normal performance status, Dicer is a positive prognostic factor. The importance of Drosha as a prognostic factor in our material seems to be related to miR-126 and possibly other microRNAs. PMID- 25525411 TI - Upregulation of microRNA-196a and microRNA-196b cooperatively correlate with aggressive progression and unfavorable prognosis in patients with colorectal cancer. AB - BACKGROUND: Both microRNA (miR)-196a and miR-196b are implicated in normal cell differentiation, proliferation, and in tumorigenesis of various cancer types. Especially, miR-196a exerts a pro-oncogenic influence in colorectal cancer (CRC) cells and miR-196b expression is upregulated in CRC tissues. The aim of this study was to evaluate the associations of miR-196a and miR-196b dysregulation with clinicopathological characteristics and prognosis in patients with CRC. METHODS: Quantitative real time-PCR (qRT-PCR) was performed to detect the expression levels of miR-196a and miR-196b in 126 pairs of fresh tumor samples matched with adjacent colorectal mucosa obtained from 126 patients with CRC. RESULTS: miR-196a and miR-196b expression levels in CRC tissues were significantly higher than those in adjacent colorectal mucosa (both P < 0.002). Interestingly, the expression levels of miR-196a in CRC tissues were positively correlated with those of miR-196b. Then, high miR-196a expression and high miR 196b expression, alone or in combination, were all statistically linked to the presence of lymph node metastasis, the poor differentiation grade, and the advanced TNM stage of CRC. Moreover, overall and disease-free survivals of CRC patients with high miR-196a expression, high miR-196b expression and miR-196a high/miR-196b-high expression tended to be shorter than the corresponding control groups (log-rank statistic, all P < 0.001). Furthermore, multivariate analysis indicated miR-196a and/or miR-196b expression as independent prognostic indicators for CRC patients (all P < 0.05). CONCLUSIONS: Both miR-196a and miR 196b may be correlated with aggressive progression and unfavorable clinical outcome in CRC patients. Combined expression of miR-196a and miR-196b may be a promising biomarker in identifying a poor prognosis group of CRC. PMID- 25525412 TI - The advent of precision therapy in gastrointestinal malignancies: Targeting the human epidermal growth factor receptor family in colorectal and esophagogastric cancer. AB - Until recently, systemic therapy for gastrointestinal malignancies was restricted to relatively noncancer-specific cytotoxic chemotherapy. Over the last 15 years targeted therapies have become available, most notably bevacizumab in the case of advanced colorectal cancer. Unfortunately, there are no predictive biomarkers to guide the use of this agent. In this review article, we describe the advent of "Precision Medicine" (in part, the use of patient-specific molecular markers to inform treatment) in gastrointestinal cancers: The use of monoclonal antibodies targeting epidermal growth factor receptor in advanced colorectal cancer, and human epidermal growth factor receptor 2-neu in advanced esophagogastric cancer. In both instances, biomarkers help in selecting appropriate patients for such treatment. PMID- 25525414 TI - Mixing it Up: Integrating Men and Women Living with HIV/AIDS in Prevention Groups. AB - AIMS: The current study was conducted to examine the impact of mixing genders in HIV prevention intervention groups targeted toward HIV positive men and women. METHODS: Men (N=310) and women (N=126) participated in a randomized clinical trial testing a behavioral risk reduction/ medication adherence intervention versus a general health control condition administered to small mixed gender groups. Gender composition of groups was examined in relation to participant group attendance and group satisfaction measures through correlations and logistic regression. RESULTS: Significant regression models were found for men in the risk reduction condition and for women in the general health condition, however, regression models were not significant for women in the risk reduction condition and men in the general health condition. DISCUSSION: The findings indicate that mixing genders in risk reduction interventions for men and women living with HIV/AIDS has no negative impact on women's group satisfaction and may positively impact men's group satisfaction. This calls into question the assumption that gender sensitive material will always make individuals uncomfortable within mixed gender groups. IMPLICATIONS FOR PRACTICE AND POLICY: In practice, mixed gender intervention groups can be a helpful option for delivering programs to diverse populations especially when resources are limited within community-based services providers and AIDS service organizations. CONCLUSION: Although more thorough investigation is needed about the consequences and possible benefits of mixing genders within HIV prevention intervention groups, this study supports the idea that mixing genders may be a viable option, in practice, without sacrificing the integrity of the intervention. PMID- 25525413 TI - Effects of mycophenolate mofetil on kidney function and phosphorylation status of renal proteins in Alport COL4A3-deficient mice. AB - BACKGROUND: We investigated the effects of mycophenolate mofetil (MMF) on kidney function and on protein phosphorylation in a mouse model for the human Alport syndrome. METHODS: COL4A3-deficient (COL4A3-/-) mice were randomly allocated to receive a placebo (PLC COL4A3-/-) or MMF treatment (MMF COL4A3-/-). Wild type mice (WT) were used as controls. Changes in serum creatinine, total protein and blood urea nitrogen (BUN), concentrations of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG), serum protein electrophoresis, urine dipstick chemistry and sediment were measured. Changes in the phosphorylation status of renal proteins and histology were analyzed. RESULTS: MMF influenced kidney function and protein phosphorylation. Serum creatinine and BUN were lower in MMF treated compared to PLC treated COL4A3-/- mice. Serum albumin and alpha-1 globulins were significantly decreased while serum creatinine, alpha-2 globulins, urine dipstick protein, leukocyte esterase, hemoglobin and red blood cells were all increased in both COL4A3-/- groups compared to WT. Differential 2DE-gel analysis identified six phosphorylated kidney protein spots that were significantly altered by MMF. CONCLUSIONS: These data suggest that the MMF treatment in this murine model moderately improved kidney function and reversed the phosphorylation status of six renal phosphoprotein spots to that seen in WT mice. PMID- 25525415 TI - Masculine ideology, norms, and HIV prevention among young Black men. AB - This study examines the relationship between masculine ideology, adherence to norms, and HIV prevention among young Black heterosexual and gay men on the campus of a historically Black college/university. The data from four focus groups and nine individual interviews (N = 35) were aggregated and two recurring themes emerged: sexual communication, and mate availability. Additional themes related to HIV prevention were stigma, protection, and testing. The importance of investigating masculinity with young men is highlighted and implications for professionals working with college students to prevent the transmission of HIV are included. PMID- 25525417 TI - Supplementation with Silk Amino Acids improves physiological parameters defining stamina in elite fin-swimmers. AB - BACKGROUND: Previous animal study has shown that supplementation with silk amino acid hydrolysate (SAA) increases stamina in mice. The presented study was the first formal evaluation of the influence of SAA supplementation on parameters defining physiological fitness level in humans. METHODS: It was a randomized controlled trial with a parallel-group design on elite male fin-swimmers. The experimental group was supplemented with 500 mg of SAA per kg of body mass, dissolved in 250 ml of a Carborade Drink(r); the control group with Carborade Drink(r) alone; 3 times a day, 30 minutes prior to the training session. RESULTS: Changes discerned in the experimental group were more pronounced than those observed in the control group. For example, the change in the serum lactic acid concentration observed in the experimental group was sevenfold less than in the control group [21.8 vs. -3.7 L% for the control and experimental groups, respectively]. An analysis of a lactate profile as a function of a maximal swimming velocity exposed a statistically significant positive shift in the swimming velocity of 0.05 m/s, at the lactate concentration of 4 mmol/L in the experimental group. There was also a positive, although statistically insignificant, increase of 2.6 L% in serum testosterone levels in the experimental group. CONCLUSIONS: This study showed that a 12-day SAA supplementation combined with an extensive and rigorous training schedule was sufficient to increase an aerobic stamina. However, this phenomenon was associated with an augmented level of muscular damage (an increased level of creatine phosphokinase in the experimental group). PMID- 25525416 TI - Prediction of methotrexate efficacy and adverse events in patients with juvenile idiopathic arthritis: a systematic literature review. AB - BACKGROUND: Methotrexate (MTX) is the cornerstone disease-modifying anti rheumatic drug in juvenile idiopathic arthritis (JIA). In JIA, it is important to start effective treatment early to avoid long-term sequelae, such as joint damage. To accomplish this goal, it is crucial to know beforehand who is going to respond well to MTX. In addition, MTX adverse effects such as MTX intolerance occur frequently, potentially hindering its efficacy. To avoid inefficacy of an otherwise effective drug, the physician should be timely aware of these adverse events. Consequently, to optimise treatment of JIA patients with MTX, predictors for efficacy and adverse events should be used in daily clinical practice. The aim of this study was to summarise the existing knowledge about such predictors. METHODS: A systematic literature search was performed in PubMed, Embase and The Cochrane Library, and 1,331 articles were identified. These were selected based on their relevance to the topic and critically appraised according to pre-defined criteria. Predictors for MTX efficacy and adverse events were extracted from the literature and tabulated. RESULTS: Twenty articles were selected. The overall quality of the studies was good. For MTX efficacy, candidate predictors were antinuclear antibody positivity, the childhood health assessment questionnaire score, the myeloid-related protein 8/14 level, long-chain MTX polyglutamates, bilateral wrist involvement and some single nucleotide polymorphisms (SNPs) in the adenosine triphosphate binding cassette and solute carrier transporter gene families. For MTX adverse events, potential predictors were alanine aminotransferase and thrombocyte level and two SNPs in the gamma-glutamyl hydrolase and methylenetetrahydrofolate reductase genes. However, validation of most predictors in independent cohorts was still lacking. CONCLUSIONS: Interesting candidate predictors were found, especially for MTX efficacy. However, most of these were not validated. This should be the goal of future efforts. A clinically relevant way to validate the predictors is by means of creating a clinical prediction model. PMID- 25525418 TI - Effects of 28-days ingestion of a slow-release energy supplement versus placebo on hematological and cardiovascular measures of health. AB - BACKGROUND: Recently, slow release tablets have been developed to prolong energy release throughout the day. The efficacy of the delivery of slow-release caffeine alone is fairly well documented; however, an assessment of safety and tolerability of prolonged use of slow-release energy supplements is lacking. Therefore the objective of this study was to investigate the effect of daily ingestion of a slow-release energy supplement for 28 days on blood chemistry and resting cardiovascular measures in healthy men and women. METHODS: Forty healthy individuals (20 males, 20 females; age: 22.73 +/- 3.06 years; height: 171.68 +/- 10.45 cm; mass: 74.49 +/- 15.51 kg; BMI: 25.08 +/- 3.66 (kg * m(2)) (-1)) participated in this randomized, double-blind, placebo controlled study. Following a 12-hour fast, participants reported for pre-testing. Testing consisted of resting heart rate (RHR) and blood pressure (BP) measures, followed by assessment of metabolic blood chemistry, blood lipids and complete cell counts. Participants then supplemented with either EnergizeTM (SUPP) or placebo (PL) for 28 days. Post-testing occurred 24-hours after ingestion of the final dose and consisted of the same protocol at the same time of day as pre-testing. RESULTS: No significant changes in outcome measures were observed. A significant difference between groups was observed for plasma glucose concentrations; however, follow-up testing revealed that pre- to post-supplementation changes were not significant for either SUPP or PL. All variables remained within normal adult reference ranges. No adverse events were reported. CONCLUSIONS: These findings indicate that 28 consecutive days ingestion of a slow release energy supplement containing caffeine in caffeine users is both safe and tolerable. PMID- 25525420 TI - The influence of individualism and drinking identity on alcohol problems. AB - This study evaluated the interactive association between individualism and drinking identity predicting alcohol use and problems. Seven hundred and ten undergraduates (Mean age =22.84, SD = 5.31, 83.1% female) completed study materials. We expected that drinking identity and individualism would positively correlate with drinking variables. We further expected that individualism would moderate the association between drinking identity and drinking such that the relationship between drinking identity and alcohol outcomes would be positively associated, particularly among those high in individualism. Our findings supported our hypotheses. These findings better explain the relationship between drinking identity, individualism, and alcohol use. Furthermore, this research encourages the consideration of individual factors and personality characteristics in order to develop culturally tailored materials to maximize intervention efficacy across cultures. PMID- 25525421 TI - Electron paramagnetic resonance study of thermally treated bismuth subgallate. AB - Complex of bismuth, an anti-inflammatory drug, was studied by EPR spectroscopy. The aim of this study was to determine concentrations and properties of free radicals formed during thermal sterilization of bismuth subgallate according to pharmacopoeia norms to optimize its sterilization process. Different temperatures (160 degrees C, 170 degrees C, and 180 degrees C) and times (120 minutes, 60 minutes, and 30 minutes) of sterilization were used. Interactions of bismuth subgallate with DPPH, the model free radical reference, were checked. g-Factors, amplitudes (A), integral intensities (I), and linewidths (DeltaB pp) were obtained. Integral intensities were obtained by double integration of the first derivative EPR lines. The influence of microwave power in the range of 2.2-70 mW on shape and parameters of the EPR spectra was examined. Thermal sterilization produced free radicals in bismuth subgallate in all tested cases. Strong interactions with free radicals were pointed out for all the analysed samples containing bismuth independent of sterilization conditions. Optimal conditions of thermal sterilization for bismuth subgallate with the lowest free radical formation are temperature 170 degrees C and time of heating 60 minutes. Strong dipolar interactions exist in thermally sterilized bismuth subgallate. EPR spectroscopy is a useful method of examination of thermal sterilization conditions. PMID- 25525419 TI - Tears in your beer: Gender differences in coping drinking motives, depressive symptoms and drinking. AB - This study evaluates associations between coping drinking motives (CDM; drinking to regulate negative affect), depressive symptoms, and drinking behavior and extends the literature by also taking into account gender differences. Two hundred forty-three college students (Mean age = 22.93, SD = 6.29, 82% female) participated. Based on previous research, we expected that CDM would be positively associated with drinking and problems, particularly among those higher in depressive symptoms, as individuals experiencing higher levels of negative affect (i.e. depressive symptoms) and who drink to cope are likely to drink more and experience more alcohol-related problems. Lastly, based on established gender differences, we expected that CDM would be positively associated with drinking and problems, especially among females higher in depressive symptoms. Unexpectedly, findings suggested that CDMs were positively related to peak drinking, especially among those lower in depressive symptoms. Results further revealed a significant three-way interaction between CDM, depressive symptoms, and gender when predicting alcohol-related problems and drinking frequency. Specifically, we found that CDM were more strongly associated with problems among women who were lower in depressive symptoms; whereas CDM were more strongly associated with problems among men who were higher in depressive symptoms. These findings offer a more comprehensive depiction of the relationship between depressive symptoms, CDM, and drinking behavior by taking into account the importance of gender differences. These results provide additional support for considering gender when designing and implementing alcohol intervention strategies. PMID- 25525422 TI - Synthesis, Spectroscopic, Molecular Structure, and Antibacterial Studies of Dibutyltin(IV) Schiff Base Complexes Derived from Phenylalanine, Isoleucine, and Glycine. AB - New series of organotin(IV) complexes and Schiff bases derived from amino acids have been designed and synthesized from condensation of 1H-indole-2,3-dione, 5 chloro-1H-indole-2,3-dione, and alpha-amino acids (phenylalanine, isoleucine, and glycine). All compounds are characterized by elemental analyses, molar conductance measurements, and molecular weight determinations. Bonding of these complexes is discussed in terms of their UV-visible, infrared, and nuclear magnetic resonance ((1)H, (13)C, and (119)Sn NMR) spectral studies. The results suggest that Schiff bases behave as monobasic bidentate ligands and coordinate with dibutyltin(IV) in octahedral geometry according to the general formula [Bu2Sn(L)2]. Elemental analyses and NMR spectral data of the ligands with their dibutyltin(IV) complexes agree with their proposed distorted octahedral structures. Few representative compounds are tested for their in vitro antibacterial activity against Gram-positive (B. cereus, Staphylococcus spp.) and Gram-negative (E. coli, Klebsiella spp.) bacteria. The results show that the dibutyltin complexes are more reactive with respect to their corresponding Schiff base ligands. PMID- 25525423 TI - Effect of Morphology of Co3O4 for Oxygen Evolution Reaction in Alkaline Water Electrolysis. AB - In this paper, three different morphological Co3O4 electrodes for oxygen evolution reaction (OER) have been synthesized. By comparing the three morphologies of Co3O4, the electrocatalytic properties show that the urchin-like spheres of Co3O4 electrode has relative low overpotential and good electrocatalysis stability, indicating that the structure of urchin-like Co3O4 spheres exhibit an easy OER for water splitting. PMID- 25525424 TI - Phosphine-Catalyzed [3+2] and [4+3]Annulation Reactions of C,N-Cyclic Azomethine Imines with Allenoates. AB - Phosphine-catalyzed [3+2] and [4+3]annulation reactions of C,N-cyclic azomethine imines with allenoates have been developed to give a variety of pharmaceutically attractive tetrahydroisoquinoline derivatives in moderate to excellent yields. The two distinct reaction pathways, [3+2] and [4+3]cyclization, depend on the nature of the nucleophilic phosphine and the allenoate. Generally, for alpha alkylallenoates, the reactions always proceed with [3 +2]cyclization as the major pathway no matter what phosphine was used; for alpha-ArCH2-substituted allenoates, the reaction pathway was controlled by the phosphine catalyst used. PMID- 25525425 TI - Label propagation with alpha-degree neighborhood impact for network community detection. AB - Community detection is an important task for mining the structure and function of complex networks. In this paper, a novel label propagation approach with alpha degree neighborhood impact is proposed for efficiently and effectively detecting communities in networks. Firstly, we calculate the neighborhood impact of each node in a network within the scope of its alpha-degree neighborhood network by using an iterative approach. To mitigate the problems of visiting order correlation and convergence difficulty when updating the node labels asynchronously, our method updates the labels in an ascending order on the alpha degree neighborhood impact of all the nodes. The alpha-degree neighborhood impact is also taken as the updating weight value, where the parameter impact scope alpha can be set to a positive integer. Experimental results from several real world and synthetic networks show that our method can reveal the community structure in networks rapidly and accurately. The performance of our method is better than other label propagation based methods. PMID- 25525426 TI - Effectiveness and safety of s-1-based therapy compared with 5-Fluorouracil-based therapy for advanced colorectal cancer: a meta-analysis. AB - Objectives. The aim of our study was to compare the efficacy and safety of S-1 based therapy (SBT) versus 5-fluorouracil-based therapy (FBT) for advanced colorectal cancer (ACRC). Methods. A meta-analysis of all eligible randomized controlled trials (RCTs) was performed using RevMan 5.1.0 software. Results. A total of 1625 patients from twelve RCTs including 820 patients in the SBT group and 805 patients in the FBT group were available for analysis. The meta-analysis of overall survival (hazards ratio HR = 0.94, 95% CI = 0.80-1.10), progression free survival (HR = 1.03, 95% CI = 0.91-1.18), and overall response rate (odds ratio OR = 1.23, 95% CI = 1.00-1.53) showed no statistical significance between SBT group and FBT group. The statistically significant differences in the meta analysis indicated less incidence of graded 3-4 neutropenia (OR = 0.49, 95% CI = 0.35-0.68) and nausea/vomit (OR = 0.41, 95% CI = 0.23-0.72) in the SBT group, and there was no statistically significant difference in the incidence of grade 3-4 anemia, thrombocytopenia, leucopenia, diarrhea, and treatment-related deaths between two groups. Conclusions. SBT had similar efficacy and better safety than FBT and was an attractive alternative to FBT for patients of ACRC, but further investigations in different populations would be needed to confirm it. PMID- 25525427 TI - Identification of ocular and auditory manifestations of congenital rubella syndrome in mbingo. AB - Purpose. Congenital rubella syndrome (CRS) is a global cause of preventable hearing impairment, blindness, and intellectual impairment. The present study sought to identify ocular and auditory manifestations of CRS in school-aged children in Mbingo, Cameroon. Design. Cross sectional study. Subjects. Students at two schools, one for children with hearing impairment, were screened for cataract, congenital glaucoma, and pigmentary retinopathy. Methods. Students underwent seven-field digital fundus photography through a dilated pupil using a Topcon NW200 nonmydriatic camera. Images were assessed by retina specialists in Canada via teleophthalmology. Clinical evidence was integrated to form case definitions for CRS based on Center for Disease Control and Prevention guidelines. Serological evidence of rubella infection was obtained using standardized IgG antibody titers. Main Outcome Measure. Number of probable and suspicious cases of CRS. Results. Between September 2009 and May 2010, 320 students participated. There were 28 (10.2%) probable cases, 104 (37.8%) suspects, and 143 (52.0%) unaffected. Rubella IgG serology was positive in 79 (48.7%) of children with hearing impairment and 11 (7.4%) of children with normal hearing. Conclusions. The present study identified 28 probable cases of CRS. Furthermore, 92.6% of students with normal hearing did not possess rubella IgG antibodies making future cases of CRS likely without intervention. PMID- 25525428 TI - Compliance of healthcare workers with hand hygiene practices in neonatal and pediatric intensive care units: overt observation. AB - Background. The objective of this study was to assess the compliance of hand hygiene (HH) of healthcare workers (HCWs) in the neonatal and pediatric intensive care unit in a tertiary university hospital in Istanbul. Methods. An observational study was conducted on the compliance of HH for the five World Health Organization (WHO) indications. HCWs were observed during routine patient care in day shift. The authors also measured the technique of HH through hand washing or hand hygiene with alcohol-based disinfectant. Results. A total of 704 HH opportunities were identified during the observation period. Overall compliance was 37.0% (261/704). Compliance differed by role: nurses (41.4%) and doctors (31.9%) [P = 0.02, OR: 1.504, CI 95%: 1.058-2.137]. HCWs were more likely to use soap and water (63.6%) compared to waterless-alcohol-based hand hygiene (36.3%) [P < 0.05]. Conclusion. Adherence to hand hygiene practice and use of alcohol-based disinfectant was found to be very low. Effective education programs that improve adherence to hand hygiene and use of disinfectants may be helpful to increase compliance. PMID- 25525429 TI - Ligand Based Pharmacophore Modeling and Virtual Screening Studies to Design Novel HDAC2 Inhibitors. AB - Histone deacetylases 2 (HDAC2), Class I histone deacetylase (HDAC) family, emerged as an important therapeutic target for the treatment of various cancers. A total of 48 inhibitors of two different chemotypes were used to generate pharmacophore model using 3D QSAR pharmacophore generation (HypoGen algorithm) module in Discovery Studio. The best HypoGen model consists of four pharmacophore features namely, one hydrogen bond acceptor (HBA), and one hydrogen donor (HBD), one hydrophobic (HYP) and one aromatic centres, (RA). This model was validated against 20 test set compounds and this model was utilized as a 3D query for virtual screening to validate against NCI and Maybridge database and the hits further screened by Lipinski's rule of 5, and a total of 382 hit compounds from NCI and 243 hit compounds from Maybridge were found and were subjected to molecular docking in the active site of HDAC2 (PDB: 3MAX). Finally eight hit compounds, NSC108392, NSC127064, NSC110782, and NSC748337 from NCI database and MFCD01935795, MFCD00830779, MFCD00661790, and MFCD00124221 from Maybridge database, were considered as novel potential HDAC2 inhibitors. PMID- 25525430 TI - Trace and Essential Elements Analysis in Cymbopogon citratus (DC.) Stapf Samples by Graphite Furnace-Atomic Absorption Spectroscopy and Its Health Concern. AB - Cymbopogon citratus (DC.) Stapf commonly known as lemon grass is used extensively as green tea and even as herbal tea ingredient across the world. Plants have the ability to uptake metals as nutrient from the soil and its environment which are so essential for their physiological and biochemical growth. Concentrations of these twelve trace elements, namely, Mg, Ca, Cr, Mn, Fe, Ni, Cu, Zn, Mo, As, Cd, and Pb, are analysed by graphite furnace-atomic absorption spectroscopy (GF-AAS) and are compared with the permissible limits of FAO/WHO, ICMR, and NIH, USA, which are found to be within permissible limits. Toxic metals like As, Cd, and Pb, analysed are within the tolerable daily diet limit and at low concentration. PMID- 25525432 TI - Oxidative Stress: A Link between Diabetes Mellitus and Periodontal Disease. AB - Objective. To investigate oxidative stress (OS) and histological changes that occur in the periodontium of subjects with type 2 diabetes mellitus without signs of periodontal disease and to establish if oxidative stress is a possible link between diabetes mellitus and periodontal changes. Materials and Methods. Tissue samples from ten adult patients with type 2 diabetes mellitus (T2D) and eight healthy adults were harvested. The specimens were examined by microscope using standard hematoxylin-eosin stain, at various magnifications, and investigated for tissue levels of malondialdehyde (MDA) and glutathione (GSH). Results. Our results showed that periodontal tissues in patients with T2D present significant inflammation, affecting both epithelial and connective tissues. Mean MDA tissue levels were 3.578 +/- 0.60 SD in diabetics versus 0.406 +/- 0.27 SD in controls (P < 0.0001), while mean GSH tissue levels were 2.48 +/- 1.02 SD in diabetics versus 9.7875 +/- 2.42 SD in controls (P < 0.0001). Conclusion. Diabetic subjects had higher MDA levels in their periodontal tissues, suggesting an increased lipid peroxidation in T2D, and decreased GSH tissue levels, suggesting an alteration of the local antioxidant defense mechanism. These results are in concordance with the histological changes that we found in periodontal tissues of diabetic subjects, confirming the hypothesis of OS implication, as a correlation between periodontal disease incidence and T2D. PMID- 25525431 TI - Prediction of extrathyroidal extension using ultrasonography and computed tomography. AB - Objectives. The aim of the present study was to evaluate the value of high resolution ultrasound (US) and computed tomography (CT) scan for preoperative prediction of the extrathyroidal extension (ETE). Methods. We analyzed the medical records of 377 patients with papillary thyroid carcinoma (PTC) with preoperative US and CT scan to calculate the sensitivity, specificity, and positive and negative predictive values of characteristics imaging features (such as contact and disruption of thyroid capsule) for the presence of ETE in postoperative pathologic examination. We also evaluated the diagnostic power for several combinations of US and CT findings. Results. ETE was present in 174 (46.2%) based on pathologic reports. The frequency of ETE was greater in the patients with greater degrees of tumor contact and disruption of capsule, as revealed by both US and CT scans (positive predictive value of 72.2% and 81.8%, resp.). Considering positive predictive values and AUC of US and CT categories, separately or combined, a combination of US and CT findings was most accurate for predicting ETE (83.0%, 0.744). Conclusions. This study suggests that ETE can be predicted most accurately by a combination of categories based on the findings of US and CT scans. PMID- 25525433 TI - Analysis of the evolution of tannic Acid stabilized gold nanoparticles using mie theory. AB - Spherical gold nanoparticles (GNPs) have been synthesized in aqueous solutions using sodium citrate (SC) and tannic acid (TA) as reducing and stabilizing agents. Upon addition of TA and compared to the GNP TA-free aqueous solutions, a reduction of the GNPs size and consequently a dramatic change of their optical properties have been observed and quantitatively analyzed using Mie theory. An increase in the concentration of TA reveals a modification of the colloidal solution refractive index that is evidenced by the shift in the peak position of the localized surface plasmon resonance (LSPR) band. The variations of the peak absorbance with the TA concentration are examined in the low and high concentration regimes. PMID- 25525434 TI - Direct metal laser sintering titanium dental implants: a review of the current literature. AB - Statement of Problem. Direct metal laser sintering (DMLS) is a technology that allows fabrication of complex-shaped objects from powder-based materials, according to a three-dimensional (3D) computer model. With DMLS, it is possible to fabricate titanium dental implants with an inherently porous surface, a key property required of implantation devices. Objective. The aim of this review was to evaluate the evidence for the reliability of DMLS titanium dental implants and their clinical and histologic/histomorphometric outcomes, as well as their mechanical properties. Materials and Methods. Electronic database searches were performed. Inclusion criteria were clinical and radiographic studies, histologic/histomorphometric studies in humans and animals, mechanical evaluations, and in vitro cell culture studies on DMLS titanium implants. Meta analysis could be performed only for randomized controlled trials (RCTs); to evaluate the methodological quality of observational human studies, the Newcastle Ottawa scale (NOS) was used. Results. Twenty-seven studies were included in this review. No RCTs were found, and meta-analysis could not be performed. The outcomes of observational human studies were assessed using the NOS: these studies showed medium methodological quality. Conclusions. Several studies have demonstrated the potential for the use of DMLS titanium implants. However, further studies that demonstrate the benefits of DMLS implants over conventional implants are needed. PMID- 25525435 TI - Post-Autologous (ASCT) Stem Cell Transplant Therapy in Multiple Myeloma. AB - Autologous stem cell transplant (ASCT) is the standard of care in transplant eligible multiple myeloma patients and is associated with significant improvement in progression-free survival (PFS), complete remission rates (CR), and overall survival (OS). However, majority of patients eventually relapse, with a median PFS of around 36 months. Relapses are harder to treat and prognosis declines with each relapse. Achieving and maintaining "best response" to initial therapy is the ultimate goal of first-line treatment and sustained CR is a powerful surrogate for extended survival especially in high-risk multiple myeloma. ASCT is often followed by consolidation/maintenance phase to deepen and/or maintain the response achieved by induction and ASCT. Novel agents like thalidomide, lenalidomide, and bortezomib have been used as single agents or in combination. Thalidomide use has been associated with a meaningful improvement in PFS and EFS, however, with substantial side effects. Data with lenalidomide maintenance after ASCT is favorable, but the optimal duration of lenalidomide maintenance is still unclear. Bortezomib use has been associated with superior outcomes, predominantly in high-risk myeloma patients. Combination regimens utilizing a proteasome inhibitor (i.e., bortezomib) with an immunomodulatory drug (thalidomide or lenalidomide) have provided the best outcomes. This review article serves as a review of the best available evidence in post-ASCT approaches in multiple myeloma. PMID- 25525437 TI - Successful rehabilitation of partial edentulous maxilla and mandible with new type of implants: molecular precision implants. AB - The extraction of teeth results in rapid bone resorption both vertically and horizontally in the first month. The loss of alveolar ridge reduces the chance of implant rehabilitation. Atraumatic extraction, implant placement in extraction socket, and an immediate prosthesis have been proposed as alternative therapies to maintain the volume and contours tissue and reduce time and cost of treatment. The immediate load of implants is a universally practiced procedure; nevertheless a successful procedure requires expertise in both the clinical and the reconstructive stages using a solid implant system. Excellent primary stability and high bone-implant contact are only minimal requirements for any type of implant procedure. In this paper we present a case report using a new type of implants. The new type of implants, due to its sophisticated control system of production, provides to the implantologist a safe and reliable implant, with a macromorphology designed to ensure a close contact with the surrounding bone. PMID- 25525436 TI - Treatment of febrile neutropenia and prophylaxis in hematologic malignancies: a critical review and update. AB - Febrile neutropenia is one of the most serious complications in patients with haematological malignancies and chemotherapy. A prompt identification of infection and empirical antibiotic therapy can prolong survival. This paper reviews the guidelines about febrile neutropenia in the setting of hematologic malignancies, providing an overview of the definition of fever and neutropenia, and categories of risk assessment, management of infections, and prophylaxis. PMID- 25525438 TI - Sudden unexpected death in a patient with tumour associated pulmonary embolism. AB - Tumour embolisms are rare and in most cases sudden causes of death. Diagnosing this rare condition is still very challenging in the daily clinical routine. In this report we present a case of a lethal sudden pulmonary tumour embolism in a 71-year-old male patient, who was admitted for elective invasive coronary angiography due to suspected coronary artery disease. The patient had suspected Ormond's disease and no previous history of tumour burden. Possible diagnostic and treatment options are discussed herein and an overview of the current literature is also presented. PMID- 25525439 TI - Ultrasound-guided pulse-dose radiofrequency: treatment of neuropathic pain after brachial plexus lesion and arm revascularization. AB - Neuropathic pain following brachial plexus injury is a severe sequela that is difficult to treat. Pulsed radiofrequency (PRF) has been proved to reduce neuropathic pain after nerve injury, even though the underlying mechanism remains unclear. This case report describes the use of ultrasound-guided PRF to reduce neuropathic pain in a double-level upper extremity nerve injury. A 25-year-old man who sustained a complete left brachial plexus injury with cervical root avulsion came to our attention. Since 2007 the patient has suffered from neuropathic pain (NP) involving the ulnar side of the forearm, the proximal third of the forearm, and the thumb. No pain relief was obtained by means of surgery, rehabilitation, and medications. Ultrasound-guided PRF was performed on the ulnar nerve at the elbow level. The median nerve received a PRF treatment at wrist level. After the treatment, the patient reported a consistent reduction of pain in his hand. We measured a 70% reduction of pain on the VAS scale. PRF treatment allowed our patient to return to work after a period of absence enforced by severe pain. This case showed that PRF is a useful tool when pharmacological therapy is inadequate for pain control in posttraumatic neuropathic pain. PMID- 25525440 TI - Off-label medicine use in pediatric inpatients: a prospective observational study at a tertiary care hospital in India. AB - Background. In the absence of standard pediatric prescribing information, clinicians often use medicines in an off-label way. Many studies have been published across the globe reporting different rates of off-label use. There is currently no study based on Indian drug formulary. Methods. The prospective observational study included pediatric patients in ages between 0 and 12 years admitted in a tertiary care hospital. Off-label use was assessed using the National Formulary of India (NFI). Predictors of off-label use were determined by logistic regression. Results. Of the 1645 medications prescribed, 1152 (70%) were off-label based on 14 possible off-label categories. Off-label medicines were mainly due to dose difference and use in restricted age limits as indicated in NFI. Respiratory medicines (82%), anti-infectives (73%), and nervous system medicines (53%) had higher off-label use. Important predictors of off-label prescribing were pediatric patients in age of 0 to 2 years (OR 1.68, 95% CI; P < 0.001) and hospital stay of six to 10 days (OR 1.91, 95% CI; P < 0.001). Conclusion. Off-label prescribing is common among pediatric patients. There is need to generate more quality data on the safety and efficacy of off-label medicines to rationalize pediatric pharmacotherapy. PMID- 25525441 TI - The StrongWomen Change Clubs: engaging residents to catalyze positive change in food and physical activity environments. AB - INTRODUCTION: The epidemic of obesity is a multifaceted public health issue. Positive policy and environmental changes are needed to support healthier eating and increased physical activity. METHODS: StrongWomen Change Clubs (SWCCs) were developed through an academic-community research partnership between researchers at Cornell University and Tufts University and community partners (cooperative extension educators) in rural towns in seven U.S. states. Extension educators served as the local leader and each recruited 10-15 residents to undertake a project to improve some aspect of the nutrition or physical activity environment. Most residents had limited (or no) experience in civic engagement. At 6 and 12 months after implementation, the research team conducted key informant interviews with SWCC leaders to capture their perceptions of program process, benchmark achievement, and self-efficacy. RESULTS: At 12 months, each SWCC had accomplished one benchmark; the majority had completed three or more benchmarks. They described common processes for achieving benchmarks such as building relationships and leveraging stakeholder partnerships. Barriers to benchmark achievement included busy schedules and resistance to and slow pace of change. CONCLUSION: Findings suggest that community change initiatives that involve stakeholders, build upon existing activities and organizational resources, and establish feasible timelines and goals can successfully catalyze environmental change. PMID- 25525442 TI - An FMRI study of neuronal specificity in acupuncture: the multiacupoint siguan and its sham point. AB - Clarifying the intrinsic mechanisms of acupuncture's clinical effects has recently been gaining popularity. Here, we choose the Siguan acupoint (a combination of bilateral LI4 and Liv3) and its sham point to evaluate multiacupoint specificity. Thirty-one healthy volunteers were randomly divided into real acupoint (21 subjects) and sham acupoint (10 subjects) groups. Our study used a single block experimental design to avoid the influence of posteffects. Functional magnetic resonance imaging data were acquired during acupuncture stimulation. Results showed extensive increase in neuronal activities with Siguan acupuncture and significant differences between stimulation at real and sham points. Brain regions that were activated more by real acupuncture stimulation than by sham point acupuncture included somatosensory cortex (the superior parietal lobule and postcentral gyrus), limbic-paralimbic system (the calcarine gyrus, precuneus, cingulate cortex, and parahippocampal gyrus), visual related cortex (the fusiform and occipital gyri), basal ganglia, and the cerebellum. In this way, our study suggests Siguan may elicit specific activities in human brain. PMID- 25525443 TI - Investigation of the lower resistance meridian: speculation on the pathophysiological functions of acupuncture meridians. AB - It was pointed out in the two earlier papers of the present author that the meridians are in fact zones in the loose connective tissue containing richer interstitial fluid and thus are lower-resistance passages for diffusion of meridian-signal carriers or mediators. Moreover, a hypothesis, which incorporates the wide variety of functions of the loose connective tissue, the circulatory system, and the nervous system into the meridian function, has been proposed and in the hypothesis the mast cell plays some key roles. In the present paper, considering also the latest knowledge on cell migration along with some existing experimental results, it is further pointed out that meridians ought to be lower resistance passages for chemotactic migration of cells and mast cells can indeed migrate longitudinally along meridians. Finally, the present paper points out that if we add the last two points to the hypothesis and keep in mind that mast cells have been known very recently to be versatile regulators of inflammation, tissue remodeling, host defense, and homeostasis, the rich pathophysiological functions of the meridian pointed out by the traditional Chinese medicine can be understood quite naturally. PMID- 25525444 TI - Anti-Inflammatory and Immunomodulatory Mechanism of Tanshinone IIA for Atherosclerosis. AB - Tanshinone IIA (Tan II A) is widely used in the treatment of cardiovascular diseases as an active component of Salvia miltiorrhiza Bunge. It has been demonstrated to have pleiotropic effects for atherosclerosis. From the anti inflammatory and immunomodulatory mechanism perspective, this paper reviewed major progresses of Tan IIA in antiatherosclerosis research, including immune cells, antigens, cytokines, and cell signaling pathways. PMID- 25525445 TI - Current evidence on auricular therapy for chemotherapy-induced nausea and vomiting in cancer patients: a systematic review of randomized controlled trials. AB - Auricular therapy (AT) has been historically viewed as a convenient approach adjunct to pharmacological therapy for cancer patients with chemotherapy-induced nausea and vomiting (CINV). The aim of this study was to assess the evidence of the therapeutic effect of AT for CINV management in cancer patients. Relevant randomized controlled trials were retrieved from 12 electronic databases without language restrictions. Meanwhile, manual search was conducted for Chinese journals on complementary medicine published within the last five years, and the reference lists of included studies were also checked to identify any possible eligible studies. Twenty-one studies with 1713 participants were included. The effect rate of AT for managing acute CINV ranged from 44.44% to 93.33% in the intervention groups and 15% to 91.67% in the control groups. For delayed CINV, it was 62.96% to 100% and 25% to 100%, respectively. AT seems to be a promising approach in managing CINV. However, the level of evidence was low and the definite effect cannot be concluded as there were significant methodological flaws identified in the analyzed studies. The implications drawn from the 21 studies put some clues for future practice in this area including the need to conduct more rigorously designed randomized controlled trials. PMID- 25525447 TI - Gene expression profile of increased heart rate in shensongyangxin-treated bradycardia rabbits. AB - Aims. The present study tries to investigate the gene expression profile of bradycardia rabbits' hearts after SSYX (SSYX, a traditional Chinese medicine) treatment. Methods. Eighteen adult rabbits were randomly assigned in three groups: sham, model, and SSYX treatment groups. Heart rate was recorded in rabbits and total RNA was isolated from hearts. Gene expression profiling was conducted and quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed to confirm the gene expression results. Patch clamp using human induced pluripotent stem cell-derived cardiomyocytes was applied to record the calcium current in the presence of SSYX. Results. The mean RR interval reduced after six weeks due to the injury of the sinoatrial node in the model group. This effect was partially reversed by 4-week SSYX treatment. cDNA microarray demonstrated that genes related with pacemaker current, calcium ion homeostasis, and signaling were altered by SSYX treatment. Results from patch clamp demonstrated that SSYX reduced the calcium current which is consistent with gene expression results. Conclusion. The present study shows mRNA remodeling of bradycardia and demonstrates that SSYX is effective in treating bradycardia by reversing altered gene expression in bradycardia models. Reduced calcium current by SSYX also confirmed the gene expression results. PMID- 25525446 TI - Systematic Analysis of the Multiple Bioactivities of Green Tea through a Network Pharmacology Approach. AB - During the past decades, a number of studies have demonstrated multiple beneficial health effects of green tea. Polyphenolics are the most biologically active components of green tea. Many targets can be targeted or affected by polyphenolics. In this study, we excavated all of the targets of green tea polyphenolics (GTPs) though literature mining and target calculation and analyzed the multiple pharmacology actions of green tea comprehensively through a network pharmacology approach. In the end, a total of 200 Homo sapiens targets were identified for fifteen GTPs. These targets were classified into six groups according to their related disease, which included cancer, diabetes, neurodegenerative disease, cardiovascular disease, muscular disease, and inflammation. Moreover, these targets mapped into 143 KEGG pathways, 26 of which were more enriched, as determined though pathway enrichment analysis and target pathway network analysis. Among the identified pathways, 20 pathways were selected for analyzing the mechanisms of green tea in these diseases. Overall, this study systematically illustrated the mechanisms of the pleiotropic activity of green tea by analyzing the corresponding "drug-target-pathway-disease" interaction network. PMID- 25525448 TI - Neurobiological mechanisms of acupuncture 2014. PMID- 25525449 TI - Changes in responses of neurons in spinal and medullary subnucleus reticularis dorsalis to acupoint stimulation in rats with visceral hyperalgesia. AB - The purpose of this study was to explore the mechanism of acupoints sensitization phenomenon at the spinal and medulla levels. Experiments were performed on adult male Sprague-Dawley rats and visceral noxious stimuli was generated by colorectal distension (CRD). The activities of wide dynamic range (WDR) and subnucleus reticularis dorsalis (SRD) neurons were recorded. The changes of the reactions of WDR and SRD neurons to electroacupuncture (EA) on acupoints of "Zusanli Shangjuxu" before and after CRD stimulation were observed. The results showed that visceral nociception could facilitate the response of neurons to acupoints stimulation. In spinal dorsal horn, EA-induced activation of WDR neurons further increased to 106.84 +/- 17.33% (1.5 mA) (P < 0.001) and 42.27 +/- 13.10% (6 mA) (P < 0.01) compared to the neuronal responses before CRD. In medulla oblongata, EA-induced activation of SRD neurons further increased to 63.28 +/- 15.96% (1.5 mA) (P < 0.001) and 25.02 +/- 7.47% (6 mA) (P < 0.01) compared to that before CRD. Taken together, these data suggest that the viscerosomatic convergence facilitation effect of WDR and SRD neurons may underlie the mechanism of acupoints sensitization. But the sensitizing effect of visceral nociception on WDR neurons is stronger than that on SRD neurons. PMID- 25525450 TI - Herbal medicines for cardiovascular diseases. PMID- 25525451 TI - Multifunctional Effects of Mangosteen Pericarp on Cognition in C57BL/6J and Triple Transgenic Alzheimer's Mice. AB - Mangosteen- (Garcinia mangostana-) based nutraceutical compounds have long been reported to possess multiple health-promoting properties. The current study investigated whether mangosteen pericarp (MP) could attenuate cognitive dysfunction. First, we found that treatment with MP significantly reduced the cell death and increased the brain-derived neurotrophic factor (BDNF) level in an organotypic hippocampal slice culture (OHSC). We then investigated the effects of age and MP diet on the cognitive function of male C57BL/6J (B6) mice. After 8 month dietary supplementation, the MP diet (5000 ppm) significantly attenuated the cognitive impairment associated with anti-inflammation, increasing BDNF level and decreasing p-tau (phospho-tau S202) in older B6 mice. We further applied MP dietary supplementation to triple transgenic Alzheimer's disease (3*Tg-AD) mice from 5 to 13 months old. The MP diet exerted neuroprotective, antioxidative, and anti-inflammatory effects and reduced the Abeta deposition and p-tau (S202/S262) levels in the hippocampus of 3*Tg-AD mice, which might further attenuate the deficit in spatial memory retrieval. Thus, these results revealed that the multifunctional properties of MP might offer a promising supplementary diet to attenuate cognitive dysfunction in AD. PMID- 25525452 TI - Transcriptome Profiling of Wheat Seedlings following Treatment with Ultrahigh Diluted Arsenic Trioxide. AB - Plant systems are useful research tools to address basic questions in homeopathy as they make it possible to overcome some of the drawbacks encountered in clinical trials (placebo effect, ethical issues, duration of the experiment, and high costs). The objective of the present study was to test the hypothesis whether 7-day-old wheat seedlings, grown from seeds either poisoned with a sublethal dose of As2O3 or unpoisoned, showed different significant gene expression profiles after the application of ultrahigh diluted As2O3 (beyond Avogadro's limit) compared to water (control). The results provided evidence for a strong gene modulating effect of ultrahigh diluted As2O3 in seedlings grown from poisoned seeds: a massive reduction of gene expression levels to values comparable to those of the control group was observed for several functional classes of genes. A plausible hypothesis is that ultrahigh diluted As2O3 treatment induced a reequilibration of those genes that were upregulated during the oxidative stress by bringing the expression levels closer to the basal levels normally occurring in the control plants. PMID- 25525453 TI - Effect of cervus and cucumis peptides on osteoblast activity and fracture healing in osteoporotic bone. AB - Osteoporosis is associated with delayed and/or reduced fracture healing. As cervus and cucumis are the traditional Chinese treatments for rheumatoid arthritis, we investigated the effect of supplementation of these peptides (CCP) on bone fracture healing in ovariectomized (OVX) osteoporotic rats in vitro and in vivo. CCP enhanced osteoblast proliferation and increased alkaline phosphatase activity, matrix mineralization, and expression of runt-related transcription factor 2 (Runx2), bone morphogenetic protein 4 (BMP4), and osteopontin. In vivo, female Sprague-Dawley rats underwent ovariectomy and the right femora were fractured and fixed by intramedullary nailing 3 months later. Rats received intraperitoneal injections of either CCP (1.67 mg/kg) or physiological saline every day for 30 days. Fracture healing and callus formation were evaluated by radiography, micro-CT, biomechanical testing, and histology. At 12 weeks after fracture, calluses in CCP-treated bones showed significantly higher torsional strength and greater stiffness than control-treated bones. Bones in CCP-treated rats reunified and were thoroughly remodeled, while two saline-treated rats showed no bone union and incomplete remodeling. Taken together, these results indicate that use of CCP after fracture in osteoporotic rats accelerates mineralization and osteogenesis and improves fracture healing. PMID- 25525454 TI - The nervous system of Paludicella articulata - first evidence of a neuroepithelium in a ctenostome ectoproct. AB - INTRODUCTION: Comparatively few data are available concerning the structure of the adult nervous system in the Ectoprocta or Bryozoa. In contrast to all other ectoprocts, the cerebral ganglion of phylactolaemates contains a central fluid filled lumen surrounded by a neuroepithelium. Preliminary observations have shown a small lumen within the cerebral ganglion of the ctenostome Paludicella articulata. Ctenostome-grade ectoprocts are of phylogenetic relevance since they are considered to have retained ancestral ectoproct features. Therefore, the ctenostome Paludicella articulata was analyzed in order to contribute to the basal neural bauplan of ctenostomes and the Ectoprocta in general. RESULTS: The presence of a lumen and a neuroepithelial organization of the nerve cells within the cerebral ganglion are confirmed. Four tentacle nerves project from the cerebral ganglion into each tentacle. Three of the tentacle nerves (one abfrontal and two latero-frontal nerves) have an intertentacular origin, whereas the medio frontal nerve arises from the cerebral ganglion. Six to eight visceral nerves and four tentacle sheath nerves are found to emanate from the cerebral ganglion and innervate the digestive tract and the tentacle sheath, respectively. CONCLUSIONS: The situation in P. articulata corresponds to the situation found in other ctenostomes and supports the notion that four tentacle nerves are the ancestral configuration in Ectoprocta and not six as proposed earlier. The presence of a lumen in the ganglion represents the ancestral state in Ectoprocta which disappears during ontogeny in all except in adult Phylactolaemata and P. articulata. It appears likely that it has been overlooked in earlier studies owing to its small size. PMID- 25525455 TI - Ant colony optimization approaches to clustering of lung nodules from CT images. AB - Lung cancer is becoming a threat to mankind. Applying machine learning algorithms for detection and segmentation of irregular shaped lung nodules remains a remarkable milestone in CT scan image analysis research. In this paper, we apply ACO algorithm for lung nodule detection. We have compared the performance against three other algorithms, namely, Otsu algorithm, watershed algorithm, and global region based segmentation. In addition, we suggest a novel approach which involves variations of ACO, namely, refined ACO, logical ACO, and variant ACO. Variant ACO shows better reduction in false positives. In addition we propose black circular neighborhood approach to detect nodule centers from the edge detected image. Genetic algorithm based clustering is performed to cluster the nodules based on intensity, shape, and size. The performance of the overall approach is compared with hierarchical clustering to establish the improvisation in the proposed approach. PMID- 25525456 TI - Altered intrinsic connectivity networks in frontal lobe epilepsy: a resting-state fMRI study. AB - Examining the resting-state networks (RSNs) may help us to understand the neural mechanism of the frontal lobe epilepsy (FLE). Resting-state functional MRI (fMRI) data were acquired from 46 patients with FLE (study group) and 46 age- and gender matched healthy subjects (control group). The independent component analysis (ICA) method was used to identify RSNs from each group. Compared with the healthy subjects, decreased functional connectivity was observed in all the networks; however, in some areas of RSNs, functional connectivity was increased in patients with FLE. The duration of epilepsy and the seizure frequency were used to analyze correlation with the regions of interest (ROIs) in the nine RSNs to determine their influence on FLE. The functional network connectivity (FNC) was used to study the impact on the disturbance and reorganization of FLE. The results of this study may offer new insight into the neuropathophysiological mechanisms of FLE. PMID- 25525458 TI - Categorical Perception for Emotional Faces. AB - Categorical perception (CP) refers to how similar things look different depending on whether they are classified as the same category. Many studies demonstrate that adult humans show CP for human emotional faces. It is widely debated whether the effect can be accounted for solely by perceptual differences (structural differences among emotional faces) or whether additional perceiver-based conceptual knowledge is required. In this review, I discuss the phenomenon of CP and key studies showing CP for emotional faces. I then discuss a new model of emotion which highlights how perceptual and conceptual knowledge interact to explain how people see discrete emotions in others' faces. In doing so, I discuss how language (emotion words included in the paradigm) contribute to CP. PMID- 25525457 TI - Isometric yoga improves the fatigue and pain of patients with chronic fatigue syndrome who are resistant to conventional therapy: a randomized, controlled trial. AB - BACKGROUND: Patients with chronic fatigue syndrome (CFS) often complain of persistent fatigue even after conventional therapies such as pharmacotherapy, cognitive behavioral therapy, or graded exercise therapy. The aim of this study was to investigate in a randomized, controlled trial the feasibility and efficacy of isometric yoga in patients with CFS who are resistant to conventional treatments. METHODS: This trial enrolled 30 patients with CFS who did not have satisfactory improvement after receiving conventional therapy for at least six months. They were randomly divided into two groups and were treated with either conventional pharmacotherapy (control group, n = 15) or conventional therapy together with isometric yoga practice that consisted of biweekly, 20-minute sessions with a yoga instructor and daily in-home sessions (yoga group, n = 15) for approximately two months. The short-term effect of isometric yoga on fatigue was assessed by administration of the Profile of Mood Status (POMS) questionnaire immediately before and after the final 20-minute session with the instructor. The long-term effect of isometric yoga on fatigue was assessed by administration of the Chalder's Fatigue Scale (FS) questionnaire to both groups before and after the intervention. Adverse events and changes in subjective symptoms were recorded for subjects in the yoga group. RESULTS: All subjects completed the intervention. The mean POMS fatigue score decreased significantly (from 21.9 +/- 7.7 to 13.8 +/ 6.7, P < 0.001) after a yoga session. The Chalder's FS score decreased significantly (from 25.9 +/- 6.1 to 19.2 +/- 7.5, P = 0.002) in the yoga group, but not in the control group. In addition to the improvement of fatigue, two patients with CFS and fibromyalgia syndrome in the yoga group also reported pain relief. Furthermore, many subjects reported that their bodies became warmer and lighter after practicing isometric yoga. Although there were no serious adverse events in the yoga group, two patients complained of tiredness and one of dizziness after the first yoga session with the instructor. CONCLUSIONS: Isometric yoga as an add-on therapy is both feasible and successful at relieving the fatigue and pain of a subset of therapy-resistant patients with CFS. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN CTR) UMIN000009646. PMID- 25525459 TI - The case for decoupling assembly and submission standards to maintain a more flexible registry of biological parts. AB - The Registry of Standard Biological Parts only accepts genetic parts compatible with the RFC 10 BioBrick format. This combined assembly and submission standard requires that four unique restriction enzyme sites must not occur in the DNA sequence encoding a part. We present evidence that this requirement places a nontrivial burden on iGEM teams developing large and novel parts. We further argue that the emergence of inexpensive DNA synthesis and versatile assembly methods reduces the utility of coupling submission and assembly standards and propose a submission standard that is compatible with current quality control strategies while nearly eliminating sequence constraints on submitted parts. PMID- 25525460 TI - Hurdles and delays in access to anti-cancer drugs in Europe. AB - Demographic changes in the world population will cause a significant increase in the number of new cases of cancer. To handle this challenge, societies will need to adapt how they approach cancer prevention and treatment, with changes to the development and uptake of innovative anticancer drugs playing an important role. However, there are obstacles to implementing innovative drugs in clinical practice. Prior to being incorporated into daily practice, the drug must obtain regulatory and reimbursement approval, succeed in changing the prescription habits of physicians, and ultimately gain the compliance of individual patients. Developing an anticancer drug and bringing it into clinical practice is, therefore, a lengthy and complex process involving multiple partners in several areas. To optimize patient treatment and increase the likelihood of implementing health innovation, it is essential to have an overview of the full process. This review aims to describe the process and discuss the hurdles arising at each step. PMID- 25525461 TI - The ninth International Conference of Anticancer Research, 6-10 October 2014, Sithonia, Greece. AB - The ninth conference of the International Institute for Anticancer Research, held in Sithonia, Greece in October 2014, included over 700 abstracts presented in 79 separate sessions and featured a wide range of topics in basic and clinical cancer research. This report describes a small but representative sample of these sessions. It covers some recent developments in research into the basic signal transduction pathways involved in carcinogenesis; a special session on the role of homeobox genes in cancer development; and clinical sessions covering advances in breast cancer, haematological cancers, and chemotherapy. PMID- 25525462 TI - How well do elderly patients with cervical cancer tolerate definitive radiochemotherapy using RapidArc? Results from an institutional audit comparing elderly versus younger patients. AB - PURPOSE: Elderly patients (65 or older) with cervical cancer often receive suboptimal radio-chemotherapy. Intensity-modulated radiotherapy (IMRT) may improve tolerance to treatment in this setting. This study was designed to compare the treatment-related toxicities and compliance with treatment in patients of cervical cancer treated definitively with RapidArc IMRT in our institute. METHODS AND MATERIALS: The treatment records of all patients treated with RapidArc IMRT between April 2012 and April 2014 were reviewed, retrospectively. Prospectively collected data regarding treatment toxicity (CTCAE 4.0), treatment outcomes and parameters related to treatment compliance were compared amongst two age groups (< 65 and >= 65 years). The results of 66 patients were identified, of whom 23 were found to be >= 65 years age. All patients completed planned external beam radiotherapy. However, significantly fewer patients in the elderly group received concurrent chemoradiation (98% versus 65%, p < 0.001). Old age (median 75 years, IQR: 74-78 years) was the commonest cause for non-receipt of chemotherapy. Incidence of grade 3 haematological toxicities (26.7% versus 16.7%) and gastrointestinal toxicity (16.7% versus 13.3%) were not significantly different between the two groups. Other treatment-related toxicities, breaks, treatment duration and early outcomes were also not significantly different between the two age groups. CONCLUSIONS: The use of IMRT did not result in excess toxicities in the elderly population and was associated with equivalent compliance to treatment. Concurrent chemoradiation can be safely combined in elderly patients with perfect organ function and performance status. PMID- 25525465 TI - Cancer education in Lithuania. AB - The aim of this article is to describe cancer education in Lithuania according to the data of 2013. In Lithuania, there are the following stages of education for physicians: basic education through integrated studies of medicine (six years), postgraduate education through residency studies (four to five years), and continuing professional development. In recent years, integrated studies of medicine have been the most popular specialty. Oncology is incorporated into the teaching courses in medicine programmes. In each university, an oncology course is mandatory during these studies. In Lithuania, there are two types of specialists related to oncology: medical oncologists and radiation oncologists. These oncologists complete multidisciplinary residency study programmes in the clinics. To receive a doctoral degree, specialists may join PhD programmes at any of the accredited universities. In recent years the number of dissertations in oncology has grown. Notably, oncology is chosen not only by students in the field of medicine. It also becomes the choice of those seeking a doctorate in the fields of nursing, public health, biochemistry, and physics. The professional development of oncologists is a lifelong commitment. In Lithuania, continuing specialist medical training is mandatory. This requirement is ensured with the process of licensing of medical practice. All Lithuanian study programmes are certificated by an independent public agency and are recognised by a number of other countries as well. PMID- 25525464 TI - T-helper 1 immunoreaction influences survival in muscle-invasive bladder cancer: proof of concept. AB - OBJECTIVE: To define immunoscore in bladder cancer studying T helper 1 (Th1) immunoreaction. To define a cancer-specific survival model based on Th1 cells infiltration. METHODS: A total of 252 patients underwent primary transurethral resection of bladder tumour at our Institution. A retrospective review of a selected cohort with pT1 and muscle-invasive bladder cancer (MIBC) lesions was performed. Pathology blocks were marked with CD3 and CD8 antibodies. Immune cells density in stromal reaction (SR) was measured on five distinct high-power field (HPF) by two dedicated uro-pathologist blinded for patients' evolution. STATISTICS: Student test or non-parametric Wilcoxon test as appropriate to compare means between two groups. Receiver operating characteristics (ROC) curve to define markers threshold. Cox model to assess survival's predictors. RESULTS: Ten pT1 and 20 MIBC consecutive cases were analysed. Median follow-up was 33.4 months. Immunohistological analysis for pT1 lesions featured limited SR. For MIBC, the mean density of lymphocytes in the SR was of 105/HPF (CD3) and 86/HPF (CD8). Survivors harboured higher lymphocytes densities versus non survivors (CD3: p = 0.0319; CD8: p = 0.0279). CD3 (p = 0.034) and CD8 (p = 0.034) lymphocytes densities were independently associated with cancer-specific survival on Cox model analyses. The retrospective design and small size of cohorts are the study limitations. CONCLUSIONS: High CD3 and CD8 lymphocytes SR densities are associated with better cancer-specific survival for MIBC. Th1 reaction against the tumour seems to be protective for bladder cancer. Further evaluation is warranted. PMID- 25525466 TI - Eurocan Platform meeting: European recommendations for biomarker-based chemoprevention trials. AB - Chemoprevention or the now more preferred 'cancer prevention' is the long-term administration of a biological or chemical agent to reduce the risk of cancer. This approach has long been active in individuals at high risk of developing breast or colon cancer. The aim of this expert meeting was to review the current status of the field of cancer prevention and potential, emerging biomarkers specifically focusing on breast, colon, and lung cancer but also with sessions on ovary and prostate. PMID- 25525463 TI - Repurposing drugs in oncology (ReDO)-cimetidine as an anti-cancer agent. AB - Cimetidine, the first H2 receptor antagonist in widespread clinical use, has anti cancer properties that have been elucidated in a broad range of pre-clinical and clinical studies for a number of different cancer types. These data are summarised and discussed in relation to a number of distinct mechanisms of action. Based on the evidence presented, it is proposed that cimetidine would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of cimetidine as an anti-cancer therapeutic is warranted. Furthermore, there is compelling evidence that cimetidine administration during the peri-operative period may provide a survival benefit in some cancers. A number of possible combinations with other drugs are discussed in the supplementary material accompanying this paper. PMID- 25525467 TI - The clinical practice of oncology nursing in Brazil: realities and challenges in the training of specialist nurses. PMID- 25525468 TI - Report from the First Latin American Urological Oncology Symposium (SLAURO) 19-21 June 2014, Vina del Mar, Chile. AB - Cancer is one of the most important diseases in Chile, with alarming incidence and mortality rates that are among the highest in Latin America. Economic growth in South America has led to demographic change, with an aging population typical of developed countries, but also a growing population with cancer. The incidence and mortality of urological cancers in Chile is significant, and has led to the formulation of health laws and policies promoting the early treatment of urological cancers. It is also well known that there are regions of Chile with extremely high incidence and mortality of bladder cancer caused by arsenic exposure. SLAURO (Simposio Latinoamericano de Urologia Oncologica [Latin American Oncological Urology Symposium]) is a new Latin American forum for discussing and promoting knowledge of urological cancers across the region. PMID- 25525470 TI - Motif mining based on network space compression. AB - A network motif is a recurring subnetwork within a network, and it takes on certain functions in practical biological macromolecule applications. Previous algorithms have focused on the computational efficiency of network motif detection, but some problems in storage space and searching time manifested during earlier studies. The considerable computational and spacial complexity also presents a significant challenge. In this paper, we provide a new approach for motif mining based on compressing the searching space. According to the characteristic of the parity nodes, we cut down the searching space and storage space in real graphs and random graphs, thereby reducing the computational cost of verifying the isomorphism of sub-graphs. We obtain a new network with smaller size after removing parity nodes and the "repeated edges" connected with the parity nodes. Random graph structure and sub-graph searching are based on the Back Tracking Method; all sub-graphs can be searched for by adding edges progressively. Experimental results show that this algorithm has higher speed and better stability than its alternatives. PMID- 25525469 TI - In silico molecular cytogenetics: a bioinformatic approach to prioritization of candidate genes and copy number variations for basic and clinical genome research. AB - BACKGROUND: The availability of multiple in silico tools for prioritizing genetic variants widens the possibilities for converting genomic data into biological knowledge. However, in molecular cytogenetics, bioinformatic analyses are generally limited to result visualization or database mining for finding similar cytogenetic data. Obviously, the potential of bioinformatics might go beyond these applications. On the other hand, the requirements for performing successful in silico analyses (i.e. deep knowledge of computer science, statistics etc.) can hinder the implementation of bioinformatics in clinical and basic molecular cytogenetic research. Here, we propose a bioinformatic approach to prioritization of genomic variations that is able to solve these problems. RESULTS: Selecting gene expression as an initial criterion, we have proposed a bioinformatic approach combining filtering and ranking prioritization strategies, which includes analyzing metabolome and interactome data on proteins encoded by candidate genes. To finalize the prioritization of genetic variants, genomic, epigenomic, interactomic and metabolomic data fusion has been made. Structural abnormalities and aneuploidy revealed by array CGH and FISH have been evaluated to test the approach through determining genotype-phenotype correlations, which have been found similar to those of previous studies. Additionally, we have been able to prioritize copy number variations (CNV) (i.e. differentiate between benign CNV and CNV with phenotypic outcome). Finally, the approach has been applied to prioritize genetic variants in cases of somatic mosaicism (including tissue-specific mosaicism). CONCLUSIONS: In order to provide for an in silico evaluation of molecular cytogenetic data, we have proposed a bioinformatic approach to prioritization of candidate genes and CNV. While having the disadvantage of possible unavailability of gene expression data or lack of expression variability between genes of interest, the approach provides several advantages. These are (i) the versatility due to independence from specific databases/tools or software, (ii) relative algorithm simplicity (possibility to avoid sophisticated computational/statistical methodology) and (iii) applicability to molecular cytogenetic data because of the chromosome-centric nature. In conclusion, the approach is able to become useful for increasing the yield of molecular cytogenetic techniques. PMID- 25525471 TI - 'Memory and molecular turnover,' 30 years after inception. AB - In 1984 Sir Francis Crick hypothesized that memory is recorded in the brain as reversible modifications to DNA and protein, but acknowledged that most biomolecules turn over too rapidly to account for long-term memories. To accommodate this possible paradox he modeled an enzymatic mechanism to maintain modifications on hemi-modified multimeric symmetrical molecules. While studies on the turnover of chromatin modifications that may be involved in memory are in their infancy, an exploration of his model in the light of modern epigenetics produced somewhat surprising results. The molecular turnover rates for two classes of chromatin modifications believed to record and store durable memories were approximated from experiments using diverse approaches and were found to be remarkably short. The half-lives of DNA cytosine methylation and post translationally modified nucleosomal histones are measured in hours and minutes, respectively, for a subset of sites on chromatin controlling gene expression. It appears likely that the turnover of DNA methylation in the brain and in neurons, in particular, is even more rapid than in other cell types and organs, perhaps accommodating neuronal plasticity, learning, and memory. The machinery responsible for the rapid turnover of DNA methylation and nucleosomal histone modifications is highly complex, partially redundant, and appears to act in a sequence specific manner. Molecular symmetry plays an important part in maintaining site-specific turnover, but its particular role in memory maintenance is unknown. Elucidating Crick's paradox, the contradiction between rapid molecular turnover of modified biomolecules and long-term memory storage, appears fundamental to understanding cognitive function and neurodegenerative disease. PMID- 25525473 TI - Supramolecular guests in solvent driven block copolymer assembly: From internally structured nanoparticles to micelles. AB - Supramolecular interactions between different hydrogen-bonding guests and poly(2 vinyl pyridine)-block-poly (styrene) can be exploited to prepare remarkably diverse self-assembled nanostructures in dispersion from a single block copolymer (BCP). The characteristics of the BCP can be efficiently controlled by tailoring the properties of a guest which preferentially binds to the P2VP block. For example, the incorporation of a hydrophobic guest creates a hydrophobic BCP complex that forms phase separated nanoparticles upon self-assembly. Conversely, the incorporation of a hydrophilic guest results in an amphiphilic BCP complex that forms spherical micelles in water. The ability to tune the self-assembly behavior and access dramatically different nanostructures from a single BCP substrate demonstrates the exceptional versatility of the self-assembly of BCPs driven by supramolecular interactions. This approach represents a new methodology that will enable the further design of complex, responsive self-assembled nanostructures. PMID- 25525472 TI - Distinct features of the piRNA pathway in somatic and germ cells: from piRNA cluster transcription to piRNA processing and amplification. AB - Transposable elements (TEs) are major components of genomes. Their mobilization may affect genomic expression and be a threat to genetic stability. This is why they have to be tightly regulated by a dedicated system. In the reproductive tissues of a large range of organisms, they are repressed by a subclass of small interfering RNAs called piRNAs (PIWI interacting RNAs). In Drosophila melanogaster, piRNAs are produced both in the ovarian germline cells and in their surrounding somatic cells. Accumulating evidence suggests that germinal and somatic piRNA pathways are far more different than previously thought. Here we review the current knowledge on piRNA production in both these cell types, and explore their similarities and differences. PMID- 25525474 TI - Toward Intraoperative Image-Guided Transoral Robotic Surgery. AB - This paper presents the development and evaluation of video augmentation on the stereoscopic da Vinci S system with intraoperative image guidance for base of tongue tumor resection in transoral robotic surgery (TORS). Proposed workflow for image-guided TORS begins by identifying and segmenting critical oropharyngeal structures (e.g., the tumor and adjacent arteries and nerves) from preoperative computed tomography (CT) and/or magnetic resonance (MR) imaging. These preoperative planned data can be deformably registered to the intraoperative endoscopic view using mobile C-arm cone-beam computed tomography (CBCT) [1, 2]. Augmentation of TORS endoscopic video defining surgical targets and critical structures has the potential to improve navigation, spatial orientation, and confidence in tumor resection. Experiments in animal specimens achieved statistically significant improvement in target localization error when comparing the proposed image guidance system to simulated current practice. PMID- 25525475 TI - The Snapping Elbow Syndrome as a Reason for Chronic Elbow Neuralgia in a Tennis Player - MR, US and Sonoelastography Evaluation. AB - BACKGROUND: Ulnar neuropathy is the second most common peripheral nerve neuropathy after median neuropathy, with an incidence of 25 cases per 100 000 men and 19 cases per 100 000 women each year. Skipping (snapping) elbow syndrome is an uncommon cause of pain in the posterior-medial elbow area, sometimes complicated by injury of the ulnar nerve. One of the reason is the dislocation of the abnormal insertion of the medial triceps head over the medial epicondyle during flexion and extension movements. Others are: lack of the Osboune fascia leading to ulnar nerve instability and focal soft tissue tumors (fibromas, lipomas, etc). Recurrent subluxation of the nerve at the elbow results in a tractional and frictional neuritis with classical symptoms of peripheral neuralgia. As far as we know snapping triceps syndrome had never been evaluated in sonoelastography. CASE REPORT: A 28yo semi-professional left handed tennis player was complaining about pain in posterior-medial elbow area. Initial US examination suggest golfers elbow syndrome which occurs quite commonly and has a prevalence of 0.3-0.6% in males and 0-3-1.1% in women and may be associated (approx. 50% of cases) with ulnar neuropathy. However subsequently made MRI revealed unusual distal triceps anatomy, moderate ulnar nerve swelling and lack of medial epicondylitis symptoms. Followed (second) US examination and sonoelastography have detected slipping of the both ulnar nerve and the additional band of the medial triceps head. DISCUSSION: Snapping elbow syndrome is a poorly known medical condition, sometimes misdiagnosed as the medial epicondylitis. It describes a broad range of pathologies and anatomical abnormalities. One of the most often reasons is the slipping of the ulnar nerve as the result of the Osborne fascia/anconeus epitrochlearis muscle absence. Simultaneously presence of two or more "snapping reasons" is rare but should be always taken under consideration. CONCLUSIONS: There are no sonoelastography studies describing golfers elbow syndrome, additional triceps band and ulnar neuritis. Our data suggest that the sonoelastography signs are similar to those seen in well described lateral epicondylitis syndrome, Achilles tendinitis and medial nerve neuralgia. PMID- 25525476 TI - Dementia Risk and Financial Decision Making by Older Households: The Impact of Information. AB - The knowledge and reasoning ability needed to manage one's finances is a form of human capital. Alzheimer's disease and other dementias cause progressive declines in cognition that lead to a complete loss of functional capacities. In this paper we analyze the impact of information about cognitive decline on the choice of household financial decision-maker. Using longitudinal data on older married couples in a novel application of survival analysis, we find that as the financial decision maker's cognition declines, the management of finances is eventually turned over to his cognitively intact spouse, often well after difficulties handling money have already emerged. However, a memory disease diagnosis increases the hazard of switching the financial respondent by over 200 percent for couples who control their retirement accounts, like 401(k) accounts, relative to those who passively receive retirement income. This finding is consistent with a model of the value of information: households with the most to gain financially from preparation are most responsive to information about cognitive decline. PMID- 25525477 TI - Protein restriction in hepatic encephalopathy is appropriate for selected patients: a point of view. AB - Since the late nineteenth century, protein restriction has been shown to improve hepatic encephalopathy. However, malnutrition has been described in up to 60 % of cirrhotic patients and is associated with increased mortality. Furthermore, emerging clinical evidence has revealed that a large proportion of cirrhotic patients may tolerate normal protein intake. However, approximately one third of cirrhotic patients with hepatic encephalopathy may need a short course of protein restriction, in addition to maximum medical therapy, to ameliorate the clinical course of their hepatic encephalopathy. For patients with chronic hepatic encephalopathy who are protein-sensitive, modifying their sources of nitrogen by using more vegetable protein, less animal protein, and branched-chain amino acids may improve their encephalopathy without further loss of lean body mass. In conclusion, among cirrhotics with hepatic encephalopathy, modulation of normal protein intake must take into account the patient's hepatic reserve, severity of hepatic encephalopathy, and current nutritional status. PMID- 25525478 TI - An incidental finding of pleomorphic adenoma of the minor salivary glands in the skin area of the lower lip. AB - Salivary gland tumors are uncommonly seen and account for less than 3% of the head and neck tumors. Pleomorphic adenoma is a well-described benign tumor of the salivary glands, originating from myoepithelial and intercalated duct cells. It is most commonly found in major salivary glands. We present a rare and unusual case of pleomorphic adenoma of the minor salivary glands in the lower lip. The tumor was diagnosed upon excision of 1.5 * 1.2 cm(2) well-circumscribed nodule at the junction of the lower lip and chin in a 46-year-old man. The histopathological analysis confirmed presence of an epithelial salivary gland tumor with islands of plasmacytoid cells, and duct-like structures within a variable and mixed stroma. PMID- 25525479 TI - Efficacy and feasibility of the submuscular implantation technique for an implantable cardiac electrical device. AB - BACKGROUND: A common complication associated with implantable cardiac electrical device implantation compromises skin lesions caused by overstretching just above a buried device that is relatively large in size. Apart from affecting the cosmetic appearance in some patients, a compromised blood supply to the skin may also lead to ischemic necrosis, which is an important complication. We describe a novel procedure for the implantation of implantable cardiac electrical devices generators under the pectoralis major muscle to avoid such skin-related complications. METHODS: Twenty-one patients were referred to plastic surgeon for surgical support for the secondary replacement of implantable cardiac electrical devices. In all cases, the leads and devices had been implanted under the skin. We decided to perform device implantation under the pectoralis major muscle, which was highly recommended in all these patients. RESULTS: In Japan, leanness is determined on the basis of body mass index less than 18.5, and 11 patients out of 21 (52%) were considered to be lean. The surgeon's participation in the procedure for implantable cardiac electrical device implantation did not exceed 5 minutes in total. CONCLUSIONS: We consider that the novel method of sub pectoralis major muscle device implantation described here minimizes the risk of the skin breakdown and improves the patient's quality of life. PMID- 25525480 TI - Use of negative pressure wound therapy with automated, volumetric instillation for the treatment of extremity and trunk wounds: clinical outcomes and potential cost-effectiveness. AB - OBJECTIVE: A growing body of literature supports use of negative pressure wound therapy (NPWT) with instillation and dwell time (NPWTi-d) with positive clinical outcomes and potential cost savings. A retrospective analysis was performed to compare clinical outcomes of wounds treated with NPWTi-d versus NPWT and to estimate cost-differences between treatments based on clinical outcomes. METHODS: Data were extracted from records of patients with extremity or trunk wounds treated with NPWT (n = 34) or NPWTi-d using saline or polyhexanide (n = 48). On the basis of outcomes data, a hypothetical economic model using cost assumptions was created to calculate cost savings for NPWTi-d (related to) number of debridements and length of therapy. Operating room debridement cost was $3393 according to Granick et al. Daily therapy cost for each modality was $194.80 (NPWTi-d) and $106.08 (NPWT) based on internal company information. RESULTS: RESULTS showed significant differences (P < 0.0001) between NPWTi-d and NPWT patients, respectively, for the following: mean operating room debridements (2.0 vs 4.4), mean hospital stay (8.1 vs 27.4 days), mean length of therapy (4.1 vs 20.9 days), and mean time to wound closure (4.1 vs 20.9 days). Hypothetical economic model showed potential average reduction of $8143 for operating room debridements between NPWTi-d ($6786) and NPWT ($14,929) patients. There was a $1418 difference in average therapy costs between groups ($799/NPWTi-d vs $2217/NPWT). CONCLUSIONS: In this study, NPWTi-d appeared to assist in wound cleansing and exudate removal, which may have allowed for earlier wound closure compared to NPWT. Hypothetical economic model findings illustrate potential cost effectiveness of NPWTi-d compared to NPWT. PMID- 25525481 TI - A systematic review of infection rates and associated antibiotic duration in acellular dermal matrix breast reconstruction. AB - INTRODUCTION: Reported infection rates in breast reconstruction with acellular dermal matrix (ADM) can exceed 31%. Prophylactic antibiotics remain controversial due to the absence of evidence-based literature. The purpose of this study was to examine published antibiotic regimens and their associated infection rates in this population. METHODS: Systematic electronic searches were performed in PubMed, OVID, and the Cochrane databases for studies that reported on prophylactic antibiotic use and infection in patients undergoing ADM breast reconstruction. Two independent authors reviewed studies between 1970 and 2012 for inclusion and data extraction. RESULTS: A total of 863 studies were identified and abstracts reviewed. A total of 24 articles were included, with 2148 patients and 3189 ADM reconstructions. Mean infection rates varied between 0% and 31.25%, with a combined average of 11.59%. When comparing antibiotic protocols of less than 24 hours and more than 24 hours, the average infection rate was 2.48% and 13.21%, respectively. CONCLUSION: The current literature lacks consensus on the necessary duration for postoperative antibiotic prophylaxis following breast reconstruction. The potential increased risk of infection associated with ADM remains controversial. Because of the lack of supportive evidence, we do not recommend prolonged postoperative antibiotics in ADM breast reconstruction. LEVEL OF EVIDENCE: Therapeutic level III evidence. PMID- 25525482 TI - Genomic and proteomic evaluation of tissue quality of porcine wounds treated with negative pressure wound therapy in continuous, noncontinuous, and instillation modes. AB - OBJECTIVE: Negative pressure wound therapy with instillation (NPWTi-d) combines NPWT with automated delivery and removal of topical wound treatment solutions. This porcine study compared genomic and proteomic responses of wounds treated with NPWTi-d with saline to wounds treated with NPWT in continuous and noncontinuous modes. METHODS: Full-thickness porcine dorsal excisional wounds were treated with continuous NPWT, intermittent NPWT, dynamic NPWT, or NPWTi-d with saline (n = 10 wounds per group). On day 7, animals were euthanized and tissues collected. Real-time quantitative polymerase chain reaction arrays profiled expression of 84 genes including extracellular matrix remodeling factors, inflammatory cytokines and chemokines, and growth factors and major signaling molecules. Concentrations of proteins associated with angiogenesis, extracellular matrix components, and cellular energetics were analyzed via enzyme linked immunosorbent assays. RESULTS: Gene expression profiles for NPWTi-d with saline and continuous NPWT were similar. There were 5 upregulated and 18 downregulated genes overexpressed in NPWTi-d compared to NPWT wounds. Protein content was comparable in all treatment groups and similar to unwounded tissue. CONCLUSIONS: Previous preclinical studies have reported an increased rate of granulation tissue formation with NPWTi-d with saline compared to NPWT in continuous and noncontinuous modes. This evaluation of gene and protein expression suggests that the granulation tissue in these wounds has a similar quality. This first look at the differences in gene expression, particularly in genes related to remodeling, cell adhesion, inflammation, and growth factors, could help to clarify the observed differences in granulation rates. PMID- 25525484 TI - Reduction of a multidrug-resistant pathogen and associated virulence factors in a burn wound infection model: further understanding of the effectiveness of a hydroconductive dressing. AB - OBJECTIVE: Drawtex's ability to remove pathogens and associated virulence factors has been demonstrated in vitro. A model of burn wound infection was used to characterize the in vivo impact of this dressing on infection and wound healing. METHODS: Paired burn wounds were created on the dorsum of Sprague Dawley rats and were inoculated with methicillin-resistant Staphylococcus aureus (MRSA). Animals were divided into 2 groups, half with wounds that received experimental dressing and the remaining half with control dressing-treated wounds. Dressings remained in place through 3, 6, 9, or 14 days after injury, and methicillin-resistant S aureus and virulence factors were quantified. Laser Doppler imaging was used to examine wound perfusion, and local host immune response was assessed through the quantification of mRNA expression. RESULTS: By day 3, less methicillin-resistant S aureus was measured in wounds treated with experimental-dressing compared to control-dressing wounds. Quantities remained lower in the experimental group through day 14 (P < .001). More methicillin-resistant S aureus was quantified in the experimental dressing itself than in control dressing at all time points (P < .05). Experimental dressing-treated wounds contained less toxic shock syndrome toxin 1 and Panton-Valentine leukocidin than controls (P < .01) on days 6, 9, and 14. Induction of toll-like receptor 2, NOD-like receptor family, pyrin domain containing 3, and interleukin 6 was significantly lower in experimental-dressing treated wounds than in controls on days 6 and 9 (P < .05). CONCLUSIONS: The hydroconductive dressing provided a significant reduction in pathogen and virulence factors compared to a control dressing. As a result of clearance of virulence factors from the wound bed, a requisite alteration in host innate immune response was observed. PMID- 25525483 TI - Comparing quantitative values of two generations of laser-assisted indocyanine green dye angiography systems: can we predict necrosis? AB - OBJECTIVE: Several devices exist today to assist the intraoperative determination of skin flap perfusion. Laser-Assisted Indocyanine Green Dye Angiography (LAICGA) has been shown to accurately predict mastectomy skin flap necrosis using quantitative perfusion values. The laser properties of the latest LAICGA device (SPY Elite) differ significantly from its predecessor system (SPY 2001), preventing direct translation of previous published data. The purpose of this study was to establish a mathematical relationship of perfusion values between these 2 devices. METHODS: Breast reconstruction patients were prospectively enrolled into a clinical trial where skin flap evaluation and excision was based on quantitative SPY Q values previously established in the literature. Initial study patients underwent mastectomy skin flap evaluation using both SPY systems simultaneously. Absolute perfusion unit (APU) values at identical locations on the breast were then compared graphically. RESULTS: 210 data points were identified on the same patients (n = 4) using both SPY systems. A linear relationship (y = 2.9883x + 12.726) was identified with a high level or correlation (R(2) = 0.744). Previously published values using SPY 2001 (APU 3.7) provided a value of 23.8 APU on the SPY Elite. In addition, postoperative necrosis in these patients correlated to regions of skin identified with the SPY Elite with APU less than 23.8. CONCLUSION: Intraoperative comparison of LAICGA systems has provided direct correlation of perfusion values predictive of necrosis that were previously established in the literature. An APU value of 3.7 from the SPY 2001 correlates to a SPY Elite APU value of 23.8. PMID- 25525485 TI - Bilateral mandibular fractures. PMID- 25525486 TI - Levamisole-Induced ANCA Vasculitis and Cutaneous Necrosis. PMID- 25525487 TI - Extensor carpi radialis longus and brevis rupture in a boxer. PMID- 25525488 TI - "Mirrored" Rolando's Fracture of the Base of the Fifth Metacarpal. PMID- 25525489 TI - Management of hydrofluoric Acid burns. PMID- 25525490 TI - Nodular swelling on the lower lip; pyogenic granuloma. PMID- 25525491 TI - Recurrent Pectus Excavatum Repair via Ravitch Technique With Rib Locking Plates. PMID- 25525492 TI - Personalized medicine: are we there yet? PMID- 25525493 TI - Rewarding innovation in drug development. PMID- 25525494 TI - Evaluation of dabigatran for appropriateness of use and bleeding events in a community hospital setting. AB - BACKGROUND: Warfarin has been the predominant anticoagulant for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). Its disadvantages are well-known and include a narrow therapeutic index, drug interactions, and the need for frequent monitoring. Dabigatran etexilate, a direct thrombin inhibitor, presents less complexity in prescribing and has emerged as an alternate therapy to warfarin. Although dabigatran does not require routine monitoring, concerns associated with its use include the lack of a reversal agent, complex dose adjustments, and limited guidance to the management of drug interactions. OBJECTIVES: The goals of this study are to describe and to evaluate the use of dabigatran at a community hospital to identify areas for improvement in its prescribing. METHODS: This retrospective chart review of patients at a community hospital in St Louis, MO, included patients who received at least 1 dose of dabigatran between December 2010 and June 2012. The appropriateness of dabigatran was evaluated based on recommendations approved by the US Food and Drug Administration for stroke prophylaxis in the setting of NVAF. The composite end point of bleeding included hospital readmission within 1 year of receiving at least 1 dose of dabigatran at the study institution secondary to bleeding, bleeding associated with a decrease in hemoglobin level by >=2 g/dL or transfusion of >=2 units of blood, or a notation of bleeding in the patient's medical record. RESULTS: Of the 458 patients included in the evaluation, 76 (16.6%) patients receiving dabigatran were using an inappropriate regimen of this drug, based on dose and frequency on the first day of therapy of dabigatran or the presence of valvular disease. Many patients (42.3%) received at least 1 dose of a concomitant parenteral anticoagulant. The composite end point for bleeding was reported in 66 (14.4%) patients, including 23 (5%) with confirmed gastrointestinal bleeding. CONCLUSIONS: High-risk medications such as dabigatran require monitoring of prescribing habits to improve patient safety and outcomes. Various initiatives, such as pharmacist interventions, therapeutic interchanges, and obtaining appropriate patient parameters, can be implemented in the practice setting to ensure the appropriate use of oral anticoagulants and improved patient outcomes. PMID- 25525495 TI - Patient preferences and treatment adherence among women diagnosed with metastatic breast cancer. AB - BACKGROUND: Given the various profiles (eg, oral vs intravenous administration, risk of hot flashes vs fatigue) of treatment options (eg, endocrine therapy, chemotherapy) for metastatic breast cancer (mBC), how patients value these attributes of their medications has implications on making treatment decisions and on adherence. OBJECTIVES: To understand how patients trade off medication side effects with improved effectiveness and/or quality of life, to provide estimates of nonadherence among women with mBC, and to quantify the association of medication nonadherence with health outcomes. METHODS: The study was a cross sectional, Internet-based survey of 181 women diagnosed with mBC who were recruited from cancer-specific online panels (response rate, 7%). Treatment information, demographics, nonadherent behaviors, and quality of life assessed by the Functional Assessment of Cancer Therapy-Breast (FACT-B) were collected in the survey, and each respondent completed a choice-based conjoint exercise to assess patient preferences. The patients' preferences were analyzed using hierarchical Bayesian logistic regression models, and the association between the number of nonadherent behaviors and the health outcomes was analyzed using general linear models. RESULTS: The mean age of the patient sample was 52.2 years (standard deviation, +/-9.1), with 93.9% of participants being non-Hispanic white. Results from the conjoint model indicated that effectiveness (overall survival) was of primary importance to patients, followed by side effects-notably alopecia, fatigue, neutropenia, motor neuropathy, and nausea/vomiting-and finally, dosing regimen. In all, 34.8% of survey respondents either discontinued their treatment or were nonadherent to their treatment regimen. Among those who have ever used oral chemotherapy (N = 95; 52.5%) and those currently using oral chemotherapy (N = 44; 24.3%), the number of nonadherent behaviors was significantly associated with a decrease in functional well-being (b [unstandardized regression coefficient] = -2.01 for patients who had ever used a targeted therapy and b = 3.14 for current users of a targeted therapy), FACT-General total score (b = 4.30 and b = -7.37, respectively), FACT-B total score (b = -3.93 and b = -6.11, respectively), and FACT trial outcome index (b = -5.22 and b = -8.63, respectively; all P <.05). CONCLUSIONS: Patients were willing to accept substantial additional risks from side effects for gains in overall survival. Approximately 33% of women with mBC reported engaging in nonadherent behaviors. Because forgetfulness and adverse events were among the most frequent reasons for nonadherence, these results suggest that less complex treatment regimens, as well as regimens with less toxic profiles, may be associated with improvements in adherence and, subsequently, could correspond to perceptible patient benefits. PMID- 25525496 TI - Synthesis and Pharmacological Evolution of Tetrahydroisoquinolines as Anti Breast Cancer Agents. AB - Breast cancer is leading cause of mortality among women, resulting in more than half a million deaths worldwide each year. Unfortunately, the recovery rate of advanced breast cancer by current available drug treatment is till unacceptably low. Chemotherapy is the main stay of cancer treatment and most of the drugs cause general toxicity to any non-proliferating cells, which can severely limit the therapeutic values of these drugs. Tetrahydroisoqinoline derivatives (THIQs) were identified as subtype selective estrogen receptor antagonists/agonists hence, potential therapeutic agents for breast cancer. Substituted THIQs were synthesized and well characterized. Antiproliferative activity against human ER (+) MCF-7 (Breast), ER(-) MDA-MB-231 (breast) and Ishikawa (endometrial) cancer cell lines were studied after 72 hours drug exposure employing CellTiter-Glo assay at concentrations ranging from 0.01-100,000 nM. The activities of these compounds were compared with Tamoxifen (TAM). In-vitro results indicated that most of the compounds showed better activity than TAM. The most active compounds obtained in this study were 6a, 6b, 6d and 6j (IC50=0.63, 0.23; 0.93, 0.21; 043, 0.01; 0.7, 0.02 MUg/ml) against MCF-7 and Ishikawa cell lines, in comparison to Tamoxifen activity (IC50=5.14, 4.55 MUg/ml). The newly synthesized molecules were docked in the active sites of the ER-alpha (PDB: 3ERT) and ER-beta (PDB: 3ERT) crystal structures and probable binding modes of this class of molecules were determined. PMID- 25525497 TI - Spatiotemporal resource distribution and foraging strategies of ants (Hymenoptera: Formicidae). AB - The distribution of food resources in space and time is likely to be an important factor governing the type of foraging strategy used by ants. However, no previous systematic attempt has been made to determine whether spatiotemporal resource distribution is in fact correlated with foraging strategy across the ants. In this analysis, I present data compiled from the literature on the foraging strategy and food resource use of 402 species of ants from across the phylogenetic tree. By categorizing the distribution of resources reported in these studies in terms of size relative to colony size, spatial distribution relative to colony foraging range, frequency of occurrence in time relative to worker life span, and depletability (i.e., whether the colony can cause a change in resource frequency), I demonstrate that different foraging strategies are indeed associated with specific spatiotemporal resource attributes. The general patterns I describe here can therefore be used as a framework to inform predictions in future studies of ant foraging behavior. No differences were found between resources collected via short-term recruitment strategies (group recruitment, short-term trails, and volatile recruitment), whereas different resource distributions were associated with solitary foraging, trunk trails, long term trail networks, group raiding, and raiding. In many cases, ant species use a combination of different foraging strategies to collect diverse resources. It is useful to consider these foraging strategies not as separate options but as modular parts of the total foraging effort of a colony. PMID- 25525498 TI - Data Sources Regarding the Nonmedical Use of Pharmaceutical Opioids in the United States. AB - OBJECTIVE: Recent increases in the nonmedical use of pharmaceutical opioids and the adverse outcomes associated with them have stimulated a large amount of research and data collection on this public health problem. Systematic organization of the available data sources is needed to facilitate ongoing research, analysis, and evaluation. This work offers a systematic categorization of data sources regarding the nonmedical use of pharmaceutical opioids in the United States. METHODS: A list of keywords regarding the nonmedical use of pharmaceutical opioids was used to conduct systematic searches in PubMed(r). Filtration of search results generated 92 peer-reviewed academic articles, published between January 1995 and April 2012, as well as a number of primary data sources. Lists of topics were developed independently by two researchers which were later compared and consolidated. All sources were then categorized according to their relevance to each of these topics and according to their capacity for geographical and longitudinal trend analysis. RESULTS: Tables cataloging data sources can be used to identify data relevant to specific topics in diversion, nonmedical use, and adverse outcomes associated with pharmaceutical opioids, and they illustrate global trends in data coverage, identifying several topics that have minimal data. A network diagram illustrates global trends in data coverage, showing variation among sources in the number of topics they cover, as well as variation among topics in the number of sources that cover them. CONCLUSIONS: The categorization of data sources is hoped to facilitate ongoing research, analysis, and evaluation of this public health problem by serving as a guide for researchers, policy makers, and others who seek data regarding the nonmedical use of pharmaceutical opioids in the United States. PMID- 25506420 TI - The electrostatic profile of consecutive Cbeta atoms applied to protein structure quality assessment. AB - The structure of a protein provides insight into its physiological interactions with other components of the cellular soup. Methods that predict putative structures from sequences typically yield multiple, closely-ranked possibilities. A critical component in the process is the model quality assessing program (MQAP), which selects the best candidate from this pool of structures. Here, we present a novel MQAP based on the physical properties of sidechain atoms. We propose a method for assessing the quality of protein structures based on the electrostatic potential difference (EPD) of Cbeta atoms in consecutive residues. We demonstrate that the EPDs of Cbeta atoms on consecutive residues provide unique signatures of the amino acid types. The EPD of Cbeta atoms are learnt from a set of 1000 non-homologous protein structures with a resolution cuto of 1.6 A obtained from the PISCES database. Based on the Boltzmann hypothesis that lower energy conformations are proportionately sampled more, and on Annsen's thermodynamic hypothesis that the native structure of a protein is the minimum free energy state, we hypothesize that the deviation of observed EPD values from the mean values obtained in the learning phase is minimized in the native structure. We achieved an average specificity of 0.91, 0.94 and 0.93 on hg_structal, 4state_reduced and ig_structal decoy sets, respectively, taken from the Decoys 'R' Us database. The source code and manual is made available at https://github.com/sanchak/mqap and permanently available on 10.5281/zenodo.7134. PMID- 25525500 TI - Hydrogen sulfide provides cardioprotection against myocardial/ischemia reperfusion injury in the diabetic state through the activation of the RISK pathway. AB - BACKGROUND: Coronary artery disease remains the principal cause of death in patients with diabetes mellitus. Diabetic mice display exacerbated injury following myocardial ischemia-reperfusion (MI/R) and are resistant to most therapeutic interventions. We have reported that sodium sulfide (Na2S) therapy confers cardioprotection during MI/R in non-diabetic mice. Here we tested the hypothesis that Na2S therapy would limit the extent of myocardial injury following MI/R when administered at the time of reperfusion. METHODS AND RESULTS: Diabetic mice (db/db, 12 weeks of age) were subjected to transient myocardial ischemia for a period of 30 minutes followed by reperfusion up to 24 hours. Na2S (0.05 to 1 mg/kg) or saline (vehicle) was administered into the left ventricular lumen at the time of reperfusion. Na2S therapy significantly decreased myocardial injury in the db/db diabetic mouse, as evidenced by a reduction in infarct size and circulating troponin-I levels. The reduction in myocardial injury was also associated with a reduction in oxidative stress and a decrease in cleaved caspase 3 expression. In an effort to evaluate the signaling mechanism responsible for the observed cardioprotection, additional groups of mice were sacrificed during early reperfusion. Hearts were excised and processed for Western blot analysis. These studies revealed that Na2S therapy activated the Erk1/2 arm of the Reperfusion Injury Salvage Kinase (RISK) pathway. CONCLUSION: These findings provide important information that myocardial Erk1/2 activation by Na2S therapy following MI/R sets into motion events, which ultimately lead to cardioprotection in the setting of diabetes. PMID- 25525499 TI - Treatment of Clostridium difficile infection: recent trial results. AB - Clostridium difficile is a major cause of infection worldwide and is associated with increasing morbidity and mortality in vulnerable patient populations. Metronidazole and oral vancomycin are the currently recommended therapies for the treatment of C. difficile infection (CDI) but are associated with unacceptably high rates of disease recurrence. Novel therapies for the treatment of CDI and prevention of recurrent CDI are urgently needed. Important developments in the treatment of CDI are currently underway and include: novel antibacterial agents with narrower antimicrobial spectra of activity, manipulation of the gut microbiota and enhancement of the host antibody immune response. PMID- 25525503 TI - Multidimensional Homophily in Friendship Networks. AB - Homophily - the tendency for individuals to associate with similar others - is one of the most persistent findings in social network analysis. Its importance is established along the lines of a multitude of sociologically relevant dimensions, e.g. sex, ethnicity and social class. Existing research, however, mostly focuses on one dimension at a time. But people are inherently multidimensional, have many attributes and are members of multiple groups. In this article, we explore such multidimensionality further in the context of network dynamics. Are friendship ties increasingly likely to emerge and persist when individuals have an increasing number of attributes in common? We analyze eleven friendship networks of adolescents, draw on stochastic actor-oriented network models and focus on the interaction of established homophily effects. Our results indicate that main effects for homophily on various dimensions are positive. At the same time, the interaction of these homophily effects is negative. There seems to be a diminishing effect for having more than one attribute in common. We conclude that studies of homophily and friendship formation need to address such multidimensionality further. PMID- 25506420 TI - The electrostatic profile of consecutive Cbeta atoms applied to protein structure quality assessment. AB - The structure of a protein provides insight into its physiological interactions with other components of the cellular soup. Methods that predict putative structures from sequences typically yield multiple, closely-ranked possibilities. A critical component in the process is the model quality assessing program (MQAP), which selects the best candidate from this pool of structures. Here, we present a novel MQAP based on the physical properties of sidechain atoms. We propose a method for assessing the quality of protein structures based on the electrostatic potential difference (EPD) of Cbeta atoms in consecutive residues. We demonstrate that the EPDs of Cbeta atoms on consecutive residues provide unique signatures of the amino acid types. The EPD of Cbeta atoms are learnt from a set of 1000 non-homologous protein structures with a resolution cuto of 1.6 A obtained from the PISCES database. Based on the Boltzmann hypothesis that lower energy conformations are proportionately sampled more, and on Annsen's thermodynamic hypothesis that the native structure of a protein is the minimum free energy state, we hypothesize that the deviation of observed EPD values from the mean values obtained in the learning phase is minimized in the native structure. We achieved an average specificity of 0.91, 0.94 and 0.93 on hg_structal, 4state_reduced and ig_structal decoy sets, respectively, taken from the Decoys 'R' Us database. The source code and manual is made available at https://github.com/sanchak/mqap and permanently available on 10.5281/zenodo.7134. PMID- 25525504 TI - Influence of health-related quality of life on time from symptom onset to hospital arrival and the risk of readmission in patients with myocardial infarction. AB - BACKGROUND: Despite increased awareness of the importance of early treatment in acute myocardial infarction (AMI), the delay from symptom onset to hospital arrival is still too long and rehospitalisations are frequent. Little is known about how health-related quality of life (HRQL) affects delay time and the frequency of readmissions. METHOD: We used quality registers to investigate whether patients' HRQL has any impact on delay time with a new AMI, and on the rate of readmissions during the first year. Patients with AMI <75 years, with HRQL assessed with EQ-5D at 1-year follow-up, and who thereafter had a new AMI registered, were evaluated for the correlation between HRQL and delay time (n=454). The association between HRQL and readmissions was evaluated among those who had an additional AMI and a new 1-year follow-up registration (n=216). RESULTS: Patients who reported poor total health status (EQ-VAS <=50), compared to those who reported EQ-VAS 81-100, had tripled risk to delay >=2 h from symptom onset to hospital arrival (adjusted OR 3.01, 95% CI 1.43 to 6.34). Patients scoring EQ-VAS <=50 had also a higher risk of readmissions in the univariate analysis (OR 3.08, 95% CI 1.71 to 5.53). However, the correlation did not remain significant after adjustment (OR 1.99, 95% CI 0.90 to 4.38). EQ-index was not independently associated with delay time or readmissions. CONCLUSIONS: Aspects of total health status post-AMI were independently associated with delay time to hospital arrival in case of a new AMI. However, the influence of total health status on the risk of readmissions was less clear. PMID- 25525505 TI - Classification of left ventricular size: diameter or volume with contrast echocardiography? AB - BACKGROUND: Left ventricular (LV) size is an important clinical variable, commonly assessed at echocardiography by measurement of the internal diameter in diastole (IDD). However, this has recognised limitations and volumetric measurement from apical views is considered superior, particularly with the use of echocardiographic contrast. We sought to determine the agreement in classification of LV size by different measures in a large population of patients undergoing echocardiography. METHODS AND RESULTS: Data were analysed retrospectively from consecutive patients (n=2008, 61% male, median 62 years) who received echocardiographic contrast for LV opacification over 3 years in a single institution. Repeat studies were not included. LVIDD was measured, and LV end diastolic volume (LVEDV) calculated using Simpson's biplane method. Both measures were indexed (i) to body surface area and categorised according to the American Society of Echocardiography (ASE) guidelines as normal, mild, moderate or severely dilated. Of 320 patients with a severely dilated LVEDVi, only 95 (30%) were similarly classified by LVIDD, with 86 patients (27%) measuring in the normal range. LVIDDi agreement was poorer, with only 43 patients (13%) classified as being severely dilated, and 173 (54%) measuring in the normal range. CONCLUSIONS: Currently recommended echocardiographic measures of LV size show limited agreement when classified according to currently recommended cut-offs. LV diameter should have a limited role in the assessment of LV size, particularly where a finding of LV dilation has important diagnostic or therapeutic implications. PMID- 25525506 TI - A decade of changes in clinical characteristics and management of elderly patients with non-ST elevation myocardial infarction admitted in Italian cardiac care units. AB - OBJECTIVE: To describe the evolution of clinical characteristics, in-hospital management and early outcome of elderly patients with non-ST elevation myocardial infarction (NSTEMI). METHODS: We analysed data from five consecutive Italian nationwide registries, conducted between 2001 and 2010, including patients with acute coronary syndromes admitted to cardiac care units (CCUs). RESULTS: Of 10 983 patients with NSTEMI enrolled in the 5 surveys, 4350 (39.6%) were >=75 years old (mean age 81+/-5 years). Some clinical characteristics such as diabetes mellitus, hypertension, renal dysfunction and previous percutaneous coronary intervention increased significantly, whereas a history of stroke, myocardial infarction and heart failure decreased over time. An invasive approach increased from 26.6% in 2001 to 68.4% in 2010 (p<0.0001) and revascularisation rates increased from 9.9% to 51.7% (p<0.0001). Early use and prescription at discharge of beta-blockers, statins and dual antiplatelet treatment increased significantly (p<0.0001). Thirty-day observed mortality decreased from 14.6% (95% CI 9.9 to 20.4) to 9.5% (95% CI 7.7 to 11.6). At the multivariate logistic regression analyses adjusted for baseline characteristics, compared with 2001, the risk of death was significantly lower in all the other studies performed at different times with reductions in adjusted mortality between 66% and 45%. CONCLUSIONS: Over the past decade, substantial changes have occurred in the clinical characteristics and management of elderly patients admitted with NSTEMI in Italian CCUs, with a greater use of revascularisation therapy and recommended medications. These variations have been associated with a reduction in 30-day adjusted mortality rate. PMID- 25525508 TI - The Impact of the Introduction of MELD on the Dynamics of the Liver Transplantation Waiting List in Sao Paulo, Brazil. AB - Until July 15, 2006, the time on the waiting list was the main criterion for allocating deceased donor livers in the state of Sao Paulo, Brazil. After this date, MELD has been the basis for the allocation of deceased donor livers for adult transplantation. Our aim was to compare the waitlist dynamics before MELD (1997-2005) and after MELD (2006-2012) in our state. A retrospective study was conducted including the data from all the liver transplant candidate waiting lists from July 1997 to December 2012. The data were related to the actual number of liver transplantations (Tr), the incidence of new patients on the list (I), and the number of patients who died while being on the waitlist (D) from 1997 to 2005 (the pre-MELD era) and from 2006 to 2012 (the post-MELD era). The number of transplantations from 1997 to 2005 and from 2006 to 2012 increased nonlinearly, with a clear trend to levelling to equilibrium at approximately 350 and 500 cases per year, respectively. The implementation of the MELD score resulted in a shorter waiting time until liver transplantation. Additionally, there was a significant effect on the waitlist dynamics in the first 4 years; however, the curves diverge from there, implying a null long-range effect on the waitlist by the MELD scores. PMID- 25525507 TI - Carbon Nanotubes and Chronic Granulomatous Disease. AB - Use of nanomaterials in manufactured consumer products is a rapidly expanding industry and potential toxicities are just beginning to be explored. Combustion generated multiwall carbon nanotubes (MWCNT) or nanoparticles are ubiquitous in non-manufacturing environments and detectable in vapors from diesel fuel, methane, propane, and natural gas. In experimental animal models, carbon nanotubes have been shown to induce granulomas or other inflammatory changes. Evidence suggesting potential involvement of carbon nanomaterials in human granulomatous disease, has been gathered from analyses of dusts generated in the World Trade Center disaster combined with epidemiological data showing a subsequent increase in granulomatous disease of first responders. In this review we will discuss evidence for similarities in the pathophysiology of carbon nanotube-induced pulmonary disease in experimental animals with that of the human granulomatous disease, sarcoidosis. PMID- 25525509 TI - Interocular symmetry in macular choroidal thickness in children. AB - Objective. To report interocular differences in choroidal thickness in children using spectral domain optical coherence tomography (SD-OCT) and correlate findings with biometric data. Methods. This observational cross-sectional study included 91 (182 eyes) healthy children aged 6 to 17 years with no ocular abnormality except refractive error. After a comprehensive eye exam and axial length measurement, high definition macular scans were performed using SD-OCT. Two observers manually measured the choroidal thickness at the foveal center and at 1500 um nasally, temporally, inferiorly, and superiorly. Interocular differences were computed; correlations with age, gender, refractive error, and axial length were performed. Results. Mean age was 10.40 +/- 3.17 years; mean axial length and refractive error values were similar between fellow eyes. There was excellent correlation between the two observers' measurements. No significant interocular differences were observed at any location. There was only a trend for right eyes to have higher values in all thicknesses, except the superior thickness. Most of the choroidal thickness measurements correlated positively with spherical equivalent but not with axial length, age, or gender. Conclusion. Choroidal thickness measurements in children as performed using SD-OCT revealed a high level of interobserver agreement and consistent interocular symmetry. Values correlated positively with spherical equivalent refraction. PMID- 25525510 TI - Evaluation of corneal topography and biomechanical parameters after use of systemic isotretinoin in acne vulgaris. AB - Purpose. We report the effect of isotretinoin on corneal topography, corneal thickness, and biomechanical parameters in patients with acne vulgaris. Method. Fifty-four eyes of 54 patients who received oral isotretinoin for treatment of acne vulgaris were evaluated. All patients underwent a corneal topographical evaluation with a Scheimpflug camera combined with Placido-disk (Sirius), ultrasonic pachymetry measurements, and corneal biomechanical evaluation with an ocular response analyzer at baseline, in the 1st, 3rd, and 6th months of treatment, and 6 months after isotretinoin discontinuation. Results. The thinnest corneal thickness measured with Sirius differed significantly in the 1st, 3rd, and 6th months compared with the baseline measurement; there was no significant change in ultrasonic central corneal thickness measurements and biomechanical parameters (corneal hysteresis and corneal resistance factor) throughout the study. Average simulated keratometry and surface asymmetry index increased significantly only in the first month of treatment according to the baseline. All changes disappeared 6 months after the end of treatment. Conclusion. Basal tear secretion and corneal morphologic properties were significantly influenced during the systemic isotretinoin treatment and the changes were reversible after discontinuation. No statistical important biomechanical differences were found to be induced by isotretinoin. PMID- 25525511 TI - Abdominal adiposity distribution in diabetic/prediabetic and nondiabetic populations: a meta-analysis. AB - Excess fat in the abdomen can be classified generally as visceral and subcutaneous adiposity. Evidence suggests that visceral adiposity has greater implications for diabetes than other fat depots. The purpose of this study is to explore the disparities in the distribution of abdominal adiposity in diabetic/prediabetic and nondiabetic populations and to identify moderators that influence the pattern of central obesity via a meta-analysis technique. The Hedges' g was used as a measure of effect size and 95% confidence interval was computed. A total of 41 relevant studies with 101 effect sizes were retrieved. Pooled effect sizes for visceral and subcutaneous adiposity were 0.69 and 0.42, respectively. Diabetic/prediabetic populations exhibited greater visceral and subcutaneous adiposity compared to nondiabetic populations (Z = 10.35, P < 0.05). Significant moderator effects of gender (Z = -2.90) and assessment method of abdominal adiposity (Z = -2.17) were found for visceral fat (P < 0.05), but not for subcutaneous fat. Type of health condition influenced both visceral (Z = 5.10) and subcutaneous (Z = -7.09) abdominal adiposity volumes (P < 0.05). Abdominal adiposity distributions were significantly altered in the diabetic/prediabetic population compared to the nondiabetic population. Gender, assessment method of abdominal adiposity, and type of health conditions (diabetic/prediabetics) were identified as crucial moderators that influence the degree of abdominal adiposity. PMID- 25525512 TI - The intake of energy and selected nutrients by thai urban sedentary workers: an evaluation of adherence to dietary recommendations. AB - Rapid changes in Thailand's nutrition and lifestyles have led to increasing diet related pathologies among people with sedentary occupations. This study examines the extent to which the dietary intake of nutrients and energy by a sample of Thai sedentary workers conforms to the Thai Dietary Reference Intakes (Thai DRIs). The nutrients and energy intake estimates were based on self-reported information collected with a single 24-hour dietary recall and nonweighed 2-day food record. The study participants were Thai adults aged 20-50 years employed in sedentary occupations. A convenience sample of 215 healthy individuals (75 males and 140 females) was based on four randomly selected worksites in the Bangkok metropolitan area. For male participants, the study found a median energy intake of 1,485 kcal/day, with 54.4% of energy coming from carbohydrate, 15.9% from protein, and 29.6% from fat. Females' median energy intake was 1,428 kcal/day, 56% of which came from carbohydrate, 16.2% from protein, and 28.6% from fat. Both genders showed insufficient intake of fiber and most micronutrients. This study provides the material for preventive public health interventions focusing on nutrition-related diseases affecting Thailand's rapidly growing sedentary workforce. PMID- 25525513 TI - Measuring outcomes in adult weight loss studies that include diet and physical activity: a systematic review. AB - Background. Measuring success of obesity interventions is critical. Several methods measure weight loss outcomes but there is no consensus on best practices. This systematic review evaluates relevant outcomes (weight loss, BMI, % body fat, and fat mass) to determine which might be the best indicator(s) of success. Methods. Eligible articles described adult weight loss interventions that included diet and physical activity and a measure of weight or BMI change and body composition change. Results. 28 full-text articles met inclusion criteria. Subjects, settings, intervention lengths, and intensities varied. All studies measured body weight (-2.9 to -17.3 kg), 9 studies measured BMI (-1.1 to -5.1 kg/m(2)), 20 studies measured % body fat (-0.7 to -10.2%), and 22 studies measured fat mass (-0.9 to -14.9 kg). All studies found agreement between weight or BMI and body fat mass or body fat % decreases, though there were discrepancies in degree of significance between measures. Conclusions. Nearly all weight or BMI and body composition measures agreed. Since body fat is the most metabolically harmful tissue type, it may be a more meaningful measure of health change. Future studies should consider primarily measuring % body fat, rather than or in addition to weight or BMI. PMID- 25525514 TI - Acute effects of exogenous hormone administration on postprandial acylation stimulating protein levels in ovariectomized rats after a fat load. AB - Background. ASP, a potent lipogenic factor, was linked to female fat metabolism in association studies. Aim. To investigate acute effects of sex hormone treatment on postprandial ASP levels in vivo. Methods. 24 female rats were randomly divided into 4 groups including controls. The rats were ovariectomized and injected with progesterone, estrogen, or testosterone. An hour later, olive oil was administered orally. Plasma ASP and triglycerides were measured at several postprandial time points. Area under the curve (TG-AUC) represented TG clearance. Results. Only the progesterone treated group had a significant postprandial ASP increase at two hours compared to basal levels (439.8 +/- 62.4 versus 253.4 +/- 59.03 MUg/mL, P = 0.04). Interestingly, increased ASP levels coordinated negatively with corresponding TG levels and TG-AUC postprandially, mostly evident in the opposite effects in the progesterone and testosterone treated groups. ASP levels increased 3-fold in the progesterone versus testosterone treated groups, whereas TG-AUC was significantly lower. Conclusion. These findings suggest that progesterone enhances ASP production and TG clearance simultaneously, supporting the notion of a stimulatory role for progesterone on ASP-mediated TG clearance. This is the first functional study demonstrating a cause-effect relationship between hormone treatment and ASP levels in vivo and may contribute to understanding the mechanism of progesterone function as a female lipogenic hormone. PMID- 25525515 TI - Gram-negative infections in adult intensive care units of latin america and the Caribbean. AB - This review summarizes recent epidemiology of Gram-negative infections in selected countries from Latin American and Caribbean adult intensive care units (ICUs). A systematic search of the biomedical literature (PubMed) was performed to identify articles published over the last decade. Where appropriate, data also were collected from the reference list of published articles, health departments of specific countries, and registries. Independent cohort data from all countries (Argentina, Brazil, Chile, Colombia, Cuba, Mexico, Trinidad and Tobago, and Venezuela) signified a high rate of ICU infections (prevalence: Argentina, 24%; Brazil, 57%). Gram-negative pathogens, predominantly Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, accounted for >50% of ICU infections, which were often complicated by the presence of multidrug-resistant strains and clonal outbreaks. Empirical use of antimicrobial agents was identified as a strong risk factor for resistance development and excessive mortality. Infection control strategies utilizing hygiene measures and antimicrobial stewardship programs reduced the rate of device-associated infections. To mitigate the poor health outcomes associated with infections by multidrug-resistant Gram-negative bacteria, urgent focus must be placed on infection control strategies and local surveillance programs. PMID- 25525516 TI - The Effect of Educational Intervention on Nurses' Attitudes and Beliefs about Depression in Heart Failure Patients. AB - Systematic depression screening is feasible, efficient, and well accepted; however the lack of consistent assessment in heart failure inpatients suggests barriers preventing its effective diagnosis and treatment. This pilot study assessed the impact of an educational intervention on nurses' beliefs about depression and their likelihood of routinely screening heart failure patients. Registered nurses (n = 35) from adult medical-surgical units were surveyed before and after an educational intervention to assess their beliefs about depression prevalence and screening in heart failure patients. There was no significant influence on nurses' beliefs about depression, but the results suggested an increased likelihood that nurses would routinely screen for depression. The moderately significant correlation between beliefs and intent to screen for depression indicates that educational intervention could ultimately have a positive influence on patient outcomes through early detection and treatment of depression in patients with cardiovascular disease; however the observed increase in the intent to screen without a corresponding change in beliefs indicates other influences affecting nurses' intent to screen heart failure patients for depression. PMID- 25525517 TI - The effect of economic, physical, and psychological abuse on mental health: a population-based study of women in the Philippines. AB - Background. The comparative effect of economic abuse and other forms of abuse in predicting depression and other mental health disorders has not been previously investigated despite its relevance for mental illness prevention. Objective. To determine the differential association of economic abuse on psychological distress and suicide attempts. Study Design. We used cross-sectional data from women aged 15-49 years in the 2008 Philippines Demographic and Health Surveys (PDHS) (N = 9,316). Results. Adjusting for sociodemographic confounders revealed positive associations between economic, physical, or psychological abuse and suicide attempts and psychological distress. Psychological and economic abuse were the strongest predictors of suicide attempts and psychological distress, respectively. Economic abuse was also negatively associated with psychological distress. Comorbidity with one mental health disorder greatly increased the odds of reporting the other mental health disorder. Conclusion. Overall, the results elucidate the differential effects of these forms of abuse on women's mental health. PMID- 25525518 TI - Comparative Effects of Some Medicinal Plants: Anacardium occidentale, Eucalyptus globulus, Psidium guajava, and Xylopia aethiopica Extracts in Alloxan-Induced Diabetic Male Wistar Albino Rats. AB - Insulin therapy and oral antidiabetic agents/drugs used in the treatment of diabetes mellitus have not sufficiently proven to control hyperlipidemia, which is commonly associated with the diabetes mellitus. Again the hopes that traditional medicine and natural plants seem to trigger researchers in this area is yet to be discovered. This research was designed to compare the biochemical effects of some medicinal plants in alloxan-induced diabetic male Wistar rats using named plants that are best at lowering blood glucose and hyperlipidemia and ameliorating other complications of diabetes mellitus by methods of combined therapy. The results obtained showed 82% decrease in blood glucose concentration after the 10th hour to the fortieth hour. There was significant increase P < 0.05 in the superoxide dismutase activity of the test group administered 100 mg/kg of A. Occidentale. There was no significant difference P > 0.05 recorded in the glutathione peroxidase activity of E. globulus (100 mg/kg) when compared to the test groups of P. guajava (250 mg/kg) and X. aethiopica (250 mg/kg). Catalase activity showed significant increase P < 0.05 in the catalase activity, compared to test groups. While at P > 0.05, there was no significant difference seen between test group and treated groups. Meanwhile, degree of significance was observed in other parameters analysed. The biochemical analysis conducted in this study showed positive result, attesting to facts from previous works. Though these individual plants extracts exhibited significant increase in amelorating diabetes complication and blood glucose control compared to glibenclamide, a synthetic antidiabetic drug. Greater performance was observed in the synergy groups. Therefore, a poly/combined formulation of these plants extracts yielded significant result as well as resolving some other complications associated with diabetics. PMID- 25525519 TI - Effects of continuous use of Entonox in comparison with intermittent method on obstetric outcomes: a randomized clinical trial. AB - BACKGROUND: Entonox (N2O2) which is an inhalational gas for relieving labor pain is commonly used intermittently; however some women are interested in continuous breathing in face mask. So we decided to compare the complications induced by two methods to find out whether it is safe to permit the mothers to use Entonox continuously or not. PATIENTS AND METHODS: This randomized clinical trial was performed in Mobini Hospital, Sabzevar, Iran. 50 parturients used Entonox intermittently and 50 cases used it continuously during labor. Then obstetrical outcomes were analyzed in two groups by spss 17 software, t-test, and Chi(2) while P < 0.05 was considered significant. RESULTS: This study showed the mean duration of second stage of labor had no significant difference (P = 0.3). Perineal laceration was less in continuous group significantly (P = 0.04). Assisted vaginal birth was not different significantly (P = 0.4). Uterine atony had no significant difference in two groups (P = 0.2). Maternal collaboration in pushing and satisfaction were higher in continuous group significantly (P = 0.03), (P < 0.0001). Apgar score of neonates at first and fifth minute was acceptable and not different significantly in two groups (P = 0.3). CONCLUSIONS: Our study demonstrated continuous method is also safe. So, it seems reasonable to set mothers free to choose the desired method of Entonox usage. PMID- 25525520 TI - Central portalization correlates with fibrosis but not with risk factors for nonalcoholic steatohepatitis in steatotic chronic hepatitis C. AB - Concomitant steatosis in chronic hepatitis C is associated with fibrosis and unfavorable treatment outcome. Central zone injury in nonalcoholic steatohepatitis (NASH) manifests as central portalization, with centrizonal microvessels and ductular reaction. We investigated whether central portalization in steatotic HCV biopsies would identify patients with metabolic risk factors for NASH. Liver biopsies with chronic hepatitis C and >10% steatosis (n = 65) were evaluated for the degree of steatosis, zonation of steatosis, fibrosis, and nonalcoholic fatty liver disease (NAFLD) activity score. The presence of centrizonal microvessels, sinusoidal capillarization, ductular reaction, and CK7 positive intermediate-phenotype hepatocytes were evaluated by CD34 and CK7 immunostain. The degree of steatosis and fibrosis showed a positive correlation. Additional positive correlations were noted between centrizonal angiogenesis and NAFLD activity score and central portalization and fibrosis. However, neither central portalization nor zonation of steatosis identified patients with metabolic risk factors for NASH. Therefore, central portalization cannot be used as a surrogate marker to identify patients with metabolic risk factors for NASH in steatotic HCV biopsies. The mechanism of centrizonal injury in steatotic HCV hepatitis is not solely attributable to the metabolic risk factors for NASH. PMID- 25525521 TI - The costs of operative complications for ankle fractures: a case control study. AB - As our healthcare system moves towards bundling payments, it is vital to understand the potential financial implications associated with treatment of surgical complications. Considering that surgical treatment of ankle fractures is common, there remains minimal data relating costs to postsurgical intervention. We aimed to identify costs associated with ankle fracture complications through case-control analysis. Using retrospective analysis at a level I trauma center, 28 patients with isolated ankle fractures who developed complications (cases) were matched with 28 isolated ankle fracture patients without complications (controls) based on ASA score, age, surgery type, and fracture type. Patient charts were reviewed for demographics and complications leading to readmission/reoperation and costs were obtained from the financial department. Wilcoxon tests measured differences in the costs between the cases and controls. 28 out of 439 patients (6.4%) developed complications. Length of stay and median costs were significantly higher for cases than controls. Specifically, differences in total costs existed for infection and hardware-related pain. This is the first study to highlight the considerable costs associated with the treatment of complications due to isolated ankle fractures. Physicians must therefore emphasize methods to control surgical and nonsurgical factors that may impact postoperative complications, especially under a global payment system. PMID- 25525522 TI - Immediate Return to Ambulation and Improved Functional Capacity for Rehabilitation in Complex Regional Pain Syndrome following Early Implantation of a Spinal Cord Stimulation System. AB - Complex regional pain syndrome (CRPS) is a neuropathic pain condition that is characterized by vasomotor, sensory, sudomotor, and motor symptoms. Spinal cord stimulation (SCS) has been successfully utilized for the treatment of pain refractory to conventional therapies. We present a case of a previously highly functioning 54-year-old female who developed a rarely reported case of idiopathic CRPS of the right ankle which spontaneously occurred four months after an uncomplicated anterior cervical disc fusion. This condition resulted in severe pain and functional impairment that was unresponsive to pharmacological management. The patient's rehabilitation was severely stymied by her excruciating pain. However, with the initiation of spinal cord stimulation, her pain was adequately controlled allowing for progression to full unassisted ambulation, advancing functional capacity, and improving quality of life. This case report supports the concept that rapid progression to neuromodulation, rather than delays that occur due to attempts at serial sympathetic blocks, may better control symptoms leading allowing for a more meaningful recovery. PMID- 25525523 TI - Hepatocellular carcinoma to the right ventricle. AB - Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer in the world, but metastatic disease to the heart is rare. We present a case of a 63-year-old man with history of hepatitis C and cirrhosis, which had progressed to HCC. The patient had undergone two prior liver transplantations. He presented to the hospital complaining of worsening lower extremity edema. His exam was also pertinent for jugular venous distension, a 3/6 crescendo-decrescendo murmur, and hepatosplenomegaly. A transthoracic echocardiogram showed a large irregular lobulated mass in the apex of the right ventricle with a mobile pedunculated component. An MRI of the heart revealed a 4.4 * 3.4 * 4.0 cm mass within the right ventricular apex, which was subsequently biopsied and found to be moderately differentiated HCC with myocardial fragments. The patient opted out of any further therapy, or intervention, and was enrolled in hospice care. PMID- 25525524 TI - A case of noncompaction at all segments of both right and left ventricles. AB - Background. Noncompaction/hypertrabeculation left ventricle (NCM/HVM) is most commonly reported in one or more segments of left ventricle and sometimes both ventricles. In this case, we present noncompaction of all segments of right and left ventricle, in a young man with mental retardation. Case Presentation. A 19 year-old male was referred to us with sudden dyspnea at rest and chest discomfort. He was a known case of mental retardation. He was born full term with birth weight = 1250 grams. On physical examination. A systolic murmur (II/VI) at left sternal border was heard. ECG showed increased voltage in precordial lead and deep ST segment depression. Chest X-ray (CXR) was within normal limits. Transthoracic echocardiography showed situs solitus, D loop, normal connection of great vessels, noncompaction LV at all segments (noncompaction/compaction = 2.5/0.5) with moderate systolic dysfunction (LVEF = 40%), diastolic dysfunction grade II, normal RV size with mild systolic dysfunction and hypertrabeculation, mild tricuspid regurgitation (TR), and normal pulmonary artery systolic pressure. After injection of agitated saline some bubbles were passed from right to left through patent foramen oval (PFO). Conclusions. Extensive sinusoid formation and trabeculation of RV and nearby all LV segments and its association with mental retardation suggest presence of strong genetic background. PMID- 25525525 TI - Cone beam computed topographic evaluation and endodontic management of a rare mandibular first molar with four distal canals. AB - Root canal system is complex to understand because of its unpredictable nature. It differs for different teeth and for the same teeth in different individuals. Successful endodontic therapy thus depends on the clinician's ability to anticipate and look for these variations. A mandibular first molar with six root canals represents a rare anatomical variant, particularly when four canals are found in distal root. This case report discusses successful nonsurgical endodontic management of two-root mandibular first molar with four distal canals and two mesial canals reported for the first time in Indian population. Cone beam computed tomography was used as a diagnostic method to confirm the position and presence of 4 root canals in the distal root. PMID- 25525526 TI - Diagnosis and Treatment of Pseudo-Class III Malocclusion. AB - Pseudo-Class III malocclusion is characterized by the presence of an anterior crossbite due to a forward functional displacement of the mandible; in most cases, the maxillary incisors present some degree of retroclination, and the mandibular incisors are proclined. Various types of appliances have been described in the literature for the early treatment of pseudo-Class III malocclusion. The objectives of this paper are to demonstrate the importance of making the differential diagnosis between a skeletal and a pseudo-Class III malocclusion and to describe the correction of an anterior crossbite. The association of maxillary expansion and a 2 * 4 appliance can successfully be used to correct anterior crossbites. PMID- 25525527 TI - Lazy lips: hyperkalemia and acute tetraparesis-a case report from an urban emergency department. AB - A 58-year-old male patient was admitted to our emergency department at a large university hospital due to acute onset of general weakness. It was reported that the patient was bradycardic at 30/min and felt an increasing weakness of the limbs. At admission to the emergency department, the patient was not feeling any discomfort and denied dyspnoea or pain. The primary examination of the nervous system showed the cerebral nerves II-XII intact, muscle strength of the lower extremities was 4/5, and a minimal sensory loss of the left hemisphere was found. In addition, the patient complained about lazy lips. During ongoing examinations, the patient developed again symptomatic bradycardia, accompanied by complete tetraplegia. The following blood test showed severe hyperkalemia probably induced by use of aldosterone antagonists as the cause of the patient's neurologic symptoms. Hyperkalemia is a rare but treatable cause of acute paralysis that requires immediate treatment. Late diagnosis can delay appropriate treatment leading to cardiac arrhythmias and arrest. PMID- 25525528 TI - The management of gas-filled eyes in the emergency department. AB - Background. Intraocular gas bubbles are commonly used in retinal surgery. There are specific management guidelines that need to be followed to ensure surgical success, and there are also unique ophthalmic and systemic complications that can occur in such patients. Objective. To educate emergency department personnel about important issues in the management of patients who have a gas-filled eye following retinal surgery. Case Report. A patient with a gas-filled eye developed several complications including pain, severe vision loss, high-grade atrioventricular (AV) block, and pneumocephalus. Conclusion. Awareness of potential problems that may arise in patients with gas-filled eyes who present to the emergency department may help minimize morbidity for such patients. PMID- 25525529 TI - An uncommon, life-threatening, traumatic hematoma in the neck area. AB - It is well known that blunt neck trauma, when compared to a penetrating injury in the same anatomical area, is very rare. We report a case of an 81-year-old Caucasian woman with a blunt life-threatening neck trauma due to a bully goat. Although rare, direct evaluation should always be done in these cases because any misinterpretation may result in unfavorable outcomes. We have to highlight that close medical attention and prompt surgical treatment should be always considered in order to avoid dramatic consequences. PMID- 25525530 TI - Pancreatic mass leading to left-sided portal hypertension, causing bleeding from isolated gastric varices. AB - Mucinous cystic neoplasms (MCN) are an uncommon form of exocrine neoplasms of the pancreas. Symptoms are most often vague and this makes the diagnosis more difficult. The current case is one of three cases yet reported where the MCN caused left-sided portal hypertension leading to the formation of isolated gastric varices and subsequent bleeding from the varices. In the previously reported cases the main symptom was hematemesis. However in the current case the patient experienced no hematemesis, only isolated incidents of dark coloured diarrhea, but the main symptoms were those of iron-deficiency anemia. We present the case report of a 34-year-old woman who presented with dizziness and lethargy and was found to have 12 cm MCN in the pancreas. PMID- 25525531 TI - Familial Essential Thrombocythemia Associated with MPL W515L Mutation in Father and JAK2 V617F Mutation in Daughter. AB - Familial essential thrombocythemia features the acquisition of somatic mutations and an evolution similar to the sporadic form of the disease. Here we report two patients-father and daughter-with essential thrombocythemia who displayed a heterogeneous pattern of somatic mutations. The JAK2 V617F mutation was found in the daughter, while the father harbored the MPL W515L mutation. This case report may constitute further proof that in familial essential thrombocythemia there are other, still undefined, constitutional, inherited genetic factors predisposing to the acquisition of various somatic mutations (e.g., JAK2 V617F and MPL). PMID- 25525532 TI - Successful Thrombolysis despite Having an Incidental Unruptured Cerebral Aneurysm. AB - Purpose. To report a case of successful thrombolysis performed in a patient with an incidental unruptured intracranial aneurysm and review the literature. Case Report. Patient admitted for ischemic stroke due to left posterior cerebral artery occlusion, with an incidental right middle cerebral artery aneurysm, who underwent treatment with tissue plasminogen activator (rtPA) resulting in clinical improvement without complications. Conclusion. The presence of unruptured intracranial aneurysms is considered as a contraindication to thrombolysis, due to a potentially higher hemorrhagic risk of aneurysm rupture. Patients, otherwise, eligible for thrombolysis are usually excluded from receiving this emergent treatment, despite its potential benefits. A reevaluation of the strict exclusion criteria for thrombolysis in acute stroke patients should be considered. PMID- 25525533 TI - Cerebral venous thrombosis in two patients with spontaneous intracranial hypotension. AB - Although few patients with spontaneous intracranial hypotension develop cerebral venous thrombosis, the association between these two entities seems too common to be simply a coincidental finding. We describe two cases of spontaneous intracranial hypotension associated with cerebral venous thrombosis. In one case, extensive cerebral venous thrombosis involved the superior sagittal sinus and multiple cortical cerebral veins. In the other case, only a right frontoparietal cortical vein was involved. Several mechanisms could contribute to the development of cerebral venous thrombosis in spontaneous intracranial hypotension. When spontaneous intracranial hypotension and cerebral venous thrombosis occur together, it raises difficult practical questions about the treatment of these two conditions. In most reported cases, spontaneous intracranial hypotension was treated conservatively and cerebral venous thrombosis was treated with anticoagulation. However, we advocate aggressive treatment of the underlying cerebrospinal fluid leak. PMID- 25525534 TI - Vaginal treatment of vaginal cuff dehiscence with visceral loop prolapse: a new challenge in reparative vaginal surgery? AB - Vaginal cuff dehiscence is a rare, but potentially morbid, complication of total hysterectomy and refers to separation of the vaginal cuff closure. The term vaginal cuff dehiscence is frequently interchanged with the terms of cuff separation or cuff rupture. All denote the separation of a vaginal incision that was previously closed at time of total hysterectomy. After dehiscence of the vaginal cuff, abdominal or pelvic contents may prolapse through the vaginal opening. Bowel evisceration, outside the vulvar introitus, can lead to serious sequelae, including peritonitis, bowel injury and necrosis, or sepsis. Therefore, although prompt surgical and medical intervention is required to replace prolapsed structures, the main problem remains the reconstruction of vaginal vault. In case of recent hysterectomy, vaginal reparation only requires the approximation of vaginal walls, including their fascia, while if dehiscence occurs after a long time from hysterectomy, the adequate suspension of the vaginal vault has to be taken into consideration. In this report we describe the case of a postmenopausal patient, undergoing surgical emergency because of the evisceration of an intestinal loop through a dehiscence of vaginal vault, after numerous reconstructive vaginal surgeries for vaginal prolapse. This paper analyzes clinical circumstances, risk factors, comorbidity, and clinical and surgical management of this complication. PMID- 25525535 TI - Management of Pregnancy in a Chilean Patient with Congenital Deficiency of Factor VII and Glanzmann's Thrombasthenia Variant. AB - Patients with inherited bleeding disorders are rare in obstetric practice but present with prolonged bleeding even after minor invasive procedures. They require a combined approach with obstetric and hematological management of each case, including the neonatal management of a possibly affected fetus. We present the case of a pregnancy in a patient with combined Factor VII deficiency and Glanzmann's thrombasthenia, the successful obstetric and hematological management of the case, and a review of the literature. PMID- 25525536 TI - Gynecologic Malignancies Post-LeFort Colpocleisis. AB - Introduction. LeFort colpocleisis (LFC) is a safe and effective obliterative surgical option for older women with advanced pelvic organ prolapse who no longer desire coital activity. A major disadvantage is the limited ability to evaluate for post-LFC gynecologic malignancies. Methods. We present the first case of endometrioid ovarian cancer diagnosed after LFC and review all reported gynecologic malignancies post-LFC in the English medical literature. Results. This is the second reported ovarian cancer post-LFC and the first of the endometrioid subtype. A total of nine other gynecologic malignancies post-LFC have been reported in the English medical literature. Conclusions. Gynecologic malignancies post-LFC are rare. We propose a simple 3-step strategy in evaluating post-LFC malignancies. PMID- 25525537 TI - Clinical manifestation of a calyceal diverticular abscess in a pregnant woman. AB - Calyceal diverticula are congenital, nonsecretory abnormalities in which the transitional cell-lined cavity communicates with the renal collecting system. Here we present the case of a calyceal diverticular abscess during pregnancy. A 40-year-old primiparous woman developed the abscess at 23 weeks of gestation, with right flank pain and a 37.8 degrees C fever. A transabdominal ultrasound revealed a 12 * 10 cm cystic mass in the right kidney. She was initially diagnosed with a simple renal cyst infection, and intravenous antibiotics were initiated. Percutaneous drainage was started at 26 weeks of gestation. When urine excretion from the cyst was confirmed by dye test using indigotindisulfonate sodium, the patient was diagnosed with a calyceal diverticular abscess. She gave birth to a 2,870 g healthy male at 38 weeks of gestation. Percutaneous drainage with low-dose antimicrobial therapy could thus allow for the continued pregnancy of women with a calyceal diverticular abscess until full term. PMID- 25525538 TI - Traumatic dislocation of the hip in a child caused by trivial force for age. AB - Traumatic hip dislocation in children has a relatively rare occurrence. There are some residual complications, such as avascular necrosis of the femoral head, growth disturbance caused by premature fusion, neurological injury, recurrent dislocation, and posttraumatic arthritis. There is no consensus in the literature about the period of non-weight bearing after reduction. A rare case of a 13-year old boy of hip dislocation caused by trivial force for age is reported followed by review of the pediatric literatures with treatment recommendation. PMID- 25525539 TI - Hypertrophic nonunion humerus mimicking an enchondroma. AB - Introduction. Although fractures of humeral shaft show excellent results with conservative management, nonunion does occur. Case Report. We bring forth the case of a young male with a 1.5-year-old hypertrophic nonunion of the humerus mimicking an enchondroma. The initial X-ray images of the patient appeared to be an enchondroma, which only on further evaluation and histopathological analysis was diagnosed conclusively to be a hypertrophic nonunion. Discussion. Enchondromas are often incidentally diagnosed benign tumours. It is however not common to misdiagnose a hypertrophic nonunion to be an enchondroma. We present this case to highlight the unique diagnostic dilemma the treating team had to face. PMID- 25525540 TI - Delayed Diagnosis of Pharyngeal Perforation following Exploding Tyre Blast Barotrauma. AB - Introduction. Pharyngoesophageal perforation secondary to barotrauma is a rare phenomenon that can have serious complications if identified late. It is challenging to detect due to nonspecific symptoms. We present a case in which detection proved difficult leading to delayed diagnosis. Case Report. A 27-year old mechanic presented with haemoptysis, dysphonia, and odynophagia after a car tyre exploded in his face. Flexible nasoendoscopy (FNE) revealed blood in the pharynx, thought to represent mucosal haemorrhage. Initial treatment consisted of IV dexamethasone and antibiotics. After 3 days, odynophagia persisted prompting a CT scan. This revealed a defect in the posterior hypopharynx and surgical emphysema in the deep neck tissues. Contrast swallow confirmed posterior hypopharyngeal leak. NG feeding was commenced until repeated contrast swallow confirmed resolution of the defect. Discussion. Prompt nonsurgical management of pharyngoesophageal perforation has good outcomes but untreated perforation can have serious complications. FNE should be performed routinely, but only a contrast swallow can diagnose a functional perforation. Clinicians should have a high index of clinical suspicion when patients present with barotrauma and odynophagia. Patients should be kept nil by mouth until perforation has been excluded. Conclusion. When faced with cases of facial barotrauma, clinicians should have a low threshold for further imaging to exclude pharyngoesophageal perforation. PMID- 25525541 TI - Perineural spread of salivary duct carcinoma to the internal auditory canal. AB - Salivary duct carcinomas (SDCs) are high-grade malignant tumors exhibiting aggressive growth with early regional and distant metastasis. We report a case of SDC in a 63-year-old male with early recurrent disease in the cerebellopontine angle (CPA) after total parotidectomy and adjuvant radiotherapy. The tendency of the tumor to recur or metastasize despite radical surgical measures and radiotherapy continues to pose a therapeutic challenge. PMID- 25525542 TI - Bilateral triple concha bullosa: a very rare anatomical variation of intranasal turbinates. AB - Pneumatization of the intranasal turbinates or concha bullosa is an anatomic variation of the lateral nasal wall. Concha bullosa is defined as the presence of air cells in turbinates. It can be best diagnosed with paranasal sinus computed tomography. Concha bullosa is a possible etiologic factor for recurrent sinusitis due to its negative effect on paranasal sinus ventilation and mucociliary clearance. Concha bullosa is most commonly seen in the middle turbinate and less frequently in the inferior or superior turbinate. Pneumatization of all turbinates is very rare. To our knowledge, there are only two publications about a case with concha bullosa in all turbinates in the current literature. Here, we present a woman with bilateral pneumatization in all three intranasal turbinates. PMID- 25525543 TI - Top Differential Diagnosis Should Be Microscopic Polyangiitis in ANCA-Positive Patient with Diffuse Pulmonary Hemorrhage and Hemosiderosis. AB - A rat model of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides reveals crescentic glomerulonephritis as seen in human renal biopsies and diffuse lung hemorrhage that is not well documented in human lung biopsies. A 64-year-old male, with shortness of breath and mild elevation of serum creatinine, was found to have a positive serum test for ANCA, but negative antiglomerular basement membrane antibody. A renal biopsy showed pauci-immune type of crescentic glomerulonephritis and focal arteritis. The prior lung wedge biopsy was retrospectively reviewed to show diffuse hemorrhage and hemosiderosis with focal giant cells. In addition, small arteries revealed subtle neutrophil aggregation, and margination along vascular endothelium, but no definitive vasculitis. The pathology of ANCA associated vasculitides results from activated neutrophils by ANCA and subsequent activation of the alternative complement cascade with endothelial injury, neutrophil aggregation and margination. Our findings, after the correlation between lung biopsy and renal biopsy, imply that the top differential diagnosis in the lung biopsy should be microscopic polyangiitis when diffuse pulmonary hemorrhage and hemosiderosis are present in this ANCA-positive patient. PMID- 25525544 TI - WHO Grade 2 Neuroendocrine Tumor in a 15-Year-Old Male: A Case Report and Literature Review. AB - Neuroendocrine tumors, distinguished from adenocarcinomas by their neuroendocrine differentiation, are the most common pediatric epithelial malignancy that most often occurs in the appendix. In 2010, the WHO classified neuroendocrine neoplasms into three grades based on morphology, mitotic count, and Ki67 proliferation index. A 15-year-old male with a history of anemia and failure to thrive was diagnosed with a well-differentiated neuroendocrine tumor in the jejunum that invaded into the subserosal soft tissue and metastasized to four lymph nodes. Pediatric neuroendocrine tumors frequently arise within hereditary tumor syndromes with pancreatic neuroendocrine tumors being the most common. Several studies also indicate an elevated risk of small intestinal neuroendocrine tumors in which children born to a parent with a history of neuroendocrine tumors in the small intestine have a significant increased risk of developing one. PMID- 25525545 TI - Paraneoplastic recurrent hypoglycaemic seizures: an initial presentation of hepatoblastoma in an adolescent male-a rare entity. AB - Hepatoblastoma (HB) is a rare malignant tumour of the liver and usually occurs in the first three years of life. Hepatoblastoma in adolescents and young adults is extremely rare; nevertheless the prognosis is much worse than in childhood, because these kinds of tumours are usually diagnosed late. Characteristic imaging and histopathological and AFP levels help in the diagnosis of hepatoblastoma. Paraneoplastic features of hepatoblastoma are not uncommon at presentation and include erythrocytosis, thrombocytosis, hypocalcaemia, isosexual precocious puberty, and rarely hypoglycaemia. Even though hypoglycaemia is commonly seen in hepatocellular carcinoma, its association with hepatoblastoma is very rare. We present a case of 15-year-old male patient presenting with complaints of recurrent hypoglycaemic seizures ultimately leading to diagnosis of hepatoblastoma. Managed successfully with neoadjuvant chemotherapy, surgery and adjuvant chemotherapy with adriamycin and cisplatin based regimens. An extensive review of literature in the PubMed and MEDLINE did not reveal much data on paraneoplastic recurrent hypoglycaemic seizures as an initial presentation of hepatoblastomas in adolescents and young adults. PMID- 25525546 TI - A case of urethral duplication arising from the posterior urethra to the scrotum with urinary stone in a 6-year-old male. AB - Urethral duplication is a rare congenital anomaly. We report a 6-year-old male with type IIA2 (Y-type) using Effmann's classification. The accessory urethra, in which a urinary stone existed, arose from the posterior urethra to the scrotum. Because of recurrent urinary tract infection and urinary discharge from the accessory urethra, surgical removal of the accessory urethra through a scrotal incision was performed. At 7-month postoperative follow-up the patient was completely free from urinary incontinence and urinary tract infection. PMID- 25525547 TI - Feigning acute intermittent porphyria. AB - Acute intermittent porphyria (AIP) is an autosomal dominant genetic defect in heme synthesis. Patients with this illness can have episodic life-threatening attacks characterized by abdominal pain, neurological deficits, and psychiatric symptoms. Feigning this illness has not been reported in the English language literature to date. Here, we report on a patient who presented to the hospital with an acute attack of porphyria requesting opiates. Diligent assessment of extensive prior treatment records revealed thirteen negative tests for AIP. PMID- 25525548 TI - Persistent genital arousal disorder: confluent patient history of agitated depression, paroxetine cessation, and a tarlov cyst. AB - We report a case of a woman suffering from persistent genital arousal disorder (PGAD) after paroxetine cessation. She was admitted to a psychiatric department and diagnosed with agitated depression. Physical investigation showed no gynaecological or neurological explanation; however, a pelvic MRI scan revealed a Tarlov cyst. Size and placement of the cyst could not explain the patient's symptoms; thus neurosurgical approach would not be helpful. Her depression was treated with antidepressant with little effect. Electroconvulsive therapy improved the patient's symptoms though they did not fully resolve. More awareness of PGAD and thorough interdisciplinary conferences are necessary to insure an unequivocal treatment strategy. PMID- 25525549 TI - Inflammatory myofibroblastic tumour: report of a rare form with exclusive pleural involvement. AB - Inflammatory myofibroblastic tumour (IMT) is a rare scleroinflammatory lesion, characterized by a myofibroblastic proliferation with inflammatory infiltrates, with many possible locations and diagnosis based on immunohistochemistry. Pleural IMT is uncommon and is usually an extension of a pulmonary involvement. We report on a 28-year-old woman with a new form of this rare entity, characterized by exclusive pleural involvement. PMID- 25525550 TI - A challenging twist in pulmonary renal syndrome. AB - Case. We report a rare case of hydralazine-induced anti-neutrophil cytoplasmic antibody-associated vasculitis. A 75-year-old African American woman with history of high blood pressure on hydralazine for 3 years presented with acute onset of shortness of breath and hemoptysis. Lab workup revealed a severe normocytic anemia and a serum creatinine of 5.09 mg/dL (baseline 0.9). Bronchoscopy demonstrated active pulmonary hemorrhage. A urine sample revealed red cell casts and a renal biopsy demonstrated pauci-immune, focally necrotizing glomerulonephritis with small crescents consistent with possible anti-neutrophil cytoplasmic antibody-positive renal vasculitis. Serologies showed high-titer MPO ANCA and high-titer anti-histone antibodies. She was treated with intravenous steroids and subsequently with immunosuppression after cessation of hydralazine. The patient was subsequently discharged from hospital after a rapid clinical improvement. Conclusion. Hydralazine-induced anti-neutrophil cytoplasmic antibody positive renal vasculitis is a rare adverse effect and can present as a severe vasculitic syndrome with multiple organ involvement. Features of this association include the presence of high titer of anti-myeloperoxidase anti-neutrophil cytoplasmic antibody with multiantigenicity, positive anti-histone antibodies, and the lack of immunoglobulin and complement deposition. Prompt cessation of hydralazine may be sufficient to reverse disease activity but immunosuppression may be needed. PMID- 25525552 TI - Automated Cell Detection and Morphometry on Growth Plate Images of Mouse Bone. AB - Microscopy imaging of mouse growth plates is extensively used in biology to understand the effect of specific molecules on various stages of normal bone development and on bone disease. Until now, such image analysis has been conducted by manual detection. In fact, when existing automated detection techniques were applied, morphological variations across the growth plate and heterogeneity of image background color, including the faint presence of cells (chondrocytes) located deeper in tissue away from the image's plane of focus, and lack of cell-specific features, interfered with identification of cell. We propose the first method of automated detection and morphometry applicable to images of cells in the growth plate of long bone. Through ad hoc sequential application of the Retinex method, anisotropic diffusion and thresholding, our new cell detection algorithm (CDA) addresses these challenges on bright-field microscopy images of mouse growth plates. Five parameters, chosen by the user in respect of image characteristics, regulate our CDA. Our results demonstrate effectiveness of the proposed numerical method relative to manual methods. Our CDA confirms previously established results regarding chondrocytes' number, area, orientation, height and shape of normal growth plates. Our CDA also confirms differences previously found between the genetic mutated mouse Smad1/5CKO and its control mouse on fluorescence images. The CDA aims to aid biomedical research by increasing efficiency and consistency of data collection regarding arrangement and characteristics of chondrocytes. Our results suggest that automated extraction of data from microscopy imaging of growth plates can assist in unlocking information on normal and pathological development, key to the underlying biological mechanisms of bone growth. PMID- 25525553 TI - Salvage Gamma Knife Radiosurgery after failed management of bilateral trigeminal neuralgia. AB - BACKGROUND: The incidence of bilateral trigeminal neuralgia (TN) is 1-6% of total number of TN cases. Gamma Knife Radiosurgery (GKRS) is effective in treating unilateral TN; however, outcomes of bilateral TN treated by GKRS have not been well evaluated. The purpose of this study is to evaluate the long-term GKRS outcomes of bilateral TN at our institution and compare with our published treatment outcomes of unilateral TN. METHODS: Between 2000 and 2006, eight patients with bilateral TN were treated with GKRS. Data available on seven patients were collected. Facial pain outcomes were defined using the Barrow Neurological Institute pain intensity scale. Outcomes and toxicities were compared to published outcomes of unilateral TN patients treated with GKRS at our institution. RESULTS: The incidence of bilateral TN in our series is 2.3%. Treatment outcomes were excellent in 5/14, good in 1/14, and poor in 8/14. Median follow-up time was 58 months. Median time-to-failure was 38 months. Pain control rate was 80% at 12 months and 65% at 36 months. Bothersome side effects were seen in 4/14 nerves treated. Compared with our long-term unilateral TN cohort, there was no statistically significant difference in outcome, time-to-failure, or rate of toxicity. CONCLUSION: Bilateral TN is rare, and effective treatment is crucial to improve the quality of life of those afflicted. Salvage GKRS is a reasonable treatment modality for individuals with bilateral TN. PMID- 25525551 TI - Invasive mold infections in solid organ transplant recipients. AB - Invasive mold infections represent an increasing source of morbidity and mortality in solid organ transplant recipients. Whereas there is a large literature regarding invasive molds infections in hematopoietic stem cell transplants, data in solid organ transplants are scarcer. In this comprehensive review, we focused on invasive mold infection in the specific population of solid organ transplant. We highlighted epidemiology and specific risk factors for these infections and we assessed the main clinical and imaging findings by fungi and by type of solid organ transplant. Finally, we attempted to summarize the diagnostic strategy for detection of these fungi and tried to give an overview of the current prophylaxis treatments and outcomes of these infections in solid organ transplant recipients. PMID- 25525554 TI - Metastatic choriocarcinoma to the lumbar spine: Case report and review of literature. AB - BACKGROUND: There are few cases of choriocarcinoma metastases to the spine that have been reported. Most occurrences are in women with the gestational form of the tumor, and these now exhibit a very high remission rate with chemotherapeutic treatment, typically circumventing the need for spinal surgery. CASE DESCRIPTION: In an effort to better understand treatment options for those rare instances when choriocarcinoma does find its way into the spine, we have synthesized a comprehensive literature review on the clinical cases of choriocarcinoma spinal metastases. We also describe our unique experience and decision-making involving the first reported case of surgical treatment of non-gestational choriocarcinoma spinal metastases in a male patient. CONCLUSION: Spinal surgery has a limited role in metastatic choriocarcinoma, but there is the potential for improving neurologic decline even in the rare and aggressive male variant of this disease. PMID- 25525555 TI - Third nerve palsy following carotid artery dissection and posterior cerebral artery thrombectomy: Case report and review of the literature. AB - BACKGROUND: Common causes of oculomotor nerve palsy are diabetes, aneurysmal compression, and uncal herniation. A lesser-known cause of third nerve dysfunction is ischemia, often due to carotid artery dissection. CASE DESCRIPTION: An 80-year-old man presented with an acute ischemic stroke with a National Institutes of Health Stroke Scale score of >20 from a high cervical internal carotid artery (ICA) dissection and a tandem ICA terminus embolic occlusion with extension of clot into the adjacent fetal posterior cerebral artery (PCA). We used a stentriever to perform selective PCA thrombectomy, with immediate postthrombectomy development of ipsilateral anisocoria. The anisocoria progressed into complete oculomotor nerve palsy over 8 h after the procedure. CONCLUSIONS: The clinical course described in this case is consistent with injury to the third nerve due to mechanical injury or occlusion of perforator supply to the nerve during thrombectomy. Oculomotor nerve palsy is a rare but known complication after ischemia; however, to our knowledge, this is the first case after thrombectomy for a PCA embolus. PMID- 25525556 TI - Successful flow reduction surgery for a ruptured true posterior communicating artery aneurysm caused by the common carotid artery ligation for epistaxis. AB - BACKGROUND: Carotid artery occlusion can lead to the development of rare true posterior communicating artery (PCoA) aneurysms because of hemodynamic stress on the PCoA. Surgical treatment of these lesions is challenging. CASE DESCRIPTION: The authors report a case of a true PCoA aneurysm that developed and ruptured 37 years after ligation of the ipsilateral common carotid artery for epistaxis. The lesion was successfully treated with clipping of the distal M1 segment of the middle cerebral artery (MCA) after the occipital artery-radial artery free graft MCA bypass, which led to extreme reduction in collateral flow through the PCoA. A cortical branch, located just proximal to the obliteration site, functioned as a sufficient flow outlet. The aneurysm shrank, and the patient has been doing well without any symptoms for 5 years after surgery. CONCLUSIONS: M1 obliteration combined with high-flow extra-intracranial bypass might be a promising option for a true PCoA aneurysm, and therapeutic design that leaves a sufficient flow outlet on the M1 is mandatory to avoid unexpected occlusion of the M1 and its perforators. PMID- 25525557 TI - Primary intracranial Parachordoma: An unusual tumor in brain. AB - BACKGROUND: Parachordomas are rare soft tissue tumors commonly occurring in limbs, chest, Abdomen, and back. The World Health Organization (WHO) classification includes parachordomas in the same group as mixed tumors and myoepitheliomas. Exact histogenesis of this tumor is unclear. CASE DESCRIPTION: A 52-year-old male presented with headache and blurring of vision since one month. Preoperative computed tomography (CT) scan of brain revealed left parieto occipital tumor extending up to the trigone. Total excision of the tumor was done. Histopathologically, the tumor was composed of relatively uniform cells with eosinophilic cytoplasm in a myxoid stroma and with cartilaginous and osseous metaplasia. The tumoral cells were immunoreactive for cytokeratin, epithelial membrane antigen (EMA), S-100, and vimentin. The constellation of findings revealed the tumor to be parachordoma. Magnetic resonance imaging (MRI) brain during follow-up at one year showed no recurrent tumor. No adjuvant therapy was given to this patient. CONCLUSION: This is the first reported case of primary intracranial parachordoma. It is difficult to diagnose the lesion preoperatively by imaging alone. Long-term follow-up is necessary in view of few reports in literature of recurrence and metastasis, of parachordomas in other anatomical locations. PMID- 25525558 TI - Spontaneous resolution of a flow-related ophthalmic-segment aneurysm after treatment of anterior cranial fossa dural arteriovenous fistula. AB - BACKGROUND: The natural history of proximal, feeding-artery aneurysms after successful obliteration of high-grade, anterior cranial fossa dural arteriovenous fistulas (dAVFs) has not been well documented. CASE DESCRIPTION: A 52-year-old Caucasian male presented with an unruptured anterior cranial fossa (dAVF) and an associated aneurysm. Cerebral angiography revealed a large, contralateral, carotid-ophthalmic segment aneurysm, enlarged feeding ophthalmic arteries, as well as cortical venous drainage. Successful surgical obliteration of the dAVF was undertaken to eliminate the risk of hemorrhage. CONCLUSION: The carotid ophthalmic aneurysm regressed significantly after surgical obliteration of the dAVF and a follow-up, planned coiling procedure to address the carotid-ophthalmic aneurysm was abandoned. This represents the first reported case of a near complete, spontaneous resolution of an unruptured carotid-ophthalmic aneurysm associated with a high-grade anterior cranial fossa dAVF. PMID- 25525559 TI - Survival Models on Unobserved Heterogeneity and their Applications in Analyzing Large-scale Survey Data. AB - In survival analysis, researchers often encounter multivariate survival time data, in which failure times are correlated even in the presence of model covariates. It is argued that because observations are clustered by unobserved heterogeneity, the application of standard survival models can result in biased parameter estimates and erroneous model-based predictions. In this article, the author describes and compares four methods handling unobserved heterogeneity in survival analysis: the Andersen-Gill approach, the robust sandwich variance estimator, the hazard model with individual frailty, and the retransformation method. An empirical analysis provides strong evidence that in the presence of strong unobserved heterogeneity, the application of a standard survival model can yield equally robust parameter estimates and the likelihood ratio statistic as does a corresponding model adding an additional parameter for random effects. When predicting the survival function, however, a standard model on multivariate survival time data can result in serious prediction bias. The retransformation method is effective to derive an adjustment factor for correctly predicting the survival function. PMID- 25525561 TI - Action Unit Models of Facial Expression of Emotion in the Presence of Speech. AB - Automatic recognition of emotion using facial expressions in the presence of speech poses a unique challenge because talking reveals clues for the affective state of the speaker but distorts the canonical expression of emotion on the face. We introduce a corpus of acted emotion expression where speech is either present (talking) or absent (silent). The corpus is uniquely suited for analysis of the interplay between the two conditions. We use a multimodal decision level fusion classifier to combine models of emotion from talking and silent faces as well as from audio to recognize five basic emotions: anger, disgust, fear, happy and sad. Our results strongly indicate that emotion prediction in the presence of speech from action unit facial features is less accurate when the person is talking. Modeling talking and silent expressions separately and fusing the two models greatly improves accuracy of prediction in the talking setting. The advantages are most pronounced when silent and talking face models are fused with predictions from audio features. In this multi-modal prediction both the combination of modalities and the separate models of talking and silent facial expression of emotion contribute to the improvement. PMID- 25525562 TI - Life Space Assessment in Older Women Undergoing Non-Surgical Treatment for Urinary Incontinence. AB - OBJECTIVES: Urinary incontinence (UI) impacts all aspects of life activities. This study aims to characterize change in mobility within the community utilizing the Life Space Assessment (LSA) questionnaire in women undergoing non-surgical UI treatment. DESIGN: Prospective cohort study, performed from July 2007 to March 2009, which followed women seeking non-surgical UI treatment and assessed their mobility and symptoms using LSA, Urogenital Distress Inventory (UDI-6), and Incontinence Impact Questionnaire (IIQ-7) at baseline and 2, 6, and 12 months post-treatment. Estimated Percent Improvement (EPI) and Patient Satisfaction Question (PSQ) were obtained post-treatment. SETTING: Outpatient tertiary-care clinic. PARTICIPANTS: 70 ambulatory, community-dwelling women, aged 65 years or older, seeking non-surgical care for UI. INTERVENTION: Multi-component behavioral and/or pharmacologic therapies. MEASUREMENTS: We hypothesized LSA would improve with treatment. Repeated measures analysis with Tukey's HSD and backwards selection linear regression model were performed. RESULTS: LSA score decreased from baseline to 2 months (mean+/-SD; 63+/-29 to 56+/-28, p<0.001) and was sustained at 6 and 12 months (54+/-28, 54+/-28). UDI scores improved from 36+/-23 to 25+/-24, p<0.001, at 2 months, and improvement persisted at 6 and 12 months (22+/-22, 21+/-24). Improvements in UDI and patient perceived improvement in UI were not associated with LSA change. Age, race, and depression impacted LSA, which decreased 1-point for each additional year of age (p=0.004), 6-points for each point higher on the Geriatric Depression Scale (GDS) (p=0.002), and 6-points for African American race (p=0.048). CONCLUSION: Decreased mobility represented by LSA was related to age, depression, and race, but not UI symptom improvement. PMID- 25525563 TI - Revisiting Anti-tuberculosis Activity of Pyrazinamide in Mice. AB - The mechanism of action of pyrazinamide, a key sterilizing drug in the treatment of tuberculosis, remains elusive; pyrazinamide is a pro-drug that requires activation by a bacterial-encoded enzyme, and its activity is most apparent on non-replicating Mycobacterium tuberculosis. Recently, it has been suggested that pyrazinamide might exert also some host-directed effect in addition to its antimicrobial activity. To address this possibility, three sequential experiments were conducted in immune-competent BALB/c and in immune-deficient, athymic nude mice. In the first experiment, BALB/c mice infected with M. bovis, which is naturally resistant to pyrazinamide because it is unable to activate the drug, were treated with standard drug regimens with and without pyrazinamide to specifically detect a host-directed effect. As no effect was observed, pyrazinamide activity was compared in M. tuberculosis-infected BALB/c and nude mice to determine whether the effect of pyrazinamide would be reduced in the immune deficient mice. As pyrazinamide did not appear to have any affect in the nude mice, a third experiment was performed in which rifampin was replaced with rifapentine (a similar drug with a longer half-life) to permanently suppress mycobacterial growth. In these experimental conditions, the antimicrobial effect of pyrazinamide was clear. Therefore, the results of our studies rule out a significant host-directed effect of pyrazinamide in the TB infected host. PMID- 25525564 TI - Cumulative Causation of Rural Migration and Initial Peri-Urbanization in China. AB - This paper posits that rural migration feeds the high demand for cheap labor in peri-urbanization, which is driven by globalization, flows of foreign capital, and entrepreneurial local governments. While the gravity model and push/pull perspective ignore the dynamics of migratory course, we use the cumulative causation of migration theory to conceptualize social expectations for outmigration and social resources from migrant networks in destinations. Four major findings are drawn from this demographic analysis based on micro data from China's 2000 Census. First, the expectation of outmigration significantly increases outmigration, and this effect is independent of push factors. Second, foreign direct investment (FDI) contributes to attracting rural labor migrants from other provinces to peri-urban areas as it does to cities. Third, social resources from migrant networks play an important role in attracting rural labor migrants to both city and noncity destinations. Fourth, the importance of wage differentials declines in gravitating rural labor migrants to peri-urban areas. These findings provide tentative evidence that rural labor migration is indispensable during initial peri-urbanization. Infused with flows of FDI and entrepreneurial local governments, rural migration has created a favorable initial condition for peri-urbanization. PMID- 25525560 TI - Imaging Neuroinflammation - from Bench to Bedside. AB - Neuroinflammation plays a central role in a variety of neurological diseases, including stroke, multiple sclerosis, Alzheimer's disease, and malignant CNS neoplasms, among many other. Different cell types and molecular mediators participate in a cascade of events in the brain that is ultimately aimed at control, regeneration and repair, but leads to damage of brain tissue under pathological conditions. Non-invasive molecular imaging of key players in the inflammation cascade holds promise for identification and quantification of the disease process before it is too late for effective therapeutic intervention. In this review, we focus on molecular imaging techniques that target inflammatory cells and molecules that are of interest in neuroinflammation, especially those with high translational potential. Over the past decade, a plethora of molecular imaging agents have been developed and tested in animal models of (neuro)inflammation, and a few have been translated from bench to bedside. The most promising imaging techniques to visualize neuroinflammation include MRI, positron emission tomography (PET), single photon emission computed tomography (SPECT), and optical imaging methods. These techniques enable us to image adhesion molecules to visualize endothelial cell activation, assess leukocyte functions such as oxidative stress, granule release, and phagocytosis, and label a variety of inflammatory cells for cell tracking experiments. In addition, several cell types and their activation can be specifically targeted in vivo, and consequences of neuroinflammation such as neuronal death and demyelination can be quantified. As we continue to make progress in utilizing molecular imaging technology to study and understand neuroinflammation, increasing efforts and investment should be made to bring more of these novel imaging agents from the "bench to bedside." PMID- 25525566 TI - Scaling analysis for electrospinning. AB - Electrospinning refers to the process of generating nanofibers from electrified viscous polymeric jets. Though relatively easy to perform, this process is quite complex in its nature, given the large number of parameters that are involved. This study attempts to derive a relation between the final fiber diameter and the major process parameters. Two new dimensionless numbers describing viscous and surface charge repulsion effects are identified from the scaling analysis of governing equation for the motion of a bent jet. Experimental data for a wide range of polymer solutions exhibit a common slope, when expressed in terms of these new dimensionless numbers. This correlation is used to derive a new scaling expression for the final fiber diameter. PMID- 25525565 TI - A Mood Management Intervention in an Internet Stop Smoking Randomized Controlled Trial Does Not Prevent Depression: A Cautionary Tale. AB - Smoking and depression are related, and mood management interventions included in smoking cessation interventions can increase smoking abstinence rates. Could a mood management intervention embedded in an Internet-based smoking cessation intervention prevent major depressive episodes? Spanish- and English-speaking smokers (N = 17,430) from 191 countries were randomized to one of four online self-help intervention conditions (two with mood management). We analyzed preventive effects among those participants without a major depressive episode at baseline. The mood management intervention did not reduce the incidence of major depressive episodes in the following 12 months. However, we found a mood management by depression risk interaction (OR = 1.77, p = .004), such that high risk participants who received the mood management intervention had an increased occurrence of major depressive episodes (32.8% vs. 26.6%), but not low-risk participants (11.6% vs. 10.8%). Further research on whether mood management interventions may have deleterious effects on subsets of smokers appears warranted. PMID- 25525567 TI - Treatment of anorexia nervosa with long-term risperidone in an outpatient setting: case study. AB - INTRODUCTION: There are currently few studies focusing on the efficacy of long term atypical antipsychotics to treat anorexia nervosa in the pediatric population. CASE DESCRIPTION: This case report follows the treatment of a 17 year old female with anorexia nervosa over her four-year undergraduate career. After two years of multidisciplinary treatment, low-dose risperidone was initiated due to persistence of her disease. She expressed decreased rigidity around meal times, her weight improved and she had resumption of menses. She was compliant with treatment through graduation and maintained her weight gain. DISCUSSION & EVALUATION: Atypical antipsychotics are a treatment option in the management of anorexia nervosa. Risperidone has not been studied as frequently as olanzapine for eating disorders. Risperidone was chosen for its more favorable side effect profile and decreased cost to the patient. Previous studies on anorexia nervosa treatment have occurred during inpatient treatment and have limited follow-up due to patients' refusal to initiate or maintain medication compliance. This case presents 17 months of outpatient data. The efficacy of risperidone therapy was evaluated with frequent weight checks, subjective decrease in rigidity, serial complete metabolic panels, and restoration of menses. CONCLUSIONS: In this case report, an adolescent female treated with low-dose risperidone had decreased rigid thinking, weight gain and resolution of secondary amenorrhea without medication side effects. Therefore, the atypical antipsychotic risperidone may be an effective long-term outpatient treatment option for patients with anorexia nervosa. PMID- 25525568 TI - Should all elective knee radiographs requested by general practitioners be performed weight-bearing? AB - The aims of this study were to: [1] Assess the number of patients with suspected knee osteoarthritis that underwent repeat weight-bearing(WB) knee radiographs in the orthopaedic clinic following initial non-WB radiograph requested by their general practitioner (GP). [2] Confirm whether repeating WB knee views changed radiology reports. [3] Determine the number of London trusts with protocols for routinely performing WB views. A Retrospective cohort study of 1968 patients aged >40 years referred to a London teaching hospital for knee radiographs over 12 months. Radiographs were identified as WB/non-WB. Subsequent repeat WB views performed in those that went on to have an orthopaedic consultation were also documented. A consultant musculoskeletal radiologist reported both images. A proforma containing a likert scale of severity for commonly reported abnormalities in knee osteoarthritis and criteria from the Kellgren and Lawrence scale was used for reporting. London NHS Trusts were surveyed to identify if protocols were in place for performing WB views. A total of 1,968 patients underwent knee radiographs, of which 1922 (97.7%) had initial non-WB radiographs. Of the 56 patients in this group that underwent required repeat WB radiographs, joint space narrowing was reported as more severe on WB versus non-WB radiographs (p = 0.035). Only 54% of departments routinely performed WB radiographs. Few patients (2.3%) referred by GPs have WB radiographs requested. Some of those referred for a specialist opinion required repeat WB views. Nearly half of London hospitals do not routinely perform WB radiographs. This represents a significant financial burden to the NHS, increased radiation exposure and wasted patient/clinician time. We propose that all GP requested knee radiographs be performed as WB unless otherwise stated. PMID- 25525569 TI - Acceptability and willingness among men who have sex with men (MSM) to use a tablet-based HIV risk assessment in a clinical setting. AB - We developed an iPad-based application to administer an HIV risk assessment tool in a clinical setting. We conducted focus group discussions (FGDs) with gay, bisexual and other men who have sex with men (MSM) to assess their opinions about using such a device to share risk behavior information in a clinical setting. Participants were asked about their current assessment of their risk or any risk reduction strategies that they discussed with their healthcare providers. Participants were then asked to provide feedback about the iPad-based risk assessment, their opinions about using it in a clinic setting, and suggestions on how the assessment could be improved. FGD participants were generally receptive to the idea of using an iPad-based risk assessment during healthcare visits. Based on the results of the FGDs, an iPad-based risk assessment is a promising method for identifying those patients at highest risk for HIV transmission. PMID- 25525570 TI - Prevalence estimates of substandard drugs in Mongolia using a random sample survey. AB - To determine the prevalence of substandard drugs in urban (Ulaanbaatar) and rural (selected provinces) areas of Mongolia, samples of 9 common, therapeutically important drugs were collected from randomly selected drug outlets in Ulaanbaatar and 4 rural provinces by "mystery shoppers". Samples were analyzed by visual inspection, registration status, and biochemical analysis. Samples failing to meet all Pharmacopeia quality tests were considered substandard. In the rural provinces, 69 out of 388 samples were substandard, giving an estimated prevalence of substandard drugs of 17.8% (95% CI: 14.1-22.0). There were 85 unregistered samples, giving a prevalence estimate of unregistered drugs of 21.9%. (95% CI: 17.9-26.3). In the urban Ulaanbaatar districts, 112 out of 848 samples were substandard, giving an estimated prevalence of substandard drugs of 13.2% (95% CI: 11.0-15.7). There were 150 unregistered samples, giving a prevalence estimate of unregistered drugs of 17.7% (95% CI: 15.2-20.4). In the rural provinces, 35 out of 85 (41.2%) unregistered samples were substandard; whereas 34 out of 303 (11.2%) registered samples were substandard. (p < 0.0001) In the urban districts, 18 out of 150 (12.0%) unregistered samples were substandard, whereas 94 out of 698 registered were substandard. (13.5%) (p = 0.6). The prevalence of substandard and unregistered drugs is higher in rural provinces. There is a significant association between substandard and unregistered drugs in the provinces but not in the urban districts. The underlying causes for substandard drugs need to be further investigated in order to help formulate strategies to improve pharmacovigilance and the drug supply quality in Mongolia. PMID- 25525572 TI - Advance modern medicine with clinical case reports. AB - Randomized clinical trial (RCT) can fail to demonstrate the richness of individual patient characteristics. Given the unpredictable nature of medicine, a patient may present in an unusual way, have a strange new pathology, or react to a medical intervention in a manner not seen before. The publication of these novelties as case reports is a fundamental way of conveying medical knowledge. Throughout history there have been famous case studies that shaped the way we view health and disease. Case reports can have the following functions: (I) descriptions of new diseases; (II) study of mechanisms; (III) discovery new therapies; (IV) recognition of side effects; and (V) education. Before submitting a case report, it is worthwhile to refer to the Case Report Check Sheet described by Green and Johnson [2006]. PMID- 25525573 TI - How are radiologists trained in South Korea? AB - Recently, many excellent doctors want to become radiologists in South Korea. The radiology residency program consists of a 4-year training period and residents need to pass a certifying exam at the end of their training to become board certified radiologists. The training program consists of several divisions of subspecialties and residents are trained one to several months in one division before rotating to another. They are trained by attending staff to read images and learn to perform various procedures in a man to man environment. Also, residents learn clinically relevant knowledge by participating in intramural or multidisciplinary conferences. Besides in-hospital training, many residents participate in various categorical courses or education programs which are organized by the Korean Society of Radiology (KSR) or other hospitals and residents can attend these courses depending on their individual needs or interests. PMID- 25525571 TI - Epithelial ovarian cancer: An overview. AB - Ovarian cancer is the second most common gynecological cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions. PMID- 25525574 TI - Radiology training in United Kingdom: current status. AB - Clinical radiology has always been one of the most competitive specialties in UK. Due to the increasing demand for radiology services the number of training posts in the UK has been increased. Clinical radiology training takes 5 years and requires completion of the Fellowship of Royal College of Radiologists (FRCR) exams, adequate evidence to demonstrate completion of the curriculum and successful appraisals. On completing training and receiving the Certificate for Completion of Training (CCT) a select proportion of trainees choose to embark on a fellowship program. This gives trainees the opportunity to further develop their subspecialty interest generating a high level of confidence in diagnostic and procedural skills. PMID- 25525575 TI - The training and practice of radiology in India: current trends. PMID- 25525576 TI - Acquiring initial American Board of Radiology certification in the United States. PMID- 25525577 TI - Implications of Web of Science journal impact factor for scientific output evaluation in 16 institutions and investigators' opinion. AB - Journal based metrics is known not to be ideal for the measurement of the quality of individual researcher's scientific output. In the current report 16 contributors from Hong Kong SAR, India, Korea, Taiwan, Russia, Germany, Japan, Turkey, Belgium, France, Italy, UK, The Netherlands, Malaysia, and USA are invited. The following six questions were asked: (I) is Web of Sciences journal impact factor (IF) and Institute for Scientific Information (ISI) citation the main academic output performance evaluation tool in your institution? and your country? (II) How does Google citation count in your institution? and your country? (III) If paper is published in a non-SCI journal but it is included in PubMed and searchable by Google scholar, how it is valued when compared with a paper published in a journal with an IF? (IV) Do you value to publish a piece of your work in a non-SCI journal as much as a paper published in a journal with an IF? (V) What is your personal view on the metric measurement of scientific output? (VI) Overall, do you think Web of Sciences journal IF is beneficial, or actually it is doing more harm? The results show that IF and ISI citation is heavily affecting the academic life in most of the institutions. Google citation and evaluation, while is being used and convenient and speedy, has not gain wide 'official' recognition as a tool for scientific output evaluation. PMID- 25525578 TI - Poly Implant Prothese (PIP) incidence of rupture: a retrospective MR analysis in 64 patients. AB - AIM OF THE STUDY: The purpose of this retrospective study was to describe the magnetic resonance imaging (MRI) features of Poly Implant Prothese (PIP) hydrogel implants in a group of 64 patients and to assess the incidence of rupture, compared to other clinical trials. MATERIAL AND METHODS: In this double-center study, we retrospectively reviewed the data sets of 64 consecutive patients (mean age, 43+/-9 years, age range, 27-65 years), who underwent breast MRI examinations, between January 2008 and October 2013, with suspected implant rupture on the basis of clinical assessment or after conventional imaging examination (either mammography or ultrasound). All patients had undergone breast operation with bilateral textured cohesive gel PIP implant insertion for aesthetic reasons. The mean time after operation was 8 years (range, 6-14 years). No patients reported history of direct trauma to their implants. RESULTS: At the time of clinical examination, 41 patients were asymptomatic, 16 complained of breast tenderness and 7 had clinical evidence of rupture. Normal findings were observed in 15 patients. In 26 patients there were signs of mild collapse, with associated not significant peri-capsular fluid collections and no evidence of implant rupture; in 23 patients there was suggestion of implant rupture, according to breast MRI leading to an indication for surgery. In particular, 14 patients showed intra-capsular rupture, with associated evidence of the linguine sign in all cases; the keyhole sign and the droplet signs were observed in 6 cases. In 9 patients there was evidence of extra-capsular rupture, with presence of axillary collections (siliconomas) in 7 cases and peri-prosthetic and mediastinal cavity siliconomas, in 5 cases. CONCLUSIONS: The results of this double center retrospective study, confirm the higher incidence (36%) of prosthesis rupture observed with the PIP implants, compared to other breast implants. PMID- 25525579 TI - Paediatric cerebrovascular CT angiography-towards better image quality. AB - BACKGROUND: Paediatric cerebrovascular CT angiography (CTA) can be challenging to perform due to variable cardiovascular physiology between different age groups and the risk of movement artefact. This analysis aimed to determine what proportion of CTA at our institution was of diagnostic quality and identify technical factors which could be improved. MATERIALS AND METHODS: a retrospective analysis of 20 cases was performed at a national paediatric neurovascular centre assessing image quality with a subjective scoring system and Hounsfield Unit (HU) measurements. Demographic data, contrast dose, flow rate and triggering times were recorded for each patient. RESULTS: Using a qualitative scoring system, 75% of studies were found to be of diagnostic quality (n=9 'good', n=6 'satisfactory') and 25% (n=5) were 'poor'. Those judged subjectively to be poor had arterial contrast density measured at less than 250 HU. Increased arterial opacification was achieved for cases performed with an increased flow rate (2.5-4 mL/s) and higher intravenous contrast dose (2 mL/kg). Triggering was found to be well timed in nine cases, early in four cases and late in seven cases. Of the scans triggered early, 75% were poor. Of the scans triggered late, less (29%) were poor. CONCLUSIONS: High flow rates (>2.5 mL/s) were a key factor for achieving high quality paediatric cerebrovascular CTA imaging. However, appropriate triggering by starting the scan immediately on contrast opacification of the monitoring vessel plays an important role and could maintain image quality when flow rates were lower. Early triggering appeared more detrimental than late. PMID- 25525580 TI - Two public chest X-ray datasets for computer-aided screening of pulmonary diseases. AB - The U.S. National Library of Medicine has made two datasets of postero-anterior (PA) chest radiographs available to foster research in computer-aided diagnosis of pulmonary diseases with a special focus on pulmonary tuberculosis (TB). The radiographs were acquired from the Department of Health and Human Services, Montgomery County, Maryland, USA and Shenzhen No. 3 People's Hospital in China. Both datasets contain normal and abnormal chest X-rays with manifestations of TB and include associated radiologist readings. PMID- 25525583 TI - Introduce fair competition mechanism in China healthcare system. PMID- 25525582 TI - MRI assessment of cardiac tumours: part 2, spectrum of appearances of histologically malignant lesions and tumour mimics. AB - Cardiac magnetic resonance imaging (MRI) is the reference standard technique for assessment and characterization of a suspected cardiac tumour. It provides an unrestricted field of view, high temporal resolution and non-invasive tissue characterization based on multi-parametric assessment of the chemical micro environment. Sarcomas account for around 95% of all primary malignant cardiac tumours with lymphoma, and primary pericardial mesothelioma making up most of the remainder of cases. By contrast cardiac metastases are much more common. In this article we review the MRI features of the spectrum of histologically malignant cardiac and pericardial tumours as well as some potential tumour mimics. PMID- 25525581 TI - MRI assessment of cardiac tumours: part 1, multiparametric imaging protocols and spectrum of appearances of histologically benign lesions. AB - Cardiac magnetic resonance imaging (MRI) is the reference standard technique for assessment and characterization of a suspected cardiac tumour. It provides an unrestricted field of view, high temporal resolution and non-invasive tissue characterization based on multi-parametric assessment of the chemical micro environment. MRI exploits differences in hydrogen proton density in conjunction with T1 and T2 relaxation properties of different tissues to help differentiation normal from abnormal and benign from malignant lesions. In this article we review specific cardiac MRI techniques, tumour protocol design and the appearance of the spectrum of histologically benign tumours. PMID- 25525584 TI - Relative income of clinical faculty members vs. science faculty members in university settings-a short survey of France, Hong Kong, India, Japan, South Korea, The Netherlands, Taiwan, UK, and USA. PMID- 25525585 TI - Passion and hard work produces high quality research in UK: response to Focus on China: should clinicians engage in research? and lessons from other countries. PMID- 25525586 TI - Inner annulus fibrosus in non-degenerated intervertebral disc shows bright signal on T2 weighted MR image. PMID- 25525587 TI - CT features of metanephric adenoma: a case report and review of the literature. AB - Metanephric adenoma (MA) is an extremely rare, benign neoplasm of the kidney. Ultrasound and computed tomography (CT) features of a case of MA in a 49-year-old woman were presented in this paper to enrich imaging manifestations of this rare entity. At plane CT, a solid mass with calcification spots was noted. After iv contrast agency, the mass showed slight irregular peripheral enhancement in the corticomedullary phase, which was obviously lower than surrounding renal cortex. Slowly filling-in was noticed in the nephrographic phase with irregular necrosis. PMID- 25525588 TI - Massive alveolar haemorrhage: a rare life threatening complication of Wegener's granulomatosis-report of a rare case. AB - Massive diffuse alveolar haemorrhage (DAH) is an unusual, frequently life threatening and still treatable complication of Wegener's granulomatosis (WG) associated with mortality in more than 66% of cases. DAH is a syndrome that can be a manifestation of variety of disorders. WG, a multisystem necrotising granulomatous vasculitis should always be considered as a possible etiological factor in these patients with or without involvement of other systems, as an early diagnosis and aggressive management with cytotoxic drugs offer best chances of survival in these patients. We report a rare case of 45-year-old woman who presented with massive hemoptysis in accident and emergency department and subsequently diagnosed as WG, and discuss the differential diagnosis and review the literature of this rare complication of WG. Approximately 41 cases have been reported so far of this rare complication. PMID- 25525589 TI - Lymphoepithelial carcinoma arising from the maxillary antrum: a clinicopathological report of a rare lesion in an unusual site. AB - Lymphoepithelial carcinoma (LEC) of the maxillary sinus is an exceedingly rare malignancy. It may be asymptomatic or present with non-specific obstructive nasal symptoms which makes its pre-operative diagnosis very challenging. This report describes our clinical and radiological findings in a 45-year-old Indian female patient with locally-advanced LEC of the right maxillary antrum. Histopathological and immunohistochemical results are also discussed. The case was effectively managed by external beam radiotherapy and the patient has remained disease-free at 20-month follow-up. PMID- 25525590 TI - Neuroendocrine tumor of the gallbladder with spectral CT. AB - Neuroendocrine tumors (NETs) are neoplasms that arise from neural crest argyrophil cells, and often occur to the elderly, female and patients with cholelithiasis. In this case, the female patient was 38 years old and admitted into the hospital for interrupted right upward abdominal pain for 2 years plus aggravated with nausea and anorexia for 1 week. Ultrasound showed gallbladder space-occupying lesions and spectral computed tomography (CT) suggested of retroperitoneal lymph node metastasis. The patient was diagnosed with gallbladder neuroendocrine carcinoma after the surgery. PMID- 25525591 TI - Gene Expression Profiling of Grass Carp (Ctenopharyngodon idellus) and Crisp Grass Carp. AB - Grass carp (Ctenopharyngodon idellus) is one of the most important freshwater fish that is native to China, and crisp grass carp is a kind of high value-added fishes which have higher muscle firmness. To investigate biological functions and possible signal transduction pathways that address muscle firmness increase of crisp grass carp, microarray analysis of 14,900 transcripts was performed. Compared with grass carp, 127 genes were upregulated and 114 genes were downregulated in crisp grass carp. Gene ontology (GO) analysis revealed 30 GOs of differentially expressed genes in crisp grass carp. And strong correlation with muscle firmness increase of crisp grass carp was found for these genes from differentiation of muscle fibers and deposition of ECM, and also glycolysis/gluconeogenesis pathway and calcium metabolism may contribute to muscle firmness increase. In addition, a number of genes with unknown functions may be related to muscle firmness, and these genes are still further explored. Overall, these results had been demonstrated to play important roles in clarifying the molecular mechanism of muscle firmness increase in crisp grass carp. PMID- 25525592 TI - The role of MRI in prostate cancer active surveillance. AB - Prostate cancer is the most common cancer diagnosis in American men, excluding skin cancer. The clinical behavior of prostate cancer varies from low-grade, slow growing tumors to high-grade aggressive tumors that may ultimately progress to metastases and cause death. Given the high incidence of men diagnosed with prostate cancer, conservative treatment strategies such as active surveillance are critical in the management of prostate cancer to reduce therapeutic complications of radiation therapy or radical prostatectomy. In this review, we will review the role of multiparametric MRI in the selection and follow-up of patients on active surveillance. PMID- 25525594 TI - Bone tissue engineering for dentistry and orthopaedics. PMID- 25525593 TI - Expression of phosphocitrate-targeted genes in osteoarthritis menisci. AB - Phosphocitrate (PC) inhibited calcium crystal-associated osteoarthritis (OA) in Hartley guinea pigs. However, the molecular mechanisms remain elusive. This study sought to determine PC targeted genes and the expression of select PC targeted genes in OA menisci to test hypothesis that PC exerts its disease modifying activity in part by reversing abnormal expressions of genes involved in OA. We found that PC downregulated the expression of numerous genes classified in immune response, inflammatory response, and angiogenesis, including chemokine (C-C motif) ligand 5, Fc fragment of IgG, low affinity IIIb receptor (FCGR3B), and leukocyte immunoglobulin-like receptor, subfamily B member 3 (LILRB3). In contrast, PC upregulated the expression of many genes classified in skeletal development, including collagen type II alpha1, fibroblast growth factor receptor 3 (FGFR3), and SRY- (sex determining region Y-) box 9 (SOX-9). Immunohistochemical examinations revealed higher levels of FCGR3B and LILRB3 and lower level of SOX-9 in OA menisci. These findings indicate that OA is a disease associated with immune system activation and decreased expression of SOX-9 gene in OA menisci. PC exerts its disease modifying activity on OA, at least in part, by targeting immune system activation and the production of extracellular matrix and selecting chondroprotective proteins. PMID- 25525595 TI - A rare cause of postpartum low back pain: pregnancy- and lactation-associated osteoporosis. AB - Pregnancy- and lactation-associated osteoporosis (PLO) is a rare form of osteoporosis. It results in severe low back pain in the last trimester of pregnancy and in the postpartum period, decreases in height, and fragility fractures, particularly in the vertebra. The current case report presents a 32 year-old patient who presented with back and low back pain that began in the last trimester of the pregnancy and worsened at two months postpartum and who was diagnosed with pregnancy- and lactation-associated osteoporosis after exclusion of other causes; the findings are discussed in view of the current literature. PLO is a rare clinical condition causing significant disability. PLO must be kept in mind in the differential diagnosis in patients presenting with low back pain during or after pregnancy. The patients must be evaluated for the risk factors of PLO, and an appropriate therapy must be initiated. PMID- 25525596 TI - Multiparametric MRI in prostate cancer. PMID- 25525597 TI - Resveratrol as a therapeutic agent for Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia, but there is no effective therapy till now. The pathogenic mechanisms of AD are considerably complex, including Abeta accumulation, tau protein phosphorylation, oxidative stress, and inflammation. Exactly, resveratrol, a polyphenol in red wine and many plants, is indicated to show the neuroprotective effect on mechanisms mostly above. Recent years, there are numerous researches about resveratrol acting on AD in many models, both in vitro and in vivo. However, the effects of resveratrol are limited by its pool bioavailability; therefore researchers have been trying a variety of methods to improve the efficiency. This review summarizes the recent studies in cell cultures and animal models, mainly discusses the molecular mechanisms of the neuroprotective effects of resveratrol, and thus investigates the therapeutic potential in AD. PMID- 25525599 TI - Quantification of an external motion surrogate for quality assurance in lung cancer radiation therapy. AB - The purpose of this work was to validate the stability of the end exhale position in deep expiration breath hold (DEBH) technique for quality assurance in stereotactic lung tumor radiation therapy. Furthermore, a motion analysis was performed for 20 patients to evaluate breathing periods and baseline drifts based on an external surrogate. This trajectory was detected using stereo infrared (IR) cameras and reflective body markers. The respiratory waveform showed large interpatient differences in the end exhale position during irradiation up to 18.8 mm compared to the global minimum. This position depends significantly on the tumor volume. Also the baseline drifts, which occur mostly in posterior direction, are affected by the tumor size. Breathing periods, which depend mostly on the patient age, were in a range between 2.4 s and 7.0 s. Fifteen out of 20 patients, who showed a reproducible end exhale position with a deviation of less than 5 mm, might benefit from DEBH due to smaller planning target volumes (PTV) compared to free breathing irradiation and hence sparing of healthy tissue. Patients with larger uncertainties should be treated with more complex motion compensation techniques. PMID- 25525598 TI - Complex network-driven view of genomic mechanisms underlying Parkinson's disease: analyses in dorsal motor vagal nucleus, locus coeruleus, and substantia nigra. AB - Parkinson's disease (PD)-classically characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta-has a caudal-rostral progression, beginning in the dorsal motor vagal nucleus and, in a less extent, in the olfactory system, progressing to the midbrain and eventually to the basal forebrain and the neocortex. About 90% of the cases are idiopathic. To study the molecular mechanisms involved in idiopathic PD we conducted a comparative study of transcriptional interaction networks in the dorsal motor vagal nucleus (VA), locus coeruleus (LC), and substantia nigra (SN) of idiopathic PD in Braak stages 4-5 (PD) and disease-free controls (CT) using postmortem samples. Gene coexpression networks (GCNs) for each brain region (patients and controls) were obtained to identify highly connected relevant genes (hubs) and densely interconnected gene sets (modules). GCN analyses showed differences in topology and module composition between CT and PD networks for each anatomic region. In CT networks, VA, LC, and SN hub modules are predominantly associated with neuroprotection and homeostasis in the ageing brain, whereas in the patient's group, for the three brain regions, hub modules are mostly related to stress response and neuron survival/degeneration mechanisms. PMID- 25525600 TI - Multiparametric MRI for localized prostate cancer: lesion detection and staging. AB - Multiparametric MRI of the prostate combines high-resolution anatomic imaging with functional imaging of alterations in normal tissue caused by neoplastic transformation for the identification and characterization of in situ prostate cancer. Lesion detection relies on a systematic approach to the analysis of both anatomic and functional imaging using established criteria for the delineation of suspicious areas. Staging includes visual and functional analysis of the prostate "capsule" to determine if in situ disease is, in fact, organ-confined, as well as the evaluation of pelvic structures including lymph nodes and bones for the detection of metastasis. Although intertwined, the protocol can be optimized depending on whether lesion detection or staging is of the highest priority. PMID- 25525601 TI - Breast stimulation in low-risk primigravidas at term: does it aid in spontaneous onset of labour and vaginal delivery? A pilot study. AB - AIMS: The aim of the study was to elicit the safety and efficacy of breast stimulation as an intervention to prevent postdatism and as an aid in spontaneous onset of labour. METHODS: Primigravidas with cephalic presentation, without any high-risk factor, were recruited between 36 to 38 weeks of gestation. 200 patients were recruited and randomized into two groups (n = 100). Breast stimulation was advised to one group but not to the other group. Bishop's scoring was done at 38 weeks and repeated at 39 weeks of gestation. Maternal and fetal outcomes were compared in two groups. RESULT: Bishop's score changed from 3.12 (+/-1.01) to 3.9 (+/-1.08) in control group and from 3.02 (+/-0.82) to 6.08 (+/ 1.29) in breast stimulation group after one week (P value < 0.0001). The period of gestation at delivery was 39.5 (+/-2.3) weeks in control group and 39.2 (+/ 2.8) weeks in intervention group (P value: 0.044). There were increased chances of vaginal delivery in intervention group (P value: 0.046). Duration of labor, hyperstimulation, presence of meconium stained liquor, postpartum hemorrhage, and neonatal outcomes were similar in both groups. CONCLUSION: Breast stimulation in low-risk primigravidas helps in cervical ripening and increases chances of vaginal delivery. PMID- 25525602 TI - Perineal ultrasound as a complement to POP-Q in the assessment of cystoceles. AB - PURPOSE: In the present study we want to propose a classification system to quantify cystoceles by perineal ultrasound (PUS). MATERIALS AND METHODS: 120 PUS data were analyzed measuring the distance between the lowest point of the bladder and the midpubic line (MPL) during rest and Valsalva. Results were classified into groups and compared to POP-Q using the kappa-coefficient. Results for exact bladder position were checked for interrater reliability using ICC and Pearson's coefficient and results for classification were checked using the kappa coefficient. Bladder positions at rest and Valsalva were correlated with the distance between these points. RESULTS: Highly significant differences concerning the position at rest and the distance between rest and Valsalva were found between the groups. For the interrater agreement, the Pearson correlation coefficient was rho = 0.98, the ICC (A-1) = 0.98, and kappa = 1.00. Comparing the classification results for POP-Q and PUS, the kappa-coefficient was kappa = 0.65. CONCLUSION: PUS using the MPL and the classification system is a highly reliable tool for the evaluation of cystoceles. PUS shows good correlation with POP-Q. Furthermore, PUS offers a doubtless identification of the descending organ. Further studies are needed to evaluate the clinical use of the classification system proposed here. PMID- 25525603 TI - Conspicuity of peripheral zone prostate cancer on computed diffusion-weighted imaging: comparison of cDWI1500, cDWI2000, and cDWI3000. AB - INTRODUCTION AND OBJECTIVE: Disadvantages associated with direct high b-value measurements may be avoided with use of computed diffusion-weighted imaging (cDWI). The purpose of this study is to assess the diagnostic performance of cDWI image sets calculated for high b-values of 1500, 2000, and 3000 s/mm(2). MATERIALS AND METHODS: Twenty-eight patients who underwent multiparametric MRI of the prostate and radical prostatectomy consecutively were enrolled in this retrospective study. Using a software developed at our institute, cDWI1500, cDWI2000, and cDWI3000 image sets were generated by fitting a monoexponential model. Index lesions on cDWI image sets were scored by two radiologists in consensus considering lesion conspicuity, suppression of background prostate tissue, distortion, image set preferability, and contrast ratio measurements were performed. RESULTS: Lesion detection rates are the same for computed b-values of 2000 and 3000 s/mm(2) and are better than b-values of 1500 s/mm(2). Best lesion conspicuity and best background prostate tissue suppression are provided by cDWI3000 image set. cDWI2000 image set provides the best zonal anatomical delineation and less distortion and was chosen as the most preferred image set. Average contrast ratio measured on these image sets shows almost a linear relation with the b-values. CONCLUSION: cDWI2000 image set with similar conspicuity and the same lesion detection rate, but better zonal anatomical delineation, and less distortion, was chosen as the preferable image set. PMID- 25525604 TI - Computer aided-diagnosis of prostate cancer on multiparametric MRI: a technical review of current research. AB - Prostate cancer (PCa) is the most commonly diagnosed cancer among men in the United States. In this paper, we survey computer aided-diagnosis (CADx) systems that use multiparametric magnetic resonance imaging (MP-MRI) for detection and diagnosis of prostate cancer. We review and list mainstream techniques that are commonly utilized in image segmentation, registration, feature extraction, and classification. The performances of 15 state-of-the-art prostate CADx systems are compared through the area under their receiver operating characteristic curves (AUC). Challenges and potential directions to further the research of prostate CADx are discussed in this paper. Further improvements should be investigated to make prostate CADx systems useful in clinical practice. PMID- 25525605 TI - Multiparametric MRI-targeted TRUS prostate biopsies using visual registration. AB - Prebiopsy multiparametric prostate MRI (mp-MRI), followed by transrectal ultrasound-guided (TRUS-G) target biopsies (TB) of the prostate is a key combination for the diagnosis of clinically significant prostate cancers (CSPCa), to avoid prostate cancer (PCa) overtreatment. Several techniques are available for guiding TB to the suspicious mp-MRI targets, but the simplest, cheapest, and easiest to learn is "cognitive," with visual registration of MRI and TRUS data. This review details the successive steps of the method (target detection, mp-MRI reporting, intermodality fusion, TRUS guidance to target, sampling simulation, sampling, TRUS session reporting, and quality insurance), how to optimize each, and the global indications of mp-MRI-targeted biopsies. We discuss the diagnostic yield of visually-registered TB in comparison with conventional biopsy, and TB performed using other registration methods. PMID- 25525606 TI - Are there differences in the health outcomes of mothers in Europe and East-Asia? A cross-cultural health survey. AB - The aim of the current study was to investigate differences in quality of life outcomes and depression of mothers in East-Asia and Central Europe. 170 women in Japan and 226 women in Austria with children between 3 and 5 answered the same cross-culturally validated questionnaires. The Quality of Life Questionnaire from the WHO (WHOQOL-Bref), the Patient Health Questionnaire (PHQ-2), the Sense of Coherence Scale (SOC-13), a Social Support Scale (MSPSS), and questions on gender orientation were used. In all dimensions of QOL (physical, psychological, social, and environmental) Japanese women had lower QOL scores compared to Austrian mothers (P < 001). Seven percent of women in both countries experienced major depression. In both countries sense of coherence, experienced stress level, satisfaction with income, social support, and gender roles had an influence on QOL and depressive symptoms. Mothers in Japan consider life events less comprehensible, manageable, and meaningful and experience less support. Consequently, creating an environment where fathers could be more involved in child rearing and mothers have more opportunities to choose between life styles and working and social environments would improve QOL not only in Japanese mothers but also in other countries all over the world. PMID- 25525607 TI - Low molecular weight fucoidan alleviates cardiac dysfunction in diabetic Goto Kakizaki rats by reducing oxidative stress and cardiomyocyte apoptosis. AB - Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction and cardiomyocyte apoptosis. Oxidative stress is suggested to be the major contributor to the development of DCM. This study was intended to evaluate the protective effect of low molecular weight fucoidan (LMWF) against cardiac dysfunction in diabetic rats. Type 2 diabetic goto-kakizaki rats were untreated or treated with LMWF (50 and 100 mg/kg/day) for three months. The establishment of DCM model and the effects of LMWF on cardiac function were evaluated by echocardiography and isolated heart perfusion. Ventricle staining with H-E or Sirius Red was performed to investigate the structural changes in myocardium. Functional evaluation demonstrated that LMWF has a beneficial effect on DCM by enhancing myocardial contractility and mitigating cardiac fibrosis. Additionally, LMWF exerted significant inhibitory effects on the reactive oxygen species production and myocyte apoptosis in diabetic hearts. The depressed activity of superoxide dismutase in diabetic heart was also improved by intervention with LMWF. Moreover, LMWF robustly inhibited the enhanced expression of protein kinase C beta, an important contributor to oxidative stress, in diabetic heart and high glucose-treated cardiomyocytes. In conclusion, LMWF possesses a protective effect against DCM through ameliorations of PKCbeta-mediated oxidative stress and subsequent cardiomyocyte apoptosis in diabetes. PMID- 25525608 TI - Effects of fenofibrate on adiponectin expression in retinas of streptozotocin induced diabetic rats. AB - Adiponectin has been associated with increased risks of microvascular complications in diabetes; however, its role in the development of diabetic retinopathy (DR) is unknown. Fenofibrate is a lipid-lowering agent that has been shown to be capable of preventing DR progression. We investigated the expression of adiponectin and its receptors in DR and evaluated the effects of fenofibrate on their expression. The mRNA and protein levels of adiponectin and its receptors were elevated in retinas of streptozotocin-induced diabetic rats and were suppressed following fenofibrate treatment. Immunofluorescence staining demonstrated that adiponectin and adipoR1 were expressed in cells located within blood vessels, the retinal ganglion, and the inner nuclear layer. AdipoR1 was strongly expressed whereas adipoR2 was only weekly expressed in vascular endothelial cells. The in vitro experiments showed that adiponectin expression was induced by high glucose concentrations in RGC-5 and RAW264.7 cells and was suppressed following fenofibrate treatment. AdipoR1 and adipoR2 levels in RGC-5 cells were elevated in high glucose concentrations and suppressed by fenofibrate. Our results demonstrated that adiponectin may be a proinflammatory mediator in diabetic retinas and fenofibrate appears to modulate the expression of adiponectin and its receptors in diabetic retinas, effectively reducing DR progression. PMID- 25525609 TI - Glyoxylate, a new marker metabolite of type 2 diabetes. AB - Type 2 diabetes (T2D) is characterized by a variety of metabolic impairments that are closely linked to nonenzymatic glycation reactions of proteins and peptides resulting in advanced glycation end-products (AGEs). Reactive aldehydes derived from sugars play an important role in the generation of AGEs. Using metabolite profiling to characterize human plasma from diabetic versus nondiabetic subjects we observed in a recent study that the reactive aldehyde glyoxylate was increased before high levels of plasma glucose, typical for a diabetic condition, could be measured. Following this observation, we explored the relevance of increased glyoxylate in diabetic subjects and in diabetic C57BLKS/J-Lepr (db/db (-/-)) mice in the pathophysiology of diabetes. A retrospective study using samples of long term blood donors revealed that glyoxylate levels unlike glucose levels became significantly elevated up to 3 years prior to diabetes diagnosis (difference to control P = 0.034). Elevated glyoxylate levels impact on newly identified mechanisms linking hyperglycemia and AGE production with diabetes-associated complications such as diabetic nephropathy. Glyoxylate in its metabolic network may serve as an early marker in diabetes diagnosis with predictive qualities for associated complications and as potential to guide the development of new antidiabetic therapies. PMID- 25525612 TI - Algebraic Statistical Model for Biochemical Network Dynamics Inference. AB - With modern molecular quantification methods, like, for instance, high throughput sequencing, biologists may perform multiple complex experiments and collect longitudinal data on RNA and DNA concentrations. Such data may be then used to infer cellular level interactions between the molecular entities of interest. One method which formalizes such inference is the stoichiometric algebraic statistical model (SASM) of [2] which allows to analyze the so-called conic (or single source) networks. Despite its intuitive appeal, up until now the SASM has been only heuristically studied on few simple examples. The current paper provides a more formal mathematical treatment of the SASM, expanding the original model to a wider class of reaction systems decomposable into multiple conic subnetworks. In particular, it is proved here that on such networks the SASM enjoys the so-called sparsistency property, that is, it asymptotically (with the number of observed network trajectories) discards the false interactions by setting their reaction rates to zero. For illustration, we apply the extended SASM to in silico data from a generic decomposable network as well as to biological data from an experimental search for a possible transcription factor for the heat shock protein 70 (Hsp70) in the zebrafish retina. PMID- 25525611 TI - Wide-field in vivo neocortical calcium dye imaging using a convection-enhanced loading technique combined with simultaneous multiwavelength imaging of voltage sensitive dyes and hemodynamic signals. AB - In vivo calcium imaging is an incredibly powerful technique that provides simultaneous information on fast neuronal events, such as action potentials and subthreshold synaptic activity, as well as slower events that occur in the glia and surrounding neuropil. Bulk-loading methods that involve multiple injections can be used for single-cell as well as wide-field imaging studies. However, multiple injections result in inhomogeneous loading as well as multiple sites of potential cortical injury. We used convection-enhanced delivery to create smooth, continuous loading of a large area of the cortical surface through a solitary injection site and demonstrated the efficacy of the technique using confocal microscopy imaging of single cells and physiological responses to single-trial events of spontaneous activity, somatosensory-evoked potentials, and epileptiform events. Combinations of calcium imaging with voltage-sensitive dye and intrinsic signal imaging demonstrate the utility of this technique in neurovascular coupling investigations. Convection-enhanced loading of calcium dyes may be a useful technique to advance the study of cortical processing when widespread loading of a wide-field imaging is required. PMID- 25525613 TI - Personality profile of parents of children with attention deficit hyperactivity disorder. AB - OBJECTIVES: The present study was carried out aiming to identify the personality profile of parents of children with Attention Deficit Hyperactivity Disorder (ADHD). METHODS: This study is of a descriptive, analytic, cross-sectional type in which parents of 6-12-year-old children with ADHD who were referred to the Bozorgmehr Psychiatric Clinic, affiliated with Tabriz University of Medical Sciences, were enrolled. ADHD was diagnosed according to the criteria of DSM-IV TR and a quasi-structured diagnostic interview (K-SADS-PL). The personality profile of the parents was assessed with the Millon Clinical Multiaxial Inventory III (MCMI-III). RESULTS: According to the findings of this study, the most common personality problems based on the assessment scales in the MCMI-III belonged to the clinical patterns of depressive personality in 43 persons (25.3%), histrionic personality in 34 persons (20%), and compulsive personality in 29 persons (17.1%). According to discriminant analysis, four scales of somatoform, sadistic, dependence, and though disorder were direct and antisocial scale was reverse significant predictors of membership in the women group. CONCLUSION: According to the findings of this pilot study, personality disorders are prevalent in parents of ADHD children and mothers suffer from personality disorders more than fathers. PMID- 25525614 TI - Optimizing the long-term operating plan of railway marshalling station for capacity utilization analysis. AB - Not only is the operating plan the basis of organizing marshalling station's operation, but it is also used to analyze in detail the capacity utilization of each facility in marshalling station. In this paper, a long-term operating plan is optimized mainly for capacity utilization analysis. Firstly, a model is developed to minimize railcars' average staying time with the constraints of minimum time intervals, marshalling track capacity, and so forth. Secondly, an algorithm is designed to solve this model based on genetic algorithm (GA) and simulation method. It divides the plan of whole planning horizon into many subplans, and optimizes them with GA one by one in order to obtain a satisfactory plan with less computing time. Finally, some numeric examples are constructed to analyze (1) the convergence of the algorithm, (2) the effect of some algorithm parameters, and (3) the influence of arrival train flow on the algorithm. PMID- 25525615 TI - Antioxidant capacity and radical scavenging effect of polyphenol rich Mallotus philippenensis fruit extract on human erythrocytes: an in vitro study. AB - Mallotus philippinensis is an important source of molecules with strong antioxidant activity widely used medicinal plant. Previous studies have highlighted their anticestodal, antibacterial, wound healing activities, and so forth. So, present investigation was designed to evaluate the total antioxidant activity and radical scavenging effect of 50% ethanol fruit glandular hair extract (MPE) and its role on Human Erythrocytes. MPE was tested for phytochemical test followed by its HPLC analysis. Standard antioxidant assays like DPPH, ABTS, hydroxyl, superoxide radical, nitric oxide, and lipid peroxidation assay were determined along with total phenolic and flavonoids content. Results showed that MPE contains the presence of various phytochemicals, with high total phenolic and flavonoid content. HPLC analysis showed the presence of rottlerin, a polyphenolic compound in a very rich quantity. MPE exhibits significant strong scavenging activity on DPPH and ABTS assay. Reducing power showed dose dependent increase in concentration absorption compared to standard, Quercetin. Superoxide, hydroxyl radical, lipid peroxidation, nitric oxide assay showed a comparable scavenging activity compared to its standard. Our finding further provides evidence that Mallotus fruit extract is a potential natural source of antioxidants which have a protective role on human Erythrocytes exhibiting minimum hemolytic activity and this justified its uses in folklore medicines. PMID- 25525616 TI - Subclinical ketosis on dairy cows in transition period in farms with contrasting butyric acid contents in silages. AB - This study examines the relationship between subclinical ketosis (SCK) in dairy cows and the butyric acid content of the silage used in their feeding. Twenty commercial farms were monitored over a period of 12 months. The feed at each farm and the silages used in its ration were sampled monthly for proximal analysis and for volatile fatty acid analysis. A total of 2857 urine samples were taken from 1112 cows to examine the ketonuria from about 30 days prepartum to 100 postpartum. Wide variation was recorded in the quality of silages used in the preparation of diets. Approximately 80% of the urine samples analyzed had no detectable ketone bodies, 16% returned values indicative of slight SCK, and the remainder, 4%, showed symptoms of ketosis. Most of the cases of hyperkenuria were associated with the butyric acid content of the silage used (r2=0.56; P<0.05). As the metabolizable energy content of the feed was similar, no relationship was observed between the proportion of cows with SCK and the energy content of the feed. In our study, the probability of dairy cows suffering SCK is higher when they are eating feed made from silage with a high butyric acid content (35.2 g/kg DM intake). PMID- 25525617 TI - Identification and antimicrobial resistance of Enterococcus spp. isolated from the river and coastal waters in northern Iran. AB - As fecal streptococci commonly inhabit the intestinal tract of humans and warm blooded animals, and daily detection of all pathogenic bacteria in coastal water is not practical, thus these bacteria are used to detect the fecal contamination of water. The present study examined the presence and the antibiotic resistance patterns of Enterococcus spp. isolated from the Babolrud River in Babol and coastal waters in Babolsar. Seventy samples of water were collected in various regions of the Babolrud and coastal waters. Isolated bacteria were identified to the species level using standard biochemical tests and PCR technique. In total, 70 Enterococcus spp. were isolated from the Babolrud River and coastal waters of Babolsar. Enterococcus faecalis (68.6%) and Enterococcus faecium (20%) were the most prevalent species. Resistance to chloramphenicol, ciprofloxacin, and tetracyclin was prevalent. The presence of resistant Enterococcus spp. in coastal waters may transmit resistant genes to other bacteria; therefore, swimming in such environments is not suitable. PMID- 25525618 TI - Robot trajectories comparison: a statistical approach. AB - The task of planning a collision-free trajectory from a start to a goal position is fundamental for an autonomous mobile robot. Although path planning has been extensively investigated since the beginning of robotics, there is no agreement on how to measure the performance of a motion algorithm. This paper presents a new approach to perform robot trajectories comparison that could be applied to any kind of trajectories and in both simulated and real environments. Given an initial set of features, it automatically selects the most significant ones and performs a statistical comparison using them. Additionally, a graphical data visualization named polygraph which helps to better understand the obtained results is provided. The proposed method has been applied, as an example, to compare two different motion planners, FM(2) and WaveFront, using different environments, robots, and local planners. PMID- 25525619 TI - Gastroretentive pulsatile release tablets of lercanidipine HCl: development, statistical optimization, and in vitro and in vivo evaluation. AB - The present study was aimed at the development of gastroretentive floating pulsatile release tablets (FPRTs) of lercanidipine HCl to enhance the bioavailability and treat early morning surge in blood pressure. Immediate release core tablets containing lercanidipine HCl were prepared and optimized core tablets were compression-coated using buoyant layer containing polyethylene oxide (PEO) WSR coagulant, sodium bicarbonate, and directly compressible lactose. FPRTs were evaluated for various in vitro physicochemical parameters, drug excipient compatibility, buoyancy, swelling, and release studies. The optimized FPRTs were tested in vivo in New Zealand white rabbits for buoyancy and pharmacokinetics. DoE optimization of data revealed FPRTs containing PEO (20% w/w) with coat weight 480 mg were promising systems exhibiting good floating behavior and lag time in drug release. Abdominal X-ray imaging of rabbits after oral administration of the tablets, confirmed the floating behavior and lag time. A quadratic model was suggested for release at 7th and 12th h and a linear model was suggested for release lag time. The FPRT formulation improved pharmacokinetic parameters compared to immediate release tablet formulation in terms of extent of absorption in rabbits. As the formulation showed delay in drug release both in vitro and in vivo, nighttime administration could be beneficial to reduce the cardiovascular complications due to early morning surge in blood pressure. PMID- 25525620 TI - Development and optimization of polymeric self-emulsifying nanocapsules for localized drug delivery: design of experiment approach. AB - The purpose of the present study was to formulate polymeric self-emulsifying curcumin nanocapsules with high encapsulation efficiency, good emulsification ability, and optimal globule size for localized targeting in the colon. Formulations were prepared using modified quasiemulsion solvent diffusion method. Concentration of formulation variables, namely, X1 (oil), X2 (polymeric emulsifier), and X3 (adsorbent), was optimized by design of experiments using Box Behnken design, for its impact on mean globule size (Y1) and encapsulation efficiency (Y2) of the formulation. Polymeric nanocapsules with an average diameter of 100-180 nm and an encapsulation efficiency of 64.85+/-0.12% were obtained. In vitro studies revealed that formulations released the drug after 5 h lag time corresponding to the time to reach the colonic region. Pronounced localized action was inferred from the plasma concentration profile (C max 200 ng/mL) that depicts limited systemic absorption. Roentgenography study confirms the localized presence of carrier (0-2 h in upper GIT; 2-4 h in small intestine; and 4-24 h in the lower intestine). Optimized formulation showed significantly higher cytotoxicity (IC50 value 20.32 MUM) in HT 29 colonic cancer cell line. The present study demonstrates systematic development of polymeric self-emulsifying nanocapsule formulation of curcumin for localized targeting in colon. PMID- 25525621 TI - NMR spectroscopy of human eye tissues: a new insight into ocular biochemistry. AB - BACKGROUND: The human eye is a complex organ whose anatomy and functions has been described very well to date. Unfortunately, the knowledge of the biochemistry and metabolic properties of eye tissues varies. Our objective was to reveal the biochemical differences between main tissue components of human eyes. METHODS: Corneas, irises, ciliary bodies, lenses, and retinas were obtained from cadaver globes 0-1/2 hours postmortem of 6 male donors (age: 44-61 years). The metabolic profile of tissues was investigated with HR MAS 1H NMR spectroscopy. RESULTS: A total of 29 metabolites were assigned in the NMR spectra of the eye tissues. Significant differences between tissues were revealed in contents of the most distant eye-tissues, while irises and ciliary bodies showed minimal biochemical differences. ATP, acetate, choline, glutamate, lactate, myoinositol, and taurine were identified as the primary biochemical compounds responsible for differentiation of the eye tissues. CONCLUSIONS: In this study we showed for the first time the results of the analysis of the main human eye tissues with NMR spectroscopy. The biochemical contents of the selected tissues seemed to correspond to their primary anatomical and functional attributes, the way of the delivery of the nutrients, and the location of the tissues in the eye. PMID- 25525622 TI - In silico approach towards designing virtual oligopeptides for HRSV. AB - HRSV (human respiratory syncytial virus) is a serious cause of lower respiratory tract illness in infants and young children. Designing inhibitors from the proteins involved in virus replication and infection process provides target for new therapeutic treatments. In the present study, in silico docking was performed using motavizumab as a template to design motavizumab derived oligopeptides for developing novel anti-HRSV agents. Additional simulations were conducted to study the conformational propensities of the oligopeptides and confirmed the hypothesis that the designed oligopeptide is highly flexible and capable of assuming stable confirmation. Our study demonstrated the best specific interaction of GEKKLVEAPKS oligopeptide for glycoprotein strain A among various screened oligopeptides. Encouraged by the results, we expect that the proposed scheme will provide rational choices for antibody reengineering which is useful for systematically identifying the possible ways to improve efficacy of existing antibody drugs. PMID- 25525610 TI - Endogenous Voltage Potentials and the Microenvironment: Bioelectric Signals that Reveal, Induce and Normalize Cancer. AB - Cancer may be a disease of geometry: a misregulation of the field of information that orchestrates individual cells' activities towards normal anatomy. Recent work identified molecular mechanisms underlying a novel system of developmental control: bioelectric gradients. Endogenous spatio-temporal differences in resting potential of non-neural cells provide instructive cues for cell regulation and complex patterning during embryogenesis and regeneration. It is now appreciated that these cues are an important layer of the dysregulation of cell: cell interactions that leads to cancer. Abnormal depolarization of resting potential (Vmem) is a convenient marker for neoplasia and activates a metastatic phenotype in genetically-normal cells in vivo. Moreover, oncogene expression depolarizes cells that form tumor-like structures, but is unable to form tumors if this depolarization is artificially prevented by misexpression of hyperpolarizing ion channels. Vmem triggers metastatic behaviors at considerable distance, mediated by transcriptional and epigenetic effects of electrically-modulated flows of serotonin and butyrate. While in vivo data on voltages in carcinogenesis comes mainly from the amphibian model, unbiased genetic screens and network profiling in rodents and human tissues reveal several ion channel proteins as bona fide oncogene and promising targets for cancer drug development. However, we propose that a focus on specific channel genes is just the tip of the iceberg. Bioelectric state is determined by post-translational gating of ion channels, not only from genetically-specified complements of ion translocators. A better model is a statistical dynamics view of spatial Vmem gradients. Cancer may not originate at the single cell level, since gap junctional coupling results in multi-cellular physiological networks with multiple stable attractors in bioelectrical state space. New medical applications await a detailed understanding of the mechanisms by which organ target morphology stored in real time patterns of ion flows is perceived or mis-perceived by cells. Mastery of somatic voltage gradients will lead to cancer normalization or rebooting strategies, such as those that occur in regenerating and embryonic organs, resulting in transformative advances in basic biology and oncology. PMID- 25525623 TI - The experience of Parkinson's disease: a systematic review and meta-ethnography. AB - There has been little attempt to summarise and synthesise qualitative studies concerning the experience and perception of living with Parkinson's disease. Bringing this information together would provide a background to understand the importance of an individual's social identity on their well-being and hope. Three primary aims were identified (a) understanding the importance of social identity and meaningful activities on individuals' well-being, (b) identifying factors and strategies that influence well-being and hope, and (c) establishing a model that relates to an individual's hope and well-being. Three stages were undertaken including a traditional electronic search, a critical appraisal of articles, and a synthesis of studies. Qualitative articles were included that considered the experience of living with Parkinson's disease. Thirty seven articles were located and included in the review. Five themes were identified and the themes were used to inform development of a new model of hope enablement. The current review furthered understanding of how physical symptoms and the experience of Parkinson's disease affect the individual's well-being and hope. Social identity was established as a key factor that influenced an individual's well-being. Being able to maintain, retain, or develop social identities was essential for the well being and hope of individuals with Parkinson's disease. Understanding the factors which prevent or can facilitate this is essential. PMID- 25525624 TI - Intraoperative neuromonitoring of the external branch of the superior laryngeal nerve during thyroidectomy: the need for evidence-based data and perioperative technical/technological standardization. AB - The external branch of the superior laryngeal nerve (EBSLN) is surgically relevant since its close anatomical proximity to the superior thyroid vessels. There is heterogeneity in the EBSLN anatomy and EBSLN damage produces changes in voice that are very heterogenous and difficult to diagnose. The reported prevalence of EBSLN injury widely ranges. EBSLN iatrogenic injury is considered the most commonly underestimated complication in endocrine surgery because vocal assessment underestimates such event and laryngoscopic postsurgical evaluation does not show standardized findings. In order to decrease the risk for EBSLN injury, multiple surgical approaches have been described so far. IONM provides multiple advantages in the EBSLN surgical approach. In this review, we discuss the current state of the art of the monitored approach to the EBSLN. In particular, we summarize, providing our additional remarks, the most relevant aspects of the standardized technique brilliantly described by the INMSG (International Neuromonitoring Study Group). In conclusion, in our opinion, there is currently the need for more prospective randomized trials investigating the electrophysiological and pathological aspects of the EBSLN for a better understanding of the role of IONM in the EBSLN surgery. PMID- 25525626 TI - In vitro evaluation of ethanolic extracts of Ageratum conyzoides and Artemisia absinthium against cattle tick, Rhipicephalus microplus. AB - In vitro efficacy of ethanolic extracts obtained from the aerial parts of Ageratum conyzoides and Artemisia absinthium was assessed on Rhipicephalus microplus using adult immersion test (AIT). Five concentrations of the extract (1.25%, 2.5%, 5%, 10%, and 20%) with three replications for each concentration were used in the bioassay. In AIT, the maximum mortality was recorded as 40% and 66.7% at 20% concentration for A. conyzoides and A. absinthium, respectively. Acaricidal activity was found to be higher in the extract of A. absinthium with LC50 and LC95 values of 11.2% and 61.7%, respectively. Egg mass weight of the live ticks treated with different concentrations of the extracts was significantly (P<0.05) lower than that of control ticks; consequently, the reproductive index and oviposition values of the treated ticks were reduced significantly (P<0.05). The A. conyzoides inhibited 90% hatching of eggs at the 20% concentration, whereas A. absinthium showed 100% inhibition at 5%, 10%, and 20% concentrations. The results show that A. absinthium has better acaricidal properties than A. conyzoides and could be useful in controlling R. microplus. PMID- 25525627 TI - Optimization of deflection of a big NEO through impact with a small one. AB - Using a small near-Earth object (NEO) to impact a larger and potentially threatening NEO has been suggested as an effective method to avert a collision with Earth. This paper develops a procedure for analysis of the technique for specific NEOs. First, an optimization method is used to select a proper small body from the database. Some principles of optimality are achieved with the optimization process. Then, the orbit of the small body is changed to guarantee that it flies toward and impacts the big threatening NEO. Kinetic impact by a spacecraft is chosen as the strategy of deflecting the small body. The efficiency of this method is compared with that of a direct kinetic impact to the big NEO by a spacecraft. Finally, a case study is performed for the deflection of the Apophis NEO, and the efficiency of the method is assessed. PMID- 25525628 TI - Causal attribution and illness perception: a cross-sectional study in Mexican patients with psychosis. AB - Health psychology researchers have begun to focus greater attention on people's beliefs about health/illness since these beliefs can clearly affect behavior. This cross-sectional study aimed at (1) identifying the most common factors psychotic patients attribute their illness to and (2) assessing the association between causal attribution and illness perception (cognitive, emotional, and comprehensibility dimensions). Sixty-two patients (56.5% females) who had been treated for psychosis at a public psychiatric hospital in Mexico answered the Angermeyer and Klusmann Illness Attribution Scale and the Brief Illness Perception Questionnaire. Results showed that most patients attributed psychosis onset to social factors and that attribution to their personality might have an overwhelmingly negative effect on their lives. Acknowledging psychotic patient attributional beliefs and considering them in clinical practice could improve treatment efficacy and overall recovery success. This is particularly important in psychosis, since symptoms are often severe and/or persistent and require long term treatment. PMID- 25525629 TI - Temperature effects on the magnetic properties of silicon-steel sheets using standardized toroidal frame. AB - This study designed a detachable and standardized toroidal test frame to measure the electromagnetic characteristic of toroidal laminated silicon steel specimens. The purpose of the design was to provide the measurements with standardized and controlled environment. The device also can withstand high temperatures (25-300 degrees C) for short time period to allow high temperature tests. The accompanying driving circuit facilitates testing for high frequency (50-5,000 Hz) and high magnetic flux (0.2-1.8 T) conditions and produces both sinusoidal and nonsinusoidal test waveforms. The thickness of the stacked laminated silicon steel sheets must be 30~31 mm, with an internal diameter of 72 mm and an outer diameter of 90 mm. With the standardized setup, it is possible to carry out tests for toroidal specimen in high temperature and high flux operation. The test results show that there is a tendency of increased iron loss under high temperature operation. The test results with various driving waveforms also provide references to the required consideration in engineering designs. PMID- 25525630 TI - Relationship of Salivary Alpha Amylase and Cortisol to Social Anxiety in Healthy Children Undergoing Laboratory Pain Tasks. AB - OBJECTIVE: Salivary alpha amylase (sAA) has been shown to be a sensitive and reliable marker of the autonomic nervous system (ANS) response to stress. A link between sAA, cortisol, and social/evaluative stress has been established in youth, but little is known about these relationships in response to other stressors in children, and how social anxiety might moderate these relationships. The current study explored the associations among sAA and salivary cortisol responses to laboratory pain tasks and self-reported social anxiety symptoms in a sample of healthy children. METHOD: Two hundred thirty-one children (114 girls; 49.4%) with a mean age 12.68 years (SD=3.0; range 7-18) participated in the study. Participants completed self-report questionnaires prior to undergoing a series of laboratory pain tasks involving cold, pressure, and heat pain. Saliva samples were collected upon arrival to the laboratory (pre-task), following the completion of the pain tasks (post-task1), and 20 minutes after the completion of the pain tasks (post-task2). RESULTS: Demographic factors (age, sex, pubertal stage) did not predict either sAA or cortisol levels. However, children reporting higher levels of social anxiety demonstrated significantly higher sAA but not cortisol levels across three salivary collection times, compared to children reporting lower levels of social anxiety. Further, it does not appear that reduced state levels of anxiety before or during the tasks buffer this relationship. CONCLUSION: These data highlight the possibility of identifying biomarkers of stress that are consistent across time and developmental stage. sAA appears to be a marker of stress response in children with self-reported social anxiety. There may also be a potentially unique relationship of sAA to stress in this population. In addition, sAA may reflect stable individual differences in levels of ANS arousal and may be a useful biomarker for identifying children at risk for stress. PMID- 25525631 TI - Beyond Safe Harbor: Automatic Discovery of Health Information De-identification Policy Alternatives. AB - Regulations in various countries permit the reuse of health information without patient authorization provided the data is "de-identified". In the United States, for instance, the Privacy Rule of the Health Insurance Portability and Accountability Act defines two distinct approaches to achieve de-identification; the first is Safe Harbor, which requires the removal of a list of identifiers and the second is Expert Determination, which requires that an expert certify the re identification risk inherent in the data is sufficiently low. In reality, most healthcare organizations eschew the expert route because there are no standardized approaches and Safe Harbor is much simpler to interpret. This, however, precludes a wide range of worthwhile endeavors that are dependent on features suppressed by Safe Harbor, such as gerontological studies requiring detailed ages over 89. In response, we propose a novel approach to automatically discover alternative de-identification policies that contain no more re identification risk than Safe Harbor. We model this task as a lattice-search problem, introduce a measure to capture the re-identification risk, and develop an algorithm that efficiently discovers polices by exploring the lattice. Using a cohort of approximately 3000 patient records from the Vanderbilt University Medical Center, as well as the Adult dataset from the UCI Machine Learning Repository, we also experimentally verify that a large number of alternative policies can be discovered in an efficient manner. PMID- 25525632 TI - Context-Aware Anomaly Detection for Electronic Medical Record Systems. PMID- 25525625 TI - Prevention of contrast-induced nephropathy through a knowledge of its pathogenesis and risk factors. AB - Contrast-induced nephropathy (CIN) is an iatrogenic acute renal failure (ARF) occurring after the intravascular injection of iodinated radiographic contrast media. During the past several years, in many patients undergoing computed tomography, iodinated contrast media have not been used for the fear of ARF, thereby compromising the diagnostic procedure. But recent studies have demonstrated that CIN is rarely occurring in patients with normal renal function and that preexisting chronic renal failure and/or diabetes mellitus represent(s) predisposing condition(s) for its occurrence. After the description of CIN and its epidemiology and pathophysiology, underlying the important role played by dehydration and salt depletion, precautions for prevention of CIN are listed, suggested, and discussed. Maximum priority has to be given to adequate hydration and volume expansion prior to radiographic procedures. Other important precautions include the need for monitoring renal function before, during, and after contrast media injection, discontinuation of potentially nephrotoxic drugs, use of either iodixanol or iopamidol at the lowest dosage possible, and administration of antioxidants. A long list of references is provided that will enable readers a deep evaluation of the topic. PMID- 25525633 TI - Tedizolid phosphate for the treatment of acute bacterial skin and skin structure infections. AB - Acute bacterial skin and skin structure infections (ABSSSI) are associated with remarkable morbidity, and often require hospitalization. The cause of most ABSSSI is aerobic Gram-positive cocci, including Staphylococcus aureus, and beta hemolytic streptococci. Tedizolid phosphate is a novel oxazolidinone prodrug whose active moiety is tedizolid. It has shown potent in vitro activity against Gram-positive pathogens, encompassing methicillin-resistant S. aureus (MRSA) and strains resistant to vancomycin or linezolid. Animal studies suggested bactericidal activity in vivo. Pharmacokinetic studies demonstrated a good penetration into skin and soft tissues, and suitability for once-daily administration, either orally or intravenously at the same dosage. Pivotal phase III studies showed that tedizolid phosphate at 200 mg once daily for 6 days is noninferior to linezolid 600 mg twice daily for 10 days in ABSSSI patients, whereas gastrointestinal disorders were less frequent with tedizolid phosphate than linezolid. Tedizolid phosphate has been approved by the U.S. FDA, as Sivextro(r) to treat adult patients with ABSSSI. PMID- 25525634 TI - Tofogliflozin: a highly selective SGLT2 inhibitor for the treatment of type 2 diabetes. AB - Diabetes mellitus impacts a substantial number of people worldwide and despite numerous antidiabetic medications available, approximately half of the drugs do not attain their recommended target, glycated hemoglobin (HbA1c). Recently, the kidney and its role in glucose reabsorption through the sodium/glucose cotransporter 2 (SGLT2) has been the target for novel antidiabetic treatments. Pharmacologic inhibition of SGLT2 in patients with diabetes results in increased urinary glucose excretion and decreased blood glucose levels, decreasing HbA1c levels. Tofogliflozin is the most selective SGLT2 inhibitor, with HbA1c reductions ranging from -0.44% to -0.99% throughout clinical studies, and it is well tolerated with a low rate of drug-related adverse events. Tofogliflozin has demonstrated efficacy and safety as monotherapy or as add-on to various antidiabetic agents, and it is currently undergoing phase IV clinical studies in Japanese patients with diabetes on background insulin therapy. Tofogliflozin is currently approved in Japan for use in patients with type 2 diabetes at a dose of 20 mg orally once daily in the morning, either before or after breakfast. PMID- 25525635 TI - Vorapaxar for the reduction of atherothrombotic events. AB - Vorapaxar is a novel platelet inhibitor that potently and selectively inhibits thrombin-mediated platelet activation without interfering with thrombin-mediated cleavage of fibrinogen via antagonism of the platelet proteinase-activated receptor PAR1. Vorapaxar is a non-peptide himbacine analogue that has been developed for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction or peripheral arterial disease. PMID- 25525636 TI - Current knowledge and future prospects for SAPHO syndrome. AB - SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome is a complex disorder characterized by osteoarticular and cutaneous symptoms. Most patients experience bone pain and dermatologic manifestations. Diagnosis of SAPHO syndrome is based on exclusion of infectious arthritis and septic osteomyelitis with findings of hyperostosis or chronic recurrent multifocal osteomyelitis involving axial or peripheral skeleton, with or without skin manifestations. The pathophysiology of SAPHO is unclear, although several hypotheses exist. Some of these hypotheses have led to the ever growing treatment options of medications. Broad varieties of medications have been used, such as nonsteroidal anti inflammatory drugs and disease-modifying agents. New therapeutic options, such as tumor necrosis factor inhibitors have evolved and have shown promising results. PMID- 25525637 TI - A report from The Liver Meeting 2014 (November 7-11 - Boston, Massachusetts, USA). AB - The first waves of winter cold were sweeping across Massachusetts at the time this year's American Academy for the Study of Liver Diseases' Liver Meeting opened gates to a crowd of scientists and researchers from across the globe. The Hynes Convention Center acted as the liver through which new research from many different sources, shaped as oral and poster presentations, was transformed into a story of hope for new, more effective treatments for common liver diseases, particularly viral hepatitis infection and nonalcoholic steatohepatitis. As summarized in the following report, novel research was also reported emphasizing novel potential therapies for liver cancer as well as a broad range of liver diseases. PMID- 25525638 TI - Editorial: implementation research for oral health. PMID- 25525639 TI - Halitosis: a review of the literature on its prevalence, impact and control. AB - Halitosis is the offensive or disagreeable odour that may emanate from the mouth. In 80%-90% of cases, bacterial activities especially on the dorsum of the tongue are implicated. Current studies on halitosis accessed from electronic databases were appraised in the light of prevalence, impact and control of halitosis. Halitosis has a worldwide occurrence with a prevalence range of 22% to 50%. Due to the associated social and psychological effects, it should be taken seriously in all affected patients. Oral healthcare professionals ought to be well informed, because their office(s) are usually the first points of call for the affected patients. PMID- 25525640 TI - Swelling-induced deformations: a materials-defined transition from macroscale to microscale deformations. AB - Swelling-induced deformations are common in many biological and industrial environments, and the shapes and patterns that emerge can vary across many length scales. Here we present an experimental study of a transition between macroscopic structural bending and microscopic surface creasing in elastomeric beams swollen non-homogeneously with favorable . We show that this transition is dictated by the materials and geometry of the system, and we develop a simple scaling model based on competition between bending and swelling energies that predicts if a given droplet would deform a polymeric structure macroscopically or microscopically. We demonstrate how proper tuning of materials and geometry can generate instabilities at multiple length scales in a single structure. PMID- 25525641 TI - Probing the secondary structure of bovine serum albumin during heat-induced denaturation using mid-infrared fiberoptic sensors. AB - Attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy using a special waveguide based on a silver halide fiber was used for probing the heat-induced secondary structure and conformation changes of bovine serum albumin (BSA). From the secondary derivative and the curve fitting of the obtained ATR FTIR spectra, the changes of the BSA secondary structure with temperature were clearly identified. Two different thermal denaturation temperature ranges (i.e., 50-52 and 80-82 degrees C, at which a change of the protein structure occurred) were determined, while only one denaturation temperature was previously identified via classical FTIR measurements. Additionally, taking advantage of two dimensional correlation spectroscopy more detailed information on changes of the protein secondary structure was revealed. The developed method facilitates in situ, sensitive, and more in-depth probing of protein secondary structures, which represents a significant advancement compared to conventional characterization methods. PMID- 25525642 TI - A mass spectrometry-based unique fragment approach for the identification of microcystins. AB - Both qualitative and quantitative methods for the analysis of microcystin variants have been established. The qualitative method involves a unique fragment approach, specific for each variant in identifying microcystins, while the quantitative method involves the quantification of microcystins in cellular matrices of cyanobacteria and reservoir water samples. For the identification of fragments associated with their respective microcystin (MC) variants, theoretically obtained fragments of microcystins were compared with tandem mass spectrometric (MS/MS) fragments obtained from an ESI-Orbitrap mass spectrometer. Here, we present the first report of MC variants produced by the model algal strain M. aeruginosa NIES-843. A robust comparative study between the unique fragments and the conventional product ions for quantitative measurements of microcystin has also been carried out. The method with high robustness was further validated by determining the MC level changes in the intracellular matrices of M. aeruginosa samples, grown under high and low nitrogen conditions, and by testing the amount of MC in environmental water samples. PMID- 25525643 TI - The facile preparation of a cobalt disulfide-reduced graphene oxide composite film as an efficient counter electrode for dye-sensitized solar cells. AB - Cobalt disulfide (CoS2)-reduced graphene oxide (RGO) composite (CSG) films, which are prepared by combining the layer by layer assembly method and thermal treatment process, are used as counter electrodes (CEs) for dye-sensitized solar cells (DSSCs). The DSSC with CSG CE exhibits comparable efficiency to the cell with the Pt CE. PMID- 25525644 TI - Thiophosphoramides as cooperative catalysts for copper-catalyzed arylation of carboxylates with diaryliodonium salts. AB - A thiophosphoramide-based co-catalyst was found to significantly accelerate copper(II) trifluoromethanesulfonate-catalyzed arylation of potassium carboxylates with diaryliodonium salts. This effect could be attributed to counterion activation of diaryliodonium salts or organocopper intermediates by thiophosphoramides. Inclusion of thiophosphoramides permits achieving significantly milder reaction conditions and expands the scope of solvents and diaryliodonium counterions that could be used for the arylation of carboxylate nucleophiles. PMID- 25525645 TI - Efficient photochemical water oxidation by a dinuclear molecular ruthenium complex. AB - Herein is described the preparation of a dinuclear molecular Ru catalyst for H2O oxidation. The prepared catalyst mediates the photochemical oxidation of H2O with an efficiency comparable to state-of-the-art catalysts. PMID- 25525646 TI - Diboron as a reductant for nickel-catalyzed reductive coupling: rational design and mechanistic studies. AB - Diboron (B2pin2) has been identified as an efficient and environmentally benign reducing reagent for reductive coupling reactions for the first time, which enables the nickel-catalyzed reductive tetramerization of alkynes to be performed with high efficiency. Mechanistic and kinetic studies indicate that the facile reductive elimination to form the B-B bond from the dinuclear Ni-Ni complexes is responsible for the high efficiency. The activation enthalpy (DeltaH(?) = 56.5 kJ mol(-1)), entropy (DeltaS(?) = -128 J mol(-1) K(-1)) and the substituent effect (rho = 1.43) on this reaction were obtained. PMID- 25525647 TI - Energy frameworks: insights into interaction anisotropy and the mechanical properties of molecular crystals. AB - We present an approach to understanding crystal packing via 'energy frameworks', that combines efficient calculation of accurate intermolecular interaction energies with a novel graphical representation of their magnitude. In this manner intriguing questions, such as why some crystals bend with an applied force while others break, and why one polymorph of a drug exhibits exceptional tabletability compared to others, can be addressed in terms of the anisotropy of the topology of pairwise intermolecular interaction energies. This approach is applied to a sample of organic molecular crystals with known bending, shearing and brittle behaviour, to illustrate its use in rationalising their mechanical behaviour at a molecular level. PMID- 25525648 TI - Graphene mediated self-assembly of fullerene nanorods. AB - A simple procedure for solution-based self-assembly of C60 fullerene nanorods on graphene substrates is presented. Using a combination of electron microscopy, X ray diffraction and Raman spectroscopy, it is shown that the size, shape and morphology of the nanorods can be suitably modified by controlling the kinetics of self-assembly. PMID- 25525649 TI - Unprecedented spin localisation in a metal-metal bonded dirhenium complex. AB - The molecular and electronic structure of edge-sharing bioctahedral [N(n Bu)4]3[Re2(mnt)5] is reported here. Despite the short intermetal bond length of 2.6654(2) A with computed bond order of 1.2, the unpaired electron is localised by the asymmetric ligand distribution, as demonstrated by its remarkable EPR spectrum. PMID- 25525650 TI - Concise synthesis of cyclic carbonyl compounds from haloarenes using phenyl formate as the carbonyl source. AB - Various cyclic carbonyl compounds were concisely synthesized by carbonylative cyclization of haloarenes bearing nucleophilic moieties under Pd catalysis. A broad substrate scope and a feasible large-scale synthesis clearly demonstrate the high applicability of the reaction as a general, user-friendly method for access to cyclic carbonyl compounds. PMID- 25525651 TI - International Study of Unruptured Intracranial Aneurysms. Response. PMID- 25525652 TI - In vitro and in vivo control of Alternaria alternata in cherry tomato by essential oil from Laurus nobilis of Chinese origin. AB - BACKGROUND: Many essential oils were reported to be used as natural, environmental friendly antimicrobial agents. The antifungal activity in vitro and in vivo of an essential oil extracted from Chinese local Laurus nobilis leaves against Alternaria alternata has been studied. RESULT: The main components of the essential oil were investigated by means of gas chromatography-mass spectrometry and 14 components were identified. The main ones were eugenol, caryophyllene and cinnamaldehyde. The antifungal test showed that at 800 MUg mL-1 of L. nobilis oil completely inhibited the growth of A. alternata. In addition, the conidial germination of the pathogen was significantly inhibited at 200 MUgmL-1, and the weight of mycelia efficiently decreased at 500 MUgmL-1. The in vivo assay indicated that 500 MUg mL-1 L. nobilis oil was effective in protecting cherry tomatoes (Lycopersicon esculentum)from infection of A. alternata, with an inhibition ratio of 33.9%. Scanning electron microscopy observations of the pathogen revealed significant morphological alterations in the hyphae. CONCLUSION: This work suggested that L. nobilis oil could be used as a potential fungicide to control the post-harvest disease caused by A. alternata. PMID- 25525653 TI - The effect of carotid endarterectomy. Response. PMID- 25525654 TI - Neuritis ossificans. Response. PMID- 25525655 TI - Minute-by-minute monitoring of autoregulation. Response. PMID- 25525656 TI - Supraorbital and transorbital minicraniotomies. Response. PMID- 25525657 TI - Weak cation-exchange monolithic column for capillary liquid chromatography of peptides and proteins. AB - A stable poly(2-carboxyethyl acrylate-co-poly(ethylene glycol) diacrylate) monolith was synthesized inside a 75-MUm id capillary by direct in situ photo initiated polymerization in a binary porogenic solvent consisting of methanol and ethyl ether. The resulting monolith was evaluated for weak cation-exchange capillary liquid chromatography of peptides and proteins. A high dynamic binding capacity of 72.7 mg lysozyme per cm3 column volume was measured. Fast mass transfer was demonstrated by steep breakthrough curves. The resulting monolith exhibited negligible hydrophobicity, leading to good separation of peptides and proteins. Peak capacities of 11 for peptides with a 10-min salt gradient and 39 for proteins with a 20-min salt gradient were measured. An efficiency of 37,000 plates/m for proteins was obtained under isocratic conditions. The effects of functional group concentration, porogenic solvent composition, mobile phase pH, salt gradient rate, and hydrophobicity on the retention of analytes were investigated. Good run-to-run relative standard deviation (RSD) <1.93% and column to-column RSD <4.63% were achieved. PMID- 25525658 TI - Response. PMID- 25525659 TI - Response. PMID- 25525660 TI - Response. PMID- 25525661 TI - Author Response. PMID- 25525662 TI - Author Response. PMID- 25525663 TI - EuroPCR 2014, Hypertension and Heart Failure Track take-home messages. PMID- 25525664 TI - Tales from another career: Douglas W. Losordo MD. PMID- 25525665 TI - The Kyrgyz Society of Cardiologists and Structure of Cardiology Services in Kyrgyzstan. PMID- 25525666 TI - Surface-enhanced Raman spectroscopy + support vector machine: a new noninvasive method for prostate cancer screening? AB - Prostate cancer is one of the most common malignancies of the older males worldwide. Early diagnosis and treatment are important to improve the survival of patients. Recently, we developed a new method for prostate cancer screening: by measuring the serum surface-enhanced Raman spectroscopy of prostate cancer patients and normal subjects, combining with classification algorithms of support vector machines, the measured surface-enhanced Raman spectroscopy spectra are successfully classified with accuracy of 98.1%. Although the practical application faces several difficulties, we believe that this label-free serum surface-enhanced Raman spectroscopy analysis technique combined with support vector machine diagnostic algorithms will become a powerful tool for noninvasive prostate cancer screening in the future. PMID- 25525667 TI - Ligand-modulated chemical and structural implications in four-, five-, and six fold coordinated aluminum heteroaryl alkenolates. AB - Synthesis and characterization (gas phase, solution, and solid-state) of a series of four-, five- and six-fold coordinated heteroaryl-alkenolato aluminum complexes were performed to demonstrate the delicate interplay of structural and chemical influences of ligands in the design of new precursors for chemical vapor deposition. We are investigating the properties of heteroaryl alkenols as O^N chelating ligands [where O^N is 3,3,3-trifluoro(pyridin-2-yl)propen-2-ol (H PyTFP), 3,3,3-trifluoro(1,3-benzimidazol-2-yl)propen-2-ol (H-BITFP), 3,3,3 trifluoro(dimethyl-1,3-oxazol-2-yl)propen-2-ol (H-DMOTFP), 3,3,3-trifluoro(1,3 benzoxazol-2-yl)propen-2-ol (H-BOTFP), 3,3,3-trifluoro(1,3-benzthiazol-2 yl)propen-2-ol (H-BTTFP), and 3,3,3-trifluoro(dimethyl-1,3-thiazol-2-yl)propen-2 ol (H-DMTTFP)] to prepare volatile and air-stable compounds. All three methyl groups in highly reactive AlMe3 could be replaced by H-PyTFP, H-BITFP, H-DMOTFP, and H-BOTFP yielding octahedral complexes of the type Al(O^N)3; under similar conditions H-BTTFP and H-DMTTFP produced heteroleptic MeAl(O^N)2 compounds with five-fold coordinated aluminum centers. Various attempts to obtain tris alkenolato derivatives by choosing higher temperatures and prolonged reaction times were not successful. The reaction of H-PyTFP with [Al(O(t)Bu)3]2 produced the dimeric heteroleptic [Al(PyTFP)(O(t)Bu)2]2 complex with Al atoms present in both octahedral (Oh) and tetrahedral (Td) coordination in a single molecular unit. The introduction of the chelating ligand H-PyTFP in the dimeric framework of [Al(O(t)Bu)3]2 enhanced the stability against hydrolyses significantly. The tendency of Al(III) centers to preferably coordinate in Td or Oh environment was elucidated by hydrolysis studies of monomeric Al(PyTFP)3, Al(BOTFP)3, and MeAl(BTTFP)2 that produced hydroxo-bridged dimers to retain the octahedral environment for Al atoms. Surprisingly, hydrolysis of monomeric MeAl(DMTTFP)2 yielded an oxo-bridged dimer with two five-fold coordinated aluminum centers. The structural features of all new complexes were investigated in solution, vapor, and solid state by multinuclear NMR spectroscopy, EI-MS spectrometry, and single crystal X-ray diffraction analyses, respectively. PMID- 25525668 TI - Mineral, fiber, and total phenolic retention in eight fruits and vegetables: a comparison of refrigerated and frozen storage. AB - Minerals, total phenolics, and fiber were analyzed in several fruit and vegetable commodities to evaluate the differences between fresh and frozen produce. Magnesium, calcium, iron, zinc, and copper were evaluated in corn, carrots, broccoli, spinach, peas, green beans, strawberries, and blueberries. Each commodity was harvested fresh and split into two batches. Half of each commodity was kept fresh, and the other half was frozen. The nutrient content was analyzed over three storage times per treatment. The retention of nutrients was highly dependent on the commodity, but the majority of the commodities showed no significant difference between fresh and frozen for all analytes (p <= 0.05). PMID- 25525669 TI - In situ amplification of intracellular microRNA with MNAzyme nanodevices for multiplexed imaging, logic operation, and controlled drug release. AB - MicroRNAs (miRNAs), as key regulators in gene expression networks, have participated in many biological processes, including cancer initiation, progression, and metastasis, indicative of potential diagnostic biomarkers and therapeutic targets. To tackle the low abundance of miRNAs in a single cell, we have developed programmable nanodevices with MNAzymes to realize stringent recognition and in situ amplification of intracellular miRNAs for multiplexed detection and controlled drug release. As a proof of concept, miR-21 and miR-145, respectively up- and down-expressed in most tumor tissues, were selected as endogenous cancer indicators and therapy triggers to test the efficacy of the photothermal nanodevices. The sequence programmability and specificity of MNAzyme motifs enabled the fluorescent turn-on probes not only to sensitively profile the distributions of miR-21/miR-145 in cell lysates of HeLa, HL-60, and NIH 3T3 (9632/0, 14147/0, 2047/421 copies per cell, respectively) but also to visualize trace amounts of miRNAs in a single cell, allowing logic operation for graded cancer risk assessment and dynamic monitoring of therapy response by confocal microscopy and flow cytometry. Furthermore, through general molecular design, the MNAzyme motifs could serve as three-dimensional gatekeepers to lock the doxorubicin inside the nanocarriers. The drug nanocarriers were exclusively internalized into the target tumor cells via aptamer-guided recognition and reopened by the endogenous miRNAs, where the drug release rates could be spatial temporally controlled by the modulation of miRNA expression. Integrated with miRNA profiling techniques, the designed nanodevices can provide general strategy for disease diagnosis, prognosis, and combination treatment with chemotherapy and gene therapy. PMID- 25525670 TI - Polyacetylenes of marine origin: chemistry and bioactivity. PMID- 25525671 TI - Are protein folding intermediates the evolutionary consequence of functional constraints? AB - High-resolution experiments on several apparently two-state proteins point to the existence of partially structured excited- or intermediate-states in dynamic equilibrium with native states. Are these intermediate states the byproducts of functional constraints that are by necessity evolutionarily conserved or are they merely the hidden imprints of evolutionary processes? To investigate this, we characterize the folding of Barstar that has a rich history of complex conformational behavior employing a combination of methods-statistical-mechanical model, electrostatic calculations, MD simulations and multiple-sequence alignment that provide a detailed yet consistent view of its landscape in agreement with experiments. We find that the multistate folding in Barstar is the direct consequence of a strong evolutionary pressure to maintain its binding affinity with Barnase through a large negative electrostatic potential on one face. A single mutation (E76K or E80K) at the binding site is shown to not only enhance the native-state stability but also alter the Barstar folding mechanism to resemble an unfrustrated two-state-like system. Our results argue that though natural proteins are expected to be minimally frustrated, functional constraints can singularly determine the folding mechanism even if it occurs at the expense of frustrated multistate folding. PMID- 25525672 TI - Comparing effects in regular practice of e-communication and Web-based self management support among breast cancer patients: preliminary results from a randomized controlled trial. AB - BACKGROUND: While Web-based interventions have been shown to assist a wide range of patients successfully in managing their illness, few studies have examined the relative contribution of different Web-based components to improve outcomes. Further efficacy trials are needed to test the effects of Web support when offered as a part of routine care. OBJECTIVE: Our aim was to compare in regular care the effects of (1) an Internet-based patient provider communication service (IPPC), (2) WebChoice, a Web-based illness management system for breast cancer patients (IPPC included), and (3) usual care on symptom distress, anxiety, depression, (primary outcomes), and self-efficacy (secondary outcome). This study reports preliminary findings from 6 months' follow-up data in a 12-month trial. METHODS: We recruited 167 patients recently diagnosed with breast cancer and undergoing treatment from three Norwegian hospitals. The nurse-administered IPPC allowed patients to send secure e-messages to and receive e-messages from health care personnel at the hospital where they were treated. In addition to the IPPC, WebChoice contains components for symptom monitoring, tailored information and self-management support, a diary, and communication with other patients. A total of 20 care providers (11 nurses, 6 physicians, and 3 social workers) were trained to answer questions from patients. Outcomes were measured with questionnaires at study entry and at study months 2, 4, and 6. Linear mixed models for repeated measures were fitted to compare effects on outcomes over time. RESULTS: Patients were randomly assigned to the WebChoice group (n=64), the IPPC group (n=45), or the usual care group (n=58). Response rates to questionnaires were 73.7% (123/167) at 2 months, 65.9 (110/167) at 4 months, and 62.3% (104/167) at 6 months. Attrition was similar in all study groups. Among those with access to WebChoice, 64% (41/64) logged on more than once and 39% (25/64) sent e-messages to care providers. In the IPPC group, 40% (18/45) sent e-messages. Linear mixed models analyses revealed that the WebChoice group reported significantly lower symptom distress (mean difference 0.16, 95% CI 0.06-0.25, P=.001), anxiety (mean difference 0.79, 95% CI 0.09-1.49, P=.03), and depression (mean difference 0.79, 95% CI 0.09-1.49, P=.03) compared with the usual care group. The IPPC group reported significant lower depression scores compared with the usual care group (mean difference 0.69, 95% CI 0.05-1.32, P=.03), but no differences were observed for symptom distress or anxiety. No significant differences in self-efficacy were found among the study groups. CONCLUSIONS: In spite of practice variations and moderate use of the interventions, our results suggest that offering Web support as part of regular care can be a powerful tool to help patients manage their illness. Our finding that a nurse-administered IPPC alone can significantly reduce depression is particularly promising. However, the multicomponent intervention WebChoice had additional positive effects. TRIAL REGISTRATION: Clinicaltrials.gov:NCT00971009; http://clinicaltrials.gov/show/NCT00971009 (Archived by WebCite at http://www.webcitation.org/6USKezP0Y). PMID- 25525674 TI - Dip-pen nanolithography-assisted protein crystallization. AB - We demonstrate the use of dip-pen nanolithography (DPN) to crystallize proteins on surface-localized functionalized lipid layer arrays. DOPC lipid layers, containing small amounts of biotin-DOPE lipid molecules, were printed on glass substrates and evaluated in vapor diffusion and batch crystallization screening setups, where streptavidin was used as a model protein for crystallization. Independently of the crystallization system used and the geometry of the lipid layers, nucleation of streptavidin crystals occurred specifically on the DPN printed biotinylated structures. Protein crystallization on lipid array patches is also demonstrated in a microfluidic chip, which opens the way toward high throughput screening to find suitable nucleation and crystal growth conditions. The results demonstrate the use of DPN in directing and inducing protein crystallization on specific surface locations. PMID- 25525673 TI - SHIP1-expressing mesenchymal stem cells regulate hematopoietic stem cell homeostasis and lineage commitment during aging. AB - Hematopoietic stem cell (HSC) self-renewal and lineage choice are subject to intrinsic control. However, this intrinsic regulation is also impacted by external cues provided by niche cells. There are multiple cellular components that participate in HSC support with the mesenchymal stem cell (MSC) playing a pivotal role. We had previously identified a role for SH2 domain-containing inositol 5'-phosphatase-1 (SHIP1) in HSC niche function through analysis of mice with germline or induced SHIP1 deficiency. In this study, we show that the HSC compartment expands significantly when aged in a niche that contains SHIP1 deficient MSC; however, this expanded HSC compartment exhibits a strong bias toward myeloid differentiation. In addition, we show that SHIP1 prevents chronic G-CSF production by the aging MSC compartment. These findings demonstrate that intracellular signaling by SHIP1 in MSC is critical for the control of HSC output and lineage commitment during aging. These studies increase our understanding of how myeloid bias occurs in aging and thus could have implications for the development of myeloproliferative disease in aging. PMID- 25525676 TI - Influence of the oxygen plasma parameters on the atomic layer deposition of titanium dioxide. AB - The influence of the oxygen plasma parameters on the morphology and optical properties of TiO2 thin films has been extensively analyzed in plasma enhanced atomic layer deposition (PEALD) processes. Crystalline aggregates with the anatase phase have been identified on the film surface at a low deposition temperature (down to 70 degrees C) under specific plasma conditions. Up to 70% surface coverage by anatase crystallites is obtained at low oxygen gas flow rates and high plasma power. The hillocks abundance is correlated with high ion flux and electron density and with the resulting enhanced ion bombardment of the surface. Altering the plasma conditions is an important parameter besides temperature to control the morphology of the titania film for specific applications such as photocatalysis or functional optical coatings. Specifically, photocatalytic titania coatings on polymer substrates could benefit of such low temperature PEALD processes with abundant anatase crystallites; whereas optical coatings require smooth, high refractive index titania as obtained with low plasma power and high oxygen flow rate. PMID- 25525675 TI - Versatile microfluidic droplets array for bioanalysis. AB - We propose a novel method to obtain versatile droplets arrays on a regional hydrophilic chip that is fabricated by PDMS soft lithography and regional plasma treatment. It enables rapid liquid dispensation and droplets array formation just making the chip surface in contact with solution. By combining this chip with a special Christmas Tree structure, the droplets array with concentrations in gradient is generated. It possesses the greatly improved performance of convenience and versatility in bioscreening and biosensing. For example, high throughput condition screening of toxic tests of CdSe quantum dots on HL-60 cells are conducted and cell death rates are successfully counted quickly and efficiently. Furthermore, a rapid biosensing approach for cancer biomarkers carcinoma embryonic antigen (CEA) is developed via magnetic beads (MBs)-based sandwich immunoassay methods. PMID- 25525677 TI - [We are sorcerers]. PMID- 25525678 TI - [Health risk railroad noise - prognosis of potential health risks subsequent to night-time exposure to railroad noise in the German part of the Transversal Rotterdam Genova]. AB - Based on risk coefficients for cardiovascular and psychiatric disease derived from a case-control study in the vicinity of a major German airport, statistics on persons exposed to night-time railroad noise in the vicinity of the Rotterdam Genova Transversal, and on health expenditure calculations by the Federal Statistical Office of Germany a prognosis on effects of railroad noise was performed. It resulted for 1 10-year period in nearly 75 000 excess cases of diseases, nearly 30 000 excess deaths and health expenditures of 3.8 billion euros. PMID- 25525679 TI - [A registry of registries and cohorts: recommendations for metadata and policies]. AB - Registries and cohort studies play a central role in patient-oriented medical research, in particular in health services research. In order to increase the transparency about ongoing registries and cohort studies in Germany, and to promote communication and cooperation between the drivers in the field a so called register portal should be established. Metadata are characteristics that are used to describe registries and cohort studies in the register portal. A limited set of characteristics, the core set, should correctly describe the projects on the one hand while reducing workload for data capture and data administration on the other hand. The core set consists of 26 data elements that had been defined in a Delphi-consensus process involving experts from the working group registries of the German Network for Health Services Research (DNVF) and the working group IT infrastructure and quality management of the Technology, Methods, and Infrastructure for Networked Medical Research (TMF). Transparent policies are required to guarantee traceability and reliability of the portal's services. Six so-called top-level-tasks and 37 use cases were defined in an interim report so far. The metadata have been agreed upon by most of the member associations of the DNVF. Metadata and rules of procedures are the starting point for the practical implementation of the register portal in the next future. PMID- 25525680 TI - [An introduction to causality principles in biomedical research]. PMID- 25525681 TI - A unique capsular polysaccharide structure from the psychrophilic marine bacterium Colwellia psychrerythraea 34H that mimics antifreeze (glyco)proteins. AB - The low temperatures of polar regions and high-altitude environments, especially icy habitats, present challenges for many microorganisms. Their ability to live under subfreezing conditions implies the production of compounds conferring cryotolerance. Colwellia psychrerythraea 34H, a gamma-proteobacterium isolated from subzero Arctic marine sediments, provides a model for the study of life in cold environments. We report here the identification and detailed molecular primary and secondary structures of capsular polysaccharide from C. psychrerythraea 34H cells. The polymer was isolated in the water layer when cells were extracted by phenol/water and characterized by one- and two-dimensional NMR spectroscopy together with chemical analysis. Molecular mechanics and dynamics calculations were also performed. The polysaccharide consists of a tetrasaccharidic repeating unit containing two amino sugars and two uronic acids bearing threonine as substituent. The structural features of this unique polysaccharide resemble those present in antifreeze proteins and glycoproteins. These results suggest a possible correlation between the capsule structure and the ability of C. psychrerythraea to colonize subfreezing marine environments. PMID- 25525682 TI - Care of the transgender patient: a survey of gynecologists' current knowledge and practice. AB - BACKGROUND: Medical school and residency curricula are lacking in content on the care of the transgender patient. As a result, many providers do not have enough experience and knowledge to adequately care for this patient population. The aim of this study was to assess gynecologists' preferences and knowledge base with regard to transgender healthcare. METHODS: This was a cross-sectional survey of obstetrics and gynecology (OBGYN) providers. An anonymous survey was sent via electronic mail to nine academic OBGYN departments across the United States. Survey questions were designed to assess provider experience and practice environment, education about transgender health practices, personal experience with transgender patients, and knowledge base regarding current recommendations for the care of gender minority patients. RESULTS: Of the 352 providers who received the survey, 141 responded, for a 40.1% response rate. Of the respondents, 61.7% (87 of 141) were generalist OBGYNs, and 86% (117 of 136) practiced in an academic institution; 80% (113 of 141) did not receive training in residency on the care of transgender patients. Time in practice was not associated with having learned about transgender care. Only 35.3% and 29% were comfortable caring for male-to-female and female-to-male transsexual patients, respectively; and, 88.7% and 80.4% were willing to perform screening Pap smears on female-to-male transsexual patients and routine breast examinations on male-to female patients, respectively. Eighty-two of 138 providers (59.4%) did not know the recommendations for breast cancer screening in male-to-female patients. CONCLUSIONS: Efforts should be made to educate trainees on the important aspects of transgender care, and comprehensive guidelines should be published for practicing providers. PMID- 25525683 TI - Aflatoxin control in maize by Trametes versicolor. AB - Aspergillus flavus is a well-known ubiquitous fungus able to contaminate both in pre- and postharvest period different feed and food commodities. During their growth, these fungi can synthesise aflatoxins, secondary metabolites highly hazardous for animal and human health. The requirement of products with low impact on the environment and on human health, able to control aflatoxin production, has increased. In this work the effect of the basidiomycete Trametes versicolor on the aflatoxin production by A. flavus both in vitro and in maize, was investigated. The goal was to propose an environmental loyal tool for a significant control of aflatoxin production, in order to obtain feedstuffs and feed with a high standard of quality and safety to enhance the wellbeing of dairy cows. The presence of T. versicolor, grown on sugar beet pulp, inhibited the production of aflatoxin B1 in maize by A. flavus. Furthermore, treatment of contaminated maize with culture filtrates of T. versicolor containing ligninolytic enzymes, showed a significant reduction of the content of aflatoxin B1. PMID- 25525684 TI - Transfer of ochratoxin A into tea and coffee beverages. AB - Ochratoxin A (OTA) is nephrotoxic, hepatotoxic, immunotoxic, neurotoxic, reprotoxic, teratogenic, and carcinogenic (group 2B), being characterized by species and sex differences in sensitivity. Despite the fact that OTA is in some aspects a controversial topic, OTA is the most powerful renal carcinogen. The aim of this study was to make a small survey concerning OTA content in black tea, fruit tea, and ground roasted coffee, and to assess OTA transfer into beverages. OTA content was measured using a validated and accredited HPLC-FLD method with a limit of quantification (LOQ) of 0.35 ng/g. The OTA amount ranged from LOQ up to 250 ng/g in black tea and up to 104 ng/g in fruit tea. Black tea and fruit tea, naturally contaminated, were used to prepare tea infusions. The transfer from black tea to the infusion was 34.8% +/- 1.3% and from fruit tea 4.1% +/- 0.2%. Ground roasted coffee naturally contaminated at 0.92 ng/g was used to prepare seven kinds of coffee beverages. Depending on the type of process used, OTA transfer into coffee ranged from 22.3% to 66.1%. OTA intakes from fruit and black tea or coffee represent a non-negligible human source. PMID- 25525685 TI - Peripheral limb vascular malformations: an update of appropriate imaging and treatment options of a challenging condition. AB - Peripheral vascular malformations encompass a wide spectrum of lesions that can present as an incidental finding or produce potentially life- or limb-threatening complications. They can have intra-articular and intraosseous extensions that will result in more diverse symptomology and present greater therapeutic challenges. Developments in classification, imaging and interventional techniques have helped to improve outcome. The onus is now placed on appropriate detailed preliminary imaging, diagnosis and classification to direct management and exclude other more common mimics. Radiologists are thus playing an increasingly important role in the multidisciplinary teams charged with the care of these patients. By fully understanding the imaging characteristics and image-guided procedures available, radiologists will be armed with the tools to meet these responsibilities. This review highlights the recent advances made in imaging and the options available in interventional therapy. PMID- 25525687 TI - Angioinvasive aspergillosis of the central nervous system. PMID- 25525688 TI - Meso-ordered PEG-based particles. AB - We report on the formation of meso-ordered hydrogel particles by cross-linking poly(ethylene glycol) diacrylate (PEG-DA) in the presence of surfactants in a confined environment. The results demonstrated that well-ordered mesoporous hydrogel particles having a pore size of about 5 nm could be formed. It is suggested that these meso-ordered hydrogel particles might have unique drug delivery capabilities. PMID- 25525686 TI - Neurotransmitter Systems in a Mild Blast Traumatic Brain Injury Model: Catecholamines and Serotonin. AB - Exposure to improvised explosive devices can result in a unique form of traumatic brain injury--blast-induced traumatic brain injury (bTBI). At the mild end of the spectrum (mild bTBI [mbTBI]), there are cognitive and mood disturbances. Similar symptoms have been observed in post-traumatic stress disorder caused by exposure to extreme psychological stress without physical injury. A role of the monoaminergic system in mood regulation and stress is well established but its involvement in mbTBI is not well understood. To address this gap, we used a rodent model of mbTBI and detected a decrease in immobility behavior in the forced swim test at 1 d post-exposure, coupled with an increase in climbing behavior, but not after 14 d or later, possibly indicating a transient increase in anxiety-like behavior. Using in situ hybridization, we found elevated messenger ribonucleic acid levels of both tyrosine hydroxylase and tryptophan hydroxylase 2 in the locus coeruleus and the dorsal raphe nucleus, respectively, as early as 2 h post-exposure. High-performance liquid chromatography analysis 1 d post-exposure primarily showed elevated noradrenaline levels in several forebrain regions. Taken together, we report that exposure to mild blast results in transient changes in both anxiety-like behavior and brain region-specific molecular changes, implicating the monoaminergic system in the pathobiology of mbTBI. PMID- 25525689 TI - Highly stable piezo-immunoglobulin-biosensing of a SiO2/ZnO nanogenerator as a self-powered/active biosensor arising from the field effect influenced piezoelectric screening effect. AB - Highly stable piezo-immunoglobulin-biosensing has been realized from a SiO2/ZnO nanowire (NW) nanogenerator (NG) as a self-powered/active biosensor. The piezoelectric output generated by the SiO2/ZnO NW NG can act not only as a power source for driving the device, but also as a sensing signal for detecting immunoglobulin G (IgG). The stability of the device is very high, and the relative standard deviation (RSD) ranges from 1.20% to 4.20%. The limit of detection (LOD) of IgG on the device can reach 5.7 ng mL(-1). The response of the device is in a linear relationship with IgG concentration. The biosensing performance of SiO2/ZnO NWs is much higher than that of bare ZnO NWs. A SiO2 layer uniformly coated on the surface of the ZnO NW acts as the gate insulation layer, which increases mechanical robustness and protects it from the electrical leakages and short circuits. The IgG biomolecules modified on the surface of the SiO2/ZnO NW act as a gate potential, and the field effect can influence the surface electron density of ZnO NWs, which varies the screening effect of free carriers on the piezoelectric output. The present results demonstrate a feasible approach for a highly stable self-powered/active biosensor. PMID- 25525690 TI - Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia. AB - BACKGROUND: Peripheral arterial disease is a major health problem, and in about 1% to 2% of patients the disease progresses to critical limb ischaemia (CLI). In a substantial number of patients with CLI, no effective treatment option other than amputation is available and around a quarter of these patients will require a major amputation during the following year. This is an update of the review first published in 2011. OBJECTIVES: To determine the effectiveness and safety of local intramuscular transplantation of autologous adult bone marrow mononuclear cells (BMMNCs) as a treatment for critical limb ischaemia (CLI). SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co ordinator searched the Specialised Register (last searched February 2014) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 1). SELECTION CRITERIA: We included all randomised controlled trials of CLI in which participants were randomly allocated to intramuscular administration of autologous adult BMMNCs or control (either no intervention or conventional conservative therapy). We excluded studies on patients with intermittent claudication. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data. Disagreements were resolved by consensus or by the third author. MAIN RESULTS: Only two small studies, with a combined total of 57 participants, met our inclusion criteria and were finally included. They were classified as having a moderate risk of bias with unclear issues regarding their methods, and according to the GRADE approach, the overall quality of the evidence would be considered as moderate. In one study the effects of intramuscular injections of BMMNCs in the ischaemic lower limbs of patients with CLI were compared with control (standard conservative treatment). No deaths were reported and no significant difference was observed between the two groups for either pain (P = 0.37) or the ankle brachial index (ABI) parameter. However, the treatment group showed a significantly smaller proportion of participants undergoing amputation compared with the control group (P = 0.026).In the other study, following subcutaneous injections of granulocyte colony-stimulating factor (G-CSF) for five days, peripheral blood derived mononuclear cells were collected and then transplanted by intramuscular injections into ischaemic lower limbs. The effects were compared with daily intravenous prostaglandin E1 injections (control group). No deaths were reported. Pain reduction was greater in the treatment group than in the control group (P < 0.001) as was increase in ABI (mean increase 0.13 versus 0.02, P < 0.01). The treatment group experienced a statistically significant increase in pain-free walking distance (PFWD) compared with the control group (mean increase 306.4 m versus 78.6 m, P = 0.007). A smaller proportion of participants underwent amputation in the treatment group compared with the control group (0% versus 36%, P = 0.007). AUTHORS' CONCLUSIONS: The data from the published trials suggest that there is insufficient evidence to support this treatment. These results were based on only two trials which had a very small number of participants. Therefore evidence from larger randomised controlled trials is needed in order to provide adequate statistical power to assess the role of intramuscular mononuclear cell implantation in patients with CLI. PMID- 25525691 TI - Reduced-Size Integer Linear Programming Models for String Selection Problems: Application to the Farthest String Problem. AB - We present integer programming models for some variants of the farthest string problem. The number of variables and constraints is substantially less than that of the integer linear programming models known in the literature. Moreover, the solution of the linear programming-relaxation contains only a small proportion of noninteger values, which considerably simplifies the rounding process. Numerical tests have shown excellent results, especially when a small set of long sequences is given. PMID- 25525692 TI - Rates and predictors of 5-year survival in a national cohort of asymptomatic elderly patients undergoing carotid revascularization. AB - BACKGROUND: Current American Heart Association guidelines recommend carotid revascularization for asymptomatic patients on the basis of life expectancy. OBJECTIVE: To determine the rates and predictors of 5-year survival in elderly patients with asymptomatic carotid artery stenosis who underwent either carotid artery stent placement (CAS) or carotid endarterectomy (CEA). METHODS: The rates of 5-year survival were determined by use of Kaplan-Meier survival methods in a representative sample of fee-for-service Medicare beneficiaries >=65 years of age who underwent CAS or CEA for asymptomatic carotid artery stenosis with postprocedural follow-up of 3.4 +/- 1.7 years. Cox proportional hazards analysis was used to assess the relative risk of all-cause mortality for patients in the presence of selected comorbidities, including ischemic heart disease, chronic renal failure, and atrial fibrillation, after adjustment for potential confounders such as age, sex, race/ethnicity, and procedure type. RESULTS: A total of 22,177 patients with asymptomatic carotid artery stenosis were treated with either CAS (n = 2144) or CEA (n = 20,033). The overall estimated 5-year survival rate (+/-SE) was 95.3 +/- 0.00149; it was 95.5% and 93.8% in patients treated with CEA and CAS, respectively. After adjustment for potential confounders, relative risk of all-cause 5-year mortality was significantly higher among patients with atrial fibrillation (relative risk, 1.8; 95% confidence interval, 1.5-2.1) and those with chronic renal failure (relative risk, 2.1; 95% confidence interval, 1.7-2.6). CONCLUSION: Risks and benefits must be carefully weighed before carotid revascularization in elderly patients with asymptomatic carotid artery stenosis who have concurrent atrial fibrillation or chronic renal failure. PMID- 25525694 TI - Traumatic brain injuries: the influence of the direction of impact. AB - BACKGROUND: Head impact direction has been identified as an influential risk factor in the risk of traumatic brain injury (TBI) from animal and anatomic research; however, to date, there has been little investigation into this relationship in human subjects. If a susceptibility to certain types of TBI based on impact direction was found to exist in humans, it would aid in clinical diagnoses as well as prevention methods for these types of injuries. OBJECTIVE: To examine the influence of impact direction on the presence of TBI lesions, specifically, subdural hematomas, subarachnoid hemorrhage, and parenchymal contusions. METHODS: Twenty reconstructions of falls that resulted in a TBI were conducted in a laboratory based on eyewitness, interview, and medical reports. The reconstructions involved impacts to a Hybrid III anthropometric dummy and finite element modeling of the human head to evaluate the brain stresses and strains for each TBI event. RESULTS: The results showed that it is likely that increased risk of incurring a subdural hematoma exists from impacts to the frontal or occipital regions, and parenchymal contusions from impacts to the side of the head. There was no definitive link between impact direction and subarachnoid hemorrhage. In addition, the results indicate that there is a continuum of stresses and strain magnitudes between lesion types when impact location is isolated, with subdural hematoma occurring at lower magnitudes for frontal and occipital region impacts, and contusions lower for impacts to the side. CONCLUSION: This hospital data set suggests that there is an effect that impact direction has on TBI depending on the anatomy involved for each particular lesion. PMID- 25525708 TI - Carbon nanotubes reinforced poly(L-lactide) scaffolds fabricated by thermally induced phase separation. AB - In tissue engineering, porous nanocomposite scaffolds can potentially mimic aspects of the nanoscale architecture of the extra-cellular matrix, as well as enhance the mechanical properties required for successful weight-bearing implants. In this paper, we demonstrate that highly porous thermoplastic poly(L lactide) nanocomposite scaffolds containing different types of functionalized multi-walled carbon nanotubes (CNTs). The nanocomposite scaffolds were manufactured by a thermally induced phase separation method. This experiment produced an uniform distribution of CNTs throughout the scaffold without obvious aggregations for funtionalized CNTs filled scaffolds by scanning electron microscope observation. The CNTs were frequently located on the pore surface, forming rough, hairy nano-textures. The pore size was reduced with the increasing of CNT loading. Parts of PLLA matrix was induced into nanofibrous structures from solid-walled state, which reduced the crystallinity of the PLLA characterized by DSC measurement. The CNT incorporation significantly improved the compression modulus of the nanocomposite scaffolds, especially the functionalized CNTs. The capacity of protein adsorption is significantly improved when the concentration of the CNTs was higher than 1.0 wt.% and the cell attachment was also enhanced by the addition of CNTs, especially N-CNT. PMID- 25525695 TI - Cerebral hypoperfusion-assisted intra-arterial deposition of liposomes in normal and glioma-bearing rats. AB - BACKGROUND: Optimizing liposomal vehicles for targeted delivery to the brain has important implications for the treatment of brain tumors. The promise of efficient, brain-specific delivery of chemotherapeutic compounds via liposomal vehicles has yet to be achieved in clinical practice. Intra-arterial injection of specially designed liposomes may facilitate efficient delivery to the brain and to gliomas. OBJECTIVE: To test the hypothesis that cationic liposomes may be effectively delivered to both normal and glioma-bearing brain tissue utilizing a strategy of intra-arterial injection during transient cerebral hypoperfusion. METHODS: Cationic, anionic, and neutral liposomes were separately injected via the internal carotid artery of healthy rats during transient cerebral hypoperfusion. Rats bearing C6 gliomas were similarly injected with cationic liposomes. Liposomes were loaded with DilC18(5) dye whose concentrations can be measured by light absorbance and fluorescence methods. RESULTS: After intra arterial injection, a robust uptake of cationic in comparison with anionic and neutral liposomes into brain parenchyma was observed by diffuse reflectance spectroscopy. Postmortem multispectral fluorescence imaging revealed that liposomal cationic charge was associated with more efficient delivery to the brain. Cationic liposomes were also readily observed within glioma tissue after intra-arterial injection. However, over time, cationic liposomes were retained longer and at higher concentrations in the surrounding, peritumoral brain than in the tumor core. CONCLUSION: This study demonstrates the feasibility of cationic liposome delivery to brain and glioma tissue after intra-arterial injection. Highly cationic liposomes directly delivered to the brain via an intracarotid route may represent an effective method for delivering antiglioma agents. PMID- 25525709 TI - Palladium-catalyzed asymmetric cycloadditions of vinylcyclopropanes and in situ formed unsaturated imines: construction of structurally and optically enriched spiroindolenines. AB - A palladium-catalyzed (3 + 2) cycloaddition of vinyl cyclopropane and alpha,beta unsaturated imines generated in situ from aryl sulfonyl indoles is reported. The reaction proceeds with high diastereoselectivity to provide the optically enriched spirocyclopentane-1,3'-indolenines in up to 74% yield and with up to 97% ee, which contains an all-carbon quaternary center and two tertiary stereocenters. The reaction involves a first conjugate addition of the carbon anion of zwitterionic pi-allylpalladium complex from vinyl cyclopropane to the in situ formed unsaturated imine followed by a palladium-catalyzed intramolecular C3 allylation of indole. PMID- 25525710 TI - Biomass burning contributions estimated by synergistic coupling of daily and hourly aerosol composition records. AB - Biomass burning (BB) is a significant source of particulate matter (PM) in many parts of the world. Whereas numerous studies demonstrate the relevance of BB emissions in central and northern Europe, the quantification of this source has been assessed only in few cities in southern European countries. In this work, the application of Positive Matrix Factorisation (PMF) allowed a clear identification and quantification of an unexpected very high biomass burning contribution in Tuscany (central Italy), in the most polluted site of the PATOS project. In this urban background site, BB accounted for 37% of the mass of PM10 (particulate matter with aerodynamic diameter<10 MUm) as annual average, and more than 50% during winter, being the main cause of all the PM10 limit exceedances. Due to the chemical complexity of BB emissions, an accurate assessment of this source contribution is not always easily achievable using just a single tracer. The present work takes advantage of the combination of a long-term daily data set, characterized by an extended chemical speciation, with a short-term high time resolution (1-hour) and size-segregated data-set, obtained by PIXE analyses of streaker samples. The hourly time pattern of the BB source, characterised by a periodic behaviour with peaks starting at about 6 p.m. and lasting all the evening-night, and its strong seasonality, with higher values in the winter period, clearly confirmed the hypothesis of a domestic heating source (also excluding important contributions from wildfires and agricultural wastes burning). PMID- 25525711 TI - Effect of zinc and glucosinolates on nutritional quality of Noccaea caerulescens and infestation by Aleyrodes proletella. AB - The Zn hyperaccumulating plant, Noccaea caerulescens, was grown under controlled conditions at a range of Zn concentrations (0-1000 mg kg(-1) dwt. soil) to determine the effectiveness of hyperaccumulation in deterring the cabbage whitefly, Aleyrodes proletella, and to establish the relationship between levels of foliar Zn and glucosinolates (organic defence compounds). Two weeks after introducing A. proletella adults to the plants, next generation nymphs were quantified. This sucking insect caused minimal damage to plant tissue and did not affect foliar glucosinolate levels. Foliar Zn concentrations increased with increasing soil Zn application and reached a maximum of ~7000 mg kg(-1). More whitefly nymphs were observed on plants as the foliar Zn concentration increased (up to ~3000 mg kg(-1)) after which numbers declined. Zn was an explanatory variable in accumulated generalised linear regression after the variation in the data due to C/N ratio had been accounted for. Nymph numbers declined with increasing C/N ratio and increased with increasing N concentration. The highest glucosinolate concentrations were in shoots with the lowest Zn concentrations; this is consistent with the 'trade-off' hypothesis which states that elemental defence mechanisms allow for lowered organic defences. PMID- 25525712 TI - Atmospheric wet deposition of sulfur and nitrogen in Jiuzhaigou National Nature Reserve, Sichuan Province, China. AB - In the last two decades, remarkable ecological changes have been observed in Jiuzhaigou National Nature Reserve (JNNR). Some of these changes might be related to excessive deposition of sulfur (S) and nitrogen (N), but the relationship has not been quantified due to lack of monitoring data, particularly S and N deposition data. In this study, we investigated the concentrations, fluxes, and sources of S and N wet deposition in JNNR from April 2010 to May 2011. The results show that SO4(2-), NO3-, and NH4+ concentrations in the wet deposition were 39.4-170.5, 6.2-34.8, and 0.2-61.2 MUeq L(-1), with annual Volume-Weighted Mean (VWM) concentrations of 70.5, 12.7, and 13.4 MUeq L(-1), respectively. Annual wet deposition fluxes of SO4(2-), NO3-, and NH4+ were 8.06, 1.29, and 1.39 kg S(N)ha(-1), respectively, accounting for about 90% of annual atmospheric inputs of these species at the monitoring site. The results of Positive Matrix Factorization (PMF) analysis show that fossil fuel combustion, agriculture, and aged sea salt contributed to 99% and 83% of annual wet deposition fluxes of SO4(2 ) and NO3-, respectively. Agriculture alone contributed to 89% of annual wet deposition flux of NH4+. Although wet deposition in JNNR was polluted by anthropogenic acids, the acidity was largely neutralized by the Ca2+ from crust and 81% of wet deposition samples had a pH higher than 6.00. However, acid rain mainly caused by SO4(2-) continued to occur in the wet season, when ambient alkaline dust concentration was lower. Since anthropogenic emissions have elevated S and N deposition and caused acid rain in JNNR, further studies are needed to better quantify the regional sources and ecological effects of S and N deposition for JNNR. PMID- 25525713 TI - Self-recovering caddisfly silk: energy dissipating, Ca(2+)-dependent, double dynamic network fibers. AB - Single fibers of the sticky underwater larval silk of the casemaker caddisfly (H. occidentalis) are viscoelastic, display large strain cycle hysteresis, and self recover 99% of their initial stiffness and strength within 120 min. Mechanical response to cyclical strains suggested viscoelasticity is due to two independent, self-recovering Ca(2+)-crosslinked networks. The networks display distinct pH dependence. The first network is attributed to Ca(2+)-stabilized phosphoserine motifs in H-fibroin, the second to Ca(2+) complexed carboxylate groups in the N terminus of H-fibroin and a PEVK-like protein. These assignments were corroborated by IR spectroscopy. The results are consolidated into a multi network model in which reversible rupture of the Ca(2+)-crosslinked domains at a critical stress results in pseudo-plastic deformation. Slow refolding of the domains results in nearly full recovery of fiber length, stiffness, and strength. The fiber toughening, energy dissipation, and recovery mechanisms, are highly adaptive for the high energy aquatic environment of caddisfly larvae. PMID- 25525693 TI - Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): a prospective longitudinal observational study. AB - BACKGROUND: Current classification of traumatic brain injury (TBI) is suboptimal, and management is based on weak evidence, with little attempt to personalize treatment. A need exists for new precision medicine and stratified management approaches that incorporate emerging technologies. OBJECTIVE: To improve characterization and classification of TBI and to identify best clinical care, using comparative effectiveness research approaches. METHODS: This multicenter, longitudinal, prospective, observational study in 22 countries across Europe and Israel will collect detailed data from 5400 consenting patients, presenting within 24 hours of injury, with a clinical diagnosis of TBI and an indication for computed tomography. Broader registry-level data collection in approximately 20,000 patients will assess generalizability. Cross sectional comprehensive outcome assessments, including quality of life and neuropsychological testing, will be performed at 6 months. Longitudinal assessments will continue up to 24 months post TBI in patient subsets. Advanced neuroimaging and genomic and biomarker data will be used to improve characterization, and analyses will include neuroinformatics approaches to address variations in process and clinical care. Results will be integrated with living systematic reviews in a process of knowledge transfer. The study initiation was from October to December 2014, and the recruitment period was for 18 to 24 months. EXPECTED OUTCOMES: Collaborative European NeuroTrauma Effectiveness Research in TBI should provide novel multidimensional approaches to TBI characterization and classification, evidence to support treatment recommendations, and benchmarks for quality of care. Data and sample repositories will ensure opportunities for legacy research. DISCUSSION: Comparative effectiveness research provides an alternative to reductionistic clinical trials in restricted patient populations by exploiting differences in biology, care, and outcome to support optimal personalized patient management. PMID- 25525714 TI - Optical behavior of substituted 4-(2'-hydroxyphenyl)imidazoles. AB - A set of tetraarylimidazoles bearing a 2-hydroxyphenyl substituent at position 4, as well as their models lacking intramolecular hydrogen bonds, was efficiently synthesized. Structural investigations proved that the hydrogen bond strength for 4-(2'-hydroxyphenyl)imidazoles is weaker than that for analogous 2-(2' hydroxyphenyl)imidazoles as estimated from dihedral angles and bond distances. Photophysical investigations revealed that these compounds have other properties than those observed for imidazoles bearing a 2-hydroxyphenyl substituent at position 2. They exhibit a negligible fluorescence quantum yield regardless of the solvent polarity. Additionally, dual fluorescence is observed in nonpolar solvents. Plausibly, although a hydrogen bond is present within their chemical structure in the solid state, it is not clear if excited-state intramolecular proton transfer occurs. The presence of OH groups triggers the radiationless deactivation channel if compared with model imidazole possessing a 2 methoxyphenyl group. PMID- 25525716 TI - Intramolecular etherification and polyene cyclization of pi-activated alcohols promoted by hot water. AB - Hot water, acting as a mildly acidic catalyst, efficiently promoted intramolecular direct nucleophilic substitution reactions of unsaturated alcohols with heteroatom or carbon nucleophiles. In a mixed solvent of water and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), polyene cyclizations using allylic alcohols as initiators gave the desired cyclized products, and in neat HFIP, a tricyclization reaction gave a tetracyclic product in 51% chemical yield. PMID- 25525715 TI - Allosteric Modulation of GABAA Receptors by an Anilino Enaminone in an Olfactory Center of the Mouse Brain. AB - In an ongoing effort to identify novel drugs that can be used as neurotherapeutic compounds, we have focused on anilino enaminones as potential anticonvulsant agents. Enaminones are organic compounds containing a conjugated system of an amine, an alkene and a ketone. Here, we review the effects of a small library of anilino enaminones on neuronal activity. Our experimental approach employs an olfactory bulb brain slice preparation using whole-cell patch-clamp recording from mitral cells in the main olfactory bulb. The main olfactory bulb is a key integrative center in the olfactory pathway. Mitral cells are the principal output neurons of the main olfactory bulb, receiving olfactory receptor neuron input at their dendrites within glomeruli, and projecting glutamatergic axons through the lateral olfactory tract to the olfactory cortex. The compounds tested are known to be effective in attenuating pentylenetetrazol (PTZ) induced convulsions in rodent models. One compound in particular, KRS-5Me-4-OCF3, evokes potent inhibition of mitral cell activity. Experiments aimed at understanding the cellular mechanism underlying the inhibitory effect revealed that KRS-5Me-4-OCF3 shifts the concentration-response curve for GABA to the left. KRS-5Me-4-OCF3 enhances GABA affinity and acts as a positive allosteric modulator of GABAA receptors. Application of a benzodiazepine site antagonist blocks the effect of KRS-5Me-4-OCF3 indicating that KRS-5Me-4-OCF3 binds at the classical benzodiazepine site to exert its pharmacological action. This anilino enaminone KRS-5Me-4-OCF3 emerges as a candidate for clinical use as an anticonvulsant agent in the battle against epileptic seizures. PMID- 25525717 TI - MALDI-MS-based quantitative analysis for ketone containing homoserine lactones in Pseudomonas aeruginosa. AB - N-Acyl homoserine lactones (AHLs), quorum sensing molecules produced by Gram negative bacteria, are used as important secondary metabolites for antibacterial drug development and cell-to-cell communication. Although various analytical techniques have been developed for detection and quantitation of AHLs from more complex bacterial culture media, only a few methods have been applied to AHL identification in physiological samples. Here, we developed a highly sensitive and reliable MALDI-based 3-oxo AHL quantitation method by employing Girard's reagent T (GT) to produce a permanent cationic charge state [M](+) at the ketone group of AHLs. After extracting AHLs from the supernatant of bacterial cultures using ethyl acetate, the extracts were subsequently derivatized with GT without any additional purification or desalting steps. The chemical derivatization of 3 oxo AHLs dramatically enhanced sensitivity (up to 60 000 times) by lowering the limit of detection (LOD, ~0.5 fmol)/limit of quantitation (LOQ, ~2.5 fmol). Additionally, the GT-derivatized 3-oxo AHLs allowed more accurate quantitative analysis from the Pseudomonas aeruginosa PAO1 culture supernatants. This method may be applied for developing high-throughput and sensitive detection methods of quorum sensing signal molecules in biofilm-related clinical applications such as virulence factor characterization and antibacterial drug development. PMID- 25525718 TI - Metal-support interaction in platinum and palladium nanoparticles loaded on nitrogen-doped mesoporous carbon for oxygen reduction reaction. AB - Mesoporous carbons are highly porous materials, which show large surface area, chemical inertness and electrochemical performances superior to traditional carbon material. In this study, we report the preparation of nitrogen-doped and undoped mesoporous carbons by an optimized hard template procedure employing silica as template, sucrose and ammonia as carbon and nitrogen source, respectively. Surface area measurements assert a value of 900 and 600 m(2) g(-1) for the best doped and undoped samples, respectively. Such supports were then thoroughly characterized by surface science and electron microscopy tools. Afterward, they were decorated with Pt and Pd nanoparticles, and it was found that the presence of nitrogen defects plays a significant role in improving the metal particles dimension and dispersion. In fact, when doped supports are used, the resulting metal nanoparticles are smaller (2-4 nm) and less prone to aggregation. Photoemission measurements give evidence of a binding energy shift, which is consistent with the presence of an electronic interaction between nitrogen atoms and the metal nanoparticles, especially in the case of Pd. The catalytic properties of electrodes decorated with such catalyst/support systems were investigated by linear sweep voltammetry and by rotating disk electrode measurements, revealing excellent stability and good activity toward oxygen reduction reaction (ORR). In particular, although Pd nanoparticles always result in lower activity than Pt ones, both Pt and Pd electrodes based on the N-doped supports show an increased activity toward ORR with respect to the undoped ones. At the same mass loading, the Tafel slope and the stability test of the Pt@N doped electrocatalysts indicate superior performances to that of a commercial Pt@C catalysts (30 wt % Pt on Vulcan XC-72, Johnson Matthey). PMID- 25525724 TI - Twenty-Ninth Transatlantic Airway Conference. Innate and adaptive immune responses in airway disease. Purpose of the conference. PMID- 25525725 TI - Chair's summary: Innate and adaptive immune responses in airway disease. PMID- 25525726 TI - Dendritic cell and epithelial cell interactions at the origin of murine asthma. AB - Dendritic cells (DCs) are ideally placed in the airways and lungs to capture inhaled allergens. Different subsets of DCs perform different tasks. Migratory conventional DCs (cDCs) expressing CD11b mediate Th2 priming to respiratory allergens, whereas cDCs expressing CD103 mediate tolerance to them. Monocyte derived DCs are poorly migratory antigen-presenting cells that mainly produce proinflammatory chemokines and are necessary for maintaining allergic airway inflammation once initiated. The function of the airway DC network is closely controlled by cytokines released from airway epithelial cells. Airway epithelial cells react to pathogen-associated molecular patterns and damage-associated molecular patterns released on allergen inhalation by producing pro-Th2 polarizing cytokines and chemokines that attract and activate DCs. This conceptual framework of epithelial and DC collaboration is very helpful in explaining the process of allergic sensitization and how this is influenced by genetics and environment. PMID- 25525727 TI - Epithelial barrier function and immunity in asthma. AB - The bronchial epithelium is constantly exposed to a wide range of environmental materials present in inhaled air, including noxious gases and anthropogenic and natural particulates, such as gas and particles from car emissions, tobacco smoke, pollens, animal dander, and pathogens. As a fully differentiated, pseudostratified mucociliary epithelium, the bronchial epithelium protects the internal milieu of the lung from these agents by forming a physical barrier involving adhesive complexes and a chemical barrier involving secretion of mucus, which traps inhaled particles that can be cleared by the mucociliary escalator. It is a testament to the effectiveness of these two barriers that most environmental challenges are largely overcome without the need to develop an inflammatory response. However, as the initial cell of contact with the environment, the bronchial epithelium also plays a pivotal role in immune surveillance and appropriate activation of immune effector cells and antigen presenting cells in the presence of pathogens or other danger signals. Thus, the bronchial epithelium plays a central role in controlling tissue homeostasis and innate immunity. This review will discuss these barrier properties and how dysregulation of these homeostatic mechanisms can contribute to disease pathologies such as asthma. PMID- 25525728 TI - Early events in the pathogenesis of chronic obstructive pulmonary disease. Smoking-induced reprogramming of airway epithelial basal progenitor cells. AB - The airway epithelium is the primary site of the earliest pathologic changes induced by smoking, contributing to the development of chronic obstructive pulmonary disease (COPD). The normal human airway epithelium is composed of several major cell types, including differentiated ciliated and secretory cells, intermediate undifferentiated cells, and basal cells (BC). BC contain the stem/progenitor cell population responsible for maintenance of the normally differentiated airway epithelium. Although inflammatory and immune processes play a significant role in the pathogenesis of COPD, the earliest lesions include hyperplasia of the BC population, suggesting that the disease may start with this cell type. Apart from BC hyperplasia, smoking induces a number of COPD-relevant airway epithelial remodeling phenotypes that are likely initiated in the BC population, including mucous cell hyperplasia, squamous cell metaplasia, epithelial-mesenchymal transition, altered ciliated and nonmucous secretory cell differentiation, and suppression of junctional barrier integrity. Significant progress has been recently made in understanding the biology of human airway BC, including gene expression features, stem/progenitor, and other functions, including interaction with other airway cell types. Accumulating evidence suggests that human airway BC function as both sensors and cellular sources of various cytokines and growth factors relevant to smoking-associated airway injury, as well as the origin of various molecular and histological phenotypes relevant to the pathogenesis of COPD. In the context of these considerations, we suggest that early BC-specific smoking-induced molecular changes are critical to the pathogenesis of COPD, and these represent a candidate target for novel therapeutic approaches to prevent COPD progression in susceptible individuals. PMID- 25525729 TI - Apoptosis and engulfment by bronchial epithelial cells. Implications for allergic airway inflammation. AB - Insult or injury to the lung epithelial cells from pathogens, pollutants, and allergens can initiate the process of apoptotic cell death. Although "Creola bodies," which are clusters of uncleared, apoptotic, epithelial cells, have been seen in the sputum of patients with asthma, the clearance of these dying epithelial cells and the consequence of failed clearance in the airway have not been directly addressed. We have observed that bronchial epithelial cells efficiently engulf their apoptotic neighbors and produce antiinflammatory cytokines when engulfing apoptotic cells. Furthermore, when the phagocytic capacity of bronchial epithelial cells was impaired, mice developed severe, IL-33 dependent, allergic airway inflammation. This inflammation could be ameliorated by exogenous administration of the antiinflammatory cytokine IL-10. Our data suggest that the process of apoptotic cell engulfment is a mechanism by which bronchial epithelial cells regulate the inflammatory environment within the lung. Collectively, these studies suggest that impaired engulfment pathways in airway epithelial cells can contribute to allergic airway inflammation and that targeting these pathways may be of benefit in human airway inflammation. PMID- 25525730 TI - Type-2 innate lymphoid cells in asthma and allergy. AB - Type-2 innate lymphoid cells (ILC2) belong to an expanding family of innate lymphocytes that provide a potent source of immune effector cytokines at the initiation of immune responses. ILC2 arise, under the control of the transcription factors RORalpha and GATA3, from lymphoid progenitors in the bone marrow, to secrete type-2 cytokines including IL-5 and IL-13. Using experimental models, ILC2 have been implicated in allergic diseases, such as asthma and atopic dermatitis, but also in metabolic homeostasis. Furthermore, recent reports have indicated that ILC2 not only play roles at the initiation of type-2 immunity but can also contribute to chronic pathology, such as fibrosis, and can impact on the priming of the adaptive T-cell response. The identification of ILC2 in patients with allergic dermatitis and allergic rhinitis indicates that these cells may represent new therapeutic targets. PMID- 25525731 TI - The regulation of pulmonary inflammation by the hypoxia-inducible factor hydroxylase oxygen-sensing pathway. AB - Although the hypoxia-inducible factor (HIF)-hydroxylase oxygen-sensing pathway has been extensively reviewed in the context of cellular responses to hypoxia and cancer biology, its importance in regulating innate immune biology is less well described. In this review, we focus on the role of the HIF-hydroxylase pathway in regulating myeloid cell responses and its relevance to inflammatory lung disease. The more specific roles of individual HIF/ prolyl hydroxylase pathway members in vivo are discussed in the context of lineage-specific rodent models of inflammation, with final reference made to the therapeutic challenges of targeting the HIF/hydroxylase pathway in immune cells. PMID- 25525732 TI - Airway fibrinogenolysis and the initiation of allergic inflammation. AB - The past 15 years of allergic disease research have produced extraordinary improvements in our understanding of the pathogenesis of airway allergic diseases such as asthma. Whereas it was previously viewed as largely an immunoglobulin E mediated process, the gradual recognition that T cells, especially Type 2 T helper (Th2) cells and Th17 cells, play a major role in asthma and related afflictions has inspired clinical trials targeting cytokine-based inflammatory pathways that show great promise. What has yet to be clarified about the pathogenesis of allergic inflammatory disorders, however, are the fundamental initiating factors, both exogenous and endogenous, that drive and sustain B- and T-cell responses that underlie the expression of chronic disease. Here we review how proteinases derived from diverse sources drive allergic responses. A central discovery supporting the proteinase hypothesis of allergic disease pathophysiology is the role played by airway fibrinogen, which in part appears to serve as a sensor of unregulated proteinase activity and which, when cleaved, both participates in a novel allergic signaling pathway through Toll-like receptor 4 and forms fibrin clots that contribute to airway obstruction. Unresolved at present is the ultimate source of airway allergenic proteinases. From among many potential candidates, perhaps the most intriguing is the possibility such enzymes derive from airway fungi. Together, these new findings expand both our knowledge of allergic disease pathophysiology and options for therapeutic intervention. PMID- 25525733 TI - Helper T-cell type 17 cytokines and immunity in the lung. AB - The HIV epidemic has clearly demonstrated the critical role CD4(+) T cells play in preventing opportunistic infections in the lung. The types of CD4(+) effector T-cell populations in the lung have significantly expanded over the last 8-10 years with the discovery of helper T type 17 cells, and this review summarizes the field and discusses how these effector cells may be exploited to augment mucosal immunity in the lung. PMID- 25525735 TI - Mechanisms of peptide immunotherapy in allergic airways disease. AB - Allergen immunotherapy with whole proteins is clinically efficacious but requires a protracted treatment period because of frequent allergic adverse events. A combination of duration of treatment and adverse events leads to poor compliance. Short synthetic peptides containing the major immunodominant T cell epitopes of allergenic proteins have been shown to reduce IgE cross-linking ability, thereby leading to fewer allergic adverse events following their administration to patients with allergies. Peptide immunotherapy has been shown to result in clinically meaningful efficacy in several Phase II, randomized, double-blind, placebo-controlled clinical trials. Exactly how peptide immunotherapy achieves its efficacy remains incompletely understood, but the mechanisms are thought to include immune deviation and induction of regulatory T cells capable of suppressing allergen-specific immune responses. Limited data are available on the effects of peptide therapy on humoral immune responses. Induction of allergen specific IgG has been observed after peptide therapy, but the levels of antibody induced were much lower than generally seen with the utilization of whole allergen approaches. Thus, the immunological mechanisms of peptide immunotherapy appear to overlap, although not completely, with those seen in whole allergen therapy. Further studies are required to fully elucidate mechanisms of action. PMID- 25525734 TI - Linking acute infection to chronic lung disease. The role of IL-33-expressing epithelial progenitor cells. AB - Respiratory infection is a common feature of the major human airway diseases, such as asthma and chronic obstructive pulmonary disease, but the precise link between acute infection and chronic lung disease is still undefined. In a mouse model of this process, parainfluenza virus infection is followed by long-term induction of IL-33 expression and release and in turn innate immune cell generation of IL-13 and consequent airway disease signified by excess mucus formation. IL-33 induction was traceable to a subset of secretoglobin-positive airway epithelial cells linked to progenitor/stem cell function. In corresponding studies of humans with chronic obstructive pulmonary disease, an increase in IL 33 production was also detected in concert with up-regulation of IL-13 and airway mucus formation. In this case, increased IL-33 production was localized to a subset of airway basal cells that maintain an endogenous capacity for increased pluripotency and ATP-regulated release of IL-33 even ex vivo. The results provide evidence of a sustainable epithelial cell population that may be activated by environmental danger signals to release IL-33 and thereby lead to IL-13-dependent disease. The progenitor nature of this IL-33-expressing ATP-responsive cell population could explain an acquired susceptibility to chronic airway disease. The findings may therefore provide a new paradigm to explain the role of viral infection and the innate immune system in chronic lung disease based on the influence of long-term epithelial progenitor cells programmed for excess IL-33 production. Further studies are needed to address the basis for this type of postviral reprogramming and the means to correct it and thereby restore airway mucosal immune function to normal. PMID- 25525736 TI - Pulmonary immunity during respiratory infections in early life and the development of severe asthma. AB - Asthma affects 10% of the population in Westernized countries, being most common in children. It is a heterogeneous condition characterized by chronic allergic airway inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR) to normally innocuous antigens. Combination therapies with inhaled corticosteroids and bronchodilators effectively manage mild to moderate asthma, but there are no cures, and patients with severe asthma do not respond to these treatments. The inception of asthma is linked to respiratory viral (respiratory syncytial virus, rhinovirus) and bacterial (Chlamydia, Mycoplasma) infections. The examination of mouse models of early-life infections and allergic airway disease (AAD) provides valuable insights into the mechanisms of disease inception that may lead to the development of more effective therapeutics. For example, early-life, but not adult, Chlamydia respiratory infections in mice permanently modify immunity and lung physiology. This increases the severity of AAD by promoting IL-13 expression, mucus hypersecretion, and AHR. We have identified novel roles for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and IL-13 in promoting infection-induced pathology in early life and subsequent chronic lung disease. Genetic deletion of TRAIL or IL-13 variously protected against neonatal infection-induced inflammation, mucus hypersecretion, altered lung structure, AHR, and impaired lung function. Therapeutic neutralization of these factors prevented infection-induced severe AAD. Other novel mechanisms and avenues for intervention are also being explored. Such studies indicate the immunological mechanisms that may underpin the association between early-life respiratory infections and the development of more severe asthma and may facilitate the development of tailored preventions and treatments. PMID- 25525737 TI - Gas6'ing the innate immune response during experimental asthma. AB - Growth arrest-specific gene 6 (Gas6) binds Tyro3, Axl, and Mertk (TAM) receptors and exerts prominent effects in many diseases, but little is known about its role in asthma. Herein, we examined the role of Gas6 and TAM receptors differentially in an experimental asthma model driven by Aspergillus fumigatus. A. fumigatus sensitized mice were challenged with live A. fumigatus conidia, and airway hyperresponsiveness and airway remodeling were determined 28 days later. When administered to mice from Days 14 to 28 after conidia challenge, anti-Axl monoclonal antibody, but not anti-Mertk monoclonal antibody, treatment significantly inhibited airway hyperresponsiveness and airway remodeling compared with the appropriate control IgG group. These results demonstrate that Gas6 has modulatory functions in fungal asthma via Axl receptor activation in immune and nonimmune cells. PMID- 25525739 TI - Vitamin D influences asthmatic pathology through its action on diverse immunological pathways. AB - The prevalence of vitamin D insufficiency and deficiency has increased markedly in recent decades to current epidemic levels (Hypponen E, et al. Am J Clin Nutr 2007;85:860-868). In parallel, there has been an increase in the incidence of a range of immune-mediated conditions ranging from cancer to autoimmune and respiratory diseases, including chronic obstructive pulmonary disease and asthma (Holick MF. N Engl J Med 2007;357:266-281; Finklea et al. Adv Nutr 2011;2:244 253). There is also an association with increased respiratory infections, which are the most common cause of asthma exacerbations (Finklea et al. Adv Nutr 2011;2:244-253). Together, this has resulted in considerable interest in the therapeutic potential of vitamin D to prevent and improve treatment of asthma and other respiratory diseases. To this end, data from clinical trials involving supplementation with active vitamin D, or more commonly a precursor, are starting to emerge. This review considers mechanisms by which vitamin D may act on the immune system to dampen inappropriate inflammatory responses in the airway while also promoting tolerance and antimicrobial defense mechanisms that collectively maintain respiratory health. PMID- 25525740 TI - Targeting immune pathways for therapy in asthma and chronic obstructive pulmonary disease. AB - Asthma and chronic obstructive pulmonary disease (COPD) are highly prevalent chronic inflammatory diseases of the airways, with differences in etiology, pathogenesis, immunologic mechanisms, clinical presentation, comorbidities, prognosis, and response to treatment. In mild to moderate early-onset allergic asthma, the Th2-driven eosinophilic airway inflammation and the ensuing disease can be well controlled with maintenance treatment with inhaled corticosteroids (ICS). In real-life settings, asthma control can be improved by facilitating adherence to ICS treatment and by optimizing inhaler technique. In patients with uncontrolled severe asthma, old and novel therapies targeting specific immunologic pathways should be added according to the underlying endotype/phenotype. In COPD, there is a high unmet need for safe and effective antiinflammatory treatments that not only prevent exacerbations but also have a beneficial impact on the course of the disease and improve survival. Although several new approaches aim to target the chronic neutrophilic pulmonary inflammation per se in patients with COPD, strategies that target the underlying causes of the pulmonary neutrophilia (e.g., smoking, chronic infection, and oxidative stress) might be more successful. In both chronic airway diseases (especially in more difficult, complex cases), the choice of the optimal treatment should be based not only on arbitrary clinical labels but also on the underlying immunopathology. PMID- 25525738 TI - Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells. AB - Airway tolerance, a state of immunological surveillance, suppresses the development of lung inflammatory disorders that are driven by various pathological effector cells of the immune system. Tolerance in the lung to inhaled antigens is primarily mediated by regulatory T cells (Treg cells) that can inhibit effector T cells via a myriad of mechanisms. Accumulating evidence suggests that regulatory antigen-presenting cells are critical for generating Treg cells and/or maintaining the suppressive environment in the lung. This review focuses on the control of airway tolerance by Treg cells and the role of regulatory lung tissue and alveolar macrophages, and lung and lymph node dendritic cells, in contributing to airway tolerance that is associated with suppression of allergic asthmatic disease. PMID- 25525741 TI - Tuning the aggregation of titanate nanowires in aqueous dispersions. AB - Electrophoretic and dynamic light scattering (DLS) measurements revealed that aggregation in aqueous dispersion of titanate nanowires (TiONWs) can be tuned by poly(diallyldimethylammonium) chloride (PDADMAC) polyelectrolyte. The nanowires possessed negative charge under alkaline conditions which was compensated by the oppositely charged PDADMAC adsorbed on the surface. Such adsorption led to charge neutralization and subsequent charge reversal at the appropriate polyelectrolyte doses. The dispersions were stable at low PDADMAC concentration where the TiONWs possessed negative charge. However, fast aggregation of the nanowires occurred close to the charge neutralization point where the overall charge of the particles was zero. Charge inversion at high polyelectrolyte doses gave rise to restabilization of the samples and slow aggregation of the TiONWs even at higher ionic strengths where the original bare TiONW dispersions were unstable. The colloid stability of the bare nanowires can be explained well qualitatively by the Derjaguin, Landau, Verwey, and Overbeek (DLVO) theory; however, polyelectrolyte adsorption led to additional patch-charge attractions and osmotic repulsion between the particles. On the basis of the knowledge generated by the present work, experimental conditions (e.g., salt level, polyelectrolyte, and particle concentrations) can be adjusted in order to design stable and processable aqueous dispersions of TiONWs for further applications. PMID- 25525742 TI - Chiral polychlorinated biphenyls (PCBs) in bioaccumulation, maternal transfer, and embryo development of chicken. AB - Polychlorinated biphenyls (PCBs) and enantiomer fractions (EFs) of PCB enantiomers (PCBs 95, 132, 135, and 149) were investigated in soil and chicken feed, chicken (Gallus domesticus) tissues, eggs on 0, 7, and 14 days after the onset of incubation, and newborn chick tissues. The EF values of PCBs 95, 132, and 149 changed significantly from soil to chicken tissues, and the values in the liver exhibited the highest deviation from the racemic ratio, indicating enantiomer-selective metabolism in hens. Congeners, which are highly resistant to degradation, such as PCBs 138, 153, and 180, exhibited the highest maternal transfer potentials when muscle and liver were used to assess the maternal transfer. However, uniform transfer ratios were observed for most of the PCB congeners when visceral fat was used. The EFs of chiral PCBs in eggs either did not match with muscle or with liver or were similar to those in visceral fat. These results indicate that hens mainly mobilized visceral fat for egg formation and PCBs were deposited in eggs by associating with these lipid materials. Further enantiomeric enrichment of PCBs 95, 132, and 149 occurred in the newborn chick tissues. However, an opposite enantioselectivity for PCB 135 in newborn chicks was observed. These results indicate that the potential toxicity of PCB enantiomers to newborn chicks may be different from that of adults. PMID- 25525743 TI - Atorvastatin treatment improves endothelial function through endothelial progenitor cells mobilization in ischemic heart failure patients. AB - OBJECTIVE: Endothelial function is an independent predictor of prognosis in heart failure (HF) subjects. Statins, beyond their lipid lowering role, exert beneficial effect in patients with atherosclerosis. In the present study we examined the impact of low and intermediate dose atorvastatin treatment on endothelial function, bone marrow-derived endothelial progenitor cells (EPC) mobilization and inflammatory status according to HF patient status. METHODS: We studied the effect of 4 weeks administration of atorvastatin in 26 patients with ischemic HF. The study was carried out on two separate arms, one with atorvastatin 40 mg/d and one with atorvastatin 10 mg/d (randomized, double-blind, cross-over design). The number of circulating CD34(+)/CD133(+)/KDR(+) EPCs was evaluated by flow cytometry. Endothelial function was evaluated by flow mediated dilation (FMD) in the brachial artery. Serum levels of tumor necrosis factor alpha (TNF-alpha) were measured by ELISA. RESULTS: Treatment with atorvastatin 40 mg/d significantly increased circulating EPC (p = 0.002), FMD (p = 0.001) and reduced TNF-alpha (p = 0.01) compared to baseline. Similarly, treatment with atorvastatin 10 mg/day increased circulating EPC (p = 0.01), FMD (p = 0.08) and reduced TNF-alpha (p = 0.01) compared to baseline. Interestingly, with 40 mg/day atorvastatin treatment the increase in EPC was higher in subjects categorized as NYHA class II compared to subjects categorized as NYHA class III (p = 0.03). CONCLUSIONS: Our results confirmed the distinct impact of atorvastatin treatment on the restoration of endothelial function due to EPC mobilization in ischemic HF subjects. Moreover, these findings provide the potential clinical significance of EPC status monitoring to individualize treatment in HF subjects. PMID- 25525744 TI - Early aortic valve inflammation precedes calcification: a longitudinal FDG-PET/CT study. AB - OBJECTIVES: Recent data shows a relationship between aortic valve (AV) inflammation and calcification. However, direct evidence linking early valve inflammation (prior to hemodynamic compromise) to subsequent calcium (Ca) deposition is lacking in humans. We sought to test the hypothesis whether local AV inflammation predisposes to subsequent AV Ca deposition. METHODS: We identified 111 individuals (age 60[49, 68], 50.5% male) without active cancer or aortic stenosis who underwent 2 PET/CT studies 1-5 years apart for cancer surveillance. AV inflammation was determined by measuring FDG uptake (maximum standardized uptake value, SUVmax) within the AV on baseline PET/CT. Subsequent deposition of AV Ca was determined by comparing baseline and follow-up CT scans, determined as an increase in AV Ca volume score (CaVS). Patients were classified as "non-progressors" or "progressors" based on Square Root difference in CaVS (using a pre-determined cut-off value of 2.5). CT and PET measurements were conducted by 2 mutually blinded laboratories. RESULTS: During follow-up, AV Ca increased in 23 patients (20.2%) classified as "progressors", of whom 9 (9.2%) demonstrated subsequent 'incident' AV Ca. The AV SUVmax (mean +/- SD) was higher in progressors vs. non-progressors (2.03 +/- 0.52 vs.1.74 +/- 0.36, p = 0.02) and especially in patients with-vs. without-incident AV Ca (2.28 +/- 0.42 vs. 1.73 +/ 0.36, p < 0.001). Moreover, AV inflammation (AV SUVmax) independently predicted subsequent calcification after adjusting for cardiovascular risk factors [OR (95%CI): 4.99 (1.30-19.15), p = 0.02]. CONCLUSION: The findings suggest that early AV inflammation may predispose to AV sclerosis. The evaluation of valvular metabolic activity may prove useful for developing a better understanding of calcific valve disease. PMID- 25525745 TI - Inflammation and calcification: the chicken or the hen? PMID- 25525746 TI - Annexin A5 haplotypes in familial hypercholesterolemia: lack of association with carotid intima-media thickness and cardiovascular disease risk. AB - OBJECTIVE: Annexin A5 (ANXA5) has been suggested to possess antiatherogenic properties. We investigated whether ANXA5 genetic variations and plasma ANXA5 levels were associated with carotid atherosclerosis and contributed to cardiovascular disease (CVD) risk in patients with familial hypercholesterolemia (FH). METHODS: We sequenced the promoter region and exon 2 of ANXA5 in 284 FH patients from the ASAP (Atorvastatin versus Simvastatin on Atherosclerosis Progression) trial. Common haplotypes (H) were constructed based on seven single nucleotide polymorphisms (SNPs). We studied whether plasma ANXA5 levels or ANXA5 haplotypes were associated with the extent of atherosclerosis (evaluated by carotid intima-media thickness (IMT). The association between ANXA5 haplotypes and the risk for CVD events was investigated in 1730 FH patients from the GIRaFH (Genetic Identification of Risk factors in Familial Hypercholesterolemia) study. RESULTS: In ASAP, individuals carrying the ANXA5 haplotype H2 exhibited lower plasma ANXA5 levels, whereas H4 carriers had increased levels of circulating ANXA5 compared to non-carriers. Plasma ANXA5 levels were not associated with carotid IMT. None of the four ANXA5 haplotypes correlated with the age-related IMT progression (ASAP study) or contributed to CVD risk (GIRaFH cohort). CONCLUSIONS: Both ANXA5 haplotypes and plasma ANXA5 levels were not associated with carotid IMT progression or CVD risk in FH patients. PMID- 25525747 TI - Patterns of temporal changes in tissue dielectric constant as indices of localized skin water changes in women treated for breast cancer: a pilot study. AB - BACKGROUND: Our goal was to characterize temporal patterns of skin Tissue Dielectric Constant (TDC) as a foundation for possible TDC use to detect and quantify lymphedema. Although limb volumes and bioimpedance analysis (BIA) are used for this purpose, potential TDC-method advantages are that it can be done in about 10 seconds at any body site to depths from 0.5 to 5.0 mm below the epidermis. METHODS AND RESULTS: TDC at forearm, biceps, axilla, and lateral thorax, and BIA values and arm volumes were measured in 80 women with breast cancer prior to surgery and in decreasing numbers at 3, 6, 12, 18, and 24 months post-surgery. Results show that TDC values, reflecting water content in the measurement volume, vary by site and depth but that at-risk/contralateral side ratio (A/C) is relatively independent of site and depth and is the preferred TDC parameter to detect tissue water changes over time in unilateral conditions. Among sites measured, lateral thorax, followed by forearm, appears most useful for TDC measurements with axilla least useful. Pre-surgery TDC inter-side values and A/C ratios showed no significant inter-side differences, suggesting that breast cancer presence per se did not alter tissue water status in this patient population. Sequential changes in TDC A/C ratios detected a greater number of patients who had inter-arm ratio increases exceeding 10% than were detected using BIA ratios. This may indicate a greater sensitivity to localized tissue water changes with the TDC-method. CONCLUSIONS: TDC is a technically viable and potentially useful method to track skin water changes in persons treated for breast cancer. PMID- 25525748 TI - Non-redox metal ion promoted oxygen transfer by a non-heme manganese catalyst. AB - This work demonstrates that non-redox metal ions as Lewis acids can sharply improve the oxygen transfer efficiency of a manganese(II) catalyst having a non heme ligand. In the absence of Lewis acid, oxidation of a manganese(II) complex will generate the known di-MU-oxo-bridged dinuclear Mn2(III,IV) core which is very sluggish for olefin epoxidation. Adding non-redox metal ions causes the dissociation of the dinuclear core, leading to sharp improvement in its oxygen transfer efficiency. PMID- 25525749 TI - Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity. AB - The somatosensory nervous system is critical for the organism's ability to respond to mechanical, thermal, and nociceptive stimuli. Somatosensory neurons are functionally and anatomically diverse but their molecular profiles are not well-defined. Here, we used transcriptional profiling to analyze the detailed molecular signatures of dorsal root ganglion (DRG) sensory neurons. We used two mouse reporter lines and surface IB4 labeling to purify three major non overlapping classes of neurons: 1) IB4(+)SNS-Cre/TdTomato(+), 2) IB4(-)SNS Cre/TdTomato(+), and 3) Parv-Cre/TdTomato(+) cells, encompassing the majority of nociceptive, pruriceptive, and proprioceptive neurons. These neurons displayed distinct expression patterns of ion channels, transcription factors, and GPCRs. Highly parallel qRT-PCR analysis of 334 single neurons selected by membership of the three populations demonstrated further diversity, with unbiased clustering analysis identifying six distinct subgroups. These data significantly increase our knowledge of the molecular identities of known DRG populations and uncover potentially novel subsets, revealing the complexity and diversity of those neurons underlying somatosensation. PMID- 25525752 TI - Sphingolipids in viral infection. AB - Viruses exploit membranes and their components such as sphingolipids in all steps of their life cycle including attachment and membrane fusion, intracellular transport, replication, protein sorting and budding. Examples for sphingolipid dependent virus entry are found for: human immunodeficiency virus (HIV), which besides its protein receptors also interacts with glycosphingolipids (GSLs); rhinovirus, which promotes the formation of ceramide-enriched platforms and endocytosis; or measles virus (MV), which induces the surface expression of its own receptor CD150 via activation of sphingomyelinases (SMases). While SMase activation was implicated in Ebola virus (EBOV) attachment, the virus utilizes the cholesterol transporter Niemann-Pick C protein 1 (NPC1) as 'intracellular' entry receptor after uptake into endosomes. Differential activities of SMases also affect the intracellular milieu required for virus replication. Sindbis virus (SINV), for example, replicates better in cells lacking acid SMase (ASMase). Defined lipid compositions of viral assembly and budding sites influence virus release and infectivity, as found for hepatitis C virus (HCV) or HIV. And finally, viruses manipulate cellular signaling and the sphingolipid metabolism to their advantage, as for example influenza A virus (IAV), which activates sphingosine kinase 1 and the transcription factor NF-kappaB. PMID- 25525750 TI - Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant. AB - In order to assess the contribution of a central clock in the hypothalamic suprachiasmatic nucleus (SCN) to circadian behavior and the organization of peripheral clocks, we generated forebrain/SCN-specific Bmal1 knockout mice by using floxed Bmal1 and pan-neuronal Cre lines. The forebrain knockout mice showed >90% deletion of BMAL1 in the SCN and exhibited an immediate and complete loss of circadian behavior in constant conditions. Circadian rhythms in peripheral tissues persisted but became desynchronized and damped in constant darkness. The loss of synchrony was rescued by light/dark cycles and partially by restricted feeding (only in the liver and kidney but not in the other tissues) in a distinct manner. These results suggest that the forebrain/SCN is essential for internal temporal order of robust circadian programs in peripheral clocks, and that individual peripheral clocks are affected differently by light and feeding in the absence of a functional oscillator in the forebrain. PMID- 25525751 TI - A genuine layer 4 in motor cortex with prototypical synaptic circuit connectivity. AB - The motor cortex (M1) is classically considered an agranular area, lacking a distinct layer 4 (L4). Here, we tested the idea that M1, despite lacking a cytoarchitecturally visible L4, nevertheless possesses its equivalent in the form of excitatory neurons with input-output circuits like those of the L4 neurons in sensory areas. Consistent with this idea, we found that neurons located in a thin laminar zone at the L3/5A border in the forelimb area of mouse M1 have multiple L4-like synaptic connections: excitatory input from thalamus, largely unidirectional excitatory outputs to L2/3 pyramidal neurons, and relatively weak long-range corticocortical inputs and outputs. M1-L4 neurons were electrophysiologically diverse but morphologically uniform, with pyramidal-type dendritic arbors and locally ramifying axons, including branches extending into L2/3. Our findings therefore identify pyramidal neurons in M1 with the expected prototypical circuit properties of excitatory L4 neurons, and question the traditional assumption that motor cortex lacks this layer. PMID- 25525753 TI - A region-based multiple testing method for hypotheses ordered in space or time. AB - We present a multiple testing method for hypotheses that are ordered in space or time. Given such hypotheses, the elementary hypotheses as well as regions of consecutive hypotheses are of interest. These region hypotheses not only have intrinsic meaning but testing them also has the advantage that (potentially small) signals across a region are combined in one test. Because the expected number and length of potentially interesting regions are usually not available beforehand, we propose a method that tests all possible region hypotheses as well as all individual hypotheses in a single multiple testing procedure that controls the familywise error rate. We start at testing the global null-hypothesis and when this hypothesis can be rejected we continue with further specifying the exact location/locations of the effect present. The method is implemented in the R package cherry and is illustrated on a DNA copy number data set. PMID- 25525754 TI - A qualitative study exploring moral distress in the ICU team: the importance of unit functionality and intrateam dynamics. AB - OBJECTIVE: Our study objectives were to determine the key sources of moral distress in diverse critical care professionals and how they manage it in the context of team-based models. DESIGN: Qualitative case study methodology using three recently resolved clinical cases. SETTING: A medical and surgical adult ICU in a 900-bed academic, tertiary Houston hospital. SUBJECTS: Twenty-nine ICU team members of diverse professional backgrounds interviewed between March 2013 and July 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All members of the ICU team reported experiencing moral distress. Intrateam discordance served as a key source of distress for all healthcare disciplines. Interviewees identified two situations where intrateam discordance creates moral distress: 1) situations involving initiation or maintenance of nonbeneficial life-sustaining treatments and 2) situations involving a lack of full disclosure about interventions. Healthcare professionals engaged in a variety of management techniques, which can be grouped according to maladaptive behaviors (pas-de-deux, "fighting," and withdrawing) and constructive behaviors (venting, mentoring networks, and building team cohesion). Maladaptive behaviors were more common in the surgical ICU. Constructive behaviors were more prevalent in the medical ICU and typically used by nurses and ancillary staff members. Physicians report becoming detached as morally distressing cases unfold, whereas nurses report becoming more emotionally invested. CONCLUSIONS: This study identified the ways in which moral distress manifests across critical care disciplines in different ICU environments. Our results have potential implications for patient care. First, when clinicians alter the content of their goals-of-care conversations with patients or families to accommodate intrateam discordance (as part of the "pas-de deux"), subsequent decisions regarding medical care may be compromised. Second, when different team members respond differently to the same case-with nurses becoming more emotionally invested and physicians becoming more withdrawn communication gaps are likely to occur at critical moral distress junctures. Finally, our findings suggest that physicians and any healthcare professionals in surgical units might be susceptible to unmitigated moral distress because they report less engagement in constructive behaviors to recalibrate their distress. PMID- 25525756 TI - LC-MS/MS Method for Determination of Teriflunomide, Over a 40,000-Fold Dynamic Range Using Overlapping Calibrators. AB - BACKGROUND: A liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been validated for use in therapeutic monitoring of the drug leflunomide in human serum and plasma. Because of concerns of teratogenicity, it is recommended that women who want to become pregnant have concentrations below 0.02 mcg/mL, although therapeutic levels are generally greater than 20 mcg/mL. Consequently, the method required a 40,000-fold dynamic range, which was achieved by dividing the curve range into 2 separate regions but with a single extraction procedure used for both. METHODS: A chromatographic separation was achieved between the parent drug and the active metabolite, teriflunomide (A77 1726), and the latter was quantified across a quantitative range of 0.005-200 mcg/mL. Samples were evaluated in an upper curve region first, with dilution, to determine whether the drug concentrations were in an appropriate therapeutic range. Samples that fell below the upper region were then reevaluated in the lower region without dilution. RESULTS: The method was shown to be reliable, with good accuracy and precision statistics, and acceptable quantitation using 4 different collection tube types. Mean accuracy over 6 control concentrations was within 5.4%, over 5 validation runs, whereas %coefficient of variation (CV) was within 8.15%. Evaluation of sodium heparin, KEDTA, NaF/K oxalate, and plain serum tubes from 6 separate individuals at the lower limit of quantification (LLOQ) showed no influence on the ability to quantify teriflunomide accurately. Regression equations for a curve range of 0.005-1 mcg/mL gave R values of 0.998 or better, whereas the range 0.8-200 mcg/mL had R values of 0.997 or better. CONCLUSIONS: The authors have developed and validated a method that allows quantification of leflunomide across a 40,000-fold range of 0.005-200 mcg/mL. PMID- 25525755 TI - Sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitates intra arrest therapeutic hypothermia in a porcine model of prolonged ventricular fibrillation. AB - OBJECTIVES: The aim of this study was to assess the effect of sodium nitroprusside-enhanced cardiopulmonary resuscitation on heat exchange during surface cooling. We hypothesized that sodium nitroprusside-enhanced cardiopulmonary resuscitation would decrease the time required to reach brain temperature less than 35 degrees C compared to active compression-decompression plus impedance threshold device cardiopulmonary resuscitation alone, in the setting of intra-cardiopulmonary resuscitation cooling. We further hypothesized that the addition of epinephrine during sodium nitroprusside-enhanced cardiopulmonary resuscitation would mitigate heat exchange. DESIGN: Prospective randomized animal investigation. SETTING: Preclinical animal laboratory. SUBJECTS: Female farm pigs (n=28). INTERVENTIONS: After 10 minutes of untreated ventricular fibrillation, animals were randomized to three different protocols: sodium nitroprusside-enhanced cardiopulmonary resuscitation (n=8), sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine (n=10), and active compression-decompression plus impedance threshold device alone (control, n=10). All animals received surface cooling at the initiation of cardiopulmonary resuscitation. Sodium nitroprusside-enhanced cardiopulmonary resuscitation included active compression-decompression plus impedance threshold device plus abdominal binding and 2 mg of sodium nitroprusside at 1, 4, and 8 minutes of cardiopulmonary resuscitation. No epinephrine was used during cardiopulmonary resuscitation in the sodium nitroprusside-enhanced cardiopulmonary resuscitation group. Control and sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine groups received 0.5 mg of epinephrine at 4.5 and 9 minutes of cardiopulmonary resuscitation. Defibrillation occurred after 10 minutes of cardiopulmonary resuscitation. After return of spontaneous circulation, an Arctic Sun (Medivance, Louiseville, CO) was applied at maximum cooling on all animals. The primary endpoint was the time required to reach brain temperature less than 35 degrees C beginning from the time of cardiopulmonary resuscitation initiation. Data are presented as mean+/-SEM. MEASUREMENTS AND MAIN RESULTS: The time required to reach a brain temperature of 35 degrees C was decreased with sodium nitroprusside-enhanced cardiopulmonary resuscitation versus control or sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine (24+/-6 min, 63+/-8 min, and 50+/-9 min, respectively; p=0.005). Carotid blood flow was higher during cardiopulmonary resuscitation in the sodium nitroprusside-enhanced cardiopulmonary resuscitation group (83+/-15 mL/min vs 26+/-7 mL/min and 35+/-5 mL/min in the control and sodium nitroprusside-enhanced cardiopulmonary resuscitation plus epinephrine groups, respectively; p=0.001). CONCLUSIONS: This study demonstrates that sodium nitroprusside-enhanced cardiopulmonary resuscitation facilitates intra-cardiopulmonary resuscitation hypothermia. The addition of epinephrine to sodium nitroprusside-enhanced cardiopulmonary resuscitation during cardiopulmonary resuscitation reduced its improvement in heat exchange. PMID- 25525757 TI - Generation of a Highly Specific Monoclonal Anti-Infliximab Antibody for Harmonization of TNF-Coated Infliximab Assays. AB - BACKGROUND: Determination of infliximab (IFX) serum concentrations has been used for treatment optimization of patients with inflammatory bowel disease. A wide range of enzyme-linked immunosorbent assays (ELISA) exists to quantitate IFX. Most of these assays lack specificity and cross-react with other anti-tumor necrosis factor (TNF) agents. The ability of these IFX assays to detect IFX in complex with antidrug antibodies is not known. The objective of our study was to develop an IFX-specific immunoassay to monitor IFX serum concentrations and to evaluate the impact of antidrug antibodies on the assay performance. METHODS: A panel of monoclonal antibodies toward IFX (MA-IFX) was generated by hybridoma technology and evaluated to replace the polyclonal antibody in a TNF-coated IFX assay. The selected monoclonal antibody-based (MA-based) IFX ELISA was benchmarked to a clinically validated, reference polyclonal antibody-based (pAb based) IFX ELISA using 209 inflammatory bowel disease serum samples. RESULTS: Fifty-five MA-IFX were generated and grouped into 9 clusters. Of the 22 monoclonal antibodies tested, MA-IFX6B7 was selected for use in the IFX ELISA and the assay was further optimized. MA-IFX6B7 is a high-affinity (KD = 1.40E-09 mol/L), noninhibitory IgG1 antibody that binds to the Fab fragment of IFX and exhibits no cross-reactivity with other anti-TNF drugs. The linearity of an IFX dose-response curve was demonstrated in the range of 1.2-37.5 ng/mL (R = 0.988). The MA-based assay showed a good Pearson correlation (R = 0.986) and agreement (intraclass correlation coefficient = 0.985) with the pAb-based assay. The MA based assay detects IFX in complex with nonneutralizing anti-IFX antibodies but not when complexed with neutralizing anti-IFX antibodies. CONCLUSIONS: In this study, a highly specific MA-IFX was developed as detection antibody in an ELISA to quantify IFX serum concentrations. The assay was benchmarked to the clinically validated reference pAb-based IFX ELISA. PMID- 25525758 TI - A Multilaboratory Commutability Evaluation of Proficiency Testing Material for Carbamazepine and Valproic Acid: A Study Within the Framework of the Dutch Calibration 2000 Project. AB - BACKGROUND: Medical laboratories are required to participate in interlaboratory comparisons of the analyses they perform. The materials used in these comparisons need to be of sufficient quality so that the comparison provides a picture of the performances. One of the main characteristics of the testing material is commutability, which is the ability of a material to yield the same numerical relationships between results of measurements as those relationships obtained when the same procedures are applied to patient samples. The aim of this study was to assess the commutability of 3 different matrices for the preparation of proficiency testing material (PTM) for the analysis of carbamazepine and valproic acid. METHODS: Patient samples and PTM containing various concentrations of carbamazepine and valproic acid were collected, prepared, and shipped to different laboratories for analysis. Reported results for patient samples from each laboratory were plotted against results for patient samples of each of the other laboratories, and the corresponding regression line was calculated. The distance of results from PTM to the regression line is a measure for commutability. The distance is expressed as a multiple of the SDwl (average within-laboratory SD as calculated from external quality assessment scheme results) and referred to as relative residual. A commutability decision limit of 2 SDwl was set. RESULTS: For carbamazepine and valproic acid, a total of 78 and 105 laboratory couples respectively could be formed. The number of relative residuals for liquid human serum outside the commutability decision limit was 1, 4, and 0 for low, medium, and high concentrations of carbamazepine, respectively and 3, 1, and 0 for low, medium, and high concentrations of valproic acid, respectively. In both liquid and lyophilized bovine sera, the number of relative residuals outside the commutability decision limit was between 2 and 15 and between 6 and 21 for carbamazepine and valproic acid, respectively. CONCLUSIONS: Although not all results for PTM with carbamazepine and valproic acid are within the commutability decision limits, a preference for human serum can be seen. PMID- 25525759 TI - Pharmacokinetic and pharmacodynamic evaluation of a nanotechnological topical formulation of lidocaine/prilocaine (nanorap) in healthy volunteers. AB - BACKGROUND: Nanorap is a new nanotechnological formulation for topical anesthesia composed of lidocaine (2.5%) and prilocaine (2.5%). This study evaluated the pharmacokinetics of Nanorap. For the determination of lidocaine and prilocaine in human plasma, a new method using high-performance liquid chromatography coupled with tandem mass spectrometry was developed. Nanorap pharmacodynamic (PD) and its physical proprieties were also evaluated. METHODS: Nanorap was administered by topical application of 2 g to healthy volunteers, and blood samples were collected for the pharmacokinetics analysis. The drugs were extracted from plasma by liquid-liquid extraction with ether/hexane (80/20, vol/vol). The chromatography separation was performed on a Genesis C18 analytical column 4 MUm (100 * 2.1 mm i.d.) with a mobile phase of methanol/acetonitrile/water (40/30/30, for lidocaine, and 50/30/20, for prilocaine, vol/vol/vol) + 2 mM of ammonium acetate and ropivacaine as internal standard. The drugs were quantified using a mass spectrometer with an electrospray source in the electrospray ionization positive mode configured for multiple reaction monitoring. The PD of Nanorap was evaluated with the use of a visual analog scale. Nanorap was characterized by cryofracture. RESULTS: The chromatography run-time was 5.5 minutes for lidocaine and 3.3 minutes for prilocaine, and the lower limit of quantification was 0.05 ng/mL for both drugs. Mean Cmax was 6.62 and 1.72 ng/mL for lidocaine and prilocaine, respectively. Median Tmax was 6.5 hours for both drugs. Nanocapsules had a mean size of 88 nm and mean drug association of 92.5% and 89% for lidocaine and prilocaine, respectively. The PD study showed that Nanorap has a sufficient analgesic effect (>30% reduction in pain) after 10 minutes of application. CONCLUSIONS: A new simple, selective, and sensitive method for determination of lidocaine and prilocaine in human plasma was developed. Nanorap generated safe plasma levels of the drugs and satisfactory analgesic effect. PMID- 25525761 TI - Limited sampling strategy for predicting area under the concentration-time curve for mycophenolic Acid in Chinese adults receiving mycophenolate mofetil and tacrolimus early after renal transplantation. AB - BACKGROUND: The objective of the study was to investigate the pharmacokinetics of mycophenolate mofetil (MMF) in Chinese adults early after renal transplantation by an enzyme multiplied immunoassay technique and to establish a limited sampling strategy to predict the area under the concentration-time curve for plasma levels of mycophenolic acid (MPA-AUC). METHODS: Fifty-eight recipients who underwent renal transplantation with an organ donated after cardiac death used a triple immunosuppressant strategy of MMF, tacrolimus, and prednisone. On the seventh day posttransplantation, plasma samples were collected at 0 hours (pre-dose) and at 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours postdose (C0h, C0.5h, C1h, C1.5h, C2h, C4h, C6h, C8h, C10h, and C12h, respectively). Enzyme multiplied immunoassay technique was used to measure mycophenolic acid concentration, and model equations were generated by multiple stepwise regression analysis to determine MPA-AUC0-12h. RESULTS: The 3-point equation obtained by multiple linear regression analysis was MPA-AUC = 7.951 + 4.04C6h + 1.893C2h + 4.542C10h (adjusted r = 0.863); the 4-point equation was MPA-AUC = 4.272 + 4.074C6h + 1.896C2h + 4.680C10h + 0.859C0.5h (adjusted r = 0.918). The % mean prediction error, % mean absolute error, and % root mean squared prediction error for the best-fit formula using C6h, C2h, C10h, and C0.5h were -0.2%, 8.7%, and 14.2%, respectively. CONCLUSIONS: In Chinese adults receiving MMF and tacrolimus early after renal transplantation, the best equation for predicting MPA-AUC0-12h is 4.272 + 4.074C6h + 1.896C2h + 4.680C10h + 0.859C0.5h. PMID- 25525762 TI - Improvement and validation of a high-performance liquid chromatography in tandem mass spectrometry method for monitoring of omeprazole in plasma. AB - BACKGROUND: Omeprazole (OME) is a proton pump inhibitor with a 58% bioavailability after a single oral dose. It is subject to marked interindividual variations and significant drug-drug interactions. The authors developed a simple and rapid method based on liquid chromatography in tandem with mass spectrometry with solid phase extraction and isotope-labeled internal standard to monitor plasma levels of OME in pharmacokinetics and drug-drug interaction studies. METHODS: OME and its internal standard (OME-D3) were eluted with a Zorbax Extend C-18 rapid resolution column (4.6 * 50 mm, 3.5 MUm) at 25 degrees C, under isocratic conditions through a mobile phase consisting of 1 mM ammonium acetate, pH 8.5 (55%), and acetonitrile (45%). The flow rate was 0.8 mL/min, and the chromatogram run time was 1.2 minutes. OME was detected and quantified by liquid chromatography in tandem with mass spectrometry with positive electrospray ionization, which operates in multiple-reaction monitoring mode. RESULTS: The method was linear in the range of 1.5-2000 ng/mL for OME. The validation assays for accuracy and precision, matrix effect, extraction recovery, and stability of the samples for OME did not deviate more than 20% for the lower limit of quantification and no more than 15% for other quality controls. CONCLUSIONS: These findings are consistent with the requirements of regulatory agencies. The method enables rapid quantification of OME concentrations and can be used in pharmacokinetic and drug-drug interaction studies. PMID- 25525760 TI - Measurement of Non-Vitamin K Antagonist Oral Anticoagulants in Patient Plasma Using Heptest-STAT Coagulation Method. AB - BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) are approved for several indications for prophylaxis of thromboembolism at fixed oral doses. The analysis of NOAC activity/concentration may be required in special patient populations. Heptest coagulation assay determines both factor Xa and thrombin inhibitors. The objective of investigations is to analyze the effects of both groups of NOACs on this assay. METHODS: The performance of a modified Heptest STAT clotting assay was compared with specific chromogenic substrate assays for factor Xa (Coamatic, HemosIL) and thrombin (direct thrombin inhibitor assay and S2238 chromogenic assays) for the determination of rivaroxaban, apixaban, and dabigatran in plasma from patients on treatment. RESULTS: For rivaroxaban (n = 74), the concentrations (mean and SD) of Heptest-STAT versus Coamatic and HemosIL assays were 179.3 +/- 85.8 ng/mL versus 199.3 +/- 105.7 ng/mL and 212.4 +/- 115.9 ng/mL (P < 0.0001), and for apixaban (n = 26) 232.8 +/- 10.0 ng/mL versus 178.4 +/- 64.4 ng/mL (P < 0.0001) and 182.1 +/- 73.1 ng/mL (P = 0.0002). For dabigatran (n = 74), the values of Heptest-STAT were 92.3 +/- 65.0 ng/mL versus 124.3 +/- 85.6 ng/mL (direct thrombin inhibitor assay, P < 0.0001) and 107.5 +/- 59.7 ng/mL (S2238 assay, P = 0.0015), respectively. The values of the intraclass coefficient of correlation ranged from 0.64 to 0.91 (Bland-Altman analysis). CONCLUSIONS: The objective of the study was achieved by demonstrating a high correlation of the Heptest-STAT coagulation assay with chromogenic assays for factor Xa inhibiting NOACs and acceptably good correlation with thrombin inhibiting NOACs in plasma samples of patients on treatment. PMID- 25525763 TI - Determination of Ethyl Glucuronide in Hair for Detection of Alcohol Consumption in Patients After Liver Transplantation. AB - BACKGROUND: Early detection of alcohol misuse in orthotopic liver transplantation recipients is essential to offer patients support and prevent organ damage. Here, ethyl glucuronide, a metabolite of ethanol found in hair (hEtG), was evaluated for detection of alcohol consumption. METHODS: In 104 transplant recipients, 31 with underlying alcoholic liver disease (ALD) and 73 with non-ALD, hEtG was determined in addition to the alcohol markers urine EtG, blood ethanol, methanol, and carbohydrate-deficient transferrin. Results were compared with patients' self reports in a questionnaire and with physicians' assessments. RESULTS: By physicians' assessments, 22% of the patients were suspected of consuming alcohol regularly, although only 6% of the patients acknowledged consumption of a moderate or high amount of alcohol. By testing all markers except for hEtG, alcohol consumption was detected in 7% of the patients. When hEtG testing was added to the assessment, consumption was detected in 17% of the patients. Hair EtG determination alone revealed chronic alcohol consumption of >10 g/d in 15% of the patients. ALD patients had a positive hEtG result significantly more often than non-ALD patients did (32% versus 8%; P = 0.003). Also, the concentration of hEtG was higher in ALD patients (P = 0.049) and revealed alcohol abuse with consumption of >60 g ethanol per day in 23% of ALD and 3% of non-ALD patients. Patients' self-reports and physicians' assessments had a low sensitivity of 27% and 67%, respectively, for detecting regular alcohol intake as indicated by hEtG. CONCLUSIONS: Hair-EtG determination improved the detection of liver transplant patients who used alcohol, and revealed regular alcohol consumption in 32% of ALD and 8% of non-ALD patients. PMID- 25525764 TI - Does Therapeutic Drug Monitoring of Ribavirin in HCV Genotype 3 Treatment With Sofosbuvir and Ribavirin Still Have a Role? PMID- 25525765 TI - Key Elements in Determining Voriconazole Protein Binding Characteristics: Comment on "Determination of Plasma Unbound Fraction of Voriconazole in Patients Treated With a Prophylactic or a Curative Treatment". PMID- 25525766 TI - Diffusion characteristics of ethylene glycol in skeletal muscle. AB - Part of the optical clearing study in biological tissues concerns the determination of the diffusion characteristics of water and optical clearing agents in the subject tissue. Such information is sufficient to characterize the time dependence of the optical clearing mechanisms-tissue dehydration and refractive index (RI) matching. We have used a simple method based on collimated optical transmittance measurements made from muscle samples under treatment with aqueous solutions containing different concentrations of ethylene glycol (EG), to determine the diffusion time values of water and EG in skeletal muscle. By representing the estimated mean diffusion time values from each treatment as a function of agent concentration in solution, we could identify the real diffusion times for water and agent. These values allowed for the calculation of the correspondent diffusion coefficients for those fluids. With these results, we have demonstrated that the dehydration mechanism is the one that dominates optical clearing in the first minute of treatment, while the RI matching takes over the optical clearing operations after that and remains for a longer time of treatment up to about 10 min, as we could see for EG and thin tissue samples of 0.5 mm. PMID- 25525767 TI - This is our first editorial to appear in an electronic-only format. Introduction. PMID- 25525768 TI - Re: fertility conserving management of early cervical cancer: our experience of LLETZ and pelvic lymph node dissection. PMID- 25525769 TI - The work place educational climate in gynecological oncology fellowships across Europe: the impact of accreditation. AB - BACKGROUND: A good educational climate/environment in the workplace is essential for developing high-quality medical (sub)specialists. These data are lacking for gynecological oncology training. OBJECTIVE: This study aims to evaluate the educational climate in gynecological oncology training throughout Europe and the factors affecting it. METHODS: A Web-based anonymous survey sent to ENYGO (European Network of Young Gynecological Oncologists) members/trainees to assess gynecological oncology training. This included sociodemographic information, details regarding training posts, and a 50-item validated Dutch Residency Educational Climate Test (D-RECT) questionnaire with 11 subscales (1-5 Likert scale) to assess the educational climate. The chi test was used for evaluating categorical variables, and the Mann-Whitney U (nonparametric) test was used for continuous variables between 2 independent groups. Cronbach alpha assessed the questionnaire reliability. Multivariable linear regression assessed the effect of variables on D-RECT outcome subscales. RESULTS: One hundred nineteen gynecological oncological fellows responded. The D-RECT questionnaire was extremely reliable for assessing the educational environment in gynecological oncology (subscales' Cronbach alpha, 0.82-0.96). Overall, trainees do not seem to receive adequate/effective constructive feedback during training. The overall educational climate (supervision, coaching/assessment, feedback, teamwork, interconsultant relationships, formal education, role of the tutor, patient handover, and overall consultant's attitude) was significantly better (P = 0.001) in centers providing accredited training in comparison with centers without such accreditation. Multivariable regression indicated the main factors independently associated with a better educational climate were presence of an accredited training post and total years of training. CONCLUSIONS: This study emphasizes the need for better feedback mechanisms and the importance of accreditation of centers for training in gynecological oncology to ensure training within higher quality clinical learning climates. PMID- 25525770 TI - Direct medical costs for patients with tuberous sclerosis complex and surgical resection of subependymal giant cell astrocytoma: a US national cohort study. AB - OBJECTIVE: To estimate direct medical costs for patients with tuberous sclerosis complex (TSC) and surgical resection of subependymal giant-cell astrocytoma (SEGA). METHODS: This retrospective cohort study selected patients who had SEGA surgery and TSC claims between 2000-2011 from three large US nationwide claims databases. Selected patients were age 35 or less and had continuous health insurance in the year before and the year after their first SEGA surgery claim. The study examined the patients' demographic and clinical characteristics and estimated inpatient, outpatient, medication, and total medical costs paid by insurance companies for the pre-surgery year, post-surgery year, and other study periods, respectively. Repeated measures analysis and bootstrapping technique were used to assess the impact of the surgery on the direct medical costs. RESULTS: Select patients (n = 47) had a mean baseline age of 11.6 years and 66% were male. Many had seizures (91.0%), hydrocephalus (59.6%), vision disorders (38.3%), stroke and hemiparesis (36.2%), and shunt (34.0%) in the pre-surgery year. The mean direct medical costs were $8543 (inpatient: $3770; outpatient: $3473; medication: $1300) for the pre-surgery year, and $85,397 (inpatient: $71,562; outpatient: $11,497; medication: $2338) for the post-surgery year. With the exclusion of the costs during the surgery month, the inpatient, outpatient, medication, and total costs in the post-surgery year were 1.6-4.3 times as much as the costs in the pre-surgery year (inpatient: 4.3:1; outpatient: 2.5:1; medication: 1.6:1; total: 3.1:1, p < 0.05). Repeated measures analysis with bootstrapping confirmed a link between the surgery and increases in direct medical costs (p < 0.05). CONCLUSIONS: SEGA surgery had a substantial impact on direct medical costs. TSC patients with the surgery experienced significant post surgery increases in their inpatient, outpatient, and medication costs. Additional research should be conducted to examine the surgery's cost-impact in a longer duration, or to compare the cost-effectiveness of the surgery vs other treatments. PMID- 25525771 TI - Healthcare utilization and costs of Veterans Health Administration patients with schizophrenia treated with paliperidone palmitate long-acting injection or oral atypical antipsychotics. AB - OBJECTIVE: This study aimed to compare real world healthcare costs and resource utilization between patients with schizophrenia treated with paliperidone palmitate long-acting injection (PP) and oral atypical antipsychotics (OAT). METHODS: Patients (18-64 years) were selected from the Veterans Health Administration dataset (1 July 2007-31 May 2012). Patients with 2+ claims for PP or 2+ claims for the same OAT comprised the two study cohorts with the first prescription date designated as the index date. Participation in the VA healthcare system for 24 months pre- and 12 months post-index, schizophrenia diagnosis (International Classification of Disease 9th Revision Clinical Modification [ICD-9-CM] code 295.1x-6x, 295.8x-9x) and >=1 claim for an antipsychotic medication during the baseline period were required. Propensity scores and Mahalanobis metric distances with calipers were used to create two matched cohorts. All-cause healthcare utilization and costs for the 12-month follow-up period were compared between matched cohorts. RESULTS: The matching process produced two cohorts of 335 patients with similar baseline characteristics. During the 12-month follow-up period, patients in the PP cohort had lower mean inpatient costs (18,560 vs $31,505, p = 0.002), lower frequency of hospitalization (34% vs 53%, p < 0.001) and fewer average inpatient days (13.24 vs 24.18, p = 0.002) vs matched OAT patients. While mean pharmacy costs were higher for the PP cohort ($10,063 vs $4167, p < 0.001), mean total healthcare costs were not significantly different ($45,529 vs $52,569, p = 0.128). CONCLUSION: VA patients, diagnosed with schizophrenia and treated with PP, had lower inpatient costs and admission rates compared to a matched cohort of OAT patients. Total healthcare costs were not significantly different. PMID- 25525772 TI - Reply to target temperature management for post-cardiac arrest patients. PMID- 25525773 TI - The relationship between drinking motives and alcohol-related interpretation biases. AB - BACKGROUND AND OBJECTIVES: Numerous studies have investigated drinking motives and alcohol-related interpretation biases (IBs) separately. However, less is known about the relationship between them. Therefore, the present study examined whether coping and enhancement drinking motives were specifically related to negative and positive alcohol-related IBs, respectively. Furthermore, it was investigated whether such biases predict future drinking, especially in individuals with low levels of executive control (EC). METHODS: Participants were male and female university students. The Drinking Motives Questionnaire-Revised (DMQ-R; Cooper, 1994) was administered to measure participants' drinking motives. To measure alcohol-related IBs, an adapted version of the Encoding Recognition Task (ERT) was used. During the ERT, participants were asked to read ambiguous alcohol-related scenarios. In a subsequent recognition phase, participants interpreted these scenarios. A classical Stroop was applied to assess levels of EC. RESULTS: Coping motives but not enhancement motives were a unique predictor of the tendency to interpret negatively valenced ambiguous alcohol-relevant situations in an alcohol-related manner. This relationship was significant even when controlling for other relevant predictors. Neither coping nor enhancement motives were predictive of positive alcohol-related IBs. Concerning the prediction of prospective drinking, results showed that particularly the negative alcohol-related IB predicted prospective drinking. However, EC did not moderate the prediction of prospective drinking by either positive or negative interpretation biases. LIMITATIONS: The alcohol-ERT might not be the most optimal paradigm for assessing implicit alcohol-related IBs. CONCLUSIONS: The present results emphasize the role of negative affect in the context of drinking motives and alcohol-related IBs. Follow-up studies are needed to test the robustness of these findings, and to further explore the general interplay between drinking motives and alcohol-related IBs. PMID- 25525774 TI - Asymmetric metal free beta-boration of alpha,beta-unsaturated imines assisted by (S)-MeBoPhoz. AB - The adduct [MeO -> Bpin-Bpin](-) efficiently mediates the beta-boration of alpha,beta-unsaturated imines formed in situ. The use of chiral phosphines as additives, and in particular the chiral phosphine (S)-MeBoPhoz, enables the catalytic asymmetric reaction to proceed with higher enantioselectivity than the analogue copper(I) mediated reaction. PMID- 25525776 TI - Celebrating 30 years of the Journal of Thoracic Imaging. PMID- 25525778 TI - 30-on-30: thirty perspectives on thirty years of publishing the Journal of Thoracic Imaging. PMID- 25525775 TI - IL-36gamma (IL-1F9) is a biomarker for psoriasis skin lesions. AB - In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not only psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/tumor necrosis factor-alpha (TNFalpha)-associated genes specifically expressed in psoriasis, among which IL 36gamma was the most outstanding marker. In subsequent immunohistological analyses, IL-36gamma was confirmed to be expressed in psoriasis lesions only. IL 36gamma peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFalpha-treatment. Furthermore, IL-36gamma immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36gamma as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL 36gamma might also provide a future drug target, because of its potential amplifier role in TNFalpha- and IL-17 pathways in psoriatic skin inflammation. PMID- 25525777 TI - Reflections on the 30th anniversary of the Journal of Thoracic Imaging. PMID- 25525780 TI - Screening for lung cancer: to be or not to be covered by medicare? AB - The National Lung Cancer Screening Trial (NLST) found a reduction in lung cancer mortality in high-risk patients aged 55 to 74 who were screened with low-dose computed tomography (LDCT) rather than chest x-ray. This reduction was 20% after 6.5 years and 16% after 7.5 years, with a 6.7% reduction in all-cause mortality after 6.5 years. The US Preventive Services Task Force recommended LDCT screening for people aged 55 to 80 who currently smoke or had quit within the last 15 years and who have a history of at least 30 pack-years of smoking. Advocates are urging Medicare to cover the cost of screening for that same targeted population, but the Medicare Evidence Development and Coverage Advisory Committee recommended against coverage, expressing their lack of confidence that the benefits would outweigh the risks for the Medicare patients likely to be screened. Data that support and refute the advocacy position regarding Medicare coverage for LDCT screening are presented. The likely benefits and risks for Medicare patients are discussed in the context of NLST data, other research findings, comparisons between NLST patients and Medicare patients of the same age and smoking histories, and Medicare policies. PMID- 25525781 TI - Developmental lung malformations in children: recent advances in imaging techniques, classification system, and imaging findings. AB - Congenital lung anomalies represent a diverse group of developmental malformations of the lung parenchyma, arterial supply, and venous drainage, which may present anywhere from the prenatal period through adulthood. It is imperative for radiologists to be aware of imaging techniques and imaging appearance of these anomalies across the pediatric age range. This review presents the spectrum of these lesions that are often encountered in daily clinical practice. Each anomaly is discussed in terms of underlying etiology, clinical presentation, and imaging characterization with emphasis on the most up-to-date research and treatment. Knowledge of these areas is essential for accurate, timely diagnosis, which aids in optimizing patient outcomes. PMID- 25525782 TI - Congenital lung disease in the adult: guide to the evaluation and management. AB - A high index of suspicion is required to consider the diagnosis of adult congenital lung disease because of the rarity of presentation in adulthood. The purpose of this article is to provide a framework for evaluation of these lesions and a guide to management. Adults may be asymptomatic, and the abnormality identified as an incidental imaging finding or the individual may present with symptoms of cough, hemoptysis, or recurrent pneumonia. The diagnosis may be readily apparent on computed tomography imaging because of a characteristic appearance, or the abnormality may require further evaluation for diagnosis with supplemental magnetic resonance imaging. Surgical resection provides a definitive diagnosis. The congenital lung malformation may be a solitary lesion or part of a complex group of abnormalities. A detailed review of all the components of the thorax is required to identify additional lesions. Management is typically surgical resection because of the propensity of these lesions to enlarge and to become infected as well as the potential risk for malignant transformation. Computed tomography surveillance may be appropriate for small asymptomatic lesions or lesions with either no or very low risk for developing malignancy. PMID- 25525783 TI - Microbiota talks cholera out of the gut. AB - In a recent Nature paper, Hsiao et al., 2014 examine microbiota contribution during and after cholera and identify commensals correlated with healing and reconstitution of the microbial community. One particular species may use intercellular communication to stymie Vibrio cholerae pathogenesis, indicating how the microbiota can restrict pathogens. PMID- 25525784 TI - Microbial bile acid metabolic clusters: the bouncers at the bar. AB - Colonization resistance refers to the ability of the colonic microbiota to prevent invasion by pathogens including Clostridium difficile. In a recent article, Buffie et al. (2014) have demonstrated that a single metabolic cluster present in the normal, colonic microflora is responsible for preventing C. difficile invasion of healthy hosts. PMID- 25525785 TI - DAF-tly depart stinky situations with elegans. AB - During acute infection our behavior tends to change. Despite how common sickness behavior is, its molecular basis is not well understood. In a study published in Cell, Kim and colleagues (Meisel et al., 2014) implicate bacterial secondary metabolites as triggers of neural TGF-? signaling, which results in behavioral change during infection. PMID- 25525786 TI - Dynamic intervention: pathogen disarmament of mitochondrial-based immune surveillance. AB - In this issue of Cell Host & Microbe, Suzuki et al. (2014) describe a Vibrio cholerae Type-III-secreted effector that targets mitochondrial dynamics to dampen host innate immune signaling. This suggests that mammalian hosts possess surveillance mechanisms to monitor pathogen-mediated alterations in the integrity of normal cellular processes and organelles. PMID- 25525787 TI - Ground control to Major Tom: "prepare for HIV landing". AB - Productive HIV-1 infection requires viral cDNA integration into the host genome, an event catalyzed by HIV-1 integrase. In this issue of Cell Host & Microbe, Demeulemeester et al. (2014) report the existence of natural integrase polymorphisms that retarget viral integration away from gene-dense regions and are associated with rapid disease progression. PMID- 25525788 TI - Barcoding influenza virus to decode transmission. AB - How much population diversity is transmitted during influenza virus infection? In this issue of Cell Host & Microbe, Varble et al. (2014) report a method of tagging influenza viruses with a unique genetic "barcode" that allows them to be traced through transmission and growth chains, providing a leap forward for the field. PMID- 25525790 TI - Hepatitis C virus RNA replication and assembly: living on the fat of the land. AB - Hepatitis C virus (HCV) is a major global health burden accounting for around 170 million chronic infections worldwide. Although highly potent direct-acting antiviral drugs to treat chronic hepatitis C have been approved recently, owing to their high costs and limited availability and a large number of undiagnosed infections, the burden of disease is expected to rise in the next few years. In addition, HCV is an excellent paradigm for understanding the tight link between a pathogen and host cell pathways, most notably lipid metabolism. HCV extensively remodels intracellular membranes to establish its cytoplasmic replication factory and also usurps components of the intercellular lipid transport system for production of infectious virus particles. Here, we review the molecular mechanisms of viral replicase function, cellular pathways employed during HCV replication factory biogenesis, and viral, as well as cellular, determinants of progeny virus production. PMID- 25525789 TI - The impact of hepatitis C virus entry on viral tropism. AB - Uptake of hepatitis C virus (HCV) into hepatocytes is an orchestrated process, involving numerous host factors, virion-associated lipoproteins, and a growing number of cell-associated factors. Several of these factors likely contribute to the hepatotropism and limited host range of this virus. Discerning the minimal set of human-specific factors required for viral uptake into nonhuman cells has facilitated the development of small animal models with inheritable HCV susceptibility. This review summarizes current knowledge of host factors required for HCV entry, the molecular mechanisms underlying HCV entry into hepatocytes, and aspects of viral entry contributing to HCV host tropism. PMID- 25525791 TI - The acetate switch of an intestinal pathogen disrupts host insulin signaling and lipid metabolism. AB - Vibrio cholerae is lethal to the model host Drosophila melanogaster through mechanisms not solely attributable to cholera toxin. To examine additional virulence determinants, we performed a genetic screen in V. cholerae-infected Drosophila and identified the two-component system CrbRS. CrbRS controls transcriptional activation of acetyl-CoA synthase-1 (ACS-1) and thus regulates the acetate switch, in which bacteria transition from excretion to assimilation of environmental acetate. The resultant loss of intestinal acetate leads to deactivation of host insulin signaling and lipid accumulation in enterocytes, resulting in host lethality. These metabolic effects are not observed upon infection with ΔcrbS or Δacs1 V. cholerae mutants. Additionally, uninfected flies lacking intestinal commensals, which supply short chain fatty acids (SCFAs) such as acetate, also exhibit altered insulin signaling and intestinal steatosis, which is reversed upon acetate supplementation. Thus, acetate consumption by V. cholerae alters host metabolism, and dietary acetate supplementation may ameliorate some sequelae of cholera. PMID- 25525792 TI - The calcium-dependent protein kinase CPK28 buffers plant immunity and regulates BIK1 turnover. AB - Plant perception of pathogen-associated molecular patterns (PAMPs) triggers a phosphorylation relay leading to PAMP-triggered immunity (PTI). Despite increasing knowledge of PTI signaling, how immune homeostasis is maintained remains largely unknown. Here we describe a forward-genetic screen to identify loci involved in PTI and characterize the Arabidopsis calcium-dependent protein kinase CPK28 as a negative regulator of immune signaling. Genetic analyses demonstrate that CPK28 attenuates PAMP-triggered immune responses and antibacterial immunity. CPK28 interacts with and phosphorylates the plasma membrane-associated cytoplasmic kinase BIK1, an important convergent substrate of multiple pattern recognition receptor (PRR) complexes. We find that BIK1 is rate limiting in PTI signaling and that it is continuously turned over to maintain cellular homeostasis. We further show that CPK28 contributes to BIK1 turnover. Our results suggest a negative regulatory mechanism that continually buffers immune signaling by controlling the turnover of this key signaling kinase. PMID- 25525793 TI - NRAV, a long noncoding RNA, modulates antiviral responses through suppression of interferon-stimulated gene transcription. AB - Long noncoding RNAs (lncRNAs) modulate various biological processes, but their role in host antiviral responses is largely unknown. Here we identify a lncRNA as a key regulator of antiviral innate immunity. Following from the observation that a lncRNA that we call negative regulator of antiviral response (NRAV) was dramatically downregulated during infection with several viruses, we ectopically expressed NRAV in human cells or transgenic mice and found that it significantly promotes influenza A virus (IAV) replication and virulence. Conversely, silencing NRAV suppressed IAV replication and virus production, suggesting that reduction of NRAV is part of the host antiviral innate immune response to virus infection. NRAV negatively regulates the initial transcription of multiple critical interferon-stimulated genes (ISGs), including IFITM3 and MxA, by affecting histone modification of these genes. Our results provide evidence for a lncRNA in modulating the antiviral interferon response. PMID- 25525803 TI - Aggregation induced emission enhancement of 4,4'-bis(diethylamino)benzophenone with an exceptionally large blue shift and its potential use as glucose sensor. AB - Optical emission from a luminogen in solid state is generally red shifted with respect to its solution phase emission. However, in our present study, we report exceptionally large blue shifted enhanced emission from aggregated hydrosol of 4,4'-bis(diethylamino)benzophenone (BZP) compared to its solution phase emission in any good solvent. This exceptional blue emission from aggregated structure of BZP arises from its locally excited states with the concomitant suppression of twisted intramolecular charge transfer (TICT) motion. This is known as aggregation induced locally excited (AILE) state emission. A broad red shifted emission is also observed in case of larger aggregated structure of BZP and it originates from the excited intramolecular charge transfer (ICT) state of planar BZP. Morphology of the aggregated BZP is also studied by scanning electron microscopy and optical microscopy. This AILE emission of the luminogen is used for sensing glucose in aqueous solution at very low concentration. The quenching of AILE in presence of glucose has been explained due to hydrogen bonded complexation between glucose and BZP molecule present at the surface of the aggregated structure and is responsible for crystal softening, i.e. loosening of crystal packing. PMID- 25525798 TI - Can wide consultation help with setting priorities for large-scale biodiversity monitoring programs? AB - Climate and other global change phenomena affecting biodiversity require monitoring to track ecosystem changes and guide policy and management actions. Designing a biodiversity monitoring program is a difficult task that requires making decisions that often lack consensus due to budgetary constrains. As monitoring programs require long-term investment, they also require strong and continuing support from all interested parties. As such, stakeholder consultation is key to identify priorities and make sound design decisions that have as much support as possible. Here, we present the results of a consultation conducted to serve as an aid for designing a large-scale biodiversity monitoring program for the province of Quebec (Canada). The consultation took the form of a survey with 13 discrete choices involving tradeoffs in respect to design priorities and 10 demographic questions (e.g., age, profession). The survey was sent to thousands of individuals having expected interests and knowledge about biodiversity and was completed by 621 participants. Overall, consensuses were few and it appeared difficult to create a design fulfilling the priorities of the majority. Most participants wanted 1) a monitoring design covering the entire territory and focusing on natural habitats; 2) a focus on species related to ecosystem services, on threatened and on invasive species. The only demographic characteristic that was related to the type of prioritization was the declared level of knowledge in biodiversity (null to high), but even then the influence was quite small. PMID- 25525804 TI - An efficient algorithm for some highly nonlinear fractional PDEs in mathematical physics. AB - In this paper, a fractional complex transform (FCT) is used to convert the given fractional partial differential equations (FPDEs) into corresponding partial differential equations (PDEs) and subsequently Reduced Differential Transform Method (RDTM) is applied on the transformed system of linear and nonlinear time fractional PDEs. The results so obtained are re-stated by making use of inverse transformation which yields it in terms of original variables. It is observed that the proposed algorithm is highly efficient and appropriate for fractional PDEs and hence can be extended to other complex problems of diversified nonlinear nature. PMID- 25525795 TI - HIV-1 integrase variants retarget viral integration and are associated with disease progression in a chronic infection cohort. AB - Distinct integration patterns of different retroviruses, including HIV-1, have puzzled virologists for over 20 years. A tetramer of the viral integrase (IN) assembles on the two viral cDNA ends, docks onto the target DNA (tDNA), and catalyzes viral genome insertion into the host chromatin. We identified the amino acids in HIV-1 IN that directly contact tDNA bases and affect local integration site sequence selection. These residues also determine the propensity of the virus to integrate into flexible tDNA sequences. Remarkably, natural polymorphisms INS119G and INR231G retarget viral integration away from gene-dense regions. Precisely these variants were associated with rapid disease progression in a chronic HIV-1 subtype C infection cohort. These findings link integration site selection to virulence and viral evolution, but also to the host immune response and antiretroviral therapy, since HIV-1 IN119 is under selection by HLA alleles and integrase inhibitors. PMID- 25525797 TI - Rhinovirus uses a phosphatidylinositol 4-phosphate/cholesterol counter-current for the formation of replication compartments at the ER-Golgi interface. AB - Similar to other positive-strand RNA viruses, rhinovirus, the causative agent of the common cold, replicates on a web of cytoplasmic membranes, orchestrated by host proteins and lipids. The host pathways that facilitate the formation and function of the replication membranes and complexes are poorly understood. We show that rhinovirus replication depends on host factors driving phosphatidylinositol 4-phosphate (PI4P)-cholesterol counter-currents at viral replication membranes. Depending on the virus type, replication required phosphatidylinositol 4-kinase class 3beta (PI4K3b), cholesteryl-esterase hormone sensitive lipase (HSL) or oxysterol-binding protein (OSBP)-like 1, 2, 5, 9, or 11 associated with lipid droplets, endosomes, or Golgi. Replication invariably required OSBP1, which shuttles cholesterol and PI4P between ER and Golgi at membrane contact sites. Infection also required ER-associated PI4P phosphatase Sac1 and phosphatidylinositol (PI) transfer protein beta (PITPb) shunting PI between ER-Golgi. These data support a PI4P-cholesterol counter-flux model for rhinovirus replication. PMID- 25525799 TI - Group-specific multiplex PCR detection systems for the identification of flying insect prey. AB - The applicability of species-specific primers to study feeding interactions is restricted to those ecosystems where the targeted prey species occur. Therefore, group-specific primer pairs, targeting higher taxonomic levels, are often desired to investigate interactions in a range of habitats that do not share the same species but the same groups of prey. Such primers are also valuable to study the diet of generalist predators when next generation sequencing approaches cannot be applied beneficially. Moreover, due to the large range of prey consumed by generalists, it is impossible to investigate the breadth of their diet with species-specific primers, even if multiplexing them. However, only few group specific primers are available to date and important groups of prey such as flying insects have rarely been targeted. Our aim was to fill this gap and develop group-specific primers suitable to detect and identify the DNA of common taxa of flying insects. The primers were combined in two multiplex PCR systems, which allow a time- and cost-effective screening of samples for DNA of the dipteran subsection Calyptratae (including Anthomyiidae, Calliphoridae, Muscidae), other common dipteran families (Phoridae, Syrphidae, Bibionidae, Chironomidae, Sciaridae, Tipulidae), three orders of flying insects (Hymenoptera, Lepidoptera, Plecoptera) and coniferous aphids within the genus Cinara. The two PCR assays were highly specific and sensitive and their suitability to detect prey was confirmed by testing field-collected dietary samples from arthropods and vertebrates. The PCR assays presented here allow targeting prey at higher taxonomic levels such as family or order and therefore improve our ability to assess (trophic) interactions with flying insects in terrestrial and aquatic habitats. PMID- 25525794 TI - Nef proteins of epidemic HIV-1 group O strains antagonize human tetherin. AB - Most simian immunodeficiency viruses use their Nef protein to antagonize the host restriction factor tetherin. A deletion in human tetherin confers Nef resistance, representing a hurdle to successful zoonotic transmission. HIV-1 group M evolved to utilize the viral protein U (Vpu) to counteract tetherin. Although HIV-1 group O has spread epidemically in humans, it has not evolved a Vpu-based tetherin antagonism. Here we show that HIV-1 group O Nef targets a region adjacent to this deletion to inhibit transport of human tetherin to the cell surface, enhances virion release, and increases viral resistance to inhibition by interferon α. The Nef protein of the inferred common ancestor of group O viruses is also active against human tetherin. Thus, Nef-mediated antagonism of human tetherin evolved prior to the spread of HIV-1 group O and likely facilitated secondary virus transmission. Our results may explain the epidemic spread of HIV 1 group O. PMID- 25525807 TI - Pulmonary hypertension: epidemiology in different CKD stages and its association with cardiovascular morbidity. AB - BACKGROUND: Pulmonary hypertension (PH) was recently recognized as a common complication of end-stage renal disease (ESRD) that causes an increased risk of mortality. Epidemiological data for this disorder in earlier stages of chronic kidney disease (CKD) and its association with cardiovascular (CV) morbidity are scarce. METHODS: We retrospectively analyzed 2,351 Chinese CKD patients with complete clinical records and echocardiography data between Jan 2008 and May 2012. The patients were divided into the following 6 groups: CKD Stages 1-4; Stage 5 for those not on or initiated on hemodialysis for <3 months; and Stage 5D for the patients undergoing hemodialysis for >=3 months. The prevalence of PH and CV morbidity was investigated, and their association was evaluated with a logistic regression model. RESULTS: PH was detected in 426 patients (18.1%). Mild, moderate and severe PH was diagnosed in 12.1%, 4.9% and 1.1% of the patients, respectively. Severe PH was detected in CKD Stages 5 and 5D. CV morbidity was found in 645 patients (27.4%). Compared with the non-PH group, the PH group had a higher risk for cardiac disease but not for cerebrovascular disease risk. PH severity was associated with cardiac morbidity risk [odds ratio (95% CI) for mild PH: 1.79 (1.30-2.47); moderate PH: 2.75 (1.73-4.37); severe PH: 3.90 (1.46-10.42)]. CONCLUSIONS: Our study showed for the first time the epidemiology profile of PH across the spectrum of CKD. Mild-to-moderate PH occurs with more frequency in advanced CKD, and severe PH is scarce in non-ESRD CKD. PH in CKD is associated with cardiac but not cerebrovascular disease, with increasing cardiac morbidity seen with increasing PH severity. Evidence from prospective studies addressing PH in this population is needed to predict cardiac events. PMID- 25525800 TI - Activation of antioxidant defenses in whole saliva by psychosocial stress is more manifested in young women than in young men. AB - Psychosocial stress has been long known to have deleterious effects on health. Nevertheless, an exposure to moderate stressors enhances resilience and promotes health benefits. Male and female organisms differ in many aspects of health and disease. The aim of this study was to investigate antioxidant activity and oxidative damage in saliva in a psychosocial stress paradigm in men and women. Here, we show that an acute stressor of moderate strength augments antioxidant activity and decreases oxidative damage in whole saliva of young people. An examination stress caused a significant increase of catalase activity, accompanied by a decrease of levels of oxidized proteins. Levels of thiobarbituric acid-reacting substances did not increase at stress, indicating that lipid peroxidation was not activated. The stress-induced alterations were more manifested in young women compared to young men. Thus, antioxidant protective mechanisms are more activated by a moderate stressor in young women than in young men. PMID- 25525810 TI - Correlations of life form, pollination mode and sexual system in aquatic angiosperms. AB - Aquatic plants are phylogenetically well dispersed across the angiosperms. Reproductive and other life-history traits of aquatic angiosperms are closely associated with specific growth forms. Hydrophilous pollination exhibits notable examples of convergent evolution in angiosperm reproductive structures, and hydrophiles exhibit great diversity in sexual system. In this study, we reconstructed ancestral characters of aquatic lineages based on the phylogeny of aquatic angiosperms. Our aim is to find the correlations of life form, pollination mode and sexual system in aquatic angiosperms. Hydrophily is the adaptive evolution of completely submersed angiosperms to aquatic habitats. Hydroautogamy and maleflower-ephydrophily are the transitional stages from anemophily and entomophily to hydrophily. True hydrophily occurs in 18 submersed angiosperm genera, which is associated with an unusually high incidence of unisexual flowers. All marine angiosperms are submersed, hydrophilous species. This study would help us understand the evolution of hydrophilous pollination and its correlations with life form and sexual system. PMID- 25525805 TI - Impact of glutathione S-transferase M1 and T1 on anti-tuberculosis drug-induced hepatotoxicity in Chinese pediatric patients. AB - BACKGROUND: Anti-tuberculosis drug induced hepatotoxicity (ATDH) is a major adverse drug reaction associated for anti-tuberculosis therapy. The glutathione S transferases (GST) plays a crucial role in the detoxification of hepatotoxic metabolites of anti-tuberculosis drugs.An association between GSTM1/GSTT1 null mutations and increased risk of ATDH has been demonstrated in adults. Given the ethnic differences and developmental changes, our study aims to investigate the potential impacts of GSTM1/GSTT1 genotypes on the development of ATDH in Han Chinese children treated with anti-tuberculosis therapy. METHODS: Children receiving anti-tuberculosis therapy with or without evidence of ATDH were considered as the cases or controls, respectively. The GSTM1 and GSTT1 genotyping were performed using the polymerase chain reaction. RESULTS: One hundred sixty three children (20 cases and 143 controls) with a mean age of 4.7 years (range: 2 months-14.1 years) were included. For the GSTM1, 14 (70.0%) cases and 96 (67.1%) controls had homozygous null mutations. For the GSTT1, 13 (65.0%) cases and 97 (67.8%) controls had homozygous null mutations. Neither the GSTM1, nor the GSTT1 polymorphism was significantly correlated with the occurrence of ATHD. CONCLUSION: Our results did not support the GSTM1 and GSTT1 polymorphisms as the predictors of ADTH in Chinese Han children treated with anti-tuberculosis drugs. An age-related association between pharmacogenetics and ATHD need to be confirmed in the further study. PMID- 25525809 TI - Maintenance of leukemia-initiating cells is regulated by the CDK inhibitor Inca1. AB - Functional differences between healthy progenitor and cancer initiating cells may provide unique opportunities for targeted therapy approaches. Hematopoietic stem cells are tightly controlled by a network of CDK inhibitors that govern proliferation and prevent stem cell exhaustion. Loss of Inca1 led to an increased number of short-term hematopoietic stem cells in older mice, but Inca1 seems largely dispensable for normal hematopoiesis. On the other hand, Inca1-deficiency enhanced cell cycling upon cytotoxic stress and accelerated bone marrow exhaustion. Moreover, AML1-ETO9a-induced proliferation was not sustained in Inca1 deficient cells in vivo. As a consequence, leukemia induction and leukemia maintenance were severely impaired in Inca1-/- bone marrow cells. The re initiation of leukemia was also significantly inhibited in absence of Inca1-/- in MLL-AF9- and c-myc/BCL2-positive leukemia mouse models. These findings indicate distinct functional properties of Inca1 in normal hematopoietic cells compared to leukemia initiating cells. Such functional differences might be used to design specific therapy approaches in leukemia. PMID- 25525815 TI - Analysis of Infants Based on Data from the German Perinatal Survey of the Years 1994-2011 in Mecklenburg-Pomerania, Germany. Classification of Infants with regard to their Gestation Duration and Birth Weight. AB - BACKGROUND: The demographic change in -Germany describes an ongoing process of population development of which the eastern German states tend to be more affected. These ongoing changes have an influence on the reproductive behavior of the population. After twenty-three years of German reunification, the present study has investigated the question to what extent the somatic classification of newborns in Mecklenburg-Pomerania (M-P), Germany, is affected. MATERIAL AND METHODS: Newborn singleton births (n=174,084) were classified from the existing data of the German Perinatal Survey between 1994 and 2011. The rate of premature birth, SGA, and LGA rate as well as the rate of low birth weight <=2,499 g were determined both gender-dependently and independently. In addition, a combined analysis of the rates has been taken into account. The obtained data material from M-P made it possible for the first time to compare by values. National and international reference studies were considered in this comparison. RESULTS: In M P, the premature birth rate is 5.2%; the rate of newborns with low birth weight <= 2,499 g is 4.4%. Among newborns of <=2,499 g and SGA newborns, girls compose a higher percentage (4.7%, 12.5%) compared to boys (4.0%, 7.4%). The premature birth rate and LGA newborns appear conversely. For these, the percentage of boys (5.6%, 12.6%) is higher than that of girls (4.8%, 7.0%). 60.6% of the gender non specific newborns <=2,499 g are simultaneously premature newborn infants. Only a very small percentage of 0.5% of SGA newborns is at the same time premature infants and newborns with low birth weight. CONCLUSIONS: By getting nationwide country-specific figures, a detailed analysis of the newborns in M-P can be performed. The analysis supports the existing national values and is a helpful addition for practice-oriented advice. PMID- 25525814 TI - An 8-month history of meningitis in an extremely low birth weight infant? - Long lasting Infection with Ureaplasma parvum. AB - INTRODUCTION: Ureaplasma spp. have been implicated in the pathogenesis of both preterm labor and neonatal morbidity including pneumonia and sepsis and the development of chronic lung disease of prematurity. Data on Ureaplasma meningitis are limited and partly controversially discussed. PATIENT: We report the unique case of a 9-month-old infant with progressive internal hydrocephalus of unknown origin and developmental delay due to a history of>200 days of inflammation of the central nervous system. The female extremely low birth weight infant had been referred to our hospital for ventriculoperitoneal shunt implantation. She had been born at 26+3 weeks of gestation with a birth weight of 940 g. With the exception of a moderate respiratory distress syndrome, postnatal period had been reported uneventful. However, internal hydrocephalus had become manifest at 4 weeks of postnatal age. Intraventricular hemorrhage had not been documented by cranial ultrasound and magnetic resonance imaging. Cerebrospinal fluid (CSF) analysis had repetitively revealed pronounced inflammation reflected by pleocytosis (50-86 leukocytes/MUL, 60% lymphocytes), CSF protein levels of 578 1,026 mg/dL and undetectable CSF glucose. Although suggesting bacterial meningitis, microbial diagnostics had not been indicative, and empirical antibiotics had not affected the CSF findings. On admission to our hospital, CSF analysis still documented significant inflammation (125 leukocytes/MUL, CSF protein 565 mg/dL, CSF glucose<2 mg/dL). RESULTS: Due to a prenatal history of cerclage, we initiated microbial diagnostics on Ureaplasma spp. and Mycoplasma hominis. U. parvum was detected in CSF by culture and PCR, no other pathogens were isolated. On intravenous treatment with chloramphenicol, CSF profile continuously normalized, and cultures and PCR became negative. Treatment was continued for 3 weeks, and the infant was discharged after uncomplicated ventriculoperitoneal shunt placement. During a 12-month observation period she has shown encouraging recovery. CONCLUSION: In preterm infants, in particular, internal hydrocephalus of unknown origin and sustained CSF inflammation are highly suggestive of Ureaplasma meningitis. Our case highlights that infection may escape detection if not explicitly considered, since microbial diagnosis requires complex media and PCR. PMID- 25525816 TI - Thermal conductivity of ordered-disordered material: a case study of superionic Ag2Te. AB - Thermoelectric devices, which can generate electricity from waste heat, offer an attractive pathway for addressing an important niche in the globally growing landscape of energy demand. In the past few decades, the search for high efficiency thermoelectrics has been guided by the concept of 'phonon-glass electron-crystal' (PGEC), i.e. an ideal thermoelectric material should have high carrier mobility and low thermal conductivity. Although remarkable progress has already been made along this line, the efficiency of thermoelectrics is still too poor to compete with other electricity producing methods. Ordered-disordered material, an emerging trend of high performance thermoelectrics under the concept of PGEC, is a new hot topic in the current thermoelectric research community. Taking superionic phase silver telluride (alpha-Ag2Te) as an example, we performed a comprehensive study of the thermal transport properties and of its physical mechanism by means of equilibrium molecular dynamic simulations. The results show that the thermal conductivity of alpha-Ag2Te is intrinsically very low. By analyzing the different contributions to the overall thermal conductivity, we revealed for the first time from atomistic simulations that the vibration of the Te(2-) sublattice dominates the thermal transport of alpha Ag2Te, while the collision between the randomly diffusing Ag(+) ions and the Te(2 ) sublattice yields a significant negative contribution to the thermal transport. We also studied the effect of isotropic compressive stain and carrier concentration on the thermal conductivity of alpha-Ag2Te. It has been found that the thermal conductivity can be largely reduced by applying compressive strain or with stoichiometric quantity modulation. Our studies shed light on the governing mechanism of thermal transport in ordered-disordered materials and could offer useful guidance for engineering the thermal transport properties of superionic conductors in terms of enhancing their thermoelectric performance. PMID- 25525808 TI - Self-recognition of one's own fall recruits the genuine bodily crisis-related brain activity. AB - While bipedalism is a fundamental evolutionary adaptation thought to be essential for the development of the human brain, the erect body is always an inch or two away from falling. Although the neural mechanism for automatically detecting one's own body instability is an important consideration, there have thus far been few functional neuroimaging studies because of the restrictions placed on participants' movements. Here, we used functional magnetic resonance imaging to investigate the neural substrate underlying whole body instability, based on the self-recognition paradigm that uses video stimuli consisting of one's own and others' whole bodies depicted in stable and unstable states. Analyses revealed significant activity in the regions which would be activated during genuine unstable bodily states: The right parieto-insular vestibular cortex, inferior frontal junction, posterior insula and parabrachial nucleus. We argue that these right-lateralized cortical and brainstem regions mediate vestibular information processing for detection of vestibular anomalies, defensive motor responding in which the necessary motor responses are automatically prepared/simulated to protect one's own body, and sympathetic activity as a form of alarm response during whole body instability. PMID- 25525796 TI - Adenovirus small E1A employs the lysine acetylases p300/CBP and tumor suppressor Rb to repress select host genes and promote productive virus infection. AB - Oncogenic transformation by adenovirus small e1a depends on simultaneous interactions with the host lysine acetylases p300/CBP and the tumor suppressor RB. How these interactions influence cellular gene expression remains unclear. We find that e1a displaces RBs from E2F transcription factors and promotes p300 acetylation of RB1 K873/K874 to lock it into a repressing conformation that interacts with repressive chromatin-modifying enzymes. These repressing p300-e1a RB1 complexes specifically interact with host genes that have unusually high p300 association within the gene body. The TGF-β, TNF-, and interleukin-signaling pathway components are enriched among such p300-targeted genes. The p300-e1a-RB1 complex condenses chromatin in a manner dependent on HDAC activity, p300 lysine acetylase activity, the p300 bromodomain, and RB K873/K874 and e1a K239 acetylation to repress host genes that would otherwise inhibit productive virus infection. Thus, adenovirus employs e1a to repress host genes that interfere with viral replication. PMID- 25525817 TI - Complexation of lysozyme with adsorbed PtBS-b-SCPI block polyelectrolyte micelles on silver surface. AB - We present a study of the interaction of the positively charged model protein lysozyme with the negatively charged amphiphilic diblock polyelectrolyte micelles of poly(tert-butylstyrene-b-sodium (sulfamate/carboxylate)isoprene) (PtBS-b-SCPI) on the silver/water interface. The adsorption kinetics are monitored by surface plasmon resonance, and the surface morphology is probed by atomic force microscopy. The micellar adsorption is described by stretched-exponential kinetics, and the micellar layer morphology shows that the micelles do not lose their integrity upon adsorption. The complexation of lysozyme with the adsorbed micellar layers depends on the micelles arrangement and density in the underlying layer, and lysozyme follows the local morphology of the underlying roughness. When the micellar adsorbed amount is small, the layers show low capacity in protein complexation and low resistance in loading. When the micellar adsorbed amount is high, the situation is reversed. The adsorbed layers both with or without added protein are found to be irreversibly adsorbed on the Ag surface. PMID- 25525818 TI - A procedure for transforming indoles into indolequinones. AB - A procedure that converts a series of structurally diverse, readily available indole derivatives to their corresponding indolequinones is described. The three step route commences with an iridium catalyzed C-H borylation to give a 7 borylindole that upon oxidation-hydrolysis affords the 7-hydroxyindole. Subsequent oxidation provides the indolequinone. PMID- 25525806 TI - A multiplex immunoassay method for simultaneous quantification of iron, vitamin A and inflammation status markers. AB - Deficiencies of vitamin A and iron affect a significant portion of the world's population, and efforts to characterize patterns of these deficiencies are hampered by a lack of measurement tools appropriate for large-scale population based surveys. Vitamin A and iron are not easily measured directly, so reliable proxy markers for deficiency status have been identified and adopted. Measurement of inflammatory markers is necessary to interpret vitamin A and iron status markers, because circulating levels are altered by inflammation. We developed a multiplex immunoassay method for simultaneous measurement of five markers relevant to assessing inflammation, vitamin A and iron status: alpha-1-acid glycoprotein, C-reactive protein, retinol binding protein 4, ferritin and soluble transferrin receptor. Serum and plasma specimens were used to optimize the assay protocol. To evaluate assay performance, plasma from 72 volunteers was assayed using the multiplex technique and compared to conventional immunoassay methods for each of the five markers. Results of the new and conventional assay methods were highly correlated (Pearson Correlations of 0.606 to 0.991, p<.0001). Inter assay imprecision for the multiplex panel varied from 1% to 8%, and all samples fell within the limits of quantification for all assays at a single dilution. Absolute values given by the multiplex and conventional assays differed, indicating a need for further work to devise a new standard curve. This multiplexed micronutrient immunoassay technique has excellent potential as a cost effective tool for use in large-scale deficiency assessment efforts. PMID- 25525819 TI - Functionalized graphene oxide nanoparticles for cancer cell-specific delivery of antitumor drug. AB - The unique reduction-triggered functional graphene oxide nanoparticles (GON) with well-defined size and uniform distribution were designed as an innovative drug delivery platform for cancer treatment for the first time, via the redox radical polymerization of methacrylic acid from the polyethylene glycol (PEG) modified GON (GON-PEG), following by cross-linking with cystamine. Thermogravimetric analysis demonstrates that the typical PMAA2-GON-PEG carriers contain about 16 wt % PEG segments and 33 wt % poly(methacrylic acid) (PMAA) brushes. PEG moieties are incorporated to make the drug delivery platforms stealthy during blood circulation. Notably, introducing the cross-linked PMAA brushes efficiently minimizes the premature release of doxorubicin (DOX) in the stimulated normal tissues, and accelerates DOX release in the stimulated tumor tissues through response to reduce agent. The carriers showed a 6-fold faster releasing rate at pH 5.0 in the presence of 10 mM glutathione (GSH) (stimulated tumor tissues) than at pH 7.4 with 10 MUM GSH (stimulated normal tissues). In vitro cytotoxicity test also showed that the cross-linked PMAA2-GON-PEG (CPMAA2-GON-PEG) carriers had remarkable cytocompatibility, and that the DOX-loaded CPMAA2-GON-PEG had excellent killing capability to SiHa cells. PMID- 25525821 TI - Probing the structural and binding mechanism heterogeneity of molecularly imprinted polymers. AB - We devised a strategy, using a de novo building approach, to construct model molecularly imprinted polymers (MIPs) and assess their ability at binding various target molecules. While our models successfully reproduce the gross experimental selectivities for two xanthines, our atomistic models reveal in detail the considerable heterogeneity of the structure and binding mechanisms of different imprints within such a material. We also demonstrate how nonimprinted regions of a MIP are also responsible for much of binding of target molecules. High levels of cross-linking are shown to produce less specific imprints. PMID- 25525820 TI - Patients' Perceptions of Trichiasis Surgery: Results from the Partnership for Rapid Elimination of Trachoma (PRET) Surgery Clinical Trial. AB - PURPOSE: While quality of life surveys have been conducted in trachomatous trichiasis (TT) surgery populations, little is known about patients' perceptions of the surgical experience and outcomes. METHODS: We interviewed a subset of Partnership for the Rapid Elimination of Trachoma (PRET) surgery trial participants 24 months after surgery. Questions focused on current ocular symptoms, perceived daily functioning, physical appearance, and overall perception of surgery. We stratified participants based on surgical outcomes: normal upper eyelid, postoperative TT, or eyelid contour abnormality (ECA) in one or both eyelids. We compared responses between sexes and surgical outcome groups using contingency tables and Fisher's exact tests. RESULTS: A total of 483 individuals participated and 86% were very satisfied with surgery results; 96% reported ocular symptom improvement. Participants with moderate to severe ECA or postoperative TT were more likely to report current ocular problems than those with normal eyelids (46% and 58% vs 34%, respectively; p = 0.01 for each comparison). The most common symptom among participants with moderate to severe postoperative TT was feeling lashes touching (blurred vision was the most common among participants with moderate to severe ECA). Overall, 83% stated surgery improved daily life; participants with ECA were less likely to report improvement than others (p = 0.002). Participants who had moderate or severe postoperative TT were least likely to state that they would undergo repeat surgery (80%), followed by participants with ECA (86%). CONCLUSIONS: Postoperative TT and ECA both reduced satisfaction with surgery, but appeared to influence different aspects of life. Improving surgical outcomes both by reducing recurrence rates and limiting ECAs are essential. PMID- 25525822 TI - Chemical constituents from Licania cruegeriana and their cardiovascular and antiplatelet effects. AB - Three new lupane-type triterpenoids: 6beta,30-dihydroxybetulinic acid glucopyranosyl ester (4), 6beta,30-dihydroxybetulinic acid (5) and 6beta hydroxybetulinic acid (6), were isolated from Licania cruegeriana Urb. along with six known compounds. Their structures were elucidated on the basis of spectroscopic methods, including IR, ESIMS, 1D- and 2D-NMR experiments, as well as by comparison of their spectral data with those of related compounds. All compounds were evaluated in vivo for their effects on the mean arterial blood pressure (MABP) and heart rate (HR) of spontaneously hypertensive rats (SHR) and also in vitro for their capacity to inhibit the human platelet aggregation. None of the isolated flavonoids 1-3 showed cardiovascular effects on SHR and among the isolated triterpenoids 4-9 only 5 and 6 produced a significant reduction in MABP (60.1% and 17.2%, respectively) and an elevation in HR (11.0% and 41.2%, respectively). Compounds 3, 4, 5 and 6 were able to inhibit human platelet aggregation induced by ADP, collagen and arachidonic acid with different selectivity profiles. PMID- 25525824 TI - A sensitive A3B porphyrin nanomaterial for CO2 detection. AB - The present report deals with the tailoring, preparation and characterization of novel nanomaterials sensitive to CO2 for use in detection of this gas during space habitation missions. A new nanostructured material based on mixed substituted asymmetrical A3B porphyrin: 5-(4-pyridyl)-10,15,20-tris(3,4 dimethoxyphenyl)-porphyrin (PyTDMeOPP) was synthesized and characterized by 1H NMR, FT-IR, UV-vis, fluorescence, MS, HPLC and AFM. Introducing one pyridyl substituent in the 5-meso-position of porphyrin macrocycle confers some degree of hydrophilicity, which may cause self-assembly properties and a better response to increased acidity. The influence of pH and nature of the solvent upon H and J aggregates of the porphyrin are discussed. Porphyrin aggregation at the air-THF interface gave a triangular type morphology, randomly distributed but uniformly oriented. When deposition was made by multiple drop-casting operations, a network of triangles of uniform size was created and a porous structure was obtained, being reorganized finally in rings. When the deposition was made from CHCl3, ring structures ranging in internal diameter from 300 nm to 1 um, but with the same width of the corona circular of approx. 200 nm were obtained. This porphyrin based material, capable of generating ring aggregates in both THF and CHCl3, has been proven to be sensitive to CO2 detection. The dependence between the intensity of porphyrin UV-vis absorption and the concentration of CO2 has a good correlation of 98.4%. PMID- 25525823 TI - Antioxidant activity of leaf extracts from different Hibiscus sabdariffa accessions and simultaneous determination five major antioxidant compounds by LC Q-TOF-MS. AB - Hibiscus sabdariffa has gained attention for its antioxidant activity. There are many accessions of H. sabdariffa in the world. However, information on the quantification of antioxidant compounds in different accessions is rather limited. In this paper, a liquid chromatography/quadrupole-time-of-flight mass spectrometry (LC-Q-TOF-MS) method for simultaneous determination of five antioxidant compounds (neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, rutin, and isoquercitrin) in H. sabdariffa leaves was developed. The method was validated for linearity, sensitivity, precision, repeatability and accuracy. The validated method has been successfully applied for determination of the five analytes in eight accessions of H. sabdariffa. The eight accessions of H. sabdariffa were evaluated for their antioxidant activities by DPPH free radical scavenging assay. The investigated accessions of H. sabdariffa were rich in rutin and exhibited strong antioxidant activity. The two accessions showing the highest antioxidant activities were from Cuba (No. 2) and Taiwan (No. 5). The results indicated that H. sabdariffa leaves could be considered as a potential antioxidant source for the food industry. The developed LC-Q-TOF-MS method is helpful for quality control of H. sabdariffa. PMID- 25525825 TI - Largely reduced grid densities in a vibrational self-consistent field treatment do not significantly impact the resultingwavenumbers. AB - Especially for larger molecules relevant to life sciences, vibrational self consistent field (VSCF) calculations can become unmanageably demanding even when only first and second order potential coupling terms are considered. This paper investigates to what extent the grid density of the VSCF's underlying potential energy surface can be reduced without sacrificing accuracy of the resulting wavenumbers. Including single-mode and pair contributions, a reduction to eight points per mode did not introduce a significant deviation but improved the computational efficiency by a factor of four. A mean unsigned deviation of 1.3% from the experiment could be maintained for the fifteen molecules under investigation and the approach was found to be applicable to rigid, semi-rigid and soft vibrational problems likewise. Deprotonated phosphoserine, stabilized by two intramolecular hydrogen bonds, was investigated as an exemplary application. PMID- 25525826 TI - Insecticidal activities of bark, leaf and seed extracts of Zanthoxylum heitzii against the African malaria vector Anopheles gambiae. AB - The olon tree, Zanthoxylum heitzii (syn. Fagara heitzii) is commonly found in the central-west African forests. In the Republic of Congo (Congo-Brazzaville) its bark is anecdotally reported to provide human protection against fleas. Here we assess the insecticidal activities of Z. heitzii stem bark, seed and leaf extracts against Anopheles gambiae s.s, the main malaria vector in Africa. Extracts were obtained by Accelerated Solvent Extraction (ASE) using solvents of different polarity and by classical Soxhlet extraction using hexane as solvent. The insecticidal effects of the crude extracts were evaluated using topical applications of insecticides on mosquitoes of a susceptible reference strain (Kisumu [Kis]), a strain homozygous for the L1014F kdr mutation (kdrKis), and a strain homozygous for the G119S Ace1R allele (AcerKis). The insecticidal activities were measured using LD50 and LD95 and active extracts were characterized by NMR spectroscopy and HPLC chromatography. Results show that the ASE hexane stem bark extract was the most effective compound against An. gambiae (LD50 = 102 ng/mg female), but was not as effective as common synthetic insecticides. Overall, there was no significant difference between the responses of the three mosquito strains to Z. heitzii extracts, indicating no cross resistance with conventional pesticides. PMID- 25525827 TI - Gas sensing properties and p-type response of ALD TiO2 coated carbon nanotubes. AB - Amorphous titanium dioxide-coated carbon nanotubes (CNTs) were prepared by atomic layer deposition (ALD) and investigated as sensing layers for resistive NO2 and O2 gas sensors. By varying ALD process conditions and CNT structure, heterostructures with different metal oxide grain size, morphology and coating thickness were synthesized. Higher responses were observed with homogeneous and continuous 5.5 nm thick films onto CNTs at an operating temperature of 150 degrees C, while CNTs decorated with either discontinuous film or TiO2 nanoparticles showed a weak response close to the one of device made of bare CNTs. An unexpected p-type behavior in presence of the target gas was also noticed, independently of the metal oxide morphology and thickness. Based on previous works, hypotheses were made in order to explain the p-type behavior of TiO2/CNT sensors. PMID- 25525828 TI - Gestational Age Assessment in the Ghana Randomized Air Pollution and Health Study (GRAPHS): Ultrasound Capacity Building, Fetal Biometry Protocol Development, and Ongoing Quality Control. AB - BACKGROUND: Four million premature deaths occur yearly as a result of smoke from cooking fires. The Ghana Randomized Air Pollution and Health Study (GRAPHS) is underway in the Kintampo North municipality and South district of rural Ghana to evaluate the impact of improved cook stoves introduced during pregnancy on birth weight and childhood pneumonia. These hypotheses are being tested in a cluster randomized intervention trial among 1415 maternal-infant pairs within 35 communities assigned to a control arm (traditional cooking) or one of two intervention arms (cooking with an improved biomass stove; cooking with liquefied petroleum gas stoves). OBJECTIVE: The trial is designed to ensure delivery of the stove intervention prior to the period of maximal fetal growth. To answer questions about the impact of household air pollution on pregnancy outcome, accurate gestational age assessment is critical. This manuscript describes in detail the development of the gestational dating protocol, intensive ultrasound training involved, ultrasound capacity building, and ultrasound quality control program. METHODS: Ultrasound training occurred in several phases over the course of 2 years. Training included a basic obstetric ultrasound course offered to all midwives performing antenatal care at the two study hospitals, followed by a more intense period of hands-on training focused on fetal biometry for a select group of providers demonstrating aptitude in the basic course. A standard operating procedure was developed describing how to obtain all fetal biometric measurements. Consensus was obtained on how biometric images are used in the trial to establish gestational age and estimate the delivery date. An ongoing ultrasound quality control program including the use of an image scorecard was also designed. RESULTS: Publication of trial results is anticipated in late 2016. CONCLUSIONS: Use of ultrasound should be strongly considered in field-based trials involving pregnant women to accurately establish gestational age, as menstrual dates may be incorrect or unknown. The inclusion of ultrasound in areas where ultrasound capacity does not previously exist requires a significant investment of time and resources. Such investment ensures appropriate training, high quality images, and accurate dating pregnancies. We outline our ultrasound training, image acquisition, quality control, and dating protocols in detail. TRIAL REGISTRATION: Clinicaltrials.gov NCT01335490; http://clinicaltrials.gov/ct2/show/NCT01335490 (Archived by WebCite at http://www.webcitation.org/6UbERJNO6). PMID- 25525829 TI - [Hospitalisation Rates and Duration of Hospital Stays of Patients from an Ambulatory Health Centre Compared to Traditional General Practices - A Practical Example]. AB - INTRODUCTION: The reduction of treatment costs in the health-care system is a great challenge for all participating persons and institutions in Germany. In particular, we notice an evident increase in the costs of hospitalisation treatment in the last 20 years. The reduction of a further increase in stationary treatment costs by reducing the hospitalisation rate and the duration of stationary treatment as managed by cooperation of general practitioners and medical specialists could be an important possibility. RESEARCH QUESTION: Is it possible to reduce the hospitalisation rate and the duration of the hospital treatment by cooperation of general practitioners and internal specialists in an ambulatory health centre? METHODS: The hospitalisation rate and the average duration of the stationary treatment of the "Praxisgemeinschaft" (PG) of the "Gesundheitscentrum Damme" (GCD) at the local hospital were retrospectively analysed for the years 2002 up to 2011 and compared with the data of the remaining general practitioner offices and the data of the "Deutsche Krankenhausstatistik" (German Hospital statistics). RESULTS: We did indeed find a slight increase for the hospitalisation rate from 0.012 to 0.019% of all the ambulant treated patient cases of the PG; but this increase was statistically significantly lower compared with the results of the remaining practitioner offices of the local area as well the data of the "Deutsche Krankenhausstatistik". Similarly, the duration of hospital treatment for the patients of the PG could be significantly more reduced from 10.80 to 6.49 days compared to the results of the 2 other above-mentioned groups. CONCLUSION: Both the hospitalisation rate as well as the duration of hospital treatment can significantly reduced by cooperation of general practitioner and internal specialist in an ambulatory health centre. PMID- 25525831 TI - Synthesis of novel polyhydroxylated pyrrolidine-triazole/-isoxazole hybrid molecules. AB - A straightforward synthesis of novel, 2-heterocyclyl polyhydroxylated pyrrolidines is described. Stereocontrolled additions of nucleophiles to cyclic nitrones generated the corresponding 2,3-trans adducts, allowing the synthesis of the corresponding pyrrolidines via key intermediates bearing an alkyne and a nitrile oxide. Three hybrid systems, including a pyrrolidine with two isoxazoles and one triazole, are efficiently prepared via 1,3-dipolar cycloaddition. Biological testing of the product alkaloids showed that subtle structural variations have drastic effects on their inhibitory activities against glucosidases. PMID- 25525830 TI - [Human Single Drug Exposures to Non-opioid Analgesics Reported to the Poisons Information Centre Erfurt from 2003 to 2012]. AB - AIM OF THE STUDY: Because of their frequency, non-opioid analgesics (NOA) single drug exposures registered by Poisons Information Centre (PIC) Erfurt have been studied over a decade. METHODS: A retrospective analysis of frequencies, circumstances of exposure, symptom severity, and age groups in NOA single drug exposures received by the PIC Erfurt from the beginning of 2003 to the end of 2012 was undertaken. RESULTS: Of all 4749 NOA single drug exposures, the 10 most frequent were caused by paracetamol (n=1 686), ibuprofen (n=1 439), acetylsalicylic acid (n=456), dipyrone (n=274), diclofenac (n=267), flupirtine (n=138), naproxen (n=41), etoricoxib (n=36), indomethacin (n=24), and dexketoprofen (n=19). Paracetamol single drug exposures increased from 158 in 2003 to 216 in 2007 and fell afterwards to 133 in 2012. Ibuprofen single drug exposures continously rose from 57 in 2003 to 258 in 2012. Adults were more often involved in NOA (53.8%) and all single drug exposures (54.1%) than children (45.9% and 45.6%, respectively). Suicidal attempts were more frequent in NOA (43.1%) than in all single drug exposures (34.2%), whereas accidental exposures or exposures in abuse were less often (33.4 and 0.2%, 46.0 and 0.9% respectively). NOA single drug exposures resulted mostly in none to minor symptoms (77.0%) and rarely in moderate (2.1%) or severe symptoms (1.0%). One adult was found dead after probable ingestion of 32 g of acetylsalicylic acid in suicidal intention. CONCLUSIONS: Because many NOA are over-the-counter drugs, it is difficult to obtain data on their use. PIC data could provide information on the NOA use in the population. PMID- 25525833 TI - Extruded superparamagnetic saloplastic polyelectrolyte nanocomposites. AB - Iron oxide nanoparticles of diameter ca. 12 nm were dispersed into polyelectrolyte complexes made from poly(styrenesulfonate) and poly(diallyldimethylammonium). These nanocomposites were plasticized with salt water and extruded into dense, tough fibers. Magnetometry of these composites showed they retained the superparamagnetic properties of their constituent nanoparticles with saturation magnetization that scaled with the loading of nanoparticles. Their superparamagnetic response allowed the composites to be heated remotely by radiofrequency fields. While the modulus of fibers was unaffected by the presence of nanoparticles the toughness and tensile strength increased significantly. PMID- 25525832 TI - Human mesenchymal stroma/stem cells exchange membrane proteins and alter functionality during interaction with different tumor cell lines. AB - To analyze effects of cellular interaction between human mesenchymal stroma/stem cells (MSC) and different cancer cells, direct co-cultures were performed and revealed significant growth stimulation of the tumor populations and a variety of protein exchanges. More than 90% of MCF-7 and primary human HBCEC699 breast cancer cells as well as NIH:OVCAR-3 ovarian adenocarcinoma cells acquired CD90 proteins during MSC co-culture, respectively. Furthermore, SK-OV-3 ovarian cancer cells progressively elevated CD105 and CD90 proteins in co-culture with MSC. Primary small cell hypercalcemic ovarian carcinoma cells (SCCOHT-1) demonstrated undetectable levels of CD73 and CD105; however, both proteins were significantly increased in the presence of MSC. This co-culture-mediated protein induction was also observed at transcriptional levels and changed functionality of SCCOHT-1 cells by an acquired capability to metabolize 5'cAMP. Moreover, exchange between tumor cells and MSC worked bidirectional, as undetectable expression of epithelial cell adhesion molecule (EpCAM) in MSC significantly increased after co culture with SK-OV-3 or NIH:OVCAR-3 cells. In addition, a small population of chimeric/hybrid cells appeared in each MSC/tumor cell co-culture by spontaneous cell fusion. Immune fluorescence demonstrated nanotube structures and exosomes between MSC and tumor cells, whereas cytochalasin-D partially abolished the intercellular protein transfer. More detailed functional analysis of FACS separated MSC and NIH:OVCAR-3 cells after co-culture revealed the acquisition of epithelial cell-specific properties by MSC, including increased gene expression for cytokeratins and epithelial-like differentiation factors. Vice versa, a variety of transcriptional regulatory genes were down-modulated in NIH:OVCAR-3 cells after co-culture with MSC. Together, these mutual cellular interactions contributed to functional alterations in MSC and tumor cells. PMID- 25525834 TI - Involvement of propionate side chains of the heme in circular dichroism of myoglobin: experimental and theoretical analyses. AB - Incorporation of the heme into globin induces a prominent circular dichroism (CD) band in the Soret region. The appearance of heme optical activity is widely believed to arise from the interaction between the heme and aromatic residues of the globin. However, hemoglobin (Hb) containing the reversed heme exhibits a CD spectrum obviously different from that of native Hb, indicating that the interactions of heme side chains with globin contribute to the appearance of heme optical activity. We examined this possibility by comparing CD spectra of native myoglobin (Mb) and those of Mb reconstituted with synthetic hemes lacking vinyl and/or propionate. Replacement of 2,4-vinyl groups with methyl induced moderate changes. In contrast, replacement of 6,7-propionate groups with carboxylate resulted in complete disappearance of the positive Soret CD band. To get theoretical basis for the contributions of 6,7-side chains on the band, we investigated the CD spectra at a time-dependent density functional theory level. In the antiparallel conformation of the 6,7-side chains, the rotational strengths were calculated to be positive, on the other hand in the parallel conformation to be negative. We also found that the weak Soret CD band in 2,4-dimethyl-6,7 dicarboxyheme can be explained by canceling between different carboxyl conformers. PMID- 25525835 TI - Prebiotic effects of a novel combination of galactooligosaccharides and maltodextrins. AB - Prebiotics are used for stimulating the growth of beneficial microorganisms in the gut. However, it is very difficult to find a suitable prebiotic mixture that exclusively supports the growth of beneficial microbes such as bifidobacteria and lactobacilli. We tested the effects of a prebiotic mixture in vitro by incubating it with fecal samples and in vivo by administration of the prebiotic supplement to healthy adult volunteers, followed by analysis of their fecal microbiota. The effect of the oligosaccharides on bacterial metabolism was studied by analyzing short-chain fatty acid (SCFA) production in vitro and the SCFA pattern for the stool samples of volunteers. In the in vitro test, a higher proportion of bifidobacteria (25.77%) was seen in the total bacterial population after cultivation on a prebiotic mixture than on the control medium (7.94%). The gram negative anaerobe count significantly decreased from 8.70 to 6.40 log CFU/g (from 35.21% to 0.60%) and the Escherichia coli count decreased from 7.41 to 6.27 log CFU/g (from 1.78% to 0.44%). Administration of a prebiotic mixture in vivo (9 g of galactooligosaccharides [GOS]+1 g of maltodextrins; daily for 5 days) significantly increased the fecal bifidobacterial count from 9.45 to 9.83 log CFU/g (from 40.80% to 53.85% of total bacteria) and reduced the E. coli count from 7.23 to 6.28 log CFU/g (from 55.35% to 45.06% of total bacteria). The mixture comprising GOS and maltodextrins thus exhibited bifidogenic properties, promoting the performance of bifidobacteria by boosting their growth and inhibiting the growth of undesirable bacteria. PMID- 25525836 TI - Catalytic, self-cleaning surface with stable superhydrophobic properties: printed polydimethylsiloxane (PDMS) arrays embedded with TiO2 nanoparticles. AB - Maintaining the long-term stability of superhydrophobic surfaces is challenging because of contamination from organic molecules and proteins that render the surface hydrophilic. Reactive oxygen species generated on a photocatalyst, such as TiO2, could mitigate this effect by oxidizing these contaminants. However, incorporation of such catalyst particles into a superhydrophobic surface is challenging because the particles become hydrophilic under UV exposure, causing the surface to transition to the Wenzel state. Here we show that a high concentration of hydrophilic TiO2 catalytic nanoparticles can be incorporated into a superhydrophobic surface by partially embedding the particles into a printed array of high aspect ratio polydimethylsiloxane posts. A stable Cassie state was maintained on these surfaces, even under UV irradiation, because of the significant degree of hierarchical roughness. By printing the surface on a porous support, oxygen could be flowed through the plastron, resulting in higher photooxidation rates relative to a static ambient. Rhodamine B and bovine serum albumin were photooxidized both in solution and after drying onto these TiO2 containing surfaces, and the effects of particle location and plastron gas composition were studied in static and flowing gas environments. This approach may prove useful for water purification, medical devices, and other applications where Cassie stability is required in the presence of organic compounds. PMID- 25525837 TI - Effect of size and N-terminal residue characteristics on bacterial cell penetration and antibacterial activity of the proline-rich peptide Bac7. AB - Bac7 is a proline-rich antimicrobial peptide, selective for Gram-negative bacteria, which acts intracellularly after membrane translocation. Progressively shortened fragments of Bac7 allowed determining the minimal sequence required for entry and antimicrobial activity as a 16-residue, N-terminal fragment, while further shortening led to a marked decrease in both functions. Furthermore, two N terminal arginine residues were required for efficient translocation and activity. Analogues in which these residues were omitted, or where the side chain steric or physicochemical characteristics were systematically altered, were tested on different Escherichia coli strains, including a mutant with a destabilized outer membrane and one lacking the relevant SbmA membrane transport protein. H-bonding capacity, stereochemistry, and charge, in that order, played a determining role for efficient transit through both the outer and cytoplasmic membranes. Our studies allowed building a more detailed model for the mode-of action of Bac7, and confirming its potential as an anti-infective agent, also suggesting it may be a vehicle for internalization of other antibiotic cargo. PMID- 25525839 TI - Minimizing morbidity in radiation oncology: a special issue from Future Oncology. PMID- 25525838 TI - Who is looking after Mom and Dad? Unregulated workers in Canadian long-term care homes. AB - Older adults living in residential long-term care or nursing homes have increasingly complex needs, including more dementia than in the past, yet we know little about the unregulated workforce providing care. We surveyed 1,381 care aides in a representative sample of 30 urban nursing homes in the three Canadian Prairie provinces and report demographic, health and well-being, and work-related characteristics. Over 50 per cent of respondents were not born in Canada and did not speak English as their first language. They reported moderately high levels of burnout and a strong sense of their work's worth. Few respondents reported attending educational sessions. This direct caregiver workforce is poorly understood, has limited training or standards for minimum education, and training varies widely across provinces. Workplace characteristics affecting care aides reflect factors that precipitate burnout in allied health professions, with implications for quality of care, staff health, and staff retention. PMID- 25525840 TI - Best of the Radiosurgery Society(r) Scientific Meeting 2014: stereotactic radiosurgery/stereotactic body radiotherapy treatment of extracranial and intracranial lesions. AB - The SRS/SBRT Scientific Meeting 2014, Minneapolis, MN, USA, 7-10 May 2014. The Radiosurgery Society((r)), a professional medical society dedicated to advancing the field of stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT), held the international Radiosurgery Society Scientific Meeting, from 7-10 May 2014 in Minneapolis (MN, USA). This year's conference attracted over 400 attendants from around the world and featured over 100 presentations (46 oral) describing the role of SRS/SBRT for the treatment of intracranial and extracranial malignant and nonmalignant lesions. This article summarizes the meeting highlights for SRS/SBRT treatments, both intracranial and extracranial, in a concise review. PMID- 25525841 TI - Chest wall and rib irradiation and toxicities of early-stage lung cancer patients treated with CyberKnife stereotactic body radiotherapy. AB - AIM: The aim of the study is to evaluate the chest wall and rib toxicities in primary lung cancer patients treated with CyberKnife-based stereotactic body radiotherapy. MATERIALS & METHODS: In this study, data were collected from the 118 patients, of which 25 patients who had longer follow-up (mean: 21.9 months) were considered. Studied parameters were maximum point dose, doses to 1-100 cm(3) of chest wall and 1-10 cm(3) of ribs. RESULTS: Three patients developed chest wall pain (grade I). 25 studied patients, on average, received 27.7 Gy to 30 cm(3) of chest wall and 50.4 Gy to 1 cm(3) of rib. Nine patients had more than 30 Gy dose to 30 cm(3) of chest wall. No rib bone fracture was found. CONCLUSION: No correlations of chest wall pain and volume of irradiation were found. PMID- 25525842 TI - The promise of combining radiation therapy and immunotherapy: morbidity and toxicity. AB - Radiation therapy and immunotherapy in partnership may have the capability of delivering a therapeutic effect exceeding the sum of its parts. The possible relationship has been demonstrated in murine models and has been extended to a variety of clinical trials. Though the standard notion of whole body radiation therapy is immunosuppressive, there is growing evidence toward the contrary for focal radiation therapy. Furthermore, if immunotherapeutic techniques can retune the immune system against cancerous cells, they should have obvious benefits for advanced treatments moving forward. Herein, we explore the promise in combining radiation therapy and immunotherapy with distinct focus on potential morbidities and toxicities through analysis of completed clinical trials. PMID- 25525843 TI - Radiation oncology: physics advances that minimize morbidity. AB - Radiation therapy has become an ever more successful treatment for many cancer patients. This is due in large part from advances in physics including the expanded use of imaging protocols combined with ever more precise therapy devices such as linear and particle beam accelerators, all contributing to treatments with far fewer side effects. This paper will review current state-of-the-art physics maneuvers that minimize morbidity, such as intensity-modulated radiation therapy, volummetric arc therapy, image-guided radiation, radiosurgery and particle beam treatment. We will also highlight future physics enhancements on the horizon such as MRI during treatment and intensity-modulated hadron therapy, all with the continued goal of improved clinical outcomes. PMID- 25525844 TI - Radioprotective agents for radiation therapy: future trends. AB - Only two radioprotective compounds, amifostine and palifermin, currently have the US FDA approval for use in radiation therapy. However, several agents have been reported that show therapeutic promise. Many of these agents are free radical scavengers/antioxidants. Superoxide dismutase and superoxide dismutase mimetics, nitroxides and dietary antioxidants are all being investigated. Recently, alternative strategies of drug development have been evolving, which focus on targeting the series of cellular insult recognition/repair responses initiated following radiation. These agents, which include cytokines/growth factors, angiotensin-converting enzyme inhibitors and apoptotic modulators, show promise of having significant impact on the mitigation of radiation injury. Herein, we review current literature on the development of radioprotectors with emphasis on compounds with proven or potential usefulness in radiation therapy. PMID- 25525845 TI - Radiobiological modifiers in clinical radiation oncology: current reality and future potential. AB - Radiation therapy can successfully ablate tumors. However, the same ionization process that destroys a cancer can also permanently damage surrounding organs resulting in unwanted clinical morbidity. Therefore, modern radiation therapy attempts to minimize dose to normal tissue to prevent side effects. Still, as tumors and normal tissues intercalate, the risk of normal tissue injury often may prevent tumoricidal doses of radiation therapy to be delivered. This paper will review current outcomes and limitations of radiobiological modifiers that may selectively enhance the radiosensitivity of tumors as well as parallel techniques that may protect normal tissues from radiation injury. Future endeavors based in part upon newly elucidated genetic pathways will be highlighted. PMID- 25525846 TI - The use of angiotensin II receptor antagonists to increase the efficacy of radiotherapy in cancer treatment. AB - Angiotensin II receptor antagonists inhibit various signaling pathways involved in the regulation of inflammation, apoptosis and angiogenesis. Radiation-induced activation of a proinflammatory cytokine network has been shown to mediate normal tissue injury induced by ionizing radiation in cancer patients, resulting in serious side effects. Hence, not only do angiotensin II receptor antagonists block inflammatory signaling both in cancer cells and in normal cells, but they are also effective in the treatment of cancer by inhibiting tumor progression, vascularization and metastasis. This review addresses the role of angiotensin II inhibitors in cancer therapy, and their potential to increase therapeutical index by protecting normal cells and sensitizing tumor cells to radiotherapy. PMID- 25525847 TI - Radiogenomics: the search for genetic predictors of radiotherapy response. AB - 'Radiogenomics' is the study of genetic variation associated with response to radiotherapy. Radiogenomics aims to uncover the genes and biologic pathways responsible for radiotherapy toxicity that could be targeted with radioprotective agents and; identify genetic markers that can be used in risk prediction models in the clinic. The long-term goal of the field is to develop single nucleotide polymorphism-based risk models that can be used to stratify patients to more precisely tailored radiotherapy protocols. The field has evolved over the last two decades in parallel with advances in genomics, moving from narrowly focused candidate gene studies to large, collaborative genome-wide association studies. Several confirmed genetic variants have been identified and the field is making progress toward clinical translation. PMID- 25525848 TI - Music therapy in cancer patients: fact or fiction? PMID- 25525849 TI - Highlights from the latest findings in tumor molecular profiling. PMID- 25525850 TI - Uncommon breast metastatic site and eribulin responsiveness in a heavily pretreated patient. AB - During the last decades, the introduction of new cytotoxics and targeted therapies resulted in a prolongation of survival and a minimization of toxicity in the treatment of metastatic breast cancer. However, to date, there was no standard of care following second-line therapy in this setting. In Phase III EMBRACE study, eribulin obtained a statistically significant improvement in the overall survival of pretreated metastatic breast cancer patients. This case report describes a heavily chemo-pretreated woman with important bone, nodal, hepatic and choroidal involvement from breast cancer who had a remarkable, unexpected and lasting disease response after treatment with eribulin. This case underlines how this well-tolerated monochemotherapy may be able to obtain a prolonged disease control and a good clinical outcome. PMID- 25525851 TI - Pleural effusion in a patient with metastatic gastrointestinal stromal tumor treated with imatinib: case report. AB - Gastrointestinal stromal tumors are rare malignancies characterized by c-kit and PDGFR-alpha mutations targeted by imatinib. Pleural effusion is a very rare side effect of imatinib treatment. A 65-year-old female with metastatic gastrointestinal stromal tumor developed electrolyte imbalance, severe peripheral edema and progressively worsening dyspnea 2 months after starting imatinib. Having excluded cardiovascular and pulmonary disorders, imatinib was discontinued and prednisone 25 mg orally daily was begun. The patient's condition improved substantially over the next 48 h with a progressive decrease in dyspnea and a reduction in pleural effusion and peripheral edema. All side effects had resolved within 1 month. In view of the partial response obtained, the patient re-started imatinib after a 1-week interruption. Prednisone was maintained and there was no further toxicity. PMID- 25525852 TI - A rare case of anal porocarcinoma treated by electrochemotherapy. AB - We report the case of an old woman with an eccrine porocarcinoma unusually localized in the perianal area treated by electrochemotherapy, a new technique, emerging as a very effective local treatment of different skin metastases and selected primary tumors. Electrochemotherapy was performed taking into account patient wishes and refusal of demolitive surgery. The electrochemotherapy treatment was well tolerated by the patient, it gave an excellent clinical response and a complete clinical regression with no sphincter dysfunction and signs of relapse observed during follow-up. The case is of particular interest for the exceptional localization of porocarcinoma for the first time treated by electrochemotherapy in this area. Electrochemotherapy could be considered as an alternative option for selected cases of cutaneous tumors. PMID- 25525853 TI - Upregulated genes at 2q24 gains as candidate oncogenes in hepatoblastomas. AB - AIM: Cytogenetic data of hepatoblastomas, a rare embryonal tumor of the liver, mostly consist of descriptions of whole-chromosome aneuploidies and large chromosome alterations. High-resolution cytogenetics may provide clues to hepatoblastoma tumorigenesis and indicate markers with clinical significance. PATIENTS & METHODS: We used array-CGH (180K) to screen for genomic imbalances in nine hepatoblastomas. Additionally, we investigated the expression pattern of selected genes exhibiting copy number changes. RESULTS: Analysis showed mainly whole-chromosome or chromosome-arm aneuploidies, but some focal aberrations were also mapped. Expression analysis of 48 genes mapped at one 10 Mb amplification at 2q24 revealed upregulation of DAPL1, ERMN, GALNT5, SCN1A and SCN3A in the set of tumors compared with differentiated livers. CONCLUSION: These genes appear as candidates for hepatoblastoma tumorigenesis. PMID- 25525854 TI - BMI variation increases recurrence risk in women with early-stage breast cancer. AB - AIMS: The prognostic role of BMI variation during and/or after treatments for early-stage breast cancer is still unknown. PATIENTS & METHODS: The chi(2) test was conducted to explore the correlation between breast cancer recurrence and BMI changes in 520 early-stage breast cancer patients. Cox proportional hazard models were used to analyze the association of BMI changes, baseline BMI, known prognostic factors and recurrences. RESULTS: BMI gain was significant determinant of recurrences (p = 0.0008). In multivariate analyses, BMI variation more than 5.71% was associated with higher rates of recurrences, as well as age less than 55 years, stage disease and molecular subtype. CONCLUSION: Women who experience BMI gain after breast cancer may be at increased risk of poor outcomes. PMID- 25525855 TI - On the contribution of S100A10 and annexin A2 to plasminogen activation and oncogenesis: an enduring ambiguity. AB - Plasminogen receptors are becoming increasingly relevant in regulating many diseases such as cancer, stroke and inflammation. However, controversy has emerged concerning the putative role of some receptors, in particular annexin A2, in binding plasminogen. Several reports failed to account for the effects of annexin A2 on the stability and conformation of its binding partner S100A10. This has created an enduring ambiguity as to the actual function of annexin A2 in plasmin regulation. Supported by a long line of evidence, we conclude that S100A10, and not annexin A2, is the primary plasminogen receptor within the annexin A2-S100A10 complex and contributes to the plasmin-mediated effects that were originally ascribed to annexin A2. PMID- 25525856 TI - Rituximab: modes of action, remaining dispute and future perspective. AB - Less than two decades ago, immunotherapy joined chemotherapy and radiotherapy as an effective approach for the treatment of cancer. The anti-CD20 monoclonal antibody, rituximab, is now used to treat almost all types of non-Hodgkin's B cell lymphomas, and it could be useful in the treatment of other diseases with B cell involvement. Upon binding, rituximab induces death of the target cells. It seems to act not only by activating immune system defense mechanisms such as complement-dependent and antibody-dependent cellular cytotoxicity, but also by inducing direct cell death. In this paper, we review current knowledge on rituximab mechanisms of action, with particular attention to its direct effects, and also highlight potential future avenues of research. PMID- 25525857 TI - Clinical and molecular prognostic and predictive biomarkers in clear cell renal cell cancer. AB - The natural history of clear cell renal cell cancer is highly unpredictable with various progressors and with populations where small renal masses may be accompanied by metastatic disease. Currently, there is a critical need to determine patient risk and optimize treatment regimes. For these patients, molecular markers may offer significant information in terms of prognostic and predictive values, as well as determination of valid therapeutic targets. Until now, only a few of the many identified clear cell renal cell cancer biomarkers have been clinically validated in large cohorts. And only several biomarkers are integrated in predictive or prognostic models. Therefore, a large cohesive effort is required to advance the field of clear cell renal cell cancer prognostic biomarkers through systematic discovery, verification, validation and clinical implementation. PMID- 25525858 TI - Genetic and molecular targets in lymphoma: implications for prognosis and treatment. AB - Lymphomas are the most common hematologic malignancies with approximately 79,000 new cases estimated for 2013 in the USA. Despite improved outcomes, relapse or recurrence remains a common problem with conventional cytotoxic therapy. Recently, many genetic and molecular mechanisms that drive various cellular events like apoptosis, angiogenesis and cell motility have been more clearly delineated. These new findings, coupled with the advent of high-throughput screening technology have led to the discovery of many compounds that can target specific mutations and/or influence deregulated transcription. In this review, we intend to provide a concise overview of genetic and molecular events that drive cellular processes in lymphomas and represent potential therapeutic targets. Additionally, we briefly discuss the prognostic significance of select biological markers. PMID- 25525859 TI - Mutual action of anticancer and antiparasitic drugs: are there any shared targets? AB - Parasites and cancers have some common features. It has been shown that some parasites interfere with tumor growth. In addition, they both have common antigens such as the Tn antigen. A communal action of anticancer and antiparasitic drugs has been reported. This shared action may be related to common targets for these drugs in cancers and parasites. In this paper, mutual action of anticancer and antiparasitic drugs, with the aim of discussing shared targets of these drugs, has been reviewed. PMID- 25525860 TI - Effects of sulfamethazine on denitrification and the associated N2O release in estuarine and coastal sediments. AB - Denitrification is an important pathway of nitrogen removal and nitrous oxide (N2O) production in estuarine and coastal ecosystems, and plays a significant role in counteracting aquatic eutrophication induced by excessive nitrogen loads. Estuarine and coastal environments also suffer from increasing antibiotic contamination because of the growing production and usage of antibiotics. In this study, sediment slurry incubation experiments were conducted to determine the influence of sulfamethazine (SMT, a sulphonamide antibiotic) on denitrification and the associated N2O production. Genes important for denitrification and antibiotic resistance were quantified to investigate the microbial physiological mechanisms underlying SMT's effects on denitrification. SMT was observed to significantly inhibit denitrification rates, but increasing concentrations of SMT enhanced N2O release rates. The negative exponential relationships between denitrifying gene abundances and SMT concentrations showed that SMT reduced denitrification rates by restricting the growth of denitrifying bacteria, although the presence of the antibiotic resistance gene was detected during the incubation period. These results imply that the wide occurrence of residual antibiotics in estuarine and coastal ecosystems may influence eutrophication control, greenhouse effects, and atmospheric ozone depletion by inhibiting denitrification and stimulating the release of N2O. PMID- 25525863 TI - Ligand-induced conformational changes with cation ejection upon binding to human telomeric DNA G-quadruplexes. AB - The rational design of ligands targeting human telomeric DNA G-quadruplexes is a complex problem due to the structural polymorphism that these sequences can adopt in physiological conditions. Moreover, the ability of ligands to switch conformational equilibria between different G-quadruplex structures is often overlooked in docking approaches. Here, we demonstrate that three of the most potent G-quadruplex ligands (360A, Phen-DC3, and pyridostatin) induce conformational changes of telomeric DNA G-quadruplexes to an antiparallel structure (as determined by circular dichroism) containing only one specifically coordinated K(+) (as determined by electrospray mass spectrometry) and, hence, presumably only two consecutive G-quartets. Control ligands TrisQ, known to bind preferentially to hybrid than to antiparallel structures, and L2H2-6M(2)OTD, known not to disrupt the hybrid-1 structure, did not show such K(+) removal. Instead, binding of the cyclic oxazole L2H2-6M(2)OTD was accompanied by the uptake of one additional K(+). Also contrasting with telomeric G-quadruplexes, the parallel-stranded Pu24-myc G-quadruplex, to which Phen-DC3 is known to bind by end-stacking, did not undergo cation removal upon ligand binding. Our study therefore evidences that very affine ligands can induce conformational switching of the human telomeric G-quadruplexes to an antiparallel structure and that this conformational change is accompanied by removal of one interquartet cation. PMID- 25525864 TI - Two-dimensional metal-organic surfaces for efficient hydrogen evolution from water. AB - Hydrogen production through the reduction of water has emerged as an important strategy for the storage of renewable energy in chemical bonds. One attractive scenario for the construction of efficient devices for electrochemical splitting of water requires the attachment of stable and active hydrogen evolving catalysts to electrode surfaces, which remains a significant challenge. We demonstrate here the successful integration of cobalt dithiolene catalysts into a metal-organic surface to generate very active electrocatalytic cathode materials for hydrogen generation from water. These surfaces display high catalyst loadings and remarkable stability even under very acidic aqueous solutions. PMID- 25525862 TI - Neurotrophins and cognitive functions in T1D compared with healthy controls: effects of a high-intensity exercise. AB - Exercise is known to have beneficial effects on cognitive function. This effect is greatly favored by an exercise-induced increase in neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF 1), especially with high-intensity exercises (HIE). As a complication of type 1 diabetes (T1D), a cognitive decline may occur, mostly ascribed to hypoglycaemia and chronic hyperglycaemia. Therefore, the purpose of this study was to examine the effects of acute HIE on cognitive function and neurotrophins in T1D and matched controls. Ten trained T1D (8 males, 2 females) participants and their matched (by age, sex, fitness level) controls were evaluated on 2 occasions after familiarization: a maximal test to exhaustion and an HIE bout (10 intervals of 60 s at 90% of their maximal wattage followed by 60 s at 50 W). Cognitive tests and analyses of serum BDNF, IGF-1, and free insulin were performed before and after HIE and following 30 min of recovery. At baseline, cognitive performance was better in the controls compared with the T1D participants (p < 0.05). After exercise, no significant differences in cognitive performance were detected. BDNF levels were significantly higher and IGF-1 levels were significantly lower in T1D compared with the control group (p < 0.05) at all time points. Exercise increased BDNF and IGF-1 levels in a comparable percentage in both groups (p < 0.05). In conclusion, although resting levels of serum BDNF and IGF-1 were altered by T1D, comparable increasing effects on BDNF and IGF-1 in T1D and healthy participants were found. Therefore, regularly repeating acute HIE could be a promising strategy for brain health in T1D. PMID- 25525865 TI - Disposing and recycling waste printed circuit boards: disconnecting, resource recovery, and pollution control. AB - Over the past decades, China has been suffering from negative environmental impacts from distempered e-waste recycling activities. After a decade of effort, disassembly and raw materials recycling of environmentally friendly e-waste have been realized in specialized companies, in China, and law enforcement for illegal activities of e-waste recycling has also been made more and more strict. So up to now, the e-waste recycling in China should be developed toward more depth and refinement to promote industrial production of e-waste resource recovery. Waste printed circuit boards (WPCBs), which are the most complex, hazardous, and valuable components of e-waste, are selected as one typical example in this article that reviews the status of related regulations and technologies of WPCBs recycling, then optimizes, and integrates the proper approaches in existence, while the bottlenecks in the WPCBs recycling system are analyzed, and some preliminary experiments of pinch technologies are also conducted. Finally, in order to provide directional guidance for future development of WPCBs recycling, some key points in the WPCBs recycling system are proposed to point towards a future trend in the e-waste recycling industry. PMID- 25525867 TI - Punctuated equilibria in publishing. PMID- 25525868 TI - Microexons go big. AB - Microexons are frequently underestimated in transcriptome analyses. Two studies published in Cell and Genome Research now independently report the identification of hundreds of microexons. Alternative splicing of some microexons is regulated by neuronal-specific RNA-binding proteins and modifies the function of proteins involved in neurogenesis, with misregulation linked to autism. PMID- 25525866 TI - Graves' ophthalmopathy: the role of diffusion-weighted imaging in detecting involvement of extraocular muscles in early period of disease. AB - OBJECTIVE: To evaluate involvement of the extraocular muscle (EOM) using diffusion-weighted imaging (DWI), to determine whether there is correlation with conventional orbital MRI and apparent diffusion coefficient (ADC) values in patients with Graves' ophthalmopathy (GO). METHODS: 35 patients known clinically with GO and 21 healthy controls were studied. Patients were assessed with clinical activity scores. All subjects underwent conventional MRI and DWI study. Involvement of the EOM was evaluated. The patients were classified as involved or uninvolved on orbital MRI and their ADC values in DWI compared. RESULTS: There was significant difference in the mean ADC value of all the EOMs in patients vs controls. The ADC values of all the EOMs were higher in patients. There were significant differences in ADC values between uninvolved muscles on conventional MRI and controls for the MR, SR and LR. There was no significant difference in ADC value between the two groups when considering the IR. ADC values of medial, lateral and superior rectus muscles were increased. CONCLUSION: Increased ADC values of the EOM in patients with GO suggest that EOM damage begins at a very early stage before being detected on routine orbital MRI. The routine MRI with DWI sequence will be a useful adjunct in the selection of a group of patients most likely to benefit from early treatment. ADVANCES IN KNOWLEDGE: This study can help to evaluate the involvement of GO in early period with MRI added DWI. PMID- 25525869 TI - Super-enhancer transcription converges on AID. AB - AID mis-targeting is poorly understood but contributes significantly to B cell genome instability. Two new papers in Cell reveal that AID mistargeting occurs primarily in gene bodies within a nuclear microenvironment characterized by high levels of transcriptional activity, interconnected transcriptional regulatory elements, and overlapping sense and antisense (convergent) transcription. PMID- 25525870 TI - Acetate fuels the cancer engine. AB - Cancer cells have distinctive nutrient demands to fuel growth and proliferation, including the disproportionate use of glucose, glutamine, and fatty acids. Comerford et al. and Mashimo et al. now demonstrate that several types of cancer are avid consumers of acetate, which facilitates macromolecular biosynthesis and histone modification. PMID- 25525871 TI - A new "spin" on recovery after spinal cord injury. AB - Functional recovery can occur after incomplete spinal cord injury. Takeoka et al. now report that such recovery relies on muscle spindle feedback that is necessary for neuronal circuit remodeling, suggesting novel targets to restore motor functions following spinal cord injuries. PMID- 25525872 TI - Host evasion and exploitation schemes of Mycobacterium tuberculosis. AB - Tuberculosis, an ancient disease of mankind, remains one of the major infectious causes of human death. We examine newly discovered facets of tuberculosis pathogenesis and explore the evolution of its causative organism Mycobacterium tuberculosis from soil dweller to human pathogen. M. tuberculosis has coevolved with the human host to evade and exploit host macrophages and other immune cells in multiple ways. Though the host can often clear infection, the organism can cause transmissible disease in enough individuals to sustain itself. Tuberculosis is a near-perfect paradigm of a host-pathogen relationship, and that may be the challenge to the development of new therapies for its eradication. PMID- 25525873 TI - A highly conserved program of neuronal microexons is misregulated in autistic brains. AB - Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide "microexons" display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein-interaction networks during neurogenesis, the misregulation of which is linked to autism. PMID- 25525874 TI - Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. AB - Activated caspases are a hallmark of apoptosis induced by the intrinsic pathway, but they are dispensable for cell death and the apoptotic clearance of cells in vivo. This has led to the suggestion that caspases are activated not just to kill but to prevent dying cells from triggering a host immune response. Here, we show that the caspase cascade suppresses type I interferon (IFN) production by cells undergoing Bak/Bax-mediated apoptosis. Bak and Bax trigger the release of mitochondrial DNA. This is recognized by the cGAS/STING-dependent DNA sensing pathway, which initiates IFN production. Activated caspases attenuate this response. Pharmacological caspase inhibition or genetic deletion of caspase-9, Apaf-1, or caspase-3/7 causes dying cells to secrete IFN-beta. In vivo, this precipitates an elevation in IFN-beta levels and consequent hematopoietic stem cell dysfunction, which is corrected by loss of Bak and Bax. Thus, the apoptotic caspase cascade functions to render mitochondrial apoptosis immunologically silent. PMID- 25525875 TI - Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. AB - The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify a mechanism by which mitochondria and downstream proapoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell intrinsic inducer of the IFN response and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a proinflammatory type of cell death. PMID- 25525876 TI - Dual proteolytic pathways govern glycolysis and immune competence. AB - Proteasomes and lysosomes constitute the major cellular systems that catabolize proteins to recycle free amino acids for energy and new protein synthesis. Tripeptidyl peptidase II (TPPII) is a large cytosolic proteolytic complex that functions in tandem with the proteasome-ubiquitin protein degradation pathway. We found that autosomal recessive TPP2 mutations cause recurrent infections, autoimmunity, and neurodevelopmental delay in humans. We show that a major function of TPPII in mammalian cells is to maintain amino acid levels and that TPPII-deficient cells compensate by increasing lysosome number and proteolytic activity. However, the overabundant lysosomes derange cellular metabolism by consuming the key glycolytic enzyme hexokinase-2 through chaperone-mediated autophagy. This reduces glycolysis and impairs the production of effector cytokines, including IFN-gamma and IL-1beta. Thus, TPPII controls the balance between intracellular amino acid availability, lysosome number, and glycolysis, which is vital for adaptive and innate immunity and neurodevelopmental health. PMID- 25525877 TI - Acetate dependence of tumors. AB - Acetyl-CoA represents a central node of carbon metabolism that plays a key role in bioenergetics, cell proliferation, and the regulation of gene expression. Highly glycolytic or hypoxic tumors must produce sufficient quantities of this metabolite to support cell growth and survival under nutrient-limiting conditions. Here, we show that the nucleocytosolic acetyl-CoA synthetase enzyme, ACSS2, supplies a key source of acetyl-CoA for tumors by capturing acetate as a carbon source. Despite exhibiting no gross deficits in growth or development, adult mice lacking ACSS2 exhibit a significant reduction in tumor burden in two different models of hepatocellular carcinoma. ACSS2 is expressed in a large proportion of human tumors, and its activity is responsible for the majority of cellular acetate uptake into both lipids and histones. These observations may qualify ACSS2 as a targetable metabolic vulnerability of a wide spectrum of tumors. PMID- 25525878 TI - Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. AB - Glioblastomas and brain metastases are highly proliferative brain tumors with short survival times. Previously, using (13)C-NMR analysis of brain tumors resected from patients during infusion of (13)C-glucose, we demonstrated that there is robust oxidation of glucose in the citric acid cycle, yet glucose contributes less than 50% of the carbons to the acetyl-CoA pool. Here, we show that primary and metastatic mouse orthotopic brain tumors have the capacity to oxidize [1,2-(13)C]acetate and can do so while simultaneously oxidizing [1,6 (13)C]glucose. The tumors do not oxidize [U-(13)C]glutamine. In vivo oxidation of [1,2-(13)C]acetate was validated in brain tumor patients and was correlated with expression of acetyl-CoA synthetase enzyme 2, ACSS2. Together, the data demonstrate a strikingly common metabolic phenotype in diverse brain tumors that includes the ability to oxidize acetate in the citric acid cycle. This adaptation may be important for meeting the high biosynthetic and bioenergetic demands of malignant growth. PMID- 25525880 TI - Muscle spindle feedback directs locomotor recovery and circuit reorganization after spinal cord injury. AB - Spinal cord injuries alter motor function by disconnecting neural circuits above and below the lesion, rendering sensory inputs a primary source of direct external drive to neuronal networks caudal to the injury. Here, we studied mice lacking functional muscle spindle feedback to determine the role of this sensory channel in gait control and locomotor recovery after spinal cord injury. High resolution kinematic analysis of intact mutant mice revealed proficient execution in basic locomotor tasks but poor performance in a precision task. After injury, wild-type mice spontaneously recovered basic locomotor function, whereas mice with deficient muscle spindle feedback failed to regain control over the hindlimb on the lesioned side. Virus-mediated tracing demonstrated that mutant mice exhibit defective rearrangements of descending circuits projecting to deprived spinal segments during recovery. Our findings reveal an essential role for muscle spindle feedback in directing basic locomotor recovery and facilitating circuit reorganization after spinal cord injury. PMID- 25525879 TI - Sirtuin 4 is a lipoamidase regulating pyruvate dehydrogenase complex activity. AB - Sirtuins (SIRTs) are critical enzymes that govern genome regulation, metabolism, and aging. Despite conserved deacetylase domains, mitochondrial SIRT4 and SIRT5 have little to no deacetylase activity, and a robust catalytic activity for SIRT4 has been elusive. Here, we establish SIRT4 as a cellular lipoamidase that regulates the pyruvate dehydrogenase complex (PDH). Importantly, SIRT4 catalytic efficiency for lipoyl- and biotinyl-lysine modifications is superior to its deacetylation activity. PDH, which converts pyruvate to acetyl-CoA, has been known to be primarily regulated by phosphorylation of its E1 component. We determine that SIRT4 enzymatically hydrolyzes the lipoamide cofactors from the E2 component dihydrolipoyllysine acetyltransferase (DLAT), diminishing PDH activity. We demonstrate SIRT4-mediated regulation of DLAT lipoyl levels and PDH activity in cells and in vivo, in mouse liver. Furthermore, metabolic flux switching via glutamine stimulation induces SIRT4 lipoamidase activity to inhibit PDH, highlighting SIRT4 as a guardian of cellular metabolism. PMID- 25525881 TI - The cellular and molecular basis of direction selectivity of Adelta-LTMRs. AB - The perception of touch, including the direction of stimulus movement across the skin, begins with activation of low-threshold mechanosensory neurons (LTMRs) that innervate the skin. Here, we show that murine Adelta-LTMRs are preferentially tuned to deflection of body hairs in the caudal-to-rostral direction. This tuning property is explained by the finding that Adelta-LTMR lanceolate endings around hair follicles are polarized; they are concentrated on the caudal (downward) side of each hair follicle. The neurotrophic factor BDNF is synthesized in epithelial cells on the caudal, but not rostral, side of hair follicles, in close proximity to Adelta-LTMR lanceolate endings, which express TrkB. Moreover, ablation of BDNF in hair follicle epithelial cells disrupts polarization of Adelta-LTMR lanceolate endings and results in randomization of Adelta-LTMR responses to hair deflection. Thus, BDNF-TrkB signaling directs polarization of Adelta-LTMR lanceolate endings, which underlies direction-selective responsiveness of Adelta-LTMRs to hair deflection. PMID- 25525882 TI - Detecting envelope stress by monitoring beta-barrel assembly. AB - The cell envelope protects bacteria from their surroundings. Defects in its integrity or assembly are sensed by signal transduction systems, allowing cells to rapidly adjust. The Rcs phosphorelay responds to outer membrane (OM)- and peptidoglycan-related stress in enterobacteria. We elucidated how the OM lipoprotein RcsF, the upstream Rcs component, senses envelope stress and activates the signaling cascade. RcsF interacts with BamA, the major component of the beta-barrel assembly machinery. In growing cells, BamA continuously funnels RcsF through the beta-barrel OmpA, displaying RcsF on the cell surface. This process spatially separates RcsF from the downstream Rcs component, which we show is the inner membrane protein IgaA. The Rcs system is activated when BamA fails to bind RcsF and funnel it to OmpA. Newly synthesized RcsF then remains periplasmic, interacting with IgaA to activate the cascade. Thus RcsF senses envelope damage by monitoring the activity of the Bam machinery. PMID- 25525884 TI - SnapShot: GPCR-Ligand Interactions. AB - G-protein-coupled receptors enable cells to recognize numerous external stimuli and to transmit corresponding signals across the plasma membrane to trigger appropriate cellular responses. Crystal structures of a number of these receptors have now been determined in inactive and active conformations bound to chemically and functionally distinct ligands. These crystal structures illustrate overall receptor organization and atomic details of ligand-receptor interactions. PMID- 25525885 TI - Synthesis, structure, and superconductivity in the new-structure-type compound: SrPt6P2. AB - A metal-rich ternary phosphide, SrPt(6)P(2), with a unique structure type was synthesized at high temperatures. Its crystal structure was determined by single crystal X-ray diffraction [cubic space group Pa3; Z = 4; a = 8.474(2) A, and V = 608.51(2) A(3)]. The structure features a unique three-dimensional anionic (Pt(6)P(2))(2-) network of vertex-shared Pt(6)P trigonal prisms. The Sr atoms occupy a 12-coordinate (Pt) cage site and form a cubic close-packed (face centered-cubic) arrangement, and the P atoms formally occupy tetrahedral interstices. The metallic compound becomes superconducting at 0.6 K, as evidenced by magnetic and resistivity measurements. PMID- 25525883 TI - X chromosome reactivation dynamics reveal stages of reprogramming to pluripotency. AB - Reprogramming to iPSCs resets the epigenome of somatic cells, including the reversal of X chromosome inactivation. We sought to gain insight into the steps underlying the reprogramming process by examining the means by which reprogramming leads to X chromosome reactivation (XCR). Analyzing single cells in situ, we found that hallmarks of the inactive X (Xi) change sequentially, providing a direct readout of reprogramming progression. Several epigenetic changes on the Xi occur in the inverse order of developmental X inactivation, whereas others are uncoupled from this sequence. Among the latter, DNA methylation has an extraordinary long persistence on the Xi during reprogramming, and, like Xist expression, is erased only after pluripotency genes are activated. Mechanistically, XCR requires both DNA demethylation and Xist silencing, ensuring that only cells undergoing faithful reprogramming initiate XCR. Our study defines the epigenetic state of multiple sequential reprogramming intermediates and establishes a paradigm for studying cell fate transitions during reprogramming. PMID- 25525886 TI - Monascus secondary metabolites monascin and ankaflavin inhibit activation of RBL 2H3 cells. AB - Monascus-fermented products have been used as dietary food and traditional medicine due to their beneficial effects on circulation and digestive systems in Asia for thousands of years. Besides, monascin and ankaflavin, secondary metabolites from Monascus-fermented products, have proven anti-inflammatory and immunomodulatory effects. In previous research, monascin and ankaflavin ameliorated ovalbumin-induced airway allergic reaction often used as a type I allergy asthma model. Additionally, mast cells play critical roles in type I allergy. Therefore, RBL-2H3 cells were used as the mast cell model to determine whether the improving effects on asthma of monascin and ankaflavin came from influencing mast cells. PMA and ionomycin are common activators of mast cells because they stimulate the main signaling molecules during mast cell activation. Forty micromolar monascin and ankaflavin inhibited PMA/ionomycin-induced mast cell degranulation and TNF-alpha secretion through suppressing the phosphorylation of PKC and MAPK family ERK, JNK, and p38. Consequently, monascin and ankaflavin affected the activation of mast cells and may have the potential to improve type I allergy. PMID- 25525889 TI - Reliability of Lymphoscintigraphy. PMID- 25525887 TI - ApoHRP-based assay to measure intracellular regulatory heme. AB - The majority of the heme-binding proteins possess a "heme-pocket" that stably binds to heme. Usually known as housekeeping heme-proteins, they participate in a variety of metabolic reactions (e.g., catalase). Heme also binds with lower affinity to the "Heme-Regulatory Motifs" (HRM) in specific regulatory proteins. This type of heme binding is known as exchangeable or regulatory heme (RH). Heme binding to HRM proteins regulates their function (e.g., Bach1). Although there are well-established methods for assaying total cellular heme (e.g., heme proteins plus RH), currently there is no method available for measuring RH independent of the total heme (TH). The current study describes and validates a new method to measure intracellular RH. This method is based on the reconstitution of apo-horseradish peroxidase (apoHRP) with heme to form holoHRP. The resulting holoHRP activity is then measured with a colorimetric substrate. The results show that apoHRP specifically binds RH but not with heme from housekeeping heme-proteins. The RH assay detects intracellular RH. Furthermore, using conditions that create positive (hemin) or negative (N-methyl protoporphyrin IX) controls for heme in normal human fibroblasts (IMR90), the RH assay shows that RH is dynamic and independent of TH. We also demonstrated that short-term exposure to subcytotoxic concentrations of lead (Pb), mercury (Hg), or amyloid-beta (Abeta) significantly alters intracellular RH with little effect on TH. In conclusion the RH assay is an effective assay to investigate intracellular RH concentration and demonstrates that RH represents ~6% of total heme in IMR90 cells. PMID- 25525888 TI - A phase 1b, open-label study of trebananib plus bevacizumab or motesanib in patients with solid tumours. AB - BACKGROUND: To examine the angiopoietin pathway inhibitor trebananib IV plus the anti-VEGF agents bevacizumab or motesanib in advanced solid tumours. METHODS: In this open-label phase 1b study, patients received IV trebananib 3 mg kg-1 QW plus bevacizumab 15 mg kg-1 Q3W (cohort 1) or motesanib orally 75 mg (cohort 2); or trebananib 10 mg kg-1 plus bevacizumab 15 mg kg-1 (cohort 3) or motesanib 125 mg (cohort 4). If <33% of patients had dose-limiting toxicities (DLTs), dose escalation occurred. Endpoints were treatment-related adverse events (AEs) incidence and pharmacokinetics (primary); anti-trebananib antibodies, biomarkers, and tumour response (secondary). RESULTS: Thirty-six patients received >= 1 dose of trebananib (cohorts 1, 2, 3, 4; n = 6, 8, 19, 3). DLT of G3 intestinal perforation and G3 tumor haemorrhage occurred in cohorts 2 and 3, respectively (both n = 1). Across both trebananib plus bevacizumab cohorts, the most common AEs included fatigue (n = 8), diarrhoea (n =4), constipation (n = 3), nausea (n = 3), and epistaxis (n = 3). Three patients across those cohorts had grade >= 3 AEs. Across the trebananib plus motesanib cohorts, the most common AEs included hypertension (n = 4), diarrhoea (n = 4), nausea (n = 3), fatigue (n = 3), vomiting (n = 2), and decreased appetite (n = 2). Two patients had grade >= 3 AEs. Trebananib did not markedly affect motesanib pharmacokinetics. Across the trebananib plus bevacizumab cohorts, two patients had a partial response; 11 patients had stable disease lasting >6 months. Across the trebananib plus motesanib cohorts, one patient had a partial response; five patients had stable disease lasting >6 months. CONCLUSION: Trebananib IV 3 mg kg-1 or 10 mg kg-1 plus bevacizumab or motesanib in advanced solid tumours may be associated with less severe toxicities relative to those emerging when combining two anti-VEGF agents. PMID- 25525890 TI - Impact of simulated hyperopia on academic-related performance in children. AB - PURPOSE: To investigate the impact of simulated hyperopia and sustained near work on children's ability to perform a range of academic-related tasks. METHODS: Fifteen visually normal children (mean [+/-SD] age, 10.9 [+/-0.8] years; 10 male and 5 female) were recruited. Performance on a range of standardized academic related outcome measures was assessed with and without 2.50 diopters of simulated bilateral hyperopia (administered in a randomized order), before and after 20 minutes of sustained near work, at two separate testing sessions. Academic related measures included a standardized reading test (the Neale Analysis of Reading Ability), visual information processing tests (the Coding and Symbol Search subtests from the Wechsler Intelligence Scale for Children), and a reading related eye movement test (the Developmental Eye Movement test). RESULTS: Simulated bilateral hyperopia and sustained near work each independently impaired reading, visual information processing, and reading-related eye movement performance (p < 0.001). A significant interaction was also demonstrated between these factors (p < 0.05), with the greatest decrement in performance observed when simulated hyperopia was combined with sustained near work. This combination resulted in performance reductions of between 5 and 24% across the range of academic-related measures. A significant moderate correlation was also found between the change in horizontal near heterophoria and the change in several of the academic-related outcome measures, after the addition of simulated hyperopia. CONCLUSIONS: A relatively low level of simulated bilateral hyperopia impaired children's performance on a range of academic-related outcome measures, with sustained near work further exacerbating this effect. Further investigations are required to determine the impact of correcting low levels of hyperopia on academic performance in children. PMID- 25525891 TI - Visual Performance of a Multifocal Contact Lens versus Monovision in Established Presbyopes. AB - PURPOSE: To compare subjective and objective visual performance of the Air Optix Aqua Multifocal lens to monovision in a group of subjects requiring a medium level of reading-addition power. METHODS: Fifty participants with reading additions between 1.25 and 2.00 diopters (inclusive) were randomized into a prospective, crossover clinical trial. They wore monovision and multifocals for 2 weeks in a randomized order. High- and low-contrast logMAR (logarithm of the minimum angle of resolution) acuity and stereopsis were measured at the beginning and end of each period. During each phase, participants performed specific tasks followed by subjective rating surveys and also completed satisfaction rating surveys on days 3, 7, and 12; all were transferred in real time using BlackBerry smartphones. A general rating survey was completed at the dispensing and 2-week visits. RESULTS: Forty-nine participants completed the study (mean age, 52 years). Distance and near high- and low-contrast acuities were significantly better (p < 0.05) with monovision at all visits. High-contrast intermediate acuity was only better (p < 0.05) with multifocals after 2 weeks. Stereopsis was equivalent after 2 weeks, but better (p < 0.05) with multifocals at dispensing. Subjective ratings were generally equivalent between modalities although there was a trend for multifocals to be rated higher for focus changing and driving, whereas monovision tended to be rated higher for near tasks. For both corrections, the satisfaction survey showed no significant change between days 3, 7, and 12, and the general survey showed that comfort was maintained but subjective vision ratings decreased significantly over the 2 weeks. Twenty-five participants (51%) preferred multifocals, 18 (37%) preferred monovision, and the remaining 6 (12%) declared both unacceptable. CONCLUSIONS: In this cohort, distance and near acuities were better with monovision, whereas the subjective ratings tended to favor the Air Optix Aqua Multifocal, with the exception of near performance. Preference was statistically similar between both corrections, with a trend toward preferring the multifocal. PMID- 25525892 TI - Arteriole tortuosity associated with diabetic retinopathy and cholesterol. AB - PURPOSE: Earlier identification of diabetic eye disease is an important research effort. Retinopathy is widely acknowledged but retinal vessel changes are not evaluated as stringently. Here, we create a multivariate model for the association between retinal vessel tortuosity (RVT) and other health factors in patients with diabetes. METHODS: Three hundred eyes of 150 patients with diabetes were included. Three investigators independently reviewed telemedicine fundus photographs and scored the level of diabetic retinopathy (DR) and RVT. These scores were evaluated for agreement and averaged. Also collected were age, duration of diabetes, presence or absence of diabetic nephropathy or neuropathy, blood pressure, total cholesterol, and hemoglobin A1c. A regression model evaluating the association of tortuosity with other factors was created. RESULTS: There was very high agreement between the three graders for level of DR (kappa = 0.84). Agreement between the three graders for RVT varied substantially: poor for venous tortuosity (kappa = 0.23) and fair for arteriole tortuosity (kappa = 0.44) and overall gut tortuosity (kappa = 0.42). The overall gut tortuosity was the most reproducible for the graders with a correlation coefficient of 0.923. There were univariate associations between arteriole tortuosity and venous tortuosity, DR level, and cholesterol. The selected best multivariate model found arteriole tortuosity to be associated with DR and cholesterol levels. CONCLUSIONS: First, RVT, particularly for venules, is difficult to grade consistently; therefore, future studies examining tortuosity should focus on arterioles. Second, the model indicates that there is an association between vessel changes, DR, and systemic cholesterol levels. Although DR and RVT are readily available to assess concurrently on a photograph, the addition of cholesterol to this model indicates that patients with RVT may warrant further follow-up on health factors, such as cholesterol levels. PMID- 25525893 TI - Zonisamide-induced angle closure and myopic shift. AB - PURPOSE: To present a previously unreported case of angle closure secondary to the sulfonamide derivative zonisamide, to introduce eye care providers to zonisamide, and to review sulfonamide-induced angle closure. Zonisamide is a relatively new sulfonamide derivative indicated for epilepsy and used off-label for migraines. Although angle closure secondary to systemic medications such as topiramate and other sulfonamide derivatives is well documented, this is the first case of zonisamide-induced angle closure and myopic shift to be reported. CASE REPORT: A 39-year-old Hispanic woman presented with sudden vision loss OU with a concurrent bilateral frontal headache. No changes in health were reported other than initiating zonisamide for refractory migraines 2 weeks prior. Ocular history was significant only for low myopia. Entering visual acuities were 20/400 OD, OS. Manifest refraction revealed a 3-diopter myopic shift OU with best corrected visual acuities of 20/20 OD, OS. On slit lamp examination, the anterior chamber angles were narrow OU and gonioscopy confirmed partially occluded angles OU. The intraocular pressures were elevated OU. B-scan ultrasonography exhibited peripheral choroidal effusion OU. With discontinuation of zonisamide, the patient experienced full recovery. CONCLUSIONS: With increasing use of zonisamide, practitioners should be aware of its sulfonamide derivative properties and the risk of secondary angle closure. PMID- 25525894 TI - Spectral Domain OCT Imaging Techniques in Tamoxifen Retinopathy. AB - PURPOSE: To highlight the use of high-density spectral domain optical coherence tomography (SD-OCT) in the detection of tamoxifen retinopathy. CASE REPORT: An 82 year-old asymptomatic woman with a history of tamoxifen therapy for breast cancer was found to have bilateral refractile retinal deposits on fundus examination. Detection on SD-OCT was compared across imaging techniques. High-density SD-OCT demonstrated hyperreflective deposits in the inner retinal layers of each eye consistent with the diagnosis of tamoxifen retinopathy. CONCLUSIONS: The optimal SD-OCT scan technique depends on the ocular condition being imaged. High-density scan techniques require longer acquisition time but may enhance the detection of focal retinal pathology. PMID- 25525895 TI - Inconsistent Denoising and Clustering Algorithms for Amplicon Sequence Data. AB - Natural microbial communities have been studied for decades using the 16S rRNA gene as a marker. In recent years, the application of second-generation sequencing technologies has revolutionized our understanding of the structure and function of microbial communities in complex environments. Using these highly parallel techniques, a detailed description of community characteristics are constructed, and even the rare biosphere can be detected. The new approaches carry numerous advantages and lack many features that skewed the results using traditional techniques, but we are still facing serious bias, and the lack of reliable comparability of produced results. Here, we contrasted publicly available amplicon sequence data analysis algorithms by using two different data sets, one with defined clone-based structure, and one with food spoilage community with well-studied communities. We aimed to assess which software and parameters produce results that resemble the benchmark community best, how large differences can be detected between methods, and whether these differences are statistically significant. The results suggest that commonly accepted denoising and clustering methods used in different combinations produce significantly different outcome: clustering method impacts greatly on the number of operational taxonomic units (OTUs) and denoising algorithm influences more on taxonomic affiliations. The magnitude of the OTU number difference was up to 40-fold and the disparity between results seemed highly dependent on the community structure and diversity. Statistically significant differences in taxonomies between methods were seen even at phylum level. However, the application of effective denoising method seemed to even out the differences produced by clustering. PMID- 25525902 TI - Five-year assessment of maintenance combined physical therapy in postmastectomy lymphedema. AB - BACKGROUND: Combined physical therapy (CPT) is the treatment of choice for patients with lymphedema. Intensive stage CPT (I-CPT) results in a substantial reduction of the size of lymphedema, while the second stage CPT (M-CPT) maintains the achieved result for many years. AIM: The article analyses the outcome M-CPT for 5 years in patients with lymphedema after mastectomy. METHODS: Forty patients had regularly been attending follow-up appointments every six months for five years (Group A). Out of the group of patients who had not been reporting for follow-up, twenty women accepted an invitation for assessment (Group B); none of them complied with the prescribed compression therapy. All patients were submitted to I-CPT and patients from group A completed M-CPT comprising compression garments and an individual program of physical exercises. RESULTS: During five-year M-CPT, the difference in limb volumes (Vo), relative size of edema (Vor) reduction achieved after I-CPT was maintained in Group A, while in Group B a considerable increase of Vo by 14% was noted. Ultimately lymphedema in these patients was more pronounced than before their physical therapy had commenced. For 40 women using compression sleeves the mean Suitability Score System was 8.3 points on maximum 11-point scale, for 15 patients wearing additional compression gloves, the mean score was 4.3 points on maximum 5 points. CONCLUSIONS: The reduction of lymphedema achieved during I-CPT can be retained during M-CPT when the patient systematically attends follow-up examinations, applies compression therapy, and follows the therapy instructions. Non-compliance is followed by a worsening of lymphedema. PMID- 25525903 TI - Facile and green assembly of nanocomposite membranes for fuel cells. AB - We report on a facile spray deposition method, which allows obtaining nanocomposite membranes for high-temperature polymer fuel cells characterized by high homogeneity and excellent proton conductivity. The proposed method is also green, as it requires much smaller amounts of solvents with respect to standard casting. PMID- 25525904 TI - Structure and function of the membrane anchoring self-assembled monolayers. AB - Structure of the self-assembled monolayers (SAMs) used to anchor phospholipid bilayers to surfaces affects the functional properties of the tethered bilayer membranes (tBLMs). SAMs of the same surface composition differing in the lateral distribution of the anchor molecule give rise to tBLMs of profoundly different defectiveness with residual conductance spanning 3 orders of magnitude. SAMs composed of anchors containing saturated alkyl chains, upon exposure to water (72 h), reconstruct to tightly packed clusters as deduced from reflection absorption infrared spectroscopy data and directly visualized by atomic force microscopy. The rearrangement into clusters results in an inability to establish highly insulating tBLMs on the same anchor layer. Unexpectedly, we also found that nanometer scale smooth gold film surfaces, populated predominantly with (111) facets, exhibit poor performance from the standpoint of the defectiveness of the anchored phospholipid bilayers, while corrugated (110) dominant surfaces produced SAMs with superior tethering quality. Although the detailed mechanism of cluster formation remains to be clarified, it appears that smooth surfaces favor lateral translocation of the molecular anchors, resulting in changes in functional properties of the SAMs. This work unequivocally establishes that conditions that favor cluster formation of the anchoring molecules in tBLM formation must be identified and avoided for the functional use of tBLMs in biomedical and diagnostic applications. PMID- 25525905 TI - Determination by GC*GC of fatty acid and conjugated linoleic acid (CLA) isomer profiles in six selected tissues of lambs fed on pasture or on indoor diets with and without rumen-protected CLA. AB - In this study GC*GC was used to study the effects of pasture, hay, concentrate (indoor), and indoor plus 8 g/day of a rumen-protected conjugated linoleic acid (indoor-CLA) diets on the detailed fatty acid (FA) profiles of six tissues (muscles, fatty tissues, and liver) collected from 36 lambs. This powerful technique allowed the quantification of 128 FAs, of which 21 SFAs, 16 MUFAs, 19 PUFAs were identified by reference standards. The diets had similar, but not identical, effects on FA profiles (g/100 g FA) in the various tissues, as both indoor diets reduced total PUFAs (from 8.91 +/- 6.27 to 8.06 +/- 5.97; p < 0.05) and n-3 PUFAs (from 2.70 +/- 2.37 to 1.50 +/- 1.69; p < 0.01) and increased n-6 PUFA (from 3.76 +/- 2.46 to 4.58 +/- 3.42; p < 0.01), branched (from 2.37 +/- 2.05 to 3.23 +/- 0.54; p < 0.01), odd-chain FAs (from 5.88 +/- 5.33 to 7.07 +/- 1.51; p < 0.01) compared to pasture. Indoor-CLA increased CLAc9,t11 (from 0.42 +/ 0.13 to 0.53 +/- 0.19; p < 0.01), CLAt10,c12 (from 0.07 +/- 0.06 to 0.12 +/- 0.22; p < 0.05), and CLAc11,t13 (from 0.02 +/- 0.04 to 0.05 +/- 0.04; p < 0.05) compared to indoor. PMID- 25525906 TI - Rapid and scalable assembly of firefly luciferase substrates. AB - Bioluminescence imaging with luciferase-luciferin pairs is a popular method for visualizing biological processes in vivo. Unfortunately, most luciferins are difficult to access and remain prohibitively expensive for some imaging applications. Here we report cost-effective and efficient syntheses of d luciferin and 6'-aminoluciferin, two widely used bioluminescent substrates. Our approach employs inexpensive anilines and Appel's salt to generate the luciferin cores in a single pot. Additionally, the syntheses are scalable and can provide multi-gram quantities of both substrates. The streamlined production and improved accessibility of luciferin reagents will bolster in vivo imaging efforts. PMID- 25525907 TI - Assessing photoreceptor structure after macular hole closure. AB - PURPOSE: To describe photoreceptor structure and recovery after macular hole (MH) closure with pars plana vitrectomy (PPV) using adaptive optics scanning light ophthalmoscopy and spectral domain optical coherence tomography. METHODS: A pilot imaging study of four eyes from four subjects undergoing PPV for MH was conducted. Imaging with spectral domain optical coherence tomography and adaptive optics scanning light ophthalmoscopy was performed at varying time points after PPV. RESULTS: Despite successful MH closure, disruption of the foveal inner segment ellipsoid zone was seen in all patients when imaged at a mean of 117 days after PPV. Disruption of the photoreceptor mosaic was seen using adaptive optics scanning light ophthalmoscopy at locations corresponding to regions of ellipsoid zone disruption on spectral domain optical coherence tomography. Cone density immediately surrounding these disruptions was normal, except for one patient. In 2 patients who were imaged serially up to 516 days after PPV, recovery of cone cells within regions of mosaic disruption could be detected over time. CONCLUSION: Photoreceptor disruption exists even after apparent MH closure. Remodeling of the foveal cone mosaic continues for many months after surgery, perhaps accounting for the delayed postoperative improvements of visual acuity in some patients. Spectral domain optical coherence tomography and adaptive optics scanning light ophthalmoscopy are useful tools for monitoring photoreceptor recovery after surgical closure of MH. PMID- 25525910 TI - Pd-catalyzed dehydrogenative aryl-aryl bond formation via double C(sp(2))-H bond activation: efficient synthesis of [3,4]-fused oxindoles. AB - A Pd(0)-catalyzed double cyclization of easily available o-bromoanilides leading to strained [3,4]-fused oxindoles was developed. The reaction proceeded through a highly ordered sequence involving key carbopalladation, 1,4-Pd migration, and C(sp(2))-H functionalization steps. PMID- 25525911 TI - Fabrication of multiple heterojunctions with tunable visible-light-active photocatalytic reactivity in BiOBr-BiOI full-range composites based on microstructure modulation and band structures. AB - The fabrication of multiple heterojunctions with tunable photocatalytic reactivity in full-range BiOBr-BiOI composites based on microstructure modulation and band structures is demonstrated. The multiple heterojunctions are constructed by precipitation at room temperature and characterized systematically. Photocatalytic experiments indicate that there are two types of heterostructures with distinct photocatalytic mechanisms, both of which can greatly enhance the visible-light photocatalytic performance for the decomposition of organic pollutants and generation of photocurrent. The large separation and inhibited recombination of electron-hole pairs rendered by the heterostructures are confirmed by electrochemical impedance spectra (EIS) and photoluminescence (PL). Reactive species trapping, nitroblue tetrazolium (NBT, detection agent of (*)O2( )) transformation, and terephthalic acid photoluminescence (TA-PL) experiments verify the charge-transfer mechanism derived from the two types of heterostructures, as well as different enhancements of the photocatalytic activity. This article provides insights into heterostructure photocatalysis and describes a novel way to design and fabricate high-performance semiconductor composites. PMID- 25525912 TI - Droplets: unconventional protocell model with life-like dynamics and room to grow. AB - Over the past few decades, several protocell models have been developed that mimic certain essential characteristics of living cells. These protocells tend to be highly reductionist simplifications of living cells with prominent bilayer membrane boundaries, encapsulated metabolisms and/or encapsulated biologically derived polymers as potential sources of information coding. In parallel with this conventional work, a novel protocell model based on droplets is also being developed. Such water-in-oil and oil-in-water droplet systems can possess chemical and biochemical transformations and biomolecule production, self movement, self-division, individuality, group dynamics, and perhaps the fundamentals of intelligent systems and evolution. Given the diverse functionality possible with droplets as mimics of living cells, this system has the potential to be the first true embodiment of artificial life that is an orthologous departure from the one familiar type of biological life. This paper will synthesize the recent activity to develop droplets as protocell models. PMID- 25525913 TI - Message from the editor-in-chief. PMID- 25525909 TI - Architectural insight into inovirus-associated vectors (IAVs) and development of IAV-based vaccines inducing humoral and cellular responses: implications in HIV-1 vaccines. AB - Inovirus-associated vectors (IAVs) are engineered, non-lytic, filamentous bacteriophages that are assembled primarily from thousands of copies of the major coat protein gp8 and just five copies of each of the four minor coat proteins gp3, gp6, gp7 and gp9. Inovirus display studies have shown that the architecture of inoviruses makes all coat proteins of the inoviral particle accessible to the outside. This particular feature of IAVs allows foreign antigenic peptides to be displayed on the outer surface of the virion fused to its coat proteins and for more than two decades has been exploited in many applications including antibody or peptide display libraries, drug design, and vaccine development against infectious and non-infectious diseases. As vaccine carriers, IAVs have been shown to elicit both a cellular and humoral response against various pathogens through the display of antibody epitopes on their coat proteins. Despite their high immunogenicity, the goal of developing an effective vaccine against HIV-1 has not yet materialized. One possible limitation of previous efforts was the use of broadly neutralizing antibodies, which exhibited autoreactivity properties. In the past five years, however, new, more potent broadly neutralizing antibodies that do not exhibit autoreactivity properties have been isolated from HIV-1 infected individuals, suggesting that vaccination strategies aimed at producing such broadly neutralizing antibodies may confer protection against infection. The utilization of these new, broadly neutralizing antibodies in combination with the architectural traits of IAVs have driven the current developments in the design of an inovirus-based vaccine against HIV-1. This article reviews the applications of IAVs in vaccine development, with particular emphasis on the design of inoviral-based vaccines against HIV-1. PMID- 25525914 TI - Message from the editors. PMID- 25525916 TI - HLA typing. PMID- 25525918 TI - Anthony Monaco, MD: Harvard transplantation surgeon and retiring editor of Transplantation, 1971-2014. PMID- 25525917 TI - The first live birth subsequent to uterus transplantation. PMID- 25525919 TI - Chronic kidney disease in disadvantaged populations. AB - The increased burden of CKD in disadavantaged populations is due to both global factors and population-specific issues. Low socioeconomic status and poor access to care contribute to health care disparities, and exacerbate the negative effects of genetic or biologic predisposition. Provision of appropriate renal care to these populations requires a two-pronged approach: expanding the reach of dialysis through development of low-cost alternatives that can be practiced in remote locations, and implementation and evaluation of cost-effective prevention strategies. Kidney transplantation should be promoted by expanding deceased donor transplant programs and use of inexpensive, generic immunosuppressive drugs. The message of WKD 2015 is that a concerted attack against the diseases that lead to ESRD, by increasing community outreach, better education, improved economic opportunity, and access to preventive medicine for those at highest risk, could end the unacceptable relationship between CKD and disadvantage in these communities. PMID- 25525920 TI - Post hoc analyses: after the facts. AB - Prospective clinical trials are constructed with high levels of internal validity. Sample size and power considerations usually address primary endpoints. Primary endpoints have traditionally included events that are becoming increasingly less common and thus have led to growing use of composite endpoints and noninferiority trial designs in transplantation. This approach may mask real clinical benefit in one or the other domain with regard to either clinically relevant secondary endpoints or other unexpected findings. In addition, endpoints solely chosen based on power considerations are prone to misjudgment of actual treatment effect size as well as consistency of that effect. In the instances where treatment effects may have been underestimated, valuable information may be lost if buried within a composite endpoint. In all these cases, analyses and post hoc analyses of data become relevant in informing practitioners about clinical benefits or safety signals that may not be captured by the primary endpoint. On the other hand, there are many pitfalls in using post hoc determined endpoints. This short review is meant to allow readers to appreciate post hoc analysis not as an entity with a single approach, but rather as an analysis with unique limitations and strengths that often raise new questions to be addressed in further inquiries. PMID- 25525922 TI - Successful repair of donation after circulatory death lungs with large pulmonary embolus using the lung organ care system for ex vivo thrombolysis and subsequent clinical transplantation. PMID- 25525921 TI - Memory B cells in transplantation. AB - Much of the research on the humoral response to allografts has focused on circulating serum antibodies and the long-lived plasma cells that produce these antibodies. In contrast, the interrogation of the quiescent memory B cell compartment is technically more challenging and thus has not been incorporated into the clinical diagnostic or prognostic toolkit. In this review, we discuss new technologies that have allowed this heretofore enigmatic subset of B cells to be identified at quiescence and during a recall response. These technologies in experimental models are providing new insights into memory B cell heterogeneity with respect to their phenotype, cellular function, and the antibodies they produce. Similar technologies are also allowing for the identification of comparable memory alloreactive B cells in transplant recipients. Although much of the focus in transplant immunology has been on controlling the alloreactive B cell population, long-term transplant patient survival is also critically dependent on protection by pathogen-specific memory B cells. Techniques are available that allow the interrogation of memory B cell response to pathogen re encounter. Thus, we are poised in our ability to investigate how immunosuppression affects allospecific and pathogen-specific memory B cells, and reason that these investigations can yield new insights that will be beneficial for graft and patient survival. PMID- 25525923 TI - Polyomavirus-cystitis associated with in situ and invasive urothelial carcinoma in a heart transplant recipient: evidence suggesting sequential progression/evolution from infection to carcinoma. PMID- 25525924 TI - Uncovering of body mass index as a risk factor for poor long-term outcome after renal transplantation. PMID- 25525925 TI - Kidney transplantation and obesity: distinct measures at different periods are associated with dissimilar outcomes. PMID- 25525926 TI - Extensive heterogeneity of human urokinase, as detected by two-dimensional mapping. AB - Urokinase (uPA, urinary plasminogen activator) is a serine protease belonging to the peptidase S1 family. Specifically, uPA cleaves the zymogen plasminogen into the active form (plasmin), which then degrades the fibrin clots. It is widely used as a fibrinolytic agent in thrombolytic therapy and it is also used clinically as a thrombolytic agent. It can be administered to improve the drainage of complicated pleural effusions and empyemas and it is the most effective drug in myocardial infarction. The enzyme was originally identified in human urine for its ability to catalyze the transformation of plasminogen into its active form (plasmin), which degrades fibrin and extracellular matrix components. The present report deals with the analysis and characterization of this preparation. PMID- 25525928 TI - DXA variations and fractures after simultaneous pancreas-renal transplantation: results of a long-term follow-up. AB - Simultaneous pancreas-kidney transplant (SPKT) has been associated with an increased risk of fracture. We prospectively evaluated the long-term effects of SPKT on bone mineral density (BMD) and fracture risk. During 1998 to 1999, 29 participants were consecutively monitored, and 18 completed the 10-year follow up. Laboratory blood parameters, lumbar-dorsal radiography, and DEXA were determined at baseline, 1 year, and 10 years. The medical record was reviewed for peripheral fragility fractures. The BMD revealed no changes between baseline and 1 or 10 years after SPKT. Lumbar-dorsal radiography showed 0% asymptomatic vertebral fractures at baseline and after 1 year with 16.7% at 10 years. Vertebral asymptomatic fractures were correlated with acute rejection episodes (P = 0.025). During the first year, no nonvertebral fractures were identified. At the end of the follow-up, 5 nonvertebral fractures in 4 patients were reported. Dorsal and lumbar spine fractures correlated with lumbar spine t score (r = 0.591, P =0.022) and peripheral fractures with femoral neck t score (r = -0.633, P = 0.013). Patients with SPKT did not show long-term significant loss of BMD. The incidence of vertebral fractures was low and related to steroid treatment; the incidence of peripheral fractures was higher and independent of clinical or biochemical parameters. PMID- 25525929 TI - Optimal interpretative strategy for preoperative parathyroid scintigraphy. AB - PURPOSE: Our objective was to retrospectively compare various scintigraphic methods to determine their relative accuracies and interobserver variabilities in preoperative localization of single-gland disease in patients with primary hyperparathyroidism. PATIENTS AND METHODS: We studied 292 patients who underwent preoperative parathyroid scintigraphy and surgical resection between June 2002 and September 2008. Imaging included early and delayed pinhole Tc-MIBI imaging (including anterior oblique images), similar I imaging, and MIBI SPECT. Seven different imaging combinations were assessed as follows: early MIBI only, delayed MIBI only, comparison of dual-phase early and delayed MIBI, visual subtraction of early MIBI and I images, all planar images, SPECT only, and all planar and SPECT images (ALL). Each data set was reviewed by 2 of 4 experienced nuclear physicians without knowledge of clinical information or final diagnosis. Imaging results were compared with surgical outcomes. RESULTS: The accuracy of ALL imaging for delineating abnormal/normal parathyroid glands by quadrant was 96%, 93%, 95%, and 95% for the 4 readers. The accuracies of visual subtraction of early MIBI and I images and all planar images were not significantly different from ALL for all 4 readers. All planar and SPECT images were significantly more accurate than early MIBI only, delayed MIBI only, or SPECT only for all 4 readers and better than comparison of dual-phase early and delayed MIBI for 3 of 4 readers. CONCLUSIONS: A rigorous combination of multiple imaging approaches yielded high accuracies across multiple readers for localization of a single offending parathyroid gland, but a more limited technique using MIBI/I subtraction imaging with anterior and anterior oblique pinhole images provided similarly high accuracy and limited interobserver variation of accuracy. PMID- 25525927 TI - Bladder cancer screening in aluminum smelter workers. AB - OBJECTIVE: To present results of a bladder cancer screening program conducted in 18 aluminum smelters in the United States from January 2000 to December 2010. METHODS: Data were collected on a cohort of workers with a history of working in coal tar pitch volatile exposed areas including urine analysis for conventional cytology and ImmunoCyt/uCyt+ assay. RESULTS: ImmunoCyt/uCyt+ and cytology in combination showed a sensitivity of 62.30%, a specificity of 92.60%, a negative predictive value of 99.90%, and a positive predictive value of 2.96%. Fourteen cases of bladder cancer were detected, and the standardized incidence ratio of bladder cancer was 1.18 (95% confidence interval, 0.65 to 1.99). Individuals who tested positive on either test who were later determined to be cancer free had undergone expensive and invasive tests. CONCLUSIONS: Evidence to support continued surveillance of this cohort has not been demonstrated. PMID- 25525930 TI - Clinical implications of medulloblastoma subgroups: incidence of CSF diversion surgery. AB - OBJECT: While medulloblastoma was initially thought to comprise a single homogeneous entity, it is now accepted that it in fact comprises 4 discrete subgroups, each with its own distinct demographics, clinical presentation, transcriptomics, genetics, and outcome. Hydrocephalus is a common complication of medulloblastoma and not infrequently requires CSF diversion. The authors report the incidence of CSF diversion surgery in each of the subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). METHODS: The medical and imaging records for patients who underwent surgery for medulloblastoma at The Hospital for Sick Children were retrospectively reviewed. The primary outcome was the requirement for CSF diversion surgery either before or within 60 days of tumor resection. The modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) was compared among subgroups. RESULTS: Of 143 medulloblastoma patients, treated from 1991 to 2013, sufficient data were available for 130 patients (15 with Wnt, 30 with Shh, 30 with Group 3, and 55 with Group 4 medulloblastomas). Of these, 28 patients (22%) ultimately underwent CSF diversion surgery: 0% with Wnt, 29% with Shh, 29% with Group 3, and 43% with Group 4 tumors. Patients in the Wnt subgroup had a lower incidence of CSF diversion than all other patients combined (p = 0.04). Wnt patients had a lower mCPPRH score (lower risk of CSF diversion, p = 0.045), were older, had smaller ventricles at diagnosis, and had no leptomeningeal metastases. CONCLUSIONS: The overall rate of CSF diversion surgery for Shh, Group 3, and Group 4 medulloblastomas is around 30%, but no patients in the present series with a Wnt medulloblastoma required shunting. The low incidence of hydrocephalus in patients with Wnt medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). The absence of hydrocephalus in patients with Wnt medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality of life than for patients in other subgroups. PMID- 25525931 TI - Carbon dioxide laser for corpus callosotomy in the pediatric population. AB - OBJECT: The authors describe the application of a flexible CO2 laser for corpus callosotomy in children with epilepsy. METHODS: This retrospective case series reviews all cases in which pediatric patients underwent a corpus callosotomy performed using the CO2 OmniGuide laser between May 2005 and October 2012. Data were collected from 8 corpus callosotomy procedures in 6 pediatric patients presenting with medically refractory epilepsy marked by drop attacks. RESULTS: Complete corpus callosotomies were performed in 6 patients (3 boys, 3 girls; ages 5-14 years). In 4 patients the complete callosotomy occurred as a single procedure, and in 2 patients an anterior two-thirds callosotomy was performed first. These 2 patients subsequently required a complete callosotomy due to inadequate control of their drop attacks. In all cases there was clean lesioning of the tract with preservation of the ependymal plane and less inadvertent thermal tissue damage due to low penetration of the laser through cerebrospinal fluid. All patients had resolution or improvement of drop attacks after surgery. No complications were encountered, and imaging demonstrated a clean sectioning of callosal fibers with preservation of normal ventricular anatomy. CONCLUSIONS: These cases illustrate the use of this device in completing corpus callosotomy in pediatric patients. The low-profile laser fiber tip was well suited for working in the depths of the interhemispheric fissure with minimal brain retraction. The flexible CO2 laser allows a precise callosal lesioning through an interhemispheric approach and is a useful adjunct to be employed in these cases. PMID- 25525932 TI - Treatment of pediatric Grade II spinal ependymomas: a population-based study. AB - OBJECT: Grade II spinal cord ependymomas occurring in pediatric patients are exceptionally rare neoplasms. In this paper the authors use a national cancer database to determine patient demographics, treatment patterns, and associated outcomes of this cohort. METHODS: The Surveillance Epidemiology and End Results (SEER) database was used to analyze subjects younger than 18 years with histologically confirmed diagnoses of Grade II spinal cord ependymoma from the years 1973 to 2008. Descriptive data on the demographic characteristics of this cohort and the associated treatment patterns are shown. The Kaplan-Meier method was used to estimate overall survival at 1, 2, 5, and 10 years. RESULTS: This cohort comprised 64 pediatric subjects with Grade II spinal ependymoma. The median age was 13 years, nearly half of the patients were male, and most were white (84%). The median follow-up was 9.2 years. Overall survival at 5 and 10 years was 86% and 83%, respectively. Gross-total resection was achieved in 57% of subjects, and radiation therapy was administered to 36%. Radiation therapy was administered to 78% of subjects after subtotal resection but only to 19% of patients after gross-total resection; this difference was significant (p < 0.001). In a multivariate regression model analyzing sex, age at diagnosis, year of diagnosis, radiotherapy, and extent of resection, female sex was found to be an independent predictor of decreased mortality (HR 0.15 [95% CI 0.02-0.94], p = 0.04). CONCLUSIONS: These data show long-term outcomes for pediatric patients with Grade II spinal ependymoma. Radiotherapy was more likely to be administered in cases of subtotal resection than in cases of gross-total resection. Female sex is associated with decreased mortality, while other demographic or treatment modalities are not. PMID- 25525933 TI - Use of intraoperative Doppler ultrasound with neuronavigation to guide arteriovenous malformation resection: a pediatric case series. AB - OBJECT: Over the last 20 years, several intraoperative adjuncts, including ultrasonography, neuronavigation, and angiography, have been said to aid the intraoperative localization and resection of cerebral arteriovenous malformations (AVMs). The authors assessed the value of intraoperative Doppler ultrasonography in conjunction with neuronavigation during surgery for cerebral AVMs in the pediatric population. METHODS: The authors reviewed all cranial AVM resections performed by a single surgeon at their institution in the period from 2007 to 2013 and here describe their experience and results in a series of 20 consecutive AVM resections in 19 pediatric patients. Intraoperative Doppler ultrasonography had been used in conjunction with preoperative CT or neuronavigational MRI. Preoperative and postoperative clinical findings, patient age, and Spetzler Martin AVM grade were identified in all patients. RESULTS: All patients, whose ages ranged from 2 to 16 years, underwent craniotomy and excision of an AVM, which was supratentorial in 18 cases and infratentorial in 2. Patients in 11 cases underwent preoperative embolization, and all other patients underwent cerebral angiography prior to surgery, except for 2 patients who were urgently surgically treated because of low Glasgow Coma Scale scores and associated hematoma. Spetzler-Martin Grades I (3 cases), II (6), III (7), and IV (4) AVMs were represented in this series. Intraoperative Doppler ultrasound provided high quality images in all cases and demonstrated the location, size, and flow characteristics of the AVM and any associated hematoma. Delayed postoperative cerebral angiography demonstrated successful AVM resection in all cases. An assessment of clinical outcomes revealed no new long-term neurological deficits at 3 months postoperatively. CONCLUSIONS: Intraoperative Doppler ultrasonography is a reliable and useful tool for intraoperative localization and guidance for AVM resection in the pediatric population. When used in conjunction with neuronavigation equipment and modern microscopes, this technique has shown a very high complete resection rate with extremely low associated morbidity. PMID- 25525941 TI - How do we choose? AB - The Hearts and Minds of Ghana project improves the lives of those who are less fortunate and have few resources. Providing clear goals for the mission, devising prior guidelines for patient selection and treatment, achieving a better understanding of local culture and expectations, and good team work, facilitate making better ethical decisions, but doesn't make them less difficult. PMID- 25525944 TI - Recent trends in treatment admissions for marijuana use during pregnancy. AB - OBJECTIVES: The objective of this study was to investigate recent trends in substance abuse treatment admissions for marijuana use during pregnancy in the United States. METHODS: Data were obtained from the Treatment Episodes Data Set from 1992 to 2012 and analyzed for trends over time using chi, Cochran-Armitage, and Moran's I tests. RESULTS: The proportion of treatment admissions for women who were pregnant remained stable at 4%; however, admissions of pregnant women reporting any marijuana use increased substantially from 29% to 43% (P < 0.01). The West North Central census division (20%) experienced the greatest increase followed by the Middle Atlantic (18%) and Pacific (14%) divisions. The demographic characteristics of pregnant marijuana admissions changed over time, with white non-Hispanic women, criminal justice referrals, and those with a psychiatric comorbidity becoming more common whereas polysubstance users decreased (P < 0.01). CONCLUSIONS: Even though more women using marijuana are seeking and receiving substance abuse treatment during pregnancy, targeting certain risk groups while improving screening and treatment referral systems by health care providers, such as prenatal caregivers, should be emphasized. PMID- 25525942 TI - Posttraumatic stress symptoms and cognitive-based smoking processes among trauma exposed, treatment-seeking smokers: the role of dysphoria. AB - OBJECTIVES: Despite the co-occurrence and clinically significant relationship between trauma exposure and smoking, there is little understanding of the mechanisms underlying the posttraumatic stress symptoms-smoking relationship. This study examined whether dysphoria (ie, a psychopathologic symptom dimension that reflects depression's core affective, cognitive, and psychomotor features) accounted for the covariance between posttraumatic stress symptom severity and an array of smoking processes among trauma-exposed daily smokers. METHODS: Participants (n = 189; 47.6% female; Mage = 41.15; SD = 12.47) were trauma exposed, treatment-seeking daily cigarette smokers who completed measures of posttraumatic stress symptom severity, dysphoria, and 4 cognitive-based smoking processes that interfere with smoking cessation-avoidance/inflexibility to smoking, perceived barriers to smoking cessation, negative affect reduction motivation for smoking, and negative affect reduction/negative reinforcement expectancies from smoking. RESULTS: Dysphoria indirectly and significantly accounted for the relationship between posttraumatic stress symptom severity and smoking outcomes. CONCLUSIONS: The present results provide initial empirical support that dysphoria accounts for the covariance between posttraumatic symptom severity and various clinically relevant smoking variables in trauma-exposed, treatment-seeking smokers. The findings suggest the potential importance of targeting dysphoria during smoking cessation among trauma-exposed individuals. PMID- 25525943 TI - Bath salts in the emergency department: a survey of emergency clinicians' experience with bath salts-intoxicated patients. AB - OBJECTIVES: Several novel synthetic amphetamines have been marketed worldwide as "bath salts." The use of bath salts is associated with severe medical consequences resulting in a US federal ban over the last 3 years on the more common substances found in this group. Bath salts intoxication has a relatively nonspecific presentation, and urine toxicology confirmation in emergency departments (EDs) is impractical because the turnaround time is several days. Emergency clinicians must therefore rely heavily on patients' self-reports to verify the diagnosis. We performed an online survey of emergency clinicians to determine their degree of exposure to bath salts-intoxicated patients, the clinically relevant features of such patients, and the typical emergency management. METHODS: We invited 124 physicians and physician assistants in 7 Cleveland Clinic EDs to participate in an online survey. RESULTS: From a total of 43 of the 124 respondents, 77% did not specifically ask patients about bath salts use. Sixty percent had encountered a bath salts-intoxicated individual. Most respondents reported that the majority of patients were male, were between 19 and 29 years old, and used other drugs in addition to bath salts. Agitation, aggression/violence, and hallucinations were reported to be the most common presentations, and intravenous/intramuscular tranquilization was reported as the most often used management. Most patients were discharged home from the ED. CONCLUSIONS: Despite the lack of toxicology screening in EDs, about two thirds of the surveyed emergency clinicians encountered bath salts-intoxicated individuals. Our study demonstrates the need for increased screening of bath salts intoxication in EDs, especially in agitated patients. PMID- 25525945 TI - Phosphonate-phosphinate rearrangement. AB - LiTMP metalated dimethyl N-Boc-phosphoramidates derived from 1-phenylethylamine and 1,2,3,4-tetrahydronaphthalen-1-ylamine highly selectively at the CH3O group to generate short-lived oxymethyllithiums. These isomerized to diastereomeric hydroxymethylphosphonamidates (phosphate-phosphonate rearrangement). However, s BuLi converted the dimethyl N-Boc-phosphoramidate derived from 1-phenylethylamine to the N-Boc alpha-aminophosphonate preferentially. Only s-BuLi deprotonated dimethyl hydroxymethylphosphonamidates at the benzylic position and dimethyl N Boc alpha-aminophosphonates at the CH3O group to induce phosphonate-phosphinate rearrangements. In the former case, the migration of the phosphorus substituent from the nitrogen to the carbon atom followed a retentive course with some racemization because of the involvement of a benzyllithium as an intermediate. PMID- 25525946 TI - [Resection and Coverage of a Bronchial Stump by Contralateral Thoracotomy - A Therapeutic Option for a Late Bronchial Stump Leak after Pneumonectomy]. PMID- 25525947 TI - ["Letter to the Editor" on the article S. Debus: "Vascular medicine of tomorrow: Presentation of a cardiovascular 'Hybrid-Care' concept"]. PMID- 25525948 TI - [Strategies to Optimise R0 Resection for Hilar Cholangiocarcinoma]. AB - BACKGROUND: Retrospective analyses have shown a 20-40 % incidence of R1 resection in hilar cholangiocarcinoma, which therefore represents a significant issue to be addressed. METHODS: We have reviewed the literature on the impact of R1 resection in hilar cholangiocarcinomas and on possible surgical options to increase the rate of complete tumour resections. RESULTS: To minimise the rate of R1 resections a preoperative risk assessment concerning the predisposed anatomic locations is required. During planning of the surgical strategy, liver function plays a central role prior to right-sided hemihepatectomies. Due to the loss of a high amount of functional liver parenchyma, contralateral portal vein embolisation is often used prior to right trisectionectomies. For left-sided hepatectomies the management of the right hepatic artery is fundamental. The right hepatic artery has a very close contact to the tumour region, although arterial invasion is rarely seen. However, the risk of manifest or occult R1 resection is relatively high along the right artery. In selected cases an arterial resection might be considered, but this increases the risk of postoperative complications. Arterial resection might be performed either via direct anastomosis or by using an interposition graft. As reserve procedures preoperative embolisation of the hepatic artery without reconstruction or an arterialisation of the portal vein are available. However, the latter two procedures come along with an increased rate of biliary complications. In selected lymph-node negative patients with irresectable hilar cholangiocarcinoma liver transplantation might be considered. CONCLUSION: Despite significant advances in surgical technique, R1 resection remains a problem, which is aggravated by the lack of evidence-based adjuvant measures. PMID- 25525949 TI - [Cost and cost-effectiveness in the treatment of peripheral arterial occlusion disease - what is proven?]. AB - BACKGROUND: This overview comments on the health-care relevance of peripheral arterial occlusive disease (PAOD) in patients with intermittent claudication (IC) and critical limb ischaemia (CLI). We evaluated different treatment modalities in terms of cost-effectiveness. METHOD: For the literature review, the Medline database (PubMed) was searched under the key words "critical limb ischemia AND cost", "critical limb ischemia AND economy", "peripheral arterial disease AND cost", "peripheral arterial disease AND economy". RESULTS: In the years 2005 to 2009, the hospitalisations of patients with PAOD rose disproportionately in Germany by 20 %, to 483,961 hospital admissions. By comparison, hospital admissions altogether increased by only 8 %. The average in-patient costs were estimated to be approximately ? 5000 per PAOD-patient - a rather conservative estimate. For the patient with IC the economic data position is clear, supervised exercise training is by far the most cost-effective treatment option, followed by percutaneous transluminal angioplasty (PTA) and finally the peripheral bypass. In accordance with the guidelines of the UK, the latter is therefore indicated only if PTA fails or is technically not possible. In patients with CLI, the situation is not obvious. Indeed, a short-term economic advantage can be calculated for the PTA, the long-term comparison of both methods, however, is impossible due to insufficient data. In addition, the risk factors for the patient have to be included in the calculation. This was indeed demonstrated in the short-term, but could not be analysed in the long-term follow-up. CONCLUSION: The issue of greater cost-effectiveness of open or endovascular treatment in patients with CLI is uncertain, the studies and patient populations are too heterogeneous. Further studies are urgently needed to structure the sequence of the various treatment options in guidelines and clinical pathways. PMID- 25525950 TI - Application of functionalized lanthanide-based nanoparticles for the detection of okadaic acid-specific immunoglobulin G. AB - Marine biotoxins are widespread in the environment and impact human health via contaminated shellfish, causing diarrhetic, amnesic, paralytic, or neurotoxic poisoning. In spite of this, methods for determining if poisoning has occurred are limited. We show the development of a simple and sensitive luminescence resonance energy transfer (LRET)-based concept which allows the detection of anti okadaic acid rabbit polyclonal IgG (mouse monoclonal IgG1) using functionalized lanthanide-based nanoparticles. Upon UV excitation, the functionalized nanoparticles were shown to undergo LRET with fluorophore-labeled anti-okadaic acid antibodies which had been captured and bound by okadaic acid-decorated nanoparticles. The linear dependence of fluorescence emission intensity with antigen-antibody binding events was recorded in the nanomolar to micromolar range, while essentially no LRET signal was detected in the absence of antibody. These results may find applications in new, cheap, and robust sensors for detecting not only immune responses to biotoxins but also a wide range of biomolecules based on antigen-antibody recognition systems. Further, as the system is based on solution chemistry it may be sufficiently simple and versatile to be applied at point-of-care. PMID- 25525951 TI - Treatment for cryoglobulinemic and non-cryoglobulinemic peripheral neuropathy associated with hepatitis C virus infection. AB - BACKGROUND: Peripheral neuropathy is the most common neurologic complication of hepatitis C virus (HCV) infection. The pathophysiology of the neuropathy associated with HCV is not definitively known; however, proposed mechanisms include cryoglobulin deposition in the vasa nervorum and HCV-mediated vasculitis. The optimal treatment for HCV-related peripheral neuropathy has not been established. OBJECTIVES: To assess the effects of interventions (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) for cryoglobulinemic or non cryoglobulinemic peripheral neuropathy associated with HCV infection. SEARCH METHODS: On 26 August 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We also searched two trials registers, the Networked Digital Library of Theses and Dissertations (NDLTD) (October 2014), and three other databases. We checked references in identified trials and requested information from trial authors to identify any additional published or unpublished data. SELECTION CRITERIA: We included all randomized controlled trials (RCTs) and quasi-RCTs involving participants with cryoglobulinemic or non-cryoglobulinemic peripheral neuropathy associated with HCV infection. We considered any intervention (including interferon alfa, interferon alfa plus ribavirin, corticosteroids, cyclophosphamide, plasma exchange, and rituximab) alone or in combination versus placebo or another intervention ('head-to-head' comparison study design) evaluated after a minimum interval to follow-up of at least six months. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. The planned primary outcome was change in sensory impairment (using any validated sensory neuropathy scale or quantitative sensory testing) at the end of the follow-up period. Other planned outcomes were: change in impairment (any validated combined sensory and motor neuropathy scale), change in disability (any validated disability scale), electrodiagnostic measures, number of participants with improved symptoms of neuropathy (global impression of change), and severe adverse events. MAIN RESULTS: Four trials of HCV-related cryoglobulinemia fulfiled selection criteria and the review authors included three in quantitative synthesis. All studies were at high risk of bias. No trial addressed the primary outcome of change in sensory impairment. No trial addressed secondary outcomes of change in combined sensory and motor impairment, disability, or electrodiagnostic measures. A single trial of HCV-related mixed cryoglobulinemia treated with pegylated interferon alfa (peginterferon alfa), ribavirin, and rituximab versus peginterferon alfa and ribavirin did not show a significant difference in the number of participants with improvement in neuropathy at 36 months post treatment (risk ratio (RR) 4.00, 95% confidence interval (CI) 0.27 to 59.31, n = 9). One study of interferon alfa (n = 22) and two studies of rituximab (n = 61) provided adverse event data. Severe adverse events were no more common with interferon alfa (RR 7.00, 95% CI 0.38 to 128.02) or rituximab (RR 3.00, 95% CI 0.13 to 67.06) compared to the control group. AUTHORS' CONCLUSIONS: There is a lack of RCTs and quasi-RCTs addressing the effects of interventions for peripheral neuropathy associated with HCV infection. At present, there is insufficient evidence from RCTs and quasi-RCTs to make evidence-based decisions about treatment. PMID- 25525952 TI - Systemic LPS and inflammatory response during consecutive days of exercise in heat. AB - This investigation studied circulating LPS activity, potential intestinal damage, and the systemic inflammatory response (SIR) during the exercise heat acclimation process. 8 healthy males (Age=24+/-3 years) ran in a hot environment on 5 consecutive days until core temperature (Tc) was elevated 2 degrees C above rest. Plasma was obtained pre-, post-, 1 h post-, and 3 h post-exercise on the 1(st), 3(rd), and 5(th) day of exercise and analyzed for TNF-alpha, IL-6, IL-10, IL-1ra, LPS, and intestinal fatty acid-binding protein (I-FABP). Plasma LPS (1.1 EU.ml( 1)+/-0.1 vs. 0.7 EU.ml(-1)+/-0.03; P<0.01) and I-FABP (930.7 pg.ml(-1)+/-149.0 vs. 640.2 pg.ml(-1)+/-125.0; P<0.001) were significantly increased post-exercise each. The SIR remained largely unchanged during the study except for TNF-alpha. Plasma TNF-alpha was significantly lower on Day 5 at 1 h (3.2 pg.ml(-1)+/-0.6 vs. 4.5 pg.ml(-1)+/-0.8; P=0.01) and 3 h (3.6 pg.ml(-1)+/-0.8 vs. 4.8 pg.ml(-1)+/ 0.9; P=0.05) post-exercise as compared to Day 1. Findings indicate that adaptations to exercise in the heat resulting in reductions of intestinal damage and plasma LPS activity require longer time periods in moderately trained males. PMID- 25525953 TI - Molecular hydrogen in sports medicine: new therapeutic perspectives. AB - In the past 2 decades, molecular hydrogen emerged as a novel therapeutic agent, with antioxidant, anti-inflammatory and anti-apoptotic effects demonstrated in plethora of animal disease models and human studies. Beneficial effects of molecular hydrogen in clinical environment are observed especially in oxidative stress-mediated diseases, such as diabetes mellitus, brain stem infarction, rheumatoid arthritis, or neurodegenerative diseases. A number of more recent studies have reported that molecular hydrogen affects cell signal transduction and acts as an alkalizing agent, with these newly identified mechanisms of action having the potential to widen its application in clinical medicine even further. In particular, hydrogen therapy may be an effective and specific innovative treatment for exercise-induced oxidative stress and sports injury, with potential for the improvement of exercise performance. This review will summarize recent research findings regarding the clinical aspects of molecular hydrogen use, emphasizing its application in the field of sports medicine. PMID- 25525954 TI - Effects of eccentric overload bout on change of direction and performance in soccer players. AB - The aims of this study were to analyse the effects of eccentric overload training (EOT) on kinetic parameters during change of direction (COD) and performance related to sprinting and jumping abilities. 20 male soccer players performed 2 different protocols: 1) 5-min cycling warm-up and 2) 5-min cycling warm-up+YoYo half-squat exercise. The outcome measured included vertical ground reaction force (vGRF) and propulsive force (PvGRF), time to vGRF (T_vGRF) and propulsive force (T_PvGRF), contact time (CT), eccentric (ECC_IMP), concentric (CONC_IMP) and total (TOT_IMP) impulses and moments (Mx, My and Mz) during 2 COD tasks. Additionally, subjects performed a counter-movement jump (CMJ) and 20 m sprint tests. Results showed a substantial better improvement (likely to almost certainly) in vGRF (ES: 0.84), vAGRF (ES: 0.72), CT (ES: 0.48), My (ES: 0.35), Mz (ES: 0.44) and ECC_IMP (ES: 0.45) during crossover cutting maneuver, whereas during side-step cutting maneuver Time_ECC (ES: 0.68), CT (ES: 0.64), vGRF (ES: 0.48) and My (ES: 0.47) were substantially enhanced (likely). Furthermore, substantial better performance was found in CMJ (ES: 0.47; very likely) and 20 m (ES: 0.20; possibly). In conclusion, EOT produced a better muscle activation during 2 different COD tasks and greater sprinting and jumping performance. PMID- 25525955 TI - Air-stable flexible organic light-emitting diodes enabled by atomic layer deposition. AB - Organic light-emitting diodes (OLED) are an energy-efficient light source with many desirable attributes, besides being an important display of technology, but its practical application has been limited by its low air-stability. This study demonstrates air-stable flexible OLEDs by utilizing two atomic-layer-deposited (ALD) films: (1) a ZnO film as both a stable electron-injection layer (EIL) and as a gas barrier in plastics-based OLED devices, and (2) an Al2O3/ZnO (AZO) nano laminated film for encapsulating the devices. Through analyses of the morphology and electrical/gas-permeation properties of the films, we determined that a low ALD temperature of 70 degrees C resulted in optimal EIL performance from the ZnO film and excellent gas-barrier properties [water vapor transmission rate (WVTR) <5 * 10(-4) g m(-2) day(-1)] from both the ZnO EIL and the AZO encapsulating film. The low-temperature ALD processes eliminated thermal damage to the OLED devices, which were severe when a 90 degrees C encapsulation process was used, while enabling them to achieve an air-storage lifetime of >10,000 h. PMID- 25525956 TI - Surface-structured bacterial cellulose with guided assembly-based biolithography (GAB). AB - A powerful replica molding methodology to transfer on-demand functional topographies to the surface of bacterial cellulose nanofiber textures is presented. With this method, termed guided assembly-based biolithography (GAB), a surface-structured polydimethylsiloxane (PDMS) mold is introduced at the gas liquid interface of an Acetobacter xylinum culture. Upon bacterial fermentation, the generated bacterial cellulose nanofibers are assembled in a three-dimensional network reproducing the geometric shape imposed by the mold. Additionally, GAB yields directional alignment of individual nanofibers and memory of the transferred geometrical features upon dehydration and rehydration of the substrates. Scanning electron and atomic force microscopy are used to establish the good fidelity of this facile and affordable method. Interaction of surface structured bacterial cellulose substrates with human fibroblasts and keratinocytes illustrates the efficient control of cellular activities which are fundamental in skin wound healing and tissue regeneration. The deployment of surface-structured bacterial cellulose substrates in model animals as skin wound dressing or body implant further proves the high durability and low inflammatory response to the material over a period of 21 days, demonstrating beneficial effects of surface structure on skin regeneration. PMID- 25525957 TI - Depression as a predictor of worse quality of life outcomes following nonoperative treatment for lumbar stenosis. AB - OBJECT: The goal of this study was to determine whether pretreatment depression is predictive of quality of life (QOL) improvement for patients with lumbar spinal stenosis (LSS) who are treated conservatively. METHODS: This retrospective cohort study included patients with LSS and concordant neurogenic claudication who were treated nonoperatively at a single institution between September 2010 and March 2013. Patient QOL measures were recorded pretreatment and then 4 months after treatment. Pretreatment depression was assessed using the Patient Health Questionnaire-9 (PHQ-9). Successful outcome was defined as posttreatment improvement in EuroQol-5D (EQ-5D) index or in Pain and Disability Questionnaire (PDQ) scores. Regression analysis was performed to identify independent predictors of outcome while controlling for confounding variables. RESULTS: A total of 502 patients were included in the study. The average age for these patients was 66.1 years, with 51% female and 90.6% white. After adjusting for baseline demographic and clinical variables, there was a statistically significant association between baseline PHQ-9 score and posttreatment change in EQ-5D index (beta = -0.007, p = 0.0002). All other things being equal, a patient with a baseline PHQ-9 score of 0 (no depression) would be expected to improve in the EQ-5D index by 0.14 points (greater than the minimum clinically important difference) more than would a patient with a baseline PHQ-9 score of 20 (major depression). There was no significant association between baseline PHQ-9 score and change in Pain and Disability Questionnaire scores. CONCLUSIONS: When controlling for other baseline characteristics, severely depressed patients with LSS who are treated nonoperatively have significantly less improvement in their QOL compared with those with little or no depression. These data are similar to the negative predictive effects of depression on posttreatment QOL following lumbar fusion surgery. PMID- 25525958 TI - Multiple-level lumbar spondylolysis and spondylolisthesis. AB - OBJECT: Lumbar spondylolysis and isthmic spondylolisthesis occur most commonly at only one spinal level. The authors report on 13 cases of lumbar spondylolysis with spondylolisthesis at multiple levels. METHODS: During July 2007-March 2012, multiple-level spondylolysis associated with spondylolisthesis was diagnosed in 13 patients (10 male, 3 female) at Qilu Hospital of Shandong University. The mean patient age was 43.5 +/- 14.6 years. The duration of low-back pain was 11.7 +/- 5.1 months. Spondylolysis occurred at L-2 in 2 patients, L-3 in 4 patients, L-4 in all patients, and L-5 in 5 patients. Spondylolysis occurred at 3 spinal levels in 3 patients and at 2 levels in 10 patients. All patients had spondylolisthesis at 1 or 2 levels. Japanese Orthopaedic Association and visual analog scale scores were used to evaluate preoperative and postoperative neurological function and low-back pain. All patients underwent pedicle screw fixation and interbody fusion or direct pars interarticularis repair. RESULTS: Both low-back pain scores improved significantly after surgery (p < 0.05). Postoperative radiographs or CT scans showed satisfactory interbody fusion or pars interarticularis healing. No breakage, dislodging, or loosening of the pedicle screw hardware was observed for any patient. CONCLUSIONS: Multiple-level lumbar spondylolysis and spondylolisthesis occurred more often in men. Most multiplelevel lumbar spondylolysis occurred at 2 spinal levels and was associated with sports, trauma, or heavy labor. Multiplelevel lumbar spondylolysis occurred mostly at L3-5; associated spondylolisthesis usually occurred at L-4 and L-5, mostly at L-4. The treatment principle was the same as that for single-level spondylolisthesis. PMID- 25525959 TI - The diagnostic value of magnetic resonance imaging measurements for assessing cervical spinal canal stenosis. AB - OBJECT: The authors investigated the relevance of 2D MRI measurements for the diagnosis of critical cervical spinal canal stenosis. Among patients who had sustained a minor cervical spine trauma, they compared MRI measurements of the cervical spine between those with acute cervical spinal cord injury (CSCI) and those without. They also investigated the correlation between the MRI measurements and the severity of CSCI as well as classification accuracy concerning the diagnosis of critical spinal canal stenosis for acute CSCI after a minor trauma. METHODS: The authors conducted a single-center retrospective radiological case-control study of patients who had sustained CSCI after a minor trauma to the cervical spine from January 2000 to August 2010. The controls were patients who had sustained a cervical trauma without clinical or radiological signs of cervical spinal cord pathology. On axial T2-weighted MR images, the following were measured: the transverse spinal canal and cord area, the transverse and sagittal cord diameter, and the sagittal canal diameter of the cervical spine (C3-7). Using these measurements, the authors calculated the cord canal-area ratio by dividing the transverse cord area by the transverse canal area, the space available for the cord by subtracting the sagittal canal diameter from the sagittal cord diameter, and the compression ratio by dividing the transverse cord diameter by its sagittal diameter. The severity of CSCI was assessed by using the motor index scores of 10 key muscles at different time points (initially, 1, 3, and 12 months after injury) obtained from the clinical records. The intra- and interobserver reliability of the MRI measurements, intra- and intergroup differences, and correlations between variables were also investigated. Receiver operating characteristic curves were calculated for evaluating the classification accuracy of the imaging variables for CSCI. RESULTS: Data for 52 CSCI patients and 77 control patients were analyzed. The intra- and interobserver reliability regarding the MRI measurements ranged from good (0.72) to perfect (0.99). Differences between the CSCI group and the control group were significant (p < 0.001) for all parameters, except for the cord area. The most prominent differences between the groups existed for the spinal canal area, cord-canal-area ratio, and space available for the cord. The classification accuracy was best for the cord-canal-area ratio and the space available for the cord; areas under the curve were 0.99 (95% CI 0.97-1.0) and 0.98 (95% CI 0.95 0.99), respectively. There was no significant (p > 0.05) correlation between any of the imaging parameters and the motor index score at any time point. CONCLUSIONS: The cord-canal-area ratio (> 0.8) or the space available for the cord (< 1.2 mm) measured on MR images can be used to reliably identify patients at risk for acute CSCI after a minor trauma to the cervical spine. However, there does not seem to be any association between spinal canal imaging characteristics and the severity of or recovery from CSCI after a minor trauma. PMID- 25525960 TI - Main thoracic curve adolescent idiopathic scoliosis: association of higher rod stiffness and concave-side pedicle screw density with improvement in sagittal thoracic kyphosis restoration. AB - OBJECT: The aim of this study was to evaluate the effects of rod stiffness and implant density on coronal and sagittal plane correction in patients with main thoracic curve adolescent idiopathic scoliosis (AIS). METHODS: The authors conducted a retrospective study of 77 consecutive cases involving 56 female and 21 male patients with Lenke Type 1 main thoracic curve AIS who underwent single stage posterior correction and instrumented spinal fusion with pedicle screw fixation between July 2009 and July 2012. The patients' mean age at surgery was 15.79 +/- 3.21 years. All patients had at least 1 year of follow-up. Radiological parameters in the coronal and sagittal planes, including Cobb angle of the major curve, side-bending Cobb angle of the major curve, thoracic kyphosis (TK), correction rates, and screw density, were measured and analyzed. Screw densities (calculated as number of screws per fusion segment * 2) of < 0.60 and >= 0.60 were defined as low and high density, respectively. Titanium rods of 5.5 mm and 6.35 mm diameter were defined as low and high stiffness, respectively. Patients were divided into 4 groups based on the type of rod and density of screw placement that had been used: Group A, low-stiffness rod with low density of screw placement; Group B, low-stiffness rod with high density of screw placement; Group C, high-stiffness rod with low density of screw placement; Group D, high stiffness rod with high density of screw placement. RESULTS: The mean coronal correction rate of the major curve, for all 77 patients, was (81.45% +/- 7.51%), and no significant difference was found among the 4 groups (p > 0.05). Regarding sagittal plane correction, Group A showed a significant decrease in TK after surgery (p < 0.05), while Group D showed a significant increase (p < 0.05); Group B and C showed no significant postoperative changes in TK (p > 0.05). The TK restoration rate was highest in Group D and lowest in Group A (A, -39.32% +/- 7.65%; B, -0.37% +/- 8.25%; C, -4.04% +/- 6.77%; D, 37.59% +/- 8.53%). Screw density on the concave side was significantly higher than that on the convex side in all the groups (p < 0.05). CONCLUSIONS: For flexible main thoracic curve AIS, both rods with high stiffness and those with low stiffness combined with high or low screw density could provide effective correction in the coronal plane; rods with high stiffness along with high screw density on the concave side could provide better outcome with respect to sagittal TK restoration. PMID- 25525961 TI - Letter to the editor: results of comprehensive medical management of lumbar disorders questioned. PMID- 25525962 TI - Effect of preservation of the C-6 spinous process and its paraspinal muscular attachment on the prevention of postoperative axial neck pain in C3-6 laminoplasty. AB - OBJECT: Axial neck pain after C3-6 laminoplasty has been reported to be significantly lesser than that after C3-7 laminoplasty because of the preservation of the C-7 spinous process and the attachment of nuchal muscles such as the trapezius and rhomboideus minor, which are connected to the scapula. The C 6 spinous process is the second longest spinous process after that of C-7, and it serves as an attachment point for these muscles. The effect of preserving the C-6 spinous process and its muscular attachment, in addition to preservation of the C 7 spinous process, on the prevention of axial neck pain is not well understood. The purpose of the current study was to clarify whether preservation of the paraspinal muscles of the C-6 spinous process reduces postoperative axial neck pain compared to that after using nonpreservation techniques. METHODS: The authors studied 60 patients who underwent C3-6 double-door laminoplasty for the treatment of cervical spondylotic myelopathy or cervical ossification of the posterior longitudinal ligament; the minimum follow-up period was 1 year. Twenty five patients underwent a C-6 paraspinal muscle preservation technique, and 35 underwent a C-6 nonpreservation technique. A visual analog scale (VAS) and VAS grading (Grades I-IV) were used to assess axial neck pain 1-3 months after surgery and at the final follow-up examination. Axial neck pain was classified as being 1 of 5 types, and its location was divided into 5 areas. The potential correlation between the C-6/C-7 spinous process length ratio and axial neck pain was examined. RESULTS: The mean VAS scores (+/- SD) for axial neck pain were comparable between the C6-preservation group and the C6-nonpreservation group in both the early and late postoperative stages (4.1 +/- 3.1 vs 4.0 +/- 3.2 and 3.8 +/- 2.9 vs 3.6 +/- 3.0, respectively). The distribution of VAS grades was comparable in the 2 groups in both postoperative stages. Stiffness was the most prevalent complaint in both groups (64.0% and 54.5%, respectively), and the suprascapular region was the most common site in both groups (60.0% and 57.1%, respectively). The types and locations of axial neck pain were also similar between the groups. The C-6/C-7 spinous process length ratios were similar in the groups, and they did not correlate with axial neck pain. The reductions of range of motion and changes in sagittal alignment after surgery were also similar. CONCLUSIONS: The C-6 paraspinal muscle preservation technique was not superior to the C6-nonpreservation technique for preventing postoperative axial neck pain. PMID- 25525963 TI - Effects of vertebroplasty on endplate subsidence in elderly female spines. AB - OBJECT: The aim in this study was to quantify the effects of vertebroplasty on endplate subsidence in treated and adjacent vertebrae and their relationship to endplate thickness and underlying trabecular bone in elderly female spines. METHODS: Vertebral compression fractures were created in female cadaveric (age range 51-88 years) thoracolumbar spine segments. Specimens were placed into either the control or vertebroplasty group (n = 9/group) such that bone mineral density, trabecular microarchitecture, and age were statistically similar between groups. For the vertebroplasty group, polymethylmethacrylate bone cement was injected into the fractured vertebral body under fluoroscopy. Cyclic compression (685-1370 N sinusoid) was performed on all spine segments for 115,000 cycles. Micro-CT scans were obtained before and after cyclic loading to quantify endplate subsidence. Maximum subsidence was compared between groups in the caudal endplate of the superior adjacent vertebra (SVcau); cranial (TVcra) and caudal (TVcau) endplates of the treated vertebra; and the cranial endplate of the inferior adjacent vertebra (IVcra). In addition, micro-CT images were used to quantify average endplate thickness and trabecular bone volume fraction. These parameters were then correlated with maximum endplate subsidence for each endplate. RESULTS: The maximum subsidence in SVcau endplate for the vertebroplasty group (0.34 +/- 0.58 mm) was significantly (p < 0.05) greater than for the control group (-0.13 +/- 0.27 mm). Maximum subsidence in the TVcra, TVcau, and IVcra endplates were greater in the vertebroplasty group, but these differences were not significant (p > 0.16). Increased subsidence in the vertebroplasty group manifested locally in the anterior region of the SVcau endplate and in the posterior region of the TVcra and TVcau endplates (p < 0.10). Increased subsidence was observed in thinner endplates with lower trabecular bone volume fraction for both vertebroplasty and control groups (R(2) correlation up to 62%). In the SVcau endplate specifically, these 2 covariates aided in understanding subsidence differences between vertebroplasty and control groups. CONCLUSIONS: Bone cement injected during vertebroplasty alters local biomechanics in elderly female spines, resulting in increased endplate disruption in treated and superior adjacent vertebrae. More specifically, bone cement increases subsidence in the posterior regions of the treated endplates and the anterior region of the superior caudal endplate. This increased subsidence may be the initial mechanism leading to subsequent compression fractures after vertebroplasty, particularly in vertebrae superior to the treated level. PMID- 25525965 TI - What do general psychiatrists do? A question posed to medical students and the general population. AB - BACKGROUND: Misconceptions about the role of a psychiatrist are anecdotally widespread but have been under researched. AIMS: This study aimed to establish views on training and working in psychiatry amongst preclinical medical students at a South London Medical School and amongst a general public sample. METHODS: A semi-structured online questionnaire was used to survey medical students, with a similar paper questionnaire being used to survey members of the public in a general practice waiting room using a convenience sampling method. RESULTS: Strikingly, the majority of the public thought that psychiatrists did not need a medical degree (54%) or postgraduate training (56%). There were significant misconceptions about treatments used in mental health, for example 16% of the public sample thought psychiatrists never use medication and 31% of medical students (and 14% of the public) thought psychiatrists never use electroconvulsive therapy (ECT). In response to "do you believe a psychiatrist is able to know what people are thinking?", 45% of students and 57% of the public answered "sometimes". CONCLUSION: The results have important implications for public education, as lack of awareness about psychiatry may inhibit help seeking for mental illness, and have a negative impact on recruitment to psychiatry amongst medical students. PMID- 25525964 TI - Metal-free C-H amination of unactivated hydrocarbons with sulfonylimino-lambda(3) bromanes generated in situ from (diacetoxybromo)benzene. AB - A simple method for direct metal-free C-H amination of unactivated hydrocarbons using easy-handling diacetoxy-lambda(3)-bromane and triflylamide or sulfamate esters was developed. The high 2 degrees /3 degrees regioselectivities and deuterium isotope effects suggest a concerted organonitrenoid transition state, analogous to C-H amination with N-triflylimino-lambda(3)-bromane. PMID- 25525966 TI - Computational analysis of the stereochemical outcome in the imidazolidinone catalyzed enantioselective (4 + 3)-cycloaddition reaction. AB - Computations show why the catalytic, asymmetric (4 + 3)-cycloaddition reaction developed in the Harmata laboratories proceeds with facial selectivity opposite to that for models proposed for related catalyzed Diels-Alder reactions. Computations with M06-2X/6-311+G(d,p)//B3LYP/6-31G(d) show that iminium ions derived from MacMillan's chiral 2-tert-butyl-5-benzylimidazolidinone and siloxypentadienals undergo (4 + 3)-cycloadditions with furans preferentially on the more crowded face. Conformational reorganization of the benzyl group, to avoid intramolecular interaction with the silyl group, is responsible for differentiating the activation barriers of top- and bottom-face attack. PMID- 25525967 TI - Parental Influences on Preschoolers' TV Viewing Time: Mediation Analyses on Australian and Belgian Data. AB - BACKGROUND: Television viewing is highly prevalent in preschoolers (3-5 years). Because of the adverse health outcomes related to this behavior, it is important to investigate associations and mediators of young children's television viewing time. This study investigated whether parental rules regarding television viewing time and parental concerns about screen viewing activities mediated the association between parents' and preschoolers' television viewing time. METHODS: Mediation analyses were performed with the product-of-coefficient test on data derived from the Australian HAPPY study (n = 947) and the Belgian sample of the ToyBox-study (n = 1527). Parents reported their own and their child's television viewing time, their rules regarding television viewing and concerns about their child's screen viewing activities. RESULTS: Parents' television viewing time was directly associated with preschoolers' television viewing time and parental rule for television viewing time mediated this association in both samples (14.4% and 8.1% in the Australian and Belgian samples, respectively). CONCLUSIONS: This study is unique in examining the mediating pathway of parental television viewing and a rule limiting TV viewing time and whether this is consistent in different samples. Due to the consistent importance, both parents' television viewing time and rules should be targeted in interventions to decrease preschoolers' television viewing time. PMID- 25525968 TI - Synthesis and characterization of coinage metal aluminum sulfur species. AB - The synthesis of heterobimetallic cluster with the Al-S-M (M = Cu and Ag) structural unit has been realized for the first time by the reaction of aluminum dithiol LAl(SH)2 (L = HC[C(Me)N(Ar)]2, Ar = 2,6-iPr2C6H3) with (MesCu)4 and (MesAg)4 (Mes = 2,4,6-Me3C6H2), respectively. The isolated clusters exhibit core structures of Al2Cu4S4 and Al4Ag8S8, respectively. During the formation of the [LAl(SAg)2]4, a side product of LAlS6 is formed. However, the reaction of LAl(SH)2 with excess of sulfur and (MesAg)4 resulted in the formation of LAlS4 as the only product soluble in organic solvents. Both of them represent rare examples of aluminum polysulfides. All compounds were characterized by spectroscopic methods and single crystal X-ray diffraction studies. PMID- 25525969 TI - Enhanced interfacial interaction and CO2 separation performance of mixed matrix membrane by incorporating polyethylenimine-decorated metal-organic frameworks. AB - Polyethylenimine (PEI) was immobilized by MIL-101(Cr) (~550 nm) via a facile vacuum-assisted method, and the obtained PEI@MIL-101(Cr) was then incorporated into sulfonated poly(ether ether ketone) (SPEEK) to fabricate mixed matrix membranes (MMMs). High loading and uniform dispersion of PEI in MIL-101(Cr) were achieved as demonstrated by ICP, FT-IR, XPS, and EDS-mapping. The PEI both in the pore channels and on the surface of MIL-101(Cr) improved the filler-polymer interface compatibility due to the electrostatic interaction and hydrogen bond between sulfonic acid group and PEI, and simultaneously rendered abundant amine carriers to facilitate the transport of CO2 through reversible reaction. MMMs were evaluated in terms of gas separation performance, thermal stability, and mechanical property. The as-prepared SPEEK/PEI@MIL-101(Cr) MMMs showed increased gas permeability and selectivity, and the highest ideal selectivities for CO2/CH4 and CO2/N2 were 71.8 and 80.0 (at a CO2 permeability of 2490 Barrer), respectively. Compared with the membranes doped with unfilled MIL-101(Cr), the ideal selectivities of CO2/CH4 and CO2/N2 for PEI@MIL-101(Cr)-doped membranes were increased by 128.1 and 102.4 %, respectively, at 40 wt % filler loading, surpassing the 2008 Robeson upper bound line. Moreover, the mechanical property and thermal stability of SPEEK/PEI@MIL-101(Cr) were enhanced. PMID- 25525971 TI - Metamemory appraisals in autobiographical event recall. AB - Two studies examined whether belief in the occurrence of events, recollecting events, and belief in the accuracy of recollections are distinct aspects of autobiographical remembering. In Study 1, 299 student participants received a cue to recall five childhood events, after which they rated each event on these constructs and other characteristics associated with remembering. Structural equation modelling revealed that variance in ratings was best explained by the three anticipated latent variables. In Study 2, an online sample of 1026 adults recalled and rated a childhood event and an event about which they were somehow uncertain. Confirmatory modelling replicated the three latent variables. The relationship of key predictors (perceptual detail, spatial detail, re experiencing, and event plausibility) to the latent variables confirmed the distinction. These studies demonstrate that belief in occurrence and belief in accuracy appraisals are distinct, the former indexing the truth status of the event and the latter the degree to which the event representation accurately reflects prior experience. Further, they suggest that belief in accuracy indexes the monitoring of the quality of recollections. PMID- 25525970 TI - How does the interaction between spelling and motor processes build up during writing acquisition? AB - How do we recall a word's spelling? How do we produce the movements to form the letters of a word? Writing involves several processing levels. Surprisingly, researchers have focused either on spelling or motor production. However, these processes interact and cannot be studied separately. Spelling processes cascade into movement production. For example, in French, producing letters PAR in the orthographically irregular word PARFUM (perfume) delays motor production with respect to the same letters in the regular word PARDON (pardon). Orthographic regularity refers to the possibility of spelling a word correctly by applying the most frequent sound-letter conversion rules. The present study examined how the interaction between spelling and motor processing builds up during writing acquisition. French 8-10 year old children participated in the experiment. This is the age handwriting skills start to become automatic. The children wrote regular and irregular words that could be frequent or infrequent. They wrote on a digitizer so we could collect data on latency, movement duration and fluency. The results revealed that the interaction between spelling and motor processing was present already at age 8. It became more adult-like at ages 9 and 10. Before starting to write, processing irregular words took longer than regular words. This processing load spread into movement production. It increased writing duration and rendered the movements more dysfluent. Word frequency affected latencies and cascaded into production. It modulated writing duration but not movement fluency. Writing infrequent words took longer than frequent words. The data suggests that orthographic regularity has a stronger impact on writing than word frequency. They do not cascade in the same extent. PMID- 25525972 TI - Influence of iron sulfides on abiotic oxidation of UO2 by nitrite and dissolved oxygen in natural sediments. AB - Iron sulfide precipitates formed under sulfate reducing conditions may buffer U(IV) insoluble solid phases from reoxidation after oxidants re-enter the reducing zone. In this study, sediment column experiments were performed to quantify the effect of biogenic mackinawite on U(IV) stability in the presence of nitrite or dissolved oxygen (DO). Two columns, packed with sediment from an abandoned U contaminated mill tailings site near Rifle, CO, were biostimulated for 62 days with an electron donor (3 mM acetate) in the presence (BRS+) and absence (BRS-) of 7 mM sulfate. The bioreduced sediment was supplemented with synthetic uraninite (UO2(s)), sterilized by gamma-irradiation, and then subjected to a sequential oxidation by nitrite and DO. Biogenic iron sulfides produced in the BRS+ column, mostly as mackinawite, inhibited U(IV) reoxidation and mobilization by both nitrite and oxygen. Most of the influent nitrite (0.53 mM) exited the columns without oxidizing UO2, while a small amount of nitrite was consumed by iron sulfides precipitates. An additional 10-day supply of 0.25 mM DO influent resulted in the release of about 10% and 49% of total U in BRS+ and BRS- columns, respectively. Influent DO was effectively consumed by biogenic iron sulfides in the BRS+ column, while DO and a large U spike were detected after only a brief period in the effluent in the BRS- column. PMID- 25525973 TI - The effect of chevron alignment signs on driver performance on horizontal curves with different roadway geometries. AB - To develop a practicable and clear guideline for implementing Chevrons on China's highways, it is necessary to understand the effect of Chevrons on driving performance in different roadway geometries. Using a driving simulator, this study tests the effect of China's Chevrons on vehicle speed and lane position on two-lane rural highway horizontal curves with different roadway geometries. The results showed a significant effect of Chevrons on speed reduction, and this function was not significantly affected by curve radius but was statistically affected by curve direction. The speed reduction caused by Chevrons was also significant at the approach of curve, middle of curve and point of tangent. The 85th percentile speed was also markedly lower when Chevrons were present. We also found a significant effect of Chevrons in encouraging participants to drive the vehicle with a more proper lane position at the first half of curves; and this function was slightly affected by curve radius. Meanwhile, the effect of Chevrons on keeping drivers staying in a more stable lane position was also statistically significant at the second half of curves. In sharp curves, the function of Chevrons to make drivers keep a stable lane position was lost. Besides, the impact of curve direction on the function of Chevrons on lane position was always present, and drivers would drive slightly away from Chevrons. Regardless of the curve radius, China's Chevrons at horizontal curves provide an advance warning, speed control and lane position guide for traffic on the nearside of Chevrons. Besides, combing with the function of Chevrons on preventing excessive speed and the benefit to make drivers keep a more proper lane position, China's Chevrons appear to be of great benefit to reduce crashes (e.g., run-off-road) in curves. PMID- 25525974 TI - Cognitive functioning differentially predicts different dimensions of older drivers' on-road safety. AB - The extent to which deficits in specific cognitive domains contribute to older drivers' safety risk in complex real-world driving tasks is not well understood. We selected 148 drivers older than 70 years of age both with and without neurodegenerative diseases (Alzheimer disease-AD and Parkinson disease-PD) from an existing driving database of older adults. Participant assessments included on road driving safety and cognitive functioning in visuospatial construction, speed of processing, memory, and executive functioning. The standardized on-road drive test was designed to examine multiple facets of older driver safety including navigation performance (e.g., following a route, identifying landmarks), safety errors while concurrently performing secondary navigation tasks ("on-task" safety errors), and safety errors in the absence of any secondary navigation tasks ("baseline" safety errors). The inter-correlations of these outcome measures were fair to moderate supporting their distinctiveness. Participants with diseases performed worse than the healthy aging group on all driving measures and differences between those with AD and PD were minimal. In multivariate analyses, different domains of cognitive functioning predicted distinct facets of driver safety on road. Memory and set-shifting predicted performance in navigation related secondary tasks, speed of processing predicted on-task safety errors, and visuospatial construction predicted baseline safety errors. These findings support broad assessments of cognitive functioning to inform decisions regarding older driver safety on the road and suggest navigation performance may be useful in evaluating older driver fitness and restrictions in licensing. PMID- 25525975 TI - Overlap of symptoms of gastroesophageal reflux disease, dyspepsia and irritable bowel syndrome in the general population. AB - INTRODUCTION: Gastroesophageal reflux disease (GERD), functional dyspepsia (FD) and irritable bowel syndrome (IBS) are common functional gastrointestinal conditions with significant impact on the daily lives of individuals. The objective was to investigate the prevalence and overlap of the three conditions in a Western general population. MATERIAL AND METHODS: A nationwide study of 100,000 individuals 20 years and above, randomly selected in the general population. A web-based questionnaire survey formed the basis of this study. Questions regarding FD and IBS were extracted from the ROME III adult questionnaire. Questions regarding GERD were developed based on the Montreal definition. Prevalence estimates for GERD, FD IBS were calculated in total and for each sex separately and for four age groups. A Venn diagram was constructed, illustrating the overlap between the three conditions. RESULTS: The overall response rate was 52.2%. The prevalence of GERD, FD and IBS was 11.2%, 7.7% and 10.5%, respectively, and overlap between two or three of these conditions was seen among 6.5% of the respondents. Among individuals meeting the criteria of one or more of the conditions GERD, FD and IBS, 30.7% had overlap between two or all three conditions. CONCLUSION: GERD, FD and IBS are common conditions in the general population and the overlap between these conditions is also quite common. When diagnosing patients with GERD, FD and IBS, physicians should keep in mind that these patients could be suffering from more than one of these conditions. PMID- 25525977 TI - Energy from CO2 using capacitive electrodes - a model for energy extraction cycles. AB - A model is presented for the process of harvesting electrical energy from CO2 emissions using capacitive cells. The principle consists of controlling the mixing process of a concentrated CO2 gas stream with a dilute CO2 gas stream (as, for example, exhaust gas and air), thereby converting part of the released mixing energy into electrical energy. The model describes the transient reactive transport of CO2 gas absorbed in water or in monoethanolamine (MEA) solutions, under the assumption of local chemical equilibrium. The model combines the selective transport of ions through ion-exchange membranes, the accumulation of charge in the porous carbon electrodes and the coupling between the ionic current and the produced electrical current and power. We demonstrate that the model can be used to calculate the energy that can be extracted by mixing concentrated and dilute CO2 containing gas streams. Our calculation results for the process using MEA solutions have various counterintuitive features, including: 1. When dynamic equilibrium is reached in the cyclical process, the electrical charge in the anode is negative both during charging and discharging; 2. Placing an anion exchange membrane (AEM) in the system is not required, the energy per cycle is just as large with or without an AEM. PMID- 25525976 TI - Investigating protein folding and unfolding in electrospray nanodrops upon rapid mixing using theta-glass emitters. AB - Theta-glass emitters are used to rapidly mix two solutions to induce either protein folding or unfolding during nanoelectrospray (nanoESI). Mixing acid denatured myoglobin with an aqueous ammonium acetate solution to increase solution pH results in protein folding during nanoESI. A reaction time and upper limit to the droplet lifetime of 9 +/- 2 MUs is obtained from the relative abundance of the folded conformer in these rapid mixing experiments compared to that obtained from solutions at equilibrium and a folding time constant of 7 MUs. Heme reincorporation does not occur, consistent with the short droplet lifetime and the much longer time constant for this process. Similar mixing experiments with acid-denatured cytochrome c and the resulting folding during nanoESI indicate a reaction time of between 7 and 25 MUs depending on the solution composition. The extent of unfolding of holo-myoglobin upon rapid mixing with theta-glass emitters is less than that reported previously ( Fisher et al. Anal. Chem. 2014 , 86 , 4581 - 4588 ), a result that is attributed to the much smaller, ~1.5 MUm, average o.d. tips used here. These results indicate that the time frame during which protein folding or unfolding can occur during nanoESI depends both on the initial droplet size, which can be varied by changing the emitter tip diameter, and on the solution composition. This study demonstrates that protein folding or unfolding processes that occur on the ~10 MUs time scale can be readily investigated using rapid mixing with theta-glass emitters combined with mass spectrometry. PMID- 25525978 TI - Facile self-assembly and stabilization of metal oxide nanoparticles. AB - This paper describes a facile method of self-assembling different metal oxide nanoparticles into nanostructured materials via di-carboxylate linkers (oxalic acid) using TiO2 as an example. In this method, the di-carboxylate linkers react with surface hydroxyls on metal oxide nanoparticles forming covalent, ester-like bonds, which enable the binding of two metal oxide particles, one at either end of the linker and facilitates efficient self-assembly of one group of metal oxide nanoparticles homogeneously distributed onto the surface of another group. The oxalate linkers can then be removed by thermal decomposition. This approach is shown to be effective using differently-sized TiO2 nanoparticles, namely in-house synthesized 3-5nm anatase nanocrystals and Degussa P25 titania particles (mean 21nm particle size). Our data show that the application of a high temperature heat treatment (450 degrees C for 30min), conventionally applied to achieve a stable porous structure by thermal decomposition of the linker molecules and by inducing inter-particle necking, damages the surface area of the nanostructured material. However, here we show that sintering at 300 degrees C for 30min or by flash near infrared radiation sintering for 12s efficiently decomposes the oxalate linkers and stabilizes the nanostructure of the material whilst maintaining its high surface area. PMID- 25525979 TI - Novel biomarkers of acute kidney injury: time for implementation? PMID- 25525980 TI - Determination of the severity of ureteropelvic junction obstruction using urinary epidermal growth factor and kidney injury molecule 1 levels. AB - AIM: This study aimed to assess the urinary concentrations of epidermal growth factor (EGF) and kidney injury molecule 1 (KIM-1) in patients with hydronephrosis. METHODS: Neonates with a history of prenatal hydronephrosis were enrolled in three groups. Group 1 included neonates with severe obstruction; group 2 included neonates with milder obstruction; and group 3 included neonates with normal findings on postnatal ultrasonography. RESULTS: 59 neonates were enrolled. The EGF: Cr and KIM-1: Cr ratios were significantly higher in group 1 than in group 2 (p = 0.016 and 0.015, respectively). The cut-off values were measured as 16.855 (sensitivity 71%, specificity 77%) and 0.4765 (sensitivity 81%, specificity 71%) for EGF:Cr and KIM-1:Cr ratios, respectively. The values were significantly higher in group 1 than in group 2. CONCLUSIONS: Evaluation of the urinary KIM-1:Cr ratio may help identify neonates with severe obstructive hydronephrosis. PMID- 25525981 TI - The identification of three novel biomarkers of major adverse kidney events. AB - AIM: To describe the prognostic value of three novel biomarkers for acute adverse kidney events compared with routine biological markers. MATERIAL & METHODS: We used high-end MS to quantify biomarkers predictive of acute kidney injury (AKI) and major adverse kidney events (MAKE) in 100 adult patients after open heart surgery (n = 100). RESULTS: Early postoperatively measured LG3 (a C-terminal fragment of perlecan), LTBP2 (latent transforming growth factor binding protein 2), Cathepsin L as well as two other renal biomarkers (NGAL, Cystatin C) had greater predictive value for AKI (n = 23) and MAKE (n = 24) compared with creatinine, urea and urine output. CONCLUSIONS: LG3, LTBP2 and Cathepsin L deserve further exploration as biomarkers for the early identification of patients at risk of MAKE. PMID- 25525982 TI - Blood HCO3- concentration predicts the long-term prognosis of acute kidney injury patients. AB - AIM: To evaluate the value of HCO3(-) concentrations in long-term prognosis after acute kidney injury. PATIENTS & METHODS: A total of 169 AKI patients were included in this study. At the 12-month follow-up, the patients were divided into recovered and unrecovered groups. RESULTS: The blood HCO3(-) concentrations were significantly correlated with poor prognosis. The area under the curve for renal prognosis of 6 months later blood HCO3(-) concentrations was 0.798. Combined HCO3(-) and Scr level area under the curve was 0.952. CONCLUSION: The blood HCO3( ) level was useful in evaluating renal prognosis of acute kidney injury patients. The combination of blood HCO3(-) concentration and Scr level increased the accuracy of prediction. PMID- 25525983 TI - Pilot study of association of catechol-O-methyl transferase rs4680 genotypes with acute kidney injury and tubular stress after open heart surgery. AB - AIM: To assess the association of genetic variants of catecholamine-O methyltransferase (COMT) genotypes with acute kidney injury (AKI) and tubular stress after open heart surgery. PATIENTS & METHODS: We genotyped 195 patients for the COMT-Val158Met polymorphism and measured creatinine, neutrophil gelatinase-associated lipocalin and midkine. We analyzed the association between such polymorphisms and these kidney-related variables. RESULTS: Nonsignificantly more COMT LL patients developed RIFLE-AKI compared with non-LL patients (p = 0.11). Compared with HL and HH patients, LL patients who developed AKI had lower increases in serum creatinine. COMT LL patients had less pronounced release of tubular stress biomarkers (neutrophil gelatinase-associated lipocalin: p = 0.045, midkine: p = 0.072). CONCLUSION: COMT genotype may associate with different patterns of renal functional changes and tubular stress biomarker release response after open heart surgery. PMID- 25525984 TI - What can we expect from biomarkers for acute kidney injury? AB - Biomarkers for acute kidney injury have numerous potential roles to play both at the bedside and in the design and conduct of clinical trials. Given the heterogeneous nature of this disease and the difficulty, so far, in developing effective therapies, a strategy that deploys all of our available tools in the treatment and in study of treatments would seem prudent. In this review, we discuss how biomarkers will change the way we do we take care of patients with and do clinical trials in acute kidney injury and why, in fact, biomarkers are necessary. PMID- 25525985 TI - Biomarkers of calcineurin inhibitor nephrotoxicity in transplantation. AB - Over 35 years of use has demonstrated the revolutionary therapeutic benefits of calcineurin inhibitors (CNI) in not only preventing transplant rejection, but also the renal and nonrenal toxicity of CNI. Acute reversible and insidious irreversible forms of CNI nephrotoxicity have been identified, with ischemia from an imbalance between vasoconstrictors and vasodilators playing an important role. The ongoing search to define toxicity pathways has been enriched by 'Omics' studies. Changes in proteins including those involved in activation of pro inflammatory responses, oxidative stress, ER stress and the unfolded protein response have been identified, and these may serve as biomarkers of toxicity. However, the current standard of CNI toxicity, histology, lacks specificity, which creates challenges for biomarker validation. This review focuses on progress in nephrotoxic pathway identification of CNI and biomarker validation. PMID- 25525986 TI - Biomarkers in IgA nephropathy. AB - IgA nephropathy is the most common primary glomerulonephritis and presents with gross hematuria and upper respiratory infection, with slow progression to end stage renal disease in up to 50% of affected patients. Kidney biopsies are the gold standard method of diagnosis and frequently are not performed as the majority of individuals are asymptomatic. Thus, there is a need to discover and validate prognostic and predictive biomarkers that can be noninvasively obtained and are specific to this disease. Here we discuss the current state of research in this area and examine validated and clinically promising biofluid and tissue biomarkers of IgA nephropathy. PMID- 25525987 TI - New avenue to inhibit Ras signaling. AB - Inhibition of Ras-stimulating enzymes is a possible avenue to treat Ras-driven diseases. In this issue of Chemistry & Biology, Evelyn and coworkers report an inhibitor for one such enzyme, Sos1, capable of impairing wild-type Ras signaling in cells. PMID- 25525988 TI - Emergent dynamics from quorum eavesdropping. AB - Numerous bacterial species utilize quorum sensing to communicate, but crosstalk often complicates the dynamics of mixed populations. In this issue of Chemistry & Biology, Wu and colleagues take advantage of synthetic gene circuits to elucidate interactions between two quorum sensing systems, with potential applications to fields from infectious diseases to biosynthesis. PMID- 25525989 TI - Structural requirements in the transmembrane domain of GLIC revealed by incorporation of noncanonical histidine analogs. AB - The cyanobacterial pentameric ligand-gated ion channel GLIC, a homolog of the Cys loop receptor superfamily, has provided useful structural and functional information about its eukaryotic counterparts. X-ray diffraction data and site directed mutagenesis have previously implicated a transmembrane histidine residue (His234) as essential for channel function. Here, we investigated the role of His234 via synthesis and incorporation of histidine analogs and alpha-hydroxy acids using in vivo nonsense suppression. Receptors were expressed heterologously in Xenopus laevis oocytes, and whole-cell voltage-clamp electrophysiology was used to monitor channel activity. We show that an interhelix hydrogen bond involving His234 is important for stabilization of the open state, and that the shape and basicity of its side chain are highly sensitive to perturbations. In contrast, our data show that two other His residues are not involved in the acid sensing mechanism. PMID- 25525990 TI - Pregnenolone functions in centriole cohesion during mitosis. AB - Cell division is controlled by a multitude of protein enzymes, but little is known about roles of metabolites in this mechanism. Here, we show that pregnenolone (P5), a steroid that is produced from cholesterol by the steroidogenic enzyme Cyp11a1, has an essential role in centriole cohesion during mitosis. During prometa-metaphase, P5 is accumulated around the spindle poles. Depletion of P5 induces multipolar spindles that result from premature centriole disengagement, which are rescued by ectopic introduction of P5, but not its downstream metabolites, into the cells. Premature centriole disengagement, induced by loss of P5, is not a result of precocious activation of separase, a key factor for the centriole disengagement in anaphase. Rather, P5 directly binds to the N-terminal coiled-coil domain of short-form of shugoshin 1 (sSgo1), a protector for centriole cohesion and recruits it to spindle poles in mitosis. Our results thus reveal a steroid-mediated centriole protection mechanism. PMID- 25525991 TI - Droplet-based microfluidics platform for ultra-high-throughput bioprospecting of cellulolytic microorganisms. AB - Discovery of microorganisms producing enzymes that can efficiently hydrolyze cellulosic biomass is of great importance for biofuel production. To date, however, only a miniscule fraction of natural biodiversity has been tested because of the relatively low throughput of screening systems and their limitation to screening only culturable microorganisms. Here, we describe an ultra-high-throughput droplet-based microfluidic system that allowed the screening of over 100,000 cells in less than 20 min. Uncultured bacteria from a wheat stubble field were screened directly by compartmentalization of single bacteria in 20 pl droplets containing a fluorogenic cellobiohydrolase substrate. Sorting of droplets based on cellobiohydrolase activity resulted in a bacterial population with 17- and 7-fold higher cellobiohydrolase and endogluconase activity, respectively, and very different taxonomic diversity than when selected for growth on medium containing starch and carboxymethylcellulose as carbon source. PMID- 25525993 TI - Evaluation of metal biouptake from the analysis of bulk metal depletion kinetics at various cell concentrations: theory and application. AB - Bioavailability of trace metals is a key parameter for assessment of toxicity on living organisms. Proper evaluation of metal bioavailability requires monitoring the various interfacial processes that control metal partitioning dynamics at the biointerface, which includes metal transport from solution to cell membrane, adsorption at the biosurface, internalization, and possible excretion. In this work, a methodology is proposed to quantitatively describe the dynamics of Cd(II) uptake by Pseudomonas putida. The analysis is based on the kinetic measurement of Cd(II) depletion from bulk solution at various initial cell concentrations using electroanalytical probes. On the basis of a recent formalism on the dynamics of metal uptake by complex biointerphases, the cell concentration-dependent depletion time scales and plateau values reached by metal concentrations at long exposure times (>3 h) are successfully rationalized in terms of limiting metal uptake flux, rate of excretion, and metal affinity to internalization sites. The analysis shows the limits of approximate depletion models valid in the extremes of high and weak metal affinities. The contribution of conductive diffusion transfer of metals from the solution to the cell membrane in governing the rate of Cd(II) uptake is further discussed on the basis of estimated resistances for metal membrane transfer and extracellular mass transport. PMID- 25525992 TI - A fluorescent hydrogel-based flow cytometry high-throughput screening platform for hydrolytic enzymes. AB - Screening throughput is a key in directed evolution experiments and enzyme discovery. Here, we describe a high-throughput screening platform based on a coupled reaction of glucose oxidase and a hydrolase (Yersinia mollaretii phytase [YmPh]). The coupled reaction produces hydroxyl radicals through Fenton's reaction, acting as initiator of poly(ethyleneglycol)-acrylate-based polymerization incorporating a fluorescent monomer. As a consequence, a fluorescent hydrogel is formed around Escherichia coli cells expressing active YmPh. We achieve five times enrichment of active cell population through flow cytometry analysis and sorting of mixed populations. Finally, we validate the performance of the fluorescent polymer shell (fur-shell) technology by directed phytase evolution that yielded improved variants starting from a library containing 10(7) phytase variants. Thus, fur-shell technology represents a rapid and nonlaborious way of identifying the most active variants from vast populations, as well as a platform for generation of polymer-hybrid cells for biobased interactive materials. PMID- 25525994 TI - Cyclization of thiocarbonyl groups in binuclear homoleptic nickel thiocarbonyls to give ligands derived from sulfur analogues of croconic and rhodizonic acids. AB - The sulfur analogue of the well-known Ni(CO)4, namely, Ni(CS)4, has been observed spectroscopically in low temperature matrices but is not known as a stable species under ambient conditions. Theoretical studies show that Ni(CS)4 with monomeric CS ligands and tetrahedrally coordinated nickel is disfavored by ~17 kcal/mol relative to unusual isomeric Ni(C2S2)2 structures. In the latter structures the CS ligands couple pairwise through C-C bond formation to give dimeric S?C?C?S ligands, which bond preferentially to the nickel atom through their C?S bonds rather than their C?C bonds. Coupling of CS ligands in the lowest energy binuclear Ni2(CS)n (n = 7, 6, 5) structures results in cyclization to give remarkable CnSn (n = 5, 6) ligands containing five- and six-membered carbocyclic rings. Such ligands, which are the sulfur analogues of the well-known croconate (n = 5) and rhodizonate (n = 6) oxocarbon ligands, function as bidentate ligands to the central Ni2 unit. Higher energy Ni2(CS)n (n = 7, 6, 5) structures contain dimeric C2S2 ligands, which can bridge the central Ni2 unit. Dimeric C2S2 ligands rather than tetrathiosquare C4S4 ligands are found in the lowest energy Ni2(CS)4 structures. PMID- 25525995 TI - Structure characterization of a novel polysaccharide from Dictyophora indusiata and its macrophage immunomodulatory activities. AB - A novel polysaccharide, here named DP1, was isolated from the fruiting body of Dictyophora indusiata using a water extraction method. Structure characterization revealed that DP1 had an average molecular weight of 1132 kDa and consisted of glucose (56.2%), galactose (14.1%), and mannose (29.7%). The main linkage type of DP1 were proven to be (1 -> 3)-linked alpha-l-Man, (1 -> 2,6)-linked alpha-d-Glc, (1 -> 6)-linked beta-d-Glc, (1 -> 6)-linked beta-d-Gal, and (1 -> 6)-linked beta d-Man by periodate oxidation-Smith degradation and nuclear magnetic resonance analysis. The immunostimulating assay indicated that DP1 could significantly promote macrophage NO, TNF-alpha, and IL-6 secretion in murine RAW 264.7 cells involving complement receptor 3 (CR3). The immune activities of DP1 were quite stable under thermal processing (100, 121, and 145 degrees C). Besides, DP1 retained stability after acidic/alkline treatment (pH 4.0-10.0), which enabled it to be an ideal complementary medicine or functional food for therapeutics of hypoimmunity and immunodeficiency diseases. PMID- 25525996 TI - Sweet syndrome with panniculitis, arthralgia, episcleritis, and neurologic involvement precipitated by antibiotics. AB - BACKGROUND: Sweet syndrome is an uncommon skin condition, often idiopathic in origin although it may be reactive to various systemic conditions, recent infections, underlying malignancies, and medications. OBJECTIVE & METHOD: To present a case highlighting a rare clinical presentation and to review the causes of Sweet syndrome with an emphasis on drug-induced etiologies. RESULTS: We describe a 45-year-old woman who developed Sweet syndrome while receiving nitrofurantoin and ciprofloxacin for a urinary tract infection. Her course of disease was complicated by arthralgias, episcleritis, headaches, and erythema nodosum-like subcutaneous involvement. There was marked improvement with discontinuation of the inciting antibiotics and initiation of systemic steroids. CONCLUSION: This case illustrates Sweet syndrome related to nitrofurantoin and/or ciprofloxacin. This is the second report of Sweet syndrome related to these antibiotics and the first associated with ocular, joint, and neurologic involvement. PMID- 25525997 TI - Primary malignant melanoma of the ovary arising in a cystic teratoma; case report and review of the literature. AB - Primary malignant melanoma of the ovary arising in a cystic teratoma is extremely rare. There is no melanocytic component in the normal ovarian tissue. However, melanocytes may be present in a cystic teratoma of the ovary, especially at the basal layer of squamous epithelium. We report a case of primary malignant melanoma of the ovary arising in a cystic teratoma. We demonstrate junctional activity of melanocytes showing malignant transformation with both radial and vertical growth phases, a feature diagnostic for primary malignant melanoma but not always demonstrated in such cases. We compiled and reviewed twelve cases that are also able to demonstrate junctional activity. PMID- 25525998 TI - A novel association of an uncommon pigmentation pattern: coexistence of cutis tricolor with intracranial teratoma and holoprosencephaly. AB - Cutis tricolor was first described in a 17-year-old male patient by Happle et al. as a rare coexistence of circumscribed hyperpigmentation and hypopigmentation close to each other on a background of normally pigmented skin. Cutis tricolor has been reported as an isolated cutaneous finding or in various associations. To the best of our knowledge, cutis tricolor in association with teratoma and holoprosencephaly has not been reported in the literature. Herein, we report a male patient who presented with a teratoma and a combination of whorl-like hypopigmentation together with hyperpigmented patches adjacent to each other on intermediately pigmented skin. This case report supports the view that cutis tricolor may be a marker of an underlying neurological abnormality. PMID- 25525999 TI - Treatment of pagetoid reticulosis with intensity modulated radiation therapy. AB - Pagetoid reticulosis, also known as Woringer-Kolopp disease, is a rare variant of cutaneous T-cell lymphoma usually presenting as an isolated patch or plaque on the extremities. Immunohistochemical staining of T-cell markers can be variable, but as the name implies the epidermotropic lymphocytes consistently display a "pagetoid" appearance. The following case demonstrates clearance of this condition with intensity modulated radiation therapy, whereas most cases are managed with electron beam therapy if radiation therapy is implemented. PMID- 25526000 TI - Cutaneous involvement in multiple myeloma: a case report with an unusual location. AB - Multiple myeloma (MM) is a rare cancer. Cutaneous involvement is uncommon with fewer than 100 cases described in the literature. We report herein a patient with MM, subtype IgA kappa, with unusual clinical presentation including the lower lip. PMID- 25526001 TI - Systemic allergic contact dermatitis associated with allergy to intraoral metals. AB - Contact (allergic) dermatitis is a skin disorder related to natural exposure to various allergens. Systemic contact dermatitis (SCD) describes a cutaneous eruption in response to systemic exposure to an allergen. The exact pathologic mechanism remains uncertain. Herein we describe a 36-year-old woman with symmetric systemic allergic contact dermatitis, unresponsive to conventional treatment, associated with dental alloy-contact hypersensitivity. We did skin patch testing and the blood lymphocyte transformation test (LTT) from the dental allergen series to assess contact allergy to restorative dental materials. On patch testing, positive allergic contact dermatitis reactions to metals occurred (nickel, potassium dichromate, and gold). Nickel hypersensitivity was confirmed by LTT, which also revealed silver-amalgam sensitization. Our case report highlights the need to consider adverse reactions to base-metal dental alloys in the differential diagnosis of cases of systemic allergic contact dermatitis. PMID- 25526002 TI - Mid-dermal elastolysis: report of a case and literature review. AB - Mid-dermal elastolysis (MDE) is an uncommon and probably underdiagnosed disorder of the elastic tissue. Clinical suspicion and histopathological confirmation are essential for the diagnosis. We report the case of a young woman who presented with this disorder after an inflammatory process during pregnancy and we review the main characteristics of this rare entity. PMID- 25526003 TI - Drug-associated skin lesions in a patient with myelofibrosis receiving ruxolitinib. AB - Ruxolitinib, a small molecule JAK-1/2 inhibitor, was approved by the U.S. Food and Drug Administration (FDA) in November 2011, as the first therapeutic for the treatment of intermediate and high-risk myelofibrosis. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of the most well-studied intracellular signaling networks. Recent advances in our understanding of the complexities of signal activation and regulation of gene expression has provided opportunities for targeted therapeutic interventions. Although numerous inhibitors of the JAK/STAT pathway are currently being evaluated in clinical trials, ruxolitinib represents the first FDA approved in class JAK inhibitor. We report a drug eruption associated with ruxolitinib. PMID- 25526004 TI - Crusted scabies of the scalp in a patient with systemic lupus erythematosus. AB - BACKGROUND: Crusted scabies is a severe, hyperkeratotic, psoriasiform disorder associated with immune suppression. Affected individuals typically present with crusted hyperkeratotic lesions in a variety of locations. This condition can lead to severe complications: institutional outbreaks and secondary bacterial infections associated with sepsis and high mortality. MAIN OBSERVATIONS: A 37 year-old woman with a 12-year history of systemic lupus erythematosus treated with prednisone, methotrexate, and plaquenil presented with a three-week history of a painful scalp rash with adherent yellow scale. Skin biopsy and tissue culture were consistent with a diagnosis of crusted scabies with superficial bacterial infection. The patient was treated with oral ivermectin and permethrin cream, as well as ciprofloxacin for the bacterial infection. At one-week follow up, the scalp was no longer tender and hyperkeratotic plaques had significantly improved. At one-month follow-up, the affected scalp demonstrated further improvement with decreasing erythema and alopecia with follicular ostia. CONCLUSIONS: Our case highlights the atypical presentation of crusted scabies with primary scalp involvement and need for vigilance in recognizing and appropriately treating this condition to prevent the consequences of longstanding infection. Combination treatment with ivermectin and permethrin is appropriate management for this condition. PMID- 25526006 TI - Hair-thread tourniquet syndrome: a case report and review of treatment. AB - Hair-thread tourniquet syndrome (HTTS) is caused by circumferential constriction of an appendage, usually by hair or thread, leading to obstruction of circulation and ischemia. Although not rare, this entity is not discussed extensively in the Dermatology literature. We present a case of HTTS and discuss the demographics and etiology, and review the most current treatment methods. PMID- 25526005 TI - Hailey-Hailey disease exacerbated by multiple pregnancies: case report and review of the literature. AB - Hailey-Hailey disease is a rare chronic skin disorder that is inherited in an autosomal dominant manner. The disease is characterized by development of vesicles and bullae typically in the intertriginous areas. On histology, there is widespread intraepidermal acantholysis causing the "dilapidated brick-wall" appearance. Mutations in the ATP2C1 gene, encoding for P-type Ca2+ transport ATPase, is the primary cause of the disease. The disease manifests around puberty and runs a chronic course with remissions and exacerbations. Ultraviolet light exposure, sweating, friction, stress, and cutaneous infections are the known precipitants of the disease. We report a case of a woman with recurrent flare-ups of Hailey-Hailey disease with repeated pregnancies and remission of her disease during non-pregnancy periods. To our knowledge, this is the first reported case of Hailey-Hailey disease exacerbated by pregnancy. PMID- 25526007 TI - Congenital eccrine nevus on the neck. AB - Eccrine nevus (EN) is a very rare hamartoma of the skin and with varying clinical manifestations. Histologically, these neoplasms present as a proliferation of normally structured eccrine sweat glands in the dermis. There have been no more than 20 cases previously have been reported in the English literature. Herein we report a 25-year-old man with eccrine nevus on the neck. To our best knowledge, this is the first case that the lesion affecting the neck. PMID- 25526008 TI - Rosacea in skin of color: not a rare diagnosis. AB - BACKGROUND: The prevalence of rosacea in skin of color is not well characterized and may be underestimated. Physicians may not recognize and diagnose rosacea correctly in skin of color. PURPOSE: To assess the prevalence of rosacea in skin of color and determine if patients of color with rosacea symptoms are receiving a diagnosis of rosaceaMethods: We analyzed the National Ambulatory Medical Care Survey (NAMCS) for 1993-2010 for racial and ethnic distribution of patients with rosacea. Common reasons for visit in rosacea patients were tabulated and frequency of rosacea diagnosis was compared in patients of each race with the relevant reasons for visit. RESULTS: Of all patients diagnosed with rosacea, 2.0% were black, 2.3% were Asian or Pacific Islander, and 3.9% were Hispanic or Latino of any race. Leading reasons for visit associated with rosacea included "other diseases of the skin", skin rash, and discoloration or abnormal pigmentation. Rosacea was the primary diagnosis for 8.3% of whites and 2.2% of blacks complaining of "other diseases of the skin", for 2.0% of whites and 0.6% of blacks complaining of skin rash, and for 3.0% of whites and 0.0% of blacks complaining of discoloration or abnormal pigmentation. The percentage of rosacea patients who were black or Asian/Pacific Islander did not change significantly over time. LIMITATIONS: No specific reason-for-visit code indicating rosacea exists in the NAMCS. Prevalence may be underestimated if some patients do not visit a physician for treatment. CONCLUSIONS: Patients of color rarely receive a diagnosis of rosacea, even when they have symptoms suggesting it. Rosacea has not become more commonly diagnosed in skin of color in recent years. PMID- 25526009 TI - Bullous hemorrhagic dermatosis distant from the site of heparin injection. AB - Enoxaparin sodium is a heparin of low molecular weight with antithrombotic properties that acts by inhibiting factor Xa. We present a 59-year-old woman who developed heparin-related bullous hemorrhagic dermatosis, at sites distant from the injections, one month after starting treatment with enoxaparin. PMID- 25526010 TI - Cetuximab-induced crusted pustular eruption with patchy alopecia. AB - A 52-year-old man with recurrent metastatic rectal carcinoma being treated with cetuximab presented to the emergency department with a diffuse papulopustular eruption on the face, scalp, chest, and groin, accompanied by patchy alopecia of the scalp and facial hair. PMID- 25526011 TI - Scabies of the nail unit. AB - Scabies limited to the nail unit is quite unusual, but may persist after treatment of crusted scabies. We present a man with a history of crusted scabies that resolved with treatment, but later the patient reported a chronic problem with crumbly, thickened nails, which were found to be harboring scabies mites. PMID- 25526012 TI - A case of cutaneous larva migrans presenting in a pregnant patient. AB - Cutaneous larva migrans (CLM) is a pruritic dermatitis caused by migration of the animal hookworm larvae into the epidermis. We present a case of CLM in a 31-year old pregnant woman. The treatment of CLM relies on antihelminthic agents, such as thiabendazole, albendazole, and ivermectin. This case was interesting in that the standard treatment options previously mentioned were contraindicated owing to the patient's pregnancy. Cryotherapy with liquid nitrogen resulted in complete resolution of her lesion and symptoms. PMID- 25526013 TI - Successful long-term thalidomide therapy for discoid lupus erythematosus-lichen planus overlap syndrome. AB - Although thalidomide is a U.S. Food and Drug Admistration (FDA) approved medication for erythema nodosum leprosum and multiple myeloma, it has many off label uses, including for discoid lupus erythematosus (DLE), Behcet's disease, apththous ulcers in HIV patients, and prurigo nodularis. Herein, we present a patient with an overlap of discoid lupus erythematosus and lichen planus who was successfully treated with thalidomide for over 19 years without significant side effects. We propose that some of the most common side effects, including peripheral neuropathy, numbness, parasthesias, sedation, and constipation, can be avoided at lower doses, typically less than 100mg/day. PMID- 25526014 TI - Can an evidence-based book club intervention delivered via a tablet computer improve physical activity in middle-aged women? AB - BACKGROUND: Fewer than 50% of middle-aged women participate in regular physical activity (PA). Innovative approaches that engage women who may not otherwise participate in PA programs are warranted. The purpose of this study was to explore the acceptability and feasibility of a 12-week tablet-based book club for improving middle-aged women's PA. MATERIALS AND METHODS: Thirty women (35-64 years of age) were randomized to the Fit Minded Tablet (n=15) and the Standard Fit Minded (i.e., face-to-face intervention) (n=15) groups. The Fit Minded Tablet was adapted from the Standard Fit Minded, a previously tested, theory-based book club intervention using books as a platform for discussion and group support to help women adopt regular PA. Both interventions met weekly for 3 months, for a total of 12 sessions. Tablet group participants accessed materials (e.g., e books, workbook, live/recorded videoconferencing) via a tablet computer; Standard group participants received materials (e.g., printed books, workbook, live face to-face meetings) in person. Feasibility (i.e., implementation and expansion) was assessed using process evaluation, qualitative interviews, satisfaction surveys, and quantitative outcome assessments. RESULTS: Women in the Tablet group attended fewer meetings (mean, 8.25) than women in the Standard group (mean, 9.9). Videoconferencing, digital literacy, and participant engagement limitations were observed in the Tablet group. Tablet participants enjoyed the e-books but thought technology barriers hindered their engagement during meetings. Women in both groups valued the support they received from other group members. Standard participants cited this support as a key contributor to their PA changes, whereas Tablet participants reported needing in-person contact to feel more connected. CONCLUSIONS: Given the popularity of tablet computers and the value that middle aged women place on group interaction to support their PA behaviors, additional research is warranted to determine best strategies for optimizing social support, mitigating technology barriers, and improving engagement in online and mobile health promotion programs targeting middle-aged women. PMID- 25526015 TI - Ability of pediatric emergency medicine physicians to identify anatomic landmarks with the assistance of ultrasound prior to lumbar puncture in a simulated obese model. AB - OBJECTIVES: Lumbar punctures (LPs) are typically performed using anatomical surface landmarks. However, as body mass index increases, identifying surface landmarks becomes more difficult. Ultrasound has been proposed as a tool for identifying these landmarks prior to LP. This study evaluates the effectiveness of a brief training program in ultrasound identification of anatomical landmarks in a simulated obese model prior to completing an LP. METHODS: Pediatric emergency medicine physicians completed a pretest questionnaire on ultrasound familiarity prior to an educational session. Participants utilized ultrasonography without the assistance of palpation on a simulation LP model saving images for review. Participants attempted LP on phantom models with simulated body mass indices of 35 and 40 kg/m. Time to image acquisition and successful aspiration of cerebrospinal fluid from the model were recorded. Two expert sonologists independently reviewed all images for correct landmark identification. RESULTS: Seven of the 19 participants had previous familiarity with ultrasound. The mean time to lumbar image acquisition significantly improved for all individuals from 176 seconds to 100 seconds (P = 0.003). Comfort level with ultrasound improved (P < 0.001) as well as comfort level in performing a lumbar ultrasound (P < 0.001). Adequate images were obtained in 96% of the attempts (55/57). The success rate at performing LP was 95% (54/57). CONCLUSIONS: After a brief education intervention, pediatric emergency medicine physicians with little to no previous training in ultrasound can obtain adequate lumbar anatomic images and successfully perform LP in a simulated obese model. Comfort level with ultrasound significantly improves with a short course in ultrasound fundamentals. PMID- 25526016 TI - Factors associated with emergency department discharge after pediatric interhospital transport: a role for outreach education? AB - OBJECTIVES: To characterize the disposition of children transported from an outside emergency department (ED) to a children's hospital ED and examine associations between patient and referring ED factors with discharge from the receiving ED. METHODS: We collected data from existing electronic data sources and telephone interviews of referring ED directors. We included all pediatric patients who were transported from an outside ED to the Children's National Medical Center ED between July 2009 and June 2010. We examined patient factors of age, diagnosis, and illness severity and referring ED factors of annual pediatric volume and staffing for associations with ED discharge. RESULTS: Of 3288 transported patients, 2230 (68%) were admitted, 1025 (31%) were discharged, and less than 1% died. In univariate analyses, discharge from the receiving ED was associated with trauma diagnoses (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.7-2.4), transports from low pediatric volume EDs (OR, 2.0; 95% CI, 1.7 2.4), and from EDs without pediatric physician staffing (OR, 2.1; 95% CI, 1.8 2.6). In multivariate analyses, discharge was associated with trauma and gastrointestinal diagnoses (adjusted OR 1.6 [95% CI, 1.2-2.2] and 1.9 [95% CI, 1.4-2.6], respectively) as well as low referring ED pediatric volume and nonpediatric physician staffing (adjusted OR, 1.7 [95% CI, 1.4-2.1] and 1.9 [95% CI, 1.5-2.5], respectively) when controlling for all other factors. CONCLUSIONS: In this single-site study, children referred from outside EDs with lower pediatric volumes and staffed by nonpediatricians were more likely to be discharged from a children's hospital ED after transport. These transports may represent unnecessary resource use. Outreach education, shared staffing models, and telemedicine are potential methods to address unnecessary transfers. PMID- 25526017 TI - Impact of a state concussion law on pediatric emergency department visits. AB - OBJECTIVE: Many states have passed concussion laws that mandate that players undergo medical clearance before returning to play. Few data have been collected on the impact of such laws on emergency department (ED) visits. This study measures the impact of Rhode Island concussion legislation on sports-related concussion visits to a pediatric ED. METHODS: International Classification of Diseases, Ninth Revision, Clinical Modification codes with injury mechanism associated E-codes were extracted from hospital databases from 2004 to 2011 for both sports-related concussions and sports-related ankle ligamentous injuries (comparison group). Visit rates for sports-related concussions were compared before and after the passage of the state concussion law.Secondary outcome measures included rates of head imaging per ED visit for concussion before and after passage of the law. Times series analysis was used to analyze season-to season count and rate changes. RESULTS: Overall rate of sports-related concussion visits more than doubled (2.2-fold increase; 95% confidence interval, 1.3-3.6; adjusted P = 0.01) during the fall sports season following the implementation of legislation (2010) relative to the previous year (3.6% vs 1.4%). Rates of sports related ankle sprain visits tended to increase during the fall sports season but did not achieve statistical significance. Rates of computed tomography scan imaging of the head did not change over time. CONCLUSIONS: The data from this study revealed an increase in pediatric ED visits for sports-related concussions, without a corresponding increase in head imaging, suggesting that the passage of a state concussion law has led to increased vigilance in evaluation of sports related concussions, without an increase in diagnostic computed tomography scans. PMID- 25526018 TI - Screening adolescents for sexually transmitted infections in the pediatric emergency department. AB - OBJECTIVES: The objectives of this study were to determine the prevalence of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) infections among adolescents presenting to a pediatric emergency department (PED), to assess the association between these infections and certain risk factors, and to assess the feasibility of routine screening for sexually transmitted infections (STIs) in the PED. METHODS: This was a prospective, observational cohort study. Three hundred seven adolescents aged 13 to 17 years in an urban PED in Bronx, NY, were enrolled in the study. Subjects provided urine samples for nucleic acid amplification testing for CT and GC and self-completed a confidential questionnaire to assess health care-seeking patterns, high-risk social behaviors, and the presence of abuse, depression, and suicidal ideation. Outcome measures include prevalence of STIs and association of STIs with responses to the confidential questionnaire. RESULTS: Twenty subjects (6.5%) tested positive for an STI. Seventeen (5.5%) were positive for CT, 2 (0.7%) for GC, and 1 (0.3%) for both. Fourteen adolescents (70%) with a positive test were asymptomatic. Logistic regression yielded 4 factors significantly associated with an STI: female sex (odds ratio [OR], 4.02; 95% confidence interval [CI], 1.1-15.2), illicit drug use (OR, 3.3; 95% CI, 1.1-9.3), disclosure of sexual activity (OR, 9.3; 95% CI, 1.1 76.9), and report of a sexual encounter resulting in pregnancy (OR, 3.7; 95% CI, 1.3-10.4). CONCLUSIONS: Sexually transmitted infections were common in asymptomatic adolescents presenting to the PED. We identified 4 risk factors that were significantly associated with STIs. Our findings may facilitate identification of adolescents at highest risk for STIs, help prevent further transmission of infection, and decrease morbidity in this marginalized population. PMID- 25526019 TI - In-hospital pediatric cardiac arrest in Honduras. AB - OBJECTIVES: The objective of this study was to analyze the characteristic and the prognostic factors of in-hospital pediatric cardiac arrest (CA) in a public hospital Honduras. METHODS: A prospective observational study was performed on pediatric in-hospital CA as a part of a multicenter international study. One hundred forty-six children were studied. The primary end point was survival at hospital discharge. Univariate and multivariate logistic regression analyses were performed to assess the influence of each factor on mortality. RESULTS: Cardiac arrest occurred in the emergency department in 66.9%. Respiratory diseases and sepsis were predominant causes of CA. Return of spontaneous circulation was achieved in 60% of patients, and 22.6% survived to hospital discharge. The factors related with mortality were nonrespiratory cause of CA (odds ratio [OR], 2.55; P = 0.045), adrenaline administration (OR, 4.96; P = 0.008), and a duration of cardiopulmonary resuscitation more than 10 minutes (OR, 3.40; P = 0.012). CONCLUSIONS: In-hospital CA in children in a developing country has low survival. Patients with nonrespiratory causes and those who need adrenaline administration and prolonged resuscitation had worse prognosis. PMID- 25526021 TI - Verapamil-sensitive idiopathic left ventricular tachycardia in a 6-month-old: unique considerations in diagnosis and management in an infant. AB - Idiopathic left ventricular tachycardia of the Belhassen type is rare in infants. We present a 6-month-old infant girl with a wide-complex tachycardia with right bundle branch block QRS morphology, a superior axis, and atrioventricular dissociation, consistent with a left anterior fascicular tachycardia. Initial echocardiogram revealed depressed ventricular function. The tachycardia was unresponsive to therapeutic trials of adenosine, esmolol, procainamide, and lidocaine. There was brief conversion of the tachycardia to sinus rhythm with transesophageal atrial overdrive pacing, suggesting a reentrant mechanism of the arrhythmia. Ultimately, the judicious administration of intravenous verapamil resulted in termination of the arrhythmia, which has been sustained on oral therapy. PMID- 25526020 TI - RNA transcriptional biosignature analysis for identifying febrile infants with serious bacterial infections in the emergency department: a feasibility study. AB - OBJECTIVES: To develop the infrastructure and demonstrate the feasibility of conducting microarray-based RNA transcriptional profile analyses for the diagnosis of serious bacterial infections in febrile infants 60 days and younger in a multicenter pediatric emergency research network. METHODS: We designed a prospective multicenter cohort study with the aim of enrolling more than 4000 febrile infants 60 days and younger. To ensure success of conducting complex genomic studies in emergency department (ED) settings, we established an infrastructure within the Pediatric Emergency Care Applied Research Network, including 21 sites, to evaluate RNA transcriptional profiles in young febrile infants. We developed a comprehensive manual of operations and trained site investigators to obtain and process blood samples for RNA extraction and genomic analyses. We created standard operating procedures for blood sample collection, processing, storage, shipping, and analyses. We planned to prospectively identify, enroll, and collect 1 mL blood samples for genomic analyses from eligible patients to identify logistical issues with study procedures. Finally, we planned to batch blood samples and determined RNA quantity and quality at the central microarray laboratory and organized data analysis with the Pediatric Emergency Care Applied Research Network data coordinating center. Below we report on establishment of the infrastructure and the feasibility success in the first year based on the enrollment of a limited number of patients. RESULTS: We successfully established the infrastructure at 21 EDs. Over the first 5 months we enrolled 79% (74 of 94) of eligible febrile infants. We were able to obtain and ship 1 mL of blood from 74% (55 of 74) of enrolled participants, with at least 1 sample per participating ED. The 55 samples were shipped and evaluated at the microarray laboratory, and 95% (52 of 55) of blood samples were of adequate quality and contained sufficient RNA for expression analysis. CONCLUSIONS: It is possible to create a robust infrastructure to conduct genomic studies in young febrile infants in the context of a multicenter pediatric ED research setting. The sufficient quantity and high quality of RNA obtained suggests that whole blood transcriptional profile analysis for the diagnostic evaluation of young febrile infants can be successfully performed in this setting. PMID- 25526022 TI - Pulse Oxygen Saturation Values in a Healthy School-Aged Population. AB - OBJECTIVES: The purpose of this study was to determine the normal values of oxygen saturation in a healthy school-aged pediatric population. METHODS: This study enrolled students in grades K-8 at an elementary and middle school in Los Angeles. Although all students were invited to participate, only pulse oximetry results among healthy students were included. Healthy students were defined as not having asthma, bronchitis, a recent cold or pneumonia within the past week, any chronic lung disease, or any heart condition. RESULTS: Two hundred forty eight students participated in the study, and 246 students met the inclusion criteria. Pulse oxygen saturation values ranged from 97% to 100% with a mean of 98.7% (95% confidence interval [CI], 98.6%-99.8%) and median of 99%. The distribution of measured pulse oximetry values were 97%: 16 (95% CI, 6.5%), 98%: 45 (95% CI, 18.3%), 99%: 184 (95% CI, 74.8%), and 100%: 1 (95% CI, 0.4%). CONCLUSIONS: Although the conventional wisdom is that pulse oximetry values 95% or greater are normal, these data suggest that the normal oxygen saturation range should be between 97% and 100%. Values of 95% and 96% should increase clinical suspicion of underlying disease. PMID- 25526023 TI - A high salt diet alters pressure-induced mechanical activity of the rat lymphatics with enhancement of myogenic characteristics. AB - BACKGROUND: The lymphatic system has become a new player for pathogenesis in salt sensitive hypertension animals. A high salt diet (HSD) evokes accumulation of Na(+) in the skin of rodents. In response to increase in Na(+)-proteoglycan complex, infiltrated macrophages stimulate secretion of vascular endothelial growth factor (VEGF)-C. Macrophage-derived VEGF-C increases density of the dermal lymph capillaries, indicating that lymphangiogenesis is advantageous to hypertensive animals by buffering elevated blood pressure. However, the effects of a high salt diet (HSD) on changes in mechanical activity of collecting lymph vessels, which directly connect with lymph capillaries, have not yet been determined. METHODS AND RESULTS: Changes in mechanical activity of isolated collecting lymphatics in normal salt diet (NSD) and HSD rats in response to increase in intraluminal pressures were measured by video-microscopy. HSD vessels had smaller % active diameters (maximum and minimum) and higher amplitude compared with NSD vessels. The frequency of lymphatic oscillation was better maintained in HSD rats than in NSD. Lymphatic pump efficiency including stroke volume index (SVI), frequency times SVI, and amplitude times frequency in HSD rats were significantly higher than those of NSD. Thus, a HSD enhances the resistance to pressure-induced decreases in lymphatic pump efficiency. CONCLUSIONS: The present ex vivo study suggest that collecting lymphatics of rats enhance myogenic activity and lymphatic pump efficiency to compensate for increase in lymph flow and/or pressure after 2 weeks salt loading. PMID- 25526024 TI - Tetraploidy and tumor development. PMID- 25526025 TI - Reciprocity in breast cancer progression. PMID- 25526026 TI - Oncotargeting G proteins: The Hippo in the room. AB - The core components of the Hippo pathway are conserved from flies to mammals. In humans, these include a kinase cascade initiated by the Hippo kinase MST1/2 associated with the adaptor protein WW45/SAV1, and LATS1/2 in complex with MOB1, which in turn, phosphorylates and inhibits the mammalian transcription co activator YAP and its related protein TAZ. YAP plays a critical role in organ size control during development, and its persistent nuclear localization and activation contributes to multiple human malignancies. The mechanisms driving YAP activation in most cancers, however, are often not clearly understood. In recent studies, we and Guan's team found that YAP activation represents a key molecular event contributing to uveal melanoma, the most frequent ocular malignancy in adults. Uveal melanoma growth is driven by gain-of-function mutations in GNAQ or GNA11 oncogenes, encoding persistently active G protein alpha subunits of the Gq family. As the signaling capacity of G proteins and their coupled receptors (GPCRs) has been extensively investigated, these findings provided an opportunity to identify cancer-associated mechanisms resulting in YAP activation, and to explore whether YAP represents a suitable oncotarget for cancer treatment. PMID- 25526027 TI - Wnt signaling, de novo lipogenesis, adipogenesis and ectopic fat. AB - Wnt signaling is as a major regulator of adipogenesis. It differentially regulates the fate of mesenchymal stem cells (MSC) by promoting osteogenesis and myogenesis, and inhibiting adipogenesis[1]. Its loss of function has been associated with impaired osteogenesis[2] and diverse congenital and adult cardiovascular disorders[3,4]. Our group has identified loss of function mutations in Wnt coreceptor LRP6 that underlie autosomal dominant early onset coronary artery (CAD), osteoporosis and most features of the metabolic syndrome, including high plasma triglyceride and LDL-C, diabetes, hypertension, hyperuricemia and fatty liver disease (unpublished data). Following we will describe our most pertinent findings related to Wnt/LRP6 regulation of de novo lipogenesis and adipogenesis and the role of impaired Wnt signaling in generation of ectopic fat, insulin resistance, elevated plasma lipids and non-alcoholic fatty liver disease (NAFLD). PMID- 25526028 TI - Surgical procedures and postsurgical tissue processing significantly affect expression of genes and EGFR-pathway proteins in colorectal cancer tissue. AB - An understanding of tissue data variability in relation to processing techniques during and postsurgery would be desirable when testing surgical specimens for clinical diagnostics, drug development, or identification of predictive biomarkers. Specimens of normal and colorectal cancer (CRC) tissues removed during colon and liver resection surgery were obtained at the beginning of surgery and postsurgically, tissue was fixed at 10, 20, and 45 minutes. Specimens were analyzed from 50 patients with primary CRC and 43 with intrahepatic metastasis of CRC using a whole genome gene expression array. Additionally, we focused on the epidermal growth factor receptor pathway and quantified proteins and their phosphorylation status in relation to tissue processing timepoints. Gene and protein expression data obtained from colorectal and liver specimens were influenced by tissue handling during surgery and by postsurgical processing time. To obtain reliable expression data, tissue processing for research and diagnostic purposes needs to be highly standardized. PMID- 25526029 TI - Development and prospective multicenter evaluation of the long noncoding RNA MALAT-1 as a diagnostic urinary biomarker for prostate cancer. AB - The current strategy for diagnosing prostate cancer (PCa) is mainly based on the serum prostate-specific antigen (PSA) test. However, PSA has low specificity and has led to numerous unnecessary biopsies. We evaluated the effectiveness of urinary metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1), a long noncoding RNA, for predicting the risk of PCa before biopsy. The MALAT-1 score was tested in a discovery phase and a multi-center validation phase. The predictive power of the MALAT-1 score was evaluated by the area under receiver operating characteristic (ROC) curve (AUC) and by decision curve analysis. As an independent predictor of PCa, the MALAT-1 score was significantly higher in men with a positive biopsy than in those with a negative biopsy. The ROC analysis showed a higher AUC for the MALAT-1 score (0.670 and 0.742) vs. the total PSA (0.545 and 0.601) and percent free PSA (0.622 and 0.627) in patients with PSA values of 4.0-10 ng/ml. According to the decision curve analysis, using a probability threshold of 25%, the MALAT-1 model would prevent 30.2%-46.5% of unnecessary biopsies in PSA 4-10 ng/ml cohorts, without missing any high-grade cancers. Our results demonstrate that urine MALAT-1 is a promising biomarker for predicting prostate cancer risk. PMID- 25526030 TI - Inhibition of Lon blocks cell proliferation, enhances chemosensitivity by promoting apoptosis and decreases cellular bioenergetics of bladder cancer: potential roles of Lon as a prognostic marker and therapeutic target in baldder cancer. AB - ATP-dependent Lon protease within mitochondrial matrix contributes to the degradation of abnormal proteins. The oxidative or hypoxic stress which represents the stress phenotype of cancer leads to up-regulation of Lon. However, the role of Lon in bladder cancer remains undefined. Here, we found that Lon expression in bladder cancer tissues was significantly higher than those in noncancerous tissues; down-regulation of Lon in bladder cancer cells significantly blocked cancer cell proliferation via suppression c-Jun N-terminal kinase (JNK) phosphorylation due to decreased reactive oxygen species (ROS) production and enhanced the sensitivity of bladder cancer cells to chemotherapeutic agents by promoting apoptosis. We further found that Lon down regulation in bladder cancer cells decreased cellular bioenergetics as determined by measuring aerobic respiration and glycolysis using extracellular flux analyzer. The tissue microarray (TMA) results showed that high expression of Lon was related to the T and TNM stage, as well as histological grade of bladder cancer patients. We also demonstrated that Lon was an independent prognostic factor for overall survival of bladder cancer. Taken together, our data suggest that Lon could serve as a potential diagnostic biomarker and therapeutic target for treatment of bladder cancer, as well as for prediction of the effectiveness of chemotherapy. PMID- 25526031 TI - Multiple myeloma cells recruit tumor-supportive macrophages through the CXCR4/CXCL12 axis and promote their polarization toward the M2 phenotype. AB - Multiple myeloma (MM) cells specifically attract peripheral-blood monocytes, while interaction of MM with bone marrow stromal cells (BMSCs) significantly increased monocyte recruitment (p<0.01). The CXCL12 chemokine, produced by both the MM and BMSCs, was found to be a critical regulator of monocyte migration. CXCL12 production was up-regulated under MM-BMSCs co-culture conditions, whereas blockage with anti-CXCR4 antibodies significantly abrogated monocyte recruitment toward a MM-derived conditioned medium (p<0.01). Furthermore, elevated levels of CXCL12 were detected in MM, but not in normal BM samples, whereas malignant MM cells often represented the source of increased CXCL12 in the BM. Blood-derived macrophages effectively supported MM cells proliferation and protected them from chemotherapy-induced apoptosis. Importantly, MM cells affected macrophage polarization, elevating the expression of M2-related scavenger receptor CD206 in macrophages and blocking LPS-induced TNFalpha secretion (a hallmark of M1 response). Of note, MM-educated macrophages suppressed T-cell proliferation and IFNgamma production in response to activation. Finally, increased numbers of CXCR4-expressing CD163+CD206+ macrophages were detected in the BM of MM patients (n=25) in comparison to MGUS (n=11) and normal specimens (n=8). Taken together, these results identify macrophages as important players in MM tumorogenicity, and recognize the CXCR4/CXCL12 axis as a critical regulator of MM-stroma interactions and microenvironment formation. PMID- 25526032 TI - DNA mismatch repair gene MLH1 induces apoptosis in prostate cancer cells. AB - Mismatch repair (MMR) enzymes have been shown to be deficient in prostate cancer (PCa). MMR can influence the regulation of tumor development in various cancers but their role on PCa has not been investigated. The aim of the present study was to determine the functional effects of the mutL-homolog 1 (MLH1) gene on growth of PCa cells. The DU145 cell line has been established as MLH1-deficient and thus, this cell line was utilized to determine effects of MLH1 by gene expression. Lack of MLH1 protein expression was confirmed by Western blotting in DU145 cells whereas levels were high in normal PWR-1E and RWPE-1 prostatic cells. MLH1-expressing stable transfectant DU145 cells were then created to characterize the effects this MMR gene has on various growth properties. Expression of MLH1 resulted in decreased cell proliferation, migration and invasion properties. Lack of cell growth in vivo also indicated a tumor suppressive effect by MLH1. Interestingly, MLH1 caused an increase in apoptosis along with phosphorylated c Abl, and treatment with MLH1 siRNAs countered this effect. Furthermore, inhibition of c-Abl with STI571 also abrogated the effect on apoptosis caused by MLH1. These results demonstrate MLH1 protects against PCa development by inducing c-Abl-mediated apoptosis. PMID- 25526034 TI - C-H activation dependent Pd-catalyzed carbonylative coupling of (hetero)aryl bromides and polyfluoroarenes. AB - The carbonylative coupling of aryl and heteroaryl bromides with polyfluoroarenes via palladium-catalyzed C-H activation is presented. This transformation proceeds efficiently at moderate reaction temperatures and does not require strong base or reactive intermediates. A near stoichiometric amount of CO is sufficient and the methodology can thus be easily expanded to include the preparation of [(13)C] acyl labeled benzopolyfluorophenones. PMID- 25526035 TI - Three-dimensional ultrasound-based image-guided hypofractionated radiotherapy for intermediate-risk prostate cancer: results of a consecutive case series. AB - External beam radiotherapy (EBRT) is a standard of care in the treatment of prostate cancer. Hypofractionation is a valid option either radiobiologically and logistically in this context. Image-guidance procedures are strongly needed to provide ballistic precision to radiation delivery. The Clarity platform allows for the acquisition of three-dimensional ultrasound scans (3D-US) to perform image-guided radiotherapy. We treated a consecutive series of intermediate-risk prostate cancer patients (according to NCCN stratification) with a hypofractionated schedule (70.2 Gy/26 fractions at 2.7 Gy/daily to the prostate gland excluding the seminal vesicles at 62.1 Gy) under 3D-US guidance with the Clarity platform. The 3-year biochemical-relapse-free survival, distant metastases-free, cancer-specific and overall survival were 98.6% (CI: 91.1 99.6%), 98.6% (CI: 91.1-99.6%), 97.5% (CI: 94.5-99.1%), and 94.3% (CI: 90.4 96.7%), respectively. Maximum detected acute GU toxicity was G0 in 22 patients (29.7%), G1 in 30 (22.7%), G2 in 19 (25.6%), G3 in 3 (4%). Maximum detected acute GI toxicity at the end of EBRT was G0 in 42 patients (56.8%), G1 in 22 (29.7%), G2 in 9 (12.1%), G3 in 1 (1.4%). The 3-year actuarial rates of >= G2 late toxicities were 6.1% for genito-urinary and 8.9% for gastrointestinal. The whole image-guidance workflow resulted in being robust and reliable. EBRT delivered employing a hypofractionated schedule under 3D-US-based image guidance proved to be a safe and effective treatment approach with consistent biochemical control and a mild toxicity profile. Hence, it has been transferred into daily clinical practice in our Department. PMID- 25526033 TI - Chemopreventive apigenin controls UVB-induced cutaneous proliferation and angiogenesis through HuR and thrombospondin-1. AB - Plant flavonoid apigenin prevents and inhibits UVB-induced carcinogenesis in the skin and has strong anti-proliferative and anti-angiogenic properties. Here we identify mechanisms, by which apigenin controls these oncogenic events. We show that apigenin acts, at least in part, via endogenous angiogenesis inhibitor, thrombospondin-1 (TSP1). TSP1 expression by the epidermal keratinocytes is potently inhibited by UVB. It inhibits cutaneous angiogenesis and UVB-induced carcinogenesis. We show that apigenin restores TSP1 in epidermal keratinocytes subjected to UVB and normalizes proliferation and angiogenesis in UVB-exposed skin. Importantly, reconstituting TSP1 anti-angiogenic function in UVB-irradiated skin with a short bioactive peptide mimetic representing exclusively its anti angiogenic domain reproduced the anti-proliferative and anti-angiogenic effects of apigenin. Cox-2 and HIF-1alpha are important mediators of angiogenesis. Both apigenin and TSP1 peptide mimetic attenuated their induction by UVB. Finally we identified the molecular mechanism, whereby apigenin did not affect TSP1 mRNA, but increased de novo protein synthesis. Knockdown studies implicated the RNA binding protein HuR, which controls mRNA stability and translation. Apigenin increased HuR cytoplasmic localization and physical association with TSP1 mRNA causing de novo TSP1 synthesis. HuR cytoplasmic localization was, in turn, dependent on CHK2 kinase. Together, our data provide a new mechanism, by which apigenin controls UVB-induced carcinogenesis. PMID- 25526040 TI - Adapting to the darkness. PMID- 25526042 TI - Manipulating mitochondria to treat disease. PMID- 25526043 TI - Reversing neurodegenerative hearing loss. PMID- 25526039 TI - Detection of methylated septin 9 in tissue and plasma of colorectal patients with neoplasia and the relationship to the amount of circulating cell-free DNA. AB - BACKGROUND: Determination of methylated Septin 9 (mSEPT9) in plasma has been shown to be a sensitive and specific biomarker for colorectal cancer (CRC). However, the relationship between methylated DNA in plasma and colon tissue of the same subjects has not been reported. METHODS: Plasma and matching biopsy samples were collected from 24 patients with no evidence of disease (NED), 26 patients with adenoma and 34 patients with CRC. Following bisulfite conversion of DNA a commercial RT-PCR assay was used to determine the total amount of DNA in each sample and the fraction of mSEPT9 DNA. The Septin-9 protein was assessed using immunohistochemistry. RESULTS: The percent of methylated reference (PMR) values for SEPT9 above a PMR threshold of 1% were detected in 4.2% (1/24) of NED, 100% (26/26) of adenoma and 97.1% (33/34) of CRC tissues. PMR differences between NED vs. adenoma and NED vs. CRC comparisons were significant (p<0.001). In matching plasma samples using a PMR cut-off level of 0.01%, SEPT9 methylation was 8.3% (2/24) of NED, 30.8% (8/26) of adenoma and 88.2% (30/34) of CRC. Significant PMR differences were observed between NED vs. CRC (p<0.01) and adenoma vs. CRC (p<0.01). Significant differences (p<0.01) were found in the amount of cfDNA (circulating cell-free DNA) between NED and CRC, and a modest correlation was observed between mSEPT9 concentration and cfDNA of cancer (R2 = 0.48). The level of Septin-9 protein in tissues was inversely correlated to mSEPT9 levels with abundant expression in normals, and diminished expression in adenomas and tumors. CONCLUSIONS: Methylated SEPT9 was detected in all tissue samples. In plasma samples, elevated mSEPT9 values were detected in CRC, but not in adenomas. Tissue levels of mSEPT9 alone are not sufficient to predict mSEPT9 levels in plasma. Additional parameters including the amount of cfDNA in plasma appear to also play a role. PMID- 25526045 TI - For lack of gut microbes, the blood-brain barrier 'leaks'. PMID- 25526046 TI - Outbred mice may better model benzene toxicity. PMID- 25526049 TI - Response to protocol review scenario: Compassionate and rational. PMID- 25526050 TI - Authority to euthanize. PMID- 25526051 TI - Response to protocol review scenario: A word from OLAW. PMID- 25526052 TI - Response to protocol review scenario: Cooperation and compassion. PMID- 25526053 TI - Response to protocol review scenario: Veterinarian's responsibility. PMID- 25526055 TI - The amount of cage bedding preferred by female BALB/c and C57BL/6 mice. AB - In order to improve the welfare of laboratory mice, a number of different environmental enrichment strategies have been developed to provide opportunities for mice to engage in naturalistic behaviors. Providing sufficient cage bedding for mice to use as a burrowing substrate could be considered an environmental enrichment strategy, but few studies have considered the welfare aspects of cage bedding amount. The authors compared the preferences of group-housed female BALB/c and C57BL/6 mice for three different volumes of cage bedding (0.5 l, 1.5 l and 6 l). Mice of both strains but especially C57BL/6 mice showed strong preferences for cages with more bedding. The results highlight the importance of providing a sufficient amount of cage bedding to laboratory mice. PMID- 25526056 TI - Approaches to animal research project evaluation in Europe after implementation of Directive 2010/63/EU. AB - Directive 2010/63/EU requires the evaluation and authorization of all research projects and training activities involving the use of animals and defines some components and expertise necessary for the evaluation process. Adoption of Directive 2010/63/EU provided an opportunity to harmonize project evaluation processes across Europe, but thus far, member states have used a variety of approaches in the transposition and implementation of Directive 2010/63/EU. The authors discuss and compare the project evaluation systems being implemented in five European Union member states (France, Germany, Spain, the Netherlands and the UK). PMID- 25526057 TI - A risk-based approach to reducing exposure of staff to laboratory animal allergens. AB - Within the biomedical research industry, people who work with laboratory animals may be at risk of developing laboratory animal allergy, which can lead to occupational asthma. Under UK and EU laws, employers must prevent or adequately control exposure to any hazardous substance, which includes animal allergens, so far as reasonably practicable, for the protection of all people on the premises. This can be achieved in part by reviewing the risk of allergen exposure in specific areas of a facility and implementing appropriate infrastructure, environmental and performance controls to minimize that risk. The authors describe the approach used at their institution to stratify risk of allergen exposure in various areas of the animal facility and to implement appropriate controls. They also discuss their use of a monitoring program to evaluate allergen concentrations in low- and high-risk areas of the animal facility and explain how the monitoring results can be applied to determine which controls are needed to minimize risk of exposure and to provide a safe working environment. PMID- 25526058 TI - Competency assessment for trainers. PMID- 25526059 TI - Understanding the nature of medication errors in an ICU with a computerized physician order entry system. AB - OBJECTIVES: We investigated incidence rates to understand the nature of medication errors potentially introduced by utilizing a computerized physician order entry (CPOE) system in the three clinical phases of the medication process: prescription, administration, and documentation. METHODS: Overt observations and chart reviews were employed at two surgical intensive care units of a 950-bed tertiary teaching hospital. Ten categories of high-risk drugs prescribed over a four-month period were noted and reviewed. Error definition and classifications were adapted from previous studies for use in the present research. Incidences of medication errors in the three phases of the medication process were analyzed. In addition, nurses' responses to prescription errors were also assessed. RESULTS: Of the 534 prescriptions issued, 286 (53.6%) included at least one error. The proportion of errors was 19.0% (58) of the 306 drug administrations, of which two thirds were verbal orders classified as errors due to incorrectly entered prescriptions. Documentation errors occurred in 205 (82.7%) of 248 correctly performed administrations. When tracking incorrectly entered prescriptions, 93% of the errors were intercepted by nurses, but two-thirds of them were recorded as prescribed rather than administered. CONCLUSION: The number of errors occurring at each phase of the medication process was relatively high, despite long experience with a CPOE system. The main causes of administration errors and documentation errors were prescription errors and verbal order processes. To reduce these errors, hospital-level and unit-level efforts toward a better system are needed. PMID- 25526062 TI - Allelic richness following population founding events--a stochastic modeling framework incorporating gene flow and genetic drift. AB - Allelic richness (number of alleles) is a measure of genetic diversity indicative of a population's long-term potential for adaptability and persistence. It is used less commonly than heterozygosity as a genetic diversity measure, partially because it is more mathematically difficult to take into account the stochastic process of genetic drift for allelic richness. This paper presents a stochastic model for the allelic richness of a newly founded population experiencing genetic drift and gene flow. The model follows the dynamics of alleles lost during the founder event and simulates the effect of gene flow on maintenance and recovery of allelic richness. The probability of an allele's presence in the population was identified as the relevant statistical property for a meaningful interpretation of allelic richness. A method is discussed that combines the probability of allele presence with a population's allele frequency spectrum to provide predictions for allele recovery. The model's analysis provides insights into the dynamics of allelic richness following a founder event, taking into account gene flow and the allele frequency spectrum. Furthermore, the model indicates that the "One Migrant per Generation" rule, a commonly used conservation guideline related to heterozygosity, may be inadequate for addressing preservation of diversity at the allelic level. This highlights the importance of distinguishing between heterozygosity and allelic richness as measures of genetic diversity, since focusing merely on the preservation of heterozygosity might not be enough to adequately preserve allelic richness, which is crucial for species persistence and evolution. PMID- 25526063 TI - Frequency of Mutations Associated with Rifampicin Resistance in Mycobacterium tuberculosis Strains Isolated from Patients in West of Iran. AB - BACKGROUND AND OBJECTIVE: Tuberculosis (TB) is a devastating infectious disease causing high mortality and morbidity worldwide. The most serious threat related to tuberculosis control is the recent emergence of drug-resistant tuberculosis strains. The aim of the present study was to identify various types of mutations in the rpoB region in rifampicin-resistant strains isolated from sputum of tuberculosis patients. MATERIALS AND METHODS: Drug susceptibility of 125 Mycobacterium tuberculosis isolates was determined using the CDC standard conventional proportional method. Target DNA of M. tuberculosis was amplified by polymerase chain reaction, hybridized, and scanned. We used the low cost density array (LCD-array) to detect mutations within the 90-bp rpoB region. Each array is a transparent, prestructured polymer support using a nonfluorescent detection principle based on the precipitation of a clearly visible dark substrate. RESULTS: Of the 125 M. tuberculosis isolates, 35 (28%) were found to be rifampicin-resistant and using the LCD array revealed point mutations at nine different codons as follows: S512T (AGC->ACC) (20%), D516V (GAC->GTC) (20%), H526D (CAC->GAC) (6%), H526R (CAC->CGC) (20%), H526Y (CAC->TAC) (23%), and S531W (TCG->TGG) (8%), and the most frequent site mutations were L511P (CCG->CTG) (46%), followed by S531l (TCG->TTG) (40%) and D516Y (GAC->TAC) (26%). CONCLUSION: Our data significantly differs from previously reported mutation frequencies for codon 526 (CAC to GAC) among Italian isolates (40.1%) and Greek isolates (17.6%). Phenotypic testing is time-consuming and requires laboratory resources. Microarray rpoB is useful in detecting rifampicin resistance-determining region associated site mutations of rifampicin-resistant M. tuberculosis isolates. PMID- 25526075 TI - Idiopathic vitritis in the setting of Boston keratoprosthesis. AB - PURPOSE: The aim of this study was to revisit the clinical paradigm attributed to Boston keratoprosthesis recipients presenting with idiopathic vitreous inflammation. METHODS: A retrospective chart review was performed of keratoprosthesis recipients at Massachusetts Eye and Ear Infirmary, from January 2000 to August 2013, for demographic data, indication(s) for surgery, timing and presentation of vitreous inflammation, and best-corrected visual acuity at baseline, on presentation, and after resolution of vitritis. RESULTS: Twenty three (23 eyes) of 346 patients developed idiopathic vitreous inflammation after keratoprosthesis implantation. Six of 23 patients presented with signs and symptoms similar to infectious endophthalmitis but were culture negative. The proportion of patients who fit the previous paradigm of sudden painless loss of vision without external signs of infection ("sterile vitritis") at their first presentation with vitritis was only 4 of 23. Vision decline was variable (median, 9 lines on Snellen chart; range, 0-24), as was time to recovery of best vision (median, 8.9 weeks; range, 0.9-36.7). Nine eyes had repeat bouts (43 episodes in 23 patients). Ten of 43 episodes did not recover to baseline vision. Seventeen of 23 eyes with idiopathic vitritis after keratoprosthesis later developed other complications. CONCLUSIONS: The current paradigm for idiopathic vitritis after keratoprosthesis implantation includes sudden painless loss of vision with full recovery of vision on treatment with periocular corticosteroids. However, idiopathic vitritis after keratoprosthesis can also mimic infectious endophthalmitis with pain and external signs of inflammation. Visual loss can be gradual. Vision may not recover to baseline despite treatment. Vitritis may be a part of a common pathway of chronic inflammation after keratoprosthesis. PMID- 25526076 TI - Rudolf Virchow's medical school dissertation on rheumatism and the cornea: overlooked tribute to the cornea in biomedical research. AB - PURPOSE: To critique Rudolf Virchow's medical school dissertation on rheumatism and the cornea and to determine whether it might have anticipated his remarkable career in medicine. METHODS: Review of the English translation of Rudolf Virchow's de Rheumate Praesertim Corneae written in 1843. RESULTS: The dissertation was more than 7000 words long. Virchow considered rheumatism as an irritant disorder not induced by acid as traditionally thought but by albumin. He concluded that inflammation was secondary to a primary irritant and that the "seat" of rheumatism was "gelatinous" (connective) tissues, which included the cornea. He divided kerato-rheumatism into different varieties. The prognosis of keratitis was variable, and would eventually lapse into "scrofulosis, syphilis, or arthritis of the cornea." CONCLUSIONS: Virchow's dissertation characterizes rheumatism in terms of chemical and tissue interactions that make little sense in the context of today's knowledge of rheumatic disease and keratitis. Ironically, many of these concepts were made obsolete by the cellular model of disease that Virchow championed. Virchow decided to pursue the study of rheumatism through the cornea because he thought that the cornea was an ideal tissue to study disease. This discernment was passed on to his students whose seminal contributions to general pathology were based on research with the cornea. It is debatable whether Virchow's insight into the importance of the cornea in biomedical research at such an early stage of his career could have predicted his monumental contributions to medicine. PMID- 25526077 TI - Hydrogen evolution reaction on palladium multilayers deposited on Au(111): a theoretical approach. AB - We have investigated the electrocatalytic properties of multilayers of Pd epitaxially deposited on Au(111). In contrast to the numerous previous works in this area, we have focused on the kinetics of the electrochemical step for hydrogen adsorption (Volmer reaction) and determined its energies of activation. We have used a combination of density functional theory calculations and our own theory of electrocatalysis, which allows us to investigate the systems in an electrochemical environment. Contrary to our previous work with a submonolayer of Pd in Au(111), the activation barrier for the hydrogen adsorption process from proton is very low or almost zero for all bimetallic systems investigated. It is about 0.2 eV for pure Pd(111). In the case of two layers of Pd on Au(111) containing absorbed hydrogen in the subsurface, the adsorption free energy is less negative and the barrier lower than for the other investigated systems. This is in agreement with experimental data that shows a larger activity for hydrogen oxidation with hydride Pd systems. PMID- 25526079 TI - Exploring the binding mechanisms of MIF to CXCR2 using theoretical approaches. AB - Macrophage migration inhibitory factor (MIF) is a multi-functional protein that acts as a cytokine and as an enzyme. Recently, MIF was identified as a non canonical ligand of G protein-coupled chemokine receptor CXCR2 with low nanomolar affinity in leukocyte arrest and chemotaxis, but the precise knowledge of the molecular determinants of the MIF-CXCR2 interface has remained unknown. Therefore, we employed homology modeling, protein-protein docking, molecular dynamics (MD) simulations, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding free energy calculations and MM/GBSA binding free energy decomposition to obtain insights into the molecular recognition of MIF with CXCR2. The predicted binding pattern of MIF-CXCR2 is in good agreement with the experimental data and sheds light on the functional role of important MIF-CXCR2 interface residues in association with binding and signaling. According to our predictions, the R11A/D44A double mutations of MIF exhibit a pronounced defect in the binding affinity of MIF to CXCR2, resulting in large conformational changes. The potential two-site binding model for the MIF-CXCR2 recognition was proposed: initialized primarily by the non-polar interactions including the van der Waals and hydrophobic interactions, the N-terminal region of CXCR2 contacts the N-like loop and beta-sheet of MIF (site 1), and then the ECL2 and ECL3 regions of CXCR2 form strong interactions with the pseudo-(E)LR motif and C-terminus of MIF, which induces the molecular thermodynamic motion of TMs for signal transduction (site 2). This study will extend our understanding to the binding mechanisms of MIF to CXCR2 and provide useful information for the rational design of potent inhibitors selectively targeting the MIF-CXCR2 interactions. PMID- 25526083 TI - An efficiency comparison of document preparation systems used in academic research and development. AB - The choice of an efficient document preparation system is an important decision for any academic researcher. To assist the research community, we report a software usability study in which 40 researchers across different disciplines prepared scholarly texts with either Microsoft Word or LaTeX. The probe texts included simple continuous text, text with tables and subheadings, and complex text with several mathematical equations. We show that LaTeX users were slower than Word users, wrote less text in the same amount of time, and produced more typesetting, orthographical, grammatical, and formatting errors. On most measures, expert LaTeX users performed even worse than novice Word users. LaTeX users, however, more often report enjoying using their respective software. We conclude that even experienced LaTeX users may suffer a loss in productivity when LaTeX is used, relative to other document preparation systems. Individuals, institutions, and journals should carefully consider the ramifications of this finding when choosing document preparation strategies, or requiring them of authors. PMID- 25526081 TI - Protective roles of sodium selenite against aflatoxin B1-induced apoptosis of jejunum in broilers. AB - The effects of aflatoxin B1 (AFB1) exposure and sodium selenite supplementation on cell apoptosis of jejunum in broilers were studied. A total of 240 one-day-old male AA broilers were randomly assigned four dietary treatments containing 0 mg/kg of AFB1 (control), 0.3 mg/kg AFB1 (AFB1), 0.4 mg/kg supplement Se (+ Se) and 0.3 mg/kg AFB1 + 0.4 mg/kg supplement Se (AFB1 + Se), respectively. Compared with the control broilers, the number of apoptotic cells, the expression of Bax and Caspase-3 mRNA were significantly increased, while the expression of Bcl-2 mRNA and the Bcl-2/Bax ratio were significantly decreased in AFB1 broilers. The number of apoptotic cells and the expression of Caspase-3 mRNA in AFB1 + Se broilers were significantly higher than those in the control broilers, but significantly lower than those in AFB1 broilers. There were no significant changes in the expression of Bax mRNA between AFB1 + Se and control broilers; the expression of Bcl-2 mRNA and the Bcl-2/Bax ratio in AFB1 + Se broilers were significantly lower than those in the control broilers, but significantly higher than those in AFB1 broilers. In conclusion, 0.3 mg/kg AFB1 in the diet can increase cell apoptosis, decrease Bcl-2 mRNA expression, and increase of Bax and Caspase-3 mRNA expression in broiler's jejunum. However, supplementation of dietary sodium selenite at the concentration of 0.4 mg/kg Se may ameliorate AFB1 induced apoptosis by increasing Bcl-2 mRNA expression, and decreasing Bax and Caspase-3 mRNA expression. PMID- 25526084 TI - An improved model for the hTERT promoter quadruplex. AB - Mutations occur at four specific sites in the hTERT promoter in >75% of glioblastomas and melanomas, but the mechanism by which the mutations affect gene expression remains unexplained. We report biophysical computational studies that show that the hTERT promoter sequence forms a novel G-quadruplex structure consisting of three contiguous, stacked parallel quadruplexes. The reported hTERT mutations map to the central quadruplex within this structure, and lead to an alteration of its hydrodynamic properties and stability. PMID- 25526086 TI - Upregulated sirtuin 1 by miRNA-34a is required for smooth muscle cell differentiation from pluripotent stem cells. AB - microRNA-34a (miR-34a) and sirtuin 1 (SirT1) have been extensively studied in tumour biology and longevity/aging, but little is known about their functional roles in smooth muscle cell (SMC) differentiation from pluripotent stem cells. Using well-established SMC differentiation models, we have demonstrated that miR 34a has an important role in SMC differentiation from murine and human embryonic stem cells. Surprisingly, deacetylase sirtuin 1 (SirT1), one of the top predicted targets, was positively regulated by miR-34a during SMC differentiation. Mechanistically, we demonstrated that miR-34a promoted differentiating stem cells' arrest at G0/G1 phase and observed a significantly decreased incorporation of miR-34a and SirT1 RNA into Ago2-RISC complex upon SMC differentiation. Importantly, we have identified SirT1 as a transcriptional activator in the regulation of SMC gene programme. Finally, our data showed that SirT1 modulated the enrichment of H3K9 tri-methylation around the SMC gene-promoter regions. Taken together, our data reveal a specific regulatory pathway that miR-34a positively regulates its target gene SirT1 in a cellular context-dependent and sequence-specific manner and suggest a functional role for this pathway in SMC differentiation from stem cells in vitro and in vivo. PMID- 25526087 TI - Loss of JUNB/AP-1 promotes invasive prostate cancer. AB - Prostate cancer is a frequent cause of male death in the Western world. Relatively few genetic alterations have been identified, likely owing to disease heterogeneity. Here, we show that the transcription factor JUNB/AP-1 limits prostate cancer progression. JUNB expression is increased in low-grade prostate cancer compared with normal human prostate, but downregulated in high-grade samples and further decreased in all metastatic samples. To model the hypothesis that this downregulation is functionally significant, we genetically inactivated Junb in the prostate epithelium of mice. When combined with Pten (phosphatase and tensin homologue) loss, double-mutant mice were prone to invasive cancer development. Importantly, invasive tumours also developed when Junb and Pten were inactivated in a small cell population of the adult anterior prostate by topical Cre recombinase delivery. The resulting tumours displayed strong histological similarity with human prostate cancer. Loss of JunB expression led to increased proliferation and decreased senescence, likely owing to decreased p16(Ink4a) and p21(CIP1) in epithelial cells. Furthermore, the tumour stroma was altered with increased osteopontin and S100 calcium-binding protein A8/9 expression, which correlated with poor prognoses in patients. These data demonstrate that JUNB/AP-1 cooperates with PTEN signalling as barriers to invasive prostate cancer, whose concomitant genetic or epigenetic suppression induce malignant progression. PMID- 25526088 TI - Spermidine induces autophagy by inhibiting the acetyltransferase EP300. AB - Several natural compounds found in health-related food items can inhibit acetyltransferases as they induce autophagy. Here we show that this applies to anacardic acid, curcumin, garcinol and spermidine, all of which reduce the acetylation level of cultured human cells as they induce signs of increased autophagic flux (such as the formation of green fluorescent protein-microtubule associated protein 1A/1B-light chain 3 (GFP-LC3) puncta and the depletion of sequestosome-1, p62/SQSTM1) coupled to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). We performed a screen to identify the acetyltransferases whose depletion would activate autophagy and simultaneously inhibit mTORC1. The knockdown of only two acetyltransferases (among 43 candidates) had such effects: EP300 (E1A-binding protein p300), which is a lysine acetyltranferase, and NAA20 (N(alpha)-acetyltransferase 20, also known as NAT5), which catalyzes the N-terminal acetylation of methionine residues. Subsequent studies validated the capacity of a pharmacological EP300 inhibitor, C646, to induce autophagy in both normal and enucleated cells (cytoplasts), underscoring the capacity of EP300 to repress autophagy by cytoplasmic (non-nuclear) effects. Notably, anacardic acid, curcumin, garcinol and spermidine all inhibited the acetyltransferase activity of recombinant EP300 protein in vitro. Altogether, these results support the idea that EP300 acts as an endogenous repressor of autophagy and that potent autophagy inducers including spermidine de facto act as EP300 inhibitors. PMID- 25526085 TI - Old, new and emerging functions of caspases. AB - Caspases are proteases with a well-defined role in apoptosis. However, increasing evidence indicates multiple functions of caspases outside apoptosis. Caspase-1 and caspase-11 have roles in inflammation and mediating inflammatory cell death by pyroptosis. Similarly, caspase-8 has dual role in cell death, mediating both receptor-mediated apoptosis and in its absence, necroptosis. Caspase-8 also functions in maintenance and homeostasis of the adult T-cell population. Caspase 3 has important roles in tissue differentiation, regeneration and neural development in ways that are distinct and do not involve any apoptotic activity. Several other caspases have demonstrated anti-tumor roles. Notable among them are caspase-2, -8 and -14. However, increased caspase-2 and -8 expression in certain types of tumor has also been linked to promoting tumorigenesis. Increased levels of caspase-3 in tumor cells causes apoptosis and secretion of paracrine factors that promotes compensatory proliferation in surrounding normal tissues, tumor cell repopulation and presents a barrier for effective therapeutic strategies. Besides this caspase-2 has emerged as a unique caspase with potential roles in maintaining genomic stability, metabolism, autophagy and aging. The present review focuses on some of these less studied and emerging functions of mammalian caspases. PMID- 25526089 TI - A unique role for p53 in the regulation of M2 macrophage polarization. AB - P53 is critically important in preventing oncogenesis but its role in inflammation in general and in the function of inflammatory macrophages in particular is not clear. Here, we show that bone marrow-derived macrophages exhibit endogenous p53 activity, which is increased when macrophages are polarized to the M2 (alternatively activated macrophage) subtype. This leads to reduced expression of M2 genes. Nutlin-3a, which destabilizes the p53/MDM2 (mouse double minute 2 homolog) complex, promotes p53 activation and further downregulates M2 gene expression. In contrast, increased expression of M2 genes was apparent in M2-polarized macrophages from p53-deficient and p53 mutant mice. Furthermore, we show, in mice, that p53 also regulates M2 polarization in peritoneal macrophages from interleukin-4-challenged animals and that nutlin-3a retards the development of tolerance to Escherichia coli lipopolysaccharide. P53 acts via transcriptional repression of expression of c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) gene by directly associating with its promoter. These data establish a role for the p53/MDM2/c-MYC axis as a physiological 'brake' to the M2 polarization process. This work reveals a hitherto unknown role for p53 in macrophages, provides further insight into the complexities of macrophage plasticity and raises the possibility that p53 activating drugs, many of which are currently being trialled clinically, may have unforeseen effects on macrophage function. PMID- 25526090 TI - Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis. AB - The role of autophagy in carcinogenesis is controversial and apparently complex. By using mice with hepatocyte-specific knockout of Atg5, a gene essential for autophagy, we longitudinally studied the role of autophagy in hepatocarcinogenesis. We found that impairing autophagy in hepatocytes would induce oxidative stress and DNA damage, followed by the initiation of hepatocarcinogenesis, which could be suppressed by the antioxidant N acetylcysteine. Interestingly, these mice developed only benign tumors with no hepatocellular carcinoma (HCC), even after the treatment with diethylnitrosamine, which induced HCC in wild-type mice. The inability of mice to develop HCC when autophagy was impaired was associated with the induction of multiple tumor suppressors including p53. Further analysis indicated that the induction of p53 was associated with the DNA-damage response. Tumorigenesis studies using an established liver tumor cell line confirmed a positive role of autophagy in tumorigenesis and a negative role of p53 in this process when autophagy was impaired. Our studies thus demonstrate that autophagy is required to maintain healthy mitochondria and to reduce oxidative stress and DNA damage to prevent the initiation of hepatocarcinogenesis. However, once hepatocarcinogenesis has been initiated, its presence is also required to suppress the expression of tumor suppressors to promote the development of HCC. PMID- 25526092 TI - DOT1L-mediated H3K79me2 modification critically regulates gene expression during cardiomyocyte differentiation. AB - Epigenetic changes on DNA and chromatin are implicated in cell differentiation and organogenesis. For the heart, distinct histone methylation profiles were recently linked to stage-specific gene expression programs during cardiac differentiation in vitro. However, the enzymes catalyzing these modifications and the genes regulated by them remain poorly defined. We therefore decided to identify the epigenetic enzymes that are potentially involved in cardiomyogenesis by analyzing the expression profile of the 85 genes encoding the epigenetic related proteins in mouse cardiomyocytes (CMs), and then study how they affect gene expression during differentiation and maturation of this cell type. We show here with gene expression screening of epigenetic enzymes that the highly expressed H3 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) drives a transitional pattern of di-methylation on H3 lysine 79 (H3K79) in CMs at different stages of differentiation in vitro and in vivo. Through a genome-wide chromatin-immunoprecipitation DNA-sequencing approach, we found H3K79me2 enriched at genes expressed during cardiac differentiation. Moreover, knockdown of Dot1L affected the expression of H3K79me2-enriched genes. Our results demonstrate that histone methylation, and in particular DOT1L-mediated H3K79me2 modification, drives cardiomyogenesis through the definition of a specific transcriptional landscape. PMID- 25526091 TI - Autophagy in the physiology and pathology of the central nervous system. AB - Neurons are highly specialized postmitotic cells that depend on dynamic cellular processes for their proper function.These include among others, neuronal growth and maturation, axonal migration, synapse formation and elimination, all requiring continuous protein synthesis and degradation. Therefore quality-control processes in neurons are directly linked to their physiology. Autophagy is a tightly regulated cellular degradation pathway by which defective or superfluouscytosolic proteins, organelles and other cellular constituents are sequestered in autophagosomes and delivered to lysosomes for degradation. Here we present emerging evidence indicating that constitutive autophagic fluxin neurons has essential roles in key neuronal processes under physiological conditions.Moreover, we discuss how perturbations of the autophagic pathway may underlie diverse pathological phenotypes in neurons associated with neurodevelopmental and neurodegenerative diseases. PMID- 25526093 TI - IKKbeta in postnatal perichondrium remotely controls endochondral ossification of the growth plate through downregulation of MCP-5. AB - IkappaB kinase beta (IKKbeta) is a catalytic subunit of the IKK complex, which activates nuclear factor-kappaB (NF-kappaB). Although its role in osteoclastogenesis is well established, the role of IKKbeta in bone formation is poorly understood. Here, we report that conditional knockout of Ikkbeta in limb bud mesenchymal cells results in the upregulation of monocyte chemoattractant protein-5 (MCP-5) in the perichondrium, which in turn inhibits the growth of longitudinal bone by compromising chondrocyte hypertrophy and increasing the apoptosis of chondrocytes within the growth plate. Contrary to expectations, IKKbeta in cells of chondrocyte or osteoblast lineage was dispensable for bone growth. On the other hand, ex vivo experiments confirmed the role of MCP-5 in the growth of longitudinal bone. Furthermore, an in vitro study demonstrated that the action of IKKbeta on MCP-5 is cell autonomous. Collectively, our results provide evidence for a previously unrecognized role of IKKbeta in the regulation of the growth plate that is mediated through stimulation-independent downregulation of MCP-5 in the perichondrium. PMID- 25526095 TI - Type III open tibia fractures: immediate antibiotic prophylaxis minimizes infection. AB - OBJECTIVE: To examine the association between antibiotic timing and deep infection of type III open tibia fractures. DESIGN: Retrospective prognostic study. SETTING: Level 1 Trauma Center. PATIENTS: The study population included 137 patients after exclusions for missing data (13), nonreconstructible limbs (9), and/or absence of 90-day outcome data (3). INTERVENTION: An observational study of antibiotic timing. MAIN OUTCOME MEASUREMENT: Deep infection within 90 days. RESULTS: Age, smoking, diabetes, injury severity score, type IIIA versus 3B/C injury, and time to surgical debridement were not associated with infection on univariate analysis. Greater than 5 days to wound coverage (P < 0.001) and greater than 66 minutes to antibiotics (P < 0.01) were univariate predictors of infection. Multivariate analysis found wound coverage beyond 5 days [odds ratio, 7.39; 95% confidence interval (CI), 2.33-23.45; P < 0.001] and antibiotics beyond 66 minutes (odds ratio, 3.78; 95% CI, 1.16-12.31; P = 0.03) independently predicted infection. Immediate antibiotics and early coverage limited the infection rate (1 of 36, 2.8%) relative to delay in either factor (6 of 59, 10.2%) or delay in both factors (17 of 42, 40.5%). CONCLUSIONS: Time from injury to antibiotics and to wound coverage independently predict infection of type III open tibia fractures. Both should be achieved as early as possible, with coverage being dependent on the condition of the wound. Given the relatively short therapeutic window for antibiotic prophylaxis (within an hour of injury), prehospital antibiotics may substantially improve outcomes for severe open fractures. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 25526094 TI - Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration. AB - Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that, in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells. PMID- 25526096 TI - Utilization of peripheral optical coherence tomography to optimize diagnosis of a vortex vein varix. PMID- 25526097 TI - Paraneoplastic sarcoid-like reactions and the eye. AB - BACKGROUND: Sarcoid-like reactions have been reported and confirmed by histopathology in patients with malignant disease. This series demonstrates the complex relationship of malignancy and sarcoidosis as pertaining to the eye, which, to the best of our knowledge, has not been previously reported in the literature. METHODS: Retrospective case study of five patients with sarcoid-like reactions. Patients 1 to 4 represent patients with ocular sarcoid-like reaction and systemic malignant disease. Patient 5 had ocular malignancy and systemic sarcoid-like reaction; workup revealed renal cell cancer. For each patient, other etiologies of nonnecrotizing granulomatous inflammation were excluded. RESULTS: Sarcoid-like reactions have been described in the literature when nonnecrotizing granulomas occur in association with malignancy and in the absence of multiorgan involvement as seen with systemic sarcoid. In our series, sarcoid-like reactions involved the vitreous in three patients, retina in one patient, and the choroid and lung in one patient. Sarcoid-like reaction preceded the diagnosis of malignancy in two patients, was found concomitantly with malignancy in one patient, and followed malignancy in two patients. Two patients had hematologic malignancy, one patient had endometrial carcinoma, one had renal cell carcinoma, and one patient had both renal cell carcinoma and uveal melanoma. Four patients had findings of nonnecrotizing granulomas confirmed by histopathology. CONCLUSION: Sarcoid-like reactions can occur in the eye, and ocular malignancies may incite sarcoid-like reaction. Ocular sarcoid-like reactions have paraneoplastic features in that they can occur at a site distant from malignancy and may precede, occur simultaneously with, or follow malignancy. PMID- 25526098 TI - Retinal vessel caliber changes in vasculitis. AB - BACKGROUND: Retinal vasculitis is a potentially sight-threatening inflammation of the retinal vessels, but little is known about the in vivo vascular changes, which occur in affected eyes. The authors therefore sought to measure vessel caliber in eyes with vasculitis. METHODS: Retrospective case-control study. Vasculitis was confirmed using fluorescein angiography. Vessel calibers were measured using validated semiautomated software. RESULTS: There were 21 eyes from 15 patients with vasculitis and 33 control eyes from 21 control subjects. Most cases were diagnosed with idiopathic vasculitis. All had periphlebitis, and one eye also had arteritis. After adjustment for age and gender, mean arteriolar caliber was 143 MUm (95% confidence interval [CI], 134-152) in cases and 158 MUm (95% CI, 151-165) in controls (P = 0.01). Venular caliber was similar in cases (229 MUm; 95% CI, 215-243) and controls (228 MUm; 95% CI, 217-234; P = 0.91), whereas arteriole-to-venule ratio was smaller in cases (0.63; 95% CI, 0.60-0.66) compared with controls (0.70; 95% CI, 0.02-0.11; P = 0.004). CONCLUSION: Retinal vasculitis was associated with narrower arteriolar caliber, whereas venular caliber was similar to controls. This resulted in a smaller arteriole-to-venule ratio in eyes with vasculitis. PMID- 25526099 TI - Eliminating antibiotic prophylaxis for intravitreal injections: a consecutive series of 18,839 injections by a single surgeon. AB - PURPOSE: By optimizing the protocol for intravitreal injections, the risk of endophthalmitis can be minimized. This study assesses the incidence of endophthalmitis and other complications after a consecutive series of intravitreal injections where all antibiotics were excluded. METHODS: Injections were performed from August 1, 1997 to October 31, 2012 in outpatient examination rooms at the Retina Center of Minnesota by a single retinal surgeon, the lead author. Most injections were performed to treat exudative age-related macular degeneration. Other reasons included diabetic macular edema, cystoid macular edema because of retinal vein occlusions, cytomegalovirus retinitis, and severe uveitis. Injections were given with topical povidone-iodine, proparacaine, and tetracaine, a sterile eyelid speculum, and clean nonsterile gloves, but without any antibiotics. Data were retrospectively analyzed using billing codes from a computer database system. RESULTS: A total of 18,839 injections were given. Of these, the following injections were administered: bevacizumab, 15,479 (82.16%); ranibizumab, 1,669 (8.86%); triamcinolone acetonide (Kenalog-40), 1,014 (5.38%); pegaptanib sodium, 370 (1.96%); aflibercept, 148 (0.79%); dexamethasone implant, 88 (0.47%); triamcinolone acetonide (Triesence), 32 (0.17%); dexamethasone, 29 (0.15%); and ganciclovir, 10 (0.05%). There was one case of postinjection endophthalmitis. The incidence of endophthalmitis per injection was 0.0053%. CONCLUSION: A low incidence of endophthalmitis can be achieved when topical antibiotics are omitted. PMID- 25526100 TI - Peau d'orange and angioid streaks: manifestations of Bruch membrane pathology. AB - PURPOSE: The aim of this study was to characterize peau d'orange and angioid streaks, characteristic findings in eyes of patients with pseudoxanthoma elasticum, by examining fundus photography and optical coherence tomography imaging. METHODS: Color photographs were evaluated directly as were the component red and green channels. Optical coherence tomography images were evaluated for reflectivity pattern of the band corresponding to the retinal pigment epithelium Bruch membrane complex. RESULTS: Eighteen eyes of 9 patients with a mean age of 48.7 years (range, 31-61 years) were examined; 7 of them were women. Color photographs showed areas of yellowish opacification that obscured visualization of the underlying choroid. At the outer edges of this confluent area, opacification were nonconfluent changes with similar appearance and these regions were typical peau d'orange. Angioid streaks occurred within and extended up to the outer border of the confluent opacification. Underlying choroidal details could be seen through the regions of peau d'orange and through the gaps in angioid streaks. The red channel image showed increased reflectivity from the confluent deposit and improved visualization of the choroidal vasculature, except where the confluent opacification was located. Optical coherence tomography imaging showed increased reflectivity from the outer border of the retinal pigment epithelium-Bruch membrane complex. CONCLUSION: The findings suggest that the confluent region is the relevant lesion, not the subconfluent zone known as peau d'orange. Imaging characteristics of the confluent area of opacity are consistent with diffuse infiltration with calcium, a chief histologic abnormality of pseudoxanthoma elasticum. The name coquille d'oeuf was suggested for the confluent area of opacity as a consequence. PMID- 25526101 TI - TRANSCONJUNCTIVAL NONVITRECTOMIZING VITREOUS SURGERY VERSUS 25-GAUGE VITRECTOMY IN PATIENTS WITH EPIRETINAL MEMBRANE: A Prospective Randomized Study. AB - PURPOSE: To compare the clinical outcomes and the rate of complications of 27 gauge transconjunctival nonvitrectomizing vitreous surgery (NVS) and of 25-gauge transconjunctival sutureless vitrectomy surgery for idiopathic epiretinal membrane removal. METHODS: In this prospective randomized study, 83 phakic eyes of 83 consecutive patients with an idiopathic epiretinal membrane were randomized to receive 27-gauge NVS (NVS-group) or 25-gauge vitrectomy (Standard-group). Main outcome measures were best-corrected visual acuity, central retinal thickness, nuclear density units' changes, and rate of complications. RESULTS: Thirty-nine eyes of the Standard-group and 40 of the NVS-group were considered in final analysis. Mean best-corrected visual acuity improved significantly in both groups, with a significant better result at 12 months in NVS-group (P = 0.039; t test). Central retinal thickness decreased significantly in both groups (P < 0.001, Tukey test), without significant difference between the two groups at any time point. At 12 months, nuclear density increased significantly in the Standard group (analysis of variance, P < 0.001), and it did not change in the NVS-group (analysis of variance, P = 0.537). Epiretinal membrane recurred in 5.1% of eyes in the Standard-group and in 7.5% of eyes in the NVS-group (Fisher's exact test, P = 1.000). CONCLUSION: The 27-gauge NVS is an effective surgical procedure in eyes with epiretinal membrane and it induces less progression of nuclear sclerosis than 25-gauge vitrectomy. PMID- 25526102 TI - Large-area preparation of high-quality and uniform three-dimensional graphene networks through thermal degradation of graphene oxide-nitrocellulose composites. AB - We demonstrate a simple method to prepare high-quality and uniform three dimensional (3D) graphene networks through thermal degradation of graphene oxide (GO)-nitrocellulose composites over a large area. The nitrocellulose simultaneously acts as a support and aids in the reduction of GO by exothermic decomposition. The graphene networks have tunable porous morphology where the pore size can be controlled by adjusting the concentration of GO in the composite. This new technique is a very simple method to obtain 3D graphene networks and has the potential to produce 3D graphene-modified substrates for use in energy storage and conversion applications, in supporting frameworks of catalyst, and in sensors. In this report, the prepared 3D graphene networks were directly used as the electrodes of supercapacitors without using a binding agent and/or conducting additive with a high specific capacitance of 162.5 F g(-1) at 0.5 A g(-1) current density. PMID- 25526103 TI - Naturally occurring hydroxytyrosol derivatives: hydroxytyrosyl acetate and 3,4 dihydroxyphenylglycol modulate inflammatory response in murine peritoneal macrophages. Potential utility as new dietary supplements. AB - This work evaluated the effects of extra virgin olive oil (EVOO) phenols, hydroxytyrosyl acetate (2) and 3,4-dihydroxyphenylglycol (3), as well as two new acyl derivatives of 3, 4-(1,2-di(butanoyloxy)ethyl)benzene-1,2-diol (7) and 4 (1,2-di(lauroyloxy)ethyl)benzene-1,2-diol (8), on LPS-stimulated murine peritoneal macrophages in comparison with hydroxytyrosol (HTy, 1). Compounds 2, 3, 7, and 8 showed a strong reactive oxygen species (ROS)-scavenging activity, reducing significantly nitrite levels with a significant decrease on iNOS expression [2 (50 MUM, 0.44 +/- 0.03; 100 MUM, 0.44 +/- 0.01; p < 0.01); 3 (50 MUM, 0.37 +/- 0.03; 100 MUM, 0.37 +/- 0.01; p < 0.001); 7 (50 MUM, 0.45 +/- 0.06; p < 0.01)] . However, only 2 and 3 down-regulated COX-2 expression [2 (50 MUM, 0.72 +/- 0.04, p < 0.05; 100 MUM, 0.54 +/- 0.06, p < 0.01); 3 (50 MUM, 0.56 +/- 0.05, p < 0.05; 100 MUM, 0.37 +/- 0.04; p < 0.001)] and prevented IKBalpha degradation [2 (100 MUM, 1.63 +/- 0.14, p < 0.01); 3 (100 MUM, 1.82 +/- 0.09; p < 0.01)] ; the diacylated compounds 7 and 8 showed worse anti-inflammatory activity than the parent 3. In conclusion, 2 and 3 phenolic derivatives could play an important role in the anti-inflammatory effect of EVOO. The implication of this study for the nutrition and general health of the population rests in the possible use of natural HTy derivatives with better hydrophilic/lipophilic balance, thus improving its pharmacodynamic and pharmacokinetic profiles, as new dietary supplements in foods. PMID- 25526104 TI - Quantum mass acquisition in spinor Bose-Einstein condensates. AB - Quantum mass acquisition, in which a massless (quasi)particle becomes massive due to quantum corrections, is predicted to occur in several subfields of physics. However, its experimental observation remains elusive since the emergent energy gap is too small. We show that a spinor Bose-Einstein condensate is an excellent candidate for the observation of such a peculiar phenomenon as the energy gap turns out to be 2 orders of magnitude larger than the zero-point energy. This extraordinarily large energy gap is a consequence of the dynamical instability. The propagation velocity of the resultant massive excitation mode is found to be decreased by the quantum corrections as opposed to phonons. PMID- 25526105 TI - Soft decoding of a qubit readout apparatus. AB - Qubit readout is commonly performed by thresholding a collection of analog detector signals to obtain a sequence of single-shot bit values. The intrinsic irreversibility of the mapping from analog to digital signals discards soft information associated with an a posteriori confidence that can be assigned to each bit value when a detector is well characterized. Accounting for soft information, we show significant improvements in enhanced state detection with the quantum repetition code as well as quantum state or parameter estimation. These advantages persist in spite of non-Gaussian features of realistic readout models, experimentally relevant small numbers of qubits, and finite encoding errors. These results show useful and achievable advantages for a wide range of current experiments on quantum state tomography, parameter estimation, and qubit readout. PMID- 25526106 TI - Enhanced fault-tolerant quantum computing in d-level systems. AB - Error-correcting codes protect quantum information and form the basis of fault tolerant quantum computing. Leading proposals for fault-tolerant quantum computation require codes with an exceedingly rare property, a transversal non Clifford gate. Codes with the desired property are presented for d-level qudit systems with prime d. The codes use n=d-1 qudits and can detect up to ~d/3 errors. We quantify the performance of these codes for one approach to quantum computation known as magic-state distillation. Unlike prior work, we find performance is always enhanced by increasing d. PMID- 25526107 TI - Path factorization approach to stochastic simulations. AB - The computational efficiency of stochastic simulation algorithms is notoriously limited by the kinetic trapping of the simulated trajectories within low energy basins. Here we present a new method that overcomes kinetic trapping while still preserving exact statistics of escape paths from the trapping basins. The method is based on path factorization of the evolution operator and requires no prior knowledge of the underlying energy landscape. The efficiency of the new method is demonstrated in simulations of anomalous diffusion and phase separation in a binary alloy, two stochastic models presenting severe kinetic trapping. PMID- 25526108 TI - Conditional probability calculations for the nonlinear Schrodinger equation with additive noise. AB - The method for the computation of the conditional probability density function for the nonlinear Schrodinger equation with additive noise is developed. We present in a constructive form the conditional probability density function in the limit of small noise and analytically derive it in a weakly nonlinear case. The general theory results are illustrated using fiber-optic communications as a particular, albeit practically very important, example. PMID- 25526110 TI - Possible role of gamma ray bursts on life extinction in the universe. AB - As a copious source of gamma rays, a nearby galactic gamma ray burst (GRB) can be a threat to life. Using recent determinations of the rate of GRBs, their luminosity function, and properties of their host galaxies, we estimate the probability that a life-threatening (lethal) GRB would take place. Amongst the different kinds of GRBs, long ones are most dangerous. There is a very good chance (but no certainty) that at least one lethal GRB took place during the past 5 gigayears close enough to Earth as to significantly damage life. There is a 50% chance that such a lethal GRB took place during the last 500*10^{6} years, causing one of the major mass extinction events. Assuming that a similar level of radiation would be lethal to life on other exoplanets hosting life, we explore the potential effects of GRBs to life elsewhere in the Galaxy and the Universe. We find that the probability of a lethal GRB is much larger in the inner Milky Way (95% within a radius of 4 kpc from the galactic center), making it inhospitable to life. Only at the outskirts of the Milky Way, at more than 10 kpc from the galactic center, does this probability drop below 50%. When considering the Universe as a whole, the safest environments for life (similar to the one on Earth) are the lowest density regions in the outskirts of large galaxies, and life can exist in only ~10% of galaxies. Remarkably, a cosmological constant is essential for such systems to exist. Furthermore, because of both the higher GRB rate and galaxies being smaller, life as it exists on Earth could not take place at z>0.5. Early life forms must have been much more resilient to radiation. PMID- 25526111 TI - Resilience of the standard predictions for primordial tensor modes. AB - We show that the prediction for the primordial tensor power spectrum cannot be modified at leading order in derivatives. Indeed, one can always set to unity the speed of propagation of gravitational waves during inflation by a suitable disformal transformation of the metric, while a conformal one can make the Planck mass time independent. Therefore, the tensor amplitude unambiguously fixes the energy scale of inflation. Using the effective field theory of inflation, we check that predictions are independent of the choice of frame, as expected. The first corrections to the standard prediction come from two parity violating operators with three derivatives. Also the correlator ?gammagammagamma? is standard and only receives higher derivative corrections. These results hold also in multifield models of inflation and in alternatives to inflation and make the connection between a (quasi-)scale-invariant tensor spectrum and inflation completely robust. PMID- 25526112 TI - Spontaneous supersymmetry breaking in the 2D N=1 Wess-Zumino model. AB - We study the phase diagram of the two-dimensional N=1 Wess-Zumino model on the lattice using Wilson fermions and the fermion loop formulation. We give a complete nonperturbative determination of the ground state structure in the continuum and infinite volume limit. We also present a determination of the particle spectrum in the supersymmetric phase, in the supersymmetry broken phase and across the supersymmetry breaking phase transition. In the supersymmetry broken phase, we observe the emergence of the Goldstino particle. PMID- 25526113 TI - Challenge to the a theorem in six dimensions. AB - The possibility of a strong a theorem in six dimensions is examined in multiflavor phi^{3} theory. Contrary to the case in two and four dimensions, we find that, in perturbation theory, the relevant quantity a[over ~] increases monotonically along flows away from the trivial fixed point. a[over ~] is a natural extension of the coefficient a of the Euler term in the trace anomaly, and it arises in any even spacetime dimension from an analysis based on Weyl consistency conditions. We also obtain the anomalous dimensions and beta functions of multiflavor phi^{3} theory to two loops. Our results suggest that some new intuition about the a theorem is in order. PMID- 25526114 TI - Charge-swapping Q balls. AB - Q balls are nontopological solitonic solutions to a wide class of field theories that possess global symmetries. Here we show that in these same theories there also exists a tower of novel composite Q-ball solutions where, within one composite Q ball, positive and negative charges coexist and swap at a frequency lower than the natural frequency of an individual Q ball. These charge-swapping Q balls are constructed by assembling Q balls and anti-Q balls tightly such that their nonlinear cores overlap. We explain why charge-swapping Q balls can form and why they swap charges. PMID- 25526115 TI - Universal bounds on the time evolution of entanglement entropy. AB - Using relative entropy, we derive bounds on the time rate of change of geometric entanglement entropy for any relativistic quantum field theory in any dimension. The bounds apply to both mixed and pure states, and may be extended to curved space. We illustrate the bounds in a few examples and comment on potential applications and future extensions. PMID- 25526116 TI - Infinite class of PT-symmetric theories from one timelike Liouville Lagrangian. AB - Logarithmic timelike Liouville quantum field theory has a generalized PT invariance, where T is the time-reversal operator and P stands for an S-duality reflection of the Liouville field phi. In Euclidean space, the Lagrangian of such a theory L=1/2(?phi)^{2}-igphiexp(iaphi) is analyzed using the techniques of PT symmetric quantum theory. It is shown that L defines an infinite number of unitarily inequivalent sectors of the theory labeled by the integer n. In one dimensional space (quantum mechanics), the energy spectrum is calculated in the semiclassical limit and the mth energy level in the nth sector is given by E_{m,n}~(m+1/2)^{2}a^{2}/(16n^{2}). PMID- 25526117 TI - Yang-Mills origin of gravitational symmetries. AB - By regarding gravity as the convolution of left and right Yang-Mills theories together with a spectator scalar field in the biadjoint representation, we derive in linearized approximation, the gravitational symmetries of general covariance, p-form gauge invariance, local Lorentz invariance, and local supersymmetry from the flat space Yang-Mills symmetries of local gauge invariance and global super Poincare symmetry. As a concrete example, we focus on the new minimal (12+12) off shell version of simple four-dimensional supergravity obtained by tensoring the off shell Yang-Mills multiplets (4+4, N_{L}=1) and (3+0, N_{R}=0). PMID- 25526118 TI - Soft gluon resummations in dijet azimuthal angular correlations in hadronic collisions. AB - We derive all order soft gluon resummation in dijet azimuthal angular correlation in hadronic collisions at the next-to-leading logarithmic level. The relevant coefficients for the Sudakov resummation factor, the soft and hard factors, are calculated. The theory predictions agree well with the experimental data from D0 Collaboration at the Tevatron. This provides a benchmark calculation for the transverse momentum dependent QCD resummation for jet productions in hadron collisions. PMID- 25526120 TI - Observation of long-range three-body coulomb effects in the decay of (16)Ne. AB - The interaction of an E/A=57.6-MeV ^{17}Ne beam with a Be target is used to populate levels in ^{16}Ne following neutron knockout reactions. The decay of ^{16}Ne states into the three-body ^{14}O+p+p continuum is observed in the High Resolution Array (HiRA). For the first time for a 2p emitter, correlations between the momenta of the three decay products are measured with sufficient resolution and statistics to allow for an unambiguous demonstration of their dependence on the long-range nature of the Coulomb interaction. Contrary to previous measurements, our measured limit Gamma<80 keV for the intrinsic decay width of the ground state is not in contradiction to the small values (of the order of keV) predicted theoretically. PMID- 25526121 TI - Novel technique for constraining r-process (n, gamma) reaction rates. AB - A novel technique has been developed, which will open exciting new opportunities for studying the very neutron-rich nuclei involved in the r process. As a proof of principle, the gamma spectra from the beta decay of ^{76}Ga have been measured with the SuN detector at the National Superconducting Cyclotron Laboratory. The nuclear level density and gamma-ray strength function are extracted and used as input to Hauser-Feshbach calculations. The present technique is shown to strongly constrain the ^{75}Ge(n,gamma)^{76}Ge cross section and reaction rate. PMID- 25526122 TI - States of carbon-12 in the Skyrme model. AB - The Skyrme model has two Skyrmion solutions of baryon number 12, with D_{3h} and D_{4h} symmetries. The first has an equilateral triangular shape and the second an extended linear shape, analogous to the triangle and linear chain structures of three alpha particles. We recalculate the moments of inertia of these Skyrmions, and deduce the energies and spins of their quantized rotational excitations. There is a good match with the ground-state band of carbon-12, and with the recently established rotational band of the Hoyle state. The ratio of the root mean square matter radii also matches the experimental value. PMID- 25526125 TI - Photofragmentation beam splitters for matter-wave interferometry. AB - Extending the range of quantum interferometry to a wider class of composite nanoparticles requires new tools to diffract matter waves. Recently, pulsed photoionization light gratings have demonstrated their suitability for high mass matter-wave physics. Here, we extend quantum interference experiments to a new class of particles by introducing photofragmentation beam splitters into time domain matter-wave interferometry. We present data that demonstrate this coherent beam splitting mechanism with clusters of hexafluorobenzene and we show single photon depletion gratings based both on fragmentation and ionization for clusters of vanillin. We propose that photofragmentation gratings can act on a large set of van der Waals clusters and biomolecules which are thermally unstable and often resilient to single-photon ionization. PMID- 25526126 TI - Collective excitation of Rydberg-atom ensembles beyond the superatom model. AB - In an ensemble of laser-driven atoms involving strongly interacting Rydberg states, the steady-state excitation probability is usually substantially suppressed. In contrast, here we identify a regime in which the Rydberg excited fraction is enhanced by the interaction. This effect is associated with the buildup of many-body coherences induced by coherent multiphoton excitations between collective states. The excitation enhancement should be observable under currently existing experimental conditions and may serve as a direct probe for the presence of coherent multiphoton dynamics involving collective quantum states. PMID- 25526127 TI - Magnetic-dipole transitions in highly charged ions as a basis of ultraprecise optical clocks. AB - We evaluate the feasibility of using magnetic-dipole (M1) transitions in highly charged ions as a basis of an optical atomic clockwork of exceptional accuracy. We consider a range of possibilities, including M1 transitions between clock levels of the same fine-structure and hyperfine-structure manifolds. In highly charged ions these transitions lie in the optical part of the spectra and can be probed with lasers. The most direct advantage of our proposal comes from the low degeneracy of clock levels and the simplicity of atomic structure in combination with negligible quadrupolar shift. We demonstrate that such clocks can have projected fractional accuracies below the 10^{-20}-10^{-21} level for all common systematic effects, such as blackbody radiation, Zeeman, ac-Stark, and quadrupolar shifts. PMID- 25526128 TI - Probing the axis alignment of an ultracold spin-polarized Rb(2) molecule. AB - We present a novel method for probing the alignment of the molecular axis of an ultracold, nonpolar dimer. These results are obtained using diatomic ^{87}Rb_{2} molecules in the vibrational ground state of the lowest triplet potential a^{3}Sigma_{u}^{+} trapped in a 3D optical lattice. We measure the molecular polarizabilities, which are directly linked to the alignment, along each of the x, y, and z directions of the lab coordinate system. By preparing the molecules in various, precisely defined rotational quantum states we can control the degree of alignment of the molecular axis with high precision over a large range. Furthermore, we derive the dynamical polarizabilities for a laser wavelength of 1064.5 nm parallel and orthogonal to the molecular axis of the dimer, alpha_{?}=(8.9+/-0.9)*10^{3} a.u. and alpha_{?}=(0.9+/-0.4)*10^{3} a.u., respectively. Our findings highlight that the depth of an optical lattice strongly depends on the rotational state of the molecule, which has to be considered in collision experiments. The present work paves the way for reaction studies between aligned molecules in the ultracold temperature regime. PMID- 25526124 TI - Measurement of double-polarization asymmetries in the quasielastic (3)He[->](e[ >],e(')d) process. AB - We present a precise measurement of double-polarization asymmetries in the ^{3}He[over ->](e[over ->],e^{'}d) reaction. This particular process is a uniquely sensitive probe of hadron dynamics in ^{3}He and the structure of the underlying electromagnetic currents. The measurements have been performed in and around quasielastic kinematics at Q^{2}=0.25(GeV/c)^{2} for missing momenta up to 270 MeV/c. The asymmetries are in fair agreement with the state-of-the-art calculations in terms of their functional dependencies on p_{m} and omega, but are systematically offset. Beyond the region of the quasielastic peak, the discrepancies become even more pronounced. Thus, our measurements have been able to reveal deficiencies in the most sophisticated calculations of the three-body nuclear system, and indicate that further refinement in the treatment of their two-and/or three-body dynamics is required. PMID- 25526129 TI - Beyond Anderson localization in 1D: anomalous localization of microwaves in random waveguides. AB - Experimental evidence demonstrating that anomalous localization of waves can be induced in a controllable manner is reported. A microwave waveguide with dielectric slabs randomly placed is used to confirm the presence of anomalous localization. If the random spacing between slabs follows a distribution with a power-law tail (Levy-type distribution), unconventional properties in the microwave-transmission fluctuations take place revealing the presence of anomalous localization. We study both theoretically and experimentally the complete distribution of the transmission through random waveguides characterized by alpha=1/2 ("Levy waveguides") and alpha=3/4, alpha being the exponent of the power-law tail of the Levy-type distribution. As we show, the transmission distributions are determined by only two parameters, both of them experimentally accessible. Effects of anomalous localization on the transmission are compared with those from the standard Anderson localization. PMID- 25526130 TI - Distinct organizational States of fully developed turbulent pipe flow. AB - Organizational states of turbulence are identified through novel analysis of large scale pipe flow experiments at a Reynolds number of 35 000. The distinct states are revealed by an azimuthal decomposition of the two-point spatial correlation of the streamwise velocity fluctuation. States with dominant azimuthal wave numbers corresponding to k_{theta}=2,3,4,5,6 are discovered and their structure revealed as a series of alternately rotating quasistreamwise vortices. Such organizational states are highly reminiscent of the nonlinear traveling wave solutions previously identified at Reynolds numbers an order of magnitude lower. PMID- 25526131 TI - Topology of megagauss magnetic fields and of heat-carrying electrons produced in a high-power laser-solid interaction. AB - The intricate spatial and energy distribution of magnetic fields, self-generated during high power laser irradiation (at Ilambda^{2}~10^{13}-10^{14} W.cm^{ 2}.MUm^{2}) of a solid target, and of the heat-carrying electron currents, is studied in inertial confinement fusion (ICF) relevant conditions. This is done by comparing proton radiography measurements of the fields to an improved magnetohydrodynamic description that fully takes into account the nonlocality of the heat transport. We show that, in these conditions, magnetic fields are rapidly advected radially along the target surface and compressed over long time scales into the dense parts of the target. As a consequence, the electrons are weakly magnetized in most parts of the plasma flow, and we observe a reemergence of nonlocality which is a crucial effect for a correct description of the energetics of ICF experiments. PMID- 25526132 TI - Bright subcycle extreme ultraviolet bursts from a single dense relativistic electron sheet. AB - Double-foil targets separated by a low density plasma and irradiated by a petawatt-class laser are shown to be a copious source of coherent broadband radiation. Simulations show that a dense sheet of relativistic electrons is formed during the interaction of the laser with the tenuous plasma between the two foils. The coherent motion of the electron sheet as it transits the second foil results in strong broadband emission in the extreme ultraviolet, consistent with our experimental observations. PMID- 25526133 TI - Direct observation of magnetochiral effects through a single metamolecule in microwave regions. AB - We report direct observation of magnetochiral (MCh) effects for the X-band microwaves through a single metamolecule consisting of a copper chiral structure and ferrite rod. A fictitious interaction between chirality and magnetism is realized in the metamolecule without intrinsic electronic interactions. The MCh effects are induced at the resonant optical activities by applying a weak dc magnetic field of 1 mT, and are increased with the magnetic field. The nonreciprocal differences in refractive indices are evaluated to be 10^{-3} at 200 mT. PMID- 25526134 TI - Coherent and incoherent electron-phonon coupling in graphite observed with radio frequency compressed ultrafast electron diffraction. AB - Radio-frequency compressed ultrafast electron diffraction has been used to probe the coherent and incoherent coupling of impulsive electronic excitation at 1.55 eV (800 nm) to optical and acoustic phonon modes directly from the perspective of the lattice degrees of freedom. A biexponential suppression of diffracted intensity due to relaxation of the electronic system into incoherent phonons is observed, with the 250 fs fast contribution dominated by coupling to the E_{2g2} optical phonon mode at the Gamma point (Gamma-E_{2g2}) and A_{1}^{'} optical phonon mode at the K point (K-A_{1}^{'}). Both modes have Kohn anomalies at these points in the Brillouin zone. The result is a unique nonequilibrium state with the electron subsystem in thermal equilibrium with only a very small subset of the lattice degrees of freedom within 500 fs following photoexcitation. This state relaxes through further electron-phonon and phonon-phonon pathways on the 6.5 ps time scale. In addition, electronic excitation leads to both in-plane and out-of-plane coherent lattice responses in graphite whose character we are able to fully determine based on spot positions and intensity modulations in the femtosecond electron diffraction data. The in-plane motion is specifically a Gamma point shearing mode of the graphene planes and the out-of-plane motion an acoustic breathing mode response of the film. PMID- 25526135 TI - Experimental identification of diffusive coupling using 2D NMR. AB - Spin relaxation based nuclear magnetic resonance (NMR) methods have been used extensively to determine pore size distributions in a variety of materials. This approach is based on the assumption that each pore is in the fast diffusion limit but that diffusion between pores can be neglected. However, in complex materials these assumptions may be violated and the relaxation time distribution is not easily interpreted. We present a 2D NMR technique and an associated data analysis that allow us to work directly with the time dependent experimental data without Laplace inversion to identify the signature of diffusive coupling between different pores. Measurements on microporous glass beads and numerical simulations are used to illustrate the technique. PMID- 25526136 TI - Nucleation at the contact line observed on nanotextured surfaces. AB - It has been conjectured that roughness plays a role in surface nucleation, the tendency for freezing to begin preferentially at the liquid-gas interface. Using high speed imaging, we sought evidence for freezing at the contact line on catalyst substrates with imposed characteristic length scales (texture). Length scales consistent with the critical nucleus size and with delta~tau/sigma, where tau is a relevant line tension and sigma is the surface tension, range from nanometers to micrometers. It is found that nanoscale texture causes a shift in the nucleation of ice in supercooled water to the three-phase contact line, while microscale texture does not. PMID- 25526137 TI - Corbino disk viscometer for 2D quantum electron liquids. AB - The shear viscosity of a variety of strongly interacting quantum fluids, ranging from ultracold atomic Fermi gases to quark-gluon plasmas, can be accurately measured. On the contrary, no experimental data exist, to the best of our knowledge, on the shear viscosity of two-dimensional quantum electron liquids hosted in a solid-state matrix. In this work we propose a Corbino disk device, which allows a determination of the viscosity of a quantum electron liquid from the dc potential difference that arises between the inner and the outer edge of the disk in response to an oscillating magnetic flux. PMID- 25526138 TI - Superionicity and polymorphism in calcium fluoride at high pressure. AB - We present a combined experimental and computational first-principles study of the superionic and structural properties of CaF_{2} at high P-T conditions. We observe an anomalous superionic behavior in the low-P fluorite phase that consists of a decrease of the normal -> superionic critical temperature with compression. This unexpected effect can be explained in terms of a P-induced softening of a zone-boundary X phonon that involves exclusively fluorine displacements. Also we find that superionic conductivity is absent in the high-P cotunnite phase. Instead, superionicity develops in a new low-symmetry high-T phase that we identify as monoclinic (space group P2_{1}/c). We discuss the possibility of observing these intriguing phenomena in related isomorphic materials. PMID- 25526139 TI - Nonclassical "explosive" nucleation in Pb/Si(111) at low temperatures. AB - Classically, the onset of nucleation is defined in terms of a critical cluster of the condensed phase, which forms from the gradual aggregation of randomly diffusing adatoms. Experiments in Pb/Si(111) at low temperature have discovered a dramatically different type of nucleation, with perfect crystalline islands emerging "explosively" out of the compressed wetting layer after a critical coverage Theta_{c}=1.22 ML is reached. The unexpectedly high island growth rates, the directional correlations in the growth of neighboring islands and the persistence in time of where mass is added in individual islands, suggest that nucleation is a result of the highly coherent motion of the wetting layer, over mesoscopic distances. PMID- 25526140 TI - Noncollinear paramagnetism of a GaAs two-dimensional hole system. AB - We have performed transport measurements in tilted magnetic fields in a two dimensional hole system grown on the surface of a (311)A GaAs crystal. A striking asymmetry of Shubnikov-de Haas oscillations occurs upon reversing the in-plane component of the magnetic field along the low-symmetry [2[over -]33] axis. As usual, the magnetoconductance oscillations are symmetric with respect to reversal of the in-plane field component aligned with the high-symmetry [011[over -]] axis. Our observations demonstrate that an in-plane magnetic field can generate an out-of-plane component of magnetization in a low-symmetry hole system, creating new possibilities for spin manipulation. PMID- 25526109 TI - Improved upper limits on the stochastic gravitational-wave background from 2009 2010 LIGO and Virgo data. AB - Gravitational waves from a variety of sources are predicted to superpose to create a stochastic background. This background is expected to contain unique information from throughout the history of the Universe that is unavailable through standard electromagnetic observations, making its study of fundamental importance to understanding the evolution of the Universe. We carry out a search for the stochastic background with the latest data from the LIGO and Virgo detectors. Consistent with predictions from most stochastic gravitational-wave background models, the data display no evidence of a stochastic gravitational wave signal. Assuming a gravitational-wave spectrum of Omega_{GW}(f)=Omega_{alpha}(f/f_{ref})^{alpha}, we place 95% confidence level upper limits on the energy density of the background in each of four frequency bands spanning 41.5-1726 Hz. In the frequency band of 41.5-169.25 Hz for a spectral index of alpha=0, we constrain the energy density of the stochastic background to be Omega_{GW}(f)<5.6*10^{-6}. For the 600-1000 Hz band, Omega_{GW}(f)<0.14(f/900 Hz)^{3}, a factor of 2.5 lower than the best previously reported upper limits. We find Omega_{GW}(f)<1.8*10^{-4} using a spectral index of zero for 170-600 Hz and Omega_{GW}(f)<1.0(f/1300 Hz)^{3} for 1000-1726 Hz, bands in which no previous direct limits have been placed. The limits in these four bands are the lowest direct measurements to date on the stochastic background. We discuss the implications of these results in light of the recent claim by the BICEP2 experiment of the possible evidence for inflationary gravitational waves. PMID- 25526141 TI - Spin-orbit fluctuations in frustrated heavy-fermion metal LiV(2)O(4). AB - Spin fluctuations were studied over a wide momentum (hQ) and energy (E) space in the frustrated d-electron heavy-fermion metal LiV_{2}O_{4} by time-of-flight inelastic neutron scattering. We observed the overall Q-E evolutions near the characteristic Q=0.6 A^{-1} peak and found another weak broad magnetic peak around 2.4 A^{-1}. The data are described by a simple response function, a partially delocalized magnetic form factor, and antiferromagnetic short-range spatial correlations, indicating that heavy-fermion formation is attributable to spin-orbit fluctuations with orbital hybridization. PMID- 25526142 TI - Flatbands under correlated perturbations. AB - Flatband networks are characterized by the coexistence of dispersive and flatbands. Flatbands (FBs) are generated by compact localized eigenstates (CLSs) with local network symmetries, based on destructive interference. Correlated disorder and quasiperiodic potentials hybridize CLSs without additional renormalization, yet with surprising consequences: (i) states are expelled from the FB energy E_{FB}, (ii) the localization length of eigenstates vanishes as xi~1/ln(E-E_{FB}), (iii) the density of states diverges logarithmically (particle hole symmetry) and algebraically (no particle-hole symmetry), and (iv) mobility edge curves show algebraic singularities at E_{FB}. Our analytical results are based on perturbative expansions of the CLSs and supported by numerical data in one and two lattice dimensions. PMID- 25526145 TI - Electron-vibration interaction in the presence of a switchable Kondo resonance realized in a molecular junction. AB - The interaction of individual electrons with vibrations has been extensively studied. However, the nature of electron-vibration interaction in the presence of many-body electron correlations such as a Kondo state has not been fully investigated. Here, we present transport measurements on a Copper-phthalocyanine molecule, suspended between two silver electrodes in a break-junction setup. Our measurements reveal both zero bias and satellite conductance peaks, which are identified as Kondo resonances with a similar Kondo temperature. The relation of the satellite peaks to electron-vibration interaction is corroborated using several independent spectroscopic indications, as well as ab initio calculations. Further analysis reveals that the contribution of vibration-induced inelastic current is significant in the presence of a Kondo resonance. PMID- 25526143 TI - Anisotropic charge Kondo effect in a triple quantum dot. AB - We predict that an anisotropic charge Kondo effect appears in a triple quantum dot, when the system has twofold degenerate ground states of (1,1,0) and (0,0,1) charge configurations. Using bosonization and refermionization methods, we find that at low temperature the system has the two different phases of massive charge fluctuations between the two charge configurations and vanishing fluctuations, which are equivalent with the Kondo-screened and ferromagnetic phases of the anisotropic Kondo model, respectively. The phase transition is identifiable by electron conductance measurement, offering the possibility of experimentally exploring the anisotropic Kondo model. Our charge Kondo effect has a similar origin to that in a negative-U Anderson impurity. PMID- 25526146 TI - Circular-polarization-sensitive metamaterial based on triple-quantum-dot molecules. AB - We propose a new type of chiral metamaterial based on an ensemble of artificial molecules formed by three identical quantum dots in a triangular arrangement. A static magnetic field oriented perpendicular to the plane breaks mirror symmetry, rendering the molecules sensitive to the circular polarization of light. By varying the orientation and magnitude of the magnetic field one can control the polarization and frequency of the emission spectrum. We identify a threshold frequency Omega, above which we find strong birefringence. In addition, Kerr rotation and circular-polarized lasing action can be implemented. We investigate the single-molecule lasing properties for different energy-level arrangements and demonstrate the possibility of circular-polarization conversion. Finally, we analyze the effect of weak stray electric fields or deviations from the equilateral triangular geometry. PMID- 25526144 TI - Electrical spin injection into high mobility 2D systems. AB - We report on spin injection into a high mobility 2D electron system confined at an (Al,Ga)As/GaAs interface, using (Ga,Mn)As Esaki diode contacts as spin aligners. We measured a clear nonlocal spin valve signal, which varies nonmonotonically with the applied bias voltage. The magnitude of the signal cannot be described by the standard spin drift-diffusion model, because at maximum this would require the spin polarization of the injected current to be much larger than 100%, which is unphysical. A strong correlation of the spin signal with contact width and electron mean free path suggests that ballistic transport in the 2D region below ferromagnetic contacts should be taken into account to fully describe the results. PMID- 25526147 TI - sd(2) Graphene: Kagome band in a hexagonal lattice. AB - Graphene, made of sp^{2} hybridized carbon, is characterized with a Dirac band, representative of its underlying 2D hexagonal lattice. The fundamental understanding of graphene has recently spurred a surge in the search for 2D topological quantum phases in solid-state materials. Here, we propose a new form of 2D material, consisting of sd^{2} hybridized transition metal atoms in hexagonal lattice, called sd^{2} "graphene." The sd^{2} graphene is characterized by bond-centered electronic hopping, which transforms the apparent atomic hexagonal lattice into the physics of a kagome lattice that may exhibit a wide range of topological quantum phases. Based on first-principles calculations, room temperature quantum anomalous Hall states with an energy gap of ~0.1 eV are demonstrated for one such lattice made of W, which can be epitaxially grown on a semiconductor surface of 1/3 monolayer Cl-covered Si(111), with high thermodynamic and kinetic stability. PMID- 25526148 TI - Effective theory of Floquet topological transitions. AB - We develop a theory of topological transitions in a Floquet topological insulator, using graphene irradiated by circularly polarized light as a concrete realization. We demonstrate that a hallmark signature of such transitions in a static system, i.e., metallic bulk transport with conductivity of order e^{2}/h, is substantially suppressed at some Floquet topological transitions in the clean system. We determine the conditions for this suppression analytically and confirm our results in numerical simulations. Remarkably, introducing disorder dramatically enhances this transport by several orders of magnitude. PMID- 25526149 TI - Fibonacci anyons from Abelian bilayer quantum Hall states. AB - The possibility of realizing non-Abelian statistics and utilizing it for topological quantum computation (TQC) has generated widespread interest. However, the non-Abelian statistics that can be realized in most accessible proposals is not powerful enough for universal TQC. In this Letter, we consider a simple bilayer fractional quantum Hall system with the 1/3 Laughlin state in each layer. We show that interlayer tunneling can drive a transition to an exotic non-Abelian state that contains the famous "Fibonacci" anyon, whose non-Abelian statistics is powerful enough for universal TQC. Our analysis rests on startling agreements from a variety of distinct methods, including thin torus limits, effective field theories, and coupled wire constructions. We provide evidence that the transition can be continuous, at which point the charge gap remains open while the neutral gap closes. This raises the question of whether these exotic phases may have already been realized at nu=2/3 in bilayers, as past experiments may not have definitively ruled them out. PMID- 25526150 TI - Reconstruction of band structure induced by electronic nematicity in an FeSe superconductor. AB - We have performed high-resolution angle-resolved photoemission spectroscopy on an FeSe superconductor (T_{c}~8 K), which exhibits a tetragonal-to-orthorhombic structural transition at T_{s}~90 K. At low temperature, we found splitting of the energy bands as large as 50 meV at the M point in the Brillouin zone, likely caused by the formation of electronically driven nematic states. This band splitting persists up to T~110 K, slightly above T_{s}, suggesting that the structural transition is triggered by the electronic nematicity. We have also revealed that at low temperature the band splitting gives rise to a van Hove singularity within 5 meV of the Fermi energy. The present result strongly suggests that this unusual electronic state is responsible for the unconventional superconductivity in FeSe. PMID- 25526151 TI - Magnetism of Ho and Er atoms on close-packed metal surfaces. AB - We investigated the magnetic properties of individual Ho atoms adsorbed on the (111) surface of Pt, which have been recently claimed to display single ion magnetic behavior. By combining x-ray absorption spectroscopy and magnetic dichroism measurements with ligand field multiplet calculations, we reveal a ground state which is incompatible with long spin relaxation times, in disagreement with former findings. A comparative study of the ground state and magnetic anisotropy of Ho and Er on Pt(111) and Cu(111) emphasizes the different interaction of the 4f orbitals with localized and delocalized substrate states. In particular, we find a striking rotation of the magnetization easy axis for Er, which changes from out of plane on Pt(111) to in plane on Cu(111). PMID- 25526152 TI - Quantum selection of order in an XXZ antiferromagnet on a Kagome lattice. AB - Selection of the ground state of the kagome-lattice XXZ antiferromagnet by quantum fluctuations is investigated by combining nonlinear spin-wave and real space perturbation theories. The two methods unanimously favor q=0 over sqrt[3]*sqrt[3] magnetic order in a wide range of the anisotropy parameter 0<=Delta?0.72. Both approaches are also in accord on the magnitude of the quantum order-by-disorder effect generated by topologically nontrivial, looplike spin flip processes. A tentative S-Delta phase diagram of the model is proposed. PMID- 25526153 TI - Quantum spin dimers from chiral dissipation in cold-atom chains. AB - We consider the nonequilibrium dynamics of a driven dissipative spin chain with chiral coupling to a one-dimensional (1D) bosonic bath, and its atomic implementation with a two-species mixture of cold quantum gases. The reservoir is represented by a spin-orbit coupled 1D quasicondensate of atoms in a magnetized phase, while the spins are identified with motional states of a separate species of atoms in an optical lattice. The chirality of reservoir excitations allows the spins to couple differently to left- and right-moving modes, which in our atomic setup can be tuned from bidirectional to purely unidirectional. Remarkably, this leads to a pure steady state in which pairs of neighboring spins form dimers that decouple from the remainder of the chain. Our results also apply to current experiments with two-level emitters coupled to photonic waveguides. PMID- 25526154 TI - Magnetic damping: domain wall dynamics versus local ferromagnetic resonance. AB - Magnetic relaxation is one of the dominating features of magnetization dynamics. Depending on the magnetic structure and the experimental approach, different magnitudes of the damping parameter are reported even for a given material. In this study, we experimentally address this issue by accessing the damping parameter in the same magnetic nanotracks using different approaches: local ferromagnetic resonance (alpha=0.0072) and field-driven domain wall dynamics (alpha=0.023). The experimental results cannot fully be accounted for by modeling only roughness in micromagnetic simulations. Consequently, we have included nonlocal texture induced damping to the micromagnetic code. We find excellent agreement with the observed increased damping in the vortex structures for the same input Gilbert alpha when texture-induced nonlocal damping is included. PMID- 25526155 TI - Imaging energy-, momentum-, and time-resolved distributions of photoinjected hot electrons in GaAs. AB - Using time-and angle-resolved photoemission spectroscopy, we determine directly energy-, momentum-, and time-resolved distributions of hot electrons photoinjected into the conduction band of GaAs, a prototypical direct-gap semiconductor. The nascent distributions of photoinjected electrons are captured for different pump photon energies and polarization. The evolutions of hot electron distributions in ultrafast intervalley scattering processes are resolved in momentum space with fs-temporal resolution, revealing an intervalley transition time as short as 20 fs. PMID- 25526156 TI - Electronic reconstruction at the isopolar LaTiO(3)/LaFeO(3) interface: an X-ray photoemission and density-functional theory study. AB - We report the formation of a nonmagnetic band insulator at the isopolar interface between the antiferromagnetic Mott-Hubbard insulator LaTiO_{3} and the antiferromagnetic charge transfer insulator LaFeO_{3}. By density-functional theory calculations, we find that the formation of this interface state is driven by the combination of O band alignment and crystal field splitting energy of the t_{2g} and e_{g} bands. As a result of these two driving forces, the Fe 3d bands rearrange and electrons are transferred from Ti to Fe. This picture is supported by x-ray photoelectron spectroscopy, which confirms the rearrangement of the Fe 3d bands and reveals an unprecedented charge transfer up to 1.2+/-0.2 e^{ }/interface unit cell in our LaTiO_{3}/LaFeO_{3} heterostructures. PMID- 25526157 TI - Protecting a solid-state spin from decoherence using dressed spin states. AB - We report experimental studies of dressing an electron spin in diamond with resonant and continuous microwave fields to protect the electron spin from magnetic fluctuations induced by the nuclear spin bath. We use optical coherent population trapping (CPT) to probe the energy level structure, optically induced spin transitions, and spin decoherence rates of the dressed spin states. Dressing an electron spin with resonant microwaves at a coupling rate near 1 MHz leads to a 50 times reduction in the linewidth of the spin transition underlying the CPT process, limited by transit-time broadening. Compared with dynamical decoupling, where effects of the bath are averaged out at specific times, the dressed spin state provides a continuous protection from decoherence. PMID- 25526158 TI - Are hydrogen-bonded charge transfer crystals room temperature ferroelectrics? AB - We present a theoretical investigation of the anomalous ferroelectricity of mixed stack charge transfer molecular crystals, based on the Peierls-Hubbard model, and first-principles calculations for its parametrization. This approach is first validated by reproducing the temperature-induced transition and the electronic polarization of TTF-CA, and then applied to a novel series of hydrogen-bonded crystals, for which room temperature ferroelectricity has recently been claimed. Our analysis shows that the hydrogen-bonded systems present a very low degree of charge transfer and hence support a very small polarization. A critical reexamination of experimental data supports our findings, shedding doubts on the ferroelectricity of these systems. More generally, our modeling allows the rationalization of general features of the ferroelectric transition in charge transfer crystals and suggests design principles for materials optimization. PMID- 25526159 TI - Predicting a polar analog of chiral blue phases in liquid crystals. AB - In liquid crystals, if flexoelectric couplings between polar order and director gradients are strong enough, the uniform nematic phase can become unstable to the formation of a modulated polar phase. Previous theories have predicted two types of modulation: twist bend and splay bend; the twist-bend phase has been found in recent experiments. Here, we investigate other types of modulation, using lattice simulations and Landau theory. In addition to twist bend and splay bend, we also find polar blue phases, with 2D or 3D modulations of both the director and the polar order. We compare polar blue phases with chiral blue phases, and discuss opportunities for observing them experimentally. PMID- 25526160 TI - Depletion-controlled starvation of a diffusing forager. AB - We study the starvation of a lattice random walker in which each site initially contains one food unit and the walker can travel S steps without food before starving. When the walker encounters food, it is completely eaten, and the walker can again travel S steps without food before starving. When the walker hits an empty site, the time until the walker starves decreases by 1. In spatial dimension d=1, the average lifetime of the walker ?tau??S, while for d>2, ?tau??exp(S^{omega}), with omega->1 as d->infinity; the latter behavior suggests that the upper critical dimension is infinite. In the marginal case of d=2, ?tau??S^{z}, with z~2. Long-lived walks explore a highly ramified region so they always remain close to sources of food and the distribution of distinct sites visited does not obey single-parameter scaling. PMID- 25526161 TI - Finite-size scaling as a way to probe near-criticality in natural swarms. AB - Collective behavior in biological systems is often accompanied by strong correlations. The question has therefore arisen of whether correlation is amplified by the vicinity to some critical point in the parameters space. Biological systems, though, are typically quite far from the thermodynamic limit, so that the value of the control parameter at which correlation and susceptibility peak depend on size. Hence, a system would need to readjust its control parameter according to its size in order to be maximally correlated. This readjustment, though, has never been observed experimentally. By gathering three dimensional data on swarms of midges in the field we find that swarms tune their control parameter and size so as to maintain a scaling behavior of the correlation function. As a consequence, correlation length and susceptibility scale with the system's size and swarms exhibit a near-maximal degree of correlation at all sizes. PMID- 25526162 TI - Rhythmicity, recurrence, and recovery of flagellar beating. AB - The eukaryotic flagellum beats with apparently unfailing periodicity, yet responds rapidly to stimuli. Like the human heartbeat, flagellar oscillations are now known to be noisy. Using the alga C. reinhardtii, we explore three aspects of nonuniform flagellar beating. We report the existence of rhythmicity, waveform noise peaking at transitions between power and recovery strokes, and fluctuations of interbeat intervals that are correlated and even recurrent, with memory extending to hundreds of beats. These features are altered qualitatively by physiological perturbations. Further, we quantify the recovery of periodic breaststroke beating from transient hydrodynamic forcing. These results will help constrain microscopic theories on the origins and regulation of flagellar beating. PMID- 25526163 TI - Reconstructing folding energy landscape profiles from nonequilibrium pulling curves with an inverse Weierstrass integral transform. AB - The energy landscapes that drive structure formation in biopolymers are difficult to measure. Here we validate experimentally a novel method to reconstruct landscape profiles from single-molecule pulling curves using an inverse Weierstrass transform (IWT) of the Jarzysnki free-energy integral. The method was applied to unfolding measurements of a DNA hairpin, replicating the results found by the more-established weighted histogram (WHAM) and inverse Boltzmann methods. Applying both WHAM and IWT methods to reconstruct the folding landscape for a RNA pseudoknot having a stiff energy barrier, we found that landscape features with sharper curvature than the force probe stiffness could not be recovered with the IWT method. The IWT method is thus best for analyzing data from stiff force probes such as atomic force microscopes. PMID- 25526164 TI - Flow-mediated interactions between two self-propelled flapping filaments in tandem configuration. AB - The mechanism by which aggregates of active swimmers are formed is an intriguing problem. In this Letter we show that, for two tandem self-propelled filaments driven by harmonic plunging motions of identical frequency and amplitude, stable configurations can be spontaneously formed by locking the trajectories onto the vortex centers. Further analysis indicates that the grouping energetics is also dictated by the wake vortex structure. The rationale behind the energetic advantage of the follower is found to be the interplay among actuation, self propulsion, and the vortical fluid environment. PMID- 25526165 TI - Extensive parallel processing on scale-free networks. AB - We adapt belief-propagation techniques to study the equilibrium behavior of a bipartite spin glass, with interactions between two sets of N and P=alphaN spins each having an arbitrary degree, i.e., number of interaction partners in the opposite set. An equivalent view is then of a system of N neurons storing P diluted patterns via Hebbian learning, in the high storage regime. Our method allows analysis of parallel pattern processing on a broad class of graphs, including those with pattern asymmetry and heterogeneous dilution; previous replica approaches assumed homogeneity. We show that in a large part of the parameter space of noise, dilution, and storage load, delimited by a critical surface, the network behaves as an extensive parallel processor, retrieving all P patterns in parallel without falling into spurious states due to pattern cross talk, as would be typical of the structural glassiness built into the network. Parallel extensive retrieval is more robust for homogeneous degree distributions, and is not disrupted by asymmetric pattern distributions. For scale-free pattern degree distributions, Hebbian learning induces modularity in the neural network; thus, our Letter gives the first theoretical description for extensive information processing on modular and scale-free networks. PMID- 25526166 TI - Mobility reversal of polyelectrolyte-grafted colloids in monovalent salt solutions. AB - We present molecular dynamics simulations on the electrophoresis of a negative colloid grafted with positive polyelectrolytes. Net-neutral colloids show a varying mobility in monovalent salt. For colloids with negative net charge the mobility is negative at low and positive at high salt concentrations. This mobility reversal is an electrokinetic effect, and thus different from that observed in multivalent salt. Our results agree with numerical calculations based on the Darcy-Brinkman formalism, with which we predict the mobility reversal to also occur for experimentally accessible colloids. PMID- 25526167 TI - Persistence-length renormalization of polymers in a crowded environment of hard disks. AB - The most conspicuous property of a semiflexible polymer is its persistence length, defined as the decay length of tangent correlations along its contour. Using an efficient stochastic growth algorithm to sample polymers embedded in a quenched hard-disk fluid, we find apparent wormlike chain statistics with a renormalized persistence length. We identify a universal form of the disorder renormalization that suggests itself as a quantitative measure of molecular crowding. PMID- 25526168 TI - Generalized energy equipartition in harmonic oscillators driven by active baths. AB - We study experimentally and numerically the dynamics of colloidal beads confined by a harmonic potential in a bath of swimming E. coli bacteria. The resulting dynamics is well approximated by a Langevin equation for an overdamped oscillator driven by the combination of a white thermal noise and an exponentially correlated active noise. This scenario leads to a simple generalization of the equipartition theorem resulting in the coexistence of two different effective temperatures that govern dynamics along the flat and the curved directions in the potential landscape. PMID- 25526169 TI - Full canonical information from grand-potential density-functional theory. AB - We present a general and formally exact method to obtain the canonical one-body density distribution and the canonical free energy from direct decomposition of classical density functional results in the grand ensemble. We test the method for confined one-dimensional hard-core particles for which the exact grand potential density functional is explicitly known. The results agree to within high accuracy with those from exact methods and our Monte Carlo many-body simulations. The method is relevant for treating finite systems and for dynamical density functional theory. PMID- 25526170 TI - Nanoscopic confinement through self-assembly: crystallization within micellar cores exhibits simple Gibbs-Thomson behavior. AB - It is well known that liquids confined to small nanoscopic pores and droplets exhibit thermal behavior very different from bulk samples. Less is known about liquids spontaneously confined through self-assembly into micellar structures. Here we demonstrate, using a very well-defined n-alkyl-poly(ethylene oxide) polymer system with a tunable structure, that n-alkane(s) forming 2-3 nm small micellar cores are affected considerably by confinement in the form of melting point depressions. Moreover, comparing the reduction in melting points, DeltaT_{m}, determined through volumetric and calorimetric methods with the micellar core radius, R_{c}, obtained from small-angle x-ray scattering, we find excellent agreement with the well-known Gibbs-Thomson equation, DeltaT_{m}~R_{c}^{-1}. This demonstrates that the reduced size, i.e., the Laplace pressure, is the dominant parameter governing the melting point depression in micellar systems. PMID- 25526171 TI - Universal power law governing pedestrian interactions. AB - Human crowds often bear a striking resemblance to interacting particle systems, and this has prompted many researchers to describe pedestrian dynamics in terms of interaction forces and potential energies. The correct quantitative form of this interaction, however, has remained an open question. Here, we introduce a novel statistical-mechanical approach to directly measure the interaction energy between pedestrians. This analysis, when applied to a large collection of human motion data, reveals a simple power-law interaction that is based not on the physical separation between pedestrians but on their projected time to a potential future collision, and is therefore fundamentally anticipatory in nature. Remarkably, this simple law is able to describe human interactions across a wide variety of situations, speeds, and densities. We further show, through simulations, that the interaction law we identify is sufficient to reproduce many known crowd phenomena. PMID- 25526172 TI - Retraction: Anomalous melting scenario of the two-dimensional core-softened system [phys. Rev. Lett. 112, 157803 (2014)]. PMID- 25526119 TI - Measurement of prompt D-meson production in p-Pb collisions at ?(s(NN))=5.02 TeV. AB - The p_{T}-differential production cross sections of the prompt charmed mesons D^{0}, D^{+}, D^{*+}, and D_{s}^{+} and their charge conjugate in the rapidity interval -0.9610 times (means +/- SD)], whereas only a mild increase of IL-6 levels occurred in Gram-positive bacteria-infected children [>2 times (means +/- SD)] and only a mild increase of IFN-gamma levels occurred in fungal culture positive children [>2 times (means +/- SD)]. Gram-positive bacterial and fungal infections did not cause a marked increase in IL-6 or IL- 10 levels. The effective rate (86.05%, N = 43) of infectious cases predicted by BIRCP was significantly higher than that obtained using traditional methods for selecting antibiotics based on clinical indications (65.45%, N = 55, P < 0.05). In summary, BIRCP can be used to predict the infections by pathogens in children with hemopathy and to select appropriate antibiotics. PMID- 25526185 TI - Novel polymorphic microsatellite markers isolated from the pen shell Atrina pectinata (Mollusca: Bivalvia: Pinnidae). AB - In this study, we isolated 21 novel polymorphic microsatellite DNA loci from the pen shell Atrina pectinata using magnetic-bead hybridization enrichment. The characteristics of these loci were tested using a population of 30 individuals collected from the Penglai coast, Shandong Province. The number of alleles ranged from 2 to 13, and polymorphism information content (PIC) varied from 0.1730 to 0.8954. Values for observed heterozygosity (HO) and expected heterozygosity (HE) ranged from 0.0714 to 0.9231 and from 0.1948 to 0.9237, respectively. Four loci deviated significantly from Hardy-Weinberg equilibrium. The newly developed microsatellite markers will be beneficial in assessing the genetic diversity, population structure and genetic conservation of A. pectinata, and in other relevant research. PMID- 25526123 TI - Exclusive J/psi photoproduction off protons in ultraperipheral p-Pb collisions at ?(s(NN))=5.02 TeV. AB - We present the first measurement at the LHC of exclusive J/psi photoproduction off protons, in ultraperipheral proton-lead collisions at sqrt[s_{NN}]=5.02 TeV. Events are selected with a dimuon pair produced either in the rapidity interval, in the laboratory frame, 2.5J/psi+p) are 33.2+/-2.2(stat)+/-3.2(syst)+/-0.7(theor) nb in p-Pb and 284+/-36(stat)_{-32}^{+27}(syst)+/-26(theor) nb in Pb-p collisions. We measure this process up to about 700 GeV in the gammap center of mass, which is a factor of two larger than the highest energy studied at HERA. The data are consistent with a power law dependence of the J/psi photoproduction cross section in gammap energies from about 20 to 700 GeV, or equivalently, from Bjorken x scaling variable between ~2*10^{-2} and ~2*10^{-5}, thus indicating no significant change in the gluon density behavior of the proton between HERA and LHC energies. PMID- 25526186 TI - Cloning and functional identification of a novel BCA3 splice. AB - The human breast cancer-associated gene (BCA3) was first discovered in breast and prostate cancer cells lines. In vivo studies have shown that BCA3 is mainly expressed in breast tumor cells and not in normal breast and prostate tissues. To date, 3 splice variants of BCA3 have been reported: a double-absent variant lacking exon 3 and exon 5 (BCA3-1), an exon 3-absent variant (BCA3-2), and full length BCA3. In this study, we investigated whether a novel BCA3 splice variant exists that lacks only the exon 5-encoding sequence. BCA3 variant splices were subcloned and sequenced using reverse transcription-polymerase chain reaction. The preliminary biological functions of the splices were identified using confocal microscopy and a luciferase assay. The absence of exon 3 and exon 5 influenced the subcellular localization of BCA3 and nuclear factor kappa B (NF kB)-dependent gene expression. Exon 3 and exon 5 of BCA3 may function together to provide a nuclear localization signal or transport sequence to enter the nucleus, and exon 3 may contain specific sequence(s) or domain(s) that influence the NF kappaB signal cascade. The discovery of novel BCA3 splicing indicates a new cancer research area, which may increase the understanding of cancer generation and development. PMID- 25526187 TI - Multivariate analysis in a genetic divergence study of Psidium guajava. AB - The family Myrtaceae is widespread in the Atlantic Forest and is well-represented in the Espirito Santo State in Brazil. In the genus Psidium of this family, guava (Psidium guajava L.) is the most economically important species. Guava is widely cultivated in tropical and subtropical countries; however, the widespread cultivation of only a small number of guava tree cultivars may cause the genetic vulnerability of this crop, making the search for promising genotypes in natural populations important for breeding programs and conservation. In this study, the genetic diversity of 66 guava trees sampled in the southern region of Espirito Santo and in Caparao, MG, Brazil were evaluated. A total of 28 morphological descriptors (11 quantitative and 17 multicategorical) and 18 microsatellite markers were used. Principal component, discriminant and cluster analyses, descriptive analyses, and genetic diversity analyses using simple sequence repeats were performed. Discrimination of accessions using molecular markers resulted in clustering of genotypes of the same origin, which was not observed using morphological data. Genetic diversity was detected between and within the localities evaluated, regardless of the methodology used. Genetic differentiation among the populations using morphological and molecular data indicated the importance of the study area for species conservation, genetic erosion estimation, and exploitation in breeding programs. PMID- 25526188 TI - Identification and bioinformatic analysis of a putative calcium-dependent protein kinase (CDPK6) from Toxoplasma gondii. AB - Toxoplasma gondii is recognized as an opportunistic human pathogen with a worldwide distribution. Development of effective vaccines is considered the only ideal way to control T. gondii infection. However, only one live vaccine is commercially available for use in sheep and goats. Therefore, the identification of more effective antigenic proteins is very important. In this study, we identified a novel putative calcium-dependent protein kinase of T. gondii, TgCDPK6, and further analyzed its potential antigenicity using a bioinformatic approach. The physical and chemical characteristics, transmembrane domain, epitopes, advanced structure, and functional sites of TgCDPK6 were predicted by multiple bioinformatic approaches. Twenty-six post-translational modification sites were identified in the protein. The secondary structure showed that 58.35% amino acids of TgCDPK6 are exposed to the solvent interface, and the high hydrophilic domains were distributed in amino acid positions 21-59, 68-81, 156 205, 245-271, 280-294, 297-324, 334-356, 367-393, 474-498, and 543-553. The advanced structure of TgCDPK6 was developed by a homology modeling method and was validated by PROCHECK, which showed that most amino acid residues were in the most favored regions. Using these analyses, 10 potential epitopes were predicted. The results indicated that TgCDPK6 could be a vaccine candidate antigen against T. gondii. PMID- 25526189 TI - Molecular cytogenetic identification of a novel 1AL.1RS translocation line with powdery mildew resistance. AB - A wheat germplasm line 13-2-2 with resistance to powdery mildew was isolated; this line was derived from common wheat cv. W770B and rye, Secale cereale L. (2n = 2x = 14, RR). The line was characterized based on cytological, genomic in situ hybridization (GISH), sequence-characterized amplified region (SCAR), and simple sequence repeat (SSR) analyses. The mitotic and meiotic investigations showed that the chromosome number and configuration of 13-2-2 were 2n = 42 = 21 II. GISH using rye genomic DNA as a probe detected a pair of R genome chromosome arms with strong hybridization signals in 13-2-2. Three 1RS chromosome-specific SCAR markers amplified 1RS specific bands in line 13-2-2. We screened 320 SSR primer pairs on the long or short arms from seven wheat homoeologous groups in the translocation line and parents. However, only three 1AS primers could not be amplified in line 13-2-2, whereas the others were amplified. Thus, these markers suggested that the line 13-2-2 was 1AL.1RS translocation line. Line 13-2-2 was immune to powdery mildew after inoculation with Blumeria graminis f. sp. tritici isolates E05 and E07 during the adult plant stages. In contrast, the maternal parent W770B, Kavkaz with Pm8, and Amigo with Pm17 were heavily infected with spores and had reaction response scores of susceptible. Thus, the new wheat-rye 1AL.1RS translocation line with resistance to powdery mildew could be a new and valuable donor source for wheat improvement. The molecular markers developed in this study might also be useful tools for marker-assisted selection. PMID- 25526190 TI - Characterization and expression analysis of somatic embryogenesis receptor-like kinase genes from Phalaenopsis. AB - Somatic embryogenesis receptor-like kinase (SERK) genes have been found to be involved in the somatic embryogenesis of several plant species. We identified and characterized 5 PhSERK genes in the Phalaenopsis orchid. The amino acid sequences of PhSERKs and other SERK proteins are highly conserved, with the highest homology observed in the leucine-rich repeat-receptor-like kinase domain. All 5 PhSERKs were expressed in all Phalaenopsis organs examined (root, leaf, shoot apical meristem, and flower), with the strongest expression, particularly for PhSERK1 and 3, in the shoot apical meristem of mature plants. Expression of all PhSERKs was downregulated during early floral bud development and was upregulated gradually until the semi-open flower stage was reached. All 5 PhSERKs were expressed during both seed germination and protocorm-like-body (PLB) development. In germinated seeds, quantitative real-time PCR revealed upregulation of all PhSERKs except PhSERK4 at 1 week and downregulation after 4 weeks. The 5 PhSERKs were differentially expressed in the early stage of PLB development and maintained substantial levels during PLB formation, with PhSERK1 and 5 upregulated 1 week after culture and PhSERK2, 3, and 4 downregulated over this period. Because physical wounding of PLB stimulates secondary PLB formation, the PhSERK5 expression peak at week 3 coincided with visible and fully developed secondary PLBs. PhSERK5 may be important in PLB induction and subsequent development. Our PhSERK expression analysis revealed that these genes have a broad role during orchid plant development. PMID- 25526191 TI - Genetic diversity and pathogenicity differentiation of Sclerotinia sclerotiorum on rapeseed (Brassica napus L.) in Anhui Province, China. AB - The pathogenicity of 47 isolates of Sclerotinia sclerotiorum from oilseed rape (Brassica napus L.) in Anhui, China, was tested by detached leaf inoculation using the susceptible rape cultivar Wanyou-14. All isolates were pathogenic to the cultivar and could be grouped into 3 categories based on the lesion length on the leaves tested: weak pathogenicity type, intermediate pathogenicity type, and strong pathogenicity type. This suggested that there was differentiation in the pathogenicity among the strains tested of S. sclerotiorum. Additionally, the intraspecific DNA polymorphisms among 47 strains of S. sclerotiorum were investigated by screening 40 pairs of inter-simple sequence repeat (ISSR) primers. Unweighted pair-group method with arithmetic average cluster analysis of these ISSR data distinguished all strains from each other and revealed considerable genetic variability among them. These strains were classified into 7 clusters according to their branching in the dendrogram, and partial correlation was observed between the genetic polymorphisms and the pathogenicity of S. sclerotiorum strains. PMID- 25526192 TI - Cassava (Manihot esculenta Krantz) genome harbors KNOX genes differentially expressed during storage root development. AB - In plants, homeodomain proteins play a critical role in regulating various aspects of plant growth and development. KNOX proteins are members of the homeodomain protein family. The KNOX transcription factors have been reported from Arabidopsis, rice, and other higher plants. The recent publication of the draft genome sequence of cassava (Manihot esculenta Krantz) has allowed a genome wide search for M. esculenta KNOX (MeKNOX) transcription factors and the comparison of these positively identified proteins with their homologs in model plants. In the present study, we identified 12 MeKNOX genes in the cassava genome and grouped them into two distinct subfamilies based on their domain composition and phylogenetic analysis. Furthermore, semi-quantitative reverse transcription polymerase chain reaction analysis was performed to elucidate the expression profiles of these genes in different tissues and during various stages of root development. The analysis of MeKNOX expression profiles of indicated that 12 MeKNOX genes display differential expressions either in their transcript abundance or expression patterns. PMID- 25526193 TI - Identification and expression analysis of cDNA encoding chitinase-like protein (CLP) gene in Japanese scallop Mizuhopecten yessoensis. AB - Chitinase-like proteins (CLP) are important members of the glycoside hydrolase family 18 (GH18) and are involved in growth control and remodeling processes. In this study, a CLP transcript was isolated and sequenced from the Japanese scallop (Mizuhopecten yessoensis) after screening expressed sequence tags. The full length complementary DNA of M. yessoensis CLP (My-Clp1) was 1555 bp in length, consisting of a 75-bp 5'-untranslated region (UTR), a 160-bp 3'-UTR, and a 1320 bp open reading frame bearing characteristics of the GH18 family. The My-Clp1 protein was well conserved, with similar domain structures and architecture across species (e.g., from mollusks to mammals). Expression analysis in healthy tissues and across developmental stages revealed a strong preference for expression; My-Clp1 was abundantly expressed in the mantle and throughout metamorphosis, which suggests the involvement of My-Clp1 in the synthesis of extracellular components, and tissue degeneration and remodeling. My-Clp1 expression was induced after infection with a bacterial pathogen, Vibrio anguillarum, suggesting its involvement in immunity against this intracellular pathogen. PMID- 25526194 TI - Correlation between IRGM genetic polymorphisms and Crohn's disease risk: a meta analysis of case-control studies. AB - This meta-analysis was performed to evaluate the relationships between single nucleotide polymorphisms (SNPs) in the immunity-related GTPase M (IRGM) gene and the risk of Crohn's disease (CD). Eleven case-control studies were included, for a total of 5183 CD patients and 5571 healthy controls. Three common SNPs (rs13361189 C>T, rs10065172 C>T, and rs4958847 A>G) in the IRGM gene were assessed. We found that the IRGM rs13361189 polymorphism was significantly associated with an increased risk of CD [C allele vs T allele: odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.05-1.61, P = 0.017; CC + CT vs TT: OR = 1.32, 95%CI = 1.06-1.64, P = 0.013]. However, we observed no correlation between the rs10065172 and rs4958847 polymorphisms in the IRGM gene with susceptibility to CD (all P > 0.05). Subgroup analysis by ethnicity revealed significant associations between IRGM genetic polymorphisms and an increased risk of CD among Caucasian populations (C allele vs T allele: OR = 1.22, 95%CI = 1.07-1.40, P = 0.004; CC + CT vs TT: OR = 1.22, 95%CI = 1.05-1.41, P = 0.009), but not among Asian populations (all P > 0.05). Meta-regression analysis also confirmed that ethnic differences may be an important source of heterogeneity (P = 0.003). Our meta-analysis results indicate that the IRGM rs13361189 polymorphism contributes to the susceptibility to CD. Thus, the IRGM rs13361189 polymorphism is promising as a biomarker for early diagnosis of CD. However, the IRGM rs10065172 and rs4958847 polymorphisms may not be the major determinants of CD risk. PMID- 25526195 TI - Germline mutations of DICER1 in Chinese women with BRCA1/BRCA2-negative familial breast cancer. AB - Germline mutations in identified breast cancer susceptibility genes account for less than 20% of Chinese familial breast cancers. Dicer is an essential component of the microRNA-producing machinery; germline mutations of DICER1 have been confirmed in familial pleuropulmonary blastoma, ovarian sex cord-stromal tumors, and other cancers. Low expression of DICER1 is frequently detected in breast cancer. However, whether germline mutations of DICER1 occur in familial breast cancers remain unknown. Sixty-five breast cancer probands from BRCA1/BRCA2 negative Chinese breast cancer families were screened for germline mutations in DICER1. In addition, 100 unrelated healthy females were enrolled as controls. A polymerase chain reaction sequencing assay was used to screen for mutations in coding regions and at the exon-intron boundaries of DICER1. All variants in introns were evaluated using the NNSplice software to determine the potential splicing effect. A total of 12 germline variants were found, including 11 variants in introns and 1 variant in the 3'-non-coding region. Four variants (IVS8-205 C>T, IVS11+131 delGAAA, IVS16+42 delTA, and IVS19+160 T>C) were novel. Three variants (IVS11+105 C>T, IVS16+42 delTA, and 6095 T>A) may affect splice sites. None of the observed variants appeared to be disease-related, suggesting that germline mutations in DICER1 are rare or absent in familial breast cancer patients. PMID- 25526196 TI - Chromosome mapping of 18S rDNA and 5S rDNA by dual-color fluorescence in situ hybridization in the half-smooth tongue sole (Cynoglossus semilaevis). AB - Half-smooth tongue sole (Cynoglossus semilaevis) is an important aquaculture flatfish in China. Cytogenetic analysis has revealed that its sex determination system is female heterogametic (ZZ/ZW). The W chromosome is morphologically larger and has been considered evolutionarily younger than any other chromosome in the set. However, the genetic origin and evolution process of this neo chromosome remains unclear. In this study, 2 tandem arrays of rRNA genes were chosen to address this question. Both the major rDNA (18S rDNA) and the minor rDNA (5S rDNA) were located on the C. semilaevis chromosomes by fluorescence in situ hybridization (FISH). Six 18S rDNA signals were observed on the centromeric regions of 3 pairs of autosomes in both males and females. In females, there was an additional 18S rDNA signal mapping to the telomeric region of the W chromosome long arm. With respect to the 5S rDNA, 12 signals were mapped to the centromeric regions of six pairs of autosomes. Two-color FISH further confirmed that the two pairs of the 5S rDNA signals were correspondingly located at the same positions of the same autosomes as those of the 18S rDNA signals. These results allowed us to speculate about the evolution process of the W chromosome. Chromosome fusions and repetitive sequence accumulations might have occurred in C. semilaevis. The synteny and non-synteny of C. semilaevis 18S rDNA and 5S rDNA might imply the original and evolutionary characteristics of this species. These findings will facilitate studies on karyotype evolution of the order Pleuronectiformes. PMID- 25526197 TI - SAHA attenuates sevoflurane-induced learning and memory impairments in fetal mice. AB - Previous studies have found that children with multiple exposures to anesthesia at an early age are at increased risk of learning and memory impairment. Sevoflurane is the most commonly used inhalational anesthetic for general anesthesia in children. Multiple exposures to sevoflurane have been shown to induce neuroinflammation, inhibit neurogenesis, and cause subsequent learning and memory impairments in fetal mice. Histone-tail acetylation has been implicated in memory formation. In this study, we employed suberanilohydroxamic acid (SAHA), an inhibitor of histone deacetylases, to treat sevoflurane-induced learning and memory impairments. Six-day-old C57BL/6 mice were exposed to sevoflurane for 2 h daily for 3 days. Morris water maze test performed to evaluate learning and memory impairments and the expression of genes related in to synaptic remodeling/plasticity, or regulated by neuronal activity or the cell cycle were detected by real-time PCR. We found that SAHA attenuated sevoflurane-induced learning and memory impairments in fetal mice. Our findings suggest that SAHA may have potential as a therapeutic agent for preventing or treating the neurotoxicity associated with anesthesia. PMID- 25526198 TI - An economical and combined method for rapid and efficient isolation of fungal DNA. AB - DNA isolation is a crucial step of conducting genetic studies in any organism. However, this process is quite difficult when studying fungi because of the need to damage the fungal cell walls of specific structures. In this study, we developed a method for the rapid and efficient isolation of fungal DNA based on simultaneous mechanical and enzymatic cell wall degradation. There are several typical modifications of the standard phenol-chloroform DNA extraction method. This method can be modified to degrade the fungal cell wall. The first step of the presented DNA extraction included manual homogenization in modified lysis buffer. Next, enzymatic digestion using 2 enzymes was conducted, including lyticase and proteinase K. To carefully select the most favorable conditions, we developed an economical, rapid, and reliable method for fungal DNA extraction that ensures both high efficiency and proper purity, which are essential for further analyses. PMID- 25526199 TI - Evaluation of Hsp47 expression in heat-stressed rat myocardial cells in vitro and in vivo. AB - The aim of the present study was to identify the correlation between expression of heat shock protein 47 (Hsp47) and stress injury in heat-stressed myocardial cells and to compare variations in Hsp47 expression in rat myocardial cells exposed to different heat stress for varying periods in vitro and in vivo. Exposure to heat stress at 42 degrees C resulted in similar induction patterns of the heart damage-related enzyme aspartate aminotransferase in the supernatants of H9c2 cells and in the serum of rats. Histological analysis revealed that both H9c2 cells and heart tissues displayed cellular degeneration in response to different periods of heat stress. Hsp47 was constitutively expressed in the cytoplasm of H9c2 cells at all time points during heat stress, which was consistent with observations in heart fibers in vivo. Immunoblotting analysis revealed no significant difference between the expression of Hsp47 in H9c2 cells and heart tissue. However, the expression of hsp47 mRNA in response to heat stress was significantly increased in H9c2 cells at 60 min (P < 0.01) and 100 min (P < 0.01), which was comparable to that at 100 min (P < 0.01) in the rat heart. Thus, Hsp47 was elevated significantly after hyperthermia at the mRNA level but not at the protein level both in vitro and in vivo. The results suggest that Hsp47 turnover may increase during heat stress or that Hsp47 consumption exceeds its production. PMID- 25526200 TI - Genetic features of a translation initiation system composed of IRES element, nucleotide context surrounding the initiation codon, and translation initiation region of classical swine fever virus RNA. AB - Nucleotide and codon usage are typically examined to investigate viral evolution. In this study, we analyzed the genetic information of 46 strains of classical swine fever virus (CSFV) RNA, nucleotide usage in the internal ribosome entry site (IRES), the nucleotide context surrounding the initiation codon, and synonymous codon usage in the translation initiation region. Phylogenetic analysis of the IRES element indicated that the genetic diversity of this element is generally similar to the phylogenetic clusters of CSFV genotypes. Nucleotides surrounding the initiation codon of CSFV RNA were generally more stable (ACAUGGCACAUGGAGUUG) compared to the internal AUG in the CSFV coding sequence. The second codon position after the initiation codon was generally selected to be GAG, which has lower tRNA abundance in pigs than its synonymous member (GAA). Regarding the synonymous codon usage bias in the CSFV translation initiation region, some codons showing low tRNA abundance in pigs are more frequently located in the translation initiation region than in the open reading frame of CSFV. Although CSFV, similarly to other RNA viruses, has a high mutation rate in nature, the regulatory features of nucleotide and synonymous codon usage of the IRES element, the nucleotide context surrounding the initiation codon and the translation initiation region in CSFV RNA have been 'branded' in the system of translation initiation to accommodate gene expression mediated by the cap independent translation mechanism. PMID- 25526201 TI - Cytochalasin B inhibits the proliferation of human glioma U251 cells through cell cycle arrest and apoptosis. AB - Cytochalasin B (CB) is known to inhibit a number of cancer types, but its effects on gliomas are unknown. We examined the in vitro effects of CB on the proliferation of human glioma U251 cells, as well as determined its mechanism of action. Cell proliferation was determined using CCK-8. The effect of CB on U251 cell morphology was observed under a transmission electron microscope. Cell cycle distribution was assessed using propidium iodine and Giemsa staining, and cell apoptosis was determined by annexin V-fluorescein isothiocyanate/propidium iodide. Cell cycle-related proteins were determined by Western blot. CB effectively inhibited U251 cell proliferation in a dose- and time-dependent manner. The 24, 48, 72, and 96 h IC50 values were 6.41 x 10(-2), 9.76 x 10(-4), 2.57 x 10(-5), and 2.08 x 10(-5) M, respectively. CB increased the proportion of cells in the G2/M phase in a dose-dependent manner, thus increasing the mitotic index and decreasing cdc2 and cyclin B1 protein levels. CB induced morphological changes in the cytoskeleton. Additionally, 10(-5) M CB induced apoptosis in 23.4 +/- 0.5% of U251 cells (P < 0.05 vs control group). Caspase-3, -8, and -9 activities were increased after CB treatment. CB inhibited U251 glioma cell proliferation by damaging the microfilament structure. CB also induced glioma cell apoptosis, suggesting that it may be an effective therapeutic agent against gliomas. PMID- 25526202 TI - Differentially expressed genes in the liver of lean and fat chickens. AB - This study aimed to investigate gene expression in the chicken liver for lean and fat broiler lines. Birds used in this study were 2 and 4 weeks of age; they were derived from the 14th generation of Northeast Agricultural University broiler lines, which were divergently selected based on abdominal fat content. Chicken Genome Arrays were used to screen differentially expressed genes in the liver tissue from lean and fat birds. At 2 and 4 weeks of age, 770 and 452 genes were differentially expressed between the 2 lines, respectively. The differentially expressed genes were involved in Wnt, insulin signaling, and cell cycle pathways. At 2 and 4 weeks, 42 shared, differentially expressed genes were revealed by the analysis. We speculate that these genes might regulate chicken lipid metabolism. PMID- 25526203 TI - Physical mapping of the Period gene on meiotic chromosomes of South American grasshoppers (Acridomorpha, Orthoptera). AB - The single-copy gene Period was located in five grasshopper species belonging to the Acridomorpha group through permanent in situ hybridization (PISH). The mapping revealed one copy of this gene in the L1 chromosome pair in Ommexecha virens, Xyleus discoideus angulatus, Tropidacris collaris, Schistocerca pallens, and Stiphra robusta. A possible second copy was mapped on the L2 chromosome pair in S. robusta, which should be confirmed by further studies. Except for the latter case, the chromosomal position of the Period gene was highly conserved among the four families studied. The S. robusta karyotype also differs from the others both in chromosome number and morphology. The position conservation of the single-copy gene Period contrasts with the location diversification of multigene families in these species. The localization of single-copy genes by PISH can provide new insights about the genomic content and chromosomal evolution of grasshoppers and others insects. PMID- 25526204 TI - Multidrug resistance gene and its relationship to ulcerative colitis and immune status of ulcerative colitis. AB - We examined the relationship among the multidrug resistance (MDR1) gene product P glycoprotein (P-gp), ulcerative colitis, and immune status under ulcerative colitis. MDR1 P-gp expression and interleukin-8 levels in ulcerative colitis were determined using immunohistochemistry and a double-antibody sandwich avidin biotin complex-enzyme-linked immunosorbent assay, respectively. Nitric oxide content and nitric oxide synthase activity in the colonic mucosa were determined using a colorimetric method; CD4(+) and CD25(+) T cell subset percentages in the peripheral blood were determined by flow cytometry. The positive expression rate of P-gp in patients with ulcerative colitis (17.4%) was significantly lower than that in the control group (31.4%). The expression rate decreased to 10.1, 9.2, and 8.3% after 12, 18, and 24 months of treatment, respectively, which were significantly lower than the expression rate before treatment (17.4%). P-gp expression levels during the remission phase and active phase of ulcerative colitis were 15.2 and 17.1%, respectively, which were significantly lower than that in normal controls (31.4%). Compared with P-gp-negative patients, nitric oxide content, nitric oxide synthase activity, and interleukin-8 levels were significantly higher in P-gp-positive patients with moderately active, severely active, early onset, chronic relapsing, chronic persistent, and acute fulminant ulcerative colitis. CD4(+) and CD25(+) T cell subsets were significantly lower in the peripheral blood of patients with severely active and acute fulminant ulcerative colitis than in control subjects. Expression of the multidrug resistance gene and its product P-gp was observed in normal colon tissues and may be closely related to ulcerative colitis. PMID- 25526205 TI - Isolation and expression studies of the ERD15 gene involved in drought-stressed responses. AB - The early response to the dehydration 15 (ERD15) gene is widely involved in the processes of signal transduction, programmed cell death, gene transcription, and stress tolerance in plants. In a previous study, the ERD15 gene was shown to be an important regulator of the abscisic acid response and salicylic acid-dependent defense pathway, acting as an important negative regulator of abscisic acid. The complete IbERD15 gene (accession No. KF723428) was isolated by reverse transcription-polymerase chain reaction. The IbERD15 gene contains an open reading frame of 504 bp, encodes a peptide of 167 amino acids, and has a molecular mass of 18.725 kDa. The transcript levels of the IbERD15 gene in a variety of tissues were examined by digital gene expression profiling. The roots of the sweet potato were treated by 3 degrees of polyethylene glycol, and the results indicate that the IbERD15 gene might play an important role in the defense response to drought stress. Moreover, the IbERD15 gene was successfully transformed into yeast cells for analysis of drought tolerance in transgenic yeast. PMID- 25526206 TI - A novel method for identifying SNP disease association based on maximal information coefficient. AB - To improve single-nucleotide polymorphism (SNP) association studies, we developed a method referred to as maximal information coefficient (MIC)-based SNP searching (MICSNPs) by employing a novel statistical approach known as the MIC to identify SNP disease associations. MIC values varied with minor allele frequencies of SNPs and the odds ratios for disease. We used a Monte Carlo-based permutation test to eliminate the effects of fluctuating MIC values and included a sliding-window based binary search whose time-cost was 0.58% that of a sequential search to save time. The experiments examining both simulation and actual data demonstrated that our method is computationally and statistically feasible after reducing the resampling count to 4 times the number of markers and applying a sliding-window based binary search to the method. We found that our method outperforms existing approaches. PMID- 25526207 TI - New loci of Lychnophora ericoides and transferability to Lychnophora pinaster, endangered medicinal species from Brazil. AB - Lychnophora ericoides and Lychnophora pinaster are species used in popular medicine as analgesic or anti-inflammatory agents to treat contusions, rheumatism, and insect bites. In this study, 21 simple sequence repeat loci of L. ericoides were developed and transferred to L. pinaster. Three populations of L. ericoides and 2 populations of L. pinaster were evaluated; they were collected in the State of Minas Gerais. Population parameters were estimated, and the mean values of observed and expected heterozygosity were 0.297 and 0.408 (L. ericoides) and 0.228 and 0.310 (L. pinaster), respectively. Greater genetic variability was observed within populations than between populations of L. ericoides (62 and 37%) and L. pinaster (97 and 2.8%). These results provide information for genetic conservation and taxonomic studies of these endangered species. PMID- 25526208 TI - Association between p53 codon 72 polymorphisms and clinical outcome of nasopharyngeal carcinoma. AB - We conducted a cohort study to investigate whether polymorphisms in p53 at codon 72 are associated with tumor response and survival time of advanced nasopharyngeal carcinoma (NPC) patients treated with radiotherapy. The study population included 127 subjects with NPC who were enrolled at Binzhou Medical University between September 2008 and December 2009. Cox proportional hazard regression was used to assess the association between polymorphisms in the p53 gene and progression-free survival (PFS) and overall survival (OS) of NPC patients. During the follow-up period, 42 patients died and 72 patients showed progression at the end of the study. Of the 127 patients, median PFS was 22.5 +/- 1.2 months (1-36 months), and the median OS time was 28.2 +/- 1.1 months (2-36 months). The p53 codon 72 Pro/Pro genotype was associated with a longer median PFS time of 30.3 months compared with 18.2 months for patients with Arg/Arg variants. Moreover, the p53 codon 72 Pro/ Pro genotype was associated with a longer median OS time of 31.6 months compared with 25.8 months for those with Arg/Arg variants; the P value was marginally significant. We showed that variants in p53 codon 72 may be an independent predictor for PFS and OS of NPC patients. PMID- 25526209 TI - Evaluating the annotation of protein-coding genes in bacterial genomes: Chloroflexus aurantiacus strain J-10-fl and Natrinema sp J7-2 as case studies. AB - Gene annotation plays a key role in subsequent biochemical and molecular biological studies of various organisms. There are some errors in the original annotation of sequenced genomes because of the lack of sufficient data, and these errors may propagate into other genomes. Therefore, genome annotation must be checked from time to time to evaluate newly accumulated data. In this study, we evaluated the gene density of 2606 bacteria or archaea, and identified 2 with extreme values, the minimum value (Chloroflexus aurantiacus strain J-10-fl) and maximum value (Natrinema sp J7-2), to conduct genome re-annotation. In the genome of C. aurantiacus strain J-10-fl, we identified 17 new genes with definite functions and eliminated 34 non-coding open-reading frames; in the genome of Natrinema sp J7-2, we eliminated 118 non-coding open reading frames. Our re annotation procedure may provide a reference for improving the annotation of other bacterial genomes. PMID- 25526210 TI - Use of elephant grass for energy production in Campos dos Goytacazes-RJ, Brazil. AB - Elephant grass is a tropical forage plant widely distributed throughout Brazil. It was first exclusively used in the livestock sector as cattle feed. The grass is characterized by its high productivity and photosynthetic capacity and is considered as an alternative source of renewable energy. Here, we estimated the general combining ability of the parents and specific combining ability of the hybrids based on morpho-agronomic biomass-quality traits. The experiment was conducted in a randomized block design with 3 replicates. The diallel was composed of 16 hybrids and 2 groups of genitors. In the diallel analysis of variance, we observed a significant difference among treatments. A significant difference was observed among genitors for dry matter production (DMP). For the general combining ability of group 1, the traits leaf blade width, DMP, height, percentage of neutral detergent fiber, percentage of hemicellulose, percentage of lignin, percentage of acid detergent fiber, and percentage of cellulose were significant. For the estimates of general combining ability of DMP, parents Porto Rico 534-B, Vruckwona, Taiwan A-146, and Mercker S. E. A. were 0.4748, 3.2819, 1.1659, and 0.4317. The parents of Mercker S. E. A. and Porto Rico 534-B produced the highest percentage of detergent fiber and percentage of lignin with values of 0.1482 and 0.0856. Thus, parents Vruckwona, Porto Rico 534-B, and Taiwan A-146 are promising for integration into breeding programs. The best hybrid combinations for DMP were 1 x 5, 1 x 8, 2 x 6, 3 x 7, and 4 x 5. PMID- 25526211 TI - Clinical study on gastric cancer susceptibility genes IL-10-1082 and TNF-alpha. AB - TNF 308 gene polymorphism and IL-10 polymorphism provided evidence in diagnosing some types of cancer. We aimed to explore the relation of gene polymorphism with gastric cancer. A total of 360 cases of gastric cancer patients were included in the study. The genotypes GG, GA, and AA of the interleukin-10-1082 gene (IL-10 1082) and the tumor necrosis factor-alpha gene (TNF-alpha) 308 polymorphism were examined by chromogenic detection. Three hundred healthy individuals' gene as control group were also examined. The GA 308 genotype of TNF-alpha differed significantly between the control group and the gastric cancer group (X(2) = 9.32, P < 0.05). Genotype frequencies of A/A (17.2%), A/G (26.2%), and G/G (9.1%) of the IL-10-1082 gene polymorphism in the gastric cancer group differed significantly compared to those of the control group (X(2) = 20.32, P < 0.05). The IL-10-1082 gene and the GA 308 genotype of the TNF-alpha gene were found to be susceptibility genes for gastric cancer. PMID- 25526212 TI - CoffeebEST: an integrated resource for Coffea spp expressed sequence tags. AB - Coffee is one of the most important commodities in the world, and its production relies mainly on two species, Coffea arabica and Coffea canephora. Although there are diverse transcriptome datasets available for coffee trees, few research groups have exploited the potential knowledge contained in these data, especially with respect to fruit and seed development. Here, we present a comparative analysis of the transcriptomes of Coffea arabica and Coffea canephora with a focus on fruit development using publicly available expressed sequence tags (ESTs). Most of the fruit and seed EST data has been obtained from C. canephora. Therefore, we performed a fruit EST analysis of the 5 developmental stages of this species (18, 22, 30, 42, and 46 weeks after flowering) comprising 29,009 sequences. We compared C. canephora fruit ESTs to reference unigenes of C. canephora (7710 contigs and 8955 singletons) and C. arabica (15,656 contigs and 16,351 singletons). Additional analyses included functional annotation based on Gene Onthology, as well as an annotation using PlantCyc, a curated plant protein database. The Coffee Bean EST (CoffeebEST) is a public database available at http://bioinfo-02.cp.utfpr.edu.br/. This database represents an additional resource for the coffee scientific community, offering a user-friendly collection of information for non-specialists in coffee molecular biology to support experimental research on comparative and functional genomics. PMID- 25526213 TI - Protocol to cryopreserve and isolate nuclei from adipose tissue without dimethyl sulfoxide. AB - Cryopreservation injuries involve nuclear DNA damage. A protocol for cryopreserving and isolating adipocyte nuclei is proposed. Adipose tissue samples were directly analyzed (NoCRYO-0h), or stored at -196 degrees C for 7 days without 10% dimethyl sulfoxide (DMSO) (CRYO-WO-DMSO) or with DMSO (CRYO-W-DMSO). To determine the effect of DMSO on cryopreservation treatment, adipose tissue samples were stored at 4 degrees C for 24 h with 10% DMSO (NoCRYO-W-DMSO-24h) and without (NoCRYO-WO-DMSO-24h). Samples were processed in isolation buffer, and nuclear integrity was measured by flow cytometry. The coefficient of variation, forward scatter, side scatter, and number of nuclei analyzed were evaluated. Pea (Pisum sativum) was used to measure the amount of DNA. All groups contained similar amounts of DNA to previously reported values and a satisfactory number of nuclei were analyzed. CRYO-W-DMSO presented a higher coefficient of variation (3.19 +/- 0.09) compared to NoCRYO-0h (1.85 +/- 0.09) and CRYO-WO-DMSO (2.02 +/- 0.02). The coefficient of variation was increased in NoCRYO-W-DMSO-24h (3.80 +/- 0.01) compared to NoCRYO-WO-DMSO-24h (2.46 +/- 0.03). These results relate DMSO presence to DNA damage independently of the cryopreservation process. CRYO-W-DMSO showed increased side scatter (93.46 +/- 5.03) compared to NoCRYO-0h (41.13 +/- 3.19) and CRYO-WO-DMSO (48.01 +/- 2.28), indicating that cryopreservation with DMSO caused chromatin condensation and/or nuclear fragmentation. CRYO-W-DMSO and CRYO-WO-DMSO presented lower forward scatter (186.33 +/- 9.33 and 196.89 +/- 26.86, respectively) compared to NoCRYO-0h (322.80 +/- 3.36), indicating that cryopreservation reduced nuclei size. Thus, a simple method for cryopreservation and isolation of adipocyte nuclei causing less damage to DNA integrity was proposed. PMID- 25526214 TI - Sequence characterization and comparative analysis of the gastrotropin gene in buffalo (Bubalus bubalis). AB - In this study, we compared the complete sequence of the FABP6 gene from an animal representing the Murrah breed of the river buffalo (Bubalus bubalis) with the gene sequence from different mammals. The buffalo FABP6 gene is 6105 bp in length and is organized into four exons (67, 176, 90, and 54 bp), three introns (1167, 1737, and 2649 bp), a 5?UTR (93 bp), and a 3?UTR (72 bp). A total of 22 repetitive elements were identified at the intronic level, and four of these (L1MC, L1M5, MIRb, and Charlie4z) were identified as being exclusive to buffalo. Comparative analysis between the FABP6 gene coding sequence and the amino acid sequence with its homologues from other mammalian species showed a percentage of identity varying from 79 to 98% at the DNA coding level and 70 to 96% at the amino acid level. In addition, the alignment of the gene sequence between the Murrah and the Mediterranean breeds revealed 20 potential single nucleotide polymorphisms, which could be candidates for validation in commercial buffalo populations. PMID- 25526215 TI - Genetic evaluation of milk yield in Alpine goats for the first four lactations using random regression models. AB - Random regression models have been used in evaluating test-day milk yield, providing accurate estimates of genetic values in animals. However, herd evaluation with only information from the first lactation may not be the best option from an economic perspective. Other factors should be taken into account, particularly other lactations. Our objective in this study was to analyze the genetic divergence between the first four lactations of Alpine goats. The RENPED software was used to perform descriptive statistics, check for errors in pedigree, recode the data, and for Pearson's and Spearman's correlations. The WOMBAT software was used to estimate the variance components and predict the breeding values. The CALC software was adopted to calculate the percentage of coincidence between the ranking of the animals and the animals kept in common at each lactation evaluation. The results show that selection using only the first lactation in small herds with a low degree of technology can be employed as a palliative measure, in view of the difficulty in evaluating all lactations. However, the selection of breeding goats and the production of catalogues should not be based only on the first lactation, because the results demonstrate inversions in the classification of the best breeders when other lactations are analyzed. PMID- 25526217 TI - Cloning and characterization of a SnRK2 gene from Jatropha curcas L. AB - Although the SnRK2 class of Ser/Thr protein kinases is critical for signal transduction and abiotic stress resistance in plants, there have been no studies to examine SnRK2 in Jatropha curcas L. In the present study, JcSnRK2 was cloned from J. curcas using the rapid amplification of cDNA end technique and characterized. The JcSnRK2 genomic sequence is 2578 base pairs (bp), includes 10 exons and 9 introns, and the 1017-bp open reading frame encodes 338 amino acids. JcSnRK2 was transcribed in all examined tissues, with the highest transcription rate observed in the roots, followed by the leaves and stalks; the lowest rate was observed in flowers and seeds. JcSnRK2 expression increased following abscisic acid treatment, salinity, and drought stress. During a 48-h stress period, the expression of JcSnRK2 showed 2 peaks and periodic up- and downregulation. JcSnRK2 was rapidly activated within 1 h under salt and drought stress, but not under cold stress. Because of the gene sequence and expression similarity of JcSnRK2 to AtSnRK2.8, primarily in the roots, an eukaryotic expression vector containing the JcSnRK2 gene (pBI121-JcSnRK2) was constructed and introduced to the Arabidopsis AtSnRK2.8 mutant snf2.8. JcSnRK2-overexpressing plants exhibited higher salt and drought tolerance, further demonstrating the function of JcSnRK2 in the osmotic stress response. J. curcas is highly resistant to extreme salt and drought conditions and JcSnRK2 was found to be activated under these conditions. Thus, JcSnRK2 is potential candidate for improving crop tolerance to salt and drought stress. PMID- 25526216 TI - Preoperative chemotherapy with a trastuzumab-containing regimen for a patient with gastric cancer and hepatic metastases. AB - Gastric cancer is the fourth most common cancer worldwide and the leading cause of tumor-related death in China. Gastric cancer is a heterogeneous disease and therefore requires different treatments based on the subtype. We describe a patient who had gastric cancer with liver metastases. Biopsy and tumor analysis using the HercepTest revealed a human epidermal growth factor receptor 2 (HER2) positive adenocarcinoma as confirmed by fluorescence in situ hybridization. The patient was treated with a regimen of trastuzumab, oxaliplatin, and S-1 (six cycles). When positron emission tomography findings suggested that the metastases had resolved, the patient underwent surgery. Histopathologically, no cancer cells were observed in the resected hepatic tissue. The patient underwent tumor resection surgery, during which the tumor and gastric lymph nodes with lesions were removed. The patient has remained disease-free for 3 months. Therefore, trastuzumab may be an effective agent in the chemotherapeutic treatment of liver metastases in patients with HER2-positive gastric adenocarcinoma. PMID- 25526218 TI - Infection of Plasmodiophora brassicae in Chinese cabbage. AB - Brassica crops infected by Plasmodiophora brassicae can produce root galls (clubroots) and be prevented from growing normally. To understand the series of changes that occur in the host root during root gall production, the resistance character of 21 Chinese cabbage lines were identified and then resistant and susceptible lines were used for infection observation. Hydroponic technology system was used for plants growing, and the infection process of P. brassicae in the roots of resistant and susceptible Chinese cabbage was examined based on morphology and microscopic characteristics using micoscope. In susceptible Chinese cabbage, the root hair infection stage occurred over approximately 7 days after inoculation, the cortical infection happened over approximatly 14 days after inoculation, and clubroots formed in approximately 30 days after inoculation. However, in resistant Chinese cabbage, the pathogen could be prevented and maintained in the root hair infection stage. This research provides a foundation for the subsequent studies of cabbage resistance of P. brassicae. PMID- 25526219 TI - Gene expression of antioxidant enzymes and coffee seed quality during pre- and post-physiological maturity. AB - Seeds collected at different maturation stages vary in physiological quality and patterns of protective antioxidant systems against deterioration. In this study we investigated the expression of genes that codify catalase (CAT), dismutase superoxide (SOD), and polyphenol oxidase (PPO) during the pre- and post physiological maturation phases in whole seeds and in endosperms and embryos extracted from the seeds. Coffea arabica L. berries were collected at the green, yellowish-green, cherry, over-ripe, and dry stages, and the seeds were examined physiologically. The transcription levels of the genes were quantified by quantitative real-time polymerase chain reaction using coffee-specific primers. The highest level of SOD expression was observed in the endosperm at the cherry and over-ripe stages; in addition, these seeds presented the greatest physiological quality (assessed via germination test). The highest CAT3 transcript expression was observed at the green stage in whole seeds, and at the green and over-ripe stages in the embryos and endosperms. High expression of the PPO transcript was observed at the green and yellowish-green stages in whole seeds. In embryos and endosperms, peak expression of the PPO transcript was observed at the green stage; subsequently, peaks at the cherry and over-ripe stages were observed. We concluded that the expression patterns of the SOD and CAT3 transcripts were similar at the more advanced maturation stages, which corresponded to enhanced physiological seed quality. High expression of the PPO transcript at the over-ripe stage, also observed in the embryos and endosperms at the cherry stage, coincided with the highest physiological seed quality. PMID- 25526220 TI - Molecular cloning and characterization of the full-length Hsp90 gene from Matricaria recutita. AB - Heat shock protein 90 (Hsp90) is one of the most abundant and conserved chaperone proteins and plays important roles in plant growth and responses to environmental stimuli. However, little is known regarding the sequence and function of Hsp90s in Matricaria recutita. In the present study, we cloned the full-length cDNA sequence of the hsp90 gene from this species. Using rapid amplification of cDNA ends technologies with 2 degenerate primers that were designed based on the hsp90 gene sequence from other members of Asteraceae, we isolated and characterized an Hsp90 homolog gene from M. recutita (Mr-Hsp90). The full-length Mr-hsp90 cDNA sequence, containing 2097 base pairs, encodes a protein of 698 amino acids. Based on amino acid sequence identity, Mr-Hsp90 showed high similarity to other cloned Hsp90 proteins. The Mr-Hsp90 protein was closely clustered with the Lactuca sativa in a phylogenetic tree. These results indicate that the cloned sequence of Mr-Hsp90 is a member of the Hsp90 family, which is reported for the first time in M. recutita. Next, we conducted a salt stress experiment to determine the protein's function under salt stress conditions. Survival of chamomile seedlings subjected to heat-shock pretreatment was significantly increased compared with groups that had not undergone heat-shock pretreatment in a salt stress environment. This indicates that Mr-Hsp90 plays an important role in the salt resistance of chamomile seedlings. PMID- 25526222 TI - Application of two direct C(sp3)-H functionalizations for total synthesis of (+) lactacystin. AB - Herein, we report a new synthetic route from (S)-pyroglutaminol to (+) lactacystin, a potent inhibitor of the 20S proteasome. The photoinduced intermolecular C(sp(3))-H alkynylation and intramolecular C(sp(3))-H acylation chemo- and stereoselectively constructed the tetra- and trisubstituted carbon centers, respectively. The obtained bicycle was transformed into the target compound in a concise manner. The present total synthesis demonstrates the power of the direct C(sp(3))-H functionalizations for the assembly of multiple functionalized structures of natural products. PMID- 25526221 TI - [Propensity score comparison of the various radical surgical techniques for high risk prostate cancer]. AB - INTRODUCTION: The optimal surgical treatment of patients with a high risk prostate cancer (PCa) in terms of radical prostatectomy (RP) is still controversial: open retropubic RP (RRP), laparoscopic RP (LRP), or robot-assisted (RARP). We aimed to investigate the influence of the different surgical techniques on pathologic outcome and biochemical recurrence. PATIENTS AND METHODS: A total of 805 patients with a high risk PCa (PSA >20 ng/mL, Gleason Score >=8, or clinical stage >=cT2c) were included. A comparison of 407 RRP patients with 398 minimally invasive cases (LRP+RARP) revealed significant confounders. Therefore all 110 RARP cases were propensity score (PS) matched 1:1 with LRP and RRP patients. PS included age, clinical stage, preoperative PSA, biopsy Gleason score, surgeon's experience and application of a nerve sparing technique. Comparison of overall survival (OS) and recurrence-free survival (RFS) was done with the log rank test. Predictors of RFS were analyzed by means of Cox regression models. RESULTS: Within the post-matching cohort of 330 patients a pathologic Gleason score < 7, = 7 and > 7 was found in 1.8, 55.5 and 42.7% for RARP, in 8.2, 36.4, 55.5% for LRP and in 0, 60.9 and 39.1% for RRP (p=0.004 for RARP vs. LRP and p=0.398 for RARP vs. RRP). Differences in histopathologic stages were not statistically significant. The overall positive surgical margin rate (PSM) as well as PSM for >= pT3 were not different. PSM among patients with pT2 was found in 15.7, 14.0 and 20.0% for RARP, LRP and RRP (statistically not significant). The respective mean 3-year RFS rates were 41.4, 77.9, 54.1% (p<0.0001 for RARP vs. LRP and p=0.686 for RARP vs. RRP). The mean 3-year OS was calculated as 95.4, 98.1 and 100% respectively (statistically not significant). CONCLUSION: RARP for patients with a high risk PCa reveals similar pathologic and oncologic outcomes compared with LRP and RRP. PMID- 25526223 TI - Regulating the cytoprotective response in cancer cells using simultaneous inhibition of Hsp90 and Hsp70. AB - Both heat shock protein 90 and 70 (Hsp90, Hsp70) are cytoprotective proteins that regulate cell death by stabilizing and folding proteins. Taking a two-pronged approach, involving simultaneous inhibition of Hsp90 and Hsp70, leads to synergistic cell death, which makes this is an appealing clinical therapy. PMID- 25526224 TI - Screening instruments for depression in primary care: a concise review for clinicians. AB - Depression is prevalent across the life span worldwide. It is a common problem encountered in primary care settings. The World Health Organization recommends the integration of mental health into general health care in order to seal the existing gap between the number of patients who need mental health care and those who actually receive it. Addressing the burden of mental health problems in primary care settings has its limitations, particularly because of the time constraints in busy primary care clinics as well as the inadequate training of staff and physicians in mental health disorders. That is why reliable, brief, and easy to administer depression screening instruments are important in helping physicians identify patients at risk. The 2-item Patient Health Questionnaire (PHQ-2) is a suitable primary screening tool for depression. If positive, other tools should be administered, such as the PHQ-9 in adults, the PHQ-9 or Geriatric Depression Scale-15 in older adults, or the Arroll's help question or the Edinburgh Postnatal Depression Scale in ante- or postpartum women. Patients with positive scores ought to be interviewed more thoroughly. Computerized depression screening instruments that are interfaced or integrated into electronic health records seem to be promising steps toward optimizing diagnosis, treatment, and follow-up. The availability of adequate management and follow-up are ethical requirements for the utilization of any screening instrument for depression. PMID- 25526225 TI - Erectile dysfunction and cardiovascular disease. AB - Erectile dysfunction (ED) is often a comorbid condition commonly associated with cardiovascular disease (CVD). It is important for physicians to understand that the relationship between ED and CVD is not a coincidence but rather a warning signal. The fact that the symptoms of ED normally arise before the symptoms of a cardiovascular event gives physicians the unique opportunity to see the possible future of their patients' cardiovascular health. Vascular disease is the most common cause of ED. This article reviews the incidence of CVD and ED, the pathophysiology of ED, the risk factors associated with ED and CVD, and the evaluation and treatment options for men with ED, and discusses how ED may serve as an early warning for cardiovascular disease. PMID- 25526226 TI - Acute histopathological responses of testicular tissues after different fractionated abdominal irradiation in rats. AB - PURPOSE: To compare the effects of different fractionated doses of abdominal radiation therapy on acute histopathological responses of testicular tissues in rats. METHODS: Thirty-three 3-week-old Wistar albino rats were randomized into 6 groups: group 1 (n = 5), control; group 2 (n = 4), hypofractionated total abdominal irradiation (TAI) of 6 Gy/1 fraction/day for 2 days; group 3 (n = 6), hypofractionated TAI of 4 Gy/1 fraction/day for 3 days; group 4 (n = 6), hypofractionated TAI of 3 Gy/1 fraction/day for 4 days; group 5 (n = 6), conventionally fractionated TAI of 2 Gy/1 fraction/day for 6 days; group 6 (n = 6), conventionally fractionated TAI of 1.7 Gy/1 fraction/day for 7 days. Mean epithelial length and diameter of seminiferous tubules of testicular tissues were determined after euthanasia. RESULTS: Initially, a highly significant decrease in both the mean tubular diameter and epithelial height of the seminiferous tubules was demonstrated in all irradiated rats compared with the control group. No significant differences regarding both damage parameters were found between different hypofractionated radiation therapies. Both conventional radiation therapies reduced the epithelial height and mean diameter of the seminiferous tubules to a lesser extent when compared with 6 Gy/1 fraction/day hypofractionated therapy. It was further shown that parameter values were comparable between rats that received 3 Gy/day hypofractionated therapy and rats that received either of the two conventional therapies. Furthermore, although 4 Gy/day hypofractionation decreased tubular diameter and epithelial length to a greater degree compared with the conventional therapy of 1.7 Gy/1 fraction/day, no statistically significant difference was found when compared with conventional therapy of 2 Gy/1 fraction/day. Additionally, no statistically significant difference was demonstrated between the two types of conventional radiotherapy application. CONCLUSION: The present study demonstrated that hypofractionated abdominal irradiation leads to more prominent tissue damage in the testes than conventional irradiation. PMID- 25526227 TI - Efficacy and safety of once-daily, extended-release hydrocodone in individuals previously receiving hydrocodone/acetaminophen combination therapy for chronic pain. AB - BACKGROUND: Hydrocodone/acetaminophen combination analgesics are frequently prescribed for chronic pain management; however, acetaminophen presents potential hepatotoxicity to patients and thus dose limitations. These opioid medications are also widely abused. Once-daily, single-entity hydrocodone (HysinglaTM ER tablets [HYD]) is a novel formulation with abuse-deterrent properties for the management of chronic pain and represents a suitable option for those patients receiving analgesics containing the same opioid analgesic, hydrocodone. This post hoc analysis evaluated the efficacy and safety of HYD in patients whose primary pre-study analgesic was hydrocodone/acetaminophen analgesics (23-31% of the study populations). METHODS: Data were analyzed from two Phase III trials, a 12-week randomized, placebo-controlled trial (RCT) and an open-label, 52-week trial. In both trials, a dose-titration period with HYD was followed by respective periods of fixed-dose double-blind (randomized controlled trial [RCT]) or open-label, flexible-dose maintenance treatment. Pain intensity was assessed using a numerical rating scale (0-10, 0 = no pain). For the RCT, primary and sensitivity analyses of pain scores used different approaches to handle missing data. Safety data for both studies were summarized. RESULTS: In the RCT, the mean baseline pain score was 7.3. Pain relief was greater with HYD than placebo during double blind treatment. In the open-label, flexible-dose trial, the majority of patients were maintained on their titrated dose. Mean baseline pain score was 6.3, about 57% of patients completed the 1-year maintenance period, and mean pain scores were between 3.6 and 4.1 during the maintenance period. Use of supplemental pain medication decreased or was maintained during the maintenance treatment with HYD. Adverse events in both trials were typical of those associated with opioid analgesics. CONCLUSION: In patients whose primary pretrial analgesic was hydrocodone/acetaminophen combination tablets, single-entity HYD was effective in reducing pain intensity and in maintaining analgesia over time without need for continued dose increase. HYD's safety and tolerability profiles were similar to other opioid analgesics. PMID- 25526229 TI - Buprenorphine transdermal system compared with placebo reduces interference in functioning for chronic low back pain. AB - OBJECTIVE: This study examines the efficacy of the buprenorphine transdermal system (BTDS) for reducing the interference of pain on physical and emotional functioning associated with chronic low back pain (CLBP). METHODS: A post-hoc analysis used data from a randomized, placebo-controlled, double-blind trial of patients with moderate-to-severe CLBP. The Brief Pain Inventory (BPI) measured pain interference at screening, following a run-in period, and during the 12-week double-blind treatment phase. Statistical analyses examined treatment arm differences (BTDS vs placebo) for the following: BPI Interference subscale items and subscale scores at the trial end point (week 12); patterns of change in the Interference subscale scores over time; proportions of patients indicating mild or no interference following treatment; and proportions of patients showing improvement (30%, 50%, 2-point, or 4-point change in score from screening to week 12) for each item and subscale. RESULTS: Mean scores for BPI Interference items and Interference subscale were significantly lower (ie, indicated less interference) for BTDS than for placebo (all P < 0.001). Treatment arm differences in Interference subscale scores emerged within 4 weeks of treatment. The BTDS patients were significantly more likely to indicate mild/no interference on 5 of 7 Interference subscale items following treatment (P < 0.05). For most comparisons, BTDS patients were significantly more likely to show criterion-level improvements in Interference item and subscale scores (P < 0.05 for differences). DISCUSSION: Results indicate the efficacy of BTDS treatment, compared with placebo, for reducing the interference of pain on physical and emotional functioning in patients with moderate-to-severe CLBP. The advantage of BTDS was observed within 4 weeks of treatment, and was maintained throughout the 12-week treatment phase. PMID- 25526230 TI - Hormone abnormalities in patients with severe and chronic pain who fail standard treatments. AB - Some patients with severe and chronic pain fail to obtain adequate pain relief with standard pharmacologic treatment agents, including low to moderate dosages of opioids. Understandably, physicians might not believe patients who claim that a standard opioid dosage is an ineffective treatment. These patients may be severely impaired, nonfunctional, and bedridden or housebound. To help characterize these individuals and develop treatment strategies for them, a serum hormone profile consisting of adrenocorticotropin, cortisol, pregnenolone, progesterone, dehydroepiandrosterone, and testosterone was obtained on 61 chronic pain patients who failed standard treatments; 49 patients (80.3%) demonstrated >= 1 hormone abnormality defined as a serum concentration or level above or below the normal range, and 7 patients (11.5%) showed a severe pituitary-adrenal gonadal deficiency as indicated by deficient serum levels of adrenocorticotropin and >= 2 adrenal-gonadal hormones. Hormone serum abnormalities are biomarkers of severe, uncontrolled pain, and, in a patient who has failed standard treatment, they are an indicator that enhanced analgesia is required and that hormone replacement may be indicated. PMID- 25526228 TI - rsfMRI effects of KB220ZTM on neural pathways in reward circuitry of abstinent genotyped heroin addicts. AB - Recently, Willuhn et al. reported that cocaine use and even non-substance-related addictive behavior increases as dopaminergic function is reduced. Chronic cocaine exposure has been associated with decreases in D2/D3 receptors and was also associated with lower activation of cues in occipital cortex and cerebellum, in a recent PET study by Volkow's et al. Therefore, treatment strategies, like dopamine agonist therapy, that might conserve dopamine function may be an interesting approach to relapse prevention in psychoactive drug and behavioral addictions. To this aim, we evaluated the effect of KB220ZTM on reward circuitry of 10 heroin addicts undergoing protracted abstinence (average 16.9 months). In a randomized placebo-controlled crossover study of KB220Z, five subjects completed a triple-blinded experiment in which the subject, the person administering the treatment, and the person evaluating the response to treatment were blinded to the treatment that any particular subject was receiving. In addition, nine subjects were genotyped utilizing the GARSDXTM test. We preliminarily report that KB220Z induced an increase in BOLD activation in caudate-accumbens-dopaminergic pathways compared to placebo following 1-hour acute administration. Furthermore, KB220Z also reduced resting-state activity in the putamen of abstinent heroin addicts. In the second phase of this pilot study of all 10 abstinent heroin dependent subjects, we observed that three brain regions of interest were significantly activated from resting state by KB220Z compared to placebo (p < 0.05). Increased functional connectivity was observed in a putative network that included the dorsal anterior cingulate, medial frontal gyrus, nucleus accumbens, posterior cingulate, occipital cortical areas, and cerebellum. These results and other quantitative electroencephalogy (qEEG) study results suggest a putative anti-craving/anti-relapse role of KB220Z in addiction by direct or indirect dopaminergic interaction. Due to small sample size, we caution definitive interpretation of these preliminary results, and confirmation with additional research and ongoing rodent and human studies of KB220Z is required. PMID- 25526231 TI - Mechanisms and efficacy of heat and cold therapies for musculoskeletal injury. AB - Nonpharmacological treatment strategies for acute musculoskeletal injury revolve around pain reduction and promotion of healing in order to facilitate a return to normal function and activity. Heat and cold therapy modalities are often used to facilitate this outcome despite prevalent confusion about which modality (heat vs cold) to use and when to use it. Most recommendations for the use of heat and cold therapy are based on empirical experience, with limited evidence to support the efficacy of specific modalities. This literature review provides information for practitioners on the use of heat and cold therapies based on the mechanisms of action, physiological effects, and the medical evidence to support their clinical use. The physiological effects of cold therapy include reductions in pain, blood flow, edema, inflammation, muscle spasm, and metabolic demand. There is limited evidence from randomized clinical trials (RCTs) supporting the use of cold therapy following acute musculoskeletal injury and delayed-onset muscle soreness (DOMS). The physiological effects of heat therapy include pain relief and increases in blood flow, metabolism, and elasticity of connective tissues. There is limited overall evidence to support the use of topical heat in general; however, RCTs have shown that heat-wrap therapy provides short-term reductions in pain and disability in patients with acute low back pain and provides significantly greater pain relief of DOMS than does cold therapy. There remains an ongoing need for more sufficiently powered high-quality RCTs on the effects of cold and heat therapy on recovery from acute musculoskeletal injury and DOMS. PMID- 25526232 TI - Safety of a novel formulation of ibuprofen sodium compared with standard ibuprofen and placebo. AB - BACKGROUND: Ibuprofen (IBU) is an efficacious over-the-counter analgesic/antipyretic with adverse event (AE) rates comparable to placebo. IBU sodium (IBU(Na)) is a newer, more soluble form that is absorbed faster than standard IBU, leading to more rapid analgesia. Although its safety and tolerability are expected to be comparable to standard IBU, this has not yet been reported. METHODS: Pooled analysis comparing the safety of single-dose IBU(Na) (512 mg; equivalent to 400 mg IBU free acid; n = 362) with standard IBU tablets (400 mg; n = 342) and placebo (n = 187) across five Phase III, randomized, placebo-controlled, double-blind studies evaluating IBU(Na) for treatment of postoperative dental pain, tension-type headache, or fever. RESULTS: Treatment emergent AEs (TEAEs) occurred in 5% of cases in the IBU(Na) group (25 events), 6.4% of cases in the standard IBU group (41 events), and 10.2% of cases in the placebo group (31 events). The most frequent TEAEs were in the following Medical Dictionary for Regulatory Activities (MedDRA) System Organ Classes: gastrointestinal disorders (2.8, 3.2, and 5.9% for IBU(Na), standard IBU, and placebo, respectively), nervous system disorders (1.4, 3.5, and 3.7% for IBU(Na), standard IBU, and placebo, respectively), and general disorders and administration-site conditions (1.1, 1.5, and 2.1% for IBU(Na), standard IBU, and placebo, respectively). Nausea was the most common TEAE (2.5, 2.6, and 5.9% for IBU(Na), standard IBU, and placebo, respectively). Only two AEs were considered related to treatment: pruritus (n = 1, IBU(Na)) and nausea (n = 1, placebo). Of those subjects reporting >= 1 TEAE, 44.4, 36.4, and 89.5% of subjects in the IBU(Na), standard IBU, and placebo groups, respectively, received rescue medication. CONCLUSION: IBU(Na) has a favorable safety profile comparable to those of standard IBU tablets and placebo in single-dose studies evaluating analgesic or antipyretic efficacy. ClinicalTrials.gov Registry Numbers: Dental pain studies: NCT01098747 and NCT01216163; headache studies: NCT01077973 and NCT01362491; pyresis study: NCT01035346. PMID- 25526233 TI - Eight principles for safer opioid prescribing and cautions with benzodiazepines. AB - The provision of long-term opioid analgesic therapy for chronic pain requires a careful risk/benefit analysis followed by clinical safety measures to identify and reduce misuse, abuse, and addiction and their associated morbidity and mortality. Multiple data sources show that benzodiazepines, prescribed for comorbid insomnia, anxiety, and mood disorders, heighten the risk of respiratory depression and other adverse outcomes when combined with opioid therapy. Evidence is presented for hazards associated with coadministration of opioids and benzodiazepines and the need for caution when initiating opioid therapy for chronic pain. Clinical recommendations follow, as drawn from 2 previously published literature reviews, one of which proffers 8 principles for safer opioid prescribing; the other review presents risks associated with benzodiazepines, suggests alternatives for co-prescribing benzodiazepines and opioids, and outlines recommendations regarding co-prescribing if alternative therapies are ineffective. PMID- 25526234 TI - Considerations regarding adherence of anti-osteoporosis therapy. AB - Osteoporosis remains a challenging disease to treat due to a number of barriers including patient adherence to therapies. One of the most recent advances has been the development of the Fracture Risk Assessment Tool, which is helpful in conveying fracture risk to patients and providing treatment guidance to clinicians. The decision to use an anti-osteoporosis therapy must be tailored to the patient's specific clinical scenario. The bisphosphonates are first-line agents in the treatment of osteoporosis and are efficacious in substantially reducing fracture risk between 25% and 70% on average depending on fracture site. Compliance with oral bisphosphonate pills can be poor, resulting in a significant deterrent to the proper management of osteoporosis. Non-pill forms of bisphosphonate and nonbisphosphonate therapy are available for the treatment of osteoporosis and may increase compliance. Among these is Binosto, a new formulation of weekly effervescent alendronate, as well as intravenous bisphosphonates, teriparatide, and subcutaneously administered denosumab, which are all costly medications and are unlikely to become the mainstay of treatment over the oral bisphosphonate pills. Having a detailed conversation between the patient and physician is essential to the development of a tailored treatment plan that will decrease fracture risk. PMID- 25526235 TI - Prevalence and treatment of hypertension in urban and riverside areas in Porto Velho, the Brazilian Amazon. AB - INTRODUCTION: Hypertension (HTN) is a preventable cause of cardiovascular morbidity and mortality. OBJECTIVES: To compare the prevalence, awareness, treatment, and control of HTN among urban and riverside populations in Porto Velho, Amazon region. METHODS: We conducted a cross-sectional study between July and December 2013 based on a household survey of individuals aged 35-80 years. Interviews by using a standardized questionnaire, and blood pressure (BP), weight, height, and waist circumference measurements were performed. HTN was defined when individuals reported having the disease, received antihypertensive medications, or had a systolic BP >= 140 mm Hg or diastolic BP >= 90 mm Hg. Awareness was based on self-reports and the use of antihypertensive medications. Control was defined as a BP <= 140/90 mm Hg. RESULTS: Among the 1410 participants, 750 (53.19%) had HTN and 473 (63.06%) had diagnosis awareness, of whom 404 (85.41%) received pharmacological treatment but with low control rate. The prevalence and treatment rates were higher in the urban areas (55.48% vs. 48.87% [p = 0.02] and 61.25% vs. 52.30% [p < 0.01], respectively). HTN awareness was higher in the riverside area (61.05% vs. 67.36% ; p < 0.01), but the control rates showed no statistically significant difference (22.11% vs. 23.43% ; p = 0.69). CONCLUSION: HTN prevalence was higher in the urban population than in the riverside population. Of the hypertensive individuals in both areas, <25% had controlled HTN. Comprehensive public health measures are needed to improve the prevention and treatment of systemic arterial HTN and prevent other cardiovascular diseases. PMID- 25526236 TI - Fluorescent polymeric assemblies as stimuli-responsive vehicles for drug controlled release and cell/tissue imaging. AB - Polymer assemblies with good biocompatibility, stimuli-responsive properties and clinical imaging capability are desirable carriers for future biomedical applications. Herein, we report on the synthesis of a novel anthracenecarboxaldehyde-decorated poly(N-(4-aminophenyl) methacryl amide oligoethyleneglycolmonomethylether methacrylate) (P(MAAPAC-MAAP-MAPEG)) copolymer, comprising fluorescent chromophore and acid-labile moiety. This copolymer can assemble into micelles in aqueous solution and shows a spherical shape with well-defined particle size and narrow particle size distribution. The pH-responsive property of the micelles has been evaluated by the change of particle size and the controlled release of guest molecules. The intrinsic fluorescence property endows the micelles with excellent cell/tissue imaging capability. Cell viability evaluation with human hepatocellular carcinoma BEL 7402 cells demonstrates that the micelles are nontoxic. The cellular uptake of the micelles indicates a time-dependent behavior. The H22-tumor bearing mice treated with the micelles clearly exhibits the tumor accumulation. These multi functional nanocarriers may be of great interest in the application of drug delivery. PMID- 25526237 TI - Detection of human polyomavirus 7 in human thymic epithelial tumors. AB - INTRODUCTION: Although the molecular genetics possibly underlying the pathogenesis of human thymoma have been extensively studied, its etiology remains poorly understood. Because murine polyomavirus consistently induces thymomas in mice, we assessed the presence of the novel human polyomavirus 7 (HPyV7) in human thymic epithelial tumors. METHODS: HPyV7-DNA Fluorescence in situ hybridization (FISH), DNA-polymerase chain reaction (PCR), and immunohistochemistry (IHC) were performed in 37 thymomas. Of these, 26 were previously diagnosed with myasthenia gravis (MG). In addition, 20 thymic hyperplasias and 20 fetal thymic tissues were tested. RESULTS: HPyV7-FISH revealed specific nuclear hybridization signals within the neoplastic epithelial cells of 23 thymomas (62.2%). With some exceptions, the HPyV7-FISH data correlated with the HPyV7-DNA PCR. By IHC, large T antigen expression of HPyV7 was detected, and double staining confirmed its expression in the neoplastic epithelial cells. Eighteen of the 26 MG-positive and 7 of the 11 MG-negative thymomas were HPyV7-positive. Of the 20 hyperplastic thymi, 40% were HPyV7-positive by PCR as confirmed by FISH and IHC in the follicular lymphocytes. All 20 fetal thymi tested HPyV7-negative. CONCLUSIONS: The presence of HPyV7-DNA and large T antigen expression in the majority of thymomas possibly link HPyV7 to human thymomagenesis. Further investigations are needed to elucidate the possible associations of HPyV7 and MG. PMID- 25526239 TI - A Sc(OTf)3-catalyzed cascade reaction of o-aminoacetophenone with methanamine: construction of dibenzo[b,h][1,6]naphthyridine derivatives. AB - An unexpected Sc(OTf)3-catalyzed and air-mediated cascade reaction of o aminoacetophenones with methanamines was discovered as an efficient synthetic approach to a novel class of fluorescent fused-four-ring dibenzo[b,h][1,6]naphthyridine derivatives. Two possible mechanisms of the reaction were proposed. The photophysical properties of the dibenzo[b,h][1,6]naphthyridine were initially considered. PMID- 25526238 TI - Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib. AB - BACKGROUND: Leptomeningeal metastases (LM) are an increasingly frequent and devastating complication of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Currently, the optimal management of LM in ALK-positive patients remains poorly understood as these patients have been routinely excluded from clinical trials. METHODS: We describe four ALK-positive patients with LM who were treated with the next-generation ALK inhibitor alectinib through single patient, compassionate use protocols at two institutions. All patients had previously been treated with both FDA-approved ALK inhibitors--crizotinib and ceritinib. Patients received alectinib at a starting dose of 600 mg twice daily. RESULTS: Four ALK-positive NSCLC patients with symptomatic leptomeningeal disease were identified. Three of four patients experienced significant clinical and radiographic improvements in LM upon treatment with alectinib. A fourth patient had stable intracranial disease for 4 months before eventual systemic disease progression. Overall, alectinib was well tolerated. One patient required dose reduction due to grade 2 hyperbilirubinemia. CONCLUSIONS: Alectinib is active in ALK-rearranged NSCLC patients with LM, including in patients previously treated with crizotinib and ceritinib. Additional prospective studies of alectinib in ALK positive patients with LM are warranted. PMID- 25526240 TI - The two-component model for calculating total body fat from body density: an evaluation in healthy women before, during and after pregnancy. AB - A possibility to assess body composition during pregnancy is often important. Estimating body density (DB) and use the two-component model (2CM) to calculate total body fat (TBF) represents an option. However, this approach has been insufficiently evaluated during pregnancy. We evaluated the 2CM, and estimated fat-free mass (FFM) density and variability in 17 healthy women before pregnancy, in gestational weeks 14 and 32, and 2 weeks postpartum based on DB (underwater weighing), total body water (deuterium dilution) and body weight, assessed on these four occasions. TBF, calculated using the 2CM and published FFM density (TBF(2CM)), was compared to reference estimates obtained using the three component model (TBF(3CM)). TBF(2CM) minus TBF(3CM) (mean +/- 2SD) was -1.63 +/- 5.67 (p = 0.031), -1.39 +/- 7.75 (p = 0.16), -0.38 +/- 4.44 (p = 0.49) and -1.39 +/- 5.22 (p = 0.043) % before pregnancy, in gestational weeks 14 and 32 and 2 weeks postpartum, respectively. The effect of pregnancy on the variability of FFM density was larger in gestational week 14 than in gestational week 32. The 2CM, based on DB and published FFM density, assessed body composition as accurately in gestational week 32 as in non-pregnant adults. Corresponding values in gestational week 14 were slightly less accurate than those obtained before pregnancy. PMID- 25526241 TI - Smokeless tobacco use and public health in countries of South-East Asia region. PMID- 25526242 TI - Influence of tobacco industry advertisements and promotions on tobacco use in India: findings from the Global Adult Tobacco Survey 2009-2010. AB - INTRODUCTION: The developing world, including countries like India, has become a major target for the tobacco industry to market its products. This study examines the influence of the marketing (advertising and promotion) of tobacco products on the use of tobacco by adults (ages 15 and over) in India. METHOD: Data from Global Adult Tobacco Survey 2009-2010 was analyzed using methods for complex (clustered) sample designs. Multivariate logistic regression was employed to predict the use of different tobacco products by level of exposure to tobacco marketing using adults who have never used tobacco as the reference category. Odds ratios (ORs) were adjusted for education, gender, age, state of residence, wealth index, and place of residence (urban/rural). RESULTS: Adults in India were almost twice as likely to be current smokers (versus never users) when they were exposed to a moderate level of bidi or cigarette marketing. For bidis, among adults with high exposure, the OR for current use was 4.57 (95% confidence interval [CI]: 1.6, 13.0). Adults were more likely to be current users of smokeless tobacco (SLT) with even a low level of exposure to SLT marketing (OR = 1.24 [95% CI: 1.1, 1.4]). For SLT, the ORs showed an increasing trend (P for trend < 0.001) with greater level of exposure (moderate, OR = 1.55 [95% CI: 1.1, 2.2]; high, OR = 2.05 [95% CI: 0.8, 5.1]). The risk of any current tobacco use rose with increasing level of exposure to any marketing (minimum, OR = 1.25 [1.1 1.4]; moderate, OR = 1.38 [1.1-1.8]; and high, OR = 2.73 [1.8-4.2]), with the trend highly significant (P < 0.001). CONCLUSION: Exposure to the marketing of tobacco products, which may take the form of advertising at the point of sale, sales or a discounted price, free coupons, free samples, surrogate advertisements, or any of several other modalities, increased prevalence of tobacco use among adults. An increasing level of exposure to direct and indirect advertisement and promotion is associated with an increased likelihood of tobacco use. PMID- 25526243 TI - Improvement in prevalence of tobacco use among teachers in Bihar after COTPA. AB - CONTEXT: A high prevalence of tobacco use, even among educated professionals like teachers, has been reported from Bihar. After passing of the Cigarette and Other Tobacco Products Act (COTPA) in 2003, there have been major improvements in tobacco control nationwide. AIMS: To compare tobacco use prevalence among school teachers in Bihar reported in 2000 with a survey in 2008 and investigate correlates of current and past tobacco-use. METHODS: Data from the baseline survey of a cluster random sample of 72 government schools conducted during the beginning of two consecutive school years was analyzed. RESULTS: The prevalence of current tobacco use was 35.5% and past use, 11.3%. Likelihood of current use compared with no use increased with age (odds ratio [OR] =3.27 for > 50 years compared to < 30, 95% confidence interval [CI]: [1.50, 7.13]); whereas that of past use compared to current use decreased (OR = 0.25, 95% CI: [0.09-0.68] for age > 50 years compared to < 30 years). DISCUSSION: Compared to the tobacco use prevalence among Bihar school teachers reported from a survey in the year 2000 (77.4%), the prevalence in this survey in 2008 was much lower and past use, much higher. In the earlier survey, lal dantmajan was counted as a tobacco product. If we do the same in the current survey, and consider ever use, the prevalence even then was 53.9%, lower than the earlier figure. Although the tobacco use among teachers in Bihar is still high, it has decreased after the implementation of COTPA and the cessation has increased. PMID- 25526244 TI - Prevalence and sociodemographic determinants of tobacco use in four countries of the World Health Organization: South-East Asia region: findings from the Global Adult Tobacco Survey. AB - INTRODUCTION: Tobacco use is a leading cause of deaths and Disability Adjusted Life Years lost worldwide, particularly in South-East Asia. Health risks associated with exclusive use of one form of tobacco alone has a different health risk profile when compared to dual use. In order to tease out specific profiles of mutually exclusive categories of tobacco use, we carried out this analysis. METHODS: The Global Adult Tobacco Survey (GATS) data was used to describe the profiles of three mutually exclusive tobacco use categories ("Current smoking only," "Current smokeless tobacco [SLT] use only," and "Dual use") in four World Health Organization South-East Asia Region countries, namely Bangladesh, India, Indonesia and Thailand. GATS was a nationally representative household-based survey that used a stratified multistage cluster sampling design proportional to population size. Prevalence of different forms of usage were described as proportions. Logistics regression analyses was performed to calculate odds ratios (OR) with 95% confidence intervals. All analyses were weighted, accounted for the complex sampling design and conducted using SPSS version 18. RESULTS: The prevalence of different forms of tobacco use varied across countries. Current tobacco use ranged from 27.2% in Thailand to 43.3% in Bangladesh. Exclusively smoking was more common in Indonesia (34.0%) and Thailand (23.4%) and less common in Bangladesh (16.1%) and India (8.7%). Exclusively using SLT was more common in Bangladesh (20.3%) and India (20.6%) and less common on Indonesia (0.9%) and Thailand (3.5%). Dual use of smoking and SLT was found in Bangladesh (6.8%) and India (5.3%), but was negligible in Indonesia (0.8) and Thailand (0.4%). Gender, age, education and wealth had significant effects on the OR for most forms of tobacco use across all four countries with the exceptions of SLT use in Indonesia and dual use in both Indonesia and Thailand. In general, the different forms of tobacco use increased among males and with increasing age; and decreased with higher education and wealth. The results for urban versus rural residence were mixed and frequently not significant once controlling for the other demographic factors. CONCLUSION: This study addressed the socioeconomic disparities, which underlie health inequities due to tobacco use. Tobacco control activities in these countries should take in account local cultural, social and demographic factors for successful implementation. PMID- 25526245 TI - Challenges of smokeless tobacco use in Myanmar. AB - Myanmar Tobacco Control Law of 2006 covers the control of all forms of tobacco use. After 7-year, tobacco use among adults did not see a decrease. The paper aimed to study the prevalence, details of the products, trade, legislation, tax, marketing, advertising and evidence on morbidity and mortality, and to make recommendations for policy options. Personal communications by authors and colleagues, and searches by keywords in PubMed and on Google, literature review and research from published reports, and various studies and surveys conducted in Myanmar and other countries. Smokeless tobacco use in Myanmar is the highest among ASEAN countries. A variety of SLT products used together with betel chewing poses a challenge; betel quid chewing has been accepted as a cultural norm in both rural and urban areas. Betel quid chewing usually starts at younger ages. Sale, marketing, and advertising of SLT are not under control and thus, road-side kiosks selling betel quid with SLT are mushrooming. Considerable trade of SLT products by illegal and legal means created an increase in access and availability. Low cost of SLT product enables high volume of use, even for the poor families. Taxation for raw tobacco and tobacco products is half the values of the tax for cigarettes. Effective enforcement, amendment of the law, and action for social change are needed. PMID- 25526246 TI - Smokeless tobacco product prices and taxation in Bangladesh: findings from the International Tobacco Control Survey. AB - INTRODUCTION: Smokeless tobacco use occupies a significant portion of overall tobacco consumption in Bangladesh. Yet very little is known about the effectiveness of tax and price policy in controlling the use of smokeless tobacco use in the country. METHODS: The paper examines the price distribution of various smoked (cigarette, bidi) and smokeless tobacco products (zarda, gul) using the univariate Epanechnikov kernel density function. It estimates the own and cross price elasticity of demand for the most widely used smokeless tobacco product zarda using two-step regression analysis. The analysis is based on data from the ITC Bangladesh Wave 3 Survey which is a nationally representative cohort survey of tobacco users and nonusers conducted in in Bangladesh during 2011-12. RESULTS: The price elasticity of lower price brands of zarda is estimated at -0.64 and of higher priced brands at -0.39, and the cross price elasticity of zarda with respect to cigarette price at 0.35. The tax increase on smokeless tobacco needs to be greater than the tax increase on smoked tobacco to bridge the wide price differential between the two types of products that currently encourages downward substitution from smoked to smokeless tobacco and discourages quitting behavior. CONCLUSIONS: This paper argues that increasing tax on smokeless tobacco simultaneously with the tax increase on smoked tobacco can have significant negative impact on the prevalence of smokeless tobacco use in Bangladesh. Finally, a specific excise system replacing the existing ad valorem excise tax can substantially contribute to the revenue collection performance from smokeless tobacco products. PMID- 25526247 TI - Quit history, intentions to quit, and reasons for considering quitting among tobacco users in India: findings from the Tobacco Control Policy Evaluation India Wave 1 Survey. AB - BACKGROUND: Global Adult Tobacco Survey India 2009-2010 revealed that more than one-third (35%) of adults in India use tobacco in some form: 21% use smokeless tobacco, 9% smoke, and 5% are mixed users (they smoke and use smokeless tobacco), and the quit rate is very low. In an effort to decrease prevalence of tobacco use, it is thus important to understand the factors that are related to intention to quit among Indian tobacco users. Research has shown consistently that intention to quit is a strong predictor of future quitting. The present study reports the factors encouraging quitting tobacco products in India. SUBJECTS AND METHODS: Cross-sectional data from Wave 1 of the International Tobacco Control Policy Evaluation India Survey conducted in four cities and surrounding rural areas (i.e. Mumbai [Maharashtra], Patna [Bihar], Indore [Madhya Pradesh], and Kolkata [West Bengal]) between August 2010 and December 2011 were analyzed. A total of 8051 tobacco users (15+ years) were randomly sampled from 8586 households: 1255 smokers, 5991 smokeless users, and 805 mixed (smoke and smokeless) users. Validated, standardized questions were asked about current tobacco use, intention to quit, and factors encouraging quitting. RESULTS: Overall, 19.6% of tobacco users intended to quit. Smokers had less intention to quit as compared to smokeless tobacco users whereas mixed users had more intention to quit (odds ratio [OR] =1.48, 95% confidence interval [CI] =1.12 1.97) compared to smokeless tobacco users. Highly educated people were more likely to report intention to quit (OR = 1.82, 95% CI = 1.09-3.02) compared to less educated. Advice by doctors to quit tobacco had a strong impact on intention to quit (OR = 1.68, CI = 1.29-2.15). Tobacco users who were exposed to antitobacco messages at work places (OR = 1.74, CI = 1.23-2.46), at restaurants (OR = 1.65, CI = 1.12-2.43), bars (OR = 1.81, CI = 1.07-3.06), on public transportation (OR = 2.14, CI = 1.49-3.08) and on tobacco packages (OR = 1.77, CI = 1.29-2.14) also expressed greater intention to quit tobacco use. CONCLUSION: Around one-fifth of tobacco users in India intended to quit tobacco use. Higher education, doctor's advice, and antitobacco messages were positively associated with users' intention to quit tobacco. PMID- 25526248 TI - Dual use of tobacco among Bangladeshi men. AB - INTRODUCTION: Dual use of tobacco (using smoking and smokeless forms) in Bangladesh is uncommon in women but common in men. Dual users are at additional risk of cancers and heart diseases compared with a single form of tobacco use. Knowledge about their socioeconomic background is necessary for planning appropriate interventions. We report here socioeconomic background of the dual users of tobacco from a nationally representative survey. METHODS: The study adopted a probability proportionate to size sampling technic of divisional population stratified into urban and rural areas to recruit men aged 25 years or older from their households. A total of 4312 men were recruited. Variables included questions on 20 household assets, tobacco use and other behavioral risk factors, and measurement of body weight and height. RESULTS: The average age of dual users was 46.7 years old compared to 43.4 and 52.3 years for smokers and smokeless tobacco users. Prevalence of "smoking only," "smokeless only" and "dual use" of tobacco was 40.6%, 15.2%, and 14.2%, respectively. Among all tobacco users, dual users constituted 20%. These dual users had lower educational achievement, rural residence, lower intake of fruit, and higher intake of alcohol. They were more undernourished as indicated by a thin body mass index compared to nonusers and smokers. Dual users were of socioeconomically deprived as measured by wealth quartiles constructed out of household assets. CONCLUSION: Dual use of tobacco is common in Bangladesh, and it is intimately linked with socioeconomic deprivation. Poverty reduction strategy and campaigns should address tobacco control not only tobacco in general, but its dual use in particular. PMID- 25526249 TI - Levels and trends of smokeless tobacco use among youth in countries of the World Health Organization South-East Asia Region. AB - BACKGROUND: At least two rounds of the Global Youth Tobacco Survey (GYTS) have been completed in most of the countries in the World Health Organization South East Asia region. Comparing findings from these two rounds provides trend data on smokeless tobacco (SLT) use for the first time. METHODS: This study uses GYTS data from Bangladesh, Bhutan, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, and Timor-Leste during 2006-2013. GYTS is a nationally representative survey of 13-15-year-old students using a consistent and standard protocol. Current SLT use is defined as using any kind of SLT products, such as chewing betel quid or nonbetel quid or snuffing any other products orally or through the nasal route, during the 30 days preceding the survey. Prevalence and 95% confidence intervals were computed using SAS/SUDAAN software. RESULTS: According to most recent GYTS data available in each country, the prevalence of current use of SLT among youth varied from 5.7% in Thailand to 23.2% in Bhutan; among boys, from 7.1% in Bangladesh to 27.2% in Bhutan; and among girls, from 3.7% in Bangladesh to 19.8% in Bhutan. Prevalence of SLT was reported significantly higher among boys than girls in Bhutan (boys 27.2%; girls 19.8%), India (boys 11.1%; girls 6.0%), Maldives (boys 9.2%; girls 2.9%), Myanmar (boys 15.2%; girls 4.0%), and Sri Lanka (boys 13.0%; girls 4.1%). Prevalence of current SLT use increased in Bhutan from 9.4% in 2009 to 23.2% in 2013, and in Nepal from 6.1% in 2007 to 16.2% in 2011. CONCLUSION: The findings call for countries to implement corrective measures through strengthened policy and enforcement. PMID- 25526250 TI - Community-based tobacco cessation program among women in Mumbai, India. AB - BACKGROUND: Globally tobacco epidemic kills nearly six million people annually. Consumption of tobacco products is on the rise in low- and middle-income countries. Tobacco is addictive; hence, tobacco users need support in quitting. AIMS: Providing tobacco cessation services to women in community enabling them to quit tobacco, identifying factors associated with quitting and documenting the processes involved to establish a replicable "model tobacco cessation program." SETTINGS AND DESIGN: This is a community based tobacco cessation program of one year duration conducted among women in a low socioeconomic area of Mumbai, India. SUBJECTS AND METHODS: It involved three interventions conducted at three months interval, comprised of health education, games and counseling sessions and a post intervention follow-up. STATISTICAL ANALYSIS: Uni and multivariate analysis was performed to find out association of various factors with quitting tobacco. RESULTS: The average compliance in three intervention rounds was 95.2%. The mean age at initiation of tobacco was 17.3 years. Tobacco use among family members and in the community was primary reasons for initiation and addiction to tobacco was an important factor for continuation, whereas health education and counseling seemed to be largely responsible for quitting. The quit rate at the end of the programme was 33.5%. Multivariate logistic regression analysis found that women in higher age groups and women consuming tobacco at multiple locations are less likely to quit tobacco. CONCLUSIONS: Changing cultural norms associated with smokeless tobacco, strict implementation of antitobacco laws in the community and work places and providing cessation support are important measures in preventing initiation and continuation of tobacco use among women in India. PMID- 25526251 TI - Compliance to Gutka ban and other provisons of COTPA in Mumbai. AB - BACKGROUND: Cigarettes and other tobacco products act 2003 (COTPA) is the principal law governing tobacco control in India. Government of Maharashtra in one of its landmark decisions also banned manufacturing, sale and distribution of gutka and pan masala since July 2012. The desired impact and level of enforcement of the COTPA legislation and the gutka and pan masala ban in Maharashtra State, however, needs assessment. Among the many provisions within COTPA, the present study seeks to assess compliance to implementation and enforcement of Section 5 and 6 of COTPA including compliance to gutka and pan masala ban in Mumbai, India. METHODOLOGY: Six educational institutes (EI) within the Mumbai metropolitan region were selected in a two stage random sampling process. Area around each EI was manually mapped and all the tobacco products selling outlets with in the 100 yards distance were listed by trained Field Social Investigators and were observed to determine compliance for Section 5 and Section 6 of the COTPA legislation and for gutka and pan masala ban. The vendors/shop owners manning these outlets were also interviewed for their personal sociodemographic details, self-tobacco use, awareness and perception about ill-effects of tobacco and existing tobacco control legislation in the country. RESULTS: A total of 222 tobacco retail outlets were listed within 100 yards of the EI in violation to the provisions of Section 6 of COTPA, of which 72 (32.4%) were selling tobacco products on mobile structures. About 53.2% of the tobacco vendors were also users of some form of tobacco. Whereas, nearly 217 (97.7%) vendors were aware about the gutka and pan masala ban in the State, only 48.2% were aware about the existence of COTPA legislation. None of the EI had a display board prohibiting the sale of tobacco products within a radius of 100 yards of their EI. Only 56.3% tobacco outlets had complied with the mandatory warning display boards indicating tobacco products will not be sold to people below 18 years of age. With regards to point of sale advertisement only 25.2% compliance was noted for display of health warning boards at the point of sale. Nearly 48.6% tobacco outlets exhibited >2 display boards and another 43.2% exhibited hoardings with brand pack photo, brand name in violation to the provision under Section 5. Violation by visible stacking and open display of tobacco products for sale was observed at 51.3% of tobacco outlets. While 41% of tobacco outlets were found displaying gutka and pan masala packets in violation to the ban. CONCLUSIONS: Enacting of the law without robust measures for enforcement has led to widespread noncompliance to the provisions with in the tobacco control legislation in the metropolitan city of Mumbai. Strong and sustainable measures needs to be incorporated both by civic administration and public health departments for its forceful implementation. PMID- 25526252 TI - Rising incidence of oral cancer in Ahmedabad city. AB - CONTEXT: In 1999, an increase in mouth cancer incidence among young men (< 50 years) in urban Ahmedabad was reported to be occurring along with decreasing mouth cancer incidence in older age groups and increasing oral submucous fibrosis incidence associated with areca nut consumption among young men in Gujarat. The aim was to investigate whether the increase in the incidence mouth cancer that had started among young men in the 1990 s was continuing. SETTINGS AND DESIGN: Ahmedabad urban population, comparison of reported mouth cancer cases in the population across four time period. METHODS: Age-specific incidence rates of mouth cancer (International Classification of Diseases [ICD]-9:143-5; ICD-10:C03 06) in five year age groups among men aged >= 15 years for the city of Ahmedabad for years 1985, 1995, 2007 and 2010 were extracted from published reports. For comparison, lung cancer (ICD-9:169; ICD-10:C33-C34) rates were also abstracted. STATISTICAL ANALYSIS USED: A cohort approach was used for further analysis of mouth cancer incidence. Age adjusted incidence rates of mouth and lung cancer for men aged >= 15 years were calculated and compared. RESULTS: The age specific incidence rates of mouth cancer among men increased over the 25-year period while lung cancer rates showed a net decrease. Using a cohort approach for mouth cancer, a rapid increase in younger age cohorts was found. CONCLUSIONS: Mouth cancer incidence increased markedly among men in urban Ahmedabad between 1985 and 2010, apparently due to increasing consumption of areca nut products, mawa and gutka. Gutka has now been banned all over India, but a more vigorous implementation is necessary. PMID- 25526253 TI - Smokeless tobacco use: a meta-analysis of risk and attributable mortality estimates for India. AB - BACKGROUND: Use of smokeless tobacco (SLT) is widely prevalent in India and Indian subcontinent. Cohort and case-control studies in India and elsewhere report excess mortality due to its use. OBJECTIVE: The aim was to estimate the SLT use-attributable deaths in males and females, aged 35 years and older, in India. MATERIALS AND METHODS: Prevalence of SLT use in persons aged 35 years and older was obtained from the Global Adult Tobacco Survey in India and population size and deaths in the relevant age-sex groups were obtained from UN estimates (2010 revision) for 2008. A meta-relative risk (RR) based population attributable fraction was used to estimate attributable deaths in persons aged 35 years and older. A random effects model was used in the meta-analysis on all-cause mortality from SLT use in India including four cohort and one case-control study. The studies included in the meta-analysis were adjusted for smoking, age and education. RESULTS: The prevalence of SLT use in India was 25.2% for men and 24.5% for women aged 35 years and older. RRs for females and males were 1.34 (1.27-1.42) and 1.17 (1.05-1.42), respectively. The number of deaths attributable to SLT use in India is estimated to be 368127 (217,076 women and 151,051 men), with nearly three-fifth (60%) of these deaths occurring among women. CONCLUSION: SLT use caused over 350,000 deaths in India in 2010, and nearly three-fifth of SLT use-attributable deaths were among women in India. This calls for targeted public health intervention focusing on SLT products especially among women. PMID- 25526254 TI - Women and tobacco: a cross sectional study from North India. AB - BACKGROUND: Tobacco is a leading risk factor for different types of diseases globally. Tobacco smoking by women is culturally unacceptable in India, but still women smoke tobacco at various times of their life. AIMS: The aim was to estimate the prevalence and pattern of tobacco use among women and to study the associated sociodemographic factors. SETTINGS AND DESIGN: This cross-sectional study was conducted among women aged 30 years or over in an urban resettlement colony for the migrant population at Chandigarh, India. METHODOLOGY: The study included women used tobacco products on one or more days within the past 30 days. Through systematic random sampling, 262 women were studied. As a part of the study 144 bidi smoking women were interviewed using detailed semi-structured questionnaire. STATISTICAL ANALYSIS: Descriptive statistics and hypothesis testing with Chi squared test and logistic regression were done using SPSS 16.0 version. RESULTS: Overall, the prevalence of tobacco use was 29.4% and that of bidi, zarda and hookah were 19.8%, 8.8%, and 2.7%, respectively. Around 6.2% women used tobacco during pregnancy. Teenage was the most common age of initiation of bidi smoking. Logistic regression analysis showed that the prevalence of tobacco use was high among Hindu unemployed women with no formal education belonged to scheduled caste, and those having grandchildren. CONCLUSIONS: This study highlighted high rates of tobacco use and explored both individual and family factors related to tobacco use among women. Affordable, culturally acceptable, sustainable and gender-sensitive individual and community-specific interventions will reduce the prevalence and effects of tobacco use. PMID- 25526255 TI - Taxation of smokeless tobacco in India. AB - BACKGROUND: The role of fiscal policy, especially taxation, though has been proved to be an effective instrument of tobacco control, its application is limited in India due to several reasons. This paper examines the tax structure, price and affordability of SLT products in order to provide evidence on how to strengthen the role of fiscal policy in tobacco control. METHOD: Secondary data on tax structure and revenue from tobacco products were collected from the Ministry of Finance, Government of India. In order to measure the rise of prices corresponding to the increase in tax rate, the retail price index (RPI) and Whole Price Index (WPI) of SLT products were compared with the price index for all commodities for the period 2006-2012. The affordability of tobacco products is calculated by dividing prices of tobacco products by per capita income. RESULTS: During the last 6 years, the tax rate on SLT has gone up leading to a rise in the prices of SLT products more than the general price rise. However, the price rise is less than the per capita income growth indicating increasing affordability. The study observed a decline in the consumption of zarda and kahini due to the price increase during 2008-2013. However, the decline in the consumption of zarda is less compared with khaini due to a very low rise in its price. CONCLUSION: The prices should be raised more than the growth in income to influence consumption. Tax administration is a major challenge for SLT products and strengthening it could enhance revenue collection from SLT products. PMID- 25526257 TI - Nasal use of snuff. PMID- 25526256 TI - The relation between price and daily consumption of cigarettes and bidis: findings from the Tobacco Control Policy Evaluation Wave 1 Survey. AB - CONTEXT: In India, 14% of the population use smoked tobacco products. Increasing prices of these products is one of the measures to curb their consumption. AIMS: This study analyzes "unit price" and "daily consumption" of cigarettes and bidis and investigates their relation with each other. SETTINGS AND DESIGN: A cross sectional survey was conducted in four states of India (Bihar, West Bengal, Madhya Pradesh and Maharashtra) as a part of the International Tobacco Control Policy (TCP) Evaluation Project (the TCP India Project) during 2010-2011. METHODS: Information was collected from adult (aged >= 15) daily exclusive smokers of cigarette/bidi regarding (a) last purchase (purchase in pack/loose, brand and price) and (b) daily consumption. Average unit price and daily consumption was calculated for different brands and states. Regression model was used to assess the impact of price on daily consumption. RESULTS: Bidis were much less expensive ([symbol in text]0.39) than cigarettes ([symbol in text]3.1). The daily consumption was higher (14) among bidi smokers than cigarette smokers (8). The prices and daily consumption of bidis ([symbol in text]0.33-0.43; 12-15) and cigarettes ([symbol in text]2.9-3.6; 5-9) varied across the four states. The unit prices of bidis and cigarettes did not influence their daily consumption. Smokers purchasing bidis in packs paid substantially less per unit and purchase of bidis and cigarettes in packs influenced their consumption positively. CONCLUSIONS: Cigarettes although more expensive than bidis, seem very cheap if compared internationally. Hence, prices of both cigarettes and bidis do not influence their consumption. PMID- 25526258 TI - No evidence for development of tolerance after repeated use of propofol for electroconvulsive therapy. AB - INTRODUCTION: The short-acting narcotic propofol is used for sedation during electroconvulsive therapy (ECT). It remains unclear whether patients develop tolerance to propofol after repeated administration. Therefore, we studied whether propofol dosage had to be increased during a course of ECT. METHODS: This retrospective study evaluated records of 39 in- and outpatients at a Swiss psychiatric hospital who underwent 10-21 ECT sessions for affective disorder over 4-28 weeks in 2011-2013. We examined the dose of propofol required to achieve deep sedation at the first and last ECT sessions. RESULTS: 13/39 patients (33.3%) needed a slightly higher propofol dose at the last ECT session than at the first (Group 1), 12 patients (30.8%) needed the same dose at the first and last sessions (Group 2) and 14 patients (35.9%) needed a lower final dose (Group 3). CONCLUSIONS: In our study patients did not appear to develop tolerance to propofol after repeated administration. Although the lack of a systematic dosing scheme in our study limits the conclusions that can be drawn, recent studies in animal models indicate that tolerance development is rather unlikely with propofol. Further studies are required to clarify the question of whether repeated use of propofol leads to tolerance. PMID- 25526259 TI - Products from pyrolysis of gas-phase propionaldehyde. AB - A hyperthermal nozzle was utilized to study the thermal decomposition of propionaldehyde, CH3CH2CHO, over a temperature range of 1073-1600 K. Products were identified with two detection methods: matrix-isolation Fourier transform infrared spectroscopy and photoionization mass spectrometry. Evidence was observed for four reactions during the breakdown of propionaldehyde: alpha-C-C bond scission yielding CH3CH2, CO, and H, an elimination reaction forming methylketene and H2, an isomerization pathway leading to propyne via the elimination of H2O, and a beta-C-C bond scission channel forming methyl radical and (*)CH2CHO. The products identified during this experiment were CO, HCO, CH3CH2, CH3CH?C?O, H2O, CH3C=CH, CH3, H2C?C?O, CH2CH2, CH3CH?CH2, HC=CH, CH2CCH, H2CO, C4H2, C4H4, and CH3CHO. The first eight products result from primary or bimolecular reactions involving propionaldehyde while the remaining products occur from reactions including the initial pyrolysis products. While the pyrolysis of propionaldehyde involves reactions similar to those observed for acetaldehyde and butyraldehyde in recent studies, there are a few unique products observed which highlight the need for further study of the pyrolysis mechanism. PMID- 25526260 TI - Correlation of atomic structure and photoluminescence of the same quantum dot: pinpointing surface and internal defects that inhibit photoluminescence. AB - In a size regime where every atom counts, rational design and synthesis of optimal nanostructures demands direct interrogation of the effects of structural divergence of individuals on the ensemble-averaged property. To this end, we have explored the structure-function relationship of single quantum dots (QDs) via precise observation of the impact of atomic arrangement on QD fluorescence. Utilizing wide-field fluorescence microscopy and atomic number contrast scanning transmission electron microscopy (Z-STEM), we have achieved correlation of photoluminescence (PL) data and atomic-level structural information from individual colloidal QDs. This investigation of CdSe/CdS core/shell QDs has enabled exploration of the fine structural factors necessary to control QD PL. Additionally, we have identified specific morphological and structural anomalies, in the form of internal and surface defects, that consistently vitiate QD PL. PMID- 25526261 TI - Delivery-corrected imaging of fluorescently-labeled glucose reveals distinct metabolic phenotypes in murine breast cancer. AB - When monitoring response to cancer therapy, it is important to differentiate changes in glucose tracer uptake caused by altered delivery versus a true metabolic shift. Here, we propose an optical imaging method to quantify glucose uptake and correct for in vivo delivery effects. Glucose uptake was measured using a fluorescent D-glucose derivative 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4 yl)Amino)-2-deoxy-D-glucose (2-NBDG) in mice implanted with dorsal skin flap window chambers. Additionally, vascular oxygenation (SO2) was calculated using only endogenous hemoglobin contrast. Results showed that the delivery factor proposed for correction, "RD", reported on red blood cell velocity and injected 2 NBDG dose. Delivery-corrected 2-NBDG uptake (2-NBDG60/RD) inversely correlated with blood glucose in normal tissue, indicating sensitivity to glucose demand. We further applied our method in metastatic 4T1 and nonmetastatic 4T07 murine mammary adenocarcinomas. The ratio 2-NBDG60/RD was increased in 4T1 tumors relative to 4T07 tumors yet average SO2 was comparable, suggesting a shift toward a "Warburgian" (aerobic glycolysis) metabolism in the metastatic 4T1 line. In heterogeneous regions of both 4T1 and 4T07, 2-NBDG60/RD increased slightly but significantly as vascular oxygenation decreased, indicative of the Pasteur effect in both tumors. These data demonstrate the utility of delivery-corrected 2-NBDG and vascular oxygenation imaging for differentiating metabolic phenotypes in vivo. PMID- 25526262 TI - Use of the zebrafish larvae as a model to study cigarette smoke condensate toxicity. AB - The smoking of tobacco continues to be the leading cause of premature death worldwide and is linked to the development of a number of serious illnesses including heart disease, respiratory diseases, stroke and cancer. Currently, cell line based toxicity assays are typically used to gain information on the general toxicity of cigarettes and other tobacco products. However, they provide little information regarding the complex disease-related changes that have been linked to smoking. The ethical concerns and high cost associated with mammalian studies have limited their widespread use for in vivo toxicological studies of tobacco. The zebrafish has emerged as a low-cost, high-throughput, in vivo model in the study of toxicology. In this study, smoke condensates from 2 reference cigarettes and 6 Canadian brands of cigarettes with different design features were assessed for acute, developmental, cardiac, and behavioural toxicity (neurotoxicity) in zebrafish larvae. By making use of this multifaceted approach we have developed an in vivo model with which to compare the toxicity profiles of smoke condensates from cigarettes with different design features. This model system may provide insights into the development of smoking related disease and could provide a cost effective, high-throughput platform for the future evaluation of tobacco products. PMID- 25526263 TI - Genome-wide SNP-genotyping array to study the evolution of the human pathogen Vibrio vulnificus biotype 3. AB - Vibrio vulnificus is an aquatic bacterium and an important human pathogen. Strains of V. vulnificus are classified into three different biotypes. The newly emerged biotype 3 has been found to be clonal and restricted to Israel. In the family Vibrionaceae, horizontal gene transfer is the main mechanism responsible for the emergence of new pathogen groups. To better understand the evolution of the bacterium, and in particular to trace the evolution of biotype 3, we performed genome-wide SNP genotyping of 254 clinical and environmental V. vulnificus isolates with worldwide distribution recovered over a 30-year period, representing all phylogeny groups. A custom single-nucleotide polymorphism (SNP) array implemented on the Illumina GoldenGate platform was developed based on 570 SNPs randomly distributed throughout the genome. In general, the genotyping results divided the V. vulnificus species into three main phylogenetic lineages and an additional subgroup, clade B, consisting of environmental and clinical isolates from Israel. Data analysis suggested that 69% of biotype 3 SNPs are similar to SNPs from clade B, indicating that biotype 3 and clade B have a common ancestor. The rest of the biotype 3 SNPs were scattered along the biotype 3 genome, probably representing multiple chromosomal segments that may have been horizontally inserted into the clade B recipient core genome from other phylogroups or bacterial species sharing the same ecological niche. Results emphasize the continuous evolution of V. vulnificus and support the emergence of new pathogenic groups within this species as a recurrent phenomenon. Our findings contribute to a broader understanding of the evolution of this human pathogen. PMID- 25526264 TI - The microbial community of the cystic fibrosis airway is disrupted in early life. AB - BACKGROUND: Molecular techniques have uncovered vast numbers of organisms in the cystic fibrosis (CF) airways, the clinical significance of which is yet to be determined. The aim of this study was to describe and compare the microbial communities of the lower airway of clinically stable children with CF and children without CF. METHODS: Bronchoalveolar lavage (BAL) fluid and paired oropharyngeal swabs from clinically stable children with CF (n = 13) and BAL from children without CF (n = 9) were collected. DNA was isolated, the 16S rRNA regions amplified, fragmented, biotinylated and hybridised to a 16S rRNA microarray. Patient medical and demographic information was recorded and standard microbiological culture was performed. RESULTS: A diverse bacterial community was detected in the lower airways of children with CF and children without CF. The airway microbiome of clinically stable children with CF and children without CF were significantly different as measured by Shannon's Diversity Indices (p = 0.001; t test) and Principle coordinate analysis (p = 0.01; Adonis test). Overall the CF airway microbial community was more variable and had a less even distribution than the microbial community in the airways of children without CF. We highlighted several bacteria of interest, particularly Prevotella veroralis, CW040 and a Corynebacterium, which were of significantly differential abundance between the CF and non-CF lower airways. Both Pseudomonas aeruginosa and Streptococcus pneumoniae culture abundance were found to be associated with CF airway microbial community structure. The CF upper and lower airways were found to have a broadly similar microbial milieu. CONCLUSION: The microbial communities in the lower airways of stable children with CF and children without CF show significant differences in overall diversity. These discrepancies indicate a disruption of the airway microflora occurring early in life in children with CF. PMID- 25526265 TI - A prospective comparative study of microscope-integrated intraoperative fluorescein and indocyanine videoangiography for clip ligation of complex cerebral aneurysms. AB - OBJECT: The authors prospectively analyzed 2 microscope-integrated videoangiography techniques using intravenous indocyanine green (ICG) and fluorescein for assessment of cerebral aneurysm obliteration and adjacent vessel patency. METHODS: The authors prospectively enrolled 22 patients who underwent clip ligation of their aneurysm and used intraoperative videoangiography to assess obliteration of the aneurysmal sac and patency of the adjacent branching and perforating arteries. Patients underwent ICG videoangiography (ICG-VA) and the newly developed fluorescein videoangiography (FL-VA) using microscope integrated fluorescence modules. Two independent observers compared the videoangiography recordings for value and quality to assess aneurysm exclusion and the patency of adjacent arteries. RESULTS: All 22 patients first underwent FL VA and then ICG-VA after clip application. In 7 cases (32%), FL-VA provided superior detail to assess perforating arteries (4 cases), distal branches (2 cases), and both (1 case); such detail was not readily available on ICG-VA. In 1 patient, ICG-VA offered better visualization of posterior communicating artery aneurysm occlusion than FL-VA because of staining artifact on the aneurysm dome from the adjacent tentorium. In 2 patients, FL-VA offered the needed advantage of real-time manipulation of the vessels and flow assessment by visualization through the operating microscope oculars. In 2 other cases, ICG-VA was more practical for repeat usage because of its more efficient clearance from the intravascular space. The ICG-VA image quality was often degraded at higher magnification in deep operative fields, partly due to chromatic aberration. Both ICG-VA and FL-VA afforded restricted views of vasculature based on the angle of surgical approach and obscuration by blood clot, aneurysm, or brain tissue. CONCLUSIONS: Compared with ICG-VA, FL-VA can potentially provide an improved visualization of vasculature at high magnification in deep surgical fields. ICG VA is more effective for repeated use during clip repositioning due to ICG's minimal vascular wall extravasation. Therefore, in certain cases, FL-VA may offer some advantages and play a complementary role along with ICG-VA in intraoperative fluorescence evaluation during microsurgical management of aneurysms. PMID- 25526266 TI - Endoscopic endonasal posterior clinoidectomy. PMID- 25526267 TI - Relationship of vocal cord paralysis to the coil diameter of vagus nerve stimulator leads. AB - OBJECT: This investigation was done to examine, following implantation of vagus nerve stimulators, the relationship of vocal cord paralysis to the inner diameter of the coils used to attach the stimulator lead to the nerve. METHODS: All data in this investigation were collected, as mandated by the FDA, by the manufacturer of vagus nerve stimulators and were made available without restrictions for analysis by the authors. The data reflect all initial device implantations in the United States for the period from 1997 through 2012. RESULTS: Vocal cord paralysis was reported in 193 of 51,882 implantations. In patients aged 18 years and older, the incidence of paralysis was 0.26% when the stimulator leads had coil diameters of 3 mm and 0.51% when the leads had 2-mm-diameter coils (p < 0.05). Across all age groups, the incidence of vocal cord paralysis increased with age at implantation for leads having 2-mm-diameter coils. CONCLUSIONS: In patients aged 18 years and older, vocal cord paralysis occurred at almost twice the rate with the implantation of vagus nerve stimulator leads having 2-mm diameter coils than with leads having 3-mm-diameter coils. The incidence of vocal cord paralysis increases with patient age at implantation. PMID- 25526268 TI - DTI in brain tumor surgery. PMID- 25526269 TI - SEEG has the lowest rate of complications. PMID- 25526270 TI - The nonsurgical nature of patients with subarachnoid or intraparenchymal hemorrhage associated with mild traumatic brain injury. AB - OBJECT: Mild traumatic brain injury (mTBI), as defined by Glasgow Coma Scale (GCS) score of 13 or higher, is a common problem in the United States and worldwide, estimated to affect more than 1 million patients yearly. When associated with intracranial hemorrhage, it is a common reason for neurosurgical consultation and transfer to tertiary care centers. The authors set out to investigate the clinical implications of subarachnoid hemorrhage (SAH) and/or intraparenchymal hemorrhage (IPH) associated with mTBI in hopes of standardization of mTBI clinical care and optimization of resource allocation. METHODS: The authors performed a retrospective review of 500 consecutively treated patients with mTBI and SAH and/or IPH admitted to a Level I trauma center in Alabama between May 2003 and May 2013. They performed a review of medical records to confirm the diagnosis, determine neurological condition at admission, and assess for episodes of neurological decline or brain injury-related complications including altered mental status, seizures, and hyponatremia. RESULTS: Of the 500 patients for whom data were reviewed, 304 (60.8%) were male and 196 (39.2%) were female. Average age was 46.3 years. Overall, 63 patients (12.6%) had isolated IPH, 411 (82.2%) had isolated SAH, and 26 (5.2%) had radiographic evidence of both IPH and SAH. One hundred forty-five patients (29%) were transferred an average distance of 64.5 miles. The authors identified no patients who experienced neurological worsening during their hospital course. Two patients experienced hyponatremia that required treatment with sodium supplementation. CONCLUSIONS: Patients with the constellation of SAH and/or IPH and mTBI do not require neurosurgical consultation, and these findings should not be used as the sole criteria to justify transfer to tertiary referral centers. PMID- 25526271 TI - Prospective randomized study comparing clinical, functional, and aesthetic results of minipterional and classic pterional craniotomies. AB - OBJECT The object of this study was to compare the clinical, functional, and aesthetic results of 2 surgical techniques, pterional (PT) and minipterional (MPT) craniotomies, for microsurgical clipping of anterior circulation aneurysms. METHODS Fifty-eight patients with ruptured and unruptured anterior circulation aneurysms were enrolled into a prospective randomized study. The first group included 28 patients who underwent the MPT technique, and the second group comprised 30 patients who underwent the classic PT craniotomy. To evaluate the aesthetic effects, patients were asked to grade on a rule from 0 to 100 the best and the worst aesthetic result. Photographs were also taken, assessed by 2 independent observers, and classified as showing excellent, good, regular, or poor aesthetic results. Furthermore, quantitative radiological assessment (percentage reduction in thickness and volumetric analysis) of the temporal muscle, subcutaneous tissue, and skin was performed. Functional outcomes were compared using the modified Rankin Scale (mRS). Frontal facial palsy, postoperative hemorrhage, cerebrospinal fistula, hydrocephalus, and mortality were also analyzed. RESULTS Demographic and preoperative characteristics were similar in both groups. Satisfaction in terms of aesthetic result was observed in 19 patients (79%) in the MPT group and 13 (52%) in the PT group (p = 0.07). The mean score on the aesthetic rule was 27 in the MPT group and 45.8 in the PT group (p = 0.03). Two independent observers analyzed the patient photos, and the kappa coefficient for the aesthetic results was 0.73. According to these observers, excellent and good results were seen in 21 patients (87%) in the MPT and 12 (48%) in the PT groups. The degree of temporal muscle, subcutaneous tissue, and skin atrophy was 14.9% in the MPT group and 24.3% in the PT group (p = 0.01). Measurements of the temporal muscle revealed 12.7% atrophy in the MPT group and 22% atrophy in the PT group (p = 0.005). The volumetric reduction was 14.6% in the MPT and 24.5% in the PT groups (p = 0.012). Mortality and mRS score were similar in both groups at the 6-month evaluation (p = 0.99). CONCLUSIONS Minipterional craniotomy provides clinical results similar to those of the PT technique. Moreover, it provides better cosmetic results. It can be used safely and effectively to surgically treat aneurysms of the anterior circulation instead of the PT approach. PMID- 25526272 TI - Venous organization in the transverse foramen: dissection, histology, and magnetic resonance imaging. AB - OBJECT: The anatomical arrangement of the venous system within the transverse foramen is controversial; there is disagreement whether the anatomy consists of a single vertebral vein or a confluence of venous plexus. Precise knowledge of this arrangement is necessary in imaging when vertebral artery dissection is suspected, as well as in surgical approaches for the cervical spine. This study aimed to better explain anatomical organization of the venous system within the transverse foramen according to the Trolard hypothesis of a transverse vertebral sinus. METHODS: This was an anatomical and radiological study. For the anatomical study, 10 specimens were analyzed after vascular injection. After dissection, histological cuts were prepared. For the radiological study, a high-resolution MRI study with 2D time-of-flight segment MR venography sequences was performed on 10 healthy volunteers. RESULTS: Vertebral veins are arranged in a plexiform manner within the transverse canal. This arrangement begins at the upper part of the transverse canal before the vertebral vein turns into a single vein along with the vertebral artery running from the transverse foramen of the C-6. This venous system runs somewhat ventrolaterally to the vertebral artery. In most cases, this arrangement is symmetrical and facilitates radiological readings. The anastomoses between vertebral veins and ventral longitudinal veins are uniform and arranged segmentally at each vertebra. CONCLUSIONS: These findings confirm recent or previous anatomical descriptions and invalidate others. It is hard to come up with a common description of the arrangement of vertebral veins. The authors suggest providing clinicians as well as anatomists with a well-detailed description of components essential to the understanding of this organization. PMID- 25526273 TI - Editorial: Clipping of neurosurgical aneurysms: the dye is cast. PMID- 25526274 TI - Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines. AB - OBJECT: Glioblastoma is a rapidly infiltrating tumor that consistently rematerializes despite various forms of aggressive treatment. Brain tumors are commonly treated with alkylating drugs, such as lomustine, which are chemotherapeutic agents. Use of these drugs, however, is associated with serious side effects. To reduce the side effects, one approach is to combine lower doses of chemotherapeutic drugs with other nontoxic anticancer agents. In this study, using glioblastoma cell lines, the authors investigated the anticancer effects of lomustine, alone and in combination with docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid normally abundant in the brain and known for its anticancer potential. METHODS: Cells were cultured from 3 human-derived tumor cell lines (U87-MG, DB029, and MHBT161) and supplemented with either DHA or lomustine to determine the growth inhibitory potential using WST-1, a mitochondrial functional indicator. Human-derived cerebral cortex microvascular endothelial cells served as a normal phenotypic control. Cellular incorporation of DHA was analyzed by gas chromatography. Using flow cytometric analysis, the DHA and/or lomustine effect on induction of apoptosis and/or necrosis was quantified; subsequently, the DHA and lomustine effect on cell cycle progression was also assessed. Western blot analysis confirmed the role of downstream cellular targets. RESULTS: U87-MG growth was inhibited with the supplementation of either DHA (ED50 68.3 MUM) or lomustine (ED50 68.1 MUM); however, growth inhibition was enhanced when U87-MG cells were administered equimolar doses of each compound, resulting in nearly total growth inhibition at 50 MUM. Gas chromatography analysis of the fatty acid profile in DHA-supplemented U87-MG cells resulted in a linear dose-dependent increase in DHA incorporation (< 60 MUM). The combination of DHA and lomustine potently induced U87-MG apoptosis and necrosis as indicated by flow cytometric analysis. Activation of caspase-3 and poly (ADP-ribose) polymerase (PARP) was evident in lomustine-treated U87-MG cells, although this activation did not appear to be dependent on DHA supplementation. Additionally, lomustine-treated cells' growth arrested in the G2/M cell cycle stage, regardless of the presence of DHA. Similar to the U87-MG observations, the combination of DHA and lomustine resulted in growth inhibition of 2 additional human-derived glioblastoma cell lines, DB029 and MHBT161. Importantly, in primary human-derived cerebral cortex endothelial cells, this combination was only growth inhibitory (40.8%) at the highest dose screened (100 MUM), which indicates a certain degree of selectivity toward glioblastoma. CONCLUSIONS: Taken together, these data suggest a potential role for a combination therapy of lomustine and DHA for the treatment of glioblastomas. PMID- 25526275 TI - Intraoperative somatosensory evoked potential recovery following opening of the fourth ventricle during posterior fossa decompression in Chiari malformation: case report. AB - The most appropriate surgical technique for posterior fossa decompression in Chiari malformation (CM) remains a matter of debate. Intraoperative electrophysiological studies during posterior fossa decompression of Type I CM (CM-I) aim to shed light on the entity's pathomechanism as well as on the ideal extent of decompression. The existing reports on this issue state that significant improvement in conduction occurs after craniotomy in all cases, but additional durotomy contributes a further improvement in only a minority of cases. This implies that craniotomy alone might suffice for clinical improvement without the need of duraplasty or even subarachnoid manipulation at the level of the craniocervical junction. In contrast to published data, the authors describe the case of a 32-year-old woman who underwent surgery for CM associated with extensive cervicothoracic syringomyelia and whose intraoperative somatosensory evoked potentials (SSEPs) did not notably improve after craniotomy or following durotomy; rather, they only improved after opening of the fourth ventricle and restoration of CSF flow through the foramen of Magendie. Postoperatively, the patient recovered completely from her preoperative neurological deficits. To the authors' knowledge, this is the first report of significant SSEP recovery after opening the fourth ventricle in the decompression of a CM-I. The electrophysiological and operative techniques are described in detail and the findings are discussed in the light of available literature. The authors conclude that there might be a subset of CM-I patients who require subarachnoid dissection at the level of the craniocervical junction to benefit clinically. Prospective studies with detailed electrophysiological analyses seem warranted to answer the question regarding the best surgical approach in CM-I decompression. PMID- 25526276 TI - Spontaneous subarachnoid hemorrhage of unknown origin: hospital course and long term clinical and angiographic follow-up. AB - OBJECT: Hemorrhagic origin is unidentifiable in 10%-20% of patients presenting with spontaneous subarachnoid hemorrhage (SAH). While the patients in such cases do well clinically, there is a lack of long-term angiographic followup. The authors of the present study evaluated the long-term clinical and angiographic follow-up of a patient cohort with SAH of unknown origin that had been enrolled in the Barrow Ruptured Aneurysm Trial (BRAT). METHODS: The BRAT database was searched for patients with SAH of unknown origin despite having undergone two or more angiographic studies as well as MRI of the brain and cervical spine. Follow up was available at 6 months and 1 and 3 years after treatment. Analysis included demographic details, clinical outcome (Glasgow Outcome Scale, modified Rankin Scale [mRS]), and repeat vascular imaging. RESULTS: Subarachnoid hemorrhage of unknown etiology was identified in 57 (11.9%) of the 472 patients enrolled in the BRAT study between March 2003 and January 2007. The mean age for this group was 51 years, and 40 members (70%) of the group were female. Sixteen of 56 patients (28.6%) required placement of an external ventricular drain for hydrocephalus, and 4 of these subsequently required a ventriculoperitoneal shunt. Delayed cerebral ischemia occurred in 4 patients (7%), leading to stroke in one of them. There were no rebleeding events. Eleven patients were lost to followup, and one patient died of unrelated causes. At the 3-year follow-up, 4 (9.1%) of 44 patients had a poor outcome (mRS > 2), and neurovascular imaging, which was available in 33 patients, was negative. CONCLUSIONS: Hydrocephalus and delayed cerebral ischemia, while infrequent, do occur in SAH of unknown origin. Long-term neurological outcomes are generally good. A thorough evaluation to rule out an etiology of hemorrhage is necessary; however, imaging beyond 6 weeks from ictus has little utility, and rebleeding is unexpected. PMID- 25526277 TI - Integrated open surgical and endovascular embolization treatment of a paracavernous venous plexus fistula: case report. AB - The authors report the treatment of a rare type of dural arteriovenous fistula of the paracavernous venous plexus. These fistulas can mimic carotid-cavernous fistulas in both imaging characteristics and clinical presentation, but the anatomical differences require differences in management. The authors describe an integrated open surgical and direct endovascular embolization approach and review of the literature pertaining to the anatomy of and treatment options for paracavernous fistulas. PMID- 25526278 TI - Regarding Bering's hypothesis on choroid plexus pulsatility. PMID- 25526279 TI - Clinical and radiographic outcomes following traumatic Grade 3 and 4 carotid artery injuries: a 10-year retrospective analysis from a Level 1 trauma center. The Parkland Carotid and Vertebral Artery Injury Survey. AB - OBJECT: Screening, management, and follow-up of Grade 3 and 4 blunt carotid artery injuries (BCAIs) remain controversial. These high-grade BCAIs were analyzed to define their natural history and establish a rational management plan based on lesion progression and cerebral infarction. METHODS: A retrospective review of a prospectively maintained database of all blunt traumatic carotid and vertebral artery injuries from August 2003 to April 2013 was performed, and Grade 3 and 4 BCAIs were identified. The authors define Grade 3 injuries as stenosis of the vessel greater than 50%, or the development of a pseudoaneurysm, and Grade 4 injuries as complete vessel occlusion. Demographic information, imaging findings, number of images obtained per individual, length of radiographic follow-up examination, radiographic outcome at end of follow-up period, treatment(s), and documentation of ischemic stroke or transient ischemic attack (TIA) were recorded. RESULTS: Fifty-three Grade 3 BCAIs in 44 patients and 5 Grade 4 BCAIs in 5 patients were identified and had available follow-up information. The mean follow-up duration for Grade 3 BCAIs was 113 days, and the mean follow-up for Grade 4 BCAIs was 78 days. Final imaging of Grade 3 BCAIs showed that 53% of cases were radiographically stable, 11% had resolved, and 11% were improved, whereas 25% had radiographically worsened. In terms of treatment, 75% of patients received aspirin (ASA) alone, 5% received various medications, and 2% received no treatment. Eighteen percent of the patients in the Grade 3 BCAI group underwent endovascular intervention, and in all of these cases, treatment with ASA was continued after the procedure. Final imaging of the Grade 4 BCAIs showed that 60% remained stable (with persistent occlusion), whereas the remaining arteries improved (with recanalization of the vessel). All patients in the Grade 4 BCAI follow-up group were treated with ASA, although in 1 patient treatment was transitioned to Coumadin. There were 3 cases of cerebral infarction that appeared to be related to Grade 3 BCAIs (7% of 44 patients in the Grade 3 group), and 1 case of stroke that appeared to be related to a Grade 4 BCAI. All identified cases of stroke developed soon after hospital admission. CONCLUSIONS: Although the posttraumatic cerebral infarction rate may be overestimated, the results of this study suggest that the Grade 3 and 4 BCAIs carry the highest stroke risk of the blunt cerebrovascular injuries, and those infarctions were identified on or shortly after hospital admission. Despite a 40% recanalization rate in the Grade 4 BCAI group and an 89% rate of persistent pseudoaneurysm in the Grade 3 BCAI group, follow-up imaging showed progressive worsening without radiographic improvement in only a small number of patients, and these findings alone did not correlate with adverse clinical outcome. Follow-up protocols may require amending; however, further prospective studies are needed to make conclusive changes as they relate to management. PMID- 25526280 TI - Exploring New Relationships Between Physical Activity Volume and Intensity and Cardiometabolic Risk in U.S. Adolescents. AB - BACKGROUND: Associations between physical activity (PA) intensity and volume and adolescents' cardiometabolic health have research, policy, and practice implications. This study compares associations between cardiometabolic risk factors and 1) moderate-to-vigorous PA (MVPA) minutes versus total PA volume (accelerometer-derived total activity counts, TAC) and 2) light PA volume (counts at light intensity, L-TAC) versus moderate-to-vigorous PA volume (counts at moderate-to-vigorous intensity, MV-TAC). METHODS: 2105 adolescents from 2003- 2006 NHANES were included. Independent variables were MVPA minutes, TAC, L-TAC, and MV-TAC. Regression models tested associations between PA variables and continuous metabolic risk index (CMRI), waist circumference, systolic and diastolic blood pressure, HDL, insulin, and triglycerides. RESULTS: TAC demonstrated a slightly stronger inverse association with CMRI (P = .004) than did MVPA (P = .013). TAC and MVPA were both associated with systolic and diastolic pressure, HDL, and insulin; associations were similar or slightly stronger for TAC. L-TAC and MV-TAC were both associated with CMRI and HDL. Only L TAC was associated with diastolic pressure. Only MV-TAC was associated with waist circumference, systolic pressure, and insulin. CONCLUSIONS: Compared with MVPA minutes, TAC demonstrates similar or slightly stronger associations with cardiometabolic risk factors. L-TAC and MV-TAC appear similarly associated with adolescents' clustered risk but differently associated with individual risk factors. PMID- 25526281 TI - In-plane aromaticity in cycloparaphenylene dications: a magnetic circular dichroism and theoretical study. AB - The electronic structures of [8]cycloparaphenylene dication ([8]CPP(2+)) and radical cation ([8]CPP(*+)) have been investigated by magnetic circular dichroism (MCD) spectroscopy, which enabled unambiguous discrimination between previously conflicting assignments of the UV-vis-NIR absorption spectral bands. Molecular orbital and nucleus-independent chemical shift (NICS) analysis revealed that [8]CPP(2+) shows in-plane aromaticity with a (4n + 2) pi-electron system (n = 7). This aromaticity appears to be the origin of the unusual stability of the dication. Theoretical calculations further suggested that not only [8]CPP(2+) but also all [n]CPP (n = 5-10) dications and dianions exhibit in-plane aromaticity. PMID- 25526282 TI - Fully transparent and rollable electronics. AB - Major obstacles toward the manufacture of transparent and flexible display screens include the difficulty of finding transparent and flexible semiconductors and electrodes, temperature restrictions of flexible plastic substrates, and bulging or warping of the flexible electronics during processing. Here we report the fabrication and performance of fully transparent and rollable thin-film transistor (TFT) circuits for display applications. The TFTs employ an amorphous indium-gallium-zinc oxide semiconductor (with optical band gap of 3.1 eV) and amorphous indium-zinc oxide transparent conductive electrodes, and are built on 15-MUm-thick solution-processed colorless polyimide (CPI), resulting in optical transmittance >70% in the visible range. As the CPI supports processing temperatures >300 degrees C, TFT performance on plastic is similar to that on glass, with typical field-effect mobility, turn-on voltage, and subthreshold voltage swing of 12.7 +/- 0.5 cm(2)/V.s, -1.7 +/- 0.2 V, and 160 +/- 29 mV/dec, respectively. There is no significant degradation after rolling the TFTs 100 times on a cylinder with a radius of 4 mm or when shift registers, each consisting of 40 TFTs, are operated while bent to a radius of 2 mm. For handling purposes, carrier glass is used during fabrication, together with a very thin (~1 nm) solution-processed carbon nanotube (CNT)/graphene oxide (GO) backbone that is first spin-coated on the glass to decrease adhesion of the CPI to the glass; peel strength of the CPI from glass decreases from 0.43 to 0.10 N/cm, which eases the process of detachment performed after device fabrication. Given that the CNT/GO remains embedded under the CPI after detachment, it minimizes wrinkling and decreases the substrate's tensile elongation from 8.0% to 4.6%. Device performance is also stable under electrostatic discharge exposures up to 10 kV, as electrostatic charge can be released via the conducting CNTs. PMID- 25526283 TI - Atmospheric emission characteristics and control policies of five precedent controlled toxic heavy metals from anthropogenic sources in China. AB - A bottom-up inventory of atmospheric emissions of five precedent-controlled toxic heavy metals (HMs), including mercury (Hg), arsenic (As), lead (Pb), cadmium (Cd), and chromium (Cr), from primary anthropogenic sources in China is established for the period 2000-2010. Total emissions of HMs demonstrate a gradually ascending trend along with the increase of coal consumption and industrial production, which are estimated at approximately 842.22 t for Hg, 4196.31 t for As, 29272.14 t for Pb, 795.29 t for Cd, and 13715.33 t for Cr for 2010. Coal combustion is found to be the primary source of HMs emissions. Owing to the dramatic differences of coal use by industrial and power sectors among provinces, spatial allocation performs remarkably uneven characteristics, and spatial distribution features are demonstrated by allocating the emissions into 0.5 degrees * 0.5 degrees grid cells with GDP and population as surrogate indexes. Further, HMs emissions from specified anthropogenic sources under three different control scenarios for the target year 2015 are projected, and collaborative and specialized control strategies are proposed to meet the demand of emission reduction goals of different regions. In the future, a whole processes control management system will be the most effective way for control of HMs. PMID- 25526284 TI - Hydrocarbon binding by proteins: structures of protein binding sites for >=C10 linear alkanes or long-chain alkyl and alkenyl groups. AB - In order to identify potential de novo enzyme templates for the cleavage of C-C single bonds in long-chain hydrocarbons, we analyzed protein structures that bind substrates containing alkyl and alkenyl functional groups. A survey of ligand containing protein structures deposited in the Protein Data Bank resulted in 874 entries, consisting of 194 unique ligands that have >=10 carbons in a linear chain. Fatty acids and phospholipids are the most abundant types of ligands. Hydrophobic amino acids forming alpha-helical structures frequently line the binding pockets. Occupation of these binding sites was evaluated by calculating both the buried surface area and volume employed by the ligands; these quantities are similar to those computed for drug-protein complexes. Surface complementarity is relatively low due to the nonspecific nature of the interaction between the long-chain hydrocarbons and the hydrophobic amino acids. The selected PDB structures were annotated on the basis of their SCOP and EC identification numbers, which will facilitate design template searches based on structural and functional homologies. Relatively low surface complementarity and ~55% volume occupancy, also observed in synthetic-host, alkane-guest systems, suggest general principles for the recognition of long-chain linear hydrocarbons. PMID- 25526285 TI - Palliative nursing and the Ebola crisis. PMID- 25526286 TI - Do place-of-death preferences for patients receiving specialist palliative care change over time? AB - BACKGROUND: Discussing preferred place of death (PPD) with patients approaching end of life is an important part of anticipatory care planning. Preferences at a specific point in time have been described; however the extent to which preferences may change is unclear. This study examines changes in PPD. METHODS: A retrospective case note review of all patients who died under the care of a specialist palliative care service during a 6-month period in 2012 was undertaken. Notes relating to 299 patients were examined by a member of the clinical team. RESULTS: Of the 204 patients who had more than one PPD assessment, 57% showed a change in preference status between the first and last assessment. The majority changed from an unclarified preference to identifying a preferred place. Only 15% of patients with two or more assessments switched from one location to another. CONCLUSIONS: Most patients under the care of a specialist palliative care service identify a preference for place of death as end of life approaches. Only a minority change their preference once a preferred place has been elicited. We recommend that patients are supported to explore their preferences for PPD as part of specialist palliative care, and that preferences are reviewed as end of life approaches. PMID- 25526287 TI - Grief experiences of nurses in Ireland who have cared for children with an intellectual disability who have died. AB - BACKGROUND: The personal grief experience of nurses who have cared for children with an intellectual disability who have died is little understood. METHOD: This descriptive qualitative study was initiated to ascertain nurses' knowledge and personal experience of grief and how this is managed. Semi-structured interview was the method used to collect data from eight nurses who had cared for a child with an intellectual disability who had died. A pragmatic approach to qualitative data analysis was adopted. RESULTS: Of the eight main themes identified, the four most prevalent are discussed in detail: grief, relationship with the child, end of life, and support. The findings demonstrate that nurses have a good understanding of grief, but the way they experience and manage it varies. CONCLUSION: The study suggests that nurses who have cared for children with an intellectual disability who have died may experience disenfranchised grief. Nurses seek support from a variety of sources. Organisational support is important for nurses following the death of a child for whom they have provided care. PMID- 25526288 TI - The experiences of patients and carers in the daily management of care at the end of life. AB - BACKGROUND: Home is the preferred location for most people with an advanced disease and at the end of life. A variety of care professionals work in community settings to provide support to this population. Patients and their spouses, who also care for them (spouse-carers), are rarely accompanied by these sources of support at all times, and have to manage independently between their contact with care professionals. AIM: To explore how patients and spouse-carers manage their involvement with care professionals in the community setting. METHOD Interpretive phenomenology informs the design of the research, whereby 16 interviews were conducted with the patients and spouse-carers. Interviews were recorded and transcribed verbatim. Data were analysed using phenomenological techniques including template analysis. FINDINGS: Patients and spouse-carers were interdependent and both parties played a role in co-ordinating care and managing relationships with professional care providers. The patients and spouse-carers actively made choices about how to manage their situation, and develop and modify managing strategies based on their experiences. CONCLUSIONS: When daily management is effective and care professionals acknowledge the dyadic nature of the patient and spouse-carer relationship, people have confidence in living with advanced disease. PMID- 25526289 TI - Palliative care in Thailand. AB - In Thailand, several barriers exist that prevent people with life-limiting illnesses from accessing good-quality palliative care, namely: lack of palliative care providers; lack of training and education for the palliative care workforce; and issues with availability and distribution of opioids. Without palliative care, people suffer needlessly during the last months of their life. This paper gives an analysis of these issues and provides recommendations for clinical practice, research and health policy that may help to alleviate these issues. PMID- 25526290 TI - Improving family carers' experiences of support at the end of life by enhancing communication: an action research study. AB - BACKGROUND: This paper builds on findings from phase one of a participatory action research study, which investigated support for family carers at the end of life in an acute hospital setting in Scotland, UK ( Dosser and Kennedy, 2012 ). The research presented here is the second phase of the participatory action research study, in which nursing staff from an acute hospital ward are involved in ongoing analysis of data and ideas guided by action cycles and reflection. METHODS: Two key change initiatives are reported; improving nurses' communication skills and improving the environment for family carers of loved ones at the end of life within the acute hospital setting. To address these points, nurses were enrolled on a communications skills course, and a new room for family carers was integrated into the hospital. RESULTS: Data were analysed from interviews and questionnaires with the nurses, and from insights gathered in a reflective diary taken by the researcher. The changes implemented improved the confidence of participants in communicating with carers as well as patients and colleagues. CONCLUSION: The findings highlight practical strategies and communication issues that can potentially impact on the grief experience of family carers, such as having a safe space nearby to rest in private, away from the bedside. PMID- 25526293 TI - Surface-enhancement Raman scattering sensing strategy for discriminating trace mercuric ion (II) from real water samples in sensitive, specific, recyclable, and reproducible manners. AB - It is of essential importance to precisely probe mercury(II) (Hg(2+)) ions for environment-protection analysis and detection. To date, there still remain major challenges for accurate, specific, and reliable detection of Hg(2+) ions at subppt level. We herein employ gold nanoparticles (AuNPs) decorated silicon nanowire array (SiNWAr) as active surface-enhanced Raman scattering (SERS) substrates to construct a high-performance sensing platform assisted by DNA technology, enabling ultrasensitive detection of trace Hg(2+) in ~64 min and with low sample consumption (~30 MUL). Typically, strong SERS signals could be detected when the single-stranded DNA structure converts to the hairpin structure in the presence of Hg(2+) ions, due to the formation of thymine (T)-Hg(2+)-T. As a result, Hg(2+) ions with a low concentration of 1 pM (0.2 ppt) can be readily discriminated, much lower than those (~nM) reported for conventional analytical strategies. Water samples spiked with various Hg(2+) concentrations are further tested, exhibiting a good linear relationship between the normalized Raman intensities and the logarithmic concentrations of Hg(2+) ranging from 1 pM to 100 nM, with a correlation coefficient of R(2) = 0.998. In addition, such SERS sensor features excellent selectivity, facilely distinguishing Hg(2+) ions from various interfering substances. Moreover, this presented SERS sensor possesses good recyclability, preserving adaptable reproducibility during 5-time cyclic detection of Hg(2+). Furthermore, unknown Hg(2+) concentration in river water can be readily determined through our sensing strategy in accurate and reliable manners, with the RSD value of ~9%. PMID- 25526294 TI - How does aging affect recognition-based inference? A hierarchical Bayesian modeling approach. AB - The recognition heuristic (RH) is a simple strategy for probabilistic inference according to which recognized objects are judged to score higher on a criterion than unrecognized objects. In this article, a hierarchical Bayesian extension of the multinomial r-model is applied to measure use of the RH on the individual participant level and to re-evaluate differences between younger and older adults' strategy reliance across environments. Further, it is explored how individual r-model parameters relate to alternative measures of the use of recognition and other knowledge, such as adherence rates and indices from signal detection theory (SDT). Both younger and older adults used the RH substantially more often in an environment with high than low recognition validity, reflecting adaptivity in strategy use across environments. In extension of previous analyses (based on adherence rates), hierarchical modeling revealed that in an environment with low recognition validity, (a) older adults had a stronger tendency than younger adults to rely on the RH and (b) variability in RH use between individuals was larger than in an environment with high recognition validity; variability did not differ between age groups. Further, the r-model parameters correlated moderately with an SDT measure expressing how well people can discriminate cases where the RH leads to a correct vs. incorrect inference; this suggests that the r-model and the SDT measures may offer complementary insights into the use of recognition in decision making. In conclusion, younger and older adults are largely adaptive in their application of the RH, but cognitive aging may be associated with an increased tendency to rely on this strategy. PMID- 25526295 TI - Y-shaped biotin-conjugated poly (ethylene glycol)-poly (epsilon-caprolactone) copolymer for the targeted delivery of curcumin. AB - In order to improve curcumin's low water-solubility and selective delivery to cancer, we reported ligand-mediated micelles based on a Y-shaped biotin-poly (ethylene glycol)-poly (epsilon-caprolactone)2 (biotin-PEG-PCL2) copolymer. Its structure was characterized by (1)H NMR. The blank and drug-loaded micelles obtained by way of thin-film hydration were characterized by dynamic light scattering, X-ray diffraction, infrared spectroscopy and hemolytic test. Curcumin was loaded into micelles with a high encapsulating efficiency (93.83%). Curcumin's water-solubility was enhanced 170,400 times higher than free curcumin. Biotin-PEG-PCL2 micelles showed slower drug release in vitro than H2N-PEG-PCL2 micelles. In vitro cellular uptake and cytotoxicity tests showed that higher dosage of curcumin might overcome the effect of slow release on cytotoxicities because of its higher uptake induced by biotin, resulting in higher anticancer activities against MDA-MB-436 cells. In brief, Y-shaped biotin-PEG-PCL2 is a promising delivery carrier for anticancer drug. PMID- 25526296 TI - Colloidal stability of iron oxide nanoparticles with multivalent polymer surfactants. AB - This paper introduces a new approach for preparing magnetic colloidal suspensions with electrostatic repulsion between particles and polyelectrolyte surfactants. The surface charge of the iron oxide particles was positive in acidic aqueous conditions; however the surface charge of the colloid was negative in basic aqueous conditions due to the amphoteric property of Fe2O3. The long-term colloidal stability and particle distribution of the multivalent charged polymers, Poly(4-vinylbenzenesulfonate sodium salt) (PSS), Poly(acrylic acid) (PAA), and Poly(allylamine hydrochloride) (PAH) were compared with the monovalent surfactant sodium dodecyl sulfate (SDS). Both mono- and multivalent surfactant molecules showed good colloidal stability for extended periods of time. However, the particle distribution was dependent on the hydrophobicity of the surfactants' functional groups. Polyelectrolytes with a negatively charged functional group showed good long-term stability of particles and a narrow particle distribution regardless of the acid dissociation constant (pKa) of the polymer. PMID- 25526297 TI - Multi-layer three-dimensionally ordered bismuth trioxide/titanium dioxide nanocomposite: synthesis and enhanced photocatalytic activity. AB - Taking polystyrene latex spheres (PS) and EO20PO70EO20 (P123) as dual templates, and TiO2 was used as substrate, a series of multi-layer three dimensionally ordered macroporous (3DOM) composites Bi2O3/TiO2 were successfully synthesized with sol-gel method and post-processing calcination. The fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), UV-vis diffuse reflectance (UV-vis/DRS), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high resolution transmission electron microscopy (HR-TEM) and nitrogen adsorption desorption measurements were employed to analyze the crystalline phase, chemical composition, morphology, and surface physicochemical properties of as-synthetized samples. The results showed that as-composites were provided with obvious crystalline phase structure and periodically highly uniform ordered macroporous structure with mesoporous walls; moreover, of which was multi-layer three dimensionally ordered structure. As a result of unique optical properties of Bi2O3 and composite material structural characteristic being propitious to reactant molecular transmission and diffusion, the photocatalytic activities of 3DOM Bi2O3/TiO2 were enhanced, and the sample 3DOM Bi2O3/TiO2-2 was significantly higher than that of direct photolysis, P25, Bi2O3, and other 3DOM Bi2O3/TiO2-X (X=1, 3, 4) during the photocatalytic degradation of crystal violet under multi modes such as UV, visible light, simulated solar light, and microwave-assisted irradiation. The centrifugal samples water solution phase of TOC analysis indicated that water solution products formed with continued ultraviolet radiation, the intermediates eventually mineralized, volatilized, or were converted to other products. In addition, the photocatalytic activity of 3DOM Bi2O3/TiO2-2 composite was basically kept even after three cycles. Meanwhile, the possible photocatalytic reaction mechanism of as-synthesized material based on the experimental results was proposed. PMID- 25526298 TI - Adding to the STING. AB - STING (also known as MITA) is a central component in innate immunity against DNA virus. In this issue of Immunity, Wang et al. (2014) demonstrate that K27-linked polyubiquitination of STING (MITA) by the ER-associated E3 ligase AMFR is essential for STING (MITA)-mediated signaling and innate antiviral response. PMID- 25526299 TI - A Swiss Army knife for CTLs. AB - Granzyme B released by leukocytes cleaves multiple intracellular substrates required for target cell lysis. In this issue of Immunity, Prakash et al. (2014) demonstrate that granzyme B cleaves basement membrane proteins and promotes cytotoxic T cell diapedesis into inflamed tissue. PMID- 25526300 TI - Treg cells and CTLA-4: the ball and chain of the germinal center response. AB - The mechanism by which regulatory T cells control the germinal center response is unknown. In this issue of Immunity, Wing et al. (2014) and Sage et al. (2014) demonstrate that CTLA-4 is a critical effector molecule used by regulatory T cells to control the germinal center. PMID- 25526301 TI - The incognito journey of a regulatory B cell. AB - Regulatory B cells have largely been reported as B cells at a developmental stage before plasma cell differentiation. Matsumoto et al. (2014) report that IL-10(+) plasmablasts restrain autoimmune inflammation and suggest an ontological connection between immature B cells and regulatory plasmablasts. PMID- 25526302 TI - IL-17 cuts to the chase in colon cancer. AB - Although interleukin-17A (IL-17A) facilitates colon cancer development, its target cells remain elusive. In this issue of Immunity, Wang et al. (2014) now demonstrate that IL-17A receptors on the intestinal epithelium promote progression of APC mutant adenomas associated with IL-6 expression and that IL 17A confers chemotherapy resistance. PMID- 25526303 TI - Take your PICS: moving from GWAS to immune function. AB - Many of the hits identified through genome-wide association studies are located outside protein-coding regions, making it difficult to define mechanism. In Nature, Farh et al., (2014) describe an approach to identify causal variants in autoimmune disease as first step to assigning function. PMID- 25526304 TI - Tissue-resident memory T cells. AB - Tissue-resident memory T (Trm) cells constitute a recently identified lymphocyte lineage that occupies tissues without recirculating. They provide a first response against infections reencountered at body surfaces, where they accelerate pathogen clearance. Because Trm cells are not present within peripheral blood, they have not yet been well characterized, but are transcriptionally, phenotypically, and functionally distinct from recirculating central and effector memory T cells. In this review, we will summarize current knowledge of Trm cell ontogeny, regulation, maintenance, and function and will highlight technical considerations for studying this population. PMID- 25526305 TI - NOD1 and NOD2: signaling, host defense, and inflammatory disease. AB - The nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the founding members of the intracellular NOD-like receptor family, sense conserved motifs in bacterial peptidoglycan and induce proinflammatory and antimicrobial responses. Here, we discuss recent developments about the mechanisms by which NOD1 and NOD2 are activated by bacterial ligands, the regulation of their signaling pathways, and their role in host defense and inflammatory disease. Several routes for the entry of peptidoglycan ligands to the host cytosol to trigger activation of NOD1 and NOD2 have been elucidated. Furthermore, genetic screens and biochemical analyses have revealed mechanisms that regulate NOD1 and NOD2 signaling. Finally, recent studies have suggested several mechanisms to account for the link between NOD2 variants and susceptibility to Crohn's disease. Further understanding of NOD1 and NOD2 should provide new insight into the pathogenesis of disease and the development of new strategies to treat inflammatory and infectious disorders. PMID- 25526307 TI - The E3 ubiquitin ligase AMFR and INSIG1 bridge the activation of TBK1 kinase by modifying the adaptor STING. AB - Stimulator of interferon genes (STING, also known as MITA, ERIS, or MPYS) is essential for host immune responses triggered by microbial DNAs. However, the regulatory mechanisms underlying STING-mediated signaling are not fully understood. We report here that, upon cytoplasmic DNA stimulation, the endoplasmic reticulum (ER) protein AMFR was recruited to and interacted with STING in an insulin-induced gene 1 (INSIG1)-dependent manner. AMFR and INSIG1, an E3 ubiquitin ligase complex, then catalyzed the K27-linked polyubiquitination of STING. This modification served as an anchoring platform for recruiting TANK binding kinase 1 (TBK1) and facilitating its translocation to the perinuclear microsomes. Depletion of AMFR or INSIG1 impaired STING-mediated antiviral gene induction. Consistently, myeloid-cell-specific Insig1(-/-) mice were more susceptible to herpes simplex virus 1 (HSV-1) infection than wild-type mice. This study uncovers an essential role of the ER proteins AMFR and INSIG1 in innate immunity, revealing an important missing link in the STING signaling pathway. PMID- 25526308 TI - Noncanonical mode of ERK action controls alternative alphabeta and gammadelta T cell lineage fates. AB - Gradations in extracellular regulated kinase (ERK) signaling have been implicated in essentially every developmental checkpoint or differentiation process encountered by lymphocytes. Yet, despite intensive effort, the molecular basis by which differences in ERK activation specify alternative cell fates remains poorly understood. We report here that differential ERK signaling controls lymphoid-fate specification through an alternative mode of action. While ERK phosphorylates most substrates, such as RSK, by targeting them through its D-domain, this well studied mode of ERK action was dispensable for development of gammadelta T cells. Instead, development of gammadelta T cells was dependent upon an alternative mode of action mediated by the DEF-binding pocket (DBP) of ERK. This domain enabled ERK to bind a distinct and select set of proteins required for specification of the gammadelta fate. These data provide the first in vivo demonstration for the role of DBP-mediated interactions in orchestrating alternate ERK-dependent developmental outcomes. PMID- 25526306 TI - Antibody light-chain-restricted recognition of the site of immune pressure in the RV144 HIV-1 vaccine trial is phylogenetically conserved. AB - In HIV-1, the ability to mount antibody responses to conserved, neutralizing epitopes is critical for protection. Here we have studied the light chain usage of human and rhesus macaque antibodies targeted to a dominant region of the HIV-1 envelope second variable (V2) region involving lysine (K) 169, the site of immune pressure in the RV144 vaccine efficacy trial. We found that humans and rhesus macaques used orthologous lambda variable gene segments encoding a glutamic acid aspartic acid (ED) motif for K169 recognition. Structure determination of an unmutated ancestor antibody demonstrated that the V2 binding site was preconfigured for ED motif-mediated recognition prior to maturation. Thus, light chain usage for recognition of the site of immune pressure in the RV144 trial is highly conserved across species. These data indicate that the HIV-1 K169 recognizing ED motif has persisted over the diversification between rhesus macaques and humans, suggesting an evolutionary advantage of this antibody recognition mode. PMID- 25526309 TI - Granzyme B promotes cytotoxic lymphocyte transmigration via basement membrane remodeling. AB - Granzyme B (GzmB) is a protease with a well-characterized intracellular role in targeted destruction of compromised cells by cytotoxic lymphocytes. However, GzmB also cleaves extracellular matrix components, suggesting that it influences the interplay between cytotoxic lymphocytes and their environment. Here, we show that GzmB-null effector T cells and natural killer (NK) cells exhibited a cell autonomous homing deficit in mouse models of inflammation and Ectromelia virus infection. Intravital imaging of effector T cells in inflamed cremaster muscle venules revealed that GzmB-null cells adhered normally to the vessel wall and could extend lamellipodia through it but did not cross it efficiently. In vitro migration assays showed that active GzmB was released from migrating cytotoxic lymphocytes and enabled chemokine-driven movement through basement membranes. Finally, proteomic analysis demonstrated that GzmB cleaved basement membrane constituents. Our results highlight an important role for GzmB in expediting cytotoxic lymphocyte diapedesis via basement membrane remodeling. PMID- 25526310 TI - The E3 ubiquitin ligase Pellino3 protects against obesity-induced inflammation and insulin resistance. AB - Diet-induced obesity can induce low-level inflammation and insulin resistance. Interleukin-1beta (IL-1beta) is one of the key proinflammatory cytokines that contributes to the generation of insulin resistance and diabetes, but the mechanisms that regulate obesity-driven inflammation are ill defined. Here we found reduced expression of the E3 ubiquitin ligase Pellino3 in human abdominal adipose tissue from obese subjects and in adipose tissue of mice fed a high-fat diet and showing signs of insulin resistance. Pellino3-deficient mice demonstrated exacerbated high-fat-diet-induced inflammation, IL-1beta expression, and insulin resistance. Mechanistically, Pellino3 negatively regulated TNF receptor associated 6 (TRAF6)-mediated ubiquitination and stabilization of hypoxia-inducible factor 1alpha (HIF1alpha), resulting in reduced HIF1alpha induced expression of IL-1beta. Our studies identify a regulatory mechanism controlling diet-induced insulin resistance by highlighting a critical role for Pellino3 in regulating IL-1beta expression with implications for diseases like type 2 diabetes. PMID- 25526312 TI - Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4. AB - CD4(+)Foxp3-expressing Treg cells, which constitutively express the inhibitory coreceptor CTLA-4, are indispensable for immune homeostasis. We determined the roles of Treg cells and T follicular regulatory (Tfr) cells in the control of humoral immune responses. Depletion of Treg cells, blocking of CTLA-4 or a Treg cell specific reduction in CTLA-4 expression, resulted in an increase in the formation of antigen-specific Tfh cells, germinal center (GC), and plasma and memory B cells after vaccination. In the absence of Treg cell-expressed CTLA-4, large numbers of Tfr cells were present but were unable to restrain Tfh cell and GC formation. Temporary Treg cell depletion during primary immunization was sufficient to enhance secondary immune responses. Treg cells directly inhibited, via CTLA-4, B cell expression of CD80 and CD86, which was essential for Tfh cell formation. Thus, Treg and Tfr cells control Tfh cell and germinal center development, via CTLA-4-dependent regulation of CD80 and CD86 expression. PMID- 25526311 TI - Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis. AB - Decreased HIV-specific CD8(+) T cell proliferation is a hallmark of chronic infection, but the mechanisms of decline are unclear. We analyzed gene expression profiles from antigen-stimulated HIV-specific CD8(+) T cells from patients with controlled and uncontrolled infection and identified caspase-8 as a correlate of dysfunctional CD8(+) T cell proliferation. Caspase-8 activity was upregulated in HIV-specific CD8(+) T cells from progressors and correlated positively with disease progression and programmed cell death-1 (PD-1) expression, but negatively with proliferation. In addition, progressor cells displayed a decreased ability to upregulate membrane-associated caspase-8 activity and increased necrotic cell death following antigenic stimulation, implicating the programmed cell death pathway necroptosis. In vitro necroptosis blockade rescued HIV-specific CD8(+) T cell proliferation in progressors, as did silencing of necroptosis mediator RIPK3. Thus, chronic stimulation leading to upregulated caspase-8 activity contributes to dysfunctional HIV-specific CD8(+) T cell proliferation through activation of necroptosis and increased cell death. PMID- 25526316 TI - Highly efficient and selective photocatalytic oxidation of sulfide by a chromophore-catalyst dyad of ruthenium-based complexes. AB - Electronic coupling across a bridging ligand between a chromophore and a catalyst center has an important influence on biological and synthetic photocatalytic processes. Structural and associated electronic modifications of ligands may improve the efficiency of photocatalytic transformations of organic substrates. Two ruthenium-based supramolecular assemblies based on a chromophore-catalyst dyad containing a Ru-aqua complex and its chloro form as the catalytic components were synthesized and structurally characterized, and their spectroscopic and electrochemical properties were investigated. Under visible light irradiation and in the presence of [Co(NH3)5Cl]Cl2 as a sacrificial electron acceptor, both complexes exhibited good photocatalytic activity toward oxidation of sulfide into the corresponding sulfoxide with high efficiency and >99% product selectivity in neutral aqueous solution. The Ru-aqua complex assembly was more efficient than the chloro complex. Isotopic labeling experiments using (18)O-labeled water demonstrated the oxygen atom transfer from the water to the organic substrate, likely through the formation of an active intermediate, Ru(IV)?O. PMID- 25526313 TI - The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. AB - The receptor CTLA-4 has been implicated in controlling B cell responses, but the mechanisms by which CTLA-4 regulates antibody production are not known. Here we showed deletion of CTLA-4 in adult mice increased Tfh and Tfr cell numbers and augmented B cell responses. In the effector phase, loss of CTLA-4 on Tfh cells resulted in heightened B cell responses, whereas loss of CTLA-4 on Tfr cells resulted in defective suppression of antigen-specific antibody responses. We also found that non-Tfr Treg cells could suppress B cell responses through CTLA-4 and that Treg and/or Tfr cells might downregulate B7-2 on B cells outside germinal centers as a means of suppression. Within the germinal center, however, Tfr cells potently suppress B cells through CTLA-4, but with a mechanism independent of altering B7-1 or B7-2. Thus, we identify multifaceted regulatory roles for CTLA-4 in Tfh, Tfr, and Treg cells, which together control humoral immunity. PMID- 25526315 TI - SnapShot: Nucleic acid immune sensors, part 2. AB - The innate immune system has evolved sensors that can detect specific molecular fingerprints of non-self RNA or DNA. At the same time, some receptors respond to nucleic acids of both exogenous and endogenous origin, yet they are spatially segregated from endogenous nucleic acids. This SnapShot schematizes families and individual members of nucleic acid sensors with a focus on their ligands and the signaling pathways they employ. PMID- 25526317 TI - Validating the scalability of soft X-ray spectromicroscopy for quantitative soil ecology and biogeochemistry research. AB - Synchrotron-based soft-X-ray scanning transmission X-ray microscopy (STXM) has the potential to provide nanoscale resolution of the associations among biological and geological materials. However, standard methods for how samples should be prepared, measured, and analyzed to allow the results from these nanoscale imaging and spectroscopic tools to be scaled to field scale biogeochemical results are not well established. We utilized a simple sample preparation technique that allows one to assess detailed mineral, metal, and microbe spectroscopic information at the nano- and microscale in soil colloids. We then evaluated three common approaches to collect and process nano- and micronscale information by STXM and the correspondence of these approaches to millimeter scale soil measurements. Finally, we assessed the reproducibility and spatial autocorrelation of nano- and micronscale protein, Fe(II) and Fe(III) densities in a soil sample. We demonstrate that linear combination fitting of entire spectra provides slightly different Fe(II) mineral densities compared to image resonance difference mapping but that difference mapping results are highly reproducible between among sample replicates. Further, STXM results scale to the mm scale in complex systems with an approximate geospatial range of 3 MUm in these samples. PMID- 25526314 TI - Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis. AB - Interleukin-17A (IL-17A) is a pro-inflammatory cytokine linked to rapid malignant progression of colorectal cancer (CRC) and therapy resistance. IL-17A exerts its pro-tumorigenic activity through its type A receptor (IL-17RA). However, IL-17RA is expressed in many cell types, including hematopoietic, fibroblastoid, and epithelial cells, in the tumor microenvironment, and how IL-17RA engagement promotes colonic tumorigenesis is unknown. Here we show that IL-17RA signals directly within transformed colonic epithelial cells (enterocytes) to promote early tumor development. IL-17RA engagement activates ERK, p38 MAPK, and NF kappaB signaling and promotes the proliferation of tumorigenic enterocytes that just lost expression of the APC tumor suppressor. Although IL-17RA signaling also controls the production of IL-6, this mechanism makes only a partial contribution to colonic tumorigenesis. Combined treatment with chemotherapy, which induces IL 17A expression, and an IL-17A neutralizing antibody enhanced the therapeutic responsiveness of established colon tumors. These findings establish IL-17A and IL-17RA as therapeutic targets in colorectal cancer. PMID- 25526318 TI - Correction to "photophysics and rotational diffusion of hydrophilic molecule in polymer and polyols". PMID- 25526319 TI - Improving energy conversion efficiency for triboelectric nanogenerator with capacitor structure by maximizing surface charge density. AB - Nanogenerators with capacitor structures based on piezoelectricity, pyroelectricity, triboelectricity and electrostatic induction have been extensively investigated. Although the electron flow on electrodes is well understood, the maximum efficiency-dependent structure design is not clearly known. In this paper, a clear understanding of triboelectric generators with capacitor structures is presented by the investigation of polydimethylsiloxane based composite film nanogenerators, indicating that the generator, in fact, acts as both an energy storage and output device. Maximum energy storage and output depend on the maximum charge density on the dielectric polymer surface, which is determined by the capacitance of the device. The effective thickness of polydimethylsiloxane can be greatly reduced by mixing a suitable amount of conductive nanoparticles into the polymer, through which the charge density on the polymer surface can be greatly increased. This finding can be applied to all the triboelectric nanogenerators with capacitor structures, and it provides an important guide to the structural design for nanogenerators. It is demonstrated that graphite particles with sizes of 20-40 nm and 3.0% mass mixed into the polydimethylsiloxane can reduce 34.68% of the effective thickness of the dielectric film and increase the surface charges by 111.27% on the dielectric film. The output power density of the triboelectric nanogenerator with the composite polydimethylsiloxane film is 3.7 W m(-2), which is 2.6 times as much as that of the pure polydimethylsiloxane film. PMID- 25526321 TI - Correction: All-solid-state Z-scheme system arrays of Fe2V4O13/RGO/CdS for visible light-driving photocatalytic CO2 reduction into renewable hydrocarbon fuel. AB - Correction for 'All-solid-state Z-scheme system arrays of Fe2V4O13/RGO/CdS for visible light-driving photocatalytic CO2 reduction into renewable hydrocarbon fuel' by Ping Li et al., Chem. Commun., 2015, 51, 800-803. PMID- 25526320 TI - Lymphatic Stomata in the Adult Human Pulmonary Ligament. AB - BACKGROUND: Lymphatic stomata are small lymphatic openings in the serosal membrane that communicate with the serosal cavity. Although these stomata have primarily been studied in experimental mammals, little is known concerning the presence and properties of lymphatic stomata in the adult human pleura. Thus, adult human pleurae were examined for the presence or absence of lymphatic stomata. METHODS AND RESULTS: A total of 26 pulmonary ligaments (13 left and 13 right) were obtained from 15 adult human autopsy cases and examined using electron and light microscopy. The microscopic studies revealed the presence of apertures fringed with D2-40-positive, CD31-positive, and cytokeratin-negative endothelial cells directly communicating with submesothelial lymphatics in all of the pulmonary ligaments. The apertures' sizes and densities varied from case to case according to the serial tissue section. The medians of these aperture sizes ranged from 2.25 to 8.75 MUm in the left pulmonary ligaments and from 2.50 to 12.50 MUm in the right pulmonary ligaments. The densities of the apertures ranged from 2 to 9 per mm(2) in the left pulmonary ligaments and from 2 to 18 per mm(2) in the right pulmonary ligaments. However, no significant differences were found regarding the aperture size (p=0.359) and density (p=0.438) between the left and the right pulmonary ligaments. CONCLUSIONS: Our study revealed that apertures exhibit structural adequacy as lymphatic stomata on the surface of the pulmonary ligament, thereby providing evidence that lymphatic stomata are present in the adult human pleura. PMID- 25526329 TI - Primary cutaneous follicle-center lymphoma. AB - We present a 64-year-old man with a three-year history of pruritic, pink papules and nodules of the face who was found to have a clonal lymphoproliferative B-cell disease that was characterized by a clonal IGH rearrangement. Although morphologic features present in the biopsy specimen were consistent with a reactive process, additional clinicopathologic correlation (anatomic presentation of lesions on the face, the absence of t(14:18) translocation, and bcl-2 and MUM1 expression) reinforced suspicion of a cutaneous B-cell lymphoma. Systemic work-up with CT/PET and a bone marrow biopsy ultimately excluded systemic disease and primary cutaneous follicle-center lymphoma (PCFCL) was a strong diagnostic consideration. The patient was treated with systemic rituximab with a partial resolution of the facial lesions. The case demonstrates both clinical and pathologic challenges to the diagnosis of primary cutaneous B-cell lymphoma (PCBCL). Furthermore, despite a newly refined classification system, the case also specifically highlights the persistent requirement for flexible clinical reasoning and pathologic correlation. Such reasoning is necessary to generate individualized strategies for diagnosis and treatment when cutaneous B-cell lymphoma is suspected. PMID- 25526322 TI - Reproducibility and Sensitivity of the 6-Minute Stepper Test in Patients with COPD. AB - The aims of this study were to test the reproducibility of the 6-minute stepper test (6MST), and evaluate its accuracy in detecting improved functional capacity after pulmonary rehabilitation (PR) in patients with chronic obstructive pulmonary disease (COPD). Thirty-five COPD outpatients performed two 6MSTs in the same session, before (6MST1 and 6MST2) and after (6MST3 and 6MST4) PR. The performance, perceived exertion, heart rate and arterial oxygen saturation were measured during each 6MST. The performance was higher during the second 6MST of the same session (before PR: 514 strokes during the 6MST2 > 471 strokes during the 6MST1, and after PR: 559 strokes during the 6MST4 > 508 strokes during the 6MST3; p = 0.04). After PR, 6MST performance was higher than before PR (6MST3 > 6MST1 and 6MST4 > 6MST2; P < 0.01). The bias (the difference in the number of strokes) between the two 6MSTs from the same session (before PR: 6MST2-6MST1 = 42 strokes vs after PR: 6MST4-6MST3 = 52 strokes) was not different (P = 0.34). However, both bias were greater than 0 (P < 0.001). The mean performances for the two 6MSTs of the same session (before PR: 6MST1 and 6MST2 and after PR: 6MST3 and 6MST4) were correlated with the bias between these performances (P < 0.01; r = 0.32). The perceived exertions were lower after PR (P < 0.02). The systematic improvement of performance (8-10%) during the second 6MST of the each session may be explained from the warming of hydraulic jacks of the stepper and/or learning effect. On the other hand, the 6MST seems sufficiently sensitive to detect functional capacity improvements after PR in patients with COPD. PMID- 25526330 TI - Indeterminate cell histiocytosis that presented clinically as benign cephalic histiocytosis. AB - Indeterminate cell histiocytosis (ICH) is a rare, heterogeneous disorder that is characterized by immunophenotypic features of both Langerhans cell histiocytosis (LCH) and non-LCH. We describe a 12-month-old boy with a four-month history of asymptomatic, small, pink-tan papules on his face. Histopathologic evaluation showed a superficial, dermal infiltrate of histiocytes that was positive for S100, CD1a, CD68, and Factor XIIIa. To our knowledge, this represents the first report of the clinical presentation of benign cephalic histiocytosis with immunohistochemical findings of ICH. We review the classification of histiocytic disorders and the clinical and immunohistochemical features of both ICH and benign cephalic histiocytosis. PMID- 25526331 TI - New world cutaneous leishmaniasis. AB - A 24-year-old Bangladeshi man presented with a 12-week history of a pruritic papule on his left elbow that had enlarged and ulcerated. He was without any constitutional or systemic symptoms. He reported a history of extensive travel in the two years prior to presentation that included Bangladesh, South and Central America, and Mexico. Histopathologic features were consistent with leishmaniasis. Speciation by the Centers for Disease Control showed L. brasiliensis. PMID- 25526332 TI - Plate-like osteoma cutis. AB - Osteoma cutis is the aberrant development of bone within the skin. The bone formation may be de novo (primary) or result from an injury to the skin (secondary). Here we present a healthy 53-year-old man with no known abnormalities in calcium or phosphate metabolism with plate-like osteoma cutis of the scalp. Plate- or plaque-like osteoma cutis was initially described as a congenital condition but has now been reported several times in the literature as an idiopathic process that occurs in adults. Treatment options are limited and are only required if the lesion is bothersome to the patient. PMID- 25526333 TI - Exogenous ochronosis. AB - We present a case of exogenous ochronosis in a 53-year-old woman with skin type IV, who used a topical hydroquinone preparation of an unknown concentration for several years. Traditionally, exogenous ochronosis was thought to occur exclusively in patients with darker skin types who use high concentrations of hydroquinone cream. Reports now document cases in patients of all skin types and in patients even using low concentrations of hydroquinone cream for short periods of time. Although the incidence of exogenous ochronosis in the United States is unclear, it may be more common than many clinicians believe. It is important for clinicians and patients to be aware of exogenous ochronosis in order to prevent exacerbation in patients with this rare side effect. PMID- 25526334 TI - White fibrous papulosis of the neck. AB - We present a 76-year old woman with a five-year history of asymptomatic, white papules that were grouped on the lateral and posterior aspects of the neck, inferior axillae, and central mid-back. The histopathologic findings showed thickened collagen bundles. A diagnosis of white fibrous papulosis of the neck was made, which is believed to be a manifestation of intrinsic aging. There are no treatments for white fibrous papulosis of the neck. One hypothesized approach is the application of a topical anti-oxidant to reduce free-radical induced aging. PMID- 25526335 TI - Netherton syndrome with ichthyosis linearis circumflexa and trichorrhexis invaginatum. AB - Netherton syndrome is a rare, autosomal recessive disorder that is characterized by congenital ichthyosis, trichorrhexis invaginata, and atopic diathesis. Ichthyosis presents at birth with erythroderma and subsequently evolves into ichthyosis linearis circumflexa; hair shaft abnormalities tend to present later. The disorder is caused by loss-of-function mutations in the SPINK5 (serine protease inhibitor Kazal-type 5) gene that encodes LEKTI (lympho-epithelial Kazal type related inhibitor), which is a protease inhibitor that counteracts epidermal proteases involved in desquamation. Use of topical medications is limited by potential for systemic absorption and toxicity in the setting of a defective skin barrier. Therapeutic options include topical glucocorticoids and retinoids, oral retinoids, and narrowband ultraviolet B phototherapy. Topical tacrolimus has been shown to be efficacious and may be used safely with careful laboratory monitoring. PMID- 25526336 TI - Cranial fasciitis. AB - A 26-year-old man presented with an 18-month history of a subcutaneous mass on his forehead that occurred shortly after being struck by a blunt object. Histopathologic examination showed a proliferation of bland spindle cells and a collagenous stroma that was consistent with cranial fasciitis. Cranial fasciitis, which is a variant of nodular fasciitis, is a benign fibroblastic neoplasm that overlies the skull and often is associated with trauma. Although its rapid onset may give the clinical impression of a malignant condition, cranial fasciitis typically is cured by simple excision without further sequelae. PMID- 25526337 TI - Nevus lipomatosus superficialis. AB - Nevus lipomatosus superficialis is an uncommon cutaneous hamartoma that is characterized by the presence of adipose tissue within the reticular dermis. We describe a 15-year-old boy with a three-year history of the classic type of nevus lipomatosus superficialis, which presented as linear arrays of soft, cerebriform papulonodules and plaques in the right inguinal fold. Investigation for chromosomal aberrations and dysregulation of Wnt signaling may provide insights into the pathogenesis of this hamartoma. Treatment is usually with surgical excision although successful use of other modalities has been described. PMID- 25526338 TI - Candida parapsilosis of the nail-bed without onychomycosis. AB - Candida parapsilosis is an emerging fungal pathogen that was once thought to be solely a colonizing organism. C. parapsilosis is increasingly becoming reported as the most common Candida species that causes onychomycosis. Clinical findings include typically severe dystrophy of the nail fold and plate as well as thickening and fragmentation of the plate, particularly in the distal plate. We present a unique case of C. parapsilosis infection of the nail bed without infection of the nail plate and with twenty-nail melanonychia. PMID- 25526339 TI - Vegetative pyoderma gangrenosum. AB - Vegetative pyoderma gangrenosum is a rare, superficial variant of pyoderma gangrenosum that is more commonly found on the trunk as single or multiple, non painful lesions. There is typically no associated underlying systemic disease. Compared to classic pyoderma gangrenosum, vegetative lesions are more likely to heal without the use of systemic glucocorticoids, although up to 39% of patients required a short course of prednisone in a review of 46 cases. Treatments for vegetative pyoderma gangrenosum include topical and intralesional glucocorticoids, minocycline or doxycycline, dapsone, colchicine, and, rarely, alternative steroid-sparing immunosuppressants. We present a case of multiple vegetative pyoderma gangrenosum lesions arising in prior surgical sites in a patient found to have IgA monoclonal gammopathy and abnormal urinary protein electrophoresis. PMID- 25526340 TI - Nail lichen planus in a patient with alopecia totalis. AB - A 67-year-old man with a three-year history of non-scarring alopecia that progressed to alopecia totalis despite intralesional glucocorticoid injections is presented. He developed 20-nail dystrophy that was recalcitrant to antifungal and anti-inflammatory treatments. Biopsy of the nail matrix showed histopathologic features of lichen planus. Alopecia totalis and isolated lichen planus of the nails are uncommon subtypes of common dermatologic disorders. Rarely reported concurrently, we provide a review of the literature of their association, which is most likely attributed to their autoimmune pathogeneses. PMID- 25526341 TI - Palmoplantar lichen planus. AB - Palmoplantar lichen planus (PPLP) is an uncommon variant of lichen planus that affects the palms and soles. Clinical findings are varied although they have been conceptualized into two large groupings, an erythematous scaly pattern and a hyperkeratotic pattern. Histopathologic features are those of classic LP. We present a case of PPLP that improved with methotrexate after failing treatment with acitretin. PMID- 25526342 TI - Dermatitis herpetiformis. AB - Dermatitis herpetiformis (DH) is an autoimmune bullous disease, which represents the cutaneous manifestation of gluten sensitivity, in the setting of celiac disease. Although classical DH is characterized clinically by grouped, vesicles on an erythematous base, primary lesions often are absent owing to the intense, associated pruritus. Instead, many cases present only with erythematous erosions with numerous overlying excoriations. As in celiac disease, the core pathogenic mechanisms of DH are likely mediated by immunoglobulin A class autoantibodies against one of several transglutaminase enzymes. As the production of these autoantibodies is directly correlated with gastrointestinal exposure to gliadin, which is an alcohol-soluble fraction of gluten, a gluten-free diet represents the cornerstone of a DH management regimen. In cases refractory to dietary management alone, dapsone is the first-line agent for the treatment of DH, although many other agents have been anecdotally reported as effective. PMID- 25526343 TI - Pemphigus foliaceus. AB - A 55-year-old woman presented after a four-year history of impetiginized eczema that was distributed over her face, scalp, chest, and back and a recent diagnosis of breast cancer. A skin biopsy specimen for direct immunofluorescence demonstrated intercellular IgG4. Anti-desmoglein 1 and 3 antibodies were present. Indirect immunofluorescence testing was positive on monkey but not rat esophagus. These findings were consistent with a diagnosis of pemphigus foliaceus in association with a malignant condition. After many years of the use of topical glucocorticoids and oral antibiotics, the patient's disease was ultimately managed with methotrexate and a small dose of prednisone. Increasing data supports a role for a steroid-sparing effect of methotrexate in pemphigus vulgaris and likely pemphigus foliaceus. PMID- 25526344 TI - Collision tumor of eccrine poroma, seborrheic keratosis, and a viral wart. AB - A 68-year-old woman presented for evaluation of a large, red-brown plaque on her left buttock with irregular borders and prominent overlying verrucous changes. The plaque had been present since childhood but over a three-year period had been enlarging with increasing nodularity and easy bleeding with trauma. Histopathologic examination demonstrated an enlarged papillated and polypoid heterogeneous lesion. In part of the specimen, there are bulbous aggregates of small squamous cells with foci of eccrine ductal differentiation. There are other areas with horn pseudocysts, hypergranulosis, and compact orthokeratosis with parakeratosis. There are scattered enlarged heavily pigmented melanocytes, some of which have long and thick dendrites. This collision tumor consisted of an eccrine poroma, a seborrheic keratosis, and a viral wart. The clinical and histopathologic features of collision tumors and poromas are reviewed. PMID- 25526345 TI - Adiposis dolorosa. AB - We report a 46-year-old woman with a nine-year history of obesity; chronic diffuse pain in the adipose tissue of her medial upper arms, lower trunk, and thighs; multiple biopsy-proven lipomas and angiolipomas; and a lipomatous pseudomass of the breast. Her systemic symptoms included generalized weakness, fatigue, memory impairment, and arthralgias. Although some of the lesions were tender, most were only appreciated with palpation. Her clinical history and histopathologic data suggested adiposis dolorosa (Dercum's disease). Owing to the chronic pain, an interdisciplinary approach with the use of analgesics and doxycycline has been initiated. PMID- 25526346 TI - Mutational landscape of intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is a fatal primary liver cancer (PLC) that affects 5-10% of all PLCs. Here we sequence tumour and matching control sample pairs of a large cohort of 103 ICC patients in China, resulting in the identification of an ICC-specific somatic mutational signature that is associated with liver inflammation, fibrosis and cirrhosis. We further uncover 25 significantly mutated genes including eight potential driver genes (TP53, KRAS, IDH1, PTEN, ARID1A, EPPK1, ECE2 and FYN). We find that TP53-defective ICC patients are more likely to be HBsAg-seropositive, whereas mutations in the oncogene KRAS are nearly exclusively found in HBsAg-seronegative ICC patients. Three pathways (Ras/phosphatidylinositol-4,5-bisphosphate 3-kinase signalling, p53/cell cycle signalling and transforming growth factor-beta/Smad signalling), genes important for epigenetic regulation and oxidative phosphorylation are substantially affected in ICC. We reveal mutations in this study that may be valuable for designing further studies, better diagnosis and effective therapies. PMID- 25526354 TI - Electrochemical modification of indium tin oxide using di(4-nitrophenyl) iodonium tetrafluoroborate. AB - Optoelectronic applications often rely on indium tin oxide (ITO) as a transparent electrode material. Improvements in the performance of such devices as photovoltaics and light-emitting diodes often requires robust, controllable modification of the ITO surface to enhance interfacial charge transfer properties. In this work, modifier films were deposited onto ITO by the electrochemical reduction of di(4-nitrophenyl) iodonium tetrafluoroborate (DNP), allowing for control over surface functionalization. The surface coverage could be tuned from submonolayer to multilayer coverage by either varying the DNP concentration or the number of cyclic voltammetry (CV) grafting scans. Modification of ITO with 0.8 mM DNP resulted in near-monolayer surface coverage (4.95 * 10(14) molecules/cm(2)). X-ray photoelectron spectroscopy (XPS) analysis confirmed the presence of 4-nitrophenyl (NO2Ph) moieties on the ITO surface through the detection of a NO2 nitrogen signal at 405.6 eV after grafting. Further XPS evidence suggests that the NO2Ph radicals do not bond to the surface indium or tin sites, consistent with modification occurring either through bonding to surface hydroxyl groups or through strong physisorption on ITO. CV in the presence of an electroactive probe and electrochemical impedance spectroscopy (EIS) were used to investigate the electronic effects that modification via DNP has on ITO. Even at submonolayer coverage, the insulating organic films can reduce the current response to ferrocene oxidation and reduction by more than 25% and increase the charge transfer resistance by a factor of 10. PMID- 25526356 TI - HiCoDG: a hierarchical data-gathering scheme using cooperative multiple mobile elements. AB - In this paper, we study mobile element (ME)-based data-gathering schemes in wireless sensor networks. Due to the physical speed limits of mobile elements, the existing data-gathering schemes that use mobile elements can suffer from high data-gathering latency. In order to address this problem, this paper proposes a new hierarchical and cooperative data-gathering (HiCoDG) scheme that enables multiple mobile elements to cooperate with each other to collect and relay data. In HiCoDG, two types of mobile elements are used: the mobile collector (MC) and the mobile relay (MR). MCs collect data from sensors and forward them to the MR, which will deliver them to the sink. In this work, we also formulated an integer linear programming (ILP) optimization problem to find the optimal trajectories for MCs and the MR, such that the traveling distance of MEs is minimized. Two variants of HiCoDG, intermediate station (IS)-based and cooperative movement scheduling (CMS)-based, are proposed to facilitate cooperative data forwarding from MCs to the MR. An analytical model for estimating the average data-gathering latency in HiCoDG was also designed. Simulations were performed to compare the performance of the IS and CMS variants, as well as a multiple traveling salesman problem (mTSP)-based approach. The simulation results show that HiCoDG outperforms mTSP in terms of latency. The results also show that CMS can achieve the lowest latency with low energy consumption. PMID- 25526355 TI - Combination of early constraint-induced movement therapy and fasudil enhances motor recovery after ischemic stroke in rats. AB - PURPOSE: Constraint-induced movement therapy (CIMT) is a promising technique for the recovery of upper extremity movement in chronic stroke patients. However, the effectiveness of its use in acute ischemia has not been confirmed. Myelin associated inhibitors, which have upregulated functions in tissues affected by acute focal infarction, limit axonal regeneration via activation of the Rho-Rho associated protein kinase (ROCK) pathway. The present study examined whether early CIMT combined with the ROCK inhibitor fasudil promotes motor recovery after acute ischemic stroke. MATERIALS AND METHODS: Rats were trained to perform the skilled-reach test and then subjected to middle cerebral artery occlusion (MCAO), producing a stroke affecting the preferred forelimb. Rats were assigned to one of four groups (N = 6/group): (nontreated) Control, CIMT, Fasudil, or CIMT+fasudil. CIMT and/or intraperitoneal infusion of fasudil were initiated 1 day postMCAO. Skilled reach and foot fault test data were collected once before and repeatedly over 4 weeks after the operation. Infarct volumes were calculated. RESULTS: All four groups showed similar forelimb impairment before treatment. The performance of CIMT alone group was similar to that of controls on both tests. Fasudil alone facilitated recovery in the foot-fault test, but not in the skilled-reach test. Rats in the CIMT+fasudil group demonstrated enhanced recovery in both tests, including better performance over time than the Fasudil group on the foot-fault test. Infarct size did not differ significantly between the groups. CONCLUSIONS: Early CIMT promotes motor recovery after acute ischemic stroke when it is administered with fasudil pharmacotherapy, but not without it. PMID- 25526357 TI - Effective low-power wearable wireless surface EMG sensor design based on analog compressed sensing. AB - Surface Electromyography (sEMG) is a non-invasive measurement process that does not involve tools and instruments to break the skin or physically enter the body to investigate and evaluate the muscular activities produced by skeletal muscles. The main drawbacks of existing sEMG systems are: (1) they are not able to provide real-time monitoring; (2) they suffer from long processing time and low speed; (3) they are not effective for wireless healthcare systems because they consume huge power. In this work, we present an analog-based Compressed Sensing (CS) architecture, which consists of three novel algorithms for design and implementation of wearable wireless sEMG bio-sensor. At the transmitter side, two new algorithms are presented in order to apply the analog-CS theory before Analog to Digital Converter (ADC). At the receiver side, a robust reconstruction algorithm based on a combination of l1-l1-optimization and Block Sparse Bayesian Learning (BSBL) framework is presented to reconstruct the original bio-signals from the compressed bio-signals. The proposed architecture allows reducing the sampling rate to 25% of Nyquist Rate (NR). In addition, the proposed architecture reduces the power consumption to 40%, Percentage Residual Difference (PRD) to 24%, Root Mean Squared Error (RMSE) to 2%, and the computation time from 22 s to 9.01 s, which provide good background for establishing wearable wireless healthcare systems. The proposed architecture achieves robust performance in low Signal-to-Noise Ratio (SNR) for the reconstruction process. PMID- 25526358 TI - All-optical graphene oxide humidity sensors. AB - The optical characteristics of graphene oxide (GO) were explored to design and fabricate a GO-based optical humidity sensor. GO film was coated onto a SU8 polymer channel waveguide using the drop-casting technique. The proposed sensor shows a high TE-mode absorption at 1550 nm. Due to the dependence of the dielectric properties of the GO film on water content, this high TE-mode absorption decreases when the ambient relative humidity increases. The proposed sensor shows a rapid response (<1 s) to periodically interrupted humid air flow. The transmission of the proposed sensor shows a linear response of 0.553 dB/% RH in the range of 60% to 100% RH. PMID- 25526359 TI - Inertial sensor-based smoother for gait analysis. AB - An off-line smoother algorithm is proposed to estimate foot motion using an inertial sensor unit (three-axis gyroscopes and accelerometers) attached to a shoe. The smoother gives more accurate foot motion estimation than filter-based algorithms by using all of the sensor data instead of using the current sensor data. The algorithm consists of two parts. In the first part, a Kalman filter is used to obtain initial foot motion estimation. In the second part, the error in the initial estimation is compensated using a smoother, where the problem is formulated in the quadratic optimization problem. An efficient solution of the quadratic optimization problem is given using the sparse structure. Through experiments, it is shown that the proposed algorithm can estimate foot motion more accurately than a filter-based algorithm with reasonable computation time. In particular, there is significant improvement in the foot motion estimation when the foot is moving off the floor: the z-axis position error squared sum (total time: 3.47 s) when the foot is in the air is 0.0807 m2 (Kalman filter) and 0.0020 m2 (the proposed smoother). PMID- 25526361 TI - An equation to calculate internuclear distances of covalent, ionic and metallic lattices. AB - This paper briefly describes the many different sets of ionic and covalent radii available. A simple model of ionic and covalent bonding is proposed and an equation to calculate internuclear distances of covalent, ionic and metallic lattices is described. Derivation of covalent radii and the use of a proposed model of metallic structure and bonding to derive ionic radii are discussed. A brief summary of the development of the simple equation for calculating internuclear distances of ionic compounds is provided. Values of internuclear distances calculated from the derived radii are compared to observed values and give good agreement, showing strong evidence that ionic and covalent radii are not additive and electronegativity influences bonding and internuclear distances. Ionic radii derived from the proposed model are applied to calculate lattice energies which agree well with literature values/values calculated by the Born Haber cycle. Work functions of transition metals are shown to be simple inverse functions of the derived radii. Internuclear distances of inter-metallic compounds are calculated and compared with observed values to show good agreement. This work shows that the proposed model of metallic structure complements the band theory and expressions introduced in this work can be used to predict ionic and covalent bond lengths (in different environments) that have not yet been determined as well as being a method for resolving bond type. PMID- 25526360 TI - The value of routine biopsy during percutaneous kyphoplasty for vertebral compression fractures. AB - OBJECTIVE: Percutaneous kyphoplasty (PKP) is now widely performed to treat VCF, which is usually caused by osteoporosis. Previous researches have reported unsuspected malignancies found by biopsy. However, the safety and cost-effective profiles of routine biopsy during PKP are unclear. The purpose of this study was to evaluate the feasibility of routine biopsy during PKP in treatment of VCF. METHODS: Ninety-three patients (September 2007-November 2010) undergoing PKP without biopsy were reviewed as the control group. One hundred and three consecutive patients (November 2010-September 2013) undergoing PKP with biopsy of every operated vertebral level were prospectively enrolled as the biopsy group. The rate of unsuspected lesions was reported, and the severe adverse events, surgical duration, cement leakage rate and pain control were compared between the two groups. RESULTS: No statistically significant differences were found between the two groups, regarding the severe adverse events, surgical duration, cement leakage rate and pain control. Four unsuspected lesions were found in the biopsy group, three of which were malignancies with a 2.9% (3/103) unsuspected malignancy rate. The economic analysis showed that routine biopsy was cost effective in finding new malignancies comparing with a routine cancer screening campaign. CONCLUSIONS: Routine biopsy during PKP was safe and cost-effective in finding unsuspected malignancies. We advocate routine biopsy in every operated vertebral level during PKP for VCF patients. PMID- 25526362 TI - Changes in pH and NADPH regulate the DNA binding activity of neuronal PAS domain protein 2, a mammalian circadian transcription factor. AB - Neuronal PAS domain protein 2 (NPAS2) is a core clock transcription factor that forms a heterodimer with BMAL1 to bind the E-box in the promoter of clock genes and is regulated by various environmental stimuli such as heme, carbon monoxide, and NAD(P)H. In this study, we investigated the effects of pH and NADPH on the DNA binding activity of NPAS2. In an electrophoretic mobility shift (EMS) assay, the pH of the reaction mixture affected the DNA binding activity of the NPAS2/BMAL1 heterodimer but not that of the BMAL1/BMAL1 homodimer. A change in pH from 7.0 to 7.5 resulted in a 1.7-fold increase in activity in the absence of NADPH, and NADPH additively enhanced the activity up to 2.7-fold at pH 7.5. The experiments using truncated mutants revealed that N-terminal amino acids 1-61 of NPAS2 were sufficient to sense the change in both pH and NADPH. We further analyzed the kinetics of formation and DNA binding of the NPAS2/BMAL1 heterodimer at various pH values. In the absence of NADPH, a change in pH from 6.5 to 8.0 decreased the KD(app) value of the E-box from 125 to 22 nM, with an 8-fold increase in the maximal level of DNA binding for the NPAS2/BMAL1 heterodimer. The addition of NADPH resulted in a further decrease in KD(app) to 9 nM at pH 8.0. Furthermore, NPAS2-dependent transcriptional activity in a luciferase assay using NIH3T3 cells also increased with the pH of the culture medium. These results suggest that NPAS2 has a role as a pH and metabolite sensor in regulating circadian rhythms. PMID- 25526365 TI - A sensitive and microscale method for drug screening combining affinity probes and single molecule fluorescence correlation spectroscopy. AB - In this paper, a sensitive and microscale method for drug screening is described using single molecule spectroscopy fluorescence correlation spectroscopy (FCS). The principle of this method is mainly based on the competition of candidate drugs to the fluorescent probe-target complexes and the excellent capacity of FCS for sensitively distinguishing the free fluorescent probes and the fluorescent probe-target complexes in solution. In this study, the screening of protein kinase inhibitors was used as a model, tyrosine-protein kinase ABL1 was used as a target and a known inhibitor dasatinib derivative labeled with a fluorescent dye was used as a fluorescent affinity probe. We firstly established the theoretical model of drug screening based on the binding process of fluorescent probes and targets, the competition of candidate drugs to the fluorescent probe-target complexes and FCS theory. Then, the dasatinib derivatives were synthesized and labeled with the fluorescent dye Alexa 488, and the binding and dissociation processes of Alexa 488-dasatinib and ABL1 were systematically investigated. The dissociation constant and the dissociation rate for the Alexa 488-dasatinib-ABL1 complex were determined. Finally, the established method was used to screen candidate drugs. The dissociation constants of ABL1 kinase to six known drugs for treating chronic myeloid leukemia (CML) were evaluated and the results obtained are well consistent with the reported values. Furthermore, a homemade chip with micro-wells was successfully utilized in FCS measurements as the carrier of samples, and the sample requirements were only 1-2 MUL in this case. Our results demonstrated that the drug screening method described here is universal, sensitive and shows small sample and reagent quantity requirements. We believe that this method will become a high throughput platform for screening of small molecule drugs. PMID- 25526364 TI - Integrated analysis of whole genome and transcriptome sequencing reveals diverse transcriptomic aberrations driven by somatic genomic changes in liver cancers. AB - Recent studies applying high-throughput sequencing technologies have identified several recurrently mutated genes and pathways in multiple cancer genomes. However, transcriptional consequences from these genomic alterations in cancer genome remain unclear. In this study, we performed integrated and comparative analyses of whole genomes and transcriptomes of 22 hepatitis B virus (HBV) related hepatocellular carcinomas (HCCs) and their matched controls. Comparison of whole genome sequence (WGS) and RNA-Seq revealed much evidence that various types of genomic mutations triggered diverse transcriptional changes. Not only splice-site mutations, but also silent mutations in coding regions, deep intronic mutations and structural changes caused splicing aberrations. HBV integrations generated diverse patterns of virus-human fusion transcripts depending on affected gene, such as TERT, CDK15, FN1 and MLL4. Structural variations could drive over-expression of genes such as WNT ligands, with/without creating gene fusions. Furthermore, by taking account of genomic mutations causing transcriptional aberrations, we could improve the sensitivity of deleterious mutation detection in known cancer driver genes (TP53, AXIN1, ARID2, RPS6KA3), and identified recurrent disruptions in putative cancer driver genes such as HNF4A, CPS1, TSC1 and THRAP3 in HCCs. These findings indicate genomic alterations in cancer genome have diverse transcriptomic effects, and integrated analysis of WGS and RNA-Seq can facilitate the interpretation of a large number of genomic alterations detected in cancer genome. PMID- 25526367 TI - Microtubule-dependent modulation of adhesion complex composition. AB - The microtubule network regulates the turnover of integrin-containing adhesion complexes to stimulate cell migration. Disruption of the microtubule network results in an enlargement of adhesion complex size due to increased RhoA stimulated actomyosin contractility, and inhibition of adhesion complex turnover; however, the microtubule-dependent changes in adhesion complex composition have not been studied in a global, unbiased manner. Here we used label-free quantitative mass spectrometry-based proteomics to determine adhesion complex changes that occur upon microtubule disruption with nocodazole. Nocodazole treated cells displayed an increased abundance of the majority of known adhesion complex components, but no change in the levels of the fibronectin-binding alpha5beta1 integrin. Immunofluorescence analyses confirmed these findings, but revealed a change in localisation of adhesion complex components. Specifically, in untreated cells, alpha5-integrin co-localised with vinculin at peripherally located focal adhesions and with tensin at centrally located fibrillar adhesions. In nocodazole-treated cells, however, alpha5-integrin was found in both peripherally located and centrally located adhesion complexes that contained both vinculin and tensin, suggesting a switch in the maturation state of adhesion complexes to favour focal adhesions. Moreover, the switch to focal adhesions was confirmed to be force-dependent as inhibition of cell contractility with the Rho associated protein kinase inhibitor, Y-27632, prevented the nocodazole-induced conversion. These results highlight a complex interplay between the microtubule cytoskeleton, adhesion complex maturation state and intracellular contractile force, and provide a resource for future adhesion signaling studies. The proteomics data have been deposited in the ProteomeXchange with identifier PXD001183. PMID- 25526368 TI - Fundamental shift in vitamin B12 eco-physiology of a model alga demonstrated by experimental evolution. AB - A widespread and complex distribution of vitamin requirements exists over the entire tree of life, with many species having evolved vitamin dependence, both within and between different lineages. Vitamin availability has been proposed to drive selection for vitamin dependence, in a process that links an organism's metabolism to the environment, but this has never been demonstrated directly. Moreover, understanding the physiological processes and evolutionary dynamics that influence metabolic demand for these important micronutrients has significant implications in terms of nutrient acquisition and, in microbial organisms, can affect community composition and metabolic exchange between coexisting species. Here we investigate the origins of vitamin dependence, using an experimental evolution approach with the vitamin B(12)-independent model green alga Chlamydomonas reinhardtii. In fewer than 500 generations of growth in the presence of vitamin B(12), we observe the evolution of a B(12)-dependent clone that rapidly displaces its ancestor. Genetic characterization of this line reveals a type-II Gulliver-related transposable element integrated into the B(12) independent methionine synthase gene (METE), knocking out gene function and fundamentally altering the physiology of the alga. PMID- 25526369 TI - The host metabolite D-serine contributes to bacterial niche specificity through gene selection. AB - Escherichia coli comprise a diverse array of both commensals and niche-specific pathotypes. The ability to cause disease results from both carriage of specific virulence factors and regulatory control of these via environmental stimuli. Moreover, host metabolites further refine the response of bacteria to their environment and can dramatically affect the outcome of the host-pathogen interaction. Here, we demonstrate that the host metabolite, D-serine, selectively affects gene expression in E. coli O157:H7. Transcriptomic profiling showed exposure to D-serine results in activation of the SOS response and suppresses expression of the Type 3 Secretion System (T3SS) used to attach to host cells. We also show that concurrent carriage of both the D-serine tolerance locus (dsdCXA) and the locus of enterocyte effacement pathogenicity island encoding a T3SS is extremely rare, a genotype that we attribute to an 'evolutionary incompatibility' between the two loci. This study demonstrates the importance of co-operation between both core and pathogenic genetic elements in defining niche specificity. PMID- 25526371 TI - Safety Perceptions of Health Care Leaders in 2 Canadian Academic Acute Care Centers. AB - OBJECTIVES: An estimated 7.4% of patients admitted to acute care facilities in Canada experience injury or death due to health care mishaps, and 38% of these events are deemed preventable. Commitment of executive leaders to a culture of safety is important for the reduction of risk to Canadian patients. The purpose of this study was to examine the safety climate from a leader's perspective in 2 Canadian acute care settings, with attention paid to high reliability organization (HRO) principles. METHODS: The Patient Safety Culture in Healthcare Organizations questionnaire was administered to leaders in 2 acute care hospitals in Ontario between June and January 2009. The primary outcome measures were senior leadership support for safety and supervisory leadership support for safety. Misalignment between the safety climate and HRO principles was defined as greater than 10% of respondents reporting problematic or neutral leadership support for safety. RESULTS: Of the 142 respondents (67% response rate), both medical/nursing leaders and tertiary care clinical leaders were significantly more likely than board/administrative leaders to report problematic/neutral responses. Overall, executive leadership perceptions of the safety climate were not aligned with HRO principles. CONCLUSIONS: The significant differences in response between board/administrative leaders and those involved in frontline patient care suggest that a weak safety culture exists in these 2 health care organizations. The cultivation of a stronger organizational safety culture, in alignment with HRO principles, could lead to lower rates of preventable mishaps and support risk identification and mitigation in perioperative settings. PMID- 25526370 TI - Dynamics in microbial communities: unraveling mechanisms to identify principles. AB - Diversity begets higher-order properties such as functional stability and robustness in microbial communities, but principles that inform conceptual (and eventually predictive) models of community dynamics are lacking. Recent work has shown that selection as well as dispersal and drift shape communities, but the mechanistic bases for assembly of communities and the forces that maintain their function in the face of environmental perturbation are not well understood. Conceptually, some interactions among community members could generate endogenous dynamics in composition, even in the absence of environmental changes. These endogenous dynamics are further perturbed by exogenous forcing factors to produce a richer network of community interactions and it is this 'system' that is the basis for higher-order community properties. Elucidation of principles that follow from this conceptual model requires identifying the mechanisms that (a) optimize diversity within a community and (b) impart community stability. The network of interactions between organisms can be an important element by providing a buffer against disturbance beyond the effect of functional redundancy, as alternative pathways with different combinations of microbes can be recruited to fulfill specific functions. PMID- 25526372 TI - Physiological and immune-biological characterization of a long-term murine model of blunt chest trauma. AB - Blunt chest trauma causes pulmonary and systemic inflammation. It is still a matter of debate whether the long-term course of this inflammatory response is associated with persistent impairment of lung function. We hypothesized that an increase of inflammatory biomarkers may still be present at later time points after blunt chest trauma, eventually, despite normalized lung mechanics and gas exchange. Anesthetized spontaneously breathing male C57BL/6J mice underwent a blast wave-induced blunt chest trauma or sham procedure. Twelve and 24 h later, blood gases and lung mechanics were measured, together with blood, bronchoalveolar lavage (BAL), and tissue cytokine concentrations (multiplex cytokine kit); heme oxygenase 1 (HO-1), activated caspase-3, Bcl-xL, and Bax expression (Western blotting); nuclear factor-kappaB activation (electrophoretic mobility shift assay); nitrotyrosine formation; and purinergic (P2XR4 and P2XR7) receptor expression (immunohistochemistry). Histological damage was assessed by hematoxylin and eosin and periodic acid-Schiff staining. High-resolution respirometry allowed assessing mitochondrial respiration in diaphragm biopsies. Chest trauma significantly increased tissue and BAL cytokine levels, associated with a significant increase in HO-1, purinergic receptor expression, and tissue nitrotyrosine formation. In contrast, lung mechanics, gas exchange, and histological damage did not show any significant difference between sham and trauma groups. Activation of the immune response remains present at later time points after murine blunt chest trauma. Discordance of the increased local inflammatory response and preserved pulmonary function may be explained by a dissociation of the immune response and lung function, such as previously suggested after experimental sepsis. PMID- 25526373 TI - Physiologic variability at the verge of systemic inflammation: multiscale entropy of heart rate variability is affected by very low doses of endotoxin. AB - INTRODUCTION: Human injury or infection induces systemic inflammation with characteristic neuroendocrine responses. Fluctuations in autonomic function during inflammation are reflected by beat-to-beat variation in heart rate, termed heart rate variability (HRV). In the present study, we determine threshold doses of endotoxin needed to induce observable changes in markers of systemic inflammation, investigate whether metrics of HRV exhibit a differing threshold dose from other inflammatory markers, and investigate the size of data sets required for meaningful use of multiscale entropy (MSE) analysis of HRV. METHODS: Healthy human volunteers (n = 25) were randomized to receive placebo (normal saline) or endotoxin/lipopolysaccharide (LPS): 0.1, 0.25, 0.5, 1.0, or 2.0 ng/kg administered intravenously. Vital signs were recorded every 30 min for 6 h and then at 9, 12, and 24 h after LPS. Blood samples were drawn at specific time points for cytokine measurements. Heart rate variability analysis was performed using electrocardiogram epochs of 5 min. Multiscale entropy for HRV was calculated for all dose groups to scale factor 40. RESULTS: The lowest significant threshold dose was noted in core temperature at 0.25 ng/kg. Endogenous tumor necrosis factor alpha and interleukin 6 were significantly responsive at the next dosage level (0.5 ng/kg) along with elevations in circulating leukocytes and heart rate. Responses were exaggerated at higher doses (1 and 2 ng/kg). Time domain and frequency domain HRV metrics similarly suggested a threshold dose, differing from placebo at 1.0 and 2.0 ng/kg, below which no clear pattern in response was evident. By applying repeated-measures analysis of variance across scale factors, a significant decrease in MSE was seen at 1.0 and 2.0 ng/kg by 2 h after exposure to LPS. Although not statistically significant below 1.0 ng/kg, MSE unexpectedly decreased across all groups in an orderly dose response pattern not seen in the other outcomes. CONCLUSIONS: By using repeated measures analysis of variance across scale factors, MSE can detect autonomic change after LPS challenge in a group of 25 subjects using electrocardiogram epochs of only 5 min and entropy analysis to scale factor of only 40, potentially facilitating MSE's wider use as a research tool or bedside monitor. Traditional markers of inflammation generally exhibit threshold dose behavior. In contrast, MSE's apparent continuous dose-response pattern, although not statistically verifiable in this study, suggests a potential subclinical harbinger of infectious or other insult. The possible derangement of autonomic complexity prior to or independent of the cytokine surge cannot be ruled out. Future investigation should focus on confirmation of overt inflammation following observed decreases in MSE in a clinical setting. PMID- 25526374 TI - Comparison of Noninvasive pH and Blood Lactate as Predictors of Mortality in a Swine Hemorrhagic Shock with Restricted Volume Resuscitation Model. AB - Recent clinical studies have demonstrated that high blood lactate in the prehospital setting and poor lactate clearance in the emergency department are predictive of in-hospital mortality. This analysis of data collected from a swine model of hemorrhage and restricted volume resuscitation investigated the hypotheses that noninvasive muscle pH (pHm) and H clearance would predict mortality, and the responses would be similar between pHm and lactate. Data from a set of 57 swine were analyzed over the first 2 h after controlled hemorrhage and uncontrolled splenic bleeding. Surviving animals were ones that lived for the full 5-h experimental period. Venous lactate was determined at baseline, shock, and at 30, 60, and 120 min after injury. Spectra were collected continuously from the posterior thigh using a prototype CareGuide 1100 Oximeter and pHm calculated from the spectra; H concentration was determined from pHm. Lactate clearance rate was calculated from the difference in lactate concentration at 120 min and shock, and H clearance was calculated in a similar manner. Comparison of the area under the receiver operator characteristic curves was used to assess prediction of survival at 5 h after injury. At 120 min after injury, lactate, lactate clearance, noninvasive pHm, and noninvasive H clearance were equivalent predictors of mortality each with a receiver operator characteristic area under the curve of 0.87. Thresholds for single lactate (<3.8 mmol/L) or pHm (>7.30) determinations were found to be consistent with a resuscitation goal targeted to reverse acidosis. Continuous, noninvasive pHm monitoring may provide a substitute for lactate measurement in trauma patients, particularly in the prehospital and emergency department settings. PMID- 25526375 TI - Ursodeoxycholyl lysophosphatidylethanolamide protects against hepatic ischemia and reperfusion injury in mice. AB - The ischemia and reperfusion (I/R) injury that occurs during liver transplantation causes severe complications leading to transplantation failure. We have designed a cytoprotective agent, ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), which promotes the survival of cultured hepatocellular cell lines and inhibits apoptosis and inflammation in the in vivo models of liver injury. Here, we show that UDCA-LPE increased the viability of mouse hepatocytes by activating the Akt/glycogen synthase kinase 3beta survival signaling pathways. We further tested whether UDCA-LPE could protect hepatic I/R injury in mice by clamping liver lobes of C57/BL6 mice for 90 min of ischemia followed by unclamping and reperfusion for 2 h. Two regimens for UDCA-LPE treatment were carried out; with a single dose of 100 mg/kg UDCA-LPE intraperitoneally injected 30 min prior to ischemia and a double dose of 50 mg/kg UDCA-LPE given 30 min prior to ischemia and just prior to reperfusion. Using histology and liver enzyme determination, we observed that hepatic I/R caused significant hepatic necrosis, which was decreased in UDCA-LPE-treated mice undergoing I/R. Ursodeoxycholyl LPE concomitantly protected against I/R-induced apoptosis (cleaved caspase 3, cleaved poly[ADP-ribose] polymerase 1), inflammation (IL-1beta, CD11b, chemokine ligands 2 and 3, chemokine receptor 2), and portal fibrogenesis (alpha-smooth muscle actin, plasminogen activator inhibitor 1), as determined by Western blot, quantitative real-time polymerase chain reaction, and immunohistochemical analyses. The protection by UDCA-LPE was found to be better in the double-dose than in the single-dose regimen. Thus, UDCA LPE promoted the survival of mouse hepatocytes and protected against hepatic I/R injury and thus may be of therapeutic use in liver transplantation settings. PMID- 25526376 TI - Inhibition effect of glycyrrhizin in lipopolysaccharide-induced high-mobility group box 1 releasing and expression from RAW264.7 cells. AB - INTRODUCTION: High-mobility group box 1 (HMGB1) is a therapeutic target for sepsis. Glycyrrhizin (GL) is the aglycone of glycyrrhizin derived from licorice. We clarified the anti-inflammatory effects of GL. We explored the anti-HMGB1 effect of GL and elucidated its molecular mechanism, which will be of benefit for sepsis treatment. METHODS: We stimulated murine macrophage-like RAW 264.7 cells with lipopolysaccharide (LPS) and LPS + GL, then measured the expression and release of HMGB1. The expression of related signal transduction factors was detected. RESULTS: High-mobility group box 1 was distributed mainly in the nucleus with lower cytoplasmic levels in RAW 264.7 cells before LPS stimulation. After stimulation, cytoplasmic HMGB1 levels increased gradually, whereas in nuclear fluctuation a trend of HMGB1 expression was observed. Significant upregulation of HMGB1 mRNA occurred 12 h after LPS stimulation. Glycyrrhizin prevented the transfer of HMGB1 from the nucleus to the cytoplasm and inhibited upregulation of HMGB1 mRNA induced by LPS. Phospho-p38 mitogen-activated protein kinase and activated activating protein 1 increased significantly 8 h after LPS stimulation. Tumor necrosis factor alpha and interleukin 6 increased 4 h after LPS stimulation and peaked at 48 h, and HMGB1 increased at 8 h. The Toll-like receptor 4/MD2/nuclear factor kappaB signaling pathway was activated 4 h after LPS stimulation. Glycyrrhizin inhibited this pathway. CONCLUSIONS: Glycyrrhizin inhibited the expression and release of HMGB1 through blocking the p38 mitogen activated protein kinase/activating protein 1 signaling pathway then inhibited the massive release of tumor necrosis factor alpha and interleukin 6. PMID- 25526378 TI - The Role of Uncoupling Protein 2 During Myocardial Dysfunction in a Canine Model of Endotoxin Shock. AB - To explore the role of uncoupling protein 2 (UCP2) during myocardial dysfunction in a canine model of endotoxin shock, 26 mongrel canines were randomly divided into the following four groups: A (control group; n = 6), B2 (shock after 2 h; n = 7), B4 (shock after 4 h; n = 7), and B6 (shock after 6 h; n = 6). Escherichia coli endotoxin was injected into the canines via the central vein, and hemodynamics were monitored. Energy metabolism, UCP2 mRNA and protein expression, and UCP2 localization were analyzed, and the correlation between energy metabolism changes, and UCP2 expression was determined. After the canine endotoxin shock model was successfully established, the expression of UCP2 mRNA and protein was found to increase, with later time points showing significant increases (P < 0.05). Immunofluorescence assays of UCP2 in heart tissue showed that UCP2 was localized in the cytoplasm, and its expression pattern was the same as that found in the mRNA and protein analyses. The energy metabolism results revealed that the ADP levels increased, but the ATP and phosphocreatine (PCr) levels and ATP/ADP and PCr/ATP ratios decreased in the model. In particular, the PCr/ATP ratio was significantly different from that of the control group 6 h after shock (P < 0.05). Furthermore, correlation analysis showed that the UCP2 protein and mRNA levels were negatively correlated with myocardial energy levels. In summary, decreased energy synthesis can occur in the myocardium during endotoxin shock, and UCP2 may play an important role in this process. The negative correlation between UCP2 expression and energy metabolism requires further study, as the results might contribute to the treatment of sepsis with heart failure. PMID- 25526377 TI - Pyruvate Dehydrogenase Activity and Quantity Decreases After Coronary Artery Bypass Grafting: a Prospective Observational Study. AB - INTRODUCTION: Pyruvate dehydrogenase (PDH) is a key gatekeeper enzyme in aerobic metabolism. The main purpose of this study was to determine if PDH activity is affected by major stress in the form of coronary artery bypass grafting (CABG), which has previously been used as a model of critical illness. METHODS: We conducted a prospective, observational study of patients undergoing CABG at an urban, tertiary care hospital. We included adult patients undergoing CABG with or without concomitant valve surgery. Measurements of PDH activity and quantity and thiamine were obtained prior to surgery, at the completion of surgery, and 6 h after surgery. RESULTS: Fourteen patients were enrolled (aged 67 +/- 10 years, 21% female). Study subjects had a mean 41.7% (SD, 27.7%) reduction in PDH activity after surgery and a mean 32.0% (SD, 31.4%) reduction 6h after surgery (P < 0.001). Eight patients were thiamine deficient (<= 7 nmol/L) after surgery compared with none prior to surgery (P = 0.002). Thiamine level was significantly associated with PDH quantity at all time points (P = 0.01). Postsurgery lactate levels were inversely correlated with postsurgery thiamine levels (r = -0.58 and P = 0.04). CONCLUSION: The stress of major surgery causes decreased PDH activity and quantity and depletion of thiamine levels. PMID- 25526379 TI - RGD peptides protects against acute lung injury in septic mice through Wisp1 integrin beta6 pathway inhibition. AB - Acute lung injury is a common consequence of sepsis, a life-threatening inflammatory response caused by severe infection. In this study, we elucidate the attenuating effects of synthetic Arg-Gly-Asp-Ser peptides (RGDs) on acute lung injury in a sepsis mouse model. We further reveal that the beneficial effects of RGDs stem from their negative regulation of the Wisp1 (WNT1-inducible signaling pathway)-integrin beta6 pathway. After inducing sepsis using cecal ligation and puncture (CLP), mice were randomized into experimental and control groups, and survival rates were recorded over 7 days, whereas only 20% of mice subjected to CLP survived when compared with untreated controls; the addition of RGDs to this treatment regimen dramatically increased the survival rate to 80%. Histological analysis revealed acute lung injury in CLP-treated mice, whereas those subjected to the combined treatment of CLP and RGDs showed a considerable decrease in lung injury severity. The addition of RGDs also dramatically attenuated other common sepsis-associated effects, such as increased white blood cell number in bronchoalveolar lavage fluid and decreased pulmonary capillary barrier function. Furthermore, treatment with RGDs decreased the serum and bronchoalveolar lavage fluid levels of inflammatory cytokines such as tumor necrosis factor alpha and interleukin 6, contrary to the CLP treatment alone that increased the levels of these proteins. Interestingly, however, RGDs had no detectable effect on bacterial invasion following sepsis induction. In addition, mice treated with RGDs showed decreased levels of wisp1 and integrin beta6 when compared with CLP treated mice. In the present study, a linkage between Wisp1 and integrin beta6 was evaluated in vivo. Most strikingly, RGDs resulted in a decreased association of Wisp1 with integrin beta6 based on coimmunoprecipitation analyses. These data suggest that RGDs ameliorate acute lung injury in a sepsis mouse model by inhibiting the Wisp1-integrin beta6 pathway. PMID- 25526380 TI - Probing the neurochemical correlates of motivation and decision making. AB - Online electrochemical detection techniques are the state-of-the-art for evaluating chemical communication in the brain underlying motivated behavior and decision making. In this Viewpoint, we discuss avenues for future technological development, as well as the requirement for increasingly sophisticated and interdisciplinary behavioral analysis. PMID- 25526381 TI - Dispersive Raman spectroscopy and multivariate data analysis to detect offal adulteration of thawed beefburgers. AB - Beef offal (i.e., kidney, liver, heart, lung) adulteration of beefburgers was studied using dispersive Raman spectroscopy and multivariate data analysis to explore the potential of these analytical tools for detection of adulterations in comminuted meat products with complex formulations. Adulterated (n = 46) and authentic (n = 36) beefburger samples were produced based on formulations derived using market knowledge and an experimental design. Raman spectral data in the fingerprint range (900-1800 cm(-1)) were examined using both a classification (partial least-squares discriminant analysis, PLS-DA) and class-modeling (soft independent modeling of class analogy, SIMCA) approach to identify offal adulterated and authentic beefburgers. PLS-DA models correctly classified 89-100% of authentic and 90-100% of adulterated samples. SIMCA models were developed using either PCA or PLS scores as input data. For authentic beefburgers, they exhibited sensitivity, specificity, and efficiency values of 0.94-1, 0.64-1, and 0.80-0.97, respectively. PLS regression quantitative models were also developed in an attempt to quantify total offal and added fat in these samples. The performance of PLS regression quantitative models for prediction of added fat may be acceptable for screening purposes, with the most accurate model producing a coefficient of determination in prediction of 0.85 and a root-mean-square error of prediction equal to 3.8% w/w. PMID- 25526382 TI - Effect of the cross-linking density on the thermoresponsive behavior of hollow PNIPAM microgels. AB - We report on the fabrication of thermally responsive hollow pNIPAM particles through the oxidation of the metal core in an Au@pNIPAM system. The selective oxidation of the Au core is achieved by addition of AuCl4(-) to an aqueous dispersion of Au@pNIPAM particles in the presence of cetyltrimethylammonium bromide (CTAB). We fabricate hollow pNIPAM particles with three cross-linking densities (N,N'-methylenebis(acrylamide), BA, at 5%, 10%, and 17.5%). The study of the effect of the amount of BA within the microgel network was performed by dynamic light scattering (DLS), transmission electron microscopy (TEM), and atomic force microscopy (AFM), showing its key role in determining the final hollow structure and thermal response. While the thermal responsiveness is largely achieved at low cross-linking densities, the hollow structure only remains at larger cross-linking densities. This was further confirmed by cryo-TEM analysis of hollow pNIPAM particles below and above the volume phase transition temperature (VPTT). Thus, it clearly shows (i) the shrinking of particle size with the temperature at low cross-linking density and (ii) the dependence of particle size on the amount of cross-linker for the final hollow pNIPAM structure. Observed differences in the hollow pNIPAM structure are attributed to different elastic contributions (Pi(elas)), showing higher elasticity for microgels synthesized at lower amount of BA. PMID- 25526384 TI - Determination of 14 nitrosamines at nanogram per liter levels in drinking water. AB - N-Nitrosamines, probable human carcinogens, are a group of disinfection byproducts under consideration for drinking water regulation. Currently, no method can determine trace levels of alkyl and tobacco-specific nitrosamines (TSNAs) of varying physical and chemical properties in water by a single analysis. To tackle this difficulty, we developed a single solid-phase extraction (SPE) method with high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for the determination of 14 nitrosamines of health concern with widely differing properties. We made a cartridge composed of a vinyl/divinylbenzene polymer that efficiently concentrated the 14 nitrosamines in 100 mL of water (in contrast to 500 mL in other methods). This single SPE-HPLC MS/MS technique provided calculated method detection limits of 0.01-2.7 ng/L and recoveries of 53-93% for the 14 nitrosamines. We have successfully demonstrated that this method can determine the presence or absence of the 14 nitrosamines in drinking water systems (eight were evaluated in Canada and the U.S.), with occurrence similar to that in other surveys. N-Nitrosodimethylamine (NDMA), N nitrosodiphenylamine, and the TSNA 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol were identified and quantified in authentic drinking water. Formation potential (FP) tests demonstrated that NDMA and TSNA precursors were present in (1) water samples in which tobacco was leached and (2) wastewater-impacted drinking water. Our results showed that prechlorination or ozonation destroyed most of the nitrosamine precursors in water. Our new single method determination of alkylnitrosamines and TSNAs significantly reduced the time and resource demands of analysis and will enable other studies to more efficiently study precursor sources, formation mechanisms, and removal techniques. It will be useful for human exposure and health risk assessments of nitrosamines in drinking water. PMID- 25526386 TI - Paying for telemedicine. PMID- 25526387 TI - Quality of end-of-life care for cancer patients: does home hospice care matter? AB - OBJECTIVES: Since metastasized cancer patients receive many treatments and services, it is important to ascertain whether home hospice (HH) care makes a meaningful contribution to end-of-life quality for terminal patients. This study examines whether people who had died from metastasized cancer-both recipients of HH care and nonrecipients-were cared for according to palliative indicators and whether HH care made a difference. STUDY DESIGN: Three to 6 months after the deaths of 193 metastatic cancer patients, members of their families were interviewed face-to-face. Information on their loved ones' utilization of healthcare services in the last 2 months of life was retrieved from computerized administrative files. RESULTS: The patients' average age was 69.5 years (SD=13.9), 56% were men, and 21% received HH care. More patients with HH care than without received opiate medication (92% vs 68%, respectively; P<.01), appropriate treatment for anxiety (57% vs 30%, respectively; P<.01), had advance directives, and received explanations about their rights. Only 5% of HH patients were treated with curative care in the last 2 month of life, compared with 40% of those without HH (P<.01). Of those who received curative care, more of them died at home (56% vs 26%, respectively; P<.01), and more died at the place of their choice (60% vs 30%, respectively; P<.01). No differences were found regarding healthcare service utilization. CONCLUSIONS: The findings demonstrate the valuable contributions of HH and palliative care. Clinicians should consider referring cancer patients to palliative care services and establishing working relationships with HH and palliative care providers. PMID- 25526388 TI - Out-of-plan pharmacy use: insights into patient behavior. AB - OBJECTIVES: The purpose of this study was to identify and describe patient rationales for filling prescriptions at an out-of-plan pharmacy (OOPP). STUDY DESIGN: A cross-sectional survey conducted in February 2013 among a random sample of 1000 patients. METHODS: Adult Kaiser Permanente Colorado (KPCO) patients who had a prescription electronically issued to an OOPP in November 2012 were surveyed. The study questionnaire was developed using items obtained from the literature and prepared de novo, as needed. The questionnaire included items regarding whether the electronic prescription issued to an OOPP was filled; if filled, which OOPP was used; factors that may have influenced the use of an OOPP; and the patient's ability to afford medications. Responses to the survey were tabulated and reported as percentages. RESULTS: The survey response rate was 38%. Respondents (N=382) had a mean age of 61 years, 35% were males, and anti hypertensives were their most common OOPP prescription. Overall, 330 (86%) respondents reported that they had their prescription filled at an OOPP. The most commonly reported OOPPs utilized were supermarket pharmacies (42%). Factors that influenced the decision to use an OOPP included the prescription being less expensive (58%), the OOPP had a discount generic prescription program (57%), and the OOPP's location was convenient (44%). Thirty-nine percent of respondents reported that using an OOPP helped them afford their prescriptions. CONCLUSIONS: Prescription cost and pharmacy convenience were identified as the most significant drivers of OOPP use. Future research should be conducted to assess the health-related consequences of OOPP use. PMID- 25526389 TI - ACO contracting with private and public payers: a baseline comparative analysis. AB - OBJECTIVES: The accountable care organization (ACO) model is currently being pursued by private insurers, as well as federal and state governments. Little is known, however, about the prevalence of private payer ACO contracts and the characteristics of contract structures or how these compare with public ACO contracts. STUDY DESIGN: and Methods Cross-sectional analysis of the National Survey of Accountable Care Organizations (n=173) on ACO contracts with public and private payers and private payer contract characteristics. RESULTS: Most ACOs had only 1 ACO contract (57%). About half of ACOs had a contract with a private payer. The single most common private payer ACO contract was an upside-only shared savings model (41%), although the majority of private contracts included some form of downside risk (56%). A large majority of contracts made shared savings contingent upon quality performance (79%), and some included bonus payments for quality performance (39%). Most private payer contracts included upfront payments, such as care management payments (56%) or capital investment (17%). Organizations with private ACO contracts were larger and more advanced than ACOs with only public payer contracts. CONCLUSIONS: While there are fewer ACOs with commercial contracts than public contracts, commercial contracts are more likely to include both downside risk and upfront payments. PMID- 25526391 TI - Reference-based pricing: an evidence-based solution for lab services shopping. AB - OBJECTIVES: To determine the effect of reference-based pricing (RBP) on the percentage of lab services utilized by members that were at or below the reference price. STUDY DESIGN: Retrospective, quasi-experimental, matched, case control pilot evaluation of an RBP benefit for lab services. METHODS: The study group included employees of a multinational grocery chain covered by a national health insurance carrier and subject to RBP for lab services; it had access to an online lab shopping tool and was informed about the RBP benefit through employer communications. The reference group was covered by the same insurance carrier but not subject to RBP. The primary end point was lab compliance, defined as the percentage of lab claims with total charges at or below the reference price. Difference-in-difference regression estimation evaluated changes in lab compliance between the 2 groups. RESULTS: Higher compliance per lab claim was evident for the study group compared with the reference group (69% vs 57%; P<.05). The online shopping tool was used by 7% of the matched-adjusted study group prior to obtaining lab services. Lab compliance was 76% for study group members using the online tool compared with 68% among nonusers who were subject to RBP (P<.01). CONCLUSIONS: RBP can promote cost-conscious selection of lab services. Access to facilities that offer services below the reference price and education about RBP improve compliance. Evaluation of the effect of RBP on higher cost medical services, including radiology, outpatient specialty, and elective inpatient procedures, is needed. PMID- 25526390 TI - Did they come to the dance? Insurer participation in exchanges. AB - OBJECTIVES: An important feature of the Affordable Care Act is the creation of insurance exchanges, which are organized marketplaces through which individuals could begin to shop for and purchase coverage beginning in 2014. This study analyzes the decisions of new insurers and incumbent insurers already operating in a major market within a state to participate in state and federally facilitated exchanges. STUDY DESIGN: Utilizing secondary data from the National Association of Insurance Commissioners* and government websites, we describe each state's insurance market in 2012, summarizing the number of incumbent insurers by size and operations in the individual market segment. Next, we investigate the organizational, market, and policy-related factors associated with incumbent insurers' participation decisions. Finally, we discuss the entry patterns of new insurers and briefly assess their potential impact on the market. METHODS: We use multivariate regression analysis to identify the organizational, market, and policy-related factors related to insurer participation in exchanges. RESULTS: Only 10% of incumbent insurers are participating in exchanges in 2014, although considerable variation exists across states. Participation is more prevalent among larger insurers, local and regional insurers, and those with prior experience in other market segments in the same state. The entry of newly formed organizations, such as cooperatives (co-ops), and of existing insurers into new states is modest. CONCLUSIONS: Robust participation of insurers is an important prerequisite to ensure competition in health insurance markets. Exchange administrators will need to better understand the strategic or operational reasons why insurers chose not to participate in the individual market exchanges in 2014. *The NAIC does not endorse any analysis or conclusions based upon the use of its data. PMID- 25526392 TI - Validating electronic cancer quality measures at Veterans Health Administration. AB - OBJECTIVES: To assess the feasibility and validity of developing electronic clinical quality measures (eCQMs) of cancer care quality from existing metrics, using electronic health records, administrative, and cancer registry data. STUDY DESIGN: Retrospective comparison of quality indicators using chart abstracted versus electronically available data from multiple sources. METHODS: We compared the sensitivity and specificity of eCQMs created from structured data from electronic health records (EHRs) linked to administrative and cancer registry data to data abstracted from patients' electronic health records. Twenty-nine measures of care were assessed in 15,394 patients with either incident lung or prostate cancer from 2007 and 2008, respectively, and who were treated in the Veteran's Health Administration (VHA). RESULTS: It was feasible to develop eCQMs for 11 of 18 (61%) lung cancer measures, 4 (22%) of which were considered to be valid measures of the care constructs. Among prostate cancer measures, 6 of 11 (55%) were feasible, and 4 (36%) were both feasible and valid. Of the 29 metrics, data was available to create eCQMs for 17 (59%) cancer care metrics, and 8 (28%) were considered valid. CONCLUSIONS: In a large integrated healthcare system with nationally standardized electronic health records, administrative, and cancer registry data, 28% of cancer quality measures developed for chart abstraction could be translated into valid eCQMs. These results raise much concern about the development of electronic clinical quality measures for cancer care, particularly in healthcare environments where data are disparate in both form and location. PMID- 25526393 TI - The open, the closed, and the empty: time-resolved fluorescence spectroscopy and computational analysis of RC-LH1 complexes from Rhodopseudomonas palustris. AB - We studied the time-resolved fluorescence of isolated RC-LH1 complexes from Rhodopseudomonas palustris as a function of the photon fluence and the repetition rate of the excitation laser. Both parameters were varied systematically over 3 orders of magnitude. On the basis of a microstate description we developed a quantitative model for RC-LH1 and obtained very good agreement between experiments and elaborate simulations based on a global master equation approach. The model allows us to predict the relative population of RC-LH1 complexes with the special pair in the neutral state or in the oxidized state P(+) and those complexes that lack a reaction center. PMID- 25526394 TI - Reference gene selection for qPCR is dependent on cell type rather than treatment in colonic and vaginal human epithelial cell lines. AB - The ability of commensal bacteria to influence gene expression in host cells under the influence of pathogenic bacteria has previously been demonstrated, however the extent of this interaction is important for understanding how bacteria can be used as probiotics. Real-time quantitative polymerase chain reaction is the most sensitive tool for evaluating relative changes to gene expression levels. However as a result of its sensitivity an appropriate method of normalisation should be used to account for any variation incurred in preparatory experimental procedures. These variations may result from differences in the amount of starting material, quality of extracted RNA, or in the efficiency of the reverse transcriptase or polymerase enzymes. Selection of an endogenous control gene is the preferred method of normalisation, and ideally a proper validation of the gene's appropriateness for the study in question should be performed. In this study we used quantitative polymerase chain reaction data and applied four different algorithms (geNorm, BestKeeper, NormFinder, and comparative DeltaCq) to evaluate eleven different genes as to their suitability as endogenous controls for use in studies involving colonic (HT-29) and vaginal (VK2/E6E7) human mucosal epithelial cells treated with probiotic and pathogenic bacteria. We found phosphoglycerate kinase 1 to be most appropriate for HT-29 cells, and ribosomal protein large P0 to be the best choice for VK2/E6E7 cells. We also showed that use of less stable reference genes can lead to less accurate quantification of expression levels of gene of interest (GOI) and also can result in decreased statistical significance for GOI expression levels when compared to control. Additionally, we found the cell type being analysed had greater influence on reference gene selection than the treatment performed. This study provides recommendations for stable endogenous control genes for use in further studies involving colonic and vaginal cell lines after bacterial challenge. PMID- 25526395 TI - Spontaneous pain-like behaviors are more sensitive to morphine and buprenorphine than mechanically evoked behaviors in a rat model of acute postoperative pain. AB - BACKGROUND: Nonevoked spontaneous pain is most problematic for postoperative patients. Physicians assess this form of pain using the human visual analog scale or verbal numeric rating scale. Recent studies have proposed that spontaneous foot-lifting (SFL) behaviors are an expression of spontaneous pain in animals after spinal nerve injury or adjuvant-induced inflammation. In the current study, we characterize SFL behaviors in a rat model of acute postoperative pain, which includes comparisons with evoked behaviors to analgesic treatments. METHODS: SFL was manually recorded over four 5-minute periods with 10-minute intervals between each testing session. Paw-withdrawal thresholds were subsequently measured with an electronic von Frey esthesiometer. To evaluate the effects of age, rats were tested in different age groups: 2, 7, and >26 months. The effects of buprenorphine and morphine were tested in a separate group of animals, which received intraperitoneal injections of saline, morphine (0.01, 0.1, 1, or 2 mg/kg), or buprenorphine (0.001, 0.01, or 0.1 mg/kg) before testing. RESULTS: SFL behaviors peaked at 3 hours after incision and significantly recovered by the 3rd or 4th postoperative day (P < 0.0001). The presentation of these behaviors did not significantly vary with animal age (2, 7, and >26 months old; P = 0.30). SFL behaviors, with the exception of rapid SFL at 3 hours after incision, did not show significant correlation with paw-withdrawal threshold behaviors. The median effective dose of buprenorphine for reversal of mechanical hyperalgesia (0.0452 mg/kg; 95% CI, 0.0259-0.0787) was significantly larger than for reversing rapid (0.0027 mg/kg; 95% CI, 0.0009-0.0083; P < 0.0001) and prolonged (0.0004 mg/kg, 95% CI, 0.0000, 0.0035; P = 0.001) SFL at 3 hours after incision. Similarly, the median effective dose of morphine for reversal of mechanical hypersensitivity behaviors (2.901 mg/kg; 95% CI, 1.132-7.436) was larger than for SFL count (0.4044 mg/kg; 95% CI, 0.1048-1.561; P = 0.0103) and SFL duration (0.0309 mg/kg; 95% CI, 0.0095-0.0998; P < 0.0001) at 3 hours after incision. CONCLUSIONS: The present study demonstrates that a hindpaw plantar incision induces SFL behaviors in rats and that these behaviors have higher bioassay sensitivity to analgesic interventions with morphine and buprenorphine compared with mechanically evoked behaviors. PMID- 25526396 TI - Regional versus general anesthesia in surgical patients with chronic obstructive pulmonary disease: does avoiding general anesthesia reduce the risk of postoperative complications? AB - BACKGROUND: Surgical patients with chronic obstructive pulmonary disease (COPD) are at increased risk of perioperative complications. In this study, we sought to quantify the benefit of avoiding general anesthesia in this patient population. METHODS: Data from the National Surgical Quality Improvement Program database (2005-2010) were used for this review. Patients who met the National Surgical Quality Improvement Program definition for COPD and underwent surgery under general, spinal, epidural, or peripheral nerve block anesthesia were included in this study. For each primary current procedural terminology code with >= 1 general and >= 1 regional (spinal, epidural, or peripheral nerve block) anesthetic, regional patients were propensity score--matched to general anesthetic patients. Propensity scoring was calculated using all available demographic and comorbidity data. This match yielded 2644 patients who received regional anesthesia and 2644 matched general anesthetic patients. These groups were compared for morbidity and mortality. RESULTS: Groups were well matched on demographics, comorbidities, and type of surgery. Compared with matched patients who received regional anesthesia, patients who received general anesthesia had a higher incidence of postoperative pneumonia (3.3% vs 2.3%, P = 0.0384, absolute difference with 95% confidence interval = 1.0% [0.09, 1.88]), prolonged ventilator dependence (2.1% vs 0.9%, P = 0.0008, difference = 1.2% [0.51, 1.84]), and unplanned postoperative intubation (2.6% vs 1.8%, P = 0.0487, difference = 0.8% [0.04, 1.62]). Composite morbidity was 15.4% in the general group versus 12.6% (P = 0.0038, difference = 2.8% [0.93, 4.67]). Composite morbidity not including pulmonary complications was 13.0% in the general group versus 11.1% (P = 0.0312, difference = 1.9% [0.21, 3.72]). Thirty-day mortality was similar (2.7% vs 3.0%, P = 0.6788, difference = 0.3% [-1.12, 0.67]). As a test for validity, we found a positive association between pulmonary end points because patients with 1 pulmonary complication were significantly more likely to have additional pulmonary complications. CONCLUSIONS: The use of regional anesthesia in patients with COPD is associated with lower incidences of composite morbidity, pneumonia, prolonged ventilator dependence, and unplanned postoperative intubation. PMID- 25526398 TI - Sarcoid-like reaction-computed tomography features in 12 patients. AB - PURPOSE: The aim of the study was to analyze the computed tomography (CT) findings of sarcoid-like reaction caused by underlying malignancy or immune modulation. METHODS: Twelve patients with pathologically proven sarcoidosis from underlying causes (malignancies, hepatitis C infection, and immune-modulatory treatment) in 2001 to 2011 were identified. All patients had chest CT scans, which were reviewed by 3 experienced thoracic radiologists. Medical records were also reviewed. Follow-up imaging, available in 11 patients, was assessed for response. RESULTS: All patients were white, 8 women and 4 men, with ages ranging from 26 to 72 years. Seven had underlying malignancy, 2 had inflammatory bowel disease, and 3 had liver disease caused by chronic hepatitis C viral infection. On CT, 92% (11/12) of patients had lymphadenopathy, 75% (9/12) had pulmonary nodules less than 5 mm, and 50% (6/12) had ground-glass opacity (GGO). In 42% (5/12) of patients, the dominant finding was discrete nodules (1-5 mm). In 33% (4/12) of patients, the dominant finding was ultrafine nodules with confluence, mimicking GGO. The most common distribution of lung nodules was perilymphatic, found in 78% (7 of the 9 patients with lung nodules). Follow-up was available in 10 patients, limited follow-up in 1, and no follow-up in 1. Six of the 11 patients who had follow-up had complete resolution of CT findings, 3 had partial resolution, and 2 had no resolution. CONCLUSIONS: Imaging features of patients with sarcoid-like reaction include lymphadenopathy, small nodules, and ultrafine nodules with confluence, mimicking GGO. Ultrafine nodules with confluence mimicking GGO were unexpectedly common in this series. PMID- 25526397 TI - Perceiving the direction of articulatory motion in point-light actions. AB - Human observers are able to perceive the motion direction of actions (either forward or backward) on the basis of the articulatory, relative motion of the limbs, even when the actions are shown under point-light conditions. However, most studies have focused on the action of walking. The primary purpose of the present study is to further investigate the perception of articulatory motion in different point-light actions (walking, crawling, hand walking, and rowing). On each trial, participants were presented with a forward or backward moving person and they had to decide on the direction of articulatory motion of the person. We analyzed sensitivity (d') as well as response bias (c). In addition to the type of action, the diagnosticity of the available information was manipulated by varying the visibility of the body parts (full body, only upper limbs, or only lower limbs) and the viewpoint from which the action was seen (from frontal view to sagittal view). We observe that, depending on the specific action, perception of direction of motion is driven by different body parts. Implications for the possible existence of a life detector, i.e., an evolutionarily old and innate visual filter that is tuned to quickly and automatically detect the presence of a moving living organism and direct attention to it, are discussed. PMID- 25526399 TI - Comparison of contrast-enhanced SPACE and CISS in evaluating cavernous sinus invasion by pituitary macroadenomas on 3-T magnetic resonance. AB - PURPOSE: SPACE (sampling perfection with application-optimized contrasts by using different flip angle evolutions) and CISS (constructive interference in steady state) are 3-dimensional sequences that can increase the signal intensity of cavernous sinus. The purpose of this study was to determine whether contrast enhanced (CE) SPACE and CE CISS can well demonstrate cavernous sinus invasion (CSI) by pituitary macroadenoma and which one performed better. METHODS: In 56 cavernous sinuses from 28 patients with pituitary macroadenoma, CSI grades and image quality were assessed by using CE SPACE and CISS. The assessment results were compared with Knops' classification on T1-weighted images. The interreader agreement of assessment results were analyzed with k statistics. Qualitative analyses were compared using the Wilcoxon signed-ranks test. RESULTS: Two radiologists were in substantial agreement of CSI evaluation on both CE SPACE (k = 0.87) and CE CISS (k = 0.83). The evaluation results on CE SPACE (k = 0.76) were more coincident with Knops' classification than CE CISS (k = 0.71). Identification of CSI worked well with either CE SPACE or CE CISS, but CE SPACE performed better (mean, 3.48 +/- 0.61 vs 3.28 +/- 0.80; P < 0.05). Contrast enhanced SPACE had significantly higher image scores than CE CISS in description of the relationship between pituitary adenoma and internal carotid artery (mean, 3.26 +/- 0.93 vs 2.96 +/- 1.01; P < 0.05). Contrast-enhanced CISS demonstrated more susceptibility artifacts (10.7% vs 0%; P < 0.05) and vessel flow artifacts (53.6% vs 0%; P < 0.05). There was no significant difference regarding contrast enhancement of pituitary adenoma and cavernous sinus (mean, 3.07 +/- 1.12 vs 3.04 +/- 0.96; P > 0.05). CONCLUSIONS: Contrast-enhanced SPACE is superior than CE CISS for identification of CSI by pituitary macroadenoma. PMID- 25526400 TI - Endoscopic placement of a large-bore covered self-expandable metallic stent for cholangitis caused by mucus from a pancreatic mucinous neoplasm. PMID- 25526401 TI - Radiosurgical endoscopy: fluoro-endoscopically guided percutaneous placement of a catheter for drainage of a complicated intrathoracic anastomotic septic collection. PMID- 25526402 TI - Over-the-scope clip (OTSC) closure of a gastrobronchial fistula after esophagectomy. PMID- 25526403 TI - Transesophageal drainage of an infected bronchogenous cyst via endoscopic ultrasound-guided implantation of a 7-Fr nasocystic drainage catheter. PMID- 25526404 TI - Fungal colonization of intragastric balloons. PMID- 25526405 TI - Nanopowder spray for temporary hemostasis in a patient presenting with esophago carotid fistula after radiation and surgery for a head and neck cancer. PMID- 25526406 TI - Duodenal perforation following bile duct endoprosthesis placement. PMID- 25526407 TI - Successful peroral endoscopic myotomy in situs inversus totalis. PMID- 25526408 TI - Snare-over-scope technique for retrieval of a proximally migrated biliary stent. PMID- 25526409 TI - A true vascular aneurysm of the hepatic artery proper as a rare cause of nonmalignant painless jaundice. PMID- 25526410 TI - Endoscopic ultrasound-guided portal-systemic pressure gradient measurement. PMID- 25526411 TI - Aberrant right posterior hepatic duct opening into the cystic duct: a very rarely seen biliary anatomic variation. PMID- 25526412 TI - Salivary gland choriostoma in the esophagus. PMID- 25526413 TI - Endoscopically visualized features of gastric submucosal tumors on submucosal endoscopy. PMID- 25526414 TI - Endoscopic management of retained patency capsules. PMID- 25526415 TI - Endoscopic ultrasound-guided fine-needle aspiration diagnosis of mixed endocrine somatostatinoma of the minor papilla in von Recklinghausen disease. PMID- 25526416 TI - Gastric intramural hematoma caused by endoscopic ultrasound-guided fine-needle biopsy. PMID- 25526417 TI - Chronic pancreatitis caused by a swallowed orthodontic device. PMID- 25526418 TI - Gastric tuberculosis resembling depressed type, early gastric cancer. PMID- 25526419 TI - Colonic schistosomiasis and early rectal cancer: coincidence or causal relationship? PMID- 25526420 TI - A novel technique for peroral direct cholangioscopy. PMID- 25526421 TI - Endoscopic management of a rare cause of upper gastrointestinal bleeding: gastric polypoid extramedullary hemopoiesis. PMID- 25526422 TI - A safe approach to perform endoscopic mucosal resection of a duodenal adenocarcinoma located close to a duodenal diverticulum. PMID- 25526423 TI - Endoscopic findings of indolent systemic mastocytosis involving the colon. PMID- 25526424 TI - Endoscopic ultrasound-guided jejunogastrostomy to perform endoscopic cholangiography in a patient with a modified Roux-en-Y hepaticojejunostomy. PMID- 25526425 TI - Endoscopic ultrasonography-guided liver abscess drainage using a dedicated, wide, fully covered self-expandable metallic stent with flared-ends. PMID- 25526426 TI - Antibiotic regimens for management of intra-amniotic infection. AB - BACKGROUND: Chorioamnionitis is a common infection that affects both mother and infant. Infant complications associated with chorioamnionitis include early neonatal sepsis, pneumonia, and meningitis. Chorioamnionitis can also result in maternal morbidity such as pelvic infection and septic shock.Clinical chorioamnionitis is estimated to occur in 1% to 2% of term births and in 5% to 10% of preterm births; histologic chorioamnionitis is found in nearly 20% of term births and in 50% of preterm births. Women with chorioamnionitis have a two to three times higher risk for cesarean delivery and a three to four times greater risk for endomyometritis, wound infection, pelvic abscess, bacteremia, and postpartum hemorrhage. OBJECTIVES: To assess the effects of administering antibiotic regimens for intra-amniotic infection on maternal and perinatal morbidity and mortality and on infection-related complications. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 October 2014), CENTRAL, MEDLINE, Embase, LILACS, and the WHO ICTRP (September 2014). We also searched reference lists of retrieved studies and contacted experts in the field. SELECTION CRITERIA: Randomized controlled trials (RCTs) that included women who experienced intra-amniotic infection. Trials were included if they compared antibiotic treatment with placebo or no treatment (if applicable), treatment with different antibiotic regimens, or timing of antibiotic therapy (intrapartum and/or postpartum). Therefore, this review assesses trials evaluating intrapartum antibiotics, intrapartum and postpartum antibiotic regimens, and postpartum antibiotics. Diagnosis of intra-amniotic infection was based on standard criteria (clinical/test), and no limit was placed on gestational age. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted data and checked them for accuracy. We assessed the quality of the evidence using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and included a 'Summary of findings' table. MAIN RESULTS: Our prespecified primary outcomes were maternal and neonatal mortality, maternal and neonatal severe infection, and duration of maternal and neonatal hospital stay.We included 11 studies (involving 1296 women) and assessed them as having low to moderate risk of bias - mainly because allocation concealment methods were not adequately reported, most studies were open, and outcome reporting was incomplete. The quality of the evidence was low to very low for most outcomes, as per the GRADE approach. The following antibiotics were assessed in the included trials: ampicillin, ampicillin/sulbactam, gentamicin, clindamycin, and cefotetan. During labor: meta-analysis of two studies found no clear differences in rates of neonatal sepsis (163 neonates; risk ratio (RR) 1.07, 95% confidence interval (CI) 0.40 to 2.86; I2 = 9%; low quality of evidence), treatment failure (endometritis) (163 participants; RR 0.86, 95% CI 0.27 to 2.70; I2 = 0%; low quality of evidence), and postpartum hemorrhage (RR 1.39, 95% CI 0.76 to 2.56; I2 = 0%; low quality of evidence) when two different dosages/regimens of gentamicin were assessed. No clear differences between groups were found for any reported maternal or neonatal outcomes. The review did not identify data for a comparison of antibiotics versus no treatment/placebo. Postpartum: meta-analysis of two studies that evaluated use of antibiotics versus placebo after vaginal delivery showed no significant differences between groups in rates of treatment failure or postpartum endometritis. No significant differences were found in rates of neonatal death and postpartum endometritis when use of antibiotics was compared with no treatment. Four trials assessing two different dosages/regimens of gentamicin or dual-agent therapy versus triple agent therapy, or comparing antibiotics, found no significant differences in most reported neonatal or maternal outcomes; the duration of hospital stay showed a difference in favor of the group of women who received short-duration antibiotics (one study, 292 women; mean difference (MD) -0.90 days, 95% CI -1.64 to -0.16; moderate quality of evidence). Intrapartum versus postpartum: one small study (45 women) evaluating use of ampicillin/gentamicin during intrapartum versus immediate postpartum treatment found significant differences favoring the intrapartum group in the mean number of days of maternal postpartum hospital stay (one trial, 45 women; MD -1.00 days, 95% CI -1.94 to - 0.06; very low quality of evidence) and the mean number of neonatal hospital stay days (one trial, 45 neonates; MD -1.90 days, 95% CI -3.91 to -0.49; very low quality of evidence). Although no significant differences were found in the rate of maternal bacteremia or early neonatal sepsis, for the outcome of neonatal pneumonia or sepsis we observed a significant difference favoring intrapartum treatment (one trial, 45 neonates; RR 0.06, 95% CI 0.00 to 0.95; very low quality of evidence). AUTHORS' CONCLUSIONS: This review included 11 studies (having low to moderate risk of bias). The quality of the evidence was low to very low for most outcomes, as per the GRADE approach. Only one outcome (duration of hospital stay) was considered to provide moderate quality of evidence when antibiotics (short duration) were compared with antibiotics (long duration) during postpartum management of intra amniotic infection. Our main reasons for downgrading the quality of evidence were limitations in study design or execution (risk of bias), imprecision, and inconsistency of results.Currently, limited evidence is available to reveal the most appropriate antimicrobial regimen for the treatment of patients with intra amniotic infection; whether antibiotics should be continued during the postpartum period; and which antibiotic regimen or what treatment duration should be used. Also, no evidence was found on adverse effects of the intervention (not reported in any of the included studies). One small RCT showed that use of antibiotics during the intrapartum period is superior to their use during the postpartum period in reducing the number of days of maternal and neonatal hospital stay. PMID- 25526427 TI - Organocatalytic enantioselective addition of thiols to ketimines derived from isatins. AB - The first catalytic enantioselective addition of thiols to ketimines derived from isatins has been developed. Excellent yields and enantioselectivities were observed for the reaction of various ketimines and thiols using a cinchona alkaloid sulfonamide catalyst. Both enantiomers of products could be obtained by using pseudoenantiomeric chiral catalysts. PMID- 25526428 TI - High integrity interconnection of silver submicron/nanoparticles on silicon wafer by femtosecond laser irradiation. AB - Welding of nanomaterials is a promising technique for constructing nanodevices with robust mechanical properties. To date, fabrication of these devices is limited because of difficulties in restricting damage to the nanomaterials during the welding process. In this work, by utilizing very low fluence (~900 MUJ cm( 2)) femtosecond (fs) laser irradiation, we have produced a metallic interconnection between two adjacent silver (Ag) submicron/nanoparticles which were fixed on a silicon (Si) wafer after fs laser deposition. No additional filler material was used, and the connected particles remain almost damage free. Observation of the morphology before and after joining and finite difference time domain simulations indicate that the interconnection can be attributed to plasmonic excitation in the Ag submicron/nanoparticles. Concentration of energy between the particles leads to local ablation followed by re-deposition of the ablated material to form a bridging link that joins the two particles. This welding technique shows potential applications in the fabrication of nanodevices. PMID- 25526429 TI - Color of intra-ocular lens and cataract type are prognostic determinants of health indices after visual and photoreceptive restoration by surgery. AB - BACKGROUND: This study compared post-operative quality of life and sleep according to the type of cataract opacity and color of the implanted intra-ocular lens (IOL). METHODS: This is a cohort study and participants were 206 patients (average age 74.1 years) undergoing cataract surgery with the implantation of a clear ultra-violet (UV)-blocking IOL (C) or a yellow blue-light-blocking IOL (Y). Participants were evaluated using the National Eye Institute Visual Function Questionnaire (VFQ-25) and Pittsburgh Sleep Quality Index (PSQI) before surgery and 2 and 7 months after surgery. Changes in sub-scale scores of VFQ-25 and PSQI were compared. RESULTS: Sub-scale analyses for improvement after surgery revealed significant differences in ocular pain scores on the VFQ-25 (Y>C; the higher the score, the better the outcome). Furthermore, there were significant differences between the two IOLs in terms of the sleep latency score (C>Y) and sleep disturbances score (C>Y). A posterior sub-capsular cataract was significantly correlated with improvements in ocular pain and sleep latency scores. These effects were successfully represented by the change in scores rather than absolute post-operative scores because individual standard of response may often change after intervention, recognized as a response shift phenomenon in patient reported outcome study. Regarding seasonal differences, patients who had surgery in summer exhibited relatively better sleep quality than those who had surgery in winter. CONCLUSIONS: Analysis of sub-scales of health indices demonstrated characteristic prognoses for each IOL and cataract type. Cataract surgery may potentially contribute to systemic health in older adults. PMID- 25526431 TI - Leukocyte count restoration under dabrafenib treatment in a melanoma patient with vemurafenib-induced leukopenia: case report. AB - Recent advances in melanoma therapy have influenced the management of metastatic patients. Inhibitors of the BRAF/MEK/ERK signaling cascade have been proven highly effective in the metastatic disease although displaying different side effects. Here, we report a patient with BRAF V600E-mutated stage IV melanoma who developed a severe leukopenia upon targeted therapy with the BRAF inhibitor vemurafenib. Interestingly, the immediate therapeutic switch to a different BRAF inhibitor 'dabrafenib? had no negative influence on the leukocyte count. This case supports recent studies, which showed a differential influence of different BRAF inhibitors on patients' leukocytes despite similar clinical efficacy in melanoma. PMID- 25526432 TI - Can perifoveal pseudocyst area be a prognostic factor in macular hole surgery?: A prospective study with quantitative data. AB - To evaluate the effect of perifoveal pseudocysts on the anatomical outcomes of the idiopathic macular hole surgery as a prognostic factor. Twenty-one eyes of 20 consecutive patients with a Gass stage 3 or 4 idiopathic macular hole were enrolled in this prospective study between March 2012 and May 2013. Demographic data, medical history, and ocular examinations were recorded preoperatively and on postoperative day 1, week 1, and month 1, 3, and 6. Five spectral domain optical coherence tomography (SD-OCT) parameters were analyzed: macular hole (MH) basal diameter, MH minimum diameter, MH height, macular hole index, and a new parameter, the area of macular pseudocysts via the software of SD-OCT device at the widest cross section of the MH formation. The mean preoperative best corrected visual acuity was 0.86+/-0.29 logarithm of the minimum angle of resolution (LogMAR) (between 0.4 and 1.3) and improved to 0.64+/-0.28 LogMAR (between 0.22 and 1.23) postoperatively (P=0.004). There was a statistical significant difference between both MH basal diameter and MH pseudocyst area with anatomical success, respectively (P=0.016 for MH basal diameter, P=0.004 for MH pseudocyst area). The anatomical closure was correlated with MH basal diameter and MH pseudocyst area (P=0.01 and P=0.001, respectively). Spearman correlation rank coefficient between with MH basal diameter and MH pseudocyst area was r=0.493 and statistically significant (P=0.02). Perifoveal pseudocysts seem to be associated with anatomic failure and may be used as a prognostic factor in MH surgery. PMID- 25526433 TI - Scoliosis in Herlyn-Werner-Wunderlich syndrome: a case report and literature review. AB - Herlyn-Werner-Wunderlich syndrome (HWWS) is a congenital Mullerian duct anomaly characterized by uterine didelphys, obstructed hemivagina, and ipsilateral renal agenesis. Little is reported about spinal deformity associated with this syndrome. This study presents a case of scoliosis occurring in the setting of HWWS and explores the possible association between the 2 diseases. A previously unreported scoliosis in HWWS is described. The patient is a 12-year-old Chinese female with scoliosis that underwent a posterior correction at thoracic 5 thoracic 12 (T5-T12) levels, using the Moss-SI (Johnson & Johnson, American) spinal system. At 24-month follow-up, the patient was clinically pain free and well balanced. Plain radiographs showed solid spine fusion with no loss of deformity correction. Six months after scoliosis correction surgery, the patient went to our clinics for the treatment of HWWS. She was performed a vaginal septum resection and detected with pyocolpos. Her follow-up was symptom free at the fourth postoperative month. The prevalence of scoliosis among patients with HWWS was 8.57% that is much higher than the incidence of congential scoliosis among general population (1/1000). To the best of our knowledge, this is the first report of HWWS with thoracic scoliosis. During surgery, surgeons and anesthesiologists must pay particular attention to the Mullerian duct anomaly and renal agenesis associated with HWWS. There is a potential association between congenital scoliosis and HWWS. PMID- 25526434 TI - PROX1 gene is differentially expressed in oral cancer and reduces cellular proliferation. AB - Homeobox genes are a family of transcription factors that play a pivotal role in embryogenesis. Prospero homeobox 1 (PROX1) has been shown to function as a tumor suppressor gene or oncogene in various types of cancer, including oral squamous cell carcinoma (OSCC). We have previously identified PROX1 as a downregulated gene in OSCC. The aim of this study is to clarify the underlying mechanism by which PROX1 regulates tumorigenicity of OSCC cells. PROX1 mRNA and protein expression levels were first investigated in 40 samples of OSCC and in nontumor margins. Methylation and amplification analysis was also performed to assess the epigenetic and genetic mechanisms involved in controlling PROX1 expression. OSCC cell line SCC9 was also transfected to stably express the PROX1 gene. Next, SCC9 PROX1-overexpressing cells and controls were subjected to proliferation, differentiation, apoptosis, migration, and invasion assays in vitro. OSCC samples showed reduced PROX1 expression levels compared with nontumor margins. PROX1 amplification was associated with better overall survival. PROX1 overexpression reduces cell proliferation and downregulates cyclin D1. PROX1-overexpressing cells also exhibited reduced CK18 and CK19 expression and transcriptionally altered the expression of WISP3, GATA3, NOTCH1, and E2F1. Our results suggest that PROX1 functions as a tumor suppressor gene in oral carcinogenesis. PMID- 25526435 TI - Coracoclavicular ligament reconstruction: a systematic review and a biomechanical study of a triple endobutton technique. AB - Operative intervention is recommended for complete acromioclavicular (AC) joint dislocation to restore AC stability, but the best operative technique is still controversial. Twelve fresh-frozen male cadaveric shoulders (average age, 62.8+/ 7.8 years) were equally divided into endobutton versus the modified Weaver-Dunn groups. Each potted scapula and clavicle was fixed in a custom made jig to allow translation and load to failure testing using a Zwick BZ2.5/TS1S material testing machine (Zwick/Roell Co, Germany). A systematic review of 21 studies evaluating reconstructive methods for coracoclavicular or AC joints using a cadaveric model was also performed. From our biomechanical study, after ligament reconstruction, the triple endobutton technique demonstrated superior, anterior, and posterior displacements similar to that of the intact state (P>0.05). In the modified Weaver-Dunn reconstruction group, however, there was significantly greater anterior (P<0.001) and posterior (P=0.003) translation after ligament reconstruction. In addition, there was no significant difference after reconstruction between failure load of the triple endobutton group and that of the intact state (686.88 vs 684.9 N, P>0.05), whereas the failure load after the modified Weaver-Dunn reconstruction was decreased compared with the intact state (171.64 vs 640.86 N, P<0.001). From our systematic review of 21 studies, which involved comparison of the modified Weaver-Dunn technique with other methods, the majority showed that the modified Weaver-Dunn procedure had significantly (P<.05) greater laxity than other methods including the endobutton technique. The triple endobutton reconstruction proved superior to the modified Weaver-Dunn technique in restoration of AC joint stability and strength. Triple endobutton reconstruction of the coracoclavicular ligament is superior to the modified Weaver-Dunn reconstruction in controlling both superior and anteroposterior displacements with a failure load that approximates the intact ligament. PMID- 25526436 TI - Hepatic angiomyolipoma mimicking hepatocellular carcinoma: magnetic resonance imaging and clinical pathological characteristics in 9 cases. AB - Hepatic angiomyolipoma (HAML) is a rare mesenchymal tumor of the liver with marked histological diversity. The present study was to review the magnetic resonance imaging (MRI) and clinical pathological features of HAML resembling hepatocellular carcinoma (HCC). Nine patients who underwent surgical resection and had pathological diagnosis of HAML were retrospectively analyzed. All of 9 patients (5 males and 4 females) had a solitary hepatic mass with a median size of 4 cm (from 1.4 cm to 15.3 cm). Seven cases were identified as incidental liver tumors during health screening and 2 patients were diagnosed for hepatic mass when visited hospitals with unspecific abdominal discomfort. Before resection, 6 cases were diagnosed as HCC on MRI. MRI on chemical shift imagings showed a large amount of lipids in 5 cases. The enhancement pattern of MRI was classified into 2 types: in 2 cases, lesions with small or no vessels that demonstrated prolonged enhancement (1 mixed subtype and 1 myomatous subtype) and in 7 cases, lesions with abundant central vessels that show rapid washout (3 mixed subtypes and 4 myomatous subtypes) in the portal venous/delayed phase. All patients underwent resection of hepatic tumor and no recurrence was observed during follow-up (range: 2-24 months) of median 10 months. By immunohistochemistry, the tumor cells demonstrated positive immunostaining for human melanoma black-45, smooth muscle actin, and CD34. In conclusion, all of 9 patients with HAML presented with none or nonspecific clinical manifestations. The diagnosis of HAML relies on disease and immunohistochemistry, but not MRI due to its resemblance to HCC. PMID- 25526437 TI - Recurrent painful perianal subcutaneous angiomatoid fibrous histiocytoma: a case report and review of the literature. AB - Angiomatoid fibrous histiocytoma (AFH) is a rare, low-grade malignant soft-tissue tumor most commonly occurring in the extremities of children and young adults and has a low potential of local recurrence and metastasis. Here, we present a case of recurrent subcutaneous perianal AFH. After an initial diagnosis as a sebaceous cyst, we were able to use immunohistochemical findings to correctly identify the mass as an AFH. The patient was effectively treated after 3 surgical resections. This case emphasizes the need to correctly diagnose soft-tissue tumors using a variety of diagnostic modalities to ensure that the patient receives proper treatment. PMID- 25526438 TI - Prior to the oral therapy, what do we know about HCV-4 in Egypt: a randomized survey of prevalence and risks using data mining computed analysis. AB - Hepatitis C virus (HCV) affects over 180 million people worldwide and it's the leading cause of chronic liver diseases and hepatocellular carcinoma. HCV is classified into seven major genotypes and a series of subtypes. In general, HCV genotype 4 (HCV-4) is common in the Middle East and Africa, where it is responsible for more than 80% of HCV infections. Although HCV-4 is the cause of approximately 20% of the 180 million cases of chronic hepatitis C worldwide, it has not been a major subject of research yet. The aim of the current study is to survey the morbidities and disease complications among Egyptian population infected with HCV-4 using data mining advanced computing methods mainly and other complementary statistical analysis. Six thousand six hundred sixty subjects, aged between 17 and 58 years old, from different Egyptian Governorates were screened for HCV infection by ELISA and qualitative PCR. HCV-positive patients were further investigated for the incidence of liver cirrhosis and esophageal varices. Obtained data were analyzed by data mining approach. Among 6660 subjects enrolled in this survey, 1018 patients (15.28%) were HCV-positive. Proportion of infected males was significantly higher than females; 61.6% versus 38.4% (P=0.0052). Around two-third of infected-patients (635/1018; 62.4%) were presented with liver cirrhosis. Additionally, approximately half of the cirrhotic patients (301/635; 47.4%) showed degrees of large esophageal varices (LEVs), with higher variceal grade observed in males. Age for esophageal variceal development was 47+/-1. Data mining analysis yielded esophageal wall thickness (>6.5 mm), determined by conventional U/S, as the only independent predictor for esophageal varices. This study emphasizes the high prevalence of HCV infection among Egyptian population, in particular among males. Egyptians with HCV-4 infection are at a higher risk to develop cirrhotic liver and esophageal varices. Data mining, a new analytic technique in medical field, shed light in this study on the clinical importance of esophageal wall thickness as a useful predictor for risky esophageal varices using decision tree algorithm. PMID- 25526439 TI - From infancy to adolescence: fifteen years of continuous treatment with hydroxyurea in sickle cell anemia. AB - Despite documented laboratory and clinical benefits of hydroxyurea for children with sickle cell anemia (SCA), the drug's long-term safety and efficacy remains poorly defined. The HUSOFT trial and extension study examined feasibility, toxicity, and hematological efficacy of hydroxyurea in infants with SCA. This report describes HUSOFT participants who have continued hydroxyurea therapy for 15 years. With IRB approval, medical records were reviewed for clinical, laboratory, and growth parameters. Twenty-eight infants enrolled in the original 2-year HUSOFT study received open-label liquid hydroxyurea at 20 mg/kg/day; 17 completed the extension study with dose escalation to 30 mg/kg/day. Eight of these 17 (6 girls and 2 boys, all HbSS) have continued on daily hydroxyurea for at least 15 years (median age at last follow-up 17.6 years) without interruption. All hematologic indices (Hb concentration, mean corpuscular volume (MCV), fetal hemoglobin) showed sustained effect after 15 years. The median maximum tolerated dose of hydroxyurea has decreased from 30 to 26 mg/kg/day (range 19.5-31.2); neutropenia [absolute neutrophil count (ANC)<1.0*109/L] prompting temporary drug discontinuation occurred a total of 10 times in 4 subjects and there was no severe neutropenia (ANC<0.5*109/L). Growth rates over 15 years continued at the 50th percentile for both height and weight, and puberty occurred without delay (age range 10-14 years). There were 5.1 vaso-occlusive events (pain and acute chest syndrome)/100 patient years, 7.3 packed red blood cell transfusions/100 patient years. No malignancies, strokes, or deaths occurred. At last follow up, all subjects were at appropriate grade level (10-12 grade) with no history of repeated grades. A cohort of young teenagers with SCA who initiated treatment in infancy have had sustained and continued hematological benefits for a decade and a half. Growth and sexual development are normal and comparable to the general pediatric population. Continuous hydroxyurea therapy since infancy appears safe and efficacious in SCA. PMID- 25526441 TI - The renal histopathology spectrum of elderly patients with kidney diseases: a study of 430 patients in a single Chinese center. AB - The elderly population has significantly increased in China. However, data regarding renal histopathology in this population is lacking. The present study retrospectively analyzed renal disease spectrum of 430 elderly patients who had received renal biopsy at Peking University First Hospital between January 2003 and December 2012. Among 6049 patients receiving renal biopsies during the same period, 430 (7.10%) were elderly (>=65 years). The ratio of male (263 patients) to female (167 patients) was 1.57:1, with an age of 70.29+/-3.99 (range 65-82) years at the time of biopsy. The most common indication for renal biopsy was nephrotic syndrome (59.53%), followed by acute kidney injury (AKI, 19.53%) and chronic glomerulonephritis (CGN, 16.05%). The most common renal histopathology in primary glomerular disease was idiopathic membranous nephropathy (iMN, 61.02%), followed by IgA nephropathy (18.22%), minimal change disease (MCD, 9.32%) and focal segmental glomerulosclerosis (6.78%). ANCA-associated vasculitis (AAV, 43.95%) was the leading secondary glomerular disease, followed by HBV-related glomerulonephritis (HBV-GN, 24.2%), and amyloidosis (14.01%). In patients with nephrotic syndrome, iMN (50%) was the leading cause, followed by HBV-GN (16.02%), MCD (7.81%), and amyloidosis (7.81%). In patients with iMN, 89.5% presented as nephrotic syndrome, 8.39% as CGN. In patients with AKI, the leading cause was AAV (48.12%), followed by acute interstitial nephritis (20.48%) and acute tubular necrosis (8.43%). In conclusion, in elderly Chinese patients, the most common renal histopathology pattern was iMN in patients with nephrotic syndrome, and AAV in patients with AKI. PMID- 25526442 TI - Neoadjuvant chemotherapy followed by surgery versus surgery alone for colorectal cancer: meta-analysis of randomized controlled trials. AB - Effects of neoadjuvant chemotherapy (NAC) on colorectal cancer (CRC) have been largely studied, while its survival and surgical benefits remain controversial. This study aimed to perform a meta-analysis of randomized controlled trials (RCTs), comparing efficacy and safety of NAC plus surgery with surgery alone (SA) for CRC. We searched systematically databases of MEDLINE, EMBASE, and the Cochrane Library for RCTs comparing NAC and surgery with SA for treating CRC. References of relevant articles and reviews, conference proceedings, and ongoing trial databases were also screened. Primary outcomes included overall and disease free survivals, total and perioperative mortalities, recurrence, and metastasis. Meta-analysis was performed where possible comparing parameters using relative risks (RRs). Safely analysis was then performed. Outcomes for stages II and III tumors were also meta-analyzed, respectively. Our study was conducted according to intention-to-treat analysis. A total of 6 RCTs comparing NAC (n=1393) with SA (n=1358) published from 2002 to 2012 were identified. Compared with SA, NAC tended to reduce overall recurrences (21.86% vs 25.15%, RR: 0.70, 95% confidence interval [CI]: 0.32-1.56, P=0.09), and prevent vascular invasion (32.30% vs 43.12%, RR: 0.73, 95% CI: 0.53-1.00, P=0.05); and significantly lowered distant metastasis (15.58% vs 23.80%, RR: 0.66, 95% CI: 0.50-0.86, P=0.002), especially liver metastasis rate (13.00% vs 18.25%, RR: 0.71, 95% CI: 0.51-0.99, P=0.04), and associated with higher incidence of ypT0-2 cases upon resection (13.04% vs 6.42%, RR: 2.36, 95% CI: 1.02-5.44, P=0.04). All other parameters were comparable. NAC-related side-effects were generally mild. NAC mainly benefited patients with stage III disease. NAC could prevent recurrence and metastasis, associates with better tumor stages upon resection, and potentially impedes vascular invasion among CRC patients. NAC does not contribute to significant survival benefits for CRC, and compares favorably with SA in tumor-free resection rates, nodal status upon resection, and postsurgical complications. This level 1a evidence does not support NAC to obviously outweigh SA in terms of survival and surgical benefits for CRC currently. PMID- 25526440 TI - Helicobacter pylori infection and eye diseases: a systematic review. AB - The connection between Helicobacter pylori (Hp) infection and eye diseases has been increasingly reported in the literature and in active research. The implication of this bacterium in chronic eye diseases, such as blepharitis, glaucoma, central serous chorioretinopathy and others, has been hypothesized. Although the mechanisms by which this association occurs are currently unknown, this review describes shared pathogenetic mechanisms in an attempt to identify a lowest common denominator between eye diseases and Hp infection. The aim of this review is to assess whether different studies could be compared and to establish whether or not Hp infection and Eye diseases share common pathogenetic aspects. In particular, it has been focused on oxidative damage as a possible link between these pathologies. Text word search in Medline from 1998 to July 2014. 152 studies were included in our review. Were taken into considerations only studies that related eye diseases more frequent and/or known. Likely oxidative stress plays a key role. All of the diseases studied seem to follow a common pattern that implicates a cellular response correlated with a sublethal dose of oxidative stress. These alterations seem to be shared by both Hp infections and ocular diseases and include the following: decline in mitochondrial function, increases in the rate of reactive oxygen species production, accumulation of mitochondrial DNA mutations, increases in the levels of oxidative damage to DNA, proteins and lipids, and decreases in the capacity to degrade oxidatively damaged proteins and other macromolecules. This cascade of events appears to repeat itself in different diseases, regardless of the identity of the affected tissue. The trabecular meshwork, conjunctiva, and retina can each show how oxidative stress may acts as a common disease effector as the Helicobacter infection spreads, supported by the increased oxidative damage and other inflammation. PMID- 25526443 TI - How much progress has been made in minimally invasive surgery for gastric cancer in Korea?: a viewpoint from Korean prospective clinical trials. AB - Gastric cancer is the most common cancer in Korea. Because the incidence of gastric cancer is still high even with early detection and because of developments in surgical instruments and technological advances, minimally invasive surgery has rapidly become an accepted treatment for gastric cancer in Korea. Many Korean gastric surgeons have contributed to the rapid adaptation of minimally invasive surgery for gastric cancer: not only the Korean Laparoscopic Gastrointestinal Surgery Study (KLASS) group, but also other expert surgeons after the 2000s. Thanks to their vigorous efforts involving active learning, education, workshops, academic communications, and international communications with active laparoscopic gastric surgeons in Korea, numerous results and well designed large-scale clinical studies have been published or are actively ongoing, thus increasing its wide acceptance as an option for gastric cancer. Now, Korea has become one of the leading countries using minimally invasive surgery for the treatment of gastric cancer. This review article will summarize the current status and issues, as well as the clinical trials that have finished or are ongoing, regarding minimally invasive surgery for gastric cancer in Korea. PMID- 25526444 TI - Stress-relaxation and tension relief system for immediate primary closure of large and huge soft tissue defects: an old-new concept: new concept for direct closure of large defects. AB - Stress-relaxation is a well-established mechanism for laboratory skin stretching, with limited clinical application in conventional suturing techniques due to the inherent, concomitant induction of ischemia, necrosis and subsequent suture failure. Skin defects that cannot be primarily closed are a common difficulty during reconstructive surgery. The TopClosure tension-relief system (TRS) is a novel device for wound closure closure, providing secured attachment to the skin through a wide area of attachment, in an adjustable manner, enabling primary closure of medium to large skin defects. The aim of this study was to evaluate the efficiency of the TopClosure TRS as a substitute for skin grafting and flaps for primary closure of large soft tissue defects by stress-relaxation. We present three demonstrative cases requiring resection of large to huge tumors customarily requiring closure by skin graft or flaps. TRS was applied during surgery serving as a tension-relief platform for tension sutures, to enable primary skin-defect closure by cycling of stress-relaxation, and following surgery as skin-secure system until complete wound closure. All skin defects ranging from 7 to 26 cm in width were manipulated by the TRS through stress-relaxation, without undermining of skin, enabling primary skin closure and eliminating the need for skin grafts and flaps. Immediate wound closure ranged 26 to 135 min. TRS was applied for 3 to 4 weeks. Complications were minimal and donor site morbidity was eliminated. Surgical time, hospital stay and costs were reduced and wound aesthetics were improved. In this case series we present a novel technology that enables the utilization of the viscoelastic properties of the skin to an extreme level, extending the limits of primary wound closure by the stress-relaxation principle. This is achieved via a simple device application that may aid immediate primary wound closure and downgrade the complexity of surgical procedures for a wide range of applications on a global scale. PMID- 25526445 TI - Predictors of success in selective laser trabeculoplasty for normal tension glaucoma. AB - To determine the predictors of success for selective laser trabeculoplasty (SLT) in normal tension glaucoma (NTG). This prospective cohort study recruited subjects with unilateral or bilateral NTG on medication. All subjects received a single session of 360 degrees SLT treatment. SLT success was defined as IOP reduction>=20% at 1-month. The following covariates were analyzed via univariate and multivariate analyses: age; sex; lens status; presenting, pre-SLT, and post SLT IOP's; number and type of medications; SLT shots and energy; and pre-SLT investigations. In 60 eyes of 32 subjects with NTG, there were 30 right eyes and 28 left eyes. The success rate of SLT was 61.7%. Using 3 types of anti-glaucoma medications (coefficient=-2.2, OR=0.1, P=0.02) and a thicker retinal nerve fiber layer thickness (coefficient=-0.04, OR=0.96, P=0.04) were associated with failure (univariate analysis). In multivariate analysis, a higher pre-SLT IOP (coefficient=1.1, OR=3.1, P=0.05) and a lower 1-week IOP (coefficient=-0.8, OR=0.5, P=0.04) were associated with success. SLT was successful in over 60% of treated NTG patients. A higher pre-SLT IOP and a greater IOP reduction at 1-week post-SLT were predictors of a successful outcome. PMID- 25526446 TI - Myxoid liposarcoma in the abdominal wall: a case report. AB - A liposarcoma is the most common type of soft tissue sarcoma, and most liposarcomas are malignant. The extremities are the most common site for liposarcomas. There are 5 histologic types of liposarcoma, as follows: well differentiated; myxoid; round cell; pleomorphic; and dedifferentiated. Myxoid liposarcomas (MLSs) represent a subgroup of liposarcomas. There has been no report of MLSs in the abdominal wall. We report a rare case of a MLS of a 43-year old male who presented with tensile force on the abdominal wall. Computed tomography (CT) found a tumor in abdominal wall. There was no other abnormal symptom and the laboratory testing was also unusual. At last, the tumor was successfully excised, which was diagnosed MLSs in pathology. Following standard principles, after complete excision, the patient received radiotherapy. The patient was followed up for 8 month and no disease recurrence was identified. MLSs are rarely seen in the clinic, irrespective of the presenting signs, but also based on histologic features. The aim of this report was to present the differential diagnosis of an abdominal wall mass, and to remind us of MLSs. PMID- 25526447 TI - The radiological feature of anterior occiput-to-axis screw fixation as it guides the screw trajectory on 3D printed models: a feasibility study on 3D images and 3D printed models. AB - Anterior occiput-to-axis screw fixation is more suitable than a posterior approach for some patients with a history of posterior surgery. The complex osseous anatomy between the occiput and the axis causes a high risk of injury to neurological and vascular structures, and it is important to have an accurate screw trajectory to guide anterior occiput-to-axis screw fixation. Thirty computed tomography (CT) scans of upper cervical spines were obtained for three dimensional (3D) reconstruction. Cylinders (1.75 mm radius) were drawn to simulate the trajectory of an anterior occiput-to-axis screw. The imitation screw was adjusted to 4 different angles and measured, as were the values of the maximized anteroposterior width and the left-right width of the occiput (C0) to the C1 and C1 to C2 joints. Then, the 3D models were printed, and an angle guide device was used to introduce the screws into the 3D models referring to the angles calculated from the 3D images. We found the screw angle ranged from alpha1 (left: 4.99+/-4.59 degrees ; right: 4.28+/-5.45 degrees ) to alpha2 (left: 20.22+/-3.61 degrees ; right: 19.63+/-4.94 degrees ); on the lateral view, the screw angle ranged from beta1 (left: 13.13+/-4.93 degrees ; right: 11.82+/-5.64 degrees ) to beta2 (left: 34.86+/-6.00 degrees ; right: 35.01+/-5.77 degrees ). No statistically significant difference was found between the data of the left and right sides. On the 3D printed models, all of the anterior occiput-to-axis screws were successfully introduced, and none of them penetrated outside of the cortex; the mean alpha4 was 12.00+/-4.11 (left) and 12.25+/-4.05 (right), and the mean beta4 was 23.44+/-4.21 (left) and 22.75+/-4.41 (right). No significant difference was found between alpha4 and beta4 on the 3D printed models and alpha3 and beta3 calculated from the 3D digital images of the left and right sides. Aided with the angle guide device, we could achieve an optimal screw trajectory for anterior occiput-to-axis screw fixation on 3D printed C0 to C2 models. PMID- 25526448 TI - Adiponectin is not associated with blood pressure in normotensives and untreated hypertensives with normal kidney function. AB - The role of adiponectin in hypertension is still a matter of debate. Obtained conflicting results could be mostly explained with diversity of subjects included in different studies. Our aim was to analyze association of adiponectin with blood pressure (BP) in a group of normotensive and untreated hypertensive subjects. Participants (N=257) were selected from a random sample of 2487 subjects enrolled in an observational cross-sectional study. Subjects with diabetes and chronic kidney diseases were excluded. BP was measured using Omron M6 device following ESH/ESC guidelines. Adiponectin concentration was determined by ELISA. There were no differences in adiponectin values (mg/L) between hypertensives and normotensives (median 9.75; iqr: 7.44-17.88 vs 11.35; iqr: 7.43 12.63; P=0.17). On univariate linear regression adiponectin was not associated with systolic or diastolic BP (P>0.05). Furthermore, multivariate analysis did not show significant contribution of log-transformed adiponectin either to systolic (beta=-0.040; P=0.43) or diastolic BP (beta=0.066; P=0.33). In our group of normotensives and untreated hypertensives with normal kidney function adiponectin was not associated with BP even after adjustment for other risk factors. Our results and conclusions should not be extrapolated to subjects with other characteristics. PMID- 25526449 TI - The role of cytochromes p450 and aldo-keto reductases in prognosis of breast carcinoma patients. AB - Metabolism of anticancer drugs affects their antitumor effects. This study has investigated the associations of gene expression of enzymes metabolizing anticancer drugs with therapy response and survival of breast carcinoma patients. Gene expression of 13 aldo-keto reductases (AKRs), carbonyl reductase 1, and 10 cytochromes P450 (CYPs) was assessed using quantitative real-time polymerase chain reaction in tumors and paired adjacent nonneoplastic tissues from 68 posttreatment breast carcinoma patients. Eleven candidate genes were then evaluated in an independent series of 50 pretreatment patients. Protein expression of the most significant genes was confirmed by immunoblotting. AKR1A1 was significantly overexpressed and AKR1C1-4, KCNAB1, CYP2C19, CYP3A4, and CYP3A5 downregulated in tumors compared with control nonneoplastic tissues after correction for multiple testing. Significant association of CYP2B6 transcript levels in tumors with expression of hormonal receptors was found in the posttreatment set and replicated in the pretreatment set of patients. Significantly higher intratumoral levels of AKR1C1, AKR1C2, or CYP2W1 were found in responders to neoadjuvant chemotherapy compared with nonresponders. Patients with high AKR7A3 or CYP2B6 levels in the pretreatment set had significantly longer disease-free survival than patients with low levels. Protein products of AKR1C1, AKR1C2, AKR7A3, CYP3A4, and carbonyl reductase (CBR1) were found in tumors and those of AKR1C1, AKR7A3, and CBR1 correlated with their transcript levels. Small interfering RNA-directed knockdown of AKR1C2 or vector-mediated upregulation of CYP3A4 in MDA-MB-231 model cell line had no effect on cell proliferation after paclitaxel treatment in vitro. Prognostic and predictive roles of drug-metabolizing enzymes strikingly differ between posttreatment and pretreatment breast carcinoma patients. Mechanisms of action of AKR1C2, AKR7A3, CYP2B6, CYP3A4, and CBR1 should continue to be further followed in breast carcinoma patients and models. PMID- 25526450 TI - Utility of PET/CT in the diagnosis and staging of extranodal natural killer/T cell lymphoma: a systematic review and meta-analysis. AB - The role of 18F-fuorodexoyglucose-positron emission tomography/computed tomography (18F-FDG-PET/CT) in the staging of Hodgkin lymphoma (HL) and aggressive B-cell non-Hodgkin lymphomas (NHL) has been demonstrated extensively. Nevertheless, the role of PET/CT in the diagnosis, staging, prognosis, and treatment evaluation of natural killer (NK)/T-cell lymphoma remains indeterminate. To systematically review and meta-analyze the publications on the value of 18F-FDG-PET/CT in the diagnosis and staging of NK/T-cell lymphoma. Pubmed, Embase, Cochrane Library, and some other database were searched for initial studies (last updated on May 8th, 2014).The eligibility criteria were studies assessing the usefulness of PET/CT in the staging of NK/T-cell lymphoma, patients were diagnosed as NK/T-cell lymphoma through pathology, or clinical and imaging follow-up. Sensitivities and specificities of 18F-FDG-PET/CT in individual studies were assessed. The summary receiver operating characteristic curve (sROC) and the area under the curve (AUC) were calculated. The "Meta-Disc 1.4" software was used for data analysis. Eight studies, with a total of 135 NK/T cell lymphoma patients, were included in this meta-analysis. In terms of the 6 studies with patient based data, the pooled sensitivity and specificity of PET/CT in the diagnosis of NK/T-cell lymphoma were 0.95 (95% CI: 0.89-0.98) and 0.40 (95% CI: 0.09-0.78), respectively. For lesion-based analysis, with 1546 lesions included, the pooled sensitivity and specificity of PET/CT in the staging of NK/T cell lymphoma were 0.98 (95% CI: 0.96-0.99) and 0.99 (95% CI: 0.99-1.00), respectively. For the patient based data, the AUC and Q index were 0.8537 and 0.7847, respectively. For lesion based data, the AUC and Q index were 0.9959 and 0.9755, respectively. The results of this current meta-analysis indicated that PET/CT could be used as a valuable diagnostic and staging tool for NK/T-cell lymphoma. PMID- 25526451 TI - Separate and joint effects of diabetes mellitus and chronic kidney disease on the risk of acute coronary syndrome: a population-based cohort study. AB - Patient with diabetes (DM) and chronic kidney disease (CKD) are at a higher risk of developing acute coronary syndrome (ACS). However, only a few studies have investigated the separate and joint effects of DM and CKD on the risk of ACS, especially population-based studies under age-, sex- and various cardiovascular risk factor-stratifications. By using a national diabetes cohort derived from the Taiwan National Health Insurance Research Database, we identified a total of 416,143 DM and 541,724 non-DM patients, including 51,208 DM/CKD and 8,894 non DM/CKD patients, in 2000 who did not have a history of ACS (ICD-9: 410.X, 413.9, 411.1) before 2000. We then prospectively investigated the incidence of ACS by linking to inpatient claims data from 2000 to 2007. A Cox proportional hazard model was used to estimate the relative risk of ACS in individuals with DM and/or CKD under various stratifications. Age- and sex-specific incidence rates were similar between the non-DM/CKD and DM/non-CKD groups, except for female patients under 45 years, in whom DM was associated with a higher risk of ACS than CKD (8.21 vs. 3.82 per 1000 person-years). In the group aged <45 years, the DM/non CKD patients were associated with a higher relative hazard of ACS than those in the non-DM/CKD group when compared with the non-DM/non-CKD group (men: adjusted hazard ratios [AHR]:1.77; 95% confidence interval [CI]:1.61-1.93 vs. 1.42 [95% CI: 0.73-2.73]; women 1.97 [95% CI: 1.76-2.20] vs. 1.13 [95% CI: 0.36-3.52]). This discrepancy in AHR was reduced with increasing age. The co-existence of DM and CKD further enhanced the AHR in a multiplicative independent manner. A significant age-modification effect was noted in the DM individuals regardless of their CKD status, but not in the non-DM/CKD group. In stratification by various cardiovascular risk factors, diabetes had a higher risk of ACS than CKD in patients with <=2 selected risk factors, with the exception of the hyperlipidemia and hypertension subgroup. When all three selected risk factors were included, CKD was associated with a higher risk of ACS than DM (AHR: 1.43 [1.27-1.60] vs. 1.25 [1.22-1.29]). In conclusion, DM and CKD were associated with different levels of risk for ACS according to age, sex and certain cardiovascular risk factors. Strategies aimed at preventing ACS should therefore be individualized according to the presence of DM, CKD and various cardiovascular risk factors. PMID- 25526452 TI - Behcet's disease complicated with thrombosis: a report of 93 Chinese cases. AB - To investigate the clinical features of Behcet's disease (BD) complicated with thrombosis. Medical records of patients with BD at Peking Union Medical College Hospital from 1993 to 2013 were reviewed to identify thrombosis. Of the 766 patients with BD, 93 patients (16 female and 77 male) developed thrombosis. The most common thrombosis was extremity vein thrombosis (86.0%), including deep vein thrombosis (n=78) and superficial thrombophlebitis (n=4). The other thrombosis types associated with BD in descending frequency of order were: vena cava thrombosis (30.1%), pulmonary thromboembolism (15.1%), cerebral venous thrombosis (CVT) (12.9%), intracardiac thrombosis (8.6%), Budd-Chiari syndrome (7.5%), and renal vein thrombosis (4.3%), etc. Venous thrombosis is more frequent than arterial thrombosis, and most of patients (94.6%) experienced multiple thrombosis. A male predominance of extremity vein thrombosis and positive pathergy test, and a female predominance of CVT and genital ulcers were noted. All of these patients exhibited active disease during the emergence of thrombotic events. After treating with glucocorticosteroids, immunosuppressants, and/or anticoagulants, the thrombosis resolved in 89 patients. Three patients died from aneurysm rupture, myocardial infarction and Budd-Chiari syndrome, respectively. One patient with septic shock discontinued therapy during follow-up. Thrombosis in BD patients is male predominance, mainly multiple and venous thrombosis is more common. Active disease patients are prone to thrombosis, which suggest the key role of immunosuppressive therapy for the complication. PMID- 25526453 TI - Uncompromised treatment efficacy in elderly patients with hepatocellular carcinoma: a propensity score analysis. AB - The number of elderly hepatocellular carcinoma (HCC) patients is expected to rise. We analyzed the impact of age on clinical presentations, treatment allocation, and long-term survival between elderly (>=75 years) and younger (<75 years) HCC patients. In this study, a total of 812 elderly and 2270 younger HCC patients were evaluated. The baseline information and long-term survival were compared in the entire population and in different treatment groups. A propensity score matching analysis with preset caliper width was utilized to compare survival differences in different patient subgroups. Elderly HCC patients had discrete characteristics compared with younger HCC patients. Elderly patients received surgical resection (SR) less frequently, while more elderly patients underwent radiofrequency ablation (RFA) and transarterial chemoembolization (TACE). Younger patients had significantly better long-term survival than the elderly patients in all patients and in patients receiving SR (both P<0.05). However, of the entire cohort, age was not an independent predictor of poor prognosis in the Cox multivariate model. The long-term survival was similar between 2 age groups in patients receiving RFA and TACE. In the propensity model, there were no significant survival differences among patients receiving SR, RFA, or TACE (all P>0.05). Among the elderly, the Cancer of the Liver Italian Program (CLIP) score provided the lowest Akaike information criterion value. In conclusion, advanced age is not associated with inferior treatment result in HCC patients receiving different therapeutic modalities. Elderly HCC patients should be encouraged for active treatment when indicated. The CLIP is an optimal prognostic model for outcome assessment. PMID- 25526454 TI - Extra- and intracranial cerebral vasculitis in giant cell arteritis: an observational study. AB - Recognizing giant cell arteritis (GCA) in patients with stroke may be challenging. We aimed to highlight the clinical spectrum and long-term follow-up of GCA-specific cerebrovascular accidents. Medical charts of all patients followed in a French Department of Internal Medicine for GCA between January 2008 and January 2014 were retrospectively reviewed. Patients with cerebrovascular accidents at GCA diagnosis were included. Diagnosis of GCA was based on American College of Rheumatology criteria. Transient ischemic attacks and stroke resulting from an atherosclerotic or cardioembolic mechanism were excluded. Clinical features, GCA-diagnosis workup, brain imaging, cerebrospinal fluid (CSF) study, treatment, and follow-up data were analyzed. From January 2008 to January 2014, 97 patients have been followed for GCA. Among them, 8 biopsy-proven GCA patients (mean age 70+/-7.8 years, M/F sex ratio 3/1) had stroke at GCA diagnosis. Six patients reported headache and visual impairment. Brain MR angiography showed involvement of vertebral and/or basilar arteries in all cases with multiple or unique ischemic lesions in the infratentorial region of the brain in all but one case. Intracranial cerebral arteries involvement was observed in 4 cases including 2 cases with cerebral angiitis. Long lasting lesions on diffusion weight brain MRI sequences were observed in 1 case. All patients received steroids for a mean of 28.1+/-12.8 months. Side effects associated with long-term steroid therapy occurred in 6 patients. Relapses occurred in 4 patients and required immunosuppressive drugs in 3 cases. After a mean follow-up duration of 36.4+/-16.4 months, all but 1 patient achieved complete remission without major sequelae. The conjunction of headache with vertebral and basilar arteries involvement in elderly is highly suggestive of stroke associated with GCA. Intracranial cerebral arteries involvement with cerebral angiitis associated with long lasting brain lesions on diffusion-weight brain MRI sequences may occur in GCA. Both frequent relapses and steroid-induced side effects argue for the use of immunosuppressive agents combined with steroids as first-line therapy. PMID- 25526456 TI - The relationship between skeletal-related events and bone scan index for the treatment of bone metastasis with breast cancer patients. AB - The aim of the present study was to investigate the relationships between the automated bone scan index (aBSI) and skeletal-related events (SRE) in breast cancer patients with bone metastasis. A computer-aided software (BONENAVITM) that was developed using an Artificial Neural Network (Artificial Neural Network) was used for the present analysis. Forty-five patients diagnosed with bone metastasis due to breast cancer from April 2005 through March 2013 were retrospectively analyzed. Before and after the time of initial treatment, aBSI, Artificial Neural Network score, and hotspot number were calculated, and the relationships between these scores and SRE were analyzed. Twenty cases showed decreased (improved) aBSI values after initial treatment (Group A), and 25 cases showed unchanged/increased (worsened) aBSI values (Group B). Chi-square analysis revealed a significant difference in incident numbers of SRE between the two groups--one case in Group A and 12 in Group B (P<0.001). Event-free survival was significantly shorter in Group B (hazard ratio: 8.31, 95% CI: 1.33-12.14, log-rank test; P<0.05). The groups were also divided by the results of 2 radiologists' visual scan interpretations, and no significant differences were shown in the number of SRE (P=0.82, P=0.10). When correlation analyses were performed between aBSI and bone metabolic or tumor markers, alkaline phosphatase was significantly correlated with aBSI at the time of initial treatment (R=0.69, P<0.05). In conclusion, aBSI is proposed as a useful and objective imaging biomarker in the detection of breast-cancer patients with bone metastasis at high risk of SRE. PMID- 25526455 TI - Efficacy of surgery and adjuvant therapy in older patients with colorectal cancer: a STROBE-compliant article. AB - The present study aimed to assess the efficacy of surgery and adjuvant therapy in older patients (age>=70 years) with colorectal cancer (CRC). Older CRC patients are under-represented in available clinical trials, and therefore their outcomes after receiving surgery and adjuvant therapy are unclear. From two prospective Swedish databases, we assessed a cohort of 1021 patients who underwent curative surgery for stage I, II, or III primary CRC, with or without adjuvant chemotherapy/radiotherapy. Of the patients with colon cancer (n=467), 182 (39%) were aged <70 years, 162 (35%) aged 70 to 80 years, and 123 (26%) were aged >=80 years. Of rectal cancer patients (n=554), 264 (48%) were aged <70 years, 234 (42%) aged 70 to 80 years, and 56 (10%) aged >=80 years. Older patients with either colon or rectal cancer had higher comorbidity than did younger patients. Older patients with colon cancer had equivalent postoperative morbidity and 30 day mortality to younger patients. Rectal cancer patients aged >=80 years had a higher 30-day mortality than younger patients (odds ratio [OR], 2.37; 95% confidence interval [CI], 1.6-4.55; P=0.03). For either colon or rectal cancer, adjuvant chemotherapy compromised the 5-year overall survival (OS) of older patients with stage II disease and had no effect on those with stage III disease. Receiving adjuvant chemotherapy was a poor factor of OS for older patients with either colon (HR 1.88, 95% CI: 1.20-4.35, P=0.03) or rectal cancer (HR 1.72, 95% CI: 1.05-2.26, P=0.004). Preoperative short-course radiotherapy improved both OS and local control for older patients with stage III rectal cancer and had no effect on those with stage II disease. Radiotherapy was a favorable factor for the OS of the older patients with rectal cancer (HR 0.42, 95% CI: 0.21-3.57, P=0.01). In conclusion, Older CRC patients had equal safety of surgery as younger patients, except rectal cancer patients aged >=80 years that had a higher mortality. Adjuvant 5FU-based chemotherapy did not benefit older CRC patient, while neoadjuvant radiotherapy improved the prognosis of older patients with stage III rectal cancer. PMID- 25526457 TI - Incidence of end stage renal disease among type 1 diabetes: a nationwide cohort study in Taiwan. AB - The aim of our study was to estimate the risk of end-stage renal disease (ESRD) in type 1 diabetes mellitus (T1DM) in Taiwanese people; in addition, our goal was to determine how the age, year, and sex at registration of T1DM affects the risk. Population-based cohort study. A nationwide cohort study of 7203 Taiwanese patients with T1DM registered in 1999 to 2010 was followed up until ESRD, death, or the end of follow-up on December 31, 2010. Annual age-, sex-, and calendar year-specific incidence rates of ESRD of the general population were used to calculate the standardized incidence ratio (SIR) of ESRD in relation to T1DM. The SIR of ESRD for male and female patients with T1DM was significantly increased at 25.85 (95% CI 23.40-28.29) and 28.08 (95% 25.45-30.71), respectively; the peak was at age 15 to 29 years for both genders. The cumulative incidence of ESRD was similar in male and female patients but was significantly higher in patients>= 30 years old than in patients<30 years old (10.25% vs. 3.57%, P<0.001). Patients aged <15 years had a significantly lower risk of ESRD as compared to those aged 15 to 29 years; patients aged 30 to 44 (adjusted HR, 1.491) and 45 to 60 years (adjusted HR, 2.111) showed significantly increased hazards. Our data also demonstrated a lower risk of ESRD in patients who were registered in later years than in earlier years. The risk of ESRD is substantially increased in T1DM in the ethnic Chinese population. The continuously declining risk of ESRD in T1DM may advocate the use of a multidisciplinary chronic kidney disease care system in Taiwan. PMID- 25526458 TI - Subtypes of metabolic syndrome and of other risk factors in Japanese women with erosive esophagitis. AB - Obesity and metabolic syndrome (MS) are strongly associated with erosive esophagitis (EE). The prevalence of MS and EE, and the distribution of adipose tissue have been known to differ markedly between men and women. Although the prevalence of EE in men with MS is known to be higher in visceral fat type MS (V type MS) than in subcutaneous fat type MS (S-type MS), the association between EE and the types of MS in women with MS is unclear. This study was a cross-sectional study elucidating the association between EE and the types of MS in women with MS. Subjects were 454 women with MS who underwent a regular health check-up. A distinction was made between V-type MS and S-type MS and the prevalence of EE and the association between EE and other data were elucidated. Although there were some significant different factors in characteristics between V-type MS and S type MS, there was no significant difference in the prevalence of EE between V type MS and S-type MS. The presence of Helicobacter pylori (H. pylori) was significantly lower than in subjects with EE (13.7%) than in subjects without EE (41.9%). The frequency of hiatal hernia was significantly higher in subjects with EE (60.8%) than in subjects without EE (24.6%). Logistic regression analysis showed hiatal hernia (odds ratio: 4.673; 95% confidence interval: 2.448-8.920; P<0.001), hemoglobin A1c (HbA1c) (2.325; 1.110-4.870; P<0.05), and the presence of H. pylori (0.239; 0.101-0.567; P<0.005) were significant predictors of the prevalence of EE. V-type MS may not be such an important factor for the prevalence of EE in women with MS as in men with MS. The absence of H. pylori, hiatal hernia, and HbA1c may be more important for the prevalence of EE than the types of MS in women with MS. PMID- 25526460 TI - Nuclear factor-kappa B1 is associated with gastric cancer in a Chinese population. AB - Activated nuclear factor-kappaB (NF-kappaB) is associated with the pathogenesis of numerous cancers, such as gastric cancer (GC). Genetic polymorphisms in the genomic region containing nuclear factor-kappaB1 (NFKB1) have a plausible role in modulating the risk of GC. To identify markers contributing to the genetic susceptibility to GC, we analyzed 15 single nucleotide polymorphisms (SNPs, rs28362491, rs3774932, rs1598856, rs230531, rs230530, rs230528, rs230521, rs230498, rs230539, rs1005819, rs3774956, rs4648055, rs3774964, rs4648068, and rs3774968) in the genomic region containing NFKB1. The participants included 401 patients with GC and 433 healthy controls. The allelic or genotypic frequencies of the rs28362491 (located in the promoter region of NFKB1), rs230521 (NFKB1 intron 4), and rs4648068 (NFKB1 intron 12) polymorphisms in the patients with GC were significantly different from those in the healthy controls. Strong linkage disequilibrium was observed in 4 blocks (D'>0.9). Significantly more A-T haplotypes (block 1, P=0.0005), A-C haplotypes (block 2, P=0.0001) and G-A-A haplotypes (block 4, P=0.016) were found in the patients with GC. Significantly more A-C haplotypes (block 1, P=0.005) and A-G haplotypes (block 2, P=0.0004) were found in the healthy controls. These findings suggest a role for NFKB1 polymorphism in GC among a Han Chinese population and may be informative for future genetic studies on gastric cancer. PMID- 25526459 TI - Patients with chronic three-vessel disease in a 15-year follow-up study: genetic and non-genetic predictors of survival. AB - Genetic and non-genetic predictors of 15-year survival in patients with chronic three-vessel disease (3VD) were investigated. Coronary angiography was performed on 810 subjects with symptoms of stable ischemic heart disease in 1998. The patients with 3VD were genotyped for 23 candidate polymorphisms covering the PPAR RXR pathway, matrix metalloproteinase-2, renin-angiotensin-aldosterone system, endothelin-1, cytokine genes, MTHFR and APO E variants. Fifteen-year survival data were obtained from the national insurance registry. All data were available in the case of 150 patients with 3VD. Statistical analysis used stepwise Cox regression with dominant, recessive, or additive mode of genetic expression. Involved variables included age, sex, BMI, blood pressure, diabetes, ejection fraction, left main stenosis, previously diagnosed coronary stenosis, myocardial infarction in personal history, and coronary bypass along with polymorphisms pre selected by log-rank tests. Out of the 23 polymorphisms, four were included in the model construction. SNP in the IL-6 gene rs1800795 (-174 G/C) has been found to be a significant predictor of survival. This SNP was in a linkage disequilibrium with rs1800797 (-597 G/A) in the same gene (D'=1.0), which was also found to constitute a significant predictor of survival when rs1800795 was not included in the model construction. Age, increased BMI, diabetes, low EF, and left main stenosis were also significant predictors in all models. Age, increased BMI, diabetes, low ejection fraction, left main stenosis, and genetic variation in the IL-6 promoter were established as significant independent risk factors for the survival of patients with three-vessel disease. PMID- 25526461 TI - Profile of differential promoter activity by nucleotide substitution at GWAS signals for multiple sclerosis. AB - This experimental study was conducted with completely randomized design. Genome wide association studies (GWAS) have revealed a large number of genetic associations of nucleotide sequence variants with susceptibility to multiple sclerosis (MS). Nevertheless, studies to identify the functional relevance of these variants lag far behind identification of the GWAS signals. Expression quantitative trait loci (eQTLs) analysis and promoter activity analysis with the variants filtered by GWAS were conducted to identify their functional alleles and haplotypes. The promoter activity was assayed with reporter constructs containing variants at 8 MS GWAS signals resulted from 18 GWAS. The promoter activity differed by alternative sequence variants at upstream regions of the CYP24A1, CYP27B1, SYK, RAD21L1, PVR, ODF3B, and RGS14 genes (P<0.05). The transcriptional regulations of sequence variants were also found by identifications of eQTLs for their corresponding genes with lymphoblastoid cells in the current study (SYK, ODF3B, RGS14, and PVR, P<8.33*10-3) and with dendritic cells in a previous study (CYP27B1, P=1.84*10-6). This study identified regulatory nucleotide sequences in the promoters of the CYP24A1, CYP27B1, SYK, RAD21L1, PVR, ODF3B, and RGS14 genes, and their variants differentially affected gene expression. This might result in their associations with MS susceptibility in previous GWAS. Further functional studies are required to understand the process of transcriptional regulation of the variants identified in the current study and the mechanisms underlying susceptibility to MS. PMID- 25526462 TI - Effect and safety of deep needling and shallow needling for functional constipation: a multicenter, randomized controlled trial. AB - Aupuncture is widely used for functional constipation. Effect of acupuncture might be related to the depth of needling; however, the evidence is limited. This trial aimed to evaluate the effect and safety of deep needling and shallow needling for functional constipation, and to assess if the deep needling and shallow needling are superior to lactulose. We conducted a prospective, superiority-design, 5-center, 3-arm randomized controlled trial. A total of 475 patients with functional constipation were randomized to the deep needling group (237), shallow needling group (119), and lactulose-controlled group (119) in a ratio of 2:1:1. Sessions lasted 30 minutes each time and took place 5 times a week for 4 weeks in 2 acupuncture groups. Participants in the lactulose group took lactulose orally for 16 continuous weeks. The primary outcome was the change from baseline of mean weekly spontaneous bowel movements (SBMs) during week 1 to 4 (changes from the baselines of the weekly SBMs at week 8 and week 16 in follow up period were also assessed simultaneously). Secondary outcomes were the weekly SBMs of each assessing week, the mean score change from the baseline of constipation-related symptoms over week 1 to 4, and the time to the first SBM. Emergency drug usage and adverse effects were monitored throughout the study.SBMs and constipation-related symptoms were all improved in the 3 groups compared with baseline at each time frame (P<0.01, all). The changes in the mean weekly SBMs over week 1 to 4 were 2 (1.75) in the deep needling group, 2 (1.75) in the shallow needling group, and 2 (2) in the lactulose group (P>0.05, both compared with the lactulose group). The changes of mean weekly SBMs at week 8 and week 16 in the follow-up period were 2 (2), 2 (2.5) in the deep needling group, 2 (3), 1.5 (2.5) in the shallow needling group, and 1 (2), 1 (2) in the lactulose group (P<0.05, all compared with the lactulose group). No significant difference was observed among the 3 groups regarding the score changes of straining, incomplete evacuation, abdominal distention during spontaneous defecating, or Cleveland Clinic Scores over week 1 to 4. However, the lactulose group got better effect than other 2 acupuncture groups in improving stool consistency (P<0.01, both) and shortening the time to the first SBM (P<0.05, both). The percentage of emergency drugs used in the 2 acupuncture groups were both lower than in the lactulose group at each time frame (P<0.01, all). No obvious adverse event was observed in the deep or shallow needling group. Deep and shallow needling at Tianshu (ST25) can improve intestinal function remarkably and safely. Therapeutic effects of deep and shallow needling are not superior to that of lactulose; however, the sustained effects of deep and shallow needling after stopping the acupuncture treatments are superior to the therapeutic effect of lactulose, which might qualify the superiority of deep and shallow needling. PMID- 25526464 TI - Renal dysfunction and thrombolytic therapy in patients with acute ischemic stroke: a systematic review and meta-analysis. AB - Renal dysfunction is a prevalent comorbidity in acute ischemic stroke patients requiring thrombolytic therapy. However, the effect of renal dysfunction on the clinical outcome of this population remains controversial. This study aimed to evaluate the safety and effectiveness of thrombolytic therapy in acute stroke patients with renal dysfunction using a meta-analysis. We systematically searched PubMed and EMBASE for studies that evaluated the relationship between renal dysfunction and intravenous tissue plasminogen activator (tPA) in patients with acute ischemic stroke. Poor outcome (modified Rankin Scale>=2), mortality, and symptomatic intracranial hemorrhage (ICH) and any ICH were analyzed. Fourteen studies were included (N=53,553 patients). The mean age ranged from 66 to 75 years. The proportion of male participants was 49% to 74%. The proportion of renal dysfunction varied from 21.9% to 83% according to different definitions. Based on 9 studies with a total of 7796 patients, the meta-analysis did not identify a significant difference in the odds of poor outcome (odds ratio [OR]=1.06; 95% confidence interval [CI]: 0.96-1.16; I=44.5) between patients with renal dysfunction and those without renal dysfunction. Patients with renal dysfunction were more likely to die after intravenous thrombolysis (OR=1.13; 95% CI: 1.05-1.21; I=70.3). No association was observed between symptomatic ICH (OR=1.02; 95% CI: 0.94-1.10; I=0) and any ICH (OR=1.07; 95% CI: 0.96-1.18; I=25.8). Renal dysfunction does not increase the risk of poor outcome and ICH after stroke thrombolysis. Renal dysfunction should not be a contraindication for administration of intravenous thrombolysis to eligible patients. PMID- 25526463 TI - BRAFV600E immunopositive melanomas show low frequency of heterogeneity and association with epithelioid tumor cells: a STROBE-compliant article. AB - Treatment of BRAFV600E-mutant melanoma by small molecule inhibitors that target BRAFV600E or MEK kinases is increasingly used in clinical practice and significantly improve patient outcome. However, patients eventually become resistant and therapeutic improvement is required. Molecular diversity within individual tumors (intratumor heterogeneity) and between tumors within a single patient (intrapatient heterogeneity) poses a significant challenge to precision medicine. Using immunohistochemistry, we determined the extent of BRAFV600E intratumor and intrapatient heterogeneity and the influence of morphological heterogeneity in a large series of 171 melanomas of 81 patients. The BRAFV600E mutation rate found in our melanoma series is 44%, with none of 22 (0%) melanoma in situ, 23 of 56 (41%) primary tumors, 28 of 59 (48%) regional metastases, and 24 of 34 (71%) distant metastases harboring the mutation. In general, a diffuse homogeneous immunostaining was seen, even in tumors consisting of more than one cell type, that is, epithelioid, spindle, and/or small cell types. Nevertheless, BRAFV600E-mutant melanomas more often had a purely epithelioid cell population (P=0.063), that is more evident among distant metastases (P=0.014). Only two of 75 (3%) mutated specimens (one primary and one metastasis) displayed heterogeneous BRAFV600E expression. The primary tumor was also morphologically heterogeneous and exclusively displayed BRAFV600E in the epithelioid component, confirming an association between BRAFV600E and epithelioid cells. Twenty-eight of 30 patients (93%) had concordant BRAFV600E mutation status between their tumors. Taken together, BRAFV600E intratumor and intrapatient heterogeneity in melanoma is diminutive, nevertheless, the identified exceptions will have important implications for the clinical management of this disease. PMID- 25526465 TI - Regional differences in treatment frequency and case-fatality rates in korean patients with acute myocardial infarction using the Korea national health insurance claims database: findings of a large retrospective cohort study. AB - Issues regarding healthcare disparity continue to increase in connection with access to quality care for acute myocardial infarction (AMI), even though the case-fatality rate (CFR) continues to decrease. We explored regional variation in AMI CFRs and examined whether the variation was due to disparities in access to quality medical services for AMI patients. A dataset was constructed from the Korea National Health Insurance Claims Database to conduct a retrospective cohort study of 95,616 patients who were admitted to a hospital in Korea from 2003 to 2007 with AMI. Each patient was followed in the claims database for information about treatment after admission or death. The procedure rate decreased as the region went "down" from Seoul to the county level, whereas the AMI CFR increased as the county level as a function of proximity to the county level (30-day AMI CFRs: Seoul, 16.4%; metropolitan areas, 16.2%, cities; 18.8%, counties, 39.4%). Even after adjusting for covariates, an identical regional variation in the odds of patients receiving treatment services and dying was identified. After adjusting for invasive and medical management variables in addition to earlier covariates, the death risk in the counties remained statistically significantly higher than in Seoul; however, the degree of the difference decreased greatly and the significant differences in metropolitan areas and cities disappeared. Policy interventions are needed to increase access to quality AMI care in county-level local areas because regional differences in the AMI CFR are likely caused by differences in the performance of medical and invasive management among the regions of Korea. Additionally, a public education program to increase the awareness of early symptoms and the necessity of visiting the hospital early should be established as the first priority to improve the outcome of AMI patents, especially in county-level local areas. PMID- 25526466 TI - Intermittent hepatic inflow occlusion during partial hepatectomy for hepatocellular carcinoma does not shorten overall survival or increase the likelihood of tumor recurrence. AB - AIM: To investigate whether the long-term outcomes of hepatocellular carcinoma (HCC) was adversely impacted by intermittent hepatic inflow occlusion (HIO) during hepatic resection. METHODS: 1549 HCC patients who underwent hepatic resection between 1998 and 2008 were identified from a prospectively maintained database. Intermittent HIO was performed in 931 patients (HIO group); of which 712 patients had a Pringle maneuver as the mechanism for occlusion (PM group), and 219 patients had selective hemi-hepatic occlusion (SO group). There were 618 patients that underwent partial hepatectomy without occlusion (occlusion-free, OF group). RESULTS: The 1-, 3-, and 5- year overall survival (OS) rates were 79%, 59%, and 42% in the HIO group, and 83%, 53%, and 35% in the OF group, respectively. The corresponding recurrence free survival (RFS) rates were 68%, 39%, and 22% in the HIO group, and 74%, 41%, and 18% in the OF group, respectively. There was no significant difference between the 2 groups in OS or RFS (P=0.325 and P=0.416). Subgroup analysis showed patients with blood loss over 3000 mL and those requiring transfusion suffered significantly shorter OS and RFS. Blood loss over 3000 mL and blood transfusion were independent risk factors to OS and RFS. CONCLUSIONS: The application of intermittent HIO (PM and SO) during hepatic resection did not adversely impact either OS or RFS in patients with HCC. Intermittent HIO is still a valuable tool in hepatic resection, because high intraoperative blood loss resulting in transfusion is associated with a reduction in both OS and RFS. PMID- 25526467 TI - CLPTM1L genetic polymorphisms and interaction with smoking and alcohol drinking in lung cancer risk: a case-control study in the Han population from northwest China. AB - Genetic variants of cleft lip and palate trans-membrane 1-like (CLPTM1L) genes in the p15.33 region of chromosome 5 were previously identified to influence susceptibility to lung cancer. We examined the association of single nucleotide polymorphisms (SNPs) in CLPTM1L genes with lung cancer and explored their potential effects on the relationship between environmental risk factors (smoking, drinking) and lung cancer in a Chinese Han population. We genotyped 9 single nucleotide polymorphisms (SNPs) of CLPTM1L in a case-control study with 228 lung cancer cases and 301 controls from northwest China. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression. We identified that the minor alleles of rs451360, rs402710, and rs31484 in CLPTM1L were associated with a 0.52-fold, 0.76-fold, and 0.70-fold decreased risk of lung cancer in allelic model analysis, respectively. In the genetic model analysis, we found rs402710 and rs401681 were associated with decreased lung cancer risk. Further stratification analysis showed that rs380286 displayed a significantly decreased lung cancer risk (OR=0.65, P=0.041) in the non-drinkers. In addition, Haplotype "GTTATCTGT" was found to be associated with decreased lung cancer risk (OR=0.50, P=0.033). Our results verified that genetic variants of CLPTM1L contribute to lung cancer susceptibility in the northwest Chinese Han population. Additionally, we found that consumption of alcohol may interact with CLPTM1L polymorphisms to contribute to overall lung cancer susceptibility. PMID- 25526468 TI - Stereotactic body radiation therapy for prostate cancer patients with old age or medical comorbidity: a 5-year follow-up of an investigational study. AB - We evaluated 5-year follow-up of stereotactic body radiation therapy (SBRT) with Cyberknife for prostate cancer patients. Forty-five men with prostate adenocarcinoma who received SBRT using Cyberknife from May 2006 to November 2012 were enrolled in this study. They were prostate cancer patients with old age and medical comorbidities who received a total of 36 Gy to the prostate in 5 fractions with either everyday or every other day schedule. Prostate-specific antigen (PSA) levels at initial diagnosis and after radiation were traced. Primary endpoints were biochemical relapse-free survival (bRFS), progression-free survival (PFS), and overall survival (OS). The definition of biochemical relapse was a PSA level of nadir+2 ng/mL. Progression was defined as biochemically or clinically detected disease and the start of salvage therapy. After median follow up of 63 months, the 5-year bRFS for all patients was estimated at 89.7%. The 5 year PFS was estimated at 71%. Four cases of biochemical relapse were observed, including two patients who experienced locoregional failure and one patient who had distant metastasis with biochemical relapse. The 5-year OS was estimated at 94.3%. There were five deaths, all of which were unrelated to prostate cancer. There was no grade 3 or higher acute complication. Grade 3 or higher late urinary toxicity was reported in 2 (4.4%) of 45 patients. The 5-year survival and toxicity outcome of SBRT using Cyberknife on prostate cancer patients with old age or comorbidities were favorable and safe in an investigational study. PMID- 25526469 TI - Vascular Ehlers-Danlos syndrome without the characteristic facial features: a case report. AB - As a type of Ehlers-Danlos syndrome (EDS), vascular EDs (vEDS) is typified by a number of characteristic facial features (eg, large eyes, small chin, sunken cheeks, thin nose and lips, lobeless ears). However, vEDs does not typically display hypermobility of the large joints and skin hyperextensibility, which are features typical of the more common forms of EDS. Thus, colonic perforation or aneurysm rupture may be the first presentation of the disease. Because both complications are associated with a reduced life expectancy for individuals with this condition, an awareness of the clinical features of vEDS is important. Here, we describe the treatment of vEDS lacking the characteristic facial attributes in a 24-year-old healthy man who presented to the emergency room with abdominal pain. Enhanced computed tomography revealed diverticula and perforation in the sigmoid colon. The lesion of the sigmoid colon perforation was removed, and Hartmann procedure was performed. During the surgery, the control of bleeding was required because of vascular fragility. Subsequent molecular and genetic analysis was performed based on the suspected diagnosis of vEDS. These analyses revealed reduced type III collagen synthesis in cultured skin fibroblasts and identified a previously undocumented mutation in the gene for a1 type III collagen, confirming the diagnosis of vEDS. After eliciting a detailed medical profile, we learned his mother had a history of extensive bruising since childhood and idiopathic hematothorax. Both were prescribed oral celiprolol. One year after admission, the patient was free of recurrent perforation. This case illustrates an awareness of the clinical characteristics of vEDS and the family history is important because of the high mortality from this condition even in young people. Importantly, genetic assays could help in determining the surgical procedure and offer benefits to relatives since this condition is inherited in an autosomal dominant manner. PMID- 25526470 TI - Effects of periodontal therapy on metabolic control in patients with type 2 diabetes mellitus and periodontal disease: a meta-analysis. AB - Epidemiologic studies have reported increased incidence, prevalence and acuity of periodontitis in adults with diabetes and some have also suggested that treating periodontal disease may improve glycemic control in diabetic patients. This meta analysis was conducted to evaluate the effects of different periodontal therapies on metabolic control in patients with type 2 diabetes mellitus (T2DM) and periodontal disease. We searched the Medline, EMBASE and Cochrane Library (Central) databases up to January 2014 for relevant studies pertaining to periodontal treatments and glycemic control in adults with T2DM. The search terms were periodontal treatment/periodontal therapy, diabetes/diabetes mellitus, periodontitis/periodontal and glycemic control. The primary outcome measure taken from the included studies was glycated hemoglobin (HbA1c). We compared differences in patients' pre- and post-intervention HbA1c results between a treatment group receiving scaling and root planing (SRP) combined with administration of oral doxycycline (n=71) and controls receiving SRP alone or SRP plus placebo (n=72). Meta-analysis was performed using Comprehensive Meta Analysis software. Nineteen randomized controlled trials (RCTs) were identified. Four trials involving a total of 143 patients with T2DM and periodontal disease were determined to be eligible for analysis. Data of 1 study were not retained for meta-analysis because HbA1c results were recorded as median with IQR. Meta analysis of the included 3 studies revealed no significant differences in HbA1c results between the periodontal treatment group (n=71) and control group (n=72) (HbA1c SMD=-0.238, 95% CI=-0.616 to 0.140; P=0.217). Systemic doxycycline added to SRP does not significantly improve metabolic control in patients with T2DM and chronic periodontitis. Current evidence is insufficient to support a significant association between periodontal therapy and metabolic control in this patient population. However, evidence suggests that periodontal therapy itself improves metabolic control and reinforces that T2DM is a risk factor for periodontitis. PMID- 25526471 TI - Economic evaluation of urgent-start peritoneal dialysis versus urgent-start hemodialysis in the United States. AB - Patients presenting late in the course of kidney disease who require urgent initiation of dialysis have traditionally received temporary vascular catheters followed by hemodialysis. Recent changes in Medicare payment policy for dialysis in the USA incentivized the use of peritoneal dialysis (PD). Consequently, the use of more expeditious PD for late-presenting patients (urgent-start PD) has received new attention. Urgent-start PD has been shown to be safe and effective, and offers a mechanism for increasing PD utilization. However, there has been no assessment of the dialysis-related costs over the first 90 days of care. The objective of this study was to characterize the costs associated with urgent start PD, urgent-start hemodialysis (HD), or a dual approach (urgent-start HD followed by urgent-start PD) over the first 90 days of treatment from a provider perspective. A survey of practitioners from 5 clinics known to use urgent-start PD was conducted to provide inputs for a cost model representing typical patients. Model inputs were obtained from the survey, literature review, and available cost data. Sensitivity analyses were also conducted. The estimated per patient cost over the first 90 days for urgent-start PD was $16,398. Dialysis access represented 15% of total costs, dialysis services 48%, and initial hospitalization 37%. For urgent-start HD, total per patient costs were $19,352, and dialysis access accounted for 27%, dialysis services 42%, and initial hospitalization 31%. The estimated cost for dual patients was $19,400. Urgent start PD may offer a cost saving approach for the initiation of dialysis in eligible patients requiring an urgent-start to dialysis. PMID- 25526472 TI - XRCC2 promotes colorectal cancer cell growth, regulates cell cycle progression, and apoptosis. AB - X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) and poly(ADP-ribose) polymerase 1 (PARP1) both play important roles in homologous recombination DNA repair. According to the theory of synthetic lethality, XRCC2 deficient cells are more sensitive to PARP1 inhibitors compared to XRCC2 expressing cells. We investigated XRCC2 expression and function in colorectal cancer (CRC), and the characteristics of sensitivity to PARP1 inhibitor in CRC cells with different XRCC2 levels. We enrolled 153 patients with CRC who had undergone surgery in this study. XRCC2 expression was assessed using immunohistochemistry. Stable CRC SW480 cell lines with low or high XRCC2 expression were constructed. Following treatment with the PARP1 inhibitor olaparib, the viability of cells with different XRCC2 levels was determined; cell cycle distribution and apoptosis were analyzed using flow cytometry. B-cell lymphoma-2 (Bcl-2) protein expression was measured by Western blotting. The positive rates of XRCC2 in primary CRC tissue were significantly higher than that in the matched adjacent noncancerous tissue, and XRCC2 expression status in primary CRC was related to tumor site, Dukes' stage, and tumor-nodes-metastasis (TNM) stage. XRCC2 overexpression inhibited CRC cell apoptosis and promoted proliferation by enriching cells in the G0/G1 phase. Moreover, olaparib suppressed proliferation, and olaparib sensitivity in CRC cells with high XRCC2 expression was greater. High XRCC2 expression promotes CRC cell proliferation and enriches cells in the G0/G1 phase but inhibits apoptosis. High XRCC2 expression cells are more sensitive to olaparib, which inhibits their viability. PMID- 25526473 TI - The effect of tuberculosis on the mortality of cirrhotic patients: a population based 3-year follow-up study. AB - Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis. It is still unknown if TB, like other infectious diseases contributes a poor prognosis in cirrhotic patients. The aim of this study was to investigate the impact of TB on the mortality of cirrhotic patients. National Health Insurance Database, derived from the Taiwan National Health Insurance Program, was used to identify 434 cirrhotic patients with new diagnosis of TB between January 1, 2007 and December 31, 2007. The comparison group consisted of 4340 selected cirrhotic patients without TB in the same period by propensity score matching analysis. The 30-day, 90-day, 1-year and 3-year mortalities were 10.1%, 24.2%, 43.1%, and 63% in the TB group, and 7.9%, 15.5%, 31.2%, and 53.4% in the non-TB group. After Cox proportional hazard regression model adjusted by the patients' gender, age, and comorbid disorders, the hazard ratios (HR) in cirrhotic patients with TB for 30-day, 30 to 90-day, 90-day to 1-year, and 1 to 3 year mortalities were 1.33 [95% confidence interval (CI) 0.97-1.83], 1.91 (95% CI 1.45-2.51), 1.46 (95% CI 1.16-1.84), and 1.10 (95% CI 0.88-1.37), compared to the non-TB group. In conclusion, TB is a risk factor for the mortality of cirrhotic patients. The effect focused on the 30-day to 1-year after diagnosis of TB. PMID- 25526475 TI - Does early PET/CT assesment of response to chemotherapy predicts survival in patients with advanced stage non-small-cell lung cancer? AB - The aim of this study is to determine the prognostic role and the timing of metabolic response to chemotherapy, based on F-fluorodeoxyglucose positron emission tomography (F-FDG-PET), in patients with metastatic non-small-cell lung cancer (NSCLC). The study included 55 patients with metastatic NSCLC that were analyzed in terms of prognostic factors and survival. F-FDG-PET/CT findings were evaluated in patients separated into 3 groups, before and after 1st, 2nd, 3rd cycle of the first line chemotherapy. Metabolic response was assessed according to PET Response Criteria in Solid Tumors (PERCIST 1.0). Among the 55 patients, 34 (62%) died, and 21 (38%) remained alive during a mean follow-up of 13.5 months. Median overall survival (OS) was 11.69 months (range 2-26.80 months) and median progression-free survival (PFS) was 6.27 months (range 1.37-20.43 months). Univariate analysis showed that the only favorable prognostic factor for OS in all the patients was the achievement of metabolic response. Metabolic response according to PERCIST, and weight lose <= 5% were also independent favorable prognostic factors predictive of survival in all patients based on multivariet analysis (metabolic response: P=0.002, OR; 1.90, 95% CI 1.26-2.89, and weight lose <=5%: P=0.022, OR; 2.24, 95% CI 1.12-4.47). Median OS in all patients with partial response (PR)-according to the PERCIST 1.0- was significantly longer than in those with progressive disease (PD) (16.36 months vs 8.14 months, P=0.008). Median OS in the patients with PR was significantly longer than in those with PD based on PET/CT performed after 2nd and 3rd cycles of chemotherapy (18.35 months vs 7.54 months, P=0.012 and 18.04 months vs 7.43 months, P<0.001, respectively), whereas, median OS did not differ significantly between patients with PR and those with PD based on PET/CT performed after the 1st cycle of chemotherapy (8.01 months vs 5.08 months, P=0.290). Metabolic response according to PERCIST and weight loss are independent factors predictive of OS. PET/CT performed after second cycle of chemotherapy may be the earliest predictor of treatment response in patients with advanced stage NSCLC. PMID- 25526474 TI - Genomic profiling of patient-derived colon cancer xenograft models. AB - Recent evidence suggests that patient derived xenograft (PDX) models can maintain certain pathological and molecular features of the original disease. However, these characterizations are limited to immunohistochemistry or by tissue microarray analysis. We conducted a high-throughput sequencing of primary colon tumor and PDX has not been reported yet. Fresh primary colon cancer tissues that originate from surgery were implanted into the subcutaneous space of 6- to 8-week old female BALB/c nu/nu or NOD/SCID mice and serially passaged in vivo. Ion AmpliSeq Cancer Hotspot Panel v2 (Ion Torrent) was used to detect frequent somatic mutations and similarity of molecular characteristics between the 10 patient tumors and matched PDX. Histologic and immunohistochemical analyses revealed a high degree of pathologic similarity including histologic architecture and expression of CEA, CK7, and CD20 between the patient and xenograft tumors. In 80% cases, all of the somatic mutations detected in primary tumor were concordantly detected in PDX models. However, 2 PDX models showed gained mutations such as PIK3CA or FBWX7 mutation. Ten patient-derived advanced colon cancer xenograft models were established. These models maintained the key characteristic features of the original tumors, suggesting useful tool for preclinical personalized medicine platform. PMID- 25526476 TI - Long non-coding RNA LSINCT5 predicts negative prognosis and exhibits oncogenic activity in gastric cancer. AB - Long non-coding RNAs (lncRNAs) are recently discovered RNA transcripts that are aberrantly expressed in many tumor types. Numerous studies have suggested that lncRNAs can be utilized for cancer diagnosis and prognosis. LSINCT5 (long stress induced non-coding transcript 5) is dramatically upregulated in breast and ovarian cancer and affects cellular proliferation. However, the expression pattern of LSINCT5 in gastrointestinal cancer and the association between aberrant expression of LSINCT5 in gastrointestinal cancer and malignancy, metastasis, or prognosis remain unknown. LSINCT5 expression was detected in gastrointestinal cancer and paired adjacent normal tissue samples or cell lines using reverse transcription quantitative PCR (RT-qPCR). We also investigated the potential relationship between tumor LSINCT5 levels and clinicopathological features of gastrointestinal cancer. Finally, we assessed whether LSINCT5 influences in vitro cell proliferation. The expression of LSINCT5 is significantly upregulated in gastrointestinal cancer tissues and cell lines relative to their normal counterparts. In addition, increased LSINCT5 expression was correlated with a larger tumor size, deeper tumor depth, and advanced clinical stage. Kaplan-Meier analysis indicated that gastric cancer (GC) and colorectal cancer (CRC) patients with higher LSINCT5 expression levels have worse disease-free survival (DFS) and disease-specific survival (DSS) rates. Moreover, multivariate analysis revealed that increased expression of LSINCT5 is an independent predictor of DFS and DSS rates in GC patients. The ectopic expression of LSINCT5 in gastrointestinal cancer cell lines resulted in an increase in cellular proliferation; conversely, knock down of LSINCT5 significantly inhibited proliferation. These results suggest that LSINCT5 may represent a novel prognostic indicator and a target for gene therapy in gastrointestinal cancer. PMID- 25526477 TI - Comparative effectiveness of different oral antibiotics regimens for treatment of urinary tract infection in outpatients: an analysis of national representative claims database. AB - There are very limited data on the postmarketing outcome comparison of different guideline antibiotic regimens for patients with urinary tract infections (UTIs). We carried out a population-based comparative effectiveness study from year 2000 through 2009, using the administrative data of 2 million patients from the National Health Informatics Project of Taiwan. Treatment failure was defined as either hospitalization or emergency department visits for UTI. Odd ratios were computed using conditional logistic regression models matched on propensity score. We identified 73,675 individuals with UTI, of whom 54,796 (74.4%) received trimethoprim-sulfamethoxazole (TMP-SMX), 4184 (5.7%) received ciprofloxacin, 3142 (4.3%) received levofloxacin, 5984 (8.1%) received ofloxacin, and 5569 (7.6%) received norfloxacin. Compared with TMP-SMX, the composite treatment failure was significantly lowered for norfloxacin in propensity score (PS) matching analyses (OR, 0.73; 95% CI, 0.54-0.99). Both norfloxacin (PS-matched OR, 0.68; 95% CI, 0.47-0.98) and ofloxacin (PS-matched OR, 0.70; 95% CI, 0.49-0.99) had significantly lowered composite treatment failure rate when compared with ciprofloxacin. Subgroup analysis suggested that both norfloxacin and ofloxacin were more effective in female patients without complications (W/O indwelling catheters, W/O bedridden status and W/O spinal cord injury), when compared with either TMP-SMX or ciprofloxacin. Among outpatients receiving oral fluoroquinolone therapy for UTIs, there was evidence of superiority of norfloxacin or ofloxacin over ciprofloxacin or TMP-SMX in terms of treatment failure. Given the observational nature of this study and regional difference in antibiotic resistance patterns, more studies are required to validate our results. PMID- 25526478 TI - Can thymidine phosphorylase be a predictive marker for gemcitabine and doxifluridine combination chemotherapy in cholangiocarcinoma?: case series. AB - Unresectable cholangiocarcinoma is poorly responded to chemotherapy, especially for the case refractory to gemcitabine and cisplatin. Here, we tested whether high expression of thymidine phosphorylase (TP) can be a predictive biomarker for the indicator for gemcitabine and doxifluridine combination chemotherapy in the cholangiocarcinoma refractory to gemcitabine and cisplatin. Immunohistochemical staining for TP was performed with a biopsy specimen. We accepted the result as positive when more than 10% of cancer cells were stained with moderate intensity. Here, we report 2 cases of TP-positive cholangiocarcinoma well controlled with gemcitabine and doxifluridine combination chemotherapy, which had been refractory to the first line treatment with gemcitabine and cisplatin combination chemotherapy. PMID- 25526479 TI - DNA methylation profile of genes involved in inflammation and autoimmunity in inflammatory bowel disease. AB - The contribution of epigenetic alterations to disease pathogenesis is emerging as a research priority. In this study, we aimed to seek DNA methylation changes in peripheral blood and tissue biopsies from patients with inflammatory bowel disease. The promoter methylation status of genes involved in inflammation and autoimmunity was profiled using the Human Inflammatory Response and Autoimmunity EpiTect Methyl II Signature PCR Array profiles. Methylation was considered to be hypermethylated if >20% according to the instructions of the manufacturer. The microarrays were validated with Quantitative Real-time PCR. Regarding Crohn disease (CD) no gene appeared hypermethylated compared to healthy controls. In ulcerative colitis (UC) 5 genes (CXCL14, CXCL5, GATA3, IL17C, and IL4R) were hypermethylated compared to healthy controls. Some of the examined genes show different methylation patterns between CD and UC. Concerning tissue samples we found that all hypermethylated genes appear the same methylation pattern and confirmed a moderate-strong correlation between methylation levels in colon biopsies and peripheral blood (Pearson coefficients r=0.089-0.779, and r=0.023 0.353, respectively). The epigenetic changes observed in this study indicate that CD and UC exhibit specific DNA methylation signatures with potential clinical applications in IBD non-invasive diagnosis and prognosis. PMID- 25526480 TI - Post-transplant malignancy in liver transplantation: a single center experience. AB - We aim to determine the incidence of malignancy after liver transplantation (LT) compared to general population. The records of patients who received LTs at our center from October 1989 and November 2012 were retrospectively reviewed. The standardized incidence ratio (SIR) of cancer in the patients was compared to general population using the data from the Taiwan Cancer Registry. Survival was estimated using the Kaplan-Meier method. A total of 444 patients were included. Malignancy was found in 46 (28 de novo and 19 recurrent malignancies) patients (10.4%) with the median follow up of 4.2+/-4.2 years. The median time of cancer occurrence after transplant was 1.2+/-1.9 years (range, 0.2-9.1 years). Post transplant lymphoproliferative disorder was the most frequent de novo malignancy (57.1% [16/28]). The cumulative incidence rates of all malignancies were 5.1%, 10.4%, 12.8%, 15.8%, and 15.8% at 1, 3, 5, 10, and 15 years, respectively. The cumulative incidence rates of de novo malignancies were 3.4%, 5.97%, 7.7%, 10.9%, and 10.9 % at 1, 3, 5, 10, and 15 years. Compared to general population, transplant recipients had significantly higher incidence of all de novo cancers (SIR: 3.26, 95% confidence interval [CI]: 2.17-4.72), hematologic (SIR: 58.4; 95% CI, 33.3-94.8), and bladder (SIR: 10.2, 95% CI: 1.1-36.7) cancers. The estimated mean survivals after transplantation in cancer-free, de novo cancer, and recurrent cancer patients were 17.7+/-0.5, 11.3+/-1.2, and 3.6+/-0.6 years, respectively. There is a significantly increased risk of malignancies after LT in the Taiwanese population. PMID- 25526481 TI - Tilted microstrip phased arrays with improved electromagnetic decoupling for ultrahigh-field magnetic resonance imaging. AB - One of the technical challenges in designing a dedicated transceiver radio frequency (RF) array for MR imaging in humans at ultrahigh magnetic fields is how to effectively decouple the resonant elements of the array. In this work, we propose a new approach using tilted microstrip array elements for improving the decoupling performance and potentially parallel imaging capability. To investigate and validate the proposed design technique, an 8-channel volume array with tilted straight-type microstrip elements was designed, capable for human imaging at the ultrahigh field of 7 Tesla. In this volume transceiver array, its electromagnetic decoupling behavior among resonant elements, RF field penetration to biological samples, and parallel imaging performance were studied through bench tests and in vivo MR imaging experiments. In this specific tilted element array design, decoupling among array elements changes with the tilted angle of the elements and the best decoupling can be achieved at certain tilted angle. In vivo human knee MR images were acquired using the tilted volume array at 7 Tesla for method validation. Results of this study demonstrated that the electromagnetic decoupling between array elements and the B1 field strength can be improved by using the tilted element method in microstrip RF coil array designs at the ultrahigh field of 7T. PMID- 25526482 TI - Clinical- and cost-effectiveness of telemedicine in type 2 diabetes mellitus: a systematic review and meta-analysis. AB - Emerging telemedicine programs offer potential low-cost solutions to the management of chronic disease. We sought to evaluate the clinical effectiveness and cost effectiveness of telemedicine approaches on glycemic control in patients with type 2 diabetes mellitus. Using terms related to type 2 diabetes and telemedicine, MEDLINE, Cochrane, EMBASE, and CINAHL Plus were searched to identify relevant studies published through February 28, 2014. Data from identified clinical trials were pooled according to telemedicine approach, and evaluated using conventional meta-analytical methods. We identified 47 articles, from 35 randomized controlled trials, reporting quantitative outcomes for hemoglobin A1c (HbA1c). Twelve of the 35 studies provided intervention via telephone, either in the form of a call or a text message; 19 studies tested internet-based programs, employing video-conferencing and/or informational websites; and four studies used interventions involving electronically transmitted recommendations made by clinicians in response to internet-based reporting by patients. Overall, pooled results from these studies revealed a small, but statistically significant, decrease in HbA1c following intervention, compared to conventional treatment (pooled difference in means=-0.37, 95% CI= 0.49 to -0.25, Z=-6.08, P<0.001). Only two of the 35 studies included assessment of cost-effectiveness. These studies were disparate, both in terms of overall expense and relative cost-effectiveness. Optimization of telemedicine approaches could potentially allow for more effective self-management of disease in type 2 diabetes patients, though evidence to-date is unconvincing. Furthermore, significant publication bias was detected, suggesting that the literature should be interpreted cautiously. PMID- 25526484 TI - Risk factors for retinopathy of prematurity in extremely preterm Chinese infants. AB - To investigate the incidence and risk factors of retinopathy of prematurity (ROP) and Type 1 ROP in extremely preterm Chinese infants. A retrospective review of medical records was performed of all extremely preterm neonates (gestational age, GA<=28 weeks) screened for ROP from 2007 to 2012 at an ophthalmology centre in Hong Kong. Thirty-three maternal and neonatal covariates were analyzed using univariate and multivariate regression analyses for both ROP and Type 1 ROP. The mean gestational age (GA) was 26.4+/-1.3 weeks and the birth weight (BW) was 855.0+/-199.0 g. The incidence of ROP development was 60.7% and 16.2% for Type 1 ROP. On univariate analysis, 6 risk factors were identified for ROP development including: lighter BW; lower GA; postnatal hypotension; inotrope use; surfactant use; and invasive mechanical ventilation (all P<=0.01). On multivariate analysis, neonatal congenital heart disease and greater GA were protective factors for ROP development (P<=0.04). On the other hand, 4 risk factors were associated with Type 1 ROP development in univariate analysis, including: lower GA, lighter BW, multiple pregnancies, and invasive mechanical ventilation (all P<=0.02); while there was no significant risk factors on multivariate analysis. A lighter BW and lower GA were the only common independent risk factors for both ROP and Type 1 ROP while neonatal congenital heart disease and greater GA were the protective factors against ROP. PMID- 25526483 TI - Diffuse interstitial brain edema in patients with end-stage renal disease undergoing hemodialysis: a tract-based spatial statistics study. AB - To investigate white matter (WM) alterations and their correlation with cognition function in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD) using diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) approach. This prospective HIPAA-complaint study was approved by our institutional review board. Eighty HD ESRD patients and 80 sex- and age-matched healthy controls were included. Neuropsychological (NP) tests and laboratory tests, including serum creatinine and urea, were performed. DTI data were processed to obtain fractional anisotropy (FA) and mean diffusivity (MD) maps with TBSS. FA and MD difference between the 2 groups were compared. We also explored the associations of FA values in WM regions of lower FA with ages, NP tests, disease, and dialysis durations, serum creatinine and urea levels of ESRD patients. Compared with controls, HD ESRD patients had lower FA value in the corpus callosum, bilateral corona radiate, posterior thalamic radiation, left superior longitudinal fasciculus, and right cingulum (P<0.05, FWE corrected). Almost all WM regions had increased MD in HD ESRD patients compared with controls (P<0.05, FWE corrected). In some regions with lower FA, FA values showed moderate correlations with ages, NP tests, and serum urea levels. There was no correlation between FA values and HD durations, disease durations, and serum creatinine levels of ESRD patients (all P>0.05). Diffuse interstitial brain edema and moderate WM integrity disruption occurring in HD ESRD patients, which correlated with cognitive dysfunction, and serum urea levels might be a risk factor for these WM changes. PMID- 25526485 TI - Interaction between angiotensin-converting enzyme gene insertion/deletion polymorphism and angiotensin-converting enzyme inhibition on survival in hemodialyzed patients. AB - The association between ACE (angiotensin-converting enzyme) gene insertion/deletion (I/D) polymorphism and mortality has been inconsistently observed in earlier studies in patients on maintenance hemodialysis. We hypothesized that the effect of ACE gene I/D polymorphism on mortality may be influenced by concurrent ACE inhibitor therapy in this population. In this prospective, multicenter cohort, observational study, data was collected from 716 prevalent chronic hemodialysis patients, blood samples were genotyped for I/D single nucleotide polymorphism. Patient mortality was assessed in tree genotype groups insertion/insertion, insertion/deletion and deletion/deletion (I/I, I/D, and D/D) using multivariate Cox proportional hazard models. The most frequent genotype was I/D (42.6%), followed by D/D (37.7%) and I/I (19.7%) genotypes. The mean age was 54.9+/-15.5 years, 53.2% of all patients were male and in the total group the prevalence of diabetes was 19.3%. ACE inhibitor therapy was prescribed for 47.9% of all patients. The median duration of dialysis before blood sampling was 23.8 months (IQR 11.2-47.1). Patients were followed for 10 years, the median follow-up time was 29.8 months (IQR 12.6-63.4). Patient characteristics were well balanced among the genotype groups. D/D genotype, was associated with inferior survival (I/I vs D/D: log-rank test: P=0.04) in patients not receiving ACE inhibitor therapy, and the presence of this therapy diminished this difference. There was no difference in survival among unselected patients with different genotypes. In multivariate Cox regression models, D/D genotype (compared to I/I) was a significant predictor of mortality only in patients without ACE inhibitor therapy (HR 0.67, 95% CI 0.46-0.97, P=0.03). Our data suggests that hemodialyzed patients with the deletion/deletion (D/D) genotype might have inferior outcome, and ACE inhibitor therapy may be associated with improved survival in this subgroup. PMID- 25526486 TI - Clinicopathologic characteristics and survival of patients with bone metastasis in Yazd, Iran: a cross-sectional retrospective study. AB - To evaluate the clinico-pathological and survival characteristics in patients with bone metastasis. This cross-sectional study was conducted on patients with bone metastasis who referred to Shahid Ramezanzadeh radiation oncology center. For all of the patients studied, demographic and survival information was recorded. SPSS was used to analyze the data. In this study, 89 men (53.3%) and 78 women (46.7%) with bone metastasis were examined. Most of the patients were in the 66 to 87 age range. Breast cancer was the most common type of cancer in women and prostate cancer was the commonest in men. In most patients, pain was the first manifestation of the disease, and the spine has been most frequently involved areas. The disease was diagnosed by isotope bone scan in the most cases. The mean survival was 31.1 months for patients with breast cancer, 12.9 months for patients with prostate cancer, 13.7 months for patients with lung cancer and the overall survival was 22.5. There was only a meaningful correlation between sex, type of cancer, radiation dose, and survival in patients. We found that age was more effective than the variable of cancer type in survival of patients with bone metastasis. The prognosis of patients with bone metastasis in our center is fair. There was a significant correlation between sex, type of cancer, radiation dose, and survival. Cox proportional hazards model showed that age was a predictor of death. PMID- 25526487 TI - Effects of early enteral nutrition on patients after emergency gastrointestinal surgery: a propensity score matching analysis. AB - Early postoperative enteral feeding has been demonstrated to improve the outcome of patients who underwent surgery for gastrointestinal (GI) malignancies, trauma, perforation, and/or obstruction. Thus, this study was conducted to assess the efficacy of early postoperative enteral nutrition (EN) after emergency surgery in patients with GI perforation or strangulation. The medical records of 484 patients, admitted between January 2007 and December 2012, were reviewed retrospectively. Patients were divided into 2 groups: the early EN (EEN, N=77) group and the late EN (LEN, N=407) group. The morbidity, mortality, length of hospital, and intensive care unit (ICU) stays were compared between the 2 groups. Propensity score matching was performed in order to adjust for any baseline differences. Patients receiving EEN had reduced in-hospital mortality rates (EEN 4.5% vs LEN 19.4%; P=0.008), pulmonary complications (EEN 4.5% vs LEN 19.4%; P=0.008), lengths of hospital stay (median: 14.0, interquartile range: 8.0-24.0 vs median: 17.0, interquartile range: 11.0-26.0, P=0.048), and more 28-day ICU free days (median: 27.0, interquartile range: 25.0-27.0 vs median: 25.0, interquartile range: 22.0-27.0, P=0.042) than those receiving LEN in an analysis using propensity score matching. The significant difference in survival between the 2 groups was also shown in the Kaplan-Meier survival curve (P=0.042). In a further analysis using the Cox proportional hazard ratio after matching on the propensity score, EEN was associated with reduced in-hospital mortality (hazard ratio, 0.03; 95% confidence interval, 0.01-0.49; P=0.015). EEN is associated with beneficial effects, such as reduced in-hospital mortality rates, pulmonary complications, lengths of hospital stay, and more 28-day ICU-free days, after emergency GI surgery. PMID- 25526488 TI - Long-term follow-up and prognostic factors for advanced thymic carcinoma. AB - The aim of this study was to evaluate the long-term survival outcomes in patients with advanced thymic carcinoma and identify prognostic factors influencing the survival. We retrospectively analyzed 90 consecutive patients with pathologically confirmed advanced thymic carcinoma (Masaoka III and IV) in our institute, from December 2000 to 2012. Age, sex, clinical characteristics, laboratory findings, Masaoka and tumor node metastasis staging, pathologic grade, and treatment modalities were analyzed to identify prognostic factors associated with the progress-free survival (PFS) and the overall survival (OS) rates. Statistical analysis was conducted using SPSS, version 19.0 (SPSS, Inc, Chicago, IL). A total of 73 (81.1%) male and 17 (18.9%) female patients participated in the study. The median follow-up time was 75 months (range, 20-158 months). The 5-year PFS and OS rates were 23.6% (95% confidence interval [CI], 14.6%-33.8%) and 35.7% (95% CI, 25.1%-46.4%), respectively. The multivariate Cox regression model analysis showed that factors improving the PFS were the normal lactate dehydrogenase (LDH) level (P<0.001), Masaoka III stage (P=0.028), and radiotherapy (RT) (P<0.001). The LDH (P<0.001), T stage (P<0.001), and the pathologic grade (P=0.047) were independently prognostic of OS. Long-term follow-up of the advanced thymic carcinoma showed poor outcomes of PFS and OS. LDH, Masaoka stage, and RT affected the PFS, and LDH, T stage, and pathologic grade seemed to affect the OS. Establishing a better staging system for predicting outcomes would be warranted. PMID- 25526489 TI - Improving depiction of temporal bone anatomy with low-radiation dose CT by an integrated circuit detector in pediatric patients: a preliminary study. AB - The purpose of this study was to determine the performance of low-dose computed tomography (CT) scanning with integrated circuit (IC) detector in defining fine structures of temporal bone in children by comparing with the conventional detector. The study was performed with the approval of our institutional review board and the patients' anonymity was maintained. A total of 86 children<3 years of age underwent imaging of temporal bone with low-dose CT (80 kV/150 mAs) equipped with either IC detector or conventional discrete circuit (DC) detector. The image noise was measured for quantitative analysis. Thirty-five structures of temporal bone were further assessed and rated by 2 radiologists for qualitative analysis. kappa Statistics were performed to determine the agreement reached between the 2 radiologists on each image. Mann-Whitney U test was used to determine the difference in image quality between the 2 detector systems. Objective analysis showed that the image noise was significantly lower (P<0.001) with the IC detector than with the DC detector. The kappa values for qualitative assessment of the 35 fine anatomical structures revealed high interobserver agreement. The delineation for 30 of the 35 landmarks (86%) with the IC detector was superior to that with the conventional DC detector (P<0.05) although there were no differences in the delineation of the remaining 5 structures (P>0.05). The low-dose CT images acquired with the IC detector provide better depiction of fine osseous structures of temporal bone than that with the conventional DC detector. PMID- 25526490 TI - PRISMA--efficacy and safety of vedolizumab for inflammatory bowel diseases: a systematic review and meta-analysis of randomized controlled trials. AB - Vedolizumab is an anti-inflammatory monoclonal antibody that exclusively targets the alpha4beta7 integrin. We aimed to systematically review the efficacy and safety of vedolizumab for patients with inflammatory bowel diseases (IBDs). PubMed, EMBASE, and the Cochrane Library were searched up to May 2014. Randomized controlled trials examining the efficacy or safety of vedolizumab in patients with IBDs were eligible for inclusion. Data were extracted independently by 2 investigators and pooled using Review Manager 5.0 software (The Cochrane Collaboration, Copenhagen). Results were expressed as the relative risk (RR) with 95% confidence intervals (CIs). Six randomized controlled trials involving 2815 patients were eligible for inclusion. Vedolizumab was more effective than placebo for patients with ulcerative colitis and Crohn disease (CD) in clinical response (RR=1.82, 95% CI, [1.43, 2.31]; RR=1.46, 95% CI [1.18,1.81]) and clinical remission (RR=2.23, 95% CI [1.35, 3.68]; RR=1.71, 95% CI [1.25, 2.34]) during induction therapy. A superior effect was found during maintenance therapy in durable clinical/CD Activity Index-100 response (RR=2.22, 95% CI [1.62, 3.05]; RR=1.48, 95% CI [1.13, 1.94]) and clinical remission (RR=2.55, 95% CI [1.38, 4.70]; RR=1.15, 95% CI [0.75, 1.77]). However, vedolizumab may be associated with serious adverse events (RR=1.25, 95% CI [1.03, 1.52]) and nasopharyngitis (RR=1.56, 95% CI [1.08, 2.25]) for patients with CD. Vedolizumab was more effective than placebo as induction and maintenance therapy for IBDs, with an acceptable short-term safety profile, and achieving cure, although it may be associated with serious adverse events and nasopharyngitis for patients with CD. PMID- 25526491 TI - Experience of gastrostomy using a quality care framework: the example of rett syndrome. AB - Rett syndrome is one of many severe neurodevelopmental disorders with feeding difficulties. In this study, associations between feeding difficulties, age, MECP2 genotype, and utilization of gastrostomy were investigated. Weight change and family satisfaction following gastrostomy were explored. Data from the longitudinal Australian Rett Syndrome Database whose parents provided data in the 2011 family questionnaire (n=229) were interrogated. We used logistic regression to model relationships between feeding difficulties, age group, and genotype. Content analysis was used to analyze data on satisfaction following gastrostomy. In those who had never had gastrostomy and who fed orally (n=166/229), parents of girls<7 years were more concerned about food intake compared with their adult peers (odds ratio [OR] 4.26; 95% confidence interval [CI] 1.29, 14.10). Those with a p.Arg168 mutation were often perceived as eating poorly with nearly a 6 fold increased odds of choking compared to the p.Arg133Cys mutation (OR 5.88; 95% CI 1.27, 27.24). Coughing, choking, or gagging during meals was associated with increased likelihood of later gastrostomy. Sixty-six females (28.8%) had a gastrostomy, and in those, large MECP2 deletions and p.Arg168 mutations were common. Weight-for-age z-scores increased by 0.86 (95% CI 0.41, 1.31) approximately 2 years after surgery. Families were satisfied with gastrostomy and felt less anxious about the care of their child. Mutation type provided some explanation for feeding difficulties. Gastrostomy assisted the management of feeding difficulties and poor weight gain, and was acceptable to families. Our findings are likely applicable to the broader community of children with severe disability. PMID- 25526492 TI - Comparison of the sensitivity and specificity of 5 image sets of dual-energy computed tomography for detecting first-pass myocardial perfusion defects compared with positron emission tomography. AB - The sensitivity and specificity of 5 different image sets of dual-energy computed tomography (DECT) for the detection of first-pass myocardial perfusion defects have not systematically been compared using positron emission tomography (PET) as a reference standard. Forty-nine consecutive patients, with known or strongly suspected of coronary artery disease, were prospectively enrolled in our study. Cardiac DECT was performed at rest state using a second-generation 128-slice dual source CT. The DECT data were reconstructed to iodine maps, monoenergetic images, 100 kV images, nonlinearly blended images, and linearly blended images by different postprocessing techniques. The myocardial perfusion defects on DECT images were visually assessed by 5 observers, using standard 17-segment model. Diagnostic accuracy of 5 image sets was assessed using nitrogen-13 ammonia PET as the gold standard. Discrimination was quantified using the area under the receiver operating characteristic curve (AUC), and AUCs were compared using the method of DeLong. The DECT and PET examinations were successfully completed in 30 patients and a total of 90 territories and 510 segments were analyzed. Cardiac PET revealed myocardial perfusion defects in 56 territories (62%) and 209 segments (41%). The AUC of iodine maps, monoenergetic images, 100 kV images, nonlinearly blended images, and linearly blended images were 0.986, 0.934, 0.913, 0.881, and 0.871, respectively, on a per-territory basis. These values were 0.922, 0.813, 0.779, 0.763, and 0.728, respectively, on a per-segment basis. DECT iodine maps shows high sensitivity and specificity, and is superior to other DECT image sets for the detection of myocardial perfusion defects in the first-pass myocardial perfusion. PMID- 25526493 TI - Correlation between blood lipid levels and chronic pancreatitis: a retrospective case-control study of 48 cases. AB - The incidence of chronic pancreatitis (CP) is increasing, and dyslipidemia severely affects the health of middle-aged and elderly people. We investigated the association between blood lipid levels and CP. The serum lipid metabolic indices of 48 patients with CP (CP group) were summarized retrospectively. The physical examination results of 40 randomly selected healthy individuals were used as the normal control (NC) group. Statistical analyses of the blood lipid data were performed between the 2 groups using the case-control study method. High-density lipoprotein-cholesterol (HDL-c) levels decreased and fasting blood glucose (GLU) levels increased in the CP group compared with those in the NC group (P<0.01). Pearson correlation analysis results showed that serum amylase (AMY) was positively correlated with low-density lipoprotein-cholesterol (LDL-c; r=0.414, P<0.05), and urine AMY (UAMY) was positively correlated with total cholesterol (TC; r=0.614, P<0.01) and LDL-c (r=0.678, P<0.01). A binary logistic regression analysis showed that GLU (odds ratio [OR], 5.052; P<0.01) and TC (OR, 1.074; P<0.01) may be risk factors for CP, whereas HDL-c may be a CP protective factor (OR, 0.833; P<0.01). The HDL-c levels decreased and GLU levels increased in the CP group compared with those in the NC group; AMY was positively correlated with LDL-c and UAMY was positively correlated with TC and LDL-c; GLU and TC may be risk factors for CP; and HDL-c may be a CP protective factor. This may be the first time that such results have been reported. These findings will contribute to primary prevention and control of CP progression. PMID- 25526494 TI - In vivo morphological features of human lumbar discs. AB - Recent biomechanics studies have revealed distinct kinematic behavior of different lumbar segments. The mechanisms behind these segment-specific biomechanical features are unknown. This study investigated the in vivo geometric characteristics of human lumbar intervertebral discs. Magnetic resonance images of the lumbar spine of 41 young Chinese individuals were acquired. Disc geometry in the sagittal plane was measured for each subject, including the dimensions of the discs, nucleus pulposus (NP), and annulus fibrosus (AF). Segmental lordosis was also measured using the Cobb method.In general, the disc length increased from upper to lower lumbar levels, except that the L4/5 and L5/S1 discs had similar lengths. The L4/5 NP had a height of 8.6+/-1.3 mm, which was significantly higher than all other levels (P<0.05). The L5/S1 NP had a length of 21.6+/-3.1 mm, which was significantly longer than all other levels (P<0.05). At L4/5, the NP occupied 64.0% of the disc length, which was significantly less than the NP of the L5/S1 segment (72.4%) (P<0.05). The anterior AF occupied 20.5% of the L4/5 disc length, which was significantly greater than that of the posterior AF (15.6%) (P<0.05). At the L5/S1 segment, the anterior and posterior AFs were similar in length (14.1% and 13.6% of the disc, respectively). The height to length (H/L) ratio of the L4/5 NP was 0.45+/-0.06, which was significantly greater than all other segments (P<0.05). There was no correlation between the NP H/L ratio and lordosis. Although the lengths of the lower lumbar discs were similar, the geometry of the AF and NP showed segment-dependent properties. These data may provide insight into the understanding of segment-specific biomechanics in the lower lumbar spine. The data could also provide baseline knowledge for the development of segment-specific surgical treatments of lumbar diseases. PMID- 25526495 TI - Artificial liver support system improves short- and long-term outcomes of patients with HBV-associated acute-on-chronic liver failure: a single-center experience. AB - For patients with acute-on-chronic liver failure (ACLF), artificial liver support system (ALSS) may help prolong lifespan and function as a bridge to liver transplantation (LT), but data on its long-term benefit are lacking. We conducted this prospective, controlled study to determine the efficacy of ALSS and the predictors of mortality in patients with hepatitis B virus (HBV)-associated ACLF.From January 2003 to December 2007, a total of 234 patients with HBV associated ACLF not eligible for LT were enrolled in our study. They were allocated to receive either plasma exchange centered ALSS plus standard medical therapy (SMT) (ALSS group, n=104) or SMT alone (control group, n=130). All the patients were followed-up for at least 5 years, or until death.At 90 days, the survival rate of ALSS group was higher than that of the control group (62/104 [60%] vs 61/130 [47%], respectively; P<0.05). Median survival was 879 days in the ALSS group (43% survival at 5 years) and 649 days in the control group (31% survival at 5 years, log-rank P<0.05). ALSS was found to be associated with favorable outcome of these patients by both univariate and multivariate analysis. Multivariate Cox regression analysis also revealed that lower serum sodium levels, higher grades of encephalopathy, presence of cirrhosis, hepatorenal syndrome, and higher model for end-stage liver disease scores were independent predictors for both 90-day and 5-year mortality due to ACLF.Our findings suggest that ALSS is safe and may improve the short- and long-term prognosis of patients with HBV-associated ACLF. PMID- 25526497 TI - Acid-promoted transformations of 1-(diphenylphosphoryl)allenes: synthesis of novel 1,4-dihydrophosphinoline 1-oxides. AB - 1-(Diphenylphosphoryl)alka-1,2-dienes (phosphonoallenes) in Bronsted (super)acids (TfOH, FSO3H, and H2SO4) at -70 to 120 degrees C for 30 min to 4 h gave, at first, (3-hydroxyalk-1-en-1-yl)diphenylphosphine oxides, as kinetically favorable reaction products, that are further converted into 1-phenyl-1,4 dihydrophosphinoline 1-oxides as thermodynamically stable compounds. The latter compounds are formed from phosphonoallenes under the action of a strong Lewis acid AlCl3 at room temperature for 10-120 min. This is a novel, simple and efficient (short reaction time, high yields) method for synthesis of such 1,4 dihydrophosphinoline 1-oxides. PMID- 25526496 TI - Cord blood-derived cytokine-induced killer cellular therapy plus radiation therapy for esophageal cancer: a case report. AB - Esophageal cancer is a serious malignancy with regards to mortality and prognosis. Current treatment options include multimodality therapy mainstays of current treatment including surgery, radiation, and chemotherapy. Cell therapy for esophageal cancer is an advancing area of research. We report a case of esophageal cancer following cord blood-derived cytokine-induced killer cell infusion and adjuvant radiotherapy. Initially, she presented with poor spirit, full liquid diets, and upper abdominal pain. Through cell therapy plus adjuvant radiotherapy, the patient remitted and was self-reliant. Recognition of this curative effect of sequent therapy for esophageal cancer is important to enable appropriate treatment. This case highlights cord blood-derived cytokine-induced killer cell therapy significantly alleviates the adverse reaction of radiation and improves the curative effect. Cell therapy plus adjuvant radiotherapy can be a safe and effective treatment for esophageal cancer. PMID- 25526498 TI - Effect of Bile Salt Hydrolase Inhibitors on a Bile Salt Hydrolase from Lactobacillus acidophilus. AB - Bile salt hydrolase (BSH), a widely distributed function of the gut microbiota, has a profound impact on host lipid metabolism and energy harvest. Recent studies suggest that BSH inhibitors are promising alternatives to antibiotic growth promoters (AGP) for enhanced animal growth performance and food safety. Using a high-purity BSH from Lactobacillus salivarius strain, we have identified a panel of BSH inhibitors. However, it is still unknown if these inhibitors also effectively inhibit the function of the BSH enzymes from other bacterial species with different sequence and substrate spectrum. In this study, we performed bioinformatics analysis and determined the inhibitory effect of identified BSH inhibitors on a BSH from L. acidophilus. Although the L. acidophilus BSH is phylogenetically distant from the L. salivarius BSH, sequence analysis and structure modeling indicated the two BSH enzymes contain conserved, catalytically important amino residues and domain. His-tagged recombinant BSH from L. acidophilus was further purified and used to determine inhibitory effect of specific compounds. Previously identified BSH inhibitors also exhibited potent inhibitory effects on the L. acidophilus BSH. In conclusion, this study demonstrated that the BSH from L. salivarius is an ideal candidate for screening BSH inhibitors, the promising alternatives to AGP for enhanced feed efficiency, growth performance and profitability of food animals. PMID- 25526499 TI - [Impulsiveness Among Short-Term Prisoners with Antisocial Personality Disorder]. AB - OBJECTIVE: The study aimed to investigate the correlation between impulsiveness and the antisocial personality disorder among short-term prisoners. METHOD: The impulsiveness was diagnosed by the Barratt Impulsiveness Scale (BIS). RESULTS: Short-term prisoners with antisocial personality disorder scored significant higher marks on the BIS total scale than those without any personality disorder. In detail, they scored higher marks on each subscale regarding attentional, motor and nonplanning impulsiveness. Moderate and high effects were calculated. CONCLUSION: It is to be considered to regard impulsivity as a conceptual component of antisociality. PMID- 25526500 TI - [Not quite the same: illness beliefs regarding burnout and depression among the general population]. AB - OBJECTIVE: This study examined illness beliefs of the lay public associated with the diagnostic labels burnout and depression. METHODS: Representative population survey in Germany 2011, using unlabelled case vignettes of a person suffering from depression. Following presentation of the vignette, respondents were asked openly how they would call the problem described. Agreement with various illness beliefs was elicited with Likert-scaled items. RESULTS: Seeing the problem as inherited predicted use of the label depression (OR 1.29, p < 0.001), while stress at work as a perceived cause was associated with use of the label burnout (OR 1.56, p < 0.001). Belief that the problem described resembled everyday experiences (belief in a symptom continuum) also predicted using the label burnout instead of depression (OR 1.31, p < 0.05). CONCLUSION: Although overlapping with beliefs about depression, the diagnostic label burnout is also associated with specific illness beliefs among the general public. PMID- 25526501 TI - [Fearlessness about Death and Suicidal Behavior: Psychometric Properties of the German Version of the Revised Acquired Capability for Suicide Scale (ACSS-FAD)]. AB - OBJECTIVES: The Acquired Capability of Suicide Scale (ACSS-FAD) assesses fearlessness about death according to the Interpersonal Theory of Suicide. Psychometric properties of the German version of the ACSS-FAD are investigated. METHODS: Dimensionality and validity were analysed in a sample of N=268 undergraduate students. RESULTS: Confirmatory factor analysis replicated the unidimensionality of the measure. Correlations with suicidal ideation (r= .05) and self-reported capability for suicide (r= .14) supported the validity of the scale, while the association with depression (r= - .20) is not in line with the theory. Male participants and participants reporting past self-injurious behaviour/suicidal attempts did not show higher levels of fearlessness about death. CONCLUSION: The study demonstrates good psychometric properties of the German ACSS-FAD and largely supports the validity of the measure. However, future research needs to further investigate the validity of the ACSS-FAD (i.e. testing the utility of the instrument in predicting suicidal behaviour in patients at risk). PMID- 25526502 TI - [Where there's a Will, there's a Way? A nationwide Online-Survey of Psychiatrists about the Use of Alternatives to Coercive Measures]. AB - AIM: A series of legal regulations on the use of coercive measures in psychiatry initiated a vivid medico-ethical debate during the last year. The changed legal bases now require the use of alternatives before applying coercion as a "last resort". In this study we investigated whether and which alternatives are applied by psychiatrists in order to prevent coercive measures in general psychiatric hospitals and which factors are associated with their application. METHODS: A sample of 343 psychiatrists was recruited by contacting psychiatric hospitals throughout Germany. In an online-survey attitudes to coercive measures and the use of alternatives to coercion were assessed by self-report. RESULTS: Before initiating their most recent coercive measures almost half (46%) of the participants employed only 2 or less alternatives. Patient related, individual and structural factors were reported as reasons for the failure of such measures. The use of alternatives was associated with a more positive assessment of their effectiveness as well as a more negative attitude towards coercive measures. CONCLUSION: Alternative measures are applied by many psychiatrists, but are not standard practice. Thus, there is a considerable room for improved practice. PMID- 25526503 TI - [Risk and Protective Factors Among Sexual Offenders: Relapse Prediction and Changes During Treatment]. AB - OBJECTIVE: Investigation of two questions: first, whether sexual/forensic therapists are able to make valid assessments for future criminal behavior and second, whether their treatment changes factors relevant for new offences. METHODS: First, the predictive validity for recidivism of HCR-20 and SAPROF were tested. Second, the dynamic scales of both instruments were analyzed concerning changes during treatment process. RESULTS: Both instruments showed good predictive validity. The dynamic scales scores of HCR-20 did not change, whereas the I- and M-scale scores of SAPROF increased statistically significant. CONCLUSION: The therapists were able to identify high-risk clients and seemed to mainly focus their interventions towards factors associated with new offences. PMID- 25526504 TI - [Child maltreatment in binge eating disorder: a systematic literature review]. AB - OBJECTIVE: This review is to provide a first overview about prevalences and associations of forms of child maltreatment in binge eating disorder (BED). METHODS: Systematic literature search in PubMed and Web of Science in December 2013. Terms considered were "binge eating disorder" AND "child* maltreatment", "child* abuse", "child* sexual abuse", "child* emotional abuse", "child* physical abuse", "child* emotional neglect" as well as "child* physical neglect". Inclusion criteria were studies published between 1990 and 2013, publications in English or German, adult patients, studies that considered patients with full DSM criteria for BED, and studies that reported prevalences of forms of child maltreatment. RESULTS: Eight studies out of 366 met criteria. Child maltreatment rates in BED were more than two times higher than in representative samples, but they were similar to psychiatric comparisons. Up to 83 % of patients with BED reported at least one form of child maltreatment. There were associations to psychiatric comorbidity, but not to gender, obesity and specific features of the eating behaviour. CONCLUSION: Child maltreatment is very prevalent among BED. Its contribution to the development and the maintenance of BED is not understood yet. PMID- 25526505 TI - Body mass index-mortality relationship in severe hypoglycemic patients with type 2 diabetes. AB - BACKGROUND: Hypoglycemia is associated with a higher risk of death. This study analyzed various body mass index (BMI) categories and mortalities of severe hypoglycemic patients with type 2 diabetes mellitus (DM) in a hospital emergency department. METHODS: The study included 566 adults with type 2 diabetes who were admitted to 1 medical center in Taiwan between 2008 and 2009 with a diagnosis of severe hypoglycemia. Mortality data, demographics, clinical characteristics and the Charlson's Comorbidity Index were obtained from the electronic medical records. Patients were stratified into 4 study groups as determined by the National Institute of Health (NIH) and World Health Organization classification for BMI, and the demographics were compared using the analysis of variance and chi2 test. Kaplan-Meier's analysis and the Cox proportional-hazards regression model were used for mortality, and adjusted hazard ratios were adjusted for each BMI category among participants. RESULTS: After controlling for other possible confounding variables, BMI <18.5 kg/m2 was independently associated with low survival rates in the Cox regression analysis of the entire cohort of type 2 DM patients who encountered a hypoglycemic event. Compared to patients with normal BMI, the mortality risk was higher (adjusted hazard ratios = 4.9; 95% confidence interval [CI] = 2.4-9.9) in underweight patients. Infection-related causes of death were observed in 101 cases (69.2%) and were the leading cause of death. CONCLUSIONS: An independent association was observed between BMI less than 18.5 kg/m2 and mortality among type 2 DM patient with severe hypoglycemic episode. Deaths were predominantly infection related. PMID- 25526506 TI - Serum sirtuin 1 levels in patients with polycystic ovary syndrome. AB - Objective of the study is to determine the human nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 level in women with polycystic ovary syndrome (PCOS). This cross-sectional study included 24 patients aged 20-38 years, who were diagnosed to have PCOS (patient group). The control group included 16 age- and body mass index-matched healthy female volunteers. The patients and controls were compared in terms of pre-prandial blood glucose, the homoeostatic model assessment for insulin resistance (HOMA-IR) index, and cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), C-reactive protein (CRP) and sirtuin 1 levels. The mean sirtuin 1 level in the patient group (6.67 +/- 2.29 ng mL(-1)) was significantly higher than that in the control group (4.69 +/- 1.85 ng mL(-1)) (P = 0.007). Correlation analysis showed that there were no significant differences between the groups in fasting blood glucose, HOMA-IR index or cholesterol, triglyceride, HD, LDL and CRP levels. The sirtuin 1 level, which is associated with inflammation, the immune system and insulin metabolism, was higher in the PCOS patients than in the healthy controls. PMID- 25526507 TI - Uterocutaneous fistula following septic abortion: can it heal without major surgical intervention? PMID- 25526508 TI - Teenage pregnancy antenatal and perinatal morbidity: results from a tertiary centre in Greece. AB - We present the experience of a tertiary referral hospital in Greece, evaluating obstetric and perinatal outcomes among teenage and average maternal age (AMA) women. We retrospectively assessed all singleton pregnancies during a twelve month period (January-December 2012). A total of 1,704 cases were reviewed and divided into two groups: one of AMA mothers (20-34 years old) (1,460 women) and the other of teenage mothers (12-19 years old) (244 women). We observed significantly higher incidence rates of preterm births (p < 0.001), preterm premature rupture of the membranes (p < 0.001), gestational hypertension (p < 0.001), preeclampsia (p = 0.043) and Apgar scores < 7 at 5 min (p = 0.015) among teenage mothers. Antenatal surveillance was decreased among teenage mothers (p < 0.001), while rates of anaemia were higher (p < 0.001). Teenage pregnancy is accompanied by significant antenatal and perinatal complications that need specific obstetrical attention. Obstetricians should be aware of these complications in order to ameliorate the antenatal outcome of childbearing teenagers. PMID- 25526509 TI - Electroconvulsive therapy in pregnancy - A review. AB - Most major psychiatric illnesses are resistant to psychotropic drugs that are approved for use during pregnancy. Maternal illness and related medications may have adverse impacts on the foetus. Electroconvulsive therapy (ECT) might be an effective and safe option for treating several psychiatric disorders in pregnant women. This study evaluates the use of ECT for treating major psychoses during pregnancy and presents an assessment of risks faced by both mother and foetus. Based on our analysis we present recommendations for safe and effective treatment of psychiatric diseases via ECT in pregnant women. PMID- 25526510 TI - Early diagnosis of heterotopic triplet pregnancy with an intrauterine and bilateral tubal pregnancy after IVF: A case report. PMID- 25526511 TI - Determination of lithium-ion distributions in nanostructured block polymer electrolyte thin films by X-ray photoelectron spectroscopy depth profiling. AB - X-ray photoelectron spectroscopy (XPS) depth profiling with C60(+) sputtering was used to resolve the lithium-ion distribution in the nanometer-scale domain structures of block polymer electrolyte thin films. The electrolytes of interest are mixtures of lithium trifluoromethanesulfonate and lamellar-forming polystyrene-poly(oligo(oxyethylene)methacrylate) (PS-POEM) copolymer. XPS depth profiling results showed that the lithium-ion concentration was directly correlated with the POEM concentration. Furthermore, chemical state and atomic composition of the film were analyzed through the deconvolution of the C1s signal, indicating that the lithium ions appear to be uniformly distributed in the POEM domains. Overall, the unique capabilities of C60(+) depth profiling XPS provide a powerful tool for the analysis of nanostructured polymer thin films in applications ranging from energy storage and generation to surface coatings and nanoscale templates. PMID- 25526512 TI - Analysing the floral elements of the lost tree of Easter Island: a morphometric comparison between the remaining ex-situ lines of the endemic extinct species Sophora toromiro. AB - Sophora toromiro (Phil) Skottsb. is a species that has been extinct in its natural habitat Easter Island (Rapa Nui) for over 50 years. However, seed collections carried out before its extinction have allowed its persistence ex situ in different botanical gardens and private collections around the world. The progenies of these diverse collections have been classified in different lines, most of them exhibiting high similarity as corroborated by molecular markers. In spite of this resemblance observed between the different lines, one of them (Titze) has dissimilar floral elements, thus generating doubts regarding its species classification. The floral elements (wing, standard and keel) belonging to three different S. toromiro lines and two related species were analyzed using geometric morphometrics. This method was applied in order to quantify the floral shape variation of the standard, wing, and keel between the different lines and control species. Geometric morphometrics analyses were able to distinguish the floral elements at both intra (lines) and inter-specific levels. The present results are on line with the cumulative evidence that supports the Titze line as not being a proper member of the S. toromiro species, but probably a hybridization product or even another species of the Edwardsia section. The reintroduction programs of S. toromiro should consider this information when assessing the authenticity and origin of the lines that will be used to repopulate the island. PMID- 25526513 TI - Recombinant antigens rLipL21, rLoa22, rLipL32 and rLigACon4-8 for serological diagnosis of leptospirosis by enzyme-linked immunosorbent assays in dogs. AB - Animal leptospirosis is one of the most common zoonotic diseases in the United States and around the world. In a previous study, we applied four recombinant antigens, rLipL21, rLoa22, rLipL32 and rLigACon4-8 of Leptospira interrogans (L. interrogans) for the serological diagnosis of equine leptospirosis (Ye et al, Serodiagnosis of equine leptospirosis by ELISA using four recombinant protein markers, Clin. Vaccine. Immunol. 21:478-483). In this study, the same four recombinant antigens were evaluated for their potential to diagnose canine leptospirosis by ELISA. A total of 305 canine sera that were Leptospira microscopic agglutination test (MAT)-negative (n = 102) and MAT-positive (n = 203) to 5 serovars (Pomona, Grippotyphosa, Icterohaemorrhagiae, Canicola and Hardjo) were tested. When individual recombinant antigens were used, the sensitivity and specificity of ELISA were 97.5% and 84.3% for rLigACon4-8; 89.7% and 81.4% for rLoa22; 92.6% and 84.3% for rLipL32 and 99.5% and 84.3% for rLipL21, respectively compared to the MAT. The sensitivity and specificity of ELISA were, 92.6% and 91.2% for rLigACon4-8 and rLipL32, 97.5% and 84.3% for rLigACon4-8 and rLipL21, 89.7% and 87.3% for rLigACon4-8 and rLoa22, 89.7% and 87.3% to rLipL21 and rLoa22, 92.6% and 91.2% for rLipL21 and rLipL32 and 89.2% and 94.1% for rLoa22 and rLipL32 when one of the two antigens was test positive. The use of all four antigens in the ELISA assay was found to be sensitive and specific, easy to perform, and agreed with the results of the standard Leptospira Microscopic Agglutination test (MAT) for the diagnosis of canine leptospirosis. PMID- 25526514 TI - The optimal number of surveys when detectability varies. AB - The survey of plant and animal populations is central to undertaking field ecology. However, detection is imperfect, so the absence of a species cannot be determined with certainty. Methods developed to account for imperfect detectability during surveys do not yet account for stochastic variation in detectability over time or space. When each survey entails a fixed cost that is not spent searching (e.g., time required to travel to the site), stochastic detection rates result in a trade-off between the number of surveys and the length of each survey when surveying a single site. We present a model that addresses this trade-off and use it to determine the number of surveys that: 1) maximizes the expected probability of detection over the entire survey period; and 2) is most likely to achieve a minimally-acceptable probability of detection. We illustrate the applicability of our approach using three practical examples (minimum survey effort protocols, number of frog surveys per season, and number of quadrats per site to detect a plant species) and test our model's predictions using data from experimental plant surveys. We find that when maximizing the expected probability of detection, the optimal survey design is most sensitive to the coefficient of variation in the rate of detection and the ratio of the search budget to the travel cost. When maximizing the likelihood of achieving a particular probability of detection, the optimal survey design is most sensitive to the required probability of detection, the expected number of detections if the budget were spent only on searching, and the expected number of detections that are missed due to travel costs. We find that accounting for stochasticity in detection rates is likely to be particularly important for designing surveys when detection rates are low. Our model provides a framework to do this. PMID- 25526515 TI - MicroRNA profiling in human colon cancer cells during 5-fluorouracil-induced autophagy. AB - Autophagy modulation is now recognized as a potential therapeutic approach for cancer (including colorectal cancer), yet the molecular mechanisms regulating autophagy in response to cellular stress are still not well understood. MicroRNAs (miRNAs) have been found to play important roles in controlling many cellular functions, including growth, metabolism and stress response. The physiological importance of the miRNA-autophagy interconnection is only beginning to be elucidated. MiRNA microarray technology facilitates analysis of global miRNA expression in certain situations. In this study, we explored the expression profile of miRNAs during the response of human colon cancer cells (HT29s) to 5-FU treatment and nutrient starvation using miRNA microarray analysis. The alteration of miRNA expression showed the same pattern under both conditions was further testified by qRT-PCR in three human colon cancer cell lines. In addition, bioinformatic prediction of target genes, pathway analysis and gene network analysis were performed to better understand the roles of these miRNAs in the regulation of autophagy. We identified and selected four downregulated miRNAs including hsa-miR-302a-3p and 27 upregulated miRNAs under these two conditions as having the potential to target genes involved in the regulation of autophagy in human colon cancer cells. They have the potential to modulate autophagy in 5-FU based chemotherapy in colorectal cancer. PMID- 25526517 TI - Paternal Lifestyle-Related Parenting Practices Mediate Changes in Children's Dietary and Physical Activity Behaviors: Findings From the Healthy Dads, Healthy Kids Community Randomized Controlled Trial. AB - BACKGROUND: This study examined potential parenting-related mediators of children's physical activity and dietary behavior change in the Healthy Dads, Healthy Kids (HDHK) community program. METHODS: A randomized controlled trial was conducted with 45 overweight/obese (mean [SD] age = 39.8 [5.4] years; BMI = 32.4 [3.8]) fathers and their children (n = 77; 58% boys; mean [SD] age = 7.7 [2.5] years). Families were randomized to either the HDHK program or wait-list control group. The program involved 7 sessions. Fathers and their children were assessed at baseline and at 14 weeks for physical activity (pedometery) and core food intake (Questionnaire). Fathers' lifestyle-related parenting practices included; self-efficacy, beliefs, modeling, logistic support, rules, cophysical activity, shared mealtime frequency and intentions. RESULTS: Significant intervention effects were found for cophysical activity and modeling physical activity. Cophysical activity mediated children's physical activity in the intervention ('mediated effect,' AB = 653, 95% CI = 4-2050) and was responsible for 59.5% of the intervention effect. Fathers' beliefs mediated children's percent energy from core foods (AB = 1.51, 95% CI = 0.05-5.55) and accounted for 72.9% of the intervention effect. CONCLUSIONS: Participation in the HDHK program positively impacted on fathers' cophysical activity with their child and beliefs about healthy eating which mediated changes in children's diet and physical activity behaviors. PMID- 25526518 TI - Electrical characteristics of metal catalyst-assisted etched rough silicon nanowire depending on the diameter size. AB - The dependence of electrical properties of rough and cylindrical Si nanowires (NWs) synthesized by diameter-controllable metal catalyst-assisted etching (MCE) on the size of the NW's diameter was demonstrated. Using a decal-printing and transfer process assisted by Al2O3 sacrificial layer, the Si NW field effect transistor (FET) embedded in a polyvinylphenol adhesive and dielectric layer were fabricated. As the diameter of Si NW increased, the mobility of FET increased from 80.51 to 170.95 cm(2)/V.s and the threshold voltage moved from -7.17 to 0 V because phonon-electron wave function overlaps, surface scattering, and defect scattering decreased and gate coupling increased as the ratio of surface-to volume got reduced. PMID- 25526516 TI - Role of the active site guanine in the glmS ribozyme self-cleavage mechanism: quantum mechanical/molecular mechanical free energy simulations. AB - The glmS ribozyme catalyzes a self-cleavage reaction at the phosphodiester bond between residues A-1 and G1. This reaction is thought to occur by an acid-base mechanism involving the glucosamine-6-phosphate cofactor and G40 residue. Herein quantum mechanical/molecular mechanical free energy simulations and pKa calculations, as well as experimental measurements of the rate constant for self cleavage, are utilized to elucidate the mechanism, particularly the role of G40. Our calculations suggest that an external base deprotonates either G40(N1) or possibly A-1(O2'), which would be followed by proton transfer from G40(N1) to A 1(O2'). After this initial deprotonation, A-1(O2') starts attacking the phosphate as a hydroxyl group, which is hydrogen-bonded to deprotonated G40, concurrent with G40(N1) moving closer to the hydroxyl group and directing the in-line attack. Proton transfer from A-1(O2') to G40 is concomitant with attack of the scissile phosphate, followed by the remainder of the cleavage reaction. A mechanism in which an external base does not participate, but rather the proton transfers from A-1(O2') to a nonbridging oxygen during nucleophilic attack, was also considered but deemed to be less likely due to its higher effective free energy barrier. The calculated rate constant for the favored mechanism is in agreement with the experimental rate constant measured at biological Mg(2+) ion concentration. According to these calculations, catalysis is optimal when G40 has an elevated pKa rather than a pKa shifted toward neutrality, although a balance among the pKa's of A-1, G40, and the nonbridging oxygen is essential. These results have general implications, as the hammerhead, hairpin, and twister ribozymes have guanines at a similar position as G40. PMID- 25526520 TI - The Dutch Linguistic Intraoperative Protocol: a valid linguistic approach to awake brain surgery. AB - Intraoperative direct electrical stimulation (DES) is increasingly used in patients operated on for tumours in eloquent areas. Although a positive impact of DES on postoperative linguistic outcome is generally advocated, information about the neurolinguistic methods applied in awake surgery is scarce. We developed for the first time a standardised Dutch linguistic test battery (measuring phonology, semantics, syntax) to reliably identify the critical language zones in detail. A normative study was carried out in a control group of 250 native Dutch-speaking healthy adults. In addition, the clinical application of the Dutch Linguistic Intraoperative Protocol (DuLIP) was demonstrated by means of anatomo-functional models and five case studies. A set of DuLIP tests was selected for each patient depending on the tumour location and degree of linguistic impairment. DuLIP is a valid test battery for pre-, intraoperative and postoperative language testing and facilitates intraoperative mapping of eloquent language regions that are variably located. PMID- 25526522 TI - Aggregation-induced emission: a simple strategy to improve chemiluminescence resonance energy transfer. AB - The emergence of aggregation-induced emission (AIE) has opened up a new avenue for scientists. There is a great demand for the development of a new generation chemiluminescence resonance energy transfer (CRET) acceptors with AIE characteristics due to the aggregation-caused chemiluminescence (CL) quenching effect commonly observed in the conventional fluorophore CL acceptors at high concentrations. However, the systematical studies involving in AIE-amplified CL are still scarce. Herein, it is the first report that the gold nanocluster aggregates (a type of well-defined AIE molecules) are used to study their influence on the bis(2,4,6-trichlorophenyl) oxalate (TCPO)-H2O2 CL reaction. Interestingly, the AIE molecules in the diluted solution are unable to boost the CL signal of the TCPO-H2O2 system, but their aggregates display a strongly enhanced CL emission compared to their counterparts of fluorophore molecules, thanks to the unique AIE effect of gold nanoclusters. In comparison to rhodamine B with the aid of an imidazole catalyst, the detection limit of the gold nanocluster aggregate-amplified CL probe for H2O2 (S/N = 3) is low in the absence of any catalyst. Finally, the other two typical AIE molecules, Au(I)-thiolate complexes and 9,10-bis[4-(3-sulfonatopropoxyl)-styryl]anthracene (BSPSA), are investigated to verify the generality of the AIE molecule-amplified CL emissions. These results demonstrate effective access to highly fluorescent AIE molecules with practical applications in avoiding the aggregation-induced CL quenching at high concentrations, which can be expected to provide a novel and sensitive platform for the CL amplified detection. PMID- 25526521 TI - Ergovaline and lolitrem B concentrations in perennial ryegrass in field culture in southern France: distribution in the plant and impact of climatic factors. AB - Perennial ryegrass (Lolium perenne) infected by Epichloe festucae var. lolii contains alkaloids that are responsible for toxicosis in several countries, but few cases are reported in Europe. Lolitrem B is generally the most abundant alkaloid and is recognized to be responsible for livestock staggers, whereas ergovaline is less frequently documented in perennial ryegrass. Lolitrem B and ergovaline were monitored over a three-year period in endophyte-infected perennial ryegrass 'Samson' sown in southern France. Alkaloid concentrations were strongly influenced by the stage of maturity of the plant; maximum concentrations were always measured at the fully ripe stage. Over the three years of analysis, variations in lolitrem B in the whole plant at the fully ripe stage were low (from 1296 to maximum 1871 MUg/kg dry matter), whereas ergovaline varied considerably (from 526 to 2322 MUg/kg dry matter), suggesting that abiotic factors play a key role in determining ergovaline levels in endophyte-infected perennial ryegrass. PMID- 25526519 TI - Nontargeted biomonitoring of halogenated organic compounds in two ecotypes of bottlenose dolphins (Tursiops truncatus) from the Southern California Bight. AB - Targeted environmental monitoring reveals contamination by known chemicals, but may exclude potentially pervasive but unknown compounds. Marine mammals are sentinels of persistent and bioaccumulative contaminants due to their longevity and high trophic position. Using nontargeted analysis, we constructed a mass spectral library of 327 persistent and bioaccumulative compounds identified in blubber from two ecotypes of common bottlenose dolphins (Tursiops truncatus) sampled in the Southern California Bight. This library of halogenated organic compounds (HOCs) consisted of 180 anthropogenic contaminants, 41 natural products, 4 with mixed sources, 8 with unknown sources, and 94 with partial structural characterization and unknown sources. The abundance of compounds whose structures could not be fully elucidated highlights the prevalence of undiscovered HOCs accumulating in marine food webs. Eighty-six percent of the identified compounds are not currently monitored, including 133 known anthropogenic chemicals. Compounds related to dichlorodiphenyltrichloroethane (DDT) were the most abundant. Natural products were, in some cases, detected at abundances similar to anthropogenic compounds. The profile of naturally occurring HOCs differed between ecotypes, suggesting more abundant offshore sources of these compounds. This nontargeted analytical framework provided a comprehensive list of HOCs that may be characteristic of the region, and its application within monitoring surveys may suggest new chemicals for evaluation. PMID- 25526523 TI - Expandable Proximal Femoral Nails (EPFNs) in Elderly Patients. AB - PURPOSE: The purpose was to study the performance of expandable proximal femoral nails (EPFNs) for the treatment of unstable intertrochanteric fractures in elderly patients. PATIENTS AND METHODS: Eighty-four patients were treated with a newly designed EPFN and followed up for one year. RESULTS: The mean operating time was 50.1 +/- 3.2 min and the mean blood loss was 112.3 +/- 5.3 ml. Patients were treated with EPFNs of 220 mm (n = 24), 240 mm (n = 59), and 340 mm (n = 1) length. At six months postoperatively, the Harris Hip Score was 74.5 +/- 5.3. At the end of follow up, 75% of patients completely recovered their preoperative function and resumed their normal activities. Seven patients died within one year postoperatively. During the operation, one patient experienced proximal femoral diaphyseal slight crack fracture. This crack fracture was treated by using a long EPFN (340 mm). Two patient developed screw cut-outs, which were solved by reoperation. And one developed deep infection resolved favorably by the appropriate antibiotic treatment. Implant failure, deep venous thrombosis, fat embolism, secondary fracture, and nonunion were not encountered. CONCLUSIONS: In conclusion, the results of the EPFNs were satisfactory in most elderly patients with unstable intertrochanteric fracture. However, during the inflation period, the pressure on the nail must be monitored carefully in order to prevent a crack fracture. PMID- 25526524 TI - Planar homotropenylium cation: a transition state with reversed aromaticity. AB - In contrast to the equilibrium structure of the homoaromatic C(s) homotropenylium cation, C8H9(+) (1), which supports a pinched diatropic ring current, the C(2v) transition state (2) for inversion of the methylene bridge of 1 is antiaromatic and supports a two-lobe paratropic pi current, as detected by plotting B3LYP/6 31G** ipsocentric current maps. Participation of the bridge CH bonds is crucial for the change in global character of the current in the transition state, as shown by the quenching of its paratropicity on substitution of H by F. Orbital based arguments allow rationalization of this transition between homoaromaticity and hyper(conjugative) antiaromaticity. More generally, the hyperconjugative ring current in a family of C(2v) planar-constrained geometries of (CR2)C(N-1)H(N 1)(q) homoannulenes (R = H, F) can be switched from paratropic (antiaromatic) to diatropic (aromatic) by variation of ring size, charge, and bridge substituent. An orbital-based counting rule accounts for these systematic trends. PMID- 25526525 TI - Testing the vesicular morphology to destruction: birth and death of diblock copolymer vesicles prepared via polymerization-induced self-assembly. AB - Small angle X-ray scattering (SAXS), electrospray ionization charge detection mass spectrometry (CD-MS), dynamic light scattering (DLS), and transmission electron microscopy (TEM) are used to characterize poly(glycerol monomethacrylate)55-poly(2-hydroxypropyl methacrylate)x (G55-Hx) vesicles prepared by polymerization-induced self-assembly (PISA) using a reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization formulation. A G55 chain transfer agent is utilized to prepare a series of G55-Hx diblock copolymers, where the mean degree of polymerization (DP) of the membrane forming block (x) is varied from 200 to 2000. TEM confirms that vesicles with progressively thicker membranes are produced for x = 200-1000, while SAXS indicates a gradual reduction in mean aggregation number for higher x values, which is consistent with CD-MS studies. Both DLS and SAXS studies indicate minimal change in the overall vesicle diameter between x = 400 and 800. Fitting SAXS patterns to a vesicle model enables calculation of the membrane thickness, degree of hydration of the membrane, and the mean vesicle aggregation number. The membrane thickness increases at higher x values, hence the vesicle lumen must become smaller if the external vesicle dimensions remain constant. Geometric considerations indicate that this growth mechanism lowers the total vesicle interfacial area and hence reduces the free energy of the system. However, it also inevitably leads to gradual ingress of the encapsulated water molecules into the vesicle membrane, as confirmed by SAXS analysis. Ultimately, the highly plasticized membranes become insufficiently hydrophobic to stabilize the vesicle morphology when x exceeds 1000, thus this PISA growth mechanism ultimately leads to vesicle "death". PMID- 25526527 TI - A systematic review and meta-analysis of the association between poor oral health and severe mental illness. AB - BACKGROUND: Psychiatric patients have increased comorbid physical illness. There is less information, however, on dental disease, especially tooth decay, despite life-style risk factors or psychotropic-induced dry mouth in this population. Importantly, poor oral health can predispose people to chronic physical disease leading to avoidable admissions to hospital for medical causes. METHODS: Using MEDLINE, PsycInfo, EMBASE, and article bibliographies, we undertook a systematic search for studies from the last 25 years regarding the oral health of people with severe mental illness (SMI). Results were compared with the general population. The two outcomes were total tooth loss (edentulism) and dental decay measured through the following standardized measures: the mean number of decayed, missing, and filled teeth or surfaces. RESULTS: We identified 25 studies that had sufficient data for a random-effects meta-analysis. These covered 5076 psychiatric patients and 39,545 controls, the latter from either the same study or community surveys. People with SMI had 2.8 the odds of having lost all their teeth compared with the general community (95% confidence interval [CI] = 1.7 4.6). They also had significantly higher decayed, missing, and filled teeth (mean difference = 5.0, 95% CI = 2.5-7.4) and surfaces scores (mean difference = 14.6, 95% CI = 4.1-25.1). CONCLUSION: The increased focus on the physical health of people with SMI should encompass oral health. Possible interventions could include oral health assessment conducted using standard checklists that can be completed by non-dental personnel, help with oral hygiene, management of iatrogenic dry mouth, and early dental referral. PMID- 25526526 TI - A spatial haplotype copying model with applications to genotype imputation. AB - Ever since its introduction, the haplotype copy model has proven to be one of the most successful approaches for modeling genetic variation in human populations, with applications ranging from ancestry inference to genotype phasing and imputation. Motivated by coalescent theory, this approach assumes that any chromosome (haplotype) can be modeled as a mosaic of segments copied from a set of chromosomes sampled from the same population. At the core of the model is the assumption that any chromosome from the sample is equally likely to contribute a priori to the copying process. Motivated by recent works that model genetic variation in a geographic continuum, we propose a new spatial-aware haplotype copy model that jointly models geography and the haplotype copying process. We extend hidden Markov models of haplotype diversity such that at any given location, haplotypes that are closest in the genetic-geographic continuum map are a priori more likely to contribute to the copying process than distant ones. Through simulations starting from the 1000 Genomes data, we show that our model achieves superior accuracy in genotype imputation over the standard spatial unaware haplotype copy model. In addition, we show the utility of our model in selecting a small personalized reference panel for imputation that leads to both improved accuracy as well as to a lower computational runtime than the standard approach. Finally, we show our proposed model can be used to localize individuals on the genetic-geographical map on the basis of their genotype data. PMID- 25526528 TI - Self-assembled block copolymer micelles with silver-carbon nanotube hybrid fillers for high performance thermal conduction. AB - The development of polymer-filled composites with an extremely high thermal conductivity (TC) that is competitive with conventional metals is in great demand due to their cost-effective process, light weight, and easy shape-forming capability. A novel polymer composite with a large thermal conductivity of 153 W m(-1) K(-1) was prepared based on self-assembled block copolymer micelles containing two different fillers of micron-sized silver particles and multi walled carbon nanotubes. Simple mechanical mixing of the components followed by conventional thermal compression at a low processing temperature of 160 degrees C produced a novel composite with both structural and thermal stability that is durable for high temperature operation up to 150 degrees C as well as multiple heating and cooling cycles of DeltaT = 100 degrees C. The high performance in thermal conduction of our composite was mainly attributed to the facile deformation of Ag particles during the mixing in a viscous thermoplastic medium, combined with networked carbon nanotubes uniformly dispersed in the nanoscale structural matrix of block copolymer micelles responsible for its high temperature mechanical stability. Furthermore, micro-imprinting on the composite allowed for topographically periodic surface micropatterns, which offers broader suitability for numerous micro-opto-electronic systems. PMID- 25526529 TI - Resemble and Inhibit: when RLR meets TGF-beta. AB - In this issue, Xu et al. (2014) show that innate antiviral RIG-I-like receptors (RLR) signaling represses TGF-beta-induced growth inhibition, epithelial mesenchyme transition (EMT), and regulatory T cell (Treg) differentiation via IRF3-mediated Smads function. PMID- 25526530 TI - Caught in the Act: R-loops are cleaved by structure-specific endonucleases to generate DSBs. AB - Unscheduled RNA-DNA hybrids promote the formation DNA double-strand breaks (DSBs) through poorly characterized mechanism. In this issue, Sollier et al. (2014) show that R-loops are processed by XPF and XPG, two structure-specific endonucleases of the NER pathway, to generate DSBs. PMID- 25526532 TI - Ligand 5,10,15,20-tetra(N-methyl-4-pyridyl)porphine (TMPyP4) prefers the parallel propeller-type human telomeric G-quadruplex DNA over its other polymorphs. AB - The binding of ligand 5,10,15,20-tetra(N-methyl-4-pyridyl)porphine (TMPyP4) with telomeric and genomic G-quadruplex DNA has been extensively studied. However, a comparative study of interactions of TMPyP4 with different conformations of human telomeric G-quadruplex DNA, namely, parallel propeller-type (PP), antiparallel basket-type (AB), and mixed hybrid-type (MH) G-quadruplex DNA, has not been done. We considered all the possible binding sites in each of the G-quadruplex DNA structures and docked TMPyP4 to each one of them. The resultant most potent sites for binding were analyzed from the mean binding free energy of the complexes. Molecular dynamics simulations were then carried out, and analysis of the binding free energy of the TMPyP4-G-quadruplex complex showed that the binding of TMPyP4 with parallel propeller-type G-quadruplex DNA is preferred over the other two G quadruplex DNA conformations. The results obtained from the change in solvent excluded surface area (SESA) and solvent accessible surface area (SASA) also support the more pronounced binding of the ligand with the parallel propeller type G-quadruplex DNA. PMID- 25526533 TI - Synthesis and characterization of nitrogen-rich macrocyclic ligands and an investigation of their coordination chemistry with lanthanum(III). AB - Derivatives of the ligand 1,4,7,10-tetraazacyclododecane (cyclen) containing pendant N-heterocyclic donors were prepared. The heterocycles pyridine, pyridazine, pyrimidine, and pyrazine were conjugated to cyclen to give 1,4,7,10 tetrakis(pyridin-2-ylmethyl)-1,4,7,10-tetraazacyclododecane (L(py)), 1,4,7,10 tetrakis(3-pyridazylmethyl)-1,4,7,10-tetraazacyclododecane (L(pyd)), 1,4,7,10 tetrakis(4-pyrimidylmethyl)-1,4,7,10-tetraazacyclododecane (L(pyr)), and 1,4,7,10 tetrakis(2-pyrazinylmethyl)-1,4,7,10-tetraazacyclododecane (L(pz)), respectively. The coordination chemistry of these ligands was explored using the La(3+) ion. Accordingly, complexes of the general formula [La(L)(OTf)](OTf)2, where OTf = trifluoromethanesulfonate and L = L(py) (1), L(pyd) (2), L(pyr) (3), and L(pz) (4), were synthesized and characterized by NMR spectroscopy. Crystal structures of 1 and 2 were also determined by X-ray diffraction studies, which revealed 9 coordinate capped, twisted square-antiprismatic coordination geometries for the central La(3+) ion. The conformational dynamics of 1-4 in solution were investigated by variable-temperature NMR spectroscopy. Dynamic line-shape and Eyring analyses enabled the determination of the activation parameters for the interconversion of enantiomeric forms of the complexes. Unexpectedly, the different pendant N-heterocycles of 1-4 give rise to varying values for the enthalpies and entropies of activation for this process. Density functional theory calculations were carried out to investigate the mechanism of this enantiomeric interconversion. Computed activation parameters were consistent with those experimentally determined for 1 but differed somewhat from those of 2-4. PMID- 25526534 TI - Transformable nanostructures of platinum-containing organosilane hybrids: non covalent self-assembly of polyhedral oligomeric silsesquioxanes assisted by Pt...Pt and pi-pi stacking interactions of alkynylplatinum(II) terpyridine moieties. AB - An alkynylplatinum(II) terpyridine complex functionalized with polyhedral oligomeric silsesquioxanes (POSS) moieties has been demonstrated to exhibit self association behavior to give various distinguishable nanostructures with interesting morphological transformation from rings to rods in response to solvent conditions through the stabilization of Pt...Pt and pi-pi stacking interactions as well as hydrophobic-hydrophobic interactions. These changes can be systemically controlled by varying the solvent composition and have been studied by (1)H NMR, electron microscopy, UV-vis absorption, and emission spectroscopies. PMID- 25526531 TI - Innate antiviral host defense attenuates TGF-beta function through IRF3-mediated suppression of Smad signaling. AB - TGF-beta signaling is essential in many processes, including immune surveillance, and its dysregulation controls various diseases, including cancer, fibrosis, and inflammation. Studying the innate host defense, which functions in most cell types, we found that RLR signaling represses TGF-beta responses. This regulation is mediated by activated IRF3, using a dual mechanism of IRF3-directed suppression. Activated IRF3 interacts with Smad3, thus inhibiting TGF-beta induced Smad3 activation and, in the nucleus, disrupts functional Smad3 transcription complexes by competing with coregulators. Consequently, IRF3 activation by innate antiviral signaling represses TGF-beta-induced growth inhibition, gene regulation and epithelial-mesenchymal transition, and the generation of Treg effector lymphocytes from naive CD4(+) lymphocytes. Conversely, silencing IRF3 expression enhances epithelial-mesenchymal transition, TGF-beta-induced Treg cell differentiation upon virus infection, and Treg cell generation in vivo. We present a mechanism of regulation of TGF-beta signaling by the antiviral defense, with evidence for its role in immune tolerance and cancer cell behavior. PMID- 25526542 TI - Photocatalytic activity and photocorrosion of atomic layer deposited ZnO ultrathin films for the degradation of methylene blue. AB - ZnO ultrathin films with varied thicknesses of 7-70 nm were prepared at 200 degrees C on Si and fused quartz substrates by atomic layer deposition (ALD). The impact of film thickness and annealing temperature on the crystallinity, morphology, optical bandgap, and photocatalytic properties of ZnO in the degradation of methylene blue (MB) dye under UV light irradiation (lambda = 365 nm) has been investigated deeply. The as-deposited 28 nm thick ZnO ultrathin film exhibits highest photocatalytic activity, ascribed to the smallest band gap of 3.21 eV and proper thickness. The photocorrosion effect of ALD ZnO ultrathin films during photocatalytic process is observed. The presence of MB significantly accelerates the dissolution of ZnO ultrathin films. The possible photoetching mechanism of ZnO in MB solution is proposed. PMID- 25526543 TI - Bioelectrical impedance for detecting and monitoring lymphedema in patients with breast cancer. Preliminary results of the florence nightingale breast study group. AB - The aim of this study was to evaluate the efficacy of bioimpedance spectroscopy for the follow-up of patients with lymphedema in Turkey and its benefits in the diagnosis of stage 0, 1, and 2 lymphedema in patients who are under treatment for breast cancer. Thirty-seven female patients with breast cancer who underwent surgical procedures in our Breast Health Centre were followed up for lymphedema using bioimpedance, and clinical measurements were taken for a minimum period of 1 year at 3-month intervals. Patients who had been monitored regularly between November, 2011, and September, 2013, were enrolled to the study. In total, 8 patients developed lymphedema with an overall rate of 21.6%. Among the 8 patients who developed lymphedema, 4 had Stage 2, 1 had Stage 1, and 3 had Stage 0 lymphedema. Stage 0 lymphedema could not be detected with clinical measurements. During the patients' 1-year follow-up period using measurements of bioimpedance, a statistically significant relationship was observed between the occurrence of lymphedema and the disease characteristics. including the number of the extracted and remaining lymph nodes and the region of radiotherapy (p=0.042, p=0.024, p=0.040). Bioimpedance analysis seems to be a practical and reliable method for the early diagnosis of lymphedema. It is believed that regular monitoring of patients in the high-risk group using bioimpedance analyses increases the ability to treat lymphedema. PMID- 25526544 TI - A new data management system for the French National Registry of human alveolar echinococcosis cases. AB - Alveolar echinococcosis (AE) is an endemic zoonosis in France due to the cestode Echinococcus multilocularis. The French National Reference Centre for Alveolar Echinococcosis (CNR-EA), connected to the FrancEchino network, is responsible for recording all AE cases diagnosed in France. Administrative, epidemiological and medical information on the French AE cases may currently be considered exhaustive only on the diagnosis time. To constitute a reference data set, an information system (IS) was developed thanks to a relational database management system (MySQL language). The current data set will evolve towards a dynamic surveillance system, including follow-up data (e.g. imaging, serology) and will be connected to environmental and parasitological data relative to E. multilocularis to better understand the pathogen transmission pathway. A particularly important goal is the possible interoperability of the IS with similar European and other databases abroad; this new IS could play a supporting role in the creation of new AE registries. PMID- 25526545 TI - Treatment of echinococcosis: albendazole and mebendazole--what else? AB - The search for novel therapeutic options to cure alveolar echinococcosis (AE), due to the metacestode of Echinococcus multilocularis, is ongoing, and these developments could also have a profound impact on the treatment of cystic echinococcosis (CE), caused by the closely related Echinococcus granulosus s.l. Several options are being explored. A viable strategy for the identification of novel chemotherapeutically valuable compounds includes whole-organism drug screening, employing large-scale in vitro metacestode cultures and, upon identification of promising compounds, verification of drug efficacy in small laboratory animals. Clearly, the current focus is targeted towards broad-spectrum anti-parasitic or anti-cancer drugs and compound classes that are already marketed, or that are in development for other applications. The availability of comprehensive Echinococcus genome information and gene expression data, as well as significant progress on the molecular level, has now opened the door for a more targeted drug discovery approach, which allows exploitation of defined pathways and enzymes that are essential for the parasite. In addition, current in vitro and in vivo models that are used to assess drug efficacy should be optimized and complemented by methods that give more detailed information on the host-parasite interactions that occur during drug treatments. The key to success is to identify, target and exploit those parasite molecules that orchestrate activities essential to parasite survival. PMID- 25526546 TI - Anthelmintic effect of carob pods and sainfoin hay when fed to lambs after experimental trickle infections with Haemonchus contortus and Trichostrongylus colubriformis. AB - The aim of the study was to compare the in vivo anthelmintic activity of sainfoin hay (Onobrychis viciifolia) and carob pod meal (Ceratonia siliqua) against gastrointestinal nematodes. Seven days before infection, 64 naive lambs were assigned to four different groups: Group S received sainfoin hay and group CAR was fed with carob pods. The remaining lambs received lucerne hay (Medicago sativa) and were assigned to positive (non-treated, NT) and negative (treated, T) control groups (treatment with albendazole). On day 0, lambs were artificially trickle infected for 6 weeks, with a mixture of infective larvae of Haemonchus contortus and Trichostrongylus colubriformis. Parasitological and pathophysiological parameters were measured repeatedly during the 2-month study. Compared to the NT group, decreases in egg excretion were observed in the CAR and S groups with significant differences only found for sainfoin (p < 0.05). At necropsy, group S showed decreases in the total worm numbers of both nematode species with significant differences for H. contortus. In contrast, no differences were noticed for the CAR group. Compared to the NT group, lower values for fecundity of female H. contortus were found in the S and CAR groups, however differences were non-significant. No differences in body weight gains were found between groups. Consistent results were found showing significantly higher packed cell volume (PCV) values in the T and S groups compared to NT and CAR groups. Overall, these results confirm a positive effect associated with the feeding of lambs with tanniniferous resources on host resilience (PCV values) and against gastrointestinal parasitic nematodes by affecting some biological traits of worm populations (e.g. eggs per gram of faeces and worm numbers). However, the anthelmintic effects differed between the two tannin-containing resources, which might be associated with the quantity and/or quality of secondary metabolites (condensed tannins and/or other polyphenols). PMID- 25526548 TI - Skin under the sun: when melanin pigment meets vitamin D. PMID- 25526547 TI - On the importance of targeting parasite stem cells in anti-echinococcosis drug development. AB - The life-threatening diseases alveolar and cystic echinococcoses are caused by larvae of the tapeworms Echinococcus multilocularis and E. granulosus, respectively. In both cases, intermediate hosts, such as humans, are infected by oral uptake of oncosphere larvae, followed by asexual multiplication and almost unrestricted growth of the metacestode within host organs. Besides surgery, echinococcosis treatment relies on benzimidazole-based chemotherapy, directed against parasite beta-tubulin. However, since beta-tubulins are highly similar between cestodes and humans, benzimidazoles can only be applied at parasitostatic doses and are associated with adverse side effects. Mostly aiming at identifying alternative drug targets, the nuclear genome sequences of E. multilocularis and E. granulosus have recently been characterized, revealing a large number of druggable targets that are expressed by the metacestode. Furthermore, recent cell biological investigations have demonstrated that E. multilocularis employs pluripotent stem cells, called germinative cells, which are the only parasite cells capable of proliferation and which give rise to all differentiated cells. Hence, the germinative cells are the crucial cell type mediating proliferation of E. multilocularis, and most likely also E. granulosus, within host organs and should also be responsible for parasite recurrence upon discontinuation of chemotherapy. Interestingly, recent investigations have also indicated that germinative cells might be less sensitive to chemotherapy because they express a beta-tubulin isoform with limited affinity to benzimidazoles. In this article, we briefly review the recent findings concerning Echinococcus genomics and stem cell research and propose that future research into anti-echinococcosis drugs should also focus on the parasite's stem cell population. PMID- 25526553 TI - RE: Testosterone treatment is a potent tumor promoter for the rat prostate. PMID- 25526549 TI - 3,5-diiodo-L-thyronine (t2) in dietary supplements: what are the physiological effects? PMID- 25526554 TI - Author's response to RE: Testosterone treatment is a potent tumor promoter for the rat prostate. PMID- 25526560 TI - Effect of polymerization on hierarchical self-assembly into nanosheets. AB - The oligomers consisting of phenyl-capped bithiophene and tetra(ethylene glycol)s linked by azide-alkyne Huisgen cycloaddition were synthesized. The relationship between the degree of polymerization and self-assembling ability was investigated in o-dichlorobenzene and dimethyl sulfoxide. From the absorption spectrum, it was confirmed that the critical degree of polymerization (CDP) for thiophene unit aggregation was 4. The morphology of the aggregated product was observed by atomic force microscopy. The oligomers 4mer and 5mer could not self-assemble into well-defined structures due to the weak driving force for the self-assembly. In the cases of 6mer and 7mer, aggregates with nonwell-defined and nanosheet structures coexisted. In the cases of 8mer and 9mer, the nanosheet was the main product. The critical point between 7mer and 8mer could be confirmed by different aggregation behaviors in the cooling process of the solution (nonsigmoidal and sigmoidal). In the cases of 8mer and 9mer, polymer folding prior to intermolecular self-assembly, which was supported by sigmoidal aggregation behavior, leads to the nanosheet formation. On the contrary, shorter oligomers than 8mer experience intermolecular aggregation prior to intramolecular polymer folding, which was supported by the nonsigmoidal aggregation behavior. This is the first report to prove the existence of CDP for folded polymer nanosheet formation which requires hierarchical self-assembly, i.e., polymer folding followed by intermolecular self-assembly. PMID- 25526561 TI - Interaction of palmatine with DNA: an environmentally controlled phototherapy drug. AB - Palmatine is one of the four main protoberberine alkaloids and is largely employed in pharmacy and medicine as a versatile drug with considerable biological activities. More recently, palmatine has been proposed as a promising DNA phototherapy drug, notably due to its ability to produce in situ singlet oxygen only when interacting with DNA. The fine mechanisms of palmatine-DNA interactions as well as its complicated photophysics are not yet fully understood. In this paper, we identify via molecular dynamic techniques two stable interaction modes between palmatine and B-DNA, namely insertion and minor groove binding, whose structural and electronic bases are analyzed and rationalized. These two competitive modes share the same UV-vis signature and estimated binding free energies, and thus they may indeed coexist. By using hybrid quantum mechanics/molecular mechanics protocols coupled to molecular dynamics, we analyze palmatine excited state properties in water solution and in interaction with DNA. The environmentally controlled production of singlet oxygen is thus rationalized in terms of the competition between local and charge transfer excited states. PMID- 25526555 TI - Proceedings of the Second Annual Deep Brain Stimulation Think Tank: What's in the Pipeline. AB - The proceedings of the 2nd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, and computational work on DBS for the treatment of neurological and neuropsychiatric disease and represent the insights of a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers and members of industry. Presentations and discussions covered a broad range of topics, including advocacy for DBS, improving clinical outcomes, innovations in computational models of DBS, understanding of the neurophysiology of Parkinson's disease (PD) and Tourette syndrome (TS) and evolving sensor and device technologies. PMID- 25526563 TI - Recent developments in beta-cell differentiation of pluripotent stem cells induced by small and large molecules. AB - Human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), hold promise as novel therapeutic tools for diabetes treatment because of their self-renewal capacity and ability to differentiate into beta (beta)-cells. Small and large molecules play important roles in each stage of beta-cell differentiation from both hESCs and hiPSCs. The small and large molecules that are described in this review have significantly advanced efforts to cure diabetic disease. Lately, effective protocols have been implemented to induce hESCs and human mesenchymal stem cells (hMSCs) to differentiate into functional beta-cells. Several small molecules, proteins, and growth factors promote pancreatic differentiation from hESCs and hMSCs. These small molecules (e.g., cyclopamine, wortmannin, retinoic acid, and sodium butyrate) and large molecules (e.g. activin A, betacellulin, bone morphogentic protein (BMP4), epidermal growth factor (EGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), noggin, transforming growth factor (TGF-alpha), and WNT3A) are thought to contribute from the initial stages of definitive endoderm formation to the final stages of maturation of functional endocrine cells. We discuss the importance of such small and large molecules in uniquely optimized protocols of beta-cell differentiation from stem cells. A global understanding of various small and large molecules and their functions will help to establish an efficient protocol for beta-cell differentiation. PMID- 25526565 TI - TXNDC5, a newly discovered disulfide isomerase with a key role in cell physiology and pathology. AB - Thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family, acting as a chaperone of endoplasmic reticulum under not fully characterized conditions As a result, TXNDC5 interacts with many cell proteins, contributing to their proper folding and correct formation of disulfide bonds through its thioredoxin domains. Moreover, it can also work as an electron transfer reaction, recovering the functional isoform of other protein disulfide isomerases, replacing reduced glutathione in its role. Finally, it also acts as a cellular adapter, interacting with the N-terminal domain of adiponectin receptor. As can be inferred from all these functions, TXNDC5 plays an important role in cell physiology; therefore, dysregulation of its expression is associated with oxidative stress, cell ageing and a large range of pathologies such as arthritis, cancer, diabetes, neurodegenerative diseases, vitiligo and virus infections. Its implication in all these important diseases has made TXNDC5 a susceptible biomarker or even a potential pharmacological target. PMID- 25526567 TI - The dynamics of DNA methylation in maize roots under Pb stress. AB - Plants adapt to adverse conditions through a series of physiological, cellular, and molecular processes, culminating in stress tolerance. However, little is known about the associated regulatory mechanisms at the epigenetic level in maize under lead (Pb) stress. Therefore, in this study, we aimed to compare DNA methylation profiles during the dynamic development of maize roots following Pb treatment to identify candidate genes involved in the response to Pb stress. Methylated DNA immunoprecipitation-sequencing (MeDIP-seq) was used to investigate the genome-wide DNA methylation patterns in maize roots under normal condition (A1) and 3 mM Pb(NO3)2 stress for 12 h (K2), 24 h (K3) and 48 h (K4). The results showed that the average methylation density was the highest in CpG islands (CGIs), followed by the intergenic regions. Within the gene body, the methylation density of the introns was higher than those of the UTRs and exons. In total, 3857 methylated genes were found in 4 tested samples, including 1805 differentially methylated genes for K2 versus A1, 1508 for K3 versus A1, and 1660 for K4 versus A1. Further analysis showed that 140 genes exhibited altered DNA methylation in all three comparisons, including some well-known stress-responsive transcription factors and proteins, such as MYB, AP2/ERF, bZIP, serine threonine/tyrosine-proteins, pentatricopeptide repeat proteins, RING zinc finger proteins, F-box proteins, leucine-rich repeat proteins and tetratricopeptide repeat proteins. This study revealed the genome-scale DNA methylation patterns of maize roots in response to Pb exposure and identified candidate genes that potentially regulate root dynamic development under Pb stress at the methylation level. PMID- 25526568 TI - Isolation and structural elucidation of antiproliferative compounds of lipidic fractions from white shrimp muscle (Litopenaeus vannamei). AB - Shrimp is one of the most popular seafood items worldwide, and has been reported as a source of chemopreventive compounds. In this study, shrimp lipids were separated by solvent partition and further fractionated by semi-preparative RP HPLC and finally by open column chromatography in order to obtain isolated antiproliferative compounds. Antiproliferative activity was assessed by inhibition of M12.C3.F6 murine cell growth using the MTT (3-(4,5-dimethyl-2 thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay. The methanolic fraction showed the highest antiproliferative activity; this fraction was separated into 15 different sub-fractions (M1-M15). Fractions M8, M9, M10, M12, and M13 were antiproliferative at 100 ug/mL and they were further tested at lower concentrations. Fractions M12 and M13 exerted the highest growth inhibition with an IC50 of 19.5 +/- 8.6 and 34.9 +/- 7.3 ug/mL, respectively. Fraction M12 was further fractionated in three sub-fractions M12a, M12b, and M12c. Fraction M12a was identified as di-ethyl-hexyl-phthalate, fraction M12b as a triglyceride substituted by at least two fatty acids (predominantly oleic acid accompanied with eicosapentaenoic acid) and fraction M12c as another triglyceride substituted with eicosapentaenoic acid and saturated fatty acids. Bioactive triglyceride contained in M12c exerted the highest antiproliferative activity with an IC50 of 11.33 +/- 5.6 ug/mL. Biological activity in shrimp had been previously attributed to astaxanthin; this study demonstrated that polyunsaturated fatty acids are the main compounds responsible for antiproliferative activity. PMID- 25526566 TI - Lidocaine sensitizes the cytotoxicity of cisplatin in breast cancer cells via up regulation of RARbeta2 and RASSF1A demethylation. AB - It has been reported that lidocaine is toxic to various types of cells. And a recent study has confirmed that lidocaine exerts a demethylation effect and regulates the proliferation of human breast cancer cell lines. To recognize a potential anti-tumor effect of lidocaine, we evaluated the DNA demethylation by lidocaine in human breast cancer lines, MCF-7 and MDA-MB-231 cells, and determined the influence of demethylation on the toxicity to these cells of cisplatin, which is a commonly utilized anti-tumor agent for breast cancer. Results demonstrated that lidocaine promoted a significant global genomic demethylation, and particularly in the promoters of tumor suppressive genes (TSGs), RARbeta2 and RASSF1A. Further, the lidocaine treatment increased cisplatin-induced apoptosis and enhanced cisplatin-induced cytotoxicity. The combined treatment with both lidocaine and cisplatin promoted a significantly higher level of MCF-7 cell apoptosis than singular lidocaine or cisplatin treatment. Moreover, the abrogation of RARbeta2 or RASSF1A expression inhibited such apoptosis. In conclusion, the present study confirms the demethylation effect of lidocaine in breast cancer cells, and found that the demethylation of RARbeta2 and RASSF1A sensitized the cytotoxicity of cisplatin in breast cancer cells. PMID- 25526570 TI - Lycopene - antioxidant with radioprotective and anticancer properties. A review. AB - Ionizing radiation may cause damage to living tissue by producing free radicals like reactive oxygen species (ROS). ROS can randomly react with lipids, proteins and nucleic acids of cell causing oxidative stress and damage in these macromolecules, leading to pathogenesis of chronic diseases and age related and also cancer. The first line of defense from the damaging effects of ROS is antioxidants, which convert the oxidants to less reactive species. Lycopene (LYC) is an acyclic isomer of beta-carotene. It synthesized by plants or autotrophic bacteria but not by animals. Red fruits and vegetables, including tomatoes, watermelons, pink grapefruits, apricots, pink guavas and papaya contain LYC. This carotenoid has very strong antioxidant properties. The many studies confirm that dietary supplementation with LYC reduces risk of cancers of many organs, but also retard the growth of the tumors. LYC has also chemopreventive effects against other diseases such as cardiovascular disease, osteoporosis, male infertility and inhibits the toxic action of other agents. Numerous in vitro and animal studies showed that LYC may provide protection against damages induced by ionizing radiation. It suggests that supplementation of LYC might be useful in diminishing of negative effect of cancer radiotherapy or in mitigating the effects of possible radiation accidents on human health. KEY WORDS: lycopene, antioxidants, anticarcinogenic agents, radioprotection. PMID- 25526571 TI - Health outcomes of vitamin D. Part II. Role in prevention of diseases. AB - Apart from the classic role of vitamin D, its hormonal active form, calcitriol is also characterized by pleiotropic effects on various organs and tissues. For the last several years, many researchers have shown an association between deficiency of vitamin D and the risk of type 2 diabetes mellitus (T2DM). Recent investigations suggested the need of vitamin D supplementation in T2DM prevention. It was shown that vitamin D deficiency decreases insulin secretion. It was also observed that proper vitamin D supplementation may improve the ability of the cells of the islets of Langerhans to synthesize many proteins de novo and to convert proinsulin to insulin. Apart from regulating bone metabolism and also calcium and phosphate homeostasis, 1,25(OH)2D3 exerts antiproliferative and pro-differentiating effects on a wide variety of cell types. It also induces apoptosis of cancer cells and slows their proliferation. In a number of major studies the relationship between low vitamin D levels and increased risk of various cancers was observed. It concerns colorectal, lung, prostate, breast and ovarian cancer. It was observed that in patients with low serum vitamin D concentrations such disorders as ischemic heart disease, heart attack, stroke, cardiac arrhythmia, and hypertension were more frequent and mortality was significantly higher. These results led the researchers to consider vitamin D deficiency as a potential risk factor for cardiovascular diseases. The possible mechanism in the pathogenesis of cardiovascular diseases that may be related to low levels of vitamin D, is its adverse effect on the renin-angiotensin aldosterone system (RAAS). Calcitriol is also an important determinant of muscle cell proliferation and differentiation, as well as inhibition of apoptosis. Vitamin D is synthesized in the skin. However, there are only a few food products that are rich in vitamin D3, e.g.: fish oils, fish and fortified-products, such as dairy products and margarines. Individuals who are vulnerable to vitamin D deficiency should be supplemented. KEY WORDS: vitamin D, diabetes mellitus, deficiency of vitamin D, cancer, cardiovascular diseases, muscle physiology. PMID- 25526569 TI - Docetaxel-encapsulating small-sized polymeric micelles with higher permeability and its efficacy on the orthotopic transplantation model of pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) elicits a dense stromal response that blocks vascular access because of pericyte coverage of vascular fenestrations. In this way, the PDAC stroma contributes to chemotherapy resistance, and the small sized nanocarrier loaded with platinum has been adopted to address this problem which is not suitable for loading docetaxel (DTX). In the present study, we used the poly(D,L-lactide)-b-polyethylene glycol-methoxy (mPEG-b-PDLLA) to encapsulate DTX and got a small-sized polymeric micelle (SPM); meanwhile we functionalized the SPM's surface with TAT peptide (TAT-PM) for a higher permeability. The diameters of both SPM and TAT-PM were in the range of 15-26 nm. In vitro experiments demonstrated that TAT-PM inhibited Capan-2 Luc PDAC cells growth more efficiently and induced more apoptosis compared to SPM and Duopafei. The in vivo therapeutic efficiencies of SPM and TAT-PM compared to free DTX was investigated on the orthotopic transplantation model of Capan-2 Luc. SPM exerted better therapeutic efficiency than free DTX, however, TAT-PM didn't outperformed SPM. Overall, these results disclosed that SPM could represent a new therapeutic approach against pancreatic cancer, but its permeability to PDAC was not the only decisive factor. PMID- 25526572 TI - Human exposure asseessment to different arsenic species in tea. AB - BACKGROUND: Inorganic forms of arsenic are much more highly toxic to humans than organic species. Their effects include being carcinogenic, genotoxic and neurotoxic, where in the latter case, above all, they affect nervous system development in the foetus, infants and children. The main foodstuffs contributing significantly to its total dietary intake are drinking water, rice (and its products), fish, seafood, cereals, seaweed, root vegetables, food supplements, mushrooms and tea. After water, tea is the second most popular beverage drunk in Poland with average consumption annually indicating that statistically every Polish inhabitant drinks at least one cup of tea daily. OBJECTIVES: The aim of the study was to determine the total and inorganic content of arsenic in various black and green teas available on the market and thus to estimate consumer exposure to inorganic arsenic from this foodstuff. MATERIALS AND METHODS: Analyses of total and inorganic arsenic were performed on 23 samples of black and green teas that consisted of tea leaves, teas in bags and granules, from various sources. The analytical method was hydride generation atomic absorption spectrometry (HGAAS), after dry ashing of samples and reduction of arsenic to arsenic hydride using sodium borohydride. In order to isolate only the inorganic forms of arsenic prior to mineralisation, samples were subjected to concentrated HCl hydrolysis, followed by reduction with hydrobromic acid and hydrazine sulphate after which triple chloroform extractions and triple 1M HCl re extractions were performed. Exposure of adults was estimated in relation to the Benchmark Dose Lower Confidence Limit (BMDL05) as set by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) that resulted in a 0.5% increase in lung cancer (3.0 MUg/kg body weight (b.w.) per day). RESULTS: Green teas were found to be more highly contaminated with both total and inorganic arsenic than black teas. Contamination of black teas total and inorganic arsenic was mean: 0.058 mg/kg (median: 0.042 mg/kg, 90th percentile: 0.114 mg/kg), and 0.030 mg/kg, (median: 0.025 mg/kg, 90th percentile: 0.030 mg/kg) respectively. Whilst for the green teas, these were correspondingly mean total arsenic content: 0.134 mg/kg (median: 0.114 mg/kg, 90th percentile: 0.234 mg/kg) and inorganic arsenic, mean: 0.100 mg/kg (median: 0.098 mg/kg, 90th percentile: 0.150 mg/kg). The estimated average adult exposures to inorganic arsenic in black and green tea were less than 1% of the BMDL05. Green tea samples, with the highest measured inorganic arsenic, were found to cause an intake exceeding 0.5% of the BMDL05 value. However when the drinking water is also accounted for when teas are prepared, then the exposure from black and green tea becomes exceeding 0.7% and 1.3% of the BMDL05 value respectively. CONCLUSIONS: Findings thus demonstrate that drinking black or green teas does not pose a significant health threat to consumers, even though contaminations in some individual samples were significant. KEY WORDS: total arsenic, inorganic arsenic, tea consumption, exposure assessment. PMID- 25526573 TI - Arsenic contents in rats' fur as an indicator of exposure to arsenic. Preliminary studies. AB - BACKGROUND: Since arsenic compounds have an affinity to thiol groups their greatest amounts can then be found in the tissues containing sulphur-rich proteins, like beta-keratin in skin, hair and nails. Accumulation of arsenic also depends on the macronutrient content in daily food ration. The deficiency and excess of both the protein and fat may contribute to a higher content of arsenic in the organism, including hair in human or fur in animals. OBJECTIVE: Hair and fur is a good indicator of population exposure to many toxic substances, including arsenic. The degree of arsenic accumulation may depend on the diet and nutritional status. The aim of this study was to determine the effect of protein and fat in diet on the accumulation of arsenic in rats' fur. MATERIALS AND METHODS: A total number of 70 male Buffalo rats (body weight 200 - 220 g, age - 6 weeks) were divided into 10 groups. Rats were housed in plastic cages (4 per cage) in a 12h light/dark cycle for 6 weeks. The diets of different protein and fat contents ware administered to the animals. Five of ten groups of rats received throughout the whole period 10 ppm sodium arsenite dissolved in distilled drinking water (about 250 ug As/animal/day). The arsenic were determined with the method of atomic adsorption spectrometry in conjunction with a graphite-furnace atomize using a Varian AA240FS apparatus. RESULTS: The highest arsenic concentrations were found in fur of rats which were given low protein diet and water with arsenic. The lowest arsenic contents were found in fur of rats, which were given control diet and high protein diet with arsenic in water. CONCLUSIONS: Balanced control diet or high protein diet protected organism from arsenic accumulation, only small increase of arsenic content in rats' fur, compared to the control group, was observed. KEY WORDS: arsenic, rats' fur, protein and fat in diet, exposure to arsenic. PMID- 25526574 TI - Organophosphate pesticide exposure and dialkyl phosphate urinary metabolites among chili farmers in northeastern Thailand. AB - BACKGROUND: Chlorpyrifos and profenofos are organophosphate pesticides (OPPs), we studied exposure and urinary metabolites in an agricultural area in the northeastern of Thailand during the chili-growing season (March - April) in 2012. OBJECTIVE: This study was designed to assess pesticide exposure concentration through dermal and inhalation pathways and to find and depict a relationship between urinary metabolites and means of exposure. MATERIALS AND METHODS: To estimate the pesticides exposure concentration, dermal wipes (hand, face, and feet), dermal patches and air samples were collected from 38 chili farmers. The morning void of pre and post application urine samples was an indicator of biological monitoring in the study which derived from 39 chili farmers. RESULTS: Chlorpyrifos and profenofos residues were detected on dermal patches, face wipes, and hand wipe samples, while no significant residues were found on the feet. Using a personal air sampling technique, all air samples detected pesticide residues. However, significant correlation between dermal pesticide exposure concentration and inhalation was not found (p>0.05). For urinary metabolite levels, there was a relationship between the first pre application morning void and post application morning void (p < 0.05); similar to the association between the first pre application morning void and the second post application morning void (p < 0.05). The main relationship between pesticide exposure and urinary metabolite was found to have been relevant to dermal exposure (r= 0.405; p < 0.05). CONCLUSIONS: The results of this study could suggested that public health education training programs, including the use of appropriate personal protective equipment (PPE), should be offered for the chili growing farmers in order to improve their ability to properly use pesticides. KEY WORDS: pesticide exposure, chili farmers, urinary metabolites, organophosphate pesticides. PMID- 25526564 TI - Protecting the melatonin rhythm through circadian healthy light exposure. AB - Currently, in developed countries, nights are excessively illuminated (light at night), whereas daytime is mainly spent indoors, and thus people are exposed to much lower light intensities than under natural conditions. In spite of the positive impact of artificial light, we pay a price for the easy access to light during the night: disorganization of our circadian system or chronodisruption (CD), including perturbations in melatonin rhythm. Epidemiological studies show that CD is associated with an increased incidence of diabetes, obesity, heart disease, cognitive and affective impairment, premature aging and some types of cancer. Knowledge of retinal photoreceptors and the discovery of melanopsin in some ganglion cells demonstrate that light intensity, timing and spectrum must be considered to keep the biological clock properly entrained. Importantly, not all wavelengths of light are equally chronodisrupting. Blue light, which is particularly beneficial during the daytime, seems to be more disruptive at night, and induces the strongest melatonin inhibition. Nocturnal blue light exposure is currently increasing, due to the proliferation of energy-efficient lighting (LEDs) and electronic devices. Thus, the development of lighting systems that preserve the melatonin rhythm could reduce the health risks induced by chronodisruption. This review addresses the state of the art regarding the crosstalk between light and the circadian system. PMID- 25526575 TI - Exposure to lead and cadmium released from ceramics and glassware intended to come into contact with food. AB - BACKGROUND: The dietary intake of harmful elements, particularly lead and cadmium constitutes a health threat and essential measures should be undertaken to reduce consumer exposure. The latest risk assessments by the European Food Safety Authority (EFSA) and Joint FAO/WHO Expert Committee on Food Additives (JECFA) have indicated that the Provisional Tolerable Weekly Intake (PTWI) for lead and cadmium do not ensure health safety and their review had to be undertaken. Migration from ceramics and glassware intended for food contact is an important source of lead and cadmium intake. OBJECTIVES: To study the release of lead and cadmium from ceramics and glassware (including decorated products) intended for food contact that are available on the Polish market and to assess the resulting health risk to the consumer. MATERIALS AND METHODS: Ceramics and glassware (mainly decorated) were sampled from the Polish market during 2010- 2012 throughout the country by staff of the Sanitary-Epidemiological Stations in accordance with monitoring procedures and guidelines designed by the National Institute of Public Health-National Institute of Hygiene. Migration of lead and cadmium was measured by incubating the samples with 4% acetic acid for 24 hours at a temperature of 22+/-2oC in the dark. Flame Atomic Absorption Spectrometry (FAAS) was used to measure these elements in food simulant according to a validated and accredited method (PN-EN ISO/IEC 17025). RESULTS: 1273 samples of ceramics and glass wares were analysed in 2010-2012. Lead and cadmium release were usually found to be below analytical detection limits. Permissible migration limits (as prescribed by the legislation) of these metals were rarely exceeded and were reported mainly in articles imported from outside the EU. Two imported and decorated ceramic flat plates released lead at 0.9 and 11.9 mg/dm2 (limit 0.8 mg/dm2) and 5 imported deep plates gave migration values of 4.7 mg/L, 4.9 mg/L, 5.6 mg/L, 6.1 mg/L, 8.6 mg/L (limit 4.0 mg/L). Lead migrations from ceramic ware rims above the 2.0 mg per product limit (as established in Polish Standard PN-B 13210:1997 [16]) were observed in 4 samples, at 2.1, 3.7, 4.2 and 14.4 mg per product, respectively. Migrations of cadmium from the ceramic samples' rims were within permissible limits. Majority of high migration results were obtained for decorated rims of glass vessels for beverages. The highest migration from the rim of an imported glass mug was reported at 163.8 mg/product for lead and at 8.96 mg/product for cadmium. Risk assessment indicated that exposures to lead and cadmium released from ceramic wares based on the migration limits set by the EU legislation lead to human intake close to, or exceeding reference doses. For a 20 kg b.w. child the lead BMDL01 value could thus be exceeded by over 30-fold and the cadmium TWI value 4-fold. CONCLUSIONS: Review of EU legislation applicable to lead and cadmium migration limits from ceramics is necessary with an intention to lower such limits. The limits applied to the rims of ceramics and glassware intended for beverages should be included. The release of lead and cadmium at the maximum permissible levels for ceramics may lead to uptakes becoming hazardous to human health. Appropriate measures are thus necessary to reduce sources of exposure. KEY WORDS: lead, cadmium, ceramic food contact articles, glass food contact articles, lead migration, cadmium migration, lead exposure, cadmium exposure, food contact articles, risk assessment. PMID- 25526576 TI - Effect of chlorpyrifos on the profile of subpopulations immunocompetent cells B, T and NK in in vivo model. AB - BACKGROUND: Current studies have indicated many environmental factors, such as pesticides, that cause immune system disorders through inducing changes in humoral and cellular responses thereby increasing the risk of contracting infectious diseases and cancer. The literature suggests that low exposures to certain organophosphorus pesticides stimulate the immune system, whilst high exposures result in decreased function. Precise mechanisms for the fall in immunocompetence are often unclear, however it can be predicted that the intimate interaction between the nervous and immune systems can potentially lead to toxicity. OBJECTIVES: To determine the effects of organophosphorus pesticide, chlorpyrifos that is often used in Poland, on selected immunological responses, such as immune-competent cell proportions formed experimentally in-vivo by cells of Wistar rats during subchronic exposures after 45 and 90 days. MATERIALS AND METHODS: The test was carried out on ten male and ten female Wistar rats in each of three test groups, who received 3 chlorpyrifos doses for 90 days intragastrically, according to OECD guidelines (No. 401). Two control groups were given olive oil. After completion, the animals were deeply anaesthetised by a mixture of ketamine (Vetaketam) and xylazine (Vetaxym). Immuno-competent cells were profiled by a commercial monoclonal antibody method. In order to measure the dynamics of any changes, the aforementioned immunological responses were investigated after 45 days using the same procedures for obtaining the relevant biological test material. RESULTS: Test animals exposed to chlorpyrifos had altered number of white bood cells which were either increased or decreased relative to controls after 45 and 90 days for all exposure levels used. CONCLUSIONS: The study demonstrated changes in white-blood cell (lymphocyte) response profiles, reflecting an immunomodulation although such changes were equivocal, where both suppression and stimulation were observed. KEY WORDS: immunomodulation, immune system, lymphocyte, organophosphorus pesticides, chlorpyrifos. PMID- 25526577 TI - Assessing patients' attitudes towards dietary supplements. AB - BACKGROUND: There is currently many over the counter products on the market that exert nutritional or physiological effects on the human body. The differences between dietary supplements and non-prescription drugs are however poorly understood by the average consumer and may thus affect their expectations as to the desired effect produced on the body. OBJECTIVES: To evaluate patients' knowledge and attitudes towards dietary supplements as compared to non prescription drugs. MATERIALS AND METHODS: Subjects were 335 patients of the Mazowiecki Voivodeship Hospital in Warsaw, Poland. The data were collected from a face-to-face interview using a single and multiple choice questionnaire with 10 questions on dietary supplements. Statistical analysis used the Chi-square (chi2) test. RESULTS: The majority of respondents were found to be familiar with the term 'dietary supplements', but had difficulties in classifying these products into appropriate categories. Over 55% do not consider dietary supplements to be foodstuffs and more than 40% considered such products to be drugs. Most respondents thought that the main purpose of taking dietary supplements is to improve nutrition, but over one third expected them to also treat disease. Over 70% declared taking notice to which category the non-prescription products they bought belongs to ie. whether non-prescription drugs (medicinal products) or dietary supplements. CONCLUSIONS: Many patients mistakenly believe that dietary supplements are drugs and can be used to treat disease and health disorders. KEY WORDS: dietary supplements, opinion on dietary supplements, nutrition, dietary supplement vs. medicinal product. PMID- 25526578 TI - Assessment of vitamin D status in children aged 1-5 with simple obesity. AB - BACKGROUND: Proper vitamin D intake is important due to its pleiotropic effect. It seems that obese population is a groups at risk of the vitamin D deficiency. OBJECTIVE: To assess the vitamin D status in 1-5-year-old children with simple obesity. MATERIALS AND METHODS: The study included 100 children: classified according to their body mass index (BMI) as obese - Group I (n=50) and non-obese Group II (n=50). Their serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined in the spring-summer and autumn-winter seasons and vitamin D intake (diet/supplements) was assessed. The study results were statistically analysed by means of Statistica 10PL. RESULTS: In Group I the mean serum 25(OH)D level was 23.6+/-10.8 ng/ml, while in Group II it reached 26.6+/-9.8 ng/ml (p=0.08). The concentration <=30 ng/ml was observed in 80% of children in Group I and in 70% of Group II. In autumn- winter and spring-summer period, respectively, 88.5% and 70.9% of the obese children had an insufficient vitamin D status (p=0.002). The mean daily intake of vitamin D was 128 IU (3.2 ug) in Group I and 188 IU (4.7 ug) in Group II. CONCLUSIONS: Children aged 1-5 (obese and non-obese) are a group at risk of the vitamin D deficiency, as a consequence of its insufficient intake and the lack of appropriate supplementation. Those particularly exposed to that risk are obese children in the autumn-winter season. Children aged 1-5 should be monitored with regard to their vitamin D status. KEY WORDS: vitamin D, obesity, children, obese children, vitamin D deficiency. PMID- 25526579 TI - Nutritional behaviours and body self-perception in polish pupils attending middle school. AB - BACKGROUND: Adolescence is a vital part of child development, where acquired eating/dietary behaviour is often associated with ones' perception of body shape. OBJECTIVES: To assess eating habits in relation to body shape perception and esteem in middle-school (junior-high) pupils. MATERIALS AND METHODS: Surveyed subjects were 170 middle-school pupils from Warsaw; 101 girls and 69 boys aged 15 years. An anonymous questionnaire was used to determine eating habits, body mass, growth and body shape perception. Anthropometric measurement cut-off points were taken according to the method of Cole et al. RESULTS: Only 29% of pupils ate 5 daily meals; of whom there were significantly more girls than boys (35% vs 20%, p = 0.042). Girls more often consumed second breakfast than boys (p < 0.001), whilst boys ate dinner more frequently than girls (p = 0.004). Eating meals was observed in 86% all pupils, where sweets (71%) and fresh fruit (69%) were most commonly eaten. Boys ate fast-food more often than girls (p = 0.004), as well as savoury snacks (p = 0.002), sweets (p = 0.009) and sweetened fizzy drinks (p < 0.001). Girls however, consumed more low-fat foodstuffs compared to boys (p = 0.003). Over- weight was more common in boys than girls (26% vs 9%, p = 0.003), whereas girls were more frequently malnourished than boys (21% vs 7%, p = 0.016). Far fewer girls were satisfied with their body shape compared to boys (51% vs 94%, p < 0.001). Girls also more commonly expressed a desire for slimming, despite either having a correct body mass or being underweight. CONCLUSIONS: Many adverse and abnormal eating habits of pupils were found, especially in boys, that could lead to over- weight and obesity. Subjects were found to incorrectly assess their body shape, particularly the girls, thereby leading to unwarranted slimming behaviour. KEY WORDS: nutritional habits, middle-school pupils, perceived body shape/image. PMID- 25526580 TI - Eating behaviours of middle- and secondary-school pupils from the upper Silesian region in Poland. AB - BACKGROUND: Eating behaviours of school-aged youth condition their emotional and psychophysical development. Moreover, they influence the effectiveness of learning and affect one's health and the quality of life at older age. OBJECTIVE: The objective of the study was the evaluation of eating behaviours of the group of pupils from cities of the Upper Silesian region, as well as the identification of differences between middle-school and secondary-school pupils' eating behaviours. MATERIALS AND METHODS: 902 pupils (474 middle-school and 428 secondary-school pupils) participated in the study. The research materials included questionnaires prepared by the author of the study, containing the questions about the pupils' eating habits. RESULTS: The middle-school pupils constituted 52.5% of the 902 pupils and the secondary-school pupils were 47.5% of the total. On average, 38.2% of the pupils consumed 4 meals daily. Wholemeal bread and/or groats were eaten daily by 34.4% of the pupils. Milk and/or milk drinks were consumed by 56.3% of the pupils every day and 33.5% of the respondents had also fermented milk drinks daily. 61.3% of the participants declared eating meat at least once a day and 44.9% of the pupils had fish once or twice a week. Vegetables and fruit were eaten daily by 61.4% and 66.6% of the pupils respectively. Sweets were consumed at least once a day by 50.6% of the pupils. Occasional consumption of fast-food products and ready-made meals was declared by 63.9% and 49.7% of the pupils respectively. CONCLUSIONS: Eating behaviours of the discussed group of pupils are mostly incorrect. There were differences found between the middle-school and secondary-school pupils' eating habits. The differences concerned the frequency of eating cheese and curd cheese, fruit, leguminous plant seeds, sweets, fast food products, sweetened drinks and ready-to made food products. KEY WORDS: eating behaviours, eating habits, eating frequency, pupils. PMID- 25526581 TI - Relationship between the intake of energy and basic nutrients and the BMI values in group of children aged 10-12. AB - BACKGROUND: According to the WHO data in January 2007, 14 million children were overweight in the countries of the European Union. The problem of childhood obesity should be considered as one of the biggest challenges facing twenty- first century nutrition and pediatrics. OBJECTIVE: The aim of this study was to show the correlation between energy, basic nutrients intake and BMI of school children aged 10-12 years, using Pearson's correlation coefficient. MATERIALS AND METHODS: 169 pupils (69 from Krakow and 100 from Skawina), aged 10-12, participated in these studies. The studies were approved by the Board of Education, school principals and the parents. On the basis of measurements of weight and height, body mass index (BMI) was calculated. 24 h dietary recalls were collected in the spring and autumn of 2006, for 4 selected days per week. RESULTS: Intake of energy, total carbohydrate and fat did not met requirements, but intake of protein was too high. Proper weight, based on BMI values in the population aged 10-12, were found in 74.9% of boys and 81.2% of girls. Deficiencies in body weight occurred in 4.2% and 3.4%, overweight in 15.6% and 10.0% while obesity in 5.3% and 5.4% of respondents. CONCLUSIONS: Inverse correlation was found between the implementation of standards for energy and BMI values of children. It was observed positive correlation between the consumption of total and animal protein and BMI value. KEY WORDS: children, underweight, obesity, BMI, nutrients, nutrition, Pearson's correlation coefficient. PMID- 25526582 TI - Assessment of physical activity, energy expenditure and energy intakes of young men practicing aerobic sports. AB - BACKGROUND: Adequate nutrition and energy intake play key rule during the training period and recovery time. The assessment of athlete's energetic needs should be calculated individually, based on personal energy expenditure and Sense Wear PRO3 Armband (SWA) mobile monitor is a useful tool to achieve this goal. However, there is still few studies conducted with use of this monitor. OBJECTIVES: To assess individual energy needs of athletes by use of SWA and to determine whether their energy intake fulfils the body's energy expenditure. MATERIALS AND METHODS: Subjects were 15 male students attending Military University of Technology in Warsaw, aged 19-24 years, practicing aerobic. The average body mass was 80.7 +/- 7.7 kg and average height was 186.9 +/- 5.2 cm, (BMI 23.09 +/- 1.85 kg/m2). Assessment of physical activity and energy expenditure (TEE) was established using SWA, which was placed on the back side of dominant hand and worn continuously for 48 hours (during the training and non training day). The presented results are the average values of these 2 days. Assessment of athletes' physical activity level was established by use of metabolic equivalent of task (MET) and number of steps (NS). Estimation of energy intake was based on three-day dietary recalls (two weekdays and one day of the weekend), evaluated using the Polish Software 'Energia' package. RESULTS: The average TEE of examined athletes was 3877 +/- 508 kcal/day and almost half of this energy was spend on physical activity (1898 +/- 634 kcal/day). The number of steps was on average 19498 +/- 5407 and average MET was 2.05 +/- 2.09. The average daily energy intake was 2727 +/- 576 kcal. CONCLUSIONS: Athletes consumed inadequate amount of energy in comparison to their energy expenditure. Examined group did not have an adequate knowledge about their energy requirement, which shows the need of nutritional consulting and education among these athletes. KEY WORDS: athletes, aerobic sports, energy expenditure, energy intake. PMID- 25526583 TI - Effect of adaptation process of Pseudomonas aeruginosa to didecyldimethylammonium chloride in 2-propanol on bactericidal efficiency of this active substance. AB - BACKGROUND: Microorganisms are characterized by two types of resistance innate and acquired. Innate resistance is associated with the construction of the surface structures. Wide use of active substances as antimicrobial compounds, especially in inhibitory concentrations, may promote the acquisition of bacterial resistance to these substances in the process of adaptation. OBJECTIVE: The aim of the study was to determine changes in efficiency of didecyldimethylammonium chloride in 2-propanol (CMAP) against the Pseudomonas aeruginosa strains, which were adapted to this active substance. MATERIALS AND METHODS: Adaptation studies were conducted using two strains: P. aeruginosa ATCC 15442 (PA), which is used in estimation of biocide efficiency and tetracycline-resistant P. aeruginosa ATCC 47085 (PAO-LAC) strain. These strains were adapted to the active substance Bardac22: 50% v/v didecyldimethylammonium chloride in 20% v/v 2-propanol (CMAP) according to the National Institute of Hygiene procedure. After adaptation, obtained isolates were classified to three groups and passaged to solid media: A strains unadapted passaged onto slant medium without active substance, control group; B - strains with adaptive resistance passaged onto slant medium with 375 mg/l CMAP; C - strains with adaptive resistance passaged onto slant medium without CMAP. Changes in susceptibility of examined strains were determined on the basis of minimum inhibitory concentrations (MICs) by broth dilution method. The minimum bactericidal concentrations (MBCs) were determined by subculture P. aeruginosa strains on solid media without CMAP. The efficiency of CMAP against isolates obtained after adaptation processes was evaluated by using phenol coefficient (PC). RESULTS: There were no differences in the adaptation process between two strains of P. aeruginosa: PA and PAO-LAC. Both isolates obtained after the adaptation process was characterized by approximately 6-8 fold higher MICs compared to the MICs of these strains before the adaptation. Strains passaged to a solid media characterized a variable sensitivity to CMAP. As compared to a control group A, the isolates of PA and PAO-LAC from group B and isolate PA from group C exhibited the highest and stable insensitivity (MIC from > 700 to >1000 mg/l) to 48-49 passages. Isolates from group C of PAO-LAC maintained insusceptibility up to 20th passage (MIC >375 mg/l). There were no statistically significant changes in the CMAP bactericidal efficacy against isolates of reduced sensitivity. CONCLUSIONS: Adaptation of P. aeruginosa strains to didecyldimethylammonium chloride in 2-propanol does not significantly change bactericidal efficacy of this active substance against isolates with reduced sensitivity. Antibiotic-resistant strain PAO-LAC showed a similar adaptability and a similar sensitivity to the CMAP as a strain PA used to assess the effectiveness of disinfectants. KEY WORDS: adaptation process, Pseudomonas aeruginosa, quaternary ammonium compounds, bactericidal efficiency. PMID- 25526584 TI - Biomechanical Comparison of Perpendicular Versus Oblique In Situ Screw Fixation of Slipped Capital Femoral Epiphysis. AB - BACKGROUND: Percutaneous in situ single screw fixation is the preferred treatment for stable and unstable slipped capital femoral epiphysis (SCFE). The recommended screw placement is in the center of the epiphysis and perpendicular to the physis, which necessitates an anterior starting point for most SCFEs. A recent clinical study has shown good clinical results with a laterally based screw for SCFE, which is oblique to the physis. We sought to biomechanically compare these 2 techniques for load to failure and hypothesized that the laterally based oblique screw is equivalent or superior to an anteriorly based perpendicular screw. METHODS: Twenty-two paired immature porcine femurs were used to compare the techniques. A SCFE model was created in all femurs using a previously published technique by performing a 30-degree posterior closing wedge osteotomy through the proximal physis. In the control group, a screw was placed perpendicular to the slip with an anterior starting point. In the experimental group, the screw was started as close to the mid-lateral cortex of the proximal femur as possible while maintaining the screw anterior to the posterior cortex of the femoral neck and ending at the apex of the epiphysis ignoring the resultant angle to the physis for the experimental group. The specimens were then potted and loaded in a physiologically relevant posteroinferior direction (30 degrees posterior from vertical) to determine load to failure (N) and stiffness (N/mm). RESULTS: No statistical difference was found between the 2 groups in maximum load to failure or stiffness (P>0.05). CONCLUSIONS: A laterally based screw oblique to the physis for in situ fixation in mild SCFE is not significantly different than an anteriorly based screw perpendicular to the physis in load to failure and stiffness in our study model. CLINICAL RELEVANCE: In light of no difference in load to failure of these 2 constructs, surgeons may be more comfortable with the traditional lateral entry point while still aiming for screw placement in the center of head. PMID- 25526586 TI - Recalling our "why". PMID- 25526585 TI - Biodegradable nasal packings for endoscopic sinonasal surgery: a systematic review and meta-analysis. AB - OBJECTIVES: To assess biodegradable nasal packing effectiveness for improving postoperative symptoms and mucosal healing after endoscopic sinonasal surgery as compared with conventional/non-packing groups. METHODS: Relevant articles were searched on PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. We included randomized controlled trials (RCTs) that compared biodegradable packings with conventional packings or no packing, reporting postoperative symptoms and/or mucosal healing outcomes. RESULTS: This review included 19 studies, of which 11 compared biodegradable packings with conventional packings. Meta-analysis found that biodegradable packings significantly improved postoperative symptoms: bleeding at removal, pain at removal, pain in situ, and nasal blockage. Mucosal healing outcomes were inconsistent within studies, with no data could be pooled. Eight studies compared biodegradable packings with non-packing group. Postoperative symptom data in this comparison could not be pooled: A protective or equal effect on postoperative bleeding was reported in different studies; no difference was reported in pain status and nasal blockage. As for mucosal healing, meta-analysis showed that two arms of comparison had similar effect on synechiae, edema, infection and granulation at each time point. CONCLUSION: The limiting evidence suggests that biodegradable nasal packings are statistically better than conventional packings in postoperative symptoms, and probably comparable to non-packing group, as in this comparison we could not carry out meta-analysis. No beneficial or detrimental effect on postoperative mucosal healing could be determined based on existing evidence. PMID- 25526587 TI - Safety evaluation of freehand lateral mass screw fixation in the subaxial cervical spine: evaluation of 1256 screws. AB - STUDY DESIGN: Prospective study. OBJECTIVE: To evaluate the safety of the lateral mass screw (LMS) fixation. SUMMARY OF BACKGROUND DATA: LMS fixation has been known to have risk of injury to vertebral artery, nerve root, or facet joints. METHODS: A consecutive series of 178 patients undergoing planned LMS fixation were studied. Screw fixation was performed using the freehand technique. Entry point of screws was 2-mm medial from the center of the lateral mass. Planned divergent angle of the screw was 30o. Bicortical fixation was tried in all cases. After the surgery, all patients underwent 3-dimensional computed tomographic scan of the cervical spine. We checked the number of screws in each level, divergent angle of the screws, and violation of foramen transversarium (FT), intervertebral foramen, or facet joint by screws. A reliability test was performed. RESULTS: Total 1256 screws were fixed with 269 at C3, 318 at C4, 331 at C5, and 338 screws at C6. Mean divergent angle of the screws were 34.7o/33.1o at C3, 33.9 o/32.1o at C4, 34.7o/32.7o at C5, and 33.6o/30.7o at C6. Incidence of FT violation was 0.876%. FT violation was most common at C6 (6/11 violations). Mean divergent angle in cases of FT violation was 15.0o and was significantly smaller than that of safe cases. There was no injury to vertebral artery. There was no violation of intervertebral foramen. Incidence of facet violation was 1.433%. Seventeen facet violations were within fusion segment. Only 1 screw violated healthy facet. Facet violation was most common at C3 (12/18 violations). CONCLUSION: LMS fixation is a safe stabilizing technique with very low incidence of violation of FT, intervertebral foramen, and facet. There is a possibility of FT violation if the divergent angle was small. FT violation was most common at C6. Facet violation was most common at C3. PMID- 25526588 TI - Posterior correction and fusion surgery using pedicle-screw constructs for Lenke type 5C adolescent idiopathic scoliosis: a preliminary report. AB - STUDY DESIGN: A retrospective case series. OBJECTIVE: To assess whether a short fusion strategy is applicable when treating adolescent idiopathic scoliosis with Lenke type 5C curve by posterior correction and fusion surgery using pedicle screw constructs. SUMMARY OF BACKGROUND DATA: Previous studies have discussed the selection of the lower instrumented vertebra to best preserve motion segments and obtain coronal balance. However, reports evaluating the selection of the upper instrumented vertebra when treating Lenke type 5C curves are not available. METHODS: We evaluated 29 patients who were treated surgically for adolescent idiopathic scoliosis with Lenke type 5C curve (mean age, 16.8 +/- 4.7 yr; range, 10-29 yr). The mean follow-up period was 28.0 +/- 6.3 months (range, 24-48 mo). We compared radiographical parameters and clinical outcomes between patients with an upper instrumented vertebra at the end vertebra (EV) (n = 10) and those treated by short fusion (S group), with a upper instrumented vertebra 1-level caudal to the EV (n = 19 patients). RESULTS: In the EV group, a preoperative mean Cobb angle of 50 degrees +/- 15 degrees was corrected to 8 degrees +/- 7 degrees , which was maintained at the final follow-up (7 degrees +/- 1 degrees ). In the S group, a mean preoperative Cobb angle of 47 degrees +/- 4 degrees was corrected to 8 degrees +/- 5 degrees , but this increased significantly to 12 degrees +/- 7 degrees at final follow-up (P = 0.033). The mean correction rate at final follow-up was significantly lower in the S group (72%) than in the EV group (86%) (P = 0.027). Coronal and sagittal balance, thoracic kyphosis, lumbar lordosis, L4 tilt, and clinical outcomes evaluated by Scoliosis Research Society patient questionnaire-22 were equivalent between the 2 groups. CONCLUSION: Scoliosis Research Society patient questionnaire-22 scores and radiographical parameters other than the correction rate were equivalent between the 2 groups. A short fusion strategy, in which the upper instrumented vertebra is 1-level caudal to the upper EV, is applicable to posterior correction and fusion surgery with pedicle-screw constructs for Lenke type 5C curves. PMID- 25526589 TI - The impact of obesity on short- and long-term outcomes after lumbar fusion. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To compare short- and long term outcomes in obese versus nonobese patients undergoing instrumented posterolateral fusion of the lumbar spine. SUMMARY OF BACKGROUND DATA: Obesity is an important public health issue due to the negative effects on quality of life. Some studies have shown an association between obesity and higher rates of complications and unfavorable outcomes after spine surgery. METHODS: We retrospectively reviewed medical records for all adult patients undergoing 1- to 3-level posterolateral fusion for degenerative spine disease between 1992 and 2012 at a single institution. Patients were divided into obese (body mass index > 30 kg/m) and nonobese cohorts to compare complications, reoperation rates, and symptom resolution at the last follow-up. A regression model was used to estimate relative risk ratios. RESULTS: During the study period, 732 patients underwent lumbar fusion, with 662 (90.44%) nonobese patients and 70 (9.56%) obese patients in the cohort. Obese patients had significantly higher blood loss intraoperatively (P = 0.002) and a longer average length of stay (P = 0.022). Moreover, obesity was independently associated with a significantly increased risk of developing a postoperative complication (risk ratio 2.14; 95% confidence interval, 1.10-4.16) and surgical site infection (risk ratio 3.11; 95% confidence interval, 1.48-6.52). At the last follow-up, a higher proportion of obese patients had radiculopathy (P = 0.018), motor deficits (P = 0.006), sensory deficits (P = 0.008), and bowel or bladder dysfunction (P = 0.006) than nonobese patients. CONCLUSION: In this study, obese patients undergoing lumbar fusion had higher blood loss, longer lengths of stay, higher complication rates, and worse functional outcomes at the last follow-up than nonobese patients. These findings suggest that both surgeons and patients should acknowledge the significantly increased morbidity profile of obese patients after lumbar fusion. PMID- 25526592 TI - Rapid and accurate detection of urinary pathogens by mobile IMS-based electronic nose: a proof-of-principle study. AB - Urinary tract infection (UTI) is a common disease with significant morbidity and economic burden, accounting for a significant part of the workload in clinical microbiology laboratories. Current clinical chemisty point-of-care diagnostics rely on imperfect dipstick analysis which only provides indirect and insensitive evidence of urinary bacterial pathogens. An electronic nose (eNose) is a handheld device mimicking mammalian olfaction that potentially offers affordable and rapid analysis of samples without preparation at athmospheric pressure. In this study we demonstrate the applicability of ion mobility spectrometry (IMS) -based eNose to discriminate the most common UTI pathogens from gaseous headspace of culture plates rapidly and without sample preparation. We gathered a total of 101 culture samples containing four most common UTI bacteries: E. coli, S. saprophyticus, E. faecalis, Klebsiella spp and sterile culture plates. The samples were analyzed using ChemPro 100i device, consisting of IMS cell and six semiconductor sensors. Data analysis was conducted by linear discriminant analysis (LDA) and logistic regression (LR). The results were validated by leave-one-out and 5-fold cross validation analysis. In discrimination of sterile and bacterial samples sensitivity of 95% and specificity of 97% were achieved. The bacterial species were identified with sensitivity of 95% and specificity of 96% using eNose as compared to urine bacterial cultures. IN CONCLUSION: These findings strongly demonstrate the ability of our eNose to discriminate bacterial cultures and provides a proof of principle to use this method in urinanalysis of UTI. PMID- 25526594 TI - Vitamin retention in eight fruits and vegetables: a comparison of refrigerated and frozen storage. AB - Four vitamins were analyzed in several fruit and vegetable commodities to evaluate the differences between fresh and frozen produce. Ascorbic acid, riboflavin, alpha-tocopherol, and beta-carotene were evaluated in corn, carrots, broccoli, spinach, peas, green beans, strawberries, and blueberries. Samples of each commodity were harvested, processed, and analyzed for nutrient content at three storage times per treatment. Ascorbic acid showed no significant difference for five of the eight commodities and was higher in frozen samples than fresh for the remaining three commodities. Apart from broccoli and peas, which were higher and lower in frozen vs fresh samples, respectively, none of the commodities showed significant differences with respect to riboflavin content. Three commodities had higher levels of alpha-tocopherol in the frozen samples, while the remaining commodities showed no significant difference between fresh and frozen. beta-Carotene was not found in significant amounts in blueberries, strawberries, and corn. Peas, carrots, and spinach were lower in beta-carotene in the frozen samples, while green beans and spinach showed no significant difference between the two storage methods. Overall, the vitamin content of the frozen commodities was comparable to and occasionally higher than that of their fresh counterparts. beta-Carotene, however, was found to decrease drastically in some commodities. PMID- 25526593 TI - Dexpramipexole is ineffective in two models of ALS related neurodegeneration. AB - Treatment options for people living with amyotrophic lateral sclerosis (ALS) are limited and ineffective. Recently, dexpramipexole (RPPX) was advanced into human ALS clinical trials. In the current studies, we investigated RPPX in two parallel screening systems: 1) appropriately powered, sibling-matched, gender-balanced survival efficacy screening in high-copy B6-SJL-SOD1G93A/Gur1 mice, and 2) high content neuronal survival screening in primary rat cortical neurons transfected with wild-type human TDP43 or mutant human TDP43. In both cases, we exposed the test systems to RPPX levels approximating those achieved in human Phase II clinical investigations. In SOD1G93A mice, no effect was observed on neuromotor disease progression or survival. In primary cortical neurons transfected with either mutant or wild-type human TDP43, a marginally significant improvement in a single indicator of neuronal survival was observed, and only at the 10 uM RPPX treatment. These systems reflect both mutant SOD1- and TDP43-mediated forms of neurodegeneration. The systems also reflect both complex non-cell autonomous and neuronal cell autonomous disease mechanisms. The results of these experiments, taken in context with results produced by other molecules tested in both screening systems, do not argue positively for further study of RPPX in ALS. PMID- 25526596 TI - Impulsive approach tendencies towards physical activity and sedentary behaviors, but not reflective intentions, prospectively predict non-exercise activity thermogenesis. AB - Understanding the determinants of non-exercise activity thermogenesis (NEAT) is crucial, given its extensive health benefits. Some scholars have assumed that a proneness to react differently to environmental cues promoting sedentary versus active behaviors could be responsible for inter-individual differences in NEAT. In line with this reflection and grounded on the Reflective-Impulsive Model, we test the assumption that impulsive processes related to sedentary and physical activity behaviors can prospectively predict NEAT, operationalized as spontaneous effort exerted to maintain low intensity muscle contractions within the release phases of an intermittent maximal isometric contraction task. Participants (n = 91) completed a questionnaire assessing their intentions to adopt physical activity behaviors and a manikin task to assess impulsive approach tendencies towards physical activity behaviors (IAPA) and sedentary behaviors (IASB). Participants were then instructed to perform a maximal handgrip strength task and an intermittent maximal isometric contraction task. As hypothesized, multilevel regression analyses revealed that spontaneous effort was (a) positively predicted by IAPA, (b) negatively predicted by IASB, and (c) was not predicted by physical activity intentions, after controlling for some confounding variables such as age, sex, usual PA level and average force provided during the maximal contraction phases of the task. These effects remained constant throughout all the phases of the task. This study demonstrated that impulsive processes may play a unique role in predicting spontaneous physical activity behaviors. Theoretically, this finding reinforces the utility of a motivational approach based on dual-process models to explain inter-individual differences in NEAT. Implications for health behavior theories and behavior change interventions are outlined. PMID- 25526597 TI - Effects of cognitive bias modification training on neural alcohol cue reactivity in alcohol dependence. AB - OBJECTIVE: In alcohol-dependent patients, alcohol cues evoke increased activation in mesolimbic brain areas, such as the nucleus accumbens and the amygdala. Moreover, patients show an alcohol approach bias, a tendency to more quickly approach than avoid alcohol cues. Cognitive bias modification training, which aims to retrain approach biases, has been shown to reduce alcohol craving and relapse rates. The authors investigated effects of this training on cue reactivity in alcohol-dependent patients. METHOD: In a double-blind randomized design, 32 abstinent alcohol-dependent patients received either bias modification training or sham training. Both trainings consisted of six sessions of the joystick approach-avoidance task; the bias modification training entailed pushing away 90% of alcohol cues and 10% of soft drink cues, whereas this ratio was 50/50 in the sham training. Alcohol cue reactivity was measured with functional MRI before and after training. RESULTS: Before training, alcohol cue-evoked activation was observed in the amygdala bilaterally, as well as in the right nucleus accumbens, although here it fell short of significance. Activation in the amygdala correlated with craving and arousal ratings of alcohol stimuli; correlations in the nucleus accumbens again fell short of significance. After training, the bias modification group showed greater reductions in cue-evoked activation in the amygdala bilaterally and in behavioral arousal ratings of alcohol pictures, compared with the sham training group. Decreases in right amygdala activity correlated with decreases in craving in the bias modification but not the sham training group. CONCLUSIONS: These findings provide evidence that cognitive bias modification affects alcohol cue-induced mesolimbic brain activity. Reductions in neural reactivity may be a key underlying mechanism of the therapeutic effectiveness of this training. PMID- 25526595 TI - Ion mobility-mass spectrometry: time-dispersive instrumentation. PMID- 25526598 TI - Reward-based spatial learning in unmedicated adults with obsessive-compulsive disorder. AB - OBJECTIVE: The authors assessed the functioning of mesolimbic and striatal areas involved in reward-based spatial learning in unmedicated adults with obsessive compulsive disorder (OCD). METHOD: Functional MRI blood-oxygen-level-dependent response was compared in 33 unmedicated adults with OCD and 33 healthy, age matched comparison subjects during a reward-based learning task that required learning to use extramaze cues to navigate a virtual eight-arm radial maze to find hidden rewards. The groups were compared in their patterns of brain activation associated with reward-based spatial learning versus a control condition in which rewards were unexpected because they were allotted pseudorandomly to experimentally prevent learning. RESULTS: Both groups learned to navigate the maze to find hidden rewards, but group differences in neural activity during navigation and reward processing were detected in mesolimbic and striatal areas. During navigation, the OCD group, unlike the healthy comparison group, exhibited activation in the left posterior hippocampus. Unlike healthy subjects, participants in the OCD group did not show activation in the left ventral putamen and amygdala when anticipating rewards or in the left hippocampus, amygdala, and ventral putamen when receiving unexpected rewards (control condition). Signal in these regions decreased relative to baseline during unexpected reward receipt among those in the OCD group, and the degree of activation was inversely associated with doubt/checking symptoms. CONCLUSIONS: Participants in the OCD group displayed abnormal recruitment of mesolimbic and ventral striatal circuitry during reward-based spatial learning. Whereas healthy comparison subjects exhibited activation in this circuitry in response to the violation of reward expectations, unmedicated OCD participants did not and instead over-relied on the posterior hippocampus during learning. Thus, dopaminergic innervation of reward circuitry may be altered, and future study of anterior/posterior hippocampal dysfunction in OCD is warranted. PMID- 25526599 TI - Developmental change in amygdala reactivity during adolescence: effects of family history of depression and stressful life events. AB - OBJECTIVE: Although heightened amygdala reactivity is observed in patients with major depression, two critical gaps in our knowledge remain. First, it is unclear whether heightened amygdala reactivity is a premorbid vulnerability or a consequence of the disorder. Second, it is unknown how and when this neural phenotype develops. The authors sought to address these gaps by evaluating developmental change in threat-related amygdala reactivity in adolescents at high or low risk for depression based on family history, before onset of disorder. METHOD: At baseline and again 2 years later, adolescents (initially 11-15 years of age) participated in a functional MRI paradigm that elicited threat-related amygdala reactivity. After quality control, data were available for 232 adolescents at wave 1 and 197 adolescents at wave 2; longitudinal data meeting quality control at both waves were available for 157 of these participants. Change in amygdala reactivity was assessed as a function of family history of depression and severity of stressful life events. RESULTS: Threat-related amygdala reactivity increased with age in participants with a positive family history regardless of the severity of life stress reported, and it increased in adolescents with a negative family history who reported relatively severe life stress. These changes in amygdala reactivity with age occurred in the absence of clinical disorder or increases in depressive symptoms. CONCLUSIONS: These results suggest that heightened amygdala reactivity emerges during adolescence, prior to the development of depression, as a function of familial risk or, in the absence of familial risk, stressful life events. PMID- 25526605 TI - Secondary plastic closure of gastroschisis is associated with a lower incidence of mechanical ventilation. AB - INTRODUCTION: Nonsurgical closure after primary silo placement, secondary plastic closure (SPC), has been used as an alternative to secondary surgical closure (SSC) in gastroschisis. The benefits described were closure without formal surgical procedure, cosmetic aspect, and minimization of intra-abdominal pressures. This study compared requirements for mechanical ventilation and general anesthesia, nutritional care, and outcomes between SPC and SSC. PATIENTS AND METHODS: We included patients with primary staged-silo reduction with a 1 year minimum follow-up. SPC was performed at bedside with sedation using a nonadherent dressing. SSC was performed in operating room under general anesthesia using standard surgical techniques. RESULTS: This retrospective study included 64 patients, 23 SPC and 41 SSC. The characteristics of the two groups were comparable. Mechanical ventilation was used for 15 SPC and 41 SSC (p=0.0001) with a comparable median duration (5.5 and 6.0 days, not significant [NS]). General anesthesia was required for 9 SPC and 41 SSC (p<0.0001). Complications included one SPC and six SSC with necrotizing enterocolitis, zero SPC and four SSC with intestinal atresia, two SPC and four SSC with small bowel obstruction, zero SPC and one SSC with abdominal compartment syndrome resulting in a short bowel syndrome (NS). Median duration of parenteral nutrition (30 and 27 days), time to first feeds (14 and 14 days), time at or above minimal enteral feeding (22 and 17 days), time to full feeds (31 and 28 days), length of stay (LOS) in neonatal intensive care unit (24 and 23.5 days) and overall hospital LOS (37 and 36 days) were not statistically different between SPC and SSC patients without complications, respectively. These data were comparable for SPC and SSC patients with complications. Five SPC and six SSC developed an umbilical hernia (NS); two patients in each group required a surgical repair (NS). CONCLUSION: Plastic closure of gastroschisis after primary silo reduction is simple, safe, reproducible, and associated with a significant lower incidence of mechanical ventilation. Nutritional management and length of hospital stay were similar to conventional surgical closure for patients. Plastic closure allows nonoperative management without general anesthesia at patient's bedside, in comparison with surgical closure that must be performed under general anesthesia in the operating room. Plastic closure does not appear to be associated with more umbilical hernias in this retrospective study. PMID- 25526601 TI - Frequency of vascular and pregnancy morbidity in patients with low vs. moderate to-high titers of antiphospholipid antibodies. AB - Antiphospholipid syndrome (APLS) is an autoimmune hypercoagulable syndrome characterized by thrombotic and obstetric manifestations. We sought to determine the rate of APLS feature in patients tested positive for antiphospholipid antibodies (APLA) regardless of the serum level of anticardiolipin (ACL) and/or anti-beta2-glycoprotein I (beta2GPI) antibodies. An inception cohort of individuals who were tested positive for ACL and/or beta2GPI IgG/IgM antibody, and/or lupus anticoagulant (LAC) on two occasions of at least 12 weeks apart. A total of 243 patients were included; their mean age was 40.1 +/- 15.9 years. Thrombotic vascular events occurred in 118 patients (48.5%) of the entire cohort, of which 62 patients (25.5%) suffered from an arterial event and 56 patients (23%) from thrombotic venous events. Obstetrical morbidity occurred in 106 female patients (43.6%). In our cohort, we found no difference in the frequency of thrombotic or obstetric manifestations of APLS between patients with ACL IgG/IgM of low serum antibody level (<40 U) and medium-to-high level (>=40 U) and/or anti beta2GPI IgG, IgM higher than the 99th percentile vs. lower (>20 U). We suggest that in 'real life' the diagnosis of APLS should not be excluded because of low titer of APLA. PMID- 25526600 TI - Functional neuroimaging of avoidance habits in obsessive-compulsive disorder. AB - OBJECTIVE: The purpose of this study was to determine the neural correlates of excessive habit formation in obsessive-compulsive disorder (OCD). The authors aimed to test for neurobiological convergence with the known pathophysiology of OCD and to infer, based on abnormalities in brain activation, whether these habits arise from dysfunction in the goal-directed or habit system. METHOD: Thirty-seven OCD patients and 33 healthy comparison subjects learned to avoid shocks while undergoing a functional MRI scan. Following four blocks of training, the authors tested whether the avoidance response had become a habit by removing the threat of shock and measuring continued avoidance. Task-related differences in brain activity in three regions of interest (the caudate, the putamen, and the medial orbitofrontal cortex) were tested at a statistical threshold set at <0.05 (family-wise-error corrected). RESULTS: Excessive habit formation in OCD patients, which was associated with hyperactivation in the caudate, was observed. Activation in this region was also associated with subjective ratings of increased urge to perform habits. The OCD group, as a whole, showed hyperactivation in the medial orbitofrontal cortex during the acquisition of avoidance; however, this did not relate directly to habit formation. CONCLUSIONS: OCD patients exhibited excessive habits that were associated with hyperactivation in a key region implicated in the pathophysiology of OCD, the caudate nucleus. Previous studies indicate that this region is important for goal-directed behavior, suggesting that habit-forming biases in OCD may be a result of impairments in this system, rather than differences in the buildup of stimulus response habits themselves. PMID- 25526606 TI - Risk factors for the recurrence of the congenital diaphragmatic hernia-report from the long-term follow-up study of Japanese CDH study group. AB - AIM OF THE STUDY: Few follow-up studies focused on the recurrence regarding the postoperative course of congenital diaphragmatic hernia (CDH) survivors. The aim of this study was to report on risk factor for CDH patients who had the recurrence during the follow-up. MATERIALS AND METHODS: A multicenter retrospective survey was conducted on neonates diagnosed to have CDH between January 2006 and December 2010. Follow-up survey was conducted between September 2013 and October 2013 (ethical approval: No. 25-222). Nine institutions agreed to participate in this survey. Out of 228, 182 (79.8%) patients were alive and 180 patients were included in this study. Two patients were excluded because the defect had not repaired at the primary operation. The patients were divided into the recurrence group (n=21) and the nonrecurrence group (n=159). Postnatal and postoperative variables were compared between these two groups. Baseline variables which showed significance in univariate analysis were entered into multiple logistic regression analysis for analyzing the recurrence. A value of p<0.05 was considered to be statistically significant by using the JMP software program (version 9; SAS Institute, Inc, Cary, North Carolina, United States). MAIN RESULTS: Out of 180, 21 (11.7%) CDH neonates had the recurrence during the course of the follow-up. Five (2.8%) patients had the recurrence before primary discharge and 16 (8.9%) patients had the recurrence after discharge. Univariate analysis showed that liver herniation (crude odds ratio [OR], 7.4; 95% confidence interval [CI], 2.73-23.68), defect size C and D, proposed by the CDH Study Group (crude OR, 7.09; 95% CI, 2.73-19.99) and patch repair (crude OR, 5.00; 95% CI, 1.91-14.70) were risk factors. Multivariate logistic regression analysis showed liver herniation (adjusted OR, 3.96; 95% CI, 1.01-16.92) was the risk factor for the recurrence. CONCLUSION: A wide spectrum of the disease severity and the rarity of the disease mask the risk of the recurrence for CDH patients. This study showed the only factor to predict the recurrence was the liver herniation. These data will be helpful for providing information for the long-term follow-up of the CDH patients. PMID- 25526607 TI - Clinical negligence claims in pediatric surgery in England: pattern and trends. AB - AIMS OF THE STUDY: We hypothesized that there has been an increase in the number of successful litigation claims in pediatric surgery in England. Our aim was to report the incidence, causes, and costs of clinical negligence claims against the National Health Service (NHS) in relation to pediatric surgery. MATERIALS AND METHODS: We queried the NHS Litigation Authority (NHSLA) on litigation claims among children undergoing pediatric surgery in England (2004-2012). We decided a priori to only examine closed cases (decision and payment made). Data included year of claim, year of payment of claim, payment per claim, paid-to-closed ratio, and severity of outcome of clinical incident. RESULTS: Out of 112 clinical negligence claims in pediatric surgery, 93 (83%) were finalized-73 (65%) were settled and damages paid to the claimant and 20 (18%) were closed with no payment, and 19 (17%) remain open. The median payment was L13,537 (600-500,000) and median total cost borne by NHSLA was L31,445 (600-730,202). Claims were lodged at a median interval of 2 (0-13) years from time of occurrence with 55 (75%) cases being settled within the 3 years of being received. The commonest reasons for claims were postoperative complications (n=20, 28%), delayed treatment (n=16, 22%), and/or diagnosis (n=14, 19%). Out of 73, 17 (23%) closed claims resulted in case fatality. Conclusion: Two-thirds of all claims in pediatric surgery resulted in payment to claimant, and the commonest reasons for claims were postoperative complications, delayed treatment, and/or diagnosis. Nearly a quarter of successful claims were in cases where negligence resulted in case fatality. Pediatric surgeons should be aware of common diagnostic and treatment shortfalls as high-risk areas of increased susceptibility to clinical negligence claims. PMID- 25526608 TI - Interventions for melanoma in situ, including lentigo maligna. AB - BACKGROUND: Malignant melanoma is a form of skin cancer associated with significant mortality once it has spread beyond the skin. Melanoma in situ (MIS) is the earliest histologically recognisable stage of malignant melanoma and represents a precursor of invasive melanoma. Lentigo maligna (LM) represents a subtype of pre-invasive intraepidermal melanoma associated specifically with chronic exposure to ultraviolet (UV) radiation. Over the past two decades, the incidence of MIS has increased significantly, even more than the invasive counterpart. There are several treatment options for MIS, but no consensus exists on the best therapeutic management of this condition. OBJECTIVES: To assess the effects of all available interventions, surgical and non-surgical, for the treatment of melanoma in situ, including LM. SEARCH METHODS: We searched the following databases up to November 2014: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2014, Issue 10), MEDLINE (from 1946), Embase (from 1974), LILACS (from 1982), African Index Medicus (from inception), IndeMED of India (from inception), and Index Medicus for the South-East Asia Region (IMSEAR) (from inception). We scanned the references of included and excluded studies for further references to relevant trials and searched five trials registries. We checked the abstracts of major dermatology and oncology conference proceedings, and we shared our lists of included and excluded studies with industry contacts and other experts in the field of melanoma to try to identify further relevant trials. SELECTION CRITERIA: We included randomised controlled trials (RCT) on the management of MIS, including LM, that compared any intervention to placebo or active treatment. We included individuals, irrespective of age and sex, diagnosed with MIS, including LM, based on histological examination. DATA COLLECTION AND ANALYSIS: Two authors independently evaluated possible studies for inclusion; extracted data from the included study using a standard data extraction form modified for our review; assessed risk of bias; and analysed data on efficacy, safety, and tolerability. They resolved any disagreements by discussion with a third author. We collected adverse effects information from included studies. MAIN RESULTS: Our search identified only 1 study eligible for inclusion (and 1 ongoing study in active recruitment stage), which was a single centre, open label, parallel group, 2-arm RCT with 90 participants, who had 91 histologically proven LM lesions.Forty-four participants, with 44 LM lesions, were treated with imiquimod 5% cream 5 days per week plus tazarotene 0.1% gel 2 days/week for 3 months, and 46 participants, with 47 LM lesions, were treated with imiquimod 5% cream 5 days per week for 3 months. Two months after cessation of topical treatment, the initial tumour footprint was excised using 2 mm margins via a staged excision. This study was open label, and analysis was not intention-to-treat, leading to a high risk of incomplete outcome data.Our primary outcome 'Histological or clinical complete response' was measured at 5 months in 29/44 participants (66%) treated with imiquimod plus tazarotene (combination therapy) and 27/46 participants (59%) treated with imiquimod (monotherapy). The difference was not statistically significant (risk ratio (RR) 1.12, 95% confidence interval (CI) 0.81 to 1.55, P value = 0.48).With regard to our secondary outcomes on recurrence and inflammation, after a mean follow up of 42 months, no local recurrences were observed among complete responders. Difference in overall inflammation score between the 2 groups was significant (mean difference (MD) 0.6, 95% CI 0.2 to 1, P value = 0.004), with the mean overall inflammation score being significantly higher in the combination group.The study authors did not clearly report on side-effects. Because of adverse effects, there was a dropout rate of 6/44 participants (13.7%) in the combination group compared with 1/46 (2.2%) in the imiquimod monotherapy group (due to excessive inflammation) before the cessation of topical treatment (first 3 months), but this was not statistically significant (RR 6.27, 95% CI 0.79 to 50.02, P value = 0.08). AUTHORS' CONCLUSIONS: There is a lack of high-quality evidence for the treatment of MIS and LM.For the treatment of MIS, we found no RCTs of surgical interventions aiming to optimise margin control (square method, perimeter technique, 'slow Mohs', staged radial sections, staged "mapped" excisions, or Mohs micrographic surgery), which are the most widely used interventions recommended as first-line therapy. The use of non-surgical interventions in selected cases (patients with contraindications to surgical interventions) may be effective and may be considered preferable for experienced providers and under close and adequate follow up.For the treatment of LM, we found no RCTs of surgical interventions, which remain the most widely used and recommended available treatment. The use of non-surgical interventions, such as imiquimod, as monotherapy may be effective and may be considered in selected cases where surgical procedures are contraindicated and used preferentially by experienced providers under close and adequate follow up. The use of topical therapies, such as 5-fluorouracil and imiquimod, as neoadjuvant therapies warrants further investigation. There is insufficient evidence to support or refute the addition of tazarotene to imiquimod as adjuvant therapy; the current evidence suggests that it can increase topical inflammatory response and withdrawal of participants because of treatment-related side-effects. PMID- 25526612 TI - Using synchronous Boolean networks to model several phenomena of collective behavior. AB - In this paper, we propose an approach for modeling and analysis of a number of phenomena of collective behavior. By collectives we mean multi-agent systems that transition from one state to another at discrete moments of time. The behavior of a member of a collective (agent) is called conforming if the opinion of this agent at current time moment conforms to the opinion of some other agents at the previous time moment. We presume that at each moment of time every agent makes a decision by choosing from the set {0,1} (where 1-decision corresponds to action and 0-decision corresponds to inaction). In our approach we model collective behavior with synchronous Boolean networks. We presume that in a network there can be agents that act at every moment of time. Such agents are called instigators. Also there can be agents that never act. Such agents are called loyalists. Agents that are neither instigators nor loyalists are called simple agents. We study two combinatorial problems. The first problem is to find a disposition of instigators that in several time moments transforms a network from a state where the majority of simple agents are inactive to a state with the majority of active agents. The second problem is to find a disposition of loyalists that returns the network to a state with the majority of inactive agents. Similar problems are studied for networks in which simple agents demonstrate the contrary to conforming behavior that we call anticonforming. We obtained several theoretical results regarding the behavior of collectives of agents with conforming or anticonforming behavior. In computational experiments we solved the described problems for randomly generated networks with several hundred vertices. We reduced corresponding combinatorial problems to the Boolean satisfiability problem (SAT) and used modern SAT solvers to solve the instances obtained. PMID- 25526611 TI - Targeted delivery of lovastatin and tocotrienol to fracture site promotes fracture healing in osteoporosis model: micro-computed tomography and biomechanical evaluation. AB - Osteoporosis is becoming a major health problem that is associated with increased fracture risk. Previous studies have shown that osteoporosis could delay fracture healing. Although there are potential agents available to promote fracture healing of osteoporotic bone such as statins and tocotrienol, studies on direct delivery of these agents to the fracture site are limited. This study was designed to investigate the effects of two potential agents, lovastatin and tocotrienol using targeted drug delivery system on fracture healing of postmenopausal osteoporosis rats. The fracture healing was evaluated using micro CT and biomechanical parameters. Forty-eight Sprague-Dawley female rats were divided into 6 groups. The first group was sham-operated (SO), while the others were ovariectomized (OVx). After two months, the right tibiae of all rats were fractured at metaphysis region using pulsed ultrasound and were fixed with plates and screws. The SO and OVxC groups were given two single injections of lovastatin and tocotrienol carriers. The estrogen group (OVx+EST) was given daily oral gavages of Premarin (64.5 ug/kg). The Lovastatin treatment group (OVx+Lov) was given a single injection of 750 ug/kg lovastatin particles. The tocotrienol group (OVx+TT) was given a single injection of 60 mg/kg tocotrienol particles. The combination treatment group (OVx+Lov+TT) was given two single injections of 750 ug/kg lovastatin particles and 60 mg/kg tocotrienol particles. After 4 weeks of treatment, the fractured tibiae were dissected out for micro-CT and biomechanical assessments. The combined treatment group (OVx+Lov+TT) showed significantly higher callus volume and callus strength than the OVxC group (p<0.05). Both the OVx+Lov and OVx+TT groups showed significantly higher callus strength than the OVxC group (p<0.05), but not for callus volume. In conclusion, combined lovastatin and tocotrienol may promote better fracture healing of osteoporotic bone. PMID- 25526613 TI - Patterns of Depression Treatment in Medicare Beneficiaries with Depression after Traumatic Brain Injury. AB - There are no clinical guidelines addressing the management of depression after traumatic brain injury (TBI). The objectives of this study were to (1) describe depression treatment patterns among Medicare beneficiaries with a diagnosis of depression post-TBI; (2) compare them with depression treatment patterns among beneficiaries with a diagnosis of depression pre-TBI; and (3) quantify the difference in prevalence of use. We conducted a retrospective analysis of Medicare beneficiaries hospitalized with TBI during 2006-2010. We created two cohorts: beneficiaries with a new diagnosis of depression pre-TBI (n=4841) and beneficiaries with a new diagnosis of depression post-TBI (n=4668). We searched for antidepressant medications in Medicare Part D drug event files and created variables indicating antidepressant use in each 30-day period after diagnosis of depression. We used provider specialty and current procedural terminology to identify psychotherapy in any location. We used generalized estimating equations to quantify the effect of TBI on receipt of depression treatment during the year after diagnosis of depression. Average monthly prevalence of antidepressant use was 42% among beneficiaries with a diagnosis of depression pre-TBI and 36% among those with a diagnosis post-TBI (p<0.001). Beneficiaries with a diagnosis of depression post-TBI were less likely to receive antidepressants compared with a depression diagnosis pre-TBI (adjusted odds ratio [OR] 0.87; 95% confidence interval [CI] 0.82, 0.92). There was no difference in receipt of psychotherapy between the two groups (OR 1.08; 95% CI 0.93, 1.26). Depression after TBI is undertreated among older adults. Knowledge about reasons for this disparity and its long-term effects on post-TBI outcomes is limited and should be examined in future work. PMID- 25526615 TI - Occupational therapists' views on using a virtual reality interior design application within the pre-discharge home visit process. AB - BACKGROUND: A key role of Occupational Therapists (OTs) is to carry out pre discharge home visits (PHV) and propose appropriate adaptations to the home environment in order to enable patients to function independently after hospital discharge. However, research shows that more than 50% of specialist equipment installed as part of home adaptations is not used by patients. A key reason for this is that decisions about home adaptations are often made without adequate collaboration and consultation with the patient. Consequently, there is an urgent need to seek out new and innovative uses of technology to facilitate patient/practitioner collaboration, engagement, and shared decision making in the PHV process. Virtual reality interior design applications (VRIDAs) primarily allow users to simulate the home environment and visualize changes prior to implementing them. Customized VRIDAs, which also model specialist occupational therapy equipment, could become a valuable tool to facilitate improved patient/practitioner collaboration, if developed effectively and integrated into the PHV process. OBJECTIVE: The intent of the study was to explore the perceptions of OTs with regard to using VRIDAs as an assistive tool within the PHV process. METHODS: Task-oriented interactive usability sessions, utilizing the think-aloud protocol and subsequent semi-structured interviews were carried out with seven OTs who possessed significant experience across a range of clinical settings. Template analysis was carried out on the think-aloud and interview data. Analysis was both inductive and driven by theory, centering around the parameters that impact upon the acceptance, adoption, and use of this technology in practice as indicated by the Technology Acceptance Model (TAM). RESULTS: OTs' perceptions were identified relating to three core themes: (1) perceived usefulness (PU), (2) perceived ease of use (PEoU), and (3) actual use (AU). Regarding PU, OTs believed VRIDAs had promising potential to increase understanding, enrich communication and patient involvement, and improve patient/practitioner shared understanding. However, it was unlikely that VRIDAs would be suitable for use with cognitively impaired patients. For PEoU, all OTs were able to use the software and complete the tasks successfully; however, participants noted numerous specialist equipment items that could be added to the furniture library. AU perceptions were positive regarding use of the application across a range of clinical settings including children/young adults, long-term conditions, neurology, older adults, and social services. However, some "fine tuning" may be necessary if the application is to be optimally used in practice. CONCLUSIONS: Participants perceived the use of VRIDAs in practice would enhance levels of patient/practitioner collaboration and provide a much needed mechanism via which patients are empowered to become more equal partners in decisions made about their care. Further research is needed to explore patient perceptions of VRIDAs, to make necessary customizations accordingly, and to explore deployment of the application in a collaborative patient/practitioner-based context. PMID- 25526617 TI - Investigating glutamatergic mechanism in attention and impulse control using rats in a modified 5-choice serial reaction time task. AB - The 5-choice serial reaction time task (5CSRTT) has been widely used to study attention and impulse control in rodents. In order to mimic cognitive impairments in psychiatry, one approach has been to use acute administration of NMDA antagonists. This disruption in glutamatergic transmission leads to impairments in accuracy, omissions, and premature responses although findings have been inconsistent. In this study, we further investigated glutamatergic mechanisms using a novel version of the 5CSRTT, which we have previously shown to be more sensitive to cognitive enhancers. We first investigated the effects of systemic treatment with NMDA antagonists. We also carried out a preliminary investigation using targeted medial prefrontal cortex infusions of a NMDA antagonist (MK801), mGluR2/3 antagonist (LY341495), and mGluR7 negative allosteric modulator (MMPIP). Acute systemic administration of the different NMDA antagonists had no specific effects on accuracy. At higher doses PCP, ketamine, and memantine, increased omissions and affected other measures suggesting a general disruption in task performance. Only MK801 increased premature responses, and reduced omissions at lower doses suggesting stimulant like effects. None of the NMDA antagonists affected accuracy or any other measures when tested using a short stimulus challenge. Infusions of MK801 had no effect on accuracy but increased premature responses following infralimbic, but not prelimbic infusion. LY341495 had no effects in either brain region but a decrease in accuracy was observed following prelimbic infusion of MMPIP. Contrary to our hypothesis, disruptions to glutamate transmission using NMDA antagonists did not induce any clear deficits in accuracy in this modified version of the 5CSRTT. We also found that the profile of effects for MK801 differed from those observed with PCP, ketamine, and memantine. The effects of MK801 in the infralimbic cortex add to the literature indicating this brain region and glutamate play an important role in impulse control. PMID- 25526618 TI - Naloxone for severe traumatic brain injury: a meta-analysis. AB - OBJECTIVE: The efficiency of naloxone for the management of secondary brain injury after severe traumatic brain injury (sTBI) remains undefined. The aim of this study is to evaluate the current evidence regarding the clinical efficiency and safety of naloxone as a treatment for sTBI in mainland China. METHODOLOGY/PRINCIPAL FINDINGS: A systematic search of the China Biology Medicine disc (CBM), China Science and Technology Journal Database (VIP), China National Knowledge Internet (CNKI), and Wan Fang Database was performed to identify randomized controlled trials (RCTs) of naloxone treatment for patients with sTBI in mainland China. The quality of the included trials was assessed, and the RevMan 5.1 software was employed to conduct this meta-analysis. Nineteen RCTs including 2332 patients were included in this study. The odds ratio (OR) showed statistically significant differences between the naloxone group and the control group (placebo) in terms of mortality at 18 months after treatment (OR, 0.51, 95%CI: 0.38-0.67; p<0.00001), prevalence of abnormal heart rates (OR, 0.30, 95%CI: 0.21-0.43; p<0.00001), abnormal breathing rate (OR, 0.25, 95%CI: 0.17 0.36; p<0.00001) at discharge, the level of intracranial pressure at discharge (OR, 2.00, 95%CI: 1.41-2.83; p = 0.0001), verbal or physical dysfunction rate (OR, 0.65, 95%CI: 0.43-0.98; p = 0.04), and severe disability rate (OR, 0.47, 95%CI: 0.30-0.73; p = 0.0001) at 18 months after the treatment. The mean difference (MD) showed statistically significant differences in awakening time at discharge (MD, -4.81, 95%CI: -5.49 to -4.12; p<0.00001), and GCS at 3 days (MD, 1.00, 95%CI: 0.70-1.30; p<0.00001) and 10 days (MD, 1.76, 95%CI: 1.55-1.97; p<0.00001) after treatment comparing naloxone with placebo group. CONCLUSIONS/SIGNIFICANCE: This study indicated that applying naloxone in the early stage for sTBI patients might effectively reduce mortality, control intracranial pressure (ICP), and significantly improve the prognosis. PMID- 25526619 TI - A hydro-economic model for water level fluctuations: combining limnology with economics for sustainable development of hydropower. AB - Water level fluctuations in lakes lead to shoreline displacement. The seasonality of flooding or beaching of the littoral area affects nutrient cycling, redox gradients in sediments, and life cycles of aquatic organisms. Despite the ecological importance of water level fluctuations, we still lack a method that assesses water levels in the context of hydropower operations. Water levels in reservoirs are influenced by the operator of a hydropower plant, who discharges water through the turbines or stores water in the reservoir, in a fashion that maximizes profit. This rationale governs the seasonal operation scheme and hence determines the water levels within the boundaries of the reservoir's water balance. For progress towards a sustainable development of hydropower, the benefits of this form of electricity generation have to be weighed against the possible detrimental effects of the anthropogenic water level fluctuations. We developed a hydro-economic model that combines an economic optimization function with hydrological estimators of the water balance of a reservoir. Applying this model allowed us to accurately predict water level fluctuations in a reservoir. The hydro-economic model also allowed for scenario calculation of how water levels change with climate change scenarios and with a change in operating scheme of the reservoir (increase in turbine capacity). Further model development will enable the consideration of a variety of additional parameters, such as water withdrawal for irrigation, drinking water supply, or altered energy policies. This advances our ability to sustainably manage water resources that must meet both economic and environmental demands. PMID- 25526616 TI - Cross-fostering increases TH1/TH2 expression in a prenatal dexamethasone exposure rat model. AB - BACKGROUND: Prenatal dexamethasone exposure has been reported to increase allergy potential in childhood possibly by interference with normal immunological development in utero. This study investigated the effects of prenatal dexamethasone on T helper cell immune responses in a rat model. METHODS: Pregnant rats received either dexamethasone 0.1 mg/kg/day or normal saline from gestational day 14-21. Off-springs were cared for by their biological mother, or cross-fostered by the opposing group. Spleen and blood samples were collected at post-natal day 7 and 120 and tested for mRNA expression and plasma cytokine levels of Th1/Th2/Th17 immune response. RESULTS: Both Th1 (T-bet) and Th2 (GATA 3) mRNA expression were shown to have a significant increase in the prenatal dexamethasone exposure group at day 120 (p<0.05). The plasma levels for Th1 (IFNgamma and IL-2) and Th2 (IL-4, IL-5, IL-13) were found to have no significant differences between the two group (p>0.05). The mRNA expression of Th17 (RORgammat) showed a significant decrease at post-natal day 120 as well as the plasma level of IL-17A at day 7 (11.21+/-1.67 vs. 6.23+/-1.06 pg/ml, p = 0.02). Cross-fostering by a dexamethasone exposed mother resulted in a significant increase in Th1/Th2 mRNA expression (p<0.05) and decrease of Th17. CONCLUSIONS: Prenatal dexamethasone exposure increased Th1, Th2 and decreased Th17 expression. Cross-fostering by a dexamethasone exposed mother results in more prominent increase of Th1 and Th2 expression. PMID- 25526620 TI - Effects of glucose and sucrose variants of the caries-promoting Diet 2000 on the feeding patterns and parotid glands of prematurely weaned rats. AB - OBJECTIVE: The hypothesis of this study was that feeding glucose instead of sucrose in the cariogenic Diet 2000 to rats weaned at age 18 days would result in greater light/dark differences in feeding activity and secretion and storage of parotid salivary enzymes. DESIGN OF STUDY: Diet 2000 and a stock commercial diet (controls) were prepared in pelleted and powdered forms, as the increased mastication required by pellets has been shown to support circadian rhythms in rats. Food jars were weighed at lights on and just prior to lights off daily. Rats were euthanized at 25 days and their parotid glands removed, weighed, and analyzed for specific activities of the salivary enzymes alpha-amylase and deoxyribonuclease I. RESULTS: Light/dark differences in feeding activity were strong in the rats fed the pelleted stock diet and both powdered and pelleted glucose 2000 diets, moderate with the pelleted sucrose 2000 diet, and not significant with the powdered sucrose 2000 and stock diets. Light/dark differences in the parotid salivary enzymes were strong with the powdered glucose 2000 diet and the pelleted forms of the glucose and sucrose 2000 and stock diets, and not significant with the powdered stock and sucrose 2000 diets. CONCLUSION: Caries reportedly is higher in sucrose than glucose fed to rats in the standard powdered form of Diet 2000, mainly due to the colonizing advantage Streptococcus mutans gains with sucrose. These results suggest that additional factors are more feeding during lights on and less stimulation of parotid salivary secretion with the sucrose powder. PMID- 25526621 TI - Unusual postero-inferior condylar movements that depend on the position of occlusal contact during fictive mastication in rabbits. AB - OBJECTIVE: The mandible can be modelled as a triangular plate supported at two joints and the point of occlusion. The mandible is stable if the vector of the jaw-closing muscle forces lies within the triangle of support. If this vector lies outside of the triangle of support, one of the three contact points will tend to separate as the mandible rotates around a line connecting the other two points. Here, we examined whether postero-inferior condylar movements (Pi-Cm) due to mandibular rotation may occur during fictive mastication in anaesthetized rabbits. METHODS: EMG activities of the masseter (MS) and lateral pterygoid (LP) muscles and movements of the condyle and incisal points were recorded. Condylar movements in the sagittal plane were recorded using a high speed CCD camera. RESULTS: Pi-Cm were observed on the working side during occlusal phase in half of the rabbits (altered-movement group), if the biting point was restricted at the posterior most tooth (M3) on the working side using a metal biting plate. Pi-Cm appeared in the period between the estimated maximum force of the MS and the LP during late occlusal phase. The MS EMG ratio between the working and balancing sides in the altered-movement group was significantly less than that in the unaltered-movement group. CONCLUSION: Since the space lying between the condyle and the articular eminence expanded during the Pi-Cm, it is likely that the posterior band of the articular disc tended to slip anteriorly. The clinical significance of the Pi-Cm is discussed concerning the anterior dislocation of the disc in patients with TMJ disorder. PMID- 25526623 TI - Effects of Epigallocatechin gallate against Enterococcus faecalis biofilm and virulence. AB - OBJECTIVE: Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea (Camellia sinesis) has been shown to exert antimicrobial effects on numerous bacterial pathogens. However its efficacy against Enterococcus faecalis biofilm, which is associated with persistent root canal infection is unknown. The aims of this study were to investigate the effects of EGCG against E. faecalis biofilm and virulence. DESIGN: Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of EGCG on E. faecalis were determined. The efficacy of EGCG on E. faecalis biofilms was tested by exposing 7-day old E. faecalis biofilm to EGCG. Flow cytometry analysis of hydroxyphenyl fluorescein (HPF) labelled E. faecalis was used to determine if EGCG induced intracellular hydroxyl radical formation. Co-treatment of EGCG with the iron chelator 2,2 dipyridyl (DIP) was carried out to determine if hydroxyl radical generated through Fenton reaction played a role in EGCG-mediated killing of E. faecalis. Furthermore, the effects of EGCG on the expression of virulence genes in E. faecalis were evaluated by quantitative polymerase chain reaction. RESULTS: EGCG exhibited a MIC and MBC of 5 MUg/mL and 20 MUg/mL respectively and effectively eradicated E. faecalis biofilms. EGCG induced the formation of hydroxyl radicals in E. faecalis. The addition of DIP protected E. faecalis against EGCG-mediated antibacterial effects. At sub-MIC, EGCG induced significant down-regulation of E. faecalis virulence genes. CONCLUSIONS: EGCG is an effective antimicrobial agent against both the planktonic and biofilm forms of E. faecalis, inhibiting bacterial growth and suppressing the expression of specific genes related to virulence and biofilm formation. The antimicrobial action of EGCG on E. faecalis occurred through the generation of hydroxyl radical. PMID- 25526622 TI - Characteristics of the saliva flow rates of minor salivary glands in healthy people. AB - OBJECTIVES: To investigate the normal range and characteristics of saliva secretion in the minor salivary glands (MSGs). DESIGN: The flow rates of MSGs were measured in 4 anatomical locations of oral mucosa, and the relationship between MSG flow rates and whole saliva flow rates were assessed in 300 healthy subjects stratified by age and sex. An additional 30 young females were further evaluated for flow symmetry, effects of stimulation, circadian effects in MSGs, and the relationship with the flow rates of major salivary glands. RESULTS: (1) The mean saliva flow rates were 2.10 +/- 0.66 (lower labial glands), 2.14 +/- 0.62 (upper labial glands), 2.88 +/- 0.72 (buccal glands) and 2.15 +/- 0.51 (palatal glands) MUl/min/cm(2), respectively. The flow rate of buccal glands was significantly higher than the rates of SMGs in other locations (P < 0.01). (2) 5 year-old children had the lowest MSG flow rates (P < 0.0001) while the 10-14-year old group had the highest (P < 0.001). (3) MSG flow rates were independent of sex (P > 0.05), right vs. left (P > 0.05), and citric acid (2.5%) stimulation (P > 0.05). (4) Only labial MSG displayed a significant secretory circadian rhythm with the highest rate in the evening (P < 0.05). (5) A weak correlation was found between the flow rate of palatal glands and that of unstimulated whole saliva (r = 0.195, P = 0.007). CONCLUSIONS: Our findings provide a reference for functional evaluation of MSGs and for donor site selection of MSG transplantation for treatment of severe dry eye syndrome. PMID- 25526624 TI - Distribution of 8 periodontal microorganisms in family members of Chinese patients with aggressive periodontitis. AB - OBJECTIVE: To date, no information on the distribution of periodontal microorganisms among family members of Chinese patients with aggressive peridontitis (AgP) is available. The aim of the present study was to investigate the probability of transmission of eight periodontal microorganisms between patients with aggressive periodontitis and their family members. DESIGN: Saliva and pooled subgingival plaque samples were collected from 103 participants from 41 nuclear families (including 41 AgP probands, 19 mothers, 22 fathers, 21 siblings). Eight periodontal microorganisms, including Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola, Campylobacter rectus, Prevotella intermedia, Prevotella nigrescens and Fusobacterium nucleatum were detected in these samples by the polymerase chain reaction (PCR). In addition, the distribution of fimA genotypes was assessed in P. gingivalis-positive individuals by PCR. RESULTS: P. gingivalis, T. forsythia, T. denticola, C. rectus and F. nucleatum were the most frequently detected species both in AgP probands and in their relatives. Kappa statistical analysis revealed that the detection of A. actinomycetemcomitans (Kappa = 0.503) and F. nucleatum (Kappa = 0.565) in probands was highly consistent with that in their relatives. Most probands shared the identical fimA genotype of P. gingivalis with their relatives. CONCLUSIONS: Our results suggested that the intrafamilial transmission of periodontal microorganisms may occur between Chinese patients with aggressive periodontitis and their relatives. PMID- 25526625 TI - Role of endogenous basic fibroblast growth factor in stem cells isolated from human exfoliated deciduous teeth. AB - OBJECTIVE: This study aimed to investigate the role of endogenous basic fibroblast growth factor (bFGF) in stem cells isolated from human exfoliated deciduous teeth. METHODS: Cells were isolated from dental pulp tissues of human exfoliated deciduous teeth. The expression of stem cell markers was determined using conventional semi-quantitative polymerase chain reaction (PCR) and flow cytometry. The multipotential differentiation ability was also examined. The lentiviral shRNA or fibroblast growth factor receptor (FGFR) inhibitor was employed to inhibit bFGF mRNA expression and signal transduction, respectively. The colony formation ability was determined by low-density cell seeding protocol. The mRNA expression was evaluated using real-time quantitative PCR. The osteogenic differentiation was examined using alkaline phosphatase enzymatic activity assay and alizarin red staining. RESULTS: The results demonstrated that the cells isolated from human exfoliated deciduous teeth (SHEDs) exhibited stem cell characteristics, regarding marker expression and multipotential differentiation ability (osteogenic, adipogenic, and neurogenic lineage). The sh bFGF transduced SHEDs had lower colony forming unit and higher mineralization than those of the control. Similarly, the decrease of colony number and the increase of mineral deposition were noted upon exposing cells to FGFR chemical inhibitor. CONCLUSION: These results imply that the endogenous bFGF may participate in the colony formation and osteogenic differentiation ability. In addition, the inhibition of bFGF signalling may be useful to enhance osteogenic differentiation of stem cells. PMID- 25526626 TI - In vitro mechanical loading models for periodontal ligament cells: from two dimensional to three-dimensional models. AB - Periodontal ligament cells (PDLCs) respond to various mechanical stimuli, including mastication and orthodontic force, and thereby play an important functional role. A number of in vitro models have been widely used to study these mechanoresponses. Here, we comprehensively review the various in vitro mechanical loading approaches used for assessing PDLCs, including their force generation properties, mechanical characteristics, and simulation of authentic bioprocesses. Furthermore, we highlight the evolution of current cytomechanical studies, from conventional two-dimensional to novel three-dimensional (3-D) cell cultures. Some representative 3-D PDLC culture and mechanical loading systems are also described, with the advantages and limitations of these discussed. From this review, we can conclude that optimal mechanical loading models must be chosen to match the specific research purpose, and that novel 3-D PDLC culture and mechanical loading models are promising for future studies. PMID- 25526627 TI - Life history and biochemical effects of chlorantraniliprole on Chironomus riparius. AB - The need to overcome pesticide resistance has led to the development of novel insecticides such as chlorantraniliprole (CAP), an anthranilic diamide. CAP disrupts calcium homeostasis in nerve and muscle cells and is used in several agricultural crops due to its potency and selectivity. However, chronic toxicity data for aquatic invertebrates are limited. Our objective was to evaluate the toxicity of CAP at different levels of biological organization using Chironomus riparius. Organismal endpoints (survival, larval growth and emergence), and 5 biomarkers associated with important physiological functions (acetylcholinesterase - AChE; catalase - CAT; glutathione-S-transferase - GST; total glutathione - TG; and lipid peroxidation - LPO) were investigated. Effects of CAP on cellular energy allocation (CEA) were also assessed. Acute tests revealed a 48 h LC50 for C. riparius of 77.5 MUg/L and life-cycle tests revealed a chronic LOEC of 3.1 MUg/L based on effects on C. riparius larval growth and emergence. C. riparius females exposed as larvae to low concentrations of CAP emerged at a smaller size which might also translate into effects on reproduction. Chironomid larvae were not under oxidative stress, since short exposures to CAP did not affect LPO levels, despite the significant inhibition of GST (0.6-9.6 MUg/L) and CAT (9.6 MUg/L). It seems that detoxification of reactive intermediates and ROS is still achieved due to glutathione consumption, since TG levels were significantly decreased in organisms exposed to CAP (0.6-9.6 MUg/L). Moreover, it was observed that CEA was disturbed due to increased activity of the electron transport system (ETS), suggesting extra energy expenditure in larvae. These results show that environmental concentrations of CAP can impair the fitness of C. riparius natural populations and at the same time that chironomids, as for most insecticides, are suitable test organisms to evaluate the organismal and biochemical effects of anthranilic diamides. PMID- 25526628 TI - Detection of oligomers and fibrils of alpha-synuclein by AIEgen with strong fluorescence. AB - We report a fluorophore, TPE-TPP, with AIE characteristics which is utilized as a fluorescence probe to monitor the alpha-synuclein (alpha-Syn) fibrillation process. Compared with ThT, TPE-TPP shows a higher sensitivity in the detection of alpha-Syn oligomers as well as fibrils with a stronger fluorescence. The performance of TPE-TPP was evaluated using fluorescence, AFM, dot blot, and SEC. PMID- 25526629 TI - The synergistic repressive effect of NF-kappaB and JNK inhibitor on the clonogenic capacity of Jurkat leukemia cells. AB - Deregulation of Nuclear Transcription Factor-kappaB (NF-kappaB) and Jun N terminal kinase (JNK) signaling is commonly detected in leukemia, suggesting an important role for these two signaling pathways in the pathogenesis of leukemia. In this study, using Jurkat cells, an acute T-lymphoblastic leukemia (T-ALL) cell line, we evaluated the effects of an NF-kappaB inhibitor and a JNK inhibitor individually and in combination on the proliferation, survival and clonogenic capacity of leukemic cells. We found that leukemic stem/progenitor cells (LSPCs) were more sensitive to NF-kappaB inhibitor treatment than were healthy hematopoietic stem/progenitor cells (HSPCs), as shown by a reduction in the clonogenic capacity of the former. Inactivation of NF-kappaB leads to the activation of JNK signaling in both leukemic cells and healthy HSPCs. Interestingly, JNK inhibitor treatment enhanced the repressive effects of NF kappaB inhibitor on LSPCs but prevented such repression in HSPCs. Our data suggest that JNK signaling stimulates proliferation/survival in LSPCs but is a death signal in HSPCs. The combination of NF-kappaB inhibitor and JNK inhibitor might provide a better treatment for T-ALL leukemia by synergistically killing LSPCs while simultaneously preventing the death of normal HPCs. PMID- 25526633 TI - Western spruce budworm outbreaks did not increase fire risk over the last three centuries: a dendrochronological analysis of inter-disturbance synergism. AB - Insect outbreaks are often assumed to increase the severity or probability of fire occurrence through increased fuel availability, while fires may in turn alter susceptibility of forests to subsequent insect outbreaks through changes in the spatial distribution of suitable host trees. However, little is actually known about the potential synergisms between these natural disturbances. Assessing inter-disturbance synergism is challenging due to the short length of historical records and the confounding influences of land use and climate changes on natural disturbance dynamics. We used dendrochronological methods to reconstruct defoliator outbreaks and fire occurrence at ten sites along a longitudinal transect running from central Oregon to western Montana. We assessed synergism between disturbance types, analyzed long-term changes in disturbance dynamics, and compared these disturbance histories with dendroclimatological moisture availability records to quantify the influence of moisture availability on disturbances. After approximately 1890, fires were largely absent and defoliator outbreaks became longer-lasting, more frequent, and more synchronous at our sites. Fires were more likely to occur during warm-dry years, while outbreaks were most likely to begin near the end of warm-dry periods. Our results show no discernible impact of defoliation events on subsequent fire risk. Any effect from the addition of fuels during defoliation events appears to be too small to detect given the overriding influence of climatic variability. We therefore propose that if there is any relationship between the two disturbances, it is a subtle synergistic relationship wherein climate determines the probability of occurrence of each disturbance type, and each disturbance type damps the severity, but does not alter the probability of occurrence, of the other disturbance type over long time scales. Although both disturbance types may increase in frequency or extent in response to future warming, our records show no precedent that western spruce budworm outbreaks will increase future fire risk. PMID- 25526632 TI - A genome wide meta-analysis study for identification of common variation associated with breast cancer prognosis. AB - OBJECTIVE: Genome wide association studies (GWAs) of breast cancer mortality have identified few potential associations. The concordance between these studies is unclear. In this study, we used a meta-analysis of two prognostic GWAs and a replication cohort to identify the strongest associations and to evaluate the loci suggested in previous studies. We attempt to identify those SNPs which could impact overall survival irrespective of the age of onset. METHODS: To facilitate the meta-analysis and to refine the association signals, SNPs were imputed using data from the 1000 genomes project. Cox-proportional hazard models were used to estimate hazard ratios (HR) in 536 patients from the POSH cohort (Prospective study of Outcomes in Sporadic versus Hereditary breast cancer) and 805 patients from the HEBCS cohort (Helsinki Breast Cancer Study). These hazard ratios were combined using a Mantel-Haenszel fixed effects meta-analysis and a p-value threshold of 5*10(-8) was used to determine significance. Replication was performed in 1523 additional patients from the POSH study. RESULTS: Although no SNPs achieved genome wide significance, three SNPs have significant association in the replication cohort and combined p-values less than 5.6*10(-6). These SNPs are; rs421379 which is 556 kb upstream of ARRDC3 (HR = 1.49, 95% confidence interval (CI) = 1.27-1.75, P = 1.1*10(-6)), rs12358475 which is between ECHDC3 and PROSER2 (HR = 0.75, CI = 0.67-0.85, P = 1.8*10(-6)), and rs1728400 which is between LINC00917 and FOXF1. CONCLUSIONS: In a genome wide meta-analysis of two independent cohorts from UK and Finland, we identified potential associations at three distinct loci. Phenotypic heterogeneity and relatively small sample sizes may explain the lack of genome wide significant findings. However, the replication at three SNPs in the validation cohort shows promise for future studies in larger cohorts. We did not find strong evidence for concordance between the few associations highlighted by previous GWAs of breast cancer survival and this study. PMID- 25526634 TI - The selective antagonism of P2X7 and P2Y1 receptors prevents synaptic failure and affects cell proliferation induced by oxygen and glucose deprivation in rat dentate gyrus. AB - Purinergic P2X and P2Y receptors are broadly expressed on both neurons and glial cells in the central nervous system (CNS), including dentate gyrus (DG). The aim of this research was to determine the synaptic and proliferative response of the DG to severe oxygen and glucose deprivation (OGD) in acute rat hippocampal slices and to investigate the contribution of P2X7 and P2Y1 receptor antagonism to recovery of synaptic activity after OGD. Extracellular field excitatory post synaptic potentials (fEPSPs) in granule cells of the DG were recorded from rat hippocampal slices. Nine-min OGD elicited an irreversible loss of fEPSP and was invariably followed by the appearance of anoxic depolarization (AD). Application of MRS2179 (selective antagonist of P2Y1 receptor) and BBG (selective antagonist of P2X7 receptor), before and during OGD, prevented AD appearance and allowed a significant recovery of neurotransmission after 9-min OGD. The effects of 9-min OGD on proliferation and maturation of cells localized in the subgranular zone (SGZ) of slices prepared from rats treated with 5-Bromo-2'-deoxyuridine (BrdU) were investigated. Slices were further incubated with an immature neuron marker, doublecortin (DCX). The number of BrdU+ cells in the SGZ was significantly decreased 6 hours after OGD. This effect was antagonized by BBG, but not by MRS2179. Twenty-four hours after 9-min OGD, the number of BrdU+ cells returned to control values and a significant increase of DCX immunofluorescence was observed. This phenomenon was still evident when BBG, but not MRS2179, was applied during OGD. Furthermore, the P2Y1 antagonist reduced the number of BrdU+ cells at this time. The data demonstrate that P2X7 and P2Y1 activation contributes to early damage induced by OGD in the DG. At later stages after the insult, P2Y1 receptors might play an additional and different role in promoting cell proliferation and maturation in the DG. PMID- 25526637 TI - Engineering an endothelialized vascular graft: a rational approach to study design in a non-human primate model. AB - After many years of research, small diameter, synthetic vascular grafts still lack the necessary biologic integration to perform ideally in clinical settings. Endothelialization of vascular grafts has the potential to improve synthetic graft function, and endothelial outgrowth cells (EOCs) are a promising autologous cell source. Yet no work has established the link between endothelial cell functions and outcomes of implanted endothelialized grafts. This work utilized steady flow, oscillatory flow, and tumor necrosis factor stimulation to alter EOC phenotype and enable the formulation of a model to predict endothelialized graft performance. To accomplish this, EOC in vitro expression of coagulation and inflammatory markers was quantified. In parallel, in non-human primate (baboon) models, the platelet and fibrinogen accumulation on endothelialized grafts were quantified in an ex vivo shunt, or the tissue ingrowth on implanted grafts were characterized after 1mth. Oscillatory flow stimulation of EOCs increased in vitro coagulation markers and ex vivo platelet accumulation. Steady flow preconditioning did not affect platelet accumulation or intimal hyperplasia relative to static samples. To determine whether in vitro markers predict implant performance, a linear regression model of the in vitro data was fit to platelet accumulation data-correlating the markers with the thromboprotective performance of the EOCs. The model was tested against implant intimal hyperplasia data and found to correlate strongly with the parallel in vitro analyses. This research defines the effects of flow preconditioning on EOC regulation of coagulation in clinical vascular grafts through parallel in vitro, ex vivo, and in vivo analyses, and contributes to the translatability of in vitro tests to in vivo clinical graft performance. PMID- 25526639 TI - Clinical significance of soluble CD26 in malignant pleural mesothelioma. AB - There is no established single diagnostic marker for malignant pleural mesothelioma (MPM). CD26 is a 110 kDa, multifunctional, membrane-bound glycoprotein that has dipeptidyl peptidase IV (DPPIV) enzyme activity. The aim of this study was to evaluate the clinical significance of soluble CD26 (sCD26) in patients with MPM. The study included 80 MPM patients, 79 subjects with past asbestos exposure (SPE), and 134 patients with other benign pleural diseases (OPD) that were included as a control group. sCD26 levels and DPPIV activity in serum and/or pleural fluid were determined using an ELISA kit. Serum sCD26 levels and DPPIV enzyme activity in patients with MPM were significantly decreased compared with those in the SPE group (P = 0.000). The level of serum sCD26 was significantly decreased in patients with advanced stages of MPM compared with those with earlier stages (P = 0.047). The median OS of patients with MPM who had higher DPPIV enzyme activity was significantly longer than that of those with lower DPPIV enzyme activity (P = 0.032). The sCD26 levels in the pleural fluid of MPM patients with an epithelioid subtype were significantly increased compared with the OPD cohort (P = 0.012). Moreover, DPPIV enzyme activity in the pleural fluid of patients with MPM with an epithelioid subtype were significantly increased compared with those in the OPD cohort (P = 0.009). Patients with MPM who had lower specific DPPIV activity, determined as DPPIV/sCD26, showed significantly prolonged survival compared with those with higher specific DPPIV activity (P = 0.028). Serum sCD26 and DPPIV enzyme activity appear to be useful biomarkers for differentiating patients with MPM from SPE. The sCD26 levels or DPPIV enzyme activity in pleural fluid appear to be biomarkers in patients with an epithelioid subtype of MPM. DPPIV activity in serum or pleural fluid appears to be predictive for the prognosis of patients with MPM. PMID- 25526640 TI - Evaluation of disulfide bond position to enhance the thermal stability of a highly stable single domain antibody. AB - Single domain antibodies are the small recombinant variable domains derived from camelid heavy-chain-only antibodies. They are renowned for their stability, in large part due to their ability to refold following thermal or chemical denaturation. In addition to refolding after heat denaturation, A3, a high affinity anti-Staphylococcal Enterotoxin B single domain antibody, possesses a melting temperature of ~84 degrees C, among the highest reported for a single domain antibody. In this work we utilized the recently described crystal structure of A3 to select locations for the insertion of a second disulfide bond and evaluated the impact that the addition of this second bond had on the melting temperature. Four double-disulfide versions of A3 were constructed and each was found to improve the melting temperature relative to the native structure without reducing affinity. Placement of the disulfide bond at a previously published position between framework regions 2 and 3 yielded the largest improvement (>6 degrees C), suggesting this location is optimal, and seemingly provides a universal route to raise the melting temperature of single domain antibodies. This study further demonstrates that even single domain antibodies with extremely high melting points can be further stabilized by addition of disulfide bonds. PMID- 25526642 TI - Effect of hemodialysis on plasma glucose profile and plasma level of liraglutide in patients with type 2 diabetes mellitus and end-stage renal disease: a pilot study. AB - The effect of hemodialysis on the plasma glucose profile and liraglutide level after liraglutide injection was investigated in patients with diabetes and end stage renal disease (ESRD). Either 0.6 mg or 0.9 mg liraglutide was subcutaneously administered daily to 10 Japanese type 2 diabetic patients with ESRD. Hemodialysis was conducted on days 1 and 3. Plasma liraglutide and glucose concentrations were measured by enzyme-linked immunosorbent assay and a continuous glucose monitoring system, respectively. The safety profile of liraglutide was also assessed. Hemodialysis had no effect on the pharmacokinetic parameters of liraglutide in patients with diabetes and ESRD; the maximum plasma concentration (Cmax), tmax, area under the concentration-time curve (AUC), and CL/f were unaltered. Similarly, hemodialysis did not affect the mean or minimum glucose levels, AUC, or duration of hyperglycemia (>180 mg/dL) and hypoglycemia (<70 mg/dL) following liraglutide administration. However, significant increases in mean amplitude of glycemic excursions (MAGE) and standard deviation (SD) as markers of glucose fluctuation, and the maximum glucose level were observed during hemodialysis. No adverse events, including hypoglycemia, were observed after liraglutide injection, either off-hemodialysis (day 2) or on-hemodialysis (day 3). Liraglutide was well tolerated in patients with type 2 diabetes and ESRD undergoing hemodialysis. The present results suggested that hemodialysis did not affect the pharmacokinetic profile of liraglutide or most glycemic indices, with the exception of MAGE, SD, and the maximum glucose level. These results suggested that it may be possible to use liraglutide during hemodialysis for diabetes with ESRD, without dose adjustment. Trial Registration UMIN Clinical Trials Registry (UMIN-CTR) UMIN000010159. PMID- 25526641 TI - PARP-1 expression is increased in colon adenoma and carcinoma and correlates with OGG1. AB - The ethiology of colon cancer is largely dependent on inflammation driven oxidative stress. The analysis of 8-oxodeoxyguanosine (8-oxodGuo) level in leukocyte DNA of healthy controls (138 individuals), patients with benign adenomas (AD, 137 individuals) and with malignant carcinomas (CRC, 169 individuals) revealed a significant increase in the level of 8-oxodGuo in leukocyte DNA of AD and CRC patients in comparison to controls. The counteracting mechanism is base excision repair, in which OGG1 and PARP-1 play a key role. We investigated the level of PARP-1 and OGG1 mRNA and protein in diseased and marginal, normal tissues taken from AD and CRC patients and in leukocytes taken from the patients as well as from healthy subjects. In colon tumors the PARP-1 mRNA level was higher than in unaffected colon tissue and in polyp tissues. A high positive correlation was found between PARP-1 and OGG1 mRNA levels in all investigated tissues. This suggests reciprocal influence of PARP-1 and OGG1 on their expression and stability, and may contribute to progression of colon cancer. PARP-1 and OGG1 proteins level was several fold higher in polyps and CRC in comparison to normal colon tissues. Individuals bearing the Cys326Cys genotype of OGG1 were characterized by higher PARP-1 protein level in diseased tissues than the Ser326Cys and Ser326Ser genotypes. Aforementioned result may suggest that the diseased cells with polymorphic OGG1 recruit more PARP protein, which is necessary to remove 8-oxodGuo. Thus, patients with decreased activity of OGG1/polymorphism of the OGG1 gene and higher 8-oxodGuo level may be more susceptible to treatment with PARP-1 inhibitors. PMID- 25526643 TI - Non-microtubular localizations of microtubule-associated protein 6 (MAP6). AB - MAP6 proteins (MAP6s), which include MAP6-N (also called Stable Tubule Only Polypeptide, or STOP) and MAP6d1 (MAP6 domain-containing protein 1, also called STOP-Like protein 21 kD, or SL21), bind to and stabilize microtubules. MAP6 deletion in mice severely alters integrated brain functions and is associated with synaptic defects, suggesting that MAP6s may also have alternative cellular roles. MAP6s reportedly associate with the Golgi apparatus through palmitoylation of their N-terminal domain, and specific isoforms have been shown to bind actin. Here, we use heterologous systems to investigate several biochemical properties of MAP6 proteins. We demonstrate that the three N-terminal cysteines of MAP6d1 are palmitoylated by a subset of DHHC-type palmitoylating enzymes. Analysis of the subcellular localization of palmitoylated MAP6d1, including electron microscopic analysis, reveals possible localization to the Golgi and the plasma membrane but no association with the endoplasmic reticulum. Moreover, we observed localization of MAP6d1 to mitochondria, which requires the N-terminus of the protein but does not require palmitoylation. We show that endogenous MAP6d1 localized at mitochondria in mature mice neurons as well as at the outer membrane and in the intermembrane space of purified mouse mitochondria. Last, we found that MAP6d1 can multimerize via a microtubule-binding module. Interestingly, most of these properties of MAP6d1 are shared by MAP6-N. Together, these results describe several properties of MAP6 proteins, including their intercellular localization and multimerization activity, which may be relevant to neuronal differentiation and synaptic functions. PMID- 25526644 TI - Hepatozoon species (Adeleorina: Hepatozoidae) of African bufonids, with morphological description and molecular diagnosis of Hepatozoon ixoxo sp. nov. parasitising three Amietophrynus species (Anura: Bufonidae). AB - BACKGROUND: Haemogregarines comprise a large group of apicomplexan blood parasites. In 1996 all anuran haemogregarines still in the genus Haemogregarina Danilewsky, 1885 were reassigned to the genus Hepatozoon Miller, 1908. Most (11/15, 73%) African anuran Hepatozoon species have been recorded from the family Bufonidae, however, all these are recorded from only two host species, Amietophrynus mauritanicus (Schlegel, 1841) and Amietophrynus regularis (Reuss, 1833) from Northern and central Africa. To the authors' knowledge the only description of an anuran haemogregarine from South Africa is Hepatozoon theileri (Laveran, 1905), parasitising Amietia quecketti (Boulenger, 1895). METHODS: Thin blood smears for morphometrics and whole blood for molecular work, were collected from 32 Amietophrynus garmani (Meek, 1897), 12 Amietophrynus gutturalis (Power, 1927), and nine Amietophrynus maculatus (Hallowell, 1854), in Ndumo Game Reserve and Kwa Nyamazane Conservancy, KwaZulu-Natal, South Africa. Smears were Giemsa stained, screened for haemogregarines, parasite stages measured, compared to each other and to other described African bufonid haemogregarines. Parasite 18S rDNA was amplified using two apicomplexan-specific primer sets, HepF300/HepR900 and 4558/2733. Resulting sequences of the haemogregarine isolates from the three Amietophrynus species were compared with each other and to comparative haemogregarine sequences selected from GenBank. RESULTS: Morphological characteristics of parasite stages, in particular characteristically capped mature gamont stages, and molecular findings, supported all three haemogregarine isolates from all three Amietophrynus species to be the same, a species of Hepatozoon, and furthermore different morphologically from other previously recorded bufonid Hepatozoon species. The haemogregarine fell within a clade comprising other anuran Hepatozoon species and furthermore, within a monophyletic sub-clade along with H. theileri and are described as Hepatozoon ixoxo sp. nov. CONCLUSIONS: This is the first morphological and molecular account of Hepatozoon species within the family Bufonidae from South Africa, a study hoped to encourage the redescription and molecular analysis of those Hepatozoon species described in the past from Amietophrynus species, as well as to promote the use of both morphological and molecular characteristics in Hepatozoon species descriptions. This will aid in comprehensive Hepatozoon descriptions, which along with the use of phylogenetic analysis will give a better indication of these parasites possible vectors and life cycle dynamics. PMID- 25526646 TI - Electrografted diazonium salt layers for antifouling on the surface of surface plasmon resonance biosensors. AB - Electrografted diazonium salt layers on the surface of surface plasmon resonance (SPR) sensors present potential for a significant improvement in antifouling coatings. A pulsed potential deposition profile was used in order to circumvent mass-transport limitations for layer deposition rate. The influence of number of pulses with respect to antifouling efficacy was evaluated by nonspecific adsorption surface coverage of crude bovine serum proteins. Instead of using empirical and rough estimated values, the penetration depth and sensitivity of the SPR instrument were experimentally determined for the calculation of nonspecific adsorption surface coverage. This provides a method to better examine antifouling surface coatings and compare crossing different coatings and experimental systems. Direct comparison of antifouling performance of different diazonium salts was facilitated by a tripad SPR sensor design. The electrografted 4-phenylalanine diazonium chloride (4-APhe) layers with zwitterionic characteristic demonstrate ultralow fouling. PMID- 25526645 TI - Anopheles arabiensis seasonal densities and infection rates in relation to landscape classes and climatic parameters in a Sahelian area of Senegal. AB - BACKGROUND: The influence of environmental and climatic factors on malaria vector bionomics and transmission is an important topic in the context of climatic change particularly at macro-geographical level. Sahelian areas could be particularly affected due to heterogeneous features including high inter-annual variability in rainfall and others associated parameters. Therefore, baseline information on the impact of environmental and climatic factors on malaria transmission at micro-geographical level is required for vector risk management and implementation of control strategies. METHODS: Malaria vectors were collected indoors by pyrethrum spray catches in 14 villages belonging to 4 different landscape classes (wooded savanna, shrubby savanna, bare soils and steppe) in the sylvo-pastoral area of Senegal. Plasmodium falciparum infection rates were determined using an indirect enzyme-linked immunosorbent assay (ELISA). RESULTS: An. arabiensis was the predominant species in all landscape classes and was the only species collected at the end of the rainy season excepted in villages located in bare soils where it cohabited with An. coluzzii. Mean temperature and relative humidity showed similar variations in all the landscape classes covered whereas rainfall was more heterogeneous in terms of pattern, frequency and amount. The mean densities of An. arabiensis displayed high seasonal differences with peaks observed in August or September. A positive non-significant correlation was observed between An. arabiensis densities for rainfall and humidity whereas a negative non-significant correlation was reported for temperature. Plasmodium falciparum-infected mosquitoes were detected only in wooded savanna and bare soils villages. CONCLUSIONS: These observations suggest key roles played by landscape classes and rainfall in malaria vector densities, infection rates and malaria transmission that could be more pronounced in villages situated in wooded savanna and bare soils. Due to the close relationship between environmental and meteorological parameters in this Sahelian region, additional studies on the impact of these parameters are required to further ascertain their association with entomological parameters involved in malaria transmission. From the public health point of view, such information could be useful for human population settlements as well as for monitoring and modelling purposes giving early warning system for implementation of interventions in these unstable transmission zones. PMID- 25526647 TI - High follicle density does not decrease sweat gland density in Huacaya alpacas. AB - When exposed to high ambient temperatures, mammals lose heat evaporatively by either sweating from glands in the skin or by respiratory panting. Like other camelids, alpacas are thought to evaporate more water by sweating than panting, despite a thick fleece, unlike sheep which mostly pant in response to heat stress. Alpacas were brought to Australia to develop an alternative fibre industry to sheep wool. In Australia, alpacas can be exposed to ambient temperatures higher than in their native South America. As a young industry there is a great deal of variation in the quality and quantity of the fleece produced in the national flock. There is selection pressure towards animals with finer and denser fleeces. Because the fibre from secondary follicles is finer than that from primary follicles, selecting for finer fibres might alter the ratio of primary and secondary follicles. In turn the selection might alter sweat gland density because the sweat glands are associated with the primary follicle. Skin biopsy and fibre samples were obtained from the mid-section of 33 Huacaya alpacas and the skin sections were processed into horizontal sections at the sebaceous gland level. Total, primary, and secondary follicles and the number of sweat gland ducts were quantified. Fibre samples from each alpaca were further analysed for mean fibre diameter. The finer-fibred animals had a higher total follicle density (P<0.001) and more sweat glands (P<0.001) than the thicker-fibred animals. The fibre diameter and total follicle density were negatively correlated (R(2)=0.56, P<0.001). Given that the finer-fibred animals had higher follicle density and more sweat glands than animals with thicker fibres, we conclude that alpacas with high follicle density should not be limited for potential sweating ability. PMID- 25526648 TI - The Rufous Hornero (Furnarius rufus) nest as an incubation chamber. AB - Foraging and incubation are mutually exclusive activities for parent birds. A trade-off is generated when a combination of food availability and temperature regulation force birds to choose one and neglect the other, at least temporarily. The Rufous Hornero builds large, oven-like, mud nests, the evolutionary cause of which remains unknown. We tested that temperature variation inside the nest is that which is expected if one function of the nest were for temperate regulation. If so, this would suggest that the nest works as an incubation chamber (but which now may serve more than one function). We divided nests into two natural treatments: nests that received more continuous direct sunshine (sun), and those that received less direct sunshine, due to shade from trees or buildings (shade). Thermometer data loggers were placed in the nest cavity and outside, in the shade of the nest, and temperature was measured every 10min. We predicted that temperatures would consistently be higher and less variable in nests than outside nests. Also, at higher ambient temperatures the nest would function better as an incubation chamber as a consequence of having evolved in a hotter climate. Thus, in Curitiba, where temperatures are lower than where the species (and nest) evolved, nests in greater sunshine should have thermal characteristics that support the incubation chamber hypothesis. Predictions were supported: with Repeated Measures ANOVA and t-tests, we found that temperatures were more constant and higher in nests, especially when in the sun, and as the season progressed (hotter ambient temperatures). We conclude that the large mud nest of the Rufous Hornero works as an incubation chamber that likely evolved to help resolve the incubation-foraging trade-off in the very seasonal and hot regions where the bird evolved. Thus, as an incubation chamber, the nest allows the bird to forage rather than incubate thereby resolving the foraging-incubation trade off and potentially favoring survival of the adults and their foraging for, rather than incubating, their young. Counter intuitively, in the study area, where the Rufous Hornero is a recent arrival following deforestation, and where the climate is very different from where it evolved, there seems to be no clear thermal benefits for the birds from their energetically expensive mud nest. PMID- 25526649 TI - Nest temperatures in a loggerhead nesting beach in Turkey is more determined by sea surface than air temperature. AB - While climate change is now fully recognised as a reality, its impact on biodiversity is still not completely understood. To predict its impact, proxies coherent with the studied ecosystem or species are thus required. Marine turtles are threatened worldwide (though some populations are recovering) as they are particularly sensitive to temperature throughout their entire life cycle. This is especially true at the embryo stage when temperature affects both growth rates and sex determination. Nest temperature is thus of prime importance to understand the persistence of populations in the context of climate change. We analysed the nest temperature of 21 loggerheads (Caretta caretta) originating from Dalyan Beach in Turkey using day-lagged generalised mixed models with autocorrelation. Surprisingly, the selected model for nest temperature includes an effect for sea surface temperature 4-times higher than for air temperature. We also detected a very significant effect of metabolic heating during development compatible with what is already known about marine turtle nests. Our new methodology allows the prediction of marine turtle nest temperatures with good precision based on a combination of air temperature measured at beach level and sea surface temperature in front of the beach. These data are available in public databases for most of the beaches worldwide. PMID- 25526650 TI - Effect of warming rate on the critical thermal maxima of crabs, shrimp and fish. AB - The threat of global warming has prompted numerous recent studies on the thermal tolerance of marine species. A widely used method to determine the upper thermal limit has been the Critical Thermal Maximum (CTMax), a dynamic method, meaning that temperature is increased gradually until a critical point is reached. This method presents several advantages over static methods, however, there is one main issue that hinders interpretation and comparison of CTMax results: the rate at which the temperature is increased. This rate varies widely among published protocols. The aim of the present work was to determine the effect of warming rate on CTMax values, using different animal groups. The influence of the thermal niche occupied by each species (intertidal vs subtidal) and habitat (intertidal vs subtidal) was also investigated. CTMax were estimated at three different rates: 1 degrees Cmin(-1), 1 degrees C30min(-1) and 1 degrees Ch(-1), in two species of crab, Eurypanopeus abbreviatus and Menippe nodifrons, shrimp Palaemon northropi and Hippolyte obliquimanus and fish Bathygobius soporator and Parablennius marmoreus. While there were significant differences in the effect of warming rates for some species, for other species warming rate produced no significant differences (H. obliquimanus and B. soporator). While in some species slower warming rates lead to lower CTMax values (P. northropi and P. marmoreus) in other species the opposite occurred (E. abbreviatus and M. nodifrons). Biological group has a significant effect with crabs' CTMax increasing at slower warming rates, which did not happen for shrimp and fish. Subtidal species presented lower CTMax, at all warming rates tested. This study highlights the importance of estimating CTMax values at realistic rates that species encounter in their environment and thus have an ecological value. PMID- 25526651 TI - Evaluation of structural and thermophysical effects on the measurement accuracy of deep body thermometers based on dual-heat-flux method. AB - To help pave a path toward the practical use of continuous unconstrained noninvasive deep body temperature measurement, this study aims to evaluate the structural and thermophysical effects on measurement accuracy for the dual-heat flux method (DHFM). By considering the thermometer's height, radius, conductivity, density and specific heat as variables affecting the accuracy of DHFM measurement, we investigated the relationship between those variables and accuracy using 3-D models based on finite element method. The results of our simulation study show that accuracy is proportional to the radius but inversely proportional to the thickness of the thermometer when the radius is less than 30.0mm, and is also inversely proportional to the heat conductivity of the heat insulator inside the thermometer. The insights from this study would help to build a guideline for design, fabrication and optimization of DHFM-based thermometers, as well as their practical use. PMID- 25526652 TI - Investigation of thermal distribution for pulsed laser radiation in cancer treatment with nanoparticle-mediated hyperthermia. AB - In this paper, we have simulated the efficacy of gold/gold sulfide (GGS) nanoshells in NIR laser hyperthermia to achieve effective targeting for tumor photothermal therapy. The problem statement takes into account the heat transfer with the blood perfusion through capillaries, and pulsed laser irradiation during the hyperthermia. Although previous researchers have used short laser pulses (nanosecond and less), in order to prevent heat leakage to the neighbor tissues, we have examined the effect of millisecond pulses, as the extent of the target volume to which hyperthermia is induced is usually larger and also the lasers with this specification are more available. A tumor with surrounding tissue was simulated in COMSOL software (a finite element analysis, solver and simulation software) and also in a phantom made of agarose and intralipid. The tumor was irradiated by 10, 20 and 30 laser pulses with durations of 15, 50 and 200ms and fluences of 20, 40 and 60J/cm(2). Experimental tests performed on a phantom prove the ability of the applied numerical model to capture the temperature distribution in the target tissue. We have shown that our simulation permits prediction of treatment outcome from computation of thermal distribution within the tumor during laser hyperthermia using GGS nanoshells and millisecond pulsed laser irradiation. The advantage of this simulation is its simplicity as well as its accuracy. Although, to develop the model completely for a given organ and application, all the parameters should be estimated based on a real vasculature of the organ, physiological conditions, and expected variation in those physiological conditions for that application in the organ. PMID- 25526653 TI - Increased expression of Hsp70 and Hsp90 mRNA as biomarkers of thermal stress in loggerhead turtle embryos (Caretta Caretta). AB - The survival and viability of sea turtle embryos is dependent upon favourable nest temperatures throughout the incubation period. Consequently, future generations of sea turtles may be at risk from increasing nest temperatures due to climate change, but little is known about how embryos respond to heat stress. Heat shock genes are likely to be important in this process because they code for proteins that prevent cellular damage in response to environmental stressors. This study provides the first evidence of an expression response in the heat shock genes of embryos of loggerhead sea turtles (Caretta caretta) exposed to realistic and near-lethal temperatures (34 degrees C and 36 degrees C) for 1 or 3 hours. We investigated changes in Heat shock protein 60 (Hsp60), Hsp70, and Hsp90 mRNA in heart (n=24) and brain tissue (n=29) in response to heat stress. Under the most extreme treatment (36 degrees C, 3h), Hsp70 increased mRNA expression by a factor of 38.8 in heart tissue and 15.7 in brain tissue, while Hsp90 mRNA expression increased by a factor of 98.3 in heart tissue and 14.7 in brain tissue. Hence, both Hsp70 and Hsp90 are useful biomarkers for assessing heat stress in the late-stage embryos of sea turtles. The method we developed can be used as a platform for future studies on variation in the thermotolerance response from the clutch to population scale, and can help us anticipate the resilience of reptile embryos to extreme heating events. PMID- 25526654 TI - Effect of tissue and atmosphere's parameters on human eye temperature distribution. AB - A three dimensional finite element method analysis was employed to investigate the effect of tissue and atmosphere parameters namely, ambient temperature, ambient convection coefficient, local blood temperature, and blood convection coefficient upon temperature distribution of human eyes. As a matter of simplification, only eye ball and skull bone are considered as the system of eye modeling. Decreasing the local blood temperature and keeping it cool is one of the most important ways to control bleeding during surgeries. By lower temperature of body organs such as the eye, the need for oxygenated blood is reduced, allowing for an extension in time for surgery. With this in mind, this study is done to see which one of parameters, such as ambient temperature, ambient convection coefficient, local blood temperature, and blood convection coefficient, has an effective role in decreasing the temperature of the eye. To this end, 3 different paths were employed to find out about the temperature distribution through the eye. The analysis of the three paths demonstrates the interaction of ambient and blood temperature in modeling temperature changes in specific locations of the eye. These data will be important in applications such as eye surgery, relaxation, and sleep therapy. PMID- 25526655 TI - The effect of ice-slushy consumption on plasma vasoactive intestinal peptide during prolonged exercise in the heat. AB - The aim of this study was to determine the effect of exercise in the heat on thermoregulatory responses and plasma vasoactive intestinal peptide concentration (VIP) and whether it is modulated by ice-slushy consumption. Ten male participants cycled at 62% VO2max for 90min in 32 degrees C and 40% relative humidity. A thermoneutral (37 degrees C) or ice-slushy (-1 degrees C) sports drink was given at 3.5mlkg(-1) body mass every 15min during exercise. VIP and rectal temperature increased during exercise (mean+/-standard deviation: 4.6+/ 4.4pmolL(-1), P=0.005; and 1.3+/-0.4 degrees C, P<0.001 respectively) and were moderately associated (r=0.35, P=0.008). While rectal temperature and VIP were not different between trials, ice-slushy significantly reduced heat storage (P=0.010) and skin temperature (time*trial interaction P=0.038). It appears that VIP does not provide the signal linking cold beverage ingestion and lower skin temperature in the heat. PMID- 25526656 TI - Consequences of experimental cortisol manipulations on the thermal biology of the checkered puffer (Sphoeroides testudineus) in laboratory and field environments. AB - Anthropogenic climate change is altering temperature regimes for coastal marine fishes. However, given that temperature changes will not occur in isolation of other stressors, it is necessary to explore the potential consequences of stress on the thermal tolerances and preferences of tropical marine fish in order to understand the thresholds for survival, and predict the associated coastal ecological consequences. In this study, we used exogenous cortisol injections to investigate the effects of a thermal challenge on checkered puffers (Sphoeroides testudineus) as a secondary stressor. There were no significant differences between control and cortisol-treated fish 48h following cortisol treatment for swimming ability (using a chase to exhaustion protocol), blood glucose concentrations or standard metabolic rate. In the lab, control and cortisol treated puffers were exposed to ambient (29.1+/-1.5 degrees C), ambient +5 degrees C (heat shock) and ambient -5 degrees C (cold shock) for 4h and to evaluate the consequences of abrupt temperature change on puff performance and blood physiology. Following cold shock, control fish exhibited increases in cortisol levels and weak 'puff' performance. Conversely, fish dosed with cortisol exhibited consistently high cortisol levels independent of thermal treatment, although there was a trend for an attenuated cortisol response in the cortisol treated fish to the cold shock treatment. A 20-day complementary field study conducted in the puffer's natural habitat, a tidal creek in Eleuthera, The Bahamas, revealed that cortisol-injected fish selected significantly cooler temperatures, measured using accumulated thermal units, when compared to controls. These results, and particularly the discrepancies between consequences documented in the laboratory and the ecological trends observed in the field, highlight the need to establish the link between laboratory and field data to successfully develop management policies and conservation initiatives with regards to anthropogenic climate change. PMID- 25526657 TI - Stage of pregnancy dictates heterothermy in temperate forest-dwelling bats. AB - Bats face high energetic requirements, as powered flight is costly and they have a disadvantageous surface-to-volume-ratio. To deal with those requirements energy saving mechanisms, such as heterothermy (torpor), have evolved. Torpor during pregnancy, however, reduces rates of foetal development and consequently prolongs pregnancy. Therefore, heterothermy has a great effect on reproduction, as an unhindered parturition can only be assured by high body temperatures. Regardless of these adverse affects of torpor the energetic requirements of bats during reproduction urge for energy savings and bats are known to enter torpor during pregnancy. The species in the current study differ in their torpor patterns and thus their heterothermic strategy. However, we hypothesized, that species specific heterothermic behaviour should be revoked at the end of pregnancy. We analyzed skin temperatures of Myotis bechsteinii, Myotis nattereri and Plecotus auritus during pregnancy and found no differences in torpor depth between species during the last phase of pregnancy. Furthermore, we could show that individuals entered torpor frequently during pregnancy and only minimized torpor during the last stage of pregnancy. This suggests that close to the end of pregnancy, heterothermy is restricted but not species-specific and the required energy is allocated otherwise. PMID- 25526658 TI - Performance limitation and the role of core temperature when wearing light-weight workwear under moderate thermal conditions. AB - The objective of this investigation was to achieve an understanding about the relationship between heat stress and performance limitation when wearing a two layerfire-resistant light-weight workwear (full-clothed ensemble) compared to an one-layer short sports gear (semi-clothed ensemble) in an exhaustive, stressful situation under moderate thermal condition (25 degrees C). Ten well trained male subjects performed a strenuous walking protocol with both clothing ensembles until exhaustion occurred in a climatic chamber. Wearing workwear reduced the endurance performance by 10% (p=0.007) and the evaporation by 21% (p=0.003), caused a more pronounced rise in core temperature during submaximal walking (0.7+/-0.3 vs. 1.2+/-0.4 degrees C; p<=0.001) and from start till exhaustion (1.4+/-0.3 vs. 1.8+/-0.5 degrees C; p=0.008), accelerated sweat loss (13+/-2 vs. 15+/-3gmin(-1); p=0.007), and led to a significant higher heart rate at the end of cool down (103+/-6 vs. 111+/-7bpm; p=0.004). Correlation analysis revealed that core temperature development during submaximal walking and evaporation may play important roles for endurance performance. However, a critical core temperature of 40 degrees C, which is stated to be a crucial factor for central fatigue and performance limitation, was not reached either with the semi-clothed or the full-clothed ensemble (38.3+/-0.4 vs. 38.4+/-0.5 degrees C). Additionally, perceived exertion did not increase to a higher extent parallel with the rising core temperature with workwear which would substantiate the critical core temperature theory. In conclusion, increased heat stress led to cardiovascular exercise limitation rather than central fatigue. PMID- 25526659 TI - Exercise in a hot environment influences plasma anti-inflammatory and antioxidant status in well-trained athletes. AB - Exercise in thermally stressful environmental conditions can enhance oxidative stress. We sought to measure the plasma antioxidant defenses and cytokine response together with oxidative damage post-exercise in a temperate versus a hot environment. The plasma concentrations of vasoactive endothelin-1 and vascular angiogenic growth factor were also evaluated. Male athletes (n=9) volunteered to participate. The athletes randomly performed two bouts of treadmill exercise of 45min at 75-80% of maximal oxygen uptake in a climatic-controlled chamber under two different conditions: temperate environment (10-12 degrees C, 40-55% humidity) and hot, humid environment (30-32 degrees C, 75-78% humidity). Venous blood samples were obtained immediately pre- and post-bout and on recovery after 2h. Serum glucose, malondialdehyde and lactate concentrations were significantly increased post-exercise in hot but maintained in the temperate environment; these post-exercise values were significantly higher after exercise in hot than in temperate. Urinary 8-hydroxy-2'-deoxyguanosine concentration, plasma phosphocreatine kinase and catalase activities, creatinine and monocyte chemoattractant protein-1, and interleukin-6 significantly increased post exercise in hot but maintained in temperate environment. The post-exercise circulating values of antioxidant enzyme paraoxonase-1 and endothelin were significantly higher in the hot than in temperate environment. Exercise in a hot and humid environment resulted in mild hyperthermia with elevated perceived exertion and thermal stress. Hyperthermic environment induced hyperglycemia, lactatecidemia and more cellular and oxidative damage than exercise in a temperate environment but also induced a post-exercise antioxidant and anti inflammatory response in plasma. These results suggest that environmental temperature needs to be taken into account when evaluating exercise-related oxidative stress and inflammation. PMID- 25526660 TI - Gross mismatch between thermal tolerances and environmental temperatures in a tropical freshwater snail: climate warming and evolutionary implications. AB - The relationship between acute thermal tolerance and habitat temperature in ectotherm animals informs about their thermal adaptation and is used to assess thermal safety margins and sensitivity to climate warming. We studied this relationship in an equatorial freshwater snail (Clea nigricans), belonging to a predominantly marine gastropod lineage (Neogastropoda, Buccinidae). We found that tolerance of heating and cooling exceeded average daily maximum and minimum temperatures, by roughly 20 degrees C in each case. Because habitat temperature is generally assumed to be the main selective factor acting on the fundamental thermal niche, the discordance between thermal tolerance and environmental temperature implies trait conservation following 'in situ' environmental change, or following novel colonisation of a thermally less-variable habitat. Whereas heat tolerance could relate to an historical association with the thermally variable and extreme marine intertidal fringe zone, cold tolerance could associate with either an ancestral life at higher latitudes, or represent adaptation to cooler, higher-altitudinal, tropical lotic systems. The broad upper thermal safety margin (difference between heat tolerance and maximum environmental temperature) observed in this snail is grossly incompatible with the very narrow safety margins typically found in most terrestrial tropical ectotherms (insects and lizards), and hence with the emerging prediction that tropical ectotherms, are especially vulnerable to environmental warming. A more comprehensive understanding of climatic vulnerability of animal ectotherms thus requires greater consideration of taxonomic diversity, ecological transition and evolutionary history. PMID- 25526661 TI - The tryptophan kynurenine pathway, neopterin and IL-6 during vulvectomy and abdominal hysterectomy. AB - BACKGROUND: Surgery has wide ranging immunomodulatory properties of which the mechanism is poorly understood. In order to investigate how different types of surgery influence inflammation, we designed a longitudinal observational study investigating two inflammatory profiles of two separate patient groups undergoing gynaecological operations of differing severity. In addition to measuring the well known inflammatory markers neopterin and IL-6, we also determined the kynurenine/tryptophan ratio. This study was a prospective, single center, two armed observational study involving 28 female patients. Plasma levels of tryptophan, kynurenine, neopterin and IL-6 were determined from samples taken at: 24 hrs pre-operative, prior to induction, ten minutes before the operation was expected to end, and at 24 and 96 hours post operative in patients undergoing abdominal hysterectomy and vulvectomy. RESULTS: There were 15 and 13 patients included in the vulvectomy and abdominal hysterectomy groups, respectively. In this study we show that anesthesia and surgery significantly increases the enzyme activity of indoleamine 2, 3 dioxygenase (IDO) as measured by the kynurenine/tryptophan ratio (P=0.003), while maintaining stable neopterin levels. However, abdominal hysterectomy causes a considerable IL-6 increase (P<0.001). CONCLUSION: Surgery and associated anesthesia cause a significant tryptophan level decrease while significantly increasing IDO activity. Both types of surgery produce nearly identical neopterin time curve relationships, with no significant change occurring in either group. However, even though neopterin is unaffected by the severity of surgery, IL-6 responded to surgical invasiveness by revealing a significant increase during abdominal hysterectomy. PMID- 25526662 TI - In the social amoeba Dictyostelium discoideum, density, not farming status, determines predatory success on unpalatable Escherichia coli. AB - BACKGROUND: The social amoeba Dictyostelium discoideum interacts with bacteria in a variety of ways. It is a predator of bacteria, can be infected or harmed by bacteria, and can form symbiotic associations with bacteria. Some clones of D. discoideum function as primitive farmers because they carry bacteria through the normally sterile D. discoideum social stage, then release them after dispersal so the bacteria can proliferate and be harvested. Some farmer-associated bacteria produce small molecules that promote host farmer growth but inhibit the growth of non-farmer competitors. To test whether the farmers' tolerance is specific or extends to other growth inhibitory bacteria, we tested whether farmer and non farmer amoebae are differentially affected by E. coli strains of varying pathogenicity. Because the numbers of each organism may influence the outcome of amoeba-bacteria interactions, we also examined the influence of amoeba and bacteria density on the ability of D. discoideum to grow and develop on distinct bacterial strains. RESULTS: A subset of E. coli strains did not support amoeba proliferation on rich medium, independent of whether the amoebae were farmers or non-farmers. However, amoebae could proliferate on these strains if amoebae numbers are high relative to bacteria numbers, but again there was no difference in this ability between farmer and non-farmer clones of D. discoideum. CONCLUSIONS: Our results show that farmer and non-farmers did not differ in their abilities to consume novel strains of E. coli, suggesting that farmer resistance to their own carried bacteria does not extend to foreign bacteria. We see that increasing the numbers of bacteria or amoebae increases their respective likelihood of competitive victory over the other, thus showing Allee effects. We hypothesize that higher bacteria numbers may result in higher concentrations of a toxic product or in a reduction of resources critical for amoeba survival, producing an environment inhospitable to amoeba predators. Greater amoeba numbers may counter this growth inhibition, possibly through reducing bacterial numbers via increased predation rates, or by producing something that neutralizes a potentially toxic bacterial product. PMID- 25526663 TI - A note on statistical and biological communication: a case study of the 2009 H1N1 pandemic. AB - BACKGROUND: Many academic fields contribute to medical and health research. As a result, due to the various backgrounds of these disciplines, inference and interpretation of study findings can be misconstrued. RESULTS: In a recent survey of the 2009 H1N1 literature we found many instances where semantic and statistical misinterpretation or miscommunication could potentially arise. We provide examples where miscommunication or misinterpretation of study results can mislead the interdisciplinary reader. We also provide some additional background on statistical methodology and theory for the interested reader. DISCUSSION: This work presented some examples where statistical misinterpretation or miscommunication could arise in the H1N1 literature. However, similar challenges are encountered in other subjects and disciplines. To reduce the probability of this occurring it is necessary that (1) readers consider papers with a critical eye and approach citations with caution; (2) authors take more care to present study methods with more clarity. Reproducibility of the study results would greatly aid readers in their ability to understand and interpret the given findings. PMID- 25526664 TI - Immunization interventions to interrupt hepatitis B virus mother-to-child transmission: a meta-analysis of randomized controlled trials. AB - BACKGROUND: This study aimed to determine the clinical efficacy of various immune interventions on mother-to-child transmission (MTCT) of hepatitis B virus (HBV). METHODS: We retrieved different immune strategies on how to prevent MTCT reported in the literature from Chinese and English electronic databases from the viewpoint of intrauterine and extrauterine prevention. Relative risk (RR) and 95% confidence interval (CI) methods were used. RESULTS: Twenty-five articles on intrauterine prevention and 16 on extrauterine prevention were included in the analysis. Intrauterine prevention could reduce infants' HBV infection rate (RR = 0.36, 95% CI: 0.28-0.45) and increase their anti-hepatitis B surface-positive rate (RR = 2.42, 95% CI: 1.46-4.01) at birth. Compared with passive immunization, passive-active immunization could reduce infants' HBV infection rate (RR = 0.66, 95% CI: 0.52-0.84) at birth, even at more than 12 months of age (RR = 0.54, 95% CI: 0.42-0.69). Subgroup analysis demonstrated similar results except for pregnant women who were hepatitis B surface antigen-positive. Funnel plots and Egger's tests showed publication bias mainly in intrauterine prevention not in extrauterine one. CONCLUSIONS: The long-term protective effect of pregnant women injected with hepatitis B immunoglobulin during pregnancy should be further validated by large-scale randomized trials. Newborns of pregnant women who carried HBV should undergo a passive-active immunization strategy. PMID- 25526665 TI - Prevalence of peripheral neuropathy and its associated demographic and health status characteristics, among people on antiretroviral therapy in Rwanda. AB - BACKGROUND: The introduction of antiretroviral therapy (ART) has dramatically reduced the mortality rate of people living with HIV (PLHIV). However, complications of both HIV and ART, such as peripheral neuropathy currently affect PLHIV. The purpose of this study was to establish the prevalence of peripheral neuropathy of the lower extremity and, its association with demographic and health status, characteristics among people on ART in Rwanda. METHODS: A cross sectional study was conducted among 507 women and men aged between 18 and 60 years, on ART, randomly selected from eight selected ART clinics in Rwanda. Brief Peripheral Neuropathy Screen was used to assess peripheral neuropathy. RESULTS: Peripheral neuropathy prevalence was 59% overall, mean age of the participants was 39.7 (+/-9.2) and a slightly older age was associated with peripheral neuropathy; [42(+/-9.2) vs 37 (+/-8.8) (p < 0.001)]. 78% of participants living in urban settings compared to 40% in rural settings reported peripheral neuropathy, 69% of participants with higher levels of education (secondary level and above) reported lower extremity neuropathy.The three factors were significantly associated with peripheral neuropathy in multivariable model analysis: older age [aOR = 1.1, 95% CI (1.0, 1.2), p < 0.001], primary education level [aOR = 0.6 95% Cl (0.3, 1.0), p = 0.04] and urban setting [aOR = 0.1, 95% CI (0.06, 0.3), p < 0.001], after adjusting for other factors. None of the health status characteristics namely; the level of CD4 cell count, duration of HIV infection and duration on ART, was independently associated with peripheral neuropathy. CONCLUSIONS: The prevalence of peripheral neuropathy among PLHIV on ART in Rwanda is high. It is unclear why urban setting has an effect on PN levels in this cross sectional study, but does suggest that unidentified social and lifestyles factors may have a role in subjective symptoms and objective signs, of PN. PMID- 25526667 TI - Transcriptome characterization of the ascidian Pyura chilensis using 454 pyrosequencing data from two distant localities on the southeast Pacific. AB - This study describes the results from transcriptomes sequenced by 454 pyrosequencing from two populations separated by 10 degrees of latitude of the endemic tunicate Pyura chilensis. Most transcripts were assembled in 43,972 contigs with an average length of 842 nucleotides. De novo assembly revealed that less than 30% of the contigs were annotated to Gene Ontology terms. A total of 71,662 single nucleotide polymorphisms (SNPs) were detected in 14,712 contigs. In silico differential expression of contigs annotated for SNPs revealed several genes differentially expressed in individuals collected from both populations. The present genomic resource will provide the basis to perform functional genomics on the species via the localization of genomic markers that can aid in determining levels of local adaptation, overall genetic structure and the genetic assessment of restocking programs for this species. PMID- 25526666 TI - Levels of metacaspase1 and chaperones related to protein quality control in alcoholic and nonalcoholic steatohepatitis. AB - Efficient management of misfolded or aggregated proteins in ASH and NASH is crucial for continued hepatic viability. Cellular protein quality control systems play an important role in the pathogenesis and progression of ASH and NASH. In a recent study, elevated Mca1 expression counteracted aggregation and accumulation of misfolded proteins and extended the life span of the yeast Saccharomyces cerevisiae (Hill et al, 2014). Mca1 may also associate with Ssa1 and Hsp104 in disaggregation and fragmentation of aggregated proteins and their subsequent degradation through the ER-associated degradation (ERAD) pathway. If degradation is not available, protection of the cellular environment from a misfolded protein is accomplished by its sequestration into two distinct inclusion bodies (Kaganovich et al., 2008) called the JUNQ (JUxta Nuclear Quality control compartment) and the IPOD (Insoluble Protein Deposit). Mca1, Hsp104, Hsp40, Ydj1, Ssa1, VCP/p97, and p62 all play important roles in protein quality control systems. This study aims to measure the expression of Mca1 and related chaperones involved in protein quality control in alcoholic steatohepatitis (ASH), and nonalcoholic steatohepatitis (NASH) compared with normal control liver biopsies. Mca1, Hsp104, Hsp40, Ydj1, Ssa1, VCP/p97, and p62 expressions were measured in three to six formalin-fixed paraffin embedded ASH and NASH liver biopsies and control normal liver specimens by immunofluorescence staining and quantified by immunofluorescence intensity. Mca1, Hsp104, Ydj1 and p62 were significantly upregulated compared to control (p<0.05) in ASH specimens. Hsp40 and VCP/p97 were also uptrending in ASH. In NASH, the only significant difference was the increased expression of Hsp104 compared to control (p<0.05). Ssa1 levels were uptrending in both ASH and NASH specimens. The upregulation of Mca1, Hsp104, Ydj1 and p62 in ASH may be elicited as a response to the chronic exposure of the hepatocytes to the toxicity of alcohol. Recruitment of Mca1, Hsp104, Ydj1 and p62 may indicate that autophagy, the ERAD, JUNQ, and IPOD systems are active in ASH. Whereas in NASH, elevated Hsp104 and uptrending Ssa1 levels may indicate that autophagy and IPOD may be the only active protein quality control systems involved. PMID- 25526669 TI - Effect of a vascular access team on central line-associated bloodstream infections in infants admitted to a neonatal intensive care unit: a systematic review. AB - OBJECTIVE: To review the effect of a vascular access team on the incidence of central line-associated bloodstream infections in infants admitted to a neonatal intensive care unit. DATA SOURCES: MEDLINE, CINAHL, Embase, Web-of-Science and the Cochrane Library were searched until December 2013. STUDY SELECTION: Studies that evaluated the implementation of a vascular access team, and focused on the incidence of central line-associated bloodstream infections in infants admitted to a neonatal intensive care unit, were selected. DATA EXTRACTION: Incidence rates of central line-associated bloodstream infections were extracted, as well as information on vascular access team tasks and team composition. The quality of studies was critically appraised using the McMaster tool for quantitative studies. DATA SYNTHESIS: Seven studies involving 136 to 414 participants were included. In general, the implementation of a vascular access team coincided with the implementation of concurrent interventions. All vascular access teams included nurses, and occasionally included physicians. Main tasks included insertion and maintenance of central lines. In all studies, a relative decrease of 45-79% in central line-associated bloodstream infections was reported. CONCLUSIONS: A vascular access team is a promising intervention to decrease central line-associated bloodstream infections in infants admitted to a neonatal intensive care unit. However, level of evidence for effectiveness is low. Future research is required to improve the strength of evidence for vascular access teams. PMID- 25526668 TI - Draft genome sequence of an agar-degrading marine bacterium Flammeovirga pacifica WPAGA1. AB - Flammeovirga pacifica WPAGA1(T), which was isolated from sediment of the west Pacific Ocean in 2009 has the ability to produce agar-oligosaccharides from Gracilaria lemaneiformis directly by enzyme-degradation. The draft genome sequence of this strain was sequenced and annotated. Its draft genome contained 6,507,364 bp with a G+C content of 33.8%. Genome sequence information provided a basis for analyzing the digestion of G. lemaneiformis. PMID- 25526670 TI - Calcaneal quantitative ultrasound and phalangeal radiographic absorptiometry alone or in combination in a triage approach for assessment of osteoporosis: a study of older women with a high prevalence of falls. AB - BACKGROUND: The objective of this study was to investigate if application of United Kingdom National Osteoporosis Society (UK-NOS) triage approach, using calcaneal quantitative ultrasound (QUS), phalangeal radiographic absorptiometry (RA), or both methods in combination, for identification of women with osteoporosis, would reduce the percentage of women who need further assessment with Dual Energy X-ray Absorptiometry (DXA) among older women with a high prevalence of falls. METHODS: We assessed 286 women with DXA of hip and spine (Hologic Discovery) of whom 221 were assessed with calcaneal QUS (Achilles Lunar), 245 were assessed with phalangeal RA (Aleris Metriscan), and 202 were assessed with all three methods. Receiver operator characteristics (ROC) curve for QUS, RA, and both methods in combination predicting osteoporosis defined by central DXA were performed. We identified cutoffs at different sensitivity and specificity values and applied the triage approach recommended by UK-NOS. The percentage of women who would not need further examination with DXA was calculated. RESULTS: Median age was 80 years (interquartile range [IQR]) [75-85], range 65-98. 66.8% reported at least one fall within the last 12 months. Prevalence of osteoporosis was 44.4%. Area under the ROC-curve (AUC) (95% confidence interval (CI)) was 0.808 (0.748-0.867) for QUS, 0.800 (0.738-0.863) for RA, and 0.848 (0.796-0.900) for RA and QUS in combination. At 90% certainty levels, UK-NOS triage approach would reduce the percentage of women who need further assessment with DXA by 60% for QUS, and 43% for RA. The false negative and false positive rates ranged from 4% to 5% for QUS and RA respectively. For the combined approach using 90% certainty level the proportion of DXAs saved was 22%, the false negative rate was 0% and false positive rate was 0.5%. Using 85% certainty level for the combined approach the proportion of DXAs saved increased to 41%, but false negative and false positive values remained low (0.5%, and 0.5% respectively). CONCLUSIONS: In a two-step, triage approach calcaneal QUS and phalangeal RA perform well, reducing the number of women who would need assessment with central DXA. Combining RA and QUS reduces misclassifications whilst still reducing the need for DXAs. PMID- 25526671 TI - The effect of the drying temperature on the properties of wet-extruded calcium stearate pellets: pellet microstructure, drug distribution, solid state and drug dissolution. AB - Although drying is widely applied during the manufacturing of solid dosage forms, its potential effect on the product's (key) properties is often underestimated. Hence, the present study addresses drying related modifications of wet-extruded pellets comprising calcium stearate (CaSt, matrix former) and ibuprofen (model drug). After spheronization, the pellets were tray dried at different temperatures. The dried pellets were evaluated regarding their microstructure, the ibuprofen distribution, solid state modifications and the resulting in-vitro dissolution profiles. The ibuprofen distribution profiles along the pellets' cross-sections varied for the different drying conditions. The profiles turned from inhomogeneous to uniform with increasing drying temperature. Temperatures above 20 degrees C yielded solid state modifications, including ibuprofen transition into the amorphous state and the formation of eutectic compositions. As none of the batches exhibited a high specific surface area associated with an open, well-interconnected pore system, the dissolution profiles were a function of the ibuprofen distribution. Differences in the solid state did not contribute to the dissolution behavior, since the CaSt matrix did not swell or dissolve in the dissolution medium. These findings show that drying may considerably affect the final product properties even for moderate drying conditions. PMID- 25526672 TI - Moisture diffusion and permeability characteristics of hydroxypropylmethylcellulose and hard gelatin capsules. AB - The primary objective of this paper is to compare the sorption characteristics of hydroxypropylmethylcellulose (HPMC) and hard gelatin (HG) capsules and their ability to protect capsule contents. Moisture sorption and desorption isotherms for empty HPMC and HG capsules have been investigated using dynamic vapour sorption (DVS) at 25 degrees C. All sorption studies were analysed using the Young-Nelson model equations which distinguishes three moisture sorption types: monolayer adsorption moisture, condensation and absorption. Water vapour diffusion coefficients (D), solubility (S) and permeability (P) parameters of the capsule shells were calculated. ANOVA was performed with the Tukey comparison test to analyse the effect of %RH and capsule type on S, P, and D parameters. The moisture uptake of HG capsules were higher than HPMC capsules at all %RH conditions studied. It was found that values of D and P across HPMC capsules were greater than for HG capsules at 0-40 %RH; whereas over the same %RH range S values were higher for HG than for HPMC capsules. S values decreased gradually as the %RH was increased up to 60% RH. To probe the effect of moisture ingress, spray dried lactose was loaded into capsules. Phase evolution was characterised by scanning electron microscopy (SEM), X-ray powder diffraction (XRD), and differential scanning calorimetry (DSC). The capsules under investigation are not capable of protecting spray dried lactose from induced solid state changes as a result of moisture uptake. For somewhat less moisture sensitive formulations, HPMC would appear to be a better choice than HG in terms of protection of moisture induced deterioration. PMID- 25526673 TI - Measurement, analysis and prediction of topical UV filter bioavailability. AB - The aim of the present study was to objectively quantify and predict bioavailability of three sunscreen agents (i.e., benzophenone-3, 2 ethylhexylsalicylate, and 2 ethylhexyl-4-methoxycinnamate) in epidermis treated by petrolatum and emulsion-based formulations for 7 and 30min on four human volunteers. Profiles of sunscreen agents through stratum corneum (SC), derived from the assessment of chemical amounts in SC layers collected by successive adhesive tape-stripping, were successfully fitted to Fick's second law of diffusion. Therefore, permeability coefficients of sunscreen agents were found lower with petrolatum than with emulsion based formulations confirming the crucial role of vehicle in topical delivery. Furthermore, the robustness of that methodology was confirmed by the linear relationship between the chemical absorption measured after 30min and that predicted from the 7-min exposure experiment. Interestingly, in this dermatopharmacokinetic method, the deconvolution of permeability coefficients in their respective partition coefficients and absorption constants allowed a better understanding of vehicle effects upon topical bioavailability mechanisms and bioequivalence of skin products. PMID- 25526674 TI - Ink-jet printing versus solvent casting to prepare oral films: Effect on mechanical properties and physical stability. AB - The aim of this work was to compare and contrast the mechanical properties and physical stabilities of oral films prepared with either thermal ink-jet printing (TIJP) or solvent casting (SC). Clonidine hydrochloride was selected as a model drug because of its low therapeutic dose and films were prepared using cellulose polymers. Mechanical testing showed that the printed films had Young's moduli and tensile strength values similar to the free film, while casted films were significantly more brittle. The drug also appeared to crystallize out of casted films during stress testing whereas printed films remained unchanged. The dissolution behavior of printed and cast films were similar, because of the rapid disintegration of the polymer. The conclusion is that printing resulted in a better film than casting because the drug resided on the film, rather than in the film where it could exert a plasticizing effect. PMID- 25526675 TI - Towards a systematic analysis of human short-chain dehydrogenases/reductases (SDR): Ligand identification and structure-activity relationships. AB - Short-chain dehydrogenases/reductases (SDRs) constitute a large, functionally diverse branch of enzymes within the class of NAD(P)(H) dependent oxidoreductases. In humans, over 80 genes have been identified with distinct metabolic roles in carbohydrate, amino acid, lipid, retinoid and steroid hormone metabolism, frequently associated with inherited genetic defects. Besides metabolic functions, a subset of atypical SDR proteins appears to play critical roles in adapting to redox status or RNA processing, and thereby controlling metabolic pathways. Here we present an update on the human SDR superfamily and a ligand identification strategy using differential scanning fluorimetry (DSF) with a focused library of oxidoreductase and metabolic ligands to identify substrate classes and inhibitor chemotypes. This method is applicable to investigate structure-activity relationships of oxidoreductases and ultimately to better understand their physiological roles. PMID- 25526677 TI - Evidence for frequent and tissue-specific sequence heteroplasmy in human mitochondrial DNA. AB - Mitochondrial point heteroplasmy is a common event observed not only in patients with mitochondrial diseases but also in healthy individuals. We here report a comprehensive investigation of heteroplasmy occurrence in human including the whole mitochondrial control region from nine different tissue types of 100 individuals. Sanger sequencing was used as a standard method and results were supported by cloning, minisequencing, and massively parallel sequencing. Only 12% of all individuals showed no heteroplasmy, whereas 88% showed at least one heteroplasmic position within the investigated tissues. In 66% of individuals up to 8 positions were affected. The highest relative number of heteroplasmies was detected in muscle and liver (79%, 69%), followed by brain, hair, and heart (36.7%-30.2%). Lower percentages were observed in bone, blood, lung, and buccal cells (19.8%-16.2%). Accumulation of position-specific heteroplasmies was found in muscle (positions 64, 72, 73, 189, and 408), liver (position 72) and brain (partial deletion at position 71). Deeper analysis of these specific positions in muscle revealed a non-random appearance and position-specific dependency on age. MtDNA heteroplasmy frequency and its potential functional importance have been underestimated in the past and its occurrence is ubiquitous and dependent at least on age, tissue, and position-specific mutation rates. PMID- 25526676 TI - Spontaneous daily torpor and fasting-induced torpor in Djungarian hamsters are characterized by distinct patterns of metabolic rate. AB - The Djungarian hamster is a rodent species that expresses both spontaneous daily torpor (SDT) when acclimated to winter conditions as well as fasting-induced torpor (FIT) during summer. In an earlier report we argued that these two thermoregulatory phenomena differ in several parameters. In the present study, we further complete this comparison by showing that metabolic rate patterns differ between both SDT and FIT. SDT bouts were significantly longer and deeper compared to FIT bouts. Additionally, respiratory quotient measures support the view that SDT is entered from a state of energetic balance while FIT appears to be an emergency shutdown of energy demanding thermogenesis due to a shortage of energy sources. In a second experiment, we also confirm that brief periods of food restriction during the hamsters' torpor season increase the frequency of SDT, but do not affect its depth or duration. Although winter-acclimated animals could flexibly alter torpor frequency in order to stay in energetic balance, we also found evidence for torpor expression patterns that resembled FIT, rather than SDT. Consequently, if energetic challenges cannot be compensated with increased SDT expression any longer, the hamsters seem to be driven in a negative energy balance resulting in FIT as a last resort. PMID- 25526678 TI - Interpreting the results of a retrospective comparison of test and reference treatments in a randomized clinical trial setting. AB - BACKGROUND AND OBJECTIVES: The retrospective comparison of test and reference treatment arms in a randomized prospective clinical trial is potentially useful in economic modeling seeking to assess the cost effectiveness of alternative therapies. METHODS: To enhance the credibility of such retrospective comparisons, we propose the application of the following adjustments to significance levels obtained from standard statistical methodology: (1) a significance test for the lower bound of the 95 % confidence interval for the observed difference, (2) a conservative Bonferroni method of adjustment for multiple comparisons, (3) an adjusted p-value calculated using Scheffe's single-step method, and (4) Bayesian 95 % credibility intervals with a prior centered at zero. RESULTS: These adjustments were applied to data from a randomized double-blind concurrent trial (SPD489-325) that established the efficacy and safety of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Prospectively planned analyses demonstrated that the reduction in the symptoms of ADHD was significantly greater than placebo in patients treated with either LDX or the reference treatment, osmotic-release oral system methylphenidate (OROS-MPH). Retrospective analyses showed that the improvement in the symptoms of ADHD was greater in patients treated with LDX than OROS-MPH. We now show that this observation remained significant after the application of the four statistical penalties. CONCLUSIONS: By adjusting the significance level, it is possible to compare quantitatively such retrospective results with prospectively defined comparisons. However, the qualitative level of such retrospective evidence should remain secondary to that obtained from prospectively specified comparisons in a randomized clinical trial. PMID- 25526679 TI - Barriers to and facilitators of partner notification for chlamydia trachomatis among health care professionals. AB - BACKGROUND: Partner notification (PN) is an essential case-finding tool in the management of sexually transmitted infections (STIs). Yet, data on the effectiveness and factors impacting implementation of PN in the Netherlands are lacking. With the aim of further exploring and improving the PN process, the current study assessed perceived barriers and facilitators among health care professionals in the STI clinical setting. In particular, we explored the management of PN in young heterosexual patients diagnosed with Chlamydia trachomatis (Ct). METHODS: We conducted semi-structured interviews among 22 health care professionals (response rate 52%) from 5 of the 8 national STI clinics in the Netherlands. We carried out qualitative content analysis using a framework approach. All participants were nurses, aged mid 20's to late 50's, and all but one were female. RESULTS: All health care professionals felt comfortable discussing PN. Other perceived facilitators for PN included: time, one-on-one consultations, interviewing skills (i.e. Motivational Interviewing) and a proactive helping style. Important barriers were identified as: sub-optimal guidelines, inaccurate sexual history, a lack of feedback regarding the motivational strategies that were used, and the lack of feedback regarding overall PN effectiveness. The health care professionals placed an emphasis on the care and treatment of the individual index patient rather than on discussion of PN, or on motivating and helping patients to engage in PN. CONCLUSIONS: Health care professionals identified several barriers that need to be overcome, and facilitators which need to be maintained. Future efforts should concentrate on introducing PN protocols, providing feedback on both the effectiveness of strategies used by health care professionals, and on the PN process as a whole, and educating health care professionals about Motivational Interviewing strategies. Moreover, the possible implementation of an Internet-based PN system should be explored. PMID- 25526680 TI - Field evaluation of selected cassava genotypes for cassava brown streak disease based on symptom expression and virus load. AB - BACKGROUND: Production of cassava (Manihot esculenta Crantz), a food security crop in sub-Saharan Africa, is threatened by the spread of cassava brown streak disease (CBSD) which manifests in part as a corky necrosis in the storage root. It is caused by either of two virus species, Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV), resulting in up to 100% yield loss in susceptible varieties. METHODS: This study characterized the response of 11 cassava varieties according to CBSD symptom expression and relative CBSV and UCBSV load in a field trial in Uganda. Relative viral load was measured using quantitative RT-PCR using COX as an internal housekeeping gene. RESULTS: A complex situation was revealed with indications of different resistance mechanisms that restrict virus accumulation and symptom expression. Four response categories were defined. Symptom expression was not always positively correlated with virus load. Substantially different levels of the virus species were found in many genotypes suggesting either resistance to one virus species or the other, or some form of interaction, antagonism or competition between virus species. CONCLUSIONS: A substantial amount of research still needs to be undertaken to fully understand the mechanism and genetic bases of resistance. This information will be useful in informing breeding strategies and restricting virus spread. PMID- 25526682 TI - Response assessment to neoadjuvant therapy in soft tissue sarcomas: using CT texture analysis in comparison to tumor size, density, and perfusion. AB - PURPOSE: To evaluate the role of computed tomography (CT) texture analysis in assessing response of soft tissue sarcoma (STS) treated with neoadjuvant bevacizumab (BVZ) plus radiotherapy in comparison to tumor size, density, and perfusion. METHODS: In the phase II clinical trial, 20 patients with STSs received BVZ alone for 2 weeks followed by BVZ plus radiotherapy for 6 weeks prior to surgery. All patients received CT perfusion at baseline, 2 and 8 weeks after the therapy, and tumor blood flow (BF) was measured. In contrast enhanced CT image at the arterial peak enhancement time, mean of positive pixels (MPP) was measured as a texture parameter using texture analysis software, and tumor size and density were also measured. The percent changes of these parameters were compared with pathological response on surgical specimen. RESULTS: After 2 weeks of the therapy, MPP and BF decreased by 10.42% and 20.08%, while changes of tumor size and density were not obvious. After 8 weeks, MPP, BF, and density decreased by 29.2% (p = 0.03), 53.2% (p = 0.001), and 30.41% (p = 0.005), respectively, without a significant change in size. The percent change of MPP after 8 weeks had a significant correlation with tumor necrosis in surgical specimen (r = -0.801, p < 0.001), whereas those of size, density, and BF did not. The receiver-operating characteristic analysis demonstrated that the percent change of MPP < -35.36% was an optimal cut-off value to differentiate pathological responders. CONCLUSION: The change of MPP is the best biomarker for the treatment response in STS. PMID- 25526681 TI - Activation of the cardiac proteasome promotes angiotension II-induced hypertrophy by down-regulation of ATRAP. AB - Proteasomal degradation is critical to maintaining cardiac function and is altered in various diseases. Angiotensin II (Ang II) acts as a growth factor to induce cardiac growth. Here we aimed to test whether proteasome is involved in the development of Ang II-induced cardiac hypertrophy and dissect its molecular mechanisms. Cardiac hypertrophy was induced by Ang II infusion (1000 ng/kg/min) using mini-osmotic pumps. Starting 1 day before implantation, the mice were injected with the proteasome inhibitor bortezomib (BTZ, 50 MUg/kg, 3 times per week) or with vehicle. After 14 days, the pool of ubiquitinated proteins was reduced but the protein expression of proteasome subunits (including beta1i, beta2i and beta5/beta5i) was markedly up-regulated in left ventricular hypertrophy versus control, which was accompanied by a significant increase in proteasome activities. Furthermore, Ang II-treated mice showed a significant increase in blood pressure but decrease in cardiac contractile function, and significant left ventricular hypertrophy, fibrosis and inflammation, which were all attenuated in BTZ-treated mice. Mechanistically, these beneficial effects were associated with the inhibition of degradation of angiotensin II type 1 receptor-associated protein (ATRAP) and inactivation of AT1R-mediated p38 MAPK and STAT3 signaling pathways. In conclusion, our data indicate that the activation of proteasome is required for the Ang II-induced cardiac hypertrophy, and suggest that the inhibition of proteasome activity by BTZ could be a potential therapeutic strategy for the treatment of cardiac hypertrophy and other heart diseases. PMID- 25526683 TI - Differential diagnosis of uterine smooth muscle tumors using diffusion-weighted imaging: correlations with the apparent diffusion coefficient and cell density. AB - The purpose of this study is to investigate the utility of the apparent diffusion coefficient (ADC) in differentiating benign and malignant uterine smooth muscle tumors classified by signal intensity (SI) on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI), and to determine the correlation between ADC and tumor cell density. This retrospective study reviewed 168 lesions in 134 cases with pathologically confirmed uterine smooth muscle tumors, including 6 leiomyosarcomas and 3 smooth muscle tumors of uncertain malignant potential, and preoperative magnetic resonance imaging examinations performed between October 2009 and November 2012. T2WI and DWI were also performed for each subject. Tumors were then classified according to SI on T2WI and DWI relative to myometrial SI. The correlation between ADC and tumor cell density was also determined. In Group 1 (high on both T2WI/DWI), mean ADC was significantly lower for leiomyosarcoma (0.91 * 10(-3) mm(2)/s) than for leiomyoma (1.30 * 10(-3) mm(2)/s; p < 0.05) and mean cell density significantly higher for leiomyosarcoma (42.9%) than for leiomyoma (22.4%; p < 0.05). A strong negative correlation was seen between ADC and tumor cell density in Group 1 (Spearman, R = -0.72; p < 0.05). ADC may help to differentiate benign from malignant uterine smooth muscle tumors, particularly tumors with high SI on T2WI and DWI. PMID- 25526684 TI - A case of undifferentiated carcinoma of the pancreas mimicking main-duct intraductal papillary mucinous neoplasm (IPMN). AB - We report here a rare case of undifferentiated carcinoma of the pancreas mimicking main-duct intraductal papillary mucinous neoplasm. In an 80-year-old woman, an approximately 8-mm papillary mass was incidentally detected at the downstream edge of a dilatated main pancreatic duct lumen on CT and MRI. Main pancreatic duct dilatation in the pancreatic body and tail and parenchymal atrophy were observed in the upstream of the mass. Histopathologically, the tumor protruded into the downstream edge of the dilatated main pancreatic duct lumen in the pancreatic body. The tumor cells had highly atypical nuclei and abundant polymorphic structures, and showed positive staining for granulocyte colony stimulating factor, which led to the diagnosis of undifferentiated carcinoma. A total of 13 cases of undifferentiated carcinoma with intraductal tumor growth have been reported to date. The case report by Bergmann et al. has been the smallest in histopathological specimen, and the present case is the smallest in size detected by radiological images. Since early undifferentiated carcinoma of the pancreas can resemble those of main-duct intraductal papillary mucinous neoplasm in cross-sectional images, we have to consider undifferentiated carcinoma in the differential diagnosis of the solitary and papillary mass with low contrast enhancement in early phase in the main pancreatic duct. PMID- 25526685 TI - Enhancement of radiofrequency ablation of the liver combined with transarterial embolization using various embolic agents. AB - PURPOSE: Reducing blood flow in the liver during radiofrequency ablation causes enlargement of the ablation area. In this animal study, we evaluated the extended effects of radiofrequency ablation combined with transarterial embolization using various embolic agents. METHODS: We treated 38 radiofrequency ablation lesions after embolization in 13 pigs using the following embolic agents: gelatin sponge (Group A); iodized oil followed by gelatin sponge (Group B); 700-900 um calibrated microspheres (Group C); and 100-300 um calibrated microspheres (Group D). Lesion size and pathological evaluations of these ablation lesions were compared with those receiving radiofrequency ablation alone (control). RESULTS: Both the long- and short-axis diameters of the ablation lesions for Groups A, B, C, and D were significantly longer than those of controls (long axis/short axis for Groups A, B, C, D, and controls were 27.2/23.2, 30.2/26.0, 28.2/22.2, 32.0/24.4, and 23.2 mm/18.5 mm, respectively) (P < 0.05). The long-axis of the ablation lesion for Group D was significantly longer than those for both Groups A and C (P < 0.05). At pathological examination, the central ablation lesions showed coagulative necrosis with a surrounding hemorrhagic rim, and the microspheres were fitted to occlude the small arteries in peripheral liver parenchyma in Groups C and D. CONCLUSIONS: The extended effects of embolization with small microspheres may be stronger than those with large microspheres and were equal to those with iodized oil followed by gelatin sponge. PMID- 25526686 TI - Influence of the adaptive iterative dose reduction 3D algorithm on the detectability of low-contrast lesions and radiation dose repeatability in abdominal computed tomography: a phantom study. AB - PURPOSE: The purpose of the study is to evaluate the influence of the adaptive iterative dose reduction (AIDR 3D) algorithm on the detectability of low-contrast focal liver lesions (FLLs) and the radiation dose repeatability of automatic tube current modulation (ATCM) in abdominal CT scans using anthropomorphic phantoms. MATERIALS AND METHODS: Three different sizes of anthropomorphic phantoms, each with 4 low-contrast FLLs, were scanned on a 320-channel CT scanner using the ATCM technique and AIDR 3D, at different radiation doses: full-dose, half-dose, and quarter-dose. Scans were repeated three times and reconstructed with filtered back projection (FBP) and AIDR 3D. Radiation dose repeatability was assessed using the intraclass correlation coefficient (ICC). Image noise, quality, and lesion conspicuity were assessed by four reviewers and the number of invisible FLLs was compared among different radiation doses and reconstruction methods. RESULTS: ICCs of radiation dose among the three CT scans were excellent in all phantoms (0.99). Image noise, quality, and lesion conspicuity in the half-dose group were comparable with full-dose FBP after applying AIDR 3D in all phantoms. In small phantoms, the half-dose group reconstructed with AIDR 3D showed similar sensitivity in visualizing low-contrast FLLs compared to full-dose FBP (P = 0.77 0.84). In medium and large phantoms, AIDR 3D reduced the number of missing low contrast FLLs [3.1% (9/288), 11.5% (33/288), respectively], compared to FBP [10.4% (30/288), 21.9% (63/288), respectively] in the full-dose group. CONCLUSION: By applying AIDR 3D, half-dose CT scans may be achievable in small sized patients without hampering diagnostic performance, while it may improve diagnostic performance in medium- and large-sized patients without increasing the radiation dose. PMID- 25526687 TI - Histone modifications involved in cassette exon inclusions: a quantitative and interpretable analysis. AB - BACKGROUND: Chromatin structure and epigenetic modifications have been shown to involve in the co-transcriptional splicing of RNA precursors. In particular, some studies have suggested that some types of histone modifications (HMs) may participate in the alternative splicing and function as exon marks. However, most existing studies pay attention to the qualitative relationship between epigenetic modifications and exon inclusion. The quantitative analysis that reveals to what extent each type of epigenetic modification is responsible for exon inclusion is very helpful for us to understand the splicing process. RESULTS: In this paper, we focus on the quantitative analysis of HMs' influence on the inclusion of cassette exons (CEs) into mature RNAs. With the high-throughput ChIP-seq and RNA seq data obtained from ENCODE website, we modeled the association of HMs with CE inclusions by logistic regression whose coefficients are meaningful and interpretable for us to reveal the effect of each type of HM. Three type of HMs, H3K36me3, H3K9me3 and H4K20me1, were found to play major role in CE inclusions. HMs' effect on CE inclusions is conservative across cell types, and does not depend on the expression levels of the genes hosting CEs. HMs located in the flanking regions of CEs were also taken into account in our analysis, and HMs within bounded flanking regions were shown to affect moderately CE inclusions. Moreover, we also found that HMs on CEs whose length is approximately close to nucleosomal-DNA length affect greatly on CE inclusion. CONCLUSIONS: We suggested that a few types of HMs correlate closely to alternative splicing and perhaps function jointly with splicing machinery to regulate the inclusion level of exons. Our findings are helpful to understand HMs' effect on exon definition, as well as the mechanism of co-transcriptional splicing. PMID- 25526689 TI - Experimental ileitis alters prostaglandin biosynthesis in mesenteric lymphatic and blood vessels. AB - Prostaglandins are important mediators responsible for many changes that occur during the inflammatory response. Specifically, in inflammatory bowel disease (IBD), prostaglandins are key players in maintenance of blood flow and mucosal defense. In blood vessels, prostaglandins modulate and inhibit transmigration. In lymphatic vessels, on the other hand, prostaglandin E2 (PGE2) and prostacyclin (PGI2) have been shown to potently inhibit lymphatic contractility. Inhibition of lymphatic contractility could impair proper tissue fluid drainage during inflammation, consequently leading to the submucosal oedema observed in IBD. Alterations in production of PGE2 and PGI2 during inflammation could have severe implications on lymphatic and vascular functions within the small intestine. Using the 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced ileitis guinea pig and rat models, we assessed by quantitative PCR changes in mRNA transcript of enzymes and receptors involved in the production and actions of prostaglandins in mesenteric lymphatic and blood vessels as well as in the affected ileum. Furthermore, we also assessed lymphatic tissue levels of PGE2 and PGI2 during inflammation. We observed significant changes in lymphatic mRNA expression of COX 1, COX-2, MPGES-1, PGIS, EP4 and IP and increases in PGE2 and PGI2 in tissues of TNBS-treated animals. Changes in mRNA in blood vessels from TNBS-treated animals included differences in COX-1, COX-2, MPGES-1, PGIS, EP1, EP2 and IP expression. Prostaglandin metabolites are differentially regulated in both lymphatic and blood vessels during intestinal inflammation. PMID- 25526688 TI - Androgen-induced hypertension in angiotensinogen deficient mice: role of 20-HETE and EETS. AB - 20-HETE is a potent inducer of endothelial ACE in vitro and administration of lisinopril or losartan attenuates blood pressure in models of 20-HETE-dependent hypertension. The present study was undertaken to further define the relationship between 20-HETE and the renin-angiotensin system in hypertension using an angiotensinogen-deficient mouse (Agt+/-). Treatment of male AGT+/- with 5alpha dihydrotestosterone (DHT) increased systolic BP from 102+/-2 to 125+/-3mmHg; in comparison, the same treatment raised BP in wild type (WT) from 110+/-2 to 138+/ 2mmHg. DHT increased vascular 20-HETE levels in AGT+/- and WT from 1.5+/-0.7 and 2.1+/-0.6 to 13.0+/-2.0 and 15.8+/-4.0ng/mg, respectively. Concurrent treatment with the 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) prevented the increases in BP in both AGT+/- and WT mice. Administration of 20 HEDE at the peak of the DHT-induced BP increase (12 days) reduced BP to basal levels after 48h. Interestingly, basal levels of renal microvascular EETs were higher in AGT+/- compared to WT (55.2+/-9.7 vs 20.0+/-4.1ng/mg) and treatment of AGT+/- with DHT decreased the levels of EETs (28.4+/-5.1ng/mg). DHT-mediated changes in vascular EET level were not observed in WT mice. Vascular Cyp4a12 and ACE protein levels were increased in both AGT+/- and WT by 30-40% and decreased with concomitant administration of 20-HEDE. Lisinopril was as effective as 20 HEDE in preventing DHT-mediated increases in BP in both AGT+/- and WT mice. This study substantiates our previous findings that the RAS plays an important role in 20-HETE-mediated hypertension. It also proposes a novel interaction between 20 HETE and EETs. PMID- 25526690 TI - Oxidative and pro-inflammatory effects of cobalt and titanium oxide nanoparticles on aortic and venous endothelial cells. AB - Ultra-fine particles have recently been included among the risk factors for the development of endothelium inflammation and atherosclerosis, and cobalt (CoNPs) and titanium oxide nanoparticles (TiNPs) have attracted attention because of their wide range of applications. We investigated their toxicity profiles in two primary endothelial cell lines derived from human aorta (HAECs) and human umbilical vein (HUVECs) by comparing cell viability, oxidative stress, the expression of adhesion molecules and the release of chemokines during NP exposure. Both NPs were very rapidly internalised, and significantly increased adhesion molecule (ICAM-1, VCAM-1, E-selectin) mRNA and protein levels and the release of monocyte chemoattractant protein-1 (MCP-1) and interleukin 8 (IL-8). However, unlike the TiNPs, the CoNPs also induced time- and concentration dependent metabolic impairment and oxidative stress without any evident signs of cell death or the induction of apoptosis. There were differences between the HAECs and HUVECs in terms of the extent of oxidative stress-related enzyme and vascular adhesion molecule expression, ROS production, and pro-inflammatory cytokine release despite the similar rate of NP internalisation, thus indicating endothelium heterogeneity in response to exogenous stimuli. Our data indicate that NPs can induce endothelial inflammatory responses via various pathways not involving only oxidative stress. PMID- 25526691 TI - High intralocus variability and interlocus recombination promote immunological diversity in a minimal major histocompatibility system. AB - BACKGROUND: The genes of the major histocompatibility complex (MHC/MH) have attracted considerable scientific interest due to their exceptional levels of variability and important function as part of the adaptive immune system. Despite a large number of studies on MH class II diversity of both model and non-model organisms, most research has focused on patterns of genetic variability at individual loci, failing to capture the functional diversity of the biologically active dimeric molecule. Here, we take a systematic approach to the study of MH variation, analyzing patterns of genetic variation at MH class IIalpha and IIbeta loci of the seahorse, which together form the immunologically active peptide binding cleft of the MH class II molecule. RESULTS: The seahorse carries a minimal class II system, consisting of single copies of both MH class IIalpha and IIbeta, which are physically linked and inherited in a Mendelian fashion. Both genes are ubiquitously expressed and detectible in the brood pouch of male seahorses throughout pregnancy. Genetic variability of the two genes is high, dominated by non-synonymous variation concentrated in their peptide-binding regions. Coding variation outside these regions is negligible, a pattern thought to be driven by intra- and interlocus recombination. Despite the tight physical linkage of MH IIalpha and IIbeta loci, recombination has produced novel composite alleles, increasing functional diversity at sites responsible for antigen recognition. CONCLUSIONS: Antigen recognition by the adaptive immune system of the seahorse is enhanced by high variability at both MH class IIalpha and IIbeta loci. Strong positive selection on sites involved in pathogen recognition, coupled with high levels of intra- and interlocus recombination, produce a patchwork pattern of genetic variation driven by genetic hitchhiking. Studies focusing on variation at individual MH loci may unintentionally overlook an important component of ecologically relevant variation. PMID- 25526692 TI - Chitosan, nanoclay and chitosan-nanoclay composite as adsorbents for Rhodamine-6G and the resulting optical properties. AB - The objective of this study was to investigate the use of chitosan-clay nanocomposite (CC) as an adsorbent for Rhodamine 6G (Rh-6G). The effects of adsorbent dose, contact time, and concentration on the adsorption process were systematically studied. Isotherm models were applied to the experimental equilibrium data obtained from spectrophotometric measurements of dye adsorption. Various Kinetic models were used to describe the kinetic data and evaluate of rate constants. Rh-6G loaded adsorbents were investigated for their optical and photophysical properties. PMID- 25526693 TI - In situ precipitation of nano-hydroxyapatite in gelatin polymatrix towards specific fluoride sorption. AB - This study investigates the synthesis of nano-hydroxyapatite (n-HAp) incorporated gelatin (Gel) biocomposite namely n-HAp@Gel composite for efficient removal of fluoride from aqueous solution. The results demonstrated that, the developed n HAp@Gel biocomposite possess an enhanced defluoridation capacity (DC) of 4157 mgF /kg. The batch experiments were optimized as a function of various influencing parameters like contact time, pH, co-ions, temperature and initial fluoride concentration. The physicochemical characteristics of n-HAp@Gel composite was examined by using different instrumental techniques like FTIR, XRD, TGA-DSC and SEM with EDAX analysis. The sorption data were fitted with various isotherm models. The acquired thermodynamic parameters showed that the sorption of fluoride onto the sorbent was endothermic and spontaneous in nature. The reaction based and diffusion-based models were used to identify the kinetics of the reaction. At field conditions, n-HAp@Gel composite reduce the fluoride concentration below the tolerance limit. A regeneration technique was proposed in order to reuse the sorbent. PMID- 25526694 TI - Carboxymethyl cellulose/silica hybrids as templates for calcium phosphate biomimetic mineralization. AB - Multiphase hybrid materials were synthesized using carboxymethyl cellulose (CMC) as bioactive polymer, silica gel as matrix assisted networks and calcium phosphate as inorganic mineral phase. These hybrids were investigated with infrared spectroscopy, X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectroscopy and transmission electron microscopy. Biomimetic crystal growth nucleated from the CMC/silica hybrids was suggested as amorphous calcium phosphate with an evidence that hydroxyapatite, the mineralized component of bone, may be formed at high CMC content. This study provides an efficient approach toward bone-like hybrids with potential bone healing applications. PMID- 25526695 TI - Anti-cancer, pharmacokinetics and tumor localization studies of pH-, RF- and thermo-responsive nanoparticles. AB - The curcumin-encapsulated chitosan-graft-poly(N-vinyl caprolactam) nanoparticles containing gold nanoparticles (Au-CRC-TRC-NPs) were developed by ionic cross linking method. After "optimum RF exposure" at 40 W for 5 min, Au-CRC-TRC-NPs dissipated heat energy in the range of ~42 degrees C, the lower critical solution temperature (LCST) of chitosan-graft-poly(N-vinyl caprolactam), causing controlled curcumin release and apoptosis to cancer cells. Further, in vivo PK/PD studies on swiss albino mice revealed that Au-CRC-TRC-NPs could be sustained in circulation for a week with no harm to internal organs. The colon tumor localization studies revealed that Au-CRC-TRC-NPs were retained in tumor for a week. These results throw light on their feasibility as multi-responsive nanomedicine for RF-assisted cancer treatment modalities. PMID- 25526696 TI - Assessing Risk of Critical Care Complications and Mortality in the Elective Bariatric Surgery Population Using a Modified Frailty Index. AB - BACKGROUND: The rate of surgical complications from bariatric procedures remains low despite an increase in volume. When serious complications occur, they are associated with an increased risk of mortality. The aim of this study is to determine if frail bariatric patients have an increased rate of Clavien level 4 and 5 complications. This study was conducted in participating hospitals in the National Surgical Quality Improvement Program (NSQIP). METHODS: The NSQIP participant use files were used to identify 104,952 patients undergoing elective bariatric procedures from 2005 to 2012. A previously described modified frailty index (mFI) was calculated based on available NSQIP variables, with a higher index suggesting more frail patients. Postoperative adverse events were stratified to Clavien levels 4 and 5 utilizing a pre-existing mapping scheme. RESULTS: Overall, 1 % of patients undergoing elective bariatric surgery experienced Clavien level 4 complications, and 0.2 % experienced a Clavien level 5 complication (mortality). Univariate analysis demonstrated that frailty was significant for both Clavien level 4 and 5 complications (p < 0.001). The mean mFI for those with Clavien level 4 complications, 0.15, was significantly higher than those without Clavien 4 complications, 0.09 (p < 0.001). Those experiencing mortality had a mean mFI of 0.17 compared to a mean mFI of 0.09 in those without mortality (p < 0.001). Frailty retained the highest odds ratio for both Clavien 4 and 5 complications in multivariate analysis compared to American Society of Anesthesiologist (ASA) class, age, sex, body mass index (BMI), and procedure type. CONCLUSIONS: Frailty may be used during patient selection to stratify bariatric surgery patients at high risk for critical care level complications. PMID- 25526699 TI - Experimental splenosis in the liver and lung spread through the vasculature. AB - To demonstrate that intra-organ splenosis can engraft and develop after being distributed through the vasculature, tiny fragments of splenic tissues were injected into the inferior vena cava or the portal vein to induce intrapulmonary and intrahepatic splenosis in rats. After 1 month, splenic autograft structures in the lung and liver were assessed for structure by histology, for immunologic compartments by immunohistochemistry, for phagocytic function by carbon uptake and for vascular formation by Microfil (a silicon rubber compound) injection. Intrapulmonary and intrahepatic splenoses were indeed able to spread through the vasculature. The intrapulmonary splenic autografts were trapped and spread out in the interstitium, without forming a capsule. White pulp was markedly developed, showing lymphocyte aggregations that consisted in B cells surrounding the dilated vessel. Splenic sinuses were not definitively observed. Although macrophages were detected by immunohistochemistry, they showed no indication of having phagocytized carbon particles from the vessels, implying a closed circulation. In contrast, intrahepatic splenic autografts formed well-developed capsules, trabeculae and red pulp with splenic sinuses. Macrophages detected by immunohistochemistry were observed capturing carbon particles, which clearly revealed an open system circulation, as seen in normal rat spleen. The development of white pulp was poor and lymphocytes consisting in B cells aggregated in the peripheral margins. These results demonstrate that intra-organ splenosis can spread through the vasculature and that the morphologic and immunologic structures formed in these regenerated autografts are influenced by the organ vasculature and extracellular matrix wherein the tissue fragments settled. PMID- 25526700 TI - Glutathione during embryonic development. AB - BACKGROUND: Glutathione (GSH) is a ubiquitous, non-protein biothiol in cells. It plays a variety of roles in detoxification, redox regulation and cellular signaling. Many processes that can be regulated through GSH are critical to developing systems and include cellular proliferation, differentiation and apoptosis. Understanding how GSH functions in these aspects can provide insight into how GSH regulates development and how during periods of GSH imbalance how these processes are perturbed to cause malformation, behavioral deficits or embryonic death. SCOPE OF REVIEW: Here, we review the GSH system as it relates to events critical for normal embryonic development and differentiation. MAJOR CONCLUSIONS: This review demonstrates the roles of GSH extend beyond its role as an antioxidant but rather GSH acts as a mediator of numerous processes through its ability to undergo reversible oxidation with cysteine residues in various protein targets. Shifts in GSH redox potential cause an increase in S glutathionylation of proteins to change their activity. As such, redox potential shifts can act to modify protein function on a possible longer term basis. A broad group of targets such as kinases, phosphatases and transcription factors, all critical to developmental signaling, is discussed. GENERAL SIGNIFICANCE: Glutathione regulation of redox-sensitive events is an overlying theme during embryonic development and cellular differentiation. Various stresses can change GSH redox states, we strive to determine developmental stages of redox sensitivity where insults may have the most impactful damaging effect. In turn, this will allow for better therapeutic interventions and preservation of normal developmental signaling. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. PMID- 25526697 TI - Probing endocytosis from the enterocyte brush border using fluorescent lipophilic dyes: lipid sorting at the apical cell surface. AB - The small intestinal brush border is a specialized cell membrane that needs to withstand the solubilizing effect of bile salts during assimilation of dietary nutrients and to achieve detergent resistance; it is highly enriched in glycolipids organized in lipid raft microdomains. In the present work, the fluorescent lipophilic probes FM 1-43 (N-(3-triethylammoniumpropyl)-4-(4 (dibutylamino)styryl)pyridinium dibromide), FM 4-64 (N-(3-triethylammoniumpropyl) 4-(6-(4-(diethylamino) phenyl)hexatrienyl)pyridinium dibromide), TMA-DPH (1-(4 trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulfonate), and CellMask Orange plasma membrane stain were used to study endocytosis from the enterocyte brush border of organ-cultured porcine mucosal explants. All the dyes readily incorporated into the brush border but were not detectably endocytosed by 5 min, indicating a slow uptake compared with other cell types. At later time points, FM 1-43 clearly appeared in distinct punctae in the terminal web region, previously shown to represent early endosomes (TWEEs). In contrast, the other dyes were relatively "endocytosis resistant" to varying degrees for periods up to 2 h, indicating an active sorting of lipids in the brush border prior to internalization. For some of the dyes, a diphenylhexatriene motif in the lipophilic tail seemed to confer the relative endocytosis resistance. Lipid sorting by selective endocytosis therefore may be a process in the enterocytes aimed to generate and maintain a unique lipid composition in the brush border. PMID- 25526701 TI - Efficient cell-specific uptake of binding proteins into the cytoplasm through engineered modular transport systems. AB - Through advances in protein scaffold engineering and selection technologies, highly specific binding proteins, which fold under reducing conditions, can be generated against virtually all targets. Despite tremendous therapeutic opportunities, intracellular applications are hindered by difficulties associated with achieving cytosolic delivery, compounded by even correctly measuring it. Here, we addressed cytosolic delivery systematically through the development of a biotin ligase-based assay that objectively quantifies cytosolic delivery in a generic fashion. We developed modular transport systems that consist of a designed ankyrin repeat protein (DARPin) for receptor targeting and a different DARPin for intracellular recognition and a bacterial toxin-derived component for cytosolic translocation. We show that both anthrax pores and the translocation domain of Pseudomonas exotoxin A (ETA) efficiently deliver DARPins into the cytosol. We found that the cargo must not exceed a threshold thermodynamic stability for anthrax pores, which can be addressed by engineering, while the ETA pathway does not appear to have this restriction. PMID- 25526702 TI - Improving drug delivery to solid tumors: priming the tumor microenvironment. AB - Malignant transformation and growth of the tumor mass tend to induce changes in the surrounding microenvironment. Abnormality of the tumor microenvironment provides a driving force leading not only to tumor progression, including invasion and metastasis, but also to acquisition of drug resistance, including pharmacokinetic (drug delivery-related) and pharmacodynamic (sensitivity-related) resistance. Drug delivery systems exploiting the enhanced permeability and retention (EPR) effect and active targeting moieties were expected to be able to cope with delivery-related drug resistance. However, recent evidence supports a considerable barrier role of tumors via various mechanisms, which results in imperfect or inefficient EPR and/or targeting effect. The components of the tumor microenvironment such as abnormal tumor vascular system, deregulated composition of the extracellular matrix, and interstitial hypertension (elevated interstitial fluid pressure) collectively or cooperatively hinder the drug distribution, which is prerequisite to the efficacy of nanoparticles and small-molecule drugs used in cancer medicine. Hence, the abnormal tumor microenvironment has recently been suggested to be a promising target for the improvement of drug delivery to improve therapeutic efficacy. Strategies to modulate the abnormal tumor microenvironment, referred to here as "solid tumor priming" (vascular normalization and/or solid stress alleviation leading to improvement in blood perfusion and convective molecular movement), have shown promising results in the enhancement of drug delivery and anticancer efficacy. These strategies may provide a novel avenue for the development of new chemotherapeutics and combination chemotherapeutic regimens as well as reassessment of previously ineffective agents. PMID- 25526703 TI - Poor sleep quality of third-trimester pregnancy is a risk factor for postpartum depression. AB - BACKGROUND: The aim of this study was to investigate whether poor sleep quality of third-trimester pregnancy is a risk factor for postpartum depression. MATERIAL AND METHODS: Third-trimester pregnant women (T0, n=293) were tested using the first socio-demographic, Pittsburgh Sleep Quality Index, and Edinburgh Postnatal Depression Scale assessments, and received a diagnosis of depression. Three months (T1, n=223) after delivery, scale filling was finished and the structured interview was performed again. RESULTS: We found that 73 persons (32.7%) were low income, 84 persons (37.7%) were middle-income, and 66 persons (29.6%) were higher income. The overall prevalence of postpartum depression was 9.4% (21 persons). After controlling for other factors, age, household income, marital satisfaction, and sleep quality were significantly related to postpartum depression, in which age and sleep quality scores (a higher score was associated with poorer sleep quality) were positively related to postpartum depression, and household income and marital satisfaction were negatively related to postpartum depression. Moreover, third-trimester sleep quality score was positively related to postpartum depressive symptoms. CONCLUSIONS: Poor third-trimester subjective sleep quality is a risk factor for postpartum depression. PMID- 25526698 TI - Listening to another sense: somatosensory integration in the auditory system. AB - Conventionally, sensory systems are viewed as separate entities, each with its own physiological process serving a different purpose. However, many functions require integrative inputs from multiple sensory systems and sensory intersection and convergence occur throughout the central nervous system. The neural processes for hearing perception undergo significant modulation by the two other major sensory systems, vision and somatosensation. This synthesis occurs at every level of the ascending auditory pathway: the cochlear nucleus, inferior colliculus, medial geniculate body and the auditory cortex. In this review, we explore the process of multisensory integration from (1) anatomical (inputs and connections), (2) physiological (cellular responses), (3) functional and (4) pathological aspects. We focus on the convergence between auditory and somatosensory inputs in each ascending auditory station. This review highlights the intricacy of sensory processing and offers a multisensory perspective regarding the understanding of sensory disorders. PMID- 25526704 TI - The nurse scheduling problem in real-life. AB - The aim of this paper is to study the scheduling process for two types of nursing teams, regular teams from care units and the float team that covers for shortages in the hospital. When managers address this problem, they either use a manual approach or have to invest in expensive commercial tool. We propose a simple heuristic approach, flexible and easy enough to be implemented on spreadsheets, and requiring almost no investment. The approach leads to streamlined process and higher-quality schedules for nurses. The multi-objective model and heuristics are presented, and additional analysis is performed to compare the performance of the approach. We show that our approach compares very well with an optimization software (CPLEX solver) and may be implemented at no cost. It addresses the lack of choice between either manual solution method or a commercial package at a high cost. PMID- 25526705 TI - Computer anxiety in nursing: an investigation from Turkish nurses. AB - The purpose of this study was to determine and analyze levels of computer anxiety in nurses at a public university hospital in Turkey. This study investigated the dimensions of computer anxiety in terms of computer literacy, self-efficacy, physical arousal, affective feelings, positive beliefs, and negative beliefs. Moreover in this study it was aimed to analyze relationships among computer anxiety and some characteristics of nurses (age, gender etc.). This study based on Beckers and Schmidt's computer anxiety model. The Beckers and Schmidt's Computer Anxiety Scale (BSCAS) was used for data collection. BSCAS comprises six factors: computer literacy, self-efficacy, physical arousal in the presence of computers, affective feelings towards computers, positive beliefs, and negative beliefs. At the end of the data collection period, 175 nurses were received from the population. The response rate was 43.75%. This study showed that a majority of nurses had medium levels of computer anxiety. Overall computer anxiety means score was 12.11+/-1.72. Computer anxiety has significant relationship with age (r=-.153; p<.05), personal computer ownership (r=.171; p<.05). The highest correlation was between overall computer anxiety and self efficacy (r=-.859), the lowest correlation was between overall computer and negative beliefs (r=-.653). Multiple regression analysis revealed that computer anxiety of nurses was predicted significantly by self efficacy, affective feelings, physical arousal, computer literacy, positive beliefs, and negative beliefs, respectively. PMID- 25526706 TI - Smartphones in medicine: emerging practices in an academic medical center. AB - Advances in mobile phone technology now provide a myriad of resources to physicians' fingertips. However, the medical profession continues to struggle with potential for misuse of these devices. There is a need for better understanding of physicians' uses of smartphones in order to establish guidelines for appropriate and professional behavior. The purpose of the current study was to survey physicians' and medical students' practices concerning smartphone use in the healthcare setting. Physicians and medical students were asked to complete anonymous surveys regarding uses of smartphones within the past month in various healthcare settings. Overall, the participants reported distinctly different patterns in the uses they made of their phones in different settings (P<.001), with most individuals engaging in most behaviors while on break but few using their smartphones while with patients or during procedures. It appears that physicians and medical students make decisions about using their smartphones according to some combination of three considerations: degree of relevance to patient care, the appropriateness of the behavior in front of patients, and the issue of how disruptive that behavior may be. PMID- 25526707 TI - Super wavelet for sEMG signal extraction during dynamic fatiguing contractions. AB - In this research an algorithm was developed to classify muscle fatigue content from dynamic contractions, by using a genetic algorithm (GA) and a pseudo-wavelet function. Fatiguing dynamic contractions of the biceps brachii were recorded using Surface Electromyography (sEMG) from thirteen subjects. Labelling the signal into two classes (Fatigue and Non-Fatigue) aided in the training and testing phase. The genetic algorithm was used to develop a pseudo-wavelet function that can optimally decompose the sEMG signal and classify the fatigue content of the signal. The evolved pseudo wavelet was tuned using the decomposition of 70% of the sEMG trials. 28 independent pseudo-wavelet evolution were run, after which the best run was selected and then tested on the remaining 30% of the trials to measure the classification performance. Results show that the evolved pseudo-wavelet improved the classification rate of muscle fatigue by 4.45 percentage points to 14.95 percentage points when compared to other standard wavelet functions (p<0.05), giving an average correct classification of 87.90%. PMID- 25526708 TI - TARDBP pathogenic mutations increase cytoplasmic translocation of TDP-43 and cause reduction of endoplasmic reticulum Ca2+ signaling in motor neurons. AB - The transactive response DNA binding protein (TDP-43) is a major component of the characteristic neuronal cytoplasmic inclusions seen in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Furthermore, pathogenic mutations in the gene encoding TDP-43, TARDBP, are found in sporadic and familial ALS cases. To study the molecular mechanisms of cellular toxicity due to TDP-43 mutations we generated a novel in vitro cellular model using a fluorescently tagged human genomic TARDBP locus carrying one of two ALS-associated mutations, A382T or M337V, which were used to generate site-specific bacterial artificial chromosome (BAC) human stable cell lines and BAC transgenic mice. In cell lines and primary motor neurons in culture, TDP-M337V mislocalized to the cytoplasm more frequently than wild-type TDP (wt-TDP) and TDP-A382T, an effect potentiated by oxidative stress. Expression of mutant TDP-M337V correlated with increased apoptosis detected by cleaved caspase-3 staining. Cells expressing mislocalized TDP-M337V spontaneously developed cytoplasmic aggregates, while for TDP-A382T aggregates were only revealed after endoplasmic reticulum (ER) stress induced by the calcium-modifying drug thapsigargin. Lowering Ca(2+) concentration in the ER of wt-TDP cells partially recapitulated the effect of pathogenic mutations by increasing TDP-43 cytoplasmic mislocalization, suggesting Ca(2+) dysregulation as a potential mediator of pathology through alterations in Bcl-2 protein levels. Ca(2+) signaling from the ER was impaired in immortalized cells and primary neurons carrying TDP-43 mutations, with a 50% reduction in the levels of luminal ER Ca(2+) stores content and delayed Ca(2+) release compared with cells carrying wt-TDP. The deficits in Ca(2+) release in human cells correlated with the upregulation of Bcl-2 and siRNA-mediated knockdown of Bcl-2 restored the amplitude of Ca(2+) oscillations in TDP-M337V cells. These results suggest that TDP-43 pathogenic mutations elicit cytoplasmic mislocalization of TDP-43 and Bcl 2 mediated ER Ca(2+) signaling dysregulation. PMID- 25526711 TI - The complex relationship between bone remodeling and the physical and material properties of bone. PMID- 25526709 TI - The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders. AB - Pyruvate oxidation defects (PODs) are among the most frequent causes of deficiencies in the mitochondrial energy metabolism and represent a substantial subset of classical mitochondrial diseases. PODs are not only caused by deficiency of subunits of the pyruvate dehydrogenase complex (PDHC) but also by various disorders recently described in the whole pyruvate oxidation route including cofactors, regulation of PDHC and the mitochondrial pyruvate carrier. Our own patients from 2000 to July 2014 and patients identified by a systematic survey of the literature from 1970 to July 2014 with a pyruvate oxidation disorder and a genetically proven defect were included in the study (n=628). Of these defects 74.2% (n=466) belong to PDHC subunits, 24.5% (n=154) to cofactors, 0.5% (n=3) to PDHC regulation and 0.8% (n=5) to mitochondrial pyruvate import. PODs are underestimated in the field of mitochondrial diseases because not all diagnostic centres include biochemical investigations of PDHC in their routine analysis. Cofactor and transport defects can be missed, if pyruvate oxidation is not measured in intact mitochondria routinely. Furthermore deficiency of the X chromosomal PDHA1 can be biochemically missed depending on the X-inactivation pattern. This is reflected by an increasing number of patients diagnosed recently by genetic high throughput screening approaches. PDHC deficiency including regulation and import affect mainly the glucose dependent central and peripheral nervous system and skeletal muscle. PODs with combined enzyme defects affect also other organs like heart, lung and liver. The spectrum of clinical presentation of PODs is still expanding. PODs are a therapeutically interesting group of mitochondrial diseases since some can be bypassed by ketogenic diet or treated by cofactor supplementation. PDHC kinase inhibition, chaperone therapy and PGC1alpha stimulation is still a matter of further investigations. PMID- 25526713 TI - Erratum to: Clinical research on the treatment effects of radioactive (125)I seeds interstitial brachytherapy on children with primary orbital rhabdomyosarcoma. PMID- 25526712 TI - Bone health management in men undergoing ADT: examining enablers and barriers to care. AB - The study determined prostate cancer specialists' knowledge and concordance to guidelines regarding the diagnosis, management, and prevention of androgen deprivation therapy-induced osteoporosis. Despite high knowledge regarding bone health, most respondents did not routinely measure bone mineral density or use fracture risk assessment tools, suggesting a significant gap in the screening/monitoring of bone health. INTRODUCTION: The purpose of this study was to determine prostate cancer specialists' knowledge, practices, self-perceived competencies and barriers to providing guideline-concordant care in the diagnosis, prevention, and management of androgen deprivation therapy (ADT) induced osteoporosis (OP). METHODS: A number of 73 Canadian radiation oncologists and 83 urologists completed questionnaires assessing (i) knowledge regarding OP and consensus guidelines for bone health management in men receiving ADT, (ii) self-assessed competencies regarding bone health management, (iii) current practices regarding OP prevention and management, and (iv) self-perceived barriers to providing guideline-concordant care. RESULTS: The majority of respondents were able to correctly identify the guideline-concordant frequency of repeat dual-energy X-Ray absorptiometry (DXA) scans (76.3%), vitamin D (70.3%), and calcium (53.2%) intake and that bisphosphonates/denosumab should always be considered for patients with a history of one low-trauma fracture (57.6%). Just under 1/3 (32.5%) reported routinely measuring bone mineral density (BMD) prior to starting ADT and routinely measuring BMD 1-2 years following the initiation of ADT (36.6%). Only 4.6% of respondents routinely used a validated fracture risk assessment tool. Lowest self-assessed competency levels were reported in providing self-management education to patients to foster the uptake of healthy bone behaviors (HBBs) and managing patients who present with or develop osteopenia and OP. The most significant barriers to providing OP prevention and management were lack of time and lack of supporting structures. CONCLUSIONS: Despite high knowledge about appropriate bone health care among prostate cancer specialists, there remain significant gaps in screening and monitoring of bone health, suggesting the need to develop innovative strategies to overcome barriers to implementation. PMID- 25526710 TI - Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data. AB - BACKGROUND: The cobalamin E (cblE) (MTRR, methionine synthase reductase) and cobalamin G (cblG) (MTR, methionine synthase) defects are rare inborn errors of cobalamin metabolism leading to impairment of the remethylation of homocysteine to methionine. METHODS: Information on clinical and laboratory data at initial full assessment and during the course of the disease, treatment, outcome and quality of life was obtained in a survey-based, retrospective study from physicians caring for patients with the CblE or CblG defect. In addition, data on enzyme studies in cultured skin fibroblasts and mutations in the MTRR and MTR gene were analysed. RESULTS: In 11 cblE and 13 cblG patients, failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms. Delay in diagnosis depended on age at first symptom and clinical pattern at presentation and correlated significantly with impaired communication abilities at follow-up. Eighteen/22 patients presented with brain atrophy or white matter disease. Biochemical response to treatment with variable combinations of betaine, cobalamin, folate was significant. The overall course was considered improving (n = 8) or stable (n = 15) in 96% of patients, however the average number of CNS symptoms per patient increased significantly over time and 16 of 23 patients were classified as developmentally delayed or severely handicapped. In vitro enzyme analysis data showed no correlation with outcome. Predominantly private mutations were detected and no genotype- phenotype correlations evident. CONCLUSIONS: The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment. PMID- 25526714 TI - Intranasal curcumin ameliorates lipopolysaccharide-induced acute lung injury in mice. AB - Lipopolysaccharide (LPS) is one of the most powerful proinflammatory factor and can induce acute pulmonary inflammation even lung injury after inhalation or systemic administration. LPS induces sepsis and multiple organ damage. Curcumin (diferuloylmethane), a major component of turmeric, exhibits protection against LPS-induced acute lung injury (ALI). We aimed to investigate effects of intranasal curcumin on LPS-induced ALI in mice where curcumin (10 mg/kg, intranasal (i.n.) was given an hour before LPS exposure. After 24 h of intranasal LPS instillation, a marked increase in neutrophil recruitment and myeloperoxidase (MPO) activity was noted which were significantly ameliorated in curcumin treatment group. Oxidative stress markers like nitric oxide (NO), malondialdehyde (MDA) level and evans blue capillary leakage assay also revealed suppression after curcumin treatment; interestingly, levels of anti-oxidative enzymes such as superoxide dismutase (SOD) and catalase were upregulated. Inflammatory cytokine, tumour necrosis factor alpha (TNF-alpha) level was significantly attenuated by curcumin. Hence, intranasal curcumin could be a novel therapeutic strategy for LPS-induced ALI by directly targeting the lungs and enhancing anti-oxidant levels. PMID- 25526715 TI - Regulatory T cells contribute to the recovery of acute lung injury by upregulating Tim-3. AB - Acute lung injury (ALI) is characterized by alveolar injury and uncontrolled inflammation. Mechanisms underlying pathogenesis of ALI are unknown. Regulatory T cells (Tregs), either natural or induced, suppress a variety of physiological and pathological immune responses. In the current study, we investigated whether Tregs were involved in the development of ALI. Proportion of CD4+CD25+FoxP3+ Tregs in the peripheral blood of 66 ALI patients and 30 healthy controls were examined by flow cytometry. Data showed that the percentage of Tregs in CD4+ T cells was significantly increased in patients than that in controls (10.8 versus 7.6%, P=0.003). Also, compared to those who died during the study, patients who survived presented significantly higher level of Tregs at the time of recruitment (P=0.041). Since Tim-3 is a negative regulatory molecule and can modulate the function of Tregs, we evaluated Tim-3 level on Tregs and identified upregulation of the molecule in patients than that in controls. Moreover, compared to those who died during the study, patients who survived showed 1.7-fold higher level of Tim-3 on Tregs at the time of recruitment (P<0.001). These results suggest that Tregs could affect the prognosis of ALI probably due to the upregulation of Tim 3. PMID- 25526716 TI - [Common and not so common nerve entrapment syndromes: diagnostics, clinical aspects and therapy]. AB - Altogether, nerve entrapment syndromes have a very high incidence. Neurological deficits attributable to a focal peripheral nerve lesion lead to the clinical diagnosis. Frequently, pain is the dominant symptom but is often not confined to the nerve supply area. Electroneurography, electromyography, and more recently also neurosonography are the most important diagnostic tools. In most patients surgical therapy is necessary, which should be carried out in a timely manner. The entrapment syndromes discussed are suprascapular nerve entrapment, carpal tunnel syndrome, cubital tunnel syndrome, meralgia paraesthetica, thoracic outlet syndrome and anterior interosseous nerve syndrome. PMID- 25526717 TI - The development of a TED-Ed online resident research training program. AB - BACKGROUND: Pediatric health research is important for improving the health and well-being of children and their families. To foster the development of physicians' research competencies, it is vital to integrate practical and context specific research training into residency programs. PURPOSE: To describe the development of a resident research training program at one tertiary care pediatric academic health sciences center in Ontario, Canada. METHODS: We surveyed residents and pediatricians/research staff to establish the need and content for a resident research training program. RESULTS: Residents and resident research supervisors agreed or strongly agreed that research training is important for residents. However, few residents and supervisors believed that their academic health sciences center provided adequate training and resources to support resident research. As such, an online resident research training program was established. Residents and supervisors agreed that the program should focus on the following topics: 1) critically evaluating research literature, 2) writing a research proposal, 3) submitting an application for research funding, and 4) writing a manuscript. DISCUSSION: This highly accessible, context-specific, and inexpensive online program model may be of interest and benefit to other residency programs as a means to enhance residents' scholarly roles. A formal evaluation of the research training program is now underway. PMID- 25526718 TI - Heat inactivation of a norovirus surrogate in cell culture lysate, abalone meat, and abalone viscera. AB - The current study examined the effects of temperature and heat treatment duration on murine norovirus-1 (MNV-1) from both viral cell culture lysate (7-8 log10 PFU) and experimentally contaminated abalone meat and viscera (5-6 log10 PFU) as a model of human norovirus (NoV). MNV-1 titers in cell culture lysate, abalone meat, and abalone viscera were gradually reduced to 1.93-4.55, 1.79-3.00, and 2.26-3.26 log10 PFU/ml, respectively, after treatment at 70 degrees C for 1-10 min. Treatment at 85 degrees C for 1-5 min gradually reduced MNV-1 titers in abalone meat to 2.71-4.15 log10 PFU/ml. MNV-1 titers in abalone viscera were gradually reduced to 2.91-3.46 log10 PFU/ml after treatment at 85 degrees C for 1-3 min. No significant difference (P > 0.05) was found in MNV-1 titers in the abalone meat and viscera among treatment groups (70 degrees C for 5 min, 70 degrees C for 3 min, and 85 degrees C for 1 min). Complete inactivation of MNV-1 in cell culture lysate was determined at 85 degrees C for >=1 min and 100 degrees C for >=0.5 min. Complete inactivation of MNV-1 in abalone was determined at 100 degrees C for >=0.5 min for meat, and 85 degrees C for 5 min and 100 degrees C for >=0.5 min for viscera. At treatments at 70 degrees C, the Td values (3 log reduction time) were significantly lower (P < 0.05) in the cell culture lysate (3.38) than for the abalone meat (6.07) and viscera (10.73). Td = 3 values were not significantly different (P > 0.05) between abalone meat (1.78) and abalone viscera (1.33) at treatments at 85 degrees C. This study suggests that 100 degrees C for >=0.5 min could potentially be used to inactivate NoV in molluscan shellfishes, including viscera. PMID- 25526720 TI - Vago-glossopharyngeal neuralgia: a literature review of neurosurgical experience. AB - Glossopharyngeal neuralgia (GPN), or better named vago-glossopharyngeal neuralgia (VGPN), is a rare disorder amounting to 1 % of the incidence of trigeminal neuralgia (TN). Pain is paroxysmal, of the electrical shooting type, and mainly provoked by stimulation of the pharynx or deep throat, especially during swallowing. Due to its rarity, VGPN is often misdiagnosed. The front line of medical treatment is based on anticonvulsants. Surgery should be considered when the pain is refractory to medications. In most patients, the cause is neurovascular conflict on root entry zone (REZ) or midcistern portion, of the IXth and/or Xth cranial nerves. Compressive vessels can be evidenced by means of a high sensibility and a high specificity resolution MR imaging in most centers. Present consensus is that the first option of neurosurgical treatment be microvascular decompression. In patients with precarious general conditions, stereotactic radiosurgery may be considered. Also, thermo-rhizotomy at the pars nervosa of foramen jugularis or tractotomy-nucleotomy at brainstem may be alternatives, but these methods entail a significant risk of deficits. In this article, the authors reviewed the main literature series on neurosurgical treatments of this disease. PMID- 25526719 TI - Comparison of methods for evaluating the thermal stability of human enteric viruses. AB - Human enteric viruses have been identified as one of the predominant causative agents of food-borne illnesses in developed countries, and it is estimated that human norovirus accounts for a majority of these illnesses each year. Not all of these viruses can be cultured and hence relatively little is known about their pathogenesis and physicochemical properties. To overcome this, researchers have utilized different virus surrogates for the study of non-cultivable human enteric viruses. In this review, we discuss various methods utilized for the evaluation of the thermal stability of human enteric viruses, compare the results of these methods, and examine how researchers may move toward a single standard approach (i.e., temperatures, virus concentrations, volume/weight of matrices, etc.) for determining thermal inactivation profiles of human enteric viruses and their surrogates. Based on our review, we found that temperature, time of exposure, type of matrix, analysis type, type of heat application, and the concentration and volume of virus used in the experiments were highly variable across virus surrogates even for the same surrogates. Because of these differences-along with the inherent limitations of using surrogate viruses-comparison of these methods and how the results may be extrapolated to human enteric viruses is quite challenging. As a result, we discuss how researchers may move toward a single standard approach for determining thermal inactivation profiles of human enteric viruses and their surrogates. PMID- 25526721 TI - Primo non nocere or maximum survival in grade 2 gliomas? A medical ethical question. AB - BACKGROUND: Maximum safe resection is the "gold standard" in surgical treatment of grade 2 gliomas (G2Gs), aiming to achieve maximal survival benefit with minimal risk of functional deficit. OBJECTIVE: To investigate the attitude of patients and experts towards more extensive surgery with a trade-off between neurological function and survival time. METHODS: Eight patients and seven experts participated in semi-structured focus group interviews. RESULTS: Both patients and experts accepted the premise of balancing neurological function versus longevity. Some patients would accept an increased risk of permanent neurological deficits in order to obtain a chance of increased survival. There was a significant variance in what constituted "quality of life" both between patients and for the individual patient over time. CONCLUSIONS: In important life changing decisions there is no "one size fits all". We find that it is ethically acceptable to offer more extensive surgery than is possible within the concept of maximal safe surgery as a treatment option, when balancing the principles of beneficence, non-maleficience, autonomy and justice supports the decision. At the same time it must be remembered that even when the patients have made a well informed decision, some will regret it. In that situation it will be our job as healthcare professionals to support them and help carry some of this burden. PMID- 25526722 TI - Relationship between socioeconomic status and quality of life in older adults: a path analysis. AB - PURPOSE: The main objective of this study was to determine the relationship between quality of life, social functioning, depressive symptoms, self-efficacy, physical function, and socioeconomic status (SES) in community-dwelling older adults. METHODS: A cross-sectional design was used to examine the relationships. A sample of 193 community-dwelling older adults completed the measurements. Structural equation modeling with full information maximum likelihood in LISREL was used to evaluate the relationships between the latent variables (SES, social functioning, depressive symptoms, self-efficacy, physical function, and quality of life). RESULTS: The path analysis exhibited significant effects of SES on physical function, social functioning, depressive symptoms, and self-efficacy (gamma = 0.42-0.73), and significant effects in regard to social functioning, depressive symptoms, and self-efficacy on quality of life (gamma = 0.27-0.61). There was no direct effect of SES on the quality of life. The model fit indices demonstrated a reasonable fit (chi (2) = 98.3, df = 48, p < 0.001), matching the relative Chi-square criterion and the RMSEA criterion. The model explained 55.5 % of the variance of quality of life. CONCLUSIONS: The path analysis indicated an indirect effect of SES on the quality of life by social functioning, depressive symptoms, and self-efficacy in community-dwelling older adults. Physical function did not have a direct effect on the quality of life. To improve the quality of life in older adults, additional focus is required on the socioeconomic psychosocial differences in the community-dwelling older population. PMID- 25526723 TI - Quality of life and comorbidity among older home care clients: role of positive attitudes toward aging. AB - PURPOSE: Comorbidity has a negative impact on quality of life (QoL). This study aimed to investigate whether the impact of comorbidity on QoL is lower in older home care clients with positive attitudes toward aging. METHODS: Totally, 361 older adults aged 50-91 years who were clients of 14 home care agencies in two regions in the Czech Republic gave an in-person interview to research nurses and completed the WHOQOL-BREF, the WHOQOL-OLD, and the Attitudes to Aging Questionnaire. The Charlson comorbidity index was calculated using ICD-10 codes. To address possible interaction between comorbidity and attitudes toward aging for QoL, the presence of additive interaction between comorbidity and attitudes toward aging on QoL was examined by synergy index. All analyses were adjusted by age, gender, education, and living arrangement. RESULTS: A higher comorbidity index was significantly associated with lower scores of both QoL measures; one index increase was associated with 3.7 [95 % confidence interval (CI) 1.5: 5.9] decreases in generic QoL and 3.6 (95 % CI 1.3: 5.9) decreases in older-specific QoL. In stratified analyses by attitudes toward aging, comorbidity showed no association with QoL among those with positive attitudes, while it was significantly associated with low QoL in those without positive attitudes. The presence of additive interactions between comorbidity and less than positive attitudes on falling in low QoL was clearly suggested. CONCLUSIONS: The negative impact of comorbidity on QoL might be mitigated by promoting a positive self perception of aging in older people. PMID- 25526724 TI - Transition of maternal dietary n-3 fatty acids from the yolk to the liver of broiler breeder progeny via the residual yolk sac. AB - The aim of the present study was to evaluate the transfer of maternal dietary fatty acids (FA) from the yolk to the developing offspring, with special emphasis on n-3 FA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Six hundred forty Ross 308 breeders were housed from 6 to 58 wk of age in 16 pens resulting in 4 replicates per dietary treatment. They were fed 1 of 4 diets: a basal diet, rich in n-6 FA (CON), or an n-3 FA enriched diet formulated to obtain an EPA/DHA ratio of 1/1 (EPA=DHA), 1/2 (DHA), or 2/1 (EPA). At 28, 43, and 58 wk of age, 20 eggs per treatment were collected and analyzed for FA composition. At these same breeder ages, 600 fertilized eggs per treatment were incubated. At hatch the residual yolks of 25 chicks per treatment were collected and analyzed for FA composition. At every hatch, 180 chicks per treatment were raised under standard conditions and livers were sampled at d 1, 14, 28, and 38 d for FA analysis. Concentrations of EPA in the yolk and residual yolk of eggs laid by EPA-fed breeders were highest, next-to-highest for EPA=DHA-fed breeders, next-to-lowest for DHA-fed breeders, and lowest in those laid by control hens, reflecting the inclusion levels in the maternal diets. Yolk and residual yolk DHA concentrations, however, were not only elevated due to DHA supplementation, compared with the control diet, but also due to EPA supplementation. Offspring hepatic EPA concentrations were elevated until d 28 in all n-3 enriched groups, whereas hepatic DHA concentrations were only affected by EPA=DHA and DHA supplementation at d 1. No differences were found in hepatic DHA concentrations at later offspring ages. Considering the role of EPA and DHA in early development and growth, the maternal supply of these n-3 FA might improve offspring health and performance. PMID- 25526726 TI - Acute myocardial infarction with no obstructive coronary atherosclerosis: mechanisms and management. AB - Myocardial infarction (MI) with no obstructive coronary atherosclerosis (MINOCA) is a syndrome with different causes. Its prevalence ranges between 5 and 25% of all MIs. The prognosis is extremely variable, depending on the causes of MINOCA. Clinical history, echocardiography, coronary angiography, and left ventriculography represent the first-level diagnostic investigations. Nevertheless, additional tests are required in order to establish its specific cause, thus allowing an appropriate risk stratification and treatment. We review pathogenesis, diagnosis, prognosis, and therapy of MINOCA and propose an algorithm for its management. PMID- 25526725 TI - Does government oversight improve access to nursing home care? Longitudinal evidence from US counties. AB - Gains in life expectancy around the world have increasingly placed pressure on governments to ensure that the elderly receive assistance with activities of daily living. This research examines the impact of government oversight of Medicaid payment policies on access to nursing home care services in the United States. Variation in price levels induced by a federal policy shift in 1997 is used to identify the effect of Medicaid reimbursements on the number of nursing homes and beds available. Court rulings prior to the policy change are used to categorically define a range of oversight treatments at the state level. Difference-in-differences estimates indicate a significant decline in access to nursing home care services for individuals living in states in which courts consistently ruled that Medicaid reimbursements did not meet the minimum standard implied by federal law. The findings suggest that nursing home care services were made more accessible through a combination of legislative and judicial oversight of Medicaid payment policies. PMID- 25526727 TI - Musical theatre. PMID- 25526728 TI - Rape and the Straw Man: A Response to Lindsay Kelland. AB - Lindsay Kelland has taken issue with a claim I made in a book titled The Second Sexism: Discrimination Against Men and Boys. In response to this claim, she has argued that when a woman is raped, it matters that her rapist is a male because "her situation as a woman under patriarchy is partly constitutive of the harm that she suffers" in being raped. In my response to her article, I show that she has taken my claim out of context and thereby misrepresented it. As a result, her article fails to respond to anything I said. PMID- 25526729 TI - Functional marker development is challenged by the ubiquity of endophytes-a practical perspective. AB - Functional markers (FMs) are supposed to assist in diagnosis, disease treatment and turning plant and animal breeding more efficient. However, efficient FM application is challenged through current insights in the multi-organism nature of life. This letter aims to raise awareness for re-thinking concepts for FM development in plant breeding and proposes a novel perspective. PMID- 25526731 TI - Facilitation of bilateral selective antegrade cerebral perfusion with axillary cannulation and retrograde coronary sinus catheter. AB - Over the past several decades, techniques for surgery of the aortic arch have undergone significant evolution. In addition, there have been refinements in the mechanism of cerebral protection utilized intraoperatively. However, significant practice variations in the strategy of antegrade selective cerebral perfusion continue to persist. Here, we describe a simple and easily reproducible technique for selective antegrade cerebral perfusion, utilizing axillary cannulation and retrograde coronary sinus balloon catheters. PMID- 25526730 TI - MacroH2A1 isoforms are associated with epigenetic markers for activation of lipogenic genes in fat-induced steatosis. AB - The importance of epigenetic changes in the development of hepatic steatosis is largely unknown. The histone variant macroH2A1 under alternative splicing gives rise to macroH2A1.1 and macroH2A1.2. In this study, we show that the macroH2A1 isoforms play an important role in the regulation of lipid accumulation in hepatocytes. Hepatoma cell line and immortalized human hepatocytes transiently transfected or knocked down with macroH2A1 isoforms were used as in vitro model of fat-induced steatosis. Gene expressions were analyzed by quantitative PCR array and Western blot. Chromatin immunoprecipitation analysis was performed to check the association of histone H3 lysine 27 trimethylation (H3K27me3) and histone H3 lysine 4 trimethylation (H3K4me3) with the promoter of lipogenic genes. Livers from knockout mice that are resistant to lipid deposition despite a high-fat diet were used for histopathology. We found that macroH2A1.2 is regulated by fat uptake and that its overexpression caused an increase in lipid uptake, triglycerides, and lipogenic genes compared with macroH2A1.1. This suggests that macroH2A1.2 is important for lipid uptake, whereas macroH2A1.1 was found to be protective. The result was supported by a high positivity for macroH2A1.1 in knockout mice for genes targeted by macroH2A1 (Atp5a1 and Fam73b), that under a high-fat diet presented minimal lipidosis. Moreover, macroH2A1 isoforms differentially regulate the expression of lipogenic genes by modulating the association of the active (H3K4me3) and repressive (H3K27me3) histone marks on their promoters. This study underlines the importance of the replacement of noncanonical histones in the regulation of genes involved in lipid metabolism in the progression of steatosis. PMID- 25526732 TI - Obesity management: applying clinical trial data to clinical care. PMID- 25526733 TI - A phase II trial of everolimus, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma: NCCTG N057K. AB - BACKGROUND: The mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy. METHODS: Newly diagnosed patients with glioblastoma multiforme were eligible for this single arm, phase II study. Everolimus (70 mg/wk) was started 1 week prior to radiation and TMZ, followed by adjuvant TMZ, and continued until disease progression. The primary endpoint was overall survival at 12 months, and secondary endpoints were toxicity and time to progression. Eleven patients were imaged with 3'-deoxy-3'-(18)F-fluorothymidine ((18)FLT)-PET/CT before and after the initial 2 doses of everolimus before initiating radiation/TMZ. Imaged patients with sufficient tumor samples also underwent immunohistochemical and focused exon sequencing analysis. RESULTS: This study accrued 100 evaluable patients. Fourteen percent of patients had grade 4 hematologic toxicities. Twelve percent had at least one grade 4 nonhematologic toxicity, and there was one treatment-related death. Overall survival at 12 months was 64% and median time to progression was 6.4 months. Of the patients who had (18)FLT-PET data, 4/9 had a partial response after 2 doses of everolimus. Focused exon sequencing demonstrated that (18)FLT-PET responders were less likely to have alterations within the PI3K/Akt/mTOR or tuberous sclerosis complex/neurofibromatosis type 1 pathway compared with nonresponders. CONCLUSION: Combining everolimus with conventional chemoradiation had moderate toxicity. (18)FLT-PET studies suggested an initial antiproliferative effect in a genetically distinct subset of tumors, but this did not translate into an appreciable survival benefit compared with historical controls treated with conventional therapy. PMID- 25526734 TI - Imaging of gliomas at 1.5 and 3 Tesla - A comparative study. AB - BACKGROUND: Glioma follow-up is based on MRI parameters, which are correlated with survival. Although established criteria are used to evaluate tumor response, radiological markers may be confounded by differences in instrumentation including the magnetic field strength. We assessed whether MRIs obtained at 3 Tesla (T) and 1.5T provided similar information. METHODS: We retrospectively compared imaging features of 30 consecutive patients with WHO grades II and III gliomas who underwent MRI at 1.5T and 3T within a month of each other, without any clinical changes during the same period. We compared lesion volumes on fluid attenuation inversion recovery (FLAIR), ratio of cerebral blood volume (rCBV) on perfusion-weighted imaging, contrast-to-noise ratio (CNR) on FLAIR, and on post gadolinium 3D T1-weighted sequences between 1.5T and 3T using intraclass correlation coefficient (ICC). Concordance between observers within and between modalities was evaluated using weighted-kappa coefficient (wkappa). RESULTS: The mean +/- SD delay between modalities (1.5T and 3T MRI) was 8.6 +/- 5.6 days. Interobserver/intraobserver concordance for lesion volume was almost perfect for 1.5T (ICC = 0.96/0.97) and 3T (ICC = 0.99/0.98). Agreement between observers for contrast enhancement was excellent at 1.5T (wkappa = 0.92) and 3T (wkappa = 0.92). The tumor CNR was significantly higher for FLAIR at 1.5T (P < .001), but it was higher at 3T (P = .012) for contrast enhancement. Correlations between modalities for lesion volume (ICC = 0.97) and for rCBV values (ICC = 0.92) were almost perfect. CONCLUSIONS: In the follow-up of WHO grades II and III gliomas, 1.5T and 3T provide similar MRI features, suggesting that monitoring could be performed on either a 1.5 or a 3T MR magnet. PMID- 25526736 TI - Regulation of Sec16 levels and dynamics links proliferation and secretion. AB - We currently lack a broader mechanistic understanding of the integration of the early secretory pathway with other homeostatic processes such as cell growth. Here, we explore the possibility that Sec16A, a major constituent of endoplasmic reticulum exit sites (ERES), acts as an integrator of growth factor signaling. Surprisingly, we find that Sec16A is a short-lived protein that is regulated by growth factors in a manner dependent on Egr family transcription factors. We hypothesize that Sec16A acts as a central node in a coherent feed-forward loop that detects persistent growth factor stimuli to increase ERES number. Consistent with this notion, Sec16A is also regulated by short-term growth factor treatment that leads to increased turnover of Sec16A at ERES. Finally, we demonstrate that Sec16A depletion reduces proliferation, whereas its overexpression increases proliferation. Together with our finding that growth factors regulate Sec16A levels and its dynamics on ERES, we propose that this protein acts as an integrator linking growth factor signaling and secretion. This provides a mechanistic basis for the previously proposed link between secretion and proliferation. PMID- 25526738 TI - A computational model of unresolved allergic inflammation in chronic asthma. AB - We have previously developed an agent-based computational model to demonstrate the feasibility of a novel hypothesis we term the inflammatory twitch. This hypothesis potentially explains the dynamics of the normal response to allergic inflammation in the lung (Pothen JJ, Poynter ME, Bates JH. J Immunol 190: 3510 3516, 2013) on the basis that antigenic stimulation sets in motion both the onset of inflammation and its subsequent resolution. The result is a self-limited inflammatory event that is similar in a formal sense to a skeletal muscle twitch. We hypothesize here that the chronic airway inflammation characteristic of asthma may represent the failure of the inflammatory twitch to resolve back to baseline. Our model provides a platform with which to perform virtual experiments aimed at investigating possible mechanisms leading to accentuation and/or prolongation of the inflammatory twitch. We used our model to determine how the inflammatory twitch is modified by knocking out certain cell types, interfering with cell activity, and altering cell lifetimes. Increasing the duration of activation of proinflammatory cells (considered to be chiefly neutrophils and eosinophils) markedly accentuated and prolonged the inflammatory twitch. This aberrant twitch behavior was largely abrogated by knocking out T-helper cells (simulating the effect of corticosteroids). The aberrant inflammatory twitch was also normalized by reducing the lifetime of the proinflammatory cells, suggesting that increasing apoptosis of these cells may be a therapeutic target in asthma. PMID- 25526735 TI - Presynaptic NMDA receptors - dynamics and distribution in developing axons in vitro and in vivo. AB - During cortical development, N-methyl-D-aspartate (NMDA) receptors (NMDARs) facilitate presynaptic terminal formation, enhance neurotransmitter release and are required in presynaptic neurons for spike-timing-dependent long-term depression (tLTD). However, the extent to which NMDARs are found within cortical presynaptic terminals has remained controversial, and the sub-synaptic localization and dynamics of axonal NMDARs are unknown. Here, using live confocal imaging and biochemical purification of presynaptic membranes, we provide strong evidence that NMDARs localize to presynaptic terminals in vitro and in vivo in a developmentally regulated manner. The NR1 and NR2B subunits (also known as GRIN1 and GRIN2B, respectively) were found within the active zone membrane, where they could respond to synaptic glutamate release. Surprisingly, NR1 also appeared in glutamatergic and GABAergic synaptic vesicles. During synaptogenesis, NR1 was mobile throughout axons - including growth cones and filopodia, structures that are involved in synaptogenesis. Upon synaptogenic contact, NMDA receptors were quickly recruited to terminals by neuroligin-1 signaling. Unlike dendrites, the trafficking and distribution of axonal NR1 were insensitive to activity changes, including NMDA exposure, local glutamate uncaging or action potential blockade. These results support the idea that presynaptic NMDARs play an early role in presynaptic development. PMID- 25526737 TI - Space radiation-associated lung injury in a murine model. AB - Despite considerable progress in identifying health risks to crewmembers related to exposure to galactic/cosmic rays and solar particle events (SPE) during space travel, its long-term effects on the pulmonary system are unknown. We used a murine risk projection model to investigate the impact of exposure to space relevant radiation (SR) on the lung. C3H mice were exposed to (137)Cs gamma rays, protons (acute, low-dose exposure mimicking the 1972 SPE), 600 MeV/u (56)Fe ions, or 350 MeV/u (28)Si ions at the NASA Space Radiation Laboratory at Brookhaven National Laboratory. Animals were irradiated at the age of 2.5 mo and evaluated 23.5 mo postirradiation, at 26 mo of age. Compared with age-matched nonirradiated mice, SR exposures led to significant air space enlargement and dose-dependent decreased systemic oxygenation levels. These were associated with late mild lung inflammation and prominent cellular injury, with significant oxidative stress and apoptosis (caspase-3 activation) in the lung parenchyma. SR, especially high energy (56)Fe or (28)Si ions markedly decreased sphingosine-1-phosphate levels and Akt- and p38 MAPK phosphorylation, depleted anti-senescence sirtuin-1 and increased biochemical markers of autophagy. Exposure to SR caused dose-dependent, pronounced late lung pathological sequelae consistent with alveolar simplification and cellular signaling of increased injury and decreased repair. The associated systemic hypoxemia suggested that this previously uncharacterized space radiation-associated lung injury was functionally significant, indicating that further studies are needed to define the risk and to develop appropriate lung-protective countermeasures for manned deep space missions. PMID- 25526739 TI - A novel fungus concentration-dependent rat model for acute invasive fungal rhinosinusitis: an experimental study. AB - BACKGROUND: Acute invasive fungal rhinosinusitis is a lethal infectious process afflicting immunocompromised individuals. Knowledge about this disease is still limited due to the scarcity of animal models designed to study the pathogenesis of this infection. Mast cells are tissue-resident immune cells that participate in a variety of allergic and inflammatory conditions. Limited attention has been given to the role of mast cells in acute invasive fungal rhinosinusitis. Therefore, the objectives of this study were to create a rat model of acute invasive fungal rhinosinusitis based on analyzing the impact of different fungal concentrations on establishing infection, and to observe the changes of mast cells in rats with this disease. METHODS: Sprague-Dawley rats were divided randomly into four groups, three of which were experimental and received different concentrations of Aspergillus fumigatus inoculations, and one was a control group (D). The inoculated Aspergillus fumigatus concentrations were 5 * 10(7) conidia/ml in group A, 10(7) conidia/ml in group B, and 10(6) conidia/ml in group C. Before fungal inoculation, rats were immunosuppressed using cyclophosphamide and cortisone acetate, and had Merocel sponges inserted into the right nares. Hematology and histopathology investigations were then performed. RESULTS: An acute invasive fungal rhinosinusitis rat model was established successfully with an incidence rate of 90% in group A, 50% in group B and 10% in group C. Aspergillus fumigatus invasion was observed in 20% of the lungs in group A, but was not seen in the remaining groups. In addition, no fungi invaded the orbital tissue, brains, livers, spleens or kidneys of any rat. Compared with the control set, the total number of mast cells in the experimental groups was not significantly increased, but mast cell degranulation, on the other hand, was only found in infected nasal cavities. CONCLUSIONS: This investigation illustrates that various fungal concentrations have different effects on the incidence of acute invasive fungal rhinosinusitis, and it also demonstrates the feasibility of using this model to study the process of fungal rhinosinusoidal invasion. In addition, the results suggest that mast cells may play a role in the protection of sinuses against acute Aspergillus fumigatus infection and in the clearance of established hyphal masses. PMID- 25526740 TI - Reservoir hosts for Gyrodactylus salaris may play a more significant role in epidemics than previously thought. AB - BACKGROUND: Gyrodactylus salaris Malmberg, 1957 has had a devastating impact on wild Norwegian stocks of Atlantic salmon Salmo salar L., and it is the only Office International des Epizooties (OIE) listed parasitic pathogen of fish. The UK is presently recognised as G. salaris-free, and management plans for its containment and control are currently based on Scandinavian studies. The current study investigates the susceptibility of British salmonids to G. salaris, and determines whether, given the host isolation since the last glaciation and potential genetic differences, the populations under test would exhibit different levels of susceptibility, as illustrated by the parasite infection trajectory over time, from their Scandinavian counterparts. METHODS: Populations of S. salar, brown trout Salmo trutta L., and grayling Thymallus thymallus (L.), raised from wild stock in UK government hatcheries, were flown to Norway and experimentally challenged with a known pathogenic strain of G. salaris. Each fish was lightly anaesthetised and marked with a unique tattoo for individual parasite counting. A single Norwegian population of S. salar from the River Laerdalselva was used as a control. Parasite numbers were assessed every seven days until day 48 and then every 14 days. RESULTS: Gyrodactylus salaris regularly leads to high mortalities on infected juveniles S. salar. The number of G. salaris on British S. salar rose exponentially until the experiment was terminated at 33 days due to fish welfare concerns. The numbers of parasites on S. trutta and T. thymallus increased sharply, reaching a peak of infection on days 12 and 19 post-infection respectively, before declining to a constant low level of infection until the termination of the experiment at 110 days. CONCLUSIONS: The ability of S. trutta and T. thymallus to carry an infection for long periods increases the window of exposure for these two hosts and the potential transfer of G. salaris to other susceptible hosts. This study demonstrates that G. salaris can persist on S. trutta for longer periods than previously thought, and that the role that S. trutta could play in disseminating G. salaris needs to be considered carefully and factored into management plans and epidemics across Europe. PMID- 25526741 TI - Chemical compositions of black carbon particle cores and coatings via soot particle aerosol mass spectrometry with photoionization and electron ionization. AB - Black carbon is an important constituent of atmospheric aerosol particle matter (PM) with significant effects on the global radiation budget and on human health. The soot particle aerosol mass spectrometer (SP-AMS) has been developed and deployed for real-time ambient measurements of refractory carbon particles. In the SP-AMS, black carbon or metallic particles are vaporized through absorption of 1064 nm light from a CW Nd:YAG laser. This scheme allows for continuous "soft" vaporization of both core and coating materials. The main focus of this work is to characterize the extent to which this vaporization scheme provides enhanced chemical composition information about aerosol particles. This information is difficult to extract from standard SP-AMS mass spectra because they are complicated by extensive fragmentation from the harsh 70 eV EI ionization scheme that is typically used in these instruments. Thus, in this work synchotron generated vacuum ultraviolet (VUV) light in the 8-14 eV range is used to measure VUV-SP-AMS spectra with minimal fragmentation. VUV-SP-AMS spectra of commercially available carbon black, fullerene black, and laboratory generated flame soots were obtained. Small carbon cluster cations (C(+)-C5(+)) were found to dominate the VUV-SP-AMS spectra of all the samples, indicating that the corresponding neutral clusters are key products of the SP vaporization process. Intercomparisons of carbon cluster ratios observed in VUV-SP-AMS and SP-AMS spectra are used to confirm spectral features that could be used to distinguish between different types of refractory carbon particles. VUV-SP-AMS spectra of oxidized organic species adsorbed on absorbing cores are also examined and found to display less thermally induced decomposition and fragmentation than spectra obtained with thermal vaporization at 200 degrees C (the minimum temperature needed to quantitatively vaporize ambient oxidized organic aerosol with a continuously heated surface). The particle cores tested in these studies include black carbon, silver, gold, and platinum nanoparticles. These results demonstrate that SP vaporization is capable of providing enhanced organic chemical composition information for a wide range of organic coating materials and IR absorbing particle cores. The potential of using this technique to study organic species of interest in seeded laboratory chamber or flow reactor studies is discussed. PMID- 25526742 TI - Plasmodium falciparum merozoite surface protein 2: epitope mapping and fine specificity of human antibody response against non-polymorphic domains. AB - BACKGROUND: Two long synthetic peptides representing the dimorphic and constant C terminal domains of the two allelic families of Plasmodium falciparum merozoite surface proteins 2 are considered promising malaria vaccine candidates. The aim of the current study is to characterize the immune response (epitope mapping) in naturally exposed individuals and relate immune responses to the risk of clinical malaria. METHODS: To optimize their construction, the fine specificity of human serum antibodies from donors of different age, sex and living in four distinct endemic regions was determined in ELISA by using overlapping 20 mer peptides covering the two domains. Immune purified antibodies were used in Western blot and immunofluorescence assay to recognize native parasite derivate proteins. RESULTS: Immunodominant epitopes were characterized, and their distribution was similar irrespective of geographic origin, age group and gender. Acquisition of a 3D7 family and constant region-specific immune response and antibody avidity maturation occur early in life while a longer period is needed for the corresponding FC27 family response. In addition, the antibody response to individual epitopes within the 3D7 family-specific region contributes to protection from malaria infection with different statistical weight. It is also illustrated that affinity-purified antibodies against the dimorphic or constant regions recognized homologous and heterologous parasites in immunofluorescence and homologous and heterologous MSP2 and other polypeptides in Western blot. CONCLUSION: Data from this current study may contribute to a development of MSP2 vaccine candidates based on conserved and dimorphic regions thus bypassing the complexity of vaccine development related to the polymorphism of full-length MSP2. PMID- 25526744 TI - Prudent care of head trauma in the elderly: a case report. AB - INTRODUCTION: Severe traumatic brain injury is a major public health problem that accounts for one-third of all deaths due to trauma in the United States. This case report illustrates some of the challenges faced by the elderly in accessing essential emergency services for traumatic brain injury. CASE PRESENTATION: A 74 year-old Caucasian man presented with head trauma at his local acute care hospital (level III/IV) in Canada at 2:30 PM. He was triaged at 4:00 PM and was seen by the emergency room physician at 4:50 PM. His vital signs were normal, and his Glasgow Coma Scale score was 15/15 upon admission. A computed tomography based diagnosis of acute subdural hematoma was subsequently made by a radiologist at 5:00 PM. A neurosurgical transfer was requested to the nearby tertiary trauma center (level I/II), but was initially refused by the neurosurgical resident on call. The patient's condition slowly deteriorated until he became unconscious at 7:45 PM. The patient was intubated and transferred to the neurosurgical unit at 8:34 PM. He was seen by a consultant neurosurgeon at 9:30 PM, but surgery (craniotomy) was deemed not viable, given the patient's age and the fact that his pupils were now fixed and dilated (Glasgow Coma Scale score 3/15). The patient was taken off life support at 1:00 AM the following morning and died shortly thereafter. The patient's family made a formal complaint, but the decision by an independent medical review panel was that "the patient's care was prudent, timely and professional." CONCLUSIONS: Geriatric patients with severe head injury are less likely than their younger counterparts to be transferred to neurosurgical trauma centers. Protocol-driven care of the elderly can reduce mortality due to head trauma through the application of the Brain Trauma Foundation guidelines. PMID- 25526743 TI - Critical role of extracellularly secreted neuronal pentraxin 1 in ischemic neuronal death. AB - BACKGROUND: Developing brain is highly susceptible to hypoxic-ischemic injury leading to severe neurological disabilities in surviving infants and children. Previously we reported induction of neuronal pentraxin 1 (NP1) in hypoxic ischemic injury in neonatal brain and NP1 co-localization with the excitatory AMPA receptors GluR1 at the synaptic sites. However, how NP1 contributes to hypoxic-ischemic neuronal injury is not completely understood. RESULTS: Here we report that extracellular secretion of NP1 is required for ischemic neuronal death. Primary cortical neurons at days in vitro (DIV) 12 were subjected to oxygen glucose deprivation (OGD), an in vitro model of ischemic stroke, for different time periods (2-8 h). Oxygen glucose deprivation showed characteristic morphological changes of dying cells, OGD time-dependent induction of NP1 (2-4 fold) and increased neuronal death. In contrast, the NP1-KO cortical neurons were healthy and showed no sign of dying cells under similar conditions. NP1gene silencing by NP1-specific small interfering RNA (NP1-siRNA) protected cortical neurons from OGD-induced death. Conditioned media (CM) collected from OGD exposed WT cortical cultures caused neurotoxicity when added to a subset of DIV 12 normoxia control WT cortical cultures. In contrast, CM from OGD-exposed NP1-KO cultures did not induce cell toxicity in control WT cultures, suggesting a role for extracellular NP1 in neuronal death. However, NP1-KO neurons, which showed normal neuronal morphology and protection against OGD, sustained enhanced death following incubation with CM from WT OGD-exposed cultures. Western blot analysis of OGD exposed WT CM showed temporal increase of NP1 protein levels in the CM. Most strikingly, in contrast to NP1-KO CM, incubation of normal cortical cultures with CM from OGD exposed NP2-KO cultures showed neurotoxicity similar to that observed with CM from OGD exposed WT neuronal cultures. Western immunoblotting further confirmed the increased presence of NP1 protein in OGD-exposed NP2-KO CM. Live immunofluorescence analysis show intense cell surface clustering of NP1 with AMPA GluR1 receptors. CONCLUSIONS: Collectively, our results demonstrate that extracellular release of NP1 promote hypoxic-ischemic neuronal death possibly via surface clustering with GluR1 at synaptic sites and that NP1, not its family member NP2, is involved in the neuronal death mechanisms. PMID- 25526745 TI - Preliminary report: neural firing patterns specific for Meniere's disease. AB - OBJECTIVE: To describe the application of a new, objective diagnostic test for Meniere's disease. INTRODUCTION: Electrovestibulography (EVestG) is a complex, newly-developed test paradigm that searches for neural firing patterns that may be diagnostic for particular neural disorders. EVestG system was previously "trained" to distinguish Meniere's disease from other patients on a set of training data. In this paper we illustrate its diagnostic application in a new group of unknown subjects. SETTING: Collaborative Academic Bioengineering Research Centre. STUDY DESIGN: Prospective, blinded human Clinical Trial. METHODS: In an attempt to understand the specific neural firing patterns that may objectively characterize latent Meniere's disease, two hundred fifty-six consecutive patients who presented for electronystagmography testing were asked to undergo EVestG testing. Ten subjects actually completed testing but data were too noisy to permit analysis for one patient. Complete data were available for nine patients with either a clinical diagnosis of either Meniere's disease (4 patients) or some other vestibular disorder (2 vestibular neuritis, 2 benign positional vertigo and 1 non-specific dizziness). None of the patients were experiencing attacks of vertigo within a week of EVestG testing. Ten normal control subjects with no history or symptoms of ear disease were also tested. EVestG was performed in a separate engineering research facility by investigators who were unaware of their clinical diagnosis. If EVestG suggested that the probability of Meniere's disease was 0.5 or greater Meniere's disease was considered present by the objective testing. The objective and clinical diagnoses were compared. RESULTS: EVestG testing correctly identified three of four Meniere's disease patients and rejected the diagnosis in 9 of the 10 controls. Two of the 5 dizzy, non-Meniere's patients were incorrectly identified as Meniere's disease. The sensitivity and specificity of EvestG testing were 75% and 80%, respectively. EVestG results were statistically significantly different for Meniere's patients versus the other dizzy patients and controls (Univariate ANOVA difference contrasts p = 0.0340) even in this small sample. CONCLUSION: The EVestG protocol appeared to show promise as an objective, diagnostic test for Meniere's disease, but our sample size is too small to generalize widely. LEVEL OF EVIDENCE: N.A. Prospective Human clinical trial. PMID- 25526746 TI - Identifying associations between sedentary time and cardio-metabolic risk factors in working adults using objective and subjective measures: a cross-sectional analysis. AB - BACKGROUND: Sedentary behavior has been reported to be associated with metabolic and vascular health independent of moderate-to-vigorous physical activity (MVPA). In order to select appropriate options to measure sedentary behavior in practice and research settings, it is worthwhile to characterize the extent to which objective and subjective measures of sedentary behavior quantify adverse health risks in the same population. This cross-sectional analysis compared accelerometer-derived and self-reported sedentary time to identify their association with cardio-metabolic risk factors. METHODS: Cross-sectional analysis was conducted using data from 661 Japanese workers (145 women) aged 20-64 years. Participants wore a tri-axial accelerometer device for 10 consecutive days and completed the Japan Atherosclerosis Longitudinal Study Physical Activity Questionnaire. Data on body mass index, waist circumference, resting blood pressure, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, total:HDL cholesterol ratio, blood glucose, and glycosylated hemoglobin (HbA1c) were obtained from annual health examinations. RESULTS: Both accelerometer-derived and self-reported sedentary time were deleteriously associated with triglycerides, HDL-cholesterol, total:HDL ratio, and HbA1c after adjustment for potential confounders including MVPA. There were no significant differences in regression coefficients between the two measures. Thus, the magnitude of the associations of both measures with cardio-metabolic risk factors was similar, despite poor agreement between them. Occupational sedentary time was correlated with both measures of total sedentary time, and more consistently associated with cardio-metabolic risk factors than sedentary leisure time. CONCLUSIONS: Both accelerometer and self-report measurements are similarly associated with cardio-metabolic risk factors in a Japanese working adult population. Subjective and objective measures of sedentary behaviors appear to capture different aspects of behaviors. Further efforts to establish data processing methods integrating objective and subjective measures are needed to more effectively assess sedentary time's relationship to health outcomes. PMID- 25526747 TI - Derivation of occupational exposure levels (OELs) of low-toxicity isometric biopersistent particles: How can the kinetic lung overload paradigm be used for improved inhalation toxicity study design and OEL-derivation? AB - BACKGROUND: Convincing evidence suggests that poorly soluble low-toxicity particles (PSP) exert two unifying major modes of action (MoA), in which one appears to be deposition-related acute, whilst the other is retention-related and occurs with particle accumulation in the lung and associated persistent inflammation. Either MoA has its study- and cumulative dose-specific adverse outcome and metric. Modeling procedures were applied to better understand as to which extent protocol variables may predetermine any specific outcome of study. The results from modeled and empirical studies served as basis to derive OELs from modeled and empirically confirmed directions. RESULTS: This analysis demonstrates that the accumulated retained particle displacement volume was the most prominent unifying denominator linking the pulmonary retained volumetric particle dose to inflammogenicity and toxicity. However, conventional study design may not always be appropriate to unequivocally discriminate the surface thermodynamics-related acute adversity from the cumulative retention volume related chronic adversity. Thus, in the absence of kinetically designed studies, it may become increasingly challenging to differentiate substance-specific deposition-related acute effects from the more chronic retained cumulative dose related effects. CONCLUSION: It is concluded that the degree of dissolution of particles in the pulmonary environment seems to be generally underestimated with the possibility to attribute to toxicity due to decreased particle size and associated changes in thermodynamics and kinetics of dissolution. Accordingly, acute deposition-related outcomes become an important secondary variable within the pulmonary microenvironment. In turn, lung-overload related chronic adversities seem to be better described by the particle volume metric. This analysis supports the concept that 'self-validating', hypothesis-based computational study design delivers the highest level of unifying information required for the risk characterization of PSP. In demonstrating that the PSP under consideration is truly following the generic PSP-paradigm, this higher level of mechanistic information reduces the potential uncertainty involved with OEL derivation. PMID- 25526748 TI - Severe persistent unremitting dermatitis, chronic diarrhea and hypoalbuminemia in a child; Hartnup disease in setting of celiac disease. AB - BACKGROUND: Celiac disease (CD) is a complex autoimmune disorder that can lead to an inflammatory small intestinal villous atrophy and malabsorption. Hartnup disease is an autosomal recessive disorder caused by increased urinary excretion of neutral amino acids. Co-occurrence of Hartnup disease and CD is extremely rare with only a single case reported. CASE PRESENTATION: We report a 3-year girl with chronic diarrhea, Hypoalbuminemia and exfoliative erythema. She was diagnosed with celiac disease, which did not improve on gluten free diet. Hartnup disease was suspected and was confirmed by neutral aminoaciduria. Niacin was started and followed by dramatic improvement. CONCLUSION: Presence of Celiac and Hartnup disease in single individual is very rare. Complete nutritional assessment of refractory celiac patient can reveal underlying nutritional deficiency. PMID- 25526749 TI - Teachable moments and missed opportunities for smoking cessation counseling in a hospital emergency department: a mixed-methods study of patient-provider communication. AB - BACKGROUND: While primary care medical clinics have been the most common setting for the delivery of advice about smoking cessation, the hospital emergency department (ED) is a valuable context for counseling medically underserved tobacco users. We conducted a secondary analysis based on a larger audio-recorded study of patient-provider communication about pain and analgesics in the ED. Within a sample of ED patients with back pain, the purpose of this mixed-methods study was to examine how physicians and nurse practitioners capitalize on "teachable moments" for health education to offer spontaneous smoking cessation counseling in the ED. METHODS: Patients presenting to an academic ED with a primary complaint of back pain were invited to participate in a study of patient provider communication. Audio-recorded encounters were transcribed verbatim. Two coders reviewed each transcript to determine whether smoking was discussed and to build a corpus of smoking-related discussions. We then developed inductively generated coding categories to characterize how providers responded when patients endorsed smoking behavior. Categories were refined iteratively to accommodate discrepancies. RESULTS: Of 52 patient-provider encounters during which smoking was discussed, two-thirds of the patients indicated that they were smokers. Providers missed opportunities for smoking cessation counseling 70% of the time. Eleven encounters contained teachable moments for smoking cessation. We identified four primary strategies for creating teachable moments: 1) positive reinforcement, 2) encouragement, 3) assessing readiness, and 4) offering concrete motivating reasons. CONCLUSIONS: Most providers missed opportunities to offer teachable moments for smoking cessation. In encounters that contained teachable moments, providers employed multiple strategies, combining general advice with motivation tailored to the patient's particular circumstances. Creating motivational links to enhance smoking cessation efforts may be possible with a minimal investment of ED resources. PMID- 25526750 TI - Determination of vancomycin and gentamicin clearance in an in vitro, closed loop dialysis system. AB - BACKGROUND: The purpose of this study was to evaluate the feasibility of utilizing an in-vitro, closed loop hemodialysis system as a method to assess drug clearance. Secondarily, this study tested the influence of variables (blood flow rate, dialysate flow rate, and type of filter) in the hemodialysis procedure on the clearance of vancomycin and gentamicin. METHODS: An in-vitro, closed loop hemodialysis system was constructed. The vancomycin (30 mg/L) and gentamicin (25 mg/L) were added to a simulated blood system (SBS). Four conditions (C1-C4) were tested by defining the filter (Polyflux 170H or F180) and the blood and dialysate flow rates (BFR and DFR). All hemodialysis sessions were 3 hours in length and each condition was completed in duplicate. Dialysate effluent was collected in a 50 gallon polyethylene drum. Samples were collected (in duplicate) from the SBS and the dialysate effluent at baseline and at the end of the hemodialysis session. Samples were analyzed for vancomycin and gentamicin with an ultrahigh performance liquid chromatography/tandem mass spectrometry method. RESULTS: A total of eight 3-hour hemodialysis sessions were conducted. For all tested conditions (C1-C4), vancomycin was undetectable in the SBS at the end of dialysis. However, total vancomycin recovery in the dialysis effluent was 85+/ 18%, suggesting that up to 15% may have adsorbed to the dialysis filter or tubing. Gentamicin clearance from SBS was >98% in all tested conditions. Average gentamicin recovery in the dialysate effluent was 99+/-15%. CONCLUSION: Both vancomycin and gentamicin were readily removed by high-flux hemodialysis under all conditions studied. No significant differences in drug clearance were observed between conditions used in this in vitro study. The clinical implications of changing these hemodialysis parameters are unknown. PMID- 25526751 TI - Social support: an important factor for quality of life in women with hirsutism. AB - BACKGROUND: Women with hirsutism have reported imparied health and health-related quality of life (HRQoL). Social support is a factor that might increase HRQoL in chronic diseases, but little is known about this association among women with hirsutism. AIM: The aim of the study was to describe social support and explore its association with HRQoL among women with hirsutism. A further aim was to compare HRQoL in women with hirsutism with a Swedish normal population. METHODS: A questionnaire including socio-demographic questions, Short-Form Health Survey (SF-36), the Multidimensional Scale of Perceived Social Support (MSPSS), and a self-estimation of hairiness using the Ferriman-Gallway scale (F-G scale) was answered by 127 women with hirsutism. RESULTS: Multiple regression analyses showed significant associations between social support and all health dimensions in the SF-36, also after the model was adjusted for age, hairiness and body mass index. Compared to the normal Swedish population, women with hirsutism reported significantly lower HRQoL in all dimensions of the SF-36 (p < 0.01). CONCLUSIONS: There is a significant positive association between social support and HRQoL, demonstrating its importance for the ability to adapt to problems associated with hirsutism. As women with hirsutism reported poorer HRQoL compared to the normal population, social support may be a factor to consider in clinical practice. PMID- 25526752 TI - A chloroplast genomic strategy for designing taxon specific DNA mini-barcodes: a case study on ginsengs. AB - BACKGROUND: Universal conventional DNA barcodes will become more and more popular in biological material identifications. However, in many cases such as processed medicines or canned food, the universal conventional barcodes are unnecessary and/or inapplicable due to DNA degradation. DNA mini-barcode is a solution for such specific purposes. Here we exemplify how to develop the best mini-barcodes for specific taxa using the ginseng genus (Panax) as an example. RESULTS: The chloroplast genome of P. notoginseng was sequenced. The genome was compared with that of P. ginseng. Regions of the highest variability were sought out. The shortest lengths which had the same discrimination powers of conventional lengths were considered the best mini-barcodes. The results showed that the chloroplast genome of P. notoginseng is 156,387 bp. There are only 464 (0.30%) substitutions between the two genomes. The intron of rps16 and two regions of the coding gene ycf1, ycf1a and ycf1b, evolved the quickest and served as candidate regions. The mini-barcodes of Panax turned out to be 60 bp for ycf1a at a discrimination power of 91.67%, 100 bp for ycf1b at 100%, and 280 bp for rps16 at 83.33%. CONCLUSIONS: The strategy by searching the whole chloroplast genomes, identifying the most variable regions, shortening the focal regions for mini-barcodes are believed to be efficient in developing taxon-specific DNA mini-barcodes. The best DNA mini barcodes are guaranteed to be found following this strategy. PMID- 25526754 TI - The role of (18)F-FDG PET/CT in the diagnosis of breast cancer and lymph nodes metastases and micrometastases may be limited. AB - Our aim was to evaluate the diagnostic accuracy of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in detecting primary invasive breast cancer (IBC) including invasive ductal breast cancer, invasive lobular breast cancer and axillary, internal mammary and supraclavicular lymph nodes. One hundred and sixty four patients with operable IBC and clinically negative lymph nodes were recruited and analyzed retrospectively. All patients underwent (18)F-FDG PET/CT scan, the results of which were compared with histopathology of dissected axillary lymph nodes (ALN). All patients were followed-up annually by ultrasonography, mammography and/or CT or MRI for relapse and distant metastases. Results showed that the (18)F-FDG PET/CT scans were positive in 141/164 (86%) patients and negative in 23/164 (14%) patients. The sensitivity of (18)F-FDG PET was 86% (141/164). Diagnostic performance of PET was significantly correlated with primary tumor grades and size (P:0.003 and P:0.0007, respectively). The sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value of (18)F-FDG PET/CT in ALN staging (SUVmax cutoff at 2.0) were 46.3%, 91.1%, 79.8%, 63.3%, and 83.6%, respectively. The false negative and false positive rate was 54% (22/41) and 9% (11/123), respectively. No relapse and metastases were found in a follow-up period of 2.42+/-2.56 months in patients with FN micrometastases in (18)F-FDG PET scan. In conclusion, (18)F-FDG PET/CT was useful in detecting the primary invasive breast cancer and its distant metastases but had a limited value in the axillary, internal mammary and supraclavicular lymph nodes. False negative (18)F FDG PET scan in case of micrometastases and of metastases in ALN indicated good prognosis. PMID- 25526755 TI - Myocardial perfusion imaging parameters: IQ-SPECT and conventional SPET system comparison. AB - Technological advancement in hardware and software development in myocardial perfusion imaging (MPI) leads to the shortening of acquisition time and reduction of the radiation burden to patients. We compared semiquantitative perfusion results and functional parameters of the left ventricle between new dedicated cardiac system with astigmatic collimators called IQ-SPECT (Siemens Medical Solutions, USA) and conventional single photon emission tomography (SPET) system equipped with standard low energy high resolution collimators. A group of randomly selected 81 patients underwent consecutively the MPI procedure on IQ SPECT and on conventional SPET systen, both without attenuation correction. The summed scores and the values of the functional parameters of the left ventricle: ejection fraction (EF), end-systolic and end-diastolic volumes (ESV, EDV) received from the automatic analysis software were compared and statistically analyzed. Our results showed that summed scores values were significantly higher for the IQ-SPECT system in comparison to the conventional one. Calculated EF were significantly lower for IQ-SPECT, whereas evaluated left ventricular volumes (LVV) were significantly higher for this system. In conclusion, we recorded significant differences in automatically calculated semiquantitative perfusion and functional parameters when compared uncorrected studies obtained by the IQ SPECT with the conventional SPET system. PMID- 25526753 TI - RNA-seq analysis reveals significant transcriptome changes in turbot (Scophthalmus maximus) suffering severe enteromyxosis. AB - BACKGROUND: Enteromyxosis caused by the intestinal myxozoan parasite Enteromyxum scophthalmi is a serious threat for turbot (Scophthalmus maximus, L.) aquaculture, causing severe catarrhal enteritis leading to a cachectic syndrome, with no therapeutic options available. There are still many aspects of host parasite interaction and disease pathogenesis that are yet to be elucidated, and to date, no analysis of the transcriptomic changes induced by E. scophthalmi in turbot organs has been conducted. In this study, RNA-seq technology was applied to head kidney, spleen and pyloric caeca of severely infected turbot with the aim of furthering our understanding of the pathogenetic mechanisms and turbot immune response against enteromyxosis. RESULTS: A huge amount of information was generated with more than 23,000 identified genes in the three organs, amongst which 4,762 were differently expressed (DE) between infected and control fish. Associate gene functions were studied based on gene ontology terms and available literature, and the most interesting DE genes were classified into five categories: 1) immune and defence response; 2) apoptosis and cell proliferation; 3) iron metabolism and erythropoiesis; 4) cytoskeleton and extracellular matrix and 5) metabolism and digestive function. The analysis of down-regulated genes of the first category revealed evidences of a connexion failure between innate and adaptive immune response, especially represented by a high number of DE interferon-related genes in the three organs. Furthermore, we found an intense activation of local immune response at intestinal level that appeared exacerbated, whereas in kidney and spleen genes involved in adaptive immune response were mainly down-regulated. The apoptotic machinery was only clearly activated in pyloric caeca, while kidney and spleen showed a marked depression of genes related to erythropoiesis, probably related to disorders in iron homeostasis. The genetic signature of the causes and consequences of cachexia was also demonstrated by the down-regulation of the genes encoding structural proteins and those involved in the digestive metabolism. CONCLUSIONS: This transcriptomic study has enabled us to gain a better understanding of the pathogenesis of enteromyxosis and identify a large number of DE target genes that bring us closer to the development of strategies designed to effectively combat this pathogen. PMID- 25526756 TI - Paediatric gastric and intestinal Crohn's disease detected by (18)F-FDG PET/CT. AB - We present a case of gastric and intestinal Crohn's disease associated with extra intestinal manifestations of fever, rash in the lower limbs in a 12 years old boy. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) was performed for the diagnosis of the disease causing fever of unknown origin. Gastroscopy showed polypoid hyperplasia and ulcers in the stomach and their pathology suggested gastric Crohn's disease. Intestinal Crohn's disease was also diagnosed. Corticosteroids were temporarily effective. During 2 years of follow-up, there were clinical remissions and relapse confirmed by endoscopy in both the stomach and the small intestine. PMID- 25526757 TI - Randomized Trial of Periodic Presumptive Treatment With High-Dose Intravaginal Metronidazole and Miconazole to Prevent Vaginal Infections in HIV-negative Women. AB - BACKGROUND: Vaginal infections are common, frequently recur, and may increase women's risk for sexually transmitted infections (STIs). We tested the efficacy of a novel regimen to prevent recurrent vaginal infections. METHODS: Human immunodeficiency virus (HIV)-negative women 18-45 years old with 1 or more vaginal infections, including bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), or Trichomonas vaginalis (TV), were randomly assigned to receive vaginal suppositories containing metronidazole 750 mg plus miconazole 200 mg or matching placebo for 5 consecutive nights each month for 12 months. Primary endpoints, evaluated every 2 months, were BV (Gram stain) and VVC (positive wet mount and culture). RESULTS: Participants (N = 234) were randomly assigned to the intervention (N = 118) or placebo (N = 116) arm. Two hundred seventeen (93%) women completed an end-of-study evaluation. The intervention reduced the proportion of visits with BV compared to placebo (21.2% vs 32.5%; relative risk [RR] 0.65, 95% confidence interval [CI] .48-.87). In contrast, the proportion of visits with VVC was similar in the intervention (10.4%) versus placebo (11.3%) arms (RR 0.92, 95% CI .62-1.37). CONCLUSIONS: Monthly treatment with intravaginal metronidazole plus miconazole reduced the proportion of visits with BV during 12 months of follow-up. Further study will be important to determine whether this intervention can reduce women's risk of STIs. PMID- 25526758 TI - Insulin degludec requires lower bolus insulin doses than does insulin glargine in Japanese diabetic patients with insulin-dependent state. AB - BACKGROUND: The study presents a comparison of the glucose-lowering effects, glycemic variability, and insulin doses during treatment with insulin degludec or insulin glargine. METHODS: In this open-label, single-center, 2-way crossover study, 13 Japanese diabetic outpatients in the insulin-dependent state on basal bolus therapy were assigned to receive either insulin glargine followed by insulin degludec, or insulin degludec followed by insulin glargine. Basal insulin doses were fixed in principle, and patients self-adjusted their bolus insulin doses. Seventy-two-hour continuous glucose monitoring was performed 2 weeks after switching the basal insulin. RESULTS: Mean blood glucose (mg/dL) was not significantly different between insulin degludec and insulin glargine over 48 hours (141.8 +/- 35.2 vs 151.8 +/- 43.3), at nighttime (125.6 +/- 40.0 vs 124.7 +/- 50.4), or at daytime (149.3 +/- 37.1 vs 163.3 +/- 44.5). The standard deviation (mg/dL) was also similar (for 48 hours: 48.9 +/- 19.4 vs 50.3 +/- 17.3; nighttime: 18.7 +/- 14.3 vs 13.7 +/- 6.7; daytime: 49.3 +/- 20.0 vs 44.3 +/- 17.7). Other indices of glycemic control, glycemic variability, and hypoglycemia were similar for both insulin analogs. Total daily insulin dose (TDD) and total daily bolus insulin dose (TDBD) were significantly lower with insulin degludec than with insulin glargine (TDD: 0.42 +/- 0.20 vs 0.46 +/- 0.22 U/kg/day, P = .028; TDBD: 0.27 +/- 0.13 vs 0.30 +/- 0.14 U/kg/day, P = .036). CONCLUSIONS: Insulin degludec and insulin glargine provided effective and stable glycemic control. Insulin degludec required lower TDD and TDBD in this population of patients. PMID- 25526759 TI - Use of an Electronic Medical Record (EMR) to Identify Glycemic Intensification Strategies in Type 2 Diabetes. AB - BACKGROUND: Current treatment guidelines for type 2 diabetes (T2D) recommend individualized intensification of therapy for glycated hemoglobin (A1C) >= 7% in most patients. The purpose of this investigation was to explore the ability of an electronic medical record (EMR) to identify glycemic intensification strategies among T2D patients receiving pharmacologic therapy. METHODS: Patient records between 2005 and 2011 with documentation of A1C and active prescriptions for any diabetes medications were queried to identify potential candidates for intensification based on A1C >= 7% while on 1-2 oral diabetes medications (ODM). Patients with follow-up A1C values within 1 year of index A1C were grouped according to intensification with insulin, GLP-1 receptor agonists (GLP-1RA), a new class of ODM, or no intensification. Changes in A1C and continuation of intensification therapy were determined. RESULTS: A total of 4921 patients meeting inclusion criteria were intensified with insulin (n = 416), GLP-1RA (n = 68), ODM (n = 1408), or no additional therapy (n = 3029). Patients receiving insulin had higher baseline (9.3 +/- 2.0 vs 8.3 +/- 1.2 vs 8.3 +/- 1.3 vs 7.6 +/- 1.0%, P < .0001) and follow-up A1C (8.1 +/- 1.6 vs 7.5 +/- 1.2 vs 7.6 +/- 1.3 vs 7.2 +/- 1.1%, P < .0001) despite experiencing larger absolute A1C reductions ( 1.2 +/- 2.1 vs -0.8 +/- 1.4 vs -0.7 +/- 1.4 vs -0.3 +/- 1.1%, P < .0001). Patients receiving GLP-1RA were more obese at baseline (BMI: 33.6 +/- 7.1 vs 37.7 +/- 6.1 vs 33.7 +/- 6.8 vs 32.9 +/- 7.1 kg/m(2), P < .0001) and follow-up (BMI: 33.9 +/- 7.3 vs 36.6 +/- 6.1 vs 33.8 +/- 7.0 vs 32.4 +/- 7.0 kg/m(2), P < .0001) despite experiencing more absolute weight reduction. Insulin was the most and GLP 1RA the least likely therapy to be continued. CONCLUSIONS: An EMR allows identification of prescribing practices and compliance with T2D treatment guidelines. Patients receiving intensification of glycemic medications had baseline A1C >8% suggesting that treatment recommendations are not being followed. PMID- 25526761 TI - Corporate influence and conflicts of interest: assessment of veterinary medical curricular changes and student perceptions. AB - The ethics document of the Association of American Veterinary Medical Colleges provides guiding principles for veterinary schools to develop conflict of interest policies. These policies regulate faculty and student interactions with industry, potentially reducing the influence companies have on students' perceptions and future prescribing practices. This paper examines the implementation of a conflict of interest policy and related instructional activities at one veterinary college in the US. To inform policy and curricular development, survey data were collected regarding veterinary students' attitudes toward pharmaceutical marketing, including their perceptions of their own susceptibility to bias in therapeutic decisions. Responses from this group of students later served as control data for assessing the effectiveness of educational programs in the content area. A conflict of interest policy was then implemented and presented to subsequent classes of entering students. Classroom instruction and relevant readings were provided on ethics, ethical decision making, corporate influences, and the issue of corporate influence in medical student training. Within seven days of completing a learning program on conflict of interest issues, another cohort of veterinary students (the treatment group) were administered the same survey that had been administered to the control group. When compared with the control group who received no instruction, survey results for the treatment group showed moderate shifts in opinion, with more students questioning the practice of industry-sponsored events and use of corporate funds to reduce tuition. However, many veterinary students in the treatment group still reported they would not be personally influenced by corporate gifts. PMID- 25526762 TI - Students' perceptions of the Script Concordance Test and its impact on their learning behavior: a mixed methods study. AB - The Script Concordance Test (SCT) is increasingly used in postgraduate and undergraduate education as a method of summative clinical assessment. It has been shown to have high validity and reliability but there is little evidence of its use in veterinary education as assessment for learning. This study investigates some students' perceptions of the SCT and its effects on their approaches to learning. Final-year undergraduates of the School of Veterinary Medicine and Science (SVMS) at the University of Nottingham participated in a mixed-methods study after completing three formative SCT assessments. A qualitative, thematic analysis was produced from transcripts of three focus group discussions. The quantitative study was a survey based on the analyses of the qualitative study. Out of 50 students who registered for the study, 18 participated in the focus groups and 28 completed the survey. Clinical experience was regarded as the most useful source of information for answering the SCT. The students also indicated that recall of facts was perceived as useful for multiple-choice questions but least useful for the SCT. Themes identified in the qualitative study related to reliability, acceptability, educational impact, and validity of the SCT. The evidence from this study shows that the SCT has high face validity among veterinary students. They reported that it encouraged them to reflect upon their clinical experience, to participate in discussions of case material, and to adopt a deeper approach to clinical learning. These findings strongly suggest that the SCT is potentially a valuable method for assessing clinical reasoning and enhancing student learning. PMID- 25526760 TI - A physiology-based model describing heterogeneity in glucose metabolism: the core of the Eindhoven Diabetes Education Simulator (E-DES). AB - Current diabetes education methods are costly, time-consuming, and do not actively engage the patient. Here, we describe the development and verification of the physiological model for healthy subjects that forms the basis of the Eindhoven Diabetes Education Simulator (E-DES). E-DES shall provide diabetes patients with an individualized virtual practice environment incorporating the main factors that influence glycemic control: food, exercise, and medication. The physiological model consists of 4 compartments for which the inflow and outflow of glucose and insulin are calculated using 6 nonlinear coupled differential equations and 14 parameters. These parameters are estimated on 12 sets of oral glucose tolerance test (OGTT) data (226 healthy subjects) obtained from literature. The resulting parameter set is verified on 8 separate literature OGTT data sets (229 subjects). The model is considered verified if 95% of the glucose data points lie within an acceptance range of +/-20% of the corresponding model value. All glucose data points of the verification data sets lie within the predefined acceptance range. Physiological processes represented in the model include insulin resistance and beta-cell function. Adjusting the corresponding parameters allows to describe heterogeneity in the data and shows the capabilities of this model for individualization. We have verified the physiological model of the E-DES for healthy subjects. Heterogeneity of the data has successfully been modeled by adjusting the 4 parameters describing insulin resistance and beta-cell function. Our model will form the basis of a simulator providing individualized education on glucose control. PMID- 25526763 TI - Prevalence of community-acquired bacteraemia in Guinea-Bissau: an observational study. AB - BACKGROUND: The burden of bloodstream infections is insufficiently studied in children in Africa and many healthcare facilities lack the capacity to identify invasive disease. Often studies have been limited to febrile patients or patients admitted to hospital. METHODS: Blood cultures and malaria diagnostics was performed on 372 consecutive children presenting with tachycardia and/or fever to a referral paediatric emergency department in Bissau, Guinea-Bissau. Bacterial species detection, antimicrobial susceptibility testing and molecular typing were performed. The capacity of clinical parameters to identify bacteraemia was evaluated. RESULTS: The prevalence of bloodstream infection was 12% (46/372) and in 46% (21/46) of the infections the child was non-febrile at presentation to the hospital. The predictive value for bacteraemia was poor for all assessed clinical parameters. Staphylococcus aureus accounted for 54% (26/48) of the isolates followed by non-typhoidal Salmonella, 10% (5/48), Streptococcus pneumoniae, 8% (4/48), and Salmonella Typhi, 6% (3/48). Among S. aureus there was a large diversity of spa types and 38% produced Pantone-Valentine leukocidin. Antibiotic resistance was low, however two out of three Klebsiella pneumoniae isolates produced extended-spectrum beta-lactamases. Malaria was laboratory confirmed in only 5% of the children but 64% (237/372) received a clinical malaria diagnosis. CONCLUSIONS: Bacteraemia was common irrespective of the presence of fever among children presenting to the hospital. The high prevalence of Staphylococcus aureus may be due to contamination. There is an imminent need to improve microbiological diagnostic facilities and to identify algorithms that can identify children at risk of bloodstream infections in Africa. PMID- 25526765 TI - Thermal transformations of self-assembled gold glyconanoparticles probed by combined nanocalorimetry and X-ray nanobeam scattering. AB - Noble metal nanoparticles with ligand shells are of interest for applications in catalysis, thermo-plasmonics, and others, involving heating processes. To gain insight into the structure-formation processes in such systems, self-assembly of carbohydrate-functionalized gold nanoparticles during precipitation from solution and during further heating to ca. 340 degrees C was explored by in situ combination of nanobeam SAXS/WAXS and nanocalorimetry. Upon precipitation from solution, X-ray scattering reveals the appearance of small 2D domains of close packed nanoparticles. During heating, increasing interpenetration of the nanoparticle soft shells in the domains is observed up to ca. 81 degrees C, followed by cluster formation at ca. 125 degrees C, which transform into crystalline gold nuclei at around 160 degrees C. Above ca. 200 degrees C, one observes the onset of coalescence and grain growth resulting in gold crystallites of average size of about 100 nm. The observed microstructural changes are in agreement with the in situ heat capacity measurements with nanocalorimetry. PMID- 25526764 TI - Anopheles gambiae salivary protein expression modulated by wild Plasmodium falciparum infection: highlighting of new antigenic peptides as candidates of An. gambiae bites. AB - BACKGROUND: Malaria is the major parasitic disease worldwide caused by Plasmodium infection. The objective of integrated malaria control programs is to decrease malaria transmission, which needs specific tools to be accurately assessed. In areas where the transmission is low or has been substantially reduced, new complementary tools have to be developed to improve surveillance. A recent approach, based on the human antibody response to Anopheles salivary proteins, has been shown to be efficient in evaluating human exposure to Anopheles bites. The aim of the present study was to identify new An. gambiae salivary proteins as potential candidate biomarkers of human exposure to P. falciparum-infective bites. METHODS: Experimental infections of An. gambiae by wild P. falciparum were carried out in semi-field conditions. Then a proteomic approach, combining 2D DIGE and mass spectrometry, was used to identify the overexpressed salivary proteins in infected salivary glands compared to uninfected An. gambiae controls. Subsequently, a peptide design of each potential candidate was performed in silico and their antigenicity was tested by an epitope-mapping technique using blood from individuals exposed to Anopheles bites. RESULTS: Five salivary proteins (gSG6, gSG1b, TRIO, SG5 and long form D7) were overexpressed in the infected salivary glands. Eighteen peptides were designed from these proteins and were found antigenic in children exposed to the Anopheles bites. Moreover, the results showed that the presence of wild P. falciparum in salivary glands modulates the expression of several salivary proteins and also appeared to induce post-translational modifications. CONCLUSIONS: This study is, to our knowledge, the first that compares the sialome of An. gambiae both infected and not infected by wild P. falciparum, making it possible to mimic the natural conditions of infection. This is a first step toward a better understanding of the close interactions between the parasite and the salivary gland of mosquitoes. In addition, these results open the way to define biomarkers of infective bites of Anopheles, which could, in the future, improve the estimation of malaria transmission and the evaluation of malaria vector control tools. PMID- 25526766 TI - ESR1 and ESR2 gene polymorphisms are associated with human reproduction outcomes in Brazilian women. AB - BACKGROUND: Important candidate genes involved in the ovarian response to exogenous FSH are the estrogen receptor genes (ESRs), since the effects of estrogens on follicle growth, maturation and oocyte release. It is known that some markers of ovarian stimulation can help to personalize the treatment, adjusting the dose of exogenous rFSH, thus preventing excessive wear of the patient. Inspired on this information we aimed to analyze four different polymorphisms in the estrogen receptor genes ESR1: rs2234693/T-397C (PvuII) and rs9340799/A-351G (Xbal) and ESR2: rs4986938/G1082A (RsaI) and rs1256049/A + 1730G (AluI), and their association with assisted reproduction outcomes in Brazilian women that underwent in vitro fertilization (IVF). METHODS: A cross-sectional study was performed involving 136 infertile women less than 39 years of age with normal ovarian reserve. Patients were divided according to the same COH protocol for statistical analysis. The Taqman assay was used for PvuII and XbaI of ESR1, and RsaI and AluI of ESR2 genotyping. Serum estradiol and FSH were measured by Elisa assay. RESULTS: The PvuII (ESR1) TT and RsaI (ESR2) GG genotypes were associated with a longer induction period and higher doses of medication (p < 0.03). The XbaI (ESR1) AA genotype was associated with better COH results, including a larger number of follicles, mature oocytes, embryos, and good quality embryos (p < 0.05). The AluI GG genotype showed an association with the Ovarian Hyperstimulation Syndrome (OHSS) (p = 0.03). According to the haplotype analysis of ER1 (PvuII/XbaI), we demonstrated that the CA combination increases by 0.68 the number of good quality embryos while the TG decreases it by 0.71 (p = 0.04). CONCLUSION: ER polymorphisms have an association with the assisted reproduction outcomes in Brazilian women. PMID- 25526767 TI - Hematological and hepatic alterations in nonsmoking residents exposed to benzene following a flaring incident at the British petroleum plant in Texas City. AB - OBJECTIVE: Human exposure to benzene is associated with multiple adverse health effects with an increased risk of developing carcinogenesis. Benzene exposure is known to affect many critical organs including the hematological, hepatic, renal, lung, and cardiac functions. The purpose of this study is to examine the health effects of benzene exposure among nonsmoking subjects from a prolonged flaring incident that occurred at the British petroleum (BP) refinery in the Texas City, Texas. METHODS: The study included nonsmoking subjects who had been exposed and unexposed to benzene. Using medical charts, clinical data including white blood cell (WBC) counts, platelet counts, hemoglobin, hematocrit, blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), aspartate amino transferase (AST), and alanine amino transferase (ALT) in nonsmoking subjects exposed to benzene were reviewed and analyzed and compared with unexposed adults. RESULTS: A total of 1422 nonsmoking subjects (benzene exposed, n=1093 and unexposed, n=329) were included. Benzene exposed subjects had significantly higher levels of WBC (*10(3) per MUL) counts (7.7+/-2.2 versus 6.8+/-1.7, P=0.001) and platelet (*10(3) per MUL) counts (288.8+/-59.0 versus 245.3+/-54.4, P=0.001) compared with the unexposed subjects. The mean serum creatinine (mg/dL) levels were also significantly increased in the benzene exposed group compared with the unexposed group (1.1+/-0.4 versus 0.8+/-0.2, P=0.001). Serum levels of ALP (IU/L) was significantly elevated in the benzene exposed subjects compared with the unexposed subjects (87.3+/-22.6 versus 69.6+/-16.5, P=0.001). Similarly, benzene exposed subjects had significantly higher levels of AST and ALT compared with those unexposed subjects. CONCLUSION: Benzene exposure from the prolonged BP flaring incident caused significant alterations in hematological and liver markers indicating that these nonsmoking residents exposed to refinery chemicals may be at a higher risk of developing hepatic or blood related disorders. PMID- 25526768 TI - Effects of eslicarbazepine acetate on acute and chronic latrunculin A-induced seizures and extracellular amino acid levels in the mouse hippocampus. AB - BACKGROUND: Latrunculin A microperfusion of the hippocampus induces acute epileptic seizures and long-term biochemical changes leading to spontaneous seizures. This study tested the effect of eslicarbazepine acetate (ESL), a novel antiepileptic drug, on latrunculin A-induced acute and chronic seizures, and changes in brain amino acid extracellular levels. Hippocampi of Swiss mice were continuously perfused with a latrunculin A solution (4 MUM, 1 MUl/min, 7 h/day) with continuous EEG and videotape recording for 3 consecutive days. Microdialysate samples were analyzed by HPLC and fluorescence detection of taurine, glycine, aspartate, glutamate and GABA. Thereafter, mice were continuously video monitored for two months to identify chronic spontaneous seizures or behavioral changes. Control EEG recordings (8 h) were performed in all animals at least once a week for a minimum of one month. RESULTS: Oral administration of ESL (100 mg/kg), previous to latrunculin A microperfusion, completely prevented acute latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity. Hippocampal extracellular levels of taurine, glycine and aspartate were significantly increased during latrunculin A microperfusion, while GABA and glutamate levels remained unchanged. ESL reversed the increases in extracellular taurine, glycine and aspartate concentrations to basal levels and significantly reduced glutamate levels. Plasma and brain bioanalysis showed that ESL was completely metabolized within 1 h after administration to mainly eslicarbazepine, its major active metabolite. CONCLUSION: ESL treatment prevented acute latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity, supporting a possible anti-epileptogenic effect of ESL in mice. PMID- 25526769 TI - Workplace physical activity interventions and moderate-to-vigorous intensity physical activity levels among working-age women: a systematic review protocol. AB - BACKGROUND: The rapid pace of modern life requires working-age women to juggle occupational, family and social demands. This modern lifestyle has been shown to have a detrimental effect on health, often associated with increased smoking and alcohol consumption, depression and cardiovascular disease risk factors. Despite the proven benefits of regular moderate-to-vigorous intensity physical activity (MVPA), few are meeting the current physical activity (PA) recommendations of 150 min of MVPA/week. It is important that appropriate and effective behavioural interventions targeting PA are developed and identified to improve the MVPA levels of working-age women. As these women spend a substantial proportion of their waking hours at work, workplaces may be an opportune, efficient and relatively controlled setting to implement programmes and strategies to target PA in an effort to improve MVPA levels and impact cardiometabolic health. The purposes of this systematic review are to compare the effectiveness of individual level workplace interventions for increasing MVPA levels in working-age women in high-income/developed countries and examine the effectiveness of these interventions for improving the known beneficial health sequelae of MVPA. METHODS/DESIGN: Eight electronic databases will be searched to identify all prospective cohort and experimental studies that examine the impact of individual level workplace interventions for increasing MVPA levels among working-age (mean age 18-65 years) women from high-income/developed countries. Grey literature including theses, dissertations and government reports will also be included. Study quality will be assessed using a modified Downs and Black checklist, and risk of bias will be assessed within and across all included studies using the Cochrane's risk of bias tool and Grades of Recommendation, Assessment, Development and Evaluation approach. Meta-analyses will be conducted where possible among studies with sufficient homogeneity. DISCUSSION: This review will determine the effectiveness of individual-level workplace interventions for increasing MVPA levels in working-age women in high-income/developed countries, and form a current, rigorous and reliable research base for policy makers and stakeholders to support the development and implementation of effective workplace interventions that increase MVPA levels in this population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014009704. PMID- 25526770 TI - Intention tremor and deficits of sensory feedback control in multiple sclerosis: a pilot study. AB - BACKGROUND: Intention tremor and dysmetria are leading causes of upper extremity disability in Multiple Sclerosis (MS). The development of effective therapies to reduce tremor and dysmetria is hampered by insufficient understanding of how the distributed, multi-focal lesions associated with MS impact sensorimotor control in the brain. Here we describe a systems-level approach to characterizing sensorimotor control and use this approach to examine how sensory and motor processes are differentially impacted by MS. METHODS: Eight subjects with MS and eight age- and gender-matched healthy control subjects performed visually-guided flexion/extension tasks about the elbow to characterize a sensory feedback control model that includes three sensory feedback pathways (one for vision, another for proprioception and a third providing an internal prediction of the sensory consequences of action). The model allows us to characterize impairments in sensory feedback control that contributed to each MS subject's tremor. RESULTS: Models derived from MS subject performance differed from those obtained for control subjects in two ways. First, subjects with MS exhibited markedly increased visual feedback delays, which were uncompensated by internal adaptive mechanisms; stabilization performance in individuals with the longest delays differed most from control subject performance. Second, subjects with MS exhibited misestimates of arm dynamics in a way that was correlated with tremor power. Subject-specific models accurately predicted kinematic performance in a reach and hold task for neurologically-intact control subjects while simulated performance of MS patients had shorter movement intervals and larger endpoint errors than actual subject responses. This difference between simulated and actual performance is consistent with a strategic compensatory trade-off of movement speed for endpoint accuracy. CONCLUSIONS: Our results suggest that tremor and dysmetria may be caused by limitations in the brain's ability to adapt sensory feedback mechanisms to compensate for increases in visual information processing time, as well as by errors in compensatory adaptations of internal estimates of arm dynamics. PMID- 25526771 TI - Metformin-associated lactic acidosis and temporary ileostomy: a case report. AB - INTRODUCTION: Lactic acidosis is a well-known complication of the anti hyperglycemic biguanide agent metformin, especially in peculiar but not rare clinical conditions. Attempts to reduce the incidence of this adverse reaction have been enforced by national agencies over the years. The Italian Medicines Agency recently released a safety recommendation on prescribing the drug and with regard to the existence of several conditions that contraindicate drug continuation, such as dehydration, infection, hypotension, surgery or hyperosmolar contrast agent infusion, but the recommendation does not mention the increased risk related to stoma. The present case report is, to our knowledge, the first in the literature of metformin-associated lactic acidosis in a patient with a recently created ileostomy and low anterior resection for rectal cancer. CASE PRESENTATION: A 70-year-old Caucasian man who had undergone low anterior resection with total mesorectal excision and temporary loop ileostomy creation at our institution returned to our department 30 days later because of nausea, vomiting, diffuse abdominal pain and anuria of about 24 hours' duration. During his physical examination, the patient appeared dehydrated and had tachypnea and a reduced level of consciousness. His laboratory tests showed that he had acute kidney injury and severe lactic acidosis. CONCLUSION: An ileostomy puts patients at high risk for output losses that can lead to dehydration and electrolyte abnormalities. The assessment of the losses through the stoma, especially the ileostomy, should be added to the recommendations issued by pharmacovigilance societies. The present clinical case illustrates the need for clinicians on surgical wards to carefully evaluate patients before resuming metformin therapy and to provide appropriate information at discharge to patients with type 2 diabetes mellitus who have undergone ileostomy. Furthermore, this case report highlights the increasing need for more training of general physicians regarding both surgical and internal medicine problems that may arise in the post-operative course after major surgery in patients with co-morbidities. PMID- 25526772 TI - Silencing BMI1 eliminates tumor formation of pediatric glioma CD133+ cells not by affecting known targets but by down-regulating a novel set of core genes. AB - Clinical outcome of children with malignant glioma remains dismal. Here, we examined the role of over-expressed BMI1, a regulator of stem cell self-renewal, in sustaining tumor formation in pediatric glioma stem cells. Our investigation revealed BMI1 over-expression in 29 of 54 (53.7%) pediatric gliomas, 8 of 8 (100%) patient derived orthotopic xenograft (PDOX) mouse models, and in both CD133+ and CD133- glioma cells. We demonstrated that lentiviral-shRNA mediated silencing of suppressed cell proliferation in vitro in cells derived from 3 independent PDOX models and eliminated tumor-forming capacity of CD133+ and CD133 cells derived from 2 PDOX models in mouse brains. Gene expression profiling showed that most of the molecular targets of BMI1 ablation in CD133+ cells were different from that in CD133- cells. Importantly, we found that silencing BMI1 in CD133+ cells derived from 3 PDOX models did not affect most of the known genes previously associated with the activated BMI1, but modulated a novel set of core genes, including RPS6KA2, ALDH3A2, FMFB, DTL, API5, EIF4G2, KIF5c, LOC650152, C20ORF121, LOC203547, LOC653308, and LOC642489, to mediate the elimination of tumor formation. In summary, we identified the over-expressed BMI1 as a promising therapeutic target for glioma stem cells, and suggest that the signaling pathways associated with activated BMI1 in promoting tumor growth may be different from those induced by silencing BMI1 in blocking tumor formation. These findings highlighted the importance of careful re-analysis of the affected genes following the inhibition of abnormally activated oncogenic pathways to identify determinants that can potentially predict therapeutic efficacy. PMID- 25526774 TI - "You can't just jump on a bike and go": a qualitative study exploring parents' perceptions of physical activity in children with type 1 diabetes. AB - BACKGROUND: Parents of children with Type 1 Diabetes Mellitus (T1DM) have an important role in supporting diabetes management behaviours and helping to maintain their child's healthy lifestyle. Physical activity has known benefits for children with T1DM [Diabet Med 31: 1163-1173], but children with chronic health conditions typically have low levels of physical activity. Research is needed to build an understanding of the experience of physical activity for children with T1DM. The purpose of this study was to understand parents' perceptions of what influences physical activity for children with T1DM and to inform the practice of those working with children who have T1DM. METHODS: Data were collected through semi-structured interviews with 20 parents (18 mothers, 2 fathers) who had a child aged 7 - 13 years with T1DM in the UK. Interviews were recorded, transcribed verbatim and data were analysed using thematic analysis [Qual Res Psychol 3: 77-101, 2006]). RESULTS: Factors believed to influence participation in physical activity are presented as 7 major themes and 15 subthemes. Themes that emerged included the conflict between planning and spontaneous activity, struggles to control blood glucose, recognition of the importance of physical activity, the determination of parents, children relying on their parents to manage physical activity, the importance of a good support system and individual factors about the children that influence physical activity participation. CONCLUSIONS: This study highlights that parents serve as gate keepers for children's physical activity. The findings provide insight into the need for T1DM knowledge and competence in personnel involved in the supervision of children's physical activities. Healthcare providers should collaborate with families to ensure understanding of how to manage physical activity. The findings sensitise professionals to the issues confronted by children with T1DM and their parents, as well as the methods used by children and their families to overcome obstacles to physical activity. The implications for further research, clinical practice, and physical activity promotion with children with T1DM are discussed. PMID- 25526773 TI - Predictors of adherence to antiretroviral therapy among people living with HIV and AIDS at the regional hospital of Sokode, Togo. AB - BACKGROUND: Adherence to antiretroviral therapy (ART) is beneficial in reducing the risk of emergence of HIV resistant strains. Adherence to ART among Persons Living with HIV/AIDS (PLWHA) is influenced by several factors related to the patient, the medication, and health facilities. In Togo, previous studies on adherence to ART have reported good adherence to ART during the first year of follow-up. However these may hide many disparities dues to cultural specificities which may differ across geographic areas of the country. We sought to determine the level of adherence to ART and document the associated factors among PLWHA at the regional hospital of Sokode, Togo. METHODS: This was an analytical cross sectional study conducted from May to July 2013 at the regional hospital of Sokode among 291 PLWHA who had been on ART for at least three months before the study. RESULTS: A total of 291 PLWHA on ART were enrolled in the study. The mean age (+/-SD) was 37.3 +/- 9.3 years and the sex ratio (Male/Female) was 0.4. Among them, 195 (67.0%) were living with their partners and 210 (72.2%) had formal education. Two-thirds (194/291; 66.7%) of the PLWHA interviewed lived in urban areas. The global adherence to ART was 78.4%; the factors associated with ART adherence were: level of education (aOR = 3.54; p = 0.027), alcohol consumption (aOR = 0.43; p = 0.033), ART perception (aOR = 2.90; p = 0.026) and HIV status disclosure to sexual partner (aOR = 7.19; p <= 0.001). CONCLUSION: Although the level of adherence to ART in this study was higher than those reported in some studies in Sub-Saharan Africa, it remains sub-optimal and needs improvement. This may therefore hinder the implementation of efficient interventions related to access to ART services. PMID- 25526775 TI - Profile of usage of a reference diagnostic service on oral pathology: a 10-year evaluation. AB - BACKGROUND: Despite the professional and academic relevance of the Brazilian oral pathology diagnostic laboratories, no information about their usage profile is available in the English literature. The objective of the present study is to report data about the histopathological and immunohistochemical exams performed in a Brazilian regional reference laboratory of oral pathology, as well as its main users. METHODS: Information about all histopathological exams performed between 2002 and 2012 was retrieved from the files of the Oral and Maxillofacial Pathology Service of the School of Dentistry of Universidade Federal de Minas Gerais. Data collected included: 1) requestor of exam; 2) diagnosis classification; and 3) immunohistochemical tests. Descriptive statistical analyses were done. RESULTS: 13,522 histopathological exams were performed, mean 1,229/year. The Public Health System of the city of Belo Horizonte was the main requestor of exams (77.13%), followed by private professionals (19.26%), and other cities (2.03%). Most lesions were considered benign (12,599/ 93.17%), with 854 malignant lesions (6.32%). 469 immunohistochemical tests were performed; 324 (69.08%) were from benign diagnosis, and 145 (30.92%) from malignant diagnosis. The most used antibodies were against S100, vimentin, smooth muscle actin, actin muscle specific HHF-35, and pan-cytokeratin AE1/AE3. CONCLUSIONS: Public Health System is the major user of the diagnostic service on oral pathology in our institution. Most diagnoses were of benign lesions, although many malignant lesions were detected. Immunohistochemistry was particularly important in solving challenging cases. PMID- 25526776 TI - A phase II clinical trial of 6-mercaptopurine (6MP) and methotrexate in patients with BRCA defective tumours: a study protocol. AB - BACKGROUND: BRCA1 and BRCA2 genes are critical in homologous recombination DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis. Tumour cells with these mutations demonstrate increased sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibitors. 6MP was identified in a screen for novel drugs and found to selectively kill BRCA defective cells in a xenograft model as effectively as the PARP inhibitor AGO14699, even after these cells had acquired resistance to a PARP inhibitor or cisplatin. Exploiting the genetic basis of these tumours enables us to develop a more tailored approach to therapy for patients with BRCA mutated cancers. METHODS: This multi-centre phase II single arm trial was designed to investigate the activity and safety of 6-mercaptopurine (6MP) 55 mg/m2 per day, and methotrexate 15 mg/m2 per week in patients with advanced breast or ovarian cancer, ECOG PS 0-2, progressing after >= one prior regimen and known to bear a BRCA1/2 germ line mutation. Accrual was planned in two stages, with treatment continuing until progression or unacceptable toxicity; in the first, if less than 3/30 evaluable patients respond at 8 weeks after commencing treatment, the trial will be stopped for futility; if not, then accrual would proceed to a second stage, in which if more than 9/65 evaluable patients are found to respond at 8 weeks, the treatment will be regarded as potentially effective and a phase III trial considered subject to satisfactory safety and tolerability. The primary outcome is objective response at 8 weeks, defined by RECISTS v1.1 as complete response, partial response or stable disease. Secondary outcomes include safety, progression- free and overall survival, and quality of life. DISCUSSION: This study aims to investigate whether 6MP might be an effective treatment for BRCA deficient tumours even after the development of resistance to PARP inhibitors or platinum drugs. The study has surpassed the first stage analysis criteria of more than 3 out of 30 evaluable patients responding at 8 weeks, and is currently in the second stage of recruitment. TRIAL REGISTRATION: NCT01432145 http://www.ClinicalTrials.gov. PMID- 25526779 TI - Functional characterization of Sporothrix schenckii glycosidases involved in the N-linked glycosylation pathway. AB - Protein glycosylation pathways are conserved metabolic processes in eukaryotic organisms and are required for cell fitness. In fungal pathogens, the N-linked glycosylation pathway is indispensable for proper cell wall composition and virulence. In Sporothrix schenckii sensu stricto, the causative agent of sporotrichosis, little is known about this glycosylation pathway. Here, using a genome-wide screening for putative members of the glycosyl hydrolase (CAZy - GH) families 47 and 63, which group enzymes involved in the processing step during N linked glycan maturation, we found seven homologue genes belonging to family 47 and one to family 63. The eight genes were individually expressed in C. albicans null mutants lacking either MNS1 (for members of family 47) or CWH41 (for the member of family 63). Our results indicate that SsCWH41 is the functional ortholog of CaCWH41, whereas SsMNS1 is the functional ortholog of CaMNS1. The remaining genes of family 47 encode Golgi mannosidases and endoplasmic reticulum degradation-enhancing alpha-mannosidase-like proteins (EDEMs). Since these GH families gather proteins used as target for drugs to control cell growth, identification of these genes could help in the design of antifungals that could be used to treat sporotrichosis and other fungal diseases. In addition, to our knowledge, we are the first to report that Golgi mannosidases and EDEMs are expressed and characterized in yeast cells. PMID- 25526778 TI - Differential identification of Sporothrix spp. and Leishmania spp. by conventional PCR and qPCR in multiplex format. AB - Sporotrichosis and cutaneous leishmaniasis are skin infections with similar clinical manifestations but different treatment methods. The present study aimed to evaluate qPCR and conventional PCR for differential detection of the etiological agents of both infections in multiplex format. Assays were designed using two sets of reported primers: SS1/SS2, designed on the 18S ribosomal RNA gene from Sporothrix spp., and JW11/JW12, designed on the kinetoplast DNA (kDNA) minicircles of Leishmania spp. qPCR detected 200 fg of DNA per reaction for both Sporothrix and Leishmania. Melting curve analysis revealed two distinctive Tm peaks for Sporothrix spp. (85.5 degrees C), and Leishmania spp. (82.6 degrees C). A detection limit of 20 pg was determined for the diagnosis of both with conventional PCR. No other clinically important organisms were detected by either PCR or qPCR. However, a Blast analysis on GenBank databases, using as query the sequence of the PCR fragment obtained with primers SS1/SS2, showed 100% identity to environmental fungi of the Ophiostomales order. Lower percentages of identity (<=80%), with mismatches at primers' sequence regions were obtained for other environmental or clinically important fungi. Proper handling of clinical samples is required to avoid false negatives due to contamination with environmental fungi of the Ophiostomales order. PMID- 25526777 TI - Streptavidin-biotin-based directional double Nanobody sandwich ELISA for clinical rapid and sensitive detection of influenza H5N1. AB - BACKGROUND: Influenza H5N1 is one subtype of the influenza A virus which can infect human bodies and lead to death. Timely diagnosis before its breakout is vital to the human health. The current clinical biochemical diagnosis for influenza virus are still flawed, and the diagnostic kits of H5N1 are mainly based on traditional monoclonal antibodies that hardly meet the requirements for clinical applications. Nanobody is a promising tool for diagnostics and treatment due to its smallest size, high specificity and stability. In this study, a novel Nanobody-based bioassay was developed for rapid, low-cost and sensitive detection of the influenza H5N1 virus. METHODS: Nanobodies specific to H5N1 virus were selected from a VHH library by phage display technology. In this system, the biotinylated Nanobody was directionally captured by streptavidin coated on ELISA plate, which can specifically capture the H5N1 virus. Another Nanobody conjugated with HRP was used as a detector. A novel directional enzyme-linked immunosorbent assay for H5N1 using specific Nanobodies was established and compared to the conventional undirected ELISA assay. RESULTS: We have successfully constructed a high quality phage display Nanobody library and isolated two Nanobodies against H5N1 with high affinity and specificity. These two Nanobodies were further used to prepare the biosensor detection system. This streptavidin-biotin-based directional double Nanobodies sandwich ELISA for H5N1 detection showed superiority over the commonly undirectional ELISA protocol. The linear range of detection for standards in this immunoassay was approximately 50-1000 ng/mL and the detection limit was 14.1 ng/mL. The average recoveries of H5N1 virus from human serum samples were in the range from 94.58% to 114.51%, with a coefficient of variation less than 6.5%. CONCLUSION: Collectively, these results demonstrated that the proposed detection system is an alternative diagnostic tool that enables a rapid, inexpensive, sensitive and specific detection of the influenza virus. PMID- 25526780 TI - Role of the rttA gene in morphogenesis, stress response, and virulence in the human pathogenic fungus Penicillium marneffei. AB - Penicillium marneffei is a human pathogenic fungus and the only thermally dimorphic species of the genus. At 25 degrees C, P. marneffei grows as a mycelium that produces conidia in chains. However, when incubated at 37 degrees C or following infection of host tissue, the fungus develops as a fission yeast. Previously, a mutant (strain I133) defective in morphogenesis was generated via Agrobacterium-mediated transformation. Specifically, the rtt109 gene (subsequently designated rttA) in this mutant was interrupted by T-DNA insertion. We characterized strain I133 and the possible roles of the mutated rttA gene in altered P. marneffei phenotypes. At 25 degrees C, the rttA mutant produces fewer conidia than the wild type and a complemented mutant strain, as well as slower rates of conidial germination; however, strain I133 continued to grow as a yeast in 37 degrees C-incubated cultures. Furthermore, whereas the wild type exhibited increased expression of rttA at 37 degrees C in response to the DNA-damaging agent methyl methane sulfonate, strain I133 was hypersensitive to this and other genotoxic agents. Under similar conditions, the rttA mutant exhibited decreased expression of genes associated with carbohydrate metabolism and oxidative stress. Importantly, when compared with the wild-type and the complemented strain, I133 was significantly less virulent in a Galleria infection model when the larvae were incubated at 37 degrees C. Moreover, the mutant exhibited inappropriate phase transition in vivo. In conclusion, the rttA gene plays important roles in morphogenesis, carbohydrate metabolism, stress response, and pathogenesis in P. marneffei, suggesting that this gene may be a potential target for the development of antifungal compounds. PMID- 25526781 TI - Global epidemiology of sporotrichosis. AB - Sporotrichosis is an endemic mycosis caused by the dimorphic fungus Sporothrix schenckii sensu lato. It has gained importance in recent years due to its worldwide prevalence, recognition of multiple cryptic species within the originally described species, and its distinctive ecology, distribution, and epidemiology across the globe. In this review, we describe the current knowledge of the taxonomy, ecology, prevalence, molecular epidemiology, and outbreaks due to S. schenckii sensu lato. Despite its omnipresence in the environment, this fungus has remarkably diverse modes of infection and distribution patterns across the world. We have delved into the nuances of how sporotrichosis is intimately linked to different forms of human activities, habitats, lifestyles, and environmental and zoonotic interactions. The purpose of this review is to stimulate discussion about the peculiarities of this unique fungal pathogen and increase the awareness of clinicians and microbiologists, especially in regions of high endemicity, to its emergence and evolving presentations and to kindle further research into understanding the unorthodox mechanisms by which this fungus afflicts different human populations. PMID- 25526782 TI - Genetic variation, heritability and genotype by environment interaction of morphological traits in a tetraploid rose population. AB - BACKGROUND: Global trade has ensured that the ornamental horticulture continues to grow worldwide, with rose hybrids being the most economically important genus (Rosa x hybrida). Due to changes in global trade and an increase in energy costs the ornamental industry has seen a shift in the production and sale of flowers from the US and Europe alone to production in Africa and Latin America. As Kenya is a major exporter of roses to Europe we studied the genetic variation and heritability of specific morphological traits in a tetraploid population grown in the Netherlands and in Kenya. The aim was to estimate genotype by environment interaction (G * E) and to investigate the implications of (G * E) for rose breeding. RESULTS: A tetraploid rose population (K5) from a cross between two tetraploid parents was field tested over two seasons in the Netherlands (summer and winter) and two locations in Kenya (Nairobi and Njoro). Ten traits were compared per genotype across the four environments. There were differences in trait association across the four environments showing that the traits were partially influenced by the environment. The traits that had a low ratio of sigma(2) ge/sigma(2) g also showed a high value for heritability. For the traits number of petals, prickles on petioles, prickles on stems the interaction is minimal. For the traits chlorophyll content, stem width and side shoots we observed a much higher interaction ratio of 0.83, 1.43 and 3.13 respectively. The trait number of petals had the highest heritability of 0.96 and the lowest sigma(2) ge/sigma(2) g ratio (0.08). The trait number of side shoots (SS) with the lowest heritability (0.40) also had the highest sigma(2) ge/sigma(2) g ratio of 3.13. CONCLUSION: Attained by this experiment showed that we have different magnitudes of non-crossover G * E interactions. For the traits number of petals, prickles on stems and prickles on petioles with a low interaction and high heritability, selection can be done at any of the environments. Thus, these traits can be confirmed at the breeding site. For the traits stem width, side shoots and chlorophyll content that had a higher interaction selection for or against these traits should be done at the production location or at least be verified there. PMID- 25526783 TI - Sequencing methods and datasets to improve functional interpretation of sleeping beauty mutagenesis screens. AB - BACKGROUND: Animal models of cancer are useful to generate complementary datasets for comparison to human tumor data. Insertional mutagenesis screens, such as those utilizing the Sleeping Beauty (SB) transposon system, provide a model that recapitulates the spontaneous development and progression of human disease. This approach has been widely used to model a variety of cancers in mice. Comprehensive mutation profiles are generated for individual tumors through amplification of transposon insertion sites followed by high-throughput sequencing. Subsequent statistical analyses identify common insertion sites (CISs), which are predicted to be functionally involved in tumorigenesis. Current methods utilized for SB insertion site analysis have some significant limitations. For one, they do not account for transposon footprints - a class of mutation generated following transposon remobilization. Existing methods also discard quantitative sequence data due to uncertainty regarding the extent to which it accurately reflects mutation abundance within a heterogeneous tumor. Additionally, computational analyses generally assume that all potential insertion sites have an equal probability of being detected under non-selective conditions, an assumption without sufficient relevant data. The goal of our study was to address these potential confounding factors in order to enhance functional interpretation of insertion site data from tumors. RESULTS: We describe here a novel method to detect footprints generated by transposon remobilization, which revealed minimal evidence of positive selection in tumors. We also present extensive characterization data demonstrating an ability to reproducibly assign semi-quantitative information to individual insertion sites within a tumor sample. Finally, we identify apparent biases for detection of inserted transposons in several genomic regions that may lead to the identification of false positive CISs. CONCLUSION: The information we provide can be used to refine analyses of data from insertional mutagenesis screens, improving functional interpretation of results and facilitating the identification of genes important in cancer development and progression. PMID- 25526784 TI - Hypoxia activation of mitophagy and its role in disease pathogenesis. AB - SIGNIFICANCE: Mitochondria utilize most of the oxygen to produce adenosine triphosphate via electron transfer coupled with oxidative phosphorylation. Hypoxia undoubtedly induces reduced energy production via decreased mitochondrial metabolic activity or altered hypoxia-inducible factor-1- and peroxisome proliferator-activated receptor gamma coactivator 1-dependent mitochondrial biogenesis. Hypoxia may also activate mitophagy to selectively remove damaged or unwanted mitochondria for both mitochondrial quantity and quality control. Increasing evidence has shown that the accumulation of damaged mitochondria is a characteristic of aging and aging-related diseases, such as metabolic disorder, cancer, and neurodegenerative disease. RECENT ADVANCES: Both receptor-dependent and PTEN-induced putative kinase 1-PARKIN-dependent mitophagy have been described. Mitophagy receptors include Atg32 in yeast, as well as NIX/BNIP3L, B cell lymphoma 2/adenovirus E1B 19-kDa-interacting protein 3 and FUN14 domain containing 1 in mammals. In response to hypoxia or mitochondrial oxidative stress, receptor-mediated mitophagy was found to be activated via both transcriptional and post-translational modification. CRITICAL ISSUES: To date, the molecular mechanisms by which hypoxia triggers mitophagy and by which mitophagy contributes to the pathogenesis of aging-related diseases remain to be explored. FUTURE DIRECTIONS: An improved understanding of the regulation of mitochondrial quality may provide a strategy for treating aging-related diseases by targeting mitochondria and mitophagy pathways. PMID- 25526785 TI - Prostaglandin E2/leukotriene B4 balance induced by Lutzomyia longipalpis saliva favors Leishmania infantum infection. AB - BACKGROUND: Eicosanoids and sand fly saliva have a critical role in the Leishmania infection. Here, we evaluated the effect of Lutzomyia longipalpis salivary gland sonicate (SGS) on neutrophil and monocyte recruitment and activation of eicosanoid production in a murine model of inflammation. METHODS: C57BL/6 mice were inoculated intraperitonealy with Lutzomyia longipalpis SGS or Leishmania infantum or both, followed by analyses of cell recruitment, parasite load and eicosanoid production. RESULTS: Intraperitoneal injection of Lutzomyia longipalpis SGS together with Leishmania infantum induced an early increased parasite viability in monocytes and neutrophils. L. longipalpis SGS increased prostaglandin E2 (PGE2), but reduced leukotriene B4 (LTB4) production ex vivo in peritoneal leukocytes. In addition, the pharmacological inhibition of cyclooxygenase 2 (COX-2) with NS-398 decreased parasite viability inside macrophages during Leishmania infection in the presence of L. longipalpis SGS arguing that PGE2 production is associated with diminished parasite killing. CONCLUSIONS: These findings indicate that L. longipalpis SGS is a critical factor driving immune evasion of Leishmania through modulation of PGE2/LTB4 axis, which may represent an important mechanism on establishment of the infection. PMID- 25526786 TI - Clinical and GAA gene mutation analysis in mainland Chinese patients with late onset Pompe disease: identifying c.2238G > C as the most common mutation. AB - BACKGROUND: Pompe disease is an autosomal recessive lysosomal glycogen storage disorder that has been reported in different ethnic populations which carry different common mutations of the acid alpha-glucosidase (GAA) gene. The GAA mutation pattern in mainland Chinese patients with late-onset Pompe disease is still not well understood. METHODS: We presented the clinical and genetic characteristics of 27 mainland Chinese late-onset Pompe patients from 24 families. RESULTS: GAA mutation analysis revealed 26 different mutations, including 10 that were novel. The allelic frequency of c.2238G > C (p.W746C) was found to be 27.08% in this patient group. Respiratory dysfunction was diagnosed in 10 of 11 patients who underwent pulmonary function evaluation, although only four required ventilator support at night. CONCLUSIONS: Our findings indicate that c.2238G > C (p.W746C) is the most common mutation in mainland Chinese late onset Pompe patients, as observed in Taiwanese patients. The novel mutations identified in this study expand the genetic spectrum of late-onset Pompe disease, and the prevalence of respiratory dysfunction highlights the importance of monitoring pulmonary function in late-onset Pompe patients. PMID- 25526787 TI - Evaluating influence of the genotypes in the follicle-stimulating hormone receptor (FSHR) Ser680Asn (rs6166) polymorphism on poor and hyper-responders to ovarian stimulation: a meta-analysis. AB - BACKGROUND/AIMS: Reported associations of controlled ovarian hyperstimulation response (COH) with genotypes of the Ser680Asn (N680S) polymorphism in the follicle stimulating hormone receptor (FSHR) gene have conflicting results. METHODS: PubMed and Embase databases were searched for studies that investigated the N680S polymorphism in the FSHR gene in COH. Parameters used to examine ovarian response were poor and hyper-responses to COH. Using the meta-analytic approach, we estimated ovarian response risk (odds ratio [OR] with 95% confidence intervals) according to genotype. RESULTS: Our findings showed that SS genotype carriers were most likely to be poor responders (OR 1.61, p = 0.08) compared to the NN and NS genotypes which showed no associations (OR 0.93-0.95, p = 0.75 0.78). Heterogeneity of these pooled ORs warranted examining its sources. We detected outlying studies in each of the three N680S genotypes. Omitting these outliers erased the heterogeneity of the recalculated pooled outcomes. It also materially altered the SS effects where carriers became slightly unlikely to be poor responders (OR 0.90, p = 0.52). The S allele carrier effect was modulated for poor responders (OR 1.24, p = 0.39) in the Non-Hispanic Caucasian (NHC) subgroup. The likelihood of the S allele carriers (OR 1.47, p = 0.02) and the unlikelihood of the N allele carriers (OR 0.64, p = 0.007) were significant in our hyper-response findings. Confined to NHC retained significance of the S allele effects (OR 1.57, p = 0.01) but not among the N allele carriers (OR 0.68, p = 0.18). CONCLUSIONS: In summary, this is a meta-analytical confirmation of the FSHR SS genotype role in COH response. Hyper-responder analysis strengths lie on the non-heterogeneity and robustness of its results. Non-robustness and heterogeneity of the poor-responder results compose its limitations. Thus, poor response findings probably require caution as to the interpretation as a susceptibility marker for ovarian response. PMID- 25526788 TI - Function and mechanism of tumor suppressor gene LRRC4/NGL-2. AB - LRRC4/NGL-2 (Leucine rich repeat containing 4/Netrin-G ligand-2), a relatively specific expressed gene in brain tissue, is a member of the LRRC4/ NGL (netrin-G ligand) family and belongs to the superfamily of LRR proteins. LRRC4/NGL-2 regulates neurite outgrowth and lamina-specific dendritic segmentation, suggesting that LRRC4/NGL-2 is important for the development of the nervous system. In addition, LRRC4/NGL-2 has been identified as a tumor suppressor gene. The overexpression of LRRC4/NGL-2 suppresses glioma cell growth, angiogenesis and invasion through complicated signaling regulation networks. LRRC4/NGL-2 also has the ability to form multiphase loops with miRNA, transcription factors and gene methylation modification; the loss of LRRC4/NGL-2 function may be an important event in multiple biological processes in gliomas. In summary, LRRC4/NGL-2 is a critical gene in the normal development and tumorigenesis of the nervous system. PMID- 25526790 TI - Treatment of an aggressive aneurysmal bone cyst with percutaneous injection of polidocanol: a case report. AB - INTRODUCTION: Aneurysmal bone cysts are benign tumours that usually present in childhood. Aggressive forms have been described, which are often treated with surgery that entails major resection and reconstruction. Polidocanol sclerotherapy has recently been reported to have excellent results and promises to replace operative treatments, but its efficacy in the case of aggressive aneurysmal bone cysts has not been documented. CASE PRESENTATION: An 18-year-old woman from Sweden presented with pain in her shoulder and a rapidly progressing cystic bone lesion. The differential diagnosis was a rare, aggressive form of aneurysmal bone cyst or a sarcoma of the proximal humerus. She was successfully treated using sequential percutaneous injections of polidocanol after exclusion of malignancy. CONCLUSIONS: Management of aggressive aneurysmal bone cysts has thus far relied on open surgery. We propose that non-operative treatment with polidocanol is efficient even in the aggressive form of the aneurysmal bone cyst. PMID- 25526789 TI - Identification and use of the sugarcane bacilliform virus enhancer in transgenic maize. AB - BACKGROUND: Transcriptional enhancers are able to increase transcription from heterologous promoters when placed upstream, downstream and in either orientation, relative to the promoter. Transcriptional enhancers have been used to enhance expression of specific promoters in transgenic plants and in activation tagging studies to help elucidate gene function. RESULTS: A transcriptional enhancer from the Sugarcane Bacilliform Virus - Ireng Maleng isolate (SCBV-IM) that can cause increased transcription when integrated into the the genome near maize genes has been identified. In transgenic maize, the SCBV-IM promoter was shown to be comparable in strength to the maize ubiquitin 1 promoter in young leaf and root tissues. The promoter was dissected to identify sequences that confer high activity in transient assays. Enhancer sequences were identified and shown to increase the activity of a heterologous truncated promoter. These enhancer sequences were shown to be more active when arrayed in 4 copy arrays than in 1 or 2 copy arrays. When the enhancer array was transformed into maize plants it caused an increase in accumulation of transcripts of genes near the site of integration in the genome. CONCLUSIONS: The SCBV-IM enhancer can activate transcription upstream or downstream of genes and in either orientation. It may be a useful tool to activate enhance from specific promoters or in activation tagging. PMID- 25526791 TI - Using base rates of low scores to interpret the ANAM4 TBI-MIL battery following mild traumatic brain injury. AB - Base rates of low ANAM4 TBI-MIL scores were calculated in a convenience sample of 733 healthy male active duty soldiers using available military reference values for the following cutoffs: <=2nd percentile (2 SDs), <=5th percentile, <10th percentile, and <16th percentile (1 SD). Rates of low scores were also calculated in 56 active duty male soldiers who sustained an mTBI an average of 23 days (SD = 36.1) prior. 22.0% of the healthy sample and 51.8% of the mTBI sample had two or more scores below 1 SD (i.e., 16th percentile). 18.8% of the healthy sample and 44.6% of the mTBI sample had one or more scores <=5th percentile. Rates of low scores in the healthy sample were influenced by cutoffs and race/ethnicity. Importantly, some healthy soldiers obtain at least one low score on ANAM4. These base rate analyses can improve the methodology for interpreting ANAM4 performance in clinical practice and research. PMID- 25526792 TI - Effects of lixisenatide on elevated liver transaminases: systematic review with individual patient data meta-analysis of randomised controlled trials on patients with type 2 diabetes. AB - OBJECTIVE: To evaluate the effects of the glucagon-like peptide-1 receptor agonist lixisenatide on elevated liver blood tests in patients with type 2 diabetes. DESIGN: Systematic review. DATA SOURCES: Electronic and manual searches were combined. STUDY SELECTION: Randomised controlled trials (RCTs) on lixisenatide versus placebo or active comparators for type 2 diabetes were included. PARTICIPANTS: Individual patient data were retrieved to calculate outcomes for patients with elevated liver blood tests. MAIN OUTCOME MEASURES: Normalisation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). DATA SYNTHESIS: The results of included trials were combined in meta analyses. Sequential, subgroup and regression analyses were performed to evaluate heterogeneity and bias. RESULTS: We included 12 RCTs on lixisenatide versus placebo and 3 RCTs with the active comparators liraglutide, exenatide or sitagliptin. The mean treatment duration was 29 weeks. Lixisenatide increased the proportion of patients with normalisation of ALT (risk difference: 0.07; 95% CI 0.01 to 0.14; number needed to treat: 14 patients, p=0.042). The effect was not confirmed in sequential analysis. No effects of lixisenatide were identified on AST, alkaline phosphatase or bilirubin. No evidence of bias was identified. Mixed effect multilevel meta-regression analyses suggest that the benefit of lixisenatide on ALT was limited to patients who were overweight or obese. CONCLUSIONS: This review suggests that lixisenatide increases the proportion of obese or overweight patients with type 2 diabetes who achieve normalisation of ALT. Additional research is needed to determine if the findings translate to clinical outcome measures. TRIAL REGISTRATION NUMBER: PROSPERO; CRD42013005779. PMID- 25526793 TI - A new screening instrument for disability in low-income and middle-income settings: application at the Iganga-Mayuge Demographic Surveillance System (IM DSS), Uganda. AB - OBJECTIVE: The measurement of disability in low-income countries is recognised as a major deficiency in health information systems, especially in Africa. The Iganga and Mayuge Demographic Surveillance System (IM-DSS) in Uganda provides a special opportunity to develop population-based data to inform national health policies and evaluate innovations in assessing the burden of disability in Uganda. In this study, we apply a new instrument to screen for physical disabilities at the IM-DSS. The study utilised a modified version of the short set of questions proposed by the Washington Group on Disability Statistics. The instrument was applied at the household level and information was collected on all individuals over the age of 5, who were residents of the IM-DSS. SETTING: The study was based at the IM-DSS, which covers the parts of Iganga and Mayuge districts in Eastern Uganda. PARTICIPANTS: 57,247 individuals were included in the survey, with 51% of the study population being women. PRIMARY OUTCOMES: Activity limitations RESULTS: The overall prevalence of physical disability at the IM-DSS was 9.4%, with vision being the most common type of difficulty reported in this population, and communication being least prevalent. Disability was less likely to be observed among males than their female counterparts (OR 0.75; 95% CI 0.71 to 0.81; p<0.001). Statistically significant associations were found between disability and increasing age, as well as disability and decreasing household wealth status. CONCLUSIONS: This study shows that the modified short set of questions can be readily applied in a DSS setting to obtain estimates on the prevalence and types of disability at the population level. This instrument could be adapted for use to screen for disability in other LMIC settings, providing estimates that are comparable across different global regions and populations. PMID- 25526794 TI - Diagnostic accuracy study of three alcohol breathalysers marketed for sale to the public. AB - OBJECTIVES: To assess the diagnostic accuracy of three personal breathalyser devices available for sale to the public marketed to test safety to drive after drinking alcohol. DESIGN: Prospective comparative diagnostic accuracy study comparing two single-use breathalysers and one digital multiuse breathalyser (index tests) to a police breathalyser (reference test). SETTING: Establishments licensed to serve alcohol in a UK city. PARTICIPANTS: Of 222 participants recruited, 208 were included in the main analysis. Participants were eligible if they were 18 years old or over, had consumed alcohol and were not intending to drive within the following 6 h. OUTCOME MEASURES: Sensitivity and specificity of the breathalysers for the detection of being at or over the UK legal driving limit (35 ug/100 mL breath alcohol concentration). RESULTS: 18% of participants (38/208) were at or over the UK driving limit according to the police breathalyser. The digital multiuse breathalyser had a sensitivity of 89.5% (95% CI 75.9% to 95.8%) and a specificity of 64.1% (95% CI 56.6% to 71.0%). The single use breathalysers had a sensitivity of 94.7% (95% CI 75.4% to 99.1%) and 26.3% (95% CI 11.8% to 48.8%), and a specificity of 50.6% (95% CI 40.4% to 60.7%) and 97.5% (95% CI 91.4% to 99.3%), respectively. Self-reported alcohol consumption threshold of 5 UK units or fewer had a higher sensitivity than all personal breathalysers. CONCLUSIONS: One alcohol breathalyser had sensitivity of 26%, corresponding to false reassurance for approximately three people in four who are over the limit by the reference standard, at least on the evening of drinking alcohol. The other devices tested had 90% sensitivity or higher. All estimates were subject to uncertainty. There is no clearly defined minimum sensitivity for this safety-critical application. We conclude that current regulatory frameworks do not ensure high sensitivity for these devices marketed to consumers for a decision with potentially catastrophic consequences. PMID- 25526795 TI - Prevalence of work-related musculoskeletal symptoms of the neck and upper extremity among dentists in China. AB - OBJECTIVES: Studies from western countries show that dentists are vulnerable to work-related musculoskeletal disorders (WMSDs) of the neck and upper extremities, but little is known about their epidemiology among members of this rapidly growing profession in China. This study aims to investigate the prevalence of WMSDs and identify potential risk factors associated with their occurrence in the dental profession in China. SETTING AND PARTICIPANTS: A cross-sectional survey was carried out in 52 different hospitals in a large metropolitan city in China. A total of 304 questionnaires were distributed to respondents identified via stratified random sampling and 272 dentists (121 females and 151 males) completed the survey. The response rate was 89.5%. OUTCOMES: Visual analogue score was used to record neck and upper limb musculoskeletal symptoms on a body chart. Work related risk factors, including physical and psychosocial factors, were accounted for in the regression analysis. RESULTS: 88% of the dentists reported at least one musculoskeletal disorder and 83.8% suffered from neck pain. In the multivariate analyses, working hours per day were associated with neck pain (OR=1.43; 95% CI 1.03 to 1.98). Inability to select the appropriate size of dental instrument was associated with shoulder (OR=2.07; 95% CI 1.00 to 4.32) and wrist/hand (OR=2.47; 95% CI 1.15 to 5.32) pain. As for psychosocial factors, high job demand was associated with symptoms in the shoulder (OR=1.09; 95% CI 1.00 to 1.18), elbow (OR=1.11; 95% CI 1.03 to 1.19) and wrist/hand (OR=1.09; 95% CI 1.02 to 1.17). Regular physical exercise was associated with decreased neck pain (OR=0.37; 95% CI 0.14 to 1.00). CONCLUSIONS: The prevalence of WMSDs among Chinese dentists is high. Specifically, long working hours, inability to select the appropriate size of dental instrument and high job demand are the most significant risk factors. PMID- 25526796 TI - The impact of exacerbation frequency on mortality following acute exacerbations of COPD: a registry-based cohort study. AB - OBJECTIVE: To examine the association between exacerbation frequency and mortality following an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). DESIGN: Cohort study using medical databases. SETTING: Northern Denmark. PARTICIPANTS: On 1 January 2005, we identified all patients with prevalent hospital-diagnosed chronic obstructive pulmonary disease (COPD) who had at least one AECOPD during 1 January 2005 to 31 December 2009. We followed patients from the first AECOPD during this period until death, emigration or 31 December 2009, whichever came first. We flagged all AECOPD events during follow up and characterised each by the exacerbation frequency (0, 1, 2 or 3+) in the prior 12-month period. MAIN OUTCOMES AND MEASURES: Using Cox regression, we computed 0-30-day and 31-365-day age-adjusted, sex-adjusted, and comorbidity adjusted mortality rate ratios (MRRs) with 95% CIs entering exacerbation frequency as a time-varying exposure. RESULTS: We identified 16,647 eligible patients with prevalent COPD, of whom 6664 (40%) developed an AECOPD and were thus included in the study cohort. The 0-30-day MRRs were 0.97 (95% CI 0.80 to 1.18), 0.90 (95% CI 0.70 to 1.15) and 1.03 (95% CI 0.81 to 1.32) among patients with AECOPD with 1, 2 and 3+ AECOPDs versus no AECOPD within the past 12 months, respectively. The corresponding MRRs were 1.47 (95% CI 1.30 to 1.66), 1.89 (95% CI 1.59 to 2.25) and 1.59 (95% CI 1.23 to 2.05) for days 31-365. CONCLUSION: Among patients with AECOPD, one or more exacerbations in the previous year were not associated with 30-day mortality but were associated with an increased 31-365 day mortality. PMID- 25526797 TI - International Clinical Trial Day and clinical trials in Ethiopia and Africa. AB - Low income countries like Ethiopia are underrepresented in clinical research. As a major public commitment to clinical research, Ethiopia celebrated the International Clinical Trial Day (ICTD) for the first time on 20 May 2014 under the auspices of Addis Ababa University. The motto for the day was 'Clinical Trials for Excellence in Patient Care'. The celebration offered an opportunity to inform academic staff, researchers, students and the leadership about clinical trials being conducted and to discuss the future of clinical trials in the country. Although clear challenges to the conduct of trials abound, clinical trials registered from Ethiopia in trial registration databases is increasing. Cross-country collaborations, international funding support, motivation of academic staff to conduct clinical trials and the commitment and engagement of the leadership in research are all improving. The overall impact of clinical trials is also encouraging. For example, some of the trials conducted in Ethiopia have informed treatment guidelines. However, administrative capacity, research infrastructure as well as financial support remain weak. There is a need for enhanced university-industry linkage and translation of research findings into locally relevant evidence. Ethiopia, as well as the whole of Africa, has an unparalleled opportunity to lead the way in clinical trials, given its prospect of development and the need to have locally relevant evidence for its growing population. In this commentary we reflect on the celebration of ICTD, the status and opportunities for conducting clinical trials and the way forward for facilitating clinical trials in Ethiopia and Africa. PMID- 25526798 TI - Statin therapy and mortality from sepsis: a meta-analysis of randomized trials. AB - BACKGROUND: Statin therapy for sepsis has been suggested by observational studies. However, randomized controlled trials have not demonstrated this benefit. We conducted a systematic review and meta-analysis of randomized trials to evaluate the effect of statin therapy on mortality in patients with sepsis. METHODS: We searched 6 electronic databases for articles published before August 2014. Randomized trials reporting the effect of statin therapy on mortality in patients with sepsis were included. The primary outcome of interest was in hospital or 28-day mortality. Two independent reviewers searched and identified studies and extracted data. Risk ratios (RRs) were pooled across studies using random-effects models and were verified using fixed-effects models. RESULTS: Seven randomized trials were included in the analyses, comprising 1720 patients. Statin therapy did not significantly decrease in-hospital mortality (RR, 1.04; 95% confidence interval, 0.87-1.24; I(2) = 0%; P = .68) or 28-day mortality (RR, 0.93; 95% confidence interval, 0.46-1.89; I(2) = 57%; P = .85) in patients with sepsis. Study quality of the included trials was high; the median Jadad score was 4.5 (range, 4-5). CONCLUSIONS: This systematic review and meta-analysis of randomized trials suggests that statin therapy does not improve mortality outcomes in patients with sepsis compared with placebo. PMID- 25526799 TI - Pilot study of home-based delivery of HIV testing and counseling and contraceptive services to couples in Malawi. AB - BACKGROUND: HIV counseling and testing for couples is an important component of HIV prevention strategies, particularly in Sub Saharan Africa. The purpose of this pilot study is to estimate the uptake of couple HIV counseling and testing (CHCT) and couple family planning (CFP) services in a single home visit in peri urban Malawi and to assess related factors. METHODS: This study involved offering CHCT and CFP services to couples in their homes; 180 couples were sampled from households in a peri-urban area of Blantyre. Baseline data were collected from both partners and follow-up data were collected one week later. A pair of male and female counselors approached each partner separately about HIV testing and counseling and contraceptive services and then, if both consented, CHCT and CFP services (pills, condoms and referrals for other methods) were given. Bivariate and multivariate logistic regression analyses were done to examine the relationship between individual partner characteristics and acceptance of the services. Selected behaviors reported pre- and post-intervention, particularly couple reports on contraceptive use and condom use at last sex, were also tested for differences. RESULTS: 89% of couples accepted at least one of the services (58% CHCT-only, 29% CHCT + CFP, 2% CFP-only). Among women, prior testing experience (p < 0.05), parity (p < 0.01), and emotional closeness to partner (p < 0.01) had significant bivariate associations with acceptance of at least one service. Reported condom use at last sex increased from 6% to 25% among couples receiving any intervention. First-ever HIV testing was delivered to 25 women and 69 men, resulting, respectively, in 4 and 11 newly detected infections. CONCLUSIONS: Home-based CHCT and CFP were very successful in this pilot study with high proportions of previously untested husbands and wives accepting CHCT and there were virtually no negative outcomes within one week. This study supports the need for further research and testing of home- and couple-based approaches to expand access to HCT and contraceptive services to prevent the undesired consequences of sexually transmitted infection and unintended pregnancy via unprotected sex. PMID- 25526800 TI - An autophagosome-based therapeutic vaccine for HBV infection: a preclinical evaluation. AB - BACKGROUND: For more than 240 million chronic HBV carriers worldwide, effective therapeutic HBV vaccines are urgently needed. Recently, we demonstrated that autophagosomes were efficient antigens carriers and capable to cross-prime robust T-cell responses and mediate regression of multiple established tumors. Here we tested whether autophagosomes derived from HBV expressing cells could also function as a therapeutic vaccine. METHODS: We generated an autophagosome-based HBV vaccine from HBV-expressing hepatoma cells and examined its ability to induce polyvalent anti-HBV T-cell responses and therapeutic efficacy in mouse models that mimic acute and chronic HBV infection in human. RESULTS: When compared to the vaccine based on recombinant HBsAg, autophagosome-based HBV vaccine cross primed multi-specific anti-HBV T-cell responses and significantly reduced HBV replication and HBcAg expression in livers of both acute and chronic mouse models. Therapeutic effect of this HBV vaccine depended on anti-HBV CD8(+) effector T cells and associated with increased HBsAg and HBcAg specific IFN-gamma producing T cells in the chronic mouse model. CONCLUSIONS: These results indicated that autophagosome-based HBV vaccine could effectively suppress the HBV replication, clear the HBV infected hepatocytes, and break the HBV tolerance in mouse model. The potential clinical application of autophagosome-based HBV vaccine is discussed. PMID- 25526801 TI - Structural basis of RGD-hirudin binding to thrombin: Tyr3 and five C-terminal residues are crucial for inhibiting thrombin activity. AB - BACKGROUND: Hirudin is an anti-coagulation protein produced by the salivary glands of the medicinal leech Hirudomedicinalis. It is a powerful and specific thrombin inhibitor. The novel recombinant hirudin, RGD-hirudin, which contains an RGD motif, competitively inhibits the binding of fibrinogen to GPIIb/IIIa on platelets, thus inhibiting platelet aggregation while maintaining its anticoagulant activity. RESULTS: Recombinant RGD-hirudin and six mutant variants (Y3A, S50A, Q53A, D55A, E57A and I59A), designed based on molecular simulations, were expressed in Pichia pastoris. The proteins were refolded and purified to homogeneity as monomers by gel filtration and anion exchange chromatography. The anti-thrombin activity of the six mutants and RGD-hirudin was tested. Further, we evaluated the binding of the mutant variants and RGD-hirudin to thrombin using BIAcore surface plasmon resonance analysis (SPR). Kinetics and affinity constants showed that the KD values of all six mutant proteins were higher than that of RGD hirudin. CONCLUSIONS: These findings contribute to a novel understanding of the interaction between RGD-hirudin and thrombin. PMID- 25526802 TI - Cost-effectiveness analysis of adjuvant chemotherapies in patients presenting with gastric cancer after D2 gastrectomy. AB - BACKGROUND: To analyze and compare the economic outcomes of adjuvant chemotherapy with capecitabine plus oxaliplatin (referred to as the XELOX strategy) and of S-1 (the S-1 strategy) for gastric cancer patients after D2 gastrectomy. METHODS: A Markov model was developed to simulate the lifetime disease course associated with stage II or III gastric cancer after D2 gastrectomy. The lifetime quality adjusted life years (QALYs), associated costs, and incremental cost-effectiveness ratios (ICERs) were estimated. The clinical data were derived from the results of pilot studies. Direct costs were estimated from the perspective of the Chinese healthcare system, and the utility data were measured from end-point observations of Chinese patients. Sensitivity analyses were used to explore the impact of uncertainty on the model's outcomes. RESULTS: The combined adjuvant chemotherapy strategy with XELOX yielded the greatest increase in QALYs over the course of the disease (8.1 QALYs compared with 7.8 QALYs for the S-1 strategy and 6.2 for surgery alone). The incremental cost per QALY gained using the XELOX strategy was significantly lower than that for the S-1 strategy ($3,502 vs. $6,837, respectively). The results were sensitive to the costs of oxaliplatin and the hazard ratio of relapse-free survival. CONCLUSION: The observations reported herein suggest that adjuvant therapy with capecitabine plus oxaliplatin is a highly cost-effective strategy and more favorable treatment option than the S-1 strategy in patients with stage II or III gastric cancer who have undergone D2 gastrectomy. PMID- 25526804 TI - High resolution melting analytical platform for rapid prenatal and postnatal diagnosis of beta-thalassemia common among Southeast Asian population. AB - BACKGROUND: High resolution melting (HRM) analysis is a powerful technology for scanning sequence alteration. We have applied this HRM assay to screen common beta-thalassemia mutations found among Southeast Asian population. METHODS: Known DNA samples with 8 common mutations were used in initial development of the methods including -28 A-G, codon 17 A-T, IVSI-1G-T, IVSI-5G-C, codon 26G-A (Hb E), codons 41/42 -TTCT, codons 71/72+A and IVSII-654 C-T. Further validation was done on 60 postnatal and 6 prenatal diagnoses of beta-thalassemia. RESULTS: Each mutation has specific HRM profile which could be used in rapid screening. Apart from those with DNA deletions, the results of HRM assay matched 100% with those of routine diagnosis made by routine allele specific PCR. In addition, the HRM assay could initially recognize three unknown mutations including a hitherto un described one in Thai population. CONCLUSIONS: The established HRM assay should prove useful for rapid and high throughput platform for screening and prenatal diagnosis of beta-thalassemia common in the region. PMID- 25526803 TI - Glucose transporter 3 is a rab11-dependent trafficking cargo and its transport to the cell surface is reduced in neurons of CAG140 Huntington's disease mice. AB - Huntington's disease (HD) disturbs glucose metabolism in the brain by poorly understood mechanisms. HD neurons have defective glucose uptake, which is attenuated upon enhancing rab11 activity. Rab11 regulates numerous receptors and transporters trafficking onto cell surfaces; its diminished activity in HD cells affects the recycling of transferrin receptor and neuronal glutamate/cysteine transporter EAAC1. Glucose transporter 3 (Glut3) handles most glucose uptake in neurons. Here we investigated rab11 involvement in Glut3 trafficking. Glut3 was localized to rab11 positive puncta in primary neurons and immortalized striatal cells by immunofluorescence labeling and detected in rab11-enriched endosomes immuno-isolated from mouse brain by Western blot. Expression of dominant active and negative rab11 mutants in clonal striatal cells altered the levels of cell surface Glut3 suggesting a regulation by rab11. About 4% of total Glut3 occurred at the cell surface of primary WT neurons. HD(140Q/140Q) neurons had significantly less cell surface Glut3 than did WT neurons. Western blot analysis revealed comparable levels of Glut3 in the striatum and cortex of WT and HD(140Q/140Q) mice. However, brain slices immunolabeled with an antibody recognizing an extracellular epitope to Glut3 showed reduced surface expression of Glut3 in the striatum and cortex of HD(140Q/140Q) mice compared to that of WT mice. Surface labeling of GABAalpha1 receptor, which is not dependent on rab11, was not different between WT and HD(140Q/140Q) mouse brain slices. These data define Glut3 to be a rab11-dependent trafficking cargo and suggest that impaired Glut3 trafficking arising from rab11 dysfunction underlies the glucose hypometabolism observed in HD. PMID- 25526806 TI - The importance of glucocorticoid receptors in systemic lupus erythaematosus. A systematic review. AB - The therapeutic management of systemic lupus erythaematosus (SLE) is still a great debate. Despite the latest innovation agents or developing trials, there is not an integrated and common approach for treating SLE. For decades, natural and synthetic glucocorticoids (GCs) have been the first and most frequently used immune suppressive agents in SLE. Therefore, GCs are the most important therapy in SLE in daily routine, however the response to GCs differs widely and long-term therapy is associated with side-effects. Still now, clinicians and physicians are unable to predict the exact and ideal dose and term of therapy for patients suffering from various symptoms and degree of disease activity of SLE. The biological mechanism of GCs is regulated through activation of glucocorticoid receptors (GRs). There are two major isoforms of GRs: GRalpha and GRbeta; however, the GRalpha is the predominant one which binds steroids and activates target genes. In the present review, we summarise the anti-inflammatory and immune suppressive effects of GCs via GRs to regulate the target genes. PMID- 25526805 TI - Uncovering the role of Sgf73 in maintaining SAGA deubiquitinating module structure and activity. AB - The SAGA (Spt-Ada-Gcn5 acetyltransferase) complex performs multiple functions in transcription activation including deubiquitinating histone H2B, which is mediated by a subcomplex called the deubiquitinating module (DUBm). The yeast DUBm comprises a catalytic subunit, Ubp8, and three additional subunits, Sgf11, Sus1 and Sgf73, all of which are required for DUBm activity. A portion of the non globular Sgf73 subunit lies between the Ubp8 catalytic domain and the ZnF-UBP domain and has been proposed to contribute to deubiquitinating activity by maintaining the catalytic domain in an active conformation. We report structural and solution studies of the DUBm containing two different Sgf73 point mutations that disrupt deubiquitinating activity. We find that the Sgf73 mutations abrogate deubiquitinating activity by impacting the Ubp8 ubiquitin-binding fingers region and they have an unexpected effect on the overall folding and stability of the DUBm complex. Taken together, our data suggest a role for Sgf73 in maintaining both the organization and the ubiquitin-binding conformation of Ubp8, thereby contributing to overall DUBm activity. PMID- 25526807 TI - DNA binding reduces the dissociation rate of STAT1 dimers and impairs the interdimeric exchange of protomers. AB - BACKGROUND: A shift between two dimer conformations has been proposed for the transcription factor STAT1 (signal transducer and activator of transcription 1) which links DNA binding of the parallel dimer to tyrosine dephosphorylation of the antiparallel dimer as two consecutive and important steps in interferon- gamma (IFNgamma)-mediated signalling. However, neither the kinetics nor the molecular mechanisms involved in this conformational transition have been determined so far. RESULTS: Our results demonstrated that the dissociation of dimers into monomers and their subsequent re-association into newly formed tyrosine-phosphorylated dimers is a relatively slow process as compared to the fast release from high-affinity DNA-binding sites, termed GAS (gamma-activated sequence). In addition, we noted an inhibitory effect of GAS binding on the exchange rate of protomers, indicating that DNA binding substantially impedes the recombination of dimeric STAT1. Furthermore, we found that reciprocal aminoterminal interactions between two STAT1 molecules are not required for the interchange of protomers, as an oligomerization-deficient point mutant displayed similar interdimeric exchange kinetics as the wild-type molecule. CONCLUSIONS: Our results demonstrate that DNA binding impairs the oscillation rate between STAT1 conformers. Furthermore, these data suggest that the rapid release from high-affinity GAS sites is not a rate-limiting step in IFNgamma-mediated signal transduction. Further investigations are needed to decipher the physiological significance of the observed dissociation/re-association process of STAT1 dimers. PMID- 25526808 TI - Discovery of a novel small secreted protein family with conserved N-terminal IGY motif in Dikarya fungi. AB - BACKGROUND: Small secreted proteins (SSPs) are employed by plant pathogenic fungi as essential strategic tools for their successful colonization. SSPs are often species-specific and so far only a few widely phylogenetically distributed SSPs have been identified. RESULTS: A novel fungal SSP family consisting of 107 members was identified in the poplar tree fungal pathogen Marssonina brunnea, which accounts for over 17% of its secretome. We named these proteins IGY proteins (IGYPs) based on the conserved three amino acids at the N-terminus. In spite of overall low sequence similarity among IGYPs; they showed conserved N- and C-terminal motifs and a unified gene structure. By RT-PCR-seq, we analyzed the IGYP gene models and validated their expressions as active genes during infection. IGYP homologues were also found in 25 other Dikarya fungal species, all of which shared conserved motifs and the same gene structure. Furthermore, 18 IGYPs from 11 fungi also shared similar genomic contexts. Real-time RT-PCR showed that 8 MbIGYPs were highly expressed in the biotrophic stage. Interestingly, transient assay of 12 MbIGYPs showed that the MbIGYP13 protein induced cell death in resistant poplar clones. CONCLUSIONS: In total, 154 IGYPs in 26 fungi of the Dikarya subkingdom were discovered. Gene structure and genomic context analyses indicated that IGYPs originated from a common ancestor. In M. brunnea, the expansion of highly divergent MbIGYPs possibly is associated with plant-pathogen arms race. PMID- 25526809 TI - [Mental health service utilization among borderline personality disorder patients inpatient]. AB - BACKGROUND: Borderline personality disorder (BPD) is characterized by a pervasive pattern of instability and impulsivity. Several North American prospective studies support the high level of mental health care utilization in this population. There is little data in other systems of health organization, such as France. Furthermore, little is known on the variables associated with the mental health service utilization among BPD patients. OBJECTIVE: The main objective was to compare the utilization of mental health care among BPD patients, to the general population and patients with another personality disorder (PD) and to describe the demographic and clinical factors associated with the group of patients who use the most health care. METHOD: A multi-center (5 public and private centers), epidemiological study. Data were collected prospectively (database of an insurance fund covering 80% of the population) and viewed, retrospectively. We used the data collected during the five years previously to the inclusion. Inclusion criteria were age (18-60 years) and membership in the health insurance fund targeted. Patients on legal protection, forced hospitalization, with a chronic psychotic disorder, manic, mental retardation, or not reading French were excluded. First, four groups were composed: BPD, other PD, control groups for PD and other PD. The first two groups were recruited from a screening of inpatients including a self-administered questionnaire (Personality Disorder Questionnaire 4+). Assessment by a psychologist including the Structured Interview for DSM-IV Personality Disorders (SIDP-IV) was given straight to those who had a score above 28. This questionnaire allowed us to distinguish one group of subjects with BPD and a group with other PD (without BPD). Clinical evaluation included Axis I (MINI), Axis II (SIDP-IV), psychopathological features (YSQ-I, DSQ-40), demographic variables and therapeutic alliance (Haq-II). Matched controls (age, sex) composed the 3rd and 4th group (BPD control and other PD control). They were randomly chosen in the health database insurance previously used. RESULTS: One hundred and thirty-seven (95.8%) screened patients agreed to answer the psychological assessment. In this sample, 44 (32.1%) had BPD, 39 (28.5%) other PD and another 39 (28.5%) did not have PD. The BPD group was compared to a sample of 165 matched subjects and the other group PD to a sample of 123 matched controls. There was no difference between BPD and other PD groups regarding the mental health utilization. However, there was an increased use of hospitalizations and deliverances of nervous system drugs in both clinical groups compared to their controls. The analysis of drugs supplied in pharmacies for BPD patients showed that the first two drugs were opiate substitutes (12.3% methadone, buprenorphine 6.7%). No anticonvulsants or atypical antipsychotics appear in the top 20 of treatments delivered. A composite variable (hospitalization for more than 6 months during previous five years and 500 supplied drugs) allowed the discrimination of two groups among patients with BPD: heavy users of care and low care users. No variables (demographics, Axis I, Axis II, self-aggressiveness, DSQ-40, Haq-II, YSQ-I) could discriminate the two groups except the number of previous psychotherapies (heavy users: n=0.4 (SD 0.5) vs low users: n=1.8 (SD 2.1) P=0.0054). CONCLUSION: This study confirms the important use of the service of BPD patients in France, as well as the possible moderating role of psychotherapy. We found a mismatch between these uses and recommendations. PMID- 25526810 TI - [The placement courses and the subjective quality of life of 6- to 11-year-old children living in child welfare institutions]. AB - BACKGROUND: Besides diseases, the concept of quality of life is increasingly used to account for the consequences of other vulnerability situations that may be encountered by individuals, including young children. However, very few studies have examined children's perception of their quality of life in the context of child welfare and protection, and they yielded mixed results. OBJECTIVES: The objectives of this study were (1) to compare the subjective quality of life of children placed in institution with that of children living in their families, by controlling for child sex, age, socioeconomic and familial status, and (2) to examine its relations with their placement course in the child welfare system. METHOD: The sample of this study was composed of 56 children aged 6 to 11, 28 of which were placed in a child welfare institution. Information about the placement course of institutionalized children was given by their social workers and the quality of life of all participants was assessed with the AUQUEI questionnaire. This self-report, which is based on children's conception of their quality of life, allows assessment of four distinct dimensions in addition to the overall score: leisure, performances, relations and family life, and separation. RESULTS: According to the results, the quality of life of children placed in institutions did not differ from that of children living in their families. However, its perception was closely related to the placement course of institutionalized children in the child welfare system. Whereas maltreated children obtained lower overall and performance scores than their neglected peers, children placed in foster families before institution had a poorer perception of their quality of life in the domains of family life and separations. DISCUSSION: These results are interpreted in light of attachment research and theory. Indeed, the relations between children's quality of life and their placement course could be explained by their high level of attachment disorganization. Finally, the results of this study suggested that children were well aware of their difficulties and that they can easily be identified by directly assessing the children's quality of life. PMID- 25526811 TI - [Specifications of motivational interviewing within a cognitive-behavioral therapy of chronic pain]. AB - OBJECTIVES: Cognitive and behavioral approach of chronic pain presents encouraging results by improving physical, functional and psychological states of chronic pain patients. This specific treatment is partially based on the acquisition of new adaptive strategies to help the patients to manage more effectively chronic pain and to improve subsequently their subjective well-being. This requires in parallel to give up noxious emotional, cognitive and behavioral attitudes towards pain. Now, we have to admit that numerous therapeutic failures are directly imputable to difficulties introducing and making the indispensable changes continue in pursuit of the fixed therapeutic objectives. Readiness to change could play a considerable role in the success or not of chronic pain treatment. The main objective of this article is to present the data of the current literature concerning the specificities of the process of change in the field of the chronic pain. METHODS: We present a review of the literature describing at first, the psychological progress made by chronic pain patients longing to manage their suffering better via the trans-theoretical model of intentional change. Secondly, we develop the contributions of the technique of motivational interviewing in the improvement of chronic pain treatment. DISCUSSION: The identification of the motivational profile of chronic pain patients will determine how motivational interviewing can be conducted to improve their readiness for change. There are several strategies used with chronic pain patients in pre-contemplative and contemplative stages. Therapists may facilitate the problem recognition (help chronic pain patients to become aware of and identify the nature of the difficulties they face when trying to cope with their physical suffering); increase the personal concern (empowering chronic pain patients so that they feel fully involved in what they offer and invest in the therapy); develop the intention of change (ensure that the change becomes truly intentional); cultivate optimism (to help chronic pain patients to consider the present situation as being less desperate than it seems); ask open-ended questions (the direct questioning can be used to specify a request or reveal ambivalence about change); present personal feedback (the therapist provides the patient with a maximum of information that may help to appreciate the true value of the effectiveness of their current management of pain); review consequences of change versus non-change (to review the plausible positive (pros) and negative (cons) consequences of change); and summarizing (to summarize the key points discussed during the interview). In the active stage, therapists may use other strategies like: developing a plan for change (to suggest the adoption of certain coping strategies with pain); providing information advice (provide information advice in order to help chronic pain patients to determine how they will take concrete steps to initiate change); and using a change plan worksheet (help chronic pain patients to develop a synthetic view of the change process they will undertake). CONCLUSION: The various strategies discussed in this article are intended to accompany chronic pain patients to a process of change to help them consider a fundamental change in their ways of managing pain, when they are insufficient, ineffective and/or unintentionally aggravating their situation. It is important to help chronic pain patients to become aware of the nature of the adaptive problems they face, but also opportunities for change that are offered in order to encourage them to manage more efficiently and more autonomously their physical and mental suffering. In this context of openness to change, motivational interviewing can be an invaluable help to build a good therapeutic alliance in order to maximize the impact of supported global and multidimensional chronic pain by including a cognitive-behavioral approach for example. PMID- 25526812 TI - [Comparison of European therapies for cannabis addiction among adolescents]. AB - BACKGROUND: In European countries, cannabis abuse and dependence among adolescents has become a public health priority. Since 2002, studies have shown that persons seeking treatment for cannabis use are increasing. Over the past ten years, the involvement of many structures working on this topic has permitted an expansion and a diversification of treatment protocols. Moreover, international scientific studies, mainly conducted in the United States, have demonstrated the effectiveness of therapies based on motivation interviews, cognitive behavioral therapy (CBT) and family approach. Among these treatments, the multi-dimensional family therapy (MDFT), developed by the team of Professor Liddle in Miami, showed great efficiency in young adolescents with cannabis abuse problems. Five European countries therefore decided to build a randomized control study (RCT) comparing MDFT to the treatments that were commonly used. For the purpose of the research, the usual treatments had to be described and were named treatment as usual (TAU). Besides the obvious interest of implementing MDFT in Europe, it seems equally important to highlight the investment that has been made by all the European structures. The goal of this article is to describe and share the previous experience of all centers that have participated in the INCANT trial including the Netherlands, Germany, Belgium, Switzerland and France in the field of cannabis adolescent abusers. METHODOLOGY: To describe and compare European treatment as usual (TAU), we visited each structure to meet and to interview the teams regarding their practices. To perform these interviews, we used a semi directive questionnaire we had built previously. We completed the therapist's interviews with their written clinical protocol (when they had one) and a video/audiotaped session or written session. Data collection took place in five addiction centers: Therapy laden in Germany, Phoenix foundation in Switzerland, Cannabis clinic in Belgium, Palm Huis in Holland and Emergence and CEDAT in France. RESULTS: In terms of monitoring arrangements, there are many similarities between the European TAU. Indeed, all European centers were practicing individual therapy mainly focusing on the adolescent, and therapists were involving parents. In almost all European countries, the teenager was seen at one session per week, the parents were seen once a month and the duration of the therapy was about 6 months. The interview analysis has revealed that between countries, despite therapeutic techniques and differences in psychopathological approach, a global care process remained quite common. The therapeutic process, in all countries, was organized in two phases: build the therapeutic alliance and assess the situation with the adolescent, and help to coach him/her to enhance changes. DISCUSSION/CONCLUSION: The comparison of the TAU highlights the difficulties to see differences between models of psychotherapies. Are the psychotherapies really different or is it just a matter of the therapists, experience and good will? The debate is open and articles have shown arguments for both hypotheses. The analysis of our TAU indeed shows a common base, but as therapists started to formalize what they usually do, differences appear. The Incant study, in which TAU was compared to a formalized family therapy, clearly indicates differences between therapies, but only with heavy cases. Perhaps the more cases became complicated, the more there's a need for formalization and of course this will lead to differences between models. PMID- 25526813 TI - [Measurement of QT interval and serotoninergic reuptake inhibitor antidepressants: A study in a university psychiatric hospital]. PMID- 25526814 TI - [Economic impact of consultation-liaison psychiatry in a French University Hospital Centre]. AB - BACKGROUND: In times of fiscal restraint for health structures, apart from the clinical input, it seems important to discuss the economic impact of liaison psychiatry. There are only a few studies on the economic added value provided by a liaison psychiatry team. In addition to this, only a few psychiatric pathologies are coded as they should be, hence we make the assumption of an additional development provided by a specialised team. METHODS: Over a short period of 4months, in three departments of the Toulouse University Hospital Centre, the added value to the general pricing system of liaison psychiatry was studied. The population was represented by all the consecutive requests for consultations from patients over 18years old, men and women, hospitalised at that time. These three departments frequently request consultations with the psychiatry liaison team. They set a diagnostic, and if this is associated with a higher Homogeneous Group of Patients (HGP), it provides added value. RESULTS: Fifty-two patients benefited from a psychiatric consultation over 4months. The results highlight a development of ? 8630.43 for the traumatology department, ? 3325.03 for the internal medicine department, and ? 513.61 for the haematology department over the study period. The overall development over this period was ? 12,469.07. CONCLUSION: To our knowledge, this approach is one of the first in France to highlight an economic impact of the intervention of liaison psychiatry in the claiming departments. PMID- 25526815 TI - Characteristics of clients who access mobile compared to clinic HIV counselling and testing services: a matched study from Cape Town, South Africa. AB - BACKGROUND: Studies within sub-Saharan African countries have shown that mobile services increase uptake of HIV counselling and testing (HCT) services when compared to clinics and are able to access different populations, but these have included provider-initiated HCT in clinics. This study aimed to compare the characteristics of clients who self-initiated HCT at either a mobile or a clinic service in terms of demographic and socio-economic variables, also comparing reasons for accessing a particular health service provider. METHODS: This study took place in eight areas around Cape Town. A matched design was used with one mobile HCT service matched with one or more clinics (offering routine HCT services) within each of the eight areas. Adult clients who self-referred for an HIV test within a specified time period at either a mobile or clinic service were invited to participate in the study. Data were collected between February and April 2011 using a questionnaire. Summary statistics were calculated for each service type within a matched pair and differences of outcomes from pairs were used to calculate effect sizes and 95% confidence intervals. RESULTS: 1063 participants enrolled in the study with 511 from mobile and 552 from clinic HCT services. The proportion of males accessing mobile HCT significantly exceeded that of clinic HCT (p < 0.001). The mean age of participants attending mobile HCT was higher than clinic participants (p = 0.023). No significant difference was found for socio-economic variables between participants, with the exception of access to own piped water (p = 0.029). Participants who accessed mobile HCT were significantly more likely to report that they were just passing, deemed an "opportunistic" visit (p = 0.014). Participants who accessed clinics were significantly more likely to report the service being close to home or work (p = 0.035). CONCLUSIONS: An HCT strategy incorporating a mobile HCT service, has a definite role to play in reaching those population groups who do not typically access HCT services at a clinic, especially males and those who take advantage of the opportunity to test. Mobile HCT services can complement clinic services. PMID- 25526816 TI - Genetic association between germline JAK2 polymorphisms and myeloproliferative neoplasms in Hong Kong Chinese population: a case-control study. AB - BACKGROUND: Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that can be characterised by a somatic mutation (JAK2V617F). This mutation causes the bone marrow to produce excessive blood cells and is found in polycythaemia vera (~95%), essential thrombocythaemia and primary myelofibrosis (both ~50%). It is considered as a major genetic factor contributing to the development of these MPNs. No genetic association study of MPN in the Hong Kong population has so far been reported. Here, we investigated the relationship between germline JAK2 polymorphisms and MPNs in Hong Kong Chinese to find causal variants that contribute to MPN development. We analysed 19 tag single nucleotide polymorphisms (SNPs) within the JAK2 locus in 172 MPN patients and 470 healthy controls. Three of these 19 SNPs defined the reported JAK2 46/1 haplotype: rs10974944, rs12343867 and rs12340895. Allele and haplotype frequencies were compared between patients and controls by logistic regression adjusted for sex and age. Permutation test was used to correct for multiple comparisons. With significant findings from the 19 SNPs, we then examined 76 additional SNPs across the 148.7-kb region of JAK2 via imputation with the SNP data from the 1000 Genomes Project. RESULTS: In single-marker analysis, 15 SNPs showed association with JAK2V617F-positive MPNs (n = 128), and 8 of these were novel MPN-associated SNPs not previously reported. Exhaustive variable-sized sliding-window haplotype analysis identified 184 haplotypes showing significant differences (P < 0.05) in frequencies between patients and controls even after multiple-testing correction. However, single-marker alleles exhibited the strongest association with V617F positive MPNs. In local Hong Kong Chinese, rs12342421 showed the strongest association signal: asymptotic P = 3.76 * 10-15, empirical P = 2.00 * 10-5 for 50,000 permutations, OR = 3.55 for the minor allele C, and 95% CI, 2.59-4.87. Conditional logistic regression also signified an independent effect of rs12342421 in significant haplotype windows, and this independent effect remained unchanged even with the imputation of additional 76 SNPs. No significant association was found between V617F-negative MPNs and JAK2 SNPs. CONCLUSION: With a large sample size, we reported the association between JAK2V617F-positive MPNs and 15 tag JAK2 SNPs and the association of rs12342421 being independent of the JAK2 46/1 haplotype in Hong Kong Chinese population. PMID- 25526818 TI - Targeting beta2 adrenergic receptors regulate human T cell function directly and indirectly. AB - It is well-established that central nervous system activation affects peripheral blood mononuclear cell (PBMCs) function through the release of the catecholamines (Epi) and norepinephrine (NE), which act on beta2-adrenergic receptors (beta2AR). However, most studies have used non-specific stimulation of cells rather than antigen-specific responses. Likewise, few studies have parsed out the direct effects of beta2AR stimulation on T cells versus indirect effects via adrenergic stimulation of antigen presenting cells (APC). Here we report the effect of salmeterol (Sal), a selective beta2AR agonist, on IFN-gamma(+) CD4 and IFN gamma(+) CD8 T cells following stimulation with Cytomegalovirus lysate (CMVL strain AD169) or individual peptides spanning the entire region of the HCMV pp65 protein (pp65). Cells were also stimulated with Staphylococcal enterotoxin B. Additionally, we investigated the effect of Epi and Sal on cytotoxic cell killing of transfected target cells at the single cell level using the CD107a assay. The results show that Sal reduced the percentage of IFN-gamma(+) CD4 and IFN-gamma(+) CD8 T cells both when applied directly to isolated T cells, and indirectly via treatment of APC. These inhibitory effects were mediated via a beta2 adrenergic dependent pathway and were stronger for CD8 as compared to CD4 T cells. Similarly, the results show that Sal suppressed cytotoxicity of both CD8 T and NK cells in vitro following stimulation with Chinese hamster ovary cell line transfected with MICA(*009) (T-CHO) and the human erythromyeloblastoid leukemic (K562) cell line. The inhibitory effect on cytotoxicity following stimulation with T-CHO was stronger in NK cells compared with CD8 T cells. Thus, targeting the beta2AR on lymphocytes and on APC leads to inhibition of inflammatory cytokine production and target cell killing. Moreover, there is a hierarchy of responses, with CD8 T cells and NK cells inhibited more effectively than CD4 T cells. PMID- 25526819 TI - Development of vaccines for prevention of Ebola virus infection. AB - Ebola virus infection causes severe hemorrhagic fevers with high fatality rates up to 90% in humans, for which no effective treatment is currently available. The ongoing Ebola outbreak in West Africa that has caused over 14,000 human infections and over 5000 deaths underscores its serious threat to the public health. While licensed vaccines against Ebola virus infection are still not available, a number of vaccine approaches have been developed and shown to protect against lethal Ebola virus infection in animal models. This review aims to summarize the advancement of different strategies for Ebola vaccine development with a focus on the discussion of their protective efficacies and possible limitations. In addition, the development of animal models for efficacy evaluation of Ebola vaccines and the mechanism of immune protection against Ebola virus infection are also discussed. PMID- 25526817 TI - CXCR4(+)CD45(-) BMMNC subpopulation is superior to unfractionated BMMNCs for protection after ischemic stroke in mice. AB - Cell-based therapy is considered to be a promising therapeutic strategy for stroke treatment. Although unfractionated bone marrow mononuclear cells (BMMNCs) have been tried in both preclinical and clinical trials, the effective subpopulations need to be identified. In this study, we used fluorescence activated cell sorting to harvest the CXCR4(+)CD45(+) and CXCR4(+)CD45(-) BMMNC subpopulations from transgenic mice that express enhanced green fluorescent protein. We then allogeneically grafted unfractionated BMMNCs or a subpopulation into mice subjected to transient middle cerebral artery occlusion (tMCAO) and compared the effects on stroke outcomes. We found that CXCR4(+)CD45(-) BMMNCs, but not CXCR4(+)CD45(+) BMMNCs, more effectively reduced infarction volume and neurologic deficits than did unfractionated BMMNCs. Brain tissue from the ischemic hemisphere of mice treated with CXCR4(+)CD45(-) BMMNCs had higher levels of vascular endothelial growth factor and lower levels of TNF-alpha than did tissue from mice treated with unfractionated BMMNCs. In contrast, CXCR4(+)CD45(+) BMMNCs showed an increase in TNF-alpha. Additionally, CXCR4(+)CD45(+) and CXCR4(+)CD45(-) populations exhibited more robust migration into the lesion areas and were better able to express cell-specific markers of different linages than were the unfractionated BMMNCs. Endothelial and astrocyte cell markers did not colocalize with eGFP(+) cells in the brains of tMCAO mice that received CXCR4(+)CD45(+) BMMNCs. In vitro, the CXCR4(+)CD45(-) BMMNCs expressed significantly more Oct-4 and Nanog mRNA than did the unfractionated BMMNCs. However, we did not detect gene expression of these two pluripotent markers in CXCR4(+)CD45(+) BMMNCs. Taken together, our study shows for the first time that the CXCR4(+)CD45(-) BMMNC subpopulation is superior to unfractionated BMMNCs in ameliorating cerebral damage in a mouse model of tMCAO and could represent a new therapeutic approach for stroke treatment. PMID- 25526820 TI - How much will linked deformable registrations decrease the quality of multi-atlas segmentation fusions? AB - BACKGROUND AND PURPOSE: Multi-atlas segmentation can yield better results than single atlas segmentation, but practical applications are limited by long calculation times for deformable registration. To shorten the calculation time pre-calculated registrations of atlases could be linked via a single atlas registered in runtime to the current patient. The primary purpose of this work is to investigate and quantify segmentation quality changes introduced by such linked registrations. We also determine the optimal parameters for fusing linked multi-atlas labels using probabilistic weighted fusion. MATERIAL AND METHODS: Computed tomography images of 10 head and neck cancer patients were used as atlases, with parotid glands, submandibular glands, the mandible and lymph node levels II-IV segmented by an experienced radiation oncologist following published consensus guidelines. The change in segmentation quality scored by Dice similarity coefficient (DSC) for linking free-form deformable registrations, modeled by B-splines, was investigated for both single- and multi-atlas label fusion by using a leave-one-out approach. RESULTS: The median decrease of the DSC was in the range 2.8% to 8.4% compared to direct registrations for all structures while reducing the computer calculation time to that of a single deformable registration. Linking several registrations showed a DSC decrease almost linear to the number of links, suggesting that extrapolation to zero links provides an observer independent measure of the inherent precision with which the segmentation guidelines can be applied. CONCLUSIONS: Linking pre-made registrations of multiple atlases via a runtime registration of a single atlas provides a feasible method for reducing computation time in multi-atlas registration. PMID- 25526821 TI - Dissociated neural representations induced by complex and simple odorant molecules. AB - An important challenge in olfaction research is to understand how percepts relate to the molecular structure of stimuli. Previous psychophysical studies showed that, whereas structurally simple odorant molecules evoked a more uniform qualitative perception as revealed by the use of a small number of labels to describe their olfactory quality, more complex odorants evoked a larger variety of olfactory qualities, reflecting a more heterogeneous qualitative perception. The present study examined how this influence of odorant molecular complexity on perception is reflected in the human brain. To this end, participants were stimulated with structurally simple and complex odorant molecules and their brain responses were assessed by functional magnetic resonance imaging (fMRI). Low- and high-complexity odorants were judged to have the same intensity, pleasantness and familiarity (p>0.05 in all cases), whereas complex odorants induced more quality labels than simple odorants (p<0.02) as expected. Imaging analysis of complex vs. simple odorants revealed significant activation in dorsal anterior cingulate gyrus, but not in primary olfactory areas. Taken together, these findings suggest dissociated neural representations of uniform and heterogeneous olfactory perception, highlighting for the first time the impact of odorant complexity on activity of the cingulate gyrus. PMID- 25526822 TI - Changes of olfactory processing in childhood and adolescence. AB - OBJECTIVES: Olfactory event-related potentials (OERPs) are widely used to study central odor processing. Only a few studies used this method in children and adolescents. Aim of the current study therefore was to measure OERP and the possible influences of age and sex on central odor processing in this age group. METHODS: A total of 81 children between 6 and 17 years of age were included in this study. OERP in response to a rose-like odor were measured from three recording positions (Fz, Cz, Pz) according to the 10-20 system. Stimuli were presented by means of a computer-controlled olfactometer. RESULTS: Age had a significant influence on the amplitudes of the late positivity with younger children showing larger amplitudes. Although age did not significantly affect the latencies of OERP, interactions of recording positions and latencies between younger and older children and between girls and boys were found. CONCLUSIONS: OERP can be used to study central odor processing in children older than 6 years of age. Central odor processing changes from childhood to adolescents possibly reflecting maturation of the brain. PMID- 25526824 TI - Do delivery routes of intranasally administered oxytocin account for observed effects on social cognition and behavior? A two-level model. AB - Accumulating evidence demonstrates the important role of oxytocin (OT) in the modulation of social cognition and behavior. This has led many to suggest that the intranasal administration of OT may benefit psychiatric disorders characterized by social dysfunction, such as autism spectrum disorders and schizophrenia. Here, we review nasal anatomy and OT pathways to central and peripheral destinations, along with the impact of OT delivery to these destinations on social behavior and cognition. The primary goal of this review is to describe how these identified pathways may contribute to mechanisms of OT action on social cognition and behavior (that is, modulation of social information processing, anxiolytic effects, increases in approach-behaviors). We propose a two-level model involving three pathways to account for responses observed in both social cognition and behavior after intranasal OT administration and suggest avenues for future research to advance this research field. PMID- 25526823 TI - Microstates in resting-state EEG: current status and future directions. AB - Electroencephalography (EEG) is a powerful method of studying the electrophysiology of the brain with high temporal resolution. Several analytical approaches to extract information from the EEG signal have been proposed. One method, termed microstate analysis, considers the multichannel EEG recording as a series of quasi-stable "microstates" that are each characterized by a unique topography of electric potentials over the entire channel array. Because this technique simultaneously considers signals recorded from all areas of the cortex, it is capable of assessing the function of large-scale brain networks whose disruption is associated with several neuropsychiatric disorders. In this review, we first introduce the method of EEG microstate analysis. We then review studies that have discovered significant changes in the resting-state microstate series in a variety of neuropsychiatric disorders and behavioral states. We discuss the potential utility of this method in detecting neurophysiological impairments in disease and monitoring neurophysiological changes in response to an intervention. Finally, we discuss how the resting-state microstate series may reflect rapid switching among neural networks while the brain is at rest, which could represent activity of resting-state networks described by other neuroimaging modalities. We conclude by commenting on the current and future status of microstate analysis, and suggest that EEG microstates represent a promising neurophysiological tool for understanding and assessing brain network dynamics on a millisecond timescale in health and disease. PMID- 25526825 TI - GABA and GABA receptors in the gastrointestinal tract: from motility to inflammation. AB - Although an extensive body of literature confirmed gamma-aminobutyric acid (GABA) as mediator within the enteric nervous system (ENS) controlling gastrointestinal (GI) function, the true significance of GABAergic signalling in the gut is still a matter of debate. GABAergic cells in the bowel include neuronal and endocrine like cells, suggesting GABA as modulator of both motor and secretory GI activity. GABA effects in the GI tract depend on the activation of ionotropic GABAA and GABAC receptors and metabotropic GABAB receptors, resulting in a potential noteworthy regulation of both the excitatory and inhibitory signalling in the ENS. However, the preservation of GABAergic signalling in the gut could not be limited to the maintenance of physiologic intestinal activity. Indeed, a series of interesting studies have suggested a potential key role of GABA in the promising field of neuroimmune interaction, being involved in the modulation of immune cell activity associated with different systemic and enteric inflammatory conditions. Given the urgency of novel therapeutic strategies against chronic immunity-related pathologies, i.e. multiple sclerosis and Inflammatory Bowel Disease, an in-depth comprehension of the enteric GABAergic system in health and disease could provide the basis for new clinical application of nerve-driven immunity. Hence, in the attempt to drive novel researches addressing both the physiological and pathological importance of the GABAergic signalling in the gut, we summarized current evidence on GABA and GABA receptor function in the different parts of the GI tract, with particular focus on the potential involvement in the modulation of GI motility and inflammation. PMID- 25526827 TI - Kindergarten food familiarization. An exploratory study of teachers' perspectives on food and nutrition in kindergartens. AB - This exploratory study employed a netnographic approach (netnography being a research methodology that adopts the practices of ethnography in an Internet based setting) to reveal opportunities for kindergarten food familiarization. The study analyses kindergarten teachers' discussions on seven Internet message boards regarding the various food and nutrition experiences in their classes. Semi-structured interviews were then conducted with seven kindergarten teachers to explore further the message board findings. Five opportunities for how food familiarization occurs in kindergartens emerged from the analysis. These opportunities were categorized as being either "overt": (1) nutrition lessons, (2) snack times, (3) cooking experiences, or "covert" (4) food as teaching materials, and (5) dramatic play centres. Overt refers to any opportunity centred on food, healthy eating, or nutrition, whereas covert refers to opportunities where food was involved but in a non-exclusive manner. The five opportunities are examined and discussed in terms of their implications for children's food preference development. Results should be useful for future researchers for two main reasons. First, the results demonstrate the wide variety of food and nutrition experiences kindergarten students encounter throughout the day, beyond healthy eating interventions or foods served during meals. And second, because the findings are preliminary they require further research using various methods of data collection and samples of teachers. PMID- 25526826 TI - Pavlovian conditioning to hedonic food cues in overweight and lean individuals. AB - Obese individuals develop heightened reactivity to environmental cues associated with hedonic foods through Pavlovian conditioning. This study examined differences between overweight (n = 16) and lean (n = 17) 18-26 year-olds in their acquisition of a swallowing response to visual cues paired with chocolate milk, tasteless water and no taste stimulus. We hypothesized that, compared to lean participants, overweight participants would demonstrate a heightened conditioned swallowing response to the visual cue paired with chocolate milk as well as a resistance to extinction of this response. Results showed that overweight participants swallowed more in response to the visual cue previously paired with chocolate than the cue previously paired with tasteless water (t(15) = -3.057, p = .008) while lean participants showed no cue discrimination (t(16) = -1.027, p = .320). The results evaluating the extinction hypothesis could not be evaluated, as the lean participants did not acquire a conditioned response. In evaluating the conditioned swallow response of overweight participants only, results indicated that there was not a significant decrease in swallowing to cues paired with chocolate milk or water, but overall, overweight participants swallowed more to cues paired with chocolate than cues paired with water. These are the first results to show differential acquisition of Pavlovian conditioned responding in overweight individuals compared to lean individuals, as well as differential conditioning to cues paired with hedonic food stimuli compared to cues paired with neutral stimuli. PMID- 25526828 TI - Identifying specific cues and contexts related to bingeing behavior for the development of effective virtual environments. AB - BACKGROUND: Binge eating behavior constitutes a central feature of both bulimia nervosa (BN) and binge eating disorder (BED). Cue exposure therapy (CET) has been proposed as an effective intervention. OBJECTIVE: To determine which situations and specific cues trigger higher levels of binge craving and to use the results in the development of virtual reality scenarios in which CET could be applied with BN and BED patients. METHOD: Participants were 101 outpatients, 50 with BED and 51 with BN, according to DSM-5 criteria, and 63 healthy undergraduate students who completed a self-administered questionnaire to assess binge craving. RESULTS: The likelihood of binge craving in the clinical group was greater when alone at home, during the afternoon/early evening and in the late evening/at night, at weekends, and at dinner time or between meals. Higher levels of craving were produced in the kitchen, bedroom, dining room, and bakery situations. With regard to the specific cues reported, the presence of and access to high calorie food and snacks was the most commonly reported cue. Although some gender differences regarding triggering factors were obtained, no statistical differences were observed between ED subtypes. BN and BED patients showed significantly higher levels of binge craving than controls in all the contexts except when feeling positive affect; in this situation, levels of craving were low in both groups. CONCLUSIONS: This information regarding trigger contexts and specific cues can be used to create valid and reliable virtual environments for CET. Indeed, the data from this study may serve to develop a wide range of situations with different levels of binge craving, in which the therapeutic aim is to extinguish conditioned responses and facilitate the generalization of craving extinction. PMID- 25526830 TI - Advances in evidence-based intervention and assessment practices for youth with an autism spectrum disorder. AB - This special series is designed to highlight recent advances in the evidence based treatment and assessment of youth with autism spectrum disorder (ASD). The seven articles for this special series include novel applications of cognitive behavioral therapy to address core aspects of ASD, empirical research that provides understanding of ways to assess and intervene with individuals with ASD, and studies that focus on the implementation of evidence-based interventions for youth with ASD. In this introductory paper, we provide an overview of the current state of the field related to the treatment and assessment of youth with ASD and discuss related themes addressed across the papers in the series. We conclude with a brief description of each of the seven papers in the series. PMID- 25526829 TI - Duplication 9p and their implication to phenotype. AB - BACKGROUND: Trisomy 9p is one of the most common partial trisomies found in newborns. We report the clinical features and cytogenomic findings in five patients with different chromosome rearrangements resulting in complete 9p duplication, three of them involving 9p centromere alterations. METHODS: The rearrangements in the patients were characterized by G-banding, SNP-array and fluorescent in situ hybridization (FISH) with different probes. RESULTS: Two patients presented de novo dicentric chromosomes: der(9;15)t(9;15)(p11.2;p13) and der(9;21)t(9;21)(p13.1;p13.1). One patient presented two concomitant rearranged chromosomes: a der(12)t(9;12)(q21.13;p13.33) and an psu i(9)(p10) which showed FISH centromeric signal smaller than in the normal chromosome 9. Besides the duplication 9p24.3p13.1, array revealed a 7.3 Mb deletion in 9q13q21.13 in this patient. The break in the psu i(9)(p10) probably occurred in the centromere resulting in a smaller centromere and with part of the 9q translocated to the distal 12p with the deletion 9q occurring during this rearrangement. Two patients, brother and sister, present 9p duplication concomitant to 18p deletion due to an inherited der(18)t(9;18)(p11.2;p11.31)mat. CONCLUSIONS: The patients with trisomy 9p present a well-recognizable phenotype due to facial appearance, although the genotype-phenotype correlation can be difficult due to concomitant partial monosomy of other chromosomes. The chromosome 9 is rich in segmental duplication, especially in pericentromeric region, with high degree of sequence identity to sequences in 15p, 18p and 21p, chromosomes involved in our rearrangements. Thus, we suggest that chromosome 9 is prone to illegitimate recombination, either intrachromosomal or interchromosomal, which predisposes it to rearrangements, frequently involving pericentromeric regions. PMID- 25526832 TI - Improving peer engagement of children with autism on the school playground: a randomized controlled trial. AB - This study aimed to test the effects of a psychosocial intervention, Remaking Recess, on peer engagement for children with autism spectrum disorder (ASD). Using a randomized, wait-list-controlled design, the intervention was implemented during recess at four elementary schools. The immediate treatment (IT) group consisted of 13 (2 female) elementary school students with ASD and the wait-list (WL) group contained 11 (4 female) students with ASD. All of the children with ASD were fully included in the general education program. Analyses revealed that time spent engaged with peers was significantly increased for the IT group and maintained over the follow-up. School playground staff in the IT group showed increased behaviors aimed at improving peer engagement for children with ASD compared to playground staff at the WL sites. These improvements did not maintain to follow-up. These results suggest that a low dose, brief intervention can be beneficial in increasing peer engagement for children with autism in inclusive settings, but continued support of playground staff is likely needed. PMID- 25526831 TI - Cognitive behavioral therapy for early adolescents with autism spectrum disorders and clinical anxiety: a randomized, controlled trial. AB - Clinically elevated anxiety is a common, impairing feature of autism spectrum disorders (ASD). A modular CBT program designed for preteens with ASD, Behavioral Interventions for Anxiety in Children with Autism (BIACA; Wood et al., 2009) was enhanced and modified to address the developmental needs of early adolescents with ASD and clinical anxiety. Thirty-three adolescents (11-15 years old) were randomly assigned to 16 sessions of CBT or an equivalent waitlist period. The CBT model emphasized exposure, challenging irrational beliefs, and behavioral supports provided by caregivers, as well as numerous ASD-specific treatment elements. Independent evaluators, parents, and adolescents rated symptom severity at baseline and posttreatment/postwaitlist. In intent-to-treat analyses, the CBT group outperformed the waitlist group on independent evaluators' ratings of anxiety severity on the Pediatric Anxiety Rating Scale (PARS) and 79% of the CBT group met Clinical Global Impressions-Improvement scale criteria for positive treatment response at posttreatment, as compared to only 28.6% of the waitlist group. Group differences were not found for diagnostic remission or questionnaire measures of anxiety. However, parent-report data indicated that there was a positive treatment effect of CBT on autism symptom severity. The CBT manual under investigation, enhanced for early adolescents with ASD, yielded meaningful treatment effects on the primary outcome measure (PARS), although additional developmental modifications to the manual are likely warranted. Future studies examining this protocol relative to an active control are needed. PMID- 25526833 TI - Not to be overshadowed or overlooked: functional impairments associated with comorbid anxiety disorders in youth with ASD. AB - This study's objective was to examine associations between comorbid anxiety disorders and difficulties commonly attributed to both anxiety and ASD (autism spectrum disorder) including self-injury, depressive symptoms, functional communication, social skill deficits and parent stress, in a well-characterized sample of youth with ASD. Fifty-nine verbally fluent participants (7-17 years; 93% Caucasian) diagnosed with ASD and their parents completed semistructured diagnostic interviews to confirm ASD diagnosis and assess for anxiety disorders. Parents completed questionnaires on child behavior and social skill as well as parental stress. Co-occurring anxiety disorders were associated with more parent reported self-injurious behavior, depressive symptoms, and parental stress in youth with ASD, after controlling for other influential variables (e.g., ASD severity, cognitive ability, medication status). In contrast, youth with co occurring anxiety disorders appeared to have significantly stronger parent reported functional communication than youth with ASD alone as well as a comparable ability, according to parents, to initiate social interaction and develop relationships. Findings support a profile of challenges and relative strengths associated with the presence of anxiety disorders in youth with ASD. Though more research is needed to determine the direction of these associations, results provide further rationale for improving recognition and targeted treatment of this comorbidity in clinical practice. PMID- 25526834 TI - Anxiety in youth with and without autism spectrum disorder: examination of factorial equivalence. AB - Although anxiety is frequently reported among children and adolescents with autism spectrum disorder (ASD), it has not been established that the manifest symptoms of anxiety in the context of ASD are the same as those seen in youth without ASD. This study sought to examine the metric and latent factor equivalence of anxiety as measured by the Multidimensional Anxiety Scale for Children, parent-report (MASC-P) and child-report (MASC-C), in youth with anxiety disorders and ASD with intact verbal ability (n=109, M(age)=11.67 years, 99 male) and a gender-matched comparison group of typically developing (TD) children and adolescents with anxiety disorders but without ASD (n=342, M(age)=11.25 years, 246 male). Multigroup factorial invariance (MFI) using structural equation modeling indicated equivalent latent factors in youth with and without ASD on the MASC-C (metric invariance). However, the item means and covariances along with the relations among the factor scores were different for the youth with ASD (i.e., lack of evidence for scalar or structural invariance). The MASC-P data did not fit the measure's established structure for either the ASD or TD group, and post-hoc exploratory factor analysis revealed a different factor structure in the ASD group. Findings suggest that the MASC-C may not measure identical constructs in anxious youth with and without ASD. Further research on the structure of the MASC in clinical samples is warranted. PMID- 25526835 TI - A tangled web: the challenges of implementing an evidence-based social engagement intervention for children with autism in urban public school settings. AB - There is growing evidence that efficacious autism-related interventions rarely are adopted or successfully implemented in public schools, in part because of the lack of fit between the intervention and the needs and capacities of the school setting. There is little systematic information available regarding the barriers to implementation of complex interventions such as those addressing social engagement for children with autism.The present study used fieldnotes from an implementation trial to explore barriers that emerged during the training of school personnel and subsequent implementation of a social engagement intervention. A number of barriers at the individual (training) and school levels (policies surrounding recess, staffing, prioritization of competing demands, level of respect and support, and availability of resources) interfered with the continued use and sustainment of the intervention. We offer potential strategies to overcome these barriers and provide directions for future research in this critical area. PMID- 25526837 TI - Toward the implementation of evidence-based interventions for youth with autism spectrum disorders in schools and community agencies. AB - Evidence-based interventions (EBIs) for youth with autism spectrum disorders (ASD) are rarely found in community settings where most youth with ASD receive services. Implementation research designed to help bridge this gap is needed. However, efforts to implement EBIs in community settings face a number of barriers. The main purpose of this article is to illustrate how making EBIs more flexible and integrative may help improve their utility and may increase their uptake by stakeholders in community mental health and school settings. We conclude with an example of a modular, stepped-care program that might help bridge the science-practice gap in the ASD field by combining elements of a number of existing EBIs into a single, flexible intervention. PMID- 25526836 TI - Professionals' reported provision and recommendation of psychosocial interventions for youth with autism spectrum disorder. AB - Children and adolescents with autism spectrum disorder (ASD) receive intervention services from multiple professionals across disciplines. Little is known about services for youth with ASD in community settings. The purpose of this study was to provide data on professionals' self-reported practices across different classes of psychosocial interventions for youth with ASD. A multidisciplinary (medicine/nursing, education, occupational/physical therapy, psychology, social work, and speech-language pathology/audiology) sample (N=709; 86% female; 86% White) of professionals who endorsed providing clinical services to youth with ASD was recruited through convenience sampling (listservs, etc.) and stratified random sampling (online provider listings). Professionals completed a survey on intervention practices with youth with ASD, specifically on their own provision of, as well as their recommendation/referral of, psychosocial interventions (focused intervention practices [FIPs], comprehensive treatment models [CTMs], and other interventions). Hierarchical multiple regression models showed discipline differences in self-reported provision and recommendation of evidence based FIPs; training variables and unfamiliarity with FIPs predicted rates of providing and recommending. FIPs were reportedly provided and recommended at higher rates than CTMs. Descriptive data are presented on professionals' reported practice of other psychosocial interventions (e.g., cognitive-behavioral therapy). This study highlights the usefulness of examining not only provision of services but also recommendation/referral practices: professionals are important sources of information for families. Implications of the results are discussed in terms of the importance of disseminating intervention information to professionals and the need for consensus on terminology used to classify interventions and on criteria used to evaluate intervention efficacy. PMID- 25526839 TI - Interpretation biases in paranoia. AB - Information in the environment is frequently ambiguous in meaning. Emotional ambiguity, such as the stare of a stranger, or the scream of a child, encompasses possible good or bad emotional consequences. Those with elevated vulnerability to affective disorders tend to interpret such material more negatively than those without, a phenomenon known as "negative interpretation bias." In this study we examined the relationship between vulnerability to psychosis, measured by trait paranoia, and interpretation bias. One set of material permitted broadly positive/negative (valenced) interpretations, while another allowed more or less paranoid interpretations, allowing us to also investigate the content specificity of interpretation biases associated with paranoia. Regression analyses (n=70) revealed that trait paranoia, trait anxiety, and cognitive inflexibility predicted paranoid interpretation bias, whereas trait anxiety and cognitive inflexibility predicted negative interpretation bias. In a group comparison those with high levels of trait paranoia were negatively biased in their interpretations of ambiguous information relative to those with low trait paranoia, and this effect was most pronounced for material directly related to paranoid concerns. Together these data suggest that a negative interpretation bias occurs in those with elevated vulnerability to paranoia, and that this bias may be strongest for material matching paranoid beliefs. We conclude that content specific biases may be important in the cause and maintenance of paranoid symptoms. PMID- 25526840 TI - Temporal associations between disordered eating and nonsuicidal self-injury: examining symptom overlap over 1 year. AB - Disordered eating (DE) and nonsuicidal self-injury (NSSI) commonly co-occur. This study compared several models of the longitudinal relationship between DE and NSSI, including concurrent and prospective models, and examined the possible moderating roles of self-objectification, impulsivity, and emotion dysregulation in these relationships. Individuals with NSSI (N=197) recruited from online forums completed measures of NSSI and DE every 3 months for 1 year. We tested the associations between NSSI and DE using hierarchical linear models. Results supported a concurrent relationship, wherein frequency of NSSI positively covaried with concurrent DE severity. Body surveillance moderated the concurrent relationship between NSSI and DE. Individuals who engaged in more body surveillance endorsed high levels of DE pathology, whereas those lower in body surveillance engaged in more frequent NSSI only at higher levels of DE. In addition, whereas DE did not prospectively predict NSSI, frequency of NSSI predicted more severe DE 3 months later. The prospective relationship between DE and later NSSI was moderated by emotion dysregulation, such that highly dysregulated individuals had a stronger relationship between DE and later NSSI, whereas this relationship was not significant among individuals low in emotion dysregulation. These findings add valuable information regarding the co occurrence of self-damaging behaviors. PMID- 25526838 TI - What changes in cognitive therapy for depression? An examination of cognitive therapy skills and maladaptive beliefs. AB - This study examined effortful cognitive skills and underlying maladaptive beliefs among patients treated with cognitive therapy (CT) for depression. Depressed patients (n=44) completed cognitive measures before and after 16 weeks of CT. Measures included an assessment of CT skills (Ways of Responding Scale; WOR), an implicit test of maladaptive beliefs (Implicit Association Test; IAT), and a self report questionnaire of maladaptive beliefs (Dysfunctional Attitude Scale; DAS). A matched sample of never-depressed participants (n=44) also completed study measures. Prior to treatment, depressed patients endorsed significantly more undesirable cognitions on the WOR, IAT, and DAS compared with never-depressed participants. Patients displayed improvement on the WOR and DAS over the course of treatment, but showed no change on the IAT. Additionally, improvements on the WOR and DAS were each related to greater reductions in depressive symptoms. Results suggest that the degree of symptom reduction among patients participating in CT is related to changes in patients' acquisition of coping skills requiring deliberate efforts and reflective thought, but not related to reduced endorsement of implicitly assessed maladaptive beliefs. PMID- 25526841 TI - Biological therapies for the treatment of severe psoriasis in patients with previous exposure to biological therapy: a cost-effectiveness analysis. AB - BACKGROUND: Biologic therapies have revolutionised the care of patients with psoriasis, although they come at significant extra cost. Guidance on their use in the UK National Health Service (NHS) has so far focused on patients who are "biologic naive", yet a minority of patients have poor response and require further treatment. OBJECTIVES: To assess the potential cost effectiveness of sequential biologic therapies in patients with psoriasis who have been exposed to previous biologic therapy. METHODS: A two-part model with a 10-year time horizon was built to model an initial 13.5-week "trial" phase and a longer-term "treatment" period with annual Markov cycles. Psoriasis Area and Severity Index (PASI) response rates from subgroup analyses of three randomised placebo controlled trials evaluating biologic agents were considered. A meta-analysis of these data provided probabilities of achieving PASI response (50/75/90) in the short term, and published evidence and assumptions were used to predict outcomes over the longer term. Benefits were measured in quality-adjusted life years (QALYs), and costs (2013-14) to the UK NHS included drugs, administration, monitoring, and hospitalisation. Costs and benefits were discounted 3.5 % per annum. Cost effectiveness of sequential biologic therapy was measured using an incremental cost-effectiveness ratio (ICER) compared to best supportive care (BSC). Extensive sensitivity analyses were performed to assess the impact of alternative assumptions on the results. RESULTS: Results indicate that over 10 years, switching to a second biologic following intolerance to or failure of a first is likely to generate more QALYs than BSC, but at a higher cost. Base case results suggest the ICER of the second biologic compared to BSC is L17,681 per QALY; however, sensitivity analyses indicate that changes in the efficacy of BSC, drug costs, dropout rates, and rates of hospitalisation have a significant impact, causing the ICER to range from less than L10,000 to over L50,000 per QALY. CONCLUSIONS: Further biologic therapy for patients with psoriasis who have previously been treated with biologic therapy may be cost effective, although there is considerable uncertainty in the results. Future studies should be designed to evaluate the clinical efficacy of biologic therapies in this subgroup with particular attention given to short-term and longer-term responses. PMID- 25526842 TI - Cost-effectiveness analysis of onabotulinumtoxinA (BOTOX((r))) for the management of urinary incontinence in adults with neurogenic detrusor overactivity: a UK perspective. AB - OBJECTIVES: To evaluate the cost effectiveness of onabotulinumtoxinA (BOTOX((r)), 200 units [200 U]) for the management of urinary incontinence (UI) in adults with neurogenic detrusor overactivity (NDO) due to subcervical spinal cord injury or multiple sclerosis that is not adequately managed with anticholinergic drugs (ACHDs). PERSPECTIVE: UK National Health Service (NHS) perspective. METHODS: A Markov state-transition model was developed, which compared onabotulinumtoxinA + best supportive care (BSC) with BSC alone (comprising behavioural therapy and pads, alone or in combination with clean intermittent catheterization and possibly with ACHDs). Non-responders were eligible for invasive procedures. Health states were defined according to the reduction in UI episodes. Efficacy data and estimates of resource utilization were pooled from 468 patients on onabotulinumtoxinA in two phase III clinical trials. Drug costs (2013) and administration costs (NHS Reference Costs 2011-2012) were obtained from published sources. The time horizon of the model was 5 years, and costs and benefits were discounted at 3.5%. Scenario, one-way and probabilistic sensitivity analyses (PSAs) were conducted to explore uncertainties around the assumptions. RESULTS: In the base case, treatment with onabotulinumtoxinA + BSC over 5 years was associated with an increase in costs of L1,689 and an increase in quality adjusted life-years (QALYs) of 0.4, compared with BSC alone, resulting in an incremental cost-effectiveness ratio of L3,850 per QALY gained. Sensitivity analyses showed that utility values had the greatest influence on model results. PSA suggests that onabotulinumtoxinA + BSC had a 100 % probability of being cost effective at a willingness to pay of 20 ng/ml, prior surgery of the prostate, or intake of 5-alpha-reductase inhibitors. Overall 357 underwent a 10- to 12-core biopsy, while 68 patients underwent 20-core biopsy. In case of a negative biopsy in the 10-12 cohort, rebiopsy was performed within 6 months, while in the 20-core group clinical follow-up determined further course of action. Endpoints of the study were the overall PCA detection rate and the rate of severe complications, which were defined as complications requiring hospital admission. The effect of the respective biopsy scheme on the PCA detection rate was assessed using uni- and multivariable logistic regression analysis. In the subanalysis, the PCA detection rates between the two groups were compared solely in patients with PSA values <=10 ng/ml. RESULTS: At initial biopsy, the overall PCA detection rate was 50.4% (214/425). In the 10-12 core group, the PCA detection rate at first biopsy was 52.4% (187/357) and rebiopsy detected a further 19 (11.2%) PCA cases, resulting in a cumulative PCA detection rate of 57.7% (206/357). In the 20-core group, the PCA detection rate was 39.7% (27/68). While the different PCA detection rates were not statistically different when the initial biopsies were compared, biopsy scheme reached independent predictor status when the cumulative PCA detection rate of the 10- to 12-core scheme was compared to the 20-core scheme (p=0.01). Comparable results were obtained only when patients with PSA <=10 ng/ml were considered. The rate of severe complications was statistically higher in the 20-core group (6.1 vs. 2.4%; p=0.01). CONCLUSION: Our data indicate that an initial 20-core biopsy does not lead to a higher PCA detection rate compared to an initial 10- to 12-core biopsy. Moreover, the cumulative PCA detection rate of a 10- to 12-core biopsy and prompt repeat biopsy was significantly higher compared to a single 20-core biopsy. PMID- 25526853 TI - Endophytes in the plant Huperzia serrata: fungal diversity and discovery of a new pentapeptide. AB - Endophytic fungi are an underexploited resource of natural products and have a capacity to produce diverse classes of plant-derived secondary metabolites. Here, we investigated the diversity of endophytic fungi from Huperzia serrata and the potential for discovering novel fungal natural products. One hundred and fifty five endophytic fungi isolates obtained from H. serrata, belonging to four classes Dothideomycetes (47.3 %), Sordariomycetes (36.8 %), Eurotiomycetes (10.6 %) and an undefined class (5.3 %, Mucoraceae), were grouped into nine genera based on morphological and molecular identification. Colletotrichum, Cladosporium, Sordariomycetes and Guignardia were the dominant genera, whereas the remaining genera were infrequent groups. To our knowledge, the fungal genera Mucor and Neurospora were first reported in Huperzia plant. Among these endophytic fungi isolates, strain B14, belonging to Penicillium oxalicum, gave a gray precipitate with Dragendorff's reagent. A new pentapeptide was isolated from the culture of strain B14, and its chemical structure was elucidated on the basis of spectroscopic data from (1)H NMR, (13)C NMR and ESI-MS/MS. Taken together, H. serrata has a significant diversity of endophytic fungi that could be a rich resource for the discovery of new natural products. PMID- 25526852 TI - [Laparascopic radical prostatectomy]. AB - BACKGROUND: Since its initial description 20 years ago, laparoscopic radical prostatectomy (LRP) is now a standard treatment option for localized prostate cancer. However, in recent years robot-assisted laparoscopic radical prostatectomy (RALP) has been gradually replacing LRP, despite high costs incurred with RALP. OBJECTIVES: The purpose of this work was to determine the oncological outcomes of LRP from selected series with a follow-up of around 10 years and to compare oncological and functional outcomes between LRP and RALP. MATERIAL AND METHODS: The outcomes of a case series of LRP with a median follow up of at least 3 years were reviewed. In addition, the outcomes of comparative studies between LRP and RALP were reviewed. RESULTS: The first case series of LRP with follow-ups of 10 years after LRP are available and show favorable oncologic outcomes. Current data show that RALP offers superior functional results (recovery of erectile function) following bilateral nerve sparing when compared to LRP. CONCLUSION: The first review a few years ago showed comparable oncologic and functional outcomes between open prostatectomy, LRP, and RALP. Recent data from comparative studies show superiority of RALP over LRP for potency following bilateral nerve sparing. The potency outcomes between LRP and RALP are, however, similar following wide excision of both neurovascular bundles. Therefore, both treatment options can be recommended for the treatment of localized PC. PMID- 25526854 TI - Behavioral measures of multisensory integration: bounds on bimodal detection probability. AB - One way to test and quantify multisensory integration in a behavioral paradigm is to compare bimodal detection probability with bounds defined by some combination of the unimodal detection probabilities. Here we (1) improve on an upper bound recently suggested by Stevenson et al. (Brain Topogr 27(6):707-730, 2014), (2) present a lower bound, (3) interpret the bounds in terms of stochastic dependency between the detection probabilities, (4) discuss some additional assumptions required for the validity of any such bound, (5) suggest some potential applications to neurophysiologic measures, and point out some parallels to the 'race model inequality' for reaction times. PMID- 25526855 TI - Partial to complete suppression of unilateral noise-induced tinnitus in rats after cyclobenzaprine treatment. AB - Some forms of tinnitus are believed to arise from abnormal central nervous system activity following a single or repeated noise exposure, for which there are no widely accepted pharmacological treatments. One central site that could be related to tinnitus awareness or modulation is the locus coeruleus, a brainstem structure associated with stress, arousal, and attention. In the present study, we evaluated the effects of cyclobenzaprine, a drug known to act on the rat locus coeruleus, on noise-induced tinnitus using Gap Prepulse Inhibition of the Acoustic Startle (GPIAS). In untreated rats, brief silent gaps presented prior to a 5-10-kHz bandpass startling stimulus produced robust GPIAS. Treatment with cyclobenzaprine alone had no effect on the ability of gaps to suppress the startle response. When animals were exposed to intense narrow-band (126 dB SPL, 16 kHz, 100 Hz BW) unilateral noise, GPIAS was significantly reduced, suggesting the presence of tinnitus. Following the noise exposure, a subset of rats that maintained a robust startle response continued to show GPIAS impairment at 6-20 kHz, 40 days post-noise, suggesting chronic tinnitus. When this subset of animals was treated with cyclobenzaprine, at a dose that had no significant effects on the startle response (0.5 mg/kg), GPIAS recovered partially or to near baseline levels at the affected frequencies. These results were consistent with the absence of tinnitus. By 48 h post-treatment, evidence of tinnitus re-emerged. Our results suggest that cyclobenzaprine was effective in transiently suppressing noise-induced tinnitus in rats. PMID- 25526856 TI - Effectiveness of a three-dimensional anorectal ultrasound in perianal Crohn's disease: incompatibility with clinical and surgical examinations. AB - PURPOSE: We have correlated the 3D anorectal ultrasound (3D ARU) findings with clinical examination and the surgical findings and examined its capacity to provide ancillary information, which potentially alters patient management. PATIENTS AND METHODS: This is a prospective analysis conducted at a tertiary academic hospital. A total of 95 patients were included. We screened for sphincter defects and the presence of perianal Crohn's disease (PACD)-related lesions. RESULTS: We performed 150 3D ARUs. Exploratory ultrasound coincided with the rationale for diagnosis in 67.7% of cases, and fistulae were detected in 79% of cases where there was clinical suspicion. Fistulae were associated with abscesses in 29 cases, and isolated abscesses were identified in 19 cases (17.7%), only 12 of which (63.2%) were clinically suspected. Sphincter defects were observed in 15 cases with 7 cases (77.8%) presenting with clinical fecal incontinence. The operative findings coincided with ultrasonographic findings in 81.3% of the analyzed cases. The inter-observer variability of endosonographic classification resulted in a kappa score of 0.86. Ultrasonographic data altered the therapeutic plan of management in 73 cases (48.6%). CONCLUSIONS: Three dimensional ARU is accurate in the diagnosis of fistula type in PACD and in the delineation of ancillary suspected and unsuspected abscess collections. Its use impacts therapeutic management in about half the cases examined. A new ultrasonographic-based PACD classification system is presented which has high inter-observer agreement but which requires future prospective validation in clinical PACD patients. PMID- 25526857 TI - The effect of the timing of antibiotics and surgical treatment on infection rates in open long-bone fractures: a 6-year prospective study after a change in policy. AB - Our current protocol in treating open long-bone fractures includes early administration of intravenous antibiotics and surgery on a scheduled trauma list. This represents a change from a previous protocol where treatment as soon as possible after injury was carried out. This review reports the infection rates in the period 6 years after the start of this protocol. Two hundred and twenty open long-bone fractures were reviewed. Data collected included time of administration of antibiotics, time to theatre and seniority of surgeon involved. The patients were followed up until clinical or radiological union occurred or until a secondary procedure for non-union or infection was performed. Clinical, radiological and haematological signs of infection were documented. If present, infection was classified as deep or superficial. Surgical debridement was performed within 6 h of injury in 45 % of cases and after 6 h in 55 % of cases. Overall infection rates were 11 and 15.7 %, respectively (p = 0.49). The overall deep infection rate was 4.3 %. There was also no statistically significant difference in the subgroups of deep (p = 0.46) and superficial (p = 0.78) infection. Intravenous antibiotics were administered within 3 h of injury in 80 % of cases and after 3 h in 20 % of cases. The infection rates were 14 and 12.5 %, respectively (p = 1.0). There was no statistically significant difference in the subgroups of deep (p = 0.62) and superficial (p = 0.73) infection. Further statistical analysis did not reveal a significant difference in infection rates for any combination of timing of antibiotics and surgical debridement. Infection rates where the most senior surgeon present was a consultant were 9.5 % as opposed to 16 % with the consultant not present, but this trend was not statistically significant. These results suggest that the change in policy may have contributed to an improvement of the deep infection rate to 4.3 % from the previous figure of 8.5 % although this decrease is not statistically significant. Surgeons may have had concerns that delaying theatre may lead to an increased infection rate, but these results do not substantiate this concern. PMID- 25526858 TI - Proximal tibiofibular dislocation: a case report and review of literature. AB - An isolated dislocation of the proximal tibiofibular joint is uncommon. The mechanism of this injury is usually sports related. We present a case where initial X-rays did not show the tibiofibular joint dislocation conclusively. It was diagnosed after comparative bilateral AP X-rays of the knees were obtained. A closed reduction was performed and followed by unrestricted mobilization after 1 week of rest. A review of the literature was conducted on PubMed MEDLINE. Thirty cases of isolated acute proximal tibiofibular joint dislocations were identified in a search from 1974. The most common direction of the dislocation was anterolateral, and common causes were sports injury or high velocity accident related. More than 75 % of the cases were successfully treated by closed reduction. Complaints, if any, at the last follow-up (averaging 10 months, range 0-108) were, in the worst cases, pain during sporting activities. We advise comparative knee X-rays if there is a presentation of lateral knee pain after injury and diagnosis is uncertain. Closed reduction is usually successful if a dislocation of the proximal tibiofibular joint is diagnosed. There is no standard for after-care, but early mobilization appears safe if there are no other knee injuries. PMID- 25526859 TI - Nitric oxide regulates multiple functions and fate of adult progenitor and stem cells. AB - Nitric oxide is an endogenous gas which exerts autocrine/paracrine actions by different signaling pathways and/or direct interactions with intracellular compounds and structures. Several processes are regulated by nitric oxide in stem cells including self-renewal, viability, migration, proliferation, and differentiation. The modulation of cell functions depends on its concentrations because opposite effects can be observed when low and high levels of nitric oxide are compared. Here, the responses to nitric oxide of adult stem/progenitor cells which are often used in regenerative medicine, including mesenchymal stem cells, hematopoietic stem cells, neural stem cells, endothelial progenitor cells, satellite cells, and fibro-adipogenic precursor cells, are reviewed. Therapeutic strategies which employ drugs releasing nitric oxide or modulating nitric oxide intracellular pathways are suggested to perform new ex vivo preconditioning or in vivo treatments suitable for stem/progenitor cell therapy and tissue engineering applications. PMID- 25526860 TI - CRMP1 Interacted with Spy1 During the Collapse of Growth Cones Induced by Sema3A and Acted on Regeneration After Sciatic Nerve Crush. AB - CRMP1, a member of the collapsin response mediator protein family (CRMPs), was reported to regulate axon outgrowth in Sema3A signaling pathways via interactions with its co-receptor protein neuropilin-1 and plexin-As through the Fyn-cyclin dependent kinase 5 (CDK5) cascade and the sequential phosphorylation of CRMP1 by lycogen synthase kinase-3beta (GSK-3beta). Using yeast two-hybrid, we identified a new molecule, Speedy A1 (Spy1), a member of the Speedy/RINGO family, with an interaction with CRMP1. Besides, for the first time, we observed the association of CRMP1 with actin. Based on this, we wondered the association of them and their function in Sema3A-induced growth cones collapse and regeneration process after SNC. During our study, we constructed overexpression plasmid and short hairpin RNA (shRNA) to question the relationship of CRMP1/Spy1 and CRMP1/actin. We observed the interactions of CRMP1/Spy1 and CRMP1/actin. Besides, we found that Spy1 could affect CRMP1 phosphorylation actived by CDK5 and that enhanced CRMP1 phosphorylation might disturb the combination of CRMP1 and actin, which would contribute to abnormal of Sema3A-induced growth cones collapse and finally lead to influent regeneration process after rat sciatic nerve crush. Through rat walk footprint test, we also observed the variance during regeneration progress, respectively. We speculated that CRMP1 interacted with Spy1 which would disturb the association of CRMP1 with actin and was involved in the collapse of growth cones induced by Sema3A and regeneration after sciatic nerve crush. PMID- 25526861 TI - Bone Marrow-Derived Endothelial Progenitor Cells Protect Against Scopolamine Induced Alzheimer-Like Pathological Aberrations. AB - Vascular endothelial dysfunction plays a key role in the pathogenesis of Alzheimer's disease (AD). Patients with AD have displayed decreased circulating endothelial progenitor cells (EPCs) which repair and maintain the endothelial function. Transplantation of EPCs has emerged as a promising approach for the management of cerebrovascular diseases including ischemic stroke, however, its impact on AD has been poorly described. Thus, the current study aimed at investigating the effects of bone marrow-derived (BM) EPCs transplantation in repeated scopolamine-induced cognitive impairment, an experimental model that replicates biomarkers of AD. Intravenously transplanted BM-EPCs migrated into the brain of rats and improved the learning and memory deficits. Meanwhile, they mitigated the deposition of amyloid plaques and associated histopathological alterations. At the molecular levels, BM-EPCs blunted the increase of hippocampal amyloid beta protein (Abeta), amyloid precursor protein (APP) and reinstated the Abeta-degrading neprilysin together with downregulation of p-tau and its upstream glycogen synthase kinase-3beta (GSK-3beta). They also corrected the perturbations of neurotransmitter levels including restoration of acetylcholine and associated esterase along with dopamine, GABA, and the neuroexitatory glutamate. Furthermore, BM-EPCs induced behavioral recovery via boosting of vascular endothelial growth factor (VEGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and its upstream cAMP response element binding (CREB), suppression of the proinflammatory tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and upregulation of interleukin-10 (IL-10). BM-EPCs also augmented Nrf2 and seladin-1. Generally, these actions were analogous to those exerted by adipose tissue-derived mesenchymal stem cells (AT-MSCs) and the reference anti-Alzheimer donepezil. For the first time, these findings highlight the beneficial actions of BM-EPCs against the memory deficits and AD-like pathological dysfunction. PMID- 25526863 TI - Erratum to: Body matters: rethinking the ethical acceptability of non-beneficial clinical research with children. PMID- 25526862 TI - Cofilin Inhibition Restores Neuronal Cell Death in Oxygen-Glucose Deprivation Model of Ischemia. AB - Ischemia is a condition associated with decreased blood supply to the brain, eventually leading to death of neurons. It is associated with a diverse cascade of responses involving both degenerative and regenerative mechanisms. At the cellular level, the changes are initiated prominently in the neuronal cytoskeleton. Cofilin, a cytoskeletal actin severing protein, is known to be involved in the early stages of apoptotic cell death. Evidence supports its intervention in the progression of disease states like Alzheimer's and ischemic kidney disease. In the present study, we have hypothesized the possible involvement of cofilin in ischemia. Using PC12 cells and mouse primary cultures of cortical neurons, we investigated the potential role of cofilin in ischemia in two different in vitro ischemic models: chemical induced oxidative stress and oxygen-glucose deprivation/reperfusion (OGD/R). The expression profile studies demonstrated a decrease in phosphocofilin levels in all models of ischemia, implying stress-induced cofilin activation. Furthermore, calcineurin and slingshot 1L (SSH) phosphatases were found to be the signaling mediators of the cofilin activation. In primary cultures of cortical neurons, cofilin was found to be significantly activated after 1 h of OGD. To delineate the role of activated cofilin in ischemia, we knocked down cofilin by small interfering RNA (siRNA) technique and tested the impact of cofilin silencing on neuronal viability. Cofilin siRNA-treated neurons showed a significant reduction of cofilin levels in all treatment groups (control, OGD, and OGD/R). Additionally, cofilin siRNA reduced cofilin mitochondrial translocation and caspase 3 cleavage, with a concomitant increase in neuronal viability. These results strongly support the active role of cofilin in ischemia-induced neuronal degeneration and apoptosis. We believe that targeting this protein mediator has a potential for therapeutic intervention in ischemic brain injury and stroke. PMID- 25526864 TI - Effects of endogenous and exogenous micronutrients in rapeseed oils on the antioxidant status and lipid profile in high-fat fed rats. AB - BACKGROUND: Micronutrients in oil reduce one or more risk factors of cardiovascular diseases, while the contents of micronutrients in oil are relatively poor, which is insufficient to reverse the metabolic disorders at different stages of progress. The aim of this study was to investigate the effects of endogenous micronutrients in optimized cold-pressed rapeseed oil and restoratively added or fortified micronutrients in traditional refined rapeseed oil (restoring micronutrients to be nearly equal to or significantly higher than levels in crude rapeseed oil) on the antioxidant status and lipid profile in high fat fed rats. METHODS: Male Wistar rats were fed high-fat diets containing different rapeseed oils for 4 weeks, including the standard refined rapeseed oil(SRO), optimized cold-pressed rapeseed oil(CRO) and the traditional refined rapeseed oil with restorative addition or fortification of micronutrients (LF, HF SRO). RESULTS: CRO exhibited significant increases in contents of tocopherols (+13%), phytosterols (+34%), polyphenols (+92%) and phospholipids (+725%) compared with SRO, as well as the total antioxidant capacities (+82-125%) (p<0.05). While the HF-SRO revealed improved antioxidant properties in vitro than the CRO, which was comparable to LF-SRO. Significant improved plasma antioxidant capacities and lipid peroxidation evaluated by T-AOC, GSH, tocopherols and MDA were found in rats fed HF-SRO when compared with CRO and LF-SRO (p<0.05). Furthermore, HF-SRO also decreased the plasma and hepatic TC levels compared to CRO and LF-SRO, accompanying higher fecal cholesterol excretion (p<0.05). CONCLUSION: The standard refined rapeseed oil with fortification, not restorative addition of micronutrients was comparable to the optimized cold-pressed rapeseed oil in improving the antioxidant status and lipid profile of high-fat fed rats. PMID- 25526865 TI - The Predictive Utility of Early Childhood Disruptive Behaviors for School-Age Social Functioning. AB - Research suggests that school-age children with disruptive behavior (DB) problems frequently demonstrate impaired social skills and experience rejection from peers, which plays a crucial role in the pathway to more serious antisocial behavior. A critical question is which DB problems in early childhood are prognostic of impaired social functioning in school-age children. This study examines the hypothesis that aggression in early childhood will be the more consistent predictor of compromised social functioning than inattentive, hyperactive-impulsive, or oppositional behavior. Participants included an ethnically diverse sample of 725 high-risk children from 3 geographically distinct areas followed from ages 2 to 8.5. Four latent growth models of DB from child ages 2 to 5, and potential interactions between dimensions, were used to predict latent parent and teacher ratings of school-age social dysfunction. Analyses were conducted in a multi-group format to examine potential differences between intervention and control group participants. Results showed that age 2 aggression was the DB problem most consistently associated with both parent- and teacher-rated social dysfunction for both groups. Early starting aggressive behavior may be particularly important for the early identification of children at risk for school-age social difficulties. PMID- 25526866 TI - Regulation of energy balance by inflammation: common theme in physiology and pathology. AB - Inflammation regulates energy metabolism in both physiological and pathological conditions. Pro-inflammatory cytokines involves in energy regulation in several conditions, such as obesity, aging (calorie restriction), sports (exercise), and cancer (cachexia). Here, we introduce a view of integrative physiology to understand pro-inflammatory cytokines in the control of energy expenditure. In obesity, chronic inflammation is derived from energy surplus that induces adipose tissue expansion and adipose tissue hypoxia. In addition to the detrimental effect on insulin sensitivity, pro-inflammatory cytokines also stimulate energy expenditure and facilitate adipose tissue remodeling. In caloric restriction (CR), inflammatory status is decreased by low energy intake that results in less energy supply to immune cells to favor energy saving under caloric restriction. During physical exercise, inflammatory status is elevated due to muscle production of pro-inflammatory cytokines, which promote fatty acid mobilization from adipose tissue to meet the muscle energy demand. In cancer cachexia, chronic inflammation is elevated by the immune response in the fight against cancer. The energy expenditure from chronic inflammation contributes to weight loss. Immune tolerant cancer cells gains more nutrients during the inflammation. In these conditions, inflammation coordinates energy distribution and energy demand between tissues. If the body lacks response to the pro-inflammatory cytokines (Inflammation Resistance), the energy metabolism will be impaired leading to an increased risk for obesity. In contrast, super-induction of the inflammation activity leads to weight loss and malnutrition in cancer cachexia. In summary, inflammation is a critical component in the maintenance of energy balance in the body. Literature is reviewed in above fields to support this view. PMID- 25526868 TI - Cluster headache associated with a clinically non-functioning pituitary adenoma: a case report. AB - INTRODUCTION: Cluster headache belongs to a group of primary headache entities: the trigeminal autonomic cephalalgias. Cluster headache is the most common variant. The headache is usually severe and it is also associated with autonomic symptoms. Secondary causes of cluster headache have been reported, such as intracranial artery aneurysms and tumors. The question of when to carry out neuroimaging in patients with cluster headache is yet unsettled. To the best of the author's knowledge, cluster headache associated with a clinically non functioning pituitary adenoma (chromophobe adenoma) has not been described. This case report describes the case of a man with cluster headache where the evaluation showed a clinically non-functioning pituitary adenoma. CASE PRESENTATION: This case involved a 49-year-old Caucasian man who presented with a one-month history of side-locked attacks of pain located in the right orbit. His symptoms fulfilled the criteria for cluster headache and a diagnosis of cluster headache was made. The patient responded to symptomatic treatment. Enhanced magnetic resonance imaging showed a pituitary adenoma. Further evaluations including hormonal screening revealed a clinically non-functioning pituitary adenoma (chromophobe adenoma). After surgery to remove the tumor, his headache attacks resolved totally. CONCLUSION: Tumors have been reported in patients with cluster headache whose clinical attacks are identical to genuine cluster headache. A clinically non-functioning pituitary adenoma can present as cluster headache. This case emphasizes the need of imaging procedures in patients with cluster headache. Contrast-enhanced magnetic resonance imaging including the sella turcica should always be done in patients with cluster headache. PMID- 25526867 TI - Genetic mapping of a new race specific resistance allele effective to Puccinia hordei at the Rph9/Rph12 locus on chromosome 5HL in barley. AB - BACKGROUND: Barley is an important cereal crop cultivated for malt and ruminant feed and in certain regions it is used for human consumption. It is vulnerable to numerous foliar diseases including barley leaf rust caused by the pathogen Puccinia hordei. RESULTS: A temporarily designated resistance locus RphCantala (RphC) identified in the Australian Hordeum vulgare L. cultivar 'Cantala' displayed an intermediate to low infection type (";12 = N") against the P. hordei pathotype 253P- (virulent on Rph1, Rph2, Rph4, Rph6, Rph8 and RphQ). Phenotypic assessment of a 'CI 9214' (susceptible) x 'Stirling' (RphC) (CI 9214/Stirling) doubled haploid (DH) population at the seedling stage using P. hordei pathotype 253P-, confirmed that RphC was monogenically inherited. Marker-trait association analysis of RphC in the CI 9214/Stirling DH population using 4,500 DArT-seq markers identified a highly significant (-log10Pvalue > 17) single peak on the long arm of chromosome 5H (5HL). Further tests of allelism determined that RphC was genetically independent of Rph3, Rph7, Rph11, Rph13 and Rph14, and was an allele of Rph12 (Rph9.z), which also maps to 5HL. CONCLUSION: Multipathotype tests and subsequent pedigree analysis determined that 14 related Australian barley varieties (including 'Stirling' and 'Cantala') carry RphC and that the likely source of this resistance is via a Czechoslovakian landrace LV-Kvasice-NA Morave transferred through common ancestral cultivars 'Hanna' and 'Abed Binder'. RphC is an allele of Rph12 (Rph9.z) and is therefore designated Rph9.am. Bioinformatic analysis using sequence arrays from DArT-seq markers in linkage disequilibrium with Rph9.am identified possible candidates for further gene cloning efforts and marker development at the Rph9/Rph12/Rph9.am locus. PMID- 25526869 TI - Metabolome-wide association study of phenylalanine in plasma of common marmosets. AB - Little systematic knowledge exists concerning the impacts of cumulative lifelong exposure, termed the exposome, on requirements for nutrients. Phenylalanine (Phe) is an essential dietary amino acid with an aromatic ring structure similar to endogenous metabolites, dietary compounds and environmental agents. Excess plasma Phe in genetic disease or nutritional deficiency of Phe has adverse health consequences. In principle, structurally similar chemicals interfering with Phe utilization could alter Phe requirement at an individual level. As a strategy to identify components of the exposome that could interfere with Phe utilization, we tested for metabolites correlating with Phe concentration in plasma of a non human primate species, common marmosets (Callithrix jacchus). The results of tests for more than 5,000 chemical features detected by high-resolution metabolomics showed 17 positive correlations with Phe metabolites and other amino acids. Positive and negative correlations were also observed for 33 other chemicals, which included matches to endogenous metabolites and dietary, microbial and environmental chemicals in database searches. Chemical similarity analysis showed many of the matches had high structural similarity to Phe. Together, the results show that chemicals in marmoset plasma could impact Phe utilization. Such chemicals could contribute to early lifecycle developmental disorders when neurological development is vulnerable to Phe levels. PMID- 25526871 TI - Occupational exposures, smoking and airway inflammation in refractory asthma. AB - BACKGROUND: The influence of occupation and ex/passive smoking on inflammatory phenotype is not well understood. The aim of this study was to examine the relationship between occupation, past smoking and current passive smoking and airway inflammation in a population of adults with refractory asthma. METHODS: Sixty-six participants with refractory asthma were characterised. Occupational exposure to asthma causing or worsening agents were identified with an asthma specific job exposure matrix. Exposure to passive cigarette smoke was determined by questionnaire and exhaled carbon monoxide assessment. The carbon content of macrophages was assessed in a sub-group of participants. RESULTS: Nineteen participants had smoked previously with low smoking pack years (median 1.7 years). Ex-smokers more commonly lived with a current smoker (26% vs. 9%, p = 0.11) and were more likely to allow smoking inside their home (26% vs. 4%, p = 0.02) compared to never smokers. Twenty participants had occupations with an identified exposure risk to an asthmagen; thirteen had exposures to irritants such as motor vehicle exhaust and environmental tobacco smoke. Sputum neutrophils were elevated in participants with asthma who had occupational exposures, particularly those who were diagnosed with asthma at a more than 30 years of age. CONCLUSIONS: Sputum neutrophils are elevated in refractory asthma with exposure to occupational asthmagens. In addition to older age, exposure to both environmental and occupational particulate matter may contribute to the presence of neutrophilic asthma. This may help explain asthma heterogeneity and geographical variations in airway inflammatory phenotypes in asthma. PMID- 25526870 TI - A mobile phone intervention to reduce binge drinking among disadvantaged men: study protocol for a randomised controlled cost-effectiveness trial. AB - BACKGROUND: Socially disadvantaged men are at a substantially higher risk of developing alcohol-related problems. The frequency of heavy drinking in a single session is high among disadvantaged men. Brief alcohol interventions were developed for, and are usually delivered in, healthcare settings. The group who binge drink most frequently, young to middle-aged disadvantaged men, have less contact with health services and there is a need for an alternative method of intervention delivery. Text messaging has been used successfully to modify other adverse health behaviours. This study will test whether text messages can reduce the frequency of binge drinking by disadvantaged men. METHODS/DESIGN: Disadvantaged men aged 25 to 44 years who drank >8 units of alcohol at least twice in the preceding month will be recruited from the community. Two recruitment strategies will be used: contacting men listed in primary care registers, and a community outreach method (time-space sampling). The intended sample of 798 men will be randomised to intervention or control, stratifying by recruitment method. The intervention group will receive a series of text messages designed to reduce the frequency of binge drinking through the formation of specific action plans. The control group will receive behaviourally neutral text messages intended to promote retention in the study. The primary outcome measure is the proportion of men consuming >8 units on at least three occasions in the previous 30 days. Secondary outcomes include total alcohol consumption and the frequency of consuming more than 16 units of alcohol in one session in the previous month. Process measures, developed during a previous feasibility study, will monitor engagement with the key behaviour change components of the intervention. The study will incorporate an economic evaluation comparing the costs of recruitment and intervention delivery with the benefits of reduced alcohol-related harm. DISCUSSION: This study will assess the effectiveness of a brief intervention, delivered by text messages, aimed at reducing the frequency of binge drinking in disadvantaged men. The process measures will identify components of the intervention which contribute to effectiveness. The study will also determine whether any benefit of the intervention is justified by the costs of intervening. TRIAL REGISTRATION: ISRCTN07695192. Date assigned: 14 August 2013. PMID- 25526872 TI - The PORTO study and the importance of cerebroplacental ratio in fetal growth restriction. Reply. PMID- 25526873 TI - Delayed cord clamping with and without cord stripping: a prospective randomized trial of preterm neonates. AB - OBJECTIVE: Autologous blood transfusion from the placenta to the neonate at birth has been proven beneficial. Transfusion can be accomplished by either delayed cord clamping or cord stripping. Both are equally effective in previous randomized trials. We hypothesized that combining these 2 techniques would further improve outcomes in preterm neonates. STUDY DESIGN: This was a prospective randomized trial for singleton deliveries with estimated gestational ages between 22 and 31 6/7 weeks. The control protocol required a 30-second delayed cord clamping, whereas the test protocol instructed a concurrent cord stripping during the delay. The primary outcome was initial fetal hematocrit. We also examined secondary outcomes of neonatal mortality, length of time on the ventilator, days to discharge, peak bilirubin, number of phototherapy days, and neonatal complication rates. RESULTS: Of the 67 patients analyzed, 32 were randomized to the control arm and 35 were randomized to the test arm. The gestational ages and fetal weights were similar between the arms. Mean hematocrit of the control arm was 47.75%, and the mean hematocrit for the test arm was 47.71% (P = .98). These results were stratified by gestational age, revealing the infants less than 28 weeks had an average hematocrit of 41.2% in the control arm and 44.7% in the test arm (P = .12). In the infants with gestational ages of 28 weeks or longer, the control arm had an average hematocrit of 52.9%, which was higher than the test arm, which averaged 49.5% (P = .04). The control arm received an average of 1.53 blood transfusions, whereas the test arm received 0.97 (P = .33). The control arm had 3 neonatal deaths, and the test arm had none (P = .10). The average number of days until discharge was 71.2 for the control arm and 67.8 for the test arm (P = .66). The average number of days on the ventilator was 4.86 for the control arm and 3.06 for the test arm (P = .34). CONCLUSION: Adding cord stripping to the delayed cord clamp does not result in an increased hematocrit. Data suggest trends in lower mortality and higher hematocrit in neonates born less than 28 weeks, but these were not statistically significant. PMID- 25526874 TI - Partnering with patients to realize the benefits of social media. AB - Despite widespread concern about the potential risks of the use of social media, we are optimistic that social networks and blogs have the potential to enhance the practice of medicine by allowing clinicians to share ideas and information within the health care community, with patients, and with the general public. In particular, we believe that there can be value in posting information related to a patient encounter on social media, but only if care has been taken to consider the consequences of such a post from the patient's perspective. Thus, having a discussion with a patient and obtaining verbal consent before posting even deidentified patient information should become standard practice for all physicians who use social media. PMID- 25526875 TI - The effects of metformin on weight loss in women with gestational diabetes: a pilot randomized, placebo-controlled trial. AB - OBJECTIVE: We sought to compare weight loss in the first 6 weeks postpartum among women with gestational diabetes mellitus (GDM) treated with metformin or placebo, a promising therapy to reduce later risk of progression to diabetes mellitus. STUDY DESIGN: We conducted a pilot, randomized trial of metformin vs placebo in postpartum women with GDM. Women with pre-GDM, unable to tolerate metformin, resumed on insulin or oral hypoglycemic agent, delivered <34 weeks' gestation, or with a body mass index <20 kg/m(2) were excluded. Women were randomized to either metformin 850 mg daily for 7 days, then metformin 850 mg twice a day for the next 5 weeks or placebo prescribed in a similar frequency. The subject, health care provider, and research staff were blinded to the treatment. The primary outcome was weight change from delivery to 6 weeks postpartum. Secondary outcomes included the percentage of women achieving their self-reported prepregnancy weight, reported medication adherence, adverse effects, and satisfaction. Differences in weight change between groups were determined by Wilcoxon rank sum test and in achieving prepregnancy weight by chi(2) test. RESULTS: Of 114 women randomized, 79 (69.3%) completed the 6 weeks; 36 (45.6%) were randomized to metformin and 43 (54.4%) to placebo. Metformin and placebo groups were similar in median weight loss (6.3 kg [range, -0.3 to 19.8] vs 6.5 kg [range, -0.3 to 12.1], P = .988) and percentage of women achieving reported prepregnancy weight (41.7 vs 37.2%, P = .69). Self-reported adherence in taking >50% of medication was 75% at 3 weeks and 97% at 6 weeks. Nausea, diarrhea, and hypoglycemia were reported in approximately 11-17% of women and 56-63% reported dissatisfaction with the medication. CONCLUSION: Women with GDM lost approximately 6 kg by 6 weeks' postpartum. This was similar in both groups and resulted in <50% of women achieving their prepregnancy weight. Although the reported adherence and satisfaction with the medication was high, adverse effects were reported with nearly 1 in 5 women including nausea, diarrhea, and hypoglycemia. Contrary to expectation, we found no evidence of benefit from metformin. However, longer treatment periods and larger studies with minimal attrition may be warranted. PMID- 25526876 TI - The PORTO study and the importance of cerebroplacental ratio in fetal growth restriction. PMID- 25526878 TI - Simplicity is the ultimate sophistication. PR electrocardiographic intervals for smart forecasting of decline in renal function. PMID- 25526879 TI - Is it time to implement a standardized oral glucose and fat load test to detect high risk patients? Probably not yet.... PMID- 25526880 TI - Simultaneous three-dimensional myocardial T1 and T2 mapping in one breath hold with 3D-QALAS. AB - BACKGROUND: Quantification of the longitudinal- and transverse relaxation time in the myocardium has shown to provide important information in cardiac diagnostics. Methods for cardiac relaxation time mapping generally demand a long breath hold to measure either T1 or T2 in a single 2D slice. In this paper we present and evaluate a novel method for 3D interleaved T1 and T2 mapping of the whole left ventricular myocardium within a single breath hold of 15 heartbeats. METHODS: The 3D-QALAS (3D-quantification using an interleaved Look-Locker acquisition sequence with T2 preparation pulse) is based on a 3D spoiled Turbo Field Echo sequence using inversion recovery with interleaved T2 preparation. Quantification of both T1 and T2 in a volume of 13 slices with a resolution of 2.0x2.0x6.0 mm is obtained from five measurements by using simulations of the longitudinal magnetizations Mz. This acquisition scheme is repeated three times to sample k space. The method was evaluated both in-vitro (validated against Inversion Recovery and Multi Echo) and in-vivo (validated against MOLLI and Dual Echo). RESULTS: In-vitro, a strong relation was found between 3D-QALAS and Inversion Recovery (R = 0.998; N = 10; p < 0.01) and between 3D-QALAS and Multi Echo (R = 0.996; N = 10; p < 0.01). The 3D-QALAS method showed no dependence on e.g. heart rate in the interval of 40-120 bpm. In healthy myocardium, the mean T1 value was 1083 +/- 43 ms (mean +/- SD) for 3D-QALAS and 1089 +/- 54 ms for MOLLI, while the mean T2 value was 50.4 +/- 3.6 ms 3D-QALAS and 50.3 +/- 3.5 ms for Dual Echo. No significant difference in in-vivo relaxation times was found between 3D-QALAS and MOLLI (N = 10; p = 0.65) respectively 3D-QALAS and Dual Echo (N = 10; p = 0.925) for the ten healthy volunteers. CONCLUSIONS: The 3D-QALAS method has demonstrated good accuracy and intra-scan variability both in-vitro and in-vivo. It allows rapid acquisition and provides quantitative information of both T1 and T2 relaxation times in the same scan with full coverage of the left ventricle, enabling clinical application in a broader spectrum of cardiac disorders. PMID- 25526882 TI - Whole blood viscosity in plasma cell dyscrasias. AB - OBJECTIVES: Plasma or serum hyperviscosity in plasma cell dyscrasias (PCD) has been described as a risk factor for circulatory disturbances. Whole blood viscosity (WBV) would theoretically be a better biomarker but has not been studied in PCD. DESIGN AND METHODS: Plasma viscosity (PV) and WBV were measured in 89 subjects with PCD and in 60 healthy blood donors by free oscillation rheometry. A complete blood count was obtained using an automated hematology analyzer. Plasma proteins were quantitated by immunoturbidimetry. RESULTS: The reference intervals for men & women were 1.16-1.36 & 1.16-1.38 mPa for PV, and 4.9-6.3 & 4.4-6.2 mPa for WBV, respectively. Of the PCD patients, 71% had PV above the reference limit and 40% were above the WBV limit. Multivariate analysis showed that WBV was independently related to hematocrit, PV, concentration of the monoclonal protein (M-protein), plasma fibrinogen concentration and albumin concentration. This model accounted for 76% of the variance in WBV. When the same model was applied to PV, only the concentration of the M-protein was significantly related and the model accounted only for 20% of the variance in PV. CONCLUSION: PV cannot be used as a surrogate marker for WBV in PCD patients. Whole blood viscosity should replace plasma viscosity in patients with PCD. PMID- 25526883 TI - B-type natriuretic peptide secretion without change in intra-cardiac pressure. AB - OBJECTIVE: In clinical cardiology, B-type natriuretic peptide (BNP) is used as a non-invasive surrogate marker for intra-cardiac filling pressures, particularly in patients with heart failure. It is unknown whether and to what extent increase in intravascular volume and/or sympathetic tone while maintaining constant intra cardiac pressures leads to an increase in levels of BNP in vivo. DESIGN AND METHODS: We aimed to test this hypothesis in an experimental in vivo model of patients directly after off-pump coronary artery bypass grafting admitted to the intensive care unit. These patients require high volumes of intravenous fluids titrated to keep intra-cardiac filling pressures and arterial blood pressure in the normal range while awakening from deep general anesthesia. In 27 consecutive patients, intra-cardiac filling pressures (using a pulmonary artery catheter) and levels of BNP were measured simultaneously every 6h. RESULTS: At 0, 6, 12, and 18h, the pulmonary capillary wedge pressure remained constant (12+/-4, 13+/-3, 12+/-3, and 13+/-3mmHg, respectively; p=0.351). Similarly, right heart filling pressures did not change during the study period. In contrast, BNP levels increased significantly during the study period: Median levels were 82 [IQR 37 162] pg/ml at 0h, 153 [92-246] pg/ml at 6h, 274 [156-392] pg/ml at 12h, and 320 [200-528] pg/ml at 18h (p<0.001). No significant correlation between BNP levels and pulmonary capillary wedge pressures was found (r=0.052; p=0.604). CONCLUSIONS: After cardiac surgery, BNP cannot be considered a reliable non invasive surrogate for PCWP. In vivo, substantial BNP secretion occurs independently of PCWP in a setting of increasing intravascular volume and consciousness/sympathetic tone. PMID- 25526881 TI - Serum glucose and risk of cancer: a meta-analysis. AB - BACKGROUND: Raised serum glucose has been linked to increased risk of many solid cancers. We performed a meta-analysis to quantify and summarise the evidence for this link. METHODS: Pubmed and Embase were reviewed, using search terms representing serum glucose and cancer. Inclusion and exclusion criteria focused on epidemiological studies with clear definitions of serum glucose levels, cancer type, as well as well-described statistical methods with sufficient data available. We used 6.1 mmol/L as the cut-off for high glucose, consistent with the WHO definition of metabolic syndrome. Random effects analyses were performed to estimate the pooled relative risk (RR). RESULTS: Nineteen studies were included in the primary analysis, which showed a pooled RR of 1.32 (95% CI: 1.20 1.45). Including only those individuals with fasting glucose measurements did not have a large effect on the pooled RR (1.32 (95% CI: 1.11-1.57). A stratified analysis showed a pooled RR of 1.34 (95% CI: 1.02-1.77) for hormonally driven cancer and 1.21 (95% CI: 1.09-1.36) for cancers thought to be driven by Insulin Growth Factor-1. CONCLUSION: A positive association between serum glucose and risk of cancer was found. The underlying biological mechanisms remain to be elucidated but our subgroup analyses suggest that the insulin- IGF-1 axis does not fully explain the association. These findings are of public health importance as measures to reduce serum glucose via lifestyle and dietary changes could be implemented in the context of cancer mortality. PMID- 25526884 TI - Linear-time computation of minimal absent words using suffix array. AB - BACKGROUND: An absent word of a word y of length n is a word that does not occur in y. It is a minimal absent word if all its proper factors occur in y. Minimal absent words have been computed in genomes of organisms from all domains of life; their computation also provides a fast alternative for measuring approximation in sequence comparison. There exists an [Formula: see text]-time and [Formula: see text]-space algorithm for computing all minimal absent words on a fixed-sized alphabet based on the construction of suffix automata (Crochemore et al., 1998). No implementation of this algorithm is publicly available. There also exists an [Formula: see text]-time and [Formula: see text]-space algorithm for the same problem based on the construction of suffix arrays (Pinho et al., 2009). An implementation of this algorithm was also provided by the authors and is currently the fastest available. RESULTS: Our contribution in this article is twofold: first, we bridge this unpleasant gap by presenting an [Formula: see text]-time and [Formula: see text]-space algorithm for computing all minimal absent words based on the construction of suffix arrays; and second, we provide the respective implementation of this algorithm. Experimental results, using real and synthetic data, show that this implementation outperforms the one by Pinho et al. The open-source code of our implementation is freely available at http://github.com/solonas13/maw . CONCLUSIONS: Classical notions for sequence comparison are increasingly being replaced by other similarity measures that refer to the composition of sequences in terms of their constituent patterns. One such measure is the minimal absent words. In this article, we present a new linear-time and linear-space algorithm for the computation of minimal absent words based on the suffix array. PMID- 25526885 TI - Mapping in the era of sequencing: high density genotyping and its application for mapping TYLCV resistance in Solanum pimpinellifolium. AB - BACKGROUND: A RIL population between Solanum lycopersicum cv. Moneymaker and S. pimpinellifolium G1.1554 was genotyped with a custom made SNP array. Additionally, a subset of the lines was genotyped by sequencing (GBS). RESULTS: A total of 1974 polymorphic SNPs were selected to develop a linkage map of 715 unique genetic loci. We generated plots for visualizing the recombination patterns of the population relating physical and genetic positions along the genome.This linkage map was used to identify two QTLs for TYLCV resistance which contained favourable alleles derived from S. pimpinellifolium. Further GBS was used to saturate regions of interest, and the mapping resolution of the two QTLs was improved. The analysis showed highest significance on Chromosome 11 close to the region of 51.3 Mb (qTy-p11) and another on Chromosome 3 near 46.5 Mb (qTy p3). Furthermore, we explored the population using untargeted metabolic profiling, and the most significant differences between susceptible and resistant plants were mainly associated with sucrose and flavonoid glycosides. CONCLUSIONS: The SNP information obtained from an array allowed a first QTL screening of our RIL population. With additional SNP data of a RILs subset, obtained through GBS, we were able to perform an in silico mapping improvement to further confirm regions associated with our trait of interest. With the combination of different ~ omics platforms we provide valuable insight into the genetics of S. pimpinellifolium-derived TYLCV resistance. PMID- 25526887 TI - Cerebrospinal fluid proteomics and protein biomarkers in frontotemporal lobar degeneration: Current status and future perspectives. AB - Frontotemporal lobar degeneration (FTLD) comprises a spectrum of rare neurodegenerative diseases with an estimated prevalence of 15-22 cases per 100,000 persons including the behavioral variant of frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA), semantic dementia (SD), FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). The pathogenesis of the diseases is still unclear and clinical diagnosis of FTLD is hampered by overlapping symptoms within the FTLD subtypes and with other neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Intracellular protein aggregates in the brain are a major hallmark of FTLD and implicate alterations in protein metabolism or function in the disease's pathogenesis. Cerebrospinal fluid (CSF) which surrounds the brain can be used to study changes in neurodegenerative diseases and to identify disease-related mechanisms or neurochemical biomarkers for diagnosis. In the present review, we will give an overview of the current literature on proteomic studies in CSF of FTLD patients. Reports of targeted and unbiased proteomic approaches are included and the results are discussed in regard of their informative value about disease pathology and the suitability to be used as diagnostic biomarkers. Finally, we will give some future perspectives on CSF proteomics and a list of candidate biomarkers which might be interesting for validation in further studies. This article is part of a Special Issue entitled: Neuroproteomics: Applications in neuroscience and neurology. PMID- 25526886 TI - Autoantigen complementarity and its contributions to hallmarks of autoimmune disease. AB - The question considered is, "What causes the autoimmune response to begin and what causes it to worsen into autoimmune disease?" The theory of autoantigen complementarity posits that the initiating immunogen causing disease is a protein complementary (antisense) to the self-antigen, rather than a response to the native protein. The resulting primary antibody elicits an anti-antibody response or anti-idiotype, consequently producing a disease-inciting autoantibody. Yet, not everyone who developes self-reactive autoantibodies will manifest autoimmune disease. What is apparent is that manifestation of disease is governed by the acquisition of multiple immune-compromising traits that increase susceptibility and drive disease. Taking into account current cellular, molecular, and genetic information, six traits, or 'hallmarks', of autoimmune disease were proposed: (1) Autoreactive cells evade deletion, (2) Presence of asymptomatic autoantibodies, (3) Hyperactivity of Fc-FcR pathway, (4) Susceptibility to environmental impact, (5) Antigenic modifications of self-proteins, (6) Microbial Infections. Presented here is a discussion on how components delineated in the theory of autoantigen complementarity potentially promote the acquisition of multiple 'hallmarks' of disease. PMID- 25526888 TI - Cerebrospinal fluid proteomics in multiple sclerosis. AB - Multiple sclerosis (MS) is an immune mediated chronic inflammatory disease of the central nervous system usually initiated during young adulthood, affecting approximately 2.5 million people worldwide. There is currently no cure for MS, but disease modifying treatment has become increasingly more effective, especially when started in the first phase of the disease. The disease course and prognosis are often unpredictable and it can be challenging to determine an early diagnosis. The detection of novel biomarkers to understand more of the disease mechanism, facilitate early diagnosis, predict disease progression, and find treatment targets would be very attractive. Over the last decade there has been an increasing effort toward finding such biomarker candidates. One promising strategy has been to use state-of-the-art quantitative proteomics approaches to compare the cerebrospinal fluid (CSF) proteome between MS and control patients or between different subgroups of MS. In this review we summarize and discuss the status of CSF proteomics in MS, including the latest findings with a focus on the last five years. This article is part of a Special Issue entitled: Neuroproteomics: Applications in Neuroscience and Neurology. PMID- 25526889 TI - Structural insights into the stabilization of the human immunodeficiency virus type 1 capsid protein by the cyclophilin-binding domain and implications on the virus cycle. AB - During infection, human immunodeficiency virus type 1 (HIV-1) interacts with the cellular host factor cyclophilin A (CypA) through residues 85-93 of the N terminal domain of HIV-1's capsid protein (CA). The role of the CA:CypA interaction is still unclear. Previous studies showed that a CypA-binding loop mutant, Delta87-97, has increased ability to assemble in vitro. We used this mutant to infer whether the CypA-binding region has an overall effect on CA stability, as measured by pressure and chemical perturbation. We built a SAXS based envelope model for the dimer of both WT and Delta87-97. A new conformational arrangement of the dimers is described, showing the structural plasticity that CA can adopt. In protein folding studies, the deletion of the loop drastically reduces CA stability, as assayed by high hydrostatic pressure and urea. We hypothesize that the deletion promotes a rearrangement of helix 4, which may enhance the heterotypic interaction between the N- and C-terminal domains of CA dimers. In addition, we propose that the cyclophilin-binding loop may modulate capsid assembly during infection, either in the cytoplasm or near the nucleus by binding to the nuclear protein Nup385. PMID- 25526890 TI - Recombination of the porcine X chromosome: a high density linkage map. AB - BACKGROUND: Linkage maps are essential tools for the study of several topics in genome biology. High density linkage maps for the porcine autosomes have been constructed exploiting the high density data provided by the PorcineSNP60 BeadChip. However, a high density SSCX linkage map has not been reported up to date. The aim of the current study was to build an accurate linkage map of SSCX to provide precise estimates of recombination rates along this chromosome and creating a new tool for QTL fine mapping. RESULTS: A female-specific high density linkage map was built for SSCX using Sscrofa10.2 annotation. The total length of this chromosome was 84.61 cM; although the average recombination rate was 0.60 cM/Mb, both cold and hot recombination regions were identified. A Bayesian probabilistic to genetic groups and revealed that the animals used in the current study for linkage map construction were likely to be carriers of X chromosomes of European origin. Finally, the newly generated linkage map was used to fine-map a QTL at 16 cM for intramuscular fat content (IMF) measured on longissimus dorsi. The sulfatase isozyme S gene constitutes a functional and positional candidate gene underlying the QTL effect. CONCLUSIONS: The current study presents for the first time a high density linkage map for SSCX and supports the presence of cold and hot recombination intervals along this chromosome. The large cold recombination region in the central segment of the chromosome is not likely to be due to structural differences between X chromosomes of European and Asian origin. In addition, the newly generated linkage map has allowed us to fine-map a QTL on SSCX for fat deposition. PMID- 25526892 TI - Patterns of prescription drug expenditures and medication adherence among medicare part D beneficiaries with and without the low-income supplement. AB - BACKGROUND: The association between the Medicare Part D low-income subsidy (LIS), gap coverage, and outcomes such as medical expenditures, prescription fills, and medication adherence is not well understood. The purpose of this study was to examine the relationship between the LIS and these measures for patients within a large, national Part D plan in the United States. METHODS: In this cross sectional, retrospective analysis, we compared total and plan expenditures, out of-pocket costs, and medication fills and adherence for three categories of Medicare beneficiaries: non-LIS beneficiaries without gap coverage (non-LIS/non GC), non-LIS beneficiaries with gap coverage (non-LIS/GC), and LIS beneficiaries (LIS). RESULTS: LIS beneficiaries, relative to non-LIS/non-GC and non-LIS/GC beneficiaries, had higher total expenditures ($1,887 vs. $1,360 vs. $1,341); lower out-of-pocket costs ($148 vs. $546 vs. $570); more expenditures exceeding the gap threshold (27.6% vs. 18.4% vs. 16.9%); and slightly higher adherence to blood pressure (65.6% vs. 64.2% vs. 62.4%); diabetes (62.5% vs. 57.7 vs. 57.4%); and lipid-lowering (59.6% vs. 57.0 vs. 55.6%) medications. CONCLUSION: LIS beneficiaries had higher total expenditures, lower out-of-pocket costs, and modestly better adherence to diabetes medications than non-LIS/non-GC and non LIS/GC beneficiaries. PMID- 25526891 TI - Policy recommendations and cost implications for a more sustainable framework for European human biomonitoring surveys. AB - The potential of Human Biomonitoring (HBM) in exposure characterisation and risk assessment is well established in the scientific HBM community and regulatory arena by many publications. The European Environment and Health Strategy as well as the Environment and Health Action Plan 2004-2010 of the European Commission recognised the value of HBM and the relevance and importance of coordination of HBM programmes in Europe. Based on existing and planned HBM projects and programmes of work and capabilities in Europe the Seventh Framework Programme (FP 7) funded COPHES (COnsortium to Perform Human Biomonitoring on a European Scale) to advance and improve comparability of HBM data across Europe. The pilot study protocol was tested in 17 European countries in the DEMOCOPHES feasibility study (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale) cofunded (50%) under the LIFE+ programme of the European Commission. The potential of HBM in supporting and evaluating policy making (including e.g. REACH) and in awareness raising on environmental health, should significantly advance the process towards a fully operational, continuous, sustainable and scientifically based EU HBM programme. From a number of stakeholder activities during the past 10 years and the national engagement, a framework for sustainable HBM structure in Europe is recommended involving national institutions within environment, health and food as well as European institutions such as ECHA, EEA, and EFSA. An economic frame with shared cost implications for national and European institutions is suggested benefitting from the capacity building set up by COPHES/DEMOCOPHES. PMID- 25526894 TI - Epigenetic mechanisms regulate NADPH oxidase-4 expression in cellular senescence. AB - Aging is a well-known risk factor for a large number of chronic diseases, including those of the lung. Cellular senescence is one of the hallmarks of aging, and contributes to the pathogenesis of age-related diseases. Recent studies implicate the reactive oxygen species (ROS)-generating enzyme, NADPH oxidase 4 (Nox4) in cellular senescence. In this study, we investigated potential mechanisms for epigenetic regulation of Nox4. We observed constitutively high levels of Nox4 gene/protein and activity in a model of replication-induced cellular senescence of lung fibroblasts. In replicative senescent fibroblasts, the Nox4 gene is enriched with the activation histone mark, H4K16Ac, and inversely associated with the repressive histone mark, H4K20Me3, supporting an active transcriptional chromatin conformation. Silencing of the histone acetyltransferase Mof, which specifically acetylates H4K16, down-regulates Nox4 gene/protein expression. The Nox4 gene promoter is rich in CpG sites; mixed copies of methylated and unmethylated Nox4 DNA were detected in both nonsenescent and senescent cells. Interestingly, the Nox4 gene is variably associated with specific DNA methyltransferases and methyl binding proteins in these two cell populations. These results indicate a critical role for histone modifications involving H4K16Ac in epigenetic activation of the Nox4 gene, while the role of DNA methylation may be contextual. Defining mechanisms for the epigenetic regulation of Nox4 will aid in the development of novel therapeutic strategies for age-related diseases in which this gene is overexpressed, in particular idiopathic pulmonary fibrosis and cancer. PMID- 25526893 TI - Observation of superoxide production during catalysis of Bacillus subtilis oxalate decarboxylase at pH 4. AB - This contribution describes the trapping of the hydroperoxyl radical at a pH of 4 during turnover of wild-type oxalate decarboxylase and its T165V mutant using the spin-trap BMPO. Radicals were detected and identified by a combination of EPR and mass spectrometry. Superoxide, or its conjugate acid, the hydroperoxyl radical, is expected as an intermediate in the decarboxylation and oxidation reactions of the oxalate monoanion, both of which are promoted by oxalate decarboxylase. Another intermediate, the carbon dioxide radical anion was also observed. The quantitative yields of superoxide trapping are similar in the wild type and the mutant while it is significantly different for the trapping of the carbon dioxide radical anion. This suggests that the two radicals are released from different sites of the protein. PMID- 25526895 TI - Mucin1 mediates autocrine transforming growth factor beta signaling through activating the c-Jun N-terminal kinase/activator protein 1 pathway in human hepatocellular carcinoma cells. AB - In a previous study, we observed by global gene expression analysis that oncogene mucin1 (MUC1) silencing decreased transforming growth factor beta (TGF-beta) signaling in the human hepatocellular carcinoma (HCC) cell line SMMC-7721. In this study, we report that MUC1 overexpression enhanced the levels of phosphorylated Smad3 linker region (p-Smad3L) (Ser-213) and its target gene MMP-9 in HCC cells, suggesting that MUC1 mediates TGF-beta signaling. To investigate the effect of MUC1 on TGF-beta signaling, we determined TGF-beta secretion in MUC1 gene silencing and overexpressing cell lines. MUC1 expression enhanced not only TGF-beta1 expression at the mRNA and protein levels but also luciferase activity driven by a TGF-beta promoter, as well as elevated the activation of c Jun N-terminal kinase (JNK) and c-Jun, a member of the activation protein 1 (AP 1) transcription factor family. Furthermore, pharmacological reduction of TGF beta receptor (TbetaR), JNK and c-Jun activity inhibited MUC1-induced autocrine TGF-beta signaling. Moreover, a co-immunoprecipitation assay showed that MUC1 directly bound and activated JNK. In addition, both MUC1-induced TGF-beta secretion and exogenous TGF-beta1 significantly increased Smad signaling and cell migration, which were markedly inhibited by either TbetaR inhibitor or small interfering RNA silencing of TGF-beta1 gene in HCC cells. The high correlation between MUC1 and TGF-beta1 or p-Smad3L (Ser-213) expression was shown in tumor tissues from HCC patients by immunohistochemical staining analysis. Collectively, these results indicate that MUC1 mediates autocrine TGF-beta signaling by activating the JNK/AP-1 pathway in HCC cells. Therefore, MUC1 plays a key role in HCC progression and could serve as an attractive target for HCC therapy. PMID- 25526896 TI - Aging alters visual processing of objects and shapes in inferotemporal cortex in monkeys. AB - Visual perception declines with age. Perceptual deficits may originate not only in the optical system serving vision but also in the neural machinery processing visual information. Since homologies between monkey and human vision permit extrapolation from monkeys to humans, data from young, middle aged and old monkeys were analyzed to show age-related changes in the neuronal activity in the inferotemporal cortex, which is critical for object and shape vision. We found an increased neuronal response latency, and a decrease in the stimulus selectivity in the older animals and suggest that these changes may underlie the perceptual uncertainties found frequently in the elderly. PMID- 25526897 TI - L-Ornithine intake affects sympathetic nerve outflows and reduces body weight and food intake in rats. AB - Ingesting the amino acid l-ornithine effectively improves lipid metabolism in humans, although it is unknown whether it affects the activities of autonomic nerves that supply the peripheral organs related to lipid metabolism, such as adipose tissues. Thus, we investigated the effects of l-ornithine ingestion on autonomic nerves that innervate adipose tissues and the feeding behaviors of rats. Intragastric injection of l-ornithine (2.5%) in urethane-anesthetized rats activated sympathetic nerve activity to white adipose tissue (WAT-SNA), and stimulated sympathetic nerve activity to brown adipose tissue (BAT-SNA). In addition, WAT-SNA responses to l-ornithine were abolished in rats with ablated abdominal vagal nerves. l-ornithine ingestion for 9 weeks also significantly reduced rats' body weight, food intake, and abdominal fat weight. Proopiomelanocortin (POMC) levels in the hypothalamus and uncoupling protein 1 (UCP1) levels in brown adipose tissue were significantly increased in rats that ingested 2.5% l-ornithine for 9 weeks. These results suggested that ingested l ornithine was taken up in the gastrointestinal organs and stimulated afferent vagal nerves and activated the central nervous system. Subsequently, increased hypothalamic POMC activated sympathetic neurotransmission to adipose tissues and accelerated energy expenditure. PMID- 25526898 TI - Differential regulation of perineuronal nets in the brain and spinal cord with exercise training. AB - Perineuronal nets (PNNs) are lattice like structures which encapsulate the cell body and proximal dendrites of many neurons and are thought to be involved in regulating synaptic plasticity. It is believed that exercise can enhance the plasticity of the Central Nervous System (CNS) in healthy and dysfunctional states by shifting the balance between plasticity promoting and plasticity inhibiting factors in favor of the former. Recent work has focused on exercise effects on trophic factors but its effect on other plasticity regulators is poorly understood. In the present study we investigated how exercise regulates PNN expression in the lumbar spinal cord and areas of the brain associated with motor control and learning and memory. Adult, female Sprague-Dawley rats with free access to a running wheel for 6 weeks had significantly increased PNN expression in the spinal cord compared to sedentary rats (PNN thickness around motoneurons, exercise=15.75+/-0.63MUm, sedentary=7.98+/-1.29MUm, p<0.01). Conversely, in areas of the brain associated with learning and memory there was a significant reduction in perineuronal net expression (number of neurons with PNN in hippocampus CA1-exercise 21+/-0.56 and sedentary 24+/-0.34, p<0.01, thickness exercised=2.37+/-0.13MUm, sedentary=4.27+/-0.21MUm; p<0.01). Our results suggest that in response to exercise, PNNs are differentially regulated in select regions of the CNS, with a general decreased expression in the brain and increased expression in the lumbar spinal cord. This differential expression may indicate different regulatory mechanisms associated with plasticity in the brain compared to the spinal cord. PMID- 25526899 TI - Exosomes, endogenous retroviruses and toll-like receptors: pregnancy recognition in ewes. AB - Conceptus-endometrial communication during the peri-implantation period of pregnancy ensures establishment of pregnancy. We hypothesized that this dialog involves exosomes, ovine endogenous jaagsiekte retroviruses (enJSRV) and toll like receptors (TLR) which regulate the secretion of interferon tau (IFNT), the pregnancy recognition signal in ruminants. First, exosomes isolated from uterine flushings from cyclic and pregnant ewes were analyzed for exosomal content and uterine expression of heat shock protein 70 (HSC70). Then, conceptus trophectoderm cells (oTr1) treated with different doses of exosomes were analyzed for the expression of genes involved in TLR-mediated cell signaling. The results revealed that exosomes contain mRNAs for enJSRV-ENV, HSC70, interleukins, and interferon (IFN)-regulatory factors. Exosomal content of enJSRV-ENV mRNA and protein decreased from days 10 and 12 to day 16 of gestation, and uterine expression of HSC70 increased in pregnant ewes compared with cyclic ewes. The oTr1 cells proliferated and secreted IFNT in a dose-dependent manner in response to exosomes from cyclic ewes. The expression of CD14, CD68, IRAK1, TRAF6, IRF6, and IRF7 mRNAs that are key to TLR-mediated expression of type 1 IFNs was significantly influenced by day of pregnancy. This study demonstrated that exosomes are liberated into the uterine lumen during the estrous cycle and early pregnancy; however, in pregnant ewes, exosomes stimulate trophectoderm cells to proliferate and secrete IFNT coordinately with regulation of TLR-mediated cell signaling. These results support our hypothesis that free and/or exosomal enJSRV act on the trophectoderm via TLR to induce the secretion of IFNT in a manner similar to that for innate immune responses of macrophages and plasmacytoid dendritic cells to viral pathogens. PMID- 25526900 TI - US cancels plan to study 100,000 children from "womb" to age 21. PMID- 25526901 TI - Optimal contouring of seminal vesicle for definitive radiotherapy of localized prostate cancer: comparison between EORTC prostate cancer radiotherapy guideline, RTOG0815 protocol and actual anatomy. AB - BACKGROUND: Intermediate- to-high-risk prostate cancer can locally invade seminal vesicle (SV). It is recommended that anatomic proximal 1-cm to 2-cm SV be included in the clinical target volume (CTV) for definitive radiotherapy based on pathology studies. However, it remains unclear whether the pathology indicated SV extent is included into the CTV defined by current guidelines. The purpose of this study is to compare the volume of proximal SV included in CTV defined by EORTC prostate cancer radiotherapy guideline and RTOG0815 protocol with the actual anatomic volume. METHODS: Radiotherapy planning CT images from 114 patients with intermediate- (36.8%) or high-risk (63.2%) prostate cancer were reconstructed with 1-mm-thick sections. The starting and ending points of SV and the cross sections of SV at 1-cm and 2-cm from the starting point were determined using 3D-view. Maximum (D1H, D2H) and minimum (D1L, D2L) vertical distance from these cross sections to the starting point were measured. Then, CTV of proximal SV defined by actual anatomy, EORTC guideline and RTOG0815 protocol were contoured and compared (paired t test). RESULTS: Median length of D1H, D1L, D2H and D2L was 10.8 mm, 2.1 mm, 17.6 mm and 8.8 mm (95th percentile: 13.5mm, 5.0mm, 21.5mm and 13.5mm, respectively). For intermediate-risk patients, the proximal 1 cm SV CTV defined by EORTC guideline and RTOG0815 protocol inadequately included the anatomic proximal 1-cm SV in 62.3% (71/114) and 71.0% (81/114) cases, respectively. While for high-risk patients, the proximal 2-cm SV CTV defined by EORTC guideline inadequately included the anatomic proximal 2-cm SV in 17.5% (20/114) cases. CONCLUSIONS: SV involvement indicated by pathology studies was not completely included in the CTV defined by current guidelines. Delineation of proximal 1.4 cm and 2.2 cm SV in axial plane may be adequate to include the anatomic proximal 1-cm and 2-cm SV. However, part of SV may be over-contoured. PMID- 25526902 TI - Late pleistocene Australian marsupial DNA clarifies the affinities of extinct megafaunal kangaroos and wallabies. AB - Understanding the evolution of Australia's extinct marsupial megafauna has been hindered by a relatively incomplete fossil record and convergent or highly specialized morphology, which confound phylogenetic analyses. Further, the harsh Australian climate and early date of most megafaunal extinctions (39-52 ka) means that the vast majority of fossil remains are unsuitable for ancient DNA analyses. Here, we apply cross-species DNA capture to fossils from relatively high latitude, high altitude caves in Tasmania. Using low-stringency hybridization and high-throughput sequencing, we were able to retrieve mitochondrial sequences from two extinct megafaunal macropodid species. The two specimens, Simosthenurus occidentalis (giant short-faced kangaroo) and Protemnodon anak (giant wallaby), have been radiocarbon dated to 46-50 and 40-45 ka, respectively. This is significantly older than any Australian fossil that has previously yielded DNA sequence information. Processing the raw sequence data from these samples posed a bioinformatic challenge due to the poor preservation of DNA. We explored several approaches in order to maximize the signal-to-noise ratio in retained sequencing reads. Our findings demonstrate the critical importance of adopting stringent processing criteria when distant outgroups are used as references for mapping highly fragmented DNA. Based on the most stringent nucleotide data sets (879 bp for S. occidentalis and 2,383 bp for P. anak), total-evidence phylogenetic analyses confirm that macropodids consist of three primary lineages: Sthenurines such as Simosthenurus (extinct short-faced kangaroos), the macropodines (all other wallabies and kangaroos), and the enigmatic living banded hare-wallaby Lagostrophus fasciatus (Lagostrophinae). Protemnodon emerges as a close relative of Macropus (large living kangaroos), a position not supported by recent morphological phylogenetic analyses. PMID- 25526903 TI - Re: "Quantile regression-opportunities and challenges from a user's perspective". PMID- 25526904 TI - Translation research: 'Back on Track', a multiprofessional rehabilitation service for cancer-related fatigue. AB - OBJECTIVES: To assess the effectiveness and acceptability of an individually tailored rehabilitation intervention for patients with cancer-related fatigue (CRF). METHODS: Eighteen individuals, (16 female, two male, aged 40-83 years), who self-reported CRF (above four on a 10-point Likert scale) took part in an 8 week physical activity intervention weekly review and optional gym-based support. Fifteen participants had a primary diagnosis of breast cancer and along with the other participants had multiple myeloma, colorectal or prostate cancer. All participants took part in a goal-oriented walking and muscle strengthening programme with dietary advice and psychological support based on the Transtheoretical Model (TTM) of behaviour change. Effectiveness was assessed by physical and psychological outcomes. Focus groups with participants and individual interviews with the professionals delivering the intervention explored the feasibility and acceptability of the intervention. RESULTS: Statistically significant improvements were seen in the primary outcome of fatigue and on the secondary outcomes of physical function, depression and in triceps skin fold thickness reduction. Participants endorsed the intervention as being highly acceptable, holistic and as important as medical treatments for cancer. The importance of team working was highlighted as key to service delivery and success. CONCLUSIONS: A multidisciplinary home-based tailored intervention with optional weekly gym attendance is acceptable to people with CRF, improving physical and psychosocial outcomes. Study limitations and suggestions for further research are discussed. PMID- 25526905 TI - Peer Rejection and Perceived Quality of Relations With Schoolmates Among Children With ADHD. AB - OBJECTIVE: The main aim of the current study was to investigate the links between ADHD diagnosis and the objective and subjective dimensions of social relationships among children from primary schools. METHOD: We used the data from 36 regular classrooms, consisting of 718 students, with each containing at least one child with an established clinical diagnosis of ADHD (38 children). RESULTS: For children with ADHD, the level of the perceived quality of social relations was lower than that of children without such a diagnosis. After controlling for sociometric status, the impact of ADHD on perceived status proved to be statistically nonsignificant but the indirect impact of ADHD on this status through sociometric status was statistically significant. CONCLUSION: Children diagnosed with ADHD are more often rejected by their peers and have a more pessimistic view of their social world. Moreover, ADHD diagnosis does not have a direct influence on the perceived quality of social relations otherwise than through sociometric status. PMID- 25526907 TI - Non-communicable disease training for public health workers in low- and middle income countries: lessons learned from a pilot training in Tanzania. AB - BACKGROUND: Non-communicable diseases (NCDs) are increasing worldwide. A lack of training and experience in NCDs among public health workers is evident in low- and middle- income countries. METHODS: We describe the design and outcomes of applied training in NCD epidemiology and control piloted in Tanzania that included a 2-week interactive course and a 6-month NCD field project. Trainees (n=14 initiated; n=13 completed) were epidemiology-trained Ministry of Health or hospital staff. We evaluated the training using Kirkpatrick's evaluation model for measuring reactions, learning, behavior and results using pre- and post-tests and closed-ended and open-ended questions. RESULTS: Significant improvements in knowledge and self-reported competencies were observed. Trainees reported applying competencies at work and supervisors reported improvements in trainees' performance. Six field projects were completed; one led to staffing changes and education materials for patients with diabetes and another to the initiation of an injury surveillance system. Workplace support and mentoring were factors that facilitated the completion of projects. Follow-up of participants was difficult, limiting our evaluation of the training's outcomes. CONCLUSIONS: The applied NCD epidemiology and control training piloted in Tanzania was well received and showed improvements in knowledge, skill and self-efficacy and changes in workplace behavior and institutional and organizational changes. Further evaluations are needed to better understand the impact of similar NCD trainings and future trainers should ensure that trainees have mentoring and workplace support prior to participating in an applied NCD training. PMID- 25526906 TI - Daidzein enhances intramuscular fat deposition and improves meat quality in finishing steers. AB - An experiment was conducted to determine the effects of soy isoflavone daidzein on carcass characteristics, fat deposition, meat quality, and blood metabolites in finishing steers. Fourteen crossbred steers were used in a 120-d finishing study. These steers were stratified by weight into groups and randomly allotted by group to one of two dietary treatments: (1) control and (2) daidzein (500 mg/kg concentrate). The steers were fed a 90% concentrate diet. Supplemental daidzein did not affect slaughter weight, hot carcass weight, and dressing percentage, but tended to reduce fat proportion (not including intramuscular fat) in carcass and backfat thickness of steers. The carcass bone proportion was greater in steers fed daidzein diets than those fed control diets. Daidzein supplementation reduced pH at 24 h after slaughtered and moisture content and increased isocitrate dehydrogenase activity, fat content (16.28% and 7.94%), marbling score (5.29 and 3.36), redness (a*), and chroma (C*) values in longissimus muscle relative to control treatment. The concentrations of blood metabolites including glucose, blood urea nitrogen, triglyceride, total cholesterol, non-esterified fatty acid, high-density lipoprotein cholesterol (HDL C), and low-density lipoprotein cholesterol (LDL-C) were all lower in steers fed daidzein diets than those fed control diets. Current results suggest that supplemental daidzein can affect lipid metabolism, increase intramuscular fat content and marbling score, and improve meat quality in finishing steers. Daidzein should be a promising feed additive for production of high-quality beef meat. PMID- 25526909 TI - The size-weight illusion induced through human echolocation. AB - Certain blind individuals have learned to interpret the echoes of self-generated sounds to perceive the structure of objects in their environment. The current work examined how far the influence of this unique form of sensory substitution extends by testing whether echolocation-induced representations of object size could influence weight perception. A small group of echolocation experts made tongue clicks or finger snaps toward cubes of varying sizes and weights before lifting them. These echolocators experienced a robust size-weight illusion. This experiment provides the first demonstration of a sensory substitution technique whereby the substituted sense influences the conscious perception through an intact sense. PMID- 25526908 TI - A blinded randomized assessment of laser Doppler flowmetry efficacy in standardizing outcome from intraluminal filament MCAO in the rat. AB - BACKGROUND: Laser Doppler flowmetry (LDF) is widely used for estimating cerebral blood flow changes during intraluminal middle cerebral artery occlusion (MCAO). No investigation has systematically examined LDF efficacy in standardizing outcome. We examined MCAO histologic and behavioral outcome as a function of LDF measurement. MATERIALS AND METHODS: Rats were subjected to 90min MCAO by 4 surgeons having different levels of MCAO surgical experience. LDF was measured in all rats during ischemia. By random assignment, LDF values were (Assisted) or were not (Blinded) made available to each surgeon during MCAO (n=12-17 per group). Neurologic and histologic outcomes were measured 7 days post-MCAO. A second study examined LDF effects on 1-day post-MCAO outcome. RESULTS: Pooled across surgeons, intra-ischemic %LDF change (P=0.12), neurologic scores (Assisted vs. Blinded=14+/-6 vs. 13+/-7, P=0.61, mean+/-standard deviation) and cerebral infarct volume (162+/-63mm(3)vs. 143+/-86mm(3), P=0.24) were not different between groups. Only for one surgeon (novice) did LDF use alter infarct volume (145+/-28mm(3)vs. 98+/-61mm(3), P=0.03). LDF use decreased infarct volume coefficient of variation (COV) by 35% (P=0.02), but had no effect on neurologic score COV. COMPARISON WITH EXISTING METHODS: We compared intraluminal MCAO outcome as a function of LDF use. CONCLUSIONS: LDF measurement altered neither neurologic nor histologic MCAO outcome. LDF did not decrease neurologic deficit COV, but did decrease infarct volume COV. LDF may allow use of fewer animals if infarct volume is the primary dependent variable, but is unlikely to impact requisite sample sizes if neurologic function is of primary interest. PMID- 25526911 TI - Variation in management of women with threatened preterm labour. PMID- 25526910 TI - Does hugging provide stress-buffering social support? A study of susceptibility to upper respiratory infection and illness. AB - Perceived social support has been hypothesized to protect against the pathogenic effects of stress. How such protection might be conferred, however, is not well understood. Using a sample of 404 healthy adults, we examined the roles of perceived social support and received hugs in buffering against interpersonal stress-induced susceptibility to infectious disease. Perceived support was assessed by questionnaire, and daily interpersonal conflict and receipt of hugs were assessed by telephone interviews on 14 consecutive evenings. Subsequently, participants were exposed to a virus that causes a common cold and were monitored in quarantine to assess infection and illness signs. Perceived support protected against the rise in infection risk associated with increasing frequency of conflict. A similar stress-buffering effect emerged for hugging, which explained 32% of the attenuating effect of support. Among infected participants, greater perceived support and more-frequent hugs each predicted less-severe illness signs. These data suggest that hugging may effectively convey social support. PMID- 25526912 TI - Management of neonatal early onset sepsis (CG149): compliance of neonatal units in the UK with NICE recommendations. PMID- 25526913 TI - Bi-specific antibodies with high antigen-binding affinity identified by flow cytometry. AB - Using conventional approaches, the antigen-binding affinity of a novel format of bi-specific antibody (BsAb) cannot be determined until purified BsAb is obtained. Here, we show that new lipoprotein A (NlpA)-based bacteria display technology, combined with flow cytometry (FCM), can be used to detect antigen-binding affinity of BsAbs, in the absence of expression and purification work. Two formats of BsAb, scFv2-CH/CL and Diabody-CH/CL, specific for human interleukin 1beta (hIL-1beta) and human interleukin 17A (hIL-17A), were constructed and displayed in Escherichia coli using NlpA-based bacteria display technology. Conversion of these cells to spheroplasts, and their incubation with fluorescently conjugated antigens resulted in the selective labeling of spheroplasts expressing BsAb; enabling their antigen-binding affinity to be analyzed with FCM. The association and dissociation of BsAbs for binding to hIL 1beta and hIL-17A were analyzed using FCM-based assays. The results showed that antigen-binding affinity of Diabody-CH/CL was significantly higher than that of scFv2-CH/CL. To confirm these results of FCM-based assays, BsAbs were expressed, purified and subjected to relative affinity measurements, in vitro and in vivo bioactivity analysis. The results showed that Diabody-CH/CL had greater relative affinities for both antigens, resulting in better blocking bioactivities on cellular level and effects on alleviating joint inflammation, and cartilage destruction and bone damage in collagen induced arthritis (CIA) mice model. These results indicate that BsAbs with good antigen-binding affinity can be identified by FCM-based assays without expression and purification work, and the indentified BsAb can serve as a lead compound for further drug development. PMID- 25526916 TI - Just a drop of cement: a case of cervical spine bone aneurysmal cyst successfully treated by percutaneous injection of a small amount of polymethyl-methacrylate cement. AB - Aneurysmal bone cyst (ABC) is a benign hemorrhagic tumor, commonly revealed by local pain. The best treatment for this lesion is still controversial. We report the case of a patient with chronic neck pain revealing an ABC of the third cervical vertebra. After percutaneous injection of a small amount of polymethyl methacrylate bone cement, the patient experienced significant clinical and radiological improvement. PMID- 25526917 TI - Cilostazol: an antiplatelet agent for the neurointerventionist? AB - Antiplatelet agents are essential for the successful management of patients undergoing a variety of neurointerventional procedures. The most commonly used anti-platelet agents are aspirin, clopidogrel and prasugrel. However, there exist an alternative class of anti-platelet agent that may prove useful for neurointerventionists. In particular a drug called cilostazol may have numerous added advantages above and beyond its antiplatelet effect that may be valuable for our patients. In this short review we aim to highlight some of these potential advantages. PMID- 25526919 TI - Correction: Synthesis, cytotoxic and hydrolytic studies of titanium complexes anchored by a tripodal diamine bis(phenolate) ligand. AB - Correction for 'Synthesis, cytotoxic and hydrolytic studies of titanium complexes anchored by a tripodal diamine bis(phenolate) ligand' by Sonia Barroso et al., Dalton Trans., 2014, 43, 17422-17433. PMID- 25526920 TI - Basophils are inept at promoting human Th17 responses. AB - Basophils are the rare granulocytes and play an important role in the polarization of Th2 responses and protection against helminth parasites. In addition, basophils contribute to the pathogenesis of several diseases such as asthma, chronic allergy and lupus. Notably, Th17 cells are also implicated in the pathogenesis of these diseases suggesting that basophils support the activation and expansion of this subset of CD4(+) T cells. Therefore, we explored whether basophils promote the expansion of human Th17 cells. We show that basophils lack the capacity to expand Th17 cells and to induce the secretion of Th17 cytokines either directly or indirectly via antigen presenting cells such as monocytes. As human basophils lack HLA-DR and co-stimulatory molecules, their inability to confer T cell receptor- and co-stimulatory molecule-mediated signals to CD4(+) T cells might explain the lack of Th17 responses when memory CD4(+) T cells were co cultured with basophils. PMID- 25526918 TI - The yeast Saccharomyces cerevisiae: an overview of methods to study autophagy progression. AB - Macroautophagy (hereafter autophagy) is a highly evolutionarily conserved process essential for sustaining cellular integrity, homeostasis, and survival. Most eukaryotic cells constitutively undergo autophagy at a low basal level. However, various stimuli, including starvation, organelle deterioration, stress, and pathogen infection, potently upregulate autophagy. The hallmark morphological feature of autophagy is the formation of the double-membrane vesicle known as the autophagosome. In yeast, flux through the pathway culminates in autophagosome vacuole fusion, and the subsequent degradation of the resulting autophagic bodies and cargo by vacuolar hydrolases, followed by efflux of the breakdown products. Importantly, aberrant autophagy is associated with diverse human pathologies. Thus, there is a need for ongoing work in this area to further understand the cellular factors regulating this process. The field of autophagy research has grown exponentially in recent years, and although numerous model organisms are being used to investigate autophagy, the baker's yeast Saccharomyces cerevisiae remains highly relevant, as there are significant and unique benefits to working with this organism. In this review, we will focus on the current methods available to evaluate and monitor autophagy in S. cerevisiae, which in several cases have also been subsequently exploited in higher eukaryotes. PMID- 25526922 TI - Breast cancer as a model to improve outcome of cancer care in low- and middle income countries. PMID- 25526921 TI - Risk of adrenocortical carcinoma in adrenal tumours greater than 8 cm. AB - BACKGROUND: Adrenocortical cancer (ACC) is a rare malignancy. In the absence of metastatic disease, the suspicion of ACC is based on size and radiological appearance. The aim of this study was to analyse the long-term outcome of patients with large adrenal cortical tumours (>8 cm). METHODS: A prospective database recorded clinical, biochemical, operative and histological data on patients operated for cortical adrenal tumours between January 2000 and February 2013. Out of 130 patients operated for cortical adrenal tumours, analysis was restricted to 37 cortical tumours >8 cm. RESULTS: There were 31 (84 %) ACCs and 6 (16 %) benign adenomas (p < 0.01). The most common presentation was that of an abdominal mass [17 (55 %) vs. 3 (50 %), ACC vs. benign, respectively]. There was no difference in size between stage II and stage III-IV tumours; however, there was a trend for tumours to be heavier in advanced stages (920 +/- 756 vs. 1,435 +/- 1,022 g, p = 0.08, stage II vs. stage III-IV, respectively). No mortality was observed in patients with benign tumours during a median follow-up of 70 months (range 36-99 months). Mortality in the ACC group occurred in 17/31 (55 %) patients. Mitotane was administered in 12 (71 %) patients with stage III-IV ACCs with a 5-year survival rate 25 % compared to 20 % in patients who did not receive Mitotane. In stage II ACC, eight (57 %) patients received Mitotane with a 50 % mortality at 5 years. CONCLUSIONS: The high incidence of ACC in cortical tumours >8 cm underlines the need for adequate surgical resection via open surgery aiming to avoid local recurrence. Beyond surgery, the impact of other therapies is not fully characterised and the efficacy of adjuvant Mitotane treatment is yet to be proven. PMID- 25526923 TI - Heller myotomy for achalasia. From the open to the laparoscopic approach. AB - The last three decades have witnessed a progressive evolution in the surgical treatment of esophageal achalasia, with a shift from open to a minimally invasive Heller myotomy. The laparoscopic approach is currently the standard of care with better short-term outcomes and similar long-term functional results when compared to open surgery. More recently, the laparoscopic single-site approach and the use of the robot have been proposed to further improve the surgical outcome in achalasia patients. PMID- 25526924 TI - Lipoic acid induces p53-independent cell death in colorectal cancer cells and potentiates the cytotoxicity of 5-fluorouracil. AB - Alpha-lipoic acid (LA), which plays a pivotal role in mitochondrial energy metabolism, is an endogenous dithiol compound with an array of antioxidative functions. It has been shown that LA triggers cell death in tumor cell lines, whereas non-transformed cells are hardly affected. In the present study, we analyzed the cytotoxicity of LA on colorectal cancer (CRC) cells differing in their p53 status and investigated a putative synergistic effect with the anticancer drug 5-fluorouracil (5-FU). We show that LA induces a dose-dependent decrease in cell viability, which was independent of the p53 status as attested in isogenic p53-proficient and p53-deficient cell lines. This effect was largely attributable to cell death induction as revealed by Annexin-V/PI staining. LA treated HCT116 cells underwent caspase-dependent and caspase-independent cell death, which was blocked by the pan-caspase inhibitor zVAD and the RIP-kinase inhibitor Necrostatin-1, respectively. In CaCO-2 and HT29 cells, LA induced caspase-dependent cell demise via activation of caspase-9, caspase-3 and caspase 7 with subsequent PARP-1 cleavage as demonstrated by immunoblot analysis, activity assays and pan-caspase inhibition. Interestingly, LA treatment did neither activate p53 nor induced genotoxic effects as shown by lack of DNA strand breaks and phosphorylation of histone 2AX. Finally, we provide evidence that LA increases the cytotoxic effect induced by the anticancer drug 5-FU as revealed by significantly enhanced cell death rates in HCT116 and CaCO-2 cells. Collectively, these findings demonstrate that LA induces CRC cell death independent of their p53 status and potentiates the cytotoxicity of 5-FU without causing DNA damage on its own, which makes it a candidate for tumor therapy. PMID- 25526926 TI - The prognostic relevance of the mitotic activity index in axillary lymph node negative breast cancer. AB - The aim of the present study is to look at the mitotic activity index (MAI) as a prognostic factor in a prospective population-based cohort of lymph node-negative invasive breast cancer patients. Analyses were based on 2,048 breast-conserving therapies in 1,971 patients, node-negative, and without any form of adjuvant systemic therapy with long-term follow-up. The 15-year distant metastases-free survival (DMFS) for women <=55 years was 88.3 % for low MAI values (<=12) versus 73.4 % for high MAI values (>12); (HR 2.8; 95 % CI 1.8-4.4; p < 0.001). Multivariate analyses for DMFS showed significance for MAI. For MAI and Bloom Richardson grading, by performing a likelihood ratio test, we showed the statistical significance for both. For women >55-years, the MAI was not an independent significant factor. We also confirmed the above findings for disease specific survival. When multi-gene assays are not available, the MAI remains a robust prognostic marker in women younger than 55 years of age with early node negative breast cancer. PMID- 25526925 TI - Epigenetic silencing of microRNA-218 via EZH2-mediated H3K27 trimethylation is involved in malignant transformation of HBE cells induced by cigarette smoke extract. AB - Abnormal expression of miRNAs has been implicated in the pathogenesis of human lung cancers, most of which are attributable to cigarette smoke. The mechanisms of action, however, remain obscure. Here, we report that there are decreased expression of miR-218 and increased expression of EZH2 and H3K27me3 during cigarette smoke extract (CSE)-induced transformation of human bronchial epithelial (HBE) cells. Depletion of EZH2 by siRNA or by the EZH2 inhibitor, 3 deazaneplanocin A, attenuated CSE-induced decreases of miR-218 levels and increases of H3K27me3, which epigenetically controls gene transcription, and BMI1, an oncogene. Furthermore, ChIP assays demonstrated that EZH2 and H3K27me3 are enriched at the miR-218-1 promoter in HBE cells exposed to CSE, indicating that EZH2 mediates epigenetic silencing of miR-218 via histone methylation. In addition, miR-218 directly targeted BMI1, through which miR-218 ablates cancer stem cells (CSCs) self-renewal in transformed HBE cells. In CSE-transformed HBE cells, the protein level of Oct-4 and mRNA levels of CD133 and CD44, indicators of the acquisition of CSC-like properties, were reduced by over-expression of miR 218, and over-expression of miR-218 decreased the malignancy of transformed HBE cells. Thus, we conclude that epigenetic silencing of miR-218 via EZH2-mediated H3K27 trimethylation is involved in the acquisition of CSC-like properties and malignant transformation of HBE cells induced by CSE and thereby contributes to the carcinogenesis of cigarette smoke. PMID- 25526927 TI - Comparison of clinical characteristics between neuromyelitis optica spectrum disorders with and without spinal cord atrophy. AB - BACKGROUND: Spinal cord lesions is one of the predominant characteristics in patients with neuromyelitis optica spectrum disorders (NMOSD). Interestingly, mounting evidence indicates that spinal cord atrophy (SCA) is one of common clinical features in multiple sclerosis (MS) patients, and correlates closely with the neurological disability. However, Clinical studies related to the SCA aspects of NMOSD are still scarce. METHODS: We retrospectively analyzed 185 patients with NMOSD, including 23 patients with SCA and 162 patients without SCA. Data were collected regarding clinical characteristics, laboratory tests, and magnetic resonance imaging findings. RESULTS: 12.4% of patients had SCA in NMOSD. Patients with SCA had a longer disease duration and higher EDSS at clinical onset and last visit. More importantly, SCA patients were more prone to reach disability milestones (EDSS >= 6.0). Bowel or bladder dysfunction, movement disorders, and sensory disturbances symptoms were more common in patients with SCA. ESR and CRP were significantly higher in patients with SCA than those without SCA. Patients with SCA were more frequently complicated with cervical cord lesions. However, the ARR, progression index, seropositive rate of NMO-IgG and OCB were similar in the two groups. Futhermore, LETM did not differ significantly between patients with SCA and without SCA in NMOSD patients. CONCLUSIONS: Patients with SCA might have longer disease duration, more severe clinical disability, and more frequently complicated with cervical spinal cord lesions. SCA might be predictive of the more severe neurologic dysfunction and worse prognosis in NMOSD. Inflammation contributes to the development of SCA in NMOSD. PMID- 25526928 TI - Willingness to pay for health insurance among the elderly population in Germany. AB - INTRODUCTION: All elderly Germans are legally obliged to have health insurance. About 90 % of this population are members of social health insurances (SHI) whose premiums are generally income-related and independent of health status. For most of these members, holding social health insurance is mandatory. As a consequence, genuine information about preferences for health insurance is not available. The aim of this study was therefore to determine and analyze the willingness to pay (WTP) for health insurance among elderly Germans. METHODS: Data from a population based 8-year follow-up of a large cohort study conducted in the Saarland, Germany was used. Participants aged 57-84 years passed a geriatric assessment and responded to a health economic questionnaire. Individuals' WTP was elicited based on a contingent valuation method with a payment card. RESULTS: Mean monthly WTP per capita for health insurance amounted to ?260. This corresponded to about 20% of individual disposable income. Regression analyses showed that WTP increased significantly with higher income, male gender, higher educational level, and privately insured status. In contrast, neither increasing morbidity level nor higher individual health care costs influenced WTP significantly. DISCUSSION: The relatively large extent of average WTP for health insurance indicates that the elderly would probably accept higher contributions to SHI rather than policy efforts to reduce contributions. The identified determinants of WTP might indicate that elderly generally approve the principle of solidarity of the SHI with contributions depending on income rather than morbidity. PMID- 25526929 TI - Cystinosis: renal glomerular and renal tubular function in relation to compliance with cystine-depleting therapy. AB - BACKGROUND AND OBJECTIVES: Nephropathic cystinosis is a lysosomal storage disorder characterized by renal tubular Fanconi syndrome in infancy and glomerular damage leading to renal failure at ~10 years of age. Therapy with the cystine-depleting agent cysteamine postpones renal failure, but the degree of compliance with this treatment has not been correlated with preservation of kidney function. METHODS: We assessed leucocyte cystine depletion by cysteamine and created the composite compliance score that incorporates the extent of leucocyte cystine depletion, as well as duration of cysteamine treatment, into a single integer. Age at renal failure was used to gauge preservation of renal function, and the Fanconi syndrome index (FSI), a measure of aminoaciduria, was used to assess renal tubular Fanconi syndrome. RESULTS: Age at renal failure varied directly and linearly with the composite compliance score (y = 0.3x +8.8; R(2) = 0.61). The slope indicated that for every year of excellent cystine depletion, nearly 1 year of renal function was preserved. Age at renal failure correlated roughly with mean leucocyte cystine level, but not with mean cysteamine dosage. There was no correlation between the FSI and the composite compliance score. CONCLUSIONS: Greater compliance with oral cysteamine therapy yields greater preservation of renal glomerular, but not tubular, function. Oral cysteamine therapy should be given at the maximum tolerated dose, within the recommended limits. PMID- 25526930 TI - Paracoccidioidomycosis in patients with lymphoma and review of published literature. AB - This paper describes four new cases of lymphomas, two Hodgkin lymphomas and two non-Hodgkin lymphomas in patients with paracoccidioidomycosis. All had mycosis diagnosed before lymphomas with Paracoccidioides brasiliensis demonstrated in several lymph nodes, as seen in the disseminated form of the disease. When lymphoma was diagnosed, one patient was under regular paracoccidioidomycosis treatment and in clinic-serological remission for this disease, another was under regular treatment but with clinic-serological mycosis activity, one had abandoned paracoccidioidomycosis treatment 6 years earlier, and the other had not yet received any kind of antifungal drugs. Three patients received treatment for lymphomas with one remaining in remission until now, one achieving tumor remission which relapsed years later, and one having only residual lymphoma in bone marrow for a decade but clinically well. All three experienced paracoccidioidomycosis clinical remission, however, serology became negative just in one. Similar previously described cases were reviewed: five Hodgkin lymphomas, three non-Hodgkin lymphomas, and one described only as "lymphoma" without specifying type; a summary of their findings is presented. Finally, there is also a brief discussion on the possible pathophysiological mechanisms involved in the concomitance of these two disorders. PMID- 25526931 TI - Matrix Production in Large Engineered Cartilage Constructs Is Enhanced by Nutrient Channels and Excess Media Supply. AB - Cartilage tissue engineering is a promising approach to resurfacing osteoarthritic joints. Existing techniques successfully engineer small-sized constructs with native levels of extracellular matrix (glycosaminoglycans [GAG] or collagen). However, a remaining challenge is the growth of large-sized constructs with properties similar to those of small constructs, due to consumption and transport limitations resulting in inadequate nutrient availability within the interior of large constructs. This study employed system specific computational models for estimating glucose requirements of large constructs, with or without channels, to enhance nutrient availability. Based on glucose requirements for matrix synthesis in cartilage constructs, computational simulations were performed to identify the media volume (MV) and the number of nutrient channels (CH) needed to maintain adequate glucose levels within tissue constructs over the 3-day period between media replenishments. In Study 1, the influence of MV (5, 10, 15 mL/construct) and number of nutrient channels (CH: 0, 3, 7, 12 per construct) on glucose availability was investigated computationally for ?10 * 2.34 mm cylindrical constructs. Results showed that the conventionally used MV 5 led to deleterious glucose depletion after only 40 h of culture, and that MV 15 was required to maintain sufficient glucose levels for all channel configurations. Study 2 examined experimentally the validity of these predictions, for tissue constructs cultured for 56 days. Matrix elaboration was highest in MV 15/CH 12 constructs (21.6% +/- 2.4%/ww GAG, 5.5% +/- 0.7%/ww collagen, normalized to wet weight (ww) on day 0), leading to the greatest amount of swelling (3.0 +/- 0.3 times day-0 volume), in contrast to the significantly lower matrix elaboration of conventional culture, MV 5/CH 0 (11.8% +/- 1.6%/ww GAG and 2.5% +/- 0.6%/ww collagen, 1.6 +/- 0.1 times day-0 volume). The computational analyses correctly predicted the need to increase the conventional media levels threefold to support matrix synthesis in large channeled engineered constructs. Results also suggested that more elaborate computational models are needed for accurate predictive tissue engineering simulations, which account for a broader set of nutrients, cell proliferation, matrix synthesis, and swelling of the constructs. PMID- 25526932 TI - Discovery and development of DNA methyltransferase inhibitors using in silico approaches. AB - Multiple strategies have evolved during the past few years to advance epigenetic compounds targeting DNA methyltransferases (DNMTs). Significant progress has been made in HTS, lead optimization and determination of 3D structures of DNMTs. In light of the emerging concept of epi-informatics, computational approaches are employed to accelerate the development of DNMT inhibitors helping to screen chemical databases, mine the DNMT-relevant chemical space, uncover SAR and design focused libraries. Computational methods also synergize with natural-product based drug discovery and drug repurposing. Herein, we survey the latest developments of in silico approaches to advance epigenetic drug and probe discovery targeting DNMTs. PMID- 25526933 TI - Severity of early childhood caries in preschool children attending Al-Ain Dental Centre, United Arab Emirates. AB - AIM: To investigate the severity of and contributing factors of early childhood caries (ECC) in preschool children presented to a paediatric dentistry department in Al-Ain Dental Centre, United Arab Emirates; to study the level of any previous dental care provided to these children and to establish a baseline database for further research and the resources required for serving preschool children in Al Ain (UAE). STUDY DESIGN: Cross-sectional prospective. METHODS: The sample consisted of all healthy children below 5 years of age who presented for their initial visits to the Department of Paediatric Dentistry during a 3-month period. A structured questionnaire was used to obtain information regarding demographic data, feeding history and dietary habits, and oral hygiene practices. The dental examination of children was conducted by the investigator with the help of a mouth mirror and Sirona dental unit light source. RESULTS: One hundred and seventy six children with a mean age of 3.7 years were included in the study and 78 (44 %) children were still bottle-fed on demand at the time of examination. More than half of the children consumed sweets more than once/day and 58 % either never or rarely brushed their teeth. Only one child was given fluoride. Two thirds of children had never visited a dentist before and 63 % had poor oral hygiene. The mean dmft and dmfs scores were 10.9 and 32.1, respectively. The care index was very low (6.4 %). CONCLUSION: The high level of dental decay could be attributed to on-demand bottle feeding, high sweet consumption, poor oral hygiene, lack of use of fluoride prevention and lack of regular dental visits. There is a great need for prospective studies and community preventive programmes to solve the continuing problem of ECC. PMID- 25526934 TI - Long-term outcome of oral health in patients with early childhood caries treated under general anaesthesia. AB - AIM: Reports on the long-term outcome of oral health in children with early childhood caries (ECC) treated under general anaesthesia (GA) are lacking. The aim of this study was to assess oral health in adolescents with history of ECC treated under GA at young age. METHODS: A total of 98 children treated under GA because of ECC at the University Hospitals of Leuven (Belgium) (1995-1996) were included in a follow-up study. Information was collected at baseline (GA) and 1 and 12 years after treatment. The children were examined clinically [oral hygiene, caries experience (CE)] and oral health behaviour was recorded using a questionnaire. RESULTS: At second recall, 46 (48 %) adolescents could be contacted; 21 of these attended the dental clinic. Their mean age was 17.5 years (SD 1.4) with mean time span since GA of 13.1 years (SD 0.8); 91 % presented with CE. Mean D3MFT was 8.2 (SD 5.6) (median 7; range 0-18); 71 % showed untreated decay. A considerable gap between knowledge of content and actual use of fluoride in toothpaste was evident. CONCLUSIONS: Individuals with a history of ECC remained at high risk for caries in their permanent dentition. There is a need for well-designed long-term studies to explore associated factors. PMID- 25526935 TI - Duration of residence and psychotropic drug use in recently settled refugees in Sweden--a register-based study. AB - INTRODUCTION: Recently settled refugee populations have consistently been reported to have high rates of mental health problems, particularly Post traumatic stress disorder, depression, and anxiety disorders. The aim of this study was to investigate psychotropic drug use among young adult refugees according to duration of residence during the first 10 years in Sweden. METHODS: Cross-sectional register study of a national cohort of 43 403 refugees and their families (23-35 years old) from Iraq, Iran, Eritrea, Ethiopia, Somalia and Afghanistan and a comparison population of 1.1 million Swedish-born residents. Logistic regression was used to assess the association between duration of residence in Sweden and the dispensing of at least one psychotropic medication during 2009 in four categories (any drug, neuroleptics, antidepressants and anxiolytics/hypnotics), adjusting for age, gender and domicile. RESULTS: Rates of dispensed psychotropic drugs among recently settled refugees were low, compared to the Swedish-born, with an increase with duration of residence. For refugee men and women from Iraq/Iran who had resided for 0-3 years the adjusted ORs compared to Swedish natives, were 0.83 (95% CI 0.77-0.90) and 0.48 (0.44-0.53) respectively; for men and women from the Horn of Africa the ORs were 0.50 (0.42 0.61) and 0.36 (0.30-0.41) respectively. After 7-10 years of residence, the ORs in these refugee groups approached the Swedish comparison population. Refugees from Afghanistan presented ORs similar to the Swedish-born, with no consistent trend by duration of residence. Women from the Horn of Africa and Iraq/Iran consumed less psychotropic drugs compared with men from these regions of origin, relative to the Swedish-born (p < 0.01). The ORs for dispensed neuroleptics were similar between the different refugee study groups, while the ORs for dispensed antidepressants differed fourfold between the group with the lowest (Horn of Africa) and the highest (Afghanistan). CONCLUSION: The rates of dispensed psychotropic drugs in the newly settled refugee populations in this study were low, with an increase with longer duration of residence. This pattern suggests barriers to access mental health care. Interventions that can lower these barriers are needed to enable newly settled refugees to access mental health care on equal terms with the native population. PMID- 25526936 TI - Why repetitive transcranial magnetic stimulation should be available for treatment resistant depression. PMID- 25526937 TI - Surveillance of hyponatremia in psychogenic polydipsia. PMID- 25526938 TI - Psychotic disorders in DSM-5: a paradigm shift? PMID- 25526939 TI - The role of Transcranial Magnetic Stimulation in treatment resistant depression. PMID- 25526940 TI - Recovery Assessment Scale - Domains and Stages (RAS-DS): Its feasibility and outcome measurement capacity. AB - OBJECTIVE: A self-report instrument of mental health recovery is needed both to facilitate collaborative, recovery-oriented practice and measure recovery-focused outcomes. The Recovery Assessment Scale - Domains and Stages (RAS-DS) has been developed to simultaneously fulfill these goals. The aim of this study was to test the feasibility and measurement properties of the RAS-DS. METHOD: Feasibility was examined by 58 consumer-staff pairs volunteering from 3 non government organisations. Consumers completed the RAS-DS, discussed it with staff, and then both completed Usefulness Questionnaires. The psychometric properties were examined using Rasch analysis with the data from these consumer participants and from additional participants recruited from two Partners in Recovery programs (N=324). RESULTS: Over 70% of consumers reported taking 15 minutes or less to complete the RAS-DS and rated the instrument as easy or very easy to use. Qualitative data from both consumers and staff indicated that, for most, the RAS-DS was an easy to use, meaningful resource that facilitated shared understandings and collaborative goal setting. However, for a very small number of consumers, the instrument was too confronting and hard to use. Rasch analysis demonstrated evidence for excellent internal reliability and validity. Raw scores were highly correlated with Rasch-generated overall scores and thus no transformation is required, easing use for clinicians. Preliminary evidence for sensitivity to change was demonstrated. CONCLUSIONS: The results provide evidence of the feasibility and psychometric strengths of the RAS-DS. Although further research is required, the RAS-DS shows promise as a potential addition to the national suite of routine outcome measures. PMID- 25526941 TI - Postpartum psychosis: a valuable misnomer. PMID- 25526942 TI - Should clozapine be available to people with early schizophrenia and suicidal ideation? PMID- 25526943 TI - How safe is repetitive Transcranial Magnetic Stimulation? PMID- 25526944 TI - Mental illness and housing outcomes among a sample of homeless men in an Australian urban centre. AB - OBJECTIVE: The over-representation of mental illness among homeless people across the globe is well documented. However, there is a dearth of Australian literature on the mental health needs of homeless individuals. Furthermore, longitudinal research examining the factors that contribute to better housing outcomes among this population is sparse. The aim of this research is to describe the mental illness profile of a sample of homeless men in an Australian urban centre (in Sydney) and examine the factors associated with better housing outcomes at 12 month follow-up. METHODS: A longitudinal survey was administered to 253 homeless men who were involved in the Michael Project: a 3-year initiative which combined existing accommodation support services with assertive case management and access to coordinated additional specialist allied health and support services. A total of 107 participants were followed up 12 months later. The survey examined the demographics of the sample and lifetime mental disorder diagnoses, and also included psychological screeners for current substance use and dependence, psychological distress, psychosis, and post-traumatic stress. RESULTS: Consistent with existing literature, the prevalence of mental illness was significantly greater amongst this sample than the general Australian population. However, mental illness presentation was not associated with housing situation at 12-month follow-up. Instead, type of support service at baseline was the best predictor of housing outcome, wherein participants who received short to medium-term accommodation and support were significantly more likely to be housed in stable, long-term housing at the 12-month follow-up than participants who received outreach or emergency accommodation support. CONCLUSIONS: This study provides evidence to support an innovative support model for homeless people in Australia and contributes to the limited Australian research on mental illness in this population. PMID- 25526945 TI - Clinical outcomes of Descemet membrane endothelial keratoplasty using eye bank prepared tissues. AB - PURPOSE: To investigate the outcomes of Descemet membrane endothelial keratoplasty (DMEK) using prestripped donor tissue prepared by an eye bank. DESIGN: Retrospective, noncomparative case series. METHODS: This retrospective, noncomparative, observational study investigated the outcomes of the first 40 consecutive DMEK procedures performed by a single surgeon using prestripped tissues prepared by a single eye bank during the period September 17, 2013 to July 1, 2014. A new technique to unfold the Descemet membrane grafts using a single cannula was described. Medical records were reviewed to obtain the prestripped and poststripped endothelial cell counts (ECC), postoperative ECC, visual acuity measurements, and complications. RESULTS: Of the 43 prestripped tissues received, 40 were transplanted. The leading indications for DMEK were Fuchs endothelial corneal dystrophy (n = 28) and bullous keratopathy (n = 11). Nine DMEK procedures were performed in combination with phacoemulsification and posterior chamber intraocular lens implantation. Six patients had undergone prior glaucoma surgeries. The mean follow-up duration was 5.3 months (range, 1 week to 11 months). Preoperative spectacle-corrected visual acuity was <=20/200 in 8 patients (20%) and <=20/40 in 37 patients (92.5%). Primary graft failure occurred in the first case. Thirty-eight patients had improved vision postoperatively. Among the 39 patients who had successful DMEK, postoperative BCVA was >=20/20 in 20 patients (51.2%), >=20/25 in 30 patients (76.9%), and >=20/40 in 34 patients (87.2%) by the last follow-up. There was no secondary graft failure. Rejection occurred in 2 patients because of self-discontinuation of topical corticosteroid. The most common complication was partial detachment requiring air injection (11 of 40 patients; 27.5%). Mean ECC loss after stripping of Descemet membrane was 3.9% (range, 6.5% gain to 14.5% loss). During the first 6 months after transplantation, the average ECC loss was 30.5% (range, 3.8%-67.4% loss). CONCLUSIONS: DMEK using eye bank-prepared tissue achieved outcomes comparable to those reported for DMEK using surgeon-prepared tissue. PMID- 25526947 TI - Descemet membrane endothelial keratoplasty postoperative year 1 endothelial cell counts. AB - PURPOSE: To report endothelial cell counts (ECC) in patients 1 year after Descemet membrane endothelial keratoplasty (DMEK) and suggest surgical techniques that may minimize intraoperative endothelial cell loss. DESIGN: Retrospective, observational case series. METHODS: This is a retrospective case series of 125 consecutive cases with 1 year of postoperative follow-up. Eight-millimeter DMEK grafts were prepared at a single institution via the submerged cornea, using backgrounds away technique. Grafts were introduced through a 2.4-mm incision and a "no-touch" technique was used to position them. RESULTS: The mean preoperative donor ECC was 2740 +/- 210 (cells/mm(2)). Mean postoperative year 1 ECC was 2210 +/- 550 for an ECC loss of 19% +/- 10%. Rebubbling was performed in 5% of cases. CONCLUSION: Postoperative year 1 endothelial cell counts in DMEK can equal and even surpass those of Descemet stripping automated endothelial cell keratoplasty (DSAEK) or even penetrating keratoplasty. Given reported decreased rejection rates in DMEK, these patients may have notably superior ECC 5 and 10 years out from surgery compared to if they had undergone DSAEK. PMID- 25526946 TI - Subconjunctival sirolimus in the treatment of autoimmune non-necrotizing anterior scleritis: results of a phase I/II clinical trial. AB - PURPOSE: To investigate the safety, tolerability and efficacy of subconjunctival sirolimus injections as a treatment for active, autoimmune, non-necrotizing anterior scleritis. DESIGN: Phase I/II, single-center, open-label, nonrandomized, prospective pilot study. METHODS: Five participants with active, autoimmune, non necrotizing anterior scleritis with scleral inflammatory grade of >=1+ in at least 1 quadrant with a history of flares were enrolled. A baseline injection was given, with the primary outcome measure of at least a 2-step reduction or reduction to grade zero in the study eye by 8 weeks. Secondary outcomes included changes in visual acuity and intraocular pressure, ability to taper concomitant immunosuppressive regimen, and number of participants who experienced a disease flare requiring reinjection. Safety outcomes included the number and severity of systemic and ocular toxicities, and vision loss >=15 ETDRS letters. The study included 6 visits over 4 months with an extension phase to 1 year for participants who met the primary outcome. RESULTS: All participants (N = 5, 100%; 95% CI [0.60, 1.00]) met the primary outcome in the study eye by the week 8 visit. There was no significant change in mean visual acuity or intraocular pressure. Three out of 5 patients (60%) experienced flares requiring reinjection. No systemic toxicities were observed. Two participants (40%) experienced a localized sterile inflammatory reaction at the site of the injection, which resolved without complication. CONCLUSIONS: Subconjunctival sirolimus leads to a short-term reduction in scleral inflammation, though relapses requiring reinjection do occur. There were no serious adverse events, though a local sterile conjunctival inflammatory reaction was observed. PMID- 25526948 TI - Relationship of central choroidal thickness with age-related macular degeneration status. AB - PURPOSE: To compare choroidal thickness in patients with intermediate or advanced age-related macular degeneration (AMD) and control subjects using enhanced-depth imaging optical coherence tomography (EDI-OCT). DESIGN: Retrospective cross sectional study of 325 eyes from 164 subjects who underwent EDI-OCT for the Age Related Eye Disease Study (AREDS) 2 Ancillary Spectral Domain OCT study. METHODS: Choroidal thickness was measured by semi-automated segmentation of EDI-OCT images from 1.5 mm nasal to 1.5 mm temporal to the fovea. Multivariate linear regression was used to evaluate the association of subfoveal choroidal thickness or average choroidal thickness across the central 3-mm segment with systemic and ocular variables. Choroidal thickness measurements were compared between eyes with no AMD (n = 154) (ie, controls), intermediate AMD (n = 109), and advanced AMD (n = 62). RESULTS: Both subfoveal and average choroidal thicknesses were associated with age (P < .001) and refractive error (P < .001), but not other variables tested. Mean average choroidal thickness was significantly reduced in advanced AMD as compared with control eyes (P = .008), with no significant difference between advanced and intermediate AMD eyes (P = .152) or between intermediate AMD and control eyes (P = .098). Choroidal thinning was also noted from 1.5 mm nasal to 1.5 mm temporal to the fovea when comparing advanced AMD with control eyes (P < .05 at all 0.5 mm interval locations). After adjustment for age and refractive error, however, there was no significant difference in subfoveal (P = .675) or average choroidal thickness (P = .746) across all 3 groups. CONCLUSIONS: When adjusted for age and refractive error, central choroidal thickness may not be significantly influenced by AMD status based on AREDS categorization. PMID- 25526949 TI - Symptomatic Exposures Among California Inmates 2011-2013. AB - Prisoners have a high prevalence of substance misuse and abuse, but few studies have examined symptomatic exposures among incarcerated populations. We sought to further characterize the nature of these exposures among this population using the California Poison Control System data. Keyword searches identified inmate cases in 2011-2013 for patients 20+ years old exposed to a single substance and taken to hospital from jail, prison, or police custody. Comparisons were made with non-inmate cases during the same period, using similar limitations. Body stuffers and body packers were analyzed as a subgroup. Seven hundred four inmate cases were compared to 106,260 non-inmate cases. Inmates were more likely to be younger, male, and to have engaged in drug misuse or abuse. They most commonly ingested methamphetamine, heroin, acetaminophen, and anticonvulsants. Inmates were more likely to receive activated charcoal (OR 9.87, 8.20-11.88), whole bowel irrigation (OR 44.50, 33.83-58.54), undergo endotracheal intubation (OR 4.09, 2.91-5.73), and to experience a major clinical outcome or death (OR 1.41, 1.05 1.89). When body stuffers and packers were removed, clinical findings were similar, though the odds of a major outcome or death became statistically non significant. Body stuffers and body packers primarily used methamphetamine and heroin, and compared with other inmates had significantly higher odds of both adverse clinical effects and poor outcome. This large series provides a profile of symptomatic exposures among inmates, a little-studied population. The potential for high morbidity among body stuffers and packers suggests that a high index of suspicion of such ingestions be maintained when evaluating patients prior to incarceration. PMID- 25526950 TI - Therapeutic effect of intratumoral injections of dendritic cells for locally recurrent gastric cancer: a case report. AB - An 80-year-old man with a history of gastric cancer and pulmonary emphysema underwent a distal gastrectomy for gastric cancer in 1997. In 2010, an endoscopic examination revealed a depressed-type lesion at the oral side of the anastomosis, which was diagnosed as signet-ring adenocarcinoma. Surgical management was considered, but was rejected because of obstructive and restrictive respiratory events. Chemotherapy was terminated because of adverse events. Endoscopy was used to administer intratumoral injections of dendritic cells (DCs) targeting synthesized peptides of Wilms tumor 1 (WT1) and mucin 1, cell-surface associated (MUC1). An immunohistochemical analysis of the tumor samples indicated positivity for WT1 and MUC1. One month after seven cycles of DC had been administered (between November 2010 and April 2011), no suspicious lesions were evident, and his biopsy results were normal. The patient has been in remission for 30 months. Intratumoral injections of DCs showed therapeutic effects in this patient, who could not undergo endoscopic submucosal dissection or surgery. PMID- 25526951 TI - Oral granulated Chinese herbal medicine (YXBCM01) plus topical calcipotriol for psoriasis vulgaris: study protocol for a double-blind, randomized placebo controlled trial. AB - BACKGROUND: Probably related to immune dysfunction, psoriasis vulgaris is a chronic, painful, disfiguring and disabling dermatological disease, carrying an increased risk of serious comorbidities. Current conventional therapies can be costly, show risks of side effects and have limited efficacy, with relapse common on treatment cessation. Chinese herbal medicine is effective in treating psoriasis vulgaris. However, any benefit of adding Chinese herbal medicine to conventional treatments when treating psoriasis vulgaris is yet to be determined. METHODS/DESIGN: This is a pilot randomized, placebo controlled, double-blinded trial. The pilot is primarily to determine the feasibility of undertaking a full size randomized trial. Thirty participants with psoriasis vulgaris and Psoriasis Area Severity Index (PASI) scores >= 7 and <= 12 will be included. Participants will be randomized (in a 1:1 ratio) to receive oral granulated Chinese herbal medicine YXBCM01 plus topical calcipotriol 0.005% or oral YXBCM01 placebo plus topical calcipotriol 0.005% treatment for 12 weeks, with a 12-week follow-up phase. The Chinese herbal medicine or placebo will be administered orally as dissolvable granules. The primary outcome measure will be PASI change (%) from baseline to the end of treatment phase. Secondary outcomes will include safety, key psoriasis-related cytokine changes (for example, IL12, IL17 and IL 23) during the entire trial and symptom relapse rates at the end of the follow-up phase. DISCUSSION: The study will evaluate the feasibility of a randomized controlled trial investigating combined conventional and Chinese herbal medicine therapy for psoriasis vulgaris. The ingredients of YXBCM01 were selected based on literature, the expert opinion on herbal medicine and pre-clinical evidence, for instance Chinese herbal medicine possesses anti-inflammatory or antiproliferative properties. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614000493640. PMID- 25526952 TI - Brief report: Anomalous neural deactivations and functional connectivity during receptive language in autism spectrum disorder: a functional MRI study. AB - Neural mechanisms that underlie language disability in autism spectrum disorder (ASD) have been associated with reduced excitatory processes observed as positive blood oxygen level dependent (BOLD) responses. However, negative BOLD responses (NBR) associated with language and inhibitory processes have been less studied in ASD. In this study, functional magnetic resonance imaging showed that the NBR in ASD participants was reduced during passive listening to spoken narratives compared to control participants. Further, functional connectivity between the superior temporal gyrus and regions that exhibited a NBR during receptive language in control participants was increased in ASD participants. These findings extend models for receptive language disability in ASD to include anomalous neural deactivations and connectivity consistent with reduced or poorly modulated inhibitory processes. PMID- 25526953 TI - Brief Report: Phenotypic Differences and their Relationship to Paternal Age and Gender in Autism Spectrum Disorder. AB - Two modes of inheritance have been proposed in autism spectrum disorder, transmission though pre-existing variants and de novo mutations. Different modes may lead to different symptom expressions in affected individuals. De novo mutations become more likely with advancing paternal age suggesting that paternal age may predict phenotypic differences. To test this possibility we measured IQ, adaptive behavior, and autistic symptoms in 830 probands from simplex families. We conducted multiple linear regression analysis to estimate the predictive value of paternal age, maternal age, and gender on behavioral measures and IQ. We found a differential effect of parental age and sex on repetitive and restricted behaviors. Findings suggest effects of paternal age on phenotypic differences in simplex families with ASD. PMID- 25526954 TI - What Explains Differences in Men's and Women's Production? : Determinants of Gendered Foraging Inequalities among Martu. AB - Researchers commonly use long-term average production inequalities to characterize cross-cultural patterns in foraging divisions of labor, but little is known about how the strategies of individuals shape such inequalities. Here, we explore the factors that lead to daily variation in how much men produce relative to women among Martu, contemporary foragers of the Western Desert of Australia. We analyze variation in foraging decisions on temporary foraging camps and find that the percentage of total camp production provided by each gender varies primarily as a function of men's average bout successes with large, mobile prey. When men target large prey, either their success leads to a large proportional contribution to the daily harvest, or their failure results in no contribution. When both men and women target small reliable prey, production inequalities by gender are minimized. These results suggest that production inequalities among Martu emerge from stochastic variation in men's foraging success on large prey measured against the backdrop of women's consistent production of small, low-variance resources. PMID- 25526955 TI - Serial monogamy as polygyny or polyandry? : marriage in the tanzanian pimbwe. AB - Applications of sexual selection theory to humans lead us to expect that because of mammalian sex differences in obligate parental investment there will be gender differences in fitness variances, and males will benefit more than females from multiple mates. Recent theoretical work in behavioral ecology suggests reality is more complex. In this paper, focused on humans, predictions are derived from conventional parental investment theory regarding expected outcomes associated with serial monogamy and are tested with new data from a postreproductive cohort of men and women in a primarily horticultural population in western Tanzania (Pimbwe). Several predictions derived from the view that serial monogamy is a reproductive strategy from which males benefit are not supported. Furthermore, Pimbwe women are the primary beneficiaries of multiple marriages. The implications for applications of sexual selection theory to humans are discussed, in particular the fact that in some populations women lead sexual and reproductive lives that are very different from those derived from a simple Bateman-Trivers model. PMID- 25526956 TI - A bioeconomic approach to marriage and the sexual division of labor. AB - Children may be viewed as public goods whereby both parents receive equal genetic benefits yet one parent often invests more heavily than the other. We introduce a microeconomic framework for understanding household investment decisions to address questions concerning conflicts of interest over types and amount of work effort among married men and women. Although gains and costs of marriage may not be spread equally among marriage partners, marriage is still a favorable, efficient outcome under a wide range of conditions. This bioeconomic framework subsumes both cooperative and conflictive views on the sexual division of labor. We test hypotheses concerning marriage markets, assortative mating, and men's labor motivations among Tsimane forager-horticulturalists of Bolivia and find that: (1) men and women both value work effort in marital partners, (2) marital labor contributions are complementary, (3) work effort is correlated between spouses, (4) total production is correlated with total reproduction, and (5) better hunters have higher fitness gains within marital unions. PMID- 25526957 TI - Demographic and social predictors of intimate partner violence in Colombia : a dyadic power perspective. AB - Intimate partner violence (IPV) is a major health and human rights problem globally. However, empirical findings on the predictors of IPV cross-culturally are highly inconsistent, and the theory of IPV is underdeveloped. We propose a new analytical framework based on cooperative game theory in which IPV is a function of the power relations of the dyadic relationship, not simply the actors involved. Using data from the 2005 Colombian Demographic and Health Survey, we test the hypothesis that IPV is predicted by large asymmetries in dyadic power using a hierarchical generalized linear model. Results suggest that education, urban residence, age at sexual debut, whether the woman has other sexual partners, and the age difference between spouses have strong effects on the log odds of a woman experiencing IPV. Cooperative game theory and social network analysis offer a general approach to the problem of intimate partner interactions which can be applied broadly cross-culturally. PMID- 25526959 TI - Induction of resistance to S. aureus in an environmental marine biofilm grown in Sydney Harbor, NSW, Australia. AB - The study of environmental biofilms is complicated by the difficulty of working with them under lab conditions. Nonetheless, knowledge of cellular activity and interactions within environmental biofilms could lead to novel biomedical applications. To address this problem we previously proposed a new technique for inducing resistance to Staphylococcus aureus in an intact environmental biofilm. In the current follow-up study we applied the new technique in a biogeographically distinct environment using a different strain of S. aureus. The proposed technique for inducing resistance to S. aureus in an environmental biofilm involves growing the environmental biofilms over several days in media reflecting their natural habitat on agar that contains spent culture supernatant from S. aureus over-night culture. We found in this second study that it was possible to induce resistance to S. aureus in an environmental biofilm from a biogeographically distinct environment, though not in the same way as we had previously observed. Environmental consortia from Sydney Harbor, Australia display an ability to inhibit biofilm formation by S. aureus; only in the case where the environmental biofilms were pretreated with UV radiation was there a difference in activity between environmental consortia grown on plain agar, and that grown on S. aureus agar. Application of the new technique in the current study also differs in that significant killing of cells within an established S. aureus biofilm by environmental consortia grown on S. aureus agar was possible. PMID- 25526960 TI - A Descriptive Analysis of Incidents Reported by Community Aged Care Workers. AB - Little is known about the types of incidents that occur to aged care clients in the community. This limits the development of effective strategies to improve client safety. The objective of the study was to present a profile of incidents reported in Australian community aged care settings. All incident reports made by community care workers employed by one of the largest community aged care provider organizations in Australia during the period November 1, 2012, to August 8, 2013, were analyzed. A total of 356 reports were analyzed, corresponding to a 7.5% incidence rate per client year. Falls and medication incidents were the most prevalent incident types. Clients receiving high-level care and those who attended day therapy centers had the highest rate of incidents with 14% to 20% of these clients having a reported incident. The incident profile indicates that clients on higher levels of care had higher incident rates. Incident data represent an opportunity to improve client safety in community aged care. PMID- 25526958 TI - Fundamental Dimensions of Environmental Risk : The Impact of Harsh versus Unpredictable Environments on the Evolution and Development of Life History Strategies. AB - The current paper synthesizes theory and data from the field of life history (LH) evolution to advance a new developmental theory of variation in human LH strategies. The theory posits that clusters of correlated LH traits (e.g., timing of puberty, age at sexual debut and first birth, parental investment strategies) lie on a slow-to-fast continuum; that harshness (externally caused levels of morbidity-mortality) and unpredictability (spatial-temporal variation in harshness) are the most fundamental environmental influences on the evolution and development of LH strategies; and that these influences depend on population densities and related levels of intraspecific competition and resource scarcity, on age schedules of mortality, on the sensitivity of morbidity-mortality to the organism's resource-allocation decisions, and on the extent to which environmental fluctuations affect individuals versus populations over short versus long timescales. These interrelated factors operate at evolutionary and developmental levels and should be distinguished because they exert distinctive effects on LH traits and are hierarchically operative in terms of primacy of influence. Although converging lines of evidence support core assumptions of the theory, many questions remain unanswered. This review demonstrates the value of applying a multilevel evolutionary-developmental approach to the analysis of a central feature of human phenotypic variation: LH strategy. PMID- 25526961 TI - Genetic influence of dopamine receptor, dopamine transporter, and nicotine metabolism on smoking cessation and nicotine dependence in a Japanese population. AB - BACKGROUND: This study investigated whether polymorphisms of the ankyrin repeat and kinase domain containing 1 gene (ANKK1), which is adjacent to the dopamine D2 receptor gene (DRD2), and the dopamine transporter (SLC6A3) and cytochrome P450 2A6 (CYP2A6) genes influence smoking cessation and nicotine dependence in a Japanese population. In 96 current and former smokers, genotyping frequencies for the ANKK1/DRD2 TaqIA, SLC6A3 VNTR, and CYP2A6 polymorphisms were subjected to chi square analysis, and regression analyses were used to determine the association of the genotypes of current smokers with a Heavy Smoking Index, in addition to evaluating the effect of the subjects' smoking history on the association. RESULTS: Genotyping results suggested that nicotine dependence among current smokers homozygous for the SLC6A3 10r allele was lower than that of smokers carrying the minor alleles, and that the CYP2A6 polymorphism might mediate this association. Furthermore, the age at which current smokers began smoking might moderate the association between their genetic polymorphisms and nicotine dependence. CONCLUSIONS: This study provides preliminary findings on the influence of genetic variants on the smoking phenotypes in a Japanese population. PMID- 25526962 TI - Comparative proteomic analysis reveals the role of hydrogen sulfide in the adaptation of the alpine plant Lamiophlomis rotata to altitude gradient in the Northern Tibetan Plateau. AB - MAIN CONCLUSION: We found the novel role of hydrogen sulfide in the adaptation of the alpine plant to altitude gradient in the Northern Tibetan Plateau. Alpine plants have developed strategies to survive the extremely cold conditions prevailing at high altitudes; however, the mechanism underlying the evolution of these strategies remains unknown. Hydrogen sulfide (H2S) is an essential messenger that enhances plant tolerance to environmental stress; however, its role in alpine plant adaptation to environmental stress has not been reported until now. In this work, we conducted a comparative proteomics analysis to investigate the dynamic patterns of protein expression in Lamiophlomis rotata plants grown at three different altitudes. We identified and annotated 83 differentially expressed proteins. We found that the levels and enzyme activities of proteins involved in H2S biosynthesis markedly increased at higher altitudes, and that H2S accumulation increased. Exogenous H2S application increased antioxidant enzyme activity, which reduced ROS (reactive oxygen species) damage, and GSNOR (S-nitrosoglutathione reductase) activity, which reduced RNS (reactive nitrogen species) damage, and activated the downstream defense response, resulting in protein degradation and proline and sugar accumulation. However, such defense responses could be reversed by applying H2S biosynthesis inhibitors. Based on these findings, we conclude that L. rotata uses multiple strategies to adapt to the alpine stress environment and that H2S plays a central role during this process. PMID- 25526963 TI - Uptake kinetics and translocation of selenite and selenate as affected by iron plaque on root surfaces of rice seedlings. AB - MAIN CONCLUSION: Iron plaque on root surfaces greatly influenced selenium uptake and played different roles in selenite and selenate uptake. Iron plaque commonly forms on rice root surfaces under flooded conditions, but little is known about the relationship between iron plaque and selenium (Se) accumulation. Here, we investigate the effects of iron plaque on Se uptake by and translocation within rice (Oryza sativa) seedlings, and the kinetics of selenite and selenate influx into rice roots (with or without iron plaque) were determined in short-term (30 min) experiments. Rice seedlings were planted in nutrient solutions containing different levels of ferrous ion for 3 days and then transplanted into nutrient solutions with selenite or selenate. Se concentrations in iron plaque were positively associated with the amounts of iron plaque in both selenite and selenate treatments and iron plaque had a higher affinity for selenite than selenate. Results showed that iron plaque on root surfaces greatly influenced Se uptake and played different roles in selenite and selenate uptake. The selenite and selenate uptake kinetics results demonstrated that the presence of iron plaque enhanced selenite uptake, but decreased selenate uptake. In addition, root Se concentrations increased with the increasing amounts of iron plaque, but Se translocation from roots to shoots was reduced with the increasing amounts of iron plaque in the +selenite treatment. Iron plaque significantly influenced selenite uptake and might act as a pool to selenite accumulation in rice plants. However, iron plaque had no significant effect on selenate uptake or even as a barrier to selenate uptake. PMID- 25526964 TI - Effect of cryoprotectant on optimal cooling rate during cryopreservation. AB - The effect of initial Me2SO concentration (cgi) inside the cell lines on the optimal cooling rate is studied using a well established water transport model. A correlation formula is proposed for the determination of optimal cooling rate of freezing biological systems which depends on the cell activation energy, reference membrane permeability, initial Me2SO concentration, and the cell geometrical parameters. Here, the optimal cooling rate is defined as the highest cooling rate for which amount of trapped water inside the cell is equal to 5% of the initial cell water content at an end temperature of -40 degrees C. It is found that the optimal cooling rate varies linearly with the reference membrane permeability and the ratio of surface area for water transport to the initial volume of intracellular water. The developed correlation is valid for cell activation energy between 20 and 80 kcal/mole and initial Me2SO concentration between 0.1 and 1.3M. It has been observed that the optimal cooling rate does not follow a single trend for the studied initial concentration of Me2SO. However, three regions are identified within which, the variation is almost similar; the three regions are: 0.1 M <= cgi <= 0.7, 0.7 M <= cgi <= 0.9, and 0.9 M <= cgi <= 1.3M. It has been shown that the predicted optimal cooling rate is in a very good agreement with the published experimental/numerical prediction. PMID- 25526966 TI - Monostotic fibrous dysplasia in the proximal tibial epiphysis: a case report. AB - INTRODUCTION: Fibrous dysplasia is one of many well-known disorders in which there is a defect in the remodeling process of immature bone to mature into lamellar bone, and it often exists in metaphyseal and diaphyseal parts of the long bone. In this report, we describe a rare case where fibrous dysplasia was found only in the proximal part of the epiphysis of the tibia without other bony lesions. CASE PRESENTATION: A 14-year-old Asian girl was referred to our hospital after slipping down with pain on the left knee. A radiograph showed an abnormal finding of a central radiolucent lesion with a marginal sclerotic border near the proximal tibial spine. A magnetic resonance image showed the lesion at low signal intensity on a T1-weighted image and at high signal intensity on a T2-weighted image. The biopsy results led us to conclude that the lesion was a fibrous dysplasia. CONCLUSION: If an abnormal lesion on the epiphysis, especially in long bones, is detected on a radiograph, several differential diagnoses can be made. Although fibrous dysplasia is usually not encountered as an epiphyseal lesion, it is important to incorporate all the clinical, radiographic and pathologic features to diagnose monostotic fibrous dysplasia when the lesion is located at the epiphyseal location. PMID- 25526965 TI - Gene expression and protein secretion during human mesenchymal cell differentiation into adipogenic cells. AB - BACKGROUND: Mesenchymal stromal cells (MSC) can be obtained from potentially any tissue from the human body, but cells purified from different sources are undoubtedly different, and for each medical application, the MSC with the best regenerative potential should be chosen. RESULTS: Bone marrow-derived mesenchymal stromal cells (BM-MSC), adipose tissue-derived mesenchymal stromal cells (AT-MSC) and Wharton's Jelly-derived mesenchymal stromal cells (WJ-MSC) were isolated from human tissues and were cultured under differentiation media supplemented with fetal bovine serum. We quantified the expression of stem cell and adipocyte genetic markers using quantitative real time PCR, as well as the secretion of cytokines, extracellular matrix components and growth factors using Luminex and ELISA. All three MSC differentiated into adipogenic cells. AT-MSC showed the highest shift in ADIPOQ, CEBPA and PPARG mRNA expression. BM-MSC kept high expression levels of stem-cell markers SOX2 and POU5F1. WJ-MSC showed the lowest increase in mRNA expression when cells were induced to differentiate into adipocytes. Regarding protein secretion, adipocyte-like cells generated from WJ MSC secreted the highest chemokine levels. AT-MSC-derived adipocyte-like cells secreted the lowest cytokine amounts and the highest quantity of collagen types I and III. Adipocyte-like cells obtained from BM-MSC secreted high amounts of most angiogenic factors, growth factors TGF-beta1 and TGF-beta2, collagens type II and IV, heparan sulfate, laminin and aggrecan. CONCLUSION: Mesenchymal stromal cells purified from different tissues have a different behavior when induced to differentiate into adipocyte-like cells. PMID- 25526967 TI - Iron bioavailability from commercially available iron supplements. AB - PURPOSE: Iron deficiency anaemia (IDA) is a global public health problem. Treatment with the standard of care ferrous iron salts may be poorly tolerated, leading to non-compliance and ineffective correction of IDA. Employing supplements with higher bioavailability might permit lower doses of iron to be used with fewer side effects, thus improving treatment efficacy. Here, we compared the iron bioavailability of ferrous sulphate tablets with alternative commercial iron products, including three liquid-based supplements. METHODS: Iron bioavailability was measured using Caco-2 cells with ferritin formation as a surrogate marker for iron uptake. Statistical analysis was performed using one way ANOVA followed by either Dunnett's or Tukey's multiple comparisons tests. RESULTS: Spatone Apple((r)) (a naturally iron-rich mineral water with added ascorbate) and Iron Vital F((r)) (a synthetic liquid iron supplement) had the highest iron bioavailability. There was no statistical difference between iron uptake from ferrous sulphate tablets, Spatone((r)) (naturally iron-rich mineral water alone) and Pregnacare Original((r)) (a multimineral/multivitamin tablet). CONCLUSION: In our in vitro model, naturally iron-rich mineral waters and synthetic liquid iron formulations have equivalent or better bioavailability compared with ferrous iron sulphate tablets. If these results are confirmed in vivo, this would mean that at-risk groups of IDA could be offered a greater choice of more bioavailable and potentially better tolerated iron preparations. PMID- 25526968 TI - Gestational dietary patterns are not associated with blood pressure changes during pregnancy and early postpartum in a Brazilian prospective cohort. AB - PURPOSE: To identify gestational dietary patterns and evaluate the association between these patterns and the blood pressure (BP) rate of change during pregnancy and the postpartum. METHODS: Prospective cohort study composed of 191 healthy pregnant women. Systolic BP (SBP) and diastolic BP (DBP) were obtained at the 5th-13th, 20th-26th, 30th-36th gestational weeks, and with 30-45 days postpartum. A food frequency questionnaire administered at the 30th-36th gestational week was used to measure dietary intake during pregnancy. Principal component analysis was performed to identify the dietary patterns. A longitudinal linear mixed-effects regression model was used to evaluate the association between the dietary patterns and BP (adjusted for time elapsed after conception and the women's age, education, parity, body mass index and total energy intake). RESULTS: Three gestational dietary patterns were identified: healthy, common Brazilian and processed. SBP/DBP mean values (SD) were 110.1 (9.0)/66.9 (7.5), 108.7 (9.0)/64.9 (6.7), 111.3 (9.2)/67.0 (6.9) and 115.0 (10.7)/73.7 (8.6) mmHg at the first, second and third gestational trimesters and postpartum, respectively. Women with higher/lower adherence to the processed pattern presented SBP of 117.9 and 113.0 mmHg (P = 0.037), respectively, during postpartum. No association was found between any of the three dietary patterns and SBP in the multiple longitudinal linear regression models, whereas 1 SD increase in the common-Brazilian pattern was associated with a small change of DBP (beta = 0.0006; 95% CI 4.66e-06, 0.001; P = 0.048). CONCLUSION: The three dietary patterns identified revealed no association with changes of SBP and DBP levels during pregnancy and at early postpartum in this sample of healthy Brazilian women. PMID- 25526969 TI - Low vitamin C values are linked with decreased physical performance and increased oxidative stress: reversal by vitamin C supplementation. AB - PURPOSE: It has been suggested that part of the failure of antioxidant supplementation to reduce oxidative stress and promote health is that it has been administered in humans with normal levels of antioxidants. METHODS: To test this hypothesis, we screened 100 males for vitamin C baseline values in blood. Subsequently, the 10 individuals with the lowest and the 10 with the highest vitamin C values were assigned in two groups. Using a placebo-controlled crossover design, the 20 selected subjects performed aerobic exercise to exhaustion (oxidant stimulus) before and after vitamin C supplementation for 30 days. RESULTS: The low vitamin C group had lower VO2max values than the high vitamin C group. Vitamin C supplementation in this group marginally increased VO2max. Baseline concentration of F2-isoprostanes and protein carbonyls was higher in the low vitamin C group compared to the high vitamin C group. Vitamin C supplementation decreased the baseline concentration of F2-isoprostanes and protein carbonyls in both groups, yet the decrease was greater in the low vitamin C group. Before vitamin C supplementation, F2-isoprostanes and protein carbonyls were increased to a greater extent after exercise in the high vitamin C group compared to the low vitamin C group. Interestingly, after vitamin C supplementation, this difference was narrowed. CONCLUSION: We show for the first time that low vitamin C concentration is linked with decreased physical performance and increased oxidative stress and that vitamin C supplementation decreases oxidative stress and might increase exercise performance only in those with low initial concentration of vitamin C. PMID- 25526970 TI - Suvorexant in Patients With Insomnia: Results From Two 3-Month Randomized Controlled Clinical Trials. AB - BACKGROUND: Suvorexant is an orexin receptor antagonist for treatment of insomnia. We report results from two pivotal phase 3 trials. METHODS: Two randomized, double-blind, placebo-controlled, parallel-group, 3-month trials in nonelderly (18-64 years) and elderly (>=65 years) patients with insomnia. Suvorexant doses of 40/30 mg (nonelderly/elderly) and 20/15 mg (nonelderly/elderly) were evaluated. The primary focus was 40/30 mg, with fewer patients randomized to 20/15 mg. There was an optional 3-month double-blind extension in trial 1. Each trial included a 1-week, randomized, double-blind run out after double-blind treatment to assess withdrawal/rebound. Efficacy was assessed at week 1, month 1, and month 3 by patient-reported subjective total sleep time and time to sleep onset and in a subset of patients at night 1, month 1, and month 3 by polysomnography end points of wakefulness after persistent sleep onset and latency to onset of persistent sleep (LPS). One thousand twenty one patients were randomized in trial 1 and 1019 patients in trial 2. RESULTS: Suvorexant 40/30 mg was superior to placebo on all subjective and polysomnography end points at night 1/week 1, month 1, and month 3 in both trials, except for LPS at month 3 in trial 2. Suvorexant 20/15 mg was superior to placebo on subjective total sleep time and wakefulness after persistent sleep onset at night 1/week 1, month 1, and month 3 in both trials and at most individual time points for subjective time to sleep onset and LPS in each trial. Both doses of suvorexant were generally well tolerated, with <5% of patients discontinuing due to adverse events over 3 months. The results did not suggest the emergence of marked rebound or withdrawal signs or symptoms when suvorexant was discontinued. CONCLUSIONS: Suvorexant improved sleep onset and maintenance over 3 months of nightly treatment and was generally safe and well tolerated. PMID- 25526971 TI - Quantitative Magnetization Transfer Imaging as a Biomarker for Effects of Systemic Inflammation on the Brain. AB - BACKGROUND: Systemic inflammation impairs brain function and is increasingly implicated in the etiology of common mental illnesses, particularly depression and Alzheimer's disease. Immunotherapies selectively targeting proinflammatory cytokines demonstrate efficacy in a subset of patients with depression. However, efforts to identify patients most vulnerable to the central effects of inflammation are hindered by insensitivity of conventional structural magnetic resonance imaging. METHODS: We used quantitative magnetization transfer (qMT) imaging, a magnetic resonance imaging technique that enables quantification of changes in brain macromolecular density, together with experimentally induced inflammation to investigate effects of systemic inflammatory challenge on human brain microstructure. Imaging with qMT was performed in 20 healthy participants after typhoid vaccination and saline control injection. An additional 20 participants underwent fluorodeoxyglucose positron emission tomography following the same inflammatory challenge. RESULTS: The qMT data demonstrated that inflammation induced a rapid change in brain microstructure, reflected in increased magnetization exchange from free (water) to macromolecular-bound protons, within a discrete region of insular cortex implicated in representing internal physiologic states including inflammation. The functional significance of this change in insular microstructure was demonstrated by correlation with inflammation-induced fatigue and fluorodeoxyglucose positron emission tomography imaging, which revealed increased resting glucose metabolism within this region following the same inflammatory challenge. CONCLUSIONS: Together these observations highlight a novel structural biomarker of the central physiologic and behavioral effects of mild systemic inflammation. The widespread clinical availability of magnetic resonance imaging supports the viability of qMT imaging as a clinical biomarker in trials of immunotherapeutics, both to identify patients vulnerable to the effects of systemic inflammation and to monitor neurobiological responses. PMID- 25526973 TI - Endogenous assessment of chronic myocardial infarction with T(1rho)-mapping in patients. AB - BACKGROUND: Detection of cardiac fibrosis based on endogenous magnetic resonance (MR) characteristics of the myocardium would yield a measurement that can provide quantitative information, is independent of contrast agent concentration, renal function and timing. In ex vivo myocardial infarction (MI) tissue, it has been shown that a significantly higher T(1rho) is found in the MI region, and studies in animal models of chronic MI showed the first in vivo evidence for the ability to detect myocardial fibrosis with native T(1rho)-mapping. In this study we aimed to translate and validate T(1rho)-mapping for endogenous detection of chronic MI in patients. METHODS: We first performed a study in a porcine animal model of chronic MI to validate the implementation of T(1rho)-mapping on a clinical cardiovascular MR scanner and studied the correlation with histology. Subsequently a clinical protocol was developed, to assess the feasibility of scar tissue detection with native T(1rho)-mapping in patients (n = 21) with chronic MI, and correlated with gold standard late gadolinium enhancement (LGE) CMR. Four T1rho-weighted images were acquired using a spin-lock preparation pulse with varying duration (0, 13, 27, 45 ms) and an amplitude of 750 Hz, and a T(1rho)-map was calculated. The resulting T(1rho)-maps and LGE images were scored qualitatively for the presence and extent of myocardial scarring using the 17 segment AHA model. RESULTS: In the animal model (n = 9) a significantly higher T(1rho) relaxation time was found in the infarct region (61 +/- 11 ms), compared to healthy remote myocardium (36 +/- 4 ms) . In patients a higher T(1rho) relaxation time (79 +/- 11 ms) was found in the infarct region than in remote myocardium (54 +/- 6 ms). Overlap in the scoring of scar tissue on LGE images and T(1rho)-maps was 74%. CONCLUSION: We have shown the feasibility of native T(1rho) mapping for detection of infarct area in patients with a chronic myocardial infarction. In the near future, improvements on the T(1rho)-mapping sequence could provide a higher sensitivity and specificity. This endogenous method could be an alternative for LGE imaging, and provide additional quantitative information on myocardial tissue characteristics. PMID- 25526972 TI - Reduced Face Preference in Infancy: A Developmental Precursor to Callous Unemotional Traits? AB - BACKGROUND: Children with callous-unemotional (CU) traits, a proposed precursor to adult psychopathy, are characterized by impaired emotion recognition, reduced responsiveness to others' distress, and a lack of guilt or empathy. Reduced attention to faces, and more specifically to the eye region, has been proposed to underlie these difficulties, although this has never been tested longitudinally from infancy. Attention to faces occurs within the context of dyadic caregiver interactions, and early environment including parenting characteristics has been associated with CU traits. The present study tested whether infants' preferential tracking of a face with direct gaze and levels of maternal sensitivity predict later CU traits. METHODS: Data were analyzed from a stratified random sample of 213 participants drawn from a population-based sample of 1233 first-time mothers. Infants' preferential face tracking at 5 weeks and maternal sensitivity at 29 weeks were entered into a weighted linear regression as predictors of CU traits at 2.5 years. RESULTS: Controlling for a range of confounders (e.g., deprivation), lower preferential face tracking predicted higher CU traits (p = .001). Higher maternal sensitivity predicted lower CU traits in girls (p = .009), but not boys. No significant interaction between face tracking and maternal sensitivity was found. CONCLUSIONS: This is the first study to show that attention to social features during infancy as well as early sensitive parenting predict the subsequent development of CU traits. Identifying such early atypicalities offers the potential for developing parent-mediated interventions in children at risk for developing CU traits. PMID- 25526975 TI - My New Year's wish is for an effective sunscreen. PMID- 25526974 TI - In vivo detection of nerve injury in familial amyloid polyneuropathy by magnetic resonance neurography. AB - Transthyretin familial amyloid polyneuropathy is a rare, autosomal-dominant inherited multisystem disorder usually manifesting with a rapidly progressive, axonal, distally-symmetric polyneuropathy. The detection of nerve injury by nerve conduction studies is limited, due to preferential involvement of small-fibres in early stages. We investigated whether lower limb nerve-injury can be detected, localized and quantified in vivo by high-resolution magnetic resonance neurography. We prospectively included 20 patients (12 male and eight female patients, mean age 47.9 years, range 26-66) with confirmed mutation in the transthyretin gene: 13 with symptomatic polyneuropathy and seven asymptomatic gene carriers. A large age- and sex-matched cohort of healthy volunteers served as controls (20 male and 20 female, mean age 48.1 years, range 30-73). All patients received detailed neurological and electrophysiological examinations and were scored using the Neuropathy Impairment Score-Lower Limbs, Neuropathy Deficit and Neuropathy Symptom Score. Magnetic resonance neurography (3 T) was performed with large longitudinal coverage from proximal thigh to ankle-level and separately for each leg (140 axial slices/leg) by using axial T2-weighted (repetition time/echo time = 5970/55 ms) and dual echo (repetition time 5210 ms, echo times 12 and 73 ms) turbo spin echo 2D sequences with spectral fat saturation. A 3D T2-weighted inversion-recovery sequence (repetition time/echo time 3000/202 ms) was acquired for imaging of the spinal nerves and lumbar plexus (50 axial slice reformations). Precise manual segmentation of the spinal/sciatic/tibial/common peroneal nerves was performed on each slice. Histogram-based normalization of nerve-voxel signal intensities was performed using the age- and sex-matched control group as normative reference. Nerve-voxels were subsequently classified as lesion-voxels if a threshold of >1.2 (normalized signal-intensity) was exceeded. At distal thigh level, where a predominant nerve lesion-voxel burden was observed, signal quantification was performed by calculating proton spin density and T2-relaxation time as microstructural markers of nerve tissue integrity. The total number of nerve-lesion voxels (cumulated from proximal-to-distal) was significantly higher in symptomatic patients (20 405 +/- 1586) versus asymptomatic gene carriers (12 294 +/- 3199; P = 0.036) and versus controls (6536 +/- 467; P < 0.0001). It was also higher in asymptomatic carriers compared to controls (P = 0.043). The number of nerve-lesion voxels was significantly higher at thigh level compared to more distal levels (lower leg/ankle) of the lower extremities (f-value = 279.22, P < 0.0001). Further signal-quantification at this proximal site (thigh level) revealed a significant increase of proton-density (P < 0.0001) and T2-relaxation-time (P = 0.0011) in symptomatic patients, whereas asymptomatic gene-carriers presented with a significant increase of proton-density only. Lower limb nerve injury could be detected and quantified in vivo on microstructural level by magnetic resonance neurography in symptomatic familial amyloid polyneuropathy, and also in yet asymptomatic gene carriers, in whom imaging detection precedes clinical and electrophysiological manifestation. Although symptoms start and prevail distally, the focus of predominant nerve injury and injury progression was found proximally at thigh level with strong and unambiguous lesion-contrast. Imaging of proximal nerve lesions, which are difficult to detect by nerve conduction studies, may have future implications also for other distally-symmetric polyneuropathies. PMID- 25526977 TI - Comprehensive two-dimensional gas chromatography for characterizing mineral oils in foods and distinguishing them from synthetic hydrocarbons. AB - Many foods are contaminated by hydrocarbons of mineral oil or synthetic origin. High performance liquid chromatography on-line coupled with gas chromatography and flame ionization detection (HPLC-GC-FID) is a powerful tool for the quantitative determination, but it would often be desirable to obtain more information about the type of hydrocarbons in order to identify the source of the contamination and specify pertinent legislation. Comprehensive two-dimensional gas chromatography (GC*GC) is shown to produce plots distinguishing mineral oil saturated hydrocarbons (MOSH) from polymer oligomeric saturated hydrocarbons (POSH) and characterizing the degree of raffination of a mineral oil. The first dimension separation occurred on a phenyl methyl polysiloxane, the second on a dimethyl polysiloxane. Mass spectrometry (MS) was used for identification, FID for quantitative determination. This shows the substantial advances in chromatography to characterize complex hydrocarbon mixtures even as contaminants in food. PMID- 25526978 TI - A novel method for measuring trace amounts of total sulphur-containing compounds in hydrogen. AB - A novel method for the analysis of total sulphur-containing impurities in a hydrogen matrix has been developed. This method has a limit of detection (LoD) significantly lower than that maximum amount fraction for sulphur-containing compounds (4 nmol mol(-1)) specified by the international standard for hydrogen to be used in fuel cell vehicles (ISO 14687-2). To measure the LoD for this method, a novel gas standard containing five different sulphur-containing compounds at low nmol mol(-1) amount fractions has been gravimetrically prepared. Stable primary gas standards that are traceable to the SI were used to successfully validate the amount fractions of the sulphur-containing compounds in this gas standards using gas chromatography with flame ionisation detection (GC FID) and sulphur chemiluminescence detection (GC-SCD). PMID- 25526976 TI - Spanish Rheumatology Society and Hospital Pharmacy Society Consensus on recommendations for biologics optimization in patients with rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. AB - OBJECTIVE: The aim of this study was to establish guidelines for the optimization of biologic therapies for health professionals involved in the management of patients with RA, AS and PsA. METHODS: Recommendations were established via consensus by a panel of experts in rheumatology and hospital pharmacy, based on analysis of available scientific evidence obtained from four systematic reviews and on the clinical experience of panellists. The Delphi method was used to evaluate these recommendations, both between panellists and among a wider group of rheumatologists. RESULTS: Previous concepts concerning better management of RA, AS and PsA were reviewed and, more specifically, guidelines for the optimization of biologic therapies used to treat these diseases were formulated. Recommendations were made with the aim of establishing a plan for when and how to taper biologic treatment in patients with these diseases. CONCLUSION: The recommendations established herein aim not only to provide advice on how to improve the risk:benefit ratio and efficiency of such treatments, but also to reduce variability in daily clinical practice in the use of biologic therapies for rheumatic diseases. PMID- 25526979 TI - The Lingulodinium circadian system lacks rhythmic changes in transcript abundance. AB - BACKGROUND: Almost all cells display circadian rhythms, approximately 24-hour period changes in their biochemistry, physiology or behavior. These rhythms are orchestrated by an endogenous circadian clock whose mechanism is based on transcription-translation feedback loops (TTFL) where the translated products of clock genes act to inhibit their own transcription. RESULTS: We have used RNA-Seq to measure the abundance of all transcripts in an RNA-Seq-derived de novo gene catalog in two different experiments. One compared midday and midnight in a light dark cycle (ZT6 and ZT18) and under constant light (CT6 and CT18). The second compared four different times (ZT2, ZT6, ZT14 and ZT18) under a light dark cycle. We show here that despite an elaborate repertoire of biological rhythms, the unicellular dinoflagellate Lingulodinium had no detectable daily variation in the abundance of any transcript in an RNA-Seq-derived de novo gene catalog. We also examined the timing of the bioluminescence and photosynthesis rhythms in the presence of the transcription inhibitors actinomycin D and cordycepin. We found that the timing of the two rhythms was unchanged even when transcription rates had decreased to roughly 5% the levels of untreated cells. CONCLUSIONS: The lack of detectable daily variation in transcript levels indicates that the endogenous circadian timer of Lingulodinium does not require rhythmic RNA. If the circadian timer is considered as a limit cycle oscillator, then cellular time in this organism must be defined by variations in state variables that do not include the amount of a clock gene transcript. PMID- 25526980 TI - Expression profiling and structural characterization of microRNAs in adipose tissues of hibernating ground squirrels. AB - MicroRNAs (miRNAs) are small non-coding RNAs that are important in regulating metabolic stress. In this study, we determined the expression and structural characteristics of 20 miRNAs in brown (BAT) and white adipose tissue (WAT) during torpor in thirteen-lined ground squirrels. Using a modified stem-loop technique, we found that during torpor, expression of six miRNAs including let-7a, let-7b, miR-107, miR-150, miR-222 and miR-31 was significantly downregulated in WAT (P<0.05), which was 16%-54% of euthermic non-torpid control squirrels, whereas expression of three miRNAs including miR-143, miR-200a and miR-519d was found to be upregulated by 1.32-2.34-fold. Similarly, expression of more miRNAs was downregulated in BAT during torpor. We detected reduced expression of 6 miRNAs including miR-103a, miR-107, miR-125b, miR-21, miR-221 and miR-31 (48%-70% of control), while only expression of miR-138 was significantly upregulated (2.91+/ 0.8-fold of the control, P<0.05). Interestingly, miRNAs found to be downregulated in WAT during torpor were similar to those dysregulated in obese humans for increased adipogenesis, whereas miRNAs with altered expression in BAT during torpor were linked to mitochondrial beta-oxidation. miRPath target prediction analysis showed that miRNAs downregulated in both WAT and BAT were associated with the regulation of mitogen-activated protein kinase (MAPK) signaling, while the miRNAs upregulated in WAT were linked to transforming growth factor beta (TGFbeta) signaling. Compared to mouse sequences, no unique nucleotide substitutions within the stem-loop region were discovered for the associated pre miRNAs for the miRNAs used in this study, suggesting no structure-influenced changes in pre-miRNA processing efficiency in the squirrel. As well, the expression of miRNA processing enzyme Dicer remained unchanged in both tissues during torpor. Overall, our findings suggest that changes of miRNA expression in adipose tissues may be linked to distinct biological roles in WAT and BAT during hibernation and may involve the regulation of signaling cascades. PMID- 25526981 TI - Association between rs1344706 of ZNF804A and schizophrenia: a meta-analysis. AB - Schizophrenia is one of the most serious mental diseases found in humans. Previous studies indicated that the single nucleotide polymorphism (SNP) rs1344706 in the gene ZNF804A encoding zinc finger protein 804A was associated with schizophrenia in Caucasian population but not in Chinese Han population. However, current results are conflicting in Asian population. In the present study, a meta-analysis was performed to revisit the association between rs1344706 and the risk of schizophrenia in Asian, Caucasian and other populations. Electronic search of PubMed database identified 25 case-control studies with available genotype frequencies of rs1344706 for the meta-analysis, involving a total of 15,788 cases and 22,654 controls. A pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association. The current meta analysis showed an association between rs1344706 and schizophrenia in Caucasian populations (P=0.028, OR=1.138, 95% CI: 1.014-1.278; P=0.004 for heterogeneity) and Asian populations (P=0.008, OR=1.092, 95% CI: 1.023-1.165; P=0.001 for heterogeneity), but not in other populations (P=0.286, OR=1.209, 95% CI: 0.853 1.714, P=0.120 for heterogeneity). Egger's test (P>0.05) and Begg's test (P>0.05) are both suggestive of the lack of publication bias for the included studies. Thus, the absence of association in other populations suggests a genetic heterogeneity in the susceptibility of schizophrenia and demonstrates the difficulties in replicating genome-wide association study findings regarding schizophrenia across different ethnic populations. To validate the association between rs1344706 and schizophrenia, further studies with larger participant populations worldwide are needed. PMID- 25526982 TI - In vitro transcriptome analysis of two Chinese isolates of Streptococcus suis serotype 2. AB - The Streptococcus suis serotype 2 (S. suis 2) isolates 05ZYH33 and 98HAH33 have caused severe human infections in China. Using a strand-specific RNA-seq analysis, we compared the in vitro transcriptomes of these two Chinese isolates with that of a reference strain (P1/7). In the 89K genomic island that is specific to these Chinese isolates, a toxin-antitoxin system showed relatively high levels of transcription among the S. suis. The known virulence factors with high transcriptional activity in these two highly-pathogenic strains are mainly involved in adhesion, biofilm formation, hemolysis and the synthesis and transport of the outer membrane protein. Furthermore, our analysis of novel transcripts identified over 50 protein-coding genes with one of them encoding a toxin protein. We also predicted over 30 small RNAs (sRNAs) in each strain, and most of them are involved in riboswitches. We found that six sRNA candidates that are related to bacterial virulence, including cspA and rli38, are specific to Chinese isolates. These results provide insight into the factors responsible for the difference in virulence among the different S. suis 2 isolates. PMID- 25526983 TI - Percutaneous and surgical tracheostomy in critically ill adult patients: a meta analysis. AB - INTRODUCTION: The aim of this study was to conduct a meta-analysis to determine whether percutaneous tracheostomy (PT) techniques are advantageous over surgical tracheostomy (ST), and if one PT technique is superior to the others. METHODS: Computerized databases (1966 to 2013) were searched for randomized controlled trials (RCTs) reporting complications as predefined endpoints and comparing PT and ST and among the different PT techniques in mechanically ventilated adult critically ill patients. Odds ratios (OR) and mean differences (MD) with 95% confidence interval (CI), and I(2) values were estimated. RESULTS: Fourteen RCTs tested PT techniques versus ST in 973 patients. PT techniques were performed faster (MD, -13.06 minutes (95% CI, -19.37 to -6.76 (P < 0.0001)); I(2) = 97% (P < 0.00001)) and reduced odds for stoma inflammation (OR, 0.38 (95% CI, 0.19 to 0.76 (P = 0.006)); I(2) = 2% (P = 0.36)), and infection (OR, 0.22 (95% CI, 0.11 to 0.41 (P < 0.00001)); I(2) = 0% (P = 0.54)), but increased odds for procedural technical difficulties (OR, 4.58 (95% CI, 2.21 to 9.47 (P < 0.0001)); I(2) = 0% (P = 0.63)). PT techniques reduced odds for postprocedural major bleeding (OR, 0.39 (95% CI, 0.15 to 0.97 (P = 0.04)); I(2) = 0% (P = 0.69)), but not when a single RCT using translaryngeal tracheostomy was excluded (OR, 0.58 (95% CI, 0.21 to 1.63 (P = 0.30)); I(2) = 0% (P = 0.89)). Eight RCTs compared different PT techniques in 700 patients. Multiple (MDT) and single step (SSDT) dilatator techniques are associated with the lowest odds for difficult dilatation or cannula insertion (OR, 0.30 (95% CI, 0.12 to 0.80 (P = .02)); I(2) = 56% (P = 0.03)) and major intraprocedural bleeding (OR, 0.29 (95% CI, 0.10 to 0.85 (P = 0.02)); I(2) = 0% (P = 0.72)), compared to the guide wire dilatation forceps technique. CONCLUSION: In critically ill adult patients, PT techniques can be performed faster and reduce stoma inflammation and infection but are associated with increased technical difficulties when compared to ST. Among PT techniques, MDT and SSDT were associated with the lowest intraprocedural risks and seem to be preferable. PMID- 25526984 TI - Side-effects of domestication: cultivated legume seeds contain similar tocopherols and fatty acids but less carotenoids than their wild counterparts. AB - BACKGROUND: Lipophilic antioxidants play dual key roles in edible seeds (i) as preservatives of cell integrity and seed viability by preventing the oxidation of fats, and (ii) as essential nutrients for human and animal life stock. It has been well documented that plant domestication and post-domestication evolution frequently resulted in increased seed size and palatability, and reduced seed dormancy. Nevertheless, and surprisingly, it is poorly understood how agricultural selection and cultivation affected the physiological fitness and the nutritional quality of seeds. Fabaceae have the greatest number of crop species of all plant families, and most of them are cultivated for their highly nutritious edible seeds. Here, we evaluate whether evolution of plants under cultivation has altered the integrated system formed by membranes (fatty acids) and lipophilic antioxidants (carotenoids and tocopherols), in the ten most economically important grain legumes and their closest wild relatives, i.e.: Arachis (peanut), Cicer (chickpea), Glycine (soybean), Lathyrus(vetch), Lens (lentil), Lupinus (lupin), Phaseolus (bean), Pisum (pea), Vicia (faba bean) and Vigna (cowpea). RESULTS: Unexpectedly, we found that following domestication, the contents of carotenoids, including lutein and zeaxanthin, decreased in all ten species (total carotenoid content decreased 48% in average). Furthermore, the composition of carotenoids changed, whereby some carotenoids were lost in most of the crops. An undirected change in the contents of tocopherols and fatty acids was found, with contents increasing in some species and decreasing in others, independently of the changes in carotenoids. In some species, polyunsaturated fatty acids (linolenic acid especially), alpha-tocopherol and gamma-tocopherol decreased following domestication. CONCLUSIONS: The changes in carotenoids, tocopherols and fatty acids are likely side-effects of the selection for other desired traits such as the loss of seed dormancy and dispersal mechanisms, and selection for seed storability and taste. This work may serve as baseline to broaden our knowledge on the integrated changes on crop fitness and nutritional quality following domestication. PMID- 25526985 TI - Immune cell transcript modules reveal leukocyte heterogeneity in synovial biopsies of seronegative spondylarthropathy patients. AB - BACKGROUND: The objective of this study was to identify leukocyte cell types found within the synovia of patients with seronegative spondylarthropathies (SpA), such as ankylosing spondylitis (AS), using transcription based analyses. METHODS: Leukocyte transcriptional profiles obtained from the NCBI's gene expression omnibus and prediction analysis of microarrays (PAM) was used to identify 25-gene leukocyte metagenes. Subsequently, transcriptional profiles from murine and clinical models of AS and SpA were interrogated to characterize the local infiltration of leukocytes in SpA synovia. RESULTS: Analysis of a proteoglycan-induced murine model of AS reveals infiltration of dendritic cells, CD4+ T cells, monocytes, and natural killer cells to the spine. In human SpA and AS patients, transcriptional analysis of synovial biopsies revealed local infiltration of dendritic cells and CD4+ T cells. CONCLUSIONS: We identified leukocyte cell types that infiltrated the synovial of SpA patients. Our results imply a role for dendritic cells and CD4+ T cells in the local inflammation that underlies pathogenesis in patients with SpA. PMID- 25526986 TI - Assessing cumulative dose distributions in combined radiotherapy for cervical cancer using deformable image registration with pre-imaging preparations. AB - BACKGROUND: The purpose of the study was to evaluate the feasibility of deformable image registration (DIR) in assessing cumulative dose distributions of the combination of external beam radiotherapy (EBRT) and fractionated intracavitary brachytherapy (ICBT) for cervical cancer. MATERIALS AND METHODS: Three-dimensional image data sets of five consecutive patients were used. The treatment plan consisted of whole pelvic EBRT (total dose: 45 Gy in 25 fractions) combined with computed tomography (CT)-based high-dose rate ICBT (>=24 Gy in 4 fractions to the high risk clinical target volume (HR-CTV)). Organs at risk and HR-CTV were contoured on each CT images and dose-volume parameters were acquired. Pre-imaging preparations were performed prior to each ICBT to minimize the uncertainty of the organ position. Physical doses of each treatment were converted to biologically equivalent doses in 2 Gy daily fractions by the linear quadratic model. Three-dimensional dose distributions of each treatment were accumulated on CT images of the first ICBT using DIR with commercially available image registration software (MIM Maestro(r)). To compare with DIR, 3D dose distributions were fused by rigid registration based on bony structure matching. To evaluate the accuracy of DIR, the Dice similarity coefficient (DSC) was measured between deformed contours and initial contours. RESULTS: The cumulative dose distributions were successfully illustrated on the CT images using DIR. Mean DSCs of the HR-CTV, rectum, and bladder were 0.46, 0.62 and 0.69, respectively, with rigid registration; and 0.78, 0.76, and 0.87, respectively, with DIR (p <0.05). The mean DSCs derived from our DIR procedure were comparable to those of previous reports describing the quality of DIR algorithms in the pelvic region. DVH parameters derived from the 2 methods showed no significant difference. CONCLUSIONS: Our results suggest that DIR-based dose accumulation may be acceptable for assessing cumulative dose distributions to assess doses to the tumor and organs at risk in combined radiotherapy for cervical cancer under pre imaging preparations. PMID- 25526987 TI - A call for better care: the impact of postnatal contact services on women's parenting confidence and experiences of postpartum care in Queensland, Australia. AB - BACKGROUND: Universal postnatal contact services are provided in several Australian states, but their impact on women's postnatal care experience has not been evaluated. Furthermore, there is lack of evidence or consensus about the optimal type and amount of postpartum care after hospital discharge for maternal outcomes. This study aimed to assess the impact of providing Universal Postnatal Contact Service (UPNCS) funding to public birthing facilities in Queensland, Australia on women's postnatal care experiences, and associations between amount and type (telephone or home visits) of contact on parenting confidence, and perceived sufficiency and quality of postnatal care. METHODS: Data collected via retrospective survey of postnatal women (N = 3,724) were used to compare women who birthed in UPNCS-funded and non-UPNCS-funded facilities on parenting confidence, sufficiency of postnatal care, and perceived quality of postnatal care. Associations between receiving telephone and home visits and the same outcomes, regardless of UPNCS funding, were also assessed. RESULTS: Women who birthed in an UPNCS-funded facility were more likely to receive postnatal contact, but UPNCS funding was not associated with parenting confidence, or perceived sufficiency or perceived quality of care. Telephone contact was not associated with parenting confidence but had a positive dose-response association with perceived sufficiency and quality. Home visits were negatively associated with parenting confidence when 3 or more were received, had a positive dose response association with perceived sufficiency and were positively associated with perceived quality when at least 6 were received. CONCLUSIONS: Funding for UPNCS is unlikely to improve population levels of maternal parenting confidence, perceived sufficiency or quality of postpartum care. Where only minimal contact can be provided, telephone may be more effective than home visits for improving women's perceived sufficiency and quality of care. Additional service initiatives may be needed to improve women's parenting confidence. PMID- 25526989 TI - Late presentation of complicated complete ureteral duplication. PMID- 25526990 TI - Renal leiomyoma. PMID- 25526991 TI - Flap versus graft 2-stage repair of severe hypospadias with chordee. Flap repair. PMID- 25526993 TI - Progress in stress incontinence surgery--are we destined to fail? PMID- 25526995 TI - Perisphincteric cavernous nerve meshwork and its importance in radical prostatectomy. PMID- 25526996 TI - Should we perform prostatectomy in the face of metastatic prostate cancer? PMID- 25526997 TI - Childhood hypospadias repairs--do they stand the test of time? PMID- 25526998 TI - Flap versus graft 2-stage repair of severe hypospadias with chordee. PMID- 25527000 TI - Erratum to: Modulation of p75(NTR) prevents diabetes- and proNGF-induced retinal inflammation and blood-retina barrier breakdown in mice and rats. PMID- 25526999 TI - Molecular genotyping and quantitation assay for rotavirus surveillance. AB - Rotavirus genotyping is useful for surveillance purposes especially in areas where rotavirus vaccination has been or will be implemented. RT-PCR based molecular methods have been applied widely, but quantitative assays targeting a broad spectrum of genotypes have not been developed. Three real time RT-PCR panels were designed to identify G1, G2, G9, G12 (panel GI), G3, G4, G8, G10 (panel GII), and P[4], P[6], P[8], P[10], P[11] (panel P), respectively. An assay targeting NSP3 was included in both G panels as an internal control. The cognate assays were also formulated as one RT-PCR-Luminex panel for simultaneous detection of all the genotypes listed above plus P[9]. The assays were evaluated with various rotavirus isolates and 89 clinical samples from Virginia, Bangladesh and Tanzania, and exhibited 95% (81/85) sensitivity compared with the conventional RT-PCR-Gel-electrophoresis method, and 100% concordance with sequencing. Real time assays identified a significantly higher rate of mixed genotypes in Bangladeshi samples than the conventional gel-electrophoresis-based RT-PCR assay (32.5% versus 12.5%, P<0.05). In these mixed infections, the relative abundance of the rotavirus types could be estimated by Cq values. These typing assays detect and discriminate a broad range of G/P types circulating in different geographic regions with high sensitivity and specificity and can be used for rotavirus surveillance. PMID- 25527002 TI - Quality of life in children with OCD before and after treatment. AB - Quality of life (QoL) is a well-established outcome measure. In contrast to adult obsessive-compulsive disorder (OCD), little is known about the effects of treatment on QoL in children with OCD. This study aimed to assess QoL after cognitive behavioural therapy (CBT) in children and adolescents with OCD compared with the general population and to explore factors associated with potential changes in QoL after treatment. QoL was assessed in 135 children and adolescents (ages 7-17; mean 13 [SD 2.7] years; 48.1% female) before and after 14 CBT sessions, using self-report and a caregivers proxy report of the Questionnaire for Measuring Health-related Quality of Life in Children and Adolescents (KINDL R). QoL was compared with an age- and gender-matched sample from the general population. Before treatment, QoL was markedly lower in children with OCD compared with the general population. QoL improved significantly in CBT responders (mean score change 7.4), to the same range as QoL in the general population. Non-responders reported no QoL changes after treatment, except for one patient. Comorbidity, family accommodation and psychosocial functioning were not associated with changes in QoL after treatment. To our knowledge, this is the first study of the changes in QoL after treatment of paediatric OCD. The assessment of QoL beyond symptoms and function in children with OCD has been shown to be reliable and informative. The results of this study support the application of QoL assessment as an additional measure of treatment outcome in children and adolescents with OCD. PMID- 25527001 TI - GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice. AB - AIMS/HYPOTHESIS: Oestrogens have previously been shown to exert beta cell protective, glucose-lowering effects in mouse models. Therefore, the recent development of a glucagon-like peptide-1 (GLP-1)-oestrogen conjugate, which targets oestrogen into cells expressing GLP-1 receptors, offers an opportunity for a cell-specific and enhanced beta cell protection by oestrogen. The purpose of this study was to compare the effects of GLP-1 and GLP-1-oestrogen during beta cell failure under glucolipotoxic conditions. METHODS: Male New Zealand obese (NZO) mice were treated with daily s.c. injections of GLP-1 and GLP-1-oestrogen, respectively. Subsequently, the effects on energy homeostasis and beta cell integrity were measured. In order to clarify the targeting of GLP-1-oestrogen, transcription analyses of oestrogen-responsive genes in distinct tissues as well as microarray analyses in pancreatic islets were performed. RESULTS: In contrast to GLP-1, GLP-1-oestrogen significantly decreased food intake resulting in a substantial weight reduction, preserved normoglycaemia, increased glucose tolerance and enhanced beta cell protection. Analysis of hypothalamic mRNA profiles revealed elevated expression of Pomc and Leprb. In livers from GLP-1 oestrogen-treated mice, expression of lipogenic genes was attenuated and hepatic triacylglycerol levels were decreased. In pancreatic islets, GLP-1-oestrogen altered the mRNA expression to a pattern that was similar to that of diabetes resistant NZO females. However, conventional oestrogen-responsive genes were not different, indicating rather indirect protection of pancreatic beta cells. CONCLUSIONS/INTERPRETATION: GLP-1-oestrogen efficiently protects NZO mice against carbohydrate-induced beta cell failure by attenuation of hyperphagia. In this regard, targeted delivery of oestrogen to the hypothalamus by far exceeds the anorexigenic capacity of GLP-1 alone. PMID- 25527004 TI - Assessment of an Expanded Functional Disability Scale for Older Adults With Diabetes. AB - Although prior literature has shown the plausibility of combining the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) items to form an expanded scale for measuring the degree of functional decline, this has not been shown in older adults with diabetes who are disproportionately affected by functional disability. Using the 2009 Medicare Current Beneficiary Survey data, we evaluated the factor structure of the pooled ADL and IADL items. Based on our study comprising 2,158 community-dwelling older adults (>=65 years) with diabetes, the unidimensional model exhibited good fit. Despite well-fitting indices, high correlations were observed between the latent constructs (>.70) of the multi-factor models, suggesting a lack of discriminant validity. These findings provide empirical support for a combined scale that can comprehensively and efficiently characterize the extent of functional disability in older adults with diabetes for research, risk adjustment, and evaluation in patient-centered medical homes. PMID- 25527003 TI - Paradoxical effects of injection stress and nicotine exposure experienced during adolescence on learning in a serial multiple choice (SMC) task in adult female rats. AB - Nicotine exposure in adolescent rats has been shown to cause learning impairments that persist into adulthood long after nicotine exposure has ended. This study was designed to assess the extent to which the effects of adolescent nicotine exposure on learning in adulthood can be accounted for by adolescent injection stress experienced concurrently with adolescent nicotine exposure. Female rats received either 0.033 mg/h nicotine (expressed as the weight of the free base) or bacteriostatic water vehicle by osmotic pump infusion on postnatal days 25-53 (P25-53). Half of the nicotine-exposed rats and half of the vehicle rats also received twice-daily injection stress consisting of intraperitoneal saline injections on P26-53. Together these procedures produced 4 groups: No Nicotine/No Stress, Nicotine/No Stress, No Nicotine/Stress, and Nicotine/Stress. On P65-99, rats were trained to perform a structurally complex 24-element serial pattern of responses in the serial multiple choice (SMC) task. Four general results were obtained in the current study. First, learning for within-chunk elements was not affected by either adolescent nicotine exposure, consistent with past work (Pickens, Rowan, Bevins, and Fountain, 2013), or adolescent injection stress. Thus, there were no effects of adolescent nicotine exposure or injection stress on adult within-chunk learning typically attributed to rule learning in the SMC task. Second, adolescent injection stress alone (i.e., without concurrent nicotine exposure) caused transient but significant facilitation of adult learning restricted to a single element of the 24-element pattern, namely, the "violation element," that was the only element of the pattern that was inconsistent with pattern structure. Thus, adolescent injection stress alone facilitated violation element acquisition in adulthood. Third, also consistent with past work (Pickens et al., 2013), adolescent nicotine exposure, in this case both with and without adolescent injection stress, caused a learning impairment in adulthood for the violation element in female rats. Thus, adolescent nicotine impaired adult violation element learning typically attributed to multiple-item learning in the SMC task. Fourth, a paradoxical interaction of injection stress and nicotine exposure in acquisition was observed. In the same female rats in which violation-element learning was impaired by adolescent nicotine exposure, adolescent nicotine experienced without adolescent injection stress produced better learning for chunk-boundary elements in adulthood compared to all other conditions. Thus, adolescent nicotine without concurrent injection stress facilitated adult chunk-boundary element learning typically attributed to concurrent stimulus-response discrimination learning and serial-position learning in the SMC task. To the best of our knowledge, the current study is the first to demonstrate facilitation of adult learning caused by adolescent nicotine exposure. PMID- 25527005 TI - alpha-Glucosidase inhibitors from the leaves of Embelia ribes. AB - A novel and rare 1,4-dehydrated ceramide, embelamide (1), and a new C glycoalkaloid which is based on a beta-carboline ring system, 1-(2'-deoxy-alpha-d ribopyranosyl)-beta-carboline (4), were isolated from the CHCl3 soluble fraction of the leaves of Embelia ribes (Myrsinaceae), together with thirteen known compounds (2-3, 5-15). Their structures were elucidated on the basis of spectroscopic data. Compounds 1, and 5-12 possessed significant alpha-glucosidase inhibitory activity in a concentration-dependent manner, and showed more potent inhibitory activity, with IC50 values ranging from 1.3 to 155.0 MUM, than that of a positive control acarbose (IC50, 214.5 MUM). PMID- 25527006 TI - Contribution of the sural nerve to postural stability and cutaneous sensation of the lower limb. AB - BACKGROUND: The sural nerve is a cutaneous nerve of the lower limb that innervates the posterolateral aspect of the lower leg, ankle, and foot. Considering this pattern, it is plausible that it contributes to the maintenance of postural stability. However, the implications of sensory loss following sural nerve injury have yet to be thoroughly investigated. Therefore, the aim of this study was to investigate the immediate effect of sural nerve sensory loss on postural stability and its variability of innervation to the lower limb. METHODS: Twenty-five healthy adult subjects participated in an observational study with a repeated-measures design. Each participant underwent a postural stability assessment using the Neurocom Balance Master under 2 conditions: 1) with the sural nerve functioning normally and 2) following a bilateral ultrasound-guided sural nerve block. The cutaneous distribution of the sural nerve was mapped for descriptive purposes. RESULTS: There were no statistically significant differences between conditions for the primary outcome measure (unilateral stance on the dominant leg with eyes closed). A statistically significant reduction in postural stability was detected during unilateral stance on the nondominant leg (with eyes closed) following the nerve block (mean increase, 2.25 deg/s; 95% confidence interval, -0.48 to 2.91; t = 2.75; df = 24; P = .01). The mean area of plantar skin innervated by the sural nerve was 17% +/- 11%, and the mean area of lateral skin was 50% +/- 6%. CONCLUSION: Our findings demonstrate that a loss in sural nerve function is unlikely to reduce postural stability during daily activities. The sural nerve has a variable innervation pattern that can involve the third digit and the plantar medial border of the heel. CLINICAL RELEVANCE: Practitioners should consider this variability when assessing for potential sensory deficits and when planning procedures requiring anesthesia to the plantar surface of the foot. PMID- 25527008 TI - Seminars in Thoracic and Cardiovascular Surgery. Introduction. PMID- 25527007 TI - Phase II study of weekly irinotecan and capecitabine treatment in metastatic colorectal cancer patients. AB - BACKGROUND: The purpose of this phase II study was to evaluate the safety and efficacy of weekly irinotecan and capecitabine (wXELIRI) treatment in patients with metastatic colorectal cancer, specifically the rate of severe diarrhea. METHODS: Patients with unresectable histologically confirmed metastatic colorectal cancer with measurable disease received weekly irinotecan 90 mg/m2 on day 1 and capecitabine 1200 mg/m2 twice daily on days 1-5. Patients naive to systemic chemotherapy for metastatic disease or who had failed FOLFOX (infusional 5-fluorouracil [5-FU], leucovorin, and oxaliplatin) or XELOX (capecitabine plus oxaliplatin) as first-line treatment were eligible. The primary endpoint was the rate of grade 3/4 diarrhea. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 52 patients were enrolled, 30 of whom received wXELIRI as first-line treatment and 22 as second-line treatment. Grade 4 diarrhea was observed in one patient and the rate of grade 3/4 diarrhea was 7.7%. The other common grade 3/4 toxicities included leukopenia (9.6%), neutropenia (17.3%), nausea (3.8%), vomiting (3.8%), fatigue (1.9%), and hand-foot syndrome (1.9%). The median progression-free survival and overall survival for the 30 patients treated in the first-line setting was 8.5 and 16.3 months, while those for the 22 patients treated in the second-line setting was 5.0 and 10.7 months, respectively. CONCLUSIONS: The wXELIRI regimen resulted in a low rate of severe diarrhea with an acceptable toxicity profile. This study provides a basis for a subsequent randomized controlled study of wXELIRI versus FOLFIRI (irinotecan, 5-FU, and folinic acid) to further explore the efficacy and safety of this regimen. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01322152. PMID- 25527009 TI - Outcomes of arterial revascularization. PMID- 25527010 TI - Multiple arterial grafting. PMID- 25527011 TI - The CoreValve US pivotal trial. AB - Transcatheter aortic valve replacement (TAVR) has been developed as a less invasive approach to address patients at high risk to extreme risk for surgical aortic valve replacement. The CoreValve US trial enrolled patients with symptomatic severe aortic stenosis into 2 separate cohorts: an extreme-risk cohort and a high-risk cohort. The study of transfemoral TAVR using the CoreValve system in extreme-risk patients achieved its primary end point of all-cause mortality or stroke at 1 year. This was achieved with a low stroke rate and low paravalvular leak rate that improved with time. The CoreValve high-risk trial is the only randomized trial of TAVR vs surgical aortic valve replacement to show superior survival of TAVR. This was achieved with a numerically lower rate of major stroke and statistically superior changes in aortic valve function from baseline to 1 year. PMID- 25527012 TI - Role of percutaneous coronary intervention in the treatment of left main coronary artery disease. AB - Revascularization with coronary artery bypass graft surgery is the choice of therapy in patients with left main (LM) coronary artery stenosis. During the last decade, the introduction of drug-eluting stents, together with antiplatelet and antithrombotic treatments, has improved the outcome of percutaneous coronary interventions (PCIs) by reducing the number of repeat revascularizations and the risk of stent thrombosis. Many institutions inside and outside the United States have adopted stent treatment of unprotected LM coronary artery disease as a more routine strategy. However, coronary bypass surgery has improved as well by using more arterial grafts, better perioperative care, and optimizing medical treatment postoperatively. The advances in stent technique may reduce the gap between coronary surgery and PCIs further, but the results of the Evaluation of Xience Prime versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization study, randomizing patients with LM coronary artery disease between coronary bypass grafting and PCIs, will be needed to test whether PCIs is noninferior to coronary bypass surgery. PMID- 25527013 TI - Novel induction therapies for pleural mesothelioma. AB - Malignant mesothelioma is becoming increasingly common, and rates of diagnosis are expected to continue to increase in the coming years because of the extensive use of asbestos in industrialized countries and the long time interval between exposure and onset of disease. Although much research has been done on the optimal treatment for this disease, the overall prognosis remains grim. The main components of therapy are surgery, chemotherapy, and radiation therapy, but there is controversy in the literature about the optimal inclusion and sequencing of these treatments, as each has unique risk profiles. We have developed a new Surgery for Mesothelioma After Radiation Therapy protocol consisting of induction accelerated hemithoracic radiation followed by extrapleural pneumonectomy. The rationale behind this protocol is to maximize both the tumoricidal and immunogenic potential of the radiotherapy while minimizing the radiation toxicity to the ipsilateral lung. Our initial trial demonstrated the feasibility of this approach and has shown encouraging results in patients with epithelial histology. In this article, we reviewed the current literature on induction chemotherapy for mesothelioma as well as described the Surgery for Mesothelioma After Radiation Therapy protocol and upcoming studies of novel induction therapies for mesothelioma. PMID- 25527014 TI - Current innovations in sentinel lymph node mapping for the staging and treatment of resectable lung cancer. AB - Despite surgical resectability, early-stage lung cancer remains a challenge to cure. Survival outcomes are hindered by variable performance of adequate lymphadenectomy and the limitations of current pathologic nodal staging. Sentinel lymph node (SLN) mapping, a mainstay in the management of breast cancer and melanoma, permits targeted nodal sampling for efficient and accurate staging that can influence both intraoperative and adjuvant treatment decisions. Unfortunately, standard SLN identification techniques with blue dye and radiocolloid tracers have not been shown to be reproducible in lung cancer. In more recent years, intraoperative near-infrared image-guided lung SLN mapping has emerged as promising technology for the identification of the tumor-associated lymph nodes most likely to contain metastatic disease. Additionally, the clinical relevance of SLN mapping for lung cancer remains pressing, as the ability to identify micrometastatic disease in SLNs could facilitate trials to assess chemotherapeutic response and the clinical effect of occult nodal disease. This review outlines the status of lung cancer lymphatic mapping and techniques in development that may help close the gap between translational research in this field and routine clinical practice. PMID- 25527017 TI - Current readings: Aortic valve-sparing operations. AB - It has been more than 2 decades since aortic valve-sparing operations were introduced to preserve the aortic valve in patients with aortic root aneurysm. Remodeling of the aortic root is physiologically superior to reimplantation of the aortic valve, mostly because it preserves the aortic annulus movement during the cardiac cycle. However, several comparative studies have shown that reimplantation of the aortic valve has provided more stable aortic valve function than remodeling of the aortic root. This difference in outcomes is largely because of patients' selection. Remodeling of the aortic root has been associated with high failure rates in patients with aneurysms associated with genetic syndromes and bicuspid aortic valves with dilated aortic annulus, but it has provided excellent long-term results in older patients with aortic root aneurysms secondary to ascending aortic aneurysms and normal aortic annulus. Thus, both techniques are useful in preserving the aortic valve. With either technique, restoration of normal aortic annulus and cusp geometry is the single most important technical aspect of these operations. In addition to having a competent valve with no or trivial aortic insufficiency at the end of the operation, there must be no cusp prolapse and the coaptation level of the cusps has to be well above the level of the nadir of the aortic annulus. PMID- 25527016 TI - Use of antiplatelet drugs after cardiac operations. AB - Unfortunately, venous bypass grafts still have a prominent role in operative coronary revascularization (coronary artery bypass graft [CABG]). Venous grafts develop pathologically occlusive disease that limits the effectiveness of CABG, and antiplatelet drugs following operation may limit this problem. The types and indications of antiplatelet drugs following CABG generate some controversy in the recent literature. This review surveys relevant evidence about the use of antiplatelet drugs following CABG to identify the controversial issues, define appropriate questions, and attempt to provide evidence-based interventions that may be helpful in limiting graft occlusion after CABG. Evidence suggests that, in most CABG patients, dual antiplatelet drugs (aspirin and clopidogrel), given after operation, minimizes early (within 1 year) graft failure and improves intermediate-term outcomes, better than single antiplatelet therapy with aspirin alone. There are gaps in the knowledge base that supports this contention, and future clinical trials will likely augment or alter this recommendation. PMID- 25527018 TI - Current readings: Percutaneous ablation for pulmonary metastatic disease. AB - Percutaneous image-guided ablation is a technique for maintaining local control of metastatic lung lesions that may, in selected patients, confer a survival benefit over no treatment or systemic therapy alone. Although the currently accepted treatment for oligometastatic pulmonary disease is surgical resection, the existing body of literature, including the recent investigations reviewed within this article, supports a role for percutaneous ablation as an important and relatively safe therapeutic option for nonsurgical and in carefully selected surgical patients, conferring survival benefits competitive with surgical metastasectomy. Continued clinical investigations are needed to further understand the nuances of thermal technologies and applications to treat lung primary and secondary pulmonary malignancy, directly compare available therapeutic options and further define the role of percutaneous image-guided ablation in the treatment of pulmonary metastatic disease. PMID- 25527015 TI - The new IASLC-ATS-ERS lung adenocarcinoma classification: what the surgeon should know. AB - In 2011, a new histologic classification of lung adenocarcinomas was proposed from a joint working group of the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society, based on the recommendation of an international and multidisciplinary panel. This classification proposed a method of comprehensive histologic subtyping (lepidic, acinar, papillary, micropapillary, and solid pattern) based on semiquantitative assessment of histologic patterns (in 5% increments), with the ultimate goal of choosing a single, predominant pattern. Prognostic subsets could then be described for the classification. Patients with completely resected adenocarcinoma in situ and minimally invasive adenocarcinomas experienced low risk of recurrence. Patients with micropapillary or solid predominant tumors have a high risk of recurrence or cancer-related death. Patients with acinar and papillary predominant tumors comprise an intermediate-risk group. Herein, we review the outline of the proposed International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society classification, a summary of published validation studies of this new classification, and then discuss the key surgical issues; we mainly focused on limited resection as an adequate treatment for early-stage lung adenocarcinomas, as well as preoperative and intraoperative diagnoses. We also review the published studies that identified the importance of histologic subtypes in predicting recurrence, both rates and patterns, in early-stage lung adenocarcinomas. This new classification for the most common type of lung cancer is useful for surgeons, as its implementation would require only hematoxylin-and eosin histology slides, which is the common type of stain used in hospitals. It can be implemented with routine pathology evaluation and with no additional costs. PMID- 25527019 TI - Current readings: Redefining minimally invasive: uniportal video-assisted thoracic surgery. AB - Minimally invasive surgery is clearly dominating the modern surgical era across multiple surgical subspecialties and thoracic surgery is no exception. Video assisted thoracic surgery (VATS) is a well-established method of performing various interventions, and it continues to gain momentum. Though small differences in VATS methods exist, it is commonly accepted as a non-rib-spreading approach into the thoracic cavity via 2-4 incisions and allows for a wide range of anatomical and nonanatomical pulmonary resections. As more experience is gained with VATS, more complex surgeries take place and greater refinement of the technique occurs. A newer single-incision or uniportal VATS has been described to minimize surgical trauma, to decrease the number and size of thoracic incisions, to reduce the number of complications, and to enable faster recovery. It allows performing a full spectrum of thoracic operations through a single incision adhering to surgical and oncological principles without compromise. PMID- 25527020 TI - Manpower: what is the future. PMID- 25527021 TI - The anatomy and morphometry of cervical zygapophyseal joint meniscoids. AB - PURPOSE: Meniscoids are folds of synovial membrane that project into the articular cavities of zygapophyseal joints throughout the cervical spine. These structures have been implicated in musculoskeletal neck pain; however, their anatomy has not been extensively investigated. The purpose of this study was to explore the morphometry and composition of the cervical zygapohyseal joint meniscoids. METHODS: Twelve adult cadaveric hemi-spines were dissected and their C2-3 to C6-7 zygapophyseal joints disarticulated (six female; six left; mean 81.5 years, SD 7.3 years). Meniscoids were identified and their surface area, protrusion length and articular cartilage degeneration measured. Specimens were then sectioned sagittally, stained with haematoxylin and eosin, and examined with a light microscope. Data were analysed descriptively and using non-parametric hypothesis testing (significance p < 0.05). RESULTS: Meniscoids were identified in 86% of zygapophyseal joints examined; 50% contained both ventral and dorsal meniscoids, 7% contained a ventral meniscoid only and 29% contained a dorsal meniscoid only. Meniscoids were classified as adipose (4%), fibrous (74%), or fibroadipose (22%) based upon histological composition. There were no significant associations between meniscoid size (surface area or protrusion length) and gender, position in joint, spinal level, or articular degeneration. Increased articular degeneration was associated with fibrous meniscoid classification. CONCLUSIONS: The morphological patterns observed, such as the association of fibrous meniscoids with cartilage degeneration, may provide insight into the significance of the zygapophyseal joint meniscoids in neck pathology. Further investigation is needed to explore the morphological qualities of these structures in a pathological population. PMID- 25527022 TI - Pancreatic carcinoma in an African clawed frog (Xenopus laevis). AB - This report describes the histologic features of a pancreatic carcinoma in an adult female African clawed frog (Xenopus laevis). The animal was found to be in poor body condition and subsequently euthanized for a complete necropsy. Histologically, the pancreas was effaced by packets of polyhedral cells consistent with a pancreatic islet cell carcinoma. Metastatic disease was not identified. Pancreatic tumors are uncommon in amphibians, and this report is the first to describe a pancreatic carcinoma in an African clawed frog. PMID- 25527024 TI - Core body temperature as adjunct to endpoint determination in murine median lethal dose testing of rattlesnake venom. AB - Median lethal dose (LD50) testing in mice is the 'gold standard' for evaluating the lethality of snake venoms and the effectiveness of interventions. As part of a study to determine the murine LD50 of the venom of 3 species of rattlesnake, temperature data were collected in an attempt to more precisely define humane endpoints. We used an 'up-and-down' methodology of estimating the LD50 that involved serial intraperitoneal injection of predetermined concentrations of venom. By using a rectal thermistor probe, body temperature was taken once before administration and at various times after venom exposure. All but one mouse showed a marked, immediate, dose-dependent drop in temperature of approximately 2 to 6 degrees C at 15 to 45 min after administration. The lowest temperature sustained by any surviving mouse was 33.2 degrees C. Surviving mice generally returned to near-baseline temperatures within 2 h after venom administration, whereas mice that did not survive continued to show a gradual decline in temperature until death or euthanasia. Logistic regression modeling controlling for the effects of baseline core body temperature and venom type showed that core body temperature was a significant predictor of survival. Linear regression of the interaction of time and survival was used to estimate temperatures predictive of death at the earliest time point and demonstrated that venom type had a significant influence on temperature values. Overall, our data suggest that core body temperature is a useful adjunct to monitoring for endpoints in LD50 studies and may be a valuable predictor of survival in venom studies. PMID- 25527026 TI - Gastrointestinal acute radiation syndrome in Gottingen minipigs (Sus scrofa domestica). AB - In the absence of supportive care, exposing Gottingen minipigs to gamma-radiation doses of less than 2 Gy achieves lethality due to hematopoietic acute radiation syndrome. Doses of 2 to 5 Gy are associated with an accelerated hematopoietic syndrome, characterized by villus blunting and fusion, the beginning of sepsis, and a mild transient reduction in plasma citrulline concentration. We exposed male Gottingen minipigs (age, 5 mo; weight, 9 to 11 kg) to gamma-radiation doses of 5 to 12 Gy (total body; (60)Co, 0.6 Gy/min) to test whether these animals exhibit classic gastrointestinal acute radiation syndrome (GI-ARS). After exposure, the minipigs were monitored for 10 d by using clinical signs, CBC counts, and parameters associated with the development of the gastrointestinal syndrome. Gottingen minipigs exposed to gamma radiation of 5 to 12 Gy demonstrate a dose-dependent occurrence of all parameters classically associated with acute GI-ARS. These results suggest that Gottingen minipigs may be a suitable model for studying GI-ARS after total body irradiation, but the use of supportive care to extend survival beyond 10 d is recommended. This study is the first step toward determining the feasibility of using Gottingen minipigs in testing the efficacy of candidate drugs for the treatment of GI-ARS after total body irradiation. PMID- 25527023 TI - Housing conditions modulate the severity of Mycoplasma pulmonis infection in mice deficient in class A scavenger receptor. AB - Mycoplasmosis is a frequent causative microbial agent of community-acquired pneumonia and has been linked to exacerbation of chronic obstructive pulmonary disease. The macrophage class A scavenger receptor (SRA) facilitates the clearance of noxious particles, oxidants, and infectious organisms by alveolar macrophages. We examined wildtype and SRA(-/-) mice, housed in either individually ventilated or static filter-top cages that were cycled with fresh bedding every 14 d, as a model of gene-environment interaction on the outcome of pulmonary Mycoplasma pulmonis infection. Intracage NH3 gas measurements were recorded daily prior to infection. Mice were intranasally infected with 1 * 10(7) cfu M. pulmonis UAB CT and evaluated at 3, 7, and 14 d after inoculation. Wildtype mice cleared 99.5% of pulmonary M. pulmonis by 3 d after infection but remained chronically infected through the study. SRA (-/-) mice were chronically infected with 40-fold higher mycoplasma numbers than were wildtype mice. M. pulmonis caused a chronic mixed inflammatory response that was accompanied with high levels of IL1beta, KC, MCP1, and TNFalpha in SRA(-/-) mice, whereas pulmonary inflammation in WT mice was represented by a monocytosis with elevation of IL1beta. Housing had a prominent influence on the severity and persistence of mycoplasmosis in SRA(-/-) mice. SRA(-/-) mice housed in static cages had an improved recovery and significant changes in surfactant proteins SPA and SPD compared with baseline levels. These results indicate that SRA is required to prevent chronic mycoplasma infection of the lung. Furthermore, environmental conditions may exacerbate chronic inflammation in M. pulmonis-infected SRA(-/-) mice. PMID- 25527025 TI - Trophoblast deportation to the lungs of cotton rats (Sigmodon hispidus). AB - Cotton rats (Sigmodon hispidus) have been used to study a variety of infectious agents, particularly human respiratory viral pathogens. During the course of comprehensive pathologic evaluations of aging breeders from our breeding colony, 6 of 22 (27%) female cotton rats had histologic evidence, limited to the lungs, of embolized cells that were confirmed to be trophoblastic in origin by HSD3B1 immunoreactivity. When pulmonary trophoblast emboli were numerous, they usually were associated with additional histologic findings in the lungs, including pulmonary edema and hemorrhage, endothelial hypertrophy, fibrinoid vascular necrosis, and abundant alveolar macrophages containing fresh fibrin and hemolyzing erythrocytes. Of the 6 cotton rats with pulmonary trophoblast emboli, 5 (83%) were at 8 to 18 d of the 27-d gestation period, with the greatest number of emboli per lung present between days 10 through 14. The remaining cotton rat had a focal pulmonary trophoblast embolus and was not pregnant but had delivered a litter 3 mo previously. Three other cotton rats in either the early or late stages of gestation showed no histologic evidence of pulmonary trophoblast deportation. This report is the first to document pulmonary trophoblast emboli in cotton rats. This finding suggests that cotton rats may be an alternative animal model for the study of normal and aberrant trophoblast deportation in routine pregnancies and gestational pathologic conditions in women. PMID- 25527027 TI - Novel technique for retroperitoneal implantation of telemetry transmitters for physiologic monitoring in Gottingen minipigs (Sus scrofa domesticus). AB - Telemetric monitoring of physiologic parameters in animal models is a critical component of chemical and biologic agent studies. The long-term collection of neurobehavioral and other physiologic data can require larger telemetry devices. Furthermore, such devices must be implanted in a location that is safe, well tolerated, and functional. Gottingen minipigs (Sus scrofa domesticus) present an ideal large animal model for chemical agent studies due to their relatively small size, characterized health status, and ease of training and handling. We report an effective approach to implanting a novel device to measure transthoracic impedance to approximate respiratory tidal volume and rate in Suidae. We tested the approach using 24 male Gottingen minipigs. A ventral midline abdominal incision extending from the umbilicus to the prepuce was followed by a paramedian incision of the parietal peritoneum and dorsal blunt dissection to create a retroperitoneal pocket. The device was anchored inside the pocket to the internal abdominal musculature with 3-0 nonabsorbable suture, biopotential leads were routed through the abdominal musculature, and the pocket was closed with 3-0 absorbable suture. Paired biopotential leads were anchored intermuscularly at the level of the seventh rib midway between spine and sternum bilaterally to provide surrogate data for respiratory function. Postoperative recovery and gross pathology findings at necropsy were used to assess safety and refine the surgical procedure. Results demonstrated that this procedure permitted effective monitoring of complex physiologic data, including transthoracic impedance, without negatively affecting the health and behavior of the animals. PMID- 25527028 TI - Noninvasive assessment of pulse-wave velocity and flow-mediated vasodilation in anesthetized Gottingen minipigs. AB - Few methods for noninvasive assessment of arterial stiffness and endothelial dysfunction in porcine models are available. The aim of this study was to evaluate methods for assessment of arterial stiffness and endothelial dysfunction in anesthetized Gottingen minipigs. Pulse-wave velocity (PWV) was assessed in male Gottingen minipigs (n = 8; age approximately 60 wk) by using applanation tonometry of the carotid and femoral arteries. In addition, flow-mediated vasodilation (FMD) was assessed by using vascular ultrasonography of the brachial artery to evaluate endothelial dysfunction. To evaluate the reproducibility of the methods, minipigs were anesthetized by intravenous infusion of ketamine and midazolam and examined every other day for a total of 3 trials. Neither examination day nor systolic, diastolic, or mean arterial blood pressure statistically influenced PWV or FMD. The median interexamination coefficient of variation was 17% for PWV and 59% for FMD. Measured values of PWV corresponded largely to those in clinically healthy humans, but FMD values were lower than expected for lean, young animals. Although the ketamine-midazolam anesthesia we used has been associated with minor hemodynamic effects in vivo, in vitro studies suggest that both drugs are vasodilatory. Therefore anesthesia might have influenced the endothelial response, contributing to the modest FMD response and the concurrent high coefficients of variation that we noted. We conclude that PWV but not FMD-showed acceptable interexamination variation for its potential application in porcine models. PMID- 25527029 TI - Prevalence and diagnosis of hemotrophic mycoplasma infection in research sheep and its effects on hematology variables and erythrocyte membrane fragility. AB - Hemotrophic mycoplasma (hemoplasma) infection in research sheep can confound experimental results and contribute to morbidity and mortality. Prevalence and clinicopathologic studies historically relied on blood-smear diagnosis, but systematic studies using current molecular techniques are warranted. Here we sought to report the prevalence of subclinical infection in our study population, compare diagnostic sensitivity and specificity between blood smears and a PCR assay, and determine the effects of infection on CBC variables and erythrocyte membrane fragility. We collected whole-blood samples from 111 convenience-sampled research sheep. All samples were tested for hemoplasmas by using a PCR assay, blood smears were evaluated for visual presence of hemoplasmas, and CBC and osmotic fragility assays were performed. Subclinical prevalence, according to PCR diagnosis, was 14.1% (14 of 99) in our study population. Relative to the PCR assay, blood-smear diagnosis was 8.3% sensitive and 100% specific for hemoplasma detection. Subclinical infection was associated with changes in MCV, MCHC, RBC distribution width, and absolute monocyte count. Acute infection was associated with changes in RBC mass, Hgb concentration, MCV, MCH, MCHC, and absolute lymphocyte and monocyte counts. Acute infection was associated with increased mean erythrocyte fragility compared with that in uninfected control and treated sheep. We demonstrated that hemoplasma infection is common in our study population, blood-smear evaluation is insensitive at detecting infection, and infection is associated with changes in CBC variables and increased erythrocyte membrane fragility. These findings raise concerns regarding the suitability of hemoplasma-infected sheep for biomedical research. PMID- 25527031 TI - Extraintestinal campylobacteriosis in rhesus macaques (Macaca mulatta). AB - Two cases of clinical disease associated with extraintestinal Campylobacter infection were recently encountered in rhesus macaques (Macaca mulatta). The first case was that of a 3-y-old, male, rhesus macaque experimentally infected with SIV, who presented with abdominal pain and a midabdominal mass and was euthanized. Pathology findings included an abscess within the median liver lobe, fibrinopurulent peritonitis, and intestinal serositis with isolation of Campylobacter fetus from the blood, liver, and the hepatic abscess. The second case was that of a 1-mo-old, female, rhesus macaque who died with no apparent history of illness. Gross pathology findings included thin body condition and diarrheic staining of the perineum; histologically, acute multifocal hepatitis with intralesional bacteria was noted. Campylobacter coli was isolated from the liver and colon. Extraintestinal Campylobacter infection is uncommon in humans, usually occurring in immunocompromised subjects and most commonly manifesting as bacteremia. Extraintestinal Campylobacter infections in animals are rare but have been associated with bacteremia and cholecystitis. The macaques presented here were either immunocompromised due to SIV infection (case 1) or more vulnerable due to young age (case 2). These factors likely contributed to the extraintestinal spread of Campylobacter. PMID- 25527030 TI - Parity modifies endocrine hormones in urine and problem-solving strategies of captive owl monkeys (Aotus spp.). AB - Parental behavior modifies neural, physiologic, and behavioral characteristics of both maternal and paternal mammals. These parenting-induced modifications extend to brain regions not typically associated with parental responses themselves but that enhance ancillary responses, such as foraging efficiency and predator avoidance. Here we hypothesized that male and female owl monkeys (Aotus spp.) with reproductive experience (RE) would demonstrate more adaptive ancillary behavioral and neuroendocrine responses than those of their nonRE counterparts. To assess cognitive skills and coping flexibility, we introduced a foraging strategy task, including a set of novel objects (coin holders) marked with different symbols representing different food rewards, to the animals. To assess endocrine responses, urine samples were assayed for cortisol and dehydroepiandrosterone (DHEA) levels and their ratios to determine physiologic measures of emotional regulation in RE and nonRE owl monkeys. Compared with nonRE monkeys, experienced parents had higher DHEA:cortisol ratios after exposure to habituation training and on the first day of testing in the foraging task. Both hormones play critical roles in the stress response and coping mechanisms, and a high DHEA:cortisol ratio usually indicates increased coping skills. In addition, RE monkeys exhibited more efficient foraging responses (by 4-fold) than did the nonRE mating pairs. We conclude that RE modifies relevant behavioral and hormonal responses of both maternal and paternal owl monkeys exposed to a challenging cognitive paradigm. Corroborating previous research demonstrating adaptive modifications in foraging efficiency and emotional responses in reproductively experienced rodents, the current results extend these findings to a monogamous primate species. PMID- 25527033 TI - Cysteamine alleviates early brain injury via reducing oxidative stress and apoptosis in a rat experimental subarachnoid hemorrhage model. AB - Oxidative stress plays an important role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). The aim of this study was to assess whether cysteamine prevents post-SAH oxidative stress injury via its antioxidative and anti-apoptotic effects. It was observed that intraperitoneal administration of cysteamine (20 mg/kg/day) could significantly alleviate EBI (including neurobehavioral deficits, brain edema, blood-brain barrier permeability, and cortical neuron apoptosis) after SAH in rats. Meanwhile, cysteamine treatment reduced post-SAH elevated the reactive oxygen species level, the concentration of malondialdehyde, 3-nitrotyrosine, and 8 hydroxydeoxyguanosine and increased the glutathione peroxidase enzymatic activity, the concentration of glutathione and brain-derived neurotrophic factor in brain cortex at 48 h after SAH. These results indicated that administration of cysteamine may ameliorate EBI and provide neuroprotection after SAH in rat models. PMID- 25527032 TI - The draft genome of the pest tephritid fruit fly Bactrocera tryoni: resources for the genomic analysis of hybridising species. AB - BACKGROUND: The tephritid fruit flies include a number of economically important pests of horticulture, with a large accumulated body of research on their biology and control. Amongst the Tephritidae, the genus Bactrocera, containing over 400 species, presents various species groups of potential utility for genetic studies of speciation, behaviour or pest control. In Australia, there exists a triad of closely-related, sympatric Bactrocera species which do not mate in the wild but which, despite distinct morphologies and behaviours, can be force-mated in the laboratory to produce fertile hybrid offspring. To exploit the opportunities offered by genomics, such as the efficient identification of genetic loci central to pest behaviour and to the earliest stages of speciation, investigators require genomic resources for future investigations. RESULTS: We produced a draft de novo genome assembly of Australia's major tephritid pest species, Bactrocera tryoni. The male genome (650-700 Mbp) includes approximately 150 Mb of interspersed repetitive DNA sequences and 60 Mb of satellite DNA. Assessment using conserved core eukaryotic sequences indicated 98% completeness. Over 16,000 MAKER-derived gene models showed a large degree of overlap with other Dipteran reference genomes. The sequence of the ribosomal RNA transcribed unit was also determined. Unscaffolded assemblies of B. neohumeralis and B. jarvisi were then produced; comparison with B. tryoni showed that the species are more closely related than any Drosophila species pair. The similarity of the genomes was exploited to identify 4924 potentially diagnostic indels between the species, all of which occur in non-coding regions. CONCLUSIONS: This first draft B. tryoni genome resembles other dipteran genomes in terms of size and putative coding sequences. For all three species included in this study, we have identified a comprehensive set of non-redundant repetitive sequences, including the ribosomal RNA unit, and have quantified the major satellite DNA families. These genetic resources will facilitate the further investigations of genetic mechanisms responsible for the behavioural and morphological differences between these three species and other tephritids. We have also shown how whole genome sequence data can be used to generate simple diagnostic tests between very closely-related species where only one of the species is scaffolded. PMID- 25527034 TI - Biomechanical factors related to occlusal load transfer in removable complete dentures. AB - Owing to economic conditions, removable dentures remain popular despite the discomfort and reduced chewing efficiency experienced by most denture wearers. However, there is little evidence to confirm that the level of mucosal load exceeds the pressure pain threshold. This discrepancy stimulated us to review the current state of knowledge on the biomechanics of mastication with complete removable dentures. The loading beneath dentures was analyzed in the context of denture foundation characteristics, salivary lubrication, occlusal forces, and the biomechanics of mastication. The analysis revealed that the interpretation of data collected in vivo is hindered due to the simultaneous overlapping effects of many variables. In turn, problems with determining the pressure beneath a denture and analyzing frictional processes constitute principal limitations of in vitro model studies. Predefined conditions of finite element method simulations should include the effects of oblique mastication forces, simultaneous detachment and sliding of the denture on its foundation, and the stabilizing role of balancing contacts. This review establishes that previous investigations may have failed because of their unsubstantiated assumption that, in a well-working balanced occlusion, force is only exerted perpendicular to the occlusal plane, allowing the denture to sit firmly on its foundation. Recent improvements in the simulation of realistic biomechanical denture behavior raise the possibility of assessing the effects of denture design on the pressures and slides beneath the denture. PMID- 25527035 TI - Caffeine improves reaction time, vigilance and logical reasoning during extended periods with restricted opportunities for sleep. AB - RATIONALE: Various occupational groups are required to maintain optimal physical and cognitive function during overnight periods of wakefulness, often with less than optimal sleep. Strategies are required to help mitigate the impairments in cognitive function to help sustain workplace safety and productivity. OBJECTIVES: To test the effectiveness of repeated 200 mg doses of caffeine on cognitive function and live-fire marksmanship with soldiers during three successive nights of sustained wakefulness followed by 4-h afternoon sleep periods. METHODS: Twenty Special Forces personnel (28.6 +/- 4.7 years, 177.6 +/- 7.5 cm and 81.2 +/- 8.0 kg) were randomly assigned to receive four 200-mg doses of caffeine (n = 10) or placebo (n = 10) during the late evening and early morning hours during three successive days. An afternoon 4-h sleep period followed. The psychomotor (PVT) and field (FVT) vigilance, logical reasoning (LRT) tests and a vigilance monitor assessed cognitive function throughout the study. Live-fire marksmanship requiring friend-foe discrimination was assessed. RESULTS: Caffeine maintained speed on the PVT (p < 0.02), improved detection of events during FVT (p < 0.001), increased number of correct responses to stimuli as assessed by the vigilance monitor (p < 0.001) and increased response speed during the LRT (p < 0.001) throughout the three overnight testing periods. Live-fire marksmanship was not altered by caffeine. CONCLUSIONS: A total daily dose of 800 mg caffeine during successive overnight periods of wakefulness is an effective strategy to maintain cognitive function when optimal sleep periods during the day are not available. PMID- 25527036 TI - Glucose, relational memory, and the hippocampus. AB - RATIONALE: Many studies suggest that glucose can temporarily enhance hippocampal dependent memories. As the hippocampus plays a key role in associative learning, we examined the influence of glucose on verbal paired associate memory. OBJECTIVE: This study examines how glucose modifies performance on a relational memory task by examining its influence on learning, subsequent forgetting and relearning. METHODS: A selective reminding procedure was used to show high and low imagability paired associates to 80 participants, who were seen twice. On the first session, they received 25 g glucose pre-learning, 25 g glucose post learning or placebo. On the second session, 1 week later, they received 25 g glucose or placebo. Cued-recall was evaluated after each learning trial, 1 week later to assess forgetting and after an opportunity to relearn the material forgotten. RESULTS: Glucose did not influence paired associate acquisition. Those given glucose pre-learning tended to forget less material the following week, and independently, glucose at retrieval facilitated cued-recall. Both forms of facilitation were equally apparent on low and high imagability pairs. The benefit of glucose pre-learning was eliminated once the paired associates had been seen again, but the benefit of glucose at retrieval extended into the second relearning trial. CONCLUSIONS: The discussion considers the cognitive processes and hippocampal basis for paired associate learning and retention and the implications for glucose's mode of action. It is proposed that glucose during encoding serves to make the delayed memories initially more available, whereas its influence during delayed retrieval makes available memories temporarily more accessible. PMID- 25527037 TI - Expression and purification of functional human glycogen synthase-1:glycogenin-1 complex in insect cells. AB - We report the successful expression and purification of functional human muscle glycogen synthase (GYS1) in complex with human glycogenin-1 (GN1). Stoichiometric GYS1:GN1 complex was produced by co-expression of GYS1 and GN1 using a bicistronic pFastBacTM-Dual expression vector, followed by affinity purification and subsequent size-exclusion chromatography. Mass spectrometry analysis identified that GYS1 is phosphorylated at several well-characterised and uncharacterised Ser/Thr residues. Biochemical analysis, including activity ratio (in the absence relative to that in the presence of glucose-6-phosphate) measurement, covalently attached phosphate estimation as well as phosphatase treatment, revealed that recombinant GYS1 is substantially more heavily phosphorylated than would be observed in intact human or rodent muscle tissues. A large quantity of highly-pure stoichiometric GYS1:GN1 complex will be useful to study its structural and biochemical properties in the future, which would reveal mechanistic insights into its functional role in glycogen biosynthesis. PMID- 25527038 TI - Neutrophil to lymphocyte ratio in Behcet's disease as a marker of disease activity. AB - INTRODUCTION: Behcet's disease (BD) is a rare autoimmune disease. The neutrophil to lymphocyte ratio (NLR) is used as a marker of inflammation in several diseases nowadays. This study investigated the NLR as an inflammation marker in BD. METHODS: Sixty-five patients diagnosed with BD and 100 healthy subjects were enrolled in this study retrospectively. The white blood cell (WBC), neutrophil, and lymphocyte counts were recorded, and the NLR was calculated from these parameters. RESULTS: The NLR and the CRP and WBC levels were higher in patients with BD than controls (p < 0.001, p < 0.001, and p = 0.026, respectively). In addition, the NLR was higher in patients with active BD than in those with inactive BD (p = 0.033). DISCUSSION: The results demonstrate that the NLR is higher in patients with active BD compared to controls and those with inactive BD. PMID- 25527039 TI - Professionals' role in implementing a cervical cancer screening program. AB - The objectives of this study were to investigate the awareness, motivation, and readiness of medical staff to take part in a cervical cancer screening program (CSP), with the ultimate aim of increasing the response rate to invitation letters and improving CSP effectiveness and coverage. Certified gynecologists (GYNs) and general practitioners (GPs) practicing in the national and private healthcare systems in Latvia were given specially designed multiple-choice questionnaires. Of 213 questionnaires distributed to GYNs, 74% were completed (32% response rate of all 486 GYNs in Latvia). GPs were sent 933 questionnaires, 24% were returned (15% response rate of all 1,455 GPs in Latvia). GPs registered for 10 years or more knew significantly less about prevention and screening for cervical cancer compared to GYNs registered for the same amount of time (p = 0.05). This finding was not seen among the GYNs (p = 0.782). In the entire study group, the average score for correct answers was 5.97 (SD 2.602). Knowledge in the GP group was significantly lower (5.03, SD 2.243) than in the GYN group (7.22, SD 2.527, p < 0.001). Irrespective of specialization and place of work, knowledge was evaluated as poorer with an increase in age (RR = 0.950; p < 0.001). The knowledge, awareness, and perception of GYNs regarding cervical cancer prevention and screening in Latvia is sufficient but not good, and that of GPs is poor. Doctors would like to learn more about preventing cervical cancer. PMID- 25527041 TI - Multiple minute digitate hyperkeratosis affecting the face and folds: clinical, dermoscopic, and histological report of a familial case. AB - A case of a generalized non-follicular digitate keratosis classified as multiple minute digitate hyperkeratosis is described with suggestive clinical, dermoscopic, and histopathogical data. The patient was a 52-year-old Caucasian woman presenting a 6-year history of multiple asymptomatic skin-colored digitate lesions, 3 to 5 mm long and 1 to 2 mm wide, distributed on the forehead, neck, and extensor surface of the arms as well as in the inframammary folds, axillae, and lower limbs, especially on the popliteal fold. She reported having a 67-year old sister and a 39-year-old niece with an identical eruption. Treatment with 15% glycolic acid (AHA) lotion and heliotherapy improved this disturbing eruption. PMID- 25527040 TI - Topical propranolol cream in treatment of superficial infantile hemangiomas: a literature review and 4 years of clinical experience. AB - The clinical efficacy and safety profile of propranolol 1% cream in treatment of superficial infantile hemangiomas (IHs) were determined in a preliminary randomized group of eight infants. Five boys and three girls, 3 to 12 months old, with an IHs superficial capillary type on the forehead, posterior side of the neck, forearm, abdomen, or posterior side of the trunk were examined at our outpatient clinic between 2011 and 2014. Topical propranolol was applied twice daily for 10 months with clinical evaluation and photographic documentation performed every 1 to 2 months. Size, texture, and color changes were monitored. Therapeutic efficacy was evaluated using the Archauer system: Grade I (bad) reduction in size < 25%, Grade II (medium) reduction between 26% and 50%, Grade III (good) reduction between 51% and 75%, and Grade IV (excellent) reduction > 75%. The majority of hemangiomas treated, 62.5%, achieved Grade IV. A Grade III outcome was noticed in one patient with an IH (12.5%) and Grade II in 25% of patients with IHs on the abdomen. The treatment was well tolerated without side effects, which indicates that topical application of 1% propranolol is a safe, effective, and cheap therapeutic option for treating superficial IHs. PMID- 25527042 TI - Eczema within port wine stain: spontaneous and laser-induced Meyerson phenomenon. AB - Port wine stain (PWS, nevus flammeus) is a relatively common vascular malformation of postcapillary venules affecting 0.3 to 0.5% of newborn children. Since the mid-1990s, a case series and several case reports have described dermatitis on PWS corresponding to Meyerson phenomenon, usually reported in the setting of melanocytic nevi. There is no universal explanation of the cause or pathogenesis of eczema occurring in PWS, but it may be precipitated by atopic disease or vascular laser treatment of the malformation. Here we described two non-atopic girls with dermatitis developing within their nevi flammei, in one temporally related to KTP laser treatment, and in the other obviously not associated with the treatment. However, in both patients the eczema responded well to a short course of topical corticosteroids. PMID- 25527043 TI - Management of fracture and lateral dislocation of the thoracic spine without any neurological deficits: three case reports and review of the literature. AB - BACKGROUND: Fracture and dislocation of the thoracic spine without neurological deficits are rare. Most of these cases are managed by non-operative methods or a posterior approach surgery. AIM: To report three cases of fracture and lateral dislocation of the thoracic spine without neurological deficits and review the literature on the management strategy. METHODS: Three patients who suffered thoracic spinal fracture and lateral dislocation without spinal cord injury underwent anterior decompression, reduction and internal fixation. The case series describe their management, surgical intervention and their follow-up. RESULTS: Reduction was satisfactory, none of the patients had any postoperative neurological deficits. Fusion was successful, and vertebral column alignment was maintained at the last follow-up. CONCLUSION: An anterior approach facilitated adequate decompression, reduction and stabilization through instrumentation in this series of injury without neurological deficits. PMID- 25527044 TI - Human-biometeorological conditions and thermal perception in a Mediterranean coastal park. AB - This study looks at the interrelation of human-biometeorological conditions, physiological thermal stress and subjective thermal perception in the design and use of a new waterfront park in Tel-Aviv, Israel. Our initial assumption was that the park's design would embody a comprehensive response to the area's ever increasing heat stress and water shortage. However, almost half of it is covered by grass lawns, irrigated with fresh water, while the remaining area is mainly covered with concrete paving, with minimal shading and sparse trees. We hypothesized that stressful thermal conditions would prevail in the park in the summer season and would be expressed in a high discomfort perception of its users. Thermo-physiological stress conditions in a typical summer month were compared with the subjective comfort perceptions of pedestrians surveyed in the park. It was found that even during mid-day hours, the level of thermal stress tends to be relatively mild, owing largely to the strong sea breeze and despite the high intensity of solar radiation. Moreover, it appears that the largely favorable perception of comfort among individuals may also result from socio cultural aspects related to their satisfaction with the park's aesthetic attractiveness and in fact its very existence. Adaptive planning is proposed for such vulnerable regions, which are expected to experience further aggravation in thermal comfort due to global as well as localized warming trends. PMID- 25527045 TI - The secreted proteins of Achlya hypogyna and Thraustotheca clavata identify the ancestral oomycete secretome and reveal gene acquisitions by horizontal gene transfer. AB - Saprotrophic and parasitic microorganisms secrete proteins into the environment to breakdown macromolecules and obtain nutrients. The molecules secreted are collectively termed the "secretome" and the composition and function of this set of proteins varies depending on the ecology, life cycle, and environment of an organism. Beyond the function of nutrient acquisition, parasitic lineages must also secrete molecules to manipulate their host. Here, we use a combination of de novo genome and transcriptome sequencing and bioinformatic identification of signal peptides to identify the putative secreted proteome of two oomycetes, the facultative parasite Achlya hypogyna and free-living Thraustotheca clavata. By comparing the secretomes of these saprolegnialean oomycetes with that of eight other oomycetes, we were able to characterize the evolution of this protein set across the oomycete clade. These species span the last common ancestor of the two major oomycete families allowing us to identify the ancestral secretome. This putative ancestral secretome consists of at least 84 gene families. Only 11 of these gene families are conserved across all 10 secretomes analyzed and the two major branches in the oomycete radiation. Notably, we have identified expressed elicitin-like effector genes in the saprotrophic decomposer, T. clavata. Phylogenetic analyses show six novel horizontal gene transfers to the oomycete secretome from bacterial and fungal donor lineages, four of which are specific to the Saprolegnialeans. Comparisons between free-living and pathogenic taxa highlight the functional changes of oomycete secretomes associated with shifts in lifestyle. PMID- 25527046 TI - High expression of CXCR3 is an independent prognostic factor in glioblastoma patients that promotes an invasive phenotype. AB - Chemokines are a superfamily of small heparin-binding cytokines that induce leukocytes to migrate to sites of inflammation or injury through interacting with specific transmembrane G protein-coupled receptors. Currently, attention is focused on chemokine/chemokine receptor pairs and their ability to promote tumor cell migration and angiogenesis. The chemokine receptor CXCR3 is involved in tumor metastasis and is used as a prognostic biomarker. However, its relationship with the clinicopathological features of primary glioblastoma multiforme (pGBM) and its potential prognostic value have yet to be investigated. Here, we report that high CXCR3 expression conferred poor survival in pGBM patients. Further analysis showed that CXCR3 served as an independent prognostic biomarker for pGBM patients. In addition, functional assays indicated that CXCR3 induced glioma cell invasion. Therefore, this evidence indicates CXCR3 is an independent prognostic factor for pGBM patients and promotes an invasive phenotype, which suggests a new potential biotarget for glioblastoma multiforme therapy. PMID- 25527047 TI - Trigeminal isolated sensory neuropathy (TISN) and FOSMN syndrome: despite a dissimilar disease course do they share common pathophysiological mechanisms? AB - BACKGROUND: Patients presenting with bilateral trigeminal hypoesthesia may go on to have trigeminal isolated sensory neuropathy, a benign, purely trigeminal neuropathy, or facial-onset sensory motor neuronopathy (FOSMN), a malignant life threatening condition. No diagnostic criteria can yet differentiate the two conditions at their onset. Nor is it clear whether the two diseases are distinct entities or share common pathophysiological mechanisms. METHODS: Seeking pathophysiological and diagnostic information to distinguish these two conditions at their onset, in this neurophysiological and morphometric study we neurophysiologically assessed function in myelinated and unmyelinated fibres and histologically examined supraorbital nerve biopsy specimens with optic and electron microscopy in 13 consecutive patients with recent onset trigeminal hypoesthesia and pain. RESULTS: The disease course distinctly differed in the 13 patients. During a mean 10 year follow-up whereas in eight patients the disease remained relatively stable, in the other five it progressed to possibly life threatening motor disturbances and extra-trigeminal spread. From two to six years elapsed between the first sensory symptoms and the onset of motor disorders. In patients with trigeminal isolated sensory neuropathy (TISN) and in those with FOSMN neurophysiological and histological examination documented a neuronopathy manifesting with trigeminal nerve damage selectively affecting myelinated fibres, but sparing the Ia-fibre-mediated proprioceptive reflex. CONCLUSIONS: Although no clinical diagnostic criteria can distinguish the two conditions at onset, neurophysiological and nerve-biopsy findings specify that in both disorders trigeminal nerve damage manifests as a dissociated neuronopathy affecting myelinated and sparing unmyelinated fibres, thus suggesting similar pathophysiological mechanisms. PMID- 25527048 TI - The safety of a dry spearmint extract in vitro and in vivo. AB - A proprietary dry spearmint extract containing 15.4% rosmarinic acid was assessed in a 90-day study with Sprague-Dawley rats that were gavaged at 0, 422 (low), 844 (mid), or 1948 (high) mg dry spearmint extract/kg bw/day, (equivalent to 0, 65, 130, or 300 mg rosmarinic acid/kg bw/day, respectively). No treatment-related clinical signs or adverse effects were observed in body weight, feed consumption, neurological parameters, hematology, clinical chemistry, gross pathology, and histopathology. However, there were statistically significant increases in the absolute and relative weight of the pituitary gland in mid- and high-dose males, absolute and relative weight of the thyroid gland in the high-dose groups of both sexes and in mid-dose males, and absolute and relative weight of the salivary glands in high-dose females compared to vehicle control group. These changes were considered non-adverse since no corresponding microscopic changes were seen. Based on these findings, the no-observed-adverse-effect level (NOAEL) for the dry spearmint extract was 1948 mg extract/kg bw/day, the highest dose tested, in Sprague-Dawley rats. In addition, the extract showed no mutagenic activity in the Ames assay using Salmonella typhimurium strains (TA98, TA100, TA102, TA1535, and TA1537) and did not induce chromosomal aberrations when tested with human peripheral blood lymphocytes. PMID- 25527050 TI - GIE 2020: a clear vision for our future. PMID- 25527049 TI - Co-acting gene networks predict TRAIL responsiveness of tumour cells with high accuracy. AB - BACKGROUND: Identification of differentially expressed genes from transcriptomic studies is one of the most common mechanisms to identify tumor biomarkers. This approach however is not well suited to identify interaction between genes whose protein products potentially influence each other, which limits its power to identify molecular wiring of tumour cells dictating response to a drug. Due to the fact that signal transduction pathways are not linear and highly interlinked, the biological response they drive may be better described by the relative amount of their components and their functional relationships than by their individual, absolute expression. RESULTS: Gene expression microarray data for 109 tumor cell lines with known sensitivity to the death ligand cytokine tumor necrosis factor related apoptosis-inducing ligand (TRAIL) was used to identify genes with potential functional relationships determining responsiveness to TRAIL-induced apoptosis. The machine learning technique Random Forest in the statistical environment "R" with backward elimination was used to identify the key predictors of TRAIL sensitivity and differentially expressed genes were identified using the software GeneSpring. Gene co-regulation and statistical interaction was assessed with q-order partial correlation analysis and non-rejection rate. Biological (functional) interactions amongst the co-acting genes were studied with Ingenuity network analysis. Prediction accuracy was assessed by calculating the area under the receiver operator curve using an independent dataset. We show that the gene panel identified could predict TRAIL-sensitivity with a very high degree of sensitivity and specificity (AUC=0.84). The genes in the panel are co-regulated and at least 40% of them functionally interact in signal transduction pathways that regulate cell death and cell survival, cellular differentiation and morphogenesis. Importantly, only 12% of the TRAIL-predictor genes were differentially expressed highlighting the importance of functional interactions in predicting the biological response. CONCLUSIONS: The advantage of co-acting gene clusters is that this analysis does not depend on differential expression and is able to incorporate direct- and indirect gene interactions as well as tissue- and cell-specific characteristics. This approach (1) identified a descriptor of TRAIL sensitivity which performs significantly better as a predictor of TRAIL sensitivity than any previously reported gene signatures, (2) identified potential novel regulators of TRAIL-responsiveness and (3) provided a systematic view highlighting fundamental differences between the molecular wiring of sensitive and resistant cell types. PMID- 25527051 TI - Poetry in motion: examining the role of peroral endoscopic myotomy in children. PMID- 25527052 TI - Endoscopic nasogallbladder tube or stent placement in acute cholecystitis: a preliminary prospective randomized trial in Japan (with videos). AB - BACKGROUND: There are currently no prospective, controlled trials of endoscopic transpapillary gallbladder drainage in patients with acute cholecystitis. OBJECTIVE: We evaluated the technical success rate and efficacy of endoscopic transpapillary gallbladder drainage by using either endoscopic nasogallbladder drainage (ENGBD) or endoscopic gallbladder stenting (EGBS) for patients with acute cholecystitis. DESIGN: Randomized, controlled study. SETTING: Tertiary-care referral centers. PATIENTS: Seventy-three consecutive patients with acute cholecystitis were randomized. INTERVENTIONS: ENGBD by using a 5F or 7F tube (n = 37) or EGBS (n = 36) by using a 7F stent. MAIN OUTCOME AND MEASUREMENTS: Technical success, clinical success, adverse events, and procedure-related pain score. RESULTS: The overall technical success rates in the ENGBD and EGBS groups were 91.9% and 86.1%, respectively (P > .05). The mean procedure times of ENGBD and EGBS were 20.3 +/- 12.1 and 22.2 +/- 14.5 minutes, respectively (P > .05). The overall clinical success rates by per protocol analysis were 94.1% and 90.3% in the ENGBD and EGBS groups, respectively, whereas the rates by intention-to treat analysis were 86.5% and 77.8%, respectively (P > .05). Moderate adverse events were observed in the ENGBD (n = 2) and EGBS (n = 1) groups. The mean visual analog score of postprocedure pain in the ENGBD group was significantly higher than that in the EGBS group (1.3 +/- 1.1 vs 0.4 +/- 0.8, respectively; P < .001). LIMITATIONS: Small sample size and the participation of multiple endoscopists who may have different levels of experience in endoscopic transpapillary gallbladder drainage. CONCLUSIONS: Both ENGBD and EGBS appear to be suitable for the treatment of acute cholecystitis in patients who are poor candidates for emergency cholecystectomy. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000012316.). PMID- 25527053 TI - The risk of post-ERCP pancreatitis and the protective effect of rectal indomethacin in cases of attempted but unsuccessful prophylactic pancreatic stent placement. AB - BACKGROUND: It is believed, based on limited observational data, that an unsuccessful attempt to place a prophylactic pancreatic stent substantially increases the risk of post-ERCP pancreatitis (PEP). OBJECTIVE: To better understand the risk of PEP in patients with failed pancreatic stent placement (FPS) and the impact of rectal indomethacin on this risk. DESIGN: Secondary analysis of randomized, controlled trial data. SETTING: University of Michigan and Indiana University. PATIENTS: A total of 577 clinical trial participants at elevated risk for PEP. INTERVENTIONS: Pancreatic stent placement. MAIN OUTCOME MEASUREMENTS: Within the placebo group, we compared PEP rates in patients with FPS, patients who underwent successful stent placement, and in those without a stent attempt. We also performed a regression analysis evaluating the association between FPS and PEP. To define the protective effect of indomethacin, we repeated these analyses in the indomethacin group and in the full study cohort. RESULTS: The incidence of PEP among patients in the placebo group who experienced FPS was 34.7%, significantly exceeding rates in patients who underwent successful stent placement (16.4%) and in those without a stent attempt (12.1%). After we adjusted for known PEP risk factors, FPS was found to be independently associated with PEP. Among the indomethacin group and in the full cohort, FPS was not associated with a higher risk of PEP. LIMITATIONS: Low event rate, FPS not prospectively captured. CONCLUSION: FPS appears to confer an increased risk of PEP, which is attenuated by rectal indomethacin administration. These findings highlight the importance of adequate training and proficiency before endoscopists attempt pancreatic stent placement and the routine use of rectal indomethacin in high risk ERCP cases. PMID- 25527054 TI - Pancreatic stent placement remains a cornerstone of prevention of post-ERCP pancreatitis, but it requires specialized techniques. PMID- 25527055 TI - EUS is superior for detection of pancreatic lesions compared with standard imaging in patients with multiple endocrine neoplasia type 1. AB - BACKGROUND: In multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (pNETs) are the leading MEN1-related cause of death. OBJECTIVE: To evaluate EUS and (11)C-5-hydroxytryptophan positron emission tomography ((11)C-5-HTP PET), compared with the recommended screening techniques in MEN1 patients for early detection of pNETs. DESIGN: Cross-sectional study. SETTING: Tertiary-care university medical center. PATIENTS: This study involved 41 patients with a proven MEN1 mutation or with one MEN1 manifestation and a mutation carrier as a first-degree family member, with recent screening by abdominal CT or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS). INTERVENTIONS: EUS by using a linear Pentax echoendoscope and Hitachi EUB-525 and (11)C-5-HTP PET. MAIN OUTCOME MEASUREMENTS: Patient-based and lesion-based positivity for pNET was calculated for all imaging techniques. The McNemar test was used to compare the yield of the 4 imaging techniques. RESULTS: In 35 of 41 patients, 107 pancreatic lesions were detected in total. EUS detected 101 pancreatic lesions in 34 patients, (11)C-5-HTP PET detected 35 lesions in 19 patients, and CT/MRI + SRS detected 32 lesions in 18 patients (P < .001). (11)C-5 HTP PET performed similarly to CT/MRI + SRS and better compared with SRS only (13 lesions in 12 patients), both at a patient-based and lesion-based level (P < .05). LIMITATIONS: Single-center study. CONCLUSION: EUS is superior to CT/MRI + SRS for pancreatic lesion detection in patients with MEN1. In this setting, (11)C 5-HTP PET is not useful. We recommend EUS as the first-choice pancreas imaging technique in patients with MEN1. ( CLINICAL TRIAL REGISTRATION NUMBER: NTR1668.). PMID- 25527056 TI - Natural orifice transluminal endoscopic surgery gastroenterostomy with a biflanged lumen-apposing stent: first clinical experience (with videos). AB - BACKGROUND: We established feasibility and safety for natural orifice transluminal endoscopic surgery (NOTES) GI anastomosis with a lumen-apposing stent in live pigs. This approach was performed in 3 patients. OBJECTIVE: Creation of a NOTES gastroduodenal anastomosis in patients. DESIGN: Case series. SETTING: Two tertiary-care referral centers at large academic hospitals in France and in the United States. PATIENTS: Patients with refractory benign duodenal stenosis and malignant duodenal obstruction. INTERVENTION: NOTES GI anastomosis with a lumen-apposing stent. MAIN OUTCOME MEASUREMENTS: Disappearence of gastric outlet obstruction. RESULTS: All 3 procedures were technically successful and uneventful, except 1 minor adverse event. There were no instances of stent occlusion or migration during follow-up. All patients resumed a normal diet. LIMITATIONS: Small case series. CONCLUSION: NOTES gastroenteric anastomosis is feasible and safe in humans. A prospective pilot study is warranted. PMID- 25527057 TI - Tracheoesophageal voice prosthesis: endoscopic appearance. PMID- 25527058 TI - Food that bites back. PMID- 25527059 TI - Pedunculated focal nodular hyperplasia masquerading as perigastric mass identified by EUS-FNA. PMID- 25527060 TI - EUS and treatment of parastomal varices: is novelty important? PMID- 25527061 TI - EUS-FNA versus ERCP-guided sampling for suspected malignant biliary obstruction: which to choose? PMID- 25527062 TI - Response. PMID- 25527063 TI - Guidelines on genetic evaluation and management of Lynch syndrome. PMID- 25527064 TI - Response. PMID- 25527065 TI - Iron metabolism in hard ticks (Acari: Ixodidae): the antidote to their toxic diet. AB - Ticks are notorious parasitic arthropods, known for their completely host-blood dependent lifestyle. Hard ticks (Acari: Ixodidae) feed on their hosts for several days and can ingest blood more than a hundred times their unfed weight. Their blood-feeding habit facilitates the transmission of various pathogens. It is remarkable how hard ticks cope with the toxic nature of their blood meal, which contains several molecules that can promote oxidative stress including iron. While it is required in several physiological processes, high amounts of iron can be dangerous because iron can also participate in the formation of free radicals that may cause cellular damage and death. Here we review the current knowledge on heme and inorganic iron metabolism in hard ticks and compare it with that in vertebrates and other arthropods. We briefly discuss the studies on heme transport, storage and detoxification, and the transport and storage of inorganic iron, with emphasis on the functions of tick ferritins. This review points out other aspects of tick iron metabolism that warrant further investigation, as compared to mammals and other arthropods. Further understanding of this physiological process may help in formulating new control strategies for tick infestation and the spread of tick-borne diseases. PMID- 25527066 TI - Rituximab: an emerging treatment for recurrent diffuse alveolar hemorrhage in systemic lupus erythematosus. AB - Diffuse alveolar hemorrhage (DAH) is a rare manifestation of systemic lupus erythematosus (SLE) and is associated with high mortality rates. Treatment typically consists of aggressive immunosuppression with pulse-dose steroids, cyclophosphamide, and plasma exchange therapy. Mortality rates remain high despite use of multiple medical therapies. We present a case of recurrent DAH in a 52-year-old female with SLE after a deceased donor renal transplant who was successfully treated with rituximab. Our report highlights the pathophysiologic importance of B-cell-mediated immunosuppression in SLE-associated DAH and suggests that rituximab may represent a viable alternative to cyclophosphamide in the treatment of this disease. We also review eight other reported cases of rituximab use in SLE-associated DAH. PMID- 25527067 TI - Care dependency and nursing care problems in nursing home residents with and without dementia: a cross-sectional study. AB - BACKGROUND AND AIM: Chronic diseases, like dementia, can lead to care dependency and nursing care problems. This study aims to compare the degree of care dependency and the prevalence of nursing care problems (pressure ulcer, incontinence, malnutrition, falls, restraints) between residents with and without dementia and between the stages of dementia. METHODS: A cross-sectional design was chosen and a total of 277 residents with and 249 residents without dementia from nine Austrian nursing homes were assessed by staff using standardized instruments. RESULTS: Significantly more residents with than without dementia are completely or to a great extent care dependent (54.5 vs. 16.9 %). The comparison of care dependency between the stages of dementia indicates a large difference between moderate and severe dementia (completely care dependent: 9.3 vs. 44.3 %). The comparison of the assessed nursing care problems between residents with and without dementia reveals a significant difference only with regard to incontinence (urinary: 84.2 vs. 53.2 %, fecal: 50.9 vs. 17.7 %, double: 49.1 vs. 14.9 %). Urinary incontinence is high even in early dementia at 64 %, reaching 94 % in severe dementia. Fecal- and double incontinence are comparatively much lower in early dementia (both types 12 %) and rise to more than 80 % (both types) in severe dementia. CONCLUSION: These results highlight areas in which dementia care needs further improvements. The authors suggest maximizing residents' independence to stabilize care dependency and improve incontinence care. Furthermore, longitudinal studies are recommended to deepen insight into the development of care dependency and nursing care problems in dementia residents. PMID- 25527068 TI - Using photosystem I as a reporter protein for 13C analysis in a coculture containing cyanobacterium and a heterotrophic bacterium. AB - (13)C metabolism analysis of a microbial community is often hindered by the time consuming and complicated separation procedure for a single species. However, a "reporter protein," produced uniquely by one cell type, retains (13)C fingerprint information in microbial consortia. This study describes the use of photosystem I (PSI), a multi-subunit protein complex universally found in oxygenic phototrophs, as a reliable reporter protein to probe microalgal metabolism (i.e., cyanobacterium Synechocystis sp. PCC 6803) in a mixed culture with heterotrophic bacteria (i.e., Escherichia coli). We demonstrate that efficient purification of PSI and subsequent (13)C-based amino acid analyses may decipher photomixotrophic metabolism of Synechocystis 6803 in the coculture. This study also indicates that a supplement of NaHCO3 at high concentration could significantly improve the robustness of cyanobacterial growth against bacterial contamination. PMID- 25527069 TI - CaPSCA: Evaluation of a Brief Cancer Prevention Education Programme to Promote Balanced Diet in French School Children. AB - This study examined the effectiveness of two cancer prevention interventions in improving balanced diet among French children aged 12-14 years. The educational techniques used were taken from the taxonomy of behaviour change techniques (BCTs; Abraham & Michie, 2008). Allocation to intervention group (intervention versus control) was randomised at the school-level, the intervention group received two interventions, each of 1-h duration, containing BCTs including advocated attitude, anticipated success/regret, behaviour modelling and barrier identification. Self-reported diet was assessed pre- and post-interventions. The resulting data were coded by a nutritionist and transformed into a novel measure representing the extent to which the participant achieved a balanced diet. Multilevel modelling indicated that, having taken into account the clustered nature of the data, gender and the differing socio-economic status of the participants, balanced diet decreased over time, b=-1.23, t(1830)=-2.79, p=0.005, but this was qualified by a significant interaction effect with intervention, b=1.42, t(1830)=1.98, p=0.047. Separate models for each intervention group revealed that balanced diet decreased over time in the control group, b=-1.25, t(1195)=-2.47, p=0.014, but did not in the intervention group, b=0.19, t(635)=0.44, p=0.66, suggesting a buffering effect of the interventions on balanced diet over time. These findings demonstrate the effectiveness of educational interventions using established behaviour change techniques, to change behaviour. PMID- 25527071 TI - Assessing the implementation effectiveness and safety of 1% tenofovir gel provision through family planning services in KwaZulu-Natal, South Africa: study protocol for an open-label randomized controlled trial. AB - BACKGROUND: The Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 trial demonstrated a 39% reduction in HIV infection, with a 54% HIV reduction in women who used tenofovir gel consistently. A confirmatory trial is expected to report results in early 2015. In the interim, we have a unique window of opportunity to prepare for and devise effective strategies for the future policy and programmatic scale-up of tenofovir gel provision. One approach is to integrate tenofovir gel provision into family planning (FP) services. The CAPRISA 008 implementation trial provides an opportunity to provide post-trial access to tenofovir gel while generating empiric evidence to assess whether integrating tenofovir gel provision into routine FP services can achieve similar levels of adherence as the CAPRISA 004 trial. METHODS/DESIGN: This is a two-arm, open label, randomized controlled non-inferiority trial. A maximum of 700 sexually active, HIV-uninfected women aged 18 years and older who previously participated in an antiretroviral prevention study will be enrolled from an urban and rural site in KwaZulu-Natal, South Africa. The anticipated study duration is 30 months, with active accrual requiring approximately 12 months (following which an open cohort will be maintained) and follow-up continuing for approximately 18 months. At each of the two sites, eligible participants will be randomly assigned to receive tenofovir gel through either FP services (intervention arm) or through the CAPRISA research clinics (control arm). As part of the study intervention, a quality improvement approach will be used to assist the FP services to expand their current services to include tenofovir gel provision. DISCUSSION: This protocol aims to address an important implementation question on whether FP services are able to effectively incorporate tenofovir gel provision for this at risk group of women in South Africa. Provision of tenofovir gel to the women from the CAPRISA 004 trial meets the ethical obligation for post-trial access, and helps identify a potential avenue for future scale-up of microbicides within the public health system of South Africa. TRIAL REGISTRATION: This trial was registered with the South Africa Department of Health (reference: DOH-27-0812 4129) and ClinicalTrials.gov (reference: NCT01691768) on 05 July 2012. PMID- 25527072 TI - In silico identification of novel ligands for G-quadruplex in the c-MYC promoter. AB - G-quadruplex DNA formed in NHEIII1 region of oncogene promoter inhibits transcription of the genes. In this study, virtual screening combining pharmacophore-based search and structure-based docking screening was conducted to discover ligands binding to G-quadruplex in promoter region of c-MYC. Several hit ligands showed the selective PCR-arresting effects for oligonucleotide containing c-MYC G-quadruplex forming sequence. Among them, three hits selectively inhibited cell proliferation and decreased c-MYC mRNA level in Ramos cells, where NHEIII1 is included in translocated c-MYC gene for overexpression. Promoter assay using two kinds of constructs with wild-type and mutant sequences showed that interaction of these ligands with the G-quadruplex resulted in turning-off of the reporter gene. In conclusion, combined virtual screening methods were successfully used for discovery of selective c-MYC promoter G-quadruplex binders with anticancer activity. PMID- 25527073 TI - A comparative study of family-specific protein-ligand complex affinity prediction based on random forest approach. AB - The assessment of binding affinity between ligands and the target proteins plays an essential role in drug discovery and design process. As an alternative to widely used scoring approaches, machine learning methods have also been proposed for fast prediction of the binding affinity with promising results, but most of them were developed as all-purpose models despite of the specific functions of different protein families, since proteins from different function families always have different structures and physicochemical features. In this study, we proposed a random forest method to predict the protein-ligand binding affinity based on a comprehensive feature set covering protein sequence, binding pocket, ligand structure and intermolecular interaction. Feature processing and compression was respectively implemented for different protein family datasets, which indicates that different features contribute to different models, so individual representation for each protein family is necessary. Three family specific models were constructed for three important protein target families of HIV-1 protease, trypsin and carbonic anhydrase respectively. As a comparison, two generic models including diverse protein families were also built. The evaluation results show that models on family-specific datasets have the superior performance to those on the generic datasets and the Pearson and Spearman correlation coefficients (R p and Rs) on the test sets are 0.740, 0.874, 0.735 and 0.697, 0.853, 0.723 for HIV-1 protease, trypsin and carbonic anhydrase respectively. Comparisons with the other methods further demonstrate that individual representation and model construction for each protein family is a more reasonable way in predicting the affinity of one particular protein family. PMID- 25527070 TI - In vitro augmentation of mesenchymal stem cells viability in stressful microenvironments : In vitro augmentation of mesenchymal stem cells viability. AB - Mesenchymal stem cells (MSCs) are under intensive investigation for use in cell based therapies because their differentiation abilities, immunomodulatory effects, and homing properties offer potential for significantly augmenting regenerative capacity of many tissues. Nevertheless, major impediments to their therapeutic application, such as low proliferation and survival rates remain as obstacles to broad clinical use of MSCs. Another major challenge to evolution of MSC-based therapies is functional degradation of these cells as a result of their exposure to oxidative stressors during isolation. Indeed, oxidative stress mediated MSC depletion occurs due to inflammatory processes associated with chemotherapy, radiotherapy, and expression of pro-apoptotic factors, and the microenvironment of damaged tissue in patients receiving MSC therapy is typically therapeutic not favorable to their survival. For this reason, any strategies that enhance the viability and proliferative capacity of MSCs associated with their therapeutic use are of great value. Here, recent strategies used by various researchers to improve MSC allograft function are reviewed, with particular focus on in vitro conditioning of MSCs in preparation for clinical application. Preconditioning, genetic manipulation, and optimization of MSC culture conditions are some examples of the methodologies described in the present article, along with novel strategies such as treatment of MSCs with secretome and MSC-derived microvesicles. This topic material is likely to find value as a guide for both research and clinical use of MSC allografts and for improvement of the value that use of these cells brings to health care. PMID- 25527074 TI - Reactive oxygen species and sperm DNA damage in infertile men presenting with low level leukocytospermia. AB - BACKGROUND: Leukocytes contribute directly and indirectly to reactive oxygen species (ROS) production. Although leukocytospermia is defined as the presence of >= 1 * 106 white blood cells/mL (WBC/mL) in a semen sample, the presence of less than 1*10(6) WBC/mL (low-level leukocytospermia) can still produce a detectable amount of ROS, impairing sperm function and lowering the chances of pregnancy. Our objective was to assess the effect of low-level leukocytospermia on semen quality, ROS levels, and DNA damage in infertile men. METHODS: Semen samples were examined from 472 patients and divided into 3 groups: no seminal leukocytes; group 2, men with low-level leukoctyospermia (0.1-1.0 * 106 WBC/mL); and group 3, frank leukocytospermia, (>1.0 * 106. WBC/mL). Semen analysis, leukoctyospermia, reactive oxygen species and DNA fragmentation was tested. RESULTS: Conventional semen parameters between the 3 groups were similar. Group 2 patients had significantly higher levels of ROS and sperm DNA fragmentation (1839.65 +/- 2173.57RLU/s; DNA damage: 26.47 +/- 19.64%) compared with group 1 (ROS: 1101.09 +/- 5557.54 RLU/s; DNA damage: 19.89 +/- 17.31%) (ROS: p=0.002; DNA damage: p=0.047). There was no significant difference in ROS levels between groups 2 and 3. CONCLUSIONS: Patients presenting with low-level leukocytospermia have seminal oxidative stress. Although these patients are not categorized as leukocytospermic by current World Health Organization (WHO) guidelines, these men may benefit by treatment with antibiotics, testing for bacterial cultures, or antioxidant supplements to reduce ROS-induced sperm DNA fragmentation and improve their chances of fertility. The WHO guidelines for leukocytospermia may need to be revised accordingly. PMID- 25527075 TI - Heterotypic control of basement membrane dynamics during branching morphogenesis. AB - Many mammalian organs undergo branching morphogenesis to create highly arborized structures with maximized surface area for specialized organ function. Cooperative cell-cell and cell-matrix adhesions that sculpt the emerging tissue architecture are guided by dynamic basement membranes. Properties of the basement membrane are reciprocally controlled by the interacting epithelial and mesenchymal cell populations. Here we discuss how basement membrane remodeling is required for branching morphogenesis to regulate cell-matrix and cell-cell adhesions that are required for cell patterning during morphogenesis and how basement membrane impacts morphogenesis by stimulation of cell patterning, force generation, and mechanotransduction. We suggest that in addition to creating mature epithelial architecture, remodeling of the epithelial basement membrane during branching morphogenesis is also essential to promote maturation of the stromal mesenchyme to create mature organ structure. Recapitulation of developmental cell-matrix and cell-cell interactions are of critical importance in tissue engineering and regeneration strategies that seek to restore organ function. PMID- 25527076 TI - Foxp1/2/4 regulate endochondral ossification as a suppresser complex. AB - Osteoblast induction and differentiation in developing long bones is dynamically controlled by the opposing action of transcriptional activators and repressors. In contrast to the long list of activators that have been discovered over past decades, the network of repressors is not well-defined. Here we identify the expression of Foxp1/2/4 proteins, comprised of Forkhead-box (Fox) transcription factors of the Foxp subfamily, in both perichondrial skeletal progenitors and proliferating chondrocytes during endochondral ossification. Mice carrying loss of-function and gain-of-function Foxp mutations had gross defects in appendicular skeleton formation. At the cellular level, over-expression of Foxp1/2/4 in chondroctyes abrogated osteoblast formation and chondrocyte hypertrophy. Conversely, single or compound deficiency of Foxp1/2/4 in skeletal progenitors or chondrocytes resulted in premature osteoblast differentiation in the perichondrium, coupled with impaired proliferation, survival, and hypertrophy of chondrocytes in the growth plate. Foxp1/2/4 and Runx2 proteins interacted in vitro and in vivo, and Foxp1/2/4 repressed Runx2 transactivation function in heterologous cells. This study establishes Foxp1/2/4 proteins as coordinators of osteogenesis and chondrocyte hypertrophy in developing long bones and suggests that a novel transcriptional repressor network involving Foxp1/2/4 may regulate Runx2 during endochondral ossification. PMID- 25527077 TI - Rapid preparation of high-purity nuclear proteins from a small number of cultured cells for use in electrophoretic mobility shift assays. AB - BACKGROUND: Highly purified nuclear protein is required when using an electrophoretic mobility shift assay (EMSA) to study transcription factors, e.g. nuclear factor-kappaB (NF-kappaB), a major transcription factor that regulates both innate and adaptive immune responses following infection. Although many protocols have been developed for nuclear protein extraction, they are not necessarily optimized for use in EMSA, often require a large number of cells and long processing times, and do not always result in complete separation of the nuclear and cytoplasmic fractions. RESULTS: We have developed a simple, rapid and cost-effective method to prepare highly purified nuclear proteins from a small number of both suspended and adherent cultured cells that yields nuclear proteins comparable to those prepared by a standard large-scale method. The efficiency of the method was demonstrated by using EMSA to show the successful detection, in multilple concurrent samples, of NF-kappaB activation upon tetradecanoyl phorbol acetate (TPA) stimulation. CONCLUSIONS: This method requires only a small number of cells and no specialized equipment. The steps have been simplified, resulting in a short processing time, which allows researchers to process multiple samples simultaneously and quickly. This method is especially optimized for use in EMSA, and may be useful for other applications that include proteomic analysis. PMID- 25527078 TI - Listen up, eye movements play a role in verbal memory retrieval. AB - People fixate on blank spaces if visual stimuli previously occupied these regions of space. This so-called "looking at nothing" (LAN) phenomenon is said to be a part of information retrieval from internal memory representations, but the exact nature of the relationship between LAN and memory retrieval is unclear. While evidence exists for an influence of LAN on memory retrieval for visuospatial stimuli, evidence for verbal information is mixed. Here, we tested the relationship between LAN behavior and memory retrieval in an episodic retrieval task where verbal information was presented auditorily during encoding. When participants were allowed to gaze freely during subsequent memory retrieval, LAN occurred, and it was stronger for correct than for incorrect responses. When eye movements were manipulated during memory retrieval, retrieval performance was higher when participants fixated on the area associated with to-be-retrieved information than when fixating on another area. Our results provide evidence for a functional relationship between LAN and memory retrieval that extends to verbal information. PMID- 25527079 TI - Isoform-specific functions of Mud/NuMA mediate binucleation of Drosophila male accessory gland cells. AB - BACKGROUND: In standard cell division, the cells undergo karyokinesis and then cytokinesis. Some cells, however, such as cardiomyocytes and hepatocytes, can produce binucleate cells by going through mitosis without cytokinesis. This cytokinesis skipping is thought to be due to the inhibition of cytokinesis machinery such as the central spindle or the contractile ring, but the mechanisms regulating it are unclear. We investigated them by characterizing the binucleation event during development of the Drosophila male accessory gland, in which all cells are binucleate. RESULTS: The accessory gland cells arrested the cell cycle at 50 hours after puparium formation (APF) and in the middle of the pupal stage stopped proliferating for 5 hours. They then restarted the cell cycle and at 55 hours APF entered the M-phase synchronously. At this stage, accessory gland cells binucleated by mitosis without cytokinesis. Binucleating cells displayed the standard karyokinesis progression but also showed unusual features such as a non-round shape, spindle orientation along the apico-basal axis, and poor assembly of the central spindle. Mud, a Drosophila homolog of NuMA, regulated the processes responsible for these three features, the classical isoform Mud(PBD) and the two newly characterized isoforms Mud(L) and Mud(S) regulated them differently: Mud(L) repressed cell rounding, Mud(PBD) and Mud(S) oriented the spindle along the apico-basal axis, and Mud(S) and Mud(L) repressed central spindle assembly. Importantly, overexpression of Mud(S) induced binucleation even in standard proliferating cells such as those in imaginal discs. CONCLUSIONS: We characterized the binucleation in the Drosophila male accessory gland and examined mechanisms that regulated unusual morphologies of binucleating cells. We demonstrated that Mud, a microtubule binding protein regulating spindle orientation, was involved in this binucleation. We suggest that atypical functions exerted by three structurally different isoforms of Mud regulate cell rounding, spindle orientation and central spindle assembly in binucleation. We also propose that Mud(S) is a key regulator triggering cytokinesis skipping in binucleation processes. PMID- 25527080 TI - Antibody transport within the brain. PMID- 25527081 TI - Revision versus primary arthroscopic rotator cuff repair: a 2-year analysis of outcomes in 360 patients. AB - BACKGROUND: Symptomatic rotator cuff tears are often treated surgically. However, there is a paucity of information regarding the outcomes of revision arthroscopic rotator cuff repairs. PURPOSE: To evaluate the outcome of revision arthroscopic rotator cuff surgery when compared with primary arthroscopic rotator cuff surgery in a large cohort of patients. STUDY DESIGN: Cohort study; Level of evidence, 3. METHOD: A consecutive series of 50 revision arthroscopic rotator cuff repairs performed by a single surgeon, with minimum 2-year follow-up, were retrospectively reviewed using prospectively collected data. As a comparison, 3 primary arthroscopic rotator cuff repair cases (primary group; n = 310) were chosen immediately before each revision case, and 3 were chosen after. Standardized patient-ranked outcomes, examiner-determined assessments, and ultrasound-determined rotator cuff integrity were assessed preoperatively at 6 months and at a minimum of 2 years after surgery. RESULTS: The revision group was older (mean age, 63 years; range, 43-80 years) compared with the primary group (mean age, 60 years; range, 18-88 years) (P < .05) and had larger tear size (mean +/- SEM) (4.1 +/- 0.5 cm(2)) compared with the primary group (3.0 +/- 0.2 cm(2)) (P < .05). Two years after surgery, the primary group reported less pain at rest (P < .02), during sleep (P < .05), and with overhead activity (P < .01) compared with the revision group. The primary group had better passive forward flexion (+13 degrees ; P < .05), abduction (+18 degrees ; P < .01), internal rotation (+2 vertebral levels; P < .001) and also significantly greater supraspinatus strength (+15 N; P < .001), lift-off strength (+9.3 N; P < .05), and adduction strength (+20 N; P < .01) compared with the revision group at 2 years. When compared with the primary group, the revision group was more satisfied with the overall shoulder function before surgery but was less satisfied with their shoulder function than the primary group at 2 years (P < .005). The retear rate for primary rotator cuff repair was 16% at 6 months and 21% at 2 years, while the retear rate for revision rotator cuff repair was 28% at 6 months and deteriorated to 40% at 2 years (P < .05). CONCLUSION: The short-term clinical outcomes of patients undergoing revision rotator cuff repair were similar to those after primary rotator cuff repair. However, these results did not persist, and by 2 years patients who had revision rotator cuff repair were twice as likely to have retorn compared with those undergoing primary repair. The increase in retear rate in the revision group at 2 years was associated with increased pain, impaired overhead function, less passive motion, weaker strength, and less overall satisfaction with shoulder function. PMID- 25527082 TI - Structural properties of the intact proximal hamstring origin and evaluation of varying avulsion repair techniques: an in vitro biomechanical analysis. AB - BACKGROUND: Although surgical repair has been reported to provide improved outcomes compared with nonoperative treatment in the management of complete proximal hamstring origin avulsions, no intact or avulsion repair biomechanical data exist to support various repair strategies or guide postoperative rehabilitation. PURPOSE: To compare failure load among 4 proximal hamstring tendon conditions: (1) intact, (2) repair with 2 small anchors (2S), (3) repair with 2 large anchors (2L), and (4) repair with 5 small anchors (5S). STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-four human cadaveric hemipelvises were randomly allocated to 1 of the 4 testing groups. Intact and repaired specimens were subjected to cyclic loading at 1 Hz between 25 N and a progressively increasing maximum load that was incremented by 200 N every 50 cycles, beginning at 200 N and increasing to 1600 N. Displacement, maximum load, stiffness, number of cycles to failure, and mode of failure during cyclic loading were recorded and analyzed. RESULTS: The intact proximal hamstring tendons failed at the highest cyclic force of all tested groups, yet no significant differences existed between the intact (1405 +/- 157 N) and 5S repair (1164 +/- 294 N) conditions. Both the 2S and the 2L repair groups failed at a level significantly lower than the intact hamstring (474 +/- 145 N [P < .001] and 543 +/- 245 N [P < .001], respectively). The maximum load attained by the 5S repairs was significantly greater than the loads attained by the 2S (P = .005) and 2L (P = .013) repairs. CONCLUSION: Repairs using 5 small anchors were similar to the intact tendon and were significantly stronger than repairs using only 2 large or 2 small anchors in the repair of complete avulsions of the proximal hamstring tendons. Additionally, no significant differences in strength were observed when only anchor size differed. CLINICAL RELEVANCE: This finding supports the clinical investigation of postoperative range of motion rehabilitation protocols that permit full flexion and extension of the hip and knee when a 5-anchor repair construct is used. PMID- 25527083 TI - From consultation to participation in public health research: reflections on a community-based research partnership. AB - BACKGROUND: Road traffic crashes and their outcomes are substantial global public health issues and public health initiatives are increasingly involving relevant community members in order to create sustainable change. This paper describes an applied research project utilizing participatory methods to establish a road trauma support service in Western Australia and reflects on the extent of participation in the community-based research partnership. Community-based participatory research (CBPR) provided the basis for the research project conducted in partnership with 34 government and non-government agency representatives and people affected personally by road trauma and which resulted in 22 recommendations for establishing the service. FINDINGS: Attempts to position the group as co-researchers highlighted the dynamic interplay of factors that hinder and enable participation in participatory research. Barriers to participation within the research process included the limited time and funds, reluctance to share authorship, and a lack of clarity regarding roles and processes. Factors that enabled participation were the recognition of each member's expertise, providing different forms and methods of communication, and the reimbursement of costs according to role. DISCUSSION: In May 2012, the Government of Western Australia announced it would fund the recommendations and Road Trauma Support Western Australia was launched in November 2013. Notwithstanding this successful outcome, there were varied experiences of participation in the research process, and this was despite the use of a research methodology that is by definition participatory, with explicit and embedded participatory structures and processes. The research project shows that elements of CBPR can be incorporated into public health research, even in projects with externally-imposed time and budget constraints. PMID- 25527084 TI - Erratum to: Acute function of secreted amyloid precursor protein fragment APPsalpha in synaptic plasticity. PMID- 25527086 TI - Neural Circuits for Motion Vision in the Fly. AB - Seeing the direction of motion is fundamental for visual navigation, predator avoidance, and prey capture. However, the direction of motion is not explicitly represented at the level of individual photoreceptors. Rather, directional motion information needs to be extracted from the photoreceptor array by comparing the signals of neighboring photoreceptors over time. The exact nature of this process as implemented in the Drosophila visual system is currently being studied in great detail, and much progress has recently been made in determining the neural circuits giving rise to directional motion information in this species. PMID- 25527085 TI - Detailed characterization of antibody responses against HIV-1 group M consensus gp120 in rabbits. AB - BACKGROUND: We recently reported induction of broadly neutralizing antibodies (bnAbs) against multiple HIV-1 (human immunodeficiency virus type 1) isolates in rabbits, albeit weak against tier 2 viruses, using a monomeric gp120 derived from an M group consensus sequence (MCON6). To better understand the nature of the neutralizing activity, detailed characterization of immunological properties of the protein was performed. Immunogenic linear epitopes were identified during the course of immunization, and spatial distribution of these epitopes was determined. Subdomain antibody target analyses were done using the gp120 outer domain (gp120-OD) and eOD-GT6, a protein based on a heterologous sequence. In addition, refined epitope mapping analyses were done by competition assays using several nAbs with known epitopes. RESULTS: Based on linear epitope mapping analyses, the V3 loop was most immunogenic, followed by C1 and C5 regions. The V1/V2 loop was surprisingly non-immunogenic. Many immunogenic epitopes were clustered together even when they were distantly separated in primary sequence, suggesting the presence of immunogenic hotspots on the protein surface. Although substantial antibody responses were directed against the outer domain, only about 0.1% of the antibodies bound eOD-GT6. Albeit weak, antibodies against peptides that corresponded to a part of the bnAb VRC01 binding site were detected. Although gp120-induced antibodies could not block VRC01 binding to eOD-GT6, they were able to inhibit VRC01 binding to both gp120 and trimeric BG505 SOSIP gp140. The immune sera also efficiently competed with CD4-IgG2, as well as nAbs 447-52D, PGT121 and PGT126, in binding to gp120. CONCLUSIONS: The results suggest that some antibodies that bind at or near known bnAb epitopes could be partly responsible for the breadth of neutralizing activity induced by gp120 in our study. Immunization strategies that enhance induction of these antibodies relative to others (e.g. V3 loop), and increase their affinity, could improve protective efficacy of an HIV-1 vaccine. PMID- 25527087 TI - Production of CNT-taxol-embedded PCL microspheres using an ammonium-based room temperature ionic liquid: as a sustained drug delivery system. AB - We describe a one-pot method for the mass production of polymeric microspheres containing water-soluble carbon-nanotube (w-CNT)-taxol complexes using an ammonium-based room temperature ionic liquid. Polycaprolactone (PCL), trioctylmethylammonium chloride (TOMAC; liquid state from -20 to 240 degrees C), and taxol were used, respectively, as a model polymer, room temperature ionic liquid, and drug. Large quantities of white colored PCL powder without w-CNT taxol complexes and gray colored PCL powders containing w-CNT-taxol (1:1 or 1:2 wt/wt) complexes were produced by phase separation between the hydrophilic TOMAC and the hydrophobic PCL. Both microsphere types had a uniform, spherical structure of average diameter 3-5MUm. The amount of taxol embedded in PCL microspheres was determined by HPLC and (1)H NMR to be 8-12MUg per 1.0mg of PCL (loading capacity (LC): 0.8-1.2%; entrapment efficiency (EE): 16-24%). An in vitro HPLC release assay showed sustain release of taxol without an initial burst over 60days at an average rate of 0.003-0.0073mg per day. The viability patterns of human breast cancer cells (MCF-7) for PCTx-1 and -2 showed dose-dependent inhibitory effects. In the presence of PCTx-1 and -2, the MCF-7 cells showed high viability in the concentration level of, respectably, <70 and <5MUg/mL. PMID- 25527088 TI - Aqueous preparation of surfactant-free copper selenide nanowires. AB - Uniform surfactant-free copper selenide (Cu2-xSe) nanowires were prepared via an aqueous route. The effects of reaction parameters such as Cu/Se precursor ratio, Se/NaOH ratio, and reaction time on the formation of nanowires were comprehensively investigated. The results show that Cu2-xSe nanowires were formed through the assembling of CuSe nanoplates, accompanied by their self-redox reactions. The resultant Cu2-xSe nanowires were explored as a potential thermoelectric candidate in comparison with commercial copper selenide powder. Both synthetic and commercial samples have a similar performance and their figures of merit are 0.29 and 0.38 at 750K, respectively. PMID- 25527089 TI - Effect of nanoporous carbon surface chemistry on the removal of endocrine disruptors from water phase. AB - Wood-based activated carbon and its sulfur-doped counterpart were used as adsorbents of endocrine disruptor chemicals (EDC) from aqueous solution. Adsorption process was carried out in dynamic conditions and Thomas model was used to predict the performance of the column. The results showed a good fitting of the theoretical curve to the experimental data. S-doped carbon exhibited a higher adsorption capacity of trimethoprim (TMP) and smaller of sulfamethoxazole (SMX) and diclofenac (DCF) in comparison with the carbon with no sulfur incorporated into the matrix. The surface features of the initial carbons and those exposed to EDC were evaluated in order to derive the adsorption mechanism and elucidate the role of surface features. An increase in the amount of TMP from a low concentration solution (10 mg/L) on sulfur-doped carbon was linked to acid base interactions and the reactive adsorption/oxidation of TMP. A decrease in SMX and DCF after sulfur doping was explained by a considerable increase in surface hydrophobicity, which does not favor the retention of polar DCF and SMX molecules. When the adsorption was measured from a high concentration solution at equilibrium conditions at the dark or under solar light irradiation different trends in the adsorption capacities were found. This was linked to the photoactivity of carbons and the degradation of EDC in the pore system promoted by visible light followed by the adsorption of the products of surface reactions. PMID- 25527090 TI - The influence of flow intensity and field frequency on continuous-flow dielectrophoretic trapping. AB - We examine the combined influence of the intensity of pressure driven background flow and the frequency of the applied field on the continuous-flow dielectrophoretic trapping behavior of micro-particles within a micro-channel. Using an embedded interdigitated electrode array, we find that the measured trapping percentage over a continuous frequency range exhibits several curious effects which are strongly dependent on the flow intensity, including an apparent shift of the cross-over frequency and low-frequency dispersion. A numerical and theoretical model accounting for the combined effects of pressure-driven flow, dielectrophoresis and alternating-current electro-osmosis on the equation of motion for the particle is used to qualitatively describe the main experimental results. PMID- 25527091 TI - Adsorption of carboxymethyl cellulose on alumina particles. AB - The polyelectrolyte adsorption on colloid particles is often used for stabilization or flocculation of water suspensions. The aim of this work is to study the adsorption of carboxymethyl cellulose (CMC) on alumina (gamma-Al2O3) colloid particles. The particles and polymer are chosen because of the capability of the metal-oxide ampholyte surface and the weak polyelectrolytes to alter their charge by pH. The measurements are done at pH 6.0 where the CMC carboxylic gropes are almost fully dissociated and the alumina surface is positively charged. The high linear charge density of the polyelectrolyte chain provides Na(+) counterions condensation on the COO(-) groups. The main employed method is the electric light scattering based on particle orientation in sinusoidal electric field. The electric polarizability and the relaxation time after field switching off (both depending on the particle charge and size) are used as criteria for polymer adsorption and particle aggregation. Micro-electrophoresis is applied as additional techniques indicating the sign and density of the surface charge. The results obtained give the conditions (time dependence, particle and polymer concentrations) where the CMC adsorption is complete and the suspension is stable. PMID- 25527092 TI - A substrate ambiguous enzyme facilitates genome reduction in an intracellular symbiont. AB - BACKGROUND: Genome evolution in intracellular microbial symbionts is characterized by gene loss, generating some of the smallest and most gene-poor genomes known. As a result of gene loss these genomes commonly contain metabolic pathways that are fragmented relative to their free-living relatives. The evolutionary retention of fragmented metabolic pathways in the gene-poor genomes of endosymbionts suggests that they are functional. However, it is not always clear how they maintain functionality. To date, the fragmented metabolic pathways of endosymbionts have been shown to maintain functionality through complementation by host genes, complementation by genes of another endosymbiont and complementation by genes in host genomes that have been horizontally acquired from a microbial source that is not the endosymbiont. Here, we demonstrate a fourth mechanism. RESULTS: We investigate the evolutionary retention of a fragmented pathway for the essential nutrient pantothenate (vitamin B5) in the pea aphid, Acyrthosiphon pisum endosymbiosis with Buchnera aphidicola. Using quantitative analysis of gene expression we present evidence for complementation of the Buchnera pantothenate biosynthesis pathway by host genes. Further, using complementation assays in an Escherichia coli mutant we demonstrate functional replacement of a pantothenate biosynthesis enzyme, 2-dehydropantoate 2-reductase (E.C. 1.1.1.169), by an endosymbiont gene, ilvC, encoding a substrate ambiguous enzyme. CONCLUSIONS: Earlier studies have speculated that missing enzyme steps in fragmented endosymbiont metabolic pathways are completed by adaptable endosymbiont enzymes from other pathways. Here, we experimentally demonstrate completion of a fragmented endosymbiont vitamin biosynthesis pathway by recruitment of a substrate ambiguous enzyme from another pathway. In addition, this work extends host/symbiont metabolic collaboration in the aphid/Buchnera symbiosis from amino acid metabolism to include vitamin biosynthesis. PMID- 25527093 TI - Development of a living membrane comprising a functional human renal proximal tubule cell monolayer on polyethersulfone polymeric membrane. AB - The need for improved renal replacement therapies has stimulated innovative research for the development of a cell-based renal assist device. A key requirement for such a device is the formation of a "living membrane", consisting of a tight kidney cell monolayer with preserved functional organic ion transporters on a suitable artificial membrane surface. In this work, we applied a unique conditionally immortalized proximal tubule epithelial cell (ciPTEC) line with an optimized coating strategy on polyethersulfone (PES) membranes to develop a living membrane with a functional proximal tubule epithelial cell layer. PES membranes were coated with combinations of 3,4-dihydroxy-l-phenylalanine and human collagen IV (Coll IV). The optimal coating time and concentrations were determined to achieve retention of vital blood components while preserving high water transport and optimal ciPTEC adhesion. The ciPTEC monolayers obtained were examined through immunocytochemistry to detect zona occludens 1 tight junction proteins. Reproducible monolayers were formed when using a combination of 2 mg ml(-1) 3,4-dihydroxy-l-phenylalanine (4 min coating, 1h dissolution) and 25 MUg ml(-1) Coll IV (4 min coating). The successful transport of (14)C-creatinine through the developed living membrane system was used as an indication for organic cation transporter functionality. The addition of metformin or cimetidine significantly reduced the creatinine transepithelial flux, indicating active creatinine uptake in ciPTECs, most likely mediated by the organic cation transporter, OCT2 (SLC22A2). In conclusion, this study shows the successful development of a living membrane consisting of a reproducible ciPTEC monolayer on PES membranes, an important step towards the development of a bioartificial kidney. PMID- 25527094 TI - The efficacy and safety of plasma exchange in patients with sepsis and septic shock: a systematic review and meta-analysis. AB - INTRODUCTION: Sepsis and septic shock are leading causes of intensive care unit (ICU) mortality. They are characterized by excessive inflammation, upregulation of procoagulant proteins and depletion of natural anticoagulants. Plasma exchange has the potential to improve survival in sepsis by removing inflammatory cytokines and restoring deficient plasma proteins. The objective of this study is to evaluate the efficacy and safety of plasma exchange in patients with sepsis. METHODS: We searched MEDLINE, EMBASE, CENTRAL, Scopus, reference lists of relevant articles, and grey literature for relevant citations. We included randomized controlled trials comparing plasma exchange or plasma filtration with usual care in critically ill patients with sepsis or septic shock. Two reviewers independently identified trials, extracted trial-level data and performed risk of bias assessments using the Cochrane Risk of Bias tool. The primary outcome was all-cause mortality reported at longest follow-up. Meta-analysis was performed using a random-effects model. RESULTS: Of 1,957 records identified, we included four unique trials enrolling a total of 194 patients (one enrolling adults only, two enrolling children only, one enrolling adults and children). The mean age of adult patients ranged from 38 to 53 years (n = 128) and the mean age of children ranged from 0.9 to 18 years (n = 66). All trials were at unclear to high risk of bias. The use of plasma exchange was not associated with a significant reduction in all-cause mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.45 to 1.52, I(2) 60%). In adults, plasma exchange was associated with reduced mortality (RR 0.63, 95% CI 0.42 to 0.96; I(2) 0%), but was not in children (RR 0.96, 95% CI 0.28 to 3.38; I(2) 60%). None of the trials reported ICU or hospital lengths of stay. Only one trial reported adverse events associated with plasma exchange including six episodes of hypotension and one allergic reaction to fresh frozen plasma. CONCLUSIONS: Insufficient evidence exists to recommend plasma exchange as an adjunctive therapy for patients with sepsis or septic shock. Rigorous randomized controlled trials evaluating clinically relevant patient centered outcomes are required to evaluate the impact of plasma exchange in this condition. PMID- 25527095 TI - Empowering biologists with multi-omics data: colorectal cancer as a paradigm. AB - MOTIVATION: Recent completion of the global proteomic characterization of The Cancer Genome Atlas (TCGA) colorectal cancer (CRC) cohort resulted in the first tumor dataset with complete molecular measurements at DNA, RNA and protein levels. Using CRC as a paradigm, we describe the application of the NetGestalt framework to provide easy access and interpretation of multi-omics data. RESULTS: The NetGestalt CRC portal includes genomic, epigenomic, transcriptomic, proteomic and clinical data for the TCGA CRC cohort, data from other CRC tumor cohorts and cell lines, and existing knowledge on pathways and networks, giving a total of more than 17 million data points. The portal provides features for data query, upload, visualization and integration. These features can be flexibly combined to serve various needs of the users, maximizing the synergy among omics data, human visualization and quantitative analysis. Using three case studies, we demonstrate that the portal not only provides user-friendly data query and visualization but also enables efficient data integration within a single omics data type, across multiple omics data types, and over biological networks. AVAILABILITY AND IMPLEMENTATION: The NetGestalt CRC portal can be freely accessed at http://www.netgestalt.org. CONTACT: bing.zhang@vanderbilt.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 25527096 TI - The Cyni framework for network inference in Cytoscape. AB - MOTIVATION: Research on methods for the inference of networks from biological data is making significant advances, but the adoption of network inference in biomedical research practice is lagging behind. Here, we present Cyni, an open source 'fill-in-the-algorithm' framework that provides common network inference functionality and user interface elements. Cyni allows the rapid transformation of Java-based network inference prototypes into apps of the popular open-source Cytoscape network analysis and visualization ecosystem. Merely placing the resulting app in the Cytoscape App Store makes the method accessible to a worldwide community of biomedical researchers by mouse click. In a case study, we illustrate the transformation of an ARACNE implementation into a Cytoscape app. AVAILABILITY AND IMPLEMENTATION: Cyni, its apps, user guides, documentation and sample code are available from the Cytoscape App Store http://apps.cytoscape.org/apps/cynitoolbox CONTACT: benno.schwikowski@pasteur.fr. PMID- 25527097 TI - CDvist: a webserver for identification and visualization of conserved domains in protein sequences. AB - SUMMARY: Identification of domains in protein sequences allows their assigning to biological functions. Several webservers exist for identification of protein domains using similarity searches against various databases of protein domain models. However, none of them provides comprehensive domain coverage while allowing bulk querying and their visualization schemes can be improved. To address these issues, we developed CDvist (a comprehensive domain visualization tool), which combines the best available search algorithms and databases into a user-friendly framework. First, a given protein sequence is matched to domain models using high-specificity tools and only then unmatched segments are subjected to more sensitive algorithms resulting in a best possible comprehensive coverage. Bulk querying and rich visualization and download options provide improved functionality to domain architecture analysis. AVAILABILITY AND IMPLEMENTATION: Freely available on the web at http://cdvist.utk.edu CONTACT: oadebali@vols.utk.edu or ijouline@utk.edu. PMID- 25527098 TI - MicroRNA modules prefer to bind weak and unconventional target sites. AB - MOTIVATION: MicroRNAs (miRNAs) play critical roles in gene regulation. Although it is well known that multiple miRNAs may work as miRNA modules to synergistically regulate common target mRNAs, the understanding of miRNA modules is still in its infancy. RESULTS: We employed the recently generated high throughput experimental data to study miRNA modules. We predicted 181 miRNA modules and 306 potential miRNA modules. We observed that the target sites of these predicted modules were in general weaker compared with those not bound by miRNA modules. We also discovered that miRNAs in predicted modules preferred to bind unconventional target sites rather than canonical sites. Surprisingly, contrary to a previous study, we found that most adjacent miRNA target sites from the same miRNA modules were not within the range of 10-130 nucleotides. Interestingly, the distance of target sites bound by miRNAs in the same modules was shorter when miRNA modules bound unconventional instead of canonical sites. Our study shed new light on miRNA binding and miRNA target sites, which will likely advance our understanding of miRNA regulation. AVAILABILITY AND IMPLEMENTATION: The software miRModule can be freely downloaded at http://hulab.ucf.edu/research/projects/miRNA/miRModule. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. CONTACT: haihu@cs.ucf.edu or xiaoman@mail.ucf.edu. PMID- 25527099 TI - Rickettsial infection among military personnel deployed in Northern Sri Lanka. AB - BACKGROUND: Military personnel deployed in field actvities report on frequent tick bites. Therefore they may run the risk of exposure to rickettsial organisms. METHODS: In order to assess the risk of exposure to rickettsial organisms, two groups of military personnel who were deployed in field activities of Nothern Sri Lanka were investigated. The first group was studied in order to assess the sero prevalence of rickettsioses and consisted of soldiers who were admitted following injuries during field activities. The second group was studied to identify the incidence of acute rickettsioses during their acute febrile presentations. They were tested with IFA-IgG against spotted fever group rickettsioses (SFG), scrub typhus (ST) and murine typhus. RESULTS: In the first group, 48/57 (84%) military personnel had serological evidence of exposure to rickettsioses (in all, IFA-IgG titer >= 1:128): 33/50 (66%) to SFG rickettsioses, 1/50 (2%) to ST and 14/50 (28%) had mixed titers for both (in all, titers were higher for SFG). While all of them were in military uniform most of the time and frequently slept on scrub land, 35/57 (61.4%) had never used insect repellents and none were on doxycycline prophylaxis. 48/57 (84%) had experienced tick bites during field activity. In the second group, there were 49 who presented with acute febrile illness with a mean duration of 8.5 days (SD 3.2). 33/49 (67.3%) were serologically positive for acute rickettsioses (IgG >=1:256); 26 (79%) due to ST and 7 (21%) due to SFG rickettsioses, CONCLUSIONS: Exposure to rickettsial disease was common among soldiers who were deployed in Northern Sri Lanka. Scrub typhus was the predominent species accounting for acute febrile illness. Further studies are needed to understand the reasons for very high sero-prevalence for SFG rickettsioses with no anticedent febrile illness. Use of preventive measures was not satisfactory. The high sero-prevelence of SFG rickettsioses is likely to interfere with serological diagnosis of acute SFG rickettsioses in this population. PMID- 25527100 TI - Cervical lymph node metastasis classified as regional nodal staging in thoracic esophageal squamous cell carcinoma after radical esophagectomy and three-field lymph node dissection. AB - BACKGROUND: Lymph node metastasis (LNM) is most common in esophageal squamous cell carcinoma (SCC). The bi-directional spread is a key feature of LNM in patients with thoracic esophageal SCC (TE-SCC). The purpose of this study was to analyze the prognostic factors of survival in patients with TE-SCC with cervical lymph node metastasis (CLM) and validate the staging system of the current American Joint Committee on Cancer (AJCC) in a cohort of Chinese patients. METHODS: Of 1715 patients with TE-SCC who underwent radical esophagectomy plus three-field lymph node dissection at a single hospital between January 1993 and March 2007, 547 patients who had pathologically confirmed CLM (296 had surgery only and 251 had surgery + postoperative radiotherapy) were included in this study. The locations of the lymph nodes (LNs) were classified based on the guidelines of the Japanese Society for Esophageal Diseases. RESULTS: The rate of CLM was 31.9% for all patients and was 44.2%, 31.5%, and 14.4% for patients with upper, middle, and lower TE-SCC, respectively (P < 0.0001). The rates of metastasis to 101 (paraesophageal lymph nodes), 104 (supraclavicular lymph nodes), 102 (deep cervical lymph nodes) and 103 (retropharyngeal lymph nodes) areas were 89.0%, 25.6%, 3.7% and 0.5%, respectively. The 5-year overall survival (OS) rate with CLM was 27.7% (median survival, 27.5 months). The 5-year OS rates were 21.3% versus 34.2% (median survival, 21.9 months versus 35.4 months) for after surgery only versus surgery + postoperative radiotherapy, respectively (P < 0.0001 for both). Multivariate analysis showed that the independent prognostic factors for survival were sex, pT stage, pN stage, number of fields with positive LNs, and treatment modality. In surgery only group, the 5-year OS rates were 24.1%, 16.2% and 11.7%, respectively, when there was metastasis to 101 LN alone, 104 LN alone or both 101 LN and 104 LN. The 5-year OS rates were 17.7%, 22.5% and 31.7%, for patients with upper, middle and lower TE-SCC , respectively (P = 0.112). The 5-year OS rates were 43.0%, 25.5%, 10.2% in patients with 1 field (cervical LNs), 2 fields (cervical + mediastinal, and/or cervical + abdominal LNs), and 3 fields (cervical + mediastinal + abdominal LNs) positive LNs, respectively (P < 0.0001). The number of fields of positive LNs did not impact the OS according to different pN stage (all P > 0.05). CONCLUSION: Patients with TE-SCC with CLM have better prognosis, which supports the current AJCC staging system for esophageal SCC. PMID- 25527101 TI - Improving the effectiveness of pharmacist-assisted tobacco cessation: a study of participant- and pharmacy-specific differences in quit rates. AB - BACKGROUND: The New Mexico Pharmaceutical Care Foundation provided a pharmacist assisted tobacco cessation program from 2004 to 2010. In evaluating the program, discrepant 6-month quit rates were observed between pharmacies. OBJECTIVE: To identify participant- and pharmacy-specific factors associated with improved quit rates. METHODS: To supplement data regarding participant characteristics and quit rates, semistructured interviews of 7 participating pharmacists were conducted. Multivariate logistic regression quantified associations between successful abstinence at 6 months and participant characteristics and pharmacy-specific factors. RESULTS: Quit rates by pharmacy ranged from 1.1% to 59.4% (mean = 19.1%). There were 1235 participants enrolled at 7 pharmacies, and because of missing participant data, 883 were included in the quantitative analysis. Three pharmacy-specific characteristics distinguished 6-month success rates: number and duration of follow-ups and format of counseling sessions. Participants followed up at least 3 times were more likely to quit at 6 months than those contacted once or twice (odds ratio [OR] =4.9; 95% CI = 1.6-15.0). Compared with follow-ups of <15 minutes, longer durations of follow-ups were associated with higher success rates: 15 to 30 minutes, OR = 7.2, 95% CI = 3.7-14.3); >30 minutes, OR = 10.0, 95% CI = 3.5-28.9. Participants who attended group sessions were more likely to quit at 6 months than those who attended individual sessions: OR = 8.2; 95% CI = 2.8-23.9. Most pharmacists (88%) noted that participants' high or low commitment to quit was associated with success or failure, respectively. Several pharmacists (43%) noted difficulties with follow-up associated with participants' relapse. Time constraints were an obstacle noted by 70% of pharmacists. CONCLUSIONS: Pharmacy-specific factors, including counseling format and program intensity, affected success. PMID- 25527102 TI - Primary prevention of atherosclerotic cardiovascular disease: controversies and clinical considerations. AB - A new guideline for the treatment of blood cholesterol was recently released by the American College of Cardiology (ACC) and the American Heart Association (AHA), serving as an update to the National Cholesterol Education Program's (NCEP) Adult Treatment Panel III cholesterol guideline first released in 2001. With significant changes to key definitions, treatment strategy, and therapy selection, the guideline has transformed the treatment of blood cholesterol and also created controversy within the health care community. This controversy is largely focused on appropriate identification and treatment of patients for the primary prevention of atherosclerotic cardiovascular disease (ASCVD). Whereas statins play an integral role in the treatment and secondary prevention of ASCVD, their use for primary prevention is less clearly defined. It is imperative that health care providers are well versed in the concepts and controversies of the new guideline recommendations for primary prevention of ASCVD and can effectively assess the risks and benefits of statin therapy in this patient population. PMID- 25527103 TI - SPOROCYTELESS is a novel embryophyte-specific transcription repressor that interacts with TPL and TCP proteins in Arabidopsis. AB - Germlines in plants are formed de novo during post-embryonic development, while little is known about the mechanism that controls this process. In Arabidopsis, the earliest gene controlling this process is SPOROCYTELESS (SPL). A decade ago, we showed that loss of SPL function abolished sporogenesis in both male and female organs of Arabidopsis. However, its function is unclear up to now. In this study, we showed that SPL belongs to a novel transcription repressor family specific in embryophyte, which consists of 173 members in the land plants so far. All of them contain a conserved SPL-motif in their N-terminal and an ethylene responsive element binding factor-associated amphiphilic repression (EAR) motif in the C-terminal, therefore designated as SPL-like, EAR-containing proteins (SPEARs). Consistently, SPL acts as a transcriptional repressor in yeast and tobacco cells, and SPEAR proteins are able to form homodimer and/or heterodimer with each other in vitro. Furthermore, SPEARs interact with the TOPLESS (TPL) co repressors via the EAR motif and TCP family transcription factors in yeast cells. Together, we propose that SPL and SPEARs most likely belong to a novel transcription repressor family in land plants which may play a variety of developmental roles in plants. PMID- 25527104 TI - G-quadruplex (G4) motifs in the maize (Zea mays L.) genome are enriched at specific locations in thousands of genes coupled to energy status, hypoxia, low sugar, and nutrient deprivation. AB - The G-quadruplex (G4) elements comprise a class of nucleic acid structures formed by stacking of guanine base quartets in a quadruple helix. This G4 DNA can form within or across single-stranded DNA molecules and is mutually exclusive with duplex B-form DNA. The reversibility and structural diversity of G4s make them highly versatile genetic structures, as demonstrated by their roles in various functions including telomere metabolism, genome maintenance, immunoglobulin gene diversification, transcription, and translation. Sequence motifs capable of forming G4 DNA are typically located in telomere repeat DNA and other non telomeric genomic loci. To investigate their potential roles in a large-genome model plant species, we computationally identified 149,988 non-telomeric G4 motifs in maize (Zea mays L., B73 AGPv2), 29% of which were in non-repetitive genomic regions. G4 motif hotspots exhibited non-random enrichment in genes at two locations on the antisense strand, one in the 5' UTR and the other at the 5' end of the first intron. Several genic G4 motifs were shown to adopt sequence specific and potassium-dependent G4 DNA structures in vitro. The G4 motifs were prevalent in key regulatory genes associated with hypoxia (group VII ERFs), oxidative stress (DJ-1/GATase1), and energy status (AMPK/SnRK) pathways. They also showed statistical enrichment for genes in metabolic pathways that function in glycolysis, sugar degradation, inositol metabolism, and base excision repair. Collectively, the maize G4 motifs may represent conditional regulatory elements that can aid in energy status gene responses. Such a network of elements could provide a mechanistic basis for linking energy status signals to gene regulation in maize, a model genetic system and major world crop species for feed, food, and fuel. PMID- 25527105 TI - Differential Notch activity is required for homeostasis of malpighian tubules in adult Drosophila. PMID- 25527106 TI - Snapshot of structural variations in the Tibetan wild boar genome at single nucleotide resolution. PMID- 25527107 TI - Two novel QTLs for heading date are identified using a set of chromosome segment substitution lines in rice (Oryza sativa L.). PMID- 25527108 TI - Chromosomal constitutions and reactions to powdery mildew and stripe rust of four novel wheat-Thinopyrum intermedium partial amphiploids. PMID- 25527109 TI - The halo sign of Q fever pneumonia. PMID- 25527110 TI - Frequency of adverse events associated to antiretroviral drugs in patients starting therapy in Salvador, Brazil. PMID- 25527111 TI - Pityriasis rosea following human papillomavirus vaccination. PMID- 25527112 TI - Neural correlates of self-deception and impression-management. AB - Self-deception and impression-management comprise two types of deceptive, but generally socially acceptable behaviours, which are common in everyday life as well as being present in a number of psychiatric disorders. We sought to establish and dissociate the 'normal' brain substrates of self-deception and impression-management. Twenty healthy participants underwent fMRI scanning at 3T whilst completing the 'Balanced Inventory of Desirable Responding' test under two conditions: 'fake good', giving the most desirable impression possible and 'fake bad' giving an undesirable impression. Impression-management scores were more malleable to manipulation via 'faking' than self-deception scores. Response times to self-deception questions and 'fake bad' instructions were significantly longer than to impression-management questions and 'fake good' instructions respectively. Self-deception and impression-management manipulation and 'faking bad' were associated with activation of medial prefrontal cortex (mPFC) and left ventrolateral prefrontal cortex (vlPFC). Impression-management manipulation was additionally associated with activation of left dorsolateral prefrontal cortex and left posterior middle temporal gyrus. 'Faking bad' was additionally associated with activation of right vlPFC, left temporo-parietal junction and right cerebellum. There were no supra-threshold activations associated with 'faking good'. Our neuroimaging data suggest that manipulating self-deception and impression-management and more specifically 'faking bad' engages a common network comprising mPFC and left vlPFC. Shorter response times and lack of dissociable neural activations suggests that 'faking good', particularly when it comes to impression-management, may be our most practiced 'default' mode. PMID- 25527113 TI - The special case of self-perspective inhibition in mental, but not non-mental, representation. AB - The ventrolateral prefrontal cortex (vlPFC) has been implicated in studies of both executive and social functions. Recent meta-analyses suggest that vlPFC plays an important but little understood role in Theory of Mind (ToM). Converging neuropsychological and functional Magnetic Resonance Imaging (fMRI) evidence suggests that this may reflect inhibition of self-perspective. The present study adapted an extensively published ToM localizer to evaluate the role of vlPFC in inhibition of self-perspective. The classic false belief, false photograph vignettes that comprise the localizer were modified to generate high and low salience of self-perspective. Using a factorial design, the present study identified a behavioural and neural cost associated with having a highly salient self-perspective that was incongruent with the representational content. Importantly, vlPFC only differentiated between high versus low salience of self perspective when representing mental state content. No difference was identified for non-mental representation. This result suggests that different control processes are required to represent competing mental and non-mental content. PMID- 25527114 TI - Bias in observational study designs: prospective cohort studies. PMID- 25527115 TI - A surgeon led smoking cessation intervention in a head and neck cancer centre. AB - BACKGROUND: The government has recognised the role of healthcare professionals in smoking cessation interventions with integrated care pathways for identification and referral of at-risk patients who smoke. Referral for suspected cancers has been suggested as a 'teachable moment', whereby individuals are motivated and more likely to adopt risk-reducing behaviours. A head and neck cancer referral clinic could therefore provide opportunities for smoking cessation intervention. This study aims to pilot a brief smoking cessation intervention during a consultation visit for patients referred with suspected head and neck cancer and evaluate its acceptability and impact. METHODS: A brief script for smoking cessation intervention which included a smoking cessation referral was designed to be delivered to patients attending a rapid access clinic. Patient outcome data was collected by the stop smoking team for patients who accepted the referral. A subset of these patients was also interviewed by telephone; these findings were combined with data provided by the stop smoking services to assess the acceptability and impact of pilot smoking cessation intervention on patients. RESULTS: In total, 473 new patients attended the clinic during the study period, of whom 102 (22%) were smokers. Of these, 80 (78%) accepted a referral to stop smoking services. A total of 75 (74%) patients were approached subsequently in a telephone survey. Of the 80 newly referred patients, 29 (36%) quit smoking at least temporarily. Another eight patients reduced their smoking or set a quit date (10%), so the experience of attending the clinic and the intervention impacted favourably on almost half of the patients (46%). The patient survey found the intervention to be acceptable for 94% (n = 50) of patients. Qualitative analysis of patient responses revealed five elements which support the acceptability of the intervention. CONCLUSIONS: The findings of this pilot study suggest that discussion of smoking cessation with patients referred for suspected head and neck cancer may have an impact and facilitate the process towards quitting. A possible diagnosis of cancer appears to present a 'teachable moment' to encourage positive health behaviour change. PMID- 25527116 TI - Hemodynamic behavior of stentless aortic valves in long term follow-up. AB - OBJECTIVES: Stentless aortic valve replacements show improved hemodynamics due to larger orifice area and lower transvalvular gradients in short and mid-term follow-up. Hemodynamic long-term behavior and the adaptation of the left ventricle as well as valve-durability in patients aged <=60 years remains unclear. METHODS: 7 to 16 years after aortic valve replacement, 54 patients (mean age at operation 53.1 +/- years) received echocardiography and clinical examination. Mean follow-up time was 10.8 +/- 2.2 years. Evaluated were NYHA class, transvalvular gradients, estimated aortic valve orifice area, degree of aortic valve insufficiency, left ventricular mass and function. RESULTS: At follow-up only one patient presented with NYHA class III. All other patients were in NYHA class I or II. Maximum and mean pressure gradients of the prostheses were 16.3 +/- 7.4 mmHg and 9.1 +/- 4.2 mmHg, respectively. Compared to echocardiography at discharge the mean pressure gradients dropped 18.0% (2.0 +/- 0.9 mmHg) and stayed stable until 14 years after the operation. Only 5 patients showed relevant regurgitation (at 13-16 years after valve replacement), 49 showed no or trivial regurgitation. Left ventricular mass had decreased 26.5% (107.9 +/- 18.5 g). Left ventricular ejection fraction (LVEF) had increased in most patients and decreased in only one. For patients with preoperatively impaired left ventricular function an increase of LVEF of 13.1 +/- 3.1% was seen. CONCLUSION: Porcine stentless aortic valves provide excellent hemodynamic long-term results without significant rise of transvalvular pressure gradients or relevant insufficiencies until 14 years after implantation, leading to sustained decrease of left ventricular mass and improvement of left ventricular function. PMID- 25527117 TI - Change in excitability of a putative decision-making neuron in Aplysia serves as a mechanism in the decision not to feed following food satiation. AB - Although decision making is a ubiquitous function, the understanding of its underlying mechanisms remains limited, particularly at the single-cell level. In this study, we used the decision not to feed that follows satiation in the marine mollusk Aplysia to examine the role of putative decision-making neuron B51 in this process. B51 is a neuron in the feeding neural circuit that exhibits decision-making characteristics in vitro, which bias the circuit toward producing the motor programs responsible for biting behavior. Once satiated, Aplysia decided not to bite for a prolonged period of time (>=24h) when presented with a food stimulus that normally elicits feeding in non-satiated animals. Twenty-four hours after satiation, suppressed feeding was accompanied by a significant decrease of B51 excitability compared to the control group of unfed animals. No differences were measured in B51 resting membrane properties or synaptic input to B51 between the satiated and control groups. When B51 properties were measured at a time point in which feeding had recovered from the suppressive effects of satiation (i.e., 96 h after satiation), no difference in B51 excitability was observed between satiated and control groups. These findings indicate that B51 excitability changes in a manner that is coherent with the modifications in biting resulting from food satiation, thus implicating this neuron as a site of plasticity underlying the decision not to bite following food satiation in Aplysia. PMID- 25527118 TI - Pharmacokinetics of treosulfan and its active monoepoxide in pediatric patients after intravenous infusion of high-dose treosulfan prior to HSCT. AB - Pro-drug treosulfan (TREO) is currently evaluated in randomized phase III clinical trials as a conditioning agent prior to HSCT. In the present paper pharmacokinetics of both TREO and its biologically active monoepoxide (S,S-EBDM) was investigated in pediatric patients for the first time. The studies were carried out in 16 children (median age 7.5 years) undergoing TREO-based preparative regimen prior to HSCT, who received 10, 12 or 14 g/m(2) of the drug as a 1h or 2h intravenous infusion. Plasma concentrations of TREO as well as S,S EBDM were determined using the validated HPLC-MS/MS method. The changes in S,S EBDM concentration over time followed TREO levels. The area under the curve (AUC) of TREO was 100-fold higher than AUC of S,S-EBDM. No statistically significant dependency of the dose-normalized AUC of either TREO or S,S-EBDM on the patients' age and body surface area was stated. Moreover, plasma C(max) as well as AUC of S,S-EBDM demonstrated linear correlation with the C(max) and AUC of TREO, respectively. The biological half-lives of TREO and S,S-EBDM were similar. This indicates that S,S-EBDM was completely eliminated from the patients' blood within relatively short time, comparable to TREO. PMID- 25527119 TI - Relationship between amino acid usage and amino acid evolution in primates. AB - Amino acid usage varies from species to species. A previous study has found a universal trend in amino acid gain and loss in many taxa and a one-way model of amino acid evolution in which the number of new amino acids increases as the number of old amino acids decreases was proposed. Later studies showed that this pattern of amino acid gain and loss is likely to be compatible with the neutral theory. The present work aimed to further study this problem by investigating the evolutionary patterns of amino acids in 8 primates (the nucleotide and protein alignments are available online http://gattaca.nju.edu.cn/pub_data.html). First, the number of amino acids gained and lost was calculated and the evolution trend of each amino acid was inferred. These values were found to be closely related to the usage of each amino acid. Then we analyzed the mutational trend of amino acid substitution in human using SNPs, this trend is highly correlated with fixation trend only with greater variance. Finally, the trends in the evolution of 20 amino acids were evaluated in human on different time scales, and the increasing rate of 5 significantly increasing amino acids was found to decrease as a function of time elapsed since divergence, and the dS/dN ratio also found to increase as a function of time elapsed since divergence. These results suggested that the observed amino acid substitution pattern is influenced by mutation and purifying selection. In conclusion, the present study shows that usage of amino acids is an important factor capable of influencing the observed pattern of amino acid evolution, and also presented evidences suggesting that the observed universal trend of amino acid gain and loss is compatible with neutral evolution. PMID- 25527120 TI - Gene expression profile analysis of rat cerebellum under acute alcohol intoxication. AB - Acute alcohol intoxication, a common disease causing damage to the central nervous system (CNS) has been primarily studied on the aspects of alcohol addiction and chronic alcohol exposure. The understanding of gene expression change in the CNS during acute alcohol intoxication is still lacking. We established a model for acute alcohol intoxication in SD rats by oral gavage. A rat cDNA microarray was used to profile mRNA expression in the cerebella of alcohol-intoxicated rats (experimental group) and saline-treated rats (control group). A total of 251 differentially expressed genes were identified in response to acute alcohol intoxication, in which 208 of them were up-regulated and 43 were down-regulated. Gene ontology (GO) term enrichment analysis and pathway analysis revealed that the genes involved in the biological processes of immune response and endothelial integrity are among the most severely affected in response to acute alcohol intoxication. We discovered five transcription factors whose consensus binding motifs are overrepresented in the promoter region of differentially expressed genes. Additionally, we identified 20 highly connected hub genes by co-expression analysis, and validated the differential expression of these genes by real-time quantitative PCR. By determining novel biological pathways and transcription factors that have functional implication to acute alcohol intoxication, our study substantially contributes to the understanding of the molecular mechanism underlying the pathology of acute alcoholism. PMID- 25527121 TI - NEDD4: The founding member of a family of ubiquitin-protein ligases. AB - Ubiquitination plays a crucial role in regulating proteins post-translationally. The focus of this review is on NEDD4, the founding member of the NEDD4 family of ubiquitin ligases that is evolutionarily conserved in eukaryotes. Many potential substrates of NEDD4 have been identified and NEDD4 has been shown to play a critical role in the regulation of a number of membrane receptors, endocytic machinery components and the tumour suppressor PTEN. In this review we will discuss the diverse pathways in which NEDD4 is involved, and the patho physiological significance of this important ubiquitin ligase. PMID- 25527122 TI - Eicosanoids mediate sHSP 20.8 gene response to biotic stress in larvae of the Chinese oak silkworm Antheraea pernyi. AB - Small heat shock proteins (sHSPs) can regulate protein folding and protect cells from stress. To investigate the role of sHSPs in the silk-producing insect Antheraea pernyi (A. pernyi; Lepidoptera: Saturniidae), cDNA encoding HSP20.8 in A. pernyi, termed Ap-sHSP20.8, was identified as a 564 bp ORF. The translated amino acid sequence encoded 187 residues with a calculated molecular mass of 20.8 kDa and an isoelectronic point (pI) of 5.98; the sequence showed homology to sHSP chaperone proteins from other insects. Ap-sHSP20.8 mRNA transcript expression was abundant in the midgut and fat body and found to be both constitutive and inducible by infectious stimuli. Therefore, Ap-sHSP20.8 may play important roles in A. pernyi immune responses under biotic stress. Furthermore, we found that eicosanoids could mediate the induction of Ap-sHSP20.8 in the fat body and midgut. Our findings show that sHSPs may be promising molecules to target in order to cripple immunity in insect pests. PMID- 25527124 TI - Ending HIV-related stigma: nursing's opportunity to lead. PMID- 25527123 TI - SC-III3, a novel scopoletin derivative, induces cytotoxicity in hepatocellular cancer cells through oxidative DNA damage and ataxia telangiectasia-mutated nuclear protein kinase activation. AB - BACKGROUND: Natural products from plants have been proven to be important resources of antitumor agents. In this study, we exploited the antitumor activity of (E)-3-(4-chlorophenyl)-N-(7-hydroxy-6-methoxy-2-oxo-2H-chromen-3-yl) acrylamide (SC-III3), a newly synthesized derivative of scopoletin, by in vitro and in vivo experiments. METHODS: Human hepatocellular carcinoma cell line HepG2 cells and xenograft of HepG2 cells in BALB/c nude mice were used to investigate the effects of SC-III3 on hepatocellular cancers. Cell cycle arrest and apoptosis were analyzed by flow cytometry. Cell cycle arrest, apoptosis and ATM-Chk pathway related proteins were characterized by western blot. RESULTS: SC-III3 selectively inhibited the viability of HepG2 cells without significant cytotoxicity against human normal liver cells LO2. In mouse xenograft model of HepG2 cells, SC-III3 showed a marked inhibition of tumor growth in a dose-dependent manner. Cell cycle analysis revealed that SC-III3 induced cells to accumulate in S phase, which was accompanied by a marked decrease of the expressions of cyclin A, cyclin B, cyclin E and Cdk2 proteins, the crucial regulators of S phase cell cycle. SC-III3 treatment resulted in DNA breaks in HepG2 cells, which might contribute to its S phase arrest. The S arrest and the activation of ATM-Chk1/Chk2-Cdc25A-Cdk2 pathways induced by SC-III3 in HepG2 cells could be efficiently abrogated by pretreatments of either Ku55933 (an inhibitor of ATM) or UCN-01 (an inhibitor of Chk1/Chk2). The activation of p53-p21 pathway by SC-III3 was also reversed by Ku55933 treatment. SC-III3 led to significant accumulation of intracellular reactive oxygen species (ROS), a breaker of DNA strand, in HepG2 cells but not LO2 cells. Pretreatment with N-acetyl-l-cysteine (NAC), a ROS scavenger, could reverse SC-III3-caused ROS accumulation, DNA damage, activation of signal pathways relevant to DNA damage, S phase arrest and cell viability decrease in HepG2 cells. CONCLUSION: SC-III3 is able to efficiently inhibit the growth of hepatocellular carcinoma through inducing the generation of intracellular ROS, DNA damage and consequent S phase arrest, but lack of significant cytotoxicity against normal liver cells. This compound deserves further studies as a candidate of anticancer drugs. PMID- 25527125 TI - Deconstructing HIV-related stigma: a dialogue with a multidisciplinary group of experts. PMID- 25527126 TI - Differences in health care utilisation between elderly from ethnic minorities and ethnic Dutch elderly. AB - INTRODUCTION: In the Netherlands, as in other Western countries, ethnic minority elderly are more often in poorer health than the indigenous population. The expectation is that this health disadvantage results in more frequent use of health care services. METHODS: We studied registered data on the proportion of health care receivers, frequency of use, and health care costs collected by a major Dutch health insurance company in 2010. Data from 10,316 Turkish, 14,490 Moroccan, 8,619 Surinamese, and 1,064 Moluccan adults aged 55 years and older were compared with data from a sample of 33,725 ethnic Dutch older adults. RESULTS: Unadjusted and adjusted (for age and gender) analyses showed the following. Moluccans had lower usage levels for all types of health care services. Use of primary health care facilities was higher for Turks, Moroccans, and Surinamese compared with the ethnic Dutch, with the exception that physical therapy was less frequently used among the Turks and Moroccans. Use of hospital care was lower, except for the Surinamese, who had a similar level of usage to that of the ethnic Dutch. CONCLUSIONS: The health disadvantage previously observed within most ethnic minority elderly populations does not result in an overall more frequent use of health care services. Further research is needed for the interpretation of the ethnic variations in health care use as potentially inequitable, by taking medical need, patient treatment preferences, and treatment adherence into account. PMID- 25527127 TI - Disappointing response to dapsone as second line therapy for primary ITP: a case series. PMID- 25527128 TI - Modulation of p75 neurotrophin receptor under hypoxic conditions induces migration and invasion of C6 glioma cells. AB - p75 neurotrophin receptor (p75NTR) has been reported to play important roles in various cancer types. However, the exact mechanism of tumorigenesis involving p75NTR is unknown. In this study, we investigated the relationship between the expression of p75NTR in malignant glioma and the impact on tumor cell migration and invasion. p75NTR and hypoxia-inducible factor-1alpha (HIF-1alpha) expression was down-regulated by short-hairpin RNA and up-regulated with expression vectors. By immunohistochemical staining and Western blot analysis, we found that p75NTR was expressed in both human and rat malignant gliomas. Knockdown of p75NTR increased the expression of vimentin, vascular endothelial growth factor, Matrix metalloproteinase 9, and TWIST, and enhanced the invasion and migration abilities assessed by transwell assay in the C6 tumor cells. Inverse expressions of p75NTR and HIF-1alpha were detected in glioma cell lines under hypoxic conditions, while increased HIF-1alpha significantly downregulated the expression of p75NTR, suggesting a HIF-1alpha-p75NTR-EMT pathway that may regulate glioma cells invasion and migration. Downregulation of p75NTR increased phosphorylation of Src, focal adhesion kinase (FAK) and paxillin. Knockdown of p75NTR also dysregulated beta-catenin-mediated cell junctions, and up-regulated the expressions of fibronectin and L1CAM in the cell-cell junctions, thus suggesting that p75NTR knockdown contributed to a more aggressive migration phenotype via FAK signaling pathway. Our studies suggested that modulation of p75NTR under hypoxic condition could enhance C6 cells migration and invasion by induction of EMT, and activation of the FAK pathway. The HIF-1alpha-p75NTR-EMT axis may play a central role in glioma tumorigenesis. PMID- 25527129 TI - A mathematical simulation to assess variability in lung nodule size measurement associated with nodule-slice position. AB - The purpose of this study is to assess the variance and error in nodule diameter measurement associated with variations in nodule-slice position in cross sectional imaging. A computer program utilizing a standard geometric model was used to simulate theoretical slices through a perfectly spherical nodule of known size, position, and density within a background of "lung" of known fixed density. Assuming a threshold density, partial volume effect of a voxel was simulated using published slice and pixel sensitivity profiles. At a given slice thickness and nodule size, 100 scans were simulated differing only in scan start position, then repeated for multiple node sizes at three simulated slice thicknesses. Diameter was measured using a standard, automated algorithm. The frequency of measured diameters was tabulated; average errors and standard deviations (SD) were calculated. For a representative 5-mm nodule, average measurement error ranged from +10 to -23% and SD ranged from 0.07 to 0.99 mm at slice thicknesses of 0.75 to 5 mm, respectively. At fixed slice thickness, average error and SD decreased from peak values as nodule size increased. At fixed nodule size, SD increased as slice thickness increased. Average error exhibited dependence on both slice thickness and threshold. Variance and error in nodule diameter measurement associated with nodule-slice position exists due to geometrical limitations. This can lead to false interpretations of nodule growth or stability that could affect clinical management. The variance is most pronounced at higher slice thicknesses and for small nodule sizes. Measurement error is slice thickness and threshold dependent. PMID- 25527130 TI - Effervescent-salt-assisted dispersive micro-solid-phase extraction using mesoporous hybrid materials coupled with ultra-performance liquid chromatography for the determination of trace-level compounds in complicated plant preparations. AB - A novel effervescent-salt-assisted dispersive micro-solid-phase extraction using mesoporous hybrid materials was developed for the extraction of minute traces of constituents in complicated plant preparations. In this study, a special tablet containing carbon dioxide sources (sodium dihydrogenphosphate and sodium carbonate) and the sorbent (mesoporous hybrid materials) was prepared. The effects of different parameters influencing the extraction efficiency such as the concentration of salts, the type and concentration of mesoporous material, pH of diluent, and desorption solvents were investigated and optimized. Results show that the proposed method using green solvents (water) as extraction solutions required low consumption of sample amount and obtained high enrichment efficiency. Moreover, under optimized conditions, the tested tanshinones exhibited good linearity (r(2) > 0.994) in the concentration range of 0.5 to 80 ng mL(-1). The limits of detection values were lower than 0.0803 pg using UV visible detection. The developed method was successfully applied for the analysis of trace tanshinones in compound Danshen dripping pill and Danqi tablet samples. PMID- 25527131 TI - Cohort Profile: Tracing Achievements, Key processes and Efforts in professional care for Children and Adolescents REsearch; TAKECARE. AB - TAKECARE is a prospective cohort study designed in The Netherlands to obtain evidence on the care chain for children and adolescents with psychosocial problems, and its long-term outcomes. Little is known about the content of care as offered and on whether the care is adequate. The cohort consists of children and adolescents entering care for psychosocial problems (care sample, n = 1382) and a random sample of the general population (community sample, n = 666). Children were eligible for participation if they were aged 4-18 years (inclusive) and had estimated IQs of 70 and over. The care sample covers the fields of Preventive Child Healthcare (PCH), Child and Adolescent Social Care (CASC) and Child and Adolescent Mental Healthcare (CAMH). Children, parents or guardians and involved practitioners completed five questionnaires (baseline, and at 3, 12, 24 and 36 months thereafter). The main categories of data concern the sociodemographic characteristics of children and their parents or guardians, the characteristics of entry into care and care content, and intermediate and final treatment outcomes. Information about data access can be requested by e-mail: c4youth@umcg.nl. PMID- 25527133 TI - Exposure estimates in epidemiological studies of Korean veterans of the Vietnam War. PMID- 25527134 TI - Response to: ME Ginevan et al. Exposure estimates in epidemiological studies of Korean veterans of the Vietnam War. PMID- 25527135 TI - Innate lymphoid cells in type 2 immune responses. AB - In recent years, several distinct innate lymphoid cell populations (ILC) have been characterized in mice and humans. Group 2 ILC function as a rapid responder population in type 2 immune responses. Thus, a wealth of data has implicated an important role for ILC2 in immunity to parasitic infection and in immune pathology in inflammatory and allergic responses. In this review, we describe recent progress in our understanding of the development and ontogeny of ILC2 populations and the mechanisms by which these cells function in a variety of infection and disease settings. Finally, we emphasize recent findings indicating functional interactions between these innate cells and their adaptive CD4(+) Th2 cell counterparts. PMID- 25527136 TI - In vitro screening for drug repositioning. AB - Drug repositioning or repurposing has received much coverage in the scientific literature in recent years and has been responsible for the generation of both new intellectual property and investigational new drug submissions. The literature indicates a significant trend toward the use of computational- or informatics-based methods for generating initial repositioning hypotheses, followed by focused assessment of biological activity in phenotypic assays. Another viable method for drug repositioning is in vitro screening of known drugs or drug-like molecules, initially in disease-relevant phenotypic assays, to identify and validate candidates for repositioning. This approach can use large compound libraries or can focus on subsets of known drugs or drug-like molecules. In this short review, we focus on ways to generate and validate repositioning candidates in disease-related in vitro and phenotypic assays, and we discuss specific examples of this approach as applied to a variety of disease areas. We propose that in vitro screens offer several advantages over biochemical or in vivo methods as a starting point for drug repositioning. PMID- 25527137 TI - The lateral lesser toe fillet flap for diabetic foot soft tissue closure: surgical technique and case report. AB - Wound closure for the diabetic foot can be challenging and often involves amputation or reconstruction. The authors describe a surgical technique and a case report of lateral lesser toe fillet flap in the management of a diabetic foot wound. The lateral lesser toe fillet flap reconstruction is a reproducible technique that incurs comparatively minimal technical complexity and provides a favorable option in the management of diabetic foot wounds where soft tissue coverage is required. PMID- 25527139 TI - Enhancement of thermostability and kinetic efficiency of Aspergillus niger PhyA phytase by site-directed mutagenesis. AB - Phytase efficiently catalyzes the hydrolysis of phytate to phosphate; it can be utilized as an animal supplement to provide animals their nutrient requirements for phosphate and to mitigate environmental pollution caused by unutilized feed phosphate. Owing to animal feed being commonly pelleted at 70 to 90 degrees C, phytase with a sufficiently high thermal stability is desirable. Based on the crystal structure of PhyA and bioinformatics analysis at variant heat treatments, 12 single and multiple mutants were introduced by site-directed mutagenesis in order to improve phytase thermostability. Mutated constructs were expressed in Pichia pastoris. The manipulated phytases were purified; their biochemical and kinetic investigation revealed that while the thermostability of six mutants was improved, P9 (T314S Q315R V62N) and P12 (S205N S206A T151A T314S Q315R) showed the highest heat stability (P < 0.05) with 24 and 22.6 % greater retention, respectively, compared with the PhyA of the wild type at 80 degrees C. The K m value of the improved thermostable P9 and P12 mutant enzymes for sodium phytate were 35 and 20 % lower (P < 0.05) with respect to the wild-type enzyme. In conclusion, it is feasible to simultaneously improve the thermostability and the catalytic efficiency of phytase to be used as an animal feed supplement. PMID- 25527138 TI - Identification and functional analysis of a Hemolin like protein from Litopenaeus vannamei. AB - Hemolin is a specific immune protein belonging to immunoglobulin superfamily and firstly identified in insects. Growing evidences suggest that Hemolin can be activated by bacterial and viral infections and may play an important role in antimicrobial immunity. In this paper, we firstly identified a Hemolin-like protein from Litopenaeus vannamei (LvHemolin). Sequence analysis showed that LvHemolin shares high similarity with insect Hemolins and is mainly composed of seven immunoglobulin (Ig) domains which form a 'horseshoe' tertiary structure. Tissue distribution analysis demonstrated that LvHemolin mainly expressed in stomach, gill, epithelium and pyloric cecum of L. vannamei. After challenge with pathogens or stimulants, expression of LvHemolin was significantly up-regulated in both gill and stomach. Agglutination analysis demonstrated that recombinant LvHemolin protein purified from Escherichia coli could accelerate the agglutination of Vibrio parahaemolyticus, E. coli, Staphylococcus aureus, and Bacillus subtilis in the presence of Ca(2+). To verify the immune function of LvHemolin in vivo, shrimps were injected with gene-specific dsRNA, followed by challenge with white spot syndrome virus (WSSV) or V. parahaemolyticus. The results revealed that silence of LvHemolin could increase the cumulative mortalities of shrimps challenged by pathogens and increase the WSSV copies in shrimp tissues. These suggested that Hemolin could play an important role in shrimp innate immune defense against bacterial and viral infections. PMID- 25527140 TI - Effect of airborne hydrogen peroxide on spores of Clostridium difficile. AB - BACKGROUND: Contamination of surfaces by spores of Clostridium difficile is a major factor influencing the spread of healthcare-associated C. difficile infection. The aim of this study was to test the effect of an automated room disinfection system that provides an aerosol of 7.5 % hydrogen peroxide (H2O2) disinfectant, on spores of two different strains of C. difficile, and to evaluate the impact of biological soiling on the efficacy of H2O2 disinfection. MATERIAL AND METHOD: The strains used were a C. difficile PCR ribotype 027 and a C. difficile ATCC 9689. Spore suspensions of each strain were applied to ceramic tiles and exposed to aerosolized H2O2 at different locations in a test room. Biological soiling was simulated by bovine serum albumin and sheep erythrocytes. At set time points spores were recovered, plated onto Columbia 5 % sheep blood agar, and surviving bacteria were counted as colony-forming units (cfu). RESULTS: No viable spores of either strain were recovered after a 3 h exposure to gaseous H2O2. Spores located inside a drawer showed recovery of approximately 1E5 cfu/ml for C. difficile ribotype 027 after 1 h. In the presence of organic matter, a more than fivefold log reduction compared with not exposed controls could be observed for spores of either strain tested. CONCLUSION: Appropriate decontamination of surfaces exposed to spores of C. difficile is challenging for conventional cleaning methods. Aerosolized H2O2 delivered by automated room disinfection systems could possibly improve surface decontamination and thereby reduce transmission of healthcare-associated C. difficile infection. Also in the presence of organic matter H2O2 disinfection appears to be an effective adjunct for decontamination of environmental surfaces. PMID- 25527141 TI - The efficacy and safety of cilostazol for the secondary prevention of ischemic stroke in acute and chronic phases in Asian population--an updated meta-analysis. AB - BACKGROUNDS: While previous meta-analysis have investigated the efficacy of cilostazol in the secondary prevention of ischemic stroke, they were criticized for their methodology, which confused the acute and chronic phases of stroke. We present a new systematic review, which differs from previous meta-analysis by distinguishing between the different phases of stroke, and includes two new randomized, controlled trials (RCTs). METHODS: All RCTs investigating the effect of cilostazol on secondary prevention of ischemic stroke were obtained. Outcomes were analyzed by Review Manager, including recurrence of cerebral infarction (ROCI), hemorrhage stroke or subarachnoid hemorrhage (HSSH), all-cause death (ACD), and modified Rankin Scale score (mRS). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessed the quality of the evidence. RESULTS: 5491 patients from six studies were included in the current study. In secondary prevention of ischemic stroke in chronic phase, cilostazol was associated with a 47% reduction in ROCI (relative risk [RR] 0.53, 95% confidence interval [CI] 0.34 to 0.81, p = 0.003), while no significant difference in HSSH and ACD compared with placebo; and 71% reduction in HSSH (RR 0.29, 95% CI 0.15 to 0.56, p = 0.0002) compared with aspirin, but not in ROCI and ACD. In the secondary prevention of ischemic stroke in acute phase, cilostazol did not show any effect in the ROCI, HSSH, ACD and mRS compared to placebo or aspirin. The quality of the evidence from chronic phase was high or moderate, and those from acute phase were moderate or low when analyzed by GRADE approach. CONCLUSION: Cilostazol provided a protective effect in the secondary prevention of the chronic phase of ischemic stroke. PMID- 25527142 TI - Controlled Electrostatic Self-Assembly of Ibuprofen-Cationic Dextran Nanoconjugates Prepared by low Energy Green Process - a Novel Delivery Tool for Poorly Soluble Drugs. AB - PURPOSE: The direct effect of electrostatic interaction between ibuprofen and cationic dextran on the system-specific physicochemical parameters and intrinsic dissolution characteristics of ibuprofen was evaluated in order to develop drug polymer nanoconjugate as a delivery strategy for poorly soluble drugs. METHODS: Amorphous ibuprofen-DEAE dextran (Ddex) nanoconjugate was prepared using a low energy, controlled amphiphile-polyelectrolyte electrostatic self-assembly technique optimized by ibuprofen critical solubility and Ddex charge screening. Physicochemical characteristics of the nanoconjugates were evaluated using FTIR, DSC, TGA, NMR and SEM relative to pure ibuprofen. The in vitro release profiles and mechanism of ibuprofen release were determined using mathematical models including zero and first order kinetics; Higuchi; Hixson-Crowell and Korsmeyer Peppas. RESULTS: Electrostatic interaction between ibuprofen and Ddex was confirmed with FT-IR, (1)H NMR and (13)C NMR spectroscopy. The broad and diffused DSC peaks of the nanoconjugate as well as the disappearance of ibuprofen melting peak provided evidence for their highly amorphous state. Low concentrations of Ddex up to 1.0 * 10(-6) g/dm(3) enhanced dissolution of ibuprofen to a maximum of 81.32% beyond which retardation occurred steadily. Multiple release mechanisms including diffusion; discrete drug dissolution; anomalous transport and super case II transport were noted. CONCLUSIONS: Controlled assembly of ibuprofen and Ddex produced a novel formulation with potential extended drug release dictated by Ddex concentration. PMID- 25527143 TI - Adaptation of a counseling intervention to address multiple cancer risk factors among overweight/obese Latino smokers. AB - More than 60% of cancer-related deaths in the United States are attributable to tobacco use, poor nutrition, and physical inactivity, and these risk factors tend to cluster together. Thus, strategies for cancer risk reduction would benefit from addressing multiple health risk behaviors. We adapted an evidence-based intervention grounded in social cognitive theory and principles of motivational interviewing originally developed for smoking cessation to also address physical activity and fruit/vegetable consumption among Latinos exhibiting multiple health risk behaviors. Literature reviews, focus groups, expert consultation, pretesting, and pilot testing were used to inform adaptation decisions. We identified common mechanisms underlying change in smoking, physical activity, and diet used as treatment targets; identified practical models of patient-centered cross-cultural service provision; and identified that family preferences and support as particularly strong concerns among the priority population. Adaptations made to the original intervention are described. The current study is a practical example of how an intervention can be adapted to maximize relevance and acceptability and also maintain the core elements of the original evidence based intervention. The intervention has significant potential to influence cancer prevention efforts among Latinos in the United States and is being evaluated in a sample of 400 Latino overweight/obese smokers. PMID- 25527144 TI - Difference in the toxicity mechanism between ion and nanoparticle forms of silver in the mouse lung and in macrophages. AB - The health effects of silver nanoparticles (AgNPs) have not been well investigated, despite AgNPs now being widely used in consumer products. We investigated the metabolic behavior and toxicity of AgNPs in comparison to silver nitrate (AgNO3) both in vivo and in vitro. AgNPs (20 nm diameter) suspended in 1% albumin solution or AgNO3 solution was injected into the mouse lung. Less than 1% of the initial dose of AgNPs and more than 7% of the initial dose of AgNO3 was recovered in the liver 4h after administration, suggesting that the ionic form of silver was absorbed by the lung tissue and entered the systemic circulation more efficiently than AgNPs. The pro-inflammatory cytokine, IL-1beta, and neutrophils in bronchoalveolar lavage fluid (BALF) increased following intratracheal instillation of AgNPs or AgNO3. AgNO3 recruited more neutrophils in the alveolar space than did AgNPs. In the in vitro study, AgNO3 was more cytotoxic than 20, 60, or 100 nm diameter AgNPs in a mouse macrophage cell line (J774.1). To investigate the intracellular distribution of Ag in detail, J774.1 cells were exposed to AgNO3 or 20 nm AgNPs and the distribution of Ag to cytosolic proteins was investigated using HPLC-inductively coupled plasma-mass spectrometry (HPLC ICP-MS). Ag was mainly distributed to metallothioneins (MT) and to high molecular weight proteins in AgNO3- and AgNPs-exposed cells, respectively. Confocal laser microscopic examination of LysoTracker((r))-labeled cells indicated that AgNPs were colocalized with lysosomes in J774.1 cells. These results suggest that AgNPs were transported to lysosomes and only gradually dissolved in the macrophages, causing milder inflammatory stimulation in the mouse lung compared to AgNO3. PMID- 25527146 TI - Color updating on the apparent motion path. AB - When a static stimulus appears successively at two distant locations, we perceive illusory motion of the stimulus across them-long-range apparent motion (AM). Previous studies have shown that when the apparent motion stimuli differ in shape, interpolation between the two shapes is perceived across the AM path. In contrast, the perceived color during AM has been shown to abruptly change from the color of the first stimulus into that of the second, suggesting interpolation does not occur for color during AM. Here, we report the first evidence to our knowledge, that an interpolated color, distinct from the colors of either apparent motion stimulus, is represented as the intermediate percept on the path of apparent motion. Using carefully chosen target colors-cyan, pink, and lime that are perceptually and neurally intermediate between blue and green, orange and magenta, and green and orange respectively, we show that detection of a target presented on the apparent motion path was impaired when the color of the target was "in-between" the initial and terminal stimulus colors. Furthermore, we show that this feature-specific masking effect for the intermediate color cannot be accounted for by color similarity between the intermediate color and the color of the terminal inducer. Our findings demonstrate that intermediate colors can be interpolated over the apparent motion trajectory as in the case of shape, possibly involving similar interpolation processes for shape and color during apparent motion. PMID- 25527147 TI - Dissociating temporal inhibition of return and saccadic momentum across multiple eye-movement tasks. AB - Saccade latencies are longer prior to an eye movement to a recently fixated location than to control locations, a phenomenon known as oculomotor inhibition of return (O-IOR). There are theoretical reasons to expect that O-IOR would vary in magnitude across different eye movement tasks, but previous studies have produced contradictory evidence. However, this may have been because previous studies have not dissociated O-IOR and a related phenomenon, saccadic momentum, which is a bias to repeat saccade programs that also influences saccade latencies. The present study dissociated the influence of O-IOR and saccadic momentum across three complex visual tasks: scene search, scene memorization, and scene aesthetic preference. O-IOR was of similar magnitude across all three tasks, while saccadic momentum was weaker in scene search. PMID- 25527145 TI - Genomic and transcriptomic differences in community acquired methicillin resistant Staphylococcus aureus USA300 and USA400 strains. AB - BACKGROUND: Staphylococcus aureus is a human pathogen responsible for substantial morbidity and mortality through its ability to cause a number of human infections including bacteremia, pneumonia and soft tissue infections. Of great concern is the emergence and dissemination of methicillin-resistant Staphylococcus aureus strains (MRSA) that are resistant to nearly all beta-lactams. The emergence of the USA300 MRSA genetic background among community associated S. aureus infections (CA-MRSA) in the USA was followed by the disappearance of USA400 CA MRSA isolates. RESULTS: To gain a greater understanding of the potential fitness advantages and virulence capacity of S. aureus USA300 clones, we performed whole genome sequencing of 15 USA300 and 4 USA400 clinical isolates. A comparison of representative genomes of the USA300 and USA400 pulsotypes indicates a number of differences in mobile genome elements. We examined the in vitro gene expression profiles by microarray hybridization and the in vivo transcriptomes during lung infection in mice of a USA300 and a USA400 MRSA strain by performing complete genome qRT-PCR analysis. The unique presence and increased expression of 6 exotoxins in USA300 (12- to 600-fold) compared to USA400 may contribute to the increased virulence of USA300 clones. Importantly, we also observed the up regulation of prophage genes in USA300 (compared with USA400) during mouse lung infection (including genes encoded by both prophages PhiSa2usa and PhiSa3usa), suggesting that these prophages may play an important role in vivo by contributing to the elevated virulence characteristic of the USA300 clone. CONCLUSIONS: We observed differences in the genetic content of USA300 and USA400 strains, as well as significant differences of in vitro and in vivo gene expression of mobile elements in a lung pneumonia model. This is the first study to document the global transcription differences between USA300 and USA400 strains during both in vitro and in vivo growth. PMID- 25527148 TI - The visibility of color breakup and a means to reduce it. AB - Color breakup is an artifact seen on displays that present colors sequentially. When the eye tracks a moving object on such a display, different colors land on different places on the retina, and this gives rise to visible color fringes at the object's leading and trailing edges. Interestingly, color breakup is also observed when the eye is stationary and an object moves by. Using a novel psychophysical procedure, we measured breakup both when viewers tracked and did not track a moving object. Breakup was somewhat more visible in the tracking than in the non-tracking condition. The video frames contained three subframes, one each for red, green, and blue. We spatially offset the green and blue stimuli in the second and third subframes, respectively, to find the values that minimized breakup. In the tracking and non-tracking conditions, spatial offsets of Deltax/3 in the second subframe (where Deltax is the displacement of the object in one frame) and 2Deltax/3 in the third eliminated breakup. Thus, this method offers a way to minimize or even eliminate breakup whether the viewer is tracking or not. We suggest ways to implement the method with real video content. We also developed a color-breakup model based on spatiotemporal filtering in color opponent pathways in early vision. We found close agreement between the model's predictions and the experimental results. The model can be used to predict breakup for a wide variety of conditions. PMID- 25527149 TI - A working memory account of refixations in visual search. AB - We tested the hypothesis that active exploration of the visual environment is mediated not only by visual attention but also by visual working memory (VWM) by examining performance in both a visual search and a change detection task. Subjects rarely fixated previously examined distracters during visual search, suggesting that they successfully retained those items. Change detection accuracy decreased with increasing set size, suggesting that subjects had a limited VWM capacity. Crucially, performance in the change detection task predicted visual search efficiency: Higher VWM capacity was associated with faster and more accurate responses as well as lower probabilities of refixation. We found no temporal delay for return saccades, suggesting that active vision is primarily mediated by VWM rather than by a separate attentional disengagement mechanism commonly associated with the inhibition-of-return (IOR) effect. Taken together with evidence that visual attention, VWM, and the oculomotor system involve overlapping neural networks, these data suggest that there exists a general capacity for cognitive processing. PMID- 25527150 TI - Oculometric assessment of dynamic visual processing. AB - Eye movements are the most frequent (~3/s), shortest-latency (~150-250 ms), and biomechanically simplest (one joint, no inertial complexities) voluntary motor behavior in primates, providing a model system to assess sensorimotor disturbances arising from trauma, fatigue, aging, or disease states. We have developed a 15-min behavioral tracking protocol consisting of randomized Rashbass (1961) step-ramp radial target motion to assess several aspects of the behavioral response to visual motion, including pursuit initiation, steady-state tracking, direction tuning, and speed tuning. We show how oculomotor data can be converted into direction- and speed-tuning oculometric functions, with large increases in efficiency over traditional button-press psychophysics. We also show how the latter two can be converted into standard visual psychometric thresholds. To assess our paradigm, we first tested for the psychometric criterion of repeatability, and report that our metrics are reliable across repeated sessions. Second, we tested for the psychometric criterion of validity, and report that our metrics show the anticipated changes as the motion stimulus degrades due to spatiotemporal undersampling. Third, we documented the distribution of these metrics across a population of 41 normal observers to provide a thorough quantitative picture of normal human ocular tracking performance, with practice and expectation effects minimized. Our method computes 10 metrics that quantify various aspects of the eye-movement response during a simple 15-min clinical test, which could be used as a screening or assessment tool for disorders affecting sensorimotor processing, including degenerative retinal disease; developmental, neurological or psychiatric disorders; strokes; and traumatic brain injury. PMID- 25527152 TI - Circulating microRNA-21 as a biomarker for the detection of various carcinomas: an updated meta-analysis based on 36 studies. AB - Cancer is a class of diseases with high mortality rate, characterized by unregulated cell growth. Early diagnosis of cancer is currently the most effective method to prevent cancer development and improve the survival rate of patients. Traditional diagnostic methods such as biopsy usually provoke discomfort and unpleasant experience. Recently, microRNAs (miRNAs) were widely reported to be potential biomarkers to detect cancers without invasiveness. MicroRNA-21 (miRNA-21, miR-21) is one of the most prevalent miRNAs. This meta analysis aims to make a comprehensive analysis of the potential role of circulating miR-21 as a biomarker in human carcinoma diagnosis. A total of 36 articles involving 2920 cancer patients and 1986 healthy controls with regard to the diagnostic value of the circulating miR-21 for cancer detection were selected from online bibliographic databases. For pooled analysis, the sensitivity, specificity, and other basic characteristics were extracted from the 36 included articles. Then, bivariate random-effects model was selected to gain pooled results. Furthermore, to explore the sources of heterogeneity, we conducted stratified and meta-regression analyses based on different race/sample groups. The pooled characteristics of all included articles were as follows: sensitivity, 0.78 (95% confidence intervals (CI), 0.73-0.82); specificity, 0.82 (95% CI, 0.79 0.86); positive likelihood ratio (PLR), 4.4 (95% CI, 3.6-5.4); negative likelihood ratio (NLR), 0.26 (95% CI, 0.21-0.33); diagnostic odds ratio (DOR), 17 (95% CI, 12-24); and area under the curve (AUC), 0.87 (95% CI, 0.84-0.90). The subgroup analyses results based on different ethnic populations revealed that the diagnostic accuracy of miR-21 tends to be higher in Asian populations than in Caucasian populations. Furthermore, another subgroup analysis performed on sample types suggested that the serum-based specimen used in cancer diagnosis appeared to be more accurate than the plasma-based specimen. Our meta-analysis shows that the circulating miR-21 may be a potential biomarker as diagnostic tool for early stage cancer diagnosis. PMID- 25527151 TI - Visual field asymmetries in visual evoked responses. AB - Behavioral responses to visual stimuli exhibit visual field asymmetries, but cortical folding and the close proximity of visual cortical areas make electrophysiological comparisons between different stimulus locations problematic. Retinotopy-constrained source estimation (RCSE) uses distributed dipole models simultaneously constrained by multiple stimulus locations to provide separation between individual visual areas that is not possible with conventional source estimation methods. Magnetoencephalography and RCSE were used to estimate time courses of activity in V1, V2, V3, and V3A. Responses to left and right hemifield stimuli were not significantly different. Peak latencies for peripheral stimuli were significantly shorter than those for perifoveal stimuli in V1, V2, and V3A, likely related to the greater proportion of magnocellular input to V1 in the periphery. Consistent with previous results, sensor magnitudes for lower field stimuli were about twice as large as for upper field, which is only partially explained by the proximity to sensors for lower field cortical sources in V1, V2, and V3. V3A exhibited both latency and amplitude differences for upper and lower field responses. There were no differences for V3, consistent with previous suggestions that dorsal and ventral V3 are two halves of a single visual area, rather than distinct areas V3 and VP. PMID- 25527153 TI - Predictive power of circulating miRNAs in detecting colorectal cancer. AB - Many studies indicate that circulating microRNAs (miRNAs) could play important roles in screening human cancers, including colorectal cancer (CRC). However, the conflicting results on the accuracy of miRNA detection lead us to conduct this meta-analysis to access the predictive value of miRNAs for predicting CRC. Eligible studies were identified from the Medline, Embase, CNKI, and Web of Science by the search strategies and screening criterion. We used random effects models to calculate the pooled results from studies. The summary receiver operator characteristic curve (SROC) and the area under the SROC curve (AUC) were used to estimate the predictive accuracy. Subgroup analyses and meta-regression were used to analyze potential sources of heterogeneity. We used Deeks' funnel plot asymmetry test to test publication bias. This meta-analysis included a total of 24 studies from 19 articles, including 1558 CRC patients and 1085 controls. The overall pooled results from the meta-analysis were as follows: sensitivity was 0.81 (95% confidence interval (CI) 0.77-0.85), specificity was 0.84 (95% CI 0.78-0.88), PLR was 5.0 (95% CI 3.5-6.9), NLR was 0.22 (95% CI 0.18-0.28), DOR was 23 (95% CI 14-37), and AUC was 0.89 (95% CI 0.86-0.91). Subgroup and meta regression analyses demonstrated that multiple miRNAs (AUC, sensitivity, and specificity of 0.92, 0.84, and 0.87, respectively) had a higher predictive accuracy than single miRNA (AUC, sensitivity, and specificity of 0.84, 0.78, and 0.78, respectively). In addition, we found that serum can be a better matrix for miRNA assays in screening CRC compared with plasma. In summary, our data suggests that circulating miRNAs, particularly multiple miRNAs, which have higher accuracy than single miRNAs, are excellent biomarker for screening CRC with good sensitivity and noninvasive nature. PMID- 25527154 TI - D-loop somatic mutations and ~5 kb "common" deletion in mitochondrial DNA: important molecular markers to distinguish oral precancer and cancer. AB - Apart from genomic DNA, mutations at mitochondrial DNA (mtDNA) have been hypothesized to play vital roles in cancer development. In this study, ~5 kb deletion and D-loop mutations in mtDNA and alteration in mtDNA content were investigated in buccal smears from 104 healthy controls and 74 leukoplakia and 117 cancer tissue samples using Taqman-based quantitative assay and re sequencing. The ~5 kb deletion in mtDNA was significantly less (9.8 and 10.5 folds, P < 0.0001) in cancer tissues compared to control and leukoplakia tissues, respectively. On the other hand, somatic mutations in D-loop, investigated in 54 controls, 50 leukoplakias and 56 cancer patients, were found to be significantly more in cancer tissues, but not in leukoplakia tissues, compared to control (Z score = 5.4). MtDNA contents were observed to be significantly more in leukoplakia (2.1 folds, P = 0.004) and cancer (1.6 folds, P = 0.03) tissues compared to control tissues. So, D-loop somatic mutations and ~5 kb deletion patterns could be used as distinguishing markers between precancer and cancer tissues. This observation further suggests that somatic mutations in D-loop may facilitate carcinogenesis and cancer cells with less ~5 kb deletion, i.e., intact mtDNA, may become resistant to apoptosis. PMID- 25527155 TI - TP53 mutation analysis in chronic lymphocytic leukemia: comparison of different detection methods. AB - TP53 gene defects represent a strong adverse prognostic factor for patient survival and treatment resistance in chronic lymphocytic leukemia (CLL). Although various methods for TP53 mutation analysis have been reported, none of them allow the identification of all occurring sequence variants, and the most suitable methodology is still being discussed. The aim of this study was to determine the limitations of commonly used methods for TP53 mutation examination in CLL and propose an optimal approach for their detection. We examined 182 CLL patients enriched for high-risk cases using denaturing high-performance liquid chromatography (DHPLC), functional analysis of separated alleles in yeast (FASAY), and the AmpliChip p53 Research Test in parallel. The presence of T53 gene mutations was also evaluated using ultra-deep next generation sequencing (NGS) in 69 patients. In total, 79 TP53 mutations in 57 (31 %) patients were found; among them, missense substitutions predominated (68 % of detected mutations). Comparing the efficacy of the methods used, DHPLC and FASAY both combined with direct Sanger sequencing achieved the best results, identifying 95 % and 93 % of TP53-mutated patients. Nevertheless, we showed that in CLL patients carrying low-proportion TP53 mutation, the more sensitive approach, e.g., ultra deep NGS, might be more appropriate. TP53 gene analysis using DHPLC or FASAY is a suitable approach for mutation detection. Ultra-deep NGS has the potential to overcome shortcomings of methods currently used, allows the detection of minor proportion mutations, and represents thus a promising methodology for near future. PMID- 25527156 TI - The prognostic nutritional index (PNI) predicts overall survival of small-cell lung cancer patients. AB - Recent studies have shown the prognostic nutritional index (PNI) had prognostic value in some solid tumors. However, no studies have examined its prognostic role in small-cell lung cancer (SCLC) patients. In this retrospective study, 724 consecutive SCLC patients were included between 2006 and 2013. Demographic, clinical, and laboratory data were collected. The PNI was calculated as 10 * serum albumin value (g/dl) + .005 * peripheral lymphocyte count (per mm(3)). Univariate and multivariate analyses were performed to assess the prognostic value of relevant factors. The optimal cut-off value of PNI for OS stratification was determined to be 52.48. A total of 464 and 260 patients were assigned to low and high PNI groups, respectively. Compared with low PNI, high PNI was associated with older age, advanced stage, and elevated lactate dehydrogenase (LDH). Median overall survival (OS) was worse in the low PNI group (low vs high, 15.90 vs 25.27 months; HR, 0.62; p < 0.001). In multivariate analysis, stage, performance status, LDH, and PNI were independent prognostic factors for OS. Subgroup analysis showed PNI was generally a significant prognostic factor in different clinical situations. The assessment of PNI could assist the identification of patients with poor prognosis and be a hierarchical factor in the future SCLC clinical trials. PMID- 25527157 TI - Effect of Golgi phosphoprotein 2 (GOLPH2/GP73) on autophagy in human hepatocellular carcinoma HepG2 cells. AB - This study aims to investigate the effect of Golgi Protein 73 (GP73) on autophagy in human hepatoma line cells HepG2. We investigated the functional effects of GP73 on autophagy in hepatoma cell line HepG2 using immunofluoscence staining, Western blotting and real-time PCR. Our data showed that specific small interference RNA (siRNA) notably induced formation of autophagic vacuoles. In addition, upregulation of GP73 significantly inhibited formation of starvation induced LC3-positive structures. We provide the first experimental evidence to show that GP73 may play an important role in the inhibitory regulation of autophagy. Therefore, our data suggest a new molecular mechanism for GP73-related hepatoma progression. PMID- 25527158 TI - Fisetin suppresses ADAM9 expression and inhibits invasion of glioma cancer cells through increased phosphorylation of ERK1/2. AB - Fisetin (3,3',4',7-tetrahydroxyflavone) is a naturally occurring flavonoid which is widely distributed in plants. It has been reported to possess some anticancer and anti-invasive capabilities. We set out to explore the effects of fisetin on antimetastatic and its mechanism of action in GBM8401 cells. The results indicated that fisetin exhibited effective inhibition of cell migration and inhibited the invasion of GBM8401 cells under non-cytotoxic concentrations. To identify the potential targets of fisetin, human proteinase antibody array analysis was performed, and the results indicated that the fisetin treatment inhibited the expression of ADAM9 protein and mRNA, which are known to contribute to the progression of glioma cancer. Our results showed that fisetin phosphorylated ERK1/2 in a sustained way that contributed to the inhibited ADAM9 protein and mRNA expression determined by Western blot and RT-PCR. Moreover, inhibition of ERK1/2 by U0126 or transfection with the siERK plasmid significantly abolished the fisetin-inhibited migration and invasion through activation of the ERK1/2 pathway. In summary, our results suggest that fisetin might be a potential therapeutic agent against human glioma cells based on its capacity to activate ERK1/2 and to inhibit ADAM9 expression. PMID- 25527159 TI - Protein interactions of cortactin in relation to invadopodia formation in metastatic renal clear cell carcinoma. AB - In the present study, we wanted to examine the predominant factor/s in the initiation of metastasis. We used samples of advanced grades of renal clear cell carcinoma with documented clinical history of vena caval spread as the experimental group. The major rationale for this selection is the fact that renal cell carcinoma metastasize extensively through the inferior vena cava up to the pulmonary bed and often exist as a continuous mass of metastatic tissue. As cortactin plays a significant role in invadopodia formation during initiation of metastasis, in the present study, we tested expression of cortactin and phospho(tyr421)-cortactin in different grades of renal cell clear carcinoma and examined its property to bind to actin. The findings of the present study suggest that the variations of the local physiological milieu are the driving forces for metastasis by enhancing molecular mechanisms for lamellipodia formation. We conclude that localization of cortactin in cancer cells and interaction between actin and its nucleators are crucial for cancer progression. PMID- 25527160 TI - The impact of prenatal exposure to a single dose of testosterone on insulin resistance, glucose tolerance and lipid profile of female rat's offspring in adulthood. AB - PURPOSE: In our previous study, we introduced a rat model of polycystic ovary syndrome (PCOS) induced by prenatal exposure to a single dose of testosterone on embryonic day 20. In the current study, we aimed to investigate whether prenatal exposure to a single dose of testosterone could also induce metabolic disturbances, especially insulin resistance in adulthood (100-110 days of age) and also to make it as an appropriate rat model of PCOS (exhibiting both reproductive and metabolic disturbances with minimum morphological disorders in reproductive system) for further studies in PCOS. METHODS: Pregnant rats in the experimental group were subcutaneously injected with 5 mg free testosterone on the gestational day 20, while controls received only the solvent. Female offspring of both groups, prenatally androgenized (PNA) rats (PCOS models of rats) and controls were examined. RESULTS: Body weight measures showed significant increase in the PNA rats compared to controls on days 30, 45, 60 of age and in adulthood (P < 0.05). PNA rats showed insulin resistance compared to controls. Impaired glucose tolerance was not observed in the PNA rats compared to controls. There were no significant differences in lipid profile between the PNA and control rats (P > 0.05). CONCLUSION: Our study suggests that metabolic disturbances in PCOS and their severity during adult life probably depend on the particular time and levels of prenatal androgen exposure. PMID- 25527161 TI - Serum 25-hydroxyvitamin D levels and peripheral neuropathy in patients with type 2 diabetes: a systematic review and meta-analysis. AB - BACKGROUND: Vitamin D is a multifunctional pro-hormone and has widespread actions in human body. Several studies showed a possible association between vitamin D deficiency and diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes, but no definite conclusion was available. METHODS: A systematic review and meta-analysis was performed to comprehensively assess the association between serum 25-hydroxyvitamin D [25(OH)D] levels and DPN in patients with type 2 diabetes. Data from eligible studies were pooled using meta-analysis. RESULTS: Six studies that involved a total of 1,484 type 2 diabetic patients were finally included into the meta-analysis. Meta-analysis showed that there were obviously decreased serum 25(OH)D levels in DPN patients [weighted mean difference (WMD) = 6.36 ng/ml, 95 % confidence interval (95 % CI) -8.57 to -4.14, P < 0.00001]. Vitamin D deficiency was also significantly associated with increased risk of DPN in patients with type 2 diabetes [odds ratio (OR) 2.88, 95 % CI 1.84-4.50, P < 0.00001]. Meta-analysis of three studies with adjusted estimates showed that vitamin D deficiency was independently associated with increased risk of DPN in patients with type 2 diabetes (OR 2.68, 95 % CI 1.67-4.30, P < 0.0001). Sensitivity analysis showed that there was no obvious change in the pooled estimates. CONCLUSION: Vitamin D is involved in the development of DPN in type 2 diabetic patients, and vitamin D deficiency is very likely to be associated with DPN in type 2 diabetic patients. Further studies are needed to validate the association between vitamin D deficiency and DPN. PMID- 25527163 TI - A salt-bridge stabilized C-terminal hook is critical for the dimerization of a Bowman Birk inhibitor. AB - Legume Bowman-Birk inhibitors (BBIs) that inhibit mammalian proteases exist as dimers in solution. The structural basis governing dimerization of HGI-III (horsegram seed BBI) was investigated. An intra-monomer salt bridge (D76-K71) stabilizes an atypical hook-like conformation at the C-terminus. We postulate that this hook, positions D75 to enable an inter-monomer salt-bridge D75(a) K24(b), which results in dimerization. We verify this by K71A and D76A mutations of HGI-III. The mutants were both monomers, likely due to destabilization of the C-terminal hook. Dimerization was sustained in a double mutant K71D/D76K that was anticipated to form a similar hook critical for dimerization. Conversely, K24(b) that interacts with D75(a) of the loop is the specificity determining residue that interacts with trypsin to inhibit its activity. The inter-monomer salt bridge D75(a)-K24(b) must be disrupted for the inhibition of trypsin, requiring HGI-III to transition into a monomer. Size exclusion studies and a model of HGI III-trypsin complex support this notion. Interestingly, isoforms of the inhibitor present in germinated seeds (HGGIs) are monomers; and most strikingly, the C termini of these inhibitors are truncated with the loss the C-terminal hook critical for dimerization. The tendency of HGI-III to self-associate seems to relate to its physiological function of a storage protein. PMID- 25527162 TI - Solubilization and stabilization of macular carotenoids by water soluble oligosaccharides and polysaccharides. AB - Xanthophyll carotenoids zeaxanthin and lutein play a special role in the prevention and treatment of visual diseases. These carotenoids are not produced by the human body and must be consumed in the diet. On the other hand, extremely low water solubility of these carotenoids and their instability restrict their practical application as components of food or medicinal formulations. Preparation of supramolecular complexes of zeaxanthin and lutein with glycyrrhizic acid, its disodium salt and the natural polysaccharide arabinogalactan allows one to minimize the aforementioned disadvantages when carotenoids are used in food processing as well as for production of therapeutic formulations with enhanced solubility and stability. In the present study, the formation of supramolecular complexes was investigated by NMR relaxation, surface plasmon resonance (SPR) and optical absorption techniques. The complexes increase carotenoid solubility more than 1000-fold. The kinetics of carotenoid decay in reactions with ozone molecules, hydroperoxyl radicals and metal ions were measured in water and organic solutions, and significant increases in oxidation stability of lutein and zeaxanthin in arabinogalactan and glycyrrhizin complexes were detected. PMID- 25527164 TI - Palmitate induces insulin resistance in human HepG2 hepatocytes by enhancing ubiquitination and proteasomal degradation of key insulin signaling molecules. AB - Obesity-associated insulin resistance is a major pathogenesis of type 2 diabetes mellitus and is characterized by defects in insulin signaling. High concentrations of plasma free fatty acids (FFAs) are involved in the etiology of obesity-associated insulin resistance. However, the detailed mechanism by which FFAs contribute to the development of insulin resistance is not yet fully understood. We investigated the molecular basis of insulin resistance elicited by FFAs using the human hepatocyte cell line HepG2. Among major human FFAs, palmitate markedly inhibited insulin-stimulated phosphorylation of key insulin signaling molecules such as insulin receptor, insulin receptor substrate-1, and Akt, indicating that palmitate is the principal inducer of insulin resistance. We revealed that palmitate facilitates ubiquitination of the key insulin signaling molecules, and subsequently elicits their proteasomal degradation. Furthermore, we demonstrated that inhibition of ubiquitination by the ubiquitin-activating enzyme E1 inhibitor PYR41 significantly prevents palmitate-inducible insulin resistance but not by the proteasome inhibitor MG132, implying that ubiquitinated signaling molecules may be dysfunctional. In conclusion, inhibition of ubiquitination of the key insulin signaling molecules may be a potential strategy for preventing and treating obesity-associated insulin resistance. PMID- 25527165 TI - Polidocanol versus hypertonic glucose for sclerotherapy treatment of reticular veins of the lower limbs: study protocol for a randomized controlled trial. AB - BACKGROUND: The prevalence of chronic venous disease is high and occurs more frequently in females. According to the clinical, etiological, anatomical, and pathological classification (CEAP) definition, the reticular veins are included in the C1 class and are mainly associated with aesthetic complaints. Several invasive techniques are used for treatment, including mini phlebectomy, laser ablation, and radiofrequency ablation. However, a wide range of sclerosing agents may serve as minimally invasive alternatives, promoting chemical sclerosis of the vein wall. Although this technique is routinely performed around the world, there is no consensus on the most efficacious and safe chemical agent to be used. METHODS/DESIGN: Inclusion criteria are women between 18 and 69 years old with at least 10 cm long reticular veins in the lower limbs, on the outer side of the leg/thigh. Patients with CEAP 2 to 6, or with allergies, pregnancy, performing breastfeeding, or with any dermatologic or clinical problems will be excluded. Patients with venous ultrasound mapping showing involvement of saphenous trunks and/or a deep venous system will also be excluded. Patients will be randomized into two groups, one receiving 75% pure glucose and the other group receiving 0.2% polidocanol diluted in 70% glucose. Just one limb and one session per patient will be performed. The sclerosing agent volume will not exceed 5 mL. Clinical follow-up will include visits on days 7 and 60, always with photographic documentation. DISCUSSION: This project aims to enroll 96 patients and subject them to a double-blind treatment after the randomization process. The design is intended to evaluate efficacy through a primary end point and safety through a secondary end point. Forty-eight patients have currently been enrolled. Preliminary results for these patients showed that 25 received treatment, 2 were excluded, and 22 returned after 7 days and showed no greater adverse events. To date, establishing efficacy criteria has not been possible, and no patients have reached the 60-day return point. These data may help doctors choose the best chemical agent for the treatment of reticular veins. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02054325, 3/02/2014. PMID- 25527166 TI - Cefazolin and linezolid penetration into sternal cancellous bone during coronary artery bypass grafting. AB - OBJECTIVES: Deep sternal wound infection is a severe complication after cardiac surgery. Insufficient antibiotic target site concentrations may account for variable success of perioperative prophylaxis. Therefore, we measured perioperative penetration of cefazolin and of linezolid into sternal cancellous bone after sternotomy in coronary artery bypass grafting (CABG) patients by in vivo microdialysis. METHODS: Nine patients underwent CABG using a skeletonized left internal mammary artery. Standard antibiotic prophylaxis consisted of 4 g cefazolin prior to skin incision and additional 2 g during skin closure. In addition, 600 mg of linezolid were administered prior to skin incision and after 12 h for study purposes. Two microdialysis probes were inserted into the sternal cancellous bone (left and right side) after sternotomy. RESULTS: First mean peak cefazolin and linezolid plasma concentrations were 273 +/- 92 ug/ml and 22.1 +/- 8.9 ug/ml, respectively. Mean peak concentrations of antibiotics in sternal cancellous bone on the left and right sternal side were 112 +/- 59 ug/ml and 159 +/- 118 ug/ml for cefazolin and 10.9 +/- 4.0 ug/ml and 12.6 +/- 6.1 ug/ml for linezolid, respectively. Cefazolin exceeded the required tissue concentrations for relevant pathogens by far, but linezolid did not gain effective tissue concentrations in all patients for some relevant pathogens. Mammary artery harvesting had no significant effect on antibiotic tissue penetration. CONCLUSIONS: Direct measurement of antibiotic concentration in sternal cancellous bone with in vivo microdialysis is technically demanding but safe and feasible. We could demonstrate sufficient antibiotic coverage with our standard cefazolin dosing regimen in the sternal cancellous bone during cardiac surgery. Mammary artery harvesting had no clinically relevant effect on tissue penetration. Linezolid concentrations were not sufficient for some relevant pathogens. PMID- 25527167 TI - Spinal cord injury after endovascular treatment for thoracoabdominal aneurysm or dissection. AB - OBJECTIVES: Postoperative spinal cord injury (SCI) is a devastating complication of surgical repair for thoracoabdominal aortic aneurysm or dissection (TAAD), despite the complex reconstruction of inter-costal or lumbar arteries involved in the surgery. As an alternative technique, endovascular thoracoabdominal aneurysm repair (EVTAR) with visceral artery reconstruction has been accepted as a treatment option for severe comorbid patients of TAAD, because there is a permissible frequency of SCI after EVTAR in spite of no reconstruction of inter costal or lumbar arteries. We report the results of EVTAR at our hospital with a focus on spinal cord injury. METHODS: We analyzed data from 54 consecutive patients with TAAD (mean age, 74 +/- 9.6 years; 42 men) who underwent EVTAR at our hospital between February 2007 and February 2014. Three types of EVTAR technique were used: fenestrated and/or branched stent graft implantation in 39 patients, a hybrid technique (bypass grafts to visceral arteries and straight stent graft implantation) in 10 patients, and intentional coverage of the coeliac artery and straight stent graft implantation in 5 patients. In all patients, mean systemic blood pressure was maintained at >=80 mmHg. Opioid use was avoided in the perioperative period. RESULTS: According to the Crawford classification, the graft coverage extent was 9% (5/54) in type I, 11% (6/54) in type II, 39% (21/54) in type III, 22%(12/54) in type IV and 19% (10/54) in type V. In most patients (74%, 40/54), cerebrospinal fluid drainage was done intraoperatively and 1 day postoperatively. Hospital mortality was 5.6% (3/54). No patient developed SCI in the perioperative period. However, in the follow-up period 2 patients developed paraplegia as a consequence of shock caused by an aortic event. CONCLUSIONS: With close attention to spinal cord protection, EVTAR may be associated with only a low incidence of SCI in the perioperative period. Therefore, EVTAR is expected to become a promising treatment option for appropriately selected patients with TAAD. PMID- 25527168 TI - Preventive analgesia in thoracic surgery: controlled, randomized, double-blinded study. AB - OBJECTIVES: Preventive analgesia is defined as a treatment that is commenced before the surgical procedure in order to diminish the physiological consequences of afferent nociceptive transmission caused by the procedure and prevent central sensitization. The analysis of randomized studies of preventive analgesia is controversial. The aim of this study was to check the analgesic efficacy of preoperative administration of dextromethorphan associated with intercostal nerve block with levobupivacaine in thoracotomy patients who refused or had a contraindication to epidural analgesia. METHODS: This study was a four-arm, double-blinded, randomized placebo-controlled trial. Patients were allocated following close block randomization into four arms: 'Group A' preoperative dextromethorphan and preoperative intercostal block (IB), 'Group B' preoperative placebo and preoperative IB, 'Group C' preoperative dextromethorphan and postoperative IB, 'Group D' preoperative placebo and postoperative block. The primary end-point was the cumulative morphine consumption (CMC) within the first 14 days after surgery. RESULTS: A total of 400 patients were enrolled and 395 completed the study. There were no statistical differences among the groups in terms of demographic and surgical data; in contrast, preoperative quality-of-life scores were heterogeneous. The mean CMCs were as follows: Group A 111.4 mg, Group B 121.5 mg, Group C 126.8 mg, Group D 138.3 mg. Group A mean was lower than the maximum (P = 0.0001). The CMC value did not correlate with age, sex, body mass index, education, type of surgery, length or width of the incision and rib fracture. Postoperative functional data and post-thoracotomy syndrome prevalence were homogeneous; female gender resulted predictive for post-thoracotomy syndrome. CONCLUSIONS: Results indicate that preoperative administration of dextromethorphan associated with preoperative IB with levobupivacaine provided preventive analgesia, decreasing analgesic administration during the early postoperative period compared with placebo and/or postoperative IB. This study failed in detecting any effect of preventive analgesia on functional items and post-thoracotomy syndrome. PMID- 25527169 TI - The correlation of morphological features of chest computed tomographic scans with clinical characteristics of thymoma. AB - OBJECTIVES: Chest computed tomography (CT) scanning has been widely utilized in thymoma identification and staging as well as in follow-up monitoring for recurrence. However, the relationship between some CT imaging features and pathological types, clinical stage, completeness of resection, or prognosis in thymoma has not been well explored. METHODS: We retrospectively reviewed preoperative CT imaging for 238 thymoma patients, who had undergone thymectomy from October 2007 to December 2011. All CT parameters were assessed in each case based on clinical and pathological data. Survival analysis was performed by using the Kaplan-Meier and log-rank tests. RESULTS: Tumour contours (P = 0.008), homogeneity (P = 0.009), degree of enhancement (P = 0.013), fat plane obliteration with adjacent structures (P < 0.001), the presence of mediastinal lymphadenopathy (P = 0.010), irregular infiltration into the lung (P = 0.012) and tumour shape (P = 0.007) were associated with the World Health Organization (WHO) histological classification. Lobulated or irregular tumour contours (P < 0.001), presence of calcifications (P = 0.002), infiltration of surrounding fat (P < 0.001), irregular infiltration into the lung (P < 0.001), irregular infiltration into vascular (P < 0.001), more abutment of vessels (P < 0.001) and pulmonary changes adjacent to the tumour (P < 0.001) were associated with the more advanced Masaoka-Koga clinical stage. Tumour contours (P < 0.001), infiltration of surrounding fat (P = 0.008), irregular infiltration into the lung (P < 0.001) and degree of abutment of vessel circumference (P = 0.001) were associated with completeness of resection. With multivariate analysis, no CT image features could reliably predict on the overall or disease-free survival rate. CONCLUSIONS: CT imaging does have some features, which are significantly correlated with the WHO classification, the Masaoka-Koga clinical staging and the completeness of resection, although it has no definite role to evaluate preoperatively the survival rate of thymoma patients. PMID- 25527170 TI - Comparable long-term results for porcine and pericardial prostheses after isolated aortic valve replacement. AB - OBJECTIVES: Outcome of aortic valve replacement may be influenced by the choice of bioprosthesis. Pericardial heart valves are described to have a favourable haemodynamic profile compared with porcine valves, although the clinical notability of this finding is still controversially debated. Herein, we compared the long-term results of two commonly implanted bioprosthesis at a single centre. METHODS: All consecutive patients undergoing isolated aortic valve replacement with either a Carpentier-Edwards Magna pericardial prosthesis or a Medtronic Mosaic porcine prosthesis between 2002 and 2008 were analysed regarding preoperative characteristics, short- and long-term survival, valve-related complications and echocardiographic findings. RESULTS: The Medtronic Mosaic was implanted in 163 patients and the Carpentier-Edwards Magna in 295 patients. The sizes of implanted valves were 22.4 +/- 1.5 mm for the Mosaic and 21.8 +/- 1.8 mm for the Magna (P = 0.001). The long-term survival rate was 76 and 56% after 5 and 10 years for the Medtronic Mosaic, which was comparable with the Carpentier Edwards Magna (77 and 57%; P = 0.92). Overall long-term survival was comparable with an age- and sex-matched Austrian general population for both groups. Valve related adverse events were similar between groups. The postoperative mean transvalvular gradient was significantly increased in the Mosaic group (24 +/- 9 mmHg vs 17 +/- 7 mmHg; P < 0.001). CONCLUSIONS: Both types of aortic bioprostheses offer excellent results after isolated aortic valve replacement. Despite relevant differences in gradients, long-term survival was comparable with the expected normal survival for both bioprostheses. Patients with a porcine heart valve had a higher postoperative transvalvular gradient. PMID- 25527171 TI - Distal aortic reintervention after surgery for acute DeBakey type I or II aortic dissection: open versus endovascular repair. AB - OBJECTIVES: Aortic dissection DeBakey type I and II may require distal reinterventions after initial proximal repair. We evaluated outcomes following open versus endovascular approaches to distal aortic pathologies after surgery for acute dissection. METHODS: One hundred and forty-one consecutive patients underwent 152 distal reinterventions after previous type I or II dissection repair [63 (first quartile, 55; third quartile, 72) years old; initially 86% DeBakey type I; 54% hemiarch, 39% isolated ascending, 7% total arch replacement] at two tertiary centres in the USA and Europe over the last 14 years. Among them, 56 and 85 required reintervention for the aortic arch and the descending aorta, respectively. The median follow-up was 2.1 (first quartile, 0.8; third quartile, 5.8) years (439 patient-years). RESULTS: The median time between acute aortic dissection repair and descending aortic reintervention was longer in the open group (2.7 (first quartile, 0.8; third quartile, 6.7) vs 0.6 (first quartile, 0.1; third quartile, 3.5) years, P < 0.01). There was one irreversible spinal ischaemia in the open and one stroke in the endovascular group. Two patients in the open and none in the endovascular group required re-exploration for bleeding. Two open and 4 endovascular patients required more than 1 distal reintervention (6 vs 8%, P = 1). Descending aortic open-repair patients experienced higher in hospital mortality (23 vs 0%, P < 0.01) and lower survival at 1 and 5 years (74 +/- 8% vs 96 +/- 3%, 65 +/- 9% vs 92 +/- 5%, P < 0.01, respectively). CONCLUSIONS: Endovascular intervention for descending aortic pathologies after DeBakey type I or II dissection surgical repair is associated with lower in hospital mortality and better survival, and does not raise the likelihood of later reinterventions at the mid-term follow-up. PMID- 25527172 TI - Results of Fontan operation in patients with atrioventricular valve regurgitation. AB - OBJECTIVES: The influence of concomitant atrioventricular valve regurgitation on the results of Fontan operation remains disputable. The goal of this study was to compare early and late results of Fontan operation performed in patients with mild or moderate-to-severe atrioventricular valve regurgitation. METHODS: For retrospective analysis, patients with atrioventricular valve insufficiency assessed by echocardiography were divided into three groups based on the severity of regurgitation and its repair or non-repair during Fontan operation: Group 1: unrepaired regurgitation 1-2+ (n = 33); Group 2: unrepaired regurgitation 3-4+ (n = 11); Group 3: repaired regurgitation 3-4+ (n = 35). Actuarial survival was estimated by the Kaplan-Meier method, followed by the log-rank test to compare survival curves between groups. RESULTS: Hospital mortality rates in Groups 1 through 3 reached 3, 27 and 14%, respectively (P = 0.015, Group 1 vs Group 2). The frequency of non-lethal complications did not significantly differ between groups. However, patients from Group 2 required significantly more intensive inotropic support, longer mechanical ventilation and had larger pleural effusion. Predicted survival after Fontan operation was the worst in Group 2 (P = 0.016, Group 2 vs Group 1). The frequency of non-lethal late complications was also the highest in Group 2 (50 vs 17 or 11%); however, the difference did not reach statistical significance (P = 0.13 and 0.069, respectively). The severity of atrioventricular valve regurgitation during the follow-up did not significantly change when compared with discharge after the repair in Group 2 or Group 3 (P = 0.19 and 0.52, respectively), and significantly increased in Group 1 (P = 0.003). However, this increase did not have clinical significance during the reported period of follow-up. CONCLUSIONS: If unrepaired, concomitant moderate-to-severe atrioventricular valve regurgitation significantly worsens the results of the Fontan procedure. Longer observation is needed to define the strategy in patients with mild atrioventricular valve regurgitation that remained unrepaired during Fontan operation. PMID- 25527173 TI - Transoesophageal spinal cord stimulation for motor-evoked potentials monitoring: feasibility, safety and stability. AB - OBJECTIVES: Specificity of transcranial motor-evoked potentials (MEPs) is low because amplitude fluctuation is common, which seems due to several technical and fundamental reasons including difficulty in electrodes positioning and fixation for transcranial stimulation and susceptibility to anaesthesia. This study aimed to investigate the feasibility, safety and stability of our novel technique of transoesophageal spinal cord stimulation to improve the stability of MEPs. METHODS: Ten anaesthetized adult beagle dogs were used. Transoesophageal stimulation was performed between the oesophageal luminal surface electrode (cathode) and a subcutaneous needle electrode (anode) at the fourth to fifth thoracic vertebra level. Stimulation was achieved with a train of five pulses delivered at 2.0-ms intervals. Compound muscle action potentials were recorded from four limbs and external anal sphincter muscles. Stability to anaesthetic agents was tested at varying speeds of propofol and remifentanil, and effects of varying concentration of sevoflurane inhalation were also evaluated. RESULTS: Transoesophageal MEPs could be recorded without difficulty in all dogs. Fluoroscopic evaluation showed that electrodes misalignment up to 5 cm cranially or caudally could be tolerated. Stimulus intensity to achieve maximum amplitude of hindlimb muscle potentials on both sides was significantly lower by transoesophageal stimulation than by transcranial stimulation (383 +/- 41 vs 533 +/- 121 V, P = 0.02) and had less interindividual variability. Latency of transoesophageal MEPs was shorter than that of transcranial MEPs at every recording point. No arrhythmia was provoked during stimulation. Animals that were allowed to recover showed no neurological abnormality. In the two sacrificed animals, the explanted oesophagus showed no mucosal injury. Stability to varying dose of anaesthetic agents was similar between transoesophageal and transcranial stimulation, except for the potentials of forelimbs by transoesophageal stimulation that were resistant to anaesthetic depression. CONCLUSIONS: Transoesophageal stimulation for MEPs monitoring was feasible without difficulty and safe. Although its stability to anaesthetic agents was similar to that of transcranial stimulation, its technical ease and small interindividual variability warrants further studies on the response to spinal cord ischaemia. PMID- 25527174 TI - Production of L-ornithine from sucrose and molasses by recombinant Corynebacterium glutamicum. AB - Sucrose and molasses are attractive raw materials for industrial fermentation. Although Corynebacterium glutamicum shows sucrose-utilizing activity, sucrose or molasses is only a fraction of carbon source used in the fermentation medium in most works. An engineered C. glutamicum strain was constructed for producing L ornithine with sucrose or molasses as a sole carbon source by transferring Mannheimia succiniciproducens beta-fructofuranosidase gene (sacC). The engineered strain, C. glutamicum DeltaAPE6937R42 (pEC-sacC), produced 22.0 g/L of L ornithine with sucrose as the sole carbon source, which is on par with that obtained by the parent strain C. glutamicum DeltaAPE6937R42 with glucose as the sole carbon. The resulting strain C. glutamicum DeltaAPE6937R42 (pEC-sacC) produced 27.0 g/L of L-ornithine with molasses as the sole carbon source, which is higher than that obtained by the parent strain C. glutamicum DeltaAPE6937R42 with glucose as the sole carbon. This strategy can be applied for developing sucrose- or molasses-utilizing industrial strains. PMID- 25527175 TI - Characterization of the 19q12 amplification including CCNE1 and URI in different epithelial ovarian cancer subtypes. AB - BACKGROUND: CCNE1 is frequently amplified in high grade serous ovarian cancer and may serve as a target for ovarian cancer treatment. URI is closely related to CCNE1 at the 19q12 amplicon and may also contribute to the oncogenic effect. Our objective was to investigate the relevance of CCNE1 and URI gene amplification and protein expression in different histological subtypes of epithelial ovarian cancer (EOC). METHODS: A novel dual-color 19q12 in situ hybridization (ISH), covering CCNE1 and URI, and chromosome 19 as a surrogate using Ventana BenchMark XT platform was developed and applied to 148 EOCs. URI and CCNE1 amplifications were separately assessed by fluorescence in situ hybridization (FISH). Immunohistochemistry using a Cyclin E1 and a novel URI monoclonal antibody was performed. RESULTS: Amplification of 19q12 was found in 36.6%, CCNE1 in 21.7%, URI in 9.9%, and both genes simultaneously in 9% of EOC cases. High Cyclin E1 and URI protein expression were observed in 52.2% and 26.1%, respectively. Amplification of 19q12 occurred in all EOC subtypes and was associated with amplification and expression of CCNE1/Cyclin E1, URI, TP53 mutation, and advanced stage. CONCLUSION: The novel 19q12 ISH probe reliably detects both CCNE1 and URI amplifications as confirmed by FISH. The combination of 19q12 amplification with Cyclin E1 and URI protein expression may help to select patients more likely to benefit from CDK2 targeted therapies. PMID- 25527176 TI - Proinflammatory cytokines modulate the chemokine CCL2 (MCP-1) in human annulus cells in vitro: CCL2 expression and production. AB - Chemokines are important secondary inflammatory mediators released in response to stimuli which act as second-order cytokines with specialized functions in inflammation. The role of many of these specialized mediators is as yet poorly understood in the human intervertebral disc. Here we investigated CCL2 (chemokine (C-C motif) ligand 2, also known as monocyte chemotactic protein-1 (MCP-1)) in a study of its immunolocalization in disc tissue, and then hypothesized that exposure of cultured human annulus cells to proinflammatory cytokines might alter CCL2 gene expression and CCL2 production. CLL2 was localized to many disc cells in both herniated and non-herniated tissue specimens. Molecular analyses showed that cells exposed to IL-1beta showed a 5.5 fold upregulation in CCL2 gene expression vs. controls, p=0.017. Cells exposed to TNF-alpha showed a 7.7 fold upregulation vs. controls, p=0.005. Cultured cells (grades II-V) showed increased MCP-1 production in IL1-beta-treated cells vs. controls (p=0.016), with no significant difference in production in TNF-alpha-treated cells. Local production of CCL2 in vivo and vitro suggests that annulus cells may be primary effector cells (as well as target cells), with the ability to mediate physiological immune related processes during disc degeneration by both autocrine and paracrine signaling. PMID- 25527179 TI - Development of a technique for improving coefficient of variation of CaSO4:Dy teflon-based TLD personnel monitoring system in low-dose region. AB - In view of the importance of zero-dose background (null signal) in influencing the coefficient of variation in low-dose region, a technique for the estimation of the same from composite (gross) signal is developed for CaSO4:Dy-based personnel monitoring system being used in India. The technique is based on simple analysis of glow curves (GCs) of unexposed and exposed dosemeters, evolution of trend/model for the zero-dose curves, generation of simulation protocol for individual zero-dose curves, establishment of characteristics of GCs of exposed dosemeters and finally preparation of an algorithm to segregate the components from composite signal. The technique offers the separation of real-time background and gives superior results over other method of approximation of the background. The results also prove efficiency of the empirical trending and simulation protocol of background GCs. The proposed technique can be implemented in routine monitoring without any extra man hours and reader time. PMID- 25527178 TI - P2X7 receptor of rat dorsal root ganglia is involved in the effect of moxibustion on visceral hyperalgesia. AB - Irritable bowel syndrome (IBS) and inflammatory bowel disease often display visceral hypersensitivity. Visceral nociceptors after inflammatory stimulation generate afferent nerve impulses through dorsal root ganglia (DRG) transmitting to the central nervous system. ATP and its activated-purinergic 2X7 (P2X7) receptor play an important role in the transmission of nociceptive signal. Purinergic signaling is involved in the sensory transmission of visceral pain. Moxibustion is a therapy applying ignited mugwort directly or indirectly at acupuncture points or other specific parts of the body to treat diseases. Heat sensitive acupoints are the corresponding points extremely sensitive to moxa heat in disease conditions. In this study, we aimed to investigate the relationship between the analgesic effect of moxibustion on a heat-sensitive acupoint "Dachangshu" and the expression levels of P2X7 receptor in rat DRG after chronic inflammatory stimulation of colorectal distension. Heat-sensitive moxibustion at Dachangshu acupoint inhibited the nociceptive signal transmission by decreasing the upregulated expression levels of P2X7 mRNA and protein in DRG induced by visceral pain, and reversed the abnormal expression of glial fibrillary acidic protein (GFAP, a marker of satellite glial cells) in DRG. Consequently, abdominal withdrawal reflex (AWR) score in a visceral pain model was reduced, and the pain threshold was elevated. Therefore, heat-sensitive moxibustion at Dachangshu acupoint can produce a therapeutic effect on IBS via inhibiting the nociceptive transmission mediated by upregulated P2X7 receptor. PMID- 25527180 TI - 30-y follow-up of a Pu/Am inhalation case. AB - In 1983, a young man inhaled accidentally a large amount of plutonium and americium. This case was carefully followed until 2013. Since no decorporation measures had been taken, the undisturbed metabolism of Pu and Am can be derived from the data. First objective was to determine the amount of inhaled radionuclides and to estimate committed effective dose. In vivo and excretion measurements started immediately after the inhalation, and for quality assurance, all types of measurements were performed by different labs in Europe and the USA. After dose assessment by various international groups were completed, the measurements were continued to produce scientific data for model validation. The data have been analysed here to estimate lung absorption parameter values for the inhaled plutonium and americium oxide using the proposed new ICRP Human Respiratory Tract Model. As supplement to the biokinetic modelling, biological data from three different cytogenetic markers have been added. The estimated committed effective dose is in the order of 1 Sv. The subject is 30 y after the inhalation, of good health, according to a recent medical check-up. PMID- 25527181 TI - Study of ageing and fading in CR-39 detectors for different storage conditions. AB - The aim of this study was to investigate the effect of ageing and fading on PADC detector response, as a function of the storage time and temperature. Several groups of CR-39 detectors provided by Radosys, Ltd. were exposed at the reference radon chamber of the Istituto Nazionale di Metrologia delle Radiazioni Ionizzanti, at the ENEA centre in Casaccia. The results indicate that low temperature storage inhibits the effect of both ageing and fading. Finally, the overall reduction in CR-39 sensitivity due to the combined ageing/fading effect was estimated. In particular, the sensitivity of the detectors continuously exposed in air at room temperature over 6 and 3 months was reduced, respectively, by 7.5 and 4 %. PMID- 25527182 TI - Review of trace mineral requirements for preterm infants: what are the current recommendations for clinical practice? AB - Inadequate nutrient stores at birth are an inevitable consequence of being born prematurely. Preterm infants also have high nutrient requirements, which increase with earlier gestational ages. As a result, early nutrition intervention is required to prevent further deficits that, if not corrected, can affect growth and long-term outcomes. Preterm infants often require several weeks of parenteral nutrition (PN) support, which includes trace mineral supplementation. Trace minerals are considered essential nutrients, unable to be synthesized in the human body. Deficiencies of trace minerals have been reported, yet evidence-based guidelines for assessment and supplementation have not been clearly defined. Food and Drug Administration-approved parenteral trace mineral intake guidelines are more than 30 years old. In an effort to more clearly define trace mineral supplementation and monitoring guidelines for preterm infants, a review of literature was performed with the purpose to (1) summarize trace mineral roles in preterm infants, (2) describe clinical signs of deficiency and toxicity, and (3) present intake recommendations and considerations for preterm infants based on current available literature. Review of literature was completed using PubMed and Cochrane databases to find relevant studies specific to trace mineral requirements for preterm infants, trace mineral supplementation of PN, human milk fortifiers, and preterm infant formulas. Review of literature supports that trace mineral depletion can lead to clinical compromise in preterm infants; therefore, suggesting that every effort be made to ensure adequate provision of trace minerals is given to preterm infants. Practical considerations for the clinical nutrition management of preterm infants were also identified in this review. PMID- 25527183 TI - Influence of environmental factors in the adherence of an atypical enteropathogenic Escherichia coli strain to epithelial cells. AB - BACKGROUND: Attachment is essential to maintain bacteria at their preferential intestinal colonization sites. There is little information on the influence of different environmental conditions in the interaction of atypical enteropathogenic Escherichia coli (aEPEC) strains with epithelial cells. In this study, we evaluated the effect of different glucose (5 and 25 mM) and CO2 (0.03 and 5%) concentrations and presence of bile salts on the adhesiveness of the aEPEC strain 1551-2. RESULTS: We found that a CO2-enriched atmosphere enhanced the adhesiveness of the aEPEC 1551-2 strain independently of glucose concentrations or presence of bile salts. Conversely, the presence of high glucose concentration altered the original localized adherence (LA) pattern observed at 5 mM glucose, which is characterized by the formation of compact bacterial clusters, to a hybrid adherence pattern (LA and an aggregative adherence-like pattern). In addition, at high glucose concentration, there was increased expression of the fimA gene, which encodes the major subunit of type 1 pilus (T1P), and an isogenic fimA mutant displayed only LA. The presence of bile salts did not interfere with the adhesion properties of the 1551-2 strain to HeLa cells. CONCLUSIONS: Our data suggest that a CO2-enriched atmosphere could favor aEPEC adhesion to the host cells, whereas enhanced T1P production under high glucose concentration could allow bacteria to access more extensive intestinal colonization sites in the host at the beginning of the infectious process. PMID- 25527185 TI - Incompliance of total hip arthroplasty (THA) patients to limited weight bearing. AB - INTRODUCTION: Limited weight bearing of the lower extremity is a commonly applied procedure in orthopedic rehabilitation following trauma surgery and joint replacement. The compliance of patients with limited weight bearing after cementless total hip arthroplasty has not yet been surveyed using sensor-loaded insoles. The objective of this study was to investigate foot loadings in patients after THA under the assumption of limited weight bearing. METHODS: Peak pressures for the hindfoot, midfoot and forefoot were obtained from 14 patients (10 women, 4 men, age 63 +/- 12 years, height 172 +/- 9 cm, weight 92 +/- 20 kg, BMI 31 +/- 6 kg/m(2)) by means of dynamic pedobarography, with full weight bearing preoperatively (baseline) and at 8-10 days after cementless total hip arthroplasty, walking again on even floor, and also walking upstairs and downstairs with a restriction of weight bearing to 10 % body weight, taught by an experienced physiotherapist with a bathroom scale. RESULTS: Foot loadings with limited weight bearing on even floor remained up to 88 % from full weight bearing preoperatively. Walking upstairs and downstairs under the same condition was approximately equal to a bisection of peak pressures from full weight bearing. CONCLUSIONS: Patients following cementless do not comply with limited weight bearing when they are trained by the use of a bathroom scale. PMID- 25527184 TI - Functional consequences of age-related morphologic changes to pyramidal neurons of the rhesus monkey prefrontal cortex. AB - Layer 3 (L3) pyramidal neurons in the lateral prefrontal cortex (LPFC) of rhesus monkeys exhibit dendritic regression, spine loss and increased action potential (AP) firing rates during normal aging. The relationship between these structural and functional alterations, if any, is unknown. To address this issue, morphological and electrophysiological properties of L3 LPFC pyramidal neurons from young and aged rhesus monkeys were characterized using in vitro whole-cell patch-clamp recordings and high-resolution digital reconstruction of neurons. Consistent with our previous studies, aged neurons exhibited significantly reduced dendritic arbor length and spine density, as well as increased input resistance and firing rates. Computational models using the digital reconstructions with Hodgkin-Huxley and AMPA channels allowed us to assess relationships between demonstrated age-related changes and to predict physiological changes that have not yet been tested empirically. For example, the models predict that in both backpropagating APs and excitatory postsynaptic currents (EPSCs), attenuation is lower in aged versus young neurons. Importantly, when identical densities of passive parameters and voltage- and calcium-gated conductances were used in young and aged model neurons, neither input resistance nor firing rates differed between the two age groups. Tuning passive parameters for each model predicted significantly higher membrane resistance (R m ) in aged versus young neurons. This R m increase alone did not account for increased firing rates in aged models, but coupling these R m values with subtle differences in morphology and membrane capacitance did. The predicted differences in passive parameters (or parameters with similar effects) are mathematically plausible, but must be tested empirically. PMID- 25527186 TI - The role of Sox9 in mouse mammary gland development and maintenance of mammary stem and luminal progenitor cells. AB - BACKGROUND: Identification and characterization of molecular controls that regulate mammary stem and progenitor cell homeostasis are critical to our understanding of normal mammary gland development and its pathology. RESULTS: We demonstrate that conditional knockout of Sox9 in the mouse mammary gland results in impaired postnatal development. In short-term lineage tracing in the postnatal mouse mammary gland using Sox9-CreER driven reporters, Sox9 marked primarily the luminal progenitors and bipotent stem/progenitor cells within the basal mammary epithelial compartment. In contrast, long-term lineage tracing studies demonstrate that Sox9+ precursors gave rise to both luminal and myoepithelial cell lineages. Finally, fate mapping of Sox9 deleted cells demonstrates that Sox9 is essential for luminal, but not myoepithelial, lineage commitment and proliferation. CONCLUSIONS: These studies identify Sox9 as a key regulator of mammary gland development and stem/progenitor maintenance. PMID- 25527187 TI - Rheumatoid arthritis prevalence in Quebec. AB - BACKGROUND: To estimate rheumatoid arthritis (RA) prevalence in Quebec using administrative health data, comparing across regions. METHODS: Cases of RA were ascertained from physician billing and hospitalization data, 1992-2008. We used three case definitions: 1) >= 2 billing diagnoses, submitted by any physician, >= 2 months apart, but within 2 years; 2) >= 1 diagnosis, by a rheumatologist; 3) >=1 hospitalization diagnosis (all based on ICD-9 code 714, and ICD-10 code M05). We combined data across these three case definitions, using Bayesian hierarchical latent class models to estimate RA prevalence, adjusting for the imperfect sensitivity and specificity of the data. We compared urban versus rural regions. RESULTS: Using our case definitions and no adjustment for error, we defined 75,760 cases for an over-all RA prevalence of 9.9 per thousand residents. After adjusting for the imperfect sensitivity and specificity of our case definition algorithms, we estimated Quebec RA prevalence at 5.6 per 1000 females and 4.1 per 1000 males. The adjusted RA prevalence estimates for older females were the highest for any demographic group (9.9 cases per 1,000), and were similar in rural and urban regions. In younger males and females, and in older males, RA prevalence estimates were lower in rural versus urban areas. CONCLUSIONS: Without adjustment for error inherent in administrative databases, RA prevalence in Quebec was approximately 1%, while adjusted estimates are approximately half that. The lower prevalence in rural areas, seen for most demographic groups, may suggest either true regional variations in RA risk, or under-ascertainment of cases in rural Quebec. PMID- 25527188 TI - Axogenesis in the antennal nervous system of the grasshopper Schistocerca gregaria revisited: the base pioneers. AB - The antennal nervous system of the grasshopper Schistocerca gregaria comprises two parallel pathways projecting to the brain, each pioneered early in embryogenesis by a pair of sibling cells located at the antennal tip. En route, the growth cones of pioneers from one pathway have been shown to contact a guidepost-like cell called the base pioneer. Its role in axon guidance remains unclear as do the cellular guidance cues regulating axogenesis in the other pathway supposedly without a base pioneer. Further, while the tip pioneers are known to delaminate from the antennal epithelium into the lumen, the origin of this base pioneer is unknown. Here, we use immunolabeling and immunoblocking methods to clarify these issues. Co-labeling against the neuron-specific marker horseradish peroxidase and the pioneer-specific cell surface glycoprotein Lazarillo identifies not only the tip pioneers but also a base pioneer associated with each of the developing antennal pathways. Both base pioneers co-express the mesodermal label Mes3, consistent with a lumenal origin, whereas the tip pioneers proved Mes3-negative confirming their affiliation with the ectodermal epithelium. Lazarillo antigen expression in the antennal pioneers followed a different temporal dynamic: continuous in the tip pioneers, but in the base pioneers, only at the time their filopodia and those of the tip pioneers first recognize one another. Immunoblocking of Lazarillo expression in cultured embryos disrupts this recognition resulting in misguided axogenesis in both antennal pathways. PMID- 25527190 TI - Corynebacterium pseudotuberculosis cp09 mutant and cp40 recombinant protein partially protect mice against caseous lymphadenitis. AB - BACKGROUND: Caseous lymphadenitis (CLA) is an infectious disease that affects small ruminants and is caused by Corynebacterium pseudotuberculosis. This disease is responsible for high economic losses due to condemnation and trim of infected carcasses, decreased leather and wool yield, loss of sales of breeding stock and deaths from internal involvement. Treatment is costly and ineffective; the most cost-effective strategy is timely immunisation. Various vaccine strategies have been tested, and recombinant vaccines are a promising alternative. Thus, in this study, different vaccine formulations using a recombinant protein (rCP40) and the CP09 live recombinant strain were evaluated. Five groups of 10 mice each were immunised with saline (G1), rCP40 (G2), CP09 (G3), a combination of CP09 and rCP40 (G4) and a heterologous prime-boost strategy (G5). Mice received two immunisations within 15 days. On day 30 after primary immunisation, all groups were challenged with a C. pseudotuberculosis virulent strain. Mice were monitored and mortality was recorded for 30 days after challenge. RESULTS: The G2, G4 and G5 groups showed high levels of IgG1 and IgG2a; G2 presented significant IgG2a production after virulent challenge in the absence of IgG1 and IgG3 induction. Thirty days after challenge, the mice survival rates were 20 (G1), 90 (G2), 50 (G3), 70 (G4) and 60% (G5). CONCLUSIONS: rCP40 is a promising target in the development of vaccines against caseous lymphadenitis. PMID- 25527191 TI - Decerebrate posturing following traumatic brain injury: MRI findings and their diagnostic value. AB - AIM: To determine the pathomorphological and clinical background to decerebrate posturing in humans following serious traumatic brain injury. MATERIALS AND METHODS: One hundred and twenty patients who had been unconscious for more than 24 h underwent diagnostic MRI within 8 days after trauma. The presence of decerebrate rigidity as the clinical parameter was correlated to MRI findings, such as traumatic lesions in defined brain areas. Significance was presumed as p < 0.05. RESULTS: On the day of MRI 43 (36%) patients exhibited decerebrate posturing: 19 (23%) cases were unilateral and 24 (77%) bilateral. There was a significant correlation between midbrain lesions and the presence of rigidity. If a midbrain lesion was found in the absence of pontine lesions, decerebrate rigidity could be concluded (p < 0.05). There was no significant correlation to the rigidity in the case of midbrain lesions accompanied by pontine lesions, and no correlation to the rigidity could be detected for other regions of the brain. Both the occurrence of decerebrate posturing and the detection of brainstem lesions at MRI correlated with the Glasgow Outcome Scale. The combination of both parameters improved the probability of predicting the outcome. CONCLUSION: The rate of decerebrate posturing increases significantly in the presence of midbrain lesions. The presence of pontine lesions appears to be of secondary importance. The chances of predicting the Glasgow Outcome Scale are improved by the combination of clinical information (decerebrate posturing) and radiological parameters (type of brainstem lesion). PMID- 25527192 TI - Correlation between penile cuff test and pressure-flow study in patients candidates for trans-urethral resection of prostate. AB - BACKGROUND: Aim of this study was to make a comparison between penile cuff test (PCT) and standard pressure-flow study (PFS) in the preoperative evaluation of patients candidates for trans-urethral resection of prostate (TURP) for benign prostatic obstruction (BPO). METHODS: We enrolled male patients with lower urinary tract symptoms candidates for TURP. Each of them underwent a PCT and a subsequent PFS. A statistical analysis was performed: sensitivity (SE), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), likelihood ratio and ratio of corrected classified were calculated. Fisher exact test was used to evaluate relationships between PCT and maximal urine flow (Qmax): a p-value < 0.05 was considered statistically significant. RESULTS: We enrolled 48 consecutive patients. Overall, at PCT 31 patients were diagnosed as obstructed and 17 patients as unobstructed. At the subsequent PFS, 21 out of 31 patients diagnosed as obstructed at PCT were confirmed to be obstructed; one was diagnosed as unobstructed; the remaining 9 patients appeared as equivocal. Concerning the 17 patients unobstructed at PCT, all of them were confirmed not to be obstructed at PFS, with 10 equivocal and 7 unobstructed. The rate of correctly classified patients at PCT was 79% (95%-CI 65%-90%). About detecting obstructed patients, PCT showed a SE of 100% and a SP of 63%. The PPV was 68%, while the NPV was 100%. CONCLUSIONS: PCT can be an efficient tool in evaluating patients candidates for TURP. In particular, it showed good reliability in ruling out BPO because of its high NPV, with a high rate of correctly classified patients overall. Further studies on a huger number of patients are needed, including post operative follow-up as well. PMID- 25527189 TI - Humanization of the mouse mammary gland by replacement of the luminal layer with genetically engineered preneoplastic human cells. AB - INTRODUCTION: The cell of origin for estrogen receptor alpha-positive (ERalpha+) breast cancer is probably a luminal stem cell in the terminal duct lobular units. To model these cells, we have used the murine myoepithelial layer in the mouse mammary ducts as a scaffold upon which to build a human luminal layer. To prevent squamous metaplasia, a common artifact in genetically-engineered breast cancer models, we sought to limit activation of the epidermal growth factor receptor (EGFR) during in vitro cell culture before grafting the cells. METHODS: Human reduction mammoplasty cells were grown in vitro in WIT medium. Epidermal growth factor in the medium was replaced with amphiregulin and neuregulin to decrease activation of EGFR and increase activation of EGFR homologs 3 and 4 (ERBB3 and ERBB4). Lentiviral vectors were used to express oncogenic transgenes and fluorescent proteins. Human mammary epithelial cells were mixed with irradiated mouse fibroblasts and Matrigel, then injected through the nipple into the mammary ducts of immunodeficient mice. Engrafted cells were visualized by stereomicroscopy for fluorescent proteins and characterized by histology and immunohistochemistry. RESULTS: Growth of normal mammary epithelial cells in conditions favoring ERBB3/4 signaling prevented squamous metaplasia in vitro. Normal human cells were quickly lost after intraductal injection, but cells infected with lentiviruses expressing CCND1, MYC, TERT, BMI1 and a short-hairpin RNA targeting TP53 were able to engraft and progressively replace the luminal layer in the mouse mammary ducts, resulting in the formation of an extensive network of humanized ducts. Despite expressing multiple oncogenes, the human cells formed a morphologically normal luminal layer. Expression of a single additional oncogene, PIK3CA-H1047R, converted the cells into invasive cancer cells. The resulting tumors were ERalpha+, Ki67+ luminal B adenocarcinomas that were resistant to treatment with fulvestrant. CONCLUSIONS: Injection of preneoplastic human mammary epithelial cells into the mammary ducts of immunodeficient mice leads to replacement of the murine luminal layer with morphologically normal human cells. Genetic manipulation of the injected cells makes it possible to study defined steps in the transformation of human mammary epithelial cells in a more physiological environment than has hitherto been possible. PMID- 25527193 TI - Increase in the rate of azithromycin-resistant Streptococcus pneumoniae isolates carrying the erm(B) and mef(A) genes in Taiwan, 2006-2010. AB - BACKGROUND: This study investigated the molecular characteristics of azithromycin resistant Streptococcus pneumoniae in Taiwan. METHODS: A total of 486 non duplicate isolates of azithromycin-resistant S. pneumoniae recovered from various clinical sources of patients treated at 22 different hospitals in Taiwan from 2006 to 2010. The presence of erm(B) and mef(A) genes using duplex PCR, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis of these isolates were studied. RESULTS: Of the isolates tested, 59% carried the erm(B) gene, 22% carried the mef(A) gene, and 19% carried both genes. The prevalence of isolates carrying the erm(B) and mef(A) genes increased from 10% (11/110) in 2006 to 25% (15/60) in 2010 (p-value = 0.0136). The majority of isolates carrying both erm(B) and mef(A) genes belonged to serotypes 19 F (64%) followed by 19 F A (24%). Of these isolates, 33% were sequence type 320 (ST320), 32% were ST236, and 12% were ST271. CONCLUSIONS: The increase in incidence of mef(A)/erm(B)-positive azithromycin-resistant S. pneumoniae isolates during the study period was primarily due to serotypes 19 F and 19A and ST236 and ST320. PMID- 25527177 TI - Cardiac purinergic signalling in health and disease. AB - This review is a historical account about purinergic signalling in the heart, for readers to see how ideas and understanding have changed as new experimental results were published. Initially, the focus is on the nervous control of the heart by ATP as a cotransmitter in sympathetic, parasympathetic, and sensory nerves, as well as in intracardiac neurons. Control of the heart by centers in the brain and vagal cardiovascular reflexes involving purines are also discussed. The actions of adenine nucleotides and nucleosides on cardiomyocytes, atrioventricular and sinoatrial nodes, cardiac fibroblasts, and coronary blood vessels are described. Cardiac release and degradation of ATP are also described. Finally, the involvement of purinergic signalling and its therapeutic potential in cardiac pathophysiology is reviewed, including acute and chronic heart failure, ischemia, infarction, arrhythmias, cardiomyopathy, syncope, hypertrophy, coronary artery disease, angina, diabetic cardiomyopathy, as well as heart transplantation and coronary bypass grafts. PMID- 25527194 TI - Endoscopic minimal invasive cholecystolithotomy vs laparoscopic cholecystectomy in treatment of cholecystolithiasis in China: a meta-analysis. AB - INTRODUCTION: Endoscopic minimal invasive cholecystolithotomy (EMIC) is recently popular in China which may offer advantages over laparoscopic cholecystectomy (LC). We try to find out the most favorable treatment for the patients underwent cholecystolithiasis. METHODS: Databases PubMed, Elsevier, Wiley Online Library, The Cochrane library, CNKI, WanFang Data, and Chongqing VIP were searched for randomized controlled trials (RCTs) and on EMIC vs LC from 2009 to 2013. Odds ratio (OR), risk difference (RD) and weight mean difference (WMD) were calculated with 95% confidence intervals (CI). RESULTS: 14 RCTs including 2030 patients were selected. No significant difference was present in operating time between EMIC and LC. EMIC shown significant less blood lost (WMD -23.45; 95% CI -30.34, 16.55; Z=6.66; P<0.00001) compared to LC. Shortened exhaust time (WMD -14.11; 95% CI -18.34, -9.88; Z=6.53; P<0.00001) and hospital stay (WMD -1.31; 95% CI -1.91, 0.71; Z=4.29; P<0.00001) were present in EMIC group. And EMIC shown decreased complication proportion (OR -0.14, 95% CI -0.09 to -0.21; Z=8.53; P<0.00001) in comparison with LC. There is no difference present in the recurrence of stones in two procedures but a significantly decreased recurrence rate of gallstones was present in EMIC compared to conventional cholecystolithotomy. CONCLUSION: Patients treated with EMIC shown faster recovery and less complication which were superior to LC. PMID- 25527195 TI - Capture of algae promotes growth and propagation in aquatic Utricularia. AB - BACKGROUND AND AIMS: Some carnivorous plants trap not only small animals but also algae and pollen grains. However, it remains unclear if these trapped particles are useless bycatch or whether they provide nutrients for the plant. The present study examines this question in Utricularia, which forms the largest and most widely spread genus of carnivorous plants, and which captures prey by means of sophisticated suction traps. METHODS: Utricularia plants of three different species (U. australis, U. vulgaris and U. minor) were collected in eight different water bodies including peat bogs, lakes and artificial ponds in three regions of Austria. The prey spectrum of each population was analysed qualitatively and quantitatively, and correlated with data on growth and propagation, C/N ratio and delta(15)N. KEY RESULTS: More than 50 % of the prey of the Utricularia populations investigated consisted of algae and pollen, and U. vulgaris in particular was found to capture large amounts of gymnosperm pollen. The capture of algae and pollen grains was strongly correlated with most growth parameters, including weight, length, budding and elongation of internodes. The C/N ratio, however, was less well correlated. Other prey, such as moss leaflets, fungal hyphae and mineral particles, were negatively correlated with most growth parameters. delta(15)N was positively correlated with prey capture, but in situations where algae were the main prey objects it was found that the standard formula for calculation of prey-derived N was no longer applicable. CONCLUSIONS: The mass capture of immotile particles confirms the ecological importance of autonomous firing of the traps. Although the C/N ratio was little influenced by algae, they clearly provide other nutrients, possibly including phosphorus and trace elements. By contrast, mosses, fungi and mineral particles appear to be useless bycatch. Correlations with chemical parameters indicate that Utricularia benefits from nutrient-rich waters by uptake of inorganic nutrients from the water, by the production of more traps per unit of shoot length, and by the capture of more prey particles per trap, as nutrient-rich waters harbour more prey organisms. PMID- 25527196 TI - Cost analysis of sentinel lymph node biopsy in melanoma. AB - INTRODUCTION AND OBJECTIVE: Sentinel lymph node biopsy (SLNB) is the most useful tool for node staging in melanoma. SLNB facilitates selective dissection of lymph nodes, that is, the performance of lymphadenectomy only in patients with sentinel nodes positive for metastasis. Our aim was to assess the cost of SLNB, given that this procedure has become the standard of care for patients with melanoma and must be performed whenever patients are to be enrolled in clinical trials. Furthermore, the literature on the economic impact of SLNB in Spain is scarce. METHOD: From 2007 to 2010, we prospectively collected data for 100 patients undergoing SLNB followed by transhilar bivalving and multiple-level sectioning of the node for histology. Our estimation of the cost of the technique was based on official pricing and fee schedules for the Spanish region of Murcia. RESULTS: The rate of node-positive cases in our series was 20%, and the mean number of nodes biopsied was 1.96; 44% of the patients in the series had thin melanomas. The total cost was estimated at between ?9486.57 and ?10471.29. Histopathology accounted for a considerable portion of the cost (?5769.36). DISCUSSION: The cost of SLNB is high, consistent with amounts described for a US setting. Optimal use of SLNB will come with the increasingly appropriate selection of patients who should undergo the procedure and the standardization of a protocol for histopathologic evaluation that is both sensitive and easy to perform. PMID- 25527198 TI - Among-character rate variation distributions in phylogenetic analysis of discrete morphological characters. AB - Likelihood-based methods are commonplace in phylogenetic systematics. Although much effort has been directed toward likelihood-based models for molecular data, comparatively less work has addressed models for discrete morphological character (DMC) data. Among-character rate variation (ACRV) may confound phylogenetic analysis, but there have been few analyses of the magnitude and distribution of rate heterogeneity among DMCs. Using 76 data sets covering a range of plants, invertebrate, and vertebrate animals, we used a modified version of MrBayes to test equal, gamma-distributed and lognormally distributed models of ACRV, integrating across phylogenetic uncertainty using Bayesian model selection. We found that in approximately 80% of data sets, unequal-rates models outperformed equal-rates models, especially among larger data sets. Moreover, although most data sets were equivocal, more data sets favored the lognormal rate distribution relative to the gamma rate distribution, lending some support for more complex character correlations than in molecular data. Parsimony estimation of the underlying rate distributions in several data sets suggests that the lognormal distribution is preferred when there are many slowly evolving characters and fewer quickly evolving characters. The commonly adopted four rate category discrete approximation used for molecular data was found to be sufficient to approximate a gamma rate distribution with discrete characters. However, among the two data sets tested that favored a lognormal rate distribution, the continuous distribution was better approximated with at least eight discrete rate categories. Although the effect of rate model on the estimation of topology was difficult to assess across all data sets, it appeared relatively minor between the unequal-rates models for the one data set examined carefully. As in molecular analyses, we argue that researchers should test and adopt the most appropriate model of rate variation for the data set in question. As discrete characters are increasingly used in more sophisticated likelihood-based phylogenetic analyses, it is important that these studies be built on the most appropriate and carefully selected underlying models of evolution. PMID- 25527199 TI - Five types of home-visit nursing agencies in Japan based on characteristics of service delivery: cluster analysis of three nationwide surveys. AB - BACKGROUND: The number of home-visit nursing agencies in Japan has greatly increased over the past 20 years since the Japanese government first introduced it in 1992 to meet the increased needs of home-bound elderly. Since then, home visit nursing has come to serve for a variety of populations such as those with terminal-stage cancer, neurological diseases, psychiatric conditions, or children with chronic conditions; currently the number of agencies has reached 6,801 (as of April 2013). Yet little has been known about the details of their characteristics in terms of patient types or differences/similarities across regions. In this study, we developed a method to categorize home-visit nursing agencies throughout Japan based on their actual service delivery, in order to help improve healthcare policies allowing better services by those agencies. METHODS: We performed a cluster analysis on data from two national databases (Survey of Institutions and Establishments for Long-term Care which is annually administered by the Ministry of Health, Labour and Welfare [dataset 1; n = 5,161] and Information Publication System for Long-term Care which is annually reported by home-visit nursing agencies to their respective prefectural governments [dataset 2; n = 4,400, matching rate to data set 1: 84.4%]), in addition to the results from our original nationwide Fax survey of the service delivery system of home-visit nursing agencies (dataset 3; n = 2,049 matching rate to data set 1: 39.3%). RESULTS: The cluster analysis suggested five categories for home-visit nursing agencies based on the type of service delivery system. For deciding of these categories, we held 13 panel discussions with specialists to confirm that the categorization of the home-visit nursing agencies appropriately reflected their actual delivery systems. The five categories were: nurse-centered (560, 10.9%), rehabilitation-centered (211, 4.1%), psychiatric-centered (360, 7.0%), urban-centered (1,784, 34.5%), and rural-centered (2246, 43.5%). CONCLUSIONS: This five categorization system of home-visit nursing agencies could ensure appropriate healthcare policies that will allow agencies to provide better home visit nursing services based on their patient and staff characteristics and regional needs. The findings would be valuable both in Japan as well as in other countries with rapidly growing aging populations. PMID- 25527197 TI - TRKing down an old oncogene in a new era of targeted therapy. AB - The use of high-throughput next-generation sequencing techniques in multiple tumor types during the last few years has identified NTRK1, 2, and 3 gene rearrangements encoding novel oncogenic fusions in 19 different tumor types to date. These recent developments have led us to revisit an old oncogene, Trk (originally identified as OncD), which encodes the TPM3-NTRK1 gene fusion and was one of the first transforming chromosomal rearrangements identified 32 years ago. However, no drug has yet been approved by the FDA for cancers harboring this oncogene. This review will discuss the biology of the TRK family of receptors, their role in human cancer, the types of oncogenic alterations, and drugs that are currently in development for this family of oncogene targets. SIGNIFICANCE: Precision oncology approaches have accelerated recently due to advancements in our ability to detect oncogenic mutations in tumor samples. Oncogenic alterations, most commonly gene fusions, have now been detected for the genes encoding the TRKA, TRKB, and TRKC receptor tyrosine kinases across multiple tumor types. The scientific rationale for the targeting of the TRK oncogene family will be discussed here. PMID- 25527200 TI - Pharyngeal pressure differences between four types of swallowing in healthy participants. AB - PURPOSE: The aim of this observational study was to identify biomechanical differences, as measured by pharyngeal manometric pressure patterns, between discrete and continuous water swallowing, as well as volitionally initiated and reflexive swallowing. METHODS: Using pharyngeal manometry, swallowing-related pressures from 24 young healthy individuals were recorded at three locations: upper pharynx, mid-pharynx and upper oesophageal sphincter (UES) during four swallowing conditions: discrete saliva swallowing, discrete 10ml water swallowing, volitional continuous water swallowing, and reflexive continuous water swallowing. Measures of peak pressure and pressure duration at each level were compared across conditions using repeated-measures analysis of variance. RESULTS: UES nadir pressure during saliva swallowing was lower than during water swallowing conditions (p<0.05). In addition, nadir pressure during discrete 10ml water swallowing was lower than during reflexive and volitional continuous water swallowing conditions (p<0.05). Saliva swallowing produced longer pressure duration than water swallowing conditions at the upper pharynx (p<0.05). Saliva swallowing produced pressure of greater duration than reflexive continuous water swallowing at mid-pharynx (p<0.05). Further, discrete 10ml water swallowing produced longer UES opening duration and longer pharyngeal pressure generation (p<0.05) than reflexive continuous water swallowing or saliva swallowing. CONCLUSION: Pressure generation differs between swallowing types and bolus types at the level of the UES in particular. These physiological differences between swallowing and bolus types may support clinical decisions for individuals with impaired swallowing. PMID- 25527202 TI - Unintentional Exposure to Online Sexual Content and Sexual Behavior Intentions Among College Students in China. AB - This study examined the relations of unintentional exposure to Internet sexual content to intentions for sex and condom use and potential mediators of these relations, including attitudes, norms, and self-efficacy, among college students in China. A sample of 524 Chinese college students completed an online questionnaire. Mediation path analyses were conducted to test the theory of planned behavior as a model of the relations between unintentional exposure and intentions to have sex and use condoms. On average, students reported being unintentionally exposed to Internet sexual content about 3 to 4 times during the past month. Unintentional exposure was indirectly associated with intention to have sex, mediated through descriptive and injunctive norms. Descriptive norm was a stronger mediator for females than males. In contrast, unintentional exposure was unrelated to condom-use intention and mediators. The theory of planned behavior provides a model for the development of Internet-based interventions with these students. PMID- 25527201 TI - Relapsing polychondritis: clinical presentations, disease activity and outcomes. AB - BACKGROUND: Relapsing polychondritis is a rare disease characterised by inflammation of cartilaginous and proteoglycan rich structures. As there are only a few published single centre case series from all across the world, we describe our experience with 26 patients at a tertiary centre in north India. METHODS: A retrospective study with all patients meeting Damiani and Levine's modification of McAdam's diagnostic criteria. Clinical details, investigations, disease activity assessment [(Relapsing Polychondritis Disease Activity Index (RPDAI)], treatment and outcomes were recorded. RESULTS: Ten men and sixteen women (median age 45 years) met the diagnostic criteria. Auricular chondritis (96%), arthritis (54%), hearing impairment (42%), ocular (42%), dermal (26%), cardiovascular (11%) and laryngotracheal involvement (11%) characterized the clinical presentations. The median RPDAI was 31 (range 9-66). Two patients died during observation. Overall survival was 92.3% (median survival 13.5 years). CONCLUSIONS: Apart from reduced laryngotracheal involvement, RP in India was clinically similar to recorded patterns elsewhere. PMID- 25527204 TI - A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors. AB - PURPOSE: Inhibition of tumor angiogenesis is an effective mechanism to limit tumor growth; dual inhibition may result in additional benefit. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), and intetumumab is a fully humanized monoclonal antibody that blocks alphav integrins when complexed with beta integrins. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus intetumumab in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. METHODS: Patients with refractory solid tumors, Karnofsky performance status >=70%, and adequate organ function were eligible. Plasma samples and wound biopsies were obtained at baseline and on-treatment. RESULTS: Twelve patients were enrolled and received study drug. No tumor responses were noted. Observed toxicities included three cases of transient uveitis likely related to intetumumab and one case of reversible posterior leukoencephalopathy syndrome likely related to bevacizumab. Biomarker analysis revealed changes in soluble endoglin, soluble E-cadherin, and soluble E-selectin as well as PlGF and VEGF-D while on treatment. There was no observed impact of bevacizumab plus intetumumab on the phosphorylated or total levels of paxillin in wound tissue; however, an increase in the ratio of phospho/total paxillin levels was noted. CONCLUSIONS: Bevacizumab and intetumumab can be administered safely in combination. Bevacizumab plus intetumumab treatment resulted in changes in the plasma levels of several extracellular matrix interacting proteins and angiogenic factors. PMID- 25527205 TI - Oxymatrine targets EGFR(p-Tyr845) and inhibits EGFR-related signaling pathways to suppress the proliferation and invasion of gastric cancer cells. AB - PURPOSE: Oxymatrine (matrine oxide, matrine N-oxide, matrine 1-oxide) is one of the quinolizidine alkaloid compounds extracted from the root of Sophora flavescens (a traditional Chinese herb). Oxymatrine has been known for its chemoresistance and cytotoxic effects on various cancer cells, but the mechanism underlying has not been explored. We study the mechanism of oxymatrine on gastric cells. METHODS: We observed the changes of proliferation, apoptosis and invasion in human gastric cells by detecting the signaling pathway in which oxymatrine plays role. RESULTS: These results showed that oxymatrine inhibited the proliferation and invasion of gastric cells through inhibition of EGFR/Cyclin D1/CDK4/6, EGFR/Akt and MEK-1/ERK1/2/MMP2 pathway by inhibiting EGFR(p-Tyr845). In addition to inducing gastric cells apoptosis, oxymatrine significantly inhibited the migration and invasion of human gastric cancer cells by decreasing phospho-Cofilin (Ser3) and phospho-LIMK1 (Thr508) without changing the total Cofilin and LIMK1 expression. CONCLUSION: Oxymatrine effectively suppressed the phosphorylation of EGFR (Tyr845), and EGFR was the target of oxymatrine. PMID- 25527206 TI - Findings from positron emission tomography and genetic analyses for cerebellar liponeurocytoma. AB - Cerebellar liponeurocytoma is a rare tumor that usually develops in adult patients, and is categorized as World Health Organization grade II. Because of the small number of reports on its radiological and pathological features, the disease remains poorly characterized. The current case involved a 59-year-old man with tumor in the upper cerebellar vermis. Preoperative positron emission tomography (PET) showed high uptake on (11)C-methionine PET, but low uptake on (18)F-fluorodeoxyglucose PET. These findings resemble those of central neurocytoma and oligodendroglioma, but are incompatible with other brain tumors. Subtotal tumor removal was performed by suboccipital craniotomy. Histopathological examinations showed sheets of small, isomorphic cells with round nuclei and clear cytoplasm, and focal vacuolated cells resembling adipose cells. On immunohistochemistry, tumor cells were positive for synaptophysin and NeuN. Vacuolated cells were immunoreactive for perilipin. Based on these findings, cerebellar liponeurocytoma was diagnosed. Genetic analyses revealed absences of both chromosome 1p/19q loss and isocitrate dehydrogenase 1 mutation, further ruling out oligodendroglioma. These radiological and genetic aspects of cerebellar liponeurocytoma, which are mostly in common with central neurocytoma, should prove helpful in differentiating this rare tumor from other tumors with similar morphology. PMID- 25527207 TI - Epigenetic alterations of the keratin 13 gene in oral squamous cell carcinoma. AB - BACKGROUND: Epigenetic modifications play important roles in the regulation of gene expression determining cellular phenotype as well as various pathologies such as cancer. Although the loss of keratin 13 (KRT13) is reportedly linked to malignant transformation of oral epithelial cells, the molecular mechanisms through which KRT13 is repressed in oral squamous cell carcinoma (OSCC) remain unclear. The aim of this study is to identify the epigenetic alterations of the KRT13 gene in OSCCs. METHODS: We investigated KRT13 expression levels and chromatin modifications of the KRT13 promoter in the three OSCC cell lines (HSC4, HSC3, and SAS). The expression levels of KRT13 protein and mRNA were analyzed by western blotting and quantitative reverse-transcription polymerase chain reaction, respectively, and the localization of KRT13 protein was detected by immunofluorescence. DNA methylation and histone modifications in the KRT13 promoter were determined by bisulfite sequencing and chromatin immunoprecipitation (ChIP), respectively. For the pharmacological depletion of Polycomb repressive complex 2 (PRC2), cells were treated with 3-deazaneplanocin A (DZNep). RESULTS: KRT13 expression was transcriptionally silenced in the HSC3 and SAS cells and post-transcriptionally repressed in the HSC4 cells, while the KRT13 promoter was hypermethylated in all of the three OSCC cell lines. ChIP analysis revealed that PRC2-mediated trimethylation of Lys 27 on histone H3 (H3K27me3) was increased in the KRT13 promoter in the HSC3 and SAS cells. Finally, we demonstrated that the treatment of SAS cells with DZNep reactivated the transcription of KRT13 gene. CONCLUSIONS: Our data provide mechanistic insights into the epigenetic silencing of KRT13 genes in OSCC cells and might be useful for the development of diagnostic markers and novel therapeutic approaches against OSCCs. PMID- 25527208 TI - Trends in the dispensation of antidepressant drugs over the past decade (2000 2010) in Andalusia, Spain. AB - PURPOSE: To study antidepressant drug dispensation in the Spanish region of Andalusia and in the Almeria Health Area (AHA) over the past decade, analyzing the variability, trends, and influential factors. METHODS: We conducted an observational ecological study of antidepressant drug dispensation between 2000 and 2010 in Andalusia. Dispensation was measured as Defined Daily Dose (DDD) per 1,000 inhabitants per day. A multilevel analysis (STATA 11.1) was performed to determine the variability among the basic health zones (BHZs) (2004-2010) and influential factors. RESULTS: Between 2000 and 2010, the total dispensation of antidepressant drugs increased by more than 100 % in Andalusia and in the AHA. This increase was primarily caused by the greater dispensation of selective serotonin reuptake inhibitors (ATC-N06AB) and other antidepressants (ATC-N06AX). Multilevel analysis revealed a wide variability in the levels and trends of antidepressant dispensation among BHZs. Urbanicity and the percentage of immigrants in the BHZ were negatively associated with their dispensation, which was positively influenced by a higher proportion of women and over 65-year-olds in the population. CONCLUSIONS: The elevated dispensation of several groups of antidepressant drugs in this study population indicates the need for health policies to rationalize their use. Further research is required into the differences in antidepressant dispensations between immigrant and native populations and the implications for public health policies. PMID- 25527209 TI - Is burnout separable from depression in cluster analysis? A longitudinal study. AB - PURPOSE: Whether burnout and depression represent distinct pathologies is unclear. The aim of this study was to examine whether burnout and depressive symptoms manifest themselves separately from each other or are so closely intertwined as to reflect the same phenomenon. METHODS: A two-wave longitudinal study involving 627 French schoolteachers (73 % female) was conducted. Burnout was assessed with the Maslach Burnout Inventory and depression with the 9-item depression module of the Patient Health Questionnaire. RESULTS: Burnout and depressive symptoms clustered both at baseline and follow-up. Cluster membership at time 1 (T1) predicted cases of burnout and depression at time 2 (T2), controlling for gender, age, length of employment, lifetime history of depression, and antidepressant intake. Changes in burnout and depressive symptoms from T1 to T2 were found to overlap. Teachers with increasing burnout experienced increases in depression and teachers with decreasing burnout experienced decreases in depression. In addition, emotional exhaustion, the core of burnout, was more strongly associated with depression than with depersonalization, the second dimension of burnout, underlining an inconsistency in the conceptualization of the burnout syndrome. CONCLUSIONS: Our results are consistent with recent findings showing qualitative and quantitative symptom overlap of burnout with depression. The close interconnection of burnout and depression questions the relevance of a nosological distinction between the two entities. Emotional exhaustion and depersonalization, the two main dimensions of burnout, may be better conceptualized as depressive responses to adverse occupational environments than as components of a separate entity. PMID- 25527210 TI - Shifting from policy relevance to policy translation: do housing and neighborhoods affect children's mental health? AB - The impact of housing and neighborhood context on children's mental health, as addressed by Flouri et al. (Soc Psychiatry Psychiatr Epidemiol, 2014), is an important, understudied topic in social epidemiology. Although the vast majority of this body of research has been descriptive, generating translational research is essential. This article offers guidance on interpreting evidence from observational studies for translation into policy, related to three policy relevant elements of housing: receipt of affordable housing subsidies, the target population to which results generalize, and operationalization and modeling of neighborhood context. Policy translation is imperative for understanding which levers outside the health sector can be manipulated to change fundamental causes of mental health related to housing and neighborhood. Shifting from policy relevance to policy translation may be challenging, especially for understanding social causation in observational studies, but it is a necessary shift for improving population health. PMID- 25527212 TI - Hyperspectral imaging in quality control of inkjet printed personalised dosage forms. AB - The aim of the study was to investigate applicability of near infra-red (NIR) hyperspectral imaging technique in quality control of printed personalised dosage forms. Inkjet printing technology was utilized to fabricate escalating doses of an active pharmaceutical ingredient (API). A solution containing anhydrous theophylline as the model drug was developed as a printable formulation. Single units solid dosage forms (SDFs) were prepared by jetting the solution onto 1 cm * 1 cm areas on carrier substrate with multiple printing passes. It was found that the number of printing passes was in excellent correlation (R(2)=0.9994) with the amount of the dispensed drug (MUg cm(-2)) based on the UV calibration plot. The API dose escalation was approximately 7.5 MUg cm(-2) for each printing pass concluding that inkjet printing technology can optimally provide solutions to accurate deposition of active substances with a potential for personalized dosing. Principal component analysis (PCA) was carried out in order to visualize the trends in the hyperspectral data. Subsequently, a quantitative partial least squares (PLS) regression model was created. NIR hyperspectral imaging proved (R(2)=0.9767) to be a reliable, rapid and non-destructive method to optimize quality control of these planar printed dosage forms. PMID- 25527211 TI - Zinc oxide as a new antimicrobial preservative of topical products: interactions with common formulation ingredients. AB - Zinc oxide (ZnO) appears as a promising preservative for pharmaceutical or cosmetic formulations. The other ingredients of the formulations may have specific interactions with ZnO that alter its antimicrobial properties. The influence of common formulation excipients on the antimicrobial efficacy of ZnO has been investigated in simple model systems and in typical topical products containing a complex formulation. A wide variety of formulation excipients have been investigated for their interactions with ZnO: antioxidants, chelating agents, electrolytes, titanium dioxide pigment. The antimicrobial activity of ZnO against Escherichia coli was partially inhibited by NaCl and MgSO4 salts. A synergistic influence of uncoated titanium dioxide has been observed. The interference effects of antioxidants and chelating agents were quite specific. The interactions of these substances with ZnO particles and with the soluble species released by ZnO were discussed so as to reach scientific guidelines for the choice of the ingredients. The preservative efficacy of ZnO was assessed by challenge testing in three different formulations: an oil-in-water emulsion; a water-in-oil emulsion and a dry powder. The addition of ZnO in complex formulations significantly improved the microbiological quality of the products, in spite of the presence of other ingredients that modulate the antimicrobial activity. PMID- 25527213 TI - Is there an association between the coverage of immunisation boosters by the age of 5 and deprivation? An ecological study. AB - OBJECTIVE: To determine whether there was an association between the coverage of booster immunisation of Diphtheria, Tetanus, acellular Pertussis and Polio (DTaP/IPV) and second Measles, Mumps and Rubella (MMR) dose by age 5 in accordance with the English national immunisation schedule by area-level socioeconomic deprivation and whether this changed between 2007/08 and 2010/11. DESIGN: Ecological study. DATA: Routinely collected national Cover of Vaccination Evaluated Rapidly data on immunisation coverage for DTaP/IPV booster and second MMR dose by age 5 and the Index of Multiple Deprivation (IMD). SETTING: Primary Care Trust (PCT) areas in England between 2007/08 and 2010/11. OUTCOME MEASURES: Population coverage (%) of DTaP/IPV booster and second MMR immunisation by age 5. RESULTS: Over the 4 years among the 9,457,600 children there was an increase in the mean proportion of children being immunised for DTaP/IPV booster and second MMR across England, increasing from 79% (standard deviation (SD12%)) to 86% (SD8%) for DTaP/IPV and 75% (SD10%) to 84% (SD6%) for second MMR between 2007/08 and 2010/11. In 2007/08 the area with lowest DTaP/IPV booster coverage was 31% compared to 54.4% in 2010/11 and for the second MMR in 2007/08 was 39% compared to 64.8% in 2010/11. A weak negative correlation was observed between average IMD score and immunisation coverage for the DTaP/IPV booster which reduced but remained statistically significant over the study period (r=-0.298, p<0.001 in 2007/08 and r=-0.179, p=0.028 in 2010/11). This was similar for the second MMR in 2007/08 (r=-0.225, p=0.008) and 2008/09 (r=-0.216, p=0.008) but there was no statistically significant correlation in 2009/10 (r=-0.108, p=0.186) or 2010/11 (r=-0.078, p=0.343). CONCLUSION: Lower immunisation coverage of DTaP/IPV booster and second MMR dose was associated with higher area-level socioeconomic deprivation, although this inequality reduced between 2007/08 and 2010/11 as proportions of children being immunised increased at PCT level, particularly for the most deprived areas. However, coverage is still below the World Health Organisation recommended 95% threshold for Europe. PMID- 25527214 TI - Effect of different chemical bonds in pegylation of zinc protoporphyrin that affects drug release, intracellular uptake, and therapeutic effect in the tumor. AB - Pegylated zinc protoporphyrin (PEG-ZnPP) is a water-soluble inhibitor of heme oxygenase-1. In this study, we prepared two types of PEG-ZnPP conjugates with different chemical bonds between PEG and ZnPP, i.e., ester bonds and ether bonds, where both conjugates also contain amide bonds. Cleavability of these bonds in vitro and in vivo, especially cancer tissue, and upon intracellular uptake, was investigated in parallel with biological activities of the conjugates. Each conjugate showed different cleavability by plasma esterases and tumor proteases, as revealed by HPLC analyses. PEG-ZnPP with ester bond (esPEG-ZnPP) was more sensitive than PEG-ZnPP with ether bond (etPEG-ZnPP) for cleavage of PEG chains. etPEG-ZnPP showed no cleavage of PEG chains and had lower intracellular uptake and antitumor activity than did esPEG-ZnPP. The degradation of esPEG-ZnPP appeared to be facilitated by both serine and cysteine proteases in tumor tissues, whereas it was significantly slower in normal organs except the liver. Depegylated products such as free ZnPP had higher intracellular uptake than did intact PEG-ZnPP. We also studied hydrolytic cleavage by blood plasma of different animal species; mouse plasma showed the fastest cleavage whereas human plasma showed the slowest. These results suggest that ester-linked conjugates manifest more efficient cleavage of PEG, and greater yield of the active principle from the conjugates in tumor tissues than in normal tissues. More efficient intracellular uptake and thus an improved therapeutic effect with ester-linked conjugates are thus anticipated with fain stability, particularly in human blood. PMID- 25527215 TI - Imaging atlas for eligibility and on-study safety of potential joint adverse events in anti-NGF studies. PMID- 25527216 TI - Serious joint-related adverse events in randomized controlled trials of anti nerve growth factor monoclonal antibodies. AB - BACKGROUND: Reports of serious joint adverse events (AEs) due to osteonecrosis were noted during randomized placebo-controlled clinical trials of monoclonal antibodies to nerve growth factor (NGF), including tanezumab and fulranumab. METHODS: All available medical records from subjects with reported cases of osteonecrosis, as well as records of subjects who underwent joint replacement during these studies, were reviewed by an independent adjudication committee that was established by each company; the committees were different for each company and included distinct individual experts. Cases were categorized as having definite osteonecrosis, normal or rapid progression of osteoarthritis (OA), another diagnosis or unable to determine the underlying diagnosis. RESULTS: The vast majority of investigator reported cases of osteonecrosis were adjudicated as either normal or rapid progression of OA. Indeed, the syndrome of rapid progression of OA associated with chondrolysis and bone destruction appears to be a safety signal that is associated with not only increasing doses of anti-NGF antibodies but also concomitant therapy with nonsteroidal anti-inflammatory drugs. CONCLUSIONS: These results have implications for future clinical trials of anti-NGF agents in OA and other painful conditions. PMID- 25527217 TI - Imaging atlas for eligibility and on-study safety of potential knee adverse events in anti-NGF studies (Part 1). AB - Monoclonal antibodies that bind and inhibit nerve growth factor (NGF) have demonstrated both, good analgesic efficacy and improvement in function in patients with osteoarthritis (OA). Despite initial promising data, trials in OA had been suspended by the Federal Food and Drug Administration (FDA) due to concerns over accelerated rates of OA progression. Imaging will play a crucial role in future clinical trials to define eligibility of potential participants and to monitor safety during the course of these studies. This will require baseline and frequent follow-up radiographs of both, the index joints and other large weight bearing joints to identify subjects at risk prior inclusion and on study so treatment can be discontinued. This imaging overview in the form of an atlas describes and illustrates potential exclusionary joint imaging findings at eligibility and potential adverse joint events on radiography and magnetic resonance imaging (MRI) in studies investigating a-NGF compounds. The overarching goal of this atlas is to facilitate trial design and to promote a common language and understanding between potential expert readers. This first section of the atlas will focus on knee joint specific findings that are relevant to a-NGF studies. PMID- 25527218 TI - The current status of imaging in anti-NGF clinical trials. PMID- 25527219 TI - Imaging atlas for eligibility and on-study safety of potential hip adverse events in anti-NGF studies (Part 2). AB - Recently, nerve growth factor (NGF) inhibitors have been introduced for treatment of osteoarthritis (OA) symptoms, and have shown good analgesic efficacy and improvement in function in patients with OA. However, anti- (a-)NGF trials in OA had been suspended by the U.S. Food and Drug Administration (FDA) due to concerns over accelerated rates of OA progression and osteonecrosis. Since a-NGF therapies offer potential as the first new class of analgesics for many years, future studies assessing a-NGF compounds will have to follow stringent eligibility criteria and will require a rigorous safety monitoring. Imaging is paramount to identify potential negative outcomes as early as possible. These imaging findings include atrophic OA, osteonecrosis and others at eligibility and especially rapid progressive OA (RPOA) during the course of treatment. This second part of the a NGF imaging atlas will present specific hip joint imaging findings that are relevant for eligibility and safety and represent potential adverse joint events on radiography and magnetic resonance imaging (MRI) in studies investigating a NGF compounds. Researchers and clinicians should become familiar with several of these entities, and especially osteonecrosis of the hip and insufficiency fractures are relatively common findings in such a patient population. As several of these diagnoses may only be detected at late stages using radiographic methods, MRI plays an important role in identifying such pathologies early and at potentially still reversible stages before irreversible joint destruction has occurred. PMID- 25527220 TI - Imaging atlas for eligibility and on-study safety of potential shoulder adverse events in anti-NGF studies (Part 3). AB - Despite promising results, the U.S. Food and Drug Administration (FDA) put on hold trials assessing anti-nerve growth factor (a-NGF) compounds due to concerns over accelerated rates of OA progression. The mechanism of these events is unclear but joint adverse events were observed particularly in patients using a NGFs in combination with non-steroidal anti-inflammatory drugs (NSAIDs), suggesting that the significantly greater analgesic effect of these separate classes of drugs prompted patients to permit increased joint load without experiencing the usual pain that would limit joint stress. Development of a-NGF drugs is continuing with stringent safety criteria included in future trials as a NGF therapies offer potential as the first new class of analgesics in many years. Potential imaging joint safety findings and exclusionary criteria for eligibility for the large weight bearing joints were presented in parts I and II of this atlas. The shoulder as a non-weight bearing joint is likely to be less affected by increased loading due to efficacious pain reduction. However, it remains prone to degeneration especially due to concomitant rotator cuff pathology and previous trauma and inflammatory disorders. This third part of the atlas illustrates imaging findings relevant for eligibility and potential joint safety findings such as osteonecrosis, incidental findings such as large cystic lesions, inflammatory disorders, bone marrow disorders and metastases. PMID- 25527221 TI - A systematic review of the efficacy and general safety of antibodies to NGF in the treatment of OA of the hip or knee. AB - To evaluate the efficacy and safety of anti-NGF antibody treatment in hip and knee osteoarthritis (OA), a systematic review and meta-analysis was undertaken utilizing the criteria described by the Cochrane collaboration. Both published and unpublished trials were identified for tanezumab, fulranumab and fasinumab in hip and knee OA; sponsors were contacted to provide and confirm data. Study quality was assessed by Jadad criteria; efficacy and safety data were extracted independently by two individuals and meta-analyses were performed using Revman 5.2. 13 randomized, controlled trials were identified: 10 of tanezumab, two of fulranumab and one with fasinumab. All agents demonstrated superiority in efficacy compared to placebo. The highest doses in the phase II studies of tanezumab had a standardized effect size for WOMAC pain of 0.73 (CI, 0.51, 0.95). Subsequent phase III studies of tanezumab and phase II studies of fulranumab and fasinumab reported standardized effect sizes for WOMAC pain of -0.15-0.5, with no clear distinction among dose levels. Tanezumab compared to NSAIDs and opioids showed greater efficacy with a standardized effect size for WOMAC pain of 0.23 (CI 0.17-0.29). WOMAC function and PGA results were similar to WOMAC pain. Safety, determined by odds ratios of withdrawals from studies due to adverse events (AEs), was better at the lower doses than higher doses and similar among all agents. These results demonstrate that antibodies to NGF provide efficacy in OA and that general safety at the lower doses appears similar to placebo. Additional data on both efficacy and safety of these antibodies are needed to define the optimal dose to maximize benefit to risk. PMID- 25527222 TI - Road to better health and integration: a Delphi study on health service models for Hong Kong migrants. AB - INTRODUCTION: In Hong Kong, migrants arriving from Mainland China often have multiple roles and responsibilities while adapting to new lives in their host destination. This paper explored the factors that contribute to the inequity in health services utilisation experienced by these migrants; and, identified the elements that could constitute an effective health delivery model to address the service gap. METHODS: Site visits and a focus group discussion (n = 13) were held with both public and private health providers before a number of innovative health delivery models were formulated. They were then circulated among the panel in two further rounds of Delphi survey (n = 11) from March-April 2012 to systematically collect opinions and select the most endorsed health service models to serve this target population. RESULTS: Focus group members perceived that most migrants were unaware of, or even ignored, their own physical and mental health needs, and had low utilisation of healthcare services, because of their pre-occupation with daily chores and hardship as well as differing health values, practices and expectations. They further identified that the structural issues such as the healthcare setting or the operation of current service provisions had failed to meet migrants' health needs. Consequently, four new service models that incorporated professional advice and empowerment, which were identified as the two most important elements, were put forward. Thus, the model of having a nurse with social work training, supported by volunteer groups, was selected as the best option to familiarise and empower patients within the labyrinth of local healthcare services. CONCLUSION: Implementation of a social empowerment model by way of targeted support and specific health information is recommended. Further evaluation of this model is needed to understand its effectiveness for improving health literacy and health status in this disadvantaged group in the long term. PMID- 25527223 TI - Risk Factors for Psychiatric Hospital Admission for Participants in California's Full-Service Partnership Program. AB - This study investigated the demographic and clinical predictors of psychiatric hospitalization during the first 2 years of treatment for adults participating in the full-service partnership (FSP) program, based on Assertive Community Treatment, in a large county in northern California. Clinical and demographic characteristics, data on prior hospitalizations, length of enrollment, and living situation for 328 FSP participants were collected from the county's internal billing system and the California Department of Health Care Services. In univariate models, the probability of hospitalization varied by diagnosis, age, and hospitalization history. In the multivariate model, younger age and frequent hospitalization prior to enrollment predicted hospitalization during enrollment. Findings support prior research on hospital recidivism and may be beneficial in refining future strategies for meeting the needs of adults with serious mental illness. PMID- 25527225 TI - The California Assessment of Stigma Change: A Short Battery to Measure Improvements in the Public Stigma of Mental Illness. AB - Contact-based anti-stigma programs delivered by people with lived experience yields stigma change. This study examined psychometrics and sensitivity of the California Assessment of Stigma Change (CASC). CASC assesses prejudicial beliefs, affirming attitudes, and willingness to seek mental healthcare. Four samples, two high school groups, college students, and hotel desk clerks, completed CASC immediately before and after a contact-based program. Two samples completed follow-up: one of the high school groups and the college students. CASC assesses stigma with a 9-item Attribution Questionnaire (AQ9), personal empowerment with a 3-item scale (ES), recovery orientation with a 3-item scale (RS), and psychological help seeking willingness with a 6-item questionnaire (CSQ). Internal consistencies ranged adequate to satisfactory for AQ9, ES, and CSQ. Concurrent validity was partially supported. Change sensitivity was demonstrated among at least half of each construct's analyses. CASC seems a psychometrically valid way to efficiently monitor attitudinal and care seeking intentions changes. Outcome monitoring can strengthen contact-based anti-stigma programs, an emerging evidence-based practice. PMID- 25527224 TI - Rate and Predictors of Persistent Major Depressive Disorder in a Nationally Representative Sample. AB - This study examined predictors of persistent major depressive disorder over 10 years, focusing on the effects of clinical variables, physical health, and social support. Data from the National Survey of Midlife Development in the United States in 1995-1996 and 2004-2006 were analyzed. Logistic regression was used to predict non-recovery from major depression among individuals who met clinical based criteria for major depressive disorder at baseline. Fifteen percent of the total sample was classified as having major depression in 1995-1996; of these individuals, 37 % had major depression in 2004-2006. Baseline variables that were significantly associated with persistent major depression at follow-up were being female, having never married, having two or more chronic medical conditions, experiencing activity limitation, and less contact with family. Therefore, treatment strategies focused on physical health, social support, and mental health needs are necessary to comprehensively address the factors that contribute to persistent major depressive disorder. PMID- 25527226 TI - New insights into the model of dopamine D1 receptor and G-proteins interactions. AB - The details of the interaction between G-proteins and the GPCRs have been subjected to extensive investigation with structural and functional assays, but still many fundamental questions regarding this macromolecular assembly and its mechanism remain unanswered. In the context of current structural data we investigated interactions of dopamine D1 receptor with cognate G-proteins (Galphas) in living cells, emphasizing the prevalence of preassembled D1-G protein complexes. We also tested the effect of D1 receptor presence on the dynamics of Galphas and Galphai3 in the cellular plasma membrane. Using fluorescence resonance energy transfer (FRET) detected by fluorescence lifetime imaging microscopy (FLIM) or fluorescence recovery after photobleaching (FRAP) microscopy, we did not detect constitutive preassociated complex between D1 receptor and G-protein in the absence of receptor activation. Our work suggests that D1 receptor alters the distribution of Galphas and Galphai3 subunits inside the membrane. We also find that non-activated D1 receptor and Galphas or Galphai3 are present in the cell membrane within the same membrane microdomains in the proximity of about 9-10 nm. PMID- 25527227 TI - Utility of feed-and-sleep cardiovascular magnetic resonance in young infants with complex cardiovascular disease. AB - Utilization of cardiovascular magnetic resonance (CMR) is limited in young children because of the need for sedation or general anesthesia (GA). It has been previously shown that CMR can be performed without sedation or GA in young infants who are prone to fall asleep after being fed and swaddled. The purpose of this study was to prospectively prove the feasibility of the feed-and-sleep CMR technique in larger cohorts in the two institutions where the technique was initially developed. This was a prospective dual-center cohort study over a two year period. All infants younger than 6 months old with complex congenital cardiovascular anomaly who required CMR were recruited for this study. The exclusion criteria included mechanical ventilation, oxygen dependence, feeding difficulties, and any contraindication to CMR. The feed-and-sleep study was performed by fasting the infant for a period of 4 h prior to the scan, placing the infant in a vacuum immobilizer, and feeding the infant just prior to the CMR. The CMR sequences were prioritized to target the area of most importance first. A study was considered complete and diagnostic if the clinical question was answered. A total of 60 infants (39 from center A and 21 from center B) were recruited for this study, 32 male and 28 female, ages ranging from 1 to 177 days (50 +/- 54). The CMR studies were diagnostic and answered the clinical questions in all patients. All infants tolerated the procedure well, and no complications were noted in any of the patients. The CMR duration ranged between 4-132 minutes (45 +/- 21). The feed-and-sleep approach in selected patients obviates the need of sedation or GA for CMR in infants younger than 6 months old. Therefore, CMR can be utilized whenever echocardiography fails to provide the complete information required for the patients' management. PMID- 25527228 TI - Resting heart rate influences right ventricular volume in repaired tetralogy of Fallot. AB - The aim of this study is to examine the impact of heart rate (HR) on right ventricular end-diastolic volume indexed to body surface area (RVEDVi) in patients with repaired tetralogy of Fallot (TOF). In this cross-sectional study, an institutional database search identified all patients with repaired TOF who underwent cardiac magnetic resonance (CMR) and had a Holter study within 3 months. The association of HR on Holter, HR at the time of CMR, and other clinical and CMR parameters on RVEDVi was explored with univariate and then multivariable models. In the study group (n = 161, median age 23 years), a lower mean Holter HR was associated with a larger RVEDVi (p = 0.004). In a model that also included pulmonary regurgitation fraction, tricuspid regurgitation grade, RV ejection fraction, age at CMR, and gender, mean Holter HR remained associated with RVEDVi (p < 0.0001); for a decrease of 1 bpm, mean RVEDVi increased by 1.09 ml/m(2). When limiting to those with a Holter within 5 days of CMR (n = 70), the impact of mean Holter HR on RVEDVi was stronger (-1.9 ml/m(2)/bpm). HR at time of CMR had a significant but less pronounced relationship to RVEDVi (-0.58 ml/m(2)/bpm, p = 0.002). In conclusion, in repaired TOF patients, a lower HR was significantly associated with a larger RVEDVi. This relationship was stronger with a shorter time interval between the Holter and CMR, and stronger for the mean HR on Holter than for the HR at CMR. Accounting for HR in the interpretation of RVEDVi may impact decisions regarding pulmonary valve replacement and the interpretation of serial CMR data. PMID- 25527230 TI - The 2014 Society of Surgical Oncology Susan G. Komen for the Cure Symposium: triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is an operational term that refers to a heterogeneous collection of breast cancers lacking expression of estrogen receptor (ER), progesterone receptor, and HER2. These tumors account for 12-17 % of all breast cancers, preferentially affect young women, are more frequent in women of African and Hispanic descent, and are enriched in the population of patients diagnosed with "interval cancers." TNBCs account for the majority of breast cancers arising in BRCA1 germline mutation carriers (approximately 80%), and approximately 11-16% of all TNBCs harbor BRCA1 or BRCA2 germline mutations. Well-known risk factors for ER-positive cancers, such as reproductive history and hormonal factors, do not appear to have the same correlations for TNBC, and histologic risk factors for TNBC have not been identified. Patients with TNBC have a higher risk of both local and distant recurrence, but this is not mitigated by bigger surgery, and standard criteria should be used to select the approach to local therapy in these patients. Although platinum drugs have shown promise in the treatment of TNBC, standard chemotherapy remains the standard of care outside of a clinical trial. PMID- 25527229 TI - Current practices in the monitoring of cardiac rhythm devices in pediatrics and congenital heart disease. AB - Although guidelines for routine follow-up of pacemakers and implantable cardioverter defibrillators (ICDs) are available for adults, minimal data supports their appropriateness in pediatrics and congenital heart disease. This study aimed to define current practices of cardiac rhythm device (CRD) follow-up among pediatric electrophysiologists. Pediatric and Congenital EP Society (PACES) members were surveyed regarding frequency of CRD in-person follow-up as well as transtelephonic monitoring (TTM) and remote monitoring (RM) practices. If home monitoring was used, the effect on in-person follow-up was also evaluated. A total of 106 PACES members responded to the survey. Uncomplicated pacemaker and ICD patients were both followed in-person at a median interval of 6 months (range 1-12 months). TTM was utilized by 67 % of responders (median interval 3 months; range 1-6 months), while RM was used by 87 % for pacemakers (median interval 3 months; range 1-6 months) and 92 % for ICDs (median interval 3 months; range 2 weeks-6 months). When TTM was used, 21 % of responders reduced their frequency of pacemaker clinic visits. In comparison, RM reduced the frequency of clinic visits for pacemakers and ICDs in 32 and 31 % of responders, respectively. Patient age was an independent factor in determining CRD follow-up for 49 % of responders. While CRD follow-up by pediatric electrophysiologists in general follows adult guidelines, individual practices widely vary. In contrast to published recommendations in adults, TTM and RM utilization does not reduce the frequency of in-person visits for the majority of pediatric electrophysiologists. PMID- 25527231 TI - Choosing the best embryo by time lapse versus standard morphology. AB - Within the past few years the morphological evaluation of in vitro fertilized embryos has been extended to include continuous surveillance, enabled by the introduction of time-lapse incubators developed specifically for IVF treatment. As a result time-lapse monitoring has been implemented in many clinics worldwide. The proposed benefits compared with culture in a standard incubator and fixed time-point evaluation are uninterrupted culture, a flexible workflow in the laboratory, and improved embryo selection. The latter is based on the reasonable assumption that more frequent observations will provide substantially more information on the relationship between development, timing, and embryo viability. Several retrospective studies have confirmed a relationship between time-lapse parameters and embryo viability evaluated by developmental competence, aneuploidy, and clinical pregnancy. Furthermore a much anticipated randomized study has shown improved pregnancy rates (PRs) after culture in a time-lapse incubator combined with selection using a hierarchical time-lapse selection model. At present this is the only randomized study on possible benefits of time lapse in human embryology. Strict evidence may still seem too weak to introduce time lapse in routine clinical setting. This aim of this review is therefore to perform a balanced discussion of the evidence for time-lapse monitoring. PMID- 25527233 TI - Building a family through in vitro fertilization--economic realities. PMID- 25527232 TI - Sperm cryopreservation in adolescents and young adults with cancer: results of the French national sperm banking network (CECOS). AB - OBJECTIVE: To determine the feasibility of fertility preservation in adolescent males with cancer. DESIGN: Large multicenter retrospective study of male patients <=20 years from 23 centers of a national network of sperm banks over a 34-year period. SETTING: Sperm banks. PATIENT(S): A total of 4,345 boys and young men aged 11 to 20 years. INTERVENTION(S): Age, cancer diagnosis, feasibility of sperm banking, and sperm parameters. MAIN OUTCOME MEASURE(S): Description of patients, and success of their fertility preservation. RESULT(S): We observed a mean yearly increase in referred patients of 9.5% (95% confidence interval, 9.1%-9.8%) between 1973 and 2007. Over the study period, the percentage of younger cancer patients who banked their sperm increased, especially in the 11-14 year age group, rising from 1% in 1986 to 9% in 2006. We found that 4,314 patients attempted to produce a semen sample, 4,004 succeeded, and sperm was banked for 3,616. The mean total sperm count was 61.75 * 10(6) for the 11-14 year age group, and 138.81 * 10(6) for the 18-20 year age group. It was noteworthy that intercenter variations in practices involving young patients seeking to preserve their fertility before cancer therapy were observed within this national network. CONCLUSION(S): Our results emphasize the need for decisive changes in public health policy to facilitate the access to reproductive health-care for young cancer patients. PMID- 25527234 TI - Transcription factor SOHLH1 potentially associated with primary ovarian insufficiency. AB - OBJECTIVE: To investigate whether gene variants of SOHLH1 exist in Chinese and Serbian patients with primary ovarian insufficiency (POI). DESIGN: Case-control genetic study. SETTING: University hospitals. PATIENT(S): A total of 364 Han Chinese and 197 Serbian women with nonsyndromic POI and ethnically matched controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): SOHLH1 gene sequencing. RESULT(S): We found 10 novel heterozygous variants in our cohorts of 561 women with POI but none in the 600 ethnically matched controls. Statistical and bioinformatic analyses indicated that three of the eight variants in Chinese POI cases are potentially disease causing. They comprise two missense variants (p.Ser317Phe and p.Glu376Lys) that might each change activity of the SOHLH1 protein as a transcription factor and one variant (c.*118C>T) located in the 3' untranslated region of the SOHLH1 gene, which might generate a new binding site for the microRNA hsa-miR-888-5p. Of the two variants in the Serbian POI cases, both were synonymous, and no missense variant was identified. The allele frequencies of some known single-nucleotide polymorphisms were statistically significantly different between patients and controls in both the Chinese and Serbian groups. CONCLUSION(S): Our results suggest that SOHLH1 may be regarded as a new candidate gene for POI. PMID- 25527235 TI - Intrauterine adhesions after hysteroscopic treatment for retained products of conception: what are the risk factors? AB - OBJECTIVE: To assess the prevalence and risk factors for intrauterine adhesions (IUAs) after hysteroscopic treatment of retained products of conception (RPOC). DESIGN: Retrospective cohort study. SETTING: Gynecologic endoscopy unit. PATIENT(S): A total of 167 women referred to our institution from 2009 to 2013. INTERVENTION(S): Operative hysteroscopy for treatment of RPOC and office hysteroscopic follow-up to assess for IUA. MAIN OUTCOME MEASURE(S): We investigated demographic characteristics, obstetrics parameters, and surgical variables to evaluate which factors could be associated with IUA formation. RESULT(S): Of 167 women treated for RPOC, 84 (50.3%) had undergone a follow-up hysteroscopic evaluation after the operative hysteroscopy and were included in the study. Intrauterine adhesions were found in 16 cases (19.0%), of which only 3 (3.6%) were severe adhesions. Multivariate analysis showed that the presence of IUA was associated with RPOC after cesarean section (5 of 10 [50.5%] developed IUA, vs. 7 of 49 [14.3%] after vaginal delivery). Intrauterine adhesions were also found in 4 of 23 women (17.4%) undergoing hysteroscopy for RPOC after abortion. Patient age, gravidity, parity, and the interval between the index pregnancy and treatment for RPOC were not associated with postoperative IUA. CONCLUSION(S): Hysteroscopic treatment for RPOC had a 3.6% incidence of severe intrauterine adhesions formation in this descriptive series. Women with RPOC occurring after delivery by cesarean section are particularly at risk for development of IUA. PMID- 25527236 TI - Plasma calprotectin and its association with cardiovascular disease manifestations, obesity and the metabolic syndrome in type 2 diabetes mellitus patients. AB - BACKGROUND: Plasma calprotectin is a potential biomarker of cardiovascular disease (CVD), insulin resistance (IR), and obesity. We examined the relationship between plasma calprotectin concentrations, CVD manifestations and the metabolic syndrome (MetS) in patients with type 2 diabetes mellitus (T2DM) in order to evaluate plasma calprotectin as a risk assessor of CVD in diabetic patients without known CVD. METHODS: An automated immunoassay for determination of plasma calprotectin was developed based on a fecal Calprotectin ELIA, and a reference range was established from 120 healthy adults. Plasma calprotectin concentrations were measured in 305 T2DM patients without known CVD. They were screened for carotid arterial disease, peripheral arterial disease (PAD), and myocardial ischemia (MI) by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy. RESULTS: The reference population had a median plasma calprotectin concentration of 2437 ng/mL (2.5-97.5% reference range: 1040-4262 ng/mL). The T2DM patients had significantly higher concentrations (3754 ng/mL, p < 0.0001), and within this group plasma calprotectin was significantly higher in patients with MetS (p < 0.0001) and also in patients with autonomic neuropathy, PAD, and MI compared with patients without (p < 0.001, p = 0.021 and p = 0.043, respectively). Plasma calprotectin was by linear regression analysis found independently associated with BMI, C-reactive protein, and HDL cholesterol. However, plasma calprotectin did not predict autonomic neuropathy, PAD, MI or CVD when these variables entered the multivariable regression analysis as separate outcome variables. CONCLUSION: T2DM patients had higher concentrations of plasma calprotectin, which were associated with obesity, MetS status, autonomic neuropathy, PAD, and MI. However, plasma calprotectin was not an independent predictor of CVD, MI, autonomic neuropathy or PAD. TRIAL REGISTRATION NUMBER: NCT00298844. PMID- 25527237 TI - [Tolerance of endotracheal tubes in patients on mechanical ventilation]. AB - BACKGROUND: Modern concepts for sedation and analgesia and guidelines recommend light analgesia and sedation, so that patients on mechanically ventilation are more awake, compared to previous concepts. Hence, these patients are more alert and able to experience their situation on the ventilator and their endotracheal tube (ETT). PROBLEM: There is currently no convincing evidence of how patients tolerate the tube under present conditions, which interventions could help them, or whether they want to be sedated deeper because of the tube. Based upon our own observations, a broad range of reactions are possible. PURPOSE: The tolerance of the ETT in intensive care patients was explored. METHOD: A systematic literature research without time constraints in the databases PubMed and CINAHL was performed. Included were quantitative and qualitative studies written in German or English that investigated tolerance of the ETT in adult intensive care patients. Excluded were anesthetic studies including in- and extubation immediately before and after operations. RESULTS: Of the 2348 hits, 14 studies were included, including 4 qualitative studies about the experience of intensive care, 8 quantitative studies including 2 randomized controlled studies, and 2 studies with a mixed approach. Within the studies different aspects could be identified, which may in- or decrease the tolerance of an ETT. Aspects like breathlessness, pain during endotracheal suctioning and inability to speak decrease the tolerance. Information, the presence of relatives and early mobilization appear to increase the tolerance. CONCLUSION: Tolerance of the ETT is a complex phenomenon. A reflected and critical evaluation of the behavior of the patient with an ETT is recommended. Interventions that increase the tolerance of the ETT should be adapted to the situation of the patient and should be evaluated daily. PMID- 25527238 TI - Comparison of variants of canonical correlation analysis and partial least squares for combined analysis of MRI and genetic data. AB - The standard analysis approach in neuroimaging genetics studies is the mass univariate linear modeling (MULM) approach. From a statistical view, however, this approach is disadvantageous, as it is computationally intensive, cannot account for complex multivariate relationships, and has to be corrected for multiple testing. In contrast, multivariate methods offer the opportunity to include combined information from multiple variants to discover meaningful associations between genetic and brain imaging data. We assessed three multivariate techniques, partial least squares correlation (PLSC), sparse canonical correlation analysis (sparse CCA) and Bayesian inter-battery factor analysis (Bayesian IBFA), with respect to their ability to detect multivariate genotype-phenotype associations. Our goal was to systematically compare these three approaches with respect to their performance and to assess their suitability for high-dimensional and multi-collinearly dependent data as is the case in neuroimaging genetics studies. In a series of simulations using both linearly independent and multi-collinear data, we show that sparse CCA and PLSC are suitable even for very high-dimensional collinear imaging data sets. Among those two, the predictive power was higher for sparse CCA when voxel numbers were below 400 times sample size and candidate SNPs were considered. Accordingly, we recommend Sparse CCA for candidate phenotype, candidate SNP studies. When voxel numbers exceeded 500 times sample size, the predictive power was the highest for PLSC. Therefore, PLSC can be considered a promising technique for multivariate modeling of high-dimensional brain-SNP-associations. In contrast, Bayesian IBFA cannot be recommended, since additional post-processing steps were necessary to detect causal relations. To verify the applicability of sparse CCA and PLSC, we applied them to an experimental imaging genetics data set provided for us. Most importantly, application of both methods replicated the findings of this data set. PMID- 25527239 TI - Bridging the gap between motor imagery and motor execution with a brain-robot interface. AB - According to electrophysiological studies motor imagery and motor execution are associated with perturbations of brain oscillations over spatially similar cortical areas. By contrast, neuroimaging and lesion studies suggest that at least partially distinct cortical networks are involved in motor imagery and execution. We sought to further disentangle this relationship by studying the role of brain-robot interfaces in the context of motor imagery and motor execution networks. Twenty right-handed subjects performed several behavioral tasks as indicators for imagery and execution of movements of the left hand, i.e. kinesthetic imagery, visual imagery, visuomotor integration and tonic contraction. In addition, subjects performed motor imagery supported by haptic/proprioceptive feedback from a brain-robot-interface. Principal component analysis was applied to assess the relationship of these indicators. The respective cortical resting state networks in the alpha-range were investigated by electroencephalography using the phase slope index. We detected two distinct abilities and cortical networks underlying motor control: a motor imagery network connecting the left parietal and motor areas with the right prefrontal cortex and a motor execution network characterized by transmission from the left to right motor areas. We found that a brain-robot-interface might offer a way to bridge the gap between these networks, opening thereby a backdoor to the motor execution system. This knowledge might promote patient screening and may lead to novel treatment strategies, e.g. for the rehabilitation of hemiparesis after stroke. PMID- 25527240 TI - Hereditary Angioedema Attacks: Local Swelling at Multiple Sites. AB - Hereditary angioedema (HAE) patients experience recurrent local swelling in various parts of the body including painful swelling of the intestine and life threatening laryngeal oedema. Most HAE literature is about attacks located in one anatomical site, though it is mentioned that HAE attacks may also involve multiple anatomical sites simultaneously. A detailed description of such multi location attacks is currently lacking. This study investigated the occurrence, severity and clinical course of HAE attacks with multiple anatomical locations. HAE patients included in a clinical database of recombinant human C1-inhibitor (rhC1INH) studies were evaluated. Visual analog scale scores filled out by the patients for various symptoms at various locations and investigator symptoms scores during the attack were analysed. Data of 219 eligible attacks in 119 patients was analysed. Thirty-three patients (28%) had symptoms at multiple locations in anatomically unrelated regions at the same time during their first attack. Up to five simultaneously affected locations were reported. The observation that severe HAE attacks often affect multiple sites in the body suggests that HAE symptoms result from a systemic rather than from a local process as is currently believed. PMID- 25527241 TI - Heterosexual couples and prostate cancer support groups: a gender relations analysis. AB - INTRODUCTION: Men diagnosed with prostate cancer (PCa) can receive supportive care from an array of sources including female partners and prostate cancer support groups (PCSGs). However, little is known about how heterosexual gender relations and supportive care play out among couples who attend PCSGs. Distilling such gender relation patterns is a key to understanding and advancing supportive care for men who experience PCa and their families. PURPOSE: This study describes connections between heterosexual gender relations and PCa supportive care among couples who attend PCSGs. METHOD: In-depth, individual interviews with 30 participants (15 men treated for PCa and their female partners) were analyzed using interpretive descriptive methods. Couples were asked about their relationships, supportive care needs, and attendance at PCSGs. A heterosexual gender relations framework was used to theorize the findings. RESULTS: Findings showed that traditional heterosexual gender relations guided most couples' PCa related support both in and out of PCSGs. Three themes were inductively derived: "Not pushing too hard"-balancing women's support with men's autonomy, "Confreres" men supporting men at PCSGs, and "Women are better at reassuring"-support from and for women. CONCLUSIONS: Couples both aligned to and resisted traditional gender roles to accommodate, explain, and rationalize how, as a couple, they approached PCa supportive care needs. PMID- 25527242 TI - Coping with physical and psychological symptoms: a qualitative study of advanced lung cancer patients and their family caregivers. AB - PURPOSE: Advanced lung cancer patients have high rates of multiple physical and psychological symptoms, and many of their family caregivers experience significant distress. However, little is known about strategies that these patients and their family caregivers employ to cope with physical and psychological symptoms. This study aimed to identify strategies for coping with various physical and psychological symptoms among advanced, symptomatic lung cancer patients and their primary family caregivers. METHODS: Patients identified their primary family caregiver. Individual semi-structured qualitative interviews were conducted with 21 advanced, symptomatic lung cancer patients and primary family caregivers. Thematic analysis of interview data was framed by stress and coping theory. RESULTS: Patients and caregivers reported maintaining a normal routine and turning to family and friends for support with symptom management, which often varied in its effectiveness. Whereas support from health-care professionals and complementary and alternative medicine were viewed favorably, reactions to Internet and in-person support groups were mixed due to the tragic nature of participants' stories. Several cognitive coping strategies were frequently reported (i.e., changing expectations, maintaining positivity, and avoiding illness-related thoughts) as well as religious coping strategies. CONCLUSIONS: Results suggest that advanced lung cancer patients and caregivers may be more receptive to cognitive and religious approaches to symptom management and less receptive to peer support. Interventions should address the perceived effectiveness of support from family and friends. PMID- 25527243 TI - Adherence to prescribed exercise time and intensity declines as the exercise program proceeds: findings from women under treatment for breast cancer. AB - PURPOSE: Adherence to prescribed exercise is a challenge for cancer patients undergoing treatment. The changing pattern of exercise adherence over time cannot be fully understood by an overall measure of adherence. This study was aimed to identify the trajectory of exercise adherence and its predictors for women with breast cancer during their chemotherapy. METHODS: Participants were 78 women with breast cancer assigned to the exercise arm of a randomized control trial. Based on the weekly adherence rates in time and intensity, patients were classified as good (>100%), acceptable (80-100%), and poor (<80%) adherents. Data were analyzed using ordinal logistic hierarchical linear modeling. RESULTS: The trajectories for both time and intensity adherence declined significantly. The decline in exercise-time adherence was significantly slower in women who reported higher interest in exercise. Women with higher perceived importance of exercise, early disease stage, and employed were more likely to be classified as good intensity adherents. Poorer weekly adherence for both exercise time and intensity was associated with higher fatigue level for that week. CONCLUSIONS: Adherence to exercise adherence in breast cancer patients declined as the dose of exercise prescription increased. Factors influencing overall adherence and adherence trend were identified. PMID- 25527244 TI - Growth and safety evaluation of infant formulae containing oligosaccharides derived from bovine milk: a randomized, double-blind, noninferiority trial. AB - BACKGROUND: A limited number of nondigestible oligosaccharides are available for use in infant formula. This study evaluated growth and safety in infants fed formula supplemented with a mixture of bovine milk-derived oligosaccharides (BMOS). This mixture, which was generated from whey permeate, contains galactooligosaccharides and other oligosaccharides from bovine milk, such as 3'- and 6'-sialyllactose. We hypothesized that growth in infants fed BMOS supplemented formula would be noninferior to that in infants fed standard formula. METHODS: Healthy term infants <=14 days old were randomly assigned to standard formula (control; n = 84); standard formula with BMOS (IF-BMOS; n = 99); or standard formula with BMOS and probiotics (Bifidobacterium longum, Lactobacillus rhamnosus) (IF-BMOS + Pro; n = 98). A breastfed reference group was also enrolled (n = 30). The primary outcome was mean weight gain/day from enrollment to age 4 months (noninferiority margin: -3.0 g/day). RESULTS: 189 (67.3%) formula-fed infants were included in the primary analysis. Mean differences in weight gain between the control and IF-BMOS and IF-BMOS + Pro groups were <1 g/day, with 97.5% confidence intervals above -3.0 g/day, indicating noninferior weight gain in the BMOS formula groups. Compared with control, infants in the BMOS groups had more frequent (p < 0.0001) and less hard (p = 0.0003) stools. No significant differences were observed between the control and BMOS groups in caregivers' reports of flatulence, vomiting, spitting up, crying, fussing, and colic. When based on clinical evaluation by the investigator, the incidence of colic was higher (p = 0.01) in IF-BMOS than in control; the incidence of investigator-diagnosed colic was not significantly different in control and IF-BMOS + Pro (p = 0.15). Stool bifidobacteria and lactobacilli counts were higher with IF-BMOS + Pro compared with control (p < 0.05), whereas Clostridia counts were lower (p < 0.05) in both BMOS groups compared with control. CONCLUSIONS: Infant formula containing BMOS either with or without probiotics provides adequate nutrition for normal growth in healthy term infants. Further studies are needed to fully explore the digestive tolerance of BMOS formula. TRIAL REGISTRATION: ClinicalTrials.gov NCT01886898 . Registered 24 June 2013. PMID- 25527245 TI - The infundibulo-tuberal syndrome caused by craniopharyngiomas: clinicopathological evidence from an historical French cohort (1705-1973). AB - PURPOSE: Infundibulo-tuberal syndrome groups endocrine, metabolic and behavioral disturbances caused by lesions involving the upper neurohypophysis (median eminence) and adjacent basal hypothalamus (tuber cinereum). It was originally described by Henri Claude and Jean Lhermitte in 1917, in a patient with a craniopharyngioma. This study investigates the clinical, pathological and surgical evidence verifying the infundibulo-tuberal syndrome caused by craniopharyngiomas (CPs). METHODS: A systematic retrospective review of craniopharyngiomas reported in French literature between 1705 and 1973 was conducted. A total of 128 well described reports providing a comprehensive clinical and pathological description of the tumors were selected. This series represents the historical French cohort of CPs reported in the pre-CT/MRI era. RESULTS: Three major syndromes caused by CPs were categorized: pituitary syndrome (35%), infundibulo-tuberal syndrome (52%) and hypothalamic syndrome (49%). CP topography was significantly related to the type of syndrome described (p < 0.001). Infundibulo-tuberal syndrome occurred in CPs which replaced or invaded the third ventricle floor. In contrast, the majority of sellar/suprasellar CPs growing below the third ventricle showed a pituitary syndrome (82%). Cases with hypothalamic syndrome were characterized by anatomical integrity of the pituitary gland and stalk (p = 0.033) and occurred predominantly in adults older than 41 years old (p < 0.005). Among infundibulo-tuberal symptoms, abnormal somnolence was not related with the presence of hydrocephalus. All squamous-papillary CPs presented psychiatric disturbances (p < 0.001). CONCLUSION: This historical CP cohort evidences a clinical-topographical correlation between the patient's type of syndrome and the anatomical structures involved by the tumor along the hypophysial-hypothalamic axis. PMID- 25527246 TI - A 4-year prospective study of the progression of periodontal disease in a rural Chinese population. AB - OBJECTIVES: The natural progression of periodontitis in the Chinese population is not well researched. We investigated the progression of periodontal disease over 4 years in 15-44-year-old Chinese villagers with no access to regular dental care. METHODS: In 1992, 486 villagers were enrolled, and in 1996, 413 villagers were re-examined. Probing depth (PD) and clinical attachment level (CAL) were examined at six sites per tooth. Sites with DeltaCAL >=3 mm were defined as active sites. Cross-sectional and longitudinal analyses were performed using means and percentile plots. RESULTS: The mean CAL increased by 0.26 mm over 4 years. The incidence of periodontitis (at least one site with CAL >=3 mm) was 8%. The incidence of periodontitis among those with no periodontal disease at baseline was 44.9%. Seventy-eight percent of the subjects had at least one active site. In the 15-24-year group, 244 of 401 active sites had gingival recession, while only 51 active sites had both gingival recession and deeper pockets. In the 25-34-year and 35-44-year groups, almost one-third of the active sites (329/1087) and more than one-third of the active sites (580/1312) respectively had a combination of gingival recession and deeper pockets. CONCLUSIONS: In this study, we demonstrated that in Chinese population without regular dental care, both the initiation of periodontitis and progression of previously existed periodontitis contributed to the natural progression of periodontitis and periodontal pocketing played a greater role with age increasing. CLINICAL SIGNIFICANCE: This rare study reports the natural progression of periodontal disease in a group of Chinese villagers (15-44 years) with virtually no access to regular dental care. PMID- 25527247 TI - Effect of hydrogen-peroxide-mediated oxidative stress on human dental pulp cells. AB - OBJECTIVES: To evaluate the effect of the oxidative stress on human dental pulp cells (HDPCs) promoted by toxic concentrations of hydrogen peroxide (H2O2) on its odontoblastic differentiation capability through time. METHODS: HDPCs were exposed to two different concentrations of H2O2 (0.1 and 0.3MUg/ml) for 30min. Thereafter, cell viability (MTT assay) and oxidative stress generation (H2DCFDA fluorescence assay) were immediately evaluated. Data were compared with those for alkaline phosphatase (ALP) activity (thymolphthalein assay) and mineralized nodule deposition (alizarin red) by HDPCs cultured for 7 days in osteogenic medium. RESULTS: A significant reduction in cell viability and oxidative stress generation occurred in the H2O2-treated cells when compared with negative controls (no treatment), in a concentration-dependent fashion. Seven days after H2O2 treatment, the cells showed significant reduction in ALP activity compared with negative control and no mineralized nodule deposition. CONCLUSION: Both concentrations of H2O2 were toxic to the cells, causing intense cellular oxidative stress, which interfered with the odontogenic differentiation capability of the HDPCs. CLINICAL SIGNIFICANCE: The intense oxidative stress on HDPCs mediated by H2O2 at toxic concentrations promotes intense reduction on odontoblastic differentiation capability in a 7-day evaluation period, which may alter the initial pulp healing capability in the in vivo situation. PMID- 25527248 TI - Clinical evaluation comparing the fit of all-ceramic crowns obtained from silicone and digital intraoral impressions based on wavefront sampling technology. AB - OBJECTIVE: The aim of this study was to compare the fit of ceramic crowns fabricated from conventional silicone impressions with the fit of ceramic crowns fabricated from intraoral digital impressions. METHODS: Twenty-five participants with 30 posterior teeth with a prosthetic demand were selected for the study. Two crowns were made for each preparation. One crown was fabricated from an intraoral digital impression system (IDI group) and the other crown was fabricated from a conventional two-step silicone impression (CI group). To replicate the interface between the crown and the preparation, each crown was cemented on its corresponding clinical preparation with ultra-flow silicone. Each crown was embedded in acrylic resin to stabilise the registered interface and then cut in 2mm thick slices in a buco-lingual orientation. The internal gap was determined as the vertical distance from the internal surface of the crown to the prepared tooth surface at four points (marginal gap, axial gap, crest gap, and occlusal fossa gap) using stereomicroscopy with a magnification of 40*. Data was analysed by using Wilcoxon signed rank test (alpha=0.05). RESULTS: Internal adaptation values were significantly affected by the impression technique (p=0.001). Mean marginal gap was 76.33 +/- 65.32 MUm for the crowns of the IDI group and 91.46 +/ 72.17 MUm for the CI group. CONCLUSION: All-ceramic crowns fabricated from intraoral digital impressions with wavefront sampling technology demonstrated better internal fit than crowns manufactured from silicone impressions. CLINICAL SIGNIFICANCE: Impressions obtained from an intraoral digital scanner based on wavefront sampling technology can be used for manufacturing ceramic crowns in the normal clinical practice with better results than conventional impressions with elastomers. PMID- 25527249 TI - Dengue fever: a new challenge for China? PMID- 25527250 TI - Core and accessory genome architecture in a group of Pseudomonas aeruginosa Mu like phages. AB - BACKGROUND: Bacteriophages that infect the opportunistic pathogen Pseudomonas aeruginosa have been classified into several groups. One of them, which includes temperate phage particles with icosahedral heads and long flexible tails, bears genomes whose architecture and replication mechanism, but not their nucleotide sequences, are like those of coliphage Mu. By comparing the genomic sequences of this group of P. aeruginosa phages one could draw conclusions about their ontogeny and evolution. RESULTS: Two newly isolated Mu-like phages of P. aeruginosa are described and their genomes sequenced and compared with those available in the public data banks. The genome sequences of the two phages are similar to each other and to those of a group of P. aeruginosa transposable phages. Comparing twelve of these genomes revealed a common genomic architecture in the group. Each phage genome had numerous genes with homologues in all the other genomes and a set of variable genes specific for each genome. The first group, which comprised most of the genes with assigned functions, was named "core genome", and the second group, containing mostly short ORFs without assigned functions was called "accessory genome". Like in other phage groups, variable genes are confined to specific regions in the genome. CONCLUSION: Based on the known and inferred functions for some of the variable genes of the phages analyzed here, they appear to confer selective advantages for the phage survival under particular host conditions. We speculate that phages have developed a mechanism for horizontally acquiring genes to incorporate them at specific loci in the genome that help phage adaptation to the selective pressures imposed by the host. PMID- 25527251 TI - Effect of ablation of frequent premature ventricular complexes on left ventricular function in patients with nonischemic cardiomyopathy. AB - BACKGROUND: Frequent idiopathic premature ventricular complexes (PVCs) can result in PVC-induced cardiomyopathy. Frequent PVCs can also aggravate ischemic cardiomyopathy. OBJECTIVE: The purpose of this study was to investigate the impact of frequent PVCs on nonischemic cardiomyopathy. METHODS: This was a consecutive series of 30 patients (mean age 59.1 +/- 12.1; 18 men; mean ejection fraction [EF] 38% +/- 15%) with structurally abnormal hearts based on the presence of scar on cardiac magnetic resonance imaging and/or a history of cardiomyopathy before the presence of frequent PVCs who were referred for ablation of frequent PVCs. RESULTS: Ablation was successful in 18 of 30 patients (60%), resulting in an increase of mean EF from 33.9% +/- 14.5% to 45.7% +/- 17% (P < .0001) during mean follow-up of 30 +/- 28 months. The PVC burden in these patients was reduced from 23.1% +/- 8.8% to 1.0% +/- 0.9% (P < .0001). Mean EF did not change in patients with a failed ablation procedure (44.4 +/- 16 vs 43.5 +/- 21, P = .85). The PVC site of origin was in scar tissue in 14 of 18 patients with a successful ablation procedure. Mean New York Heart Association functional class improved from 2.3 +/- 0.6 to 1.1 +/- 0.2 (P < .0001) in patients with a successful outcome and remained unchanged in patients with an unsuccessful outcome (1.9 +/- 0.9 vs 1.9 +/- 0.7, P = 1). CONCLUSION: In patients with frequent PVCs and nonischemic cardiomyopathy, EF and functional class can be improved but not always normalized by successful PVC ablation. In most patients with an effective ablation, the arrhythmogenic substrate was located in scar tissue. PMID- 25527252 TI - Metabolism profiling of amino-noscapine. AB - Amino-noscapine is a promising noscapine derivative undergoing R&D as an efficient anti-tumor drug. In vitro phase I metabolism incubation system was employed. In vitro samples were analyzed using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. In vitro recombinant CYP isoforms screening was used to identify the drug-metabolizing enzymes involved in the metabolism of amino noscapine. Multiple metabolics were formed, including the formation of metabolite undergoing cleavage of methylenedioxy group, hydroxylated metabolites, demethylated metabolites, and metabolites undergoing C-C cleavage. Nearly, all the CYP isoforms were involved in the metabolism of metabolites II, III, VII, IX, and X. CYP1A1 was demonstrated to be the major CYP isoform for the formation of metabolites IV and V. CYP1A1 and CYP3A4 mainly catalyzed the formation of metabolite VI. The metabolic formation of VIII was mainly catalyzed by CYP2C19 and CYP3A4. CYP3A4 was the main enzyme for the formation of XI. CYP2C9 mainly catalyzed the generation of metabolite XII. In conclusion, the metabolic pathway of amino-noscapine was elucidated in the present study using in vitro phase I incubation experiment, including the structural elucidation of metabolites and involved phase I drug-metabolizing enzymes. This information was helpful for the R&D of amino-noscapine. PMID- 25527253 TI - Efficacy of venlafaxine XR for the treatment of pain in patients with spinal cord injury and major depression: a randomized, controlled trial. AB - OBJECTIVES: To (1) determine the efficacy of venlafaxine XR for the treatment of pain (secondary aim) in individuals with spinal cord injury (SCI) enrolled in a randomized controlled trial (RCT) on the efficacy of venlafaxine XR for major depressive disorder (MDD) (primary aim); and (2) test the hypothesis that venlafaxine XR would be effective for both neuropathic and nociceptive pain. DESIGN: Multisite, double-blind, randomized (1:1) controlled trial with subjects block randomized and stratified by site, lifetime history of substance abuse, and prior history of MDD. SETTING: Six Departments of Physical Medicine and Rehabilitation in university-based medical schools. PARTICIPANTS: Individuals (N=123) with SCI and major depression between 18 and 64 years of age, at least 1 month post-SCI who also reported pain. INTERVENTION: Twelve-week trial of venlafaxine XR versus placebo using a flexible titration schedule. OUTCOME MEASURES: A 0-to-10 numeric rating scale for pain, pain interference items of the Brief Pain Inventory; 30% and 50% responders. RESULTS: The effect of venlafaxine XR on neuropathic pain was similar to that of placebo. However venlafaxine XR resulted in statistically significant and clinically meaningful reductions in nociceptive pain site intensity and interference even after controlling for anxiety, depression, and multiple pain sites within the same individual. For those who achieved a minimally effective dose of venlafaxine XR, some additional evidence of effectiveness was noted for those with mixed (both neuropathic and nociceptive) pain sites. CONCLUSIONS: Venlafaxine XR could complement current medications and procedures for treating pain after SCI and MDD that has nociceptive features. Its usefulness for treating central neuropathic pain is likely to be limited. Research is needed to replicate these findings and determine whether the antinociceptive effect of venlafaxine XR generalizes to persons with SCI pain without MDD. PMID- 25527254 TI - Gingival wound healing: an essential response disturbed by aging? AB - Gingival wound healing comprises a series of sequential responses that allow the closure of breaches in the masticatory mucosa. This process is of critical importance to prevent the invasion of microbes or other agents into tissues, avoiding the establishment of a chronic infection. Wound healing may also play an important role during cell and tissue reaction to long-term injury, as it may occur during inflammatory responses and cancer. Recent experimental data have shown that gingival wound healing is severely affected by the aging process. These defects may alter distinct phases of the wound-healing process, including epithelial migration, granulation tissue formation, and tissue remodeling. The cellular and molecular defects that may explain these deficiencies include several biological responses such as an increased inflammatory response, altered integrin signaling, reduced growth factor activity, decreased cell proliferation, diminished angiogenesis, reduced collagen synthesis, augmented collagen remodeling, and deterioration of the proliferative and differentiation potential of stem cells. In this review, we explore the cellular and molecular basis of these defects and their possible clinical implications. PMID- 25527255 TI - Improved self-management skills in Chinese diabetes patients through a comprehensive health literacy strategy: study protocol of a cluster randomized controlled trial. AB - BACKGROUND: Diabetes self-management often involves the interpretation and application of oral, written, or quantitative information. Numerous diabetes patients in China have limited health literacy, which likely leads to poorer clinical outcomes. This study is designed to examine the efficacy and cost effectiveness of addressing health literacy to improve self-management skills and glycemic control in Chinese diabetes patients. METHODS/DESIGN: This is a cluster randomized controlled trial (RCT) conducted in 20 community healthcare sites in Shanghai, China. Overall, 800 diabetes patients will be randomized into intervention and control arms and will have a baseline hemoglobin A1c (HbA1c) assay and undergo a baseline survey which includes measures of health literacy and diabetes numeracy using revised Chinese versions of the Health Literacy Management Scale and Diabetes Numeracy Test Scale. During the 1-year period of intervention, while the control group will receive usual care, the intervention group will be supplemented with a comprehensive health literacy strategy which includes i) training healthcare providers in effective health communication skills that address issues related to low literacy, and ii) use of an interactive Diabetes Education Toolkit to improve patient understanding and behaviors. Assessments will be conducted at both patient and healthcare provider levels, and will take place upon admission and after 3, 6, 12, and 24 months of intervention. The primary outcome will be the improvement in HbA1c between Intervention group and Control group patients. Secondary outcomes at the patient level will include improvement in i) clinical outcomes (blood pressure, fasting lipids, body mass index, weight, smoking status), ii) patient reported self-management behaviors, and iii) patient-reported self-efficacy. Outcomes at the provider level will include: i) provider satisfaction and ii) intensity and type of care provided. The effects of the intervention will be examined in multivariable general linear models. Both cost-effectiveness and cost-utility analyses will be performed. DISCUSSION: The main strengths of this study are its large sample size and RCT design, involvement of both patients and healthcare providers, and the long term follow-up (24-months). This project will help to demonstrate the value of addressing health literacy and health communication to improve self-management and clinical outcomes among Chinese diabetes patients. TRIAL REGISTRATION: ISRCTN76130594, Registration date: Sept 22, 2014. PMID- 25527256 TI - Peptide amphiphile micelles self-adjuvant group A streptococcal vaccination. AB - Delivery system design and adjuvant development are crucially important areas of research for improving vaccines. Peptide amphiphile micelles are a class of biomaterials that have the unique potential to function as both vaccine delivery vehicles and self-adjuvants. In this study, peptide amphiphiles comprised of a group A streptococcus B cell antigen (J8) and a dialkyl hydrophobic moiety (diC16) were synthesized and organized into self-assembled micelles, driven by hydrophobic interactions among the alkyl tails. J8-diC16 formed cylindrical micelles with highly alpha-helical peptide presented on their surfaces. Both the micelle length and secondary structure were shown to be enhanced by annealing. When injected into mice, J8-diC16 micelles induced a strong IgG1 antibody response that was comparable to soluble J8 peptide supplemented with two classical adjuvants. It was discovered that micelle adjuvanticity requires the antigen be a part of the micelle since separation of J8 and the micelle was insufficient to induce an immune response. Additionally, the diC16 tail appears to be non-immunogenic since it does not stimulate a pathogen recognition receptor whose agonist (Pam3Cys) possesses a very similar chemical structure. The research presented in this paper demonstrates the promise peptide amphiphile micelles have in improving the field of vaccine engineering. PMID- 25527258 TI - Effect of wearing an N95 respirator on infrared tympanic membrane temperature measurements. AB - To determine the impact of wearing an N95 filtering facepiece respirator (N95 FFR) on tympanic temperature measurements. TMT measurements, with and without wearing an N95 filtering facepiece respirator (N95 FFR) were obtained at the onset and termination of 1 h of treadmill exercise in 21 subjects, and at staggered time intervals (0, 20, 40, 60 min) during combined sedentary activity and exercise of another 46 subjects, to determine any effect on TMT. A total of 877 TMT measurements were obtained that demonstrated a mean TMT increase of 0.05 degrees C in the first study group (p = 0.04) and a 0.19 degrees C decrease in the second study group (p < 0.001) with the wearing of an N95 FFR, both of which were lower than controls. Wearing an N95 FFR for 1 h, at different levels of activity, results in significantly lower TMT values than not wearing an N95 FFR, but the magnitude of the changes would likely have minimal clinical significance. PMID- 25527257 TI - Neurochemical excitation of thoracic propriospinal neurons improves hindlimb stepping in adult rats with spinal cord lesions. AB - Using an in vitro neonatal rat brainstem-spinal cord preparation, we previously showed that cervicothoracic propriospinal neurons contribute to descending transmission of the bulbospinal locomotor command signal, and neurochemical excitation of these neurons facilitates signal propagation. The present study examined the relevance of these observations to adult rats in vivo. The first aim was to determine the extent to which rats are able to spontaneously recover hindlimb locomotor function in the presence of staggered contralateral hemisections (left T2-4 and right T9-11) designed to abolish all long direct bulbospinal projections. The second aim was to determine whether neurochemical excitation of thoracic propriospinal neurons in such animals facilitates hindlimb stepping. In the absence of intrathecal drug injection, all animals (n=24) displayed some degree of hindlimb recovery ranging from weak ankle movements to brief periods of unsupported hindlimb stepping on the treadmill. The effect of boluses of neurochemicals delivered via an intrathecal catheter (tip placed midway between the rostral and caudal thoracic hemisections) was examined at post lesion weeks 3, 6 and 9. Quipazine was particularly effective facilitating hindlimb stepping. Subsequent complete transection above the rostral (n=3) or caudal (n=2) hemisections at week 9 had no consistent effect on drug-free locomotor performance, but the facilitatory effect of drug injection decreased in 4/5 animals. Two animals underwent complete transection at T3 as the first and only surgery and implantation of two intrathecal catheters targeted to the mid thoracic and lumbar regions, respectively. A similar facilitatory effect on stepping was observed in response to drugs administered via either catheter. The results indicate that partial spontaneous recovery of stepping occurs in adult rats after abolishing all long direct bulbospinal connections, in contrast to previous studies suggesting that hindlimb stepping after dual hemisections either does not occur or is observed only if the second hemisection surgery is delayed relative to the first. The results support the hypothesis that artificial modulation of propriospinal neuron excitability may facilitate recovery of motor function after spinal cord injury. However, whether this facilitation is due to enhanced transmission of a descending locomotor signal or is the result of excitation of thoracolumbar circuits independent of supraspinal influence, requires further study. PMID- 25527259 TI - Attenuation of fibrosis with selective inhibition of c-Abl by siRNA in systemic sclerosis dermal fibroblasts. AB - Cellular abelson (c-Abl), a non-receptor tyrosine kinase, is an important molecule in the pathogenesis of systemic sclerosis. There have been reports of beneficial effects of pharmacological tyrosine kinase inhibitors, such as imatinib mesylate, on fibrosis. However, these inhibitors affect multiple tyrosine kinases including c-Abl, c-kit, and platelet-derived growth factor receptor. The effects of selective inhibition of c-Abl using small interfering RNA (siRNA) on dermal fibrosis have not yet been explored. The aim of this study is to evaluate whether specific inhibition of c-Abl by siRNA can influence the transforming growth factor-beta1 (TGF-beta1)-induced fibrotic responses. Dermal fibroblasts from systemic sclerosis patients and healthy controls were transfected with c-Abl siRNA. The expression levels of collagen type I, fibronectin, connective tissue growth factor (CTGF), and alpha-smooth muscle actin (alpha-SMA) were measured at both the mRNA and protein levels in the absence or presence of TGF-beta1 pro-fibrotic cytokine. In healthy dermal fibroblasts, the expression of collagen type 1, fibronectin, alpha-SMA, and CTGF mRNAs and proteins that were upregulated after stimulation with TGF-beta1 was markedly decreased by c-Abl siRNA. Silencing of c-Abl via siRNA efficiently reduced the basal synthesis of collagen type I, fibronectin, alpha-SMA, and CTGF mRNAs and proteins in systemic sclerosis fibroblasts, but it had no effect on the baseline expression of these genes and proteins in healthy dermal fibroblasts. In conclusion, specific c-Abl gene silencing using siRNA effectively reduced fibrosis-related gene expression. Inhibition of c-Abl by siRNA may be a potential therapeutic approach for fibrotic diseases such as systemic sclerosis. PMID- 25527261 TI - Activation of gab cluster transcription in Bacillus thuringiensis by gamma aminobutyric acid or succinic semialdehyde is mediated by the Sigma 54-dependent transcriptional activator GabR. AB - BACKGROUND: Bacillus thuringiensis GabR is a Sigma 54-dependent transcriptional activator containing three typical domains, an N-terminal regulatory domain Per ARNT-Sim (PAS), a central AAA(+) (ATPases associated with different cellular activities) domain and a C-terminal helix-turn-helix (HTH) DNA binding domain. GabR positively regulates the expression of the gabT gene of the gab gene cluster, which is responsible for the gamma-aminobutyric acid (GABA) shunt. RESULTS: Purified GabR was shown to specifically bind to a repeat region that mapped 58 bp upstream of the gabT start codon. The specific signal factors GABA and succinic semialdehyde (SSA) activated gabT expression, whereas GABA- and SSA inducible gabT transcription was abolished in sigL and gabR mutants. GABA and SSA did not induce the expression of either SigL or GabR. Deletion of the PAS domain of GabR resulted in increased gabT transcriptional activity, both in the presence and absence of GABA. CONCLUSIONS: This study identified the GabR-binding site on the gabT promoter; however, GabR does not bind to its own promoter. gabT transcription is induced by GABA and SSA, and inducible expression is dependent on SigL and activated by GabR. The PAS domain in GabR is repressing its enhancer transcriptional activity on the gabT promoter. Repression is released upon GABA addition, whereupon transcription is induced. PMID- 25527262 TI - Effects of stretching and warm-up routines on stability and balance during weight lifting: a pilot investigation. AB - BACKGROUND: The efficacy of warm-up and stretching in weight-lifting remains unknown, especially for the weight-lifter's stability and balance during lifting. METHODS: 13 subjects were randomly assigned a 10-minute stretching routine (SR) or a 10-minute warm-up routine (WR) and compared against 5 controls (no stretching or warm-up). Before and after the individually assigned routine, the participants' centre of pressure (CoP) was assessed using plantar-pressure sensors. The subjects were measured during 10 repetitions of air squat (no load, "AS"), front squat (FS; 20 kg/15 kg bar), overhead squat (OHS; m: 20 kg / f: 15 kg bar), and a deadlift lifting exercise ("DL"; 20 kg/15 kg bar). The impact on CoP dynamics of the warm-up and stretching routines were examined with repeated two-factor analysis of variances (ANOVA) of the mean and the coefficient of variance (CV, shown in %), as proxies for stability and balance. RESULTS: After stretching, the SR athletes shifted the mean CoP towards the toes (~1 cm; p < 0.01) while the WR athletes shifted the CoP towards the heels (~1 cm; p < 0.01) during AS. For the remaining exercises, the SR athletes shifted the CoP towards the heels (between 0.8 cm and 5.7 cm) compared to WR (~1.9 cm towards the heels in FS, no significant change in OHS (~1 mm) and DL (~3 mm)). The controls did not show any change between pre- and post-datasets. After stretching, the CV decreased for the AS and OHS exercises (AS: 10.2% to 7.0%, OHS 9.8% to 7.8%), but increased after WR (AS: 7.1% to 10.1%) or did not change significantly (OHS). Both WR and SR resulted in increased CV values for FS and DL. No change of CV was observed in the controls. CONCLUSIONS: SR had a stronger impact on CoP during the assessed exercises than either WR or controls. A reduction in CV after SR exercises (AS, OHS) suggests a clear improvement in stability and balance during weight-lifting. The lack of a significant effect for complex movements (OHS) suggests only a limited effect of a 10-minute warm-up routine on CoP features. 10 minutes stretching might therefore be more efficient for improving stability than a general 10 minute warm-up. PMID- 25527260 TI - Temporal genomic evolution of bird sex chromosomes. AB - BACKGROUND: Sex chromosomes exhibit many unusual patterns in sequence and gene expression relative to autosomes. Birds have evolved a female heterogametic sex system (male ZZ, female ZW), through stepwise suppression of recombination between chrZ and chrW. To address the broad patterns and complex driving forces of Z chromosome evolution, we analyze here 45 newly available bird genomes and four species' transcriptomes, over their course of recombination loss between the sex chromosomes. RESULTS: We show Z chromosomes in general have a significantly higher substitution rate in introns and synonymous protein-coding sites than autosomes, driven by the male-to-female mutation bias ('male-driven evolution' effect). Our genome-wide estimate reveals that the degree of such a bias ranges from 1.6 to 3.8 among different species. G + C content of third codon positions exhibits the same trend of gradual changes with that of introns, between chrZ and autosomes or regions with increasing ages of becoming Z-linked, therefore codon usage bias in birds is probably driven by the mutational bias. On the other hand, Z chromosomes also evolve significantly faster at nonsynonymous sites relative to autosomes ('fast-Z' evolution). And species with a lower level of intronic heterozygosities tend to evolve even faster on the Z chromosome. Further analysis of fast-evolving genes' enriched functional categories and sex-biased expression patterns support that, fast-Z evolution in birds is mainly driven by genetic drift. Finally, we show in species except for chicken, gene expression becomes more male-biased within Z-linked regions that have became hemizygous in females for a longer time, suggesting a lack of global dosage compensation in birds, and the reported regional dosage compensation in chicken has only evolved very recently. CONCLUSIONS: In conclusion, we uncover that the sequence and expression patterns of Z chromosome genes covary with their ages of becoming Z-linked. In contrast to the mammalian X chromosomes, such patterns are mainly driven by mutational bias and genetic drift in birds, due to the opposite sex-biased inheritance of Z vs. X. PMID- 25527263 TI - Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma. PMID- 25527264 TI - DARS-associated leukoencephalopathy can mimic a steroid-responsive neuroinflammatory disorder. AB - OBJECTIVE: To describe the expanding clinical spectrum of a recently described hereditary leukoencephalopathy, hypomyelination with brainstem and spinal cord involvement and leg spasticity, which is caused by mutations in the aspartyl tRNA synthetase encoding gene DARS, including patients with an adolescent onset. METHODS: Three patients with mutations in DARS were identified by combining MRI pattern recognition and genetic analysis. RESULTS: One patient had the typical infantile presentation, but 2 patients with onset in late adolescence had a disease mimicking an acquired inflammatory CNS disorder. Adolescent-onset patients presented with subacute spastic paraplegia and had positive response to steroids. They had only minor focal supratentorial white matter abnormalities, but identical spinal cord changes involving dorsal columns and corticospinal tracts. Clinical presentation included subacute spastic paraplegia with partial improvement on steroids. CONCLUSIONS: Focal T2 hyperintense white matter changes on brain MRI in combination with spinal cord signal abnormalities usually suggest acquired inflammatory conditions such as multiple sclerosis, especially in the context of relapsing course and a positive response to steroid treatment. Adolescents with mutations in DARS can present with a comparable clinical picture, broadening the clinical spectrum of hypomyelination with brainstem and spinal cord involvement and leg spasticity. PMID- 25527266 TI - Ataxin-2 expands insight into the ALS clinical spectrum. PMID- 25527267 TI - Comment: Medical therapy for recurrent or progressive meningiomas remains elusive. PMID- 25527268 TI - The amygdala: functional organization and involvement in neurologic disorders. PMID- 25527265 TI - ATXN2 polyQ intermediate repeats are a modifier of ALS survival. AB - OBJECTIVE: To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27-33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort). METHODS: PolyQ repeats were assessed in 672 patients with incident ALS in Piemonte and Valle d'Aosta regions, Italy, in the 2007-2012 period (discovery cohort); controls were 509 neurologically healthy age- and sex matched subjects resident in the study area. The validation cohort included 661 patients with ALS consecutively seen between 2001 and 2013 in the ALS Clinic Center of the Catholic University in Rome, Italy. RESULTS: In the discovery cohort, the frequency of >=31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs 1 control, p = 0.0001; odds ratio 14.8, 95% confidence interval 1.9-110.8). Patients with an increased number of polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ >=31, 1.8 years, interquartile range [IQR] 1.3-2.2; polyQ <31, 2.7 years, IQR 1.6-5.1; p = 0.001). An increased number of polyQ repeats remained independently significant at multivariable analysis. In the validation cohort, patients with >=31 polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ >=31, 2.0 years, IQR 1.5-3.4; polyQ <31, 3.2 years, IQR 2.0-6.4; p = 0.007). CONCLUSIONS: ATXN2 polyQ intermediate-length repeat is a modifier of ALS survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS. PMID- 25527269 TI - Leukoencephalopathy: "Before concluding treatment efficacy...". PMID- 25527271 TI - The good, the bad, and the ugly. PMID- 25527270 TI - Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma. AB - OBJECTIVE: A subset of meningiomas recur after surgery and radiation therapy, but no medical therapy for recurrent meningioma has proven effective. METHODS: Pasireotide LAR is a long-acting somatostatin analog that may inhibit meningioma growth. This was a phase II trial in patients with histologically confirmed recurrent or progressive meningioma designed to evaluate whether pasireotide LAR prolongs progression-free survival at 6 months (PFS6). Patients were stratified by histology (atypical [World Health Organization grade 2] and malignant [grade 3] meningiomas in cohort A and benign [grade 3] in cohort B). RESULTS: Eighteen patients were accrued in cohort A and 16 in cohort B. Cohort A had median age 59 years, median Karnofsky performance status 80, 17 (94%) had previous radiation therapy, and 11 (61%) showed high octreotide uptake. Cohort B had median age 52 years, median Karnofsky performance status 90, 11 (69%) had previous radiation therapy, and 12 (75%) showed high octreotide uptake. There were no radiographic responses to pasireotide LAR therapy in either cohort. Twelve patients (67%) in cohort A and 13 (81%) in cohort B achieved stable disease. In cohort A, PFS6 was 17% and median PFS 15 weeks (95% confidence interval: 8-20). In cohort B, PFS6 was 50% and median PFS 26 weeks (12-43). Treatment was well tolerated. Octreotide uptake and insulin-like growth factor-1 levels did not predict outcome. Expression of somatostatin receptor 3 predicted favorable PFS and overall survival. CONCLUSIONS: Pasireotide LAR has limited activity in recurrent meningiomas. The finding that somatostatin receptor 3 is associated with favorable outcomes warrants further investigation. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with recurrent or progressive meningioma, pasireotide LAR does not significantly increase the proportion of patients with PFS at 6 months. PMID- 25527272 TI - An international cross-sectional survey of antimicrobial stewardship programmes in hospitals. AB - OBJECTIVES: To report the extent and components of global efforts in antimicrobial stewardship (AMS) in hospitals. METHODS: An Internet-based survey comprising 43 questions was disseminated worldwide in 2012. RESULTS: Responses were received from 660 hospitals in 67 countries: Africa, 44; Asia, 50; Europe, 361; North America, 72; Oceania, 30; and South and Central America, 103. National AMS standards existed in 52% of countries, 4% were planning them and 58% had an AMS programme. The main barriers to implementing AMS programmes were perceived to be a lack of funding or personnel, a lack of information technology and prescriber opposition. In hospitals with an existing AMS programme, AMS rounds existed in 64%; 81% restricted antimicrobials (carbapenems, 74.3%; quinolones, 64%; and cephalosporins, 58%); and 85% reported antimicrobial usage, with 55% linking data to resistance rates and 49% linking data to infection rates. Only 20% had electronic prescribing for all patients. A total of 89% of programmes educated their medical, nursing and pharmacy staff on AMS. Of the hospitals, 38% had formally reviewed their AMS programme: reductions were reported by 96% of hospitals for inappropriate prescribing, 86% for broad-spectrum antibiotic use, 80% for expenditure, 71% for healthcare-acquired infections, 65% for length of stay or mortality and 58% for bacterial resistance. CONCLUSIONS: The worldwide development and implementation of AMS programmes varies considerably. Our results should inform and encourage the further evaluation of this with a view to promoting a worldwide stewardship framework. The prospective measurement of well defined outcomes of the impact of these programmes remains a significant challenge. PMID- 25527273 TI - Genomic insights into the rapid emergence and evolution of MDR in Staphylococcus pseudintermedius. AB - OBJECTIVES: MDR methicillin-resistant Staphylococcus pseudintermedius (MRSP) strains have emerged rapidly as major canine pathogens and present serious treatment issues and concerns to public health due to their, albeit low, zoonotic potential. A further understanding of the genetics of resistance arising from a broadly susceptible background of S. pseudintermedius is needed. METHODS: We sequenced the genomes of 12 S. pseudintermedius isolates of varied STs and resistance phenotypes. RESULTS: Nine distinct clonal lineages had acquired either staphylococcal cassette chromosome (SCC) mec elements and/or Tn5405-like elements carrying up to five resistance genes [aphA3, sat, aadE, erm(B), dfrG] to generate MRSP, MDR methicillin-susceptible S. pseudintermedius and MDR MRSP populations. The most successful and clinically problematic MDR MRSP clones, ST68 SCCmecV(T) and ST71 SCCmecII-III, have further accumulated mutations in gyrA and grlA conferring resistance to fluoroquinolones. The carriage of additional mobile genetic elements (MGEs) was highly variable, suggesting that horizontal gene transfer is frequent in S. pseudintermedius populations. CONCLUSIONS: Importantly, the data suggest that MDR MRSP evolved rapidly by the acquisition of a very limited number of MGEs and mutations, and that the use of many classes of antimicrobials may co-select for the spread and emergence of MDR and XDR strains. Antimicrobial stewardship will need to be comprehensive, encompassing human medicine and veterinary disciplines to successfully preserve antimicrobial efficacy. PMID- 25527275 TI - Connecting cognition and consumer choice. AB - We describe what can be gained from connecting cognition and consumer choice by discussing two contexts ripe for interaction between the two fields. The first context effects on choice-has already been addressed by cognitive science yielding insights about cognitive process but there is promise for more interaction. The second is learning and representation in choice where relevant theories in cognitive science could be informed by consumer choice, and in return, could pose and answer new questions. We conclude by discussing how these two fields of research stand to benefit from more interaction, citing examples of how interfaces of cognitive science with other fields have been illuminating for theories of cognition. PMID- 25527274 TI - Cancer progression by breast tumors with Pit-1-overexpression is blocked by inhibition of metalloproteinase (MMP)-13. AB - INTRODUCTION: The POU class 1 homeobox 1 transcription factor (POU1F1, also known as Pit-1) is expressed in the mammary gland and its overexpression induces profound phenotypic changes in proteins involved in cell proliferation, apoptosis, and invasion. Patients with breast cancer and elevated expression of Pit-1 show a positive correlation with the occurrence of distant metastasis. In this study we evaluate the relationship between Pit-1 and two collagenases: matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-13 (MMP-13), which have been related to metastasis in breast cancer. METHODS: We began by transfecting the MCF-7 and MDA-MB-231 human breast adenocarcinoma cell lines with the Pit-1 overexpression vector (pRSV-hPit-1). Afterward, the mRNA, protein, and transcriptional regulation of both MMP-1 and MMP-13 were evaluated by real-time PCR, Western blot, chromatin immunoprecipitation (ChIP), and luciferase reporter assays. We also evaluated Pit-1 overexpression with MMP-1 and MMP-13 knockdown in a severe combined immunodeficiency (SCID) mouse tumor xenograft model. Finally, by immunohistochemistry we correlated Pit-1 with MMP-1 and MMP-13 protein expression in 110 human breast tumors samples. RESULTS: Our data show that Pit-1 increases mRNA and protein of both MMP-1 and MMP-13 through direct transcriptional regulation. In SCID mice, knockdown of MMP-13 completely blocked lung metastasis in Pit-1-overexpressing MCF-7 cells injected into the mammary fat pad. In breast cancer patients, expression of Pit-1 was found to be positively correlated with the presence of both MMP-1 and MMP-13. CONCLUSIONS: Our data indicates that Pit-1 regulates MMP-1 and MMP-13, and that inhibition of MMP-13 blocked invasiveness to lung in Pit-1-overexpressed breast cancer cells. PMID- 25527276 TI - Clinical efficacy of 9-oxo-10, 11-dehydroageraphorone extracted from Eupatorium adenophorum against Psoroptes cuniculi in rabbits. AB - BACKGROUND: Animal acariasis is one of the important veterinary skin diseases. Chemical drugs have been widely used to treat and control this kind of disease. But many chemicals control could increase resistance in target species, toxicity and environmental hazards. We found that the 9-oxo-10, 11-dehydroageraphorone (euptox A) extracted from E. adenophorum has strong toxicity against P. cuniculi in vitro, but the in vivo acaricidal actions of euptox A have yet to be investigated. RESULTS: A 14-day experiment was performed using rabbits that were naturally infested with P. cuniculi on a farm. Rabbits were randomly divided into five groups; animals in groups A, B and C were treated in each ear topically with 4.0 ml of 2.0 and 1.0 g/L (w/v) euptox A, respectively. Animals in groups D and E were treated with ivermectin (by injection; positive controls) and glycerol with water only (by embrocation; negative controls), respectively. Each rabbit was treated twice with separate treatments on days 0 and 7. Rabbits were observed daily and detailed examinations were performed on days 0, 7 and 14, to inspect the presence or absence of mites and scabs/crusts. Seven days after the initial treatment, the mean clinical scores (presence of scabs/crusts) decreased from 3.48, 3.37, 3.43 and 3.45 to 0.37, 0.42, 0.78 and 0.38 in the ears of animals in groups A, B , C and D, respectively, which were similar to the observations recorded in the positive control rabbits. However, the clinical score for negative control rabbits did not increase significantly (P > 0.05) during the experiment, and this changed from 3.32 to 3.37 in the ears, and there were no significant differences in clinical efficacy between left and right ears. After two treatments (0 and 7 d), the rabbits in groups A, B, C and D had recovered completely 14 days after the last treatment and no recurrences of infection were observed. CONCLUSIONS: These results indicate that euptox A was potent compounds for the effective control of animal P. cuniculi in vivo. PMID- 25527278 TI - Validity and reliability of OIDP and OHIP-14: a survey of Chinese high school students. AB - BACKGROUND: To determine the impact of oral diseases on everyday life, measures of oral quality of life are needed. In complementing traditional disease-based measures, they assess the need for oral care to evaluate oral health care programs and management of treatment. To assess the reliability and validity of the Oral Impact of Daily Performance (OIDP) and the short-form Oral Health Impact Profile (OHIP-14) among high school students in Xi'an, the capital of Shanxi province, China. METHODS: Cross-sectional one-stage stratified random cluster sample using high schools as the primary sampling unit. Students completed self administered questionnaires at school. The survey included the OHIP-14 and OIDP inventories, translated and culturally adapted for China, and global oral health and socio-behavioral measures. RESULTS: A total of 5,608 students participated in the study, with a 93% response rate (mean age 17.2, SD 0.8, 52% females, 45.3% urban residents).The proportion experiencing at least one impact (at any frequency) during the previous six months was 62.9% for the OHIP-14 and 45.8% for the OIDP. Cronbach's alpha measured internal consistency at 0.85 for OHIP-14 and 0.75 for OIDP while Cohen's kappa varied between 0.27 and 0.58 for OHIP-14 items and between 0.23 and 0.65 for OIDP items. Kappa scores for the OHIP-14 and OIDP additive scores were 0.52 and 0.66, respectively. Both measures varied systematically and in the expected direction, with global oral health measures showing criterion validity. The correlation between OIDP and OHIP-14 was rs +0.65. That both measures varied systematically with socio-behavioral factors indicates construct validity. CONCLUSION: Both the OIDP and OHIP-14 inventories had reasonable reliability and construct validity in relation to subjective global oral health indicators among adolescents attending high schools in China and thus appear to be useful oral health -related quality of life measures in this context. Overall, the OHIP-14 and OIDP performed equally well, although OHIP 14 had superior content validity due to its sensitivity towards less severe impacts. PMID- 25527277 TI - Alpha-galactosylceramide enhances protective immunity induced by DNA vaccine of the SAG5D gene of Toxoplasma gondii. AB - BACKGROUND: Toxoplasmosis caused by the intracellular parasite Toxoplasma gondii (T. gondii) is a global epidemic parasitic disease. DNA vaccines play an important role in preventing the spread of toxoplasmosis. SAG family genes encoding particular surface proteins of T. gondii are the best candidates of DNA vaccine. As a member of SAG family genes, SAG5 gene has been proved to have better antigenic than SAG1. In addition, alpha-Galactosylceramide (alpha-GalCer) was used to be an adjuvant in malaria vaccine and received positive results. In this study, the effect of the DNA vaccine enhanced by alpha-GalCer was evaluated by immunizing BALB/c mice. METHODS: In the present study, SAG5D gene of T. gondii was cloned, sequenced, and biologically characterized. BALB/c mice were randomly divided into five groups, including three experimental groups (pEGFP-C1-SAG5D, alpha-GalCer and alpha-GalCer/pEGFP-C1-SAG5D) and two control groups (PBS and pEGFP-C1), and were immunized intramuscularly three times. The levels of IgG antibodies and cytokine productions in mouse sera were determined by enzyme linked immunosorbent assays (ELISA). Two weeks after the last immunization, all mice were challenged intraperitoneally with 1 * 10(4) tachyzoites of T. gondii and the survival time of mice was recorded. RESULTS: A significant level of increase of IgG response against the soluble tachyzoite antigens (STAg) was detected by ELISA in experimental group. It revealed relatively high level of IFN gamma production by the spleen cells. There were higher productions of interleukin-4 (IL-4) in alpha-GalCer treated groups compared to control groups. Challenge experiment showed a longer survival period (11 days compared with 5 days in control) in SAG5D DNA vaccinated mice was found after a lethal challenge with T. gondii RH strain. CONCLUSIONS: The present study suggested that T. gondii SAG5D was a novel and positive DNA vaccine candidate against toxoplasmosis. In addition, the adjuvant (alpha-GalCer) enhanced the body's cellular immune response and prolonged the survival time of mice after challenge. PMID- 25527280 TI - Differentiating left ventricular hypertrophy in athletes from that in patients with hypertrophic cardiomyopathy. PMID- 25527279 TI - Inherited 15q24 microdeletion syndrome in twins and their father with phenotypic variability. AB - BACKGROUND: Deletions including chromosome 15q24 have been delineated in recent years as a separate syndrome with phenotypic variability. Here we report a familial 15q24 deletion and further contribute to the phenotypic description of this syndrome. METHODS: Molecular karyotyping and description of the phenotype of three patients in the same family with a 15q24 deletion. RESULTS: Parental transmission of the 15q24 deletion syndrome is described in the same family. The affected, the father and his twin offspring, all exhibit the typical facial features, signs and symptoms consistent with the syndromic phenotype. A distinct phenotypic variability is nevertheless noted although they all share the same deletion. CONCLUSIONS: These three patients are to our knowledge the first described cases of 15q24 syndrome in the same family. Urogenital malformations have previously been described as a part of this syndrome. Our adult male patient exhibits no such malformations but has a documented reduced fertility. This fact points to other factors such as haploinsufficiency of one and/or further genes on 15q24 as being responsible for the infertility. Array analysis could be considered as a first hand analysis in the investigation of cases of infertility and intellectual deficiency in adults in analogy to the existing consensus regarding cases of intellectual deficiency in children. PMID- 25527281 TI - Age as a factor to predict postpericardiotomy syndrome. PMID- 25527282 TI - Meta-analysis on risk of bleeding with apixaban in patients with renal impairment. AB - Apixaban is a novel oral anticoagulant which is approved for the management of atrial fibrillation and venous thromboembolism prophylaxis. There have been concerns regarding bleeding risks with apixaban in patients with renal impairment. We performed a systematic review and meta-analysis to evaluate the risk of bleeding with apixaban in these patients. Relevant studies were identified through electronic literature searches of MEDLINE, EMBASE, Cochrane library, and clinicaltrials.gov (from inception to February 24, 2014). Phase III randomized controlled trials that compared apixaban with conventional agents (vitamin K antagonist and/or warfarin, low molecular weight heparin, aspirin, and placebo) were included. We defined mild renal impairment as creatinine clearance of 50 to 80 ml/min and moderate to severe renal impairment as creatinine clearance <50 ml/min. Study-specific risk ratios were calculated, and between study heterogeneity was assessed using the I(2) statistics. In 6 trials involving 40,145 patients, the risk of bleeding with apixaban in patients with mild renal impairment was significantly less (risk ratio 0.80, 95% confidence interval 0.66 to 0.96, I(2) = 13%) compared with conventional anticoagulants. In patients with moderate to severe renal impairment, the risk of bleeding with was found to be similar (risk ratio 1.01, 95% confidence interval 0.49 to 2.10, I(2) = 72%). In conclusion, compared with the conventional agents, bleeding risk with apixaban in patients with mild and moderate to severe renal insufficiency is lower and similar, respectively. PMID- 25527283 TI - Sociodemographic factors associated with the use of mental health services in depressed adults: results from the Korea National Health and Nutrition Examination Survey (KNHANES). AB - BACKGROUND: The aims of this study were to determine the utilization of mental health services (MHSs) by adults with a depressive mood and to identify the influencing sociodemographic factors, using a nationwide representative Korean sample. METHODS: The study included 2735 subjects, aged 19 years or older, who had experienced a depressive mood continuously for over 2 weeks within the previous year, using the data from the KNHANES IV (Fourth Korea National Health and Nutrition Examination Survey), which was performed between 2007 and 2009, and involved a nationally representative sample of the Korean community population who were visited at home. A multivariate logistic regression analysis was used to estimate the adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for the use of MHSs, which was defined as using healthcare institutions, consulting services, and inpatient or outpatient treatments due to mental health problems. RESULTS: MHSs had been used by 9.6% of the subjects with a depressive mood. The use of the MHSs was significantly associated with age, education level, and employment status, after adjusting for sociodemographic and health-related factors. Specifically, the OR for the nonuse of MHSs by the elderly (>=65 years) relative to subjects aged 19-34 years was 2.55 (95% CI = 1.13-5.76), subjects with a lower education level were less likely to use MHSs compared to those with a higher education level (7-9 years, OR = 2.35, 95% CI = 1.19-4.64; 10-12 years, OR = 1.66, 95% CI = 1.07-2.56; >=13 years, reference), and the OR of unemployed relative to employed was 0.47 (95% CI = 0.32-0.67). CONCLUSIONS: Among Korean adults with a depressive mood, the elderly, those with a lower education level, and the employed are less likely to use MHSs. These findings suggest that mental health policies should be made based on the characteristics of the population in order to reduce untreated patients with depression. Greater resources and attention to identifying and treating depression in older, less educated, and employed adults are warranted. PMID- 25527284 TI - N-Hydroxyphthalimide catalyzed allylic oxidation of steroids with t-butyl hydroperoxide. AB - A new and optimized procedure for the allylic oxidation of Delta(5)-steroids with t-butyl hydroperoxide in the presence of catalytic amounts of N hydroxyphthalimide (NHPI) under mild conditions was developed, showing excellent regioselectivity and chemoselectivity (functional group compatibility). It was found that Co(OAc)2 could enhance the catalytic ability of NHPI resulting in better yields and shorter reaction times. The reaction mechanism and the scope of the reaction with a variety of Delta(5)-steroidal substrates were also investigated. PMID- 25527285 TI - Neuropeptide receptors NPR-1 and NPR-2 regulate Caenorhabditis elegans avoidance response to the plant stress hormone methyl salicylate. AB - Methyl salicylate (MeSa) is a stress hormone released by plants under attack by pathogens or herbivores . MeSa has been shown to attract predatory insects of herbivores and repel pests. The molecules and neurons underlying animal response to MeSa are not known. Here we found that the nematode Caenorhabditis elegans exhibits a strong avoidance response to MeSa, which requires the activities of two closely related neuropeptide receptors NPR-1 and NPR-2. Molecular analyses suggest that NPR-1 expressed in the RMG inter/motor neurons is required for MeSa avoidance. An NPR-1 ligand FLP-18 is also required. Using a rescuing npr-2 promoter to drive a GFP transgene, we identified that NPR-2 is expressed in multiple sensory and interneurons. Genetic rescue experiments suggest that NPR-2 expressed in the AIZ interneurons is required for MeSa avoidance. We also provide evidence that the AWB sensory neurons might act upstream of RMGs and AIZs to detect MeSa. Our results suggest that NPR-2 has an important role in regulating animal behavior and that NPR-1 and NPR-2 act on distinct interneurons to affect C. elegans avoidance response to MeSa. PMID- 25527286 TI - Guanine nucleotide exchange factor OSG-1 confers functional aging via dysregulated Rho signaling in Caenorhabditis elegans neurons. AB - Rho signaling regulates a variety of biological processes, but whether it is implicated in aging remains an open question. Here we show that a guanine nucleotide exchange factor of the Dbl family, OSG-1, confers functional aging by dysregulating Rho GTPases activities in C. elegans. Thus, gene reporter analysis revealed widespread OSG-1 expression in muscle and neurons. Loss of OSG-1 gene function was not associated with developmental defects. In contrast, suppression of OSG-1 lessened loss of function (chemotaxis) in ASE sensory neurons subjected to conditions of oxidative stress generated during natural aging, by oxidative challenges, or by genetic mutations. RNAi analysis showed that OSG-1 was specific toward activation of RHO-1 GTPase signaling. RNAi further implicated actin binding proteins ARX-3 and ARX-5, thus the actin cytoskeleton, as one of the targets of OSG-1/RHO-1 signaling. Taken together these data suggest that OSG-1 is recruited under conditions of oxidative stress, a hallmark of aging, and contributes to promote loss of neuronal function by affecting the actin cytoskeleton via altered RHO-1 activity. PMID- 25527287 TI - R/qtlcharts: interactive graphics for quantitative trait locus mapping. AB - Every data visualization can be improved with some level of interactivity. Interactive graphics hold particular promise for the exploration of high dimensional data. R/qtlcharts is an R package to create interactive graphics for experiments to map quantitative trait loci (QTL) (genetic loci that influence quantitative traits). R/qtlcharts serves as a companion to the R/qtl package, providing interactive versions of R/qtl's static graphs, as well as additional interactive graphs for the exploration of high-dimensional genotype and phenotype data. PMID- 25527288 TI - Marker-based estimation of heritability in immortal populations. AB - Heritability is a central parameter in quantitative genetics, from both an evolutionary and a breeding perspective. For plant traits heritability is traditionally estimated by comparing within- and between-genotype variability. This approach estimates broad-sense heritability and does not account for different genetic relatedness. With the availability of high-density markers there is growing interest in marker-based estimates of narrow-sense heritability, using mixed models in which genetic relatedness is estimated from genetic markers. Such estimates have received much attention in human genetics but are rarely reported for plant traits. A major obstacle is that current methodology and software assume a single phenotypic value per genotype, hence requiring genotypic means. An alternative that we propose here is to use mixed models at the individual plant or plot level. Using statistical arguments, simulations, and real data we investigate the feasibility of both approaches and how these affect genomic prediction with the best linear unbiased predictor and genome-wide association studies. Heritability estimates obtained from genotypic means had very large standard errors and were sometimes biologically unrealistic. Mixed models at the individual plant or plot level produced more realistic estimates, and for simulated traits standard errors were up to 13 times smaller. Genomic prediction was also improved by using these mixed models, with up to a 49% increase in accuracy. For genome-wide association studies on simulated traits, the use of individual plant data gave almost no increase in power. The new methodology is applicable to any complex trait where multiple replicates of individual genotypes can be scored. This includes important agronomic crops, as well as bacteria and fungi. PMID- 25527289 TI - Inferring epidemiological dynamics with Bayesian coalescent inference: the merits of deterministic and stochastic models. AB - Estimation of epidemiological and population parameters from molecular sequence data has become central to the understanding of infectious disease dynamics. Various models have been proposed to infer details of the dynamics that describe epidemic progression. These include inference approaches derived from Kingman's coalescent theory. Here, we use recently described coalescent theory for epidemic dynamics to develop stochastic and deterministic coalescent susceptible-infected removed (SIR) tree priors. We implement these in a Bayesian phylogenetic inference framework to permit joint estimation of SIR epidemic parameters and the sample genealogy. We assess the performance of the two coalescent models and also juxtapose results obtained with a recently published birth-death-sampling model for epidemic inference. Comparisons are made by analyzing sets of genealogies simulated under precisely known epidemiological parameters. Additionally, we analyze influenza A (H1N1) sequence data sampled in the Canterbury region of New Zealand and HIV-1 sequence data obtained from known United Kingdom infection clusters. We show that both coalescent SIR models are effective at estimating epidemiological parameters from data with large fundamental reproductive number [Formula: see text] and large population size [Formula: see text]. Furthermore, we find that the stochastic variant generally outperforms its deterministic counterpart in terms of error, bias, and highest posterior density coverage, particularly for smaller [Formula: see text] and [Formula: see text]. However, each of these inference models is shown to have undesirable properties in certain circumstances, especially for epidemic outbreaks with [Formula: see text] close to one or with small effective susceptible populations. PMID- 25527290 TI - Nitrogen starvation and TorC1 inhibition differentially affect nuclear localization of the Gln3 and Gat1 transcription factors through the rare glutamine tRNACUG in Saccharomyces cerevisiae. AB - A leucine, leucyl-tRNA synthetase-dependent pathway activates TorC1 kinase and its downstream stimulation of protein synthesis, a major nitrogen consumer. We previously demonstrated, however, that control of Gln3, a transcription activator of catabolic genes whose products generate the nitrogenous precursors for protein synthesis, is not subject to leucine-dependent TorC1 activation. This led us to conclude that excess nitrogen-dependent down-regulation of Gln3 occurs via a second mechanism that is independent of leucine-dependent TorC1 activation. A major site of Gln3 and Gat1 (another GATA-binding transcription activator) control occurs at their access to the nucleus. In excess nitrogen, Gln3 and Gat1 are sequestered in the cytoplasm in a Ure2-dependent manner. They become nuclear and activate transcription when nitrogen becomes limiting. Long-term nitrogen starvation and treatment of cells with the glutamine synthetase inhibitor methionine sulfoximine (Msx) also elicit nuclear Gln3 localization. The sensitivity of Gln3 localization to glutamine and inhibition of glutamine synthesis prompted us to investigate the effects of a glutamine tRNA mutation (sup70-65) on nitrogen-responsive control of Gln3 and Gat1. We found that nuclear Gln3 localization elicited by short- and long-term nitrogen starvation; growth in a poor, derepressive medium; Msx or rapamycin treatment; or ure2Delta mutation is abolished in a sup70-65 mutant. However, nuclear Gat1 localization, which also exhibits a glutamine tRNACUG requirement for its response to short-term nitrogen starvation or growth in proline medium or a ure2Delta mutation, does not require tRNACUG for its response to rapamycin. Also, in contrast with Gln3, Gat1 localization does not respond to long-term nitrogen starvation. These observations demonstrate the existence of a specific nitrogen-responsive component participating in the control of Gln3 and Gat1 localization and their downstream production of nitrogenous precursors. This component is highly sensitive to the function of the rare glutamine tRNACUG, which cannot be replaced by the predominant glutamine tRNACAA. Our observations also demonstrate distinct mechanistic differences between the responses of Gln3 and Gat1 to rapamycin inhibition of TorC1 and nitrogen starvation. PMID- 25527291 TI - Ubiquitin Ser65 phosphorylation affects ubiquitin structure, chain assembly and hydrolysis. AB - The protein kinase PINK1 was recently shown to phosphorylate ubiquitin (Ub) on Ser65, and phosphoUb activates the E3 ligase Parkin allosterically. Here, we show that PINK1 can phosphorylate every Ub in Ub chains. Moreover, Ser65 phosphorylation alters Ub structure, generating two conformations in solution. A crystal structure of the major conformation resembles Ub but has altered surface properties. NMR reveals a second phosphoUb conformation in which beta5-strand slippage retracts the C-terminal tail by two residues into the Ub core. We further show that phosphoUb has no effect on E1-mediated E2 charging but can affect discharging of E2 enzymes to form polyUb chains. Notably, UBE2R1- (CDC34), UBE2N/UBE2V1- (UBC13/UEV1A), TRAF6- and HOIP-mediated chain assembly is inhibited by phosphoUb. While Lys63-linked poly-phosphoUb is recognized by the TAB2 NZF Ub binding domain (UBD), 10 out of 12 deubiquitinases (DUBs), including USP8, USP15 and USP30, are impaired in hydrolyzing phosphoUb chains. Hence, Ub phosphorylation has repercussions for ubiquitination and deubiquitination cascades beyond Parkin activation and may provide an independent layer of regulation in the Ub system. PMID- 25527292 TI - Tox: a multifunctional transcription factor and novel regulator of mammalian corticogenesis. AB - Major efforts are invested to characterize the factors controlling the proliferation of neural stem cells. During mammalian corticogenesis, our group has identified a small pool of genes that are transiently downregulated in the switch of neural stem cells to neurogenic division and reinduced in newborn neurons. Among these switch genes, we found Tox, a transcription factor with hitherto uncharacterized roles in the nervous system. Here, we investigated the role of Tox in corticogenesis by characterizing its expression at the tissue, cellular and temporal level. We found that Tox is regulated by calcineurin/Nfat signalling. Moreover, we combined DNA adenine methyltransferase identification (DamID) with deep sequencing to characterize the chromatin binding properties of Tox including its motif and downstream transcriptional targets including Sox2, Tbr2, Prox1 and other key factors. Finally, we manipulated Tox in the developing brain and validated its multiple roles in promoting neural stem cell proliferation and neurite outgrowth of newborn neurons. Our data provide a valuable resource to study the role of Tox in other tissues and highlight a novel key player in brain development. PMID- 25527296 TI - Decision-making under risk and ambiguity in low-birth-weight pigs. AB - Low birth weight (LBW) in humans is a risk factor for later cognitive, behavioural and emotional problems. In pigs, LBW is associated with higher mortality, but little is known about consequences for surviving piglets. Alteration in hypothalamic-pituitary-adrenal axis function in LBW pigs suggests altered emotionality, but no behavioural indicators have been studied. Decision making under uncertain conditions, e.g., risk or ambiguity, is susceptible to emotional influences and may provide a means of assessing long-term effects of LBW in piglets. We tested LBW (N = 8) and normal-birth-weight (NBW; N = 8) male pigs in two decision-making tasks. For decision-making under risk, we developed a simple two-choice probabilistic task, the Pig Gambling Task (PGT), where an 'advantageous' option offered small but frequent rewards and a 'disadvantageous' option offered large but infrequent rewards. The advantageous option offered greater overall gain. For decision-making under ambiguity, we used a Judgement Bias Task (JBT) where pigs were trained to make an active response to 'positive' and 'negative' tone cues (signalling large and small rewards, respectively). Responses to ambiguous tone cues were rated as more or less optimistic. LBW pigs chose the advantageous option more often in later blocks of the PGT, and were scored as less optimistic in the JBT, than NBW pigs. Our findings demonstrate that LBW pigs have developed different behavioural strategies with respect to decision-making. We propose that this is guided by changes in emotionality in LBW piglets, and we provide behavioural evidence of increased negative affect in LBW piglets. PMID- 25527293 TI - Specific but interdependent functions for Arabidopsis AGO4 and AGO6 in RNA directed DNA methylation. AB - Argonaute (AGO) family proteins are conserved key components of small RNA-induced silencing pathways. In the RNA-directed DNA methylation (RdDM) pathway in Arabidopsis, AGO6 is generally considered to be redundant with AGO4. In this report, our comprehensive, genomewide analyses of AGO4- and AGO6-dependent DNA methylation revealed that redundancy is unexpectedly negligible in the genetic interactions between AGO4 and AGO6. Immunofluorescence revealed that AGO4 and AGO6 differ in their subnuclear co-localization with RNA polymerases required for RdDM. Pol II and AGO6 are absent from perinucleolar foci, where Pol V and AGO4 are co-localized. In the nucleoplasm, AGO4 displays a strong co-localization with Pol II, whereas AGO6 co-localizes with Pol V. These patterns suggest that RdDM is mediated by distinct, spatially regulated combinations of AGO proteins and RNA polymerases. Consistently, Pol II physically interacts with AGO4 but not AGO6, and the levels of Pol V-dependent scaffold RNAs and Pol V chromatin occupancy are strongly correlated with AGO6 but not AGO4. Our results suggest that AGO4 and AGO6 mainly act sequentially in mediating small RNA-directed DNA methylation. PMID- 25527295 TI - Efficacy and tolerability of fixed-combination bimatoprost/timolol versus fixed combination dorzolamide/brimonidine/timolol in patients with primary open-angle glaucoma or ocular hypertension: a multicenter, prospective, crossover study. AB - BACKGROUND: Fixed-combination ocular hypotensives have multiple advantages, but triple-therapy dorzolamide/brimonidine/timolol (dorz/brim/tim) is only available in Latin and South America, and information on its relative efficacy is limited. This study compares the efficacy and tolerability of fixed-combination bimatoprost/timolol (bim/tim) and dorz/brim/tim in Mexican patients with primary open-angle glaucoma or ocular hypertension. METHODS: In this investigator-masked, crossover study, patients with unmet target intraocular pressure (IOP) on once daily bim/tim or twice-daily dorz/brim/tim received the opposite medication for 3 months before returning to their pre-baseline medication for 3 months. IOP was evaluated before and after morning instillation at months 2, 3, 5 and 6. Primary endpoints were mean IOP change and Ocular Surface Disease Index(c) (OSDI) score at each visit. The intent-to-treat population was the a priori analysis population, but due to the number of discontinuations, the per-protocol and intent-to-treat populations were used for the primary efficacy and sensitivity analyses, respectively. RESULTS: Seventy-eight and 56 patients were included in the intent-to-treat and per-protocol populations, respectively. At month 3, statistically significant IOP reductions from baseline were observed in the bim/tim (P < 0.01) and dorz/brim/tim (P < 0.0001) groups, regardless of assessment time. At month 6, patients returned to bim/tim exhibited no significant IOP increase (regardless of assessment time), but patients returned to dorz/brim/tim exhibited a statistically significant IOP increase (P < 0.001) when assessed before instillation of study treatment. Results were similar in both intent-to-treat and per-protocol analysis populations. In the per-protocol analysis, 70% of patients on bim/tim at month 3 had an IOP <14 mm Hg, which declined to 58% (P = 0.0061) at month 6 (ie, after 3 months of dorz/brim/tim treatment). In patients receiving dorz/brim/tim at month 3, 38% had an IOP <14 mm Hg, which remained comparable after return to bim/tim. OSDI scores and incidence of adverse events were similar in both groups. CONCLUSIONS: In this first direct comparison of the efficacy of dorz/brim/tim and bim/tim, patients switched from dorz/brim/tim to bim/tim demonstrated improved/lower IOP; when returned to dorz/brim/tim, IOP increased to levels seen at study initiation, suggesting that once-daily bim/tim may have greater IOP-lowering efficacy. Both bim/tim and dorz/brim/tim were well tolerated with minimal ocular surface damage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01737853 (registered October 9, 2012). PMID- 25527294 TI - Antifungal innate immunity: recognition and inflammatory networks. AB - A large variety of fungi are present in the environment, among which a proportion colonizes the human body, usually without causing any harm. However, depending on the host immune status, commensals can become opportunistic pathogens that induce diseases ranging from superficial non-harmful infection to life-threatening systemic disease. The interplay between the host and the fungal commensal flora is being orchestrated by an efficient recognition of the microorganisms, which in turn ensures a proper balance between tolerance of the normal fungal flora and induction of immune defense mechanisms when invasion occurs. Pattern recognition receptors (PRRs) play a significant role in maintaining this balance due to their capacity to sense fungi and induce host responses such as the induction of proinflammatory cytokines involved in the activation of innate and adaptive immune responses. In the present review, we will discuss the most recent findings regarding the recognition of Candida albicans and Aspergillus fumigatus and the different types of immune cells that play a role in antifungal host defense. PMID- 25527297 TI - Mosquito control pesticides and sea surface temperatures have differential effects on the survival and oxidative stress response of coral larvae. AB - The declining health of coral reefs is intensifying worldwide at an alarming rate due to the combined effects of land-based sources of pollution and climate change. Despite the persistent use of mosquito control pesticides in populated coastal areas, studies examining the survival and physiological impacts of early life-history stages of non-targeted marine organisms are limited. In order to better understand the combined effects of mosquito pesticides and rising sea surface temperatures, we exposed larvae from the coral Porites astreoides to selected concentrations of two major mosquito pesticide ingredients, naled and permethrin, and seawater elevated +3.5 degrees C. Following 18-20 h of exposure, larvae exposed to naled concentrations of 2.96 ug L(-1) or greater had significantly reduced survivorship compared to controls. These effects were not detected in the presence of permethrin or elevated temperature. Furthermore, larval settlement, post-settlement survival and zooxanthellae density were not impacted by any treatment. To evaluate the sub-lethal stress response of larvae, several oxidative stress endpoints were utilized. Biomarker responses to pesticide exposure were variable and contingent upon pesticide type as well as the specific biomarker being employed. In some cases, such as with protein carbonylation and catalase gene expression, the effects of naled exposure and temperature were interactive. In other cases pesticide exposure failed to induce any sub-lethal stress response. Overall, these results demonstrate that P. astreoides larvae have a moderate degree of resistance against short-term exposure to ecologically relevant concentrations of pesticides even in the presence of elevated temperature. In addition, this work highlights the importance of considering the complexity and differential responses encountered when examining the impacts of combined stressors that occur on varying spatial scales. PMID- 25527298 TI - Maternal offloading of organochlorine contaminants in the yolk-sac placental scalloped hammerhead shark (Sphyrna lewini). AB - Elasmobranchs are a group of animals that typically occupy upper trophic levels in food webs and have a propensity to accumulate high contaminant concentrations. To date, few studies have investigated maternal offloading processes in sharks, despite the fact that this process represents a substantial source of exposure for young sharks and is a significant pathway for contaminant redistribution within marine ecosystems. Comparable to mammalian systems, scalloped hammerhead sharks (Sphyrna lewini) utilize a yolk-sac placental strategy to nourish young in utero, which may allow females to transfer contaminants to young. Organic contaminants (PCBs and chlorinated pesticides) were measured in livers of both females and males from several age classes that were collected from U.S. Atlantic waters, including two near-term pregnant females and their embryos. Adult female hammerheads (n = 3) were found to have lower levels of PCBs compared to the younger, adult male (mean +/- SD, 11.1 +/- 1.0 vs. 22.8 MUg g(-1) lw), but had substantially higher concentrations of pesticides (4.1 +/- 0.9 vs. 1.9 MUg g(-1) lw). Embryos from the two litters (n = 36) had similar levels of summed organic contaminant concentrations (4.6 +/- 0.9 MUg g(-1) lw) and pregnant females were estimated to offload approximately 0.03-2.3% of their hepatic contaminant load to offspring. While the potential health impacts of these transferred contaminants is unknown, this is the first study to demonstrate that scalloped hammerheads are exposed to a substantial amount of contaminants prior to birth and document maternal offloading of organochlorines in a pseudo-placental shark species. Therefore, future research should continue to investigate the potential adverse effects these contaminants have on elasmobranch physiology. PMID- 25527299 TI - [The Midfoot Fusion Bolt: a new perspective?]. AB - BACKGROUND: There is no current guideline nor consensus regarding optimal surgical treatment of the midfoot Charcot. Due to the vast diversity of locations, it is difficult to make a general statement. Various different types of screws and plates are currently being used since they have been tested and declared to be most stable. The Midfoot Fusion Bolt is a new device which needs approval since long-term results are lacking. A short summary of currently published papers and results from our own institution are provided. OBJECTIVES: The aim of this study was to investigate short-term results including complications and review published surveys. METHODS: The Midfoot Fusion Bolt is a solid, intramedullary screw. An antegrade as well as a retrograde technique are postulated for insertion. A total of 16 patients/17 feet in two specialized foot and ankle centers were included. BMI, HbA1c, satisfaction rates, complication rates, and expert opinions were recorded. RESULTS: The bolts were used an average of 21.17 months (range 3-55 months) in 16 patients/17 feet. Between 2009 and 2014, six bolts had to be removed. We encountered 4 cases of postoperative ulceration: 2 cases healed postoperatively, while the other 2 cases led to amputation. The average fusion rate was 92.35 %. CONCLUSION: The Midfoot Fusion Bolt is no longer advised for single-device use only since there have been issues in terms of insufficient stability. However, stable conditions could be achieved with additional screws or plates, respectively. Prospective studies and biomechanical testing for general conclusions are still required to make a meaningful assessment. PMID- 25527300 TI - [Wrist arthroscopy : challenging procedure of modern hand surgery]. AB - Arthroscopy of the wrist has developed in the shadow of arthroscopy of the large joints. Nowadays, wrist arthroscopy has a relevant importance in the diagnostics and therapy in hand surgery and is indispensable for serious surgery of the wrist. Special equipment and extensive knowledge of the surgeon are necessary for carrying out the procedure. PMID- 25527301 TI - Fishtail deformity--a delayed complication of distal humeral fractures in children. AB - BACKGROUND: Concavity in the central portion of the distal humerus is referred to as fishtail deformity. This entity is a rare complication of distal humeral fractures in children. OBJECTIVE: The purpose of this study is to describe imaging features of post-traumatic fishtail deformity and discuss the pathophysiology. MATERIALS AND METHODS: We conducted a retrospective analysis of seven cases of fishtail deformity after distal humeral fractures. RESULTS: Seven children ages 7-14 years (five boys, two girls) presented with elbow pain and history of distal humeral fracture. Four of the seven children had limited range of motion. Five children had prior grade 3 supracondylar fracture treated with closed reduction and percutaneous pinning. One child had a medial condylar fracture and another had a lateral condylar fracture; both had been treated with conservative casting. All children had radiographs, five had CT and three had MRI. All children had a concave central defect in the distal humerus. Other imaging features included joint space narrowing with osteophytes and subchondral cystic changes in four children, synovitis in one, hypertrophy or subluxation of the radial head in three and proximal migration of the ulna in two. CONCLUSION: Fishtail deformity of the distal humerus is a rare complication of distal humeral fractures in children. This entity is infrequently reported in the radiology literature. Awareness of the classic imaging features can result in earlier diagnosis and appropriate treatment. PMID- 25527302 TI - CT chest under general anesthesia: pulmonary, anesthetic and radiologic dilemmas. PMID- 25527304 TI - Paretic hand unimanual force control: Improved submaximal force production and regularity. AB - The purpose was to investigate force control capabilities in paretic hands during unimanual movements after coupled bimanual movement training and neuromuscular stimulation on impaired muscles. Nineteen chronic stroke participants completed 90 min of rehabilitation per week for six consecutive weeks. Before and after training, volunteers performed unimanual submaximal force control tasks at 5% and 50% of maximum voluntary contraction with their paretic and non-paretic hands. Force control measures included submaximal force production, force variability, accuracy, and regularity. Two major findings on paretic hands after training revealed: (a) greater submaximal force production across force levels and (b) less regular force outputs. Paretic hand control improved after coupled bimanual movement training as evidenced by submaximal force production and force regularity. PMID- 25527303 TI - Cognitive function in a general population of men and women: a cross sectional study in the European Investigation of Cancer-Norfolk cohort (EPIC-Norfolk). AB - BACKGROUND: Although ageing is strongly associated with cognitive decline, a wide range of cognitive ability is observed in older populations with varying rates of change across different cognitive domains. METHODS: Cognitive function was measured as part of the third health examination of the European Prospective Investigation of Cancer in Norfolk (EPIC-Norfolk 3) between 2006 and 2011 (including measures from the pilot phase from 2004 to 2006). This was done using a battery consisting of seven previously validated cognitive function tests assessing both global function and specific domains. The battery included a shortened version of the Extended Mental State Exam (SF-EMSE); letter cancellation task; Hopkins Verbal Learning Test (HVLT); Cambridge Neuropsychological Test Automated Battery Paired Associates Learning Test (CANTAB PAL); Visual Sensitivity Test (VST); Shortened version of the National Adult Reading Test (Short-NART) and a task to test for prospective memory. We report the distribution of cognitive function in different cognitive domains by age and sex and compare the utility of a number of assessment tests in a general population of older men and women. RESULTS: Cognitive test data were available for 8585 men and women taking part in EPIC-Norfolk 3. Increasing age was generally associated with declining mean cognitive function, but there was a wide range observed within each age group as well as variability across different cognitive domains. Some sex differences were also observed. CONCLUSION: Descriptive data are presented for this general population sample of older men and women. There is a wide range of cognitive performance seen in this population. Though average performance declines with age, there is large individual variability across different cognitive domains. These variations may provide insights into the determinants of cognitive function in later life. PMID- 25527305 TI - Munch's SCREAM: A spontaneous movement by zebrafish larvae featuring strong abduction of both pectoral fins often associated with a sudden bend. AB - Stereotyped movement of paired pectoral fins in zebrafish larvae could be considered a simple model with which to investigate the neural basis of behavior. Using a high-speed camera, we explored the repertoire of pectoral fin movements by naturally behaving larvae at 5-6 days post-fertilization. Previously, two types of fin movements were characterized in association with locomotion: 'CRAWLing,' an alternating fin movement associated with slow swimming, and 'TUCKing,' the adduction of both fins associated with fast swimming. We here describe a third mode of fin movement, which we call 'Munch's SCREAM', in which both pectoral fins were flipped anteriorly so that they reached the skin on the sides of the head, thus covering the otic vesicles. This behavior occurred spontaneously and was often associated with a slight regression or a sudden bending and change in body orientation. It could be also induced effectively in the agarose-embedded larvae by tactile stimulation on the skin around the eye and nose, some of which are associated with struggling, in which waves of bending propagate from the tail to the head. Larvae can still CRAWL and perform the SCREAM even when their forebrain and midbrain have been removed, suggesting that the neural circuits involved in the SCREAM are present in the hindbrain and/or spinal cord. PMID- 25527306 TI - Regulatory role of BMP-9 in steroidogenesis by rat ovarian granulosa cells. AB - BMPs expressed in the ovary differentially regulate steroidogenesis by granulosa cells. BMP-9, a circulating BMP, is associated with cell proliferation, apoptosis and differentiation in various tissues. However, the effects of BMP-9 on ovarian function have yet to be elucidated. Here we investigated BMP-9 actions on steroidogenesis using rat primary granulosa cells. BMP-9 potently suppressed FSH induced progesterone production, whereas it did not affect FSH-induced estradiol production by granulosa cells. The effects of BMP-9 on FSH-induced steroidogenesis were not influenced by the presence of oocytes. FSH-induced cAMP synthesis and FSH-induced mRNA expression of steroidogenic factors, including StAR, P450scc, 3betaHSD2 and FSHR, were suppressed by treatment with BMP-9. BMP-9 mRNA expression was detected in granulosa cells but not in oocytes. BMP-9 readily activated Smad1/5/8 phosphorylation and Id-1 transcription in granulosa cells. Analysis using ALK inhibitors indicated that BMP-9 actions were mediated via type I receptors other than ALK-2, -3 and -6. Furthermore, experiments using extracellular domains (ECDs) for BMP type-I and -II receptor constructs revealed that the effects of BMP-9 were reversed by ECDs for ALK-1 and BMPRII. Thus, the functional receptors for BMP-9 in granulosa cells were most likely to be the complex of ALK-1 and BMPRII. Collectively, the results of the present study showed that BMP-9 can affect luteinization and that there are two possible sources of BMP-9, serum and granulosa cells in the ovary. PMID- 25527307 TI - Cerebral venous sinus thrombosis due to spontaneous, progressive, and retrograde jugular vein thrombosis causing sudden death in a young woman. AB - Cerebral venous sinus thrombosis (CVST) is a rare cerebrovascular condition that affects approximately 5 per 1 million people annually, and develops in 0.5% of all stroke patients. Herein we report a case involving a 31-year-old woman with CVST. She initially presented with a 2-month history of intermittent headaches at the nape of her neck with cervical pain. Other than these symptoms, she was in apparently good health and was a nonsmoker. She had no children and did not take contraceptives. She became comatose with unequal pupil size and CVST was diagnosed. An autopsy revealed CVST that extended from the confluence of the sinuses to the transverse sinuses and tip of the superior sagittal sinus, as well as a thrombus that obstructed the right internal jugular vein. A correct and early diagnosis of CVST combined with heparin-based therapy and/or interventional endovascular strategies may be of benefit by preventing intracerebral extension of jugular venous thrombosis and subsequent serious or even fatal neurological sequelae. PMID- 25527309 TI - Whither biomechanics. PMID- 25527308 TI - Splitting hairs: differentiating between entomological activity, taphonomy, and sharp force trauma on hair. AB - PURPOSE: The analysis of hair can provide useful information for the correct evaluation of forensic cases, but studies of trauma on hair are extremely rare. Hair may present lesions caused by traumatic events or by animals: in fact, signs of sharp force weapons on hair may provide important information for the reconstruction of the manner of death, and, for example, may suggest fetishist practice. This study stemmed from a judicial case where it was fundamental to distinguish between sharp force lesions and insect activity on hair. METHODS: In order to highlight differences between sharp force lesions and insect feeding activity, different experiments were performed with high power microscopy: hair samples were subjected to several lesions by blunt and sharp force trauma; then samples were used as pabulum for two taxa of insects: the common clothes moth (Tineola bisselliella Lepidoptera, Tineidae) and the carpet beetle (Anthrenus sp., Coleoptera, Dermestidae). Hairs were examined from a macroscopic and microscopic point of view by stereomicroscopy and scanning electron microscopy (SEM): the morphological characteristics of the lesions obtained from the different experimental samples were compared. RESULTS: Results show that sharp force trauma produces lesions with regular edges, whereas insects leave concave lesions caused by their "gnawing" activity. These two types of lesions are easily distinguishable from breaking and tearing using SEM. CONCLUSIONS: This study demonstrates that insect activity leaves very specific indications on hair and sheds some light on different hair lesions that may be found in forensic cases. PMID- 25527310 TI - Causal diagrams and multivariate analysis III: confound it! AB - This commentary concludes my series concerning inclusion of variables in multivariate analyses. We take up the issues of confounding and effect modification and summarize the work we have thus far done. Finally, we provide a rough algorithm to help guide us through the maze of possibilities that we have outlined. PMID- 25527311 TI - Image quality and dose distributions of three linac-based imaging modalities. AB - BACKGROUND AND PURPOSE: Linac-based patient imaging is possible with a variety of techniques using different photon energies. The purpose of this work is to compare three imaging systems operating at 6 MV, flattening free filter (FFF) 1 MV, and 121 kV. PATIENTS AND METHODS: The dose distributions of all pretreatment set-up images (over 1,000) were retrospectively calculated on the planning computed tomography (CT) images for all patients with prostate and head-and-neck cancer treated at our institution in 2013. We analyzed the dose distribution and the dose to organs at risk. RESULTS: For head-and-neck cancer patients, the imaging dose from 6-MV cone beam CT (CBCT) reached maximum values at around 8 cGy. The 1-MV CBCT dose was about 63-79 % of the 6-MV CBCT dose for all organs at risk. Planar imaging reduced the imaging dose from CBCT to 30-40 % for both megavoltage modalities. The dose from the kilovoltage CBCT was 4-10 % of the 6-MV CBCT dose. For prostate cancer patients, the maximum dose from 6-MV CBCT reached 13-15 cGy, and was reduced to 66-73 % for 1 MV. Planar imaging reduces the MV CBCT dose to 10-20 %. The kV CBCT dose is 15-20 % of the 6-MV CBCT dose, slightly higher than the dose from MV axes. The dose distributions differ markedly in response to the different beam profiles and dose-depth characteristics. PMID- 25527313 TI - Scent and synaesthesia: The medical use of spice bags in early China. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The history of Chinese spices has received increasing attention in recent years, but little research been carried out on where they fit on the food-medicine continuum for early China, during the formation of the classical medical system. This paper describes how the synaesthetic qualities of spices attracted a particular analysis in that emerging system which serves to mark them as different to other medical materials and foodstuffs. We aim to clarify the special role created for spices to accommodate their boundary-crossing synaesthetic action on the body. MATERIAL AND METHODS: This paper analyses the contents of several spice bags excavated in 1972 from a tomb that was closed in the second century BCE. It uses archaeological reports of material culture together with the early Chinese textual record, extant in both manuscripts and received texts, to bring out the role of spices in ritual, food and medicine. RESULTS: Noting that the flavours and aromas of early China were assigned physiological potency in the first centuries BCE, we argue that by medieval times the unique synaesthetic role that spices played in mediating the senses was systematically medicalised. While being deployed for the purpose of curing disease in medicine, they also remained within the realm of everyday healthcare, and religious practice, deployed both as aromatics to perfume the environment, attracting benign spirits, but also to ward off the agents of disease, as well as for enhancing health through their use in cookery. CONCLUSION: While foodstuffs entered the digestive system spices were all considered 'pungent' in the emerging clasical medical system. They acted on the body through the nose and lungs, making them neither food nor drug. This implicit categorisation medicalised spices which, like music, could affect the passions and lighten the spirit, codifying observations about the impact on the body of the ritual environment. PMID- 25527312 TI - The pearl millet mitogen-activated protein kinase PgMPK4 is involved in responses to downy mildew infection and in jasmonic- and salicylic acid-mediated defense. AB - Plant mitogen-activated protein kinases (MPKs) transduce signals required for the induction of immunity triggered by host recognition of pathogen-associated molecular patterns. We isolated a full-length cDNA of a group B MPK (PgMPK4) from pearl millet. Autophosphorylation assay of recombinant PgMPK4 produced in Escherichia coli confirmed it as a kinase. Differential accumulation of PgMPK4 mRNA and kinase activity was observed between pearl millet cultivars 852B and IP18292 in response to inoculation with the downy mildew oomycete pathogen Sclerospora graminicola. This increased accumulation of PgMPK4 mRNA, kinase activity as well as nuclear-localization of PgMPK protein(s) was only detected in the S. graminicola resistant cultivar IP18292 with a ~tenfold peak at 9 h post inoculation. In the susceptible cultivar 852B, PgMPK4 mRNA and immuno-detectable nuclear PgMPK could be induced by application of the chemical elicitor beta-amino butyric acid, the non-pathogenic bacteria Pseudomonas fluorescens, or by the phytohormones jasmonic acid (JA) or salicylic acid (SA). Furthermore, kinase inhibitor treatments indicated that PgMPK4 is involved in the JA- and SA-mediated expression of three defense genes, lipoxygenase, catalase 3 and polygalacturonase inhibitor protein. These findings indicate that PgMPK/s contribute to pearl millet defense against the downy mildew pathogen by activating the expression of defense proteins. PMID- 25527314 TI - Demographic and medication characteristics of traditional Chinese medicine users among dementia patients in Taiwan: a nationwide database study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Few studies have reported on the utilization of traditional Chinese medicine (TCM) among dementia patients. The aim of the present study is to analyze factors associated with TCM users in the dementia populations and to investigate the medical conditions related to TCM visits. MATERIALS AND METHODS: A total of 18,141 dementia patients were screened from the one million sample of the National Health Insurance Research Database. The dementia patients were then divided into TCM users and non-TCM users according to their medical records between 1997 and 2008. Demographic characteristics included gender, age, insured amount, and geographic location and medical conditions including comorbidity diseases, behavioral and psychological symptoms, and anti dementia medication were also investigated. Their tendency of TCM usage was investigated using a multivariate logistic regression. RESULTS: In Taiwan, 43.3% dementia patients had sought TCM treatments. The inclination of TCM usage was inversely proportional to age; the younger and early-onset dementia (age less than 55 years) patients constituted the high usage group. Female, living in central Taiwan, and higher insured amount were also associated with higher tendency of TCM use. Multilevel Poisson regression analysis showed that the Adjust odds ratios (OR) of TCM use were 1.80 (95% CI=1.68-1.94), 2.52 (95% CI=2.30-2.76), and 3.41 (95% CI=3.01-3.86) for those with one, two, three or more behavioral and psychological symptoms of dementia (BPSD), respectively compared with dementia sufferers without BPSD. In addition, polypharmacy led to higher utilization of TCM (one type: Adjust OR=1.41, 95% CI=1.28-1.56, two types: Adjust OR=1.97, 95% CI=1.63-2.00; three or more types: Adjust OR=2.95, 95% CI=2.27 2.78). More than 70% TCM visits were treated with Chinese herbal remedies, while others used acupuncture and manipulative therapies. Qi-Ju-Di-Huang-Wan (9.7%) was the most frequently prescribed formula, followed by Jia-Wei-Xiao-Yao-San and Ban Xia-Bai-Zhu-Tian-Ma-Tang. CONCLUSION: More than 40% of the dementia patients in Taiwan used TCM. Young-onset dementia, higher number of BPSD, multiple chronic diseases, and polypharmacy were independent predictors for dementia patients seeking TCM medical advice. On the basis of the current findings, additional clinical or epidemiologic study on the prescription patterns of TCM in dementia treatment, or the herb-drug interaction and safety issue can be conducted. PMID- 25527315 TI - Herbal medicine in the Marquesas Islands. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This manuscript reports data on medicinal plants used in Marquesas Islands traditional medicine. The subject is interesting due to the extreme geographical isolation of this archipelago and the scarcity of data on this subject. The hypothesis of the authors was that traditional knowledge in this area should be consequently largely preserved. The usual ethnobotanical collection of use/symptom was completed by an additional quantitative ethnobotany analysis providing two indices: the relative frequency of plant uses for a given affliction (RF) and the Informant Consensus Factor (ICF). MATERIALS AND METHODS: Our ethnopharmacological study was carried out between 2009 and 2012 in several parts of the archipelago by collecting the accurate names of the medicinal plants, their uses, the methods of preparation of the remedies and the associated traditional nosology. Two methods were applied: ex situ focus groups with scientists and local association partners, using fresh plant specimens, dried specimens, and photographs, guided by an outline of simple questions, and in situ semi-structured interviews of informants during walk in the woods or homegarden sampling. RESULTS: 96 plant species were pointed out as medicine for which we collected 1774 use reports; 77 of these species cited by more than 1 informant are listed with their frequency of use. Three species account for one-third of use reports: Cocos nucifera (coconut), Gardenia taitensis (tiare Tahiti) and Microsorum grossum. Native species (either indigenous or endemic) represent only one quarter of all used species. The Polynesian introductions (plants introduced during Polynesian migrations) represent 42% of the Marquesan medicinal plants. On the other hand, one-third are modern introductions, introduced, for most of them, less than 200 years ago. Diseases are analyzed according to Marquesan concepts. In the present study, a special attention was focused on the descriptions of the local diseases. Their translation in French was discussed and verified in focus groups involving both scientists and Marquesan language specialists from the "Academie des Marquises". 40 plant species showed a high frequency of citation for a given affliction (RF>20). Despite the complex nosology the ICF to Marquesan traditional illness categories showed generally high ICF values, suggesting their strong coherence. CONCLUSIONS: An overview of the Marquesan pharmacopoeia, linked with ethnomedicinal practices, is presented in this paper. Marquesan traditional medicine survived until now despite the culture shock faced by the Marquesan population switching to numerous introduced plants commonly found in their close environment and easily gathered. Marquesan herbal medicine appears to draw its inspiration from a common Polynesian root. However further investigations on Marquesan nosologies are necessary to appreciate the originality of the Marquesan pharmacopoeia. Finally, the crossing of ICF and RF indices shows that 36 species have at least one significant use (frequencies>20%) with high ICF value (>0.5). This suggests that some key phytochemical ingredients may be present in these plants which require further phytopharmacological studies to a better knowledge of their medicinal properties. PMID- 25527316 TI - Effect of the aqueous extract of Senecio biafrae (Oliv. & Hiern) J. Moore on some fertility parameters in immature female rat. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Senecio biafrae is a plant from the huge family of Asteraceae used in the African pharmacopoeia for the treatment of many ailments among which is infertility. MATERIAL AND METHODS: The aqueous extract, which was primarily subjected to polyphenol analysis, has been administered to immature female rats for 20 days at 8, 32, 64 and 128 mg/kg of body weight. The day following the treatment, the animals were sacrificed; their serum, ovary and uterus were retained respectively for reproductive hormones, ovarian and uterine proteins, and ovarian cholesterol assays. RESULTS: Light body weight gain variation of treated animals was observed during the experimental period. A significant increase (p ? 0.05) in serum estradiol and proteins as well as in uterine weight (p ? 0.01) of all Senecio biafrae treated animals was noted. No significant variation was noticed in the ovarian weight and follicle numbers. CONCLUSION: The various biochemical and physiological parameters of fertility were significantly improved with the aqueous extract of Senecio biafrae, thus attesting some of its traditional usage. PMID- 25527317 TI - The binucleate cell of okapi and giraffe placenta shows distinctive glycosylation compared with other ruminants: a lectin histochemical study. AB - The placenta of ruminants contains characteristic binucleate cells (BNC) with a highly conserved glycan structure which evolved early in Ruminant phylogenesis. Giraffe and Okapi placentae also contain these cells and it is not known whether they have a similar glycan array. We have used lectin histochemistry to examine the glycosylation of these cells in these species and compare them with bovine BNC which have a typical ruminant glycan composition. Two placentae, mid and near term, from Giraffe (Giraffa camelopardalis) and two term placenta of Okapi (Okapia johnstoni) were embedded in resin and stained with a panel of 23 lectins and compared with near-term bovine (Bos taurus) placenta. Significant differences were found in the glycans of Giraffe and Okapi BNC compared with those from the bovine, with little or no expression of terminal alphaN-acetylgalactosamine bound by Dolichos biflorus and Vicia villosa agglutinins which instead bound to placental blood vessels. Higher levels of N-acetylglucosamine bound by Lycopersicon esculentum and Phytolacca americana agglutinins were also apparent. Some differences between Okapi and Giraffe were evident. Most N-linked glycans were similarly expressed in all three species as were fucosyl residues. Interplacentomal areas in Giraffe and Bovine showed differences from the placentomal cells though no intercotyledonary BNC were apparent in Okapi. In conclusion, Giraffidae BNC developed different glycan biosynthetic pathways following their split from the Bovidae with further differences evolving as Okapi and Giraffe diverged from each other, affecting both inter and placentomal BNC which may have different functions during development. PMID- 25527318 TI - An Energetic Model of Low Frequency Isometric Neuromuscular Electrical Stimulation. AB - The objective of this study was to evaluate whether an adapted Hill-type model of muscle energetics could account for the relatively high energy turnover observed during low frequency isometric Neuromuscular Electrical Stimulation (NMES). A previously validated Hill-based model was adapted to estimate the energy consumption due to muscle activation, force maintenance and internal shortening of the muscle during isometric NMES. Quadriceps muscle model parameters were identified for 10 healthy subjects based on the experimentally measured torque response to isometric stimulation at 8 Hz. Model predictions of torque and energy consumption rates across the stimulation range 1-12 Hz were compared with experimental data recorded from the same subjects. The model provided estimates in close agreement with the experimental values for the group mean energy consumption rate across the frequency range tested, (R adj (2) = 0.98), although prediction of individual data points for all frequencies and all subjects was more variable, (R adj (2) = 0.70). The model suggests that approximately one third of the energy between 4 and 6 Hz is due to shortening heat. The model provides a means of identifying optimal therapeutic stimulation patterns for sustained incremental oxygen uptake at minimum torque output for a given muscle and provides insight into the energetic components involved. PMID- 25527319 TI - Analysis of Low Density Lipoprotein (LDL) Transport Within a Curved Artery. AB - To elucidate the mechanism of the effect of LDL concentration on the thickening of intima in a curved artery, LDL transport in each layer of the curved arterial wall is studied analytically. A comprehensive concentration distribution expression of LDL in each layer of the curved artery wall is presented along with the characterization and estimation of the effect of curvature on the growth of atherosclerosis within the arterial wall. The effect of curvature on species concentration distribution is analyzed and the results are thoroughly benchmarked against prior pertinent works. The concentration at the interface of lumen and endothelium will directly affect the concentration profile inside the arterial wall layers. The results show that the average concentration in the circumferential direction is actually decreasing in the axial direction for a curved artery compared with a straight artery. Small radius ratio and Reynolds number will augment the LDL accumulation at the lumen endothelium interface. The increase in concentration at the lumen/endothelium interface in the axial direction has a minor effect on the concentration profile at the other wall interface layers. PMID- 25527321 TI - The evolution of computational hemodynamics as a clinical tool in decision making, patient specific treatment and clinical management. PMID- 25527320 TI - Progression of abdominal aortic aneurysm towards rupture: refining clinical risk assessment using a fully coupled fluid-structure interaction method. AB - Rupture of abdominal aortic aneurysm (AAA) is associated with high mortality rates. Risk of rupture is multi-factorial involving AAA geometric configuration, vessel tortuosity, and the presence of intraluminal pathology. Fluid structure interaction (FSI) simulations were conducted in patient based computed tomography scans reconstructed geometries in order to monitor aneurysmal disease progression from normal aortas to non-ruptured and contained ruptured AAA (rAAA), and the AAA risk of rupture was assessed. Three groups of 8 subjects each were studied: 8 normal and 16 pathological (8 non-ruptured and 8 rAAA). The AAA anatomical structures segmented included the blood lumen, intraluminal thrombus (ILT), vessel wall, and embedded calcifications. The vessel wall was described with anisotropic material model that was matched to experimental measurements of AAA tissue specimens. A statistical model for estimating the local wall strength distribution was employed to generate a map of a rupture potential index (RPI), representing the ratio between the local stress and local strength distribution. The FSI simulations followed a clear trend of increasing wall stresses from normal to pathological cases. The maximal stresses were observed in the areas where the ILT was not present, indicating a potential protective effect of the ILT. Statistically significant differences were observed between the peak systolic stress and the peak stress at the mean arterial pressure between the three groups. For the ruptured aneurysms, where the geometry of intact aneurysm was reconstructed, results of the FSI simulations clearly depicted maximum wall stress at the a priori known location of rupture. The RPI mapping indicated several distinct regions of high RPI coinciding with the actual location of rupture. The FSI methodology demonstrates that the aneurysmal disease can be described by numerical simulations, as indicated by a clear trend of increasing aortic wall stresses in the studied groups, (normal aortas, AAAs and rAAAs). Ultimately, the results demonstrate that FSI wall stress mapping and RPI can be used as a tool for predicting the potential rupture of an AAA by predicting the actual rupture location, complementing current clinical practice by offering a predictive diagnostic tool for deciding whether to intervene surgically or spare the patient from an unnecessary risky operation. PMID- 25527322 TI - Engineered Fibrin Gels for Parallel Stimulation of Mesenchymal Stem Cell Proangiogenic and Osteogenic Potential. AB - Mesenchymal stem/stromal cells (MSCs) are under examination for use in cell therapies to repair bone defects resulting from trauma or disease. MSCs secrete proangiogenic cues and can be induced to differentiate into bone-forming osteoblasts, yet there is limited evidence that these events can be achieved in parallel. Manipulation of the cell delivery vehicle properties represents a candidate approach for directing MSC function in bone healing. We hypothesized that the biophysical properties of a fibrin gel could simultaneously regulate the proangiogenic and osteogenic potential of entrapped MSCs. Fibrin gels were formed by supplementation with NaCl (1.2, 2.3, and 3.9% w/v) to modulate gel biophysical properties without altering protein concentrations. MSCs entrapped in 1.2% w/v NaCl gels were the most proangiogenic in vitro, yet cells in 3.9% w/v gels exhibited the greatest osteogenic response. Compared to the other groups, MSCs entrapped in 2.3% w/v gels provided the best balance between proangiogenic potential, osteogenic potential, and gel contractility. The contribution of MSCs to bone repair was then examined when deployed in 2.3% w/v NaCl gels and implanted into an irradiated orthotopic bone defect. Compared to acellular gels after 3 weeks of implantation, defects treated with MSC-loaded fibrin gels exhibited significant increases in vessel density, early osteogenesis, superior morphology, and increased cellularity of repair tissue. Defects treated with MSC loaded gels exhibited increased bone formation after 12 weeks compared to blank gels. These results confirm that fibrin gel properties can be modulated to simultaneously promote both the proangiogenic and osteogenic potential of MSCs, and fibrin gels modified by supplementation with NaCl are promising carriers for MSCs to stimulate bone repair in vivo. PMID- 25527323 TI - Influence of clinical experience of the Macintosh laryngoscope on performance with the Pentax-AWS Airway Scope((r)), a rigid video-laryngoscope, by paramedics in Japan. AB - PURPOSE: We sought to establish the clinical utility of the Pentax-AWS Airway Scope((r)) (AWS) when used by paramedics to intubate the trachea, and to evaluate whether their performance was influenced by previous clinical experience with the Macintosh laryngoscope (ML). METHODS: Twenty paramedics attempted tracheal intubation using the AWS in five patients each in the operating room. We recorded the success rate, the number of intubation attempts, and the time for intubation and adverse events, and compared these based on the paramedics' previous clinical experience with the ML. Ten paramedics had no prior clinical experience of the ML (group A) and 10 had used it on more than 30 occasions (group B). RESULTS: The intubation success rate was 99 % (99/100). Notably, 96 % (47/49) of intubations were achieved on the first attempt by the inexperienced paramedics in group A, compared with 64 % (32/50) by the experienced paramedics in group B (p = 0.0001). The time to intubation (mean +/- SD) was significantly shorter in group A than in group B (37 +/- 24 vs. 48 +/- 21 s, p = 0.002). There were marked variations in the times taken to intubate, but no apparent improvement as the intubators gained experience between their first and fifth cases. No complications were encountered in either group. CONCLUSION: We found that paramedics could achieve a high tracheal intubation success rate using the AWS independent of previous airway management experience. Better intubation performance with the AWS was observed in paramedics without clinical experience with the ML. PMID- 25527324 TI - pH-responsive modulation of insulin aggregation and structural transformation of the aggregates. AB - Over the past two decades, much information has appeared on electrostatically driven molecular mechanisms of protein self-assembly and formation of aggregates of different morphology, varying from soluble amorphous structures to highly ordered amyloid-like fibrils. Protein aggregation represents a special tool in biomedicine and biotechnology to produce biological materials for a wide range of applications. This has awakened interest in identification of pH-triggered regulators of transformation of aggregation-prone proteins into structures of higher order. The objective of the present study is to elucidate the effects of low-molecular-weight biogenic agents on aggregation and formation of supramolecular structures of human recombinant insulin, as a model therapeutic protein. Using dynamic light scattering, turbidimetry, circular dichroism, fluorescence spectroscopy, atomic force microscopy, transmission electron microscopy, and nuclear magnetic resonance, we have demonstrated that the amino acid l-arginine (Arg) has the striking potential to influence insulin aggregation propensity. It was shown that modification of the net charge of insulin induced by changes in the pH level of the incubation medium results in dramatic changes in the interaction of the protein with Arg. We have revealed the dual effects of Arg, highly dependent on the pH level of the solution - suppression or acceleration of the aggregation of insulin at pH 7.0 or 8.0, respectively. These effects can be regulated by manipulating the pH of the environment. The results of this study may be of interest for development of appropriate drug formulations and for the more general insight into the functioning of insulin in living systems, as the protein is known to release by exocytosis from pancreatic beta cells in a pH-dependent manner. PMID- 25527325 TI - Combination of carvacrol and rosiglitazone ameliorates high fat diet induced changes in lipids and inflammatory markers in C57BL/6J mice. AB - Type 2 diabetes mellitus is a chronic metabolic disease with the highest rates of prevalence and mortality worldwide. Hyperlipidemia has been ranked as one of the greatest risk factors. This study was undertaken to evaluate the antihyperlipidemic and anti-inflammatory effect of carvacrol (CVL) and rosiglitazone (RSG) combination on diabetic mice. HFD-induced C57BL/6J diabetic mice showed an elevation in total cholesterol (TC), triglycerides (TG), phospholipids (PL) and free fatty acids (FFA) in plasma and tissues. Further, increased levels of very low density lipoproteins-cholesterol (VLDL-C), low density lipoproteins-cholesterol (LDL-C) and decreased level of high density lipoproteins-cholesterol (HDL-C) were observed in the plasma of diabetic mice. Diabetic mice treated with CVL and RSG significantly modulates all these parameters towards normality. Histopathological analysis of adipose tissues and immunohistochemical analysis of liver tissue for inflammatory cytokines (TNF alpha and IL-6) were in agreement with the biochemical parameters. These findings suggest that combination of CVL and RSG has better antihyperlipidemic and anti inflammatory effect than treatment with individual compound. PMID- 25527326 TI - Optimizing sentinel node identification: a step toward novel tools and improved strategies--exciting times are here! PMID- 25527327 TI - An RNA sequencing transcriptome analysis of the high-temperature stressed tall fescue reveals novel insights into plant thermotolerance. AB - BACKGROUND: Tall fescue (Festuca arundinacea Schreb.) is major cool-season forage and turf grass species worldwide, but high-temperature is a major environmental stress that dramatically threaten forage production and turf management of tall fescue. However, very little is known about the whole-genome molecular mechanisms contributing to thermotolerance. The objectives of this study were to analyzed genome-wide gene expression profiles in the leaves of two tall fescue genotypes, heat tolerant 'PI578718' and heat sensitive 'PI234881' using high-throughput RNA sequencing. RESULTS: A total of 262 million high-quality paired-end reads were generated and assembled into 31,803 unigenes with an average length of 1,840 bp. Of these, 12,974 unigenes showed different expression patterns in response to heat stress and were categorized into 49 Gene Ontology functional subcategories. In addition, the variance of enrichment degree in each functional subcategory between PI578718 and PI234881 increased with increasing treatment time. Cell division and cell cycle genes showed a massive increase in transcript abundance in heat-stressed plants and more activated genes were detected in PI 578718 by Kyoto Encyclopedia of Genes and Genomes pathways analysis. Low molecular weight heat shock protein (LMW-HSP, HSP20) showed activated in two stressed genotypes and high molecular weight HSP (HMW-HSP, HSP90) just in PI578718. Assimilation such as photosynthesis, carbon fixation, CH4, N, S metabolism decreased along with increased dissimilation such as oxidative phosphorylation. CONCLUSIONS: The assembled transcriptome of tall fescue could serve as a global description of expressed genes and provide more molecular resources for future functional characterization analysis of genomics in cool-season turfgrass in response to high-temperature. Increased cell division, LMW/HMW-HSP, dissimilation and antioxidant transcript amounts in tall fescue were correlated with successful resistance to high temperature stress. PMID- 25527328 TI - The effect of the earth's and stray magnetic fields on mobile mass spectrometer systems. AB - Development of small, field-portable mass spectrometers has enabled a rapid growth of in-field measurements on mobile platforms. In such in-field measurements, unexpected signal variability has been observed by the authors in portable ion traps with internal electron ionization. The orientation of magnetic fields (such as the Earth's) relative to the ionization electron beam trajectory can significantly alter the electron flux into a quadrupole ion trap, resulting in significant changes in the instrumental sensitivity. Instrument simulations and experiments were performed relative to the earth's magnetic field to assess the importance of (1) nonpoint-source electron sources, (2) vertical versus horizontal electron beam orientation, and (3) secondary magnetic fields created by the instrument itself. Electron lens focus effects were explored by additional simulations, and were paralleled by experiments performed with a mass spectrometer mounted on a rotating platform. Additionally, magnetically permeable metals were used to shield (1) the entire instrument from the Earth's magnetic field, and (2) the electron beam from both the Earth's and instrument's magnetic fields. Both simulation and experimental results suggest the predominant influence on directionally dependent signal variability is the result of the summation of two magnetic vectors. As such, the most effective method for reducing this effect is the shielding of the electron beam from both magnetic vectors, thus improving electron beam alignment and removing any directional dependency. The improved ionizing electron beam alignment also allows for significant improvements in overall instrument sensitivity. PMID- 25527329 TI - Performance evaluation of a Loeb-Eiber mass filter at 1 Torr. AB - The Loeb-Eiber mass filter is best operated at relatively high pressures-such as 1 Torr-where collisional dampening of ions up to the mass filter thermalizes the ions' kinetic energy, which is a requirement for effective filtering. The inter electrode gaps of ~8 MUm require rf amplitudes on the order of 0-5 V p-p at approximately 50 MHz to achieve mass filtering up to m/z 40. Mass filtering between the 25-MUm diameter wires, therefore, takes place on time frames less than the collision frequency at ~1 Torr. The low power and high pressure capabilities of the Loeb-Eiber mass filter make it ideally suited for miniaturization, where power and space are a premium. In the present work, a Loeb Eiber mass filter was constructed using commercial silicon-on-insulator (SOI) microfabrication techniques. Ions transmitting through the chip-based Loeb-Eiber mass filter were characterized in real time using a traditional linear quadrupole mass analyzer in series with the Loeb-Eiber mass filter. The new hybrid instrument has enabled us to verify several important claims regarding the operation of the Loeb-Eiber mass filter: (1) that ions can be effectively filtered at ~1 Torr, (2) that for ions of a fixed mass-to-charge ratio, the ion transmission current decreases linearly with increasing rf amplitude on the Loeb Eiber mass filter, (3) that the cutoff voltage at which all ions of a particular m/z value are effectively blocked is linearly related to mass-to-charge, and (4) that square waveforms can filter ions more effectively than sinusoidal waveforms for a given peak-to-peak rf amplitude. PMID- 25527330 TI - Binding mode of the oxidized alpha-anomer of NAD+ to RSP, a Rex-family repressor. AB - The Rex-family repressors sense redox levels by alternative binding to NADH or NAD(+). RSP is the homologue of Rex in Thermoanaerobacter ethanolicus JW200(T) and regulates ethanol fermentation in this obligate anaerobe. The dimeric repressor binds to DNA by an open conformation. The crystal structure of RSP/alpha-NAD(+) complex shows a different set of ligand interactions mainly due to the unique configuration of the nicotinamide moiety. The positively charged ring is covered by the Tyr102 side chain and interacts with a sulfate ion adjacent to the N-terminus of helix alpha8. Consequently, the RSP dimer may be locked in a closed conformation that does not bind to DNA. However, alpha-NAD(+) does not show a higher affinity to RSP than beta-NAD(+). It has to be improved for possible use as an effector in modulating the repressor. PMID- 25527331 TI - ATP-binding cassette transporter 1 C69T and V825I polymorphisms in the development of atherosclerosis: a meta-analysis of 18,320 subjects. AB - INTRODUCTION: ATP-binding cassette transporter 1 (ABCA1), a member of the ATP binding cassette family, plays a critical role in the development of atherosclerosis (AS). This meta-analysis was performed to assess the associations of ABCA1 C69T and V825I polymorphisms with AS susceptibility. MATERIALS AND METHODS: A comprehensive search was conducted to identify all eligible studies from PubMed, Embase, Web of Science, Cochrane database, CBMdisc, CNKI and Google Scholar. Additionally, hand searching of the references of identified articles was performed. All statistical analyses were done with Review Manager 5.1.4 and Stata 11.0. RESULTS: Eleven articles involving 14 studies were included in the final meta-analysis. For the ABCA1 C69T polymorphism, six studies involving 1854 AS cases and 5744 controls were combined showing significant association between this variant and AS risk (for T allele vs. C allele: OR =1.44, 95% CI =1.04-1.24, p =0.005; for T/T vs. C/C: OR =1.39, 95% CI =1.12-1.73, p =0.003; for T/T vs. C/T+C/C: OR =1.34, 95% CI =1.09-1.65, p =0.006; for T/T+C/T vs. C/C: OR =1.13, 95% CI =1.01-1.27, p =0.040). For the ABCA1 V825I polymorphism, eight studies involving 2026 AS cases and 8696 controls were combined. There was no significant association between the variant and AS risk (for I allele vs. V allele: OR =1.18, 95% CI =0.90-1.53, p =0.230; for I/I vs. V/V: OR =1.29, 95% CI =0.75-2.23, p =0.360; for I/I vs. V/I+V/V: OR =1.40, 95% CI =0.87-2.26, p =0.160; for I/I+V/I vs. V/V: OR =1.15, 95% CI =1.00-1.33, p =0.060). CONCLUSIONS: This meta-analysis suggested that the ABCA1 C69T polymorphism was associated with an increased AS risk. Furthermore, there was no significant association between the ABCA1 V825I polymorphism and AS risk. PMID- 25527332 TI - The BCR-ABL inhibitor ponatinib inhibits platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling, platelet activation and aggregate formation under shear. AB - BACKGROUND: Treatment of chronic myelogenous leukemia (CML) with the BCR-ABL tyrosine kinase inhibitor (TKI) imatinib significantly improves patient outcomes. As some patients are unresponsive to imatinib, next generation BCR-ABL inhibitors such as nilotinib have been developed to treat patients with imatinib-resistant CML. The use of some BCR-ABL inhibitors has been associated with bleeding diathesis, and these inhibitors have been shown to inhibit platelet functions, which may explain the hemostasis impairment. Surprisingly, a new TKI, ponatinib, has been associated with a high incidence of severe acute ischemic cardiovascular events. The mechanism of this unexpected adverse effect remains undefined. OBJECTIVE AND METHODS: This study used biochemical and functional assays to evaluate whether ponatinib was different from the other BCR-ABL inhibitors with respect to platelet activation, spreading, and aggregation. RESULTS AND CONCLUSIONS: Our results show that ponatinib, similar to other TKIs, acts as a platelet antagonist. Ponatinib inhibited platelet activation, spreading, granule secretion, and aggregation, likely through broad spectrum inhibition of platelet tyrosine kinase signaling, and also inhibited platelet aggregate formation in whole blood under shear. As our results indicate that pobatinib inhibits platelet function, the adverse cardiovascular events observed in patients taking ponatinib may be the result of the effect of ponatinib on other organs or cell types, or disease-specific processes, such as BCR-ABL+cells undergoing apoptosis in response to chemotherapy, or drug-induced adverse effects on the integrity of the vascular endothelium in ponatinib-treated patients. PMID- 25527333 TI - Antiretroviral treatment outcome in HIV-1-infected patients routinely followed up in capital cities and remote areas of Senegal, Mali and Guinea-Conakry. AB - INTRODUCTION: Access to antiretroviral treatment (ART) becomes more and more effective in resource-limited settings (RLS). However, this global effort would be even more profitable if the access to laboratory services especially in decentralized settings was strengthened. We report the virological outcome and HIV-1 drug resistance in three West African countries using dried blood spots (DBS) samples. METHODS: We included HIV-1-infected adults on ART >=6 months and followed up in capital cities and decentralized sites in Senegal, Mali and Guinea Conakry. Patients were consecutively enrolled and DBS were collected in field conditions and kept at ambient temperature before transfer to the reference laboratory. Viral load (VL) was quantified using the NucliSENS EasyQ HIV-1 v1.2. Genotyping of HIV-1 pol gene was performed using in-house protocol. RESULTS: Of the 407 participants, 119, 152 and 136 were from Senegal, Mali and Guinea Conakry, respectively. The median treatment duration was 36 months [IQR: 6-136]. Virological failure (VF) (VL>=3log10 copies/mL) was observed in 26% (95% confidence interval (CI), 18-35; n=31), 11% (95% CI, 6-17; n=16) and 24% (95% CI, 17-32; n=33) of patients in Senegal, Mali and Guinea-Conakry, respectively (p=0.001). Of samples presenting VL>=3log10 copies/mL (n=80), 70 were successfully genotyped. At least one drug resistance mutation (DRM) was detected in the following proportions: 70% (95% CI, 50-86; n=19), 93% (95% CI, 68-100; n=14) and 68% (95% CI, 48-84; n=19) in Senegal, Mali and Guinea-Conakry, respectively (p=0.22). Twenty-six per cent (26%; 95% CI, 16-38; n=18) of patients in VF harboured wild-type viruses, which is likely indicative of weak adherence. Phylogenetic analysis showed the predominance of CRF02_AG subtype (73%; 95% CI, 61-83; n=51). CONCLUSIONS: We describe the ART outcome in capital and rural settings of Senegal, Mali and Guinea-Conakry. Our results in all of the three countries highlight the need to reinforce the ART adherence in order to minimize the occurrence of drug resistance. In addition, these findings provide additional evidence that the use of DBS as a sampling support could assist virological monitoring of patients on ART in remote areas. PMID- 25527334 TI - mRNA and miRNA regulatory networks reflective of multi-walled carbon nanotube induced lung inflammatory and fibrotic pathologies in mice. AB - Multi-walled carbon nanotubes (MWCNTs) are known for their transient inflammatory and progressive fibrotic pulmonary effects; however, the mechanisms underlying these pathologies are unknown. In this study, we used time-series microarray data of global lung mRNA and miRNA expression isolated from C57BL/6J mice exposed by pharyngeal aspiration to vehicle or 10, 20, 40, or 80 ug MWCNT at 1, 7, 28, or 56 days post-exposure to determine miRNA and mRNA regulatory networks that are potentially involved in MWCNT-induced inflammatory and fibrotic lung etiology. Using a non-negative matrix factorization method, we determined mRNAs and miRNAs with expression profiles associated with pathology patterns of MWCNT-induced inflammation (based on bronchoalveolar lavage score) and fibrosis (based on Sirius Red staining measured with quantitative morphometric analysis). Potential binding targets between pathology-related mRNAs and miRNAs were identified using Ingenuity Pathway Analysis and the miRTarBase, miRecords, and TargetScan databases. Using these experimentally validated and predicted binding targets, we were able to build molecular signaling networks that are potentially reflective of and play a role in MWCNT-induced lung inflammatory and fibrotic pathology. As understanding the regulatory networks between mRNAs and miRNAs in different disease states would be beneficial for understanding the complex mechanisms of pathogenesis, these identified genes and pathways may be useful for determining biomarkers of MWCNT-induced lung inflammation and fibrosis for early detection of disease. PMID- 25527336 TI - Accuracy of race, ethnicity, and language preference in an electronic health record. AB - BACKGROUND: Collection of data on race, ethnicity, and language preference is required as part of the "meaningful use" of electronic health records (EHRs). These data serve as a foundation for interventions to reduce health disparities. OBJECTIVE: Our aim was to compare the accuracy of EHR-recorded data on race, ethnicity, and language preference to that reported directly by patients. DESIGN/SUBJECTS/MAIN MEASURES: Data collected as part of a tobacco cessation intervention for minority and low-income smokers across a network of 13 primary care clinics (n = 569). KEY RESULTS: Patients were more likely to self-report Hispanic ethnicity (19.6 % vs. 16.6 %, p < 0.001) and African American race (27.0 % vs. 20.4 %, p < 0.001) than was reported in the EHR. Conversely, patients were less likely to complete the survey in Spanish than the language preference noted in the EHR suggested (5.1 % vs. 6.3 %, p < 0.001). Thirty percent of whites self reported identification with at least one other racial or ethnic group, as did 37.0 % of Hispanics, and 41.0 % of African Americans. Over one-third of EHR documented Spanish speakers elected to take the survey in English. One-fifth of individuals who took the survey in Spanish were recorded in the EHR as English speaking. CONCLUSION: We demonstrate important inaccuracies and the need for better processes to document race/ ethnicity and language preference in EHRs. PMID- 25527337 TI - Repositioning. PMID- 25527335 TI - MicroRNA-122: a novel hepatocyte-enriched in vitro marker of drug-induced cellular toxicity. AB - Emerging hepatic models for the study of drug-induced toxicity include pluripotent stem cell-derived hepatocyte-like cells (HLCs) and complex hepatocyte non-parenchymal cellular coculture to mimic the complex multicellular interactions that recapitulate the niche environment in the human liver. However, a specific marker of hepatocyte perturbation, required to discriminate hepatocyte damage from non-specific cellular toxicity contributed by non-hepatocyte cell types or immature differentiated cells is currently lacking, as the cytotoxicity assays routinely used in in vitro toxicology research depend on intracellular molecules which are ubiquitously present in all eukaryotic cell types. In this study, we demonstrate that microRNA-122 (miR-122) detection in cell culture media can be used as a hepatocyte-enriched in vitro marker of drug-induced toxicity in homogeneous cultures of hepatic cells, and a cell-specific marker of toxicity of hepatic cells in heterogeneous cultures such as HLCs generated from various differentiation protocols and pluripotent stem cell lines, where conventional cytotoxicity assays using generic cellular markers may not be appropriate. We show that the sensitivity of the miR-122 cytotoxicity assay is similar to conventional assays that measure lactate dehydrogenase activity and intracellular adenosine triphosphate when applied in hepatic models with high levels of intracellular miR-122, and can be multiplexed with other assays. MiR-122 as a biomarker also has the potential to bridge results in in vitro experiments to in vivo animal models and human samples using the same assay, and to link findings from clinical studies in determining the relevance of in vitro models being developed for the study of drug-induced liver injury. PMID- 25527339 TI - Leadership development programs for physicians: a systematic review. AB - BACKGROUND: Physician leadership development programs typically aim to strengthen physicians' leadership competencies and improve organizational performance. We conducted a systematic review of medical literature on physician leadership development programs in order to characterize the setting, educational content, teaching methods, and learning outcomes achieved. METHODS: Articles were identified through a search in Ovid MEDLINE from 1950 through November 2013. We included articles that described programs designed to expose physicians to leadership concepts, outlined teaching methods, and reported evaluation outcomes. A thematic analysis was conducted using a structured data entry form with categories for setting/target group, educational content, format, type of evaluation and outcomes. RESULTS: We identified 45 studies that met eligibility criteria, of which 35 reported on programs exclusively targeting physicians. The majority of programs focused on skills training and technical and conceptual knowledge, while fewer programs focused on personal growth and awareness. Half of the studies used pre/post intervention designs, and four studies used a comparison group. Positive outcomes were reported in all studies, although the majority of studies relied on learner satisfaction scores and self-assessed knowledge or behavioral change. Only six studies documented favorable organizational outcomes, such as improvement in quality indicators for disease management. The leadership programs examined in these studies were characterized by the use of multiple learning methods, including lectures, seminars, group work, and action learning projects in multidisciplinary teams. DISCUSSION: Physician leadership development programs are associated with increased self assessed knowledge and expertise; however, few studies have examined outcomes at a system level. Our synthesis of the literature suggests important gaps, including a lack of programs that integrate non-physician and physician professionals, limited use of more interactive learning and feedback to develop greater self-awareness, and an overly narrow focus on individual-level rather than system-level outcomes. PMID- 25527341 TI - Initial management of Parkinson's disease. AB - Parkinson's disease is one of the most common neurodegenerative disorders seen in the United States and United Kingdom. The disease is characterised by two processes-cellular degeneration and the resulting biochemical deficiency of dopamine. Although these processes are inter-related, they are approached separately in the clinical setting. Currently, no proven neuroprotective or disease modifying treatment is available for Parkinson's disease. Several agents can be used to treat the motor symptoms associated with dopamine deficiency, and it is important to choose wisely when starting treatment. Drugs can have mild, moderate, or high potency, and the patient's goals, comorbidities, and the short and long term implications of choosing a specific agent should be taken into account when selecting the appropriate agent. Non-motor symptoms, such as depression, fatigue, and disorders of sleep and wakefulness, also need to be evaluated and treated. Research is under way to deliver dopaminergic therapy more effectively, but studies aimed at slowing or stopping disease progression have not shown promise. PMID- 25527340 TI - Physician burnout: coaching a way out. AB - Twenty-five to sixty percent of physicians report burnout across all specialties. Changes in the healthcare environment have created marked and growing external pressures. In addition, physicians are predisposed to burnout due to internal traits such as compulsiveness, guilt, and self-denial, and a medical culture that emphasizes perfectionism, denial of personal vulnerability, and delayed gratification. Professional coaching, long utilized in the business world, provides a results-oriented and stigma-free method to address burnout, primarily by increasing one's internal locus of control. Coaching enhances self-awareness, drawing on individual strengths, questioning self-defeating thoughts and beliefs, examining new perspectives, and aligning personal values with professional duties. Coaching utilizes established techniques to increase one's sense of accomplishment, purpose, and engagement, all critical in ameliorating burnout. Coaching presumes that the client already possesses strengths and skills to handle life's challenges, but is not accessing them maximally. Although an evidence base is not yet established, the theoretical basis of coaching's efficacy derives from the fields of positive psychology, mindfulness, and self determination theory. Using a case example, this article demonstrates the potential of professional coaching to address physician burnout. PMID- 25527342 TI - Binding of HIV-1 virions to alpha4beta 7 expressing cells and impact of antagonizing alpha4beta 7 on HIV-1 infection of primary CD4+ T cells. AB - HIV-1 envelope glycoprotein is reported to interact with alpha4beta7, an integrin mediating the homing of lymphocytes to gut-associated lymphoid tissue, but the significance of alpha4beta7 in HIV-1 infection remains controversial. Here, using HIV-1 strain BaL, the gp120 of which was previously shown to be capable of interacting with alpha4beta7, we demonstrated that alpha4beta7 can mediate the binding of whole HIV-1 virions to alpha4beta7-expressing transfectants. We further constructed a cell line stably expressing alpha4beta7 and confirmed the alpha4beta7-mediated HIV-1 binding. In primary lymphocytes with activated alpha4beta7 expression, we also observed significant virus binding which can be inhibited by an anti-alpha4beta7 antibody. Moreover, we investigated the impact of antagonizing alpha4beta7 on HIV-1 infection of primary CD4(+) T cells. In alpha4beta7-activated CD4(+) T cells, both anti-alpha4beta7 antibodies and introduction of short-hairpin RNAs specifically targeting alpha4beta7 resulted in a decreased HIV-1 infection. Our findings indicate that alpha4beta7 may serve as an attachment factor at least for some HIV-1 strains. The established approach provides a promising means for the investigation of other viral strains to understand the potential roles of alpha4beta7 in HIV-1 infection. PMID- 25527343 TI - Fluorescent activated cell sorting: an effective approach to study dendritic cell subsets in human atherosclerotic plaques. AB - Different immune cell types are present within atherosclerotic plaques. Dendritic cells (DC) are of special interest, since they are considered as the 'center of the immuniverse'. Identifying inflammatory DC subtypes within plaques is important for a better understanding of the lesion pathogenesis and pinpoints their contribution to the atherosclerotic process. We have developed a flow cytometry-based method to characterize and isolate different DC subsets (i.e. CD11b(+), Clec9A(+) and CD16(+) conventional (c)DC and CD123(+) plasmacytoid (p)DC) in human atherosclerotic plaques. We revealed a predominance of pro inflammatory CD11b(+) DC in advanced human lesions, whereas atheroprotective Clec9A(+) DC were almost absent. CD123(+) pDC and CD16(+) DC were also detectable in plaques. Remarkably, plaques from distinct anatomical locations exhibited different cellular compositions: femoral plaques contained less CD11b(+) and Clec9A(+) DC than carotid plaques. Twice as many monocytes/macrophages were observed compared to DC. Moreover, relative amounts of T cells/B cells/NK cells were 6 times as high as DC numbers. For the first time, fluorescent activated cell sorting analysis of DC subsets in human plaques indicated a predominance of CD11b(+) cDC, in comparison with other DC subsets. Isolation of the different subsets will facilitate detailed functional analysis and may have significant implications for tailoring appropriate therapy. PMID- 25527344 TI - Quantitation of residual trypsin in cell-based therapeutics using immobilized alpha-1-antitrypsin or SBTI in an ELISA format. AB - An Enzyme-Linked Immunosorbent Assay (ELISA) has been developed for the quantitation of porcine trypsin as a process residual in cell therapy products based on its capture by either of two immobilized anti-trypsins, alpha-1 antitrypsin (alpha1AT) or soybean trypsin inhibitor (SBTI) followed by detection with a polyclonal goat anti-porcine trypsin-IgG conjugated with peroxidase. It was demonstrated that an extended range of antigen quantitation could be achieved that covered nearly three orders of magnitude of trypsin concentration. The utility of the assay was demonstrated by its application to samples generated in a cell-based therapeutic manufacturing setting. PMID- 25527345 TI - Specific IgM, IgG and IgG1 directed against Toxoplasma gondii detected by flow cytometry and their potential as serologic tools to support clinical indirect fundoscopic presumed diagnosis of ocular disease. AB - In the present study we evaluated the anti-Toxoplasma gondii immunoglobulin profiles of a group of 118 individuals living in an endemic area. The aim of the study was to select biomarkers to support the ophthalmological diagnosis of retinal/retinochoroidal scars presumably caused by T. gondii infection. Overall anti-T. gondii reactivity of the IgM, IgG, IgA, IgE and IgG subclasses was investigated by flow cytometry-based anti-fixed tachyzoite antibodies (FC-AFTA) in four groups of subjects, referred to as: i) TOXO(L)--seropositive patients with retinal/retinochoroidal scars presumably caused by T. gondii infection; these patients were further subdivided according to morphological aspects of their ocular scar lesions as A, B or C; ii) TOXO(NL)--seropositive patients without ocular scar lesions; iii) NEG(L)--T. gondii seronegative patients presenting retinal lesions; and iv) NEG(NL)--T. gondii seronegative without retinal lesions (negative controls). Our data demonstrated that anti-T. gondii IgG profiles were able to discriminate the mean reactivity of TOXO(L) from all other clinical groups. Analysis of anti-T. gondii immunoglobulin profiles revealed that IgM and IgG were good biomarkers capable of discriminating between individual reactivity in patients with retinal/retinochoroidal scars presumably caused by T. gondii infection [TOXO(L)] from those caused by other clinical conditions. Furthermore, anti-T. gondii IgG1 reactivity was able to discriminate TOXO(L) from all other clinical groups. In conclusion, the pre-selected IgM, IgG and IgG1 anti-T. gondii antibody subclasses were able to segregate both TOXO(L) and the other subgroups, including the scar lesion group types (A, B, C), from other clinical conditions. These results suggest the applicability of this technique in the clinical laboratory to detect putative biomarker for diagnosis of ocular lesions in T. gondii-infected patients. Studies in other areas implementing the methods described in the present study would be of value and enable evaluation of a system for classification of presumed ocular toxoplasmosis scar lesions. This classification would make comparative studies on ocular toxoplasmosis conducted in different regions around the world possible. PMID- 25527347 TI - Stereoisomeric analysis of 6,10,14-trimethylpentadecan-2-ol and the corresponding ketone in wing extracts from African Bicyclus butterfly species. AB - Gas chromatography (GC) and mass spectrometry (MS) were used to determine the stereoisomeric compositions of 6,10,14-trimethylpentadecan-2-ol and 6,10,14 trimethylpentadecan-2-one in wing extracts from 17 Bicyclus butterfly species from different regions of Africa. All samples were purified using solid phase extraction (SPE). Since some species contained both alcohol and ketone, these were separated and the ketone was reduced to the alcohol before analysis as either (R)-trans-chrysanthemoyl or (S)-2-acetoxypropionyl esters. A novel asymmetric synthesis was developed for a reference mixture of (2R/S,6S,10R) 6,10,14-trimethylpentadecan-2-ol with known composition of the eight stereoisomers. The mixture then was used as the (R)-trans-chrysanthemoyl esters to correlate each of the eight gas chromatographic peaks to a specific stereoisomer of the extracted wing compounds. Seven butterfly species showed (2R,6R,10R)-configuration of the alcohol, four species contained minute amounts of alcohol too small to determine the stereochemistry, nine species showed (6R,10R)-configuration of the ketone, and one species contained minute amounts of ketone too small to determine the stereochemistry. No other stereoisomers of alcohol or ketone could be detected in the extracts, and the quantities of the compounds in the wing extracts varied from 5 to 900 ng per sample for each species. PMID- 25527346 TI - Chemical polymorphism in defense secretions during ontogenetic development of the millipede Niponia nodulosa. AB - A mixture of defense compounds (benzaldehyde, benzoyl cyanide, benzoic acid, mandelonitrile, and mandelonitrile benzoate), found commonly in cyanogenic polydesmid millipedes, was identified in the non-cyanogenic millipede Niponia nodulosa. These compounds were major components in 1st-4th instars, but were absent in older instars and adults. Extracts of older instars and adults contained 1-octen-3-ol, 2-methyl-2-bornene, E-2-octen-1-ol, 2-methyl-isoborneol, and geosmin; these compounds were minor components in 1st-4th instars. This ontogenetic allomone shift may be explained by the high cost of biosynthesis of polydesmid compounds from L-phenylalanine being offset by their potency in protecting the insect during fragile and sensitive growth stages. However, as the cuticle hardens in older juveniles (5th, 6th, 7th instars) and adults, this allows for a switch in defense to using less effective and less costly volatile organic compounds (presumably microbial in origin) that are ubiquitous in the millipede's habitat or are produced by symbiotic microbes and may be readily available through food intake or aspiration. PMID- 25527348 TI - Clinical implications of first and multiple locoregional breast cancer recurrences. AB - PURPOSE: Often breast cancer can be treated by breast-conserving surgery (BCS), after which 10 % locoregional recurrences (LRR) occur within 10 years. After BCS mastectomy is recommended at first LRR, although another BCS could be possible. Changes in clinical parameters and in tumor biology from primary breast cancer to first and multiple LRR are described and correlated with further LRR and overall survival (OS). METHODS: 380 patients with >=1 <=3 LRR (1997-2007) were evaluated retrospectively and followed until 5/2009. Patients' age, tumor size, nodal involvement, distant metastases, histological subtype, hormone receptor (HR) and Her-2/neu status were assessed. LRR therapy options were evaluated. RESULTS: 247 patients had one LRR (94 two and 39 three). Mean OS was 10.1 years. Number of LRR was not correlated with OS. Positive HR status was significantly correlated with longer OS. Patients, who changed from primarily ER negative to positive at first LRR had a significantly longer OS compared to those, who remained or changed to ER negative (p < 0.01). Tumor size and grading correlated inversely with OS (both: p < 0.001). BCS at first LRR correlated with a significantly better OS than mastectomy (p < 0.001). LRR cases with chemotherapy had a shorter OS. Irradiation and/or endocrine therapy after LRR were not correlated with OS. CONCLUSIONS: Patients with positive HR status had the best survival data. HR should always be determined. In positive cases, endocrine therapy is recommended. As clinical data are good, BCS at first LRR can be suggested for more patients. PMID- 25527349 TI - Evaluation of Lp-PLA2 mass, vitronectin and PAI-1 activity levels in patients with preeclampsia. AB - PURPOSE: The aim of the current study is to determine, correlate and compare the plasma lipoprotein-associated phospholipase A2 (Lp-PLA2), vitronectin (Vn), Plasminogen activator inhibitor-1 (PAI-1) activity and tissue plasminogen activator (t-PA) levels in early-onset preeclampsia, late-onset preeclampsia and in control pregnant women. METHODS: A total of 79 individuals, 30 early-onsets, and 22 late-onset preeclamptic and 27 control pregnant women were included into the scope of this study. Enzyme-linked immunosorbent assay procedure was used to determine the serum Lp-PLA2 and plasma Vn, t-PA antigen and PAI-1 activity levels. Serum C-reactive protein (CRP) levels were measured immunoturbidimetrically in routine clinical chemistry analyser. RESULTS: In patients with preeclampsia, Lp-PLA2, PAI-1, t-PA, CRP and blood pressures levels were increased (p = 0.000) and correlated with each other. Vn levels were decreased (p = 0.016) but not correlated with other parameters in preeclamptic patients. CONCLUSION: We are of the opinion that increased Lp-PLA2 levels may partially contribute to endothelial dysfunction by the progression of inflammation. In addition, increased complex formation with Vn is likely to bring about the increase of PAI-1 activity in patients with preeclampsia. Moreover, increased t-PA and decreased Vn levels may also be the consequences of compensatory mechanisms against disease progression. PMID- 25527350 TI - Systematic expression analysis of Hox genes at adulthood reveals novel patterns in the central nervous system. AB - Hox proteins are key regulators of animal development, providing positional identity and patterning information to cells along the rostrocaudal axis of the embryo. Although their embryonic expression and function are well characterized, their presence and biological importance in adulthood remains poorly investigated. We provide here the first detailed quantitative and neuroanatomical characterization of the expression of the 39 Hox genes in the adult mouse brain. Using RT-qPCR we determined the expression of 24 Hox genes mainly in the brainstem of the adult brain, with low expression of a few genes in the cerebellum and the forebrain. Using in situ hybridization (ISH) we have demonstrated that expression of Hox genes is maintained in territories derived from the early segmental Hox expression domains in the hindbrain. Indeed, we show that expression of genes belonging to paralogy groups PG2-8 is maintained in the hindbrain derivatives at adulthood. The spatial colinearity, which characterizes the early embryonic expression of Hox genes, is still observed in sequential antero-posterior boundaries of expression. Moreover, the main mossy and climbing fibres precerebellar nuclei express PG2-8 Hox genes according to their migration origins. Second, ISH confirms the presence of Hox gene transcripts in territories where they are not detected during development, suggesting neo-expression in these territories in adulthood. Within the forebrain, we have mapped Hoxb1, Hoxb3, Hoxb4, Hoxd3 and Hoxa5 expression in restricted areas of the sensory cerebral cortices as well as in specific thalamic relay nuclei. Our data thus suggest a requirement of Hox genes beyond their role of patterning genes, providing a new dimension to their functional relevance in the central nervous system. PMID- 25527351 TI - Treatment of feline asthma with ciclosporin in a cat with diabetes mellitus and congestive heart failure. AB - A 5-year-old domestic shorthair cat that had been previously diagnosed with diabetes mellitus was presented for episodes of coughing and respiratory distress. Diagnostic testing revealed congestive heart failure secondary to hypertrophic cardiomyopathy and concurrent asthma. All clinical signs and eosinophilic airway inflammation resolved with oral ciclosporin while the cat was concurrently receiving medications for treatment of heart failure (furosemide and enalapril). Ciclosporin should be considered for treatment of feline asthma in patients with concurrent diseases (eg, diabetes mellitus, severe heart disease) that may contraindicate use of oral glucocorticoid therapy. PMID- 25527352 TI - Participation of childbearing international migrant women in research: the ethical balance. AB - Fear of burdening or harming childbearing, migrant women, particularly refugees or others who have experienced war, torture, abuse, or rape, can result in their exclusion from research. This exclusion prohibits health issues and related solutions to be identified for this population. For this reason, while it may be challenging to include these women in studies, it is ethically problematic not to do so. Using ethical guidelines for research involving humans as a framework, and drawing on our research experiences. This discussion article proposes a number of strategies to improve the conditions for childbearing migrant women to participate in health research. What emerged as key for studying this diverse population and ensuring an ethically responsible approach are the use of methods that are adapted to the circumstances of childbearing migrant women and the involvement and support from "migrant-friendly" organizations. Ensuring migrant women are involved in the research process and knowledge produced is also critical. The more researchers working in this field communicate their experiences, the more will be learnt about how best to approach research with migrants. More migration and health research will enable a greater contribution to the knowledge base upon which the needs of this population can be met and their strengths maximized. PMID- 25527353 TI - Ethical challenges when intensive care unit patients refuse nursing care: A narrative approach. AB - BACKGROUND: Less sedated and more awake patients in the intensive care unit may cause ethical challenges. RESEARCH OBJECTIVES: The purpose of this study is to describe ethical challenges registered nurses experience when patients refuse care and treatment. RESEARCH DESIGN: Narrative individual open interviews were conducted, and data were analysed using a phenomenological hermeneutic method developed for researching life experiences. PARTICIPANTS AND RESEARCH CONTEXT: Three intensive care registered nurses from an intensive care unit at a university hospital in Norway were included. ETHICAL CONSIDERATIONS: Norwegian Social Science Data Services approved the study. Permission was obtained from the intensive care unit leader. The participants' informed and voluntary consent was obtained in writing. FINDINGS: Registered nurses experienced ethical challenges in the balance between situations of deciding on behalf of the patient, persuading the patient and letting the patient decide. Ethical challenges were related to patients being harmful to themselves, not keeping up personal hygiene and care or hindering critical treatment. DISCUSSION: It is made apparent how professional ethics may be threatened by more pragmatic arguments. In recent years, registered nurses are faced with increasing ethical challenges to do no harm and maintain dignity. CONCLUSION: Ethically challenging situations are emerging, due to new targets including conscious and aware critical care patients, leaving an altered responsibility on the registered nurses. Reflection is required to adjust the course when personal and professional ideals no longer are in harmony with the reality in the clinical practice. RNs must maintain a strong integrity as authentic human beings to provide holistic nursing care. PMID- 25527354 TI - Ethics rounds: An appreciated form of ethics support. AB - BACKGROUND: Ethics rounds are one way to support healthcare personnel in handling ethically difficult situations. A previous study in the present project showed that ethics rounds did not result in significant changes in perceptions of how ethical issues were handled, that is, in the ethical climate. However, there was anecdotal evidence that the ethics rounds were viewed as a positive experience and that they stimulated ethical reflection. AIM: The aim of this study was to gain a deeper understanding of how the ethics rounds were experienced and why the intervention in the form of ethics rounds did not succeed in improving the ethical climate for the staff. RESEARCH DESIGN: An exploratory and descriptive design with a qualitative approach was adopted, using individual interviews. PARTICIPANTS AND RESEARCH CONTEXT: A total of 11 healthcare personnel, working in two different psychiatry outpatient clinics and with experience of participating in ethics rounds, were interviewed. ETHICAL CONSIDERATIONS: The study was based on informed consent and was approved by one of the Swedish Regional Ethical Review Boards. FINDINGS: The participants were generally positive about the ethics rounds. They had experienced changes by participating in the ethics rounds in the form of being able to see things from different perspectives as well as by gaining insight into ethical issues. However, these changes had not affected daily work. DISCUSSION: A crucial question is whether or not increased reflection ability among the participants is a good enough outcome of ethics rounds and whether this result could have been measured in patient-related outcomes. Ethics rounds might foster cooperation among the staff and this, in turn, could influence patient care. CONCLUSION: By listening to others during ethics rounds, a person can learn to see things from a new angle. Participation in ethics rounds can also lead to better insight concerning ethical issues. PMID- 25527355 TI - Comparison of professional values between nursing students in Taiwan and China. AB - BACKGROUND: People in both Taiwan and China originally descended from the Han Chinese, but the societies have been separated for approximately 38 years. Due to different political systems, variations exist in healthcare and nursing education systems in Taiwan and China. OBJECTIVE: The purpose of this study was to examine the professional values of nursing students in Taiwan and China. DESIGN: A cross sectional design was applied in this study. The Nursing Professional Value Scale Revised was used to measure the professional values of the students. The questionnaire was distributed to eligible undergraduate students in a classroom setting. ETHICAL CONSIDERATIONS: This study was approved by the Institutional Review Board at the first investigator's university. Participants were informed that completion and return of the questionnaire was voluntary, and confidentiality was ensured by keeping the responses anonymous. PARTICIPANTS: A convenience sample included 292 Taiwanese students and 654 Chinese students. FINDINGS: A total of 11 individual Nursing Professional Value Scale-Revised items showed significant differences between the two groups. These results reflect the differences in the perceived importance of these items between the groups. There was no significant difference between the two groups in the mean overall scores for the Nursing Professional Value Scale-Revised (p = .766) and three subscales (all p > .05). CONCLUSION: There are some differences in professional values between nursing students in Taiwan and China. Given the increasingly frequent and close interactions between Taiwan and China and the globalization of nursing, understanding these differences may help nursing educators identify students' perceptions of their professional values and support the development of strategies to improve weaknesses in professional values. PMID- 25527356 TI - PD-L1 Expression Correlates with Tumor-Infiltrating Lymphocytes and Response to Neoadjuvant Chemotherapy in Breast Cancer. AB - Programmed death 1 ligand 1 (PD-L1) is an immune regulatory molecule that limits antitumor immune activity. Targeting of PD-L1 and other immune checkpoint proteins has shown therapeutic activity in various tumor types. The expression of PD-L1 and its correlation with response to neoadjuvant chemotherapy in breast cancer has not been studied extensively. Our goal was to assess PD-L1 expression in a cohort of breast cancer patients treated with neoadjuvant chemotherapy. Pretreatment biopsies from 105 patients with breast cancer from Yale New Haven Hospital that subsequently received neoadjuvant chemotherapy were assessed for PD L1 protein expression by automated quantitative analysis with a rabbit monoclonal antibody (E1L3N) to the cytoplasmic domain of PD-L1. In addition, tumor infiltrating lymphocytes (TIL) were assessed on hematoxylin and eosin slides. PD L1 expression was observed in 30% of patients, and it was positively associated with hormone-receptor-negative and triple-negative status and high levels of TILs. Both TILs and PD-L1 measured in the epithelium or stroma predicted pathologic complete response (pCR) to neoadjuvant chemotherapy in univariate and multivariate analyses. However, because they are strongly associated, TILs and PD L1 cannot both be included in a significant multivariate model. PD-L1 expression is prevalent in breast cancer, particularly hormone-receptor-negative and triple negative patients, indicating a subset of patients that may benefit from immune therapy. Furthermore, PD-L1 and TILs correlate with pCR, and high PD-L1 predicts pCR in multivariate analysis. PMID- 25527357 TI - B7-H4 expression by nonhematopoietic cells in the tumor microenvironment promotes antitumor immunity. AB - The B7 family plays a critical role in both positive and negative regulation of immune responses by engaging a variety of receptors on lymphocytes. Importantly, blocking coinhibitory molecules using antibodies specific for CTLA-4 and PD-1 enhances tumor immunity in a subset of patients. Therefore, it is critical to understand the role of different B7 family members since they may be suitable therapeutic targets. B7-H4 is another member that inhibits T-cell function, and it is also upregulated on a variety of tumors and has been proposed to promote tumor growth. Here, we investigate the role of B7-H4 in tumor development and show that B7-H4 expression inhibits tumor growth in two mouse models. Furthermore, we show that B7-H4 expression is required for antitumor immune responses in a mouse model of mammary tumorigenesis. We found that the expression levels of B7-H4 correlate with MHC class I expression in both mouse and human samples. We show that IFNgamma upregulates B7-H4 expression on mouse embryo fibroblasts and that the upregulation of B7-H4 on tumors is dependent on T cells. Notably, patients with breast cancer with increased B7-H4 expression show a prolonged time to recurrence. These studies demonstrate a positive role for B7-H4 in promoting antitumor immunity. PMID- 25527359 TI - Prevalence, behavioral manifestations and associated individual and climatic factors of seasonality in the Korean general population. AB - BACKGROUNDS: Seasonality, an individual trait of seasonal variations in mood and behavior, has received clinical attention for its association with mood disorders. This study aimed to explore the prevalence, specific manifestation, and associated individual and climatic factors of seasonality in the non-elderly adult population. METHODS: Five hundred fifty-two participants [male n=220; female n=332; mean age 34.92years, standard deviation (SD) 10.18] with no psychiatric history were recruited from the Seoul metropolitan area (37 degrees 33'58.87"N 126 degrees 58'40.63"E). Seasonality was evaluated using the Seasonal Pattern Assessment Questionnaire. Climatic variables used in analyses were averaged over recent 5years (from 2008 to 2013) on a monthly basis. RESULTS: The mean global seasonality score (GSS) was 5.53 (SD 3.91), and 16.2% (n=89) of participants had seasonal affective disorder (SAD) or sub-SAD. The "feeling worst" month in most of the participants with significant seasonality were winter (41.6%) or summer (38.2%). Socio-demographic factors including age and sex were not related to the seasonality. Decreased sunlight amount and diurnal temperature range in a given and previous month, and increased humidity in a previous month showed significant associations with the percentage of participants with the worst mood. The most frequently reported symptom related to seasonality was 'changes in energy level'. Specific manifestations were not significantly different between the winter type and the summer type. CONCLUSION: The summer and winter type seasonality in the non-clinical adult population did not differ in terms of behavioral manifestations. Decreased sunlight amount, diurnal temperature range, and increased humidity appeared to be major climatic factors associated with seasonality. PMID- 25527358 TI - Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen. AB - The immune-modulating effects of radiotherapy (XRT) have gained considerable interest recently, and there have been multiple reports of synergy between XRT and immunotherapy. However, additional preclinical studies are needed to demonstrate the antigen-specific nature of radiation-induced immune responses and elucidate potential mechanisms of synergy with immunotherapy. Here, we demonstrate the ability of stereotactic XRT to induce endogenous antigen-specific immune responses when it is combined with anti-PD-1 checkpoint blockade immunotherapy. Using the small animal radiation research platform (SARRP), image guided stereotactic XRT delivered to B16-OVA melanoma or 4T1-HA breast carcinoma tumors resulted in the development of antigen-specific T cell- and B cell mediated immune responses. These immune-stimulating effects of XRT were significantly increased when XRT was combined with either anti-PD-1 therapy or regulatory T cell (Treg) depletion, resulting in improved local tumor control. Phenotypic analyses of antigen-specific CD8 T cells revealed that XRT increased the percentage of antigen-experienced T cells and effector memory T cells. Mechanistically, we found that XRT upregulates tumor-associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increases T-cell infiltration into tumors. These findings demonstrate the ability of XRT to prime an endogenous antigen-specific immune response and provide an additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic. PMID- 25527360 TI - Expression of plant ferredoxin-like protein (PFLP) enhances tolerance to heat stress in Arabidopsis thaliana. AB - Under adverse environments, plants produce reactive oxygen species (ROS), which can trigger cell death when their accumulation surpasses the antioxidant capacity of ROS scavenging systems. These systems function in chloroplasts mainly through the ascorbate-mediated water-water cycle, in which ascorbate is photoreduced by ferredoxin in the photosynthetic system. Our previous study showed that the fraction of the reduced form of ascorbate was increased in ferredoxin-transgenic Arabidopsis (CPF) plants which overexpressed plant ferredoxin-like protein (PFLP) in their chloroplasts. Thus, we hypothesized that expression of PFLP could alter the tolerance of plants to abiotic stresses through increasing reduced form of ascorbate. In this study, we found that two CPF lines exhibited lower mortality rates at five days, following two days of heat treatment. Compared to non transgenic wild type (Col-0) plants, CPF plants exhibited decreased H2O2 content, MDA accumulation, and ion leakage after heat treatment. To confirm the efficacy of ferredoxin against heat stress in chloroplasts, we evaluated two RNA interference (RNAi) lines on two endogenous ferredoxin isoforms, Atfd1 or Atfd2, of Arabidopsis plants. Both lines not only decreased their amounts of ascorbate, but also exhibited adverse reactions following heat treatment. Based on these results, we conclude that expression of PFLP in chloroplasts can confer tolerance to heat stress. This tolerance might be associated with the increasing of ascorbate in plants. PMID- 25527362 TI - Application of a bioengineered composite neotrachea in a dog model. AB - BACKGROUND: Surgical treatment of extensive tracheal lesions remains a major challenge because of lack of an ideal airway substitute that is well vascularized, rigid, and autologous. We describe a novel surgical technique of tracheal reconstruction using a combination of a polypropylene mesh material and anterior cervical myocutaneous flap in a dog model. MATERIALS AND METHODS: A 3.5 4 cm length of cervical trachea was resected in 16 dogs and replaced with a myocutaneous cervical neck flap wrapped around the plain polypropylene tube (group 1, n = 7) or wrapped around a composite of polypropylene tube with an implanted Z-type metallic-covered stent (group 2, n = 9). The cervical tracheal defect was repaired with the previously mentioned substitute that was directly sutured to the remaining tracheal ends. Dogs were followed up using bronchoscopy and x-rays and euthanized at predetermined times for histologic examination. RESULTS: In group 1, four dogs died within 2 wk from respiratory failure with varying degrees of airway collapse and difficulties in expectoration. In group 2, eight dogs survived, whereas one died of anastomotic dehiscence 1 wk after surgery. Necropsy and histologic examination of the anastomotic sites revealed good healing tissue. Pathologic examination also revealed excellent healing of the squamous epithelium of the neotrachea and the columnar epithelium of the native tracheal mucosa. CONCLUSIONS: The tissue compatibility of the polypropylene mesh material and anterior cervical myocutaneous skin flap makes this a promising therapeutic substitute for treatment of patients with extensive tracheal lesions. PMID- 25527361 TI - Thrombomodulin improves rat survival after extensive hepatectomy. AB - BACKGROUND: Recombinant human soluble thrombomodulin (rTM) protects against disseminated intravascular coagulopathy by inhibiting coagulation, inflammation, and apoptosis. This study tests the hypothesis that rTM is hepatoprotective after extensive hepatectomy (Hx) and investigates the mechanisms underlying this effect. MATERIALS AND METHODS: Experiment 1: rats (15 per group) were injected with rTM (1.0 or 2.0 mg/kg) or saline just before 95% Hx and their 7-d survival assessed. Experiment 2: rats were assigned to either a treated (2.0 mg/kg rTM just before Hx) or control group (n = 5 per group). Five rats per group were euthanized immediately after surgery, and at 1, 3, 6, 12, and 24 h postoperatively; serum and liver remnant samples were collected for biochemical and histologic analysis, as well as reverse-transcription polymerase chain reaction and Western blotting. RESULTS: All saline-injected rats died within 52 h of Hx, whereas injection of 2.0 mg/kg rTM prolonged survival (P = 0.003). rTM increased the number of Ki67-positive cells and reduced the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. The number of myeloperoxidase-positive cells and the expression of high-mobility group box 1 protein did not differ. Reverse-transcription polymerase chain reaction revealed that rTM significantly enhanced protease-activated receptor-1 and sphingosine kinase 1 messenger RNA expression and significantly reduced plasminogen activator inhibitor-1 and Bax messenger RNA expression. Immunohistochemistry and Western blotting demonstrated that protease-activated receptor-1 expression 24 h after Hx was significantly higher in rTM-treated than in control rats. CONCLUSIONS: rTM may improve survival after extensive Hx by inhibiting apoptosis and promoting liver regeneration. PMID- 25527363 TI - Three-dimensional modeling of the human fallopian tube fimbriae. AB - OBJECTIVE: Ovarian cancer is the most lethal gynecological malignancy that affects women. Recent data suggests that the disease may originate in the fallopian fimbriae; however, the anatomical origin of ovarian carcinogenesis remains unclear. This is largely driven by our lack of knowledge regarding the structure and function of normal fimbriae and the relative paucity of models that accurately recapitulate the in vivo fallopian tube. Therefore, a human three dimensional (3D) culture system was developed to examine the role of the fallopian fimbriae in serous tumorigenesis. METHODS: Alginate matrix was utilized to support human fallopian fimbriae ex vivo. Fimbriae were cultured with factors hypothesized to contribute to carcinogenesis, namely; H2O2 (1mM) a mimetic of oxidative stress, insulin (5MUg/ml) to stimulate glycolysis, and estradiol (E2, 10nM) which peaks before ovulation. Cultures were evaluated for changes in proliferation and p53 expression, criteria utilized to identify potential precursor lesions. Further, secretory factors were assessed after treatment with E2 to identify if steroid signaling induces a pro-tumorigenic microenvironment. RESULTS: 3D fimbriae cultures maintained normal tissue architecture up to 7days, retaining both epithelial subtypes. Treatment of cultures with H2O2 or insulin significantly induced proliferation. However, p53 stabilization was unaffected by any particular treatment, although it was induced by ex vivo culturing. Moreover, E2-alone treatment significantly induced its canonical target PR and expression of IL8, a factor linked to poor outcome. CONCLUSIONS: 3D alginate cultures of human fallopian fimbriae provide an important microphysiological model, which can be further utilized to investigate serous tumorigenesis originating from the fallopian tube. PMID- 25527364 TI - Is the endometrial evaluation routinely required in patients with adult granulosa cell tumors of the ovary? AB - OBJECTIVE: Granulosa cell tumors (GCTs) are the most common estrogen-secreting ovarian tumors; perhaps due to the persistent hyperestrogenism, a wide spectrum of associated endometrial pathologies ranging from endometrial hyperplasia to carcinoma has been documented in patients with GCTs. The aim of this study is to evaluate the incidence of endometrial pathologies in a large series of GCT patients treated in MITO centers. METHODS: A retrospective multi-institutional review of patients with granulosa cell tumors of the ovary treated or referred to MITO centers was conducted. Descriptive statistics were used to characterize the patient population and to assess the association of GCT and endometrial abnormalities at the time of diagnosis; multivariate regression analysis was also performed to identify independent predictors of endometrial abnormalities. RESULTS: A total of 150 patients with primary adult GCT was identified. During the preoperative assessment, endometrial pathology was found in 35.9% of symptomatic patients and in 90.9% of asymptomatic women with endometrial thickening at transvaginal ultrasound. At the time of surgery, hyperplasia was documented in 29.2% of patients, whereas endometrial cancer occurred in 7.5% of patients. Almost all of the patients (97.6%) with endometrial hyperplasia were older than 40years. All patients with endometrial cancer were older than 40years and postmenopausal. CONCLUSIONS: Endometrial carcinoma/atypical hyperplasia were commonly observed in GCT patients >40years; based on these data, endometrial sampling should be performed in symptomatic women at least 40years of age. In asymptomatic women <40years, endometrial sampling is of low yield. PMID- 25527365 TI - Fungal endophyte diversity and bioactivity in the Mediterranean cypress Cupressus sempervirens. AB - Fungal endophytes were isolated from the Mediterranean cypress Cupressus sempervirens. Eleven taxa of fungi, all within the Ascomycota, were identified based on PCR amplification and sequencing of the internal transcribed spacer sequences of nuclear ribosomal DNA (ITS rDNA) with taxonomic identity assigned using the NCBI nucleotide megablast search tool. The endophytic fungi included Alternaria multiformis, Didymella sp., Phoma sp., Phoma herbarum, Pyrenochaeta sp. (Dothideomycetes), Penicillium brevicompactum, Talaromyces sp. (Eurotiomycetes), Ascorhizoctonia sp. (Pezizomycetes), Thielavia microspora, and Thielavia spp. (Sordariomycetes). Considering the former findings in US, this indicates that similar ascomycetous classes of fungi, all from Pezizomycotina, associate with the healthy Cupressaceous trees in Iran. The recovered endophytes produced antifungal and antiproliferative metabolites which may contribute to the protection and survival of the host. We speculate that endophyte-infected C. sempervirens may benefit from their fungal associates by their influence on the ecology and biotic stress tolerance of the host plant. Moreover, a novel niche for the identified fungal species is being introduced. PMID- 25527366 TI - Yeast biogeography and the effects of species recognition approaches: the case study of widespread basidiomycetous species from birch forests in Russia. AB - Understanding diversity and distribution patterns of fungi, including yeasts, ultimately depends on accuracy of species recognition. However, different approaches to yeast species recognition often result in different entities or operational taxonomic units. We studied the effects of using different yeast species recognition approaches, namely morphological species recognition (MSR) and phylogenetic species recognition (PSR), on the distribution patterns of widespread basidiomycetous yeasts. Hence, we have revised a collection of yeast fungi isolated from spatially remote birch forests in the Moscow Region and Western Siberia with molecular typing and identification tools. PCR fingerprinting and rDNA sequencing analyses of strains of nine species previously identified on the basis of morphological and physiological tests (MSR) yielded 21 phylogenetic species (PSR), including three currently undescribed taxa. The number of distinct phylogenetic species comprised within a single morphospecies ranged from one to seven. A total of ten species were found in both regions, whereas the distribution of 11 yeasts was restricted to a single region only. Both geographical region and type of substrate (plant or soil) influence yeast distribution. Cryptococcus wieringae, C. victoriae, C. magnus, and Leucosporidium scottii were frequently found on plant substrates, whereas C. terricola and C. podzolicus were associated to soil substrates. Occurrence of C. magnus, C. albidus and Sporobolomyces roseus was found to depend on the geographical region. Microsatellite-PCR fingerprinting, MSP-PCR, applied to studying yeast intraspecific variability revealed three different types of distribution: (a) variability that depends on geographical factors (Curvibasidium cygneicollum, C. podzolicus, C. victoriae), (b) genetic identity irrespectively of the region of isolation (Rhodotorula pinicola, C. terricola), and (c) high degree of genetic variability that did not correlate with region of sampling (C. albidus and C. magnus). PMID- 25527367 TI - Bilateral thalamic stroke due to nasal ephedrine and naphazoline use. PMID- 25527368 TI - Italian neuropsychology in the second half of the twentieth century. AB - Since the early 1960s, human neuropsychology, the study of brain-behavior interrelations, mainly based on the analysis of their pathological variations, brought about by brain damage, has had a remarkable systematical development in Italy. All this started in Milan, with the neurologist Ennio de Renzi, and his collaborators (Luigi Vignolo, then Anna Basso, Pietro Faglioni, Hans Spinnler, Francois Boller, and, more autonomously, Edoardo Bisiach), in the Clinic of Nervous and Mental Diseases. Scientists of the "Milan group" investigated several neuropsychological deficits caused by focal hemispheric lesions in large series of left- and right-brain-damaged patients, and control participants, comparable for cultural and demographic variables. Standardized tests and advanced statistical methods were used, which also applied to the diagnosis and rehabilitation of aphasia. Subsequently, neuropsychology developed in Italy extensively, reaching high international reputation. Leading neuropsychologists have been the neurologists Guido Gainotti (Rome), and Franco Denes (Padua), the physicians and psychologists Luigi Pizzamiglio (Rome), and Carlo Umilta (Parma, with fruitful interactions with the neurophysiologists Giovanni Berlucchi, Giacomo Rizzolatti, and Carlo Marzi, from the school of Giuseppe Moruzzi in Pisa) A second scientific generation of neuropsychologists has then developed in the 1970s, trained by the abovementioned scientists, further boosting and spreading high-level basic and applied research (diagnosis and rehabilitation of neuropsychological deficits of patients with brain damage or dysfunction throughout the life span, from childhood to the elderly). Available techniques include structural and functional imaging (CT, PET, SPET, MRI and fMRI Scans, DTI), electrophysiological recording (EEG, ERPs), non-invasive brain stimulation (TMS, tES), and their combined use. PMID- 25527370 TI - Plasma fibroblast growth factor 23 and risk of cardiovascular disease: results from the EPIC-Germany case-cohort study. AB - Increased fibroblast growth factor 23 (FGF23) concentrations have emerged as a novel risk factor for heart failure and stroke but not for myocardial infarction (MI). Yet, most studies on MI were conducted in coronary artery disease (CAD) patients and the elderly. Evidence is unclear in subjects without CAD and for stroke subtypes. We investigated the relationships between FGF23 and overall major cardiovascular endpoints, incident MI, ischemic (IS) and haemorrhagic stroke (HS) in middle-aged adults without pre-existing cardiovascular disease. We used a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition-Germany, including a randomly drawn subcohort (n = 1,978), incident MI (n = 463) and stroke cases (n = 359 IS; n = 88 HS) identified during a mean follow-up of 8.2 years. Compared with participants with FGF23 levels in the lowest quartile, those in the highest quartile had a 36% increased risk for cardiovascular events [hazard ratio: 1.36, 95% confidence interval (CI): 1.02-1.82] after adjustment for established cardiovascular risk factors, patahyroid hormone and 25-hydroxyvitamin D3 levels, dietary calcium and phosphorus intake, and kidney function. However, sub-analyses revealed significant relationships with risk of MI and HS, but not IS. Compared with the lowest quartile, individuals in the top two FGF23 quartiles had a 1.62 (95% CI 1.07-2.45) fold increased risk for MI and a 2.61 (95% CI 1.23-5.52) fold increase for HS. Increased FGF23 emerged as a risk factor for both MI and HS. Further studies are warranted to confirm these results and to identify underlying mechanisms. PMID- 25527371 TI - The global impact of non-communicable diseases on households and impoverishment: a systematic review. AB - The global economic impact of non-communicable diseases (NCDs) on household expenditures and poverty indicators remains less well understood. To conduct a systematic review and meta-analysis of the literature evaluating the global economic impact of six NCDs [including coronary heart disease, stroke, type 2 diabetes mellitus (DM), cancer (lung, colon, cervical and breast), chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD)] on households and impoverishment. Medline, Embase and Google Scholar databases were searched from inception to November 6th 2014. To identify additional publications, reference lists of retrieved studies were searched. Randomized controlled trials, systematic reviews, cohorts, case-control, cross-sectional, modeling and ecological studies carried out in adults and assessing the economic consequences of NCDs on households and impoverishment. No language restrictions. All abstract and full text selection was done by two independent reviewers. Data were extracted by two independent reviewers and checked by a third independent reviewer. Studies were included evaluating the impact of at least one of the selected NCDs and on at least one of the following measures: expenditure on medication, transport, co-morbidities, out-of-pocket (OOP) payments or other indirect costs; impoverishment, poverty line and catastrophic spending; household or individual financial cost. From 3,241 references, 64 studies met the inclusion criteria, 75% of which originated from the Americas and Western Pacific WHO region. Breast cancer and DM were the most studied NCDs (42 in total); CKD and COPD were the least represented (five and three studies respectively). OOP payments and financial catastrophe, mostly defined as OOP exceeding a certain proportion of household income, were the most studied outcomes. OOP expenditure as a proportion of family income, ranged between 2 and 158% across the different NCDs and countries. Financial catastrophe due to the selected NCDs was seen in all countries and at all income levels, and occurred in 6-84% of the households depending on the chosen catastrophe threshold. In 16 low- and middle-income countries (LMIC), 6-11% of the total population would be impoverished at a 1.25 US dollar/day poverty line if they would have to purchase lowest price generic diabetes medication. NCDs impose a large and growing global impact on households and impoverishment, in all continents and levels of income. The true extent, however, remains difficult to determine due to the heterogeneity across existing studies in terms of populations studied, outcomes reported and measures employed. The impact that NCDs exert on households and impoverishment is likely to be underestimated since important economic domains, such as coping strategies and the inclusion of marginalized and vulnerable people who do not seek health care due to financial reasons, are overlooked in literature. Given the scarcity of information on specific regions, further research to estimate impact of NCDs on households and impoverishment in LMIC, especially the Middle Eastern, African and Latin American regions is required. PMID- 25527372 TI - Treatment for acute arsine poisoning with blood purification. PMID- 25527373 TI - Response to Grunwell: Dexamethasone pretreatment for 24 h versus 6 h for prevention of postextubation airway obstruction in children. PMID- 25527374 TI - Postoperative pneumonia or ventilator-induced lung injury? PMID- 25527369 TI - The Generation R Study: Biobank update 2015. AB - The Generation R Study is a population-based prospective cohort study from fetal life until adulthood. The study is designed to identify early environmental and genetic causes and causal pathways leading to normal and abnormal growth, development and health from fetal life, childhood and young adulthood. In total, 9,778 mothers were enrolled in the study. Data collection in children and their parents include questionnaires, interviews, detailed physical and ultrasound examinations, behavioural observations, Magnetic Resonance Imaging and biological samples. Efforts have been conducted for collecting biological samples including blood, hair, faeces, nasal swabs, saliva and urine samples and generating genomics data on DNA, RNA and microbiome. In this paper, we give an update of the collection, processing and storage of these biological samples and available measures. Together with detailed phenotype measurements, these biological samples provide a unique resource for epidemiological studies focused on environmental exposures, genetic and genomic determinants and their interactions in relation to growth, health and development from fetal life onwards. PMID- 25527375 TI - The ten diseases that look like ARDS. PMID- 25527376 TI - Postoperative pneumonia or ventilator-induced lung injury? Response to Schultz. PMID- 25527377 TI - Alkane production by the marine cyanobacterium Synechococcus sp. NKBG15041c possessing the alpha-olefin biosynthesis pathway. AB - The production of alkanes in a marine cyanobacterium possessing the alpha-olefin biosynthesis pathway was achieved by introducing an exogenous alkane biosynthesis pathway. Cyanobacterial hydrocarbons are synthesized via two separate pathways: the acyl-acyl carrier protein (ACP) reductase/aldehyde-deformylating oxygenase (AAR/ADO) pathway for the alkane biosynthesis and the alpha-olefin synthase (OLS) pathway for the alpha-olefin biosynthesis. Coexistence of these pathways has not yet been reported. In this study, the marine cyanobacterium Synechococcus sp. NKBG15041c was shown to produce alpha-olefins similar to those of Synechococcus sp. PCC7002 via the alpha-olefin biosynthesis pathway. The production of heptadecane in Synechococcus sp. NKBG15041c was achieved by expressing the AAR/ADO pathway genes from Synechococcus elongatus PCC 7942. The production yields of heptadecane in Synechococcus sp. NKBG15041c varied with the expression level of the aar and ado genes. The maximal yield of heptadecane was 4.2 +/- 1.2 MUg/g of dried cell weight in the transformant carrying a homologous promoter. Our results also suggested that the effective activation of ADO may be more important for the enhancement of alkane production by cyanobacteria. PMID- 25527378 TI - Maintaining confidentiality in qualitative publications. PMID- 25527379 TI - The structural sheath protein of aphids is required for phloem feeding. AB - Aphids produce two types of saliva that mediate their interactions with plants. Watery saliva is secreted during cell penetration and ingestion, whereas gel saliva is secreted during stylet movement through the apoplast where it forms a sheath around the stylet to facilitate penetration and seal puncture sites on cell membranes. In order to study the function of the sheath when aphids interact with plants, we used RNA interference (RNAi) to silence the aphid structural sheath protein (SHP) in the pea aphid Acyrthosiphon pisum. The injection of 50 ng of double stranded RNA completely disrupted sheath formation, as confirmed by scanning electron microscopy. Aphid behavior was monitored using the electrical penetration graph technique, revealing that disrupted sheath formation prevented efficient long-term feeding from sieve tubes, with a silencing effect on reproduction but not survival. We propose that sealing the stylet penetration site in the sieve tube plasma membrane is part of a two-step mechanism to suppress sieve-tube occlusion by preventing calcium influx into the sieve tube lumen. The SHP is present in several aphid species and silencing has a similar impact to aphid-resistant plants, suggesting that SHP is an excellent target for RNAi-mediated pest control. PMID- 25527380 TI - Critical care of sub-lethal irradiated transgenic mice using a complete soft food formula-DietGel76ATM. AB - The objective of this research is to determine whether the administration of a complete soft food formula to sub-lethal irradiated animals from three different transgenic mouse strains over a period of 21 consecutive days will have a significant impact on the clinical signs, and the general survival rate of the animals. Our hypothesis is that using DietGel76ATM, along with an antibiotic treatment, strict handling and manipulation procedures, the general mortality rate, as well as the onset of the clinical signs between the treated animals and the control animals, will be significantly lower. This hypothesis was confirmed for the C57BL/6 mice. However, the treatment with DietGel76ATM had only a very limited impact on the recovery of more irradiation sensitive strains (CD45.1 and mostly NRG). Further studies must be conducted on mice from these strains in order to assess whether mice belonging to more sensitive strains should be on DietGel76ATM for a longer period of time (at least 42days post irradiation). PMID- 25527381 TI - [Otoplasty and quality of life]. AB - The main aim of every aesthetic surgery is to offer patients a subjective benefit. Today, the construct "health-related quality of life" (HRQOL) is considered one of the most important parameters in the evaluation of treatment. Several recent studies using validated tools to measure HRQOL show that otoplasty leads to a significant and long-lasting increase in the HRQOL of children and adults suffering from protruding ears. However, irreversible auricular deformities after failed otoplasty can be more emotionally draining for the patient than the preoperative state. The respective risk is higher when using cartilage rasping or cutting techniques compared with pure suture techniques. PMID- 25527382 TI - [Destructive lesion of the middle ear]. PMID- 25527383 TI - [An alternative to percutaneous bone-anchored hearing systems]. PMID- 25527384 TI - A model of chlorophyll fluorescence in microalgae integrating photoproduction, photoinhibition and photoregulation. AB - This paper presents a mathematical model capable of quantitative prediction of the state of the photosynthetic apparatus of microalgae in terms of their open, closed and damaged reaction centers under variable light conditions. This model combines the processes of photoproduction and photoinhibition in the Han model with a novel mathematical representation of photoprotective mechanisms, including qE-quenching and qI-quenching. For calibration and validation purposes, the model can be used to simulate fluorescence fluxes, such as those measured in PAM fluorometry, as well as classical fluorescence indexes. A calibration is carried out for the microalga Nannochloropsis gaditana, whereby 9 out of the 13 model parameters are estimated with good statistical significance using the realized, minimal and maximal fluorescence fluxes measured from a typical PAM protocol. The model is further validated by considering a more challenging PAM protocol alternating periods of intense light and dark, showing a good ability to provide quantitative predictions of the fluorescence fluxes even though it was calibrated for a different and somewhat simpler PAM protocol. A promising application of the model is for the prediction of PI-response curves based on PAM fluorometry, together with the long-term prospect of combining it with hydrodynamic and light attenuation models for high-fidelity simulation and optimization of full-scale microalgae production systems. PMID- 25527385 TI - Euglenoid flagellates: a multifaceted biotechnology platform. AB - Euglenoid flagellates are mainly fresh water protists growing in highly diverse environments making them well-suited for a multiplicity of biotechnology applications. Phototrophic euglenids possesses complex chloroplasts of green algal origin bounded by three membranes. Euglena nuclear and plastid genome organization, gene structure and gene expression are distinctly different from other organisms. Our observations on the model organism Euglena gracilis indicate that transcription of both the plastid and nuclear genome is insensitive to environmental changes and that gene expression is regulated mainly at the post transcriptional level. Euglena plastids have been proposed as a site for the production of proteins and value added metabolites of biotechnological interest. Euglena has been shown to be a suitable protist species to be used for production of several compounds that are used in the production of cosmeceuticals and nutraceuticals, such as alpha-tocopherol, wax esters, polyunsaturated fatty acids, biotin and tyrosine. The storage polysaccharide, paramylon, has immunostimulatory properties and has shown a promise for biomaterials production. Euglena biomass can be used as a nutritional supplement in aquaculture and in animal feed. Diverse applications of Euglena in environmental biotechnology include ecotoxicological risk assessment, heavy metal bioremediation, bioremediation of industrial wastewater and contaminated water. PMID- 25527386 TI - Segmental hypertrophy mimicking liver tumor in a patient with primary sclerosing cholangitis. PMID- 25527387 TI - A steady-state target calculation method based on "point" model for integrating processes. AB - Aiming to eliminate the influences of model uncertainty on the steady-state target calculation for integrating processes, this paper presented an optimization method based on "point" model and a method determining whether or not there is a feasible solution of steady-state target. The optimization method resolves the steady-state optimization problem of integrating processes under the framework of two-stage structure, which builds a simple "point" model for the steady-state prediction, and compensates the error between "point" model and real process in each sampling interval. Simulation results illustrate that the outputs of integrating variables can be restricted within the constraints, and the calculation errors between actual outputs and optimal set-points are small, which indicate that the steady-state prediction model can predict the future outputs of integrating variables accurately. PMID- 25527388 TI - Recurrent cerebrospinal fluid basophilia in neurosarcoidosis. PMID- 25527389 TI - A comparison between rate of nonmotor symptom development in essential tremor and Parkinson's disease. AB - In the last decade our perspective on essential tremor (ET) as a pure motor system disorder has begun to change. By virtue of recent studies of nonmotor symptoms (NMSs) that are used to characterize Parkinson's disease (PD), these symptoms have also been added to the definition of ET. There is increasing evidence to suggest that ET might not be as benign and monosymptomatic as we previously thought. The aim of this study was to evaluate nonmotor symptoms in ET, and to compare them with PD. We studied 37 ET and 23 PD patients. Tremor rate was evaluated using the Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) in ET patients. The patients with PD were scored for motor symptoms using the unified Parkinson's disease rating scale (UPDRS)-III and the Hoehn-Yahr scale. Cognitive functions were assessed with the Montreal Cognitive Assessment (MoCA) test. NMSs were evaluated with the nonmotor symptoms questionnaire (NMSQuest). In the ET group, the most common NMSs were forgetting things, feeling sad, nocturia, urgency, and difficulty concentrating. The mean NMSQuest score was 8.43 +/- 4.14 in the ET group and 14.06 +/- 5.44 in the PD group (p value <0.001). However, except for 12 items in NMSQuest, in comparing items one by one there was no statistical difference between them. The mean MoCA total score was 17.81 +/- 4.56 in the ET group and 17.08 +/- 4.08 in the PD group (p value 0.675). There were no significant differences in MoCA subgroup scores. Evaluation of nonmotor symptoms in ET may help us to understand this emerging definition of ET. This study contributes evidence toward this new concept. PMID- 25527390 TI - Novel brain magnetic resonance imaging finding in a patient with trisomy 9p syndrome. PMID- 25527391 TI - Bacterial communities in the rhizosphere of Vitis vinifera L. cultivated under distinct agricultural practices in Argentina. AB - Plants interact with a myriad of microbial cells in the rhizosphere, an environment that is considered to be important for plant development. However, the differential structuring of rhizosphere microbial communities due to plant cultivation under differential agricultural practices remains to be described for most plant species. Here we describe the rhizosphere microbiome of grapevine cultivated under conventional and organic practices, using a combination of cultivation-independent approaches. The quantification of bacterial 16S rRNA and nifH genes, by quantitative PCR (qPCR), revealed similar amounts of these genes in the rhizosphere in both vineyards. PCR-DGGE was used to detect differences in the structure of bacterial communities, including both the complete whole communities and specific fractions, such as Alphaproteobacteria, Betaproteobacteria, Actinobacteria, and those harboring the nitrogen-fixing related gene nifH. When analyzed by a multivariate approach (redundancy analysis), the shifts observed in the bacterial communities were poorly explained by variations in the physical and chemical characteristics of the rhizosphere. These approaches were complemented by high-throughput sequencing (67,830 sequences) based on the V6 region of the 16S rRNA gene, identifying the major bacterial groups present in the rhizosphere of grapevines: Proteobacteria, Actinobacteria, Firmicutes, Bacteriodetes, Acidobacteria, Cloroflexi, Verrucomicrobia and Planctomycetes, which occur in distinct proportions in the rhizosphere from each vineyard. The differences might be related to the selection of plant metabolism upon distinct reservoirs of microbial cells found in each vineyard. The results fill a gap in the knowledge of the rhizosphere of grapevines and also show distinctions in these bacterial communities due to agricultural practices. PMID- 25527392 TI - Desktop MRI as a promising tool for mapping intra-aneurismal flow. AB - In this work we evaluate the performance of a 40-mm diameter bore 0.2T desktop Halbach tomograph to obtain 2D and 3D velocity maps for studying intra-aneurismal flow in the presence or absence of nitinol meshed implants with the aim of optimizing the flow diverter efficacy. Phantoms with known spatial velocity distribution were used to determine the performance of the MRI system. Maximum velocities of about 200mm/s could be measured with a precision of 1% at a spatial resolution of 0.5*0.5*1mm(3). This accuracy is suitable to evaluate in vitro intra-aneurismal flow under different conditions such as variable flow rates, different vessel-aneurysm geometry, as well as the influence of metallic flow diverters on the intra-aneurismal flow distribution. The information obtained non invasively with desktop tomographs can be used to complement in vivo studies in order to decide the optimum flow diverter. PMID- 25527393 TI - Evidence of altered age-related brain cytoarchitecture in mouse models of down syndrome: a diffusional kurtosis imaging study. AB - Mouse models of Down syndrome (DS) exhibit abnormal brain developmental and neurodegenerative changes similar to those seen in individuals with DS. Although DS mice have been well characterized cognitively and morphologically there are no prior reports utilizing diffusion MRI. In this study we investigated the ability of diffusional kurtosis imaging (DKI) to detect the progressive developmental and neurodegenerative changes in the Ts65Dn (TS) DS mouse model. TS mice displayed higher diffusional kurtosis (DK) in the frontal cortex (FC) compared to normal mice at 2months of age. At 5months of age, TS mice had lower radial kurtosis in the striatum (ST), which persisted in the 8-month-old mice. The TS mice exhibited lower DK metrics values in the dorsal hippocampus (HD) at all ages, and the group difference in this region was larger at 8-months. Regression analysis showed that normal mice had a significant age-related increase in DK metrics in FC, ST and HD. On the contrary, the TS mice lacked significant age-related increase in DK metrics in FC and ST. Although preliminary, these results demonstrate that DK metrics can detect TS brain developmental and neurodegenerative abnormalities. PMID- 25527394 TI - Sodium magnetic resonance imaging using ultra-short echo time sequences with anisotropic resolution and uniform k-space sampling. AB - A method for uniform k-space sampling of 3D ultra-short echo time (UTE) techniques with anisotropic resolution in one direction is introduced to increase signal-to-noise ratio (SNR). State-of-the-art acquisition schemes for sodium MRI with radial (projection reconstruction) and twisting (twisted projection imaging (TPI)) trajectories are investigated regarding SNR efficiency, blurring behavior under T2(*) decay, and measurement time in case of anisotropic field-of-view and resolution. 3D radial and twisting trajectories are redistributed in k-space for UTE sodium MRI with homogeneous noise distribution and optimal SNR efficiency, if T2(*) decay can be neglected. Simulations based on Voronoi tessellations and phantom simulations/measurements were performed to calculate SNR efficiency. Point-spread functions were simulated to demonstrate the influence of T2(*) decay on SNR and resolution. Phantom simulations/measurements and in vivo measurements confirm the SNR gain obtained by simulations based on Voronoi cells. An increase in SNR of up to 21% at an anisotropy factor of 10 could be theoretically achieved by TPI with projection adaption compared to the same sequence but without redistribution of projections in k-space. Sodium MRI with anisotropic resolution and uniform k-space sampling is demonstrated by in vivo measurements of human intervertebral disks and heart at 3 T. The SNR gain can be invested in a measurement time reduction of up to 32%, which is important especially for sodium MRI. PMID- 25527395 TI - Evaluation of suspected soft tissue lesion in the prostate bed after radical prostatectomy using 3T multiparametric magnetic resonance imaging. AB - PURPOSE: To investigate the usefulness of multiparametric MR imaging (mp-MRI) at 3T for evaluating suspected soft tissue lesion in the prostate bed after radical prostatectomy (RP). MATERIALS AND METHODS: Forty-three patients with biochemical recurrence (BCR) who received RP underwent mp-MRI at 3T with a phased-array coil, including T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI) and dynamic contrast-enhanced imaging (DCE-MRI) and were enrolled in this study. All patients with BCR had a suspected soft tissue lesion in the prostate bed, followed by transrectal ultrasound-guided biopsy. As a control group, 14 consecutive patients without BCR who received RP were also enrolled. Two experienced radiologists independently analyzed four different imaging datasets. RESULTS: For predicting local recurrence, the specificity, accuracy and area under the curve for both readers were significantly greater on all combined imaging datasets than on T2WI alone (P<0.05). The sensitivity of all combined imaging datasets in both readers was not statistically different with T2WI alone (P>0.05), except for combined T2WI and DWI. Inter-reader agreements for the four different imaging datasets were moderate. CONCLUSION: DCE-MRI or DWI in combination with T2WI at 3T with a phased-array coil appears to be more useful than T2WI alone in evaluating suspected soft tissue lesion of the prostate bed after RP. PMID- 25527396 TI - Molecular characterization of HIV-1 infection in Northwest Spain (2009-2013): Investigation of the subtype F outbreak. AB - BACKGROUND: HIV-1 subtype B is the predominant one in European regions several, while other subtypes and recombinants are also circulating with high prevalence. A sub-epidemic of subtype F with specific characteristics and low response to treatment has been recently identified in Galicia. In this study we investigated the characteristics of the HIV-1 subtype F sub-epidemic in A Coruna and Santiago de Compostela in Northwest Spain. METHODS: 420 newly HIV-1 diagnosed patients during 2009-2013 were enrolled in this study. HIV-1 subtyping was carried out using automated subtyping tools and phylogenetic analysis. Molecular epidemiology investigation of subtypes B and F was performed by means of phylogenetic analysis using fast maximum likelihood. Phylodynamic analysis was performed using Bayesian method as implemented in BEAST v1.8. RESULTS: Subtype B found to be the predominant (61.2% and 70.4%) followed by subtype F (25.6% and 12.0%) in both areas (A Coruna and Santiago de Compostela, respectively). The latter found to mainly spread among men having sex with men (MSM). The vast majority of subtype F lineages from both areas clustered monophyletically, while subtype B sequences clustered in several tree branches. The exponential growth of subtype F sub epidemic dated back in 2008 by means of phylodynamic analysis. Most of new infections during 2009-2013 occurred within the subtype F transmission cluster. CONCLUSIONS: Subtype F circulates at high prevalence in A Coruna and Santiago de Compostela in Northwest Spain, suggesting that the HIV-1 epidemic in this region has distinct characteristics to the rest of Spain. Subtype F has being spreading among MSM and is currently the most actively spreading network. The single cluster spread of this local sub-epidemic might provide an explanation for the distinct characteristics and the low response to antiretroviral treatment. PMID- 25527397 TI - Mitochondrial function in rat cerebral cortex and hippocampus after short- and long-term hypobaric hypoxia. AB - Taking into account the importance of aerobic metabolism in brain, the aim of the present work was to evaluate mitochondrial function in cerebral cortex and hippocampus in a model of sustained hypobaric hypoxia (5000 m simulated altitude) during a short (1 mo) and a long (7 mo) term period, in order to precise the mechanisms involved in hypoxia acclimatization. Hippocampal mitochondria from rats exposed to short-term hypobaric hypoxia showed lower respiratory rates than controls in both states 4 (45%) and 3 (41%), and increased NO production (1.3 fold) as well as eNOS and nNOS expression associated to mitochondrial membranes, whereas mitochondrial membrane potential decreased (7%). No significant changes were observed in cortical mitochondria after 1 mo hypobaric hypoxia in any of the mitochondrial functionality parameters evaluated. After 7 mo hypobaric hypoxia, oxygen consumption was unchanged as compared with control animals both in hippocampal and cortical mitochondria, but mitochondrial membrane potential decreased by 16% and 8% in hippocampus and cortex respectively. Also, long-term hypobaric hypoxia induced an increase in hippocampal NO production (0.7 fold) and in eNOS expression. A clear tendency to decrease in H2O2 production was observed in both tissues. Results suggest that after exposure to hypobaric hypoxia, hippocampal mitochondria display different responses than cortical mitochondria. Also, the mechanisms responsible for acclimatization to hypoxia would be time dependent, according to the physiological functions of the brain studied areas. Nitric oxide metabolism and membrane potential changes would be involved as self protective mechanisms in high altitude environment. PMID- 25527398 TI - Antinociceptive action against colonic distension by brain orexin in conscious rats. AB - Increasing evidence has suggested that brain orexins are implicated in a wide variety of physiological functions. With regard to gastrointestinal functions, orexin-A acts centrally to regulate gastrointestinal functions such as gastric and pancreatic secretion, and gastrointestinal motility. Visceral sensation is also known as one of key gastrointestinal functions which are controlled by the central nervous system. Little is, however, known about a role of central orexin in visceral sensation. This study was therefore performed to clarify whether brain orexin may be involved in the process of visceral sensation. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered orexin-A dose-dependently increased the threshold volume of colonic distension-induced AWR. In contrast, neither intraperitoneal injection of orexin-A nor intracisternal orexin-B altered the threshold volume. While intracisternal SB334867, an orexin 1 receptor antagonist, by itself failed to change the threshold volume, SB334867 injected centrally completely blocked the morphine-induced antinociceptive action against colonic distension. These results suggest for the first time that orexin-A specifically acts centrally in the brain to enhance antinociceptive response to colonic distension. We would furthermore suggest that endogenous orexin-A indeed mediates the antinociceptive effect of morphine on visceral sensation through the orexin 1 receptors. All these evidence might indicate that brain orexin plays a role in the pathophysiology of functional gastrointestinal disorders such as irritable bowel syndrome because visceral hypersensitivity of the gut is considered to play a vital role in the diseases. PMID- 25527399 TI - Neurobiological model of stimulated dopamine neurotransmission to interpret fast scan cyclic voltammetry data. AB - Fast-scan cyclic voltammetry (FSCV) is an electrochemical method that can assess real-time in vivo dopamine (DA) concentration changes to study the kinetics of DA neurotransmission. Electrical stimulation of dopaminergic (DAergic) pathways can elicit FSCV DA responses that largely reflect a balance of DA release and reuptake. Interpretation of these evoked DA responses requires a framework to discern the contribution of DA release and reuptake. The current, widely implemented interpretive framework for doing so is the Michaelis-Menten (M-M) model, which is grounded on two assumptions- (1) DA release rate is constant during stimulation, and (2) DA reuptake occurs through dopamine transporters (DAT) in a manner consistent with M-M enzyme kinetics. Though the M-M model can simulate evoked DA responses that rise convexly, response types that predominate in the ventral striatum, the M-M model cannot simulate dorsal striatal responses that rise concavely. Based on current neurotransmission principles and experimental FSCV data, we developed a novel, quantitative, neurobiological framework to interpret DA responses that assumes DA release decreases exponentially during stimulation and continues post-stimulation at a diminishing rate. Our model also incorporates dynamic M-M kinetics to describe DA reuptake as a process of decreasing reuptake efficiency. We demonstrate that this quantitative, neurobiological model is an extension of the traditional M-M model that can simulate heterogeneous regional DA responses following manipulation of stimulation duration, frequency, and DA pharmacology. The proposed model can advance our interpretive framework for future in vivo FSCV studies examining regional DA kinetics and their alteration by disease and DA pharmacology. PMID- 25527400 TI - Attentional bias modification facilitates attentional control mechanisms: evidence from eye tracking. AB - Social anxiety is thought to be maintained by biased attentional processing towards threatening information. Research has further shown that the experimental attenuation of this bias, through the implementation of attentional bias modification (ABM), may serve to reduce social anxiety vulnerability. However, the mechanisms underlying ABM remain unclear. The present study examined whether inhibitory attentional control was associated with ABM. A non-clinical sample of participants was randomly assigned to receive either ABM or a placebo task. To assess pre-post changes in attentional control, participants were additionally administered an emotional antisaccade task. ABM participants exhibited a subsequent shift in attentional bias away from threat as expected. ABM participants further showed a subsequent decrease in antisaccade cost, indicating a general facilitation of inhibitory attentional control. Mediational analysis revealed that the shift in attentional bias following ABM was independent to the change in attentional control. The findings suggest that the mechanisms of ABM are multifaceted. PMID- 25527401 TI - Surgery for plasma cell neoplasia patients with spinal instability or neurological impairment caused by spinal lesions as the first clinical manifestation. AB - PURPOSE: Multiple myeloma (MM) and solitary plasmacytoma of bone (SPB) are two independent subtypes of plasma cell dyscrasias which often occur in spine. However, little is known about the surgical treatment of patients with spinal instability or neurological impairment caused by spinal lesions as the first clinical manifestation. The present study aimed to investigate the surgical outcome of these patients. METHODS: We retrospectively reviewed the data of a total of 64 patients receiving spinal surgery in our center, in which 30 were diagnosed as MM and 34 as SPB. Univariate and multivariate analyses were used to identify factors associated with overall survival (OS) and progression-free survival (PFS) of patients. RESULTS: Surgical treatment led to favorable results including pain relief, resumption of ambulatory ability as well as improvement of neurological function and life quality. Univariate analysis suggested that the potential prognostic factors for OS of MM patients were bisphosphonate treatment, post-surgical ambulatory status, Karnofsky Performance Score (KPS) and Frankel scale, and for PFS of MM patients were age at surgery, resection mode, postoperative ambulation status, KPS and Frankel scale, while the PFS of SPB patients was only significantly related to postoperative adjuvant therapies. Multivariate analysis indicated that postoperative ambulation status was the only independent risk factor for both OS and PFS of MM patients. CONCLUSIONS: Surgery may be beneficial to patients with spinal instability or neurological impairment caused by spinal lesions as the first clinical manifestation, in which MM patients with postoperative ambulatory ability display better prognosis. PMID- 25527402 TI - Effectiveness and safety of transforaminal lumbar interbody fusion in patients with previous laminectomy. AB - PURPOSE: To determine the efficacy and safety of transforaminal lumbar interbody fusion (TLIF) for revision lumbar spine surgery in patients with previous laminectomy. The secondary objective was to evaluate the clinical and radiological outcome after such a procedure. METHODS: Retrospective case series study. Eighty-two patients were included. There were 48 women (58.5 %) and 34 men (41.5 %) with a mean age of 51 years (range 26-84) at the time of index procedure. The outpatient and inpatient charts were reviewed to identify patients' demographic data, preoperative, perioperative, and postoperative data. The outcome measures were assessed by Oswestry Disability Index (ODI) and visual analog scale (VAS) for back and leg pain. An independent spine surgeon and musculoskeletal radiologist reviewed the imaging studies. RESULTS: The average operative time was 160 min (range 131-250). The average estimated blood loss was 652 cc (100-1,400 cc). Nineteen patients (23.1 %) required blood transfusion. Five patients (6 %) had dural tear. One patient (1.2 %) had a surgical site infection. Two patients (2.4 %) had thromboembolic events. The average hospital stay was 3.8 days (2-5 days). At a mean follow-up of 28 months, there were statically significant improvement in the ODI and VAS for back and leg pain. None of the patients' radiographs showed hardware failure or pedicle screw loosening and no patient returned to the operating room for pseudarthrosis. CONCLUSIONS: The current study confirmed that TLIF approach in patients with previous laminectomy is effective and safe with good outcomes. PMID- 25527403 TI - Does addition of crosslink to pedicle-screw-based instrumentation impact the development of the spinal canal in children younger than 5 years of age? AB - PURPOSE: Use of pedicle screws has been popularized in the treatment of pediatric spinal deformity. Despite many studies regarding the effect of pedicle screws on the immature spine, there is no study concerning the impact of addition of crosslink to pedicle-screw-based instrumentation on the development of the spinal canal in young children. This study aims to determine the influence of the screw rod-crosslink complex on the development of the spinal canal. METHODS: This study reviewed 34 patients with congenital scoliosis (14 boys and 20 girls) who were treated with posterior-only hemivertebrectomy and pedicle-screw-based short segment instrumentation before the age of 5 years. The mean age at surgery in this cohort was 37 +/- 11 months (range 21-57 months). They were followed up for at least 24 months. Of these patients, 10 underwent only pedicle screw instrumentation without crosslink, and 24 with additional crosslink placement. The vertebrae were divided into three regions as follows: (1) S-CL (screw crosslink) region, in which the vertebrae were inserted with bilateral pedicle screws and two rods connected with the crosslink; (2) S (screw) region, in which the vertebrae were inserted with bilateral pedicle screws but without crosslink; (3) NS (no screws) region, which comprised vertebrae cephalad or caudal to the instrumented region. The area, anteroposterior and transverse diameters of the spinal canal were measured at all vertebrae on the postoperative and last follow up computed tomography axial images. The instrumentation-related parameters were also measured, including the distance between the bilateral screws and the screw base angles. The changes in the above measurements were compared between each region to evaluate the instrumentation's effect on the spinal canal growth. RESULTS: The mean follow-up was 37 +/- 13 months (range 24-68 months) and the mean age at the last follow-up was 74 +/- 20 months (range 46-119 months). In each region, the spinal canal dimensions significantly increased during the follow-up period. There was no significant difference in the spinal canal growth rate between the S and NS regions or between the S-CL and NS regions. Besides, a comparison of the S-CL and S regions regarding the changes in the measurements of the instrumentation construct revealed no significant differences. CONCLUSION: Pedicle-screw-based instrumentation does not cause retardation of the development of the spinal canal in young children. Moreover, use of the crosslink added to the screw-rod instrumentation also demonstrates no negative effect on the growth of the spinal canal. Thus, the addition of the crosslink to short screw-based instrumentation is recommended as an alternative to increase fixation stability in growing patients, even in very young pediatric population. PMID- 25527404 TI - Gender disparity in BMD conversion: a comparison between Lunar and Hologic densitometers. AB - Female-derived inter-conversion and standardised BMD equations at the lumbar spine and hip have not been validated in men. This study of 110 male subjects scanned on Hologic and Lunar densitometers demonstrates that published equations may not applicable to men at the lumbar spine. Male inter-conversion equations have also been derived. PURPOSE: Currently, available equations for inter manufacturer conversion of bone mineral density (BMD) and calculation of standardised BMD (sBMD) are used in both males and females, despite being derived and validated only in women. Our aim was to test the validity of the published equations in men. METHODS: One hundred ten men underwent lumbar spine (L2-4), femoral neck (FN) and total hip (TH) dual X-ray absorptiometry (DXA) using Hologic and Lunar scanners. Hologic BMD was converted to Lunar using published equations derived from women for L2-4 and FN. Actual Lunar BMD (A-Lunar) was compared to converted (Lunar equivalent) Hologic BMD values (H-Lunar). sBMD was calculated separately using Hologic (sBMD-H) and Lunar BMD (sBMD-L) at L2-4, FN and TH. Conversion equations in men for Hologic to Lunar BMD were derived using Deming regression analysis. RESULTS: There was a strong linear correlation between Lunar and Hologic BMD at all skeletal sites. A-Lunar BMD was however significantly higher than derived H-Lunar BMD (p < 0.001) at L2-L4 (mean difference, 0.07 g/cm(2)). There was no significant difference at the FN (mean difference, 0.01 g/cm(2)). sBMD-L at the spine was significantly higher than sBMD H (mean difference, 0.06 g/cm(2), p < 0.001), whilst there was little difference at the FN and TH (mean difference, 0.01 g/cm(2)). CONCLUSION: Published conversion equations for Lunar BMD to Hologic BMD, and formulae for lumbar spine sBMD, derived in women may not be applicable to men. PMID- 25527405 TI - Differential responses of Africanized and European honey bees (Apis mellifera) to viral replication following mechanical transmission or Varroa destructor parasitism. AB - For the first time, adults and brood of Africanized and European honey bees (Apis mellifera) were compared for relative virus levels over 48 h following Varroa destructor parasitism or injection of V. destructor homogenate. Rates of increase of deformed wing virus (DWV) for Africanized versus European bees were temporarily lowered for 12h with parasitism and sustainably lowered over the entire experiment (48 h) with homogenate injection in adults. The rates were also temporarily lowered for 24h with parasitism but were not affected by homogenate injection in brood. Rates of increase of black queen cell virus (BQCV) for Africanized versus European bees were similar with parasitism but sustainably lowered over the entire experiment with homogenate injection in adults and were similar for parasitism and homogenate injection in brood. Analyses of sac brood bee virus and Israeli acute paralysis virus were limited as detection did not occur after both homogenate injection and parasitism treatment, or levels were not significantly higher than those following control buffer injection. Lower rates of replication of DWV and BQCV in Africanized bees shows that they may have greater viral resistance, at least early after treatment. PMID- 25527406 TI - Comparative virulence and competition between Nosema apis and Nosema ceranae in honey bees (Apis mellifera). AB - Honey bees (Apis mellifera) are infected by two species of microsporidia: Nosema apis and Nosemaceranae. Epidemiological evidence indicates that N. ceranae may be replacing N. apis globally in A. mellifera populations, suggesting a potential competitive advantage of N. ceranae. Mixed infections of the two species occur, and little is known about the interactions among the host and the two pathogens that have allowed N. ceranae to become dominant in most geographical areas. We demonstrated that mixed Nosema species infections negatively affected honey bee survival (median survival=15-17days) more than single species infections (median survival=21days and 20days for N. apis and N. ceranae, respectively), with median survival of control bees of 27days. We found similar rates of infection (percentage of bees with active infections after inoculation) for both species in mixed infections, with N. apis having a slightly higher rate (91% compared to 86% for N. ceranae). We observed slightly higher spore counts in bees infected with N. ceranae than in bees infected with N. apis in single microsporidia infections, especially at the midpoint of infection (day 10). Bees with mixed infections of both species had higher spore counts than bees with single infections, but spore counts in mixed infections were highly variable. We did not see a competitive advantage for N. ceranae in mixed infections; N. apis spore counts were either higher or counts were similar for both species and more N. apis spores were produced in 62% of bees inoculated with equal dosages of the two microsporidian species. N. ceranae does not, therefore, appear to have a strong within-host advantage for either infectivity or spore growth, suggesting that direct competition in these worker bee mid-guts is not responsible for its apparent replacement of N. apis. PMID- 25527407 TI - Ubiquitin acetylation inhibits polyubiquitin chain elongation. AB - Ubiquitylation is a versatile post-translational modification (PTM). The diversity of ubiquitylation topologies, which encompasses different chain lengths and linkages, underlies its widespread cellular roles. Here, we show that endogenous ubiquitin is acetylated at lysine (K)-6 (AcK6) or K48. Acetylated ubiquitin does not affect substrate monoubiquitylation, but inhibits K11-, K48-, and K63-linked polyubiquitin chain elongation by several E2 enzymes in vitro. In cells, AcK6-mimetic ubiquitin stabilizes the monoubiquitylation of histone H2B which we identify as an endogenous substrate of acetylated ubiquitin-and of artificial ubiquitin fusion degradation substrates. These results characterize a mechanism whereby ubiquitin, itself a PTM, is subject to another PTM to modulate mono- and polyubiquitylation, thus adding a new regulatory layer to ubiquitin biology. PMID- 25527408 TI - RNA-processing proteins regulate Mec1/ATR activation by promoting generation of RPA-coated ssDNA. AB - Eukaryotic cells respond to DNA double-strand breaks (DSBs) by activating a checkpoint that depends on the protein kinases Tel1/ATM and Mec1/ATR. Mec1/ATR is activated by RPA-coated single-stranded DNA (ssDNA), which arises upon nucleolytic degradation (resection) of the DSB. Emerging evidences indicate that RNA-processing factors play critical, yet poorly understood, roles in genomic stability. Here, we provide evidence that the Saccharomyces cerevisiae RNA decay factors Xrn1, Rrp6 and Trf4 regulate Mec1/ATR activation by promoting generation of RPA-coated ssDNA. The lack of Xrn1 inhibits ssDNA generation at the DSB by preventing the loading of the MRX complex. By contrast, DSB resection is not affected in the absence of Rrp6 or Trf4, but their lack impairs the recruitment of RPA, and therefore of Mec1, to the DSB. Rrp6 and Trf4 inactivation affects neither Rad51/Rad52 association nor DSB repair by homologous recombination (HR), suggesting that full Mec1 activation requires higher amount of RPA-coated ssDNA than HR-mediated repair. Noteworthy, deep transcriptome analyses do not identify common misregulated gene expression that could explain the observed phenotypes. Our results provide a novel link between RNA processing and genome stability. PMID- 25527409 TI - Expression of estrogen receptor beta and Ki 67 in benign & malignant human prostate lesions by immunohistochemistry. AB - Estrogen regulates the growth of prostate through two receptors Estrogen receptor alpha & beta of which ERbeta is proposed to be antiproliferative. There is a wide variation in the results of various studies regarding the localisation, level of expression of ERbeta in benign & malignant lesions of prostate and its relation to the grade of tumor emphasizing the need for additional studies to standardize the distribution of this receptor in prostate. This was a prospective study conducted in Department of Pathology, UCMS, Delhi, evaluating ERbeta & Ki 67 immunoexpression in 60 cases of benign and malignant lesions of prostate (30 each). Tissue for study included prostatic core biopsy and TURP chips. After histomorphological diagnosis, immunohistochemical staining was performed using a monoclonal antibody. Nuclear expression of ERbeta & Ki67 was evaluated and compared between the two study groups (benign & malignant lesions) using Pearson chi square test. ERbeta was predominantly localized to nuclei of secretory epithelium of prostatic glands. Expression of ERbeta was higher in benign glands compared to carcinoma. However, majority of carcinomas retained ERbeta expression though at much lower levels. Expression of Ki 67 was higher in carcinoma than benign hyperplasia. There was no correlation between the ERbeta status, Ki 67 expression & grade of tumor. Expression of ERbeta is downregulated in carcinoma compared to benign hyperplasia and is consistent with its chemopreventive role in prostate. It might have a therapeutic implication as agonists' targeting this receptor could be a part of treatment protocol for those patients of carcinoma who retain this receptor at significant levels. PMID- 25527410 TI - Susceptibility to gastric cancer and polymorphisms of insertion/deletion at the intron 3 of the XRCC4 and VNTR at the promoter region of the XRCC5. AB - The genes encoding X-ray repair cross-complementing group 4 (XRCC4; OMIM: 194363) and 5 (XRCC5; OMIM: 194364) are involved in repair of DNA double-strand breaks. To investigating the associations between polymorphisms of Insertion/Deletion (I/D, rs28360071) in the intron 3 of the XRCC4 and VNTR in the promoter region of the XRCC5 and risk of gastric cancer, the present study was carried out. We included 159 (56 females, 103 males) with gastric cancer and 242 (75 females, 167 males) healthy blood donors frequency matched for age and gender. Using PCR-based methods, the genotypes of the study polymorphisms were determined. The alleles of VNTR XRCC5 polymorphism divided into two groups: L (0 and 1 repeats) and H (2 and 3 repeats) alleles. For the I/D XRCC4 polymorphism, after stratification of the subjects according to their family history (FH) of cancer, either the ID (OR = 3.19, 95%CI: 1.35-7.50, P = 0.008) or the DD genotypes (OR = 4.62, 95%CI: 1.63 13.0, P = 0.004) among positive FH persons, increased the risk of gastric cancer compared with the reference group (persons who have negative FH and II genotype). For the VNTR XRCC5 polymorphism, the LH + HH genotypes among positive FH persons, increased the risk of gastric cancer compared with the reference group (persons who have negative FH and LL genotype) (OR = 2.88, 95%CI: 1.34-6.18, P = 0.006). Sensitivity analysis showed that the above mentioned associations were not occurred due to the maldistribution of the genotypes among missing data. The present study suggests that both polymorphisms of the XRCC4 and XRCC5 might be risk factors for gastric cancer development especially among persons with positive FH. PMID- 25527411 TI - Quality of life and audiologic performance through the ability to phone of cochlear implant users. AB - This study aimed to evaluate the impact of cochlear implantation on quality of life (QoL), using general and cochlear implant (CI) specific questionnaires and to determine the relationship of phone ability with QoL, speech recognition abilities and tinnitus. Twenty-six adult volunteers with a post-lingual profound deafness, unilaterally implanted with a CI, were included in this study. All subjects had used a CI for at least 1 year. The Glasgow benefit inventory (GBI) and Nijmegen cochlear implant questionnaire (NCIQ) were administered to assess QoL. Speech recognition was tested using phonemic Lafon's lists. The subjective tinnitus severity scale (STSS) questionnaire was used to determine the effects of tinnitus. CI users were split into four groups according to their phone ability. There was an improvement in QoL after cochlear implantation. The NCIQ showed significant (p < 0.001) improvements in the total score and in all subdomains after CI. A significant relationship between phone ability, QoL and speech recognition was found. Improving phone ability led to higher QoL (p < 0.05) and speech recognition (p < 0.01) scores. The CI use decreased significantly the occurrence of tinnitus, but its severity was not correlated with QoL. Post surgery assessment should include speech recognition measures and QoL evaluation. The NCIQ appeared more effective than the GBI in its ability to detect improvements in QoL. Assessing phone ability represents an easy and fast approach to evaluate hearing performances and QoL, and may reflect global outcomes of CI. PMID- 25527413 TI - Genetics of superior growth traits in trees are being mapped but will the faster growing risk-takers make it in the wild? PMID- 25527414 TI - New research rankings put Oxford, Cambridge, and King's College London as top three in UK. PMID- 25527412 TI - Fibrinogen is not a prognostic factor for response to HELP-apheresis in sudden sensorineural hearing loss (SSHL). AB - Higher levels of fibrinogen or cholesterol were associated with improved hearing recovery in SSHL patients after treatment with HELP-apheresis (Heparin-induced extracorporeal LDL precipitation apheresis). The present trial was performed to demonstrate HELP-related effects on relevant metabolic and inflammatory parameters in the context of SSHL treatment. In the framework of a single arm non controlled trial, we investigated the variation of metabolic and inflammatory parameters using HELP-apheresis for a defined group of 100 patients with SSHL. Based on cut off inclusion criteria (Serum LDL-cholesterol >1.6 g/l and/or fibrinogen >2.0 g/l, SSHL in minimum three frequencies more than 30 dB, time after event not longer than 6 days), the protocol followed a strict time line with one single shot HELP-apheresis and follow-up monitoring including laboratory parameters at six defined time points. If HELP-apheresis could not effect improvement of hearing on day 5, additional corticosteroid treatment was applied. Concentration of anti-inflammatory IL-10 increased while other proinflammatory parameters declined. Serum levels of all measured sterols and apolipoproteins decreased significantly. None of the investigated parameters were suitable to predict hearing improvement of the patients. Levels of fibrinogen and LDL cholesterol were not prognostic for outcome after HELP-apheresis. A significant (p < 0.001) increase of anti-inflammatory IL-10 after apheresis was notable, while most of the proinflammatory parameters declined. Despite the limited validity of a single arm non-controlled trial, these alterations on immune modulating factors indicate possible secondary pleiotropic effects caused by HELP apheresis. PMID- 25527415 TI - Nit-picking around second line in EGFRwt NSCLC: just an academic effort. PMID- 25527416 TI - Socioeconomic disparities in survival from childhood leukemia in the United States and globally: a meta-analysis. AB - BACKGROUND: Despite advancements in the treatment of childhood leukemia, socioeconomic status (SES) may potentially affect disease prognosis. This study aims to evaluate whether SES is associated with survival from childhood leukemia. METHODS: The US National Cancer Institute Surveillance, Epidemiology and End Results Program (SEER) 1973-2010 data were analyzed; thereafter, results were meta-analyzed along with those from survival (cohort) studies examining the association between SES indices and survival from childhood leukemia (end-of search date: 31 March 2014). Random-effects models were used to calculate pooled effect estimates (relative risks, RRs); meta-regression was also used. RESULTS: We included 29 studies yielding 28 804 acute lymphoblastic leukemia (ALL), 3208 acute myeloblastic leukemia (AML) and 27 650 'any' leukemia (denoting joint reporting of all subtypes) cases. According to individual-level composite SES indices, children from low SES suffered from nearly twofold higher death rates from ALL (pooled RR: 1.83, 95% confidence interval 1.00-3.34, based on four study arms); likewise, death RRs derived from an array of lower area-level SES indices ranged between 1.17 and 1.33 (based on 11 study arms). Importantly, the survival gap between higher and lower SES seemed wider in the United States, with considerably (by 20%-82%) increased RRs for death from ALL in lower SES. Regarding AML, poorer survival was evident only when area-level SES indices were used. Lastly, remoteness indices were not associated with survival from childhood leukemia. CONCLUSION: Children with lower SES suffering childhood leukemia do not seem to equally enjoy the impressive recent survival gains. Special health policy strategies and increased awareness of health providers might minimize the effects of socioeconomic disparities. PMID- 25527417 TI - TEMHEAD: a single-arm multicentre phase II study of temsirolimus in platin- and cetuximab refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) of the German SCCHN Group (AIO). AB - BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is a common disease, which has a poor prognosis after failure of therapy. Activation of the PI3K-AKT-mTOR axis is commonly detected in recurrent or metastatic SCCHN, and provided the rationale for the clinical phase II trial in pretreated SCCHN. PATIENTS AND METHODS: The primary end point was the progression-free survival rate (PFR) at 12 weeks. Forty eligible patients have been recruited after failure of platinum chemotherapy and cetuximab. A preplanned futility analysis was successfully passed after >=1 success was detected in 20 patients. Secondary objectives consisted of progression-free survival (PFS), disease control rate (DCR), overall survival (OS), safety and tolerability, and predictive biomarkers for KRAS, BRAF, PIK3CA mutations, and HPV status. Archived tumor tissue was analyzed for DNA sequence. RESULTS: A total of 40 patients were eligible. The PFR at 12 weeks was 40% (95% CI 25.0-54.6). The median PFS and OS were 56 days (95% CI 36-113 days) and 152 days (76-256 days), respectively. In 33 assessable patients, disease stabilization occurred in 57.6%, with tumor shrinkage in 13 patients (39.4%). Overall, the treatment was well tolerated. Fatigue (47.5%), anemia (25.0%), nausea (20.0%), and pneumonia (20.0%) were the most common adverse events. Neither PIK3CA mutations, nor HPV status were predictive for success with temsirolimus treatment. No mutations were found for KRAS or BRAF. CONCLUSION: Tumor shrinkage and efficacy parameter indicate that inhibition of the PI3K-AKT-mTOR axis was a putative novel treatment paradigm for SCCHN. We could not identify parameters predictive for treatment success of temsirolimus, which underscores the need for refinement of the molecular analysis in future studies. CLINICAL TRIALS NUMBER: NCT01172769. PMID- 25527418 TI - Reviewing manuscripts for the Journal of Genetic Counseling: practical suggestions. AB - The Journal of Genetic Counseling is the literary voice of our profession and our scholarship is only as good as the articles that are accepted. A quality review assists the editor in making publication decisions and enhances the manuscripts that are published, ultimately benefitting our profession and the public. Perhaps you are new to the reviewing process and/or you wonder about the sorts of things that make for a good review. The purpose of this article is to provide general guidance to enhance your experience of peer review. While the focus is research manuscripts, many of the guidelines will be similar for case reports, reviews, or professional issues papers. PMID- 25527420 TI - The elementary fusion modalities of osteoclasts. AB - The last step of the osteoclast differentiation process is cell fusion. Most efforts to understand the fusion mechanism have focused on the identification of molecules involved in the fusion process. Surprisingly, the basic fusion modalities, which are well known for fusion of other cell types, are not known for the osteoclast. Here we show that osteoclast fusion partners are characterized by differences in mobility, nuclearity, and differentiation level. Our demonstration was based on time-laps videos of human osteoclast preparations from three donors where 656 fusion events were analyzed. Fusions between a mobile and an immobile partner were most frequent (62%), while fusion between two mobile (26%) or two immobile partners (12%) was less frequent (p<0.001). In general, the immobile fusion partner contained more nuclei than the mobile one (p<0.01). Furthermore, enrichment in nuclei of an osteoclast with three or more nuclei resulted from fusion with a mono-nucleated cell in 67% of the cases (p<0.001), while mono-nucleated cells fused with a multinucleated cell in 61% of the cases (p<0.05). This observation suggested that a more mature osteoclast prefers to fuse with a less mature pre-osteoclast. This hypothesis was supported by a nucleus-tracing approach in a co-culture of more and less differentiated pre osteoclasts/osteoclasts. Furthermore, we found that osteoclast fusion proceeds through primarily two different types of cell contacts: phagocytic-cup and broad contact-surfaces (>80% of all fusions). We conclude that osteoclasts most often gain nuclei by addition of one nucleus at a time, and that this nucleus is most often delivered by a moving cell to an immobile cell. These characteristics fit the in vivo observations where mono-nucleated precursors migrating from the bone marrow fuse with more mature osteoclasts sitting on the bone surface. They also fit the fusion modalities of other cell types. PMID- 25527419 TI - Anti-LeY antibody enhances therapeutic efficacy of celecoxib against gastric cancer by downregulation of MAPKs/COX-2 signaling pathway: correlation with clinical study. AB - INTRODUCTION: Helicobacter pylori (H. pylori) is a major causative agent for the induction of chronic gastritis, gastric ulcer and gastric cancer. Celecoxib (COX 2 inhibitor) inhibits gastric cancer cell proliferation, but with low treatment efficacy, limiting its applications. It is important to develop a better strategy to improve the efficacy of celecoxib. Lewis Y (LeY) is a difucosylated oligosaccharide, highly expressed in 60-90% of human epithelial cancers, including gastric cancer. We previously found that H. pylori infection was associated with high level of LeY in gastric cancer. MATERIAL AND METHODS: Herein, we analyzed the correlation between H. pylori and cyclo-oxygenase-2 (COX 2), LeY, gastric markers (CA724 and GRN) in gastric patient's tissue and serum samples by IHC and ELISA. Furthermore, we treated the primary gastric cancer cells with celecoxib, anti-LeY antibody or the combination, and analyzed their therapeutic efficacy on CA724, GRN and COX-2 expression by Western blot, flow cytometry and ELISA. RESULTS: We found that gastric cancer had significantly high expression of H. pylori, COX-2, CA724, and GRN compared to gastric ulcers and chronic gastritis (P < 0.0001). H. pylori level showed significant correlation with COX-2 (R--0.552), LeY (R--0.861), CA724 (R--0.714) and GRN (R--0.664) (P < 0.0001). Additionally, the combination therapy led to impressive inhibition of gastric cancer cell proliferation, with decreased expression of COX-2, CA724 and GRN through downregulation of MAPKs/COX-2 pathway (P < 0.01). CONCLUSIONS: Our findings suggest that anti-LeY antibody enhances the cancer cell proliferation inhibitory effects of celecoxib, which might be a new feasible way for gastric cancer therapy. PMID- 25527421 TI - Transient gamma-secretase inhibition accelerates and enhances fracture repair likely via Notch signaling modulation. AB - Approximately 10% of skeletal fractures result in healing complications and non union, while most fractures repair with appropriate stabilization and without pharmacologic intervention. It is the latter injuries that cannot be underestimated as the expenses associated with their treatment and subsequent lost productivity are predicted to increase to over $74 billion by 2015. During fracture repair, local mesenchymal stem/progenitor cells (MSCs) differentiate to form new cartilage and bone, reminiscent of events during skeletal development. We previously demonstrated that permanent loss of gamma-secretase activity and Notch signaling accelerates bone and cartilage formation from MSC progenitors during skeletal development, leading to pathologic acquisition of bone and depletion of bone marrow derived MSCs. Here, we investigated whether transient and systemic gamma-secretase and Notch inhibition is capable of accelerating and enhancing fracture repair by promoting controlled MSC differentiation near the fracture site. Our radiographic, microCT, histological, cell and molecular analyses reveal that single and intermittent gamma-secretase inhibitor (GSI) treatments significantly enhance cartilage and bone callus formation via the promotion of MSC differentiation, resulting in only a moderate reduction of local MSCs. Biomechanical testing further demonstrates that GSI treated fractures exhibit superior strength earlier in the healing process, with single dose GSI treated fractures exhibiting bone strength approaching that of un-fractured tibiae. These data further establish that transient inhibition of gamma-secretase activity and Notch signaling temporarily increases osteoclastogenesis and accelerates bone remodeling, which coupled with the effects on MSCs likely explains the accelerated and enhanced fracture repair. Therefore, we propose that the Notch pathway serves as an important therapeutic target during skeletal fracture repair. PMID- 25527422 TI - Perivascular Adipose Tissue: A Novel Regulator of Vascular Tone in the Rat Pregnancy. AB - Perivascular adipose tissue (PVAT) contributes to vasoregulation. The role of this adipose tissue bed in pregnancy has not been examined. Here, we tested the hypothesis that PVAT in pregnant rats decreases resistance artery tone. Mesenteric arteries from nonpregnant (NP) and late pregnant (LP) rats were exposed to phenylephrine (PHE) or KCl in the presence (+) versus absence (-) of PVAT. The LP PVAT(+) vessels showed a 44% decrease in sensitivity to PHE in the presence of PVAT. There was no attenuation of the contractile response to KCl when PVAT was present. The LP arteries perfused with LP or NP PVAT underwent vasodilation; unexpectedly, NP vessels in the presence of PVAT from LP rats sustained a 48% vasoconstriction. The PVAT attenuates vasoconstriction by a mechanism that involves hyperpolarization. The vasoconstriction observed when nonpregnant vessels were exposed to pregnant PVAT suggests pregnant vessels adapt to the vasoconstricting influence of pregnant PVAT. PMID- 25527423 TI - Differential Expression of Long Noncoding RNAs in Human Cumulus Cells Related to Embryo Developmental Potential: A Microarray Analysis. AB - Long noncoding RNAs (lncRNAs), which are prevalently transcribed in the genome, are involved in a variety of biological functions, yet little is known about their abundance in human cumulus cells (CCs) during oocyte development. Here, we describe the expression profile of lncRNAs in 3 pairs of cumulus cells from mature oocytes that result in high-quality embryo (H-CCs) and from oocytes that result in poor-quality embryo (P-CCs) using microarray analysis. In this study, a total of 20 563 lncRNAs were expressed in human CCs. One hundred and twenty four lncRNAs were consistently upregulated, and 509 lncRNAs were consistently downregulated in all samples analyzed (fold change >= 2.0, P < .05). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate 5 upregulated and 7 downregulated lncRNAs. The qRT-PCR results in the study were confirmed to be consistent with the microarray results. Network analysis was used for further research. The results displayed the differentially expressed lncRNAs in P-CCs between H-CCs, which suggested that lncRNAs may contribute to the processes of oocyte and early embryo development. PMID- 25527424 TI - Rottlerin-induced BKCa channel activation impairs specific contractile responses and promotes vasodilation. AB - BACKGROUND: Activation of large conductance calcium-activated potassium (BKCa) channels is cardioprotective for ischemic injury and can enhance vasorelaxation. Rottlerin has recently been identified as a potent BKCa activator. We demonstrated that rottlerin improves cardiac function and increases coronary flow when used as a cardioplegia additive in rat and mouse models of cardioplegic arrest and reperfusion. In this study we examined the effectiveness and specificity of the putative BKCa activator rottlerin on vascular reactivity in response to specific contractile and dilatory agonists. METHODS: Aortic rings from wild-type (wt) and BKCa knock-out (KO) mice were mounted in a tissue bath with force transducers. The vasodilatory effect of rottlerin was evaluated after pre-constriction with U46619. Dose responses to the contractile agonists U46619 and phenylephrine (PE), and vasodilation responses to rottlerin, hydrogen sulfide (H2S), and sodium nitroprusside (SNP) were performed after pretreatment with rottlerin. Similar studies were performed in pig coronary vessels. RESULTS: The BKCa KO mouse aortic rings exhibited spontaneous contraction and had greater contractile responses to U46619 and reduced vasodilation to SNP compared with wt mice. The wt and KO responses to phenylephrine were similar. Rottlerin dose dependently dilated wild-type vessels, but not in BKCa KO animals. Pretreatment with rottlerin caused depressed U46619 responses, but had no effect on PE, SNP, or H2S-mediated responses. However, pig coronary vessels pretreated with rottlerin exhibited reduced contractile responses and enhanced nitric oxide dependent dilation. CONCLUSIONS: Rottlerin directly causes vasodilation through BKCa channel dependent mechanisms. The BKCa channel activator pretreatment enhances vasodilatory responses and impairs specific vasoconstrictive agonists. PMID- 25527425 TI - Trends in hospitalizations among medicare survivors of aortic valve replacement in the United States from 1999 to 2010. AB - BACKGROUND: Mortality rates after aortic valve replacement have declined, but little is known about the risk of hospitalization among survivors and how that has changed with time. METHODS: Among Medicare patients who underwent aortic valve replacement from 1999 to 2010 and survived to 1 year, we assessed trends in 1-year hospitalization rates, mean cumulative length of stay (average number of hospitalization days per patient in the entire year), and adjusted annual Medicare payments per patient toward hospitalizations. We characterized hospitalizations by principal diagnosis and mean length of stay. RESULTS: Among 1 year survivors of aortic valve replacement, 43% of patients were hospitalized within that year, of whom 44.5% were hospitalized within 30 days (19.2% for overall cohort). Hospitalization rates were higher for older (50.3% for >85 years), female (45.1%), and black (48.9%) patients. One-year hospitalization rate decreased from 44.2% (95% confidence interval, 43.5 to 44.8) in 1999 to 40.9% (95% confidence interval, 40.3 to 41.4) in 2010. Mean cumulative length of stay decreased from 4.8 days to 4.0 days (p < 0.05 for trend); annual Medicare payments per patient were unchanged ($5,709 to $5,737; p = 0.32 for trend). The three most common principal diagnoses in hospitalizations were heart failure (12.7%), arrhythmia (7.9%), and postoperative complications (4.4%). Mean length of stay declined from 6.0 days to 5.3 days (p < 0.05 for trend). CONCLUSIONS: Among Medicare beneficiaries who survived 1 year after aortic valve replacement, 3 in 5 remained free of hospitalization; however, certain subgroups had higher rates of hospitalization. After the 30-day period, the hospitalization rate was similar to that of the general Medicare population. Hospitalization rates and cumulative days spent in hospital decreased with time. PMID- 25527426 TI - Contemporary outcomes of operations for tricuspid valve infective endocarditis. AB - BACKGROUND: Tricuspid valve infective endocarditis (TVIE) is uncommon. Patients are traditionally treated with antibiotics alone, and indications for operation are not clearly established. We report our operative single-center experience. METHODS: We retrospectively reviewed 56 patients who underwent operations for TVIE between January 2002 and December 2012. RESULTS: Methicillin-resistant Staphylococcus aureus was present in 41% of patients, septic pulmonary emboli in 63%, moderate/severe tricuspid regurgitation in 66%, and 86% were intravenous drug abusers. Patients underwent early operation if there was concomitant left sided endocarditis with indications for operation (n = 18), atrial septal defect (n = 6), infected pacemaker lead (n = 4), or prosthetic TVIE (n = 1). The remaining 27 patients were treated with intravenous antibiotics. Five patients completed a 6-week course of intravenous antibiotics before requiring an operation for symptomatic severe tricuspid regurgitation or persistent bacteremia. Twenty-two patients did not complete the antibiotic therapy and underwent operation for symptomatic severe tricuspid regurgitation (n = 15), persistent fevers/bacteremia (n = 3), or patient-specific factors (n = 4). Valve repair was successful in 57% of patients. Overall operative mortality was 7.1%. No operative deaths occurred in patients with isolated native TVIE. Recurrent TVIE was diagnosed in 21% (5 of 24) of the replacement group and in 0% (0 of 32) in the repair group. Use of repair was strongly protective against recurrent TVIE (p < 0.01). CONCLUSIONS: In contrast to previously published reports of high operative mortality with TVIE, this experience demonstrates improved outcomes with low morbidity and mortality, particularly for native isolated TVIE. Future prospective comparisons between surgically and medically treated patients may help to further define indications and timing for operation for patients with TVIE. PMID- 25527427 TI - Impact of sulfation pattern on the conformation and dynamics of sulfated fucan oligosaccharides as revealed by NMR and MD. AB - Sulfated fucans from sea urchin egg jelly express well-defined chemical structures that vary with species. This species specificity regulates the sperm acrosome reaction, a critical step to assure intra-specific fertilization. In addition, these polysaccharides are involved in other biological activities such as anticoagulation. Although sulfation patterns are relevant to the levels of response in both activities, conformation and dynamics of these glycans are also contributing factors. However, data about these features of sulfated fucans are very rare. To address this, we have employed nuclear magnetic resonance experiments combined with molecular dynamics on structurally defined oligosaccharides derived from two sulfated fucans. The results have indicated that the oligosaccharides are flexible in solution. Ring conformation of their composing units displays just the (1)C4 chair configuration. In a particular octasaccharide, composed of two tetrasaccharide sequences, inter-residual hydrogen bonds play a role to decrease dynamics in these repeating units. Conversely, the linking disaccharide [-3)-alpha-L-Fucp-2(OSO3(-))-(1-3)-alpha-L Fucp-4(OCO3(-))-(1-] located right between the two tetrasaccharide units has amplified motions suggested to be promoted by electrostatic repulsion of sulfates on opposite sides of the central glycosidic bond. This conjunction of information about conformation and dynamics of sulfated fucan oligosaccharides provides new insights to explain how these glycans behave free in solution and influenced by sulfation patterns. It may also serve for future studies concerning structure function relationship of sulfated fucans, especially those involving sea urchin fertilization and anticoagulation. PMID- 25527428 TI - Rapid nuclear transit and impaired degradation of amyloid beta and glypican-1 derived heparan sulfate in Tg2576 mouse fibroblasts. AB - Anhydromannose (anMan)-containing heparan sulfate (HS) derived from S nitrosylated glypican-1 is generated in endosomes by an endogenously or ascorbate induced S-nitrosothiol-catalyzed reaction. Expression and processing of amyloid precursor protein (APP) is required to initiate formation and endosome-to-nucleus translocation of anMan-containing HS in wild-type mouse embryonic fibroblasts (WT MEF). HS is then transported to autophagosomes and finally degraded in lysosomes. To investigate how APP-derived amyloid beta (Abeta) peptide affects intracellular trafficking of HS, we have studied nuclear transit as well as autophagosome/lysosome targeting and degradation in transgenic Alzheimer disease mouse (Tg2576) MEF which produce increased amounts of Abeta. Deconvolution immunofluorescence microscopy with an anMan-specific monoclonal antibody showed anMan staining in the nuclei of Tg2576 MEF after 5 min of ascorbate treatment and after 15 min in WT MEF. There was also greater nuclear accumulation of HS in Tg2576 MEF as determined by (35)S-sulfate-labeling experiments. Tg2576 MEF was less sensitive to inhibition of NO production and copper-chelation than WT MEF. By using APP- and Abeta-recognizing antibodies, we observed nuclear translocation of Abeta peptide in Tg2576 MEF but not in WT MEF. HS remained in the nucleus of WT MEF for at least 8 h and was then transported to autophagosomes. By 8 h, HS had disappeared from the nuclei of Tg2576 MEF but colocalized poorly with the autophagosome marker LC3. Abeta also disappeared rapidly from the nuclei of Tg2576 MEF. Initially, it appeared in acidic vesicles and later it accumulated extracellularly. Thus, in Tg2576 MEF there is nuclear accumulation as well as secretion of Abeta and impaired degradation of HS. PMID- 25527430 TI - The white matter of the human cerebrum: part I The occipital lobe by Heinrich Sachs. AB - This is the first complete translation of Heinrich Sachs' outstanding white matter atlas dedicated to the occipital lobe. This work is accompanied by a prologue by Prof Carl Wernicke who for many years was Sachs' mentor in Breslau and enthusiastically supported his work. PMID- 25527429 TI - Single molecule study of heterotypic interactions between mucins possessing the Tn cancer antigen. AB - Mucins are linear, heavily O-glycosylated proteins with physiological roles that include cell signaling, cell adhesion, inflammation, immune response and tumorgenesis. Cancer-associated mucins often differ from normal mucins by presenting truncated carbohydrate chains. Characterization of the binding properties of mucins with truncated carbohydrate side chains could thus prove relevant for understanding their role in cancer mechanisms such as metastasis and recognition by the immune system. In this work, heterotypic interactions of model mucins that possess the Tn (GalNAcalphaThr/Ser) and T (Galbeta1 3GalNAcalphaThr/Ser) cancer antigens derived from porcine submaxillary mucin (PSM) were studied using atomic force microscopy. PSM possessing only the Tn antigen (Tn-PSM) was found to bind to PSM analogs possessing a combination of T, Tn and STn antigens as well as biosynthetic analogs of the core 1 blood group A tetrasaccharide (GalNAcalpha1-3[Fucalpha1-2] Galbeta1-3GalNAcalphaSer/Thr). The rupture forces for the heterotypic interactions ranged from 18- to 31 pN at a force-loading rate of ~0.5 nN/s. The thermally averaged distance from the bound complex to the transition state (xbeta) was estimated to be in the range 0.37 0.87 nm for the first barrier of the Bell Evans analysis and within 0.34-0.64 nm based on a lifetime analysis. These findings reveal that the binding strength and energy landscape for heterotypic interactions of Tn-PSM with the above mucins, resemble homotypic interactions of Tn-PSM. This suggests common carbohydrate epitope interactions for the Tn cancer antigen with the above mucin analogs, a finding that may be important to the role of the Tn antigen in cancer cells. PMID- 25527431 TI - Intravoxel incoherent motion diffusion-weighted imaging in the liver: comparison of mono-, bi- and tri-exponential modelling at 3.0-T. AB - PURPOSE: To determine whether a mono-, bi- or tri-exponential model best fits the intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) signal of normal livers. MATERIALS AND METHODS: The pilot and validation studies were conducted in 38 and 36 patients with normal livers, respectively. The DWI sequence was performed using single-shot echoplanar imaging with 11 (pilot study) and 16 (validation study) b values. In each study, data from all patients were used to model the IVIM signal of normal liver. Diffusion coefficients (Di +/- standard deviations) and their fractions (fi +/- standard deviations) were determined from each model. The models were compared using the extra sum-of squares test and information criteria. RESULTS: The tri-exponential model provided a better fit than both the bi- and mono-exponential models. The tri exponential IVIM model determined three diffusion compartments: a slow (D1 = 1.35 +/- 0.03 * 10(-3) mm(2)/s; f1 = 72.7 +/- 0.9 %), a fast (D2 = 26.50 +/- 2.49 * 10(-3) mm(2)/s; f2 = 13.7 +/- 0.6 %) and a very fast (D3 = 404.00 +/- 43.7 * 10( 3) mm(2)/s; f3 = 13.5 +/- 0.8 %) diffusion compartment [results from the validation study]. The very fast compartment contributed to the IVIM signal only for b values <=15 s/mm(2) CONCLUSION: The tri-exponential model provided the best fit for IVIM signal decay in the liver over the 0-800 s/mm(2) range. In IVIM analysis of normal liver, a third very fast (pseudo)diffusion component might be relevant. KEY POINTS: * For normal liver, tri-exponential IVIM model might be superior to bi-exponential * A very fast compartment (D = 404.00 +/- 43.7 * 10 ( 3) mm (2) /s; f = 13.5 +/- 0.8 %) is determined from the tri-exponential model * The compartment contributes to the IVIM signal only for b <= 15 s/mm(2). PMID- 25527432 TI - PYY3-36: Beyond food intake. AB - The gastrointestinal hormone peptide tyrosine tyrosine 3-36 (PYY(3-36)) has attained broad recognition with respect to its involvement in energy homeostasis and the control of food intake. It is mainly secreted by distal intestinal enteroendocrine L-cells in response to eating and exerts neurally mediated, paracrine and endocrine effects on various target organs. In addition to its gastrointestinal effects, PYY(3-36) has long been known to inhibit food intake. Recent closer examination of the effects of PYY(3-36) revealed that this gut derived peptide also influences a wide spectrum of behavioral and cognitive functions that are pivotal for basic processes of perception and judgment, including central information processing, salience learning, working memory, and behavioral responding to novelty. Here, we review the effects of PYY(3-36) that go beyond food intake and provide a conceptual framework suggesting that several apparently unrelated behavioral actions of PYY(3-36) may actually reflect different manifestations of modulating the central dopamine system. PMID- 25527433 TI - The effect of functional forms of nitrogen on fuel-NOx emissions. AB - This work explores the effects of different nitrogen functional forms on fuel-NOx emissions at 900 degrees C. The majority of tests are performed with an excess air coefficient of 1.4. Fuel-NOx is detected by measuring N-(1-naphthyl) ethylenediamine dihydrochloride (C12H16Cl2N2) via spectrophotometry. The different functional forms of nitrogen in the raw materials are identified by using X-ray photoelectron spectroscopy (XPS). A reliable density functional theory (DFT) method at the B3LYP/6-311++G** level is employed to investigate the reaction pathways of all functional forms of nitrogen during combustion. The results indicate that the functional forms of nitrogen influence the formation of nitrogen oxides. While under the same experimental conditions, fuel-NOx emissions increase by using less activation energy and nitrogen-containing groups with poor thermal stability. It is determined that fuel-NOx emissions vary in the following order: glycine > pyrrole > pyridine > methylenedi-p-phenylene diisocyanate (MDI). Glycine is the chain structure of amino acids in waste-leather and has low activation energy and poor thermal stability. With these properties, it is noted that glycine produces the most fuel-NOx in all of the raw materials studied. More pyrrole than pyridine in coal lead to high yields of fuel-NOx. The lowest yields of fuel-NO x are obtained using polyurethanes in waste-PU. PMID- 25527434 TI - Distribution of heavy metals in sediment cores of Lake Pamvotis (Greece): a pollution and potential risk assessment. AB - Concentrations and vertical distributions of metals in surface sediments of Lake Pamvotis (NW Greece) were assessed using energy-dispersive X-ray fluorescence spectrometry. A wide range of values was determined, associated with the specific types of contaminating effluents draining into different parts of the lake. Overall, Cr levels ranged from 43 to 3295 mg kg(-1), Ni from 13 to 372 mg kg(-1), Cu from 15 to 24,985 mg kg(-1), Zn from 129 to 22,983 mg kg(-1), Zr from 64 to 4063 mg kg(-1) and Pb from 19 to 2634 mg kg(-1). Principal component analysis revealed distinct elemental fingerprints in each sampling location, while correlation analysis and hierarchical agglomerative cluster analysis provided insight to metal association and pollution sources. Enrichment factors and geoaccumulation indices were calculated to quantify sediment contamination, and potential ecotoxic effects were evaluated based on sediment quality guidelines. Moderate to very severe enrichment in Zn, Cu and Pb was evidenced in sediments near the lake's outflow. The proximity of these sampling points to a heavy traffic national road suggests that roadway runoff is the dominant source of elevated metal levels. Contribution from municipal sewage water discharges from the nearby communities should also be accounted for. Moderate to very severe Zn and Pb enrichment was determined in the vicinity on the main lake's inflow, primarily associated with runoff and leaching from agricultural land. Very severe to extremely severe Cr enrichment was detected in the same location, most likely associated with wastewater discharged into the lake over several decades, by nearby-operating leather tanneries. The above two locations were ranked at the highest priority level in terms of potential ecological risk. PMID- 25527435 TI - An evaluation of potential sampling locations in a reservoir with emphasis on conserved spatial correlation structure. AB - In this study, kernel density estimation (KDE) was coupled with ordinary two dimensional kriging (OK) to reduce the number of sampling locations in measurement and kriging of dissolved oxygen (DO) concentrations in Porsuk Dam Reservoir (PDR). Conservation of the spatial correlation structure in the DO distribution was a target. KDE was used as a tool to aid in identification of the sampling locations that would be removed from the sampling network in order to decrease the total number of samples. Accordingly, several networks were generated in which sampling locations were reduced from 65 to 10 in increments of 4 or 5 points at a time based on kernel density maps. DO variograms were constructed, and DO values in PDR were kriged. Performance of the networks in DO estimations were evaluated through various error metrics, standard error maps (SEM), and whether the spatial correlation structure was conserved or not. Results indicated that smaller number of sampling points resulted in loss of information in regard to spatial correlation structure in DO. The minimum representative sampling points for PDR was 35. Efficacy of the sampling location selection method was tested against the networks generated by experts. It was shown that the evaluation approach proposed in this study provided a better sampling network design in which the spatial correlation structure of DO was sustained for kriging. PMID- 25527436 TI - Programme for genetic diagnosis of rare diseases proves feasible for routine clinical practice. PMID- 25527437 TI - Focusing on results after meniscus surgery. PMID- 25527438 TI - Improvement of catechin production in Escherichia coli through combinatorial metabolic engineering. AB - Reconstruction of highly efficient biosynthesis pathways is essential for the production of valuable plant secondary metabolites in recombinant microorganisms. In order to improve the titer of green tea catechins in Escherichia coli, combinatorial strategies were employed using the ePathBrick vectors to express the committed catechin pathway: flavanone 3beta-hydroxylase (F3H), dihydroflavonol 4-reductase (DFR), and leucoanthocyanidin reductase (LAR). Three F3H, three DFR, and two LAR genes originating from different plant species were selected and synthesized, to create 18 pathway variants to be screened in E. coli. Constructs containing F3H(syn) originally from Camellia sinensis, DFR(syn) from Anthurium andraeanum, C. sinensis, or Fragaria ananass, and LAR(syn) from Desmodium uncinatum (p148, p158 and p168) demonstrated high conversion efficiency with either eriodictyol or naringenin as substrate. A highly efficient construct was created by assembling additional copies of DFR(syn) and LAR(syn) enabling a titer of 374.6 +/- 43.6 mg/L of (+)-catechin. Improving the NADPH availability via the DeltapgiDeltappc mutation, BLDeltapgiDeltappc-p148 produced the highest titer of catechin at 760.9 +/- 84.3 mg/L. After utilizing a library of scaffolding proteins, the strain BLDeltapgiDeltappc-p168-759 reached the highest titer of (+)-catechin of 910.9 +/- 61.3 mg/L from 1.0 g/L of eriodictyol in batch culture with M9 minimal media. The impact of oxygen availability on the biosynthesis of catechin was also investigated. PMID- 25527439 TI - Engineering validamycin production by tandem deletion of gamma-butyrolactone receptor genes in Streptomyces hygroscopicus 5008. AB - Paired homologs of gamma-butyrolactone (GBL) biosynthesis gene afsA and GBL receptor gene arpA are located at different positions in genome of Streptomyces hygroscopicus 5008. Inactivation of afsA homologs dramatically decreased biosynthesis of validamycin, an important anti-fungal antibiotic and a critical substrate for antidiabetic drug synthesis, and the deletion of arpA homologs increased validamycin production by 26% (DeltashbR1) and 20% (DeltashbR3). By double deletion, the DeltashbR1/R3 mutant showed higher transcriptional levels of adpA-H (the S. hygroscopicus ortholog of the global regulatory gene adpA) and validamycin biosynthetic genes, and validamycin production increased by 55%. Furthermore, by engineering a high-producing industrial strain via tandem deletion of GBL receptor genes, validamycin production and productivity were enhanced from 19 to 24 g/L (by 26%) and from 6.7 to 9.7 g/L(-1) d(-1) (by 45%), respectively, which was the highest ever reported. The strategy demonstrated here may be useful to engineering other Streptomyces spp. with multiple pairs of afsA arpA homologs. PMID- 25527440 TI - Conserved microRNA function as a basis for Chinese hamster ovary cell engineering. AB - The use of microRNAs (miRNAs) for improving the efficiency of recombinant protein production by CHO cells is gaining considerable interest for their ability to regulate entire molecular networks. Differential miRNA expression profiling and large-scale transient screening have been the prerequisite for the selection of miRNA candidates for stable manipulation, reported in CHO cells expressing a range of recombinant products. We selected a potent and well characterised tumour suppressor miRNA, miR-34a, as a high priority candidate for CHO cell engineering based on the conservation of both its sequence and function across species and cell type. Ectopic expression of miR-34a retained its functional conservation in CHO-SEAP cells by inhibiting growth by 90% in addition to decreasing the viable cell population by 30% when compared to controls. When the miR-34 family was stably depleted using a miRNA sponge decoy vector, the overall product yield was enhanced by ~2-fold in both fed-batch and small scale clonal batch cultures, despite having a negative impact on cell growth. These findings further strengthen the utility of miRNAs as engineering tools to modify and improve CHO cell performance. PMID- 25527441 TI - Eliciting Personhood Within Clinical Practice: Effects on Patients, Families, and Health Care Providers. AB - CONTEXT: Failure to acknowledge personhood is often the cause of patient and family dissatisfaction. We developed the Patient Dignity Question (PDQ) as a simple means of inquiring about personhood: "What do I need to know about you as a person to give you the best care possible?" OBJECTIVES: This study aimed to evaluate the impact of the PDQ on patients and families, evaluate its influence on health care providers (HCPs), and determine if HCP characteristics mediate receptivity to PDQ-elicited information. METHODS: Palliative care patients or their family members were asked to respond to the PDQ. Responses were summarized, read to participants to ensure accuracy, and with permission, placed in their charts. Patient, family, and HCP responses to the PDQ were then elicited. RESULTS: A total of 126 participants (66 patients and 60 family members) responded to the PDQ; 99% indicated that the summaries were accurate, 97% permitted the summary to be placed in the chart, 93% felt that the information was important for HCPs to know, and 99% would recommend the PDQ for others. A total of 137 HCPs completed 293 evaluations of individual PDQs; 90% indicated that they learned something new from it, 64% that they were emotionally affected by it, 59% that it influenced their sense of empathy, and 44% that it influenced their care. HCP empathy, job satisfaction, having a meaningful life, and social support mediated responsiveness to PDQ-elicited information. CONCLUSION: The PDQ offers an effective way of eliciting personhood, enhancing patient, family, and HCP experience alike. PMID- 25527442 TI - Preoperative Breast Pain Predicts Persistent Breast Pain and Disability After Breast Cancer Surgery. AB - CONTEXT: Approximately 30% of the women report pain in the affected breast before breast cancer surgery. OBJECTIVES: The purpose of this secondary analysis of our prospective study was to determine how women who experienced both preoperative and persistent postsurgical breast pain (n=107) differed from women who did not report preoperative breast pain and did (n=158) or did not (n=122) experience persistent postsurgical breast pain. METHODS: Differences in demographic and clinical characteristics were evaluated. Linear mixed effects (LME) modeling was used to evaluate for group differences in symptom severity, function, sensation, and quality of life (QOL) over time. RESULTS: Between-group differences in demographic and clinical characteristics as well as trajectories of shoulder function and QOL were identified. Women with both preoperative and persistent postsurgical breast pain were younger; were more likely to report swelling, strange sensations, hardness, and numbness in the affected breast before surgery; and were more likely to have reconstruction at the time of surgery. Women with both preoperative and persistent postsurgical breast pain had more biopsies in the prior year, more lymph nodes removed, and reported more severe acute postsurgical pain than women without preoperative breast pain. The LME modeling revealed significant group effects for most outcomes evaluated. Over the six months of the study, women with both preoperative and persistent postsurgical pain had persistently poorer shoulder flexion and physical well-being than women without preoperative breast pain. CONCLUSION: Investigations of the etiology and molecular mechanisms of preoperative breast pain, as well as interventions for this high-risk group, are needed. PMID- 25527443 TI - "Their Stories Have Changed My Life": Clinicians' Reflections on Their Experience with and Their Motivation to Conduct Asylum Evaluations. AB - Many clinicians perform asylum evaluations yet no studies describe the motivation to perform them or their perceived rewards. The number of asylum seekers in the US is increasing and more clinicians are needed as evaluators. A survey to an asylum evaluators' network asked participants to qualitatively reflect on their experience and motivation. Answers were analyzed for themes and sentiment. Respondents cited commitment to humanistic and moral values, noted personal and family experiences, having skills, expertise, and career interests as drivers. They found the experience very rewarding personally and professionally, and in their perceived benefit to asylees. Negative sentiment was less frequent and centered on emotions related to client narratives. Process-oriented frustrations were also noted. This is the first published study describing clinicians' motivation and experience with asylum evaluations. It may illuminate clinicians' drive to volunteer, and serve as a resource for organizations for recruitment and education. PMID- 25527444 TI - Involvement of MAPK ERK activation in upregulation of water channel protein aquaporin 1 in a mouse model of Bell's palsy. AB - The aim of this study is to immunolocalize the aquaporin 1 water channel protein (AQP1) in Schwann cells of idiopathic facial nerve and explore its possible role during the development of facial palsy induced by herpes simplex virus type 1 (HSV-1). HSV-1 was inoculated into the surface of posterior auricle of mouse to establish a paralyzed animal model. In HSV-1-induced facial palsy mice, protein levels of AQP1 significantly increased on the 9th to 16th day after inoculation of HSV-1. The upregulation of AQP1 was closely related to the intratemporal facial nerve edema in facial nerve canal, which was also consistent with the symptom of facial palsy in mice. In a hypoxia model of Schwann cells in vitro, we found that U0126, an ERK antagonist, inhibited not only morphological changes of cultures Schwann cells but also upregulation of both AQP1 and phosphorylated ERK. Combined with increased phosphorylated ERK in HSV-1-induced facial palsy mice, we inferred that ERK MAPK pathway might also be involved in increased AQP1 in mouse model of Bell's palsy. Although the precise mechanism needs to be further explored, our findings suggest that AQP1 in Schwann cells of intratemporal facial nerve is involved in the evolution of facial palsy induced by HSV-1 and may play an important role in the pathogenesis of this disease. AQP1 might be a potential target, and the ERK antagonist U0126 could be a new drug for the treatment of HSV 1-induced Bell's palsy in an early stage. PMID- 25527445 TI - Epigenetic modifications in sex heterochromatin of vole rodents. AB - The genome of some vole rodents contains large blocks of heterochromatin coupled to the sex chromosomes. While the DNA content of these heterochromatic blocks has been extensively analyzed, little is known about the epigenetic modifications controlling their structure and dynamics. To better understand its organization and functions within the nucleus, we have compared the distribution pattern of several epigenetic marks in cells from two species, Microtus agrestis and Microtus cabrerae. We first could show that the heterochromatic blocks are identifiable within the nuclei due to their AT enrichment detectable by DAPI staining. By immunostaining analyses, we demonstrated that enrichment in H3K9me3 and HP1, depletion of DNA methylation as well as H4K8ac and H3K4me2, are major conserved epigenetic features of this heterochromatin in both sex chromosomes. Furthermore, we provide evidence of transcriptional activity for some repeated DNAs in cultivated cells. These transcripts are partially polyadenylated and their levels are not altered during mitotic arrest. In summary, we show here that enrichment in H3K9me3 and HP1, DNA demethylation, and transcriptional activity are major epigenetic features of sex heterochromatin in vole rodents. PMID- 25527447 TI - Impact of same-day antibiotic susceptibility testing on time to appropriate antibiotic treatment of patients with bacteraemia: a randomised controlled trial. AB - Inadequate therapy in bloodstream infections is suggested to be associated with higher mortality. We evaluated the reduction in inappropriate antibiotic therapy using rapid identification and antibiotic susceptibility testing (FAST) compared to standard of care (SOC) testing in patients with bloodstream infections. The FAST method used polymerase chain reaction (PCR) for identification and to detect growth in the presence or absence of antibiotics after only 6 h. For SOC testing, the BD Phoenix system was used. Patients with blood cultures growing Staphylococcus, Streptococcus or Enterococcus species or Gram-negative rods were randomised for FAST or SOC tests. A total of 129 patients were randomised for FAST and 121 patients for the SOC group. At the time SOC results became available, 78 patients in the FAST group could have been switched to more appropriate therapy. Although FAST results were highly accurate (agreement with SOC was 94%), they were only implemented in a minority (16) of patients. However, significantly fewer patients in the FAST group used inappropriate therapy at the time of SOC results (p = 0.025). The time to results in the FAST group was reduced by 15.6 h (p < 0.001). In the patients switched after FAST, this was done after a mean of 42.3 h compared to 61.4 h in those switched after SOC tests (p < 0.001). In bacteraemic patients, FAST resulted in significantly more patients using appropriate antibiotic therapy at the time SOC results were available and 15.6 h earlier than SOC tests. However, the implementation of FAST results was not optimal and no benefit on clinical outcome was shown. PMID- 25527446 TI - Analysis of Bordetella pertussis clinical isolates circulating in European countries during the period 1998-2012. AB - Despite more than 50 years of vaccination, pertussis is still an endemic disease, with regular epidemic outbreaks. With the exception of Poland, European countries have replaced whole-cell vaccines (WCVs) by acellular vaccines (ACVs) in the 1990s. Worldwide, antigenic divergence in vaccine antigens has been found between vaccine strains and circulating strains. In this work, 466 Bordetella pertussis isolates collected in the period 1998-2012 from 13 European countries were characterised by multi-locus antigen sequence typing (MAST) of the pertussis toxin promoter (ptxP) and of the genes coding for proteins used in the ACVs: pertussis toxin (Ptx), pertactin (Prn), type 2 fimbriae (Fim2) and type 3 fimbriae (Fim3). Isolates were further characterised by fimbrial serotyping, multi-locus variable-number tandem repeat analysis (MLVA) and pulsed-field gel electrophoresis (PFGE). The results showed a very similar B. pertussis population for 12 countries using ACVs, while Poland, which uses a WCV, was quite distinct, suggesting that ACVs and WCVs select for different B. pertussis populations. This study forms a baseline for future studies on the effect of vaccination programmes on B. pertussis populations. PMID- 25527448 TI - Cost-Effectiveness Evaluation of the 10-Valent Pneumococcal Non-typeable Haemophilus influenzae Protein D Conjugate Vaccine and 13-Valent Pneumococcal Vaccine in Japanese Children. AB - INTRODUCTION: Diseases caused by Streptococcus pneumoniae represent a major public health problem. The purpose of this study was to compare, in the Japanese context, the projected health benefits, costs and cost-effectiveness of the latest generation of pneumococcal conjugate vaccines which may provide important insight into the potential public health impact of interventions in the context of local disease-specific epidemiology. METHODS: A Markov model was used to compare two vaccination strategies which involve routine infant immunization with either the 13-valent pneumococcal conjugate vaccine (PCV-13; Prevenar 13TM, Pfizer, Pearl River, NY, USA) or the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; SynflorixTM, GlaxoSmithKline Biologicals SA, Rixensart, Belgium) over a time horizon of 5 years from the healthcare provider and societal perspectives. Estimates for key model parameters were obtained from locally available databases and published literature. Incremental benefits in terms of costs and quality-adjusted life-year and cost-effectiveness were assessed. RESULTS: A 3 + 1 vaccination schedule for infants with PHiD-CV is expected to have a similar impact on invasive pneumococcal disease and pneumonia and a larger impact on acute otitis media related outcomes compared with PCV-13. Assuming price parity for these vaccines, the model projected that vaccination with PHiD-CV would result in cost savings of 1.9 and 3.9 billion Japanese yen from the provider and societal perspectives, respectively. This was largely due to a reduction in highly prevalent acute otitis media. Vaccination with PHiD-CV was expected to generate a gain of 433 quality-adjusted life-years compared to PCV-13 translating into dominance over PCV-13. Sensitivity analyses showed robustness of model outcome to changes in key model parameters and substantiated that the model outcome was consistently driven by the incremental benefit of PHiD-CV in averting acute otitis media. CONCLUSION: In comparison to PCV-13, vaccination with PHiD-CV is projected to be cost saving for Japan from both the healthcare provider and societal perspectives. PMID- 25527449 TI - Renal cancer treatment with recipient lymphocyte infusion enhanced the antitumor effect of nonmyeloablative allogeneic stem cell transplantation. AB - BACKGROUND: Nonmyeloablative allogeneic stem cell transplantation (SCT) is an option for the treatment of metastatic renal cancer. Mature donor T cells cause graft versus-host disease (GVHD) although they are also the main mediators of the beneficial graft-versus-tumor (GVT) activity associated with this treatment. Hence, the segregation of GVT activity from GVHD is an important challenge in managing the clinical course of treatment. We previously reported a series of studies regarding the allograft tolerance induced by allogeneic spleen cells (with bone marrow cells) and cyclophosphamide in mice. METHODS: The aim of the present study was to modify the cyclophosphamide-using cell therapy to reduce the risk of GVHD while preserving the antitumor activity against RENCA, a murine carcinogen-induced renal cell carcinoma with recipient lymphocyte infusion (RLI). RESULTS: Regarding the in vivo antitumor effect, there was a significant difference between RLI and no lymphocyte infusion after the cyclophosphamide treatment, whereas the histologic findings of the small intestine showed that the cyclophosphamide-using cell therapy with RLI decreased the risk of GVHD as compared with donor lymphocyte infusion. In addition, the acquired immunity against RENCA was clearly observed in RLI-treated mice. CONCLUSIONS: Our results show that RLI during cyclophosphamide-using nonmyeloablative cell therapy can dissociate GVT effects from GVHD by reducing the risk of GVHD. We considered that this was the first report to provide the evidence of nonmyeloablative allogeneic SCT with RLI for the treatment of renal cell carcinoma which never induce complete chimerism. PMID- 25527451 TI - Tumor vasculature and glioma stem cells: Contributions to glioma progression. AB - Glioblastoma multiforme (GBM), the most malignant of brain tumors, is characterized by extensive vascularization and a high degree of invasion. The current standard of care is not very effective, resulting in tumor recurrence with patients rarely surviving over 2 years. This tumor recurrence is attributed to the presence of chemo and radiation resistant glioma stem cells (GSCs). These cells are associated with vascular niches which regulate GSC self-renewal and survival. Recent studies suggest that while blood vessels support glioma stem cells, these tumor cells in turn may regulate and contribute to the tumor vasculature by transdifferentiating into endothelial cells directly or through the secretion of regulatory growth factors such as vascular endothelial growth factor (VEGF) and hepatoma derived growth factor (HDGF). The relationship between the tumor vasculature and the glioma stem cells is the subject of this review. PMID- 25527450 TI - Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer. AB - Angiogenesis remains a sensible target for pancreatic ductal adenocarcinoma (PDAC) therapy. VEGF, PDGF, FGF and their receptors are expressed at high levels and correlate with poor prognosis in human PDAC. Nintedanib is a triple angiokinase inhibitor that targets VEGFR1/2/3, FGFR1/2/3 and PDGFRalpha/beta signaling. We investigated the antitumor activity of nintedanib alone or in combination with the cytotoxic agent gemcitabine in experimental PDAC. Nintedanib inhibited proliferation of cells from multiple lineages found in PDAC, with gemcitabine enhancing inhibitory effects. Nintedanib blocked PI3K/MAPK activity and induced apoptosis in vitro and in vivo. In a heterotopic model, net local tumor growth compared to controls (100%) was 60.8 +/- 10.5% in the gemcitabine group, -2.1 +/- 9.9% after nintedanib therapy and -12.4 +/- 16% after gemcitabine plus nintedanib therapy. Effects of therapy on intratumoral proliferation, microvessel density and apoptosis corresponded with tumor growth inhibition data. In a PDAC survival model, median animal survival after gemcitabine, nintedanib and gemcitabine plus nintedanib was 25, 31 and 38 days, respectively, compared to 16 days in controls. The strong antitumor activity of nintedanib in experimental PDAC supports the potential of nintedanib-controlled mechanisms as targets for improved clinical PDAC therapy. PMID- 25527452 TI - Blockade of estrogen-stimulated proliferation by a constitutively-active prolactin receptor having lower expression in invasive ductal carcinoma. AB - A comprehensive understanding of prolactin's (PRL's) role in breast cancer is complicated by disparate roles for alternatively-spliced PRL receptors (PRLR) and crosstalk between PRL and estrogen signaling. Among PRLRs, the short form 1b (SF1b) inhibits PRL-stimulated cell proliferation. In addition to ligand dependent PRLRs, constitutively-active varieties, missing the S2 region of the extracellular domain (DeltaS2), naturally occur. Expression analysis of the DeltaS2 version of SF1b (DeltaS2SF1b) showed higher expression in histologically normal contiguous tissue versus invasive ductal carcinoma. To determine the function of DeltaS2SF1b, a T47D breast cancer line with inducible expression was produced. Induction of DeltaS2SF1b blocked estrogen-stimulated cell proliferation. Unlike intact SF1b, induction of DeltaS2SF1b had no effect on PRL mediated activation of Stat5a. However induction inhibited estrogen's stimulatory effects on serine-118 phosphorylation of estrogen receptor alpha, serine-473 phosphorylation of Akt, serine-9 phosphorylation of GSK3beta, and c-myc expression. In addition, induction of DeltaS2SF1b increased expression of the cell cycle-inhibiting protein, p21. Thus, increased expression of DeltaS2SF1b, such as we demonstrate occurs with the selective PRLR modulator, S179D PRL, would create a physiological state in which estrogen-stimulated proliferation was inhibited, but differentiative responses to PRL were maintained. PMID- 25527453 TI - Pharmacologic co-inhibition of Mnks and mTORC1 synergistically suppresses proliferation and perturbs cell cycle progression in blast crisis-chronic myeloid leukemia cells. AB - The Ras/Raf/MAPK and PI3K/Akt/mTORC1 cascades are two most aberrantly regulated pathways in cancers. As MAPK-interacting kinases (Mnks) are part of the convergent node of these two pathways, and play a pivotal role in cellular transformation, targeting Mnks has emerged as a potential therapeutic strategy. Herein, a dual-specific Mnk1/2 inhibitor MNKI-57 and a potent Mnk2-specific inhibitor MNKI-4 were selected for a panel screen against 28 human cancer cell lines. The study reveals that MNKI-57 and MNKI-4 are most potent against leukemia cells KYO-1 (i.e. BC-CML) and KG-1 (i.e. AML). Interestingly, we found that sensitivity of selected leukemia cells to Mnk inhibitors is correlated with the level of phosphorylated 4E-BP1 at Thr70. The anti-proliferative effects of Mnk inhibitors are cytostatic in the sensitive KYO-1 cells, inducing significant G1 arrest via down-regulation of cyclin D1 expression. In KYO-1 cells where Akt is not constitutively active, Mnk inhibitors increase the sensitivity of cells to rapamycin, resulting in a more pronounced anti-proliferative activity. Remarkably, the synergistic anti-proliferative effects are associated with a marked de-phosphorylation of 4E-BP1 at Thr70. Collectively, these data highlight the importance of 4E-BP1 as a key integrator in the MAPK and mTORC1 cascades, and suggest that a combined pharmacologic inhibition of mTORC1 and Mnk kinases offers an innovative therapeutic opportunity in BC-CML. PMID- 25527454 TI - Inhibition of nestin suppresses stem cell phenotype of glioblastomas through the alteration of post-translational modification of heat shock protein HSPA8/HSC71. AB - Nestin, a class VI intermediate filament, was first described as a neuronal stem/progenitor cell marker. We previously reported that knockdown of nestin expression in human glioblastoma cells suppresses cell proliferation, migration, and invasion. In the present study, we examined the effect of nestin on stemness, and identified molecules involved in modulating nestin function in glioblastoma cells. Nestin expression was shown to be higher in high-grade gliomas than in low grade gliomas. Furthermore, compared with control cells, nestin short hairpin RNA (shRNA)-transfected glioblastoma cells exhibited reduced sphere formation, decreased expression of NANOG, N-cadherin, CD133, and Oct-4, and decreased tumor size in vivo. To examine the proteins regulated by nestin in glioblastomas, we carried out two-dimensional electrophoresis using nestin shRNA-transfected glioblastoma cells. As a result, nestin shRNA-transfected glioblastoma cells exhibited a decrease in the level of phosphorylation of heat shock cognate 71 kDa protein (HSC71; gene HSPA8). From immunoprecipitation experiments, we demonstrated the direct binding of nestin, HSC71, and cyclin D1 in vitro. Overexpression of nestin in glioblastoma cells increased cell growth, sphere formation, and cell invasion. Transfection with HSC71 siRNA restored nestin expression and cell behavior; therefore, HSC71 knockdown will interfere with enhanced tumorigenic properties of glioblastoma cells that ectopically overexpress nestin. We have demonstrated that HSC71 and nestin regulate each other's expression levels or patterns, and that cyclin D1 is located downstream of nestin and HSC71. In conclusion, nestin regulates stemness, cell growth, and invasion in glioblastoma cells through the alteration of HSC71. Inhibition of nestin and HSC71 may thus be a useful molecular target in the treatment of glioblastomas. PMID- 25527455 TI - The tumor marker score is an independent predictor of survival in patients with recurrent hepatocellular carcinoma. AB - PURPOSE: Alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) are prognostic factors for hepatocellular carcinoma (HCC). The impact of these tumor markers in recurrent HCC on the prognosis remains to be fully elucidated. METHODS: Two hundred and seventeen patients whose AFP and DCP levels were measured at recurrence were enrolled in the present study. AFP levels >10 ng/mL and DCP levels >=40 mAU/mL were defined as AFP positive (AFP+) and DCP positive (DCP+), respectively. The patterns of tumor markers were scored as AFP-/DCP-, 0; AFP+/DCP- or AFP-/DCP+, 1 and AFP+/DCP+, 2. RESULTS: The median survival period after recurrence in patients with a score of 2 (26.6 months) was significantly lower than that in patients with scores of 1 or 0 (43.5 months, P < 0.01; 75.3 months, P < 0.01, respectively). A multivariate analysis showed that a tumor marker score of 2 at recurrence was an independent predictor for poor survival after recurrence (hazard ratio 2.12, P = 0.03). The prognosis after recurrence in the patients with a decreased tumor maker score was significantly better than that in the patients with no change in the tumor marker score compared to the primary surgery (P = 0.048). CONCLUSIONS: The present study shows that measurements of both AFP and DCP are useful for predicting the prognosis of recurrent HCC. PMID- 25527456 TI - Effects of bowel cleansing on the intestinal microbiota. AB - OBJECTIVE: An adequate bowel cleansing is essential for a successful colonoscopy. Although purgative consumption is safe for the patient, there is little consensus on how the intestinal microbiota is affected by the procedure, especially regarding the potential long-term consequences. DESIGN: 23 healthy subjects were randomised into two study groups consuming a bowel preparation (Moviprep), either in two separate doses of 1 L or as a single 2-L dose. Participants donated faecal samples at the baseline, after bowel cleansing, 14 and 28 days after the treatment. The intestinal microbiota composition was determined with phylogenetic microarray as well as quantitative PCR analysis and correlated with the previously quantified faecal serine proteases. RESULTS: The lavage introduced an instant and substantial change to the intestinal microbiota. The total microbial load was decreased by 31-fold and 22% of the participants lost the subject specificity of their microbiota. While the bacterial levels and community composition were essentially restored within 14 days, the rate of recovery was dose dependent: consumption of the purgative in a single dose had a more severe effect on the microbiota composition than that of a double dose, and notably increased the levels of Proteobacteria, Fusobacteria and bacteria related to Dorea formicigenerans. The abundance of the latter also correlated with the amount of faecal serine proteases that were increased after purging. CONCLUSIONS: Our results suggest that the bowel cleansing using two separate dosages introduces fewer alterations to the intestinal microbiota than a single dose and hence may be preferred in clinical practice. PMID- 25527457 TI - Unique stability of femoral neck fractures treated with the novel biplane double supported screw fixation method: a biomechanical cadaver study. AB - Osteosynthesis of femoral neck fractures is related to 20-46% complication rate. Filipov's novel method for biplane double-supported screw fixation (BDSF), using three cannulated screws, has demonstrated excellent clinical results since 2007. Its two calcar-buttressed screws are oriented in different coronal inclinations with steeper angles to the diaphyseal axis and intended to provide constant fixation strength under different loading situations. The aim of this study was to biomechanically evaluate BDSF fixation strength and compare it with the conventional fixation (CFIX) using three parallel cannulated screws. METHODS: Eight fresh-frozen and six embalmed human femoral pairs with simulated AO/OTA31 B2.2 fracture were fixed applying either CFIX or BDSF. Quasistatic tests were performed in anteroposterior (AP) bending, followed by axial quasistatic, cyclic and destructive quasistatic tests run in 10 degrees flexion with 7 degrees or 16 degrees varus specimen inclination. RESULTS: Initial axial stiffness was significantly higher for BDSF in comparison with CFIX at 7 degrees inclination (p=0.02) and not significantly different between BDSF and CFIX at 16 degrees inclination. Compared with the intact state, it decreased significantly at 7 degrees inclination only for CFIX (p=0.01), but not for BDSF. Interfragmentary displacement during cyclic testing was significantly smaller for BDSF than CFIX at 7 degrees inclination (p<=0.04) and not significantly different between BDSF and CFIX at 16 degrees inclination. Failure load did not differ significantly between BDSF and CFIX at both inclinations. CONCLUSIONS: Femoral neck fracture stability can be substantially increased applying BDSF due to better cortical screw support and screw orientation. Having two calcar-buttressed screws oriented in different inclinations, BDSF can enhance constant stability during various patient activities. The more unstable the situation, the better BDSF stability is in comparison to CFIX. PMID- 25527458 TI - Larger ATV engine size correlates with an increased rate of traumatic brain injury. AB - INTRODUCTION: Since the introduction of all-terrain vehicles (ATV) to the United States in 1971, injuries and mortalities related to their use have increased significantly. Furthermore, these vehicles have become larger and more powerful. As there are no helmet requirements or limitations on engine-size in the State of Alabama, we hypothesised that larger engine size would correlate with an increased incidence of traumatic brain injury (TBI) in patients following an ATV crash. METHODS: Patient and ATV data were prospectively collected on all ATV crashes presenting to a level one trauma centre from September 2010 to May 2013. Collected data included: demographics, age of driver, ATV engine size, presence of helmet, injuries, and outcomes. The data were grouped according to the ATV engine size in cubic centimetres (cc). For the purposes of this study, TBI was defined as any type of intracranial haemorrhage on the initial computed tomography scan. RESULTS: There were 61 patients identified during the study period. Two patients (3%) were wearing a helmet at the time of injury. Patients on an ATV with an engine size of 350 cc or greater had higher Injury Severity Scores (13.9 vs. 7.5, p <= 0.05) and an increased incidence of TBI (26% vs. 0%, p <= 0.05) when compared to patients on ATV's with an engine size less than 350 cc. CONCLUSIONS: Patients on an ATV with an engine size of 350 cc or greater were more likely to have a TBI. The use of a helmet was rarely present in this cohort. Legislative efforts to implement rider protection laws for ATVs are warranted. PMID- 25527459 TI - Significance of clinical examination, CT and MRI scan in the diagnosis of posterior pelvic ring fractures. AB - INTRODUCTION: Patients with a fracture in the anterior pelvic ring often simultaneously demonstrate pain in the posterior pelvic ring. The aim of the present prospective study was to assess the sensitivity of CT, MRI and clinical examination in the detection of fractures in the posterior pelvic ring in patients with fractures of the anterior pelvic ring diagnosed in conventional radiographs. METHODS: Sixty patients with radiographic signs of an anterior pelvic ring injury were included in this prospective analysis. Following a focused clinical examination of the posterior pelvis, all patients underwent both a CT and then a MRI scan of their pelvis. Two board certified radiologists evaluated the CT and MRI scans independently. To estimate the presence of osteoporosis the Hounsfield units of the vertebral body of L5 were measured in each case. RESULTS: Fifty-three women and seven men, with a mean age of 74.7+/ 15.6 years were included into the study. A fracture of the posterior pelvic ring was found in fourty-eight patients (80%) patients using MRI. Fractures of the posterior pelvic ring would have been missed in eight cases (17%), if only CT had been used. Eighty-five percent of the patients with a posterior fracture had an osteoporosis. The majority of the cases suffered from a low energy trauma. Thirty eight patients (83%) with positive clinical signs at the posterior pelvic ring actually had a fracture of the posterior pelvic ring in the MRI. The clinical examination proved to be equally effective to CT in detecting posterior pelvic ring fractures. CONCLUSION: The significance of both, clinical examination and CT was confirmed in the detection of fractures in the posterior pelvic ring. MRI examination of the pelvis however, was found to be superior in detecting undislocated fractures in a cohort of patients with a high incidence of osteoporosis. Using MRI may be beneficial in select cases, especially when reduced bone density is suspected. PMID- 25527460 TI - Quantum yield measurements of light-induced H2 generation in a photosystem I [FeFe]-H2ase nanoconstruct. AB - The quantum yield for light-induced H2 generation was measured for a previously optimized bio-hybrid cytochrome c 6-crosslinked PSI(C13G)-1,8-octanedithiol [FeFe]-H2ase(C97G) (PSI-H2ase) nanoconstruct. The theoretical quantum yield for the PSI-H2ase nanoconstruct is 0.50 molecules of H2 per photon absorbed, which equates to a requirement of two photons per H2 generated. Illumination of the PSI H2ase nanoconstruct with visible light between 400 and 700 nm resulted in an average quantum yield of 0.10-0.15 molecules of H2 per photon absorbed, which equates to a requirement of 6.7-10 photons per H2 generated. A possible reason for the difference between the theoretical and experimental quantum yield is the occurrence of non-productive PSI(C13G)-1,8-octanedithiol-PSIC13G (PSI-PSI) conjugates, which would absorb light without generating H2. Assuming the thiol-Fe coupling is equally efficient at producing PSI-PSI conjugates as well as in producing PSI-H2ase nanoconstructs, the theoretical quantum yield would decrease to 0.167 molecules of H2 per photon absorbed, which equates to 6 photons per H2 generated. This value is close to the range of measured values in the current study. A strategy that purifies the PSI-H2ase nanoconstructs from the unproductive PSI-PSI conjugates or that incorporates different chemistries on the PSI and [FeFe]-H2ase enzyme sites could potentially allow the PSI-H2ase nanoconstruct to approach the expected theoretical quantum yield for light induced H2 generation. PMID- 25527461 TI - Fluorescence relaxation in intact cells of photosynthetic bacteria: donor and acceptor side limitations of reopening of the reaction center. AB - The dark relaxation of the yield of variable BChl fluorescence in the 10(-5)-10 s time range is measured after laser diode (808 nm) excitation of variable duration in intact cells of photosynthetic bacteria Rba. sphaeroides, Rsp. rubrum, and Rvx. gelatinosus under various treatments of redox agents, inhibitors, and temperature. The kinetics of the relaxation is complex and much wider extended than a monoexponential function. The longer is the excitation, the slower is the relaxation which is determined by the redox states, sizes, and accessibility of the pools of cytochrome [Formula: see text] and quinone for donor and acceptor side-limited bacterial strains, respectively. The kinetics of fluorescence decay reflects the opening kinetics of the closed RC. The relaxation is controlled preferentially by the rate of re-reduction of the oxidized dimer by mobile cytochrome [Formula: see text] in Rba. sphaeroides and Rsp. rubrum and by the rate constant of the [Formula: see text] interquinone electron transfer, (350 MUs)(-1) and/or the quinol/quinone exchange at the acceptor side in Rvx. gelatinosus. The commonly used acceptor side inhibitors (e.g., terbutryn) demonstrate kinetically limited block of re-oxidation of the primary quinone. The observations are interpreted in frame of a minimum kinetic and energetic model of electron transfer reactions in bacterial RC of intact cells. PMID- 25527462 TI - Re-emergence of a genetic outlier strain of equine arteritis virus: Impact on phylogeny. AB - Equine arteritis virus (EAV) is the causative agent of equine viral arteritis (EVA), a respiratory and reproductive disease of equids, which is notifiable in some countries including the Great Britain (GB) and to the OIE. Herein, we present the case of a persistently infected stallion and the phylogenetic tracing of the virus strain isolated. Discussing EAV occurrence and phylogenetic analysis we review features, which may aid to harmonise and enhance the classification of EAV. PMID- 25527463 TI - Derivation of cell-adapted Sacbrood virus (SBV) from the native Korean honeybee. AB - Sacbrood virus (SBV), a causative agent of larval death in honeybees, is one of the most devastating diseases in bee industry throughout the world. Lately the Korean Sacbrood virus (KSBV) induced great losses in Korean honeybee (Apis cerana) colonies. However, there is no culture system available for honeybee viruses, including SBV, therefore, the research on honeybee viruses is practically limited until present. In this study, we investigated the growth and replication of SBV in cell cultures. The replication signs of KSBV after passages from mammalian cells was identified and confirmed by using combined approaches with nested, quantitative, negative-strand PCR and electron microscopy along with in vivo experiment. The results revealed that mammalian cell lines, including Vero cells could support the replication KSBV. Although there were no signs of cytopathic effect (CPE) in cells, it was for the first time demonstrated that SBV could be replicated in cells through the sequential passages linked with cell adaptation. KSBV from the present study would be a valuable source to understand the mechanism of pathogenicity of sacbrood virus in the future. PMID- 25527464 TI - Glycosylation at hemagglutinin Asn-167 protects the H6N1 avian influenza virus from tryptic cleavage at Arg-201 and maintains the viral infectivity. AB - Cleavage of the hemagglutinin (HA) precursor (HA0) by trypsin, which produces the active HA1 and HA2 complex, is a critical step for activating the avian influenza virus (AIV). However, other tryptic cleavage sites on HA might also cause HA degradation and affect the virulence. Otherwise, HA is modified by glycosylation in the host cell. The conjugated glycans on HA may hinder the antigenic epitopes, and thus prevent the virus from being recognized and attacked by the antibodies. In this study, we observed that glycosylation at the Asn-167 (N167) site on the HA1 of the H6N1 AIV strain A/chicken/Taiwan/2838V/00 (2838V) protected Arg-201 (R201) from tryptic cleavage. The 2838V HA protein became sensitive to tryptic cleavage, whereas the glycans at N167 were removed by N-glycosidase F (PNGase-F). Furthermore, the infectivity of 2838V decreased when pretreated with PNGase-F and trypsin. Our observations suggest that the inaccessibility of the R201 residue of HA1 for tryptic cleavage, which is sterically hindered by glycosylation at N167, is a crucial factor for determining the infectivity of the AIV. PMID- 25527465 TI - Radiological imaging features and clinicopathological correlation of hemosiderotic fibrolipomatous tumor: experience in a single tertiary cancer center. AB - OBJECTIVE: To determine the imaging features of hemosiderotic fibrolipomatous tumor (HFLT), which has a propensity towards local recurrence and the potential to transform into myxoinflammatory fibroblastic sarcoma (MIFS). MATERIALS AND METHODS: The study included 8 patients with a diagnosis of HFLT and imaging at a tertiary cancer center. Imaging studies included radiographs (n = 2), ultrasound (n = 3), and MRI (n = 16). Imaging features were evaluated including location, calcification, sonographic echogenicity, vascular flow, size, border, signal characteristics, contrast enhancement, and blooming on MRI. RESULTS: The HFLT was located in the ankle/foot in 4 out of 8 and was subcutaneous in 8 out of 8, ranging in size from 2 to 18 cm. Histology at initial diagnosis was HFLT in 5 out of 8 and HFLT with MIFS in 3 out of 8. None was calcified on radiography. On ultrasound 2 out of 3 were heterogeneously echogenic with >=10 foci of vascular flow. Two out of 8 patients had MRI only at local recurrence. The tumor border was infiltrative in 4 out of 6 at initial diagnosis and in 2 patients with MRI at recurrence only. Fat and septae were present in 7 out of 8 at initial diagnosis and at recurrence. Signal intensity was iso-/hypointense to muscle on T1-weighted sequences in more than two thirds of the tumor in 4 out of 7 and hyperintense to muscle in at least one third of the tumor on fluid-sensitive sequences in 6 out of 8. Contrast enhancement was heterogeneous in 7 out of 7; blooming in two thirds of the tumor on gradient-echo sequence MRI indicated hemorrhage. CONCLUSION: The HFLT commonly presents as a mass with an infiltrative border, interspersed fat and septations at initial diagnosis and local recurrence on MRI regardless of histology of HFLT alone or with MIFS. Hemosiderin deposits may be detected as blooming on gradient-echo sequences. PMID- 25527466 TI - Posteromedial knee friction syndrome: an entity with medial knee pain and edema between the femoral condyle, sartorius and gracilis. AB - OBJECTIVE: To describe MRI features of an entity consisting of medial knee pain and edema between the posteromedial femoral condyle (PMFC), sartorius and/or gracilis tendons and determine whether reduced tendon-bone distances may account for these findings. METHODS: We retrospectively identified MRI cases of edema between the PMFC, sartorius and/or gracilis tendons (25 subjects, 26 knees). Two musculoskeletal radiologists independently graded edema and measured the sartorius- and gracilis-PMFC distances and knee flexion angle. Age- and gender matched subjects with normal knee MRIs (27 subjects, 27 knees) served as controls for measurements. Statistical analyses compared abnormal to control subjects. RESULTS: Sartorius-PMFC and gracilis-PMFC spaces were narrower in abnormal compared to control subjects (1.6 +/- 1.0 vs. 2.1 +/- 1.2 mm, P = 0.04; 2.3 +/- 2.0 vs. 4.6 +/- 3.0 mm, P = 0.002, respectively). The knee flexion angle was similar between groups (P > 0.05). In subjects with clinical information, medial knee pain was the main complaint in 58 % (15/26) of abnormal subjects, with 42 % (11/26) having clinical suspicion of medial meniscal tear. Edema between the PMFC, sartorius and/or gracilis was mild in 54 % (14/26), moderate in 35 % (9/26) and severe in 12 % (3/26), and it was most frequent deep to both the sartorius and gracilis (50 %, 13/26). CONCLUSIONS: Edema between the PMFC, sartorius and/or gracilis tendons identified on knee MRI may be associated with medial knee pain and may represent a friction syndrome. PMID- 25527467 TI - Use of MR arthrography in detecting tears of the ligamentum teres with arthroscopic correlation. AB - OBJECTIVE: To demonstrate the normal appearance of the ligamentum teres on MR arthrography (MRA) and evaluate the accuracy of MRA in detecting ligamentum teres tears with arthroscopic correlation. MATERIALS AND METHODS: Institutional Review Board approval was obtained with a waiver for informed consent because of the retrospective study design. A total of 165 cases in 159 patients (111 females, 48 males; mean age 41 +/- 12 years) who underwent both MRA and hip arthroscopy were evaluated for appearance of the ligamentum teres, including the size, number of bundles, and ligamentum teres tears. Marrow edema of the fovea capitis adjacent to the ligamentum teres insertion and the presence of hip plicae were also recorded. RESULTS: The mean thickness and length of the ligamentum teres were 3.5 +/- 1.5 mm and 25.2 +/- 3.8 mm, respectively. Sensitivity, specificity, positive and negative predictive value, and accuracy of MRA for the detection of ligamentum teres tears were 78, 97, 74, 97, and 95%, respectively. CONCLUSION: MRA is an accurate method to evaluate the normal morphology and to detect tears of the ligamentum teres. PMID- 25527468 TI - Limited access to drugs for resistant tuberculosis: a call to action. AB - Although the rate of new tuberculosis (TB) cases has been falling worldwide, progress toward the targets for diagnosis and treatment of drug-resistant TB is far off-track. In countries with no reliable TB surveillance system, setbacks and progression of TB control is barely reflected and little is known on the situation in the field. Interviews with health professionals in Gabon revealed limited access to first- and second-line TB drugs and important deficiencies in basic TB control. National and international action needs to be taken to meet the global TB control targets. PMID- 25527470 TI - Syphilis rate rises in the US. PMID- 25527471 TI - Intravascular versus surface cooling speed and stability after cardiopulmonary resuscitation. AB - BACKGROUND AND OBJECTIVE: Mild therapeutic hypothermia (MTH) is used to limit neurological injury and improve survival after cardiac arrest (CA) and cardiopulmonary resuscitation, but the optimal mode of cooling is controversial. We therefore compared the effectiveness of MTH using invasive intravascular or non-invasive surface cooling with temperature feedback control. METHODS: This retrospective study in post-CA patients studied the effects of intravascular cooling (CoolGard, Zoll, n=97), applied on the intensive care unit (ICU) in one university hospital compared with those of surface cooling (Medi-Therm, Gaymar, n=76) applied in another university hospital. RESULTS: Time to reach target temperature and cooling speeds did not differ between groups. During the maintenance phase, mean core temperature was 33.1 degrees C (range 32.7-33.7 degrees C) versus 32.5 degrees C (range 31.7-33.4 degrees C) at targets of 33.0 and 32.5 degrees C in intravascularly versus surface cooled patients, respectively. The variation coefficient for temperature during maintenance was higher in the surface than the intravascular cooling group (mean 0.85% vs 0.35%, p<0.0001). ICU survival was 60% and 50% in the intravascularly and surface cooled groups, respectively (NS). Lower age (OR 0.95; 95% CI 0.93 to 0.98; p<0.0001), ventricular fibrillation/ventricular tachycardia as presenting rhythm (OR 7.6; 95% CI 1.8 to 8.9; p<0.0001) and lower mean temperature during the maintenance phase (OR 0.52; 95% CI 0.25 to 1.08; p=0.081) might be independent determinants of ICU survival, while cooling technique and temperature variability did not contribute. CONCLUSIONS: In post-CA patients, intravascular cooling systems result in equal cooling speed, but less variation in temperature during the maintenance phase, as surface cooling. This may not affect the outcome. PMID- 25527472 TI - Interventions targeting the elderly population to reduce emergency department utilisation: a literature review. AB - OBJECTIVE: High utilisation of emergency department (ED) among the elderly is of worldwide concern. This study aims to review the effectiveness of interventions targeting the elderly population in reducing ED utilisation. METHODS: Major biomedical databases were searched for relevant studies. Qualitative approach was applied to derive common themes in the myriad interventions and to critically assess the variations influencing interventions' effectiveness. Quality of studies was appraised using the Effective Public Health Practice Project (EPPHP) tool. RESULTS: 36 studies were included. Nine of 16 community-based interventions reported significant reductions in ED utilisation. Five of 20 hospital-based interventions proved effective while another four demonstrated failure. Seven key elements were identified. Ten of 14 interventions associated with significant reduction on ED use integrated at least three of the seven elements. All four interventions with significant negative results lacked five or more of the seven elements. Some key elements including multidisciplinary team, integrated primary care and social care often existed in effective interventions, while were absent in all significantly ineffective ones. CONCLUSIONS: The investigated interventions have mixed effectiveness. Our findings suggest the hospital-based interventions have relatively poorer effects, and should be better connected to the community-based strategies. Interventions seem to achieve the most success with integration of multi-layered elements, especially when incorporating key elements such as a nurse-led multidisciplinary team, integrated social care, and strong linkages to the longer-term primary and community care. Notwithstanding limitations in generalising the findings, this review builds on the growing body of evidence in this particular area. PMID- 25527469 TI - Circulating Tumor Cells: Who is the Killer? AB - This article is a critical note on the subject of Circulating Tumor Cells (CTC). It takes into account the tumor identity of Circulating Tumor Cells as cancer seeds in transit from primary to secondary soils, rather than as a "biomarker", and considers the help this field could bring to cancer patients. It is not meant to duplicate information already available in a large number of reviews, but to stimulate considerations, further studies and development helping the clinical use of tumor cells isolated from blood as a modern personalized, non-invasive, predictive test to improve cancer patients' life. The analysis of CTC challenges, methodological bias and critical issues points out to the need of referring to tumor cells extracted from blood without any bias and identified by cytopathological diagnosis as Circulating Cancer Cells (CCC). Finally, this article highlights recent developments and identifies burning questions which should be addressed to improve our understanding of the domain of CCC and their potential to change the clinical practice. PMID- 25527473 TI - Air ambulance tasking: mechanism of injury, telephone interrogation or ambulance crew assessment? AB - OBJECTIVE: The identification of serious injury is critical to the tasking of air ambulances. London's Air Ambulance (LAA) is dispatched by a flight paramedic based on mechanism of injury (MOI), paramedical interrogation of caller (INT) or land ambulance crew request (REQ).This study aimed to demonstrate which of the dispatch methods was most effective (in accuracy and time) in identifying patients with serious injury. METHODS: A retrospective review of 3 years of data (to December 2010) was undertaken. Appropriate dispatch was defined as the requirement for LAA to escort the patient to hospital or for resuscitation on scene. Inaccurate dispatch was where LAA was cancelled or left the patient in the care of the land ambulance crew. The chi(2) test was used to calculate p values; with significance adjusted to account for multiple testing. RESULTS: There were 2203 helicopter activations analysed: MOI 18.9% (n=417), INT 62.4% (n=1375) and REQ 18.7% (n=411). Appropriate dispatch rates were MOI 58.7% (245/417), INT 69.7% (959/1375) and REQ 72.2% (297/411). INT and REQ were both significantly more accurate than MOI (p<0.0001). There was no significant difference in accuracy between INT and REQ (p=0.36). Combining MOI and INT remotely identified 80.2% of patients, with an overtriage rate of 32.8%. Mean time to dispatch (in minutes) was MOI 4, INT 8 and REQ 21. CONCLUSIONS: Telephone interrogation of the caller by a flight paramedic is as accurate as ground ambulance crew requests, and both are significantly better than MOI in identifying serious injury. Overtriage remains an issue with all methods. PMID- 25527474 TI - Trichomes related to an unusual method of water retention and protection of the stem apex in an arid zone perennial species. AB - It is well known that trichomes protect plant organs, and several studies have investigated their role in the adaptation of plants to harsh environments. Recent studies have shown that the production of hydrophilic substances by glandular trichomes and the deposition of this secretion on young organs may facilitate water retention, thus preventing desiccation and favouring organ growth until the plant develops other protective mechanisms. Lychnophora diamantinana is a species endemic to the Brazilian 'campos rupestres' (rocky fields), a region characterized by intense solar radiation and water deficits. This study sought to investigate trichomes and the origin of the substances observed on the stem apices of L. diamantinana. Samples of stem apices, young and expanded leaves were studied using standard techniques, including light microscopy and scanning and transmission electron microscopy. Histochemical tests were used to identify the major groups of metabolites present in the trichomes and the hyaline material deposited on the apices. Non-glandular trichomes and glandular trichomes were observed. The material deposited on the stem apices was hyaline, highly hydrophilic and viscous. This hyaline material primarily consists of carbohydrates that result from the partial degradation of the cell wall of uniseriate trichomes. This degradation occurs at the same time that glandular trichomes secrete terpenoids, phenolic compounds and proteins. These results suggest that the non-glandular trichomes on the leaves of L. diamantinana help protect the young organ, particularly against desiccation, by deposition of highly hydrated substances on the apices. Furthermore, the secretion of glandular trichomes probably repels herbivore and pathogen attacks. PMID- 25527475 TI - Genetic diversity and floral width variation in introduced and native populations of a long-lived woody perennial. AB - Populations of introduced species in their new environments are expected to differ from native populations, due to processes such as genetic drift, founder effects and local adaptation, which can often result in rapid phenotypic change. Such processes can also lead to changes in the genetic structure of these populations. This study investigated the populations of Rhododendron ponticum in its introduced range in Ireland, where it is severely invasive, to determine both genetic and flower width diversity and differentiation. We compared six introduced Irish populations with two populations from R. ponticum's native range in Spain, using amplified fragment length polymorphism and simple sequence repeat genetic markers. We measured flower width, a trait that may affect pollinator visitation, from four Irish and four Spanish populations by measuring both the width at the corolla tip and tube base (nectar holder width). With both genetic markers, populations were differentiated between Ireland and Spain and from each other in both countries. However, populations displayed low genetic diversity (mean Nei's genetic diversity = 0.22), with the largest proportion (76-93 %) of genetic variation contained within, rather than between, populations. Although corolla width was highly variable between individuals within populations, tube width was significantly wider (>0.5 mm) in introduced, compared with native, populations. Our results show that the same species can have genetically distinct populations in both invasive and native regions, and that differences in floral width may occur, possibly in response to ecological sorting processes or local adaptation to pollinator communities. PMID- 25527476 TI - Pollinator limitation on reproductive success in Iris tuberosa. AB - Variation in plant and floral size can have conflicting effects on pollination and fruit production in flowering plants. This research examines the contributions of plant height, flower size and pollinator visitation to reproductive success in four populations of Iris tuberosa. The plants were pollinated exclusively by hymenopteran species, primarily during sunny days. Pollination supplementation increased the proportion of flowers that matured into fruit, with 95 % fruit set for hand-pollinated compared with 74.15 % for naturally pollinated flowers. The pollinator visitation rate and the proportion of fruit produced were not significantly different between tall and short plants or between small and large flowers. Furthermore, the increase in plant size and floral display did not increase the frequency of pollinator visitations and so did not increase the fruit set. Thus, despite the widespread effects of flowering plant size on pollinator attraction and plant reproduction in other species, these effects are lacking in I. tuberosa. This study quantifies the role of pollinators in the reproductive success of I. tuberosa. Pollinators visited tall/short plants and large/small flowers in equal proportion, suggesting that plant and floral display size do not affect pollinator attraction and reproductive success in I. tuberosa. These results suggest that sexual reproduction of I. tuberosa is fairly limited by pollinators and not by resource limitation. PMID- 25527478 TI - MRI scanner environment increases pain perception in a standardized nociceptive paradigm. AB - Functional magnetic resonance imaging (MRI) has been widely used in neuroscientific studies to investigate neural correlates of perception and higher cognitive functions. Early on, the MR-scanning procedure itself has been identified to create discomfort and anxiety in some individuals, which may influence task performance and perception. The present study analyzed behavioral differences in pain intensity ratings obtained in two distinct situations: MR environment and laboratory setting. Within our longitudinal study design twenty healthy volunteers were exposed daily to an identical paradigm consisting of 60 repeated noxious heat stimuli (46 degrees C) on 21 consecutive days. After each block of ten stimuli, participants were prompted to rate pain intensity on a visual analog scale (VAS). On days 1, 8, 14, and 21 ratings scores were obtained during a functional imaging scan, whereas on the remaining days the sessions were conducted in a laboratory. It has come to our attention that pain intensity ratings acquired in MR environment were significantly higher than behavioral data collected in the lab setting. Given that the stimuli were standardized and no task or distraction confounded the ratings, it is likely that the attentional focus on noxious stimulation was identical in both conditions. It seems that the highly artificial scanner environment as such is sufficient to increase awareness/alertness. Given that salience rather than pure nociceptive input has been suggested to explain functional imaging results in painful conditions, these findings highlight concerns regarding the comparability of behavioral data assembled across inconsistent settings. PMID- 25527477 TI - De novo transcriptome assembly and the identification of gene-associated single nucleotide polymorphism markers in Asian and American ginseng roots. AB - We performed de novo transcriptome sequencing for Panax ginseng and Panax quinquefolius accessions using the 454 GS FLX Titanium System and discovered annotation-based genome-wide single-nucleotide polymorphism (SNPs) using next generation ginseng transcriptome data without reference genome sequence. The comprehensive transcriptome characterization with the mature roots of four ginseng accessions generated 297,170 reads for 'Cheonryang' cultivar, 305,673 reads for 'Yunpoong' cultivar, 311,861 reads for the G03080 breeding line, and 308,313 reads for P. quinquefolius. In transcriptome assembly, the lengths of the sample read were 156.42 Mb for 'Cheonryang', 161.95 Mb for 'Yunpoong', 165.07 Mb for G03080 breeding line, and 166.48 Mb for P. quinquefolius. A total of 97 primer pairs were designed with the homozygous SNP presented in all four accessions. SNP genotyping using high-resolution melting (HRM) analysis was performed to validate the putative SNP markers of 97 primer pairs. Out of the 73 primer pairs, 73 primer pairs amplified the target sequence and 34 primer pairs showed polymorphic melting curves in samples from 11 P. ginseng cultivars and one P. quinquefolius accession. Among the 34 polymorphic HRM-SNP primers, four primers were useful to distinguish ginseng cultivars. In the present study, we demonstrated that de novo transcriptome assembly and mapping analyses are useful in providing four HRM-SNP primer pairs that reliably show a high degree of polymorphism among ginseng cultivars. PMID- 25527479 TI - A new classification of Diabetic Nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy. AB - The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease. In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labour and Welfare of Japan. Major revisions to the Classification are summarized as follows: (1) eGFR is substituted for GFR in the Classification; (2) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated; (3) stage 4 (kidney failure) has been redefined as a GFR less than 30 mL/min/1.73 m(2), regardless of the extent of albuminuria; and (4) stress has been placed on the differential diagnosis of diabetic nephropathy versus non-diabetic kidney disease as being crucial in all stages of diabetic nephropathy. PMID- 25527480 TI - Effects of walking speeds and carrying techniques on intra-abdominal pressure in women. AB - INTRODUCTION AND HYPOTHESIS: Walking speed and carrying technique affect intra abdominal pressure (IAP) in women. In this study, we tested the feasibility of monitoring IAP outside the laboratory environment and compared IAP while study participants were (1) carrying 13.6 kg (similar to a 3-month old in car seat) in six different ways while walking 100 m; and (2) while walking 400 m at self selected slow, normal, and fast paces. METHODS: Forty-six healthy women between 19 and 54 years completed the walking and lifting activities; the order for each was randomized. IAP was monitored with an intravaginal pressure transducer that wirelessly transmitted pressure data to a portable base station. We analyzed maximal peak IAP and area under the curve (AUC) IAP. RESULTS: Monitoring IAP outside of the laboratory was feasible. Mean maximal IAP during walking increased as pace increased: 42.5 [standard deviation (SD) 10.2], 50.5 (10.9), and 62.0 (12.1) cmH2O for slow, medium, and fast speeds, respectively: p < 0.0001 by mixed model analysis of variance (ANOVA). The corresponding AUC of IAP for walking decreased as pace increased. The awkward carry, side carry, and front carry activities each resulted in higher mean maximal IAP [65.8 (10.6), 67.7 (12.8), and 77.3 (13.1) cmH2O, respectively] than the carry-in-backpack activity [55.5 (11.4) cmH2O; p < 0.0001]. CONCLUSION: Subtle variations in walking speed or method of carrying a toddler-size load can produce significant changes in IAP. Whether these changes increase the risk of pelvic floor disorders is not yet clear. However, these data suggest that further inquiry into optimal methods and appliances to assist women in carrying may create a lower IAP profile. PMID- 25527481 TI - Multidisciplinary approach for management of obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) syndrome and rectal prolapse. AB - INTRODUCTION AND HYPOTHESIS: Mullerian duct anomalies are frequently associated with congenital anomalies of other organ systems, and in particular, the urinary system. A multidisciplinary approach is often required for successful diagnosis and surgical management of complex pelvic anomalies. The objective of this video is to provide a guide for diagnosis of complex female pelvic anomalies and robotic-assisted approach to surgical management with a multidisciplinary team of surgeons. METHODS: The patient presented is a 24-year-old nulligravida with obstructed hemivagina and ipsilateral renal dysplasia, ipsilateral ectopic ureter, and rectal prolapse. This video outlines the methods used to obtain the correct diagnosis and steps for successful treatment using a robotically assisted surgical approach. RESULTS: Complex Mullerian anomalies involving multiple organ systems may require the use of advanced three-dimensional imaging to achieve the correct diagnosis, and a minimally invasive surgical approach with robotic assistance is an effective strategy for management. CONCLUSIONS: A multidisciplinary approach is often required to successfully diagnose and treat women with complex Mullerian anomalies. PMID- 25527482 TI - A pilot randomized trial of levator injections versus physical therapy for treatment of pelvic floor myalgia and sexual pain. AB - INTRODUCTION AND HYPOTHESIS: Our aim was to determine the effects of pelvic floor physical therapy (PT) and levator-directed trigger-point injections (LTPI) on sexual function and levator-related pelvic pain. STUDY DESIGN: A randomized trial among women with pelvic floor myalgia (PFM) was performed wherein participants received either PT or LTPI. Pain was assessed and 1 month posttreatment completion. Levator-based pain was assessed using a numeric rating scale (NRS) and the Patient Global Impression of Improvement (PGI-I) scale. Sexual function was assessed using the Female Sexual Function Index (FSFI). RESULTS: Twenty-nine women completed the study (17 had PT, 12 had LTPI). Both groups reported reduction in vaginal pain: mean NRS change from baseline of 4.47 [standard deviation (SD) 2.12) for PT and 4.67 (SD 1.72) for LTPI (p = 0.8)]. A >50 % improvement in NRS was documented among 59 % of women receiving PT and 58 % receiving LTPI (p = 1.0). Consistent with NRS scores, mean PGI-I score was 2.50 (SD 1.17) for PT and 2.17 (SD 1.01) for LTPI (p = 0.5). Mean change in FSFI favored PT [PT +8.87 (SD 5.60), LTPI +4.00 (SD 5.24), p = 0.04], reflecting improvement in the sexual pain domain favoring PT (p = 0.02). However, the time in weeks to effect improvement favored LTPI if controlling for the degree of change in NRS (p = 0.01) and FSFI (p = 0.01). CONCLUSIONS: Vaginal myalgia and sex-related pain improved with pelvic floor PT and LTPI. Time-to-effect improvement and significance of therapy are dependent on treatment type. PMID- 25527483 TI - Vaginal hysterectomy and training. PMID- 25527484 TI - Vaginal hysterectomy and training: response to Melendez. PMID- 25527485 TI - Effects of Physical Exercise on Neuroinflammation, Neuroplasticity, Neurodegeneration, and Behavior: What We Can Learn From Animal Models in Clinical Settings. AB - Physical exercise is a cornerstone in the management of many neurodegenerative disorders, such as Parkinson's disease, dementia, and stroke. However, much of its beneficial effects on improving motor functions and cognition as well as decreasing neurodegeneration and neuroinflammation are not yet well understood. The obvious limitations of studying the protective mechanisms behind exercise, for example, brain plasticity and neurodegeneration, could be overcome by generating novel animal models of neurodegenerative disorders. In this narrative review, we discuss the beneficial effects of exercise performed in animal models of neurodegenerative disorders and how the results from animal studies can be used in clinical settings. From preclinical studies, the positive effects of exercise have been related to increased levels of neurotrophic factors, elevated expression of anti-inflammatory cytokines, and reduced levels of pro-inflammatory cytokines and activated microglia. It is clear that parameters influencing the effect of exercise, such as intensity, still remain to be investigated in animal studies in order to find the optimal program that can be translated into exercise interventions for patients with neurodegenerative diseases. PMID- 25527487 TI - Hand and Arm Bimanual Intensive Therapy Including Lower Extremity (HABIT-ILE) in Children With Unilateral Spastic Cerebral Palsy: A Randomized Trial. AB - BACKGROUND: Intensive bimanual training results in more improvement in hand function in children with unilateral spastic cerebral palsy (USCP) than lower intensity conventional interventions. However, it is not known whether combined upper and lower extremity training in an intensive protocol is more efficacious for upper and lower functional abilities than conventional therapies provided in usual customary care. OBJECTIVE: To determine the efficacy of Hand and Arm Bimanual Intensive Therapy Including Lower Extremity (HABIT-ILE) for children with USCP. METHODS: Twenty-four children with USCP were randomized into 2 groups: an immediate HABIT-ILE group (IHG, initially receiving HABIT-ILE, 10 days = 90 hours), and a delayed HABIT-ILE group (DHG), which continued their conventional/ongoing treatment for an intended total duration of 90 hours. In phase 2, children in the DHG were crossed over to receive HABIT-ILE and children of the IHG were followed in their ongoing conventional therapy. Children were assessed using the Assisting Hand Assessment (AHA, primary outcome), the ABILHAND Kids, and the Pediatric Evaluation of Disability Inventory. Dexterity (Box and Blocks Test [BBT]) and pinch strength were also measured. Locomotor abilities were assessed with Six-Minute Walk Test (6MWT, primary outcome) and ABILOCO-kids. Social participation was measured with the Assessment of Life-HABITs. RESULTS: A 2 (groups) * 3 (test sessions) analysis of variance indicated significant improvements for primary outcomes (AHA, P < .001; 6MWT, P = .002) and all secondary assessments except BBT, step length and bodyweight distribution following HABIT-ILE, but not conventional therapy. CONCLUSION: The findings suggest that combined upper and lower extremity in an intensive training protocol may be efficacious for improving both upper and lower extremity function in children with USCP. PMID- 25527486 TI - Enduring Poststroke Motor Functional Improvements by a Well-Timed Combination of Motor Rehabilitative Training and Cortical Stimulation in Rats. AB - BACKGROUND: In animal stroke models, peri-infarct cortical stimulation (CS) combined with rehabilitative reach training (RT) enhances motor functional outcome and cortical reorganization, compared with RT alone. It was unknown whether the effects of CS + RT (a) persist long after treatment, (b) can be enhanced by forcing greater use of the paretic limb, and (C) vary with treatment onset time. OBJECTIVE: To test the endurance, time sensitivity, and the potential for augmentation by forced forelimb use of CS + RT treatment effects following ischemic stroke. METHODS: Adult rats that were proficient in skilled reaching received unilateral ischemic motor cortical lesions. RT was delivered for 3 weeks alone or concurrently with 100-Hz cathodal epidural CS, delivered at 50% of movement thresholds. In study 1, this treatment was initiated at 14 days postinfarct, with some subgroups receiving an overlapping period of continuous constraint of the nonparetic forelimb to force use of the paretic limb. The function of the paretic limb was assessed weekly for 9 to 10 months posttreatment. In study 2, rats underwent CS, RT, and the combination during the chronic postinfarct period. RESULTS: Early onset CS + RT resulted in greater functional improvements than RT alone. The CS-related gains persisted for 9 to 10 months posttreatment and were not significantly influenced by forced use of the paretic limb. When treatment onset was delayed until 3 months post-infarct, RT alone improved function, but CS + RT was no more effective than RT alone. CONCLUSION: CS can enhance the persistence, as well as the magnitude of RT-driven functional improvements, but its effectiveness in doing so may vary with time postinfarct. PMID- 25527488 TI - A Randomized Controlled Trial of the Effect of Early Upper-Limb Training on Stroke Recovery and Brain Activation. AB - BACKGROUND: Upper-limb (UL) dysfunction is experienced by up to 75% of patients poststroke. The greatest potential for functional improvement is in the first month. Following reperfusion, evidence indicates that neuroplasticity is the mechanism that supports this recovery. OBJECTIVE: This preliminary study hypothesized increased activation of putative motor areas in those receiving intensive, task-specific UL training in the first month poststroke compared with those receiving standard care. METHODS: This was a single-blinded, longitudinal, randomized controlled trial in adult patients with an acute, first-ever ischemic stroke; 23 participants were randomized to standard care (n = 12) or an additional 30 hours of task-specific UL training in the first month poststroke beginning week 1. Patients were assessed at 1 week, 1 month, and 3 months poststroke. The primary outcome was change in brain activation as measured by functional magnetic resonance imaging. RESULTS: When compared with the standard care group, the intensive-training group had increased brain activation in the anterior cingulate and ipsilesional supplementary motor areas and a greater reduction in the extent of activation (P = .02) in the contralesional cerebellum. Intensive training was associated with a smaller deviation from mean recovery at 1 month (Pr>F0 = 0.017) and 3 months (Pr>F = 0.006), indicating more consistent and predictable improvement in motor outcomes. CONCLUSION: Early, more-intensive, UL training was associated with greater changes in activation in putative motor (supplementary motor area and cerebellum) and attention (anterior cingulate) regions, providing support for the role of these regions and functions in early recovery poststroke. PMID- 25527489 TI - BDNF Induced by Treadmill Training Contributes to the Suppression of Spasticity and Allodynia After Spinal Cord Injury via Upregulation of KCC2. AB - BACKGROUND: Spasticity and allodynia are major sequelae that affect the quality of life and daily activities of spinal cord injury (SCI) patients. Although rehabilitation ameliorates spasticity and allodynia, the molecular mechanisms involved in these processes remain elusive. OBJECTIVE: To investigate the molecular mechanisms by which rehabilitation ameliorates spasticity and allodynia after SCI in rats. METHODS: The expression levels of brain-derived neurotrophic factor (BDNF) and potassium-chloride cotransporter-2 (KCC2), as well as the localization of KCC2, were examined in the lumbar enlargements of untrained and treadmill-trained thoracic SCI model rats. Spasticity and allodynia were determined via behavioral and electrophysiological analyses. The effects of BDNF on spasticity, allodynia, and KCC2 activation were determined by inhibition of BDNF signaling via intrathecal administration of TrkB-IgG. The effects of SCI and training on the expression levels of functional phospholipase C-gamma in the lumbar enlargement were also examined. RESULTS: Treadmill training after SCI upregulated endogenous BDNF expression and posttranslational modification of KCC2 in the lumbar enlargement significantly. There were also significant correlations between increased KCC2 expression and ameliorated spasticity and allodynia. Administration of TrkB-IgG abrogated the training-induced upregulation of KCC2 and beneficial effects on spasticity and allodynia. The expression level of functional phospholipase C-gamma was reduced significantly after SCI, which may have contributed to the change in the function of BDNF, whereby it did not trigger short-term downregulation or induce long-term upregulation of KCC2 expression secondary to training. CONCLUSIONS: BDNF-mediated restoration of KCC2 expression underlies the suppression of spasticity and allodynia caused by rehabilitation. PMID- 25527490 TI - Occlusion and malocclusion in the cat: what's normal, what's not and when's the best time to intervene? AB - PRACTICAL RELEVANCE: Malocclusion affecting cats, and treatment thereof, has not been widely described in the veterinary literature, yet is a condition seen in a growing number of breeds, often causing pain and discomfort to the patient. Recognising the problem, and certainly whether it is a hereditary problem (eg, a skeletal malocclusion), is important for the longer term health of pedigree breeds. CLINICAL CHALLENGES: If there is a malocclusion, the mouth may be painful and a thorough occlusal assessment of the conscious patient may be difficult. Occlusal assessment should always be accompanied by a thorough oral examination and, where necessary, further investigation under general anaesthesia, including dental radiography. Recognising what is normal, and what is not, can be challenging; so, too, can be determining the correct time to intervene. AUDIENCE: This article is intended to help fill the gap in dental education regarding the range of developmental and acquired malocclusions seen in cats. Treatment options are also briefly reviewed. EVIDENCE BASE: The guidance contained in this article is based on a combination of the published literature, the author's personal experience and that of colleagues. PMID- 25527492 TI - Tooth resorption in cats: pathophysiology and treatment options. AB - PRACTICAL RELEVANCE: Tooth resorption is common in the domestic cat and the incidence has been reported to increase with increasing age. Cats with clinically missing teeth have also been found to be more likely to have tooth resorption. All types of teeth in the feline dentition may be affected, but lesions seem to be more common in certain teeth. CLINICAL CHALLENGES: Tooth resorption can be difficult to detect, with cats often masking signs of oral discomfort or pain. Routine radiography is required for timely diagnosis, as clinical (visual and tactile) methods only detect late-stage lesions - that is, when they become evident in the crown. The aetiology of many tooth resorptions is not clear. A large number of lesions appear to be idiopathic and, to date, there is no known treatment that prevents the development and/or progression of this category of tooth resorption. Tooth extraction is the gold standard treatment but teeth with resorptive lesions are notoriously difficult to extract and coronal amputation is often indicated. Determining the best treatment option in an individual case again relies on radiography. AUDIENCE: This review is aimed at feline and general practitioners, as well as veterinarians with expertise in dentistry. EVIDENCE BASE: The author draws on the published literature and her clinical experience and own research to review current thinking about the epidemiology, aetiology and pathogenesis of tooth resorptions, and to offer advice on diagnosis and treatment options. PMID- 25527491 TI - Perioperative anaesthetic care of the cat undergoing dental and oral procedures: key considerations. AB - CLINICAL CHALLENGES: Anaesthesia for dental and oral procedures in cats can be challenging and many factors need to be taken into consideration. Often it is older patients requiring these procedures and, while old age itself is not a contraindication for general anaesthesia, older patients tend to have limited homeostatic reserves and are, therefore, more prone to anaesthesia-induced insults of vital organs. Most sedative and anaesthetic agents have cardiovascular side effects, which may result in detrimental consequences in older patients in which organ reserves are likely reduced. AIMS: The need for good patient assessment and management during the entire perianaesthetic period cannot be overemphasised. This article describes how both anaesthetic protocol and intravenous fluid therapy should be tailored to the individual cat's needs. Application of a multimodal analgesic protocol (the combination of different analgesic agents) and a balanced anaesthetic technique incorporating local nerve blocks is highly recommended and a particular focus of the review. The use of local anaesthetic agents for the latter not only provides optimal pre-emptive analgesia, but also reduces the amount of anaesthetic agents needed to maintain an adequate level of anaesthesia and, therefore, limits their side effects. Other key aspects of perianaesthetic care of the feline dental and oral patient include airway protection, monitoring and maintenance of body temperature, eye protection, and analgesia extending well into the post-anaesthetic period. EVIDENCE BASE: The authors draw on their clinical experience and the referenced literature to provide a practical overview of this critical but often-overlooked aspect of feline dentistry. PMID- 25527493 TI - Periodontal disease in cats: back to basics--with an eye on the future. AB - PRACTICAL RELEVANCE: Periodontal disease is commonly encountered in feline practice. Gingivitis, followed by inflammation of the rest of the periodontal tissues, can lead to chronic oral infection, bacteraemia, pain and ultimately tooth loss. Given adequate plaque control and thorough, consistent dental home care, gingivitis is a reversible and controllable condition. Periodontitis, however, is an essentially irreversible and progressive condition. Treatment aims to control tissue inflammation, returning the gingiva to clinical health and preventing destruction of the periodontium in other parts of the mouth. CLINICAL CHALLENGES: Diagnosis must be established using a combination of oral examination under anaesthesia and dental radiography. Periodontitis leads to tooth attachment loss, and given the short length of most cat teeth, probing depths of 1 mm or more should alert the clinician to the presence of periodontitis. The decision of whether to extract or preserve affected teeth needs careful consideration. In practice, as periodontitis is often associated with type 1 tooth resorption, extraction is often required, but the slender and delicate nature of feline tooth roots, compounded by the destructive nature of tooth resorption, can frustrate extraction attempts. As highlighted in this article, iatrogenic damage to teeth is also a real risk if periodontal therapy procedures (including scaling and polishing) are not performed carefully. The challenges of providing home care in the cat are additionally discussed. EVIDENCE BASE: The authors have drawn upon, wherever possible, an evidence base relating strictly to the feline patient. Where there is a lack of published research, evidence from canine and human studies is assessed. PMID- 25527494 TI - Globe penetration in a cat following maxillary nerve block for dental surgery. AB - CLINICAL SUMMARY: Dental treatment was carried out in an 8.5-year-old castrated male domestic shorthair cat found to have tooth resorption. Right mandibular, and right and left maxillary nerve blocks were administered using a 1 ml syringe attached to a 25 G x 5/8 inch needle and an intraoral technique. The following day the cat displayed blepharospasm of the right eye. The ocular signs progressed and 5 days later an ophthalmologist confirmed a blind, glaucomatous right eye. It was suspected that the eye had suffered a penetrating injury during dental surgery. Enucleation of the right eye was performed and gross and histopathological examination revealed a penetrating wound consistent with a needle tract injury. PRACTICAL RELEVANCE: Complications arising from veterinary dental regional anaesthesia appear to be rare; however, it may be that they are under-reported. This case report highlights the risks involved and reviews the safest and most efficacious regional anaesthesia technique for the feline maxilla. PMID- 25527496 TI - Methyl-CpG binding protein 2 (MeCP2) localizes at the centrosome and is required for proper mitotic spindle organization. AB - Mutations in MECP2 cause a broad spectrum of neuropsychiatric disorders of which Rett syndrome represents the best defined condition. Both neuronal and non neuronal functions of the methyl-binding protein underlie the related pathologies. Nowadays MeCP2 is recognized as a multifunctional protein that modulates its activity depending on its protein partners and posttranslational modifications. However, we are still missing a comprehensive understanding of all MeCP2 functions and their involvement in the related pathologies. The study of human mutations often offers the possibility of clarifying the functions of a protein. Therefore, we decided to characterize a novel MeCP2 phospho-isoform (Tyr 120) whose relevance was suggested by a Rett syndrome patient carrying a Y120D substitution possibly mimicking a constitutively phosphorylated state. Unexpectedly, we found MeCP2 and its Tyr-120 phospho-isoform enriched at the centrosome both in dividing and postmitotic cells. The molecular and functional connection of MeCP2 to the centrosome was further reinforced through cellular and biochemical approaches. We show that, similar to many centrosomal proteins, MeCP2 deficiency causes aberrant spindle geometry, prolonged mitosis, and defects in microtubule nucleation. Collectively, our data indicate a novel function of MeCP2 that might reconcile previous data regarding the role of MeCP2 in cell growth and cytoskeleton stability and that might be relevant to understand some aspects of MeCP2-related conditions. Furthermore, they link the Tyr-120 residue and its phosphorylation to cell division, prompting future studies on the relevance of Tyr-120 for cortical development. PMID- 25527497 TI - PINK1 kinase catalytic activity is regulated by phosphorylation on serines 228 and 402. AB - Mutations in the PINK1 gene cause early-onset recessive Parkinson disease. PINK1 is a mitochondrially targeted kinase that regulates multiple aspects of mitochondrial biology, from oxidative phosphorylation to mitochondrial clearance. PINK1 itself is also phosphorylated, and this might be linked to the regulation of its multiple activities. Here we systematically analyze four previously identified phosphorylation sites in PINK1 for their role in autophosphorylation, substrate phosphorylation, and mitophagy. Our data indicate that two of these sites, Ser-228 and Ser-402, are autophosphorylated on truncated PINK1 but not on full-length PINK1, suggesting that the N terminus has an inhibitory effect on phosphorylation. We furthermore establish that phosphorylation of these PINK1 residues regulates the phosphorylation of the substrates Parkin and Ubiquitin. Especially Ser-402 phosphorylation appears to be important for PINK1 function because it is involved in Parkin recruitment and the induction of mitophagy. Finally, we identify Thr-313 as a residue that is critical for PINK1 catalytic activity, but, in contrast to previous reports, we find no evidence that this activity is regulated by phosphorylation. These data clarify the regulation of PINK1 through multisite phosphorylation. PMID- 25527498 TI - Rho GTPases and the downstream effectors actin-related protein 2/3 (Arp2/3) complex and myosin II induce membrane fusion at self-contacts. AB - Actin regulation is required for membrane activities that drive cell adhesion and migration. The Rho GTPase family plays critical roles in actin and membrane dynamics; however, the roles of the Rho GTPase family are not limited to cell adhesion and migration. Using micron-sized obstacles to induce the formation of self-contacts in epithelial cells, we previously showed that self-adhesion is distinct from cell-to-cell adhesion in that self-contacts are eliminated by membrane fusion. In the current study, we identified Rho GTPases, RhoA, Rac1, and Cdc42, as potential upstream regulators of membrane fusion. The RhoA downstream effector myosin II is required for fusion as the expression of mutant myosin light chain reduced membrane fusion. Furthermore, an inhibitor of the Arp2/3 complex, a downstream effector of Rac1 and Cdc42, also reduced self-contact induced membrane fusion. At self-contacts, while the concentration of E-cadherin diminished, the intensity of GFP-tagged Arp3 rapidly fluctuated then decreased and stabilized after membrane fusion. Taken together, these data suggest that the Arp2/3 complex-mediated actin polymerization brings two opposing membranes into close apposition by possibly excluding E-cadherin from contact sites, thus promoting membrane fusion at self-contacts. PMID- 25527499 TI - The essential autophagy gene ATG7 modulates organ fibrosis via regulation of endothelial-to-mesenchymal transition. AB - Pulmonary fibrosis is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix components. Although the origin of fibroblasts is multifactorial, recent data implicate endothelial-to-mesenchymal transition as an important source of fibroblasts. We report herein that loss of the essential autophagy gene ATG7 in endothelial cells (ECs) leads to impaired autophagic flux accompanied by marked changes in EC architecture, loss of endothelial, and gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition. Loss of ATG7 also up regulates TGFbeta signaling and key pro-fibrotic genes in vitro. In vivo, EC specific ATG7 knock-out mice exhibit a basal reduction in endothelial-specific markers and demonstrate an increased susceptibility to bleomycin-induced pulmonary fibrosis and collagen accumulation. Our findings help define the role of endothelial autophagy as a potential therapeutic target to limit organ fibrosis, a condition for which presently there are no effective available treatments. PMID- 25527500 TI - Cross-talk between endoplasmic reticulum (ER) stress and the MEK/ERK pathway potentiates apoptosis in human triple negative breast carcinoma cells: role of a dihydropyrimidone, nifetepimine. AB - Triple negative breast cancers (TNBC) are among the most aggressive and therapy resistant breast tumors and currently possess almost no molecular targets for therapeutic options in this horizon. In the present study we discerned the molecular mechanisms of potential interaction between the endoplasmic reticulum (ER) stress response and the MEK/ERK pathway in inducing apoptosis in TNBC cells. Here we observed that induction of ER stress alone was not sufficient to trigger significant apoptosis but simultaneous inhibition of the MEK/ERK pathway enhanced ER stress-induced apoptosis via a caspase-dependent mechanism. Our study also demonstrated nifetepimine, a dihydropyrimidone derivative as a potent anti-cancer agent in TNBC cells. Nifetepimine down-regulated the MEK/ERK pathway in MDAMB-231 and MDAMB-468 cells and resulted in blockage of ER stress-mediated GRP78 up regulation. Detailed mechanistic studies also revealed that nifetepimine by down regulating pERK expression also declined the promoter binding activity of TFII-I to the GRP78 promoter and in turn regulated GRP78 transcription. Studies further extended to in vivo Swiss albino and SCID mice models also revalidated the anti carcinogenic property of nifetepimine. Thus our findings cumulatively suggest that nifetepimine couples two distinct signaling pathways to induce the apoptotic death cascade in TNBC cells and raises the possibility for the use of nifetepimine as a potent anti-cancer agent with strong immune-restoring properties for therapeutic intervention for this group of cancer bearers. PMID- 25527501 TI - The paired basic amino acid-cleaving enzyme 4 (PACE4) is involved in the maturation of insulin receptor isoform B: an opportunity to reduce the specific insulin receptor-dependent effects of insulin-like growth factor 2 (IGF2). AB - Gaining the full activity of the insulin receptor (IR) requires the proteolytic cleavage of its proform by intra-Golgi furin-like activity. In mammalian cells, IR is expressed as two isoforms (IRB and IRA) that are responsible for insulin action. However, only IRA transmits the growth-promoting and mitogenic effects of insulin-like growth factor 2. Here we demonstrate that the two IR isoforms are similarly cleaved by furin, but when this furin-dependent maturation is inefficient, IR proforms move to the cell surface where the proprotein convertase PACE4 selectively supports IRB maturation. Therefore, in situations of impaired furin activity, the proteolytic maturation of IRB is greater than that of IRA, and accordingly, the amount of phosphorylated IRB is also greater than that of IRA. We highlight the ability of a particular proprotein convertase inhibitor to effectively reduce the maturation of IRA and its associated mitogenic signaling without altering the signals emanating from IRB. In conclusion, the selective PACE4-dependent maturation of IRB occurs when furin activity is reduced; accordingly, the pharmacological inhibition of furin reduces IRA maturation and its mitogenic potential without altering the insulin effects. PMID- 25527502 TI - The use of carbohydrate binding modules (CBMs) to monitor changes in fragmentation and cellulose fiber surface morphology during cellulase- and Swollenin-induced deconstruction of lignocellulosic substrates. AB - Although the actions of many of the hydrolytic enzymes involved in cellulose hydrolysis are relatively well understood, the contributions that amorphogenesis inducing proteins might contribute to cellulose deconstruction are still relatively undefined. Earlier work has shown that disruptive proteins, such as the non-hydrolytic non-oxidative protein Swollenin, can open up and disaggregate the less-ordered regions of lignocellulosic substrates. Within the cellulosic fraction, relatively disordered, amorphous regions known as dislocations are known to occur along the length of the fibers. It was postulated that Swollenin might act synergistically with hydrolytic enzymes to initiate biomass deconstruction within these dislocation regions. Carbohydrate binding modules (CBMs) that preferentially bind to cellulosic substructures were fluorescently labeled. They were imaged, using confocal microscopy, to assess the distribution of crystalline and amorphous cellulose at the fiber surface, as well as to track changes in surface morphology over the course of enzymatic hydrolysis and fiber fragmentation. Swollenin was shown to promote targeted disruption of the cellulosic structure at fiber dislocations. PMID- 25527503 TI - Functional characterization of CaValpha2delta mutations associated with sudden cardiac death. AB - L-type Ca(2+) channels play a critical role in cardiac rhythmicity. These ion channels are oligomeric complexes formed by the pore-forming CaValpha1 with the auxiliary CaVbeta and CaValpha2delta subunits. CaValpha2delta increases the peak current density and improves the voltage-dependent activation gating of CaV1.2 channels without increasing the surface expression of the CaValpha1 subunit. The functional impact of genetic variants of CACNA2D1 (the gene encoding for CaValpha2delta), associated with shorter repolarization QT intervals (the time interval between the Q and the T waves on the cardiac electrocardiogram), was investigated after recombinant expression of the full complement of L-type CaV1.2 subunits in human embryonic kidney 293 cells. By performing side-by-side high resolution flow cytometry assays and whole-cell patch clamp recordings, we revealed that the surface density of the CaValpha2delta wild-type protein correlates with the peak current density. Furthermore, the cell surface density of CaValpha2delta mutants S755T, Q917H, and S956T was not significantly different from the cell surface density of the CaValpha2delta wild-type protein expressed under the same conditions. In contrast, the cell surface expression of CaValpha2delta D550Y, CaValpha2delta S709N, and the double mutant D550Y/Q917H was reduced, respectively, by ~30-33% for the single mutants and by 60% for the latter. The cell surface density of D550Y/Q917H was more significantly impaired than protein stability, suggesting that surface trafficking of CaValpha2delta was disrupted by the double mutation. Co-expression with D550Y/Q917H significantly decreased CaV1.2 currents as compared with results obtained with CaValpha2delta wild type. It is concluded that D550Y/Q917H reduced inward Ca(2+) currents through a defect in the cell surface trafficking of CaValpha2delta. Altogether, our results provide novel insight in the molecular mechanism underlying the modulation of CaV1.2 currents by CaValpha2delta. PMID- 25527504 TI - Nuclear calcium signaling induces expression of the synaptic organizers Lrrtm1 and Lrrtm2. AB - Calcium transients in the cell nucleus evoked by synaptic activity in hippocampal neurons function as a signaling end point in synapse-to-nucleus communication. As an important regulator of neuronal gene expression, nuclear calcium is involved in the conversion of synaptic stimuli into functional and structural changes of neurons. Here we identify two synaptic organizers, Lrrtm1 and Lrrtm2, as targets of nuclear calcium signaling. Expression of both Lrrtm1 and Lrrtm2 increased in a synaptic NMDA receptor- and nuclear calcium-dependent manner in hippocampal neurons within 2-4 h after the induction of action potential bursting. Induction of Lrrtm1 and Lrrtm2 occurred independently of the need for new protein synthesis and required calcium/calmodulin-dependent protein kinases and the nuclear calcium signaling target CREB-binding protein. Analysis of reporter gene constructs revealed a functional cAMP response element in the proximal promoter of Lrrtm2, indicating that at least Lrrtm2 is regulated by the classical nuclear Ca(2+)/calmodulin-dependent protein kinase IV-CREB/CREB-binding protein pathway. These results suggest that one mechanism by which nuclear calcium signaling controls neuronal network function is by regulating the expression of Lrrtm1 and Lrrtm2. PMID- 25527507 TI - Effect of continuous positive airway pressure on leptin levels in patients with obstructive sleep apnea: a meta-analysis. AB - OBJECTIVES: Continuous positive airway pressure (CPAP) is an effective treatment for obstructive sleep apnea hypopnea syndrome (OSAHS), but previous studies assessing the effect of CPAP on leptin in patients with OSAHS yielded conflicting results. In this study, we conducted a meta-analysis to determine whether CPAP therapy could reduce serum leptin levels. DATA SOURCES: Databases of PubMed, Elsevier, and SCI were thoroughly searched by 2 independent reviewers. METHODS: RevMan (version 5.2) was used for data synthesis. Weighted mean difference (WMD) before and after CPAP therapy was calculated to estimate the effects of CPAP therapy. RESULTS: A total of 11 studies involving 413 participants were included. Meta-analysis showed that the total WMD for leptin levels was 1.44 units (95% confidence interval: 1.11-1.77, P < .01) before and after CPAP therapy. Subgroup analysis exhibited that leptin was decreased within 3 days after the therapy, and it was further reduced within 1 to 3 months and beyond. CONCLUSIONS: The results of our meta-analysis showed that CPAP could significantly reduce leptin levels in OSAHS patients without concomitant weight loss. PMID- 25527505 TI - A sorting signal suppresses IFITM1 restriction of viral entry. AB - The interferon-induced transmembrane proteins (IFITMs) broadly inhibit virus infections, particularly at the viral entry level. However, despite this shared ability to inhibit fusion, IFITMs differ in the potency and breadth of viruses restricted, an anomaly that is not fully understood. Here, we show that differences in the range of viruses restricted by IFITM1 are regulated by a C terminal non-canonical dibasic sorting signal KRXX that suppresses restriction of some viruses by governing its intracellular distribution. Replacing the two basic residues with alanine (KR/AA) increased restriction of jaagsiekte sheep retrovirus and 10A1 amphotropic murine leukemia virus. Deconvolution microscopy revealed an altered subcellular distribution for KR/AA, with fewer molecules in LAMP1-positive lysosomes balanced by increased levels in CD63-positive multivesicular bodies, where jaagsiekte sheep retrovirus pseudovirions are colocalized. IFITM1 binds to cellular adaptor protein complex 3 (AP-3), an association that is lost when the dibasic motif is altered. Although knockdown of AP-3 itself decreases some virus entry, expression of parental IFITM1, but not its KR/AA mutant, potentiates inhibition of viral infections in AP-3 knockdown cells. By using the substituted cysteine accessibility method, we provide evidence that IFITM1 adopts more than one membrane topology co-existing in cellular membranes. Because the C-terminal dibasic sorting signal is unique to human IFITM1, our results provide novel insight into understanding the species- and virus-specific antiviral effect of IFITMs. PMID- 25527508 TI - Peripheral nerve blocks, steroid injections and their niche in headache medicine. PMID- 25527506 TI - Crosstalking between androgen and PI3K/AKT signaling pathways in prostate cancer cells. AB - Both androgen action and PI3K medicated signaling pathways have been implicated in prostate tumorigenesis. Our androgen receptor (AR) conditional transgenic mice developed murine prostatic intraepithelial neoplasia (mPIN) and prostatic adenocarcinoma lesions recapitulating human prostate cancer development and progression. Role of transgenic AR contributing to malignancy was demonstrated by high degree of transgenic AR expression in atypical and tumor cells in mPIN as well as prostatic adenocarcinoma lesions of the transgenic mice, but not in adjacent normal tissue. Interestingly, reduced PI3K/Akt activation also appeared in these mouse atypical and tumor cells, suggesting an interaction between androgen and PI3K/AKT pathways. In this study, we further investigated this interaction. We showed that the androgen depletion or knockdown of AR expression results in elevated levels of active phosphorylated AKT in prostate cancer cells. Castration of conditional Pten knock-out mice showed increased Akt, phosphorylated Akt, and pS6 expression in the mouse prostate. Using a series of newly generated Ar reporter and Pten knock-out compound mice, we showed that Pten loss directly represses endogenous Ar expression in prostatic epithelial cells. Moreover, Pten loss and PI3K/Akt activation reduced Ar-mediated transcription in purified Pten-null cells. This study provides novel evidence demonstrating interplay between androgen and PI3K pathways, as well as introduces unique and relevant mouse models for further studies of PI3K and AR pathways in the context of prostate tumorigenesis. PMID- 25527510 TI - Standard immunohistochemistry efficiently screens for anaplastic lymphoma kinase rearrangements in differentiated thyroid cancer. AB - The anaplastic lymphoma kinase (ALK) gene is frequently rearranged in various types of cancer and is highly responsive to targeted therapeutics. We developed a system to detect rearrangement of ALK in a large group of Korean thyroid cancer patients. We screened 474 malignant or benign thyroid tumor cases to identify ALK fusions. Expression and translocation of the ALK gene were analyzed by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and digital multiplexed gene expression (DMGE) analysis in formalin-fixed paraffin embedded tissues. Four cases of rearrangement of ALK were detected by IHC, and these cases were validated with FISH on 189 samples. On the other hand, DMGE analysis using Nanostring detected three out of four IHC-positive cases. Two rearrangements of ALK were striatin (STRN)-ALK fusions, which were identified by 5' RACE analysis. Rearrangements of ALK were found exclusively in v-raf murine sarcoma viral oncogene homolog B (BRAF) WT papillary carcinomas. Given the wide availability and accuracy of IHC for detecting ectopic expression of ALK in the thyroid, we suggest that IHC-based screening can be a practical method for identifying patients with ALK rearrangements in differentiated thyroid cancer. PMID- 25527509 TI - Is IGSF1 involved in human pituitary tumor formation? AB - IGSF1 is a membrane glycoprotein highly expressed in the anterior pituitary. Pathogenic mutations in the IGSF1 gene (on Xq26.2) are associated with X-linked central hypothyroidism and testicular enlargement in males. In this study, we tested the hypothesis that IGSF1 is involved in the development of pituitary tumors, especially those that produce growth hormone (GH). IGSF1 was sequenced in 21 patients with gigantism or acromegaly and 92 healthy individuals. Expression studies with a candidate pathogenic IGSF1 variant were carried out in transfected cells and immunohistochemistry for IGSF1 was performed in the sections of GH producing adenomas, familial somatomammotroph hyperplasia, and in normal pituitary. We identified the sequence variant p.N604T, which in silico analysis suggested could affect IGSF1 function, in two male patients and one female with somatomammotroph hyperplasia from the same family. Of 60 female controls, two carried the same variant and seven were heterozygous for other variants. Immunohistochemistry showed increased IGSF1 staining in the GH-producing tumor from the patient with the IGSF1 p.N604T variant compared with a GH-producing adenoma from a patient negative for any IGSF1 variants and with normal control pituitary tissue. The IGSF1 gene appears polymorphic in the general population. A potentially pathogenic variant identified in the germline of three patients with gigantism from the same family (segregating with the disease) was also detected in two healthy female controls. Variations in IGSF1 expression in pituitary tissue in patients with or without IGSF1 germline mutations point to the need for further studies of IGSF1 action in pituitary adenoma formation. PMID- 25527511 TI - Sleep deprivation in parents caring for children with complex needs at home: a mixed methods systematic review. AB - A significant number of children with a range of complex conditions and health care needs are being cared for by parents in the home environment. This mixed methods systematic review aimed to determine the amount of sleep obtained by these parents and the extent to which the child-related overnight health or care needs affected parental sleep experience and daily functioning. Summary statistics were not able to be determined due to the heterogeneity of included studies, but the common themes that emerged are that parents of children with complex needs experience sleep deprivation that can be both relentless and draining and affects the parents themselves and their relationships. The degree of sleep deprivation varies by diagnosis, but a key contributing factor is the need for parents to be vigilant at night. Of particular importance to health care professionals is the inadequate overnight support provided to parents of children with complex needs, potentially placing these parents at risk of poorer health outcomes associated with sleep deprivation and disturbance. This needs to be addressed to enable parents to remain well and continue to provide the care that their child and family require. PMID- 25527517 TI - Hemorrhoid, internal iliac vein reflux and peripheral varicose vein: Affecting each other or affected vessels? PMID- 25527512 TI - Child welfare caseworkers as brokers of mental health services: a pilot evaluation of Project Focus Colorado. AB - Youth in the child welfare system (CWS) have substantially higher rates of mental health needs compared to the general population, yet they rarely receive targeted, evidence-based practices (EBPs). Caseworkers play the critically important role of "service broker" for CWS youth and families. This study examines preliminary caseworker-level outcomes of Project Focus Colorado (PF-C), a training and consultation program designed to improve access to EBPs for CWS youth. PF-C evaluation occurred in four child welfare offices (two intervention [n = 16 caseworkers] vs. two practice-as-usual, wait-list control [WLC; n = 12 caseworkers]). Receipt of PF-C was associated with significantly increased caseworker knowledge of (a) EBPs, (b) child mental health problems, (c) evidence based treatment components targeting mental health problem areas, and (d) mental health screening instruments, compared to WLC. Dose of training and consultation was associated with greater ability to correctly classify mental health problems and match them to EBPs. These preliminary results suggest that targeted training and consultation help to improve caseworker knowledge of children's mental health needs, EBPs for mental health, and mental health screening instruments. PMID- 25527518 TI - Frank Bernand Cockett 1916-2014. PMID- 25527519 TI - The diagnosis and management of antibiotic allergy in children: Systematic review to inform a contemporary approach. AB - BACKGROUND: Adverse drug reactions (ADRs) to antibiotics are commonly reported among children, with some representing genuine drug allergies. Accurate diagnostic tests are required. Drug provocation testing (DPT) is accepted as the gold standard investigation among children with suspected antibiotic allergy. We conducted this review to ascertain the strength of current evidence for using DPT as the first-line investigation for suspected antibiotic allergy among children. METHODS: Medline was searched in June 2014 for publications investigating antibiotic allergy among children. RESULTS: 865 publications were retrieved and 76 studies selected. ADRs are most common among children of 0-4 years, however only some reveal drug allergies. The best evidence demonstrates that around 0.21% of general paediatric outpatients demonstrate positive antibiotic intradermal (ID) testing or DPTs, while 6.8% of children attending emergency departments for suspected beta-lactam allergy may fulfil DPT reactions. Four studies used DPT based protocols to investigate suspected antibiotic allergy, with two of these conducting ID testing and DPTs across all participants. beta-lactam and clarithromycin ID testing had sensitivities of 66.7% and 75%, with positive predictive values of 36% and 33%, respectively, when compared with DPT data. CONCLUSIONS: Our literature review found four (6%) publications that performed DPTs to subjects' index antibiotic across all participants. No rigorous evidence supports using skin prick, ID or in vitro diagnostic testing; indeed, the testing regimens, extracts and positivity criteria used are inconsistent. We recommend that suspected non-serious antibiotic allergy should be primarily investigated using DPT-based clinical protocols. Data examining their safety, acceptability and diagnostic performance are required. PMID- 25527520 TI - Angioplasty for renovascular hypertension in 78 children. AB - OBJECTIVES: To evaluate the outcome of percutaneous transluminal angioplasty (PTA) in children with renovascular hypertension (RVH) treated at a single centre over 29 years. METHODS: A retrospective study of the medical charts of all children with RVH who underwent PTA between 1984 and 2012. The primary outcome measurement was blood pressure (BP) achieved after the procedure. The BP before the procedure was compared with that at last available follow-up, 6 (range 0.6 16) years after the initial procedure. RESULTS: Seventy-eight children with median (range) age of 6.5 (0.5-17) years were studied. Twenty-three (29.5%) had an underlying syndrome, 35 (44.9%) children had bilateral renal artery stenosis (RAS), 18 (23%) intrarenal disease and 11(14%) showed bilateral RAS and intrarenal disease. Twenty (25.6%) children had mid-aortic syndrome and 14 (17.9%) cerebrovascular disease. One hundred and fourteen PTA procedures were carried out including 31 stent insertions. Following PTA, BP was improved in 49 (62.8%) children and of those 18 (23.1%) were cured. Children with involvement of only the main renal arteries showed improved BP control in 79.9% of the children with cure in 39.5%. BP was intentionally maintained above the 95th centile for age and height in four children with coexistent cerebrovascular disease. No change in BP was seen in 18 children despite observed technical success of the PTA, and in seven children due to technical failure of the procedure. CONCLUSIONS: PTA provided a clinical benefit in 62.8% of children with RVH. PMID- 25527521 TI - An unusual presentation of stridor in an infant. PMID- 25527522 TI - Cardiovascular disease predicts diabetic peripheral polyneuropathy in subjects with type 2 diabetes: A 10-year prospective study. AB - BACKGROUND: The relationship between cardiovascular disease and diabetic peripheral neuropathy is mainly sustained by data retrieved from cross-sectional studies focused on cardiovascular risk factors. We aimed to assess the presence of cardiovascular disease as a risk factor for developing diabetic peripheral neuropathy in a type 2 diabetes mellitus population. METHOD: A 10-year prospective, primary care, multicentre study in a randomly selected cohort. Cardiovascular disease presence included stroke, coronary artery disease and/or peripheral ischaemia. Diabetic peripheral neuropathy diagnosis was based on clinical neurological examination as well as the neuropathy symptoms score and nerve conduction studies. RESULTS: Three hundred and ten (N=310) patients were initially recruited. Two-hundred and sixty seven (N=267) patients were included in the study. Diabetic peripheral neuropathy cumulative incidence was 18.3% (95% confidence intervals 14.1-23.4; N=49). Diabetic peripheral neuropathy development was significantly more frequent in participants presenting with cardiovascular disease at baseline (P=0.01). In the final logistic regression analysis, the presence of cardiovascular disease remained associated with an increased risk for diabetic peripheral neuropathy (odds ratio 2.32, 95% confidence intervals 1.03 5.22) in addition to diabetes duration and low density lipoprotein-cholesterol levels. CONCLUSIONS: In our series, type 2 diabetes mellitus patients with cardiovascular disease at baseline present with an increased risk of developing diabetic peripheral neuropathy at 10 years of follow-up. Our results suggest that measures aimed at the prevention, control and treatment of cardiovascular disease can also help prevent diabetic peripheral neuropathy development. PMID- 25527523 TI - A fungal sarcolemmal membrane-associated protein (SLMAP) homolog plays a fundamental role in development and localizes to the nuclear envelope, endoplasmic reticulum, and mitochondria. AB - Sarcolemmal membrane-associated protein (SLMAP) is a tail-anchored protein involved in fundamental cellular processes, such as myoblast fusion, cell cycle progression, and chromosomal inheritance. Further, SLMAP misexpression is associated with endothelial dysfunctions in diabetes and cancer. SLMAP is part of the conserved striatin-interacting phosphatase and kinase (STRIPAK) complex required for specific signaling pathways in yeasts, filamentous fungi, insects, and mammals. In filamentous fungi, STRIPAK was initially discovered in Sordaria macrospora, a model system for fungal differentiation. Here, we functionally characterize the STRIPAK subunit PRO45, a homolog of human SLMAP. We show that PRO45 is required for sexual propagation and cell-to-cell fusion and that its forkhead-associated (FHA) domain is essential for these processes. Protein protein interaction studies revealed that PRO45 binds to STRIPAK subunits PRO11 and SmMOB3, which are also required for sexual propagation. Superresolution structured-illumination microscopy (SIM) further established that PRO45 localizes to the nuclear envelope, endoplasmic reticulum, and mitochondria. SIM also showed that localization to the nuclear envelope requires STRIPAK subunits PRO11 and PRO22, whereas for mitochondria it does not. Taken together, our study provides important insights into fundamental roles of the fungal SLMAP homolog PRO45 and suggests STRIPAK-related and STRIPAK-unrelated functions. PMID- 25527524 TI - SUMOylation is developmentally regulated and required for cell pairing during conjugation in Tetrahymena thermophila. AB - The covalent attachment of small ubiquitin-like modifier (SUMO) to target proteins regulates numerous nuclear events in eukaryotes, including transcription, mitosis and meiosis, and DNA repair. Despite extensive interest in nuclear pathways within the field of ciliate molecular biology, there have been no investigations of the SUMO pathway in Tetrahymena. The developmental program of sexual reproduction of this organism includes cell pairing, micronuclear meiosis, and the formation of a new somatic macronucleus. We identified the Tetrahymena thermophila SMT3 (SUMO) and UBA2 (SUMO-activating enzyme) genes and demonstrated that the corresponding green fluorescent protein (GFP) tagged gene products are found predominantly in the somatic macronucleus during vegetative growth. Use of an anti-Smt3p antibody to perform immunoblot assays with whole cell lysates during conjugation revealed a large increase in SUMOylation that peaked during formation of the new macronucleus. Immunofluorescence using the same antibody showed that the increase was localized primarily within the new macronucleus. To initiate functional analysis of the SUMO pathway, we created germ line knockout cell lines for both the SMT3 and UBA2 genes and found both are essential for cell viability. Conditional Smt3p and Uba2p cell lines were constructed by incorporation of the cadmium-inducible metallothionein promoter. Withdrawal of cadmium resulted in reduced cell growth and increased sensitivity to DNA-damaging agents. Interestingly, Smt3p and Uba2p conditional cell lines were unable to pair during sexual reproduction in the absence of cadmium, consistent with a function early in conjugation. Our studies are consistent with multiple roles for SUMOylation in Tetrahymena, including a dynamic regulation associated with the sexual life cycle. PMID- 25527525 TI - Septin4_i1 regulates apoptosis in hepatic stellate cells through peroxisome proliferator-activated receptor-gamma/Akt/B-cell lymphoma 2 pathway. AB - Apoptosis of activated hepatic stellate cells (HSCs) has been verified as a potential mechanism to aid in hepatic fibrosis remission. Earlier research suggests that Septin4_i1 may sensitize hepatocellular carcinoma cells to serum starvation-induced apoptosis. Here, we aimed to investigate the effect of Septin4_i1 on HSC apoptosis and explore the associated signaling pathways. We found that Septin4_i1 can induce apoptosis in LX-2 cells and that this is accompanied by an up-regulation in cleaved-caspase-3 and peroxisome proliferator activated receptor-gamma (PPAR-gamma) expression and a down-regulation in alpha SMA expression. Over-expression of Septin4_i1 reduced phosphorylated Akt and B cell lymphoma 2 (Bcl-2) expression but had no effect on the expression of p53 and death receptor (DR)-5. The decreased expression of Bcl-2 and the increased expression of cleaved-caspase-3 induced by Sept4_i1 could be reversed by GW501516, a PPAR-beta/delta agonist that has been reported by others to enhance Akt signaling. In addition, GW9662, an antagonist of PPAR-gamma, could also inhibit apoptosis in LX-2 cells induced by Sept4_i1. In conclusion, our data suggest that Sept4_i1 induces HSC apoptosis by inhibiting Akt and Bcl-2 expression and up-regulating PPAR-gamma expression. PMID- 25527526 TI - Cumulative contextual and individual disadvantages over the life course and adult functional somatic symptoms in Sweden. AB - BACKGROUND: Disadvantage, originating in one's residential context or in one's past life course, has been shown to impact on health in adulthood. There is however little research on the accumulated health impact of both neighbourhood and individual conditions over the life course. This study aims to examine whether the accumulation of contextual and individual disadvantages from adolescence to middle-age predicts functional somatic symptoms (FSS) in middle age, taking baseline health into account. METHODS: The sample is the age 16, 21, 30 and 42 surveys of the prospective Northern Swedish Cohort, with analytical sample size n = 910 (85% of the original cohort). FSS at age 16 and 42, and cumulative socioeconomic disadvantage, social adversity and material adversity between 16 and 42 years were operationalized from questionnaires, and cumulative neighbourhood disadvantage between 16 and 42 years from register data. RESULTS: Results showed accumulation of disadvantages jointly explained 9-12% of FSS variance. In the total sample, cumulative neighbourhood and socioeconomic disadvantage significantly predicted FSS at age 42 in the total sample. In women, neighbourhood disadvantage but not socioeconomic disadvantage contributed significantly, whereas in men, socioeconomic but not neighbourhood disadvantage contributed significantly. In all analyses, associations were largely explained by the parallel accumulation of social and material adversities, but not by symptoms at baseline. CONCLUSION: In conclusion, the accumulation of diverse forms of disadvantages together plays an important role for somatic complaints in adulthood, independently of baseline health. PMID- 25527529 TI - Identifying Adolescent Patients at Risk for Sexually Transmitted Infections: Development of a Brief Sexual Health Screening Survey. AB - This study examined the association between survey responses to health behaviors, personality/psychosocial factors, and self-reported sexually transmitted infections (STIs) to create a brief survey to identify youth at risk for contracting STIs. Participants included 200 racially diverse 14- to 18-year-old patients from a pediatric primary care clinic. Two sexual behavior variables and one peer norm variable were used to differentiate subgroups of individuals at risk of contracting a STI based on reported history of STIs using probability (decision tree) analyses. These items, as well as sexual orientation and having ever had oral sex, were used to create a brief sexual health screening (BSHS) survey. Each point increase in total BSHS score was associated with exponential growth in the percentage of sexually active adolescents reporting STIs. Findings suggest that the BSHS could serve as a useful tool for clinicians to quickly and accurately detect sexual risk among adolescent patients. PMID- 25527527 TI - Thinking ahead--the need for early Advance Care Planning for people on haemodialysis: A qualitative interview study. AB - BACKGROUND: There is a need to improve end-of-life care for people with end-stage kidney disease, particularly due to the increasingly elderly, frail and co-morbid end-stage kidney disease population. Timely, sensitive and individualised Advance Care Planning discussions are acceptable and beneficial for people with end-stage kidney disease and can help foster realistic hopes and goals. AIM: To explore the experiences of people with end-stage kidney disease regarding starting haemodialysis, its impact on quality of life and their preferences for future care and to explore the Advance Care Planning needs of this population and the timing of this support. STUDY DESIGN: Semi-structured qualitative interview study of people receiving haemodialysis. Interviews were analysed using thematic analysis. Recruitment ceased once data saturation was achieved. SETTING/PARTICIPANTS: A total of 20 patients at two UK National Health Service hospitals, purposively sampled by age, time on haemodialysis and symptom burden. RESULTS: Themes emerged around: Looking Back, emotions of commencing haemodialysis; Current Experiences, illness and treatment burdens; and Looking Ahead, facing the realities. Challenges throughout the trajectory included getting information, communicating with staff and the 'conveyor belt' culture of haemodialysis units. Participants reported a lack of opportunity to discuss their future, particularly if their health deteriorated, and variable involvement in treatment decisions. However, discussion of these sensitive issues was more acceptable to some than others. CONCLUSION: Renal patients have considerable unmet Advance Care Planning needs. There is a need to normalise discussions about preferences and priorities in renal and haemodialysis units earlier in the disease trajectory. However, an individualised approach is essential - one size does not fit all. PMID- 25527528 TI - Association of goals of care meetings for hospitalized cancer patients at risk for critical care with patient outcomes. AB - BACKGROUND: Caring for cancer patients with advanced and refractory disease requires communication about care preferences, particularly when patients become ill enough to be at risk for critical care interventions potentially inconsistent with their preferences. AIM: To describe the use of goals of care discussions in patients with advanced/refractory cancer at risk for critical care interventions and evaluate associations between these discussions and outcomes. DESIGN: Cohort study describing patients/families' perceptions of goals of care meetings and comparing health care utilization outcomes of patients who did and did not have discussions. SETTING/PARTICIPANTS: Inpatient units of an academic cancer center. Included patients had metastatic solid tumors or relapsed/refractory lymphoma or leukemia and were at risk for critical care, defined as requiring supplemental oxygen and/or cardiac monitor. RESULTS: Of 86 patients enrolled, 34 (39%) had a reported goals of care discussion (study group). Patients/families reported their needs and goals were addressed moderately to quite a bit during the meetings. Patients in the study group were less likely to receive critical care (0% vs 22%, p = 0.003) and more likely to be discharged to hospice (48% vs 30%, p = 0.04) than the control group. Only one patient in the study group died during the index hospitalization (on comfort care) (3%) compared with 9(17%) in the control group (p = 0.08). CONCLUSION: Goals of care meetings for advanced/refractory cancer inpatients at risk for critical care interventions can address patient and family goals and needs and improve health care utilization. These meetings should be part of routine care for these patients. PMID- 25527530 TI - Growing pains in children: solved and resolved. PMID- 25527531 TI - Engineering of Glarea lozoyensis for exclusive production of the pneumocandin B0 precursor of the antifungal drug caspofungin acetate. AB - Pneumocandins produced by the fungus Glarea lozoyensis are acylated cyclic hexapeptides of the echinocandin family. Pneumocandin B0 is the starting molecule for the first semisynthetic echinocandin antifungal drug, caspofungin acetate. In the wild-type strain, pneumocandin B0 is a minor fermentation product, and its industrial production was achieved by a combination of extensive mutation and medium optimization. The pneumocandin biosynthetic gene cluster was previously elucidated by a whole-genome sequencing approach. Knowledge of the biosynthetic cluster suggested an alternative way to produce exclusively pneumocandin B0. Disruption of GLOXY4, encoding a nonheme, alpha-ketoglutarate-dependent oxygenase, confirmed its involvement in l-leucine cyclization to form 4S-methyl-l proline. The absence of 4S-methyl-l-proline abolishes pneumocandin A0 production, and 3S-hydroxyl-l-proline occupies the hexapeptide core's position 6, resulting in exclusive production of pneumocandin B0. Retrospective analysis of the GLOXY4 gene in a previously isolated pneumocandin B0-exclusive mutant (ATCC 74030) indicated that chemical mutagenesis disrupted the GLOXY4 gene function by introducing two amino acid mutations in GLOXY4. This one-step genetic manipulation can rationally engineer a high-yield production strain. PMID- 25527532 TI - Prevalence of carriage of Shiga toxin-producing Escherichia coli serotypes O157:H7, O26:H11, O103:H2, O111:H8, and O145:H28 among slaughtered adult cattle in France. AB - The main pathogenic enterohemorrhagic Escherichia coli (EHEC) strains are defined as Shiga toxin (Stx)-producing E. coli (STEC) belonging to one of the following serotypes: O157:H7, O26:H11, O103:H2, O111:H8, and O145:H28. Each of these five serotypes is known to be associated with a specific subtype of the intimin encoding gene (eae). The objective of this study was to evaluate the prevalence of bovine carriers of these "top five" STEC in the four adult cattle categories slaughtered in France. Fecal samples were collected from 1,318 cattle, including 291 young dairy bulls, 296 young beef bulls, 337 dairy cows, and 394 beef cows. A total of 96 E. coli isolates, including 33 top five STEC and 63 atypical enteropathogenic E. coli (aEPEC) isolates, with the same genetic characteristics as the top five STEC strains except that they lacked an stx gene, were recovered from these samples.O157:H7 was the most frequently isolated STEC serotype. The prevalence of top five STEC (all serotypes included) was 4.5% in young dairy bulls, 2.4% in young beef bulls, 1.8% in dairy cows, and 1.0% in beef cows. It was significantly higher in young dairy bulls (P<0.05) than in the other 3 categories. The basis for these differences between categories remains to be elucidated. Moreover,simultaneous carriage of STEC O26:H11 and STEC O103:H2 was detected in one young dairy bull. Lastly, the prevalence of bovine carriers of the top five STEC, evaluated through a weighted arithmetic mean of the prevalence by categories, was estimated to 1.8% in slaughtered adult cattle in France. PMID- 25527533 TI - Exopolysaccharide production and ropy phenotype are determined by two gene clusters in putative probiotic strain Lactobacillus paraplantarum BGCG11. AB - Lactobacillus paraplantarum BGCG11, a putative probiotic strain isolated from a soft, white, artisanal cheese, produces a high molecular-weight heteropolysaccharide, exopolysaccharide (EPS)-CG11, responsible for the ropy phenotype and immunomodulatory activity of the strain. In this study, a 26.4-kb region originating from the pCG1 plasmid, previously shown to be responsible for the production of EPS-CG11 and a ropy phenotype, was cloned, sequenced, and functionally characterized. In this region 16 putative open reading frames (ORFs), encoding enzymes for the production of EPS-CG11, were organized in specific loci involved in the biosynthesis of the repeat unit, polymerization, export, regulation, and chain length determination. Interestingly, downstream of the eps gene cluster, a putative transposase gene was identified, followed by an additional rfb gene cluster containing the rfbACBD genes, the ones most probably responsible for dTDP-L-rhamnose biosynthesis. The functional analysis showed that the production of the high-molecular-weight fraction of EPS-CG11 was absent in two knockout mutants, one in the eps and the other in the rfb gene cluster, as confirmed by size exclusion chromatography analysis. Therefore, both eps and rfb genes clusters are prerequisites for the production of high-molecular-weight EPS CG11 and for the ropy phenotype of strain L. paraplantarum BGCG11. PMID- 25527534 TI - Hierarchy in pentose sugar metabolism in Clostridium acetobutylicum. AB - Bacterial metabolism of polysaccharides from plant detritus into acids and solvents is an essential component of the terrestrial carbon cycle. Understanding the underlying metabolic pathways can also contribute to improved production of biofuels. Using a metabolomics approach involving liquid chromatography-mass spectrometry, we investigated the metabolism of mixtures of the cellulosic hexose sugar (glucose) and hemicellulosic pentose sugars (xylose and arabinose) in the anaerobic soil bacterium Clostridium acetobutylicum. Simultaneous feeding of stable isotope-labeled glucose and unlabeled xylose or arabinose revealed that,as expected, glucose was preferentially used as the carbon source. Assimilated pentose sugars accumulated in pentose phosphate pathway (PPP) intermediates with minimal flux into glycolysis. Simultaneous feeding of xylose and arabinose revealed an unexpected hierarchy among the pentose sugars, with arabinose utilized preferentially over xylose. The phosphoketolase pathway (PKP) provides an alternative route of pentose catabolism in C. acetobutylicum that directly converts xylulose-5-phosphate into acetyl-phosphate and glyceraldehyde-3 phosphate, bypassing most of the PPP. When feeding the mixture of pentose sugars, the labeling patterns of lower glycolytic intermediates indicated more flux through the PKP than through the PPP and upper glycolysis, and this was confirmed by quantitative flux modeling. Consistent with direct acetyl-phosphate production from the PKP, growth on the pentose mixture resulted in enhanced acetate excretion. Taken collectively, these findings reveal two hierarchies in clostridial pentose metabolism: xylose is subordinate to arabinose, and the PPP is used less than the PKP. PMID- 25527535 TI - Escherichia coli enoyl-acyl carrier protein reductase (FabI) supports efficient operation of a functional reversal of beta-oxidation cycle. AB - We recently used a synthetic/bottom-up approach to establish the identity of the four enzymes composing an engineered functional reversal of the -oxidation cycle for fuel and chemical production in Escherichia coli (J. M. Clomburg, J. E. Vick, M. D. Blankschien, M. Rodriguez-Moya, and R. Gonzalez, ACS Synth Biol 1:541-554, 2012, http://dx.doi.org/10.1021/sb3000782).While native enzymes that catalyze the first three steps of the pathway were identified, the identity of the native enzyme(s) acting as the trans-enoyl coenzyme A (CoA) reductase(s) remained unknown, limiting the amount of product that could be synthesized (e.g., 0.34 g/liter butyrate) and requiring the overexpression of a foreign enzyme (the Euglena gracilis trans-enoyl-CoA reductase [EgTER]) to achieve high titers (e.g., 3.4 g/liter butyrate). Here, we examine several native E. coli enzymes hypothesized to catalyze the reduction of enoyl-CoAs to acyl-CoAs. Our results indicate that FabI, the native enoyl-acyl carrier protein (enoyl-ACP) reductase (ENR) from type II fatty acid biosynthesis, possesses sufficient NADH-dependent TER activity to support the efficient operation of a -oxidation reversal. Overexpression of FabI proved as effective as EgTER for the production of butyrate and longer-chain carboxylic acids. Given the essential nature of fabI, we investigated whether bacterial ENRs from other families were able to complement a fabI deletion without promiscuous reduction of crotonyl-CoA. These characteristics from Bacillus subtilis FabL enabled deltaffabI complementation experiments that conclusively established that FabI encodes a native enoyl-CoA reductase activity that supports the beta-oxidation reversal in E. coli. PMID- 25527536 TI - XoxF-type methanol dehydrogenase from the anaerobic methanotroph "Candidatus Methylomirabilis oxyfera". AB - "Candidatus Methylomirabilis oxyfera" is a newly discovered anaerobic methanotroph that, surprisingly, oxidizes methane through an aerobic methane oxidation pathway. The second step in this aerobic pathway is the oxidation of methanol. In Gramnegative bacteria, the reaction is catalyzed by pyrroloquinoline quinone (PQQ)-dependent methanol dehydrogenase (MDH). The genome of "Ca. Methylomirabilis oxyfera" putatively encodes three different MDHs that are localized in one large gene cluster: one so-called MxaFI-type MDH and two XoxF type MDHs (XoxF1 and XoxF2). MxaFI MDHs represent the canonical enzymes, which are composed of two PQQ-containing large (alpha) subunits (MxaF) and two small (beta) subunits (MxaI). XoxF MDHs are novel, ecologically widespread, but poorly investigated types of MDHs that can be phylogenetically divided into at least five different clades. The XoxF MDHs described thus far are homodimeric proteins containing a large subunit only. Here, we purified a heterotetrameric MDH from "Ca. Methylomirabilis oxyfera" that consisted of two XoxF and two MxaI subunits. The enzyme was localized in the periplasm of "Ca. Methylomirabilis oxyfera" cells and catalyzed methanol oxidation with appreciable specific activity and affinity (Vmax of 10 micromole min(-1) mg(-1) protein, Km of 17 microM). PQQ was present as the prosthetic group,which has to be taken up from the environment since the known gene inventory required for the synthesis of this cofactor is lacking. The MDH from "Ca. Methylomirabilis oxyfera" is the first representative of type 1 XoxF proteins to be described. PMID- 25527537 TI - Phaeobacter sp. strain Y4I utilizes two separate cell-to-cell communication systems to regulate production of the antimicrobial indigoidine. AB - The marine roseobacter Phaeobacter sp. strain Y4I synthesizes the blue antimicrobial secondary metabolite indigoidine when grown in a biofilm or on agar plates. Prior studies suggested that indigoidine production may be, in part, regulated by cell-to-cell communication systems. Phaeobacter sp. strain Y4I possesses two luxR and luxI homologous N-acyl-L-homoserine lactone (AHL)-mediated cell-to-cell communication systems, designated pgaRI and phaRI. We show here that Y4I produces two dominantAHLs, the novel monounsaturated N-(3-hydroxydodecenoyl) L-homoserine lactone (3OHC(12:1)-HSL) and the relatively common N-octanoyl-L homoserine lactone (C8-HSL), and provide evidence that they are synthesized by PhaI and PgaI, respectively.A Tn5 insertional mutation in either genetic locus results in the abolishment (pgaR::Tn5) or reduction (phaR::Tn5) of pigment production. Motility defects and denser biofilms were also observed in these mutant backgrounds, suggesting an overlap in the functional roles of these systems. Production of the AHLs occurs at distinct points during growth on an agar surface and was determined by isotope dilution high-performance liquid chromatography-tandem mass spectrometry (ID-HPLC-MS/MS) analysis.Within 2 h of surface inoculation, only 3OHC(12:1)-HSL was detected in agar extracts. As surface-attached cells became established (at approximately 10 h), the concentration of 3OHC(12:1)-HSL decreased, and the concentration of C8-HSL increased rapidly over 14 h.After longer (>24-h) establishment periods, the concentrations of the two AHLs increased to and stabilized at approximately 15 nM and approximately 600 nM for 3OHC12:1-HSL and C8-HSL, respectively. In contrast, the total amount of indigoidine increased steadily from undetectable to 642 Mby 48 h. Gene expression profiles of the AHL and indigoidine synthases (pgaI, phaI, and igiD) were consistent with their metabolite profiles. These data provide evidence that pgaRI and phaRI play overlapping roles in the regulation of indigoidine biosynthesis, and it is postulated that this allows Phaeobacter sp. strain Y4I to coordinate production of indigoidine with different growth-phase dependent physiologies. PMID- 25527538 TI - Colonization in the photic zone and subsequent changes during sinking determine bacterial community composition in marine snow. AB - Due to sampling difficulties, little is known about microbial communities associated with sinking marine snow in the twilight zone. A drifting sediment trap was equipped with a viscous cryogel and deployed to collect intact marine snow from depths of 100 and 400 m off Cape Blanc (Mauritania). Marine snow aggregates were fixed and washed in situ to prevent changes in microbial community composition and to enable subsequent analysis using catalyzed reporter deposition fluorescence in situ hybridization (CARD-FISH). The attached microbial communities collected at 100 m were similar to the free-living community at the depth of the fluorescence maximum (20 m) but different from those at other depths (150, 400, 550, and 700 m). Therefore, the attached microbial community seemed to be "inherited" from that at the fluorescence maximum. The attached microbial community structure at 400 m differed from that of the attached community at 100 m and from that of any free-living community at the tested depths, except that collected near the sediment at 700 m. The differences between the particle associated communities at 400 m and 100 m appeared to be due to internal changes in the attached microbial community rather than de novo colonization, detachment, or grazing during the sinking of marine snow. The new sampling method presented here will facilitate future investigations into the mechanisms that shape the bacterial community within sinking marine snow, leading to better understanding of the mechanisms which regulate biogeochemical cycling of settling organic matter. PMID- 25527539 TI - Diversity of methane-cycling archaea in hydrothermal sediment investigated by general and group-specific PCR primers. AB - The zonation of anaerobic methane-cycling Archaea in hydrothermal sediment of Guaymas Basin was studied by general primerpairs (mcrI, ME1/ME2, mcrIRD) targeting the alpha subunit of methyl coenzyme M reductase gene (mcrA) and by new group specific mcrA and 16S rRNA gene primer pairs. The mcrIRD primer pair outperformed the other general mcrA primer pairs indetection sensitivity and phylogenetic coverage. Methanotrophic ANME-1 Archaea were the only group detected with group specific primers only. The detection of 14 mcrA lineages surpasses the diversity previously found in this location. Most phylotypes have high sequence similarities to hydrogenotrophs, methylotrophs, and anaerobic methanotrophs previously detected at Guaymas Basin or at hydrothermal vents, cold seeps, and oil reservoirs worldwide. Additionally, five mcrA phylotypes belonging to newly defined lineages are detected. Two of these belong to deeply branching new orders, while the others are new species or genera of Methanopyraceae and Methermicoccaceae. Downcore diversity decreases from all groups detected in the upper 6 cm(2 to 40 degrees C, sulfate measurable to 4 cm) to only two groups below 6 cm (>40 degrees C). Despite the presence of hyperthermophilic genera (Methanopyrus, Methanocaldococcus) in cooler surface strata, no genes were detected below 10 cm (>60 degrees C). While mcrAbased and 16S rRNA gene-based community compositions are generally congruent, the deeply branching mcrA cannot be assigned to specific 16S rRNA gene lineages. Our study indicates that even among well-studied metabolic groups and in previously characterized model environments, major evolutionary branches are overlooked. Detecting these groups by improved molecular biological methods is a crucial first step toward understanding their roles in nature. PMID- 25527540 TI - Functional expression of full-length TrkA in the prokaryotic host Magnetospirillum magneticum AMB-1 by using a magnetosome display system. AB - Tropomyosin receptor kinase A (TrkA), a receptor tyrosine kinase, is known to be associated with various diseases. Thus, TrkA has become a major drug-screening target for these diseases. Despite the fact that the production of recombinant proteins by prokaryotic hosts has advantages, such as fast growth and ease of genetic engineering, the efficient production of functional receptor tyrosine kinase by prokaryotic hosts remains a major experimental challenge. Here, we report the functional expression of full-length TrkA on magnetosomes in Magnetospirillum magneticum AMB-1 by using a magnetosome display system. TrkAwas fused with the magnetosome-localized protein Mms13 and expressed on magnetosome surfaces. Recombinant TrkA showed both nerve growth factor (NGF)-binding and autophosphorylation activities. TrkA expressed on magnetosomes has the potential to be used, not only for further functional analysis of TrkA, but also for ligand screening. PMID- 25527541 TI - Phosphoryl transfer from alpha-d-glucose 1-phosphate catalyzed by Escherichia coli sugar-phosphate phosphatases of two protein superfamily types. AB - The Cori ester alpha-d-glucose 1-phosphate (alphaGlc 1-P) is a high-energy intermediate of cellular carbohydrate metabolism. Its glycosidic phosphomonoester moiety primes alphaGlc 1-P for flexible exploitation in glucosyl and phosphoryl transfer reactions. Two structurally and mechanistically distinct sugar-phosphate phosphatases from Escherichia coli were characterized in this study for utilization of alphaGlc 1-P as a phosphoryl donor substrate. The agp gene encodes a periplasmic alphaGlc 1-P phosphatase (Agp) belonging to the histidine acid phosphatase family. Had13 is from the haloacid dehydrogenase-like phosphatase family. Cytoplasmic expression of Agp (in E. coli Origami B) gave a functional enzyme preparation (kcat for phosphoryl transfer from alphaGlc 1-P to water, 40 s(-1)) that was shown by mass spectrometry to exhibit no free cysteines and the native intramolecular disulfide bond between Cys(189) and Cys(195). Enzymatic phosphoryl transfer from alphaGlc 1-P to water in H2 (18)O solvent proceeded with complete (18)O label incorporation into the phosphate released, consistent with catalytic reaction through O-1-P, but not C-1-O, bond cleavage. Hydrolase activity of both enzymes was not restricted to a glycosidic phosphomonoester substrate, and d-glucose 6-phosphate was converted with a kcat similar to that of alphaGlc 1-P. By examining phosphoryl transfer from alphaGlc 1-P to an acceptor substrate other than water (d-fructose or d-glucose), we discovered that Agp exhibited pronounced synthetic activity, unlike Had13, which utilized alphaGlc 1 P mainly for phosphoryl transfer to water. By applying d-fructose in 10-fold molar excess over alphaGlc 1-P (20 mM), enzymatic conversion furnished d-fructose 1-phosphate as the main product in a 55% overall yield. Agp is a promising biocatalyst for use in transphosphorylation from alphaGlc 1-P. PMID- 25527542 TI - Gut symbionts from distinct hosts exhibit genotoxic activity via divergent colibactin biosynthesis pathways. AB - Secondary metabolites produced by nonribosomal peptide synthetase (NRPS) or polyketide synthase (PKS) pathways are chemical mediators of microbial interactions in diverse environments. However, little is known about their distribution, evolution, and functional roles in bacterial symbionts associated with animals. A prominent example is colibactin, a largely unknown family of secondary metabolites produced by Escherichia coli via a hybrid NRPS-PKS biosynthetic pathway that inflicts DNA damage upon eukaryotic cells and contributes to colorectal cancer and tumor formation in the mammalian gut. Thus far, homologs of this pathway have only been found in closely related Enterobacteriaceae, while a divergent variant of this gene cluster was recently discovered in a marine alphaproteobacterial Pseudovibrio strain. Herein, we sequenced the genome of Frischella perrara PEB0191, a bacterial gut symbiont of honey bees and identified a homologous colibactin biosynthetic pathway related to those found in Enterobacteriaceae. We show that the colibactin genomic island (GI) has conserved gene synteny and biosynthetic module architecture across F. perrara, Enterobacteriaceae, and the Pseudovibrio strain. Comparative metabolomics analyses of F. perrara and E. coli further reveal that these two bacteria produce related colibactin pathway-dependent metabolites. Finally, we demonstrate that F. perrara, like E. coli, causes DNA damage in eukaryotic cells in vitro in a colibactin pathway-dependent manner. Together, these results support that divergent variants of the colibactin biosynthetic pathway are widely distributed among bacterial symbionts, producing related secondary metabolites and likely endowing its producer with functional capabilities important for diverse symbiotic associations. PMID- 25527543 TI - Novel reporter for identification of interference with acyl homoserine lactone and autoinducer-2 quorum sensing. AB - Two reporter strains were established to identify novel biomolecules interfering with bacterial communication (quorum sensing [QS]). The basic design of these Escherichia coli-based systems comprises a gene encoding a lethal protein fused to promoters induced in the presence of QS signal molecules. Consequently, these E. coli strains are unable to grow in the presence of the respective QS signal molecules unless a nontoxic QS-interfering compound is present. The first reporter strain designed to detect autoinducer-2 (AI-2)-interfering activities (AI2-QQ.1) contained the E. coli ccdB lethal gene under the control of the E. coli lsrA promoter. The second reporter strain (AI1-QQ.1) contained the Vibrio fischeri luxI promoter fused to the ccdB gene to detect interference with acyl homoserine lactones. Bacteria isolated from the surfaces of several marine eukarya were screened for quorum- quenching (QQ) activities using the established reporter systems AI1-QQ.1 and AI2-QQ.1. Out of 34 isolates, two interfered with acylated homoserine lactone (AHL) signaling, five interfered with AI-2 QS signaling, and 10 were demonstrated to interfere with both signal molecules. Open reading frames (ORFs) conferring QQ activity were identified for three selected isolates (Photobacterium sp., Pseudoalteromonas sp., and Vibrio parahaemolyticus). Evaluation of the respective heterologously expressed and purified QQ proteins confirmed their ability to interfere with the AHL and AI-2 signaling processes. PMID- 25527544 TI - Multilocus sequence analysis of xanthomonads causing bacterial spot of tomato and pepper plants reveals strains generated by recombination among species and recent global spread of Xanthomonas gardneri. AB - Four Xanthomonas species are known to cause bacterial spot of tomato and pepper, but the global distribution and genetic diversity of these species are not well understood. A collection of bacterial spot-causing strains from the Americas, Africa, Southeast Asia, and New Zealand were characterized for genetic diversity and phylogenetic relationships using multilocus sequence analysis of six housekeeping genes. By examining strains from different continents, we found unexpected phylogeographic patterns, including the global distribution of a single multilocus haplotype of X. gardneri, possible regional differentiation in X. vesicatoria, and high species diversity on tomato in Africa. In addition, we found evidence of multiple recombination events between X. euvesicatoria and X. perforans. Our results indicate that there have been shifts in the species composition of bacterial spot pathogen populations due to the global spread of dominant genotypes and that recombination between species has generated genetic diversity in these populations. PMID- 25527545 TI - Genetic engineering activates biosynthesis of aromatic fumaric acid amides in the human pathogen Aspergillus fumigatus. AB - The Aspergillus fumigatus nonribosomal peptide synthetase FtpA is among the few of this species whose natural product has remained unknown. Both FtpA adenylation domains were characterized in vitro. Fumaric acid was identified as preferred substrate of the first and both l-tyrosine and l-phenylalanine as preferred substrates of the second adenylation domain. Genetically engineered A. fumigatus strains expressed either ftpA or the regulator gene ftpR, encoded in the same cluster of genes, under the control of the doxycycline-inducible tetracycline induced transcriptional activation (tet-on) cassette. These strains produced fumaryl-l-tyrosine and fumaryl-l-phenylalanine which were identified by liquid chromatography and high-resolution mass spectrometry. Modeling of the first adenylation domain in silico provided insight into the structural requirements to bind fumaric acid as peptide synthetase substrate. This work adds aromatic fumaric acid amides to the secondary metabolome of the important human pathogen A. fumigatus which was previously not known as a producer of these compounds. PMID- 25527546 TI - CATCh, an ensemble classifier for chimera detection in 16S rRNA sequencing studies. AB - In ecological studies, microbial diversity is nowadays mostly assessed via the detection of phylogenetic marker genes, such as 16S rRNA. However, PCR amplification of these marker genes produces a significant amount of artificial sequences, often referred to as chimeras. Different algorithms have been developed to remove these chimeras, but efforts to combine different methodologies are limited. Therefore, two machine learning classifiers (reference based and de novo CATCh) were developed by integrating the output of existing chimera detection tools into a new, more powerful method. When comparing our classifiers with existing tools in either the reference-based or de novo mode, a higher performance of our ensemble method was observed on a wide range of sequencing data, including simulated, 454 pyrosequencing, and Illumina MiSeq data sets. Since our algorithm combines the advantages of different individual chimera detection tools, our approach produces more robust results when challenged with chimeric sequences having a low parent divergence, short length of the chimeric range, and various numbers of parents. Additionally, it could be shown that integrating CATCh in the preprocessing pipeline has a beneficial effect on the quality of the clustering in operational taxonomic units. PMID- 25527547 TI - Community structure and biogeochemical impacts of microbial life on floating pumice. AB - Volcanic eruptions are a widespread force of geological and ecological disturbance and present recurrent opportunities for the study of biological responses to novel habitat formation. However, scientific study of such events is difficult given their short duration and often distant location. Here we report results from opportunistic sampling of unique volcano-generated habitats formed during the 2011 explosive eruption in the Puyehue-Cordon Caulle complex (Chile), when massive amounts of pumice were ejected, creating novel floating substrata that have never before been characterized from a microbiological perspective. DNA sequencing revealed a dynamic community of microbes that came to inhabit the pumice, with a unique composition distinct from that of the lakes' surface waters and with suggestions of ecological convergence across lakes and sampling times. Furthermore, biogeochemical studies of net nutrient fluxes showed that, while the fresh pumice arriving to the lakes was an initial source of phosphorus (P), colonized pumice had high rates of nitrogen (N) and P uptake and was sufficiently abundant to represent a significant lake-wide nutrient sink. These findings highlight the remarkable versatility of microbes in exploiting novel environments and are consistent with a recent proposal of floating pumice as a favorable environment for the initial origins of life on early Earth. PMID- 25527548 TI - Mechanisms of methods for hepatitis C virus inactivation. AB - Virus inactivation by chemical disinfectants is an important instrument for infection control in medical settings, but the mechanisms involved are poorly understood. In this study, we systematically investigated the effects of several antiviral treatments on hepatitis C virus (HCV) particles as model for enveloped viruses. Studies were performed with authentic cell culture-derived viruses, and the influence of chemical disinfectants, heat, and UV treatment on HCV was analyzed by the determination of infectious particles in a limiting-dilution assay, by quantitative reverse transcription-PCR, by core enzyme-linked immunosorbent assay, and by proteolytic protection assay. All different inactivation methods resulted in a loss of HCV infectivity by targeting different parts of the virus particle. Alcohols such as ethanol and 2-propanol did not affect the viral RNA genome integrity but disrupted the viral envelope membrane in a capsid protection assay. Heat and UV treatment of HCV particles resulted in direct damage of the viral genome since transfection of viral particle-associated RNA into permissive cells did not initiate RNA replication. In addition, heat incubation at 80 degrees C disrupted the HCV envelope, rendering the viral capsid susceptible to proteolytic digest. This study demonstrated the molecular processes of viral inactivation of an enveloped virus and should facilitate the development of effective disinfection strategies in infection control not only against HCV but also against other enveloped viruses. PMID- 25527549 TI - Rapid method using two microbial enzymes for detection of L-abrine in food as a marker for the toxic protein abrin. AB - Abrin is a toxic protein produced by the ornamental plant Abrus precatorius, and it is of concern as a biothreat agent. The small coextracting molecule N-methyl-l tryptophan (l-abrine) is specific to members of the genus Abrus and thus can be used as a marker for the presence or ingestion of abrin. Current methods for the detection of abrin or l-abrine in foods and other matrices require complex sample preparation and expensive instrumentation. To develop a fast and portable method for the detection of l-abrine in beverages and foods, the Escherichia coli proteins N-methyltryptophan oxidase (MTOX) and tryptophanase were expressed and purified. The two enzymes jointly degraded l-abrine to products that included ammonia and indole, and colorimetric assays for the detection of those analytes in beverage and food samples were evaluated. An indole assay using a modified version of Ehrlich's/Kovac's reagent was more sensitive and less subject to negative interferences from components in the samples than the Berthelot ammonia assay. The two enzymes were added into food and beverage samples spiked with l abrine, and indole was detected as a degradation product, with the visual lower detection limit being 2.5 to 10.0 MUM (~0.6 to 2.2 ppm) l-abrine in the samples tested. Results could be obtained in as little as 15 min. Sample preparation was limited to pH adjustment of some samples. Visual detection was found to be about as sensitive as detection with a spectrophotometer, especially in milk-based matrices. PMID- 25527550 TI - Integrative conjugative elements are widespread in field isolates of Mycoplasma species pathogenic for ruminants. AB - Comparative genomics have revealed massive horizontal gene transfer (HGT) between Mycoplasma species sharing common ruminant hosts. Further results pointed toward an integrative conjugative element (ICE) as an important contributor of HGT in the small-ruminant-pathogen Mycoplasma agalactiae. To estimate the prevalence of ICEs in ruminant mycoplasmas, we surveyed their occurrence in a collection of 166 field strains representing 4 (sub)species that are recognized as major pathogens. Based on available sequenced genomes, we first defined the conserved, minimal ICE backbone as composed of 4 coding sequences (CDSs) that are evenly distributed and predicted to be essential for ICE chromosomal integration-excision and horizontal transfer. Screening of the strain collection revealed that these 4 CDSs are well represented in ruminant Mycoplasma species, suggesting widespread occurrence of ICEs. Yet their prevalence varies within and among species, with no correlation found with the individual strain history. Extrachromosomal ICE forms were also often detected, suggesting that ICEs are able to circularize in all species, a first and essential step in ICE horizontal transfer. Examination of the junction of the circular forms and comparative sequence analysis of conserved CDSs clearly pointed toward two types of ICE, the hominis and spiroplasma types, most likely differing in their mechanism of excision-integration. Overall, our data indicate the occurrence and maintenance of functional ICEs in a large number of field isolates of ruminant mycoplasmas. These may contribute to genome plasticity and gene exchanges and, presumably, to the emergence of diverse genotypes within pathogenic mycoplasmas of veterinary importance. PMID- 25527551 TI - Clearance of Escherichia coli O157:H7 infection in calves by rectal administration of bovine lactoferrin. AB - Enterohemorrhagic Escherichia coli (EHEC) strains, of which E. coli O157:H7 is the best-studied serotype, are an important group of foodborne pathogens causing severe illness in humans worldwide. The main reservoirs for EHEC are ruminants, mostly cattle, which harbor the bacteria in their intestinal tracts without showing clinical symptoms. In this study, we used bovine lactoferrin, a natural occurring bactericidal and immunomodulating protein, as an antibacterial agent against EHEC infection in cattle. Nine 3-month-old Holstein-Friesian calves were experimentally infected with EHEC (strain NCTC12900). Three animals received a daily rectal spray treatment with bovine lactoferrin, three animals received an oral treatment, and three animals served as a control group. Blood samples were collected weekly and fecal samples twice weekly to monitor antibody responses and fecal excretion, respectively. Animals in the rectal group ceased shedding within 26 days of the experimental treatment and remained negative. This beneficial effect of bovine lactoferrin was not observed in the oral group, where animals were still shedding at the time of euthanasia (day 61). All groups developed serum responses, but no clear differences could be observed between the groups. However, the results indicate that the use of bovine lactoferrin as a rectal treatment can be a useful strategy to preclude further transmission of EHEC infections from cattle to humans. PMID- 25527552 TI - Organic substances interfere with reverse transcription-quantitative PCR-based virus detection in water samples. AB - Reverse transcription (RT)-PCR-based virus detection from water samples is occasionally hampered by organic substances that are co-concentrated during virus concentration procedures. To characterize these organic substances, samples containing commercially available humic acid, which is known to inhibit RT-PCR, and river water samples were subjected to adsorption-elution-based virus concentration using an electronegative membrane. In this study, the samples before, during, and after the concentration were analyzed in terms of organic properties and virus detection efficiencies. Two out of the three humic acid solutions resulted in RT-quantitative PCR (qPCR) inhibition that caused >3-log10 unit underestimation of spiked poliovirus. Over 60% of the organics contained in the two solutions were recovered in the concentrate, while over 60% of the organics in the uninhibited solution were lost during the concentration process. River water concentrates also caused inhibition of RT-qPCR. Organic concentrations in the river water samples increased by 2.3 to 3.9 times after the virus concentration procedure. The inhibitory samples contained organic fractions in the 10- to 100-kDa size range, which are suspected to be RT-PCR inhibitors. According to excitation-emission matrices, humic acid-like and protein-like fractions were also recovered from river water concentrates, but these fractions did not seem to affect virus detection. Our findings reveal that detailed organic analyses are effective in characterizing inhibitory substances. PMID- 25527553 TI - Using a genome-scale metabolic model of Enterococcus faecalis V583 to assess amino acid uptake and its impact on central metabolism. AB - Increasing antibiotic resistance in pathogenic bacteria necessitates the development of new medication strategies. Interfering with the metabolic network of the pathogen can provide novel drug targets but simultaneously requires a deeper and more detailed organism-specific understanding of the metabolism, which is often surprisingly sparse. In light of this, we reconstructed a genome-scale metabolic model of the pathogen Enterococcus faecalis V583. The manually curated metabolic network comprises 642 metabolites and 706 reactions. We experimentally determined metabolic profiles of E. faecalis grown in chemically defined medium in an anaerobic chemostat setup at different dilution rates and calculated the net uptake and product fluxes to constrain the model. We computed growth associated energy and maintenance parameters and studied flux distributions through the metabolic network. Amino acid auxotrophies were identified experimentally for model validation and revealed seven essential amino acids. In addition, the important metabolic hub of glutamine/glutamate was altered by constructing a glutamine synthetase knockout mutant. The metabolic profile showed a slight shift in the fermentation pattern toward ethanol production and increased uptake rates of multiple amino acids, especially l-glutamine and l glutamate. The model was used to understand the altered flux distributions in the mutant and provided an explanation for the experimentally observed redirection of the metabolic flux. We further highlighted the importance of gene-regulatory effects on the redirection of the metabolic fluxes upon perturbation. The genome scale metabolic model presented here includes gene-protein-reaction associations, allowing a further use for biotechnological applications, for studying essential genes, proteins, or reactions, and the search for novel drug targets. PMID- 25527554 TI - Bacterial communities associated with surfaces of leafy greens: shift in composition and decrease in richness over time. AB - The phyllosphere is colonized by a wide variety of bacteria and fungi; it harbors epiphytes, as well as plant-pathogenic bacteria and even human pathogens. However, little is known about how the bacterial community composition on leafy greens develops over time. The bacterial community of the leafy-green phyllosphere obtained from two plantings of rocket salad (Diplotaxis tenuifolia) and three plantings of lettuce (Lactuca sativa) at two farms in Norway were profiled by an Illumina MiSeq-based approach. We found that the bacterial richness of the L. sativa samples was significantly greater shortly (3 weeks) after planting than at harvest (5 to 7 weeks after planting) for plantings 1 and 3 at both farms. For the second planting, the bacterial diversity remained consistent at the two sites. This suggests that the effect on bacterial colonization of leaves, at least in part must, be seasonally driven rather than driven solely by leaf maturity. The distribution of phyllosphere communities varied between D. tenuifolia and L. sativa at harvest. The variability between these species at the same location suggests that the leaf-dwelling bacteria are not only passive inhabitants but interact with the host, which shapes niches favoring the growth of particular taxa. This work contributes to our understanding of host plant-specific microbial community structures and shows how these communities change throughout plant development. PMID- 25527555 TI - Transcriptomic analysis of xylan utilization systems in Paenibacillus sp. strain JDR-2. AB - Xylans, including methylglucuronoxylans (MeGX(n)) and methylglucuronoarabinoxylans (MeGAXn), are the predominant polysaccharidesin hemicellulose fractions of dicots and monocots available for conversion to biofuels and chemicals. Paenibacillus sp. strain JDR-2 (Pjdr2) efficiently depolymerizes MeGX(n) and MeGAX(n) and assimilates the generated oligosaccharides, resulting in efficient saccharification and subsequent metabolism of these polysaccharides. A xylan utilization regulon encoding a cellassociated GH10 (glycoside hydrolase family 10) endoxylanase, transcriptional regulators, ABC (ATP binding cassette) transporters, an intracellular GH67 glucuronidase, and other glycoside hydrolases contributes to complete metabolism. This GH10/GH67 system has been proposed to account for preferential utilization of xylans compared to free oligo- and monosaccharides. To identify additional genes contributing to MeGX(n) and MeGAXn utilization, the transcriptome of Pjdr2 has been sequenced following growth on each of these substrates as well as xylose and arabinose. Increased expression of genes with different substrates identified pathways common or unique to the utilization of MeGX(n) or MeGAX(n). Coordinate upregulation of genes comprising the GH10/GH67 xylan utilization regulon is accompanied with upregulation of genes encoding a GH11 endoxylanase and a GH115 glucuronidase, providing evidence for a novel complementary pathway for processing xylans. Elevated expression of genes encoding a GH43 arabinoxylan arabinofuranohydrolase and an arabinose ABC transporter on MeGAX(n) but not on MeGX(n) supports a process in which arabinose may be removed extracellularly followed by its rapid assimilation.Further development of Pjdr2 for direct conversion of xylans to targeted products or introduction of these systems into fermentative strains of related bacteria may lead to biocatalysts for consolidated bioprocessing of hemicelluloses released from lignocellulose. PMID- 25527556 TI - Genomic potential for polysaccharide deconstruction in bacteria. AB - Glycoside hydrolases are important enzymes that support bacterial growth by enabling the degradation of polysaccharides (e.g., starch, cellulose, xylan, and chitin) in the environment. Presently, little is known about the overall phylogenetic distribution of the genomic potential to degrade these polysaccharides in bacteria. However, knowing the phylogenetic breadth of these traits may help us predict the overall polysaccharide processing in environmental microbial communities. In order to address this, we identified and analyzed the distribution of 392,166 enzyme genes derived from 53 glycoside hydrolase families in 8,133 sequenced bacterial genomes. Enzymes for oligosaccharides and starch/glycogen were observed in most taxonomic groups, whereas glycoside hydrolases for structural polymers (i.e., cellulose, xylan, and chitin) were observed in clusters of relatives at taxonomic levels ranging from species to genus as determined by consenTRAIT. The potential for starch and glycogen processing, as well as oligosaccharide processing, was observed in 85% of the strains, whereas 65% possessed enzymes to degrade some structural polysaccharides (i.e., cellulose, xylan, or chitin). Potential degraders targeting one, two, and three structural polysaccharides accounted for 22.6, 32.9, and 9.3% of genomes analyzed, respectively. Finally, potential degraders targeting multiple structural polysaccharides displayed increased potential for oligosaccharide deconstruction. This study provides a framework for linking the potential for polymer deconstruction with phylogeny in complex microbial assemblages. PMID- 25527557 TI - In situ prebiotics for weaning piglets: in vitro production and fermentation of potato galacto-rhamnogalacturonan. AB - Postweaning diarrhea (PWD) in pigs is a leading cause of economic loss in pork production worldwide. The current practice of using antibiotics and zinc to treat PWD is unsustainable due to the potential of antibiotic resistance and ecological disturbance, and novel methods are required. In this study, an in vitro model was used to test the possibility of producing prebiotic fiber in situ in the gastrointestinal (GI) tract of the piglet and the prebiotic activity of the resulting fiber in the terminal ileum. Soluble fiber was successfully produced from potato pulp, an industrial waste product, with the minimal enzyme dose in a simulated upper GI tract model extracting 26.9% of the initial dry matter. The fiber was rich in galactose and galacturonic acid and was fermented at 2.5, 5, or 10 g/liter in a glucose-free medium inoculated with the gut contents of piglet terminal ileum. Fermentations of 5 g/liter inulin or 5 g/liter of a purified potato fiber were used as controls. The fibers showed high fermentability, evident by a dose-dependent drop in pH and an increase in the organic acid content, with lactate in particular being increased. Deep sequencing showed a significant increase in the numbers of Lactobacillus and Veillonella organisms and an insignificant increase in the numbers of Clostridium organisms as well as a decrease in the numbers of Streptococcus organisms. Multivariate analysis showed clustering of the treatment groups, with the group treated with purified potato fiber being clearly separated from the other groups, as the microbiota composition was 60% Lactobacillus and almost free of Clostridium. For animal studies, a dosage corresponding to the 5-g/liter treatment is suggested. PMID- 25527558 TI - Deletion of PHO13, encoding haloacid dehalogenase type IIA phosphatase, results in upregulation of the pentose phosphate pathway in Saccharomyces cerevisiae. AB - The haloacid dehalogenase (HAD) superfamily is one of the largest enzyme families, consisting mainly of phosphatases. Although intracellular phosphate plays important roles in many cellular activities, the biological functions of HAD enzymes are largely unknown. Pho13 is 1 of 16 putative HAD enzymes in Saccharomyces cerevisiae. Pho13 has not been studied extensively, but previous studies have identified PHO13 to be a deletion target for the generation of industrially attractive phenotypes, namely, efficient xylose fermentation and high tolerance to fermentation inhibitors. In order to understand the molecular mechanisms underlying the improved xylose-fermenting phenotype produced by deletion of PHO13 (pho13Delta), we investigated the response of S. cerevisiae to pho13Delta at the transcriptomic level when cells were grown on glucose or xylose. Transcriptome sequencing analysis revealed that pho13Delta resulted in upregulation of the pentose phosphate (PP) pathway and NADPH-producing enzymes when cells were grown on glucose or xylose. We also found that the transcriptional changes induced by pho13Delta required the transcription factor Stb5, which is activated specifically under NADPH-limiting conditions. Thus, pho13Delta resulted in the upregulation of the PP pathway and NADPH-producing enzymes as a part of an oxidative stress response mediated by activation of Stb5. Because the PP pathway is the primary pathway for xylose, its upregulation by pho13Delta might explain the improved xylose metabolism. These findings will be useful for understanding the biological function of S. cerevisiae Pho13 and the HAD superfamily enzymes and for developing S. cerevisiae strains with industrially attractive phenotypes. PMID- 25527559 TI - Use of mCherry Red fluorescent protein for studies of protein localization and gene expression in Clostridium difficile. AB - Fluorescent proteins are powerful reporters in biology, but most require O2 for chromophore maturation, making them inherently difficult to use in anaerobic bacteria. Clostridium difficile, a strict anaerobe with a genomic GC content of only 29%, is the leading cause of hospital-acquired diarrhea in developed countries, and new methods for studying this pathogen are sorely needed. We recently demonstrated that a cyan fluorescent protein called CFPopt that has been codon optimized for production in low-GC bacteria can be used to study protein localization in C. difficile provided the cells are fixed prior to exposure to air. We describe here a codon-optimized variant of mCherry (mCherryOpt) that exhibits faster acquisition of fluorescence and a better signal-to-noise ratio than CFPopt. We utilized mCherryOpt to construct plasmids for studying protein localization (pRAN473) and gene expression (pDSW1728) in C. difficile. Plasmid pRAN473 is an mCherryOpt fusion vector with a tetracycline-inducible promoter. To document its biological utility, we demonstrated septal localization of two cell division proteins, MldA and ZapA. Plasmid pDSW1728 is designed for cloning a promoter of interest upstream of mCherryOpt. As proof of principle, we studied the expression of the pdaV operon, which is required for lysozyme resistance. In confirmation and extension of previous reports, we found that expression of the pdaV operon requires the alternative sigma factor sigma(v) and that induction by lysozyme is dose dependent and uniform across the population of lysozyme-treated cells. PMID- 25527561 TI - Hedgehog pathway mutations in T-cell acute lymphoblastic leukemia. PMID- 25527560 TI - Improved antimicrobial activities of synthetic-hybrid bacteriocins designed from enterocin E50-52 and pediocin PA-1. AB - Two hybrid bacteriocins, enterocin E50-52/pediocin PA-1 (EP) and pediocin PA 1/enterocin E50-52 (PE), were designed by combining the N terminus of enterocin E50-52 and the C terminus of pediocin PA-1 and by combining the C terminus of pediocin PA-1 and the N terminus of enterocin E50-52, respectively. Both hybrid bacteriocins showed reduced MICs compared to those of their natural counterparts. The MICs of hybrid PE and EP were 64- and 32-fold lower, respectively, than the MIC of pediocin PA-1 and 8- and 4-fold lower, respectively, than the MIC of enterocin E50-52. In this study, the effect of hybrid as well as wild-type (WT) bacteriocins on the transmembrane electrical potential (DeltaPsi) and their ability to induce the efflux of intracellular ATP were investigated. Enterocin E50-52, pediocin PA-1, and hybrid bacteriocin PE were able to dissipate DeltaPsi, but EP was unable to deplete this component. Both hybrid bacteriocins caused a loss of the intracellular concentration of ATP. EP, however, caused a faster efflux than PE and enterocin E50-52. Enterocin E50-52 and hybrids PE and EP were active against the Gram-positive and Gram-negative bacteria tested, such as Micrococcus luteus, Salmonella enterica serovar Enteritidis 20E1090, and Escherichia coli O157:H7. The hybrid bacteriocins designed and described herein are antimicrobial peptides with MICs lower those of their natural counterparts. Both hybrid peptides induce the loss of intracellular ATP and are capable of inhibiting Gram-negative bacteria, and PE dissipates the electrical potential. In this study, the MIC of hybrid bacteriocin PE decreased 64-fold compared to the MIC of its natural peptide counterpart, pediocin PA-1. Inhibition of Gram negative pathogens confers an additional advantage for the application of these peptides in therapeutics. PMID- 25527563 TI - Contiguous follicular lymphoma and follicular lymphoma in situ harboring N glycosylated sites. PMID- 25527562 TI - Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia. AB - This study aimed to determine the impact of tyrosine kinase inhibitors given pre- and post-allogeneic stem cell transplantation on long-term outcome of patients allografted for Philadelphia chromosome-positive acute lymphoblastic leukemia. This retrospective analysis from the EBMT Acute Leukemia Working Party included 473 de novo Philadelphia chromosome-positive acute lymphoblastic leukemia patients in first complete remission who underwent an allogeneic stem cell transplantation using a human leukocyte antigen-identical sibling or human leukocyte antigen-matched unrelated donor between 2000 and 2010. Three hundred and ninety patients received tyrosine kinase inhibitors before transplant, 329 at induction and 274 at consolidation. Kaplan-Meier estimates of leukemia-free survival, overall survival, cumulative incidences of relapse incidence, and non relapse mortality at five years were 38%, 46%, 36% and 26%, respectively. In multivariate analysis, tyrosine-kinase inhibitors given before allogeneic stem cell transplantation was associated with a better overall survival (HR=0.68; P=0.04) and was associated with lower relapse incidence (HR=0.5; P=0.01). In the post-transplant period, multivariate analysis identified prophylactic tyrosine kinase inhibitor administration to be a significant factor for improved leukemia free survival (HR=0.44; P=0.002) and overall survival (HR=0.42; P=0.004), and a lower relapse incidence (HR=0.40; P=0.01). Over the past decade, administration of tyrosine kinase inhibitors before allogeneic stem cell transplantation has significantly improved the long-term allogeneic stem cell transplantation outcome of adult Philadelphia chromosome-positive acute lymphoblastic leukemia. Prospective studies will be of great interest to further confirm the potential benefit of the prophylactic use of tyrosine kinase inhibitors in the post transplant setting. PMID- 25527564 TI - Episodic angioedema with eosinophilia (Gleich syndrome) is a multilineage cell cycling disorder. AB - Episodic angioedema with eosinophilia (Gleich syndrome) is a rare disorder characterized by episodes of angioedema and eosinophilia that occur at monthly intervals and resolve spontaneously without therapy. Despite the striking periodicity of this disorder, its similarity to other cyclic hematopoietic disorders with multilineage involvement has not been assessed. To characterize the involvement of cell lineages in the etiology and pathogenesis of episodic angioedema with eosinophilia, four subjects were evaluated by blood counts and other analyses over the course of 1-2 months. Surface marker expression was assessed on T cells by flow cytometry and clonality by polymerase chain reaction. Intracellular cytokine evaluation, bone marrow and skin biopsies were performed during different parts of the cycle. Cycling of multiple cell lineages, including neutrophils, lymphocytes and eosinophils, was observed in the four subjects with the disorder with a periodicity of 25-35 days. An aberrant CD3(-)CD4(+) T-cell population was detected in all four subjects, and T-cell receptor rearrangement studies showed a clonal pattern in three subjects. A peak of type II cytokines was detected in the serum of subjects prior to the onset of symptoms and eosinophil cycling and corresponded to ex-vivo type II cytokines detected intracellularly in CD3(+)CD4(+)CD154(+) T cells. Although the etiology of episodic angioedema with eosinophilia is not yet known, multiple lineages, including lymphocytes, neutrophils and mast cells, are involved and may be related to disease pathogenesis. Whether these cells act directly or promote eosinophilia and eosinophil activation remains to be elucidated. All subjects gave informed consent and were evaluated under an Institutional Review Board approved protocol (NCT00001406). PMID- 25527565 TI - Bleeding before prophylaxis in severe hemophilia: paradigm shift over two decades. PMID- 25527566 TI - Refractory anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in SF3B1 or other spliceosome genes accompanied by JAK2V617F and ASXL1 mutations. PMID- 25527567 TI - Correlation between peripheral blood and bone marrow regarding FLT3-ITD and NPM1 mutational status in patients with acute myeloid leukemia. PMID- 25527568 TI - Cytogenetic heterogeneity negatively impacts outcomes in patients with acute myeloid leukemia. AB - Clonal heterogeneity is a hallmark of malignant transformation. In acute myeloid leukemia, acquired cytogenetic abnormalities are important independent predictors of initial response to therapy, remission duration, and overall survival. However, whether the presence of multiple cytogenetically characterized clones affects outcomes in acute myeloid leukemia is still not well defined. The aim of this study was to assess the prognostic impact of cytogenetic clonal heterogeneity in acute myeloid leukemia. This analysis included 1403 newly diagnosed acute myeloid leukemia patients fit for intensive chemotherapy, aged between 15 and 88 years, enrolled on Southwest Oncology Group protocols. The presence of multiple cytogenetic clones was found in 164 (24%) patients with abnormal karyotype. The proportion of patients with clonal heterogeneity increased with age, being present in 20% of patients under 40 years of age, but in 30% of those aged over 70 years (P=0.03). Clonal heterogeneity was significantly more common in association with unfavorable karyotype. Clonal heterogeneity was associated with decreased response rates and inferior event free, relapse-free and overall survival, and was confirmed as an independent predictor of poor prognosis in multivariable analysis. Subgroup analysis showed that clonal heterogeneity adds prognostic information particularly in the unfavorable karyotype group. Our results confirm the negative prognostic impact of clonal heterogeneity in acute myeloid leukemia patients with abnormal karyotype. (clinicaltrials.gov identifiers: 014343329; 01338974; 00899171; 1059734; 01059734; 00899743; 0143329; 00023777; 00085709; 01360125; 00004217). PMID- 25527569 TI - Identification of IG-clonality status as a pre-treatment predictor for mortality in patients with immunodeficiency-associated Epstein-Barr virus-related lymphoproliferative disorders. PMID- 25527570 TI - Dementia, women and sexuality: How the intersection of ageing, gender and sexuality magnify dementia concerns among lesbian and bisexual women. AB - There is a growing appreciation of the significance of socio-cultural context for the experiences of an individual living with dementia. There is, too, an emergent awareness that dementia is a gendered issue, disproportionately affecting women compared with men. However, little attention has been given as yet to the experiences of lesbian and bisexual women living with dementia. This article addresses this gap in knowledge, exploring the significance of the intersection of ageing, gender and sexuality for lesbian and bisexual women with dementia. It suggests that stigma and social marginalisation associated with dementia and with ageing, gender and sexuality intersect to compound the social exclusion of lesbians and bisexual women. This has implications for early diagnosis and treatment. Moreover, community care policy, which is predicated on heterosexist norms fails to take into account older lesbians and bisexual women's support networks and so is less likely to be attuned to their needs. Residential care provision is perceived by older lesbians and bisexual women as being heteronormative at best and homophobic at worst. Services which do not recognise, validate and support their identities will compound their anxiety, confusion and distress. This may be contrary to Equality and Human Rights legislation and UK social policies. This paper draws upon, and analyses, extracts from a range of authorship, synthesising the material to present novel insights into the significance of gender and sexuality for the experience of dementia and dementia care. PMID- 25527571 TI - Synanthropy and temporal variability of Calliphoridae living in Cosenza (Calabria, southern Italy). AB - The aim of this study was to investigate the synanthropy of Diptera: Calliphoridae, insects of forensic importance, in Calabria (southern Italy). The study lasted 2 years, from February 2010 to January 2012, and was carried out in three areas of Cosenza province representing "urban", "rural", and "wild" environments. Bottle traps baited with pork were used to catch Calliphoridae. Six species were identified, Calliphora vicina Robineau-Desvoidy 1830, Calliphora vomitoria (L.), Chrysomya albiceps (Wiedemann 1819), Lucilia ampullacea Villeneuve 1922, Lucilia caesar (L.), and Lucilia sericata (Meigen 1826). Data on phenologies in the study areas are reported for these species and the Synanthropy Index was calculated to evaluate their relationship with the human environment. PMID- 25527572 TI - Biological characteristics of Grapholita molesta (Lepidoptera: Tortricidae) induced to diapause in laboratory. AB - In southern Brazil, Grapholita molesta (Busck) (Lepidoptera: Tortricidae) uses diapause as survival strategy during the winter (May-August). In our study, we evaluated the effect of diapause on biological characteristics of the species for 4 months in laboratory. Newly hatched larvae of G. molesta were induced to diapause changing the photoperiod and temperature (T) (12 +/- 1 degrees C), relative humidity (RH) (70 +/- 10%), and a photophase of 12 h and, when they started diapause in the prepupal stage, the conditions were kept for 4 months. Afterwards, the insects were induced to finalize the diapause process at T 25 +/- 1 degrees C, RH 70 +/- 10%, and a photophase of 16 h. We evaluated the duration and viability of the larval stages and pupae, pupae weight at 24 h and sex ratio (sr), periods of preoviposition, oviposition, and postoviposition; adult life span (males and females); fecundity (daily and total); embryonic period duration and eggs viability, comparing the data with insects nondiapause. The results show that diapause greatly affected the viability of pupal-adult stages of the population (21.8%) when compared with insects' nondiapause (80.0%). Total fecundity (83.0 eggs) and mean life span (12.0 d) of insects diapause was significantly lower compared with insects nondiapause (173.0 and 17.0), respectively. However, these differences were not observed in the sr, which was similar to insects diapause (sr = 0.41) and insects nondiapause (sr = 0.49). The diapause induced for 4 months negatively affects reproduction and life span of adults of G. molesta. PMID- 25527573 TI - Host selection behavior and the fecundity of Plutella xylostella (Lepidoptera: Plutellidae) on multiple host plants. AB - Insect herbivores often have higher densities on host plants grown in monocultures than those in diverse environments. The underlying mechanisms are thought to be that polyphagous insects have difficulty in selecting food or oviposition sites when multiple host plants exist. However, this hypothesis needs to be extensively investigated. Our field experiments revealed that the population of the diamondback moths, Plutella xylostella (L.) (Lepidoptera: Plutellidae), significantly decreased in a mixed cropping field compared with a monoculture. To determine the reasons for the reduction in population in the mixed cropping field, the takeoff behavior and fecundity of females in no-choice and free-choice laboratory environments were compared by video recordings of host selection by P. xylostella. Adults displayed a significantly higher takeoff frequency in free-choice environments than those in no-choice treatments and preferred landing on Brassica campestris (L.) or Brassica juncea (Coss) plants in contrast with Brassica oleracea (L.). Female adults in the free-choice environment also laid fewer eggs compared with the monoculture. Olfaction experiments demonstrated orientation by P. xylostella to host volatiles when presented with a choice between plant odors and clean air, but females showed no preference when odors from three Brassicaceae species were presented simultaneously. We conclude that mixed cropping alters the host-finding behavior of P. xylostella resulting in reduced oviposition. PMID- 25527574 TI - Seasonal and nocturnal activities of the rhinoceros borer (Coleoptera: Scarabaeidae) in the north Saharan oases ecosystems. AB - The rhinoceros borer Oryctes agamemnon Burmeister (Coleoptera: Scarabaeidae) is a date palm insect pest that causes damage to trunk and roots of palm trees in several countries, including Tunisia, the United Arab Emirates (UAE), Oman, and Saudi Arabia. The aim of this study was to monitor the seasonal and nocturnal activities of this beetle. Experiments were performed on a date palm of Rjim Maatoug during a 6-yr period (2004-2007, 2009-2010). Field survey using light traps shows that O. agamemnon is a univoltine, with a single population peak. Adults appear in the field around late May-early June and the population continued to build until maximum numbers are reached between the end of July and the beginning of August in the same year. No adults were found after first 10 d of November. This peak was characterized by female dominance in number. The monitoring of nocturnal activity showed that it starts its activities roughly 40 min after the sundown and continues until approximately 1 h before sunrise. The highest number of trapped beetles was remarked in the two first hours of flight activity, with a dominance of female in the first hour and a dominance of male in the second hour. We remarked that the sex ratio (female:male) of the cumulated number of trapped adults in the different years and nights of survey was in favor of females. PMID- 25527575 TI - Effect of temperatures and cold storage on performance of Tetrastichus brontispae (Hymenoptera: Eulophidae), a parasitoid of Brontispa longissima (Coleptera: Chrysomelidae). AB - Laboratory studies were conducted to determine the effect of temperature and cold storage on the performance of Tetrastichus brontispae (Ferriere) (Hymenoptera: Eulophidae), one of the major endoparasitoids against coconut hispine beetle, Brontispa longissima (Gestro) (Coleptera: Chrysomelidae). The results revealed that T. brontispae could successfully parasitize host pupae under all seven tested temperatures, but no adult emergence was observed at 32 degrees C. It was also revealed that temperatures between 24 and 26 degrees C appeared to be the optimum temperatures for parasitism, as these temperatures resulted in the most parasitized pupae and a significantly higher emergence rate and progeny production. These measurements significantly declined at 20, 30, and 32 degrees C. This study confirmed developmental periods of parasitoid progeny decreased as the temperature increased, and sex ratio of this female-biased parasitoid was not affected by rearing temperatures. More importantly, this study indicated that cold storage of parasitized pupae could extend up to 30 d at 10 degrees C, and a longer storage period had a significant adverse effect on mean adult emergence and parasitism performance. Ten days might be the optimum cold-storage period at 10 degrees C, as parasitism performance, emergence rate, and progeny production at this storage period were similar to the control of 26 degrees C. Furthermore, the developmental period, emergence rate, and sex ratio of progeny that emerged from cold-stored parasitized pupae were not influenced by storage periods, whereas parasitism performance of progeny decreased as storage period increased. This study suggests that about 24-26 degrees C would be the optimal temperature for mass production and release of T. brontispae for biological control of B. longissima. These results also provide novel findings that a period of 10 d at 10 degrees C may be more suitable and acceptable for ideal cold storage of parasitized pupae of T. brontispae. PMID- 25527576 TI - Tolerance of low temperature and sterilizing irradiation in males of Glossina pallidipes (Diptera: Glossinidae). AB - Investigations into the possibility of using the chilled adult release system are continuing as an alternative method to the release of sterile tsetse flies, Glossina pallidipes Austen (Diptera: Glossinidae) in cardboard boxes. Exposing tsetse flies to 4 degrees C for 6 h caused negligible mortality. A combination of chilling and irradiation resulted in reduced quantities of seminal contents being transferred to females. Mortality of flies after bulk irradiation was lower when a thermos flask was used than expanded polystyrene. Mortality after removal from cold storage increased with age. Flies that did not have a blood meal for 3 d prior to exposure to cold had a lower overnight survival than flies that were deprived of a blood meal for 1 or 2 d. Exposure of adult male tsetse flies to low temperature should be for as short a duration as is practical, so that the fitness of the released sterile flies is not unduly compromised. It is also necessary to ensure that losses are minimized during bulk irradiation of adult flies. It would be desirable to have minimal losses after the combined effects of irradiation, cold, and transportation, such that a sufficient number of sterile male flies will still be available to successfully compete for mating opportunities with wild females. PMID- 25527577 TI - Distinction of Indian commercial lac insect lines of Kerria spp. (Homoptera: Coccoidea) based on their morphometrics. AB - The lac insects belong to the genus Kerria (Hemiptera: Coccoidea: Kerriidae) and are commercially exploited worldwide for the production of lac, which comes from their waxy test and has diverse industrial applications. The insects are maintained by the Indian Institute of Natural Resins and Gums as distinctive lines that are cultivated and commercialized in the lac producing areas of India. The lines are all considered to belong to the genus Kerria but without validation of their taxonomic characters, and their identity to species has not been ascertained. This study used single-factor analysis of variance and several multivariate analyses, such as principal component analysis, discriminant function analysis, and canonical discriminant analysis to explore the morphometrics of some of the adult female lac insect lines. The results have enabled the identification of some taxonomically significant characters in adult females, which has grouped the 32 lac insect lines studied into 15 species along with validation of the most significant characters. Distinctive grouping patterns for the species of Kerria have been brought out using morphometrics. PMID- 25527578 TI - Preliminary studies on the susceptibility level of Ceutorchynhus assimilis (Coleoptera: Curculionidae) to acetamiprid and chlorpyrifos in Poland and resistance mechanisms of the pest to acetamiprid. AB - The cabbage seed weevil, Ceutorchynhus assimilis (Paykull) (Coleoptera: Curculionidae) is a pest that more and more often causes large financial losses for rapeseed cultivators in Poland and other European countries. One of the reasons of these problems is the resistance of the pest to certain active substances of insecticides. The aim of the study was to assess the susceptibility level of the pest to chlorpyrifos, an organophosphate substance, and acetamiprid, a neonicotinoid, and to determine its enzymatic mechanisms of susceptibility to acetamiprid using synergists, i.e., blockers of particular enzyme groups. The presented research is the first to discuss the mechanisms of the resistance of the cabbage seed weevil to acetamiprid. The achieved results showed medium, high, or very high resistance of the cabbage seed weevil to acetamiprid and its lack of resistance to chlorpyrifos. The research on the mechanisms of the resistance of the pest to acetamiprid revealed the participation of hydrolytic enzymes blocked by S,S,S-tributylphosphorotrithioate and glutathione transferases blocked by diethyl malonate in the metabolism of acetamiprid. The results did not show the participation of oxidative enzymes and esterases blocked by piperonyl butoxide in the detoxification of acetamiprid. PMID- 25527579 TI - Logrank test and Interval Overlap Test for Bactericera cockerelli (Hemiptera: Triozidae) under different fertilization treatments for 7705 tomato hybrid. AB - It is known that some nutrients can have both negative and positive effects on some populations of insects. To test this, the Logrank test and the Interval Overlap Test were evaluated for two crop cycles (February-May and May-August) of the 7705 tomato hybrid, and the effect on the psyllid, Bactericera cockerelli (Sulc.) (Hemiptera: Triozidae), was examined under greenhouse conditions. Tomato plants were in polythene bags and irrigated with the following solutions: T1 Steiner solution, T2-Steiner solution with nitrogen reduced to 25%, T3-Steiner solution with potassium reduced to 25%, and T4-Steiner solution with calcium reduced to 25%. In the Logrank test, a significant difference was found when comparing the survival parameters of B. cockerelli generated from the treatment cohorts: T1-T2; T1-T3; T1-T4; T2-T3; and T3-T4, while no significant differences were found in the T2-T4 comparison in the February-May cycle. In the May-August cycle, significant differences were found when comparing the survival parameters generated from the treatment cohorts: T1-T2; T1-T3; and T1-T4, while no significant differences were found in the T2-T3; T2-T4; and T3-T4 comparisons of survival parameters of B. cockerelli fed with the 7705 tomato hybrid. Also, the Interval Overlap Test was done on the treatment cohorts (T1, T2, T3, and T4) in the February-May and May-August cycles. T1 and T2 compare similarly in both cycles when feeding on the treatments up to 36 d. Similarly, in T1 and T3, the behavior of the insect is similar when feeding on the treatments up to 40 and 73 d, respectively. Comparisons T2-T3 and T2-T4 are similar when feeding on both treatments up to 42, 38 and 37, 63 d, respectively. Finally, the T3-T4 comparison was similar when feeding in both treatments up to 20 and 46 d, respectively. PMID- 25527580 TI - Comparison of RNA isolation methods from insect larvae. AB - Isolating RNA from insects is becoming increasingly important in molecular entomology. Four methods including three commercial kits RNeasy Mini Kit (Qiagen), SV Total RNA isolation system (Promega), TRIzol reagent (Invitrogen), and a cetyl trimethylammonium bromide (CTAB)-based method were compared regarding their ability to isolate RNA from whole-body larvae of Thaumatotibia leucotreta (Meyrick), Thanatophilus micans (F.), Plutella xylostella (L.), and Tenebrio molitor (L.). A difference was observed among the four methods regarding RNA quality but not quantity. However, RNA quality and quantity obtained was not dependent on the insect species. The CTAB-based method produced low-quality RNA and the Trizol reagent produced partially degraded RNA, whereas the RNeasy Mini Kit and SV Total RNA isolation system produced RNA of consistently high quality. However, after reverse transcription to cDNA, RNA produced using all four extraction methods could be used to successfully amplify a 708 bp fragment of the cytochrome oxidase I gene. Of the four methods, the SV Total RNA isolation system showed the least amount of DNA contamination with the highest RNA integrity number and is thus recommended for stringent applications where high-quality RNA is required. This is the first comparison of RNA isolation methods among different insect species and the first to compare RNA isolation methods in insects in the last 20 years. PMID- 25527581 TI - Seasonal distributions of the western cherry fruit fly (Diptera: Tephritidae) among host and nonhost fruit trees. AB - Seasonal distributions of the western cherry fruit fly, Rhagoletis indifferens Curran (Diptera: Tephritidae), in sweet cherry (Prunus avium (L.) L.) (major host), black hawthorn (occasional developmental host) (Crataegus douglasii Lindley), and other trees were determined in a ponderosa pine ecosystem in Washington state, USA. The hypothesis that most fly dispersal from cherry trees occurs after fruit senesce or drop was tested, with emphasis on movement to black hawthorn trees. Sweet cherry fruit developed earlier than black hawthorn, bitter cherry (common host), choke cherry, and apple fruit. Flies were usually captured first in sweet cherry trees but were caught in bitter cherry and other trees throughout the season. Peak fly capture periods in sweet cherry began around the same time or slightly earlier than in other trees. However, peak fly capture periods in black hawthorn and other nonsweet cherry trees continued after peak periods in sweet cherry ended, or relative fly numbers within sweet cherry declined more quickly than those within other trees. Larvae were reared from sweet and bitter cherry but not black hawthorn fruit. Results provide partial support for the hypothesis in that although R. indifferens commonly disperses from sweet cherry trees with fruit, it could disperse more, or more flies are retained in nonsweet cherry trees after than before sweet cherries drop. This could allow opportunities for the flies to use other fruit for larval development. Although R. indifferens infestation in black hawthorn was not detected, early season fly dispersal to this and other trees and fly presence in bitter cherry could make fly management in sweet cherry difficult. PMID- 25527582 TI - Different expression profiles suggest functional differentiation among chemosensory proteins in Nilaparvata lugens (Hemiptera: Delphacidae). AB - Chemosensory proteins (CSPs) play various roles in insect physiology including olfaction and development. The brown planthopper, Nilaparvata lugens Stal, is one of the most notorious rice pests worldwide. The wing-from variation and annually long distance migration imply that olfaction would play a key role in N. lugens behavior. In this study, full-length cDNAs of nine CSPs were cloned by the rapid amplification of cDNA ends procedure, and their expression profiles were determined by the quantitative real-time Polymerase Chain Reaction (qPCR), with regard to developmental stage, wing-form, gender, and tissues of short-wing adult. These NlugCSP genes showed distinct expression patterns, indicating different roles they play. In particular, NlugCSP5 was long wing form biased and highly expressed in female wings among tissues; NlugCSP1 was mainly expressed in male adults and abdomen; NlugCSP7 was widely expressed in chemosensory tissues but little in the nonchemosensory abdomen. The function of NlugCSP7 in olfaction was further explored by the competitive fluorescence binding assay using the recombinant protein. However, the recombinant NlugCSP7 showed no obvious binding with all tested volatile compounds, suggesting that it may participate in physiological processes other than olfaction. Our results provide bases and some important clues for the function of NlugCSPs. PMID- 25527584 TI - Gynaikothrips uzeli (Thysanoptera: Phlaeothripidae), new record from Tartous, Syria. AB - The weeping fig thrips Gynaikothrips uzeli Zimmermann (Thysanoptera: Phlaeothripidae) is newly recorded for the first time in the leaf galls of the weeping fig tree Ficus benjamina L. (Rosales: Moraceae) in the coastal area of Tartous, Syria. The thrips caused purplish red spots on the leaf surface of the host plant and the leaves curl. G. uzeili appears to be successfully adapted to this area. PMID- 25527583 TI - Infection with the secondary tsetse-endosymbiont Sodalis glossinidius (Enterobacteriales: Enterobacteriaceae) influences parasitism in Glossina pallidipes (Diptera: Glossinidae). AB - The establishment of infection with three Trypanosoma spp (Gruby) (Kinetoplastida: Trypanosomatidae), specifically Trypanosoma brucei brucei (Plimmer and Bradford), T. b. rhodesiense (Stephen and Fatham) and T. congolense (Broden) was evaluated in Glossina pallidipes (Austen) (Diptera: Glossinidae) that either harbored or were uninfected by the endosymbiont Sodalis glossinidius (Dale and Maudlin) (Enterobacteriales: Enterobacteriaceae). Temporal variation of co-infection with T. b. rhodesiense and S. glossinidius was also assessed. The results show that both S. glossinidius infection (chi(2)= 1.134, df = 2, P = 0.567) and trypanosome infection rate (chi(2)= 1.85, df = 2, P = 0.397) were comparable across the three infection groups. A significant association was observed between the presence of S. glossinidius and concurrent trypanosome infection with T. b. rhodesiense (P = 0.0009) and T. congolense (P = 0.0074) but not with T. b. brucei (P = 0.5491). The time-series experiment revealed a slight decrease in the incidence of S. glossinidius infection with increasing fly age, which may infer a fitness cost associated with Sodalis infection. The present findings contribute to research on the feasibility of S. glossinidius-based paratransgenic approaches in tsetse and trypanosomiasis control, in particular relating to G. pallidipes control. PMID- 25527585 TI - Diversity and spatiotemporal distribution of larval odonate assemblages in temperate neotropical farm ponds. AB - Farm ponds help maintain diversity in altered landscapes. However, studies on the features that drive this type of property in the Neotropics are still lacking, especially for the insect fauna. We analyzed the spatial and temporal distribution of odonate larval assemblages in farm ponds. Odonates were sampled monthly at four farm ponds from March 2008 to February 2009 in a temperate montane region of southern Brazil. A small number of genera were frequent and accounted for most of the dominant fauna. The dominant genera composition differed among ponds. Local spatial drivers such as area, hydroperiod, and margin vegetation structure likely explain these results more than spatial predictors due to the small size of the study area. Circular analysis detected seasonal effect on assemblage abundance but not on richness. Seasonality in abundance was related to the life cycles of a few dominant genera. This result was explained by temperature and not rainfall due to the temperate climate of the region studied. The persistence of dominant genera and the sparse occurrence of many taxa over time probably led to a lack in a seasonal pattern in assemblage richness. PMID- 25527586 TI - Habitat preferences of Boros schneideri (Coleoptera: Boridae) in the natural tree stands of the Bialowieza Forest. AB - We analyzed habitat requirements of Boros schneideri (Panzer, 1796) (Coleoptera: Boridae) in the natural forests of the continental biogeographical region, using data collected in the Bialowieza Forest. This species has been found on the six host trees, but it preferred dead, standing pine trees, characterized by large diameter, moderately moist and moist phloem but avoided trees in sunny locations. It occurred mostly in mesic and wet coniferous forests. This species demonstrated preferences for old tree stands (over 140-yr old), and its occurrence in younger tree-stand age classes (minimum 31-40-yr old) was not significantly different from random distribution. B. schneideri occupied more frequently locations distant from the forest edge, which were less affected by logging. Considering habitat requirements, character of occurrence, and decreasing number of occupied locations in the whole range of distribution, this species can be treated as relict of primeval forests. PMID- 25527587 TI - Comparative analysis of the dorsal chaetotaxy of Troglopedetes, Trogolaphysa, and Campylothorax supports the synonymization of tribes Paronellini and Troglopedetini (Collembola: Paronellidae). AB - Genera in subfamily Paronellinae have been grouped into five tribes, in part based on chaetotaxy. Tribes Bromacanthini, Paronellini, and Troglopedetini are characterized by having rounded scales and reduced or no macrochaetae, and although Bromacanthini harbors two well-differentiated genera, the core genera in tribes Paronellini and Troglopedetini form a homogeneous group where even generic diagnoses were, until recently, unclear. The genera assigned to Troglopedetini (Troglopedetes Absolon, Trogolaphysa Mills, and Cyphoderopsis Carpenter) harbor many species with reduced eyes number, whereas the tribe Paronellini (genera Paronella Schott, Dicranocentruga Wray and Campylothorax Schott) includes species with 6-8 eyes. Recent analyses of the chaetotaxy of Trogolaphysa and Cyphoderopsis suggest that these genera represent specialized forms related to species in Paronellini. The taxonomy of Troglopedetes, the type genus of Troglopedetini, is based almost exclusively on claw and mucro shape and dorsal macrochaetae pattern, and few details of the complete dorsal chaetotaxy of the species are known. This contribution presents a comparative analysis of the complete dorsal chaetotaxy of two species of Troglopedetes from Spain (one new to science), two new species of Trogolaphysa from the Dominican Republic and Martinique, and Campylothorax sabanus with the purpose of identifying aspects of the chaetotaxy that could provide diagnostic characters for the separation of Trogolaphysa and Troglopedetes, and a new diagnosis for tribe Troglopedetini. The analysis shows that neither the number of chaetae nor its organization or pattern of macrochaeta provides diagnostic differences between Trogolaphysa and Troglopedetes. It is also concluded that the separation of Paronellini and Troglopedetini is not justified. Troglopedetini is here synonymized with Paronellini, and a new diagnosis of Paronellini is provided. PMID- 25527588 TI - Effects of the antibiotics Gentamicin on the postembryonic development of Chrysomya putoria (Diptera: Calliphoridae). AB - We evaluate the effects the antibiotic Gentamicin on the development of Chrysomya putoria (Wiedemann, 1818). Third-generation, first-instar larvae were reared in a climatic chamber on 60 g of homogenate + agar 65% and were treated with three concentrations of Gentamicin: 4.44 mg/ml, 13.33 mg/ml, and 66.66 mg/ml. The control consisted of distilled water. The relationships between mean body mass of mature larvae (measured after diet abandonment, in batches of five individuals), duration of larval and pupal stages, and overall duration of development were analyzed. The actual sex ratio was compared against the expected using the chi square. None of the parameters measured differed significantly among the four treatments, with one exception: when Gentamicin concentration was 13.33 mg/ml, larval viability differed significantly from the control. All larvae from all treatments were considered normal. We conclude that the antibiotic did not significantly alter the development of C. putoria (Wiedemann) (Diptera: Calliphoridae). PMID- 25527589 TI - Embryonic development of Rhynchophorus palmarum (Coleoptera: Curculionidae): dynamics of energy source utilization. AB - Energy homeostasis is an essential process during oogenesis, nutrients are required for suitable embryonic development, and recently, studies have investigated metabolic activity during this process. This work aims the investigation of dynamics of energy source utilization of Rhynchophorus palmarum during embryogenesis. For this, we first evaluated the mobilization kinetics of the lipids and glycogen. Thereafter, the synthesis of RNA, protein, and the involvement of enzyme of the glycolytic and pentose-phosphate pathways. Results showed that lipid content decreased in contrast with the lipase activity. The total glycogen amounts it was partly consumed and the glucose content increased, but then values remained stable until hatching. Total RNA content increased, and no significant changes in total protein content were observed. A study of the glycolytic pathway data showed activity of hexokinase and pyruvate kinase at the beginning of embryogenesis. Furthermore, glucose-6-phosphate formed is driven into the pentose-phosphate pathway viewed the high activity of glucose-6 phosphate dehydrogenase. Finally, these results showed that mobilization of different energy sources together with different enzymatic activities has an important role in embryonic development of R. palmarum. PMID- 25527590 TI - Property of midgut alpha-amylase from Mythimna separata (Lepidoptera: Noctuidae) larvae and its responses to potential inhibitors in vitro. AB - Midgut alpha-amylase is an important digestive enzyme involved in larval energy metabolism and carbohydrate assimilation. In this article, the properties of midgut alpha-amylase from the Oriental armyworm, Mythimna separata (Lepidoptera: Noctuidae), larvae were characterized, and its in vitro responses to chemical inhibitors were also determined. The kinetic parameters Km and Vmax of midgut alpha-amylase were 0.064 M, 4.81 U mg pro(-1) in phosphate buffer, and 0.128 M, 1.96 U mg pro(-1) in barbiturate-acetate buffer; alpha-amylase activity linearly increased as starch concentration increased. alpha-Amylase activity was not influenced by amino acids such as Pro, Met, Try, His, Ala, and Phe but was strongly activated by antioxidants. Reduced glutathione, 1,4-dithiothreitol, beta mercaptoethanol, and ascorbic acid improved the activity of alpha-amylase about 2.06, 3.46, 3.37, and 6.38 times, respectively, relative to the control. Ethylenediaminetetraacetic acid, sodium dodecyl sulfonate, and N-bromosuccinimide (NBS) strongly inhibited alpha-amylase. alpha-, beta-, and gamma-cyclodextrin were not the preferred substrates for alpha-amylase. Kinetic analysis showed that IC50 value of NBS against alpha-amylase was 1.52 (+/-0.26) uM, and the mode of action of NBS with Ki as 2.53 (0.35) uM was a mixed-type inhibition that indicated a combination of partial competitive and pure noncompetitive inhibition. The midgut alpha-amylase of armyworm larvae may be a potential target for novel insecticide development and pest control. PMID- 25527591 TI - Biology and life table parameters of Brevicoryne brassicae (Hemiptera: Aphididae) on cauliflower cultivars. AB - In this article, the biology and fertility life table parameters of the cabbage aphid, Brevicoryne brassicae (L.) (Hemiptera: Aphididae), were studied on cauliflower leaves, Brassica oleracea var. botrytis (Brassicales: Brassicaceae), of the cultivars Smilla, Snow mystique, White cloud, Buris, Galiblanka, Snow crown, SG, and Tokita. This study was conducted under controlled conditions: 25 +/- 2 degrees C, 65 +/- 5% relative humidity (RH), and 16:8 (L:D) h photoperiods. Statistical analysis showed that there was a significant difference (P < 0.05) between the different growth stages and the mean number of laid nymphs. Further, the maximum and minimum growth periods were observed on Galiblanka and Buris cultivars, respectively. The shortest nymphal instar growth period was observed on the Smilla cultivar (6.70 d), and the longest lifespan was seen on the White cloud (8.10 d). The Smilla cultivar (39%), in an adult emergence stage, and the SG (88%) revealed the lowest and highest rates of survival, respectively. Aphids reared on the Smilla cultivar were found to have increased due to the high intrinsic (r(m)) and finite (lambda) rate of increase and the low doubling time (DT). The results indicated that the application of cultivars affecting adult reproductive parameters could be a good solution to cabbage aphid control management. PMID- 25527592 TI - Evidence to support a conspecific nature of allopatric cytological races of Anopheles nitidus (Diptera: Culicidae) in Thailand. AB - Metaphase karyotype investigation on two allopatric strains of Anopheles nitidus Harrison, Scanlon, and Reid (Diptera: Culicidae) was conducted in Thailand during 2011-2012. Five karyotypic forms, i.e., Form A (X1, Y1), Form B (X1, Y2), Form C (X2, Y3), Form D (X1, X3, Y4), and Form E (X1, X2, X3, Y5) were obtained from a total of 21 isofemale lines. Forms A, B, and C were confined to Phang Nga Province, southern Thailand, whereas Forms D and E were restricted to Ubon Ratchathani Province, northeastern Thailand. Cross-mating experiments among the five isofemale lines, which were representative of five karyotypic forms of An. nitidus, revealed genetic compatibility by providing viable progenies and synaptic salivary gland polytene chromosomes through F2 generations. The results suggest that the forms are conspecific, and An. nitidus comprises five cytological races. The very low intraspecific sequence variations (average genetic distances = 0.002-0.008) of the nucleotide sequences in ribosomal DNA (internal transcribed spacer 2) and mitochondrial DNA (cytochrome c oxidase subunits I and II) among the five karyotypic forms were very good supportive evidence. PMID- 25527593 TI - Comparison of phenotypic value changes in pure lines of Bombyx mori (Lepidoptera: Bombycidae) during consecutive generations following initial selection on cocoon weight. AB - The experiments reported here were conducted to investigate the effect of selection on three quantitative traits, namely cocoon weight, cocoon shell weight, and cocoon shell percentage, during four generations by rearing six pure breeds of domesticated silkworm, Bombyx mori L. (Lepidoptera: Bombycidae) of Chinese and Japanese origin compared with random unselected groups as controls. All stages of rearing and data recording were performed over four rearing periods, with generations 1-3 during successive spring seasons and generation 4 during the autumn season in year 3. Each pure line contained two groups of selected and random (control) groups. Comparisons included the effect of selection methods, pure line, and generation on the phenotypic values. We found strong main effects of pure line, generation, sex, and group and support for nearly all interactions between these main effects for all three response traits. The results indicated that cocoon weight and cocoon shell weight in the selected group were higher than in the control or nonselected group. Both selected and nonselected groups had the lowest cocoon weight, cocoon shell weight, and cocoon shell percentage in the fourth generation when environmental conditions during the autumn season were less favorable than spring. The cocoon weight and cocoon shell weight averages were higher for nonselected groups in the second and third generations, and for the selected group in the first generation due to the direct effect of selection. PMID- 25527594 TI - Supercooling capacity and cold hardiness of band-winged grasshopper eggs (Orthoptera: Acrididae). AB - The band-winged grasshopper, Oedaleus asiaticus Bei-Bienko, is one of the most dominant and economically important grasshopper species in the steppe grasslands and farming-pastoral ecotone in northern China. It is a univoltine species and overwinters as eggs in soil. The cold hardiness of its eggs was examined in the laboratory. Water content in soil significantly affected the supercooling points (SCPs), water content and fat content of prediapause eggs. With the increase of water content in soil, the SCP, and water content of prediapause eggs rose whereas the fat content declined. There was a significant relationship between the SCP and water content or fat content of prediapause eggs. The SCPs of prediapause and diapause eggs varied from -7.6 to -28.4 degrees C and the SCPs of eggs 30 d after oviposition could be divided into two groups. The means of high SCP group (-11.0 to -11.9 degrees C) were much higher than those of low SCP group (-21.8 to -21.9 degrees C), and the majority belonged to the latter (90.48 93.33%). The SCPs of prediapause eggs and early-diapause eggs 30 d after oviposition were significantly higher than those of deep-diapause eggs 60 d after oviposition. The survival rates of diapause eggs were significantly different among different temperature treatments. The survival rate was higher than 88% at greater than -20 degrees C and declined significantly to 57% at -25 degrees C, and suddenly dropped to zero at -30 degrees C. The lower lethal temperature (Ltemp50) for 12 h exposure was -25.3 degrees C and the lower lethal time (Ltime50) at -20 degrees C was 32.8 d. As the mean SCPs of diapause eggs were similar to their Ltemp50, the SCP of eggs can be considered as a good indicator of cold hardiness for O. asiaticus and that this grasshopper is a freeze intolerant insect. PMID- 25527595 TI - Short-term effects of a revegetation program on the Orthopteran diversity in oak forests of the southern Iberian Peninsula. AB - Orthopterans are insects closely linked to vegetation as primary consumers as well as for other biological processes such as oviposition and development. This research aims to assess the effect of a revegetation program that began in 2007 in the compensation area linked to the construction of the Brena II dam on Orthopteran diversity within several different human-created and natural habitats (forest-islands, hedges, and river-copses). We assessed vegetation and orthopteran communities during monthly sampling performed during March through September 2011. For the Orthopterans, two replicates per habitat type were sampled in each of the eight selected sampling plots, providing 48 observations per environment per month. To characterize the structure of communities, diversity, dominance, and evenness were calculated, and posterior comparisons were made using bootstrapping analysis. Additionally, rarefaction curves were obtained. We found large between-habitat differences in plant abundance but smaller differences in diversity. The high degree of vegetational homogeneity likely explains the structural similarity among the Orthopteran communities in the different habitats. Although Caelifera were more abundant and diverse in unmanaged biotopes, Ensifera seem to be favored in revegetated areas. Because accurate management requires documenting diversity at the field scale, work like that presented here should increase the efficiency of future assessments of Orthopteran habitat suitability for diversity conservation. PMID- 25527597 TI - An assessment of cold hardiness and biochemical adaptations for cold tolerance among different geographic populations of the Bactrocera dorsalis (Diptera: Tephritidae) in China. AB - The cold hardiness of larvae, pupae, and adults of the oriental fruit fly, Bactrocera Dorsalis (Hendel) (Diptera: Tephritidae) was characterized first, and then body water, total sugar and glycerol contents, and activities of superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and alcohol dehydrogenase (ADH) of different geographical populations subjected to suitable rearing conditions and under sublethal low-temperature stress were compared. The cold hardiness of different populations was well correlated with the latitudes of distributions. The northern marginal population (31.6 degrees N) had higher cold tolerance than southern populations (23.1 degrees N and 24.3 degrees N). Among different life stages, larvae had the least cold tolerance, whereas pupae had the most tolerance. Under suitable rearing conditions, the marginal population had lower activities of all four tested enzymes than that of the southern populations and also had lower body water and higher total sugar and glycerol contents. The low-temperature stress induced higher SOD, CAT, POD, and ADH activities of all tested life stages and of all tested populations with higher increase intensity in adults and pupae than in larvae. The increase intensity was higher in the marginal population than in the southern populations. Pupae in the marginal population and adults in the southern populations showed the largest activity enhancement, which agreed with the insect's overwinter stages in their respective locations. Lower temperature stress lowered body water and total sugar contents and increased glycerol contents. The results revealed a strong correlation between the cold hardiness of a population and the concentration or activity of various biochemicals and enzymes known to be involved in cold tolerance. The marginal population of B. dorsalis might have evolved a new biotype with better adaption to low temperature. PMID- 25527596 TI - Haploid, diploid, and triploid--discrimination ability against polyploid mating partner in the parasitic wasp, Bracon brevicornis (Hymenoptera: Braconidae). AB - Because the quality of mating partners varies, females of several taxa have evolved the ability to discriminate against low-quality mates. Although males in the Hymenoptera are usually haploid, diploid males may occur in species with complementary sex determination. Diploid males are almost always sterile in most of the species studied so far. They are thus of very low quality as mating partners, especially when females mate only once in life. We hypothesize that hymenopteran females might have evolved the ability to discriminate against infertile diploid males and avoid mating with them. To test this hypothesis, we studied diploid male fitness in the parasitoid wasp Bracon brevicornis Wesmael (Hymenoptera: Braconidae) by measuring survival rate and fertility and then estimated their chances of actually mating with a female. Flow cytometry was used to determine the ploidy level of wasps. The fitness costs of mating a diploid male are indeed high in this species: only 15% were able to sire daughters, of which 97% were triploid and hardly able to produce viable offspring. In contrast to the hypothesis of unsuitable mate discrimination though, no evidence was found for increased rejection of diploid males by females. Male discrimination against an unsuitable partner did also not occur: triploid females elicited the same intensity of courtship behavior in males than did diploid ones. PMID- 25527598 TI - Morphology and chemical analysis of the metathoracic scent glands system in Adelphocoris suturalis (Hemiptera: Miridae). AB - The morphological structure of the metathoracic scent glands (MTGs) in Adelphocoris suturalis was observed by utilizing scanning electron microscope (SEM). Also, the secretions of MTGs in male and female were analyzed by using gas chromatography-mass spectrometry (GC-MS). The result showed that the MTGs comprised a reservoir and paired lateral glands, which are connected to a reservoir by duct. The MTGs belong to the diastomian type. A usually depressed channel extends from opening downward the middle of metathorax, a tongue-like structure was covered by bristles and mushroom-shaped cuticular structures, known as evaporative area. In GC-MS investigation, differences were found in quantitative or qualitative compositions of the substances between the two sexes. In our study, hexyl butyrate was the most abundant compound in the MTGs of A. suturalis, comprising ~85% of total secretions in both female and male, respectively. 4-oxo-(E)-2-hexenal (5.22%) was the second most abundant compound in female MTGs secretions, whereas octacosane (2.42%) followed hexyl butyrate in male MTGs secretions. PMID- 25527599 TI - Diapause induction, color change, and cold tolerance physiology of the diapausing larvae of the Chouioia cunea (Hymenoptera: Eulophidae). AB - The chalcid wasp Chouioia cunea Yang (Hymenoptera: Eulophidae) is one of the most dominant pupal parasitoids of Hyphantria cunea (Drury) (Lepidoptera: Arctiidae), an invasive pest of many forestry trees and agricultural crops. For mass rearing C. cunea for biological control purposes, the pupae of Antheraea pernyi (Guerin Meneville) (Lepidoptera: Saturniidae) have been widely used as a substitute host in China. In this article, photoperiodic effect on diapause induction in C. cunea within the pupae of A. pernyi was investigated, and the differences in cold tolerance physiology including supercooling point, water content, and activities of three protective enzymes (Peroxidase [POD], Catalase [CAT], and Superoxide dismuase [SOD]) between diapause and nondiapause mature larvae were comparatively determined. Our results revealed that C. cunea possess a short-day induced larval diapause. The critical photoperiods for diapause induction in C. cunea were estimated to be between a photoperiod of 13:11 and 14:10 (L:D) h at 18 degrees C, or between a photoperiod of 12:12 and 13:11 (L:D) h at 21 degrees C or 24 degrees C. We also found that the color of C. cunea diapausing larvae was taupe, while the normally developed (nondiapausing) individuals were light yellow. This body color change can be used as an indicator of diapause entry of C. cunea larave. The average supercooling point of diapausing mature larvae were lower than those of nondiapausing ones. There were significant differences in the activity of three protective enzymes (POD, CAT, and SOD) between diapausing and nondiapausing mature larvae. PMID- 25527600 TI - Quantitative classification and environmental interpretation of secondary forests 18 years after the invasion of pine forests by Bursaphelenchus xylophilus (Nematoda: Aphelenchoididae) in China. AB - With growing concerns over the serious ecological problems in pine forests (Pinus massoniana, P. thunbergii) caused by the invasion of Bursaphelenchus xylophilus (the pine wood nematode), a particular challenge is to determine the succession and restoration of damaged pine forests in Asia. We used two-way indicator species analysis and canonical correlation analysis for the hierarchical classification of existing secondary forests that have been restored since the invasion of B. xylophilus 18 years ago. Biserial correlation analysis was used to relate the spatial distribution of species to environmental factors. After 18 years of natural recovery, the original pine forest had evolved into seven types of secondary forest. Seven environmental factors, namely soil depth, humus depth, soil pH, aspect, slope position, bare rock ratio, and distance to the sea, were significantly correlated with species distribution. Furthermore, we proposed specific reform measures and suggestions for the different types of secondary forest formed after the damage and identified the factors driving the various forms of restoration. These results suggest that it is possible to predict the restoration paths of damaged pine forests, which would reduce the negative impact of B. xylophilus invasions. PMID- 25527601 TI - First record of Diaphorina citri (Hemiptera: Psyllidae) in Ecuador infesting urban citrus and orange jasmine trees. AB - Adults and nymphs of the Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Psyllidae), were collected in the Guayaquil, Samborondon, and Duran cantons in coastal Ecuador. Psyllids were found in high numbers in citrus (Citrus spp., Sapindales: Rutaceae) and orange jasmine (Murraya exotica [L.] Jack, Sapindales: Rutaceae) trees within the Guayaquil-Samborondon-Duran conurbation; however, none was found during scoutings in the main citrus producing areas in coastal Ecuador. To the best of our knowledge, this is the first report of D. citri in Ecuador and the Pacific coastal plain of South America. PMID- 25527602 TI - The diagnosis of primary cardiac lymphoma was facilitated by computed tomographic coronary angiography. AB - Primary cardiac lymphoma (PCL) is a rare entity that leads to fatal symptoms such as serious arrhythmia. The present case was an 80-year-old female with severe dyspnea caused by 30 bpm bradycardia. Computed tomography revealed a tumor invading to the right inferior myocardium. A computed tomographic coronary angiography (CTCA) study revealed the right coronary artery penetrating the tumor with no invasion by the surrounding tumor. Because a percutaneous biopsy was unsuccessful, video-assisted thoracic surgery (VATS) was performed. The final pathological diagnosis was diffuse large B cell lymphoma. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) chemotherapy reduced the size of the tumor, and the symptoms thereafter improved. An observation of the coronary artery penetrating the tumor without tumor invasion may be a characteristic finding of PCL. CTCA is useful to detect this finding. When a percutaneous biopsy is unavailable, VATS should be considered as a minimally invasive procedure to obtain a reliable diagnosis of PCL. PMID- 25527603 TI - Occult closed posterior elbow dislocation with intimal rupture of the brachial artery in a 71-year-old male?. AB - Posterior elbow dislocation with vascular injury is rarely encountered, but it is crucial for every emergency physician to diagnose it. Missing these injuries can result in neurovascular compromise, which in turn can lead to limb ischemia, compartment syndrome and potential limb loss. Having a normal X-ray on presentation makes this injury more difficult to diagnose. In this study, we present a case of occult posterior elbow dislocation with an intimal injury of the brachial artery. The rarity of these cases, the diagnostic modalities and the treatment options will be reviewed. PMID- 25527604 TI - An early look at changes in employer-sponsored insurance under the Affordable Care Act. AB - Critics frequently characterize the Affordable Care Act (ACA) as a threat to the survival of employer-sponsored insurance. The Medicaid expansion and Marketplace subsidies could adversely affect employers' incentives to offer health insurance and workers' incentives to take up such offers. This article takes advantage of timely data from the Health Reform Monitoring Survey for June 2013 through September 2014 to examine, from the perspective of workers, early changes in offer, take-up, and coverage rates for employer-sponsored insurance under the ACA. We found no evidence that any of these rates have declined under the ACA. They have, in fact, remained constant: around 82 percent, 86 percent, and 71 percent, respectively, for all workers and around 63 percent, 71 percent, and 45 percent, respectively, for low-income workers. To date, the ACA has had no effect on employer coverage. Economic incentives for workers to obtain coverage from employers remain strong. PMID- 25527605 TI - Hepatic or intestinal ABCG5 and ABCG8 are sufficient to block the development of sitosterolemia. PMID- 25527606 TI - Weather warnings predict fall-related injuries among older adults. AB - BACKGROUND: weather predictions are a useful tool for informing public health planning and prevention strategies for non-injury health outcomes, but the association between winter weather warnings and fall-related injuries has not been assessed previously. OBJECTIVE: to examine the association between fall related injuries among older adults and government-issued winter weather warnings. METHODS: using a dynamic cohort of individuals >=65 years of age who lived in Montreal between 1998 and 2006, we identified all fall-related injuries from administrative data using a validated set of diagnostic and procedure codes. We compared rates of injuries on days with freezing rain or snowstorm warnings to rates observed on days without warnings. We also compared the incidence of injuries on winter days to non-winter days. All analyses were performed overall and stratified by age and sex. RESULTS: freezing rain alerts were associated with an increase in fall-related injuries (incidence rate ratio [IRR] = 1.20, 95% confidence interval [CI]: 1.08-1.32), particularly among males (IRR = 1.31, 95% CI: 1.10-1.56), and lower rates of injuries were associated with snowstorm alerts (IRR = 0.89, 95% CI: 0.80-0.99). The rate of fall-related injuries did not differ seasonally (IRR = 1.00, 95% CI: 0.97-1.03). CONCLUSIONS: official weather warnings are predictive of increases in fall-related injuries among older adults. Public health agencies should consider using these warnings to trigger initiation of injury prevention strategies in advance of inclement weather. PMID- 25527607 TI - Comparing the perceptions of academics and members of the public about patient and public involvement in ageing research. AB - BACKGROUND: public and patient involvement (PPI) in clinical research is increasingly advocated by funding and regulatory bodies. However, little is known about the views of either academics or members of the public about perceptions of the practical realities of PPI, particularly in relation to ageing research. OBJECTIVE: to survey current levels of PPI in biomedical and clinical research relating to ageing at one institution. To compare and contrast the views of academics and the public about PPI relating to research about ageing. DESIGN: electronic survey of senior academics, postgraduate students and members of a local user group for older people. SETTING AND PARTICIPANTS: thirty-three academics (18 principal investigators and 15 PhD students) at a biomedical research institution. Fifty-four members of a local user group for older people. RESULTS: thirty per cent (10/33) of projects described some PPI activity. Older adults were more positive about active involvement in research about ageing than academics. The perceived benefits of and barriers to involvement in research were similar among all groups, although older members of the public were more likely than academics to acknowledge potential barriers to involvement. CONCLUSION: academics and older people share some perceptions about PPI in ageing research, but members of the public are more optimistic about active involvement. Further correspondence between these groups may help to identify feasible involvement activities for older people and encourage collaborative research about ageing. PMID- 25527608 TI - Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic beta cells but not alpha-cells. AB - Little is known about responses of intestinal L-cells to chemical or cytokine mediated attack and how these compare with pancreatic beta- or alpha-cells. Administration of streptozotocin to mice induced severe diabetes, islet lymphocytic infiltration, increased alpha-cell proliferation and decreased numbers of beta- and L-cells. In vitro, streptozotocin and cytokines reduced cell viability with higher lethal dose 50 values for alpha-TC1 cells. mRNA expression of Glut2 was lower and Cat was greater in GLUTag and alpha-TC1 cells compared with MIN6 cells. Cytotoxins affected the transcription of genes involved in secretion in GLUTag and MIN6 cells. They are also involved in upregulation of antioxidant defence enzymes, transcription of NfkappaB and Nos2, and production of nitrite in all cell types. Cytotoxin-induced DNA damage and apoptosis were apparent in all cells, but alpha-TC1 cells were less severely affected. Thus, responses of GLP1-secreting L-cells to cytotoxicity resemble beta-cells, whereas alpha-cells are resistant due to differences in the expression of genes involved in cytotoxicity or antioxidant defence. PMID- 25527609 TI - Review of the impact of water quality on reliable laboratory testing and correlation with purification techniques. AB - In recent years, many rapid and automated instruments with highly complex testing methodologies have been introduced to our laboratories, almost all of which require the use of water. Many investigators have discussed the impact of water quality on the accuracy and reliability of clinical laboratory testing and technologies. Evaluation of water quality and specifications according to international standards and guidelines has helped laboratories to judge water quality before using the water in question as part of testing. In the past few years, dramatic introduction of different water purification technologies has shown significant improvements in laboratory testing accuracy. In this review, we delve into the intricate factors that influence water quality. PMID- 25527610 TI - Nocardia as a Complication in a 30-year-old Immunocompromised Hispanic Woman. PMID- 25527611 TI - Strict requirement for vector-induced type I interferon in efficacious antitumor responses to virally encoded IL12. AB - Host responses are increasingly considered important for the efficacious response to experimental cancer therapies that employ viral vectors, but little is known about the specific nature of host responses required. In this study, we investigated the role of host type I interferons (IFN-I) in the efficacy of virally delivered therapeutic genes. Specifically, we used a Semliki Forest virus encoding IL12 (SFV-IL12) based on its promise as an RNA viral vector for cancer treatment. Intratumoral injection of SFV-IL12 induced production of IFN-I as detected in serum. IFN-I production was abolished in mice deficient for the IFNbeta transcriptional regulator IPS-1 and partially attenuated in mice deficient for the IFNbeta signaling protein TRIF. Use of bone marrow chimeric hosts established that both hematopoietic and stromal cells were involved in IFN I production. Macrophages, plasmacytoid, and conventional dendritic cells were each implicated based on cell depletion experiments. Further, mice deficient in the IFN-I receptor (IFNAR) abolished the therapeutic activity of SFV-IL12, as did a specific antibody-mediated blockade of IFNAR signaling. Reduced efficacy was not caused by an impairment in IL12 expression, because IFNAR-deficient mice expressed the viral IL12 transgene even more strongly than wild-type (WT) hosts. Chimeric host analysis for the IFNAR involvement established a strict requirement in hematopoietic cells. Notably, although tumor-specific CD8 T lymphocytes expanded robustly after intratumoral injection of WT mice with SFV-IL12, this did not occur in mice where IFNAR was inactivated genetically or pharmacologically. Overall, our results argued that the antitumor efficacy of a virally based transgene therapeutic relied strongly on a vector-induced IFN-I response, revealing an unexpected mechanism of action that is relevant to a broad array of current translational products in cancer research. PMID- 25527612 TI - Managing psychological stress in the multiple sclerosis medical visit: Patient perspectives and unmet needs. AB - Psychological stress can negatively impact multiple sclerosis. To further understand how stress is addressed in the multiple sclerosis medical visit, 34 people with multiple sclerosis participated in focus groups. Transcripts were analyzed by inductive thematic analysis. The majority of participants did not discuss stress with their provider, citing barriers to communication such as lack of time, poor coordination between specialties, physician reliance on pharmaceutical prescription, and patient lack of self-advocacy. Participants recommended several ways to better manage psychological well-being in the clinical setting. These findings provide a foundation for future studies aimed at minimizing the detrimental effect of stress in multiple sclerosis. PMID- 25527613 TI - The use of morphokinetics as a predictor of implantation: a multicentric study to define and validate an algorithm for embryo selection. AB - STUDY QUESTION: Can we use morphokinetic markers to select the embryos most likely to implant and are the results likely to be consistent across different clinics? SUMMARY ANSWER: Yes, morphokinetic markers can be used to select the embryos most likely to implant and the results were similar in different IVF clinics that share methods and organization to some extent. WHAT IS KNOWN ALREADY: With the introduction of time-lapse technology several authors have proposed the use of kinetic markers to improve embryo selection. The majority of these markers can be detected as early as Day 2 of development. Morphology remains the gold standard but kinetic markers have been proven as excellent tools to complement our decisions. Nevertheless, the majority of time-lapse studies are based on small data sets deriving from one single clinic. STUDY DESIGN, SIZE, DURATION: Retrospective multicentric study of 1664 cycles of which 799 were used to develop an algorithm (Phase 1 of the study) and 865 to test its predictive power (Phase 2 of the study). PARTICIPANTS/MATERIALS, SETTING, METHODS: University-affiliated infertility centres patients undergoing first or second ICSI cycle using their own or donated oocytes. Embryo development was analysed with a time-lapse imaging system. Variables studied included the timing to two cells (t2), three cells (t3), four cells (t4) and five cells (t5) as well as the length of the second cell cycle (cc2 = t3 - t2) and the synchrony in the division from two to four cells (s2 = t4 - t3). Implantation (IR) and clinical pregnancy (CPR) rates were also analysed. MAIN RESULTS AND THE ROLE OF CHANCE: During Phase 1 of the study we identified three variables most closely related to implantation: t3 (34-40 h), followed by cc2 (9-12 h) and t5 (45-55 h). Based on these results we elaborated an algorithm that classified embryos from A to D according to implantation potential. During Phase 2 of the study the algorithm was validated in a different group of patients that included 865 cycles and 1620 embryos transferred. In this phase of the study, embryos were categorized based on the algorithm and significant differences in IR were observed between the different categories ('A' 32%, 'B' 28%, 'C' 26%, 'D' 20% and 'E' 17%, P < 0.001). In addition we identified three quality criteria: direct cleavage from one to three cells, uneven blastomere size in second cell cycle and multinucleation in third cell cycle. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study limits its potential value, although the use of one database to generate the algorithm (embryos from this database were not selected by any morphokinetic criteria) and one database to validate it reinforces our conclusions. WIDER IMPLICATIONS OF THE FINDINGS: The elaboration of an algorithm based on a larger database derived from different (albeit related) clinics raises the possibility that such algorithms could be applied in different clinical settings. PMID- 25527614 TI - Surrogate mothers 10 years on: a longitudinal study of psychological well-being and relationships with the parents and child. AB - STUDY QUESTION: How do the psychological health and experiences of surrogate mothers change from 1 year to 10 years following the birth of the surrogacy child? SUMMARY ANSWER: The psychological well-being of surrogate mothers did not change 10 years following the birth, with all remaining positive about the surrogacy arrangement and the majority continuing to report good mental health. WHAT IS KNOWN ALREADY: Studies have found that surrogates may find the weeks following the birth difficult, but do not experience psychological problems 6 months or 1 year later. Research has also shown that surrogates can form close relationships with the intended parents during the pregnancy which may continue after the birth. STUDY DESIGN, SIZE, DURATION: This study used a prospective longitudinal design, in which 20 surrogates were seen at two time points: 1 year following the birth of the surrogacy child and 10 years later. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 20 surrogates (representing 59% of the original sample) participated in a semi-structured interview and completed self-report questionnaires. Eleven surrogates were gestational carriers and nine surrogates had used their own oocyte (genetic surrogacy). Four were previously known to the intended parents and 16 were previously not known. MAIN RESULTS AND THE ROLE OF CHANCE: Ten years following the birth of the surrogacy child, surrogate mothers scored within the normal range for self-esteem and did not show signs of depression as measured by the Beck Depression Inventory. Marital quality remained positive over time. All surrogates reported that their expectations of their relationship with the intended parents had been either met or exceeded and most reported positive feelings towards the child. In terms of expectations for the future, most surrogates reported that they would like to maintain contact or would be available to the child if the child wished to contact them. None expressed regrets about their involvement in surrogacy. LIMITATIONS, REASONS FOR CAUTION: The sample size of this study was small and the women may not be representative of all surrogates. Therefore the extent to which these findings can be generalized is not known. WIDER IMPLICATIONS OF THE FINDINGS: Contrary to concerns about the potentially negative long-term effect of surrogacy, the findings suggest that surrogacy can be a positive experience for some women at least. These findings are important for policy and practice of surrogacy around the world. PMID- 25527615 TI - MBE citation classics (2015 edition). PMID- 25527620 TI - Modulation of monocarboxylate transporter 8 oligomerization by specific pathogenic mutations. AB - The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS). These membrane-spanning proteins facilitate translocation of a variety of substrates, MCT8 specifically transports iodothyronines. Mutations in MCT8 are the underlying cause of severe X-linked psychomotor retardation. At the molecular level, such mutations led to deficiencies in substrate translocation due to reduced cell-surface expression, impaired substrate binding, or decreased substrate translocation capabilities. However, the causal relationships between genotypes, molecular features of mutated MCT8, and patient characteristics have not yet been comprehensively deciphered. We investigated the relationship between pathogenic mutants of MCT8 and their capacity to form dimers (presumably oligomeric structures) as a potential regulatory parameter of the transport function of MCT8. Fourteen pathogenic variants of MCT8 were investigated in vitro with respect to their capacity to form oligomers. Particular mutations close to the substrate translocation channel (S194F, A224T, L434W, and R445C) were found to inhibit dimerization of MCT8. This finding is in contrast to those for other transporters or transmembrane proteins, in which substitutions predominantly at the outer-surface inhibit oligomerization. Moreover, specific mutations of MCT8 located in transmembrane helix 2 (del230F, V235M, and ins236V) increased the capacity of MCT8 variants to dimerize. We analyzed the localization of MCT8 dimers in a cellular context, demonstrating differences in MCT8 dimer formation and distribution. In summary, our results add a new link between the functions (substrate transport) and protein organization (dimerization) of MCT8, and might be of relevance for other members of the MFS. Finally, the findings are discussed in relationship to functional data combined with structural-mechanistical insights into MCT8. PMID- 25527623 TI - Sexual Violence and Abuse Against Children: A First Review Through the Lens of Environmental Criminology. AB - Most criminal justice responses to address sexual violence and abuse against children are aimed at identifying and incarcerating offenders or at best, trying to prevent them from reoffending. This policy situation, primarily characterized by tertiary intervention strategies, is exacerbated by a lack of evidence-based knowledge about the circumstances in which this phenomenon occurs. This specific information can inform certain types of primary and secondary prevention strategies. In this study, we are taking the first steps to address this situation by (a) organising and reviewing for the first time the empirical knowledge on this phenomenon according to questions asked by environmental criminologists and crime analysts, that is, the who, what, where, when, and how this phenomenon occurs, and (b) discussing directions for future research. By engaging in this exercise, we argue that environmental criminology can substantially contribute to understanding and informing prevention practices in the field of sexual violence and abuse against children. PMID- 25527621 TI - Secretome analysis of an osteogenic prostate tumor identifies complex signaling networks mediating cross-talk of cancer and stromal cells within the tumor microenvironment. AB - A distinct feature of human prostate cancer (PCa) is the development of osteoblastic (bone-forming) bone metastases. Metastatic growth in the bone is supported by factors secreted by PCa cells that activate signaling networks in the tumor microenvironment that augment tumor growth. To better understand these signaling networks and identify potential targets for therapy of bone metastases, we characterized the secretome of a patient-derived xenograft, MDA-PCa-118b (PCa 118b), generated from osteoblastic bone lesion. PCa-118b induces osteoblastic tumors when implanted either in mouse femurs or subcutaneously. To study signaling molecules critical to these unique tumor/microenvironment-mediated events, we performed mass spectrometry on conditioned media of isolated PCa-118b tumor cells, and identified 26 secretory proteins, such as TGF-beta2, GDF15, FGF3, FGF19, CXCL1, galectins, and beta2-microglobulin, which represent both novel and previously published secreted proteins. RT-PCR using human versus mouse specific primers showed that TGFbeta2, GDF15, FGF3, FGF19, and CXCL1 were secreted from PCa-118b cells. TGFbeta2, GDF15, FGF3, and FGF19 function as both autocrine and paracrine factors on tumor cells and stromal cells, that is, endothelial cells and osteoblasts. In contrast, CXCL1 functions as a paracrine factor through the CXCR2 receptor expressed on endothelial cells and osteoblasts. Thus, our study reveals a complex PCa bone metastasis secretome with paracrine and autocrine signaling functions that mediate cross-talk among multiple cell types within the tumor microenvironment. PMID- 25527624 TI - Metformin beyond diabetes: pleiotropic benefits of metformin in attenuation of atherosclerosis. AB - BACKGROUND: Clinical studies show that metformin attenuates all-cause mortality and myocardial infarction compared with other medications for type 2 diabetes, even at similar glycemic levels. However, there is paucity of data in the euglycemic state on the vasculoprotective effects of metformin. The objectives of this study are to evaluate the effects of metformin on ameliorating atherosclerosis. METHODS AND RESULTS: Using ApoE-/- C57BL/6J mice, we found that metformin attenuates atherosclerosis and vascular senescence in mice fed a high fat diet and prevents the upregulation of angiotensin II type 1 receptor by a high-fat diet in the aortas of mice. Thus, considering the known deleterious effects of angiotensin II mediated by angiotensin II type 1 receptor, the vascular benefits of metformin may be mediated, at least in part, by angiotensin II type 1 receptor downregulation. Moreover, we found that metformin can cause weight loss without hypoglycemia. We also found that metformin increases the antioxidant superoxide dismutase-1. CONCLUSION: Pleiotropic effects of metformin ameliorate atherosclerosis and vascular senescence. PMID- 25527625 TI - Recent developments in the understanding and management of fibromuscular dysplasia. PMID- 25527627 TI - Rv0494 is a starvation-inducible, auto-regulatory FadR-like regulator from Mycobacterium tuberculosis. AB - Fatty acid metabolism plays an important role in the survival and pathogenesis of Mycobacterium tuberculosis. Lipids are assumed to be the major source of energy during dormancy. Here, we report the characterization of a starvation-inducible, lipid-responsive transcriptional regulator, Rv0494, divergently transcribed from the Rv0493c probable operon. The striking difference in the transcriptional regulatory apparatus between mycobacteria and other well-studied organisms, such as Escherichia coli, is the organization of mycobacterial promoters. Mycobacterial promoters have diverse architectures and most of these promoters function inefficiently in E. coli. In this study, we characterized the promoter elements of Rv0494 along with the sigma factors required for transcription initiation. Rv0494 promoter activity increased under nutrient starvation conditions and was transcribed via two promoters: the promoter proximal to the translational start site was active under standard growth conditions, whilst both promoters contributed to the increased activity seen during starvation, with the major contribution from the distal promoter. Furthermore, Rv0494 translation initiated at a codon located 9 bp downstream of the annotated start codon. Rv0494 bound to its upstream sequence to auto-regulate its own expression; this binding was responsive to long-chain fatty acyl-CoA molecules. We further report Rv0494 mediated transcriptional regulation of the Rv2326c gene - a probable transmembrane ATP-binding transporter encoding gene. PMID- 25527626 TI - Traumatic brain injury disrupts cerebrovascular tone through endothelial inducible nitric oxide synthase expression and nitric oxide gain of function. AB - BACKGROUND: Traumatic brain injury (TBI) has been reported to increase the concentration of nitric oxide (NO) in the brain and can lead to loss of cerebrovascular tone; however, the sources, amounts, and consequences of excess NO on the cerebral vasculature are unknown. Our objective was to elucidate the mechanism of decreased cerebral artery tone after TBI. METHODS AND RESULTS: Cerebral arteries were isolated from rats 24 hours after moderate fluid percussion TBI. Pressure-induced increases in vasoconstriction (myogenic tone) and smooth muscle Ca2+ were severely blunted in cerebral arteries after TBI. However, myogenic tone and smooth muscle Ca2+ were restored by inhibition of NO synthesis or endothelium removal, suggesting that TBI increased endothelial NO levels. Live native cell NO, indexed by 4,5-diaminofluorescein (DAF-2 DA) fluorescence, was increased in endothelium and smooth muscle of cerebral arteries after TBI. Clamped concentrations of 20 to 30 nmol/L NO were required to simulate the loss of myogenic tone and increased (DAF-2T) fluorescence observed following TBI. In comparison, basal NO in control arteries was estimated as 0.4 nmol/L. Consistent with TBI causing enhanced NO-mediated vasodilation, inhibitors of guanylyl cyclase, protein kinase G, and large-conductance Ca2+-activated potassium (BK) channel restored function of arteries from animals with TBI. Expression of the inducible isoform of NO synthase was upregulated in cerebral arteries isolated from animals with TBI, and the inducible isoform of NO synthase inhibitor 1400W restored myogenic responses following TBI. CONCLUSIONS: The mechanism of profound cerebral artery vasodilation after TBI is a gain of function in vascular NO production by 60-fold over controls, resulting from upregulation of the inducible isoform of NO synthase in the endothelium. PMID- 25527628 TI - Comparison of endotoxin levels in cow's milk samples derived from farms and shops. AB - The observations on the protective effect of bacterial endotoxin in farm-derived cow's milk on childhood asthma and allergy are contradictory. The aim of this study was to determine the endotoxin levels in 'farm-derived whole raw' and 'processed shop' sources of cow's milk, and to test how the temperature and storing conditions might alter their endotoxin concentrations. Milk was collected from farms and shops. The level of endotoxin was measured by micro (gel-clot) Limulus amebocyte lysate test expressed as EU/ml. The concentration ranges of endotoxin were much higher and more widely scattered in the samples of whole raw farm milk than in the processed shop milk. Cold storage or heating increased the endotoxin concentrations in all samples of farm milk, but not in the processed shop milk. These results show that elevated levels of endotoxin in raw farm milk samples can occur from the cowshed or be formed during storage. In processed shop milk, storage does not cause any changes in the amount of endotoxin. Therefore, it is consistent that the handling and storage of raw milk alters the endotoxin concentrations, which may explain previous contradictory findings regarding the beneficial modulating effects on innate immunity toward allergy prevention in early childhood. PMID- 25527629 TI - Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes. AB - BACKGROUND: Germline mutations in the phosphatase PTEN are associated with diverse human pathologies, including tumour susceptibility, developmental abnormalities and autism, but any genotype-phenotype relationships are poorly understood. METHODS: We have studied the functional consequences of seven PTEN mutations identified in patients diagnosed with autism and macrocephaly and five mutations from severe tumour bearing sufferers of PTEN hamartoma tumour syndrome (PHTS). RESULTS: All seven autism-associated PTEN mutants investigated retained the ability to suppress cellular AKT signalling, although five were highly unstable. Observed effects on AKT also correlated with the ability to suppress soma size and the length and density of dendritic spines in primary neurons. Conversely, all five PTEN mutations from severe cases of PHTS appeared to directly and strongly disrupt the ability to inhibit AKT signalling. CONCLUSIONS: Our work implies that alleles causing incomplete loss of PTEN function are more commonly linked to autism than to severe PHTS cases. PMID- 25527630 TI - Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family. AB - BACKGROUND: Intellectual disability (ID) is a highly heterogeneous condition affecting 2% of the population worldwide. In a field study conducted in a highly inbred area of Northeastern Brazil, we investigated a consanguineous family in which seven adults presented syndromic ID. METHODS: Genome-Wide Human SNP Array 6.0 (Affymetrix) microarray was used to determine regions of homozygosity-by descent and whole exome sequencing (WES) was performed in one affected individual using Extended Nextera Rapid-Capture Exome and Illumina HiSeq2500. RESULTS: We found two regions with an logarithm of the odds (LOD) score of 3.234: a region spanning 4.0 Mb in 19q13.32-q13.33 and a pericentromeric 20 Mb area in chromosome 2 (2p12-q11.2). WES disclosed in the critical region of chromosome 19 a homozygous variant (c.418C>T, p.Arg140Trp) in Mediator complex subunit 25 (MED25), predicted as deleterious by PolyPhen-2, Provean, Mutation Taster and Sorting Intolerant From Tolerant (SIFT). MED25 is a component of the Mediator complex, involved in regulation of transcription of nearly all RNA polymerase II dependent genes. Deleterious mutations in MED12, MED17 and MED23 have already been associated with ID. CONCLUSIONS: These findings demonstrate that the combination of field investigation of families in highly inbred regions with modern technologies is an effective way for identifying new genes associated with ID. PMID- 25527631 TI - Risk Assessment in Child Sexual Abusers Working With Children. AB - Child sexual abuse occurring in a child- or youth-serving institution or organization has attracted great public and scientific attention. In light of the particular personal and offense-related characteristics of men who have abused children within such an institution or organization, it is of special importance to evaluate the predictive performance of currently applied risk assessment instruments in this offender population. Therefore, the present study assessed the risk ratings and predictive performance of four risk assessment instruments and one instrument assessing protective factors concerning any, violent and sexual recidivism in child sexual abusers working with children (CSA-W) in comparison with extra-familial child sexual abusers (CSA-E) and intra-familial child sexual abusers (CSA-I). The results indicate that CSA-W mostly recidivate with a sexual offense. Although all included risk measures seem to function with CSA-W, the Static-99 seems to be the instrument that performs best in predicting sexual recidivism in CSA-W. CSA-W had the most protective factors measured with the Structured Assessment of PROtective Factors (SAPROF). While the SAPROF could not predict desistance from recidivism in CSA-W, it predicted desistance from any recidivism in all CSA. As CSA-W frequently hold many indicators for pedophilic sexual interests but only a few for antisocial tendencies, it can be suggested that CSA-W are at an increased risk for sexual recidivism and thus risk measures especially designed for sexual recidivism work best in CSA-W. Nevertheless, CSA-W also hold many protective factors; however, their impact on CSA-W is not clear yet and needs further study. PMID- 25527632 TI - Assessing protective factors of youth who sexually offended in singapore: preliminary evidence on the utility of the DASH-13 and the SAPROF. AB - Sexual offending has attracted increasing public concern because of its long-term effects. Although there is an increasing amount of research on the risk factors for recidivism among youth who have sexually offended, there is a dearth of research on the protective factors for desistence from recidivism. The current study investigated the associations between protective factors and recidivism among 97 Singaporean youth who sexually offended (YSO). In addition, the predictive validity with regard to two new measures of protective factors-the Desistence for Adolescents Who Sexually Harm (DASH-13), and Structured Assessment of Protective Factors for Violence Risk (SAPROF)-were also evaluated. Results indicated that both the DASH-13 and the SAPROF were inversely related to the Estimate of Risk of Adolescent Sexual Offense Recidivism (ERASOR). However, neither the DASH-13 nor the SAPROF were found to have adequate predictive validity or incremental validity for sexual or nonsexual recidivism. The implications for the assessment and management of YSO are discussed. PMID- 25527634 TI - Mechanisms of Overcoming Intrinsic Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma through the Redox Modulation. AB - Pancreatic ductal adenocarcinoma (PDAC) frequently develops therapeutic resistances, which can be divided into extrinsic and intrinsic resistance. The extrinsic resistance that arises from the surrounding dense tumor stroma is much better understood. However, the mechanisms of intrinsic resistance are not well understood. Here, we report that reactive oxygen species (ROS) induced by gemcitabine treatment, a newly discovered cytotoxic activity, served as a probe in our study to reveal the mechanisms of the intrinsic therapeutic resistance. Our results showed that gemcitabine-induced ROS is generated by NOX and through the increase of p22(-phox) expression via NF-kappaB activation. As a feedback mechanism, nuclear translocation of Nrf2 stimulated the transcription of cytoprotective antioxidant genes, especially genes encoding enzymes that catalyze glutathione (GSH) production to reduce elevated ROS as an intrinsic resistance countermeasure. RNAi-mediated depletion of Nrf2 or addition of beta-phenylethyl isothiocyanate inhibited the ROS detoxification process by reducing GSH levels, which, in turn, increased the efficacy of gemcitabine in vitro and in vivo. Thus, our study suggests that a redox-mediated pathway contributes to the intrinsic resistance of PDAC to gemcitabine and provides a basis for developing strategies to preferentially kill PDAC cells through ROS-mediated mechanism. The combination of gemcitabine and PEITC has a selective cytotoxic effect against pancreatic cancer cells in vivo and could thus prove valuable as a cancer treatment. PMID- 25527635 TI - Inhibition of the GTPase Rac1 mediates the antimigratory effects of metformin in prostate cancer cells. AB - Cell migration is a critical step in the progression of prostate cancer to the metastatic state, the lethal form of the disease. The antidiabetic drug metformin has been shown to display antitumoral properties in prostate cancer cell and animal models; however, its role in the formation of metastases remains poorly documented. Here, we show that metformin reduces the formation of metastases to fewer solid organs in an orthotopic metastatic prostate cancer cell model established in nude mice. As predicted, metformin hampers cell motility in PC3 and DU145 prostate cancer cells and triggers a radical reorganization of the cell cytoskeleton. The small GTPase Rac1 is a master regulator of cytoskeleton organization and cell migration. We report that metformin leads to a major inhibition of Rac1 GTPase activity by interfering with some of its multiple upstream signaling pathways, namely P-Rex1 (a Guanine nucleotide exchange factor and activator of Rac1), cAMP, and CXCL12/CXCR4, resulting in decreased migration of prostate cancer cells. Importantly, overexpression of a constitutively active form of Rac1, or P-Rex, as well as the inhibition of the adenylate cyclase, was able to reverse the antimigratory effects of metformin. These results establish a novel mechanism of action for metformin and highlight its potential antimetastatic properties in prostate cancer. PMID- 25527636 TI - Connectomics: comprehensive approaches for whole-brain mapping. AB - The aim of connectomics analysis is to understand whole-brain neural connections. This is accomplished using new biotechnologies. Here, we provide an overview of the recent progress in connectomics analysis. The entire neural network of an organism was revealed for the first time in the nematode. Caenorhabditis elegans (C. elegans) have an advantage of their limited number of neurons and their transparency, allowing the neural network to be visualized using light and electron microscopes (EMs). It is practically impossible to adopt the same approach for mammals because of the large number of neural cells and the opacity of the central nervous system. A variety of new technologies are being developed to perform computer-assisted high-throughput image acquisition and analysis to obtain whole-brain maps for higher species, including mammals. Diffusion tensor magnetic resonance imaging and tractography and three-dimensional imaging with the EM are examples of novel approaches to connectomics. These new technologies will soon be applied not only to Drosophila, C. elegans and rodent research, but also to comprehensive connectomics analysis in a wide range of species including humans and primates. In the near future, results from connectomics analysis will reveal the neural circuitry of the whole brain and enhance our understanding of the human mind and neuropsychiatric diseases. PMID- 25527633 TI - IRS2 copy number gain, KRAS and BRAF mutation status as predictive biomarkers for response to the IGF-1R/IR inhibitor BMS-754807 in colorectal cancer cell lines. AB - Insulin-like growth factor receptor 1 (IGF-1R)-targeting therapies are currently at an important crossroad given the low clinical response rates seen in unselected patients. Predictive biomarkers for patient selection are critical for improving clinical benefit. Coupling in vitro sensitivity testing of BMS-754807, a dual IGF-1R/IR inhibitor, with genomic interrogations in 60 human colorectal cancer cell lines, we identified biomarkers correlated with response to BMS 754807. The results showed that cell lines with BRAF(V600E) or KRAS(G13D) mutation were resistant, whereas cell lines with wild-type of both KRAS and BRAF were particularly sensitive to BMS-754807 if they have either higher RNA expression levels of IR-A or lower levels of IGFBP6. In addition, the cell lines with KRAS mutations, those with either insulin receptor substrate 2 (IRS2) copy number gain (CNG) or higher IGF-1R expression levels, were more sensitive to the drug. Furthermore, cell lines with IRS2 CNG had higher levels of ligand stimulated activation of IGF-1R and AKT, suggesting that these cell lines with IGF-IR signaling pathways more actively coupled to AKT signaling are more responsive to IGF-1R/IR inhibition. IRS2 siRNA knockdown reduced IRS2 protein expression levels and decreased sensitivity to BMS-754807, providing evidence for the functional involvement of IRS2 in mediating the drug response. The prevalence of IRS2 CNG in colorectal cancer tumors as measured by qPCR-CNV is approximately 35%. In summary, we identified IRS2 CNG, IGF-1R, IR-A, and IGFBP6 RNA expression levels, and KRAS and BRAF mutational status as candidate predictive biomarkers for response to BMS-754807. This work proposed clinical development opportunities for BMS-754807 in colorectal cancer with patient selection to improve clinical benefit. PMID- 25527637 TI - Group exercise to improve quality of life among substance use disorder patients. AB - BACKGROUND: Quality of life (QoL) is a well-established outcome within clinical practice. Despite the adverse effects of substance use disorders on a wide range of patients' functionality and the multidimensional composition of QoL, the treatment field does not yet systematically assess QoL among patients. Exercise has established positive effects on the QoL of healthy and numerous clinical populations. The potential to integrate exercise within treatment, in order to improve QoL has not been satisfactorily explored. AIMS: To measure changes in QoL after group exercise among residential substance use disorder patients and to explore the feasibility of the program within a treatment setting. METHODS: We enrolled 35 patients in four long-term residential substance use disorder treatment facilities in Oslo, into a 10-week group exercise program. We analyzed the 24 participants who exercised as completers, while the 11 participants who did not were analyzed as non-completers. We measured QoL, mental distress, somatic health burden and addiction severity at the beginning and end of the program. RESULTS: The program was feasible for participants and the completion rate was 69%. Completers' physical health domain and psychological health domain of QoL improved significantly. The program engaged the most physically and mentally vulnerable participants, and flexibility and motivational factors were important elements. CONCLUSIONS: This study provided promising evidence that low doses of group exercise can yield appreciable benefits, even to patients with more severe health problems. PMID- 25527638 TI - Potent trypanocidal curcumin analogs bearing a monoenone linker motif act on trypanosoma brucei by forming an adduct with trypanothione. AB - We have previously reported that curcumin analogs with a C7 linker bearing a C4 C5 olefinic linker with a single keto group at C3 (enone linker) display midnanomolar activity against the bloodstream form of Trypanosoma brucei. However, no clear indication of their mechanism of action or superior antiparasitic activity relative to analogs with the original di-ketone curcumin linker was apparent. To further investigate their utility as antiparasitic agents, we compare the cellular effects of curcumin and the enone linker lead compound 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (AS-HK014) here. An AS HK014-resitant line, trypanosomes adapted to AS-HK014 (TA014), was developed by in vitro exposure to the drug. Metabolomic analysis revealed that exposure to AS HK014, but not curcumin, rapidly depleted glutathione and trypanothione in the wild-type line, although almost all other metabolites were unchanged relative to control. In TA014 cells, thiol levels were similar to untreated wild-type cells and not significantly depleted by AS-HK014. Adducts of AS-HK014 with both glutathione and trypanothione were identified in AS-HK014-exposed wild-type cells and reproduced by chemical reaction. However, adduct accumulation in sensitive cells was much lower than in resistant cells. TA014 cells did not exhibit any changes in sequence or protein levels of glutathione synthetase and gamma glutamylcysteine synthetase relative to wild-type cells. We conclude that monoenone curcuminoids have a different mode of action than curcumin, rapidly and specifically depleting thiol levels in trypanosomes by forming an adduct. This adduct may ultimately be responsible for the highly potent trypanocidal and antiparasitic activity of the monoenone curcuminoids. PMID- 25527641 TI - Do we really need another article on minimally invasive colorectal cancer surgery? PMID- 25527640 TI - Incidence of minimally invasive colorectal cancer surgery at National Comprehensive Cancer Network centers. AB - BACKGROUND: Laparoscopic colectomy has been shown to have equivalent oncologic outcomes to open colectomy for the management of colon cancer, but its adoption nationally has been slow. This study investigates the prevalence and factors associated with laparoscopic colorectal resection at National Comprehensive Cancer Network (NCCN) centers. METHODS: Data on patients undergoing surgery for colon and rectal cancer at NCCN centers from 2005 to 2010 were obtained from chart review of medical records for the NCCN Outcomes Project and included information on socioeconomic status, insurance coverage, comorbidity, and physician-reported Eastern Cooperative Oncology Group (ECOG) performance status. Associations between receipt of minimally invasive surgery and patient and clinical variables were analyzed with univariate and multivariable logistic regression. All statistical tests were two-sided. RESULTS: A total of 4032 patients, diagnosed between September 2005 and December 2010, underwent elective colon or rectal resection for cancer at NCCN centers. Median age of colon cancer patients was 62.6 years, and 49% were men. The percent of colon cancer patients treated with minimally invasive surgery (MIS) increased from 35% in 2006 to 51% in 2010 across all centers but varied statistically significantly between centers. On multivariable analysis, factors associated with minimally invasive surgery for colon cancer patients who had surgery at an NCCN institution were older age (P = .02), male sex (P = .006), fewer comorbidities (P <= .001), lower final T-stage (P < .001), median household income greater than or equal to $80000 (P < .001), ECOG performance status = 0 (P = .02), and NCCN institution (P <= .001). CONCLUSIONS: The use of MIS increased at NCCN centers. However, there was statistically significant variation in adoption of MIS technique among centers. PMID- 25527639 TI - Annotation of genomics data using bidirectional hidden Markov models unveils variations in Pol II transcription cycle. AB - DNA replication, transcription and repair involve the recruitment of protein complexes that change their composition as they progress along the genome in a directed or strand-specific manner. Chromatin immunoprecipitation in conjunction with hidden Markov models (HMMs) has been instrumental in understanding these processes, as they segment the genome into discrete states that can be related to DNA-associated protein complexes. However, current HMM-based approaches are not able to assign forward or reverse direction to states or properly integrate strand-specific (e.g., RNA expression) with non-strand-specific (e.g., ChIP) data, which is indispensable to accurately characterize directed processes. To overcome these limitations, we introduce bidirectional HMMs which infer directed genomic states from occupancy profiles de novo. Application to RNA polymerase II associated factors in yeast and chromatin modifications in human T cells recovers the majority of transcribed loci, reveals gene-specific variations in the yeast transcription cycle and indicates the existence of directed chromatin state patterns at transcribed, but not at repressed, regions in the human genome. In yeast, we identify 32 new transcribed loci, a regulated initiation-elongation transition, the absence of elongation factors Ctk1 and Paf1 from a class of genes, a distinct transcription mechanism for highly expressed genes and novel DNA sequence motifs associated with transcription termination. We anticipate bidirectional HMMs to significantly improve the analyses of genome-associated directed processes. PMID- 25527642 TI - A novel model of demyelination and remyelination in a GFP-transgenic zebrafish. AB - Demyelinating diseases consist of a variety of autoimmune conditions in which the myelin sheath is damaged due to genetic and/or environmental factors. During clinical treatment, some patients undergo partial remyelination, especially during the early disease stages. However, the mechanisms that regulate demyelination remain unclear. The myelin structure, myelin formation and myelin related gene expression are highly conserved between mammals and zebrafish. Therefore, the zebrafish is an ideal model organism to study myelination. In this study, we generated a transgenic zebrafish Tg(mbp:nfsB-egfp) expressing a fusion protein composed of enhanced green fluorescent protein (EGFP) and NTR from the myelin basic protein (mbp) promoter. Tg(mbp:nfsB-egfp) expressed NTR-EGFP reproducibly and hereditarily in oligodendrocytes along the spinal cord. Treatment of zebrafish larvae Tg(mbp:nfsB-egfp) with metronidazole (Mtz) resulted in the selective ablation of oligodendrocytes and led to demyelination, accompanied by behavioral changes, including decreased total movement distance, velocity, total movement time and fast movement time. After withdrawal of Mtz for a seven day recovery period, the expression of EGFP and MBP protein was observed again which indicates remyelination. Additionally, locomotor capacity was restored. Collectively, Tg(mbp:nfsB-egfp), a heritable and stable transgenic line, provides a novel, powerful tool to study the mechanisms of demyelination and remyelination. PMID- 25527644 TI - Fast-starting after a breath: air-breathing motions are kinematically similar to escape responses in the catfish Hoplosternum littorale. AB - Fast-starts are brief accelerations commonly observed in fish within the context of predator-prey interactions. In typical C-start escape responses, fish react to a threatening stimulus by bending their body into a C-shape during the first muscle contraction (i.e. stage 1) which provides a sudden acceleration away from the stimulus. Recently, similar C-starts have been recorded in fish aiming at a prey. Little is known about C-starts outside the context of predator-prey interactions, though recent work has shown that escape response can also be induced by high temperature. Here, we test the hypothesis that air-breathing fish may use C-starts in the context of gulping air at the surface. Hoplosternum littorale is an air-breathing freshwater catfish found in South America. Field video observations reveal that their air-breathing behaviour consists of air gulping at the surface, followed by a fast turn which re-directs the fish towards the bottom. Using high-speed video in the laboratory, we compared the kinematics of the turn immediately following air-gulping performed by H. littorale in normoxia with those of mechanically-triggered C-start escape responses and with routine (i.e. spontaneous) turns. Our results show that air-breathing events overlap considerably with escape responses with a large stage 1 angle in terms of turning rates, distance covered and the relationship between these rates. Therefore, these two behaviours can be considered kinematically comparable, suggesting that air-breathing in this species is followed by escape-like C-start motions, presumably to minimise time at the surface and exposure to avian predators. These findings show that C-starts can occur in a variety of contexts in which fish may need to get away from areas of potential danger. PMID- 25527643 TI - Rab11a is required for apical protein localisation in the intestine. AB - The small GTPase Rab11 plays an important role in the recycling of proteins to the plasma membrane as well as in polarised transport in epithelial cells and neurons. We generated conditional knockout mice deficient in Rab11a. Rab11a deficient mice are embryonic lethal, and brain-specific Rab11a knockout mice show no overt abnormalities in brain architecture. In contrast, intestine-specific Rab11a knockout mice begin dying approximately 1 week after birth. Apical proteins in the intestines of knockout mice accumulate in the cytoplasm and mislocalise to the basolateral plasma membrane, whereas the localisation of basolateral proteins is unaffected. Shorter microvilli and microvillus inclusion bodies are also observed in the knockout mice. Elevation of a serum starvation marker was also observed, likely caused by the mislocalisation of apical proteins and reduced nutrient uptake. In addition, Rab8a is mislocalised in Rab11a knockout mice. Conversely, Rab11a is mislocalised in Rab8a knockout mice and in a microvillus atrophy patient, which has a mutation in the myosin Vb gene. Our data show an essential role for Rab11a in the localisation of apical proteins in the intestine and demonstrate functional relationships between Rab11a, Rab8a and myosin Vb in vivo. PMID- 25527645 TI - Brain nonapeptide and gonadal steroid responses to deprivation of heterosexual contact in the black molly. AB - Fish may respond to different social situations with changes in both physiology and behaviour. A unique feature of fish is that social interactions between males and females strongly affect the sexual characteristics of individuals. Here we provide the first insight into the endocrine background of two phenomena that occur in mono-sex groups of the black molly (Poecilia sphenops): masculinization in females and same-sex sexual behaviour, manifested by gonopodial displays towards same-sex tank mates and copulation attempts in males. In socially controlled situations, brain neurohormones impact phenotypic sex determination and sexual behaviour. Among these hormones are the nonapeptides arginine vasotocin (AVT) and isotocin (IT), counterparts of the well-known mammalian arginine vasopressin and oxytocin, respectively. To reveal potential hormone interactions, we measured the concentrations of bioactive AVT and IT in the brain, along with those of the sex steroids 17beta-estradiol and 11 ketotestosterone in the gonads, of females, masculinized females, males displaying same-sex sexual behaviour and those who did not. These data were supplemented by morphological and histological analyses of the gonads. Correlations between brain nonapeptides and gonadal steroids strongly suggest a cross talk between hormonal systems. In the black molly, the masculinization process was associated with the production of brain AVT and gonadal steroids, whereas same-sex sexual behaviour involves both brain nonapeptides, but neither of the sex steroids. This study extends current knowledge of endocrine control of phenotypic sex and sexual behaviour in fish and for the first time links brain nonapeptides with the occurrence of male-male sexual behaviour in lower vertebrates. PMID- 25527646 TI - Seasonal and reproductive effects on wound healing in the flight membranes of captive big brown bats. AB - The flight membranes of bats serve a number of physiological functions important for survival. Although flight membrane injuries are commonly observed in wild caught bats, in most cases the damage heals completely. Previous studies examining wound healing in the flight membranes of bats have not taken into consideration energy constraints that could influence healing times. Wound healing results in increased energy demands, therefore we hypothesized that wound healing times would be slower during periods of energy conservation and/or energy output. In this study we used an 8 mm diameter circular punch tool to biopsy the wing membranes of healthy adult female big brown bats (Eptesicus fuscus) from a captive research colony to test the hypothesis that healing times will vary with seasonal temperature changes between the summer and winter seasons, and with reproductive condition between lactating and non-reproductive females. As expected, membrane biopsies took significantly longer to heal during the winter when bats were hibernating compared to the summer when bats were active. Surprisingly, no difference in healing time was observed between lactating and non-reproductive females. The wings of most bats fully healed, although some individuals showed wound expansion demonstrating that impaired healing is occasionally observed in otherwise healthy subjects. PMID- 25527649 TI - Reply to Eisenhut. PMID- 25527647 TI - Comparing GFR Estimating Equations Using Cystatin C and Creatinine in Elderly Individuals. AB - Current guidelines recommend reporting eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations unless other equations are more accurate, and recommend the combination of creatinine and cystatin C (eGFRcr-cys) as more accurate than either eGFRcr or eGFRcys alone. However, preferred equations and filtration markers in elderly individuals are debated. In 805 adults enrolled in the community-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we measured GFR (mGFR) using plasma clearance of iohexol, standardized creatinine and cystatin C, and eGFR using the CKD-EPI, Japanese, Berlin Initiative Study (BIS), and Caucasian and Asian pediatric and adult subjects (CAPA) equations. We evaluated equation performance using bias, precision, and two measures of accuracy. We first compared the Japanese, BIS, and CAPA equations with the CKD-EPI equations to determine the preferred equations, and then compared eGFRcr and eGFRcys with eGFRcr-cys using the preferred equations. Mean (SD) age was 80.3 (4.0) years. Median (25th, 75th) mGFR was 64 (52, 73) ml/min per 1.73 m(2), and the prevalence of decreased GFR was 39% (95% confidence interval, 35.8 to 42.5). Among 24 comparisons with the other equations, CKD-EPI equations performed better in 9, similar in 13, and worse in 2. Using the CKD-EPI equations, eGFRcr-cys performed better than eGFRcr in four metrics, better than eGFRcys in two metrics, and similar to eGFRcys in two metrics. In conclusion, neither the Japanese, BIS, nor CAPA equations were superior to the CKD-EPI equations in this cohort of community-dwelling elderly individuals. Using the CKD-EPI equations, eGFRcr-cys performed better than eGFRcr or eGFRcys. PMID- 25527650 TI - We must halt the progression of multidrug-resistant tuberculosis to extensively drug-resistant tuberculosis, no matter what the cost. PMID- 25527651 TI - Analysis of Green Light Committee implementation and acquisition of second-line drug resistance. PMID- 25527652 TI - Extensively drug-resistant tuberculosis: you can teach an old dog new tricks. PMID- 25527653 TI - Acquired drug resistance: we can do more than we think! PMID- 25527654 TI - Reply to Soman et al, Alffenaar et al, Metcalfe et al, and Raoult. PMID- 25527655 TI - Severe hemolysis as a potential contributing factor in the pathophysiology of cerebral malaria. PMID- 25527656 TI - Don't ask, sometimes tell. A survey of men who have sex with men sexual orientation disclosure in general practice. AB - Despite advances in lesbian, gay, bisexual and transgender equality in recent years, some men who have sex with men remain at increased risk of ill-health. Positive interventions in primary care include psychological support and strategies for risk reduction. It is important that men who have sex with men can disclose sexual orientation in primary care. To quantify disclosure of sexual orientation by men who have sex with men attending general practice and identify barriers to disclosure we surveyed a group of Scottish men. A questionnaire was distributed by voluntary organisations and the National Health Service in the West of Scotland, to rural and urban populations. Two hundred and four gave evaluable responses, with all ages represented. A total of 199 (98%) were registered with a General Practitioner and 167 (83%) attended in the previous year. A total of 81 (40%) stated staff were aware of their sexual orientation. A total of 93/121 (75%) men who have sex with men whose GP was unaware stated this was because they had never been asked. A total of 36/81(44%) men who have sex with men rated support from practices since disclosure as 'excellent' and qualitative responses were positive. It is reassuring that almost all respondents were registered with GPs and attending primary care services. However, only 40% had disclosed sexual orientation. This was not because of fear of negative impact on care but because men who have sex with men felt it was irrelevant to their attendance. GPs appear to be reluctant to raise the issue of sexual orientation without prompting. PMID- 25527657 TI - Nontargeted metabolite profiling discriminates diet-specific biomarkers for consumption of whole grains, fatty fish, and bilberries in a randomized controlled trial. AB - BACKGROUND: Nontargeted metabolite profiling allows for concomitant examination of a wide range of metabolite species, elucidating the metabolic alterations caused by dietary interventions. OBJECTIVE: The aim of the current study was to investigate the effects of dietary modifications on the basis of increasing consumption of whole grains, fatty fish, and bilberries on plasma metabolite profiles to identify applicable biomarkers for dietary intake and endogenous metabolism. METHODS: Metabolite profiling analysis was performed on fasting plasma samples collected in a 12-wk parallel-group intervention with 106 participants with features of metabolic syndrome who were randomly assigned to 3 dietary interventions: 1) whole-grain products, fatty fish, and bilberries [healthy diet (HD)]; 2) a whole-grain-enriched diet with the same grain products as in the HD intervention but with no change in fish or berry consumption; and 3) refined-wheat breads and restrictions on fish and berries (control diet). In addition, correlation analyses were conducted with the food intake data to define the food items correlating with the biomarker candidates. RESULTS: Nontargeted metabolite profiling showed marked differences in fasting plasma after the intervention diets compared with the control diet. In both intervention groups, a significant increase was observed in 2 signals identified as glucuronidated alk(en)-ylresorcinols [corrected P value (Pcorr) < 0.05], which correlated strongly with the intake of whole-grain products (r = 0.63, P < 0.001). In addition, the HD intervention increased the signals for furan fatty acids [3 carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF)], hippuric acid, and various lipid species incorporating polyunsaturated fatty acids (Pcorr < 0.05). In particular, plasma CMPF correlated strongly with the intake of fish (r = 0.47, P < 0.001) but not with intakes of any other foods. CONCLUSIONS: Novel biomarkers of the intake of health-beneficial food items included in the Nordic diet were identified by the metabolite profiling of fasting plasma and confirmed by the correlation analyses with dietary records. The one with the most potential was CMPF, which was shown to be a highly specific biomarker for fatty fish intake. This trial was registered at clinicaltrials.gov as NCT00573781. PMID- 25527658 TI - Glutamine enhances tight junction protein expression and modulates corticotropin releasing factor signaling in the jejunum of weanling piglets. AB - BACKGROUND: Dysfunction of tight junction integrity is associated with decreased nutrient absorption and numerous gastrointestinal diseases in humans and piglets. Although l-glutamine has been reported to enhance intestinal-mucosal mass and barrier function under stressful conditions, in vivo data to support a functional role for l-glutamine on intestinal tight junction protein (TJP) expression in weanling mammals are limited. OBJECTIVE: This study tested the hypothesis that glutamine regulates expression of TJPs and stress-related corticotropin-releasing factor (CRF) signaling in the jejunum of weanling piglets. METHODS: Piglets were reared by sows or weaned at 21 d of age to a corn and soybean meal-based diet that was or was not supplemented with 1% l-glutamine for 7 d. Growth performance, intestinal permeability, TJP abundance, and CRF expression were examined. RESULTS: Weaning caused increases (P < 0.05) in intestinal permeability by 40% and in CRF concentrations by 4.7 times in association with villus atrophy (P < 0.05). Western blot analysis showed reductions (P < 0.05) in jejunal expression of occludin, claudin-1, zonula occludens (ZO) 2, and ZO-3, but no changes in the abundance of claudin-3, claudin-4, or ZO-1 in weanling piglets compared with age matched suckling controls. Glutamine supplementation improved (P < 0.05) intestinal permeability and villus height, while reducing (P < 0.05) jejunal mRNA and protein levels for CRF and attenuating (P < 0.05) weanling-induced decreases in occludin, claudin-1, ZO-2, and ZO-3 protein abundances. CONCLUSION: Collectively, our results support an important role for l-glutamine in regulating expression of TJPs and CRF in the jejunum of weanling piglets. PMID- 25527659 TI - In HepG2 cells, coexisting carnitine deficiency masks important indicators of marginal biotin deficiency. AB - BACKGROUND: A large number of birth defects are related to nutrient deficiencies; concern that biotin deficiency is teratogenic in humans is reasonable. Surprisingly, studies indicate that increased urinary 3 hydroxyisovalerylcarnitine (3HIAc), a previously validated marker of biotin deficiency, is not a valid biomarker in pregnancy. OBJECTIVE: In this study we hypothesized that coexisting carnitine deficiency can prevent the increase in 3HIAc due to biotin deficiency. METHODS: We used a 2-factor nutrient depletion design to induce isolated and combined biotin and carnitine deficiency in HepG2 cells and then repleted cells with carnitine. To elucidate the metabolic pathogenesis, we quantitated intracellular and extracellular free carnitine, acylcarnitines, and acylcarnitine ratios using liquid chromatography-tandem mass spectrometry. RESULTS: Relative to biotin-sufficient, carnitine-sufficient cells, intracellular acetylcarnitine increased by 90%, propionylcarnitine more than doubled, and 3HIAc increased by >10-fold in biotin-deficient, carnitine sufficient (BDCS) cells, consistent with a defensive mechanism in which biotin deficient cells transesterify the acyl-coenzyme A (acyl-CoA) substrates of the biotin-dependent carboxylases to the related acylcarnitines. Likewise, in BDCS cells, the ratio of acetylcarnitine to malonylcarnitine and the ratio of propionylcarnitine to methylmalonylcarnitine both more than tripled, and the ratio of 3HIAc to 3-methylglutarylcarnitine (MGc) increased by >10-fold. In biotin-deficient, carnitine-deficient (BDCD) cells, the 3 substrate-derived acylcarnitines changed little, but the substrate:product ratios were masked to a lesser extent. Moreover, carnitine repletion unmasked biotin deficiency in BDCD cells as shown by increases in acetylcarnitine, propionylcarnitine, and 3HIAc (each increased by >50-fold). Likewise, ratios of acetylcarnitine:malonylcarnitine, propionylcarnitine:methylmalonylcarnitine, and 3HIAc:MGc all increased by >8-fold. CONCLUSIONS: Our findings provide strong evidence that coexisting carnitine deficiency masks some indicators of biotin deficiency and support the potential importance of the ratios of acylcarnitines arising from the acyl-CoA substrates and products for biotin-dependent carboxylases in detecting the biotin deficiency that is masked by coexisting carnitine deficiency. PMID- 25527660 TI - Oligosaccharide composition of breast milk influences survival of uninfected children born to HIV-infected mothers in Lusaka, Zambia. AB - BACKGROUND: Human milk oligosaccharides (HMOs) have multiple immunomodulatory functions that influence child health. OBJECTIVE: In this study we investigated whether HMO composition influences survival to 2 y of age in HIV-infected and HIV exposed, uninfected (HEU) children during and after breastfeeding. METHODS: In the context of an early weaning trial in 958 HIV-infected women in Lusaka, Zambia, we conducted a nested case-cohort analysis of mortality to 2 y of age among 103 HIV-infected and 143 HEU children. Breast-milk samples collected at 1 mo postpartum were analyzed for HMO content. Samples were selected to include mothers of all HIV-infected children detected by 6 wk of age, of whom 63 died at <2 y of age; mothers of all HEU children who died at <2 y of age (n = 66); and a random sample of 77 HEU survivors. Associations before and after weaning in HIV infected and HEU infants separately were investigated by using Cox models. RESULTS: Among HEU children, higher maternal breast-milk concentrations of 2 linked fucosylated HMOs [2'-fucosyllactose and lacto-N-fucopentaose (LNFP) I] (HR: 0.33; 95% CI: 0.14, 0.74) as well as non-2-linked fucosylated HMOs (3 fucosyllactose and LNFP II/III; HR: 0.28; 95% CI: 0.13, 0.67) were significantly associated with reduced mortality during, but not after, breastfeeding after adjustment for confounders. Breastfeeding was protective against mortality only in HEU children with high concentrations of fucosylated HMOs. Among HIV-infected children, no consistent associations between HMOs and mortality were observed, but breastfeeding was protective against mortality. CONCLUSIONS: The oligosaccharide composition of breast milk may explain some of the benefits of breastfeeding in HEU children. HIV infection may modulate some of the consequences of HMOs on child survival. PMID- 25527661 TI - Protein requirements of healthy pregnant women during early and late gestation are higher than current recommendations. AB - BACKGROUND: Adequate maternal dietary protein intake is necessary for healthy pregnancy. However, current protein intake recommendations for healthy pregnant women are based on factorial calculations of nitrogen balance data derived from nonpregnant adults. Thus, an estimate of protein requirements based on pregnancy specific data is needed. OBJECTIVE: The objective of this study was to determine protein requirements of healthy pregnant women at 11-20 (early) and 31-38 (late) wk of gestation through use of the indicator amino acid oxidation method. METHODS: Twenty-nine healthy women (24-37 y) each randomly received a different test protein intake (range: 0.22-2.56 g . kg(-1) . d(-1)) during each study day in early (n = 35 observations in 17 women) and late (n = 43 observations in 19 women) gestation; 7 women participated in both early and late gestation studies. The diets were isocaloric and provided energy at 1.7 * resting energy expenditure. Protein was given as a crystalline amino acid mixture based on egg protein composition, except phenylalanine and tyrosine, which were maintained constant across intakes. Protein requirements were determined by measuring the oxidation rate of L-[1-(13)C]phenylalanine to (13)CO2 (F(13)CO2). Breath and urine samples were collected at baseline and isotopic steady state. Linear regression crossover analysis identified a breakpoint (requirement) at minimal F(13)CO2 in response to different protein intakes. RESULTS: The estimated average requirement (EAR) for protein in early and late gestation was determined to be 1.22 (R(2) = 0.60; 95% CI: 0.79, 1.66 g . kg(-1) . d(-1)) and 1.52 g . kg(-1) . d(-1) (R(2) = 0.63; 95% CI: 1.28, 1.77 g . kg(-1) . d(-1)), respectively. CONCLUSIONS: These estimates are considerably higher than the EAR of 0.88 g . kg( 1) . d(-1) currently recommended by the Dietary Reference Intakes. To our knowledge, this study is the first to directly estimate gestational stage specific protein requirements in healthy pregnant women and suggests that current recommendations based on factorial calculations underestimate requirements. This trial was registered at clinicaltrials.gov as NCT01784198. PMID- 25527662 TI - Obesity is associated with increased red blood cell folate despite lower dietary intakes and serum concentrations. AB - BACKGROUND: Folates are essential cofactors in metabolic pathways that facilitate biological methylation and nucleotide synthesis, and therefore have widespread effects on health and diseases. Although obesity is prevalent worldwide, few studies have investigated how obesity interacts with folate status. OBJECTIVE: Based on data from the NHANES, this study aims to examine the association between body mass index (BMI) and obesity-related metabolic factors with blood folate status. METHODS: A nationally representative sample of 3767 adults from the NHANES (2003-2006) was used as the study population. Regression analyses, with and without adjustment for demographic factors and dietary intakes, were performed to examine associations between BMI and metabolic factors with serum and RBC folate. RESULTS: The results indicate serum folate concentrations were lower in obese groups compared to the desirable BMI and overweight categories, paralleling lower intakes in this group. In contrast, RBC folate increased incrementally with BMI. Regression analyses demonstrated an inverse relation between BMI and serum folate but a positive relation for RBC folate (P < 0.01). Waist circumference, serum triglycerides, and fasting plasma glucose each displayed significant positive relations with RBC folate (P < 0.01), although relations with serum folate were not significant and consistent. CONCLUSIONS: In summary, obesity is associated with decreased serum folate, which parallels decreased folate intakes. In contrast, obesity is positively associated with RBC folate. Therefore, RBC folate, in addition to serum folate, should also be considered as a critical biomarker for folate status, especially in the obese population. Future research is needed to understand how obesity differentially alters serum and RBC folate status because they are associated with a variety of medical complications. PMID- 25527665 TI - Maternal folate status, but not that of vitamins B-12 or B-6, is associated with gestational age and preterm birth risk in a multiethnic Asian population. AB - BACKGROUND: Maternal folate, vitamin B-12, and vitamin B-6 concentrations during pregnancy have been shown to influence birth outcomes, but the evidence is inconclusive. OBJECTIVE: We aimed to examine the associations of maternal B vitamin status with gestational age, birth weight, and length in a birth cohort study in Singapore. METHODS: Maternal blood samples (n = 999) collected during weeks 26-28 of gestation were assayed for plasma folate, vitamin B-12, and vitamin B-6 concentrations. Birth weight and gestational age data were obtained from hospital records, and other anthropometric variables were measured within 72 h after birth. Relations between B-vitamin status and birth outcomes were assessed by linear or logistic regression with adjustment for potential confounders. RESULTS: Median (IQR) plasma concentrations were 34.4 (24.5-44.6) nmol/L for folate, 209 (167-258) pmol/L for vitamin B-12, and 61.8 (25.9-113) nmol/L for vitamin B-6. We found that higher plasma folate concentrations were associated with a longer gestational age (0.12 wk per SD increase in folate; 95% CI: 0.02, 0.21) and tended to be associated with lower risk of all preterm birth (delivery at <37 wk of gestation; OR: 0.79; 95% CI: 0.63, 1.00) and spontaneous preterm birth (OR: 0.76; 95% CI: 0.56, 1.04). Overall, concentrations of maternal folate, vitamin B-12, and vitamin B-6 were not independently associated with birth weight or being born small for gestational age (SGA; birth weight <10th percentile for gestational age). CONCLUSIONS: Higher maternal folate concentrations during late pregnancy were associated with longer gestational age and tended to be associated with a lower risk of preterm birth in this multiethnic Asian population. In contrast, the results of our study suggested little or no benefit of higher folate concentrations for reducing the risk of SGA or of higher vitamin B-6 and vitamin B-12 concentrations for reducing the risk of preterm birth or SGA. PMID- 25527664 TI - Derivation and validation of homocysteine score in u.s. Men and women. AB - BACKGROUND: One-carbon metabolism, which is crucial in DNA synthesis and genomic stability, is an interrelated network of biochemical reactions involved in several dietary and lifestyle factors. The development of the homocysteine score using these factors may be useful to reflect the status of one-carbon metabolism in large epidemiologic studies without biologic samples to measure homocysteine directly. OBJECTIVE: The aim of this study was to develop an homocysteine score that reflects one-carbon metabolism better than individual dietary or lifestyle factors. METHODS: We divided 2023 participants with measured plasma total homocysteine data in the Nurses' Health Study and the Health Professionals Follow Up Study into training (n = 1619) and testing (n = 404) subsets. Using multivariable linear regression, we selected lifestyle determinants of plasma homocysteine in the training set and derived the homocysteine score weighted by the beta coefficient for each predictor. The validation of the homocysteine score was assessed using the plasma homocysteine in the independent samples of the training set. RESULTS: In the training set, smoking, multivitamin use, and caffeine, alcohol, and dietary and supplemental folate intake were significant independent determinants of plasma homocysteine in multivariable linear regression (P <= 0.01) and were included in the derivation of the homocysteine score. The Pearson correlation of the homocysteine score with plasma homocysteine was 0.30 in the testing subset (P < 0.001). The homocysteine score was positively associated with the plasma homocysteine concentration in the testing subset and in an independent population of women; the mean difference of plasma homocysteine concentration between the extreme quintiles of homocysteine score ranged from 0.83 MUmol/L to 1.52 MUmol/L. Population misclassification either from the lowest quintile of plasma homocysteine into the highest quintile of the homocysteine score or from the highest quintile of plasma homocysteine into the lowest quintile of the homocysteine score was <=12%. CONCLUSION: These data indicate that the homocysteine score may be used with relatively inexpensive and simple questionnaires to rank an individual's one-carbon metabolism status when homocysteine data are not available. PMID- 25527663 TI - Metabolite profile analysis reveals association of vitamin B-6 with metabolites related to one-carbon metabolism and tryptophan catabolism but not with biomarkers of inflammation in oral contraceptive users and reveals the effects of oral contraceptives on these processes. AB - BACKGROUND: The use of oral contraceptives (OCs) has been associated with low plasma pyridoxal 5'-phosphate (PLP). The functional consequences are unclear. OBJECTIVES: To determine whether functional vitamin B-6 insufficiency occurs in OC users and is attributable to OCs, we investigated the associations of PLP with metabolites of one-carbon metabolism, tryptophan catabolism, and inflammation in OC users, and evaluated the effects of OCs on these metabolites. METHODS: Plasma metabolite concentrations were measured in 157 OC users (20-40 y of age). Associations between PLP and the metabolites were analyzed through use of generalized additive models and partial least squares-discriminant analysis (PLS DA). Additionally, data from 111 of the 157 OC users were compared to previously reported data from 11 nonusers, at adequate and low vitamin B-6 status, with use of multivariate ANOVA. RESULTS: PLP showed significant (P < 0.05) negative nonlinear association with homocysteine, glutathione, and ratios of asymmetric dimethylarginine to arginine, 3-hydroxykynurenine to 3-hydroxyanthranilic acid, and 3-hydroxykynurenine to kynurenic acid. PLS-DA supported these conclusions and identified 3-hydroxykynurenine and the 3-hydroxykynurenine-to-kynurenine ratio as discriminating biomarkers in women with PLP <=30 nmol/L. Among the many differences, OC users had significantly higher plasma pyridoxal (157% at adequate and 195% at low vitamin B-6 status), 4-pyridoxic acid (154% at adequate and 300% at low vitamin B-6 status), xanthurenic acid (218% at low vitamin B-6 status), 3 hydroxyanthranilic acid (176% at adequate and 166% at low vitamin B-6 status), quinolinic acid (127% at low vitamin B-6 status), and nicotinamide (197% at low vitamin B-6 status). Biomarkers of inflammation were not associated with PLP, and no differences were found between the 2 groups. CONCLUSIONS: PLP is associated with biomarkers of one-carbon metabolism and tryptophan catabolism but not with biomarkers of inflammation in OC users. Independent of vitamin B-6 status, OCs have effects on metabolites and ratios of one-carbon metabolism and tryptophan catabolism but not on biomarkers of inflammation. This study was registered at clinicaltrials.gov as NCT01128244. The study from which data for nonusers was derived was registered as NCT00877812. PMID- 25527666 TI - Vitamin D status is associated with mortality, morbidity, and growth failure among a prospective cohort of HIV-infected and HIV-exposed Tanzanian infants. AB - BACKGROUND: Vitamin D is a potent immunomodulator, but its impact on morbidity and mortality among infants remains unclear. OBJECTIVE: The objective of the study was to prospectively assess the association of vitamin D status with mortality, morbidity, and growth during the first 2 y of life. METHODS: A prospective cohort of 253 HIV-infected and 948 HIV-exposed Tanzanian infants enrolled in a randomized trial of multivitamins (not including vitamin D) was studied. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured at 5-7 wk of age and infants were followed at monthly clinic visits until 24 mo. Physicians performed a clinical exam every 3 mo or when an illness was noted. RESULTS: Serum 25(OH)D concentrations were (means +/- SDs) 18.6 +/- 10.3 ng/mL and 18.1 +/- 9.2 ng/mL for HIV-infected and HIV-exposed infants, respectively. Unexpectedly, serum 25(OH)D concentrations >=30 ng/mL were significantly associated with higher mortality as compared to the 20-29.9 ng/mL reference for HIV-infected (HR: 2.47; 95% CI: 1.13, 5.44; P = 0.02) and HIV-exposed (HR: 4.00; 95% CI: 1.67, 9.58; P < 0.01) infants after multivariate adjustment. We found no statistically significant association between 25(OH)D concentrations <10 ng/mL and mortality for HIV-infected (HR: 1.43; 95% CI: 0.74, 2.78; P = 0.29) and HIV exposed (HR: 1.56; 95% CI: 0.60, 4.03; P = 0.36) infants. Among HIV-exposed infants, 25(OH)D concentrations >=30 ng/mL were significantly associated with clinical [incidence ratio rate (IRR): 1.34; 95% CI: 1.06,1.70; P = 0.02] and confirmed (IRR: 1.71; 95% CI: 1.71; 1.15, 2.54; P < 0.01) malaria diagnoses, whereas concentrations of <10 ng/mL were associated with oral candidiasis (IRR: 1.47; 95% CI: 1.00-2.15; P = 0.046) and wasting (HR: 1.71; 95% CI: 1.20, 2.43; P < 0.01). CONCLUSION: The observational design of this study does not allow for causal interpretation; however, the results indicate a strong need for additional studies of vitamin D among HIV-infected and -exposed children, particularly in malaria-endemic settings. The parent trial was registered at clinicaltrials.gov as NCT00197730. PMID- 25527667 TI - A dietary guideline adherence score is positively associated with dietary biomarkers but not lipid profile in healthy children. AB - BACKGROUND: Whether dietary indexes are associated with biomarkers of children's dietary intake is unclear. OBJECTIVE: The study aim was to examine the relations between diet quality and selected plasma biomarkers of dietary intake and serum lipid profile. METHODS: The study sample consisted of 130 children aged 4-13 y (mean +/- SD: 8.6 +/- 2.9 y) derived by using baseline data from an intervention study. The Dietary Guideline Index for Children and Adolescents (DGI-CA) comprises the following 11 components with age-specific criteria: 5 core food groups, whole-grain bread, reduced-fat dairy foods, discretionary foods (nutrient poor; high in saturated fat, salt, and added sugar), healthy fats/oils, water, and diet variety (possible score of 100). A higher score reflects greater compliance with dietary guidelines. Venous blood was collected for measurements of serum lipids, fatty acid composition, plasma carotenoids, lutein, lycopene, and alpha-tocopherol. Linear regression was used to examine the relation between DGI-CA score (independent variable) and concentrations of biomarkers by using the log-transformed variable (outcome), controlling for confounders. RESULTS: DGI-CA score was positively associated (P < 0.05) with plasma concentrations of lutein (standardized beta = 0.17), alpha-carotene (standardized beta = 0.28), beta carotene (standardized beta = 0.26), and n-3 (omega-3) fatty acids (standardized beta = 0.51) and inversely associated with plasma concentrations of lycopene (standardized beta = -0.23) and stearic acid (18:0) (standardized beta = -0.22). No association was observed between diet quality and alpha-tocopherol, n-6 fatty acids, or serum lipid profile (all P > 0.05). CONCLUSION: Diet quality, conceptualized as adherence to national dietary guidelines, is cross-sectionally associated with plasma biomarkers of dietary exposure but not serum lipid profile. This trial was registered with the Australia New Zealand Clinical Trial Registry (www.anztr.org.au) as ACTRN12609000453280. PMID- 25527668 TI - Genetic hemoglobin disorders rather than iron deficiency are a major predictor of hemoglobin concentration in women of reproductive age in rural prey Veng, Cambodia. AB - BACKGROUND: Anemia is common in Cambodian women. Potential causes include micronutrient deficiencies, genetic hemoglobin disorders, inflammation, and disease. OBJECTIVES: We aimed to investigate factors associated with anemia (low hemoglobin concentration) in rural Cambodian women (18-45 y) and to investigate the relations between hemoglobin disorders and other iron biomarkers. METHODS: Blood samples were obtained from 450 women. A complete blood count was conducted, and serum and plasma were analyzed for ferritin, soluble transferrin receptor (sTfR), folate, vitamin B-12, retinol binding protein (RBP), C-reactive protein (CRP), and alpha1 acid glycoprotein (AGP). Hemoglobin electrophoresis and multiplex polymerase chain reaction were used to determine the prevalence and type of genetic hemoglobin disorders. RESULTS: Overall, 54% of women had a genetic hemoglobin disorder, which included 25 different genotypes (most commonly, hemoglobin E variants and alpha(3.7)-thalassemia). Of the 420 nonpregnant women, 29.5% had anemia (hemoglobin <120 g/L), 2% had depleted iron stores (ferritin <15 MUg/L), 19% had tissue iron deficiency (sTfR >8.3 mg/L), <3% had folate deficiency (<3 MUg/L), and 1% had vitamin B-12 deficiency (<150 pmol/L). Prevalences of iron deficiency anemia (IDA) were 14.2% and 1.5% in those with and without hemoglobin disorders, respectively. There was no biochemical evidence of vitamin A deficiency (RBP <0.7 MUmol/L). Acute and chronic inflammation were prevalent among 8% (CRP >5 mg/L) and 26% (AGP >1 g/L) of nonpregnant women, respectively. By using an adjusted linear regression model, the strongest predictors of hemoglobin concentration were hemoglobin E homozygous disorder and pregnancy status. Other predictors were 2 other heterozygous traits (hemoglobin E and Constant Spring), parity, RBP, log ferritin, and vitamin B-12. CONCLUSIONS: Multiple biomarkers for anemia and iron deficiency were significantly influenced by the presence of hemoglobin disorders, hence reducing their diagnostic sensitivity. Further investigation of the unexpectedly low prevalence of IDA in Cambodian women is warranted. PMID- 25527670 TI - Implausible results from the use of invalid methods. PMID- 25527669 TI - Dietary fiber is positively associated with cognitive control among prepubertal children. AB - BACKGROUND: Converging evidence now indicates that aerobic fitness and adiposity are key correlates of childhood cognitive function and brain health. However, the evidence relating dietary intake to executive function/cognitive control remains limited. OBJECTIVE: The current study assessed cross-sectional associations between performance on an attentional inhibition task and dietary fatty acids (FAs), fiber, and overall diet quality among children aged 7-9 y (n = 65). METHODS: Attentional inhibition was assessed by using a modified flanker task. Three-day food records were used to conduct nutrient-level analyses and to calculate diet quality (Healthy Eating Index-2005) scores. RESULTS: Bivariate correlations revealed that socioeconomic status and sex were not related to task performance or diet measures. However, age, intelligence quotient (IQ), pubertal staging, maximal oxygen uptake (VO2max), and percentage of fat mass (%fat mass) correlated with task accuracy. Hierarchical regression models were used to determine the relation between diet variables and task accuracy and reaction time across both congruent and incongruent trials of the flanker task. After adjustment of confounding variables (age, IQ, pubertal staging, VO2max, and %fat mass), congruent accuracy was positively associated with insoluble fiber (beta = 0.26, P = 0.03) and total dietary fiber (beta = 0.23, P = 0.05). Incongruent response accuracy was positively associated with insoluble fiber (beta = 0.35, P < 0.01), pectins (beta = 0.25, P = 0.04), and total dietary fiber (beta = 0.32, P < 0.01). Higher diet quality was related to lower accuracy interference (beta = 0.26, P = 0.03), whereas higher total FA intake was related to greater accuracy interference (beta = 0.24, P = 0.04). No statistically significant associations were observed between diet variables and reaction time measures. CONCLUSION: These results demonstrate that children's diet quality, specifically dietary fiber, is an important correlate of performance on a cognitive task requiring variable amounts of cognitive control. PMID- 25527674 TI - Dietary substitutions for refined carbohydrate that show promise for reducing risk of type 2 diabetes in men and women. AB - Both genetics and lifestyle contribute to type 2 diabetes (T2D), a condition of elevated circulating glucose induced by a collection of metabolic defects including peripheral insulin resistance, elevated hepatic glucose output, and impaired pancreatic insulin secretion. Because the prevalence of T2D and its modifiable risk factors (overweight/obesity, dyslipidemia, hypertension, and physical inactivity) have been increasing in recent decades, there has been growing interest in lifestyle interventions that target T2D management and prevention. Although it is increasingly recognized that lifestyle interventions aimed at encouraging physical activity and reducing body weight can improve insulin sensitivity, nutritional contributions to T2D risk reduction are less clear. Evidence from prospective cohort and randomized controlled trials suggests that diets rich in refined dietary carbohydrate [particularly those with a high glycemic index (GI)] may elevate T2D risk; however, the appropriate combination of macronutrients to optimize metabolic health has not been fully described. To date, the collective evidence suggests that diets rich in low-GI carbohydrates, cereal fiber, resistant starch, fat from vegetable sources (unsaturated fat), and lean sources of protein should be emphasized, whereas refined sugars and grains (high-GI carbohydrates) are to be avoided in order to lower risk of T2D and its related risk factors and comorbidities. PMID- 25527675 TI - Dietary protein is important in the practical management of prediabetes and type 2 diabetes. AB - Many misconceptions surround the role of dietary protein in the management of diabetes. Although dietary recommendations for managing diabetes have changed greatly over the centuries, recommended protein intake has remained relatively constant. Currently, recommendations for protein intake are based on individual assessment and the consideration of other health issues and implications, such as the extent of glycemic control, the presence of kidney disease, overweight and obesity, and the age of the patient. Two common misconceptions about dietary protein in diabetes management are that a certain amount of the protein consumed is converted into blood glucose and that consuming too much protein can lead to diabetic kidney disease. These misconceptions have been disproven. For many people with type 2 diabetes, aiming for 20-30% of total energy intake as protein is the goal. Exceptions may be for those individuals with impaired renal function. A protein intake of this amount can be beneficial by improving glycemic control, aiding in satiety and preservation of lean body mass during weight loss in those with both diabetes and prediabetes, and providing for the increased protein requirements of the older adult. Health care providers should discuss the role of dietary protein with their patients, reinforce sources of protein in the diet, and use simple but effective teaching tools, such as the plate method, to convey important nutrition messages. In addition, health care providers should recognize that persons with diabetes are attempting to manage many other aspects of their diabetes, including blood glucose monitoring, physical activity, taking of medication, risk reduction, and problem solving. PMID- 25527676 TI - Differing statistical approaches affect the relation between egg consumption, adiposity, and cardiovascular risk factors in adults. AB - BACKGROUND: Associations between food patterns and adiposity are poorly understood. OBJECTIVE: Two statistical approaches were used to examine the potential association between egg consumption and adiposity. METHODS: Participants (n = 18,987) aged >=19 y were from the 2001-2008 NHANES who provided 24-h diet recall data, body mass index (BMI) and waist circumference (WC) determined adiposity measures, and blood pressure, circulating insulin, glucose, and lipid concentrations were considered cardiovascular risk factors (CVRFs). Covariate-adjusted least-squares means +/- SEs were generated. RESULTS: The first statistical approach categorized participants into egg consumers or nonconsumers. Consumers had higher mean BMI (in kg/m(2); 28.7 +/- 0.19; P = 0.006) and WC (98.2 +/- 0.43 cm; P = 0.002) than did nonconsumers (28.2 +/- 0.10 and 96.9 +/- 0.23 cm, respectively). Second, cluster analysis identified 8 distinct egg consumption patterns (explaining 39.5% of the variance in percentage of energy within the food categories). Only 2 egg patterns [egg/meat, poultry, fish (MPF)/grains/vegetables and egg/MPF/grains], consumed by <=2% of the population, drove the association (compared with the no-egg pattern) between egg consumption and BMI and WC. Another analysis controlled for the standard covariates and the other food groups consumed with eggs in those 2 egg patterns. Only the egg/MPF/other-grains pattern remained associated with BMI and WC (both P <= 0.0063). The pattern analyses identified associations between an egg pattern (egg/MPF/other grains/potatoes/other beverages) and diastolic blood pressure (DBP) and serum LDL cholesterol (both P <= 0.0063). A final analysis was conducted by adding percentage of energy from fast foods and medication use for diabetes to the covariates. The association between the egg/MPF/grains pattern and BMI and the egg/MPF/potatoes/other beverages and DBP and LDL cholesterol disappeared. CONCLUSIONS: Care needs to be taken with data interpretation of diet and health risk factors and the choice of statistical analyses and covariates used in the analyses because these studies are typically used to generate hypotheses. Additional studies are needed to better understand these relations. PMID- 25527678 TI - Application of ripple mapping to visualize slow conduction channels within the infarct-related left ventricular scar. AB - BACKGROUND: Ripple mapping (RM) displays each electrogram at its 3-dimensional coordinate as a bar changing in length according to its voltage-time relationship with a fiduciary reference. We applied RM to left ventricular ischemic scar for evidence of slow-conducting channels that may act as ventricular tachycardia (VT) substrate. METHODS AND RESULTS: CARTO-3(c) (Biosense Webster Inc, Diamond Bar, CA) maps in patient undergoing VT ablation were analyzed on an offline MatLab RM system. Scar was assessed for sequential movement of ripple bars, during sinus rhythm or pacing, which were distinct from surrounding tissue and termed RM conduction channels (RMCC). Conduction velocity was measured within RMCCs and compared with the healthy myocardium (>1.5 mV). In 21 maps, 77 RMCCs were identified. Conduction velocity in RMCCs was slower when compared with normal left ventricular myocardium (median, 54 [interquartile range, 40-86] versus 150 [interquartile range, 120-160] cm/s; P<0.001). All 7 sites meeting conventional criteria for diastolic pathways coincided with an RMCC. Seven patients had ablation colocating to all identified RMCCs with no VT recurrence during follow up (median, 480 [interquartile range, 438-841] days). Fourteen patients had >=1 RMCC with no ablation lesions. Five had recurrence during follow-up (median, 466 [interquartile range, 395-694] days). One of the 2 patients with no RMCC locations ablated had VT recurrence at 605 days post procedure. RMCCs were sensitive (100%; negative predictive value, 100%) for VT recurrence but the specificity (43%; positive predictive value, 35.7%) may be limited by blind alleys channels. CONCLUSIONS: RM identifies slow conduction channels within ischemic scar and needs further prospective investigation to understand the role of RMCCs in determining the VT substrate. PMID- 25527677 TI - A lower-carbohydrate, higher-fat diet reduces abdominal and intermuscular fat and increases insulin sensitivity in adults at risk of type 2 diabetes. AB - BACKGROUND: Obesity, particularly visceral and ectopic adiposity, increases the risk of type 2 diabetes. OBJECTIVE: The aim of this study was to determine if restriction of dietary carbohydrate is beneficial for body composition and metabolic health. METHODS: Two studies were conducted. In the first, 69 overweight/obese men and women, 53% of whom were European American (EA) and 47% of whom were African American (AA), were provided with 1 of 2 diets (lower-fat diet: 55%, 18%, and 27% of energy from carbohydrate, protein, and fat, respectively; lower-carbohydrate diet: 43%, 18%, and 39%, respectively) for 8 wk at a eucaloric level and 8 wk at a hypocaloric level. In the second study, 30 women with polycystic ovary syndrome (PCOS) were provided with 2 diets (lower-fat diet: 55%, 18%, and 27% of energy from carbohydrate, protein, and fat, respectively; lower-carbohydrate diet: 41%, 19%, and 40%, respectively) at a eucaloric level for 8 wk in a random-order crossover design. RESULTS: As previously reported, among overweight/obese adults, after the eucaloric phase, participants who consumed the lower-carbohydrate vs. the lower-fat diet lost more intra-abdominal adipose tissue (IAAT) (11 +/- 3% vs. 1 +/- 3%; P < 0.05). After weight loss, participants who consumed the lower-carbohydrate diet had 4.4% less total fat mass. Original to this report, across the entire 16-wk study, AAs lost more fat mass with a lower-carbohydrate diet (6.2 vs. 2.9 kg; P < 0.01), whereas EAs showed no difference between diets. As previously reported, among women with PCOS, the lower-carbohydrate arm showed decreased fasting insulin (-2.8 MUIU/mL; P < 0.001) and fasting glucose (-4.7 mg/dL; P < 0.01) and increased insulin sensitivity (1.06 arbitrary units; P < 0.05) and "dynamic" beta-cell response (96.1 . 10(9); P < 0.001). In the lower-carbohydrate arm, women lost both IAAT ( 4.8 cm(2); P < 0.01) and intermuscular fat (-1.2 cm(2); P < 0.01). In the lower fat arm, women lost lean mass (-0.6 kg; P < 0.05). Original to this report, after the lower-carbohydrate arm, the change in IAAT was positively associated with the change in tumor necrosis factor alpha (P < 0.05). CONCLUSION: A modest reduction in dietary carbohydrate has beneficial effects on body composition, fat distribution, and glucose metabolism. This trial was registered at clinicaltrials.gov as NCT00726908 and NCT01028989. PMID- 25527679 TI - Ebola virus disease: the 'Black Swan' in West Africa. PMID- 25527680 TI - Primary pulmonary lymphoma in a patient with advanced AIDS. AB - Non-Hodgkin's lymphoma (NHL) is an AIDS defining lesion and risk of NHL most likely correlates with the degree of immunosuppression from HIV. Risk of NHL is highest among patients with CD4 count <50 cells/mL. Primary pulmonary lymphoma (PPL) is an infrequent cause of AIDS-related lymphoma. The authors report a patient with advanced AIDS presenting with recurrent fever and pulmonary nodule seen on the CT scan. The patient remained febrile despite being on broad spectrum antibiotics with no clear source of infection. The patient underwent a bronchoscopy with biopsy of the pulmonary lesion which was most consistent with diffuse large B-cell lymphoma. The patient was started on dose-adjusted etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone (EPOCH) and was noted to be afebrile and a repeat CT scan few weeks later showed resolution of her pulmonary nodule. This case highlights the importance of considering NHL in patients with advanced AIDS presenting with pulmonary nodule and fever. PMID- 25527681 TI - Human botfly infestation: the tip of the iceberg. AB - A retired man in his 60s was referred to the on call orthopaedic team by his general practitioner following several attempts to extricate a human botfly larva from his forearm. While on holiday in Belize with his daughter 8 weeks previously they both were bitten by some insects. She developed an infestation which was treated locally. Once back in the UK, he subsequently reported of localised itching and discomfort. A botfly larva was successfully removed in the emergency department following local anaesthetic infiltration. PMID- 25527682 TI - Coexistence of pulmonary tuberculosis and sarcoidosis: a diagnostic dilemma. AB - Tuberculosis and sarcoidosis are multisystem diseases having different aetiology and management; however, they have similar clinical and histological characteristics. Very rarely they may coexist. We report a rare case of a 38-year old woman who presented with chronic cough, low-grade fever and respiratory distress that was initially diagnosed as miliary tuberculosis. Diagnosis was supported by positive mycobacterial culture and initially responded to antitubercular treatment, but later recurrences led to further investigations and the diagnosis of coexisting sarcoidosis. PMID- 25527683 TI - Bilateral otorrhagia: a rare complication of laparoscopic abdominopelvic surgery. AB - An 80-year-old woman without any previous otological symptoms underwent laparoscopic abdominoperineal resection for T3N0M0 low rectal carcinoma 4-5 cm from the anal verge. The total operative time was 6 h, of which she spent long hours in the Trendelenburg (35 degrees ) position due to difficult pelvic dissection. Midway through the procedure, she developed spontaneous non-traumatic bilateral otorrhagia. This case highlights the potential risk of increased intracranial pressure during prolonged periods of being in a steep Trendelenburg position caused either by the position itself or in combination with carbon dioxide pneumoperitoneum. We also consider the effect of a sudden change from this position to supine as a potential risk. PMID- 25527684 TI - A ghost covered in lice: a case of severe blood loss with long-standing heavy pediculosis capitis infestation. AB - An 11-year-old child presented with poor school attendance, and signs and symptoms of severe anaemia. He was heavily covered in lice. He was investigated for other causes of anaemia. Following treatment for head lice and also iron supplementation, he was back in full-time education. This case highlights the link between head lice (pediculosis capitis) infestation and iron-deficiency anaemia. PMID- 25527685 TI - Endoscopic and percutaneous extraction of two biliary stents migrated to distinct abdominal locations. PMID- 25527686 TI - Pulmonary arteriovascular malformation: a rare cause of unexplained hypoxia and acute dyspnoea in young patients. AB - Pulmonary arteriovenous malformations (PAVMs) are anomalous vascular connections between arteries and veins in the lung and comprise of two types, simple and complex. PAVMs are associated with congenital conditions such as hereditary haemorrhagic telengiectasia along with acquired causes. We present a case of a 26 year-old man who presented with dyspnoea, palpitations and decreased oxygen saturation as an initial presentation of PAVM, which was treated successively with embolisation. PMID- 25527687 TI - Epidural abscess secondary to acute appendicitis. AB - A 62-year-old man presented via the emergency department with a 1-week history of back pain, on a background of non-insulin-dependent diabetes mellitus and rectal carcinoma for which he had undergone abdominoperineal resection, chemotherapy and radiotherapy. He exhibited signs of sepsis, midline lumbar spine tenderness and reduced hip flexion. CT of the abdomen and pelvis showed a presacral collection contiguous with the tip of the appendix, and MRI lumbar spine revealed abscess invation into the epidural space extending to T9. He underwent a laparotomy with washout of the presacral abscess and appendicectomy and prolonged course intravenous antibiotic therapy. At 3 months after initial presentation he had made a full clinical recovery with progressive radiological resolution of the epidural abscess. The objective of the case report is to highlight a unique and clinically significant complication of a very common pathology (appendicitis) and to briefly discuss other intra-abdominal sources of epidural abscess. PMID- 25527688 TI - Treatment of ureterovaginal fistula using a Memokath stent. AB - Ureterovaginal fistula (UVF) is a challenging problem for patients and doctors, especially in patients who have been treated by radiation for malignancy. UVF may occur in conjunction with surgeries involving the uterus. A success rate of 70 100% has been reported for fistula repair with the best results in non-radiated patients. Meanwhile, conservative treatment using ureteral stents in selected patients has resulted in reported success rates of 71%. We present the case of a 24-year-old woman with UVF due to surgery and radiotherapy for cervix cancer. The patient has been successfully treated with the insertion of a Memokath 051 stent (PNN Medical A/S, Denmark), which is a thermoexpandable, nickel-titanium alloy stent. The patient has been totally continent during a follow-up period of 3 years. The Memokath stent has been changed twice within this period due to dysfunction. PMID- 25527689 TI - Broca aphasia. PMID- 25527690 TI - Varicella zoster virus encephalomyelitis as a late complication following haematopoietic stem cell transplantation. AB - Varicella zoster virus (VZV) causes the primary infection manifesting as varicella or chickenpox, with possibility of reactivation later in life. A 71 year-old man presented with headache and lower extremity weakness. There was no evidence of skin lesions to suggest a recent zoster infection. The patient had a history of multiple myeloma diagnosed 2 years earlier, treated with chemotherapy and autologous stem cell transplant. Antimicrobial prophylaxis was discontinued 12 months after the transplant. MRI of the brain demonstrated areas of T2/fluid attenuated inversion recovery hyperintensity in bilateral cerebral white matter and MRI of the spine demonstrated enhancement along the cauda equine. Cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis and VZV DNA was detected by PCR in the CSF. The patient was treated with 8 weeks of antiviral therapy with complete resolution of symptoms. VZV should be considered in patients with haematopoietic stem cell transplantation presenting with similar neurological manifestations even in the absence of dermatological signs. PMID- 25527691 TI - Demand management: an audit of chemical pathology test rejections by an electronic gate-keeping system at an academic hospital in Cape Town. AB - BACKGROUND: Demand management is an area of laboratory activity, which is becoming increasingly important. Within the health-care system, demand management can be defined as the use of health resources to maximise its utility. Tygerberg Hospital has introduced an electronic gate-keeping system. Chemistry tests which generate the highest cost are subjected to this system and may be automatically rejected according to a set of rules. This study aimed: (1) to identify the number of chemistry tests rejected by the eGK; (2) to identify which of these rejected tests were subsequently restored and (3) to assess the impact of rejections on clinical outcome and cost-saving. METHODS: A retrospective audit was conducted to determine the number of chemistry tests rejected and subsequently restored over a 6-month period. The case-notes of patients for whom requested tests previously rejected had been restored were randomly selected and investigated to assess clinical impact. Any cost-saving was calculated. RESULTS: A total of 68,480 tests were subjected to gate-keeping, and 4605 tests (6.7%) were rejected while 679 (14.7%) of these were restored by the requestor phoning the laboratory after obtaining authorisation. After examining a subset of clinical notes it was found that in most cases (80%), patient care was unaffected. The total cost saved was L 25,387. CONCLUSIONS: The majority of the rejected tests were unnecessary and following rejection, real savings were made. Electronic gate-keeping is a simple, effective and sustainable method of demand management. PMID- 25527692 TI - Visual impairment due to retinopathy of prematurity (ROP) in New Zealand: a 22 year review. AB - AIM: To evaluate retinopathy of prematurity (ROP)-related visual impairment in New Zealand children. METHODS: 22-year retrospective review of medical records of children with moderate to severe visual impairment registered with the Blind and Low Vision Education Network New Zealand. The cohort was divided into two periods (1991-2004; 2005-2012) for analysis. RESULTS: 232 children with ROP were treated in the study period (109 in period 1, 123 in period 2). 36 children, 63.9% of whom were of male sex, were identified with subsequent significant visual impairment (27 in period 1, 9 in period 2). The incidence of new cases of visual impairment from ROP declined from 271.6 infants/100 000 live very preterm births per annum (period 1) to 146.1 per annum (period 2). Mean gestational age and mean birth weight were comparable between the two study periods. 75% of children with visual impairment from ROP received treatment for their condition (period 1, 74.1%; period 2, 77.8%) and modalities used changed significantly over time. The modal visual outcome overall was Snellen visual acuity <6/18-6/60 (55.6%) (period 1, 51.9%; period 2, 66.7%). The proportion of children with no light perception bilaterally decreased over time (period 1, 3.7%; period 2, 0%). CONCLUSIONS: There has been a reduction in the incidence of infants with significant visual impairment from ROP over time in New Zealand, likely due to progress in clinical management of ROP. Our study suggests the current ROP screening criteria of <31 weeks' gestation or <1250 g are of sufficient breadth. PMID- 25527693 TI - Morphological characteristics of conjunctival squamous papillomas in relation to human papillomavirus infection. AB - OBJECTIVE: To determine the prevalence of a broad spectrum of human papillomavirus (HPV) types in conjunctival papillomas and a possible difference in clinical and histopathological presentation of HPV-positive and HPV-negative papillomas. METHODS: Formalin-fixed, paraffin-embedded papilloma tissue specimens obtained from 25 patients were analysed using six different PCR-based methods targeting 87 HPV types from four different papillomavirus (PV) genera: alpha-PV, beta-PV, gamma-PV and u-PV, and in situ hybridisation for HPV-6/HPV-11. Slides were reviewed for pedunculated or sessile growth, the presence of goblet cells, keratinising or non-keratinising epithelium, elastosis, atypia and koilocytes. RESULTS: alpha-PV types HPV-6 and HPV-11 were detected in 19/25 (76%) conjunctival papilloma tissue specimens, 9 (47%) of which were also HPV-6/HPV-11 positive with in situ hybridisation. Six different beta-PV types-HPV-9, HPV-12, HPV-20, HPV-21, HPV-22, HPV-24-were additionally detected in four cases, all of which were also HPV-6/HPV-11 positive. No gamma-PVs or u-PVs were found in any of the tested tissues samples. Extralimbal location (p=0.021), presence of goblet cells (p=0.005), non-keratinising squamous epithelium (p=0.005), and absence of elastosis (p=0.005) were associated with the presence of HPV-6/HPV-11. CONCLUSIONS: We demonstrated that certain clinical and histological features are more frequently associated with HPV infection and that HPV genera other than alpha-PV are most probably not significant factors in conjunctival papilloma occurrence. PMID- 25527694 TI - Mutation spectrum of CYP1B1 in Chinese patients with primary open-angle glaucoma. AB - PURPOSE: The CYP1B1 gene has been shown to be related to primary open-angle glaucoma (POAG). This study aimed to identify the mutation profile of CYP1B1 in Chinese individuals with POAG. METHODS: The study included 416 unrelated cases diagnosed as POAG by standard ophthalmological examinations, and 657 unrelated healthy controls in a Chinese population. Genomic DNA was collected from peripheral blood of all the participants. The coding sequence of CYP1B1 was amplified by PCR from genomic DNA, followed by direct DNA sequencing. RESULTS: Among 416 patients with POAG, 13 missense mutations, including nine reported mutations and four novel mutations (p.P93S, p.R259C, p.A295T, p.L475P), were detected in 25 patients. All these mutations were found as heterozygotes and the reported mutations have been previously found in primary congenital glaucoma and/or POAG patients. Three of them (p.L107V, p.E229K, p.V320L) were also found in healthy controls. In addition, six previously reported single nucleotide polymorphisms (p.R48G, p.A119S, p.V243V, p.V432L, p.D449D, p.N453S) were also observed in POAG patients and controls, and they showed no obvious frequency difference between patients and controls. CONCLUSIONS: This study provides a mutation spectrum of CYP1B1 resulting in POAG development in a Chinese population, which may demonstrate an involvement of the gene in a proportion of subjects with POAG and help to improve our understanding of the pathogenesis of CYP1B1-associated POAG. PMID- 25527695 TI - Spontaneous long-term course of persistent peripheral graft detachments after Descemet's membrane endothelial keratoplasty. AB - BACKGROUND: Peripheral corneal graft detachment after Descemet's membrane endothelial keratoplasty (DMEK) is a frequently occurring postoperative complication. The natural course of these persistent peripheral detachments over time is not known. METHODS: 166 patients were surveyed by slit-lamp-adapted optical coherence tomography (SL-OCT) directly after surgery, during first postoperative week, 4 weeks, 3, 6 and 12 months, postoperatively. Patients with a persistent peripheral graft detachment 4 weeks after DMEK (n=16) were observed for their spontaneous course up to 1 year postoperatively. RESULTS: Persistent graft detachments could be characterised into two phenotypes: peripheral roll (n=11; 69%) and laminar detachment (n=5; 31%). Maximal length of the detachment did not change in peripheral rolls during observation period (12 months vs 4 weeks, 578+/-122 um vs 593+/-106 um, p=0.74), whereas laminar detachments spontaneously attached to the host's stroma (12 months vs 4 weeks, 0 um vs 1088+/ 295 um, p<=0.001). Central corneal thickness and (peripheral) corneal thickness above the detached area did not significantly change in either group. CONCLUSIONS: Persistent peripheral graft detachments after DMEK occurred in 10% of patients and had two distinct OCT-phenotypes. Peripheral rolls did not change during the first 12 months, postoperatively. By contrast, peripheral laminar detachments attached spontaneously even months after surgery. Corneal thickness reduction was only observed above peripheral laminar detachment, but not above peripheral rolls. PMID- 25527696 TI - Outcomes of epiretinal membrane surgery in highly myopic eyes: a case-control study. AB - AIMS: To evaluate the outcomes of epiretinal membrane (ERM) surgery in highly myopic eyes and to compare them with those from non-highly myopic eyes. METHODS: Retrospective nested case-control study from a cohort of 1776 consecutive patients (1776 eyes) who underwent surgery for ERM. Fifty-seven highly myopic eyes (with axial length longer than 26 mm) were included in the study group and were matched for preoperative visual acuity and duration of symptoms with 57 non highly myopic control eyes selected from the same cohort. The best-corrected visual acuity (BCVA), the relationship between axial length and visual improvement, the central macular thickness (CMT) and the surgical complications were analysed. RESULTS: The mean axial length was 27.3+/-1.1 mm in highly myopic eyes and 23.1+/-1 mm in controls (p<0.001). At the 1-year final examination, the mean BCVA significantly improved from 0.62+/-0.23 logarithm of minimal angle of resolution (logMAR) to 0.27+/-0.21 logMAR in the study group (p<0.001) and from 0.61+/-0.22 logMAR to 0.25+/-0.15 logMAR in the control group (p<0.001). Similarly, the mean CMT significantly decreased in both groups (p<0.001). The two groups did not differ statistically in terms of visual and anatomical changes as well as surgical complications. There was no significant correlation between axial length and visual recovery. CONCLUSIONS: ERM surgery resulted in similar anatomical and functional outcomes in both groups. Longer axial length does not seem to affect visual improvement and the complication rate. PMID- 25527697 TI - Physical activity and survival among men diagnosed with prostate cancer. AB - BACKGROUND: Few studies have investigated the association between post-diagnosis physical activity and mortality among men diagnosed with prostate cancer. The aim of this study was to investigate the effect of physical activity after a prostate cancer diagnosis on both overall and prostate cancer-specific mortality in a large cohort. METHODS: Data from 4,623 men diagnosed with localized prostate cancer 1997-2002 and followed-up until 2012 were analyzed. HRs with 95% confidence intervals (CI) were estimated using Cox proportional hazards models to examine the association between post-diagnosis recreational MET-h/d, time spent walking/bicycling, performing household work or exercising, and time to overall and prostate cancer-specific death. All models were adjusted for potential confounders. RESULTS: During the follow-up, 561 deaths of any cause and 194 deaths from prostate cancer occurred. Statistically significantly lower overall mortality rates were found among men engaged in >=5 recreational MET-h/d (HR, 0.63; 95% CI, 0.52-0.77), walking/bicycling >=20 min/d (HR, 0.70; 95% CI, 0.57 0.86), performing household work >=1 h/d (HR, 0.71; 95% CI, 0.59-0.86), or exercising >=1 h/wk (HR, 0.74; 95% CI, 0.61-0.90), compared with less active men within each activity type. For prostate cancer-specific mortality, statistically significantly lower mortality rates were seen among men walking/bicycling >=20 min/d (HR, 0.61; 95% CI, 0.43-0.87) or exercising >=1 h/wk (HR, 0.68; 95% CI, 0.48-0.94). CONCLUSIONS: Higher levels of physical activity were associated with reduced rates of overall and prostate cancer-specific mortality. IMPACT: Our study further strengthens previous results indicating beneficial effects of physical activity on survival among men with prostate cancer. PMID- 25527698 TI - Cardiac sarcoidosis: epidemiology, characteristics, and outcome over 25 years in a nationwide study. AB - BACKGROUND: This study was designed to assess the epidemiology, characteristics, and outcome of cardiac sarcoidosis (CS) in Finland. METHODS AND RESULTS: We identified in retrospect all adult (>18 years of age) patients diagnosed with histologically confirmed CS in Finland between 1988 and 2012. A total of 110 patients (71 women) 51+/-9 years of age (mean+/-SD) were found and followed up for outcome events to the end of 2013. The annual detection rate of CS increased >20-fold during the 25-year period, reaching 0.31 in 1*10(5) adults between 2008 and 2012. The 2012 prevalence of CS was 2.2 in 1*10(5). Nearly two thirds of patients had clinically isolated CS. Altogether, 102 of the 110 patients received immunosuppressive therapy, and 56 received an intracardiac defibrillator. Left ventricular function was impaired (ejection fraction <50%) in 65 patients (59%) at diagnosis and showed no overall change over 12 months of steroid therapy. During follow-up (median, 6.6 years), 10 patients died of a cardiac cause, 11 patients underwent transplantation, and another 11 patients suffered an aborted sudden cardiac death. The Kaplan-Meier estimates for 1-, 5-, and 10-year transplantation-free cardiac survival were 97%, 90%, and 83%, respectively. Heart failure at presentation predicted poor outcome (log-rank P=0.0001) with a 10-year transplantation-free cardiac survival of only 53%. CONCLUSIONS: The detection rate of CS has increased markedly in Finland over the last 25 years. With current therapy, the prognosis of CS appears better than generally considered, but patients presenting with heart failure still have poor long-term outcome. PMID- 25527699 TI - Endocarditis pathogen promotes vegetation formation by inducing intravascular neutrophil extracellular traps through activated platelets. AB - BACKGROUND: Endocarditis-inducing streptococci form multilayered biofilms in complex with aggregated platelets on injured heart valves, but the host factors that interconnect and entrap these bacteria-platelet aggregates to promote vegetation formation were unclear. METHODS AND RESULTS: In a Streptococcus mutans endocarditis rat model, we identified layers of neutrophil extracellular traps interconnecting and entrapping bacteria-platelet aggregates inside vegetation that could be reduced significantly in size along with diminished colonizing bacteria by prophylaxis with intravascular DNase I alone. The combination of activated platelets and specific immunoglobulin G-adsorbed bacteria are required to induce the formation of neutrophil extracellular traps through multiple activation pathways. Bacteria play key roles in coordinating the signaling through spleen tyrosine kinase, Src family kinases, phosphatidylinositol-3 kinase, and p38 mitogen-activated protein kinase pathways to upregulate the expression of P-selectin in platelets, while inducing reactive oxygen species dependent citrullination in the arm of neutrophils. Neutrophil extracellular traps in turn serve as the scaffold to further enhance and entrap bacteria platelet aggregate formation and expansion. CONCLUSIONS: Neutrophil extracellular traps promote and expand vegetation formation through enhancing and entrapping bacteria-platelet aggregates on the injured heart valves. PMID- 25527700 TI - Proteasome-mediated reduction in proapoptotic molecule Bim renders CD4+CD28null T cells resistant to apoptosis in acute coronary syndrome. AB - BACKGROUND: The number of CD4(+)CD28(null) (CD28(null)) T cells, a unique subset of T lymphocytes with proinflammatory and cell-lytic phenotype, increases markedly in patients with acute coronary syndrome (ACS). ACS patients harboring high numbers of CD28(null) T cells have increased risk of recurrent severe acute coronary events and unfavorable prognosis. The mechanisms that govern the increase in CD28(null) T cells in ACS remain elusive. We investigated whether apoptosis pathways regulating T-cell homeostasis are perturbed in CD28(null) T cells in ACS. METHODS AND RESULTS: We found that CD28(null) T cells in ACS were resistant to apoptosis induction via Fas-ligation or ceramide. This was attributable to a dramatic reduction in proapoptotic molecules Bim, Bax, and Fas in CD28(null) T cells, whereas antiapoptotic molecules Bcl-2 and Bcl-xL were similar in CD28(null) and CD28(+) T cells. We also show that Bim is phosphorylated in CD28(null) T cells and degraded by the proteasome. Moreover, we demonstrate for the first time that proteasomal inhibition restores the apoptosis sensitivity of CD28(null) T cells in ACS. CONCLUSIONS: We show that CD28(null) T cells in ACS harbor marked defects in molecules that regulate T-cell apoptosis, which tips the balance in favor of antiapoptotic signals and endows these cells with resistance to apoptosis. We demonstrate that the inhibition of proteasomal activity allows CD28(null) T cells to regain sensitivity to apoptosis. A better understanding of the molecular switches that control the apoptosis sensitivity of CD28(null) T cells may reveal novel strategies for targeted elimination of these T cells in ACS patients. PMID- 25527702 TI - Simultaneous Determination of 10 Bioactive Components of Lophatherum gracile Brongn by HPLC-DAD. AB - A high-performance liquid chromatography method coupled with diode array detection (HPLC-DAD) was developed for simultaneous determination of two coumarins and eight flavonoids in Lophatherum gracile Brongn (Gramineae), namely 5-O-coumaroylquinic acid (i), 4-O-coumaroylquinic acid (ii), luteolin 6-C-beta-d galactopyranosiduronic acid (1->2)-beta-d-glucopyranoside (iii), 7-O-beta-d glucopyranosyl-6-C-alpha-l-arabinopy ranoside (iv), isoorientin (v), swertiajaponin (vi), luteolin 6-C-beta-d-galactopyranosiduronic acid (1->2)-alpha l-arabinopyranoside (vii), Saponaretin (viii), swertisin (ix) and apigenin 6-C beta-d-galactopyranosiduronic acid (1->2)-alpha-l-arabinopyranoside (x). The analysis was performed on Cosmosil MS-IIII C18 column (250 * 4.6 mm, 5 um) with gradient elution of 0.1% aqueous acetic acid and acetonitrile. The detection wavelength was 330 nm. The developed method was able to determine the bioactive compounds with excellent resolution, precision and recovery. The validated method was successfully applied for the analysis of the 10 bioactive compounds in n samples from different cultivated regions. The results indicated that the developed method can be used as a suitable quality control method for L. gracile. PMID- 25527703 TI - Early prediction of life-threatening arrhythmias in non-ST elevation myocardial infarction--does it change clinical practice? PMID- 25527701 TI - What can crystal structures of aminergic receptors tell us about designing subtype-selective ligands? AB - G protein-coupled receptors (GPCRs) are integral membrane proteins that represent an important class of drug targets. In particular, aminergic GPCRs interact with a significant portion of drugs currently on the market. However, most drugs that target these receptors are associated with undesirable side effects, which are due in part to promiscuous interactions with close homologs of the intended target receptors. Here, based on a systematic analysis of all 37 of the currently available high-resolution crystal structures of aminergic GPCRs, we review structural elements that contribute to and can be exploited for designing subtype selective compounds. We describe the roles of secondary binding pockets (SBPs), as well as differences in ligand entry pathways to the orthosteric binding site, in determining selectivity. In addition, using the available crystal structures, we have identified conformational changes in the SBPs that are associated with receptor activation and explore the implications of these changes for the rational development of selective ligands with tailored efficacy. PMID- 25527704 TI - Author response. PMID- 25527705 TI - Myths of exercise induced right ventricular injury: the bright side of the moon. PMID- 25527706 TI - Long-term risk of upper gastrointestinal hemorrhage after advanced AKI. AB - BACKGROUND AND OBJECTIVES: There are few reports on temporary dialysis-requiring AKI as a risk factor for future upper gastrointestinal bleeding (UGIB). This study sought to explore the long-term association between dialysis-requiring AKI and UGIB. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This nationwide cohort study used data from the Taiwan National Health Insurance Research Database. Patients who recovered from dialysis-requiring AKI and matched controls were selected from hospitalized patients age >=18 years between 1998 and 2006. The cumulative incidences of long-term de novo UGIB were calculated, and the risk factors of UGIB and mortality were identified using time-varying Cox proportional hazard models adjusted for subsequent CKD and ESRD after AKI. RESULTS: A total of 4565 AKI-recovery patients and the same number of matched patients without AKI were analyzed. After a median follow-up time of 2.33 years (interquartile range, 0.97-4.81 years), the incidence rates of UGIB were 50 (by stringent criterion) and 69 (by lenient criterion) per 1000 patient-years in the AKI-recovery group and 31 (by stringent criterion) and 48 (by lenient criterion) per 1000 patient years in the non-AKI group (both P<0.001). When compared with patients in the non AKI group, the multivariate hazard ratio (HR) for UGIB was 1.30 (95% confidence interval [95% CI], 1.14 to 1.48) for dialysis-requiring AKI, 1.83 (95% CI, 1.53 to 2.20) for time-varying CKD, and 2.31 (95% CI, 1.92 to 2.79) for time-varying ESRD (all P<0.001). Finally, the risk for long-term mortality increased after UGIB (HR, 1.24; 95% CI, 1.12 to 1.38) and dialysis-requiring AKI (HR, 1.66; 95% CI, 1.54 to 1.78). CONCLUSIONS: Recovery from dialysis-requiring AKI was associated with future UGIB and mortality. PMID- 25527708 TI - Genetic perturbation of the maize methylome. AB - DNA methylation can play important roles in the regulation of transposable elements and genes. A collection of mutant alleles for 11 maize (Zea mays) genes predicted to play roles in controlling DNA methylation were isolated through forward- or reverse-genetic approaches. Low-coverage whole-genome bisulfite sequencing and high-coverage sequence-capture bisulfite sequencing were applied to mutant lines to determine context- and locus-specific effects of these mutations on DNA methylation profiles. Plants containing mutant alleles for components of the RNA-directed DNA methylation pathway exhibit loss of CHH methylation at many loci as well as CG and CHG methylation at a small number of loci. Plants containing loss-of-function alleles for chromomethylase (CMT) genes exhibit strong genome-wide reductions in CHG methylation and some locus-specific loss of CHH methylation. In an attempt to identify stocks with stronger reductions in DNA methylation levels than provided by single gene mutations, we performed crosses to create double mutants for the maize CMT3 orthologs, Zmet2 and Zmet5, and for the maize DDM1 orthologs, Chr101 and Chr106. While loss-of function alleles are viable as single gene mutants, the double mutants were not recovered, suggesting that severe perturbations of the maize methylome may have stronger deleterious phenotypic effects than in Arabidopsis thaliana. PMID- 25527709 TI - Pregnane X receptor modulates the inflammatory response in primary cultures of hepatocytes. AB - Bacterial sepsis is characterized by a rapid increase in the expression of inflammatory mediators to initiate the acute phase response in liver. Inflammatory mediator release is counterbalanced by the coordinated expression of anti-inflammatory molecules such as interleukin 1 receptor antagonist (IL1-Ra) through time. This study determined whether activation of pregnane X receptor (PXR, NR1I2) alters the lipopolysaccharide (LPS)-inducible gene expression program in primary cultures of hepatocytes (PCHs). Preactivation of PXR for 24 hours in PCHs isolated from wild-type mice suppressed the subsequent LPS inducible expression of the key inflammatory mediators interleukin 1beta (IL 1beta), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNFalpha) but not in PCHs isolated from Pxr-null (PXR-knockout [KO]) mice. Basal expression of key inflammatory cytokines was elevated in PCHs from PXR-KO mice. Stimulation of PCHs from PXR-KO mice with LPS alone produced enhanced levels of IL-1beta when compared with wild-type mice. Experiments performed using PCHs from both humanized-PXR transgenic mice as well as human donors indicate that prolonged activation of PXR produces an increased secretion of IL1-Ra from cells through time. Our data reveal a working model that describes a pivotal role for PXR in both inhibiting as well as in resolving the inflammatory response in hepatocytes. Understanding the molecular details of how PXR is converted from a positive regulator of drug-metabolizing enzymes into a transcriptional suppressor of inflammation in liver will provide new pharmacologic strategies for modulating inflammatory-related diseases in the liver and intestine. PMID- 25527707 TI - The root hair "infectome" of Medicago truncatula uncovers changes in cell cycle genes and reveals a requirement for Auxin signaling in rhizobial infection. AB - Nitrogen-fixing rhizobia colonize legume roots via plant-made intracellular infection threads. Genetics has identified some genes involved but has not provided sufficient detail to understand requirements for infection thread development. Therefore, we transcriptionally profiled Medicago truncatula root hairs prior to and during the initial stages of infection. This revealed changes in the responses to plant hormones, most notably auxin, strigolactone, gibberellic acid, and brassinosteroids. Several auxin responsive genes, including the ortholog of Arabidopsis thaliana Auxin Response Factor 16, were induced at infection sites and in nodule primordia, and mutation of ARF16a reduced rhizobial infection. Associated with the induction of auxin signaling genes, there was increased expression of cell cycle genes including an A-type cyclin and a subunit of the anaphase promoting complex. There was also induction of several chalcone O methyltransferases involved in the synthesis of an inducer of Sinorhizobium meliloti nod genes, as well as a gene associated with Nod factor degradation, suggesting both positive and negative feedback loops that control Nod factor levels during rhizobial infection. We conclude that the onset of infection is associated with reactivation of the cell cycle as well as increased expression of genes required for hormone and flavonoid biosynthesis and that the regulation of auxin signaling is necessary for initiation of rhizobial infection threads. PMID- 25527710 TI - HIV-1 reprograms the migration of macrophages. AB - Macrophages are motile leukocytes, targeted by HIV-1, thought to play a critical role in host dissemination of the virus. However, whether infection impacts their migration capacity remains unknown. We show that 2-dimensional migration and the 3-dimensional (3D) amoeboid migration mode of HIV-1-infected human monocyte derived macrophages were inhibited, whereas the 3D mesenchymal migration was enhanced. The viral protein Nef was necessary and sufficient for all HIV-1 mediated effects on migration. In Nef transgenic mice, tissue infiltration of macrophages was increased in a tumor model and in several tissues at steady state, suggesting a dominant role for mesenchymal migration in vivo. The mesenchymal motility involves matrix proteolysis and podosomes, cell structures constitutive of monocyte-derived cells. Focusing on the mechanisms used by HIV-1 Nef to control the mesenchymal migration, we show that the stability, size, and proteolytic function of podosomes are increased via the phagocyte-specific kinase Hck and Wiskott-Aldrich syndrome protein (WASP), 2 major regulators of podosomes. In conclusion, HIV-1 reprograms macrophage migration, which likely explains macrophage accumulation in several patient tissues, which is a key step for virus spreading and pathogenesis. Moreover, Nef points out podosomes and the Hck/WASP signaling pathway as good candidates to control tissue infiltration of macrophages, a detrimental phenomenon in several diseases. PMID- 25527711 TI - FDG PET-CT in follicular lymphoma: a case-based evidence review. PMID- 25527712 TI - Helping people with schizophrenia to quit smoking. PMID- 25527713 TI - NHS regulator delays inspections as it struggles to fill posts in tougher regime. PMID- 25527714 TI - Uncovering male and female experiences of irritable bowel syndrome. PMID- 25527715 TI - Gibberellins interfere with symbiosis signaling and gene expression and alter colonization by arbuscular mycorrhizal fungi in Lotus japonicus. AB - Arbuscular mycorrhiza is a mutualistic plant-fungus interaction that confers great advantages for plant growth. Arbuscular mycorrhizal (AM) fungi enter the host root and form symbiotic structures that facilitate nutrient supplies between the symbionts. The gibberellins (GAs) are phytohormones known to inhibit AM fungal infection. However, our transcriptome analysis and phytohormone quantification revealed GA accumulation in the roots of Lotus japonicus infected with AM fungi, suggesting that de novo GA synthesis plays a role in arbuscular mycorrhiza development. We found pleiotropic effects of GAs on the AM fungal infection. In particular, the morphology of AM fungal colonization was drastically altered by the status of GA signaling in the host root. Exogenous GA treatment inhibited AM hyphal entry into the host root and suppressed the expression of Reduced Arbuscular Mycorrhization1 (RAM1) and RAM2 homologs that function in hyphal entry and arbuscule formation. On the other hand, inhibition of GA biosynthesis or suppression of GA signaling also affected arbuscular mycorrhiza development in the host root. Low-GA conditions suppressed arbuscular mycorrhiza-induced subtilisin-like serine protease1 (SbtM1) expression that is required for AM fungal colonization and reduced hyphal branching in the host root. The reduced hyphal branching and SbtM1 expression caused by the inhibition of GA biosynthesis were recovered by GA treatment, supporting the theory that insufficient GA signaling causes the inhibitory effects on arbuscular mycorrhiza development. Most studies have focused on the negative role of GA signaling, whereas our study demonstrates that GA signaling also positively interacts with symbiotic responses and promotes AM colonization of the host root. PMID- 25527717 TI - Inability to balance on one leg reflects risk of brain bleed, study shows. PMID- 25527716 TI - Open All Night Long: the dark side of stomatal control. PMID- 25527719 TI - Reply to Abatzoglou et al.: Atmospheric controls on northwest United States air temperatures, 1948-2012. PMID- 25527718 TI - RORgammat-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells. AB - The nuclear hormone receptor retinoic acid-related orphan receptor gamma t (RORgammat) is a transcription factor (TF) specific to TH17 cells that produce interleukin (IL)-17 and have been implicated in a wide range of autoimmunity. Here, we developed a novel therapeutic strategy to modulate the functions of RORgammat using cell-transducible form of transcription modulation domain of RORgammat (tRORgammat-TMD), which can be delivered effectively into the nucleus of cells and into the central nerve system (CNS). tRORgammat-TMD specifically inhibited TH17-related cytokines induced by RORgammat, thereby suppressing the differentiation of naive T cells into TH17, but not into TH1, TH2, or Treg cells. tRORgammat-TMD injected into experimental autoimmune encephalomyelitis (EAE) animal model can be delivered effectively in the splenic CD4(+) T cells and spinal cord-infiltrating CD4(+) T cells, and suppress the functions of TH17 cells. The clinical severity and incidence of EAE were ameliorated by tRORgammat TMD in preventive and therapeutic manner, and significant reduction of both infiltrating CD4(+) IL-17(+) T cells and inflammatory cells into the CNS was observed. As a result, the number of spinal cord demyelination was also reduced after tRORgammat-TMD treatment. With the same proof of concept, tTbet-TMD specifically blocking TH1 differentiation improved the clinical incidence of rheumatoid arthritis (RA). Therefore, tRORgammat-TMD and tTbet-TMD can be novel therapeutic reagents with the natural specificity for the treatment of inflammatory diseases associated with TH17 or TH1. This strategy can be applied to treat various diseases where a specific transcription factor has a key role in pathogenesis. PMID- 25527720 TI - Questionable evidence of natural warming of the northwestern United States. PMID- 25527721 TI - The comet assay: a heavenly method! AB - The contributions to this special issue of Mutagenesis have been selected to cover the main research areas served by the comet assay, namely genotoxicology, environmental toxicology, human biomonitoring and fundamental investigations into mechanisms of DNA damage and repair. Innovative methods are described, technical issues are explored, and guidelines are given for venturing into relatively new or unexploited areas of research. The popularity of the comet assay in a historical context is illustrated by a bibliometric survey. PMID- 25527722 TI - New developments in comet-FISH. AB - The comet assay combined with fluorescence in-situ hybridisation (FISH) is a powerful technique for comparative analyses of damage induction and repair in genomes and in specific DNA sequences within single cells. Recent advances in the methodology of comet-FISH will be considered here, with particular attention to the design and generation of fluorescent probes. In general, all the approaches must fulfil a few basic requirements: the probes should be no longer than ~300 nucleotides in length (single or double stranded) to be able to penetrate the gel in which the target genomic DNA is embedded, they should be sequence-specific, and their signal should be detectable and distinct from the background fluorescence and the dye used to stain the DNA. PMID- 25527723 TI - Micropatterned comet assay enables high throughput and sensitive DNA damage quantification. AB - The single cell gel electrophoresis assay, also known as the comet assay, is a versatile method for measuring many classes of DNA damage, including base damage, abasic sites, single strand breaks and double strand breaks. However, limited throughput and difficulties with reproducibility have limited its utility, particularly for clinical and epidemiological studies. To address these limitations, we created a microarray comet assay. The use of a micrometer scale array of cells increases the number of analysable comets per square centimetre and enables automated imaging and analysis. In addition, the platform is compatible with standard 24- and 96-well plate formats. Here, we have assessed the consistency and sensitivity of the microarray comet assay. We showed that the linear detection range for H2O2-induced DNA damage in human lymphoblastoid cells is between 30 and 100 MUM, and that within this range, inter-sample coefficient of variance was between 5 and 10%. Importantly, only 20 comets were required to detect a statistically significant induction of DNA damage for doses within the linear range. We also evaluated sample-to-sample and experiment-to-experiment variation and found that for both conditions, the coefficient of variation was lower than what has been reported for the traditional comet assay. Finally, we also show that the assay can be performed using a 4* objective (rather than the standard 10* objective for the traditional assay). This adjustment combined with the microarray format makes it possible to capture more than 50 analysable comets in a single image, which can then be automatically analysed using in-house software. Overall, throughput is increased more than 100-fold compared to the traditional assay. Together, the results presented here demonstrate key advances in comet assay technology that improve the throughput, sensitivity, and robustness, thus enabling larger scale clinical and epidemiological studies. PMID- 25527724 TI - Does the duration of lysis affect the sensitivity of the in vitro alkaline comet assay? AB - The alkaline comet assay is now the method of choice for measuring different kinds of DNA damage in cells. Several attempts have been made to identify and evaluate the critical points affecting the comet assay outcome, highlighting the requirement of arriving at a standardised protocol in order to be able to compare the results obtained in different laboratories. However, reports on the effect of modifying the time of lysis are lacking. Here we tested different times of lysis (from no lysis to 1 week) in control HeLa cells and HeLa cells treated with different concentrations of methyl methanesulfonate (MMS) or H2O2. We also tested different times of lysis in the comet assay combined with formamidopyrimidine DNA glycosylase (FPG) in untreated and Ro 19-8022 plus light-treated HeLa cells. The same DNA damage levels were detected in the absence of lysis or after 1h of lysis when the standard comet assay was used to detect the MMS- and H2O2-induced lesions; the response increased when longer lysis was used, up to at least 1 week. When FPG was used, a minimum lysis period of 5 min was necessary to allow the enzyme to reach the DNA; the same DNA damage levels were detected after 5 min or 1h of lysis and the response increased up to 24h. In conclusion, the time of lysis can be varied depending on the sensitivity needed in both versions of the assay, and a constant time of lysis should be used if results from different experiments or laboratories are to be compared. PMID- 25527725 TI - Comparison of DNA damage by the comet assay in fresh versus cryopreserved peripheral blood mononuclear cells obtained following dietary intervention. AB - Endogenous and oxidatively induced DNA damage, as evaluated by the comet assay, are widely used as biomarkers of oxidative stress in numerous dietary intervention studies. This analysis can be performed on fresh peripheral blood mononuclear cells (PBMCs) or on cryopreserved cells. However, information pertaining to the effects of cryopreservation on DNA damage is often missing, and this may be crucial in studies in which samples are analysed before and after intervention. The purpose of this study was to compare DNA damage in fresh versus cryopreserved PBMCs obtained from subjects following a 6-week intervention with wild blueberry drink or placebo drink. Fresh and 12-month-stored PBMCs were analysed for formamidopyrimidine-DNA glycosylase (FPG)-sensitive sites and H2O2 induced DNA damage. The levels of FPG-sensitive sites were significantly higher in the cryopreserved compared with the fresh cells (P < 0.001), while H2O2 induced DNA damage was significantly lower after storage (P < 0.001). Both the fresh and cryopreserved samples showed reductions in FPG-sensitive sites following the wild blueberry treatment (fresh PBMCs: from 12.50 +/- 5.61% to 9.62 +/- 3.52%, P = 0.039; cryopreserved PBMCs: from 22.7 +/- 6.1% to 19.1 +/- 7.0%, P = 0.012). In contrast, the decrease in H2O2-induced DNA damage observed in the cryopreserved cells masked the protective effect of the wild blueberry drink documented in the fresh samples (fresh PBMCs: from 44.73 +/- 7.46% to 36.34 +/- 9.27%, P < 0.001; cryopreserved PBMCs: from 25.8 +/- 4.6% to 23.9 +/- 4.6%, P = 0.414). In conclusion, our results suggest that FPG-sensitive sites, and more importantly, H2O2-induced DNA damage could be significantly modified following the long-term storage of samples obtained from individuals participating in a dietary intervention study. Because storage may affect the assessment of the protective role of diet against DNA damage as a marker of oxidative stress, further research is needed. PMID- 25527726 TI - Recommendations for increasing alkaline comet assay reliability in plants. AB - In plants, an increasing interest for the comet assay was shown in the last decade. This versatile technique appears to be promising to detect the genotoxic effect of pollutants and to monitor the environment. However, the lack of a standardised protocol and the low throughput of the assay limit its use in plants. The aims of this paper are to identify key factors affecting comet assay performance and to improve its reliability and reproducibility. We examined the effect of varying several parameters on four different plant species: broad bean (Vicia faba), white clover (Trifolium repens), English ryegrass (Lolium perenne) and miscanthus (Miscanthus x giganteus). The influence of both internal (different nucleus isolation methods, presence or absence of filtration and lysis steps) and external (room temperature, light intensity) parameters were evaluated. Results clearly indicate that short chopping is more efficient to isolate nuclei than the standard slicing method. Filtration and lysis steps were shown to be unnecessary and thus should be skipped. Data also demonstrate that high room temperatures and light could induce DNA damage in isolated nuclei. Calibration tests with H2O2 or ethyl methanesulfonate revealed that a special attention should be paid to plant growing stage, leaf position and exposure duration. PMID- 25527727 TI - DNA repair after X-irradiation: lessons from plants. AB - The effects of low-dose radiation causing DNA damage continue to be subjects of interest. Problems with existing approaches to low-dose DNA damage are that single-strand breaks (the predominant radiation-induced lesion) are very rapidly repaired and that results using current methods for measuring DNA damage can be difficult to interpret. As a novel approach, we conducted studies using plants (rye grass and the model plant Arabidopsis) exposed to X-rays and used the alkaline comet assay to measure DNA damage and repair after exposures. Consistent with previous studies, we detected so-called 'rapid' and 'slow' phases of DNA repair after acute exposures of 5 and 15 Gy. After exposures corresponding to 2 Gy and lower, 'rapid' repair was so fast that it was difficult to detect. We also found that the so-called 'slow' phase in both plants actually consisted of two components; an initial period of negligible repair lasting 80-120 min followed by a period of rapid repair lasting <30 min. Using Arabidopsis mutants homozygous for both ATM and BRCA1, we found that both of these genes are required for DNA repair during the 3-h period of our experiments, indicating that the 'slow' phase involves a homologous repair (HR) of double-strand breaks and clustered single strand breaks. The lag of repair in the 'slow' phase presumably involves induction of expression of genes involved in HR repair such as BRCA1 and RAD51. PMID- 25527728 TI - Experiences with the in vivo and in vitro comet assay in regulatory testing. AB - The in vivo comet assay has recently been implemented into regulatory genotoxicity testing of pharmaceuticals with inclusion into the ICH S2R1 guidance. Regulatory genotoxicity testing aims to detect DNA alterations in form of gene mutations, larger scale chromosomal damage and recombination and aneuploidy. The ICH S2R1 guideline offers two options of standard batteries of tests for the detection of these endpoints. Both options start with an AMES assay and option 1 includes an in vitro mammalian cell assay and an in vivo micronucleus assay in rodent, whereas option 2 includes an in vivo micronucleus assay in bone marrow in rodent and a second in vivo assay in a second tissue with a second endpoint. The test recommended as second in vivo test is the comet assay in rat liver. The in vivo comet assay is considered as mature enough to ensure reliable detection of relevant in vivo genotoxicants in combination with the micronucleus test in bone marrow and the AMES assay. Although lots of research papers have been published using the in vitro comet assay, the in vitro version has not been implemented into official regulatory testing guidelines. A survey of the years 1999-2014 revealed 27 in vivo comet assays submitted to BfArM with market authorisation procedures, European and national advice procedures and clinical trial applications. In three procedures, in vitro comet assays had been submitted within the genetic toxicology packages. PMID- 25527729 TI - Effect of silver nanoparticles on mitogen-activated protein kinases activation: role of reactive oxygen species and implication in DNA damage. AB - Large quantities of engineered nanoparticles (NP), such as nanosilver (AgNP), have been widely applied, leading to an increased exposure and potential health concerns. Herein, we have examined the ability of AgNP to induce reactive oxygen species (ROS), their role in genotoxic effects and the involvement of mitogen activated protein kinases (MAPK). AgNP exposure induced ROS production in human epithelial embryonic cells which could be decreased by diphenyleneiodonium (DPI), an inhibitor of NADPH oxidases. Extracellular signal-regulated kinase (ERK) and c Jun N-terminal kinase (JNK) phosphorylation, induced by AgNP, was an early response but not sustained in time. Furthermore, JNK and ERK activation could be inhibited by both DPI and a free radicals scavenger N-acetyl cysteine. We also investigated the role of MAPK in the DNA damage. Using a modified comet assay for the specific detection of hOGG1 sensitive sites, we showed that AgNP induced DNA oxidation after 30-min treatment, whereas no response was observed after 2h. In conclusion, AgNP seem to induce DNA damage via a mechanism involving ROS formation. The oxidative DNA damage observed was transient, likely due to DNA repair; furthermore, higher damage was achieved upon inhibition of ERK activation by pre-treatment with U0126, suggesting a role for ERK in DNA damage repair. Activation of different MAPK might play an important role in the NP toxicity outcomes; understanding this process may be helpful for the identification of NP toxicity. PMID- 25527730 TI - Applications of the comet assay in particle toxicology: air pollution and engineered nanomaterials exposure. AB - Exposure to ambient air particles is associated with elevated levels of DNA strand breaks (SBs) and endonuclease III, formamidopyrimidine DNA glycosylase (FPG) and oxoguanine DNA glycosylase-sensitive sites in cell cultures, animals and humans. In both animals and cell cultures, increases in SB and in oxidatively damaged DNA are seen after exposure to a range of engineered nanomaterials (ENMs), including carbon black, carbon nanotubes, fullerene C60, ZnO, silver and gold. Exposure to TiO2 has generated mixed data with regard to SB and oxidatively damaged DNA in cell cultures. Nanosilica does not seem to be associated with generation of FPG-sensitive sites in cell cultures, while large differences in SB generation between studies have been noted. Single-dose airway exposure to nanosized carbon black and multi-walled carbon nanotubes in animal models seems to be associated with elevated DNA damage levels in lung tissue in comparison to similar exposure to TiO2 and fullerene C60. Oral exposure has been associated with augmented DNA damage levels in cells of internal organs, although the doses have been typically very high. Intraveneous and intraperitoneal injection of ENMs have shown contradictory results dependent on the type of ENM and dose in each set of experiments. In conclusion, the exposure to both combustion-derived particles and ENMs is associated with increased levels of DNA damage in the comet assay. Particle size, composition and crystal structure of ENM are considered important determinants of toxicity, whereas their combined contributions to genotoxicity in the comet assay are yet to be thoroughly investigated. PMID- 25527731 TI - Critical factors to be considered when testing nanomaterials for genotoxicity with the comet assay. AB - The comet assay is widely used to test the genotoxicity of engineered nanomaterials (ENMs) but outcomes may vary when results from different laboratories, or even within one laboratory, are compared. We address some basic methodological considerations, such as the importance of carrying out physico chemical characterisation of the ENMs in test-medium, performing uptake and cytotoxicity tests, and testing several genotoxicity-related endpoints. In this commentary, we discuss the different ways in which concentration of ENMs can be expressed, and stress the need to include appropriate controls and reference standards to monitor variation and avoid interference. Treatment conditions, including cell number, cell culture plate format and volume of treatment medium on the plate are crucial factors that may impact on results and thus should be kept constant within the study. PMID- 25527732 TI - The comet assay in Environmental Risk Assessment of marine pollutants: applications, assets and handicaps of surveying genotoxicity in non-model organisms. AB - Determining the genotoxic effects of pollutants has long been a priority in Environmental Risk Assessment (ERA) for coastal ecosystems, especially of complex areas such as estuaries and other confined waterbodies. The acknowledged link between DNA damage, mutagenicity and carcinogenicity to the exposure to certain toxicants has been responsible to the growing interest in determining the genotoxic effects of xenobiotics to wildlife as a measure of environmental risk. The comet assay, although widely employed in in vivo and in vitro toxicology, still holds many constraints in ERA, in large part owing to difficulties in obtaining conclusive cause-effect relationships from complex environments. Nevertheless, these challenges do not hinder the attempts to apply the alkaline comet assay on sentinel organisms, wild or subjected to bioassays in or ex situ (from fish to molluscs) as well to standardise protocols and establish general guidelines to the interpretation of findings. Fish have been regarded as an appealing subject due to the ease of performing the comet assay in whole blood. However, the application of the comet assay is becoming increasingly common in invertebrates (e.g. in molluscan haemocytes and solid tissues such as gills). Virtually all sorts of results have been obtained from the application of the comet assay in ERA (null, positive and inconclusive). However, it has become clear that interpreting DNA damage data from wild organisms is particularly challenging due to their ability to adapt to continuous environmental stressors, including toxicants. Also, the comet assay in non-model organisms for the purpose of ERA implies different constraints, assumptions and interpretation of findings, compared with the in vitro procedures from which most guidelines have been derived. This paper critically reviews the application of the comet assay in ERA, focusing on target organisms and tissues; protocol developments, case studies plus data handling and interpretation. PMID- 25527733 TI - Assessment of oxidative damage to DNA, transcriptional expression of key genes, lipid peroxidation and histopathological changes in carp Cyprinus carpio L. following exposure to chronic hypoxic and subsequent recovery in normoxic conditions. AB - In fish, a complex set of mechanisms deal with environmental stresses including hypoxia. In order to probe the hypothesis that hypoxia-induced stress could be manifested in varieties of pathways, a model species, mirror carp (Cyprinus carpio), were chronically exposed to hypoxic condition (dissolved oxygen level: 1.80 +/- 0.6 mg/l) for 21 days and subsequently allowed to recover under normoxic condition (dissolved oxygen level: 8.2 +/- 0.5 mg/l) for 7 days. At the end of these exposure periods, an integrated approach was applied to evaluate several endpoints at different levels of biological organisation. These included determination of (i) oxidative damage to DNA in erythrocytes (using modified comet assay), (ii) lipid peroxidation in liver samples by measuring the malondialdehyde production using the 2-thiobarbituric acid [i.e. thiobarbituric acid reactive substances (TBARS) assay] and (iii) histopathological changes in gills. In addition, transcriptional expression of hypoxia-inducible factor 1 alpha (HIF-1alpha) and genes involved in the repair of oxidative damage to DNA (i.e. ogg1) and base excision repair (i.e. xrcc1) using reverse transcription polymerase chain reaction in liver samples were also determined. The results suggested significantly enhanced expression of these genes in response to hypoxia compared to concurrent normoxic controls. While the expression of HIF-1alpha reverted to control values within 7 days exposure to normoxic condition (P < 0.05), the transcriptional expression of the two genes involved in DNA repair process remained significantly high under the recovery period, which complemented the induction of oxidative damage to DNA. Hypoxic groups showed significantly increased values for TBARS level (~2-fold) and histopathological changes in gill tissues compared to both normoxic and recovery groups. Overall, oxidative damage to DNA determined by modified comet assay reflected the observed biological responses in other tissues of the fish. Along with other parameters, this integrated experimental design further strengthens the applications of the comet assay as an important technique to assess stress-induced DNA damage in ecotoxicological studies. PMID- 25527734 TI - Cytotoxic and genotoxic responses of the RTgill-W1 fish cells in combination with the yeast oestrogen screen to determine the sediment quality of Lagos lagoon, Nigeria. AB - Economic advancements in developing countries have seen an increase in urbanisation and industrialisation with a rise in the levels of discharge of effluents and municipal waste into aquatic ecosystems. Unfortunately, aquatic environmental regulations in these countries are often rudimentary and the development of environmental monitoring programmes will help identify ecological risks. As an example, the current study assesses the pollution status of 11 sampling sites in Lagos lagoon, Nigeria. The organic solvent sediment extracts were assessed for cytotoxicity and genotoxicity in rainbow trout gill-W1 cells. The induction of oestrogenic activities using the yeast oestrogen screen was also determined. The sediments were analysed for polycyclic aromatic hydrocarbons (PAHs) and other contaminants (polychlorinated biphenyls, organochlorine and organophosphate pesticides). Only sediments from three sites were cytotoxic at both 25 and 12.5mg eQsed/ml using the Alamar Blue cell viability assay. The alkaline Comet assay showed that all sites caused significant DNA damage at 7 mg eQsed/ml; the extent of the damage was site specific. The measure of oxidative damage to DNA via the formamidopyrimidine DNA-glycosylase-modified Comet assay revealed similar results. Toxicity to yeast cells was observed in extracts from six sites; of the remaining sites, only two exhibited oestrogenic activity. There was no strong consistent relationship between sediment PAH concentrations and the cell toxicity endpoints. The dynamic nature of Lagos lagoon with its tides and freshwater inputs are suggested as factors that make it difficult to link the sources of pollution observed at each site with PAH levels and toxic endpoints. The study has demonstrated that the Comet assay is a sensitive endpoint to identify sediments that possess genotoxic contaminants, and this in vitro bioassay has the potential to be incorporated into an environmental monitoring framework for Lagos lagoon. PMID- 25527735 TI - Redox-linked effects of green tea on DNA damage and repair, and influence of microsatellite polymorphism in HMOX-1: results of a human intervention trial. AB - Green tea has many reported health benefits, including genoprotective and antioxidant effects, but green tea has pro-oxidant activity in vitro. A tea induced pro-oxidant shift that triggers cytoprotective adaptations has been postulated, but human data are lacking. We investigated effects on oxidation induced DNA damage and redox-linked cytoprotective factors, including 8 oxoguanine glycosylase (hOGG1) and heme oxygenase 1 (HMOX-1) in lymphocytes in a randomised, placebo-controlled, cross-over supplementation trial. hOGG1 catalyses the first step in base excision repair; increased HMOX-1 is a sign of cytoprotective response to pro-oxidant change. The influence of microsatellite polymorphisms in the HMOX-1 promoter region was also explored. Higher numbers of GT repeats [GT(n)] in this region reportedly diminish response to pro-oxidant change. Green tea [2 * 150 ml of 1% w/v tea/day (or water as control)] was taken for 12 weeks by 43 Type 2 diabetes subjects {20 with short [S/S; GT(n) < 25] and 23 with long [L/L; GT(n) >= 25]}. Fasting venous blood was collected before and after each treatment. The formamidopyrimidine DNA glycosylase-assisted comet assay was used to measure DNA damage in lymphocytes. For measuring hOGG1 activity, we used photo-damaged HeLa cells incubated with lymphocyte extracts from test subjects, in combination with the comet assay. Lymphocyte HMOX-1 and hOGG1 protein concentrations and expression (mRNA) of redox-sensitive genes, including HMOX-1 and hOGG1, were also investigated. Results showed significantly (P < 0.01) lower (~15%) DNA damage, higher (~50%) hOGG1 activity and higher (~40%) HMOX-1 protein concentration after tea. No changes in mRNA expression were seen. Baseline HMOX-1 protein and hOGG1 activity were higher (P < 0.05) in the S/S group, but tea-associated responses were similar in both GT(n) groups. Green tea is clearly associated with lowered DNA damage, increased hOGG1 activity and higher HMOX-1 protein levels. Further study is needed to confirm a cause and effect relationship and to establish if these effects are mediated by post translational changes in proteins or by increased gene expression. PMID- 25527736 TI - Assessment of DNA damage using comet assay in middle-aged overweight/obese subjects after following a hypocaloric diet supplemented with cocoa extract. AB - Nutrient excess and unbalanced diets can result in overproduction of reactive oxygen species (ROS), which are associated with oxidative stress. Cocoa extract contains antioxidants that inhibit the harmful effects of ROS. This trial analysed the effect of cocoa extract consumption integrated as a bioactive compound into ready-to-eat meals, on oxidative stress at the level of DNA in overweight/obese subjects. Fifty volunteers [57.26(5.24) years, 30.59(2.33)kg/m(2)] participated in a 4-week double-blind, randomised, placebo controlled parallel nutritional intervention. Half of the volunteers received meals supplemented with 1.4 g/day cocoa extract, while the other half received control meals, both within a 15% energy restriction diet. Lymphocytes were isolated and endogenous strand breaks, oxidised bases and resistance to H2O2 induced damage were measured by the comet assay. The intake of ready-to-eat meals supplemented with cocoa extract did not show relevant changes in the oxidative status of DNA. However, in the cocoa group, oxidised bases negatively correlated with methyl epicatechin-O-sulphate (r = -0.76; P = -0.007) and epicatechin sulphate (r = -0.61; P = -0.046). When volunteers of both groups were analysed together, a marginal decrease (P = 0.072) in oxidised bases was observed, which attributed to weight loss. Subjects who started the intervention with higher levels of damage showed a greater reduction in oxidised bases after 4 weeks (P = 0.040) compared to those who had lower baseline levels. In conclusion, even if 1.4 g of cocoa supplementation for 4 weeks did not show notable changes in terms of antioxidant status of DNA, the energy restriction showed a slightly decrease in oxidised bases and this was seen to a greater extent in subjects who started the intervention with higher levels of damage. On the other hand, the inverse associations found between oxidised bases and some cocoa-derived metabolites suggest that a protective effect might be seen in a longer period of time or in subjects with higher baseline DNA damage. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01596309). PMID- 25527737 TI - The impact of six months strength training, nutritional supplementation or cognitive training on DNA damage in institutionalised elderly. AB - Aging and its aligned loss of muscle mass are associated with higher levels of DNA damage and deteriorated antioxidant defence. To improve the body's overall resistance against DNA damage, maintaining a healthy and active lifestyle is desirable, especially in the elderly. As people age, many have to change their residence from home living to an institution, which is often accompanied by malnutrition, depression and inactivity. The current study aimed at investigating the effect of a 6-month progressive resistance training (RT), with or without protein and vitamin supplementation (RTS), or cognitive training (CT), on DNA strand breaks in 105 Austrian institutionalised women and men (65-98 years). DNA damage was detected by performing the single cell gel electrophoresis (comet) assay. Physical fitness was assessed using the chair rise, the 6-min-walking and the handgrip strength test. In addition, antioxidant enzyme activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were analysed. Basal DNA damage (lysis) increased significantly after 3 months of intervention in the RT group (T1 - T2 + 20%, P = 0.001) and the RTS group (T1 - T2 + 17%, P = 0.002) and showed a similar tendency in the CT group (T1 - T2 + 21%, P = 0.059). %DNA in tail decreased in cells exposed to H2O2 significantly in the RT (T1 - T2 - 24%, P = 0.030; T1 - T3 - 18%, P = 0.019) and CT (T1 - T2 - 21%, P = 0.004; T1 - T3 - 13%, P = 0.038) groups. Only RT and RTS groups showed significant differences overtime in enzyme activity (RT + 22% CAT-activity T1 - T3, P = 0.013; RTS + 6% SOD-activity T2 - T3, P = 0.005). Contrary to the time effects, no difference between groups was detected for any parameter at any time point. Our results suggest that both CT and RT improve resistance against H2O2 induced DNA damage and that a nutritional supplement has no further protective effect in institutionalised elderly. PMID- 25527738 TI - Worldwide interest in the comet assay: a bibliometric study. AB - The comet assay is a rapid, sensitive and relatively simple method for measuring DNA damage. A bibliometric study was performed to evaluate temporal and geographical trends, research quality and main areas of interest in scientific production in this field. A PubMed search strategy was developed and 7674 citations were retrieved in the period 1990-2013. Notably, the MeSH (Medical Subject Headings) term 'comet assay', officially introduced in 2000, is used by indexers only in two thirds of papers retrieved. Articles on the comet assay were published in 78 countries, spread over the 5 continents. The EU contributed the greatest output, producing >2900 articles with IF (42.0%) and totalling almost 10000 IF points, and was followed by USA. In the new millennium, research with this assay reached a plateau or slow decline in the most industrialised areas (USA, Germany, UK, Italy), while its use has boomed in emerging countries, with increases of 5- to 7-fold in the last 10 years in China, India and Brazil, for instance. This transition resulted in a slow decrease of scientific production quality, as the countries that increased their relative weight typically had lower mIFs. The most common MeSH terms used in papers using the comet assay referred to wide areas of interest, such as DNA damage and repair, cell survival and apoptosis, cancer and oxidative stress, occupational and environmental health. Keywords related to humans, rodents and cell culture were also frequently used. The top journal for the comet assay articles was found to be Mutation Research, followed by Mutagenesis. Most papers using the comet assay as a biomarker were published in genetic and toxicology journals, with a stress on environmental and occupational disciplines. PMID- 25527740 TI - CRISPR-based self-cleaving mechanism for controllable gene delivery in human cells. AB - Controllable gene delivery via vector-based systems remains a formidable challenge in mammalian synthetic biology and a desirable asset in gene therapy applications. Here, we introduce a methodology to control the copies and residence time of a gene product delivered in host human cells but also selectively disrupt fragments of the delivery vehicle. A crucial element of the proposed system is the CRISPR protein Cas9. Upon delivery, Cas9 guided by a custom RNA sequence cleaves the delivery vector at strategically placed targets thereby inactivating a co-expressed gene of interest. Importantly, using experiments in human embryonic kidney cells, we show that specific parameters of the system can be adjusted to fine-tune the delivery properties. We envision future applications in complex synthetic biology architectures, gene therapy and trace-free delivery. PMID- 25527741 TI - Angiotensin II-mediated GFR decline in subtotal nephrectomy is due to acid retention associated with reduced GFR. AB - BACKGROUND: Angiotensin II (AII) mediates glomerular filtration rate (GFR) decline in animals with subtotal nephrectomy (Nx), but the mechanisms for increased AII activity are unknown. Because reduced GFR of Nx is associated with acid (H(+)) retention that increases kidney AII, AII-mediated GFR decline might be induced by H(+) retention. METHODS: We measured GFR and kidney microdialyzate H(+) and AII content in Sham and 2/3 Nx rats in response to amelioration of H(+) retention with dietary NaHCO3, to AII receptor antagonism and to both. RESULTS: GFR was lower in Nx than that in Sham. Nx but not Sham GFR was lower at Week 24 than that at Week 1. Despite no differences in plasma acid-base parameters or urine net acid excretion, kidney H(+) content was higher in Nx than that in Sham, consistent with H(+) retention. Plasma and kidney microdialyzate AII were higher in Nx than that in Sham and dietary NaHCO3 reduced each in Nx but not in Sham. AII receptor antagonism was associated with higher Week 24 GFR in Nx with H(+) retention but not in Sham or in Nx in which H(+) retention had been corrected with dietary NaHCO3. Week 24 GFR after dietary NaHCO3 was higher than after AII receptor antagonism. Week 24 GFR was not different after adding AII receptor antagonism to dietary NaHCO3. CONCLUSIONS: AII-mediated GFR decline in 2/3 Nx was induced by H(+) retention and its amelioration with dietary HCO3 conserved GFR better than AII receptor antagonism in this CKD model. H(+) retention might induce AII-mediated GFR decline in patients with reduced GFR, even without metabolic acidosis. PMID- 25527742 TI - Fiber man meets microbial man. PMID- 25527743 TI - Economic considerations in the choice between treatments. PMID- 25527744 TI - Sleeping more to improve appetite and body weight control: dream or reality? PMID- 25527745 TI - Systematic research review of observational approaches used to evaluate mother child mealtime interactions during preschool years. AB - BACKGROUND: The family meal and social interactions during the meal are important events in a child's life. Specifically, mealtime interactions have been linked to child weight status, the development of children's eating patterns, and socialization. Mealtime interactions may be observed and evaluated to provide insights into this important event beyond self-reported measurements. OBJECTIVE: We aimed to identify, review, and examine studies in which mother-child mealtime behaviors were measured through observation. DESIGN: MEDLINE Complete, PsycINFO, and PsycARTICLES were systematically searched by using sensitive search strategies. We included observational studies of mother-child eating and mealtimes and associations between mother-child interactions and preschool child eating or weight status published to March 2014. RESULTS: Thirteen articles were included in our review. All studies but one were cross-sectional, and none of the studies evaluated how mutual dimensions (e.g., parent responsiveness to the child and child responsiveness to the parent) of dyadic interactions between mothers and children influence maternal feeding practices, children's eating, and weight. The parenting style was associated with maternal feeding practices but not directly with children's eating. Parental discouragements to eat and negative statements about food were associated with higher child weight status. Parental encouragement to eat was associated with higher child weight status as well as maternal body mass index. No associations were shown between maternal reports of feeding practices and observed maternal feeding practices. CONCLUSIONS: Parents' overarching attitudes and approaches to parenting appear to be associated with their feeding practices or styles. Future studies should implement longitudinal observational methods with the capacity to measure levels of dimensions within bidirectional parent-child interactions and the extent to which these factors influence maternal practices, children's eating, and weight status. PMID- 25527746 TI - Psychological aspects of eating behavior as predictors of 10-y weight changes after surgical and conventional treatment of severe obesity: results from the Swedish Obese Subjects intervention study. AB - BACKGROUND: There is a need for a better understanding of the factors that influence long-term weight outcomes after bariatric surgery. OBJECTIVE: We examined whether pretreatment and posttreatment levels of cognitive restraint, disinhibition, and hunger and 1-y changes in these eating behaviors predict short and long-term weight changes after surgical and conventional treatments of severe obesity. DESIGN: Participants were from an ongoing, matched (nonrandomized) prospective intervention trial of the Swedish Obese Subjects (SOS) study. The current analyses included 2010 obese subjects who underwent bariatric surgery and 1916 contemporaneously matched obese controls who received conventional treatment. Physical measurements (e.g., weight and height) and questionnaires (e.g., Three-Factor Eating Questionnaire) were completed before the intervention and 0.5, 1, 2, 3, 4, 6, 8, and 10 y after the start of the treatment. Structural equation modeling was used as the main analytic strategy. RESULTS: The surgery group lost more weight and reported greater decreases in disinhibition and hunger at 1- and 10-y follow-ups (all P < 0.001 in both sexes) than the control group did. Pretreatment eating behaviors were unrelated to subsequent weight changes in surgically treated patients. However, patients who had lower levels of 6-mo and 1-y disinhibition and hunger (beta = 0.13-0.29, P < 0.01 in men; beta = 0.11-0.28, P < 0.001 in women) and experienced larger 1-y decreases in these behaviors (beta = 0.31-0.48, P < 0.001 in men; beta = 0.24 0.51, P < 0.001 in women) lost more weight 2, 6, and 10 y after surgery. In control patients, larger 1-y increases in cognitive restraint predicted a greater 2-y weight loss in both sexes. CONCLUSION: A higher tendency to eat in response to various internal and external cues shortly after surgery predicted less successful short- and long-term weight outcomes, making postoperative susceptibility for uncontrolled eating an important indicator of targeted interventions. PMID- 25527747 TI - Effect of mastication on lipid bioaccessibility of almonds in a randomized human study and its implications for digestion kinetics, metabolizable energy, and postprandial lipemia. AB - BACKGROUND: The particle size and structure of masticated almonds have a significant impact on nutrient release (bioaccessibility) and digestion kinetics. OBJECTIVES: The goals of this study were to quantify the effects of mastication on the bioaccessibility of intracellular lipid of almond tissue and examine microstructural characteristics of masticated almonds. DESIGN: In a randomized, subject-blind, crossover trial, 17 healthy subjects chewed natural almonds (NAs) or roasted almonds (RAs) in 4 separate mastication sessions. Particle size distributions (PSDs) of the expectorated boluses were measured by using mechanical sieving and laser diffraction (primary outcome). The microstructure of masticated almonds, including the structural integrity of the cell walls (i.e., dietary fiber), was examined with microscopy. Lipid bioaccessibility was predicted by using a theoretical model, based on almond particle size and cell dimensions, and then compared with empirically derived release data. RESULTS: Intersubject variations (n = 15; 2 subjects withdrew) in PSDs of both NA and RA samples were small (e.g., laser diffraction; CV: 12% and 9%, respectively). Significant differences in PSDs were found between these 2 almond forms (P < 0.05). A small proportion of lipid was released from ruptured cells on fractured surfaces of masticated particles, as predicted by using the mathematical model (8.5% and 11.3% for NAs and RAs, respectively). This low percentage of lipid bioaccessibility is attributable to the high proportion (35-40%) of large particles (>500 MUm) in masticated almonds. Microstructural examination of the almonds indicated that most intracellular lipid remained undisturbed in intact cells after mastication. No adverse events were recorded. CONCLUSIONS: Following mastication, most of the almond cells remained intact with lipid encapsulated by cell walls. Thus, most of the lipid in masticated almonds is not immediately bioaccessible and remains unavailable for early stages of digestion. The lipid encapsulation mechanism provides a convincing explanation for why almonds have a low metabolizable energy content and an attenuated impact on postprandial lipemia. PMID- 25527749 TI - Impact of a 6-wk olive oil supplementation in healthy adults on urinary proteomic biomarkers of coronary artery disease, chronic kidney disease, and diabetes (types 1 and 2): a randomized, parallel, controlled, double-blind study. AB - BACKGROUND: Olive oil (OO) consumption is associated with cardiovascular disease prevention because of both its oleic acid and phenolic contents. The capacity of OO phenolics to protect against low-density lipoprotein (LDL) oxidation is the basis for a health claim by the European Food Safety Authority. Proteomic biomarkers enable an early, presymptomatic diagnosis of disease, which makes them important and effective, but understudied, tools for primary prevention. OBJECTIVE: We evaluated the impact of supplementation with OO, either low or high in phenolics, on urinary proteomic biomarkers of coronary artery disease (CAD), chronic kidney disease (CKD), and diabetes. DESIGN: Self-reported healthy participants (n = 69) were randomly allocated (stratified block random assignment) according to age and body mass index to supplementation with a daily 20-mL dose of OO either low or high in phenolics (18 compared with 286 mg caffeic acid equivalents per kg, respectively) for 6 wk. Urinary proteomic biomarkers were measured at baseline and 3 and 6 wk alongside blood lipids, the antioxidant capacity, and glycation markers. RESULTS: The consumption of both OOs improved the proteomic CAD score at endpoint compared with baseline (mean improvement: 0.3 for low-phenolic OO and -0.2 for high-phenolic OO; P < 0.01) but not CKD or diabetes proteomic biomarkers. However, there was no difference between groups for changes in proteomic biomarkers or any secondary outcomes including plasma triacylglycerols, oxidized LDL, and LDL cholesterol. CONCLUSION: In comparison with low-phenolic OO, supplementation for 6 wk with high-phenolic OO does not lead to an improvement in cardiovascular health markers in a healthy cohort. PMID- 25527750 TI - Fiber supplementation influences phylogenetic structure and functional capacity of the human intestinal microbiome: follow-up of a randomized controlled trial. AB - BACKGROUND: In our published randomized, double-blind, placebo-controlled, 3 period crossover trial, healthy adult men (n = 21) consumed bars containing no supplemental fiber (placebo; NFC), polydextrose (21 g/d), and soluble corn fiber (SCF; 21 g/d) for 21 d each. Fecal specimens were collected between days 16 and 21 for fermentative end-product analysis and 16S ribosomal RNA bacterial gene amplification for bacterial taxa identification. Fiber supplementation decreased fecal putrefaction compounds and shifted abundances of several bacterial taxa. OBJECTIVE: The objective was to perform whole-genome shotgun 454 pyrosequencing on the same fecal specimens collected in that clinical trial to obtain comprehensive fecal bacterial genome sequencing coverage and explore the full range of bacterial genetic information in the fecal microbiome, thereby using a systematic approach to study the impact of dietary fiber supplementation on fecal metabolites, bacterial taxa, and bacterial metagenomes. DESIGN: Fecal samples were subjected to whole-genome shotgun 454 pyrosequencing to identify both fecal bacterial populations present and their functional genetic capacity. RESULTS: Whole-genome shotgun sequencing results revealed that fiber consumption shifted the Bacteroidetes:Firmicutes ratio, increasing the relative abundance of Bacteroidetes 12 +/- 2% and 13 +/- 2% with polydextrose and SCF, respectively, compared with NFC. Bivariate correlations showed a positive correlation between the Bacteroidetes:Firmicutes ratio and total dietary fiber intake but not body mass index. Principal coordinates analysis of Bray-Curtis distances indicated that bacterial gene composition was more similar in participants consuming fibers (polydextrose and SCF combined) in comparison with NFC. Shifts in bacterial gene abundances after polydextrose and SCF supplementation included genes associated with carbohydrate, amino acid, and lipid metabolism, as well as metabolism of cofactors and vitamins. CONCLUSION: This study conveys novel information about the impact of dietary fiber supplementation on the phylogenetic structure and functional capacity of the fecal microbiome of healthy adults. PMID- 25527748 TI - Palmitoleic acid is elevated in fatty liver disease and reflects hepatic lipogenesis. AB - BACKGROUND: Biochemical evidence has linked the coordinate control of fatty acid (FA) synthesis with the activity of stearoyl-CoA desaturase-1 (SCD1). The ratio of 16:1n-7 to 16:0 [SCD116] in plasma triacylglycerol FA has been used as an index to reflect liver SCD116 activity and has been proposed as a biomarker of FA synthesis, although this use has not been validated by comparison with isotopically measured de novo lipogenesis (DNL(Meas)). OBJECTIVE: We investigated plasma lipid 16:1n-7 and FA indexes of elongation and desaturation in relation to lipogenesis. DESIGN: In this cross-sectional investigation of metabolism, 24 overweight adults, who were likely to have elevated DNL, consumed D2O for 10 d and had liver fat (LF) measured by magnetic resonance spectroscopy. Very-low density lipoprotein (VLDL)-triacylglycerols and plasma free FA [nonesterified fatty acids (NEFAs)] were analyzed by using gas chromatography for the FA composition (molar percentage) and gas chromatography-mass spectrometry and gas chromatography-combustion isotope ratio mass spectrometry for deuterium enrichment. RESULTS: In all subjects, VLDL-triacylglycerol 16:1n-7 was significantly (P < 0.01) related to DNL(Meas) (r = 0.56), liver fat (r = 0.53), and adipose insulin resistance (r = 0.56); similar positive relations were shown with the SCD116 index, and the pattern in NEFAs echoed that of VLDL triacylglycerols. Compared with subjects with low LF (3.1 +/- 2.7%; n = 11), subjects with high LF (18.4 +/- 3.6%; n = 13) exhibited a 45% higher VLDL triacylglycerol 16:1n-7 molar percentage (P < 0.01), 16% of subjects had lower 18:2n-6 (P = 0.01), and 27% of subjects had higher DNL as assessed by using a published DNL index (ratio of 16:0 to 18:2n-6; P = 0.03), which was isotopically confirmed by DNL(Meas) (increased 2.5-fold; P < 0.01). Compared with 16:0 in the diet, the low amount of dietary 16:1n-7 in VLDL-triacylglycerols corresponded to a stronger signal of elevated DNL. CONCLUSION: The current data provide support for the use of the VLDL-triacylglycerol 16:1n-7 molar percentage as a biomarker for elevated liver fat when isotope use is not feasible; however, larger-scale confirmatory studies are needed. PMID- 25527751 TI - Proton magnetic resonance spectroscopy reveals increased hepatic lipid content after a single high-fat meal with no additional modulation by added protein. AB - BACKGROUND: Fat accumulation in nonadipose tissue is linked to insulin resistance and metabolic diseases. Earlier studies have shown that hepatic lipid accumulation can occur after 4 d of a high-fat diet in humans, and this fat accumulation can be blunted by the ingestion of additional proteins. OBJECTIVES: In this study, we explored whether a single high-fat meal increased the lipid content in liver and skeletal muscle as measured by using in vivo proton magnetic resonance spectroscopy (1H-MRS) and whether the addition of protein can modulate the postprandial ectopic lipid storage. DESIGN: Intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) concentrations were determined by using 1H-MRS before and 3 and 5 h after a high-fat with added protein meal (61.5% of energy from fat) or a high-fat without added protein meal (mean +/- SEM: 51.1 +/- 7.9 g of protein; 191.9 +/- 9.9 kcal added) in a randomized crossover study. IHL and IMCL concentrations were converted to absolute concentrations (g/kg wet weight) by using water as an internal reference. RESULTS: Nine lean, healthy subjects [6 men and 3 women; mean (+/-SD) age: 22.7 +/- 3.0 y; mean body mass index (in kg/m2): 21.8 +/- 1.8] were included in this study. IHL concentrations increased ~20% (P < 0.01) at 3 h after the meal and did not further increase after 5 h. In contrast, IMCL concentrations were not altered during the postprandial period (P = 0.74). The addition of protein to a single high-fat meal did not change the postprandial accumulation of fat in the liver (P = 0.93) or skeletal muscle (P = 0.84). CONCLUSIONS: In this study, we showed that a single energy-dense, high-fat meal induced net lipid accumulation in the liver, which was detected by using in vivo 1H-MRS. This noninvasive approach might bring new opportunities to study postprandial hepatic lipid dynamics. The addition of protein did not change the ectopic lipid retention after a single high-fat meal. PMID- 25527752 TI - Fish consumption and risk of non-gallstone-related acute pancreatitis: a prospective cohort study. AB - BACKGROUND: Epidemiologic data on the role of diet in acute pancreatitis are sparse. OBJECTIVE: We examined the association of total fish consumption, as well as of consumption of fatty fish and lean fish separately, with risk of non gallstone-related acute pancreatitis. DESIGN: We used data from 2 prospective cohorts, the Cohort of Swedish Men and the Swedish Mammography Cohort, that included 39,267 men and 32,191 women who were aged 45-84 y at the start of a 13-y follow-up period (1998-2010). Fish consumption was assessed by using a food frequency questionnaire at baseline, and cases of incident non-gallstone-related acute pancreatitis were identified by linkage to the Swedish National Patient Register. HRs were estimated by using Cox proportional hazard models. RESULTS: During a total follow-up of 860,176 person-years, 320 cases (209 cases in men and 111 cases in women) of incident non-gallstone-related acute pancreatitis were identified. We observed that total fish consumption <=2.0-3.0 servings/wk was associated with a significantly decreased risk of the disease (P-nonlinearity = 0.017). In comparison with 0.9 servings/wk, multivariable-adjusted HRs were 0.86 (95% CI: 0.76, 0.96), 0.77 (95% CI: 0.62, 0.96), and 0.85 (95% CI: 0.65, 1.10) for 1.4, 2.4, and 3.5 servings/wk, respectively. In the analysis of fatty fish and lean fish, we observed that the consumption of each subtype had a similarly shaped association with risk of non-gallstone-related acute pancreatitis as that observed for total fish consumption, although neither was significant. Multivariable-adjusted HRs were 0.83 for fatty fish (95% CI: 0.65, 1.04) and 0.87 for lean fish (95% CI: 0.69, 1.11) when 0.6-2.0 servings/wk was compared with <=0.5 servings/wk. CONCLUSION: Our data suggest that the consumption of total fish (fatty fish and lean fish combined) may be associated with decreased risk of non-gallstone-related acute pancreatitis. PMID- 25527753 TI - Cost-effectiveness of intestinal transplantation for adult patients with intestinal failure: a simulation study. AB - BACKGROUND: Home parenteral nutrition (HPN) and intestinal transplantation (ITx) are the 2 treatment options for irreversible intestinal failure (IF). OBJECTIVE: This study simulated the disease course of irreversible IF and both of these treatments--HPN and ITx--to estimate the cost-effectiveness of ITx. DESIGN: We simulated IF treatment in adults as a discrete event model with variables derived from the Dutch Registry of Intestinal Failure and Intestinal Transplantation, the Intestinal Transplant Registry, hospital records, the literature, and expert opinions. Simulated patients were enrolled at a rate of 40/mo for 10 y. The maximum follow-up was 40 y. Survival was simulated as a probabilistic function. ITx was offered to 10% of patients with <12 mo of remaining life expectancy with HPN if they did not undergo ITx. Costs were calculated according to Dutch guidelines, with discounting. We evaluated the cost-effectiveness of ITx by comparing models conducted with and without ITx and by calculating the cost difference per life-year gained [incremental cost-effectiveness ratio (ICER)]. RESULTS: The average survival was 14.6 y without ITx and 14.9 y with ITx. HPN costs were ?13,276 for treatment introduction, followed by ?77,652 annually. The costs of ITx were ~?73,000 during the first year and then ?13,000 annually. The ICER was ?19,529 per life-year gained. CONCLUSION: Our simulations show that ITx slightly improves survival of patients with IF in comparison with HPN at an additional cost of ?19,529 per life-year gained. PMID- 25527754 TI - Dairy products, calcium, and prostate cancer risk: a systematic review and meta analysis of cohort studies. AB - BACKGROUND: Dairy product and calcium intakes have been associated with increased prostate cancer risk, but whether specific dairy products or calcium sources are associated with risk is unclear. OBJECTIVE: In the Continuous Update Project, we conducted a meta-analysis of prospective studies on intakes of dairy products and calcium and prostate cancer risk. DESIGN: PubMed and several other databases were searched up to April 2013. Summary RRs were estimated by using a random-effects model. RESULTS: Thirty-two studies were included. Intakes of total dairy products [summary RR: 1.07 (95% CI: 1.02, 1.12; n = 15) per 400 g/d], total milk [summary RR: 1.03 (95% CI: 1.00, 1.07; n = 14) per 200 g/d], low-fat milk [summary RR: 1.06 (95% CI: 1.01, 1.11; n = 6) per 200 g/d], cheese [summary RR: 1.09 (95% CI: 1.02, 1.18; n = 11) per 50 g/d], and dietary calcium [summary RR: 1.05 (95% CI: 1.02, 1.09; n = 15) per 400 mg/d] were associated with increased total prostate cancer risk. Total calcium and dairy calcium intakes, but not nondairy calcium or supplemental calcium intakes, were also positively associated with total prostate cancer risk. Supplemental calcium was associated with increased risk of fatal prostate cancer. CONCLUSIONS: High intakes of dairy products, milk, low-fat milk, cheese, and total, dietary, and dairy calcium, but not supplemental or nondairy calcium, may increase total prostate cancer risk. The diverging results for types of dairy products and sources of calcium suggest that other components of dairy rather than fat and calcium may increase prostate cancer risk. Any additional studies should report detailed results for subtypes of prostate cancer. PMID- 25527756 TI - Dietary consumption of advanced glycation end products and pancreatic cancer in the prospective NIH-AARP Diet and Health Study. AB - BACKGROUND: Advanced glycation end products (AGEs) are a heterogeneous group of compounds present in uncooked foods as well as in foods cooked at high temperatures. AGEs have been associated with insulin resistance, oxidative stress, and chronic inflammation in patients with diabetes. Dietary AGEs are an important contributor to the AGE pool in the body. N(epsilon) (carboxymethyl)lysine (CML) AGE is one of the major biologically and chemically well-characterized AGE markers. The consumption of red meat, which is CML-AGE rich, has been positively associated with pancreatic cancer in men. OBJECTIVES: With the use of a published food CML-AGE database, we estimated the consumption of CML AGE in the prospective NIH-AARP Diet and Health Study and evaluated the association between CML-AGE consumption and pancreatic cancer and the mediating effect of CML AGE on the association between red meat consumption and pancreatic cancer. DESIGN: Multivariate Cox proportional hazard regression models were used to estimate HRs and 95% CIs for pancreatic cancer. RESULTS: During an average of 10.5 y of follow-up, we identified 2193 pancreatic cancer cases (1407 men and 786 women) from 528,251 subjects. With the comparison of subjects in the fifth and the first quintiles of CML-AGE consumption, we observed increased pancreatic cancer risk in men (HR: 1.43; 95% CI: 1.06, 1.93, P-trend = 0.003) but not women (HR: 1.14; 95% CI: 0.76, 1.72, P-trend = 0.42). Men in the highest quintile of red meat consumption had higher risk of pancreatic cancer (HR: 1.35; 95% CI: 1.07, 1.70), which attenuated after adjustment for CML-AGE consumption (HR: 1.20; 95% CI: 0.95, 1.53). CONCLUSION: Dietary CML-AGE consumption was associated with modestly increased risk of pancreatic cancer in men and may partially explain the positive association between red meat and pancreatic cancer. PMID- 25527755 TI - Fiber intake and risk of subsequent prostate cancer in Japanese men. AB - BACKGROUND: Dietary fiber may reduce the risk of prostate cancer, possibly by increasing circulating concentrations of sex hormone-binding globulin and improving insulin sensitivity. However, results from previous epidemiologic studies of fiber intake and prostate cancer are inconsistent, and to our knowledge, no study has comprehensively evaluated the effects of soluble and insoluble fiber on prostate cancer in Asia. OBJECTIVE: The objective was to examine the association between fiber intake and prostate cancer in Japanese men. DESIGN: We conducted a population-based prospective study in 43,435 Japanese men aged 45-74 y. Participants responded to a validated questionnaire, which included 138 food items. Follow-up was from 1995 through 2009. HRs and 95% CIs of incidence were calculated according to quartiles of fiber intake. RESULTS: During the 11.6-y follow-up, of the 825 men newly diagnosed with prostate cancer, 213 had advanced-stage cancer, 582 had organ-localized disease, and 30 had an undetermined stage of disease. Among them, 217 cases were detected by subjective symptoms. Total fiber was not associated with total or advanced prostate cancer, with respective multivariable HRs for the highest and lowest quartiles of 1.00 (95% CI: 0.77, 1.29; P-trend = 0.97) and 0.67 (95% CI: 0.42, 1.07; P-trend = 0.30). Total fiber and insoluble fiber intake were associated with a decreased risk of advanced cancers detected by subjective symptoms, with multivariate HRs (95% CIs) across increasing quartiles of 1.00, 0.58, 0.62, and 0.44 (0.21, 0.92; P-trend = 0.05) for total fiber and 1.00, 0.60, 0.52, and 0.46 (0.22, 0.93; P trend = 0.04) for insoluble fiber. Soluble fiber intake showed no association with prostate cancer. CONCLUSIONS: Dietary fiber is inversely associated with advanced prostate cancer detected by subjective symptoms even among populations with relatively low intake, such as Japanese. These results suggest that a very low intake of dietary fiber is associated with an increased risk of prostate cancer. PMID- 25527758 TI - Multivitamin use and cardiovascular disease in a prospective study of women. AB - BACKGROUND: Although multivitamins are widely used, there are limited prospective studies investigating their association with both long- and short-term risk of cardiovascular disease (CVD). OBJECTIVE: The objective was to investigate how multivitamin use is associated with the long- and short-term risk of CVD. DESIGN: A prospective cohort study was conducted of 37,193 women from the Women's Health Study aged >=45 y and free of CVD and cancer at baseline who were followed for an average of 16.2 y. At baseline, women self-reported a wide range of lifestyle, clinical, and dietary factors. Women were categorized into 1) no current use and 2) current use of multivitamins. Duration and updated measures over the course of the follow-up to address short-term effects were also considered. Women were followed for major CVD events, including myocardial infarction (MI), stroke, and CVD death. RESULTS: During the follow-up, 1493 incident cases of CVD [defined as myocardial infarction (MI), stroke, and CVD death] occurred. In multivariable analyses, multivitamin use compared with no use was not associated with major CVD events (HR: 1.01; 95% CI: 0.89, 1.15), MI (HR: 1.04; 95% CI: 0.84, 1.27), stroke (HR: 0.99; 95% CI: 0.83, 1.18), or CVD death (HR: 1.10; 95% CI: 0.84, 1.45). A nonsignificant inverse association was observed between baseline multivitamin use and major CVD events among women aged >=70 y (P-interaction = 0.04) and those consuming <3 servings/d of fruit and vegetables (P-interaction = 0.01). When updating information on multivitamin use during the course of follow-up, no associations were observed for major CVD events (HR: 0.91; 95% CI: 0.82, 1.02), MI (HR: 0.89; 95% CI: 0.74, 1.06), stroke (HR: 0.91; 95% CI: 0.78, 1.06), and CVD death (HR: 0.91; 95% CI: 0.71, 1.16). CONCLUSIONS: In this study of middle-aged and elderly women, neither baseline nor time-varying multivitamin use was associated with the long-term risk of major CVD events, MI, stroke, cardiac revascularizations, or CVD death. Additional studies are needed to clarify the role of multivitamins on CVD. PMID- 25527757 TI - Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants. AB - BACKGROUND: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake. OBJECTIVES: We examined associations between habitual sleep duration, body mass index (BMI), and macronutrient intake and assessed whether CLOCK variants modify these associations. DESIGN: We conducted inverse-variance weighted, fixed-effect meta analyses of results of adjusted associations of sleep duration and BMI and macronutrient intake as percentages of total energy as well as interactions with CLOCK variants from 9 cohort studies including up to 14,906 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. RESULTS: We observed a significant association between sleep duration and lower BMI (beta +/- SE = 0.16 +/- 0.04, P < 0.0001) in the overall sample; however, associations between sleep duration and relative macronutrient intake were evident in age- and sex-stratified analyses only. We observed a significant association between sleep duration and lower saturated fatty acid intake in younger (aged 20-64 y) adults (men: 0.11 +/- 0.06%, P = 0.03; women: 0.10 +/- 0.05%, P = 0.04) and with lower carbohydrate (-0.31 +/- 0.12%, P < 0.01), higher total fat (0.18 +/- 0.09%, P = 0.05), and higher PUFA (0.05 +/- 0.02%, P = 0.02) intakes in older (aged 65-80 y) women. In addition, the following 2 nominally significant interactions were observed: between sleep duration and rs12649507 on PUFA intake and between sleep duration and rs6858749 on protein intake. CONCLUSIONS: Our results indicate that longer habitual sleep duration is associated with lower BMI and age- and sex-specific favorable dietary behaviors. Differences in the relative intake of specific macronutrients associated with short sleep duration could, at least in part, explain previously reported associations between short sleep duration and chronic metabolic abnormalities. In addition, the influence of obesity-associated CLOCK variants on the association between sleep duration and macronutrient intake suggests that longer habitual sleep duration could ameliorate the genetic predisposition to obesity via a favorable dietary profile. PMID- 25527759 TI - Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study. AB - BACKGROUND: Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes. OBJECTIVES: We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n-9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and vaccenic acid (18:1n-7)] and estimated dietary SFAs and MUFAs. DESIGN: In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively. RESULTS: At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs or MUFAs were not significantly associated with incident diabetes. CONCLUSIONS: In this large prospective cohort, circulating palmitic acid and stearic acid were associated with higher diabetes risk, and vaccenic acid was associated with lower diabetes risk. These results indicate a need for additional investigation of biological mechanisms linking specific fatty acids in the DNL pathway to the pathogenesis of diabetes. PMID- 25527762 TI - Energy and nutrient density of foods in relation to their carbon footprint. AB - BACKGROUND: A carbon footprint is the sum of greenhouse gas emissions (GHGEs) associated with food production, processing, transporting, and retailing. OBJECTIVE: We examined the relation between the energy and nutrient content of foods and associated GHGEs as expressed as g CO2 equivalents. DESIGN: GHGE values, which were calculated and provided by a French supermarket chain, were merged with the Composition Nutritionnelle des Aliments (French food-composition table) nutrient-composition data for 483 foods and beverages from the French Agency for Food, Environmental and Occupational Health and Safety. Foods were aggregated into 34 food categories and 5 major food groups as follows: meat and meat products, milk and dairy products, frozen and processed fruit and vegetables, grains, and sweets. Energy density was expressed as kcal/100 g. Nutrient density was determined by using 2 alternative nutrient-density scores, each based on the sum of the percentage of daily values for 6 or 15 nutrients, respectively. The energy and nutrient densities of foods were linked to log transformed GHGE values expressed per 100 g or 100 kcal. RESULTS: Grains and sweets had lowest GHGEs (per 100 g and 100 kcal) but had high energy density and a low nutrient content. The more-nutrient-dense animal products, including meat and dairy, had higher GHGE values per 100 g but much lower values per 100 kcal. In general, a higher nutrient density of foods was associated with higher GHGEs per 100 kcal, although the slopes of fitted lines varied for meat and dairy compared with fats and sweets. CONCLUSIONS: Considerations of the environmental impact of foods need to be linked to concerns about nutrient density and health. The point at which the higher carbon footprint of some nutrient-dense foods is offset by their higher nutritional value is a priority area for additional research. PMID- 25527761 TI - Calcium and phosphorus intake and prostate cancer risk: a 24-y follow-up study. AB - BACKGROUND: High calcium intake has been associated with an increased risk of advanced-stage and high-grade prostate cancer. Several studies have found a positive association between phosphorus intake and prostate cancer risk. OBJECTIVE: We investigated the joint association between calcium and phosphorus and risk of prostate cancer in the Health Professionals Follow-Up Study, with a focus on lethal and high-grade disease. DESIGN: In total, 47,885 men in the cohort reported diet data in 1986 and every 4 y thereafter. From 1986 to 2010, 5861 cases of prostate cancer were identified, including 789 lethal cancers (fatal or metastatic). We used Cox proportional hazards models to assess the association between calcium and phosphorus intake and prostate cancer, with adjustment for potential confounding. RESULTS: Calcium intakes >2000 mg/d were associated with greater risk of total prostate cancer and lethal and high-grade cancers. These associations were attenuated and no longer statistically significant when phosphorus intake was adjusted for. Phosphorus intake was associated with greater risk of total, lethal, and high-grade cancers, independent of calcium and intakes of red meat, white meat, dairy, and fish. In latency analysis, calcium and phosphorus had independent effects for different time periods between exposure and diagnosis. Calcium intake was associated with an increased risk of advanced-stage and high-grade disease 12-16 y after exposure, whereas high phosphorus was associated with increased risk of advanced stage and high-grade disease 0-8 y after exposure. CONCLUSIONS: Phosphorus is independently associated with risk of lethal and high-grade prostate cancer. Calcium may not have a strong independent effect on prostate cancer risk except with long latency periods. PMID- 25527760 TI - Rice consumption and risk of cardiovascular disease: results from a pooled analysis of 3 U.S. cohorts. AB - BACKGROUND: Health concerns have been raised about rice consumption, which may significantly contribute to arsenic exposure. However, little is known regarding whether habitual rice consumption is associated with cardiovascular disease (CVD) risk. OBJECTIVE: We examined prospectively the association of white rice and brown rice consumption with CVD risk. DESIGN: We followed a total of 207,556 women and men [73,228 women from the Nurses' Health Study (1984-2010), 92,158 women from the Nurses' Health Study II (1991-2011), and 42,170 men from the Health Professionals Follow-Up Study (1986-2010)] who were free of CVD and cancer at baseline. Validated semiquantitative food-frequency questionnaires were used to assess consumption of white rice, brown rice, and other food items. Fatal and nonfatal CVD (coronary artery disease and stroke) was confirmed by medical records or self-reports. RESULTS: During 4,393,130 person-years of follow-up, 12,391 cases of CVD were identified. After adjustment for major CVD risk factors, including demographics, lifestyle, and other dietary intakes, rice consumption was not associated with CVD risk. The multivariable-adjuted HR of developing CVD comparing >=5 servings/wk with <1 serving/wk was 0.98 (95% CI: 0.84, 1.14) for white rice, 1.01 (0.79, 1.28) for brown rice, and 0.99 (0.90, 1.08) for total rice. To minimize the potential impact of racial difference in rice consumption, we restricted the analyses to whites only and obtained similar results: the HRs of CVD for >=5 servings/wk compared with <1 serving/wk were 1.04 (95% CI: 0.88, 1.22) for white rice and 1.01 (0.78, 1.31) for brown rice. CONCLUSIONS: Greater habitual consumption of white rice or brown rice is not associated with CVD risk. These findings suggest that rice consumption may not pose a significant CVD risk among the U.S. population when consumed at current amounts. More prospective studies are needed to explore these associations in other populations. PMID- 25527763 TI - Fatty acid composition of adipose tissue and colorectal cancer: a case-control study. AB - BACKGROUND: Unlike experimental results, epidemiologic studies that used dietary questionnaires were not convincing as regards the relations between dietary fatty acids (FAs) and risk of colorectal cancer (CRC). The FA composition of adipose tissue, which is considered to be an indicator of dietary intake over 2-3 y because of the slow turnover rate, appears promising but has so far been rarely used to explore the relation between CRC and exogenous or endogenously produced FAs. OBJECTIVE: In this case-control study, we aimed to investigate associations between risk of CRC and the FA composition of subcutaneous adipose tissue and product-to-precursor ratios as indexes of enzymatic activities. DESIGN: From 2008 to 2011, we recruited 203 cases with newly diagnosed CRC and elective surgery with a curative intent and 223 control subjects with planned abdominal surgery for benign disease and no history of CRC or polyp resection. During surgery, abdominal subcutaneous adipose tissue samples were optimally collected, stored, and analyzed by using high-performance gas chromatography. Multivariate logistic regression was used to estimate ORs for CRC in relation to individual FAs divided into tertiles according to the FA distribution in controls. RESULTS: After adjustment, significant positive associations with CRC risk were observed in highest compared with lowest tertiles of 16:1n-9 (OR: 1.75; 95% CI: 1.00, 3.06; P trend = 0.045), 20:3n-6 (OR: 1.79; 95% CI: 1.01, 3.17; P-trend = 0.038), 22:5n-3 (OR: 1.82; 95% CI: 1.06, 3.12; P-trend = 0.023), and the ratio of 18:2n-6 to 18:3n-3 (OR: 2.34; 95% CI: 1.37, 3.98; P-trend = 0.001). Significant inverse associations were observed for 18:3n-3 (OR: 0.48; 95% CI: 0.29, 0.81; P-trend = 0.007). Several product-to-precursor ratios showed significant differences between cases and controls in particular ratios that reflected elongase 2/5 activity. CONCLUSIONS: CRC patients presented higher concentrations of some FAs but lower concentrations of alpha-linolenic acid in their subcutaneous adipose tissue than did controls. These results may reflect both dietary patterns and altered FA metabolism but require mechanistic explorations. PMID- 25527764 TI - Variation in the SLC23A1 gene does not influence cardiometabolic outcomes to the extent expected given its association with L-ascorbic acid. AB - BACKGROUND: Observational studies showed that circulating L-ascorbic acid (vitamin C) is inversely associated with cardiometabolic traits. However, these studies were susceptible to confounding and reverse causation. OBJECTIVES: We assessed the relation between L-ascorbic acid and 10 cardiometabolic traits by using a single nucleotide polymorphism in the solute carrier family 23 member 1 (SLC23A1) gene (rs33972313) associated with circulating L-ascorbic acid concentrations. The observed association between rs33972313 and cardiometabolic outcomes was compared with that expected given the rs33972313-L-ascorbic acid and L-ascorbic acid-outcome associations. DESIGN: A meta-analysis was performed in the following 5 independent studies: the British Women's Heart and Health Study (n = 1833), the MIDSPAN study (n = 1138), the Ten Towns study (n = 1324), the British Regional Heart Study (n = 2521), and the European Prospective Investigation into Cancer (n = 3737). RESULTS: With the use of a meta-analysis of observational estimates, inverse associations were shown between L-ascorbic acid and systolic blood pressure, triglycerides, and the waist-hip ratio [the strongest of which was the waist-hip ratio (-0.13-SD change; 95% CI: -0.20-, 0.07-SD change; P = 0.0001) per SD increase in L-ascorbic acid], and a positive association was shown with high-density lipoprotein (HDL) cholesterol. The variation at rs33972313 was associated with a 0.18-SD (95% CI: 0.10-, 0.25-SD; P = 3.34 * 10-6) increase in L-ascorbic acid per effect allele. There was no evidence of a relation between the variation at rs33972313 and any cardiometabolic outcome. Although observed estimates were not statistically different from expected associations between rs33972313 and cardiometabolic outcomes, estimates for low-density lipoprotein cholesterol, HDL cholesterol, triglycerides, glucose, and body mass index were in the opposite direction to those expected. CONCLUSIONS: The nature of the genetic association exploited in this study led to limited statistical application, but despite this, when all cardiometabolic traits were assessed, there was no evidence of any trend supporting a protective role of L-ascorbic acid. In the context of existing work, these results add to the suggestion that observational relations between L ascorbic acid and cardiometabolic health may be attributable to confounding and reverse causation. PMID- 25527765 TI - Effectiveness evaluation of the food fortification program of Costa Rica: impact on anemia prevalence and hemoglobin concentrations in women and children. AB - BACKGROUND: Food fortification is one approach for addressing anemia, but information on program effectiveness is limited. OBJECTIVE: We evaluated the impact of Costa Rica's fortification program on anemia in women aged 15-45 y and children aged 1-7 y. DESIGN: Reduced iron, an ineffective fortificant, was replaced by ferrous fumarate in wheat flour in 2002, and ferrous bisglycinate was added to maize flour in 1999 and to liquid and powdered milk in 2001. We used a one-group pretest-posttest design and national survey data from 1996 (baseline; 910 women, 965 children) and 2008-2009 (endline; 863 women, 403 children) to assess changes in iron deficiency (children only) and anemia. Data were also available for sentinel sites (1 urban, 1 rural) for 1999-2000 (405 women, 404 children) and 2008-2009 (474 women, 195 children), including 24-h recall data in children. Monitoring of fortification levels was routine. RESULTS: Foods were fortified as mandated. Fortification provided about one-half the estimated average requirement for iron in children, mostly and equally through wheat flour and milk. Anemia was reduced in children and women in national and sentinel site comparisons. At the national level, anemia declined in children from 19.3% (95% CI: 16.8%, 21.8%) to 4.0% (95% CI: 2.1%, 5.9%) and in women from 18.4% (95% CI: 15.8%, 20.9%) to 10.2% (95% CI: 8.2%, 12.2%). In children, iron deficiency declined from 26.9% (95% CI: 21.1%, 32.7%) to 6.8% (95% CI: 4.2%, 9.3%), and iron deficiency anemia, which was 6.2% (95% CI: 3.0%, 9.3%) at baseline, could no longer be detected at the endline. CONCLUSIONS: A plausible impact pathway suggests that fortification improved iron status and reduced anemia. Although unlikely in the Costa Rican context, other explanations cannot be excluded in a pre/post comparison. PMID- 25527766 TI - Common variants in CYP2R1 and GC genes are both determinants of serum 25 hydroxyvitamin D concentrations after UVB irradiation and after consumption of vitamin D3-fortified bread and milk during winter in Denmark. AB - BACKGROUND: Little is known about how the genetic variation in vitamin D modulating genes influences ultraviolet (UV)B-induced 25-hydroxyvitamin D [25(OH)D] concentrations. In the Food with vitamin D (VitmaD) study, we showed that common genetic variants rs10741657 and rs10766197 in 25-hydroxylase (CYP2R1) and rs842999 and rs4588 in vitamin D binding protein (GC) predict 25(OH)D concentrations at late summer and after 6-mo consumption of cholecalciferol (vitamin D3)-fortified bread and milk. OBJECTIVES: In the current study, called the Vitamin D in genes (VitDgen) study, we analyzed associations between the increase in 25(OH)D concentrations after a given dose of artificial UVB irradiation and 25 single nucleotide polymorphisms located in or near genes involved in vitamin D synthesis, transport, activation, or degradation as previously described for the VitmaD study. Second, we aimed to determine whether the genetic variations in CYP2R1 and GC have similar effects on 25(OH)D concentrations after artificial UVB irradiation and supplementation by vitamin D3 fortified bread and milk. DESIGN: The VitDgen study includes 92 healthy Danes who received 4 whole-body UVB treatments with a total dose of 6 or 7.5 standard erythema doses during a 10-d period in winter. The VitmaD study included 201 healthy Danish families who were given vitamin D3-fortified bread and milk or placebo for 6 mo during the winter. RESULTS: After UVB treatments, rs10741657 in CYP2R1 and rs4588 in GC predicted UVB-induced 25(OH)D concentrations as previously shown in the VitmaD study. Compared with noncarriers, carriers of 4 risk alleles of rs10741657 and rs4588 had lowest concentrations and smallest increases in 25(OH)D concentrations after 4 UVB treatments and largest decreases in 25(OH)D concentrations after 6-mo consumption of vitamin D3-fortified bread and milk. CONCLUSION: Common genetic variants in the CYP2R1 and GC genes modify 25(OH)D concentrations in the same manner after artificial UVB-induced vitamin D and consumption of vitamin D3-fortified bread and milk. PMID- 25527768 TI - Assessing magnesium by 24-h urinary excretion. PMID- 25527767 TI - Healthy Nordic diet downregulates the expression of genes involved in inflammation in subcutaneous adipose tissue in individuals with features of the metabolic syndrome. AB - BACKGROUND: Previously, a healthy Nordic diet (ND) has been shown to have beneficial health effects close to those of Mediterranean diets. OBJECTIVE: The objective was to explore whether the ND has an impact on gene expression in abdominal subcutaneous adipose tissue (SAT) and whether changes in gene expression are associated with clinical and biochemical effects. DESIGN: Obese adults with features of the metabolic syndrome underwent an 18- to 24-wk randomized intervention study comparing the ND with the control diet (CD) (the SYSDIET study, carried out within Nordic Centre of Excellence of the Systems Biology in Controlled Dietary Interventions and Cohort Studies). The present study included participants from 3 Nordic SYSDIET centers [Kuopio (n = 20), Lund (n = 18), and Oulu (n = 18)] with a maximum weight change of +/-4 kg, highly sensitive C-reactive protein concentration <10 mg/L at the beginning and the end of the intervention, and baseline body mass index (in kg/m2) <38. SAT biopsy specimens were obtained before and after the intervention and subjected to global transcriptome analysis with Gene 1.1 ST Arrays (Affymetrix). RESULTS: Altogether, 128 genes were differentially expressed in SAT between the ND and CD (nominal P < 0.01; false discovery rate, 25%). These genes were overrepresented in pathways related to immune response (adjusted P = 0.0076), resulting mainly from slightly decreased expression in the ND and increased expression in the CD. Immune-related pathways included leukocyte trafficking and macrophage recruitment (e.g., interferon regulatory factor 1, CD97), adaptive immune response (interleukin32, interleukin 6 receptor), and reactive oxygen species (neutrophil cytosolic factor 1). Interestingly, the regulatory region of the 128 genes was overrepresented for binding sites for the nuclear transcription factor kappaB. CONCLUSION: A healthy Nordic diet reduces inflammatory gene expression in SAT compared with a control diet independently of body weight change in individuals with features of the metabolic syndrome. PMID- 25527769 TI - Reply to MM Joosten et al. PMID- 25527773 TI - Knockdown of angiopoietin like-2 protects against angiotensin II-induced cerebral endothelial dysfunction in mice. AB - Angiopoietin like-2 (angptl2) is a circulating pro-inflammatory and pro-oxidative protein, but its role in regulating cerebral endothelial function remains unknown. We hypothesized that in mice knockdown (KD) of angptl2, cerebral endothelial function would be protected against ANG II-induced damage. Subcutaneous infusion of ANG II (200 ng.kg(-1).min(-1), n = 15) or saline (n = 15) was performed in 20-wk-old angptl2 KD mice and wild-type (WT) littermates for 14 days. In saline-treated KD and WT mice, the amplitude and the sensitivity of ACh-induced dilations of isolated cerebral arteries were similar. However, while endothelial nitric oxide (NO) synthase (eNOS)-derived O2 (-)/H2O2 contributed to dilation in WT mice, eNOS-derived NO (P < 0.05) was involved in KD mice. ANG II induced cerebral endothelial dysfunction only in WT mice (P < 0.05), which was reversed (P < 0.05) by either N-acetyl-l-cysteine, apocynin, gp91ds-tat, or indomethacin, suggesting the contribution of reactive oxygen species from Nox2 and Cox-derived contractile factors. In KD mice treated with ANG II, endothelial function was preserved, likely via Nox-derived H2O2, sensitive to apocynin and PEG-catalase (P < 0.05), but not to gp91ds-tat. In the aorta, relaxation similarly and essentially depended on NO; endothelial function was maintained after ANG II infusion in all groups, but apocynin significantly reduced aortic relaxation in KD mice (P < 0.05). Protein expression levels of Nox1/2 in cerebral arteries were similar among all groups, but that of Nox4 was greater (P < 0.05) in saline-treated KD mice. In conclusion, knockdown of angptl2 may be protective against ANG II-induced cerebral endothelial dysfunction; it favors the production of NO, likely increasing endothelial cell resistance to stress, and permits the expression of an alternative vasodilatory Nox pathway. PMID- 25527775 TI - Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy. AB - Emerging evidence suggests a potential role of neutrophil extracellular traps (NETs) in linking sterile inflammation and thrombosis. We hypothesized that NETs would be induced during myocardial ischemia-reperfusion (I/R), and NET-mediated microthrombosis may contribute to myocardial "no-reflow". Male Wistar rats were randomly divided into I/R control, DNase (DNase I, 20 MUg/rat), recombinant tissue-type plasminogen activator (rt-PA, 420 MUg/rat), DNase + rt-PA, and sham control groups after 45-min myocardial ischemia. In situ NET formation, the anatomic "no re-flow" area, and infarct size were evaluated immediately after 3 h of reperfusion. Long-term left ventricular (LV) functional and histological analyses were performed 45 days after operation. Compared with the I/R controls, the DNase + rt-PA group exhibited reduced NET density [8.38 +/- 1.98 vs. 26.86 +/ 3.07 (per 200 * field), P < 0.001] and "no-flow" area (15.22 +/- 0.06 vs. 34.6 +/- 0.05%, P < 0.05) in the ischemic region, as well as reduced infarct size (38.39 +/- 0.05 vs. 71.00 +/- 0.03%, P < 0.001). Additionally, compared with the I/R controls, DNase + rt-PA treatment significantly ameliorated I/R injury induced LV remodeling (LV ejection fraction: 64.22 +/- 3.37 vs. 33.81 +/- 2.98%, P < 0.05; LV maximal slope of the LV systolic pressure increment: 3,785 +/- 216 vs. 2,596 +/- 299 mmHg/s, P < 0.05). The beneficial effect was not observed in rats treated with DNase I or rt-PA alone. Our study provides evidence for the existence of NETs in I/R-challenged myocardium and confirms the long-term benefit of a novel DNase-based reperfusion strategy (DNase I + rt-PA), which might be a promising option for the treatment of myocardial I/R injury and coronary no reflow. PMID- 25527774 TI - Menstrual cycle and sex effects on sympathetic responses to acute chemoreflex stress. AB - This study aimed to examine the effects of sex (males vs. females) and sex hormones (menstrual cycle phases in women) on sympathetic responsiveness to severe chemoreflex activation in young, healthy individuals. Muscle sympathetic nerve activity (MSNA) was measured at baseline and during rebreathing followed by a maximal end-inspiratory apnea. In women, baseline MSNA was greater in the midluteal (ML) than early-follicular (EF) phase of the menstrual cycle. Baseline MSNA burst incidence was greater in men than women, while burst frequency and total MSNA were similar between men and women only in the ML phase. Chemoreflex activation evoked graded increases in MSNA burst frequency, amplitude, and total activity in all participants. In women, this sympathoexcitation was greater in the EF than ML phase. The sympathoexcitatory response to chemoreflex stimulation of the EF phase in women was also greater than in men. Nonetheless, changes in total peripheral resistance were similar between sexes and menstrual cycle phases. This indicates that neurovascular transduction was attenuated during the EF phase during chemoreflex activation, thereby offsetting the exaggerated sympathoexcitation. Chemoreflex-induced increases in mean arterial pressure were similar across sexes and menstrual cycle phases. During acute chemoreflex stimulation, reduced neurovascular transduction could provide a mechanism by which apnea-associated morbidity might be attenuated in women relative to men. PMID- 25527777 TI - Assessment and comparison of left ventricular shear in normal and situs inversus totalis hearts by means of magnetic resonance tagging. AB - Situs inversus totalis (SIT) is characterized by complete mirroring of gross cardiac anatomy and position combined with an incompletely mirrored myofiber arrangement, being normal at the apex but inverted at the base of the left ventricle (LV). This study relates myocardial structure to mechanical function by analyzing and comparing myocardial deformation patterns of normal and SIT subjects, focusing especially on circumferential-radial shear. In nine control and nine SIT normotensive human subjects, myocardial deformation was assessed from magnetic resonance tagging (MRT) image sequences of five LV short-axis slices. During ejection, no significant difference in either circumferential shortening (epsiloncc) or its axial gradient (Deltaepsiloncc) is found between corresponding LV levels in control and SIT hearts. Circumferential-radial shear (epsiloncr) has a clear linear trend from apex-to-base in controls, while in SIT it hovers close to zero at all levels. Torsion as well as axial change in epsiloncr (Deltaepsiloncr) is as in controls in apical sections of SIT hearts but deviates significantly towards the base, changing sign close to the LV equator. Interindividual variability in torsion and Deltaepsiloncr values is higher in SIT than in controls. Apex-to-base trends of torsion and Deltaepsiloncr in SIT, changing sign near the LV equator, further substantiate a structural transition in myofiber arrangement close to the LV equator itself. Invariance of epsiloncc and Deltaepsiloncc patterns between controls and SIT subjects shows that normal LV pump function is achieved in SIT despite partial mirroring of myocardial structure leading to torsional and shear patterns that are far from normality. PMID- 25527776 TI - Activation of SIRT3 by resveratrol ameliorates cardiac fibrosis and improves cardiac function via the TGF-beta/Smad3 pathway. AB - Sirtuins [sirtuin (SIRT)1-SIRT7] mediate the longevity-promoting effects of calorie restriction in yeast, worms, flies, and mice. Additionally, SIRT3 is the only SIRT analog whose increased expression has been shown to be associated with longevity in humans. The polyphenol resveratrol (RSV) is the first compound discovered able to mimic calorie restriction by stimulating SIRTs. In the present study, we report that RSV activated SIRT3 in cardiac fibroblasts both in vivo and in vitro. Moreover, in wild-type mice, RSV prevented cardiac hypertrophy in response to hypertrophic stimuli. However, this protective effect was not observed in SIRT3 knockout mice. Additionally, the activation of SIRT3 by RSV ameliorated collagen deposition and improved cardiac function. In isolated cardiac fibroblasts, pretreatment with RSV suppressed fibroblast-to-myoblast transformation by inhibiting the transforming growth factor-beta/Smad3 pathway. Therefore, these data indicate that the activation of SIRT3 by RSV could ameliorate cardiac fibrosis and improve cardiac function via the transforming growth factor-beta/Smad3 pathway. PMID- 25527778 TI - Cardiac sympathetic afferent stimulation induces salt-sensitive sympathoexcitation through hypothalamic epithelial Na+ channel activation. AB - The cardiac sympathetic afferent (CSA), which plays an important role in heart brain communication for sympathoexcitation, is stimulated in heart failure. Additionally, high salt intake leads to further sympathoexcitation due to activation of hypothalamic epithelial Na(+) channels (ENaCs) in heart failure. In the present study, we stimulated the CSA in adult male mice by epicardial application of capsaicin and using ethanol as a control to determine whether CSA stimulation led to activation of hypothalamic ENaCs, resulting in salt-induced sympathoexcitation. Three days after capsaicin treatment, an upregulation of hypothalamic alpha-ENaCs, without activation of mineralocorticoid receptors, was observed. We also examined expression levels of the known ENaC activator TNF alpha. Hypothalamic TNF-alpha increased in capsaicin-treated mice, whereas intracerebroventricular infusion of the TNF-alpha blocker etanercept prevented capsaicin-induced upregulation of alpha-ENaCs. To examine brain arterial pressure (AP) sensitivity toward Na(+), we performed an intracerebroventricular infusion of high Na(+)-containing (0.2 M) artificial cerebrospinal fluid. AP and heart rate were significantly increased in capsaicin-treated mice compared with control mice. CSA stimulation also caused excitatory responses with high salt intake. Compared with a regular salt diet, the high-salt diet augmented AP, heart rate, and 24-h urinary norepinephrine excretion, which is an indirect marker of sympathetic activity with mineralocorticoid receptor activation, in capsaicin treated mice but not in ethanol-treated mice. Treatment with etanercept or the ENaC blocker benzamil prevented these salt-induced excitatory responses. In summary, we show that CSA stimulation leads to an upregulation of hypothalamic alpha-ENaCs mediated via an increase in TNF-alpha and results in increased salt sensitivity. PMID- 25527779 TI - Single-wire pressure and flow velocity measurement for quantifying microvascular dysfunction in patients with coronary vasospastic angina. AB - Endothelial and vascular smooth muscle dysfunction of epicardial coronary arteries play a pivotal role in the pathogenesis of vasospastic angina (VSA). However, coronary microvascular (MV) function in patients with VSA is not fully understood. In the present study, subjects without coronary obstruction were divided into two groups according to the acetylcholine provocation test: VSA group (n = 29) and non-VSA group (n = 21). Hyperemic MV resistance (hMR) was measured using a dual-sensor (Doppler velocity and pressure)-equipped guidewire, and guidewire-derived hemodynamic parameters were compared. There were no between group differences in clinical demographics, including potential factors affecting MV function (e.g., diabetes). Although coronary flow velocity reserve was similar between the two groups [2.4 +/- 1.0 (VSA group) vs. 2.4 +/- 0.9 (non-VSA group); P = 0.8], coronary vessel resistance and hMR were significantly elevated in the VSA group compared with the non-VSA group (2.6 +/- 3.1 vs. 1.2 +/- 0.8, P = 0.04; 1.9 +/- 0.6 vs. 1.6 +/- 0.5, P = 0.03, respectively). Coronary vasospasm, older age, E/e', and estimated glomerular filtration rate were significantly associated with MV dysfunction [defined as >= median value of hMR (1.6)] in univariate analysis. Coronary vasospasm most strongly predicted higher hMR in multivariate logistic regression analysis (odds ratio, 4.61; 95% confidence interval, 0.98 21.60; P = 0.053). In conclusion, coronary MV resistance is impaired in patients with VSA compared with non-VSA patients, whereas coronary flow velocity reserve is maintained at normal levels in both groups. In vivo assessment of hMR might be a promising index of coronary MV dysfunction in patients with VSA. PMID- 25527781 TI - Diving and exercise: the interaction of trigeminal receptors and muscle metaboreceptors on muscle sympathetic nerve activity in humans. AB - Swimming involves muscular activity and submersion, creating a conflict of autonomic reflexes elicited by the trigeminal receptors and skeletal muscle afferents. We sought to determine the autonomic cardiovascular responses to separate and concurrent stimulation of the trigeminal cutaneous receptors and metabolically sensitive skeletal muscle afferents (muscle metaboreflex). In eight healthy men (30 +/- 2 yr) muscle sympathetic nerve activity (MSNA; microneurography), mean arterial pressure (MAP; Finometer), femoral artery blood flow (duplex Doppler ultrasonography), and femoral vascular conductance (femoral artery blood flow/MAP) were assessed during the following three experimental conditions: 1) facial cooling (trigeminal nerve stimulation), 2) postexercise ischemia (PEI; muscle metaboreflex activation) following isometric handgrip, and 3) trigeminal nerve stimulation with concurrent PEI. Trigeminal nerve stimulation produced significant increases in MSNA total activity (Delta347 +/- 167%) and MAP (Delta21 +/- 5%) and a reduction in femoral artery vascular conductance (Delta-17 +/- 9%). PEI also evoked significant increases in MSNA total activity (Delta234 +/- 83%) and MAP (Delta36 +/- 4%) and a slight nonsignificant reduction in femoral artery vascular conductance (Delta-9 +/- 12%). Trigeminal nerve stimulation with concurrent PEI evoked changes in MSNA total activity (Delta341 +/- 96%), MAP (Delta39 +/- 4%), and femoral artery vascular conductance (Delta-20 +/- 9%) that were similar to those evoked by either separate trigeminal nerve stimulation or separate PEI. Thus, excitatory inputs from the trigeminal nerve and metabolically sensitive skeletal muscle afferents do not summate algebraically in eliciting a MSNA and cardiovascular response but rather exhibit synaptic occlusion, suggesting a high degree of convergent inputs on output neurons. PMID- 25527780 TI - Caveolin-1 prevents sustained angiotensin II-induced resistance artery constriction and obesity-induced high blood pressure. AB - The type 1 angiotensin II (ANG II) receptor (AT1R) undergoes internalization following stimulation by ANG II. Internalization reduces cell surface AT1Rs, and it is required for AT1R resensitization. In this process AT1R may interact with caveolin-1 (Cav1), the main scaffolding protein of caveolae. We hypothesized that the interaction between Cav1 and AT1R delays AT1R resensitization and thereby prevents sustained ANG II-induced resistance artery (RA) constriction under normal conditions and in experimental obesity. In rat and mouse skeletal muscle RA (diameter: ~90-120 MUm) ANG II-induced constrictions were reduced upon repeated (30-min apart) administrations. Upon disruption of caveolae with methyl beta-cyclodextrin or in RA of Cav1 knockout mice, repeated ANG II applications resulted in essentially maintained constrictions. In vascular smooth muscle cells, AT1R interacted with Cav1, and the degree of cell surface interactions was reduced by long-term (15-min), but not short-term (2-min), exposure to ANG II. When Cav1 was silenced, the amount of membrane-associated AT1R was significantly reduced by a short-term ANG II exposure. Moreover, Cav1 knockout mice fed a high fat diet exhibited augmented and sustained RA constriction to ANG II and had elevated systemic blood pressure, when compared with normal or high-fat fed wild type mice. Thus, Cav1, through a direct interaction, delays internalization and subsequent resensitization of AT1R. We suggest that this mechanism prevents sustained ANG II-induced RA constriction and elevated systemic blood pressure in diet-induced obesity. PMID- 25527782 TI - Impaired oxidative metabolism and calcium mishandling underlie cardiac dysfunction in a rat model of post-acute isoproterenol-induced cardiomyopathy. AB - Stress-induced cardiomyopathy, triggered by acute catecholamine discharge, is a syndrome characterized by transient, apical ballooning linked to acute heart failure and ventricular arrhythmias. Rats receiving an acute isoproterenol (ISO) overdose (OV) suffer cardiac apex ischemia-reperfusion damage and arrhythmia, and then undergo cardiac remodeling and dysfunction. Nevertheless, the subcellular mechanisms underlying cardiac dysfunction after acute damage subsides are not thoroughly understood. To address this question, Wistar rats received a single ISO injection (67 mg/kg). We found in vivo moderate systolic and diastolic dysfunction at 2 wk post-ISO-OV; however, systolic dysfunction recovered after 4 wk, while diastolic dysfunction worsened. At 2 wk post-ISO-OV, cardiac function was assessed ex vivo, while mitochondrial oxidative metabolism and stress were assessed in vitro, and Ca(2+) handling in ventricular myocytes. These were complemented with sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), phospholamban (PLB), and RyR2 expression studies. Ex vivo, basal mechanical performance index (MPI) and oxygen consumption rate (MVO2) were unchanged. Nevertheless, upon increase of metabolic demand, by beta-adrenergic stimulation (1-100 nM ISO), the MPI versus MVO2 relation decreased and shifted to the right, suggesting MPI and mitochondrial energy production uncoupling. Mitochondria showed decreased oxidative metabolism, membrane fragility, and enhanced oxidative stress. Myocytes presented systolic and diastolic Ca(2+) mishandling, and blunted response to ISO (100 nM), and all these without apparent changes in SERCA, PLB, or RyR2 expression. We suggest that post-ISO-OV mitochondrial dysfunction may underlie decreased cardiac contractility, mainly by depletion of ATP needed for myofilaments and Ca(2+) transport by SERCA, while exacerbated oxidative stress may enhance diastolic RyR2 activity. PMID- 25527783 TI - Elevated peripheral blood mononuclear cell-derived superoxide production in healthy young black men. AB - Several studies have demonstrated that blacks exhibit elevations in systemic oxidative stress. However, the source(s) and mechanism(s) contributing to the elevation in oxidative stress remain unclear. Given that peripheral blood mononuclear cells (PBMCs) can be a major source of NADPH oxidase-derived superoxide production, we tested the hypothesis that young black men demonstrate greater superoxide production and NADPH oxidase expression in PBMCs compared with whites. PBMCs were freshly isolated from whole blood in young normotensive black (n = 18) and white (n = 16) men. Intracellular superoxide production in PBMCs was measured using dihydroethidium fluorescence, protein expression of NADPH oxidase subunits, gp91(phox) (membranous) and p47(phox) (cytosolic) in PBMCs were assessed using Western blot analysis, and plasma protein carbonyls were measured as a marker of systemic oxidative stress. Black men showed elevated intracellular superoxide production (4.3 +/- 0.5 vs. 2.0 +/- 0.6 relative fluorescence units; black men vs. white men, P < 0.05), increased protein expression for gp91(phox) and p47(phox) (e.g., p47(phox): 1.1 +/- 0.2, black men vs. 0.4 +/- 0.1, white men, P < 0.05) in PBMCs and higher circulating protein carbonyl levels (22 +/- 4 vs. 14 +/- 2 nmol/ml; black men vs. white men, P < 0.05). Interestingly, a positive family history of hypertension in black men did not further enhance PBMC derived intracellular superoxide production or NADPH oxidase subunit protein expression. These findings indicate that black men exhibit greater resting PBMC derived superoxide production and an upregulation of the NADPH oxidase pathway with a possible contribution to increases in systemic oxidative stress. PMID- 25527784 TI - Improving vitamin A and D intake among Inuit and Inuvialuit in Arctic Canada: evidence from the Healthy Foods North study. AB - BACKGROUND: People in Arctic Canada are undergoing a nutritional transition and increased prevalence of chronic disease. The Healthy Foods North diet and physical activity intervention was developed in 2007-2008 while working with populations in six communities in Nunavut and the Northwest Territories, Canada. METHODS: Four communities received the 1-year intervention (eg, conducting workshops, cooking classes and walking clubs) and two communities served as controls. Among the 263 adult evaluation participants, food frequency questionnaires were used to assess dietary intake at baseline and postintervention. Changes in mean nutrient intakes, nutrient density and dietary adequacy from baseline to postintervention were determined. The intervention impact on nutrient intakes was assessed through multivariate linear regression analysis. RESULTS: Post-intervention assessment showed a reductions in total fat, saturated, monounsaturated and polyunsaturated fatty acids, and increases in iron intake, only in the intervention group. More than a 4%-increase in the percentage of adherence to vitamins A and D recommendations was observed in the intervention group. After adjusting the regression models, respondents in the intervention communities significantly reduced their energy intake and increased their vitamins A and D intake. CONCLUSIONS: The Healthy Foods North is an effective programme to improve dietary quality among populations of the Canadian Arctic. Long-term interventions are expected to be important factors in the prevention of diet-related chronic diseases in these communities. PMID- 25527785 TI - IL-10 and regulatory T cells cooperate in allergen-specific immunotherapy to ameliorate allergic asthma. AB - Human studies demonstrated that allergen-specific immunotherapy (IT) represents an effective treatment for allergic diseases. IT involves repeated administration of the sensitizing allergen, indicating a crucial contribution of T cells to its medicinal benefit. However, the underlying mechanisms of IT, especially in a chronic disease, are far from being definitive. In the current study, we sought to elucidate the suppressive mechanisms of IT in a mouse model of chronic allergic asthma. OVA-sensitized mice were challenged with OVA or PBS for 4 wk. After development of chronic airway inflammation, mice received OVA-specific IT or placebo alternately to airway challenge for 3 wk. To analyze the T cell mediated mechanisms underlying IT in vivo, we elaborated the role of T-bet expressing Th1 cells, T cell-derived IL-10, and Ag-specific thymic as well as peripherally induced Foxp3(+) regulatory T (Treg) cells. IT ameliorated airway hyperresponsiveness and airway inflammation in a chronic asthma model. Of note, IT even resulted in a regression of structural changes in the airways following chronic inhaled allergen exposure. Concomitantly, IT induced Th1 cells, Foxp3(+), and IL-10-producing Treg cells. Detailed analyses revealed that thymic Treg cells crucially contribute to the effectiveness of IT by promoting IL-10 production in Foxp3-negative T cells. Together with the peripherally induced Ag-specific Foxp3(+) Treg cells, thymic Foxp3(+) Treg cells orchestrate the curative mechanisms of IT. Taken together, we demonstrate that IT is effective in a chronic allergic disease and dependent on IL-10 and thymic as well as peripherally induced Ag-specific Treg cells. PMID- 25527786 TI - Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice. AB - Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus) infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-beta-generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-beta-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-beta-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-beta-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT. PMID- 25527787 TI - Neutrophil priming occurs in a sequential manner and can be visualized in living animals by monitoring IL-1beta promoter activation. AB - Rapid enhancement of phagocyte functionality is a hallmark of neutrophil priming. GeneChip analyses unveiled elevated CD54, dectin-2, and IL-1beta mRNA expression by neutrophils isolated from inflammatory sites. In fact, CD54 and dectin-2 protein expression was detected on neutrophils recovered from skin, peritoneal, and lung inflammation lesions but not on those in bone marrow or peripheral blood. Neutrophils increased CD54 and dectin-2 mRNA during migration in Boyden chambers and acquired CD54 and dectin-2 surface expression after subsequent exposure to GM-CSF. Neutrophils purified from IL-1beta promoter-driven DsRed transgenic mice acquired DsRed signals during cell migration or exposure to GM CSF. CD54 and dectin-2 were expressed by DsRed(+) (but not DsRed(-)) neutrophils in GM-CSF-supplemented cultures, and neutrophils recovered from inflammatory sites exhibited strong DsRed signals. The dynamic process of neutrophil priming was studied in chemically induced inflammatory skin lesions by monitoring DsRed expression using confocal microscopy. A majority (>80%) of Ly6G(+) neutrophils expressed DsRed, and those DsRed(+)/Ly6G(+) cells exhibited crawling motion with a higher velocity compared with their DsRed(-)/Ly6G(+) counterparts. This report unveils motile behaviors of primed neutrophils in living animals. We propose that neutrophil priming occurs in a sequential manner with rapid enhancement of phagocyte functionality, followed by CD54 and dectin-2 mRNA and protein expression, IL-1beta promoter activation, and accelerated motility. Not only do these findings provide a new conceptual framework for our understanding of the process of neutrophil priming, they also unveil new insights into the pathophysiology of many inflammatory disorders that are characterized by neutrophil infiltration. PMID- 25527788 TI - IL-2Rbeta-dependent signaling and CD103 functionally cooperate to maintain tolerance in the gut mucosa. AB - A network of mechanisms operates to maintain tolerance in the gut mucosa. Although CD103 marks many lymphoid cells within the gut, its direct functional role in intestinal tolerance is poorly understood. CD103 may be part of a redundant pathway, as CD103(-/-) mice do not exhibit autoimmunity. To reduce such redundancy, CD103(-/-) mice were crossed to mice (designated Y3) whose T cells expressed a mutant IL-2Rbeta-chain that lowers IL-2R signaling. Unlike overtly healthy Y3 mice, all Y3/CD103(-/-) mice rapidly developed severe colitis. The large intestine of these mice contained an increase in CD4(+) Th1 and Th17 effector cells and a reduced ratio of regulatory T cells (Tregs). Importantly, colitis was effectively prevented by the transfer of wild-type Tregs into Y3/CD103(-/-) mice. Impaired intestinal tolerance was not attributed to an obvious lack of CD103-dependent gene regulation or intestinal homing/retention by Tregs nor a lack of functional activities typically associated with CD103(+) dendritic cells, such as peripherally induced Treg development or imprinting CCR9 and alpha4beta7 homing molecules on Tregs and T effector cells. Transcriptome analysis of Tregs was consistent with altered homeostasis due to impaired IL 2Rbeta-dependent signaling with minimal dysregulation added by the absence of CD103. Rather, the absence of CD103 functioned to alter the localization of the cells within the gut microenvironment that may alter Treg homeostasis. Thus, IL 2Rbeta-dependent signaling and CD103 normally cooperate through distinctive processes to promote Treg homeostasis and immune tolerance. PMID- 25527789 TI - Anti-IL-12/23 p40 antibody attenuates experimental chronic graft-versus-host disease via suppression of IFN-gamma/IL-17-producing cells. AB - Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-gamma/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL 12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-gamma single-positive (IL-17(-)) and IFN-gamma/IL-17 double positive cells were suppressed in anti-p40 mAb-treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-gamma and IL-17 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients. T-bet expression of donor IL-17(+) CD4(+) T cells was reduced significantly in anti-p40 mAb-treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-gamma/IL-17-producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD. PMID- 25527790 TI - Not second class: the first class II MHC crystal structure. PMID- 25527791 TI - Pillars article: three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature. 1993. 364: 33-39. PMID- 25527792 TI - Natural antibodies bridge innate and adaptive immunity. AB - Natural Abs, belonging to isotypes IgM, IgG3, and IgA, were discovered nearly half a century ago. Despite knowledge about the role of the polyreactive natural IgM in pathogen elimination, B cell survival and homeostasis, inflammatory diseases, and autoimmunity, there is a lack of clarity about the physiological role of natural IgG and natural IgA because they appear incapable of recognizing Ags on their own and are perceived as nonreactive. However, recent research revealed exciting functions of natural IgG in innate immunity. Natural IgG:lectin collaboration swiftly and effectively kills invading pathogens. These advances prompt further examination of natural Abs in immune defense and homeostasis, with the potential for developing novel therapeutics. This review provides new insights into the interaction between natural Abs and lectins, with implications on how interactions between molecules of the innate and adaptive immune systems bridge these two arms of immunity. PMID- 25527793 TI - Mechanisms of Jak/STAT signaling in immunity and disease. AB - More than two decades ago, experiments on the antiviral mechanisms of IFNs led to the discovery of JAKs and their downstream effectors, the STAT proteins. This pathway has since become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors, including cytokines and hormones, mediate their diverse functions. Jak/STAT research has not only impacted basic science, particularly in the context of intercellular communication and cell extrinsic control of gene expression, it also has become a prototype for transition from bench to bedside, culminating in the development and clinical implementation of pathway-specific therapeutics. This brief review synthesizes our current understanding of Jak/STAT biology while taking stock of the lessons learned and the challenges that lie ahead. PMID- 25527794 TI - The new biologics in pregnancy. AB - Growing numbers of women of reproductive age are prescribed new biological agents. This is resulting in more pregnancies exposed to these drugs. What are the new biologics (also referred to as biologicals) and what are their indications? How are they currently used in pregnant women? What are the concerns when treating pregnant women with biologics? What do we know about the reproductive safety of these agents? Current and future research is discussed.